PMID- 27214059 TI - Development of an Ethanol-induced Fibrotic Liver Model in Zebrafish to Study Progenitor Cell-mediated Hepatocyte Regeneration. AB - Sustained liver fibrosis with continuation of extracellular matrix (ECM) protein build-up results in the loss of cellular competency of the liver, leading to cirrhosis with hepatocellular dysfunction. Among multiple hepatic insults, alcohol abuse can lead to significant health problems including liver failure and hepatocellular carcinoma. Nonetheless, the identity of endogenous cellular sources that regenerate hepatocytes in response to alcohol has not been properly investigated. Moreover, few studies have effectively modeled hepatocyte regeneration upon alcohol-induced injury. We recently reported on establishing an ethanol (EtOH)-induced fibrotic liver model in zebrafish in which hepatic progenitor cells (HPCs) gave rise to hepatocytes upon near-complete hepatocyte loss in the presence of fibrogenic stimulus. Furthermore, through chemical screens using this model, we identified multiple small molecules that enhance hepatocyte regeneration. Here we describe in detail the procedures to develop an EtOH-induced fibrotic liver model and to perform chemical screens using this model in zebrafish. This protocol will be a critical tool to delineate the molecular and cellular mechanisms of how hepatocyte regenerates in the fibrotic liver. Furthermore, these methods will facilitate potential discovery of novel therapeutic strategies for chronic liver disease in vivo. PMID- 27214060 TI - CONTINUOUS GLUCOSE MONITORING: A CONSENSUS CONFERENCE OF THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY. AB - OBJECTIVE/METHODS: Barriers to continuous glucose monitoring (CGM) use continue to hamper adoption of this valuable technology for the management of diabetes. The American Association of Clinical Endocrinologists and the American College of Endocrinology convened a public consensus conference February 20, 2016, to review available CGM data and propose strategies for expanding CGM access. RESULTS: Conference participants agreed that evidence supports the benefits of CGM in type 1 diabetes and that these benefits are likely to apply whenever intensive insulin therapy is used, regardless of diabetes type. CGM is likely to reduce healthcare resource utilization for acute and chronic complications, although real-world analyses are needed to confirm potential cost savings and quality of life improvements. Ongoing technological advances have improved CGM accuracy and usability, but more innovations in human factors, data delivery, reporting, and interpretation are needed to foster expanded use. The development of a standardized data report using similar metrics across all devices would facilitate clinician and patient understanding and utilization of CGM. Expanded CGM coverage by government and private payers is an urgent need. CONCLUSION: CGM improves glycemic control, reduces hypoglycemia, and may reduce overall costs of diabetes management. Expanding CGM coverage and utilization is likely to improve the health outcomes of people with diabetes. ABBREVIATIONS: A1C = glycated hemoglobin AACE = American Association of Clinical Endocrinologists ACE = American College of Endocrinology ASPIRE = Automation to Simulate Pancreatic Insulin Response CGM = continuous glucose monitoring HRQOL = health-related quality of life ICER = incremental cost-effectiveness ratio JDRF = Juvenile Diabetes Research Foundation MARD = mean absolute relative difference MDI = multiple daily injections QALY = quality-adjusted life years RCT = randomized, controlled trial SAP = sensor-augmented pump SMBG = self-monitoring of blood glucose STAR = Sensor-Augmented Pump Therapy for A1C Reduction T1D = type 1 diabetes T2D = type 2 diabetes. PMID- 27214061 TI - Reduced transfer of affective value to instrumental behavior in violent offenders. AB - Instrumental or goal-directed aggression is a core feature in violent offenders with psychopathic tendencies. To understand this type of behavior, previous work in the field of aggression has focused on affective processing, with mixed results. We propose that instrumental aggression is best understood in terms of the consequences of affective processing for instrumental behavior rather than affective processing per se. Therefore, we assessed the degree of affective biasing of instrumental action in a group of violent offenders with psychopathic tendencies and healthy controls using a validated affective decision-making task. Participants learned whole body approach-avoidance actions upon instrumental targets based on monetary feedback, while being primed by aversive versus appetitive facial stimuli. Unlike controls, instrumental behavior in violent offenders was not influenced by the affective stimuli. Specifically, violent offenders showed reduced instrumental avoidance in the context of aversive (vs. appetitive) stimuli relative to controls. This finding suggests that reduced affective biasing of instrumental behavior may underlie the behavioral anomalies observed in violent offenders with psychopathic tendencies. More generally, the finding underscores the relevance of examining the interaction between affect and instrumental behavior for a better understanding of dysfunctional behaviors in psychiatric populations. (PsycINFO Database Record PMID- 27214062 TI - The dimensional nature of eating pathology: Evidence from a direct comparison of categorical, dimensional, and hybrid models. AB - Eating disorders are conceptualized as categorical rather than dimensional in the current major diagnostic system (Diagnostic and Statistical Manual of Mental Disorders; 5th ed.; American Psychiatric Association, 2013) and in many previous studies. However, previous research has not critically evaluated this assumption or tested hybrid models (e.g., modeling latent variables with both dimensional and categorical features). Accordingly, the current study directly compared categorical, dimensional, and hybrid models for eating pathology in a large, population-based sample. Participants included 3,032 female and male twins (ages 9-30 years) from the Michigan State University Twin Registry. The Minnesota Eating Behaviors Survey was used to assess disordered eating symptoms including body dissatisfaction, weight preoccupation, binge eating, and compensatory behaviors. Results showed that dimensional models best fit the data in the overall sample as well as across subgroups divided by sex and pubertal status (e.g., prepubertal vs. postpubertal). It is interesting to note that the results favored more categorical models when using a case-control subset of our sample with participants who either endorsed substantial eating pathology or no/little eating pathology. Overall, findings provide support for a dimensional conceptualization of eating pathology and underscore the importance of using community samples to capture the full range of severity of eating pathology when investigating questions about taxonomy. (PsycINFO Database Record PMID- 27214063 TI - Azole-Anion-Based Aprotic Ionic Liquids: Functional Solvents for Atmospheric CO2 Transformation into Various Heterocyclic Compounds. AB - The chemical transformation of atmospheric CO2 is of great significance yet still poses a great challenge. Herein, azole-anion-based aprotic ionic liquids (ILs) were synthesized by the deprotonation of weak proton donors (e.g., 2 methylimidazole, 4-methylimidazole, and 2,4-dimethylimidazole) with tetrabutylphosphonium hydroxide, [Bu4 P][OH]. We found that these ILs, such as [Bu4 P][2-MIm], could activate atmospheric CO2 through the formation of carbamates. The resultant carbamate intermediates could further react with various types of substrate, including propargylic alcohols, 2-aminobenzonitriles, ortho-phenylenediamines, and 2-aminothiophenol, thereby producing alpha alkylidene cyclic carbonates, quinazoline-2,4(1 H,3 H)-diones, benzimidazolones, and benzothiazoline, respectively, in moderate-to-good yields. Thus, we have achieved the transformation of CO2 at atmospheric pressure, and we expect this method to open up new routes for the synthesis of various oxygen-containing heterocyclic compounds under metal-free conditions. PMID- 27214064 TI - Characterization, Quantification and Compound-specific Isotopic Analysis of Pyrogenic Carbon Using Benzene Polycarboxylic Acids (BPCA). AB - Fire-derived, pyrogenic carbon (PyC), sometimes called black carbon (BC), is the carbonaceous solid residue of biomass and fossil fuel combustion, such as char and soot. PyC is ubiquitous in the environment due to its long persistence, and its abundance might even increase with the projected increase in global wildfire activity and the continued burning of fossil fuel. PyC is also increasingly produced from the industrial pyrolysis of organic wastes, which yields charred soil amendments (biochar). Moreover, the emergence of nanotechnology may also result in the release of PyC-like compounds to the environment. It is thus a high priority to reliably detect, characterize and quantify these charred materials in order to investigate their environmental properties and to understand their role in the carbon cycle. Here, we present the benzene polycarboxylic acid (BPCA) method, which allows the simultaneous assessment of PyC's characteristics, quantity and isotopic composition ((13)C and (14)C) on a molecular level. The method is applicable to a very wide range of environmental sample materials and detects PyC over a broad range of the combustion continuum, i.e., it is sensitive to slightly charred biomass as well as high temperature chars and soot. The BPCA protocol presented here is simple to employ, highly reproducible, as well as easily extendable and modifiable to specific requirements. It thus provides a versatile tool for the investigation of PyC in various disciplines, ranging from archeology and environmental forensics to biochar and carbon cycling research. PMID- 27214065 TI - Increasing frequency and fatality of poison control center reported exposures involving medication and multiple substances: data from reports of the American Association of Poison Control Centers 1984-2013. AB - CONTEXT: Medication use has become increasingly prevalent in the United States, with up trending use of both prescription and over the counter medication. The increasing use and availability of medication may be changing the nature of poisoning fatality. OBJECTIVE: To evaluate changes in fatal poisoning over time, with respect to fatalities involving one or more medications, using annual reports published by the American Association of Poison Control Centers (AAPCC). MATERIALS AND METHODS: AAPCC annual reports were reviewed from 1984 to 2013. Data from tables in each annual report titled Number of Substances Involved in Human Exposure Cases and Summary of Fatal Exposures were abstracted. Fatality rates and changes in these rates over time were calculated for exposures to 1, 2, or >= 3 substances. All substances detailed in Summary of Fatal Exposures tables were then coded as medication or non-medication. The percentage of fatalities involving 1, 2, or >= 3 medications was calculated and trended over time. Subset analysis was performed to compare the periods 1984-2005 and 2006-2013 in order to limit confounding from changes in reporting. Secondary analysis linking the number of substances cases were exposed to and the fatality rate was performed for data from 2006-2013. RESULTS: There were 59,866,357 human exposures and 29,659 fatalities reported from 1984 to 2013. There were 49.5 fatalities per 100,000 exposures. The majority of fatalities (52.2%) involved more than one substance, although multiple substances were involved in only 8.3% of exposures. Fatality rates increased over time and were higher for cases involving multiple substances. Medications were involved in 79.2% of fatalities, a percentage that increased from 70% in the 1980s to nearly 90% after 2010. In recent years, the majority of fatalities have involved multiple medications. For data from 2006 2013 there was a strong association between fatality rate and number of substances involved in an exposure (221 additional fatalities per 100,000 exposures for each additional substance involved in an exposure). DISCUSSION AND CONCLUSION: Multiple substance exposures have become a greater percentage of cases reported to the AAPCC and have higher fatality rates than single substance exposures. The majority of fatal poisonings reported to the AAPCC between 1984 and 2013 involved medication. The percentage of fatal poisonings involving medication increased over the interval, as did the percentage of fatalities involving more than one medication. Fatalities involving multiple medications are now the most common type of fatal poisoning reported to the AAPCC. PMID- 27214066 TI - The art of single-tasking. PMID- 27214067 TI - Primary care management of depression in children and adolescents. AB - Depression is the most common mental health disorder in children and adolescents, and primary care is often the first point of contact for children and adolescents with depression. Depression impacts all areas of life, impairing academics and interactions with family and friends. The purpose of this article is to help NPs identify and treat children and adolescents presenting with depression in the primary care setting. PMID- 27214068 TI - Biological and Nonbiological Antioxidant Activity of Some Essential Oils. AB - Fifteen essential oils, four essential oil fractions, and three pure compounds (thymol, carvacrol, and eugenol), characterized by gas chromatography and gas chromatography-mass spectrometry, were investigated for biological and nonbiological antioxidant activity. Clove oil and eugenol showed strong DPPH (2,2 diphenyl-1-picrylhydrazyl) free-radical scavenging activity (IC50 = 13.2 MUg/mL and 11.7 MUg/mL, respectively) and powerfully inhibited reactive oxygen species (ROS) production in human neutrophils stimulated by PMA (phorbol 12-myristate 13 acetate) (IC50 = 7.5 MUg/mL and 1.6 MUg/mL) or H2O2 (IC50 = 22.6 MUg/mL and 27.1 MUg/mL). Nutmeg, ginger, and palmarosa oils were also highly active on this test. Essential oils from clove and ginger, as well as eugenol, carvacrol, and bornyl acetate inhibited NO (nitric oxide) production (IC50 < 50.0 MUg/mL). The oils of clove, red thyme, and Spanish oregano, together with eugenol, thymol, and carvacrol showed the highest myeloperoxidase inhibitory activity. Isomers carvacrol and thymol displayed a disparate behavior in some tests. All in all, clove oil and eugenol offered the best antioxidant profile. PMID- 27214069 TI - Bendamustine, etoposide and dexamethasone to mobilize peripheral blood hematopoietic stem cells for autologous transplantation in patients with multiple myeloma. AB - Chemotherapeutic agents without cross-resistance to prior therapies may enhance PBSC collection and improve patient outcomes by exacting a more potent direct antitumor effect before autologous stem cell transplant. Bendamustine has broad clinical activity in transplantable lymphoid malignancies, but concern remains over the potential adverse impact of this combined alkylator-nucleoside analog on stem cell mobilization. We performed a prospective, nonrandomized phase II study including 34 patients with multiple myeloma (MM) (n=34; International Staging System (ISS) stages I (35%), II (29%) and III (24%); not scored (13%)) to evaluate bendamustine's efficacy and safety as a stem cell mobilizing agent. Patients received bendamustine (120 mg/m2 IV days 1, 2), etoposide (200 mg/m2 IV days 1-3) and dexamethasone (40 mg PO days 1- 4) (bendamustine, etoposide and dexamethasone (BED)) followed by filgrastim (10 MUg/kg/day SC; through collection). All patients (100%) successfully yielded stem cells (median of 21.60 * 106/kg of body weight; range 9.24-55.5 * 106/kg), and 88% required a single apheresis. Six nonhematologic serious adverse events were observed in 6 patients including: neutropenic fever (1, grade 3), bone pain (1, grade 3) and renal insufficiency (1, grade 1). In conclusion, BED safely and effectively mobilizes hematopoietic stem cells. PMID- 27214070 TI - Lost in Transplantation? Unexpected shift from multipotent to late lymphomyeloid hematopoietic stem and progenitor cells in patients 1 year after hematopoietic stem cell transplantation. PMID- 27214071 TI - Confounding factors affecting the National Institutes of Health (NIH) chronic Graft-Versus-Host Disease Organ-Specific Score and global severity. AB - The 2005 NIH chronic GVHD (cGVHD) organ severity is based on the assessment of current status regardless of whether abnormalities are due to GVHD. The score assignment does not require knowledge of past manifestations, attribution or whether cGVHD is still active. The aim of this study is to describe confounding factors affecting organ scores in patients with cGVHD. The study included 189 consecutive cGVHD patients evaluated at our center in 2013. Providers completed the NIH 0-3 organ-specific scoring evaluation with two questions added for each organ to identify abnormalities that were (i) not attributed to cGVHD or (ii) attributed to cGVHD plus other causes. Abnormalities attributed to causes other than GVHD were recorded. Eighty (14%) abnormalities were not attributed to cGVHD in at least one organ, and 41 (7%) abnormalities were attributed to cGVHD plus other causes in at least one organ. A total of 436 (78%) abnormalities were attributed only to cGVHD. Abnormalities not attributed to cGVHD were observed most frequently in the lung, gastrointestinal tract and skin. Most common abnormalities included pre-transplant condition, sequelae from GVHD, deconditioning, infections and medications. Our results support the 2014 NIH consensus recommendation to consider attribution when scoring organ abnormalities. PMID- 27214072 TI - A retrospective comparison of toxicity and initial efficacy of two autologous stem cell transplant conditioning regimens for relapsed lymphoma: LEAM and BEAM. PMID- 27214073 TI - The addition of ofatumumab to the conditioning regimen does not improve the outcome of patients with high-risk CLL undergoing reduced intensity allogeneic haematopoietic cell transplantation: a pilot trial from the GETH and GELLC (CLL4 trial). PMID- 27214074 TI - IV pentamidine for Pneumocystis jiroveci pneumonia prophylaxis in pediatric allogeneic stem cell transplant patients. PMID- 27214075 TI - Identification of high-risk amino-acid substitutions in hematopoietic cell transplantation: a challenging task. AB - Allogeneic hematopoietic cell transplantation (HCT) offers the potential to cure hematologic malignancies. In the absence of an HLA-matched donor, HLA mismatched unrelated donors may be used, although risks of GvHD and treatment-related mortality (TRM) are higher. Identification and avoidance of amino-acid substitution and position types (AASPT) conferring higher risks of TRM and GvHD would potentially improve the success of transplantation from single HLA mismatched unrelated donors. Using random forest and logistic regression analyses, we identified 19 AASPT associated with greater risks for at least one adverse transplant outcome: grade III-IV acute GvHD, TRM, lower disease-free survival or worse overall survival relative to HLA-matched unrelated donors and to other AASPT. When tested in an independent validation cohort of 3530 patients, none of the AASPT from the training set were validated as high risk, however. Review of the literature shows that failure to validate original observations is the rule and not the exception in immunobiology and emphasizes the importance of independent validation before clinical application. Our current data do not support avoiding any specific class I AASPT for unrelated donors. Additional studies should be performed to fully understand the role of AASPT in HCT outcomes. PMID- 27214076 TI - Antibiotic prophylaxis in allogeneic stem cell transplantation-what is the correct choice? PMID- 27214077 TI - Similar outcome of calreticulin type I and calreticulin type II mutations following RIC allogeneic haematopoietic stem cell transplantation for myelofibrosis. PMID- 27214078 TI - Reliability of immune receptor rearrangements as genetic markers for minimal residual disease monitoring. PMID- 27214079 TI - Clinical relevance of galectin-1 in hematologic malignancies treated with non myeloablative hemopoietic stem cell transplantation. PMID- 27214080 TI - All is not lost in accelerated phase/blast crisis and after tyrosine kinase inhibitors fail in chronic myeloid leukaemia: a retrospective study of allogeneic stem cell transplant outcomes in Australia and New Zealand. PMID- 27214081 TI - The experience of survival following allogeneic haematopoietic stem cell transplantation in New South Wales, Australia. AB - Allogeneic haematopoietic stem cell transplantation (allo-HSCT) entails long-term morbidities that impair survivors' quality of life through broad physical and psychosocial sequelae. Current data and survival measurements may be inadequate for contemporary Australian allo-HSCT recipients. This study sought to comprehensively describe survivorship in an up-to-date, local setting through validated measurements and a novel questionnaire designed to complement and address limitations of current instruments. All adults who received an allo-HSCT between 2000 and 2012 in New South Wales were eligible and included, if alive, those literate and consenting to the study, which encompassed seven survey instruments. Four hundred and forty-three survivors participated, which is 76% of contactable (n=583) and 66% of eligible survivors (n= 669). Chronic GVHD (cGVHD) and co-morbidity rates were similar to published data. Noteworthy results include prevalent sexual dysfunction (66% females, 52% males), loss of income (low income increased from 21 to 36%, P<0.001) and employment (full-time employment fell from 64 to 33%, P<0.001), suboptimal vaccination (31% complete), and health screening (~50%). Risk factors for poor vaccination and health screening were cGVHD, younger age, less education, rural/regional residence and transplantation <2 years. This study suggests that improvement in survivorship may necessitate structural changes in the current delivery of health services. PMID- 27214082 TI - Impact of pretransplant red cell transfusion on outcome after allogeneic stem cell transplantation in adult patients with severe aplastic anemia. AB - The aim of this study was to evaluate the impact of pretransplant transfusion of packed red cells (PRCs) on outcome after allogeneic stem cell transplantation (SCT) in severe aplastic anemia (SAA). A total of 221 adult SAA patients receiving allogeneic SCT were analyzed. The patients were divided into two groups according to the amount of pretransplant transfusion before SCT: the low transfusion group (?32 PRC units, n=164) and the high transfusion group (>32 PRC units, n=57). The incidence of engraftment failure was not different between the two groups. The incidence of acute GvHD (grades II-IV) was higher in the high transfusion group than in the low transfusion group (P=0.04), and the incidences of chronic extensive GVHD were not significantly different (P=0.136). The high transfusion group had higher 5-year transplant-related mortality (TRM) (24.8% vs 6.8%, P<0.001) and lower overall survival (OS) (72.3% vs 91.9%, P<0.001) than those in the low transfusion group. Multivariate analysis revealed that the high transfusion group and unrelated donor type were independent prognostic factors affecting OS. These results indicate that a history of higher pretransplant transfusion of PRCs was associated with increased TRM and decreased OS, suggesting that iron overload had a negative impact on outcome after SCT in SAA. PMID- 27214083 TI - Follicular Variant of Papillary Thyroid Carcinoma: Hybrid or Mixture? PMID- 27214084 TI - Coeliac disease and the gluten-free diet: a review of the burdens; factors associated with adherence and impact on health-related quality of life, with specific focus on adolescence. AB - Adherence and non-adherence to a gluten-free diet (GFD) may impact negatively on health-related quality of life (HRQoL). Understanding the factors that influence compliance could help inform management and also guide support. With a particular focus on adolescence, this narrative review critiques current literature on the burdens associated with following a GFD and the factors associated with adherence. Studies highlight a variety of burdens faced by individuals with coeliac disease, including the cost, access and availability of gluten-free (GF) foods, as well as the dilemmas experienced when eating out, travelling and socialising with friends. A number of studies report that adolescents face stigmatisation and feel isolated in social situations and at school. Additional burdens that are highlighted are a lack of knowledge regarding CD and GFD difficulties in interpreting food labels, as well as dissatisfaction with the organoleptic properties of GF foods. Factors associated with poor adherence in adolescence include older age, an absence of immediate symptoms, difficulties eating out and poor palatability of GF foods. Conversely, better emotional support and stronger organisation skills have been associated with superior adherence. Significant associations have been reported between HRQoL measures and adherence, although the findings are inconsistent. Limitations in research methodologies exist and data are restricted to just a few countries. Further research specific to adolescence is required to identify independent predictors of adherence. PMID- 27214085 TI - Effect of lead on oxidative status, antioxidative response and metal accumulation in Coronopus didymus. AB - A screenhouse experiment was conducted to assay the effect of Lead (Pb) on oxidative status, antioxidative response and metal accumulation in Coronopus didymus after 6 weeks. Results revealed a good Pb tolerance and accumulation potential of C. didymus towards the increasing Pb concentrations (500, 900, 1800, 2900 mg kg(-1)) in soil. The content of Pb in roots and shoots elevated with higher Pb levels and reached a maximum of 3684.3 mg kg(-1) and 862.8 mg kg(-1) Pb dry weight, respectively, at 2900 mg kg(-1) treatment. Pb exposure stimulated electrolyte leakage, H2O2 level, MDA content and the activities of antioxidant machinery (SOD, CAT, APX, GPX and GR). However, at the highest Pb concentration, the activities of SOD and CAT declined. The H2O2 level and MDA content in roots increased significantly up to ~500% and 213%, respectively, over the control, at 2900 mg kg(-1) Pb treatment. Likewise, concurrent findings were noticed in shoots of C. didymus, with the increasing Pb concentration. The present work suggests that C. didymus exhibited a good accumulation potential for Pb and can tolerate Pb-induced oxidative stress by an effective antioxidant defense mechanism. PMID- 27214086 TI - Enhanced cadmium accumulation and tolerance in transgenic tobacco overexpressing rice metal tolerance protein gene OsMTP1 is promising for phytoremediation. AB - One of the most grievous heavy metal pollutants in the environment is cadmium (Cd), which is not only responsible for the crop yield loss owing to its phytotoxicity, but also for the human health hazards as the toxic elements usually accumulate in the consumable parts of crop plants. In the present study, we aimed to isolate and functionally characterize the OsMTP1 gene from indica rice (Oryza sativa L. cv. IR64) to study its potential application for efficient phytoremediation of Cd. The 1257 bp coding DNA sequence (CDS) of OsMTP1 encodes a ~46 kDa protein belonging to the cation diffusion facilitator (CDF) or metal tolerance/transport protein (MTP) family. The OsMTP1 transcript in rice plant was found to respond during external Cd stress. Heterologous expression of OsMTP1 in tobacco resulted in the reduction of Cd stress-induced phytotoxic effects, including growth inhibition, lipid peroxidation, and cell death. Compared to untransformed control, the transgenic tobacco plants showed enhanced vacuolar thiol content, indicating vacuolar localization of the sequestered Cd. The transgenic tobacco plants exhibited significantly higher biomass growth (2.2-2.8 folds) and hyperaccumulation of Cd (1.96-2.22-folds) compared to untransformed control under Cd exposure. The transgenic plants also showed moderate tolerance and accumulation of arsenic (As) upon exogenous As stress, signifying broad substrate specificity of OsMTP1. Together, findings of our research suggest that the transgenic tobacco plants overexpressing OsMTP1 with its hyperaccumulating activity and increased growth rate could be useful for future phytoremediation applications to clean up the Cd-contaminated soil. PMID- 27214087 TI - Significant natriuretic and antihypertensive action of the epithelial sodium channel blocker amiloride in diabetic patients with and without nephropathy. AB - OBJECTIVE: Diabetic nephropathy is associated with aberrant glomerular filtration of serine proteases. The study was designed to test the hypothesis that the epithelial sodium channel is activated proteolytically by urine plasmin in diabetic nephropathy and mediates renal sodium retention. METHODS: In an open label intervention study on type 1 diabetes patients on standardized NaCl intake (200 mmol/day) with (n = 15) and without diabetic nephropathy (control, n = 12), urinary Na excretion in response to oral amiloride (20 or 40 mg/day for 2 days) was compared. RESULTS: A total of 27 patients completed the study and nine diabetic nephropathy and eight control study participants were compliant (24-h urine Na excretion of 200 mmol +/- 30%). Amiloride increased significantly total and fractional Na excretion in both groups. Total natriuresis and weight loss were significantly larger in the control group compared with diabetic nephropathy at day 1 of amiloride, whereas fractional Na excretion did not differ. Amiloride intervention increased plasma renin concentration only in diabetic nephropathy group; it reduced SBP in both groups, whereas DBP was reduced in diabetic nephropathy group only. Albuminuria was reduced significantly by amiloride in diabetic nephropathy group. Urine total amiloride concentration was not different between groups (12 +/- 1 and 16 +/- 1 MUmol/l, respectively). Urine total plasminogen and active plasmin were reduced after amiloride in diabetic nephropathy. CONCLUSION: Amiloride increased renal Na excretion, reduced blood pressure, albuminuria, and total and active plasmin in urine. It is concluded that epithelial sodium channel is an attractive target to attain blood pressure control in long-term type I diabetes with no enhanced activity associated with nephropathy. PMID- 27214088 TI - Acute eprosartan-induced intrarenal vasodilation in hypertensive humans is not influenced by dietary sodium intake or angiotensin II co-infusion. AB - BACKGROUND: Angiotensin II (Ang II) is thought to play an important role in the development of hypertension. Nevertheless, knowledge on the angiotensin II type-1 receptors (AT1Rs) in the hypertensive kidney and the influence of sodium intake and renin-angiotensin system activity on intrarenal AT1R blockade is scarce. To improve our understanding of renal AT1Rs in hypertensive patients, we studied the effects of acute, local administration of AT1R-blocker eprosartan in kidneys of patients with essential hypertension (off medication). METHOD: In 73 hypertensive patients who were scheduled for diagnostic renal angiography, we measured renal blood flow (Xenon washout method) before and during intrarenal infusion of two incremental doses of eprosartan (3 and 10 MUg/kg/min for 15 min per dose). We hypothesized that the vasodilatory effects of eprosartan would be enhanced by low sodium intake and would be reduced during Ang II co-infusion. Therefore, we allocated the patients to either a high or a low sodium diet and coinfused Ang II (1 ng/kg/min) in a subgroup. RESULTS: Eprosartan infusion resulted in intrarenal vasodilation in all groups. No differences in the magnitude of this effect were found between the groups. No correlation was found between 24-h urinary sodium excretion (a proxy for dietary sodium intake) and the effect of eprosartan. CONCLUSION: Eprosartan-induced vasodilation is not influenced by sodium intake and/or co-infusion of Ang II. These rather unexpected findings could be explained by differences between circulating and tissue Ang II levels, variations in AT1R expression, and/or stimulation of other vasodilatory pathways. PMID- 27214089 TI - Methodology and technology for peripheral and central blood pressure and blood pressure variability measurement: current status and future directions - Position statement of the European Society of Hypertension Working Group on blood pressure monitoring and cardiovascular variability. AB - Office blood pressure measurement has been the basis for hypertension evaluation for almost a century. However, the evaluation of blood pressure out of the office using ambulatory or self-home monitoring is now strongly recommended for the accurate diagnosis in many, if not all, cases with suspected hypertension. Moreover, there is evidence that the variability of blood pressure might offer prognostic information that is independent of the average blood pressure level. Recently, advancement in technology has provided noninvasive evaluation of central (aortic) blood pressure, which might have attributes that are additive to the conventional brachial blood pressure measurement. This position statement, developed by international experts, deals with key research and practical issues in regard to peripheral blood pressure measurement (office, home, and ambulatory), blood pressure variability, and central blood pressure measurement. The objective is to present current achievements, identify gaps in knowledge and issues concerning clinical application, and present relevant research questions and directions to investigators and manufacturers for future research and development (primary goal). PMID- 27214090 TI - Self-antigens and rejection: a proteomic analysis. AB - PURPOSE OF REVIEW: Allo- and autoantibodies have been found to play important roles in both acute and chronic allograft rejection in organ transplantation, although only recently have non-human leukocyte antigen (non-HLA), nondonor specific antibodies been given a more in-depth treatment. This review summarizes recent reports about investigations and proteomic approaches to identify self antigens and corresponding autoantibodies that are associated with acute and chronic allograft rejection. Finally, we discuss the insights gained from these, challenges, and future prospects. RECENT FINDINGS: Significant discoveries have been made regarding the presence and role of autoantibodies and alloantibodies, both those formed pretransplant and posttransplant, in acute and chronic rejection. These discoveries are made possible because of the publication of the human genome and subsequent development in the ability of expression and analysis of human proteome. SUMMARY: Antibodies play a critical role in survival and dysfunction of a transplanted kidney. Even though HLA antibodies have been given the majority of the scientific community's attention for the past few decades, antibodies against autoantigens and that of non-HLA origin are gaining attention. Recent publications have identified novel self-antigens that are associated with acute and chronic rejection that have added to our understanding of new players in immune-related transplant rejection. PMID- 27214091 TI - Perovskite Materials for Light-Emitting Diodes and Lasers. AB - Organic-inorganic hybrid perovskites have cemented their position as an exceptional class of optoelectronic materials thanks to record photovoltaic efficiencies of 22.1%, as well as promising demonstrations of light-emitting diodes, lasers, and light-emitting transistors. Perovskite materials with photoluminescence quantum yields close to 100% and perovskite light-emitting diodes with external quantum efficiencies of 8% and current efficiencies of 43 cd A(-1) have been achieved. Although perovskite light-emitting devices are yet to become industrially relevant, in merely two years these devices have achieved the brightness and efficiencies that organic light-emitting diodes accomplished in two decades. Further advances will rely decisively on the multitude of compositional, structural variants that enable the formation of lower dimensionality layered and three-dimensional perovskites, nanostructures, charge transport materials, and device processing with architectural innovations. Here, the rapid advancements in perovskite light-emitting devices and lasers are reviewed. The key challenges in materials development, device fabrication, operational stability are addressed, and an outlook is presented that will address market viability of perovskite light-emitting devices. PMID- 27214092 TI - Efficient Synthesis of Topologically Linked Three-Ring DNA Catenanes. AB - Topologically controlled DNA catenanes are promising elements for the construction of molecular machines but present a significant effort in DNA nanotechnology. We report an efficient approach for preparing linear three-ring catenanes (L3C) composed of single-stranded DNA. The linking number was strictly controlled by using short complementary regions (6 nt) between each two DNA rings. High efficiency of forming three-ring catenanes (yield as high as 63 %) was obtained by using an 80 nt oligonucleotide as the scaffold to draw close the three pre-rings for hybridization between short complementary DNA. After assembly, three pre-rings were closed by DNA ligation using three 12 nt oligonucleotides as splints to form interlocked three-ring catenanes. L3C nanostructures were imaged in air by AFM: the catenane exhibited a smooth circular shape and was arranged in a line with well-defined structure, as expected. PMID- 27214093 TI - Syncope Following Orthotopic Heart Transplant: Sinoatrial or Atrioventricular Nodal Block? PMID- 27214094 TI - Dose down-titration of biological DMARDs in patients with rheumatoid arthritis over time and in daily clinical practice. AB - OBJECTIVES: To describe and compare dosing optimisation in biological DMARDs (bDMARDs) and relapses after that, in a cohort of rheumatoid arthritis (RA) during clinical practice. METHODS: Observational retrospective longitudinal study of RA patients taking bDMARDs from December 1999 to November 2013. Optimisation was defined as a 15% decrease in dose either reducing single dose or separating dose interval administration, for at least 4 times the recommended period between dosages. Relapse was defined as suspension or starting again with the recommended dose after optimisation. Incidence rates (IR) per 100 patient-years were estimated using survival techniques. Cox multivariate models were conducted to compare bDMARDs expressed in hazard ratios (HR) and confidence intervals [95%CI]. RESULTS: 443 patients and 752 different courses of bDMARDs treatments were included. We observed 146 optimisations with an IR of 8.1. The HR of optimisation in: a) adalimumab, etanercept and rituximab compared to infliximab was 1.56 [1.01 2.4], 1.5 [0.9-2.4] and 0.6 [0.3-1.4], respectively; b) adalimumab, etanercept compared to rituximab were 2.3 [1.2-4.5] and 2.2 [1.2-4.3]. There were no statistically significant differences between adalimumab and etanercept. Following optimisation, 36% relapsed (78% due to disease activity). The IR related to disease activity was 6.3, and was lower for adalimumab and etanercept compared to infliximab (HR: 0.42; [0.19-0.94]; HR: 0.34; [0.13-0.89], respectively). There were no statistically significant differences between etanercept and adalimumab. No patients on rituximab relapsed. CONCLUSIONS: Optimisation was similar between adalimumab and etanercept, and was lower for infliximab and rituximab. After optimisation, rituximab did not relapse, but infliximab did with the highest hazard. PMID- 27214095 TI - Prolonged Use of Proton Pump Inhibitors as Stricture Prophylaxis in Infants with Reconstructed Esophageal Atresia. AB - Introduction Proton pump inhibitors (PPIs) are used as prophylaxis, guarding against anastomotic stricture (AS) in the aftermath of reconstructed esophageal atresia (EA). The incidence of stricture formation was studied in this setting, comparing outcomes of 3- and 12-month PPI prophylactic regimens. Patients and Methods Patient characteristics (gestational age, birth weight, prevalence of chromosomal aberrations, and other malformations), as well as rates of survival, AS formation, and required balloon dilation, were recorded in the following therapeutic subsets: (1) all infants undergoing primary surgical anastomosis for EA in years 2010-2014 and given postoperative PPI prophylaxis for 12 months and (2) all infants similarly treated for EA in years 2001-2009 but given postoperative PPI prophylaxis for 3 months only. Duration of follow-up was 1 year in each group. Results Patient characteristics and survival rates in 12-month (n = 33) and in 3-month (n = 30) treatment groups did not differ significantly. The prevalence of AS was 42%/43% in each group (12 months, 14/33; 3 months, 13/30; p = 1). Median number of dilations required was 3 (range, 1-9) per patient in each group (p = 0.69). Median age at initial dilation was 163 days and 63 days in 12- and 3-month groups, respectively (p = 0.04). Conclusion Development of AS in the first year after reconstruction of EA was not reduced by prolonged PPI prophylaxis (12 vs. 3 months), but initial balloon dilation procedures were performed later in infants who were treated longer. PMID- 27214096 TI - Biomarkers to distinguish functional constipation from irritable bowel syndrome with constipation. AB - Treatments for functional constipation (FC) and irritable bowel syndrome with constipation (IBS-C) differ, but symptom criteria do not reliably distinguish between them; some regard FC and IBS-C as parts of a single constipation spectrum. Our goal was to review studies comparing FC and IBS-C to identify possible biomarkers that separate them. A systematic review identified 15 studies that compared physiologic tests in FC vs IBS-C. Pain thresholds were lower in IBS C than FC for 3/5 studies and not different in 2/5. Colonic motility was decreased more in FC than IBS-C for 3/3 studies, and whole gut transit was delayed more in FC than IBS-C in 3/8 studies and not different in 5/8. Pelvic floor dyssynergia was unrelated to diagnosis. Sympathetic arousal, measured in only one study, was greater in IBS-C than FC. The most reliable separation of FC from IBS-C was shown by a novel new magnetic resonance imaging technique described in this issue of the journal. These authors showed that drinking one liter of polyethylene glycol laxative significantly increased water content in the small intestine, volume of contents in the ascending colon, and time to first evacuation in FC vs IBS-C; and resulted in less colon motility and delayed whole gut transit in FC compared to IBS-C. Although replication is needed, this well tolerated, non-invasive test promises to become a new standard for differential diagnosis of FC vs IBS-C. These data suggest that FC and IBS-C are different disorders rather than points on a constipation spectrum. PMID- 27214097 TI - Simultaneous urodynamic and anorectal manometry studies in children: insights into the relationship between the lower gastrointestinal and lower urinary tracts. AB - BACKGROUND: Children with urinary incontinence (UI) have associated functional constipation (FC) and fecal incontinence (FI). The physiology between lower urinary tract (LUT) and anorectum in children has not been elucidated. AIMS: Observe the effect of rectal distention (RD) on LUT function, and bladder filling and voiding on anorectal function. METHODS: Children with voiding dysfunction referred to Boston Children's Hospital were prospectively enrolled in combined urodynamic (UDS) and anorectal manometry (ARM). Anorectal and urodynamic parameters were simultaneously measured. Patients underwent two micturition cycles, first with rectal balloon deflated and second with it inflated (RD). Lower urinary tract and anorectal parameters were compared between cycles. KEY RESULTS: Ten children (seven UI, four recurrent UTIs, nine FC +/- FI) were enrolled. Postvoid residual (PVR) increased (p = 0.02) with RD. No differences were observed in percent of bladder filling to expected bladder capacity, sensation, and bladder compliance with and without RD. Bladder and abdominal pressures increased at voiding with RD (p < 0.05). Intra-anal pressures decreased at voiding (p < 0.05), at 25% (p = 0.03) and 50% (p = 0.06) of total volume of bladder filling. CONCLUSIONS & INFERENCES: The PVR volume increased with RD. Stool in the rectum does not alter filling cystometric capacity but decreases the bladder's ability to empty predisposing patients with fecal retention to UI and UTIs. Bladder and abdominal pressures increased during voiding, demonstrating a physiological correlate of voiding dysfunction. Intra-anal pressures decreased during bladder filling and voiding. This is the first time intra-anal relaxation during bladder filling and voiding has been described. PMID- 27214098 TI - Priming mobilized peripheral blood mononuclear cells with the "activated platelet supernatant" enhances the efficacy of cell therapy for myocardial infarction of rats. AB - AIM: Various methods are used to augment the efficacy of cell therapy in myocardial infarction (MI). In this study, we used the "activated platelet supernatant (APS)" to prime autologous "granulocyte colony-stimulating factor mobilized peripheral blood mononuclear cells ((mob) PBMCs)" and investigated the efficacy of cell-based therapy in MI. METHOD: Rat (mob) PBMCs were isolated after daily subcutaneous injections of G-CSF at 100 MUg/kg for 3 days. APS was isolated separately after activating rat platelets with thrombin 0.5 U/mL for 2 hours. Priming was performed with APS for 6 hours. To check the paracrine effect of primed (mob) PBMCs, we used the 36-hour culture supernatant of the primed cells. A rat MI model was used for an in vivo model. RESULT: Cytokines such as IL-1beta, IL-10, and TGFbeta were 3.7+/-0.9-fold, 3.4+/-1.2-fold, and 1.2+/-0.1-fold higher in APS, respectively, compared with naive platelet supernatant. By APS priming, (mob) PBMCs showed M2 polarization and upregulation of angiogenic molecules (i.e., TEK, IL-10, CXCL1, and CX3CR1). APS-primed (mob) PBMCs had a 2.3-fold increased adhesion ability, induced by upregulated integrins. Rat endothelial cells cultured in the 36-hour culture supernatant of APS-primed (mob) PBMCs showed a 1.6-fold augmented proliferation and capillary network formation. In vivo transplantation of APS-primed (mob) PBMCs into rat MI models showed a significant trend of reduction in fibrosis area (P=.001) and wall thinning (P=.030), which lead to improvement in cardiac function measured by echocardiography. CONCLUSION: Our data reveal that APS priming can enhance the wound-healing potential of (mob) PBMCs. APS priming may be a promising method for cell-based therapy of MI. PMID- 27214099 TI - Evaluation of a novel point-of-care test for active matrix metalloproteinase-8: agreement between qualitative and quantitative measurements and relation to periodontal inflammation. AB - BACKGROUND AND OBJECTIVES: Severe periodontitis affects about 10% of the world population. In addition, associations between periodontitis and systemic diseases exist. Therefore, the diagnosis should be made quickly and at an early stage. Matrix metalloproteinase-8 (MMP-8) is the most prominent collagenase found in inflamed periodontal tissues. Its active form (aMMP-8) is increasingly used as a diagnostic biomarker. Aim of the present study is to evaluate the diagnostic accuracy of a novel aMMP-8 point-of-care (POC) test in comparison to the standard laboratory test to diagnose the disease rapidly and reliably. MATERIAL AND METHODS: In a prospective, mono-center, double-blinded, case-control study, participants with healthy gums (n = 35), gingivitis (n = 60) and periodontitis (n = 35) were investigated before and after therapy. Beside clinical variables for plaque and inflammation, aMMP-8 concentrations were determined in oral rinsing specimens by the enzyme-linked immunosorbent assay (ELISA) and by POC. Positive and negative percent agreements with their exact one-sided lower 95% confidence limits were calculated. RESULTS: Of 130 participants, 111 finished the study. Overall, positive percent agreements were 75.8% (57.7-88.9) before treatment and 73.7% (56.9-86.6) after treatment. Negative percent agreements were 92.8% (85.7 97.0) before and 93.3% (85.1-97.8) after treatment. Positive test results (POC and ELISA) ranged from 5.7% to 8.6% in healthy patients, 25.0-29.8% in patients with gingivitis and 40.0-48.1% in patients with periodontitis. Patients who had positive aMMP-8 test results (POC) showed higher scores for plaque and inflammation. CONCLUSIONS: The novel POC test to detect aMMP-8 has proved to agree strongly with the standard method, ELISA. The test can be recommended to screen patients at risk for periodontitis in dental offices, at the general practitioner and at specialists for associated diseases. PMID- 27214101 TI - "Are cognitive interventions effective in Alzheimer's disease? A controlled meta- analysis of the effects of bias": Correction to Oltra-Cucarella et al. (2016). AB - Reports an error in "Are Cognitive Interventions Effective in Alzheimer's Disease? A Controlled Meta-Analysis of the Effects of Bias" by Javier Oltra Cucarella, Ruben Perez-Elvira, Raul Espert and Anita Sohn McCormick (Neuropsychology, Advanced Online Publication, Apr 7, 2016, np). In the article the first sentence of the third paragraph of the Source of bias subsection in the Statistical Analysis subsection of the Correlational Meta-Analysis section should read "For the control condition bias, three comparison groups were differentiated: (a) a structured cognitive intervention, (b) a placebo control condition, and (c) a pharma control condition without cognitive intervention or no treatment at all." (The following abstract of the original article appeared in record 2016-16656-001.) OBJECTIVE: There is limited evidence about the efficacy of cognitive interventions for Alzheimer's disease (AD). However, aside from the methodological quality of the studies analyzed, the methodology used in previous meta-analyses is itself a risk of bias as different types of effect sizes (ESs) were calculated and combined. This study aimed at examining the results of nonpharmacological interventions for AD with an adequate control of statistical methods and to demonstrate a different approach to meta-analysis. METHOD: ESs were calculated with the independent groups pre/post design. Average ESs for separate outcomes were calculated and moderator analyses were performed so as to offer an overview of the effects of bias. RESULTS: Eighty-seven outcomes from 19 studies (n = 812) were meta-analyzed. ESs were small on average for cognitive and functional outcomes after intervention. Moderator analyses showed no effect of control of bias, although ESs were different from zero only in some circumstances (e.g., memory outcomes in randomized studies). Cognitive interventions showed no more efficacy than placebo interventions, and functional ESs were consistently low across conditions. CONCLUSIONS: cognitive interventions delivered may not be effective in AD probably due to the fact that the assumptions behind the cognitive interventions might be inadequate. Future directions include a change in the type of intervention as well as the use of outcomes other than standardized tests. Additional studies with larger sample sizes and different designs are needed to increase the power of both primary studies and meta analyses. (PsycINFO Database Record PMID- 27214100 TI - Brief Report: HLA-DRB1, DQA1, and DQB1 in Juvenile-Onset Systemic Sclerosis. AB - OBJECTIVE: Systemic sclerosis (SSc) is a rare disease that is particularly uncommon in children. Specific HLA alleles have been associated with SSc in adults. This study was undertaken to investigate HLA class II alleles in juvenile onset SSc. METHODS: DRB1, DQA1, and DQB1 alleles were determined by DNA-based HLA typing. Analyses were conducted comparing Caucasian patients with juvenile-onset SSc (n = 76) to healthy Caucasian controls (n = 581). RESULTS: Initial analyses focused on HLA class II associations previously reported in adult Caucasian patients with SSc. The frequency of DRB1*11 was not significantly increased in juvenile-onset SSc (22.4% of patients with juvenile-onset SSc versus 17.6% of controls; odds ratio [OR] 1.35, P = 0.34), nor were the specific DRB1*11:01 or *11:04 alleles. DQA1*05, a risk factor previously identified in adult men with SSc, was increased in patients with juvenile-onset SSc versus controls (57.9% versus 44.1%; OR 1.76, P = 0.027), as was DRB1*03 (34.2% versus 22.5%; OR 1.79, P = 0.031). Secondary analyses of all DRB1 allele groups revealed an association with DRB1*10 (10.5% of patients with juvenile-onset SSc versus 1.5% of controls; OR 7.48, P = 0.0002). As this is a new observation, correction was made for multiple comparisons of 13 different DRB1 allele groups; results nevertheless remained significant (P = 0.003). Also, a lower frequency of DRB1*01 was observed in patients with juvenile-onset SSc who were younger at disease onset (OR 0.06, P = 0.01) and in those with antibodies to topoisomerase (OR 0.14, P = 0.024). CONCLUSION: Associations of HLA alleles with juvenile-onset SSc differed from associations with SSc in women, but were similar to associations with SSc in men. Additionally, a novel association with DRB1*10 was observed in children. The greatest proportion of genetic risk of SSc is contributed by the HLA complex, and the current study reveals the importance of the association of HLA class II genes in juvenile-onset SSc. PMID- 27214102 TI - Amorphous nanosilica particles evoke vascular relaxation through PI3K/Akt/eNOS signaling. AB - There have been several reported studies on the distribution and/or toxicity of nanosilica particles. However, the influence of these particles on blood vessels through which they are distributed is poorly understood. Hence, we investigated the effects of nano- and micromaterials on blood vessel shrinkage and relaxation. Nanosilica particles with diameters of 70 nm (nSP70) were used as the nanomaterial, and particles of 300 and 1000 nm (nSP300 and mSP1000, respectively) were used as micromaterials. A rat thoracic aorta was used as the test blood vessel. The nano- and micromaterials had no effect on vessel shrinkage. Of the nano- and micromaterials tested, only nSP70 strongly evoked vascular relaxation. Vascular relaxation evoked by nSP70 was almost completely inhibited by the phosphoinositide 3-kinase (PI3K) inhibitor wortmannin. In addition, the selective nitric oxide synthesis inhibitor NG-nitro-l-arginine methyl ester, which inhibits endothelial nitric oxide synthase (eNOS) downstream of PI3K signaling, inhibited vascular relaxation evoked by nSP70. In an analysis using bovine aortic endothelial cells (bAECs), nSP70 phosphorylated protein kinase B (AKT) and eNOS acted downstream of PI3K signaling. PI3K inhibition by wortmannin reduced AKT and eNOS phosphorylation. These results demonstrated that 70-nm amorphous nanosilica particles evoked vascular relaxation through PI3K/Akt/eNOS signaling. Moreover, it was suggested that nanomaterials, in general, control or disrupt vascular function by activating a known signal cascade. PMID- 27214103 TI - Online, Absolute Quantitation of Propranolol from Spatially Distinct 20- and 40 MUm Dissections of Brain, Liver, and Kidney Thin Tissue Sections by Laser Microdissection-Liquid Vortex Capture-Mass Spectrometry. AB - Spatial resolved quantitation of chemical species in thin tissue sections by mass spectrometric methods has been constrained by the need for matrix-matched standards or other arduous calibration protocols and procedures to mitigate matrix effects (e.g., spatially varying ionization suppression). Reported here is the use of laser "cut and drop" sampling with a laser microdissection-liquid vortex capture electrospray ionization tandem mass spectrometry (LMD-LVC/ESI MS/MS) system for online and absolute quantitation of propranolol in mouse brain, kidney, and liver thin tissue sections of mice administered with the drug at a 7.5 mg/kg dose, intravenously. In this procedure either 20 MUm * 20 MUm or 40 MUm * 40 MUm tissue microdissections were cut and dropped into the flowing solvent of the capture probe. During transport to the ESI source drug related material was completely extracted from the tissue into the solvent, which contained a known concentration of propranolol-d7 as an internal standard. This allowed absolute quantitation to be achieved with an external calibration curve generated from standards containing the same fixed concentration of propranolol-d7 and varied concentrations of propranolol. Average propranolol concentrations determined with the laser "cut and drop" sampling method closely agreed with concentration values obtained from 2.3 mm diameter tissue punches from serial sections that were extracted and quantified by HPLC/ESI-MS/MS measurements. In addition, the relative abundance of hydroxypropranolol glucuronide metabolites were recorded and found to be consistent with previous findings. PMID- 27214104 TI - The Haemophilia Centre Twinning Programme. PMID- 27214105 TI - Factor XI deficiency and its management: Meeting at the Royal Free Hospital, London, 11 December 1995. AB - The meeting offered participants, mostly interested in the manufacture or clinical application of factor XI concentrates, an opportunity to review evidence of their efficacy and some recent concerns about their safety. PMID- 27214106 TI - Types of bleeding seen during the first 30 months of life in children with severe haemophilia A and B. AB - In view of excellent preservation of joint structure and function in Swedish patients started on primary prophylaxis at 1-2 years of age, it has recently been recommended that primary prophylaxis be considered optimal management for U.S. children with severe haemophilia (< 1% FVIII or FIX). In order to determine the age at which joint bleeding began, we reviewed (49) patients with severe haemophilia who were seen at our haemophilia centre for all bleeding episodes from birth on. Eight of the 49 children were first treated during the first few days of life for bleeding related to circumcision (6), spontaneous splenic rupture (1) or soft tissue haematoma (1). None had intracranial haemorrhage (ICH) in the immediate neonatal period. Other bleeding episodes for which children were treated during the first 30 months of life included soft tissue haematoma (42 episodes), tongue and mouth bleeding (37 episodes), ICH (four children) or for surgery (five children). Joint bleeding occurred in 16/49 children with severe haemophilia. Four of the 16 had haemophilia B, while 13 had haemophilia A. A single episode of severe joint bleeding occurred in each of the five patients before 12 months of age. Eight patients had 12 episodes of joint bleeding between 12 and 18 months of age and three patients accounted for 15 episodes between 18 and 24 months of age. Three children had a total of four joint haemorrhages between 25 and 30 months, and 33/49 children did not have any joint bleeding before 30 months of age. It is noteworthy that two children had recurrent bleeding into the same joint. One with haemophilia A had recurrent bleeding into the knees (at 14, 18, 20, 21 months), while one with haemophilia B had recurrent bleeding into one ankle starting at age 16 months. It would thus seem appropriate to begin primary prophylaxis in children with severe haemophilia once joint bleeding has begun (one or two episodes), rather than at a standard age. PMID- 27214107 TI - Management of haemophilia in developing countries: an Indian experience. AB - Haemophilia A and B remain the most common hereditary bleeding disorders in India, with 58% of the patients being below 10 years of age. CNS haemorrhage was observed in 5.8% and HIV infection was present in 8.7% of the patients. The main source of factor replacement therapy was fresh frozen plasma and cryoprecipitate. Only 48% of the patients with mild to moderate bleeding episodes received adequate factor therapy (more than 80% of the required factor level). Inadequate availability of fresh frozen plasma and cryoprecipitate and the prohibitive cost of commercial concentrate preparation are the chief limiting factors for adequate factor replacement therapy in India. PMID- 27214108 TI - A controlled neuropsychological study of HIV-seropositive and HIV-seronegative adolescent haemophiliacs. AB - Sixty-four males with haemophilia were assessed with a series of neuropsychological tests and a structured interview for psychiatric symptoms. Thirty-one had been infected with human immunodeficiency virus (HIV) before the age of 18 and were in various stages of the disease at the time of testing and 33 were HIV negative. Sixteen male control subjects were recruited to match in age with the haemophilia group. The HIV-seropositive group were older than the HIV negative group due to the cohort effect of the time of infection. Contrary to predictions from the known effects of HIV on the central nervous system the HIV seropositive group performed better on many of the tests than the HIV seronegative group. In some but not all of the tests this may have been an age effect. There was very little psychiatric morbidity, consistent with the view that high levels of psychological support provided by the haemophilia units can alleviate the effects of the illness on emotions and behaviour. These findings form a baseline for a 2-year follow-up study which is in progress. PMID- 27214109 TI - Potency measurement of factor VIII in recombinant concentrates. AB - In preliminary studies on the stability of recombinant factor VIII (rFVIII) concentrates post reconstitution, a rise in potency to 200% of labelled values was observed in concentrates stored at 22 degrees C over 24 h. This was observed in potency estimates by the one-stage clotting, but not the two-stage clotting or chromogenic assays, and was not observed for intermediate-purity product derived from plasma (IPVIII). Use of human serum albumin (HSA), rather than the usual bovine material (BSA), to dilute product for the stability study abolished the rise in potency. Incorporating purified von Willebrand Factor (VWF) in the diluent buffer abolished the rise observed in BSA. A similar rise was observed upon incubating rFVIII in the presence of 10(-4) u of thrombin per mL in HSA buffer. Potency estimates using the HSA in the dilution buffer resulted in severe underpotency in relation to the label claim when using the two-stage clotting and the chromogenic assays, but not the one-stage clotting assay. Predilution in severe haemophilic plasma restored potency levels to those claimed. We conclude that (i) commercial preparations of BSA may be unsuitable for inclusion in buffers for rFVIII studies; (ii) FVIII in rFVIII concentrates is exquisitely sensitive to activation by thrombin, presumably as a result of the lack of VWF; (iii) accurate potency estimation in the two-stage assay systems requires VWF in the assay system. PMID- 27214110 TI - Pharmacokinetic properties of two factor VIII concentrates with single and double viral inactivation. AB - In order to assess whether addition of a modified pasteurization step to the manufacture of a solvent/detergent-treated factor VIII concentrate of high purity has affected its properties, three sets of pharmacokinetic studies were performed. In an open, controlled study with seven patients and a double-blind cross-over study with nine patients, the pharmacokinetic parameters of the double virus-inactivated preparation were compared with those of a mono-inactivated product, using a one-stage clotting assay. In a longitudinal study comparison was made between baseline and 8 months after treatment with the double virus inactivated product in six patients, using three different factor VIII assays. There were no differences in recovery, clearance or half-life between the single- and double-inactivated products. After 8 months of treatment, the half-life and mean residence time were longer with the one-stage clotting assay, whereas the chromogenic assay showed a lower recovery, a faster cleareance and smaller area under the curve with the double virus-inactivated product. All differences were small and none was consistent in all three methods. In conclusion, the double virus inactivation does not appear to have affected the pharmacokinetic characteristics of this factor VIII preparation. PMID- 27214111 TI - Comparison of the quality of life between HIV-positive haemophilia patients and HIV-negative haemophilia patients. AB - In a prospective study, we tested the hypothesis that an already reduced quality of life in haemophilia patients is further diminished in those haemophilia patients who contracted the human immunodeficiency virus (HIV) as a result of transfusion of coagulation factor preparations. From an available pool of 92 males with haemophilia A or B, 18 patients seropositive for HIV infection and 11 seronegative patients were randomly selected for the study. We applied two instruments to measure the quality of life (QOL) in our patients. The first instrument was the quality of well-being (QWB) scale that unifies QOL into a single score based upon an assessment of the patient's symptoms and health related reductions in mobility, physical activity and social activity. The second instrument was SF-36, the questionnaire from the Medical Outcome Study (MOS) that measures six dimensions of health status (physical functioning, role functioning, social functioning, pain, mental health and health perception). Measurements were obtained with both instruments at three interviews with each patient over a 1 year interval. As expected, HIV disease reduces QOL in haemophiliacs. The number of bleeding episodes within 2 months of interview was increased in the HIV positive cohort but not within 6 days of interview, indicating that HIV disease independently affects QOL in haemophilia patients. In a typical 30-year-old patient, haemophilia itself has reduced quality of their lives by 9.3 years, and HIV disease additionally from 8.5 to 20 years. On the MOS scales, the two patient groups differed significantly only in the dimensions of health perception and pain magnitude. Although HIV disease led to a decrement in QOL of haemophilia patients, it also appears that haemophilia patients are able to develop coping skills to prevent more drastic effects of HIV disease on their QOL. Future studies will need to explore the nature and mechanisms of this 'buffering' effect. PMID- 27214112 TI - Successful treatment of acute subdural haemorrhage with continuous intravenous infusion of factor VIII in a 17 year old with haemophilia A. AB - Intracranial haemorrhage is a common complication of haemophilia, occurring in 2 8% of sufferers [1]. Half of the cases give a history of trauma and despite developments in the management of acute bleeding the condition still carries a mortality of approximately 30% [2]. Surgery may be required, most commonly for evacuation of a subdural haematoma which carries a mortality of up to 40% [3]. We present the case of a 17-year-old haemophiliac with a traumatic subdural haemorrhage, who was treated with a continuous intravenous infusion of factor VIII and made a complete recovery without recourse to surgery. We have found no reference in the world literature of such treatment for acute subdural haemorrhage in a haemophiliac. PMID- 27214113 TI - Hepatocellular failure from hepatitis C infection in two recipients of a single batch infusion of plasma-derived blood products. AB - We report two patients with mild inherited bleeding disorders who acquired hepatitis C infection after receiving single infusion of plasma-derived concentrates prior to the introduction of donor screening and viral inactivation procedures. Both these patients became clinically jaundiced at the time of hepatitis C infection. Despite being HIV antibody negative, an absence of other risk factors of chronic liver disease and treatment with interferon, they progressed to hepatocellular failure in 5 and 12 years following seroconversion. The natural history of hepatitis C infection is still uncertain [1], although it is usually considered that hepatitis C infection progresses slowly, only resulting in clinically manifest liver disease after several decades. In view of the apparent rapidity of onset of liver damage in these two patients, we wonder if older age at time of infection, jaundice during the seroconversion illness or a mild coagulopathy with consequent infrequent exposure to blood products are adverse prognostic features. PMID- 27214114 TI - William Hewson and the blood which issued last but clotted first: the beginning of the story of desmopressin in haemophilia and vWD. PMID- 27214116 TI - Are pseudotumours of bone an additional risk factor for recurrent bacterial infection in HIV-infected haemophiliacs? PMID- 27214117 TI - Preparation of trans-2-Substituted-4-halopiperidines and cis-2-Substituted-4 halotetrahydropyrans via AlCl3-Catalyzed Prins Reaction. AB - A general and practical method for the preparation of trans-2-substituted-4 halopiperidines and cis-2-substituted-4-halotetrahydropyrans is reported. Using 5 mol % of AlCl3 as the catalyst and 2 equiv of trimethylsilyl halides as the halide sources, aza-Prins cyclization of N-tosyl homoallylamine or Prins cyclization of homoallylic alcohol with carbonyl compounds could be readily realized, giving the corresponding trans-2-substituted-4-halopiperidines or cis-2 substituted-4-halotetrahydropyrans in high yields and satisfactory diastereoselectivity. PMID- 27214118 TI - Measuring Diagnostic Health Care Costs in Stable Coronary Artery Disease: Should We Follow the Money? PMID- 27214119 TI - The impact of premature ejaculation on the subjective perception of orgasmic intensity: validation and standardisation of the 'Orgasmometer'. AB - To the best of our knowledge, no psychometric tools have been specifically developed to measure if premature ejaculation (PE) is related to low sexual pleasure in terms of perception of orgasmic intensity. Hence, the aim of this study was to evaluate if men with PE suffer from a low perception of orgasmic intensity using a new tool, the 'Orgasmometer', to quantitatively measure the intensity of orgasmic pleasure. Among 329 subjects attending our andrological unit for suspected PE, 257 men fulfilled the inclusion criteria. Of these, 156 (60.7%; 156/257) were affected by PE (PE group) and 101 (39.3%; 101/257) did not have any sexual dysfunction (Control group). Men were requested to fill out the Premature Ejaculation Diagnostic Tool (PEDT) and the Orgasmometer, a new visual tool recording orgasm intensity on a Likert scale. Interestingly, MANCOVA analysis revealed a statistically significant difference between the two groups (p = 0.044) in the subjective perception of orgasm intensity with the PE group scoring lower on the Orgasmometer (mean 5.8; 95% CI 5.191-6.409) than the Control group (mean 7.95; 95% CI 7.033-8.87). In addition, multiple linear regression revealed an inverse correlation between the PEDT and the Orgasmometer scores (p < 0.0001). Hence, higher PEDT scores were associated with a lower subjective perception of orgasmic intensity. The Orgasmometer was well understood, had good test-retest reliability and a high AUC in differentiating between men with high and low orgasmic pleasure intensity. The ROC curve analysis showed that a cut-off <=6 had 87.7% sensitivity (95% CI 79.6-92.6), 95% specificity (95% CI 88.7-98.4), 95.3% positive predictive value (PPV) and 86.4% negative predictive value (NPV). Men affected by premature ejaculation perceived significantly lower orgasmic intensity than sexually healthy men. The Orgasmometer is an easy-to-perform, user friendly tool for measuring orgasmic intensity. PMID- 27214120 TI - Mercury Sulfide Dimorphism in Thioarsenate Glasses. AB - Crystalline mercury sulfide exists in two drastically different polymorphic forms in different domains of the P,T-diagram: red chain-like insulator alpha-HgS, stable below 344 degrees C, and black tetrahedral narrow-band semiconductor beta HgS, stable at higher temperatures. Using pulsed neutron and high-energy X-ray diffraction, we show that these two mercury bonding patterns are present simultaneously in mercury thioarsenate glasses HgS-As2S3. The population and interconnectivity of chain-like and tetrahedral dimorphous forms determine both the structural features and fundamental glass properties (thermal, electronic, etc.). DFT simulations of mercury species and RMC modeling of high-resolution diffraction data provide additional details on local Hg environment and connectivity implying the (HgS2/2)m oligomeric chains (1 <= m <= 6) are acting as a network former while the HgS4/4-related mixed agglomerated units behave as a modifier. PMID- 27214121 TI - Porphyromonas gingivalis attenuates the insulin-induced phosphorylation and translocation of forkhead box protein O1 in human hepatocytes. AB - OBJECTIVE: Porphyromonas gingivalis (P. gingivalis) is a pathogen involved in periodontal disease. Recently, periodontal disease has been demonstrated to increase the risk of developing diabetes mellitus, although the molecular mechanism is not fully understood. Forkhead box protein O1 (FoxO1) is a transcriptional factor that regulates gluconeogenesis in the liver. Gluconeogenesis is a key process in the induction of diabetes mellitus; however, little is known regarding the relationship between periodontal disease and gluconeogenesis. In this study, to investigate whether periodontal disease influences hepatic gluconeogenesis, we examined the effects of P. gingivalis on the phosphorylation and translocation of FoxO1 in insulin-induced human hepatocytes. DESIGN: The human hepatocyte HepG2 was treated with insulin and Akt and FoxO1 phosphorylation was detected by western blot analysis. The localization of phosphorylated FoxO1 was detected by immunocytochemistry and western blot analysis. HepG2 cells were treated with SNAP26b-tagged P. gingivalis (SNAP-P.g.) before insulin stimulation, and then the changes in Akt and FoxO1 were determined by western blot analysis and immunocytochemistry. RESULTS: Insulin (100nM) induced FoxO1 phosphorylation 60min after treatment in HepG2 cells. Phosphorylated FoxO1 translocated to the cytoplasm. SNAP-P.g. internalized into HepG2 cells and decreased Akt and FoxO1 phosphorylation induced by insulin. The effect of insulin on FoxO1 translocation was also attenuated by SNAP-P.g. CONCLUSIONS: Our study shows that P. gingivalis decreases the phosphorylation and translocation of FoxO induced by insulin in HepG2 cells. Our results suggest that periodontal disease may increase hepatic gluconeogenesis by reducing the effects of insulin on FoxO1. PMID- 27214122 TI - Accounting for adaptive capacity and uncertainty in assessments of species' climate-change vulnerability. AB - Climate-change vulnerability assessments (CCVAs) are valuable tools for assessing species' vulnerability to climatic changes, yet failure to include measures of adaptive capacity and to account for sources of uncertainty may limit their effectiveness. We took a more comprehensive approach that incorporates exposure, sensitivity, and capacity to adapt to climate change. We applied our approach to anadromous steelhead trout (Oncorhynchus mykiss) and nonanadromous bull trout (Salvelinus confluentus), threatened salmonids within the Columbia River Basin (U.S.A.). We quantified exposure on the basis of scenarios of future stream temperature and flow, and we represented sensitivity and capacity to adapt to climate change with metrics of habitat quality, demographic condition, and genetic diversity. Both species were found to be highly vulnerable to climate change at low elevations and in their southernmost habitats. However, vulnerability rankings varied widely depending on the factors (climate, habitat, demographic, and genetic) included in the CCVA and often differed for the 2 species at locations where they were sympatric. Our findings illustrate that CCVA results are highly sensitive to data inputs and that spatial differences can complicate multispecies conservation. Based on our results, we suggest that CCVAs be considered within a broader conceptual and computational framework and be used to refine hypotheses, guide research, and compare plausible scenarios of species' vulnerability to climate change. PMID- 27214123 TI - Protein-losing enteropathy with intestinal lymphangiectasia in skeletal dysplasia with Lys650Met mutation. AB - Protein-losing enteropathy is a primary or secondary manifestation of a group of conditions, and etiologies which are broadly divisible into those with mucosal injury on the basis of inflammatory and ulcerative conditions, mucosal injury without erosions or ulcerations, and lymphatic abnormalities. We describe the first case of protein-losing enteropathy in a pediatric patient, with severe skeletal dysplasia consistent with thanatophoric dysplasia type I and DNA analysis that revealed a c.1949A>T (p.Lys650Met) in exon 15 of the FGFR3 gene. She presented with protein-losing enteropathy in her 6th month. Post-mortem examination revealed lymphangiectasia in the small intestine. To our knowledge, this is the first report of intestinal lymphangiectasia as a complication of skeletal dysplasia resulting in severe protein-losing enteropathy. (c) 2016 Wiley Periodicals, Inc. PMID- 27214124 TI - Association between neonatal morbidities and head growth from birth until discharge in very-low-birthweight infants born preterm: a population-based study. AB - AIM: To evaluate the possible association between major neonatal morbidities and poor head growth from birth to discharge home in very-low-birthweight (VLBW) infants born preterm. METHOD: Population-based observational study comprising 12 992 infants (6340 male, 6652 female) of 24 to 32 weeks' gestation, and birthweight <=1500g. Severe head growth failure (HGF) was defined as a decrease in head circumference z-score >2 z-scores, and moderate HGF as a decrease of 1 to 2 z-scores. Multinomial logistic regression analysis was applied to determine morbidities associated with HGF. RESULTS: Severe HGF occurred in 4.5% and moderate HGF in 20.9% of infants. Each unit increase in head circumference z score at birth was associated with increased odds for severe and moderate HGF (odds ratios [OR] 5.29, 95% confidence intervals [CI] 4.67-6.00, and OR 2.38, 95% CI 2.23-2.54 respectively). Both severe and moderate HGF were associated with respiratory distress syndrome (OR 2.03, 95% CI 1.58-2.62, and OR 1.66, 95% CI 1.48-1.85 respectively); bronchopulmonary dysplasia (OR 3.38, 95% CI 2.33-4.91, and OR 1.87, 95% CI 1.52-2.30 respectively); necrotizing enterocolitis (OR 2.89, 95% CI 2.04-4.09, and OR 1.72, 95% CI 1.38-2.16 respectively), and sepsis (OR 2.06, 95% CI 1.69-2.50, and OR 1.38, 95% CI 1.24-1.53 respectively). INTERPRETATION: Major neonatal morbidities were associated with HGF in VLBW infants born preterm. Identification of whether this is a direct effect of these morbidities or mediated through nutritional or growth factors may enable interventions to improve postnatal head growth of infants born preterm. PMID- 27214125 TI - Distorted Graphene Sheet Structure-Derived Latent Nanoporosity. AB - High surface area graphene monoliths consist mainly of single graphene layers wider than 10 nm. The interlayer porosity of high temperature treated nanoporous graphene monoliths with tuned intergraphene layer structures is evaluated by hybrid analysis of Ar adsorption at 87 K, N2 adsorption at 77 K, high resolution transmission electron microscopic observation, and small-angle X-ray scattering (SAXS) measurements. SAXS analysis results in surface areas that are 1.4 and 4.5 times larger than those evaluated by Ar adsorption for graphene monoliths nontreated and treated at 2273 K, respectively. A distorted graphene sheet structure model is proposed for the high surface area graphene monoliths on the basis of the hybrid analysis. PMID- 27214126 TI - Isotopic Composition of Gaseous Elemental Mercury in the Free Troposphere of the Pic du Midi Observatory, France. AB - Understanding the sources and transformations of mercury (Hg) in the free troposphere is a critical aspect of global Hg research. Here we present one year of observations of atmospheric Hg speciation and gaseous elemental Hg (GEM) isotopic composition at the high-altitude Pic du Midi Observatory (2860 m above sea level) in France. Biweekly integrated GEM from February 2012 to January 2013 revealed significant variations in delta(202)HgGEM (-0.040/00 to 0.520/00) but not in Delta(199)HgGEM (-0.170/00 to -0.270/00) or Delta(200)HgGEM (-0.100/00 to 0.050/00). delta(202)HgGEM was negatively correlated with CO and reflected air mass origins from Europe (high CO, low delta(202)HgGEM) and from the Atlantic Ocean (low CO, high delta(202)HgGEM). We suggest that the delta(202)HgGEM variations represent mixing of recent low delta(202)HgGEM European anthropogenic emissions with high delta(202)HgGEM northern hemispheric background GEM. In addition, Atlantic Ocean free troposphere air masses showed a positive correlation between delta(202)HgGEM and gaseous oxidized Hg (GOM) concentrations, indicative of mass-dependent Hg isotope fractionation during GEM oxidation. On the basis of atmospheric delta(202)HgGEM and speciated Hg observations, we suggest that the oceanic free troposphere is a reservoir within which GEM is readily oxidized to GOM. PMID- 27214127 TI - Female rats induced with mammary cancer as a relevant animal model for doxorubicin-induced chemobrain in vivo. PMID- 27214128 TI - Three-dimensional organotypic culture of human salivary glands: the slice culture model. AB - OBJECTIVE: A challenge in studying human salivary glands is to maintain the cells ex vivo in their three-dimensional (3D) morphology with an intact native extracellular matrix (ECM) environment. This paper established a human salivary 3D organotypic slice culture model that could maintain its physiological functions as well as allowing a direct visualization of the cells. METHODS: Human salivary biopsies from six patients were embedded in agarose and submerged in cold buffer for thin (50 MUm) sectioning using a vibratome. 'Salivary slices' were mechanically supported by a porous membrane insert that allowed an air liquid interface and cultured in serum-free culture media. Cell viability, proliferation, apoptosis, physiological functions, and gene expression were assessed during 14 days of culture. RESULTS: Human salivary slices maintained cell survival (70-40%) and proliferation (6-17%) for 14 days ex vivo. The protein secretory (amylase) function decreased, but fluid (intracellular calcium mobilization) function was maintained. Acinar, ductal, and myoepithelial cell populations survived and maintained their 3D organization within the slice culture model. CONCLUSION: The human salivary slice culture model kept cells alive ex vivo for 14 days as well as maintaining their 3D morphology and physiological functions. PMID- 27214129 TI - Correction: The Value of Long-Term Stream Invertebrate Data Collected by Citizen Scientists. AB - [This corrects the article DOI: 10.1371/journal.pone.0153713.]. PMID- 27214130 TI - Standardisation of uterine natural killer (uNK) cell measurements in the endometrium of women with recurrent reproductive failure. AB - Considerable work is being carried out on endometrial NK cells to determine whether they play a role in successful pregnancy outcome. In addition there is debate about whether measurements of uNK should be included in the clinical assessment for women with recurrent implantation failure or recurrent miscarriage. A hindrance to taking this forward is the fact that the density of uNK cells reported by different centres is very different. The aim of this study was to determine the reason for these differences and to develop a standardised method. Three centres participated in the study. Each centre exchanged five formalin fixed, wax embedded sections of endometrium from five women. Sections were immunostained for CD56. Images were taken of 10 random fields at *400 magnification; total stromal and uNK cells were counted using Image J. Results were expressed as % positive uNK cells and the variation in counts obtained in each centre was compared. After initial analysis a standardised protocol was agreed and the process repeated. Significant variation was seen in the counts obtained after initial analysis (Centre A vs.B, mean difference=-0.72 P<0.001; A vs.C mean difference=-0.47 P<0.001; B vs.C, mean difference=0.25 P=0.085). Analysis suggested that differences may be due to duration of tissue fixation, the embedding and sectioning processes, selection of areas for assessment, definition of immunopositive cells and inclusion or exclusion of blood vessels. Adoption of a standardised protocol reduced the variation (Centre A vs.B mean difference=-0.105 P=0.744; A vs.C mean difference=0.219 P=0.150; B vs.C mean difference=0.32 P=0.031). Use of a standardised method is needed to establish a normal range for uNK cells and to develop a meaningful clinical test for uNK cell measurements. PMID- 27214131 TI - Control of Brain Activity in hMT+/V5 at Three Response Levels Using fMRI-Based Neurofeedback/BCI. AB - A major challenge in brain-computer interface (BCI) research is to increase the number of command classes and levels of control. BCI studies often use binary control level approaches (level 0 and 1 of brain activation for each class of control). Different classes may often be achieved but not different levels of activation for the same class. The increase in the number of levels of control in BCI applications may allow for larger efficiency in neurofeedback applications. In this work we test the hypothesis whether more than two modulation levels can be achieved in a single brain region, the hMT+/V5 complex. Participants performed three distinct imagery tasks during neurofeedback training: imagery of a stationary dot, imagery of a dot with two opposing motions in the vertical axis and imagery of a dot with four opposing motions in vertical or horizontal axes (imagery of 2 or 4 motion directions). The larger the number of motion alternations, the higher the expected hMT+/V5 response. A substantial number (17 of 20) of participants achieved successful binary level of control and 12 were able to reach even 3 significant levels of control within the same session, confirming the whole group effects at the individual level. With this simple approach we suggest that it is possible to design a parametric system of control based on activity modulation of a specific brain region with at least 3 different levels. Furthermore, we show that particular imagery task instructions, based on different number of motion alternations, provide feasible achievement of different control levels in BCI and/or neurofeedback applications. PMID- 27214132 TI - Proteomic Analysis of Early Mid-Trimester Amniotic Fluid Does Not Predict Spontaneous Preterm Delivery. AB - OBJECTIVE: The aim of this study was to identify early proteomic biomarkers of spontaneous preterm delivery (PTD) in mid-trimester amniotic fluid from asymptomatic women. METHODS: This is a case-cohort study. Amniotic fluid from mid trimester genetic amniocentesis (14-19 weeks of gestation) was collected from 2008 to 2011. The analysis was conducted in 24 healthy women with subsequent spontaneous PTD (cases) and 40 randomly selected healthy women delivering at term (controls). An exploratory phase with proteomics analysis of pooled samples was followed by a verification phase with ELISA of individual case and control samples. RESULTS: The median (interquartile range (IQR: 25th; 75th percentiles) gestational age at delivery was 35+5 (33+6-36+6) weeks in women with spontaneous PTD and 40+0 (39+1-40+5) weeks in women who delivered at term. In the exploratory phase, the most pronounced differences were found in C-reactive protein (CRP) levels, that were approximately two-fold higher in the pooled case samples than in the pooled control samples. However, we could not verify these differences with ELISA. The median (25th; 75th IQR) CRP level was 95.2 ng/mL (64.3; 163.5) in women with spontaneous PTD and 86.0 ng/mL (51.2; 145.8) in women delivering at term (p = 0.37; t-test). CONCLUSIONS: Proteomic analysis with mass spectrometry of mid-trimester amniotic fluid suggests CRP as a potential marker of spontaneous preterm delivery, but this prognostic potential was not verified with ELISA. PMID- 27214133 TI - The authors' comments on the editorial by Specht. PMID- 27214134 TI - Structure of the Cellulose Synthase Complex of Gluconacetobacter hansenii at 23.4 A Resolution. AB - Bacterial crystalline cellulose is used in biomedical and industrial applications, but the molecular mechanisms of synthesis are unclear. Unlike most bacteria, which make non-crystalline cellulose, Gluconacetobacter hansenii extrudes profuse amounts of crystalline cellulose. Its cellulose synthase (AcsA) exists as a complex with accessory protein AcsB, forming a 'terminal complex' (TC) that has been visualized by freeze-fracture TEM at the base of ribbons of crystalline cellulose. The catalytic AcsAB complex is embedded in the cytoplasmic membrane. The C-terminal portion of AcsC is predicted to form a translocation channel in the outer membrane, with the rest of AcsC possibly interacting with AcsD in the periplasm. It is thus believed that synthesis from an organized array of TCs coordinated with extrusion by AcsC and AcsD enable this bacterium to make crystalline cellulose. The only structural data that exist for this system are the above mentioned freeze-fracture TEM images, fluorescence microscopy images revealing that TCs align in a row, a crystal structure of AcsD bound to cellopentaose, and a crystal structure of PilZ domain of AcsA. Here we advance our understanding of the structural basis for crystalline cellulose production by bacterial cellulose synthase by determining a negative stain structure resolved to 23.4 A for highly purified AcsAB complex that catalyzed incorporation of UDP glucose into beta-1,4-glucan chains, and responded to the presence of allosteric activator cyclic diguanylate. Although the AcsAB complex was functional in vitro, the synthesized cellulose was not visible in TEM. The negative stain structure revealed that AcsAB is very similar to that of the BcsAB synthase of Rhodobacter sphaeroides, a non-crystalline cellulose producing bacterium. The results indicate that the crystalline cellulose producing and non-crystalline cellulose producing bacteria share conserved catalytic and membrane translocation components, and support the hypothesis that it is the extrusion mechanism and order in linearly arrayed TCs that enables production of crystalline cellulose. PMID- 27214135 TI - Rapid and Slow Progressors Show Increased IL-6 and IL-10 Levels in the Pre-AIDS Stage of HIV Infection. AB - Cytokines are intrinsically related to disease progression in HIV infection. We evaluated the plasma levels of Th1/Th2/Th17 cytokines in extreme progressors, including slow (SPs) and rapid (RPs) progressors, who were thus classified based on clinical and laboratory follow-up covering a period of time before the initiation of HAART, ranging from 93-136.5 months for SPs and 7.5-16.5 months for RPs. Analyses were also performed based on the different stages of HIV infection (chronic, pre-HAART individuals-subjects sampled before initiating HAART but who initiated therapy from 12 to 24 months-and those receiving HAART). The plasma cytokine levels of 16 HIV-infected rapid progressors and 25 slow progressors were measured using a Human Th1/Th2/Th17 CBA kit. The IL-6 and IL-10 plasma levels differed significantly between the stages of HIV infection. The IL-6 levels were higher in slow progressors pre-HAART than in chronically infected SPs and HIV seronegative individuals. The IL-10 levels were higher in slow progressors pre HAART than in slow progressors receiving HAART and HIV-seronegative controls, and in rapid progressors, the IL-10 levels were higher in pre-HAART subjects than in HIV-seronegative controls. The results reflect the changes in the cytokine profile occurring during different clinical stages in HIV+ subjects. Our results suggest an association between increased IL-6 and IL-10 levels and pre-HAART stages independent of the slow or rapid progression status of the subjects. Thus, increased IL-6 and IL-10 levels could indicate a global inflammatory status and could be used as markers of the disease course in HIV-infected individuals. PMID- 27214136 TI - Environmental and personal determinants of the uptake of disinfection by-products during swimming. AB - BACKGROUND: Trihalomethanes (THMs) in exhaled breath and trichloroacetic acid (TCAA) in urine are internal dose biomarkers of exposure to disinfection by products (DBPs) in swimming pools. OBJECTIVE: We assessed how these biomarkers reflect the levels of a battery of DBPs in pool water and trichloramine in air, and evaluated personal determinants. METHODS: A total of 116 adults swam during 40min in a chlorinated indoor pool. We measured chloroform, bromodichloromethane, dibromochloromethane and bromoform in exhaled breath and TCAA in urine before and after swimming, trichloramine in air and several DBPs in water. Personal determinants included sex, age, body mass index (BMI), distance swum, energy expenditure, heart rate and 12 polymorphisms in GSTT1, GSTZ1 and CYP2E1 genes. RESULTS: Median level of exhaled total THMs and creatinine adjusted urine TCAA increased from 0.5 to 14.4ug/m(3) and from 2.5 to 5.8umol/mol after swimming, respectively. The increase in exhaled brominated THMs was correlated with brominated THMs, haloacetic acids, haloacetonitriles, haloketones, chloramines, total organic carbon and total organic halogen in water and trichloramine in air. Such correlations were not detected for exhaled chloroform, total THMs or urine TCAA. Exhaled THM increased more in men, urine TCAA increased more in women, and both were affected by exercise intensity. Genetic variants were associated with differential increases in exposure biomarkers. CONCLUSION: Our findings suggest that, although affected by sex, physical activity and polymorphisms in key metabolizing enzymes, brominated THMs in exhaled breath could be used as a non invasive DBP exposure biomarker in swimming pools with bromide-containing source waters. This warrants confirmation with new studies. PMID- 27214137 TI - Extreme precipitation events and increased risk of campylobacteriosis in Maryland, U.S.A. AB - Consumption of contaminated poultry, raw milk and water are significant risk factors for Campylobacter infection. Previous studies also have investigated the association between weather (temperature and precipitation) and increased risk of campylobacteriosis, but limited information exists regarding the impacts of extreme heat and precipitation events on campylobacteriosis risk, and how such risk may differentially impact coastal communities. We obtained Campylobacter case data 2002-2012; n=4804) from the Maryland Foodborne Diseases Active Surveillance Network (FoodNet). We identified extreme heat and extreme precipitation events during this time (2002-2012) using location and calendar day specific thresholds (95th percentile for extreme heat and 90th percentile for extreme precipitation) that were computed based on a 30-year baseline (1960 1989). We linked these datasets using GIS and used negative binomial generalized estimating equations adjusted for demographic confounders to calculate the association between exposure to extreme events and risk of campylobacteriosis in Maryland. We observed that a one-day increase in exposure to extreme precipitation events was associated with a 3% increase in risk of campylobacteriosis in coastal areas of Maryland (Incidence Rate Ratio (IRR): 1.03, 95% confidence interval (CI): 1.01, 1.05), but such an association was not observed in noncoastal areas. Furthermore, the risk associated with extreme precipitation events was considerably higher during La Nina periods (IRR: 1.09, 95% CI: 1.05, 1.13), while there was no evidence of elevated risk during El Nino or ENSO Neutral periods. Exposure to extreme heat events was not associated with an increased risk of campylobacteriosis, except during La Nina periods (IRR: 1.04, 95% CI: 1.01, 1.08). Extreme precipitation events could result in flooding within coastal areas that may bring water contaminated with bacterial pathogens (originating from sources such as septic systems, municipal wastewater treatment plants and concentrated animal feeding operations) into close proximity with individuals, where frequency of contact may be higher. PMID- 27214138 TI - Posttransplant Hyponatremia Predicts Graft Failure and Mortality in Kidney Transplantation Recipients: A Multicenter Cohort Study in Korea. AB - Although hyponatremia is related to poorer outcomes in several clinical settings, its significance remains unresolved in kidney transplantation. Data on 1,786 patients who received kidney transplantations between January 2000 and December 2011 were analyzed. The patients were divided into two groups according to the corrected sodium values for serum glucose 3 months after their transplantations (<135 mmol/L vs. >=135 mmol/L). Subsequently, the hazard ratios (HRs) for biopsy proven acute rejection, graft failure, and all-cause mortality were calculated after adjustments for several immunological and non-immunological covariates. 4.0% of patients had hyponatremia. Patients with hyponatremia had higher risks for graft failure and all-cause mortality than did the counterpart normonatremia group; the adjusted HRs for graft failure and mortality were 3.21 (1.47-6.99) and 3.03 (1.21-7.54), respectively. These relationships remained consistent irrespective of heart function. However, hyponatremia was not associated with the risk of acute rejection. The present study addressed the association between hyponatremia and graft and patient outcomes in kidney transplant recipients. Based on the study results, our recommendation is to monitor serum sodium levels after kidney transplantations. PMID- 27214140 TI - Synthesis and biological screening for cytotoxic activity of N-substituted indolines and morpholines. AB - Development of novel anticancer drugs is inevitable to improve treatment of cancers. In this study, novel derivatives of indoline and morpholine were synthesized and tested for their cytotoxic effects on osteosarcoma and Human Embryonic Kidney cells. To characterize cytotoxicity and the mechanism of cell death, we used cytotoxicity, migration, apoptosis markers and mitochondrial calcium assays. Among the compounds tested, the indoline derivatives, generally, produced a higher cytotoxic effect compared to the morpholine derivatives, in osteosarcoma cells. Specifically, new indoline derivative N-(2-hydroxy-5 nitrophenyl(4'-methylphenyl)methyl)indoline exhibited effective cytotoxic activity, with an IC50 of ~74 MUM. The same molecule induced cell death by apoptosis and inhibited migration of the cells. Further, analysis of mitochondrial calcium levels revealed the existence of calcium dependent cell death mechanisms in different cell types. Therefore, N-(2-hydroxy-5 nitrophenyl(4'-methylphenyl)methyl)indoline can be considered as a potential drug lead compound towards the discovery of new anti-cancer agents. PMID- 27214139 TI - Socioeconomic Differences in Dietary Patterns in an East African Country: Evidence from the Republic of Seychelles. AB - BACKGROUND: In high income countries, low socioeconomic status (SES) is related to unhealthier dietary patterns, while evidence on the social patterning of diet in low and middle income countries is scarce. OBJECTIVE: In this study, we assess dietary patterns in the general population of a middle income country in the African region, the Republic of Seychelles, and examine their distribution according to educational level and income. METHODS: Data was drawn from two independent national surveys conducted in the Seychelles among adults aged 25-64 years in 2004 (n = 1236) and 2013 (n = 1240). Dietary patterns were assessed by principal component analysis (PCA). Educational level and income were used as SES indicators. Data from both surveys were combined as no interaction was found between SES and year. RESULTS: Three dietary patterns were identified: "snacks and drinks", "fruit and vegetables" and "fish and rice". No significant associations were found between SES and the "snacks and drinks" pattern. Low vs. high SES individuals had lower adherence to the "fruit and vegetables" pattern [prevalence ratio (95% CI) 0.71 (0.60-0.83)] but a higher adherence to the traditional "fish and rice" pattern [1.58 (1.32-1.88)]. Income modified the association between education and the "fish and rice" pattern (p = 0.02), whereby low income individuals had a higher adherence to this pattern in both educational groups. CONCLUSION: Low SES individuals have a lower consumption of fruit and vegetables, but a higher consumption of traditional foods like fish and rice. The Seychelles may be at a degenerative diseases stage of the nutrition transition. PMID- 27214141 TI - Melanoma-targeted delivery system (part 2): Synthesis, radioiodination and biological evaluation in B16F0 bearing mice. AB - Here we report the synthesis and radiolabelling with iodine-125 of a melanoma selective prodrug (17a*) and its parent drug IUdR. The in vivo and ex vivo biodistributions of [(125)I](17a*) and [(125)I]IUdR were evaluated in a model of melanoma B16F0-bearing mice. The pharmacokinetic profile of [(125)I](17a*) suggests rapid release of the active drug [(125)I]IUdR after i.v. administration of [(125)I](17a*). Preliminary metabolism studies in dedicated compartments (i.e. blood, urine and tumour) yielded results consistent with this hypothesis. PMID- 27214142 TI - Health Research and the World Humanitarian Summit-Not a Thousand Miles Apart. AB - As the World Humanitarian Summit and the World Health Assembly convene on the same day in different cities, The PLOS Medicine Editors support a role for health in the UN Agenda for Humanity. PMID- 27214143 TI - Biofilms: Microbial Shelters Against Antibiotics. AB - Biofilms are communities of aggregated bacterial cells embedded in a self produced extracellular polymeric matrix. Biofilms are recalcitrant to antibiotic treatment and immune defenses and are implicated in many chronic bacterial and fungal infections. In this review, we provide an overview of the contribution of biofilms to persistent infections resistant to antibiotic treatment, the impact of multispecies biofilms on drug resistance and tolerance, and recent advances in the development of antibiofilm agents. Understanding the mechanisms of antibiotic resistance and tolerance in biofilms is essential for developing new preventive and therapeutic strategies and curbing drug resistance. PMID- 27214144 TI - Impact of awake blood pressure variability on cerebrovascular atherosclerosis in Chinese patients with acute ischemic stroke. AB - BACKGROUND: Blood pressure (BP) variability has been shown to be an independent risk factor of stroke and target organ damage because of hypertension, but so far, there have been very few studies investigating the impact of BP variability on cerebrovascular atherosclerosis. METHODS: A total of 409 participants were enrolled and classified according to patterns of cerebrovascular atherosclerosis (i.e. large or small artery atherosclerosis; extracranial; or intracranial artery atherosclerosis). Coefficient of variation (CV) was used as a marker of BP variability. Multivariate binary logistical regression was used to analyze the associations between BP variability and the risk of different patterns of cerebrovascular atherosclerosis. RESULTS: The risk of large artery atherosclerosis and extracranial arterial stenosis, respectively, had a dose responsive positive relationship with the tertiles of awake systolic blood pressure (SBP) CVs [large artery atherosclerosis, the second tertile, adjusted odds ratio (OR)=2.839, 95% confidence interval (CI) 1.593-5.059, P<0.001; the third tertile, adjusted OR=4.010, 95% CI 1.859-8.651, P<0.001; extracranial arterial stenosis, the second tertile, adjusted OR=2.274, 95% CI 1.189-4.348, P=0.013; the third tertile, adjusted OR=2.568, 95% CI 1.230-5.360, P=0.012, when referenced to the first tertile], but not with those of mean awake SBP. The third tertile of awake SBP CVs indicated a significantly higher risk of intracranial arterial stenosis (adjusted OR=2.253, 95% CI 1.118-4.538, P=0.023) and advanced intracranial arterial stenosis (adjusted OR=5.073, 95% CI 2.064-12.466, P<0.001) when referenced to the first tertile. CONCLUSION: In Chinese patients with acute atherosclerotic stroke, higher awake BP variability (measured in the subacute stage) might be associated with a higher risk of large artery atherosclerosis. PMID- 27214145 TI - Safety, Pharmacokinetics and Pharmacodynamics of the Selective Glucocorticoid Receptor Modulator AZD5423 after Inhalation in Healthy Volunteers. AB - AZD5423 is a selective glucocorticosteroid receptor modulator developed for the inhaled use in asthma and COPD. This study reports the initial, first-in-man, single and repeat dose-escalating studies in healthy male individuals, including one cohort of male Japanese individuals. Inhaled, nebulized AZD5423 was safe and well tolerated up to and including the highest doses tested for up to 2 weeks of once-daily treatment. Plasma exposure suggested dose-proportional pharmacokinetics and dose-related effects on 24-hr plasma and urine cortisol. There were no or marginal effects on other biomarkers tested (osteocalcin, TRAP5b, DHEA-S and 4beta-OH-cholesterol). No clinically relevant differences in safety or pharmacokinetics could be distinguished between the two study populations, although hypothalamus-pituitary-adrenal (HPA) effects appeared to be marginally greater in the Japanese- versus the Caucasian-dominant study population. AZD5423, inhaled via nebulization, can be used in healthy individuals at doses of at least 300 MUg for 2 weeks. The effects on the HPA axis reported herein, together with efficacy data reported elsewhere, indicate that benefit risk ratio may be improved relative to conventional inhaled steroids. PMID- 27214146 TI - Engineering phosphopeptide-decorated magnetic nanoparticles as efficient photothermal agents for solid tumor therapy. AB - Due to the high therapeutic efficiency and minimum damage towards normal tissues, phototherapy has drawn a great deal of attention in recent decades. Herein, we reported the synthesis of novel phosphopeptide-decorated magnetic nanoparticles (peptide-Fe3O4 nanoparticles), and their usages in photothermal therapy against solid tumor. By using a classical coprecipitation method and a facile ligand exchange route, these peptide-Fe3O4 nanoparticles were prepared with inexpensive inhesion. Upon the irradiation of a near-infrared (NIR) light, these nanoagents exhibited great photothermal effect with high photo-stability. In vitro biocompatibility studies of these peptide-Fe3O4 nanoparticles indicated their low cytotoxicity, negligible hemolysis, and no effect on blood coagulation. As expected, 4T1 murine breast cancer cells could be effectively damaged by these light-mediated nanoagents. Significantly, animal experiments demonstrated that these nanoagents held great solid tumor ablation effect with the assistance of a NIR laser irradiation. Additional studies focused on the long-term toxicity of these nanoagents indicated their high bio-compatibility. Thus, these peptide Fe3O4 nanoparticles could bring more opportunities to a new generation of photothermal agents in the field of biomedicine. PMID- 27214147 TI - Thermal transport characteristics of combined electroosmotic and pressure driven flow in soft nanofluidics. AB - The present study deals with thermal transport characteristics of an electrolyte solution flowing through a slit nanochannel with polyelectrolyte walls, known as soft nanochannel. The sources of the fluid flow are the pressure gradient along the channel axis and the electrokinetic effects that trigger an electroosmotic flow under the impact of a uniformly applied electric field. The polyelectrolyte layer (PEL) is denoted as a fixed charge layer (FCL) and the electrolyte ions can be present both inside and outside the PEL. Therefore, the PEL-electrolyte interface acts as a semi-penetrable membrane. To the best of our knowledge, the thermal analysis of mixed electrokinetically and pressure driven flow in such soft nanochannels has never been addressed. The Poisson-Boltzmann equation is solved assuming the Debye-Huckel linearization for the low electric potential to provide us with analytical closed form solutions for the conservation equations. The conservation equations are solved to obtain the electric potential; velocity and temperature distributions in terms of governing dimensionless parameters. Also results for the Nusselt number are presented and discussed in detail. PMID- 27214148 TI - Colloidal europium nanoparticles via a solvated metal atom dispersion approach and their surface enhanced Raman scattering studies. AB - Chemistry of lanthanide metals in their zerovalent state at the nanoscale remains unexplored due to the high chemical reactivity and difficulty in synthesizing nanoparticles by conventional reduction methods. In the present study, europium(0) nanoparticles, the most reactive of all the rare earth metals have been synthesized by solvated metal atom dispersion (SMAD) method using hexadecyl amine as the capping agent. The as-prepared europium nanoparticles show surface Plasmon resonance (SPR) band in the visible region of the electromagnetic spectrum. This lead to the investigation of its surface enhanced Raman scattering (SERS) using visible light excitation source. The SERS activity of europium nanoparticles has been followed using 4-aminothiophenol and biologically important molecules such as hemoglobin and Cyt-c as the analytes. This is the first example of lanthanide metal nanoparticles as SERS substrate which can possibly be extended to other rare-earth metals. Since hemoglobin absorbs in the visible region, the use of visible light excitation source leads to surface enhanced resonance Raman spectroscopy (SERRS). The interaction of biomolecules with Eu(0) has been followed using FT-IR and UV-visible spectroscopy techniques. The results indicate that there is no major irreversible change in the structure of biomolecules upon interaction with europium nanoparticles. PMID- 27214149 TI - Synthesis of waterborne polyurethane-urea dispersions with chain extension step in homogeneous and heterogeneous media. AB - HYPOTHESIS: The possibility of tailoring the final properties of environmentally friendly waterborne polyurethane and polyurethane-urea dispersions and the films they produce makes them attractive for a wide range of applications. Both the reagents content and the synthesis route contribute to the observed final properties. EXPERIMENTS: A series of polyurethane-urea and polyurethane aqueous dispersions were synthesized using 1,2-ethanediamine and/or 1,4-butanediol as chain extenders. The diamine content was varied from 0 to 4.5wt%. Its addition was carried out either by the classical heterogeneous reaction medium (after phase inversion step), or else by the alternative homogeneous medium (prior to dispersion formation). Dispersions as well as films prepared from dispersions have been later extensively characterized. FINDINGS: 1,2-Ethanediamine addition in heterogeneous medium leads to dispersions with high particle sizes and broad distributions whereas in homogeneous medium, lower particle sizes and narrow distributions were observed, thus leading to higher uniformity and cohesiveness among particles during film formation. Thereby, stress transfer is favored adding the diamine in a homogeneous medium; and thus the obtained films presented quite higher stress and modulus values. Furthermore, the higher uniformity of films tends to hinder water molecules transport through the film, resulting, in general, in a lower water absorption capacity. PMID- 27214150 TI - Nontoxic Metal-Cyclam Complexes, a New Class of Compounds with Potency against Drug-Resistant Mycobacterium tuberculosis. AB - Tuberculosis (TB) accounted for 1.5 million deaths in 2014, and new classes of anti-TB drugs are required. We report a class of functionalized 1,8-disubstituted cyclam derivatives that display low micromolar activity against pathogenic mycobacteria. These compounds inhibit intracellular growth of Mycobacterium tuberculosis, are nontoxic to human cell lines, and are active against multidrug resistant M. tuberculosis strains, indicating a distinct mode of action. These compounds warrant further appraisal as novel agents to control TB in humans. PMID- 27214151 TI - A multicentre comparison between Child Pugh and Albumin-Bilirubin scores in patients treated with sorafenib for Hepatocellular Carcinoma. AB - BACKGROUND & AIMS: The Albumin-Bilirubin (ALBI) grade was proposed as an objective means to evaluate liver function in patients with Hepatocellular Carcinoma (HCC). ALBI grade 1 vs 2 were proposed as stratification factors within the Child Pugh (CP) A class. However, the original publication did not provide comparison with the subclassification by points (5-15) within the CP classification. METHODS: We retrospectively analysed data from patients treated with sorafenib for HCC from 17 centres in United Kingdom and France. Overall survival (OS) was analysed using the Kaplan-Meier method and a Cox regression model. Discriminatory abilities of the classifications were assessed with the log likelihood ratio, Harrell's C statistics and Akaike information criterion. RESULTS: Data from 1019 patients were collected, of which 905 could be assessed for both scores. 92% of ALBI grade 1 were CP A5 while ALBI 2 included a broad range of CP scores of which 44% were CP A6. Median OS was 10.2, 7.0 and 3.6 months for CP scores A5, A6 and >A6, respectively (P < 0.001), Hazard Ratio (HR) = 1.60 (95%CI: 1.35-1.89, P < 0.001) for A6 vs A5. Median OS was 10.9, 6.6 and 3.0 months for ALBI grade 1, 2 and 3, respectively (P < 0.001), HR = 1.68 (1.43 1.97, P < 0.001) for grade 2 vs 1. Discriminatory abilities of CP and ALBI were similar in the CP A population, but better for CP in the overall population. CONCLUSIONS: Our findings support the use CP class A as an inclusion criterion, and ALBI as a stratification factor in trials of systemic therapy. PMID- 27214152 TI - Symphalangism. PMID- 27214153 TI - Two-fluid model for heavy electron physics. AB - The two-fluid model is a phenomenological description of the gradual change of the itinerant and local characters of f-electrons with temperature and other tuning parameters and has been quite successful in explaining many unusual and puzzling experimental observations in heavy electron materials. We review some of these results and discuss possible implications of the two-fluid model in understanding the microscopic origin of heavy electron physics. PMID- 27214154 TI - Neuronavigation-guided Repetitive Transcranial Magnetic Stimulation for Aphasia. AB - Repetitive transcranial magnetic stimulation (rTMS) is widely used for several neurological conditions, as it has gained acknowledgement for its potential therapeutic effects. Brain excitability is non-invasively modulated by rTMS, and rTMS to the language areas has proved its potential effects on treatment of aphasia. In our protocol, we aim to artificially induce virtual aphasia in healthy subjects by inhibiting Brodmann area 44 and 45 using neuronavigational TMS (nTMS), and F3 of the International 10-20 EEG system for conventional TMS (cTMS). To measure the degree of aphasia, changes in reaction time to a picture naming task pre- and post-stimulation are measured and compare the delay in reaction time between nTMS and cTMS. Accuracy of the two TMS stimulation methods is compared by averaging the Talairach coordinates of the target and the actual stimulation. Consistency of stimulation is demonstrated by the error range from the target. The purpose of this study is to demonstrate use of nTMS and to describe the benefits and limitations of the nTMS compared to those of cTMS. PMID- 27214155 TI - Palladium-Catalyzed Highly Chemoselective Intramolecular C-H Aminocarbonylation of Phenethylamines to Six-Membered Benzolactams. AB - A palladium-catalyzed highly selective intramolecular C-H aminocarbonylation of Br-functionalized phenethylamines in the presence of CO was achieved while leaving the C-Br bond unreacted to afford six-membered benzolactams with good to high yields. The remaining C-Br group in the cyclized product was successfully used as a reactive center for further functionalization through various palladium catalyzed coupling reactions. PMID- 27214156 TI - Cells Cultured on Core-Shell Photonic Crystal Barcodes for Drug Screening. AB - The development of effective drug screening platforms is an important task for biomedical engineering. Here, a novel methacrylated gelatin (GelMA) hydrogel encapsulated core-shell photonic crystal (PhC) barcode particle was developed for three-dimensional cell aggregation culture and drug screening. The GelMA shells of the barcode particles enable creation of a three-dimensional extracellular matrix (ECM) microenvironment for cell adhesion and growth, while the PhC cores of the barcode particles provide stable diffraction peaks that can encode different cell spheroids during culture and distinguish their biological response during drug testing. The applicability of this cell spheroids-on-barcodes platform was investigated by testing the cytotoxic effect of tegafur (TF), a prodrug of 5-fluorouracil (5-FU), on barcode particle-loaded liver HepG2 and HCT 116 colonic tumor cell spheroids. The cytotoxicity of TF against the HCT-116 tumor cell spheroids was enhanced in systems using cocultures of HepG2 and NIH 3T3 cells, indicating the effectiveness of this multiple cell spheroids-on barcodes platform for drug screening. PMID- 27214157 TI - Preparation of a magnetic molecularly imprinted polymer by atom-transfer radical polymerization for the extraction of parabens from fruit juices. AB - A silica-based surface magnetic molecularly imprinted polymer for the selective recognition of parabens was prepared using a facile and general method that combined atom-transfer radical polymerization with surface imprinting technique. The prepared magnetic molecularly imprinted polymer was characterized by transmission electron microscopy, Fourier transform infrared spectrometry and physical property measurement. The isothermal adsorption experiment and kinetics adsorption experiment investigated the adsorption property of magnetic molecularly imprinted polymer to template molecule. The four parabens including methylparaben, ethylparaben, propylparaben, and butylparaben were used to assess the rebinding selectivity. An extraction method, which used magnetic molecularly imprinted polymer as adsorbents coupled with high-performance liquid chromatography for the determination of the four parabens in fruit juice samples was developed. Under the optimal conditions, the limits of detections of the four parabens were 0.028, 0.026, 0.021, and 0.026 mg/L, respectively. The precision expressed as relative standard deviation ranging from 2.6 to 8.9% was obtained. In all three fortified levels, recoveries of parabens were in the range of 72.5 89.4%. The proposed method has been applied to different fruit juice samples including orange juice, grape juice, apple juice and peach juice, and satisfactory results were obtained. PMID- 27214158 TI - Analysis of gene expression for microminipig liver transcriptomes using parallel long-read technology and short-read sequencing. AB - The microminipig is one of the smallest minipigs that has emerged as a possible experimental animal model, because it shares many anatomical and/or physiological similarities with humans, including the coronary artery distribution in the heart, the digestive physiology, the kidney size and its structure, and so on. However, information on gene expression profiles, including those on drug metabolizing phase I and II enzymes, in the microminipig is limited. Therefore, the aim of the present study was to identify transcripts in microminipig livers and to determine gene expression profiles. De novo assembly and expression analyses of microminipig transcripts were conducted with liver samples from three male and three female microminipigs using parallel long-read and short-read sequencing technologies. After unique sequences had been automatically aligned by assembling software, the mean contig length of 50843 transcripts was 707 bp. The expression profiles of cytochrome P450 (P450) 1A2, 2C, 2E1 and 3A genes in livers in microminipigs were similar to those in humans. Liver carboxylesterase (CES) precursor, liver CES-like, UDP-glucuronosyltransferase (UGT) 2C1-like, amine sulfotransferase (SULT)-like, N-acetyltransferases (NAT8) and glutathione S transferase (GST) A2 genes, which are relatively unknown genes in pigs and/or humans, were expressed strongly. Furthermore, no significant gender differences were observed in the gene expression profiles of phase I enzymes, whereas UGT2B17, SULT1E1, SULT2A1, amine SULT-like, NAT8 and GSTT4 genes were different between males and females among phase II enzyme genes under the present sample conditions. These results provide a foundation for mechanistic studies and the use of microminipigs as model animals for drug development in the future. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27214159 TI - In silico evaluation of warfarin-bucolome therapy. AB - PURPOSE: Some reports have suggested that bucolome, an inhibitor of cytochrome P450 2C9, is useful for decreasing inter-patient variation in warfarin clearance. The purpose of the present study was to evaluate the utility of the concomitant administration of bucolome and warfarin using an in silico approach. METHODS: In vitro data regarding the enzymatic kinetics of (S)-warfarin and bucolome were collected from the literature. As a validation study, the geometric mean (GM) of the oral unbound clearance of (S)-warfarin and its inter-patient variation (assessed using the standard deviation of its natural logarithm (sigma)) were predicted using a physiologically based population pharmacokinetic simulator (Simcyp(TM) ) and compared with clinical data. The utility of the concomitant administration was evaluated by comparing the GM and sigma values predicted under various conditions (the prediction study). RESULTS AND DISCUSSION: The sigma values in the presence and absence of bucolome were predicted to be 0.73 and 0.68, respectively, suggesting that bucolome might increase the inter-patient variation, as clinically observed. In the prediction study, the sigma value of the bucolome co-administered group was greater in almost all of the examined conditions. In conclusion, the concomitant administration of bucolome might not be useful for reducing the inter-patient variation of (S)-warfarin pharmacokinetics. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27214160 TI - From Submission to Final Publication: Revisiting Our Processes. PMID- 27214161 TI - Reply to "Is It Time for a Nonionizing Radiation Technique for Biopsy of Anterior Mediastinal Masses?". PMID- 27214162 TI - The Age Factor in the Treatment of Glioblastoma. PMID- 27214163 TI - Influences of iron and calcium carbonate on wastewater treatment performances of algae based reactors. AB - The influences of iron and calcium carbonate (CaCO3) addition in wastewater treatments reactors performance were investigated. Adding different concentrations of Fe(3+) (5, 10, 30 and 50mmol/m(3)), iron and CaCO3 powder led to changes in algal characteristics and physico-chemical and microbiological properties. According to the investigation results, nutrient removal efficiency in algae based reactors was obviously increased by the addition of 10mmol/m(3) Fe(3+), iron (5mmol/m(3)) and CaCO3 powder (0.2gm(-3)) and the removal efficiencies of BOD5, TN, and TP in Stage 2 were respectively increased by 28%, 8.9%, and 22%. The improvements in physico-chemical performances were verified by microbial community tests (bacteria quantity, activity and community measured in most probable number, extracellular enzymes activity, and Biolog Eco Plates). Microbial variations indicated the coexistence of Fe ions and carbonate bicarbonate, which triggered the synergistic effect of physico-chemical action and microbial factors in algae based reactors. PMID- 27214164 TI - Aromatics extraction from pyrolytic sugars using ionic liquid to enhance sugar fermentability. AB - Fermentative bioethanol production from pyrolytic sugars was improved via aromatics removal by liquid-liquid extraction. As solvents, the ionic liquid (IL) trihexyltetradecylphosphonium dicyanamide (P666,14[N(CN)2]) and ethyl acetate (EA) were compared. Two pyrolytic sugar solutions were created from acid-leached and untreated pinewood, with levoglucosan contents (most abundant sugar) of 29.0% and 8.3% (w/w), respectively. In a single stage extraction, 70% of the aromatics were effectively removed by P666,14[N(CN)2] and 50% by EA, while no levoglucosan was extracted. The IL was regenerated by vacuum evaporation (100mbar) at 220 degrees C, followed by extraction of aromatics from fresh pyrolytic sugar solutions. Regenerated IL extracted aromatics with similar extraction efficiency as the fresh IL, and the purified sugar fraction from pretreated pinewood was hydrolyzed to glucose and fermented to ethanol, yielding 0.46g ethanol/(g glucose), close to the theoretical maximum yield. PMID- 27214165 TI - Preparation and Analysis of In Vitro Three Dimensional Breast Carcinoma Surrogates. AB - Three dimensional (3D) culture is a more physiologically relevant method to model cell behavior in vitro than two dimensional culture. Carcinomas, including breast carcinomas, are complex 3D tissues composed of cancer epithelial cells and stromal components, including fibroblasts and extracellular matrix (ECM). Yet most in vitro models of breast carcinoma consist only of cancer epithelial cells, omitting the stroma and, therefore, the 3D architecture of a tumor in vivo. Appropriate 3D modeling of carcinoma is important for accurate understanding of tumor biology, behavior, and response to therapy. However, the duration of culture and volume of 3D models is limited by the availability of oxygen and nutrients within the culture. Herein, we demonstrate a method in which breast carcinoma epithelial cells and stromal fibroblasts are incorporated into ECM to generate a 3D breast cancer surrogate that includes stroma and can be cultured as a solid 3D structure or by using a perfusion bioreactor system to deliver oxygen and nutrients. Following setup and an initial growth period, surrogates can be used for preclinical drug testing. Alternatively, the cellular and matrix components of the surrogate can be modified to address a variety of biological questions. After culture, surrogates are fixed and processed to paraffin, in a manner similar to the handling of clinical breast carcinoma specimens, for evaluation of parameters of interest. The evaluation of one such parameter, the density of cells present, is explained, where ImageJ and CellProfiler image analysis software systems are applied to photomicrographs of histologic sections of surrogates to quantify the number of nucleated cells per area. This can be used as an indicator of the change in cell number over time or the change in cell number resulting from varying growth conditions and treatments. PMID- 27214166 TI - THE LARGE GAPS IN TRANSGENDER MEDICAL KNOWLEDGE AMONG PROVIDERS MUST BE MEASURED AND ADDRESSED. PMID- 27214167 TI - Far-Red Emission of mPlum Fluorescent Protein Results from Excited-State Interconversion between Chromophore Hydrogen-Bonding States. AB - Fluorescent proteins with large Stokes shifted emission beyond 600 nm are actively sought for live-cell imaging applications. The mechanism of excited state relaxation leading to the Stokes shift in the mPlum fluorescent protein, which emits at a peak wavelength of 650 nm, has been previously investigated by both ultrafast spectroscopy and theoretical methods. Here, we report that femtosecond time-resolved area-normalized emission spectra of mPlum show a clear isoemissive point. This feature can only result from a system with two emitting states, rather than a system that undergoes a continuous spectral red shift, for example, as expected from typical solvation. Global analysis of the femtosecond time-resolved fluorescence spectra reveals time constants associated with chromophore relaxation, excited-state population transfer, and an excited-state lifetime of the final state. The observations confirm the findings of recent quantum chemical calculations on mPlum. PMID- 27214168 TI - Women with alcohol dependence: A randomized trial of couple versus individual plus couple therapy. AB - Couple therapy for women with alcohol use disorders (AUDs) yields positive drinking outcomes, but many women prefer individual to conjoint treatment. The present study compared conjoint cognitive-behavioral therapy (CBT) for women with AUDs to a blend of individual and conjoint therapy. Participants were 59 women with AUDs (95% Caucasian, mean age = 46 years) and their male partners randomly assigned to 12 sessions of Alcohol Behavioral Couple Therapy (ABCT) or to a blend of 5 individual CBT sessions and 7 sessions of ABCT (Blended-ABCT). Drinking and relationship satisfaction were assessed during and for 1-year posttreatment. Treatment conditions did not differ significantly on number of treatment sessions attended, percentage of drinking days (PDD), or percentage of heavy drinking days (PDH), during or in the 12 months following treatment. However, effect size estimates suggested a small to moderate effect of Blended-ABCT over ABCT in number of treatment sessions attended (d = -.41), and first- and second-half within treatment PDD (d = -.41, d = -.28), and PDH (d = -.46, d = -.38). Moderator analyses found that women lower in baseline sociotropy had lower PDH across treatment weeks 1-8 than in Blended-ABCT than ABCT and that women lower in self-efficacy had lower PDH during follow-up in Blended-ABCT than in ABCT. The 2 treatment groups did not differ significantly in within-treatment or posttreatment relationship satisfaction. Results suggest that blending individual and conjoint treatment yields similar or slightly better outcomes than ABCT, is responsive to women's expressed desire for individual sessions as part of their treatment, and decreases the challenges of scheduling conjoint sessions. (PsycINFO Database Record PMID- 27214169 TI - Misperception and accurate perception of close friend substance use in early adolescence: Developmental and intervention implications. AB - Misperceptions of peer substance use (SU) are believed to be a robust correlate of adolescent SU; however, perceived peer SU is biased in the direction of an adolescent's own SU raising questions about the validity of perceived peer SU (social norms; Henry, Kobus, & Schoeny, 2011). In addition, social norm theories emphasize inaccurate perceptions of peer SU while other theories emphasize actual peer behavior and selection of friends as motivators of adolescent SU. Furthermore, no theories consider the role of accurate perceptions, suggesting the need to more carefully consider the coevolution of perceived peer norms, actual peer behavior, and adolescent SU. To do this, we modeled the latent structure of accurate and inaccurate perceptions of peer SU while including an adolescent's own SU using latent class analysis and tested the natural evolution of the classes using latent transition analysis. The design included 3 annual assessments of peer and perceptions of peer SU and 6 assessments of adolescent SU (N = 765; age = 10-13 at Wave 1; female = 53%). Latent class analysis findings largely replicated Henry et al. (2011), suggesting that misperceptions of peer SU were biased by an adolescent's own SU. We also found 3 distinct pathways to a high risk class that predicted high levels of later adolescent SU, 2 in which adolescent and perceived peer SU preceded peer SU (age = 10-12 and 12-14) and another in which peer SU preceded adolescent SU and perceptions of peer SU (age = 12-14). Implications for peer influence theories are discussed. (PsycINFO Database Record PMID- 27214170 TI - The role of romantic relationship status in pathways of risk for emerging adult alcohol use. AB - Dating several people in emerging adulthood has been associated with higher alcohol use compared with being single or being in an exclusive relationship. As a follow-up to that report, we examined whether romantic relationship status is part of a pathway of risk between antecedent alcohol use risk factors and subsequent alcohol outcomes. Participants were 4,410 emerging adults assessed at 2 time-points during their first year of college. We found that a parental history of alcohol problems was indirectly related to dating several people via 2 modestly correlated pathways. The first pathway was through conduct problems. The second pathway was through positive urgency (i.e., a positive emotion-based predisposition to rash action). In turn, dating several people was associated with higher alcohol use. Our results suggest that these familial and individual level alcohol risk factors are related to emerging adults' selection into subsequent romantic relationship experiences that are associated with higher alcohol use. These findings have implications for how romantic relationship experiences may fit into developmental models of the etiology of alcohol use. (PsycINFO Database Record PMID- 27214171 TI - The associations among prior drinking consequences, subjective evaluations, and subsequent alcohol outcomes. AB - Although the many positive and negative psychosocial consequences of alcohol use are well documented, evidence of the association between prior drinking consequences and subsequent alcohol-related outcomes is mixed. Social learning theory highlights that cognitive appraisals of prior drinking consequences play a crucial intermediate role in the relation of prior drinking consequences with subsequent alcohol-related outcomes. This prospective study was designed to test the mediating effects of subjective evaluations (i.e., perceived valence and controllability) in the association of prior drinking consequences with change in binge drinking and drinking consequences over time. Participants were 171 college students (69% female, 74% White, M age = 18.95 years, SD = 1.35) who completed 2 online surveys, with an average interval of 68 days (SD = 10.22) between assessments. Path analyses of the data did not support mediational effects of perceived valence or controllability of prior drinking consequences on subsequent alcohol-related outcomes. Specifically, greater frequency of negative consequences was associated with lower perceived valence and controllability, and greater frequency of positive consequences was associated with lower perceived controllability of the experienced consequences. However, perceptions of valence and controllability were not in turn associated with subsequent binge drinking and drinking consequences. Instead, greater frequency of positive consequences was directly associated with greater subsequent frequency of binge drinking. Findings highlight the importance of prior positive consequences in the escalation of binge drinking over a short period of time, although this relation may not be accounted for by perceptions of valence and controllability of the prior drinking consequences. (PsycINFO Database Record PMID- 27214172 TI - Prevalence and correlates of cannabis use in an outpatient VA posttraumatic stress disorder clinic. AB - Recent research has documented high rates of comorbidity between cannabis use disorders and posttraumatic stress disorder (PTSD) in veterans. However, despite possible links between PTSD and cannabis use, relatively little is known about cannabis use in veterans who present for PTSD treatment, particularly among samples not diagnosed with a substance use disorder. This study examined the prevalence of cannabis use and the psychological and functional correlates of cannabis use among a large sample of veterans seeking treatment at a Veterans Affairs (VA) PTSD specialty clinic. Male veterans (N = 719) who presented at a VA specialty outpatient PTSD clinic completed measures of demographic variables, combat exposure, alcohol, cannabis and other drug use, and PTSD and depressive symptoms. The associations among demographic, psychological, and functional variables were estimated using logistic regressions. Overall, 14.6% of participants reported using cannabis in the past 6 months. After controlling for age, race, service era, and combat exposure, past 6-month cannabis use was associated with unmarried status, use of tobacco products, other drug use, hazardous alcohol use, PTSD severity, depressive symptom severity, and suicidality. The present findings show that cannabis use is quite prevalent among veterans seeking PTSD specialty treatment and is associated with poorer mental health and use of other substances. It may be possible to identify and treat individuals who use cannabis in specialty clinics (e.g., PTSD clinics) where they are likely to present for treatment of associated mental health issues. (PsycINFO Database Record PMID- 27214173 TI - Speciation of Selenium in Selenium-Enriched Sunflower Oil by High-Performance Liquid Chromatography-Inductively Coupled Plasma Mass Spectrometry/Electrospray Orbitrap Tandem Mass Spectrometry. AB - The reaction of sunflower oil with selenite produces a complex mixture of selenitriglycerides with antioxidant and anticancer properties. To obtain insight into the identity and characteristics of the species formed, an analytical approach based on the combination of high-performance liquid chromatography (HPLC) with (78)Se-specific selenium detection by inductively coupled plasma mass spectrometry (ICP MS) and high-resolution (100 000), high mass accuracy (<1 ppm) molecule-specific detection by electrospray-Orbitrap MS(3) was developed. For the first time, a non-aqueous mobile phase gradient was used in reversed-phase HPLC ICP MS for the separation of a complex mixture of selenospecies and a mathematical correction of the background signal was developed. The identical chromatographic conditions served for the sample introduction into electrospray MS. Two types of samples were analyzed: sunflower oil dissolved in isopropanol and methanol extract of the oil containing 65% selenium. HPLC-ICP MS showed 14 peaks, 11 of which could also be detected in the methanol extract. Isotopic patterns corresponding to molecules with one or two selenium atoms could be attributed by Orbitrap MS at the retention times corresponding to the HPLC-ICP MS peak apexes. Structural data for these species were acquired by MS(2) and MS(3) fragmentation of protonated or sodiated ions using high-energy collisional dissociation (HCD). A total of 11 selenium-containing triglycerol derivatives resulting from the oxidation of one or two double bonds of linoleic acid and analogous derivatives of glycerol-mixed linoleate(s)/oleinate(s) have been identified for the first time. The presence of these species was confirmed by the targeted analysis in the total oil isopropanol solution. Their identification corroborated the predicted elution order in reversed-phase chromatography: LLL (glycerol trilinoleate), LLO (glycerol dilinoleate-oleinate), LOO (glycerol linoleate-dioleinate), OOO (glycerol trioleinate), of which the extrapolation allowed for the prediction of the identity [glycerol dioleinate-stearate (OOS) and glycerol oleinate-distearate (OSS)] of the nonpolar species detected by ICP MS in the oil but not detected by electrospray MS. PMID- 27214174 TI - Targeting Biofilm Associated Staphylococcus aureus Using Resazurin Based Drug susceptibility Assay. AB - Most pathogenic bacteria are able to form biofilms during infection, but due to the difficulty of manipulating and assessing biofilms, the vast majority of laboratory work is conducted with planktonic cells. Here, we describe a peg plate biofilm assay as performed with Staphylococcus aureus. Bacterial biofilms are grown on pegs attached to a 96-well microtiter plate lid, washed through gentle submersion in buffer, and placed in a drug challenge plate. After subsequent incubation they are again washed and moved to a final recovery plate, in which the fluorescent dye resazurin serves as a viability indicator. This assay offers greatly increased ease-of-use, reliability, and reproducibility, as well as a wealth of data when conducted as a kinetic read. Moreover, this assay can be adapted to a medium-throughput drug screening approach by which an endpoint fluorescent readout is taken instead, offering a path for drug discovery efforts. PMID- 27214175 TI - Four-Dimensional Screening Anti-Counterfeiting Pattern by Inkjet Printed Photonic Crystals. AB - A four-dimensional screening anti-counterfeiting QR code composed of differently shaped photonic crystal (PC) dots has been fabricated that could display four images depending on different lighting conditions. By controlling the rheology of poly(dimethylsiloxane) (PDMS), three kinds of PC dots could be sequentially integrated into one pattern using the layer-by-layer printing strategy. The information can be encoded and stored in shapes and read out by the difference in optical properties. PMID- 27214176 TI - Preterm Breech Presentation: A Comparison of Intended Vaginal and Intended Cesarean Delivery. PMID- 27214177 TI - Trying to Conceive After an Early Pregnancy Loss: An Assessment on How Long Couples Should Wait. PMID- 27214178 TI - In Reply. PMID- 27214183 TI - Practice Bulletin No. 164 Summary: Diagnosis and Management of Benign Breast Disorders. AB - Breast-related symptoms are among the most common reasons women present to obstetrician-gynecologists. Obstetrician-gynecologists are in a favorable position to diagnose benign breast disease in their patients. The purpose of a thorough understanding of benign breast disease is threefold: 1) to alleviate, when possible, symptoms attributable to benign breast disease, 2) to distinguish benign from malignant breast disease, and 3) to identify patients with an increased risk of breast cancer so that increased surveillance or preventive therapy can be initiated. Obstetrician-gynecologists may perform diagnostic procedures when indicated or may make referrals to physicians who specialize in the diagnosis and treatment of breast disease. The purpose of this Practice Bulletin is to outline common benign breast disease symptoms in women who are not pregnant or lactating and discuss appropriate evaluation and management. The obstetrician-gynecologist's role in the screening and management of breast cancer is beyond the scope of this document and is addressed in other publications of the American College of Obstetricians and Gynecologists (1-3). PMID- 27214184 TI - Obstetric Care Consensus No. 4 Summary: Periviable Birth. AB - Approximately 0.5% of all births occur before the third trimester of pregnancy, and these very early deliveries result in the majority of neonatal deaths and more than 40% of infant deaths. A recent executive summary of proceedings from a joint workshop defined periviable birth as delivery occurring from 20 0/7 weeks to 25 6/7 weeks of gestation. When delivery is anticipated near the limit of viability, families and health care teams are faced with complex and ethically challenging decisions. Multiple factors have been found to be associated with short-term and long-term outcomes of periviable births in addition to gestational age at birth. These include, but are not limited to, nonmodifiable factors (eg, fetal sex, weight, plurality), potentially modifiable antepartum and intrapartum factors (eg, location of delivery, intent to intervene by cesarean delivery or induction for delivery, administration of antenatal corticosteroids and magnesium sulfate), and postnatal management (eg, starting or withholding and continuing or withdrawing intensive care after birth). Antepartum and intrapartum management options vary depending upon the specific circumstances but may include short-term tocolytic therapy for preterm labor to allow time for administration of antenatal steroids, antibiotics to prolong latency after preterm premature rupture of membranes or for intrapartum group B streptococci prophylaxis, and delivery, including cesarean delivery, for concern regarding fetal well-being or fetal malpresentation. Whenever possible, periviable births for which maternal or neonatal intervention is planned should occur in centers that offer expertise in maternal and neonatal care and the needed infrastructure, including intensive care units, to support such services. This document describes newborn outcomes after periviable birth, provides current evidence and recommendations regarding interventions in this setting, and provides an outline for family counseling with the goal of incorporating informed patient preferences. Its intent is to provide support and guidance regarding decisions, including declining and accepting interventions and therapies, based on individual circumstances and patient values. PMID- 27214185 TI - Committee Opinion No. 663 Summary: Aromatase Inhibitors in Gynecologic Practice. AB - Aromatase inhibitors have been used for the treatment of breast cancer, ovulation induction, endometriosis, and other estrogen-modulated conditions. For women with breast cancer, bone mineral density screening is recommended with long-term aromatase inhibitor use because of risk of osteoporosis due to estrogen deficiency. Based on long-term adverse effects and complication safety data, when compared with tamoxifen, aromatase inhibitors are associated with a reduced incidence of thrombosis, endometrial cancer, and vaginal bleeding. For women with polycystic ovary syndrome and a body mass index greater than 30, letrozole should be considered as first-line therapy for ovulation induction because of the increased live birth rate compared with clomiphene citrate. Lifestyle changes that result in weight loss should be strongly encouraged. Aromatase inhibitors are a promising therapeutic option that may be helpful for the management of endometriosis-associated pain in combination therapy with progestins. PMID- 27214186 TI - Committee Opinion No. 664 Summary: Refusal of Medically Recommended Treatment During Pregnancy. AB - One of the most challenging scenarios in obstetric care occurs when a pregnant patient refuses recommended medical treatment that aims to support her well being, her fetus's well-being, or both. In such circumstances, the obstetrician gynecologist's ethical obligation to safeguard the pregnant woman's autonomy may conflict with the ethical desire to optimize the health of the fetus. Forced compliance-the alternative to respecting a patient's refusal of treatment-raises profoundly important issues about patient rights, respect for autonomy, violations of bodily integrity, power differentials, and gender equality. The purpose of this document is to provide obstetrician-gynecologists with an ethical approach to addressing a pregnant woman's decision to refuse recommended medical treatment that recognizes the centrality of the pregnant woman's decisional authority and the interconnection between the pregnant woman and the fetus. PMID- 27214187 TI - Committee Opinion No. 665 Summary: Guidelines for Adolescent Health Research. AB - Considerable uncertainty exists about what constitutes appropriate levels of protection for adolescents as research participants and about the need for parental permission. The ethical principles that govern research include respect for individuals, beneficence, and justice, as articulated in the Belmont Report. Researchers should be familiar with and adhere to current federal regulations 45 C.F.R. S 46, and federal and state laws that affect research with minors. Investigators should understand the importance of caregiver permission-and ethically appropriate situations in which to waive caregiver permission-for the protection of adolescent research participants. PMID- 27214188 TI - Committee Opinion No. 666 Summary: Optimizing Postpartum Care. AB - In the weeks after birth, postpartum care often is fragmented among maternal and pediatric health care providers, and communication between inpatient and outpatient settings is inconsistent. To optimize postpartum care, anticipatory guidance should begin during pregnancy. During antenatal care, it is recommended that the patient and her obstetrician-gynecologist or other obstetric care provider formulate a postpartum care plan and identify the health care professionals who will comprise the postpartum care team for the woman and her infant. Ideally, during the postpartum period, a single health care practice assumes responsibility for coordinating the woman's care. At discharge from maternity care, the woman should receive contact information for her postpartum care team and written instructions regarding the timing of follow-up postpartum care. It is recommended that all women undergo a comprehensive postpartum visit within the first 6 weeks after birth. This visit should include a full assessment of physical, social, and psychological well-being. Systems should be implemented to ensure each woman can receive her desired form of contraception during the comprehensive postpartum visit, if not done earlier. At the conclusion of the postpartum visit, the woman and her obstetrician-gynecologist or other obstetric care provider should determine who will assume primary responsibility for her ongoing care. If responsibility is transferred to another primary care provider, the obstetrician-gynecologist or other obstetric care provider is responsible for ensuring that there is communication with the primary care provider so that he or she can understand the implications of any pregnancy complications for the woman's future health and maintain continuity of care. PMID- 27214189 TI - Practice Bulletin No. 164: Diagnosis and Management of Benign Breast Disorders. AB - Breast-related symptoms are among the most common reasons women present to obstetrician-gynecologists. Obstetrician-gynecologists are in a favorable position to diagnose benign breast disease in their patients. The purpose of a thorough understanding of benign breast disease is threefold: 1) to alleviate, when possible, symptoms attributable to benign breast disease, 2) to distinguish benign from malignant breast disease, and 3) to identify patients with an increased risk of breast cancer so that increased surveillance or preventive therapy can be initiated. Obstetrician-gynecologists may perform diagnostic procedures when indicated or may make referrals to physicians who specialize in the diagnosis and treatment of breast disease. The purpose of this Practice Bulletin is to outline common benign breast disease symptoms in women who are not pregnant or lactating and discuss appropriate evaluation and management. The obstetrician-gynecologist's role in the screening and management of breast cancer is beyond the scope of this document and is addressed in other publications of the American College of Obstetricians and Gynecologists (). PMID- 27214190 TI - Obstetric Care Consensus No. 4: Periviable Birth. AB - Approximately 0.5% of all births occur before the third trimester of pregnancy, and these very early deliveries result in the majority of neonatal deaths and more than 40% of infant deaths. A recent executive summary of proceedings from a joint workshop defined periviable birth as delivery occurring from 20 0/7 weeks to 25 6/7 weeks of gestation. When delivery is anticipated near the limit of viability, families and health care teams are faced with complex and ethically challenging decisions. Multiple factors have been found to be associated with short-term and long-term outcomes of periviable births in addition to gestational age at birth. These include, but are not limited to, nonmodifiable factors (eg, fetal sex, weight, plurality), potentially modifiable antepartum and intrapartum factors (eg, location of delivery, intent to intervene by cesarean delivery or induction for delivery, administration of antenatal corticosteroids and magnesium sulfate), and postnatal management (eg, starting or withholding and continuing or withdrawing intensive care after birth). Antepartum and intrapartum management options vary depending upon the specific circumstances but may include short-term tocolytic therapy for preterm labor to allow time for administration of antenatal steroids, antibiotics to prolong latency after preterm premature rupture of membranes or for intrapartum group B streptococci prophylaxis, and delivery, including cesarean delivery, for concern regarding fetal well-being or fetal malpresentation. Whenever possible, periviable births for which maternal or neonatal intervention is planned should occur in centers that offer expertise in maternal and neonatal care and the needed infrastructure, including intensive care units, to support such services. This document describes newborn outcomes after periviable birth, provides current evidence and recommendations regarding interventions in this setting, and provides an outline for family counseling with the goal of incorporating informed patient preferences. Its intent is to provide support and guidance regarding decisions, including declining and accepting interventions and therapies, based on individual circumstances and patient values. PMID- 27214191 TI - Committee Opinion No. 663: Aromatase Inhibitors in Gynecologic Practice. AB - Aromatase inhibitors have been used for the treatment of breast cancer, ovulation induction, endometriosis, and other estrogen-modulated conditions. For women with breast cancer, bone mineral density screening is recommended with long-term aromatase inhibitor use because of risk of osteoporosis due to estrogen deficiency. Based on long-term adverse effects and complication safety data, when compared with tamoxifen, aromatase inhibitors are associated with a reduced incidence of thrombosis, endometrial cancer, and vaginal bleeding. For women with polycystic ovary syndrome and a body mass index greater than 30, letrozole should be considered as first-line therapy for ovulation induction because of the increased live birth rate compared with clomiphene citrate. Lifestyle changes that result in weight loss should be strongly encouraged. Aromatase inhibitors are a promising therapeutic option that may be helpful for the management of endometriosis-associated pain in combination therapy with progestins. PMID- 27214192 TI - Committee Opinion No. 664: Refusal of Medically Recommended Treatment During Pregnancy. AB - One of the most challenging scenarios in obstetric care occurs when a pregnant patient refuses recommended medical treatment that aims to support her well being, her fetus's well-being, or both. In such circumstances, the obstetrician gynecologist's ethical obligation to safeguard the pregnant woman's autonomy may conflict with the ethical desire to optimize the health of the fetus. Forced compliance-the alternative to respecting a patient's refusal of treatment-raises profoundly important issues about patient rights, respect for autonomy, violations of bodily integrity, power differentials, and gender equality. The purpose of this document is to provide obstetrician-gynecologists with an ethical approach to addressing a pregnant woman's decision to refuse recommended medical treatment that recognizes the centrality of the pregnant woman's decisional authority and the interconnection between the pregnant woman and the fetus. PMID- 27214193 TI - Committee Opinion No. 665: Guidelines for Adolescent Health Research. AB - Considerable uncertainty exists about what constitutes appropriate levels of protection for adolescents as research participants and about the need for parental permission. The ethical principles that govern research include respect for individuals, beneficence, and justice, as articulated in the Belmont Report. Researchers should be familiar with and adhere to current federal regulations 45 C.F.R. S 46, and federal and state laws that affect research with minors. Investigators should understand the importance of caregiver permission-and ethically appropriate situations in which to waive caregiver permission-for the protection of adolescent research participants. PMID- 27214194 TI - Committee Opinion No. 666: Optimizing Postpartum Care. AB - In the weeks after birth, postpartum care often is fragmented among maternal and pediatric health care providers, and communication between inpatient and outpatient settings is inconsistent. To optimize postpartum care, anticipatory guidance should begin during pregnancy. During antenatal care, it is recommended that the patient and her obstetrician-gynecologist or other obstetric care provider formulate a postpartum care plan and identify the health care professionals who will comprise the postpartum care team for the woman and her infant. Ideally, during the postpartum period, a single health care practice assumes responsibility for coordinating the woman's care. At discharge from maternity care, the woman should receive contact information for her postpartum care team and written instructions regarding the timing of follow-up postpartum care. It is recommended that all women undergo a comprehensive postpartum visit within the first 6 weeks after birth. This visit should include a full assessment of physical, social, and psychological well-being. Systems should be implemented to ensure each woman can receive her desired form of contraception during the comprehensive postpartum visit, if not done earlier. At the conclusion of the postpartum visit, the woman and her obstetrician-gynecologist or other obstetric care provider should determine who will assume primary responsibility for her ongoing care. If responsibility is transferred to another primary care provider, the obstetrician-gynecologist or other obstetric care provider is responsible for ensuring that there is communication with the primary care provider so that he or she can understand the implications of any pregnancy complications for the woman's future health and maintain continuity of care. PMID- 27214195 TI - Effects of a fungicide formulation on embryo-larval development, metamorphosis, and gonadogenesis of the South American toad Rhinella arenarum. AB - Sublethal toxicity of the formulated fungicide Maxim((r)) XL on embryonic, larval and juvenile development of Rhinella arenarum was evaluated by means of standardized bioassays. Maxim((r)) XL, one of the most used fungicides in Argentina, is based on a mixture of two active ingredients: Fludioxonil and Metalaxyl-M. Maxim((r)) XL exposure induced severe sublethal effects on the embryos, expressed as general underdevelopment, axial flexures, microcephaly, cellular dissociation, abnormal pigmentation, underdeveloped gills, marked edema and wavy tail. As the embryo development advanced, alterations in behavior as spasmodic contractions, general weakness and inanition were observed. Maxim((r)) XL did not affect neither the time required to complete metamorphosis nor sex proportions, but gonadal development and differentiation were impaired. Gross gonadal analysis revealed a significant proportion of exposed individuals with underdevelopment of one or both gonads. Histological analysis confirmed that 18% and 10% of the individuals exposed to 0.25 and 2mg/L Maxim((r)) XL, respectively, exhibited undifferentiated gonads characterized by a reduced number (or absence) of germ cells. Taking into account the risk evaluation performed by means of Hazard Quotients, this fungicide could be a threat to R. arenarum populations under chronic exposure. This study represents the first evidence of toxic effects exerted by Maxim((r)) XL on amphibians. Finally, our findings highlight the properties of this fungicide that might jeopardize non-target living species exposed to it in agricultural environments. PMID- 27214196 TI - Structured Liquids with pH-Triggered Reconfigurability. AB - Through pH-tuning of electrostatic interactions between polymer ligands and nanoparticles at structured-liquid interfaces, liquid droplets can be directed between a jammed nonequilibrium state and a dynamic reconfigurable state. The nanoparticle-surfactant dynamics highly depend on the pH, so that the liquids can be structured using an external field and under variation of pH, or alternatively being realized by remote photo-triggering. PMID- 27214197 TI - The effect of soy or isoflavones on homocysteine levels: a meta-analysis of randomised controlled trials. AB - BACKGROUND: The present study aimed to evaluate the effect of soy or isoflavones on blood homocysteine levels via a systematic review and meta-analysis. METHODS: Pubmed, Embase, Web of Science and the Cochrane Library (up to 16 December 2015) were used for the literature review. Only randomised controlled trials were included. The primary outcome was the standard mean difference (SMD) of blood homocysteine levels between the experimental and control groups. RESULTS: Nineteen randomised controlled studies were included for qualitative analysis. Eighteen studies were included in the data synthesis. Soy or isoflavones were found to have no effect on homocysteine levels, with a SMD of -0.21 (95% confidence interval = -0.43 to 0.00, I2 =67.7%, random effect model). No publication bias was found among those studies (P = 0.296 for Egger's test, and P = 0.198 for Begg's test). CONCLUSIONS: Soy or isoflavones were not found to be associated with a reduction in homocysteine levels. Further studies might still be needed in carefully selected populations. PMID- 27214198 TI - A Flexible and Integrated System for the Remote Acquisition of Neuropsychological Data in Stroke Research. AB - BACKGROUND: Neuropsychological testing is a central aspect of stroke research because it provides critical information about the cognitive-behavioral status of stroke survivors, as well as the diagnosis and treatment of stroke-related disorders. Standard neuropsychological methods rely upon face-to-face interactions between a patient and researcher, which creates geographic and logistical barriers that impede research progress and treatment advances. INTRODUCTION: To overcome these barriers, we created a flexible and integrated system for the remote acquisition of neuropsychological data (RAND). The system we developed has a secure architecture that permits collaborative videoconferencing. The system supports shared audiovisual feeds that can provide continuous virtual interaction between a participant and researcher throughout a testing session. Shared presentation and computing controls can be used to deliver auditory and visual test items adapted from standard face-to-face materials or execute computer-based assessments. Spoken and manual responses can be acquired, and the components of the session can be recorded for offline data analysis. MATERIALS AND METHODS: To evaluate its feasibility, our RAND system was used to administer a speech-language test battery to 16 stroke survivors with a variety of communication, sensory, and motor impairments. The sessions were initiated virtually without prior face-to-face instruction in the RAND technology or test battery. RESULTS: Neuropsychological data were successfully acquired from all participants, including those with limited technology experience, and those with a communication, sensory, or motor impairment. Furthermore, participants indicated a high level of satisfaction with the RAND system and the remote assessment that it permits. CONCLUSIONS: The results indicate the feasibility of using the RAND system for virtual home-based neuropsychological assessment without prior face-to-face contact between a participant and researcher. Because our RAND system architecture uses off-the-shelf technology and software, it can be duplicated without specialized expertise or equipment. In sum, our RAND system offers a readily available and promising alternative to face-to-face neuropsychological assessment in stroke research. PMID- 27214199 TI - Diagnosis and management of hair loss in children. AB - PURPOSE OF REVIEW: Hair loss is common in infants and children and the ability to distinguish why a child is losing hair enables providers to distinguish hair loss that is related to infection, autoimmune conditions, nutrition, medications, trauma/traction, or underlying genetic disorders such as ectodermal dysplasias. Making these distinctions leads to best management and guidance for patients and their families. RECENT FINDINGS: Careful physical examination of the hair, scalp, skin, and nails coupled with dermoscopy or trichoscopy, or both, can yield more accurate and faster diagnosis. Biopsy is rarely needed in children for hair loss conditions. SUMMARY: Hair loss, particularly on the scalp, can affect all ages and can impact patients socially and emotionally. The majority of hair loss in children is nonscarring. Diagnosis begins with a good history, including personal and family history, medication use, a thorough physical examination, and use of dermoscopy or trichoscopy, or both. With these, providers can begin to divide hair loss into congenital vs. acquired, and then further subdivide into focal vs. diffuse and scarring vs. nonscarring. Secondary change, including scale and erythema, can further help with diagnosis. PMID- 27214200 TI - Colorectal Cancer Screening With Colonoscopy. PMID- 27214201 TI - Correction: Identification of an Extracellular Endoglucanase That Is Required for Full Virulence in Xanthomonas citri subsp. citri. AB - [This corrects the article DOI: 10.1371/journal.pone.0151017.]. PMID- 27214202 TI - The Impact of Azathioprine-Associated Lymphopenia on the Onset of Opportunistic Infections in Patients with Inflammatory Bowel Disease. AB - BACKGROUND: Thiopurines are known to cause lymphopenia (<1,500 lymphocytes/MUl). As severe lymphopenia (<500C/MUl) is associated with opportunistic infections, we investigated severity of thiopurine-related lymphopenia and development of opportunistic infections in our tertiary referral centre. METHODS: We retrospectively screened medical records of 1,070 IBD patients and identified 100 individuals that developed a total of 161 episodes of lymphopenia during thiopurine treatment between 2002 and 2014. Occurrence of opportunistic infections was documented. A control group consisted of IBD patients receiving thiopurines but without developing lymphopenia. RESULTS: Of a total of 161 episodes of lymphopenia, 23% were severe (<500C/MUl). In this subgroup, thiopurine dosing was modified in 64% (dosage reduction: 32%, medication discontinued: 32%). We identified 9 cases (5.5%) of opportunistic infections, of which only two occurred during severe lymphopenia. One opportunistic infection (4.5%) was identified in the control group. No association was found between opportunistic infections and severity of lymphopenia. All patients who suffered from opportunistic infections were receiving additional immunosuppressive medication. CONCLUSION: Our patients treated with thiopurines rarely developed severe lymphopenia and opportunistic infections did not occur more often than in the control group. A careful monitoring of lymphocytes and prophylactic adjustment of thiopurine therapy might contribute to this low incidence. PMID- 27214203 TI - Mobile Health Apps to Facilitate Self-Care: A Qualitative Study of User Experiences. AB - OBJECTIVE: Consumers are living longer, creating more pressure on the health system and increasing their requirement for self-care of chronic conditions. Despite rapidly-increasing numbers of mobile health applications ('apps') for consumers' self-care, there is a paucity of research into consumer engagement with electronic self-monitoring. This paper presents a qualitative exploration of how health consumers use apps for health monitoring, their perceived benefits from use of health apps, and suggestions for improvement of health apps. MATERIALS AND METHODS: 'Health app' was defined as any commercially-available health or fitness app with capacity for self-monitoring. English-speaking consumers aged 18 years and older using any health app for self-monitoring were recruited for interview from the metropolitan area of Perth, Australia. The semi structured interview guide comprised questions based on the Technology Acceptance Model, Health Information Technology Acceptance Model, and the Mobile Application Rating Scale, and is the only study to do so. These models also facilitated deductive thematic analysis of interview transcripts. Implicit and explicit responses not aligned to these models were analyzed inductively. RESULTS: Twenty two consumers (15 female, seven male) participated, 13 of whom were aged 26-35 years. Eighteen participants reported on apps used on iPhones. Apps were used to monitor diabetes, asthma, depression, celiac disease, blood pressure, chronic migraine, pain management, menstrual cycle irregularity, and fitness. Most were used approximately weekly for several minutes per session, and prior to meeting initial milestones, with significantly decreased usage thereafter. Deductive and inductive thematic analysis reduced the data to four dominant themes: engagement in use of the app; technical functionality of the app; ease of use and design features; and management of consumers' data. CONCLUSIONS: The semi-structured interviews provided insight into usage, benefits and challenges of health monitoring using apps. Understanding the range of consumer experiences and expectations can inform design of health apps to encourage persistence in self monitoring. PMID- 27214204 TI - Benign and Deleterious Cystic Fibrosis Transmembrane Conductance Regulator Mutations Identified by Sequencing in Positive Cystic Fibrosis Newborn Screen Children from California. AB - BACKGROUND: Of the 2007 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutations, 202 have been assigned disease liability. California's racially diverse population, along with CFTR sequencing as part of newborn screening model, provides the opportunity to examine the phenotypes of children with uncategorized mutations to help inform disease liability and penetrance. METHODS: We conducted a retrospective cohort study based on children screened from 2007 to 2011 and followed for two to six years. Newborns that screened positive were divided into three genotype groups: those with two CF-causing mutations (CF-C); those with one mutation of varying clinic consequence (VCC); and those with one mutation of unknown disease liability (Unknown). Sweat chloride tests, pancreatic sufficiency status, and Pseudomonas aeruginosa colonization were compared. RESULTS: Children with two CF-causing mutations had a classical CF phenotype, while 5% of VCC (4/78) and 11% of Unknown (27/244) met diagnostic criteria of CF. Children carrying Unknown mutations 2215insG with D836Y, and T1036N had early and classical CF phenotype, while others carrying 1525-42G>A, L320V, L967S, R170H, and 296+28A>G had a benign clinical presentation, suggesting that these are non CF causing. CONCLUSIONS: While most infants with VCC and Unknown CFTR mutations do not meet diagnostic criteria for CF, a small proportion do. These findings highlight the range of genotypes and phenotypes in the first few years of life following CF newborn screening when CFTR sequencing is performed. PMID- 27214205 TI - Cholesterol Corrects Altered Conformation of MHC-II Protein in Leishmania donovani Infected Macrophages: Implication in Therapy. AB - BACKGROUND: Previously we reported that Kala-azar patients show progressive decrease in serum cholesterol as a function of splenic parasite burden. Splenic macrophages (MPhi) of Leishmania donovani (LD) infected mice show decrease in membrane cholesterol, while LD infected macrophages (I-MPhi) show defective T cell stimulating ability that could be corrected by liposomal delivery of cholesterol. T helper cells recognize peptide antigen in the context of class II MHC molecule. It is known that the conformation of a large number of membrane proteins is dependent on membrane cholesterol. In this investigation we tried to understand the influence of decreased membrane cholesterol in I-MPhi on the conformation of MHC-II protein and peptide-MHC-II stability, and its bearing on the antigen specific T-cell activation. METHODOLOGY/PRINCIPAL FINDINGS: MPhi of CBA/j mice were infected with Leishmania donovani (I-MPhi). Two different anti Akappa mAbs were used to monitor the status of MHC-II protein under parasitized condition. One of them (11.5-2) was conformation specific, whereas the other one (10.2.16) was not. Under parasitized condition, the binding of 11.5-2 decreased significantly with respect to the normal counterpart, whereas that of 10.2.16 remained unaltered. The binding of 11.5-2 was restored to normal upon liposomal delivery of cholesterol in I-MPhi. By molecular dynamics (MD) simulation studies we found that there was considerable conformational fluctuation in the transmembrane domain of the MHC-II protein in the presence of membrane cholesterol than in its absence, which possibly influenced the distal peptide binding groove. This was evident from the faster dissociation of the cognate peptide from peptide-MHC complex under parasitized condition, which could be corrected by liposomal delivery of cholesterol in I-MPhi. CONCLUSION: The decrease in membrane cholesterol in I-MPhi may lead to altered conformation of MHC II, and this may contribute to a faster dissociation of the peptide. Furthermore, liposomal delivery of cholesterol in I-MPhi restored its normal antigen presenting function. This observation brings strength to our previous observation on host directed therapeutic application of liposomal cholesterol in experimental visceral leishmaniasis. PMID- 27214206 TI - Life Course Pathways of Adversities Linking Adolescent Socioeconomic Circumstances and Functional Somatic Symptoms in Mid-Adulthood: A Path Analysis Study. AB - While research examining the health impact of early socioeconomic conditions suggests that effects may exist independently of or jointly with adult socioeconomic position, studies exploring other potential pathways are few. Following a chain of risk life course model, this prospective study seeks to examine whether pathways of occupational class as well as material and social adversities across the life course link socioeconomic disadvantage in adolescent to functional somatic symptoms in mid-adulthood. Applying path analysis, a multiple mediator model was assessed using prospective data collected during 26 years through the Northern Swedish Cohort. The sample contained 987 individuals residing in the municipality of Lulea, Sweden, who participated in questionnaire surveys at age 16, 21, 30 and 42. Socioeconomic conditions (high/low) in adolescence (age 16) were operationalized using the occupation of the parents, while occupational class in adulthood (manual/non-manual) was measured using the participant's own occupation at age 21 and 30. The adversity measurements were constructed as separate age specific parcels at age 21 and 30. Social adversity included items pertaining to stressful life events that could potentially harm salient relationships, while material adversity was operationalized using items concerning unfavorable financial and material circumstances. Functional somatic symptoms at age 42 was a summary measure of self-reported physical symptoms, palpitation and sleeping difficulties that had occurred during the last 12 months. An association between socioeconomic conditions at age 16 and functional somatic symptoms at age 42 (r = 0.068) which was partially explained by people's own occupational class at age 21 and then material as well as social adversity at age 30 was revealed. Rather than proposing a direct and independent health effect of the socioeconomic conditions of the family, the present study suggests that growing up in an unfavorable socioeconomic environment might be a source for a chain of adverse material and social living situations, which in turn affects adult health. PMID- 27214207 TI - TrmBL2 from Pyrococcus furiosus Interacts Both with Double-Stranded and Single Stranded DNA. AB - In many hyperthermophilic archaea the DNA binding protein TrmBL2 or one of its homologues is abundantly expressed. TrmBL2 is thought to play a significant role in modulating the chromatin architecture in combination with the archaeal histone proteins and Alba. However, its precise physiological role is poorly understood. It has been previously shown that upon binding TrmBL2 covers double-stranded DNA, which leads to the formation of a thick and fibrous filament. Here we investigated the filament formation process as well as the stabilization of DNA by TrmBL2 from Pyroccocus furiosus in detail. We used magnetic tweezers that allow to monitor changes of the DNA mechanical properties upon TrmBL2 binding on the single-molecule level. Extended filaments formed in a cooperative manner and were considerably stiffer than bare double-stranded DNA. Unlike Alba, TrmBL2 did not form DNA cross-bridges. The protein was found to bind double- and single stranded DNA with similar affinities. In mechanical disruption experiments of DNA hairpins this led to stabilization of both, the double- (before disruption) and the single-stranded (after disruption) DNA forms. Combined, these findings suggest that the biological function of TrmBL2 is not limited to modulating genome architecture and acting as a global repressor but that the protein acts additionally as a stabilizer of DNA secondary structure. PMID- 27214208 TI - Dicationic Surfactants with Glycine Counter Ions for Oligonucleotide Transportation. AB - Gemini surfactants are good candidates to bind, protect, and deliver nucleic acids. Herein, the concept of amino acids (namely glycine) as counter ions of gemini surfactants for gene therapy application was explored. This study was conducted on DNA and RNA oligomers and two quaternary bis-imidazolium salts, having 2,5-dioxahexane and 2,8-dioxanonane spacer groups. The toxicity level of surfactants was assessed by an MTT assay, and their ability to bind nucleic acids was tested through electrophoresis. The nucleic acid conformation was established based on circular dichroism and infrared spectroscopic analyses. The structures of the formed complexes were characterized by small-angle scattering of synchrotron radiation. Both studied surfactants appear to be suitable for gene therapy; however, although they vary by only three methylene groups in the spacer, they differ in binding ability and toxicity. The tested oligonucleotides maintained their native conformations upon surfactant addition and the studied lipoplexes formed a variety of structures. In systems based on a 2,5-dioxahexane spacer, a hexagonal phase was observed for DNA-surfactant complexes and a micellar phase was dominant with RNA. For the surfactant with a 2,8-dioxanonane spacer group, the primitive cubic phase prevailed. PMID- 27214209 TI - Antibiotic prophylaxis for skin toxicity induced by antiepidermal growth factor receptor agents: a systematic review and meta-analysis. AB - Topical and systemic prophylactic measures, which are administered before the development of epidermal growth factor receptor (EGFR)-related acneiform rash, are appropriate interventions to mitigate the intensity of skin toxicity. We have performed a systematic review and meta-analysis to evaluate whether prophylactic antibiotics may reduce the occurrence and severity of anti-EGFR drug-related skin rashes. A systematic review was performed by searching Medline, Scopus, Embase, CINAHL, LILACS, Web of Science and the Cochrane Library from inception until March 2016 for publications regarding the pre-emptive role of antibiotics for EGFR-induced skin rashes. Fixed- or random-effects meta-analyses, according to heterogeneity, were used to summarize odds ratios of skin toxicity with antibiotic use. Of the 827 citations found in the search, 13 studies comprising 1073 patients were included in the analysis. In 12 studies, patients in the prophylactic antibiotic arms had a lower risk of developing a skin rash (odds ratio 0.53, 95% confidence interval 0.39-0.72, P < 0.01) than patients without antibiotic prophylaxis. In particular, moderate-to-severe toxicities (grades 2-4) were reduced by nearly two-thirds (odds ratio 0.36, 95% confidence interval 0.22 0.60, P < 0.01) in 13 studies. This translated to a 26% absolute difference of high-grade skin rash compared with the control arms (from 50% to 24%). The results of this meta-analysis show that the risk of skin rash after treatment with anti-EGFR agents for solid tumours was significantly lower in patients taking prophylaxis with antibiotics than in those who were not. Therefore, taking pre-emptive tetracyclines for several weeks at the start of anti-EGFR treatment can significantly reduce the incidence and severity of cutaneous acneiform rash. PMID- 27214210 TI - Do vaccinations affect the clinical course of systemic necrotising vasculitis? A prospective observational web-based study. AB - OBJECTIVES: To estimate the impact of vaccinations, infections and traumatic life events on the disease activity of a web-based cohort of systemic necrotising vasculitis (SNV) patients. METHODS: Adults diagnosed with SNV self-reported vaccinations, infectious episodes and traumatic life events every 3 months during follow-up on a secure dedicated website. Participants reported information on disease activity assessed with 3 scores: the French version of the Medical Outcome Study Short Form-36 (SF-36), the visual numerical scale for Patient Global Assessment (PGA) and the modified Disease Extent Index (mDEI). RESULTS: Between December 2005 and October 2008, 145 participants (mean +/- SD age 53+/-13 years; 57% males) were included. Mean follow-up was 445+/-325 days. SNVs were distributed as follows: 46% granulomatosis with polyangiitis (Wegener's), 22% eosinophilic granulomatosis with polyangiitis (Churg-Strauss), 18% polyarteritis nodosa and 8% microscopic polyangiitis. During follow-up, 94 vaccinations, 57 acute infectious episodes and 274 traumatic life events were reported. In univariate and multivariate analyses, only traumatic life events were significantly associated with decreased SF-36 mental and physical component scores. No significant SF-36, PGA and mDEI scores variations were reported during the 3 months following acute infectious episode or vaccine administration. CONCLUSIONS: No significant clinical impact of vaccinations on SNV activity was found in this prospective observational study. PMID- 27214213 TI - Editorial. PMID- 27214211 TI - DNA Scrunching in the Packaging of Viral Genomes. AB - The motors that drive double-stranded DNA (dsDNA) genomes into viral capsids are among the strongest of all biological motors for which forces have been measured, but it is not known how they generate force. We previously proposed that the DNA is not a passive substrate but that it plays an active role in force generation. This "scrunchworm hypothesis" holds that the motor proteins repeatedly dehydrate and rehydrate the DNA, which then undergoes cyclic shortening and lengthening motions. These are captured by a coupled protein-DNA grip-and-release cycle to rectify the motion and translocate the DNA into the capsid. In this study, we examined the interactions of dsDNA with the dodecameric connector protein of bacteriophage phi29, using molecular dynamics simulations on four different DNA sequences, starting from two different conformations (A-DNA and B-DNA). In all four simulations starting with the protein equilibrated with A-DNA in the channel, we observed transitions to a common, metastable, highly scrunched conformation, designated A*. This conformation is very similar to one recently reported by Kumar and Grubmuller in much longer MD simulations on B-DNA docked into the phi29 connector. These results are significant for four reasons. First, the scrunched conformations occur spontaneously, without requiring lever-like protein motions often believed to be necessary for DNA translocation. Second, the transition takes place within the connector, providing the location of the putative "dehydrator". Third, the protein has more contacts with one strand of the DNA than with the other; the former was identified in single-molecule laser tweezer experiments as the "load-bearing strand". Finally, the spontaneity of the DNA-protein interaction suggests that it may play a role in the initial docking of DNA in motors like that of T4 that can load and package any sequence. PMID- 27214212 TI - [Perioperative Anticoagulation in Elective Hand Surgery: A Literature Review]. AB - This review highlights pathways regarding the handling of anticoagulation in elective hand surgery based on current literature. PMID- 27214214 TI - Considerations for current and future management of haemophilia and its complications. PMID- 27214215 TI - Haemophilia: a global challenge. PMID- 27214216 TI - In vivo recovery and early half-life of infused factor VIII in haemophilia A. AB - Between 1980 and 1994, 169 in vivo recovery studies were performed in one haemophilia centre on casually-recruited outpatients with severe haemophilia A, and 149 early-phase half-life studies were performed on patients scheduled for elective surgery. Average recoveries improved from 80% to 97% of the expected values over the study period. No relationship of recovery to level of product purification was seen. In the disappearance studies, plasma factor VIII levels fell to half the peak levels by 3.25h after infusion, on average. PMID- 27214217 TI - Clinical experience with a highly purified factor IX concentrate in patients undergoing surgical operations. AB - The haemostatic efficacy of a new highly purified factor IX concentrate, prepared by metal chelate affinity chromatography, was assessed in 13 patients with haemophilia B undergoing a variety of surgical operations. Four of the patients had developed post-operative thromboembolic complications following previous operations, when treated with a prothrombin complex concentrate. None of the patients in the present series developed any evidence of post-operative thrombotic complications. Effective haemostasis was achieved in all patients, with the exception of a surgical bleed in one case, and late post-operative bleeding in a second patient when the factor IX activity fell below 20iu/dl. The product is treated with a solvent-detergent process that destroys lipid-enveloped viruses, while the affinity chromatography process during manufacture removes in excess of 4 log10 of a non-lipid-enveloped virus. In follow-up studies, none of the patients has shown evidence of fresh infection from the concentrate, when assessed by virological markers. It is concluded that this high-purity concentrate (tradenane 'Replenine') is effective for the treatment of patients with haemophilia B who undergo surgical operations. PMID- 27214218 TI - Immune tolerance therapy in paediatric haemophiliacs with factor VIII inhibitors: 14 years follow-up. AB - We report our clinical experience in the immune tolerance (IT) therapy of 21 paediatric haemophiliacs with FVIII inhibitor: high responders (16HR) received initially FVIII twice daily at a dosage of 50-300 U/kg/day, 11/16 received a concomitant treatment with activated prothrombin complex concentrate (100-200 U/kg/day). Low responders (five LR) received 20-100 FVIII U/kg every second or third day. Inhibitor elimination was achieved in 19/21 patients in a median time of 4 months in HR and 1.5 months in LR. The outcome and length of time needed to induce IT was significantly correlated with FVIII exposure between the first inhibitor detection and onset of IT therapy and to interruption of IT therapy. For a rapid elimination of FVIII inhibitors it is important to start continuous administration of high-dose FVIII (>= 100 FVIII U/kg/day) before repeated exposure to FVIII, in order to prevent rebooster effects, prolongation of elimination time, and to reduce expense. PMID- 27214219 TI - Long-term survival of HIV-infected patients with haemophilia. AB - In France, patients with haemophilia were infected by HIV up until October 1985, with a maximum of seroconversion between 1983 and 1985. There was a progressive development of AIDS in the 1158 infected patients as reported by Health Authorities. By the end of 1992, 32% of the haemophilia population had developed AIDS and 38 had developed clinical or biological symptoms of immunodeficiency. However, 27% had no clinical symptoms and no severe disorder of the immune system. The present study was established to determine factors common to patients with prolonged survival. PMID- 27214220 TI - Prophylaxis for Pneumocystis carinii pneumonia: its impact on the natural history of HIV infection in men with haemophilia. AB - It has been suggested that the range of AIDS-defining conditions witnessed in patients with HIV infection has changed since the early years of the HIV epidemic. In this paper we consider the range of AIDS-defining conditions in a cohort of 111 HIV-positive men with haemophilia registered at the Royal Free Hospital Haemophilia Centre. In particular we assess whether the incidence of Pneumocystis carinii pneumonia (PCP) has changed over time. The men were all infected between 1979 and 1985 after treatment with infected blood products and have now been followed prospectively for up to 13 years from HIV seroconversion. By the end of 1992, 44/111 patients had developed AIDS. Of the 44 men, 18 (41%) presented with PCP as their first AIDS-defining condition (ADC), mainly before the initiation of primary prophylaxis in 1989. The remaining 26 patients presented with a range of conditions as their first ADC, but there were no more than four cases in any one disease category. It is estimated that patients suffer from 0.7 further ADCs per year after being diagnosed with AIDS. After taking account of the increased levels of immuno-suppression in the cohort with time, it appears that the incidence of PCP, both as the first ADC or as any ADC, has declined since the introduction of primary prophylaxis for the disease in 1989. However, non-compliance with prophylaxis for PCP appears to have played a major role in the continuing occurrence of PCP since 1988. Improvements in compliance with therapy should result in a further reduction in the incidence of PCP both as a first ADC and as any ADC. PMID- 27214221 TI - Effect and side-effects of alpha interferon treatment in haemophilia patients with chronic hepatitis C. AB - To evaluate the effect and side-effects of alpha interferon 2B (IFN) treatment in haemophilia patients with chronic hepatitis C (positive HCV antibody test, positive HCV-RNA test and ALT levels >2.5 * upper limit of normal) eight HIV and HBs-ag negative haemophilia patients were treated with IFN for 26 weeks in a dosage of 5 mega units (MU) daily for 2 weeks, 2.5 MU daily for 4 weeks and 1.5 MU 3 times a week for 20 weeks. Patients who were transient or non-responders after 26 weeks of IFN therapy were treated for 2.5 years with 5 MU IFN three times a week. At the end of 3 years follow-up, four patients were considered complete responders (HCV-RNA negative) with complete and sustained ALT normalization and disappearance from HCV-RNA from blood, two patients only showed a transient response and two patients were non-responders. All patients experienced the common side-effects of IFN treatment. Two patients complained about feelings of depression and impotence. For both this was the reason to stop IFN treatment. In one patient, IFN treatment was stopped 90 weeks after start of therapy because of persistent fatigue. In another patient the dosage was adjusted because of a decrease in platelet count. No effect of IFN on bleeding frequency and chronic arthopathy was seen. We conclude that the clinical effects and side effects of IFN therapy in patients with haemophilia and chronic hepatitis C are comparable with those of non-haemophilia patients with chronic hepatitis C. Haemophilia patients can be treated for chronic hepatitis C infection in the same way as patients without haemophilia. PMID- 27214222 TI - Alpha interferon for hepatitis C virus infection in haemophilic patients. AB - We have conducted a controlled trial in 20 haemophilic patients in which intravenous recombinant interferon alpha-2a, 3 mega units thrice weekly, was used to treat chronic hepatitis C infection. The study endpoints included complete and paritial normalization of serum ALT, and loss of serum HCV RNA as determined by polymerase chain reaction (PCR). Interferon treatment was effective, and resulted in improvement in ALT in nine (45%) and a loss of HCV RNA in five patients (26%), but a sustained normalization of ALT has been seen in only one case. Responses were poor in those with HIV coinfection or with HCV genotype 1 (Simmonds classification). Troublesome side-effects were reported in 80%. The occurrence of a factor VIIIc inhibitor during the study was possibly an autoimmune complication of interferon. In conclusion, we have shown lower response rates than those seen in post-transfusion hepatitis C infection and suspect that current interferon regimes are unlikely to influence the natural history of HCV infection in haemophilia. Consideration should be given to trials of higher dosage interferon, and of long-term maintenance therapy for those who relapse. PMID- 27214224 TI - Early rapid decline in CD4 count reversed by splenectomy in HIV infection. PMID- 27214223 TI - Results in three Australian haemophilia B patients with high-responding inhibitors treated with the Malmo model. AB - Development of inhibitors to factor IX (F IX) is a serious complication of the treatment of patients with severe haemophilia B. Three Australian haemophilia B patients, a 22-year-old man and two 5-year-old identical twins, with high responding inhibitors and resistant to treatment, were admitted to the centre in Malmo, Sweden, for tolerance induction according to the Malmo treatment model. This tratment consists of a combination of cyclophosphamide, F VIII of F IX, and high-dose intravenous IgG. Extracorporeal adsorption to protein A in columns, which is included in the protocol when the inhibitor titre is high at the start of treatment, had to be perforemed in the case of the twin brothers. High-purity F IX concentrates were used. The tolerance inductin was successful in the 22-year old man and in one of the twins; they been toleant for 4 and 2 years, respectively, and are now on a home-treatment programme taking 30-40 IU F IX/kg twice weekly. These patients have no demonstrable coagulation inhibitory antibodies and in vivo reovery and half-life of infused F IX are normal. In the other twin it has not been possible to induce tolerance, though after removal of the antibodies by protein A adsorpation it is possible to achieve significant circulalting levels of F IX for 8-10 days. PMID- 27214225 TI - Hepatitis as a complication of blood transfusion. PMID- 27214227 TI - Comparative Profiling of microRNA Expression in Soybean Seeds from Genetically Modified Plants and their Near-Isogenic Parental Lines. AB - MicroRNAs (miRNAs) have been widely demonstrated to play fundamental roles in gene regulation in most eukaryotes. To date, there has been no study describing the miRNA composition in genetically modified organisms (GMOs). In this study, small RNAs from dry seeds of two GM soybean lines and their parental cultivars were investigated using deep sequencing technology and bioinformatic approaches. As a result, several differentially expressed gma-miRNAs were found between the GM and non-GM soybeans. Meanwhile, more differentially expressed gma-miRNAs were identified between distantly relatednon-GM soybeans, indicating that the miRNA components of soybean seeds varied among different soybean lines, including the GM and non-GM soybeans, and the extent of difference might be related to their genetic relationship. Additionally, fourteen novel gma-miRNA candidates were predicted in soybean seeds including a potential bidirectionally transcribed miRNA family with two genomic loci (gma-miR-N1). Our findings firstly provided useful data for miRNA composition in edible GM crops and also provided valuable information for soybean miRNA research. PMID- 27214228 TI - Deprotonations in the Reaction of Flavin-Dependent Thymidylate Synthase. AB - Many microorganisms use flavin-dependent thymidylate synthase (FDTS) to synthesize the essential nucleotide 2'-deoxythymidine 5'-monophosphate (dTMP) from 2'-deoxyuridine 5'-monophosphate (dUMP), 5,10-methylenetetrahydrofolate (CH2THF), and NADPH. FDTSs have a structure that is unrelated to the thymidylate synthase used by humans and a very different mechanism. Here we report nuclear magnetic resonance evidence that FDTS ionizes N3 of dUMP using an active-site arginine. The ionized form of dUMP is largely responsible for the changes in the flavin absorbance spectrum of FDTS upon dUMP binding. dUMP analogues also suggest that the phosphate of dUMP acts as the base that removes the proton from C5 of the dUMP-methylene intermediate in the FDTS-catalyzed reaction. These findings establish additional differences between the mechanisms of FDTS and human thymidylate synthase. PMID- 27214229 TI - Regulation of viral gene expression by the herpes simplex virus 1UL24 protein (HSV-1UL24 inhibits accumulation of viral transcripts). AB - UL24 is conserved among all Herpesviridae. In herpes simplex virus 1 (HSV-1), UL24 mutations lead to reduced viral titers both in cell culture and in vivo, and reduced pathogenicity. The human cytomegalovirus ortholog of UL24 has a gene regulatory function; however, it is not known whether other UL24 orthologs also affect gene expression. We discovered that in co-transfection experiments, expression of UL24 correlated with a reduction in the expression of several viral proteins and transcripts. Substitution mutations targeting conserved residues in UL24 impaired this function. Reduced transcript levels did not appear attributable to changes in mRNA stability. The UL24 ortholog of Herpes B virus exhibited a similar activity. An HSV-1 mutant that does not express UL24 produced more viral R1 and R2 transcripts than the wild type or rescue virus relative to the amount of viral DNA. These results reveal a new role for HSV-1UL24 in regulating viral mRNA accumulation. PMID- 27214230 TI - Thymidine Kinase Type 1 and C-Reactive Protein Concentrations in Dogs with Spontaneously Occurring Cancer. AB - BACKGROUND: Serum thymidine kinase type 1 (TK1) and canine C-Reactive Protein (cCRP) might be useful in detecting dogs with cancer. Algorithms combining biomarkers are sometimes more accurate than results of individual tests. OBJECTIVES: The aim of this study was to compare serum TK1 and cCRP and Neoplasia Index (NI) in healthy and tumor-bearing dogs. ANIMALS: Client-owned dogs with (n = 253) and without (n = 156) cancer. METHODS: Retrospective case-control study. Dogs with cancer were identified after submission of samples for commercial assay and case details were retrospectively collected. Healthy dogs (control) were identified through breed groups and health status was confirmed by health questionnaire for a minimum of 6 months. Serum TK1 activity was measured using a quantitative chemiluminescent assay and serum cCRP was measured using a quantitative ELISA assay. RESULTS: TK1 activity in the cancer (n = 253) and control group (n = 156) were 7.0 MU/L (median, range <0.5 to >100) and 1.8 MU/L (median, range 0.4 to 55.3), respectively (P < .001). cCRP concentrations in the cancer and control group were 6.0 mg/L (median, range <0.5 to >50) and 1.6 mg/L (median, range 0.09 to >50), respectively (P < .001). The NI in the cancer and control group were 6.4 (median, range 0-9.9) and 0.9 (median, range 0-7.6), respectively (P < .001). ROC AUCs of the NI and TK1 for all cancers were greater than 0.8, highest for lymphoma and histiocytic sarcoma. CONCLUSIONS AND CLINICAL IMPORTANCE: Increased concentrations of TK1 and cCRP, when present in dogs with cancer, might be useful in confirming a diagnosis and monitoring response to treatment. PMID- 27214231 TI - Correction: Correlative Gene Expression to Protective Seroconversion In Rift Valley Vaccinates. AB - [This corrects the article DOI: 10.1371/journal.pone.0147027.]. PMID- 27214232 TI - Clinical and Imaging Signs of Spondyloarthritis in First-Degree Relatives of HLA B27-Positive Ankylosing Spondylitis Patients: The Pre-Spondyloarthritis (Pre-SpA) Cohort Study. AB - OBJECTIVE: To investigate whether seemingly healthy first-degree relatives of patients with ankylosing spondylitis (AS) have clinical, laboratory, or imaging features of spondyloarthritis (SpA). METHODS: First-degree relatives (ages 18-40 years) of HLA-B27-positive AS patients were included in the pre-spondyloarthritis (Pre-SpA) cohort, a prospective inception cohort study. Clinical, biologic, and imaging features were recorded. First-degree relatives were classified according to several sets of SpA classification criteria. RESULTS: We report baseline features of 51 first-degree relatives included in this study. Twenty-nine (57%) had back pain, 2 (4%) had psoriasis, 1 (2%) had inflammatory bowel disease, and 1 (2%) had uveitis. Three (6%) had low-grade sacroiliitis, 1 (2%) had cervical syndesmophytes on radiography, and 10 (20%) had bone marrow edema on magnetic resonance imaging of the sacroiliiac joints. Seventeen of 51 first-degree relatives (33%) fulfilled SpA classification criteria: 7 (14%) fulfilled both Assessment of SpondyloArthritis international Society (ASAS) axial SpA and European Spondylarthropathy Study Group (ESSG) classification criteria, 6 (12%) fulfilled only ASAS axial SpA classification criteria, and 4 (8%) fulfilled only ESSG classification criteria; 3 (6%) also fulfilled the Amor criteria. None fulfilled other SpA classification criteria. First-degree relatives fulfilling the ASAS axial SpA and/or ESSG classification criteria had more frequent inflammatory back pain, had a higher level of disease activity, and had more psoriasis. No differences were found in parameters of inflammation, peripheral and extraarticular disease other than psoriasis, and HLA-B27 positivity between those who did and those who did not fulfill the ASAS axial SpA and/or ESSG classification criteria. Four first-degree relatives (12%) who did not fulfill the ASAS axial SpA and/or ESSG classification criteria had imaging abnormalities suggestive of SpA. CONCLUSION: A substantial proportion of seemingly healthy first-degree relatives of HLA-B27-positive AS patients have clinical and/or imaging abnormalities suggestive of SpA. Thirty-three percent could be classified as having SpA. Further follow-up will show which first-degree relatives will develop clinically manifest SpA. PMID- 27214233 TI - Imposed Optical Defocus Induces Isoform-Specific Up-Regulation of TGFbeta Gene Expression in Chick Retinal Pigment Epithelium and Choroid but Not Neural Retina. AB - PURPOSE: This study investigated the gene expression of TGFbeta isoforms and their receptors in chick retina, retinal pigment epithelium (RPE), and choroid and the effects of short-term imposed optical defocus. METHODS: The expression of TGFbeta isoforms (TGF-beta1, 2, 3) and TGFbeta receptors (TGFBR1, 2, 3) was examined in the retina, RPE, and choroid of young White-Leghorn untreated chicks (19 days-old). The effects on the expression of the same genes of monocular +10 and -10 D defocusing lenses, worn for either 2 or 48 h by age-matched chicks, were also examined by comparing expression in treated and untreated fellow eyes. RNA was purified, characterized and then reverse transcribed to cDNA. Differential gene expression was quantified using real-time PCR. RESULTS: All 3 isoforms of TGFbeta and all 3 receptor subtypes were found to be expressed in all 3 ocular tissues, with apparent tissue-dependent differences in expression profiles. Data are reported as mean normalized expression relative to GAPDH. Sign dependent optical defocus effects were also observed. Optical defocus did not affect retinal gene expression but in the RPE, TGF-beta2 expression was significantly up-regulated with +10 D lenses, worn for either 2 h (349% increase +/- 88%, p < 0.01) or 48 h (752% increase +/- 166%, p < 0.001), and in the choroid, the expression of TGF-beta3 was up-regulated with -10 D lenses, worn for 48 h (147% increase +/- 9%, p < 0.01). CONCLUSIONS: The effects of short term exposure to optical defocus on TGFbeta gene expression in the RPE and choroid, which were sign-dependent and isoform specific, provide further supporting evidence for important roles of members of the TGFbeta family and these two tissues in local signal cascades regulating ocular growth. PMID- 27214235 TI - IMDAF Cascade Approach toward the Synthesis of the Alkaloid (+/-)-Minfiensine. AB - The total synthesis of the Strychnos alkaloid (+/-)-minfiensine was achieved via an intramolecular amidofuran Diels-Alder cycloaddition/rearrangement followed by an iminium ion/cyclization cascade sequence. This domino process provides for a rapid access to the unique 1,2,3,4-tetrahydro-9a,4a-iminoethanocarbazole core structure found in the alkaloid minfiensine (2). In this paper, the full account of our synthetic study is described, highlighting the successful application of the cascade sequence to form the A/B/C/D rings of (+/-)-minfiensine (2) in high yield. A palladium-catalyzed enolate coupling reaction was then used to furnish the final E ring and complete the total synthesis of (+/-)-minfiensine (2). PMID- 27214234 TI - Unraveling the Sex Chromosome Heteromorphism of the Paradoxical Frog Pseudis tocantins. AB - The paradoxical frog Pseudis tocantins is the only species in the Hylidae family with known heteromorphic Z and W sex chromosomes. The Z chromosome is metacentric and presents an interstitial nucleolar organizer region (NOR) on the long arm that is adjacent to a pericentromeric heterochromatic band. In contrast, the submetacentric W chromosome carries a pericentromeric NOR on the long arm, which is adjacent to a clearly evident heterochromatic band that is larger than the band found on the Z chromosome and justify the size difference observed between these chromosomes. Here, we provide evidence that the non-centromeric heterochromatic bands in Zq and Wq differ not only in size and location but also in composition, based on comparative genomic hybridization (CGH) and an analysis of the anuran PcP190 satellite DNA. The finding of PcP190 sequences in P. tocantins extends the presence of this satellite DNA, which was previously detected among Leptodactylidae and Hylodidae, suggesting that this family of repetitive DNA is even older than it was formerly considered. Seven groups of PcP190 sequences were recognized in the genome of P. tocantins. PcP190 probes mapped to the heterochromatic band in Wq, and a Southern blot analysis indicated the accumulation of PcP190 in the female genome of P. tocantins, which suggests the involvement of this satellite DNA in the evolution of the sex chromosomes of this species. PMID- 27214236 TI - Early Transcriptional Signatures of the Immune Response to a Live Attenuated Tetravalent Dengue Vaccine Candidate in Non-human Primates. AB - BACKGROUND: The development of a vaccine against dengue faces unique challenges, including the complexity of the immune responses to the four antigenically distinct serotypes. Genome-wide transcriptional profiling provides insight into the pathways and molecular features that underlie responses to immune system stimulation, and may facilitate predictions of immune protection. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we measured early transcriptional responses in the peripheral blood of cynomolgus macaques following vaccination with a live, attenuated tetravalent dengue vaccine candidate, TDV, which is based on a DENV-2 backbone. Different doses and routes of vaccine administration were used, and viral load and neutralizing antibody titers were measured at different time-points following vaccination. All 30 vaccinated animals developed a neutralizing antibody response to each of the four dengue serotypes, and only 3 of these animals had detectable serum viral RNA after challenge with wild-type dengue virus (DENV), suggesting protection of vaccinated animals to DENV infection. The vaccine induced statistically significant changes in 595 gene transcripts on days 1, 3, 5 and 7 as compared with baseline and placebo-treated animals. Genes involved in the type I interferon (IFN) response, including IFI44, DDX58, MX1 and OASL, exhibited the highest fold-change in transcript abundance, and this response was strongest following double dose and subcutaneous (versus intradermal) vaccine administration. In addition, modules of genes involved in antigen presentation, dendritic cell activation, and T cell activation and signaling were enriched following vaccination. Increased abundance of gene transcripts related to T cell activation on day 5, and the type I IFN response on day 7, were significantly correlated with the development of high neutralizing antibody titers on day 30. CONCLUSIONS/SIGNIFICANCE: These results suggest that early transcriptional responses may be predictive of development of adaptive immunity to TDV vaccination in cynomolgus macaques, and will inform studies of human responses to dengue vaccines. PMID- 27214237 TI - High Level Expression and Purification of Recombinant Proteins from Escherichia coli with AK-TAG. AB - Adenylate kinase (AK) from Escherichia coli was used as both solubility and affinity tag for recombinant protein production. When fused to the N-terminus of a target protein, an AK fusion protein could be expressed in soluble form and purified to near homogeneity in a single step from Blue-Sepherose via affinity elution with micromolar concentration of P1, P5- di (adenosine-5') pentaphosphate (Ap5A), a transition-state substrate analog of AK. Unlike any other affinity tags, the level of a recombinant protein expression in soluble form and its yield of recovery during each purification step could be readily assessed by AK enzyme activity in near real time. Coupled to a His-Tag installed at the N-terminus and a thrombin cleavage site at the C terminus of AK, the streamlined method, here we dubbed AK-TAG, could also allow convenient expression and retrieval of a cleaved recombinant protein in high yield and purity via dual affinity purification steps. Thus AK-TAG is a new addition to the arsenal of existing affinity tags for recombinant protein expression and purification, and is particularly useful where soluble expression and high degree of purification are at stake. PMID- 27214238 TI - Streamlined mean field variational Bayes for longitudinal and multilevel data analysis. AB - Streamlined mean field variational Bayes algorithms for efficient fitting and inference in large models for longitudinal and multilevel data analysis are obtained. The number of operations is linear in the number of groups at each level, which represents a two orders of magnitude improvement over the naive approach. Storage requirements are also lessened considerably. We treat models for the Gaussian and binary response situations. Our algorithms allow the fastest ever approximate Bayesian analyses of arbitrarily large longitudinal and multilevel datasets, with little degradation in accuracy compared with Markov chain Monte Carlo. The modularity of mean field variational Bayes allows relatively simple extension to more complicated scenarios. PMID- 27214239 TI - Complete prewetting. AB - We study continuous interfacial transitions, analagous to two-dimensional complete wetting, associated with the first-order prewetting line, which can occur on steps, patterned walls, grooves and wedges, and which are sensitive to both the range of the intermolecular forces and interfacial fluctuation effects. These transitions compete with wetting, filling and condensation producing very rich phase diagrams even for relatively simple prototypical geometries. Using microscopic classical density functional theory to model systems with realistic Lennard-Jones fluid-fluid and fluid-substrate intermolecular potentials, we compute mean-field fluid density profiles, adsorption isotherms and phase diagrams for a variety of confining geometries. PMID- 27214240 TI - Predictive role of the overexpression for CXCR4, C-Met, and VEGF-C among breast cancer patients: A meta-analysis. AB - BACKGROUND: The overexpression of CXCR4, C-Met and VEGF-C present widely in breast tumors, they may be markers of resistance to treatment. However, the studies are still controversial. Thus, this meta-analysis aims to research the relationship between the overexpression of CXCR4, C-Met, VEGF-C and clinical prognosis among breast cancer patients. METHODS: PubMed and EMBASE databases were searched for eligible literature. The outcomes of interest were progression-free survival (PFS), relapse-free survival (RFS) and overall survival (OS). All tests of statistical significance were two sided. RESULTS: A total of 7830 patients from 28 eligible studies were assessed. The overexpression of the CXCR4 and C-Met both implied significantly worse PFS compared with normal expression [HR = 2.56, 95% CI = 1.34-4.91, P = 0.005; and HR = 1.63 95% CI = 1.20-2.22, P = 0.002]. Meanwhile, if patients had high expression of CXCR4, they would have worse OS [HR = 2.56 95% CI = 1.52-4.31, P = 0.000]. However, the overexpression of C-Met did not relate to OS for breast cancer patients [HR = 1.16, 95% CI = 0.69-1.95, P = 0.570]. Meanwhile, no statistically significant different was observed with respect to PFS and OS between VEGF-C overexpression and normal expression [HR = 0.99, 95% CI = 0.64-1.52, P = 0.968; and HR = 0.76, 95% CI = 0.43-1.33, P = 0.333]. CONCLUSIONS: Our meta-analysis showed that CXCR4 and C-Met were efficient prognostic factors for breast cancer. Nevertheless, highly expressing VEGF-C was not related to progression-free survival and overall survival. Due to the small samples and insufficient date, further studies should be conducted to clarify the association between the overexpression of CXCR4 or C-Met or VEGF-C and the prognosis about breast cancer patients. PMID- 27214241 TI - Evaluation of sentinel lymph node biopsy after previous breast surgery for breast cancer: GATA study. AB - AIM: Sentinel lymph node (SLN) biopsy was recently recommended after prior breast tumour surgery and lymphadenectomy is not the gold standard anymore for nodal staging after a lesion's removal. The purpose of our study was to evaluate the good practices of use of SLN biopsy in this context. PATIENTS AND METHODS: From 2006 to 2012, 138 patients having undergone a surgical biopsy without prior diagnosis of an invasive carcinoma with a definitive histological analysis in favour of this diagnosis were included in a prospective observational multicentric study. Each patient had a nodal staging following SLN biopsy with subsequent systematic lymphadenectomy. RESULTS: The detection rate of SLN was 85.5%. The average number of SLNs found was 1.9. The relative detection failure risk rate was multiplied by 4 in the event of an interval of less than 36 days between the SLN biopsy and the previous breast surgery, and by 9 in the event of using a single-tracer detection method. The false negative rate was 6.25%. The prevalence of metastatic axillary node involvement was 11.6%. In 69% of cases only the SLN was metastatic. The post-operative seroma rate was 19.5%. CONCLUSION: Previous conservative breast tumour surgery does not affect the accuracy of the SLN biopsy. A sufficient interval of greater than 36 days between the two operations could allow to improve the SLN detection rate, although further studies are needed to validate this statement. CLINICAL TRIAL REGISTRATION NUMBER: NCT00293865. PMID- 27214243 TI - The dynamic control ratio at the equilibrium point (DCRe): introducing relative and absolute reliability scores. AB - Analytical methods to assess thigh muscle balance need to provide reliable data to allow meaningful interpretation. However, reproducibility of the dynamic control ratio at the equilibrium point has not been evaluated yet. Therefore, the aim of this study was to compare relative and absolute reliability indices of its angle and moment values with conventional and functional hamstring-quadriceps ratios. Furthermore, effects of familiarisation and angular velocity on reproducibility were analysed. A number of 33 male volunteers participated in 3 identical test sessions. Peak moments (PMs) were determined unilaterally during maximum concentric and eccentric knee flexion (prone) and extension (supine position) at 0.53, 1.57 and 2.62 rad . s-1. A repeated measure, ANOVA, confirmed systematic bias. Intra-class correlation coefficients and standard errors of measurement indicated relative and absolute reliability. Correlation coefficients were averaged over respective factors and tested for significant differences. All balance scores showed comparable low-to-moderate relative (<0.8-0.9) and good absolute reliability (<10%). Relative reproducibility of dynamic control equilibrium parameters augmented with increasing angular velocity, but not with familiarisation. At 2.62 rad . s-1, high (moment: 0.906) to moderate (angle: 0.833) relative reliability scores with accordingly high absolute indices (4.9% and 6.4%) became apparent. Thus, the dynamic control equilibrium is an equivalent method for the reliable assessment of thigh muscle balance. PMID- 27214242 TI - Multifunctional oxidosqualene cyclases and cytochrome P450 involved in the biosynthesis of apple fruit triterpenic acids. AB - Apple (Malus * domestica) accumulates bioactive ursane-, oleanane-, and lupane type triterpenes in its fruit cuticle, but their biosynthetic pathway is still poorly understood. We used a homology-based approach to identify and functionally characterize two new oxidosqualene cyclases (MdOSC4 and MdOSC5) and one cytochrome P450 (CYP716A175). The gene expression patterns of these enzymes and of previously described oxidosqualene cyclases were further studied in 20 apple cultivars with contrasting triterpene profiles. MdOSC4 encodes a multifunctional oxidosqualene cyclase producing an oleanane-type triterpene, putatively identified as germanicol, as well as beta-amyrin and lupeol, in the proportion 82 : 14 : 4. MdOSC5 cyclizes 2,3-oxidosqualene into lupeol and beta-amyrin at a ratio of 95 : 5. CYP716A175 catalyses the C-28 oxidation of alpha-amyrin, beta amyrin, lupeol and germanicol, producing ursolic acid, oleanolic acid, betulinic acid, and putatively morolic acid. The gene expression of MdOSC1 was linked to the concentrations of ursolic and oleanolic acid, whereas the expression of MdOSC5 was correlated with the concentrations of betulinic acid and its caffeate derivatives. Two new multifuntional triterpene synthases as well as a multifunctional triterpene C-28 oxidase were identified in Malus * domestica. This study also suggests that MdOSC1 and MdOSC5 are key genes in apple fruit triterpene biosynthesis. PMID- 27214244 TI - Influence of volatile organic compounds emitted by Pseudomonas and Serratia strains on Agrobacterium tumefaciens biofilms. AB - The ability to form biofilms plays an important role in bacteria-host interactions, including plant pathogenicity. In this work, we investigated the action of volatile organic compounds (VOCs) produced by rhizospheric strains of Pseudomonas chlororaphis 449, Pseudomonas fluorescens B-4117, Serratia plymuthica IC1270, as well as Serratia proteamaculans strain 94, isolated from spoiled meat, on biofilms formation by three strains of Agrobacterium tumefaciens which are causative agents of crown-gall disease in a wide range of plants. In dual culture assays, the pool of volatiles emitted by the tested Pseudomonas and Serratia strains suppressed the formation of biofilms of A. tumefaciens strains grown on polycarbonate membrane filters and killed Agrobacterium cells in mature biofilms. The individual VOCs produced by the tested Pseudomonas strains, that is, ketones (2-nonanone, 2-heptanone, 2-undecanone), and dimethyl disulfide (DMDS) produced by Serratia strains, were shown to kill A. tumefaciens cells in mature biofilms and suppress their formation. The data obtained in this study suggest an additional potential of some ketones and DMDS as protectors of plants against A. tumefaciens strains, whose virulence is associated with the formation of biofilms on the infected plants. PMID- 27214246 TI - Association of spinal deformity and pelvic tilt with gait asymmetry in adolescent idiopathic scoliosis patients: Investigation of ground reaction force. AB - BACKGROUND: Adolescent idiopathic scoliosis is a prevalent orthopedic problem in children ages 10 to 16years. Although genetic, physiological and biomechanical factors are considered to contribute to the onset and progression of adolescent idiopathic scoliosis, the underlying mechanisms are not yet clear. The purpose of this study was to investigate the association between spinal deformity and inter leg ground reaction force asymmetry during walking in adolescent idiopathic scoliosis patients. METHODS: Fourteen patients (3 males and 11 females) participated in this study. Maximum Cobb's angle, adjusted Cobb's angle, and pelvic tilt were calculated from X-ray images. Asymmetry indices between legs were also calculated from ground reaction force magnitude and time variables from their preferred speed walking. Pearson coefficients of correlation were used to investigate associations of asymmetry indices with angle variables. FINDINGS: Asymmetry indices of ground reaction force magnitudes positively correlated with adjusted Cobb's angle and maximum Cobb's angle mainly during the peak of braking phase, average of braking phase, while asymmetry indices of ground reaction force time variables showed no significant correlation with adjusted or maximum Cobb's angle. In contrast, asymmetry indices of ground reaction force time variables positively correlated with pelvic tilt during stance phase. INTERPRETATION: We concluded that the spinal deformity of adolescent idiopathic scoliosis patients estimated using the maximum and adjusted Cobb's angles is generally associated with greater asymmetry of ground reaction force magnitudes in walking, while the pelvic tilt is associated with the greater asymmetry of ground reaction force time variables. PMID- 27214245 TI - Psychological Distress and Posttraumatic Stress Symptoms in Adolescents and Young Adults with Cancer and Their Parents. AB - PURPOSE: To investigate the prevalence and predictors of psychological distress in adolescent and young adult (AYA) cancer patients and their parent caregivers. METHODS: In a cross-sectional study design, AYA participants (n = 196) and parent caregivers (n = 204) were recruited from 18 sites across Australia. AYAs were aged 15-25 years at cancer onset and within 6-24 months of diagnosis. AYAs and parents completed a survey that includes validated measures of psychological distress (anxiety, depression, and posttraumatic stress symptoms [PTSS]). Additional measures included validated and study-specific questionnaires related to sociodemographic and medical information, social supports, cancer impacts, and life stressors. RESULTS: Nearly half the sample (48% AYAs and 42% parents) scored above a clinical cutoff score for PTSS, indicating further assessment was warranted. Nearly one third of AYAs and parents (31% AYAs and 28% parents) reported moderate to severely elevated symptoms of anxiety and depression. Factors associated with elevated AYA distress included female gender, less social support, and self-image and identity issues. For parents, living outside the metropolitan area, other life stressors, and impact on plans for the future and broader family were factors associated with increased distress. CONCLUSION: Despite numerous studies of AYA cancer survivors, very few studies have examined the psychosocial and psychological impacts of cancer when onset occurs during adolescence and young adulthood. Almost no studies have examined the impacts on their parent caregivers. The findings of this study support the need for early identification of psychological distress, appropriate developmental perspectives to understand AYA distress, and the need for family-based psychological assessment and interventions. PMID- 27214247 TI - Trunk-pelvis coordination during turning: A cross sectional study of young adults with and without a history of low back pain. AB - BACKGROUND: During steady-state locomotion, symptomatic individuals with low back pain demonstrate reduced ability to modulate coordination between the trunk and the pelvis in the axial plane. It is unclear if this is also true during functional locomotor perturbations such as changing direction, or if this change in coordination adaptability persists between symptomatic episodes. The purpose of this study was to compare trunk-pelvis coordination during walking turns in healthy individuals and asymptomatic individuals with a history of low back pain. METHODS: Participants performed multiple ipsilateral turns. Axial plane inter segmental coordination and stride-to-stride coordination variability were quantified using the vector coding technique. Frequency of coordination mode and amplitude of coordination variability was compared between groups using Wilcoxon signed-rank tests and paired t-tests respectively. FINDINGS: During stance phase of the turn, there was no significant difference in either inter-segmental coordination or coordination variability between groups. Inter-segmental coordination between the trunk and the pelvis was predominantly inphase during this part of the turn. During swing phase, patterns of coordination were more diversified, and individuals with a history of low back pain had significantly greater trunk phase coordination than healthy controls. Coordination variability was the same in both groups. INTERPRETATION: Changes in trunk-pelvis coordination are evident between symptomatic episodes in individuals with a history of low back pain. However, previously demonstrated decreases in coordination variability were not found between symptomatic episodes in individuals with recurrent low back pain and therefore may represent a response to concurrent pain rather than a persistent change in motor control. PMID- 27214248 TI - The combined effects of guidance force, bodyweight support and gait speed on muscle activity during able-bodied walking in the Lokomat. AB - BACKGROUND: The ability to provide automated movement guidance is unique for robot assisted gait trainers such as the Lokomat. For the design of training protocols for the Lokomat it is crucial to understand how movement guidance affects the patterning of muscle activity that underlies walking, and how these effects interact with settings for bodyweight support and gait speed. METHODS: Ten healthy participants walked in the Lokomat, with varying levels of guidance (0, 50 and 100%), bodyweight support (0 or 50% of participants' body weight) and gait speed (0.22, 0.5 or 0.78m/s). Surface electromyography of Erector Spinae, Gluteus Medius, Vastus Lateralis, Biceps Femoris, Medial Gastrocnemius and Tibialis Anterior were recorded. Group averaged levels of muscle activity were compared between conditions, within specific phases of the gait cycle. FINDINGS: The provision of guidance reduced the amplitude of activity in muscles associated with stability and propulsion (i.e. Erector Spinae, Gluteus Medius, Biceps Femoris and Medial Gastrocnemius) and normalized abnormally high levels of activity observed in a number of muscles (i.e. Gluteus Medius, Biceps Femoris, and Tibialis anterior). The magnitude of guidance effects depended on both speed and bodyweight support, as reductions in activity were most prominent at low speeds and high levels of bodyweight support. INTERPRETATION: The Lokomat can be effective in eliciting normal patterns of muscle activity, but only under specific settings of its training parameters. PMID- 27214249 TI - Multicolor Fluorescence Detection for Droplet Microfluidics Using Optical Fibers. AB - Fluorescence assays are the most common readouts used in droplet microfluidics due to their bright signals and fast time response. Applications such as multiplex assays, enzyme evolution, and molecular biology enhanced cell sorting require the detection of two or more colors of fluorescence. Standard multicolor detection systems that couple free space lasers to epifluorescence microscopes are bulky, expensive, and difficult to maintain. In this paper, we describe a scheme to perform multicolor detection by exciting discrete regions of a microfluidic channel with lasers coupled to optical fibers. Emitted light is collected by an optical fiber coupled to a single photodetector. Because the excitation occurs at different spatial locations, the identity of emitted light can be encoded as a temporal shift, eliminating the need for more complicated light filtering schemes. The system has been used to detect droplet populations containing four unique combinations of dyes and to detect sub-nanomolar concentrations of fluorescein. PMID- 27214250 TI - Effect of Cataract Opacity Type and Glaucoma Severity on Visual Field Index. AB - PURPOSE: To determine the effect of cataract opacity type and glaucoma severity on the visual field index (VFI). METHODS: A total of 152 eyes of 152 patients were analyzed. Patients with glaucoma, previous evaluation with the Swedish Interactive Threshold Algorithm-standard 24-2 VFs, visually significant cataracts, and VFs before surgery were included in this study. Cataract opacity was classified as cortical, nuclear sclerotic, or posterior subcapsular. The patients underwent phacoemulsification cataract extraction surgery. A postoperative VF test was done within 10 months of the previous VF. Glaucoma severity was classified by the postoperative mean deviation (MD) value. Changes in MD, pattern standard deviation (PSD), and VFI value before and after surgery were compared according to cataract opacity and glaucoma severity. RESULTS: The mean age at cataract surgery was 72 +/- 10 years. The MD, PSD, and VFI values were less influenced by nuclear sclerotic cataract opacity. In patients with early glaucoma (MD > -6), particularly with cortical cataract opacity, MD, PSD, and VFI improved after cataract extraction (p < 0.05). Cataract opacity could make interpreting the VF indices more difficult in patients with early glaucoma. VFI was a reliable index that was less affected by cataract extraction, except in patients with early glaucoma (MD > -6) and cortical cataract opacity. CONCLUSIONS: Existing cataract opacity and the type of cataract opacity may affect the VF test results. Therefore, both glaucoma severity and the type of cataract opacity should be considered when interpreting VF results. PMID- 27214252 TI - Short-Term Visual Performance of Novel Extended Depth-of-Focus Contact Lenses: Erratum. PMID- 27214251 TI - Effects of Temporal Modulation on Crowding, Visual Span, and Reading. AB - PURPOSE: Crowding, the increased difficulty in recognizing a target due to the proximity of adjacent objects, is identified as the main sensory constraint for the size of the visual span (the number of letters recognized without moving the eyes) and reading speed in peripheral vision. The goal of the present study is to assess the impact of temporal modulation on crowding, visual span, and reading in the periphery. METHODS: Six normally sighted young adults participated in the study. Four temporal modulation patterns were examined: (1) moving scotoma (sequentially masking the component letters in a letter string or word), (2) moving window (sequentially presenting the component letters), (3) flashing (repeatedly masking and presenting all letters simultaneously), and (4) static (the control condition; no temporal changes during the presentation). For each condition, we obtained the spatial extent of crowding, the size of the visual span, and reading speeds measured by the rapid serial visual presentation method. RESULTS: Compared with the static condition, the spatial extent of crowding was reduced in the moving window condition. Both the moving window and moving scotoma conditions led to a faster reading speed for print sizes smaller than critical print size (the smallest print size that allows maximum reading speed). However, none of the temporal modulations increased the size of the visual span and reading speed for print sizes larger than critical print size. CONCLUSIONS: The results suggest that the temporal modulation patterns are of limited benefit for peripheral reading despite the substantial improvement for slow reading when print size is close to acuity threshold. PMID- 27214257 TI - Antifeedant Activity of Ginkgo biloba Secondary Metabolites against Hyphantria cunea Larvae: Mechanisms and Applications. AB - Ginkgo biloba is a typical relic plant that rarely suffers from pest hazards. This study analyzed the pattern of G. biloba pest hazards in Beijing; tested the antifeedant activity of G. biloba extracts, including ginkgo flavonoids, ginkgolide, and bilobalide, against Hyphantria cunea larvae; determined the activities of glutathione transferase (GSTs), acetylcholinesterase (AChE), carboxylesterase (CarE) and mixed-functional oxidase (MFO), in larvae after feeding on these G. biloba secondary metabolites; and screened for effective botanical antifeedants in the field. In this study, no indicators of insect infestation were found for any of the examined leaves of G. biloba; all tested secondary metabolites showed significant antifeedant activity and affected the activity of the four larval detoxifying enzymes. Ginkgolide had the highest antifeedant activity and the most significant effect on the detoxifying enzymes (P<0.05). Spraying leaves with G. biloba extracts or ginkgolide both significantly repelled H. cunea larvae in the field (P<0.05), although the former is more economical and practical. This study investigated the antifeedant activity of G. biloba secondary metabolites against H. cunea larvae, and the results provide new insights into the mechanism of G. biloba pest resistance. This study also developed new applications of G. biloba secondary metabolites for effective pest control. PMID- 27214258 TI - Mavoglurant in Parkinson's patients with l-Dopa-induced dyskinesias: Two randomized phase 2 studies. AB - BACKGROUND: Two phase 2 randomized, double-blind studies were designed to evaluate efficacy and safety of immediate-release (study 1) and modified-release (study 2) mavoglurant formulations in PD l-dopa-induced dyskinesia. METHODS: Patients were randomized to mavoglurant 100-mg or placebo (4:3) groups (study 1) and mavoglurant 200-mg, mavoglurant 150-mg, or placebo (2:1:1) groups (study 2). Primary outcome was antidyskinetic efficacy, as measured by change from baseline to week 12 in modified Abnormal Involuntary Movement Scale total score. RESULTS: Differences in least-squares mean (standard error) change in modified Abnormal Involuntary Movement Scale total score in week 12 did not reach statistical significance in either study (study 1: mavoglurant 100 mg twice a day versus placebo, 1.7 [1.31]; study 2: mavoglurant 150 mg twice a day (-1.3 [1.16]) and 200 mg twice a day (-0.2 [1.03]) versus placebo). Adverse events incidence was higher with mavoglurant than with placebo. CONCLUSIONS: Both studies failed to meet the primary objective of demonstrating improvement of dyskinesia with mavoglurant treatment. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27214259 TI - Efficacy of hydrogen peroxide treatment for control of hairy root disease caused by rhizogenic agrobacteria. AB - AIMS: Rhizogenic Agrobacterium strains are the causative agent of hairy root disease (HRD), an increasing problem in the hydroponic cultivation of tomato and cucumber in Europe. A previous study has demonstrated that different lineages of rhizogenic agrobacteria are able to form biofilms. Although hydrogen peroxide (H2 O2 ) is a frequently used biocide in hydroponic systems, until now its effectiveness to remove rhizogenic agrobacteria has not been unequivocally demonstrated. Therefore, the main objective of this study was to assess the efficacy of H2 O2 in controlling Agrobacterium-containing biofilms. METHODS AND RESULTS: Using lab-scale experiments, we found a huge variation between different rhizogenic Agrobacterium strains in EC50 values, ranging from 18.8 to 600 ppm H2 O2 , representing the lowest and highest concentration tested respectively. Using pilot-scale experiments in which different H2 O2 concentrations were tested, treatment with 25 ppm H2 O2 was found to be ineffective. In contrast, treatment with 50 ppm significantly affected a catalase-negative Agrobacterium population, while a catalase-positive population was only marginally affected. For the catalase-positive Agrobacterium population, a treatment of 100 ppm H2 O2 was required to be effective. Finally, H2 O2 treatment of HRD in two commercial greenhouses was monitored, and showed that the H2 O2 concentration decreased considerably towards the end of the irrigation circuits. Further, a clear correlation was found between the actual concentration of H2 O2 and the incidence of HRD. CONCLUSION: We showed that H2 O2 may be effective to reduce biofilm formation by rhizogenic bacteria. Nevertheless, it was clear from our results that the required H2 O2 concentration depends on the particular Agrobacterium strain(s) present in the greenhouse. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study that examined the effectiveness of H2 O2 to control HRD in hydroponic systems, and the effect of catalase activity on H2 O2 effectiveness. Our study has direct relevance for the highly intensive horticultural sector. PMID- 27214260 TI - Endostatin is higher and associated with pulmonary involvement in primary Sjogren's syndrome. AB - OBJECTIVES: To investigate serum levels of endostatin in a well characterised cohort of patients with primary Sjogren's syndrome (pSS) and healthy controls (HC) and assess associations between these mediators and clinical parameters. METHODS: All patients (n=144) were recruited from the Norwegian systemic connective tissue disease and vasculitis registry (NOSVAR) and fulfilled American European classification criteria for pSS. Pulmonary involvement was based on clinical symptoms and abnormal findings on high-resolution computed tomography of the lungs. The controls were 100 healthy blood donors. Serum levels of endostatin was determined by enzyme immunoassay. RESULTS: We found higher mean levels of serum endostatin in patients with pSS compared with the controls (p<0.001). The patients with interstitial lung disease (ILD) had higher levels compared with those without pulmonary involvement. CONCLUSIONS: Our results indicate that endostatin is increased in patients with pSS and particularly in those with ILD. PMID- 27214261 TI - Effects of Hand-Rearing on Reproductive Success in Captive Large Cats Panthera tigris altaica, Uncia uncia, Acinonyx jubatus and Neofelis nebulosa. AB - Species Survival Plans and European Endangered Species Programmes have been developed for several species of endangered felids in order to build up captive reserve populations and support their conservation in the wild. The Siberian tiger (Panthera tigris altaica), snow leopard (Uncia uncia), cheetah (Acinonyx jubatus) and clouded leopard (Neofelis nebulosa) are managed in such ex situ conservation programmes. Many zoological institutions hand-rear offspring if rearing by the mother fails. Hand-rearing can cause behavioural problems, resulting in decreased copulation and lower breeding success in some species. In this study, studbook data subsets were examined: from 1901 to 2011; and 2000 to 2011. We analysed records from 4273 Siberian tigers, 2045 snow leopards, 3435 cheetahs, and 804 clouded leopards. We assessed the number of offspring produced, litter size, age at first reproduction, longevity, infant mortality and generational rearing of hand-reared versus parent-reared individuals. Hand-reared Siberian tigers (p<0.01; p = 0.0113), snow leopards (p<0.01), male cheetahs (p<0.01) and female clouded leopards (p<0.01) produced fewer offspring than parent-reared individuals. Hand-reared snow leopard breeding pairs had larger litters than parent-reared pairs (p = 0.0404). Hand-reared snow leopard females reproduced later in life (p<0.01). Hand-reared female Siberian tigers lived shorter lives, while hand-reared cheetahs lived longer (p<0.01; p = 0.0107). Infant mortality was higher in hand-reared snow leopards (p<0.01) and male cheetahs (p = 0.0395) in the 1901-2011 dataset and lower in hand-reared female Siberian tiger and male snow leopard cubs (p = 0.0404; p = 0.0349) in the 2000 2011 dataset. The rearing of the mother and subsequent rearing of offspring showed a significant relationship for all species (p<0.01 for Siberian tiger and snow leopard cubs; p<0.001 for cheetah and snow leopard cubs). Taking into account the limited carrying capacity of zoos, the results of this study highlight that careful consideration should be taken when deciding whether or not to hand-rear individuals that are part of Species Survival Plans and European Endangered Species Programmes. PMID- 27214262 TI - Synthesis and Chiroptical Properties of a Ring-Fused BODIPY with a Skewed Chiral pi Skeleton. AB - A twisted chiral boron-dipyrrin complex (BODIPY) was synthesized by oxidative annulation of the biphenyl units at the beta positions. The chiral BODIPY has two asymmetric carbons in the large planar skeleton, which were generated upon the ring-fused reaction. Its pi-elongated and twisted structure resulted in the Cotton effect in the red region (lambdamax = 614 nm, Deltaepsilon = 60 M(-1).cm( 1)) as well as the strong fluorescence (PhiF = 0.73) and circularly polarized luminescence (CPL). PMID- 27214263 TI - Substantiating Appropriate Motion Capture Techniques for the Assessment of Nordic Walking Gait and Posture in Older Adults. AB - Nordic walking (NW) has become a safe and simple form of exercise in recent years, and in studying this gait pattern, various data collection techniques have been employed, each with positives and negatives. The aim was to determine the effect of NW on older adult gait and posture and to determine optimal use of different data collection systems in both short and long duration analysis. Gait and posture during NW and normal walking were assessed in 17 healthy older adults (age: 69 +/- 7.3). Participants performed two trials of 6 Minute Walk Tests (6MWT) (1 with poles (WP) and 1 without poles (NP)) and 6 trials of a 5m walk (3 WP and 3 NP). Motion was recorded using two systems, a 6-sensor accelerometry system and an 8-camera 3-dimensional motion capture system, in order to quantify spatial-temporal, kinematic, and kinetic parameters. With both systems, participants demonstrated increased stride length and double support and decreased gait speed and cadence WP compared to NP (p <0.05). Also, with motion capture, larger single support time was found WP (p <0.05). With 3-D capture, smaller hip power generation and moments of force were found at heel contact and pre-swing as well as smaller knee power absorption at heel contact, pre-swing, and terminal swing WP compared to NP, when assessed over one cycle (p <0.05). Also, WP yielded smaller moments of force at heel contact and terminal swing along with larger moments at mid-stance of a gait cycle (p <0.05). No changes were found for posture. NW seems appropriate for promoting a normal gait pattern in older adults. Three-dimensional motion capture should primarily be used during short duration gait analysis (i.e. single gait cycle), while accelerometry systems should be primarily employed in instances requiring longer duration analysis such as during the 6MWT. PMID- 27214264 TI - Efficient Energy Transfer and Metal Coupling in Cyanide-Bridged Heterodinuclear Complexes Based on (Bipyridine)(terpyridine)ruthenium(II) and (Phenylpyridine)iridium(III) Complexes. AB - We report a series of cyanide-bridged, heterodinuclear iridium(III)-ruthenium(II) complexes with the generalized formula [Ir((R2)2-ppy)2(CN)(MU-CN)Ru(bpy)(tpy R1)]PF6 (ppy = 2-phenylpyridine, bpy = 2,2'-bipyridine, and tpy = 2,2':6',2" terpyridine). The structural, spectroscopic, and electrochemical properties were analyzed in the context of variation of the electron-withdrawing (e.g., -F, -Br, CHO) and -donating (e.g., -Me) and extended pi-conjugated groups at several positions. In total, ten dinuclear complexes and the appropriate model complexes have been prepared. The iridium(III)-based emission is almost fully quenched in these complexes, and only the ruthenium(II)-based emission is observed, which indicates an efficient energy transfer toward the Ru center. Upon oxidation of the Ru center, the fluorinated complexes 2 exhibit a broad intervalence charge transfer transition in the near-infrared region. The complexes are assigned to a weakly coupled class II system according to the Robin-Day classification. The electronic structure was evaluated by density functional theory (DFT) and time dependent DFT calculations to corroborate the experimental data. PMID- 27214265 TI - Posttransplant Lymphoproliferative Disorders in Irish Renal Transplant Recipients: Insights From a National Observational Study. AB - BACKGROUND: Posttransplant lymphoproliferative disorders (PTLD) are a common malignancy after renal transplantation with a high incidence of PTLD described in the first posttransplant year. We sought to determine incidence and risk determinants of PTLD in Irish kidney transplant recipients. METHODS: Retrospective observational study of 1996 adult first kidney transplant recipients between 1991 and 2010 in the Republic of Ireland. Recipients were cross-referenced with the National Cancer Registry to determine incidence of PTLD. Kaplan-Meier analysis was performed for PTLD-free survival, allograft survival, and patient survival after PTLD. Cox proportional hazards models were used to identify independent risk factors for PTLD in our population. RESULTS: We identified 31 cases of PTLD during the study period. Histological subgroups included: early lesions (n = 1); polymorphic PTLD (n = 1); monomorphic PTLD (n = 27), Hodgkin disease (n = 2). Median time to PTLD diagnosis was 8.3 (range, 1.2 13.9) years. Cumulative incidence (95% CI) of PTLD at 1, 2, 3, 5, 10, and 15 years was 0%, 0.16% (0.05-0.5%), 0.21% (0.08-0.57%), 0.21% (0.08-0.57%), 1.76% (1.15-2.69%), and 3.07% (2.1-4.43%), respectively. Allograft survival after PTLD diagnosis was 94.4% (66.6-99.2%) at 5 years. Patient survival after PTLD diagnosis was 64% at 1 year, 53% at 2 years, 48% at 5 years, and 37% at 10 years. No risk factors for PTLD were identified. CONCLUSIONS: We found a paucity of early onset PTLD in our cohort with no cases in the first posttransplant year. Potential contributing factors included a high prevalence of previous Epstein Barr virus exposure and a relatively low immunological risk profile in our recipient cohort compared with prior studies. Further studies are required to reevaluate the epidemiology of PTLD in the modern era of transplant immunosuppression. PMID- 27214266 TI - Transparent Electronic Health Records and Lagging Laws. PMID- 27214267 TI - Blocking Oxidation Failures of Carbon Nanotubes through Selective Protection of Defects. AB - The selective growth of Al2 O3 islands over defect sites on the surface of carbon nanotubes significantly increases the oxidation breakdown threshold to 6.8 W cm( 2) , more than double than that of unprotected films. The elevated input power enables thermoacoustic emissions at loud audible sound pressure levels of 90.1 dB, which are inaccessible with the unprotected films. PMID- 27214268 TI - Direct Measurements of Quantum Kinetic Energy Tensor in Stable and Metastable Water near the Triple Point: An Experimental Benchmark. AB - This study presents the first direct and quantitative measurement of the nuclear momentum distribution anisotropy and the quantum kinetic energy tensor in stable and metastable (supercooled) water near its triple point, using deep inelastic neutron scattering (DINS). From the experimental spectra, accurate line shapes of the hydrogen momentum distributions are derived using an anisotropic Gaussian and a model-independent framework. The experimental results, benchmarked with those obtained for the solid phase, provide the state of the art directional values of the hydrogen mean kinetic energy in metastable water. The determinations of the direction kinetic energies in the supercooled phase, provide accurate and quantitative measurements of these dynamical observables in metastable and stable phases, that is, key insight in the physical mechanisms of the hydrogen quantum state in both disordered and polycrystalline systems. The remarkable findings of this study establish novel insight into further expand the capacity and accuracy of DINS investigations of the nuclear quantum effects in water and represent reference experimental values for theoretical investigations. PMID- 27214269 TI - A Microfluidic Model of Biomimetically Breathing Pulmonary Acinar Airways. AB - Quantifying respiratory flow characteristics in the pulmonary acinar depths and how they influence inhaled aerosol transport is critical towards optimizing drug inhalation techniques as well as predicting deposition patterns of potentially toxic airborne particles in the pulmonary alveoli. Here, soft-lithography techniques are used to fabricate complex acinar-like airway structures at the truthful anatomical length-scales that reproduce physiological acinar flow phenomena in an optically accessible system. The microfluidic device features 5 generations of bifurcating alveolated ducts with periodically expanding and contracting walls. Wall actuation is achieved by altering the pressure inside water-filled chambers surrounding the thin PDMS acinar channel walls both from the sides and the top of the device. In contrast to common multilayer microfluidic devices, where the stacking of several PDMS molds is required, a simple method is presented to fabricate the top chamber by embedding the barrel section of a syringe into the PDMS mold. This novel microfluidic setup delivers physiological breathing motions which in turn give rise to characteristic acinar air-flows. In the current study, micro particle image velocimetry (uPIV) with liquid suspended particles was used to quantify such air flows based on hydrodynamic similarity matching. The good agreement between uPIV results and expected acinar flow phenomena suggest that the microfluidic platform may serve in the near future as an attractive in vitro tool to investigate directly airborne representative particle transport and deposition in the acinar regions of the lungs. PMID- 27214270 TI - Theoretical vibrational spectroscopy of intermediates and the reaction mechanism of the guanosine triphosphate hydrolysis by the protein complex Ras-GAP. AB - The structures and vibrational spectra of the reacting species upon guanosine triphosphate (GTP) hydrolysis to guanosine diphosphate and inorganic phosphate (Pi) trapped inside the protein complex Ras-GAP were analyzed following the results of QM/MM simulations. The frequencies of the phosphate vibrations referring to the reactants and to Pi were compared to those observed in the experimental FTIR studies. A good correlation between the theoretical and experimental vibrational data provides a strong support to the reaction mechanism of GTP hydrolysis by the Ras-GAP enzyme system revealed by the recent QM/MM modeling. Evolution of the vibrational bands associated with the inorganic phosphate Pi during the elementary stages of GTP hydrolysis is predicted. PMID- 27214271 TI - Spectroscopic analysis of Ahlat stone (ignimbrite) and pumice formed by volcanic activity. AB - Natural materials such as ignimbrites are preferred commonly not only in historical places but also in houses or in different kind of buildings all over the world especially around Ahlat in Bitlis-Turkey. Durability, lightness and good-insulation are the significative properties of these stones. Also, pumice is an another preferred material because of its advantages in construction industry. In this paper, four kinds of ignimbrite (light-yellow, yellow, black and white) and pumice from Ahlat region have been investigated by EPR method to determine magnetic properties of them. The results obtained by EPR, EDS and XRD methods are evaluated together. SEM technique is also used to understand the surface morphology of the samples. PMID- 27214272 TI - The detection for hypochlorite by UV-Vis and fluorescent spectra based on oxidized ring opening and successive hydrolysis reaction. AB - In this work, two high selective and sensitive fluorescent probes for ClO(-), 7 Hydroxycoumarin and 4-Hydroxycoumarin were designed. The reaction mechanism that we speculated was the oxidized ring opening reaction and hydrolysis. The detection could be realized in quasi-aqueous phase and the detection limits of probe [7] and probe [4] for ClO(-) were found to be 56.8nM and 70.5nM. Furthermore, the probes can be used to cell imagings. PMID- 27214273 TI - Binding affinities of Schiff base Fe(II) complex with BSA and calf-thymus DNA: Spectroscopic investigations and molecular docking analysis. AB - The binding interaction of a synthesized Schiff base Fe(II) complex with biological macromolecules viz., bovine serum albumin (BSA) and calf thymus(ct) DNA have been investigated using different spectroscopic techniques coupled with viscosity measurements at physiological pH and 298K. Regular amendments in emission intensities of BSA upon the action of the complex indicate significant interaction between them, and the binding interaction have been characterized by Stern Volmer plots and thermodynamic binding parameters. On the basis of this quenching technique one binding site with binding constant (Kb=(7.6+/ 0.21)*10(5)) between complex and protein have been obtained at 298K. Time resolved fluorescence studies have also been encountered to understand the mechanism of quenching induced by the complex. Binding affinities of the complex to the fluorophores of BSA namely tryptophan (Trp) and tyrosine (Tyr) have been judged by synchronous fluorescence studies. Secondary structural changes of BSA rooted by the complex has been revealed by CD spectra. On the other hand, hypochromicity of absorption spectra of the complex with the addition of ct-DNA and the gradual reduction in emission intensities of ethidium bromide bound ct DNA in presence of the complex indicate noticeable interaction between ct-DNA and the complex with the binding constant (4.2+/-0.11)*10(6)M(-1). Life-time measurements have been studied to determine the relative amplitude of binding of the complex to ct-DNA base pairs. Mode of binding interaction of the complex with ct-DNA has been deciphered by viscosity measurements. CD spectra have also been used to understand the changes in ct-DNA structure upon binding with the metal complex. Density functional theory (DFT) and molecular docking analysis have been employed in highlighting the interactive phenomenon and binding location of the complex with the macromolecules. PMID- 27214274 TI - Hydride generation-resonance Rayleigh scattering and SERS spectral determination of trace Bi. AB - In acidic solutions, Bi(III) was reduced by NaBH4 to form BiH3 gas. Using I3( )graphene oxide (GO) as absorption solution, the BiH3 gas reacted with I3(-) to form I(-) that resulted in the I3(-) concentration decreasing. In the absence of BiH3, the I3(-) concentration was high, and as receptors it was closed to the surfaces of GO which was as donors. Then the surface plasmon resonance Rayleigh scattering (RRS) energy of GO transfers to I3(-) heavily, and results in the RRS quenching severely. With the increase of the Bi(III) concentration, the receptors and the RRS energy transfer (RRS-ET) decreased, so the RRS intensity enhanced linearly at 370nm. The RRS intensity was linear to the Bi(III) concentration in 0.05-5.5MUmol/L, with a detection limit of 4ng/mL Bi. A new RRS-ET spectral method was developed for the determination of trace Bi(III). Using I3(-) as the absorption solution, silver nanorod (AgNR) as sol substrate and Vitoria blue B (VBB) as molecular probe, a SERS method was developed for detection of Bi. PMID- 27214275 TI - Relationship between left coronary artery bifurcation angle and restenosis after stenting of the proximal left anterior descending artery. AB - INTRODUCTION: Restenosis after a percutaneous coronary intervention for proximal left anterior descending (pLAD) coronary artery disease remains a clinical challenge. However, the relationship between the left main trunk (LMT)/LAD bifurcation angle and the pLAD artery restenosis is unclear. This study examined the relationship between the LMT-LAD bifurcation angle and restenosis after stent implantation for pLAD disease. METHODS: We analysed the data of 177 consecutive patients who underwent stent implantation for pLAD disease, followed by coronary angiography between December 2008 and September 2013. The LMT-LAD bifurcation angle was measured in the left or the right anterior oblique caudal (CAU) angiographic view. RESULTS AND DISCUSSION: Out of 177 patients, 12 developed in stent restenosis and 21 developed in-segment restenosis. The mean angle in patients with in-stent restenosis (52.2 degrees +/-14.5 degrees ) in the left anterior oblique CAU view was significantly larger than that in patients without restenosis (32.0 degrees +/-18.1 degrees ; P<0.001). The LMT-LAD angle in the right anterior oblique CAU view was significantly larger in patients with in segment restenosis (27.3 degrees +/-14.3 degrees ) than in patients without restenosis (17.5 degrees +/-10.1 degrees ; P<0.001). Moreover, by multivariate analysis, the LMT-LAD angle was an independent predictor of in-stent and in segment restenosis, after adjustment for significant confounders such as diabetes, hypertension, dyslipidaemia, final minimum lesion diameter and lesion length. CONCLUSION: This study suggests that a wide LMT-LAD angle is a predictor of restenosis after stent implantation for pLAD artery disease. PMID- 27214276 TI - Retained wire with intra-aortic migration presenting with hemoptysis: case studies of the Massachusetts General Hospital. PMID- 27214277 TI - Sensory quality and chemical composition of meat from lambs fed diets enriched with fish and rapeseed oils, carnosic acid and seleno-compounds. AB - The aim of the study was to evaluate longissimus muscle quality in lambs fed diets including fish oil (FO), rapeseed oil (RO), carnosic acid (CA) and seleno compounds. Lambs were fed one of diets: Group I - the basal diet (BD) with 3% RO; Group II - BD with 2% RO and 1% FO; Group III - BD with 2% RO, 1% FO and 0.1% CA; Group IV - BD with 2% RO, 1% FO, 0.1% CA and 0.35ppm Se as selenized-yeast; Group V - BD with 2% RO, 1% FO, 0.1% CA and 0.35ppm Se as selenate. The addition of FO and FO, CA and selenium in the inorganic form was characterized by lowest tenderness and juiciness (P<0.05). The lowest concentration of fatty acids (SigmaFAs), atherogenic-FAs (A(SFA)) and thrombogenic-FAs (T(SFA)) in the muscle was found for Group V (P<0.05). Experimental diets decreased indexes of A(SFA) and T(SFA) in muscle. The lowest ratio (P<0.05) of n-6polyunsaturated-FAs to n 3polyunsaturated-FAs was obtained for Group III. PMID- 27214278 TI - Effect of fresh pork meat conditioning on quality characteristics of salami. AB - The aim of this work was to evaluate the effect of pork meat conditioning under different relative humidity (RH) values on salami quality characteristics. During a 6days conditioning period at 0 degrees C under two levels of RH (95% vs. 80%), meat pH and weight loss were measured. Salami characteristics (moisture, weight loss, texture, appearance properties) were evaluated during 20days of ripening. Results showed that conditioning at 80% RH yielded a significantly drier meat, being the weight loss rate 1.6 times higher than at 95% RH. The lower water content of meat allowed a shorter salami ripening phase, guaranteeing an appropriate weight loss and the development of the desired texture, while maintaining good appearance properties. The acceleration of this production phase represents a clear economic advantage for producers and consumers, leading to higher profit margins and lower retail prices. The possibility of using FT-NIR spectroscopy as a valid tool for the rapid evaluation of salami ripening was also demonstrated. PMID- 27214279 TI - Primary-cilium-dependent autophagy controls epithelial cell volume in response to fluid flow. AB - Autophagy is an adaptation mechanism that is vital for cellular homeostasis in response to various stress conditions. Previous reports indicate that there is a functional interaction between the primary cilium (PC) and autophagy. The PC, a microtubule-based structure present at the surface of numerous cell types, is a mechanical sensor. Here we show that autophagy induced by fluid flow regulates kidney epithelial cell volume in vitro and in vivo. PC ablation blocked autophagy induction and cell-volume regulation. In addition, inhibition of autophagy in ciliated cells impaired the flow-dependent regulation of cell volume. PC dependent autophagy can be triggered either by mTOR inhibition or a mechanism dependent on the polycystin 2 channel. Only the LKB1-AMPK-mTOR signalling pathway was required for the flow-dependent regulation of cell volume by autophagy. These findings suggest that therapies regulating autophagy should be considered in developing treatments for PC-related diseases. PMID- 27214280 TI - The metabolic co-regulator PGC1alpha suppresses prostate cancer metastasis. AB - Cellular transformation and cancer progression is accompanied by changes in the metabolic landscape. Master co-regulators of metabolism orchestrate the modulation of multiple metabolic pathways through transcriptional programs, and hence constitute a probabilistically parsimonious mechanism for general metabolic rewiring. Here we show that the transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC1alpha) suppresses prostate cancer progression and metastasis. A metabolic co-regulator data mining analysis unveiled that PGC1alpha is downregulated in prostate cancer and associated with disease progression. Using genetically engineered mouse models and xenografts, we demonstrated that PGC1alpha opposes prostate cancer progression and metastasis. Mechanistically, the use of integrative metabolomics and transcriptomics revealed that PGC1alpha activates an oestrogen-related receptor alpha (ERRalpha)-dependent transcriptional program to elicit a catabolic state and metastasis suppression. Importantly, a signature based on the PGC1alpha ERRalpha pathway exhibited prognostic potential in prostate cancer, thus uncovering the relevance of monitoring and manipulating this pathway for prostate cancer stratification and treatment. PMID- 27214281 TI - The polycystin complex mediates Wnt/Ca(2+) signalling. AB - WNT ligands induce Ca(2+) signalling on target cells. PKD1 (polycystin 1) is considered an orphan, atypical G-protein-coupled receptor complexed with TRPP2 (polycystin 2 or PKD2), a Ca(2+)-permeable ion channel. Inactivating mutations in their genes cause autosomal dominant polycystic kidney disease (ADPKD), one of the most common genetic diseases. Here, we show that WNTs bind to the extracellular domain of PKD1 and induce whole-cell currents and Ca(2+) influx dependent on TRPP2. Pathogenic PKD1 or PKD2 mutations that abrogate complex formation, compromise cell surface expression of PKD1, or reduce TRPP2 channel activity suppress activation by WNTs. Pkd2(-/-) fibroblasts lack WNT-induced Ca(2+) currents and are unable to polarize during directed cell migration. In Xenopus embryos, pkd1, Dishevelled 2 (dvl2) and wnt9a act within the same pathway to preserve normal tubulogenesis. These data define PKD1 as a WNT (co)receptor and implicate defective WNT/Ca(2+) signalling as one of the causes of ADPKD. PMID- 27214282 TI - Fluoroquinolone-Resistant Sequence Type 131 Subgroups O25b and O16 Among Extraintestinal Escherichia coli Isolates from Community-Acquired Urinary Tract Infections. AB - The multidrug-resistant sequence type 131 (ST131) Escherichia coli is a spreading epidemiological burden particularly among isolates resistant to fluoroquinolones. We aimed to evaluate the commonality of ST131-O25b and ST131-O16 among fluoroquinolone-resistant E. coli isolates causing community-acquired urinary tract infections (UTIs) at Fayoum University Hospital, in Egypt. Ninety-two fluoroquinolone-resistant E. coli isolates were subjected to multiplex PCR for detection of ST131 of either O25b or O16 subgroups. Positive isolates were then assessed for antimicrobial susceptibility and virulence genotyping. Out of 92 fluoroquinolone-resistant E. coli isolates, 56 (60.9%) isolates were O25b/O16 subgroups of ST131, including 44 (78.6%) ST131-O25b and 12 (21.4%) ST131-O16 subgroups. All the O25b/O16 ST131 isolates were sensitive to meropenem, where ST131-O25b isolates were significantly more resistant to extended spectrum cephalosporins compared to S131-O16 strains. All the O25b/O16 ST131 isolates harbored three or more of the virulence factors associated with extraintestinal pathogenic E. coli status. ST131-O16 showed a significantly higher virulence score than ST131-O25b isolates. Our results bring to highlight the emergence of O25b/O16 ST131 isolates between community acquired UTIs among Egyptian patients. This is the first report for the presence of O16 isolates in Egypt, showing a lower predominance than the O25b subgroup. The high prevalence of O25b/O16 ST131 isolates requires strict stewardship on antimicrobial use, notably fluoroquinolones, to control the endemicity of such emerging multidrug-resistant clone in the community. PMID- 27214283 TI - Variation in airborne 134Cs, 137Cs, particulate 131I and 7Be maximum activities at high-altitude European locations after the arrival of Fukushima-labeled air masses. AB - The Fukushima-labeled air mass arrival, and later the cesium-134 (134Cs), cesium 137 (137Cs) and particulate iodine-131 (hereafter noted 131Ip) maximum levels were registered in Europe at different dates depending on the location. Most of those data were obtained at low-altitude sampling areas. Here, we compare the airborne levels registered at different high-altitude European locations (from 850 m to about 3500 m). The integrated 137Cs activity concentration was not uniform with regard to the altitude even after a long travel time/distance from Japan. Moreover, the relation of integrated 137Cs vs. altitude showed a linear decrease up to an altitude of about 3000 m. A similar trend was noticed for 131Ip (particulate fraction) while it increased above 3000 m. Comparison with 7Be activity concentration showed that, as far as the high altitude location is concerned, the 137Cs and 134Cs maximum concentrations corresponded to the 7Be maximum, suggesting downdraft movements from high tropospheric or stratospheric layers to be responsible for 137,134Cs increase and peak values. This was also confirmed by high potential vorticity and low relative humidity registered during the peak values. PMID- 27214284 TI - Outdoor thoron and progeny in a thorium rich area with old decommissioned mines and waste rock. AB - Radon (222Rn), thoron (220Rn) and their decay products may reach high levels in areas of high natural background radiation, with increased risk associated with mining areas. Historically, the focus has mostly been placed upon radon and progeny (RnP), but recently there have been reports of significant contributions to dose from thoron progeny (TnP). However, few direct measurements of TnP exist under outdoor conditions. Therefore, we assessed the outdoor activity concentrations of radon, thoron and TnP in an area of igneous bedrock with extreme levels of radionuclides in the thorium decay series. The area is characterized by decommissioned mines and waste rock deposits, which provide a large surface area for radon and thoron emanation and high porosity enhancing exhalation. Extreme levels of thorium and thoron have previously been reported from this area and to improve dose rate estimates we also measured TnP using filter sampling and time-integrating alpha track detectors. We found high to extreme levels of thoron and TnP and the associated dose rates relevant for inhalation were up to 8 MUSvh-1 at 100 cm height. Taking gamma irradiation and RnP into account, significant combined doses may result from occupancies in this area. This applies to recreational use of the area and especially previous and planned road-works, which in the worst case could involve doses as large as 23.4 mSv y-1. However, radon and thoron levels were much more intense on a hot September day than during time-integrated measurements made the subsequent colder and wetter month, especially along the ground. This may be explained by cold air observed flowing out from inside the mines through a drainage pipe adjacent to the measurement stations. During warm periods, activity concentrations may therefore be due to both local exhalation from the ground and air ventilating from the mines. However, a substantially lower level of TnP was measured on the September day using filter sampling, as compared to what was measured with time integrative alpha track detectors. A possible explanation could be reduced filter efficiency related to the attached progeny of some aerosol sizes, but a more likely cause is an upwards bias on TnP detectors associated with assumed deposition velocity, which may be different in outdoor conditions with wind or a larger fraction of unattached progeny. There is thus a need for better instrumentation when dealing with outdoor TnP. PMID- 27214285 TI - Migration of the FDNPP-derived 134Cs and 137Cs along with 226Ra and 228Ra concentrations across the northwestern North Pacific Ocean. AB - We examined lateral distributions of 134Cs, 137Cs, 226Ra, and 228Ra in the surface seawaters around the Kuril Islands and the Kamchatka Peninsula in the northwestern North Pacific Ocean during June 2014. The sampling area included three water current areas, the Oyashio Current, the current from the Okhotsk Sea, and the coastal current along the east Kamchatka Peninsula. 226Ra and 228Ra distributions differed along the three currents. Low levels of 134Cs were detected in the surface waters of the Oyashio Current (0.09-0.35 mBq/L), but it was <~0.1 mBq/L at the surface along the other two currents. This indicates that the distribution of Fukushima Dai-ichi Nuclear Power Plant (FDNPP)-derived radiocesium in surface waters off the Kamchatka and along the Kuril Islands is predominantly governed by the Oyashio current system. PMID- 27214286 TI - The study of natural and artificial radionuclides incorporation in teeth and head bones of animals lived nearby Caetite uranium mine, Brazil. AB - This study aimed at assessing the incorporation of radionuclides in animals in the proximity of the uranium mine in Caetite, Brazil. In 2014, samples of bovine and equine teeth and skull bones were collected and their contents of natural and artificial isotopes were assessed using nuclear spectrometry techniques. Gamma ray emission from 226,228Ra and 40K isotopes was determined using high-purity germanium (HPGe) spectrometry, 90Sr radioactivity was measured with liquid scintillation, and 234,238U, 232,230,228Th, 210Po and 239+240Pu radioactivity was assessed with alpha-spectrometry. Prior to the measurements, sample dissolutions and isotope separations were performed. Our results indicate a high 228Th isotope content in the skull bones and the teeth of animals, up to 179 Bq per kg of ash. The 226Ra and 228Ra concentrations were slightly lower. Activity concentrations of other isotopes were significantly lower or below the detection limit. We could not identify sources of technologically enhanced levels of 228Ra in the area we investigated; therefore we suggest that their origin is natural. PMID- 27214287 TI - Modelling Deposition and Erosion rates with RadioNuclides (MODERN) - Part 1: A new conversion model to derive soil redistribution rates from inventories of fallout radionuclides. AB - The measurement of fallout radionuclides (FRN) has become one of the most commonly used tools to quantify sediment erosion or depositional processes. The conversion of FRN inventories into soil erosion and deposition rates is done with a variety of models, which suitability is dependent on the selected FRN, soil cultivation (ploughed or unploughed) and movement (erosion or deposition). The authors propose a new conversion model, which can be easily and comprehensively used for different FRN, land uses and soil redistribution processes. The new model MODERN (Modelling Deposition and Erosion rates with RadioNuclides) considers the precise depth distribution of any FRN at the reference site, and allows adapting it for any specific site conditions. MODERN adaptability and performance in converting different FRN inventories is discussed for a theoretical case as well as for two already published case studies i.e. a 137Cs study in an alpine and unploughed area in the Aosta valley (Italy) and a 210Pbex study on a ploughed area located in the Transylvanian Plain (Romania). The tests highlight a highly significant correspondence (i.e. correlation factor of 0.91) between the results of MODERN and the published results of other models currently used by the FRN scientific community (i.e. the Profile Distribution Model and the Mass Balance Model). The development and the cost free accessibility of MODERN (see modern.umweltgeo.unibas.ch) will ensure the promotion of wider application of FRNs for tracing soil erosion and sedimentation. PMID- 27214288 TI - Measurement of tritium in the Sava and Danube Rivers. AB - Two nuclear power plants (NPP), the KrskoNPP (Slovenia) on the Sava River and the Paks NPP (Hungary) on the Danube River, are located in the immediate vicinity of Croatia and Serbia. Some of the radioactivity monitoring around the NPPs involves measuring tritium activity in the waters of rivers and wells. The authors present the tritium measurement results taken over several years from the Sava and Danube Rivers, and groundwater. The measurements were carried out in two laboratories including an impact assessment of the tritium released into the rivers and groundwater. The routine methods for determining tritium (with/without electrolytic enrichment) were tested in two laboratories using two different instruments, a Tri-Carb 3180 and Quantulus 1220. Detection limits for routine measurements were calculated in compliance with ISO 11929 and Currie relations, and subsequently the results were compared with those determined experimentally. This has shown that tritium can be reliably determined within a reasonable period of time when its activity is close to the calculated detection limit. The Krsko NPP discharged 62 TBq of tritium into the River Sava over a period of 6 years (23% of permitted activity, 45 TBq per year). The natural level of tritium in the Sava River and groundwater is 0.3-1 Bq/l and increases when discharges exceed 1 TBq per month. Usually, the average monthly activity in the Sava River and groundwater is maintained at a natural level. The maximum measured activity was 16 Bq/l in the Sava River and 9.5 Bq/l in groundwater directly linked to the river. In the majority of water samples from the Danube River, measured tritium activity ranged between 1 and 2 Bq/l. The increased tritium levels in the Danube River are more evident than in the Sava River because tritium activity above 1.5 Bq/l appears more frequently on the Danube River. All measured values were far below the allowed tritium limit in drinking water. Dose assessment has shown that tritium released from NPPs contributes negligibly to annual doses in comparison to natural sources. PMID- 27214291 TI - Materials design for new superconductors. AB - Since the announcement in 2011 of the Materials Genome Initiative by the Obama administration, much attention has been given to the subject of materials design to accelerate the discovery of new materials that could have technological implications. Although having its biggest impact for more applied materials like batteries, there is increasing interest in applying these ideas to predict new superconductors. This is obviously a challenge, given that superconductivity is a many body phenomenon, with whole classes of known superconductors lacking a quantitative theory. Given this caveat, various efforts to formulate materials design principles for superconductors are reviewed here, with a focus on surveying the periodic table in an attempt to identify cuprate analogues. PMID- 27214290 TI - Paracelsus Revisited: The Dose Concept in a Complex World. AB - At the time that Paracelsus coined his famous dictum, 'What is there that is not poison? All things are poison and nothing is without poison. Solely the dose determines that a thing is not a poison', embryonic toxicology was a fairly focused discipline that mainly dealt with occupational poisonings and side effects of pharmaceuticals, such as mercury. While Paracelsus paved the way for the modern threshold concept and the no-adverse effect level, modern-day toxicology is now tussling with highly complex issues, such as developmental exposures, genetic predisposition and other sources of hypersusceptibility, multiple causes of underestimated toxicity, and the continuous presence of uncertainty, even in regard to otherwise well-studied mercury compounds. Further, the wealth of industrial chemicals now challenges the 'untested-chemical assumption', that the lack of documentation means that toxic potentials can be ignored. Unfortunately, in its ambition to provide solid evidence, toxicology has been pushed into almost endless replications, as evidenced by the thousands of toxicology publications every year that focus on toxic metals, including mercury, while less well-known hazards are ignored. From a public health viewpoint, toxicology needs to provide better guidance on decision-making under ever-present uncertainty. In this role, we need to learn from the stalwart Paracelsus the insistence on relying on facts rather than authority alone to protect against chemical hazards. PMID- 27214289 TI - Muscle Biopsy Findings in Combination With Myositis-Specific Autoantibodies Aid Prediction of Outcomes in Juvenile Dermatomyositis. AB - OBJECTIVE: Juvenile dermatomyositis (DM) is a rare and severe autoimmune condition characterized by rash and proximal muscle weakness. While some patients respond to standard treatment, others do not. This study was carried out to investigate whether histopathologic findings and myositis-specific autoantibodies (MSAs) have prognostic significance in juvenile DM. METHODS: Muscle biopsy samples (n = 101) from patients in the UK Juvenile Dermatomyositis Cohort and Biomarker Study were stained, analyzed, and scored for severity of histopathologic features. In addition, autoantibodies were measured in the serum or plasma of patients (n = 90) and longitudinal clinical data were collected (median duration of follow-up 4.9 years). Long-term treatment status (on or off medication over time) was modeled using generalized estimating equations. RESULTS: Muscle biopsy scores differed according to MSA subgroup. When the effects of MSA subgroup were accounted for, increased severity of muscle histopathologic features was predictive of an increased risk of remaining on treatment over time: for the global pathology score (histopathologist's visual analog scale [hVAS] score), 1.48-fold higher odds (95% confidence interval [95% CI] 1.12-1.96; P = 0.0058), and for the total biopsy score (determined with the standardized score tool), 1.10-fold higher odds (95% CI 1.01-1.21; P = 0.038). A protective effect was identified in patients with anti-Mi-2 autoantibodies, in whom the odds of remaining on treatment were 7.06-fold lower (95% CI 1.41-35.36; P = 0.018) despite muscle biopsy scores indicating more severe disease. In patients with anti-nuclear matrix protein 2 autoantibodies, anti-transcription intermediary factor 1gamma autoantibodies, or no detectable autoantibody, increased histopathologic severity alone, without adjustment for the effect of MSA subtype, was predictive of the risk of remaining on treatment: for the hVAS global pathology score, 1.61-fold higher odds (95% CI 1.16-2.22; P = 0.004), and for the total biopsy score, 1.13-fold higher odds (95% CI 1.03-1.24; P = 0.013). CONCLUSION: Histopathologic severity, in combination with MSA subtype, is predictive of the risk of remaining on treatment in patients with juvenile DM and may be useful for discussing probable treatment length with parents and patients. Understanding these associations may identify patients at greater risk of severe disease. PMID- 27214292 TI - Destruction of Bacillus cereus spores in a thick soy bean paste (doenjang) by continuous ohmic heating with five sequential electrodes. AB - This study selected spores from Bacillus cereus FSP-2 strain (the isolate from a commercial doenjang processing line) as the test strain which showed significantly higher thermal resistance (P < 0.05) than B. cereus reference strain (ATCC 27348). The spores in doenjang were subjected to ohmic heating (OH) at 95, 105, 115 and 125 degrees C for 30, 60 or 90 s using a five sequential electrode system (electrical field: 26.7 V cm(-1) ; alternating current frequency: 25 kHz). OH at 105 degrees C for 30-90 s reduced the B. cereus spore count in doenjang samples to <4 log CFU g(-1) . Since OH treatment at 115 and 125 degrees C caused a perceivable colour change in the product (>1.5 National Bureau of Standards units), treatment at 105 degrees C for 60 s was selected and applied on a large scale (500 kg of product). Reliable and reproducible destruction of B. cereus spores occurred; the reductions achieved (to < 4 log CFU g(-1) ) met the Korean national standards. Scanning electron microscopy revealed microstructural alterations in the spores (shrinkage and a distorted outer spore coat). OH is an effective method for destroying B. cereus spores to ensure the microbiological quality and safety of a thick, highly viscous sauce. SIGNIFICANCE AND IMPACT OF THE STUDY: This study shows that an ohmic heating (OH) using a five sequential electrode system can effectively destroy highly heat-resistant Bacillus cereus spores which have been frequently found in a commercial doenjang processing line without perceivable quality change in the product. In addition, it may demonstrate high potential of the unique OH system used in this study that will further contribute to ensure microbiological quality and safety of crude sauces containing high levels of electrolyte other than doenjang as well. PMID- 27214293 TI - Formation of Hierarchical Structure Composed of (Co/Ni)Mn-LDH Nanosheets on MWCNT Backbones for Efficient Electrocatalytic Water Oxidation. AB - Active, stable, and cost-effective electrocatalysts are attractive alternatives to the noble metal oxides that have been used in water splitting. The direct nucleation and growth of electrochemically active LDH materials on chemically modified MWCNTs exhibit considerable electrocatalytic activity toward oxygen evolution from water oxidation. CoMn-based and NiMn-based hybrids were synthesized using a facile chemical bath deposition method and the as-synthesized materials exhibited three-dimensional hierarchical configurations with tunable Co/Mn and Ni/Mn ratio. Benefiting from enhanced electrical conductivity with MWCNT backbones and LDH lamellar structure, the Co5Mn-LDH/MWCNT and Ni5Mn LDH/MWCNT could generated a current density of 10 mA cm(-2) at overpotentials of ~300 and ~350 mV, respectively, in 1 M KOH. In addition, the materials also exhibited outstanding long-term electrocatalytic stability. PMID- 27214294 TI - A Novel Metallo-beta-Lactamase Involved in the Ampicillin Resistance of Streptococcus pneumoniae ATCC 49136 Strain. AB - Streptococcus pneumoniae, a penicillin-sensitive bacterium, is recognized as a major cause of pneumonia and is treated clinically with penicillin-based antibiotics. The rapid increase in resistance to penicillin and other antibiotics affects 450 million people globally and results in 4 million deaths every year. To unveil the mechanism of resistance of S. pneumoniae is thus an important issue to treat streptococcal disease that might consequently save millions of lives around the world. In this work, we isolated a streptococci-conserved L-ascorbate 6-phosphate lactonase, from S. pneumoniae ATCC 49136. This protein reveals a metallo-beta-lactamase activity in vitro, which is able to deactivate an ampicillin-based antibiotic by hydrolyzing the amide bond of the beta-lactam ring. The Michaelis parameter (Km) = 25 MUM and turnover number (kcat) = 2 s(-1) were obtained when nitrocefin was utilized as an optically measurable substrate. Through confocal images and western blot analyses with a specific antibody, the indigenous protein was recognized in S. pneumoniae ATCC 49136. The protein overexpressed S. pneumonia exhibits a high ampicillin-tolerance ability in vivo. In contrast, the protein-knockout S. pneumonia reveals the ampicillin-sensitive feature relative to the wild type strain. Based on these results, we propose that this protein is a membrane-associated metallo-beta-lactamase (MBL) involved in the antibiotic-resistant property of S. pneumoniae. PMID- 27214295 TI - BEYOND DXA: ADVANCES IN CLINICAL APPLICATIONS OF NEW BONE IMAGING TECHNOLOGY. AB - Dual-energy X-ray absorptiometry (DXA) is generally a very useful tool for assessing bone mineral density (BMD) and fracture risk. However, observational studies have shown that in certain instances, BMD as measured by DXA systematically over- or underestimates fracture risk. We herein describe the clinical conundrums encountered when assessing fracture risk by DXA in patients with primary hyperparathyroidism or type 2 diabetes and those of Chinese ethnicity. Furthermore, we discuss how advanced imaging technology that examines skeletal microarchitecture is furthering our understanding of fracture risk in these clinical situations. ABBREVIATIONS: BMD = bone mineral density BMI = body mass index BMS = bone material strength BMT = bone microindentation testing 3D = 3-dimensional DM2 = type 2 diabetes mellitus DXA = dual-energy X-ray absorptiometry MUFEA = microstructural finite element analysis FRAX = fracture risk assessment tool HRpQCT = high-resolution peripheral quantitative computed tomography ID = indentation distance IDI = indentation distance increase ITS = individual trabecular segmentation PHPT = primary hyperparathyroidism PTH = parathyroid hormone TBS = trabecular bone score. PMID- 27214296 TI - VENOUS SAMPLING FOR CUSHING DISEASE: COMPARISON OF INTERNAL JUGULAR VEIN AND INFERIOR PETROSAL SINUS SAMPLING. AB - OBJECTIVE: Because magnetic resonance imaging (MRI) fails to detect many adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas, inferior petrosal sinus sampling (IPSS) is considered the gold standard to differentiate Cushing disease (CD) from ectopic ACTH secretion syndrome (EAS). Some authors have suggested internal jugular vein sampling (IJVS) as an alternative to IPSS. METHODS: We simultaneously compared IJVS to IPSS in 30 consecutive patients referred for ACTH-dependent Cushing syndrome and equivocal MRI exams. Five sites were simultaneously sampled in each patient (right and left IPS, right and left IJV, and femoral vein) before and after the administration of corticotrophin releasing hormone or desmopressin. The test was considered consistent with CD when the IPS to peripheral ratio was >2 at baseline or >3 after stimulus and the IJV to peripheral ratio was >1.7 at baseline or >2 after stimulus. RESULTS: In 27 of 30 patients, IPSS results were consistent with a central source of ACTH. Two of the other 3 patients had EAS (one lung carcinoid and one occult), and 1 patient had pathology-proven CD. The sensitivity of IPSS was 96.4%. Only 64.2% of these patients had results meeting criteria for a central source of ACTH by IJVS criteria. Twenty patients with centralizing IPPS have undergone pituitary surgery. Of these, the central origin of excessive ACTH was confirmed with certainty in 16 patients. Among these 16 patients, the IPSS sensitivity was 93.8%, whereas 5 patients had false-negative IJVS (68.7% sensitivity). CONCLUSION: These results do not support the routine use of IJVS in establishing if the pituitary is the source of excessive ACTH. ABBREVIATIONS: ACTH = adrenocorticotropic hormone CD = Cushing disease CRH = corticotrophin-releasing hormone CS = Cushing syndrome DDAVP = desmopressin EAS = ectopic ACTH secretion IJVS = internal jugular vein sampling IPSS = inferior petrosal sinus sampling JVS = jugular venous sampling MRI = magnetic resonance imaging. PMID- 27214297 TI - TRANSGENDER CARE MATTERS. PMID- 27214298 TI - ROLE OF IMAGING TESTS FOR PREOPERATIVE LOCATION OF PATHOLOGIC PARATHYROID TISSUE IN PATIENTS WITH PRIMARY HYPERPARATHYROIDISM. AB - OBJECTIVE: Primary hyperparathyroidism (PHPT) can be cured by parathyroidectomy, and the preoperative location of enlarged pathologic parathyroid glands is determined by imaging studies, especially cervical ultrasonography and scintigraphy scanning. The aim of this retrospective study was to evaluate the use of preoperative cervical ultrasonography and/or parathyroid scintigraphy in locating pathologic parathyroid tissue in a group of patients with PHPT followed in the same endocrine center. METHODS: We examined the records of 61 patients who had undergone parathyroidectomy for PHPT following (99m)Tc-sestamibi scintigraphy scan and/or cervical ultrasonography. Scintigraphic and ultrasonographic findings were compared to histopathologic results of the surgical specimens. RESULTS: Ultrasonography detected enlarged parathyroid glands in 87% (48/55) of patients with PHPT and (99m)Tc-sestamibi scintigraphy in 79% (37/47) of the cases. Ultrasonography was able to correctly predict the surgical findings in 75% (41/55) of patients and scintigraphy in 72% (34/47). Of 7 patients who had negative ultrasonography, scintigraphy correctly predicted the surgical results in 2 (29%). Of 10 patients who had negative scintigraphy, ultrasonography correctly predicted the surgical results in 4 (40%). When we analyzed only patients with solitary eutopic parathyroid adenomas, the predictive positive values of ultrasonography and scintigraphy were 90% and 86%, respectively. CONCLUSION: Cervical ultrasonography had a higher likelihood of a correct positive test and a greater predictive positive value for solitary adenoma compared to (99m)Tc-sestamibi and should be used as the first diagnostic tool for preoperative localization of affected parathyroid glands in PHPT. ABBREVIATIONS: Ca = calcium IEDE = Instituto Estadual de Diabetes e Endocrinologia Luiz Capriglione PHPT = primary hyperparathyroidism PTH = parathyroid hormone. PMID- 27214300 TI - EVALUATION OF LANREOTIDE DEPOT/AUTOGEL EFFICACY AND SAFETY AS A CARCINOID SYNDROME TREATMENT (ELECT): A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL. AB - OBJECTIVE: To evaluate the efficacy and safety of lanreotide depot/autogel 120 mg for the control of carcinoid syndrome (CS) symptoms in patients with neuroendocrine tumors (NETs). METHODS: This was a 16-week, randomized, double blind, phase 3 trial (Clinicaltrials.gov: NCT00774930). Patients with/without prior somatostatin analog (SSA) use were randomized to lanreotide depot/autogel 120 mg or placebo every 4 weeks, with access to short-acting octreotide as rescue medication. The primary endpoint was the percentage of days in which short-acting octreotide was used, which was assessed from daily diaries using an analysis of covariance including the stratification variables baseline short-acting octreotide use and frequency of diarrhea/flushing. The proportions of patients experiencing treatment success was a supportive analysis. Adverse events were recorded at all visits. RESULTS: A total of 115 patients were enrolled (lanreotide, n = 59; placebo, n = 56). The adjusted mean (95% confidence interval [CI]) percentage of days with rescue octreotide use (primary endpoint) was significantly lower in the lanreotide (33.7%; 95% CI, 25.0%-42.4%) versus the placebo group (48.5%; 95% CI, 39.6%-57.4%), representing an absolute difference of -14.8% (95% CI, -26.8% to -2.8%; P = .017). The odds ratio of full/partial treatment success (<=3 days short-acting octreotide use weeks 12 to 15) was significantly greater with lanreotide than placebo (2.4; 95% CI, 1.1-5.3; P = .036). No new safety concerns were identified, and lanreotide was well tolerated. CONCLUSION: Lanreotide depot/autogel is effective for the control of CS symptoms in patients (SSA-naive or experienced) with NETs. ABBREVIATIONS: AE = adverse event BMI = body mass index CS = carcinoid syndrome ELECT = Evaluating Lanreotide Efficacy and safety as a Carcinoid-syndrome Treatment HRQoL = health-related quality of life LTOLE = long-term open-label extension NET = neuroendocrine tumor OL = open label SSA = somatostatin analog. PMID- 27214302 TI - PREDICTIVE VALUE OF SOMATIC MUTATIONS FOR THE DEVELOPMENT OF MALIGNANCY IN THYROID NODULES BY CYTOPATHOLOGY. AB - OBJECTIVE: The purpose of our prospective longitudinal study was to evaluate the predictive efficacy of genetic testing for malignancies in fine-needle aspiration biopsy samples that are cytologically benign at the time of biopsy. METHODS: A total of 779 aspirated cytological samples collected from thyroid nodules of 626 patients were included in a 3-year follow-up study. Consecutive patients with cytologically benign thyroid nodules by the Bethesda System for Reporting Thyroid Cytopathology were enrolled in the study. At enrollment, somatic 1-point nucleotide polymorphisms of BRAF and RAS family genes were tested by melting point analysis, while RET/PTC and PAX8/PPAR-gamma rearrangements were examined by real-time polymerase chain reaction. The genetic test was considered to be positive if a somatic mutation was found. Malignant cytopathologic diagnoses were confirmed by histopathology. RESULTS: In samples collected from 779 thyroid nodules, there were 39 BRAF, 33 RAS mutations, and 1 RET/PTC rearrangements found at the beginning of the study. No PAX8/PPAR-gamma rearrangement was identified. There were 52 malignant thyroid tumors removed during follow-up, out of which 24 contained a somatic mutation. The specificity of the presence of somatic mutations for malignancies was as high as 93.3%, and sensitivity was 46.2%. The negative predictive value of genetic testing reached 96.0%. CONCLUSION: Our results show that our set of genetic tests can predict the appearance of malignancy in benign thyroid nodules (at the beginning of follow-up) with high specificity and strong negative predictive value. ABBREVIATIONS: BRAF = v-raf murine sarcoma viral oncogene homolog B1 FLUS = follicular lesion of undetermined significance FNAB = fine-needle aspiration biopsy FTC = follicular thyroid carcinoma HRAS = homologous to the oncogene from the Harvey rat sarcoma virus KRAS = homologous to the oncogene from the Kirsten rat sarcoma virus NRAS = first isolated from a human neuroblastoma/neuroblastoma RAS = viral oncogene homolog PAX8 = paired box 8 PCR = polymerase chain reaction PPAR-gamma = peroxisome proliferator-activated receptor gamma PTC = papillary thyroid carcinoma RAS = rat sarcoma RET = rearranged during transfection tyrosine-kinase proto-oncogene SM = somatic mutation SNP = single-nucleotide polymorphism. PMID- 27214303 TI - Evaluation of the in vitro biocompatibility of a new fast-setting ready-to-use root filling and repair material. AB - AIM: To evaluate the in vitro biocompatibility of iRoot FS (Innovative BioCeramix Inc., Vancouver, BC, Canada) and to compare its performance with those of iRoot BP Plus (Innovative BioCeramix Inc.) and ProRoot mineral trioxide aggregate (MTA; Dentsply Tulsa Dental, Tulsa, OK, USA). METHODOLOGY: MC3T3-E1 cells were cultured for 1, 2 and 3 days in various dilutions of iRoot FS, iRoot BP Plus and MTA extracts after 7 days of setting to assess cell viability using a cell counting kit-8 (Dojindo, Kumamoto, Japan). The cell apoptosis induced by the set material extracts was evaluated through annexin V-propidium iodide flow cytometry. Changes in the cytoskeletal organization and stress fibres were observed through immunofluorescence by labelling the fibrous actin and nuclei of the cells. Cell attachment was observed under a scanning electron microscope after the MC3T3-E1 cells were cultured on the surface of a material disc set for 1 day. The data were analysed using one-way anova. RESULTS: iRoot FS extracts induced higher cell viability than the control extracts (P < 0.05) at levels comparable to those of iRoot BP Plus and MTA. Compared with the control group, iRoot FS did not promote cell apoptosis. Stretched stress fibres and cytoskeletons were detected in the cells treated with iRoot FS extracts. Scanning electron microscopy revealed that the MC3T3-E1 cells attached to iRoot FS appeared flatter and exhibited better stretch than those attached to the other extracts. CONCLUSIONS: iRoot FS displayed in vitro biocompatibility with MC3T3-E1 cells by promoting cellular proliferation and attachment without causing cell apoptosis. PMID- 27214304 TI - Correction to Collagen-Poly(N-isopropylacrylamide) Hydrogels with Tunable Properties. PMID- 27214305 TI - Efficacy and safety of darbepoetin alpha in patients with myelodysplastic syndromes: a systematic review and meta-analysis. AB - We conducted a systematic review and meta-analysis to estimate the efficacy of darbepoetin alpha (DA) for treatment of myelodysplastic syndrome (MDS)-related anaemia. Eligible studies were prospective, interventional, and reported World Health Organization, French-American-British, or International Prognostic Scoring System (IPSS) criteria. Outcomes included erythroid response rate (primary); haemoglobin response; change in haemoglobin, transfusion status, and quality-of life (QoL); and safety. Ten studies (N = 647) were analysed. Erythroid response rate range was 38-72%; median response duration range was 12-51+ months. Patients with erythropoietin (EPO) <100 iu/l had 35% [95% confidence interval (CI): 22 48%; P < 0.001) better response than patients with EPO >100 iu/l. Erythropoesis stimulating agent (ESA)-naive patients had 17% (95% CI: 3-32%; P = 0.022) greater response rate than those previously treated with ESA. Nonetheless, previously treated patients had response rates of 25-75%. Higher baseline haemoglobin levels, higher dose, transfusion-independence and low-risk IPSS status were reported by several studies to be associated with better response. QoL, transfusion rates and haemoglobin levels improved with treatment. Hypertension, thromboembolism and progression to acute myeloid leukaemia were reported in 2%, 1% and 1% of patients, respectively. This meta-analysis suggests that DA treatment can be useful for improving erythroid response in MDS patients with anaemia, even among patients previously treated with ESA. PMID- 27214306 TI - AlaScan: A Graphical User Interface for Alanine Scanning Free-Energy Calculations. AB - Computation of the free-energy changes that underlie molecular recognition and association has gained significant importance due to its considerable potential in drug discovery. The massive increase of computational power in recent years substantiates the application of more accurate theoretical methods for the calculation of binding free energies. The impact of such advances is the application of parent approaches, like computational alanine scanning, to investigate in silico the effect of amino-acid replacement in protein-ligand and protein-protein complexes, or probe the thermostability of individual proteins. Because human effort represents a significant cost that precludes the routine use of this form of free-energy calculations, minimizing manual intervention constitutes a stringent prerequisite for any such systematic computation. With this objective in mind, we propose a new plug-in, referred to as AlaScan, developed within the popular visualization program VMD to automate the major steps in alanine-scanning calculations, employing free-energy perturbation as implemented in the widely used molecular dynamics code NAMD. The AlaScan plug-in can be utilized upstream, to prepare input files for selected alanine mutations. It can also be utilized downstream to perform the analysis of different alanine scanning calculations and to report the free-energy estimates in a user-friendly graphical user interface, allowing favorable mutations to be identified at a glance. The plug-in also assists the end-user in assessing the reliability of the calculation through rapid visual inspection. PMID- 27214307 TI - Lignans from the Australian Endemic Plant Austrobaileya scandens. AB - The sole species of the vascular plant family Austrobaileyaceae, Austrobaileya scandens, is endemic to the tropical rainforest of northeastern Queensland, Australia. A single lead-like enhanced fraction of A. scandens showed potent inhibition against human prostate cancer PC3 cells. Chemical investigation of this plant resulted in the isolation of two new aryltetralin lignans, austrobailignans 8 and 9 (1 and 2), and the synthetic compound nicotlactone B (3), newly identified as a natural product together with nine known lignans (4 12). Their structures were established on the basis of spectroscopic analyses. Absolute configurations of the new compounds were determined by quantum chemical electronic circular dichroism (ECD) calculations employing time-dependent density functional theory. The ECD calculations were also used to assign the absolute configuration of marphenol K (4) and revise the absolute configuration of kadsurindutin C (20). Ten out of the 12 isolated compounds inhibited the growth of PC3 cells with IC50 values ranging from micromolar to nanomolar. Marphenol A (5) was found for the first time to induce apoptosis and arrest the S cell cycle phase of PC3 cells. PMID- 27214308 TI - Growth Hormone and Cerebral Amyloidosis. AB - Great interest has recently been focused on a paper reporting characteristic deposits of amyloid-beta protein associated with Alzheimer's disease in brains of adults who died of Creutzfeldt-Jakob disease. As they had contracted such disease after treatment with prion-contaminated human growth hormone extracted from cadaver-derived pituitaries, the authors have suggested that interhuman transmission of Alzheimer's disease had occurred. Our previous research led us to find that amyloid-forming peptides share amino acid sequence homology, summarized by a motif. Here, we probed the amino acid sequence of human growth hormone for such a motif, and found that 2 segments fit the motif and are potentially amyloid forming. This finding was confirmed by Aggrescan, another well-known software for the prediction of amyloidogenic peptides. Our results, taken together with data from the literature that are missing in the aforementioned paper and associated commentaries, minimize the contagious nature of the iatrogenically-acquired coexistence of Creutzfeldt-Jakob disease and Alzheimer's disease. In particular, the above mentioned paper misses literature data on intratumoral amyloidosis in growth hormone- and prolactin-secreting adenomas, tumors relatively frequent in adults, which are often silent. It cannot be excluded that some pituitaries used to extract growth hormone contained clinically silent microadenomas, a fraction of which containing amyloid deposits, and patients might had received a fraction of growth hormone (with or without prolactin) that already was an amyloid seed. The intrinsic amyloidogenicity of growth hormone, in the presence of contaminating prion protein (and perhaps prolactin as well) and amyloid-beta contained in some cadavers' pituitaries, may have led to the observed co occurring of Creutzfeldt-Jakob disease and Alzheimer's disease. PMID- 27214310 TI - Protective Role of PEDF-Derived Synthetic Peptide Against Experimental Diabetic Nephropathy. AB - Pigment epithelium-derived factor (PEDF) is a glycoprotein with complex neuroprotective, anti-angiogenic, and anti-inflammatory properties, all of which could potentially be exploited as a therapeutic option for vascular complications in diabetes. We have previously shown that PEDF-derived synthetic peptide, P5-3 (FIFVLRD) has a comparable ability with full PEDF protein to inhibit rat corneal neovascularization induced by chemical cauterization. However, the effects of PEDF peptide on experimental diabetic nephropathy remain unknown. To address the issue, we modified P5-3 to stabilize and administered the modified peptide (d-Lys d-Lys-d-Lys-Gln-d-Pro-P5-3-Cys-amide, 0.2 nmol/day) or vehicle to streptozotocin induced diabetic rats (STZ-rats) intraperitoneally by an osmotic mini pump for 2 weeks. We further examined the effects of modified peptide on human proximal tubular cells. Renal PEDF expression was decreased in STZ-rats. Although the peptide administration did not affect blood glucose or blood pressure, it decreased urinary excretion levels of 8-hydroxy-2'-deoxyguanosine, an oxidative stress marker, and reduced plasminogen activator inhibitor-1 (PAI-1) gene expression, and suppressed glomerular expansion in the diabetic kidneys. High glucose or advanced glycation end products stimulated oxidative stress generation and PAI-1 gene expression in tubular cells, all of which were significantly suppressed by 10 nM modified P5-3 peptide. Our present study suggests that PEDF derived synthetic modified peptide could protect against experimental diabetic nephropathy and inhibit tubular cell damage under diabetes-like conditions through its anti-oxidative properties. Supplementation of modified P5-3 peptide may be a novel therapeutic strategy for diabetic nephropathy. PMID- 27214309 TI - Renal Handling of Sclerostin in Response to Acute Glomerular Filtration Decline. AB - Deterioration of glomerular filtration rate (GFR) is associated with alterations of bone metabolism. It translates clinically to bone fragility and increased fractures rate among patients with impaired GFR. Recently, sclerostin (SCL) gained much attention as an important factor in pathogenesis of mineral and bone disturbances in patients with renal diseases. There is no data about SCL behaviour in patients with acute GFR decline. The aim of this study was to evaluate the renal handling of SCL. This is a prospective, single-centre observational study in patients undergoing nephrectomy due to urological indications. Serum and urinary SCL levels were measured prior and after nephrectomy. 25 patients were enrolled. After surgery, eGFR significantly declined (from 87.4+/-19.7 to 67.7+/-25.7 ml/min/1.73 m(2), p<0.0001). Nephrectomy caused more than 20 times higher renal fractional excretion of SCL [0.15 (interquartile range, IQR 0.09-0.40) vs. 2.78 (IQR 1.51-4.02)%, p<0.001], while its serum level remained intact [0.69 (IQR 0.57-0.90 vs. 0.65 (IQR 0.53 0.88) ng/ml, p=0.4]. The magnitude of eGFR reduction was associated inversely with change in urinary SCL fractional excretion (r=-0.6, p=0.001) and with alteration in serum SCL level (r=-0.5, p=0.01). Our results suggest that increased serum SCL concentrations at moderately reduced GFR are not due to diminished renal clearance. At more severely decreased GFR, elevated SCL concentration results from both increased production and reduced renal elimination. PMID- 27214311 TI - Differential Expression of Glucocorticoid Receptor Noncoding RNA Repressor Gas5 in Autoimmune and Inflammatory Diseases. AB - Glucocorticoids have strong regulatory actions on the immune system and act as potent therapeutic compounds for autoimmune and inflammatory diseases. We previously reported that the long noncoding RNA growth arrest-specific 5 (Gas5), which accumulates inside the cells in response to cellular starvation/growth arrest, functions as a potent repressor of the glucocorticoid receptor (GR) through its RNA "glucocorticoid response element (GRE)". To evaluate potential roles of Gas5 in immune-related disorders, we examined Gas5 RNA levels in various autoimmune, inflammatory, and infectious diseases using the microarray data available in the Gene Expression Omnibus. We found that Gas5 levels were altered in whole blood or leukocytes of the patients with rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and sarcoidosis. Gas5 levels were also altered in infectious diseases, such as by the human immunodeficiency virus type 1 and influenza virus, and bacterial sepsis. In our experimental analysis using mice, Gas5 levels were kept at high basal levels and did not respond to fasting in immune organs, such as spleen and thymus, while its levels in metabolic organs, including liver, fat, and skeletal muscles, were low at baseline and were highly elevated upon this treatment, possibly through suppression of the mTOR pathway. These results suggest that Gas5 plays a role in the regulation of immune functions and pathogenesis/pathophysiology of autoimmune, inflammatory, and infectious diseases in part through modulation of the GR transcriptional activity via its decoy RNA "GRE". Changes in the Gas5 levels may also influence disease response to immunosuppressive glucocorticoid therapy. PMID- 27214312 TI - Corticosteroid-Binding Globulin: A Review of Basic and Clinical Advances. AB - Corticosteroid-binding globulin (CBG, transcortin) is the primary cortisol binding protein. It is a non-inhibitory serine protease inhibitor, capable of conformational change from a high cortisol-binding affinity form to a low affinity form upon cleavage of its reactive centre loop by various proteases, such as neutrophil elastase. The burgeoning inflammatory role of CBG applies to acute, severe inflammation where depletion is associated with mortality, and to chronic inflammation where defects in cortisol delivery may perpetuate inflammation. Naturally occurring human mutations influence a wide range of CBG properties and point toward a role in hitherto unexplained chronic musculoskeletal pain and fatigue disorders as well as potentially affecting fertility outcomes including offspring gender. In vitro and knock-out animal models of CBG propose a role for CBG in cortisol transport to the brain, providing a foundation for understanding the human observations in those with CBG mutations and sex differences in stress-related mood and behaviour. Finally, CBG measurement has a practical role in the estimation of free cortisol, useful in clinical circumstances where CBG levels or cortisol binding affinity is reduced. Taken together, novel data suggest a role for cortisol in targeted cortisol delivery, with implications in acute and chronic inflammation, as well as roles in metabolism and neurocognitive function, implying that CBG is a multifaceted component in the mechanisms of hypothalamic-pituitary-adrenal axis related homeostasis. PMID- 27214313 TI - Size-Dependent Disorder-Order Transformation in the Synthesis of Monodisperse Intermetallic PdCu Nanocatalysts. AB - The high performance of Pd-based intermetallic nanocatalysts has the potential to replace Pt-containing catalysts for fuel-cell reactions. Conventionally, intermetallic particles are obtained through the annealing of nanoparticles of a random alloy distribution. However, this method inevitably leads to sintering of the nanoparticles and generates polydisperse samples. Here, monodisperse PdCu nanoparticles with the ordered B2 phase were synthesized by seed-mediated co reduction using PdCu nanoparticle seeds with a random alloy distribution (A1 phase). A time-evolution study suggests that the particles must overcome a size dependent activation barrier for the ordering process to occur. Characterization of the as-prepared PdCu B2 nanoparticles by electron microscopy techniques revealed surface segregation of Pd as a thin shell over the PdCu core. The ordered nanoparticles exhibit superior activity and durability for the oxygen reduction reaction in comparison with PdCu A1 nanoparticles. This seed-mediated co-reduction strategy produced monodisperse nanoparticles ideally suited for structure-activity studies. Moreover, the study of their growth mechanism provides insights into the size dependence of disorder-order transformations of bimetallic alloys at the nanoscale, which should enable the design of synthetic strategies toward other intermetallic systems. PMID- 27214314 TI - The inheritance and molecular genetics of von Willebrand's disease. PMID- 27214315 TI - Haemophilic ankle problems: orthopaedic solutions. PMID- 27214316 TI - The administration of desmopressin by nasal spray: a dose-determination study in patients with mild haemophilia A or von Willebrand's disease. AB - Desmopressin is an important haemostatic agent in many types of bleeding disorders. The intranasal route for administration of desmopressin has attracted much interest because it is convenient and makes self-treatment possible. In the present study the effects of three doses (300, 450 and 600 MUg) of desmopressin delivered by nasal spray and those of 0.3 MUg/kg injected intravenously were compared in five patients with haemophilia A and 11 with von Willebrand's disease. There was no statistically significant difference in peak VIII:C concentration in the haemophilia patients and no difference in peak vWF concentration in von Willebrand patients between the four desmopressin dosages. Bleeding time response was comparable after all four dosages. We recommend a spray dosage of 300 MUg for home treatment. As cover for major surgery or in connection with severe bleedings, however, intravenous administration is to be recommended. PMID- 27214317 TI - The feasibility of using concentrates containing factor IX for continuous infusion. AB - We have investigated the feasibility of continuous infusion of undiluted factor IX (F IX) over several days using minipumps. The stabilities of seven different reconstituted F IX products were substantially better than those declared by the manufacturers. Several concentrates maintained factor activities 80% of baseline for the entire period of 4 weeks at 4-8dC as did one product at 20-23dA. At 37dC the latter concentrate was stable for at least 1 week. The stability seemed to correlate with the purity of the product. Analysis of two prothrombin comples concentrates by gel electrophoresis demonstrated degradation of prothrombin to prethrombin-1 and fragment 1 at 37dC and in one of the concentrates also at 20 23dC. In two F IX concentrates the corresponding analysis did not reveal any degradation. Four patients were treated with continuous infusion with a pure F IX concentrate (MononineTM, Armour) after surgery or for serious haemorrhage (two each) with good haemostatic effect, an initial progressive decrease of the F IX clearance, and no side-effects. Continuous infusion with F IX, using a minipump and undiluted reconstituted factor, is therefore feasible and effective, and can be conveniently prepared for several days at a time. Pure F IX products are more stable and probably safer for this purpose. PMID- 27214318 TI - Long-term surveillance for human anti-murine antibodies of a group of haemophiliacs treated only with immunoaffinity-purified FVIII concentrates. AB - An immunoaffinity purified, solvent/detergent virally inactivated factor VIII (FVIII) concentrate (Hemofil(r) M) has been in clinical use in persons with haemophilia A since March 1987 and under clinical trial prior to licencing in the USA, Europe and Japan. The specification set and consistently met for the monoclonal antibody (mAb) content of the final product is 0.1 ng/IU FVIII. This level was considered non-immunogenic, based upon animal studies, recommendations of the European PHarmacopoeia with ovalbumin contamination of influenza vaccine and also the experience during clinical research studies using aAb for diagnostic or other clinical purpose as reported in the medical literature. This research communication documents the surveillance for human anti-murine antibodies (HAMA) in 13 patients with serve haemophilia A. These patients have been treated with a large amount of product (mean 14,026 IU), numerous different lots of Hemofil M (total 45; mean 17) over a substantial period of time (mean 28 months). The data generated from this group of 13 patients before and during therapeutic Hemofil M administration failed to show the development of any HAMA response at any timepoint. Therefore Hemofil M prepared by mAb resin immunoaffinity column chromatography under the currently set specifications for mAb contaminant of 0.1 ng/IU FVIII or less is a safe therapeutic agent in the management and prevention of bleeding episodes in persons with haemophilia A. PMID- 27214319 TI - Seroprevalence of parvovirus B19, cytomegalovirus, hepatitis A virus and hepatitis E virus antibodies in haemophiliacs treated exclusively with clotting factor concentrates considered safe against human immunodeficiency and hepatitis C viruses. AB - Clotting-factor concentrates (CFC) are a potential source of transmission of blood-borne viruses. Newer physical and chemical methods (pasteurization, wet heating, solvent/detergent treating) developed to inactivate viruses are effective against HIV, HBV and HCV. However, it is not clear if these methods protect against other pathogenic viruses such as parvovirus B19, cytomegalovirus (CMV), hepatitis A virus (HAV) and hepatitis E virus (HEV). To evaluate the safety of current CFC we have studied seroprevalence of parovirus B19, CMV, HAV and HEV antibodies in 22 HIV and HCV negative haemophiliacs who were treated exclusively with clotting-factor concentrates considered safe with respect to HIV and HCV transmission, 22 healthy individuals served as controls. Neither HAV nor HEV antibodies were detected in haemophiliacs or controls. Two controls and two haemophiliacs were seropositive for CMV. Five controls (32% prevalence) and 15 haemophiliacs (77%) were positive to parovirus B19. No statistical differences can be established for seropositivity with CMV, HAV and HEV between haemophilic patients and controls. In the case of parvovirus B19 the differences are statistically significant (P= 0.0128). The relative risk of parvovirus B19 is 2.4 in the case of haemophiliacs. CFC considered safe against HIV and HCV are not safe against parvovirus B19, although they seem to be safe against CMV, HAV and HEV. PMID- 27214320 TI - Long-term follow-up of liver function in Italian haemophilic patients. AB - A 14-year follow-up of 153 haemophilic patients treated with clotted factor concentrates was made to assess liver function. Investigations included measurement of alanine amino transferase (ALT), immunoglobulins, HIV antibody, HBsAg, antibody to HBs and HBc antigens, antibodies to HCV (assayed by ELISA-2 and by RIBA-2) and HCV viraemia assessed by PCR. Assessment of liver function also included liver ultrasound scan and oesophageal X-ray. A positive correlation was found between abnormal liver function and age, HIV infection, HBV infection, HCV infection and hepatomegaly. However, there was no correlation between abnormal liver function and annual clotting factor concentrate use. The increasing incidence of liver insufficiency with increasing age is likely to result in substantial morbidity and mortality amongst haemophilic patients. PMID- 27214321 TI - Didanosine treatment of haemophilic patients infected with HIV. AB - Twenty-six haemophilic patients with advanced HIV infection who had developed resistance or intolerance to zidovudine were treated with didanosine (ddI). 11 patients continue to take ddI at a median time of 14 months from commencement (range 7-18 months). Five of these patients showed an increase in CD4 lymphocyte count, reaching a maximum at a median time of 4 months. Four patients with HIV related symptoms improved clinically. In general, the CD4 count and clinical improvements were not sustained. 11 patients discontinued ddI after a median of 3 months (range 3 days to 10 months), most commonly due to gastrointestinal side effects. No case of pancreatitis or peripheral neuropathy was seen. Six patients, all with very advanced HIV disease, died. HIV-infected haemophilic patients who become resistant or intolerant to zidovudine may derive benefit from ddI, although this is usually transient. PMID- 27214322 TI - Communication about safer sex and serostatus disclosure in HIV-positive adolescents with haemophilia. AB - OBJECTIVES: To assess the attitudes, beliefs and feelings of adolscents and young men with severe haemophilia with respect to discussing safer sex and disclosing their human immunodeficiency virus (HIV) seropositivity to potential sex partners. METHODS: Fifty-nine males with haemophilia from throughout the US answered open-ended questions. RESULTS: Talking about avoidance of transmitting AIDS and disclosing one's seropositivity was beneficial, moral and wise. Nevertheless, this was exceedingly, difficult, unpleasant, and fraught with fear of rejection and alienation. Communication was approved by family, friends, and health-care providers. Facilitators of communication were: knowledge and an accepting attitude about persons with HIV, a supportive person to assist with discussion, and environmental cues. CONCLUSION: This first report of HIV-infected adolescents and young adults reveals that although they endorse discussing safer sex and disclosing their HIV seropositivity, they are painfully aware of the social and interpersonal risks of such extremely difficult communications. PMID- 27214323 TI - A study to evaluate the effectiveness of 'Air-Stirrup' splints as a means of reducing the frequency of ankle haemarthroses in children with haemophilia A and B. AB - With the introduction of readily available factor VIII and IX concentrates and programmes for home therapy and prophylaxis, most severe haemophilic arthropathies can be prevented. However, despite these programmes, bleeds into the ankle joints still occur during the years of growth. It is suggested that ankle haemarthroses may be caused by unrecognized inversion injuries by the patient. The history from a small child is not always accurate and when a child presents with a swollen ankle it is not uncommon for the medical team to make a diagnosis of haemarthrosis without really searching for the pathogenesis. This paper describes a clinical study using the 'Air-Stirrup'; (AS) ankle splint which is designed to restrict inversion. Children between the ages of 3 and 18 years with a history of recurrent ankle haemorrhages were entered into a 6-month trial. Results showed a positive reduction in the number of ankle haemorrhages experienced by the children. PMID- 27214324 TI - Spontaneous infection of soft tissue haematomas in two HIV seropositive haemophilia patients. AB - Two HIV seropostiive haemophilic patients with spontaneous infected soft tissue haematomas are described. In one patient the prepatellar bursa was infected, and in the other the posterior aspect of the shoulder. Treatmetn included evacuation of the suppurative focus, antibiotic therapy and prompt rehabilitation. The results were good in both cases and therefore operative management is recommended. PMID- 27214325 TI - Obstetric management in von Willebrand's disease: a report of 24 pregnancies and a reivesw of the literature. AB - The case records of 13 patients (24 pregnancies) with von Willebrand's disease (vWD) were studies rettospectively. The overall incidence of primary and secondary post-partum haemorrhage (PPH) was 15.8% and 25% respectively, all primary PPH occurring in tyre 2 discase (3/14 deliveries, 21.4%). The risk of primary PPH in type 2 patients who did not receive prophylactic factor VIII was 37.5% (3/8 deliveries). Factor VIII coagulant activity (VIII:C) and von Willebrand factor antigen (vWF:Ag) rose above bascline values by a factor of at least 1.5 during the pregnancy in most case. More severely affected patients were less likely to benefit significatntly. A baseline VIII:C of <15 iu/dl (4/14 cases) was predictive of a third trimester level of <15 iu/dl. Improvements in the von Willebrand factor activity were less marked. The baseline von Willebrand factor activity was <15 iu/dl in all patients with serial data, none of whom achieved a third-trimester von Willebrand factor activity of >50 iu/dl. The bleeding times were unaltered significantly in all but one of the cases, reflecting a general failure of the primary haemostatic defect to improve with pregnancy. The findings demonstrate that coagulation parameters do not universally improve in pregnancy in vWD, especially when preconception levels are low. The risk of primary PPH is generally higher in type 2 diseases. The level of factor VIII:C is not a good predictor of the risk of primary PPH in type 2 patients. Secondary PPH is a significatnt risk in both type 1 and type 2 patients. PMID- 27214326 TI - Haemophilia and AIDS. PMID- 27214328 TI - Exacerbation risk in severe asthma is stratified by inflammatory phenotype using longitudinal measures of sputum eosinophils. AB - BACKGROUND: Airway inflammatory phenotyping is increasingly applied to subjects with asthma. However, its relationship to clinical outcomes in difficult asthma is incompletely elucidated. OBJECTIVE: The goal of our study was to determine the relationship between exacerbation rates and phenotypes of difficult asthma based on the longitudinal measures of sputum eosinophils and neutrophils. METHODS: Subjects in the longitudinal observational study from two tertiary care centres that completed 1 year of observation and provided at least three sputum samples were classified by inflammatory phenotypes using previously established thresholds. Kaplan-Meier curves and univariable and multivariable Cox proportional hazard models were used to determine the association between inflammatory phenotypes and exacerbation rate. RESULTS: During the study, 115 exacerbations occurred in 73 severe asthmatic subjects. Subjects with the persistently eosinophilic phenotype had a significantly shorter time to first exacerbation and greater risk of exacerbation over a 1-year period than those with the non-eosinophilic phenotype based on the univariable and multivariable Cox proportional hazard model (hazard ratio [HR], 3.24; 95% confidence interval [CI], 1.35-7.72; adjusted HR, 3.90; 95% CI, 1.34-11.36). No significant differences in time to first exacerbation or exacerbation risk over a 1-year period were observed among the neutrophilic phenotypes. CONCLUSIONS: The persistent eosinophilic phenotype is associated with increased exacerbation risk compared with the non-eosinophilic phenotype in severe asthma. No differences in time to first exacerbation or exacerbation risk over a 1-year period were detected among neutrophilic phenotypes. PMID- 27214329 TI - Collaborative Partnerships: Raising the Professional Practice of Nursing. AB - The journey to Magnet(r) provides the ideal platform to demonstrate the impact of nursing and how strong interprofessional partnerships advance care and problem solving in an increasingly complex healthcare arena. Nurses in Magnet organizations use collaborative partnerships to forge innovative solutions, improve nursing care across the continuum, advance health in populations, effect desired change, and improve outcomes. PMID- 27214330 TI - Using a Triad Leadership Model at the System Level to Achieve Outcomes. AB - Nurses must partner with physicians and other health professionals in redesigning healthcare. What do nurse executives need to learn to participate and lead as part of a highly functioning executive triad? In this column, a former system chief nursing officer will share personal experiences and highlights of outcomes that were improved. PMID- 27214331 TI - Beyond Making the Case, Creating the Space for Innovation. AB - Disruptive innovation results in something different from incremental change. Instead of focusing on improving an existing process, product, or service through performance improvement, disruptive innovation disregards status quo service or work and uses very different approaches to change, seeking to design the product, process, or service according to the consumer's perspective versus the providers' By its very nature, disruptive innovation provokes organizational, professional, and cultural controversy. PMID- 27214332 TI - The Influence of Emerging Nursing Social and Community Partnership Leaders: An Interview With Dr Debbie Chatman Bryant. AB - This department highlights emerging nursing leaders who have demonstrated leadership in advancing innovation and patient care in practice policy, research, education, and theory. This interview profiles Debbie Chatman Bryant, DNP, RN, director, Partnerships for Healthcare Quality Research, and director, Community Outreach, Hollings Cancer Center, Medical University of South Carolina. PMID- 27214333 TI - Evolution of Structural Empowerment: Moving From Shared to Professional Governance. AB - OBJECTIVE: The aim of this study is to describe the maturation of the concept of shared governance to professional governance as a framework for structural empowerment. BACKGROUND: An analysis of the literature and concept clarification of structural empowerment and shared governance demonstrate that the concept and attributes of shared governance have evolved toward professional governance. METHODS: A comprehensive, deductive literature review and concept clarification of structural empowerment, shared governance, and related constructs was completed. RESULTS: The concept and practice of shared governance has matured to a concept of professional governance with the attributes of accountability, professional obligation, collateral relationships, and effective decision-making. PMID- 27214334 TI - SUPPORT: An Evidence-Based Model for Leaders Addressing Moral Distress. AB - OBJECTIVE: The aim of this study is to explore nurse leaders' experiences working in ethically difficult situations and helping nurses cope with moral distress. BACKGROUND: Moral distress is associated with ethically complex situations where nurses feel voiceless and powerless. Moral distress can lead to disengagement, burnout, and decreased quality of care. METHODS: The critical incident technique was used to collect descriptions of ethically complex situations from 100 nurse leaders in California. Responses were qualitatively coded, categorized, and subsequently counted. RESULTS: Participants noted affective, behavioral, cognitive, physical, and relational signs of moral distress. System-level factors along with team conflict and different perspectives were perceived to increase the probability of ethical conflicts. Key actions to address moral distress included acknowledging its presence, creating a culture of care, and increasing nurses' resilience to difficult circumstances through education, support, and collaboration. CONCLUSIONS: On the basis of study findings, we created the SUPPORT model as an action guide for addressing moral distress. PMID- 27214335 TI - Caregiver Fatigue: Implications for Patient and Staff Safety, Part 1. AB - OBJECTIVE: This article describes the profound impact of fatigue and the process by which 1 academic medical center assessed fatigue levels, and associated factors, among nursing personnel in their effort to develop a comprehensive fatigue management program. BACKGROUND: To adequately perform amid high patient acuity and in today's fast paced healthcare environment, nurses must be attentive and react quickly and appropriately with clear judgment and reasoning-abilities that can be greatly impaired by fatigue. Nursing leaders are instrumental in systematically addressing work-related fatigue and implementing processes designed to prevent fatigue and overwork; however, baseline measures are necessary if the efficacy of these initiatives is to be assessed. METHODS: The 15 item Occupational Fatigue Exhaustion/Recovery scale was used to assess current fatigue levels among nursing staff at a university medical center. Demographic and schedule-related questions were used to examine the characteristics of the population and identify any associated factors. RESULTS: Work-related fatigue is prevalent among all nursing staff, but differences were noted based on the respondent's position, age, and typical work shift. CONCLUSIONS: Nursing administrators and shared governance councils can address the factors contributing to work-related fatigue and negatively impacting nursing personnel's ability to rest and recuperate. Nurse leader involvement is needed to develop comprehensive fatigue reduction strategies. PMID- 27214336 TI - The Long-term Effect of a Nurse Residency Program, 2005-2012: Analysis of Former Nurse Residents. AB - OBJECTIVE: Research on nurse residency programs (NRPs) typically focuses on retention within the 1-year NRP or perhaps an additional year beyond. Few have evaluated the long-term impact of NRP, and none have adopted a longitudinal approach to follow cohorts over time. This study, conducted in a large urban academic medical center (AMC), examines the effects of the NRPs on former nurse residents (NRs) in 8 cohorts (2005-2012) and compares those who left the institution with those who remain. BACKGROUND: Nurse residency programs have increased from home-grown programs to a standardized 1-year curriculum from national models designed for different types of RNs. Evidence exists that NRPs reduce attrition among new graduates and the Institute of Medicine recommends that all new RNs have access to NRPs. METHODS: Using data from human resources, administrative data, and online survey of former NRs, this is a retrospective, longitudinal study of former NRs in 1 AMC. Nine hundred eighty-seven new graduates completed the NRP from 2005 to 2012; 646 (63.5%) have stayed (stayers) at the institution. A total of 425 stayers responded to survey (65.8%), and 108 surveys were completed by former NRs who had left (leavers) (62.4%). RESULTS: On average, leavers stay for 2.18 years at the institution; stayers typically remained for 4.86 years, suggesting that retention beyond 2 years is dependent on complex set of circumstances beyond the "treatment effect" of the NRP program. Regardless of staying or leaving, respondents hold positive attitudes about the program; achieve high levels of certification, advanced education, and professional accomplishments; and report "transitioning from beginner to competent RN" and "senior staff support" as most valuable aspects of NRP. CONCLUSIONS: Retention among new graduates has improved significantly with the introduction of NRPs at this institution. Former NRPs report favorable assessments of the NRP, regardless of number of years since completion of the program and regardless of whether the individual remains employed in the institution. In addition, former NRs report high levels of professional accomplishments and commitment to nursing. However, without additional research, we cannot definitively tie these outcomes to the NRP. PMID- 27214337 TI - Rhodioloside ameliorates depressive behavior via up-regulation of monoaminergic system activity and anti-inflammatory effect in olfactory bulbectomized rats. AB - Rhodioloside, a major constituent from roots of Rhodiola rosea, has been previously confirmed to alleviate the hyperactivity in olfactory bulbectomized (OBX) rats exposed to the open field and to decrease the immobility time in the forced swimming test (FST) and tail suspension test (TST). However, its antidepressant effects and mechanisms remain unclear. This study aimed to evaluate the antidepressant effect and the potential mechanisms of rhodioloside in OBX rats. ELISA kits, HPLC-MS and western blot analysis were applied to explore the underlying antidepressant mechanisms of rhodioloside. Rhodioloside (20, 40mg/kg) significantly reversed OBX-induced reduction in sucrose consumption. It was also observed that administration of rhodioloside (20, 40mg/kg) decreased pro-inflammatory cytokines interleukin-1 beta (IL-1beta) and interleukin-6 (IL-6) levels and inhibits nuclear factor-kappa B (NF-kappaB) activation, as well as normalized the monoaminergic system changes in prefrontal cortex (PFC) of OBX rats. These results confirmed the antidepressant-like effect of rhodioloside, which might be primarily based on its up-regulation of the monoaminergic system activity and anti-inflammatory effect. PMID- 27214338 TI - Chicken egg yolk antibodies (IgY) modulate the intestinal mucosal immune response in a mouse model of Salmonella typhimurium infection. AB - This study determined the effects of chicken egg yolk antibodies (IgY) on immune responses in the intestinal mucosal of mice infected with Salmonella typhimurium. Sixty, 28-day-old mice were divided into 4 groups and treated with streptomycin or sterile water for 2days followed by 1day without treatment. The control group was unchallenged whereas the mice in the other three groups were treated twice with 10(9)CFUmL(-1)S. typhimurium. For the next 3days, control mice continued to receive no treatment whereas the mice in the remaining three groups were orally administered with 20mgmL(-1) of specific IgY, 20mgmL(-1) of nonspecific IgY or PBS. S. typhimurium activated gut-associated lymphoid tissue, increasing the release of IFN-gamma and TNF-alpha in the mucosa and increased the number of activated T-lymphocytes and cytotoxic T-gammadelta. Specific IgY attenuated the increase in IFN-gamma and TNF-alpha and the decrease in IL-10. S. typhimurium induced mobilization of CD8(+) and CD8(+) TCRgammadelta T cells in the epithelium and CD4(+) and CD8(+) T cells in the lamina propria reflecting an inflammatory process that was attenuated by IgY. These results suggest that specific IgY modulates intestinal mucosal immune responses during a S. typhimurium infection. PMID- 27214339 TI - Evaluation of posttreatment stability after orthodontic treatment in the mixed and permanent dentitions. AB - OBJECTIVE: To investigate posttreatment changes in the maxillary and mandibular arches in patients who underwent orthodontic treatment during the mixed and permanent dentitions. MATERIALS AND METHODS: The sample was collected retrospectively from three private practices and consisted of 42 patients who were at least 10 years out of orthodontic treatment. The longitudinal records of study casts and cephalometric radiographs were analyzed to quantify posttreatment changes. RESULTS: Minimal changes in maxillary and mandibular irregularity occurred after an average of 16.98 years from completion of treatment. More than 10 years posttreatment, approximately 81% of the maxillary anterior teeth and 88% of the mandibular anterior teeth showed clinically acceptable incisor alignment (<3.5 mm). Mandibular fixed retainers greatly aided in maintaining the stability of the mandibular incisor alignment. However, posttreatment changes in maxillary incisor irregularity did not appear to be influenced by the presence of a mandibular fixed retainer. When compared with longitudinal changes observed in untreated subjects, the increase in incisor irregularity resembled a pattern similar to the regression line of untreated subjects and seems to be entirely age related. Arch width and arch depth was consistently decreased after treatment, but the magnitude of change was minimal at about 1 mm. No associations were found between any of the cephalometric measurements and changes in incisor irregularities. CONCLUSIONS: Orthodontic treatment stability can be achieved and mandibular fixed retention appears to be a valuable contributor, especially in patients with further growth expected. PMID- 27214340 TI - Association Between Body Mass Index and Parkinson Disease. PMID- 27214341 TI - Copper, Silver and Sodium Salt-Mediated Quaternization by Arylation: Syntheses of N-Heterocyclic Carbene Precursors and 6-H-Phenanthridine Derivatives. AB - We have developed a Cu(II) -, Ag(I) -, and NaOTf-mediated intramolecular quaternization by arylation reactions to synthesize a variety of N-heterocyclic carbene (NHC) precursors with a benzene-fused backbone. The methodology also provides a convenient alternative route for the synthesis of 6-H-phenanthridine derivatives. A novel silver-NHC complex was prepared by treatment of Ag2 O with the free carbene, which was in situ prepared from the deprotonation of a representative quinazolinonium salt. PMID- 27214342 TI - Probing the Methyl Torsional Barriers of the E and Z Isomers of Butadienyl Acetate by Microwave Spectroscopy. AB - The Fourier transform microwave spectra of the E and Z isomers of butadienyl acetate were measured in the frequency range from 2 to 26.5 GHz under molecular jet conditions. The most stable conformer of each isomer, in which all heavy atoms are located in a symmetry plane, was identified after analyzing the spectrum by comparison with the results from quantum-chemical calculations. The barriers to internal rotation of the acetyl methyl group were found to be 149.1822(20) and 150.2128(48) cm(-1) for the E and Z isomers, respectively, which are similar to that of vinyl acetate. A comparison between two theoretical approaches treating internal rotation, the rho axis method and combined axis method, was also performed. The influence of the alkyl R chain on the methyl torsional barriers in CH3 -COOR acetates was explored. PMID- 27214343 TI - Association of Presence of Band Cells and Toxic Neutrophils with Systemic Inflammatory Response Syndrome and Outcome in Horses with Acute Disease. AB - BACKGROUND: Band cells and toxic neutrophils are thought to indicate acute and severe systemic illness but no studies have investigated their importance in adult equine emergency admissions. OBJECTIVES: The objective of this study was to evaluate the association of band cells and toxic neutrophils with systemic inflammatory response syndrome (SIRS) and outcome in horses. ANIMALS: One hundred and five adult horses admitted on emergency basis to a private primary referral practice. METHODS: Prospective observational study with sample collection. All horses admitted on emergency basis over the study period were included in the study if they had a CBC and a blood smear collected on admission. RESULTS: The detection of band neutrophils on admission was associated with the SIRS status of the horse (RR = 2.80; 95% CI = 1.57-4.99; P < .001) and with poor outcome (RR = 1.88; 95% CI: 1.05-3.37; P = .038). Similarly, the presence of a neutrophil toxic grade higher than 3 was associated with SIRS (RR = 1.71; 95% CI: 1.03-2.82; P = .034) and death (RR = 2.34; 95% CI: 1.22-4.50, P = .007). The information gained from the blood smear review could not be captured by looking at only the WBC or neutrophil count. CONCLUSIONS AND CLINICAL IMPORTANCE: The microscopic review of blood smears from critically ill horses to detect band cells or neutrophil toxic change is valuable and could help in assessing disease severity and prognosis in adult equine emergency admissions. PMID- 27214344 TI - Development of an ultrasound-assisted emulsification microextraction method for the determination of chlorpyrifos and organochlorine pesticide residues in honey samples using gas chromatography with mass spectrometry. AB - A simple, rapid, and efficient ultrasound-assisted emulsification microextraction method followed by gas chromatography mass spectrometry in selected ion monitoring mode was developed for the determination of organochlorine pesticides in honey samples. The type and volume of organic extraction solvent, pH, effect of added salt content, and centrifuging time and speed were investigated. Under the optimum extraction conditions, 30 MUL of 1, 2-dibromoethane (extraction solvent) was immersed into an ultrasonic bath for 1 min at 40 degrees C. The limits of detection and quantification for all target pesticides were 0.003-0.06 and 0.01-0.2 ng/g, respectively. The extraction recovery was 91-100% and the enrichment factors were 168-192. The relative standard deviation for the method was <6% for intraday (n = 6) and <8% for interday precision (n = 4). The proposed method was successfully applied for the analysis of organochlorine pesticides in honey samples. PMID- 27214345 TI - Relationship between performance deterioration of a polyamide reverse osmosis membrane used in a seawater desalination plant and changes in its physicochemical properties. AB - While it is known that the performance of reverse osmosis membranes is dependent on their physicochemical properties, the existing literature studying membranes used in treatment facilities generally focuses on foulant layers or performance changes due to fouling, not on the performance and physicochemical changes that occur to the membranes themselves. In this study, the performance and physicochemical properties of a polyamide reverse osmosis membrane used for three years in a seawater desalination plant were compared to those of a corresponding unused membrane. The relationship between performance changes during long-term use and changes in physicochemical properties was evaluated. The results showed that membrane performance deterioration (i.e., reduced water flux, reduced contaminant rejection, and increased fouling propensity) occurred as a result of membrane use in the desalination facility, and that the main physicochemical changes responsible for performance deterioration were reduction in PVA coating coverage and bromine uptake by polyamide. The latter was likely promoted by oxidant residual in the membrane feed water. Our findings indicate that the optimization of membrane materials and processes towards maximizing the stability of the PVA coating and ensuring complete removal of oxidants in feed waters would minimize membrane performance deterioration in water purification facilities. PMID- 27214346 TI - The symbiotic relationship of sediment and biofilm dynamics at the sediment water interface of oil sands industrial tailings ponds. AB - Within the oil sands industry, tailings ponds are used as a means of retaining tailings until a reclamation technology such as end pit lakes (EPLs) can be developed and optimized to remediate such tailings with a water cap (although dry land strategies for tailing reclamation are also being developed). EPLs have proven successful for other mining ventures (e.g. metal rock mines) in eventually mitigating contaminant loads to receiving waters once biochemical remediation has taken place (although the duration for this to occur may be decades). While the biological interactions at the sediment water interface of tailings ponds or EPLs have been shown to control biogeochemical processes (i.e. chemical fluxes and redox profiles), these have often been limited to static microcosm conditions. Results from such experiments may not tell the whole story given that the sediment water interface often represents a dynamic environment where erosion and deposition may be occurring in association with microbial growth and decay. Mobilization of sediments and associated contaminants may therefore have a profound effect on remediation rates and, as such, may decrease the effectiveness of EPLs as viable reclamation strategies for mining industries. Using a novel core erosion system (U-GEMS), this paper examines how the microbial community can influence sediment water interface stability and how the biofilm community may change with tailings age and after disturbance (biofilm reestablishment). Shear strength, eroded mass measurements, density gradients, high-resolution microscopy, and microbial community analyses were made on 2 different aged tailings (fresh and ~38 years) under biotic and abiotic conditions. The same experiments were repeated as duplicates with both sets of experiments having consolidation/biostabilization periods of 21 days. Results suggest that the stability of the tailings varies between types and conditions with the fresh biotic tailings experiencing up to 75% more biostabilization than the same abiotic tailings. Further, greater microbial diversity in the aged pond could be a contributing factor to the overall increase in stability of this material over the fresh tailings source. PMID- 27214347 TI - Organic loading rate: A promising microbial management tool in anaerobic digestion. AB - This study investigated the effect of changes in organic loading rate (OLR) and feedstock on the volatile fatty acids (VFAs) production and their potential use as a bioengineering management tool to improve stability of anaerobic digesters. Digesters were exposed to one or two changes in OLR using the same or different co-substrates (Fat Oil and Grease waste (FOG) and/or glycerol). Although all the OLR fluctuations produced a decrease in biogas and methane production, the digesters exposed twice to glycerol showed faster recovery towards stable conditions after the second OLR change. This was correlated with the composition of the VFAs produced and their mode of production, from parallel to sequential, resulting in a more efficient recovery from inhibition of methanogenesis. The change in acids processing after the first OLR increase induced a shift in the microbial community responsible of the process optimisation when the digesters were exposed to a subsequent OLR increase with the same feedstock. When the digesters were exposed to an OLR change with a different feedstock (FOG), the recovery took 7d longer than with the same one (glycerol). However, the microbial community showed functional resilience and was able to perform similarly to pre exposure conditions. Thus, changes in operational conditions can be used to influence microbial community structure for anaerobic digestion (AD) optimisation. Finally, shorter recovery times and increased resilience of digesters were linked to higher numbers of Clostridia incertae sedis XV, suggesting that this group may be a good candidate for AD bioaugmentation to speed up recovery after process instability or OLR increase. PMID- 27214348 TI - Are UV photolysis and UV/H2O2 process efficient to treat estrogens in waters? Chemical and biological assessment at pilot scale. AB - In this study, UV based treatments were implemented at pilot scale to assess their ability to remove hormones from treated wastewater, especially with the view to equip small and medium size Wastewater Treatment Plants (WTPs). To this end, the degradation of a mixture of estrogenic hormones (Estrone (E1), beta Estradiol (E2), and 17alpha-Ethinyl Estradiol (EE2)) in waters by UV photolysis and UV/H2O2 process was investigated in real conditions. A particular attention was paid at designing a well validated laboratory scale pilot in order to optimise oxidant concentrations and UV fluence. A Low pressure lamp (254 nm) was used in a flow through commercial reactor. The effects of water matrices (drinking water and treated wastewater) and H2O2 concentrations (10, 40, and 90 mg/L) on the pilot efficiency were first determined. Only E1 could be partially degraded by UV photolysis whereas hormones were all well removed by UV/H2O2 process in both matrices. The second part of the study focused on a chemical and biological assessment of UV photolysis and UV/H2O2 process (30 and 50 mg/L). Degradation rate constants of hormones as well as changes in estrogenic activity (YES bioassay) and toxicity (Vibrio fischeri) were followed at the same time. UV photolysis could not remove neither estrogens nor estrogenic activity at relevant UV fluence in waters. However 80% of initial estrogenic compounds and estrogenic activity could be removed from treated wastewater by combining UV fluence of 423 and 520 mJ/cm(2) with 50 and 30 mg/L of H2O2, respectively. No high estrogenic or toxic by-products were detected by the two bioassays following UV photolysis or UV/H2O2 process. Operating costs were estimated for a full scale pilot. H2O2 was the major cost. By combining the appropriate concentration of H2O2 and UV fluence, it could be possible to design a cost effective treatment for treating estrogens in small and medium size WTPs. PMID- 27214350 TI - Improving Visual Saliency Computing With Emotion Intensity. AB - Saliency maps that integrate individual feature maps into a global measure of visual attention are widely used to estimate human gaze density. Most of the existing methods consider low-level visual features and locations of objects, and/or emphasize the spatial position with center prior. Recent psychology research suggests that emotions strongly influence human visual attention. In this paper, we explore the influence of emotional content on visual attention. On top of the traditional bottom-up saliency map generation, our saliency map is generated in cooperation with three emotion factors, i.e., general emotional content, facial expression intensity, and emotional object locations. Experiments, carried out on National University of Singapore Eye Fixation (a public eye tracking data set), demonstrate that incorporating emotion does improve the quality of visual saliency maps computed by bottom-up approaches for the gaze density estimation. Our method increases about 0.1 on an average of area under the curve of receiver operation characteristic curve, compared with the four baseline bottom-up approaches (Itti's, attention based on information maximization, saliency using natural, and graph-based vision saliency). PMID- 27214349 TI - Myeloid-Derived Suppressor Cells Induce the Expansion of Regulatory B Cells and Ameliorate Autoimmunity in the Sanroque Mouse Model of Systemic Lupus Erythematosus. AB - OBJECTIVE: This study was undertaken to assess the effect of myeloid-derived suppressor cells (MDSCs) on various B cell subsets, including regulatory B cells, as well as to assess the potential therapeutic effects of MDSC infusion in an animal model of systemic lupus erythematosus (SLE). METHODS: Splenocytes were cultured with MDSCs, and the populations of various B cells and effector T cell subsets were analyzed by flow cytometry. Lupus mice (roquinsan/san mice) were treated intravenously with MDSCs obtained from C57BL/6 mice, and the levels of serum autoantibodies, degree of proteinuria, histologic changes in the kidney, and populations of various B cell and T cell subsets in the spleen were analyzed. RESULTS: Coculture of MDSCs with splenocytes from C57BL/6 mice resulted in an expansion of the population of interleukin-10-producing B cells. The expansion of regulatory B cells was completely blocked by the addition of NG -monomethyl-l arginine, an inhibitor of inducible nitric oxide synthase (iNOS). Infusion of MDSCs resulted in a reduction of serum anti-double-stranded DNA antibody levels and degree of proteinuria and an improvement in renal pathology in the roquinsan/san mice. MDSC coculture also resulted in a decrease in the population of effector B cells, such as germinal center B cells and plasma cells. Moreover, infusion of MDSCs resulted in an expansion of the regulatory B cell population as well as a decrease in follicular helper T cells, Th1 cells, and Th17 cells in the spleens of roquinsan/san mice. CONCLUSION: Our results indicate the MDSCs induce expansion of regulatory B cells via iNOS and ameliorate autoimmunity in a murine model of SLE. These findings indicate that MDSCs may be a promising therapeutic strategy for targeting B cell-mediated autoimmune diseases. PMID- 27214351 TI - Dissimilarity-Based Ensembles for Multiple Instance Learning. AB - In multiple instance learning, objects are sets (bags) of feature vectors (instances) rather than individual feature vectors. In this paper, we address the problem of how these bags can best be represented. Two standard approaches are to use (dis)similarities between bags and prototype bags, or between bags and prototype instances. The first approach results in a relatively low-dimensional representation, determined by the number of training bags, whereas the second approach results in a relatively high-dimensional representation, determined by the total number of instances in the training set. However, an advantage of the latter representation is that the informativeness of the prototype instances can be inferred. In this paper, a third, intermediate approach is proposed, which links the two approaches and combines their strengths. Our classifier is inspired by a random subspace ensemble, and considers subspaces of the dissimilarity space, defined by subsets of instances, as prototypes. We provide insight into the structure of some popular multiple instance problems and show state-of-the art performances on these data sets. PMID- 27214352 TI - A FT-NIR spectroscopy methodology to estimate firing distance based on the direct analysis of the bullet impact surface. AB - A new methodology to estimate firing distance based on the direct analysis of organic components of gunshot residues (GSRs) on the bullet impact surface using Fourier transform near-infrared (FT-NIR) spectroscopy is proposed. Mathematical models relating firing distance with spectral information were developed using data obtained from a series of shots performed with a Glock model 17C (114 mm barrel length and 9 * 19 mm cartridges) at different distances, from 20 to 90 cm, against a white 40 * 40 cm square cloth (70% polyester/30% cotton) target. The study was repeated with two different types of ammunition. Spectra were obtained around the bullet entrance hole at 4 perpendicular directions and at 5 radial distances in diffuse reflectance mode with the assistance of a fiber optic probe. Principal component analysis showed that FT-NIRS displayed sensitivity in the recognition of the differences between the GSRs from the two different types of ammunition. Partial least squares regression models allowed the estimation of firing distance for both types of ammunition. Prediction errors lower than 11 cm were obtained for shots up to 90 cm. PMID- 27214353 TI - Correction: Analysis of Cytoplasmic Effects and Fine-Mapping of a Genic Male Sterile Line in Rice. AB - [This corrects the article DOI: 10.1371/journal.pone.0061719.]. PMID- 27214354 TI - Continuous infusion instead of bolus injections of factor concentrate? PMID- 27214355 TI - AIDS-associated lymphomas and other cancers in individuals with haemophilia. AB - Non-Hodgkin's lymphoma is the most common malignancy in individuals with haemophilia and human immunodeficiency virus (HIV) infection. Among individuals with haemophilia, lymphoma accounts for 5% of primary AIDS diagnoses, and it is the sixth most common primary AID-defining diagnosis in this group. At the time of AIDS-lymphoma diagnosis, the median age in haemophiliacs is 32 years, the mean CD4 count is 116 MUL(-1) , and the mean time from seroconversion to development of AIDS-lymphoma is 8 years. The most common primary site of AIDS-lymphomas in haemophiliacs is the gastrointestinal tract, and the most common histological type is large cell lymphoma. EBV has been detected at a molecular level in half of all haemophilia AIDS-lymphomas and its presence is predictive of shorter survival than in those without detectable EBV. The median survival after diagnosis is 6 months, with or without treatment. An increasing proportion of these tumours are occurring as secondary AIDS diagnoses, associated with the longer duration of immunosuppression afforded by antiviral therapy. This paper reviews the natural history, immunological and viral features, clinical characteristics, and risk factors associated with AIDS-lymphoma in the haemophilia population. PMID- 27214356 TI - Direct mutation analysis as the preferred method for carrier diagnosis in families with isolated cases of haemophilia B. AB - Approximately one-third of haemophilia B cases are described as isolated due to their occurrence in families with no prior history of the disorder. In this report, two families with isolated haemophilia B were studied by the standard method of restriction fragment length polymorphism (RFLP) analysis coupled with factor IX activity and antigen levels with the aim of achieving carrier diagnoses. The limitations of using this approach in the determination of carrier status were highlighted by diagnostic problems arising in both families. The problems included difficulty in interpreting bioassay results, homozygosity for the RFLP marker in a key family member and the possibility of germline mosaicism. Unequivocal carrier diagnosis in the two families was ultimately achieved by direct mutation analysis. PMID- 27214357 TI - A prospective study of patterns of bleeding in boys with haemophilia. AB - To describe the patterns of bleeding and clotting factor concentrate use in boys with haemophilia over a 6-month period, daily diary records of bleeding, factor use, levels of physical activity, chore performance and school attendance were collected from parents of 96 males between 4 and 17 years of age with haemophilia A or B followed at six comprehensive haemophilia treatment centres in Massachusetts, Rhode Island and Tennessee. 14 243 person days were available for analysis. The sample cohort averaged approximately nine bleeding episodes (1.5 per months), almost two-thirds of which were haemarthroses. 44% of bleeds were associated with injury and the average duration was 1.4 days. New bleeding episodes were significantly more likely to begin on weekdays (Monday-Thursday) than on weekends (Friday-Sunday). Boys with more severe disease had significantly more bleeding episodes and a higher frequency of haemarthroses. Boys with the most severe disease were also more likely to have joints involved when they bled and to have more spontaneous bleedings without apparent preceding trauma. Bleeding was associated with increased school absence, decreased levels of physical activity and decreased rates of household task performance. Relatively high rates of bleeding associated with trauma suggest the need for preventive interventions. PMID- 27214358 TI - Home therapy with continuous infusion of factor VIII after minor surgery or serious haemorrhage. AB - Administration of factor VIII (F VIII) concentrates by continuous infusion is now routinely used at several haemophilia centers but almost exclusively for hospitalized patients. We evaluated various aspects of home therapy with continuous infusion of an immunoaffinity purified F VIII concentrate (Monoclate P(r), Armour) in patients who would normally have been treated with high doses in bolus injections or with continuous infusion as in-patients. Twenty haemophilia A patients, eight after minor surgery and 12 for serious haemorrhage, received continuous infusion with undiluted F VIII by a minipump for a mean of 0.9 days in the hospital, followed by 3.3 days at home. Infusion bags were exchanged every 2.5 days. No haemorrhagic complications occurred, and five haemorrhages that had been resistant to treatment with bolus injections responded promptly to the continuous infusion. There were no technical problems and patient compliance and acceptance was good. We find this mode of therapy safe, efficacious and convenient for the patients as well as for the staff. PMID- 27214359 TI - Socioeconomic impact of haemophilia care: results of a pilot study. AB - Fifty consecutive haemophiliacs were entered into a pilot study of socioeconomic impact of haemophilia treatment. The Short Form 36 was used as an instrument for the assessment of quality of life. Direct and indirect costs were analysed. Incremental cost-effectiveness was expressed as additional costs per joint bleed avoided by prophylactic treatment over on-demand treatment. Thirtynine patients (mean age 35.14 years) were substituting factor VIII according to an on-demand and 11 patients according to a modified prophylactic regimen. There were an average of 9.84 joint bleeds per patient across all patients during the 6-month observation period: on-demand group 10.74 bleeds, prophylactic group 6.64 bleeds. This difference was not statistically different. Significant differences between haemophiliac patients and healthy men were seen in the assessment of their limitations of physical activities, limiting pain and general health. The total cost per patient during the 6 months was DM 24 601 in all patients, DM 17 253 in those on an on-demand base and DM 28 245 in the modified prophylactic group. Patients experienced an average 4.71 days off work: on demand 5.81 days, prophylactic regimen 0 days. The total indirect cost per patient was DM 683; therapy cost per patient was DM 25 284; cost per avoided bleed DM 1680 for on demand therapy and DM 4228 on prophylaxis. The incremental cost-effectiveness, i.e. the additional costs to avoid one additional joint bleed by prophylactic treatment, was DM 2536. In conclusion, patients receiving prophylactic clotting factor therapy require less additional health care resources, mainly due to the reduction in the number of joint bleeds. PMID- 27214360 TI - Laboratory assessment of von Willebrand factor: differential influence of prolonged ambient temperature specimen storage on assay results. AB - The laboratory assessment of von Willebrand factor (VWF) is typically performed at specialist laboratory sites, particularly when performed as a battery of laboratory tests in a thorough workup for the diagnosis of von Willebrand's disease (VWD). In these cases, specimens could derive from a variety of off-site sources, including smaller laboratories, and general clinical practitioners. Because of the potential for lack of control by the specialist laboratory over the method of specimen handling and transport from these sources, and recent VWF methodological advances, we investigated the effect of prolonged ambient temperature specimen storage on laboratory assay results. Thus, specimens were collected from 10 separate individuals, and each variably processed to provide an ideal ('control') plasma specimen, and additional specimens that were then stored at ambient temperature for up to 7 days. Specifically, specimens were stored either as whole blood, or as separated plasma, and VWF tested in isolated plasma, post 24 h, post 48 h and post 7 days storage. Three separate laboratory assays for VWF were performed; (i) a standard 'antigen' (antisera-ELISA-based) assay (VWF:Ag), (ii) a standard ristocetin-dependent-platelet-agglutination procedure (VWF:RCof) and (iii) a more recently described ELISA-based functional collagen VWF binding assay (VWF:CBA). Results can be summarized as follows, (i) Plasma storage: there was no (statistically significant) change in VWF:Ag or VWF:RCof assay results over the 7-day storage period; however, there was a small but statistically significant fall (P= 0.009) in VWF:CBA assay results after 7 days storage of plasma. (ii) Whole blood storage: there was no (statistically significant) change in VWF:Ag, VWF:CBA or VWF:RCof assay results over the 7-day storage period, although the data suggested a trend towards increasing VWF:Ag over time. As a result of the change in assayed VWF:CBA following prolonged plasma storage, a similar small but statistically significant (P= 0.009) change (increase) in the VWF:Ag to VWF:CBA ratio was observed. This ratio has previously been determined to be useful in the differential diagnosis of VWD subtypes, with high VWF:Ag to VWF:CBA ratios potentially indicative of Type 2 VWD. Fortunately, the absolute magnitude of the altered ratio following prolonged plasma storage is unlikely in practice to affect the diagnosis of VWD in most testing cases. Nevertheless, there will be occasional borderline normal cases in whom the change in VWF:CBA, or in the calculated VWF:Ag to VWF:CBA ratio, may otherwise influence a clinical diagnosis of VWD. Caution is therefore suggested in the interpretation of laboratory-derived VWF data, particularly if the specimen is derived as an off site referral. PMID- 27214361 TI - Immune tolerance induction in haemophiliacs with inhibitor to FVIII: high- or low dose programme. AB - In 1993-94, 15 high responders were treated in our centre according to the Malmo protocol which was modified as follows: serial plasmapheresis was performed instead of extracorporeal adsorbtion to protein A for reducing inhibitor levels and, after the bolus dose to neutralize the inhibitor, factor VIII concentrate was administered by a continuous infusion. Thus, this regimen included continuous infusion of factor VIII(FVIII) for 1-4 weeks, iv cyclophosphamide for 2 days and orally for 8-10 days, and intravenous immunoglobulin (IVIG) from the fourth day for 5 days. All patients had been qualified for the treatment when the antibody level was < 15 BU mL(-1) . Tolerance was induced in 10 patients (66.6% very good and good results). The treatment failed in five cases in which, due to a high inhibitor level, it was not possible to maintain a measurable factor VIII:C concentration throughout the whole period of infusion. We compared these results with results of our low-dose regimen: 25 IU FVIII kg(-1) b.w. twice a week (1985 89, 11 high responders). The modified Malmo Protocol is much shorter than the low dose programme and this is a method of first choice in patients undergoing surgery in the near future. PMID- 27214362 TI - Hepatitis B serology and DNA detection in multitransfused haemophiliacs and factor VIII and IX concentrates. AB - To assess the effect of HIV infection and the introduction of virus-inactivated concentrates, we conducted a retrospective 20-year longitudinal study of hepatitis B virus (HBV) serology and look for HBV DNA in recent serum samples of 63 multiply transfused haemophiliacs. Of 63 haemophiliacs, 51 had evidence of previous HBV infection and 12 vaccinees had anti-HBs only. Of 40 HIV-negative, two had persistent HBsAg but all were HBV DNA negative. All 23 HIV-positive were HBsAg-negative. Loss of anti-HBc(46% vs. 17.5%) and anti-HBs (32% vs. 14%) was more commonly seen in HIV-infected compared with noninfected individuals. One HIV positive individual had HBV DNA detectable by PCR. Restrospective testing demonstrated that re-emergence was associated with loss of anti-HBs and advanced HIV infection (CD4<50 * 10(6-1) L CDC II), although eight other with CDC IV disease were HBV DNA negative. Forty-three batches of concentrates produced between 1965 and 1992 from both commercial and volunteer donors and subjected to different donor screening and virus inactivation methods were negative for HBV DNA. Some of these may have been infectious for HBV and therefore being negative for HBV may not equate with noninfectivity. We conclude that both HIV-positive and -negative haemophiliacs have lost protective antibodies against HBV since 1984 and that virus replication may re-emerge at least in the HIV-positive group. These observations may have implications for the management of their chronic liver disease and the risk of infection of sexual partners and medical attendants. PMID- 27214363 TI - A study to assess the immunogenicity, reactogenicity and safety of hepatitis A vaccine administered subcutaneously to patients with congenital coagulation disorders. AB - The objective was to compare the immunogenicity, reactogenicity and safety of an inactivated hepatitis A vaccine administered subcutaneously to patients with congenital coagulation disorders. Subjects, 97 patients with congenital coagulation disorders (67 men aged > 16 and 30 children aged <= 16 years), received hepatitis A vaccine administered at 1440 ELISA (enzyme linked immunosorbent assay) units (ELU) to the adult group and at 720 ELU to the child group at 0 and 6 months by the subcutaneous route. The vaccine was well tolerated, with the incidence of adverse events decreasing with subsequent administration of vaccine. Overall, 90% of subjects seroconverted 1 month after the booster (95% confidence interval 76-97%), with 100% seroconversion occurring in the child group compared with 85% in the adult group. There was a corresponding progressive rise in geometric mean titres in each group and no significant difference in the geometric mean titres was found between the two groups. Of the subjects, 29% were HIV positive, 3% of children compared with 40% of adults. A lower rate of seroconversion was observed in subjects with low CD4 counts. Administration of two doses of an inactivated hepatitis A vaccine at 1440 ELU in adults and 720 ELU in children is safe and highly immunogenic when given by the subcutaneous route. PMID- 27214364 TI - Successful long-term treatment with porcine factor VIII of a patient with haemophilia A and an inhibitor to factor VIII. PMID- 27214365 TI - De novo mutation causing sporadic type 2A von Willebrancd's disease: report of three cases. AB - Chemical mismatch detection has been used to screen selectively part of the A2 domain of exon 28 of the von Willebrand factor gene of three unrelated patients with apparently sporadic type 2A von Willebrand disease (vWD) and their parents and siblings. Mismatches have been defined by DNA sequencing and mutations authenticated by restriction enzyme analysis. While a mutation was identified in all three patients, no evidence of mutation could be found in their asymptomatic/un-affected parents or siblings, proving the disease to be truly sporadic in these cases. Of these, two with severe clinical bleeding had a serine 743 to leucine substitution while the third patient with clinically less severe bleeding had an arginine 834 to tryptophan substitution. The possible genetic mechanisms for sporadic type 2A vWD in these families are discussed. PMID- 27214366 TI - Inherited combined deficiency of factors XI and XII with von Willebrand's disease. AB - Combined hereditary deficiency of factors XI (FXI) and XII (FXII) associated with the deficeincy of von Willebrand factor (vWF) in a single patient has not been reported so far in the literature. We report on two brothers of non-Jewish stock with defciency of FXI, FXII and vWF. The family studies disclosed FXI and FXII deficiency in the mother of propositi. A maternal niece had FXII deficiency. The father of propositi had vWF deficiency. This study suggests possible existence of a regulatory factor common to genes specifying FXI and FXII. Associated vWF deficiency is coincidental. PMID- 27214367 TI - Factor IX: Today and Tomorrow. PMID- 27214368 TI - The haemophilic dogs of Chapel Hill, North Carolina. PMID- 27214369 TI - Factor IX inhibitors and anaphylaxis in haemophilia B. PMID- 27214370 TI - Is liver biopsy really necessary in haemophiliacs with chronic hepatitis C? PMID- 27214372 TI - Tend to Compare and Tend to Be Fair: The Relationship between Social Comparison Sensitivity and Justice Sensitivity. AB - Social comparison is a prerequisite for processing fairness, although the two types of cognition may be associated with different emotions. Whereas social comparison may induce envy, the perception of unfairness may elicit anger. Yet, it remains unclear whether people who tend to have a strong sense of fairness also tend to compare themselves more with others. Here, Study 1 used a modified ultimatum game (UG) and a social comparison game (SCG) to examine the relationship between justice sensitivity and social comparison sensitivity in 51 young adults. Study 2 examined self-reported social comparison and justice sensitivity in 142 young adults. Both studies showed a positive correlation between social comparison sensitivity and justice sensitivity. We reason that social comparison and justice sensitivity have an important positive correlation in human decision-making. The rejection of self-disadvantageous inequality offers may be due to the social comparison effect, which suggests that the tendency to compare oneself with others may contribute to having a strong sense of justice. Our findings suggest that the predictions of game theory may vary depending on the social culture context and incorporating notions of fairness and social comparison tendency may be essential to better predict the actual behavior of players in social interactive situations. PMID- 27214373 TI - Inhibition of Cardiac Kir Current (IK1) by Protein Kinase C Critically Depends on PKCbeta and Kir2.2. AB - BACKGROUND: Cardiac inwardly rectifying Kir current (IK1) mediates terminal repolarisation and is critical for the stabilization of the diastolic membrane potential. Its predominant molecular basis in mammalian ventricle is heterotetrameric assembly of Kir2.1 and Kir2.2 channel subunits. It has been shown that PKC inhibition of IK1 promotes focal ventricular ectopy. However, the underlying molecular mechanism has not been fully elucidated to date. METHODS AND RESULTS: In the Xenopus oocyte expression system, we observed a pronounced PKC induced inhibition of Kir2.2 but not Kir2.1 currents. The PKC regulation of Kir2.2 could be reproduced by an activator of conventional PKC isoforms and antagonized by pharmacological inhibition of PKCbeta. In isolated ventricular cardiomyocytes (rat, mouse), pharmacological activation of conventional PKC isoforms induced a pronounced inhibition of IK1. The PKC effect in rat ventricular cardiomyocytes was markedly attenuated following co-application of a small molecule inhibitor of PKCbeta. Underlining the critical role of PKCbeta, the PKC-induced inhibition of IK1 was absent in homozygous PKCbeta knockout-mice. After heterologous expression of Kir2.1-Kir2.2 concatemers in Xenopus oocytes, heteromeric Kir2.1/Kir2.2 currents were also inhibited following activation of PKC. CONCLUSION: We conclude that inhibition of cardiac IK1 by PKC critically depends on the PKCbeta isoform and Kir2.2 subunits. This regulation represents a potential novel target for the antiarrhythmic therapy of focal ventricular arrhythmias. PMID- 27214374 TI - Assessment of impaired coordination between respiration and deglutition in children and young adults with ataxia telangiectasia. AB - AIM: This cross-sectional investigation aimed to assess the value of non-invasive measures of temporal respiratory-swallow coupling in individuals with ataxic swallowing. METHOD: Twenty participants (11 males, 9 females; range 9-21y) with ataxia telangiectasia were presented with water and pudding boluses. Their 193 swallows were compared with 2200 swallows from 82 age-matched healthy controls. The two components of airway protection during swallowing that were analyzed were: direction of peri-deglutitive airflow and duration of deglutitive inhibition of respiratory airflow (DIORA). RESULTS: Safe expiratory patterns of peri-deglutitive airflow occurred significantly less often in participants with ataxia telangiectasia than in age-matched control participants (younger p<0.015 and older p<0.001). The frequency of an expiratory pattern of peri-deglutitive airflow increased with age in participants in the comparison group (p=0.006), but not in those with ataxia telangiectasia (p=0.234). With age, mean duration of DIORA decreased in controls (p<0.001) but was unchanged in participants with ataxia telangiectasia (p=0.164). INTERPRETATION: Non-invasive quantitative measures of respiratory-swallow coupling capture temporal relationships that plausibly contribute to airway compromise from dysphagia. Changes in respiratory swallow coupling observed with advancing age in control participants were not seen in participants with ataxia telangiectasia. Measures of perturbations may herald swallowing problems prior to development of pulmonary and nutritional sequelae. PMID- 27214375 TI - OMIP-032: Two multi-color immunophenotyping panels for assessing the innate and adaptive immune cells in the mouse mammary gland. PMID- 27214376 TI - A Maturing Use of Defibrillators. PMID- 27214377 TI - Next-generation sequencing in systemic mastocytosis: Derivation of a mutation augmented clinical prognostic model for survival. AB - In routine practice, the World Health Organization classification of systemic mastocytosis (SM) is also the de facto prognostic system; a core value is distinguishing indolent (ISM) from advanced SM (includes aggressive SM [ASM], SM with associated hematological neoplasm [SM-AHN] and mast cell leukemia [MCL]). We sequenced 27 genes in 150 SM patients to identify mutations that could be integrated into a clinical-molecular prognostic model for survival. Forty four patients (29%) had ISM, 25 (17%) ASM, 80 (53%) SM-AHN and 1 (0.7%) MCL; overall KITD816V prevalence was 75%. In 87 patients, 148 non-KIT mutations were detected; the most frequently mutated genes were TET2 (29%), ASXL1 (17%), and CBL (11%), with significantly higher mutation frequency in SM-AHN > ASM > ISM (P < 0.0001). In advanced SM, ASXL1 and RUNX1 mutations were associated with inferior survival. In multivariate analysis, age > 60 years (HR = 2.4), hemoglobin < 10 g/dL or transfusion-dependence (HR = 1.7), platelet count < 150 * 10(9) /L (HR = 3.2), serum albumin < 3.5 g/dL (HR = 2.6), and ASXL1 mutation (HR = 2.3) were associated with inferior survival. A mutation-augmented prognostic scoring system (MAPSS) based on these parameters stratified advanced SM patients into high-, intermediate-, and low-risk groups with median survival of 5, 21 and 86 months, respectively (P < 0.0001). These data should optimize risk-stratification and treatment selection for advanced SM patients. Am. J. Hematol. 91:888-893, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27214378 TI - Disease Outcomes in Glucocorticosteroid-Naive Patients With Systemic Lupus Erythematosus. AB - OBJECTIVE: The phenotype of patients who remain naive of glucocorticosteroids has not been described, and the type and rate of their damage accrual remains largely unknown. The objective of this study was to compare the type, amount, rate, and nature of organ damage accrual, mortality, and atherosclerotic comorbidities in glucocorticosteroid-naive and glucocorticosteroid-exposed patients with systemic lupus erythematosus (SLE). METHODS: Inception patients from the University of Toronto Lupus Clinic who had never taken glucocorticosteroids and had a minimum of 3 years of followup were compared to patients who received glucocorticosteroids within the first 6 months of SLE diagnosis and for at least 3 years. All patients had no damage at inception. RESULTS: A total of 86 glucocorticosteroid-naive and 173 glucocorticosteroid-exposed patients were included. There were more females and whites among the glucocorticosteroid-naive patients, whereas the glucocorticosteroid-exposed patients had higher Systemic Lupus Erythematosus Disease Activity Index 2000 scores on first examination. Overall mortality was higher in the glucocorticosteroid-exposed group, but the deaths occurred late. There was no difference in the frequency of coronary artery disease overall or at each of the time points. Damage accrual was higher in glucocorticosteroid-exposed patients overall and at 5 and 8 years. Individual damage items that were higher in glucocorticosteroid-exposed patients included ocular (cataracts) and musculoskeletal (osteoporosis with fragility fractures, and osteonecrosis) components. CONCLUSION: Mortality is more frequent in patients taking glucocorticosteroids for at least the first 3 years of their lupus compared to patients who are glucocorticosteroid-naive. In addition, patients taking glucocorticosteroids accumulate more damage by 5 years of disease, and damage tends to be glucocorticosteroid related, including cataracts and musculoskeletal components. PMID- 27214379 TI - Correction: Characterization of Lethal Zika Virus Infection in AG129 Mice. AB - [This corrects the article DOI: 10.1371/journal.pntd.0004682.]. PMID- 27214380 TI - The logic in language: How all quantifiers are alike, but each quantifier is different. AB - Quantifier words like each, every, all and three are among the most abstract words in language. Unlike nouns, verbs and adjectives, the meanings of quantifiers are not related to a referent out in the world. Rather, quantifiers specify what relationships hold between the sets of entities, events and properties denoted by other words. When two quantifiers are in the same clause, they create a systematic ambiguity. "Every kid climbed a tree" could mean that there was only one tree, climbed by all, or many different trees, one per climbing kid. In the present study, participants chose a picture to indicate their preferred reading of different ambiguous sentences - those containing every, as well as the other three quantifiers. In Experiment 1, we found large systematic differences in preference, depending on the quantifier word. In Experiment 2, we then manipulated the choice of a particular reading of one sentence, and tested how this affected participants' reading preference on a subsequent target sentence. We found a priming effect for all quantifiers, but only when the prime and target sentences contained the same quantifier. For example, all-a sentences prime other all-a sentences, while each-a primes each-a, but sentences with each do not prime sentences with all or vice versa. In Experiment 3, we ask whether the lack of priming across quantifiers could be due to the two sentences sharing one fewer word. We find that changing the verb between the prime and target sentence does not reduce the priming effect. In Experiment 4, we discover one case where there is priming across quantifiers - when one number (e.g. three) is in the prime, and a different one (e.g. four) is in the target. We discuss how these findings relate to linguistic theories of quantifier meaning and what they tell us about the division of labor between conceptual content and combinatorial semantics, as well as the mental representations of quantification and of the abstract logical structure of language. PMID- 27214381 TI - Wnt Pathway Stabilizes MeCP2 Protein to Repress PPAR-gamma in Activation of Hepatic Stellate Cells. AB - PPAR-gamma is essential for differentiation of hepatic stellate cells (HSC), and its loss due to epigenetic repression by methyl-CpG binding protein 2 (MeCP2) causes HSC myofibroblastic activation mediated in part via Wnt pathway, the key cellular event in liver fibrosis. Decreased miR-132 was previously proposed to promote MeCP2 protein translation for Ppar-gamma repression in activated HSC (aHSC). The present study aimed to test this notion and to better understand the mechanisms of MeCP2 upregulation in aHSC. MeCP2 protein is increased on day 3 to 7 as HSC become activated in primary culture on plastic, but this is accompanied by increased but not reduced miR-132 or miR-212 which is also expected to target MeCP2 due to its similar sequence with miR-132. The levels of these mRNAs are decreased 40~50% in aHSCs isolated from experimental cholestatic liver fibrosis but increased 6-8 fold in aHSC from hepatotoxic liver fibrosis in rats. Suppression of either or both of miR132 and miR212 with specific anti-miRNA oligonucleotides (anti-oligo), does not affect MeCP2 protein levels in aHSCs. The Wnt antagonist FJ9 which inhibits HSC activation, increases miR-132/miR-212, reduces MeCP2 and its enrichment at 5' Ppar-gamma promoter, and restores Ppar gamma expression but the anti-oligo do not prevent Ppar-gamma upregulation. The pan-NADPH oxidase (NOX) inhibitor diphenyleneiodonium (DPI) also reduces both MeCP2 and stabilized non-(S33/S37/Thr41)-phospho beta-catenin and reverts aHSC to quiescent cells but do not affect miR-132/miR-212 levels. Wnt antagonism with FJ9 increases MeCP2 protein degradation in cultured HSC, and FJ9-mediated loss of MeCP2 is rescued by leupeptin but not by proteasome and lysozome inhibitors. In conclusion, canonical Wnt pathway increases MeCP2 protein due to protein stability which in turn represses Ppar-gamma and activates HSC. PMID- 27214382 TI - The transfer matrix approach to circular graphene quantum dots. AB - We adapt the transfer matrix (T-matrix) method originally designed for one dimensional quantum mechanical problems to solve the circularly symmetric two dimensional problem of graphene quantum dots. Similar to one-dimensional problems, we show that the generalized T-matrix contains rich information about the physical properties of these quantum dots. In particular, it is shown that the spectral equations for bound states as well as quasi-bound states of a circular graphene quantum dot and related quantities such as the local density of states and the scattering coefficients are all expressed exactly in terms of the T-matrix for the radial confinement potential. As an example, we use the developed formalism to analyse physical aspects of a graphene quantum dot induced by a trapezoidal radial potential. Among the obtained results, it is in particular suggested that the thermal fluctuations and electrostatic disorders may appear as an obstacle to controlling the valley polarization of Dirac electrons. PMID- 27214383 TI - The randomized clinical trial of coenzyme Q10 for the prevention of periprocedural myocardial injury following elective percutaneous coronary intervention. AB - INTRODUCTION: Periprocedural myocardial injury (PMI) following elective percutaneous coronary intervention (PCI) is an important therapeutic concern with remaining some mortality and morbidity. To the best of our knowledge, there is no published study that investigates the potential benefit of CoQ10 in preventing PMI following elective PCI. METHODS: In a randomized, clinical trial, 100 patients who scheduled for elective PCI were allocated in to the intervention (n=50) and control group (n=50). The intervention received a 300 mg loading dose CoQ10 12 hours before procedure. The level of CK-MB and troponin-I was measured before procedure, and 8 and 24 hours after. Furthermore, hs-CRP was measured at baseline and 24 hours after. All patients were assessed for the incidence of major adverse cardiac effects (MACEs) after 1 month. RESULTS: The CK-MB elevation (above the upper limit normal) was occurred in 22% (n=11) of CoQ10 and 20% (n=10) of control (P=.806). The elevation of troponin-I was documented in 8% (n=4) of both groups. No significant change in the level of cardiac biomarkers was noted. However, the significant reduction in hs-CRP level was occurred in CoQ10 group (P=.032). CONCLUSION: The results showed that pretreatment with 300 mg CoQ10 12 hours before procedure could not reduce PMI following elective PCI, however, significantly decreased hs-CRP. PMID- 27214384 TI - IL-4 Causes Hyperpermeability of Vascular Endothelial Cells through Wnt5A Signaling. AB - Microvascular leakage due to endothelial barrier dysfunction is a prominent feature of T helper 2 (Th2) cytokine mediated allergic inflammation. Interleukin 4 (IL-4) is a potent Th2 cytokine, known to impair the barrier function of endothelial cells. However, the effectors mediating IL-4 induced cytoskeleton remodeling and consequent endothelial barrier dysfunction remain poorly defined. Here we have used whole genome transcriptome profiling and gene ontology analyses to identify the genes and processes regulated by IL-4 signaling in human coronary artery endothelial cells (HCAEC). The study revealed Wnt5A as an effector that can mediate actin cytoskeleton remodeling in IL-4 activated HCAEC through the regulation of LIM kinase (LIMK) and Cofilin (CFL). Following IL-4 treatment, LIMK and CFL were phosphorylated, thereby indicating the possibility of actin stress fiber formation. Imaging of actin showed the formation of stress fibers in IL-4 treated live HCAEC. Stress fiber formation was notably decreased in the presence of Wnt inhibitory factor 1 (WIF1). Non-invasive impedance measurements demonstrated that IL-4 increased the permeability and impaired the barrier function of HCAEC monolayers. Silencing Wnt5A significantly reduced permeability and improved the barrier function of HCAEC monolayers upon IL-4 treatment. Our study identifies Wnt5A as a novel marker of IL-4 activated vascular endothelium and demonstrates a critical role for Wnt5A in mediating IL-4 induced endothelial barrier dysfunction. Wnt5A could be a potential therapeutic target for reducing microvascular leakage and edema formation in Th2 driven inflammatory diseases. PMID- 27214385 TI - Social and Physical Environmental Factors Influencing Adolescents' Physical Activity in Urban Public Open Spaces: A Qualitative Study Using Walk-Along Interviews. AB - Most previous studies examining physical activity in Public Open Spaces (POS) focused solely on the physical environment. However, according to socio ecological models the social environment is important as well. The aim of this study was to determine which social and physical environmental factors affect adolescents' visitation and physical activity in POS in low-income neighbourhoods. Since current knowledge on this topic is limited, especially in Europe, qualitative walk-along interviews were used to obtain detailed and context-specific information. Participants (n = 30, aged 12-16 years, 64% boys) were recruited in POS in low-income neighbourhoods in Brussels, Ghent and Antwerp (Belgium). Participants were interviewed while walking in the POS with the interviewer. Using this method, the interviewer could observe and ask questions while the participant was actually experiencing the environment. All audio recorded interviews were transcribed and analysed using Nvivo 10 software and thematic analysis was used to derive categories and subcategories using a grounded theory approach. The most important subcategories that were supportive of visiting POS and performing physical activity in POS were; accessibility by foot/bicycle/public transport, located close to home/school, presence of (active) friends and family, cleanliness of the POS and features, availability of sport and play facilities, large open spaces and beautiful sceneries. The most important subcategories that were unsupportive of visiting POS and physical activity in POS were; presence of undesirable users (drug users, gangs and homeless people), the behaviour of other users and the cleanliness of the POS and features. Social factors appeared often more influential than physical factors, however, it was the combination of social and physical factors that affected adolescents' behaviour in POS. Easily accessible POS with high quality features in the proximity of adolescents' home or school may stimulate physical activity, if adolescents also experience a safe and familiar social environment. PMID- 27214386 TI - Current Techniques for Treating Gastrointestinal Stromal Tumors in the Upper Gastrointestinal Tract. AB - Most gastrointestinal stromal tumors (GISTs) arise from the proper muscle layer of the upper gastrointestinal (GI) tract and have a low malignant potential. They are sometimes accompanied by symptoms, but in most cases are detected by chance. Endoscopic surgery of subepithelial tumors in the upper GI tract has been actively performed, and its merits include the need for fewer medical devices compared with other surgical procedures and post-resection organ preservation. However, because endoscopic procedures are still limited to small or pilot studies, a multidisciplinary approach combining laparoscopy and endoscopy is needed for more effective and pathologically acceptable management of GISTs. Many new endoscopic surgeries have been developed, and this review describes the current status of and the new approaches for endoscopic surgery of GISTs in the upper GI tract. PMID- 27214387 TI - Effects of kinetics of light-induced stomatal responses on photosynthesis and water-use efficiency. AB - Both photosynthesis (A) and stomatal conductance (gs ) respond to changing irradiance, yet stomatal responses are an order of magnitude slower than photosynthesis, resulting in noncoordination between A and gs in dynamic light environments. Infrared gas exchange analysis was used to examine the temporal responses and coordination of A and gs to a step increase and decrease in light in a range of different species, and the impact on intrinsic water use efficiency was evaluated. The temporal responses revealed a large range of strategies to save water or maximize photosynthesis in the different species used in this study but also displayed an uncoupling of A and gs in most of the species. The shape of the guard cells influenced the rapidity of response and the overall gs values achieved, with different impacts on A and Wi . The rapidity of gs in dumbbell shaped guard cells could be attributed to size, whilst in elliptical-shaped guard cells features other than anatomy were more important for kinetics. Our findings suggest significant variation in the rapidity of stomatal responses amongst species, providing a novel target for improving photosynthesis and water use. PMID- 27214388 TI - Generation of ESC-derived Mouse Airway Epithelial Cells Using Decellularized Lung Scaffolds. AB - Lung lineage differentiation requires integration of complex environmental cues that include growth factor signaling, cell-cell interactions and cell-matrix interactions. Due to this complexity, recapitulation of lung development in vitro to promote differentiation of stem cells to lung epithelial cells has been challenging. In this protocol, decellularized lung scaffolds are used to mimic the 3-dimensional environment of the lung and generate stem cell-derived airway epithelial cells. Mouse embryonic stem cell are first differentiated to the endoderm lineage using an embryoid body (EB) culture method with activin A. Endoderm cells are then seeded onto decellularized scaffolds and cultured at air liquid interface for up to 21 days. This technique promotes differentiation of seeded cells to functional airway epithelial cells (ciliated cells, club cells, and basal cells) without additional growth factor supplementation. This culture setup is defined, serum-free, inexpensive, and reproducible. Although there is limited contamination from non-lung endoderm lineages in culture, this protocol only generates airway epithelial populations and does not give rise to alveolar epithelial cells. Airway epithelia generated with this protocol can be used to study cell-matrix interactions during lung organogenesis and for disease modeling or drug-discovery platforms of airway-related pathologies such as cystic fibrosis. PMID- 27214389 TI - The Relationship Between Brain MR Spectroscopy and Disability in Multiple Sclerosis: 20-Year Data from the U.S. Glatiramer Acetate Extension Study. AB - BACKGROUND AND PURPOSE: Conventional MRI techniques do not necessarily provide information about multiple sclerosis (MS) disease pathology or progression. Nonconventional MRI techniques, including proton magnetic resonance spectroscopy (1 H-MRS), are increasingly used to improve the qualitative and quantitative specificity of MR images. This study explores potential correlations between MRI measures of disease and disability progression as measured by the Expanded Disability Status Scale (EDSS), Functional Systems (FS), and ambulation index scores in a unique cohort of MS patients treated with glatiramer acetate that has been closely monitored for over 20 years. METHODS: This was a multicenter, open label, cross-sectional MRI substudy among participants in the GA-9004 open-label extension of the 36-month, double-blind GA-9001 study, timed to coincide with the prospectively planned 20-year clinical exam. RESULTS: Of 64 patients who participated in the MRI substudy, results are presented for the 39 patients (61%) who had a 1 H-MRS assessment at 20 years of treatment. Both total N acetylaspartate relative to total creatinine (tNAA/tCr) concentration ratio and T1 lesion volume were found to be robustly associated with disability levels with different statistical approaches. Gray matter (GM) volume was found to be a more consistent parameter than white matter (WM) volume for disability allocation. The elastic net algorithm showed a trade-off between WM and GM volumes for disability estimation when different disability definitions were used. CONCLUSIONS: Among patients with MS receiving long-term glatiramer acetate therapy, consistent effects on disability levels indicated by EDSS and pyramidal FS score thresholds were found for tNAA/tCr concentration ratio and T1 lesion volume. PMID- 27214390 TI - A Supramolecular Shear-Thinning Anti-Inflammatory Steroid Hydrogel. AB - Shear-thinning and self-healing steroid-drug-based hydrogels are presented, which exhibit rapid and complete recovery of their mechanical properties within seconds following stress-induced flow. The hydrogels release steroid drug in vivo with no visible residue when release is complete. PMID- 27214391 TI - Induction of Experimental Autoimmune Encephalomyelitis in Mice and Evaluation of the Disease-dependent Distribution of Immune Cells in Various Tissues. AB - Multiple sclerosis is presumed to be an inflammatory autoimmune disease, which is characterized by lesion formation in the central nervous system (CNS) resulting in cognitive and motor impairment. Experimental autoimmune encephalomyelitis (EAE) is a useful animal model of MS, because it is also characterized by lesion formation in the CNS, motor impairment and is also driven by autoimmune and inflammatory reactions. One of the EAE models is induced with a peptide derived from the myelin oligodendrocyte protein (MOG)35-55 in mice. The EAE mice develop a progressive disease course. This course is divided into three phases: the preclinical phase (day 0 - 9), the disease onset (day 10 - 11) and the acute phase (day 12 - 14). MS and EAE are induced by autoreactive T cells that infiltrate the CNS. These T cells secrete chemokines and cytokines which lead to the recruitment of further immune cells. Therefore, the immune cell distribution in the spinal cord during the three disease phases was investigated. To highlight the time point of the disease at which the activation/proliferation/accumulation of T cells, B cells and monocytes starts, the immune cell distribution in lymph nodes, spleen and blood was also assessed. Furthermore, the levels of several cytokines (IL-1beta, IL-6, IL-23, TNFalpha, IFNgamma) in the three disease phases were determined, to gain insight into the inflammatory processes of the disease. In conclusion, the data provide an overview of the functional profile of immune cells during EAE pathology. PMID- 27214392 TI - Selective intestinal decontamination with norfloxacin enhances a regulatory T cell-mediated inflammatory control mechanism in cirrhosis. AB - BACKGROUND & AIMS: Norfloxacin exerts immunomodulatory effects in cirrhosis beyond its bactericidal activity. We aimed at identifying the role of regulatory T (Treg) cells in the norfloxacin mechanism that compensates the inflammatory environment in cirrhosis. PATIENTS & METHODS: Consecutively admitted patients with cirrhosis and ascitic fluid (AF) with: spontaneous bacterial peritonitis (SBP), non-infected AF, and norfloxacin as secondary SBP prophylaxis (SID group). Tregs were defined by flow-cytometry as CD4+ CD25+ FoxP3+ cells. Dendritic cells (DCs) were purified for co-stimulatory signalling evaluation and norfloxacin and IL-10 levels were measured in serum. Wildtype and recombination activating gene 1 (Rag1)-deficient mice with CCl4 -induced cirrhosis were used for adoptive transfer experiments using naive CD4+ T cells and Tregs. RESULTS: Eighty-four patients were included. Treg percentage was significantly increased in SID patients compared with SBP or non-infected AF patients. A positive correlation was observed between Tregs and serum norfloxacin and IL-10 levels. DCs from SID patients showed a significantly decreased expression of CD80 and CD86 compared with SBP and non-infected AF patients and correlated with norfloxacin levels. Modulation of co-stimulatory signalling by norfloxacin was not detected in Rag1 deficient mice and Rag1-deficient mice reconstituted with naive T-cells. However, reconstitution with naive T-cells and Tregs was associated with significantly downregulated CD80 and CD86 expression in the presence of norfloxacin. Norfloxacin immunomodulatory effect on IL-2 and IFN-gamma reduction and on the increase of IL-10 was significantly achieved only when the Tregs were restored in Rag1-deficient mice. CONCLUSIONS: These results provide a plausible mechanism for the immunomodulatory effects of norfloxacin in cirrhosis beyond its bactericidal effect. PMID- 27214393 TI - Intestinal dysbiosis and innate immune responses in axial spondyloarthritis. AB - PURPOSE OF REVIEW: Inflammatory innate and adaptive immune cell responses to commensal bacteria underlie the pathogenesis of human chronic inflammatory diseases. Intestinal dysbiosis has been described in patients with spondyloarthritis (SpA) and seems to be correlated with histologic and immunologic alterations. Purpose of this review is to discuss the relationship occurring between intestinal dysbiosis and innate immune responses in patients with axial SpA. RECENT FINDINGS: Intestinal dysbiosis and differential activation of intestinal immune responses in patients with SpA have been demonstrated. Furthermore, innate cells that appear to be involved in the pathogenesis of SpA may control intestinal homeostasis through induction of apoptotic cell death and deletion of activated commensal bacteria-specific T cells. SUMMARY: Although the evidence shows that dysbiosis occurs in SpA, it is not clear the role of dysbiosis in regulating innate immune responses in SpA. Relationships between cause and effect remain to be answered. VIDEO ABSTRACT: http://links.lww.com/COR/A34. PMID- 27214394 TI - Pancreatic Squamous Cell Carcinoma: A Population-Based Study of Epidemiology, Clinicopathologic Characteristics and Outcomes. AB - OBJECTIVES: Squamous metaplasia is commonly detected in pancreatic parenchyma; however, primary pancreatic squamous cell carcinoma (SCC) is a rare malignancy with unknown incidence and unclear prognosis. METHODS: Surveillance, Epidemiology, and End Results (SEER) registries were examined identifying pancreatic SCC and adenocarcinoma cases from 2000 to 2012. Age-adjusted incidence rates were calculated. Patients with SCC versus adenocarcinoma were compared by clinical features and relative survival outcomes. RESULTS: We identified 214 patients with SCC and 72,860 with adenocarcinoma. For SCC, incidence rates tripled between 2000 and 2012. Significantly higher SCC incidence rates were observed in older age groups, blacks, and males. Greater proportion of patients with SCC than those with adenocarcinoma had poorly differentiated histology (73.0% vs 43.7%, P < 0.001). In both subtypes, majority of patients had stage IV disease, 59.0% for adenocarcinoma versus 62.6% for SCC. The 1- and 2-year relative survival rate was significantly lower in patients with SCC versus adenocarcinoma. The 1-year relative survival was 14.0% (95% confidence interval, 9.5%-19.4%) for SCC, compared with 24.5% (95% confidence interval, 24.2%-24.8%) for adenocarcinoma. CONCLUSIONS: Although primary pancreatic SCC is a rare neoplasm, incidence rates for this subtype are increasing. Relative to adenocarcinoma, pancreatic SCC is characterized by poorly differentiated histology and worse survival. PMID- 27214395 TI - The role of macrophage transcription factor MafB in atherosclerotic plaque stability. AB - BACKGROUND AND AIMS: Macrophage differentiation is associated with the development of atherosclerosis and plaque vulnerability and is regulated by transcription factor MafB. We previously reported that MafB attenuates macrophage apoptosis, which is associated with atherosclerotic plaque instability. The aim of this study was to elucidate the role of MafB in the progression of atherosclerotic plaque. METHODS: We generated macrophage-specific dominant negative (DN) MafB transgenic mice and intercrossed DN-MafB mice with apolipoprotein E (ApoE) knockout (KO) mice. RESULTS: There was no significant difference in advanced atherosclerotic lesion area between DN-MafB/ApoE KO mice and littermate control ApoE KO mice 9 weeks after high-cholesterol diet. However, DN-MafB/ApoE KO mice showed significantly larger necrotic cores and lower collagen content in atherosclerotic plaques than ApoE KO mice. Although there was no difference in intraplaque macrophage infiltration and efferocytosis, DN MafB/ApoE KO mice showed significantly more apoptotic macrophages at the plaque edges than did ApoE KO mice. Real-time PCR analysis revealed that peritoneal macrophages of DN-MafB/ApoE KO mice had a greater increase in matrix metalloproteinase-9 and mRNA expression of inflammatory/M1 macrophage markers (tissue necrosis factor-alpha, interleukin-6, CD11c, and p47phox) after lipopolysaccharide stimulation than those of ApoE KO mice. CONCLUSION: Macrophage specific inhibition of MafB may destabilize atherosclerotic plaques in advanced lesions. PMID- 27214396 TI - Predictors of cardiovascular events after one year of molecular screening for Familial hypercholesterolemia. AB - BACKGROUND AND AIMS: This study reports the first year follow-up of individuals enrolled in Brazil's genetic cascade screening program for Familial Hypercholesterolemia (FH), Hipercol Brasil. Predictors for the occurrence of cardiovascular (CV) events in individuals screened for FH were studied. METHODS: This is an open prospective cohort of individuals who were included in a cascade genetic screening program for FH. The first prospective follow-up was carried out one year after patients received their genetic test result. Individuals included in this study were index cases (probands) and relatives with identified (M +) or not genetic mutations (M -). Logistic regression analysis was performed to determine predictive variables for the occurrence of CV events censored at one year of follow-up. RESULTS: A total of 818 subjects were included, 47 first CV events were ascertained, with 14 (29.7%) being fatal. For index cases, the only factor independently associated with increased risk of CV events was the presence of corneal arcus (OR: 9.39; 95% CI: 2.46-35.82). There was an inverse association of CV events with higher HDL-cholesterol levels (OR: 0.95; 95% CI: 0.90-0.99). For M+ relatives, risk factors associated with increased CV events risk were diabetes mellitus (OR: 7.97; 95% CI: 2.07-30.66) and tobacco consumption (OR: 3.70; 95% CI: 1.09-12.50). CONCLUSIONS: A high one-year incidence of CV events was found in this cascade-screening cohort. Predictors of events differed between index cases and relatives and can be useful for the development of preventive efforts in this highly susceptible group of individuals. PMID- 27214397 TI - One year in review: systemic vasculitis. AB - Systemic vasculitis are complex and heterogenous disorders. During the past months great efforts have been made aimed at clarifying disease pathogenesis and at improving patient management and treatment. In this review we summarise the most important scientific contributions on vasculitis pathogenesis, diagnostic tools and treatment published in 2015. PMID- 27214399 TI - Game movement demands and physical profiles of junior, senior and elite male and female rugby sevens players. AB - To inform recruitment, selection, training and testing of male and female rugby sevens players game running movement patterns and physical characteristics were quantified across junior, senior, and elite playing levels. Anthropometric and physical testing (40 m sprint, vertical jump, Yo-Yo IR1) occurred prior to players' national championships or international tournaments (n = 110 players), while game movements were obtained via GPS (n = 499 game files). The game movements of male players were similar across playing levels except for number of impacts >10 g which were 2 to 4-fold higher in elite (25.0 +/- 11.2 impacts . game-1; mean +/- SD), than junior (6.3 +/- 3.5) and senior (11.8 +/- 6.6) players. In men, there were fewer substantial correlations between on- and off field measures which may reflect similar physical attributes across playing levels, and that other (strength, technical or tactical) factors may better differentiate these players. In females, elite players had more favourable on- and off-field performance measures than juniors and seniors, with moderate to strong correlations between on- and off-field variables. Female players should benefit from additional fitness training, while male players need to balance fitness with other technical and tactical factors. PMID- 27214398 TI - Kisspeptin Responsiveness Signals Emergence of Reproductive Endocrine Activity: Implications for Human Puberty. AB - CONTEXT: Some patients with idiopathic hypogonadotropic hypogonadism (IHH) undergo spontaneous activation of their hypothalamic-pituitary-gonadal axis resulting in normalization of steroidogenesis and/or gametogenesis, a phenomenon termed reversal. OBJECTIVE: To assess the responsiveness of the GnRH neuronal network to exogenous kisspeptin administration in IHH patients who have undergone reversal. PARTICIPANTS: Six men with congenital IHH and evidence for reversal. INTERVENTION: Subjects underwent q10 min blood sampling to measure GnRH-induced LH secretion at baseline and in response to iv boluses of kisspeptin (0.24-2.4 nmol/kg) and GnRH (75 ng/kg). RESULTS: Individuals with sustained reversal of their hypogonadotropism (spontaneous LH pulses) responded to exogenous kisspeptin with a GnRH-induced LH pulse. Individuals who had reversal but then subsequently suffered relapse of their IHH (loss of spontaneous LH pulsatility) did not respond to kisspeptin. CONCLUSIONS: The ability of kisspeptin to stimulate a GnRH induced LH pulse correlates with the presence of endogenous LH pulses. These data suggest that reversal of hypogonadotropism, and by extension sexual maturation, may be due to the acquisition of kisspeptin responsiveness. PMID- 27214400 TI - Robust NaO2 Electrochemistry in Aprotic Na-O2 Batteries Employing Ethereal Electrolytes with a Protic Additive. AB - Aprotic metal-oxygen batteries, such as Li-O2 and Na-O2 batteries, are of topical research interest as high specific energy alternatives to state-of-the-art Li-ion batteries. In particular, Na-O2 batteries with NaO2 as the discharge product offer higher practical specific energy with better rechargeability and round-trip energy efficiency when compared to Li-O2 batteries. In this work, we show that the electrochemical deposition and dissolution of NaO2 in Na-O2 batteries is unperturbed by trace water impurities in Na-O2 battery electrolytes, which is desirable for practical battery applications. We find no evidence for the formation of other discharge products such as Na2O2.H2O. Furthermore, the electrochemical efficiency during charge remains near ideal in the presence of trace water in electrolytes. Although sodium anodes react with trace water leading to the formation of a high-impedance solid electrolyte interphase, the increase in discharge overpotential is only ~100 mV when compared to cells employing nominally anhydrous electrolytes. PMID- 27214401 TI - An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells. AB - The KDM5 family of histone demethylases catalyzes the demethylation of histone H3 on lysine 4 (H3K4) and is required for the survival of drug-tolerant persister cancer cells (DTPs). Here we report the discovery and characterization of the specific KDM5 inhibitor CPI-455. The crystal structure of KDM5A revealed the mechanism of inhibition of CPI-455 as well as the topological arrangements of protein domains that influence substrate binding. CPI-455 mediated KDM5 inhibition, elevated global levels of H3K4 trimethylation (H3K4me3) and decreased the number of DTPs in multiple cancer cell line models treated with standard chemotherapy or targeted agents. These findings show that pretreatment of cancer cells with a KDM5-specific inhibitor results in the ablation of a subpopulation of cancer cells that can serve as the founders for therapeutic relapse. PMID- 27214402 TI - NSUN3 methylase initiates 5-formylcytidine biogenesis in human mitochondrial tRNA(Met). AB - In human mitochondria, the AUA codon encodes methionine via a mitochondrial transfer RNA for methionine (mt-tRNA(Met)) that contains 5-formylcytidine (f(5)C) at the first position of the anticodon (position 34). f(5)C34 is required for deciphering the AUA codon during protein synthesis. Until now, the biogenesis and physiological role of f(5)C34 were unknown. We demonstrate that biogenesis of f(5)C34 is initiated by S-adenosylmethionine (AdoMet)-dependent methylation catalyzed by NSUN3, a putative methyltransferase in mitochondria. NSUN3-knockout cells showed strong reduction in mitochondrial protein synthesis and reduced oxygen consumption, leading to deficient mitochondrial activity. We reconstituted formation of 5-methylcytidine (m(5)C) at position 34 (m(5)C34) on mt-tRNA(Met) with recombinant NSUN3 in the presence of AdoMet, demonstrating that NSUN3 mediated m(5)C34 formation initiates f(5)C34 biogenesis. We also found two disease-associated point mutations in mt-tRNA(Met) that impaired m(5)C34 formation by NSUN3, indicating that a lack of f(5)C34 has pathological consequences. PMID- 27214404 TI - The prognostic significance of survivin expression in gallbladder carcinoma. AB - Gallbladder cancers (GBC) are characterized by rapid progression, early metastasis, and poor prognosis; the molecular mechanisms of the various signaling pathways involved should be elucidated to develop effective therapies. Survivin, an apoptosis inhibitor protein expressed in the G2/M phase of the cell cycle, plays a role in cell division and affects both cell survival and proliferation. Survivin has been investigated in many types of cancer, and this study aims to examine the relationship of survivin expression in gallbladder cancer patients with clinicopathological features and prognosis. We evaluated demographic characteristics (age, gender), tumor characteristics (histopathological type, differentiation, perineural, and lymphovascular invasion; serosal invasion, surgical margin positivity and lymphocytic response), and Survivin expression immunohistochemically, and we analysed the relationship between these characteristics and prognosis in 47 gallbladder carcinoma cases from 2000 to 2011. Immunohistochemically, while survivin expression was observed in 36 cases, it was absent in 11 cases. Follow-up data were obtained from 32 patients. Two (8.7%) of 23 cases with a Survivin-positive tumor were alive at 74th and 35th months, whereas 5 (%55.6) of nine cases with Survivin-negative tumor were alive at 50th, 89th, 124th, 126th, 131th months. Survivin expression was correlated with short survival (p = 0.043), and the univariate analysis showed that reduced overall survival was associated with age (p = 0.043), male gender (p = 0.038), infiltrative pattern (p = 0.019), lymphovascular invasion (p = 0.004), perineural invasion (p = 0.009), serosal invasion (p = 0.027), ulcer (p = 0.033), and surgical margin positivity (p = 0.022). Despite the low number of patients in our study, the analysis results suggest that survivin positivity might actually be a significant prognostic factor. This finding could be a reference point for targeted treatment studies. However, further studies involving broader series and longer follow-up are still required for highly lethal gallbladder cancers. PMID- 27214403 TI - Structural analysis of human KDM5B guides histone demethylase inhibitor development. AB - Members of the KDM5 (also known as JARID1) family are 2-oxoglutarate- and Fe(2+) dependent oxygenases that act as histone H3K4 demethylases, thereby regulating cell proliferation and stem cell self-renewal and differentiation. Here we report crystal structures of the catalytic core of the human KDM5B enzyme in complex with three inhibitor chemotypes. These scaffolds exploit several aspects of the KDM5 active site, and their selectivity profiles reflect their hybrid features with respect to the KDM4 and KDM6 families. Whereas GSK-J1, a previously identified KDM6 inhibitor, showed about sevenfold less inhibitory activity toward KDM5B than toward KDM6 proteins, KDM5-C49 displayed 25-100-fold selectivity between KDM5B and KDM6B. The cell-permeable derivative KDM5-C70 had an antiproliferative effect in myeloma cells, leading to genome-wide elevation of H3K4me3 levels. The selective inhibitor GSK467 exploited unique binding modes, but it lacked cellular potency in the myeloma system. Taken together, these structural leads deliver multiple starting points for further rational and selective inhibitor design. PMID- 27214405 TI - Staphylococcus epidermidis biofilm on implant material is reduced by a covalently linked thiophenone. AB - AIMS: The present aims were firstly to coat metal implant material with a quorum sensing inhibitory thiophenone molecule, and secondly to assess the inhibitory effect on Staphylococcus epidermidis biofilm accumulation on thiophenone-coated coupons. METHOD AND RESULTS: Thiophenone- and control-coated metal coupons were prepared by silane hydrolysis and dip coating. The linking of thiophenone to the surface was confirmed by X-ray photoelectron spectroscopy analyses. Biofilm by Staph. epidermidis, a frequent cause of implant-associated infections, was allowed to form under flowing conditions for 48 h. The biofilm accumulations were significantly reduced on the thiophenone-coated coupons. This was confirmed by confocal scanning microscopy. CONCLUSION: This study showed for the first time how a synthetic thiophenone may be covalently linked to a stainless steel surface, and that biofilm accumulations on such surfaces are significantly reduced. SIGNIFICANCE AND IMPACT OF THE STUDY: Functionalizing surfaces by covalent linking of thiophenones might open a wide array of applications. Thiophenone coating of medical implants represents a novel and promising approach to prevent implant-associated infections. PMID- 27214407 TI - Unconventional methods of imaging: computational microscopy and compact implementations. AB - In the past two decades or so, there has been a renaissance of optical microscopy research and development. Much work has been done in an effort to improve the resolution and sensitivity of microscopes, while at the same time to introduce new imaging modalities, and make existing imaging systems more efficient and more accessible. In this review, we look at two particular aspects of this renaissance: computational imaging techniques and compact imaging platforms. In many cases, these aspects go hand-in-hand because the use of computational techniques can simplify the demands placed on optical hardware in obtaining a desired imaging performance. In the first main section, we cover lens-based computational imaging, in particular, light-field microscopy, structured illumination, synthetic aperture, Fourier ptychography, and compressive imaging. In the second main section, we review lensfree holographic on-chip imaging, including how images are reconstructed, phase recovery techniques, and integration with smart substrates for more advanced imaging tasks. In the third main section we describe how these and other microscopy modalities have been implemented in compact and field-portable devices, often based around smartphones. Finally, we conclude with some comments about opportunities and demand for better results, and where we believe the field is heading. PMID- 27214406 TI - Tractography-Based Ventral Intermediate Nucleus Targeting: Novel Methodology and Intraoperative Validation. AB - BACKGROUND: The ventral intermediate nucleus of the thalamus is not readily visible on structural magnetic resonance imaging. Therefore, a method for its visualization for stereotactic targeting is desirable. OBJECTIVE: The objective of this study was to define a tractography-based methodology for the stereotactic targeting of the ventral intermediate nucleus. METHODS: The lateral and posterior borders of the ventral intermediate nucleus were defined by tracking the pyramidal tract and medial lemniscus, respectively. A thalamic seed was then created 3 mm medial and anterior to these borders, and its structural connections were analyzed. The application of this method was assessed in an imaging cohort of 14 tremor patients and 15 healthy controls, in which we compared the tractography-based targeting to conventional targeting. In a separate surgical cohort (3 tremor and 3 tremor-dominant Parkinson's disease patients), we analyzed the accuracy of this method by correlating it with intraoperative neurophysiology. RESULTS: Tractography of the thalamic seed revealed the tracts corresponding to cerebellar input and motor cortical output fibers. The tractography-based target was more lateral (12.5 [1.2] mm vs 11.5 mm for conventional targeting) and anterior (8.5 [1.1] mm vs 6.7 [0.3] mm, anterior to the posterior commissure). In the surgical cohort, the Euclidian distance between the ventral intermediate nucleus identified by tractography and the surgical target was 1.6 [1.1] mm. The locations of the sensory thalamus, lemniscus, and pyramidal tracts were concordant within <1 mm between tractography and neurophysiology. INTERPRETATION: The tractography-based methodology for identification of the ventral intermediate nucleus is accurate and useful. This method may be used to improve stereotactic targeting in functional neurosurgery procedures. (c) 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. PMID- 27214408 TI - Welcome to the PNAE Congress 2016. PMID- 27214409 TI - What matters to you? AB - We asked the children, their families and the staff and found so much hidden but useful and valuable information in creating a new ward for children. PMID- 27214410 TI - Priorities for children and young people - opportunities and challenges for children and young people's nurses. AB - Across Europe children's nurses today face many challenges, including rising childhood obesity, the soaring incidence of issues with the mental health of children and young people, the effects of social media, child maltreatment and the impact of poverty, war and conflict on children and families. There are opportunities for children's nurses to undertake new roles and to influence both policy and practice to improve the health outcomes of children and young people, and thereby the future health of the population. PMID- 27214411 TI - 'Touchpoints' by nurses: impact on maternal representations, child development, quality of mother-infant interaction, and mothers' perception of the quality of relationships with nurses. AB - AIM: To investigate the effect of implementing the Touchpoints methodology by nurses in the following variables: quality of mother-infant interaction; infant development; maternal representations of child temperament and mothers' perception of the quality of relationship with nurses. METHODS: Quasi experimental longitudinal study, including 86 child-mother dyads distributed equally for: Group with Intervention (GI) (n=43), Group without Intervention (GWI) (n=43). These groups belonged to paired samples according to the following criteria: maternal age; socio-economic class; family structure; child health; parents' physical or psychological health; twins; family's nationality; risk during pregnancy; baby APGAR. Paired samples with the same routine visits allowed comparing the impact of Touchpoints intervention on the above mentioned variables. The monitoring of the two groups took place in a period of between 11 and 24 months of children's life (four moments of assessment), being held two Touchpoints sessions in the GI at 12 and 18 months. Two Touchpoints interventions sessions were applied in the GI as follows: the first time, at 12 months; the second time, at 24 months, child age. The instruments used for data collection were: Schedule of Growing Skills II (SGS II); CARE-Index; Temperament Scale; Parent-Caregiver Relationship Scale - parents' version. RESULTS: Infant Locomotor development (p=.036) and maternal representations about the child and motherhood (Z=5.737; p=.019) improved in the GI. No significant results were found for mother-infant interaction in this direct comparison. Nevertheless, findings indicate that maternal sensitivity and infant cooperative behaviour increased from 12 to 24 months in the GI [t(41)=4.513; p<.001], whereas it decreased in the GWI (from 8.62 at 12 months to 8.40 at 24 months). The means of mothers' perceptions of Trust/Caring towards nurses in the GI were higher than in GWI after six months of the Touchpoints intervention [t(84)=2.146; p<.001; M_GI=34.07, SD=3.71; M_GWI=31.79], Collaboration/Partnership [t(84)=2.817; p<.001; M_GI=62.79, SD=4.809; M_GWI=59.89, SD=6.538] and Relational/Emotional [t(84)= 2.334; p<.001; M_GI=60.53, SD=3.838; M_GWI=58.30, SD=5.638]. Children at risk for developmental problems in the GI and GWI improved their development in Speech and Language (Z=4.772; p<.05; M_GI at risk =13.64 SD=.30 vs. M_GWI at risk=13.00, SD=.29), Hearing and Language (Z=4.341; p<.05; M_GI at risk=15.08, SD=.37 vs M_GWI at risk=14.0, SD=.36) and in Self-care Social (Z=4.0; p<.05 vs M_GI at risk=11.96, SD=.35; M_GWI at risk=11.46, SD=.34) after the intervention with Touchpoints. Also, maternal sensitivity and infant cooperative behaviour increased after Touchpoints intervention in dyads of 'children at risk' for developmental problems when compared to the dyads of 'children at risk without' these problems. CONCLUSION: The intervention using Touchpoints methodology by nurses had a positive effect on the following dimensions: infant development; maternal representations about the child and motherhood; maternal sensitivity and infant cooperative behaviour; perceptions of Trust/Caring towards nurses. This was particularly significant among children who were identified as having potential development risks. Further research is needed to better explain these findings. PMID- 27214412 TI - The power of early interventions in families with preterm born children. AB - The Tromso Intervention Study on Preterms (TISP) started in 1999 and we may now present results on children's socio-emotional and behavioural development, parental wellbeing and perceptions of the children's quality of life until children's age of nine. PMID- 27214413 TI - Evidence-based paediatric nursing: paediatric early warning systems. AB - In hospital cardiac arrest are rare events in paediatrics. Most children receive appropriate care without experiencing undetected severe clinical deterioration during hospital admission. Outcomes of paediatric cardiac arrests are however generally poor, with high mortality rates and neurological damage at survival. A review of child mortality in the UK showed that a high proportion of unexpected deaths were preventable ( Pearsons 2008 ). Several studies of patient records of children who suffered cardiac arrests showed the presence of clear signs of clinical deterioration up to 24 hours before (Tume 2006). Appropriate recognition of clinical deterioration could have led to timely intervention to stabilise the patient. Missed deterioration may be due to lack of staff situational awareness, communication failure among professionals or between staff and families and other human factors ( Brady 2014 ). PMID- 27214414 TI - Design of paediatric hospitals. AB - The impact of healthcare environments on children and young people's (CYP) health and psychosocial wellbeing has attracted much attention in recent years. This sits within the realm of the political drive for enhanced awareness of the need to take account of the rights and voice of the child. Perhaps as a direct result of the United Nations Convention on the Rights of the Child, and recognition from evidence in adult population studies of the impact of healthcare environments on psychosocial healing, contemporary times have witnessed a discernible movement towards enhancing quality care by promoting child and adolescent-friendly hospital environments. The Council of Europe guidelines on child-friendly health care moved to place the rights and needs of children at the heart of health care. The Council acknowledges that the delivery of child-oriented services, which includes the notion of family-centred care, should be delivered in child and family friendly environments. However, knowledge about what constitutes a child friendly healthcare environment from CYP's perspective is often lacking with hospital architectural blueprints predominantly designed around adult proxy reported assumptions about the needs and desires of children. PMID- 27214415 TI - Through the lens of young people: use of photography in hospital design. AB - Whilst arts in hospitals have been perceived as therapeutic to patients, this paper will share evidence and research to support that photography and photo elicitation has an important role in preference and choice about hospital design. The paper will initially draw on studies that used participatory photography in children's hospital design in international settings. PMID- 27214416 TI - OC01 - The effect of an Interactive Therapeutic Play Training Program on the anxiety levels of children having heart surgery and their mothers. AB - Theme: Child protection and managing risk. PMID- 27214417 TI - OC02 - Promoting the university research of paediatric nurses. AB - Theme: Nursing education, management and leadership. PMID- 27214418 TI - OC04 - A weaning plan for high flow nasal therapy (HFNT) in bronchiolitis - a nurse-led initiative. AB - Theme: Nursing education, management and leadership. INTRODUCTION: The use of HFNT in bronchiolitis is a new phenomenon in paediatrics, with insufficient evidence on its effectiveness (Beggs et al 2014). This paper reports the findings of a clinical audit which resulted in the development of a nurse-led weaning plan to support infant recovery with the potential to reduce hospital stay. OBJECTIVE: To highlight the effectiveness of a nurse-led weaning plan in a general paediatric unit. METHOD: The data of 32 infants were analysed between October 2014 and March 2015. Further data will be collected between October 2015 and March 2016. Data will then be compared. RESULTS: Initial data demonstrates the average time infants spent on HFNT was 2.6 days compared to five days in previous studies (Bressan et al 2013). DISCUSSION: A nurse-led weaning plan has been developed from data collected. CONCLUSION: The audit demonstrates a clinical need for efficient weaning of infants on HFNT. PMID- 27214419 TI - OC03 - Multiple employment: perceptions of nurses regarding the quality of nursing care. AB - Theme: Accreditation and quality improvement. OBJECTIVES: To identify factors related to multiple employment that nurses consider as an influence to the care provided; analyze the perceptions of nurses regarding the influence that these factors have on quality of care provided. METHODS: The study is a qualitative study, with a sample of 17 nurses, seven currently working in multiple employments, five who have worked in multiple employments but currently do not, and five who have never worked in context. CONCLUSIONS: The majority of nurses who have worked in multiple employment and those who have never worked in multiple employment consider that there are negative implications for the quality of care when a nurse is working in a multiple employments context. However, most of the nurses working in multiple employments do not consider it as the direct cause for the implications in the quality of care, because fatigue can have different precipitating factors, whether social, family, psychological or emotional. PMID- 27214420 TI - OC06 - Involving parents in their child's care - where next? AB - Theme: Complex health care and chronic disease management. INTRODUCTION: Health policy advocates that professionals involve parents in care and care decisions, yet models advocating involvement are not embedded into practice. AIM: Identify the shared antecedents and key attributes associated with embedding family centred care (FCC) and partnership-in-care (PiC) into practice. METHODS: A concept synthesis was undertaken by searching three databases (Scopus, CINAHL, BNI 1999-2014); shared antecedents and attributes were extrapolated from the 30 studies that met defined inclusion criteria. RESULTS: Unclear roles and boundaries, entrenched professional practices and lack of guidelines hinder FCC/PiC implementation. An alternative framework was developed based on the actions and skills required to support parents' involvement in care and care decisions. DISCUSSION: Greater focus on the skills required to facilitate involvement may negate the challenges of embedding FCC/PiC. CONCLUSION: The framework for involvement can help guide nurses' actions towards building effective relationships and involving parents in care decisions. PMID- 27214421 TI - OC05 - Tokenism or true partnership - parental involvement in a child's acute pain care. AB - Theme: Parenting/parenthood. INTRODUCTION: Family-centred care (FCC) is widely acknowledged as underpinning children's nursing. Delivering FCC requires nurses to advocate for family involvement, particularly in areas where evidence suggest the child's needs are not being met, such as pain care. AIM: To explore parental involvement in their child's acute pain care. METHODS: A qualitative ethnographical approach was adopted, with non-participant observation and follow up interviews. The framework approach underpinned data analysis. RESULTS: Partnership between nurses and parents is not overtly evident in relation to pain care. Involvement is often 'unspoken', indicating that neither the nurse nor parent are clear about the extent to which parents can, or are, involved in care. DISCUSSION: Parents want greater involvement in their child's pain care and often initiate involvement by advocating for their child, with or without support from nurses. CONCLUSIONS: The 'Pillars of Partnership in Pain Care' model offers an alternative approach to involving parents. PMID- 27214422 TI - OC07 - Why should parents and health professionals collaborate to manage childhood long-term conditions? AB - Theme: Complex health care and chronic disease management Introduction: Interactions between carers and health professionals often have a power imbalance; professionals seem reluctant to acknowledge carers' expertise and unwilling to relinquish control over the management of the child's condition. AIM: To explore parents' and professionals' perceptions of collaborative healthcare practice to manage childhood long-term conditions. METHODS: Qualitative study using focus groups to elicit carers' and health professionals' views of collaborative practice, with the framework approach underpinning data analysis. DISCUSSION: To facilitate parents' care-giving roles, health professionals must move from a position of care prescriber to collaborator. Yet collaboration is complex and difficult to operationalise in practice, partly because there is discordance between the views of health professionals and carers about the purpose of collaborating. CONCLUSION: Health professionals need to understand, value and respect carers' expertise and desire to be involved in care and find ways to integrate carer expertise into care and care planning. PMID- 27214423 TI - OC09 - Early maternal contact has an impact on preterm infants' brain systems that manage stress. AB - Theme: Parenting/parenthood. INTRODUCTION: Early maternal contact can protect the infants' brain from harmful effects of stress while deprivation increases the stress level and leads to increased sensitivity to stress. AIM: To evaluate the effects of continuous skin-to-skin contact (SSC) after preterm birth on stress. METHODS: Late preterm infants from two neonatal care units were randomized to either SSC or standard care. Salivary cortisol was measured in response to a nappy change at one month, and again at four months in response to a still-face procedure. RESULTS: Infants randomized to SSC had a significantly lower salivary cortisol reactivity at one month and there was a correlation between the mothers' and the preterm infants' salivary cortisol levels at four months. CONCLUSIONS: The results show that close parental contact and human touch have a buffering effect on the infant's stress reactivity and stimulate a more rapid development of regularity. PMID- 27214424 TI - OC08 - Care for the children with severe forms of atopic dermatitis. AB - Theme: Complex health care and chronic disease management. PMID- 27214425 TI - OC10 - Inter-rater agreement of the Paediatric Early Warning Score tools used in the central Denmark region. AB - Theme: Patient safety Background: Paediatric Early Warning Score (PEWS) tools can assist healthcare providers in the rapid detection and recognition of changes in patient condition. In the central Denmark region two different PEWS tools tested in large-scale RCT study. However, data from PEWS instruments are only as reliable and accurate as the caregiver who obtains and documents the parameters. AIM: The purpose was to evaluate the inter-rater agreement among nurses using the PEWS systems. DESIGN: The study was conducted in five paediatrics departments. Inter-observer reliability was investigated through simultaneous blinded PEWS assessment on the same patients by two nurses. Fleiss' kappa was utilized to determine the level of agreement among the raters. CONCLUSION: With a paucity of published reliability testing studies, this research attempts to address identified research gaps and will thus inform nursing practice. PMID- 27214426 TI - OC12 - A journey suspended in time: parents' experiences of caring for their child who is 'technology dependent' with complex ongoing healthcare needs at home. AB - Theme: Complex health care and chronic disease management. INTRODUCTION: Increasing numbers of children with complex healthcare needs who are also dependent on medical technology are surviving and being cared for at home by their parents. AIM: To gain an in-depth understanding of the lives of parents and the impact of their caregiver role on their family when they care for their child at home. METHOD: An interpretative phenomenological design was deployed to interpret the narratives of sixteen parents through interviews and digital audio diaries. DISCUSSION: The complex journey parents undertake as caregivers to their child at home. CONCLUSION: The understanding revealed will prompt practitioners to reflect on how to promote best practice for this group of children, their parents and their families by recognising the complexity of the care parents provide for their child and the support required in order to sustain their caregiver role at home. PMID- 27214427 TI - OC11 - Social support and intervention focus to minimize the effects of oncological disease in healthy siblings. AB - Theme: Complex health care and chronic disease management. INTRODUCTION: The entire process underlying cancer disease not only affects the sick child, but also the healthy siblings, which should be the centre of attention from parents and nurses. OBJECTIVES: To identify the impact of the disease in healthy siblings and know the importance of social support to minimise its impact in healthy siblings. METHODOLOGY: Descriptive, correlational study, a sample of 128 families of children with oncological diseases, between August 2011 and January 2013. In order to do our research we used the following tools: Assessment questionnaire of the children's oncological diseases impact on the family and Satisfaction Scale Social Support. RESULTS: Families with a higher impact on family structure and more accrued expenses showed greater impact of the disease in healthy siblings, the most satisfied with their social support showed less improvement. CONCLUSIONS: Nurses should seek interventions that increase the perception of the need for social support of families. PMID- 27214428 TI - OC13 - Parents' support needs during and following the death of their baby. AB - Theme: Complex health care and chronic disease management. INTRODUCTION: Support for bereaved parents after the death of a baby in the neonatal period is variable in the UK. AIM: To explore parents' experiences and perceptions of support needs during and following the death of their baby. METHODS: An interpretative phenomenological study using unstructured interviews was undertaken. Analysis was undertaken using interpretative phenomenological analysis. RESULTS: Parental grief journeys are complicated by events experienced at the end of their baby's life. A variety of support systems are needed to facilitate parental grief journeys. DISCUSSION: The variation in availability of support for parents after a neonatal death needs addressing. Whilst parental need is individualised, most parents need support in some format. CONCLUSIONS: Health professionals have a key role to play in supporting parents and signposting other supportive mechanisms after a neonatal death. PMID- 27214429 TI - OC14 - Implementation of an educational program in children's post - operative pain. AB - Theme: Nursing education, management and leadership. INTRODUCTION: Successful pain management contributes to high-quality postoperative care. OBJECTIVE: To estimate the intensity of postoperative pain in children after an educational intervention. METHOD: Surgical ward nurses after educational intervention recorded 146 children (0-16 years) postoperative pain scores, applying FLACC, FACES, NRS according to child's age during December 2012 to March 2014. RESULTS: The mean values of children's pain scores at the reception, 24h and 48h after surgery was 0,99 +/- 1,68, 0,6 +/- 1,43 and 0,13 +/- 0,79 respectively. The median pain scores for the 1st and 2nd 24-hour seemed to correlate with the duration of surgery (p = 0.048). Only 20% of cases applied some form of non pharmacological pain method that was associated with the child's age (p = 0,001). DISCUSSION: Special care should be taken about using non-pharmacological pain control methods. CONCLUSIONS: Postoperative pain management programs contribute to effective deal. PMID- 27214430 TI - OC15 - Leading nursing educational progress in child mental health. AB - Theme: Nursing education, management and leadership. Given the increasingly complex mental health needs of children and young people and the critical shortage of proficient mental health specialists, a study of US nursing education programs was done. Does the current paediatric nursing workforce preparation best meet the distinct needs of young people with behavioral and mental health challenges is the key question? Experts in the field of child psychiatric nursing practice, education and research came together to find model nursing programs for educational and clinical preparation. This presentation will report an analysis of the content of curricula-preparing psychiatric mental health nurse practitioners, models for adaptation to paediatric nurses' training and recommendations for leadership strategies. OBJECTIVES: Describe existing US nursing education models for child and youth mental health care. Propose strategies for education leadership. PMID- 27214431 TI - OC16 - Calculation skills and e-learning platform: study pre-post test on students of paediatric nursing in Italy. AB - Theme: Child protection and managing risk. Errors in medication is a very recurring problem in paediatric units and for that reason paediatric nursing students have to possess good mathematical skills (Doherty C, 2012). It is important to evaluate these competences during their university nursing degree (Harvey 2009). This problem has been discussed and it was subsequently decided to introduce 'Clinical and Practical pharmacology' lessons like a mandatory subject. AIM: Evaluate the paediatric nursing students learning curve before and after 'Clinical and Practical pharmacology' lessons, job placement and through an e learning platform. METHODS: A before and after experimental study, using a non randomized test, administered at different academic phases was used. RESULTS: Learning curve had an increase from 54.09 % to 82.65 %. In particular, that result is significant before 'Clinical and Practical pharmacology' lessons and at final test (p<0.00578). CONCLUSION: These study results are helpful for increased training action and to develop a customized e-learning platform. PMID- 27214432 TI - OC17 - Merging the person and the illness: the lived experience of emerging adults with childhood onset chronic illness. AB - Theme: Transition of care. PMID- 27214433 TI - OC18 - Neurodevelopmental outcomes following congenital heart surgery. AB - Theme: Complex health care and chronic disease management. INTRODUCTION: Congenital heart disease (CHD) may have a very important impact on central nervous system function and neurodevelopment. PURPOSE: Critical evaluation of literature concerning the neurodevelopmental outcomes following congenital heart surgery. METHODS: Systematic review of 28 articles published after 2000 in PubMed, Scopus and CINAHL. RESULTS: Neurodevelopment morbidities can have a negative impact on early childhood development, academic performance and later transition to adulthood. The spectrum of neurodevelopment impairment is wide, depending on the complexity of CHD and it is characterized by mild cognitive impairment, impaired social interaction, and impairments in core communication skills, including pragmatic language, as well as inattention, impulsive behavior and impaired executive function. A number of important determinants are presented. CONCLUSIONS: Children with CHD are at increased risk for neurodevelopmental delay. Screening and evaluation of neurodevelopmental delay, along with regular follow up, are essential steps to guide appropriate interventions to optimize their overall development. PMID- 27214434 TI - OC19 - Measuring feasibility, reliability and validity of the Greek version of PedsQL cardiac module. AB - Theme: Cardiology Introduction: Measuring quality of life (QoL) in children and adolescents with congenital heart disease (CHD) is of great clinical importance. OBJECTIVE: The aim of the study was: (a) to adapt the PedsQL Cardiac Module for children aged two to 18 years with CHD in a sample of the Greek population; (b) to determine its reliability and validity. METHODS: Forward and backward translation methodology was used. Parents and children completed the instrument during: (a) hospitalization and (b) visits in the paediatric cardiology outpatient department. Cross-informant variance between children and parents was thoroughly assessed. RESULTS: Missing item responses did not exceed 5%. All internal consistency reliability coefficients for the inventory exceeded the minimum standards for group comparisons, over 0.75. Hypothesized correlations between cardiac module and core scales were statistically significant, (p<0.05). Agreement between children and parents was relatively high. Pilot study results will be additionally presented. CONCLUSION: The findings support the feasibility, reliability and validity of the Greek translation of the PedsQL Cardiac Module in children with congenital heart defect (CHD). PMID- 27214435 TI - OC20 - Skin-to-skin contact in the first hour of life. AB - Theme: Child protection and managing risk. BACKGROUND: Skin-to-skin contact in the first hour of life has benefits for the mother and the newborn, as well as a major role in establishing breastfeeding. OBJECTIVES: Determine the prevalence of skin-to-skin contact and breastfeeding within the first hour of life. METHOD: A systematic review of literature followed by a quantitative and simple descriptive cross-sectional study, according to a non-probability analyzing of 382 clinic records of postpartum mothers. RESULTS: Evidence that early skin-to-skin contact immediately after birth is a potential sensory stimulus, which covers the newborn warming, tactile and active stimulation, respiratory rates and level of blood glucose, reduces baby crying and promotes breastfeeding. In the sample, about 92.6% of the mothers put the baby to the breast in the first hour of life, but only 26.6% made skin-to-skin contact with the baby. CONCLUSION: Despite the scientific evidence of the benefits of skin-to-skin contact immediately after birth, this practice is still not widely used as, according to the study results, and is only applied to one in every four newborns. PMID- 27214436 TI - OC22 - Light House Project. PMID- 27214437 TI - OC21 - Psychosocial functioning of parents of infants diagnosed with complex congenital heart defect. AB - Theme: Parenting/parenthood. INTRODUCTION: The diagnosis of complex CHD impacts the psychosocial status of parents and their functioning. PURPOSE: A critical evaluation of the literature concerning the psychosocial parental response to their infant's diagnosis of complex CHD. METHODS: Systematic review of 18 articles published after 2000 in PubMed and CINAHL. RESULTS: The impact of an infant's CHD on the family functioning is determined both by child's medical condition and family's psychosocial factors. The majority of parents experience intense loss and numerous stressors. Nurses and physicians need to be sensitive to the needs, thoughts and experiences of the parents when discussing treatment options. Families with poor social support networks may have the greatest need for professional interventions. CONCLUSIONS: Appropriate interventions assist the majority of parents to adapt to the diagnosis of complex CHD. However, there are a number of parents with an increased psychosocial risk associated with higher rates of emotional distress. PMID- 27214438 TI - OC23 - Expert mentoring: a path to leadership. AB - Theme: Nursing education, management and leadership. PMID- 27214439 TI - OC24 - An algorithm proposal to oral feeding in premature infants. AB - Theme: Transition of care. INTRODUCTION: Oral feeding is one of the hardest steps for premature infants after respiratory independence and is a challenge for nurses in neonatology. OBJECTIVES: To know the characteristics of preterm infants, essential for oral feeding; to know the nurses' opinion on nursing interventions, that promote the transition of gavage feeding for oral feeding in preterm infants. METHODS: An exploratory, descriptive study with a qualitative approach was used. Semi-structured interviews with neonatal nurses were conducted and data was submitted to content analysis. RESULTS: Weight, gestational age, physiological stability, sucking coordination, swallowing and breathing, and the overall look and feeding involvement are fundamental parameters to begin oral feeding. Positioning the baby, reflexes stimulation, control stress levels, monitoring the temperature and the milk flow are nursing interventions that promote the development of feeding skills. CONCLUSION: An algorithm for the oral feeding of preterm infants was developed grounded in the opinions of nurses. PMID- 27214440 TI - OC25 - Helping parents spot the deteriorating child: co-production of safety netting interventions. AB - Theme: Child protection and managing risk. INTRODUCTION: Providing families with a safety net of information is a crucial component in the care of children with acute illnesses at home (Jones et al 2013). Safety netting is recommended by UK national bodies and has been found to reduce re-consultation safely (Maguire et al 2011). AIM: To provide parents with information to help them determine when to seek help for an acutely ill child. METHODS: Research programme encompassed five projects: a systematic review; a qualitative exploration of safety netting information used by parents and professionals; a mixed methods development of content, format and delivery modes for the first intervention; video capture of children with acute illness; and co-design of the content of the intervention with parents and professionals. CONCLUSION: ASK SNIFF projects repeatedly demonstrate the need for professionally endorsed, co-produced safety-netting resources for parents with varying information needs, literacy levels and ability to use information technology. PMID- 27214441 TI - OC26 - Parents of young children in research: informants, consultants and collaborators. AB - Theme: ETHICAL ISSUES: dignity and humanity. INTRODUCTION: Patient and public involvement in research is recognised as best practice in the UK, as services developed with service users are more likely to meet their needs. In child health this often means engaging with parents of young children. AIM: To share experiences of engaging with parents of young children in research projects at varying levels of participation. METHODS: Methods include parents as participants, as parent panels and as research team members reflecting various steps on the participation ladder (Hart 1992). RESULTS: Parents report personal benefits and a range of different challenges when engaging in child health research which impact the management/delivery of research projects. CONCLUSION: Key elements of working with parents include time to plan involvement, building respect/mutual understanding, equal access to project activities, continual support for parents, reward and recognition. Research projects need to cost and plan for parents' engagement in research for it to be successful. PMID- 27214442 TI - OC28 - Effect of mode of delivery on early oral colonization and childhood dental caries: a systematic review. AB - Theme: Multidisciplinary team working. BACKGROUND: Oral colonization starts at birth by vertical transmission. OBJECTIVE: To determine whether mode of delivery influences the oral colonization of infants and contributes to the risk of childhood dental caries. METHODS: A systematic review was conducted in the electronic database Web of Science for articles published from January 1995 to December 2015 by using a set of keywords. RESULTS: From 2,644 citations identified through electronic search, ten studies met the inclusion criteria. According to the studies mode of delivery influences oral microbial density, oral microbial profile and the timing of oral colonization by cariogenic microbiota. However, there are no consistent results concerning either the prevalence of children harboring cariogenic microbiota or the prevalence of early childhood caries by mode of delivery. CONCLUSION: Mode of delivery influences early oral colonization. However, it seems that other determinants rather than mode of delivery could be major contributors to the development of early childhood caries. PMID- 27214443 TI - OC27 - How to manage teenagers' emotions? Proposal of an algorithm for nursing intervention. AB - Theme: Complex health care and chronic disease management. PMID- 27214444 TI - OC29 - Caregiver burden in childhood asthma. AB - Theme: Parenting/parenthood. INTRODUCTION: As delivering care is an inherent part of becoming parents, providing high-level care to the child with health problems might be a burden for the caregiver. AIM: This systematic review investigated the effects of caregiver burden of parents who are primarily responsible for the caring of children with asthma. METHODS: PubMed, CINAHL, Web of Science and Scopus databases were searched for the studies published between 2000-2015. Key search terms used were 'caregiver', 'burden, 'childhood asthma' and 'parent'. RESULTS: A total of 23 studies were examined for this review. DISCUSSION: Providing care to the child with asthma affects parents as caregivers negatively. Caregivers of the children with asthma often experience anxiety, fear, disappointment, grief, physical distress and low quality of life as the outcomes of caregiving burden. CONCLUSIONS: It is absolutely crucial to determine caregiver burden risks and protective factors since wellness level of caregivers affect the asthma management practices and decisions. PMID- 27214445 TI - OC30 - Fracture reduction with nitrous oxide at the children's emergency department shortens the length of stay and reduces the use of full anaesthesia in the operating department. AB - Theme: Accreditation and quality improvement. AIM: Dislocated fractures are common in the children's emergency department (ER). All forms of fracture reduction are very painful requiring nitrous oxide. The purpose is to shorten the length of stay in the hospital as well as sustain a high quality of care. METHODS: All nurses received theoretical and practical training in the use of nitrous oxide. Evaluations with the families were made by telephone. RESULT: A total of 40 enclosed fracture reductions were made at the ER, leading to a reduction of 33 patients in the operating department and the length of stay was shortened - this compared to the same time in 2014. No adverse event was reported and no patient felt any increase in pain during the treatment. All patients would repeat the procedure if necessary. CONCLUSION: The treatment has reduced the length of stay in the hospital without affecting the other patients in the ER or the quality of care. PMID- 27214446 TI - OC31 - Tobacco consumption by adolescents: a study in the north of Portgual. AB - Theme: School health. AIMS: To characterize the adolescents' habits of smoking in a Portuguese School; to identify if the adolescents have information on the harmful effects of tobacco and their health education needs. METHODS: Quantitative, exploratory and descriptive study. Data collection in 2011 through a self-answered questionnaire. RESULTS: The sample comprised 441 students; mean age of 14.5 years old; 53.1% were male; 18,6% were smokers; boys smoked more than girls; they started to smoke between 7-18; the tobacco consumption is significantly related with: age (p<0,001); gender (p=0,002); interest of the family about the adolescents' problems (p=0,028) among others. The adolescents have information about the harmful effects of tobacco and the ones interested in receiving more information wanted it from the health professionals. CONCLUSIONS: Prevention and delaying the age of initiation of consumption should be taken into account in a target intervention plan, which should be led by the school health nurse. PMID- 27214447 TI - OC33 - Young people's eating behaviours in Vila Nova de Famalicao. PMID- 27214448 TI - OC32 - Nursing interventions for empowering parents of premature infants before discharge from the neonatal intensive care unit: a scoping review. AB - Theme: Complex health care and chronic disease management. PMID- 27214449 TI - OC35 - Child Friendly Healthcare Initiative, implementation project in a paediatric department in Greece. AB - Theme: Accreditation and quality improvement. INTRODUCTION: Child Friendly Healthcare Initiative (CFHI) aims to improve quality of experience and health care given to children and families by improving realisation of children's rights and reducing unnecessary fear, anxiety and suffering during and because of health care. AIM: To present results of preliminary CFH assessment. METHODS: Implementation was initiated in a paediatric department of a University Hospital in Athens, Greece, consisting of a 37-bed ward, Outpatient Clinic and Emergency Department. For the preliminary assessment of the CFHI tool No1, which is for parents-caregiverschildren and health workers, this was translated into Greek. 112 parents-caregivers and six children were interviewed by an independent interviewer. In total, 24 health workers - 5 paediatricians, 11 residents and 8 nurses - responded to the CFHI tool No 1. RESULTS: Issues highlighted were mostly about CFH Standard 3 and Standard 7. Suggestions for improvement in all Standards were suggested. CONCLUSIONS: Preliminary assessment revealed the quality of care needs improvement. The next step is the training health workers, planning and making improvements. PMID- 27214450 TI - OC34 - Paediatric rehabilitation: humanizing nursing care to children and their families. AB - Theme: Ethical issues - dignity and humanity. INTRODUCTION: The child with special health care needs in a rehabilitation center for their vulnerable condition requires a clinical practice centered on ethics and humanization. OBJECTIVES: To know the parents' and nurses opinions on humanized care in a paediatric rehabilitation unit and to identify needs and strategies that promote the humanization of care in a paediatric rehabilitation unit. METHODS: Qualitative, descriptive, exploratory study, using interviews with nurses and questionnaires to parents of hospitalized children. RESULTS: This study enhances the importance that nurses should have in human relationships, with special attention to each child and their parents, but also to the structural and functioning conditions of the unit. DISCUSSION: The results are in agreement with the literature, highlighting the particular aspects of children with special needs and their parents. CONCLUSION: The results contribute to more humanized care and could be a basis for a Charter of Humanization. PMID- 27214451 TI - OC36 - Diagnostic approach of primary cilia dyskinesia: Greek experience. AB - Theme: Complex health care and chronic disease management. INTRODUCTION: Primary Cilia Dyskinesia (PCD) is a rare, genetically heterogeneous disease that causes chronic pulmonary inflammation and progressive loss of lung function due to the dysfunction of cilia. AIM: To present the Greek experience in development and implementation of standardized operational procedures (SOP) in diagnostic testing of PCD. METHODS: After special training, SOP consisting of nasal NO (nNO) measurement, high speed videomicroscopy (HVM), transmission electron microscopy (TEM) and shipment of the sample for high resolution immunofluorescence (IF) microscopy in difficult cases, were applied. RESULTS: From September 2014 until December 2015 197 tests were performed to 147 suspected patients. 17 patients were finally diagnosed with PCD. CONCLUSIONS: PCD is a rare disease that can be diagnosed through SOP. Early diagnosis and appropriate treatment of PCD will reduce not only the morbidity and mortality to patients, but also the burden of healthcare costs. PMID- 27214452 TI - OC38 - Beyond boundaries: inter-professional simulation in children and young people's nursing - three pilot projects. AB - Theme: Nursing education, management and leadership. PMID- 27214453 TI - OC37 - Adolescents with cystic fibrosis: their perspective. AB - Theme: Complex health care and chronic disease management. INTRODUCTION: The adolescent with cystic fibrosis suffers from organic distresses and requires support to deal with the physical symptoms and the psychosocial adaptation. AIM: Realize the experience of growing up with cystic fibrosis from the adolescent point of view. METHODOLOGY: Data grounded theory as investigation method and interpretation by Meleis Theory. Study group with 16 adolescents and data collected by interview. RESULTS: From the content analysis of the interviews, we established that the adolescents were living development and health-illness type transitions. We identified the dimension 'developing trust and coping' as adjustment strategy to new contexts. DISCUSSION: The adolescents' speeches reflected behaviors of involvement in the transition process, being a positive result to the psychosocial development and positive life experience at this stage. CONCLUSION: The follow up from healthcare professionals may transform a stressful situation into a state of trust. It can also reveal and pinpoint resource strategies to enable adaptation to new circumstances. PMID- 27214454 TI - OC39 - The efficacy of a participatory approach in reducing pain related to venepuncture in children. AB - Theme: ETHICAL ISSUES: dignity and humanity. INTRODUCTION: Venepuncture represents traumatic experience in childhood due to pain and discomfort. AIMS: To compare the efficacy of a participatory approach with preliminary ice application to the skin. METHODS: Two age-groups (respectively 3-7 and *8 years) were considered during day-hospital, hospitalization, and ER accesses. Venepuncture was described to patients with fables or illustration according to the age-group. Ice or cool-water-pack was randomly applied to skin for one minute before venepuncture. Pain measurement scales were Wong-Baker and VAS. RESULTS: Preliminary data (55 patients) showed that the 3-7 years age group had better pain tolerance with a participatory approach, whilst ice was better in the older group. Generally previous venepunctures seem to worsen pain feeling. DISCUSSION: Imagination seems to influence pain feeling in the 3-7 age group, while ice is more important in the older group. Previous experiences mark negatively successive venepunctures. CONCLUSIONS: Participatory approaches can be cost effective and influences positively venepuncture in the future. PMID- 27214455 TI - OC41 - Families of children with Down syndrome: a cross-cultural study. PMID- 27214456 TI - OC40 - Family participation in caring for hospitalized children - nurses' perspectives. AB - Theme: Professional issues Aim: To understand nurses' perspective about the presence and participation of parents/caregivers during child's hospitalization. METHOD: Quantitative, descriptive and exploratory study. Data collection in 2011 through questionnaire. RESULTS: The sample comprised 146 nurses that work in paediatric wards in five different hospitals in the North of Portugal; aged between 23 to 59 years old; 93.1% were female; the average professional time was 10.7 years with 9.4 years of professional practice in an inpatient paediatric ward; 89% recognize the importance of parents/caregivers staying at hospital all day with their children during hospitalization; 63.4% always promote the involvement of parents/caregivers in the basic care; 42.5% involved them in more complex care; 9.6% didn't have the habit of explaining the nursing care to the parents before performing them. CONCLUSIONS: It is important that nurses recognize the benefits of effectively involving parents/caregivers in the care, negotiation and decision-making process regarding the child's care. PMID- 27214457 TI - OC43 - Reproductive decision-making in families of children with Down syndrome. PMID- 27214458 TI - OC42 - What do parents know about fever? AB - Theme: Parenting/parenthood. INTRODUCTION: Due to lack of information, the fever in the child brings anxiety and fear to their parents. OBJECTIVES: To identify parents' knowledge towards the child with fever and the sources of information they have used. METHODS: Cross-sectional, descriptive-correlational study. Convenience not probabilistic sample of 360 parents with children in child health surveillance consultation, in central Portugal. Data collection was performed by a questionnaire about fever in children. RESULTS: Knowledge of the fever was found to be weak among parents aged * 38 years (36.2%) with a partner (77.0%), living in rural areas (69.3%) and having completed the ninth grade (53.9%). Parents up to 37 years (68.2%) with a partner (89.0%), living in urban area (53.0%) and having higher education (43.3%) showed good knowledge. The main sources of information were the doctor (65.8%) and nurses (50.6%). CONCLUSION: Nurses need to invest in training parents more on this subject. PMID- 27214459 TI - OC45 - Towards family-centred care in neonatal intensive care unit. AB - Theme: Complex health care and chronic disease management. PMID- 27214460 TI - OC44 - Supporting the behavioural health of children: temperament-based interventions to support development and reduce risk. PMID- 27214461 TI - OC46 - NIDCAP at hospital Sao Joao - the journey. AB - Theme: Complex health care and chronic disease management. PMID- 27214462 TI - OC47 - NICUs and family-centred care, from the leadership to the design, the results of a survey in Italy (by FCC Italian NICU study group). AB - Theme: Leadership, management, nursing education. INTRODUCTION: Family-centered care (FCC) in NICUs is related to staff culture and the organization of the unit. AIM: To describe the organizational characteristics and services for families in Italian NICUs. METHODS: This survey involved 105 NICUs in Italy. The Italian version of the 'FCC in the NICUs: A Self-Assessment Inventory' developed by the Institute for FCC was sent to the nurse managers in January 2015. RESULTS: Forty seven NICUs answered (49%). The means of the NICU characteristics are number of beds: 20; newborns discharged/year: 331, of which very low birth weight infant: 68; unit's rooms: 3.7). The total mean score of the 10 areas explored by questionnaire was 2.6 (on 5 points Likert scale) for the 'status' and of 2.3 (on 3 points scale) for priority for change. CONCLUSION: The results show an organizational lack, but also the consciousness of the need of change. Sharing new organizational strategies could be an important issue for the future. PMID- 27214463 TI - OC48 - Hurtology: an online course. AB - Theme: School health. BACKGROUND: The prevalence of anxiety and depression suggests a need to improve on the mental health education of young people. The school setting can provide a venue for offering such knowledge to adolescents. OBJECTIVES: This study explored whether a video game enhances lessons designed to help adolescents become more receptive to learning about mental health concepts. METHODS: This study used a quantitative between-subjects design. The first group experienced a set of computer-based lessons. The second group received the same content, but also played a video game designed to reinforce topics explored in the other materials. RESULTS: The findings showed that game players demonstrated deeper learning on at least one measure. DISCUSSION: Helping adolescents develop better ways to understand the relevance of emotional health is a worthwhile endeavour. CONCLUSIONS: New technologies can be used to improve learning and help young people become more receptive to addressing mental health concerns. PMID- 27214494 TI - Diels-Alder Reactions of Furans with Itaconic Anhydride: Overcoming Unfavorable Thermodynamics. AB - Unfavorable thermodynamics often render furans reluctant to engage in high yielding Diels-Alder (DA) cycloaddition reactions. Here, we report the highly efficient conversion of the biosourced reactants itaconic anhydride (IA) and furfuryl alcohol (FA) to a single DA adduct. The free energy advantages provided by anhydride ring opening and crystal lattice energy of the product overcome the loss of aromaticity of the furanoid diene. Detailed (1)H NMR studies provided valuable insights about relevant kinetic and thermodynamic features. PMID- 27214495 TI - Indirect Fabrication of Lattice Metals with Thin Sections Using Centrifugal Casting. AB - One of the typical methods to manufacture 3D lattice metals is the direct-metal additive manufacturing (AM) process such as Selective Laser Melting (SLM) and Electron Beam Melting (EBM). In spite of its potential processing capability, the direct AM method has several disadvantages such as high cost, poor surface finish of final products, limitation in material selection, high thermal stress, and anisotropic properties of parts. We propose a cost-effective method to manufacture 3D lattice metals. The objective of this study is to provide a detailed protocol on fabrication of 3D lattice metals having a complex shape and a thin wall thickness; e.g., octet truss made of Al and Cu alloys having a unit cell length of 5 mm and a cell wall thickness of 0.5 mm. An overall experimental procedure is divided into eight sections: (a) 3D printing of sacrificial patterns (b) melt-out of support materials (c) removal of residue of support materials (d) pattern assembly (e) investment (f) burn-out of sacrificial patterns (g) centrifugal casting (h) post-processing for final products. The suggested indirect AM technique provides the potential to manufacture ultra-lightweight lattice metals; e.g., lattice structures with Al alloys. It appears that the process parameters should be properly controlled depending on materials and lattice geometry, observing the final products of octet truss metals by the indirect AM technique. PMID- 27214496 TI - Extended-spectrum beta-lactamase producing Escherichia coli isolated from wild birds in Saskatoon, Canada. AB - The epidemiology of antimicrobial resistance is extremely complex and involves humans, domestic animals (companion and agricultural) and wildlife. In North America there have been very few investigations targeting antimicrobial-resistant organisms in wildlife. In this study, we characterized the susceptibility of Escherichia coli isolated from 75 birds including great horned owls, crows and American robins from the region of Saskatoon, Canada. The recovery rate of E. coli varied significantly between species from 44.8% of robins to 92% of crows. The majority (88.2%) of colonized birds carried only pan-susceptible organisms. Among isolates resistant to at least one antimicrobial, ampicillin resistance was most commonly identified. Three birds carried multidrug-resistant isolates (resistant to >=3 drug classes), and extended-spectrum beta-lactamase (ESBL) producing organisms (CTX-M-15 and SHV2a) were grown from two. We identified a significant relationship between the presence of drug-resistant E. coli and an urban (vs rural) origin of the bird. Our findings suggest that crows, due to their ubiquity and high rate of colonization with E. coli, may be efficient targets for future resistance surveillance studies targeting urban wildlife. SIGNIFICANCE AND IMPACT OF THE STUDY: Antimicrobial resistance is a global problem affecting people and animals. Few investigations describing the presence drug-resistant organisms in wildlife in North America have been published. In this study, resistant Escherichia coli, including extended-spectrum beta lactamase-producing strains, were isolated from wild birds in the Saskatoon region of Canada. We found that the recovery rate of E. coli varied significantly by species and was highest among crows. There was also a significant association between drug resistance and urban vs rural birds. Our results suggest that crows may be a good target for future studies investigating antimicrobial resistance in urban wildlife. PMID- 27214498 TI - Rhenium(I) Tricarbonyl Complexes of meso-Tetraaryl-21,23-diheteroporphyrins. AB - The dithia/diselena meso-tetraarylporphyrins have a lesser tendency to form metal complexes because of the larger size of the heteroatom(s), which shrinks the cavity size, and the heteroatoms also have poor coordinating ability to bind metal ions. The first example of a rhenium(I) tricarbonyl complex of 21,23 diselenaporphyrin was synthesized by treating 5,10,15,20-tetra-p-tolyl-21,23 diselenaporphyrin with Re(CO)5Cl in chlorobenzene at reflux temperature and its structural properties were compared with our earlier reported rhenium(I) complex of tetraaryl-21,23-dithiaporphyrin. The crystal structures of rhenium(I) complexes of diheteroporphyrins revealed that the Re(I) ion binds to both the Se/S atoms and one of the N atoms of the porphyrin core along with three terminal carbonyl groups in an octahedral fashion. The rhenium(I) complexes of 21,23 diheteroporphyrins are stabilized by a large counterion, the trichloro-bridged dirhenium(I) ion. We also present a detailed account of the spectral and redox properties of rhenium(I) tricarbonyl complexes of 21,23-diheteroporphyrins. PMID- 27214497 TI - Brain Temperature in Spontaneously Hypertensive Rats during Physical Exercise in Temperate and Warm Environments. AB - This study aimed to evaluate brain temperature (Tbrain) changes in spontaneously hypertensive rats (SHRs) subjected to two different physical exercise protocols in temperate or warm environments. We also investigated whether hypertension affects the kinetics of exercise-induced increases in Tbrain relative to the kinetics of abdominal temperature (Tabd) increases. Male 16-week-old normotensive Wistar rats (NWRs) and SHRs were implanted with an abdominal temperature sensor and a guide cannula in the frontal cortex to enable the insertion of a thermistor to measure Tbrain. Next, the animals were subjected to incremental-speed (initial speed of 10 m/min; speed was increased by 1 m/min every 3 min) or constant-speed (60% of the maximum speed) treadmill running until they were fatigued in a temperate (25 degrees C) or warm (32 degrees C) environment. Tbrain, Tabd and tail skin temperature were measured every min throughout the exercise trials. During incremental and constant exercise at 25 degrees C and 32 degrees C, the SHR group exhibited greater increases in Tbrain and Tabd relative to the NWR group. Irrespective of the environment, the heat loss threshold was attained at higher temperatures (either Tbrain or Tabd) in the SHRs. Moreover, the brain abdominal temperature differential was lower at 32 degrees C in the SHRs than in the NWRs during treadmill running. Overall, we conclude that SHRs exhibit enhanced brain hyperthermia during exercise and that hypertension influences the kinetics of the Tbrain relative to the Tabd increases, particularly during exercise in a warm environment. PMID- 27214499 TI - Great nature's second course: Introduction to the special issue on the behavioral neuroscience of sleep. AB - Sleep is necessary for normal psychological functioning, and psychological function in turn affects sleep integrity. Recent investigations delineate the relation of sleep to a broad array of processes ranging from learning and memory to emotional reactivity and mood, and use a variety of methodological approaches (imaging, electrophysiological, behavioral) to reveal the complex relations between sleep and the functioning of the awake brain. The articles in this issue advance our fundamental knowledge of the relation of sleep to psychological function. In addition, several of the articles discuss how sleep is affected by or affects human clinical conditions, including insomnia, epilepsy, mild cognitive impairment, bipolar disorder, and cancer. Together, the articles of this special issue highlight recent progress in understanding the behavioral neuroscience of sleep and identify promising areas for future research, including the possibility of sleep-based interventions to improve psychological health. (PsycINFO Database Record PMID- 27214500 TI - The impact of napping on memory for future-relevant stimuli: Prioritization among multiple salience cues. AB - Prior research has demonstrated that sleep enhances memory for future-relevant information, including memory for information that is salient due to emotion, reward, or knowledge of a later memory test. Although sleep has been shown to prioritize information with any of these characteristics, the present study investigates the novel question of how sleep prioritizes information when multiple salience cues exist. Participants encoded scenes that were future relevant based on emotion (emotional vs. neutral), reward (rewarded vs. unrewarded), and instructed learning (intentionally vs. incidentally encoded), preceding a delay consisting of a nap, an equivalent time period spent awake, or a nap followed by wakefulness (to control for effects of interference). Recognition testing revealed that when multiple dimensions of future relevance co occur, sleep prioritizes top-down, goal-directed cues (instructed learning, and to a lesser degree, reward) over bottom-up, stimulus-driven characteristics (emotion). Further, results showed that these factors interact; the effect of a nap on intentionally encoded information was especially strong for neutral (relative to emotional) information, suggesting that once one cue for future relevance is present, there are diminishing returns with additional cues. Sleep may binarize information based on whether it is future-relevant or not, preferentially consolidating memory for the former category. Potential neural mechanisms underlying these selective effects and the implications of this research for educational and vocational domains are discussed. (PsycINFO Database Record PMID- 27214501 TI - Sleep to the beat: A nap favours consolidation of timing. AB - Growing evidence suggests that sleep is important for procedural learning, but few studies have investigated the effect of sleep on the temporal aspects of motor skill learning. We assessed the effect of a 90-min day-time nap on learning a motor timing task, using 2 adaptations of a serial interception sequence learning (SISL) task. Forty-two right-handed participants performed the task before and after a 90-min period of sleep or wake. Electroencephalography (EEG) was recorded throughout. The motor task consisted of a sequential spatial pattern and was performed according to 2 different timing conditions, that is, either following a sequential or a random temporal pattern. The increase in accuracy was compared between groups using a mixed linear regression model. Within the sleep group, performance improvement was modeled based on sleep characteristics, including spindle- and slow-wave density. The sleep group, but not the wake group, showed improvement in the random temporal, but especially and significantly more strongly in the sequential temporal condition. None of the sleep characteristics predicted improvement on either general of the timing conditions. In conclusion, a daytime nap improves performance on a timing task. We show that performance on the task with a sequential timing sequence benefits more from sleep than motor timing. More important, the temporal sequence did not benefit initial learning, because differences arose only after an offline period and specifically when this period contained sleep. Sleep appears to aid in the extraction of regularities for optimal subsequent performance. (PsycINFO Database Record PMID- 27214502 TI - "Moderate Stress Enhances Immediate and Delayed Retrieval of Educationally Relevant Material in Healthy Young Men": Correction to Hupbach and Fieman (2012). AB - Reports an error in "Moderate stress enhances immediate and delayed retrieval of educationally relevant material in healthy young men" by Almut Hupbach and Rachel Fieman (Behavioral Neuroscience, 2012[Dec], Vol 126[6], 819-825). In the article there are computational errors in the last sentence of the Memory Performance section. "(M = .30, SD = .11 for CPS, and M = .13, SD = 17 for the warm water control)." should read instead: "(M = .03, SD = .11 for CPS, and M = .13, SD = .17 for the warm water control)." (The following abstract of the original article appeared in record 2012-27908-001.) Retrieval practice is a powerful memory enhancer. However, in educational settings, test taking is often experienced as a stressful event. While it is known that stress can impair retrieval processes, little is known about the delayed consequences of testing memory for educationally relevant material under stressful conditions, which is the focus of the present study. Participants (38 women, 37 men) memorized a scientific text passage on Day 1. On Day 2, they were either exposed to a stressor (cold pressor test; CPS) or a warm water control, and immediately afterward, they were asked to recall the text passage (i.e., retrieval under stress vs. control). Salivary cortisol was measured as an index of the stress response before, and 20 min after the CPS versus control treatment. The delayed effects of testing under stress were assessed with a final recall test on Day 3. In comparison to the control condition, CPS caused significant increases in salivary cortisol, and, surprisingly resulted in enhanced memory in men. Importantly, this enhancement was not only observed in the test that immediately followed the stressor, but also in the delayed test. In women, CPS caused only marginal increases in cortisol concentrations, and retrieval remained unaffected. Our study suggests that moderate stress can improve memory performance for educationally relevant material in a long-lasting manner in healthy young men. (PsycINFO Database Record PMID- 27214503 TI - Mesenchymal Stem Cell Transplantation in Systemic Sclerosis: Comment on the Article by Maria et al. PMID- 27214504 TI - Novel Mutations in the Nonselective Sodium Leak Channel (NALCN) Lead to Distal Arthrogryposis with Increased Muscle Tone. AB - Distal arthrogryposis (DA) is a feature in genetically and clinically heterogeneous groups of disorders. Mostly myopathic and neurogenic defects have been described, but many patients remain without genetic diagnosis. We are elaborating on the clinical presentation of neonatal cases with DA who carry novel mutations in the nonselective sodium leak channel (NALCN). Two patients reported herein were remarkable for central hypertonicity in addition to DA. By trio-whole exome sequencing, two undescribed de novo mutations in NALCN were revealed. Both mutations (p.F317C and p.V595F) are located on pore-forming segments of NALCN. Dominant NALCN mutations in the pore-forming segments have been identified in similar patients, whereas recessive mutations outside the pore forming segments result in different phenotypes. Our findings with central hypertonia broaden the phenotypic spectrum of de novo mutations in the pore forming segments of NALCN. Recent findings of successful acetazolamide treatment in patients with channelopathies might point to potential therapies based on the ion channel similarities and the location of the mutation. PMID- 27214505 TI - Povidone Iodine Ointment Application to the Vaccination Site Does Not Alter Immunoglobulin G Antibody Response to Smallpox Vaccine. AB - U.S. military personnel deployed to high-risk areas receive the live vaccinia virus (VACV) smallpox vaccine ACAM2000. VACV shedding from the vaccination site can result in autoinoculation and contact transmission. We previously found that the application of povidone iodine ointment (PIO) to the scarification site reduced viral shedding without altering the antibody response, as measured by plaque reduction neutralization or enzyme-linked immunosorbent assays. In this study, we used protein microarray assays to measure the amount of immunoglobulin G antibody bound to (1) ACAM2000 itself and (2) individual VACV antigens that are present within ACAM2000. We assessed antibody binding in sera from primary smallpox vaccinees who applied PIO to the scarification site beginning on day 7 (PIO group) and from those who did not apply PIO (control group). In both cohorts, the postvaccination antibody response-in terms of antibody binding, both to ACAM2000 and to 11 individual VACV antigens-was significantly greater than the prevaccination response (all p < 0.0001). The postvaccination antibody binding levels of vaccinees in the PIO group did not differ from those of control vaccinees. These findings further support the topical application of PIO, starting on day 7, to reduce the viral shedding associated with smallpox vaccination. PMID- 27214506 TI - Biomedical analytical monitor of artificial kidney operation: Monitoring of creatinine removal. AB - A general concept for the development of flow analysis system for non-invasive, bloodless monitoring of uremic toxins' removal in the course of clinical hemodialysis treatment is presented. The monitor operates in both (discrete and continuous) modes of measurements. In this study as a model uremic marker creatinine has been chosen. The monitor is based on solenoid operated microdevices (pumps and valves) and an optoelectronic flow-through detector made of paired light emitting diodes allowing photometric determination of this metabolite using Jaffe method. Additionally, a simple two microsolenoid pump based module allowing the modeling of toxin removal by artificial kidney has been developed. The developed monitor has been validated with real samples of postdialysate fluid produced by artificial kidney in the course of clinical hemodialysis treatment. The results of hemodialysis monitoring are fully comparable with those obtained using reference off-line method. PMID- 27214507 TI - Synthesis, structures, molecular docking, cytotoxicity and bioimaging studies of two novel Zn(II) complexes. AB - Two novel compounds [Zn2(Endc)2(bipy)2(H2O)3].4(H2O).2(O)(1), [Zn2(Endc)2(phen)2(H2O)].(O)(2) (bipy = 2,2-bipyridine, phen = 1,10 phenanthroline, and Endc = endo-norbornene-cis-5,6-dicarboxylicacid) have been synthesized and characterized. In this paper abbreviations are FS-DNA (fish sperm DNA), HeLa (human cervix epithelia carcinoma cells), KB (human oral epithelial carcinoma cells), LO2 (human liver cell L-O2), EtBr (ethidium bromide), DMF (Dimethyl Formamide), MTT ([3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium]). The binding of complexes with Fish Sperm DNA were measured by electronic absorption spectra and fluorescence spectroscopy. The ability of these complexes to cleave the pBR322 plasmid DNA or the KB and HeLa DNA extracted in our laboratory was demonstrated by gel electrophoresis assay. The cytotoxic effects of these complexes were examined on two tumor cell lines, HeLa, KBr and one normal cell line LO-2. UV absorption and fluorescence spectra indicate the ability of the complexes bond to DNA with different binding affinity. Gel electrophoresis assay demonstrates which one complex more effective DNA-cleavage activity. The cytotoxic activity of the complexes was tested against two different cancer and one normal cell lines. The two complexes exhibited cytotoxic specificity and significant cancer cell inhibitory rate and lower cytotoxicity toward the normal cell lines. The unique interaction mode with DNA and cancer cells inhibition effect clearly revealed the relationship between the structure and the activity of the novel antitumor agent Zn(II) complexes. PMID- 27214508 TI - Straightforward synthesis of 2,4,6-trisubstituted 1,3,5-triazine compounds targeting cysteine cathepsins K and S. AB - The synthesis and evaluation against various cysteine cathepsins with endopeptidase activity, of two new families of hitherto unknown 1,3,5-triazines, substituted by a nitrile function and either a cyclohexylamine moiety (5-like) or a piperazine moiety (9-like) are described. The structure-activity relationship was discussed; from 16 synthesized novel compounds, 9h was the most active and selectively inhibitor of Cat K (IC50 = 28 nM) and Cat S (IC50 = 23 nM). Molecular docking of 9h to X-ray crystal structure of cathepsins K and S confirmed a common binding mode with a crucial covalent bond with Cys25. We observed for 9h that p trifluorophenyl group is located in S2 pocket and possess hydrophobic interactions with Tyr67 and Met68. Triazine and piperazine moieties are located in S'1 pocket and interact with Gly23, Cys63, Gly64 and Gly65. Altogether, these results indicate that the new analogs can make them effective agents against some viruses for which the glycoprotein cleavage is mediated by an array of proteases. PMID- 27214509 TI - Synthesis, characterization and antitubercular activities of novel pyrrolyl hydrazones and their Cu-complexes. AB - Novel pyrrolyl hydrazones and their copper complexes have been synthesized and characterized using analytical and spectral techniques to show the tetrahedral geometry for Cu(II) complexes. Biological activities of hydrazones have been assessed to understand the role of metal ion on their biological activity and the effect of pyrrolyl hydrazones. In vitro antitubercular activity against Mycobacterium tuberculosis of the metal complexes (13b and 13r) exhibited the highest antitubercular activity that are quite close to rifampicin (0.4 MUg/mL), giving a MIC of 0.8 MUg/mL. All other compounds showed good activity with the MIC values ranging from 1.6 to 100 MUg/mL. A comparative study of inhibition values of the ligands and their complexes showed higher antimicrobial activity of the complexes than the ligands. Some compounds have a good activity against InhA and in particular, compounds 12r, 13b and 13r exhibited more than 60% binding with the enzyme even at 5 MUM (exhibited good IC50 upto 2.4 MUM). Most of the active molecules have a very less cytotoxicity against the human lung cancer cell-line A549. The docking and 3D-QSAR studies have been carried out to provide some insights into the mechanism of action for this class of compounds. PMID- 27214510 TI - Synthesis and anticholinesterase activity of coumarin-3-carboxamides bearing tryptamine moiety. AB - A number of N-(2-(1H-indol-3-yl)ethyl)-2-oxo-2H-chromene-3-carboxamides were synthesized and tested against AChE and BuChE. The in vitro assessment of the synthesized compounds 4a-o revealed that most of them had significant activity toward AChE. The SAR study demonstrated that the introduction of benzyloxy moiety on the 7-position of coumarin scaffold can improve the anti-AChE activity. The best result was obtained with 7-(4-fluorobenzyl)oxy moiety in the case of compound 4o, displaying IC50 value of 0.16 MUM. Based on the docking study of AChE, the prototype compound 4o was laid across the active site and occupied both peripheral anionic site (PAS) and catalytic anionic site (CAS). PMID- 27214511 TI - Antidepressant-like effects and mechanisms of flavonoids and related analogues. AB - Flavonoids, possessing a basic phenylbenzopyrone core, are important components of the human diet, and are found in many medicinal plants. Flavonoids include chalcones, flavanones and their derivatives. Synthetic and natural isolated flavonoids display an enormous number of biological activities such as antitumor, antiplatelet, anti-malarial, anti-inflammatory, antidepressant and anticonvulsant properties. This review article focuses on the antidepressant-like effect, structure-activity relationship and mechanism of action of total flavonoid extracts isolation from natural sources, flavonoid compounds and their related analogues. PMID- 27214512 TI - Synthesis and antiproliferative evaluation of novel 2-(4H-1,2,4-triazole-3 ylthio)acetamide derivatives as inducers of apoptosis in cancer cells. AB - In this study, a series of thiosemicarbazide derivatives 12-14, 1,2,4-triazol-3 thione derivatives 15-17 and compounds bearing 2-(4H-1,2,4-triazole-3 ylthio)acetamide structure 18-32 have been synthesized starting from phenolic compounds such as 2-naphthol, paracetamol and thymol. Structures and purity of the target compounds were confirmed by the use of their chromatographic and spectral data besides microanalysis. All of the synthesized new compounds 12-32 were evaluated for their anti-HIV activity. Among these compounds, three representatives 18, 19 and 25 were selected and evaluated by the National Cancer Institute (NCI) against the full panel of 60 human cancer cell lines derived from nine different cancer types. Antiproliferative effects of the selected compounds were demonstrated in human tumor cell lines K-562, A549 and PC-3. These compounds inhibited cell growth assessed by MTT assay. Compound 18, 19 and 25 exhibited anti-cancer activity with IC50 values of 5.96 MUM (PC-3 cells), 7.90 MUM (A549/ATCC cells) and 7.71 MUM (K-562 cells), respectively. After the cell viability assay, caspase activation and Bcl-2 activity of the selected compounds were measured and the loss of mitochondrial membrane potential (MMP) was detected. Compounds 18, 19 and 25 showed a significant increase in caspase-3 activity in a dose-dependent manner. This was not observed for caspase-8 activity with compound 18 and 25, while compound 19 was significantly elevated only at the dose of 50 MUM. In addition, all three compounds significantly decreased the mitochondrial membrane potential and expression of Bcl-2. PMID- 27214513 TI - Cellobiohydrolases Produce Different Oligosaccharides from Chitosan. AB - Chito-oligosaccharides (COSs) are bioactive molecules with interesting characteristics; however, their exploitation is still restricted due to limited amounts accessible with current production strategies. Here we present a strategy for the production of COSs based on hydrolysis of chitosan by using readily available glycosidases. Cellobiohydrolases (EC 3.2.1.91) were compared with chitosanases (EC 3.2.1.132) regarding their ability for COS production, and the resulting fractions were analyzed by MS and NMR. The oligosaccharides had a degree of polymerization between three and six units, and the degree of acetylation (DA) varied depending on the applied enzyme. Different cellobiohydrolases produced COSs with varying DA, and based on comprehensive NMR analysis the preferred cleavage sites of the respective enzymes that show chitosanase and chitinase activity were elucidated. The study reveals the high potential of readily available cellulolytic enzymes besides chitosanases for the production of COSs with distinct structure facilitating access to this bioactive compound class. PMID- 27214514 TI - Electrostatic Assemblies of Well-Dispersed AgNPs on the Surface of Electrospun Nanofibers as Highly Active SERS Substrates for Wide-Range pH Sensing. AB - Surface-enhanced Raman scattering (SERS) has shown high promise in analysis and bioanalysis, wherein noble metal nanoparticles (NMNPs) such as silver nanoparticles were employed as substrates because of their strong localized surface plasmon resonance (LSPR) properties. However, SERS-based pH sensing was restricted because of the aggregation of NMNPs in acidic medium or biosamples with high ionic strength. Herein, by using the electrostatic interaction as a driving force, AgNPs are assembled on the surface of ethylene imine polymer (PEI)/poly(vinyl alcohol) (PVA) electrospun nanofibers, which are then applied as highly sensitive and reproducible SERS substrate with an enhancement factor (EF) of 10(7)-10(8). When p-aminothiophenol (p-ATP) is used as an indicator with its b2 mode, a good and wide linear response to pH ranging from 2.56 to 11.20 could be available, and the as-prepared nanocomposite fibers then could be fabricated as excellent pH sensors in complicated biological samples such as urine, considering that the pH of urine could reflect the acid-base status of a person. This work not only emerges a cost-effective, direct, and convenient approach to homogeneously decorate AgNPs on the surface of polymer nanofibers but also supplies a route for preparing other noble metal nanofibrous sensing membranes. PMID- 27214515 TI - Genomic Alteration-Driven Clinical Trial Designs in Oncology. AB - The established molecular heterogeneity of human cancers necessitates the development of new paradigms to serve as a reliable basis for precision medicine. The assumptions underlying some of the conventional approaches to clinical trial design and analysis are no longer appropriate because of the molecular heterogeneity of tumors of a given primary site. This article reviews some clinical trial designs that have been actively applied in the codevelopment of therapeutics and predictive biomarkers to inform their use in oncology. These include the enrichment design, the basket design, and the umbrella design. Oncology leads most other therapeutic areas in development of personalized or precision medicine. Personalized or precision medicine is practiced daily in oncology on the basis of tumor genomics and may evolve in other therapeutic areas as it has in oncology, rather than according to inherited polymorphisms as so often imagined. Consequently, some of the clinical trial designs described here may serve as a possible blueprint for therapeutic development in fields other than oncology. PMID- 27214516 TI - Clinical use of blood and blood components in post-abortion care in Botswana. AB - BACKGROUND: Understanding the pattern and gaps in blood product utilisation in post-abortion care is crucial for evidence-based planning and priority setting. OBJECTIVE: To describe the current use of blood and blood components in post abortion care in Botswana. METHODS: We conducted a retrospective cross-sectional study across four hospitals in Botswana using routine patients' records. We included all patients admitted for an abortion between January and August 2014. Descriptive statistics are used to report the results. RESULTS: Whole blood and red cell concentrates were used in 59/619 (9.5%) of patients. Plasma and platelet use was 1.3 and 0.7%, respectively. The mean admission haemoglobin level was 10.07 g dL(-1) (SD 2.69) and differed significantly between referral and district hospitals. The mean number of blood units transfused per patient was 2.23 (standard deviation (SD) 1.23), with 15/55 (27.3%) receiving a single unit. A total of 43/288 (14.9%) of the patients had haemoglobin levels below 7 g dL(-1) but did not receive any transfusion. There was a moderate positive correlation between admission haemoglobin level and time to transfusion (Spearman's rho = 0.37, P = 0.01). The number of blood units given increased with decreasing admission haemoglobin level. The strength of this association was moderate (Spearman's rho = -0.48, P < 0.001). CONCLUSION: There is a relatively low utilisation of blood and blood components in post-abortion care in Botswana despite an apparent clinical need in some instances. The reason for this shortfall, as well as its impact on morbidity and mortality, needs to be explored and be a focus of health systems research in Botswana. PMID- 27214517 TI - Design of new patient-reported outcome measures to assess quality of life, symptoms and treatment satisfaction in patients with abdominal aortic aneurysm. AB - BACKGROUND: No condition-specific patient-reported outcome measures exist for patients with abdominal aortic aneurysm (AAA). The aim of this work was to develop three questionnaires to assess quality of life (QoL), symptoms and treatment satisfaction in patients with AAA. METHODS: Semistructured interview techniques were used to explore patients' experiences of having an AAA in a series of focus groups and in-depth interviews. The information gathered was used to inform design and selection of items for the new tools; the overall structure of the new questionnaires was based on tools developed previously for patients with diabetes and other conditions. RESULTS: Fifty-four patients (51 men, 3 women; mean age 71.9 years) were recruited from four NHS Trusts to participate in focus groups or interviews, either while under surveillance, or following AAA repair (using open or endovascular techniques). The Aneurysm-Dependent Quality of Life Questionnaire (AneurysmDQoL) is an individualized measure of the impact of AAA on patients' QoL. Twenty-three domains were chosen specifically for their relevance to patients with AAA, with a further two overview items to assess overall QoL and the impact of AAA on QoL. The Aneurysm Symptom Rating Questionnaire (AneurysmSRQ) is a 44-item measure assessing physical and psychological symptoms reported by patients with AAA. The Aneurysm Treatment Satisfaction Questionnaire (AneurysmTSQ) contains 11 items, suitable for patients before and after surgical intervention. CONCLUSION: The iterative development process reported here has confirmed that these three new tools have good face and content validity for patients with AAA. PMID- 27214518 TI - Identification and Initial Characterization of Prophages in Vibrio campbellii. AB - Phages are bacteria targeting viruses and represent the most abundant biological entities on earth. Marine environments are exceptionally rich in bacteriophages, harboring a total of 4x10(30) viruses. Nevertheless, marine phages remain poorly characterized. Here we describe the identification of intact prophage sequences in the genome of the marine gamma-proteobacterium Vibrio campbellii ATCC BAA-1116 (formerly known as V. harveyi ATCC BAA-1116), which presumably belong to the family of Myoviridae. One prophage was found on chromosome I and shows significant similarities to the previously identified phage PhiHAP-1. The second prophage region is located on chromosome II and is related to Vibrio phage kappa. Exposure of V. campbellii to mitomycin C induced the lytic cycle of two morphologically distinct phages and, as expected, extracellular DNA from induced cultures was found to be specifically enriched for the sequences previously identified as prophage regions. Heat stress (50 degrees C, 30 min) was also found to induce phage release in V. campbellii. Notably, promoter activity of two representative phage genes indicated heterogeneous phage induction within the population. PMID- 27214520 TI - Associations Between Sensorimotor Impairments in the Upper Limb at 1 Week and 6 Months After Stroke. AB - BACKGROUND AND PURPOSE: Longitudinal information regarding the prevalence of upper limb somatosensory deficits and the association with motor impairment and activity limitations is scarce. The aim of this prospective cohort study was to map the extent and distribution of somatosensory deficits, and to determine associations over time between somatosensory deficits and motor impairment and activity limitations. METHODS: We recruited 32 participants who were assessed 4 to 7 days after stroke, and reassessed at 6 months. Somatosensory measurements included the Erasmus-modified Nottingham sensory assessment (Em-NSA), perceptual threshold of touch, thumb finding test, 2-point discrimination, and stereognosis subscale of the NSA. Evaluation of motor impairment comprised the Fugl-Meyer assessment, Motricity Index, and Action Research Arm Test. In addition, at 6 months, activity limitation was determined using the adult assisting hand assessment stroke, the ABILHAND, and hand subscale of the Stroke Impact Scale. RESULTS: Somatosensory impairments were common, with 41% to 63% experiencing a deficit in one of the modalities within the first week and 3% to 50% at 6 months. In the acute phase, there were only very low associations between somatosensory and motor impairments (r = 0.03-0.20), whereas at 6 months, low to moderate associations (r = 0.32-0.69) were found for perceptual threshold of touch, thumb finding test, and stereognosis with motor impairment and activity limitations. Low associations (r = 0.01-0.29) were found between somatosensory impairments in the acute phase and motor impairments and activity limitations at 6 months. DISCUSSION AND CONCLUSIONS: This study showed that somatosensory impairments are common and suggests that the association with upper limb motor and functional performance increases with time after stroke.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A138). PMID- 27214521 TI - Do smear-layer removal agents affect the push-out bond strength of calcium silicate-based endodontic sealers? AB - AIM: To evaluate the effect of 17% ethylenediaminetetraacetic acid (EDTA), 2.25% peracetic acid (PA) or 10% citric acid (CA) on the push-out bond strength of calcium silicate-based endodontic sealers [MTA Fillapex (Angelus, Londrina, Brazil) and Total Fill BC Sealer (FKG, La Chaux-de-Fonds, Switzerland)] to root dentine after different periods of immersion in phosphate-buffered saline (PBS). AH Plus (Dentsply DeTrey, Konstaz, Germany) was used as a reference material for comparison. METHODOLOGY: Thirty human maxillary incisors were selected and three 1-mm discs were obtained from the middle third of each root. On the axial surface of each disc, three 0.8-mm-diameter holes were drilled through the dentine. After standardized irrigation, each dentine disc from the same root was treated for smear-layer removal with one of the three tested chelating solutions: EDTA, PA or CA. After that, the holes were dried with paper points and filled with one of the three test root canal sealers. The filled dental slices were further immersed in PBS solution (pH 7.2) for 7 days (T1) or 30 days (T2) at 37 degrees C, before the push-out assay. Friedman, Kruskal-Wallis and Mann-Whitney tests were used respectively to estimate the impact of the independent variables (solutions, sealers and period of PBS immersion) on the push-out bond strength. The level for significance was set at alpha = 5% and data were further subjected to a Bonferroni correction. RESULTS: Solutions and periods of immersion did not significantly influence the displacement resistance (P = 0.285, and P = 0.104, respectively) of sealers to root dentine. On the other hand, the type of sealer significantly affected the push-out bond strength (P = 0.000). AH Plus was associated with greater resistance to dislodgment compared with Total Fill BC Sealer and MTA Fillapex (P = 0.000). MTA Fillapex resulted in the lowest push-out bond strength (P = 0.000). CONCLUSION: The use of different chelating agents did not influence the push-out bond strength of endodontic sealers. Calcium silicate based sealers had lower push-out bond strength values compared with a conventional epoxy resin-based sealer (AH Plus). PMID- 27214522 TI - Aged garlic extract ameliorates immunotoxicity, hematotoxicity and impaired burn healing in malathion- and carbaryl-treated male albino rats. AB - Malathion and carbaryl are the most widely used organophosphate and carbamate insecticides, respectively, especially in developing countries; they pose a potential health hazard for both humans and animals. Here, we evaluated the protective effects of an odorless (free from allicin) Kyolic aged garlic extract (AGE, containing 0.1% S-allylcysteine; 200 mg/kg body weight) on the toxicity induced by 0.1 LD50 of malathion (89.5 mg/kg body weight) and/or carbaryl (33.9 mg/kg body weight) in male Wistar rats. Doses were orally administered to animals for four consecutive weeks. The present study showed that AGE completely modulated most adverse effects induced by malathion and/or carbaryl in rats including the normocytic normochromic anemia, immunosuppression, and the delay in the skin-burning healing process through normalizing the count of blood cells (erythrocytes, leucocytes and platelets), hemoglobin content, hematocrit value, blood glucose-6-phosphodehydrogenase activity, weights and cellularity of lymphoid organs, serum gamma-globulin concentration, and the delayed type of hypersensitivity response to the control values, and accelerating the inflammatory and proliferative phases of burn-healing. In addition, AGE completely modulated the decrease in serum reduced glutathione (GSH) concentration and the increase in clotting time in malathion alone and carbaryl alone treated rats. Moreover, AGE induced a significant increase (P < 0.001) in serum GSH concentration (above the normal value) and accelerating burn-healing process in healthy rats. In conclusion, AGE was effective in modulating most adverse effects induced in rats by malathion and carbaryl, and hence may be useful as a dietary adjunct for alleviating the toxicity in highly vulnerable people to insecticides intoxication. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 789-798, 2017. PMID- 27214523 TI - Early life trauma is associated with altered white matter integrity and affective control. AB - Early life trauma (ELT) has been shown to impair affective control and attention well into adulthood. Neuroimaging studies have further shown that ELT was associated with decreased white matter integrity in the prefrontal areas in children and adults. However, no study to date has looked at the relationship between white matter integrity and affective control in individuals with and without a history of ELT. To examine this, we tested 240 Veterans with (ELT N = 80) and without (NoELT N = 160) a history of childhood sexual abuse, physical abuse or family violence. Affective control was measured with the Affective Go/No Go (AGN) and attention was indexed with the Test of Variable Attention (TOVA). White matter integrity was measured using fractional anisotropy (FA). Results showed greater number of errors on the AGN in ELT compared to NoELT. There was no difference on the TOVA. While there were no mean differences in FA, there was an interaction between FA and reaction time to positive stimuli on the AGN where the ELT group showed a positive relationship between FA and reaction time in right frontal and prefrontal areas, whereas the NoELT group showed a negative or no association between FA and reaction time. This suggests that ELT may be associated with a distinct brain-behavior relationship that could be related to other determinants of FA than those present in healthy adults. PMID- 27214524 TI - The long-term burden of military deployment on the health care system. AB - Health care providers need to be aware that stress complaints that result from deployment can emerge even after many years. This has important implications for health care policies. The main aim of this study is to investigate the relation between the development of posttraumatic stress and other mental health complaints and the burden on (mental) health care after a deployment. For this study we used data from a large prospective cohort study on stress-factors related to deployment in 1007 Dutch soldiers, who were deployed to Afghanistan. Participants were assessed at six follow up times up until five years after deployment. In a Generalized Estimated Equations model we estimated the relation between mental health complaints and the utilization of psychological treatment and a general practitioner, respectively. Moreover, we studied the relation between mental health complaints and health care costs using bootstrap techniques. The results showed that higher scores for PTSD, depression and fatigue relate to increased use of a psychologist. And lower PTSD scores and higher depression, anxiety and somatization scores relate to increased odds to visit a GP. Furthermore, mental health complaints relate to higher costs. In conclusion, monitoring soldiers is important in order to be informed on the current demand for (mental) health care to satisfy the health care need of veterans. Early treatment, which is enabled by lowering barriers to care, relates to positive results and therefore, lower health care costs. PMID- 27214525 TI - State-dependent increase in the levels of neurotrophin-3 and neurotrophin-4/5 in patients with bipolar disorder: A meta-analysis. AB - Bipolar disorder (BD) is one of the most serious psychiatric disorders in the world, but its pathophysiology is still unclear. Regulation of neurotrophic factors have been thought to play a role in this process. There have been inconsistent findings regarding the differences in blood neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) between patients with BD and healthy controls (HCs). The aim of the current meta-analysis is to examine the changes in the levels of NT-3 and NT-4/5 in BD patients at different affective states. Eight articles (including 465 BD patients and 353 HCs) were included in the analysis, and their results were pooled by using a random effects model. We found the levels of both NT-3 (p = 0.0046) and NT-4/5 (p = 0.0003) were significantly increased in BD patients, compared to HCs. Through subgroup analysis, this increase persisted only in patients in depressed state (p = 0.0038 for NT-3 and p = 0.0001 for NT-4/5), but not in manic or euthymic state. In addition, we found the differences in NT-3 and NT-4/5 were significantly associated with the duration of illness, but not by the mean age or female proportion. Our results suggest a state-dependent increase in NT-3 and NT-4/5 levels in patients with BD. Further studies are needed to examine dynamic changes of these neurotrophins in BD patients along the disease course. PMID- 27214527 TI - Pregnancy-induced thymic involution is associated with suppression of chemokines essential for T-lymphoid progenitor homing. AB - During normal pregnancy, the thymus undergoes a severe reduction in size and thymocyte output, which may contribute to maternal-fetal tolerance. It is presently unknown whether the pregnancy-induced thymic involution also affects nonlymphoid thymic cell populations and whether these changes in stromal cells play a role in the reduction in thymocyte numbers. Here, we characterize the changes in thymic lymphoid and nonlymphoid cells and show that pregnancy results in a reduction of all major thymic lymphoid cell populations, including the early T-lymphoid progenitors (TLPs) and thymic regulatory T cells. In addition to the thymocytes, the thymic involution also includes all major nonlymphoid cell populations, which show a profound reduction in cell numbers. We also show that during pregnancy, the thymic nonlymphoid cells exhibit decreased expression of chemokines that are essential for TLP homing: CCL25, CXCL12, CCL21, and CCL19. In addition, the expression of these chemokines was substantially downregulated by short-term treatment with progesterone but not estrogen. Collectively, these findings suggest a novel mechanism for the pregnancy-induced reduction in TLP homing and the resulting thymic involution. PMID- 27214526 TI - Early life stress predicts thalamic hyperconnectivity: A transdiagnostic study of global connectivity. AB - Early life stress (ELS) is an established risk factor for psychiatric illness and is associated with altered functional connectivity within- and between intrinsic neural networks. The widespread nature of these disruptions suggests that broad imaging measures of neural connectivity, such as global based connectivity (GBC), may be particularly appropriate for studies of this population. GBC is designed to identify brain regions having maximal functional connectedness with the rest of the brain, and alterations in GBC may reflect a restriction or broadening of network synchronization. We evaluated whether ELS severity predicted GBC in a sample (N = 46) with a spectrum of ELS exposure. Participants included healthy controls without ELS, those with at least moderate ELS but without psychiatric disorders, and a group of patients with ELS- related psychiatric disorders. The spatial distribution of GBC peaked in regions of the salience and default mode networks, and ELS severity predicted increased GBC of the left thalamus (corrected p < 0.005, r = 0.498). Thalamic connectivity was subsequently evaluated and revealed reduced connectivity with the salience network, particularly the dorsal anterior cingulate cortex (corrected p < 0.005), only in the patient group. These findings support a model of disrupted thalamic connectivity in ELS and trauma-related negative affect states, and underscore the importance of a transdiagnostic, dimensional neuroimaging approach to understanding the sequelae of trauma exposure. PMID- 27214528 TI - Isolation and Structure of Cancer Cell Growth Inhibitory Tetracyclic Triterpenoids from the Zimbabwean Monadenium lugardae. AB - The Zimbabwean medicinal plant Monadenium lugardae was evaluated as a potential source of new anticancer constituents. Four new tetracyclic triterpene (1-4) were isolated, accompanied by four previously known triterpenes (5-8). Against a panel of human tumor cell lines, lugardstatins 1 (1) and 2 (2) had good cancer cell growth inhibitory activity. All of the triterpene structures (1-8) were established by 1D and 2D NMR spectrometric and HR mass spectrometric analysis. PMID- 27214530 TI - Testing Vitamin D Levels and Choosing Wisely. PMID- 27214531 TI - Recombinant coagulation factor products. AB - There are numerous new coagulation factor concentrates that are being manufactured using recombinant technology. Some are available for use currently for the treatment of bleeding disorders and others are in clinical trials. Recombinant factor VIII concentrates are licenced in most countries and one FVIII concentrate with the B domain deleted should be available in the near future. Recombinant VIIa concentrate is in advanced phase III testing for the treatment of patients with inhibitor antibodies. Recombinant factor IX has been used successfully in animals and will be tested in humans shortly. This paper reviews these products and discusses their uses and possible side-effects. PMID- 27214532 TI - The laboratory diagnosis of haemophilia: Recommendations by the Laboratory Activities Committee of the World Federation of Hemophilia. PMID- 27214533 TI - Two decades of haemophilia treatment in the Netherlands, 1972-92. AB - Four questionnaire surveys were conducted over a period of 20 years to evaluate long-term effects of haemophilia treatment in the Netherlands. The response to the prestructured questionnaires in 1972, 1978, 1985 and 1992 varied between 70% and 84%. Data concerned treatment modalities, bleeding episodes, hospitalization, absenteeism, joint impairment and employment. Results over the period 1972-92 for patients with severe and moderately severe haemophilia showed that the use of prophylaxis had sharply increased (from 21% to 45%), as was the case for home treatment (from 4% to 62%). Consequently, the annual mean number of bleeds diminished from 19 to 13. Absence from school was markedly reduced (from 32 to 5 days), and sick leave in employed patients had also diminished (from 26 to 22 days). Furthermore, the use of inpatient hospital facilities, as well as employment in haemophilia patients, had nearly equalled that of the general Dutch male population. The self-reported degree of joint impairment showed no overall improvement, but in patients aged under 35 years there seemed to be a slight reduction in severe impairment. Patients aged under 15 years finally had no severe impairment at all. Social participation can only be further improved if arthropathy is prevented from an early age. Therefore adequate prophylactic regimens and close monitoring of joint impairment in young adults are needed. PMID- 27214534 TI - Implementation of a nurse practitioner policy for the requisition and administration of drugs in a haemophilia comprehensive care centre. AB - The evolution of comprehensive care centres for haemophilia has altered the work of those involved in the care of haemophilia patients. The role of the haemophilia sister has expanded and the concept of the haemophilia nurse specialist has emerged. We describe the implementation of a local policy which has enabled haemophilia nurse specialists to requisition and administer clotting factor concentrates, DDAVP, tranexamic acid and hepatitis vaccines independently, in hospital and community settings. Since the introduction of this policy on 2 August 1994, prescribing practice has not changed in the haemophilia centre, nor has the involvement of medical staff in the care of haemophilia patients. This approach is widely applicable in other centres and should be a logical progression of the haemophilia nurse specialist's role. PMID- 27214535 TI - A new approach to immunologic identification of factor VIII antibodies. AB - We tested for antibodies against factor VIII by using monoclonal antibody purified factor VIII preparation as a source of antigen. The factor VIII was adsorbed on nitrocellulose membranes and stored in a refrigerator until later use. Plasma or serum was incubated with the factor VIII containing strip and the antibody was detected by another incubation with peroxidase-labelled antihuman immunoglobulin antibodies. The test was efficient in detecting antibodies in haemophilic and normal subjects with acquired inhibitors to factor VIII. It also detected antibodies to the factor VIII protein in a haemophilic subject with no evidence of inhibitor. The technique is simple, readily applicable, and serves as a useful screening tool for detecting factor VIII antibodies. The stability of the antigen-containing strips in a refrigerator is a practical advantage with potential commercial application. PMID- 27214536 TI - Cytolytic activity against mycobacterial antigens: differences between haemophiliacs with and without HIV infection. AB - Although asymptomatic haemophiliacs have been shown to have abnormalities of their immune response, independent of HIV, clinical evidence of significant immunosuppression is limited. The only clinical report has been an outbreak of M. tuberculosis in which a group of haemophilic boys appeared unduly susceptible to infection. These boys are now all HIV seropositive. Along with a group of HIV seronegative children with coagulation disorders and non-haemophilic HIV seropositive men, these boys have been restudied to examine immune response to PPD. The HIV seropositive haemophilic boys that had had M. tuberculosis infection had reduced cytolytic response to PPD pulsed macrophages comparable to the non haemophilic HIV seropositive men. The HIV seronegative children with coagulation disorders showed a reduction in cytolytic activity at low effector:target ratios compared to normal controls. In vitro studies showed that exogenous factor VIII concentrate could inhibit cytolytic activity to PPD pulsed macrophages. The possible role of chronic blood-borne virus infection and factor VIII concentrates in the original outbreak are discussed. PMID- 27214537 TI - Polymorphisms associated with the FVIII and FIX genes in the Turkish population. AB - In order to determine the gene frequencies of nine polymorphic sites associated with FVIII and FIX genes in the Turkish population a sample of 50-235 unrelated X chromosomes from healthy individuals were analysed by using PCR-based assays. The Turkish population was found to be as polymorphic as Europeans in the FVII and FIX genes. Analysis of FIX haplotypes revealed that the most frequent haplotype observed in European populations and Anglo-Americans was also very common among Turks. The present population-based study indicates that two marker loci, namely HindIII and St14 in the factor VIII gene and DdeI and HhaI in the factor IX gene, are highly informative and useful markers that can be used in DNA linkage analysis for the assessment of haemophilia carriers and affected fetuses in the Turkish population. PMID- 27214538 TI - The impact of prenatal diagnosis on the incidence of haemophilia in Sweden. AB - A demographic survey was made of all children (n= 137) born with severe or moderate haemophilia in Sweden during the period 1970-92. Bn addition, all prenatal diagnoses (n= 86) performing during the period were evaluated. The annual incidence of severe and moderate haemophilia, having remained constant for decades, increased from 0.78/10,000 males in the 1970s to 1.34 in the 1980s, levelling off at 1.31 in the 1990s. Although prenatal diagnosis did not affect the incidence of haemophilia in the 1970s and 1980s, it did so in the 1990s, because the incidence would have been 40% higher (1.83) had not prental diagnosis been available and 16 affected fetuses been aborted. The average proportion of sporadic cases, 62%, remained almost unchanged during the study period, suggesting mutation rates to be constant. There were fewere children in families with known haemophilia than in sporadic families, but no evidence was found to suggest that the frequency of female offspring (i.e. potential carriers) born in haemophilia families had increased since the option of prenatal diagnosis was introduced. PMID- 27214539 TI - Seroprevalence of total antibodies to hepatitis A virus in haemophiliacs in the West of Scotland. AB - Serum samples taken from 73 patients with haemophilia A were tested for the presence of total antibody against hepatitis A (antiHAV) by radiommunoassay. 29 (39.7%) were antiHAV positive and 44 (60.3%) were antiHAV negative. These figures are comparable with local prevalence figures for immunity (40.3%) and susceptibility (59.7%) to HAV in adults. 30 patients were subsequently exposed to Scottish National Blood Transfusion Service High-Purity Factor VIII (SNBTS HPVIII). They were re-tested for the presence of antiHAV at a median of 5 months after exposure. Of these, 25 (83.3%) were antiHAV negative and five (16.7%) were antiHAV positive. All five of these antiHAV-positive patients were positive on samples taken prior to exposure. No cases of seroconversion to hepatitis A occurred. PMID- 27214540 TI - Hepatitis A immunization in HIV-infected haemophilic patients. AB - Forty-seven HIV-infected haemophilic patients were entered into a hepatitis A vaccination programme. 10 patients (21%) were lgG seropositive for hepatitis A consistent with past exposure. Of the 37 patients offered vaccination, one refused and 31 completed the vaccination course, 17/13 (55%) seroconverted, nine after the second and eight after the third injection, and 14 patients failed to seroconvert. The CD4 lymphocyte counts immediately prior to vaccination were significantly higher in the patients who developed immunity compared to the nonresponders (median CD4 count in the immune group 380 * 10(6) /1 (range 170 1290), median CD4 count in nonimmune group 110 * 10(6) /1 (range 10-590), P== 0.003). No patient with a CD4 count < 170 * 10(6) /1 seroconverted and five patients with well-preserved CD4 counts also failed to seroconvert. We conclude that HIV-infected haemophilic patients, especially those with more advanced disease, have an impaired response to hepatitis A vaccination. Due to the likely failure of response in patients with CD4 counts < 150 * 10(6) /1, it is reasonable not to include these patients in a hepatitis A vaccination programme. PMID- 27214541 TI - A description of two cases of factor V deficiency. AB - We report two cases of factor V deficiency. A 12-year-old girl with thalassemia major was admitted for bone marrow transplant (mismatched). She was found to have a heterozygous deficiency of factor V (21%), but this was considered compatible with the transplant, which was performed without the support of suppernatant cryoprecipitate. A 14-year-old girl (factor V 2%) with a negative history (menarche at age 12, menstrual cycle regular and normal in quantity and length). One year previously she had complained of menorrhagia (length of period, 9 days); tests revealed server anaemia (Hb 4.9 g/dl). We show how even severe cases of factor V deficiency may often be silent, and not require transfusion in surgical procedures, thus avoiding the risks associated with such therapy. PMID- 27214542 TI - PCP pneumonia with bilateral pneumothoraces in a haemophiliac with factor VIII inhibitors. AB - Pneumocystis carinii pneumonia (PCP) infection is a well-recognized feature of advanced HIV infection in all risk groups. This serious opportunistic parasitic infection is almost invariably fatal if left untreated. When associated with bilateral pneumo-thoraces in a patient with severe haemophilia A and factor VIII inhibitors, it poses a critical management problem and can be life-threatening. We report the case of a young man with severe haemophilia A with factor VIII inhibitors presenting with bilateral pneumothoraces which was successfully managed with conservative therapy only. PMID- 27214543 TI - Carrier detection and prenatal diagnosis by intron 22 inversion analysis of the factor VIII gene. AB - In approximately 50% of severe haemophilia A patients the mutation is present in the form of a large chromosomal disruption in the factor VIII gene; this disruption is described as an inversion. It results in the physical breakage and separation of exons 1-2 and exons 23-26 of the factor VIII gene. PMID- 27214544 TI - Hepatitis C and haemophilia: a report of a meeting held at The Royal Free Hospital, London, 12 December 1994. PMID- 27214545 TI - The first patient to receive factor IX concentrate in the UK: a recollection. PMID- 27214546 TI - Abstracts of papers on haemophilia from other journals. AB - Surgical synovectomy in haemophilic arthropathy of the knee. Rodriguez Merchan EC, Galindo E, Ladreda JMM, Pardo JA Definition of the bleeding tendency in factor XI deficient kindreds: a clinical and laboratory study. Bolton-Maggs PHB, Patteson DA, Wensley RT, Tuddenham EGD. Rapid genotype analysis in type 2B von Willebrand's disease using a universal heteroduplex generator. Wood N, Standen G, Murray EW, Lillicrap D, Holmberg L, Peake IR, Bidwell J Biological effect of desmopressin in eight patients with type 2N ('Normandy') von Willebrand disease. Mazurier C, Gaucher C, Jorieux S, Goudemand M. Heterogeneity of hepatitis C virus genotypes in haemophilia: relationship with chronic liver disease. Preston FE, Jarvis LM, Makris M, Philp L, Underwood JCE, Ludlam CA, Simonds P. PMID- 27214548 TI - Corrigendum. PMID- 27214547 TI - Route of administration for immunizations in haemophiliacs. PMID- 27214549 TI - Increased mitochondrial arginine metabolism supports bioenergetics in asthma. AB - High levels of arginine metabolizing enzymes, including inducible nitric oxide synthase (iNOS) and arginase (ARG), are typical in asthmatic airway epithelium; however, little is known about the metabolic effects of enhanced arginine flux in asthma. Here, we demonstrated that increased metabolism sustains arginine availability in asthmatic airway epithelium with consequences for bioenergetics and inflammation. Expression of iNOS, ARG2, arginine synthetic enzymes, and mitochondrial respiratory complexes III and IV was elevated in asthmatic lung samples compared with healthy controls. ARG2 overexpression in a human bronchial epithelial cell line accelerated oxidative bioenergetic pathways and suppressed hypoxia-inducible factors (HIFs) and phosphorylation of the signal transducer for atopic Th2 inflammation STAT6 (pSTAT6), both of which are implicated in asthma etiology. Arg2-deficient mice had lower mitochondrial membrane potential and greater HIF-2alpha than WT animals. In an allergen-induced asthma model, mice lacking Arg2 had greater Th2 inflammation than WT mice, as indicated by higher levels of pSTAT6, IL-13, IL-17, eotaxin, and eosinophils and more mucus metaplasia. Bone marrow transplants from Arg2-deficient mice did not affect airway inflammation in recipient mice, supporting resident lung cells as the drivers of elevated Th2 inflammation. These data demonstrate that arginine flux preserves cellular respiration and suppresses pathological signaling events that promote inflammation in asthma. PMID- 27214550 TI - Autoantibodies against thrombospondin type 1 domain-containing 7A induce membranous nephropathy. AB - Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults, and one-third of patients develop end-stage renal disease (ESRD). Circulating autoantibodies against the podocyte surface antigens phospholipase A2 receptor 1 (PLA2R1) and the recently identified thrombospondin type 1 domain containing 7A (THSD7A) are assumed to cause the disease in the majority of patients. The pathogenicity of these antibodies, however, has not been directly proven. Here, we have reported the analysis and characterization of a male patient with THSD7A-associated MN who progressed to ESRD and subsequently underwent renal transplantation. MN rapidly recurred after transplantation. Enhanced staining for THSD7A was observed in the kidney allograft, and detectable anti-THSD7A antibodies were present in the serum before and after transplantation, suggesting that these antibodies induced a recurrence of MN in the renal transplant. In contrast to PLA2R1, THSD7A was expressed on both human and murine podocytes, enabling the evaluation of whether anti-THSD7A antibodies cause MN in mice. We demonstrated that human anti-THSD7A antibodies specifically bind to murine THSD7A on podocyte foot processes, induce proteinuria, and initiate a histopathological pattern that is typical of MN. Furthermore, anti THSD7A antibodies induced marked cytoskeletal rearrangement in primary murine glomerular epithelial cells as well as in human embryonic kidney 293 cells. Our findings support a causative role of anti-THSD7A antibodies in the development of MN. PMID- 27214552 TI - The Fukushima nuclear disaster is ongoing. AB - The 5th anniversary of the Fukushima disaster and the 30th anniversary of the Chernobyl disaster, the two most catastrophic nuclear accidents in history, both occurred recently. Images of Chernobyl are replete with the international sign of radioactive contamination (a circle with three broad spokes radiating outward in a yellow sign). In contrast, ongoing decontamination efforts at Fukushima lack international warnings about radioactivity. Decontamination workers at Fukushima appear to be poorly protected against radiation. It is almost as if the effort is to make the Fukushima problem disappear. A more useful response would be to openly acknowledge the monumental problems inherent in managing a nuclear plant disaster. Lessons from Chernobyl are the best predictors of what the Fukushima region of Japan is coping with in terms of health and environmental problems following a nuclear catastrophe. PMID- 27214551 TI - Foxc1 and Foxc2 deletion causes abnormal lymphangiogenesis and correlates with ERK hyperactivation. AB - The lymphatic vasculature is essential for maintaining interstitial fluid homeostasis, and dysfunctional lymphangiogenesis contributes to various pathological processes, including inflammatory disease and tumor metastasis. Mutations in FOXC2 are dominantly associated with late-onset lymphedema; however, the precise role of FOXC2 and a closely related factor, FOXC1, in the lymphatic system remains largely unknown. Here we identified a molecular cascade by which FOXC1 and FOXC2 regulate ERK signaling in lymphatic vessel growth. In mice, lymphatic endothelial cell-specific (LEC-specific) deletion of Foxc1, Foxc2, or both resulted in increased LEC proliferation, enlarged lymphatic vessels, and abnormal lymphatic vessel morphogenesis. Compared with LECs from control animals, LECs from mice lacking both Foxc1 and Foxc2 exhibited aberrant expression of Ras regulators, and embryos with LEC-specific deletion of Foxc1 and Foxc2, alone or in combination, exhibited ERK hyperactivation. Pharmacological ERK inhibition in utero abolished the abnormally enlarged lymphatic vessels in FOXC-deficient embryos. Together, these results identify FOXC1 and FOXC2 as essential regulators of lymphangiogenesis and indicate a new potential mechanistic basis for lymphatic associated diseases. PMID- 27214553 TI - Uropathogenic Escherichia coli strain CFT073 disrupts NLRP3 inflammasome activation. AB - Successful bacterial pathogens produce an array of virulence factors that allow subversion of the immune system and persistence within the host. For example, uropathogenic Escherichia coli strains, such as CFT073, express Toll/IL-1 receptor-containing (TIR-containing) protein C (TcpC), which impairs TLR signaling, thereby suppressing innate immunity in the urinary tract and enhancing persistence in the kidneys. Here, we have reported that TcpC also reduces secretion of IL-1beta by directly interacting with the NACHT leucin-rich repeat PYD protein 3 (NLRP3) inflammasome, which is crucial for recognition of pathogens within the cytosol. At a low MOI, IL-1beta secretion was minimal in CFT073 infected macrophages; however, IL-1beta release was markedly increased in macrophages infected with CFT073 lacking tcpC. Induction of IL-1beta secretion by CFT073 and tcpC-deficient CFT073 required the NLRP3 inflammasome. TcpC attenuated activation of the NLRP3 inflammasome by binding both NLRP3 and caspase-1 and thereby preventing processing and activation of caspase-1. Moreover, in a murine urinary tract infection model, CFT073 infection rapidly induced expression of the NLRP3 inflammasome in the bladder mucosa; however, the presence of TcpC in WT CFT073 reduced IL-1beta levels in the urine of infected mice. Together, these findings illustrate how uropathogenic E. coli use the multifunctional virulence factor TcpC to attenuate innate immune responses in the urinary tract. PMID- 27214554 TI - MicroRNA-140-5p and SMURF1 regulate pulmonary arterial hypertension. AB - Loss of the growth-suppressive effects of bone morphogenetic protein (BMP) signaling has been demonstrated to promote pulmonary arterial endothelial cell dysfunction and induce pulmonary arterial smooth muscle cell (PASMC) proliferation, leading to the development of pulmonary arterial hypertension (PAH). MicroRNAs (miRs) mediate higher order regulation of cellular function through coordinated modulation of mRNA targets; however, miR expression is altered by disease development and drug therapy. Here, we examined treatment naive patients and experimental models of PAH and identified a reduction in the levels of miR-140-5p. Inhibition of miR-140-5p promoted PASMC proliferation and migration in vitro. In rat models of PAH, nebulized delivery of miR-140-5p mimic prevented the development of PAH and attenuated the progression of established PAH. Network and pathway analysis identified SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1) as a key miR-140-5p target and regulator of BMP signaling. Evaluation of human tissue revealed that SMURF1 is increased in patients with PAH. miR-140-5p mimic or SMURF1 knockdown in PASMCs altered BMP signaling, further supporting these factors as regulators of BMP signaling. Finally, Smurf1 deletion protected mice from PAH, demonstrating a critical role in disease development. Together, these studies identify both miR-140-5p and SMURF1 as key regulators of disease pathology and as potential therapeutic targets for the treatment of PAH. PMID- 27214555 TI - Paracellular epithelial sodium transport maximizes energy efficiency in the kidney. AB - Efficient oxygen utilization in the kidney may be supported by paracellular epithelial transport, a form of passive diffusion that is driven by preexisting transepithelial electrochemical gradients. Claudins are tight-junction transmembrane proteins that act as paracellular ion channels in epithelial cells. In the proximal tubule (PT) of the kidney, claudin-2 mediates paracellular sodium reabsorption. Here, we used murine models to investigate the role of claudin-2 in maintaining energy efficiency in the kidney. We found that claudin-2-null mice conserve sodium to the same extent as WT mice, even during profound dietary sodium depletion, as a result of the upregulation of transcellular Na-K-2Cl transport activity in the thick ascending limb of Henle. We hypothesized that shifting sodium transport to transcellular pathways would lead to increased whole kidney oxygen consumption. Indeed, compared with control animals, oxygen consumption in the kidneys of claudin-2-null mice was markedly increased, resulting in medullary hypoxia. Furthermore, tubular injury in kidneys subjected to bilateral renal ischemia-reperfusion injury was more severe in the absence of claudin-2. Our results indicate that paracellular transport in the PT is required for efficient utilization of oxygen in the service of sodium transport. We speculate that paracellular permeability may have evolved as a general strategy in epithelial tissues to maximize energy efficiency. PMID- 27214556 TI - Transcription factor TLX1 controls retinoic acid signaling to ensure spleen development. AB - The molecular mechanisms that underlie spleen development and congenital asplenia, a condition linked to increased risk of overwhelming infections, remain largely unknown. The transcription factor TLX1 controls cell fate specification and organ expansion during spleen development, and Tlx1 deletion causes asplenia in mice. Deregulation of TLX1 expression has recently been proposed in the pathogenesis of congenital asplenia in patients carrying mutations of the gene encoding transcription factor SF-1. Herein, we have shown that TLX1-dependent regulation of retinoic acid (RA) metabolism is critical for spleen organogenesis. In a murine model, loss of Tlx1 during formation of the splenic anlage increased RA signaling by regulating several genes involved in RA metabolism. Uncontrolled RA activity resulted in premature differentiation of mesenchymal cells and reduced vasculogenesis of the splenic primordium. Pharmacological inhibition of RA signaling in Tlx1-deficient animals partially rescued the spleen defect. Finally, spleen growth was impaired in mice lacking either cytochrome P450 26B1 (Cyp26b1), which results in excess RA, or retinol dehydrogenase 10 (Rdh10), which results in RA deficiency. Together, these findings establish TLX1 as a critical regulator of RA metabolism and provide mechanistic insights into the molecular determinants of human congenital asplenia. PMID- 27214557 TI - Long term survival in persons with hemophilia and chronic hepatitis C: 40 year outcomes of a large single center cohort. AB - We studied the course of chronic HCV infections in a cohort of 222 persons with hemophilia (PWH) and von Willebrand disease followed at our center since 1973. Twenty two (10%) developed end stage liver disease (ESLD). Forty years after HCV infection, cumulative incidence of ESLD was 12.3% and overall survival was 45.5%. Those who were infected with HCV only (n = 100) had a survival of 75.2%, while those infected with HIV (n = 122) had a survival of 24% (P < 0.001). Survivals were significantly longer for those infected with HCV at younger age (< 15 years) compared to those infected over age 30 years (P = 0.014). Cause specific deaths for ESLD and bleeding were 8.8% and 8.3% respectively. For HIV negative subjects, the annual hazard of death from ESLD and bleeding was near zero for the first 10 years, and then rose slowly over the next 20 years to 0.4/100py for ESLD and 0.2/100py for bleeding. Sixty subjects completed 79 treatment episodes. Sustained viral response rates increased from 7/21 (33%) between 1990 and 2001, to 17/29 (58%) between 2002 and 2011, and to 27/29 (93%), since 2012 with the advent of the directly acting antiviral agents. These results confirm the very slow ESLD progression rate in HIV negative PWH. However, the risk of death from both ESLD and bleeding increases steadily with longer duration of HCV infection. More aggressive surveillance to detect those with early fibrosis is needed now that curative treatment is possible in >95% of individuals. Am. J. Hematol. 91:E335 E340, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27214558 TI - Neurite Orientation Dispersion and Density Imaging Color Maps to Characterize Brain Diffusion in Neurologic Disorders. AB - PURPOSE: Neurite orientation dispersion and density imaging (NODDI) has recently been developed to overcome diffusion technique limitations in modeling biological systems. This manuscript reports a preliminary investigation into the use of a single color-coded map to represent NODDI-derived information. MATERIALS AND METHODS: An optimized diffusion-weighted imaging protocol was acquired in several clinical neurological contexts including demyelinating disease, neoplastic process, stroke, and toxic/metabolic disease. The NODDI model was fitted to the diffusion datasets. NODDI is based on a three-compartment diffusion model and provides maps that quantify the contributions to the total diffusion signal in each voxel. The NODDI compartment maps were combined into a single 4-dimensional volume visualized as RGB image (red for anisotropic Gaussian diffusion, green for non-Gaussian anisotropic diffusion, and blue for isotropic Gaussian diffusion), in which the relative contributions of the different microstructural compartments can be easily appreciated. RESULTS: The NODDI color maps better describe the heterogeneity of neoplastic as well inflammatory lesions by identifying different tissue components within areas apparently homogeneous on conventional imaging. Moreover, NODDI color maps seem to be useful for identifying vasogenic edema differently from tumor-infiltrated edema. In multiple sclerosis, the NODDI color maps enable a visual assessment of the underlying microstructural changes, possibly highlighting an increased inflammatory component, within lesions and potentially in normal-appearing white matter. CONCLUSION: The NODDI color maps could make this technique valuable in a clinical setting, providing comprehensive and accessible information in normal and pathological brain tissues in different neurological pathologies. PMID- 27214560 TI - Hybridization and hybrid speciation under global change. AB - Contents 1170 I. 1170 II. 1172 III. 1175 IV. 1180 V. 1183 1184 References 1184 SUMMARY: An unintended consequence of global change is an increase in opportunities for hybridization among previously isolated lineages. Here we illustrate how global change can facilitate the breakdown of reproductive barriers and the formation of hybrids, drawing on the flora of the British Isles for insight. Although global change may ameliorate some of the barriers preventing hybrid establishment, for example by providing new ecological niches for hybrids, it will have limited effects on environment-independent post-zygotic barriers. For example, genic incompatibilities and differences in chromosome numbers and structure within hybrid genomes are unlikely to be affected by global change. We thus speculate that global change will have a larger effect on eroding pre-zygotic barriers (eco-geographical isolation and phenology) than post-zygotic barriers, shifting the relative importance of these two classes of reproductive barriers from what is usually seen in naturally produced hybrids where pre zygotic barriers are the largest contributors to reproductive isolation. Although the long-term fate of neo-hybrids is still to be determined, the massive impact of global change on the dynamics and distribution of biodiversity generates an unprecedented opportunity to study large numbers of unpredicted, and often replicated, hybridization 'experiments', allowing us to peer into the birth and death of evolutionary lineages. PMID- 27214559 TI - Projecting Lifetime Risk of Symptomatic Knee Osteoarthritis and Total Knee Replacement in Individuals Sustaining a Complete Anterior Cruciate Ligament Tear in Early Adulthood. AB - OBJECTIVE: To estimate the lifetime risk of knee osteoarthritis (OA) and total knee replacement (TKR) in persons sustaining anterior cruciate ligament (ACL) tear by age 25 years. METHODS: We used the Osteoarthritis Policy Model to project the cumulative incidence of symptomatic knee OA requiring TKR in varying situations: no prevalent or incident injury; isolated ACL tear, surgically treated; isolated ACL tear, nonoperatively treated; or a prevalent history or surgically treated ACL and meniscal tear (MT). We estimated MT prevalence and incidence and increased risk of knee OA associated with ACL injury and MT from published literature. We conducted a range of sensitivity analyses to examine the impact of uncertainty in input parameters. RESULTS: Estimated lifetime risk of symptomatic knee OA was 34% for the cohort with ACL injury and MT, compared to 14% for the no-injury cohort. ACL injury without MT was associated with a lifetime risk of knee OA between 16% and 17%, depending on ACL treatment modality. Estimated lifetime risk of TKR ranged from 6% in the no-injury cohort to 22% for the ACL injury and MT cohort. Subjects in the ACL injury and MT cohort developed OA approximately 1.5 years earlier (55.7 versus 57.1) and underwent TKR approximately 2 years earlier (66 versus 68) than the cohort without knee injuries. CONCLUSION: Sustaining ACL injury early in adulthood leads to greater lifetime risk and earlier onset of knee OA and TKR; concomitant MTs compound this risk. These data provide insight into the impact of sustainable injury prevention interventions in young adults. PMID- 27214562 TI - The use of Ethics Decision-Making Frameworks by Canadian Ethics Consultants: A Qualitative Study. AB - In this study, Canadian healthcare ethics consultants describe their use of ethics decision-making frameworks. Our research finds that ethics consultants in Canada use multi-purpose ethics decision-making frameworks, as well as targeted frameworks that focus on reaching an ethical resolution to a particular healthcare issue, such as adverse event reporting, or difficult triage scenarios. Several interviewees mention the influence that the accreditation process in Canadian healthcare organizations has on the adoption and use of such frameworks. Some of the ethics consultants we interviewed also report on their reluctance to use these tools. Limited empirical work has been done previously on the use of ethics decision-making frameworks. This study begins to fill this gap in our understanding of the work of healthcare ethics consultants. PMID- 27214563 TI - Sleep-Disordered Breathing in Patients with Pulmonary Valve Incompetence Complicating Congenital Heart Disease. AB - OBJECTIVE: Long standing pulmonary regurgitation results in deleterious effects on right heart size and function with late consequences of right heart volume overload including ventricular dilatation, propensity to arrhythmia and right heart failure. As sleep disordered breathing may predispose to elevations in pulmonary vascular resistance and associated negative effects on right ventricular function, we sought to assess this in patients with underlying congenital heart disease. DESIGN: We performed a pilot study to evaluate the incidence of sleep-disordered breathing in a patient population with a history of long standing pulmonary valve incompetence in patients with congenital heart disease using overnight oximetry. PATIENTS: Patients with a background of tetralogy of Fallot repair or residual pulmonary incompetence following previous pulmonary valve intervention for congenital pulmonary stenosis were included. RESULTS: Twenty-two patients underwent overnight oximetry. The mean age of the cohort was 34.3 +/- 15.2 years with no patients observed to have severe underlying pulmonary hypertension. Abnormal overnight oximetry was seen in 13/22 patients (59.1%) with 2/22 (9.1%) patients considered to have severe abnormalities. CONCLUSIONS: An important proportion of patients with a background of pulmonary incompetence complicating congenital heart disease are prone to the development of sleep-disordered breathing as assessed by overnight oximetry. Further study into the prevalence and mechanisms of sleep-disordered breathing in a larger cohort are warranted. PMID- 27214564 TI - Implication of different initial beta blockers on treatment persistence: atenolol vs new-generation beta blocker, a population-based study. AB - AIM: Potential heterogeneity within the same class of drug in terms of persistence may lead to different clinical implications. Given that the increased risks of mortality and cardiovascular events are due, in part, to the lack of persistent use of antihypertensive medications, the objective of this study was to evaluate 1-year persistence of new-generation beta blockers compared to atenolol in antihypertensive treatment-naive patients. METHODS: A total of 9978 patients aged 18 years or older with hypertension newly diagnosed in 2012, without hypertension-related complication and initiated treatment with beta blocker monotherapy during 2012 were included in the analysis. Rate and duration of treatment and drug persistence were compared between atenolol and new generation beta blockers. Hazards of discontinuation in nonatenolol compared to atenolol were evaluated using a multivariate Cox proportional model. RESULTS: The rate of treatment persistence was higher in the nonatenolol group (57.35% vs 53.40%, P<.0001), and the time to treatment discontinuation was earlier in the atenolol group with a minimal difference in the average (243.2 vs 254 days, P<.0001). New-generation beta blockers demonstrated a lower risk of treatment discontinuation (HR: 0.91, 95% CI: 0.86-0.96) compared to atenolol; a notable improvement was observed with carvedilol and nebivolol (HR: 0.74, 95% CI: 0.69 0.80 and HR: 0.79, 95% CI: 0.70-0.89, respectively), whereas betaxolol showed a substantially greater hazard for discontinuation compared to atenolol. CONCLUSIONS: This study demonstrated a meaningful improvement in treatment persistence with new-generation beta blockers compared to atenolol, with betaxolol as exception. PMID- 27214565 TI - Microinjection for Transgenesis and Genome Editing in Threespine Sticklebacks. AB - The threespine stickleback fish has emerged as a powerful system to study the genetic basis of a wide variety of morphological, physiological, and behavioral phenotypes. The remarkably diverse phenotypes that have evolved as marine populations adapt to countless freshwater environments, combined with the ability to cross marine and freshwater forms, provide a rare vertebrate system in which genetics can be used to map genomic regions controlling evolved traits. Excellent genomic resources are now available, facilitating molecular genetic dissection of evolved changes. While mapping experiments generate lists of interesting candidate genes, functional genetic manipulations are required to test the roles of these genes. Gene regulation can be studied with transgenic reporter plasmids and BACs integrated into the genome using the Tol2 transposase system. Functions of specific candidate genes and cis-regulatory elements can be assessed by inducing targeted mutations with TALEN and CRISPR/Cas9 genome editing reagents. All methods require introducing nucleic acids into fertilized one-cell stickleback embryos, a task made challenging by the thick chorion of stickleback embryos and the relatively small and thin blastomere. Here, a detailed protocol for microinjection of nucleic acids into stickleback embryos is described for transgenic and genome editing applications to study gene expression and function, as well as techniques to assess the success of transgenesis and recover stable lines. PMID- 27214566 TI - Dynamics of osseointegration in various human and animal models - a comparative analysis. AB - OBJECTIVE: To investigate the sequential events of osseointegration in various model situations. MATERIAL AND METHODS: A series of eight recent sequential studies on the early phases of osseointegration performed in various species analyzing new bone apposition and parent bone resorption at the implant surfaces have been studied. One human, six dog and one rabbit studies were analyzed for old and new bone percentages, assessed at least at 4 periods of the early osseointegration. Data on new and old parent bone in contact with the implant surfaces were collected. The interception point of the two proportions of new and old bone was calculated in terms of osseointegration (y; %) and period of the interceptions (x; days). RESULTS: It has been shown that the interception point of old and new bone proportions was strongly influenced by the choice of the model adopted (human, dog, rabbit), by the density of the surrounding bone (cortical, spongy, trabecular) and by the implant geometry. Implant surface configuration, time of implantation and load influenced the interception point to a lesser degree. The fastest rate of osseointegration was observed in the rabbit model followed by the dog model. The slowest osseointegration rate was seen in humans. Osseointegration was documented best in spongiosa bone when compared to cortical bone. The moderately rough surfaces gave rise to faster osseointegration than did the turned implant surfaces. CONCLUSIONS: The interception points may provide information on efficacy of early osseointegration. The slope of the line (m) is related to the efficacy of bone appositions. PMID- 27214567 TI - Hedgehog signaling promotes basal progenitor expansion and the growth and folding of the neocortex. AB - The unique mental abilities of humans are rooted in the immensely expanded and folded neocortex, which reflects the expansion of neural progenitors, especially basal progenitors including basal radial glia (bRGs) and intermediate progenitor cells (IPCs). We found that constitutively active Sonic hedgehog (Shh) signaling expanded bRGs and IPCs and induced folding in the otherwise smooth mouse neocortex, whereas the loss of Shh signaling decreased the number of bRGs and IPCs and the size of the neocortex. SHH signaling was strongly active in the human fetal neocortex but Shh signaling was not strongly active in the mouse embryonic neocortex, and blocking SHH signaling in human cerebral organoids decreased the number of bRGs. Mechanistically, Shh signaling increased the initial generation and self-renewal of bRGs and IPC proliferation in mice and the initial generation of bRGs in human cerebral organoids. Thus, robust SHH signaling in the human fetal neocortex may contribute to bRG and IPC expansion and neocortical growth and folding. PMID- 27214568 TI - Evaluation of ambiguous associations in the amygdala by learning the structure of the environment. AB - Recognizing predictive relationships is critical for survival, but an understanding of the underlying neural mechanisms remains elusive. In particular, it is unclear how the brain distinguishes predictive relationships from spurious ones when evidence about a relationship is ambiguous, or how it computes predictions given such uncertainty. To better understand this process, we introduced ambiguity into an associative learning task by presenting aversive outcomes both in the presence and in the absence of a predictive cue. Electrophysiological and optogenetic approaches revealed that amygdala neurons directly regulated and tracked the effects of ambiguity on learning. Contrary to established accounts of associative learning, however, interference from competing associations was not required to assess an ambiguous cue-outcome contingency. Instead, animals' behavior was explained by a normative account that evaluates different models of the environment's statistical structure. These findings suggest an alternative view of amygdala circuits in resolving ambiguity during aversive learning. PMID- 27214569 TI - Professional online community membership and participation among healthcare providers: An extension to nurse practitioners and physician assistants. AB - BACKGROUND AND PURPOSE: Professional online communities allow healthcare providers to exchange ideas with their colleagues about best practices for patient care. Research on this topic has focused almost exclusively on primary care physicians and specialists, to the exclusion of advanced practice providers such as nurse practitioners and physician assistants. We expand this literature by examining membership and participation on these websites among each of these provider groups. METHODS: Participants (N = 2008; approximately 500 per provider group) responded to an Internet-based survey in which they were asked if they use professional online communities to dialogue with colleagues and if so, what their motivation is for doing so. CONCLUSIONS: Nearly half of the participants in our sample reported utilizing professional online communities. Select differences were observed between provider groups, but overall, similar patterns emerged in their membership and participation on these websites. IMPLICATIONS FOR PRACTICE: Nurse practitioners and physician assistants utilize professional online communities in similar proportion to primary care physicians and specialists. Providers should be cognizant of the impact this use may have for both themselves and their patients. Researchers are urged to take into account the various professional roles within the healthcare community while developing research on this topic. PMID- 27214571 TI - Optically detected magnetic resonance of high-density ensemble of NV- centers in diamond. AB - Optically detected magnetic resonance (ODMR) is a way to characterize the ensemble of NV-centers. Recently, a remarkably sharp dip was observed in the ODMR with a high-density ensemble of NV centers. The model (Zhu et al 2014 Nat. Commun. 5 3424) indicated that such a dip was due to the spin-1 properties of the NV- centers. Here, we present many more details of the analysis to show how this model can be applied to investigate the properties of the NV- centers. By using our model, we have reproduced the ODMR with and without applied external magnetic fields. Additionally, we investigate how the ODMR is affected by the typical parameters of the ensemble NV- centers such as strain distributions, inhomogeneous magnetic fields, and homogeneous broadening width. Our model provides a way to characterize the NV- center from the ODMR, which would be crucial to realize diamond-based quantum information processing. PMID- 27214572 TI - TDP-43 Proteinopathy: Aggregation and Propagation in the Pathogenesis of Amyotrophic Lateral Sclerosis. PMID- 27214570 TI - Identification of Putative Mek1 Substrates during Meiosis in Saccharomyces cerevisiae Using Quantitative Phosphoproteomics. AB - Meiotic recombination plays a key role in sexual reproduction as it generates crossovers that, in combination with sister chromatid cohesion, physically connect homologous chromosomes, thereby promoting their proper segregation at the first meiotic division. Meiotic recombination is initiated by programmed double strand breaks (DSBs) catalyzed by the evolutionarily conserved, topoisomerase like protein Spo11. Repair of these DSBs is highly regulated to create crossovers between homologs that are distributed throughout the genome. This repair requires the presence of the mitotic recombinase, Rad51, as well as the strand exchange activity of the meiosis-specific recombinase, Dmc1. A key regulator of meiotic DSB repair in Saccharomyces cerevisiae is the meiosis-specific kinase Mek1, which promotes interhomolog strand invasion and is required for the meiotic recombination checkpoint and the crossover/noncrossover decision. Understanding how Mek1 regulates meiotic recombination requires the identification of its substrates. Towards that end, an unbiased phosphoproteomic approach utilizing Stable Isotope Labeling by Amino Acids in Cells (SILAC) was utilized to generate a list of potential Mek1 substrates, as well as proteins containing consensus phosphorylation sites for cyclin-dependent kinase, the checkpoint kinases, Mec1/Tel1, and the polo-like kinase, Cdc5. These experiments represent the first global phosphoproteomic dataset for proteins in meiotic budding yeast. PMID- 27214573 TI - Polycatenar Mesogens with Various Degree of Flexibility of Molecular Structure. AB - A series of newly synthesised rod-like polycatenar mesogens forms columnar phases, with the number of molecules in the column cross section depending on the core rigidity. For non-symmetric molecules, an additional density modulation, namely helical arrangement of molecules with a periodicity of approximately 10 molecular distances develops along the columns. For one of the compounds, a new type of columnar liquid crystal phase with 3D positional order is observed. Introducing a stilbene unit in the mesogenic core enhances the fluorescent properties of the compounds. In the hexagonal columnar phase, polarised light emission is observed. PMID- 27214574 TI - A Case of Giant Colonic Muco-submucosal Elongated Polyps Associated with Intussusception. AB - Colonic muco-submucosal elongated polyp (CMSEP), a newly categorized non neoplastic colorectal polyp, is a pedunculated and elongated polyp composed of normal mucosal and submucosal layers without any proper muscle layer. We herein report a giant variant of CMSEP associated with intussusception in the rectosigmoid colon, with a review of the literature. A 48-year-old woman underwent a laparoscopic low anterior resection due to multiple large submucosal polypoid masses associated with intussusception. Grossly, the colonic masses were multiple pedunculated polyps with a long stalk and branches ranging in size from a few millimeters to 14.0 cm in length. Microscopically, there was no evidence of hyperplasia, atypia, or active inflammation in the mucosa. The submucosal layers were composed of edematous and fibrotic stroma with fat tissue, dilated vessels, and lymphoid follicles. PMID- 27214575 TI - Magnetic Anisotropy in Functionalized Bipyridyl Cryptates. AB - The magnetic properties of molecular lanthanoid complexes are very important for a variety of scientific and technological applications, with the unique magnetic anisotropy being one of the most important features. In this context, a very rigid tris(bipyridine) cryptand was synthesized with a primary amine functionality for future bioconjugation. The magnetic anisotropy was investigated for the corresponding paramagnetic ytterbium cryptate. With the use of a combination of density functional theory calculations and lanthanoid-induced NMR shift analysis, the magnetic susceptibility tensor was determined and compared to the unfunctionalized cryptate analogue. The size and orientation of the axial and rhombic tensor components show remarkably great resilience toward the decrease of local symmetry around the metal and anion exchange in the inner coordination sphere. In addition, the functionalized ytterbium cryptate also exhibits efficient near-IR luminescence. PMID- 27214576 TI - Quantification of MRI and MRS characteristics changes in a rat model at different stage of cerebral ischemia. AB - BACKGROUND: A better understanding the mechanisms of cerebral ischemia is important both for diagnosis and treatment. OBJECTIVE: The study aimed to quantify several characteristics of magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) to indicate the brain tissue changes at different stage of cerebral ischemia in rats. METHODS: In the present study, a rat model of cerebral ischemia was established by middle cerebral artery occlusion (MCAO) in the left hemisphere. MRI and MRS were performed on 15 Sprague Dawley rats 4 H, 24 H, and 1 W after MCAO. Apparent diffusion coefficient (ADC), relative ADC including FNR, PNR, PNF, and metabolite ratio NCC were proposed to reflect the changes of water diffusion and metabolism in brain tissue. RESULTS: ADCs of focal zone and penumbra zone from 1 W group were significantly larger than those from 4H group, respectively (both p < 0.05). PNR and PNF of 24H and 1 W groups were significantly less than 4H group (all p < 0.01). NCCs of focal zone and penumbra zone were significantly less than the normal zone within 4H, 24H, and 1 W groups, respectively (both p < 0.01). While NCCs of penumbra zone from 24H and 1 W groups were significantly larger than 4H group (both p < 0.01). CONCLUSION: We conclude that combination of MRI and MRS characteristics can provide significant indicators for ischemic damage at different stage of cerebral ischemia in a rat model. PMID- 27214577 TI - Dithienylthienothiophenebisimide, a Versatile Electron-Deficient Unit for Semiconducting Polymers. AB - A novel electron-deficient building unit, dithienylthienothiophenebisimide, and its polymers (PTBIs) are reported. Organic photovoltaic (OPV) cells based on PTBIs as p-type material exhibit 8.0% efficiencies with open-circuit voltages higher than 1 V. Interestingly, PTBIs also function as n-type material in OPVs depending on the molecular structure. These polymers also exhibit p-channel, n channel, and ambipolar behaviors in field-effect transistors. PMID- 27214578 TI - Female bladder outlet obstruction: an update on diagnosis and management. AB - PURPOSE OF REVIEW: The diagnosis and evaluation of bladder outlet obstruction (BOO) in women remains a challenging topic. The goal of this study is to review recent literature and summarize the diagnosis and management of BOO with special focus on recent progress. RECENT FINDINGS: In recent years, numerous advances in the area of female BOO have taken place including a movement towards unified diagnostic criteria, summary of functional and anatomic causes, and exploration of potential diagnostic options. SUMMARY: This review discusses the known diagnosis and management of female bladder outlet obstruction, yet highlights specific functional causes, new criteria available for diagnosis, and long-term results of treatment options. PMID- 27214579 TI - The practice of transition urology and congenitalism. PMID- 27214581 TI - Update on ablative therapies of renal tumors. AB - PURPOSE OF REVIEW: To summarize the recent literature on ablative therapies for the management of renal tumors. RECENT FINDINGS: Recent studies show excellent long-term oncological outcome data for cryoablation and radiofrequency ablation with a minimal risk of major complications and excellent preservation of renal function. For properly selected patients, oncological outcomes appear to be similar to partial nephrectomy. Ablation is also feasible in T1b tumors and for metastatic sites. In case of local recurrence, salvage surgery is challenging because of perinephric fibrosis but offers excellent oncological control. Papillary renal cell carcinoma may respond better to ablation than clear cell. Microwave ablation and irreversible electroporation are evolving ablation techniques, but their efficacy needs to be proven. SUMMARY: Although high-quality randomized data are lacking, evidence shows that ablation of renal tumors achieves excellent long-term oncological results in properly selected patients. Cryoablation and radiofrequency ablation are the standard procedures, while other techniques require further evaluation. PMID- 27214580 TI - Optimizing safety and accuracy of prostate biopsy. AB - PURPOSE OF REVIEW: The objective of this article is to examine the safety of prostate biopsy and discuss the emerging role of MRI-ultrasound fusion technology in improving diagnostic accuracy. RECENT FINDINGS: Men undergoing prostate biopsy frequently experience minor complications, including hematospermia, hematuria, and infection. Quinolone-resistant bacteria are a growing concern; thus, transperineal access or modification of antibiotic prophylaxis based on local antibiograms is now used to avoid infectious complications.Multiparametric MRI allows visualization of many prostate cancers, and by fusing MRI with real-time ultrasound, a biopsy needle can be directed by a urologist into suspicious regions of interest. Using this new method, detection of clinically significant prostate cancer has increased and the incidence of falsely negative biopsies has decreased. SUMMARY: Prostate biopsy is generally a safe procedure, and with attention to local patterns of antibiotic resistance, infectious complications can be minimized. MRI-ultrasound fusion has significantly improved the accuracy of prostate biopsy, allowing tracking and targeting not previously possible. PMID- 27214582 TI - A triarylmethyl spin label for long-range distance measurement at physiological temperatures using T1 relaxation enhancement. AB - Site-directed spin labeling (SDSL) in combination with electron paramagnetic resonance (EPR) spectroscopy has become an important tool for measuring distances in proteins on the order of a few nm. For this purpose pairs of spin labels, most commonly nitroxides, are site-selectively introduced into the protein. Recent efforts to develop new spin labels are focused on tailoring the intrinsic properties of the label to either extend the upper limit of measurable distances at physiological temperature, or to provide a unique spectral lineshape so that selective pairwise distances can be measured in a protein or complex containing multiple spin label species. Triarylmethyl (TAM) radicals are the foundation for a new class of spin labels that promise to provide both capabilities. Here we report a new methanethiosulfonate derivative of a TAM radical that reacts rapidly and selectively with an engineered cysteine residue to generate a TAM containing side chain (TAM1) in high yield. With a TAM1 residue and Cu(2+) bound to an engineered Cu(2+) binding site, enhanced T1 relaxation of TAM should enable measurement of interspin distances up to 50A at physiological temperature. To achieve favorable TAM1-labeled protein concentrations without aggregation, proteins are tethered to a solid support either site-selectively using an unnatural amino acid or via native lysine residues. The methodology is general and readily extendable to complex systems, including membrane proteins. PMID- 27214583 TI - High Resolution Quantification of Crystalline Cellulose Accumulation in Arabidopsis Roots to Monitor Tissue-specific Cell Wall Modifications. AB - Plant cells are surrounded by a cell wall, the composition of which determines their final size and shape. The cell wall is composed of a complex matrix containing polysaccharides that include cellulose microfibrils that form both crystalline structures and cellulose chains of amorphous organization. The orientation of the cellulose fibers and their concentrations dictate the mechanical properties of the cell. Several methods are used to determine the levels of crystalline cellulose, each bringing both advantages and limitations. Some can distinguish the proportion of crystalline regions within the total cellulose. However, they are limited to whole-organ analyses that are deficient in spatiotemporal information. Others relying on live imaging, are limited by the use of imprecise dyes. Here, we report a sensitive polarized light-based system for specific quantification of relative light retardance, representing crystalline cellulose accumulation in cross sections of Arabidopsis thaliana roots. In this method, the cellular resolution and anatomical data are maintained, enabling direct comparisons between the different tissues composing the growing root. This approach opens a new analytical dimension, shedding light on the link between cell wall composition, cellular behavior and whole-organ growth. PMID- 27214584 TI - Monitoring weekly heart rate variability in futsal players during the preseason: the importance of maintaining high vagal activity. AB - This study aimed to compare the weekly natural log of the root-mean-square difference of successive normal inter-beat (RR) intervals (ln RMSSDWeekly) and its coefficient of variation (ln RMSSDCV) in response to 5 weeks of preseason training in professional male futsal players. A secondary aim was to assess the relationship between ln RMSSDWeekly and ln RMSSDCV. The ln RMSSD is a measure of cardiac-vagal activity, and ln RMSSDCV represents the perturbations of cardiac autonomic homeostasis, which may be useful for assessing how athletes are coping with training. Ten futsal players had their resting ln RMSSD recorded prior to the first daily training session on four out of approximately five regular training days . week-1. Session rating of perceived exertion (sRPE) was quantified for all training sessions. Despite weekly sRPE varying between 3455 +/ 300 and 5243 +/- 463 arbitrary units (a.u.), the group changes in ln RMSSDWeekly were rated as unclear (using magnitude-based inference), although large inter individual variability in ln RMSSD responses was observed. The ln RMSSDCV in weeks 4 and 5 were likely lower than the previous weeks. A large and significant negative correlation (r = -0.53; CI 90%: -0.36; -0.67) was found between ln RMSSD and ln RMSSDCV. Therefore, monitoring individual ln RMSSD responses is suggested since large inter-individual variations may exist in response to futsal training. In addition, higher values of ln RMSSD are associated with lower oscillations of cardiac autonomic activity. PMID- 27214585 TI - Fecal microbiota transplantation for recurrent Clostridium difficile infection in hematopoietic stem cell transplant recipients. AB - Recurrent Clostridium difficile infection (CDI) is a consequence of intestinal dysbiosis and is particularly common following hematopoietic stem cell transplantation (HSCT). Fecal microbiota transplantation (FMT) is an effective method of treating CDI by correcting intestinal dysbiosis by passive transfer of healthy donor microflora. FMT has not been widely used in immunocompromised patients, including HSCT recipients, owing to concern for donor-derived infection. Here, we describe initial results of an FMT program for CDI at a US HSCT center. Seven HSCT recipients underwent FMT between February 2015 and February 2016. Mean time post HSCT was 635 days (25-75 interquartile range [IQR] 38-791). Five of the patients (71.4%) were on immunosuppressive therapy at FMT; 4 had required long-term suppressive oral vancomycin therapy because of immediate recurrence after antibiotic cessation. Stool donors underwent comprehensive health and behavioral screening and laboratory testing of serum and stool for 32 potential pathogens. FMT was administered via the naso-jejunal route in 6 of the 7 patients. Mean follow-up was 265 days (IQR 51-288). Minor post-FMT adverse effects included self-limited bloating and urgency. One patient was suspected of having post-FMT small intestinal bacterial overgrowth. No serious adverse events were noted and all-cause mortality was 0%. Six of 7 (85.7%) patients had no recurrence; 1 patient recurred at day 156 post FMT after taking an oral antibiotic and required repeat FMT, after which no recurrence has occurred. Diarrhea was improved in all patients and 1 patient with gastrointestinal graft versus-host disease was able to taper off systemic immunosuppression after FMT. With careful donor selection and laboratory screening, FMT appears to be a safe and effective therapy for CDI in HSCT patients and may confer additional benefits. Larger studies are necessary to confirm safety and efficacy and explore other possible effects. PMID- 27214586 TI - Hydrogen Absorption of Palladium Thin Films Observed by in Situ Transmission Electron Microscopy with an Environmental Cell. AB - A window type of the environmental cell system for a high-voltage electron microscope was developed and applied to in situ observation of a palladium (Pd) thin film. For in situ hydrogenation of Pd thin films, the distances of the lattice fringes were 0.20 and 0.23 nm, which correspond to the lattice d spacings of beta-phase (200) and (111) planes. Expansion of the Pd lattice happened as a result of phase transformation from the alpha phase to the beta phase. In particular, the lattice fringes were clearly distinguished, and the dislocation behavior during Pd hydrogenation was easily recognized according to the corresponding inverse fast fourier transform images. Furthermore, significant growth in the number of dislocations was observed at the grain boundary during increasing hydrogen pressure in the cell. PMID- 27214587 TI - Simultaneous Spectroscopic and Topographic Imaging of Single-Molecule Interfacial Electron-Transfer Reactivity and Local Nanoscale Environment. AB - The fundamental information related to the energy flow between molecules and substrate surfaces as a function of surface site geometry and molecular structure is critical for understanding interfacial electron-transfer (ET) dynamics. The inhomogeneous nanoscale molecule-surface and molecule-molecule interactions are presumably the origins of the complexity in interfacial ET dynamics; thus, identifying the environment of molecules at nanoscale is crucial. We have developed atomic force microscopy (AFM) correlated single-molecule fluorescence intensity/lifetime imaging microscopy (AFM-SMFLIM) capable of identifying and characterizing individual molecules distributed across the heterogeneous surface at the nanometer length scale. Using the novel AFM-SMFLIM imaging, we are able to obtain nanoscale morphology and interfacial ET dynamics at a single-molecule level. Moreover, the observed blinking behavior and lifetime of each molecule in combination with the topography of the environment at nanoscale provide the location of each molecule on the surface (TiO2 vs cover glass) at nanoscale and the coupling strength of each molecule with TiO2 nanoparticles. PMID- 27214588 TI - Responses of the Acutely Injured Spinal Cord to Vibration that Simulates Transport in Helicopters or Mine-Resistant Ambush-Protected Vehicles. AB - In the military environment, injured soldiers undergoing medical evacuation via helicopter or mine-resistant ambush-protected vehicle (MRAP) are subjected to vibration and shock inherent to the transport vehicle. We conducted the present study to assess the consequences of such vibration on the acutely injured spinal cord. We used a porcine model of spinal cord injury (SCI). After a T10 contusion compression injury, animals were subjected to 1) no vibration (n = 7-8), 2) whole body vibration at frequencies and amplitudes simulating helicopter transport (n = 8), or 3) whole body vibration simulating ground transportation in an MRAP ambulance (n = 7). Hindlimb locomotor function (using Porcine Thoracic Injury Behavior Scale [PTIBS]), Eriochrome Cyanine histochemistry and biochemical analysis of inflammatory and neural damage markers were analyzed. Cerebrospinal fluid (CSF) expression levels for monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-6, IL-8, and glial fibrillary acidic protein (GFAP) were similar between the helicopter or MRAP group and the unvibrated controls. Spared white/gray matter tended to be lower in the MRAP-vibrated animals than in the unvibrated controls, especially rostral to the epicenter. However, spared white/gray matter in the helicopter-vibrated group appeared normal. Although there was a relationship between the extent of sparing and the extent of locomotor recovery, no significant differences were found in PTIBS scores between the groups. In summary, exposures to vibration in the context of ground (MRAP) or aeromedical (helicopter) transportation did not significantly impair functional outcome in our large animal model of SCI. However, MRAP vibration was associated with increased tissue damage around the injury site, warranting caution around exposure to vehicle vibration acutely after SCI. PMID- 27214589 TI - Label-free biomarkers of human embryonic stem cell differentiation to hepatocytes. AB - Four different label-free, minimally invasive, live single cell analysis techniques were applied in a quantitative comparison, to characterize embryonic stem cells and the hepatocytes into which they were differentiated. Atomic force microscopy measures the cell's mechanical properties, Raman spectroscopy measures its chemical properties, and dielectrophoresis measures the membrane's capacitance. They were able to assign cell type of individual cells with accuracies of 91% (atomic force microscopy), 95.5% (Raman spectroscopy), and 72% (dielectrophoresis). In addition, stimulated Raman scattering (SRS) microscopy was able to easily identify hepatocytes in images by the presence of lipid droplets. These techniques, used either independently or in combination, offer label-free methods to study individual living cells. Although these minimally invasive biomarkers can be applied to sense phenotypical or environmental changes to cells, these techniques have most potential in human stem cell therapies where the use of traditional biomarkers is best avoided. Destructive assays consume valuable stem cells and do not characterize the cells which go on to be used in therapies; whereas immunolabeling risks altering cell behavior. It was suggested how these four minimally invasive methods could be applied to cell culture, and how they could in future be combined into one microfluidic chip for cell sorting. (c) 2016 International Society for Advancement of Cytometry. PMID- 27214590 TI - Metal-Free Reduction of Aromatic Nitro Compounds to Aromatic Amines with B2pin2 in Isopropanol. AB - A metal-free reduction of aromatic nitro compounds to the corresponding amines has been achieved by a combination of B2pin2 and KOtBu in isopropanol. A series of nitro compounds containing various reducible functional groups were chemoselectively reduced in good to excellent yields. PMID- 27214591 TI - The Development of Tracheal Intubation Proficiency Outside the Operating Suite During Pediatric Critical Care Medicine Fellowship Training: A Retrospective Cohort Study Using Cumulative Sum Analysis. AB - OBJECTIVE: Tracheal intubation is a core technical skill for pediatric critical care medicine fellows. Limited data exist to describe current pediatric critical care medicine fellow tracheal intubation skill acquisition through the training. We hypothesized that both overall and first-attempt tracheal intubation success rates by pediatric critical care medicine fellows improve over the course of training. DESIGN: Retrospective cohort study at a single large academic children's hospital. MATERIALS AND METHODS: The National Emergency Airway Registry for Children database and local QI database were merged for all tracheal intubations outside the Operating Suite by pediatric critical care medicine fellows from July 2011 to January 2015. Primary outcomes were tracheal intubation overall success (regardless of number of attempts) and first attempt success. Patient-level covariates were adjusted in multivariate analysis. Learning curves for each fellow were constructed by cumulative sum analysis. RESULTS: A total of 730 tracheal intubation courses performed by 33 fellows were included in the analysis. The unadjusted overall and first attempt success rates were 87% and 80% during the first 3 months of fellowship, respectively, and 95% and 73%, respectively, during the past 3 months of fellowship. Overall success, but not first attempt success, improved during fellowship training (odds ratio for each 3 months, 1.08; 95% CI, 1.01-1.17; p = 0.037) after adjusting for patient-level covariates. Large variance in fellow's tracheal intubation proficiency outside the operating suite was demonstrated with a median number of tracheal intubation equal to 26 (range, 19-54) to achieve a 90% overall success rate. All fellows who completed 3 years of training during the study period achieved an acceptable 90% overall tracheal intubation success rate. CONCLUSIONS: Tracheal intubation overall success improved significantly during the course of fellowship; however, the tracheal intubation first attempt success rates did not. Large variance existed in individual tracheal intubation performance over time. Further investigations on a larger scale across different training programs are necessary to clarify intensity and duration of the training to achieve tracheal intubation procedural competency. PMID- 27214592 TI - Serine and threonine residues of plant STN7 kinase are differentially phosphorylated upon changing light conditions and specifically influence the activity and stability of the kinase. AB - STN7 kinase catalyzes the phosphorylation of the globally most common membrane proteins, the light-harvesting complex II (LHCII) in plant chloroplasts. STN7 itself possesses one serine (Ser) and two threonine (Thr) phosphosites. We show that phosphorylation of the Thr residues protects STN7 against degradation in darkness, low light and red light, whereas increasing light intensity and far red illumination decrease phosphorylation and induce STN7 degradation. Ser phosphorylation, in turn, occurs under red and low intensity white light, coinciding with the client protein (LHCII) phosphorylation. Through analysis of the counteracting LHCII phosphatase mutant tap38/pph1, we show that Ser phosphorylation and activation of the STN7 kinase for subsequent LHCII phosphorylation are heavily affected by pre-illumination conditions. Transitions between the three activity states of the STN7 kinase (deactivated in darkness and far red light, activated in low and red light, inhibited in high light) are shown to modulate the phosphorylation of the STN7 Ser and Thr residues independently of each other. Such dynamic regulation of STN7 kinase phosphorylation is crucial for plant growth and environmental acclimation. PMID- 27214593 TI - Effects of Delta-9-Tetrahydrocannabinol and Cannabidiol on Cisplatin-Induced Neuropathy in Mice. AB - Sativex, a cannabinoid extract with a 1 : 1 ratio of tetrahydocannabinol and cannabidiol, has been shown to alleviate neuropathic pain associated with chemotherapy. This research examined whether tetrahydocannabinol or cannabidiol alone could attenuate or prevent cisplatin-induced tactile allodynia. In experiment 1, mice (C57BL/6) received eight administrations of 2.3 mg/kg cisplatin or saline solution IP every other day to induce tactile allodynia. Mice were then administered vehicle, 100 mg/kg gabapentin, 2 mg/kg tetrahydocannabinol, or 2 mg/kg cannabidiol IP and tested 60 min later on an electronic Von Frey. In experiment 2, prevention studies, cannabidiol (0.0, 0.5, 1.0, and 2.0 mg/kg) or tetrahydocannabinol (0.0, 0.5, 1.0, and 2.0 mg/kg) was given IP 30 min prior to cisplatin administration (2.3 or 1.0 mg/kg) utilizing a six-dose alternate day protocol. In both studies, tactile responses to the hind paws were quantified in g of force using an electronic Von Frey prior to and after the cisplatin administration protocol. Cisplatin produced a reduction in g of force indicative of neuropathy that was attenuated by gabapentin, tetrahydocannabinol, and cannabidiol but not prevented by either cannabinoid. These data demonstrate that each of the major constituents of Sativex alone can achieve analgesic effects against cisplatin neuropathy. PMID- 27214594 TI - High Prevalence and Properties of Enterotoxin-Producing Staphylococcus aureus ST5 Strains of Food Sources in China. AB - Staphylococcus aureus with the ability of staphylococcal enterotoxins (SEs) production is one of the most common causes of bacterial foodborne outbreaks worldwide. In our study, 336 S. aureus isolates were recovered from 3476 food samples during 2010-2014. A total of 86 S. aureus isolates were proved to be enterotoxin-producing strains with PCR and enzyme-linked immunosorbent assay. In the 86 isolates, 20 STs were identified using multilocus sequence typing (MLST) and 20 isolates were typed as sequence type 5 (ST5), which was the most prevalent ST using MLST. There were six SE profiles and high carrier rates of sec (50%) and sed (75%) genes in the 20 S. aureus ST5 isolates. Additionally, 8 antibiotic resistance patterns were observed, and 10 multidrug-resistant isolates (50%) and 4 methicillin-resistant S. aureus isolates were identified. Our findings illustrate high prevalence of S. aureus ST5 isolates from food sources and diversity in SE profiles and antibiotic resistance patterns. These results indicate that great difference in the ability of obtaining SE production and antimicrobial resistance may exist between different genetic lineages of S. aureus strains. PMID- 27214595 TI - Reply. PMID- 27214596 TI - Reduced graphene oxide-nickel nanoparticles/biopolymer composite films for the sub-millimolar detection of glucose. AB - Hybrid conjugates of graphene with metallic/semiconducting nanostructures can improve the sensitivity of electrochemical sensors due to their combination of well-balanced electrical/electrocatalytic properties and superior surface-to volume ratio. In this study, the synthesis and physical characterization of a hybrid conjugate of reduced graphene oxide and nickel nanoparticles (rGO-Ni NPs) is presented. The conjugate was further deposited onto a glassy carbon electrode as a nanocomposite film of chitosan and glucose oxidase. The electrochemical response and morphology of the films were investigated using SEM, CV, and EIS, and their applications as a glucose biosensor explored for the first time in proof-of-concept tests. The low operating potential along with the good linearity and sensitivity (up to 129 MUA cm(-2) mM(-1)) found in the sub-millimolar range suggest potential applications in the self-management of hypoglycemia from blood samples or in the development of non-invasive assays for body fluids such as saliva, tears or breath. PMID- 27214597 TI - Economic Outcomes With Anatomical Versus Functional Diagnostic Testing for Coronary Artery Disease. AB - BACKGROUND: PROMISE (PROspective Multicenter Imaging Study for Evaluation of Chest Pain) found that initial use of at least 64-slice multidetector computed tomography angiography (CTA) versus functional diagnostic testing strategies did not improve clinical outcomes in stable symptomatic patients with suspected coronary artery disease (CAD) requiring noninvasive testing. OBJECTIVE: To conduct an economic analysis for PROMISE (a major secondary aim of the study). DESIGN: Prospective economic study from the U.S. perspective. Comparisons were made according to the intention-to-treat principle, and CIs were calculated using bootstrap methods. (ClinicalTrials.gov: NCT01174550). SETTING: 190 U.S. centers. PATIENTS: 9649 U.S. patients enrolled in PROMISE between July 2010 and September 2013. Median follow-up was 25 months. MEASUREMENTS: Technical costs of the initial (outpatient) testing strategy were estimated from Premier Research Database data. Hospital-based costs were estimated using hospital bills and Medicare cost-charge ratios. Physician fees were taken from the Medicare Physician Fee Schedule. Costs were expressed in 2014 U.S. dollars, discounted at 3% annually, and estimated out to 3 years using inverse probability weighting methods. RESULTS: The mean initial testing costs were $174 for exercise electrocardiography; $404 for CTA; $501 to $514 for pharmacologic and exercise stress echocardiography, respectively; and $946 to $1132 for exercise and pharmacologic stress nuclear testing, respectively. Mean costs at 90 days were $2494 for the CTA strategy versus $2240 for the functional strategy (mean difference, $254 [95% CI, -$634 to $906]). The difference was associated with more revascularizations and catheterizations (4.25 per 100 patients) with CTA use. After 90 days, the mean cost difference between the groups out to 3 years remained small. LIMITATION: Cost weights for test strategies were obtained from sources outside PROMISE. CONCLUSION: Computed tomography angiography and functional diagnostic testing strategies in patients with suspected CAD have similar costs through 3 years of follow-up. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute. PMID- 27214598 TI - Dual-earner couples' weekend recovery support, state of recovery, and work engagement: Work-linked relationship as a moderator. AB - Despite growing recovery research, little is known about couple-dyadic processes of recovery from work. Given that dual-earner couples experience most of their recovery opportunities during nonwork times when they are together, partners in a couple relationship may substantially affect recovery and work engagement. In this study, we propose a couple-dyadic model in which weekend partner recovery support (reported by the recipient partner) is positively related to the recipient partner's state of recovery after the weekend which, in turn, increases the recipient's work engagement the following week (actor-actor mediation effect). We also test the effect of one's state of recovery on the partner's subsequent work engagement (partner effect). Additionally, work-linked relationship status is tested as a moderator of the partner effect. Actor-partner interdependence mediation modeling is used to analyze the data from 167 dual earner couples who answered surveys on 4 measurement occasions. The results support the indirect effect of partner recovery support on work engagement through the postweekend state of recovery. Multigroup analysis results reveal that the partner effect of state of recovery on work engagement is significant for work-linked couples only and is absent for non-work-linked couples. Theoretical and practical implications, limitations, and future research directions are discussed. (PsycINFO Database Record PMID- 27214599 TI - "Let it be and keep on going! Acceptance and daily occupational well-being in relation to negative work events": Correction to Kuba and Scheibe (2017). AB - Reports an error in "Let It Be and Keep on Going! Acceptance and Daily Occupational Well-Being in Relation to Negative Work Events" by Katharina Kuba and Susanne Scheibe (Journal of Occupational Health Psychology, Advanced Online Publication, Feb 25, 2016, np). In the article, there were errors in the Participants subsection in the Method section. The last three sentences should read "Job tenure ranged from less than 1 year to 32 years, with an average of 8.83 years (SD 7.80). Participants interacted with clients on average 5.44 hr a day (SD 2.41). The mean working time was 7.36 hr per day (SD 1.91)." (The following abstract of the original article appeared in record 2016-09702-001.) Negative work events can diminish daily occupational well-being, yet the degree to which they do so depends on the way in which people deal with their emotions. The aim of the current study was to examine the role of acceptance in the link between daily negative work events and occupational well-being. We hypothesized that acceptance would be associated with better daily occupational well-being, operationalized as low end-of-day negative emotions and fatigue, and high work engagement. Furthermore, we predicted that acceptance would buffer the adverse impact of negative work events on daily well-being. A microlongitudinal study across 10 work days was carried out with 92 employees of the health care sector, yielding a total of 832 daily observations. As expected, acceptance was associated with lower end-of-day negative emotions and fatigue (though there was no association with work engagement) across the 10-day period. Furthermore, acceptance moderated the effect of negative event occurrence on daily well-being: Highly accepting employees experienced less increase in negative emotions and less reduction in work engagement (though comparable end-of-day fatigue) on days with negative work events, relative to days without negative work events, than did less accepting employees. These findings highlight affective, resource saving, and motivational benefits of acceptance for daily occupational well-being and demonstrate that acceptance is associated with enhanced resilience to daily negative work events. (PsycINFO Database Record PMID- 27214600 TI - Bus operators' responses to job strain: An experimental test of the job demand control model. AB - The research aim was to test the Job Demand-Control (JDC) Model demands * Control interaction (or buffering) hypothesis in a simulated bus driving experiment. The buffering hypothesis was tested using a 2 (low and high demands) * 2 (low and high decision latitude) design with repeated measures on the second factor. A sample of 80 bus operators were randomly assigned to the low (n = 40) and high demands (n = 40) conditions. Demands were manipulated by increasing or reducing the number of stops to pick up passengers, and decision latitude by imposing or removing restrictions on the Rapid Transit Bus (BRT) operators' pace of work. Outcome variables include physiological markers (heart rate [HR], heart rate variability [HRV], breathing rate [BR], electromyography [EMG], and skin conductance [SC]), objective driving performance and self-report measurements of psychological wellbeing (psychological distress, interest/enjoyment [I/E], perceived competence, effort/importance [E/I], and pressure/tension [P/T]). It was found that job decision latitude moderates the effect of job demands on both physiological arousal (BR: F(1, 74) = 4.680, p = .034, SC: F(1, 75) = 6.769, p = .011, and EMG: F(1, 75) = 6.550, p = .013) and psychological well-being (P/T: F(1, 75) = 4.289, p = .042 and I/E: F(1, 74) = 4.548, p = .036). Consistently with the JDC model buffering hypothesis, the experimental findings suggest that increasing job decision latitude can moderate the negative effect of job demands on different psychophysiological outcomes. This finding is useful for designing organizational and clinical interventions in an occupational group at high risk of work stress-related disease. (PsycINFO Database Record PMID- 27214601 TI - Autoantibodies against lamin C, NA14 and CK15 in primary vasculitides or autoimmune diseases with secondary vasculitis. AB - OBJECTIVES: Autoantibodies may play a role in the pathogenesis of primary vasculitides (PVs) like giant cell arteritis (GCA). We recently identified 3 cytoskeletal proteins (lamin C [laC], nuclear autoantigen of 14kD [NA14] and cytokeratin 15 [CK15]) as autoantigens in GCA and postulated a frequent autoantibody response against these antigens in PVs. METHODS: To test this hypothesis we studied a cohort of patients with PVs (n=61) and healthy individuals (n=27) for the presence of these autoantibodies using a recombinant cDNA expression library. To define their specifity for PV, we also examined patients with other autoimmune diseases such as rheumatoid arthritis (RA) and connective tissue diseases (CTD). RESULTS: We found no statistically significant differences in autoantibody responses between patients with PV and healthy controls, although there was a trend for an association between PVs and the occurrence of antibodies against laC and CK15. However, in patients with RA (n=33) or Sjogren's syndrome (SS, n=11) with vasculitides we observed more frequently autoantibodies against NA14, laC and CK15 compared to healthy controls. In patients with systemic lupus erythematosus (SLE, n=23) autoantibodies against laC were more frequent. The presence of autoantibodies in RA, SS and SLE was associated with systemic secondary vasculitis (SSV). In RA, laC- and NA14-seropositive patients were in a more advanced disease stage than seronegative patients with more frequent extraarticular manifestations (p=0.004). In SLE laC-autoantibody-positive patients had a higher SLE activity index (p<0.001). CONCLUSIONS: Serum autoantibodies against laC and NA14 are frequent in patients with RA and CTD and are associated with extensive disease and SSV. The potential pathogenic and prognostic role of these antibodies should be further investigated. PMID- 27214602 TI - Lycopene Improves Diet-Mediated Recuperation in Rat Model of Nonalcoholic Fatty Liver Disease. AB - The aim of the present study was to evaluate the synergic effect of lycopene (LYC) treatment with a dietary control in a nonalcoholic fatty liver disease (NAFLD) model induced with a high-fat diet (HFD). Sprague-Dawley rats were fed during 4 weeks with a normal diet (ND.4w) or an HFD (HFD.4w) to produce an NAFLD model. Then, rats from the ND.4w group continued during 4 weeks with the same diet (ND.8w), and rats from HFD were fed during 4 weeks with an ND (HFD.4w+ND.4w) or an ND plus LYC (HFD.4w+ND+LYC.4w). LYC (20 mg/kg) was administered daily by gavage. ND and ND+LYC diets partially reverted the following alterations due to HFD: liver weight, serum low-density lipoproteins (LDL), hepatic total cholesterol (TC), and catalytic activity of hepatic superoxide dismutase, catalase, and glutathione peroxidase, as well as macroscopic and microscopic images of livers. A higher recuperation to reach normality was obtained with ND+LYC in: liver weight, hepatic TC, serum LDL, and, in some instances, macroscopic and microscopic images of livers. Failures to recovery with both NDs were observed for malondialdehyde level and serum aspartate aminotransferase activity. Taken together, the results from this study suggest the potentially protective role of LYC against NAFLD; however, more clinical trials are needed to support this idea. PMID- 27214603 TI - The value of adjuvant radiotherapy on survival and recurrence in triple-negative breast cancer: A systematic review and meta-analysis of 5507 patients. AB - BACKGROUND: The value of adjuvant radiotherapy in triple negative breast cancer (TNBC) remains unclear. A systematic review and meta-analysis was conducted in TNBC patients to assess survival and recurrence outcomes associated with radiotherapy following either breast conserving therapy (BCT) or post-mastectomy radiotherapy (PMRT). METHODS: Four electronic databases were searched from January 2000 to November 2015 (PubMed, MEDLINE, EMBASE and Web of Science). Studies investigating overall survival and/or recurrence in TNBC patients according to radiotherapy administration were included. A random effects meta analysis was conducted using mastectomy only patients as the reference. RESULTS: Twelve studies were included. The pooled hazard ratio (HR) for locoregional recurrence comparing BCT and PMRT to mastectomy only was 0.61 (95% confidence interval [CI] 0.41-0.90) and 0.62 (95% CI 0.44-0.86), respectively. Adjuvant radiotherapy was not significantly associated with distant recurrence. The pooled HR for overall survival comparing BCT and PMRT to mastectomy only was 0.57 (95% CI 0.36-0.88) and HR 1.12 (95% CI 0.75, 1.69). Comparing PMRT to mastectomy only, tests for interaction were not significant for stage (p=0.98) or age at diagnosis (p=0.85). However, overall survival was improved in patients with late-stage disease (T3-4, N2-3) pooled HR 0.53 (95% CI 0.32-0.86), and women <40years, pooled HR 0.30 (95% CI 0.11-0.82). CONCLUSIONS: Adjuvant radiotherapy was associated with a significantly lower risk of locoregional recurrence in TNBC patients, irrespective of the type of surgery. While radiotherapy was not consistently associated with an overall survival gain, benefits may be obtained in women with late-stage disease and younger patients. PMID- 27214604 TI - Discovery and characterization of antibody variants using mass spectrometry-based comparative analysis for biosimilar candidates of monoclonal antibody drugs. AB - Liquid chromatography mass spectrometry (LC-MS) is the most commonly used technique for the characterization of antibody variants. MAb-X and mAb-Y are two approved IgG1 subtype monoclonal antibody drugs recombinantly produced in Chinese hamster ovary (CHO) cells. We report here that two unexpected and rare antibody variants have been discovered during cell culture process development of biosimilars for these two approved drugs through intact mass analysis. We then used comprehensive mass spectrometry-based comparative analysis including reduced light, heavy chains, and domain-specific mass as well as peptide mapping analysis to fully characterize the observed antibody variants. The "middle-up" mass comparative analysis demonstrated that the antibody variant from mAb-X biosimilar candidate was caused by mass variation of antibody crystalline fragment (Fc), whereas a different variant with mass variation in antibody antigen-binding fragment (Fab) from mAb-Y biosimilar candidate was identified. Endoproteinase Lys C digested peptide mapping and tandem mass spectrometry analysis further revealed that a leucine to glutamine change in N-terminal 402 site of heavy chain was responsible for the generation of mAb-X antibody variant. Lys-C and trypsin coupled non-reduced and reduced peptide mapping comparative analysis showed that the formation of the light-heavy interchain trisulfide bond resulted in the mAb-Y antibody variant. These two cases confirmed that mass spectrometry-based comparative analysis plays a critical role for the characterization of monoclonal antibody variants, and biosimilar developers should start with a comprehensive structural assessment and comparative analysis to decrease the risk of the process development for biosimilars. PMID- 27214605 TI - Purification of alpha2-macroglobulin from Cohn Fraction IV by immobilized metal affinity chromatography: A promising method for the better utilization of plasma. AB - As an abundant plasma protein, alpha2-macroglobulin (alpha2-M) participates widely in physiological and pathological activities including coagulation regulation, antitumor activities, and regulation of cytokines. It also presents a therapeutic potential for radiation injury. A two-step isolation method for the purification of alpha2-M from Cohn Fraction IV is described. This process includes a salting-out method and immobilized metal affinity chromatography. The LC-ESI-MS/MS analysis and a comparison of the amino acid composition demonstrated that the final product was alpha2-M. The final protein, with a purity of approximately 95% and a yield of nearly 45%, was obtained from Cohn Fraction IV regardless of plasma haptoglobin type, although all but type 1-1 have previously been considered unfavorable for alpha2-M preparation. The effects of temperature, pH, and methylamine on alpha2-M activity were evaluated to avoid activity loss during preparation and preservation. The results suggested that alpha2-M activity could be readily inactivated at temperatures above 50 degrees C, at pH levels above 9.0 or below 4.0, or in the presence of methylamine. Cohn Fraction IV is usually discarded as a biological waste product in the human serum albumin production process; because the simple process developed in this study is relatively inexpensive, the preparation of alpha2-M from Cohn Fraction IV may better utilize human plasma, a valuable resource. PMID- 27214606 TI - The consequences of sublethal exposure to insecticide on the survivorship and mobility of Halyomorpha halys (Hemiptera: Pentatomidae). AB - BACKGROUND: The direct lethal effects of conventional and organic insecticides have been investigated thoroughly for all life stages of Halyomorpha halys. However, the sublethal effects of insecticides on the behavior of H. halys have not been well documented. Our aims were to evaluate the impact of a brief 5 min exposure to residues of bifenthrin, dinotefuran, methomyl, thiamethoxam and thiamethoxam + lambda-cyhalothrin on survivorship, horizontal and vertical movement, and flight capacity of adult H. halys under laboratory conditions. RESULTS: Over half of the insecticide-exposed adults were classified as affected, moribund or dead after the 5 min exposure, compared with only 6% of the adults in the water-only control. We found that the horizontal movement, vertical climbing and flight capacity of adults exposed to insecticides were decreased by 20-60% overall relative to the water-only control. The most lethal insecticide was bifenthrin. CONCLUSION: Many insecticide-exposed H. halys adults retained significant mobility and flight capacity, with flight most pronounced immediately after exposure. These results suggest that brief exposure periods to efficacious insecticides will result in high dispersal and low mortality. Therefore, management strategies that enhance the retention of H. halys on insecticide coated surfaces should be considered to ensure that adults are exposed to a lethal dose of insecticide. (c) 2016 Society of Chemical Industry. PMID- 27214607 TI - Can cross-talk occur in human myelinated nerve fibers? AB - INTRODUCTION: The possibility that impulse cross-talk can occur between myelinated human nerve fibers was explored. METHODS: Instances of impulse conduction without decrement were found, and published recordings of compound action potentials of functionally homogeneous fibers were scrutinized. RESULTS: Both analytical approaches yielded results consistent with cross-talk occurring in some nerves after electrical stimulation. CONCLUSIONS: The possible ionic current paths in and out of neighboring fibers, which could be responsible for the phenomenon, have been considered in the light of seminal work on unmyelinated single axons. Muscle Nerve 54: 361-365, 2016. PMID- 27214609 TI - Mycotoxin Analysis Using Imprinted Materials Technology: Recent Developments. AB - Molecular imprinting technology is an attractive, cost-effective, and robust alternative to address the limitations of highly selective natural receptors, such as antibodies and aptamers. The field of molecular imprinting has seen a recent surge in growth, and several commercially available products are of great interest for sample cleanup to improve mycotoxin analysis. Current research trends are in specific applications of imprinting technology for small-molecule sensing and chromatographic cleanup procedures in new commodities. The choice of components and imprinting template are critical factors for mycotoxin recovery or detection optimization. Template mimics offer a means to reduce toxic exposure during polymer synthesis and address issues of leaching template from the imprinted polymer. Recent reports of molecularly imprinted polymers for aflatoxins, ochratoxins, fumonisins, fusaric acid, citrinin, patulin, zearalenone, deoxynivalenol, and T-2 toxin are reviewed. PMID- 27214608 TI - Free fatty acids sensitize dendritic cells to amplify TH1/TH17-immune responses. AB - Obesity is associated with body fat gain and impaired glucose metabolism. Here, we identified both body fat gain in obesity and impaired glucose metabolism as two independent risk factors for increased serum levels of free fatty acids (FFAs). Since obesity is associated with increased and/or delayed resolution of inflammation observed in various chronic inflammatory diseases such as psoriasis, we investigated the impact of FFAs on human monocyte-derived and mouse bone marrow-derived dendritic cell (DCs) functions relevant for the pathogenesis of chronic inflammation. FFAs such as palmitic acid (PA) and oleic acid (OA) did not affect the pro-inflammatory immune response of DCs. In contrast, PA and OA sensitize DCs resulting in augmented secretion of TH1/TH17-instructive cytokines upon pro-inflammatory stimulation. Interestingly, obesity in mice worsened a TH1/TH17-driven psoriasis-like skin inflammation. Strong correlation of the amount of total FFA, PA, and OA in serum with the severity of skin inflammation points to a critical role of FFA in obesity-mediated exacerbation of skin inflammation. Our data suggest that increased levels of FFAs might be a predisposing factor promoting a TH1/TH17-mediated inflammation such as psoriasis in response to an inflammatory danger signal. PMID- 27214610 TI - From Classical to Quantum and Back: A Hamiltonian Scheme for Adaptive Multiresolution Classical/Path-Integral Simulations. AB - Quantum delocalization of atomic nuclei affects the physical properties of many hydrogen-rich liquids and biological systems even at room temperature. In computer simulations, quantum nuclei can be modeled via the path-integral formulation of quantum statistical mechanics, which implies a substantial increase in computational overhead. By restricting the quantum description to a small spatial region, this cost can be significantly reduced. Herein, we derive a bottom-up, rigorous, Hamiltonian-based scheme that allows molecules to change from quantum to classical and vice versa on the fly as they diffuse through the system, both reducing overhead and making quantum grand-canonical simulations possible. The method is validated via simulations of low-temperature parahydrogen. Our adaptive resolution approach paves the way to efficient quantum simulations of biomolecules, membranes, and interfaces. PMID- 27214611 TI - The pharmacokinetics of factor VIII and factor IX: methodology, pitfalls and applications. AB - This article reviews the pharmacokinetics of exogenous factor VIII and factor IX in patients with haemophilia. It focuses on the methodology (and inherent pitfalls) of pharmacokinetic studies, then summarizes available pharmacokinetic data and finally discusses some applications of pharmacokinetics for optimization of prophylactic treatment of haemophilia and for comparison of coagulation factor concentrates. PMID- 27214612 TI - Counselling guidelines for managing musculoskeletal problems in haemophilia in the 1990s. AB - Complex medical, psychological and social factors affect how patients with haemophilia and their families respond to bleeding episodes. Prompt, adequate treatment for bleeds remains the best way to preserve optimal musculoskeletal health. Untreated and under treated bleeding episodes into muscles and joints can cause pain, deformity and severely limit the daily activities of patients with haemophilia. Viral infections over the last decade have, to some extent, diverted attention away from musculoskeletal problems. The orthopaedic contribution to haemophilia care remains important and can be enhanced through regular review clinics and developing focused approaches to identifying and addressing musculoskeletal problems. PMID- 27214613 TI - An intermediate-purity factor VIII concentrate supports platelet adhesion under flow conditions. AB - Von Willebrand factor (vWF) binds to platelets and mediates platelet adhesion to subendothelium to support haemostasis. Factor VIII concentrates containing vWF have been recommended for treatment of bleeding episodes in von Willebrand disease (vWD) types 2 and 3. Their clinical efficacy in normalizing FVIII coagulant levels, shortening the bleeding time, stopping or preventing clinical bleeding and safety have been tested. However, the basic mechanisms of their effects on haemostasis have not been fully characterized. We have analysed the ability of vWF present in an intermediate-purity factor VIII concentrate (Haemate P, Centeon) to bind to platelets (ultrastructural studies) and to support platelet adhesion under flow conditions (perfusion studies). For this purpose, Haemate-P or cryoprecipitate was added to washed platelet suspensions, or to vWF depleted reconstituted healthy anticoagulated blood. Immunoelectron microscopy (IEM) revealed vWF arrangements on platelet surfaces which have been exposed to mixtures of the vWF-rich concentrate plus ristocetin. vWF levels in perfusates were confirmed by determination of ristocetin co-factor and vWF-antigen. Baumgartner's perfusion method and computer-assisted morphometry were used to evaluate platelet adhesion of the perfusates onto everted rabbit aorta subendothelium under standardized conditions (shear rate, 800 s(-1) , 10 min, 37 degrees C). vWF-depleted perfusates showed 15.8% (SEM 1.7) total covered surface (CS) with platelets. An increase in CS resulted when 0.40 or 0.80 IU vWF mL(-1) from Haemate-P (30.1%, SEM 3.0, P<0.05; 39.4%, SEM 3.1, P<0.008, respectively) were added. A similar increase was observed when cryoprecipitate was added to perfusates (28.6%, SEM 2.4, P<0.05 for 0.40 IU vWF mL(-1) ; 27.2%, SEM 2.9, P<0.01 for 0.80 IU vWF mL(-1) ). IEM confirmed that vWF from concentrates binds to platelets. Furthermore, perfusion studies revealed that the fractionated vWF supports platelet adhesion, thus providing experimental evidence of the therapeutic benefits exerted by Haemate-P. PMID- 27214614 TI - In-vitro stability of porcine factor VIII (Hyate:C((r)) ). AB - The stability of porcine factor VIII (Hyate:C((r)) ) 30 units mL(-1) , 15 units mL(-1) and 5 units mL(-1) prepared aseptically in 0.9% sodium chloride injection was studied. Solutions were stored in plastic syringes at room temperature and ambient light, and at body temperature protected from light. Samples obtained immediately after mixing and at 4, 24, 48 and 72 h were assayed for FVIII activity using a one-stage FVIII assay. Samples were considered stable if FVIII activity did not decline more than 10% compared with baseline values. Hyate:C((r)) 5 units mL(-1) stored at room temperature retained FVIII activity within 90% of baseline values for at least 24 h. When stored at body temperature, FVIII activity of Hyate:C((r)) 5 units mL(-1) declined to less than 90% of baseline values within 4 h. Stability of Hyate:C((r)) 15 units mL(-1) and 30 units mL(-1) stored at room temperature was retained for at least 72 h. When Hyate:C((r)) 15 units mL(-1) and 30 units mL(-1) were stored at body temperature, stability was retained for 24 h. Results of this study will permit further evaluation of Hyate:C((r)) stability when administered by ambulatory infusion pumps. PMID- 27214615 TI - Liver failure and mortality in HIV-positive haemophiliacs: FOURTEEN-YEAR EXPERIENCE AND LITERATURE REVIEW. AB - Progression to clinical liver failure has been observed in hepatitis C (HCV) infected, HIV-seropositive haemophiliacs. We studied the records of 176 haemophiliacs who were infected with HIV and/or HCV seen between 1980 and 1993. Thirty-two of 113 (28%) HIV-seropositive patients died during the study period. Ten of these patients died of liver failure, representing 31% of all mortality. An additional four HIV-seropositive patients who died of other causes had end stage liver disease. Clinical liver failure occurred in 12% of the HIV-infected cohort. None of the HIV-seronegative, HCV-infected patients suffered from liver failure. Among HIV-infected patients, liver failure was associated with advanced age and decreased CD4 counts. Severe, sporadic ALT elevations were associated with liver failure; persistent transaminase elevations were associated with mortality. We conclude that HIV infection enhances progression of HCV infection to clinical liver failure, and that liver failure is a major cause of mortality in HIV-positive haemophiliacs. PMID- 27214616 TI - Partial inhibition of platelet aggregation by nebulized pentamidine in severe haemophiliacs. AB - The antiparasite agent pentamidine has been shown to inhibit human platelet aggregation in vitro at concentrations that (potentially) may be attained in patient plasma after the administration of the drug by nebulizer. We measured platelet aggregation in platelet-rich plasma (PRP) before and after the administration of 300 mg nebulized pentamidine to 10 HIV-positive patients with severe haemophilia on prophylaxis against Pneumocystis carinii pneumonia. All patients had normal platelet counts. PAF-acether, U46619, collagen and ADP at different concentrations were used as agonists. Platelet aggregation was lower in PRP samples taken at the end of pentamidine administration and 1 h thereafter than in samples taken at the same time points in control experiments (without the administration of pentamidine). The inhibition of platelet aggregation was mild and tended to be overcome by higher concentrations of platelet agonists. The bleeding time was prolonged from 5 to 15 min in one patient but did not change in the remaining nine patients. In conclusion, this controlled study shows that nebulized pentamidine inhibits platelet aggregation in HIV-positive haemophiliacs without significantly affecting their bleeding times. Although this mild inhibitory effect may not be clinically relevant in haemophiliacs with normal platelet counts despite their defect in intrinsic coagulation, patients with HIV related thrombocytopenia should be monitored to detect any excessive prolongation of their bleeding times after nebulized pentamidine. PMID- 27214617 TI - DDI and liver tests in HIV-1 seropositive haemophiliacs. AB - Many patients with haemophilia who are HIV-1 seropositive are co-infected with the hepatitis C virus with variable degrees of underlying liver disease. To evaluate whether the use of the antiretroviral agent Dideoxyinosine (DDI) causes worsening of hepatic dysfunction as measured by liver enzyme tests, we reviewed our cohort of patients previously treated with monotherapy with Zidovudine (AZT) and subsequently changed to DDI. Seventeen patients (median age: 34 years, median absolute CD4 lymphocyte cell count: 86 cells MUL(-1) ) were included in this study. None had coincident use of other hepatotoxic agents. The median duration of treatment with AZT and DDI was 18 and 15 months, respectively. There was no significant change in liver function tests with the use of DDI and no development of clinical signs of hepatotoxicity. Neither duration of treatment, absolute CD4 lymphocyte cell count, pre-existing elevation of baseline aminotransferase levels nor the use of Pneumocystis carinii prophylaxis therapy resulted in further elevation of liver function tests. Monotherapy with DDI was well tolerated in this cohort of HIV-1-seropositive haemophiliacs with coincident hepatitis C infection. PMID- 27214618 TI - Emotional adjustment of children and adolescents with haemophilia in relation to the HIV threat. AB - A Dutch nation-wide study on young haemophilia patients, whose former treatment placed them at risk for HIV infection, was done to examine the effect of HIV testing, HIV status, disclosure of HIV status and the child's experiences with disease-related information on emotional adjustment. In the Netherlands HIV tests are not routinely performed for paediatric haemophilia patients, but the number of HIV-infected children is estimated to be low (8%). Seventy-two boys with haemophilia, five HIV positive, 51 HIV negative and 16 not tested, and their mothers were interviewed and administered standardized questionnaires. Multiple regression analyses showed no differences in anxiety and depression between HIV positive, HIV-negative or untested boys, nor between children who were informed or not informed about their HIV status. Conversely, children who experienced more difficulties to obtain information about the their disease were significantly more anxious and tended to be more depressed. No significant differences in emotional distress were found between the patients and a standardization sample of healthy peers. The data provide evidence that children and adolescents with haemophilia cope effectively with their disease and the emotional impact of the HIV threat. There seems to be no reason to protect children from testing or knowing their HIV status. In the absence of compelling medical reasons, however, health care workers should not forcefully advocate testing or early disclosure. Distinct disease and treatment-related factors as well as social factors modify disclosure practices. PMID- 27214619 TI - Visceral leishmaniasis in haemophiliac patients with HIV: four case reports. AB - Visceral leishmaniasis (VL), an endemic parasitosis in Spain, is increasing as an important opportunistic infection in AIDS patients. We describe four cases of severe haemophilic patients with end-stage HIV disease who present with visceral leishmaniasis. We report the clinical course, methods of diagnosis and response to therapy. From the assessed clinical data it does not appear to be any difference with regard to VL either in other HIV risk groups or in immunocompetent groups. In contrast with previous reports, we have found that despite their immunodepressed state, positive serology for Leishmania was found in three of the four cases. A similar observation has been made in patients with VL who are immunodepressed because of other reasons. We also confirm previous reports of poor response and intolerance of antimony treatment, the deteriorating course of the disease in AIDS patients and that there is only a slight relationship between the disease and the cause of patient death. We agree with the proposition that this pathology ought to be included in the definition critera for AIDS. PMID- 27214620 TI - Multifocal pseudotumour in a single limb. AB - A 13-year-old boy with severe haemophilia presented at the National Centre with gross swelling of his foot and infrapatella area, and reported that several months previously he had kicked a football and had instantly developed a bleed in his foot. Despite replacement factor the swelling failed to subside. He had ambulated for a while using crutches and when he eventually presented himself the X-rays revealed two separate pseudotumours. The patient underwent a transfemoral amputation. PMID- 27214622 TI - Correspondence. PMID- 27214621 TI - Recombinant factor VIIa in the management of a pseudotumour in acquired haemophilia. AB - Bleeding in nonhaemophilic patients with high-titre factor VIII autoantibodies is often severe, life-threatening and refractory to treatment with factor VIII concentrates. In this report, we describe an elderly woman who required surgical excision of a large haemophilic pseudotumour adjacent to the left gluteal muscle. The Bethesda titre of 11 U precluded treatment with human factor VIII, and the patient had an anaphylactic reaction to porcine factor VIII. However, haemostasis was successfully achieved with recombinant factor VIIa and the pseudotumour was removed. The patient was treated with repeated cycles of cyclophosphamide, vincristine, and prednisone. The Bethesda titre eventually declined to 0.7 U and the factor VIII rose to 20%. During an 18-month follow-up period there has been no recurrence of bleeding or of the pseudotumour. PMID- 27214623 TI - GUIDELINES ON THERAPEUTIC PRODUCTS TO TREAT HAEMOPHILIA AND OTHER HEREDITARY COAGULATION DISORDERS. PMID- 27214624 TI - Palliative Care for Patients With End-Stage Cardiovascular Disease and Devices: A Report From the Palliative Care Working Group of the Geriatrics Section of the American College of Cardiology. PMID- 27214626 TI - Factor XI deficiency: a review. PMID- 27214625 TI - Strain-Mediated Interfacial Dynamics during Au-PbS Core-Shell Nanostructure Formation. AB - An understanding of the hierarchical nanostructure formation is of significant importance for the design of advanced functional materials. Here, we report the in situ study of lead sulfide (PbS) growth on gold (Au) nanorod seeds using liquid cell transmission electron microscopy (TEM). By tracking the formation dynamics of Au-PbS core-shell nanoparticles, we found the preferential heterogeneous nucleation of PbS on the ends of a Au nanorod prior to the development of a complete PdS shell. During PbS shell growth, drastic sulfidation of Au nanorod was observed, leading to large volume shrinkage (up to 50%) of the initial Au nanorod seed. We also captured intriguing wavy interfacial behavior, which can be explained by our DFT calculation results that the local strain gradient at the core-shell interface facilitates the mass transport and mediates reversible phase transitions of Au <-> Au2S during the PbS shell growth. PMID- 27214627 TI - Haemophilia control in the 'LES' nations-problems and priorities: a personal view. PMID- 27214628 TI - Clinical experience of factor XI deficiency: the role of fresh frozen plasma and factor XI concentrate. AB - Factor XI deficiency is a rare autosomally transmitted coagulopathy that is associated with a variable bleeding tendency. Recently there have been reports of thrombotic events following the administration of a virally inactivated factor XI concentrate (BPL) to factor XI deficient patients. We have therefore reviewed a single centre's experience of the use of factor XI concentrate over a 6-year period and compared this to our previous experience of either no treatment or treatment with fresh frozen plasma (FFP) in 103 patients. There were 156 procedures performed without haemo- static cover. The incidence of bleeding was greatest following tonsillectomy (71%) and dental extraction (Sl'h). There was a trend for bleeding complications to be associated with lower levels of factor XI but patients with all levels of factor XI suffered bleeding complica- tions. There were 38 procedures carried out under FFP cover, with only one patient suffering excessive bleeding and no serious complications. Factor XI concentrate was given to 25 patients to cover 45 episodes. There were no bleeding complications. Three patients suffered serious complications. One patient, with a previous history of cardiovascular disease, died of a myocardial infarction and a second had an ischaemic episode resulting in a %day hospital admission. These episodes both occurred on the same day as the factor XI infusion. A third patient suffered bilateral pulmonary emboli 7 weeks after a prolonged course of factor XI concentrate. These finding suggest that factor XI concentrate should be contraindicated in patients with a history of cardiovascular disease, when FFP should be used. Guide- lines for the use of factor XI concentrates should be revised, and work performed to establish the mechanism of these thrombotic events. PMID- 27214629 TI - The knowledge and perception of factor concentrate in persons with haemophilia A. AB - Objectiues. To evaluate haemophilia patients' knowledge and understanding of factor concentrate products and to assess their feelings regarding purity and viral safety of these products. METHODS: Sixty questionnaires were distributed and completed by patients or parents of patients with severe/ moderate haemophilia A at two large comprehensive haemophilia centres in the USA and Italy. RESULTS: Most patients knew what brand of factor concentrate they used, but less than half were aware of how their concentrate was virally inactivated. The majority of responders perceived recombinant factor VlII as being the concentrate with the highest degree of purity. The majority felt the decision of which concentrate to use should be the care-givers not the patients. CONCLUSIONS: It appears that patients need more education concerning the concentrate they are using, and its method of viral inactivation and purity. PMID- 27214630 TI - Prevalence of inhibitor formation in a cohort of haemophilic children exposed to several products of various purities. AB - To evaluate the frequency and potency of inhibitor formation based on the product used, we retrospectively reviewed the records of 99 children with various types and severity of haemophilia (haemophilia A 82, severe 46; haemophilia B 10, severe 6; vWD 7) treated for the last 20 years. After a mean observation period of 8 years an overall of 23 patients (23.2'/0) developed an inhibitor (haernophilia A 26.8%; severe 4O%, moderate 20%, mild 3.8%). None of the haemophilia B patients presented with an inhibitor, and only one child with bevere vWD (1/7, 14.3%) showed a transient inhibitor under cryoprecipitate therapy. Inhibitor titre was low (< 5 BU) in most cases (91.3%) and in only two patients (8.75%) was 6 and 8 BU respectively. Antibodies to FVIII were transient (detected only once) in four (17.4%) and intermittent in 19 patients (82.6%). By the age of 12 years, 17/23 patients (73.9%) had demonstrated an inhibitor. The inhibitor detection seemed to be higher in the groups of patients exposed to monoclonal (3115, 20%), SID-treated (10159, 16.9%) or H/T FVIII concentrates (6/41, 14.6%), compared to groups of patients who received cryo/plasma (9.5%) or unmodified concentrates (5.1%); nevertheless the differences were not statistically significant. Surprisingly, none of the 52 patients who received a S/D + chromatography-treated factor VIIl concentrate developed an inhibitor after a mean observation period of 1.7 years (range 0.2-2 years). The overall prevalence of inhibitor formation in previously untreated haemophiliacs was 14.3% (4/28), irrespective of the product used. Our data indicate that a high proportion of our haemophilic children exposed to several products of various purities have developed a low-titre inhibitor which in most cases was transient or intermittent. However, despite the presence of the antibody, none of the patients needed a change in the mode of treatment. PMID- 27214631 TI - A longitudinal study of immunological status in Chinese haemophiliacs: importance of the heat viral inactivation of factor concentrates. I. Immunological associations with the consumption of factor concentrates. AB - Twenty-four of 117 cases of haemophilia A (20.5%) and none of 18 cases of haemophilia B reported in this study had an antibody to the human immuno deficiency virus (HIV). Both groups of patients showed similar immunological alterations. HIV-seropositive haemophilia A patients had an increased CD8 cell count and a similarly decreased CD4/CD8 ratio as compared to HIV-seronegative haemophilia A patients. Multiple regression analysis for the association of CD4/CD8 ratio with HIV infection status and dosage of plasma products in haemophilia A and B patients, respectively, revealed that there was a significant negative association of ln(CD4/CD8) with dosage of factor VlII concentrates (P = 0.0435) and factor IX concentrates (P = O.O028), respectively. N o association occurred between CD4/CD8 ratio and HIV infection as well as dosage of other plasma products. These data indicate that the immunological abnormalities of our haemophilia A and B patients in their early years were primarily caused by various viral infections and/or a suppressive effect of allogeneic protein through infusion of factor concentrates and not caused simply by HIV infection. PMID- 27214632 TI - The impact of hepatitis C antibody screening of source plasma donors on hepatitis C virus RNA in factor VIII concentrates. AB - We have used the polymerase chain reaction technique for the detection of hepatitis C RNA in nine different plasma-derived factor VllI concentrates and in two factor IX concentrates. Four concentrates were investigated both prior to and after the introduction of donor screening for hepatitis C antibodies. A negative reaction was consistently found in the ultra-pure factor VIII concentrates Octonativ-M (Pharmacia) and Hemofil M (Baxter), both prepared by affinity purification with factor VI1I:C monoclonal antibodies and virus inacti- vated hy solvent/detergent procedures, as well as in both the low-purity factor IX concentrates. I f produced from unscreened plasma, the other factor VIII concentrates manifested positive reactions irrespective of preparation procedure and type of virus inactivation or the temperature at which it was performed. We conclude that the preparation procedure of clotting factor concentrates, rather than type of virus inactivation, determines the degree of contamination by hepatitis C virus RNA, and that screening of source plasma seems effective in removing hepatitis C RNA from the final product as determined with a sensitive PCR method. I t is important to stress that the presence of viral RNA does not necessarily imply clinical infectivity. PMID- 27214633 TI - Psychological status of men with haemophilia and HIV infection: two-year follow up. AB - This study aimed to assess the psychological status of men with haemophilia and HIV infection and to monitor changes in psychlogical status over time, in order to evaluate the need for psychological support. The study included 24 HIV seropositive men and a control group of 21 HIV seronegative men who attended the Haemophilia Centre in Bari (Italy). Subjects underwent psychological tests (STAl Y: State and Trait Anxiety Inventory; SDS: Self-Rating Depression Scale) and completed a questionnaire on the emotional impact of AIDS. Assessment was repeated at 6-monthly intervals over a 2-year period. Contrary to expectation, HIV seronegative men with haemophilia had worse anxiety and depression scores, reported more confusion and fear, and had more reluctance towards the use of blood products (despite their present safety) than HIV seropositives. Possible reasons for these findings are considered, and their implications for clinical practice discussed. PMID- 27214634 TI - Resection of the radial head and partial open synovectomy of the elbow in the young adult with haemophilia: long-term results. AB - Resection of the radial head and partial open synovectomy of the elbow have been used in the treatment of repeated haemarthroses of the elbows in 15 patients with haemophilia. The indications for the index operation were: severe pain and bleeding in the elbow that occurred in spite of appropriate, episodic, replacement therapy over a period of more than 6 months, associated with hypertrophy of the radial head and a significant loss of pronation-supination. The long-term results were assessed retrospectively according to the classification recommended by the Orthopaedic Advisory Committee of the World Federation of Hemophilia. In the operated group, three patients had a good result, seven were fair, and five poor. It is concluded that this procedure appears to reduce the incidence of haemarthrosis but did not slow the rate of evolution of radiographic changes. PMID- 27214635 TI - Use of plasma-derived factor VIIa in a child with inhibitors of FVIII for the placement of an implantable intravenous access device. AB - We treated a 20-month-old boy with severe haemophilia A who developed a high level factor VIII (FVIII) inhibitor. An implantable intravenous access device (IVAD) was safely placed on the lateral chest under anaesthesia using plasma derived factor VIIa (FVIIa). Implantation of an IVAD into a haemophilic child with an inhibitor requires considerable care, because the area of subdermal invasion is broader than in the implantation of a central venous line. However, placement of an IVAD provides very convenient access to the central venous line and is an appropriate tool for frequent injection, such as the induction of immunotolerance to FVIII. PMID- 27214636 TI - Ipsilateral total shoulder and elbow prosthetic replacement in a patient with severe haemophilia B. AB - Since factor replacement concentrates became widely available in the 1970s, total prosthetic replacement of joints in haemophilic patients has become increasingly common, with success particularly in the knee and hip. However, there has been no published series of elbow or shoulder replacements large enough to draw conclusions about the advisability of these procedures in this group of patients. We report a case of prosthetic replacement of the shoulder in a 58-year-old man with haemophilia B, and replacement of the elbow joint of the same limb 21 months later. The results are initially very encouraging, with no pain in either joint since the early post-operative period. There have been no bleeds into either joint since surgery. Ranges of movement are satisfactory. Follow-up is now 37 months for the shoulder and 16 months for the elbow. PMID- 27214637 TI - Low-dose activated factor IX complex concentrates (FEIBA(R) ) for post-operative haemostasis in a patient with high responding factor VIII inhibitors. AB - Replacement therapy in patients with severe haemophilia A is associated with the development of inhibitory antibodies in about 15% [1,2]. The presence of inhibitors of factor VIII greatly complicates and compromises the treatment of these patients because of the lack of any completely satisfactory product to treat them. Haemostatic management for surgery in patients with inhibitors is very difficult. A product frequently used to treat bleeding episodes in such patients is prothrombin complex concentrate (PCC) [3] or its activated derivative (APCC) [4]. Activated recombinant human factor VII is another option [5]. For both these modalities of treatment, there are no laboratory tests that can be used to monitor clinical efficacy [5, 6]. Porcine factor VII is therefore the preferred product for surgery in patients with high-responding factor VIII inhibitors [7]. Unfortunately, none of these products are readily available in most developing countries, including India. We report the management of a patient with high-responding factor VIII inhibitor using low doses of FEIBA(R) (Immuno, Austria) in the post-operative period. PMID- 27214638 TI - Mr Lane and the blood of a stout young woman. PMID- 27214640 TI - Why Are Verbs So Hard to Remember? Effects of Semantic Context on Memory for Verbs and Nouns. AB - Three experiments test the theory that verb meanings are more malleable than noun meanings in different semantic contexts, making a previously seen verb difficult to remember when it appears in a new semantic context. Experiment 1 revealed that changing the direct object noun in a transitive sentence reduced recognition of a previously seen verb, whereas changing the verb had little impact on noun recognition. Experiment 2 revealed that verbs exhibited context effects more similar to those shown by superordinate nouns rather than basic-level nouns. Experiment 3 demonstrated that the degree of meaning change in a target word resulting from changes in semantic context influenced the magnitude of context effects, but context effects remained larger for verbs than for nouns even when the degree of meaning change was similar for nouns and verbs. These results are discussed with respect to the imageability and grammatical roles played by nouns and verbs in a sentence. PMID- 27214641 TI - Complications of Percutaneous Endoscopic Gastrostomy in Dogs and Cats Receiving Corticosteroid Treatment. AB - BACKGROUND: Corticosteroid treatment is commonly required in veterinary patients for treatment of inflammatory, immune-mediated, neurologic, and neoplastic diseases, which also may require assisted enteral nutrition via percutaneous endoscopic gastrostomy (PEG). OBJECTIVE: To evaluate complications associated with PEG use in dogs and cats receiving corticosteroid treatment. ANIMALS: Forty two animals were included in the study: 12 dogs and 2 cats in the steroid group and 26 dogs and 2 cats in the control group. METHODS: Medical records, between January 2006 and March 2015, were reviewed. Patients were included if the PEG tube was in use for at least 24 hours and if complete medical records were available. Patients were assigned to the control group if they were not treated with corticosteroids during PEG use or to the steroid group if they had received corticosteroids during PEG tube use. Complications were classified as minor, moderate, and major in severity. Maximum severity complication rate was compared between groups. RESULTS: The general prevalence of complications was found to be similar between groups (P = .306), but in the steroid group, 43% of the cases developed a major severity complication compared with 18% of the control group (P = .054). CONCLUSION AND CLINICAL IMPORTANCE: Owners of dogs and cats receiving corticosteroids, in which PEG is planned, should be counseled about possible complications beyond those associated with PEG tube usage alone. PMID- 27214642 TI - An Empirical IR Frequency Map for Ester C?O Stretching Vibrations. AB - We present an approach for parametrizing spectroscopic maps of carbonyl groups against experimental IR absorption spectra. The model correlates electric fields sampled from molecular dynamics simulations with vibrational frequencies and line shapes in different solvents. We perform an exhaustive search of parameter combinations and optimize the parameter values for the ester carbonyl stretching mode in ethyl acetate by comparing to experimental FTIR spectra of the small molecule in eight different solvents of varying polarities. Hydrogen-bonding solvents require that the peaks are fit independently for each hydrogen bond ensemble to compensate for improper sampling in molecular dynamics simulations. Spectra simulated using the optimized electrostatic map reproduce C?O IR absorption spectra of ethyl acetate with a line center RMSD error of 4.9 cm(-1) over 12 different solvents whose measured line centers span a 45 cm(-1) range. In combination with molecular dynamics simulations, this spectroscopic map will be useful in interpreting spectra of ester groups in heterogeneous environments such as lipid membranes. PMID- 27214643 TI - MiRNA expression profile of ionizing radiation-induced liver injury in mouse using deep sequencing. AB - In order to investigate the potential regulatory roles of microRNAs (miRNAs) in mouse response to ionizing radiation (IR), the small RNA libraries from liver tissues of mice with or without ionizing radiation (IR) were sequenced by high throughput deep sequencing technology. A total of 270 miRNAs including 212 known and 58 potentially novel miRNAs were identified. Within these miRNAs, there were 48 miRNAs that were differentially expressed, including 27 known and 21 novel miRNAs. The results of quantitative RT-polymerase chain reaction (qRT-PCR) were in consistent with the sequencing analysis. Target gene prediction, function annotation, and pathway of the identified miRNAs were analyzed using RNAhybrid, miRanda software and Swiss-Prot, Gene Ontology (GO), Clusters of Orthologous Groups (COG), Kyoto Encyclopedia of Genes, and Genomes (KEGG) and non-redundant (NR) databases. These results should be useful to investigate the biological function of miRNAs under IR-induced liver injury. PMID- 27214644 TI - Opioids and tumour metastasis: does the choice of the anesthetic-analgesic technique influence outcome after cancer surgery? AB - PURPOSE OF REVIEW: Cancer is now one of the leading causes of death worldwide, and excisional surgery is an essential treatment for the four most common adult cancers. Opioids remain the most commonly prescribed analgesics in the perioperative period of cancer surgery, yet the question of whether opioids could influence recurrence or metastasis remains unanswered. RECENT FINDINGS: In-vitro cell culture, live animal models, and retrospective clinical reviews investigating the effects of opioids on outcomes after cancer surgery have yielded conflicting results, with findings ranging from deleterious, null to potentially protective effects. SUMMARY: Prospective randomized trials are required to investigate this important topic further. Several are currently ongoing. Until the results of these are available for scrutiny, there is currently insufficient evidence to recommend any changes to current clinical practice. Opioids continue to play an important role in the perioperative period. PMID- 27214646 TI - Effects of root decomposition on plant-soil feedback of early- and mid successional plant species. AB - Plant-soil feedback (PSF) is an important driver of plant community dynamics. Many studies have emphasized the role of pathogens and symbiotic mutualists in PSFs; however, less is known about the contribution of decomposing litter, especially that of roots. We conducted a PSF experiment, where soils were conditioned by living early- and mid-successional grasses and forbs with and without decomposing roots of conspecific species (conditioning phase). These soils were used to test growth responses of conspecific and heterospecific plant species (feedback phase). The addition of the roots of conspecifics decreased the biomass of both early- and mid-successional plant species in the conditioning phase. In the feedback phase, root addition had positive effects on the biomass of early-successional species and neutral effects on mid-successional species, except when mid-successional grasses were grown in soils conditioned by conspecifics, where effects were negative. Biomass of early- and mid-successional forbs was generally reduced in soils conditioned by conspecifics. We conclude that root decomposition may increase short-term negative PSF effects, but that the effects can become neutral to positive over time, thereby counteracting negative components of PSF. This implies that root decomposition is a key element of PSF and needs to be included in future studies. PMID- 27214645 TI - Risk of Malignancy Among Patients With Sarcoidosis: A Population-Based Cohort Study. AB - OBJECTIVE: To investigate the risk of malignancy in patients with sarcoidosis in a population-based cohort. METHODS: A cohort of Olmsted County, Minnesota, residents diagnosed with sarcoidosis between January 1, 1976 and December 31, 2013 was identified based on individual medical record review. For each sarcoidosis subject, 2 sex- and age-matched comparator subjects without sarcoidosis were randomly selected. Cases and comparators were then cross-indexed with the Mayo Clinic Cancer Registry, which collected data on every type of malignancy except for nonmelanoma skin cancer, for malignancy ascertainment. RESULTS: A total of 345 incident cases of sarcoidosis and 690 comparators were identified. There was no difference in the prevalence of malignancy at the index date between the 2 groups (4.3% among cases and 4.3% among comparators; P = 1.0). During followup, 36 patients with sarcoidosis and 91 subjects without sarcoidosis developed malignancy, with a cumulative incidence at 10 years of 3.8% and 7.1%, respectively. The difference corresponded to a hazard ratio (HR) of 0.72 (95% confidence interval [95% CI] 0.49-1.06). The cumulative incidences at 10 years for individual types of malignancy were also similar between the 2 groups, with nonsignificant HRs. However, subgroup analysis found that cases with extrathoracic involvement were at higher risk of incident hematologic malignancy compared with cases without extrathoracic involvement (HR 1.87 [95% CI 1.09 3.22]). CONCLUSION: Risk of malignancy was similar among patients with sarcoidosis compared to nonsarcoidosis subjects. However, the risk of incident hematologic malignancy was significantly higher among patients with sarcoidosis with extrathoracic involvement compared to patients without extrathoracic disease. PMID- 27214647 TI - (-)/(+)-Sparteine induced chirally-active carbon nanoparticles for enantioselective separation of racemic mixtures. AB - Chiral carbon nanoparticles (CCNPs) were developed by surface passivation using the chiral ligand (-)-sparteine or (+)-sparteine (denoted (-)-SP/CNP and (+) SP/CNP, respectively). The chirality of the prepared CCNPs was demonstrated by circular dichroism and polarimetry and employed as an enantioselective separation platform for representative racemic mixtures. PMID- 27214649 TI - Purification of flavonoids from licorice using an off-line preparative two dimensional normal-phase liquid chromatography/reversed-phase liquid chromatography method. AB - An orthogonal (71.9%) off-line preparative two-dimensional normal-phase liquid chromatography/reversed-phase liquid chromatography method coupled with effective sample pretreatment was developed for separation and purification of flavonoids from licorice. Most of the nonflavonoids were firstly removed using a self-made Click TE-Cys (60 MUm) solid-phase extraction. In the first dimension, an industrial grade preparative chromatography was employed to purify the crude flavonoids. Click TE-Cys (10 MUm) was selected as the stationary phase that provided an excellent separation with high reproducibility. Ethyl acetate/ethanol was selected as the mobile phase owing to their excellent solubility for flavonoids. Flavonoids co-eluted in the first dimension were selected for further purification using reversed-phase liquid chromatography. Multiple compounds could be isolated from one normal-phase fraction and some compounds with bad resolution in one-dimensional liquid chromatography could be prepared in this two dimensional system owing to the orthogonal separation. Moreover, this two dimensional liquid chromatography method was beneficial for the preparation of relatively trace flavonoid compounds, which were enriched in the first dimension and further purified in the second dimension. Totally, 24 flavonoid compounds with high purity were obtained. The results demonstrated that the off-line two dimensional liquid chromatography method was effective for the preparative separation and purification of flavonoids from licorice. PMID- 27214648 TI - Life Lessons from Women with HIV: Mutuality, Self-Awareness, and Self-Efficacy. AB - Women with HIV in the United States cope with multiple traumas that influence adherence to antiretroviral therapy (ART) and well-being. Narrative themes from three life turning points and a projective story task were compared for two groups of women with HIV (HIV well-managed vs. HIV not well-managed, matched on demographics and narrative word count) to understand predictors of successful outcomes. The well-managed group (n = 10) was virally suppressed and reported >=95% ART adherence; the not well-managed group (n = 10) had detectable viral load and reported <95% ART adherence. Women were predominantly African American with low socioeconomic status and averaged 46.51 years. A three-stage coding process (with coders blind to group status in stages 1 and 2) involved (1) line by line thematic analyses that generated 155 subthemes reflecting six content areas (interpersonal relationships; culture and community; sense of self; relationship to past, present, and future experiences; self-care; and motivators for change); (2) absence/presence of the 155 subthemes was compared for the two groups; the frequency of 37 subthemes was found to significantly differ; and (3) the 37 differentiating subthemes were conceptually integrated, revealing that the well-managed group's narratives more frequently reflected (a) mutuality (growth fostering relationships involving reciprocal care and empathy); (b) self awareness (recognition of personal strengths and weaknesses and multiple factors contributing to life choices and trajectories); and (c) self-efficacy (active coping, self-advocacy, and utilizing resources). Implications for treatment and interconnections among themes are discussed, emphasizing the factors that enable women to care for themselves and others. PMID- 27214651 TI - Immunomodulatory and angiogenic responses induced by graphene oxide scaffolds in chronic spinal hemisected rats. AB - Attractive physic-chemical features of graphene oxide (GO) and promising results in vitro with neural cells encourage its exploration for biomedical applications including neural regeneration. Fueled by previous findings at the subacute state, we herein investigate for the first time chronic tissue responses (at 30 days) to 3D scaffolds composed of partially reduced GO (rGO) when implanted in the injured rat spinal cord. These studies aim to define fibrotic, inflammatory and angiogenic changes at the lesion site induced by the chronic implantation of these porous structures. Injured animals receiving no scaffolds show badly structured lesion zones and more cavities than those carrying rGO materials, thus pointing out a significant role of the scaffolds in injury stabilization and sealing. Notably, GFAP(+) cells and pro-regenerative macrophages are evident at their interface. Moreover, rGO scaffolds support angiogenesis around and, more importantly, inside their structure, with abundant and functional new blood vessels in whose proximities inside the scaffolds some regenerated neuronal axons are found. On the contrary, lesion areas without rGO scaffolds show a diminished quantity of blood vessels and no axons at all. These findings provide a foundation for the usefulness of graphene-based materials in the design of novel biomaterials for spinal cord repair and encourage further investigation for the understanding of neural tissue responses to this kind of materials in vivo. PMID- 27214650 TI - Temporally degradable collagen-mimetic hydrogels tuned to chondrogenesis of human mesenchymal stem cells. AB - Tissue engineering strategies for repairing and regenerating articular cartilage face critical challenges to recapitulate the dynamic and complex biochemical microenvironment of native tissues. One approach to mimic the biochemical complexity of articular cartilage is through the use of recombinant bacterial collagens as they provide a well-defined biological 'blank template' that can be modified to incorporate bioactive and biodegradable peptide sequences within a precisely defined three-dimensional system. We customized the backbone of a Streptococcal collagen-like 2 (Scl2) protein with heparin-binding, integrin binding, and hyaluronic acid-binding peptide sequences previously shown to modulate chondrogenesis and then cross-linked the recombinant Scl2 protein with a combination of matrix metalloproteinase 7 (MMP7)- and aggrecanase (ADAMTS4) cleavable peptides at varying ratios to form biodegradable hydrogels with degradation characteristics matching the temporal expression pattern of these enzymes in human mesenchymal stem cells (hMSCs) during chondrogenesis. hMSCs encapsulated within the hydrogels cross-linked with both degradable peptides exhibited enhanced chondrogenic characteristics as demonstrated by gene expression and extracellular matrix deposition compared to the hydrogels cross linked with a single peptide. Additionally, these combined peptide hydrogels displayed increased MMP7 and ADAMTS4 activities and yet increased compression moduli after 6 weeks, suggesting a positive correlation between the degradation of the hydrogels and the accumulation of matrix by hMSCs undergoing chondrogenesis. Our results suggest that including dual degradation motifs designed to respond to enzymatic activity of hMSCs going through chondrogenic differentiation led to improvements in chondrogenesis. Our hydrogel system demonstrates a bimodal enzymatically degradable biological platform that can mimic native cellular processes in a temporal manner. As such, this novel collagen-mimetic protein, cross-linked via multiple enzymatically degradable peptides, provides a highly adaptable and well defined platform to recapitulate a high degree of biological complexity, which could be applicable to numerous tissue engineering and regenerative medicine applications. PMID- 27214652 TI - Tuning the Carbon Dioxide Absorption in Amino Acid Ionic Liquids. AB - One of the possible solutions to prevent global climate change is the reduction of CO2 emissions, which is highly desired for the sustainable development of our society. In this work, the chemical absorption of carbon dioxide in amino acid ionic liquids was studied through first-principles methods. The use of readily accessible and biodegradable amino acids as building blocks for ionic liquids makes them highly promising replacements for the widely applied hazardous aqueous solutions of amines. A detailed insight into the reaction mechanism of the CO2 absorption was obtained through state-of-the-art theoretical methods. This allowed us to determine the reason for the specific CO2 capacities found experimentally. Moreover, we have also conducted a theoretical design of ionic liquids to provide valuable insights into the precise tuning of the energetic and kinetic parameters of the CO2 absorption. PMID- 27214653 TI - Ranking occupational contexts associated with risk of non-Hodgkin lymphoma. AB - BACKGROUND: Risk factors associated with non-Hodgkin lymphoma (NHL) remain unknown, but certain occupational contexts (OCs) have been implicated. The objective of this study was to inventory, from the accumulated knowledge, associations between OCs and NHL risk. METHODS: Literature was used to identify the NHL-associated OCs. For each context, items were ranked both by scientific interest and the association strength. RESULTS: Three ranked lists of OCs related to NHL were constructed. We found that NHL was associated with 31 occupational activities, 91 occupational exposures, and 35 occupational activity-exposure combinations. Among them, 5 activities, 2 exposures, and 3 combinations, involving agricultural or industrial sector and solvents or pesticides, were highlighted with the highest publications number and the strongest association with NHL risk. CONCLUSION: These results could be useful in both providing a ranked inventory of OCs associated with NHL risk and highlighting "hot" occupational activities and exposures. Am. J. Ind. Med. 59:561-574, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27214654 TI - The longitudinal effect of the aldehyde dehydrogenase 2*2 allele on the risk for nonalcoholic fatty liver disease. AB - Aldehyde dehydrogenase 2 (ALDH2) detoxifies toxic aldehydes and has a key role in protecting the liver. An elevated gamma-glutamyl transferase (GGT) level is related to oxidative stress and nonalcoholic fatty liver disease (NAFLD). We herein investigated the association between inactive ALDH2*2 allele (rs671) and the risk of NAFLD, including the relationship to the GGT level. A retrospective follow-up study (mean 5.4+/-1.1 years) was conducted among 341 Japanese health screening program participants. The receiver operating characteristic curve indicated that the GGT level predicted the development of NAFLD (area under the curve: 0.65, P<0.05) with a cutoff value of 25.5 IUl(-1). The longitudinal risk of NAFLD was higher in the ALDH2*2 allele carriers than in the noncarriers (odds ratio (OR): 2.30, 95% confidence interval (CI): 1.21-4.40), and the risk was further increased among the *2 allele carriers with GGT values ?25.5 IUl(-1) (OR: 4.28, 95% CI: 1.80-10.19). On the other hand, there were no significant changes in the subjects' body weight and body mass index during observation period. The ALDH2*2 allele, in relation to the GGT level, may potentially be a novel risk factor for NAFLD. PMID- 27214656 TI - Normotension, hypertension and body fluid regulation: brain and kidney. AB - The fraction of hypertensive patients with essential hypertension (EH) is decreasing as the knowledge of mechanisms of secondary hypertension increases, but in most new cases of hypertension the pathophysiology remains unknown. Separate neurocentric and renocentric concepts of aetiology have prevailed without much interaction. In this regard, several questions regarding the relationships between body fluid and blood pressure regulation are pertinent. Are all forms of EH associated with sympathetic overdrive or a shift in the pressure natriuresis curve? Is body fluid homoeostasis normally driven by the influence of arterial blood pressure directly on the kidney? Does plasma renin activity, driven by renal nerve activity and renal arterial pressure, provide a key to stratification of EH? Our review indicates that (i) a narrow definition of EH is useful; (ii) in EH, indices of cardiovascular sympathetic activity are elevated in about 50% of cases; (iii) in EH as in normal conditions, mediators other than arterial blood pressure are the major determinants of renal sodium excretion; (iv) chronic hypertension is always associated with a shift in the pressure natriuresis curve, but this may be an epiphenomenon; (v) plasma renin levels are useful in the analysis of EH only after metabolic standardization and then determination of the renin function line (plasma renin as a function of sodium intake); and (vi) angiotensin II-mediated hypertension is not a model of EH. Recent studies of baroreceptors and renal nerves as well as sodium intake and renin secretion help bridge the gap between the neurocentric and renocentric concepts. PMID- 27214655 TI - Calorie-induced ER stress suppresses uroguanylin satiety signaling in diet induced obesity. AB - BACKGROUND/OBJECTIVES: The uroguanylin-GUCY2C gut-brain axis has emerged as one component regulating feeding, energy homeostasis, body mass and metabolism. Here, we explore a role for this axis in mechanisms underlying diet-induced obesity (DIO). SUBJECTS/METHODS: Intestinal uroguanylin expression and secretion, and hypothalamic GUCY2C expression and anorexigenic signaling, were quantified in mice on high-calorie diets for 14 weeks. The role of endoplasmic reticulum (ER) stress in suppressing uroguanylin in DIO was explored using tunicamycin, an inducer of ER stress, and tauroursodeoxycholic acid (TUDCA), a chemical chaperone that inhibits ER stress. The impact of consumed calories on uroguanylin expression was explored by dietary manipulation. The role of uroguanylin in mechanisms underlying obesity was examined using Camk2a-Cre-ER(T2)-Rosa STOP(loxP/loxP)-Guca2b mice in which tamoxifen induces transgenic hormone expression in brain. RESULTS: DIO suppressed intestinal uroguanylin expression and eliminated its postprandial secretion into the circulation. DIO suppressed uroguanylin through ER stress, an effect mimicked by tunicamycin and blocked by TUDCA. Hormone suppression by DIO reflected consumed calories, rather than the pathophysiological milieu of obesity, as a diet high in calories from carbohydrates suppressed uroguanylin in lean mice, whereas calorie restriction restored uroguanylin in obese mice. However, hypothalamic GUCY2C, enriched in the arcuate nucleus, produced anorexigenic signals mediating satiety upon exogenous agonist administration, and DIO did not impair these responses. Uroguanylin replacement by transgenic expression in brain repaired the hormone insufficiency and reconstituted satiety responses opposing DIO and its associated comorbidities, including visceral adiposity, glucose intolerance and hepatic steatosis. CONCLUSIONS: These studies reveal a novel pathophysiological mechanism contributing to obesity in which calorie-induced suppression of intestinal uroguanylin impairs hypothalamic mechanisms regulating food consumption through loss of anorexigenic endocrine signaling. The correlative therapeutic paradigm suggests that, in the context of hormone insufficiency with preservation of receptor sensitivity, obesity may be prevented or treated by GUCY2C hormone replacement. PMID- 27214657 TI - Hydrogel-Framed Nanofiber Matrix Integrated with a Microfluidic Device for Fluorescence Detection of Matrix Metalloproteinases-9. AB - Matrix metalloproteinases (MMPs) play a pivotal role in regulating the composition of the extracellular matrix and have a critical role in vascular disease, cancer progression, and bone disorders. This paper describes the design and fabrication of a microdevice as a new platform for highly sensitive MMP-9 detection. In this sensing platform, fluorescein isocyanate (FITC)-labeled MMP-9 specific peptides were covalently immobilized on an electrospun nanofiber matrix to utilize an enzymatic cleavage strategy. Prior to peptide immobilization, the nanofiber matrix was incorporated into hydrogel micropatterns for easy size control and handling of the nanofiber matrix. The resultant hydrogel-framed nanofiber matrix immobilizing the peptides was inserted into microfluidic devices consisting of reaction chambers and detection zones. The immobilized peptides were reacted with the MMP-9-containing solution in a reaction chamber, which resulted in the cleavage of the FITC-containing peptide fragments and subsequently generated fluorescent flow at the detection zone. As higher concentrations of the MMP-9 solution were introduced or larger peptide immobilizing nanofiber areas were used, more peptides were cleaved, and a stronger fluorescence signal was observed. Due to the huge surface area of the nanofiber and small dimensions of the microsystem, a faster response time (30 min) and lower detection limit (10 pM) could be achieved in this study. The hydrogel-framed nanofiber matrix is disposable and can be replaced with new ones immobilizing either the same or different biomolecules for various bioassays, while the microfluidic system can be continuously reused. PMID- 27214659 TI - Association Between Body Mass Index and Parkinson Disease-Reply. PMID- 27214658 TI - Real-time monitoring of specific oxygen uptake rates of embryonic stem cells in a microfluidic cell culture device. AB - Oxygen plays a key role in stem cell biology as a signaling molecule and as an indicator of cell energy metabolism. Quantification of cellular oxygen kinetics, i.e. the determination of specific oxygen uptake rates (sOURs), is routinely used to understand metabolic shifts. However current methods to determine sOUR in adherent cell cultures rely on cell sampling, which impacts on cellular phenotype. We present real-time monitoring of cell growth from phase contrast microscopy images, and of respiration using optical sensors for dissolved oxygen. Time-course data for bulk and peri-cellular oxygen concentrations obtained for Chinese hamster ovary (CHO) and mouse embryonic stem cell (mESCs) cultures successfully demonstrated this non-invasive and label-free approach. Additionally, we confirmed non-invasive detection of cellular responses to rapidly changing culture conditions by exposing the cells to mitochondrial inhibiting and uncoupling agents. For the CHO and mESCs, sOUR values between 8 and 60 amol cell(-1) s(-1) , and 5 and 35 amol cell(-1) s(-1) were obtained, respectively. These values compare favorably with literature data. The capability to monitor oxygen tensions, cell growth, and sOUR, of adherent stem cell cultures, non-invasively and in real time, will be of significant benefit for future studies in stem cell biology and stem cell-based therapies. PMID- 27214661 TI - Lung clearance index and moment ratios at different cut-off values in infant multiple-breath washout measurements. AB - BACKGROUND: Multiple-breath washout (MBW) is increasingly used for infant lung function testing. Current guidelines recommend calculating lung clearance index (LCI) and functional residual capacity (FRC) at 2.5% of normalized tracer gas concentration, without clear recommendation for moment ratios (MR). Whether the 2.5% cut-off has the highest discriminative power to detect ventilation inhomogeneity in infants with lung diseases is unknown. METHODS: We used sulfur hexafluoride MBW measurements from 32 infants with cystic fibrosis, 32 preterm infants, and 32 healthy controls at postmenstrual age of 41-54 weeks. We compared the discriminative power to detect pathological values above the upper limit of normal for 12 different cut-offs between 20% and 1.5% for first and second MR (MR1, MR2), LCI, and FRC. RESULTS: MR and LCI results changed significantly at different cut-offs. Mean MR2 in infants with cystic fibrosis increased from 2.4 to 7.2 units between 20% and 1.5% SF6 . The ability of MR and LCI to discriminate between health and disease increased significantly with lower cut-offs. The 1.5% cut-off showed highest discriminative power: in infants with cystic fibrosis pathological MR2 values were found in 27 out of 89 (30%) and for LCI in 28/89 (32%). In preterm infants, pathological MR2 values were detected in 39 out of 73 (53%), and for LCI in 35/73 (48%). FRC remained stable throughout the washout. CONCLUSION: In infants, the diagnostic performance of MBW strongly depends on the point of analysis. The cut-off with the highest discriminative power to detect ventilation inhomogeneity in infants with cystic fibrosis and after preterm birth was at 1.5% tracer gas concentration. Pediatr Pulmonol. 2016;51:1373-1381. (c) 2016 Wiley Periodicals, Inc. PMID- 27214660 TI - New endoscopic ultrasonography techniques for pancreaticobiliary diseases. AB - Endoscopic ultrasonography (EUS) is widely used to evaluate pancreaticobiliary diseases, especially pancreatic masses. EUS has a good ability to detect pancreatic masses, but it is not sufficient for the differential diagnosis of various types of lesions. In order to address the limitations of EUS, new techniques have been developed to improve the characterization of the lesions detected by EUS. EUS-guided fine needle aspiration (EUS-FNA) has been used for diagnosing pancreatic tumors. In order to improve the histological diagnostic yield, a EUS-FNA needle with a core trap has recently been developed. Contrast enhanced harmonic EUS is a new imaging modality that uses an ultrasonographic contrast agent to visualize blood flow in fine vessels. This technique is useful in the diagnosis of pancreatic solid lesions and in confirming the presence of vascularity in mural nodules for cystic lesions. EUS elastography analyzes several different variables to measure tissue elasticity, color patterns, and strain ratio, using analytical techniques such as hue-histogram analysis, and artificial neural networks, which are useful for the diagnosis of chronic pancreatitis and pancreatic cancer. PMID- 27214662 TI - Cyclic Anti-Azacarboxylation of 2-Alkynylanilines with Carbon Dioxide. AB - Direct anti-azacarboxylation of 2-alkynylanilines with CO2 mediated by ZnEt2 was observed to afford indole-3-carboxylic acids, a class of important compounds for the synthesis of many biologically active compounds, efficiently under 1 atm of CO2. The readily available nature of the different starting materials and tolerance of various functional groups provide vast opportunities for the efficient construction of diversified libraries for bioactive compounds listed in Figure 1 . As an example, this methodology has been applied to the synthesis of Lotronex, a drug molecule used for the treatment of irritable bowel syndrome. PMID- 27214663 TI - New insights on frequency combinations and 'forbidden frequencies' in the de Haas van Alphen spectrum of kappa-(ET)2Cu(SCN)2. AB - de Haas-van Alphen oscillations of the organic metal kappa-(ET)2Cu(SCN)2 have been measured up to 55 T at liquid helium temperatures. The Fermi surface of this charge transfer salt is a textbook example of a linear chain of orbits coupled by magnetic breakdown. Accordingly, the oscillation spectrum is composed of linear combinations of the frequencies linked to the alpha and magnetic breakdown induced beta orbits. The field and temperature dependence of all the observed Fourier components, in particular the 'forbidden frequency' [Formula: see text] which cannot correspond to a classical orbit, are quantitatively accounted for by analytical calculations based on a second order development of the free energy, i.e. beyond the first order Lifshitz-Kosevich formula. PMID- 27214665 TI - Symposium: How to calibrate clinical diagnosis by feedback through neuropathology: how doctors are tricked. PMID- 27214664 TI - A Phase 2A Trial of the Novel mGluR5-Negative Allosteric Modulator Dipraglurant for Levodopa-Induced Dyskinesia in Parkinson's Disease. AB - BACKGROUND: The metabotropic glutamate receptor 5-negative allosteric modulator dipraglurant reduces levodopa-induced dyskinesia in the MPTP-macaque model. The objective of this study was to assess the safety, tolerability (primary objective), and efficacy (secondary objective) of dipraglurant on levodopa induced dyskinesia in Parkinson's disease (PD). METHODS: The study was a phase 2A double-blind, placebo-controlled, randomized (2:1), 4-week, parallel-group, multicenter dose-escalation (from 50 mg once daily to 100 mg 3 times daily) clinical trial involving 76 PD subjects with moderate to severe levodopa-induced dyskinesia. Safety and tolerability were assessed based on clinical and biological examination and adverse events recording. Secondary efficacy outcome measures included the modified Abnormal Involuntary Movement Scale, UPDRS, and diaries. Pharmacokinetics were measured at 3 visits following a single dose. RESULTS: Fifty-two patients were exposed to dipraglurant and 24 to placebo. There were no major safety concerns. Two subjects did not complete the study because of adverse events. Most frequent adverse events included dyskinesia, dizziness, nausea, and fatigue. Dipraglurant significantly reduced peak dose dyskinesia (modified Abnormal Involuntary Movement Scale) on day 1 (50 mg, 20%; P = 0.04) and on day 14 (100 mg, 32%; P =0 .04) and across a 3-hour postdose period on day 14 (P = 0.04). There was no evidence of worsening of parkinsonism. Dipraglurant was rapidly absorbed (tmax = 1 hour). The 100-mg dose led to a mean Cmax of 1844 ng/mL on day 28. CONCLUSIONS: Dipraglurant proved to be safe and well tolerated in its first administration to PD patients. Its efficacy in reversing levodopa induced dyskinesia warrants further investigations in a larger number of patients. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27214666 TI - Laparoscopic complete mesocolic excision with central vascular dissection for splenic flexure tumour - a video vignette. PMID- 27214668 TI - Foreword. PMID- 27214667 TI - The detection of content-based invalid responding: a meta-analysis of the MMPI-2 Restructured Form's (MMPI-2-RF) over-reporting validity scales. AB - OBJECTIVE: This study synthesized research evaluation of the effectiveness of the over-reporting validity scales of the Minnesota Multiphasic Personality Inventory 2-Restructured Form (MMPI-2-RF) for detecting intentionally feigned over endorsements of symptoms using a moderated meta-analysis. METHOD: After identifying experimental and quasi-experimental studies for inclusion (k = 25) in which the validity scales of the MMPI-2-RF were compared between groups of respondents, moderated meta-analyses were conducted for each of its five over reporting scales. These meta-analyses explored the general effectiveness of each scale across studies, as well as the impact that several moderators had on scale performance, including comparison group, study type (i.e. real versus simulation), age, education, sex, and diagnosis. RESULTS: The over-reporting scales of the MMPI-2-RF act as effective general measures for the detection of malingering and over endorsement of symptoms with individual scales ranging in effectiveness from an effect size of 1.08 (Symptom Validity; FBS-r) to 1.43 (Infrequent Pathology; Fp-r), each with different patterns of moderating influence. CONCLUSIONS: The MMPI-2-RF validity scales effectively discriminate between groups of respondents presenting in either an honest manner or with patterned exaggeration and over-endorsement of symptoms. The magnitude of difference observed between honest and malingering groups was substantially narrower than might be expected using traditional cut-scores for the validity scales, making interpretation within the evaluation context particularly important. While all over-reporting scales are effective, the FBS-r and RBS scales are those least influenced by common and context specific moderating influences, such as respondent or comparison grouping. PMID- 27214669 TI - Beyond Baby Steps: An Empirical Study of the Impact of Environmental Justice Executive Order 12898. AB - This study evaluated the impact of Executive Order (EO) 12898 to advance environmental justice. We conducted a review evaluating the frequency and effective use of EO 12898 since execution with particular focus following President Obama's Plan EJ 2014. We found that both EO 12898 and Plan EJ 2104 had little, if any, impact on federal regulatory decision making. To the extent federal agencies discussed EO 12898, most did so in boilerplate rhetoric that satisfied compliance but was devoid of detailed thought or analysis. In the 21st year, with the exception of the Environmental Protection Agency, very little federal regulatory activity included references to EO 12898. PMID- 27214670 TI - Inequitable Chronic Lead Exposure: A Dual Legacy of Social and Environmental Injustice. AB - Both historic and contemporary factors contribute to the current unequal distribution of lead in urban environments and the disproportionate impact lead exposure has on the health and well-being of low-income minority communities. We consider the enduring impact of lead through the lens of environmental justice, taking into account well-documented geographic concentrations of lead, legacy sources that produce chronic exposures, and intergenerational transfers of risk. We discuss the most promising type of public health action to address inequitable lead exposure and uptake: primordial prevention efforts that address the most fundamental causes of diseases by intervening in structural and systemic inequalities. PMID- 27214671 TI - Health Status and Residential Exposure to Air Toxics: What Are the Effects on Children's Academic Achievement? AB - This article examines the effects of children's subjective health status and exposure to residential environmental toxins on academic performance for the first time, while adjusting for school-level effects using generalized estimating equations. The analysis employs National Air Toxics Assessment risk estimates and individual-level data collected through a mail survey. Results indicate that poorer subjective health status and higher levels of residential air toxins are statistically significantly associated with lower grade point averages, meaning that there is an independent effect of air pollution on children's academic achievement that cannot be explained by poor health alone. PMID- 27214672 TI - Using Community-Based Participatory Research to Identify Environmental Justice Issues in an Inner-City Community and Inform Urban Planning. AB - The Southeast CARE Coalition has been using community-based participatory research to examine environmental degradation in the Southeast Community, Newport News, Virginia. A survey was developed to collect assessment data. Up to 66% of respondents were concerned about environmental problems in their community. Those with health conditions were significantly more likely to identify specific environmental problems. The top 5 environmental concerns included coal dust, air quality, crime, water quality, and trash. The community-based participatory research process is building community capacity and participation, providing community input into strategic planning, and empowering community members to take control of environmental justice issues in their community. PMID- 27214673 TI - Losing Ground: Racial Disparities in Medical Debt and Home Foreclosure in the Deep South. AB - Medical debt is a persistent problem in the United States. This study examined the role of medical debt in relation to home foreclosure in a Deep South county with high rates of poverty, health disparities, and a racial gap in homeownership. Statistical analysis and geographic information systems mapping of municipal court records for 890 foreclosees indicated disproportionately high rates of medical debt among African Americans who lived in racially distinct neighborhoods. Both nonmedical and medical debt judgments were more numerous among African Americans than among whites; foreclosees in both groups had a higher medical debt burden compared with nonforeclosees. These results help to explain medical debt as a driver of foreclosure and racial disparities in homeownership. PMID- 27214674 TI - Family Structure Types and Adequate Utilization of Antenatal Care in Kenya. AB - Features of the health care delivery system may not be the only expounding factors of adequate utilization of antenatal care among women. Other social factors such as the family structure and its environment contribute toward pregnant women's utilization of antenatal care. An understanding of how women in different family structure types and social groups use basic maternal health services is important toward developing and implementing maternal health care policy in the post-Millennium Development Goal era, especially in the sub-Saharan Africa where maternal mortality still remains high. PMID- 27214675 TI - Giving Economically Disadvantaged, Minority Food Pantry Patrons' a Voice: Implications for Equitable Access to Sufficient, Nutritious Food. AB - This study provides economically disadvantaged, minority food pantry patrons (hereafter, patrons) a meaning-ful voice by examining their experiences trying to obtain sufficient, nutritious food. Five focus groups were conducted using a semistructured discussion guide. Atlast.ti software was used to manage and analyze the data. Patrons reported that pantry staff who preserved their dignity by showing compassion were highly valued. Stigma and shame associated with pantry use were major concerns. Patrons suggested environmental and policy changes to improve their food acquisition experiences. These findings suggest that multilevel interventions addressing food access, food distribution policies, and patron-staff interactions are warranted. PMID- 27214676 TI - Reclaim Northside: An Environmental Justice Approach to Address Vacant Land in Pittsburgh. AB - Urban decline, disinvestment, and blight have not traditionally been addressed by the environmental conservation movement. In this article, we describe an environmental justice-focused intervention located in Pittsburgh, Pennsylvania, that aimed to increase community empowerment to address urban environmental injustices by training residents to reclaim vacant land. We use a case study approach to illustrate resident perceptions of the impact of vacant land and urban decay. The results suggest that these residents viewed vacancy as an important indicator of community well-being and social inequality. We use a social and environmental justice framework to describe results and implications for practitioners and researchers. PMID- 27214677 TI - Pull of Gravity: A Media Review Focusing on the Social and Environmental Effects of Recidivism. AB - Recidivism is defined as reincarceration, reconviction and/or being reimprisoned. This article focuses on the issues of recidivism while incorporating Pull of Gravity, a documentary, which highlights the challenges ex-offenders encounter during postrelease. This article explores 3 sociological issues closely related to recidivism: (1) types of populations that are recidivating, (2) communities' ex-offenders are returning home to, and (3) challenges they face in their transition. This article integrates research on issues of reentry and utilizes real-life experiences reflected through this film to give readers a tangible perception on the challenges that are currently faced. It explores possible resolutions while prompting critical thinking for everyone; individuals who are familiar with this topic and those who are foreign. PMID- 27214678 TI - Objective and subjective methods for quantifying training load in wheelchair basketball small-sided games. AB - The aim of the present study was to analyse the training load in wheelchair basketball small-sided games and determine the relationship between heart rate (HR)-based training load and perceived exertion (RPE)-based training load methods among small-sided games bouts. HR-based measurements of training load included Edwards' training load and Stagno's training impulses (TRIMPMOD) while RPE-based training load measurements included cardiopulmonary (session RPEres) and muscular (session RPEmus) values. Data were collected from 12 wheelchair basketball players during five consecutive weeks. The total load for the small-sided games sessions was 67.5 +/- 6.7 and 55.3 +/- 12.5 AU in HR-based training load (Edwards' training load and TRIMPMOD), while the RPE-based training loads were 99.3 +/- 26.9 (session RPEres) and 100.8 +/- 31.2 AU (session RPEmus). Bout-to bout analysis identified greater session RPEmus in the third [P < 0.05; effect size (ES) = 0.66, moderate] and fourth bouts (P < 0.05; ES = 0.64, moderate) than in the first bout, but other measures did not differ. Mean correlations indicated a trivial and small relationship among HR-based and RPE-based training loads. It is suggested that HR-based and RPE-based training loads provide different information, but these two methods could be complementary because one method could help us to understand the limitations of the other. PMID- 27214679 TI - Micro and Nano Material Carriers for Immunomodulation. AB - Modulation of the immune system through the use of micro and nano carriers offers opportunities in transplant tolerance, autoimmunity, infectious disease, and cancer. In particular, polymeric, lipid, and inorganic materials have been used as carriers of proteins, nucleic acids, and small drug molecules to direct the immune system toward either suppressive or stimulatory states. Current technologies have focused on the use of particulates or scaffolds, the modulation of materials properties, and the delivery of biologics or small drug molecules to achieve a desired response. Discussed are relevant immunology concepts, the types of biomaterial carriers used for immunomodulation highlighting their benefits and drawbacks, the material properties influencing immune responses, and recent examples in the field of transplant tolerance. PMID- 27214680 TI - The clinical outcomes of deep gray matter injury in children with cerebral palsy in relation with brain magnetic resonance imaging. AB - In the present study we investigated the nature and extent of clinical outcomes using various classifications and analyzed the relationship between brain magnetic resonance imaging (MRI) findings and the extent of clinical outcomes in children with cerebral palsy (CP) with deep gray matter injury. The deep gray matter injuries of 69 children were classified into hypoxic ischemic encephalopathy (HIE) and kernicterus patterns. HIE patterns were divided into four groups (I-IV) based on severity. Functional classification was investigated using the gross motor function classification system-expanded and revised, manual ability classification system, communication function classification system, and tests of cognitive function, and other associated problems. The severity of HIE pattern on brain MRI was strongly correlated with the severity of clinical outcomes in these various domains. Children with a kernicterus pattern showed a wide range of clinical outcomes in these areas. Children with severe HIE are at high risk of intellectual disability (ID) or epilepsy and children with a kernicterus pattern are at risk of hearing impairment and/or ID. Grading severity of HIE pattern on brain MRI is useful for predicting overall outcomes. The clinical outcomes of children with a kernicterus pattern range widely from mild to severe. WHAT THIS PAPER ADDS: Delineation of the clinical outcomes of children with deep gray matter injury, which are a common abnormal brain MRI finding in children with CP, is necessary. The present study provides clinical outcomes for various domains in children with deep gray matter injury on brain MRI. The deep gray matter injuries were divided into two major groups; HIE and kernicterus patterns. Our study showed that severity of HIE pattern on brain MRI was strongly associated with the severity of impairments in gross motor function, manual ability, communication function, and cognition. These findings suggest that severity of HIE pattern can be useful for predicting the severity of impairments. Conversely, children with a kernicterus pattern showed a wide range of clinical outcomes in various domains. Children with severe HIE pattern are at high risk of ID or epilepsy and children with kernicterus pattern are at risk of hearing impairment or ID. The strength of our study was the assessment of clinical outcomes after 3 years of age using standardized classification systems in various domains in children with deep gray matter injury. PMID- 27214681 TI - The relationship between motor skills, ADHD symptoms, and childhood body weight. AB - BACKGROUND: Research has suggested an important association between motor proficiency and overweight/obesity. Many children with motor difficulties experience ADHD symptoms which have also been linked with overweight/obesity. Previous research has not considered both ADHD and motor performance when investigating their relationship with overweight/obesity. AIMS: To investigate the relationships between motor performance, ADHD symptoms, and overweight/obesity in children. METHODS AND PROCEDURES: A cross-sectional study was conducted involving189 children aged six to 10 years. Symptoms of ADHD were identified using the SNAP-IV rating scale. Motor impairment (MI) was identified using the Movement Battery Assessment for Children-2. Body composition was estimated from the Body Mass Index (BMI) based on World Health Organization child growth standards. OUTCOMES AND RESULTS: Balance was the only motor skill associated with BMI even after controlling for gender and ADHD. Group comparisons revealed that the proportion of overweight ADHD children was significantly less than the proportion of overweight control children and overweight MI children; the proportion of underweight ADHD children was significantly greater than the proportion of underweight MI children. CONCLUSIONS AND IMPLICATIONS: The results highlight the importance of taking into consideration both ADHD symptoms and motor difficulties in the assessment and intervention of physical health outcomes in children with ADHD and/or movement problems. PMID- 27214682 TI - Cognitive stimulation of pupils with Down syndrome: A study of inferential talk during book-sharing. AB - In the education of pupils with Down syndrome, "simplifying" literal talk and concrete stimulation have typically played a dominant role. This explorative study investigated the extent to which teachers stimulated abstract cognitive functions via inferential talk during book-sharing and how pupils with Down syndrome responded. Dyadic interactions (N=7) were videotaped, transcribed and coded to identify levels of abstraction in teacher utterances and to evaluate the adequacy of pupil responses. One-third of the teachers' utterances contained high levels of abstraction and promoted inferential talk. Six of the seven children predominantly responded in ways which revealed inferential thinking. Dialog excerpts highlighted individual, contextual and interactional factors contributing to variations in the findings. Contrary to previous claims, the children with Down syndrome in the current sample appear able to draw inferences beyond the "here-and-now" with teacher support. This finding highlights the educational relevance and importance of higher-order cognitive stimulation of pupils with intellectual disabilities, to foster independent metacognitive skills. PMID- 27214683 TI - Why do children with language impairment have difficulties with narrative macrostructure? AB - BACKGROUND: Research has produced conflicting findings about the effects of language impairment (LI) on narrative macrostructure outcomes. AIMS: The present study investigated if children with LI perform weaker than typically developing (TD) controls on narrative macrostructure in different tasks, whether this changes over time and if between-group differences stem from linguistic or cognitive factors. METHODS AND PROCEDURES: A group of monolingual Dutch children with LI (n=84) and a TD control group (n=45) were tested with a story comprehension and a story generation task. All children were five or six at wave 1 and six or seven at wave 2. Information was collected on vocabulary, grammar, verbal memory and sustained attention. OUTCOMES AND RESULTS: At wave 1, the LI group performed weaker than the TD group in both tasks. At wave 2, the groups performed similarly on story comprehension. On story generation, the TD group still outperformed the LI group. Sustained attention mediated the relationship between group and story generation. CONCLUSIONS AND IMPLICATIONS: Effects of LI on narrative macrostructure are moderated by age and task and may stem from sustained attention weaknesses. These findings have implications for using narrative tasks in educational and diagnostic settings and may direct future interventions. PMID- 27214684 TI - Aerosolized ribavirin: the most expensive drug for pneumonia. AB - Dramatic, overnight cost increases of important orphan and generic medications have recently come under public and government scrutiny. We highlight the case of aerosolized ribavirin, an important antiviral agent in hematopoietic stem cell transplantation which, because of substantial price increases, may now cost more than the transplant procedure itself. PMID- 27214685 TI - Graphene Oxide Membranes with Strong Stability in Aqueous Solutions and Controllable Lamellar Spacing. AB - Graphene oxide (GO) membranes become emerging efficient filters for molecular or ionic separation due to their well-defined two-dimensional nanochannels formed by closely spaced GO sheets and tunable physicochemical properties. The stability of GO membranes in aqueous solutions is a prerequisite for their applications. Here we show a novel and easy strategy for fabricating GO membranes with strong stability in aqueous solutions and controllable lamellar spacing by simply doping with partially reduced graphene oxide (prGO) sheets. With our prGO-doping strategy, the interlayer stabilizing force in GO membranes is enhanced due to the weakened repulsive hydration and enhanced pi-pi attraction between GO sheets; as a result, the fabricated GO membranes are featured with controllable lamellar spacing and extraordinary stability in water or even strong acid and base solutions as well as strong mechanical properties, which will expand the application scope of GO membranes and provide ever better performances in their applications with aqueous solution environments. PMID- 27214686 TI - The role of asymmetric dimethylarginine alone and in combination with N-terminal pro-B-type natriuretic peptide as a screening biomarker for systemic sclerosis related pulmonary arterial hypertension: a case control study. AB - OBJECTIVES: Asymmetric dimethylarginine (ADMA) is a novel biomarker of endothelial cell dysfunction. In this proof of concept study, we sought to evaluate the role of ADMA as a screening biomarker for incident systemic sclerosis-related pulmonary arterial hypertension (SSc-PAH). METHODS: ADMA levels were measured using high performance liquid chromatography in 15 consecutive treatment-naive patients with newly-diagnosed SSc-PAH and compared with 30 SSc controls without PAH. Logistic regression models were used to evaluate the independent association of ADMA with PAH. The optimal cut-point of ADMA for SSc PAH screening was determined. NT-proBNP levels were previously measured in the same patients and the optimal cut-point of NT-proBNP of >=210ng/mL was coupled with the optimal cut-point of ADMA to create a screening model that combined the two biomarkers. RESULTS: The PAH group had significantly higher mean ADMA levels than the control group (0.76+/-0.14 MUM versus 0.59+/-0.07 MUM; p<0.0001). ADMA levels remained significantly associated with PAH after the adjustment for specific disease characteristics, cardiovascular risk factors and other SSc related vascular complications (all p<0.01). An ADMA level >=0.7 MUM had a sensitivity of 86.7%, specificity of 90.0% and AUC of 0.86 for diagnosing PAH. A screening model that combined an NT-proBNP >=210ng/mL and/ or ADMA >=0.7 ng/mL resulted in a sensitivity of 100% and specificity of 90% for the detection of SSc PAH. CONCLUSIONS: In this small study, use of ADMA in combination with NT-proBNP produced excellent sensitivity and specificity for the non-invasive identification of SSc-PAH. The role of ADMA as a screening biomarker for SSc-PAH merits further evaluation. PMID- 27214687 TI - Frizzled3 Shapes the Development of Retinal Rod Bipolar Cells. AB - PURPOSE: Frizzled3 (Fzd3), a member of the core planar cell polarity (PCP) family in mammals, contributes to visual development by guiding axonal projections of some retinal ganglion cells. However, its other functions in the maturation of the visual system, especially the retina, remain elusive. The present study explores the role of Fzd3 in retinal development by focusing on rod bipolar cells (RBCs). METHODS: Frizzled3 was conditionally removed from the retina of Isl1 Cre;Fzd3f/- mice using the Cre-loxP system. Electroretinograms (ERGs) were performed to measure the light response of retinas. Frizzled3 expression was monitored by beta-galactosidase (beta-gal) staining and anti-beta-gal immunostaining. Immunofluorescence was used to examine cellular distribution and morphology during development, and electron microscopy was applied to visualize the dendritic invaginations of RBCs. RESULTS: Electroretinograms showed decreased b-wave amplitudes, and lower b- to a-wave ratios in Isl1-Cre;Fzd3f/- than in control (Isl1-Cre;Fzd3f/+) mice. In RBCs, where Fzd3 was expressed and inactivated, the planar organization, shape, and orientation of somas were disrupted. From P10, dendrites of these RBCs displayed reduced arborization with mistargeting. Furthermore, their dendritic invaginations into rod terminals were suppressed, and the density of rod ribbons in the OPL was reduced. CONCLUSIONS: Frizzled3 is required to shape the pattern of RBC somas and dendrites, and the structural and functional connectivity between rods and RBCs. Our results highlight novel functions for Fzd3 in regulating retinal development. PMID- 27214688 TI - Evaluation of Central and Peripheral Visual Field Concordance in Glaucoma. AB - PURPOSE: The purpose of this study was to characterize the extent to which central visual field (VF) loss reflects peripheral VF loss in patients with varying degrees of glaucoma severity. METHODS: A total of 232 patients with glaucoma or suspect glaucoma completed static central VF testing using the 24-2 pattern and peripheral VF testing using the suprathreshold 30-60 pattern. Points from 24-2 tests were reclassified as normal/abnormal based on pattern deviation values. RESULTS: Strong positive correlations (r >= 0.7) were observed between the proportion of abnormal central and peripheral points for the full VF, superior hemifield, and inferior hemifield, although the percentage of total central and peripheral abnormal points differed by >=10% in 45% of eyes. In eyes with an average of 10%-40% abnormal points in the central and peripheral VFs, 12.0% more abnormal peripheral points were noted compared with the percentage of abnormal central points (P < 0.001; SD, 16.7%; range, 61% more to 37% less). In eyes with an average of 60%-90% abnormal points in the central and peripheral VFs, 16.4% fewer abnormal peripheral points were noted compared with the percentage of abnormal central points (P = 0.04; SD, 20.9%; range, 19% more to 49% less). CONCLUSIONS: Central 24-2 testing generally reflects the extent of damage to the more peripheral VF in glaucoma, although significant disagreement exists for individual eyes. Further work is needed to determine whether integration of peripheral test points can improve detection of true VF loss in early glaucoma or be useful in monitoring progressive glaucomatous damage to areas of preserved VF in advanced glaucoma. PMID- 27214689 TI - An anisotropic hyperelastic constitutive model of brain white matter in biaxial tension and structural-mechanical relationships. AB - Computational models of the brain require accurate and robust constitutive models to characterize the mechanical behavior of brain tissue. The anisotropy of white matter has been previously demonstrated; however, there is a lack of data describing the effects of multi-axial loading, even though brain tissue experiences multi-axial stress states. Therefore, a biaxial tensile experiment was designed to more fully characterize the anisotropic behavior of white matter in a quasi-static loading state, and the mechanical data were modeled with an anisotropic hyperelastic continuum model. A probabilistic analysis was used to quantify the uncertainty in model predictions because the mechanical data of brain tissue can show a high degree of variability, and computational studies can benefit from reporting the probability distribution of model responses. The axonal structure in white matter can be heterogeneous and regionally dependent, which can affect computational model predictions. Therefore, corona radiata and corpus callosum regions were tested, and histology and transmission electron microscopy were performed on tested specimens to relate the distribution of axon orientations and the axon volume fraction to the mechanical behavior. These measured properties were implemented into a structural constitutive model. Results demonstrated a significant, but relatively low anisotropic behavior, yet there were no conclusive mechanical differences between the two regions tested. The inclusion of both biaxial and uniaxial tests in model fits improved the accuracy of model predictions. The mechanical anisotropy of individual specimens positively correlated with the measured axon volume fraction, and, accordingly, the structural model exhibited slightly decreased uncertainty in model predictions compared to the model without structural properties. PMID- 27214690 TI - Finite element simulation for the mechanical characterization of soft biological materials by atomic force microscopy. AB - The characterization of the mechanical properties of soft materials has been traditionally performed through uniaxial tensile tests. Nevertheless, this method cannot be applied to certain extremely soft materials, such as biological tissues or cells that cannot be properly subjected to these tests. Alternative non destructive tests have been designed in recent years to determine the mechanical properties of soft biological tissues. One of these techniques is based on the use of atomic force microscopy (AFM) to perform nanoindentation tests. In this work, we investigated the mechanical response of soft biological materials to nanoindentation with spherical indenters using finite element simulations. We studied the responses of three different material constitutive laws (elastic, isotropic hyperelastic and anisotropic hyperelastic) under the same process and analyzed the differences thereof. Whereas linear elastic and isotropic hyperelastic materials can be studied using an axisymmetric simplification, anisotropic hyperelastic materials require three-dimensional analyses. Moreover, we established the limiting sample size required to determine the mechanical properties of soft materials while avoiding boundary effects. Finally, we compared the results obtained by simulation with an estimate obtained from Hertz theory. Hertz theory does not distinguish between the different material constitutive laws, and thus, we proposed corrections to improve the quantitative measurement of specific material properties by nanoindentation experiments. PMID- 27214691 TI - A theoretical model to predict tensile deformation behavior of balloon catheter. AB - In this technical note, a simple theoretical model was proposed to express the tensile deformation and fracture of balloon catheter tested by the ISO standard using piece-wise linear force-displacement relations. The model was then validated by comparing with the tensile force-displacement behaviors of two types of typical balloon catheters clinically used worldwide. It was shown that the proposed model can effectively be used to express the tensile deformation behavior and easily be handled by physicians who are not familiar with mechanics of materials. PMID- 27214692 TI - Regenerating Perfection. PMID- 27214693 TI - Acute hypertensive response in ischemic stroke is associated with increased aortic stiffness. AB - BACKGROUND AND AIMS: Acute hypertensive response (AHR) affects more than 60% of patients with ischemic stroke and is associated with poor outcomes. We hypothesized that its development is related to arterial stiffening. "The gold standard" estimate of arterial stiffness is carotid-femoral pulse wave velocity (CF-PWV). We compared CF-PWV and indirect indices of arterial stiffness (central augmentation index (cAIxHR), central systolic (cSBP) and pulse (cPP) pressures) between acute ischemic stroke patients who developed AHR and those who were normotensive in the early phase of stroke. METHODS: AHR was assessed through hourly BP measurements within 24 h from admission using an oscillometric device. The stiffness was assessed using applanation tonometry with a SphygmoCor((r)) device (Atcor, Sydney, Australia) 7 +/- 2 days after stroke. RESULTS: Among 102 patients with acute ischemic stroke, 73(71.5%) met AHR criteria. In an univariate analysis, CF-PWV, cAIxHR, cSBP and cPP were higher in those who developed AHR (10.9 vs. 8.3 m/s, p < 0.001; 30.8 vs. 23.9%, p = 0.004; 138.2 vs. 117.2 mmHg, p < 0.001; 54.6 vs. 44 mmHg, p = 0.005, respectively). In a multivariate logistic regression analysis, CF-PWV was independently associated with AHR after adjustment for age and peripheral mean blood pressure (pMBP) (p = 0.04), for age, pMBP and diabetes mellitus (DM) (p = 0.045), and age, pMBP, DM and hypertension (p = 0.047). CONCLUSION: This study revealed for the first time that AHR in ischemic stroke is associated with elevated aortic stiffness independently of other clinical factors including age and hypertension preceding stroke. A potential pathophysiological mechanism responsible for this relationship includes impaired baroreceptor function in stiff arteries resulting in impaired BP autoregulation. PMID- 27214694 TI - Longitudinal changes in fetal biometry and cerebroplacental hemodynamics in fetuses with congenital heart disease. AB - OBJECTIVES: To determine the longitudinal behavior of fetal biometric measures and cerebroplacental hemodynamics throughout gestation in fetuses with congenital heart disease (CHD). METHODS: Fetal biometry and Doppler hemodynamics (uterine artery (UtA), umbilical artery (UA) and fetal middle cerebral artery (MCA)) were measured serially in a cohort of consecutive fetuses diagnosed with CHD. Evaluations were made at various time points, from diagnosis (20-25 weeks) to delivery, with at least two measurements per fetus that were at least 2 weeks apart. Fetuses were classified into three groups according to the pattern of blood supply to the brain (placental vs systemic) that would be expected on the basis of the type of CHD. All parameters were transformed into Z-scores. A linear mixed model to analyze repeated measurements was constructed for each parameter to assess its behavior throughout gestation. RESULTS: Four hundred and forty-four ultrasound examinations were performed in 119 CHD fetuses, with a median of two measurements per fetus. The fetuses presented a small head at diagnosis (biparietal diameter (BPD) Z-score, -1.32 +/- 0.99; head circumference (HC) Z score, -0.79 +/- 1.02), which remained small throughout gestation. UtA and UA pulsatility indices (PI) showed a significant increase towards the end of pregnancy, whereas no significant changes were observed in MCA-PI or cerebroplacental ratio (CPR) with gestational age. Both MCA and CPR presented significant differences in longitudinal behavior between CHD groups, while BPD and HC did not. CONCLUSIONS: CHD fetuses have a relatively small head from the second trimester of pregnancy, regardless of the type of CHD anomaly, and increasing resistance in the UtA and UA as pregnancy progresses, suggestive of increasing degree of placental impairment. Our findings indicate the early onset of mechanisms that could lead to poorer neurodevelopment later in life. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 27214695 TI - Lauren H. Sansing, MD, MS. PMID- 27214696 TI - Intracerebral Hemorrhage. PMID- 27214697 TI - Critical Care Management of Intracerebral Hemorrhage. AB - Spontaneous intracerebral hemorrhage (ICH), the most devastating and debilitating form of stroke, remains a major healthcare concern all over the world. Intracerebral hemorrhage is frequently managed in critical care settings where intensive monitoring and treatment are employed to prevent and address primary and secondary brain injury as well as other medical complications that may arise. Although there has been increasing data guiding the management of ICH in the past decade, prognosis remains dismal. In this article, the authors discuss the risk factors for ICH, the role of imaging, the major targets of neurocritical care management, the etiology and management of raised intracranial pressure, as well as prevention of and prompt response to the emergence of medical complications. They also discuss the effect of early withdrawal of life-sustaining therapy on prognosis. Finally, we outline several clinical trials that hold promise in improving our management of ICH in the near future. PMID- 27214698 TI - Sporadic Cerebral Amyloid Angiopathy: Pathophysiology, Neuroimaging Features, and Clinical Implications. AB - Sporadic cerebral amyloid angiopathy is a small vessel disorder defined pathologically by progressive amyloid deposition in the walls of cortical and leptomeningeal vessels resulting from disruption of a complex balance between production, circulation, and clearance of amyloid-beta peptide (Abeta) in the brain. Cerebral amyloid angiopathy is a major cause of lobar symptomatic intracerebral hemorrhage, transient focal neurologic episodes, and a key contributor to vascular cognitive impairment. The mechanisms and consequences of amyloid-beta deposition at the pathological level and its neuroimaging manifestations, clinical consequences, and implications for patient care are addressed in this review. PMID- 27214699 TI - Macrovascular Lesions Underlying Spontaneous Intracerebral Hemorrhage. AB - Spontaneous intracerebral hemorrhage (ICH) is a morbid disease with a high case fatality rate. Prognosis, rehemorrhage rates, and acute, clinical decision making are greatly affected by the underlying etiology of hemorrhage. This review focuses on the evaluation, diagnosis, and management of structural, macrovascular lesions presenting with ICH, including ruptured aneurysms, brain arteriovenous malformations, cranial dural arteriovenous fistulas, and cerebral cavernous malformations. PMID- 27214700 TI - Predicting Outcome for Intracerebral Hemorrhage Patients: Current Tools and Their Limitations. AB - Accurate outcome prognostication is critical to the management of patients with primary or spontaneous intracerebral hemorrhage (ICH). Prognostication may guide the decision to pursue aggressive acute management or to plan proper goals of care for patients who will likely suffer long-term severe disability. In particular, early predictions of poor outcome for ICH patients routinely influence discussions with surrogate decision makers to pursue do-not-resuscitate orders or comfort care, practices that may often be appropriate, but that are at risk for self-fulfilling prophecies. The authors review the literature pertaining to these concepts. Currently available baseline severity scores, with a focus on the ICH Score, are summarized and compared, with a discussion of the limitations and biases of such clinical scales derived from observational cohorts. New research on the accuracy of the subjective early clinical judgment of physicians and nurses for predicting ICH functional outcome as it compares to that of baseline severity scores, is also summarized. PMID- 27214701 TI - Surgical Strategies for Spontaneous Intracerebral Hemorrhage. AB - In recent decades, the surgical treatment of intracerebral hemorrhage (ICH) has become a focus of scientific inquest. This effort has been led by an international group of neurologists and neurosurgeons with the goal of studying functional recovery and developing new surgical techniques to facilitate improved clinical outcomes. Currently, the two most pressing ICH investigational goals are (1) early blood pressure control, and (2) safe hematoma volume reduction. Achieving these goals would support decision-making, level-of-care choices, and the global research strategy of developing biologically informed treatments. Herein the authors review conventional and minimally invasive surgical approaches to spontaneous ICH, articulating the scope of the problem, recent clinical trials, management issues, and relevant questions for future research. The authors propose that strategies using minimally invasive techniques including clot aspiration with stereotactic guidance may give better results with improved clinical outcomes compared with standard open surgical approaches. PMID- 27214702 TI - Blood Pressure Management in Intracerebral Hemorrhage. AB - Intracerebral hemorrhage (ICH) is associated with devastating outcomes. Admission to the intensive care unit has been the only proven course to improve outcomes. All other treatment modalities have failed so far. The majority of patients presenting with ICH have an elevated blood pressure (BP). Initial data on the safety and efficacy of BP treatment in acute ICH have been conflicting. This has led to large prospective and randomized clinical trials to assess the safety and efficacy of early BP lowering in acute ICH. These trials showed safety and a tendency toward improved functional outcomes. In fact, the results of three subsequent meta-analyses also showed safety and possible efficacy of early lowering of BP in ICH. Based on the results of the published clinical trials and meta-analyses, the American Heart Association and the European Stroke Association concluded that early intensive treatment of BP in acute ICH is safe and might improve functional outcome. The authors advocate that-pending additional data from ongoing trials-health care professionals should maintain the SBp < 140 mm Hg in patients presenting with acute ICH. PMID- 27214703 TI - Diagnosis and Management of Coagulopathy-Related Intracerebral Hemorrhage. AB - Coagulopathy, defined as impaired clot formation, is common in intensive care units (ICUs). Many physiological derangements lead to dysfunctional hemostasis in the ICU; most of these are acquired rather than congenital. Coagulopathies in the ICU are often related to systemic diseases, autoimmune dysfunction, acute infection, organ dysfunction, therapeutic medications, and/or other medical treatments. A significant complication of coagulopathy in the critically ill is major bleeding, defined as fatal hemorrhage, hemodynamic instability, transfusion requirement, or intracranial hematomas. Coagulopathy in the ICU often poses complex management dilemmas, especially when coagulopathy coexists with a thrombotic state. Coagulopathy associated with intracerebral hemorrhage (ICH) bears directly on neurologic prognosis and functional outcome. There is a paucity of high-quality evidence for the management of coagulopathies in neurocritical care; however, data derived from studies of patients with ICH may inform treatment decisions. This article focuses on acquired conditions such as pharmacological therapies, organ failure, and platelet dysfunction that are often associated with defective clot formation in the ICU that result in or exacerbate ICH. PMID- 27214705 TI - Genetic Determinants of Risk, Severity, and Outcome in Intracerebral Hemorrhage. AB - Spontaneous, nontraumatic intracerebral hemorrhage (ICH) is the most severe manifestation of common forms of cerebral small vessel disease. Although ICH represents only 15% of all strokes, it accounts for a large proportion of stroke related costs and mortality. Preventive and acute treatments remain limited. Because genetic variation contributes substantially to ICH, genomic analyses constitute a powerful tool to identify new biological mechanisms involved in its occurrence. Through translational research efforts, these newly identified mechanisms can become targets for innovative therapeutic interventions. Here, the authors summarize the most recent genetic discoveries for ICH. They also introduce the Platform for Accelerating Genetic Discovery for Cerebrovascular Disease, a newly created resource that aims to create a common workspace for genetic analyses that will bring together 100,000 stroke cases and suitable controls from numerous institutions in several countries. PMID- 27214704 TI - Stages of the Inflammatory Response in Pathology and Tissue Repair after Intracerebral Hemorrhage. AB - Intracerebral hemorrhage (ICH) is a major health concern, with high rates of mortality and morbidity and no highly effective clinical interventions. Basic research in animal models of ICH has provided insight into its complex pathology, in particular revealing the role of inflammation in driving neuronal death and neurologic deficits after hemorrhage. The response to ICH occurs in four distinct phases: (1) initial tissue damage and local activation of inflammatory factors, (2) inflammation-driven breakdown of the blood-brain barrier, (3) recruitment of circulating inflammatory cells and subsequent secondary immunopathology, and (4) engagement of tissue repair responses that promote tissue repair and restoration of neurologic function. The development of CNS inflammation occurs over many days after initial hemorrhage and thus may represent an ideal target for treatment of the disease, but further research is required to identify the mechanisms that promote engagement of inflammatory versus anti-inflammatory pathways. In this review, the authors examine how experimental models of ICH have uncovered critical mediators of pathology in each of the four stages of the inflammatory response, and focus on the role of the immune system in these processes. PMID- 27214707 TI - Evaluation of Small Molecules as Front Cell Donor Materials for High-Efficiency Tandem Solar Cells. AB - Three small molecules as front cell donors for tandem cells are thoroughly evaluated and a high power conversion efficiency of 11.47% is achieved, which demonstrates that the oligomer-like small molecules offer a good choice for high performance tandem solar cells. PMID- 27214706 TI - Recovery and Rehabilitation after Intracerebral Hemorrhage. AB - About half of patients survive intracerebral hemorrhage (ICH), but most are left with significant disability. Rehabilitation after ICH is the mainstay of treatment to reduce impairment, improve independence in activities, and return patients to meaningful participation in the community. The authors discuss the neuroplastic mechanisms underlying recovery in ICH, preclinical and clinical interventional studies to augment recovery, and the rehabilitative and medical management of post-ICH patients. PMID- 27214708 TI - How Hand Osteoarthritis, Comorbidity, and Pain Interact to Determine Functional Limitation in Older People: Observations From the European Project on OSteoArthritis Study. AB - OBJECTIVE: To examine the role of comorbidity and pain in the associations of hand osteoarthritis (OA) with self-reported and performance-based physical function in a general population of elderly persons. METHODS: We studied data from 2,942 participants ages 65-85 years in the European Project on OSteoArthritis, a collaborative observational study of 6 European cohorts (from Germany, Italy, The Netherlands, Spain, Sweden, and the UK). Outcome measures included self-reported physical function of the hands measured by the AUStralian/CANadian Osteoarthritis Hand Index (AUSCAN) for hand OA physical function subscale and performance-based grip strength measured using a strain gauge dynamometer. RESULTS: Comorbidity was not a confounder in the association of hand OA with self-reported and performance-based functional limitations, while the role of pain as a mediator was confirmed. Anxiety, depression, stroke, and osteoporosis were associated with AUSCAN scores reflecting more impairment. Depression and osteoporosis were associated with less grip strength. CONCLUSION: Although comorbidity was decidedly and independently associated with hand functional limitation, it had no effect on the relationship of hand OA with physical function. Hand OA was found to be associated with both self-reported and performance-based physical function impairment; the association was found to be partially mediated by pain, which reduced its impact. PMID- 27214709 TI - The Monoiodoacetate Model of Osteoarthritis Pain in the Mouse. AB - A major symptom of patients with osteoarthritis (OA) is pain that is triggered by peripheral as well as central changes within the pain pathways. The current treatments for OA pain such as NSAIDS or opiates are neither sufficiently effective nor devoid of detrimental side effects. Animal models of OA are being developed to improve our understanding of OA-related pain mechanisms and define novel pharmacological targets for therapy. Currently available models of OA in rodents include surgical and chemical interventions into one knee joint. The monoiodoacetate (MIA) model has become a standard for modelling joint disruption in OA in both rats and mice. The model, which is easier to perform in the rat, involves injection of MIA into a knee joint that induces rapid pain-like responses in the ipsilateral limb, the level of which can be controlled by injection of different doses. Intra-articular injection of MIA disrupts chondrocyte glycolysis by inhibiting glyceraldehyde-3-phosphatase dehydrogenase and results in chondrocyte death, neovascularization, subchondral bone necrosis and collapse, as well as inflammation. The morphological changes of the articular cartilage and bone disruption are reflective of some aspects of patient pathology. Along with joint damage, MIA injection induces referred mechanical sensitivity in the ipsilateral hind paw and weight bearing deficits that are measurable and quantifiable. These behavioral changes resemble some of the symptoms reported by the patient population, thereby validating the MIA injection in the knee as a useful and relevant pre-clinical model of OA pain. The aim of this article is to describe the methodology of intra-articular injections of MIA and the behavioral recordings of the associated development of hypersensitivity with a mind to highlight the necessary steps to give consistent and reliable recordings. PMID- 27214710 TI - Risk of venous thrombosis in persons with increased body mass index and interactions with other genetic and acquired risk factors. AB - Essentials Obesity, factor V Leiden (FVL) and blood group non-O are common. We studied the combined effect of these factors on the risk of venous thrombosis (VT). The combination of obesity, non-O blood group and FVL increased VT risk up to ten-fold. Identifying high VT may be beneficial in thrombosis prevention. SUMMARY: Background Overweight/obesity has a substantial effect on the occurrence of venous thrombosis (VT). Blood group non-O has a high prevalence in Western populations, and the factor V Leiden mutation could be present in 5% of Caucasians. These frequent prothrombotic risk factors will have a considerable impact on the incidence of VT, especially when combined. Objectives We investigated whether FV Leiden with blood group non-O modifies VT risk in individuals with different body mass index (BMI) strata in a case-control study (n = 11253). Results We observed a progressively increasing risk of VT with higher BMI, with an odds ratio of 1.9 (95% confidence interval [CI] 1.6-2.3) for those in the upper BMI tertile (BMI > 26.7 kg m(-2) ), as compared with the first BMI tertile (BMI < 23.5 kg m(-2) , blood group O, and no FV Leiden) (reference group). The addition of FV Leiden and blood group non-O to the model increased the risk in all BMI tertiles; the odds ratios were 3.8 (95% CI 3.2-4.6) in the third BMI tertile of individuals with blood group non-O, and 5.4 (95% CI 3.5-8.5) in the third BMI tertile of individuals with FV Leiden. When both FV Leiden and blood group non-O were present, the odds ratios were 9.1 (95% CI 5.9-14.0) in the first BMI tertile, 9.4 (95% CI 6.6-13.5) in the second BMI tertile, and 12.5 (95% CI 8.9-17.6) in the third BMI tertile. Conclusion Individuals with a high BMI, blood group non-O and/or FV Leiden have a high VT risk. The high VT risks in some subgroups may justify targeted screening and thromboprophylaxis decisions in these patients. PMID- 27214711 TI - Timing and utilization of antenatal care services in Liberia: Understanding the pre-Ebola epidemic context. AB - In Liberia, 75% of those who died from 2014 Ebola epidemic were women and the effects of this gruelling epidemic were more severely felt by pregnant women. This immediately raised fears about the long-term impacts of the epidemic on maternal and child health. As part of a larger study, this paper uses Andersen's behavioural model of health care utilization and Goffman's stigma theory to explain the timing and utilization of maternal health services before the outbreak of the Ebola epidemic as a background to the potential long-term effects on maternal health. We conducted survival and multiple regression analysis using the 2007 (N = 3524) and 2013 (N = 5127) Liberia's Demographic and Health Survey (LDHS) data. Our sample consisted of women of reproductive age (15-49 years) that had given birth in the last five years preceding the survey year. The findings show that from 2007 to 2013, there was an overall improvement in the timing of first antenatal care (ANC) visits (TR = 0.92, p < 0.001), number of ANC visits and delivery with skilled birth attendants. The results also show county and regional disparities in the utilization of ANC services with South Eastern A region emerging as a relatively vulnerable place. Also, access to ANC services defined by distance to a health facility strongly predicted utilization. We argue that the Ebola epidemic likely eroded many of the previous gains in maternal health care, and may have left a lingering negative effect on the access and utilization of maternal health services in the long-term. The study makes relevant policy recommendations. PMID- 27214713 TI - Brief report: Using global positioning system (GPS) enabled cell phones to examine adolescent travel patterns and time in proximity to alcohol outlets. AB - As adolescents gain freedom to explore new environments unsupervised, more time in proximity to alcohol outlets may increase risks for alcohol and marijuana use. This pilot study: 1) Describes variations in adolescents' proximity to outlets by time of day and day of the week, 2) Examines variations in outlet proximity by drinking and marijuana use status, and 3) Tests feasibility of obtaining real time data to study adolescent proximity to outlets. U.S. adolescents (N = 18) aged 16-17 (50% female) carried GPS-enabled smartphones for one week with their locations tracked. The geographic areas where adolescents spend time, activity spaces, were created by connecting GPS points sequentially and adding spatial buffers around routes. Proximity to outlets was greater during after school and evening hours. Drinkers and marijuana users were in proximity to outlets 11/2 to 2 times more than non-users. Findings provide information about where adolescents spend time and times of greatest risk, informing prevention efforts. PMID- 27214714 TI - Obstetric management of carriers of haemophilia. PMID- 27214712 TI - Lifestyle behaviors and ethnic identity among diverse women at high risk for type 2 diabetes. AB - BACKGROUND: Diet and physical activity lifestyle behaviors are modifiable risk factors for type 2 diabetes and are shaped by culture, potentially influencing diabetes health disparities. OBJECTIVES: We examined whether ethnic identity-the strength of attachment to one's ethnic group, and a long-standing focus of psychological research-could help account for variations in lifestyle behaviors within a diverse population at high risk for chronic disease. METHODS: Using data from the Gestational Diabetes' Effects on Moms trial, this US-based cross sectional study included 1463 pregnant women (74% from minority ethnic/racial groups; 46% born outside the US) with gestational diabetes (GDM), a common pregnancy complication conferring high risk for type 2 diabetes after delivery. Mixed linear regression models examined whether ethnic identity is associated with lifestyle behaviors after adjusting for demographic, clinical, and acculturative characteristics (e.g., nativity and length of residence in the US). RESULTS: In the overall sample, a one-unit increase in ethnic identity score was significantly associated with 3% greater fiber intake, 4% greater fruit/vegetable intake, 11% greater total activity, and 11% greater walking (p values < 0.01). Within ethnic/racial groups, a one-unit increase in ethnic identity score was significantly associated with 17% greater fiber intake among Filipina women; 5% lower total caloric intake among non-Hispanic White women; and 40% greater total activity, 35% greater walking, and 8% greater total caloric intake among Latina women (p values <= 0.03). CONCLUSION: Results from this large study suggest that ethnic group attachment is associated with some lifestyle behaviors, independent of acculturation indicators, among young women with GDM who are at high risk for type 2 diabetes. Stronger ethnic identity may promote certain choices known to be associated with reduced risk of type 2 diabetes. Prospective research is needed to clarify the temporal nature of associations between ethnic identity and modifiable diabetes risk factors. PMID- 27214715 TI - Lower limb prosthetic considerations in persons with coagulopathies. AB - Most able-bodied amputees use artificial limbs for ambulation. Special considerations are required for persons with coagulopathies because excess pressure or friction may result in soft-tissue haemorrhages. Persons with haemophilia have multi-articular pathologies, hence the necessity to consider carefully the use of accessory walking aids. The use of walking aids results in biomechanical forces being applied through the upper limb joints and this may cause haemarthroses. PMID- 27214716 TI - Central venous catheter infection in haemophiliacs undergoing prophylaxis or immune tolerance with clotting factor concentrate. AB - The risk of infection in individuals with haemophilia using central vascular access devices for administration of clotting factor concentrates for prophylaxis or immune tolerance is unknown. We conducted a survey of US haemophilia treatment centres to determine the incidence and clinical characteristics of infection associated with the use of central venous catheters. Seventy (38.3%) of 183 patients using central lines developed device-associated infection, including 30 (28.0%) on prophylaxis and 40 (52.6%) on immune tolerance, P < 0.005. Over half (54.8%) the infections occurred in those 3 years of age. Implanted/tunnelled devices (port catheters) were more likely to become infected in the first 30 days after insertion, 11 of 41 (26.8%), than external catheters (broviac/hickman), none of 29 (0%), P= 0.00003. The median time to infection from initial device placement, 124 days, varied with age, 57 days in those 2 years of age vs. 161 days in those > 2 years of age, P= 0.0008, but not with type of device or treatment. Staphylococcal infections were more common with implanted devices (ports), 30 (73.2%), than external catheters, 12 (41.4%), P < 0.01, and Gram negative infections were more common with external catheters, 17 (58.6%), than tunnelled devices, 7 (17.1%), P < 0.005. In summary, the rate of infection with central venous access devices in haemophiliacs is high, and alternative approaches to venous access should be explored. PMID- 27214717 TI - Improved cost-effectiveness by pharmacokinetic dosing of factor VIII in prophylactic treatment of haemophilia A. AB - The aim of the study was to investigate the feasibility of optimizing prophylactic dosing of factor VIII by the use of individual pharmacokinetic data. Twenty-one patients were enrolled in a randomized cross-over study on standard dosage regimens vs. dosing according to pharmacokinetic principles. The study period was 2*6 months. Using single-dose pharmacokinetic data for each patient, plasma factor VIII procoagulant activity ( FVIII: C) curves following various doses and intervals were computer-simulated. From these calculations, a suitable dosage was chosen. FVIII: C was also repeatedly measured during study periods. Trough levels of FVIII: C, numbers of spontaneous joint bleedings and amounts of factor concentrate used during the two study periods were compared for each patient. There was a close correlation between predicted and measured values of FVIII: C. As the half-lives of FVIII: C in the patients varied from 7.8 to 18.3 h, it was obviously beneficial to base the dosage on individual pharmacokinetic data. Fourteen patients completed both study periods. Mean trough level of exogenous FVIII: C was raised from 0.89 (SD 0.73) U dL(-1) during standard dosage to 2.2 (1.5) U dL(-1) during pharmacokinetic dosage. Concomitantly, mean 6-month consumption of factor VIII was decreased from 124 000 (SD 30 000) units to 84 000 (31 000) units. Numbers of reported bleedings were generally similar during both periods. The study demonstrates the usefulness of individual pharmacokinetics as a tool for cost-effective utilization of factor VIII in the prophylactic treatment of haemophilia A. PMID- 27214718 TI - Lack of immune response to mouse IgG in previously untreated haemophilia A and haemophilia B patients treated with monoclonal antibody purified factor VIII and factor IX preparations. AB - Immunoaffinity purification of factor VIII and factor IX results in the inclusion of trace quantities (50 ng 100 IU(-1) ) of mouse protein in the final product. It is possible that infusion of extremely low levels of proteins might induce human antimouse antibody (HAMA) responses. To test this possibility, IgG, IgM and IgE antibodies to mouse IgG were assessed in previously untreated haemophilia A and haemophilia B patients (n = 9 and n = 11, respectively) who received monoclonal antibody (MAb) purified factor VIII (Monoclate-P(r) Antihaemophilic Factor [Human] Centeon, King of Prussia, PA) or factor IX (Mononine(r) Coagulation Factor IX [Human] Centeon). HAMA were evaluated prior to and 2-42 months after initial treatment. IgE antibodies to mouse IgG were undetectable (< 19 ng ML(-1) ) at all time points. Antimouse IgG levels for Monoclate-P-treated patients averaged (mean+/-SD) 0.40+/-0.18 MUg mL(-1) prior to treatment, and 0.64+/-0.43 MUg mL(-1) at the time of last observation (P > 0.05, not significant [n.s.]). Respective values for antimouse IgM in these patients were 2.48+/-1.20 MUg mL(-1) and 2.85+/-1.63 MUg mL(-1) (P > 0.05, n.s.). Antimouse IgG levels for Mononine treated patients averaged 0.48+/-0.52 MUg mL(-1) prior to treatment, and 0.66+/ 0.59 MUg mL(-1) after 3 months of therapy (P > 0.05, n.s.). Respective values for antimouse IgM in these pa-tients were 1.94+/-1.52 MUg mL(-1) and 1.77+/-0.99 MUg mL(-1) (P > 0.05, n.s.). Lack of immunogenicity of traces of mouse protein in these preparations is supported in that none of the patients assessed developed anaphylactoid reactions during treatment. PMID- 27214719 TI - The role of a 3-year period of continuous prophylactic concentrate substitution on later development of haemophilic arthropathy. AB - This study evaluated the effect of a period of up to 3 years of continuous prophylactic clotting factor concentrate therapy in haemophilia on the degree of arthropathy as measured 10-15 years later. Left and right elbows, knees and ankles of 115 severe and moderate haemophiliacs were evaluated clinically and radiographically after 13.9 years of follow-up, on average, after the period of prophylactic treatment. The average age at final evaluation was 15.4 years. Three groups were compared: (1) Group D, patients treated on demand only; (2) Group D+P, patients treated on demand except for a period of prophylaxis between 1978 and 1981, and (3) six patients who had had inhibitors for more than 10 years. The results were analysed by assessing the degree of change in the 'patient score', i.e. the sum of the orthopaedic scores for the six joints. No statistical differences were found among the study groups. Thus, no benefit of the earlier 3 year period of prophylaxis could be demonstrated. PMID- 27214720 TI - Osteonecrosis of the femoral head in haemophiliacs: not all joint disease is haemophilic arthropathy. AB - Osteonecrosis (ON) is rare while arthropathy is common in persons with haemophilia. A recent case of bilateral ON of the femoral head prompted us to review our experience with hip arthroplasty. We identified nine patients with presumed end-stage haemophilic arthropathy. Four of the nine individuals had radiographic findings suggestive of ON, but without unequivocal microscopic evidence of ON. It is important to recognize ON at an early stage because there are surgical interventions which may prolong the life of the joint and improve quality of life. We suggest that ON should be included in the differential diagnosis of hip pathology in persons with haemophilia presenting with hip pain or dysfunction. PMID- 27214721 TI - Chemical synovectomy vs. radioactive synovectomy for the treatment of chronic haemophilic synovitis: a prospective short-term study. AB - Between January 1992 and December 1994, a prospective study was performed in two centres comparing chemical synovectomy using repeated weekly injections (range, 1 17) of Rifampicin (Group R) vs. radioactive synovectomy using 1-2 injections of Yttrium-90 (Group Y). The study was performed on 38 joints in a total of 35 haemophilic patients suffering from chronic haemophilic synovitis unresponsive to 3 months of conservative treatment (substitution therapy with the deficient coagulation factor plus a rehabilitation protocol). Group R included 18 patients with an average age of 9 years, with an average follow-up time of 25 months. In Group R, 19 joints were treated: nine knees, four elbows and six ankles. Group Y included 17 patients with an average age of 18 years, with an average follow-up time of 23 months. In Group Y, 19 joints were treated: 14 knees, two elbows and three ankles. The joints were evaluated according to the frequency of bleeding episodes and the Pettersson radiographic score. On the basis of the radiographic scale at the time of the synoviortheses, the joints were categorized as stage I (0 points), stage II (1-2 points), stage III (3-7 points), stage IV (8-10 points) and stage V (11-13 points). The overall results showed that in Group R, bleeding decreased in 12 joints, remained the same in six and worsened in one. In Group Y, bleeding decreased in 11 joints, remained the same in seven and worsened in one. In both Groups, bleeding was controlled best if joints were in stages I and II. In stages III, IV and V, synoviorthesis should not be carried out in haemophilia because it is not effective. Use of radioactive substances in persons under the age of 9 years has been discouraged in the past and therefore only Rifampicin was used in this age group. However, in patients over 9 years of age, this study showed similar decrease of bleeding in both treatment groups. Taking into account the advantages and disadvantages of both agents, we suggest the use of Rifampicin in elbows and ankles but prefer Yttrium-90 for the knees. PMID- 27214722 TI - Identifying carriers at high risk for negative reactions when performing prenatal diagnosis of haemophilia. AB - The aim of the current study was to determine which pregnant carriers of haemophilia are at particularly high risk for having notably negative psychological reactions in association with prenatal diagnosis (PND) by fetal blood sampling of offspring haemophilia. Among 29 carriers of haemophilia A or B, notable psychiatric or psychosomatic symptoms in association with PND were significantly related to the woman's having a negative view of herself in general and of being a gene carrier, a planned pregnancy, high education, a good general knowledge of haemophilia and a guiding philosophy of life. Women with strong negative reactions significantly more often reported signs of depressive mood at follow-up. The results suggest that giving more information and promoting increased knowledge about the disease and the PND procedure will, by itself, not help women to cope better emotionally. Provision of prospective psychosocial support is recommended. PMID- 27214723 TI - Virological characteristics of HCV infection in Japanese haemophiliacs. AB - It has been found that almost all haemophiliacs treated with pooled concentrates of clotting factor VIII or IX before 1985/6 have been infected with hepatitis C virus (HCV). In order to clarify the characteristics of HCV infection in Japanese haemophiliacs, we investigated the HCV genotype and HCV-RNA level in 80 patients with haemophilia who had been confirmed to be positive by a second-generation HCV antibody test. HCV-RNA was detected in 60 (75.0%) individuals and various HCV genotypes were found. Although 80% (48/60) of the patients had genotype 1b, the frequency of each genotype was quite different from that in HCV-infected non haemophiliac Japanese. Particularly, multiple HCV genotypes were observed in 27 (46.7%) patients. The mean (+/- SD) level of HCV-RNA was 5.3 * 10(5) +/- 1.1 * 10(6) copies mL(-1) . The viral load in patients with genotype 2a was significantly less common than those with genotype 1a (P= 0.0007), genotype 1b (P= 0.0009) and combined genotype 1a/1b (P= 0.0019). In patients co-infected with human immunodeficiency virus (HIV), the HCV-RNA level was significantly higher (P= 0.05) than in those without co-infection. However, there was no significant difference (P= 0.25) in the HCV-RNA level with HCV/HIV co-infection among the 40 patients with group 1 genotypes. We conclude that this biased distribution of HCV genotypes in Japanese haemophiliacs reflects their specific mode of HCV infection. Moreover, these results suggest that super-infection with HIV does not greatly influence the HCV load in patients with no marked immunological deterioration. PMID- 27214724 TI - Serological and virological markers of human parvovirus B19 infection in patients with haemophilia. AB - Clotting factor concentrates prepared from human plasma are a potential route of parvovirus B19 (B19) infection in patients with coagulation disorders. However, it is not clear whether B19 transmits and persistently infects patients with haemophilia, especially those with HIV infection. We examined serological and virological markers of B19 in samples from 40 patients with haemophilia who had been receiving several brands of clotting factor concentrates. All of them were anti-B19 IgG seropositive and anti-B19 IgM seronegative. The levels of anti-B19 IgG were significantly higher in haemophiliacs than in healthy donors, whereas there was no difference between the level of anti-B19 IgG in haemophiliacs with HIV infection and those without HIV infection. Moreover, there was no difference between the level of anti-B19 IgG in haemophiliacs receiving recombinant factor VIII and that in those receiving plasma-derived clotting factors. Although by using polymerase chain reaction (PCR) B19 DNA was detected at very low levels (< 40 DNA copies mL(-1) , in 3 out of 40 haemophiliacs, persistent B19 infection was negligible. PMID- 27214725 TI - Rectal adenocarcinoma in an HIV-infected haemophiliac: case report and review. AB - Colorectal adenocarcinoma, a relatively uncommon malignancy associated with HIV infection, is now being increasingly recognized. Most reports have been in homosexuals and intravenous drug users and there are no reports of its occurrence in haemophiliacs acquiring HIV via infused factor VIII and without other obvious risk factors or a family history. The present report describes the case of a young heterosexual haemophiliac with HIV infection and no other risk factors who developed rectal carcinoma. The relevant literature is discussed and the clinical importance of recognizing this possible association is emphasized. PMID- 27214726 TI - Haemophilia A and chronic hepatopathy caused by extrahepatic biliary atresia: two congenital diseases cured by orthotopic liver transplantation. AB - Since the publication of the first successful liver transplantation in a patient with severe haemophilia A by Lewis et al. in 1985, different authors have reported clinical cure of haemophilia A by orthotopic liver transplantation. In the published cases liver transplantation was performed due to end-stage chronic liver disease secondary to factor replacement therapy for haemophilia A or haemophilia B. Congenital biliary atresia is the most common cause of obstructive jaundice in the neonatal period and the most common indication for liver transplantation in childhood. In this article we report the first successful orthotopic liver transplantation performed in Spain, carried out in the youngest patient thus far described, a 5-year-old boy with haemophilia A and chronic liver disease secondary to congenital biliary atresia. PMID- 27214727 TI - Haemophilia care - answering the needs of the patient. PMID- 27214728 TI - 'An account of an hemorrhagic disposition existing in certain families'. PMID- 27214729 TI - Abstracts of papers on haemophilia from other journals. PMID- 27214730 TI - Variations in the distal branches of the superficial fibular sensory nerve. AB - INTRODUCTION: We evaluated anatomic variations of distal branches of the superficial fibular sensory nerve electrophysiologically. METHODS: Orthodromic nerve conduction studies (NCS) of the first and third branches (M-I, M-III) of the medial dorsal cutaneous nerve and the fourth and fifth branches (I-IV, I-V) of the intermediate dorsal cutaneous nerve (IDCN) were performed. To find anomalous innervations from the dorsal sural nerve (DSN) in the IDCN territory, NCS of the fourth and fifth branches (S-IV, S-V) of the DSN were also performed. RESULTS: All sensory nerve action potentials (SNAPs) of M-I and M-III could be obtained bilaterally from 31 healthy Japanese volunteers. SNAPs of I-IV and I-V were recordable in 85.5% and 43.5% of feet, respectively. Anomalous innervations from the DSN were confirmed in 71.0% of S-IV and 93.5% of S-V. CONCLUSION: These results suggest that anatomical variations in the IDCN territory are very frequent in Japanese subjects. Muscle Nerve 55: 74-76, 2017. PMID- 27214732 TI - Introduction. PMID- 27214731 TI - Population-Based Colonoscopy Screening for Colorectal Cancer: A Randomized Clinical Trial. AB - IMPORTANCE: Although some countries have implemented widespread colonoscopy screening, most European countries have not introduced it because of uncertainty regarding participation rates, procedure-related pain and discomfort, endoscopist performance, and effectiveness. To our knowledge, no randomized trials on colonoscopy screening currently exist. OBJECTIVE: To investigate participation rate, adenoma yield, performance, and adverse events of population-based colonoscopy screening in several European countries. DESIGN, SETTING, AND POPULATION: A population-based randomized clinical trial was conducted among 94 959 men and women aged 55 to 64 years of average risk for colon cancer in Poland, Norway, the Netherlands, and Sweden from June 8, 2009, to June 23, 2014. INTERVENTIONS: Colonoscopy screening or no screening. MAIN OUTCOMES AND MEASURES: Participation in colonoscopy screening, cancer and adenoma yield, and participant experience. Study outcomes were compared by country and endoscopist. RESULTS: Of 31 420 eligible participants randomized to the colonoscopy group, 12 574 (40.0%) underwent screening. Participation rates were 60.7% in Norway (5354 of 8816), 39.8% in Sweden (486 of 1222), 33.0% in Poland (6004 of 18 188), and 22.9% in the Netherlands (730 of 3194) (P < .001). The cecum intubation rate was 97.2% (12 217 of 12 574), with 9726 participants (77.4%) not receiving sedation. Of the 12 574 participants undergoing colonoscopy screening, we observed 1 perforation (0.01%), 2 postpolypectomy serosal burns (0.02%), and 18 cases of bleeding owing to polypectomy (0.14%). Sixty-two individuals (0.5%) were diagnosed with colorectal cancer and 3861 (30.7%) had adenomas, of which 1304 (10.4%) were high-risk adenomas. Detection rates were similar in the proximal and distal colon. Performance differed significantly between endoscopists; recommended benchmarks for cecal intubation (95%) and adenoma detection (25%) were not met by 6 (17.1%) and 10 of 35 endoscopists (28.6%), respectively. Moderate or severe abdominal pain after colonoscopy was reported by 601 of 3611 participants (16.7%) examined with standard air insufflation vs 214 of 5144 participants (4.2%) examined with carbon dioxide (CO2) insufflation (P < .001). CONCLUSIONS AND RELEVANCE: Colonoscopy screening entails high detection rates in the proximal and distal colon. Participation rates and endoscopist performance vary significantly. Postprocedure abdominal pain is common with standard air insufflation and can be significantly reduced by using CO2. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00883792. PMID- 27214733 TI - Methods of haemophilia care delivery: regular prophylaxis versus episodic treatment. PMID- 27214734 TI - Guidelines for therapy and optimal dosages of coagulation factors for treatment of bleeding and surgery in haemophilia. PMID- 27214735 TI - Viral safety of plasma-derived and recombinant products used in the management of haemophilia A and B. PMID- 27214736 TI - Modern treatment of haemophilia: choice of products for the treatment of haemophilia A and B. PMID- 27214737 TI - Management of patients with HIV and/or hepatitis. PMID- 27214738 TI - Inhibitors of factor VIII and IX. PMID- 27214739 TI - The role of gene therapy in haemophilia. PMID- 27214740 TI - Management of haemophilia in developing countries with available resources. PMID- 27214741 TI - PAUPAR lncRNA suppresses tumourigenesis by H3K4 demethylation in uveal melanoma. AB - Uveal melanoma (UM) is the most common primary intraocular tumour in adults and has a high incidence. Nearly 50% of patients with UM develop metastases after diagnosis. Long noncoding RNAs (lncRNAs) are involved in both oncogenic and tumour suppression pathways. We show that lncRNA PAUPAR is present at low levels in UM tissues and cell lines and modulates the tumourigenesis of UM in vitro and in vivo. The ectopic expression of PAUPAR in UM cells revealed that PAUPAR acts as a necessary UM suppressor and induces the silencing of HES1 expression, which significantly reduces tumour metastasis. Mechanistically, PAUPAR modulates HES1 expression by inhibiting histone H3K4 methylation. These data support a role of this lncRNA as a novel therapeutic target in cancer prevention and treatment. PMID- 27214742 TI - Receptor-Mediated Entry of Pristine Octahedral DNA Nanocages in Mammalian Cells. AB - DNA offers excellent programming properties for the generation of nanometer scaled polyhedral structures with a broad variety of potential applications. Translation to biomedical applications requires improving stability in biological fluids, efficient and selective cell binding, and/or internalization of the assembled DNA nanostructures. Here, we report an investigation on the selective mechanism of cellular uptake of pristine DNA nanocages in cells expressing the receptor "oxidized low-density lipoprotein receptor-1" (LOX-1), a scavenger receptor associated with cardiovascular diseases and, more recently, identified as a tumor marker. For this purpose a truncated octahedral DNA nanocage functionalized with a single biotin molecule, which allows DNA cage detection through the biotin-streptavidin assays, was constructed. The results indicate that DNA nanocages are stable in biological fluids, including human serum, and are selectively bound and very efficiently internalized in vesicles only in LOX-1 expressing cells. The amount of internalized cages is 30 times higher in LOX-1 expressing cells than in normal fibroblasts, indicating that the receptor mediated uptake of pristine DNA nanocages can be pursued for a selective cellular internalization. These results open the route for a therapeutic use of pristine DNA cages targeting LOX-1-overexpressing tumor cells. PMID- 27214743 TI - Unraveling the Alkaline Phosphatase Inhibition, Anticancer, and Antileishmanial Potential of Coumarin-Triazolothiadiazine Hybrids: Design, Synthesis, and Molecular Docking Analysis. AB - A series of new coumarin-triazolothiadiazine hybrid compounds (5a-j) was designed and synthesized by using the molecular hybridization concept. The cyclocondensation reaction involves the coumarinyl 4-amino-1,2,4-triazole and a range of bromo-acetophenones, delivering the desired products in good yields. The structures of the synthesized compounds were established on the basis of spectro analytical data. The prepared compounds were evaluated against alkaline phosphatase (ALP) where compound 5j incorporating bis-coumarinyl motifs at the 3- and 6-positions of the heteroaromatic core turned out to be a potent inhibitor with an IC50 value of 1.15 +/- 1.0 uM. The synthesized compounds were also tested against Leishmania major and 5h was the lead member with an IC50 value of 0.89 +/ 0.08 MUM. Anticancer activity was also determined using kidney fibroblast (BHK 21) and lung carcinoma (H-157) cancer cell lines. Compound 5i showed highest cytotoxic potential against H-157 cells with an IC50 value of 1.01 +/- 0.12 MUM, which is an improved inhibition compared to the standards (vincristine and cisplatin) used in this assay. Molecular docking studies were carried out on the synthesized library of coumarin-triazolothiadiazine hybrids against ALP. Almost all of the compounds showed strong interactions with the key residues of the active site of the receptor. In case of compounds 5a-c, 5h, and 5j, docking results positively complemented the experimental screening. These results provided substantial evidence for the further development of these compounds as potent inhibitors of ALP. PMID- 27214744 TI - Simultaneous Determination of Metformin, Glipizide, Repaglinide, and Glimepiride or Metformin and Pioglitazone by a Validated LC Method: Application in the Presence of Metformin Impurity (1-Cyanoguanidine). AB - A rapid, simple, and precise RPLC method was developed for the simultaneous determination of the widely used oral antidiabetic, metformin hydrochloride (MTF), with some commonly coadministered oral antidiabetics from different pharmacological classes-glipizide (GPZ), pioglitazone hydrochloride (PGZ), glimepiride (GLM), and repaglinide (RPG)-in bulk, laboratory-prepared mixtures and pharmaceutical formulations in the presence of metformin-reported impurity [1 cyanoguanidine (CNG)]. Chromatographic separation was achieved using isocratic elution mode with a mobile phase of acetonitrile: 0.02 M potassium dihydrogen phosphate (pH 3.17; 50-50, v/v) flowing through a CN Phenomenex column (Phenosphere Next, 250 * 4.6 mm, 5 MUm) at a rate of 1.5 mL/min at ambient temperature. UV detection was carried out at 220 nm. The method was validated according to International Conference on Harmonization guidelines. Linearity, accuracy, and precision were satisfactory for concentration ranges: 0.175-350 MUg/mL for MTF, 0.0525-105 MUg/mL for GPZ, 0.125-250 MUg/mL for PGZ, and 0.05-100 MUg/mL for GLM and RPG. Correlation coefficients were >0.99 for all analytes. LOQs were 0.009 MUg/mL for MTF, 0.009 MUg/mL for GPZ, 0.04 MUg/mL for GLM, 0.124 MUg/mL for PGZ, and 0.044 MUg/mL for RPG. The developed method is specific, accurate, and suitable for the QC and routine analysis of the cited drugs in their pharmaceutical products. PMID- 27214745 TI - Seroprevalence of Borrelia burgdorferi in Horses Presented for Coggins Testing in Southwest Virginia and Change in Positive Test Results Approximately 1 Year Later. AB - BACKGROUND: Lyme disease can affect people, dogs, and horses, but it remains poorly understood, especially in the horse. Determining the seroprevalence of Borrelia burgdorferi in horses in different geographic areas will enable better understanding of the epidemiology of the disease, thus improving diagnosis and treatment of affected animals. HYPOTHESIS: To determine the seroprevalence of B. burgdorferi in horses in southwest Virginia. ANIMALS: Horses presented for routine Coggins testing from January 2013 to January 2014 had additional blood drawn for Lyme Multiplex Assay testing. METHODS: Of 492 samples collected, 250 samples were analyzed using the Lyme Multiplex Assay. Of the 83 horses that had positive test results to at least 1 outer surface protein (Osp), 63 were available for follow-up testing 5-17 months later (June 2014). RESULTS: Thirty three percent of horses had positive results for antibodies to at least 1 Osp. Horses with a positive outer surface protein F (OspF) result were older (14.5 +/- 0.79) than horses with a negative OspF result (11.6 +/- 0.53). Of the horses available for follow-up testing, 63% had the same result as that of the initial test. There was no difference in test result between initial and follow-up testing. CONCLUSIONS: Horses seropositive to B. burgdorferi are common in Virginia, and older horses are more likely to have a positive test result for OspF than younger horses. Follow-up testing indicated that the majority of horses that were positive on initial testing did not have a different test result 5-17 months later. PMID- 27214747 TI - Sodium nitrite enhances generation of reactive oxygen species that decrease antioxidant power and inhibit plasma membrane redox system of human erythrocytes. AB - Nitrite/nitrate salts are used in fertilizers and as food preservatives. Human exposure to high levels of nitrite results in its uptake and subsequent entry into blood where it can interact with erythrocytes. We show that treatment of human erythrocytes with sodium nitrite (NaNO2 ) results in a dose-dependent increase in the production of reactive oxygen species. This was accompanied by a decrease in the antioxidant power which lowered the free radical quenching and metal-reducing ability. NaNO2 treatment also inhibited plasma membrane redox system (PMRS) of erythrocytes. These changes increase the susceptibility of erythrocytes to oxidative damage, decrease the antioxidant power of whole blood, and can be a major cause of nitrite-induced cellular toxicity. PMID- 27214746 TI - Incidence, Prevalence, and Survival of Biopsy-Proven Giant Cell Arteritis in Northern Italy During a 26-Year Period. AB - OBJECTIVE: To investigate the epidemiology and mortality in patients with biopsy proven giant cell arteritis (GCA) in northern Italy. METHODS: All patients with incident temporal-artery biopsy-positive GCA, diagnosed between 1986 and 2012 and living in the Reggio Emilia area, were identified by using a pathology register and by reviewing all histopathologic specimens. For each patient, we identified 1 comparison subject from the same geographic area, matched for age and sex. Mortality rates and specific causes of death were reported. RESULTS: There were 285 incident cases of biopsy-proven GCA (210 women) during the 26-year study period. The overall age- and sex-adjusted incidence per 100,000 persons ages >=50 years was 5.8 (95% confidence interval [95% CI] 5.1, 6.5). Incidence was significantly higher in women (7.8 [95% CI 6.7, 8.9]) than in men (3.3 [95% CI 2.6, 4.1]) (P < 0.0001). Annual age- and sex-adjusted incidence rates significantly increased by 15.9% per 3 years from 1986 to 2000, then significantly fell by -4.8% per 3 years from 2001-2012. The prevalence of GCA on December 31, 2012 was 87.9 (95% CI 75.8, 101.4). No significant differences in the mortality rates were observed between GCA patients (4.9 per 100 person-years [95% CI 4.1, 5.8]) and non-GCA subjects (5.6 [95% CI 4.7, 6.6]). No significant differences in causes of death were observed comparing GCA patients to non-GCA subjects. CONCLUSION: This large population-based study of biopsy-proven GCA confirmed the lower incidence of GCA in Mediterranean countries and did not observe any increased mortality risk. PMID- 27214748 TI - Parenteral or enteral nutrition: do you have the choice? AB - PURPOSE OF REVIEW: The review focuses on the use of parenteral nutrition and enteral nutrition in critically ill patients to optimize the nutrition care throughout the ICU stay. The key message is: you have the choice! RECENT FINDINGS: Enteral nutrition has been recommended for critically ill patients, whereas parenteral nutrition has been considered harmful and to be avoided. However, recent studies have challenged this theory. They demonstrated that enteral nutrition is frequently associated with energy and protein undernutrition, whereas parenteral nutrition becomes deleterious only if overfeeding is induced. Measuring energy expenditure by indirect calorimetry, in most cases, enables accurate determination of the energy needs to optimize the prescription of nutrition. Protein targets should also be considered for adequate feeding. Parenteral nutrition can be used as a supplement or as an alternative to enteral nutrition in case of gastrointestinal intolerance, to enable adequate energy, and protein provision. SUMMARY: Parenteral nutrition is a powerful tool to optimize nutrition care of critically ill patients to improve clinical outcome, if prescribed according to the individual needs of the patients. After 3 4 days of attempt to feed enterally, enteral nutrition or parenteral nutrition can be used alternatively or combined, as long as the target is reached with special attention to avoid hypercaloric feeding. PMID- 27214749 TI - Evolution of tonoplast P-ATPase transporters involved in vacuolar acidification. AB - Petunia mutants (Petunia hybrida) with blue flowers defined a novel vacuolar proton pump consisting of two interacting P-ATPases, PH1 and PH5, that hyper acidify the vacuoles of petal cells. PH5 is similar to plasma membrane H(+) P3A ATPase, whereas PH1 is the only known eukaryoticP3B -ATPase. As there were no indications that this tonoplast pump is widespread in plants, we investigated the distribution and evolution of PH1 and PH5. We combined database mining and phylogenetic and synteny analyses of PH1- and PH5-like proteins from all kingdoms with functional analyses (mutant complementation and intracellular localization) of homologs from diverse angiosperms. We identified functional PH1 and PH5 homologs in divergent angiosperms. PH5 homologs evolved from plasma membrane P3A ATPases, acquiring an N-terminal tonoplast-sorting sequence and new cellular function before angiosperms appeared. PH1 is widespread among seed plants and related proteins are found in some groups of bacteria and fungi and in one moss, but is absent in most algae, suggesting that its evolution involved several cases of gene loss and possibly horizontal transfer events. The distribution of PH1 and PH5 in the plant kingdom suggests that vacuolar acidification by P-ATPases appeared in gymnosperms before flowers. This implies that, next to flower color determination, vacuolar hyper-acidification is required for yet unknown processes. PMID- 27214750 TI - Implementing Pharmacogenomics at Your Institution: Establishment and Overcoming Implementation Challenges. PMID- 27214751 TI - The Use of Mobile Health Applications Among Youth and Young Adults Living with HIV: Focus Group Findings. AB - The objective of this study was to conduct focus groups with youth (18-29 years old) living with HIV (YLWH) to better understand preferences for mobile applications in general and to inform the design of a mobile health application aimed at improving retention and engagement in healthcare and adherence to antiretroviral therapy. We conducted four focus groups with YLWH to elicit the names and characteristics of applications that they commonly used, reasons they deleted applications, and the features of an ideal mobile health application. A diverse sample of youth (N = 17) with a mean age of 25 years, 88.2% male, and 29.4% African American participated in four focus groups. Positive attributes of applications included informative, simple, allowing for networking, timely updates, little overlap with other applications, unlimited access to entertainment, and with ongoing advancement. Participants identified several reasons for deleting applications, including engaging in excessive behaviors (e.g., spending money), for hook ups only, too many notifications or restrictions, occupied too much space on device, or required wireless connectivity or frequent updates. Participants suggested that a mobile health application that they would find useful should have the ability to connect to a community of other YLWH, readily access healthcare providers, track personal data and information (such as laboratory data), and obtain health news and education. Privacy was a key factor in a mobile health application for all participants. Researchers can use the information provided by focus group participants in creating mobile health applications for YLWH. PMID- 27214752 TI - 3D Freeze-Casting of Cellular Graphene Films for Ultrahigh-Power-Density Supercapacitors. AB - 3D cellular graphene films with open porosity, high electrical conductivity, and good tensile strength, can be synthesized by a method combining freeze-casting and filtration. The resulting supercapacitors based on 3D porous reduced graphene oxide (RGO) film exhibit extremely high specific power densities and high energy densities. The fabrication process provides an effective means for controlling the pore size, electronic conductivity, and loading mass of the electrode materials, toward devices with high energy-storage performance. PMID- 27214753 TI - Electrochemical Surface Plasmon Resonance Fiber-Optic Sensor: In Situ Detection of Electroactive Biofilms. AB - Spectroelectrochemistry has been found to be an efficient technique for revealing extracellular electron transfer (EET) mechanism of electroactive biofilms (EABs). Herein, we propose a novel electrochemical surface plasmon resonance (EC-SPR) optical fiber sensor for monitoring EABs in situ. The sensor uses a tilted fiber Bragg grating (TFBG) imprinted in a commercial single-mode fiber and coated with nanoscale gold film for high-efficiency SPR excitation. The wavelength shift of the surface plasmon resonance (SPR) over the fiber surface clearly identifies the electrochemical activity of the surface localized (adjacent to the electrode interface) bacterial cells in EABs, which differs from the "bulk" detections of the conventional electrochemical measurements. A close relationship between the variations of redox state of the EABs and the changes of the SPR under potentiostatic conditions has been achieved, pointing to a new way to study the EET mechanism of the EABs. Benefiting from its compact size, high sensitivity, and ease of use, together with remote operation ability, the proposed sensor opens up a multitude of opportunities for monitoring EABs in various hard-to reach environments. PMID- 27214754 TI - Titanium Dioxide/Upconversion Nanoparticles/Cadmium Sulfide Nanofibers Enable Enhanced Full-Spectrum Absorption for Superior Solar Light Driven Photocatalysis. AB - In this work, we demonstrate an electrospinning technique to fabricate TiO2 /upconversion nanoparticles (UCNPs)/CdS nanofibers on large scale. In addition, the as-prepared TiO2 nanofibers are incorporated with a high population of UCNPs and CdS nanospheres; this results in Forster resonance energy-transfer configurations of the UCNPs, TiO2 , and CdS nanospheres that are in close proximity. Hence, strong fluorescent emissions for the Tm(3+) ions including the (1) G4 ->(3) H6 transition are efficiently transferred to TiO2 and the CdS nanoparticles through an energy-transfer process. The as-prepared TiO2 /UCNPs/CdS nanofibers exhibit full-spectrum solar-energy absorption and enable the efficient degradation of organic dyes by fluorescence resonance energy transfer between the UCNPs and TiO2 (or CdS). The UCNPs/TiO2 /CdS nanofibers may also have enhanced energy-transfer efficiency for wide applications in solar cells, bioimaging, photodynamics, and chemotherapy. PMID- 27214755 TI - Enantiomeric high-performance liquid chromatography resolution and absolute configuration of 6beta-benzoyloxy-3alpha-tropanol. AB - The absolute configuration of the naturally occurring isomers of 6beta-benzoyloxy 3alpha-tropanol (1) has been established by the combined use of chiral high performance liquid chromatography with electronic circular dichroism detection and optical rotation detection. For this purpose (+/-)-1, prepared in two steps from racemic 6-hydroxytropinone (4), was subjected to chiral high-performance liquid chromatography with electronic circular dichroism and optical rotation detection allowing the online measurement of both chiroptical properties for each enantiomer, which in turn were compared with the corresponding values obtained from density functional theory calculations. In an independent approach, preparative high-performance liquid chromatography separation using an automatic fraction collector, yielded an enantiopure sample of OR (+)-1 whose vibrational circular dichroism spectrum allowed its absolute configuration assignment when the bands in the 1100-950 cm(-1) region were compared with those of the enantiomers of esters derived from 3alpha,6beta-tropanediol. In addition, an enantiomerically enriched sample of 4, instead of OR (+/-)-4, was used for the same transformation sequence, whose high-performance liquid chromatography follow up allowed their spectroscopic correlation. All evidences lead to the OR (+) (1S,3R,5S,6R) and OR (-)-(1R,3S,5R,6S) absolute configurations, from where it follows that samples of 1 isolated from Knightia strobilina and Erythroxylum zambesiacum have the OR (+)-(1S,3R,5S,6R) absolute configuration, while the sample obtained from E. rotundifolium has the OR (-)-(1R,3S,5R,6S) absolute configuration. PMID- 27214756 TI - Total Economic Consequences of an Influenza Outbreak in the United States. AB - Pandemic influenza represents a serious threat not only to the population of the United States, but also to its economy. In this study, we analyze the total economic consequences of potential influenza outbreaks in the United States for four cases based on the distinctions between disease severity and the presence/absence of vaccinations. The analysis is based on data and parameters on influenza obtained from the Centers for Disease Control and the general literature. A state-of-the-art economic impact modeling approach, computable general equilibrium, is applied to analyze a wide range of potential impacts stemming from the outbreaks. This study examines the economic impacts from changes in medical expenditures and workforce participation, and also takes into consideration different types of avoidance behavior and resilience actions not previously fully studied. Our results indicate that, in the absence of avoidance and resilience effects, a pandemic influenza outbreak could result in a loss in U.S. GDP of $25.4 billion, but that vaccination could reduce the losses to $19.9 billion. When behavioral and resilience factors are taken into account, a pandemic influenza outbreak could result in GDP losses of $45.3 billion without vaccination and $34.4 billion with vaccination. These results indicate the importance of including a broader set of causal factors to achieve more accurate estimates of the total economic impacts of not just pandemic influenza but biothreats in general. The results also highlight a number of actionable items that government policymakers and public health officials can use to help reduce potential economic losses from the outbreaks. PMID- 27214757 TI - Nonstandard Exception Requests Impact Outcomes for Pediatric Liver Transplant Candidates. AB - Nonstandard exceptions requests (NSERs), in which transplant centers appeal on a case-by-case basis for Pediatric End-Stage Liver Disease/Mayo End-Stage Liver Disease points, have been highly utilized for pediatric liver transplant candidates. We evaluated whether NSE outcomes are associated with waitlist and posttransplant mortality. United Network for Organ Sharing (UNOS) Scientific Registry of Transplant Recipients data on pediatric liver transplant candidates listed in 2009-2014 were analyzed after excluding those granted automatic UNOS exceptions. Of 2581 pediatric waitlist candidates, 44% had an NSE request. Of the 1134 children with NSERs, 93% were approved and 7% were denied. For children 2-18 years at listing, NSER denial increased the risk of waitlist mortality or removal for being too sick (subhazard ratio 2.99, 95% confidence interval [CI] 1.26-7.07, p = 0.01 in multivariate analysis). For children younger than 2 years, NSER denial did not impact waitlist mortality/removal. Children with NSER approved had reduced risk of graft loss 3 years posttransplant in univariate but not multivariable analysis (odds ratio 0.73, 95% CI 0.53-1.01, p = 06). Those with NSER denial had a higher risk of posttransplant death than those with no NSER (hazard ratio 2.43, 95% CI 0.99-5.95, p = 0.05, multivariable analysis), but NSER approval did not impact posttransplant death. Further research on NSER utilization in pediatric liver transplant is needed to optimize organ allocation and outcomes for children. PMID- 27214758 TI - Contribution of next generation sequencing to early detection of cytomegalovirus UL97 emerging mutants and viral subpopulations analysis in kidney transplant recipients. AB - BACKGROUND: Cytomegalovirus (CMV) is the major opportunistic virus encountered after transplantation, and resistant variants challenge antiviral treatment. We studied the emergence and evolution of the canonical UL97 L595S mutation in four kidney recipients by comparing Sanger sequencing with a specific next-generation sequencing (NGS) assay, and assessed the global evolution of UL97 gene variability. STUDY DESIGN: Plasmids harbouring wild-type and/or L595S mutated UL97 genes were used to assess the analytical performances of NGS assay. UL97 gene was retrospectively analysed in patients' samples drawn during CMV infection follow-up, Shannon entropy (Sn) was calculated and phylogenetic analyses were performed. RESULTS: Wild-type and L595S plasmids PCR products were mixed to obtain L595S concentrations of 0, 1, 2, 5, 10, 20 and 100%. Mean triplicate NGS results were 0, 0.71, 1.79, 5.30, 13.17, 17 and 100%, respectively, while Sanger sequencing only detected L595S when above 20%. The NGS mean error rate was 0.196+/-0.07%. In the four patients, emergence of L595S mutation under ganciclovir treatment was followed-up. After foscarnet rescue therapy, leading to undetectable CMV viral load, in two patients, L595S mutant re-emerged, but was only detected by NGS technology (14% and 9.6%). Using NGS data, phylogenetic trees and Sn showed a complex evolution of concomitant viral subpopulations. CONCLUSIONS: NGS technology allowed a deeper discrimination of the emergence and persistence of a drug resistance mutation, which could be pertinent to investigate when routine Sanger sequencing detects only wild-type strains. Moreover, NGS improved sensitivity helps in studying viral abundance, dynamics and diversity, less approachable with Sanger sequencing. PMID- 27214759 TI - Quantitative definition and monitoring of the host cell protein proteome using iTRAQ - a study of an industrial mAb producing CHO-S cell line. AB - There are few studies defining CHO host cell proteins (HCPs) and the flux of these throughout a downstream purification process. Here we have applied quantitative iTRAQ proteomics to follow the HCP profile of an antibody (mAb) producing CHO-S cell line throughout a standard downstream purification procedure consisting of a Protein A, cation and anion exchange process. We used both 6 sample iTRAQ experiment to analyze technical replicates of three samples, which were culture harvest (HCCF), Protein A flow through and Protein A eluate and an 8 sample format to analyze technical replicates of four sample types; HCCF compared to Protein A eluate and subsequent cation and anion exchange purification. In the 6 sample iTRAQ experiment, 8781 spectra were confidently matched to peptides from 819 proteins (including the mAb chains). Across both the 6 and 8 sample experiments 936 proteins were identified. In the 8 sample comparison, 4187 spectra were confidently matched to peptides from 219 proteins. We then used the iTRAQ data to enable estimation of the relative change of individual proteins across the purification steps. These data provide the basis for application of iTRAQ for process development based upon knowledge of critical HCPs. PMID- 27214760 TI - Aqueous solubilization of C60 fullerene by natural protein surfactants, latherin and ranaspumin-2. AB - C60 fullerene is not soluble in water and dispersion usually requires organic solvents, sonication or vigorous mechanical mixing. However, we show here that mixing of pristine C60 in water with natural surfactant proteins latherin and ranaspumin-2 (Rsn-2) at low concentrations yields stable aqueous dispersions with spectroscopic properties similar to those previously obtained by more vigorous methods. Particle sizes are significantly smaller than those achieved by mechanical dispersion alone, and concentrations are compatible with clusters approximating 1:1 protein:C60 stoichiometry. These proteins can also be adsorbed onto more intractable carbon nanotubes. This promises to be a convenient way to interface a range of hydrophobic nanoparticles and related materials with biological macromolecules, with potential to exploit the versatility of recombinant protein engineering in the development of nano-bio interface devices. It also has potential consequences for toxicological aspects of these and similar nanoparticles. PMID- 27214761 TI - Molecular medicine - To be or not to be. AB - Molecular medicine is founded on the synergy between Chemistry, Physics, Biology and Medicine, with the ambitious goal of tackling diseases from a molecular perspective. This Review aims at retracing a personal outlook of the birth and development of molecular medicine, as well as at highlighting some of the most urgent challenges linked to aging and represented by incurable neurodegenerative diseases caused by protein misfolding. Furthermore, we emphasize the emerging role of the retromer dysfunctions and improper protein sorting in Alzheimer's disease and other important neurological disordered. PMID- 27214762 TI - Once daily vs multiple daily mesalamine therapy for mild to moderate ulcerative colitis: a meta-analysis. AB - AIM: 5-Aminosalicylic acid is the first-line drug for mild to moderate ulcerative colitis (UC). The most commonly used 5-aminosalicylic acid is mesalamine. Several systematic reviews have demonstrated that mesalamine is effective in inducing and maintaining remission. Efficacy, safety and adherence to once daily (OD) and multiple daily (MD) dosing of mesalamine for the induction and maintenance of remission in mild to moderate UC were systematically reviewed and compared. METHOD: PubMed, Embase and the Cochrane Central Register of Controlled Trials were searched from inception to November 2014. Only randomized controlled trials were considered eligible. STATA software (version 12.0) was used to calculate the pooled risk ratios with 95% confidence interval. RESULTS: Seventeen randomized studies containing 5439 patients were identified. No significant differences were noted in comparisons between OD and MD dosing for maintenance and induction of remission. No significant differences were noted in rates of medication adherence or adverse events between OD and MD dosing. With regard to mesalamine suppository, no significant differences were noted for comparisons between dosing regimens and adverse events for induction of remission. CONCLUSION: OD dose of mesalamine is as effective and safe as MD doses for the induction and maintenance treatment of mild to moderate UC. OD mesalamine given as a suppository can attain the same effect and safety as MD mesalamine in inducing remission of mild to moderate ulcerative colitis. PMID- 27214763 TI - [FeFe]-Hydrogenase with Chalcogenide Substitutions at the H-Cluster Maintains Full H2 Evolution Activity. AB - The [FeFe]-hydrogenase HYDA1 from Chlamydomonas reinhardtii is particularly amenable to biochemical and biophysical characterization because the H-cluster in the active site is the only inorganic cofactor present. Herein, we present the complete chemical incorporation of the H-cluster into the HYDA1-apoprotein scaffold and, furthermore, the successful replacement of sulfur in the native [4FeH ] cluster with selenium. The crystal structure of the reconstituted pre mature HYDA1[4Fe4Se]H protein was determined, and a catalytically intact artificial H-cluster variant was generated upon in vitro maturation. Full hydrogen evolution activity as well as native-like composition and behavior of the redesigned enzyme were verified through kinetic assays, FTIR spectroscopy, and X-ray structure analysis. These findings reveal that even a bioinorganic active site with exceptional complexity can exhibit a surprising level of compositional plasticity. PMID- 27214764 TI - Corrigendum: CpG island erosion, polycomb occupancy and sequence motif enrichment at bivalent promoters in mammalian embryonic stem cells. PMID- 27214765 TI - Combined-Modality Therapy With Radiation and Chemotherapy for Elderly Patients With Glioblastoma in the Temozolomide Era: A National Cancer Database Analysis. AB - IMPORTANCE: The optimal management for elderly patients with glioblastoma (GBM) is controversial. Following maximal safe resection or biopsy, accepted treatment paradigms for elderly patients with GBM include combined-modality therapy (CMT) with both radiotherapy (RT) and chemotherapy (CT), RT alone, and CT alone. OBJECTIVE: To evaluate the overall survival (OS) outcomes associated with RT, CT, and CMT for elderly patients with GBM in the modern temozolomide era. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study of a prospectively maintained, multi-institutional national cancer registry, the National Cancer Database was queried for elderly patients (>=65 years) with newly diagnosed GBM from January 1, 2005, through December 31, 2011, with complete data sets for RT, CT, tumor resection, Charlson-Deyo comorbidity scores, age, sex, and year of diagnosis. Data analysis was performed from October 2015 through December 2015. INTERVENTIONS: Combined-modality therapy, RT, CT. MAIN OUTCOMES AND MEASURES: Survival by treatment cohort was estimated using the Kaplan-Meier method and analyzed using the log rank test, univariate and multivariate Cox models, and propensity score-matched analyses. RESULTS: A total of 16 717 patients (median [range] age, 73 [65->=90 y]; 8870 [53%] male) were identified. The median OS by treatment was 9.0 (95% CI, 8.8-9.3) months with CMT (8435 patients), 4.7 (95% CI, 4.5-5.0) months with RT alone (1693 patients), 4.3 (95% CI, 4.0-4.7) months with CT alone (1018 patients), and 2.8 (95% CI, 2.8-2.9) months with no therapy (5571 patients) (P < .001). On multivariate analysis, CMT was superior to both CT alone (hazard ratio, 1.50 [95% CI, 1.40-1.60]; P < .001) and RT alone (hazard ratio, 1.47 [95% CI, 1.39-1.55]; P < .001), whereas no differences were observed between CT alone vs RT alone (P = .60). Propensity score-matched analyses redemonstrated improved OS with CMT over CT alone (P = .002) and RT alone (P < .001); no differences were observed between CT alone vs RT alone (P = .44). On subgroup analyses, a consistent OS advantage was observed with CMT over both CT alone and RT alone across each age stratification (65-69, 70-74, 75-79, and >=80 years) and among patients treated with or without tumor resection (all P < .001). CONCLUSIONS AND RELEVANCE: In this analysis of multimodality therapy for elderly patients with GBM, OS was superior with CMT compared with CT alone and RT alone. Survival was similar between CT alone and RT alone, and both CT alone and RT alone were superior to no therapy. This analysis supports the use of CMT for suitable elderly candidates. PMID- 27214766 TI - Parkinsonian Rest Tremor Is Associated With Modulations of Subthalamic High Frequency Oscillations. AB - BACKGROUND: High frequency oscillations (>200 Hz) have been observed in the basal ganglia of PD patients and were shown to be modulated by the administration of levodopa and voluntary movement. OBJECTIVE: The objective of this study was to test whether the power of high-frequency oscillations in the STN is associated with spontaneous manifestation of parkinsonian rest tremor. METHODS: The electromyogram of both forearms and local field potentials from the STN were recorded in 11 PD patients (10 men, age 58 [9.4] years, disease duration 9.2 [6.3] years). Patients were recorded at rest and while performing repetitive hand movements before and after levodopa intake. High-frequency oscillation power was compared across epochs containing rest tremor, tremor-free rest, or voluntary movement and related to the tremor cycle. RESULTS: We observed prominent slow (200-300 Hz) and fast (300-400 Hz) high-frequency oscillations. The ratio between slow and fast high-frequency oscillation power increased when tremor became manifest. This increase was consistent across nuclei (94%) and occurred in medication ON and OFF. The ratio outperformed other potential markers of tremor, such as power at individual tremor frequency, beta power, or low gamma power. For voluntary movement, we did not observe a significant difference when compared with rest or rest tremor. Finally, rhythmic modulations of high-frequency oscillation power occurred within the tremor cycle. CONCLUSIONS: Subthalamic high frequency oscillation power is closely linked to the occurrence of parkinsonian rest tremor. The balance between slow and fast high-frequency oscillation power combines information on motor and medication state. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27214768 TI - Editorial. PMID- 27214767 TI - Comparing a tapering strategy to the standard dosing regimen of TNF inhibitors in rheumatoid arthritis patients with low disease activity. AB - OBJECTIVES: The aim of this study is to compare clinical outcomes, incidence of flares and administered drug reduction between rheumatoid arthritis (RA) patients under TNF inhibitors (TNFi) tapering strategy and RA patients on standard regimen. METHODS: Two groups of RA patients on TNFi with DAS28<3.2 were compared: the tapering group (TG: 67 pts from Spain) and the control group with standard therapy regimen (CG: 77 pts from the Netherlands). DAS28 was measured at different time points: visit 0 (prior starting TNFi), visit 1 (prior to start tapering in TG and with DAS28<3.2 in TG and CG), visit 2 (6 months after visit 1), visit 3 (1 year after visit 1), visit 4 (the last visit available after visit 1) and visit-flare (visit with the worst flare between visit 1 and visit 4). RESULTS: Despite the reduction of administered drug at visit 4 in the TG (interval elongation of 32.8% in infliximab, 52.9% in adalimumab and 52.6% in etanercept), the DAS28 remained similar between groups at the end of the study (DAS28: 2.7+/-0.9 in TG vs. 2.5+/-1 in CG, p=0.1). No differences were seen in the number of patients with flares [26/67 (38.9%) in the TG vs. 30/77 (39%) in the CG, p=0.324] and only nineteen out of 136 patients (14%) had anti-drug antibodies at the end of the study. CONCLUSIONS: The tapering strategy of TNFi in RA patients result in a reduction of the drug administered, while the disease control is not worse than patients on the standard regimen. PMID- 27214769 TI - Official Call: 2016 Annual Business Meeting of the American Osteopathic Association. PMID- 27214770 TI - Proposed Amendments to the AOA Constitution, Bylaws, and Code of Ethics. PMID- 27214771 TI - Glycated Hemoglobin Testing to Identify Undiagnosed Diabetes Mellitus in the Inpatient Setting. AB - BACKGROUND: Hyperglycemia is commonly seen in hospitalized patients. Glycated hemoglobin (HbA1c) correlates with the average blood glucose level over the previous 8 to 12 weeks. Thus, an HbA1c test offers a longitudinal view that reduces etiologic ambiguity of disease. Screening of HbA1c levels plays an important role in the diagnosis and management of diabetes mellitus in the outpatient setting but remains underused in the evaluation of hyperglycemia with undiagnosed diabetes in the inpatient setting. The underuse of the HbA1c test may be a missed opportunity for early diabetes detection in the hospital. OBJECTIVE: To examine the use of HbA1c tests in identifying previously undiagnosed diabetes mellitus among patients with hyperglycemia in a rural inpatient setting. METHODS: A retrospective review of medical records of hospitalized patients with hyperglycemia in a rural community teaching hospital in the Midwest. Descriptive and inferential statistical methods were used. RESULTS: Medical records of 348 unique patients with hyperglycemia were reviewed. Fifty patients treated for hyperglycemia had medical records with no known history of diabetes (NKHD). Of the 50 patients with NKHD, 31 (62%) had an HbA1c test. Of the 31 patients tested, 6 (19%) had HbA1c levels consistent with the diagnosis of prediabetes, and 18 (58%) had levels consistent with diabetes. Seventeen (55%) of the 31 patients had a discharge diagnosis that included diabetes. Of the 19 patients with NKHD who did not have an HbA1c test, 2 (11%) received a discharge diagnosis that included diabetes. CONCLUSION: Hospitalized patients with NKHD and hyperglycemia are more likely to receive an appropriate diagnosis if HbA1c is measured. Failing to fully use HbA1c tests in the inpatient setting constitutes a missed opportunity to distinguish transient hyperglycemia from chronic disease. The HbA1c level can elucidate the course of dys-glycemia and trigger mechanisms for timely intervention. PMID- 27214772 TI - Correlation of Somatic Dysfunction With Gastrointestinal Endoscopic Findings: An Observational Study. AB - CONTEXT: Gastrointestinal (GI) endoscopy provides a novel means of correlating visceral abnormalities with somatic dysfunction. OBJECTIVE: To assess the correlation of palpatory findings of somatic dysfunction with GI abnormalities determined by endoscopy and to identify which types of somatic dysfunction were most commonly correlated with GI abnormalities. METHODS: In this observational, cross-sectional study, participants who were scheduled to receive an esophagogastroduodenoscopy (EGD), colonoscopy, or both were examined by 2 osteopathic physicians immediately prior to endoscopy for the presence of vertebral tenderness, asymmetry, restricted range of motion, and tissue texture abnormalities (TART findings); tenderness of anterior Chapman reflex points; and tenderness of visceral sphincters. Each type of somatic dysfunction and the somatic dysfunction burden (sum of findings) were compared with the type of endoscopic procedure and abnormal endoscopic findings. RESULTS: Sixty-six adults participated: 43 received an EGD, 40 received a colonoscopy, and 17 received both. The incidence of vertebral TART findings ranged from 70% at T12 to 98% at the sacrum. Participants who received only EGD had a higher somatic dysfunction burden than those who received only colonoscopy and those who received both procedures (P=.002). The incidence of abnormal endoscopic findings ranged from 98% in the stomach to 0% at the ileocecal valve. Statistically significant positive associations were found between specific vertebral TART findings and abnormalities of the esophagus, gastroesophageal junction, pylorus, ascending colon, and sigmoid colon; specific Chapman reflex point tenderness and abnormalities of the esophagus, gastroesophageal junction, pylorus, ascending colon, descending colon, sigmoid colon, and rectum; and specific visceral sphincter tenderness and abnormalities of the duodenum, ascending colon, and sigmoid colon. CONCLUSIONS: The current study found numerous associations between somatic dysfunction and abnormal endoscopic findings. However, the high incidence of vertebral TART findings and the lack of normal controls for many GI regions made establishing meaningful relationships between specific somatic dysfunction and specific GI abnormalities challenging. Future investigations should include more participants to ensure a higher number of normal endoscopic findings and limit the physical examination to elements of somatic dysfunction with a high level of variability between vertebrae within an individual participant and between participants, such as tenderness and tissue texture abnormalities. (ClinicalTrials.gov number NCT01394198). PMID- 27214773 TI - Cancer Mortality Trends in Medically Underserved Counties in Virginia. AB - CONTEXT: Cancer mortality rates in the United States have improved during the past 40 years. The improvement in mortality rates is not equal for all types of cancer or all geographic locations, however. OBJECTIVE: To compare trends in cancer mortality rates in Virginia counties from 2005 through 2009. METHODS: Publicly available data from the National Cancer Institute, the State Cancer Profile, and the Virginia Department of Health were accessed for this analysis. For all counties in Virginia with all-cancer and lung cancer mortality data available, the authors compared counties considered medically underserved areas (VMUAs) with non-VMUAs to examine trends in cancer mortality rates that increased, remained stable, or decreased from 2005 through 2009. The significance level for all data was set at P<=.05. RESULTS: Of 136 counties in Virginia, 134 had all-cancer and 123 had lung cancer mortality data available. The VMUAs had a 48% lower decreasing all-cancer mortality rate than non-VMUAs (13 [26%] vs 37 [74%], respectively; P=.004). Non-VMUAs had a 33.3% higher stable all-cancer mortality rate than VMUAs (50 [66.6%] vs 25 [33.3%], respectively; P=.004) and a 55.2% higher lung cancer mortality rate (17 [22.4%] vs 59 [77.6%], respectively; P<.001). CONCLUSION: The all-cancer and lung cancer mortality rates were found to either remain stable or, in the case of all-cancer mortality, to increase in VMUAs. PMID- 27214774 TI - Comprehensive Evaluation for Obesity: Beyond Body Mass Index. AB - Many factors contribute to the diagnosis of obesity in a patient. Anthropometric measurements, such as the waist circumference and percentage of body fat, are used in the newly released obesity algorithm to risk stratify patients. Staging methods, which use the identification of comorbidities and disease burden to assess the severity of obesity, can result in treating a patient sooner than if the traditional body mass index is used. Obesity is a growing concern in the medical field, and providing additional avenues through which to diagnose obesity and address obesity-related health risks can improve prevention efforts and lead to expedited weight management. Obesity is a growing concern in the medical field, and providing additional avenues through which to diagnose obesity and address obesity-related health risks can improve prevention efforts and lead to expedited weight management. PMID- 27214775 TI - Ten Tips for Maximizing the Effectiveness of Emergency Medicine Procedure Laboratories. AB - Incorporating simulation-based medical education techniques is paramount to ongoing training of emergency physicians. Effective procedure laboratories give learners hands-on experience in life-saving procedures they may otherwise not have clinical exposure to and also prevent skill decay. Using procedural education, adult learning theory, deliberate practice, and mastery learning strategies, the authors offer 10 tips to educators for designing an effective emergency medicine procedure laboratory. PMID- 27214776 TI - Osteopathic Manipulative Treatment Technique Scores on the COMLEX-USA Level 2-PE: An Analysis of the Skills Assessed. AB - CONTEXT: The National Board of Osteopathic Medical Examiners uses the Osteopathic Manipulative Treatment (OMT) Global Rating Tool to score candidate performance in OMT during standardized patient encounters. To the authors' knowledge, no validity research has been published on the underlying constructs measured by this instrument to date. OBJECTIVE: To evaluate whether the OMT Global Rating Tool measures 1 holistic skill or multiple skill sets. METHODS: Structural equation models were fit to data from first-time test-takers who took the Comprehensive Osteopathic Medical Licensing Examination-USA Level 2-Performance Evaluation (COMLEX-USA Level 2-PE) between July 7, 2014, and April 30, 2015. Two theoretical models were evaluated: a model that posited a single underlying skill set, and a model that posited 2 related but distinct skill sets. RESULTS: The 1 factor and 2-factor models were fit to data from 4673 third- and fourth-year osteopathic medical students. Fit statistics indicated that the data were best fit by a model representing 2 factors: pre- and post-OMT technique assessment and OMT technique (r=0.47). CONCLUSION: The OMT Global Rating Tool seems to measure 2 distinct but related skills. Although the results of this study are applicable to broad populations and cannot be used to provide skill-specific subscores, it might be helpful to remediation efforts to target pre- and post-OMT technique assessments and OMT techniques as distinct areas for intervention. PMID- 27214777 TI - Cullen Sign and Grey Turner Sign Revisited. AB - Cullen sign and Grey Turner sign, named after Thomas Stephen Cullen, MB, and George Grey Turner, MBBS, respectively, are signs of abdominal wall hemorrhage and are generally associated with acute pancreatitis. However, the research from which these signs arose was documented long before Cullen and Grey Turner made their contributions. The present article examines the history, pathologic mechanisms, and clinical application of these signs in relation to acute pancreatitis and ectopic pregnancy. PMID- 27214778 TI - Disseminated Varicella-Zoster Virus After Vaccination in an Immunocompetent Patient. AB - Severe adverse events associated with varicella-zoster virus (VZV) vaccination are rare. The authors describe a 53-year-old woman with no known immunodeficiency who presented with diffuse pruritic rash 17 days after receiving the varicella virus vaccine live. She had a low level of white blood cells and received a diagnosis of thrombocytopenia with elevated aminotransferase levels. Punch biopsy demonstrated positive VZV immunostaining and viral culture positive for VZV. After treatment with acyclovir, her rash improved and her white blood cell and platelet counts returned to normal. Mild reactions to vaccines including localized rash are well recognized. Disseminated infections have been reported in patients with congenital and acquired immunodeficiency, but systemic postvaccination infections are rare in immunocompetent adults. This case highlights the importance of recognizing adverse events associated with vaccination. PMID- 27214779 TI - Gout Flare With a Draining Tophus. PMID- 27214780 TI - Phosphono Bisbenzguanidines as Irreversible Dipeptidomimetic Inhibitors and Activity-Based Probes of Matriptase-2. AB - Matriptase-2, a type II transmembrane serine protease, plays a key role in human iron homeostasis. Inhibition of matriptase-2 is considered as an attractive strategy for the treatment of iron-overload diseases, such as hemochromatosis and beta-thalassemia. In the present study, synthetic routes to nine dipeptidomimetic inactivators were developed. Five active compounds (41-45) were identified and characterized kinetically as irreversible inhibitors of matriptase-2. In addition to a phosphonate warhead, these dipeptides possess two benzguanidine moieties as arginine mimetics to provide affinity for matriptase-2 by binding to the S1 and S3/S4 subpockets, respectively. This binding mode was strongly supported by covalent docking analysis. Compounds 41-45 were obtained as mixtures of two diastereomers and were therefore separated into the single epimers. Compound 45 A, with S configuration at the N-terminal amino acid and R configuration at the phosphonate carbon atom, was the most potent matriptase-2 inactivator with a rate constant of inactivation of 2790 m(-1) s(-1) and abolished the activity of membrane-bound matriptase-2 on the surface of intact cells. Based on the chemotyp of phosphono bisbenzguanidines, the design and synthesis of a fluorescent probe (51 A) by insertion of a coumarin label is described. The in-gel fluorescence detection of matriptase-2 was demonstrated by applying 51 A as the first activity based probe for this enzyme. PMID- 27214781 TI - Synthetic Two-Dimensional Materials: A New Paradigm of Membranes for Ultimate Separation. AB - Microporous membranes act as selective barriers and play an important role in industrial gas separation and water purification. The permeability of such membranes is inversely proportional to their thickness. Synthetic two-dimensional materials (2DMs), with a thickness of one to a few atoms or monomer units are ideal candidates for developing separation membranes. Here, groundbreaking advances in the design, synthesis, processing, and application of 2DMs for gas and ion separations, as well as water desalination are presented. This report describes the syntheses, structures, and mechanical properties of 2DMs. The established methods for processing 2DMs into selective permeation membranes are also discussed and the separation mechanism and their performances addressed. Current challenges and emerging research directions, which need to be addressed for developing next-generation separation membranes, are summarized. PMID- 27214782 TI - Facebook use and its relationship with sport anxiety. AB - Social media (e.g., Facebook and Twitter) use has increased considerably since its inception; however, research examining the relationship between social media use and sport has not progressed as rapidly. The purpose of the current study was to explore the prevalence rates of Facebook use among athletes around and during sport competitions and to investigate the relationships between sport anxiety and Facebook use. Two hundred and ninety-eight athletes of varying levels completed measures for sport anxiety and Facebook use, which included descriptive information about Facebook use prior to, during and following competitions. Results indicated that 31.9% of athletes had used Facebook during a competition and 68.1% had accessed Facebook within 2 h prior to competition. Time spent on Facebook prior to competition was significantly (and positively) correlated with the concentration disruption component of sport anxiety. Furthermore, regression analyses revealed that having push notifications enabled on an athletes' phone predicted 4.4% of the variability in sport anxiety. The percentage of athletes who accessed Facebook within 2 h of, or during, a competition is somewhat alarming considering the importance of psychological preparation in sport, which may compromise optimal psychological readiness and may lead to increased sport anxiety. PMID- 27214783 TI - Hypoglossal nerve palsy: 245 cases. AB - INTRODUCTION: Apart from a case series of 100 subjects in 1996 and several small cohorts, there have been no large retrospective series of cranial nerve XII (CN XII) palsy. METHODS: From 1984 to 2014, 245 cases of CN XII palsy were identified via retrospective chart review using historical and exam findings that confirmed the diagnosis. In addition to clinical characteristics, univariate and multivariate models were investigated to predict neoplastic CN XII palsy. RESULTS: Major etiologic categories included: postoperative (29.3%), idiopathic (15.1%), primary neoplastic (14.2%), metastatic malignancy (13.0%), inflammatory (7.3%), radiation (6.1%), and traumatic (4.1%). A multivariate model revealed male gender and a personal history of cancer as predictive of neoplastic CN XII palsy. CONCLUSIONS: The most frequent etiologies and disease categories of CN XII palsy were identified, and male gender and personal history of cancer were found to be predictive of a neoplastic cause of CN XII palsy. Muscle Nerve 54: 1050 1054, 2016. PMID- 27214784 TI - Janus emulsion mediated porous scaffold bio-fabrication. AB - A three dimensional biopolymer network structure with incorporated nano-porous calcium phosphate (CaP) balls was fabricated by using gelatin-chitosan (GC) polymer blend and GC stabilized olive/silicone oil Janus emulsions, respectively. The emulsions were freeze-dried, and the oil droplets were washed out in order to prepare porous scaffolds with larger surface area. The morphology, pore size, chemical composition, thermal and swelling behavior was studied by Scanning Electron Microscopy (SEM), Fourier Transform Infrared Spectroscopy (FTIR) and micro-Differential Scanning Calorimetry (micro-DSC). Microscopic analysis confirmed that the pore size of the GC based sponges after freeze-drying may be drastically reduced by using Janus emulsions. Besides, the incorporation of nanoporous calcium phosphate balls is also lowering the pore size and enhancing thermal stability. PMID- 27214785 TI - Composite bi-layered erodible films for potential ocular drug delivery. AB - Bi-layered hydroxypropylmethylcellulose and Eudragit based films were formulated as potential ocular drug delivery systems using chloramphenicol as a model antibiotic. Films were plasticized with polyethylene glycol 400 present in the Eudragit layer or both Eudragit and hydroxypropylmethylcellulose layers, and loaded with chloramphenicol (0.5% w/v in solution) in the hydroxypropylmethylcellulose layer. The weight, thickness and folding endurance of the optimized formulations were measured and further characterised for transparency, tensile, mucoadhesive, swelling and in vitro drug dissolution properties. The physical form of chloramphenicol within the films was evaluated using differential scanning calorimetry (DSC), and X-ray diffraction (XRD), complimented with scanning electron microscopy and energy dispersive X-ray spectroscopy. Fourier transform infrared spectroscopy was used to assess the interactions between the drug and the film components and confirm chloramphenicol's presence within the sample. Optimum films showed high transparency (>=80% transmittance), ease of peeling from Petri dish and folding endurance above 250. Average thickness was lower than contact lenses (0.4-1mm), confirming them as thin ocular films. The tensile properties showed a good balance between toughness and flexibility, and mucoadhesivity showed that they could potentially adhere to the ocular surface for prolonged periods. The drug loaded films showed swelling capacity that was greater than 300% of their original weight. The physical form of chloramphenicol within the films was amorphous (DSC and XRD) whilst in vitro drug dissolution showed sustained drug release from the films for four hours, before complete erosion. The chloramphenicol loaded films represent a potential means of treating common eye infections. PMID- 27214786 TI - Chitosan nanoparticles for lipophilic anticancer drug delivery: Development, characterization and in vitro studies on HT29 cancer cells. AB - The aim of this study was to develop chitosan-based nanoparticles that could encapsulate lipophilic molecules and deliver them to cancer cells. Nanoparticles were prepared with different molar ratios of chitosan, hyaluronic acid and sulphobutyl-ether-beta-cyclodextrin and with or without curcumin. The nanosystems were characterized in terms of their size, zeta potential, morphology, encapsulation efficiency and stability in different media. Intestinal epithelial and colorectal cancer cells were treated with unloaded nanoparticles in order to study their effect on cellular membrane organization and ROS production. Finally, in vitro assays on both cellular lines were performed in order to evaluate the ability of nanoparticles to promote curcumin internalization and to study their effect on cell proliferation and cell cycle. Results show that nanoparticles were positively charged and their size increased with the increasing amounts of the anionic excipient. Nanoparticles showed good encapsulation efficiency and stability in water. Unloaded nanoparticles led to a change in lipid organization in the cellular membrane of both cell lines, without inducing ROS generation. Confocal microscopy, cell proliferation and cell cycle studies allowed the selection of the best formulation to limit curcumin cytotoxicity in normal intestinal epithelial cells and to reduce cancer cell proliferation. The latter was the result of the increase of expression for genes involved in apoptosis. PMID- 27214787 TI - Aminodextran polymer-functionalized reactive magnetic emulsions for potential theranostic applications. AB - Aminodextran (AMD) polymer was prepared via chemical grafting of hexamethylenediamine on oxidized dextran. Magnetic latex particles were successfully obtained by adsorption of positively charged AMD on negatively charged submicron magnetic emulsion. The adsorbed amount was found to be ranged from 20 to 1280mg of AMD per gram of dried magnetic dispersion. The AMD-coated magnetic emulsions were characterized by positive zeta potential in the pH range from 3 to 9 compared to bare seed magnetic emulsion. All the samples showed to be superparamagnetic property, even after the adsorption of the polymer. The developed magnetic submicron particles exhibited good potential for in vivo biomedical diagnosis applications as demonstrated by their higher T2 contrast ability compared to Gd in magnetic resonance imaging (MRI) and hyperthermia. PMID- 27214789 TI - Characterization of the Fluorescence Properties of 4-Dialkylaminochalcones and Investigation of the Cytotoxic Mechanism of Chalcones. AB - Understanding the mechanisms responsible for the various biological activities of chalcones, particularly the direct cellular targets, presents an unmet challenge. Here, we prepared a series of fluorescent chalcone derivatives as chemical probes for their mechanistic investigation. Upon systematic physicochemical characterization, we explored their potential to elucidate the mode of action of chalcones' cytotoxicity. The fluorescence of the chalcones was found to be highly sensitive to structural and environmental factors. Structurally, a 4-dialkylamino group on the B ring, suitable electronic properties of the A ring substituents, and the planar conformation of the chalcone's core structure were essential for optimal fluorescence. Environmental factors influencing fluorescence included solvent polarity, pH, and the interactions of the chalcones with proteins and detergents. It was found that 18 chalcones showed a fluorescent brightness greater than 6000 M(-1) cm(-1) in DMSO. However, water dramatically quenched the fluorescence, although it could be partially recovered in the presence of BSA or detergents. As expected, these fluorescent chalcones showed a sharp structure activity relationship in their cellular cytotoxicity, leading to the identification of structurally similar cytotoxic and non-cytotoxic fluorescent chalcones as chemical probes. Confocal microscopy results revealed the co localization of the cytotoxic probe C8 and tubulin in cells, supporting tubulin as the direct cellular target responsible for the cytotoxicity of chalcones. PMID- 27214788 TI - Review: Long Noncoding RNAs in the Regulation of Inflammatory Pathways in Rheumatoid Arthritis and Osteoarthritis. PMID- 27214790 TI - Understanding the structure of skill through a detailed analysis of Individuals' performance on the Space Fortress game. AB - In this paper we describe a novel approach to the study of individual differences in acquired skilled performance in complex laboratory tasks based on an extension of the methodology of the expert-performance approach (Ericsson & Smith, 1991) to shorter periods of training and practice. In contrast to more traditional approaches that study the average performance of groups of participants, we explored detailed behavioral changes for individual participants across their development on the Space Fortress game. We focused on dramatic individual differences in learning and skill acquisition at the individual level by analyzing the archival game data of several interesting players to uncover the specific structure of their acquired skill. Our analysis revealed that even after maximal values for game-generated subscores were reached, the most skilled participant's behaviors such as his flight path, missile firing, and mine handling continued to be refined and improved (Participant 17 from Boot et al., 2010). We contrasted this participant's behavior with the behavior of several other participants and found striking differences in the structure of their performance, which calls into question the appropriateness of averaging their data. For example, some participants engaged in different control strategies such as "world wrapping" or maintaining a finely-tuned circular flight path around the fortress (in contrast to Participant 17's angular flight path). In light of these differences, we raise fundamental questions about how skill acquisition for individual participants should be studied and described. Our data suggest that a detailed analysis of individuals' data is an essential step for generating a general theory of skill acquisition that explains improvement at the group and individual levels. PMID- 27214791 TI - NEDD8 ultimate buster-1 regulates the abundance of TRF1 at telomeres by promoting its proteasomal degradation. AB - The human telomeric protein TRF1 negatively regulates telomere length by inhibiting the access of telomerase to telomeres. Here, we describe a novel function of NEDD8 ultimate buster-1 (NUB1) for regulating the levels of TRF1 at telomeres. NUB1 is a NEDD8-interacting protein, which down-regulates the NEDD8 conjugation system. We showed that NUB1 physically interacts with TRF1 and promotes its degradation by the proteasome in the absence of NEDD8 conjugation. We also demonstrated that TRF1 is conjugated to NEDD8, and that neddylated TRF1 is targeted to the proteasome for degradation in a NUB1-dependent manner. These data suggest that NUB1 participates in telomere maintenance by regulating the levels of TRF1 at telomeres through both NEDD8-dependent and NEDD8-independent pathways. PMID- 27214792 TI - Hyperosmotic stimulus study discloses benefits in ATP supply and reveals miRNA/mRNA targets to improve recombinant protein production of CHO cells. AB - Biopharmaceuticals are predominantly produced by Chinese hamster ovary (CHO) cells cultivated in fed-batch mode. Hyperosmotic culture conditions (>= 350 mOsmol kg(?1) ) resulting from feeding of nutrients may enhance specific product formation rates (qp ). As an improved ATP supply was anticipated to enhance qp this study focused on the identification of suitable miRNA/mRNA targets to increase ATP levels. Therefor next generation sequencing and a compartment specific metabolomics approach were applied to analyze the response of an antibody (mAB) producing CHO cell line upon osmotic shift (280 -> 430 mOsmol kg( 1) ). Hyperosmotic culture conditions caused a ~2.6-fold increase of specific ATP formation rates together with a ~1.7-fold rise in cytosolic and mitochondrial ATP pools, thus showing increased ATP supply. mRNA expression analysis identified several genes encoding glycosylated proteins with strictly tissue related function. In addition, hyperosmotic culture conditions induced an upregulation of miR-132-3p, miR-132-5p, miR-182, miR-183, miR-194, miR-215-3p, miR-215-5p which have all been related to cell cycle arrest/proliferation in cancer studies. In relation to a previous independent CHO study miR-183 may be the most promising target to enhance qp by stable overexpression. Furthermore, deletion of genes with presumably dispensable function in suspension growing CHO cells may enhance mAB formation by increased ATP levels. PMID- 27214793 TI - Disgusted by Sexual Abuse: Exploring the Association Between Disgust Sensitivity and Posttraumatic Stress Symptoms Among Mothers of Sexually Abused Children. AB - Nonoffending mothers of sexually abused children often exhibit high levels of posttraumatic stress (PTS) symptoms. Emerging evidence suggests that trait-like individual differences in sensitivity to disgust play a role in the development of PTS symptoms. One such individual difference, disgust sensitivity, has not been examined as far as we are aware among victims of secondary traumatic stress. The current study examined associations between disgust sensitivity and PTS symptoms among mothers of sexually abused children (N = 72). Mothers completed the Impact of Event Scale-Revised and the Three Domain Disgust Scale (Tybur, Lieberman, & Griskevicius, 2009). More than one third of mothers scored above a suggested cutoff (mean score = 1.5) for high levels of PTS symptoms. Hierarchical linear regression analysis results indicated that sexual disgust sensitivity (beta = .39, p = .002) was associated with PTS symptoms (R(2) = .18). An interaction analysis showed that sexual disgust sensitivity was associated with maternal PTS symptoms only when the perpetrator was not biologically related to the child (beta = -.32, p = .047; R(2) = .28). Our findings suggested that sexual disgust sensitivity may be a risk factor for developing PTS symptoms among mothers of sexually abused children. PMID- 27214796 TI - Manipulation of flowering time and branching by overexpression of the tomato transcription factor SlZFP2. AB - Flowering of higher plants is orchestrated by complex regulatory networks through integration of various environmental signals such as photoperiod, temperature, light quality and developmental cues. In Arabidopsis, transcription of the flowering integrator gene FLOWERING LOCUS T (FT) that several flowering pathways converge to is directly regulated by more than ten transcription factors. However, very little is known about the transcriptional regulation of the FT homolog SINGLE FLOWER TRUESS (SFT) in the day-neutral plant tomato (Solanum lycopersicum). Previously, we showed that the zinc finger transcription factor SlZFP2 plays important roles in regulation of seed germination and fruit ripening in tomato and also found that overexpression of SlZFP2 impacted flowering and branching. Here, we characterized in detail the early flowering and high branching phenotypes by overexpression of this transcription factor. Our data showed that overexpression of SlZFP2 accelerated flowering in an SFT-dependent manner as demonstrated by elevated SFT expression in the leaves and the transcription factor's binding ability to SFT promoter in vitro and in vivo. Furthermore, overexpression of the SlZFP2 gene in the sft plants failed to rescue the mutant's late flowering. Through analysis of grafting phenotype, growth response of branches to auxin application and transcriptome profiling by RNA sequencing, we also showed that overexpression of SlZFP2 affected shoot apical dominance through multiple regulatory pathways. Our results suggest that the transcription factor SlZFP2 has potential applications in genetic modification of plant architecture and flowering time for tomato production and other crops as well. PMID- 27214797 TI - Caregiver burden and fatigue in caregivers of people with dementia: Measuring human herpesvirus (HHV)-6 and -7 DNA levels in saliva. AB - PURPOSE: We examined chronic fatigue, which has not been investigated in detail, in family caregivers for people with dementia. METHODS AND MATERIALS: Forty-four community-dwelling family caregivers (the caregiver group: CG) and 50 elderly control participants (the non-caregiver group: NCG) participated in this study. We measured salivary human herpesvirus (HHV)-6 and -7 DNA levels and the Chalder fatigue scale (CFS) to assess levels of fatigue; we also measured the Center for Epidemiologic Studies-Depression Scale, Physical Activity Scale for the Elderly, Zarit Caregiver Burden Interview, Mini-Mental State Examination, Assessment of Motor and Process Skills, and Dementia Behavior Disturbance Scale. RESULTS: For CG, the salivary HHV-6 DNA levels and CFS scores were significantly higher than those in NCG. The salivary HHV-6 DNA levels in CG were significantly correlated with depressive symptoms, the cognitive function of the patients, and the activities of daily living/instrumental activities of daily living (ADL/IADL) abilities of the patients. The CFS scores in CG significantly correlated with caregiver burden, depression symptoms, leisure physical activity, the number of other family caregivers, and the hours spent for caregiving per week, as well as with behavior disturbances and ADL/IADL abilities. CONCLUSIONS: The salivary HHV 6 DNA levels may be added as a new biomarker for caregiver exhaustion. We concluded that fatigue assessments should be performed by not only a questionnaire, such as the CFS, but also by a biomarker search, such as HHV-6, when estimating the caregiver burden for family caregivers of people with dementia. PMID- 27214799 TI - Factor X and its deficiency states. AB - Factor X is one of the vitamin-K-dependent serine proteases. As a result of its position at the convergence of the intrinsic and extrinsic pathways of the clotting cascade, it plays a crucial role in blood coagulation. Factor X interacts with components of both pathways of coagulation, leading to its activation and the formation of the prothrombinase complex. The gene for factor X has been cloned and sequenced and maps to the long arm of chromosome 13, approximately 2.8 kb downstream of the factor VII gene. Each of the exons of factor X encodes a specific functional domain within the protein. In terms of its gene structure and amino acid sequence, factor X shows significant homology with other vitamin-K-dependent clotting factors, suggesting an origin in some common ancestral protein. Factor X deficiency is one of the rarest of the inherited coagulation disorders. Such deficiencies are inherited in an autosomal recessive manner and are characterized by a variable bleeding tendency. In its homozygous form, factor X deficiency has an estimated prevalence of 1:500 000 but in its heterozygous form it has an estimated frequency of ~1:500 although affected individuals are often clinically asymptomatic. Acquired deficiencies of factor X are uncommon and in isolation are seen most frequently in patients with amyloidosis and in association with upper respiratory tract infections. Treatment of the deficiency state involves factor X replacement with either fresh frozen plasma or prothrombin complex concentrates. However, the latter may be associated with an increased risk of thrombosis. PMID- 27214798 TI - Superselective intra-arterial chemotherapy in the primary management of advanced intra-ocular retinoblastoma: first 4-year experience from a single institution in Turkey. AB - PURPOSE: To report our 4-year experience in Turkey, with advanced intra-ocular retinoblastoma managed primarily with intra-arterial chemotherapy (IAC). METHODS: From October 2011 to September 2015, 26 group D eyes of 24 treatment-naive retinoblastoma patients managed primarily with IAC were evaluated in this prospective study. RESULTS: Of 76 procedures, ophthalmic artery cannulation failed in two patients with unilateral involvement. In the remaining 22 patients (24 eyes), the mean age at diagnosis was 18 months (range, 6-55 months). Each eye received a mean of 3 IAC sessions/eye (range, 2-5 sessions). After a median follow-up of 29 months (range, 6-55 months), complete regression of the main tumour was achieved in 23 of 24 eyes. One eye with partial regression required enucleation due to ciliary body involvement by the tumour. Overall, 16 eyes (66.6%) were salvaged with primary IAC with or without additional local treatments, and eight (33.3%) required enucleation. The main IAC-related periocular complications included transient eyelid oedema (n = 13), ptosis (n = 6) and forehead hyperpigmentation (n = 3), each resolving in 2 weeks to 4 months. Intra-ocular complications included chorioretinal atrophy (n = 9), newly noted retinal detachment (n = 5) and vitreous haemorrhage (n = 1). Kaplan-Meier eye estimates of enucleation-free survival rates were 83.3% (95% CI, 68.4-98.1%), 69.1% (95% CI, 49.8-88.3%) and 62.9 (95% CI, 41.9-83.8%) at 6 months, 1 and 2 years, respectively, and stable thereafter. CONCLUSION: Our first 4-year experience in Turkey showed that enucleation or external-beam radiotherapy could be avoided in two-thirds of eyes with advanced intra-ocular retinoblastoma managed primarily with IAC. PMID- 27214800 TI - The introduction of high-purity products in Canada. AB - In October 1993, the Canadian Blood Agency, the agent for the provinces/territories in Canada, agreed to the introduction of high-purity coagulation products, either recombinant or highly purified factor concentrates, for the management of coagulation deficiencies. This represented a cost increase of approximately $30 million (40%) for the national coagulation product inventory. Representatives of the relevant recipients of the products, some of the treaters, the distributor and the funders met on a regular basis in order to monitor the impact of these new products. The Association of Hemophilia Clinic Directors of Canada also agreed to include some specific outcome studies over a longer period of time to include evaluation of inhibitor formation, prophylaxis regimens, immune status and the incidence of thrombosis. The 'Hemophilia and Von Willebrand's Disease' clinical practice guidelines were also developed under their auspices. A usage monitoring system has been implemented and has been continuously managed by the Canadian Blood Agency. This resulted in trends of practice and rationales for unexpected use being identified early for planning and funding purposes. The Working Group set up under the auspices of the Canadian Blood Agency was an effective vehicle to evaluate the conversion and the impact of these new products in the country and can serve as a model for future endeavours. PMID- 27214801 TI - Analysis of the haemophilia A mutation in sporadic patients registered at the Royal London Hospital and their families. AB - The families of sporadic haemophilia A patients registered at the Royal London Hospital and with living grandparents were selected for study. Twelve of the 13 known families agreed to collaborate. Of these 11 had a patient with severe and one a patient with mild haemophilia. Five of the severely affected patients had inversions of type 1, that is involving int22h-1 and int22h-3, and two had inversions of type 2, that is involving int22h-1 and int22h-2. The remaining four patients with severe disease had single base substitutions causing two different non-sense (Gln592->Stop; Trp2313->Stop) and two different mis-sense mutations (His267->Pro; Arg2209->Gln). A single base substitution causing a mis-sense mutation (His1961->Asp) was also found in the patient with mild haemophilia. The Arg2209->Gln mutation has previously been found in other patients while the other single base substitutions have not hitherto been observed. Three mutations (all single base substitutions) appear to have arisen in the germline of the patient's mother, while seven mutations originated in the gonad of one of the patient's grandparents. In two of the latter families (both with inversion type 2) the origin of muta-tions could be clearly assigned to the grandpaternal gonad. Data on parental age at the onset of mutation were ob-tained in the families investigated. In addition, further evidence was obtained that the int-22h-related inversions arise by intrachromatid, intrachromosome homologous re-combination as the int22h repeat sequences of a patient were found to be identical to those of the maternal grand-father whose germline represents the origin of mutation. PMID- 27214794 TI - Stromal dynamic reciprocity in cancer: intricacies of fibroblastic-ECM interactions. AB - Stromal dynamic reciprocity (SDR) consists of the biophysical and biochemical interplay between connective tissue elements that regulate and maintain organ homeostasis. In epithelial cancers, chronic alterations of SDR result in the once tumor-restrictive stroma evolving into a 'new' tumor-permissive environment. This altered stroma, known as desmoplasia, is initiated and maintained by cancer associated fibroblasts (CAFs) that remodel the extracellular matrix (ECM). Desmoplasia fuels a vicious cycle of stromal dissemination enriching both CAFs and desmoplastic ECM. Targeting specific drivers of desmoplasia, such as CAFs, either enhances or halts tumor growth and progression. These conflicting effects suggest that stromal interactions are not fully understood. This review highlights known fibroblastic-ECM interactions in an effort to encourage therapies that will restore cancer-restrictive stromal cues. PMID- 27214802 TI - Acquired haemophilia: experience of two Italian centres with 17 new cases. AB - Acquired haemophilia is a rare but often catastrophic haemorrhagic disorder associated with a high mortality rate. No single therapeutic approach has been consistently successful and clinical experience remains mainly anecdotal. This report describes 17 new cases diagnosed at two Italian haemophilia centres between 1979 and 1995. There was no difference in sex distribution. Mean age at diagnosis was 50 years. Fifty-nine per cent of cases had associated disorders and 29% developed an inhibitor post-partum. Eleven (64%) patients required substitutive therapy. Desmopressin was successfully used in five cases for minor bleeding. Immunosuppressive drugs (steroid, cyclophosphamide or experimental therapy) were used in 14 (82%) cases. Eight of 15 (52%) evaluable cases achieved complete remission (four post-partum). Fatal haemorrhage occurred in 2/15 (13%) of patients within 2 days from diagnosis. Acquired haemophilia is a severe coagulopathy. Prompt diagnosis with characterization and intensive treatment is usually required. However, particular subsets of patients such as those with inhibitor occurring post-partum or with low inhibitor titre at diagnosis usually show a more favourable clinical outcome. PMID- 27214803 TI - Factor IX inhibition and epitope localization of factor IX inhibitor antibodies in haemophilia B patients with anaphylactoid reactions. AB - We describe the results of immunological studies, reaction kinetics and epitope localization of six inhibitor antibodies to factor IX (FIX) developed in severe haemophilia B patients. Three of the six patients had suffered recent anaphylactoid reactions to FIX concentrates, two others had in the past and one had none. All six inhibitors rapidly inactivated FIX activity in vitro, and the prominent immunoglobulin (IgG) subclass of the antibody was IgG4 when analysed with ELISA. Interestingly, we found an additional IgG1 component in the antibody samples from the patients who had recently experienced anaphylactoid reactions to FIX. When analysed with Western blotting in these three patients, the IgG4 antibody bound with enhanced affinity to the heavy chain or the light chain of FIX, and in two of the three the IgG1 antibody also bound strongly to the FIX heavy chain. The results suggest that the heavy chain of FIX might play a more significant role than the light chain in the pathogenesis of anaphylactoid reactions in haemophilia B patients with FIX inhibitors. PMID- 27214804 TI - Use of central venous catheters in children with haemophilia: one haemophilia treatment centre experience. AB - We report our clinic experience with central venous catheters (CVCs) in 23 children with haemophilia, who, in total, had 35 catheters. Seventeen of the 23 children had Broviac catheters (external), 6/23 had an implantable device (Port-A Cath) only, while four had Broviac and Port-A-Cath at different times. The age of the patients at the time of initial catheter placement ranged from 4 months to 18 years; 11 were under age 3 years. Indications for CVC placement included induction of immune tolerance, treatment of HIV-related complications, prophylactic therapy following intracranial haemorrhage, primary prophylaxis and secondary prophylaxis. Catheter-related infection was the most common complication, occurring in 84% of the external catheters. Of these infections 79% occurred in HIV-negative subjects. Staph and strep species were the most common infectious organisms isolated. Minor bleeding around the catheter occurred in 20% of cases even with adequate correction of haemophilia. Three children accidentally removed the external catheter (12%). Thrombosis of the catheter was uncommon (8%), occurring in only two patients, one of whom had a small newborn size external catheter. When presenting with line sepsis, haemophilic children who were HIV negative had transient temperature spikes approximately 1 h after catheter flushing. This presentation was different from our oncology or HIV positive patients with CVC-related sepsis. Our experience with ports (Port-A Cath) in haemophilic children is limited, but catheter-related infection (40%) seems to be less of a problem with the implantable device and the ports have been well accepted by our haemophilic patients and their parents. PMID- 27214805 TI - Absence of intrafamilial transmission of hepatitis C in patients with inherited bleeding disorders. AB - Hepatitis 'C' virus (HCV) infection has caused significant anxiety in patients with inherited bleeding disorders. A significant number of patients with HCV have developed chronic liver disease, cirrhosis and hepatocellular carcinoma. The exact risk of heterosexual and contact transmission is unclear at the moment. A test for antibody to hepatitis 'C' was offered, after counselling, to spouses and family members of 118 known hepatitis 'C' antibody positive patients with inherited bleeding disorders. Two hundred and fifteen family members were tested, 73 partners and 142 household contacts; all were found negative for hepatitis 'C'. Our experience confirms the low risk of heterosexual and contact transmission of hepatitis 'C' virus. PMID- 27214806 TI - Safety and potential usefulness of liver biopsy in HIV-seropositive haemophiliacs employing a transjugular venous approach. AB - Chronic liver disease has affected a majority of haemophiliacs exposed to factor VIII and factor IX concentrates before effective viral attenuation techniques were introduced. Progressive hepatitis and liver failure have increasingly become causes of morbidity, especially in haemophilia patients also seropositive for HIV. Encouraging reports of recombinant alpha interferon to reverse the histological, laboratory and clinical deterioration of chronic active hepatitis justifies obtaining liver biopsies to assess the severity of liver damage; however, the percutaneous method carries a significant risk of bleeding. Therefore, we employed a transjugular venous approach for liver biopsies in six HCV-, HBSAb- and HIV-seropositive adults with severe haemophilia A (n = 5) or B (n = 1) with persistent liver function abnormalities. Adequacy of the specimens and lack of haemorrhagic complications leads us to conclude that this procedure appears to be safe and effective in individuals with severe haemophilia or other congenital or acquired coagulopathies. PMID- 27214807 TI - Clinical outcome of HIV-infected haemophiliac patients in Hong Kong. AB - About half of the haemophiliacs in Hong Kong have been infected by human immunodeficiency virus (HIV). This study aimed to determine their clinical course of progression. Forty-seven adult patients with congenital coagulation factor deficiency being followed up regularly from January 1992 onward in the Department of Medicine of Queen Mary Hospital, Hong Kong, were included in this study. Twenty were positive for HIV antibody and the remaining 27 were negative. Three other HIV-positive patients who died before 1992 were excluded. From January 1992 to June 1996, the 47 patients included in the study were followed up in the clinic every 3-6 months with regular CD4, CD8 lymphocyte counts and beta2 microglobulin levels. At the initiation of the study in January 1992, the HIV infected patients had already a lower mean CD4 count (360.4 MUL(-1) versus 658.8 MUL(-1) , P<0.01), a reversed CD4/CD8 ratio (0.53) and a higher mean serum beta2 microglobulin level (1.853 MUg mL(-1) versus 1.315 MUg mL(-1) , P>0.05). On regular follow-up, HIV-positive patients had a more significant progressive fall in their mean CD4 count (301.6 MUL(-1) versus 360.4 MUL(-1) , P<0.01) and rise in their mean serum beta2 microglobulin level (2.60 MUg mL(-1) , versus 1.853 MUg mL(-1) , P<0.05). The CD4 and CD8 counts of HIV-positive patients were falling at a rate of 1.44 MUL(-1) month(-1) and 4.03 MUL(-1) month(-1) respectively. During the follow-up period, two of the 20 HIV-positive patients developed clinical acquired immunodeficiency syndrome (AIDS) at 15 and 36 months from the initiation of the study. Both patients had typical features of AIDS with a low CD4 count, reversed CD4/CD8 ratio and elevated beta2 microglobulin level. The former patient eventually died of fungal brain abscess. The remaining 18 HIV-positive patients so far remained clinically asymptomatic. Eleven patients were put on antiretroviral drug therapy when their CD4 counts fell below 200 MUL(-1) . Only two of the 20 HIV-infected patients developed AIDS during the observation period of 4 years; this figure of 10% is relatively slow. Two of our patients died of AIDS before the study was initiated in 1992. Even if they were included, still only 17.4% had progressed. The figure is in the lowest rate of progression expected from Western experience. Although our study population is small, it remains unclear why our HIV-infected Chinese haemophiliacs have a slow rate of progression to AIDS. PMID- 27214808 TI - Safer and much cheaper circumcision using fibrin glue in severe haemophilia. AB - Circumcision is a traditional ceremony for Muslims and Jewish people. In order to reduce the high cost of factor concentrates, we administered locally manufactured heat-treated fibrin glue during operation. Circumcision can be performed safely and is much cheaper using fibrin glue plus a small amount of factor concentrates. PMID- 27214809 TI - Acquired inhibitor to factor VIII: report of two unusual cases. AB - The present report describes two unusual cases of bleeding due to development of inhibitor against factor VIII. One of the patients was known to have severe haemophilia B (factor IX < 1%) and the other, a healthy male of 46 years, spontaneously started to bleed and was found to have developed inhibitors to factor VIII:C along with other autoantibodies. Development of inhibitors to coagulation factors is a serious clinical problem in de-veloped countries and is more so in developing countries where treatment options are often limited. PMID- 27214810 TI - Use of recombinant factor VIIa in surgery in factor-VII-deficient patients. AB - Patients suffering from severe factor VII deficiency may present with serious bleeding problems. No clear guidelines exist regarding therapy in such patients in case of a large bleeding or surgery. Indeed, it has been postulated that some patients with severe factor VII deficiency may never present with overt bleeding problems. However, in factor-VII-deficient patients who have previously demonstrated a clinical tendency to bleed, surgery is expected to cause excessive bleeding. We present two females suffering from a severe factor VII deficiency (FVII:C < 0.01 U mL(-1) ) with a distinct history of haemorrhagic diathesis. Due to recurrent bleeding in the past, or for circumstantial reasons, surgery was demanded over a 4-year period on a total of seven occasions. To assist haemostasis during and after joint surgery on five occasions and for embolization and subsequent removal of a large haemangioma of the occipital region, recombinant factor VIIa (NovoSeven) was utilized in doses approximating 20 MUg kg(-1) b.w. every 6 h beginning immediately before surgery and continued until 30 h to 13 days postoperatively, depending of the size of the respective procedure. Using this approach, we observed normal haemostasis, and there were no signs of excessive postoperative bleeding or wound haematoma. No adverse reactions or side effects were observed, and there were no complaints or clinical signs indicative of thrombotic complications. As judged from the clinical course of these seven minor and major surgeries, recombinant factor VIIa appears to be highly efficaceous and safe in the treatment patients with severe factor VII deficiency undergoing surgery. PMID- 27214811 TI - Hepatitis E in Portuguese haemophiliacs and blood donors. PMID- 27214812 TI - Protease inhibitors and unusual bleeding in haemophiliacs. PMID- 27214813 TI - Haemophilia in Orthopaedics. PMID- 27214814 TI - How It Was: Pathology at UNC 1896-1973. PMID- 27214815 TI - The haemophilic boy in school. PMID- 27214816 TI - Factor IX inhibitors and anaphylaxis in hemophilia B. PMID- 27214817 TI - Hepatitis G viral RNA in serum and in peripheral blood mononuclear cells and its relation to HCV-RNA in patients with clotting disorders. PMID- 27214818 TI - Extravascular administration of factor IX: potential for replacement therapy of canine and human hemophilia B. PMID- 27214819 TI - A multicenter study of recombinant factor VIII (Recombinate(TM) ) in previously treated patients with hemophilia A. PMID- 27214820 TI - Hemophilia and nonprogressing human immunodeficiency virus type 1 infection. PMID- 27214821 TI - Hypoglycosylation is a common finding in antithrombin deficiency in the absence of a SERPINC1 gene defect. AB - Essentials We investigated the molecular base of antithrombin deficiency in cases without SERPINC1 defects. 27% of cases presented hypoglycosylation, transient in 62% and not restricted to antithrombin. Variations in genes involved in N glycosylation underline this phenotype. These results support a new form of thrombophilia. Click here to listen to Dr Huntington's perspective on thrombin inhibition by the serpins SUMMARY: Background Since the discovery of antithrombin deficiency, 50 years ago, few new thrombophilic defects have been identified, all with weaker risk of thrombosis than antithrombin deficiency. Objective To identify new thrombophilic mechanisms. Patients/methods We studied 30 patients with antithrombin deficiency but no defects in the gene encoding this key anticoagulant (SERPINC1). Results A high proportion of these patients (8/30: 27%) had increased hypoglycosylated forms of antithrombin. All N-glycoproteins tested in these patients (alpha1-antitrypsin, FXI and transferrin) had electrophoretic, HPLC and Q-TOF patterns indistinguishable from those of the congenital disorders of glycosylation (rare recessive multisystem disorders). However, all except one had no mental disability. Moreover, intermittent antithrombin deficiency and hypoglycosylation was recorded in five out of these eight patients, all associated with moderate alcohol intake. Genetic analysis, including whole exome sequencing, revealed mutations in different genes involved in the N-glycosylation pathway. Conclusions Our study provides substantial and novel mechanistic insights into two disease processes, with potential implications for diagnosis and clinical care. An aberrant N-glycosylation causing a recessive or transient antithrombin deficiency is a new form of thrombophilia. Our data suggest that congenital disorders of glycosylation are probably underestimated, especially in cases with thrombosis as the main or only clinical manifestation. PMID- 27214822 TI - Towards targeting anticancer drugs: ruthenium(ii)-arene complexes with biologically active naphthoquinone-derived ligand systems. AB - Anticancer active metal complexes with biologically active ligands have the potential to interact with more than one biological target, which could help to overcome acquired and/or intrinsic resistance of tumors to small molecule drugs. In this paper we present the preparation of 2-hydroxy-[1,4]-naphthoquinone derived ligands and their coordination to a Ru(II)(eta(6)-p-cymene)Cl moiety. The synthesis of oxime derivatives resulted in the surprising formation of nitroso naphthalene complexes, as confirmed by X-ray diffraction analysis. The compounds were shown to be stable in aqueous solution but reacted with glutathione and ascorbic acid rather than undergoing reduction. One-electron reduction with pulse radiolysis revealed different behavior for the naphthoquinone and nitroso naphthalene complexes, which was also observed in in vitro anticancer assays. PMID- 27214823 TI - Reductive Etherification of Fatty Acids or Esters with Alcohols using Molecular Hydrogen. AB - In the presence of a catalyst system consisting of a ruthenium/triphos complex and the Bronsted acid trifluoromethanesulfonimide, mixtures of fatty acids and aliphatic alcohols are converted into the corresponding ethers at 70 bar H2 . The protocol allows the sustainable one-step synthesis of valuable long-chain ether fragrances, lubricants, and surfactants from renewable sources. The reaction protocol is extended to various fatty acids and esters both in pure form and as mixtures, for example, tall oil acids or rapeseed methyl ester (RME). Even the mixed triglyceride rapeseed oil was converted in one step. PMID- 27214824 TI - Myostatin deficiency but not anti-myostatin blockade induces marked proteomic changes in mouse skeletal muscle. AB - Pharmacologic blockade of the myostatin (Mstn)/activin receptor pathway is being pursued as a potential therapy for several muscle wasting disorders. The functional benefits of blocking this pathway are under investigation, in particular given the findings that greater muscle hypertrophy results from Mstn deficiency arising from genetic ablation compared to post-developmental Mstn blockade. Using high-resolution MS coupled with SILAC mouse technology, we quantitated the relative proteomic changes in gastrocnemius muscle from Mstn knockout (Mstn(-/-) ) and mice treated for 2-weeks with REGN1033, an anti-Mstn antibody. Relative to wild-type animals, Mstn(-/-) mice had a two-fold greater muscle mass and a >1.5-fold change in expression of 12.0% of 1137 quantified muscle proteins. In contrast, mice treated with REGN1033 had minimal changes in muscle proteome (0.7% of 1510 proteins >1.5-fold change, similar to biological difference 0.5% of 1310) even though the treatment induced significant 20% muscle mass increase. Functional annotation of the altered proteins in Mstn(-/-) mice corroborates the mutiple physiological changes including slow-to-fast fiber type switch. Thus, the proteome-wide protein expression differs between Mstn(-/-) mice and mice subjected to specific Mstn blockade post-developmentally, providing molecular-level insights to inform mechanistic hypotheses to explain the observed functional differences. PMID- 27214826 TI - Systems Biology in Kidney Transplantation: The Application of Multi-Omics to a Complex Model. AB - In spite of reduction of rejection rates and improvement in short-term survival post-kidney transplantation, modest progress has occurred in long-term graft attrition over the years. Timely identification of molecular events that precede clinical and histopathological changes might help in early intervention and thereby increase the graft half-life. Evolution of "omics" tools has enabled systemic investigation of the influence of the whole genome, epigenome, transcriptome, proteome and microbiome on transplant function and survival. In this omics era, systemic approaches, in-depth clinical phenotyping and use of strict validation methods are the key for further understanding the complex mechanisms associated with graft function. Systems biology is an interdisciplinary holistic approach that focuses on complex and dynamic interactions within biological systems. The complexity of the human kidney transplant is unlikely to be captured by a reductionist approach. It appears essential to integrate multi-omics data that can elucidate the multidimensional and multilayered regulation of the underlying heterogeneous and complex kidney transplant model. Herein, we discuss studies that focus on genetic biomarkers, emerging technologies and systems biology approaches, which should increase the ability to discover biomarkers, understand mechanisms and stratify patients and responses post-kidney transplantation. PMID- 27214825 TI - Predicting Survival in Dementia With Lewy Bodies With Hippocampal Volumetry. AB - BACKGROUND: The clinical course of dementia with Lewy bodies patients is heterogeneous. The ability to more accurately prognosticate survival is important. OBJECTIVE: The objective of this study was to investigate hippocampal volume as a predictor of survival in dementia with Lewy bodies patients. METHODS: Survival analysis for time from onset of cognitive symptoms to death was carried out using Cox proportional hazards models. Given their age and total intracranial volume, patients were dichotomized into low/medium (0%-66.7%) and high (66. 7% 100%) hippocampal volume categories. The models using these categories to predict survival were adjusted for field strength, APOE epsilon4 status, and estimated onset age of cognitive problems. RESULTS: We investigated 167 consecutive patients with dementia with Lewy bodies. The median age at MRI was 72 years (interquartile range 67-76), and 80% were male. The median time from estimated first cognitive symptom to death was 7.4 years (interquartile range:5.7-10.2). Lower hippocampal volumes were significantly associated with higher risk of death (hazard ratio 1.28; 95% confidence interval 1.04-1.58; P = .024). The predicted median survival for participants with onset of cognitive symptoms at age 68 was 10.63 years (95% confidence interval 8.66-14.54) for APOE epsilon4 negative, high hippocampal volume participants; 8.89 years (95% confidence interval 7.56-12.36) for APOE epsilon4 positive, high hippocampal volume participants; 8.10 years (95% confidence interval 7.34-11.08) for APOE epsilon4 negative, low/medium hippocampal volume participants; and 7.38 (95% confidence interval 6.74-9.29) years for APOE epsilon4 positive, low/medium hippocampal volume participants. CONCLUSIONS: Among patients with clinically diagnosed dementia with Lewy bodies, those with neuroimaging evidence of hippocampal atrophy have shorter survival times. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27214828 TI - Oncological and complication assessment of CO2 laser-assisted endoscopic surgery for T1-T2 glottic tumours: clinical experience. AB - Several therapeutic options are used for treatment of early stage glottic carcinoma (Tis/T1/T2): open partial laryngectomy (OPL), radiotherapy and CO2 laser-assisted endoscopic surgery. Laser surgery has gradually gained approval in the management of laryngeal cancer. We present our experience in endoscopic laser surgery for early stage glottic carcinomas. This was a retrospective analysis of 72 patients with T1-T2 glottic cancer treated with laser cordectomy between 2006 and 2012. All patients had at least a 36-month follow-up period. Percentages for disease-specific survival, disease-free survival (DFS) and laryngeal preservation rates were 98.6%, 84.7% and 97.2% respectively. Considering neoplastic features that could predict long-term oncological outcome, tumoural involvement of anterior commissure and pathological staging (pT) significantly correlate with local recurrence (p = 0.021 and p = 0.035) and with a lowered DFS (p = 0.017 and p = 0.023). Other variables such as clinical staging, type of cordectomy, involvement of other structures and surgical margin status showed no significant impact on oncological endpoints. CO2 laser surgery is a reliable technique for T1 T2 glottic cancer considering oncological outcomes. The recurrence rate seems to be affected by involvement of anterior commissure and pT stage. PMID- 27214827 TI - A review of new insights on the association between hearing loss and cognitive decline in ageing. AB - Age-related hearing loss (ARHL) has a multifactorial pathogenesis and it is an inevitable hearing impairment associated with reduction of communicative skills related to ageing. Increasing evidence has linked ARHL to more rapid progression of cognitive decline and incidental dementia. Many aspects of daily living of elderly people have been associated to hearing abilities, showing that hearing loss (HL) affects the quality of life, social relationships, motor skills, psychological aspects and function and morphology in specific brain areas. Epidemiological and clinical studies confirm the assumption of a relationship between these conditions. However, the mechanisms are still unclear and are reviewed herein. Long-term hearing deprivation of auditory inputs can impact cognitive performance by decreasing the quality of communication leading to social isolation and depression and facilitate dementia. On the contrary, the limited cognitive skills may reduce the cognitive resources available for auditory perception, increasing the effects of HL. In addition, hearing loss and cognitive decline may reflect a 'common cause' on the auditory pathway and brain. In fact, some pathogenetic factors are recongised in common microvascular disease factors such as diabetes, atherosclerosis and hypertension. Interdisciplinary efforts to investigate and address HL in the context of brain and cognitive ageing are needed. Surprisingly, few studies have been adressed on the effectiveness of hearing aids in changing the natural history of cognitive decline. Effective interventions with hearing aids or cochlear implant may improve social and emotional function, communication, cognitive function and positively impact quality of life. The aim of this review is to overview new insights on this challenging topic and provide new ideas for future research. PMID- 27214829 TI - Unravelling the risk factors that underlie laryngeal surgery in elderly. AB - Older patients are not considered good candidates to undergo more challenging therapeutic treatments, e.g. highly invasive surgery and complex chemotherapy. However, their exclusion from standard therapeutic options is not justifiable. Herein, we reviewed 212 patients aged >= 70, affected with laryngeal squamous cell carcinoma, and treated with transoral laser microsurgery or open neck (partial / total) laryngectomy with radical intent. The main aim was to compare patient outcomes to identify predictive factors that can be used by surgeons to choose the most appropriate treatment option. In our cohort, patients affected with more advanced tumour and hence treated by invasive open neck surgeries (above all TL) are more prone to develop complications and undergo fatal outcome than those with early disease treated by laser microsurgery, independently of age at surgery. In conclusion, elderly patients affected by laryngeal cancer can be treated similarly to younger patients, keeping in mind that more invasive surgeries are associated with a higher risk of developing complications. The advantages of mini-invasive surgery make it a possible first choice treatment in very old and frail patients suffering from laryngeal cancer, especially considering the recent success in treatment of some advanced stage tumours. Furthermore, comorbidities, by themselves, should not be used as exclusion criteria for subjecting an elderly patient to a different treatment that is from standard therapy. PMID- 27214830 TI - Septal flip flap for anterior skull base reconstruction after endoscopic resection of sinonasal cancers: preliminary outcomes. AB - Over the past decade surgery for sinonasal malignancies encroaching into the anterior skull base (ASB) has evolved from open craniofacial resection to the use of minimally invasive transnasal endoscopic approaches. Using these techniques, ASB reconstruction is most often performed in a multilayer fashion with autologous free grafts (fascia lata or iliotibial tract) which leads to the production of abundant nasal crusting in the postoperative months and discomfort for patients. In carefully selected cases, we propose harvesting a flap from the contralateral nasal septum based on the septal branches of the anterior and posterior ethmoidal arteries (Septal Flip Flap, SFF), which can be rotated to resurface the ASB defect. The exclusion criteria for using the SFF were as follows: cases where the tumour extended to both ethmoid complexes; cases where there was nasal septum or planum spheno-ethmoidalis involvement by the disease; cases of sinonasal malignant tumour with multifocal histology. In our tertiary care referral centre, skull base reconstruction using the SFF was performed in four patients; one was affected by ethmoidal teratocarcinosarcoma, one by persistence of sinonasal undifferentiated carcinoma after radio-chemotherapy, another by olfactory cleft esthesioneuroblastoma and the fourth by ethmoidal squamous cell carcinoma. Successful skull base reconstruction was obtained in all four cases without any intra- or post-operative complications. Post-operatively, nasal crusting was significantly reduced with faster healing of the surgical cavity. No recurrences of disease have been observed after a mean follow-up of 15 months. The SFF can be considered as a safe and effective technique for ASB reconstruction with high success rates similar to those obtained with other pedicled flaps. This flap also ensured a faster healing process with reduction of nasal crusting and improvement in the quality of life of patients in the postoperative period. This technique appears to be a safe and effective option for ASB reconstruction after endonasal resection of sinonasal malignancies in selected cases. Larger case series with a longer follow-up are needed to validate the preliminary results obtained with such an innovative and promising surgical technique. PMID- 27214831 TI - Radiofrequency volumetric inferior turbinate reduction: long-term clinical results. AB - The aim of our study was to assess long-term results of radiofrequency volumetric tissue reduction of inferior turbinates (RVTR). We performed a prospective long term longitudinal evaluation of 305 patients affected by rhinitis (114 allergic and 191 non-allergic) who were unresponsive to medical treatment and underwent RVTR (January 2004 - December 2010). Subjects were followed for a mean period of 39.70 +/- 19.41 months (range 24-60). Patients completed the NOSE-scale questionnaire pre- and post-operatively after 1 month and yearly for 5-years. Recurrence was assumed if the post-operative total NOSE score increased by at least 75% during follow-up and the patient restarted medical treatments. Estimation of relapse over time was performed by Kaplan-Meyer analyses. We documented overall good satisfaction of patients regarding the procedure, with a good rate of pain control and a low rate of complications. Post-operatively there was a significant improvement in nasal stuffiness, nasal obstruction and mouth breathing (p < 0.05). We observed a worsening trend for symptoms after 36 months with progressive increasing rate of recurrences that were significantly higher in allergic than non-allergic patients (p < 0.05). We also observed a slight worsening trend of global satisfaction of patients. Our study confirms the minor discomfort and low risk of side effects of RVTR. Our data showed good efficacy of the procedure in the majority of patients for at least 36 months after surgery, and in fact in this time period the cumulative probability to remain relapse-free was up to 0.8. In the following 2 years, we observed a worse temporal trend in term of recurrence rate, and in particular in allergic patients with a significant difference vs non-allergic individuals (p < 0.05). PMID- 27214832 TI - Outcomes of long-term audiological rehabilitation in charge syndrome. AB - The aim of this paper is to assess the long-term audiological features and outcomes of hearing rehabilitation in a large group of individuals with CHARGE Syndrome. The study has been conducted retrospectively, on a paediatric patient database, at the Audiology Department of the University Hospitals of Ferrara and Padua. The study sample included 31 children presenting with different degrees of hearing impairment associated with CHARGE syndrome. Hearing was assessed using auditory brainstem responses (ABRs) and/or electrocochleography, or conditioned audiometry (visual reinforcement audiometry [VRA] or play audiometry). Auditory perceptual outcomes in terms of communication skills and expressive language were also recorded. The effects of hearing rehabilitation (with hearing aids or cochlear implants) in this group of children and language outcomes after rehabilitation were monitored during long-term follow-up. The outcomes of rehabilitation measures differed in relation to the heterogeneous and often severe disabilities associated with CHARGE syndrome, e.g. developmental delay, intellectual delay, visual impairment, thin 8(th) nerve with retrocochlear auditory dysfunction (as described in cases of auditory neuropathy/dyssynchrony). Oral expressive language was severely impaired in most cases, even after lengthy follow-up, suggesting the need for alternative augmentative communication modes. The early identification of sensorineural hearing loss, and carefully planned rehabilitation treatments, can be of some benefit in children with CHARGE syndrome. PMID- 27214833 TI - Point prevalence of vertigo and dizziness in a sample of 2672 subjects and correlation with headaches. AB - Vertigo and dizziness are common symptoms in the general population, with an estimated prevalence between 20% and 56%. The aim of our work was to assess the point prevalence of these symptoms in a population of 2672 subjects. Patients were asked to answer a questionnaire; in the first part they were asked about demographic data and previous vertigo and or dizziness. Mean age of the sample was 48.3 +/- 15 years, and 46.7% were males. A total of 1077 (40.3%) subjects referred vertigo/dizziness during their lifetime, and the mean age of the first vertigo attack was 39.2 +/- 15.4 years; in the second part they were asked about the characteristics of vertigo (age of first episode, rotational vertigo, relapsing episodes, positional exacerbation, presence of cochlear symptoms) and lifetime presence of moderate to severe headache and its clinical features (hemicranial, pulsatile, associated with phono and photophobia, worse on effort). An age and sex effect was demonstrated, with symptoms 4.4 times more elevated in females and 1.8 times in people over 50 years. In the total sample of 2672 responders, 13.7% referred a sensation of spinning, 26.3% relapsing episodes, 12.9% positional exacerbation and 4.8% cochlear symptoms; 34.8% referred headache during their lifetime. Subjects suffering from headache presented an increased rate of relapsing episodes, positional exacerbation, cochlear symptoms and a lower age of occurrence of the first vertigo/dizziness episode. In the discussion, our data are compared with those of previous studies, and we underline the relationship between vertigo/dizziness from one side and headache with migrainous features on the other. PMID- 27214834 TI - Long-term surgical results in microvascular decompression for hemifacial spasm: efficacy, morbidity and quality of life. AB - Hemifacial spasm is a condition that may severely reduce patients' quality of life. Microvascular decompression is the neurosurgical treatment of choice. The objective of this work was to describe the efficacy and morbidity of microvascular decompression for hemifacial spasm, evaluate the long-term efficacy on the quality of life and investigate prognostic factors for failure of the procedure. A retrospective study of 446 cases of hemifacial spasm treated by 511 retrosigmoid microvascular decompression over 22 years was conducted. Epidemiological, clinical and imaging findings, treatment modalities and outcomes of patients with pre- and postoperative HSF-8 quality of life questionnaire were studied. Success rate was 82% after first surgery and 91.6% after revision surgery. A low rate of perioperative morbidity was found. Facial palsy was mostly transient (5.5% transient and 0.2% permanent) and cochleovestibular deficit was seen in 4.8% of patients. Revision surgery increased nervous lesions (10.6% to 20.7%). Mean quality of life scores were significantly improved from 18 to 2 over 32, evaluated 7.3 years after surgery. Predictive factors of surgical failure were single conflicts (p = 0.041), atypical vasculo-nervous conflicts involving other vessel than postero-inferior cerebellar artery (p = 0.036), such as vein (p = 0.045), and other compression sites than root exit zone (p = 0.027). Retrosigmoid microvascular decompression is a safe and effective treatment of hemifacial spasm. Revision surgery is not to be excluded in case of failure, but does place patients at risk for more complications. Quality of life is improved in the long-term, indicating objective and subjective satisfaction. PMID- 27214835 TI - Considerations on "Endoscopic endonasal approach to the craniocervical junction: the importance of anterior C1 arch preservation or its reconstruction". PMID- 27214837 TI - Introduction. PMID- 27214838 TI - The purification of factor VIII and the characterization of the human factor VIII gene. PMID- 27214836 TI - Further characterisation of the recently described SLC26A4 c.918+2T>C mutation and reporting of a novel variant predicted to be damaging. AB - Pendred syndrome (PS) is the second most common type of autosomal recessive syndromic hearing loss (HL). It is characterised by sensorineural HL and goiter with occasional hypothyroidism. These features are generally accompanied by malformations of the inner ear, as enlarged vestibular aqueduct (EVA). In about 50% of probands, mutations in the SLC26A4 gene are the cause of the disease. Here we report the case of a Portuguese female, aged 47, presenting with severe to profound HL and hypothyroidism. Her mother and sister, both deceased, had suffered from HL and goiter. By MRI and CT, an enlarged vestibular aqueduct and endolymphatic sac were observed. Molecular study of the patient included screening for GJB2 coding mutations and GJB6 common deletions followed by screening of all SLC26A4 exons, as well as intronic regions 8 and 14. Mutation c.918+2T>C was found for the first time in homozygosity in the intronic region 7 of the SLC26A4 gene. Whilst sequencing the control samples, a novel mutation c.821C>G was found in heterozygosity in the exon 7 of SLC26A4 gene and was predicted to be damaging. This study thus led to the finding of two novel SLC26A4 genotypes and provides new insight on the phenotypic features associated with PS. PMID- 27214839 TI - Haemophilia in the UK: past, present and future. PMID- 27214840 TI - The epidemiology of HIV disease in men with haemophilia in the UK. PMID- 27214841 TI - Immune function in patients receiving recombinant factor VIII (rFVIII, Kogenate) and other very-high-purity factor VIII products. PMID- 27214842 TI - Future perspectives in paediatric haemophilia. PMID- 27214843 TI - Factor VIII inhibitors. PMID- 27214844 TI - Virus safety considerations for recombinant factor VIII (rFVIII, Kogenate). PMID- 27214846 TI - Clinical development of recombinant factor VIII (rFVIII, Kogenate). PMID- 27214845 TI - Prophylaxis versus purse strings: is safety an issue? PMID- 27214847 TI - Association of Blood Pressure, Blood Glucose, and Temperature With Neurological Outcome After Childhood Stroke. AB - IMPORTANCE: To our knowledge, no evidence-based guidelines are available for the best medical management of blood pressure, blood glucose levels, and temperature in pediatric patients after arterial ischemic stroke. OBJECTIVE: To determine the prevalence of abnormal blood pressure, blood glucose levels, and temperature in pediatric patients with acute arterial ischemic stroke and to explore any association between these measures and neurological outcome. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective review of children aged 29 days to 18 years with their first arterial ischemic stroke between January 2009 and December 2013 at a tertiary academic children's hospital. Ninety-eight children with stroke were identified by an International Classification of Diseases, Ninth Revision, code search and medical record review. Blood pressure, blood glucose, and temperature data were collected for 5 days after the stroke. Hypertension was defined as systolic blood pressure at or above the 95th percentile for age, sex, and height for 2 consecutive recordings and 2 consecutive days. Hypotension was defined as systolic and/or diastolic blood pressure below the fifth percentile for age, sex, and height for 2 consecutive recordings. Hyperglycemia was defined as a blood glucose level of 200 mg/dL or greater. Morbidity and mortality at 3 months were documented. Data analyses were performed from July 1, 2014, to December 31, 2015. INTERVENTIONS OR EXPOSURES: Abnormal blood pressure, blood glucose levels, and fever in the setting of arterial ischemic stroke. MAIN OUTCOMES AND MEASURES: The a priori outcome measure was poor clinical outcome, defined as a Pediatric Stroke Outcome Measure score of 1 or greater, which represents a moderate neurological deficit. RESULTS: The median (interquartile range) age of the 98 children was 6.0 (0.6-14.3) years, and 58 (59.2%) were male. Hypertension was present in 64 (65.3%), hypotension in 67 (68.4%), hyperglycemia in 17 (18.1%), and fever in 37 (37.8%). The strongest association with poor neurological outcome was an infarct size of 4% or greater of brain volume (odds ratio, 5.6; 95% CI, 2.0-15.4; P = .001). Hyperglycemia was also independently associated with poor neurological outcome (odds ratio, 3.9; 95% CI, 1.2-12.4; P = .02). Hypertension and fever were not significantly associated with infarct size, poor outcome, or death. Hypertension was not documented in 24 of 87 surviving children (27.6%) at 3-month follow-up and was not associated with poor neurological outcome. CONCLUSIONS AND RELEVANCE: Abnormalities of blood pressure, blood glucose levels, and temperature are prevalent in children with arterial ischemic stroke. Infarct volume and hyperglycemia were associated with poor neurological outcome but hypertension and fever were not. Prospective studies that systematically record blood pressure, blood glucose, and temperature data are required to further assess the associations between these potentially modifiable physiological parameters and pediatric stroke outcome. PMID- 27214848 TI - Association Between Genetic Variation in FOXO3 and Reductions in Inflammation and Disease Activity in Inflammatory Polyarthritis. AB - OBJECTIVE: Genetic variation in FOXO3 (tagged by rs12212067) has been associated with a milder course of rheumatoid arthritis (RA) and shown to limit monocyte driven inflammation through a transforming growth factor beta1-dependent pathway. This genetic association, however, has not been consistently observed in other RA cohorts. We sought to clarify the contribution of FOXO3 to prognosis in RA by combining detailed analysis of nonradiographic disease severity measures with an in vivo model of arthritis. METHODS: Collagen-induced arthritis, the most commonly used mouse model of RA, was used to assess how Foxo3 contributes to arthritis severity. Using clinical, serologic, and biochemical methods, the arthritis that developed in mice carrying a loss-of-function mutation in Foxo3 was compared with that which occurred in littermate controls. The association of rs12212067 with nonradiographic measures of RA severity, including the C-reactive protein level, the swollen joint count, the tender joint count, the Disease Activity Score in 28 joints, and the Health Assessment Questionnaire score, were modeled longitudinally in a large prospective cohort of patients with early RA. RESULTS: Loss of Foxo3 function resulted in more severe arthritis in vivo (both clinically and histologically) and was associated with higher titers of anticollagen antibodies and interleukin-6 in the blood. Similarly, rs12212067 (a single-nucleotide polymorphism that increases FOXO3 transcription) was associated with reduced inflammation, both biochemically and clinically, and with lower RA activity scores. CONCLUSION: Consistent with its known role in restraining inflammatory responses, FOXO3 limits the severity of in vivo arthritis and, through genetic variation that increases its transcription, is associated with reduced inflammation and disease activity in RA patients, effects that result in less radiographic damage. PMID- 27214849 TI - Trifluoromethylation of Arylsilanes with [(phen)CuCF3 ]. AB - A method for the trifluoromethylation of arylsilanes is reported. The reaction proceeds with [(phen)CuCF3 ] as the CF3 source under mild, oxidative conditions with high functional-group compatibility. This transformation complements prior trifluoromethylation of arenes in several ways. Most important, this method converts arylsilanes formed by the silylation of aryl C-H bonds to trifluoromethylarenes, thereby allowing the conversion of arenes to trifluoromethylarenes. The unique capabilities of the reported method are demonstrated by the conversion of a C-H bond into a C-CF3 bond in active pharmaceutical ingredients which do not undergo this overall transformation by alternative functionalization processes, including a combination of borylation and trifluoromethylation. PMID- 27214850 TI - Evidence of Shared Genome-Wide Additive Genetic Effects on Interpersonal Trauma Exposure and Generalized Vulnerability to Drug Dependence in a Population of Substance Users. AB - Exposure to traumatic experiences is associated with an increased risk for drug dependence and poorer response to substance abuse treatment (Claus & Kindleberger, 2002; Jaycox, Ebener, Damesek, & Becker, 2004). Despite this evidence, the reasons for the observed associations of trauma and the general tendency to be dependent upon drugs of abuse remain unclear. Data (N = 2,596) from the Study of Addiction: Genetics and Environment were used to analyze (a) the degree to which commonly occurring single nucleotide polymorphisms (SNPs; minor allele frequency > 1%) in the human genome explains exposure to interpersonal traumatic experiences, and (b) the extent to which additive genetic effects on trauma are shared with additive genetic effects on drug dependence. Our results suggested moderate additive genetic influences on interpersonal trauma, h(2) SNP-Interpersonal = .47, 95% confidence interval (CI) [.10, .85], that are partially shared with additive genetic effects on generalized vulnerability to drug dependence, h(2) SNP-DD = .36, 95% CI [.11, .61]; rG-SNP = .49, 95% CI [.02, .96]. Although the design/technique does not exclude the possibility that substance abuse causally increases risk for traumatic experiences (or vice versa), these findings raise the possibility that commonly occurring SNPs influence both the general tendency towards drug dependence and interpersonal trauma. PMID- 27214851 TI - Defining Arthritis for Public Health Surveillance: Methods and Estimates in Four US Population Health Surveys. AB - OBJECTIVE: To determine the variability of arthritis prevalence in 4 US population health surveys. METHODS: We estimated annualized arthritis prevalence in 2011-2012, among adults age >=20 years, using 2 definition methods, both based on self-report: 1) doctor-/health care provider-diagnosed arthritis in the Behavioral Risk Factor Surveillance Survey (BRFSS), National Health and Nutrition Examination Survey (NHANES), National Health Interview Survey (NHIS), and Medical Expenditure Panel Survey (MEPS); and 2) three arthritis definitions based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) criteria in MEPS (National Arthritis Data Workgroup on Arthritis and Other Rheumatic Conditions [NADW-AORC], Clinical Classifications Software [CCS], and Centers for Disease Control and Prevention [CDC]). RESULTS: Diagnosed arthritis prevalence percentages using the surveys were within 3 points of one another (BRFSS 26.2% [99% confidence interval (99% CI) 26.0-26.4], MEPS 26.1% [99% CI 25.0-27.2], NHIS 23.5% [99% CI 22.9-24.1], NHANES 23.0% [99% CI 19.2 26.8]), and those using ICD-9-CM were within 5 percentage points of one another (CCS 25.8% [99% CI 24.6-27.1]; CDC 28.3% [99% CI 27.0-29.6]; and NADW-AORC 30.7% [99% CI 29.4-32.1]). The variation in the estimated number (in millions) affected with diagnosed arthritis was 7.8 (BRFSS 58.5 [99% CI 58.1-59.1], MEPS 59.3 [99% CI 55.6-63.1], NHANES 51.5 [99% CI 37.2-65.5], and NHIS 52.6 [99% CI 50.9-54.4]), and using ICD-9-CM definitions it was 11.1 (CCS 58.7 [99% CI 54.5-62.9], CDC 64.3 [99% CI 59.9-68.6], and NADW 69.9 [99% CI 65.2-74.5]). Most (57-70%) reporting diagnosed arthritis also reported ICD-9-CM arthritis; respondents reporting diagnosed arthritis were older than those meeting ICD-9-CM definitions. Proxy response status affected arthritis prevalence differently across surveys. CONCLUSION: Public health practitioners and decision makers are frequently charged with choosing a single number to represent arthritis prevalence in the US population. We encourage them to consider the surveys' purpose, design, measurement methods, and statistical precision when choosing an estimate. PMID- 27214852 TI - No evidence of general CO2 insensitivity in ferns: one stomatal control mechanism for all land plants? AB - Stomatal regulation of plant carbon uptake and water loss under changing environmental conditions was a crucial evolutionary step in the colonization of land by plants. There are currently two conflicting models describing the nature of stomatal regulation across terrestrial vascular plants: the first is characterized by a fundamental mechanistic similarity across all lineages, and the second is characterized by the evolution of major differences in angiosperms compared with more ancient lineages. Specifically, the second model posits that stomata of ferns lack a response to elevated atmospheric CO2 concentration (ca ) and therefore cannot regulate leaf intercellular CO2 concentration (ci ). We compared stomatal sensitivity to changes in ca in three distantly related fern species and a representative angiosperm species. Fern and angiosperm stomata responded strongly and similarly to changes in ca . As a result, ci /ca was maintained within narrow limits during ca changes. Our results challenge the model in which stomata of ferns generally lack a response to elevated ca and that angiosperms evolved new dynamic mechanisms for regulating leaf gas exchange that differ fundamentally from ferns. Instead, the results are consistent with a universal stomatal control mechanism that is fundamentally conserved across ferns and angiosperms, and therefore likely all vascular plant divisions. PMID- 27214853 TI - Detection of Helicobacter pylori by Real-Time PCR for 16s rRNA in Stools of NonInfected Healthy Children, Using ELISA Antigen Stool Test as the Gold Standard. AB - BACKGROUND: We previously detected Helicobacter pylori infection by stool antigen ELISA assay in 33-41% of asymptomatic Chilean children between 2-3 years of age, of which 11-20% had a transient infection and 21-22% a persistent infection. A total of 88% of ELISA-positive samples were also rtPCR positive, while 37/133 (33%) of ELISA-negative stool samples were rtPCR positive. The significance of a ELISA-negative/rtPCR-positive sample requires clarification. We aimed to determine whether rtPCR is able to detect persistent infections not detected by ELISA. MATERIALS AND METHODS: We selected 36 children with an ELISA negative/rtPCR-positive stool sample, of which 25 were never H. pylori infected according to ELISA, and 11 had a transient infection with an ELISA-positive sample before or after the discordant sample. At least two additional consecutive ELISA-negative samples per child were tested in duplicate by rtPCR for the 16s rRNA gene. RESULTS: A total of 14 of 78 (17.9%) rtPCR reactions were positive, but only 4/78 (5.1%) were positive in both duplicates, representing a total of 3/36 (8.3%) children with an additional rtPCR-positive sample, only one of whom was persistently negative by ELISA. One child with a transient infection had two positive rtPCR reactions despite negative ELISA samples. CONCLUSIONS: In H. pylori noninfected or transiently infected children, as determined by stool ELISA, additional ELISA-negative/rtPCR-positive stool samples were found in 8.3% of children, but a possible persistent infection was only identified in 2.7% of children. Thus, the characterization of infection dynamics in children is not being misrepresented by application of stool ELISA. Furthermore, rtPCR does not significantly improve dynamic characterization. PMID- 27214854 TI - Validation of the Reveal((r)) 2.0 Group D1 Salmonella Test for Detection of Salmonella Enteritidis in Raw Shell Eggs and Poultry-Associated Matrixes. AB - A study was conducted to assess the performance of the Reveal((r)) 2.0 Group D1 Salmonella lateral flow immunoassay for use in detection of Salmonella Enteritidis (SE) in raw shell eggs and poultry-associated matrixes, including chicken carcass rinse and poultry feed. In inclusivity testing, the Reveal 2.0 test detected all 37 strains of SE tested. The test also detected all but one of 18 non-Enteritidis somatic group D1 Salmonella serovars examined. In exclusivity testing, none of 42 strains tested was detected. The exclusivity panel included Salmonella strains of somatic groups other than D1, as well as strains of other genera of Gram-negative bacteria. In matrix testing, performance of the Reveal 2.0 test was compared to that of the U.S. Department of Agriculture, Food Safety and Inspection Service Microbiology Laboratory Guidebook reference culture procedure for chicken carcass rinse and to that of the U.S. Food and Drug Administration Bacteriological Analytical Manual for raw shell eggs and poultry feed. For all matrixes evaluated, there were no significant differences in the ability to detect SE when comparing the Reveal 2.0 method and the appropriate reference culture procedure as determined by probability of detection statistical analysis. The ability of the Reveal 2.0 test to withstand modest perturbations to normal operating parameters was examined in robustness experiments. Results showed that the test can withstand deviations in up to three operating parameters simultaneously without significantly affecting performance. Real-time stability testing of multiple lots of Reveal 2.0 devices established the shelf life of the test device at 16 months postmanufacture. PMID- 27214855 TI - A dual enzyme system composed of a polyester hydrolase and a carboxylesterase enhances the biocatalytic degradation of polyethylene terephthalate films. AB - TfCut2 from Thermobifida fusca KW3 and the metagenome-derived LC-cutinase are bacterial polyester hydrolases capable of efficiently degrading polyethylene terephthalate (PET) films. Since the enzymatic PET hydrolysis is inhibited by the degradation intermediate mono-(2-hydroxyethyl) terephthalate (MHET), a dual enzyme system consisting of a polyester hydrolase and the immobilized carboxylesterase TfCa from Thermobifida fusca KW3 was employed for the hydrolysis of PET films at 60 degrees C. HPLC analysis of the reaction products obtained after 24 h of hydrolysis showed an increased amount of soluble products with a lower proportion of MHET in the presence of the immobilized TfCa. The results indicated a continuous hydrolysis of the inhibitory MHET by the immobilized TfCa and demonstrated its advantage as a second biocatalyst in combination with a polyester hydrolase for an efficient degradation oft PET films. The dual enzyme system with LC-cutinase produced a 2.4-fold higher amount of degradation products compared to TfCut2 after a reaction time of 24 h confirming the superior activity of his polyester hydrolase against PET films. PMID- 27214856 TI - Backseat drivers: passenger mutations take control of experimental phenotypes. PMID- 27214857 TI - GB virus C/hepatitis G virus. PMID- 27214858 TI - Clinical manifestations in 28 Italian and Iranian patients with severe factor VII deficiency. AB - There has been wide variation in the reported haemorrhagic manifestations of factor VII deficiency. We examined type and frequency of clinical manifestations in 28 Iranian and Italian patients with severe deficiency (factor VII coagulant activity 2% or less). The most frequent symptoms were epistaxis and menorrhagia, whereas soft tissue bleeding such as haemarthrosis and muscle haematoma was less frequent. Only 5 of 9 patient who underwent surgery without factor VII replacement therapy had postoperative bleeding severe enough to require blood transfusion. No thrombotic manifestation occurred. A factor VII functional assay based on the use of human thromboplastin was a better predictor of the bleeding tendency of these patients than a rabbit thromboplastin-based functional assay or immunoassay. On the whole, this study shows that in severe factor VII deficiency bleeding in mucosal tracts is not uncommon. Surgery can sometimes be performed without replacement therapy and without haemorrhagic complications. PMID- 27214859 TI - Efficacy and safety of monoclonal antibody purified factor IX concentrate in haemophilia B patients undergoing surgical procedures. AB - The present study summarizes results of the efficacy and safety of monoclonal antibody (MAb) purified factor IX concentrate [Mononine(r) Coagulation Factor IX (Human), Centeon L.L.C., King of Prussia, PA, USA] for surgical prophylaxis in 74 patients with mild, moderate or severe haemophilia B who underwent a total of 81 different operative interventions. Surgical procedures included joint replacement/arthroplasty (n= 12), gastrointestinal (GI) or rectal surgery (n= 6), synovectomy/osteotomy (n= 8), hernia repair (n= 4), central catheter insertion (n= 3), ENT surgery (n= 4), dental procedures (n= 14), biopsies (n= 2), gynaecological procedures (n= 4), ophthalmological surgery (n= 4), spinal surgery (n= 4), urogenital surgery (n= 2), other orthopaedic surgery (n= 4) or other miscellaneous procedures (n= 10). All patients demonstrated haemostasis rated as 'excellent' by the investigators. No patients experienced clinically evident thromboembolic complications during treatment with MAb factor IX. These results, from a large and varied random group of patients, demonstrate that this highly purified factor IX concentrate is safe and effective for surgical prophylaxis in patients with haemophilia B, including those patients who have experienced thromboembolic complications during prior treatment with prothrombin complex concentrates. PMID- 27214860 TI - Porcine factor VIII (Hyate: C(r)): in vitro stability, microbiological safety and effect of heparin. AB - The in vitro stability of porcine factor VIII (PF VIII) was evaluated when it was reconstituted with sterile water (PF VIIISW ) to ~ 30 U PFVIII mL(-1) , as per the manufacturer's recommendations, and stored in plastic syringes at room temperature, with and without heparin and at four different dilutions. PF VIII was prepared antiseptically without laminar airflow and remained sterile at room temperature for 1 week. PF VIIISW retained at least 88% of baseline activity for 48 h and 74-86% for 72 h. Addition of heparin 1 unit mL(-1) solution resulted in a decrease in the stability of PF VIIISW to 72-74 % of baseline values by 24 h. Reconstituted PF VIIISW , further diluted with normal saline to 10-24 U PF VIII mL(-1) , retained 98% of baseline activity for 48 h and 84% of baseline for 72 h. PF VIII diluted to 6 U mL(-1) , however, retained 100% baseline activity for only 24 h, and declined to 71% and 64 % of baseline by 48 and 72 h, respectively. PF VIII reconstituted with normal saline, instead of sterile water, retained 90% or more of baseline activity for a minimum of 4 days. Once reconstituted, PF VIII appeared to be more stable at room temperature than when stored in the refrigerator. These in vitro stability studies confirm that PF VIII (30 U mL(-1) ) can be given effectively by prolonged continuous infusion, since it retains 88% baseline activity at room temperature in a plastic syringe for a minimum of 48 h, remains sterile and will maintain baseline PF VIII levels when further diluted with saline. PMID- 27214861 TI - Variability of the factor VIII response to DDAVP in a large kindred with mild haemophilia A. AB - Since 1977, desmopressin acetate (DDAVP) has established its important role in the clinical management of bleeding in milder cases of von Willebrand's disease and haemophilia A. We present in vivo DDAVP response data from a large kindred suffering from mild haemophilia A. Levels of FVIII: C in 22 affected family members ranged from 0.11 to 0.24 IU mL(-1) of FVIII: C (0.18 +/- 0.04, mean +/- SD), increasing to 0.22-0.92 IU mL(-1) after DDAVP, giving a mean response ratio of 3.5. Response rates by various routes of administration did not differ significantly, being 3.3 for subcutaneous administration (n= 17), 3.7 for intravenous administration (n= 4) and 3.2 for intranasal spray application (n= 1). No significant correlation was found between the pretreatment level and the response rate. In three individuals, the post-DDAVP level of FVIII: C was below 0.40 IU mL(-1) , the value we arbitrarily regard as the lower limit of a successful response for haemostatic efficacy suited for self-management purposes, demonstrating that the response rate in a given member of the family cannot be predicted from previous experiences with other haemophilic members of the same subset. PMID- 27214862 TI - Effect of intermediate- and high-purity factor VIII concentrates on immune function in HIV-seropositive haemophiliacs as assessed by quantitative CD 4 counts. AB - Intermediate-purity factor VIII (FVIII) concentrates are believed to adversely influence cellular immune function and accelerate HIV progression in haemophiliac patients. There are reports that cellular immunity, as measured by serial CD4 lymphocyte counts, is better preserved in HIV-infected haemophiliacs who receive high-purity concentrates compared with those receiving intermediate- or low purity products. We retrospectively evaluated the rate of CD4 cell count decrease in 44 asymptomatic HIV-seropositive severe haemophilia A patients whose purity of prescribed FVIII concentrate was primarily determined by State of residence. Prior to January 1989 all study subjects received treatment with intermediate- or low-purity products. In January 1989 the patients from Mississippi (n = 15) began to exclusively receive a high-purity, monoclonal antibody purified, plasma derived product from their State Department of Health. The Mississippi cohort was subsequently converted to a high-purity, recombinant FVIII product in May 1993. Patients from Tennessee and Arkansas (n = 29) received intermediate-purity factor during the entire analysis period. Patients were monitored for an average of 68 months with an average of 11 CD4 cell count measurements. The rate of CD4 cell count decrease was derived from the calculated slope of a simple regression in order to account for large individual CD4 count fluctuations during the study period. There was no statistically significant difference in starting CD4 cell count between the 2 study groups. The rate of CD4 cell count decrease was 21.8 +/ 52.9 cells MUL(-1) year(-1) and 17.0 +/- 32.6 cells MUL(-1) year(-1) in the high purity FVIII group and inter-mediate-purity FVIII group, respectively (P = 0.83). The difference in rate of CD4:CD8 ratio decrease between the two groups was also not statistically significant (P = 0.41). These data suggest that the use of the more costly, high-purity monoclonal antibody purified and recombinant FVIII concentrates does not influence the rate of decrease in CD4 cell count in HIV seropositive haemophiliacs compared with concentrates of lower specific activity obtained using standard chromatographic techniques. PMID- 27214863 TI - Health care provider and self-assessment of health status and sexual behaviour in HIV-seropositive young men with haemophilia. AB - We hypothesized that persons with HIV who perceive themselves as having waning health status may participate in fewer sexual behaviours than HIV-infected persons without HIV-related health problems. The object-ives of this study were to compare health care provider responses with participant responses for health status and for sexual activity and to examine the relationship of HIV-related health status to the sexual behaviour of HIV-seropositive adolescents and young men with haemophilia. A detailed questionnaire designed by researchers from 11 participating US haemophilia treatment sites and CDC personnel was administered to 306 HIV-seropositive young men with haemophilia aged 12-25 years. A health care provider from the haemophilia treatment centre also completed a questionnaire on each respondent. Self-assessment of HIV-related health status was similar to provider assessment of health status. Providers accurat-ely assessed participant sexual activity (overall Kappa = 0.62). Participation in vaginal intercourse and condom use was independent of health status. Following extensive educational efforts, most HIV-seropositive adolescents and young men with haemophilia are aware of the relationship between their HIV seropositivity and health status. Waning health status does not reduce participation in penetrative sexual behaviours or increase use of condoms. HIV prevention efforts should continue for this population. PMID- 27214864 TI - HIV-disease progression in Swedish haemophiliacs and the influence of replacement therapy. AB - HIV-disease progression in terms of the decline in CD4(+) cell count, the development of AIDS-related symptoms and death was studied in 100 Swedish HIV positive haemophiliacs and correlated to age and haemophilia treatment. On average 15 years after seroconversion, 66% of the patients had CD4(+) cell counts of < 200*10(6) L(-1) , 48% had developed AIDS and 56% had died. Age was found to correlate to all three endpoints, also after adjustment for age, annual clotting factor concentrate (CFC) consumption and HIV-related therapy, i.e. pneumocystis prophylaxis and antiretroviral drugs (P < 0.05). Total annual CFC consumption showed no significant relationship to the decline in CD4(+) cell counts but was inversely correlated to both the development of AIDS-related symptoms (P = 0.033) and mortality (P = 0.014). Prophylactic treatment was not associated with significantly better survival than on-demand treatment after adjustment for age, CFC consumption and HIV-therapy. The use of monoclonal-antibody-purified CFCs was not found to stabilize the decline in CD4(+) cell counts. However, the use of these CFCs was inversely correlated both to the development of AIDS-related symptoms and to mortality (P = 0.042 and 0.027, respectively). A similar trend was associated with the use of low- and intermediate-purity CFCs. As compared with the severe haemophilia A subgroup, the moderate haemophilia A patients showed a trend toward slower disease progression, possibly attributable to a lower incidence of haemarthrosis and arthropathy among the latter. We conclude that replacement therapy in HIV-infected haemophiliacs is important also for HIV disease progression, whereas the purity of the CFCs and the regimen used are of minor importance. PMID- 27214865 TI - Hepatitis G virus infection in Japanese haemophiliacs. AB - The recently identified hepatitis G virus (HGV) (also known as GB virus-C) has been considered as a blood-transmissible agent. As many haemophiliacs have risk factors for infectious agents, to clarify the frequency of HGV infection is important. HGV-RNA was investigated in 77 Japanese haemophiliacs who had been treated with nonvirus-inactivated concentrates derived from pooled plasma. Detection of HGV-RNA was performed with a nested RT-PCR that recognizes the 5' NCR of the HGV genome. HGV-RNA was detected in 19 (24.7%), including four (21.0%) infected with HGV alone, 12 (63.2%) co-infected with HCV and three (15.8%) who were HBV carriers. The patients infected with HGV alone showed a normal ALT level of 18.7 +/- 4.1 IU L(-1) . Most (36/37, 97.3%) of the patients with abnormal ALT levels had HCV-RNA. Patients infected with HCV alone or co-infected with HCV and HGV showed higher ALT levels of 108.8 +/- 90.2 IU L(-1) (n= 39) and 67.6 +/- 62.6 IU L(-1) (n= 11), respectively. However, there was no significant difference (P= 0.16) in ALT levels between HCV infection alone and HCV/HGV co-infection. On the other hand, four of the patients who could be followed over 10 years showed HGV RNA persistently. In two who underwent liver biopsy, the histological evidence showed no definitive fibrotic and necro-inflammatory changes. These results indicate that HGV infection has frequently occurred in haemophiliacs. It is possible that HGV infection does not cause aggressive hepatitis with elevated ALT levels, and that co-infection with HGV may not aggravate hepatitis caused by HCV. PMID- 27214866 TI - Identification and eradication of Helicobacter pylori infection in haemophilic patients. AB - The aim of this study was to identify and eradicate H. pylori infection in patients with haemophilia. Patients were screened for IgG antibodies against H. pylori; active infection was determined using a (13) C-urea breath test and infected patients were given combination therapy with antibiotics to eradicate infection. Seventy-eight of 219 (36%) patients with haemophilia were found to have an elevated serum antibody titre against H. pylori; of 36 antibody-positive patients with confirmatory testing, 14 were found to have active H. pylori infection. H. pylori infection was successfully eradicated in every infectedpatient using acombination of ranitidine plus two antibiotics (usually amoxycillin and metronidazole). It is concluded that eradication of H. pylori infection is likely to be a cost-effective screening strategy in patients with haemophilia, to prevent complications of peptic ulcer disease. PMID- 27214867 TI - Incidence of hereditary bleeding disorders in Bradford, UK: variation with ethnic group. AB - We have studied the number of patients registered with congenital bleeding disorders at the Haemophilia Centre, Bradford, UK, according to ethnic group. The large Pakistani population in Bradford presents a different spectrum of disorders compared with the indigenous Caucasian population with a significantly higher number of cases of factor VII deficiency and platelet disorders. Other haemophilia centres in the developed world serving large immigrant communities may also manage increased numbers of these rarer disorders with similar implications for resource allocation. PMID- 27214869 TI - Fourth Musculoskeletal Congress of the World Federation of Hemophilia, Madrid, Spain, 6-9 April 1997: a review of the scientific programme. PMID- 27214868 TI - Subdural haemorrhage as a predisposing factor for hyponatraemic convulsions in an infant undergoing test dose DDAVP infusion. AB - The infusion of desmopressin (DDAVP) is important in the investigation and treatment of selected bleeding diatheses. The potential toxicity of DDAVP is well known. In infants, hyponatraemic convulsions have been reported mostly with repeated infusions of DDAVP and rarely in the context of a single, test dose of DDAVP. We report a case of an infant with a small, resolving spontaneous subdural haematoma in whom a standard test dose infusion of DDAVP resulted in severe hyponatraemia and convulsions. Urinary arginine vasopressin analysis retrospectively identified a subclinical form of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) as a likely predisposing factor. We conclude that even in patients with normal plasma sodium levels, DDAVP testing should be performed with caution and preferably deferred where the possibility of SIADH exists. PMID- 27214871 TI - 'Dose requirement for replacement therapy in hemophilia A'. PMID- 27214872 TI - Identification of four plastid-localized protein kinases. AB - In chloroplasts, protein phosphorylation regulates important processes, including metabolism, photosynthesis, gene expression, and signaling. Because the hitherto known plastid protein kinases represent only a fraction of existing kinases, we aimed at the identification of novel plastid-localized protein kinases that potentially phosphorylate enzymes of the tetrapyrrole biosynthesis (TBS) pathway. We screened publicly available databases for proteins annotated as putative protein kinase family proteins with predicted chloroplast localization. Additionally, we analyzed chloroplast fractions which were separated by sucrose density gradient centrifugation by mass spectrometry. We identified four new candidates for protein kinases, which were confirmed to be plastid localized by expression of GFP-fusion proteins in tobacco leaves. A phosphorylation assay with the purified kinases confirmed the protein kinase activity for two of them. PMID- 27214873 TI - Platinum(iv) anticancer prodrugs - hypotheses and facts. AB - In this manuscript we focus on Pt(iv) anticancer prodrugs. We explore the main working hypotheses for the design of effective Pt(iv) prodrugs and note the exceptions to the common assumptions that are prevalent in the field. Special attention was devoted to the emerging class of "dual action" Pt(iv) prodrugs, where bioactive ligands are conjugated to the axial positions of platinum in order to obtain orthogonal or complementary effects that will increase the efficacy of killing the cancer cells. We discuss the rationale behind the design of the "dual action" prodrugs and the results of the pharmacological studies obtained. Simultaneous release of two bioactive moieties inside the cancer cells often triggers several processes that together determine the fate of the cell. Pt(iv) complexes provide many opportunities for applying new concepts in targeting, synergistic cell killing and exploiting novel nanodelivery systems. PMID- 27214874 TI - Splenic Irradiation for the Treatment of Severe Antibody-Mediated Rejection. AB - Patients requiring desensitization prior to renal transplantation are at risk for developing severe antibody-mediated rejection (AMR) refractory to treatment with plasmapheresis and intravenous immunoglobulin (PP/IVIg). We have previously reported success at graft salvage, long-term graft survival and protection against transplant glomerulopathy with the use of eculizumab and splenectomy in addition to PP/IVIg. Splenectomy may be an important component of this combination therapy and is itself associated with a marked reduction in donor specific antibody (DSA) production. However, splenectomy represents a major operation, and some patients with severe AMR have comorbid conditions that substantially increase their risk of complications during and after surgery. In an effort to spare recipients the morbidity of a second operation, we used splenic irradiation in lieu of splenectomy in two incompatible live donor kidney transplant recipients with severe AMR in addition to PP/IVIg, rituximab and eculizumab. This novel approach to the treatment of severe AMR was associated with allograft salvage, excellent graft function and no short- or medium-term adverse effects of the radiation therapy. One-year surveillance biopsies did not show transplant glomerulopathy (tg) on light microscopy, but microcirculation inflammation and tg were present on electron microscopy. PMID- 27214875 TI - Survival Among Infants Born at 22 or 23 Weeks' Gestation Following Active Prenatal and Postnatal Care. AB - IMPORTANCE: Rates of survival for infants born at the border of viability are still low and vary considerably among neonatal intensive care units. OBJECTIVE: To determine whether higher survival rates and better short-term outcomes for infants born at 22 or 23 weeks' gestation may be achieved by active prenatal and postnatal care. DESIGN, SETTING, AND PARTICIPANTS: Retrospective study of 106 infants born at 22 or 23 weeks of gestation at a level III neonatal intensive care unit at the University of Cologne Medical Centre in Cologne, Germany, between January 1, 2010, and December 31, 2014. Data analysis was performed in June 2015. EXPOSURES: Active prenatal and postnatal care. MAIN OUTCOMES AND MEASURES: Survival until hospital discharge and survival without neonatal or short-term severe complications (defined as high-grade intraventricular hemorrhage, surgery for abdominal complications, bronchopulmonary dysplasia, or retinopathy of prematurity). RESULTS: Of 106 liveborn infants (45 born at 22 weeks and 61 born at 23 weeks and 6 days), 20 (19%) received palliative care (17 born at 22 weeks and 3 born at 23 weeks), and 86 (81%) received active care (28 born at 22 weeks and 58 born at 23 weeks). Of the 86 infants who received active care (mean [SD] maternal age, 32 [6] years), 58 (67%) survived until hospital discharge (17 born at 22 weeks and 41 born at 23 weeks). Eighty-five infants survived without severe complications, with 1 infant born at 22 weeks excluded because of missing data (6 of 27 [22%] born at 22 weeks, and 16 of 58 [28%] born at 23 weeks). Survival was predicted by the Apgar score after 5 minutes (odds ratio, 0.62 [95% CI, 0.46-0.84]) and birth weight (odds ratio, 0.001 [95% CI, 0.00-0.40]). CONCLUSIONS AND RELEVANCE: One in 4 infants born at the border of viability and offered active care survived without severe complications. This finding should be considered for individualized parental approaches and decision making. Active follow-up information is required to determine childhood outcomes. PMID- 27214876 TI - Advances in quadrupole and time-of-flight mass spectrometry for peptide MRM based translational research analysis. AB - The application of unit resolution tandem quadrupole and high-resolution orthogonal acceleration ToF mass spectrometers for the quantitation and translational analysis of proteolytic peptides is described. The MS platforms were contrasted in terms of sensitivity and linear response. Moreover, the selectivity of the platforms was investigated and the effect on quantitative precision studied. Chromatographic LC conditions, including gradient length and configuration, were investigated with respect to speed/throughput, while minimizing isobaric interferences, thereby providing information with regard to practical sample cohort size limitations of LC-MS for large cohort experiments. In addition to these fundamental analytical performance metrics, precision and linear dynamic ranges were also studied. An LC-MS configuration that encompasses the best combination of throughput and analytical accuracy for translational studies was chosen, despite the MS platforms giving similar quantitative performance, and instances were identified where alternative combinations were found to be beneficial. This configuration was utilized to demonstrate that proteolytically digested nondepleted samples from heart failure patients could be classified with good discriminative power using a subset of proteins previously suggested as candidate biomarkers for cardiovascular diseases. PMID- 27214877 TI - Controlling Bone Graft Substitute Microstructure to Improve Bone Augmentation. AB - Vertical bone augmentation procedures are frequently carried out to allow successful placement of dental implants in otherwise atrophic ridges and represent one of the most common bone grafting procedures currently performed. Onlay autografting is one of the most prevalent and predictable techniques to achieve this; however, there are several well documented complications and drawbacks associated with it and synthetic alternatives are being sought. Monetite is a bioresorbable dicalcium phosphate with osteoconductive and osteoinductive potential that has been previously investigated for onlay bone grafting and it is routinely made by autoclaving brushite to simultaneously sterilize and phase convert. In this study, monetite disc-shaped grafts are produced by both wet and dry heating methods which alter their physical properties such as porosity, surface area, and mechanical strength. Histological observations after 12 weeks of onlay grafting on rabbit calvaria reveal higher bone volume (38%) in autoclaved monetite grafts in comparison with the dry heated monetite grafts (26%). The vertical bone height gained is similar for both the types of monetite grafts (up to 3.2 mm). However, it is observed that the augmented bone height is greater in the lateral than the medial areas of both types of monetite grafts. It is also noted that the higher porosity of autoclaved monetite grafts increases the bioresorbability, whereas the dry heated monetite grafts having lower porosity but higher surface area resorb to a significantly lesser extent. This study provides information regarding two types of monetite onlay grafts prepared with different physical properties that can be further investigated for clinical vertical bone augmentation applications. PMID- 27214878 TI - Postprocessing of Compressed Images via Sequential Denoising. AB - In this paper, we propose a novel postprocessing technique for compression artifact reduction. Our approach is based on posing this task as an inverse problem, with a regularization that leverages on existing state-of-the-art image denoising algorithms. We rely on the recently proposed Plug-and-Play Prior framework, suggesting the solution of general inverse problems via alternating direction method of multipliers, leading to a sequence of Gaussian denoising steps. A key feature in our scheme is a linearization of the compression decompression process, so as to get a formulation that can be optimized. In addition, we supply a thorough analysis of this linear approximation for several basic compression procedures. The proposed method is suitable for diverse compression techniques that rely on transform coding. In particular, we demonstrate impressive gains in image quality for several leading compression methods-JPEG, JPEG2000, and HEVC. PMID- 27214879 TI - Joint Data Filtering and Labeling Using Gaussian Processes and Alternating Direction Method of Multipliers. AB - Sequence labeling aims at assigning a label to every sample of a signal (or pixel of an image) while considering the sequentiality (or vicinity) of the samples. To perform this task, many works in the literature first filter and then label the data. Unfortunately, the filtering, which is performed independently from the labeling, is far from optimal and frequently makes the latter task harder. In this paper, a novel approach that trains a Gaussian process classifier and estimates the coefficients of an optimal filter jointly is presented. The new approach, based on Bayesian modeling and alternating direction method of multipliers (ADMMs) optimization, performs both tasks simultaneously. All unknowns are treated as stochastic variables, which are estimated using variational inference and filtering and labeling are linked with the use of ADMM. In the experimental section, synthetic and real experiments are presented to compare the proposed method with other existing approaches. PMID- 27214880 TI - Self-Reflection: Using Journal Entries to Enhance Teaching and Orthopedic Resident Communication. PMID- 27214881 TI - Massive Rotator Cuff Tears: Trends in Surgical Management. AB - Compared with smaller tears, massive rotator cuff tears present significant clinical management dilemmas for the treating surgeon because they are often fraught with structural failure and poor outcomes. To optimize healing, current surgical methods look to optimize footprint coverage and enhance the biological environment for healing. Double-row techniques have demonstrated clear biomechanical advantages in controlled cadaveric studies, but have yet to demonstrate clear clinical efficacy over more simple repair techniques. When repairs for massive rotator cuff tears fail, options include revision repair or superior capsular reconstruction, an option to bridge the tissue gap with human dermal allograft or fascia lata autograft in hopes of containing the humeral head from superior migration and precluding rotator cuff arthropathy. Although latissimus transfers remain a reasonable option for massive, irreparable rotator cuff tears in appropriately indicated patients, clinical results are often unpredictable. Older patients with chronic, massive rotator cuff tears with pseudoparalysis can achieve predictable, often excellent clinical results with a reverse total shoulder arthroplasty. [Orthopedics. 2016; 39(3):145-151.]. PMID- 27214882 TI - Corrections to "Neural Data-Driven Musculoskeletal Modeling for Personalized Neurorehabilitation Technologies". AB - Presents corrections made to author names for the paper, ""Neural data-driven musculoskeletal modeling for personalized neurorehabilitation technologies," (Sartori, M., et al) IEEE Trans. Biomed. Eng., vol. 63, no. 5, pp. 879-893, May 2016. PMID- 27214883 TI - 2D and 3D Mechanobiology in Human and Nonhuman Systems. AB - Mechanobiology involves the investigation of mechanical forces and their effect on the development, physiology, and pathology of biological systems. The human body has garnered much attention from many groups in the field, as mechanical forces have been shown to influence almost all aspects of human life ranging from breathing to cancer metastasis. Beyond being influential in human systems, mechanical forces have also been shown to impact nonhuman systems such as algae and zebrafish. Studies of nonhuman and human systems at the cellular level have primarily been done in two-dimensional (2D) environments, but most of these systems reside in three-dimensional (3D) environments. Furthermore, outcomes obtained from 3D studies are often quite different than those from 2D studies. We present here an overview of a select group of human and nonhuman systems in 2D and 3D environments. We also highlight mechanobiological approaches and their respective implications for human and nonhuman physiology. PMID- 27214884 TI - Thalamic Visual Prosthesis. AB - Glaucoma is a neurological disorder leading to blindness initially through the loss of retinal ganglion cells, followed by loss of neurons higher in the visual system. Some work has been undertaken to develop prostheses for glaucoma patients targeting tissues along the visual pathway, including the lateral geniculate nucleus (LGN) of the thalamus, but especially the visual cortex. This review makes the case for a visual prosthesis that targets the LGN. The compact nature and orderly structure of this nucleus make it a potentially better target to restore vision than the visual cortex. Existing research for the development of a thalamic visual prosthesis will be discussed along with the gaps that need to be addressed before such a technology could be applied clinically, as well as the challenge posed by the loss of LGN neurons as glaucoma progresses. PMID- 27214885 TI - Corticomuscular Coherence With Time Lag With Application to Delay Estimation. AB - Functional coupling between the motor cortex and muscle activity is usually detected and characterized using the spectral method of corticomuscular coherence (CMC). This functional coupling occurs with a time delay, which, if not properly accounted for, may decrease the coherence and make the synchrony difficult to detect. In this paper, we introduce the concept of CMC with time lag (CMCTL), that is the coherence between segments of motor cortex electroencephalogram (EEG) and electromyography (EMG) signals displaced from a central observation point. This concept is motivated by the need to compensate for the unknown delay between coupled cortex and muscle processes. We demonstrate using simulated data that under certain conditions the time lag between EEG and EMG segments at points of local maxima of CMCTL corresponds to the average delay along the involved corticomuscular conduction pathways. Using neurophysiological data, we then show that CMCTL with appropriate time lag enhances the coherence between cortical and muscle signals, and that time lags which correspond to local maxima of CMCTL provide estimates of delays involved in corticomuscular coupling that are consistent with the underlying physiology. PMID- 27214886 TI - An Information-Theoretic Framework to Map the Spatiotemporal Dynamics of the Scalp Electroencephalogram. AB - We present the first application of the emerging framework of information dynamics to the characterization of the electroencephalography (EEG) activity. The framework provides entropy-based measures of information storage (self entropy, SE) and information transfer (joint transfer entropy (TE) and partial TE), which are applied here to detect complex dynamics of individual EEG sensors and causal interactions between different sensors. The measures are implemented according to a model-free and fully multivariate formulation of the framework, allowing the detection of nonlinear dynamics and direct links. Moreover, to deal with the issue of volume conduction, a compensation for instantaneous effects is introduced in the computation of joint and partial TE. The framework is applied to resting state EEG measured from healthy subjects in the eyes open (EO) and eyes closed (EC) conditions, evidencing condition-dependent patterns indicative of how information is distributed in the EEG sensor space. The SE was uniformly low during EO and significantly higher in the posterior areas during EC. The joint and partial TE were saturated by instantaneous effects, documenting how volume conduction blurs the detection of information flow in the EEG. However, the use of compensated TE measures led us to evidence meaningful patterns like the presence of local sinks of information flow and propagation motifs, and the emergence of prevalent front-to-back EEG propagation during EC. These findings support the feasibility of our information-theoretic approach to assess the spatiotemporal dynamics of the scalp EEG in different conditions. PMID- 27214887 TI - On the Merits of Tetrapolar Impedance Spectroscopy for Monitoring Lithium Concentration Variations in Human Blood Plasma. AB - Bipolar disorder is characterized as a manic-depressive psychiatric syndrome with life-threatening risks to the patient. Diagnosed individuals undergo long-term lithium therapy which has proven to be effective for mood stabilization. Maintaining blood lithium concentration levels within a narrow therapeutic window between 0.6 and 1.5 mM is vital for the patient as slightly elevated concentrations of the order of 0.1 mM can be toxic. This paper aims to evaluate the merits of tetrapolar electrical impedance spectroscopy as an alternative method in monitoring blood lithium levels. Measurements were performed using a custom-made tetrapolar probe in human blood plasma with lithium concentrations covering the therapeutic range. The results indicate a limit of detection less than 0.1 mM and a response time of less than 5 s. Prediction of lithium concentration levels using impedance values is in good agreement with conventional standard techniques to approximately 0.05 mM. This technique provides a basis for further development of instrumentation for point of care healthcare technologies. PMID- 27214891 TI - Face Verification via Class Sparsity Based Supervised Encoding. AB - Autoencoders are deep learning architectures that learn feature representation by minimizing the reconstruction error. Using an autoencoder as baseline, this paper presents a novel formulation for a class sparsity based supervised encoder, termed as CSSE. We postulate that features from the same class will have a common sparsity pattern/support in the latent space. Therefore, in the formulation of the autoencoder, a supervision penalty is introduced as a joint-sparsity promoting l2,1-norm. The formulation of CSSE is derived for a single hidden layer and it is applied for multiple hidden layers using a greedy layer-by-layer learning approach. The proposed CSSE approach is applied for learning face representation and verification experiments are performed on the LFW and PaSC face databases. The experiments show that the proposed approach yields improved results compared to autoencoders and comparable results with state-of-the-art face recognition algorithms. PMID- 27214892 TI - Enhancing the Velocity Data From 4D Flow MR Images by Reducing its Divergence. AB - Velocity measurements from 4D flow MRI are prone to be affected by several imperfections of the MR system. Assuming that blood is incompressible, we propose a novel method for enhancing the velocity field by reducing its divergence. To enhance the velocity data, we added a corrector velocity to each voxel such that the divergence is minimized. The method was validated using an analytical Womersley flow model for different settings of resolution and noise levels. The performance of the proposed method was also assessed in volunteers and patients. Results demonstrated a significant reduction of the divergence depending on the size of the regularization term, obtaining a reduction close to 50% of the mean divergence with negligible modification of flow parameters. Remarkably, we found that the reduction of the divergence, in percentage, was independent of volunteers, resolution or noise. PMID- 27214893 TI - Accelerating Convolutional Sparse Coding for Curvilinear Structures Segmentation by Refining SCIRD-TS Filter Banks. AB - Deep learning has shown great potential for curvilinear structure (e.g., retinal blood vessels and neurites) segmentation as demonstrated by a recent auto-context regression architecture based on filter banks learned by convolutional sparse coding. However, learning such filter banks is very time-consuming, thus limiting the amount of filters employed and the adaptation to other data sets (i.e., slow re-training). We address this limitation by proposing a novel acceleration strategy to speed-up convolutional sparse coding filter learning for curvilinear structure segmentation. Our approach is based on a novel initialisation strategy (warm start), and therefore it is different from recent methods improving the optimisation itself. Our warm-start strategy is based on carefully designed hand crafted filters (SCIRD-TS), modelling appearance properties of curvilinear structures which are then refined by convolutional sparse coding. Experiments on four diverse data sets, including retinal blood vessels and neurites, suggest that the proposed method reduces significantly the time taken to learn convolutional filter banks (i.e., up to -82%) compared to conventional initialisation strategies. Remarkably, this speed-up does not worsen performance; in fact, filters learned with the proposed strategy often achieve a much lower reconstruction error and match or exceed the segmentation performance of random and DCT-based initialisation, when used as input to a random forest classifier. PMID- 27214895 TI - Enhanced Actuation Performance and Reduced Heat Generation in Shear-Bending Mode Actuator at High Temperature. AB - The actuation performance, strain hysteresis, and heat generation of the shear bending mode actuators based on soft and hard BiScO3-PbTiO3 (BS-PT) ceramics were investigated under different thermal (from room temperature to 300 degrees C) and electrical loadings (from 2 to 10 kV/cm and from 1 to 1000 Hz). The actuator based on both soft and hard BS-PT ceramics worked stably at the temperature as high as 300 degrees C. The maximum working temperature of this shear-bending actuators is 150 degrees C higher than those of the traditional piezoelectric actuators based on commercial Pb(Zr, Ti)O3 materials. Furthermore, although the piezoelectric properties of soft-type ceramics based on BS-PT ceramics were superior to those of hard ceramics, the maximum displacement of the actuator based on hard ceramics was larger than that fabricated by soft ceramics at high temperature. The maximum displacement of the actuator based on hard ceramics was [Formula: see text] under an applied electric field of 10 kV/cm at 300 degrees C. The strain hysteresis and heat generation of the actuator based on hard ceramics was smaller than those of the actuator based on soft ceramics in the wide temperature range. These results indicated that the shear-bending actuator based on hard piezoelectric ceramics was more suitable for high-temperature piezoelectric applications. PMID- 27214894 TI - Optimization-Based Speckle Tracking Algorithm for Left Ventricle Strain Estimation: A Feasibility Study. AB - Speckle tracking echocardiography (STE) is a widespread method for calculating myocardial strains and estimating left ventricle function. Since echocardiographic clips are corrupted by speckle decorrelation noise, resulting in irregular, nonphysiological tissue displacement fields, smoothing is performed on the displacement data, affecting the strain results. Thus, strain results may depend on the specific implementations of 2-D STE, as well as other systems' characteristics of the various vendors. A novel algorithm (called K-SAD) is introduced, which integrates the physiological constraint of smoothness of the displacement field into an optimization process. Simulated B-mode clips, modeling healthy and abnormal cases, were processed by K-SAD. Peak global and subendocardial longitudinal strains, as well as regional strains, were calculated. In addition, 410 healthy subjects were also processed. The results of K-SAD are compared with those of one of the leading commercial product. K-SAD provides global mid-wall strain values, as well as subendocardial and regional strain values, all in good agreement with the ground-truth-simulated phantom data. K-SAD peak global longitudinal systolic strain values for 410 healthy subjects are quite similar for the different regions: - 17.02 +/- 4.02%, - 19.00 +/- 3.45%, and - 19.72 +/- 5.06% at the basal, mid, and apical regions, respectively. Improved performance under noisy conditions was demonstrated by comparing a subgroup of 40 subjects with the best image quality with the remaining 370 cohort: K-SAD provides statistically similar global and regional results for the two cohorts. Our study indicates that the sensitivity of strain values to speckle noise, caused by the post block-matching weighted smoothing, can be significantly reduced and accuracy enhanced by employing an integrated one stage, physiologically constrained optimization process. PMID- 27214896 TI - Structure and Ferroelectric Properties of High Tc BiScO3-PbTiO3 Epitaxial Thin Films. AB - Piezoelectric ceramics of new composition with higher Curie temperature Tc are extensively studied for better piezoelectric microelectromechanical systems (MEMS). Apart from the compositional research, enhanced Tc could be achieved in a modified structure. We have considered that a designed laminated structure of Pb(Zr, Ti)O3 (PZT)-based thin film, i.e., relaxed heteroepitaxial epitaxial thin film, is one of the promising modified structures to enhance Tc . This structure exhibits an extraordinarily high Tc , i.e., [Formula: see text] (bulk [Formula: see text]). In this paper, we have fabricated the designed laminated structure of high Tc (1-x)BiScO3-xPbTiO3. Tc of BS-0.8PT thin films was found to be extraordinarily high, i.e., [Formula: see text] (bulk Tc , [Formula: see text]). Their ferroelectric performances were comparable to those of PZT-based thin films. The present BS-xPT thin films have a high potential for fabrication of high-temperature-stable piezoelectric MEMS. The mechanism of the enhanced Tc is probably the presence of the mechanically stable interface to temperature in the laminated structure. We believe this designed laminated structure can extract fruitful properties of bulk ferroelectric ceramics. PMID- 27214897 TI - Full-Duplex Airborne Ultrasonic Data Communication Using a Pilot-Aided QAM-OFDM Modulation Scheme. AB - Orthogonal frequency division multiplexing (OFDM) has been extensively used in a variety of broadband digital wireless communications applications because of its high bandwidth utilization efficiency and effective immunity to multipath distortion. This paper has investigated quadrature amplitude modulation and OFDM methods in air-coupled ultrasonic communication, using broadband capacitive ultrasonic transducers with high- k dielectric layers. OFDM phase noise was discussed and corrected using a pilot-aided estimation algorithm. The overall system data rate achieved was up to 400 kb/s with a spectral efficiency of 2 b/s/Hz. An ultrasonic propagation model for signal prediction considered atmospheric absorption of sound in air, beam divergence, and transducer frequency response. The simulations were compared with the experimental results, and good agreement was found between the two. Two-way communication through air was also implemented successfully by applying three-way handshaking initialization and an adaptive modulation scheme with variable data rates depending on the transmission distance, estimated using received signal strength indication measurement. It was shown that the error-free transmission range could be extended up to 2.5 m using different system transfer rates from 400 kb/s down to 100 kb/s. In full-duplex transmission mode, the overall error-free system data rate achieved was 0.8 Mb/s up to 1.5 m. PMID- 27214898 TI - A Non-Local Low-Rank Approach to Enforce Integrability. AB - We propose a new approach to enforce integrability using recent advances in non local methods. Our formulation consists in a sparse gradient data-fitting term to handle outliers together with a gradient-domain non-local low-rank prior. This regularization has two main advantages: 1) the low-rank prior ensures similarity between non-local gradient patches, which helps recovering high-quality clean patches from severe outliers corruption and 2) the low-rank prior efficiently reduces dense noise as it has been shown in recent image restoration works. We propose an efficient solver for the resulting optimization formulation using alternate minimization. Experiments show that the new method leads to an important improvement compared with previous optimization methods and is able to efficiently handle both outliers and dense noise mixed together. PMID- 27214900 TI - Connected Component Model for Multi-Object Tracking. AB - In multi-object tracking, it is critical to explore the data associations by exploiting the temporal information from a sequence of frames rather than the information from the adjacent two frames. Since straightforwardly obtaining data associations from multi-frames is an NP-hard multi-dimensional assignment (MDA) problem, most existing methods solve this MDA problem by either developing complicated approximate algorithms, or simplifying MDA as a 2D assignment problem based upon the information extracted only from adjacent frames. In this paper, we show that the relation between associations of two observations is the equivalence relation in the data association problem, based on the spatial temporal constraint that the trajectories of different objects must be disjoint. Therefore, the MDA problem can be equivalently divided into independent subproblems by equivalence partitioning. In contrast to existing works for solving the MDA problem, we develop a connected component model (CCM) by exploiting the constraints of the data association and the equivalence relation on the constraints. Based upon CCM, we can efficiently obtain the global solution of the MDA problem for multi-object tracking by optimizing a sequence of independent data association subproblems. Experiments on challenging public data sets demonstrate that our algorithm outperforms the state-of-the-art approaches. PMID- 27214901 TI - Online Deformable Object Tracking Based on Structure-Aware Hyper-Graph. AB - Recent advances in online visual tracking focus on designing part-based model to handle the deformation and occlusion challenges. However, previous methods usually consider only the pairwise structural dependences of target parts in two consecutive frames rather than the higher order constraints in multiple frames, making them less effective in handling large deformation and occlusion challenges. This paper describes a new and efficient method for online deformable object tracking. Different from most existing methods, this paper exploits higher order structural dependences of different parts of the tracking target in multiple consecutive frames. We construct a structure-aware hyper-graph to capture such higher order dependences, and solve the tracking problem by searching dense subgraphs on it. Furthermore, we also describe a new evaluating data set for online deformable object tracking (the Deform-SOT data set), which includes 50 challenging sequences with full annotations that represent realistic tracking challenges, such as large deformations and severe occlusions. The experimental result of the proposed method shows considerable improvement in performance over the state-of-the-art tracking methods. PMID- 27214902 TI - Dimension Reduction With Extreme Learning Machine. AB - Data may often contain noise or irrelevant information, which negatively affect the generalization capability of machine learning algorithms. The objective of dimension reduction algorithms, such as principal component analysis (PCA), non negative matrix factorization (NMF), random projection (RP), and auto-encoder (AE), is to reduce the noise or irrelevant information of the data. The features of PCA (eigenvectors) and linear AE are not able to represent data as parts (e.g. nose in a face image). On the other hand, NMF and non-linear AE are maimed by slow learning speed and RP only represents a subspace of original data. This paper introduces a dimension reduction framework which to some extend represents data as parts, has fast learning speed, and learns the between-class scatter subspace. To this end, this paper investigates a linear and non-linear dimension reduction framework referred to as extreme learning machine AE (ELM-AE) and sparse ELM-AE (SELM-AE). In contrast to tied weight AE, the hidden neurons in ELM AE and SELM-AE need not be tuned, and their parameters (e.g, input weights in additive neurons) are initialized using orthogonal and sparse random weights, respectively. Experimental results on USPS handwritten digit recognition data set, CIFAR-10 object recognition, and NORB object recognition data set show the efficacy of linear and non-linear ELM-AE and SELM-AE in terms of discriminative capability, sparsity, training time, and normalized mean square error. PMID- 27214903 TI - Extinction-Optimized Volume Illumination. AB - We present a novel method to optimize the attenuation of light for the single scattering model in direct volume rendering. A common problem of single scattering is the high dynamic range between lit and shadowed regions due to the exponential attenuation of light along a ray. Moreover, light is often attenuated too strong between a sample point and the camera, hampering the visibility of important features. Our algorithm employs an importance function to selectively illuminate important structures and make them visible from the camera. With the importance function, more light can be transmitted to the features of interest, while contextual structures cast shadows which provide visual cues for perception of depth. At the same time, more scattered light is transmitted from the sample point to the camera to improve the primary visibility of important features. We formulate a minimization problem that automatically determines the extinction along a view or shadow ray to obtain a good balance between sufficient transmittance and attenuation. In contrast to previous approaches, we do not require a computationally expensive solution of a global optimization, but instead provide a closed-form solution for each sampled extinction value along a view or shadow ray and thus achieve interactive performance. PMID- 27214905 TI - Benefits of Using a Voice and EMG-Driven Actuated Glove to Support Occupational Therapy for Stroke Survivors. AB - Many mechatronic devices exist to facilitate hand rehabilitation, however few directly address deficits in muscle activation patterns while also enabling functional task practice. We developed an innovative voice and electromyography driven actuated (VAEDA) glove, which is sufficiently flexible/portable for incorporation into hand-focused therapy post-stroke. The therapeutic benefits of this device were examined in a longitudinal intervention study. Twenty-two participants with chronic, moderate hand impairment [Chedoke-McMaster Stroke Assessment Stage of Hand (CMSA-H = 4)] enrolled > 8 months post-stroke for 18 1-h training sessions ( 3 * week) employing a novel hand-focused occupational therapy paradigm, either with (VAEDA) or without (No-VAEDA) actuated assistance. Outcome measures included CMSA-H, Wolf Motor Function Test (WMFT), Action Research Arm Test, Fugl-Meyer Upper Extremity Motor Assessment (FMUE), grip and pinch strength and hand kinematics. All outcomes were recorded at baseline and endpoint (immediately after and four weeks post-training). Significant improvement was observed following training for some measures for the VAEDA group (n = 11) but for none of the measures for the No-VAEDA group (n = 11). Specifically, statistically significant gains were observed for CMSA-H (p = 0.038) and WMFT (p = 0.012) as well as maximum digit aperture subset (p = 0.003, n = 7), but not for the FMUE or grip or pinch strengths. In conclusion, therapy effectiveness appeared to be increased by employment of the VAEDA glove, which directly targets deficits in muscle activation patterns. PMID- 27214906 TI - txCoords: A Novel Web Application for Transcriptomic Peak Re-Mapping. AB - Since the development of new technologies such as RIP-Seq and m6A-seq, peak calling has become an important step in transcriptomic sequencing data analysis. However, many of the reported genomic coordinates of transcriptomic peaks are incorrect owing to negligence of the introns. There is currently a lack of a convenient tool to address this problem. Here, we present txCoords, a novel and easy-to-use web application for transcriptomic peak re-mapping. txCoords can be used to correct the incorrectly reported transcriptomic peaks and retrieve the true sequences. It also supports visualization of the re-mapped peaks in a schematic figure or from the UCSC Genome Browser. Our web server is freely available at http://www.bioinfo.tsinghua.edu.cn/txCoords. PMID- 27214907 TI - Benchmark Dataset for Whole Genome Sequence Compression. AB - : The research in DNA data compression lacks a standard dataset to test out compression tools specific to DNA. This paper argues that the current state of achievement in DNA compression is unable to be benchmarked in the absence of such scientifically compiled whole genome sequence dataset and proposes a benchmark dataset using multistage sampling procedure. Considering the genome sequence of organisms available in the National Centre for Biotechnology and Information (NCBI) as the universe, the proposed dataset selects 1,105 prokaryotes, 200 plasmids, 164 viruses, and 65 eukaryotes. This paper reports the results of using three established tools on the newly compiled dataset and show that their strength and weakness are evident only with a comparison based on the scientifically compiled benchmark dataset. AVAILABILITY: The sample dataset and the respective links are available @ https://sourceforge.net/projects/benchmarkdnacompressiondataset/. PMID- 27214910 TI - Wearable Noncontact Armband for Mobile ECG Monitoring System. AB - One of the best ways to obtain health information is from an electrocardiogram (ECG). Through an ECG, characteristics such as patients' heartbeats, heart conditions, and heart disease can be analyzed. Unfortunately, most available healthcare devices do not provide clinical data such as information regarding patients' heart activities. Many researchers have tried to solve this problem by inventing wearable heart monitoring systems with a chest strap or wristband, but their performances were not feasible for practical applications. Thus, the aim of this study is to build a new system to monitor heart activity through ECG signals. The proposed system consists of capacitive-coupled electrodes embedded in an armband. It is considered to be a reliable, robust, and low-power transmission ECG monitoring system. The reliability of this system was achieved by the careful placement of sensors in the armband. Bluetooth low energy (BLE) was used as the protocol for data transmission; this protocol was proposed to develop the low-power-transmission system. For robustness, the proposed system is equipped with analysis capabilities-e.g., real-time heartbeat detection and a filter algorithm to ignore distractions from body movements or noise from the environment. PMID- 27214911 TI - A 5 nW Quasi-Linear CMOS Hot-Electron Injector for Self-Powered Monitoring of Biomechanical Strain Variations. AB - Piezoelectricity-driven hot-electron injectors (p-HEI) are used for self-powered monitoring of mechanical activity in biomechanical implants and structures. Previously reported p-HEI devices operate by harvesting energy from a piezoelectric transducer to generate current and voltage references which are then used for initiating and controlling the process of hot-electron injection. As a result, the minimum energy required to activate the device is limited by the power requirements of the reference circuits. In this paper we present a p-HEI device that operates by directly exploiting the self-limiting capability of an energy transducer when driving the process of hot-electron injection in a pMOS floating-gate transistor. As a result, the p-HEI device can activate itself at input power levels less than 5 nW. Using a prototype fabricated in a 0.5- [Formula: see text] bulk CMOS process we validate the functionality of the proposed injector and show that for a fixed input power, its dynamics is quasi linear with respect to time. The paper also presents measurement results using a cadaver phantom where the fabricated p-HEI device has been integrated with a piezoelectric transducer and is used for self-powered monitoring of mechanical activity. PMID- 27214912 TI - Proposal for an All-Spin Artificial Neural Network: Emulating Neural and Synaptic Functionalities Through Domain Wall Motion in Ferromagnets. AB - Non-Boolean computing based on emerging post-CMOS technologies can potentially pave the way for low-power neural computing platforms. However, existing work on such emerging neuromorphic architectures have either focused on solely mimicking the neuron, or the synapse functionality. While memristive devices have been proposed to emulate biological synapses, spintronic devices have proved to be efficient at performing the thresholding operation of the neuron at ultra-low currents. In this work, we propose an All-Spin Artificial Neural Network where a single spintronic device acts as the basic building block of the system. The device offers a direct mapping to synapse and neuron functionalities in the brain while inter-layer network communication is accomplished via CMOS transistors. To the best of our knowledge, this is the first demonstration of a neural architecture where a single nanoelectronic device is able to mimic both neurons and synapses. The ultra-low voltage operation of low resistance magneto-metallic neurons enables the low-voltage operation of the array of spintronic synapses, thereby leading to ultra-low power neural architectures. Device-level simulations, calibrated to experimental results, was used to drive the circuit and system level simulations of the neural network for a standard pattern recognition problem. Simulation studies indicate energy savings by ~ 100* in comparison to a corresponding digital/analog CMOS neuron implementation. PMID- 27214913 TI - All Spin Artificial Neural Networks Based on Compound Spintronic Synapse and Neuron. AB - Artificial synaptic devices implemented by emerging post-CMOS non-volatile memory technologies such as Resistive RAM (RRAM) have made great progress recently. However, it is still a big challenge to fabricate stable and controllable multilevel RRAM. Benefitting from the control of electron spin instead of electron charge, spintronic devices, e.g., magnetic tunnel junction (MTJ) as a binary device, have been explored for neuromorphic computing with low power dissipation. In this paper, a compound spintronic device consisting of multiple vertically stacked MTJs is proposed to jointly behave as a synaptic device, termed as compound spintronic synapse (CSS). Based on our theoretical and experimental work, it has been demonstrated that the proposed compound spintronic device can achieve designable and stable multiple resistance states by interfacial and materials engineering of its components. Additionally, a compound spintronic neuron (CSN) circuit based on the proposed compound spintronic device is presented, enabling a multi-step transfer function. Then, an All Spin Artificial Neural Network (ASANN) is constructed with the CSS and CSN circuit. By conducting system-level simulations on the MNIST database for handwritten digital recognition, the performance of such ASANN has been investigated. Moreover, the impact of the resolution of both the CSS and CSN and device variation on the system performance are discussed in this work. PMID- 27214914 TI - Self-Powered Wireless Affinity-Based Biosensor Based on Integration of Paper Based Microfluidics and Self-Assembled RFID Antennas. AB - This paper presents a wireless, self-powered, affinity-based biosensor based on the integration of paper-based microfluidics with our previously reported method for self-assembling radio-frequency (RF) antennas. At the core of the proposed approach is a silver-enhancement technique that grows portions of a RF antenna in regions where target antigens hybridize with target specific affinity probes. The hybridization regions are defined by a network of nitrocellulose based microfluidic channels which implement a self-powered approach to sample the reagent and control its flow and mixing. The integration substrate for the biosensor has been constructed using polyethylene and the patterning of the antenna on the substrate has been achieved using a low-cost ink-jet printing technique. The substrate has been integrated with passive radio-frequency identification (RFID) tags to demonstrate that the resulting sensor-tag can be used for continuous monitoring in a food supply-chain where direct measurement of analytes is typically considered to be impractical. We validate the proof-of concept operation of the proposed sensor-tag using IgG as a model analyte and using a 915 MHz Ultra-high-frequency (UHF) RFID tagging technology. PMID- 27214915 TI - Mapping Generative Models onto a Network of Digital Spiking Neurons. AB - Stochastic neural networks such as Restricted Boltzmann Machines (RBMs) have been successfully used in applications ranging from speech recognition to image classification, and are particularly interesting because of their potential for generative tasks. Inference and learning in these algorithms use a Markov Chain Monte Carlo procedure called Gibbs sampling, where a logistic function forms the kernel of this sampler. On the other side of the spectrum, neuromorphic systems have shown great promise for low-power and parallelized cognitive computing, but lack well-suited applications and automation procedures. In this work, we propose a systematic method for bridging the RBM algorithm and digital neuromorphic systems, with a generative pattern completion task as proof of concept. For this, we first propose a method of producing the Gibbs sampler using bio-inspired digital noisy integrate-and-fire neurons. Next, we describe the process of mapping generative RBMs trained offline onto the IBM TrueNorth neurosynaptic processor-a low-power digital neuromorphic VLSI substrate. Mapping these algorithms onto neuromorphic hardware presents unique challenges in network connectivity and weight and bias quantization, which, in turn, require architectural and design strategies for the physical realization. Generative performance is analyzed to validate the neuromorphic requirements and to best select the neuron parameters for the model. Lastly, we describe a design automation procedure which achieves optimal resource usage, accounting for the novel hardware adaptations. This work represents the first implementation of generative RBM inference on a neuromorphic VLSI substrate. PMID- 27214917 TI - Vibrotactile Spatial Acuity and Intensity Discrimination on the Lower Back Using Coin Motors. AB - Tactile vision substitution devices are assistive devices for the blind that redirect visual information to the skin. The amount of visual information that can be presented on a tactile display is limited mainly by the spatial resolution of the skin and the ability to distinguish between various vibration intensities. In this study, we have determined the two-point discrimination (TPD) threshold and intensity-discrimination threshold (just-noticeable difference, or JND) on the lower back using coin motors. Given the importance of stimulus timing, we have determined TPD threshold and JND at different stimulus onset asynchronies (SOAs). The JND was determined between two coin motors with a distance equal to the TPD threshold. In this way, we could establish the contrast sensitivity at the maximal theoretical resolution. TPD thresholds tended to decrease at longer SOAs, from 52 mm edge-to-edge at an SOA of 0 ms, to 28 mm at 200 ms. The JND did not depend on SOA, and the average Weber fraction was 0.14. A median of 5 JNDs was available across the available dynamic range. Together, these data provide the predicted spatial resolution and contrast resolution achievable with a back worn tactile display based on coin motors. PMID- 27214916 TI - Mid-Air Tactile Stimulation Using Indirect Laser Radiation. AB - In this paper, we demonstrate that a laser irradiated on a thin light-absorbing elastic medium attached on the skin can elicit a tactile sensation of mechanical tap. First, we present simulation results that show laser irradiation to the elastic medium creates inner elastic waves on the basis of thermoelastic effects and these elastic waves trigger the bending deformation of the medium, which then stimulates the skin. Second, we analyze the physical properties of the associated stimulus by measuring its force profile. Third, we identify the perceptual characteristics of the stimulus in comparison to those of mechanical and electrical stimuli by means of a perceptual experiment employing dissimilarity rating. All the evidence indicates that indirect laser radiation provides a sensation of short mechanical tap. Furthermore, little individual difference was observed in the results of the perceptual experiment. To the best of our knowledge, this study is the first in reporting the feasibility of indirect laser radiation for mid-air tactile rendering. PMID- 27214918 TI - An Adaptive NN-Based Approach for Fault-Tolerant Control of Nonlinear Time Varying Delay Systems With Unmodeled Dynamics. AB - This paper presents an adaptive neural network (NN)-based fault-tolerant control approach for the compensation of actuator failures in nonlinear systems with time varying delay. The novelty of this paper lies in the fact that both the lock in place and loss of effectiveness faults, unmodeled dynamics, and dynamic disturbances are catered for simultaneously. Furthermore, this is achieved by the adaptation of only one parameter, which simplifies the computation of the control effort, and therefore extends its applicability. In the approach, the Razumikhin lemma and a dynamic signal are employed. It is shown that the output of the system converges to a neighborhood of the reference signal and the semiglobal boundedness of all signals is guaranteed. A simulation example is used to illustrate the validity and efficacy of the approach. PMID- 27214923 TI - Reference Adaptation for Robots in Physical Interactions With Unknown Environments. AB - In this paper, we propose a method of reference adaptation for robots in physical interactions with unknown environments. A cost function is constructed to describe the interaction performance, which combines trajectory tracking error and interaction force between the robot and the environment. It is minimized by the proposed reference adaptation based on trajectory parametrization and iterative learning. An adaptive impedance control is developed to make the robot be governed by the target impedance model. Simulation and experiment studies are conducted to verify the effectiveness of the proposed method. PMID- 27214924 TI - Improving the Lives of Fragile Newborns: What Does Nursing Have to Offer? AB - This brief summarizes evidence of nursing's effects on NICU outcomes and recommends policies to bolster and support nursing practice in NICUs. Adequate staffing and a supportive work environment are associated with better outcomes for very low birth weight infants. PMID- 27214925 TI - On Medicare But At Risk: A State-Level Analysis of Beneficiaries Who Are Underinsured or Facing High Total Cost Burdens. AB - Medicare provides essential health coverage for older and disabled adults, yet it does not limit out-of-pocket costs for covered benefits and excludes dental, hearing, and longer-term care. The resulting out-of-pocket costs can add up to a substantial share of income. Based on U.S. Census surveys, nearly a quarter of Medicare beneficiaries (11.5 million) were underinsured in 2013-14, meaning they spent a high share of their income on health care. Adding premiums to medical care expenses, we find that 16 percent of beneficiaries (8 million) spent 20 percent or more of their income on insurance plus care. At the state level, the proportion of beneficiaries underinsured ranged from 16 percent to 32 percent, while the proportion with a high total cost burden ranged from 11 percent to 26 percent. Low-income beneficiaries were most at risk. The findings underscore the need to assess beneficiary impacts of any proposal to redesign Medicare. PMID- 27214926 TI - Changes in Consumer Cost-Sharing for Health Plans Sold in the ACA's Insurance Marketplaces, 2015 to 2016. AB - This brief examines changes in consumer health plan cost-sharing--deductibles, copayments, coinsurance, and out-of-pocket limits--for coverage offered in the Affordable Care Act's marketplaces between 2015 and 2016. Three of seven measures studied rose moderately in 2016, an increase attributable in part to a shift in the mix of plans offered in the marketplaces, from plans with higher actuarial value (platinum and gold plans) to those that have less generous coverage (bronze and silver plans). Nearly 60 percent of enrollees in marketplace plans receive cost-sharing reductions as part of income-based assistance. For enrollees without cost-sharing reductions, average copayments, deductibles, and out-of-pocket limits remain considerably higher under bronze and silver plans than under employer-based plans; cost-sharing is similar in gold plans and employer plans. Marketplace plans are more likely than employer-based plans to impose a deductible for prescription drugs but no less likely to do so for primary care visits. PMID- 27214927 TI - How Will Section 1115 Medicaid Expansion Demonstrations Inform Federal Policy? AB - Section 1115 of the Social Security Act allows the U.S. Department of Health and Human Services and states to test innovations in Medicaid and other public welfare programs without formal legislative action. Six states currently operate their Medicaid expansions as demonstrations and several more are expected to seek permission to do so. While the current Medicaid expansion demonstrations vary, they share a major focus: increasing beneficiaries' financial responsibility for the cost of coverage and care. Demonstrations include requirements that Medicaid beneficiaries pay enrollment fees and cost-sharing that exceed traditional Medicaid limits. Others propose tying beneficiaries' financial responsibility to behavioral changes in health and wellness, while still others impose penalties for nonpayment of enrollment fees. Evaluations must consider the impact of these requirements on access, use of care, and health status, as well as the feasibility of demonstration reforms and their impact on administrative efficiency, providers, and health plans. PMID- 27214928 TI - Oceania. PMID- 27214929 TI - Asia. PMID- 27214930 TI - Europe. PMID- 27214931 TI - Release or not? PMID- 27214932 TI - INFORMATION GOVERNANCE FOR OFFSITE DATA SECURITY. PMID- 27214933 TI - Bringing physician practices into the HIM Fold. PMID- 27214934 TI - IFHIMA Organizing a World of HIM. PMID- 27214935 TI - OCR Clarifies Policy on Medical Record Request Fees. PMID- 27214937 TI - Managing PHI Consent Standards. PMID- 27214936 TI - Treating LGBT Status as a Patient Safety Issue. PMID- 27214938 TI - The Information Governance Road Map Mile Marker 1--Travel Planning. PMID- 27214939 TI - Understanding Cybersecurity: A Primer for HIM Professionals. PMID- 27214940 TI - Wound Care in the Outpatient Setting. PMID- 27214941 TI - Finding the New Normal with ICD-10-CM/PCS. PMID- 27214942 TI - [Teaching and learning to meet the demands of today and tomorrow]. PMID- 27214943 TI - [New nursing education is working; and it is urgently needed]. PMID- 27214944 TI - [... no, it harms the economy, education and society]. PMID- 27214945 TI - [The future belongs to the interprofessionals]. PMID- 27214946 TI - [Interprofessional learning experience in nursing and medical education]. PMID- 27214947 TI - [Nursing profession reform regulation - who will work in geriatric nursing in the future?]. PMID- 27214948 TI - [Innovative curriculum combines social work and nursing]. PMID- 27214949 TI - [Internal logic]. PMID- 27214950 TI - [Test anxiety - a topic for nursing faculty?]. PMID- 27214951 TI - [Counseling services for students]. PMID- 27214952 TI - [Pragmatically finding trustworthy literature on the internet]. PMID- 27214953 TI - [E-learning for nurses]. PMID- 27214954 TI - [1: Oral anticoagulants]. PMID- 27214955 TI - [Seven errors in personnel shortage management in nursing - and how they can be solved]. PMID- 27214956 TI - "Nursing needs to have a place at the top table". PMID- 27214957 TI - DH jobs threat stokes fear of reduced nurse influence. PMID- 27214958 TI - Revalidation system launched. PMID- 27214959 TI - Virtual hub resource launched for care sector nurses. PMID- 27214960 TI - Failed applications put literacy and numeracy under spotlight. PMID- 27214961 TI - Nursing director to take up new NMC education role. PMID- 27214962 TI - Sufficient nurse numbers 'key to safer weekend discharge'. PMID- 27214963 TI - Nursing review in Northern Ireland accompanies extra course places. PMID- 27214964 TI - UK nurse in Brussels praises 'spectacular' emergency response to terrorist bombing. PMID- 27214965 TI - "Hospice staff deserve whatever sign of thanks we are able to give". PMID- 27214966 TI - Why cancer patients should keep active. PMID- 27214967 TI - "Support staff need to know how important they are". PMID- 27214968 TI - Using volunteers to support end-of-life care. AB - The role of volunteers in end-of-life care in the acute hospital setting is not widely established. This article reports on an innovative model of care using trained volunteers that was introduced at a Liverpool trust in 2012. The volunteers were to provide a listening ear, comfort and support for patients who were dying, their families and friends. A training programme was developed and reviewed, with views from volunteers, staff and relatives evaluated. Psychological support for the volunteers was regularly provided. PMID- 27214969 TI - Enabling specialist nurses to prove their value. AB - As pressures on healthcare resources and staff continue to increase, all must prove their worth. Specialist nurses are no exception, but the nature of their work and their role within a wider multidisciplinary team can make it harder for them to gather data specific to their roles. This article describes a programme that was developed by Multiple Sclerosis Trust charity to demonstrate the value of multiple sclerosis specialist nurses. The model is transferable to other specialist groups and has been adopted by Dementia UK. PMID- 27214970 TI - The meaning behind communication. AB - This article is the fourth of a seven-part series that explores how patient narratives help us reflect on patient care. In previous articles we have explored themes related to communication, consent and power. This article explores how we use language to explain treatment in care and how it can be interpreted differently by patients and staff. PMID- 27214971 TI - 60 Second With Eileen White. PMID- 27214972 TI - Nursing around the world. PMID- 27214973 TI - Women with bipolar disorder at high risk of relapse after childbirth. PMID- 27214974 TI - Underestimating risk in women delays diagnosis of CVD. AB - CVD remains the most common cause of mortality in women. In 2007, the annual mortality in women secondary to CAD was 4.7 times that of breast cancer. Around 2.8 million women are living with CVD in the UK. There has been an increase in the prevalence of MI in women aged 35 to 54, while a decline in prevalence was observed in age-matched men. Difficulty in evaluating symptoms of ischaemic heart disease in women is well documented and remains challenging because of their atypical nature. The main gender difference is that women tend to present less frequently with exertional symptoms of chest pain before an AMI. Although men and women share classic cardiovascular risk factors the relative importance of each risk factor may be gender specific. The impact of smoking is greater in women than men, especially in those under 50. Diabetes is a more potent risk factor for fatal CHD in women than men. Risk factors specific to women include postmenopausal status, hysterectomy and complications during pregnancy. Women who develop gestational diabetes mellitus or pre-eclampsia more than double their risk of CVD later in life. Transition to the menopause is associated with a worsening CHD risk profile. After the menopause women may experience an increase in weight, alteration in fat distribution and an increase in other CVD risk factors such as diabetes and a more adverse lipid profile. Pharmacological stress testing is preferred for diagnosing CAD in females with lower exercise capacity. Stress cardiomyopathy is triggered by intense, unexpected emotional or physical stress and is characterised by transient apical systolic dysfunction or ballooning of the left ventricle. The syndrome predominantly affects postmenopausal women. Women presenting with STEMI have worse outcomes compared with men. However, in those presenting with NSTEMI there were no differences in outcomes. PMID- 27214975 TI - Managing debilitating menopausal symptoms. AB - Severity and duration of menopausal symptoms varies markedly. Eight out of ten women experience symptoms and on average these last four years, with one in ten women experiencing symptoms for up to 12 years. A recent study found that women whose vasomotor symptoms started before the menopause suffered longest, median 11.8 years. Women whose hot flushes and night sweats started after the menopause had symptoms for a median of 3.4 years. Menopausal symptoms can begin years before menstruation ceases. Menopausal status needs to be evaluated based on history and symptoms. Testing for FSH levels should only be considered in women aged 40-45 with menopausal symptoms or those under 40 with suspected early menopause. In general, the benefits of short-term HRT outweigh the risks in the majority of symptomatic women, especially in those under 60. There is no evidence that HRT confers any cardiovascular protection (or harm) or protection against the development of dementia. Cardiovascular risk should be assessed. Women with cardiovascular disease are not necessarily unsuitable for HRT but need their cardiovascular health optimised. In those women with a high risk of venous thromboembolism a thrombophilia screen should be considered (although even if this is negative, it does not absolve risk). If there is a history of arterial disease a lipid profile should be considered. If there is a high risk of breast cancer, counsel the woman with regards to her risk and consider referring for mammography. PMID- 27214976 TI - Early diagnosis of oesophageal cancer improves outcomes. AB - There are two main types of oesophageal cancer, oesophageal squamous cell carcinoma (OSCC) and oesophageal adenocarcinoma (OAC). They present in the same manner and both carry a five-year survival of only 16%. In the UK there is a 2:1 male to female ratio for oesophageal cancer. Peak incidence at presentation is in the 65-75 age group, with 95% of cases presenting in those over 50. Smoking is a major risk factor for both types and is linked to an estimated 66% of cases in the UK. OSCC is linked to alcohol, smoking, and chewing betel quid. OAC is associated with the presence of GORD, and its duration, and obesity (especially increased waist circumference). Oesophageal cancer commonly presents with dysphagia or odynophagia. This can be associated with weight loss and vomiting. All patients with recent onset dysphagia should be referred for rapid access endoscopy. Referral for urgent endoscopy should still be considered in the presence of dysphagia regardless of previous history or medication. Dysphagia is not always present so all patients with alarm symptoms should be considered for endoscopy. NICE recommends referral for urgent direct access upper GI endoscopy to assess for oesophageal cancer for patients with dysphagia or aged 55 and over with weight loss and any of the following: upper abdominal pain; reflux; dyspepsia. PMID- 27214977 TI - MALINGERING IN SOLDIERS. PMID- 27214979 TI - Choosing the right words. PMID- 27214978 TI - Fungal infections. PMID- 27214980 TI - [COURSE OF BILIARY SLUDGE ON THE BACKGROUND NON-ALCOHOLIC FATTY LIVER DISEASE]. AB - To date, the factors significantly reduces the tolerance of the liver against the development of NAFLD and GSD. At the stage of biliary sludge cholelithiasis is found in more than half of the patients suffering from NAFLD. BS violates jelchnokamennouu and releaxation activity of hepatocytes, thereby slowing the passage of bile through the intrahepatic and extrahepatic bile ducts that aggravate the course of NAFLD. The reasons for the formation of sludge is not completely understood. To date there are no accepted tactics of conducting and treatment of patients with HB in the background of NAFLD. In our work we demonstrate one possible way to tackle this important problem. PMID- 27214981 TI - [EFFICIENCY OF URSODEOXYCHOLIC ACID APPLICATION IN NONALCOCHOLIC STEATOHEPATITIS]. AB - AIM: to estimate the efficiency of ursodeoxycholic acid (UDHC) in nonalcocholic steatohepatitis (NASH) by analysis of conventional clinical datas, apoptosis and liver perfusion parameters. MATERIALS AND METHODS: UDHC was used as monotherapy in treatment of 92 NASH patients in daily dose 10-15 mg/kg. We have observed 44 (47.8%) males, 48 (52.2%) females, age was 56.8 +/- 7.2 years, BMI was 28.4 +/- 2.3 kg/m2, waist circumference was 93.8 +/- 8.3 cm. Functional liver tests (ALAT, ASAT, alcaline phosphatase--APh, gamma-glutamyltranspeptidase--GGTP), abdominal ultrasonography and dopplerography of liver blood flow, kaspase-3, 6, 8, 9 genes expression in blood leucocytes were estimated. Periods of controls research and UDCA treatment were: 4-8 weeks in 92 patients, 20-24 weeks in 18 (19.6%) patients and 40-48 weeks in 13 (14.1%) patients. RESULTS: Significant positive dynamics of liver functional tests and decrease of kaspase-3, 6, 9 genes expression in blood leucocytes were observed over 4-8 weeks, normalization of liver tests--over 20-24 weeks and significant amelioration of venous and arterial liver perfusion parameters--over 40-48 weeks. CONCLUSION: Ursodeoxycholic acid in daily dose of 10-15 mg/kg in nonalcocholic steatohepatitis caused positive dynamics of cytolytic and cholestasis parameters, leucocytic apoptosis and venous and arterial liver blood flow parameters. PMID- 27214982 TI - [FAMILIAL CLUSTERS OF HEPATITIS DELTA IN ENDEMIC REGION (REPUBLIC TYVA)]. AB - AIM: Clinical and virological characteristic of hepatitis delta familial clusters in region of Russia that is endemic for this infection (Republic Tuva). MATERIALS AND METHODS: Total 383 patients with HBV/HDV coinfection and their family members (3 generations) were followed. Serum samples for HDV and HBV markers testing were available for 42 patients from 18 families. HBsAg, anti-HBc, HBeAg, anti-HBe and anti-HDV were tested using commercial ELISA tests; HDV RNA and HBV DNA were tested using in house nested PCR tests. RESULTS: 30 family (63 people) clusters were identified, in which close living persons have been infected with HDV and HBV. The biological material for determining of HDV and HBV markers has been available from 18 families (42 people belonging to 1-3 generations (parents and children, husband and wife, brother and sister). The mean age was 35 +/- 14 years (10-58 years). Chronic hepatitis (CH) was in 30 (71.4%) patients, liver cirrhosis (LC)--in 10 (23.8%) and HCC was developed in 2 (4.8%) person on the background of long infections. The incidence of HBeAg was 14.3% (6/42), HBV DNA--19% (8/42); HDV RNA--35.7% (15/42). In 2 cases (mother) replication markers of both viruses were found, it contributed to the increased risk of infection in children. So HDV RNA was detected in the blood serum of their daughters (15 and 17), that does not exclude the possibility of vertical transmission. An illustration describes four families. CONCLUSION: The epidemic process of delta infection in the Republic of Tyva is characterized by intrafamilial infection of HBV and HDV. PMID- 27214983 TI - [INSULIN-LIKE GROWTH FACTOR-1: THE INFLUENCE ON THE LIVER FUNCTION AND RELATIONSHIPS WITH RESISTIN IN PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE AND ITS COMBINATION WITH TYPE 2 DIABETES MELLITUS]. AB - The study was designed to assess the relationship between the level of plasma concentration of insulin-like growth factor-1 (IGF-1) and indices of the functional state of the liver and the level of resistin in patients with non alcoholic fatty liver disease (NAFLD) and its combination with diabetes mellitus (DM) 2 types depending on the trophological status. MATERIALS AND METHODS: It were examined 90 patients with non-alcoholic fatty liver disease and its combination with type 2 diabetes mellitus--with normal body weight and obesity, as well as 20 healthy individuals. The study was carried out using the following methods: clinical, laboratory and instrumental (including liver biopsy). RESULTS: It was found an inverse relationship between the level of IGF-1, and the level of AST, ALT, AST/ALT, total and conjugated bilirubin, alkaline phosphatase in groups of patients with comorbid disorder and also an inverse relationship between the level of IGF-1 and resistin. There was established the significant decrease of plasma level of IGF-1, significant increase of plasma level of resistin and also impairment of liver function indices in all groups in comparison with the controls, and most pronounced changes in patients with comorbid disorders and obesity. CONCLUSION: The established relationships suggests that the decrease of IGF-1 may represent the presence of syndromes of cytolysis and cholestasis in patients with NAFLD, type 2 DM and obesity. In order to determination the disorder of the reparative function of the liver is recommended to determine the level of IGF-1 in patients with combination of NAFLD and type 2 DM. Patients with the level of IGF-1 (< 143.9 +/- 4.92 ng/ml) should refer to the risk of progression of liver function disorders. The inverse correlation between resistin levels and the level of IGF-1 in plasma confirms the existing relationship between their productions. PMID- 27214984 TI - [VISCOELASTISITY AND ELECTRICAL PARAMETERS OF ERYTHROCYTES IN GILBERT SYNDROME]. AB - Results of viscoelastic and electrical properties of erythrocytes study in patients with genetically confirmed Gilbert's syndrome (n = 81) are presented. Dielectrophoresis of erythrocytes in a nonuniform an alterning electric field was performed in81 patients with Gilbert's syndrome and in 20 persons of the comparison group without of the pathology identified by thelaboratory and instrumental examination. The significant differences in viscoelasticity properties of erythrocytes in Gilbert'ssyndrome were obtained. The amplitude of the deformation, the speed of movement to the electrodes and the polarizability on electric field's of all frequencies were significantly lower, but generalized rigidity index, viscosity, index of aggregationand degradation on electric field's of all frequencies were higher than in the comparison group. A number of electricalparameters (conductivity, the capacity of the cells and the relative polarizability) were also higher than in the comparisongroup. Some differences in the parameters of erythrocytes were obtained from homozygous and heterozygous carriers of A(TA), TAA of gene UGT1A1 promotor. PMID- 27214985 TI - [DIAGNOSIS AND CLINICAL MANIFESTATIONS OF CIRRHOTIC CARDIOMYOPATHY]. AB - The aim of the study was to determine the incidence of cirrhotic cardiomyopathy (CCMP), features of its recognition and clinical manifestations. MATERIALS AND METHODS: The study included 102 patients with alcoholic and viral liver cirrhosis (LC) without cardiovascular history, without viremia and signs of acute alcoholic hepatitis. Echocardiography, electrocardiography (ECG) and brain natriuretic hormone (proBNP) level were investigated in all patients. RESULTS: CCMP signs were detected in 65 (63.7%) of the 102 patients examined. All patients showed signs of electrophysiological myocardial abnormalities in ECG, signs of myocardial injury and the presence of heart failure in echocardiography, increase in proBNP. Interval QT length (0.4689 +/- 0.012 s.) was significantly (p = 0.0461) higher than that of the control group. Violation of diastolic relaxation of the left ventricle was detected in 36 (55.6%) patients. The average level of proBNP was 540.85 +/- 236.43 pg/ml, significantly different from the level of proBNP in healthy individuals--89.45 +/- 26.43 pg/ml. The incidence of CCMP increased progressively with the severity of the Child-Pugh class and was 42.4% in patients of A class, 84.6% (p = 0.0132) in patients of B Class and 100% in patients of C class (p = 0.0219). The length of the QT interval, the proBNP level and frequency of diastolic dysfunction increased with increasing of liver cirrhosis severity. CONCLUSION: The frequency of detection of cirrhotic cardiomyopathy was 63.7%. More pronounced CCMP signs were observed in alcoholic liver cirrhosis than in viral. The frequency of detection and severity of cirrhotic cardiomyopathy progres sively increased with the severity of liver cirrhosis. Brain natriuretic peptide was the most sensitive indicator of myocardial damage in liver cirrhosis irrespective of its etiology. PMID- 27214986 TI - [CHANGES IN MICROBIOCENOSIS OF THE COLON IN PATIENTS WITH CHRONIC LIVER DISEASE AND LATENT HEPATIC ENCEPHALOPATHY]. AB - Interest in the study of complications of liver disease, in particular latent hepatic encephalopathy, due to its wide distribution, difficulty in diagnosis, the lack of differentiated treatment approaches. The correlation dependence of the influence degree of dysbiosis in the development of latent hepatic encephalopathy contributes to the formation of multiple organ pathology, including associated with the violation of the intestinal microbiota in chronic liver disease, is a separate link in the pathogenesis of hepatic encephalopathy. Dysbiosis of the colon in patients with chronic dislivoniami the liver is the triggering factor in the development of latent hepatic encephalopathy, and its level directly correlated with the execution time of the tests of numbers and lines, the manifestation of asthenovegetative syndrome, intestinal dyspepsia, cytolysis, cholestasis, hepatocellular nedostatusnosti. PMID- 27214987 TI - [[ENDOTHELIAL DYSFUNCTION AND ITS LOW-LEVEL LASER THERAPY CORRECTION IN PATIENTS WITH CHRONIC VIRAL HEPATITIS]. AB - The aim of the work to study the influence of the low-intensive laser therapy on the endothelium function in chronic virus hepatitis patients. RESEARCH METHODS: All patients have been divided into three groups: In the first (control) group (30 persons) the traditiona medicamentous therapy was used only, the patients of the experimental 11 group (45 person) alongside with complex medicamentous therapy received the course of intravenous laser therapy and Ill group of patients (45 person) received a rate complex medicamental and laser (cutaneous) therapy. RESULTS: Medicamentous therapy of patients chronic virus hepatites is not accompanied by authentic improvement of the maintenance in plasma of blood NOx, and inclusion in a complex of medical actions of laser therapy promotes authentic improvement of parameters in plasma of blood NOx. THE CONCLUSION: Various methods of laser therapy improve NO--producing function endothelium, improve a functionacondition of vascular endothelium. PMID- 27214988 TI - [FEATURES OF FUNCTIONAL DISORDERS GASTRODUODENOBILIARY SYSTEM IN PATIENTS WITH CELIAC DISEASE]. AB - The disturbances in synchronous functioning of gastroduodenal and biliary system and in their consequent interaction underlies functional disorders of the digestive tract. Motor and evacuation functioning of the gastrointestinal tract depends on the bile flow to the duodenum, which influences on digestive processes. Functional disorders of the biliary tract, contributing disturbances of the gastrointestinal motor activity, cause gastrointestinal symptoms. The cause of biliary dysfunctions often are gallbladder anomalies, which are accompanied by disturbances in drainage system of bile flow, development of the pathological refluxes, inflammation and formation of the biliary sludge. The progression of the biliary system deflux dysfunction leads to motor and evacuation dysfunction of the gut. According to the numerous data, gall bladder anomalies, which underlies functional disorders in bile deflux, are common in patients with coeliac disease. The results, obtained in the conducted research, revealed hypertonic hyperkinetic motor disorders of the upper part of the gastrointestinal tract and inflammation changes of the gastroduodenal zone in patients with coeliac disease with fixed bend in the gallbladder neck, necking and different deformation of the gallbladder, which are the visceral signs of undifferentiated connective tissue dysplasia. Disorders in every component of the digestive tract upper part motor activity lead to the corresponding clinical manifestations. PMID- 27214989 TI - [CHRONOLOGICAL APPROACH TO COMPLEX TREATMENT OF PATIENTS WITH CHRONIC CHOLECYSTITIS IN COMBINATION WITH THE OPISTHORCHIASIS]. AB - The development of new technologies of medical rehabilitation of patients with chronic cholecystitis in combination with a chronic opisthorchiasis, remains an actual problem of clinical gastroenterology. The use of a group chronobiological approach to the complex treatment of these patients including EHF-therapy allows to increase efficiency of the conducted measures. The analysis of results testified to beneficial effect of such approach on indicators of a functional condition of hepatobiliarity system and an organism in general. The positive dynamics of all studied indicators provided high thera- peutic effect (to 84.8%), and the revealed contingency of these results to features of carrying out treatment, allowed to establish their interrelation (chi2 = 104.13; p = 0.0001; Kramer's V-coefficient = 0.35). It guarantees (is a predictor) receiving of high therapeutic effect (Percent Concordant of = 86.4%; the standardized coefficient = 2.54; r = 0.001) of the complex treatment including EHF-therapy with use of chronobiological approach to treatment of patients with chronic cholecystitis in combination with a chronic opisthorchiasis. The established dependences have a great practical importance and can be used in a choice of tactics of treatment of this category of patients. PMID- 27214990 TI - [PATHOGENETIC ASPECTS OF REHABILITATION OF PATIENTS AFTER CHOLECYSTECTOMY]. AB - Investigation of efficiency of liquid synbiotics and structure-resonance electric magnetic therapy (SRMT) among patients after cholecystectomy. MATERIALS AND METHODS: 90 patients after cholecystectomy have been investigated (CE). Along with general clinical meth-ods of investigation, patients passed US investigation of abdomen, biochemical blood tests, bacteriological test of faeces, investigation of short-chain fatty acids (SCFA) by gas-liquid osteal chromatographic analysis. State of vegetative nervous system passed analysis according to variability of heart rhythm (VHR) by spectral analysis method using "Cardiac technic 4000 AD" cardiac monitor in frame of 24-hr ECG monitoring. Estimation of life quality (LQ) of patients after cholecystectomy has been conducted by "SF-36 Health status survey". Patients have been divided into 3 groups, comparable according to the main clinical and functional indicators. Patients of first group (30 people) passed correction of dysbiosis by liquid synbiotics. Patients of a second group (30 persons) passed complex treatment of SRMT and liquid synbiotics. Control group was composed by 30 patients after cholecystectomy who had been receiving diet therapy. RESULTS AND CONCLUSIONS: In term of investigation 90% of patients have shown decrease of number and methabolic activity of microflora, change of activity of anaerobic microorganisms. Analysis of variability of heart rhythm have displayed relative prevalence of sympathetic modulation of a rhythm on the background of elevated ergotropic component of the total capacity of a spectrum; estimation of life quality (LQ) has shown that limitation of physical activity is a most considerable contribution to decrease of LQ among patients after cholecystectomy. After a course of liquid synbiotics and SMRT recovery and improvement of intestines and improvement of all indicator of life quality is observed. PMID- 27214991 TI - [IMPROVING THE RESULTS OF SURGICAL TREATMENT OF GALLSTONE DISEASE]. AB - THE PURPOSE OF THE STUDY: optimization measures for postoperative management of patients after laparoscopic cholecystectomy. MATERIAL AND METHODS: In the study group included 102 women and 302 men. At the 303 patients (75%) for specific indications ERCP was performed. Age of patients varied from 16 to 80 years and averaged 47.7 +/- 12.9 years. It should be noted that at 298 (98.3%) patients ERCP was performed prior to laparoscopic cholecystectomy with diagnostic or therapeutic purposes. To assess the effectiveness of treatment comparison group (control group) consisted of 20 patients with postoperative complications identified after cholecystectomy; patients received basic diet. Main group--25 patients, where in treatment as an additional therapeutic agent administered vegetables "Hepartea". Liver function was assessed by biochemical studies (total protein, urea, ALT and AST). Were determined the quality of life of patients immediately after surgery and at certain stages of rehabilitation after the application of supportive therapy. RESULTS: According to clinical, laboratory and morphological studies acute cholecystitis abscess was observed at 0.25 +/- 0.25%; chronic calculous cholecystitis in 75.7 +/- 2.13%. Among the total surveyed hospitalized patients in 16 (5.3%) patients ERCP was performed with diagnostic, and in 287 (94.7%) cases--with curative intent. Statistical analysis of data obtained from the structural components of the SF-36 in 30 days after completion of conservative therapy with herbal preparation revealed some nnormalization of protein metabolism, enzyme activity and other indicators of liver function. CONCLUSION: dates on the main group of the patients noted relatively fast dynamics of normalization of stimulating cell-mediated immunity, evidenced by a more pronounced and significant decrease in protein damage and reduction of urea. Chemical analysis of peripheral blood and clinical trials show greater therapeutic effect of herbal drug when used in the early postoperative period after laparoscopic cholecystectomy. Using herbal drug in treatment of complications of laparoscopic cholecystectomy can effectively stop clinical and biochemical manifestations of inflammation, reduce the incidence of postoperative complications and reduce the time of rehabilitation, which has a significant beneficial impact on the quality of life of patients. PMID- 27214992 TI - [FEATURES OF THE MIRIZZI SYNDROME TREATMENT]. AB - Analysis of the possibilities of application of minimally invasive approaches in Mirizzi syndrome. Analyzed the treatment of 70 patients with the syndrome Mirizzi treated from 2002 to 2012. The study describes the features of the application of minimally invasive interventions in Mirizzi syndrome. Application of minimally invasive techniques in the treatment of Mirizzi syndrome is permissible when assessing the diagnostic characteristics obtained at the preoperative and intraoperative phases. Frequency conversion during minilaparotomic access at Mirizzi syndrome lower than for laparoscopic. Performing intraoperative cholangiography before main stages of the opera helps to concretize optimum volume of intervention. PMID- 27214993 TI - [FATTY LIVER AND DEVELOPMENT OF ATHEROSCLEROSIS IN ELDERLY AND SENILE AGE]. AB - AIM OF STUDY: Search for scientific information on the relation fatty liver with the development of atherosclerotic lesions of arteries. Currently fatty liver regarded as hepatic manifestation of metabolic syndrome, regardless of the presence or absence of traditional risk factors and components of metabolic syndrome, fatty liver is associated with a greater degree of atherosclerotic vascular disease. In addition fatty liver may occur long before the development of metabolic problems, thus creating preconditions for the development of possible metabolic disorders in the human body. PMID- 27214994 TI - [CLINICAL CASE OF COMBINATION OF PRIMARY SCLEROSING CHOLANGITIS WITH NONSPECIFIC ULCERATIVE COLITIS IN TWINS MONOZYGOTIC]. AB - The article presents discussion of basic hypotheses of pathogenesis of primary sclerosing cholangitis (PSC): genetically conditioned pathology, autoimmune pathology, result of inflammatory reaction in bile ducts, cholangiopathy. The authors presents a clinical case of monozygotic twins with association of PSC and nonspecific ulcerative colitis (NUC). The first twin had a severe course of PSC and mild course of NUC; he died due to bacterial complications of cholangitis. The second twin--patient B--had an opposite situation: severe course of NUC, while PSC was suspected only after determination of cholestasis biochemical markers. As soon as cholestasis was revealed, patients B was treated with Ursofalk and Budenofalk (2001). He received Salofalk as a remedy of basic therapy for NUC. Repeated liver biopsy (2005) showed no progression of PSC, but there were present minimal biochemical signs of cholestasis. So, it is necessary to investigate the first degree relatives of patients with PSC. The timely administered treatment in some cases gives the possibility of the control of the disease course. PMID- 27214995 TI - [THE USE OF COMBINATION ANTIVIRAL THERAPY IN LIVER CIRRHOSIS HCV ETIOLOGY]. AB - Is a clinical example of combination antiviral therapy drugs interferon and ribavirin in the treatment of liver cirrhosis in chronic HCV infection, class A on Child-Pugh which made the transition of liver cirrhosis in the F1 fibrosis (the Metavir) and achieved sustained antiviral response (SVR). PMID- 27214996 TI - Eye Science is transferred to AME Publishing Company to be in charge of its publication. PMID- 27214997 TI - Professor Jin Yuan in ZOC Won the "Grand Challenge 2015 Young Scientist" Award. AB - Professor Yuan Jin from Zhongshan Ophthalmic Center (ZOC) affiliated with Sun Yat sen University has recently won the "Grand Challenge 2015 Young Scientist" award in "2015 Innovation Challenge Annual Meeting" held in Beijing. The meeting is organized by the Ministry of Science and Technology of the People Republic of China (MOST), the Bill & Melinda Gates Foundation in the United States and the US Agency for International Development. The journal Eye Science (ES) is the official publication of ZOC, sponsored by Sun Yat-sen University. PMID- 27214998 TI - Is macular hole a risk factor for retinal detachment? PMID- 27214999 TI - The role of outdoor activity in myopia prevention. PMID- 27215000 TI - Mesenchymal stem cell secretome to control inflammation in allergic conjunctivitis. PMID- 27215001 TI - Time spent outdoors and myopia: establishing an evidence base. PMID- 27215002 TI - Ophthalmic profile and systemic features of pediatric facial nerve palsy. AB - BACKGROUND: Facial nerve palsy (FNP) occurs less frequently in children as compared to adults but most cases are secondary to an identifiable cause. These children may have a variety of ocular and systemic features associated with the palsy and need detailed ophthalmic and systemic evaluation. METHODS: This was a retrospective chart review of all the cases of FNP below the age of 16 years, presenting to a tertiary ophthalmic hospital over the period of 9 years, from January 2000 to December 2008. RESULTS: A total of 22 patients were included in the study. The average age at presentation was 6.08 years (range, 4 months to 16 years). Only one patient (4.54%) had bilateral FNP and 21 cases (95.45%) had unilateral FNP. Seventeen patients (77.27%) had congenital palsy and of these, five patients had a syndromic association, three had birth trauma and nine patients had idiopathic palsy. Five patients (22.72%) had an acquired palsy, of these, two had a traumatic cause and one patient each had neoplastic origin of the palsy, iatrogenic palsy after surgery for hemangioma and idiopathic palsy. Three patients had ipsilateral sixth nerve palsy, two children were diagnosed to have Moebius syndrome, one child had an ipsilateral Duane's syndrome with ipsilateral hearing loss. Corneal involvement was seen in eight patients (36.36%). Amblyopia was seen in ten patients (45.45%). Neuroimaging studies showed evidence of trauma, posterior fossa cysts, pontine gliosis and neoplasms such as a chloroma. Systemic associations included hemifacial macrosomia, oculovertebral malformations, Dandy Walker syndrome, Moebius syndrome and cerebral palsy CONCLUSIONS: FNP in children can have a number of underlying causes, some of which may be life threatening. It can also result in serious ocular complications including corneal perforation and severe amblyopia. These children require a multifaceted approach to their care. PMID- 27215003 TI - Age-determined referral criteria of myopia for large-scale vision screening. AB - BACKGROUND: This study aimed to explore the best screening measure of myopia and its associated optimal referral criteria for children aged between 6 and 16. METHODS: After informed consent of cycloplegia was obtained, a total of 6,321 children aged between 6 and 16 from 53 primary or junior middle schools in Jiading District of Shanghai were included in our population-based study. Receiver operating characteristic (ROC) curve was performed to determine the best cutoff points, sensitivities and specificities of different screening tests, including uncorrected visual acuity (UCVA), noncycloplegic autorefraction (NCAR) and the combination of these two tests. RESULTS: There was significant difference in prevalence of myopia between boys and girls (chi2 = 6.358, P = 0.012). Compared with children of low age, the prevalence of older children was significantly higher (chi2 = 1,386.404, P < 0.001). For the combination of UCVA and NCAR, the best cutoff point was UCVA less than or equal to 0.2 logarithm of minimum angle of resolution (MAR) (20/30) and NCAR spherical equivalent refraction (SER) less than or equal to -0.75 diopters (D), with associated sensitivity and specificity of 75.0% and 85.0%, respectively, which were higher than those of UCVA and NCAR alone. After stratified by age, the best cutoff points were varied among children. The accuracy for children aged between 9 and 12 was higher than that for other ages. CONCLUSIONS: The best screening measure of myopia was the combination of UCVA and NCAR. The optimal referral criteria of myopia for children should be age-determined. PMID- 27215004 TI - Relationship between full-thickness macular hole and retinal break/lattice degeneration. AB - BACKGROUND: The purpose is to investigate the relationship between full-thickness macular hole (MH) and retinal break (RB) and/or lattice degeneration. METHODS: Patients diagnosed as full-thickness MH and referred to Dr. Lin Lu from January 2009 to December 2013 were evaluated. All patients underwent general ophthalmologic examinations, fundus examination and optical coherence tomography (OCT). The RB and/or lattice degeneration were recorded. RESULTS: Totally 183 eyes of 167 patients were included. The sex ratio of men to women was 1:2.88. A total of 17 eyes were pseudophakic and 166 eyes were phakic. RB and/or lattice degeneration were found in 62 eyes (33.88%). The prevalence of RB and/or lattice degeneration was similar between men and women (P = 0.344 > 0.05). There was no statistical difference between the pseudophakic eyes and phakic eyes (P = 0.138 > 0.05). All of the RB and/or lattice degeneration were located near or anterior to the equator. The inferior quadrants and the vertical meridian were affected more often than the superior quadrants and the horizontal meridian. CONCLUSIONS: We identified a high incidence of RB/lattice degeneration in cases of full-thickness MH. Carefully examination of the peripheral retina and prophylactic treatment of RB and/or lattice degeneration are critical. PMID- 27215005 TI - The safety and efficacy of modified minimally invasive trabeculectomy for the treatment of primary chronic angle-closure glaucoma. AB - BACKGROUND: Primary chronic angle-closure glaucoma (PCACG) is one of the main types of glaucoma in China. Trabeculectomy is the most commonly used glaucoma filtration surgery for glaucoma in the world. Conventional trabeculectomy is prone to anesthesia-related complications intraoperative and operation-related complications postoperative in PCACG treatment. Modified minimally invasive trabeculectomy maybe can reduce the incidence of complications. METHODS: We conducted a prospective case series study and performed modified fornix-based trabeculectomy in 27 patients (30 eyes) under topical anesthesia; we then observed intraoperative anesthesia and cooperation effect, intraoperative and postoperative complications, preoperative and postoperative visual acuity, intraocular pressure (IOP), visual field, and the use of ocular hypotensive drugs. The patients were followed up for at least 12 months. RESULTS: All operations were completed successfully with no intraoperative complications. All 27 patients (30 eyes) were followed up for at least 12 months. No significant decrease in visual acuity was observed at days 1 or 7 and at months 1, 3, 6, and 12 after operation; however, a significant decrease in IOP was observed at days 1 and 7 and at months 1, 3, 6, and 12 after operation. Moreover, no significant progression in visual field mean defect was observed at month 12 after operation, and the number of ocular hypotensive drugs required was significantly reduced at months 6 and 12 after operation. By month 12 after operation, the overall success rate was 93.33% (28/30). CONCLUSIONS: Modified minimally invasive trabeculectomy is safe and effective for the treatment of PCACG. PMID- 27215006 TI - Analysis of different vision charts used for visual acuity assessment after retinal surgery. AB - BACKGROUND: Different visual acuity chart can be targeted to evaluate the visual function of patients with different eye diseases. We conducted a comparative analysis of the digital logarithm of the minimum angle of resolution (LogMAR) vision chart and the standard logarithmic vision chart for the measurement of visual acuity after retinal detachment surgery. METHODS: We used the digital LogMAR vision chart and the standard logarithmic vision chart to measure the visual acuity of 100 patients (100 eyes) who underwent retinal detachment surgery at our hospital using the LogMAR recording method and compared the differences between the mean measurements obtained by both methods for all patients and for different age groups. RESULTS: When all of the patients were analyzed, the mean visual acuity differed between the digital LogMAR vision chart and the standard logarithmic vision chart by -0.07 LogMAR units. No significant difference was observed in the mean visual acuity between the two vision charts in the 10-20 year and 21-40 year age groups (P > 0.05), while a significant difference was observed in post-operative mean visual acuity between the two vision charts for patients aged 41-65 years (P < 0.05). CONCLUSIONS: Both the digital LogMAR vision chart and the standard vision chart were effective and reliable for the measurement of visual acuity. The visual acuity measured by the standard vision chart was higher than that measured by the digital LogMAR vision chart. We recommend using the digital LogMAR vision chart as the preferred chart for measuring visual acuity after retinal detachment surgery. PMID- 27215007 TI - Meta-analysis of the effect of perioperative injection of Lucentis on intraoperative bleeding in patients with proliferative diabetic retinopathy. AB - BACKGROUND: The effect of perioperative injection of Lucentis on intraoperative bleeding in patients with proliferative diabetic retinopathy (PDR) was systematically evaluated using a meta-analysis. METHODS: Reports of surgical eye treatment with and without perioperative intravitreal injection of Lucentis in Medline, the Cochrane Library, PubMed, the Chinese Biomedical Literature Database, and China Academic Journals Full-text Database were included in the study. A meta-analysis was performed on all included literature. A computerized search was performed in the above databases. In addition, relevant books, journals, and conference proceedings and their bibliographies were manually searched. Published literature was screened according to the inclusion and exclusion criteria. Data extraction was performed on included studies. RevMan5.2 software was used for the statistical analyses. Dichotomous variables are presented as odds ratios (ORs) and 95% confidence intervals (CIs). The major indicator was the occurrence of intraoperative retinal hemorrhaging during vitrectomy. RESULTS: A total of seven studies were included in the analysis. The treatment group included 159 eyes and control group included 149 eyes. The amount of intraoperative bleeding in the treatment group (perioperative Lucentis injection) was significantly lower than that in the control group (OR, 56.93; 95% CI: 21.81-148.57, P < 0.01). CONCLUSIONS: Intravitreal Lucentis injection before a vitrectomy significantly reduced intraoperative bleeding in PDR patients. PMID- 27215008 TI - An updated review of long-term outcomes from randomized controlled trials in approved pharmaceuticals for diabetic macular edema. AB - Diabetic macular edema (DME) is a major sight-threatening cause in diabetic patients. We review the long-term outcome of four approved pharmacotherapy for treating DME, including intravitreal injections of corticosteroids (dexamethasone implants and fluocinolone acetonide inserts) and anti-vascular endothelial growth factor (VEGF) (ranibizumab and aflibercept). They all show superior ability to improve vision and reduce macular thickness, comparing with sham injections or macular focal/grid laser treatment. Anti-VEGF agents result in low incidence of severe ocular or systemic adverse effects, but glaucoma and cataract should be aware after intravitreal corticosteroids. Prompt treatment with these agents can lead to a better outcome PMID- 27215009 TI - Construction of databases: advances and significance in clinical research. AB - Widely used in clinical research, the database is a new type of data management automation technology and the most efficient tool for data management. In this article, we first explain some basic concepts, such as the definition, classification, and establishment of databases. Afterward, the workflow for establishing databases, inputting data, verifying data, and managing databases is presented. Meanwhile, by discussing the application of databases in clinical research, we illuminate the important role of databases in clinical research practice. Lastly, we introduce the reanalysis of randomized controlled trials (RCTs) and cloud computing techniques, showing the most recent advancements of databases in clinical research. PMID- 27215010 TI - Application of visual electrophysiology for the diagnosis and treatment of cataracts. AB - Visual electrophysiology is widely used in clinical ophthalmology. It is also of significant value in the objective assessment of visual function in adult and pediatric cataract patients and for the diagnosis of and research on retinal and visual pathway diseases. This article systematically reviews visual electrophysiology techniques, their applications in the diagnosis and treatment of adult and pediatric cataracts, and factors influencing the application of visual electrophysiology during surgical treatment for cataracts. PMID- 27215011 TI - Approved pharmacotherapy for myopic choroidal neovascularization: a review of randomized controlled trials in ranibizumab and aflibercept. AB - Myopic choroidal neovascularization (mCNV) can cause severe visual impairment in highly myopic patients. We review the randomized trials of two approved pharmacotherapy for treating mCNV, including intravitreal injections of ranibizumab and aflibercept. These two vascular endothelial growth factor (VEGF) antagonists show superior ability to improve vision and reduce macular thickness, comparing with sham injections or verteporfin photodynamic therapy (vPDT). There is no severe ocular or systemic adverse reaction reported in studies associated with ranibizumab and aflibercept for mCNV. Prompt treatment with these agents can lead to a better outcome. PMID- 27215012 TI - Intravitreal aflibercept for rubeosis iridis secondary to proliferative diabetic retinopathy. AB - The purpose of this article is to report a case with rubeosis iridis treated by intravitreal aflibercept. A 61-year-old man had iris neovascularization and scanty vitreous hemorrhage secondary to proliferative diabetic retinopathy in the right eye. Neither neovascularization of angle nor elevation of intraocular pressure was found. Single intravitreal aflibercept 2 mg injection was performed. Rubeosis iridis disappeared on the next day. Scattered retinal laser photocoagulation was added 1 week later. There was no recurrence after 3-month follow-up. Aflibercept may serve as another anti-vascular endothelial growth factor (anti-VEGF) for treating rubeosis iridis. PMID- 27215013 TI - External drainage for exudative retinal detachment secondary to central serous chorioretinopathy. AB - BACKGROUND: To report the outcomes of external drainage of subretinal fluid (SRF) in exudative retinal detachment secondary to central serous chorioretinopathy (CSCR). METHODS: Retrospective observational analysis of six eyes with exudative retinal detachment secondary to CSCR who underwent external drainage of SRF between 2004 and 2014 was performed. Collected data included demographics, steroid usage, surgical details, and visual acuity preoperatively and postoperative visual acuity and clinical examination data were collected. RESULTS: Six eyes of six subjects were included with mean age of 45 years (range, 32 to 61 years). All subjects were male. Mean duration of symptoms was 4.6 months (range, 3 to 8 months). The pre-operative best-corrected visual acuity (BCVA) ranged from perception of light to 20/60. Four eyes were treated with conventional external drainage and two underwent Chandelier-assisted external drainage. Three cases had laser treatment before drainage and one case underwent photodynamic therapy (PDT) after drainage. The BCVA at last follow-up ranged from 20/2,000 (counting fingers at 2 feet) to 20/20. No recurrences were noted in any of the cases till the last follow-up. Mean duration of follow-up was 38 months. CONCLUSIONS: Our study demonstrates successful management of exudative retinal detachment secondary to CSCR with external SRF drainage without any complications. PMID- 27215014 TI - A mini review: Tau transgenic mouse models and olfactory dysfunction in Alzheimer's Disease. AB - Alzheimer's Disease (AD) is a chronic neurodegenerative disease that usually takes many years from preclinical phase to prodromal phase characterized by mild symptoms before the onset of dementia. Once diagnosed with AD, the brain is already severely damaged and the disease will process quickly to the most severe stages since there is no medications that reverse the neuronal injuries in the brain. Thus, simple, inexpensive, and widely available methods for detecting potential AD patients during their preclinical phases are urgently needed. In such case, olfactory testing may offer a chance for early diagnosis of AD. However, there are limitations in these olfactory tests due to the complexity of the brain areas it extends to and the frequently olfactory fatigue occurred in the behavioral olfactory tests. Great efforts have been done epidemiologically to investigate the correlation between olfactory functions and possibility of developing AD. Different patterns of olfactory dysfunction have been found in AD at early stages and even mild cognitive impairment (MIC), but the cause of the dysfunction remained unclear. Various kinds of AD animal models have been used in the field to clarify the existence of olfactory dysfunctions and thus study the underling mechanism of the dysfunction. In this review we discuss (1) the function of Tau physiologically and pathologically; (2) the genetic background and biological characteristics of the most commonly used Tau transgenic mice; (3) the structural and molecule basis of olfaction; (4) the possible relationship between Tau pathology and olfactory dysfunction. Finally, we suggest that the tau transgenic mouse models may be helpful in studying the possible mechanisms of the dysfunction. PMID- 27215015 TI - Stereotactic radiation therapy in the era of precision medicine for cancer. AB - Unlike conventional radiation therapy, stereotactic radiation therapy (SRT) is an emerging tumor-ablative radiation technology with a high-dose delivery to targets while dramatically sparing adjacent normal tissues. The strengths of SRT involve noninvasive and short-course treatment, high rates of tumor local control with a low risk of side effects. Although the scientific concepts of radiobiology fail to be totally understood currently, SRT has shown its potential and advantages against various tumors, especially for those adjacent to less tolerable normal organs (spinal cord, optic nerve, bowels, etc.). Nowadays, the clinical efficacy of SRT has been widely confirmed in certain patients, especially for those medically inoperable, unwilling to undergo surgery, medicine ineffective with tumor progression. Moreover, SRT could be properly used as palliative treatment aiming at relieving local symptoms and pain, and eventually achieving a potential survival benefit of several months. However, the weaknesses of SRT relate to inevitable radiation-induced toxicities as well as the inaccessibility of prophylactic irradiation. In general, one flaw cannot obscure the splendor of the jade. The emergence and development of SRT has opened the new era of precision radiation therapy, and SRT will probably step gloriously onto the remarkable stage for precision medicine. PMID- 27215016 TI - The physiological effects of resveratrol and its potential application in high altitude medicine. AB - Resveratrol, as a natural polyphenolic compound, has a wide range of beneficial effects, which includes anti-tumor, cardiovascular protection, anti-oxidant and estrogen-like effects, and so on. Its various physiological properties are closely related to the therapeutic principle for prevention and treatment of high altitude hypoxia injury. Resveratrol may play an important role in relieving or curing high altitude diseases, especially high altitude polycythemia(HAPC). However, the literature about study and application of resveratrol in plateau medicine field is rarely reported up to now. In this review, we summarized the physiological effects of resveratrol, discussed the possible main principle of resveratrol for HAPC therapy, and looked forward to resveratrol's perspective or potential application in high altitude medicine. PMID- 27215017 TI - Ethical Inspection about laboratory animals. AB - Laboratory animals and animal experiments are foundations and important support conditions for life sciences, especially for medical research. The animal experiments have drawn extensive attention from the society because of the ethical issue. This paper takes Wenzhou Medical University as an example to give a brief introduction to the ethical review about laboratory animals in the university so as to further draw attention and concerns from the public about the ethical issue of laboratory animals. We successively introduce its scientific projects, nurturing environment and ethical review of laboratory animals. PMID- 27215018 TI - Better parameters of ventilation-CO2output relationship predict death in CHF patients. AB - OBJECTIVE: Measures of ventilation-CO2output relationship have been shown to be more prognostic than peak O2uptake in assessing life expectancy in patients with chronic heart failure (CHF). Because both the ratios (VE/Vco2) and slopes (VE-vs Vco2) of ventilation-co2 output of differing durations can be used, we aim to ascertain which measurements best predicted CHF life expectancy. METHODS: Two hundred and seventy-one CHF patients with NYHA class II-IV underwent incremental cardiopulmonary exercise testing (CPET) and were followed-up for a median duration of 479 days. Four different linear regression VE-vs- Vco2 slopes were calculated from warm-up exercise onset to: 180 s, anaerobic threshold (AT), ventilatory compensation point (VCP); and peak exercise. Five VE/Vco2 ratios were calculated for the following durations: rest (120 s), warm-up (30 s), AT (60 s), lowest value (90 s), and peak exercise (30 s). Death or heart transplant were considered end-points. Multiple statistical analyses were performed. RESULTS: CHF patients had high lowest VE/Vco2 (41.0 +/- 9.2, 141 +/- 30%pred), high VE/Vco2 at AT (42.5 +/- 10.4, 145 +/- 35%pred), and high VE-vs-Vco2 slope to VCP (37.6 +/- 12.1, 126 +/- 41%pred). The best predictor of death was a higher lowest VE/Vco2 (>= 42, >= 141%pred), whereas the VE-vs-Vco2slope to VCP was less variable than other slopes. For death prognosis in 6 months, %pred values were superior: for longer times, absolute values were superior. CONCLUSION: The increased lowest VE/Vco2 ratio easily identifiable and simply measured during exercise, is the best measurement to assess the ventilation-co2output relationship in prognosticating death in CHF patients. PMID- 27215019 TI - Association between endothelial nitric oxide synthase (ENOS) G894T polymorphism and high altitude (HA) adaptation: a meta-analysis. AB - OBJECTIVE: Highland natives adapt well to the hypoxic environment at high altitude (HA). Several genes have been reported to be linked to HA adaptation. Previous studies showed that the endothelial ni- tric oxide synthase (ENOS) G894T polymorphism contributed to the physiology and pathophysiology of hu- mans at HA by regulating the production of NO. In this meta-analysis, we evaluate the association between the ENOS G894T polymorphism and HA adaptation through analyzing the published data. METHODS: We searched all relevant literature about the ENOS G894T polymorphism and HA adaptation in PubMed, Med- line, and Embase before Step 2015. A random-effects model was applied (Revman 5.0), and study quality was assessed in duplicate. Six studies with 634 HA native cases and 621 low-altitude controls were included in this meta-analysis. RESULTS: From the results, we observed that the wild-type allele G was significantly overrepresented in the HA groups (OR = 1.85; 95% Cl, 1.47-2.33; P < 0.0001). In addition, the GG genotype was significantly associated with HA adaptation (OR = 1.99; 95% Cl, 1.54-2.57; P < 0.0001). CONCLUSION: Our results showed that in 894 G allele carriers, the GG genotype might be a beneficial factor for HA adaptation through enhancing the level of NO. However, more studies were needed to confirm our findings due to the limited sample size. PMID- 27215020 TI - Flow cytometric analysis of circulating microvesicles derived from myocardial Ischemic preconditioning and cardioprotection of Ischemia/reperfusion Injury in rats. AB - OBJECTIVE: To establish a flow cytometric method to detect the alteration of phenotypes and concentration of circulating microvesicles (MVs) from myocardial ischemic preconditioning (IPC) treated rats (IPC-MVs), and to investigate the effects of IPC-MVs on ischemia/reperfusion (I/R) injury in rats. METHODS: Myocardial IPC was elicited by three.cycles of 5-min ischemia and 5-min reperfusion of the left anterior descending (LAD) coronary artery. Platelet-free plasma (PFP) was isolated through two steps of centrifugation at room temperature from the peripheral blood, and IPC-MVs were isolated by ultracentrifugation from PFR PFP was incubated with anti-CD61, anti-CD144, anti-CD45 and anti-Erythroid Cells, and added 1, 2 um latex beads to calibrate and absolutely count by flow cytometry. For functional research, I/R injury was induced by 30-min ischemia and 120-min reperfusion of LAD. IPC-MVs 7 mg/kg were infused via the femoral vein in myocardial I/R injured rats. Mean arterial blood pressure (MAP), heart rate (HR) and ST-segment of electro-cardiogram (ECG) were monitored throughout the experiment. Changes of myocardial morphology were observed after hematoxylin eosin (HE) staining. The activity of plasma lactate dehydrogenase (LDH) was tested by Microplate Reader. Myocardial infarct size was measured by TTC staining. RESULTS: Total IPC-MVs and different phenotypes, including platelet derived MVs (PMVs), endothelial cell-derived MVs (EMVs), leucocyte-derived MVs (LMVs) and erythrocyte-derived MVs (RMVs) were all isolated which were identified membrane vesicles (<1 Vm) with corresponding antibody positive. The numbers of PMVs, EMVs and RMVs were significantly increased in circulation of IPC treated rats (P<0.05, respectively). In addition, at the end of 120-min reperfusion in I/R injured rats, IPC-MVs markedly increased HR (P<0.01), decreased ST-segment and LDH activity (P < 0.05, P < 0.01). The damage of myocardium was obviously alleviated and myocardial infarct size was significantly lowered after IPC-MVs treatment (P < 0.01). CONCLUSION: The method of flow cytometry was successfully established to detect the phenotypes and concentration alteration of IPC-MVs, including PMVs, EMVs, LMVs and RMVs. Furthermore, circulating IPC-MVs protected myocardium against I/R injury in rats. PMID- 27215021 TI - Synergisms of cardiovascular effects between iptakalim and amlodipine, hydrochlorothiazide or propranolol in anesthetized rats. AB - The primary object of this fundamental research was to survey the synergistic cardiovascular effects of iptakalim, a novel ATP-sensitive potassium channel (K(ATP)) opener, and clinical first-line antihypertensive drugs, such as calcium antagonists, thiazide diuretics and beta receptor blockers by a 2 x 2 factorial design experiment. It would provide a theoretical basis for the development of new combined antihypertensive therapy program after iptakalim is applied to the clinic. Amlodipine besylate, hydrochlorothiazide and propranolol were chosen as clinical first-line antihypertensive drugs. Blood pressure, heart rate (HR) and cardiac functions were observed in anesthetized normal rats by an eight-channel physiological recorder. The results showed that iptakalim monotherapy in a low dose could produce significant antihypertensive effect. There was no interaction between iptakalim and amlodipine on the maximal changes of systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MABP), the left ventricular systolic pressure (LVSP), and the left ventricular end-diastolic pressure (LVEDP) (P > 0.05). However, the effects of combination iptakalim/amlodipine on the maximal changes of SBP, DBP, MABP, LVSP and LVEDP were more obvious than those of iptakalim or amlodipine monotherapy. And there was strong positive interaction between iptakalim and amlodipine on the maximal changes of HR (P>0.05). According to the maximal changes of DBP, MABP, LVSP and LVEDP (P < 0.05) of combination iptakalim with hydrochlorothiazide, there was strong positive interaction between them. But there was no interaction between iptakalim and hydrochlorothiazide on the maximal drop of SBP and HR (P > 0.05). According to the maximal drops of DBP, MABP of combination iptakalim with propranolol, there was strong positive interaction between them (P < 0.05). But there was no interaction between iptakalim and propranolol on the maximal changes of SBP, LVSP, LVEDP and HR (P > 0.05). In conclusion, it was the first time to study the effects of amlodipine, hydrochlorothiazide or propranolol, which had different mechanisms of action from iptakalim, on cardiovascular effects of iptakalim in anesthetized normal rats. This study proved that the combination of iptakalim with hydrochlorothiazide or propranolol respectively had significant synergism on lowering blood pressure, while the combination of iptakalim/amlodipine had additive action on lowering blood pressure. Meanwhile the antihypertensive effect was explicit, stable and long-lasting. Iptakalim thus appears suitable for the clinical treatment of hypertensive people who need two or more kinds of antihypertensive agents. PMID- 27215022 TI - Effects of curcumin on sodium currents of dorsal root ganglion neurons in type 2 diabetic neuropathic pain rats. AB - Along with the development of economy and society, type 2 diabetic mellitus (T2DM) has become one of the most common diseases at the global level. As one of the complications of T2DM, diabetic neuropathic pain (DNP) stubbornly and chronically affects the health and life of human beings. In the pain field, dorsal root ganglion (DRG) is generally considered as the first stage of the sensory pathway where the hyperexcitability of injured neurons is associated with different kinds of peripheral neuropathic pains. The abnormal electrophysiology is mainly due to the changed properties of voltage-gated sodium channels (VGSCs) and the increased sodium currents (I(Na)). Curcumin is an active ingredient extracted from turmeric and has been demonstrated to ameliorate T2DM and its various complications including DNP effectively. The present study demonstrates that the I(Na) of small-sized DRG neurons are significantly increased with the abnormal electrophysiological characteristics of VGSCs in type 2 diabetic neuropathic pain rats. And these abnormalities can be ameliorated efficaciously by a period of treatment with curcumin. PMID- 27215023 TI - Leptin receptor of the hind brain nuclei is involved in the conditioned taste preference of rats. AB - OBJECTIVE: Conditioned taste preference (CTP) is a taste learning reflex by which an animal learns to prefer a substance which tastes not well and has been studied with much interest in recent years. However, the neural substrates of CTP are less known. This study aimed to determine the possible neural path- ways of CTP and whether serum leptin level and the leptin receptor (OB-Rb) in the hind brain are involved following CTP formation. METHODS: We established CTP of quinine in rats with a 2-bottle preference test. The serum leptin concentrations were detected, the expression of c-fos in the rat brain was tested to determine the nuclei in relation with establishment of CTR Finally, the OB-Rb mRNA expression was examined by RT-qPCR assay in parabrachial nucleus (PBN) and the nucleus of the solitary tract (NST) of the hind brain. RESULTS: Compared with control group, the level of serum leptin was higher in the CTP group (4.58 +/- 0.52 vs 1.67 +/- 0.25 ug/L, P < 0.01); increased c-fos positive cells were found in the anterior hypothalamus (AH, 221.75 +/- 4.96 vs. 178.50 +/- 6.63 cells/mm2, P < 0.05), the basal lateral amygdala (BLA, 70.75 +/- 6.17 vs 56.50 +/- 3.62 cells/ mm2, P < 0.05) and the nucleus of the solitary tract (NST, 41.25 +/- 1.32 vs 32.50 +/- 1.02 cells/mm2, P < 0.05). But in ventromedial nucleus of the hypothalamus (VMH, 20.75 +/- 2.73 vs 38.5 +/- 1.54 per 1 mm2, P < 005), PBN (21.50 +/- 2.24 vs 36.25 +/- 1.49 cells/mm2, P < 0.05) and the central nucleus of the amygdala (CeA, 22.25 +/- 1.53 vs 35.50 +/- 2.11 cells/mm2, P < 0.05), the number of c-fos positive cells was decreased in the CTP group. In addition, we found OB-Rb mRNA expression in PBN of CTP group rats was higher than that of control group (0.95 +/- 0.055 vs 0.57 +/- 0.034, P < 0.05), while there was no significant difference of OB-Rb mRNA expression in NST between the two groups. CONCLUSION: Nuclei AH, BLA, NST, VMH, PBN and CeA participate in the formation of CTP. Leptin and its receptor in PBN may be involved in the formation and maintenance of CTP. PMID- 27215024 TI - Establishment and evaluation of a mouse model of bronchial asthma with Yin deficiency syndrome. AB - OBJECTIVE: To establish and evaluate a mouse model of bronchial asthma with Yin deficiency syndrome. METHODS: The mouse model of bronchial asthma with Yin deficiency syndrome was established by the treatment with injecting ovalbumin (OVA) two times to sensitize, inhaling OVA 14 times to stimulate, and using thyroxin through lavage during late stimulation. This model was evaluated through body weight, asthmatic behaviors, respiratory function, autonomous activity, lung pathology, and pulmonary fluid clearance. RESULTS: OVA combined with thyroxin was an appropriate method to induce the mouse model with increased food and water intake, autonomous activity, asthmatic behaviors score, and respiratory rate, decreased body weight, tidal volume, and wet/dry ratio of lung, and changed with pathology of lung tissue. The changes of the above mentioned parameters indicated that the model was the bronchial asthma with Yin deficiency syndrome. CONCLUSION: The OVA combined with thyroxin is a good pattern to establish a mouse model of bronchial asthma with Yin deficiency syndrome successfully, which can highly simulate the clinical symptoms of this disease. PMID- 27215025 TI - Ultrastructural study on route of gut bacterial translocation in a rat after spinal cord injury. AB - OBJECTIVE: To observe the ultrastructural change of the route of gut bacterial translocation in a rat with spinal cord injury (SCI). METHODS: Forty Wistar rats were divided into the following groups: control group and 3 SCI groups (10 in each group). The rats in the SCI groups were established SCI model at 24 h, 48 h, and 72 h after SCI. Small intestine mucous membrane tissue was identified and assayed by transmission electron microscope, scanning electron microscope and immunofluorescence microscopy. RESULTS: Small intestine mucous membrane tissue in control group was not damaged significantly, but those in SCI groups were damaged significantly. Proliferation bacteria in gut lumen attached on microvilli. The extracellular bacteria torn the intestinal barrier and perforated into the small intestinal mucosal epithelial cell. The bacteria and a lot of particles of the seriously damaged region penetrated into the lymphatic system and the blood system directly. Some bacteria were internalized into the goblet cell through the apical granule. Some bacteria and particles perforated into the submucosa of the M cell running the long axis of M cells through the tight junctions. In the microcirculation of mucosa, the bacteria that had already broken through the microvilli into blood circulation swim accompanying with erythrocytes. CONCLUSION: The routes of bacterial translocation interact and format a vicious circle. At early step, the transcellular pathway of bacterial translocation is major. Following with the destroyed small intestine mucous, the routes of bacterial translocation through the lymphatic system and the blood system become direct pathways. The goblet cell-dendritic cell and M cell pathway also play an important role in the bacterial translocation. PMID- 27215026 TI - Impacts of exposure to 900 MHz mobile phone radiation on liver function in rats. AB - OBJECTIVE: To study the impacts of exposure to electromagnetic radiation (EMR) on liver function in rats. METHODS: Twenty adult male Sprague-Dawley rats were randomly divided into normal group and radiated group. The rats in normal group were not radiated, those in radiated group were exposed to EMR 4 h/ d for 18 consecutive days. Rats were sacrificed immediately after the end of the experiment. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and those of malondialdehyde (MDA) and glutathione (GSH) in liver tissue were evaluated by colorimetric method. The liver histopathological changes were observed by hematoxylin and eosin staining and the protein expression of bax and bcl- 2 in liver tissue were detected by immunohistochemical method. Terminal-deoxynucleotidyl transferase mediated nick and labelling (TUNEL) method was used for analysis of apoptosis in liver. RESULTS: Compared with the normal rats, the serum levels of ALT and AST in the radiated group had no obvious changes (P>0.05), while the contents of MDA increased (P < 0.01) and those of GSH decreased (P < 0.01) in liver tissues. The histopathology examination showed diffuse hepatocyte swelling and vacuolation, small pieces and focal necrosis. The immunohistochemical results displayed that the expression of the bax protein was higher and that of bcl-2 protein was lower in radiated group. The hepatocyte apoptosis rates in radiated group was higher than that in normal group (all P < 0.01). CONCLUSION: The exposure to 900 MHz mobile phone 4 h/d for 18 days could induce the liver histological changes, which may be partly due to the apoptosis and oxidative stress induced in liver tissue by electromagnetic radiation. PMID- 27215027 TI - Wnt/beta-catenin pathway might underlie the MET in trans- differentiation from MSC to MSC-derived neuron. AB - OBJECTIVE: To observe MET-associated alteration during the trans-differentiation from MSCs to neuron-like cells, and to explore the possible molecular mechanism. METHODS: Bone marrow MSCs were isolated from rat femur and purified in continuous cell culture. After induced differentiation to neuron-like cells by the combination of butylated hydroxyanisole (BHA) and dimethyl sulfoxide (DMSO), cells were tested by comparative polymerase chain reaction (PCR) for the relative expression of MET biomarkers and transcription factors, and for cell cycle by flow cytometry. Meanwhile, target genes of Wnt/beta-catenin pathway were also analyzed by comparative PCR to determine the possible involvement. RESULTS: In MSC-induced neuron-like cells, MET-associated transcription factors such as Snail, Slug, ZEB1, ZEB2, and Twist were significantly attenuated in expression level. The Mesenchymal marker Vimentin expression level was increased. Membrane protein E-cad was slightly down-regulated, while N-cad level was marginally elevated. Percentage of proliferating cells (S phase in cell cycle) markedly shrank from 40.42% for MSCs to 6.76% for MSC-derived neuron. Additionally, Wnt/beta-catenin target genes beta-catenin and c-myc were decreasingly expressed. CONCLUSION: Chemically induced trans-differentiation from MSC to neuron caused similar MET-featured alteration in gene expression and proliferation to known MET, which might be underlied by deactivation of Wnt/beta-catenin pathway. PMID- 27215028 TI - [Symbiogenesis as a Model for Reconstructing the Early Stages of Genome Evolution]. AB - Symbiogenic evolution, which involves transformations of bacteria into the cellular organelles, is represented as a model for reconstructing the early stages of genome evolution, including the origin of DNA genomes from RNA genomes and the emergence of template processes on the basis of self-replicating molecular complexes in the ancestral metabolic systems. The antiquity of RNA genomes is supported by an increased evolutionary stability of ribosomal protein synthesis (translation) with respect to the DNA-dependent template processes (replication, transcription, recombination, and reparation). This stability is demonstrated by analysis of the deeply reduced genomes of symbiotic bacteria and cellular organelles as well as the "minimal" genomes which are common to phylogenetically diverse organisms. Higher evolutionary conservation of template biosynthetic processes with respect to step processes determining the metabolism and development in cells does not support the hypothesis about emergence ofgenomes within the ancestral cellular metabolic systems which are thought to be of abiogenic origin, instead suggesting dualistic origin of life on Earth. We suppose that the genome-free organelles of some eukaryotes (mitosomes, many hydrogenosomes, and some plastids) represent the products of reversion of symbiotic bacteria into ancestral forms which implemented their basic cellular functions using the informational macromolecules of exogenic origin. In the framework of this hypothesis the eukaryotic cells functioning based on the massive transfer of gene products (RNAs, proteins) from cytosol to organelles may represent the analogs of ancestral biocenoses that possessed integral hereditary systems (metagenomes). PMID- 27215029 TI - ["Matreshka" Genes with Alternative Reading Frames]. AB - Although a relatively small part of the human genome contains protein encoding genes, the latest data on the discovery of alternative open reading frames (ORFs) in conventional mRNAs has highlighted the expanded coding potential of these genes. Until recently, it was believed that each mRNA transcript encodes a single protein. Recent proteogenomics data indicate the existence of exceptions to this rule, which greatly changes the usual meaning of the term "gene". The topology of a gene with overlapping ORFs resembles a Russian "matreshka" toy. There are two levels of "matreshka" genetic systems. First, the chromosomal level, when the "nested" gene is located within introns and exons of the main chromosomal gene, both in the sense and antisense orientation relative to the external gene. The second level is a mature mRNA molecule containing overlapping ORFs or an ORF with an alternative-start codon. In this review we will focus on the properties of "matreshka" genes of the second type and methods for their detection and verification. Particular attention is paid to the biological properties of the polypeptides encoded by these genes. PMID- 27215030 TI - [SWI/SNF Protein Complexes Participate in the Initiation and Elongation Stages of Drosophila hsp70 Gene Transcription]. AB - The participation of the SWI/SNF chromatin remodeling complex in the stimulation of the RNA polymerase II binding to gene promotors was demonstrated in all model eukaryotic organisms. It was shown eight years ago that the SWI/SNF complex influence on transcription is not limited to its role in initiation but also includes participation in elongation and alternative splicing. In the current work, we describe the subunit composition of the SWI/SNF complexes participating in initiation, preparing for the elongation and elongation of hsp70 gene transcription in Drosophila melanogaster. The data reveal the high mobility of the SWI/SNF complex composition during the hsp 70 gene transcription process. We suggest a model describing the process of sequential SWI/SNF complex formation during heat-shock induced transcription of the hsp 70 gene. PMID- 27215032 TI - [Genealogical Analysis of the Use of Two Wheatgrass (Agropyron) Species in Common Wheat (Triticum aestivum L.) Breeding for Disease Resistance]. AB - During the last 80 years, in order to increase the genetic variability of wheat, translocations containing nine elongated wheatgrass (Agropyron elongatum) and eight intermediate wheatgrass (Agropyron intermedium) genes, which control resistance to pathogens, were transferred to this crop culture. Genealogical and statistical analysis of 1500 varieties developed using the wheatgrass gave evidence of the continuing increase in the proportion of such varieties in the total number of wheat varieties over the last half-century. Translocations from Ag. elongatum most commonly occur in the pedigrees of the varieties from the United States, less frequently they can be found in Australian and Chinese varieties, and they are extremely rare--in European and African ones. Ag. intermedium most frequently occurs in the pedigrees of the Eastern European varieties, mainly in those from Russia, as well as in the varieties from China. The observed uneven distribution of such varieties may be associated with either the effectiveness of the translocation in the development of resistance to the local populations of pathogens or with the effect of the translocation on the adaptive traits of plants. By computer tracking of pedigrees, we performed an inventory of the translocation donors from A. elongatum and A. intermedium used in the breeding programs in the United States, Russia, Australia, India, and China. The most widely occurring combinations of the gene complex Lr24/Sr24 of Ag. elongatum with other resistance genes were revealed. In Russia there were developed varieties in which the 6D chromosome was substituted by the 6Ai chromosome of Ag. intermedium, which controls disease resistance and the adaptivity of plants. The identification and introgression of new translocations indicates that the possibilities of using wheatgrass species for broadening of genetic variability of wheat are far from being exhausted. PMID- 27215031 TI - [Prevalence of VRN1 Locus Alleles among Spring Common Wheat Cultivars Cultivated in Western Siberia]. AB - With the use of allele-specific primers developed for the VRN1 loci, the allelic diversity of the VRN-A1, VRN-B1, and VRN-D1 genes was studied in 148 spring common wheat cultivars cultivated under the conditions of Western Siberia. It was demonstrated that modern Western Siberian cultivars have the VRN-A1a allele, which is widely distributed in the world (alone or in combination with the VRN B1a and VRN-B1c alleles). It was established that the main contribution in acceleration of the.seedling-heading time is determined by a dominant VRN-A1a allele, while the VRN-A1b allele, on the contrary, determines later plant heading. Cultivars that have the VRN-A1b allele in the genotype are found with a frequency of 8%. It was shown that cultivars with different allele combinations of two dominant genes (VRN-A1a + VRN-B1c and VRN-A1a + VRN-B1a) are characterized by earlier heading and maturing. PMID- 27215033 TI - [Genetic Diversity of the Cytochrome b Gene Fragment Haplotypes in Red-Backed Vole Myodes (Clethrionomys) rutilus Pallas, 1779]. AB - For the first time, genetic analysis of the cytochrome b gene fragment haplotypes encoding the identical and the most common cytochrome b polypeptide (F1) in M. rutilus from Eastern and Beringian mateml lineages was carried out. The F1 frequencies for the vole populations from Northern Priokhotye and the Kolyma basin were calculated. Considerable polymorphism of the cytochrome b F1 haplotypes within two major phylo- groups of red-backed vole was supported by high molecular diversity indices for these clades. The proportion of genetic variation between the maternal lineages of F1 red-backed vole individuals (60.71%) was considerably higher than inter-(24.44%) and intrapopulation (14.85%) components. The data obtained make it possible to advance a hypothesis on the convergence of the cytochrome b polypeptide structure upon sequence divergence of the corresponding gene. PMID- 27215034 TI - [Genome-Wide Analysis of Across Herd F(st) Heterogeneity in Holsteinized Livestock]. AB - To form a reference population necessary for genomic selection of dairy cattle, it is important to acquire information on the genetic diversity of the original population. Our report is the first among the studies on breeding of farm animals to implement Wright's F-statistics for this purpose. Genotyping of animals was performed using BovineSNP50 chip. In total, we genotyped 499 heifers from 13 breeding farms in the Leningrad oblast. We calculated Weir and Cockerham's F(st) estimate for all pairwise combinations of herds of breeding farms and the values obtained were in the range of 0.016-0.115 with the mean of 0.076 +/- 0.002. Theoretical F(st) values for the same pairwise combinations of herds were calculated using the ADMIXTURE program. These values were significantly (p < 0.05) higher than Weir and Cockerham's F(st) estimates and fell in the range of 0.063-0.136 with the mean of 0.100 +/- 0.001. We discuss the reasons for this discrepancy between the two sets of F(st) data. The obtained F(st) values were used to identify reliable molecular and genetic differences between the herds. The ADMIXTURE program breaks the pool of 476 heifers into 16 subpopulations, the number of which is close to the number of herds used in the experiment. Results of the comparison between F(st) values obtained using SNP markers with published data obtained on microsatellites are in support of the common opinion that microsatellite analysis results in underestimation of F(st) values. On the whole, the obtained across-herd F(st) values are in the range F(st) data reported for cattle breeds. Results of comparison of F(st) values with the data on the origin of bulls imported from different countries lead to the conclusion on the expediency of the use of F(st) indicators to assess heterogeneity of the herds. Thus, we have demonstrated that use of F(st) data provides the means to assess genetic diversity of cattle herds and is a necessary step in the formation of a reference population for dairy cattle. PMID- 27215035 TI - [Expression of Catechol-O-Methyltransferase (Comt), Mineralocorticoid Receptor (Mlr), and Epithelial Sodium Channel (ENaC) Genes in Kidneys of Hypertensive ISIAH Rats at Rest and during Response to Stress]. AB - Emotional stress plays a significant role in the processes of the development of arterial hypertension, especially in the presence of genetic predisposition. The origin and maintenance of hypertensive status during stress development can be activated by the sympathetic nervous system. An increase in sympathetic stimulation can, in turn, result in a change in the functions of kidneys, which provide fluid and electrolyte balance of the organism. A comparative study of the mRNA expression level of catechol-o-methyltransferase (Comt), mineralocorticoid receptor (Mlr), and beta-subunit of epithelial sodium channel (beta-ENaC) genes was conducted on the kidneys of hypertensive ISIAH rats and normotensive WAG rats at rest and after the effect of emotional stress. The discovered changes in the expression level of the selected genes confirm their involvement in increased sympathetic stimulation of the kidney, along with changes in the function of kidney regulation of fluid and electrolyte balance, which is an important factor of the development of sustained hypertension in the ISIAH rats strain. PMID- 27215036 TI - [Influence of Acetylcysteine on Cytogenetic Effects of Etoposide in Mouse Oocytes]. AB - The influence of N-acetylcysteine (ACC) on the cytogenetic effects of etoposide in F1 CBA x C57BL/6 mice was studied. Etoposide introduced intraperitoneally in doses of 10, 20, 40, and 60 mg/kg has a dose-dependent clastogenic activity and has an aneugenic effect with the induction of mainly hypohaploid oocytes. ACC significantly decreases the aneugenic and clastogenic activity of etoposide (20 mg/kg) in oocytes of 6-, 9-, and 12-week-old mice during triple introduction at a dose 200 mg/kg per os. The most pronounced anticlastogenic ACC activity (an 80% decrease) was registered in 9-week-old females; a 100% decrease in aneugenesis was detected in 6-week-old female mice. PMID- 27215037 TI - [Genetic Structure of Urban Population of the Common Hamster (Cricetus cricetus)]. AB - Over the past half-century, the common hamster (Cricetus cricetus), along with range-wide decline of natural populations, has actively populated the cities. The study of the genetic structure of urban populations of common hamster may shed light on features of the habitation of this species in urban landscapes. This article is focused on the genetic structure of common hamster populations in Simferopol (Crimea), one of the largest known urban populations of this species. On the basis of the analysis of nucleotide sequences of the cytochrome b gene and mtDNA control region, and the allelic composition of ten microsatellite loci of nDNA, we revealed that, despite the fact that some individuals can move throughout the city at considerable distances, the entire population of the city is represented by separate demes confined to different areas. These demes are characterized by a high degree of the genetic isolation and reduced genetic diversity compared to that found for the city as a whole. PMID- 27215038 TI - [Reliability of the Search for 19 Common Mutations in the CFTR Gene in Russian Cystic Fibrosis Patients and the Calculated Frequency of the Disease in Russian Federation]. AB - A study of Russian cystic fibrosis (CF) patient DNA was conducted to assess the incidence frequency of 19 mutations, namely CFTRdele2,3(21kb), F508del, I507del, 1677delTA, 2143delT, 2184insA, 394delTT, 3821delT, L138ins, 604insA, 3944delGT, G542X, W128X, N1303K, R334W, and 3849+10kbC>T, S1196X, 621+1g>t, and E92K of the CFTR gene. We also sought to determine the estimated CF frequency in Russian Federation. In addition, we determined the total information content of the approach for 19 common mutations registration in the CFTR gene, 84.6%, and the allelic frequencies of the examined mutations: three mutations were observed with a frequency exceeding 5% (F508del, 53.98%, E92K, 6.47%, CFTRdele2,3(21kb), 5.35%); other mutations were observed with frequencies ranging from 0.13% to 3.0%. The CF population carrier frequency was 1 in 38 subjects, while the predicted CF frequency was 1 in 5776 newborns. PMID- 27215039 TI - [Polymorphism (353)R>Q of Gene of Blood Clotting Factor FVII and Plasma Hemostasis]. AB - A comparative estimation was conducted to assess the prevalence of genotypes and alleles of the (353)R>Q polymorphism of the coagulation factor FVII gene between a group of the Russian adolescents with essential arterial hypertension and a group of Russian adolescents without such health problems. The RR genotype was diagnosed in 55 adolescents (75.34%) of the control group and in 99 adolescents (84.61%) of the adolescents suffering from essential arterial hypertension (chi2 = 1.949, p = 0.163). The frequency of the R-allel was 85% and 91.9%, respectively (chi2 = 3.110, p = 0.078). The role of the FVII gene in the determination of the F7 plasma activity was defined in adolescents with essential arterial hypertension and holders of different alleles. Holders of the R allele had significantly higher activity of coagulation factor F7 (97.66 +/- 15.48 against 83.37 +/- 15.16, p = 0.002) and factor F2 (107.45 +/- 6.03 against 103.75 +/- 6.81, p = 0.023) than holders of the Q allele. This relationship was not found in adolescents of the control group. PMID- 27215040 TI - The T -786C, G894T, and Intron 4 VNTR (4a/b) Polymorphisms of the Endothelial Nitric Oxide Synthase Gene in Prostate Cancer Cases. AB - In previously conducted some studies it has been revealed that nitric oxide (NO) and nitric oxide synthase (NOS) system play a significant role in carcinogenesis. Nitric oxide (NO) is regulated by endothelial nitric oxide synthase (eNOS) enzyme which is one of the isoenzymes of NO synthase (NOS). In this study we have tried to come to a conclusion about whether eNOS gene T -786C, G894T and Intron 4 VNTR (4a/b) polymorphisms might be considered as a risk factor causing prostate cancer (PCa) or not. A total of 200 subjects were included in this research. 84 patients with PCa (mean age 70.0 +/- 6.4) and 116 healthy controls (mean age 69.9 +/- 7.5) were recruited in this case-control study. Genomic DNA was extracted using the QIAamp DNA Blood Mini Kit (QIAGEN GmbH, Maryland, USA), according to the manufacturer's guidelines. The T-786C, G894T and Intron 4 VNTR (4a/b) polymorphisms were amplified using polymerase chain reation (PCR), detected by restriction fragment length polymorphism (RFLP). For T -786C polymorphism CC genotype [odds ratio (OR): 0.34, 95% confidence interval (CI): 0.15-0.78, P = 0.009)] and allele frequency (OR: 0.631, CI: 0.421-0.946, P = 0.026) is significant for control. In patients with PCa eNOS G894T polymorphism, both GT (OR: 0.069, CI: 0.027-0.174; P = 0.0001) and TT (OR: 0.040, CI: 0.013-0.123; P = = 0.0001) genotype distribution, and also T allele frequency (OR: 0.237, CI: 0.155-0.362, P = 0.0001) were considered significant statistically. While genotype distribution for the other polymorphism eNOS, intron 4 VNTR (4a/b), is insignificant statistically, "a" allele frequency was found out to be significant (OR: 2.223, CI: 1.311-3.769, P = 0.003). In this study we indicated that genotype and allele frequencies of eNOS T -786C and G894T polymorphisms are statistically significant in patients with PCa. eNOS T -786C and G894T polymorphisms may be associated with PCa susceptibility in the Turkish population. In contrast, intron 4 VNTR (4a/b) polymorphism may not be related to PCa susceptibility in these patients. PMID- 27215041 TI - A COMPARATIVE ANALYSIS OF METHYLATION STATUS OF TUMOR SUPPRESSOR GENES IN PAIRED BIOPSY AND SERUM SAMPLES FROM CERVICAL CANCER PATIENTS AMONG NORTH INDIAN POPULATION. AB - Tumor-specific genetic or epigenetic alterations have been detected in serum DNA in case of various types of cancers. In breast cancer, the detection of tumor suppressor gene hypermethylation has been reported in several body fluids. Promoter hypermethylation of some genes like MYOD1, CALCA, hTERT etc. has also been detected in serum samples from cervical cancer. The present study is the first report on the comparison of promoter hypermethylation of tumor suppressor genes likep14, p15, p16, p21, p27, p57, p53, p73, RARbeta2, FHIT, DAPK, STAT1 and RB1 genes in paired biopsy and serum samples from cervical cancer patients among north Indian population. This is also the first report on the hypermethylation of these genes in serum samples from cervical cancer patients among north Indian population. According to the results of the present study, promoter hypermethylation of these genes can also be detected in serum samples of cervical cancer patients. The sensitivity of detection of promoter hypermethylation in serum samples of cervical cancer patients as compared to paired biopsy samples was found to be around 83.3%. It was observed that promoter hypermethylation was mainly observed in the serum samples in the higher stages and very rarely in the lower stages. The present study clearly showed that serum of patients with cervical cancer can also be used to study methylated genes as biomarkers. PMID- 27215042 TI - [Genetic Differentiation among Natural Populations of the Lizard Complex Darevskia raddei as Inferred from Genome Microsatellite Marking]. AB - The article presents the genetic parameters of the populations of lizards of the Darevskia raddei complex (D. raddei nairensis and D. raddei raddei) and the populations of D. valentini calculated on the basis of the analysis of variability of 50 allelic variants of the three nuclear genome microsatellite containing loci of 83 individuals. It was demonstrated that the F(st) genetic distances between the populations of D. raddei nairensis and D. raddei raddei were not statistically significantly different from the F(st) genetic distances between the populations of different species, D. raddei and D. valentini. At the same time, these distances were statistically significantly higher than the F(st) distances between the populations belonging to one species within the genus Darevskia. These data suggest deep divergence between the populations of D. raddei raddei and D. raddei nairensis of the D. raddei complex and there arises the question on considering them as separate species. PMID- 27215043 TI - Charity Care. PMID- 27215044 TI - Radiation Associated Angiosarcoma: Case Series from a Community Cancer Center and Review of the Literature. AB - BACKGROUND: Radiation associated angiosarcoma (RAAS) of the breast is a rare, but lethal complication of breast conserving surgery (BCS). Early recognition and knowledge of treatment modalities is imperative for successful treatment. We present the experience of a large community cancer center, with review of the literature. METHODS: The Christiana Care Department of Pathology and the Helen F. Graham Cancer Center and Research Institute databases were queried from 2001-2011 and 2011-2015 respectively for soft tissue neoplasms of the breast. A total of 2,153 patients with diagnosis of malignant neoplasm of the breast not otherwise specified (NOS) were identified. There were seven cases of RAAS identified. RESULTS: Seven patients with RAAS were identified. Average age at presentation was 70 years with a range of 58-87. Time from radiation therapy to diagnosis was 8.5 years with a range of 4.0 years to 14.9 years. Five of seven patients presented with skin lesions, all with varying clinical signs. Clinical lymphedema was not identified in any of these patients. CONCLUSION: Radiation associated angiosarcoma of the breast is an aggressive tumor with poor prognosis. Larger studies are needed to evaluate adjuvant treatments; however the small number of cases makes this prohibitive. Genetic testing and potentially targeted therapies are emerging as options for treatment and prevention of this complicated disease process. PMID- 27215045 TI - Tobacco Cessation for Patients with Coronary Artery Disease. PMID- 27215046 TI - Deep Transcranial Magnetic Stimulation: A Promising Drug-Free Treatment Modality in the Treatment of Chronic Low Back Pain. AB - Deep Transcranial Magnetic Stimulation (dTMS) is the next generation of technology used to treat Major Depressive Disorder (MDD). dTMS has been proven to be a safe and effective treatment modality for MDD and may have secondary benefits in patients with chronic low back pain by reducing pain related morbidity. We are presenting two case studies with MDD and chronic low back pain to demonstrate the effectiveness of both the antidepressant and analgesic effects of dTMS. BACKGROUND: Transcranial Magnetic Stimulation (rTMS) utilizes MRI strength magnetic pulses outside the cranium to stimulate the brain to a depth of approximately 1 cm. The technique was approved by the US Food and Drug Administration (FDA) for the treatment of Major Depressive Disorder (MDD) in 2008. In 2013 the Brainsway Deep Transcranial Magnetic Stimulation (dTMS) device, which has the potential for cranial penetration up to 5 cm received FDA clearance for pharmacotherapy and psychotherapy resistant MDD. The mechanism of action of dTMS in MDD is not completely understood. However, its clinical efficacy is proven.' The effect of dTMS on the brain has been studied since 1985 in clinical trials and has been demonstrated as an effective treatment modality for refractory depressive symptoms. The mechanism of action of dTMS is thought to be mediated by increased connectivity between the dorsolateral prefrontal cortex (DLPFC) and the thalamus and reduced subgenual cingulate to caudate connectivity. These brain areas are believed to be responsible for modulating mood. Chronic pain is often accompanied by MDD. Specifically, chronic low back pain is highly prevalent and accompanied by significant disability.2 Low back pain is defined as chronic when the pain is continuous for more than three months. The current chronic pain treatment algorithm includes judicious use of non pharmacological interventions like physical therapy, chiropractic adjustments, therapeutic massage, or acupuncture combined with pharmacological interventions that utilize non-narcotic or narcotic oral medications, spinal/paraspinal injections and, in selected cases, surgery. In patients who fail this extensive algorithm for chronic pain management and are left with significant morbidity and disability, coincident MDD frequently becomes refractory to therapy. Two illustrative examples of chronic low back pain patients with medically refractory MDD treated successfully using dTMS are presented here to discuss the potential therapeutic benefits for both MDD and chronic low back pain in this setting. PMID- 27215047 TI - When Exhaustion Equals Errors. PMID- 27215048 TI - Is a HIPPO Running Your EMS Agency?. PMID- 27215049 TI - How to Develop a Fleet Replacement Strategy. PMID- 27215050 TI - Ambulance Safety: Signs of Progress. PMID- 27215051 TI - SIX CONSIDERATIONS FOR THE Assessment and Management of Homeless Patients. Six considerations for the assessment and management of homeless patients. PMID- 27215052 TI - Firefighter Down! How to Rapidly Remove Turnout Gear. AB - The rescue of an injured colleague--and probably a good friend--is an emotionally charged event. A common initial response could be to remove everything as quickly as possible. Keep in mind that we have accepted practices for the removal of motorcycle equipment and football gear. There are also procedures for removing a patient from a vehicle or swimming pool. These all exist to protect a patient from further injury. We now have established practices for removing a firefighter from a window, or down a ladder. Why then do the procedures stop? Once a firefighter is rescued from a hot zone, he deserves the same level of consideration a football player, motorcycle rider or any other patient receives. We should not be in such a hurry that we don't care how we remove a protective ensemble. The injured firefighter deserves a system, or a procedure, that may be practiced by others and reduce the chance of further injury during PMID- 27215053 TI - Getting the Most From Your History and Physical. PMID- 27215054 TI - Taking Care TO THE STREETS. PMID- 27215055 TI - Do You Like Your Job? PMID- 27215056 TI - Engaging health care providers to improve the referral and evaluation processes for potential transplant candidates--The Toronto General Hospital Experience. AB - The Kidney Transplant Program (KTP) at the Toronto General Hospital has taken great strides in preparing to meet the needs of patients and health care providers, as the number of end-stage renal disease patients in Ontario increases. The KTP has begun the process of increasing engagement and collaboration with various stakeholders from the pre- to the post-transplant phase through (1) the development of innovative programs to increase the number of live kidney donations, (2) the development and maintenance of information technology solutions that work simultaneously to provide data to manage and treat patients, and conduct research, and (3) the development, implementation, and delivery of educational presentations and tools to various stakeholders both at the referring centres and the transplant program. Future steps for the KTP include evaluating the impact of these programmatic tools and activities on the number of referrals received and the subsequent effect on the number of transplants performed. PMID- 27215057 TI - Update on phosphate binders: The old and the new. PMID- 27215058 TI - An overview of advance care planning for patients with advanced chronic kidney disease: The basics. AB - As the number of Canadians living with end-stage kidney disease (ESKD) continues to grow, even higher numbers are living with advanced chronic kidney disease (CKD). Many of these people will eventually require renal replacement therapy (RRT), either dialysis or transplantation. More than 50% of patients starting RRT today are aged 65 or older, with the fastest growing group being patients 75 years and older. Despite advances to dialysis technology and dialysis care, the mortality rates remain high and dialysis patients' end-of-life care may not align with their preferences or values. Advance care planning (ACP) is an essential component of quality comprehensive kidney care. Kidney care teams develop strong relationships with their patients and are well positioned to integrate ACP into routine kidney care. This article defines ACP, outlines the essential components of ACP, and discusses the benefits, challenges, and special considerations of ACP. By enhancing the kidney care team's understanding of ACP, this article aims to assist in integrating ACP into routine kidney care for patients with advanced CKD. PMID- 27215059 TI - Water--The first ingredient of the dialysis prescription. PMID- 27215060 TI - Making home-made phantom models for hemodialysis ultrasound vascular access assessment and real-time guided cannulation training. PMID- 27215061 TI - Fatigue in chronic kidney disease: Definition, assessment and treatment. AB - Chronic fatigue--an overwhelming subjective feeling of mental or physical exhaustion--impacts patients' everyday functioning and quality of life, delays recovery after hemodialysis, and increases mortality. There are a number of factors that may perpetuate clinically significant fatigue among individuals with chronic kidney disease, including sleep disorders, depression, sedentary lifestyle, anemia, and chronic inflammation. Some of these factors (i.e., anemia and inflammation) are in the forefront of clinical attention, whereas the other contributing factors often remain unrecognized. This article provides a pragmatic overview of the definition, assessment, maintaining factors, and management of fatigue in chronic kidney disease. Given that chronic fatigue is a major determinant of patients' quality of life, nurses can bring about a fundamental improvement in patients' well-being if they recognize the most common fatigue perpetuating factors and facilitate fatigue management interventions. PMID- 27215062 TI - Without a home. Nurses offer care, hope to those in need. PMID- 27215063 TI - Collaboration, connection key to culture of safety in mental health care. PMID- 27215064 TI - No health without mental health. PMID- 27215065 TI - Recognizing quality care. PMID- 27215066 TI - Nurses have made gains but more needs to be done. PMID- 27215067 TI - Laboratory Diagnosis of Factor XIII Deficiency, Routine Coagulation Tests with Quantitative and Qualitative Methods. AB - BACKGROUND: Factor XIII (FXIII) deficiency is a severe bleeding disorder with normal routine coagulation tests that makes diagnosis of the disorder complicated. After normal results in routine coagulation tests, clot solubility test, and FXIII activity, antigen assays along with molecular methods can be used for precise diagnosis of disorder. In the present study, we described routine coagulation tests along with clot solubility test and FXIII activity and antigen assays. METHODS: Data were collected from all relevant publications until 2015. RESULTS: All routine coagulation tests including prothrombin time (PT), partial thromboplastin time (PTT), thrombin time (TT), and platelet count are normal in FXIII deficiency (FXIIID) but different conditions such as blood collection, transport, and storage can result in abnormal results in these first line screening tests. In addition to these tests, clot solubility tests as the most common screening tests of FXIIID can influenced by different factors including clotting and solubilizing agents. Different commercial kits are available for FXIII activity and antigen assays with different sensitivity and specificity which could affect diagnosis of FXIIID. CONCLUSIONS: Results of routine coagulation tests as well as clot solubility tests along with specific coagulation tests can affect diagnosis of FXIIID; therefore, all steps of these tests should be under control. PMID- 27215068 TI - Autoantibodies Against DFS70/LEDGF Exclusion Markers for Systemic Autoimmune Rheumatic Diseases (SARD). AB - BACKGROUND: Antinuclear antibodies (ANA) are considered as a key serological feature of systemic autoimmune rheumatic diseases (SARD) which include syndromes like systemic lupus erythematodes (SLE), systemic sclerosis (SSc), mixed connective tissue disease (MCTD), Sjogren's syndrome (SS) or dermatomyositis/polymyositis (DM/PM). ANA, commonly detected by indirect immunofluorescence assays on HEp-2 cells (IF-ANA), recommended as the screening test of choice (ACR), comprise a plethora of antibody specificities, a part of which are important serological markers of the diagnostic armamentarium in SARD. However, the applicability of IF-ANA as global screening test is hampered by its limited diagnostic specificity for resulting positive in up to 20% of apparently healthy individuals. About half of IF-ANA in healthy individuals target the chromosome associated protein DFS70/LEDGF, which tethers transcriptional coactivators or lentiviral integrases to transcriptionally active chromatin moieties and induces pro-survival stress factor transcriptions. Because of their rare prevalence in SARD patients, isolated anti-DFS70 antibodies are being increasingly considered as important biomarker to exclude the diagnosis of SARD. METHODS: Scrutinizing the relevant articles cited in NCBI concerning the DFS70/LEDGF protein, the diverse methods of anti-DFS70 determination in human sera supplemented by own experiences and critical review of the complete literature relevant to anti-DFS70 and SARD. RESULTS: Antibodies to DFS70/LEDGF (anti-DFS70), disclosed by IF-ANA, are characterized by a dense fine speckled (DFS) nucleoplasmic fluorescence pattern (DFS-ANA) accompanied by a striking staining of the condensed chromosomes in mitotic cells. By means of various methods anti-DFS70 may be found in 7.8 +/- 6.2% (MD 7.6%) of apparently healthy individuals, may sometimes display rather high antibody titers and antibody carriers do not seem to manifest SARD symptoms within a five year interval. Their prevalence in non-selected cohorts originating from routine IF-ANA screenings (38643 tested individuals) fluctuates between 0.8 and 8.4% (MD 1.7%), depending on patient selection criteria and test performance. The proper appreciation of these data is hampered partially because of missing verification of antibody specificities partially by lack of specifications of associated disease or accompanying SARD specific marker antibodies. A metaanalysis of five studies including 1243 SARD patients confirms the rare mean prevalence of solitary anti DFS70 (0.7 +/- 0.9%, MD 0.45%) in SARD patients. The mean prevalence of anti DFS70 accompanied by SARD specific markers is 3.8 +/- 2.9% (MD 2.9%). In patients exclusively harbouring anti-DFS70 the likelihood ratio (LR+) for the absence of SARD approaches a significant value of 10.9. CONCLUSIONS: Since anti-DFS70 according to the available data may being regarded as a possible biomarker for ruling out the diagnosis of a systemic autoimmune rheumatic disease, it seems to be indispensable to identify properly DFS-ANA patterns in the routine IF-ANA screening, to confirm the anti-DFS70 specificity by appropriate confirmation assays and to communicate the results with annotating comments to the clinician, in order to ameliorate the proper assessment of the pathological significance of serological results and the selection of adequate follow-up investigations. PMID- 27215069 TI - Performance Evaluation of a Novel Chemiluminescence Assay Detecting Treponema Pallidum Antibody as a Syphilis Screening Method. AB - BACKGROUND: Syphilis is a major concern to global public health with increasing incidence. So its screening test should have sufficient sensitivity and specificity. We evaluated the performance of the Lumipulse G TP-N assay detection for syphilis screening and compared it with the InTec ELISA test kit for TP, which is widely used. METHODS: Samples of several patient groups including 133 clinical and serologically characterized syphilitic sera, 175 samples containing potentially interfering agents, and 2290 unselected samples submitted for routine screening were detected by both the Lumipulse G TP-N assay and the InTec ELISA test kit for TP. Inconsistent samples were confirmed by RecomLine Treponema IgG, IgM immunoblot. RESULTS: Coefficient of variations of the Lumipulseo G TP-N assay at both levels were below 5% and of the InTec ELISA test kit for TP both over 5%. The sensitivity of the Lumipulse G TP-N assay and the InTec ELISA test kit for TP were 100% for all stages of syphilis. The two methods had consistent analytical specificity of 100% (95% CI: 97.21 - 100.00), while the clinical specificity was 100% (95% CI: 99.79 - 100.00) and 99.82% (95% CI: 99.51 - 99.94), respectively. Between them, Spearman's correlation coefficient was 0.455 and kappa value was 0.986. The overall sensitivity and specificity of the Lumipulse G TP-N assay was higher than the InTec ELISA test kit for TP (sensitivity: 100.0 versus 99.5, specificity: 100.0 versus 99.8). CONCLUSIONS: The automated Lumipulse G TP-N assay demonstrated excellent diagnostic sensitivity and specificity when evaluated as a screening test for syphilis. Thus, it can be an alternative to the treponemal screening test. PMID- 27215070 TI - Abnormal Circulating Levels of Metalloproteinase and Their Inhibitor in Hypertensive Patients. AB - BACKGROUND: The aim of this study was to determine the plasmatic levels matrix metalloproteinases (MMPs): MMP-2, MMP-3, MMP-9, and their inhibitors (TIMPs): TIMP-1 and TIMP-2 in hypertensive patients and healthy subjects. METHODS: The study involved 60 hypertensive patients and 61 adult healthy controls. Pro-MMP-9 and pro-MMP-2 activity was determined by the gelatin zymography method and MMP-3, TIMP-1, and TIMP-2 levels were determined by ELISA method. RESULTS: The mean plasma activity of pro-MMP-9 in the hypertensive group and the control group were significantly different (153.33 +/- 129.33 vs. 90.38 +/- 97.49 x 10(3) densitometric units/MUL; p < 0.01). MMP-3 plasmatic level was significantly higher in hypertensive subjects than healthy subjects (20.24 +/- 8.63 vs. 16.41 +/- 6.8 ng/mL; p < 0.05), whereas the plasma concentration of TIMP-1 in the hypertensive group was lower than the control group 88.96 +/- 26.9 vs. 93.96 +/- 27.28 ng/mL. The MMP-3/ TIMP-1 and the MMP-3/TMP-2 ratios were higher in hypertensive subjects than healthy subjects. Also, we have found a significant positive correlation between systolic blood pressure and pro-MMP-9 (r = 0.311, p < 0.001). CONCLUSIONS: The present study identified the existence of abnormalities in plasma markers for extracellular matrix metabolism in hypertensive patients. PMID- 27215071 TI - Pro-Inflammatory Cytokines are Elevated in Pregnant Women with Systemic Lupus Erythematosus in Association with the Activation of TLR4. AB - BACKGROUND: Autoimmune systemic lupus erythematosus (SLE) is associated with inflammatory activity and frequently causes complications in pregnant women. The aim of the current study was to investigate the serum levels of chemokines and cytokines (CKs) in SLE women during pregnancy and to examine the activation of toll-like receptor 4 (TLR-4) signaling in the deregulation of chemokines and CKs. METHODS: Blood samples from pregnant women with or without SLE were assayed for the levels of CKs (interleukin (IL)-1beta, IL-6, IL-8, and IFN-alpha), chemokines (IP-10 and RANTES) with enzyme-linked immunosorbent assay (ELISA) and were examined for toll like receptor (TLR)-2, -4, -7, -8 and -9. Then the peripheral blood mononuclear cells (PBMCs) from the SLE or normal pregnant women were treated with lipopolysaccharide (LPS) and were assayed for the CKs promotion. RESULTS: It was demonstrated that there were higher serum concentrations of IL 1p, IL-8, IFN-t, and IP-10 (p < 0.05, p < 0.01 or p < 0.0001) in the SLE pregnant women than in the non-SLE pregnant women. Additionally, the TLR-4 at the mRNA level in the PBMCs was also significantly higher in the SLE pregnant women than in the non-SLE pregnant women (p < 0.05). Moreover, the upregulated IL-1beta, IL 8, IFN-alpha or IP-10 was associated with the promoted TLR-4 level in PBMCs of those SLE patients. In addition, the PBMCs from the SLE pregnant women were more responsive to LPS stimulation. There was more promoted IL-1beta, IL-8, or IFN alpha in the PBMCs from the SLE pregnant women. CONCLUSIONS: High levels of pro inflammatory CKs and chemokines were promoted during pregnancy in women with SLE, possibly increasing their risk for pregnancy complications. In addition, the TLR4 signaling might play an important role in such CKs promotion. PMID- 27215072 TI - Thalassemia Screening Using Different Automated Blood Cell Counters: Consideration of Appropriate Cutoff Values. AB - BACKGROUND: To evaluate the use of MCV and MCH cutoffs for thalassemia screening in areas with a high frequency of thalassemia and hemoglobinopathies using different hematology analyzers. METHODS: Blood samples of known alpha(0) thalassemia and beta-thalassemia carriers were analyzed to establish the appropriate cutoffs for each analyzer. These selected cutoffs were validated prospectively for screening of alpha-thalassemia, beta-thalassemia in combination with the dichlorophenolindophenol test for hemoglobin E on another 288 Thai and 325 Laotian students. Genotypes were defined by standard hemoglobin and DNA analyses. RESULTS: The appropriate cutoffs for the Sysmex XS-800i and Sysmex XN 1000, Coulter LH 780, and Pentra ES-60 were found to be 78 fL for MCV and 25 pg for MCH. These were 82 fL and 25 pg for the Cell-Dyn Ruby. Further validation on Thai and Laotian students revealed 100% sensitivity and specificity of higher than 80% for all analyzers. CONCLUSIONS: While using MCV in screening requires establishment of appropriate cutoffs, MCH appears to be applicable to all analyzers. Each analyzer should be evaluated and appropriate cutoffs should be established before application in the field. PMID- 27215073 TI - Antibodies Against Epstein-Barr Virus Glycoprotein gp42 for the Diagnosis of Nasopharyngeal Carcinoma. AB - BACKGROUND: Assessment of immunoglobulin A (IgA) antibody responses to Epstein Barr virus (EBV) antigen is important for the early diagnosis of nasopharyngeal carcinoma (NPC). EBV glycoprotein gp42 has been shown to play an essential role in membrane fusion with B cells. The aim of the present study was to assess whether the antibodies to EBV glycoprotein gp42 in serum could be a novel marker for diagnosis of NPC. METHODS: EBV glycoprotein gp42 expressed in the recombinant baculovirus system was used in an enzyme-linked immunosorbent assay (ELISA) to detect antibodies to gp42 in serum. The blood samples were obtained from 406 participants (n = 208 patients with NPC and 198 healthy controls). Receiver operating characteristics (ROC) was used to calculate diagnostic accuracy. RESULTS: The ROC curves showed that IgA-gp42 ELISA had a sensitivity of 76.4%, specificity of 78.3% and an area under the curve (AUC) of 0.856 (95% CI, 0.82 - 0.891) to diagnose NPC. Furthermore, gp42 maintained diag- nostic capacity in NPC patients who were IgA-viral capsid antigen (VCA) negative (87.5%, 64.1% and 0.844 [95% CI, 0.776 - 0.912]). Combining gp42 and VCA improved the diagnostic capacity compared with the individual tests (89.9%, 94.4% and 0.973 [95% CI, 0.959 - 0.9871). CONCLUSIONS: The EBV glycoprotein complex gp42 acts as a novel biomarker for diagnosis of NPC and improves identification of patients with VCA-negative NPC. PMID- 27215074 TI - Kinetics of Ischemia-Modified Albumin Following Exercise-Induced Myocardial Ischemia. AB - BACKGROUND: Ischemia-modified albumin (IMA) is a potentially valuable biochemical marker of myocardial ischemia. The aim of our study was to define the kinetics and to determine the diagnostic value of IMA in detection of myocardial ischemia by using a model of exercise-stress induced transitory ischemia. METHODS: The study included 43 consecutive patients with positive exercise stress test and coronary artery disease confirmed by coronary angiography (ischemic group) and 22 healthy volunteers with negative exercise stress test (control group). IMA plasma levels were measured before and at nine time points after exercise over a 6-hour period. RESULTS: IMA kinetics was significantly different between the ischemic and control group (p = 0.03). In the ischemic group, IMA plasma levels peaked between the 3rd and 4th hour after exercise. However, due to large interindividual differences in the time-to-peak IMA values, a standard IMA kinetics curve could not be defined for the patients with transitory myocardial ischemia. On the other hand, with the cutoff value of a 10.6% relative increase, sensitivity and specificity of IMA for the detection of myocardial ischemia were sufficiently high at 81% and 82%, respectively. CONCLUSIONS: Although an optimum time for the detection of recent myocardial ischemia by a single IMA sampling could not be defined, serial measurements of IMA can be a useful biochemical tool for the detection of myocardial ischemia in patients with doubtful exercise stress test results. PMID- 27215075 TI - MiR-153 as a Tumor Suppressor in Glioblastoma Multiforme is Downregulated by DNA Methylation. AB - BACKGROUND: Aberrant DNA hypermethylation contributes to many cancers by silencing structurally normal tumor suppressive genes. MicroRNA-153 (miR-153) exerts a tumor suppressive function in glioblastoma multiforme (GBM) by silencing oncogenic targets. However, the mechanism underlying miR-153 regulation in glioma cells has not been studied. METHODS: The expression levels of miR-153 were determined by real-time PCR and genomic bisulfite modification technique was used to detect the DNA methylation status in the upstream region of miR-153 in GBM, their matched normal adjacent tissues, and the glioblastoma U87 cell line. Following treatment of cells with 5-aza-2'-deoxycitidine (5-aza-dC), the DNA methylation, gene expression and target proteins levels of miR-153 were determined. RESULTS: This study confirmed that miR-153 is significantly downregulated and hypermethylated in GBM tissues compared to their matched normal adjacent tissues. Increased methylation level of miR-153 was significantly correlated with reduced miR-153 expression in GBM tissue specimens. Demethylation of cells by 5-aza-dC treatment led to reduction of miR-153 methylation level, re expression of candidate microRNA, and downregulation of its target proteins levels. CONCLUSIONS: Our data indicated that miR-153 acts as a tumor suppressor in GBM and is down-regulated by DNA methylation, suggesting that miR-153 may serve as a potential diagnostic or therapeutic target of GBM. (Clin. Lab. 2016;62:573-580. DOI: 10.7754/Clin.Lab.2015.150738) PMID- 27215076 TI - Improvement and Evaluation of a Staining Method for Measuring Sperm Lactate Dehydrogenase C4 Activity. AB - BACKGROUND: This study sought to improve and evaluate a 2-hydroxyvaleric acid based staining method for detection of lactate dehydrogenase C4 (LDH-C4) activity in human spermatozoa. METHODS: A staining method for measuring sperm LDH-C4 activity with the substrate 2-hydroxyvaleric acid was improved. Expression level of LDH-C4 was assessed by Western blotting. The diagnostic performance was evaluated by plotting the receiver operating characteristic (ROC) curve. RESULTS: The positive products were black purple lumps concentrated in the neck segment of spermatozoa. Expression level of LDH-C4 was significantly reduced in the low activity infertile cases as compared to the matched contrasts. Decreased LDH-C4 level was significantly correlated with the declined enzyme activity (r = 0.702, p = 0.000). The ROC curve allowed for the discrimination between low and normal LDH-C4 activity cases with a sensitivity of 0.912 and specificity of 0.895, corresponding to an area under curve (AUC) of 0.941. CONCLUSIONS: The improved method hallmarks a promising accuracy in evaluating sperm LDH-C4 activity. Down regulated LDH-C4 level is a culprit for the decreased LDH-C4 activity in spermatozoa. PMID- 27215077 TI - Elevated Serum Levels of Sclerostin are Associated with High Disease Activity and Functional Impairment in Patients with Axial Spondyloarthritis. AB - BACKGROUND: Recent research suggests that biomarkers may be useful in assessing disease activity, structural damage, and response to therapy in axial spondyloarthritis (axSpA). Our study aims at evaluating the relationship between inflammation and bone remodeling markers and variables assessing disease activity and functional disability in patients with axSpA. METHODS: Serum levels of sclerostin, matrix metalloproteinase-3 (MMP-3), interleukin-17 (IL-17), and IL-23 were measured in 60 patients with axSpA and 20 healthy controls. Disease activity was evaluated using Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Ankylosing Spondylitis Disease Activity Score (ASDAS), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). Functional status was assessed by Bath Ankylosing Spondylitis Function Index (BASFI) and measures of spinal mobility. RESULTS: Sclerostin levels were more elevated in axSpA patients with high disease activity than in those with low disease activity and in controls. They were significantly correlated with BASFI values (r = 0.29, p = 0.03) and measures of spinal mobility, but not with the classical markers of disease activity (BASDAI, ASDAS, CRP, and ESR). Although both MMP-3 and IL-17 levels were elevated in patients with active disease, they were not correlated with markers of disease activity or with functional disability. The levels of sclerostin, MMP-3, IL-17, and IL-23 were similar in axSpA patients and healthy controls. CONCLUSIONS: Elevated levels of sclerostin, MMP-3, and IL-17 were observed in axSpA patients with active disease, suggesting their potential role in assessing disease activity. In axSpA patients, sclerostin levels might be equally influenced by inflammation and level of physical activity. Further studies are required to confirm our findings in order to understand their clinical value. PMID- 27215078 TI - The Efficacy and Safety of Dendritic Cells Co-Cultured with Cytokine-Induced Killer Cell Therapy in Combination with TACE-Predominant Minimally-Invasive Treatment for Hepatocellular Carcinoma: a Meta-Analysis. AB - BACKGROUND: To evaluate the efficacy and safety of dendritic cells (DCs) co cultured with cytokine-induced killer cell (CIK) immunotherapy combined with transcatheter arterial chemoembolization (TACE) or TACE plus local ablation therapy for hepatocellular carcinoma (HCC). METHODS: Our meta-analysis included a comprehensive search for relevant studies published through December 12, 2014. We used Cochrane Library, PubMed, CBM, VIP, CNKI, and Wanfang data. Depending on the heterogeneity among the included studies, we calculated the pooled odds ratio (OR) and mean difference (MD) using fixed- or random-effects models. Publication biases were assessed using funnel plots and Begg's tests. Sensitivity analyses were also performed. RESULTS: Seven randomized controlled trials (RCTs) and one controlled clinical trial (CCT) that included 693 patients and met the inclusion criteria were analyzed. Pooled results showed that DC-CIK immunotherapy combined with TACE or TACE plus local ablation therapy significantly improved 1-year (OR = 2.00, p = 0.02) and 2-year overall survival (OR = 1.77, p = 0.04). A favored overall response rate (ORR) (OR = 1.51, p = 0.03), disease control rate (DCR) (OR = 1.81, p = 0.01), and better quality of life (OR = 3.30, p < 0.01) were observed in the DC-CIK group. Additionally, when tumor-associated T lymphocyte subsets were compared, our analyses demonstrated that the percentage of CD3+ T cells (MD(CD3+) = 21.37, p = 0.005) and the ratio of CD4+/CD8+ (MD(CD4+/CD8+) = 2.83, p = 0.02) were significantly increased in the DC-CIK therapy group. CONCLUSIONS: The combination of DC-CIK immunotherapy and TACE or TACE plus local ablation therapy improves 1- and 2-year overall survival, ORR, DCR, and provides a better quality of life for patients with HCC. PMID- 27215079 TI - Impact of TGF-beta1 Gene Polymorphism (rs1800469) on Treatment Response to Pegylated Interferon/Ribavirin in Iranian Patients with Hepatitis C. AB - BACKGROUND: Hepatitis C virus as a major cause of chronic liver disease affects more than 170 million people worldwide. Recent studies have claimed that single nucleotide polymorphisms (SNPs) for the transforming growth factor-beta1 (TGF beta1) gene were strongly associated with the antiviral treatment response. Thus, the present study aimed at the determination of distribution of the rs1800469 (C/T) polymorphism among Iranian with chronic hepatitis C. METHODS: A total of 165 blood samples including 68 SVR positive and 21 non-responder samples from individuals suffering chronic hepatitis C and also 76 healthy individual controls were analyzed in this cross-sectional study. DNA was isolated from the samples using a DNA extraction standard kit. Then the frequency of the polymorphism was analyzed using PCR-RFLP method. Eventually, the products of interest were detected on 2.5% agarose gel electrophoresis. RESULTS: The distribution of the C/T polymorphism between healthy individuals and patients were obtained as TT: 22.4%, TC: 46%, CC: 31.6%, and TT: 19.1%, TC: 48.3%, CC: 32.6%, respectively. Furthermore, the CC genotype was identified in 20 patients of whom 68 achieved SVR, while the CT heterozygous was found in 43 patients and SVR was achieved in 38. Finally, the TT was detected in 17 patients, and 7 patients did not achieve SVR. CONCLUSIONS: We observed a significant difference of C allele frequency with SVR as compared to the T allele among patients (p = 0.064). On the other hand, there is no correlation between the polymorphism and susceptibility to HCV infection. However, further studies with more samples seem to be necessary. PMID- 27215080 TI - Comparison of In-House Multiplex Real Time PCR, Diagcor GenoFlow HPV Array Test and INNO-LiPA HPV Genotyping Extra Assays with LCD- Array Kit for Human Papillomavirus Genotyping in Cervical Liquid Based Cytology Specimens and Genital Lesions in Tehran, Iran. AB - BACKGROUND: Human papillomavirus is a major etiologic agent for some human common cancers. Cervical precancer and cancer is the most prevalent dysplasia by HPV genotypes. Various rapid and sensitive methods have been developed into readily HPV genotyping. METHODS: In the present study, we compared the performance of Real Time PCR, GenoFlow HPV Array, and INNO-LiPA HPV Genotyping Extra Assays with LCD- Array. RESULTS: From 108 cervical samples, HPV was detected in 33 women (30.55%). Among detected HPV genotypes, HPV 6 and 11 were dominant genotypes. Comparing these methods revealed that for Real Time PCR, Genoflow, and INNO-LiPA in comparison with LCD Array, sensitivity and specificity were 94.2%, 93%; 76.7%, 93%; 64%, 96.5%, respectively. Overall, accuracy and precision of these methods were more than 80% and 90%, respectively. CONCLUSIONS: It seems that these methods are reliable and suitable for detection and genotyping of HPVs in cervical disorders and other dysplasia associated with human papillomaviruses. PMID- 27215081 TI - Evaluation of Argatroban as a Potential Anticoagulant for Clinical Laboratory Analysis: Precision, Stability and Interference Study. AB - BACKGROUND: Argatroban is a small, synthetic molecule which is a direct thrombin inhibitor and has been confirmed to be a potent anticoagulant in clinical treatments. However, only a few applications related to laboratory medicine have been reported. The purpose of this study was to understand the performance and value of argatroban as an anticoagulant for clinical laboratory analysis in a single test tube. METHODS: We examined 93 blood samples and evaluated the anticoagulation time, precision, stability, and interference of argatroban in routine laboratory tests. RESULTS: The anticoagulation time was associated positively with the concentration of argatroban. Chemical and hematological results for argatroban-treated samples were similar to those obtained with serum or ethylenediaminetetraacetic acid treated specimens. Only the white blood cell count was decreased in the first 5 hours after blood collection and the difference was outside clinically acceptable limits; the mean corpuscular hemoglobin concentration was affected slightly by different concentrations of argatroban. CONCLUSIONS: Argatroban is an attractive candidate for use as a laboratory anticoagulant that can be used for evaluation of chemical and hematological analytes in a single test tube in routine laboratory work. PMID- 27215082 TI - Elevated Serum Inflammatory Cytokines in Lupus Nephritis Patients, in Association with Promoted hsa-miR-125a. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is a clinically heterogeneous, human systemic autoimmune disease characterized by autoantibody formation. MicroRNAs (miRNA) have emerged as an important new class of modulators of gene expression and have been confirmed to regulate the lymphocyte tolerance and autoimmunity in SLE. METHODS: In this study, we investigated the serum miRNA profile in lupus nephritis (LN) patients with microarray technology. TaqMan-based stem-loop real-time polymerase chain reaction was used for validation. We also examined the serum cytokines and chemokines, such as IL-beta, IL-6, TNF-beta, and IP-10, and then analyzed the association of the upregulated IL-beta, IL-6, TNF alpha, and IP-10 with each miRNA. RESULTS: Microarray analysis of miRNA indicated 17 upregulated miRNAs in LN patients. Such upregulation of hsa-miR-150, hsa-miR 200c, hsa-miR-181a, hsa-miR-125a, and hsa-miR-675 was also confirmed by RT-qPCR. We also recognized the significant upregulation of serum IL-beta, IL-6, TNF alpha, and IP-10 in those LN patients. Moreover, the upregulated IL-beta, IL-6, and TNF-alpha was significantly associated with serum hsa-miR-125a. CONCLUSIONS: Our study recognized the upregulation of miRNAs such as hsa-miR-150, hsa-miR 200c, hsa-miR-181a, hsa-miR-125a, and hsa-miR-675 and the upregulation of such cytokines and chemokines as IL-beta, IL-6, TNF-alpha, and IP-10. The upregulated miR-125a contributed to the upregulation of inflammatory IL-beta, IL-6, and TNF alpha in LN. Our findings demonstrate that miR-125a can be a novel biomarker for SLE, and help elucidate pathogenic mechanisms of lupus nephritis. PMID- 27215083 TI - Polymorphisms Associated with Increased Cardiovascular Risk in the General Population do not Predict Acute Events in Hemodialysis Patients. AB - BACKGROUND: Cardiovascular diseases are the leading cause of morbidity and mortality in hemodialysis patients (HP). The aim of the study was to analyze a series of polymorphisms (known to be associated with increased cardiovascular risk in the general population) in HP, in order to better understand the mechanisms of cardiovascular disease and to find new prevention strategies. METHODS: 102 hemodialysis patients were investigated for polymorphisms associated with increased cardiovascular risk in unselected population (FV Leiden R506Q; FV H1299R; FII G20210A; PAI-1 var 4G/5G; GpIIIA T1565C; FXIII var G/T; beta FIBRINOGENO var G/A; ACE I/D; AGT var M/T; ATR-1A1166C; APOE T112C; APOE T158C; MTHFR C677T; MTHFR A1298C; CBS 844ins68). RESULTS: No difference was observed in the prevalence of the analysed polymorphisms between HP and Caucasian unselected population, with the exception of FV H1299R, PAI-1 (4G/5G), and Factor XIII V34L, which were significantly higher in HP. However none of the genetic factors analysed was associated in HP with the cardiovascular events (non-fatal and fatal) recorded at the time of recruitment or during the eighteen months -follow up. CONCLUSIONS: In HP, the traditional genetic risk factors for cardiovascular disease are not able to predict acute cardiac events, peripheral vascular events, and cerebral vascular events recorded during a follow up period of eighteen months. PMID- 27215084 TI - Increased Levels of Serum Ischemia Modified Albumin in Patients with Ankylosing Spondylitis. AB - BACKGROUND: The aim of the study was to investigate oxidant/antioxidant status by determining serum ischemia-modified albumin (IMA) levels with oxidative/antioxidant parameters in patients with ankylosing spondylitis (AS) compared to the controls. METHODS: The serum concentrations of IMA, IMA/albumin ratio (IMAR), malondialdehyde (MDA), total oxidant status (TOS), oxidative stress index (OSI), superoxide dismutase (SOD), glutathione peroxidase (GPx), and total antioxidant capacity (TAC) were measured in 40 AS patients and 35 healthy controls. RESULTS: Mean serum IMA, IMAR, MDA, TOS, and OSI levels were increased in patients with AS when compared to the control group (p < 0.05 for all). Serum levels of SOD and GPx were significantly lower in the patient group than in the healthy subjects (p < 0.001 for both). Serum TAC levels were decreased in patients with AS compared to the controls but the statistical difference was not significant. Serum IMA levels were found to be positively correlated with BASDAI, BASFI, BASMI, and ASDAS-CRP (r = 0.356, r = 0.370, r = 0.412, r = 0.353, respectively, and p < 0.05 for all). IMAR values showed significant correlations with BASFI, BASMI, and ASDAS-CRP (r = 0.351, p = 0.026; r = 0.400, p = 0.010; and r = 0.379, p = 0.016, respectively). CONCLUSIONS: Depletion in antioxidant systems and overproduction of free radicals leading to formation of the oxidative stress may play a role in the development of AS. Increased levels of IMA might provide important contributions to the underlying oxidative stress in AS. PMID- 27215085 TI - Expression Levels of MMP9 and PIWIL2 in Prostate Cancer: a Case-Control Study. AB - BACKGROUND: Prostate cancer is the second most prevalent cancer in humans. Also, this is the most common malignancy and the sixth most important cause of death in men worldwide. The most routine diagnostic test for prostate cancer is PSA test which is associated with some limitations like too many false positive results. This study intends to investigate the role of MMP9 and PIWIL2 expression levels as different biomarkers in prostate cancer biopsy specimens. This study is one of the most brilliant studies in the field of prostate cancer research for the first time focusing on the investigation of the role of two different genes in prostate cancer in biopsy specimens and on formalin-fixed paraffin-embedded tissue types in order to detect the progression and prognosis of prostate cancer patients in early stages. METHODS: Seventy formalin-fixed paraffin embedded samples (35 normal and 35 cancerous cases) were selected. Expression levels of PIWIL2 and MMP9 genes were evaluated, using real-time PCR. RESULTS: MMP9 and PIWIL2 expression levels in cancerous tissues were significantly higher than the adjacent normal tissues (p < 0.05). The survival analysis showed a significant correlation between expression level of PIWIL2 and survival rate (p < 0.05), but such correlation was not observed in case of MMP9 (p > 0.05). Higher levels of MMP9 and PIWIL2 expression were strongly related to the Gleason score and age, using Pearson's correlation co- efficient test; however, this kind of association was not evident between prostate specific antigen (PSA) and expression levels of the genes of interest. The expression level of PIWIL2 had a significant correlation with metastasis rate, but this relationship was not seen in the case of MMP9. CONCLUSIONS: The results confirmed the validity of PIWIL2 expression as a valuable prognostic biomarker for early diagnosis of prostate cancer. PMID- 27215086 TI - The Value of Preoperative Neutrophil to Lymphocyte Ratio in Indicating Lymph Node Metastasis in Patients with Resectable T2 Stage Gastric Adenocarcinoma. AB - BACKGROUND: Lymph node metastasis (LNM) is closely associated with poor prognosis in patients with resectable T2 stage gastric adenocarcinoma (RT2-GA). Preoperative blood neutrophil to lymphocyte ratio (NLR) has been identified to be a very valuable predictor for prognosis in patients with diverse cancers. The aim of this investigation was to assess the relationship between NLR and LNM in RT2 GA. METHODS: This retrospective study reviewed 230 patients who underwent surgery for removal of primary T2-GA from August 2002 to December 2013 in a single hospital. Preoperative routine blood test data were collected and the relationship between NLR and LNM in RT2-GA was evaluated by X2 test and multivariate logistic regression analysis. RESULTS: The median value of NLR was 2.18 among 230 patients. Based on the median NLR value, the patients were categorized into two groups: low NLR group (NLR <= 2.18) and high NLR group (NLR > 2.18). chi2 test results exhibited that the preoperative NLR was significantly associated with the numbers of metastatic lymph nodes (<= 6 and > 6) (p = 0.003) and status of lymph node involvement (N0, N1, and N2 stage) (p = 0.032). Multivariate analyses further confirmed that NLR > 2.18 was significantly associated with increased risk of appearing more numbers of metastatic lymph node or higher N stage which exhibited a 4.15- or 7.09-fold elevated risk compared to that of NLR <= 2.18. CONCLUSIONS: The preoperative NLR is closely associated with LNM in patients with RT2-GA, which may be used as a predictor indicating more serious LNM in this type of cancer. PMID- 27215087 TI - Delta-He, Ret-He and a New Diagnostic Plot for Differential Diagnosis and Therapy Monitoring of Patients Suffering from Various Disease-Specific Types of Anemia. AB - BACKGROUND: The present study was aimed to prove the usefulness of a new diagnostic plot (Hema-Plot), illustrating the relationship between the hemoglobin content of reticulocytes (Ret-He) as a marker of functional iron deficiency and the difference between the reticulocyte and erythrocyte hemoglobin content (Delta He) as a marker of an impaired hemoglobinization of newly formed reticulocytes occurring during inflammatory processes, to differentiate between various disease specific types of anemia. METHODS: A complete blood and reticulocyte count was performed on routine EDTA blood samples from 345 patients with and without various disease-specific types of anemia using the Sysmex XN-9000 hematology analyzer: blood healthy newborns (n = 23), blood healthy adults (n = 31), patients suffering from anemia of chronic disease (ACD) due to diverse oncological, chronic inflammatory, or autoimmune diseases (total n = 138) with (n = 65) and without therapy (n = 73), patients with thalassemia and/or hemoglobinopathy (n = 18), patients with iron deficiency anemia (IDA) (n = 35), patients with a combination of ACD and IDA (n = 17), as well as patients suffering from sepsis (total n = 83) with (n = 32) and without therapy (n = 51). The results for Ret-He, Delta-He, and C-reactive protein (CRP) were statistically compared (Mann-Whitney U Test) between the particular patient groups and the diagnostic plots were drawn. RESULTS: Delta-Hemoglobin showed a statistically significant difference between blood healthy newborns and blood healthy adults (p <= 0.05), while Ret-He and C-reactive protein did not. In addition, of all three biomarkers only Delta-He showed a statistically significant difference (p <= 0.05) between the ACD/IDA and IDA cohort. Delta-He, Ret-He, and CRP showed a statistically significant difference between patient cohorts with and without therapy suffering from ACD, ACD/IDA, and sepsis before and after medical therapy (p <= 0.05). The Hema-Plot illustrated the dynamic character of Ret-He and Delta He, notably in inflammation-based types of anemia like ACD or ACD/ IDA. CONCLUSIONS: Delta-He is a new biomarker clearly distinguishing between inflammation-based types of anemia before and after medical therapy, as well as between ACD/IDA and IDA. The new Hema-Plot is a helpful tool for differential diagnosis and disease-monitoring in various types of disease-specific anemia, especially in ACD and ACD/IDA. The Hema-Plot can be used to identify non-adherent patients or an insufficient therapy. PMID- 27215088 TI - Role of Presepsin for the Assessment of Acute Cholangitis Severity. AB - BACKGROUND: Presepsin is a new emerging inflammatory biomarker. The primary purpose of this study was to elucidate the predictive usability of presepsin for severity assessment in patients with acute cholangitis (AC). METHODS: A total of 119 treatment-naive patients with AC (64 males, 55 females) were enrolled in this study. Patients were classified with Grade I (mild), Grade II (moderate), or Grade III (severe) AC based on severity assessment guidelines. Presepsin concentrations were measured on admission. RESULTS: The median presepsin concentrations were 297 pg/mL (interquartile range (IQR) 234 - 386 pg/mL), 590 pg/mL (IQR 559 - 619 pg/mL), and 857 pg/mL (IQR 740 - 960 pg/mL) in patients with mild, moderate, and severe AC, respectively. Presepsin concentrations were significantly higher in patients with severe AC than in patients with moderate AC (p < 0.01), and in patients with moderate AC than in patients with mild AC (p < 0.01). With the receiver operating characteristic (ROC) analysis, the areas under the curves (AUCs) for presepsin to discriminate patients with moderate and severe AC were 0.935 (95% confidence interval (CI) 0.877 to 0.993, p < 0.001) and 0.942 (95% CI 0.885 to 0.998, p < 0.001), respectively. CONCLUSIONS: Compared with other conventional biochemical indicators such as WBC, CRP, and PCT, presepsin may be a useful parameter for the severity assessment of AC. PMID- 27215089 TI - Comparison of Next-Generation Sequencing, Quantitative PCR, and Sanger Sequencing for Mutation Profiling of EGFR, KRAS, PIK3CA and BRAF in Clinical Lung Tumors. AB - BACKGROUND: The clinical application of next-generation sequencing technologies has offered a more comprehensive understanding of the mutational profile of tumor samples. The study was aimed to evaluate the feasibility of the NextDaySeq-Lung panel, which is an NGS-based assay for mutation analysis of key driver genes in lung cancer, in a clinical setting. METHODS: A total of 138 FFPE samples of non small cell lung cancer (NSCLC) were examined in parallel with assays developed on the next-generation sequencing (NGS), quantitative PCR (QPCR), and Sanger sequencing (Sanger) platforms for somatic mutations in EGFR, KRAS, PIK3CA, and BRAF. The assays with the three platforms were compared and analyzed. RESULTS: Compared with Sanger, NGS and QPCR assays have significant higher sensitivity, as Sanger failed to detect variants with mutation rates lower than 15%. Meanwhile, NGS and QPCR assays showed similar analytical sensitivity, specificity, and high concordance. In addition, the NGS assay exhibited advantages over QPCR in providing accurate information of allele sequence and mutation frequency, and detecting non-hotspot mutations. CONCLUSIONS: We reported the validation of NextDaySeq-Lung panel for mutation analysis in the clinical samples of lung cancer. The NGS assay has significant technical advantages over Sanger and QPCR assays. It shows good potential as a solid molecular diagnostics assay in the clinical setting. PMID- 27215090 TI - Repeated Aurora-A siRNA Transfection Results in Effective Apoptosis of A549 Cells Compared to Single Transfection. AB - BACKGROUND: Suppression of Aurora kinase A (Aurora-A, AURKA) by Aurora-A siRNA has been proposed for lung tumor treatment. However, protocols using single administration have shown little benefit in some types of lung tumor. Given that transfection efficiency of Aurora-A siRNA is low due to tightly packed cells in the tumor, we hypothesized that repeated administration would result in efficient cell apoptosis. METHODS: We compared single vs. repeated transfection (thrice) in A549 cells by transfecting Aurora-A siRNA (siA) on the 1st or 1st, 2nd and 3rd day after cell seeding. A random sequence was used as the negative siRNA control (siC). Cells in the single transfection group received only transfection reagent without siRNAs on the 2nd and 3rd day. RESULTS: Two days after the third transfection, both single and repeated siA administration decreased mRNA expression of Aurora-A and cell viability compared to no administration and siC single administration. However, the decrease in these two indices with repeated transfection was more obvious than that following single administration: cell viability decreased to 72.8 +/- 3.05% (p < 0.05) following siA single transfection and to 64.2 +/- 1.99% (p < 0.05) following siA repeated transfection, compared with normal control cells, respectively. Gene expression decreased to 17 +/- 16.6% (p < 0.05 vs. normal control) following siA repeated transfection and to 43.2 +/- 13.0% (p < 0.05 vs. normal control) following siA single transfection. CONCLUSIONS: Compared to single transfection, repeated Aurora-A siRNA transfection decreased Aurora-A, which, in turn, resulted in effective apoptosis of A549 cells. PMID- 27215091 TI - The Influence of Blood Collection Tubes on Measurement of Cardiac Biomarkers. AB - BACKGROUND: The tube used to collect a blood specimen may have an effect on some test results. This study evaluated three different types of blood collection tubes manufactured in China for use in testing three cardiac biomarkers. METHODS: Blood samples were drawn from 42 patients in the Intensive Care Unit and were sampled into three different types of blood collection tubes at the same time. All samples were subjected to analysis of myoglobin (MYO), creatine kinase MB (CK MB), and high-sensitive cardiac troponin T (hs-cTnT) using the Roche Cobas e411 chemistry analyzer. RESULTS: There was no statistically significant difference in the test results for MYO and CK-MB among the three different types of blood collection tubes. However, there was a statistically significant difference in the measured level of hs-cTnT. The hs-cTnT values in tubes with clot activator were significantly lower than the values from tubes with no additive (p = 0.000) or lithium heparin (p = 0.002). CONCLUSIONS: Three types of blood collection tubes are safe for myoglobin and CK-MB determination without altering the results. However, the hs-cTnT value was lower in clot activator tubes than in tubes with no additive or with heparin lithium. Thus, we conclude that using clot activator tubes can affect the determination of hs-cTnT concentration which should be noted in clinical practice. PMID- 27215092 TI - MiR-31 Functions as a Tumor Suppressor in Lung Adenocarcinoma Mainly by Targeting HuR. AB - BACKGROUND: Gene expression is widely regulated by miRNAs and RNA binding proteins. In this study, we mainly focused on miR-31 and a RNA binding protein, HuR (Hu antigen R). METHODS: The levels of miR-31 and HuR in lung carcinoma cells and lung cancer tissues were explored using RT-qPCR and western blot, respectively. Luciferase reporter assay was used to determine the target gene of miR-31. Cell apoptosis and migration were studied using flow cytometry and the transwell invasion assay. The down-stream genes of HuR were explored with western blot assay. RESULTS: miR-31 was decreased in lung carcinoma cells and lung cancer tissues, while the protein level of HuR was increased. HuR was the target gene of miR-31. Inhibition of miR-31 and overexpression of HuR resulted in the upregulation of cyclins A2, B1, D1 and VEGF (vascular endothelial growth factor). Furthermore, overexpression of miR-31 prompted lung cancer cell apoptosis and inhibited cell migration. CONCLUSIONS: Reduction of miR-31 expression enhanced lung cancer proliferation and migration by repressing HuR expression. PMID- 27215093 TI - Measurement of Serum Sodium and Magnesium by Inductively Coupled Plasma Mass Spectrometry with Aluminum as Internal Standard. AB - BACKGROUND: Serum sodium and magnesium are important clinical laboratory tests and accurate testing results are needed for the correct interpretation of the tests. Standardization of serum sodium and magnesium measurements requires simple and reliable reference methods. METHODS: Inductively coupled plasma mass spectrometry (ICP-MS) methods for the measurement of serum sodium and magnesium were developed. Aluminum was used as an internal standard. Serum samples were spiked with the internal standard, digested with 69% nitric acid at 150 degrees C and measured for 23Na/27Al and 24Mg/27Al ratios by ICP-MS. The measurements were calibrated by bracketing calibrators and serum sodium and magnesium concentrations were calculated by comparing the ion ratios of the serum samples with that of the calibrators. RESULTS: The correlation coefficients between the measured ion ratios and the analyte concentrations were all > 0.9999 for both sodium and magnesium. The coefficients of variation of the measurements were 0.07% - 0.14% for sodium and 0.21% - 0.36% for magnesium. No significant interferences were detected and the analytical recoveries were 100.25% and 100.11% for sodium and magnesium, respectively. The accuracy of the measurements was also verified through measurement of certified reference materials and participation in international interlaboratory comparisons. CONCLUSIONS: New ICP MS methods for serum sodium and magnesium have been developed. The methods are specific, precise, simple and low in cost and may be used as candidate reference methods in the standardization of serum sodium and magnesium measurements. PMID- 27215094 TI - Lactase Non-Persistence Genotyping: Comparison of Two Real-Time PCR Assays and Assessment of Concomitant Fructose/Sorbitol Malabsorption Rates. AB - BACKGROUND: Genetic testing is a standard technique for the diagnosis of primary adult-type hypolactasia, also referred to as lactase non-persistence. The aim of this study was to compare the lactase gene (LCT) C/T-13910 polymorphism genotyping results of two commercially available real-time (RT)-PCR assays in patients referred to our outpatient clinic for primary lactose malabsorption testing. Furthermore, concomitant conditions of fructose/sorbitol malabsorption were assessed. METHODS: Samples obtained from 100 patients were tested in parallel using the LCT T-13910C ToolSet for Light Cycler (Roche, Rotkreuz, Switzerland) and the LCT-13910C>T RealFast Assay (ViennaLab Diagnostics GmbH, Vienna, Austria). Additionally, patients were also screened for the presence of fructose/sorbitol malabsorption by functional hydrogen (H2)/methane (CH4) breath testing (HMBT). Cohen's Kappa (kappa) was used to calculate the agreement between the two genotyping methods. The exact Chi-Square test was performed to compare fructose/sorbitol HMBT with LCT genotyping results. RESULTS: Twenty-one (21.0%) patients had a LCT C/C-13910 genotype suggestive of lactase non-persistence, and 79 (79.0%) patients were identified with either a LCT T/C-13910 or T/T-13910 genotype (i.e., lactase persistence). In all genotype groups, concordance between the two RT-PCR assays was 100%. Cohen's kappa demonstrated perfect observed agreement (p < 0.001, kappa = 1). Fructose and sorbitol malabsorption was observed in 13/100 (13.0%) and 25/100 (25.0%) individuals, respectively. CONCLUSIONS: Both RT-PCR assays are robust and reliable LCT genotyping tools in a routine clinical setting. Concomitant fructose and/or sorbitol malabsorption should be considered in individuals with suspected lactase-non-persistence. However, standardization of clinical interpretation of laboratory HMBT results is required. PMID- 27215095 TI - Mutation Analysis of PRKAR1A Gene in a Patient with Atrial Myxoma. AB - BACKGROUND: Intracardiac myxomas are frequent benign tumors of the heart and typically localize in the left atri- um and interatrial septum. When myxomas generate at other sites, they are designated as atypical. Mutations in the PRKAR1A gene (a tumor suppressor gene that encodes a protein kinase A [PKA] regulatory 1-alpha subunit) have been identified in both syndromic and non syndromic cardiac atypical myxomas. METHODS: We report the case of a 33-year old woman suffering from night fever, weight loss, asthenia, and progressive dyspnea. RESULTS: The blood laboratory tests revealed microcytic anemia, leukocytosis, thrombocytosis, increased serum levels of C-reactive protein level, and negative blood cultures. Physical examination also demonstrated a 2/6 systolic murmur. Transthoracic and trans-esophageal echocardiography showed a voluminous, mobile mass in the left atrium with a secondary dynamic obstruction of the left cardiac chamber and a significant functional mitral stenosis. A myxoma was supposed and the patient underwent surgery. Histologically, the lesion was identified as myxomatous tumor with gelatinous pattern. No germline mutations of the PRKAR1A gene were detected. The postoperative course did not present any complications, and the patient was discharged on the sixth postoperative day in good clinical condition. Accordingly, there was an improvement in the laboratory tests' results and a resolution of symptoms. CONCLUSIONS: The patient presented an atrial giant gelatinous myxoma with peculiarity of fever of unknown origin, without PRKAR1A gene germline mutations. PMID- 27215096 TI - Evaluation of the Urine Protein/Creatinine Ratio Measured with the Dipsticks Clinitek Atlas PRO 12. AB - BACKGROUND: Screening for urine proteins is recommended for the detection of albuminuria in high risk groups. The aim of this study was to compare the Clinitek Atlas PRO12 reagent urine strip with quantitative methods for the determination of protein/creatinine ratio and to evaluate the usefulness of the semi-quantitative Clinitek Atlas PRO12 reagent urine strip as a tool in the early detection of albuminuria among the general population. METHODS: Six hundred first morning urine specimens were collected from outpatients with various clinical conditions. RESULTS: The results showed that the test data for the urine dipstick Clinitek Atlas PRO12 show good agreement with the quantitative measurement of protein, creatinine and protein/creatinine ratio. In addition, this study shows that 97.2% of the samples which gave "normal" protein/creatinine ratios by the semi-quantitative method, showed albumin/creatinine ratio < 30 mg/g by the quantitative methods. CONCLUSIONS: Our results show that Clinitek Atlas PRO12 reagent strips can be used for the purposes of albuminuria screening in the general population. PMID- 27215097 TI - Performance Evaluation of the FREND Cardiac Triple Cartridge on the FREND System. AB - BACKGROUND: We evaluated the performance of the FREND Cardiac Triple cartridge on the FREND system in the detection of cardiac markers-myoglobin, cardiac troponin I (cTnI), and creatine kinase-MB (CK-MB). METHODS: Quantitative immunoassays were performed using the FREND system (NanoEnTek, Seoul, Korea) and its cartridge. The precision, detection limits, linearity, and correlation with the Siemens Dimension Vista 500 (Siemens Healthcare Diagnostics, Deerfield, IL, USA) were evaluated. The cutoff value for each marker was calculated in healthy individuals (men and women, n = 138 each). RESULTS: The coefficients of variation for imprecision were less than 19.0% at low and high serum concentrations. The lower limits of quantification for myoglobin, cTnI, and CK-MB were 3.11, 0.073, and 0.70 ng/mL, respectively. Acceptable linearity was achieved for each marker (R2 < 0.99). The results from the FREND system were in good agreement with those from the Siemens Dimension Vista (correlation coefficients > 0.9). The cutoff values in male and female individuals (n = 138 each) were 104.3 and 98.9 ng/mL, respectively, for myoglobin, and 4.35 and 5.37 ng/mL, respectively, for CK-MB. The cutoff value for cTnI was 0.073 ng/mL. CONCLUSIONS: The FREND Cardiac Triple cartridge exhibited good precision, clinically acceptable linearity, and reliable correlation with the Dimension Vista. PMID- 27215098 TI - High-Sensitivity Cardiac Troponin T: a Preanalytical Evaluation. AB - BACKGROUND: Little is known about the effects of preanalytical conditions on high sensitivity cardiac troponin T (hs-cTnT) concentrations. METHODS: Variations of hs-cTnT concentrations were evaluated under the following preanalytical conditions: 1) serum vs. lithium-heparin (Li-Hep) plasma, with or without separator gel; 2) centrifugation time (15-minutes vs. 10-minutes) and speed (1467 to 3756 g); 3) stability in Li-Hep plasma at room temperature and +4 degrees C for 4 days and at -80 degrees C for up to 12 months, for three concentrations; 4) four freeze-thaw cycles at -20 degrees C and -80 degrees C, for three concentrations. RESULTS: No significant changes were found regarding the type of blood collection tube, the centrifugation, and storage conditions. Minor decreases were observed after four freeze-thaw cycles at -20 degrees C (< 6.5%) and -80 degrees C (< 3.4%). CONCLUSIONS: High-sensitivity cardiac troponin T may be considered as not impacted by usual preanalytical conditions, thus strengthening its reliability in laboratory practice and clinical research. PMID- 27215099 TI - Confusing Hairy Cells in a Case of IgG Kappa Plasma Cell Leukemia. PMID- 27215101 TI - 2016: A year of change for healthcare finance. PMID- 27215100 TI - ICD-10: Targeting reporting and reimbursement. PMID- 27215102 TI - Five steps to promote accuracy in the wake of ICD-10. PMID- 27215103 TI - CMS: Assess your ICD-10 KPIs. PMID- 27215104 TI - RelayHealth Financial reports claim denial trends. PMID- 27215105 TI - Do health apps work?. PMID- 27215106 TI - The beginning of a new era. PMID- 27215107 TI - Phone it in: A perfect storm takes telemedicine to new heights. PMID- 27215108 TI - VMI: The no-data-footprint path to mobile security. PMID- 27215109 TI - BYOD done the smarter way. PMID- 27215110 TI - BYOD adaption is hampered by lax security. PMID- 27215111 TI - Risking a breach. PMID- 27215112 TI - Holding data hostage. PMID- 27215113 TI - Four steps to a winning accountable care strategy. PMID- 27215114 TI - [MEDICAL CANNABIS - A SOURCE FOR A NEW TREATMENT FOR AUTOIMMUNE DISEASE?]. AB - Medical uses of Cannabis sativa have been known for over 6,000 years. Nowadays, cannabis is mostly known for its psychotropic effects and its ability to relieve pain, even though there is evidence of cannabis use for autoimmune diseases like rheumatoid arthritis centuries ago. The pharmacological therapy in autoimmune diseases is mainly based on immunosuppression of diffefent axes of the immune system while many of the drugs have major side effects. In this review we set out to examine the rule of Cannabis sativa as an immunomodulator and its potential as a new treatment option. In order to examine this subject we will focus on some major autoimmune diseases such as diabetes type I and rheumatoid arthritis. PMID- 27215115 TI - [MEDICAL CANNABIS]. AB - The cannabis plant has been known to humanity for centuries as a remedy for pain, diarrhea and inflammation. Current research is inspecting the use of cannabis for many diseases, including multiple sclerosis, epilepsy, dystonia, and chronic pain. In inflammatory conditions cannabinoids improve pain in rheumatoid arthritis and:pain and diarrhea in Crohn's disease. Despite their therapeutic potential, cannabinoids are not free of side effects including psychosis, anxiety, paranoia, dependence and abuse. Controlled clinical studies investigating the therapeutic potential of cannabis are few and small, whereas pressure for expanding cannabis use is increasing. Currently, as long as cannabis is classified as an illicit drug and until further controlled studies are performed, the use of medical cannabis should be limited to patients who failed conventional better established treatment. PMID- 27215116 TI - [Does Cannabis have a role in the tehrapy of rehumatic conditions?]. PMID- 27215117 TI - [SOROKA UNIVERSITY MEDICAL CENTER: THE ROAD TO LEADERSHIP IN QUALITY OF MEDICAL CARE, SERVICE AND RESEARCH]. AB - Soroka University Medical Center is a tertiary hospital, and the sole medical center in the Negev, the southern part of Israel. Soroka has invested in quality, service and research. The region has developed joint programs in order to advance the quality of medical care whilst optimizing the utilization of available resources. In this editorial we describe the path to leadership in quality of medical care, service and research. PMID- 27215118 TI - [BRUCELLA MELITENSIS (BM) BACTEREMIA IN HOSPITALIZED ADULT PATIENTS IN SOUTHERN ISRAEL]. AB - BACKGROUND: Southern Israel is endemic for Brucella melitensis (BM) infection. AIMS: This study aims to describe clinical manifestations and laboratory abnormalities in hospitalized adults with BM-bacteremia and to assess the relationship between various laboratory parameters, outcomes and complications of brucellosis. METHODS: This is a retrospective study. All BM bacteremic patients hospitalized in the Soroka University Medical Center (SUMC) during 2006-2011 were included. Demographic, clinical data and laboratory results were collected from the medical records. RESULTS: A total of 114 patients were included in the study, mostly of Bedouin-Arab origin (92%). The average age was 44 years (+/-18.4) and included 62 females (54%) of whom 11 were pregnant. Most of the subjects were exposed to sheep or their milk or meat products. The main symptoms included fever, arthralgia, myalgia, headache, and low back pain. Complications were present in 22 patients (19%): arthritis and osteomyelitis (59%), spontaneous abortion (36% of pregnant woman), endocarditis and epididymitis. The incidence of complications was correlated to anemia and leukopenia (p=0.03) and to a low neutrophil count (p=0.009). A decrease of albumin by one unit correlated with an increased hospitalization length by 1.9 days; older age also correlated with a prolonged stay. Complications were present in 45% of pregnant women vs. 10% in non-pregnant women (p=0.011. Relapse occurred in nine patients (8%); only one of these received adequate antibiotic treatment. CONCLUSIONS: MB-bacteremia in southern Israel occurs mainly in Bedouin-Arabs after exposure to sheep or their products. Older age and low albumin levels increase hospitalization. Leukopenia, mainly low neutrophil count, and low thrombocyte count can predict complications. Pregnant women have a higher incidence of complications. Relapse is rare under adequate antibiotic treatment. PMID- 27215120 TI - [RISK FACTORS, COMPLICATIONS AND OUTCOMES OF PREGNANCIES WITH VELAMENTOUS CORD INSERTION]. AB - INTRODUCTION: A velamentous cord insertion (VCI) describes a peripheral umbilical cord insertion to the placenta with blood vessels from the cord traversing fetal membranes before reaching the placental margin. These vessels remain unprotected and exposed to pressure and injury during pregnancy and labor. OBJECTIVES: To determine the risk factors for VCI, and assess the risk for complications and adverse outcomes of pregnancies with VCI. METHODS: A retrospective cohort study of women who gave birth at Soroka Medical Center between the years 1988 to 2011. We examined the risk factors, complications and adverse outcomes of pregnancies with VCI compared to those without VCI. RESULTS: During the study period there were 246,488 births, of which 200 had VCI. Multifetal gestation (OR = 9.2), infertility treatments (OR = 4.3) and chronic hypertension (OR = 2.2 were found as independent risk factors for VCI. In addition, intrauterine growth retardation (OR = 4.3), polyhydramnion (OR = 2.3), fetal malformations (OR = 2.2), placental abruption (OR = 8.2), preterm birth (OR = 4.6), cesarean delivery (OR = 3.3) and low Apgar score (OR = 2.3) had significant correlation to VCI. Finally, the presence of VCI was found as an independent risk factor (OR = 4.07) for perinatal mortality. CONCLUSION: Multifetal gestation and infertility treatments were the most important risk factors for VCI. These pregnancies had more complications and perinatal mortality. Given the results, we should consider close monitoring of pregnancies with the mentioned risk factors for the presence of VCI. PMID- 27215119 TI - [TREATMENT DILEMMAS IN BEHCET'S SYNDROME]. AB - Behcet's disease is an inflammatory systemic disorder, characterized by a relapsing and remitting course, it manifests with oral and genital ulcerations, skin lesions, uveitis, vasculitis, central nervous system and gastrointestinal involvement. The main histopathological finding is widespread vasculitis of the arteries and veins. Therapy is variable and depends largely on the severity of the disease and organ involvement. There is common practice to treat with anticoagulation in patients suffering from vessel thrombosis, but there are no control trials to support this tendency. Anticoagulation treatment can cause major bleeding events in patients suffering from aneurysms. In this case report we describe a treatment dilemma in a patient suffering from deep vein thrombosis and pulmonary aneurysms. PMID- 27215121 TI - [THE EFFECT OF 5 DAYS IMMERSION IN DEAD SEA WATER ON BLOOD GLUCOSE LEVELS IN TYPE 2 DIABETES MELLITUS PATIENTS]. AB - BACKGROUND: Body immersion in plain water or mineral water induces significant and unique physiological changes in most body systems. In a previous pilot study, a significant reduction in blood glucose levels among diabetes mellitus (DM) patients was found following a single immersion in Dead Sea water but not after immersion in plain water. OBJECTIVE: To study the immediate and long term effects of immersion in mineral water for five consecutive days on blood glucose in patients with type 2 DM. METHODS: A total of 34 patients with type 2 DM were divided into 2 groups: The first immersed in a plain water pool and the second immersed in a Dead Sea water pool; both pools were warmed to a temperature of 35 degrees C. Immersions for 20 minutes occurred twice daily: two hours after breakfast and before dinner. Seven samples of capillary blood glucose levels were taken: fasting, before and after every immersion, prior to lunch and before bedtime. Hemoglobin A1C (HbA1c) was taken prior to the study and a re-check was conducted during the 12 weeks following the study. RESULTS: Blood glucose levels significantly decreased immediately after immersion both in Dead Sea water and plain water compared to their values prior to immersion (p<0.001). No significant difference was noted between both types of water. A decrease in fasting glucose levels was observed only in the group immersed in Dead Sea water when compared to plain water (6.83+/-5.68 mg/dl versus 4.37+/-1.79 respectively and the difference was close to statistical significance (p=0.071. There were no changes in HbA1c levels. CONCLUSION: Immersion for 20 minutes in water (Dead Sea or plain water) at a temperature of 35 degrees C induced an immediate reduction in glucose levels in patients with type 2 DM. PMID- 27215122 TI - [FERTILITY PRESERVATION BY CRYOPRESERVATION OF TESTICULAR TISSUE FROM PRE PUBERTAL BOYS UNDERGOING GONADOTOXIC TREATMENT - PRELIMINARY RESULTS]. AB - INTRODUCTION: Fertility preservation consideration prior to gonadotoxic aggressive treatment is now mandatory. Nevertheless, while cryopreservation of mature sperm cells is a well-established technique, preserving fertitity from testicular tissue of pre-pubertal male children in whom only spermatogonial stem cells are avaitable is still under investigation. In rodents, our group was able to demonstrate in-vitro maturation of spermatogonial stem cells to a mature sperm cell which undergoes acrosome reaction. AIM: To culture, expand and preserve spermatogonial stem cells in-vitro in order to allow future fertility to pre pubertal male children undergoing aggressive gondotoxic treatment. METHODS: Pre pubertal male children scheduled for aggressive gonadotoxic treatment were referred to the Soroka University Medical Center. Testicular biopsy was performed from one testicle. Most of the tissue was cryopreserved for future fertility. A minor part of the tissue was transferred to the research laboratory for culturing and further growth and differentiation. Testicular cells were isolated by enzymatic digestion. RESULTS: This is a first published account in humans of cells from testicular tissue that were cultured for more than two months. In this culture, isolated and groups of cells were observed. Some of the cells expressed pre-meiotic markers, while meiotic markers were expressed by other cells after culture. CONCLUSION: Preliminary results indicate a possible culturing technique from human testicular tissue in-vitro. Furthermore, meiotic activity may indicate the beginning of differentiation. Further studies are required to develop growth and differentiation techniques and for examining the cell for possible genetic and epigenetic changes before injecting them to mature oocytes for the purpose of fertilization and embryo development. PMID- 27215123 TI - [THE UTILITY OF BRONCHOSCOPY IN INTENSIVE CARE UNIT PATIENTS WITH VENTILATOR ASSOCIATED PNEUMONIA]. AB - BACKGROUND: Ventilator associated pneumonia (VAPI is a common complication leading to lengthier hospitalizations and higher mortality. Prompt adequate initial antibiotic coverage is the crucial issue affecting survival. Currently, there is no gold standard diagnostic test. No conclusive data regarding the benefit of bronchoscopy exists in the literature reviewed. AIM: This study aims to evaluate the change of prognosis for patients who developed VAP, following a positive culture from bronchoalveolar lavage (BAL). DESIGN: This is a retrospective cohort study. SETTING: General intensive care unit in a tertiary university healthcare center. PARTICIPANTS: All patients who were admitted to Surgical ICU and developed VAP and who then underwent diagnostic bronchoscopy with BAL between the period 01/02/2007 - 31/02/2011. MEASUREMENTS AND RESULTS: A total of 66 patients who were admitted to the ICU, developed VAP and underwent bronchoscopy while ventilated; 30 patients were excluded. The positive BAL culture group was compared to the negative BAL culture group; there was no difference between demographic and clinical characteristics, mortality rates (for 30 days) or therapy change between the two groups. No complications were reported regarding the bronchoscopy procedure. CONCLUSIONS: Our findings demonstrate that performing y a diagnostic bronchoscopy with BAL does not improve the prognosis of patients with VAP. Furthermore, expanded prospective studies will be needed to conclude regarding its benefit in diagnosis and subsequent rectifying of therapy. PMID- 27215124 TI - [THE ROLE OF CLOSED PLEURAL BIOPSY IN THE DIAGNOSIS OF TUBERCULOUS PLEURISY IN A POPULATION AT-RISK]. AB - BACKGROUND: Tuberculous pleurisy is the most common form of extrapulmonary tuberculosis, and a common cause of exudative pleural effusion. Closed pleural biopsy can be used for diagnosis. In recent years, more invasive methods are used for the diagnostic process in the western world. Contrary to the global trend, physicians at the Pulmonary Institute of the Soroka University Medical Center still perform a closed pleural biopsy as the first diagnostic step. In this article, we report our experience in the diagnosis of tuberculous pleurisy by closed pleural biopsy. METHODS: A retrospective cohort analysis, conducted among patients, who were admitted for investigation of pleural effusion between 2008 and 2013, and underwent closed pleural biopsy with an Abrams needle in the evaluation of tuberculous pleurisy (n=25). Histopathological evidence of tuberculosis bacterium infection included a positive staining for acid-fast bacteria, identification of Langerhans giant cells, demonstration of chronic granulomatous inflammation or demonstration of granulomas with central necrosis in samples of pleural fluid or pleural biopsy. RESULTS: Closed pleural biopsy was performed in 22/25 (88%) of patients. In 15/22 subjects (68%) histopathotogical evidence of tuberculous pleurisy was found. No significant complications were evident after the procedure. In addition, it was found that acid-fast bacteria in sputum samples, gastric fluid and pleural fluid is of very low diagnostic yield for the diagnosis of tuberculous pleurisy, while in cultures of sputum, gastric fluid or pleural fluid infection it was diagnosed in 27, 28 and 28% of subjects respectively. CONCLUSIONS: In subjects with a high probability for tuberculous pleurisy, closed pleural biopsy using Abrams needle is available, inexpensive and has a good diagnostic yield and low complication rate. We believe that there is great importance in preserving the ability to perform a closed pleural biopsy in all. medical centers in Israel. PMID- 27215125 TI - [BALINT GROUP AS A-MEANS FOR BURNOUT PREVENTION AND IMPROVEMENT OF THERAPIST PATIENT RELATIONSHIP IN A GENERAL HOSPITAL - THE SOROKA EXPERIENCE]. AB - Balint group (BG) is an experiential discussion group which deals with the various aspects of the therapist-patient relationship. BG was found to be effective for stress and burnout prevention among medical professionals. Burnout is expressed by emotional fatigue, de-personalization and sense of failure. Recent articles found connections between burnout and personal and systemic factors such as: workload, work conflicts, and work-life conflicts. Burnout can lead to medical mistakes, loss of empathy for the patient, coronary disease, and leaving work. Until now, BGs were held in community settings. We first describe organizing and leading BG for physicians and nurses in the Nephrology-Dialysis department. We present the process of group setting and leading as a procedure that also takes into consideration the organizational limits of the hospital setting. Conclusions and future suggestions will be presented. PMID- 27215126 TI - ['TESTED, BUT NOT TRIED' - WHY IS BEHAVIORAL MEDICINE RARELY IMPLEMENTED IN CLINICAL PRACTICE?]. AB - BACKGROUND: Behavioral Medicine is an inter-disciplinary field concerned with the integration of behavioral and biomedical knowledge for the purposes of diagnosis, prevention, treatment and rehabilitation of conditions pertaining to health and illness. Behavioral treatments (such as: hypnosis, relaxation training, meditation, biofeedback and cognitive-behavioral therapy) have been shown to be effective in reducing physical symptoms as well as improving health-related behaviors and quality of life across a wide variety of illnesses, such as: chronic pain, somatic symptoms, diabetes, inflammatory bowel diseases, coronary heart disease and more. The usefulness of behavioral techniques in modern medicine has been sufficiently proven so as to have been referred to as the "third therapeutic revolution" in treating human illness, after pharmacological and surgical treatments. THE PROBLEM: Despite the fact that the bio-psycho-social model is the dominant model in 21st century medicine and despite the plethora of studies demonstrating the efficacy of behavioral interventions, these tools are underused in today's medical system. The reasons for this have to do with a dichotomous view of mind and body rooted in the biomedical approach, which was the dominant paradigm in the medical world up until the latter half of the previous century. In accordance with this paradigm, diseases were "assigned" either to medicine (i.e. they are physiological) or to the mental health professions (i.e. they are psychological), but never to both fields simultaneously. As an extension of this position, behavioral medicine was not included in Israel's socialized health care plan, making the use of behavioral techniques largely impractical, so that even physicians who agree with and believe in the importance of the bio-psycho-social model are often untrained or unable to provide effective behavioral treatments which would address the psycho social aspects of their patients' illness. DISCUSSION: In Israel today there exist a number of facilities which provide behavioral treatments, however, there is, as yet, no public body in charge of organizing and promoting the knowledge and use of behavioral medicine in Israel. For the sake of patients, physicians and the medical system itself, it is imperative that, in the future, medical and paramedical professionals, including students and interns, are exposed to and trained in the use of behavioral techniques. In addition, thought must be given as to the integration of such techniques in routine medical care. For that purpose, we propose a number of guiding principles for effectively implementing' behavioral techniques in the day-to-day practice of modern; medicine. PMID- 27215127 TI - [ACADEMIC SURGICAL SERVICES IN A TERTIARY MEDICAL CENTER IN THE NEGEV-DESERT, PERIPHERY OF ISRAEL: IS IT A HYBRID?]. AB - Soroka Medical Center, a major affiliated hospital of the Faculty of Health Sciences in Ben Gurion University of the Negev, serving 1,000,000 citizens in the south part of Israel and is designated as a "peripheral hospital". Herein, we address the factors that influence our high level academic surgical training program with its broad base surgical experience, which focused on the "spirit of Beer Sheba". Should we call our program a hybrid? PMID- 27215128 TI - Six new physalins from Physalis alkekengi var. franchetii and their cytotoxicity and antibacterial activity. AB - Six new physalin steroids, 7beta-methoxylisophysalin B (1), 7beta methoxylphysalin C (2), physalin V (3), physalin VI (4), physalin VII (5), isophysalin I (6), together with 20 known physalins (7-26) were isolated from calyces of Physalis alkekengi var. franchetii. Structures of the new compounds were revealed through 1D and 2D NMR and mass spectroscopic methods. Compounds 1 26 were evaluated for cytotoxicity against human HL-60, SMMC-7721, A-549, MCF-7 and SW-480, and the results indicated that compounds 8, 11, and 14 displayed potent cytotoxicities (IC50<5MUM) in vitro. Further antibacterial assay indicated that compounds 8, 14, and 19 showed high antibacterial activities against Bacillus subtilis and Escherichia coli. PMID- 27215129 TI - Anti-inflammatory and antioxidant effects of a combination of cannabidiol and moringin in LPS-stimulated macrophages. AB - Inflammatory response plays an important role in the activation and progress of many debilitating diseases. Natural products, like cannabidiol, a constituent of Cannabis sativa, and moringin, an isothiocyanate obtained from myrosinase mediated hydrolysis of the glucosinolate precursor glucomoringin present in Moringa oleifera seeds, are well known antioxidants also endowed with anti inflammatory activity. This is due to a covalent-based mechanism for ITC, while non-covalent interactions underlie the activity of CBD. Since these two mechanisms are distinct, and the molecular endpoints are potentially complementary, we investigated in a comparative way the protective effect of these compounds alone or in combination on lipopolysaccharide-stimulated murine macrophages. Our results show that the cannabidiol (5MUM) and moringin (5MUM) combination outperformed the single constituents that, at this dosage had only a moderate efficacy on inflammatory (Tumor necrosis factor-alpha, Interleukin-10) and oxidative markers (inducible nitric oxide synthase, nuclear factor erythroid 2-related factor 2, nitrotyrosine). Significant upregulation of Bcl-2 and downregulation of Bax and cleaved caspase-3 was observed in cells treated with cannabidiol-moringin combination. Treatment with the transient receptor potential vanilloid receptor 1 antagonist was detrimental for the efficacy of cannabidiol, while no effect was elicited by cannabinoid receptor 1 and cannabinoid receptor 2 antagonists. None of these receptors was involved in the activity of moringin. Taken together, our in vitro results testify the anti-inflammatory, antioxidative, and anti-apoptotic effects of the combination of cannabidiol and moringin. PMID- 27215130 TI - Novel tirucallane triterpenoids from the stem bark of Toona sinensis. AB - Phytochemical investigation on the stem bark of Toona sinensis was carried out by various chromatographic techniques resulting in the isolation and elucidation of two novel tirucallane triterpenoids, named (20S)-3-oxo-tirucalla-25-nor-7-en-24 oic acid (1) and (20S)-5alpha,8alpha-epidioxy-3-oxo-24-nor-6.9(11)-dien-23-oic acid (2), along with fifteen known triterpenoids (3-17), their structures were determined by extensive spectroscopic methods, including 1D-, 2D-NMR and HR-ESI MS experiments. Compound 2 is uncommon in nature, which possesses a peroxide bridge cross C-5 and C-8 in the triterpenoid skeleton. All isolated compounds were evaluated for cytotoxicity against five human tumor cell lines (A-549, Hela, HepG2, SGC-7901 and SW-480), among them, compound 17 displayed strongest cytotoxic activity against A-549 cells and the results indicated that its cytotoxicity against A-549 cells was mediated by the intrinsic mitochondrial apoptotic pathway. In addition, ROS production-inhibitory activities were also evaluated, but none of them was active. PMID- 27215133 TI - Benzoxazinone-Mediated Triazine Degradation: A Proposed Reaction Mechanism. AB - The role of benzoxazinones (Bx, 2-hydroxy-2H-1,4-benzoxazin-3(4H)-one) in triazine resistance in plants has been studied for over half a century. In this research, fundamental parameters of the reaction between DIBOA-Glc (2-beta-d glucopyranosyloxy-4-hydroxy-1,4-benzoxazin-3-one) and atrazine (ATR, 6-chloro-N ethyl-N'-(1-methylethyl)-1,3,5-triazine-2,4-diamine) were examined. Through a series of experiments employing a variety of chromatographic and spectroscopic techniques, the DIBOA-Glc/ATR reaction was characterized in terms of reactant and product kinetics, stoichiometry, identification of a reaction intermediate, and reaction products formed. Results of these experiments demonstrated that the reaction mechanism proceeds via nucleophilic attack of the hydroxamic acid moiety of DIBOA-Glc at the C-2 position of the triazine ring to form hydroxyatrazine (HA, 2-hydroxy-4-ethylamino-6-isopropylamino-s-triazine), with associated degradation of DIBOA-Glc. Degradation of reactants followed first-order kinetics with a noncatalytic role of DIBOA-Glc. A reaction intermediate was identified as a DIBOA-Glc-HA conjugate, indicating a 1:1 DIBOA-Glc:ATR stoichiometry. Reaction products included HA and Cl(-), but definitive identification of DIBOA-Glc reaction product(s) was not attained. With these reaction parameters elucidated, DIBOA-Glc can be evaluated in terms of its potential for a myriad of applications, including its use to address the problem of widespread ATR contamination of soil and water resources. PMID- 27215135 TI - Use of ISTH bleeding assessment tool to predict inherited platelet dysfunction in resource constrained settings. AB - BACKGROUND: The International Society of Thrombosis & Hemostasis (ISTH) bleeding assessment tool (ISTH-BAT) is used to record bleeding symptoms in patients with possible bleeding disorders. AIM: To investigate the utility of the ISTH-BAT in predicting platelet dysfunction in individuals with suspected inherited platelet function disorders. METHOD: Individuals with clinical evidence of bleeding and suspected inherited platelet function disorder and healthy volunteers were included in the study. The ISTH-BAT questionnaire was applied prior to light transmission aggregometry (LTA). RESULTS: A total of 261 participants were included (100 healthy volunteers, and 161 with suspected inherited platelet function disorders). The ISTH-BAT score in participants with suspected inherited platelet function disorders (median 2; interquartile range [IQR] 5-1) was significantly higher than in healthy volunteers (median 0; IQR 2-0). There was also a significant difference between participants with suspected inherited platelet function disorders with a platelet defect detected by LTA (median 4; IQR 8-3) and those with normal platelet function (median 2; IQR 3-1) (p < 0.001). The ISTH-BAT score was associated with a demonstrable platelet defect on platelet function testing (area under the receiver operating characteristic curve = 0.8 [95% confidence interval 0.72-0.87, p = < 0.001] and odds ratio 3.25 [95% confidence interval 2.13-4.37, p = < 0.001]). CONCLUSION: The ISTH-BAT is a useful tool for documenting bleeding symptoms and the score obtained is also predictive of the presence of a platelet defect on LTA in patients with suspected inherited platelet dysfunction. PMID- 27215136 TI - The values of occupational therapy: Perceptions of occupational therapists in Quebec. AB - OBJECTIVE: Recently, there has been increasing interest in the values of occupational therapy and the values held by occupational therapists. A wide range of values has been reported in the literature. Furthermore, despite the fact that values are an important part of professional identity, empirical studies have demonstrated that several occupational therapists possess an ambiguous professional identity. This study was undertaken to explore the values of Canadian occupational therapists, specifically French-speaking occupational therapists in Quebec. METHODS: Semi-structured interviews were conducted with 26 occupational therapists. Their narratives were subject to hermeneutic analysis, a method of textual analysis common in philosophical research. RESULTS: A total of 16 values were identified in the discourses of the occupational therapists interviewed: autonomy; human dignity; occupational participation; social justice and equity; professionalism; holism; partnership, environment, or ecological approach; quality of life; solicitude; honesty; integrity; health; creativity; professional autonomy; effectiveness; and spirituality. CONCLUSIONS: The results of this study are, in general, consistent with those reported in the few other empirical studies that have documented the values perceptions of occupational therapists. Finally, the explanation of the values of occupational therapists may reinforce their professional identity and favour best, or at least desirable, professional practices related to ethics and culture. PMID- 27215138 TI - American Association of Hip and Knee Surgeons and Outcome Measures After Total Joint Arthroplasty. PMID- 27215137 TI - Luteinizing Hormone Secretion during Gonadotropin-Releasing Hormone Stimulation Tests in Obese Girls with Central Precocious Puberty. AB - OBJECTIVE: Girls with precocious puberty have high luteinizing hormone (LH) levels and advanced bone age. Obese children enter puberty at earlier ages than do non-obese children. We analyzed the effects of obesity on LH secretion during gonadotropin-releasing hormone (GnRH) tests in girls with precocious puberty. METHODS: A total of 981 subjects with idiopathic precocious puberty who had undergone a GnRH stimulation testing between 2008 and 2014 were included in the study. Subjects were divided into three groups based on body mass index (BMI). Auxological data and gonadotropin levels after the GnRH stimulation test were compared. RESULTS: In Tanner stage 2 girls, peak stimulated LH levels on GnRH test were 11.9+/-7.5, 10.4+/-6.4, and 9.1+/-6.1 IU/L among normal-weight, overweight, and obese subjects, respectively (p=0.035 for all comparisons). In Tanner stage 3 girls, peak stimulated LH levels were 14.9+/-10.9, 12.8+/-7.9, and 9.6+/-6.0 IU/L, respectively (p=0.022 for all comparisons). However, in Tanner stage 4 girls, peak stimulated LH levels were not significantly different among normal, overweight, and obese children. On multivariate analysis, BMI standard deviation score was significantly and negatively associated with peak LH (beta= 1.178, p=0.001). CONCLUSION: In girls with central precocious puberty, increased BMI was associated with slightly lower peak stimulated LH levels at early pubertal stages (Tanner stages 2 and 3). This association was not valid in Tanner stage 4 girls. PMID- 27215139 TI - Building a Patient-Reported Outcome Metric Database: One Hospital's Experience. AB - BACKGROUND: A number of provisions exist within the Patient Protection and Affordable Care Act that focus on improving the delivery of health care in the United States, including quality of care. From a total joint arthroplasty perspective, the issue of quality increasingly refers to quantifying patient reported outcome metrics (PROMs). This article describes one hospital's experience in building and maintaining an electronic PROM database for a practice of 6 board-certified orthopedic surgeons. METHODS: The surgeons advocated to and worked with the hospital to contract with a joint registry database company and hire a research assistant. They implemented a standardized process for all surgical patients to fill out patient-reported outcome questionnaires at designated intervals. RESULTS: To date, the group has collected patient-reported outcome metric data for >4500 cases. The data are frequently used in different venues at the hospital including orthopedic quality metric and research meetings. In addition, the results were used to develop an annual outcome report. The annual report is given to patients and primary care providers, and portions of it are being used in discussions with insurance carriers. CONCLUSION: Building an electronic database to collect PROMs is a group undertaking and requires a physician champion. A considerable amount of work needs to be done up front to make its introduction a success. Once established, a PROM database can provide a significant amount of information and data that can be effectively used in multiple capacities. PMID- 27215140 TI - Reply to Letter to the Editor. PMID- 27215141 TI - Individualized lipid-lowering therapy to further reduce residual cardiovascular risk. AB - Hypercholesterolemia is a major risk factor for cardiovascular diseases. Serum cholesterol concentrations are regulated by enteral absorption, biliary secretion, and hepatic synthesis. Statins inhibit the rate-limiting enzyme of cholesterol synthesis, HMG-CoA-reductase, and reduce serum cholesterol concentrations as well as cardiovascular morbidity and mortality. Some studies indicate that patients with high baseline cholesterol absorption may show only a small response to statin treatment in terms of cholesterol lowering. Data from genetic association studies and from the IMPROVE-IT trial show that reducing intestinal cholesterol absorption via NCP1L1 further reduces cardiovascular risk. However, some patients do not attain LDL-cholesterol targets on combination therapy. For these patients PCSK9-antibody treatment and lipid-apheresis are options to be considered. This article reviews the current literature on this issue and suggests 'individualized lipid-lowering therapy' as an approach to optimize and personalize lipid-lowering treatment of patients with hypercholesterolemia to further reduce residual cardiovascular risk. PMID- 27215143 TI - MicroRNAs in non-small cell lung cancer invasion and metastasis: from the perspective of the radiation oncologist. AB - INTRODUCTION: MicroRNAs (miRs), small sequences of RNA regulating various cellular processes, are implicated to play major roles in cancer. Herein, we discuss the association of several miRs with non-small cell lung cancer (NSCLC), specifically relating to tumor invasion and metastasis to lymphatics and/or distant organs, which can often be correlated with overall prognosis. AREAS COVERED: There exists strong evidence that presence of several miR combinations correlates with prognosis in both early- and advanced-stage NSCLCs. Principally, miR alterations could be useful in enhancing current imaging-based methods to more accurately estimate the extent of invasion/metastases.Expert Commentary: Despite the immature nature of this subject, its large ramifications on clinical oncology are clearly evident. Based on miR signature-related stratification, radiotherapy could be potentially personalized beyond current treatment standards. PMID- 27215142 TI - Usefulness of preoperative CT colonography for colon cancer. AB - BACKGROUND: Computed tomographic colonography (CTC) is reported to be feasible for screening of colorectal polyps; however, its efficacy in preoperative workup remains unknown. This study was done to define our CTC methodology and assess CTC's potential for preoperative examination in patients with colon cancer. METHODS: A total of 86 colon cancer patients underwent CTC prior to laparoscopic colectomy in our department from February 2014 to November 2015. The location of primary colon cancer determined by CTC was compared with that confirmed during the surgery. CTC was performed just after preoperative colonoscopy; for a small colon cancer, we performed clipping during colonoscopy to enhance CTC detectability. We classified wall deformities and compared them with the pathological T stage. RESULTS: CTC accurately located all 87 primary colon cancers prior to surgery. No patient experienced complications associated with CTC. The deformity classification correlated significantly with the pathological T stage (p < 0.001, Kruskal-Wallis nonparametric tests). CTC provided reconstructed images depicting the feeding artery of the primary colon cancer; feeding artery information obtained by CTC facilitated precise lymph node dissection. CONCLUSION: CTC appears to be a feasible and useful preoperative examination modality for colon cancer treatment. PMID- 27215144 TI - Prevalence of Sexual Dysfunction and Associated Risk Factors in Middle-Aged and Elderly Korean Men in Primary Care. AB - Although several studies have individually investigated the risk factors for erectile dysfunction (ED), premature ejaculation (PE), and late-onset hypogonadism (LOH), few studies have considered ED, PE, and LOH as categories of sexual dysfunction (SD) within the same population. We therefore aimed to investigate the prevalence of SD and its associated risk factors among men in primary care. Study participants were enrolled by 18 family physicians from 15 hospital-based family practices in Korea between August 2010 and May 2011. Participants answered a questionnaire regarding their demographic characteristics and lifestyle factors as well as the Korean versions of the Androgen Deficiency in the Aging Male, the International Index of Erectile Function, and the Premature Ejaculation Diagnostic Tool questionnaires. SD prevalence was 64.9% among study participants who were >= 40 years of age. ED prevalence was 43.7%, PE prevalence was 38.6%, and LOH prevalence was 16.8%. SD prevalence was significantly associated with increased age, overweight, hypertension, diabetes, and depression. These findings highlight the importance of screening questions for SD in primary care, especially among older male patients with the identified risk factors. PMID- 27215145 TI - Zwitterionic phosphonium ligands: synthesis, characterization and application in telomerization of 1,3-butadiene. AB - Novel zwitterionic phosphonium alkylsulfonate ligands are chemoselectively synthesized from N-heterocyclic phosphines and cyclic sulfones in one step in good to excellent yields. Their in situ generated palladium complexes showed high productivity in the industrial telomerization of 1,3-butadiene with methanol. Optimal results are obtained in the presence of cyclohexyl-substituted ligands under mild conditions and at metal loadings as low as 0.001 mol%. PMID- 27215146 TI - Role of JAK-STAT pathway in reducing cardiomyocytes hypoxia/reoxygenation injury induced by S1P postconditioning. AB - This experiment was designed to explore the protection of sphingosine1-phosphate (S1P) postconditioning on rat myocardial cells injured by hypoxia/reoxygenation acting via the Janus kinase-signal transducer and activator of transcription (JAK STAT) signal pathway. The data showed that S1P could significantly increase cell viability, lower the rate of apoptosis, decrease the content of lactate dehydrogenase (LDH) and caspase3 activity in the culture medium, increase the activity of total superoxide dismutase (T-SOD) and manganese superoxide dismutase (Mn-SOD), reduce the loss of mitochondrial membrane potential and the fluorescence intensity of intracellular calcium, as well as increase the phosphorylation of JAK2 and STAT3 in comparison with the H/R group. When the JAK inhibitor AG490 or the STAT inhibitor stattic were added, the effects of S1P were inhibited. Our date shows that S1P protects H9c2 cells from hypoxia/reoxygenation injury and that the protection by S1P was inhibited by AG490 and stattic. Therefore S1P protects H9c2 cells against hypoxia/reoxygenation injury via the JAK-STAT pathway. PMID- 27215147 TI - Cochrane review summary: interventions to facilitate shared decision making to address antibiotic use for acute respiratory tract infections in primary care. PMID- 27215148 TI - Satisfaction with life after burn: A Burn Model System National Database Study. AB - OBJECTIVES: While mortality rates after burn are low, physical and psychosocial impairments are common. Clinical research is focusing on reducing morbidity and optimizing quality of life. This study examines self-reported Satisfaction With Life Scale scores in a longitudinal, multicenter cohort of survivors of major burns. Risk factors associated with Satisfaction With Life Scale scores are identified. METHODS: Data from the National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR) Burn Model System (BMS) database for burn survivors greater than 9 years of age, from 1994 to 2014, were analyzed. Demographic and medical data were collected on each subject. The primary outcome measures were the individual items and total Satisfaction With Life Scale (SWLS) scores at time of hospital discharge (pre-burn recall period) and 6, 12, and 24 months after burn. The SWLS is a validated 5-item instrument with items rated on a 1-7 Likert scale. The differences in scores over time were determined and scores for burn survivors were also compared to a non-burn, healthy population. Step-wise regression analysis was performed to determine predictors of SWLS scores at different time intervals. RESULTS: The SWLS was completed at time of discharge (1129 patients), 6 months after burn (1231 patients), 12 months after burn (1123 patients), and 24 months after burn (959 patients). There were no statistically significant differences between these groups in terms of medical or injury demographics. The majority of the population was Caucasian (62.9%) and male (72.6%), with a mean TBSA burned of 22.3%. Mean total SWLS scores for burn survivors were unchanged and significantly below that of a non-burn population at all examined time points after burn. Although the mean SWLS score was unchanged over time, a large number of subjects demonstrated improvement or decrement of at least one SWLS category. Gender, TBSA burned, LOS, and school status were associated with SWLS scores at 6 months; scores at 12 months were associated with LOS, school status, and amputation; scores at 24 months were associated with LOS, school status, and drug abuse. CONCLUSIONS: In this large, longitudinal, multicenter cohort of burn survivors, satisfaction with life after burn was consistently lower than that of non-burn norms. Furthermore mean SWLS scores did not improve over the two-year follow-up period. This study demonstrates the need for continued efforts to improve patient-centered long term satisfaction with life after burn. PMID- 27215149 TI - Fibroblast growth factor 23 in acute burn patients: Novel insights from an intact form assay. AB - INTRODUCTION: Fibroblast growth factor 23 (FGF23) is a key regulator in phosphate and vitamin D metabolism When measured with c-terminal assay, it has been shown to be increased following burn. Progress in understanding FGF23 physiology has emphasized the importance of assessing the intact form of FGF23. METHODS: The present cohort study is a complementary analysis of a previously published work. Patients >18 years, admitted within 24h after injury with burn surface area (BSA) >10% were included. C-terminal (c-term) and intact (i) FGF23 assay were performed at admission and every week during 4 weeks of follow-up. Inflammation and iron status were assessed at the same time points. RESULTS: Twenty patients were initially included and 12 were followed until day 28. The c-term FGF23 tended to gradually increase during the 4 weeks of follow-up while iFGF23 was quite stable into normal ranges. Iron status showed a typical inflammatory profile. C-term FGF23 was significantly positively correlated with c-reactive protein (CRP) and negatively correlated with iron levels. iFGF23 was not correlated with CRP or iron. CONCLUSION: FGF23 status following burn is characterized by a dissociation between c-term FGF23 and iFGF23. The hypothesis of an increased cleavage may be raised. Respective role of inflammation and iron levels in such deregulation need to be specified. Both c-term and intact assays should be performed in further studies aiming to increase knowledge on FGF23 regulation and effects in burn patients. PMID- 27215150 TI - Response to Letter to the Editor: 'The Burn Outcome Questionnaires: Patient and Family Reported Outcome Metrics for Children of All Ages'. PMID- 27215151 TI - Diagnostic accuracy of laser Doppler imaging in burn depth assessment: Systematic review and meta-analysis. AB - BACKGROUND AND OBJECTIVE: Accurate assessment of burn depth is important for determination of treatment modality. Laser Doppler imaging (LDI) is known to be an objective and effective measurement tool in burn depth assessment. Our study evaluated the diagnostic accuracy of LDI across enrolled studies and subgroups. METHODS: A systematic literature review and meta-analysis were performed using MEDLINE, EMBASE, and Cochrane databases. Data from LDI cases were extracted from all primary studies and categorized into four cell values (true positives, false positives, true negatives, and false negatives). Subgroup analyses were performed according to perfusion units of LDI, clinical criteria of superficial and deep burns during the treatment period, and publication date of enrolled studies. RESULTS: The search strategy identified 321 publications. After screening, 10 articles were selected for review. The pooled sensitivity and specificity of LDI in all enrolled studies and subgroups were found to be similarly high. However, the sensitivity of LDI in our meta-analysis was not as high as that identified in previous studies. CONCLUSION: Although LDI in burn depth assessment was identified as an accurate measurement tool in this meta-analysis, careful clinical assessment should be performed along with LDI in patients with deep burns. PMID- 27215152 TI - Response to Letter to the Editor: 'High-frequency percussive ventilation and initial biomarker levels of lung injury after smoke inhalation - Not straightforward to interpret'. PMID- 27215153 TI - Onychomycosis: Evaluation, Treatment Options, Managing Recurrence, and Patient Outcomes. AB - Onychomycosis is the most common nail disease seen in podiatric practice. Effective long-term management remains problematic. We need to treat onychomycosis effectively to prevent its progression into a severe, debilitating, and painful condition, and to manage recurrence. With new agents now available and greater discussion on management strategies, this article reviews the appropriate evaluation of the disease, treatment options, and optimal patient outcomes. PMID- 27215154 TI - Dermatologic Manifestations of the Lower Extremity: Nail Surgery. AB - Nail surgery is a fundamental component of podiatric surgery. Nail disorders are common and may cause significant morbidity and occasionally mortality. Diagnosis of inflammatory and infectious conditions, and of benign or malignant tumors, often requires a biopsy of the nail unit. Excisional surgery may also be curative for certain tumors. This article reviews key elements of nail anatomy, surgical preparation, local anesthesia, and methods to achieve and maintain a bloodless field. A familiarity with these concepts should allow clinicians to develop a surgical plan and approach when patients present with a nail disorder requiring biopsy or surgical treatment. PMID- 27215156 TI - Psoriasis: Pathogenesis, Assessment, and Therapeutic Update. AB - Psoriasis is a chronic condition that affects more than 7 million Americans. This article explores the pathogenesis and physical signs of psoriasis. Over the past 2 decades enhanced understanding of the immunologic basis of psoriasis has led to the development of new systemic agents that have revolutionized the management of this disease, and these modalities, along with traditional therapies, are described. PMID- 27215155 TI - The Human Papillomavirus and Its Role in Plantar Warts: A Comprehensive Review of Diagnosis and Management. AB - Viral warts or verruca pedis (plantar warts) are common skin conditions seen in both children and adults. Human papilloma virus (HPV), a DNA virus, is responsible for plantar verrucae. It needs an epidermal abrasion and a transiently impaired immune system to inoculate a keratinocyte. These entities are a therapeutic conundrum for many practitioners. This article discusses HPV infiltration and its subtypes involved in plantar warts; the evaluation of patients with plantar warts; and subsequent treatment options, such as laser, Candida albicans immunotherapy, topical therapy such as phytotherapy, and surgical excision. PMID- 27215157 TI - Dermatologic Concerns of the Lower Extremity in the Pediatric Patient. AB - As the largest organ in the body, skin can prove the most daunting to diagnose and manage due to the large number of conditions and their uncanny ability to have similar qualities visually. Skin can reflect current trauma or infections or can be a harbinger of an underlying systemic disorder. With knowledge of the most common pediatric skin conditions, it is possible for practitioners to start a child on a basic treatment regimen and then refer to an appropriate specialist for more complex or rare disorders. This article covers the most common skin conditions seen on the lower extremity in the pediatric population. PMID- 27215158 TI - Importance of Vehicles in Topical Treatment of Fungal Infections. AB - Topical drug therapies are commonly used to manage dermatologic diseases and their manifestations in the skin, hair, nails, and mucous membranes. Compared with systemic treatment, topical drug delivery provides 2 notable benefits in the management of skin diseases. In addition to delivering the active drug, a well designed vehicle can have supportive effects on the skin, whereas a poorly designed vehicle can have detrimental effects. In many cases, the same active drug is available in several dosage forms, offering the prescriber the ability to tailor treatment to the patient's unique presentation and needs. PMID- 27215159 TI - Adverse Drug Reactions of the Lower Extremities. AB - Adverse drug reactions (ADRs) are a common cause of dermatologic consultation, involving 2 to 3 per 100 medical inpatients in the United States. Female patients are 1.3 to 1.5 times more likely to develop ADRs, except in children less than 3 years of age, among whom boys are more often affected. Certain drugs are more frequent causes, including aminopenicillins, trimethoprim-sulfamethoxazole, and nonsteroidal antiinflammatory drugs. Chemotherapeutic agents commonly cause adverse reactions to the skin and nails, with certain agents causing particular patterns of reactions. ADRs can involve any area of the skin; the appendages, including hair and nails; as well as mucosa. PMID- 27215160 TI - Melanoma of the Foot. AB - Melanoma is a rare form of skin cancer that is responsible for most skin cancer deaths globally. Tumors arising on the foot continue to be a particular challenge. Patients present later and lesions are frequently misdiagnosed, leading to more advanced disease with an overall poorer prognosis then melanoma elsewhere. In order to improve early recognition, this article reviews the clinical features of the disease along with published algorithms. Emerging assessment techniques such as dermoscopy are also discussed as tools to improve clinical decision making. Contemporary drug therapies in the treatment of advanced disease are also discussed. PMID- 27215161 TI - Cutaneous Markers of Systemic Disease in the Lower Extremity. AB - The skin of the lower extremity can be a helpful diagnostic tool for systemic disease. Diabetes, renal disease, genetic disorders, and even cancer can have cutaneous manifestations in the legs and feet; moreover, proper diagnosis can facilitate earlier treatment of these diseases and not only clear up the skin symptoms but also bring about resolution of the systemic disease causing them. Although not comprehensive, this article discusses many of these disorders presenting with integumentary manifestations in the lower extremities. Where appropriate, it also enumerates the treatments involved, both systemic and localized. PMID- 27215162 TI - Plantar Hyperhidrosis: An Overview. AB - Plantar hyperhidrosis, excessive sweating on the soles of feet, can have a significant impact on patients' quality of life and emotional well-being. Hyperhidrosis is divided into primary and secondary categories, depending on the cause of the sweating, with plantar hyperhidrosis typically being primary and idiopathic. There is an overall increased risk of cutaneous infection in the presence of hyperhidrosis, including fungal, bacterial, and viral infections. This article discusses a range of treatment options including topical aluminum chloride, iontophoresis, injectable botulinum toxin A, glycopyrrolate, oxybutynin, laser, and endoscopic lumbar sympathectomy. Lifestyle changes regarding hygiene, shoe gear, insoles, and socks are also discussed. PMID- 27215163 TI - Lower Extremity Skin Manifestations. PMID- 27215164 TI - Lower Extremity Skin Manifestations: A Multidisciplinary Effort. PMID- 27215165 TI - High-pressure anaerobic digestion up to 100 bar: influence of initial pressure on production kinetics and specific methane yields. AB - To ensure an efficient use of biogas produced by anaerobic digestion, in some cases it would be advisable to upgrade the biogenic gases and inject them into the transnational gas grids. To investigate biogas production under high-pressure conditions up to 100 bar, new pressure batch methane reactors were developed for preliminary lab-scale experiments with a mixture of grass and maize silage hydrolysate. During this investigation, the effects of different initial pressures (1, 50 and 100 bar) on pressure increase, gas production and the specific methane yield using nitrogen as inert gas were determined. Based on the experimental findings increasing initial pressures alter neither significantly, further pressure increases nor pressure increase rates. All supplied organic acids were degraded and no measurable inhibition of the microorganisms was observed. The results show that methane reactors can be operated at operating pressures up to 100 bar without any negative effects on methane production. PMID- 27215167 TI - Older Adults and Emerging Digital Service Delivery: A Mixed Methods Study on Information and Communications Technology Use, Skills, and Attitudes. AB - Based on data from a survey (n = 3291) and 14 qualitative interviews among Danish older adults, this study investigated the use of, and attitudes toward, information communications technology (ICT) and the digital delivery of public services. While age, gender, and socioeconomic status were associated with use of ICT, these determinants lost their explanatory power when we controlled for attitudes and experiences. We identified three segments that differed in their use of ICT and attitudes toward digital service delivery. As nonuse of ICT often results from the lack of willingness to use it rather than from material or cognitive deficiencies, policy measures for bridging the digital divide should focus on skills and confidence rather than on access or ability. PMID- 27215166 TI - Genome-scale RNA interference screen identifies antizyme 1 (OAZ1) as a target for improvement of recombinant protein production in mammalian cells. AB - For the purpose of improving recombinant protein production from mammalian cells, an unbiased, high-throughput whole-genome RNA interference screen was conducted using human embryonic kidney 293 (HEK 293) cells expressing firefly luciferase. A 21,585 human genes were individually silenced with three different siRNAs for each gene. The screen identified 56 genes that led to the greatest improvement in luciferase expression. These genes were found to be included in several pathways involved in spliceosome formation and mRNA processing, transcription, metabolic processes, transport, and protein folding. The 10 genes that most enhanced protein expression when downregulated, were further confirmed by measuring the effect of their silencing on the expression of three additional recombinant proteins. Among the confirmed genes, OAZ1-the gene encoding the ornithine decarboxylase antizyme1-was selected for detailed investigation, since its silencing improved the reporter protein production without affecting cell viability. Silencing OAZ1 caused an increase of the ornithine decarboxylase enzyme and the cellular levels of putrescine and spermidine; an indication that increased cellular polyamines enhances luciferase expression without affecting its transcription. The study shows that OAZ1 is a novel target for improving expression of recombinant proteins. The genome-scale screening performed in this work can establish the foundation for targeted design of an efficient mammalian cell platform for various biotechnological applications. Biotechnol. Bioeng. 2016;113: 2403-2415. (c) 2016 Wiley Periodicals, Inc. PMID- 27215168 TI - Choledochal cysts in pregnancy A case report and literature review. AB - AIM: Aim is to demonstrate that surgery can be the best way to reduce the risk of malignancy in choledochal cysts (CC) and how hard can be the diagnosis and the treatment during pregnancy. CASE REPORT: We report a case of a pregnant young woman (36 week) with a Todani's score II CC. After caesarean, due to increasing jaundice, she underwent magnetic resonance cholangiopancreatography (MRCP) and Endoscopic retrograde cholangiopancreatography (ERCP) that confirmed the diagnosis. Surgical operation consisted in "cholecystectomy, resection of the choledocal cyst and poli-jejunum anastomosis. drainage of the abscess in the iv hepatic segment". DISCUSSION: This case report highlights the difficult diagnosis and consequently treatment of a CC, especially during pregnancy. A significant association of biliary duct cyst and hepato-bilio-pancreatic malignancy has been reported with an age-related incidence. CONCLUSION: Surgery is considered as the best treatment with a close follow-up because of the risk of recurrent cholangitis and malignant degeneration. This case represents also a challenge because of physiological changes in pregnancy and also because of the risk of fetal mortality and maternal morbidity. KEY WORDS: Choledochal cyst, Colangiocarcinoma, Pregnancy, Todani's score. PMID- 27215169 TI - Reducing safety risk among underserved caregivers with an Alzheimer's home safety program. AB - OBJECTIVES: Older adults living with Alzheimer's disease (AD) experience more of the types of accidents and injuries prevalent among older adults. Relatively few studies specifically on safety risks have included older adults of color and tested interventions. This pilot study tested the feasibility and evaluability of educating Hispanic and African American caregivers of patients living with AD about reducing safety risks in their homes. METHODS: This outpatient memory clinic-based intervention study included a pre-/post-test survey design with two nonequivalent groups and predominately serves Hispanic and African Americans. Of 60 eligible caregivers, 67% participated in a tailored, safety training class with an optional follow-up call. RESULTS: The results indicate a reduction in some safety risks compared to baseline and/or a no intervention group, respectively, including leaving patients at home alone part-time (p < .01 and p < .01), getting lost (p < .05 and p < .05), going outdoors alone less often (p < .05 and p < .01), and giving themselves medicine (p < .05 and p < .01). At post test, 47 clinically significant instances occurred, in which caregivers who participated in the intervention self-reported patients living with AD to be 'completely safe' in one or more of the safety risk items compared to 8 instances among those who did not. CONCLUSIONS: This pilot pre/post design with non equivalent groups study needs refinement in a future randomized control trial. Despite limitations, this pilot study demonstrates the first feasible and evaluable intervention with both statistically and clinically significant results that suggest potential for reducing safety risks among at-risk minority patients living with AD in future research. PMID- 27215171 TI - Influence of different mechanical stimuli in a multi-scale mechanobiological isotropic model for bone remodelling. AB - This work represents a study of a mathematical model that describes the biological response to different mechanical stimuli in a cellular dynamics model for bone remodelling. The biological system discussed herein consists of three specialised cellular types, responsive osteoblasts, active osteoblasts and osteoclasts, three types of signalling molecules, transforming growth factor beta (TGF-beta), receptor activator of nuclear factor kappa-b ligand (RANKL) and osteoprotegerin (OPG) and the parathyroid hormone (PTH). Three proposals for mechanical stimuli were tested: strain energy density (SED), hydrostatic and deviatoric parts of SED. The model was tested in a two-dimensional geometry of a standard human femur. The spatial discretization was performed by the finite element method while the temporal evolution of the variables was calculated by the 4th order Runge-Kutta method. The obtained results represent the temporal evolution of the apparent density distribution and the mean apparent density and thickness for the cortical bone after 600 days of remodelling simulation. The main contributions of this paper are the coupling of mechanical and biological models and the exploration of how the different mechanical stimuli affect the cellular activity in different types of physical activities. The results revealed that hydrostatic SED stimulus was able to form more cortical bone than deviatoric SED and total SED stimuli. The computational model confirms how different mechanical stimuli can impact in the balance of bone homeostasis. PMID- 27215170 TI - Galectin-3 Enhances Migration of Minature Pig Bone Marrow Mesenchymal Stem Cells Through Inhibition of RhoA-GTP Activity. AB - Bone marrow mesenchymal stem cells (BM-MSCs) are used in tissue engineering because of their migration characters. However, BM-MSCs have limitations in terms of reaching injuries and self-renewal. Therefore, enhancement of BM-MSC migration is important for therapeutic applications. Here, we assessed whether galectin-3 (Gal-3) increases the migration of minature pig BM-MSCs. Gal-3 was knocked down by short hairpin RNA (shRNA) or overexpressed using a lentiviral vector in Wuzhishan minature pig BM-MSCs. Proliferation and migration assays showed that knockdown of Gal-3 impaired BM-MSC proliferation and migration, whereas Gal-3 overexpression promoted these behaviors. RhoA-GTP activity was upregulated in Gal 3 shRNA-transfected BM-MSCs, while Rac-1- and Cdc42-GTP showed no changes. Western blotting indicated downregulation of p-AKT (ser473) and p-Erk1/2 after serum starvation for 12 h in Gal-3-knockdown BM-MSCs. p-AKT (ser473) expression was upregulated after serum starvation for 6 h, and p-Erk1/2 expression was unchanged in Gal-3-overexpressing BM-MSCs. Treatment with C3 transferase or Y27632 enhanced migration, whereas Gal-3 knockdown impaired migration in treated cells. These results demonstrate that Gal-3 may enhance BM-MSC migration, mainly through inhibiting RhoA-GTP activity, increasing p-AKT (ser473) expression, and regulating p-Erk1/2 levels. Our study suggests a novel function of Gal-3 in regulating minature pig BM-MSC migration, which may be beneficial for therapeutic applications. PMID- 27215172 TI - Facilitatory effect of paired-pulse stimulation by transcranial magnetic stimulation with biphasic wave-form. AB - Transcranial magnetic stimulation (TMS) is used to probe corticospinal excitability by stimulating the motor cortex. Our aim was to enhance the effects of biphasic TMS by coupling a suprathreshold test pulse and a following subthreshold priming pulse to induce short-interval intracortical facilitation (SICF), which is conventionally produced with monophasic TMS. Biphasic TMS could potentially induce the SICF effect with better energy-efficiency and with lower stimulus intensities. This would make the biphasic paired-pulses better applicable in patients with reduced cortical excitability. A prototype stimulator was built to produce biphasic paired-pulses. Resting motor thresholds (rMTs) from the right and left hand abductor pollicis brevis muscles, and the right tibialis anterior muscle of eight healthy volunteers were determined using single-pulse paradigm with neuronavigated TMS. The rMTs and MEPs were measured using single pulses and three paired-pulse setups (interstimulus interval, ISI of 3, 7 or 15ms). The rMTs were lower and MEPs were higher with biphasic paired-pulses compared to single-pulses. The SICF effect was greatest at 3ms ISI. This suggests that the application of biphasic paired-pulses to enhance stimulation effects is possible. PMID- 27215173 TI - A Rapid Method for Refolding Cell Surface Receptors and Ligands. AB - Production of membrane-associated cell surface receptors and their ligands is often a cumbersome, expensive, and time-consuming process that limits detailed structural and functional characterization of this important class of proteins. Here we report a rapid method for refolding inclusion-body-based, recombinant cell surface receptors and ligands in one day, a speed equivalent to that of soluble protein production. This method efficiently couples modular on-column immobilized metal ion affinity purification and solid-phase protein refolding. We demonstrated the general utility of this method for producing multiple functionally active immunoreceptors, ligands, and viral decoys, including challenging cell surface proteins that cannot be produced using typical dialysis- or dilution-based refolding approaches. PMID- 27215174 TI - Angiotensins processing activities in the venom and epidermic mucus of Scorpaena plumieri. AB - The venom of marine animals is a rich source of compounds with remarkable selectivity and functional diversity. Scorpaena plumieri is the most venomous fish in the Brazilian fauna and is responsible for relatively frequent accidents involving anglers and bathers. In humans, its venom causes edema, erythema, ecchymoses, anxiety, nausea, vomiting, and syncope. The venom is chemically characterized by Sp-CTx, a enzyme able to generate an initial endothelium dependent relaxation response, followed by a contraction response. This study sought to investigate the proteolytic activities regarding vasopeptides angiotensin I and II. Both the venom and the epidermal mucus presented angiotensin conversion activity for angiotensin I, as well as a capacity to form Ang 1-7 directly via Ang I and II. Captopril (10 MUM) and EDTA (1 mM) were able to abolish the converting activity of the venom and the epidermal mucus, representing the first description of a converting activity in S. plumieri venom and epidermal mucus. PMID- 27215175 TI - Editorial Comment. PMID- 27215176 TI - Reverse-phase high-performance liquid chromatography for the simultaneous determination of sildenafil and N-desmethyl sildenafil in plasma of children. AB - Sildenafil is a selective inhibitor of cGMP-specific type 5 phosphodiesterase used for the treatment of pulmonary arterial hypertension (PAH) in the adults. In pediatrics, PAH treatment options include the off-label use of sildenafil. Sildenafil is metabolized in the liver by cytocrome P450 into its active metabolite, N-desmethyl sildenafil. The determination of plasma levels of sildenafil and N-desmethyl sildenafil could be useful for therapy optimization and pharmacokinetic studies. We have developed and validated a method for the quantification of sildenafil and its metabolite in plasma of children by rapid extraction, using high-performance liquid chromatography with ultraviolet detection. The calibration range was fitted at least square model (r2 >= 0.999), with an accuracy and an intra- and inter-day relative standard deviation <15% for both analytes. The mean recovery was 102.5% for sildenafil and 101.8% for N desmethyl sildenafil. This simple method could be successfully used in children with PAH under treatment with sildenafil. PMID- 27215177 TI - Video-assisted endoscopic resection of left ventricular papillary fibroelastoma through the aortic valve. AB - Papillary fibroelastoma is a rare, benign cardiac tumor. Surgical resection is indicated to prevent embolization. We herein report a case of a 78-year-old asymptomatic man who was found to have a mobile left ventricular papillary fibroelastoma anchoring deep in the left ventricle by incidental transthoracic echocardiography. The tumor was resected under visualization by a video-assisted rigid endoscope with a flexible head inserted through the aortic valve into the left ventricle. Intraoperative frozen section analysis provided a pathological diagnosis of papillary fibroelastoma. The postoperative course was uneventful. This technique is recommended for the observation and resection of a tumor anchoring deep in the left ventricle and is helpful for avoiding the adverse effects of left ventriculotomy. PMID- 27215178 TI - The signal transducer and activator of transcription factors lodge in immunopathogenesis of rheumatoid arthritis. AB - Rheumatoid arthritisis (RA) is a chronic autoimmune disorder that affects ~1-2% of the world's population and damages synovial joints. RA is characterized by inflammation, autoantibody production, cartilage and bone destruction and synovial hyperplasia. Inflammation induces systemic and articular synthesis of pro-inflammatory cytokines, such as tumor necrosis factor alpha and interleukin-6 that play essential roles in joint and other organ damage in this disease. Considering the role of signal transducer and activator of transcription factors (STATs) in signaling of these cytokines, these proteins may be involved in the pathogenesis of RA. The expression and activity of STATs can contribute to the onset, progression and severity of RA. All STAT family members (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6) have been associated with autoimmune diseases, as highlighted in several studies. In this review we aim to describe the immunobiology of STATs and its family members and the role of these proteins in the immunopathogenesis of RA. PMID- 27215179 TI - Lifestyle and dietary habits of patients with gout followed in rheumatology settings. AB - Diet and lifestyles modification are core aspects of the non-pharmacological management of gout, but a poor consistency with suggested guidelines is reported. This study aimed to investigate dietary and lifestyle habits of patients with gout followed in rheumatology settings. Data were retrieved from the baseline dataset of the KING study, a multicentre cohort study of patients with gout followed in rheumatology settings. Dietary habits were assessed with the Italian National Institute of Statistics (ISTAT) food-frequency questionnaire and compared with reported data about general population. The relative increase of exposure was estimated by standardized prevalence ratios adjusted for gender, age and geographical distribution. The study population included 446 patients, with a mean age of 63.9 years and a M/F ratio of 9:1. Compared to the Italian population, gouty patients showed a higher prevalence of obesity [1.82 (1.52 2.18)] and a higher consumption of wine [1.85 (1.48-2.32)] and beer [2.21 (1.68 2.90)], but a lower prevalence of smoking and a lower intake of liquor. They showed a lower intake of red meat [0.80 (0.71-0.91)], but a similar intake of other tested dietary factors. Gouty patients' lifestyle is still partially different from the recommended. PMID- 27215180 TI - Predictive value of isolated DLCO reduction in systemic sclerosis patients without cardio-pulmonary involvement at baseline. AB - Impaired diffusing capacity of the lung for carbon monoxide (DLCO) was frequently observed in systemic sclerosis (SSc) patients, generally related to the presence of interstitial lung disease (ILD) and/or pulmonary arterial hypertension (PAH). However, in clinical practice abnormally low DLCO values may be found also in the absence of these SSc complications. The objective was to investigate the prospective clinical relevance of isolated DLCO reduction at baseline in SSc patients. Ninety-seven SSc female patients (age at the diagnosis: 51.3+/-14.5 years; disease duration: 10.4+/-6.6 years; limited/diffuse skin subsets: 92/5), without any clinical, radiological (high resolution computed tomography), and echocardiographic manifestations of ILD or PAH at baseline, nor other lung or heart diseases able to affect DLCO, were recruited at our Rheumatology Centre. Patients with DLCO <55% (15 patients; group A) were compared with those with normal DLCO (82 patients; group B), at baseline and at the end of follow-up. At baseline, patients of group A showed significantly higher percentage of anticentromere autoantibodies compared to group B (13/15, 86.6% vs 48/82, 58.5%; p=0.044). More interestingly, at the end of long-lasting clinical follow-up (11.6+/-6.7 years), pre-capillary PAH (right heart catheterization) solely developed in some patients of group A (3/15, 20% vs 0/82; p=0.003). In SSc patients, the presence at baseline of isolated, marked DLCO reduction (<55% of predicted) and serum anticentromere autoantibodies might characterize a peculiar SSc subset that may precede the development of PAH. Therefore, careful clinical follow-up of patients with isolated moderate-severe DLCO reduction should be mandatory. PMID- 27215181 TI - Inflammatory optic neuropathy in Behcet's disease. AB - Inflammatory optic neuropathy (ON) is a rare event in Behcet's disease (BD). We report herein a series of ten BD Tunisian patients with ON and describe its clinical features among them. A retrospective review of BD patients (International Study Group for BD criteria) was performed. The patients were divided into two groups: those presenting an inflammatory ON, and those none. The diagnosis of inflammatory ON was based on the clinical examination, visual field and visual evoked potentials. We analyzed the characteristics of the two groups. Ten patients (2.3%) presented an inflammatory ON among our 440 patients. Inflammatory ON was inaugural in 8 cases. Clinical manifestations were as follows: blurred vision (7 cases) and periorbital pain (3 cases). In two cases, the patients did not complain from ophthalmological symptoms. The fundus revealed a papilledema (2 cases), papillary pallor (4 cases), and was normal in 5 cases. Visual field realized in only three patients showed a scotoma in all cases. Visual evoked potentials revealed increased latency in all cases. All patients received corticosteroids associated to an immunosuppressive agent. The comparative study between the two groups revealed that inflammatory ON was significantly more associated to neurological involvement (p<0.0001) and that the disease was more severe in the ON group (p<0.0001). Inflammatory ON in BD is rare and may occur at an early stage of the clinical course of the disease. Its prevalence is certainly underestimated. A systematic visual evoked potential may be interesting as a screening tool. PMID- 27215182 TI - Systemic vasculitis in a patient with rhupus syndrome. AB - Rhupus is a rare syndrome characterized by overlap of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Previous reports mentioned that rhupus patients have prominent RA associated clinical manifestations and only mild organic damage related to SLE. Progressive or life-threatening manifestations are rare in rhupus patients. Our patient diagnosed as rhupus was a young women, presented with multi-organ involvement of systemic vasculitis. Rheumatologists should be aware of possibility that rhupus may be accompanied by progressive or life-threatening conditions such as vasculitis. PMID- 27215183 TI - Giant cell arteritis and polymyalgia rheumatica as first manifestation of typical pulmonary carcinoid tumor. AB - Giant cell arteritis (GCA), a systemic vasculitis of unknown origin, may appear rarely as a paraneoplastic syndrome. Cases secondary to pulmonary neuroendocrine tumors have not been reported. A 75-year-old female developed prednisone responsive GCA/polymyalgia rheumatica (PMR) shortly followed by syndrome of inappropriate antidiuretic hormone secretion. An 8 mm carcinoid lung tumor with positron emission tomography normal uptake was found. After a thoracoscopic tumor resection the patient experienced complete clinical and laboratory remission. This is the first report of GCA with PMR in the context of carcinoid lung tumor. It emphasizes the role of paraneoplastic vasculitis as a possible cause of GCA. PMID- 27215184 TI - KRas, ROS and the initiation of pancreatic cancer. AB - Oncogenic mutations of KRAS are the most frequent driver mutations in pancreatic cancer. Expression of an oncogenic allele of KRAS leads to metabolic changes and altered cellular signaling that both can increase the production of intracellular reactive oxygen species (ROS). Increases in ROS have been shown to drive the formation and progression of pancreatic precancerous lesions by upregulating survival and growth factor signaling. A key issue for precancerous and cancer cells is to keep ROS at levels where they are beneficial for tumor development and progression, but below the threshold that leads to induction of senescence or cell death. In KRas-driven neoplasia aberrantly increased ROS levels are therefore balanced by an upregulation of antioxidant genes. PMID- 27215185 TI - "It's the Way That You Do It": Developing an Ethical Framework for Community Psychology Research and Action. AB - In the 50 years since the 1965 Swampscott conference, the field of community psychology has not yet developed a well-articulated ethical framework to guide research and practice. This paper reviews what constitutes an "ethical framework"; considers where the field of community psychology is at in its development of a comprehensive ethical framework; examines sources for ethical guidance (i.e., ethical principles and standards) across multiple disciplines, including psychology, evaluation, sociology, and anthropology; and recommends strategies for developing a rich written discourse on how community psychology researchers and practitioners can address ethical conflicts in our work. PMID- 27215186 TI - Remarkable enhancement of the electrical conductivity of carbon nanostructured thin films after compression. AB - In this work, we demonstrate a significant improvement in the electrical conductivity of carbon nanostructured thin films, composed of graphene nanosheets and multiwalled carbon nanotubes, by compression/polishing. It is shown that the sheet resistance of compressed thin films of carbon nanostructures and hybrids is remarkably decreased in comparison with that of as-deposited films. The number of the interconnections, the distance between the nanostructures as well as their orientation are highly altered by the compression favoring the electrical conductivity of the compressed samples. PMID- 27215188 TI - Soluble CD59 is a Novel Biomarker for the Prediction of Obstructive Chronic Lung Allograft Dysfunction After Lung Transplantation. AB - CD59 is a complement regulatory protein that inhibits membrane attack complex formation. A soluble form of CD59 (sCD59) is present in various body fluids and is associated with cellular damage after acute myocardial infarction. Lung transplantation (LTx) is the final treatment for end-stage lung diseases, however overall survival is hampered by chronic lung allograft dysfunction development, which presents itself obstructively as the bronchiolitis obliterans syndrome (BOS). We hypothesized that, due to cellular damage and activation during chronic inflammation, sCD59 serum levels can be used as biomarker preceding BOS development. We analyzed sCD59 serum concentrations in 90 LTx patients, of whom 20 developed BOS. We observed that BOS patients exhibited higher sCD59 serum concentrations at the time of diagnosis compared to clinically matched non-BOS patients (p = 0.018). Furthermore, sCD59 titers were elevated at 6 months post LTx (p = 0.0020), when patients had no BOS-related symptoms. Survival-analysis showed that LTx patients with sCD59 titers >=400 pg/ml 6 months post-LTx have a significant (p < 0.0001) lower chance of BOS-free survival than patients with titers <=400 pg/ml, 32% vs. 80% respectively, which was confirmed by multivariate analysis (hazard ratio 6.2, p < 0.0001). We propose that circulating sCD59 levels constitute a novel biomarker to identify patients at risk for BOS following LTx. PMID- 27215190 TI - A kernel-based clustering method for gene selection with gene expression data. AB - Gene selection is important for cancer classification based on gene expression data, because of high dimensionality and small sample size. In this paper, we present a new gene selection method based on clustering, in which dissimilarity measures are obtained through kernel functions. It searches for best weights of genes iteratively at the same time to optimize the clustering objective function. Adaptive distance is used in the process, which is suitable to learn the weights of genes during the clustering process, improving the performance of the algorithm. The proposed algorithm is simple and does not require any modification or parameter optimization for each dataset. We tested it on eight publicly available datasets, using two classifiers (support vector machine, k-nearest neighbor), compared with other six competitive feature selectors. The results show that the proposed algorithm is capable of achieving better accuracies and may be an efficient tool for finding possible biomarkers from gene expression data. PMID- 27215191 TI - Survivorship After Primary Total Hip Arthroplasty in Solid-Organ Transplant Patients. AB - BACKGROUND: Although a growing number of primary total hip arthroplasties (THAs) are being performed on solid-organ transplant (SOT) recipients, long-term patient and implant survivorships have not been well studied in contemporary transplant and arthroplasty practices. METHODS: A total of 136 THAs (105 patients) with prior SOT were retrospectively reviewed from 2000 to 2013 at mean clinical follow up of 5 years. The mean age was 59 years, with 39% being females. The most common SOT was renal (56%), followed by liver (24%). RESULTS: Patient mortality was 3.8% and 13.3% at 2 and 5 years, respectively. There were 9 revisions (6.6%), including 5 (4%) for deep periprosthetic infection. Implant survivorship free of any revision was 95% and 94% at 2 and 5 years, respectively. Transplant type or surgical indication did not significantly impact patient or implant survivorship. CONCLUSION: Compared with the general population, SOT patients undergoing THA have slightly higher mortality rates at 5 years. Implant survivorship free of revision was slightly lower than the general population, primarily due to an increased risk of periprosthetic joint infection. PMID- 27215192 TI - Metal on Metal or Ceramic on Ceramic for Cementless Total Hip Arthroplasty: A Meta-Analysis. AB - BACKGROUND: Hard bearings, metal on metal (MOM) and ceramic on ceramic (COC), have been developed to overcome polyethylene wear-related osteolysis, but comparisons between these 2 hard bearings are limited. We performed a meta analysis to determine revision rates for (1) any reason, (2) aseptic loosening, (3) periprosthetic joint infection (PJI), and (4) recurrent dislocation between MOM and COC bearings in cementless total hip arthroplasty. METHODS: This analysis included 3 studies comparing COC and MOM bearings and 56 studies reporting outcomes of MOM or COC bearings. We conducted a comparison meta-analysis (with a fixed-effects model) on the 3 comparative studies and a proportional meta analysis on the data from the 59 articles to determine a consensus. RESULTS: In the comparison meta-analysis, MOM showed higher revision rate than COC for any reason (odds ratio = 2.39, P = .046) and PJI (odds ratio = 6.21, P = .015). In the proportion meta-analysis, the MOM group showed significantly higher revision rate than COC group for any reason, aseptic loosening, and PJI. CONCLUSION: MOM bearings were associated with a higher risk of revision for any reason and PJI than COC bearings after cementless total hip arthroplasty. PMID- 27215194 TI - Protein labelling. PMID- 27215193 TI - Purkinje cell injury, structural plasticity and fusion in patients with Friedreich's ataxia. AB - Purkinje cell pathology is a common finding in a range of inherited and acquired cerebellar disorders, with the degree of Purkinje cell injury dependent on the underlying aetiology. Purkinje cells have an unparalleled resistance to insult and display unique regenerative capabilities within the central nervous system. Their response to cell injury is not typical of most neurons and likely represents both degenerative, compensatory and regenerative mechanisms. Here we present a pathological study showing novel and fundamental insights into Purkinje cell injury, remodelling and repair in Friedreich's ataxia; the most common inherited ataxia. Analysing post-mortem cerebellum tissue from patients who had Friedreich's ataxia, we provide evidence of significant injury to the Purkinje cell axonal compartment with relative preservation of both the perikaryon and its extensive dendritic arborisation. Axonal remodelling of Purkinje cells was clearly elevated in the disease. For the first time in a genetic condition, we have also shown a disease-related increase in the frequency of Purkinje cell fusion and heterokaryon formation in Friedreich's ataxia cases; with evidence that underlying levels of cerebellar inflammation influence heterokaryon formation. Our results together further demonstrate the Purkinje cell's unique plasticity and regenerative potential. Elucidating the biological mechanisms behind these phenomena could have significant clinical implications for manipulating neuronal repair in response to neurological injury. PMID- 27215196 TI - A de novo transcriptome analysis shows that modulation of the JAK-STAT signaling pathway by salmonid alphavirus subtype 3 favors virus replication in macrophage/dendritic-like TO-cells. AB - BACKGROUND: The Janus kinase (Jak) and signaling transducer activator of transcription (Stat) pathway mediates the signaling of genes required for cellular development and homeostasis. To elucidate the effect of type I IFN on the Jak/stat pathway in salmonid alphavirus subtype 3 (SAV3) infected macrophage/dendritic like TO-cells derived from Atlantic salmon (Salmo salar L) headkidney leukocytes, we used a differential transcriptome analysis by RNA-seq and the Kyoto encyclopedia of genes and genomes (KEGGs) pathway analysis to generate a repertoire of de novo assembled genes from type I IFN treated and non treated TO-cells infected with SAV3. RESULTS: Concurrent SAV3 infection with type I IFN treatment of TO-cells suppressed SAV3 structural protein (SP) expression by 2log10 at 2 days post infection compared to SAV3 infection without IFN treatment which paved way to evaluating the impact of type I IFN on expression of Jak/stat pathway genes in SAV3 infected TO-cells. In the absence of type I IFN treatment, SAV3 downregulated several Jak/stat pathway genes that included type I and II receptor genes, Jak2, tyrosine kinase 2 (Tyk2), Stat3 and Stat5 pointing to possible failure to activate the Jak/stat signaling pathway and inhibition of signal transducers caused by SAV3 infection. Although the suppressor of cytokine signaling (SOCS) genes 1 and 3 were upregulated in the IFN treated cells, only SOCS3 was downregulated in the SAV3 infected cells which points to inhibition of SOCS3 by SAV3 infection in TO-cells. CONCLUSION: Data presented in this study shows that SAV3 infection downregulates several genes of the Jak/stat pathway, which could be an immune evasion strategy, used to block the transcription of antiviral genes that would interfere with SAV3 replication in TO-cells. Overall, we have shown that combining de novo assembly with pathway based transcriptome analyses provides a contextual approach to understanding the molecular networks of genes that form the Jak/stat pathway in TO-cells infected by SAV3. PMID- 27215195 TI - Mesenchymal stem cells are sensitive to bleomycin treatment. AB - Mesenchymal stem cells (MSCs) have been shown to attenuate pulmonary damage induced by bleomycin-based anticancer treatments, but the influence of bleomycin on the stem cells themselves remains largely unknown. Here, we demonstrate that human bone marrow-derived MSCs are relatively sensitive to bleomycin exposure compared to adult fibroblasts. MSCs revealed increased levels of apoptosis after bleomycin treatment, while cellular morphology, stem cell surface marker expression and the ability for adhesion and migration remained unchanged. Bleomycin treatment also resulted in a reduced adipogenic differentiation potential of these stem cells. MSCs were found to efficiently repair DNA double strand breaks induced by bleomycin, mostly through non-homologous end joining repair. Low mRNA and protein expression levels of the inactivating enzyme bleomycin hydrolase were detected in MSCs that may contribute to the observed bleomycin-sensitive phenotype of these cells. The sensitivity of MSCs against bleomycin needs to be taken into consideration for ongoing and future treatment protocols investigating these stem cells as a potential treatment option for bleomycin-induced pulmonary damage in the clinic. PMID- 27215198 TI - Crystal Structure of Hypothetical Fructose-Specific EIIB from Escherichia coli. AB - We have solved the crystal structure of a predicted fructose-specific enzyme IIB(fruc) from Escherichia coli (EcEIIB(fruc)) involved in the phosphoenolpyruvate-carbohydrate phosphotransferase system transferring carbohydrates across the cytoplasmic membrane. EcEIIB(fruc) belongs to a sequence family with more than 5,000 sequence homologues with 25-99% amino-acid sequence identity. It reveals a conventional Rossmann-like alpha-beta-alpha sandwich fold with a unique beta-sheet topology. Its C-terminus is longer than its closest relatives and forms an additional beta-strand whereas the shorter C-terminus is random coil in the relatives. Interestingly, its core structure is similar to that of enzyme IIB(cellobiose) from E. coli (EcIIB(cel)) transferring a phosphate moiety. In the active site of the closest EcEIIB(fruc) homologues, a unique motif CXXGXAHT comprising a P-loop like architecture including a histidine residue is found. The conserved cysteine on this loop may be deprotonated to act as a nucleophile similar to that of EcIIB(cel). The conserved histidine residue is presumed to bind the negatively charged phosphate. Therefore, we propose that the catalytic mechanism of EcEIIB(fruc) is similar to that of EcIIB(cel) transferring phosphoryl moiety to a specific carbohydrate. PMID- 27215199 TI - A unique annulation of 7-azaindoles with alkenyl esters to produce pi-conjugated 7-azaindole derivatives. AB - Rhodium(iii)-catalyzed N-directed ortho C-H activation and subsequent roll-over C H activation represents an important strategy to synthesize fused polycyclic compounds. Herein, the novel methodology broadens the scope of the coupling partner to alkenes, which working smoothly with 7-azaindoles has been proven to be an efficient and atom-economical strategy to access complex pi-conjugated 7 azaindole derivatives. PMID- 27215197 TI - RNA-Seq Analysis of the Arabidopsis Transcriptome in Pluripotent Calli. AB - Plant cells have a remarkable ability to induce pluripotent cell masses and regenerate whole plant organs under the appropriate culture conditions. Although the in vitro regeneration system is widely applied to manipulate agronomic traits, an understanding of the molecular mechanisms underlying callus formation is starting to emerge. Here, we performed genome-wide transcriptome profiling of wild-type leaves and leaf explant-derived calli for comparison and identified 10,405 differentially expressed genes (> two-fold change). In addition to the well-defined signaling pathways involved in callus formation, we uncovered additional biological processes that may contribute to robust cellular dedifferentiation. Particular emphasis is placed on molecular components involved in leaf development, circadian clock, stress and hormone signaling, carbohydrate metabolism, and chromatin organization. Genetic and pharmacological analyses further supported that homeostasis of clock activity and stress signaling is crucial for proper callus induction. In addition, gibberellic acid (GA) and brassinosteroid (BR) signaling also participates in intricate cellular reprogramming. Collectively, our findings indicate that multiple signaling pathways are intertwined to allow reversible transition of cellular differentiation and dedifferentiation. PMID- 27215201 TI - Comparison of outcomes in patients with methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia who are treated with beta-lactam vs vancomycin empiric therapy: a retrospective cohort study. AB - BACKGROUND: Prior studies suggested that vancomycin may be inferior to beta lactams for the empiric treatment of methicillin-susceptible S. aureus (MSSA) bacteremia. We assessed whether empiric therapy with beta-lactams compared to vancomycin was associated with differences in clinical outcomes in patients with MSSA bacteremia. METHODS: We conducted a retrospective cohort study of adult inpatients with their first episode of MSSA bacteremia at two tertiary care hospitals in Vancouver, Canada, between 2007 and 2014. Exposure was either empiric beta-lactam or vancomycin therapy. All patients received definitive treatment with cloxacillin or cefazolin. The primary outcome was 28-day mortality. Secondary outcomes were 90-day mortality, recurrent infection at 6 months, duration of bacteremia and hospital length-of-stay. Outcomes were adjusted using multivariable logistic regression. RESULTS: Of 814 patients identified, 400 met inclusion criteria (beta-lactam = 200, vancomycin = 200). Overall 28-day mortality was 8.5 % (n=34). There were more cases of infective endocarditis in the beta-lactam than in the vancomycin group [45 (22.5 %) vs 23 (11.5 %), p < 0.01]. Adjusted mortality at 28 days was similar between the two groups (OR: 1.14; 95 % CI: 0.49-2.64). No differences in secondary outcomes were observed. Transition to cloxacillin or cefazolin occurred within a median of 67.8 h in the vancomycin group. CONCLUSIONS: Empiric therapy with beta-lactams was not associated with differences in all-cause mortality, recurrent infection, microbiological cure or hospital length-of-stay compared to vancomycin. Vancomycin monotherapy may be appropriate for the empiric treatment of MSSA bacteremia if definitive therapy with cloxacillin or cefazolin can be initiated within 3 days. PMID- 27215200 TI - Therapeutic Potential of Polyphenols from Epilobium Angustifolium (Fireweed). AB - Epilobium angustifolium is a medicinal plant used around the world in traditional medicine for the treatment of many disorders and ailments. Experimental studies have demonstrated that Epilobium extracts possess a broad range of pharmacological and therapeutic effects, including antioxidant, anti proliferative, anti-inflammatory, antibacterial, and anti-aging properties. Flavonoids and ellagitannins, such as oenothein B, are among the compounds considered to be the primary biologically active components in Epilobium extracts. In this review, we focus on the biological properties and the potential clinical usefulness of oenothein B, flavonoids, and other polyphenols derived from E. angustifolium. Understanding the biochemical properties and therapeutic effects of polyphenols present in E. angustifolium extracts will benefit further development of therapeutic treatments from this plant. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27215202 TI - Progranulin Protects Hippocampal Neurogenesis via Suppression of Neuroinflammatory Responses Under Acute Immune Stress. AB - Immune stress is well known to suppress adult neurogenesis in the hippocampus. We have demonstrated that progranulin (PGRN) has a mitogenic effect on neurogenesis under several experimental conditions. We have also shown that PGRN suppresses excessive neuroinflammatory responses after traumatic brain injury. However, the role of PGRN in modulating neurogenesis under acute immune stress is yet to be elucidated. In the present study, we evaluated the involvement of PGRN in neurogenesis and inflammatory responses in the hippocampus using a lipopolysaccharide (LPS)-induced immune stress model. Treatment of mice with LPS significantly increased the expression of PGRN in activated microglia and decreased neurogenesis in the dentate gyrus of the hippocampus. PGRN deficiency increased CD68-immunoreactive area and exacerbated suppression of neurogenesis following LPS treatment. The expression levels of lysosomal genes including lysozyme M, macrophage expressed gene 1, and cathepsin Z were higher in PGRN deficient than in wild-type mice, while PGRN deficiency decreased mammalian target of rapamycin (mTOR) mRNA levels, suggesting that PGRN suppresses excessive lysosomal biogenesis by promoting mTOR signaling. LPS treatment also increased the expression of proinflammatory genes such as interleukin (IL)-1beta, tumor necrosis factor-alpha, and microsomal prostaglandin E synthase-1 (mPGES-1) in the hippocampus, and PGRN deficiency further enhanced gene expression of IL-6 and mPGES-1. These results suggest that PGRN plays a protecting role in hippocampal neurogenesis at least partially by attenuating neuroinflammatory responses during LPS-induced acute immune stress. PMID- 27215203 TI - Cyanidin-3-rutinoside attenuates methylglyoxal-induced protein glycation and DNA damage via carbonyl trapping ability and scavenging reactive oxygen species. AB - BACKGROUND: Advanced glycation end-products (AGEs) play a significant role in the development and progression of vascular complication in diabetes. Anthocyanin has been recently reported to possess antiglycating activity. This study aimed to determine whether a naturally occurring anthocyanin, cyanidin-3-rutinoside (C3R) inhibits methylglyoxal (MG) induced protein glycation and oxidative protein and DNA damage. METHODS: C3R (0.125-1 mM) was incubated with bovine serum albumin and MG (1 mM) for 2 weeks. The formation of fluorescent AGEs was measured by using spectrofluorometer and thiol group content were used to detect protein oxidative damage. Gel electrophoresis was used to determine whether C3R (0.125-1 mM) reduced DNA strand breakage in a glycation model comprising lysine, MG and/or Cu(2+). The generation of superoxide anions and hydroxyl radicals were detected by the cytochrome c reduction assay and the thiobarbituric acid reactive substances assay. MG-trapping capacity was assessed by high performance liquid chromatography (HPLC). RESULTS: C3R (0.25-1 mM) reduced the formation of fluorescent AGEs and depleted protein thiol groups in bovine serum albumin mediated by MG. At 1 mM C3R inhibited oxidative DNA damage in the glycation model (p < 0.05) and at 0.5-1 mM prevented Cu(2+) induced DNA strand breakage in the presence of lysine and MG. The findings showed that C3R reduced the formation of superoxide anion and hydroxyl radicals during the glycation reaction of MG with lysine. C3R directly trapped MG in a concentration and time dependent manner (both p < 0.001). CONCLUSIONS: These findings suggest that C3R protects against MG-induced protein glycation and oxidative damage to protein and DNA by scavenging free radicals and trapping MG. PMID- 27215204 TI - Spondyloarthropathies: IL-6 blockade in psoriatic arthritis - a new therapeutic option? PMID- 27215205 TI - Osteoarthritis: Yet another death knell for paracetamol in OA. PMID- 27215206 TI - Purification and characterization of thermostable serine proteases encoded by the genes ttha0099 and ttha01320 from Thermus thermophilus HB8. AB - As an important class of proteases, serine proteases are required to show high activity under diverse conditions, especially at high temperatures. In the current study, two serine proteases SP348 and SP404 were analyzed by different bioinformatics tools. Both proteins are comprised of a trypsin domain and a PDZ domain, and belong to the trypsin family of proteases. The proteins were successfully expressed with Trx-tags as soluble proteins in the specialized Escherichia coli Rosetta-gami B(DE3)pLysS strain. A simple three-step purification protocol involving heat treatment, Ni-NTA purification and gel filtration was adopted to purify SP404. The molecular weight of recombinant SP404 was about 64 kDa. According to the circular dichroism spectroscopy analysis, SP404 is thermostable at 70 degrees C with alpha-helix, beta-sheet and random coil contents of about 8, 22 and 70 %, respectively. Our findings may broaden the range of microorganism-derived proteases and have a wide potential for industrial and fundamental studies. PMID- 27215207 TI - Identification and characterization of yeasts isolated from sedimentary rocks of Union Glacier at the Antarctica. AB - The study of the yeasts that inhabit cold environments, such as Antarctica, is an active field of investigation oriented toward understanding their ecological roles in these ecosystems. In a great part, the interest in cold-adapted yeasts is due to several industrial and biotechnological applications that have been described for them. The aim of this work was to isolate and identify yeasts from sedimentary rock samples collected at the Union Glacier, Antarctica. Furthermore, the yeasts were physiologically characterized, including the production of metabolites of biotechnological interest. The yeasts isolated that were identified at the molecular level belonged to genera Collophora (1 isolate), Cryptococcus (2 isolates), Sporidiobolus (4 isolates), Sporobolomyces (1 isolate) and Torrubiella (2 isolates). The majority of yeasts were basidiomycetous and psychrotolerant. By cross-test assays for anti-yeast activity, it was determined that Collophora sp., Sporidiobolus salmonicolor, and Sporobolomyces roseus secreted a protein factor that kills Sporidiobolus metaroseus. The colored yeasts Sp. salmonicolor, Sp. metaroseus and Collophora sp. produced several carotenoid pigments that were identified as 2,3 dihydroxy-gamma-carotene, -carotene, 4 ketotorulene, torulene beta-cryptoxanthin and spirilloxanthin. Concerning analysis of mycosporines, these metabolites were only found in the yeasts Torrubiella sp. and Cryptococcus sp. T11-10-1. Furthermore, the yeasts were evaluated for the production of extracellular hydrolytic activities. Of the twelve activities analyzed, alkaline phosphatase, invertase, gelatinase, cellulase, amylase, and protease enzyme activities were detected. The yeasts Cryptococcus sp. T11-10-1 and Sporidiobolus metaroseus showed the highest number of different enzyme activities. PMID- 27215209 TI - [Big Biology : Supersizing Wissenschaft zu Beginn des 21. Jahrhunderts]. PMID- 27215208 TI - "A year-long, fortnightly, observational survey in three European countries of patients with respiratory allergies induced by house dust mites: Methodology, demographics and clinical characteristics". AB - BACKGROUND: House dust mite (HDM) allergens constitute the leading trigger for the symptoms of persistent respiratory allergies (such as allergic rhinitis and asthma). However, the fluctuating, pernicious nature of the symptoms has given rise to a perception that HDM-induced respiratory allergy is not a "real" disease. METHODS: In order to assess the self-reported disease profile and behaviour of adult patients with a self-reported history of severe, poorly controlled, physician-diagnosed HDM respiratory allergy, we performed an observational, international, multicentre survey in three European countries (France, Italy and Spain). Participants were included in the survey if they passed a short Internet-based screening questionnaire. Following completion of a detailed post-inclusion questionnaire, 28 fortnightly telephone interviews were used to gather extensive data on the participants' symptom prevalence and intensity, medical consultations, disease burden, quality of life, and medication use from late May 2012 to early July 2013. RESULTS: Twenty-two thousand nine hundred ninety five individuals completed the Internet screening questionnaire and 339 respondents (67 % female) met all the inclusion criteria. 313 of the 339 (92 %) completed the post-inclusion questionnaire (n = 114 in Italy, 92 in France and 107 in Spain). The median time since the first symptoms of HDM allergy was over 13 years in all three countries. The response rate for the fortnightly interviews averaged 75 % (range: 29 to 97 %). The reported fortnightly prevalence of nasal and ocular symptoms peaked in the autumn (September to November) and spring (March to May). These peaks in prevalence coincided with increased reports of symptom worsening and higher physician consultation rates. In participants not allergic to pollen, the autumn and spring peaks were accompanied by a third peak in late December 2012. Very few participants reported that their symptoms had never improved (4 %) or never worsened (11 %) during the survey period. CONCLUSIONS: In a survey in France, Italy and Spain, patients with severe HDM induced respiratory allergies experienced a complex set of changing, troublesome symptoms throughout the year, with peaks in spring, autumn and (to a lesser extent) mid-winter. PMID- 27215210 TI - Characterization and differential expression analysis of Toxocara canis aquaporin 1 gene. AB - Toxocara canis is an intestinal nematode of canids with a worldwide distribution, causing an important but neglected parasitic zoonosis in humans. Aquaporins (AQP) are a family of water channel proteins, which function as membrane channels to regulate water homeostasis. In this study, the coding sequence of aquaporin-1 gene of T. canis (Tc-aqp-1) was cloned and characterized. The obtained Tc-aqp-1 coding sequence was 933 bp in length, which predicted to encode 311 amino acids. Two conserved asparagine-proline-alanine (NPA) motifs were identified in the multiple sequence alignments. Phylogenetic analysis revealed the closest relationship between T. canis and Opisthorchis viverrini based on aquaporin-1 amino acid sequence. A structure was predicted with ligand binding sites predicted at H93, N95, N226, L94, I79, and I210 and with active sites predicted at I256 and G207. Gene Ontology (GO) annotations predicted its cellular component term of integral component of plasma membrane (GO: 0005887), molecular function term of channel activity (GO: 0015250), and biological process term of water transport (GO: 0006833). Tissue expression analysis revealed that the Tc-aqp-1 was highly expressed in the intestine of adult male. The findings of the present study provide the basis for further functional studies of T. canis aquaporin-1. PMID- 27215211 TI - Mechanically-enhanced three-dimensional scaffold with anisotropic morphology for tendon regeneration. AB - Tissue engineering has showed promising results in restoring diseased tendon tissue functions. Herein, a hybrid three-dimensional (3D) porous scaffold comprising an outer portion rolled from an electrohydrodynamic jet printed poly(E caprolactone) (PCL) fiber mesh, and an inner portion fabricated from uniaxial stretching of a heat-sealed PCL tube, was developed for tendon tissue engineering (TE) application. The outer portion included three layers of micrometer-scale fibrous bundles (fiber diameter: ~25 um), with an interconnected spacing and geometric anisotropy along the scaffold length. The inner portion showed orientated micro-ridges/grooves in a parallel direction to that of the outer portion. Owning to the addition of the inner portion, the as-fabricated scaffold exhibited comparable mechanical properties to those of the human patellar tendon in terms of Young's modulus (~227 MPa) and ultimate tensile stress (~50 MPa). Compared to the rolled electrospun fibers, human tenocytes cultured in the tendon scaffolds showed increased cellular metabolism. Furthermore, the 3D tendon scaffold resulted in up-regulated cell alignment, cell elongation and formation of collagen type I. These results demonstrated the potential of mechanically enhanced 3D fibrous scaffold for applications in tendon TE, with desired cell alignment and functional differentiation. PMID- 27215213 TI - The Mesenteric Approach in Pancreatoduodenectomy. AB - Isolated pancreatoduodenectomy (PD) is an ideal surgery for pancreatic head cancer. In cancer surgery, 'isolated' means en bloc resection using a non-touch isolation technique. I have been developing isolated PD for pancreatic cancer since 1981. In this operation, the most important and first step is to use a mesenteric approach instead of Kocher's maneuver. The precise surgical techniques of the mesenteric approach are introduced in this paper. PMID- 27215212 TI - Association of common genetic variation in the protein C pathway genes with clinical outcomes in acute respiratory distress syndrome. AB - BACKGROUND: Altered plasma levels of protein C, thrombomodulin, and the endothelial protein C receptor are associated with poor clinical outcomes in patients with acute respiratory distress syndrome (ARDS). We hypothesized that common variants in these genes would be associated with mortality as well as ventilator-free and organ failure-free days in patients with ARDS. METHODS: We genotyped linkage disequilibrium-based tag single-nucleotide polymorphisms in the ProteinC, Thrombomodulin and Endothelial Protein C Reptor Genes among 320 self identified white patients of European ancestry from the ARDS Network Fluid and Catheter Treatment Trial. We then tested their association with mortality as well as ventilator-free and organ-failure free days. RESULTS: The GG genotype of rs1042580 (p = 0.02) and CC genotype of rs3716123 (p = 0.002), both in the thrombomodulin gene, and GC/CC genotypes of rs9574 (p = 0.04) in the endothelial protein C receptor gene were independently associated with increased mortality. An additive effect on mortality (p < 0.001), ventilator-free days (p = 0.01), and organ failure-free days was observed with combinations of these high-risk genotypes. This association was independent of age, severity of illness, presence or absence of sepsis, and treatment allocation. CONCLUSIONS: Genetic variants in thrombomodulin and endothelial protein C receptor genes are additively associated with mortality in ARDS. These findings suggest that genetic differences may be at least partially responsible for the observed associations between dysregulated coagulation and poor outcomes in ARDS. PMID- 27215214 TI - Use of big data in the surveillance of veterinary diseases: early detection of tick paralysis in companion animals. AB - BACKGROUND: Tick paralysis, resultant from envenomation by the scrub-tick Ixodes holocyclus, is a serious threat for small companion animals in the eastern coast of Australia. We hypothesise that surveillance systems that are built on Internet search queries may provide a more timely indication of high-risk periods more effectively than current approaches. METHODS: Monthly tick paralysis notifications in dogs and cats across Australia and the states of Queensland (QLD) and New South Wales (NSW) were retrieved from Disease WatchDog surveillance system for the period 2011-2013. Internet search terms related to tick paralysis in small companion animals were identified using Google Correlate, and corresponding search frequency metrics were downloaded from Google Trends. Spearman's rank correlations and time series cross correlations were performed to assess which Google search terms lead or are synchronous with tick paralysis notifications. RESULTS: Metrics data were available for 24 relevant search terms at national level, 16 for QLD and 18 for NSW, and they were all significantly correlated with tick paralysis notifications (P < 0.05). Among those terms, 70.8, 56.3 and 50 % showed strong Spearman's correlations, at national level, for QLD, and for NSW respectively, and cross correlation analyses identified searches which lead notifications at national or state levels. CONCLUSION: This study demonstrates that Internet search metrics can be used to monitor the occurrence of tick paralysis in companion animals, which would facilitate early detection of high-risk periods for tick paralysis cases. This study constitutes the first application of the rapidly emerging field of Internet-based surveillance to veterinary science. PMID- 27215215 TI - Reversal of Newer Direct Oral Anticoagulant Drugs (DOACs). AB - Anticoagulation therapy is indicated for management of various clinical conditions to prevent adverse events and introduction of direct oral anticoagulants (DOACs) has ushered in a new era in anticoagulation therapy. Major advantages of DOACS include fewer drug interactions and that they do not need periodic monitoring. Several patients who were not on anticoagulation before due to older age, polypharmacy/drug interaction concerns, and logistics of periodic monitoring are now on anticoagulation with DOACs. Despite their many advantages, a challenge while prescribing DOACs is very limited availability of specific reversal agents and lack of understanding or guidance about the treatment strategy in case of major life threatening bleeding or need for urgent surgery. So far only one reversal agent has been approved by the Food and Drug Administration (FDA), idarucizumab for one of the DOACs i.e., dabigatran. Several other reversal agents are under final phases of development such as andexanet alfa and PER977 (ciraparantag) and will help in developing specific strategies for reversal of these agents. In this article, we review current strategies to manage bleeding with DOACs and provide guidance to clinicians of inhibiting LF activity in vitro and in cells, as well as in animal models of anthrax infection. PMID- 27215216 TI - Reliable transformation system for Microbotryum lychnidis-dioicae informed by genome and transcriptome project. AB - Microbotryum lychnidis-dioicae is a member of a species complex infecting host plants in the Caryophyllaceae. It is used as a model system in many areas of research, but attempts to make this organism tractable for reverse genetic approaches have not been fruitful. Here, we exploited the recently obtained genome sequence and transcriptome analysis to inform our design of constructs for use in Agrobacterium-mediated transformation techniques currently available for other fungi. Reproducible transformation was demonstrated at the genomic, transcriptional and functional levels. Moreover, these initial proof-of-principle experiments provide evidence that supports the findings from initial global transcriptome analysis regarding expression from the respective promoters under different growth conditions of the fungus. The technique thus provides for the first time the ability to stably introduce transgenes and over-express target M. lychnidis-dioicae genes. PMID- 27215217 TI - Genome analysis of a clinical isolate of Shewanella sp. uncovered an active hybrid integrative and conjugative element carrying an integron platform inserted in a novel genomic locus. AB - Shewanella spp. are currently considered to be emerging pathogens that can code for a blaOXA carbapenemase in their chromosome. Complete genome analysis of the clinical isolate Shewanella sp. Sh95 revealed that this strain is a novel species, which shares a lineage with marine isolates. Characterization of its resistome showed that it codes for genes drfA15, qacH and blaOXA-48. We propose that Shewanella sp. Sh95 acts as reservoir of blaOXA-48. Moreover, analysis of mobilome showed that it contains a novel integrative and conjugative element (ICE), named ICESh95. Comparative analysis between the close relatives ICESpuPO1 from Shewanella sp. W3-18-1 and ICE SXTMO10 from Vibrio cholerae showed that ICESh95 encompassed two new regions, a type III restriction modification system and a multidrug resistance integron. The integron platform contained a novel arrangement formed by gene cassettes drfA15 and qacH, and a class C-attC group II intron. Furthermore, insertion of ICESh95 occurred at a unique target site, which correlated with the presence of a different xis/int module. Mobility of ICESh95 was assessed and demonstrated its ability to self-transfer with high efficiency to different species of bacteria. Our results show that ICESh95 is a self transmissible, mobile element, which can contribute to the dissemination of antimicrobial resistance; this is clearly a threat when natural bacteria from water ecosystems, such as Shewanella, act as vectors in its propagation. PMID- 27215218 TI - Tocilizumab in Autoimmune Encephalitis Refractory to Rituximab: An Institutional Cohort Study. AB - A considerable portion of autoimmune encephalitis (AE) does not respond to conventional immunotherapies and subsequently has poor outcomes. We aimed to determine the efficacy of tocilizumab, an anti-interleukin-6 antibody, in rituximab-refractory AE compared with other treatment options. From an institutional cohort of AE, 91 patients with inadequate clinical response to first-line immunotherapy and following rituximab were retrospectively reviewed. Patients were grouped according to their further immunotherapy strategies. Thirty (33.0 %) patients were included in the tocilizumab group, 31 (34.0 %) in the additional rituximab group, and 30 (33.0 %) in the observation group. Outcomes were defined as the favorable modified Rankin Scale scores (<=2) at 1 and 2 months from the initiation of each treatment strategy and at the last follow-up. Favorable clinical response (improvement of the modified Rankin Scale scores by >= 2 points or achievement of the mRS scores <= 2) at the last follow-up was also analyzed. The tocilizumab group showed more frequent favorable mRS scores at 2 months from treatment initiation and at the last follow-up compared with those at the relevant time points of the remaining groups. The majority (89.5 %) of the patients with clinical improvement at 1 month from tocilizumab treatment maintained a long-term favorable clinical response. No serious adverse effects of rituximab or tocilizumab were reported. Therefore, we suggest that tocilizumab might be a good treatment strategy for treating AE refractory to conventional immunotherapies and rituximab. The tocilizumab-mediated clinical improvement manifests as early at 1 month after treatment initiation. PMID- 27215219 TI - B-Cell Depletion with CD20 Antibodies as New Approach in the Treatment of Inflammatory and Immunological Events Associated with Spinal Cord Injury. AB - Spinal cord injury (SCI) is a highly debilitating pathology that has irreversible impacts and results in functional loss. We evaluated the anti-inflammatory and immunologic role of antibody-mediated depletion of B cells through the glycoengineered anti-muCD20 antibody (18B12) in an experimental model of spinal cord compression, in vivo and ex vivo. Intraperitoneal 18B12 was administered at a dose of 30 mg/kg, 1 h and 6 h after SCI, and mice were sacrificed 24 h after trauma. We demonstrated, in vivo, that 18B12 slowed severe hindlimb motor dysfunction (Basso Mouse Scale score) and neuronal death by histological evaluation in SCI mice, as well as decreased expression of nuclear factor-kB, inducible nitric oxide synthase, cytokines, and glial fibrillary acidic protein. Also, 18B12 reduced expression of microglia, just as it lowered the expression of B and T lymphocytes. Moreover, in spinal cord organotypic cultures, pretreatment with 18B12 significantly reduced nitric oxide expression and protected cells from cell death [3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay]. In this study, we showed that 18B12 treatment reduces the development of inflammation and tissue injury by alteration of the immune system associated with SCI. This study increases the current knowledge that B-cell depletion is able to exert immunomodulating actions in damaged spinal cords. PMID- 27215220 TI - Role of the Egami score to predict immunoglobulin resistance in Kawasaki disease among a Western Mediterranean population. AB - Kawasaki disease is an acute self-limited systemic vasculitis common in childhood. Intravenous immunoglobulin (IVIG) is an effective treatment, and it reduces the incidence of cardiac complications. Egami score has been validated to identify IVIG non-responder patients in Japanese population, and it has shown high sensitivity and specificity to identify these non-responder patients. Although its effectiveness in Japan, Egami score has shown to be ineffective in non-Japanese populations. The aim of this study was to apply the Egami score in a Western Mediterranean population in Catalonia (Spain). Observational population based study that includes patients from all Pediatric Units in 33 Catalan hospitals, both public and private management, between January 2004 and March 2014. Sensitivity and specificity for the Egami score was calculated, and a logistic regression analysis of predictors of overall response to IVIG was also developed. Predicting IVIG resistance with a cutoff for Egami score >=3 obtained 26 % sensitivity and 82 % specificity. Negative predictive value was 85 % and positive predictive value 22 %. This low sensitivity implies that three out of four non-responders will not be identified by the Egami score. Besides, logistic regression models did not found significance for the use of the Egami score to predict IVIG resistance in Catalan population although having an area under the ROC curve of 0.618 (IC 95 % 0.538-0.698, p < 0.001). Although regression models found an area under the ROC curve >0.5 to predict IVIG resistance, the low sensitivity excludes the Egami score as a useful tool to predict IVIG resistance in Catalan population. PMID- 27215221 TI - Facioscapulohumeral Dystrophy. AB - Facioscapulohumeral muscular dystrophy (FSHD) is a clinically recognizable and relatively common muscular dystrophy. It is inherited mostly as an autosomal dominant disease or in a minority of cases, in a digenic pattern. The disease manifestation is variable and most likely dependent on genetic and epigenetic factors. We review the history, epidemiology, clinical presentation, and genetics of the disease, present the recently elucidated molecular pathogenesis, discuss the pathology and the possible consequence of the inflammation seen in the muscle biopsies, and consider future treatments. PMID- 27215222 TI - Vascular Structures of the Right Colon: Incidence and Variations with Their Clinical Implications. AB - BACKGROUND AND AIMS: There is a demand for a better understanding of the vascular structures around the right colonic area. Although right hemicolectomy with the recent concept of meticulous lymph node dissection is a standardized procedure for malignant diseases among most surgeons, variations in the actual anatomical vascular are not well understood. The aim of the present review was to present a detailed overview of the vascular variation pertinent to the surgery for right colon cancer. MATERIALS AND METHODS: Medical literature was searched for the articles highlighting the vascular variation relevant to the right colon cancer surgery. RESULTS: Recently, there have been many detailed studies on applied surgical vascular anatomy based on cadaveric dissections, as well as radiological and intraoperative examinations to overcome misconceptions concerning the arterial supply and venous drainage to the right colon. Ileocolic artery and middle colic artery are consistently present in all patients arising from the superior mesenteric artery. Even though the ileocolic artery passes posterior to the superior mesenteric vein in most of the cases, in some cases courses anterior to the superior mesenteric artery. The right colic artery is inconsistently present ranging from 63% to 10% across different studies. Ileocolic vein and middle colic vein is always present, while the right colic vein is absent in 50% of patients. The gastrocolic trunk of Henle is present in 46%-100% patients across many studies with variation in the tributaries ranging from bipodal to tetrapodal. Commonly, it is found that the right colonic veins, including the right colic vein, middle colic vein, and superior right colic vein, share the confluence forming the gastrocolic trunk of Henle in a highly variable frequency and different forms. CONCLUSION: Understanding the incidence and variations of the vascular anatomy of right side colon is of crucial importance. Failure to recognize the variation during surgery can result in troublesome bleeding especially during minimal invasive surgery. PMID- 27215223 TI - Is it getting better? An analytical method to test trends in health disparities, with tobacco use among sexual minority vs. heterosexual youth as an example. AB - BACKGROUND: Previous studies have documented higher health risks for lesbian, gay, and bisexual youth compared to heterosexual youth. However, none has reported whether the sexual orientation-based gaps have widened, narrowed, or remained unchanged over time. The purpose of this study was to develop a way to test differences in trends between sexual minority and heterosexual youth cohorts in population-based studies, with cigarette smoking as an exemplar. METHODS: We analysed the Minnesota Student Survey of 1998-2010, a repeated, cross-sectional census of adolescent health in grades 9 and 12. Our sample was students with recent sexual experience (Ns = 17,376-19,617). Sexual orientation was measured by gender of sexual partners in the past 12 months: students with only opposite gender partner(s) (OPPOS), students with both male and female partners (BOTH), students with only same-gender partner(s) (SAME). We used logistic regressions to examine trends in prevalence of past-month cigarette smoking from 1998 to 2010, separately for each orientation group. We then applied novel interaction analyses to test whether disparities in smoking prevalence between OPPOS and SAME/BOTH changed over time. RESULTS: Recent smoking rates decreased over time among all orientation groups. BOTH adolescents were more likely than OPPOS adolescents to report past 30-day smoking, but there were no significant differences between SAME adolescents and OPPOS adolescents. Year-by-orientation interactions indicated the gap between BOTH adolescents and OPPOS adolescents widened from 1998 to 2004, then persisted between 2004 and 2010. No significant interaction effects were observed between SAME adolescents and OPPOS adolescents. CONCLUSIONS: All orientation groups had decreasing trends in recent cigarette smoking; however, disparities in smoking rates remain between heterosexual adolescents and bisexual adolescents. These results provide a new method of not just documenting trends within minority groups, but examining whether health equity is improving for them compared to dominant groups. PMID- 27215224 TI - Living donor liver transplantation indicated for compensated liver cirrhosis with symptomatic gallstone diseases: report of two cases. AB - BACKGROUND: Surgical interventions for symptomatic gallstone disease could be dangerous in patients with severe comorbid conditions including liver cirrhosis. Here, we report our experience of living donor liver transplantation (LDLT) indicated for two patients with liver cirrhosis complicated with gallstone diseases. CASE 1: A 70-year-old woman with a history of hepatitis C virus infection was diagnosed as symptomatic choledocholithiasis. She had open cholecystectomy and choledochotomy with choledocholithotomy, which complicated with postoperative liver failure. Her Child-Pugh score increased from 7 to 12 points and Model for End-Stage Liver Disease (MELD) score from 11 to 36. She underwent LDLT, using the right lobe graft donated by her 47-year-old daughter. The post-transplant graft function was excellent, and the patient was discharged from the hospital on postoperative day 27. CASE 2: A 46-year-old man with a history of hepatitis B virus infection was diagnosed as cholecystitis. He had cholecystostomy without any complications and his Child-Pugh score remained to be 9 and MELD score 17, followed by LDLT using the right lobe graft donated by his 45-year-old wife. The post-transplant graft function was excellent, and the patient was discharged from the hospital on postoperative day 44. CONCLUSION: LDLT is one of treatment options when patients with Child-Pugh B cirrhosis accompanied with gallstone diseases, likely to be deteriorating their liver functions in the near future. PMID- 27215225 TI - Pulmonary artery reconstruction using autologous pulmonary vein for surgical treatment of locally advanced lung cancer: a case report. AB - BACKGROUND: Resection and reconstruction of the pulmonary artery during lobectomy is a safe and effective procedure for centrally located lung cancer. We usually choose a pericardial conduit to repair a large defect of the pulmonary artery. The use of an autologous pulmonary vein conduit for reconstruction was first described in 2009. CASE PRESENTATION: A 64-year-old woman with left upper lung adenocarcinoma with mediastinal and hilar adenopathy was referred to our hospital. Hilar nodes had extensively infiltrated the pulmonary artery. We interposed an autologous superior pulmonary vein between the cut ends of the pulmonary artery. She was discharged without any complication on the ninth postoperative day. CONCLUSIONS: A pulmonary vein conduit is a good option for reconstruction of the pulmonary artery. We report the successful use of an autologous pulmonary vein conduit. PMID- 27215226 TI - Bony mallet finger injuries: assessment of stability with extension stress testing. AB - Bony mallet injuries with a large dorsal fracture fragment may sublux giving a poor outcome. The hypothesis that was tested was that subluxation could be predicted by extension stress lateral radiographs. It was anticipated that the main distal fracture fragment would glide and be stable or pivot and be unstable. There were 32 bony mallet injuries with dorsal fracture fragments of >1/3 in 31 patients. There were three patterns shown on lateral extension stress radiographs: gliding, pivoting, and tilting - a combination of the former two. Defining stability as congruence or subluxation ?1 mm at final radiographs and instability as subluxation >1 mm, there was a very strong association with pivoting and subluxation, and gliding and congruence (p < 0.001). Tilting gave mixed results. There was significant difference in the size of the fracture fragment in stable (mean 49%) and unstable injuries (54%) (p = 0.044). Extension stress testing has a sensitivity of 89% and a specificity of 100%. Extension stress testing highlights that instability is not just a function of fracture fragment size and is a more reliable method of predicting subluxation than any previously described. LEVEL OF EVIDENCE: V. PMID- 27215227 TI - Postpartum depression can be prevented in low-income mothers using interpersonal psychotherapy. PMID- 27215228 TI - A qualitative investigation of eating difficulties in adolescents with chronic fatigue syndrome/myalgic encephalomyelitis. AB - BACKGROUND: An estimated 10% of children and adolescents with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) experience eating difficulties; however, little is known about why these difficulties develop, what the impact is or how to manage them. METHODS: Semi-structured interviews were conducted with adolescents (aged 12-17 years) attending a specialist service who have a primary diagnosis of CFS/ME and experience nausea, abdominal pain and/or eating difficulties. A total of 11 adolescents were interviewed (eight female, mean age: 15 years). Transcripts were analysed thematically using techniques of constant comparison which commenced soon after data collection and informed further interview protocols. RESULTS: Adolescents perceived their eating difficulties were caused by abdominal symptoms, being too fatigued to eat and changes to their senses of taste and smell. Some of the adolescents recognised how their eating difficulties were exacerbated and maintained by psychological factors of low mood and anxiety. The adolescents eating difficulties had a negative impact on their weight, fatigue, socialising and family life. They perceived helpful interventions to include modifying their diets, families adjusting and also medical interventions (e.g. medication). Adolescents identified that early education and support about diet and eating habits would have been helpful. CONCLUSIONS: If adolescents diagnosed with CFS/ME develop eating difficulties, this has a significant impact on their quality of life, illness and on their families. Not eating increases fatigue, low mood and anxiety which further exacerbates the eating difficulties. Clinicians should screen for eating difficulties in those with symptoms of nausea and abdominal pain, warn adolescents and their families of the risk of developing eating difficulties and provide interventions and support as early as possible. PMID- 27215229 TI - Effector Regulatory T Cells Reflect the Equilibrium between Antitumor Immunity and Autoimmunity in Adult T-cell Leukemia. AB - The regulatory T cells (Treg) with the most potent immunosuppressive activity are the effector Tregs (eTreg) with a CD45RA(-)Foxp3(++)CCR4(+) phenotype. Adult T cell leukemia (ATL) cells often share the Treg phenotype and also express CCR4. Although mogamulizumab, a monoclonal antibody to CCR4, shows marked antitumor effects against ATL and peripheral T-cell lymphoma, concerns have been raised that it may induce severe autoimmune immunopathology by depleting eTregs. Here, we present case reports for two patients with ATL who responded to mogamulizumab but developed a severe skin rash and autoimmune brainstem encephalitis. Deep sequencing of the T-cell receptor revealed that ATL cells and naturally occurring Tregs within the cell population with a Treg phenotype can be clearly distinguished according to CADM1 expression. The onset of skin rash and brainstem encephalitis was coincident with eTreg depletion from the peripheral blood, whereas ATL relapses were coincident with eTreg recovery. These results imply that eTreg numbers in the peripheral blood sensitively reflect the equilibrium between antitumor immunity and autoimmunity, and that mogamulizumab might suppress ATL until the eTreg population recovers. Close monitoring of eTreg numbers is crucial if we are to provide immunomodulatory treatments that target malignancy without severe adverse events. Cancer Immunol Res; 4(8); 644-9. (c)2016 AACR. PMID- 27215230 TI - Medical Tourism and Telemedicine: A New Frontier of an Old Business. AB - In October 2015, the "Chinese American Physicians E-Hospital" celebrated its "grand opening" online. All physicians affiliated with this E-Hospital are bilingual Chinese American physicians, who provide services ranging from initial teleconsulting to international transfer and treatment in the United States. Such telemedicine platform for medical tourism not only saves the patients from the hassles of identifying and connecting with an appropriate health service provider but also minimizes the language and cultural barriers. As a growing number of patients from middle- and low-income countries travel to the United States (US) for medical care, we face promising opportunities as well as mounting challenges. The Centers for Disease Control (CDC) in the US has guidance for Americans seeking care overseas, but is not available for international patients seeking care in US. This article opens a dialogue on the challenges associated with flourishing medical tourism and telemedicine, including quality assessment, risk communication, ethical guidelines, and legal concerns. PMID- 27215232 TI - Running on empty: a review of nutrition and physicians' well-being. AB - Resident and physician burnout is a complex issue. Adequate nutrition and hydration play important roles in the maintenance of health and well-being of all individuals. Given the high prevalence of burnout in physicians, we believe that in addition to issues related to heavy workload, structure and length of shifts, the current status of physicians' nutrition and hydration and their effects on their work performance and well-being should also be addressed. In this review, we summarise the current evidence on the potential effects of nutrition and hydration on physicians' occupational well-being and performance, identify gaps and discuss opportunities to address nutrition as one of the important means of improving physicians' well-being. PMID- 27215231 TI - Association of GSTT1 and GSTM1 gene polymorphisms with coronary artery disease in North Indian Punjabi population: a case-control study. AB - BACKGROUND: Glutathione S-transferases are metabolic enzymes which are responsible for detoxification of endogenous (products of oxidative stress) as well as exogenous (drugs, pesticides, herbicides, environmental pollutants and carcinogens) products. Dysfunctional detoxification enzymes are responsible for the production of oxidative stress; a major contributor to the development of coronary artery disease (CAD). OBJECTIVES: The present case-control study aimed to investigate the association of GSTT1 and GSTM1 gene polymorphisms with CAD. METHODS: In the present study, 200 patients diagnosed with CAD and 200 age, sex and population subgroup matched healthy controls were enrolled. The GSTT1 and GSTM1 gene polymorphisms were examined using multiplex PCR. RESULTS: The frequency of GSTT1 null genotype was significantly (p=0.038) lower in patients with CAD (6.00%) than in controls (12.50%). The GSTT1 null genotype showed protection against CAD (OR=0.45, 95% CI 0.22 to 0.92, p=0.028). The frequency of GSTM1 null genotype was significantly (p=0.004) higher in patients (31%) compared with controls (18%). The GSTM1 null genotype conferred twofold increased risk of developing CAD (OR=2.05, 95% CI 1.28 to 3.27, p=0.003). CONCLUSIONS: The results concluded that the GSTT1 null genotype showed protection against CAD while the GSTM1 null genotype might be involved in the pathogenesis and development of CAD. PMID- 27215234 TI - C1q-binding anti-HLA antibody assay: A test dilemma. AB - Detection of donor-specific anti-HLA antibodies in patients with kidney graft, or awaiting kidney graft, acts as a predictor for antibody mediated rejection. Several methods are in practice for the detection of anti-HLA antibodies; including the latest introduction of C1q-binding anti-HLA antibody method. This method depends on detecting complement fixing anti-HLA antibodies on single antigen beads using C1q as the marker for the presence of those antibodies. Here we discuss recent data on this method and present a working hypothesis for explaining the inability of this method to detect low titer anti-HLA antibodies. PMID- 27215233 TI - Association of PTPN22 rs2476601 Polymorphism with Rheumatoid Arthritis and Celiac Disease in Khuzestan Province, Southwestern Iran. AB - BACKGROUND: Single-nucleotide polymorphism (SNP) rs2476601 within protein tyrosine phosphatase non-receptor type 22 gene (PTPN22) has been shown to be a risk factor for different autoimmune diseases. This study explored the association of 1858 C/T SNP with rheumatoid arthritis (RA) and celiac disease (CD) in a region covering south-west of Iran. METHODS: Totally, 52 patients with CD, 120 patients with RA, and 120 healthy subjects were selected. The samples were genotyped for the rs2476601 in PTPN22 gene using the tetra-amplification refractory mutation system polymerase chain reaction. RESULTS: The frequency of +1858T risk allele was significantly increased in both RA (P=0.021, OR=2.56, 95%CI=1.19-5.47) and CD (P=0.002, OR=3.87, 95%CI=1.68-8.95) patients, as compared to the control group. However, no association was found between the +1858C/T PTPN22 gene SNP and the anti-cyclic citrullinated peptide and rheumatoid factor positivity in RA patients. CONCLUSIONS: PTPN22 gene could play a crucial role in people's susceptibility to certain autoimmune diseases. PMID- 27215235 TI - Is there an association between Vitamin D level and inflammatory markers in hemodialysis patients? A cross-sectional study. AB - Vitamin D deficiency is very prevalent among the patients with end-stage renal disease. The etiology of this is multifactorial, including nutritional deficiency, insufficient exposure to sunlight, race, obesity and not the least, impaired Vitamin D synthesis and metabolism in chronic kidney disease patients. We hypothesized that lower Vitamin D level will be associated with higher inflammatory burden and low immunological response to hepatitis B vaccination in hemodialysis (HD) population. The study was carried out in March 2013 among 100 HD patients who were identified to be eligible for the study. This was a cross sectional study analyzing the relationship between Vitamin D level and inflammatory markers in HD patients. A relationship between Vitamin D level and markers of mineral bone disorder was also analyzed. We also analyzed the relationship between Vitamin D level and hemoglobin and erythropoietin dosage. Hemoglobin, transferrin saturation, and erythropoietin dose were used to study the relationship between Vitamin D and markers of anemia. Antibodies to hepatitis B surface antigen were measured to study the response between Vitamin D level and immune response to hepatitis B vaccine. Vitamin D levels were significantly lower in females compared to males (P = 0.009) and diabetics compared to non-diabetics (P = 0.02). No significant association was observed between Vitamin D levels with immune response to hepatitis B vaccine (P = 0.89), C-reactive protein (P = 0.19), serum albumin (P = 0.17), hemoglobin level (P = 0.18,) and erythropoietin requirement (P = 0.87), parathyroid hormone (PTH) levels (P = 0.57), calcium levels (P = 0.79) and phosphate level (P = 0.1). PMID- 27215236 TI - Evaluation of continuous ambulatory peritoneal dialysis fluid C-reactive protein in patients with peritonitis. AB - Severe peritonitis causing death is one of the most devastating complications of peritoneal dialysis (PD). Since the predictive value of C-reactive protein (CRP) in PD fluid has not been assessed, the objective of the present study is to evaluate its predictive value and clinical correlation in patients on PD with peritonitis. One hundred and twenty patients on continuous ambulatory PD (CAPD) were enrolled and their serum and fluid CRP (Fl. CRP) were evaluated at the start of CAPD. All patients who developed peritonitis were further evaluated for serum and fluid CRP. The patients were categorized into four groups, namely: normal patients (control group), patients with peritonitis, patients with peritonitis leading to catheter removal, and death due to peritonitis. Sixty-five patients developed peritonitis of whom, catheter removal was performed in eight patients. Five patients died due to peritonitis-related complications. Fl. CRP showed a significant difference among the three groups, unlike S. CRP. Estimation of CRP in the peritoneal fluid may be a useful marker to monitor the onset of peritonitis. PMID- 27215237 TI - The association between glycemic control and microalbuminuria in Type 2 diabetes. AB - Microalbuminuria is an independent risk factor for cardiovascular and renal out- come in a patient with Type 2 diabetes. The evidence that intensive glycemic control reduces the microvascular complications of diabetes is based almost exclusively on prevention of micro- albuminuria. To evaluate the association between microalbuminuria and glycemic control and other factors in Type 2 diabetes, we studied retrospectively 551 patients with Type 2 diabetes. The patients were divided into two groups: 175 patients with microalbuminuria in the case group and 376 with normal urine albumin-creatinine ratio in the control group. Our data indicated that there was a significant association between the uncontrolled glycemia and development of microalbuminuria and that was more obvious if HbA1c level was >11%. Our data also indicate that there was a statistical significant association between male gender, age, the systolic and diastolic blood pressure (DBP) levels, and the microalbuminuria in crude odds ratios (ORs). We conclude that there was a clear association between the glycemic control and microalbuminuria, and microalbuminuria was associated with older age, male gender, and systolic and DBP in crude ORs. PMID- 27215238 TI - Renal impairment in multiple myeloma: A single center experience. AB - To determine the features of the different forms of kidney diseases associated with multiple myeloma (MM), we retrospectively studied 144 patients with kidney injury and MM at our institute from 1974 to 2014. The mean age of the patients was 60.1 years and the male:female ratio was 1.25. Renal disease was concomitant with the discovery of MM in 92% of cases. The mean follow-up of our patients was 2.1 years. Initial renal insufficiency was found in 131 (91%) patients. Cast nephropathy of the distal tubule was found in 110 (26%) patients, renal amyloidosis in 16 (11.1%), and light chain deposition disease in five (3.47%). Twelve (8.3%) patients had chronic glomerular nephropathy. Twenty-six patients reached end-stage renal failure within 13.4 months. Renal survival was 30.45 months. Predictive factors for improvement of renal function undergoing chemotherapy included serum creatinine <250 umol/L, proteinuria <1 g/24 h, and the non-use of renal replacement therapy. Multiple pathogenic mechanisms can contribute to kidney injury in myeloma patients. Novel myeloma agents have shown considerable promise in reversing renal failure in some patients and improving outcomes. PMID- 27215239 TI - The effect of phototherapy on urinary calcium excretion in term neonates. AB - Phototherapy is the most common, most effective, and least dangerous treatment method for neonatal hyperbilirubinemia and is the treatment of the first choice for neonatal icterus. Hypocalcemia is one of the lesser-known complications of phototherapy. Some studies have shown a relationship between increased urinary calcium excretion and phototherapy-induced hypocalcemia. We aimed to assess the effect of phototherapy on urinary calcium excretion in term neonates. This before after study was performed on 80 term neonates having hyper- bilirubinemia referred to the 17(th) Shahrivar Hospital, Rasht, Guilan Province, Northern Iran, over a one-year period from May 2013 to May 2014. Electrocardiography was performed to measure QTc in all neonates at admission and 48 h after phototherapy. Blood and urine samples were taken from all neonates before and 48 h after phototherapy. Phototherapy was performed using four lamps with similar wavelengths from a distance of 20 cm. The serum and urinary calcium and sodium levels and urinary creatinine level before and after phototherapy were measured and compared. Data were analyzed using SPSS software, version 16. The mean age of the study subjects was 7.01 +/- 4.13 days. We did not find any significant difference between urinary calcium levels (P = 0.0001), urinary creatinine levels (P = 0.954), or the calcium/creatinine ratio (P = 0.086) before and after phototherapy. The neonates' mean +/- standard deviation plasma as well as urinary sodium levels differed before and after phototherapy; the difference was not statistically significant (P = 0.658). Phototherapy might increase urinary calcium excretion although it does not cause hypocalcemia. PMID- 27215240 TI - Contribution of glomerular morphometry to the diagnosis of pediatric nephropathies. AB - Only a few studies describe histopathological changes in renal biopsies performed in pediatric patients. This study was conducted to identify an association between morphometric data in renal biopsies and renal function of these patients. Fifty-nine individuals with ages between 2 and 18 years old were selected, who were divided into six groups consisting of frequent nephropathies in children and adolescents and one control group. Proteinuria, urea, and creatinine values of the patients were recorded. Interactive image analysis software Leica QWin[(r)]was used for morpho- metric analysis of Bowman's capsule, glomerular capillary tuft, and Bowman's space area. The mean glomerular tuft area was higher in the membranous glomerulopathy group than in the podo- cytopathy group (57,101 +/- 25,094 vs. 27,420 c +/- 6279 um(2); P <0.05). The median of Bowman's space area was higher in the control group than in the podocytopathy group and in the thin basement membrane/Alport syndrome group [12,210 (7676-26,945) vs. 5801 (3031 7852) um(2); P <0.01 and 12210 (7676-26,945) vs. 4183 (3797-7992) um(2); P <0.01, respectively]. There was a positive and significant correlation between Bowman's capsule area and the levels of proteinuria, creatinine, and urea of the patients, as well as between the glomerular tuft area and the levels of proteinuria, creatinine, and urea in the patients, regardless of their nephropathy. Glomerular morphometry may contribute to the diagnosis of some glomerulopathies and the association between glomerular morphometric parameters, and laboratory data may promote a better understanding of the prognosis of these patients. PMID- 27215241 TI - Prevalence of asymptomatic urinary abnormalities among adolescents. AB - To determine the prevalence of asymptomatic urinary abnormalities in adolescents, first morning clean mid-stream urine specimens were obtained from 2500 individuals and examined by dipstick and light microscopy. Adolescents with abnormal screening results were reexamined after two weeks and those who had abnormal results twice were subjected to systemic clinical examination and further clinical and laboratory investigations. Eight hundred and three (32.1%) individuals had urinary abnormalities at the first screening, which significantly decreased to 345 (13.8%) at the second screening, (P <0.001). Hematuria was the most common urinary abnormalities detected in 245 (9.8%) adolescents who had persistent urine abnormalities; 228 (9.1%) individuals had non glomerular hematuria. The hematuria was isolated in 150 (6%) individuals, combined with leukocyturia in 83 (3.3%) individuals, and combined with proteinuria in 12 (0.5%) individuals. Leukocyturia was detected in 150 (6%) of all studied adolescents; it was isolated in 39 (1.6%) individuals and combined with proteinuria in 28 (1.1%) of them. Asymptomatic bacteriuria was detected in 23 (0.9%) of all studied adolescents; all the cases were females. Proteinuria was detected in 65 (2.6%) of all the studied adolescents; 45 (1.8%) individuals had <0.5 g/day and twenty (0.8%) individuals had 0.5-3 g/day. Asymptomatic urinary abnormalities were more common in males than females and adolescents from rural than urban areas (P <0.01) and (P <0.001), respectively. The present study found a high prevalence of asymptomatic urinary abnormalities among adolescents in our population. PMID- 27215242 TI - Neurological and cardiac complications in a cohort of children with end-stage renal disease. AB - Adult patients with chronic kidney disease are at risk of major neurologic and cardiac complications. The purpose of this study is to review the neurological and cardiac complications in children with end-stage renal disease (ESRD). A retrospective review of medical records of children with ESRD at Jordan University Hospital was performed. All neurological and cardiac events were recorded and analyzed. Data of a total of 68 children with ESRD presenting between 2002 and 2013 were reviewed. Neurological complications occurred in 32.4%; seizures were the most common event. Uncontrolled hypertension was the leading cause of neurological events. Cardiac complications occurred in 39.7%, the most common being pericardial effusion. Mortality from neurological complications was 45%. Neurological and cardiac complications occurred in around a third of children with ESRD with a high mortality rate. More effective control of hypertension, anemia, and intensive and gentle dialysis are needed. PMID- 27215243 TI - The effects of dual and triple combinations of trandolapril, telmisartan, and verapamil on overt proteinuria in the patients with diabetic nephropathy. AB - Diabetic nephropathy (DN) is one of the most important causes of the end-stage renal failure and its prevalence is found to be increasing. The presence of hypertension and progressive proteinuria is among the important findings. In this study, the effects of double and triple combinations of trandolapril, telmisartan, and verapamil on proteinuria were investigated in diabetic patients with nephropathy. Seventy-eight patients (mean age: 56.11 +/- 11.26 years; 47 females and 31 males) with overt proteinuria and DN were included in this study. The patients were divided into four groups: Group I (n: 18, trandolapril + telmisartan), Group II (n: 20, trandolapril + verapamil), Group III (n: 20, trandolapril +telmisartan + verapamil), and Group IV (n: 20, telmisartan + verapamil). At the end of a three-month therapy, within and between group comparisons were done about the effects of the use of double or triple drug combinations on proteinuria, glomerular filtration rate (GFR), electrolytes, serum albumin, low-density lipoprotein (LDL)- cholesterol, and HbA1C. There was no significant difference among groups in terms of age, gender, diabetes duration, body mass index, and retinopathy frequency. The decreases in proteinuria and mean arterial blood pressure (MABP) were significant in all groups. The decrease in proteinuria was independent of the decrease in MABP [the reduction rate in proteinuria was 39% (P <0.001) in Group I, 37% (P <0.001) in Group II, 42% (P <0.001) in Group III, and 43% (P <0.001) in Group IV; the reduction rate in MABP was 10.6% (P <0.001) in Group I, 13.7% (P <0.001) in Group II, 17.5% (P <0.001) in Group III, and 15.4% (P <0.001) in Group IV]. Decrease in HbA1C (before and after treatment) was significant in Groups III and IV when com- pared to Groups I and II. Any adverse event, like hyperkalemia, was not observed. There was no significant difference among the groups in terms of GFR, LDL cholesterol, albumin, and potassium. All the patients tolerated the drugs well. In conclusion, in patients with DN, both double or triple combinations of trandolapril, telmisartan and verapamil resulted in significant decreases in proteinuria and MABP. Triple combinations did not have any superiority over double combinations. Therefore, the suitable drug combinations may be chosen according to the clinical status of a patient. PMID- 27215244 TI - Na/K citrate versus sodium bicarbonate in prevention of contrast-induced nephropathy. AB - Contrast-induced nephropathy (CIN) is one of the important complications of radiographic procedures, especially in patients with chronic kidney disease. It is also one of the common causes of acute kidney injury. The pathogenesis is postulated to be the effect of oxygen- free radicals and hyperosmolar stress on the renal medulla. It is reported that the production of superoxide is most active at acid environment. K/Na citrate is well known as a urine alkalinization medium, and this has been evaluated earlier with standard hydration for reduction of CIN and was stated to be efficient. We aimed to determine the efficacy of Na/K citrate in reducing the frequency of CIN in comparison to sodium bicarbonate in patients after coronary angiography. Two hundred and ten patients with renal dysfunction [estimated glomerular filtration rate (eGFR), 60 mL/min/1.73 m(2) or less] who underwent elective or emergency coronary angiography (CAG) with/without percutaneous coronary intervention (PCI) at our institution were enrolled into the study. The patients were randomized into two groups, Group 1-Taking Na/K citrate and Group 2-Taking sodium bicarbonate. Radiographic contrast agent iohexol was used. Change in creatinine, percent change in creatinine, percent change in eGFR, change in serum potassium, and urine pH were all compared between the two groups. There was no significant difference for prevention of CIN when comparing the Na/K citrate with sodium bicarbonate solution in patients exposed to CAG with or without PCI. Mean absolute change in eGFR after 48 h after administration of contrast between sodium bicarbonate group and Na/K citrate group was -0.60 +/- 1.58 versus -0.71 +/- 1.38. Serum potassium decreased postprocedure in the sodium bicarbonate group than in the citrate group (3.90 +/- 0.33 vs. 4.14 +/- 0.39). Both agents are equally effective in reducing the incidence of CIN, but the citrate would possibly be a safer option for patients at risk of hypokalemia. PMID- 27215245 TI - Primary hyperoxaluria in infants. AB - The infantile form of primary hyperoxaluria type-1 (PH-1) is characterized by a rapid progression to the end-stage renal disease (ESRD) due to both increased oxalate load and reduced glomerular filtration rate. In the literature, data on this form are limited. The purpose of this study is to analyze retrospectively the clinical, biological, and radiological features of children who were diagnosed with PH-1 during the 1(st) year of life. We reviewed the records of all children with PH-1 diagnosed and followed-up at our department between January 1995 and December 2013. Among them, only infants younger than 12 months of age were retrospectively enrolled in the study. Fourteen infants with the median age of two months were enrolled in the study. At diagnosis, 11 patients had ESRD. All patients had nephrocalcinosis and two of them had calculi. The diagnosis was established in nine patients on the basis of the positive family history of PH-1, bilateral nephrocalcinosis, and quantitative crystalluria. In four patients, the diagnosis was made with molecular analysis of DNA. Kidney biopsy contributed to the diagnosis in one patient. During follow-up, two patients were pyridoxine sensitive and preserved renal function. Seven among 11 patients who had ESRD died, four patients are currently undergoing peritoneal dialysis. Children with infantile PH and ESRD are at high risk of early death. Peritoneal dialysis is not a treatment of choice. Combined liver-kidney transplantation is mandatory. PMID- 27215246 TI - Comparison between doppler ultrasound resistive index, serum creatinine, and histopathologic changes in patients with kidney transplant dysfunction in early posttransplantation period: A single center study with review of literature. AB - To determine the relationship between resistive index (RI) measured by Doppler ultrasound, serum creatinine (SCr), and histopathological changes on biopsy during kidney trans- plant dysfunction in early postoperative period, we studied 47 kidney transplant patients; 61% of the patients had acute transplant rejection, 19% had acute tubular necrosis, 4% had calcineurin inhibitor toxicity, 11% had normal morphology in biopsy, and 5% had changes compatible with pyelonephritis. None of the study patients had interstitial fibrosis or tubular atrophy on biopsy. We found that the sensitivity and specificity of RI in diagnosing transplant dysfunction was highly variable depending on the selected cutoff value. Sensitivity of RI decreased and its specificity increased with increasing the RI thresholds. Using an RI threshold of 0.7 resulted in a high sensitivity of 78% at a cost of very low specificity 40%, whereas using an RI threshold of 0.9 resulted in 100% specificity at a cost of very low sensitivity 16%. Acceptable specificity was only achieved at the expense of very low sensitivity, resulting in poor utility of RI as a screening tool for dysfunction. We found that there were no significant differences in the mean RI value between patients with and without biopsy-proven transplant dysfunction. However, we found a significant correlation between SCr value and RI of 0.383, P = 0.007. PMID- 27215247 TI - Serum sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of patients with membranous nephropathy and focal and segmental glomerulosclerosis. AB - Diagnosis of membranous nephropathy (MN) and focal and segmental glomerulo- sclerosis (FSGS) needs a renal biopsy, which is an invasive procedure with potentially serious complications. Proteomics may be applied for the development of a biomarker for these diseases which will obviate the need of biopsy. Serum sodium dodecyl sulfate-polyacrylamide gel electro-phoresis (SDS-PAGE) analysis gives an idea of the various proteins with different molecular weights (MWs) in a given sample. This study was conducted to analyze proteins with different MWs in patients with MN and FSGS and to compare the two groups with regard to their protein profile. This was a comparative, experimental study performed from June 2013 to July 2014 in the Department of Nephrology, Sir Sunderlal Hospital, Banaras Hindu University, Varanasi. Twenty-three histologically diagnosed cases of primary MN and 25 cases of FSGS were included in the study. Patients were categorized as having mild, moderate, and severe proteinuria with 24 h urinary protein levels of <4, 4- 8 and >=8 g/24 h, respectively. SDS-PAGE analysis was performed by the method of Laemmli and revealed a significantly higher number of patients with FSGS (80%) having a protein corresponding to 29 kDa MW, than those with MN (39.1%) (P = 0.004). Protein of 5 kDa MW was present in a significantly higher number of patients with moderate (80%) and severe (100%) proteinuria than those with mild proteinuria (25%) (P <0.001). Thus, protein of MW 29 kDa may be a marker for FSGS and needs further characterization. Similarly, 5 kDa protein, present in patients with moderate and severe proteinuria, might be either contributing to or be a marker of severe illness. PMID- 27215248 TI - The relationship between concentrations of magnesium and oxidized low-density lipoprotein and Beta2-microglobulin in the serum of patients on the end-stage of renal disease. AB - The end-stage of renal disease is associated with increased oxidative stress and oxidative modification of low-density lipoproteins (LDLs). Beta2 microglobulin (beta2M) is accumulated in the serum of dialysis patients. Magnesium (Mg) plays a protective role in the development of oxidative stress in healthy subjects. We studied the relationship between concentrations of magnesium and oxidized LDL (ox LDL) and beta2M in the serum of patients on the end stage of renal disease. In 96 patients on on-line- predilution hemodiafiltration, beta2M and intact parathormone were measured by radioimmunoassays. High-sensitivity C-reactive protein (hsCRP) and ox-LDL were measured using EpsilonLISA. Serum bicarbonate levels were measured in the blood gas analyser gas machine. We performed logistic regression analysis models to investigate Mg as an important independent predictor of elevated ox-LDL and high beta2M serum concentrations, after adjustment to traditional and specific for dialysis patients' factors. We observed a positive correlation of Mg with ox-LDL (r = 0.383, P = 0.001), but the association of Mg with beta2M, hsCRP, and serum bicarbonate levels was significantly inverse (r = -0.252, P = 0.01, r = -0.292, P = 0.004, and r = 0.282, P = 0.04 respectively). The built logistic-regression analysis showed that Mg act as a significant independent factor for the elevated ox-LDL and beta2M serum concentrations adjusting to traditional and specific factors for these patients. We observed a positive relationship between magnesium and acidosis status- related ox-LDL concentrations, but the inverse association between magnesium and beta2M serum concentrations in hemodialysis patients. PMID- 27215249 TI - Hemodialysis safety: Evaluation of clinical practice. AB - Hemodialysis (HD) safety has become a clinical priority; therefore, the use of checklists for making the dialysis session safe is now widely adopted. The aim of our study was to assess different shortcomings in the clinical practice of nurses working in different Moroccan dialysis centers and to discuss the interest of using such checklists. This cross-sectional study was performed in 13 chronic HD centers. Clinical practice of nurses was evaluated through checklists used in European outpatient dialysis units. We noted several deficiencies mainly related to the clinical evaluation of dialysis patients and to aspects related to hygiene and protection measures against contamination. Optimal safety of dialysis sessions requires the use of simple and reproducible means that improve clinical skills of the health staff. PMID- 27215250 TI - Clinicopathological correlations of renal pathology: A single center experience. AB - To evaluate the clinicopathological correlation of renal pathology and outline the frequencies of different renal diseases, beside assessment of lupus nephritis (LN), we studied 150 patients [72 (48%) males and mean age of 33.82 +/- 15.4 years] who were subjected to native renal biopsy; 112 (72.8%) biopsied patients were diagnosed to have glomerulonephritis (GN). The most frequent clinical renal syndrome was nephrotic syndrome found in 55 (36.6%) patients, followed by nephritic syndrome in 38 (25.3%) patients, chronic kidney disease in 28 (18.6%) patients, acute kidney injury (AKI) in 17 (11.3 %) patients, and subnephrotic proteinuria (SNP) in 12 (8%) patients. Focal segmental glomerulosclerosis (FSGS) was the most common patterns in primary GN (16.6%), LN was the most common pathology in secondary GN (33.3%). LN represented 18.1% of nephrotic syndrome, 68.3% of nephritic syndrome, 35.2% of AKI, and 58% of SNP. FSGS was the most common pattern in obese patients (58%), membranoproliferative GN (MPGN) was the most common pattern in hepatitis-C virus +ve patients (66.6%) and mem- branous GN was the most common pattern in hepatitis-B virus +ve patients (66.6%). In conclusion, GN was the most common pathology in this study, FSGS and MPGN were the most common patterns in primary GN. PMID- 27215251 TI - Characteristics and outcome of living kidney donors after donation: A report from Cote d'Ivoire. AB - Kidney transplantation from living kidney donors (LKDs) because of its good results represents a good option for the treatment of patients with the end-stage renal disease. Kidney donation is a relatively safe procedure according to several studies. We conducted this cross-sectional study in order to describe the demographic, clinical, and renal outcome of LKD in Cote d'Ivoire. From March to November 2014, LKD residing in Cote d'Ivoire at the time of investigation and having donated the kidney more than one year ago were considered for the study. They were evaluated through a questionnaire. Of the 29 LKD listed in Cote d'Ivoire, only 14 responded to the questionnaire. The mean age at donation was 43.29 +/- 9.12 years (27-59) and 10 of the LKD were women. Eight were related to the recipients, and the remaining were spouses. Laparoscopic nephrectomy was performed in nine LKD. The left kidney was harvested in ten cases. The main motivation for donation in all donors was the desire to save a life. At the time of the survey, the average duration after the donation was 4.57 +/- 2.56 years (1 8). Only five donors had a regular nephrological follow-up. Hypertension was observed in one donor, seven had significant proteinuria, and six had glomerular filtration rate <60 mL/min but >30 mL/min. Significantly higher proteinuria was noted in donors under 45 years as compared to those over 45 years (0.43 +/- 0.17 g/24 h vs. 0.22 +/- 0.03 g/24 h, P = 0.01). Our study suggests that renal disease in LKD in Cote d'Ivoire is low after a mean follow-up period of four years. A donor registry is essential to ensure better follow-up of donors in order to detect potential adverse effects of kidney donation in the medium as well as in the long-term. PMID- 27215252 TI - A study of outcome and complications associated with temporary hemodialysis catheters in a Nigerian dialysis unit. AB - Hemodialysis (HD) catheters are commonly used as temporary vascular access in patients with kidney failure who require immediate HD. The use of these catheters is limited by complications such as infections, thrombosis resulting in poor blood flow. We studied the complications and outcomes of nontunneled catheters used for vascular access in our dialysis unit. The records of all patients, with renal failure who were dialyzed over a two-year period and had a double lumen nontunneled catheter inserted, were retrieved. Catheter insertion was carried out under ultrasound guidance using the modified Seldinger technique. The demographic data of patients, etiology of chronic kidney disease, and complications and outcomes of these catheters were noted. Fifty-four patients with mean age 43.7 +/ 15.8 years had 69 catheters inserted for a cumulative total of 4047 catheter days. The mean catheter patency was 36.4 +/- 37.2 days (range: 1-173 days). Thrombosis occluding the catheters was the most common complication and occurred in 58% of catheters leading to catheter malfunction, followed by infections in18.8% of catheters. During follow-up, 30 (43.5%) catheters were removed, 14 (20.3%) due to catheter malfunction, eight (11.6%) due to infection, five (7.2%) elective removal, and three (4.3%) due to damage. Thrombotic occlusion of catheters was a major limiting factor to the survival of HD catheters. Improvement in catheter patency can be achieved with more potent lock solutions. PMID- 27215253 TI - Histopathological types in adult nephrotic syndrome. AB - In Bangladesh, there are very few studies about biopsy proven adult Nephrotic syndrome (NS) with histological types and their clinical findings. To determine the histological types of glomerulonephritis (GN) in adult NS and correlate them with the clinical presentations and biochemical parameters, we studied 100 biopsies in 87 patients who underwent ultrasonography- guided renal biopsy in Rangpur Medical College and Hospital from July 2010 to June 2012. The mean age of the patients was 32.8 +/- 13.2 years; male was preponderance (72.4%) and most of the patients (67.8%) came from rural areas. Membranoproliferative GN (MPGN) was the most common underlying cause that was found in 32 (36.8%) patients followed by mesangial proliferative GN in 27 (31%) patients, membranous GN in 16 (18.4%) cases, minimal change disease in four (4.6%) patients, diffuse proliferative GN in four (4.6%) patients, focal segmental GN, and focal proliferative GN in two (2.4%) patients each. High proteinuria level was found in minimal change disease, which was 7.59 +/- 0.24 g/24 h (mean +/- standard deviation). The most common symptoms were oliguria (92%) and edema (86.2%) followed by hematuria (dark urine) (72.4%) and hypertension (35.6%). MPGN was the most common histological type of adult NS in Rangpur. PMID- 27215255 TI - Nonocclusive mesenteric ischemia after renal transplantation: A case report and literature review. AB - Nonocclusive mesenteric ischemia (NOMI) is a very rare occurrence after renal transplantation. This disorder is difficult to diagnose and can even be fatal. We describe a 51- year-old man with end-stage renal disease who developed intestinal ischemia and infarction due to NOMI three days after deceased donor kidney transplantation, which was managed success- fully and his renal graft function was saved. To the best of our knowledge, this is one of the few cases of NOMI occurring after renal transplantation reported in the literature. PMID- 27215254 TI - Severe hemorrhage complicating early transplant nephrectomy due to sepsis. AB - Compared to the general population, transplant patients receiving immuno- suppression have an increased risk of wound and systemic infection that might lead to hemorrhage. We present a case of severe bleeding from the external iliac artery secondary to a pelvic abscess following renal transplantation and transplant nephrectomy. A 73-year-old man received an extended criteria donor organ from a 49-year-old person who died from systemic sepsis. The patient bled from the Carrel's patch while awaiting a computed tomographic scan- guided drainage of an infected peritransplant collection. At exploration, a nonviable allograft surrounded by about 1 L of thick pus was removed. Bleeding from a 2 mm hole in the Carrel's patch was repaired by prolene suture as the external iliac vessels could not be mobilized due to a frozen pelvis. The patient died 72 h later from a massive bleed confirmed at postmortem to have originated from the external iliac artery distal to the anastomosis. Diversion of blood flow away from an affected area (with or without excision of the infected vessels) through a bypass procedure probably represents the best option in avoiding such sequelae. PMID- 27215256 TI - Renal manifestations of human brucellosis: First report of minimal change disease. AB - Human brucellosis is considered a great example of the complexity of clinical manifestations possibly affecting multiple organs or systems. Renal manifestations of human brucellosis have been documented in few case reports and one case series. Herein, we present a case of Nephrotic syndrome (NS) due to minimal change disease in the course of acute brucellosis. A 53-year-old male farmer was admitted to our department with acute brucellosis and NS. Renal biopsy revealed minimal change disease. Combined treatment with prednisone (1 mg/kg), rifampicin (600 mg/day), and doxycycline (200 mg/day) was initiated. Complete remission of NS was achieved at the end of the fourth week. One year later, the patient remained in complete remission of NS without any sign of relapse of brucellosis. PMID- 27215257 TI - Baclofen-induced neurotoxicity in a patient with end-stage renal disease. AB - Baclofen, predominantly excreted by the kidneys is accumulated in patients with renal insufficiency leading to the central nervous system toxicity. Here the author reports a patient with end-stage renal disease on maintenance hemodialysis (HD) who developed drowsiness and became unresponsive within a day after taking single 10 mg dose of baclofen. Patient improved completely after two sessions of HD. PMID- 27215258 TI - Infantile nephropathic cystinosis with incomplete fanconi syndrome, hypothyroidism, hydro-uretero-nephrosis, and megacystis. AB - Cystinosis is an autosomal recessive lysosomal storage disorder characterized by the accumulation of the amino-acid cysteine in various organs and tissues. Infantile nephropathic cystinosis is the most severe form of the disorder. We describe the clinical features in a four and a half-year-old Indian boy with infantile nephropathic cystinosis that presented with the incomplete Fanconi syndrome, hydro-uretero-nephrosis with megacystis, and hypothyroidism. PMID- 27215259 TI - Anti-neutrophil cytoplasmic antibody negative crescentic paucimmune glomerulonephritis in a case of scleroderma with systemic lupus erythematosus overlap. AB - Renal Involvement in scleroderma is a known problem and the manifestations are well described. Renal involvement in systemic lupus erythematosus (SLE) is also well known. However, in scleroderma and SLE overlap syndrome, the renal findings may vary being a combination of features of immune complex mediated glomerulonephritis as well as thrombotic microangiopathy. We report a case in which the renal manifestation in such a situation was of a focal necrotising pauci-immune glomerulonephritis with crescents, anti-neutrophil cytoplasmic antibody negative. To the best of our knowledge, such manifestations have not been described before. Renal dysfunction in a normotensive setting in such a case should direct one towards evaluation for other causes and should prompt a kidney biopsy. This would be valuable in delineating the pathological process in the kidney and would help in guiding therapy. PMID- 27215260 TI - Primary hyperoxaluria in an adult male: A rare cause of end-stage kidney disease yet potentially fatal if misdiagnosed. AB - Primary hyperoxaluria is an autosomal recessive disorder due to a deficiency in the activity of the peroxisomal hepatic enzyme alanine-glyoxylate aminotransferase. It is a common cause of urolithiasis and end-stage kidney disease in children contrary to the adult phenotypic presentation which is considered a mild disorder with occasional urolithiasis. In this case report, we describe a 25-year-old man who presented with advanced and irreversible kidney failure within three months following strenuous physical training in the police academy. He had nephrocalcinosis and stones in one kidney. Diagnosis was confirmed by establishing the existence of extensive tubular and interstitial crystal deposition in his kidneys and molecular genetic testing. The case illustrates the need to establish an early diagnosis of this disorder to prevent the need for combined liver and kidney transplantation. PMID- 27215261 TI - An unusual presentation of juvenile lupus nephritis. AB - The incidence of juvenile lupus varies widely ranging between 4 and 250 per 100,000 population. Most common organ involvement in juvenile lupus is kidney. Neurological, cutaneous and hematological involvements are also involved. Skeletal muscle involvement in the form of myositis is rare. Myositis as presenting manifestation in juvenile lupus is also unusual. Herein, we report one such case wherein myositis preceded the onset of lupus nephritis. PMID- 27215262 TI - Report of a kidney recipient with inguinal herniation of the transplant ureter. PMID- 27215263 TI - Remarks about the study on evaluation of thyroid hormone levels in chronic kidney disease patients. PMID- 27215264 TI - Remarks about the study of eosinophilic cystitis and idiopathic hyper eosinophilic syndrome in a eight-year-old girl. PMID- 27215265 TI - Restless leg syndrome and its treatment. PMID- 27215266 TI - Remarks about the study on immunoglobulin G4-related disease: Two case reports and review of the recent literature. PMID- 27215267 TI - Adrenal insufficiency in snake envenomation: Another piece of puzzle? PMID- 27215268 TI - Remarks about the study of an unusual presentation of venous thrombosis in a child with idiopathic membranous nephropathy. PMID- 27215269 TI - Effects of type of body weight type on acute kidney injury diagnosis. PMID- 27215270 TI - Prevalence of dental caries and influencing factors, time trends over a 30-year period in an adult population. Epidemiological studies between 1983 and 2013 in the county of Dalarna, Sweden. AB - OBJECTIVE: The aim of this study was to investigate the prevalence of dental caries in an adult population using four different cross-sectional studies over a 30-year period and to assess its possible associations with socio-economic and socio-behavioural factors. MATERIALS AND METHODS: Four cross-sectional epidemiological studies were performed in the county of Dalarna, Sweden, in 1983, 2003, 2008 and 2013. Random samples of 1012-2244 individuals, aged 20-85 years, who answered a questionnaire about socio-economic and socio-behavioural factors, were radiographically and clinically examined. RESULTS: The proportion of individuals with at least one decayed surface (DS) was 58% in 1983 and significantly lower, 34% in 2008 (p < 0.05) and 33% in 2013; the mean number of DS was 2.0 in 1983 and 1.1 in 2013 in the age group 35-75 (p < 0.05). In the age group 85, the mean number of DS was 1.2 in 2008 and 2.4 in 2013. Adjusted for age and number of teeth, irregular dental visits, limited financial resources for dental care, smoking, education below university, male gender, daily medication and single living were positively and statistically associated with manifest caries. CONCLUSION: The declining trend in the prevalence of manifest caries seems to be broken. In the oldest age group mean number of DS was higher in 2013 compared with 2008, indicating a possible beginning of an increase. This needs special attention as this group increases in the population, retaining natural teeth high up in age. Manifest caries was found to be associated with socio economic and socio-behavioural factors. PMID- 27215271 TI - Assessment of the clinical application of detecting EGFR, KRAS, PIK3CA and BRAF mutations in patients with non-small cell lung cancer using next-generation sequencing. AB - BACKGROUND: Next-generation sequencing (NGS) has been widely applied in clinical research, while its application in routine clinical molecular testing requires careful validation. The aim of our study was to assess the clinical usefulness of the NextDaySeq Lung panel on Ion TorrentTM PGM in mutation detection of actionable genes in lung cancer. METHODS: The NextDaySeq assay was evaluated by blinded comparisons to Quantitative Real-Time PCR (qPCR) assays with 188 consecutive samples from Chinese patients with non-small cell lung cancer (NSCLC) to detect mutations in EGFR, KRAS, PIK3CA and BRAF. Discordant variants were further validated by Sanger sequencing and independent qPCR and NGS assays. RESULTS: Our results showed 93.3% concordance of reportable variants mutually covered in both NGS and qPCR assays, with a clinical sensitivity of 89.9%, specificity of 97.5%. Through the comparison, the NGS assays demonstrated its advantages in offering more clinical relevant information, such as detecting non hotspot mutations and providing mutation allele frequencies (MAF) and accurate mutation sequences. The analytical sensitivity of NGS to detect mutations with low MAF needs further improvement. CONCLUSIONS: The NextDaySeq Lung panel exhibited good clinical performance, strongly supporting the implementation of the NGS assay in routine clinical use to facilitate therapeutic decision-making for lung cancer patients. PMID- 27215272 TI - Evidence-Based Programs for Older Adults: A Disconnect Between U.S. National Strategy and Local Senior Center Implementation. AB - While U.S. national policies have been developed to support evidence-based (EB) lifestyle programs for older adults, there has been limited research to determine the extent to which these programs actually reach local communities. This study sought to identify factors that impact the implementation of EB physical activity, nutrition, and chronic disease management programs at regional (Area Agencies on Aging [AAAs]) and community levels (senior Centers [SCs]). Interviews were conducted with directors of four AAAs and 12 SCs to understand their perspectives on EB program implementation. Narratives revealed differences between AAAs and SCs regarding knowledge about EB programs and reasons to promote and adopt these programs. The only agreement occurred when discussing concerns about funding and program inflexibility. Substantial gaps exist between how EB lifestyle programs are promoted and implemented at the regional and community levels. PMID- 27215273 TI - Has the American Public's Interest in Information Related to Relationships Beyond "The Couple" Increased Over Time? AB - Finding romance, love, and sexual intimacy is a central part of our life experience. Although people engage in romance in a variety of ways, alternatives to "the couple" are largely overlooked in relationship research. Scholars and the media have recently argued that the rules of romance are changing, suggesting that interest in consensual departures from monogamy may become popular as people navigate their long-term coupling. This study utilizes Google Trends to assess Americans' interest in seeking out information related to consensual nonmonogamous relationships across a 10-year period (2006-2015). Using anonymous Web queries from hundreds of thousands of Google search engine users, results show that searches for words related to polyamory and open relationships (but not swinging) have significantly increased over time. Moreover, the magnitude of the correlation between consensual nonmonogamy Web queries and time was significantly higher than popular Web queries over the same time period, indicating this pattern of increased interest in polyamory and open relationships is unique. Future research avenues for incorporating consensual nonmonogamous relationships into relationship science are discussed. PMID- 27215274 TI - Andrographis paniculata decreases fatigue in patients with relapsing-remitting multiple sclerosis: a 12-month double-blind placebo-controlled pilot study. AB - BACKGROUND: Andrographis paniculata (A. paniculata), a medicinal plant, has shown anti-inflammatory, neuroprotective and antifibrotic effects in animal models as well as clinical efficacy in different studies, including an anti-fatigue effect in autoimmune diseases such as rheumatoid arthritis. In multiple sclerosis (MS), fatigue is rated as one of the most common and disabling symptoms. In the present trial, we investigated the effect of A. paniculata on relapse rate and fatigue in relapsing-remitting MS (RRMS) patients receiving interferon beta. METHODS: A randomised double-blind placebo-controlled trial assessed the effects of 170 mg of A. paniculata dried extract tablet b.i.d. p.o. on relapse rate and fatigue using the Fatigue Severity Scores (FSS) over 12 months in RRMS patients receiving interferon. The Expanded Disability Status Scale (EDSS) score, inflammatory parameters and radiological findings were also investigated. Twenty-five patients were enrolled, and twenty-two patients were ultimately analysed and randomised to the active or placebo group. RESULTS: Patients treated with A. paniculata showed a significant reduction in their FSS score as compared to the placebo, equivalent to a 44 % reduction at 12 months. No statistically significant differences were observed for relapse rate, EDSS or inflammatory parameters, with a trend in reducing new lesions among the A. paniculata group. One patient in the A. paniculata group presented with a mild and transient skin rash, which was alleviated with anti-histamine treatment for three weeks. CONCLUSION: A. paniculata was well tolerated in patients and no changes in clinical parameters were observed. A. paniculata significantly reduces fatigue in patients with RRMS receiving interferon beta in comparison to placebo and only interferon beta treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02280876 ; Trial registration date: 20.10.2014. PMID- 27215275 TI - Erratum: prevalence of plasmid-bearing and plasmid-free chlamydia trachomatis infection among women who visited obstetrics and gynecology clinics in Malaysia. PMID- 27215277 TI - Social care and support needs of community-dwelling people with dementia and concurrent visual impairment. AB - OBJECTIVES: This study explored the social care and support needs of people with dementia and visual impairment, and the barriers and facilitators for meeting these needs. METHOD: Twenty-six semi-structured interviews were conducted: 21 joint and 5 individual interviews with the person with dementia and visual impairment (n=4) or their family/paid carer (n=1). Interviews were analysed thematically. RESULTS: Three themes are presented. (1) Social care needs: having dementia can reduce an individual's ability to cope with their visual impairment, and lead to increased dependency and reduced daily stimulation. (2) Barriers to using technology to meet social care needs: difficulties were reported with learning to use unfamiliar technology and the cost of visual impairment aids, and for some, the presence of dementia made visual impairment aids unusable and vice versa. (3) Familiarity as a facilitator for meeting social care needs: living at home or taking furnishings and ornaments into a new home facilitated independence, and continuity of paid carers/volunteers facilitated the caring relationship between the individual and staff/volunteer. CONCLUSION: Care workers will better serve older people if they are aware of the social care and support needs that arise from having both dementia and visual impairment. PMID- 27215278 TI - Contemporary issues and future directions in autoimmune hepatitis. AB - INTRODUCTION: Autoimmune hepatitis (AIH) is a severe life-threatening hepatopathy of unknown etiology, affecting both pediatric and adult populations, and characterised by inflammatory liver histology, circulating non-organ-specific autoantibodies, and hypergammaglobulinaemia. AIH is a very heterogeneous disease with a variety of clinical presentations, ranging from asymptomatic liver test abnormalities to acute severe hepatitis or even acute liver failure. It responds very well to immunosuppressive treatment with prednisolone with or without azathioprine. Patients who are intolerant or fail to respond to standard therapy are candidates for alternative immunosuppressive regimens, the combination of steroids with mycophenolate mofetil or calcineurin inhibitors being the most frequently reported. The pathogenesis of AIH remains not completely understood, although there is evidence that genetic predisposition, molecular mimicry and defective immunoregulatory mechanisms contribute to the autoimmune liver damage. AREAS COVERED: A literature search was conducted using the key-words 'autoimmune hepatitis', 'immunogenetics', 'regulatory T-cells' and 'immunosuppression'. The aim of this review is to discuss recent breakthroughs in the understanding AIH pathogenesis, diagnosis and treatment. Expert commentary: Progress in the understanding of AIH pathogenesis is likely to contribute to the development of novel therapeutic strategies, such as the adoptive transfer of autologous expanded antigen-specific regulatory T-cells. PMID- 27215279 TI - Comparison of the effect of increased hepatitis B vaccine dosage on immunogenicity in healthy children and adults. AB - Hepatitis B (HepB) infection remains a global public health problem, particularly in China. Vaccination for children and adult who are unvaccinated is an effective method for preventing the disease. In this study, we aimed to compare the effects of increased dosage of HepB vaccine on immunogenicity in healthy children and adults. A phase III, controlled, double-blinded clinical trial was performed. The subjects were assigned into groups I (age 5-14 y), II (age 15-24 y), and III (age >= 25 y). Subjects were randomly administered either 10 or 5 MUg recombinant HepB vaccine; blood samples were collected before and after vaccination to estimate immunogenicity. The results showed that the seroconversion rate and geometric mean concentration of antibody to hepB surface antigen (anti-HBs) did not differ significantly between the dosages in each age group. Anti-HBs levels were reduced with age, and this effect was more obvious in adults administered 5 MUg HepB vaccine. In conclusion, both vaccine dosages could be used to immunize children, and the 10 MUg vaccine could be used for adults ages 15-24 y, whereas a higher dosage of the HepB vaccine may be required for adults ages 25 y and older. PMID- 27215280 TI - Effectiveness of simulation-based nursing education depending on fidelity: a meta analysis. AB - BACKGROUND: Simulation-based nursing education is an increasingly popular pedagogical approach. It provides students with opportunities to practice their clinical and decision-making skills through various real-life situational experiences. However, simulation approaches fall along a continuum ranging from low-fidelity to high-fidelity simulation. The purpose of this study was to determine the effect size of simulation-based educational interventions in nursing and compare effect sizes according to the fidelity level of the simulators through a meta-analysis. METHOD: This study explores the quantitative evidence published in the electronic databases EBSCO, Medline, ScienceDirect, ERIC, RISS, and the National Assembly Library of Korea database. Using a search strategy including the search terms "nursing," "simulation," "human patient," and "simulator," we identified 2279 potentially relevant articles. Forty studies met the inclusion criteria and were retained in the analysis. RESULTS: This meta analysis showed that simulation-based nursing education was effective in various learning domains, with a pooled random-effects standardized mean difference of 0.70. Subgroup analysis revealed that effect sizes were larger for high-fidelity simulation (0.86), medium-fidelity simulation (1.03), and standardized patients (0.86) than they were for low-fidelity and hybrid simulations. In terms of cognitive outcomes, the effect size was the largest for high-fidelity simulation (0.50). Regarding affective outcome, high-fidelity simulation (0.80) and standardized patients (0.73) had the largest effect sizes. CONCLUSIONS: These results suggest that simulation-based nursing educational interventions have strong educational effects, with particularly large effects in the psychomotor domain. Since the effect is not proportional to fidelity level, it is important to use a variety of educational interventions to meet all of the educational goals. PMID- 27215281 TI - Postural risk assessment of mechanised firewood processing. AB - The study assessed the postural risk of mechanised firewood processing with eight machines, representing the main technology solutions available on the market. Assessment was conducted with the Ovako Working posture Analysis System (OWAS) on 1000 still frames randomly extracted from videotaped work samples. The postural risk associated with firewood processing was variable and associated with technology type. Simple, manually operated new machines incurred a higher postural risk compared with semi- or fully automatic machines. In contrast, new semi-automatic and automatic machines were generally free from postural risk. In all cases, attention should be paid to postural risk that may occur during blockage resolution. The study did not cover the postural risk of firewood processing sites as a whole. The study provided useful information for selecting firewood processing machinery and for improving firewood machinery design, as part of a more articulate strategy aimed at enhancing the safety of firewood processing work sites. Practitioner Summary: The postural risk associated with mechanised firewood processing (eg cutting and splitting) depends on the type of equipment. Postural risk is highest (OWAS Action Category 2) with new in-line machines, designed for operation by a single worker. Fully automatic machines present minimum postural risk, except during blockage resolution. PMID- 27215282 TI - Li-Ion Conduction and Stability of Perovskite Li3/8Sr7/16Hf1/4Ta3/4O3. AB - A solid Li-ion conductor with a high room temperature Li-ion conductivity and small interfacial resistance is required for its application in next-generation Li-ion batteries. Here, we prepared a cubic perovskite-related oxide with the general formula Li3/8Sr7/16Hf1/4Ta3/4O3 (LSHT) by a conventional solid-state reaction method, which was studied by X-ray diffraction, electrochemical impedance spectroscopy, and (7)Li MAS NMR. Li3/8Sr7/16Hf1/4Ta3/4O3 has a high Li ion conductivity of 3.8 * 10(-4) S cm(-1) at 25 degrees C and a low activation energy of 0.36 eV in the temperature range 298-430 K. It exhibits both high stability and small interfacial resistance with commercial organic liquid electrolytes, which makes it promising as a separator in Li-ion batteries. PMID- 27215283 TI - Photoactivation of Diiodido-Pt(IV) Complexes Coupled to Upconverting Nanoparticles. AB - The preparation, characterization, and surface modification of upconverting lanthanide-doped hexagonal NaGdF4 nanocrystals attached to light sensitive diiodido-Pt(IV) complexes is presented. The evaluation for photoactivation and cytotoxicity of the novel carboxylated diiodido-Pt(IV) cytotoxic prodrugs by near infrared (NIR) light (lambda = 980 nm) is also reported. We attempted two different strategies for attachment of light-sensitive diiodido-Pt(IV) complexes to Yb,Er- and Yb,Tm-doped beta-NaGdF4 upconverting nanoparticles (UCNPs) in order to provide nanohybrids, which offer unique opportunities for selective drug activation within the tumor cells and subsequent spatiotemporal controlled drug release by NIR-to-visible light-upconversion: (A) covalent attachment of the Pt(IV) complex via amide bond formation and (B) carboxylate exchange of oleate on the surface of the UCNPs with diiodido-Pt(IV) carboxylato complexes. Initial feasibility studies showed that NIR applied by a 980 nm laser had only a slight effect on the stability of the various diiodido-Pt(IV) complexes, but when UCNPs were present more rapid loss of the ligand-metal-charge transfer (LMCT) bands of the diiodido-Pt(IV) complexes was observed. Furthermore, Pt released from the Pt(IV) complexes platinated calf-thymus DNA (ct-DNA) more rapidly when NIR was applied compared to dark controls. Of the two attachment strategies, method A with the covalently attached diiodido-Pt(IV) carboxylates via amide bond formation proved to be the most effective method for generating UCNPs that release Pt when irradiated with NIR; the released Pt was also able to bind irreversibly to calf thymus DNA. Nonetheless, only ca. 20% of the Pt on the surface of the UCNPs was in the Pt(IV) oxidation state, the rest was Pt(II), indicating chemical reduction of the diiodido-Pt(IV) prodrug by the UCNPs. Cytotoxicity studies with the various UCNP-Pt conjugates and constructs, tested on human leukemia HL60 cells in culture, indicated a substantial increase in cytotoxicity when modified UCNPs were combined with five rounds of 30 min irradiation with NIR compared to dark controls, but NIR alone also had a significant cytotoxic effect at this duration. PMID- 27215284 TI - The MK2/HuR signaling pathway regulates TNF-alpha-induced ICAM-1 expression by promoting the stabilization of ICAM-1 mRNA. AB - BACKGROUND: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are characterized by acute lung inflammation. Intercellular adhesion molecule-1 (ICAM-1) and interleukin-8 (IL-8) play an important role in the development of these diseases. Mitogen-activated protein kinase (MAPK) p38/activated protein kinase 2 (MK2) regulates the expression of ICAM-1 and IL-8 in human lung microvascular endothelial cells (HPMECs) stimulated by tumor necrosis factor-alpha (TNF-alpha); however, the underlying molecular mechanism remains unclear. Here, we show that human antigen R (HuR), an RNA binding protein which binds preferentially to AU-rich elements (AREs) and stabilizes mRNAs, regulates TNF-alpha-induced ICAM-1 expression in the MK2/HuR signaling pathway. METHOD: MK2 and HuR were silenced respectively in HPMECs and then HPMECs were stimulatied with TNF-alpha. Nucleo-cytoplasmic shuttling of HuR was detected by subcellular fractionation and confocal microscopy in MK2 knockdown HPMECs. In HuR silencing cells, protein and mRNA levels of ICAM-1 and IL-8 were measured by western blot analysis, ELISA and real-time PCR; mRNA stabilization were measured by real-time PCR after actinomycin D (ActD) blocking transcription. Furthermore, we performed neutrophil adhesion assay to assess the adhering capacity after HuR silencing. RESULTS: MK2 were subjected to a knockdown by interfering RNA, the mRNA and protein levels of HuR in human pulmonary microvascular endothelial cells (HPMECs) were not affected. However, after the stimulation of TNF-alpha, silencing MK2 inhibited HuR accumulation to cytoplasm from nucleus in HPMECs. Consequently, knockdown of HuR by RNA interference in HPMECs, there was reduction in the stability of ICAM-1 mRNA and ICAM-1 protein level. This event was accompanied by a decrease in the adhesion of neutrophils towards HPMECs. Nevertheless, HuR silencing had no effect on the mRNA and protein levels of IL-8. CONCLUSION: These results indicate that MK2 post-transcriptionally regulates TNF alpha-induced ICAM-1 expression by altering the cytoplasmic localization of HuR in HPMECs. PMID- 27215285 TI - Whole-grain consumption and the risk of all-cause, CVD and cancer mortality: a meta-analysis of prospective cohort studies. AB - Results of the relationships between dietary whole-grain consumption and the risk of all-cause, CVD and cancer-specific mortality are mixed. We summarised the evidence based on a meta-analysis of prospective cohort studies. Pertinent studies were identified by searching articles in the MEDLINE and EMBASE databases up to 20 January 2016 and by reviewing the reference lists of the retrieved articles. Random-effects models were used to calculate summary relative risks (SRR) and 95 % CI. In all, eleven prospective studies (ten publications) were included in the meta-analysis. There were a total of 816 599 subjects and 89 251 cases of all-cause mortality. On the basis of the highest v. the lowest categories of intake, whole grains may be associated with a lower risk of mortality from all causes (SRR 0.87; 95 % CI 0.84, 0.90), CVD (SRR 0.81; 95 % CI 0.75, 0.89) and all cancers (SRR 0.89; 95 % CI 0.82, 0.96). For each 3 servings/d increase in whole-grain intake, there was a 19 % reduction in the risk of all cause mortality (SRR 0.81; 95 % CI 0.76, 0.85), a 26 % reduction in CVD mortality (SRR 0.74; 95 % CI 0.66, 0.83) and a 9 % reduction in cancer mortality (SRR 0.91; 95 % CI 0.84, 0.98). The current meta-analysis provides some evidence that high intake of whole grains was inversely associated with the risk of all-cause, CVD and cancer-specific mortality. Further well-designed studies, including clinical trials and in different populations, are required to confirm our findings. PMID- 27215286 TI - The emerging role of viral vectors as vehicles for DMD gene editing. AB - Duchenne muscular dystrophy (DMD) is a genetic disorder caused by mutations in the dystrophin-encoding DMD gene. The DMD gene, spanning over 2.4 megabases along the short arm of the X chromosome (Xp21.2), is the largest genetic locus known in the human genome. The size of DMD, combined with the complexity of the DMD phenotype and the extent of the affected tissues, begs for the development of novel, ideally complementary, therapeutic approaches. Genome editing based on the delivery of sequence-specific programmable nucleases into dystrophin-defective cells has recently enriched the portfolio of potential therapies under investigation. Experiments involving different programmable nuclease platforms and target cell types have established that the application of genome-editing principles to the targeted manipulation of defective DMD loci can result in the rescue of dystrophin protein synthesis in gene-edited cells. Looking towards translation into the clinic, these proof-of-principle experiments have been swiftly followed by the conversion of well-established viral vector systems into delivery agents for DMD editing. These gene-editing tools consist of zinc-finger nucleases (ZFNs), engineered homing endoculeases (HEs), transcription activator like effector nucleases (TALENs), and RNA-guided nucleases (RGNs) based on clustered, regularly interspaced, short palindromic repeats (CRISPR)-Cas9 systems. Here, we succinctly review these fast-paced developments and technologies, highlighting their relative merits and potential bottlenecks, when used as part of in vivo and ex vivo gene-editing strategies. PMID- 27215287 TI - Multiple Drugs Causing Severe Anemia in Infective Endocarditis. AB - Ceftriaxone and linezolid are commonly used antibiotics in infective endocarditis. Here we present a rare case of severe anemia caused by both the drugs via different mechanisms. Drugs have shown significant contribution in inducing anemia via hemolysis and bone marrow suppression in an infective endocarditis patient. PMID- 27215288 TI - Effects of the Herbicide Imazethapyr on Photosynthesis in PGR5- and NDH-Deficient Arabidopsis thaliana at the Biochemical, Transcriptomic, and Proteomic Levels. AB - Photosynthesis is a very important metabolic pathway for plant growth and crop yield. This report investigated the effect of the herbicide imazethapyr on photosynthesis in the Arabidopsis thaliana pnsB3 mutant (a defect in the NDH pathway) and pgr5 mutant (a defect in the PGR5 pathway) to determine which cyclic electron transport chain (CET) of the NDH and PGR5 pathways is more important for protecting the photosynthetic system under herbicide stress. The results showed that 20 MUg/L imazethapyr markedly inhibited the growth of the three ecotypes of A. thaliana and produced more anthocyanins and reactive oxygen species (ROS), particularly in the pgr5 mutant. The chlorophyll fluorescence results showed that PSII was severely damaged in the pgr5 mutant. Additionally, the CET was significantly stimulated to protect the photosynthetic system from light damage in Wt and the pnsB3 mutant but not the pgr5 mutant. The real-time PCR analysis indicated that imazethapyr treatment considerably decreased the transcript levels of most photosynthesis-related genes in the three treated groups. Several genes in the PGR5 pathway were significantly induced in the pnsB3 mutant, but no genes in the NDH pathway were induced in the pgr5 mutant. The gene transcription analysis showed that the pgr5 mutant cannot compensate for the deficit in the PGR5 pathway by stimulating the NDH pathway, whereas the pnsB3 mutant can compensate for the deficit in the CET cycle by regulating the PGR5 pathway. The iTRAQ analyses also showed that the photosynthesis system, glycolysis, and TCA cycle suffered the most severe damage in the pgr5 mutant. All of these results showed that the PGR5 pathway is more critical for electron transfer around PSI than the NDH pathway to resist herbicide stress. PMID- 27215291 TI - Use of fluorescence signals generated by elastic scattering under monochromatic incident light for determining the scattering efficiencies of various plasmonic nanoparticles. AB - We present a route that estimates the scattering/absorption characteristics of plasmonic nanoparticles by using fluorescence and UV-visible spectroscopy. Because elastic scattering of nanoparticles caused by a monochromatic incident light is reflected in fluorescence emission spectra when recording at the excitation wavelength, the scattering intensities at the excitation wavelength during fluorescence emission scans are used to compare the scattering characteristics of various plasmonic nanoparticles under conditions where the extinction values of all of the nanoparticles are kept constant at this wavelength. For the two excitation wavelengths (519 and 560 nm) we investigated, the scattering intensities of spherical gold nanoparticles increase with increasing size (15, 33, 51, 73, and 103 nm in diameter). These results are correlated with the nanoparticles' scattering efficiencies (the ratios of scattering to the extinction cross-sections), which are theoretically calculated in the literature using Mie theory. Then, linear calibration equations at each wavelength are derived to estimate the scattering efficiencies of two Au nanorods, Au nanocages, and spherical Ag nanoparticles (15, 25, 37, and 62 nm). The values are very comparable with literature values. For various purposes such as biomedicine and optoelectronics, the present method could be beneficial to those who wish to easily compare and determine the scattering characteristics of various plasmonic nanoparticles at a certain wavelength by using commercially available spectroscopic techniques. PMID- 27215290 TI - PBDE flame retardants, thyroid disease, and menopausal status in U.S. women. AB - BACKGROUND: Women have elevated rates of thyroid disease compared to men. Environmental toxicants have been implicated as contributors to this dimorphism, including polybrominated diphenyl ethers (PBDEs), flame retardant chemicals that disrupt thyroid hormone action. PBDEs have also been implicated in the disruption of estrogenic activity, and estrogen levels regulate thyroid hormones. Post menopausal women may therefore be particularly vulnerable to PBDE induced thyroid effects, given low estrogen reserves. The objective of this study was to test for an association between serum PBDE concentrations and thyroid disease in women from the United States (U.S.), stratified by menopause status. METHODS: Serum PBDE concentrations (BDEs 47, 99, 100 and 153) from the National Health and Examination Survey (NHANES) and reports on thyroid problems were available in the NHANES 2003-2004 cycle. Odds ratios (ORs) were calculated using multivariate logistic regression models accounting for population-weighted survey techniques and controlling for age, body mass index (BMI), education, smoking, alcohol consumption and thyroid medication. Menopause status was obtained by self reported absence of menstruation in the previous 12 months and declared menopause. RESULTS: Women in the highest quartile of serum concentrations for BDEs 47, 99, and 100 had increased odds of currently having thyroid disease (ORs: 1.5, 1.8, 1.5, respectively) compared to the reference group (1st and 2nd quartiles combined); stronger associations were observed when the analysis was restricted to postmenopausal women (ORs: 2.2, 3.6, 2.0, respectively). CONCLUSION: Exposure to BDEs 47, 99, and 100 is associated with thyroid disease in a national sample of U.S. women, with greater effects observed post-menopause, suggesting that the disruption of thyroid signaling by PBDEs may be enhanced by the altered estrogen levels during menopause. PMID- 27215292 TI - Supportive medical care in life-threatening illness: A pilot study. AB - OBJECTIVE: The goal of this pilot study was to identify the processes by which healing occurs in patients who experience a life-threatening illness. METHOD: Healing was examined by using two qualitative studies that employed a semistructured interview process (interviews lasted between 30 and 115 minutes). There were 10 cardiac event survivors and 9 cancer survivors. These participants came from a community hospital setting (cardiac), nonmedical holistic services organization (cancer), and a research hospital (cancer). Before participants could take part in the study, they were administered preliminary screening measurements, the first of which was an instrument similar to the Distress Thermometer. Participants then self-reported their positive life-transforming changes. If one to three changes were reported six months after onset of the illness, participants were deemed to have passed the screening. Finally, participants were tested for speaking volume and clarity. RESULTS: An overall theme that was prevalent throughout the interviews was medical support. Participants found that their positive, life-transforming changes were typically connected with supportive caregivers who helped to create a culture of care. They also indicated that an absence of this medical supportive care hindered development of such life-transforming changes. SIGNIFICANCE OF RESULTS: Our results indicate that a medical care team will be more effective if a positive culture of care is created. This can be implemented if the team provides comfort, which involves being more engaged in the treatment of patients as well as being more attentive to their psychosocial needs. PMID- 27215293 TI - An Arterial Conduit is Not a Risk Factor for Survival Following Orthotopic Liver Transplantation: An Analysis of 20 Years of Liver Transplantation in Innsbruck. AB - BACKGROUND In adult liver transplantation, arterial conduits have been associated with increased risk for vascular complications and inferior outcome. MATERIAL AND METHODS Complication rates and outcomes of adult patients undergoing liver transplantation in our center between 1990 and 2012 were analyzed retrospectively. Characteristics, transplantation-related factors, and survival rates of patients with conduit grafts (n=43) were compared to patients with a standard arterial anastomosis (n=904) by univariate and multivariate analysis. RESULTS Patients in the conduit group were younger but had a significantly higher proportion of high-urgency and re-transplantations. While patient survival was comparable between the groups, graft survival was inferior for patients with a conduit (1-year, 5-year, and 10-year survival, control vs. conduit group: 87.3%, 78.8% and 71.5% vs. 72.4%, 63.8%, and 41.8%, respectively, p=0.008). In univariate analysis, an arterial conduit was associated with more arterial and biliary complications. However, an arterial conduit was not an independent risk factor for graft or patient survival in a Cox regression analysis. CONCLUSIONS An arterial conduit is associated with more vascular complications, yet a conduit per se does not influence graft survival. The inferior outcome may reflect the complex situation of the sicker liver transplant patients needing a non-standard arterial anastomosis. PMID- 27215294 TI - In Vivo Efficacy and Tolerability of Artesunate-Azithromycin for the Treatment of Falciparum Malaria in Vietnam. AB - Safe and effective antimalarial drugs are required for the treatment of pregnant women. We report a 3-day regimen of artesunate (4 mg/kg/day)-azithromycin (25 mg/kg/day) (ASAZ) to be efficacious (polymerase chain reaction-corrected cure rate of 96.7%) and well tolerated in the treatment of Plasmodium falciparum malaria in children (N = 11) and adults (N = 19), in Vietnam in 2010. In comparison, the cure rate for artesunate (4 mg/kg on day 0, 2 mg/kg on days 1-6) was 90.0% in children (N = 7) and adults (N = 23). Because azithromycin is considered safe in pregnancy, our findings provide further evidence that ASAZ should be evaluated for the treatment of pregnant women with malaria. PMID- 27215296 TI - Azithromycin for Malaria? PMID- 27215295 TI - Serodiagnosis of Acute Typhoid Fever in Nigerian Pediatric Cases by Detection of Serum IgA and IgG Against Hemolysin E and Lipopolysaccharide. AB - Inexpensive, easy-to-use, and highly sensitive diagnostic tests are currently unavailable for typhoid fever. To identify candidate serodiagnostic markers, we have probed microarrays displaying the full Salmonella enterica serovar Typhi (S. Typhi) proteome of 4,352 different proteins + lipopolysaccharides (LPSs), with sera from Nigerian pediatric typhoid and other febrile cases, Nigerian healthy controls, and healthy U.S. adults. Nigerian antibody profiles were broad (~500 seropositive antigens) and mainly low level, with a small number of stronger "hits," whereas the profile in U.S. adults was < 1/5 as broad, consistent with endemic exposure in Nigeria. Nigerian profiles were largely unaffected by clinical diagnosis, although the response against t1477 (hemolysin E) consistently emerged as stronger in typhoid cases. The response to LPS was also a strong discriminator of healthy controls and typhoid, although LPS did not discriminate between typhoid and nontyphoidal Salmonella (NTS) disease. As a first step toward the development of a point-of-care diagnostic, t1477 and LPS were evaluated on immunostrips. Both provided good discrimination between healthy controls and typhoid/NTS disease. Such a test could provide a useful screen for salmonellosis (typhoid and NTS disease) in suspected pediatric cases that present with undefined febrile disease. PMID- 27215297 TI - The Imaramagambo Onchocerciasis Focus in Southwestern Uganda: Interruption of Transmission After Disappearance of the Vector Simulium neavei and Its Associated Freshwater Crabs. AB - It was not until early 1990s that, when the Imaramagambo focus of southwest Uganda was mapped, mass treatment with a single annual dose of ivermectin for onchocerciaisis control commenced. However, comprehensive investigations on its transmission were launched after a nationwide policy for onchocerciasis elimination in 2007. Entomological surveys throughout the focus from 2007 to 2015 have yielded few or no freshwater crabs (Potamonautes aloysiisabaudiae), which serve as the obligate phoretic host of the larvae and pupae of the vector Simulium neavei No S. neavei flies have been observed or collected since 2007. Skin snips (microscopy) from 294 individuals in 2008 were negative for skin microfilariae, and of the 462 persons analyzed by polymerase chain reaction skin snip poolscreen in 2009, only five (1.08%) persons were indicated as infected with onchocerciasis. All five of the positive persons were at least 40 years old. Serosurvey results showed negative exposure among 3,332 children in 2012 and 3,108 children in 2015. Both were within the upper bound of the 95% confidence interval of the prevalence estimate of 0.06%, which confirmed the elimination of onchocerciasis. Treatment coverage in Imaramagambo was generally poor, and transmission interruption of onchocerciasis could not be attributed solely to annual mass treatment with ivermectin. There was sufficient evidence to believe that the possible disappearance of the S. neavei flies, presumed to have been the main vector, may have hastened the demise of onchocerciasis in this focus. PMID- 27215298 TI - Subsidized Sachet Water to Reduce Diarrheal Disease in Young Children: A Feasibility Study in Accra, Ghana. AB - Use of drinking water sold in plastic bags (sachet water) is growing rapidly in west Africa. The impact on water consumption and child health remains unclear, and a debate on the taxation and regulation of sachet water is ongoing. This study assessed the feasibility of providing subsidized sachet water to low-income urban households in Accra and measured the resultant changes in water consumption. A total of 86 children, 6-36 months of age in neighborhoods lacking indoor piped water, were randomized to three study arms. The control group received education about diarrhea. The second arm received vouchers for 15 L/week/child of free water sachets (value: $0.63/week) plus education. The third arm received vouchers for the same water sachet volume at half price plus education. Water consumption was measured at baseline and followed for 4 months thereafter. At baseline, 66 of 81 children (82%) drank only sachet water. When given one voucher/child/week, households redeemed an average 0.94 vouchers/week/child in the free-sachet-voucher arm and 0.82 vouchers/week/child in the half-price arm. No change in water consumption was observed in the half price arm, although the study was not powered to detect such differences. In the free-sachet-voucher arm, estimated sachet water consumption increased by 0.27 L/child/day (P = 0.03). The increase in sachet water consumption by children in the free-sachet-voucher arm shows that provision of fully subsidized water sachets might improve the quality of drinking water consumed by children. Further research is needed to quantify this and any related child health impacts. PMID- 27215299 TI - Isolation of Madre de Dios Virus (Orthobunyavirus; Bunyaviridae), an Oropouche Virus Species Reassortant, from a Monkey in Venezuela. AB - Oropouche virus (OROV), genus Orthobunyavirus, family Bunyaviridae, is an important cause of human illness in tropical South America. Herein, we report the isolation, complete genome sequence, genetic characterization, and phylogenetic analysis of an OROV species reassortant, Madre de Dios virus (MDDV), obtained from a sick monkey (Cebus olivaceus Schomburgk) collected in a forest near Atapirire, a small rural village located in Anzoategui State, Venezuela. MDDV is one of a growing number of naturally occurring OROV species reassortants isolated in South America and was known previously only from southern Peru. PMID- 27215302 TI - Water in asymmetric organocatalytic systems: a global perspective. AB - Asymmetric organocatalysis often operates under near ambient conditions, which means it is air and moisture compatible. However, in many examples water is indeed necessary for achieving excellent catalytic results. Ranging from the addition of small amounts of water to a reaction, to complex catalytic systems in the presence of water as the only reaction medium, this review offers an illustrative classification of the uses of water in asymmetric organocatalysis. PMID- 27215300 TI - Elevated Values of Clinically Relevant Transferases Induced by Imported Infectious Diseases: A Controlled Cross-Sectional Study of 14,559 Diseased German Travelers Returning from the Tropics and Subtropics. AB - The aim of this controlled cross-sectional study was to assess the clinical validity of elevated values of three clinically relevant transferase enzymes (aspartate transaminase [AST], alanine transaminase [ALT], and gamma-glutamyl transferase [GGT]) induced by imported infectious diseases (IDs) seen among patients consulting the Division of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich (from 1999 to 2014) after being in the sub-/tropics. Data sets of 14,559 diseased German travelers returning from Latin America (2,715), Africa (4,574), or Asia (7,270) and of 1,536 healthy controls of German origin without recent travels were analyzed. Among the cases, the proportions of those with elevated values of AST (7.8%) and of ALT (13.4%) were significantly larger than among controls (4.0% and 10.6%, respectively), whereas for GGT, no significant difference was found (cases: 10.0%; controls: 11.4%). The study identified IDs with significantly larger proportions of both AST and ALT (hepatitis A [100%/100%], cytomegalovirus [CMV] infection [77%/81%], chronic hepatitis C [67%/67%], infectious mononucleosis [65%/77%], typhoid fever [50%/50%], cyclosporiasis [45%/66%], dengue fever [43%/35%], malaria [20%/27%], and rickettsiosis [20%/24%]), of AST alone (paratyphoid fever [42%]), of ALT alone (giardiasis [20%]), and of GGT (hepatitis A [100%], infectious mononucleosis [71%], CMV infection [58%], rickettsiosis (20%], and dengue fever [19%]). The study demonstrates that the determination of AST and ALT among travelers returning from the sub-/tropics has a high clinical validity, as their elevated values are typically caused by several imported viral, bacterial, and protozoan IDs, whereas no additional clinical validity was found by the determination of GGT. PMID- 27215303 TI - Variability of Uncrossmatched Blood Use by Helicopter EMS Programs in the United States. AB - STUDY OBJECTIVE: Some helicopter emergency medical services (HEMS) maintain an independent supply of blood for use during transport, although practice is variable and not well described. We aimed to characterize the blood-carrying practices by HEMS programs across the United States. METHODS: Online surveys were sent to the leadership of the 261 HEMS programs nationwide listed in the 2011 Atlas and Database of Air Medical Services (ADAMS) database. We examined blood carrying practices in aggregate, including typical transport time, proportion of scene transports, and local population density. A GIS (Geographic Information System) and multivariable logistic regression models were used to estimate the impact of characteristics of local practice on each program's decision to carry blood. RESULTS: A total of 235 (91%) programs responded to the survey, representing 857 of the 929 (92.2%) HEMS rotor wing aircraft nationwide. Fifty nine (25.3%) programs independently carried blood. A higher proportion of interfacility transports (OR 1.023; 95% CI 1.010-1.036) and decreased local population density (OR 1.006; 95% CI 1.001-1.011) were associated with increased odds of carrying blood. Transport time (OR 1.006; 95% CI 0.991-1.020) and number of transports (OR 1.000; CI 1.000-1.000) were not associated with a program's blood carrying practices. There was no effect of local practices on a program's decision to carry blood (OR 1.002; 95% CI 0.980-1.026). CONCLUSION: There is great variability in the utilization of blood by HEMS programs in the United States. Programs that serve more rural areas and programs with a larger percentage of interfacility transports are more likely to independently carry blood. PMID- 27215309 TI - Biosynthesis of poly(3-hydroxybutyrate) copolymers by Azotobacter chroococcum 7B: A precursor feeding strategy. AB - A precursor feeding strategy for effective biopolymer producer strain Azotobacter chroococcum 7B was used to synthesize various poly(3-hydroxybutyrate) (PHB) copolymers. We performed experiments on biosynthesis of PHB copolymers by A. chroococcum 7B using various precursors: sucrose as the primary carbon source, various carboxylic acids and ethylene glycol (EG) derivatives [diethylene glycol (DEG), triethylene glycol (TEG), poly(ethylene glycol) (PEG) 300, PEG 400, PEG 1000] as additional carbon sources. We analyzed strain growth parameters including biomass and polymer yields as well as molecular weight and monomer composition of produced copolymers. We demonstrated that A. chroococcum 7B was able to synthesize copolymers using carboxylic acids with the length less than linear 6C, including poly(3-hydroxybutyrate-co-3-hydroxy-4-methylvalerate) (PHB 4MHV) using Y-shaped 6C 3-methylvaleric acid as precursor as well as EG containing copolymers: PHB-DEG, PHB-TEG, PHB-PEG, and PHB-HV-PEG copolymers using short-chain PEGs (with n <= 9) as precursors. It was shown that use of the additional carbon sources caused inhibition of cell growth, decrease in polymer yields, fall in polymer molecular weight, decrease in 3-hydroxyvalerate content in produced PHB-HV-PEG copolymer, and change in bacterial cells morphology that were depended on the nature of the precursors (carboxylic acids or EG derivatives) and the timing of its addition to the growth medium. PMID- 27215310 TI - An observation of prescription behaviors and adherence to guidelines in patients with COPD: real world data from October 2012 to September 2014. AB - INTRODUCTION: GOLD guideline recommendations are currently the "gold standard" for the treatment of COPD patients. OBJECTIVES: The objective of this analysis was to evaluate compliance with GOLD guidelines in managing COPD patients' treatment by general practitioners (GPs) and pulmonologists. Since inhaled corticosteroid (ICS) use is defined as inappropriate in mild and moderate COPD patients, special attention was paid to ICS therapy use in these classes. METHODS: The study was based on the Italian GP database IMS Health Longitudinal Patient Database (IMS Health LPD) and on the Patient Analyzer specialist IMS Health database. The observed cohort included all patients with a diagnosis of COPD, aged 40 years or more, with at least one ATC R03 class prescription, visited by GPs and pulmonologists during four timeframes: October 2012 - March 2013 (cohort 1), April 2013 - September 2013 (cohort 2), October 2013 - March 2014 (cohort 3); April 2014 - September 2014 (cohort 4). Patients were classified into disease severity groups following 2008 GOLD guidelines, based on FEV1 value. RESULTS: Cohorts were quite similar in size (about two thousand patients per cohort). Pulmonologists visited more severe patients than GPs. About 50% of GPs' mild and moderate patients received treatments containing inhaled corticosteroids. Pulmonologists were more adherent to guidelines, with smaller percentages of mild patients treated with therapies containing ICS (ranging from 19.0% to 30.1%). An improvement in adherence was observed during the four time periods, with a decrease in the use of therapies containing ICS in mild and moderate patients. In absolute terms, it emerged that GPs more often prescribe ICS improperly to patients in the mild and moderate severity classes than pulmonologists. CONCLUSION: Real world data indicate that adherence to GOLD guidelines is only partially met by GPs in their general practice and shows higher prescription appropriateness by pulmonologists. PMID- 27215312 TI - Correlation of Genetic Heterogeneity with Cytopathological and Epidemiological Findings of Leishmania major Isolated from Cutaneous Leishmaniasis in Southern Iran. AB - OBJECTIVE: Cutaneous leishmaniasis (CL) has recently grown into a major public health problem in 88 countries of the world, including Iran. It is a polymorphic disease which may show various clinicopathological features. Although the effect of the genetic diversity of the parasite has been demonstrated as one of the factors influencing clinical manifestations in CL, no data exist regarding the genetic variation of Leishmania major and its microscopical features. STUDY DESIGN: Fine-needle aspiration, touch smears and the histological sections of 100 patients were examined for Leishmania amastigotes, using Giemsa and hematoxylin and eosin. Diverse types of inflammatory cells in the 40 positive and 5 negative smears were differentiated. Kinetoplast DNA (kDNA) was amplified using nested PCR and subsequently sequenced. Sequencing analysis of the amplified kDNA was used to investigate the genetic variations among L. major isolates and to correlate the findings with microscopical features and geographical origins. RESULTS: The quantified amastigote density in the 40 positive touch smears was blindly classified by 3 observers. Grade I, II, III and IV had 7, 13, 9 and 11 cases, respectively. The microscopical features, the mean percentage of neutrophils, lymphocytes and other inflammatory cells, and the leishmanial density of the grades and negative cytopathological samples were contrasting. kDNA amplification of L. major was detected from the cutaneous lesion, and 21 of these amplicons were successfully sequenced. CONCLUSIONS: These results indicate that L. major strains causing CL in southern Iran are genetically diverse; furthermore, a correlation between the genetic heterogeneity of the parasite, the microscopical manifestation and the geographical regions of the disease in humans was found. PMID- 27215314 TI - Profiles of African American College Students' Alcohol Use and Sexual Behaviors: Associations With Stress, Racial Discrimination, and Social Support. AB - Though studies show that alcohol use and sexual activity increase during emerging adulthood, few studies examine within-ethnic group differences, particularly among African American college students. This investigation utilized a latent class analytic methodology to identify risk behavior profiles of alcohol use (frequency and amount of alcohol consumed), sexual activity (number of intimate partners), and co-occurring risk behaviors (drinking before sexual intercourse) among 228 African American college students. This investigation also examined whether identified risk behavior profiles were associated with stress (interpersonal, intrapersonal, academic, and environmental), experiences of racial discrimination, and social support (from family, friends, and the college community). Results identified five distinct profiles within this sample: (a) High Sexual Risk-above-average sexual activity; (b) Abstainers-below-average alcohol use and sexual activity; (c) Low Risk-average alcohol use and sexual activity; (d) Alcohol Risk-above-average alcohol use and below-average sexual activity; and (e) Co-Occurring Risk-above-average alcohol use and sexual activity. Identified profiles differed across interpersonal and environmental stress, and self-reported frequency of experiences with racial discrimination. Implications for prevention programs and interventions aimed at reducing alcohol and sexual activity for African American college students are discussed. PMID- 27215315 TI - Severe necrotic dermatitis in the combs of line 63 chickens infected with Marek's disease virus. AB - Marek's disease virus (MDV), the aetiological agent of Mareks' disease (MD), is a highly cell-associated oncogenic alpha-herpesvirus that replicates in chicken lymphocytes and establishes a latent infection within CD4(+) T cells. We investigated the possible effect of MDV infection on the exacerbation of necrotic dermatitis in the combs of MD-susceptible (72) and MD-resistant (63) chicken lines at 21 days post infection. MDV-infected birds of line 63 are relatively resistant to tumour development but exhibit an unusual necrosis of combs, wattles, and footpads that is intensified when infected with MDV. Chickens from line 72, on the other hand, are highly susceptible to MDV infection and tumour development. Real-Time PCR analysis revealed that IL-6, IL-8, IL-12, IL-18, iNOS, and IFNgamma were all up regulated in the comb tissues of MDV-infected susceptible line 72 with no visible necrotic damage. With the exception of IL-8 and iNOS, the expression of all the other tested genes was barely detected in the necrotic combs of the resistant line 63. Real-Time PCR analysis revealed the MDV meq oncogene transcripts in the spleen tissues of both infected lines but in the comb tissues of only the susceptible line 72. A significant infiltration of macrophages and lymphocytes was detected in the comb tissues of both resistant and susceptible lines. Histopathological analysis also showed thinning and erosion of epidermis and inflammation, lympho-plasmocytic infiltration, heterophilic, and histocytic cellulitis within the connective tissues of the necrotic combs. Gram stain of the sectioned frozen comb samples exposed the presence of Gram-positive micrococcus. PMID- 27215316 TI - Association of long noncoding RNA and c-JUN expression in hepatocellular carcinoma. AB - BACKGROUND: Long noncoding RNAs(lncRNAs) have emerged as key elements in modulating gene expression in different biological contexts. PATIENTS AND METHODS: We used quantitative real-time PCR (Qpcr) to evaluate the expression of lncRNA-UCA1 and C-JUN in serum of 70 patients with hepatocellular carcinoma (HCC), 32 patients chronic hepatitis C (CHC) and 38 healthy subjects and their correlation with different clinicopathological factors. RESULTS: The expression of lncRNA-UCA1 and C-JUN was positive in 91.4%HCC patients with strong discriminating power between HCC and healthy subjects and CHC patients as well. The median follow up period was 29 months. The survival analysis showed that both lncRNA-UCA1 and C-JUN were independent prognostic factors. Of note, we identified C-JUN expression changes consistent with the lncRNA-UCA1 target regulation. CONCLUSION: This information sheds light on the possible role of lncRNA-UCA1 and C-JUN mRNA as promising diagnostic and prognostic markers as well as potential therapeutic targets in HCC. PMID- 27215317 TI - Inducible limb-shaking transitory ischemic attacks: a video-documented case report and review of the literature. AB - BACKGROUND: Limb-shaking transient ischemic attack (TIA) is a well-recognized, but rare observation in contralateral carotid steno-occlusive disease. Consequently, most clinicians have not had the chance to witness an attack. CASE PRESENTATION: We present the story of a 64-year old gentleman with exercise induced weakness associated with tremor in his right arm. His left internal carotid artery was occluded at the bifurcation. Administration of statin and antiplatelet did not relieve his symptoms, and his stereotypic, exercise-induced "limb-shaking" episodes persisted. He underwent successful extracranial to intracranial (EC-IC) bypass, which stopped his symptoms. The patient, however, returned to our department and reported that he was able to recreate his original symptoms by compressing the bypass graft manually. CONCLUSION: To our knowledge, this is the first case with video documentation of the clinical appearance of a limb-shaking TIA. We hope this case report will increase the physicians' understanding of the clinical nature of limb-shaking TIAs. PMID- 27215318 TI - Biochemical and spectroscopic characterization of purified Latex Clearing Protein (Lcp) from newly isolated rubber degrading Rhodococcus rhodochrous strain RPK1 reveals novel properties of Lcp. AB - BACKGROUND: Biodegradation of rubber (polyisoprene) is initiated by oxidative cleavage of the polyisoprene backbone and is performed either by an extracellular rubber oxygenase (RoxA) from Gram-negative rubber degrading bacteria or by a latex clearing protein (Lcp) secreted by Gram-positive rubber degrading bacteria. Only little is known on the biochemistry of polyisoprene cleavage by Lcp and on the types and functions of the involved cofactors. RESULTS: A rubber-degrading bacterium was isolated from the effluent of a rubber-processing factory and was taxonomically identified as a Rhodococcus rhodochrous species. A gene of R. rhodochrous RPK1 that coded for a polyisoprene-cleaving latex clearing protein (lcp Rr ) was identified, cloned, expressed in Escherichia coli and purified. Purified LcpRr had a specific activity of 3.1 U/mg at 30 degrees C and degraded poly(1,4-cis-isoprene) to a mixture of oligoisoprene molecules with terminal keto and aldehyde groups. The pH optimum of LcpRr was higher (pH 8) than for other rubber-cleaving enzymes (~ pH 7). UVvis spectroscopic analysis of LcpRr revealed a cytochrome-specific absorption spectrum with an additional feature at long wavelengths that has not been observed for any other rubber-cleaving enzyme. The presence of one b-type haem in LcpRr as a co-factor was confirmed by (i) metal analysis, (ii) solvent extraction, (iii) bipyridyl assay and (iv) detection of haem-b specific m/z values via mass-spectrometry. CONCLUSIONS: Our data point to substantial differences in the active sites of Lcp proteins obtained from different rubber degrading bacteria. PMID- 27215319 TI - Negative occasion setting in juvenile rats. AB - Prior findings indicate that adolescent rats exhibit difficulty using negative occasion setters to guide behavior compared to adult rats (Meyer and Bucci, 2014). Here, additional groups of juvenile rats were trained in the same negative occasion setting procedure to further define the development of negative occasion setting. Beginning on either postnatal day (PND) 30, 40, or 50, rats received daily training sessions in which a tone was paired with food reinforcement on some trials, while on other trials a light preceded the tone and no reinforcement was delivered. We found that rats that began training on PND 50 required 10 training sessions to discriminate between the two types of trials, consistent with prior findings with young adult rats. Interestingly, rats in the PND 30 group (pre-adolescents) also required just 10 training sessions, in stark contrast to adolescent rats that began training on PND 35 (adolescents) and required 18 sessions (Meyer and Bucci, 2014). Rats that began training on PND 40 (adolescents) also required more sessions than the PND 30 group. These data indicate that the development of negative occasion setting is non-linear and have direct bearing on understanding the behavioral and neural substrates that underlie suboptimal behavioral control in adolescents. PMID- 27215320 TI - Associations between perceived institutional support, job enjoyment, and intentions to work in the United Kingdom: national questionnaire survey of first year doctors. AB - BACKGROUND: Identifying factors that improve job satisfaction of new doctors and ease the difficult transition from student to doctor is of great interest to public health agencies. Studies to date have focused primarily on the value of changes to medical school curricula and induction processes in this regard, but have overlooked the extent to which institutional support can influence new doctors' enjoyment of and attitude to work. Here, we examine variation in the perceived level of support received by new medical graduates in the United Kingdom (UK) from their employer and whether this influences enjoyment of and attitudes to the first postgraduate year, and whether doctors who perceived a lower level of support were less inclined to intend a long term career in medicine in the UK. METHODS: All UK medical graduates of 2012 were surveyed in 2013 in a cross-sectional study, towards the end of their first post-graduate year (the 'F1' year of the 2-year Foundation Training Programme for new UK doctors). We used linear regression to assess whether the level of support doctors reported receiving from their employing Trust (Very Good, Good, Adequate, Poor, or Very Poor) was associated with the extent to which they enjoyed their F1 year. Similarly, we assessed the strength of associations between self-reported level of Trust support and doctors' responses to 12 statements about fundamental aspects of their working lives, each assessed on a 5-point scale of agreement. Using chi (2) tests we examined whether doctors' intentions to practise medicine in the UK varied with the level of support they reported receiving from their Trust. RESULTS: The response rate was 45 % (2324/5171). Of 2324 responding junior doctors, 63.8 % reported receiving 'Very Good' (23.6 %) or 'Good' (40.2 %) initial support from their Trust, while a further 27.4 % stated they received 'Adequate' support. 'Poor' support was reported by 5.8 % and 'Very Poor' support by 2.2 %. We found very strong positive associations between the institutional support doctors reported receiving and their enjoyment of the F1 year and their self-expressed attitudes to aspects of their first year of work. Crucially, doctors who reported receiving lower levels of support ('Poor' or 'Very Poor') were significantly less likely to express intentions to continue practising medicine in the UK. CONCLUSIONS: The provision of effective institutional support for graduate doctors may promote workplace satisfaction and could help safeguard the long-term retention of junior doctors. PMID- 27215321 TI - Metabolomics reveals significant variations in metabolites and correlations regarding the maturation of walnuts (Juglans regia L.). AB - The content of walnut metabolites is related to its nutritive value and physiological characteristics, however, comprehensive information concerning the metabolome of walnut kernels is limited. In this study we analyzed the metabolites of walnut kernels at five developmental stages from filling to ripening using GC-MS-based untargeted metabolomics; of a total 252 peaks identified, 85 metabolites were positively identified. Further statistical analysis revealed that these 85 metabolites covered different types of metabolism pathways. PCA scores revealed that the metabolic compositions of the embryo are different at each stage, while the metabolic composition of the endotesta could not be significantly separated into distinct groups. Additionally, 7225 metabolite-metabolite correlations were detected in walnut kernel by a Pearson correlation coefficient approach; during screening of the calculated correlations, 463 and 1047 were determined to be significant with r(2)>=0.49 and had a false discovery rate (FDR) <=0.05 in endotesta and embryo, respectively. This work provides the first comprehensive metabolomic study of walnut kernels and reveals that most of the carbohydrate and protein-derived carbon was transferred into other compounds, such as fatty acids, during the maturation of walnuts, which may potentially provide the basis for further studies on walnut kernel metabolism. PMID- 27215322 TI - De novo actin polymerization is required for model Hirano body formation in Dictyostelium. AB - Hirano bodies are eosinophilic, actin-rich inclusions found in autopsied brains in numerous neurodegenerative diseases. The mechanism of Hirano body formation is unknown. Mass spectrometry analysis was performed to identify proteins from partially purified model Hirano bodies from Dictyostelium This analysis identified proteins primarily belonging to ribosomes, proteasomes, mitochondria and cytoskeleton. Profilin, Arp/2/3 and WASH identified by mass spectrometry were found to colocalise with model Hirano bodies. Due to their roles in actin regulation, we selected these proteins for further investigation. Inhibition of the Arp2/3 complex by CK666 prevented formation of model Hirano bodies. Since Arp2/3 activation occurs via the WASH or WAVE complex, we next investigated how these proteins affect Hirano body formation. Whereas model Hirano bodies could form in WASH-deficient cells, they failed to form in cells lacking HSPC300, a member of the WAVE complex. We identified other proteins required for Hirano body formation that include profilin and VASP, an actin nucleation factor. In the case of VASP, both its G- and F-actin binding domains were required for model Hirano body formation. Collectively, our results indicate that de novo actin polymerization is required to form model Hirano bodies. PMID- 27215323 TI - SMN and coilin negatively regulate dyskerin association with telomerase RNA. AB - Telomerase is a ribonucleoprotein comprising telomerase RNA and associated proteins. The formation of the telomerase holoenzyme takes place in the Cajal body (CB), a subnuclear domain that participates in the formation of ribonucleoproteins. CBs also contribute to the delivery of telomerase to telomeres. The protein WRAP53 is enriched within the CB and is instrumental for the targeting of telomerase RNA to CBs. Two other CB proteins, SMN and coilin, are also suspected of taking part in some aspect of telomerase biogenesis. Here we demonstrate newly discovered associations between SMN and coilin with telomerase components, and further show that reduction of SMN or coilin is correlated with increased association of telomerase RNA with one these components, dyskerin. These findings argue that SMN and coilin may negatively regulate the formation of telomerase. Furthermore, clinically defined SMN mutants found in individuals with spinal muscular atrophy are altered in their association with telomerase complex proteins. Additionally, we observe that a coilin derivative also associates with dyskerin, and the amount of this protein in the complex is regulated by SMN, WRAP53 and coilin levels. Collectively, our findings bolster the link between SMN, coilin and the coilin derivative in the biogenesis of telomerase. PMID- 27215324 TI - Zebrafish fin regeneration after cryoinjury-induced tissue damage. AB - Although fin regeneration following an amputation procedure has been well characterized, little is known about the impact of prolonged tissue damage on the execution of the regenerative programme in the zebrafish appendages. To induce histolytic processes in the caudal fin, we developed a new cryolesion model that combines the detrimental effects of freezing/thawing and ischemia. In contrast to the common transection model, the damaged part of the fin was spontaneously shed within two days after cryoinjury. The remaining stump contained a distorted margin with a mixture of dead material and healthy cells that concomitantly induced two opposing processes of tissue debris degradation and cellular proliferation, respectively. Between two and seven days after cryoinjury, this reparative/proliferative phase was morphologically featured by displaced fragments of broken bones. A blastemal marker msxB was induced in the intact mesenchyme below the damaged stump margin. Live imaging of epithelial and osteoblastic transgenic reporter lines revealed that the tissue-specific regenerative programmes were initiated after the clearance of damaged material. Despite histolytic perturbation during the first week after cryoinjury, the fin regeneration resumed and was completed without further alteration in comparison to the simple amputation model. This model reveals the powerful ability of the zebrafish to restore the original appendage architecture after the extended histolysis of the stump. PMID- 27215325 TI - Non-Smc element 5 (Nse5) of the Smc5/6 complex interacts with SUMO pathway components. AB - The Smc5/6 complex in Saccharomyces cerevisiae contains six essential non-Smc elements, Nse1-6. With the exception of Nse2 (also known as Mms21), which is an E3 small ubiquitin-like modifier (SUMO) ligase, very little is understood about the role of these components or their contribution to Smc5/6 functionality. Our characterization of Nse5 establishes a previously unidentified relationship between the Smc5/6 complex and factors of the SUMO pathway. Nse5 physically associates with the E2 conjugating enzyme, Ubc9, where contacts are stabilized by non-covalent interactions with SUMO. SUMO also mediates the interactions between Nse5 and the two PIAS family E3 SUMO ligases, Siz1 and Siz2. Cells carrying the nse5-ts1 allele or lacking either SIZ1 or SIZ2 exhibit a reduction in Smc5 sumoylation upon MMS treatment and demonstrate functional redundancy for SUMO mediated events in the presence of DNA damage. Overall, given the extensive connection between Nse5 and components of the SUMO pathway, we speculate that one function of the Smc5/6 complex might be as a scaffold center to enable sumoylation events in budding yeast. PMID- 27215326 TI - Physiological profiles associated with ceasing growth of unfertilized eggs produced by unmated queens in the subterranean termite Reticulitermes chinensis. AB - In Reticulitermes chinensis, a close relative of R. speratus with asexual queen succession, unfertilized eggs can be produced but do not hatch as larvae. To explain this phenomenon, we analyzed the physiological differences between unfertilized eggs/unmated queens and fertilized eggs/mated queens. Fertilized eggs had significantly lower quantities of five amino acids (Cys, Met, Ile, Leu and Tyr), Ca, protein and cholesterol during development. The higher levels of four trace elements (Na, K, Zn and Fe) in fertilized eggs and their lower levels in mated queens indicated that mated queens might transfer these trace elements to fertilized eggs to aid development. The higher levels of Mn, triglycerides and serotonin in mated queens and higher levels of Mn and glucose in fertilized eggs suggested that these substances are very important for normal ovarian and embryonic growth. The different expression of three reproductive genes (vtg 1, rab 11 and JHE 1) suggested that they might be involved in the regulation of ovarian and embryonic growth. Overall, changes in these physiological indices may substantially affect ovarian and embryonic growth and inhibit development of unfertilized eggs in R. chinensis. PMID- 27215327 TI - Amyloids assemble as part of recognizable structures during oogenesis in Xenopus. AB - A hallmark of Alzheimer's, Huntington's and similar diseases is the assembly of proteins into amyloids rather than folding into their native state. There is an increasing appreciation that amyloids, under specific conditions, may be non pathogenic. Here we show that amyloids form as a normal part of Xenopus oocyte development. Amyloids are detectable in the cytosol and the nucleus using an amyloid binding dye and antibodies that recognize amyloid structure. In the cytosol, yolk platelets are amyloid reactive, as are a number of yet to be characterized particles. In the nucleus, we find particles associated with transcription by RNA polymerase I, II and III and RNA processing contain amyloids. Nuclear amyloids remain intact for hours following isolation; however, RNase treatment rapidly disrupts nuclear amyloids. PMID- 27215328 TI - Spermidine, but not spermine, is essential for pigment pattern formation in zebrafish. AB - Polyamines are small poly-cations essential for all cellular life. The main polyamines present in metazoans are putrescine, spermidine and spermine. Their exact functions are still largely unclear; however, they are involved in a wide variety of processes affecting cell growth, proliferation, apoptosis and aging. Here we identify idefix, a mutation in the zebrafish gene encoding the enzyme spermidine synthase, leading to a severe reduction in spermidine levels as shown by capillary electrophoresis-mass spectrometry. We show that spermidine, but not spermine, is essential for early development, organogenesis and colour pattern formation. Whereas in other vertebrates spermidine deficiency leads to very early embryonic lethality, maternally provided spermidine synthase in zebrafish is sufficient to rescue the early developmental defects. This allows us to uncouple them from events occurring later during colour patterning. Factors involved in the cellular interactions essential for colour patterning, likely targets for spermidine, are the gap junction components Cx41.8, Cx39.4, and Kir7.1, an inwardly rectifying potassium channel, all known to be regulated by polyamines. Thus, zebrafish provide a vertebrate model to study the in vivo effects of polyamines. PMID- 27215329 TI - Interactive digital interventions to promote self-management in adults with asthma: systematic review and meta-analysis. AB - BACKGROUND: To identify, summarise and synthesise the evidence for using interactive digital interventions to support patient self-management of asthma, and determine their impact. METHODS: Systematic review with meta-analysis. We searched MEDLINE, EMBASE, CINAHL, PsycINFO, ERIC, Cochrane Library, DoPHER, TROPHI, Social Science Citation Index and Science Citation Index. The selection criteria requirement was studies of adults (16 years and over) with asthma, interventions that were interactive digital interventions and the comparator was usual care. Outcomes were change in clinical outcomes, cost effectiveness and patient-reported measures of wellbeing or quality of life. Only Randomised Controlled Trials published in peer-reviewed journals in English were eligible. Potential studies were screened and study characteristics and outcomes were extracted from eligible papers independently by two researchers. Where data allowed, meta-analysis was performed using a random effects model. RESULTS: Eight papers describing 5 trials with 593 participants were included, but only three studies were eligible for inclusion for meta-analysis. Of these, two aimed to improve asthma control and the third aimed to reduce the total dose of oral prednisolone without worsening control. Analyses with data from all three studies showed no significant differences and extremely high heterogeneity for both Asthma Quality of Life (AQLQ) (Standardised Mean Difference (SMD) 0.05; 95 % Confidence Interval (CI) 0.32 to -0.22: I2 96.8) and asthma control (SMD 0.21; 95 % CI -0.05 to .42; I2 = 87.4). The removal of the third study reduced heterogeneity and indicated significant improvement for both AQLQ (SMD 0.45; 95 % CI 0.13 to 0.77: I2 = 0.34) and asthma control (SMD 0.54; 95 % CI 0.22 to 0.86: I2 = 0.11). No evidence of harm was identified. CONCLUSION: Digital self management interventions for adults with asthma show promise, with some evidence of small beneficial effects on asthma control. Overall, the evidence base remains weak due to the lack of large, robust trials. PMID- 27215330 TI - Environment-driven somatic mosaicism in brain disorders. AB - The identification of somatic mosaicism in the brain lends a new perspective to our understanding of the role of gene and environment interactions in psychiatric disease risk. Somatic mutations, such as retrotransposon insertions, that are precipitated by modern environmental factors may alter neuronal function and neurological traits, increasing the societal prevalence of mental disorders. PMID- 27215332 TI - Lack of Association Between SLC24A4 Polymorphism and Late-onset Alzheimer's Disease in Han Chinese. AB - Recently, a single nucleotide polymorphism rs10498633 on solute carrier family 24 member 4 (SLC24A4) was revealed to be closely related to the risk of late-onset Alzheimer's disease (LOAD) in a large genome-wide association study containing 74046 individuals in Caucasians. However, no study was performed to validate this relation in other ethnic populations, including Han Chinese. Therefore, we recruited 992 LOAD patients and 1358 age- and sex- matched healthy controls to validate the association between rs10498633 and LOAD susceptibility in Han Chinese. In our total sample, no significant difference was observed between the minor (T) allele of rs10498633 and LOAD risk under a dominant genetic model (OR=0.903, 95% CI: 0.738-1.104, P=0.320). In addition, no significant relation was noted between rs10498633 and LOAD risk in neither apolipoprotein E (APOE) epsilon4 carriers nor non-carriers after adjusting for age and gender. Therefore, our findings indicate that rs10498633 may not play a major role in LOAD susceptibility in Han Chinese. PMID- 27215333 TI - Novel chitosan/diclofenac coatings on medical grade stainless steel for hip replacement applications. AB - Corrosion resistance, biocompatibility, improved osteointegration, as well the prevention of inflammation and pain are the most desired characteristics of hip replacement implants. In this study we introduce a novel multi-layered coating on AISI 316LVM stainless steel that shows promise with regard to all mentioned characteristics. The coating is prepared from alternating layers of the biocompatible polysaccharide chitosan and the non-steroid anti-inflammatory drug (NSAID), diclofenac. Electrochemical methods were employed to characterize the corrosion behavior of coated and uncoated samples in physiological solution. It is shown that these coatings improve corrosion resistance. It was also found that these coatings release the incorporated drug in controlled, multi-mechanism manner. Adding additional layers on top of the as-prepared samples, has potential for further tailoring of the release profile and increasing the drug dose. Biocompatibility was proven on human-derived osteoblasts in several experiments. Only viable cells were found on the sample surface after incubation of the samples with the same cell line. This novel coating could prove important for prolongation of the application potential of steel-based hip replacements, which are these days often replaced by more expensive ceramic or other metal alloys. PMID- 27215334 TI - 3D statistical failure analysis of monolithic dental ceramic crowns. AB - For adhesively retained ceramic crown of various types, it has been clinically observed that the most catastrophic failures initiate from the cement interface as a result of radial crack formation as opposed to Hertzian contact stresses originating on the occlusal surface. In this work, a 3D failure prognosis model is developed for interface initiated failures of monolithic ceramic crowns. The surface flaw distribution parameters determined by biaxial flexural tests on ceramic plates and point-to-point variations of multi-axial stress state at the intaglio surface are obtained by finite element stress analysis. They are combined on the basis of fracture mechanics based statistical failure probability model to predict failure probability of a monolithic crown subjected to single cycle indentation load. The proposed method is verified by prior 2D axisymmetric model and experimental data. Under conditions where the crowns are completely bonded to the tooth substrate, both high flexural stress and high interfacial shear stress are shown to occur in the wall region where the crown thickness is relatively thin while high interfacial normal tensile stress distribution is observed at the margin region. Significant impact of reduced cement modulus on these stress states is shown. While the analyses are limited to single-cycle load to-failure tests, high interfacial normal tensile stress or high interfacial shear stress may contribute to degradation of the cement bond between ceramic and dentin. In addition, the crown failure probability is shown to be controlled by high flexural stress concentrations over a small area, and the proposed method might be of some value to detect initial crown design errors. PMID- 27215336 TI - Single-Dose Electrospun Nanoparticles-in-Nanofibers Wound Dressings with Enhanced Epithelialization, Collagen Deposition, and Granulation Properties. AB - Phenytoin (Ph), an antiepileptic drug, was reported to exhibit high wound healing activity. However, its limited solubility, bioavailability, and inefficient distribution during topical administration limit its use. Therefore, this study aims to develop new single-dose electrospun nanoparticles-in-nanofibers (NPs-in NFs) wound dressings that allow a well-controlled release of Ph. These NPs-in-NFs systems are based on enhanced chitosan (CS)/poly(ethylene oxide) (PEO) electrospun nanofibers (NFs) incorporating optimized Ph-loaded nanocarriers. First, a study was conducted to investigate Ph loading efficiency into polymeric nanocarriers of different types; pluronic nanomicelles and poly(lactic-co glycolic) acids nanoparticles (PLGA NPs). The drug release profile from the nanocarriers was further optimized via lecithin coating. Second, different electrospinning parameters were manipulated to fabricate beads-free homogeneous NFs with optimized polymer ratios. Plain and Ph-loaded nanocarriers were characterized using Fourier transform infrared (FTIR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic light scattering (DLS), and scanning electron microscopy (SEM). Both entrapment efficiency of Ph (EE%) and its release profile in phosphate buffer saline (PBS; pH 5.5), simulating the wound environment, were studied. Biodegradability, swelling, vapor permeability, and porosity of the developed Ph-loaded NPs-in-NFs wound dressings were investigated. Morphology of the NPs-in-NFs was also studied using SEM and confocal laser microscopy (CLSM). Besides, the release profiles of Ph from the optimized NPs-in-NFs were assessed. The newly developed wound dressings were evaluated in vitro for their cytotoxicity using human fibroblasts and in vivo using a wound healing mice model. Nanocarriers with particle size ranging from 100 to 180 nm were successfully prepared. All nanocarriers attained a high drug entrapment efficiency exceeding 94% and showed promising sustained release profiles compared to free Ph. Results also demonstrated that NFs incorporating the optimized lecithin-coated Ph-loaded PLGA NPs could be the most promising candidate for efficient wound healing. These NPs-in-NFs systems conferred a well controlled and sustained release of Ph over 9 days. Moreover, they showed the best re-epithelization and healing quality during the in vivo study with minimal inflammatory and necrotic cells formation. PMID- 27215335 TI - Characterization of clinical extensively drug-resistant Pseudomonas aeruginosa in the Hunan province of China. AB - BACKGROUND: Pseudomonas aeruginosa strains that are classed as extensively drug resistant (XDR-PA) are resistant to all antibiotics except for one or two classes and are frequently the cause of hard-to-treat infections worldwide. Our study aimed to characterize clinical XDR-PA isolates recovered during 2011-2012 at nine hospitals in the Hunan province of China. METHODS: Thirty-seven non-repetitive XDR-PA strains from 37 patients were investigated for genes encoding antimicrobial resistance determinants, efflux pumps, outer membrane proteins, and movable genetic elements using polymerase chain reaction (PCR). The expression of genes encoding the efflux pump component MexA and the outer membrane protein OprD was measured using real-time PCR. In addition, clonal relatedness of these XDR-PA isolates was analyzed by pulsed-field gel electrophoresis (PFGE). RESULTS: Various genes encoding antimicrobial resistance determinants were found in all isolates. In particular, the bla TEM-1, bla CARB, armA, bla IMP-4, bla VIM-2, and rmtB, were found in 100, 37.8, 22, 22, 19 and 5 % of the isolates, respectively. Remarkably, two isolates coharbored bla IMP-4, bla VIM-2, and armA. In all 37 antibiotic-resistant strains, the relative expression of oprD was decreased while mexA was increased compared to the expression of these genes in antibiotic susceptible P. aeruginosa strains. All of the XDR-PA isolates harbored class I integrons as well as multiple other mobile genetic elements, such as tnpU, tnp513, tnpA (Tn21), and merA. A high genotypic diversity among the strains was detected by PFGE. CONCLUSIONS: Multiple antibiotic-resistance mechanisms contributed to the drug resistance of the XDR-PA isolates investigated in this study. Thus, the XDR-PA isolates in this area were not clonally related. Instead, multiple types of movable genetic elements were coharbored within each XDR-PA isolate, which may have aided the rapid development of these XDR-PA strains. This is the first report of XDR-PA strains that coharbor bla IMP-4, bla VIM-2, and armA. PMID- 27215337 TI - Vitamin B12 Grafted Layer-by-Layer Liposomes Bearing HBsAg Facilitate Oral Immunization: Effect of Modulated Biomechanical Properties. AB - Adhesion forces of nanoparticulate materials toward biological membrane are crucial for designing a delivery system for therapeutic molecules and vaccines. The present study aims to investigate the impact of surface roughness of the nanoparticulate system in oral delivery of antigen and its targeting to toward intestinal antigen presenting cells. To evaluate this hypothesis, layer-by-layer coated liposomes (LBL-Lipo) were fabricated using sodium alginate and Vitamin B12 conjugated Chitosan (VitB12-Chi) as anionic and cationic polyelectrolyte, respectively. Change in surface roughness was observed on changes in pH from gastric to intestinal conditions attributed to increase and decrease in charge density on VitB12-Chi. Surface roughness was measured in terms of root-mean square measured by topographical analysis using atomic force microscopy. LBL-Lipo were further characterized for their size, zeta potential, and release behavior to evaluate the potential for oral vaccine delivery. In vitro cell uptake in macrophage cells (J-744) shows about 2- and 3.1-fold increased uptake of rough LBL-Lipo over smooth LBL-Lipo at 37 degrees C (endocytosis) and 4 degrees C (endocytosis inhibition) indicating improved biological interaction. Further in vivo immunization study revealed that prototype formulations were able to produce 4.8- and 3.3-fold higher IgG and IgA levels in serum and feces, respectively, in comparison to smooth LBL-Lipo. PMID- 27215341 TI - Impacts of proline on the central metabolism of an industrial erythromycin producing strain Saccharopolyspora erythraea via (13)C labeling experiments. AB - Saccharopolyspora erythraea E3 is an important industrial strain for erythromycin production and knowledge on its metabolism is limited. In the present work, (13)C labeling experiments were conducted to characterize the metabolism of S. erythraea E3. We found that S. erythraea E3 was difficult to grow on minimal medium with glucose as sole carbon source and the addition of proline remarkably improved the cell growth. The activity of EMP pathway was very low and ED pathway was alternatively the main glucose utilization pathway. The addition of proline resulted in remarkable changes in the fluxes of central metabolism. The fluxes in PP pathway, in TCA cycle and in ED pathway were 90% higher, 64% and 31% lower on Glc/Pro than on Glc, respectively. The maintenance energy on Glc/Pro was 58.4% lower than that on Glc. The energy charge was lower on Glc than on Glc/Pro, indicating that the cells on Glc suffered from energy burden. This study elucidates the impacts of proline on the central metabolism of S. erythraea and deepens the understanding of its metabolism. PMID- 27215342 TI - Impact of Adenovirus infection in host cell metabolism evaluated by (1)H-NMR spectroscopy. AB - Adenovirus-based vectors are powerful vehicles for gene transfer applications in vaccination and gene therapy. Although highly exploited in the clinical setting, key aspects of the adenovirus biology are still not well understood, in particular the subversion of host cell metabolism during viral infection and replication. The aim of this work was to gain insights on the metabolism of two human cell lines (HEK293 and an amniocyte-derived cell line, 1G3) after infection with an adenovirus serotype 5 vector (AdV5). In order to profile metabolic alterations, we used (1)H-NMR spectroscopy, which allowed the quantification of 35 metabolites in cell culture supernatants with low sample preparation and in a relatively short time. Significant differences between both cell lines in non infected cultures were identified, namely in glutamine and acetate metabolism, as well as by-product secretion. The main response to AdV5 infection was an increase in glucose consumption and lactate production rates. Moreover, cultures performed with or without glutamine supplementation confirmed the exhaustion of this amino acid as one of the main causes of lower AdV5 production at high cell densities (10- and 1.5-fold less specific yields in HEK293 and 1G3 cells, respectively), and highlighted different degrees of glutamine dependency of adenovirus replication in each cell line. The observed metabolic alterations associated with AdV5 infection and specificity of the host cell line can be useful for targeted bioprocess optimization. PMID- 27215339 TI - Correspondence between symptom development of Colletotrichum graminicola and fungal biomass, quantified by a newly developed qPCR assay, depends on the maize variety. AB - BACKGROUND: Penetration attempts of the hemibiotroph Colletotrichum graminicola may activate PAMP-triggered immunity (PTI) on different cultivars of Zea mays to different extent. However, in most events, this does not prevent the establishment of a compatible pathogenic interaction. In this study, we investigate the extent to which the host variety influences PTI. Furthermore, we assess whether visual disease symptoms occurring on different maize varieties reliably reflect fungal biomass development in planta as determined by qPCR and GFP tracing. RESULTS: Employing a set of four maize varieties, which were selected from a panel of 27 varieties, for in-depth assessment of pathogenesis of the wild type strain of C. graminicola, revealed considerable differences in susceptibility as evidenced by symptom severity that decreased from variety Golden Jubilee to Mikado to Farmtop to B73. However, a newly developed qPCR assay and microscopical observation of a GFP-labelled strain showed that disease symptoms are in some instances inconsistent when compared with other indicators of susceptibility. Of the four varieties assessed, either Golden Jubilee, Mikado and B73, or Golden Jubilee, Farmtop and B73 showed a direct correlation between symptom and fungal biomass development. In a pairwise comparison, however, Mikado and Farmtop showed an inverse correlation for these features. CONCLUSIONS: The genotype of maize contributes to the severity of symptoms resulting from an infection with C. graminicola. Partially, this may be attributed to the extent of PTI activated in different varieties, as reflected by papilla formation. Furthermore, when evaluating the susceptibility of a variety, it should be considered that symptom severity must not have to reflect the extent of fungal growth in the infected tissue. PMID- 27215346 TI - Fasting-induced daily torpor in desert hamsters (Phodopus roborovskii). AB - Daily torpor is frequently expressed in small rodents when facing energetically unfavorable ambient conditions. Desert hamsters (Phodopus roborovskii, ~20g) appear to be an exception as they have been described as homeothermic. However, we hypothesized that they can use torpor because we observed reversible decreases of body temperature (Tb) in fasted hamsters. To test this hypothesis we (i) randomly exposed fasted summer-acclimated hamsters to ambient temperatures (Tas) ranging from 5 to 30 degrees C or (ii) supplied them with different rations of food at Ta 23 degrees C. All desert hamsters showed heterothermy with the lowest mean Tb of 31.4+/-1.9 degrees C (minimum, 29.0 degrees C) and 31.8+/-2.0 degrees C (minimum, 29.0 degrees C) when fasted at Ta of 23 degrees C and 19 degrees C, respectively. Below Ta 19 degrees C, the lowest Tb and metabolic rate increased and the proportion of hamsters using heterothermy declined. At Ta 5 degrees C, nearly all hamsters remained normothermic by increasing heat production, suggesting that the heterothermy only occurs in moderately cold conditions, perhaps to avoid freezing at extremely low Tas. During heterothermy, Tbs below 31 degrees C with metabolic rates below 25% of those during normothermia were detected in four individuals at Ta of 19 degrees C and 23 degrees C. Consequently, by definition, our observations confirm that fasted desert hamsters are capable of shallow daily torpor. The negative correlation between the lowest Tbs and amount of food supply shows that heterothermy was mainly triggered by food shortage. Our data indicate that summer-acclimated desert hamsters can express fasting-induced shallow daily torpor, which may be of significance for energy conservation and survival in the wild. PMID- 27215345 TI - Effects of thermal increase on aerobic capacity and swim performance in a tropical inland fish. AB - Rising water temperature associated with climate change is increasingly recognized as a potential stressor for aquatic organisms, particularly for tropical ectotherms that are predicted to have narrow thermal windows relative to temperate ectotherms. We used intermittent flow resting and swimming respirometry to test for effects of temperature increase on aerobic capacity and swim performance in the widespread African cichlid Pseudocrenilabrus multicolor victoriae, acclimated for a week to a range of temperatures (2 degrees C increments) between 24 and 34 degrees C. Standard metabolic rate (SMR) increased between 24 and 32 degrees C, but fell sharply at 34 degrees C, suggesting either an acclimatory reorganization of metabolism or metabolic rate depression. Maximum metabolic rate (MMR) was elevated at 28 and 30 degrees C relative to 24 degrees C. Aerobic scope (AS) increased between 24 and 28 degrees C, then declined to a level comparable to 24 degrees C, but increased dramatically 34 degrees C, the latter driven by the drop in SMR in the warmest treatment. Critical swim speed (Ucrit) was highest at intermediate temperature treatments, and was positively related to AS between 24 and 32 degrees C; however, at 34 degrees C, the increase in AS did not correspond to an increase in Ucrit, suggesting a performance cost at the highest temperature. PMID- 27215343 TI - Raised serum levels of IGFBP-1 and IGFBP-2 in idiopathic pulmonary fibrosis. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic lung disorder of unknown origin, which ultimately leads to death. Several growth factors such as IGFs (insulin-like-growth factor) and IGFBPs (insulin like growth factor binding proteins) seem to take part to the pathogenesis. We evaluated IGFs and IGFBPs in serum from patients with IPF and healthy subjects including 24 untreated IPF and 26 IPF receiving anti-fibrotic therapy and to compare them with healthy subjects. METHODS: Serum of 50 idiopathic pulmonary fibrosis and 55 healthy subjects (HS) were analysed by ELISA for IGFs and IGFBPs, TGF-beta and KL-6, the latter being tested as positive control in IPF. RESULTS: Serum levels of IGFBP-1 and IGFBP-2 and KL-6 were significantly higher in the IPF group than in the healthy subjects (p < 0.05, p < 0.001 and p < 0.0001 respectively) while the picture was inversed regarding IGFs. By contrast there was no significant difference between the groups with respect to TGF-beta. IGFBP-2 was significantly reduced in the patients with specific anti-fibrotic therapy pirfenidone and nintedanib compared to untreated patients (p < 0.05) but still significantly elevated in comparison to HS (p < 0.001). CONCLUSION: Serum IGFBP-1 and -2 are increased in idiopathic pulmonary fibrosis and IGFBP-2 may be reduced by anti-fibrosing therapy. IGFBPs may be promising biomarkers in IPF. PMID- 27215347 TI - New algorithm for constructing area-based index with geographical heterogeneities and variable selection: An application to gastric cancer screening. AB - To optimally allocate health resources, policy planners require an indicator reflecting the inequality. Currently, health inequalities are frequently measured by area-based indices. However, methodologies for constructing the indices have been hampered by two difficulties: 1) incorporating the geographical relationship into the model and 2) selecting appropriate variables from the high-dimensional census data. Here, we constructed a new area-based health coverage index using the geographical information and a variable selection procedure with the example of gastric cancer. We also characterized the geographical distribution of health inequality in Japan. To construct the index, we proposed a methodology of a geographically weighted logistic lasso model. We adopted a geographical kernel and selected the optimal bandwidth and the regularization parameters by a two stage algorithm. Sensitivity was checked by correlation to several cancer mortalities/screening rates. Lastly, we mapped the current distribution of health inequality in Japan and detected unique predictors at sampled locations. The interquartile range of the index was 0.0001 to 0.354 (mean: 0.178, SD: 0.109). The selections from 91 candidate variables in Japanese census data showed regional heterogeneities (median number of selected variables: 29). Our index was more correlated to cancer mortalities/screening rates than previous index and revealed several geographical clusters with unique predictors. PMID- 27215344 TI - Circulating secretory IgA antibodies against cyclic citrullinated peptides in early rheumatoid arthritis associate with inflammatory activity and smoking. AB - BACKGROUND: A possible association between mucosal immunization and inflammation, as well as the initiation and propagation of rheumatoid arthritis (RA), is attracting renewed interest. The aim of this study was to evaluate the possible occurrence and clinical correlations of circulating secretory immunoglobulin A (SIgA) antibodies against the second-generation cyclic citrullinated peptides (CCP) among patients with recent-onset RA followed prospectively over 3 years. METHODS: Baseline serum samples from 636 patients with recent-onset RA were analyzed for SIgA anti-CCP antibodies by using an enzyme-linked immunosorbent assay with a secondary antibody directed against secretory component. SIgA anti CCP status at baseline was analyzed in relation to smoking, HLA-DRB1/shared epitope (SE), and the disease course over 3 years. Significant findings were evaluated in regression analysis that included age, sex, smoking, and SE. RESULTS: Seventeen percent of the patients tested positive for circulating SIgA anti-CCP, and the occurrence was confirmed by detection of secretory component in an affinity-purified IgA anti-CCP fraction. SIgA anti-CCP positivity at baseline was associated with slightly higher baseline erythrocyte sedimentation rate (ESR) (mean 38 vs. 31 mm/first hour, p = 0.004) and C-reactive protein (CRP) (mean 30 vs. 23 mg/L, p = 0.047). During follow-up, SIgA anti-CCP-positive patients had a higher mean AUC regarding ESR (adjusted p = 0.003), although there were no significant differences regarding CRP, tender and swollen joint counts, or radiological joint damage (median Larsen progression 1.0 vs. 1.0, p = 0.22). SIgA anti-CCP was associated significantly with smoking (79 % ever smokers among SIgA anti-CCP-positive patients vs. 59 % in SIgA anti-CCP-negative patients, adjusted OR 2.19, 95 % CI 1.01-4.37, p = 0.027) but not with carriage of the SE (80 % vs. 73 %, p = 0.62). CONCLUSIONS: Circulating SIgA anti-CCP, which is present in a subgroup of patients with early RA, is not related to SE, but it is environmentally linked to cigarette smoking. This finding strengthens the hypothesis that immunization against citrullinated peptides and/or proteins may occur at mucosal surfaces of the airways. Analysis of SIgA antibodies in serum may be a convenient and more versatile means to investigate the "mucosal connection" in RA compared with analyses in mucosal fluid samples. PMID- 27215348 TI - The characteristics of railway service disruption: implications for disruption management. AB - Rail disruption management is central to operational continuity and customer satisfaction. Disruption is not a unitary phenomenon - it varies by time, cause, location and complexity of coordination. Effective, user-centred technology for rail disruption must reflect this variety. A repertory grid study was conducted to elicit disruption characteristics. Construct elicitation with a group of experts (n = 7) captured 26 characteristics relevant to rail disruption. A larger group of operational staff (n = 28) rated 10 types of rail incident against the 26 characteristics. The results revealed distinctions such as business impact and public perception, and the importance of management of the disruption over initial detection. There were clear differences between those events that stop the traffic, as opposed to those that only slow the traffic. The results also demonstrate the utility of repertory grid for capturing the characteristics of complex work domains. Practitioner Summary: The aim of the paper is to understand how variety in rail disruption influences socio-technical design. It uses repertory grid to identify and prioritise 26 constructs, and group 10 disruption types, identifying critical factors such as whether an incident stops or merely slows the service, and business reputation. PMID- 27215351 TI - Swampscott in International Context: Expanding Our Ecology of Knowledge. AB - In this paper, I offer reflections as someone from outside the United States about the Swampscott conference. I refer to Fryer and Fox's (The Community Psychologist, 24, 2014, 1) critique of the "Swampscott discourse" and its role in fixing the birthplace of community psychology. While the critique is important, I note the growing references to international community psychology and the need to view the discipline as a product of social political realities in different contexts, as well as dynamics of dominance and marginality in knowledge production in psychology. The work in the Global South presents opportunities to contribute to developing a decolonizing community psychology through expanding the ecology of knowledge. PMID- 27215350 TI - Correlation Between Interleukin-1beta-511 C/T Polymorphism and Gastric Cancer in Chinese Populations: A Meta-Analysis. AB - BACKGROUND Several studies have indicated that interleukin (IL)-1beta-511 C/T polymorphism may contribute to individual susceptibility to gastric cancer, but the results vary among regions and races. No relevant meta-analysis has been conducted in a Chinese population. Therefore, we performed the current meta analysis to investigate the possible correlation between IL-1beta-511 C/T polymorphism and gastric cancer susceptibility in Chinese subjects. MATERIAL AND METHODS PubMed, EmBase, Cochrane Library, Chinese Biology Medicine (CBM), Chinese National Knowledge Infrastructure (CNKI), and Wanfang databases were searched for case-control studies published before 21 January 2015 and investigating a correlation between IL-1beta-511 C/T polymorphism and gastric cancer susceptibility. Two investigators independently screened the studies, extracted data, and evaluated the quality of included studies with the Newcastle-Ottawa scale. Meta-analysis was conducted with STATA 12.0. RESULTS A total of 27 articles from 28 case-control studies were collected. Meta-analysis showed that IL-1beta-511C/T polymorphism was related to increased susceptibility to gastric cancer in Chinese subjects [T vs. C: OR=1.21, 95%CI (1.07-1.37), P<0.01; TT vs. CC: OR=1.41, 95%CI (1.11-1.80), P<0.01; CT vs. CC: OR=1.26, 95% CI (1.05-1.50), P<0.01; TT+CT vs. CC: OR=1.31, 95%CI (1.08-1.58), P<0.01; and TT vs. CT+CC: OR=1.24, 95%CI (1.05-1.47), P<0.01]. Subgroup analysis showed a significant correlation between IL-1beta-511C/T polymorphism and susceptibility to gastric cancer in residents of southern China and in patients with intestinal-type gastric cancer, but not in residents of northern China or in patients with diffuse gastric cancer. Moreover, H. pylori-infected subjects carrying T (CT+TT) exhibited a relatively higher risk of GC [OR=2.4, 95% CI (1.2-5.1), P=0.02]. CONCLUSIONS IL-1beta-511C/T polymorphism is significantly associated with increased susceptibility to gastric cancer in residents of southern China and in intestinal-type gastric cancer. We also found a synergistic interaction between IL-1beta-511C/T polymorphism and H. pylori infection in the development of GC. PMID- 27215353 TI - Sedation and Analgesia in Transportation of Acutely and Critically Ill Patients. AB - Transportation of acutely or critically ill patients is a challenge for health care providers. Among the difficulties that providers face is the balance between adequate sedation and analgesia for the transportation event and maintaining acceptable respiratory and physiologic parameters of the patient. This article describes common challenges in providing sedation and analgesia during various phases of transport. PMID- 27215352 TI - Reengineering of MeSH thesauri for term selection to optimize literature retrieval and knowledge reconstruction in support of stem cell research. AB - BACKGROUND: PubMed is a widely used database for scientists to find biomedical related literature. Due to the complexity of the selected research subject and its interdisciplinary nature, as well as the exponential growth in the number of disparate pieces of biomedical literature, it is an overwhelming challenge for scientists to define the right search strategies and quickly locate all related information. Specialized subsets and groupings of controlled vocabularies, such as Medical Subject Headings (MeSH), can enhance information retrieval in specialized domains, such as stem cell research. There is a need to develop effective search strategies and convenient solutions for knowledge organization in stem cell research. The understanding of the interrelationships between these MeSH terms also facilitates the building of knowledge organization systems in related subject fields. METHODS: This study collected empirical data for MeSH related terms from stem cell literature and developed a novel approach that uses both automation and expert-selection to create a set of terms that supports enhanced retrieval. The selected MeSH terms were reconstructed into a classified thesaurus that can guide researchers towards a successful search and knowledge organization of stem cell literature. RESULTS: First, 4253 MeSH terms were harvested from a sample of 5527 stem cell related research papers from the PubMed database. Next, unrelated terms were filtered out based on term frequency and specificity. Precision and recall measures were used to help identify additional valuable terms, which were mostly non-MeSH terms. The study identified 15 terms that specifically referred to stem cell research for information retrieval, which would yield a higher precision (97.7 %) and recall (94.4 %) rates in comparison to other approaches. In addition, 128 root MeSH terms were selected to conduct knowledge organization of stem cell research in categories of anatomy, disease, and others. CONCLUSIONS: This study presented a novel strategy and procedure to reengineer term selections of the MeSH thesaurus for literature retrieval and knowledge organization using stem cell research as a case. It could help scientists to select their own search terms and build up a thesaurus-based knowledge organization system in interested and interdisciplinary research subject areas. PMID- 27215354 TI - Tolerance and Withdrawal Issues with Sedatives in the Intensive Care Unit. AB - Prolonged use of sedative medications continues to be a concern for critical care practitioners, with potential adverse effects including tolerance and withdrawal. The amount of sedatives required in critically ill patients can be lessened and tolerance delayed with the use of pain and/or sedation scales to reach the desired effect. The current recommendation for prolonged sedation is to wean patients from the medications over several days to reduce the risk of drug withdrawal. It is important to identify patients at risk for iatrogenic withdrawal and create a treatment strategy. PMID- 27215355 TI - Sleep Disturbances and Critical Illness. AB - Sleep disturbances are common in the intensive care unit setting. This article describes the causal factors associated with alterations in sleep in the intensive care setting, effects of sleep disturbances for patients, and strategies to mitigate sleep disturbances. A review of normal sleep architecture is provided, as is a discussion of the methods of measuring sleep in the critical care setting. PMID- 27215356 TI - The Impact of Liver and Renal Dysfunction on the Pharmacokinetics and Pharmacodynamics of Sedative and Analgesic Drugs in Critically Ill Adult Patients. AB - The use of sedative and analgesic drug therapy is often necessary for the care of critically ill patients. Renal and hepatic dysfunction, which occurs frequently in this patient population, can significantly alter drugs' pharmacokinetic and pharmacodynamics properties. By anticipating how these medications may be affected by liver or kidney dysfunction, health care practitioners may be able to provide tailored dosing regimens that ensure optimal comfort while minimizing the risk of adverse events. PMID- 27215357 TI - Sleep and Mechanical Ventilation in Critical Care. AB - Sleep disturbances in critically ill mechanically ventilated patients are common. Although many factors may potentially contribute to sleep loss in critical care, issues around mechanical ventilation are among the more complex. Sleep deprivation has systemic effects that may prolong the need for mechanical ventilation and length of stay in critical care and result in worse outcomes. This article provides a brief review of the physiology of sleep, physiologic changes in breathing associated with sleep, and the impact of mechanical ventilation on sleep. A summary of the issues regarding research studies to date is also included. Recommendations for the critical care nurse are provided. PMID- 27215358 TI - Toward Solving the Sedation-Assessment Conundrum: Neurofunction Monitoring. AB - The sedation-assessment conundrum is the struggle to balance the need for sedation against the need to awaken the patient and perform a neurologic examination. This article discusses the nuances of the sedation-assessment conundrum as well as approaches to resolve this and reduce the negative impact of abruptly stopping sedative infusions. Both oversedation and undersedation affect critically ill patients. This article discusses methods of assessing sedation and interpreting individualized patient responses to sedation. The use of neurofunction monitors and periods of sedation interruption are discussed within the context of addressing the sedation-assessment conundrum. PMID- 27215359 TI - Obstructive Sleep Apnea and Modifications in Sedation: An Update. AB - One factor that may contribute to an increased risk for airway compromise is obstructive sleep apnea (OSA). Sedation in this population carries an increased risk for hypopnea. Critical care nurses must decide on the amount and type of sedation to administer at the point of care. It is important for them to understand OSA and the routinely prescribed sedatives that may affect this disorder. This article discusses the pathophysiology of OSA and traits that may help identify patients with undiagnosed OSA. The most commonly prescribed sedative pharmacologic agents and adjunctive airway support mechanisms are reviewed for use in this population. PMID- 27215360 TI - Complications of Sedation in Critical Illness: An Update. AB - Sedation is a necessary component of care for the critically ill. Oversedation, however, is associated with immediate complications and long-term problems, termed post-intensive care unit syndrome. It also contributes to unnecessary costs of care. This article describes the physical, functional, psychiatric, and cognitive complications of oversedation, and multiple research-based strategies that minimize complications. PMID- 27215361 TI - Application of Clinical Practice Guidelines for Pain, Agitation, and Delirium. AB - Critically ill patients experience several severe, distressing, and often life altering symptoms during their intensive care unit stay. A clinical practice guideline released by the American College of Critical Care Medicine provides a template for improving the care and outcomes of the critically ill through evidence-based pain, agitation, and delirium assessment, prevention, and management. Key strategies include the use of valid and reliable assessment tools, setting a desired sedation level target, a focus on light sedation, choosing appropriate sedative medications, the use of nonpharmacologic symptom management strategies, and engaging and empowering patients and their family to play an active role in their intensive care unit care. PMID- 27215362 TI - Sleep Disturbances in Acutely Ill Patients with Cancer. AB - Intensive care units may place acutely ill patients with cancer at additional risk for sleep loss and associated negative effects. Research suggests that communication about sleep in patients with cancer is suboptimal and sleep problems are not regularly assessed or adequately treated throughout the cancer trajectory. However, many sleep problems and fatigue can be managed effectively. This article synthesizes the current literature regarding the prevalence, cause, and risk factors that contribute to sleep disturbance in the context of acute cancer care. It describes the consequences of poor sleep and discusses appropriate assessment and treatment options. PMID- 27215363 TI - An Update on Sleep and Sedation Issues in Critical Care. PMID- 27215364 TI - Biosimilars in Inflammatory Bowel Disease: Facts and Fears of Extrapolation. AB - Biologic drugs such as infliximab and other anti-tumor necrosis factor monoclonal antibodies have transformed the treatment of immune-mediated inflammatory conditions such as Crohn's disease and ulcerative colitis (collectively known as inflammatory bowel disease [IBD]). However, the complex manufacturing processes involved in producing these drugs mean their use in clinical practice is expensive. Recent or impending expiration of patents for several biologics has led to development of biosimilar versions of these drugs, with the aim of providing substantial cost savings and increased accessibility to treatment. Biosimilars undergo an expedited regulatory process. This involves proving structural, functional, and biological biosimilarity to the reference product (RP). It is also expected that clinical equivalency/comparability will be demonstrated in a clinical trial in one (or more) sensitive population. Once these requirements are fulfilled, extrapolation of biosimilar approval to other indications for which the RP is approved is permitted without the need for further clinical trials, as long as this is scientifically justifiable. However, such justification requires that the mechanism(s) of action of the RP in question should be similar across indications and also comparable between the RP and the biosimilar in the clinically tested population(s). Likewise, the pharmacokinetics, immunogenicity, and safety of the RP should be similar across indications and comparable between the RP and biosimilar in the clinically tested population(s). To date, most anti-tumor necrosis factor biosimilars have been tested in trials recruiting patients with rheumatoid arthritis. Concerns have been raised regarding extrapolation of clinical data obtained in rheumatologic populations to IBD indications. In this review, we discuss the issues surrounding indication extrapolation, with a focus on extrapolation to IBD. PMID- 27215365 TI - New Endoscopic Technologies and Procedural Advances for Endoscopic Hemostasis. AB - Endoscopic interventions are first-line therapy for upper and lower gastrointestinal bleeding. Injection therapy in combination with a second endoscopic modality has reduced re-bleeding, need for surgery and mortality in non-variceal bleeding. For variceal bleeding endoscopic banding or cyanoacrylate injection techniques are recommended interventions. However, despite ease of application and general acceptance of these techniques, there is an ongoing re bleeding rate associated with significant in-hospital mortality. We discuss current literature on new advances in endoscopic technologies and procedural techniques that have emerged to improve patient outcomes. PMID- 27215367 TI - A Unique Case of Diffuse Intestinal and Colonic Leiomyomatosis. PMID- 27215366 TI - Enhancing High Value Care in Gastroenterology Practice. AB - BACKGROUNG & AIMS: The objective of this review is to identify common areas in gastroenterology practice where studies performed provide an opportunity for enhancing value or lowering costs. METHODS: We provide examples of topics in gastroenterology where clinicians could enhance value by either using less invasive testing, choosing a single best test, or by using patient symptoms to guide additional testing. RESULTS: The topics selected for review are selected in esophageal, pancreatic, and colorectal cancer; functional gastrointestinal diseases (irritable bowel syndrome, bacterial overgrowth, constipation); immune mediated gastrointestinal diseases; and pancreaticobiliary pathology. We propose guidance to alter practice based on current evidence. CONCLUSIONS: These studies support the need to review current practice and to continue performing research to further validate the proposed guidance to enhance value of care in gastroenterology and hepatology. PMID- 27215368 TI - A Cu-catalyzed four-component cascade reaction to construct beta-ester-gamma amino ketones. AB - Herein, a novel Cu-catalyzed four-component cascade reaction, which encompasses styrenes, diazo compounds, amines, and tert-butyl hydroperoxide (TBHP), was developed for the synthesis of beta-ester-gamma-amino ketones. Mechanistically, this transformation was initiated by the interception of an electrophilic Cu based carbene with nucleophilic alpha-aminoalkyl radicals, followed by a radical cascade process and an ionic Kornblum-DeLaMare reaction. The methodology was also distinguished by its wide substrate scope, easily available starting materials, and operational simplicity. PMID- 27215370 TI - Editorial: Lipidic Nano-carrier Delivery of "Big" Molecules. PMID- 27215369 TI - Chemical structure and pharmacokinetics of novel quinolone agents represented by avarofloxacin, delafloxacin, finafloxacin, zabofloxacin and nemonoxacin. AB - Quinolones are potent antimicrobial agents with a basic chemical structure of bicyclic ring. Fluorine atom at position C-6 and various substitutions on the basic quinolone structure yielded fluoroquinolones, namely norfloxacin, ciprofloxacin, levofloxacin, moxifloxacin and numerous other agents. The target molecules of quinolones and fluoroquinolones are bacterial gyrase and topoisomerase IV enzymes. Broad-spectrum and excellent tissue penetration make fluoroquinolones potent agents but their toxic side effects and increasing number of resistant pathogens set limits on their use. This review focuses on recent advances concerning quinolones and fluoroquinolones, we will be summarising chemical structure, mode of action, pharmacokinetic properties and toxicity. We will be describing fluoroquinolones introduced in clinical trials, namely avarofloxacin, delafloxacin, finafloxacin, zabofloxacin and non-fluorinated nemonoxacin. These agents have been proved to have enhanced antibacterial effect even against ciprofloxacin resistant pathogens, and found to be well tolerated in both oral and parenteral administrations. These features are going to make them potential antimicrobial agents in the future. PMID- 27215371 TI - Lipid Nanoparticles to Deliver miRNA in Cancer. AB - MicroRNAs (miRNAs) are a class of post-transcriptional gene expression modulators. In the past two decades, over 1500 human miRNAs were discovered. These small non-coding RNAs regulate various biological processes, including cell growth, proliferation, differentiation, and cell death. Thus, miRNAs have been proposed as new therapeutical agents in different multifactorial diseases such as cancer. Since miRNAs therapies represent a great promise, many research studies have been focused on the development of delivery strategies to overcome miRNAs biopharmaceutical issues. Lipid delivery systems are undoubtedly the non-viral carriers most largely investigated due to their biocompatibility, biodegradability, easy production, low toxicity and immunogenicity, possibility to easily modify the carriers for targeting strategies. In this mini-review we provide a rapid and updated overview on the lipid delivery system currently used to deliver miRNAs, pointing out the progresses achieved in the optimization of these nanovectors, which led up to the first clinical trial. PMID- 27215376 TI - Cumulative number of hospital bed days among older adults in the last year of life: A retrospective cohort study. AB - AIM: To determine whether age, proximity to death and long-term care insurance certification are related to receiving hospital inpatient care; the number of hospital bed days (HBD) among older Japanese adults in the last year of life; and to estimate the total number of HBD. METHODS: Using health insurance claims and death certificate data, the present retrospective cohort study examined the HBD of city residents aged >=65 years who died between September 2006 and October 2009 in Soma City, Japan. Using a two-part model, factors associated with receiving hospital inpatient care and the total number of HBD in each quarter in the last year of life were examined. RESULTS: The total number of HBD in the last year of life varied widely; 13% had no admission, and 27% stayed >=90 days. Younger age, approaching death and having long-term care insurance certification were significantly associated with being more likely to receive hospital inpatient care during each quarterly period in the last year of life. In contrast, having long-term care insurance certification and the last 3-month period before death, compared with the first 3-month period, were significantly associated with a fewer number of HBD. CONCLUSIONS: The present study showed that older age was associated with being less likely to receive hospital inpatient care. The findings regarding the risk of inpatient care and total number of HBD in the last year of life help to understand resource use among older dying adults, and to develop evidence-based healthcare policies within aging societies. Geriatr Gerontol Int 2017; 17: 737-743. PMID- 27215377 TI - Progression of motor axon dysfunction and ectopic Nav1.8 expression in a mouse model of Charcot-Marie-Tooth disease 1B. AB - Mice heterozygously deficient for the myelin protein P0 gene (P0+/-) develop a slowly progressing neuropathy modeling demyelinating Charcot-Marie-Tooth disease (CMT1B). The aim of the study was to investigate the long-term progression of motor dysfunction in P0+/- mice at 3, 7, 12 and 20months. By comparison with WT littermates, P0+/- showed a decreasing motor performance with age. This was associated with a progressive reduction in amplitude and increase in latency of the plantar compound muscle action potential (CMAP) evoked by stimulation of the tibial nerve at ankle. This progressive functional impairment was in contrast to the mild demyelinating neuropathy of the tibial nerve revealed by histology. "Threshold-tracking" studies showed impaired motor axon excitability in P0+/- from 3months. With time, there was a progressive reduction in threshold deviations during both depolarizing and hyperpolarizing threshold electrotonus associated with increasing resting I/V slope and increasing strength-duration time constant. These depolarizing features in excitability in P0+/- as well as the reduced CMAP amplitude were absent in P0+/- NaV1.8 knockouts, and could be acutely reversed by selective pharmacologic block of NaV1.8 in P0+/-. Mathematical modeling indicated an association of altered passive cable properties with a depolarizing shift in resting membrane potential and increase in the persistent Na(+) current in P0+/-. Our data suggest that ectopic NaV1.8 expression precipitates depolarizing conduction failure in CMT1B, and that motor axon dysfunction in demyelinating neuropathy is pharmacologically reversible. PMID- 27215378 TI - Coronary computed tomography angiography and calcium scoring in routine clinical practice for identification of patients who require revascularization. AB - BACKGROUND: The predictive value of CCTA to predict coronary artery disease is high in particular in the absence of coronary calcification. However, the consideration of both CCTA and the calcium score, in addition to the risk factors to determine the indication for coronary revascularization, has not been yet studied. MATERIALS AND METHODS: This study included 2302 patients (mean age: 60+/ 9.8 years, 46% men), without known coronary artery disease (CAD), who underwent 320-row CCTA. Logistic regression, c-statistic and net reclassification improvement (NRI) were used to assess the role of coronary artery calcium score (CACS) in predicting revascularization after CCTA. RESULTS: The revascularization rates were 0.75% in patients with a CACS of 0, and there were no adverse events during the follow-up period. The revascularization rates were 3.3% in patients with a CACS of 1-99, 15.4% in patients with a CACS of 100-399, 25.6% in patients with a CACS of 400-999, and 42.4% in patients with a CACS>=1000. The crude and adjusted odds ratios (95% confidence interval) for revascularization per CACS group category were 2.89 (2.53-2.3) and 2.71 (2.33-3.15), respectively; the area under the ROC curve (AUC) was 0.85 (0.83-0.88). The addition of CACS to conventional risk factors improved the accuracy of risk prediction model for revascularization (AUC 0.74 vs 0.63, P=0.001), but it did not reclassify a substantial proportion of patients with positive CACS to risk categories (NRI= 0.023, P=0.66). CONCLUSIONS: The 320-row CCTA might rule out CAD in low- to intermediate-risk patients. However, its accuracy in identifying patients who require revascularization is limited. The CACS added to the conventional risk factors did not improve the identification of patients who require revascularization. PMID- 27215379 TI - Determination of the anti-inflammatory and cytoprotective effects of l-glutamine and l-alanine, or dipeptide, supplementation in rats submitted to resistance exercise. AB - We evaluated the effects of chronic oral supplementation with l-glutamine and l alanine in their free form or as the dipeptide l-alanyl-l-glutamine (DIP) on muscle damage, inflammation and cytoprotection, in rats submitted to progressive resistance exercise (RE). Wistar rats (n 8/group) were submitted to 8-week RE, which consisted of climbing a ladder with progressive loads. In the final 21 d before euthanasia, supplements were delivered in a 4 % solution in drinking water. Glutamine, creatine kinase (CK), lactate dehydrogenase (LDH), TNF-alpha, specific IL (IL-1beta, IL-6 and IL-10) and monocyte chemoattractant protein-1 (MCP-1) levels were evaluated in plasma. The concentrations of glutamine, TNF alpha, IL-6 and IL-10, as well as NF-kappaB activation, were determined in extensor digitorum longus (EDL) skeletal muscle. HSP70 level was assayed in EDL and peripheral blood mononuclear cells (PBMC). RE reduced glutamine concentration in plasma and EDL (P<0.05 v. sedentary group). However, l-glutamine supplements (l-alanine plus l-glutamine (GLN+ALA) and DIP groups) restored glutamine levels in plasma (by 40 and 58 %, respectively) and muscle (by 93 and 105 %, respectively). GLN+ALA and DIP groups also exhibited increased level of HSP70 in EDL and PBMC, consistent with the reduction of NF-kappaB p65 activation and cytokines in EDL. Muscle protection was also indicated by attenuation in plasma levels of CK, LDH, TNF-alpha and IL-1beta, as well as an increase in IL-6, IL-10 and MCP-1. Our study demonstrates that chronic oral l-glutamine treatment (given with l-alanine or as dipeptide) following progressive RE induces cyprotective effects mediated by HSP70-associated responses to muscle damage and inflammation. PMID- 27215380 TI - Requirement for the Mitochondrial Pyruvate Carrier in Mammalian Development Revealed by a Hypomorphic Allelic Series. AB - Glucose and oxygen are two of the most important molecules transferred from mother to fetus during eutherian pregnancy, and the metabolic fates of these nutrients converge at the transport and metabolism of pyruvate in mitochondria. Pyruvate enters the mitochondrial matrix through the mitochondrial pyruvate carrier (MPC), a complex in the inner mitochondrial membrane that consists of two essential components, MPC1 and MPC2. Here, we define the requirement for mitochondrial pyruvate metabolism during development with a progressive allelic series of Mpc1 deficiency in mouse. Mpc1 deletion was homozygous lethal in midgestation, but Mpc1 hypomorphs and tissue-specific deletion of Mpc1 presented as early perinatal lethality. The allelic series demonstrated that graded suppression of MPC resulted in dose-dependent metabolic and transcriptional changes. Steady-state metabolomics analysis of brain and liver from Mpc1 hypomorphic embryos identified compensatory changes in amino acid and lipid metabolism. Flux assays in Mpc1-deficient embryonic fibroblasts also reflected these changes, including a dramatic increase in mitochondrial alanine utilization. The mitochondrial alanine transaminase GPT2 was found to be necessary and sufficient for increased alanine flux upon MPC inhibition. These data show that impaired mitochondrial pyruvate transport results in biosynthetic deficiencies that can be mitigated in part by alternative anaplerotic substrates in utero. PMID- 27215382 TI - Histone Demethylase KDM6A Controls the Mammary Luminal Lineage through Enzyme Independent Mechanisms. AB - Establishment of the mammary luminal cell lineage is controlled primarily by hormones and through specific transcription factors (TFs). Previous studies have linked histone methyltransferases to the differentiation of mammary epithelium, thus opening the possibility of biological significance of counteracting demethylases. We have now demonstrated an essential role for the H3K27me3 demethylase KDM6A in generating a balanced alveolar compartment. Deletion of Kdm6a in the mammary luminal cell lineage led to a paucity of luminal cells and an excessive expansion of basal cells, both in vivo and in vitro The inability to form structurally normal ducts and alveoli during pregnancy resulted in lactation failure. Mutant luminal cells did not exhibit their distinctive transcription factor pattern and displayed basal characteristics. The genomic H3K27me3 landscape was unaltered in mutant tissue, and support for a demethylase independent mechanism came from mice expressing a catalytically inactive KDM6A. Mammary tissue developed normally in these mice. Chromatin immunoprecipitation sequencing (ChIP-seq) experiments demonstrated KDM6A binding to putative enhancers enriched for key mammary TFs and H3K27ac. This study demonstrated for the first time that the mammary luminal lineage relies on KDM6A to ensure a transcription program leading to differentiated alveoli. Failure to fully implement this program results in structurally and functionally impaired mammary tissue. PMID- 27215381 TI - Calpain Genetic Disruption and HSP90 Inhibition Combine To Attenuate Mammary Tumorigenesis. AB - Calpain is an intracellular Ca(2+)-regulated protease system whose substrates include proteins involved in proliferation, survival, migration, invasion, and sensitivity to therapeutic drugs. Genetic disruption of calpain attenuated the tumorigenic potential of breast cancer cells and hypersensitized cells to 17AAG, an inhibitor of the molecular chaperone HSP90. Calpain-1 or -2 overexpression rendered cells resistant to 17AAG, whereas downregulation or inhibition of calpain-1/2 led to increased cell death in multiple breast cancer cell lines, including models of HER2(+) (SKBR3) and triple-negative basal-cell-like (MDA-MB 231) breast cancer. In an MDA-MB-231 orthotopic xenograft model, calpain knockdown or 17AAG treatment independently attenuated tumor growth and metastasis, while the combination was most effective. Calpain knockdown was associated with increased 17AAG-induced degradation of the HSP90 clients cyclin D1 and AKT and multidrug resistance protein 2, which correlated with increased expression of antimitogenic p27(KIP1) and proapoptotic BIM proteins. Like other therapeutics, 17AAG can be effluxed by specific ABC transporters. Calpain expression positively correlated with the expression of P glycoprotein in mouse embryonic fibroblasts. Importantly, we show that calpain affects ABC transporter function and efflux of clinically relevant doxorubicin. These observations provide a compelling rationale for exploring the combination of calpain inhibition with new or existing cancer therapeutics. PMID- 27215383 TI - A Mutation in the Flavin Adenine Dinucleotide-Dependent Oxidoreductase FOXRED1 Results in Cell-Type-Specific Assembly Defects in Oxidative Phosphorylation Complexes I and II. AB - Complex I (NADH ubiquinone oxidoreductase) is a large multisubunit enzyme that catalyzes the first step in oxidative phosphorylation (OXPHOS). In mammals, complex I biogenesis occurs in a stepwise manner, a process that requires the participation of several nucleus-encoded accessory proteins. The FAD-dependent oxidoreductase-containing domain 1 (FOXRED1) protein is a complex I assembly factor; however, its specific role in the assembly pathway remains poorly understood. We identified a homozygous missense mutation, c.1308 G->A (p.V421M) in FOXRED1 in a patient who presented with epilepsy and severe psychomotor retardation. A patient myoblast line showed a severe reduction in complex I, associated with the accumulation of subassemblies centered around ~340 kDa, and a milder decrease in complex II, all of which were rescued by retroviral expression of wild-type FOXRED1. Two additional assembly factors, AIFM1 and ACAD9, coimmunoprecipitated with FOXRED1, and all were associated with a 370-kDa complex I subassembly that, together with a 315-kDa subassembly, forms the 550-kDa subcomplex. Loss of FOXRED1 function prevents efficient formation of this midassembly subcomplex. Although we could not identify subassemblies of complex II, our results establish that FOXRED1 function is both broader than expected, involving the assembly of two flavoprotein-containing OXPHOS complexes, and cell type specific. PMID- 27215384 TI - SCFFbl12 Increases p21Waf1/Cip1 Expression Level through Atypical Ubiquitin Chain Synthesis. AB - The cyclin-dependent kinase (CDK) inhibitor p21 is an unstructured protein regulated by multiple turnover pathways. p21 abundance is tightly regulated, and its defect causes tumor development. However, the mechanisms that underlie the control of p21 level are not fully understood. Here, we report a novel mechanism by which a component of the SCF ubiquitin ligase, Fbl12, augments p21 via the formation of atypical ubiquitin chains. We found that Fbl12 binds and ubiquitinates p21. Unexpectedly, Fbl12 increases the expression level of p21 by enhancing the mixed-type ubiquitination, including not only K48- but also K63 linked ubiquitin chains, followed by promotion of binding between p21 and CDK2. We also found that proteasome activator PA28gamma attenuates p21 ubiquitination by interacting with Fbl12. In addition, UV irradiation induces a dissociation of p21 from Fbl12 and decreases K63-linked ubiquitination, leading to p21 degradation. These data suggest that Fbl12 is a key factor that maintains adequate intracellular concentration of p21 under normal conditions. Our finding may provide a novel possibility that p21's fate is governed by diverse ubiquitin chains. PMID- 27215385 TI - GATA1 Binding Kinetics on Conformation-Specific Binding Sites Elicit Differential Transcriptional Regulation. AB - GATA1 organizes erythroid and megakaryocytic differentiation by orchestrating the expression of multiple genes that show diversified expression profiles. Here, we demonstrate that GATA1 monovalently binds to a single GATA motif (Single-GATA) while a monomeric GATA1 and a homodimeric GATA1 bivalently bind to two GATA motifs in palindromic (Pal-GATA) and direct-repeat (Tandem-GATA) arrangements, respectively, and form higher stoichiometric complexes on respective elements. The amino-terminal zinc (N) finger of GATA1 critically contributes to high occupancy of GATA1 on Pal-GATA. GATA1 lacking the N finger-DNA association fails to trigger a rate of target gene expression comparable to that seen with the wild type GATA1, especially when expressed at low level. This study revealed that Pal GATA and Tandem-GATA generate transcriptional responses from GATA1 target genes distinct from the response of Single-GATA. Our results support the notion that the distinct alignments in binding motifs are part of a critical regulatory strategy that diversifies and modulates transcriptional regulation by GATA1. PMID- 27215386 TI - Allosteric Interactions by p53 mRNA Govern HDM2 E3 Ubiquitin Ligase Specificity under Different Conditions. AB - HDM2 and HDMX are key negative regulatory factors of the p53 tumor suppressor under normal conditions by promoting its degradation or preventing its trans activity, respectively. It has more recently been shown that both proteins can also act as positive regulators of p53 after DNA damage. This involves phosphorylation by ATM on serine residues HDM2(S395) and HDMX(S403), promoting their respective interaction with the p53 mRNA. However, the underlying molecular mechanisms of how these phosphorylation events switch HDM2 and HDMX from negative to positive regulators of p53 is not known. Our results show that these phosphorylation events reside within intrinsically disordered domains and change the conformation of the proteins. The modifications promote the exposition of N terminal interfaces that support the formation of a new HDMX-HDM2 heterodimer independent of the C-terminal RING-RING interaction. The E3 ubiquitin ligase activity of this complex toward p53 is prevented by the p53 mRNA ligand but, interestingly, does not affect the capacity to ubiquitinate HDMX and HDM2. These results show how ATM-mediated modifications of HDMX and HDM2 switch HDM2 E3 ubiquitin ligase activity away from p53 but toward HDMX and itself and illustrate how the substrate specificity of HDM2 E3 ligase activity is regulated. PMID- 27215387 TI - Poly(rC)-Binding Protein 2 Regulates Hippo Signaling To Control Growth in Breast Epithelial Cells. AB - Poly(rC)-binding proteins (PCBPs) are multifunctional adapters that mediate interactions between nucleic acids, iron cofactors, and other proteins, affecting the fates and activities of the components of these interactions. Here, we show that PCBP2 forms a complex with the Hippo pathway components Salvador (Sav1), Mst1, Mst2, and Lats1 in human cells and mouse tissues. Hippo is a kinase cascade that functions to phosphorylate and inactivate the transcriptional coactivators YAP and TAZ, which control cell growth and proliferation. PCBP2 specifically interacts with the scaffold protein Sav1 and prevents proteolytic cleavage of the Mst1 kinase, resulting in increased signaling through Hippo and suppressed activity of YAP and TAZ. Human breast epithelial cells lacking PCBP2 exhibit impaired proteasomal degradation of TAZ. They accumulate TAZ in both the nucleus and the cytosol, increase expression of YAP and TAZ connective tissue growth factor (CTGF) and Cyr61 target genes, and exhibit anchorage-independent growth. Thus, PCBP2 can function as a component of the Hippo complex, enhancing signaling, suppressing activity of YAP and TAZ, and altering the growth characteristics of cells. PMID- 27215388 TI - Novel Grb14-Mediated Cross Talk between Insulin and p62/Nrf2 Pathways Regulates Liver Lipogenesis and Selective Insulin Resistance. AB - A long-standing paradox in the pathophysiology of metabolic diseases is the selective insulin resistance of the liver. It is characterized by a blunted action of insulin to reduce glucose production, contributing to hyperglycemia, while de novo lipogenesis remains insulin sensitive, participating in turn to hepatic steatosis onset. The underlying molecular bases of this conundrum are not yet fully understood. Here, we established a model of selective insulin resistance in mice by silencing an inhibitor of insulin receptor catalytic activity, the growth factor receptor binding protein 14 (Grb14) in liver. Indeed, Grb14 knockdown enhanced hepatic insulin signaling but also dramatically inhibited de novo fatty acid synthesis. In the liver of obese and insulin resistant mice, downregulation of Grb14 markedly decreased blood glucose and improved liver steatosis. Mechanistic analyses showed that upon Grb14 knockdown, the release of p62/sqstm1, a partner of Grb14, activated the transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2), which in turn repressed the lipogenic nuclear liver X receptor (LXR). Our study reveals that Grb14 acts as a new signaling node that regulates lipogenesis and modulates insulin sensitivity in the liver by acting at a crossroad between the insulin receptor and the p62 Nrf2-LXR signaling pathways. PMID- 27215389 TI - The MicroRNA 29 Family Promotes Type II Cell Differentiation in Developing Lung. AB - Lung alveolar type II cells uniquely synthesize surfactant, a developmentally regulated lipoprotein that is essential for breathing. Expression of the gene (SFTPA) encoding the major surfactant protein, SP-A, in midgestation human fetal lung (HFL) is dramatically induced by cyclic AMP (cAMP). cAMP induction of SP-A expression is repressed by transforming growth factor beta (TGF-beta) and by hypoxia. In this study, we found that expression of the microRNA 29 (miR-29) family was significantly upregulated in epithelial cells isolated from mouse fetal lung during late gestation and in epithelial cells isolated from HFL explants during type II cell differentiation in culture. miR-29 expression in cultured HFL epithelial cells was increased by cAMP and inhibited by hypoxia, whereas the miR-29 target, TGF-beta2, was coordinately decreased. Knockdown of the miR-29 family in cultured HFL type II cells blocked cAMP-induced SP-A expression and accumulation of surfactant-containing lamellar bodies, suggesting their physiological relevance. This occurred through derepression of TGF-beta signaling. Notably, cAMP increased binding of endogenous thyroid transcription factor 1 (TTF-1/Nkx2.1) to the miR-29ab1 promoter in HFL type II cells, and TTF-1 increased miR-29ab1 promoter-driven luciferase activity in cotransfection assays. Together, these findings identify miR-29 family members as TTF-1-driven mediators of SP-A expression and type II cell differentiation through repression of TGF beta signaling. PMID- 27215390 TI - Metastasis suppressor proteins in cutaneous squamous cell carcinoma. AB - Cutaneous squamous cell carcinomas (cSCCs) are common human carcinomas. Despite having metastasizing capacities, they usually show less aggressive progression compared to squamous cell carcinoma (SCC) of other organs. Metastasis suppressor proteins (MSPs) are a group of proteins that control and slow-down the metastatic process. In this study, we established the importance of seven well-defined MSPs including NDRG1, NM23-H1, RhoGDI2, E-cadherin, CD82/KAI1, MKK4, and AKAP12 in cSCCs. Protein expression levels of the selected MSPs were detected in 32 cSCCs, 6 in situ SCCs, and two skin cell lines (HaCaT, A-431) by immunohistochemistry. The results were evaluated semi-quantitatively using the HSCORE system. In addition, mRNA expression levels were detected by qRT-PCR in the cell lines. The HSCOREs of NM23-H1 were similar in cSCCs and normal skin tissues, while RGHOGDI2, E-cadherin and AKAP12 were significantly downregulated in cSCCs compared to normal skin. The levels of MKK4, NDRG1 and CD82 were partially conserved in cSCCs. In stage I SCCs, nuclear staining of NM23-H1 (NM23-H1nuc) was significantly lower than in stage II/III SCCs. Only nuclear staining of MKK4 (MKK4nuc) showed significantly higher scores in in situ carcinomas compared to invasive SCCs. In conclusion, similar to other human tumors, we have demonstrated complex differential expression patterns for the MSPs in in-situ and invasive cSCCs. This complex MSP signature warrants further biological and experimental pathway research. PMID- 27215392 TI - Advanced therapies in Parkinson's disease: Long-term retrospective study. AB - BACKGROUND: Levodopa/carbidopa intestinal gel infusion (LCIG) and subthalamic nucleus deep brain stimulation (STN-DBS) are approved therapies for advanced Parkinson's disease (PD) whose long-term comparability remains unclear. METHODS: We reviewed the 5-year data on activities of daily living (ADL) and motor complications (OFF time, dyskinesia duration, and dyskinesia severity), as measured by the Unified Parkinson Disease Rating Scale (UPDRS) section-II and section-IV (items 39, 32, and 33, respectively) in 60 PD patients exposed to STN DBS (n = 20), LCIG (n = 20), and oral medical therapy (OMT) (n = 20) at similar baseline disability and cognitive state. RESULTS: STN-DBS and LCIG showed a similar magnitude of deterioration in ADL (+6.1 vs. +5.7 UPDRS-II; p = 0.709), but lesser than with OMT (+13.7 UPDRS-II; p = 0.005). OFF time also improved to the same extent in STN-DBS and LCIG (-62% vs. -54.5%; p = 0.830), while worsened with OMT (+78.6%; p < 0.001). STN-DBS and LCIG yielded greater improvement on dyskinesia compared to OMT (dyskinesia duration: -66.1% vs. -9.0% vs. +24.2% [p = 0.001]; dyskinesia severity: -68.8% vs. -18.0% vs. +16.2% [p = 0.002]), with relative superiority of STN-DBS over LCIG (p = 0.004 for duration; p = 0.014 for severity). The annualized rate of complication was lower in STN-DBS vs. LCIG (0.13 vs. 0.68; p < 0.001) but not different between STN-DBS and OMT (0.13 vs. 0.10; p = 0.795). CONCLUSIONS: STN-DBS and LCIG showed comparable efficacy in ADL and OFF time, superior to OMT. STN-DBS yielded greater improvement in dyskinesia and lower long-term rate of complications than LCIG. PMID- 27215391 TI - Targeted therapy in ovarian cancer. AB - Among female-specific cancers worldwide, ovarian cancer is the leading cause of death from gynecologic malignancy in the western world. Despite radical surgery and initial high response rates to first-line chemotherapy, up to 70% of patients experience relapses with a median progression-free survival of 12-18 months. There remains an urgent need for novel targeted therapies to improve clinical outcomes in ovarian cancer. This review aims to assess current understanding of targeted therapy in ovarian cancer and evaluate the evidence for targeting growth dependent mechanisms involved in its pathogenesis. Of the many targeted therapies currently under evaluation, the most promising strategies developed thus far are antiangiogenic agents and PARP inhibitors. PMID- 27215393 TI - Profiling cognitive and neuropsychiatric heterogeneity in Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD) is a highly heterogeneous disease, in which motor symptom subtypes are often-described. While it is recognized that motor, cognitive and affective neuropsychiatric symptoms negatively influence the patients' quality of life, it is currently unknown how these symptoms contribute to phenotypic subtypes. The objective of this study was to assess subtypes of motor, cognitive and affective symptoms in PD. METHODS: A hierarchical cluster analysis was conducted on clinical data of 226 PD patients screened at the VU University Medical Center using comprehensive assessment of cognitive, affective and motor symptoms. Subsequent linear discriminant analyses were conducted to investigate discriminating constructs between clusters. RESULTS: The cluster analysis yielded four clusters: (1) a young-age (59.9 years), mildly affected cluster (N = 86), (2) an old-age (72.3 years) cluster with severe motor and non motor symptoms (N = 15), (3) a cluster (age 64.7 years) with mild motor symptoms, below-average executive functioning and affective symptoms (N = 46) and (4) a cluster (age 64.8 years) with severe motor symptoms, affective symptoms and below average verbal memory (N = 79). CONCLUSIONS: Cluster 1 and 2 seem to represent opposite ends of the PD disease stages. Patients in clusters 3 and 4 had similar age, educational level and disease duration but different symptom profiles - we therefore suggest that these clusters represent different pathways of disease progression, presumably with distinct underlying pathology localization. Future research on the neuropathophysiological characteristics of these two clusters and monitoring of disease progression is required. PMID- 27215394 TI - Exogenous melatonin for Parkinson's disease: 'Waking up' to the need for further trials. PMID- 27215395 TI - Nuclear size effects in vibrational spectra. AB - We present a theoretical study of nuclear volume in the rovibrational spectra of diatomic molecules which is an extension of a previous study restricted to rotational spectra [Chem. Phys., 2012, 401, 103]. We provide a new derivation for the electron-nucleus electrostatic interaction energy which is basically independent of the choice of model for the nuclear charge distribution. Starting from this expression we derive expressions for the electronic, rotational and vibrational field shift parameters in terms of effective electron density and its first and second derivatives with respect to internuclear distance. The effective density is often approximated by the contact density, but we demonstrate that this leads to errors on the order of 10% and is furthermore not necessary since the contact and effective densities can be obtained at the same computational cost. We calculate the field shift parameters at the 4-component relativistic coupled-cluster singles-and-doubles level and find that our results confirm the experimental findings of Tiemann and co-workers [Chem. Phys., 1982, 68(21), 1982, Ber. Bunsenges. Phys. Chem., 1982, 86, 821], whereas we find no theoretical justification for a scaling factor introduced in later work [Chem. Phys., 1985, 93, 349]. For lead sulfide we study the effective density as a function of internuclear distance and find a minimum some 0.2 A inside the equilibrium bond distance. We also discuss Bigeleisen-Goeppert-Mayer theory of isotope fractionation in light of our results. PMID- 27215396 TI - A transcriptome-based global map of signaling pathways in the ovarian cancer microenvironment associated with clinical outcome. AB - BACKGROUND: Soluble protein and lipid mediators play essential roles in the tumor environment, but their cellular origins, targets, and clinical relevance are only partially known. We have addressed this question for the most abundant cell types in human ovarian carcinoma ascites, namely tumor cells and tumor-associated macrophages. RESULTS: Transcriptome-derived datasets were adjusted for errors caused by contaminating cell types by an algorithm using expression data derived from pure cell types as references. These data were utilized to construct a network of autocrine and paracrine signaling pathways comprising 358 common and 58 patient-specific signaling mediators and their receptors. RNA sequencing based predictions were confirmed for several proteins and lipid mediators. Published expression microarray results for 1018 patients were used to establish clinical correlations for a number of components with distinct cellular origins and target cells. Clear associations with early relapse were found for STAT3-inducing cytokines, specific components of WNT and fibroblast growth factor signaling, ephrin and semaphorin axon guidance molecules, and TGFbeta/BMP-triggered pathways. An association with early relapse was also observed for secretory macrophage-derived phospholipase PLA2G7, its product arachidonic acid (AA) and signaling pathways controlled by the AA metabolites PGE2, PGI2, and LTB4. By contrast, the genes encoding norrin and its receptor frizzled 4, both selectively expressed by cancer cells and previously not linked to tumor suppression, show a striking association with a favorable clinical course. CONCLUSIONS: We have established a signaling network operating in the ovarian cancer microenvironment with previously unidentified pathways and have defined clinically relevant components within this network. PMID- 27215397 TI - Whole genome sequencing of Gyeongbuk Araucana, a newly developed blue-egg laying chicken breed, reveals its origin and genetic characteristics. AB - Chicken, Gallus gallus, is a valuable species both as a food source and as a model organism for scientific research. Here, we sequenced the genome of Gyeongbuk Araucana, a rare chicken breed with unique phenotypic characteristics including flight ability, large body size, and laying blue-shelled eggs, to identify its genomic features. We generated genomes of Gyeongbuk Araucana, Leghorn, and Korean Native Chicken at a total of 33.5, 35.82, and 33.23 coverage depth, respectively. Along with the genomes of 12 Chinese breeds, we identified genomic variants of 16.3 million SNVs and 2.3 million InDels in mapped regions. Additionally, through assembly of unmapped reads and selective sweep, we identified candidate genes that fall into heart, vasculature and muscle development and body growth categories, which provided insight into Gyeongbuk Araucana's phenotypic traits. Finally, genetic variation based on the transposable element insertion pattern was investigated to elucidate the features of transposable elements related to blue egg shell formation. This study presents results of the first genomic study on the Gyeongbuk Araucana breed; it has potential to serve as an invaluable resource for future research on the genomic characteristics of this chicken breed as well as others. PMID- 27215398 TI - Sea Buckthorn (Hippophae rhamnoides ssp. rhamnoides) Berries in Nordic Environment: Compositional Response to Latitude and Weather Conditions. AB - Flavonol glycosides (FGs) in sea buckthorn (Hippophae rhamnoides ssp. rhamnoides) berries of varieties 'Tytti' and 'Terhi', cultivated in northern Finland (68 degrees 02' N) for six years and southern Finland (60 degrees 23' N) for seven years, were investigated and compared by HPLC-DAD-ESI-MS/MS. The average total content of 23 identified glycosides of isorhamnetin and quercetin was 103 +/- 23 and 110 +/- 21 mg/100 g fresh berries in 'Terhi' and 'Tytti', respectively. The total contents of FGs, flavonol diglycosides, and triglycosides in both varieties were higher in the north than in the south, whereas total flavonol monoglycoside content behaved vice versa (p < 0.05). Among the 89 weather variables studied, the sum of the daily mean temperatures that are 5 degrees C or higher from the start of growth season until the day of harvest was the most important variable which associated negatively with the accumulation of FGs in berries. Such influence was much stronger in berries from the north than from the south. PMID- 27215399 TI - Oligo-based aCGH analysis reveals cryptic unbalanced der(6)t(X;6) in pediatric t(12;21)-positive acute lymphoblastic leukemia. AB - Secondary chromosomal aberrations are necessary for development of overt leukemia in t(12;21)/ETV6-RUNX1-positive acute lymphoblastic leukemia (ALL). Conventional cytogenetic analysis supplemented with locus-specific FISH analyses is gold standard to detect important clonal aberrations in this disease group. However, adequate chromosome banding analysis may often be hampered by poor chromosome morphology and banding patterns in pediatric ALL cases, which may hinder identification of possible clinical important additional chromosomal aberrations. We used oligo-based high-resolution aCGH (oaCGH) analysis as an adjunct tool to enhance conventional cytogenetic analysis in pediatric acute B-cell lymphoblastic leukemia in a prospective single center study during a 4-year period (2012-2015). In a consecutive series of 45 pediatric B-ALLs, we identified eight patients with t(12;21)/ETV6-RUNX1 fusion by FISH analysis. In three of the patients, oaCGH analysis revealed concurrent Xq duplication and 6q deletion, which was cryptic by G-banded analysis. FISH analyses with whole chromosome painting probes confirmed the imbalances and showed an unbalanced translocation der(6)t(X;6) in all three patients. A search in the literature revealed two additional pediatric patients with cryptic der(6)t(X;6) in t(12;21)-positive ALLs. No common break points on Xq or 6q could be determined between the five patients. This study highlights the importance of oaCGH analysis as an adjunct cytogenetic tool to detect cryptic chromosomal aberrations. Further, the study adds to understanding the full spectrum of secondary chromosomal aberrations in the very common t(12;21) positive pediatric ALL disease group. We suggest that the unbalanced der(6)t(X;6), which is cryptic to conventional cytogenetics, is a non-random secondary event in this disease group. It might be that the specific combination of concurrent Xq duplication and 6q-deletion results in gain of possible oncogenes on Xq and loss of possible tumor suppressor genes on 6q that are important for the leukemic propagation of t(12;21)-positive hematopoietic cells in a subset of ALLs. PMID- 27215400 TI - Comparison of next generation sequencing, SNaPshot assay and real-time polymerase chain reaction for lung adenocarcinoma EGFR mutation assessment. AB - BACKGROUND: The epidermal growth factor receptor (EGFR) mutation status assessment has become increasingly important given the significant impact of tyrosine kinase inhibitors in lung cancer management. Our aim was to compare real life operational characteristics for three EGFR mutation assays - two targeted approaches and a next generation sequencing (NGS) technique. METHODS: EGFR mutation status was assessed for lung adenocarcinoma samples (formalin fixed- paraffin embedded samples) using qPCR, SNaPshot and NGS (Ion TorrentTM) techniques. RESULTS: A total of 15 high clinical significance mutations were identified by at least one technique from the total of 64 samples. All mutations were identified by the TaqMan qPCR technique while SNaPshot in conjunction with fragment analysis identified 11 EGFR mutations. The NGS approach followed by an automatic analysis using the default calling parameters identified 10 mutations from the SNaPshot/qPCR panel and other three insertions, five point mutations and 58 silent variants; manual data review identified all 15 high significance mutations. CONCLUSIONS: Performance was similar for high tumor content samples but careful data analysis and post hoc variant calling filter alterations were necessary in order to obtain robust results from low tumor content samples by NGS. NGS is able to generate a comprehensive mutational profile albeit at a higher cost and workload. Result interpretation should take into account not only general run parameters such as mean read depth but also relative coverage and read distribution; currently there is an acute need to define firm recommendations/standards concerning NGS data interpretation and quality control. PMID- 27215402 TI - Erratum To: Peptide Arrays on Planar Supports. PMID- 27215401 TI - The influence of a modified lipopolysaccharide O-antigen on the biosynthesis of xanthan in Xanthomonas campestris pv. campestris B100. AB - BACKGROUND: The exopolysaccharide xanthan is a natural product which is extensively used in industry. It is a thickening agent in many fields, from oil recovery to the food sector. Xanthan is produced by the Gram negative bacterium Xanthomonas campestris pv. campestris (Xcc). We analyzed the lipopolysaccharide (LPS) of three mutant strains of the Xcc wild type B100 to distinguish if the xanthan production can be increased when LPS biosynthesis is affected. RESULTS: The Xcc B100 O-antigen (OA) is composed of a linear main chain of rhamnose residues with N-acetylfucosamine (FucNAc) side branches at every second rhamnose. It is the major LPS constituent. The O-antigen was missing completely in the mutant strain H21012 (deficient in wxcB), since neither rhamnose nor FucNAc could be detected as part of the LPS by MALDI-TOF-MS, and only a slight amount of rhamnose and no FucNAc was found by GC analysis. The LPS of two other mutants was analyzed, Xcc H28110 (deficient in wxcK) and H20110 (wxcN). In both of them no FucNAc could be detected in the LPS fraction, while the rhamnose moieties were more abundant than in wild type LPS. The measurements were carried out by GC and confirmed by MALDI-TOF-MS analyses that indicated an altered OA in which the branches are missing, while the rhamnan main chain seemed longer than in the wild type. Quantification of xanthan confirmed our hypothesis that a missing OA can lead to an increased production of the extracellular polysaccharide. About 6.3 g xanthan per g biomass were produced by the Xcc mutant H21012 (wxcB), as compared to the wild type production of approximately 5 g xanthan per g biomass. In the two mutant strains with modified OA however, Xcc H28110 (wxcK) and Xcc H20110 (wxcN), the xanthan production of 5.5 g and 5.3 g, respectively, was not significantly increased. CONCLUSIONS: Mutations affecting LPS biosynthesis can be beneficial for the production of the extracellular polysaccharide xanthan. However, only complete inhibition of the OA resulted in increased xanthan production. The inhibition of the FucNAc side branches did not lead to increased production, but provoked a novel LPS phenotype. The data suggests an elongation of the linear rhamnan main chain of the LPS OA in both the Xcc H28110 (wxcK) and Xcc H20110 (wxcN) mutant strains. PMID- 27215403 TI - Genetic diversity of the prion protein gene (PRNP) coding sequence in Czech sheep and evaluation of the national breeding programme for resistance to scrapie in the Czech Republic. AB - Of 34 breeds kept in the Czech Republic 45,604 sheep were genotyped for codons 136, 154 and 171 in the prion protein gene (PRNP) during the years 2006-2014. In this cohort, haplotypes ARR, ARQ, ARH, AHQ, VRQ, AHR and ARK were detected. The haplotype AF141RQ associated with susceptibility to atypical scrapie was observed in nine out of 30 breeds analysed for this purpose. In addition, six rare nonsynonymous substitutions producing haplotypes AT137RQ, AN138RQ, AG151RQ, AH151RQ, ARL168Q and ARQE175 were identified in various breeds. Due to their low frequencies, these polymorphisms are of no potential importance for the breeding programme. With regard to their genetic particularity, Sumavka, Valachian and Cameroon breeds were screened for additional polymorphisms. Further haplotypes, AR143RQ and AS146RQ, were found in Sumavka and Cameroon, and in Valachian sheep, respectively. Frequencies of the ARR (resistance-associated), VRQ (susceptibility associated) haplotypes, and of the most resistant ARR/ARR genotype calculated for sheep born in the years 2001-2003 and 2011-2013 documented effects of the 10 year lasting national breeding programme. The total frequency of ARR doubled from 36.8 to 75.8 %, while the frequency of VRQ decreased from 4 to 0.7 %. The total frequency of the ARR/ARR genotype increased from 17.7 to 59 %. These data show that the national scrapie resistance breeding programme has had an important desirable effect on haplotype and genotype frequencies of PRNP in Czech sheep. PMID- 27215404 TI - Regulation of neuroendocrine cells and neuron factors in the ovary by zinc oxide nanoparticles. AB - The pubertal period is an important window during the development of the female reproductive system. Development of the pubertal ovary, which supplies the oocytes intended for fertilization, requires growth factors, hormones, and neuronal factors. It has been reported that zinc oxide nanoparticles (ZnO NPs) cause cytotoxicity of neuron cells. However, there have been no reports of the effects of ZnO NPs on neuronal factors and neuroendocrine cells in the ovary (in vivo). For the first time, this in vivo study investigated the effects of ZnO NPs on gene and protein expression of neuronal factors and the population of neuroendocrine cells in ovaries. Intact NPs were detected in ovarian tissue and although ZnO NPs did not alter body weight, they reduced the ovary organ index. Compared to the control or ZnSO4 treatments, ZnO NPs treatments differentially regulated neuronal factor protein and gene expression, and the population of neuroendocrine cells. ZnO NPs changed the contents of essential elements in the ovary; however, they did not alter levels of the steroid hormones estrogen and progesterone. These data together suggest that intact ZnO NPs might pose a toxic effect on neuron development in the ovary and eventually negatively affect ovarian developmental at puberty. PMID- 27215405 TI - Next-Generation Sequencing in the Diagnosis of Juvenile Neuronal Ceroid Lipofuscinosis. PMID- 27215406 TI - Pediatric Idiopathic Intervertebral Disc Calcification. PMID- 27215407 TI - Breast Cancer Subtypes in Patients Aged 70 Years and Older. AB - Recurrence and survival pattern in breast cancer (bc) patients (pts) >= 70 years subcategorized according to subtype and age are still an area of uncertainty. Tumor characteristics, patient demographics, therapies applied, and recurrence pattern were compared between luminal A (LA), luminal B (LB), Her2/neu overexpressing (Her+) and triple-negative (TN) bc subtypes and the age subcategories 70-74, 75-79, >=80 years. Based on univariate Cox-regression analyses distant-disease-free-survival (DDFS) differed significantly for bc subtypes (p = 0.0002), notably for Her+ vs. LA (p = 0.0014), TN vs. LA (p < 0.001), and TN vs. LB (p = 0.0086). Not age, but Her+ and TN represented prognostic factors for DDFS. PMID- 27215408 TI - Algorithm Variability in the Estimation of Lung Nodule Volume From Phantom CT Scans: Results of the QIBA 3A Public Challenge. AB - RATIONALE AND OBJECTIVES: Quantifying changes in lung tumor volume is important for diagnosis, therapy planning, and evaluation of response to therapy. The aim of this study was to assess the performance of multiple algorithms on a reference data set. The study was organized by the Quantitative Imaging Biomarker Alliance (QIBA). MATERIALS AND METHODS: The study was organized as a public challenge. Computed tomography scans of synthetic lung tumors in an anthropomorphic phantom were acquired by the Food and Drug Administration. Tumors varied in size, shape, and radiodensity. Participants applied their own semi-automated volume estimation algorithms that either did not allow or allowed post-segmentation correction (type 1 or 2, respectively). Statistical analysis of accuracy (percent bias) and precision (repeatability and reproducibility) was conducted across algorithms, as well as across nodule characteristics, slice thickness, and algorithm type. RESULTS: Eighty-four percent of volume measurements of QIBA-compliant tumors were within 15% of the true volume, ranging from 66% to 93% across algorithms, compared to 61% of volume measurements for all tumors (ranging from 37% to 84%). Algorithm type did not affect bias substantially; however, it was an important factor in measurement precision. Algorithm precision was notably better as tumor size increased, worse for irregularly shaped tumors, and on the average better for type 1 algorithms. Over all nodules meeting the QIBA Profile, precision, as measured by the repeatability coefficient, was 9.0% compared to 18.4% overall. CONCLUSION: The results achieved in this study, using a heterogeneous set of measurement algorithms, support QIBA quantitative performance claims in terms of volume measurement repeatability for nodules meeting the QIBA Profile criteria. PMID- 27215410 TI - Erratum to: Self-reported flares are predictors of radiographic progression in rheumatoid arthritis patients in 28-joint disease activity score remission: a 24 month observational study. PMID- 27215409 TI - Plumbagin, a Plant-Derived Compound, Exhibits Antifungal Combinatory Effect with Amphotericin B against Candida albicans Clinical Isolates and Anti-hepatitis C Virus Activity. AB - Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone), the major active constituent of Plumbago indica L., has been shown to be effective against a wide range of infectious microbes. In this study, plumbagin has been evaluated in vitro for its antifungal combinatory effect with amphotericin B against Candida albicans (C. albicans) clinical isolates and anti-hepatitis C virus (HCV) activity. Antifungal activity was determined by broth microdilution method, and combinatory effect was evaluated by checkerboard assay according to SigmaFIC indices, while cytotoxicity was determined by MTT assay. Anti-HCV activity was determined in infected Huh7.5 cells using quantitative real-time reverse transcription PCR, and cytotoxicity was evaluated by MTT assay. Plumbagin exerted inhibitory effect against all C. albicans strains with minimum inhibitory concentration values ranging from 7.41 to 11.24 ug/mL. The additive effect of plumbagin when combined with amphotericin B at concentrations of (0.12, 0.13 and 0.19, 1.81 ug/mL, respectively) was obtained against five of seven strains tested with SigmaFIC ranging from 0.62 to 0.91. In addition, plumbagin was found to be used safely for topical application when combined with amphotericin B at concentrations corresponding to the additive effect. Plumbagin exerted anti-HCV activity compared with that of telaprevir with IC50 values of 0.57 and 0.01 MUM/L, respectively, and selectivity indices SI = 53.7 and SI = 2127, respectively. Our results present plumbagin as a potential therapeutic agent in the treatment of C. albicans and HCV infections. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27215411 TI - An overview of food safety and bacterial foodborne zoonoses in food production animals in the Caribbean region. AB - Foodborne diseases (FBDs) in the Caribbean have a high economic burden. Public health and tourism concerns rise along with the increasing number of cases and outbreaks registered over the last 20 years. Salmonella spp., Shigella spp., and Campylobacter spp. are the main bacteria associated with these incidents. In spite of undertaking limited surveillance on FBD in the region, records related to bacterial foodborne zoonoses in food-producing animals and their associated epidemiologic significance are poorly documented, giving rise to concerns about the importance of the livestock, food animal product sectors, and consumption patterns. In this review, we report the available published literature over the last 20 years on selected bacterial foodborne zoonoses in the Caribbean region and also address other food safety-related aspects (e.g., FBD food attribution, importance, surveillance), mainly aiming at recognizing data gaps and identifying possible research approaches in the animal health sector. PMID- 27215413 TI - Erratum to: Impact of nucleic acid self-alignment in a strong magnetic field on the interpretation of indirect spin-spin interactions. PMID- 27215412 TI - Progesterone receptor blockade in human breast cancer cells decreases cell cycle progression through G2/M by repressing G2/M genes. AB - BACKGROUND: The synthesis of specific, potent progesterone antagonists adds potential agents to the breast cancer prevention and treatment armamentarium. The identification of individuals who will benefit from these agents will be a critical factor for their clinical success. METHODS: We utilized telapristone acetate (TPA; CDB-4124) to understand the effects of progesterone receptor (PR) blockade on proliferation, apoptosis, promoter binding, cell cycle progression, and gene expression. We then identified a set of genes that overlap with human breast luteal-phase expressed genes and signify progesterone activity in both normal breast cells and breast cancer cell lines. RESULTS: TPA administration to T47D cells results in a 30 % decrease in cell number at 24 h, which is maintained over 72 h only in the presence of estradiol. Blockade of progesterone signaling by TPA for 24 h results in fewer cells in G2/M, attributable to decreased expression of genes that facilitate the G2/M transition. Gene expression data suggest that TPA affects several mechanisms that progesterone utilizes to control gene expression, including specific post-translational modifications, and nucleosomal organization and higher order chromatin structure, which regulate access of PR to its DNA binding sites. CONCLUSIONS: By comparing genes induced by the progestin R5020 in T47D cells with those increased in the luteal-phase normal breast, we have identified a set of genes that predict functional progesterone signaling in tissue. These data will facilitate an understanding of the ways in which drugs such as TPA may be utilized for the prevention, and possibly the therapy, of human breast cancer. PMID- 27215414 TI - An efficient genome-wide association test for mixed binary and continuous phenotypes with applications to substance abuse research. AB - We propose a new genome-wide association test for mixed binary and continuous phenotypes that uses an efficient numerical method to estimate the empirical distribution of the Fisher's combination statistic under the null hypothesis. Our simulation study shows that the proposed method controls the type I error rate and also maintains its power at the level of the permutation method. More importantly, the computational efficiency of the proposed method is much higher than the one of the permutation method. The simulation results also indicate that the power of the test increases when the genetic effect increases, the minor allele frequency increases, and the correlation between responses decreases. The statistical analysis on the database of the Study of Addiction: Genetics and Environment demonstrates that the proposed method combining multiple phenotypes can increase the power of identifying markers that may not be, otherwise, chosen using marginal tests. PMID- 27215415 TI - Demand for Emergency Services Trends in New South Wales Years 2010-2014 (DESTINY): Age and Clinical Factors Associated with Ambulance Transportation to Emergency Departments. AB - OBJECTIVES: The study aimed to analyze ambulance transportations to Emergency Departments (EDs) in New South Wales (NSW) and to identify temporal changes in demographics, acuity, and clinical diagnoses. METHODS: This was a retrospective analysis of a population based registry of ED presentations in New South Wales. The NSW Emergency Department data collection (EDCC) collects patient level data on presentations to designated EDs across NSW. Patients that presented to EDs by ambulance between January 2010 and December 2014 were included. Patients dead on arrival, transferred from another hospital, or planned ED presentations were excluded. RESULTS: A total of 10.8 million ED attendances were identified of which 2.6 million (23%) were transported to ED by ambulance. The crude rate of ambulance transportations to EDs across all ages increased by 3.0% per annum over the five years with the highest rate observed in those 85 years and over (620.5 presentations per 1,000 population). There was an increase in the proportion of category 1 and 2 (life-threatening or potentially life-threatening) cases from 18.1% to 24.0%. CONCLUSION: Demand for ambulance services appears to be driven by older patients presenting with higher acuity problems. Alternative models of acute care for elderly patients need to be planned and implemented to address these changes. PMID- 27215416 TI - 3D printing enables separation of orthogonal functions within a hydrogel particle. AB - Multifunctional particles with distinct physiochemical phases are required by a variety of applications in biomedical engineering, such as diagnostic imaging and targeted drug delivery. This motivates the development of a repeatable, efficient, and customizable approach to manufacturing particles with spatially segregated bioactive moieties. This study demonstrates a stereolithographic 3D printing approach for designing and fabricating large arrays of biphasic poly (ethylene glycol) diacrylate (PEGDA) gel particles. The fabrication parameters governing the physical and biochemical properties of multi-layered particles are thoroughly investigated, yielding a readily tunable approach to manufacturing customizable arrays of multifunctional particles. The advantage in spatially organizing functional epitopes is examined by loading superparamagnetic iron oxide nanoparticles (SPIONs) and bovine serum albumin (BSA) in separate layers of biphasic PEGDA gel particles and examining SPION-induced magnetic resonance (MR) contrast and BSA-release kinetics. Particles with spatial segregation of functional moieties have demonstrably higher MR contrast and BSA release. Overall, this study will contribute significant knowledge to the preparation of multifunctional particles for use as biomedical tools. PMID- 27215417 TI - [PCSK9 - "missing link" in familial hypercholesterolemia : New therapeutic options in hypercholesterolemia and coronary artery disease]. AB - Lowering plasma low-density lipoprotein cholesterol (LDL-C) levels to individual therapeutic goals is one of the most effective measures for the prevention of cardiovascular disease. Besides dietary measures, this can be achieved pharmaceutically by inhibition of hepatic cholesterol synthesis with statins or inhibition of intestinal cholesterol absorption (e.g., ezetimibe and bile acid sequestrants). Decisive for lowering LDL is an increased hepatic uptake of circulating LDL via an increase in LDL receptors (LDLR) in hepatic cell membranes. The formation of new LDLR and recirculation of existing LDLR play a decisive role in this process. An important modulator of LDLR is proprotein convertase subtilisin/kexin type 9 (PCSK9). In the last years genetic studies have identified several mutations in the PCSK9 gene leading to a gain of function and carriers of these mutations suffer from autosomal dominant hypercholesterolemia. In contrast, carriers of PCSK9 loss of function mutations show very low plasma LDL-C concentrations and a markedly reduced risk for coronary artery disease. These fundamental discoveries have sparked the development of a completely novel therapeutic approach to treating hypercholesterolemia. At present, inhibition of PCSK9 by monoclonal antibodies presents the most promising therapeutic approach. First human antibodies were recently approved as the first immunotherapeutic agents for the treatment of severe hypercholesterolemia and in patients with statin intolerance. An additional PCSK9 antibody is presently being studied in phase III clinical trials. PMID- 27215418 TI - [PCSK9 inhibitors : New treatment option in clinical practice]. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipoprotein (LDL) receptors leading to their degradation in the liver. Inhibition of PCSK9 leads to an increase in LDL receptors and as a result to a reduction of LDL cholesterol in blood. Currently, two antibodies against PCSK9 are available for clinical treatment in Germany, evolocumab (Repatha(r)) and alirocumab (Praluent(r)). Clinical studies have shown that treatment with these antibodies, which must be subcutaneously injected by patients every 2 or 4 weeks, in addition to an already existing lipid therapy can lower the LDL cholesterol level in blood by an average of 50-60 %. Data from previous study programs show that this treatment is safe although long-term data are still lacking. The results of currently running cardiovascular endpoint studies are not yet available, whereby a beneficial effect is to be expected after the preliminary analyses. These novel effective therapy approaches open up new perspectives for the treatment of patients whose LDL cholesterol values are still in excess of the corresponding target values despite previous maximum lipid-reducing therapy and suffer from a preexisting cardiovascular disease, statin intolerance, genetic forms of familiar hypercholesterolemia and patients on LDL apheresis. PMID- 27215420 TI - Prevalence of High-Grade Intraepithelial Neoplasia in Patients with Cytology Presenting Atypical Squamous Cells of Undetermined Significance. AB - OBJECTIVES: To evaluate the prevalence of histological high-grade lesions and cervical cancer in patients with ASCUS cytology. METHODS: This is a cross sectional prospective study involving 703 women with a uterus and atypical squamous cells of undetermined significance (ASCUS). The patients were submitted to a colposcopy and underwent a guided biopsy when changes on the colposcopy were detected. RESULTS: The findings revealed 456 (64.9%) women with a normal colposcopy and 247 (35.1%) with colposcopic abnormalities. The biopsy results were: cervical intraepithelial neoplasia grade 1 (CIN 1) in 51 (20.6%) patients, CIN 2 in 11 (4.5%) patients, CIN 3 in 8 (3.2%) patients, and a negative result in 177 (71.7%) patients; no cases of cancer were detected. Tallying of 456 normal colposcopies and 177 negative biopsies yielded a total of 90.04% negative exams. Furthermore, around 7.2% (51/703) of the patients exhibited CIN 1, a lesion associated with a high potential for regression. The biopsy results were not associated with patient age or menopausal status. CONCLUSION: We conclude that cytological surveillance of patients with ASCUS is feasible and safe given the low risk of CIN 2/3 or cervical cancer. PMID- 27215421 TI - Call to Publish in an Undergraduate Medical Course: Dissemination of the Final Year Research Project. AB - PROBLEM: Today's medical doctors must not only have the clinical skills to treat patients effectively but also keep current with new advances in medicine and critically analyze evidence to choose the best treatments and explain the risks and benefits of different options. In this article, we aim to share the approach taken at a Portuguese medical school to promote a close connection between research and learning. INTERVENTION: In a blended-learning approach, students studied research and scientific methods and undertook one of three faculty supervised research and dissemination projects. To support immediate application of new research knowledge, students were offered optional short lectures and problem sets. All course information was featured on a website that also supported a discussion forum. We analyzed 1,350 theses leading to the medical degree, defended in six consecutive academic years (2007-2013). Our aim was to estimate the publication rates and factors associated with publication of the final-year undergraduate research projects. CONTEXT: The present research curriculum was developed at the University of Porto Faculty of Medicine as part of the Bologna process curriculum implemented in the 2007-2008 academic year. From May to June 2014 we looked for corresponding articles published over the period of September 2007 to April 2014. We searched PubMed, Scielo, Scopus, and IndexRMP databases to locate publications resulting from student theses. OUTCOMES: Over 6 years, the diffusion of knowledge produced by medical students, who engaged in clinical practice concurrently with research projects, was fairly low (10.4%). Program modifications that increased student accountability and engagement allowed for an increased rate of publication from 1.0% to 23.9%. Factors associated with publication were research area, publication as a performance assessment criterion, and publication language. LESSONS LEARNED: The results of this study suggest that it is helpful to provide research opportunities that allow aspiring future medical doctors to begin their research careers. Further research is needed to understand difficulties students and supervisors face in project development and to achieve greater balance in topic coverage among projects and, consequently, in departmental involvement in the program. PMID- 27215422 TI - The Learning Curve in Robotic Pancreaticoduodenectomy. AB - BACKGROUND/PURPOSE: Few data are available on the learning curve (LC) in robot assisted pancreaticoduodenectomy (RAPD) and no study specifically addresses the LC of a single surgeon. METHODS: The LC of a single surgeon in RAPD was determined using the cumulative sum method, based on operative time (OT). Data were extracted from a prospectively maintained database and analyzed retrospectively considering all events occurring within 90 days of index operation. RESULTS: Seventy RAPD were analyzed. One operation was converted to open surgery (1.4%). One patient died within 30 days (1.4%) and one within 90 days (2.8%). Postoperative complications occurred in 53 patients (75.7%) and exceeded Clavien-Dindo grade IIIb in 7 patients (10%). OT dropped after 33 operations from a mean of 564 +/- 101.7 min to a mean of 484.1 +/- 77.9 min (p = 0.0005) and was associated to reduced incidence of delayed gastric emptying (72.7 vs. 48.7%; p = 0.039). The rate of hospital readmission improved after 40 operations from 20.0 (8 of 40) to 3.3% (1 of 30) (p = 0.04). CONCLUSIONS: RAPD was safely feasible in selected patients. OT dropped after the first 33 operations and was associated with reduced rate of delayed gastric emptying. Readmission rate improved after 40 operations. PMID- 27215419 TI - [Impact of lipid metabolism parameters on the development and progression of coronary artery disease : An update]. AB - Disorders of lipid metabolism play a major role in the development and progression of coronary artery disease. Dyslipidemia therefore plays a central role in therapeutic approaches for prevention and treatment of cardiovascular events associated with coronary artery disease. Epidemiological studies have shown an association between various lipid metabolism parameters, the risk of developing coronary artery disease and progression of a pre-existing disease. In particular, increased levels of low-density lipoprotein cholesterol (LDL-C), reduced levels of HDL cholesterol (HDL-C), as well as high levels of triglycerides and increased lipoprotein(a) [Lp(a)] levels can be taken into account when assessing the risk stratification of patients for primary prevention of coronary artery disease. Lifestyle and dietary changes, intensified statin therapy and possibly the addition of ezetimibe remain the major interventions in both primary and secondary prevention of coronary artery disease, as they improve the prognosis particularly by lowering levels of LDL-C. Recently, genetic studies have contributed to extending our understanding of the relationship between lipid metabolism and coronary artery disease. A causal role for progression of coronary artery disease could be demonstrated for LDL-C, Lpa and triglyceride-rich lipoproteins (TRL), which could not be demonstrated for HDL-C in various studies. Furthermore, the effect of reduction of LDL-C by proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition and by the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib on cardiovascular events is currently being investigated in large clinical outcome study programs. PMID- 27215423 TI - Low Occurrence of Extended-Spectrum beta-lactamase-Producing Escherichia coli in Finnish Food-Producing Animals. AB - ESBL/AmpC-producing Escherichia coli is increasingly isolated from humans and animals worldwide. The occurrence of ESBL/AmpC-producing E. coli was studied in food-producing animals in Finland, a country with a low and controlled use of antimicrobials in meat production chain. A total of 648 cattle, 531 pig, 495 broiler and 35 turkey faecal samples were collected from four Finnish slaughterhouses to determine the presence of extended-spectrum beta-lactamase (ESBL/AmpC)-producing E. coli. In addition, 260 broiler and 15 turkey samples were screened for carbapenemase-producing E. coli. Susceptibility to different class of cephalosporins and meropenem was determined with disc diffusion tests according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Determination of ESBL/AmpC production was performed with a combination disc diffusion test according to the recommendations of the European Food Safety Authority (EFSA). Plasmidic blaESBL/AmpC genes were characterized by polymerase chain reaction and sequencing. A collection of isolates producing AmpC enzyme but not carrying plasmidic blaAmpC was analysed by PCR and sequencing for possible chromosomal ampC promoter area mutations. Altogether ESBL/AmpC-producing E. coli was recovered from five cattle (0.8%), eight pig (1.5%) and 40 broiler samples (8.1%). No ESBL/AmpC-producing E. coli was found in turkey samples. Carbapenem resistance was not detected. Altogether ESBL/AmpC-producing E. coli was found on 4 (2.0%), 3 (4.5%) and 14 (25%) cattle, pig and broiler farms, respectively. From cattle samples 3 (27%) blaCTX-M-1 and from broiler samples 13 (33%) blaCTX-M-1 and 22 (55%) blaCMY-2 gene-carrying isolates were detected. In pigs, no plasmidic blaESBL/AmpC gene-carrying isolates were found. In all analysed isolates, the same mutations in the promoter region of chromosomal ampC were detected. The results showed low occurrence of ESBL/AmpC-producing E. coli in Finnish food producing animals. In pigs, plasmidic blaESBL/AmpC -carrying E. coli was not detected at all. PMID- 27215424 TI - Investigation of newly identified G-quadruplexes and their application to DNA detection. AB - G-quadruplexes are guanine-rich nucleic acid sequences that can act as universal signal-transducers and generate colorimetric, fluorescence, and chemiluminescence signals when complexed with different ligands. Due to their merits including easy modification and low cost, it is of great importance to explore new G quadruplexes with improved performance. Herein the properties of newly identified G-quadruplexes 9th-3-35 and 10th-2-40 were investigated in detail with UV-vis spectra, circular dichroism (CD) spectra and fluorescence spectra. The results indicated that 9th-3-35 and 10th-2-40 exhibited excellent peroxidase-like activity, as well as fluorescence enhancement of thioflavin T (ThT). Furthermore, the application of G-quadruplexes to DNA detection was performed on account of the ThT fluorescence enhancement, and the limit of detection was as low as 8 pM. This study implied that 9th-3-35 and 10th-2-40 are competitive candidates as signal-transducers in the design of bioassays. PMID- 27215425 TI - Prostate cancer: Prudent practice optimizes screening outcomes. PMID- 27215427 TI - Prostate cancer: Genetics of mCRPC tracked in ctDNA. PMID- 27215426 TI - Advances in laparoscopic surgery in urology. AB - In the past 10 years, laparoscopy has been challenged by robotic surgery; nevertheless, laparoscopic techniques are subject to continuous change. Ultrahigh definition is the next development in video technology, it delivers fourfold more detail than full high definition resulting in improved fine detail, increased texture, and an almost photographic emulsion of smoothness of the image. New 4K ultrahigh-definition technology might remove the current need for the use of polarized glasses. New devices for laparoscopy include advanced sealing devices, instruments with six degrees of freedom, ergonomic platforms with armrests and a chest support, and camera holders. A manually manipulated robot-like device is still at the experimental stage. Robot-assisted surgery has substantially revolutionized laparoscopy, increasing its distribution; however, robot-assisted surgery is associated with considerable costs. All technical improvements of laparoscopic surgery are extremely valuable to further simplify the use of classical laparoscopy. PMID- 27215428 TI - Prostate cancer: ADT after radical prostatectomy - when and how? PMID- 27215430 TI - The triangles of Grynfeltt and Petit and the lumbar tunnel: an anatomo-radiologic study. AB - PURPOSE: Lumbar hernias are protrusions of intra-abdominal contents classically through the superior (Grynfeltt) and inferior (Petit) lumbar triangles. The anatomy of the triangles is variable and quantitative data are few. No radiological data on the anatomy of the triangles are available. METHODS: Fifty computed tomography angiography of the upper abdomen (M25, F25, mean age 72.5 year-old) were analyzed. The dimensions and the contents of the lumbar triangles were analyzed. The characteristics of the space between the two triangles were also documented. RESULTS: The superior lumbar triangle showed a mean surface area of 5.10 +/- 2.6 cm2. In the area of the triangle, the 12th intercostal pedicle and the 1st lumbar branches of the iliolumbar vessels were found in 42 and 46 %, respectively. The inferior lumbar triangle had a mean surface of area 18.7 +/- 8.4 cm2. In this area, the 2nd, 3rd, and 4th lumbar branches were found in 9, 67, and 8 %, respectively. On oblique coronal images, a direct tunnel between the superior and the inferior lumbar triangles was found, showing an oblique course, with a postero-anterior direction (mean length 36.5 +/- 5.8 mm, mean caliber 7.4 +/- 3.1 mm). CONCLUSIONS: Among the anatomical factors of weakening of the abdominal wall, the course of branches of the lumbar vessels was documented not only in the superior but also in the inferior lumbar triangle. A real musculoaponeurotic tunnel between the superior and the inferior lumbar triangles located in the oblique coronal plane was found, that could play a role in the development of incarceration or strangulation of lumbar hernias. PMID- 27215431 TI - Predicting pulmonary fibrosis in humans after exposure to multi-walled carbon nanotubes (MWCNTs). AB - The increased production and use of multi-walled carbon nanotubes (MWCNTs) in a diverse array of consumer, medical, and industrial applications have raised concerns about potential human exposure to these materials in the workplace and ambient environments. Inhalation is a primary route of exposure to MWCNTs, and the existing data indicate that they are potentially hazardous to human health. While a 90-day rodent inhalation test (e.g., OECD Test No. 413: subchronic inhalation toxicity: 90-day study or EPA Health Effects Test Guidelines OPPTS 870.3465 90-day inhalation toxicity) is recommended by the U.S. Environmental Protection Agency Office of Pollution Prevention and Toxics for MWCNTs (and other CNTs) if they are to be commercially produced (Godwin et al. in ACS Nano 9:3409 3417, 2015), this test is time and cost-intensive and subject to scientific and ethical concerns. As a result, there has been much interest in transitioning away from studies on animals and moving toward human-based in vitro and in silico models. However, given the multiple mechanisms of toxicity associated with subchronic exposure to inhaled MWCNTs, a battery of non-animal tests will likely be needed to evaluate the key endpoints assessed by the 90-day rodent study. Pulmonary fibrosis is an important adverse outcome related to inhalation exposure to MWCNTs and one that the non-animal approach should be able to assess. This review summarizes the state-of-the-science regarding in vivo and in vitro toxicological methods for predicting MWCNT-induced pulmonary fibrosis. PMID- 27215433 TI - Photonic Quantum Networks formed from NV(-) centers. AB - In this article we present a simple repeater scheme based on the negatively charged nitrogen vacancy centre in diamond. Each repeater node is built from modules comprising an optical cavity containing a single NV(-), with one nuclear spin from (15)N as quantum memory. The module uses only deterministic processes and interactions to achieve high fidelity operations (>99%), and modules are connected by optical fiber. In the repeater node architecture, the processes between modules by photons can be in principle deterministic, however current limitations on optical components lead the processes to be probabilistic but heralded. Our resource-modest repeater architecture contains two modules at each node, and the repeater nodes are then connected by entangled photon pairs. We discuss the performance of such a quantum repeater network with modest resources and then incorporate more resource-intense strategies step by step. Our architecture should allow large-scale quantum information networks with existing or near future technology. PMID- 27215434 TI - The Use of Medical Marijuana in Cancer. AB - The use of medical marijuana in cancer care presents a dilemma for both patients and physicians. The scientific evidence is evolving, yet much of the known information is still insufficient to adequately inform patients as to risks and benefits. In addition, evidence-based dosing and administration information on medical marijuana is lacking. Medical marijuana is now legal, on some level, in 24 states plus the District of Columbia, yet is not legal on the federal level. This review addresses the current state of the research, including potential indications, risks and adverse effects, preliminary data on anticancer effects, as well as legal and quality issues. A summary of the clinical trials underway on medical marijuana in the oncology setting is discussed. PMID- 27215429 TI - Oncolytic virotherapy for urological cancers. AB - Oncolytic virotherapy is a cancer treatment in which replication-competent viruses are used that specifically infect, replicate in and lyse malignant tumour cells, while minimizing harm to normal cells. Anecdotal evidence of the effectiveness of this strategy has existed since the late nineteenth century, but advances and innovations in biotechnological methods in the 1980s and 1990s led to a renewed interest in this type of therapy. Multiple clinical trials investigating the use of agents constructed from a wide range of viruses have since been performed, and several of these enrolled patients with urological malignancies. Data from these clinical trials and from preclinical studies revealed a number of challenges to the effectiveness of oncolytic virotherapy that have prompted the development of further sophisticated strategies. Urological cancers have a range of distinctive features, such as specific genetic mutations and cell surface markers, which enable improving both effectiveness and safety of oncolytic virus treatments. The strategies employed in creating advanced oncolytic agents include alteration of the virus tropism, regulating transcription and translation of viral genes, combination with chemotherapy, radiotherapy or gene therapy, arming viruses with factors that stimulate the immune response against tumour cells and delivery technologies to ensure that the viral agent reaches its target tissue. PMID- 27215435 TI - Personalised Treatment in Gastric Cancer: Myth or Reality? AB - Despite recent diagnostic and therapeutic advances, the survival of patients with gastric cancer is still poor. The majority of patients are diagnosed with advanced disease and chemotherapy represents the only possible therapeutic approach. However, chemotherapy seems to have reached an efficacy plateau in this setting. Gastric cancer is a complex and heterogeneous disease because it emerges from multiple interactions of genetic, environmental and host factors. A better understanding of its molecular characteristics may lead to an improvement of outcomes. The recent molecular classification by The Cancer Genome Atlas project divides gastric cancer into four subtypes that could be taken into consideration in future clinical trials with targeted agents. So far trastuzumab, a monoclonal antibody addressing the HER2 receptor, is the only targeted agent approved in the first-line setting, but only in patients overexpressing HER2. Negative data have been obtained in first-line therapy when antiangiogenics, anti-EGFR or anti-MET monoclonal antibodies have been studied in randomised controlled trials. Ramucirumab, a monoclonal antibody binding to VEGFR2, is the only antiangiogenic agent currently recommended in patients progressing after first-line treatment. In this review, we discuss whether personalised therapy may have a role in gastric cancer. PMID- 27215436 TI - Influences of BRAF Inhibitors on the Immune Microenvironment and the Rationale for Combined Molecular and Immune Targeted Therapy. AB - The identification of key driver mutations in melanoma has led to the development of targeted therapies aimed at BRAF and MEK, but responses are often limited in duration. There is growing evidence that MAPK pathway activation impairs antitumor immunity and that targeting this pathway may enhance responses to immunotherapies. There is also evidence that immune mechanisms of resistance to targeted therapy exist, providing the rationale for combining targeted therapy with immunotherapy. Preclinical studies have demonstrated synergy in combining these strategies, and combination clinical trials are ongoing. It is, however, becoming clear that additional translational studies are needed to better understand toxicity, proper timing, and sequence of therapy, as well as the utility of multidrug regimens and effects of other targeted agents on antitumor immunity. Insights gained through translational research in preclinical models and clinical studies will provide mechanistic insight into therapeutic response and resistance and help devise rational strategies to enhance therapeutic responses. PMID- 27215437 TI - A Novel Approach to the Nutrigenetics and Nutrigenomics of Obesity and Weight Management. AB - Nutrigenetics and nutrigenomics, as well as diet and exercise, play an important role in the development and treatment of obesity and its comorbidities. If an individual's susceptibility to becoming obese and their responsiveness to weight loss interventions are to be understood, then it needs to be addressed at a molecular and metabolic level, including genetic interaction. This review proposes a three-pillar approach to more fully comprehend the complexity of diet gene interactions in obesity. Peroxisomal proliferating-activated receptor gamma (PPARG) and mitochondrial uncoupling protein-1 (UCP-1) are explored in detail. Illustrating how an understanding of nutritional biochemistry, nutrigenomics, and nutrigenetics may be the key to understanding differences observed in the obese phenotype that vary both within and across populations. PMID- 27215438 TI - A wheat histone variant gene TaH2A.7 enhances drought tolerance and promotes stomatal closure in Arabidopsis. AB - KEY MESSAGE: We found a histone variant enhances drought tolerance partially via promoting stomatal closure other than osmotic stress resistance, indicating the crucial and complicated contribution of epigenetic regulation to abiotic stress response. Histone variants epigenetically regulate gene transcription through remodeling chromatin. They have been implicated in modulating plant abiotic stress response, however, the role(s) is not well documented. Here, we identified an abiotic stress responsive H2A variant gene TaH2A.7 from wheat. TaH2A.7 shared high identity with H2A homologs and localized to the nucleus. TaH2A.7 overexpression in Arabidopsis significantly enhanced drought tolerance, but had no effect on the response to saline, osmotic and oxidative stresses. TaH2A.7 lowered water loss rate, and promoted ABA-induced stomatal closure. In TaH2A.7 overexpression plants, the mRNA levels of numerous genes involved in the ABA pathway and stomatal movement signaling pathway were elevated, H2O2 level in guard cells was increased, as well. Together, TaH2A.7 can enhance drought tolerance via, at least in part, promoting stomatal closure, and appears to be a promising target for molecular breeding. PMID- 27215440 TI - Role of Colloidal Drug Delivery Carriers in Taxane-mediated Chemotherapy: A Review. AB - Chemotherapy is one of the most frequently employed and reliable treatment options for the management of a variety of cancers. Taxanes (paclitaxel, docetaxel and cabazitaxel) are frequently prescribed to treat breast cancer, hormone refractory prostate cancer, non-small cell lung cancer and ovarian cancer. Most of the commercial products of taxanes are available as injectables, which are not patient compliant and are associated with frequent side effects like ototoxicity, baldness and neurotoxicity. Most of these concerns are ascribable to the presence of toxic solvents in these commercial formulations, which are used to solubilize these drug(s). However, there have been several attempts to develop toxic solvent free taxane formulations, especially employing novel drug delivery systems (NDDS). These systems have been reported to result in the advancement of anticancer activity, therapeutic index, stability, biocompatibility, tissue or organ targeting, encapsulation capacity, tissue permeability, oral bioavailability, reduced toxicity and reduced incidences of abnormal reactions, sustained and controlled release in comparison to the conventional solvent-based formulations. The review is an attempt to analyze the potential of NDDS-mediated taxane delivery for safer and effective cancer chemotherapy. PMID- 27215439 TI - A low-temperature-responsive element involved in the regulation of the Arabidopsis thaliana At1g71850/At1g71860 divergent gene pair. AB - KEY MESSAGE: The bidirectional promoter of the Arabidopsis thaliana gene pair At1g71850/At1g71860 harbors low-temperature-responsive elements, which participate in anti-correlated transcription regulation of the driving genes in response to environmental low temperature. A divergent gene pair is defined as two adjacent genes organized head to head in opposite orientation, sharing a common promoter region. Divergent gene pairs are mainly coexpressed, but some display opposite regulation. The mechanistic basis of such anti-correlated regulation is not well understood. Here, the regulation of the Arabidopsis thaliana gene pair At1g71850/At1g71860 was investigated. Semi-quantitative RT-PCR and Genevestigator analyses showed that while one of the pair was upregulated by exposure to low temperature, the same treatment downregulated the other. Promoter::GUS fusion transgenes were used to show that this behavior was driven by a bidirectional promoter, which harbored an as-1 motif, associated with the low-temperature response; mutation of this sequence produced a significant decrease in cold-responsive expression. With regard to the as-1 motif in the native orientation repressing the promoter's low-temperature responsiveness, the same as-1 motif introduced in the reverse direction showed a slight enhancement in the promoter's responsiveness to low-temperature exposure, indicating that the orientation of the motif was important for the promoter's activity. These findings provide new insights into the complex transcriptional regulation of bidirectional gene pairs as well as plant stress response. PMID- 27215441 TI - Closed loop control of lactate concentration in mammalian cell culture by Raman spectroscopy leads to improved cell density, viability, and biopharmaceutical protein production. AB - Accumulation of lactate in mammalian cell culture often negatively impacts culture performance, impeding production of therapeutic proteins. Many efforts have been made to limit the accumulation of lactate in cell culture. Here, we describe a closed loop control scheme based on online spectroscopic measurements of glucose and lactate concentrations. A Raman spectroscopy probe was used to monitor a fed-batch mammalian cell culture and predict glucose and lactate concentrations via multivariate calibration using partial least squares regression (PLS). The PLS models had a root mean squared error of prediction (RMSEP) of 0.27 g/L for glucose and 0.20 g/L for lactate. All glucose feeding was controlled by the Raman PLS model predictions. Glucose was automatically fed when lactate levels were beneath a setpoint (either 4.0 or 2.5 g/L) and glucose was below its own setpoint (0.5 g/L). This control scheme was successful in maintaining lactate levels at an arbitrary setpoint throughout the culture, as compared to the eventual accumulate of lactate to 8.0 g/L in the historical process. Automated control of lactate by restricted glucose feeding led to improvements in culture duration, viability, productivity, and robustness. Culture duration was extended from 11 to 13 days, and harvest titer increased 85% over the historical process. Biotechnol. Bioeng. 2016;113: 2416-2424. (c) 2016 Wiley Periodicals, Inc. PMID- 27215442 TI - Mathematical modelling of cardiovascular response to the Valsalva manoeuvre. AB - The Valsalva manoeuvre (VM) used for clinical autonomic testing results in a complex cardiovascular response with a concomitant action of several regulatory mechanisms whose nonlinear interactions are difficult to analyse without the aid of a mathematical model. The article presents a new non-pulsatile compartmental model of the human cardiovascular system with a variable intrathoracic pressure enabling the simulation of the haemodynamic response to the VM. The model is based on physiological data and includes three baroreflex mechanisms acting on heart rate, systemic resistance and venous unstressed volume. New nonlinear functions have been proposed to model cardiac output dependence on preload and afterload. Following the individual fitting of some parameters with a clear physiological meaning, the model is able to fit clinical data from patients with both typical and abnormal haemodynamic response to the VM. The sensitivity analysis showed that the model is most sensitive to the parameters describing the vascular pressure-volume relationships (the maximal volume of systemic veins and the relative level of vascular compliance). The use of nonlinear pressure-volume relationships for systemic veins proved crucial for the accurate modelling of the VM. On the contrary, the introduction of aroreflex time delays did not change significantly the haemodynamic response to the manoeuvre. The model can be a useful tool for aiding the interpretation of patient's response to the VM and provides a framework for analysing the interactions between the cardiovascular system and autonomic regulatory mechanisms. PMID- 27215443 TI - Application of a LC-MS/MS method developed for the determination of p phenylenediamine, N-acetyl-p-phenylenediamine and N,N-diacetyl-p-phenylenediamine in human urine specimens. AB - Cases of poisoning by p-phenylenediamine (PPD) are detected sporadically. Recently an article on the development and validation of an LC-MS/MS method for the detection of PPD and its metabolites, N-acetyl-p-phenylenediamine (MAPPD) and N,N-diacetyl-p-phenylenediamine (DAPPD) in blood was published. In the current study this method for detection of these compounds was validated and applied to urine samples. The analytes were extracted from urine samples with methylene chloride and ammonium hydroxide as alkaline medium. Detection was performed by LC MS/MS using electrospray positive ionization under multiple reaction-monitoring mode. Calibration curves were linear in the range 5-2000 ng/mL for all analytes. Intra- and inter-assay imprecisions were within 1.58-9.52 and 5.43-9.45%, respectively, for PPD, MAPPD and DAPPD. Inter-assay accuracies were within -7.43 and 7.36 for all compounds. The lower limit of quantification was 5 ng/mL for all analytes. The method, which complies with the validation criteria, was successfully applied to the analysis of PPD, MAPPD and DAPPD in human urine samples collected from clinical and postmortem cases. PMID- 27215444 TI - Trauma-Specific Brain Abnormalities in Suspected Mild Traumatic Brain Injury Patients Identified in the First 48 Hours after Injury: A Blinded Magnetic Resonance Imaging Comparative Study Including Suspected Acute Minor Stroke Patients. AB - We assessed the utility of a brief MRI protocol, appropriate for the acute setting, to detect acute traumatic brain injury (TBI) in patients with suspected mild TBI (mTBI) and distinguish traumatic from nontraumatic brain injury by comparing trauma with nontrauma patients. Twenty-two patients with suspected mTBI were included in this exploratory study over a period of 9 months. Median time from injury to MR scanning was 5.4 h (interquartile range 3.6-15.3). To determine the specificity of certain findings for TBI, 61 patients presenting with suspected minor acute stroke were included as a comparative group using the same MRI methods. A selected series of MRI sequences (diffusion-weighted imaging, fluid attenuated inversion recovery [FLAIR], and T2* weighted) were independently evaluated by two neuroradiologists blinded to clinical diagnosis, for presence of specific findings. In a separate session, all cases in which at least one MRI sequence above was positive were classified as TBI, stroke, or indeterminate. Intracranial MRI abnormalities were observed in 47 (57%) of the 83 studied patients. Based on findings on MRI, 12 (55%) of 22 suspected mTBI patients were classified as having traumatic injury. Nine (47%) of the 19 suspected mTBI patients with a negative CT had findings on MRI. Abnormalities on MRI consistent with trauma were observed most frequently on postcontrast FLAIR (83%) and T2* weighted (58%) sequences. We demonstrated the ability of a fast MRI protocol to identify trauma-related abnormalities not seen on CT, and differentiate acute trauma from nonspecific chronic disease in a blinded cohort of mTBI patients. PMID- 27215445 TI - Mapping the landscape of metabolic goals of a cell. AB - Genome-scale flux balance models of metabolism provide testable predictions of all metabolic rates in an organism, by assuming that the cell is optimizing a metabolic goal known as the objective function. We introduce an efficient inverse flux balance analysis (invFBA) approach, based on linear programming duality, to characterize the space of possible objective functions compatible with measured fluxes. After testing our algorithm on simulated E. coli data and time-dependent S. oneidensis fluxes inferred from gene expression, we apply our inverse approach to flux measurements in long-term evolved E. coli strains, revealing objective functions that provide insight into metabolic adaptation trajectories. PMID- 27215446 TI - Peripheral cytokines, C-X-C motif ligand10 and interleukin-13, are associated with Malaysian Alzheimer's disease. AB - AIM: Cytokines released from chronically-activated microglia could result in neuroinflammation. An accurate profile of the relationship between cytokines and Alzheimer's disease (AD) pathogenesis, as well as the patterns of these inflammatory mediators in AD patients could lead to the identification of peripheral markers for the disease. The present study was undertaken to identify pro- and anti-inflammatory cytokines associated with AD in the Malaysian population. METHODS: Further to informed consent from 39 healthy subjects and 39 probable AD patients, 8.5 mL of peripheral blood was collected and serum was extracted. The differential levels of 12 serum cytokines extracted from peripheral blood samples were measured using Procarta Multiplex Cytokine and enzyme-linked immunoassay kits. Concentrations of cytokines were measured at 615 nm using a fluorometer. RESULTS: Except for tumor necrosis factor-alpha, all classical pro-inflammatory cytokines (interleukin [IL]-1beta, IL-6, IL-12 and interferon-gamma) were found to be significantly upregulated (P < 0.001) in AD patients. Three of the five non-classical pro-inflammatory cytokines (C-X-C motif ligand 10 [CXCL-10], monocyte chemoattractant protein-1 and macrophage inflammatory protein-1alpha) showed similar patterns. Both classical IL-10 and non-classical IL-13 anti-inflammatory cytokines were significantly downregulated (P < 0.001) in AD patients when compared with non-AD controls. Receiver operating characteristic curve analyses for both CXCL-10 (IP-10) and IL-13 showed a high level of diagnostic accuracy (area under curve = 1 [95% confidence interval]). Both CXCL-10 and IL-13 also showed sensitivity of 100% and specificity of 100% for diagnosis of AD (cut-off values >53.65 rhog/mL and <9.315 rhog/mL, respectively). CONCLUSIONS: Both the non-classical pro-inflammatory CXCL-10 and anti-inflammatory IL-13 cytokines showed promising potential as blood-based cytokine biomarkers for AD. This is the first study of non-classical cytokine profiles of Malaysian AD patients. Geriatr Gerontol Int 2017; 17: 839-846. PMID- 27215448 TI - This is Not a History Lesson; This is Agitation: A Call for a Methodology of Diffraction in US-Based Community Psychology. AB - Agitation, as deployed by the Industrial Areas Foundation (IAF), occurs when imaginations and curiosities are piqued, and self-interest is made visible. In this framework, agitation is a step in creating change. In this paper, I outline two agitations within US-based community psychology. I then describe a third agitation that is underway; I add my voice and call for a methodology of diffraction as a contribution to critical reflexivity practices within US-based community psychology. Consistent with the IAF framework, I do not provide solutions. I write this paper as a provocation to help us think imaginatively and creatively about our actions and future, so that we can consider the paradigm shifts needed to move into critical ways of understanding connection, responsibility, accountability, and creating change-of interest during Swampscott and today. PMID- 27215447 TI - The safety of monoclonal antibodies in asthma. AB - INTRODUCTION: In the last two decades the knowledge of the mechanisms of the inflammatory processes underlying asthma rapidly evolved, several key mediators (cytokines and receptors) were identified, and the laboratory techniques have allowed us to synthesize monoclonal antibodies highly specific for those target molecules. Nowadays, many biological agents are investigated in asthma (with anti IgE being the only commercially available). The clinical efficacy of some biologics was demonstrated in many cases, however, the safety issue has progressively emerged and has been recognized as a crucial aspect. AREAS COVERED: We summarized the currently available knowledge on the safety and side effects of biologics in asthma, as derived by reviews, meta analyses and clinical trials. PubMed was searched with the terms anti IL-x [AND] safety [OR] side effects, within the categories "clinical trial", meta-analysis" and "review". Case reports were excluded. The authors collegially selected the relevant entries to be included. EXPERT OPINION: Overall, the safety of most of the investigated agents seems to be satisfactory, a certain risk of side effects remains present, and is variable for the different molecules. Thus caution must be paid in evaluating the risk to benefit ratio. Specific biomarkers to predict the response to each biological are urgently needed to improve the safety profile. PMID- 27215449 TI - Palliative Short-Course Radiation Therapy in Rectal Cancer: A Phase 2 Study. AB - PURPOSE: The management of patients with symptomatic rectal cancer not amenable to curative treatment may be challenging. The aim of this phase 2 study was to evaluate the efficacy of short-course radiation therapy in patients with obstructing rectal cancer. METHODS AND MATERIALS: Patients who were not candidates for surgical resection because of synchronous metastases, age, and/or comorbidities were considered eligible. The sample size was calculated based on the 2-stage design of Simon. Short-course radiation therapy was delivered with an isocentric 4-field box technique (total, 25 Gy; 5 fractions in 5 days). Chemotherapy was suspended during radiation treatment. Clinical outcome measures were symptomatic response rate, toxicity, colostomy-free survival, and overall survival. RESULTS: From October 2003 to November 2012, 18 patients (median age, 77.5 years) were enrolled. The median follow-up was 11.5 months (range, 3-36 months). Four weeks after treatment, a complete response (ie, complete symptom resolution) was observed in 38.9% of patients and a partial response in 50.0% cases, whereas 11.1% had no response. The rates of reduction or resolution of pain and bleeding were 87.5% and 100%, respectively. The 1-, 2-, and 3-year colostomy-free survival rates were 100%, 71.4%, and 47.6%, respectively (median, 30 months). The 1-, 2-, and 3-year cumulative overall survival rates were 85.2%, 53%, and 39.8%, respectively (median, 25 months). No patients stopped treatment because of gastrointestinal or genitourinary toxicities: 38.9% of patients had grade 1 to 2 toxicity, and 16.7% had grade 3 toxicity. Only 1 patient had hematologic grade 2 toxicity, and 2 patients had grade 2 skin toxicity. CONCLUSIONS: Short-course radiation therapy may represent a safe and effective alternative treatment option in patients with obstructing rectal cancer not eligible for curative treatment, allowing colostomy to be avoided in a substantial proportion of patients. PMID- 27215450 TI - [Radiosensitization Induced by ANTP-SmacN7 Fusion Peptide in H460 Cell Line]. AB - BACKGROUND: The curative effect of radiotherapy may be limited by the radioresistance of tumor. Mimetic compounds of Second mitochondria-derived activator of caspase (Smac) were hopeful to become new drugs of radiosensitization for tumor because they can increase radiation induced apoptosis in tumor cells. The aim of present study is to observe the radiosensitization effect of a new Smac mimetic ANTP-SmacN7 fusion peptide in H460 cell line. METHODS: In order to observe if the fusion peptide can enter into tumor cell, ANTP-SmacN7 fusion peptide was synthesized and linked by FITC. H460 cell was divided into control, radiation only, ANTP-SmacN7 only and ANTP-SmacN7 combined with radiation group. The cells were exposed by 0, 2, 4 and 6 Gy and the concentration of ANTP-SmacN7 was 20 MUmol/L. Proliferation of H460 tumor cell was detected by WST-1 assay. There are four groups in the present study: control group, radiation group, ANTP-SmacN7 group and ANTP-SmacN7 combined with radiation group. Apoptosis was detected by flow cytometry at 24 and 48 hours after the treatment of all the groups. The level of caspase3 and cleaved caspase3 were detected by Western blot assay. RESULTS: ANTP-SmacN7 can enter into cells and promote the radiosensitization of H460 cell obviously (F=25.1, P<0.01, sensitivity enhancement ratio was 1.86). The treatment of ANTP-SmacN7 combined with radiation decreased the cloning forming efficiency (chi2=45.2, P<0.01; chi2=40.3, P<0.01), activated caspase3 by promoting the expression of cleaved caspase3 and increased the apoptosis of H460 cell line. CONCLUSIONS: ANTP-SmacN7 fusion peptide had remarkably radiosensitization effect on H460 cell line. ANTP SmacN7 fusion peptide might be hopeful to be applied in radiosensitization therapy as a new Smac mimetic polypeptide in the future. PMID- 27215451 TI - [Comprehensive Identification of MicroRNAs Regulated by Long Non-coding RNA MALAT1]. AB - BACKGROUND: Long non-coding RNA (lncRNA) plays important regulatory roles in the development and invasion of various cancers. The aim of current study is to comprehensively identify microRNAs (miRNA) regulated by lncRNA MALAT1 via experimental and bioinformatics methods. METHODS: Antisense oligonucleotides (ASO) specifically targeting MALAT1 were designed and synthesized. After knockdown of MALAT1 by ASO in A549 cells, miRNA expression changes were profiled by TqaMan Low Density Array (TLDA). Gene set enrichment analysis (GSEA) was used to search enriched miRNAs among differentially expressed genes after knockdown of MALAT1. RESULTS: After efficient knockdown of MALAT1 by ASO, 153 miRNAs were differentially expressed, 131 up-regulated and 22 down-regulated. Among the 458 differentially expressed genes after MALAT1 silence, GSEA results revealed lots of enriched miRNAs. There were 28 overlapped miRNAs between TLDA and GSEA results, suggesting these 28 miRNAs are regulated by MALAT1. CONCLUSIONS: This study comprehensively identified MALAT1 regulated miRNAs, providing resources for further research. PMID- 27215452 TI - [Efficacy and Security of Intrathecal with Methotrexate in the Treatment of Meningeal Carcinomatosis]. AB - BACKGROUND: Leptomeningeal carcinomatosis is a rare type of metastatic tumors of the central nervous system. In recent years, with the improvement of neoplasms therapies and longer survival of patients by better systemic control, incidence of leptomeningeal metastases has increased every year. However, there is still lack of effective therapies. The aim of this study is to investigate the efficacy, security and prognosis of intrathecal chemotherapy with methotrexate (MTX) in the treatment of neoplastic meningitis. METHODS: A total of 27 patients were enrolled. We investigated clinical features and cerebrospinal fluid (CSF) examination results retrospectively, and analyzed the adverse reactions as well as prognosis after intrathecal chemotherapy. RESULTS: All 27 patients were treated by intrathecal MTX, 70.4% had clinical remission, however, there was no significant difference in CSF pressure and CSF biochemical changes. We observed that 55.6% patients were all appropriate, 25.9% appeared lower limb numbness and mild pain, no serious irreversible adverse reactions occurred. Median overall survival was 4 months. CONCLUSIONS: We suggest that intrathecal administration of MTX is associated with improvement of symptoms of leptomeningeal metastasis patients and no severe adverse events observed. PMID- 27215453 TI - [Clinical Analysis of 107 NSCLC Patients Harboring KRAS Mutation]. AB - BACKGROUND: Kirsten rat sarcoma viral oncogene (KRAS) mutation is one of the major driver genes of non-small cell lung cancer (NSCLC). KRAS is a resistant predictor of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), which raises controversy because of its role in chemotherapy sensitivity and prognosis. The aim of this study is to accumulate clinical experience in treating NSCLC patients harboring KRAS mutation. METHODS: A total of 107 NSCLC patients harboring KRAS mutation were analyzed retrospectively. The efficacy was analyzed in terms of first-line chemotherapy or EGFR-TKIs therapy. RESULTS: The objective response rate (ORR) to first-line chemotherapy of 52 patients with advanced disease harboring KRAS mutation was 9.6%. The disease control rate (DCR) was 53.8%, and the median progression-free survival (PFS) was 3 months. The ORR to EGFR-TKIs therapy in 21 patients harboring KRAS mutation and EGFR/KRAS co mutation was 9.5%; the DCR was 23.8%, and the median PFS was 1 month. The ORR and DCR to EGFR-TKIs therapy of patients with EGFR/KRAS co-mutation were significantly higher than those of patients with KRAS mutation (50% vs 0, P=0.029; 75% vs 11.8%, P=0.043); the median PFS was also significantly longer (3 months vs 1 month, P=0.004). CONCLUSIONS: The efficacy to first-line chemotherapy and EGFR-TKIs therapy in NSCLC patients harboring KRAS mutation was poor; thus, new drugs should be developed. Furthermore, the existence of EGFR/KRAS co mutation was confirmed. Hence, EGFR-TKIs therapy should be administered to patients with EGFR/KRAS co-mutation. PMID- 27215454 TI - [Efficacy of Cetuximab in Combination with Chemotherapy in Advanced Non-small Cell Lung Cancer]. AB - BACKGROUND: Cetuximab is a monoclonal antibody directed against epidermal growth factor receptor. Emerging evidence showed improved efficacy with the addition of cetuximab to chemotherapy in advanced non-small cell lung cancer (NSCLC), but the data in oriental population are limited. The aim of this study is to investigate the efficacy of cetuximab in combination with chemotherapy in Chinese patients with advanced NSCLC. METHODS: NSCLC patients receiving cetuximab in combination with chemotherapy in Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College were enrolled and retrospectively analyzed. Clinical characteristic, efficacy, outcome and toxicity data were analyzed. RESULTS: A total of 40 patients were enrolled into this study in which 29 were male, 36 with adenocarcinoma. In the 23 patients who had received palliative chemotherapy previously (with a median of 2 prior chemotherapy regimens), the median progression-free survival (PFS) after the last prior chemotherapy regimen was 2.3 months. For the overall population, 13 (32.5%) patients achieved partial response after cetuximab in combination with chemotherapy. Response rate were 52.9% (9/17) and 17.4% (4/23) in chemotherapy-naive patients and chemotherapy-treated patients, respectively (P=0.018). The median PFS was 4.8 months for the overall population. In chemotherapy-naive patients and chemotherapy-treated patients, the median PFS was 8.4 months and 4.1 months, respectively (P=0.062). The estimated median overall survival was 17.1 months. Toxicities were generally manageable and no treatment-related deaths occurred. CONCLUSIONS: Cetuximab in addition to chemotherapy appears to be associated with promising efficacy and acceptable toxicity profile in Chinese patients with advanced NSCLC. Further validation is needed. PMID- 27215455 TI - [CT Guided Radiofrequency Ablation Followed Intratumoral Chemotherapy ?in the Treatment of Early Stage Non-small Cell Lung Cancer]. AB - BACKGROUND: Radiofrequency ablation (RFA) has become one of the local treatment for inoperable early stage non-small cell lung cancer (NSCLC). This study observes effectiveness and safety of computed tomography (CT) guided RFA followed intratumoral chemotherapy (RFA-ITC). METHODS: From 2005 to 2015, our group perspectively enrolled inoperable early stage NSCLC underwent RFA-ITC duo to poor cardiopulmonary function or with other diseases or patient can't tolerate or reject surgery. RFA was performed by a directive apparatus assisted CT guided semi real-time and step-by-step puncture method, conformal umbrella-shaped electrode and single or multiple targets ablation. While the plan finished and CT showed normal lung tissue around the tumor present ground-glass opacity (GGO), the procedure ended, then 200 mg of carboplatinum were injected into the tumor via the electrode needle. Safety and effectiveness were evaluated by follow-up. RESULTS: Technical success rates of 125 RFA-ITC treatments of 110 patients were 100%. The median survival was 48.0 months, overall survival (OS) was 55.4 months, progression-free survival was 55.1 months, 1, 2, 3, 5-year OS rates were 100%, 90.7%, 62.7%, 21.9%, respectively. Survival of GGO presence or not was 68.3 months and 40.1 months, respectively (P=0.001). The survival rates of the N1 staging and tumor size was no significant difference. No perioperative deaths occurred, the main complications i.e. pneumothorax, pulmonary hemorrhage, pleural effusion, fever, intraoperative chest pain, subcutaneous emphysema, intraoperative cough were slight and tolerable. CONCLUSIONS: CT guided RFA-ITC provides a good method for treatment of inoperable early stage NSCLC with better survival, less complication and small damage.?. PMID- 27215456 TI - [Three Dimensional Volumetric Analysis of Solid Pulmonary Nodules on Chest CT: ?Cancer Risk Assessment]. AB - BACKGROUND: The management of pulmonary nodules relies on cancer risk assessment, in which the only widely accepted criterion is diameter. The development of volumetric computed tomography (CT) and three-dimensional (3D) software enhances the clarity in displaying the nodules' characteristics. This study evaluated the values of the nodules' volume and 3D morphological characteristics (edge, shape and location) in cancer risk assessment. METHODS: The CT data of 200 pulmonary nodules were retrospectively evaluated using 3D volumetric software. The malignancy or benignity of all the nodules was confirmed by pathology, histology or follow up (>2 years). Logistic regression analysis was performed to calculate the odds ratios (ORs) of the 3D margin (smooth, lobulated or spiculated/irregular), shape (spherical or non-spherical), location (purely intraparenchymal, juxtavascular or pleural-attached), and nodule volume in cancer risk assessment for total and sub-centimeter nodules. The receiver operating characteristic (ROC) curve was employed to determine the optimal threshold for the nodule volume. RESULTS: Out of 200 pulmonary nodules, 78 were malignant, whereas 122 were benign. The Logistic regression analysis showed that the volume (OR=3.3; P<0.001) and the 3D margin (OR=13.4, 9.8; both P=0.001) were independent predictive factors of malignancy, whereas the location and 3D shape exhibited no total predictive value (P>0.05). ROC analysis showed that the optimal threshold for malignancy was 666 mm3. For sub-centimeter nodules, the 3D margin was the only valuable predictive factor of malignancy (OR=60.5, 75.0; P=0.003, 0.007). CONCLUSIONS: The volume and 3D margin are important factors considered to assess the cancer risk of pulmonary nodules. Volumes larger than 666 mm3 can be determined as high risk for pulmonary nodules; by contrast, nodules with lobulated, spiculated, or irregular margin present a high malignancy probability. PMID- 27215458 TI - [Evaluation of Pulmonary Hypertension with CMR: Pulmonary Hypertension ?Patients and Healthy Volunteers Control Study]. AB - BACKGROUND: The clinical course of pulmonary hypertension (PH) is one of progressive deterioration interspersed with episodes of acute decompensation. It is difficult to predict when patients will die because death may come either suddenly or slowly due to progressive heart failure. The aim of this study is to investigate morphology, function and hemodynamics in PH, compared with healthy people, and to investigate the clinical value of detection of PH by use of cardiac magnetic resonance (CMR) parameters. METHODS: CMR was performed in 56 PH patients collected from Tianjin Medical University General Hospital from January 2012 to December 2014 and 22 healthy controls. The following parameters were calculated: right ventricle (RV) end-diastolic volume (EDV), end-systolic volume (ESV), ejection fraction (EF), myocardial mass (MM), RV fractional area change (RVFAC), interventricular septal curvature (CIVS), left ventricular free wall curvature (CFW), and CIVS/CFW, main pulmonary artery (MPA) positive peak velocity, maximal area, minimal area and distensibility. Comparisons of CMR measurements between PH patients and controls were analyzed by using the student t-tests. Receiver operating characteristic (ROC) curve analysis was used to compare the PH diagnostic abilities for four parameters (MPA positive peak velocity, distensibility, curvature ratio, and RVFAC) and combined CMR parameter. P<0.05 was considered significant. RESULTS: Compared with healthy controls, RV morphology, function and hemodynamics of PH group declined and deteriorate obviously. The ROC curve analysis showed that among the four parameters distensibility of MPA had the highest AUC value (AUC=0.95). Additionally, combined CMR parameter (positive peak velocity+distensibility+curvature ratio+RVFAC) had even higher AUC (AUC=0.988). CONCLUSIONS: Comprehensive CMR parameters is conducive to accurately reflect the overall state RV-pulmonary circulation in patients with PH.?. PMID- 27215457 TI - [Classification and Risk-factor Analysis of Postoperative Cardio-pulmonary ?Complications after Lobectomy in Patients with Stage I Non-small Cell Lung Cancer]. AB - BACKGROUND: There are incresing lung cancer patients detected and diagnosed at the intermediate stage when the pre-malignant or early lesions are amenable to resection and cure, owing to the progress of medical technology, the renewal of detection methods, the popularity of medical screening and the improvement of social health consciousness. The aim of this study is to investigate the risk factors of the occurrence of postoperative cardio-pulmonary complications in stage I non-small cell lung cancer (NSCLC) patients, based on routine laboratory tests, basic characteristics, and intraoperative variables in hospital. METHODS: The 421 patients after lobectomy in patients with stage I NSCLC at the West China Hospital of Sichuan University from January 2012 to December 2013 were included into the study and stratified into complication group and non-complication group, according to whether to occur postoperative cardio-pulmonary complications after lobectomy in 30 days. RESULTS: Of them, 64 (15.2%) patients were finally identified and selected into the complication group, compared with 357 (84.8%) in non-complication group: pneumonia (8.8%, 37/421) was the primary complication, and other main complications included atelectasis (5.9%, 25/421), pleural effusion (>=middle) (5.0%, 21/421), persistent air leak (3.6%, 15/421); The operation time (P=0.007), amount of blood loss (P=0.034), preoperative chronic obstructive pulmonary disease (COPD) (P=0.027), white blood cell (WBC) count (P<0.001), neutrophil-lymphocyte ratio (NLR) (P<0.001) were significantly different between the two groups. According to the binary logistics regression analysis, preoperative COPD (OR=0.031, 95%CI: 0.012-0.078, P<0.001) and WBC count (OR=1.451, 95%CI: 1.212-1.736, P<0.001) were independent risk factors for postoperative cardio-pulmonary complications. CONCLUSIONS: Among an array of clinical variables in hospital, operation time, preoperative white blood cell count, preoperative COPD, may be the independent risk factors of the occurrence of postoperative cardio-pulmonary complications. PMID- 27215459 TI - [Treatment Outcomes and Prognostic Factors of Pulmonary Metastasectomy for Bone and Soft Tissue Sarcoma: a High Volume Academic Institution Experience]. AB - BACKGROUND: The bone and soft tissue sarcoma can metastasize to distant sites, most commonly the lungs. Some cases can be cured by radical metastasectomy, but its role, indication and prognostic factors remains controversial. The rarity of the disease combined with the diverse number of subtypes can make bone and soft tissue sarcomas very difficult to study. There are few randomized control studies or international high volume results, and such reports in China are seldom seen. The aim of this study is to investigate surgical treatment outcomes and prognostic factors of pulmonary metastatic bone and soft tissue sarcoma patients. METHODS: From January 2007 to December 2015, patients with bone and soft tissue sarcoma who underwent multimodality therapy including definitive surgery for the primary lesion and at least one pulmonary metastasectomy were enrolled in the retrospective study. All the relevant clinical variables were collected, and then statistically analyzed and interpreted with the aid of univariate and multivariate Cox proportional hazard regression method. RESULTS: Totally 155 pulmonary metastasectomies in 144 patients were analyzed. Incomplete R0 resection, a less than 1-year interval from a previous surgery, more than three detected nodules; and the summed maximum diameter of more than 45 mm for pulmonary metastases were independent prognostic indicators by multivariate analysis. CONCLUSIONS: We suggest that metastatic bone and soft tissue sarcoma patients can benefit most from aggressive surgical intervention of pulmonary metastasectomy. Its prognostic factors include R0 resection, a longer interval from a previous surgery, smaller total number and total size of pulmonary metastases. PMID- 27215460 TI - [Research Progress in Diagnosis and Management Strategies ?of Multiple Primary Lung Cancer]. AB - Although the morbidity of multiple primary lung cancer (MPLC) has been increasing year by year, it is still controversial about pathogenesis, differential diagnosis and management strategies of MPLC. This review provides a snapshot of the main progress of pathogenesis, differential diagnosis and management strategies of MPLC. PMID- 27215461 TI - [Application of Non-intubated Anesthesia in VATS]. AB - Tracheal intubation general anesthesia technique is widely used in video-assisted thoracic surgery (VATS) because it can improve the safety of VATS, but the complications of tracheal intubation can not be avoided. How to develop a "minimally invasive" surgery (including micro anesthesia) has become a hot topic in the field of minimally invasive surgery. Along with the progress of the anesthesia management technology and the risk management in the operation, the technology of non-intubated anesthesia was successfully applied to VATS, namely using local anesthesia to maintain patients intraoperative independent ventilation and intraoperative only mild sedation or fully conscious state of implementation of thoracoscope surgery, therefore is also called awake VATS. The anesthesia method not only reduces the anesthesia injury of tracheal intubation, but also conforms to the idea of rapid rehabilitation surgery. Based on non intubated anesthesia in VATS in the brief history of development, the anesthesia selection, operation advantages and risks are reviewed in this paper. PMID- 27215462 TI - Progress in mass spectrometry for the analysis of set-off phenomena in plastic food packaging materials. AB - In most cases, food packaging materials contain inks whose components can migrate to food by diffusion through the material as well as by set-off phenomena. In this work, different mass spectrometry approaches had been used in order to identify and confirm the presence of ink components in ethanol (95%) and Tenax((r)) as food simulants. Three different sets of materials, manufactured with different printing technologies and with different structures, were analyzed. Sample analysis by ultra performance liquid chromatography mass spectrometry (UPLC-MS), using a quadrupole-time of flight (Q-TOF) as a mass analyser proved to be an excellent tool for identification purposes while ion mobility mass spectrometry (IM-MS) shown to be very useful for the confirmation of the candidates proposed. The results showed the presence of different non volatile ink components in migration such as colorants (Solvent Red 49), plasticizers (dimethyl sebacate, tributyl o-acetyl citrate) or surfactants (SchercodineM, triethylene glycol caprilate). An oxidation product of an ink additive (triphenyl phosphine oxide) was also detected. In addition, a surface analysis technique, desorption electrospray mass spectrometry (DESI-MS), was used for analyzing the distribution of some ink components (tributyl o-acetyl citrate Schercodine L, phthalates) in the material. The detection of some of these compounds in the back-printed side confirmed the transference of this compound from the non-food to the food contact side. The results also showed that concentration of ink migrants decreased when an aluminum or polypropylene layer covered the ink. When aluminum was used, concentration of most of ink migrants decreased, and for 5 out of the 9 even disappeared. PMID- 27215463 TI - Analysis of 76 veterinary pharmaceuticals from 13 classes including aminoglycosides in bovine muscle by hydrophilic interaction liquid chromatography tandem mass spectrometry. AB - A multiresidue/multiclass method for the simultaneous determination of 76 veterinary drugs and pharmaceuticals in bovine muscle tissue has been developed and validated according to the requirements of European Commission Decision 2002/657/EC. The analytes belong in 13 different classes, including aminoglycoside antibiotics, whose different physicochemical properties (extremely polar character) render their simultaneous determination with other veterinary drugs quite problematic. The method combines a two-step extraction procedure (extraction with acetonitrile followed by an acidic aqueous buffer extraction) with hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) determination, allowing confirmation and quantification in a single chromatographic run. Further cleanup with solid phase extraction was performed using polymeric SPE cartridges. A thorough ionization study of aminoglycosides was performed in order to increase their sensitivity and significant differences in the abundance of the precursor ions of the analytes were revealed, depending on the composition of the mobile phase tested. Further gradient elution optimization and injection solvent optimization were performed for all target analytes.The method was validated according to the European Commission Decision 2002/657. Quantitative analysis was performed by means of standard addition calibration. Recoveries varied from 37.4% (bromhexine) to 106% (kanamycin) in the lowest validation level and 82% of the compounds showed recovery >70%. Detection capability (CCbeta) varied from 2.4 (salinomycin) to 1302 (apramycin) MUgkg(-1). PMID- 27215464 TI - Quantitative analysis of antibiotics in aquifer sediments by liquid chromatography coupled to high resolution mass spectrometry. AB - A highly effective analytical method for multi-residue determination of antibiotics in aquifer sediments was first established in this study. Microwave assisted solvent extraction (MASE) and solid-phase extraction were used for sample pre-concentration and purification, ultra-high performance liquid chromatography coupled to hybrid quadrupole-high resolution Orbitrap mass spectrometry (UHPLC-Q-Orbitrap) was applied for detection. For high resolution mass spectrometry (HRMS), the target compounds were tentatively identified by retention time and accurate mass which was measured with precursor ions in Target SIM scan, and then confirmed by the monitoring of daughter ion fragments which were generated in dd-MS(2) scan. The results provided good mass accuracy with mass deviations below 2ppm (except norfloxacin with -2.3ppm) for quantitative analysis of the compounds by HRMS. Reasonable recoveries of all analytes were obtained more than 60% (except doxytetracycline) in fortification samples at concentrations higher than 10MUgkg(-1). Relative standard deviations of repeatability and inter-day precision were below 21% and 11%. Limits of detection (LOD) ranged from 0.1 to 3.8MUgkg(-1), whereas limits of quantification (LOQ) were established between 0.3-9.0MUgkg(-1). The method was applied to analyze real aquifer sediment samples in different aquifer depth of 4.0, 7.5, 13.0 and 18.0m. Chlorotetracycline and ofloxacin were observed at relative high concentrations of 53 and 19MUgkg(-1) respectively in 18.0m deepness. The exposure to low doses of these compounds in subsurface environment increases concerns on long-term ecological security of underground system. PMID- 27215465 TI - On-line coupling of surface plasmon resonance optical sensing to size-exclusion chromatography for affinity assessment of antibody samples. AB - Surface plasmon resonance (SPR) is an optical technique that measures biomolecular interactions. Stand-alone SPR cannot distinguish different binding components present in one sample. Moreover, sample matrix components may show non specific binding to the sensor surface, leading to detection interferences. This study describes the development of coupled size-exclusion chromatography (SEC) SPR sensing for the separation of sample components prior to their on-line bio interaction analysis. A heterogeneous polyclonal human serum albumin antibody (anti-HSA) sample, which was characterized by proteomics analysis, was used as test sample. The proposed SEC-SPR coupling was optimized by studying system parameters, such as injection volume, flow rate and sample concentration, using immobilized HSA on the sensor chip. Automated switch valves were used for on-line regeneration of the SPR sensor chip in between injections and for potential chromatographic heart cutting experiments, allowing SPR detection of individual components. The performance of the SEC-SPR system was evaluated by the analysis of papain-digested anti-HSA sampled at different incubation time points. The new on-line SEC-SPR methodology allows specific label-free analysis of real-time interactions of eluting antibody sample constituents towards their antigenic target. PMID- 27215466 TI - Engineering a 3D microfluidic culture platform for tumor-treating field application. AB - The limitations of current cancer therapies highlight the urgent need for a more effective therapeutic strategy. One promising approach uses an alternating electric field; however, the mechanisms involved in the disruption of the cancer cell cycle as well as the potential adverse effects on non-cancerous cells must be clarified. In this study, we present a novel microfluidic device with embedded electrodes that enables the application of an alternating electric field therapy to cancer cells in a 3D extracellular matrix. To demonstrate the potential of our system to aid in designing and testing new therapeutic approaches, cancer cells and cancer cell aggregates were cultured individually or co-cultured with endothelial cells. The metastatic potential of the cancer cells was reduced after electric field treatment. Moreover, the proliferation rate of the treated cancer cells was lower compared with that of the untreated cells, whereas the morphologies and proliferative capacities of the endothelial cells were not significantly affected. These results demonstrate that our novel system can be used to rapidly screen the effect of an alternating electric field on cancer and normal cells within an in vivo-like microenvironment with the potential to optimize treatment protocols and evaluate synergies between tumor-treating field treatment and chemotherapy. PMID- 27215467 TI - GPR55: Metabolic Help or Hindrance? AB - Since the discovery of the lysophospholipid-sensitive receptor GPR55, hopes have been raised that targeting this G protein-coupled receptor (GPCR) may represent a novel approach for the treatment of metabolic disorders. We discuss conflicting evidence surrounding GPR55 physiology and highlight its potential as a novel target for the treatment of obesity and diabetes. PMID- 27215468 TI - Mitochondria-Power Players in Kidney Function? AB - A recent study has highlighted the relationship between mitochondrial ATP generation and protection against organ injury following ischaemia-reperfusion injury in the kidney. Kidneys are fuel-hungry organs and only second to the heart in mitochondrial number and oxygen consumption. This article speculates on why this might be so. PMID- 27215469 TI - Pressure coefficients for direct optical transitions in MoS2, MoSe2, WS2, and WSe2 crystals and semiconductor to metal transitions. AB - The electronic band structure of MoS2, MoSe2, WS2, and WSe2, crystals has been studied at various hydrostatic pressures experimentally by photoreflectance (PR) spectroscopy and theoretically within the density functional theory (DFT). In the PR spectra direct optical transitions (A and B) have been clearly observed and pressure coefficients have been determined for these transitions to be: alphaA = 2.0 +/- 0.1 and alphaB = 3.6 +/- 0.1 meV/kbar for MoS2, alphaA = 2.3 +/- 0.1 and alphaB = 4.0 +/- 0.1 meV/kbar for MoSe2, alphaA = 2.6 +/- 0.1 and alphaB = 4.1 +/ 0.1 meV/kbar for WS2, alphaA = 3.4 +/- 0.1 and alphaB = 5.0 +/- 0.5 meV/kbar for WSe2. It has been found that these coefficients are in an excellent agreement with theoretical predictions. In addition, a comparative study of different computational DFT approaches has been performed and analyzed. For indirect gap the pressure coefficient have been determined theoretically to be -7.9, -5.51, 6.11, and -3.79, meV/kbar for MoS2, MoSe2, WS2, and WSe2, respectively. The negative values of this coefficients imply a narrowing of the fundamental band gap with the increase in hydrostatic pressure and a semiconductor to metal transition for MoS2, MoSe2, WS2, and WSe2, crystals at around 140, 180, 190, and 240 kbar, respectively. PMID- 27215471 TI - A Relation for Nanodroplet Diffusion on Smooth Surfaces. AB - In this work, we study the diffusion of nanodroplets on smooth surfaces through molecular dynamics (MD) simulations and theoretical analyses. Molecular dynamics simulations show that nanodroplet surface diffusion is different from that of single molecules and solid particles. The dependence of nanodroplet diffusion coefficient on temperature undergoes a transition from linear to nonlinear as the surface wettability is weakened due to the coupling of temperature and surface energy. We also develop a simple relation for the diffusion coefficient by using the contact angle and contact radius of the droplet. It works well for a wide range of surface wettabilities and different sized nanodroplets, as confirmed by MD simulations. PMID- 27215473 TI - Septicemia after Barium Reduction in a Pediatric Patient with Intussusception. PMID- 27215472 TI - The value of modular hemiarthroplasty for unstable femoral neck fractures in elderly patients with coxarthrosis. AB - BACKGROUND: Displaced femoral neck fractures are common in the elderly patient. The surgical treatment options consist of a hemiarthroplasty (HA) or total hip arthroplasty (THA). However, the best surgical choice is still under debate. Bipolar HAs do not address preexisting arthritic changes of the acetabulum, which may lead to an unfavorable clinical outcome. The purpose of the present study was to conduct a long term follow-up analysis of the bipolar hemiarthroplasty with particular focus on the influence of preoperative acetabular osteoarthritis on the functional outcome. METHODS: In a retrospective observational study, the medical charts of consecutive patients treated with a bipolar hemiarthroplasty at a level one trauma center between 2004 and 2008 were reviewed before a final radiographic and clinical follow-up was performed. The outcome variables consisted of arthritic findings on the pre- and postoperative x-rays with particular focus on double fond osteophyte (DFO) and posterior wall sign (PWS) as well as the revision rate and functional scores. RESULTS: This study included 102 patients with a mean age of 77.2 years. Most patients (75 %) had a Kellgren Lawrence grading scale (KLGS) of 2 or 3. While only 30 % of patients had a DFO, most patients (73 %) had a PWS. The DFO correlated significantly with the KLGS, but no correlation was seen with the clinical outcome. Most patients showed a decreased offset by a mean of -7.8 mm. The mean modified Harris Hip Score (HHS) of 90.3 and the mean Merle d'Aubigne score of 10.8 correlated significantly. Despite a significant correlation of the HSS subcategory of pain and the preoperative KLGS, there was no statistical relationship between the arthritic x ray measurements and the clinical outcome. CONCLUSIONS: In the presented study population, the presence of radiographic acetabular osteoarthritis did not influence the clinical outcome after bipolar hemiarthroplasty for displaced femoral neck fractures. PMID- 27215474 TI - Efficacy of Medical Treatment for Infantile Hypertrophic Pyloric Stenosis: A Meta analysis. AB - BACKGROUND: Infantile hypertrophic pyloric stenosis (IHPS) is a common disease in infancy. Pyloromyotomy is universally considered the treatment for IHPS; however, oral or intravenous atropine has been reappraised for the treatment of IHPS in the past 20 years. We investigated the efficacy of atropine in the medical management of IHPS by using meta-analysis and investigated the sonographic changes of the pyloric canal, as well as the efficacy and adverse effects of atropine. METHODS: Information was retrieved from PubMed, Ovid, and MEDLINE. The efficacy and adverse effects of atropine treatment for IHPS were reviewed using the standard process of meta-analysis. RESULTS: Eleven articles were obtained. Five reports showed that 77 of 110 (70%) infants who were administered oral atropine benefitted by the induced remission of IHPS. Six reports showed that 288 of 345 (83.5%) patients who were treated initially with intravenous atropine then changed to oral atropine showed beneficial effects and had no serious side effects. Time to pyloric muscle normalization ranged from 5 weeks to 15 months. CONCLUSION: The study results indicate that atropine is a possible alternative treatment for IHPS, particularly in infants with major concurrent disease, and is safe without obvious side effects. PMID- 27215475 TI - Picky Eating Behaviors Linked to Inappropriate Caregiver-Child Interaction, Caregiver Intervention, and Impaired General Development in Children. AB - BACKGROUND: To investigate the differences in eating behaviors between picky and nonpicky eaters, and to correlate parental management of children's eating problems with qualities of general development in children. METHODS: This was a cross-sectional analysis of parental observations on their children's eating behavior, sampled from three major cities in Taiwan. We used a structured questionnaire during face-to-face interviews to collect information on each child's picky eating habits and behaviors, caregiver-child interaction and intervention during feeding, and the child's qualities of general development. Analysis of variance was used to determine significant differences between picky and nonpicky eaters. RESULTS: Sixty-two percent of the children were considered to be picky eaters. Lack of appropriate caregiver-child interactions (e.g., repeated food attempt, persuasion, and encouragement) and the presence of inappropriate parental interactions (e.g., threatening, snacking, and nutrient supplementation) were significantly more common in picky eaters. Picky eaters also tended to exhibit low development quality in the domains of learning ability, interpersonal relationships, and physical performance, particularly in their attention span and uncooperativeness. CONCLUSION: There is a relationship between inappropriate parental interaction and interventions in children's eating problems and the low quality of general development in picky eaters. PMID- 27215476 TI - Whole-genome sequencing in the prediction of antimicrobial resistance. PMID- 27215477 TI - Genetically Induced Retrograde Amnesia of Associative Memories After Neuroplastin Ablation. AB - BACKGROUND: Neuroplastin cell recognition molecules have been implicated in synaptic plasticity. Polymorphisms in the regulatory region of the human neuroplastin gene (NPTN) are correlated with cortical thickness and intellectual abilities in adolescents and in individuals with schizophrenia. METHODS: We characterized behavioral and functional changes in inducible conditional neuroplastin-deficient mice. RESULTS: We demonstrate that neuroplastins are required for associative learning in conditioning paradigms, e.g., two-way active avoidance and fear conditioning. Retrograde amnesia of learned associative memories is elicited by inducible neuron-specific ablation of Nptn gene expression in adult mice, which shows that neuroplastins are indispensable for the availability of previously acquired associative memories. Using single-photon emission computed tomography imaging in awake mice, we identified brain structures activated during memory recall. Constitutive neuroplastin deficiency or Nptn gene ablation in adult mice causes substantial electrophysiologic deficits such as reduced long-term potentiation. In addition, neuroplastin deficient mice reveal profound physiologic and behavioral deficits, some of which are related to depression and schizophrenia, which illustrate neuroplastin's essential functions. CONCLUSIONS: Neuroplastins are essential for learning and memory. Retrograde amnesia after an associative learning task can be induced by ablation of the neuroplastin gene. The inducible neuroplastin-deficient mouse model provides a new and unique means to analyze the molecular and cellular mechanisms underlying retrograde amnesia and memory. PMID- 27215478 TI - Protective effects of hydrogen-rich saline against N-methyl-N-nitrosourea-induced photoreceptor degeneration. AB - The N-methyl-N-nitrosourea (MNU)-treated rat is typically used as an animal model of chemically-induced retinitis pigmentosa (RP). Reactive oxygen species (ROS) have been recognized as the crucial contributor to the retinal photoreceptor apoptosis seen in MNU-treated rats. In the present study, we explored the therapeutic effects of hydrogen-rich saline (HRS), a selective ROS scavenger, on MNU-induced photoreceptor degeneration. Intraperitoneal (IP) administration of HRS ameliorated MNU-induced photoreceptor degeneration in terms of morphology and function: Sharply decreased thickness of the retinal outer nuclear layer (ONL) and flattened photopic and scotopic electroretinogram (ERG) waveforms, typically seen in response to MNU treatment, were substantially rescued in rats cotreated with MNU and HRS (MNU + HRS). Moreover, the terminal deoxyuridine triphosphate nick-end labeling (TUNEL) assay revealed a smaller number of apoptotic photoreceptors in the MNU + HRS group compared that in the MNU group. Compared to MNU-treated rats, retinal malondialdehyde (MDA) content in MNU + HRS rats significantly decreased while superoxide dismutase (SOD) activity significantly increased. Morphological and multi-electrode array (MEA) analyses revealed more efficient preservation of the architecture and field potential waveforms in particularly the peripheral regions of the retinas within the MNU + HRS group, compared to that in the MNU group. However, this enhanced protection of structure and function in the peripheral retina is unlikely the result of site-dependent variation in the efficacy of HRS; rather, it is most likely due to reduced susceptibility of peripheral photoreceptors to MNU-induced degeneration. Inner retinal neuron function in the MNU + HRS rats was better preserved, with fewer apoptotic photoreceptors in the ONL. Collectively, these results support the rationale for future clinical evaluation of HRS as a therapeutic agent for human RP. PMID- 27215479 TI - Retraction Note: Effects of Bariatric Surgery on Incidence of Obesity-Related Cancers: A Meta-Analysis. AB - In the article entitled, "Effects of Bariatric Surgery on Incidence of Obesity Related Cancers: A Meta-Analysis" which was published in Medical Science Monitor 2015;21: 1350-1357, sections in the text have been directly copied from a previously published article, entitled, "The Effects of Bariatric Surgery on Colorectal Cancer Risk: Systematic Review and Meta-Analysis", Sorena Afshar, Seamus B. Kelly, Keith Seymour, Jose Lara, Sean Woodcock, John C. Mathers in Obesity Surgery 2014; 24(10):1793-1799. Thus owing to duplicity of text, the article is being retracted. Reference: 1. Xiang-wu Yang, Peng-zhou Li, Li-yong Zhu, Shaihong Zhu Effects of Bariatric Surgery on Incidence of Obesity-Related Cancers: A Meta-Analysis Medical Science Monitor 2015;21: 1350-1357 DOI: 10.12659/MSM.893553. PMID- 27215480 TI - Re: Thiel et al: Mayo Adhesive Probability Score Is Associated With Localized Renal Cell Carcinoma Progression-free Survival (Urology 2016;89:54-62). PMID- 27215481 TI - Reply. PMID- 27215482 TI - Hemostatic Efficacy and Histopathological Effects of Ankaferd Blood Stopper in an Experimental Rat Model of Cyclophosphamide-induced Hemorrhagic Cystitis. AB - OBJECTIVE: To evaluate the hemostatic efficacy and histopathological effects of Ankaferd Blood Stopper (ABS) in an experimental rat model of cyclophosphamide induced (CYP) hemorrhagic cystitis (HC). MATERIALS AND METHODS: Forty male Sprague-Dawley rats were included in the study. Firstly, 10 rats were divided equally into 2 groups where the first group was administered only an intraperitoneal (i.p.) injection of normal saline to constitute the negative control group (CON). The remaining 5 rats were administered only a single i.p. injection of CYP (without any further treatment) for induction of HC to constitute the positive control group (HC). Subsequently, the remaining 30 rats, which also received i.p. CYP for induction of HC, were divided into 3 groups to which intravesical saline (SAL group), epinephrine (EPN group), and ABS (ANK group) were administered for 3 consecutive days. Ten days after the third instillation, cystectomy was performed for histopathological examination. Specimens were evaluated for presence of congestion, edema, necrosis, ulceration, and regenerated epithelium, and scores were given for each parameter according to the severity. RESULTS: No statistically significant difference was observed for congestion, edema, necrosis, and ulceration between HC-SAL, and also between CON ANK groups (all P values >.05). There was a significant difference for total scores between EPN and ANK groups (P = .009). There was statistically significant difference for regenerating epithelium between CON-EPN, CON-ANK, HC-ANK, and SAL ANK groups. CONCLUSION: Intravesical administration of ABS is at least as efficacious as EPN in terms of congestion, edema, necrosis, and ulceration. Moreover, ABS can be considered as a better option in inducing regenerating epithelium than EPN. PMID- 27215484 TI - Re: Blackburne et al: Endoscopic Management of Urolithiasis in the Horseshoe Kidney (Urology 2016;90:45-49). PMID- 27215483 TI - Altered Expression of the Transcription Factor Forkhead Box A1 (FOXA1) Is Associated With Poor Prognosis in Urothelial Carcinoma of the Upper Urinary Tract. AB - OBJECTIVE: To determine the prognostic significance of Forkhead Box A1 (FOXA1) expression in patients with upper tract urothelial carcinoma (UTUC) undergoing radical nephroureterectomy (RNU). MATERIALS AND METHODS: A retrospective analysis of 566 patients undergoing RNU at seven academic medical centers was performed. Tissue microarrays were subjected to immunohistochemistry using a commercially available polyclonal FOXA1 antibody. Logistic regression determined the association of FOXA1 expression with pathologic features and survival outcomes. RESULTS: Three hundred twenty-two men and 244 women were included. The pathologic distribution of specimens included 53% muscle-invasive or greater (>=pT2), 74% high-grade, 16% with flat architecture, 13% with necrosis, 21% with lymphovascular invasion, 18% with concomitant carcinoma in situ, and 8% with positive lymph nodes. The median FOXA1 score was 5.0 (range: 0-8). Lower FOXA1 expression was significantly correlated with advanced pathologic stage (>=pT3) (P = .02), concomitant carcinoma in situ (P = .006), and renal pelvis (vs ureter) location (P < .0001). At a median follow-up of 27.0 months (range: 3-196), 139 patients (25%) experienced disease recurrence and 121 (21%) died from the disease. In a multivariate model, lower FOXA1 expression was independently associated with disease recurrence (hazard ratio [HR]: 1.11, 95% confidence interval [CI]: 1.05-1.62, P = .04), cancer-specific mortality (HR: 1.17, 95% CI: 1.03-1.92, P = .04), and all-cause mortality (HR: 1.08, 95% CI: 1.02-1.18, P = .05). CONCLUSION: Lower FOXA1 expression is associated with adverse pathologic features and inferior survival outcomes for UTUC patients undergoing RNU. These data indicate lower FOXA1 expression may be a marker of aggressive disease in UTUC. PMID- 27215485 TI - Kidney Cancer in Rural Illinois: Lower Incidence Yet Higher Mortality Rates. AB - OBJECTIVE: To determine if rural status was associated with kidney and renal pelvis cancer (KCa) incidence and mortality in Illinois while controlling for known KCa risk factors and access to care variables. MATERIALS AND METHODS: Age adjusted KCa incidence rates from 1991 to 2010 were calculated from Illinois State Cancer Registry data. Age-adjusted KCa mortality rates were obtained from health statistics embedded within SEER*Stat. Rural Urban Continuum Codes designated Illinois' 102 counties as urban, rural adjacent to, and rural non adjacent to a metropolitan area. County-level demographics and physician density were obtained from the Area Health Resource File. Behavioral Risk Factor Surveillance System data were used for smoking, obesity, and hypertension prevalence. Analysis of variance, correlation, and regression analyses were used. RESULTS: The incidence of KCa was found to be higher among urban compared to rural counties after controlling for known risk factors (P < .01). A larger proportion of cases were diagnosed at a localized stage in urban counties (<0.01). Mortality rates were significantly higher in rural counties (P = .02). The final regression model found rural status, higher incidence rate, fewer with localized stage at diagnosis, and lower urologist density to be variables significantly associated with higher KCa mortality. CONCLUSION: KCa incidence was higher in urban counties whereas mortality was higher in rural counties. The higher number of KCa cases diagnosed at a localized stage in urban counties and lower urologist density in rural counties suggest that poorer access to care may contribute to higher KCa mortality in rural Illinois. Telemedicine may be an opportunity to improve this disparity. PMID- 27215487 TI - Magnetic Force Nanoprobe for Direct Observation of Audio Frequency Tonotopy of Hair Cells. AB - Sound perception via mechano-sensation is a remarkably sensitive and fast transmission process, converting sound as a mechanical input to neural signals in a living organism. Although knowledge of auditory hair cell functions has advanced over the past decades, challenges remain in understanding their biomechanics, partly because of their biophysical complexity and the lack of appropriate probing tools. Most current studies of hair cells have been conducted in a relatively low-frequency range (<1000 Hz); therefore, fast kinetic study of hair cells has been difficult, even though mammalians have sound perception of 20 kHz or higher. Here, we demonstrate that the magnetic force nanoprobe (MFN) has superb spatiotemporal capabilities to mechanically stimulate spatially-targeted individual hair cells with a temporal resolution of up to 9 MUs, which is equivalent to approximately 50 kHz; therefore, it is possible to investigate avian hair cell biomechanics at different tonotopic regions of the cochlea covering a full hearing frequency range of 50 to 5000 Hz. We found that the variation of the stimulation frequency and amplitude of hair bundles creates distinct mechanical responsive features along the tonotopic axis, where the kinetics of the hair bundle recovery motion exhibits unique frequency-dependent characteristics: basal, middle, and apical hair bundles can effectively respond at their respective ranges of frequency. We revealed that such recovery kinetics possesses two different time constants that are closely related to the passive and active motilities of hair cells. The use of MFN is critical for the kinetics study of free-standing hair cells in a spatiotemporally distinct tonotopic organization. PMID- 27215486 TI - JNK and p38 mitogen-activated protein kinase pathways contribute to porcine epidemic diarrhea virus infection. AB - The mitogen-activated protein kinase (MAPK) pathways, which are central building blocks in the intracellular signaling network, are often manipulated by viruses of diverse families to favor their replication. Among the MAPK family, the extracellular signal-regulated kinase (ERK) pathway is known to be modulated during the infection with porcine epidemic diarrhea virus (PEDV); however, involvement of stress-activated protein kinases (SAPKs) comprising p38 MAPK and c Jun NH2-terminal kinase (JNK) remains to be determined. Therefore, in the present study, we investigated whether activation of p38 MAPK and JNK cascades is required for PEDV replication. Our results showed that PEDV activates p38 MAPK and JNK1/2 up to 24h post-infection, whereas, thereafter their phosphorylation levels recede to baseline levels or even fall below them. Notably, UV-irradiated inactivated PEDV, which can enter cells but cannot replicate inside them, failed to induce phosphorylation of p38 MAPK and JNK1/2 suggesting that viral biosynthesis is essential for activation of these kinases. Treatment of cells with selective p38 or JNK inhibitors markedly impaired PEDV replication in a dose dependent manner and these antiviral effects were found to be maximal during the early times of the infection. Furthermore, direct pharmacological inhibition of p38 MAPK or JNK1/2 activation resulted in a significant reduction of viral RNA synthesis, viral protein expression, and progeny release. However, independent treatments with either SAPK inhibitor did not inhibit PEDV-induced apoptotic cell death mediated by activation of mitochondrial apoptosis-inducing factor (AIF) suggesting that SAPKs are irrelevant to the apoptosis pathway during PEDV infection. In summary, our data demonstrated critical roles of the p38 and JNK1/2 signaling pathways in facilitating successful viral infection during the post entry steps of the PEDV life cycle. PMID- 27215488 TI - Progresses in vaginal microflora physiology and implications for bacterial vaginosis and candidiasis. PMID- 27215489 TI - Reply. PMID- 27215491 TI - Migration and allergic diseases in a rural area of a developing country. PMID- 27215490 TI - Claudin-18 deficiency is associated with airway epithelial barrier dysfunction and asthma. AB - BACKGROUND: Epithelial barrier dysfunction and increased permeability may contribute to antigen sensitization and disease progression in asthma. Claudin 18.1 is the only known lung-specific tight junction protein, but its contribution to airway barrier function or asthma is unclear. OBJECTIVES: We sought to test the hypotheses that claudin-18 is a determinant of airway epithelial barrier function that is downregulated by IL-13 and that claudin-18 deficiency results in increased aeroantigen sensitization and airway hyperresponsiveness. METHODS: Claudin-18.1 mRNA levels were measured in airway epithelial brushings from healthy controls and patients with asthma. In patients with asthma, claudin-18 levels were compared with a three-gene-mean marker of TH2 inflammation. Airway epithelial permeability changes due to claudin-18 deficiency were measured in 16HBE cells and claudin-18 null mice. The effect of IL-13 on claudin expression was determined in primary human airway epithelial cells and in mice. Airway hyperresponsiveness and serum IgE levels were compared in claudin-18 null and wild-type mice following aspergillus sensitization. RESULTS: Epithelial brushings from patients with asthma (n = 67) had significantly lower claudin-18 mRNA levels than did those from healthy controls (n = 42). Claudin-18 levels were lowest among TH2-high patients with asthma. Loss of claudin-18 was sufficient to impair epithelial barrier function in 16HBE cells and in mouse airways. IL-13 decreased claudin-18 expression in primary human cells and in mice. Claudin-18 null mice had significantly higher serum IgE levels and increased airway responsiveness following intranasal aspergillus sensitization. CONCLUSIONS: These data support the hypothesis that claudin-18 is an essential contributor to the airway epithelial barrier to aeroantigens. Furthermore, TH2 inflammation suppresses claudin-18 expression, potentially promoting sensitization and airway hyperresponsiveness. PMID- 27215492 TI - Basophil activation test determination of CD63 combined with CD203c is not superior to CD203c alone in identifying allergic bronchopulmonary aspergillosis in cystic fibrosis. PMID- 27215493 TI - Correlation of the depletion layer with the Helmholtz layer in the anatase TiO2 H2O interface via molecular dynamics simulations. AB - Molecular dynamics simulations have been conducted to study the interaction between anatase TiO2(001), (100), and (101) surfaces and water at room temperature. The dynamic interfacial structure and properties of water on anatase TiO2 surfaces are obtained by analyzing the water density, the diffusion coefficient of water, the surface charge distribution, electric fields and the electrostatic potential distribution. The simulation results have revealed that a highly-ordered water layer structure can be formed near to the anatase TiO2 surface and have also given the Helmholtz layer width and potential drop at the water-TiO2 interface. By correlating the Helmholtz layer with the depletion layer, the depletion layer widths of three surfaces (001), (100), and (101) have been calculated as 474 A, 237 A and 99 A, respectively. The resulting order of the photoelectrochemical activity of the anatase TiO2 surfaces is (001) > (100) > (101), which is consistent with the experimental results. This study may provide a useful correlation of the depletion layer with the Helmholtz layer based on simulations results for the prediction of the behavior and the control of photon energy conversion devices. PMID- 27215494 TI - Empirical analysis of RNA robustness and evolution using high-throughput sequencing of ribozyme reactions. AB - RNA molecules provide a realistic but tractable model of a genotype to phenotype relationship. This relationship has been extensively investigated computationally using secondary structure prediction algorithms. Enzymatic RNA molecules, or ribozymes, offer access to genotypic and phenotypic information in the laboratory. Advancements in high-throughput sequencing technologies have enabled the analysis of sequences in the lab that now rivals what can be accomplished computationally. This has motivated a resurgence of in vitro selection experiments and opened new doors for the analysis of the distribution of RNA functions in genotype space. A body of computational experiments has investigated the persistence of specific RNA structures despite changes in the primary sequence, and how this mutational robustness can promote adaptations. This article summarizes recent approaches that were designed to investigate the role of mutational robustness during the evolution of RNA molecules in the laboratory, and presents theoretical motivations, experimental methods and approaches to data analysis. PMID- 27215495 TI - Comparison of different methods to study effects of silver nanoparticles on the pro- and antioxidant status of human keratinocytes and fibroblasts. AB - In times of antibiotic-resistant bacteria new strategies to avoid the septic inducing threat of dangerous microorganisms are needed. Silver ions (Ag+) in the forms of silver nitrate or silver sulfadiazine have been used as antimicrobial agents for years. A step further was the development of micro and silver particles (AgNP). In contrast to other Ag+ ion sources, AgNP allow a sustained release of Ag+ ions, due to their high surface to volume ratio. However, AgNP are also toxic to eukaryotic cells and the mechanisms of cytotoxicity have not yet been fully elucidated. In this study, the impact of different AgNP preparations on a human keratinocyte cell line was investigated. The intracellular radical formation was confirmed by the 2',7'-dichlorodihydrofluorescein di-acetate (H2DCF DA) assay on two cell types (HaCaT cells and normal human dermal fibroblasts) as well as by electron paramagnetic resonance (EPR) spectroscopy, which showed comparable results. EPR spectroscopy was performed for the first time for 24h in experiments using keratinocytes. Drastic changes in the mitochondrial activity were induced in cells incubated with AgNP containing high concentrations of Ag+ ions. It was also possible to show that the quantitative uptake of AgNP was dependent on the AgNP concentration. In addition, the effects of AgNP on the GSH/GSSG system were elucidated. The results showed a batch- and concentration dependent decrease of the total glutathione concentration which correlated well with the decrease of cell viability. Furthermore, the results suggest a direct reaction of GSH molecules with Ag+ ions. In conclusion, this study proves the efficacy of the H2DCF-DA assay and the EPR spectroscopy. The investigations show that AgNP formulations containing high amounts of released Ag+ ions induce radicals in human keratinocytes and deplete them of their natural anti-oxidative molecules. On the contrary, nanoparticles prepared and stored under argon did not induce significant adverse effects, suggesting that slowing down the release of Ag+ may help to reduce AgNP-related side effects without affecting the antibacterial impact. PMID- 27215496 TI - Presence of rhinovirus in the respiratory tract of adolescents and young adults with asthma without symptoms of infection. AB - BACKGROUND: Viral respiratory infections have been associated with up to 80% of wheezing episodes and asthma exacerbations. However, studies on the role of these viruses in asthmatic patients in the interval between exacerbations are sparse. This study aimed to determine the presence of respiratory viruses, without symptoms of infection, in the airways of young asthmatics as compared to healthy controls. MATERIAL AND METHODS: Patients 10-35 years of age with stable asthma and a group of healthy controls were analyzed regarding the presence of RNA from common respiratory viruses in nasopharyngeal aspirates by PCR. Self-reported asthma control and quality of life, fraction of exhaled nitric oxide (FeNO), spirometry, and bronchial responsiveness to methacholine were recorded. Blood samples were collected to assess IgE sensitisation and eosinophil cationic protein (ECP) levels. RESULTS: In 354 patients with asthma and 108 healthy controls, human rhinovirus (HRV) was the only virus detected (4.5% of asthmatics vs. 0.9% of controls; p = 0.08). HRV(+) asthma patients had a higher degree of aeroallergen IgE sensitisation (median 37.7 vs. 10.4 kUA/L, p = 0.04), and a tendency for higher levels of serum ECP (median 17.2 vs. 12.6 MUg/L, p = 0.07), as compared to their HRV(-) counterparts. CONCLUSIONS: Absence of symptoms of respiratory tract infection notwithstanding, HRV seems to be more prevalent in the airways of adolescents and young adults with asthma and a high degree of aeroallergen IgE sensitisation than in controls. The presence of HRV seems also to be related to systemic eosinophilic inflammation despite ongoing treatment with inhaled corticosteroids. PMID- 27215497 TI - Assessing biomarkers in a real-world severe asthma study (ARIETTA). AB - The prognostic value of asthma biomarkers in routine clinical practice is not fully understood. ARIETTA (NCT02537691) is an ongoing, prospective, longitudinal, international, multicentre real-world study designed to assess the relationship between asthma biomarkers and disease-related health outcomes. The trial aims to enrol and follow for 52 weeks approximately 1200 severe asthma patients from approximately 160 sites in more than 20 countries. Severe asthmatics, treated with daily inhaled corticosteroid (>=500 MUg of fluticasone propionate or equivalent) and at least 1 second controller medication are to be included. In this real-world study, patients will be treated according to the investigator's routine clinical practices and no treatment regimen will be implemented as part of the trial. At baseline and again at 26 and 52 weeks, FEV1, FeNO, serum periostin, blood eosinophil count and serum IgE will be measured. Asthma-related symptom and quality of life questionnaires will be administered at the visits and during telephone interviews at Weeks 13 and 39. Data about medication use, asthma exacerbation data, asthma-related healthcare utilization and events raising safety concerns will also be collected. This study design, unique in both its scope and scale, will address fundamental unanswered questions regarding asthma biomarkers and their interrelationship, as well as predict deviations in the course of asthma in a real-world setting. PMID- 27215498 TI - High prevalence of obstructive lung disease in non-smoking farmers: The Irish farmers lung health study. AB - BACKGROUND: Mortality rates within the Irish farming community are increasing, whilst that of the general population falls. The aim of this cross-sectional study was to determine the prevalence of respiratory disease amongst Irish farmers. METHODS: All study participants were farming volunteers attending an agricultural exhibition. Data collected by questionnaire included baseline demographics, respiratory history, presence of respiratory symptoms and occupational exposures. Spirometry was performed on all participants. RESULTS: Data from 372 farmers was analysed. The majority were male (76%) with median age of 55 years. 61% were never smokers. 13% were previously diagnosed with airway disease (Chronic Obstructive Pulmonary Disease(COPD)/Asthma/Inhaler use) with 14% reporting hayfever/allergies. Almost two-thirds reported one or more chronic respiratory symptom. Forty-four (12%) had obstructive spirometry using fixed FEV1/FVC < 0.70 criterion and 29 (7.8%) using FEV1/FVC < 5% lower limit of normal. The majority, two-thirds, were never smokers. Amongst never smokers with obstruction (13%), there was a significantly higher proportion with a prior diagnosis of airway disease and hayfever/allergies. There was no significant association between specific occupational exposures and obstruction. CONCLUSION: The majority of Irish farmers are never smokers. They have a high prevalence of respiratory symptoms. 13% of never smokers have airflow obstruction (FEV1/FVC < 0.70). The presence of airflow obstruction is significantly associated with self reported allergy history and prior airway disease. Further studies are needed to identify the workplace factors accounting for these findings. PMID- 27215499 TI - Does gastroesophageal reflux increase chronic obstructive pulmonary disease exacerbations? AB - BACKGROUND: The relationship between chronic obstructive pulmonary disease (COPD) exacerbations and gastroesophageal reflux (GER) has been investigated less than asthma-GER. We aimed to evaluate the presence of GER in patients with COPD and its impact on exacerbations. METHODS: We included 24 patients with stable mild moderate stage COPD and 19 volunteers as the control group. We conducted a gastroesophageal reflux disease (GERD) symptom questionnaire, gastroscopy, manometry, and an ambulatory 24-h pH-impedance study. RESULTS: According to the GERD questionnaire, only 5 (20.8%) patients with COPD had typical GER symptoms. According to the 24-h pH-impedance study, the mean DeMeester score (DMS) was 38.1 +/- 34.6 in the COPD group and 13.3 +/- 16.8 in the control group (p = 0.01). The acid reflux (DMS > 14.7) rate was higher in patients with COPD than in controls (73.9% vs 26.3%, p = 0.01). The symptom association probability positivity rate was 17.4% (n = 4) in the COPD group, which was similar to the controls (p = 0.11). The mean proximal extension rate of reflux (Z 17 cm) was 26.4 +/- 12.9% in the COPD group. The proximal extent of reflux was positively correlated with the number of COPD exacerbations per year (p = 0.03, r = 0.448). In the motility results, only 2 (20%) patients in the control group had a minor motility disorder. Seventeen (70.8%) patients in the COPD group had a minor motility disorder, and 4 (16.7%) had major motility disorders (p < 0.001). CONCLUSION: In our study, gastroesophageal reflux was frequent in patients with COPD, but only a quarter had typical reflux symptoms. The proximal extent of reflux may trigger frequent exacerbations of COPD. PMID- 27215500 TI - Impact of invasive ventilation on survival when non-invasive ventilation is ineffective in patients with Duchenne muscular dystrophy: A prospective cohort. AB - BACKGROUND: Many patients with DMD undergo tracheostomy. Tracheostomy is associated with certain complications, however its effect on prognosis is not known. METHODS: The relationship between type of mechanical ventilation and survival at 12 years was evaluated in a prospective cohort of patients with Duchenne muscular dystrophy followed in a French reference center for Neuromuscular Diseases. Cox proportional-hazards regressions were used to estimate the hazard ratios associated with risk of switching from non-invasive to invasive ventilation, and with risk of death. RESULTS: One hundred and fifty patients were included. Initial use of invasive ventilation was associated with an episode of acute respiratory failure (p < 0.0001) and with a severe clinical status (p < 0.05). Risk of death was associated with swallowing disorders (2.51, IC [1.12-5.66], p < 0.03) and cardiac failure (p < 0.05) but not with type of mechanical ventilation. CONCLUSION: Switching to invasive ventilation is appropriate when non-invasive ventilation is ineffective. PMID- 27215501 TI - A bundled care approach to patients with idiopathic pulmonary fibrosis improves transplant-free survival. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with poor prognosis and limited therapeutic options. The 2011 ATS/ERS/JRS/ALAT consensus statement provided a number of recommendations for the management of IPF patients. The primary objective of this study was to determine if "bundling" these recommendations in the management of patients with IPF impacts clinical outcomes. METHODS: We conducted a single center, retrospective cohort study of 284 patients diagnosed with IPF. The proposed bundle of care (BOC) components were: (1) visits to a specialized interstitial lung diseases clinic with evaluation of pulmonary function tests at least twice yearly; (2) referral to pulmonary rehabilitation yearly; (3) timed walk test yearly; (4) echocardiogram yearly; and (5) gastroesophageal reflux therapy. Each component of the BOC was given a score of "1" per year of follow up, and the average sum of the scores (ranging from 0 to 5) was determined for the entire period of follow-up (BOCS), as well as during the first year of follow-up (BOCY1). The primary outcome measure was transplant-free survival. RESULTS: Age, gender, smoking status, BMI, %FVC, %DLCO did not differ between levels of BOCS and BOCY1. Lowest BOCS (<=1) was associated with a lower transplant-free survival independent of age and %FVC compared to patients with the highest BOCS (>4) (HR 2.274, CI 1.12-4.64, p = 0.024). Lower BOCY1 was associated with a higher risk for transplant or death independent of age and %FVC in comparison to patients with highest BOCY1 (<=1 vs. >4, HR 2.23, p = 0.014; >1 to 2 vs. >4, HR 1.87, p = 0.011; >2 to 3 vs. >4, HR 1.72, p = 0.019). CONCLUSION: IPF patients with higher BOC scores had improved transplant-free survival. Prospective studies are needed to confirm these findings and determine the best strategies for the management of patients with IPF. PMID- 27215502 TI - Long-term safety of glycopyrrolate: A randomized study in patients with moderate to-severe COPD (GEM3). AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the United States. Long-acting muscarinic antagonists (LAMAs) are a class of medications used as maintenance therapy for COPD. The GEM3 (Glycopyrrolate Effect on syMptoms and lung function) study assessed the long term safety and efficacy of a LAMA, glycopyrrolate (GLY) 15.6 MUg twice daily (b.i.d.), compared with an approved long-acting beta2-agonist (LABA), indacaterol (IND) 75 MUg once daily (q.d.) in patients with stable, symptomatic COPD with moderate-to-severe airflow limitation. METHODS: This 52-week, multicenter, double blind, parallel-group study randomized patients (1:1) of the United States to receive GLY 15.6 MUg b.i.d. or IND 75 MUg q.d. both delivered via the Neohaler((r)) device. The primary objective was to assess the safety and tolerability in terms of adverse event (AE) reporting rates over 52 weeks. Safety was also determined by evaluating multiple secondary endpoints, including vital signs, electrocardiograms (ECGs), and time to first moderate or severe exacerbation. Efficacy-related secondary endpoints included pre-dose forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). RESULTS: Of the 511 randomized patients (GLY, n = 254; IND, n = 257), 81.6% completed the study. The overall incidences of AEs (GLY, 77.3%; IND, 77.0%) and serious AEs (GLY, 13.1%; IND, 13.3%) were comparable between the groups. The incidence of major adverse cardiovascular events was low and comparable between the groups. No clinically relevant differences for vital signs or ECG parameters were observed between the treatment groups. The three sudden deaths reported within 30 days of the treatment (GLY, n = 2; IND, n = 1) were adjudicated as unrelated to the study medication. In terms of efficacy, GLY 15.6 MUg b.i.d. showed improvements in pre dose FEV1 and FVC from baseline, which was comparable to those with IND 75 MUg q.d., with no statistically significant differences. No significant differences were observed between the treatment groups in the time to first moderate or severe COPD exacerbation. CONCLUSION: GLY 15.6 MUg b.i.d. showed a long-term safety profile comparable to that of IND 75 MUg q.d. and provided rapid and sustained bronchodilation over 52 weeks in patients with COPD with moderate-to severe airflow limitation. CLINICAL TRIAL REGISTRATION NUMBER: NCT01697696. PMID- 27215503 TI - Increased levels of serum Wisteria floribunda agglutinin-positive Mac-2 binding protein in idiopathic pulmonary fibrosis. AB - BACKGROUND: Mac-2 binding protein (M2BP) is a cell-adhesive glycoprotein of the extracellular matrix secreted as a ligand of galectin-3 (Mac-2). Recently, a Wisteria floribunda agglutinin positive-M2BP (WFA(+)-M2BP) assay developed using a lectin-antibody sandwich immunoassay has shown promise as a new fibrotic marker in liver fibrosis to detect unique fibrosis-related glycoalteration. The aim of this study is to evaluate the utility of serum WFA(+)-M2BP levels in patients with idiopathic pulmonary fibrosis (IPF). METHODS: We measured serum WFA(+)-M2BP levels in 116 patients with IPF and 42 healthy volunteers. We examined the relationship between serum WFA(+)-M2BP levels and clinical parameters and further investigated the prognostic significance of serum WFA(+)-M2BP levels in patients with IPF. RESULTS: Serum WFA(+)-M2BP levels were significantly higher in patients with IPF than in healthy controls (1.09 +/- 0.89 cutoff index [COI], 0.57 +/- 0.24 COI, respectively; P < 0.001). In patients with IPF, a significant positive correlation was found between serum WFA(+)-M2BP levels and age, KL-6, neutrophils in BAL, reticulation and honeycombing scores in HRCT, and fibrotic foci scores in pathological findings, and a significant negative correlation was found between serum WFA(+)-M2BP levels and FVC, %DLco and macrophages in BAL. Furthermore, patients with high serum WFA(+)-M2BP levels had a significantly worse prognosis than those with low levels (log-rank test, P = 0.0209), and a high serum WFA(+) M2BP level was a significant prognostic factor in Cox proportional hazards regression analysis. CONCLUSIONS: Our results suggest that the serum WFA(+)-M2BP level is a potential biomarker in patients with IPF. PMID- 27215504 TI - Self-reported influenza vaccination and protective serum antibody titers in a cohort of COPD patients. AB - BACKGROUND: COPD patients are advised vaccination against seasonal influenza, yet few studies have evaluated the protective antibody titers obtained in this patient group. AIMS: 1) To describe protective titers in COPD patients who self reported influenza vaccination compared with vaccinated subjects without COPD and unvaccinated COPD patients, 2) analyze whether clinical parameters predicted influenza-specific antibody titers, and 3) whether antibody titers to influenza A at baseline could predict exacerbation risk or 5 years all-cause mortality. METHODS: Influenza A (H1N1 and H3N2) titers were measured by haemagglutination inhibition assay in serum from 432 COPD patients and 77 controls in the Bergen COPD Cohort Study, at yearly visits between 2006/09. Titers of 40 or above were considered protective. We examined the variables sex, age, body composition, smoking, GOLD stage, yearly exacerbations, inhaled steroids, and Charlson score as predictive of titers, both univariately and in a multivariable model estimated by generalized estimating equations. The exacerbation incidence rate ratios and mortality hazard ratios were assessed by negative binominal and cox regression models respectively. RESULTS: At baseline, 59% of COPD patients reported influenza vaccination during the last season. Levels of predictive titers varied considerably each season, but trended lower in COPD patients compared with controls. Neither sex, age, body composition, smoking, comorbidities, GOLD stage nor use of inhaled steroids consistently predicted titers. Having high titers at baseline did not impact later risk for exacerbations, but seemed to be associated with higher all-cause mortality, even after adjustment for COPD disease characteristics. CONCLUSION: Vaccination coverage for influenza is imperfect for COPD patients in Norway, and there is a concern that immunization is suboptimal. PMID- 27215505 TI - Lung transplantation for non-cystic fibrosis bronchiectasis. AB - BACKGROUND: Lung transplantation (LTx) is a well-established treatment for end stage pulmonary disease. However, data regarding microbiology and outcome of patients with non-cystic fibrosis bronchiectasis (NCFB) after lung transplantation are limited. METHODS: A retrospective analysis between August 1992 and September 2014 of all patients undergoing lung transplantation at our program of all recipients with a primary diagnosis of bronchiectasis was performed. Microbiology of sputum and bronchoalveolar lavage specimens, lung function and clinical parameters pre- and post-LTx were assessed retrospectively. Overall survival was compared to the total cohort of lung transplant recipients at institution. The survival and development of chronic lung allograft dysfunction (CLAD) was compared in patients with and without chronic Pseudomonas aeruginosa (PSA) infection after LTx. RESULTS: 34 patients were transplanted. Median age at transplantation was 40 (IQR 33-52) years. The most common etiologies of bronchiectasis were idiopathic (41%), chronic obstructive pulmonary disease (COPD) (21%) and post-infectious (15%). The most common organism of pre- and posttransplant chronic airway infection was PSA. One-year Kaplan-Meier survival for patients with bronchiectasis was 85% and 5-year survival was 73% and similar to the entire cohort. All three patients with an associated diagnosis of immunodeficiency died due to infection and sepsis within the first year. Patients with persistent colonization with Pseudomonas aeruginosa after transplantation had worse long-term survival by trend and developed chronic lung allograft dysfunction more frequently. CONCLUSIONS: Overall survival of patients with bronchiectasis after LTx is comparable to other underlying diseases. A reduced survival was observed in patients with the underlying diagnosis of immunodeficiency. PMID- 27215506 TI - Respiratory deterioration following laparoscopic adjustable gastric banding: A three-year follow-up of over 3,000 subjects. AB - BACKGROUND: Obesity is considered a global epidemic. Until recently, laparoscopic adjustable gastric binding (LAGB) was routinely offered as a means of weight reduction for selected patient populations. Previous case series have documented several pulmonary complications following LAGB. In the current study, we explored the rate of long-term respiratory deterioration associated with LAGB. METHODS: The study is a historical cohort study of medical records of subjects who underwent LAGB at Soroka University Medical Center in Israel between January 1997 and July 2008. After the exclusion of short-term respiratory events, respiratory morbidity during the three years following the operation was compared with that three years prior to the operation. Subjects whose respiratory status worsened following surgery were further compared with those whose status either remained unchanged or improved. RESULTS: The final analysis included 3084 subjects, of whom 709 (22.9%) had documented respiratory morbidity following surgery. Compared to pre-operative respiratory status, respiratory deterioration following LAGB was found in 590 subjects (19.1%). Risk factors associated with the worsening of respiratory status were age <=28 or >=46 years (odds ratio [OR] = 1.32, 95% confidence interval [CI]: 1.02-1.71 and OR = 1.42, 95% CI: 1.09-1.85, respectively), female gender (OR = 1.31, 95% CI: 1.06-1.63), and pre-operative documentation of respiratory morbidity. CONCLUSIONS: The rate of deterioration in the respiratory status observed among subjects who underwent LAGB was high. Consequently, physicians should be aware of the possible link, even years after the surgery, between respiratory symptoms and a history of LAGB. PMID- 27215507 TI - Efficacy of adalimumab in sarcoidosis patients who developed intolerance to infliximab. AB - BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) inhibitors are regarded as the third-line therapy in sarcoidosis, the first choice generally being infliximab. To date, data regarding response to adalimumab in sarcoidosis patients intolerant to infliximab are lacking. The objective of this retrospective observational study was to establish if adalimumab could achieve stabilization or improvement of the disease in refractory sarcoidosis patients who developed intolerance to infliximab. MATERIAL AND METHODS: Sarcoidosis patients referred to St Antonius Interstitial Lung Diseases Center of Excellence, Nieuwegein, The Netherlands, between January 2008 and April 2015 who switched from infliximab to adalimumab were included. Changes in organ function, inflammatory biomarker levels, and adverse events were retrieved from medical records. RESULTS: Out of 142 infliximab treated patients, 18 (13%) had to discontinue treatment due to antibody formation or severe adverse events and switched to adalimumab therapy. Organ function improved in 7 patients (39%), was stable in 6 patients (33%), and worsened in 5 patients (28%) after 12 months of treatment or after 6 months if evaluation after 12 months was not available (n = 4). In none of the patients biomarker levels of soluble interleukin-2 receptor (sIL-2R) deteriorated. Median decrease in sIL-2R was 3614 pg/mL. Most reported adverse event was infection (n = 10). CONCLUSIONS: Adalimumab is an effective alternative for patients intolerant to infliximab. The switch to adalimumab achieved clinical improvement in 39% and stabilization in 33% of patients intolerant to infliximab. Further research is needed to develop guidelines on how to use adalimumab for sarcoidosis in terms of dosing regimen. PMID- 27215509 TI - [Prevalence and trend of gastrointestinal malignant tumors in the elderly over 75 years old in China]. AB - Gastrointestinal malignant tumors are the most common malignant neoplasms among the elderly people over 75 years old in China. There are 122.1 thousand new gastric cases and 78.2 thousand new colorectal cancer cases diagnosed each year in China, which accounts for 42.73% and 18.08% respectively of the cases with same age in the world. The gastric cancer accounts for 25.13% and colorectal cancer accounts for 28.86%of all the malignancies in the elderly. The gastric cancer death accounts for 36.38% and colorectal cancer death accounts for 44.68% in those people over 75 years old in China. It was estimated that the risk of developing gastrointestinal malignant tumors of these elderly people was about 5 6 times and the risk of death of gastrointestinal malignant tumors was about 7-8 times of the general population. Compared with the general population and the people of 55-74 years old, the incidence of gastric cancer in the elderly decreased more slowly and the incidence of colorectal cancer increased more quickly over the past 40 years, which brought significant double burden. The survival rate of gastrointestinal malignant tumors in these elderly was lower than that of the general population. We summarized the incidence, mortality, survival and trend of gastrointestinal malignant tumors in the Chinese elderly, in order to provide data for predicting the age distribution and disease burden in the future, to improve the awareness for cancer prevention and control among these elderly, and to call attention to epidemiology, preclinical and clinical medicine for the elderly, especially in the field of study on the influence between comorbidity and cancer treatment, with the aim of improving survival and quality of life among the elderly. PMID- 27215508 TI - Health literacy and health outcomes in chronic obstructive pulmonary disease. AB - BACKGROUND: There is little information worldwide about the impact of health literacy (HL) on clinical outcomes of COPD. Our aim was to quantify inadequate HL in Spain, as measured by the Short Assessment of Health Literacy for Spanish Adults questionnaire, and to examine the associations between HL and both COPD outcomes and health status. METHODS: 296 COPD patients of 68(SD = 9) years and a FEV1%predicted of 53%(SD = 18%) were enrolled and followed-up for one year. 59% showed "inadequate" HL. RESULTS: Individuals with inadequate HL were older (70[SD = 9] vs 65[SD = 8] years; p < 0.001) and had less knowledge of their disease, as measured by the low HL-COPD questionnaire, (6.9[SD = 2.3] vs 7.5[SD = 1.9]; p < 0.001). While their lung function was no different, they reported significant differences in mMRC (1.6[SD = 1] vs 1.4[SD = 1]; p < 0.001), CAT (19.2[SD = 8.1] vs 18.3[SD = 7.5]; p = 0.049), and EQ-5 (3.1[SD = 2.2] vs 2.3[SD = 1.9]; p < 0.00). Those with inadequate HL had also higher risk of having >=2 comorbidities (OR = 1.87; 95%CI = 1.14-3.08), need of assistance (OR = 2.5; 95%CI = 1.5-4.2), anxiety/depression (OR = 1.9; 95%CI = 1.2-3.0), admissions or visits to the emergency department (OR = 1.70; 95%CI = 1.1-2.7), and all-cause deaths in the following year (3.8% (SE = 1.1%) vs 0%; p = 0.051). CONCLUSIONS: Inadequate HL is prevalent among COPD patients and it is related to health status and relevant clinical outcomes of the disease. HL needs to be considered when planning the care for COPD patients. PMID- 27215510 TI - [Full attention to several key issues in surgical treatment for the elderly patients with gastrointestinal cancer]. AB - With the development of population aging in our country, the incidence of gastrointestinal cancer is increasing. The risk of developing gastrointestinal cancer in elderly over 75 years was 5-6 times and the risk of death of gastrointestinal cancer was 7-8 times of the general population. As compared to non-elderly, the incidence of gastric cancer was not decreased obviously but the total incidence of colorectal cancer was increased more quickly. Therefore, screening of gastrointestinal cancer should be performed in the elderly for early discovery, diagnosis and treatment. Because of the insidious onset of the illness in elderly patients, gastrointestinal cancers are mostly diagnosed at advanced or late stage (stage III or IV). Well differentiated cancer is more common, such as papillary or tubular adenocarcinoma. Lauren type, Borrmann II or III are more common in gastric cancer, which are relatively favorable. Compared with non elderly patients, many elderly patients also suffer from comorbid diseases with higher operation risk and postoperative complication rates. Therefore, we must pay great attention to the perioperative management and the surgical operation for the elderly patients. In this paper, several key issues involved the development trend of incidence and mortality of gastrointestinal cancer, the clinicopathological characteristics, the comorbidity and surgical treatment in the elderly patients with gastrointestinal cancer will be elaborated, aiming at promoting further attention to the clinical therapeutic strategies, management measures and prognostic factors for the elderly patients with gastrointestinal cancer. PMID- 27215511 TI - [Features of elderly patients over 75 years old with gastric cancer and surgical strategy]. AB - The new cases and mortality of gastric cancer in the population aged over 75 years account for 21% and 30% of the cases in the whole population respectively. These elderly patients with gastric cancer are characteristic of nonspecific clinical manifestations, high proportion of upper gastric carcinoma, larger tumor size, advanced TNM stage, concomitant diseases, poor body function and high risk of complications. Specialists should pay more attention to the diagnosis and treatment of these patients. Comprehensive and systemic assessment should be performed, and concomitant diseases should be treated. Accurate preoperative staging should be accessed by EUS and CT. Individualized treatment according to the principle of precise surgery and enhanced recovery after surgery (ERAS) should be performed as follows. For early gastric cancer with low risk of lymph node metastasis, endoscopic submucosal dissection (ESD) is recommended for expanded indications. For resectable advanced gastric cancer, "downsizing" surgery obtaining >=4 cm incisal margin is recommended, which must be based on accurate preoperative stage. And gasless laproscopy is applicable for these patients. For unresectable advanced gastric cancer, conversion therapy is not the priority unless patients with high response rate. Palliative chemotherapy, immunotherapy and best supportive care should be applied in turn. ERAS techniques application in elderly patients with gastric cancer requires careful selection. PMID- 27215512 TI - [Clinicopathological characteristics of colorectal carcinoma in the elderly]. AB - Elderly patients with colorectal cancer have different clincopathological characteristics from younger patients. Colorectal cancers tend to localize in the proximal colon, from cecum to the splenic flexure in the elderly patients. Changes in the stools, rectal bleeding or black stool, abdominal pain, fatigue, weight loss and anemia are the common symptoms. Analysis showed that age is one of independent risk factors for lower completion rates of colonoscopy. Therefore, the choice of diagnosis methods in elderly patients should be careful. Achieving a clear diagnosis and avoiding complications should be considered at the same time. Most colorectal cancers in elderly are highly and moderately differentiated adenocarcinomas and locally advanced, and have less lymphatic and blood metastasis. The proportion of poorly differentiated adenocarcinoma increases with the increase of age, which should be concerned. Multiple colorectal cancers and colorectal cancer with extra-colorectal malignancy are not rare in the elderly patients. The common extra-colorectal tumors consist of gastric cancer, lung cancer, biliary carcinoma, pancreas cancer and malignancy from blood system. Molecular events, such as mutations of KARS, BRAF, TP53 and deficiency of DNA mismatch repair, are more frequent in elderly colorectal cancer patients. Many factors have impact on treatment decision in elderly patients with colorectal cancer, including age, comorbidities, physiological functions of organs and willingness of patients and their relatives. Although surgery is still the main treatment, the proportion of radical surgery is lower and emergency surgery is higher as compared to younger patients. With the development of minimally invasive surgical techniques and advances in anesthesia and perioperative management, laparoscopic surgery has become widespread in elderly patients with colorectal cancer. In addition, more attention should be paid to adjuvant therapy. Comprehensive individualized treatment plan should be taken to improve outcomes. PMID- 27215513 TI - [Robotic surgery for colorectal cancer in elderly patients]. AB - The outstanding advantages of robotic surgery include the stable and three dimension image and the convenience of surgery manipulation. The disadvantages include the lack of factile feedback, high cost and prolonged surgery time. It was reported that robotic surgery was associated with less trauma stress and faster recovery in elderly patients(>=75 years old) when compared with open surgery. Elderly people have a higher incidence of carcinogenesis and also have more comorbidities and reduced functional reserve. Clinical data of patients over 75 years old treated by robotic surgery in Zhongshan Hospital affiliated to Fudan University from March 2011 to October 2014 were analyzed retrospectively. A total of 24 consecutive patients were included with a median age of 77.8 years old. There were 18 male and 6 female patients. Among them, 14 patients were diagnosed with descending and sigmoid colon cancers while 10 with rectal cancers; 19 had tumor size larger than 5 cm; 16 were diagnosed with ulcerative adenocarcinoma. Fourteen patients were complicated with hypertension, 6 with cardiopulmonary diseases, 4 with diabetes mellitus and 3 with cerebrovascular diseases. Twenty two patients underwent low anterior resection and 2 abdominoperineal resection. The estimated blood loss was 85 ml; the median operation time was (123.1+/-45.2) min; the median number of retrieved lymph node was 12.4. Postoperative pathologic results showed that 3 patients were stage I, 10 stage II, and 11 stage III. Postoperative complication was observed in 3 patients: urinary infection in 1 case, intraperitoneal infection in 1 case and atria fibrillation in 1 case, respectively. Median time to first postoperative flatus was 2.8 days. Our results indicated that robotic surgery is safe and feasible in the elderly patients. The next generation of robotic system may make up for these deficiencies through new technologies. With the advantage of more advanced surgical simulator, robotic surgery will play a more important role in the treatment of colorectal cancer patients. PMID- 27215514 TI - [Therapy of both surgical and non-surgical related complication of gastric cancer for the elderly]. AB - Gastric cancer is one of the most common digestive malignant tumors. More and more elderly gastric cancer patients are diagnosed and need to undergo surgical treatment as the population ages. Since the elderly patients decrease in organ function and increase in internal diseases, the tolerance to anesthesia and surgery is poor. As a result, the incidence of surgical and postoperative complications is obviously higher. Complications can be divided into surgical complications and non-surgical related complications. Surgical complications consist mainly of hemorrhage, anastomotic leakage, anastomotic dehiscence and intestinal obstruction, while non-surgical related complications include deep venous thrombosis, pulmonary infection, anesthesia-related complication, abdominal infection, urinary infection, incision infection, poor wound healing, gastroparesis, gastroesophageal reflux disease, dumping syndrome and so on. Hence, we should consider more about the elderly patients' physical condition instead of the extent of radical operation. To reduce complications, we should evaluate the organ function and take an active role in underlying diseases before operation. Meanwhile, high quality nursing, powerful analgesia, anti inflammation, keeping water electrolyte balance and nutrition support are also required postoperatively. Moreover, laparoscopic surgery and enhanced recovery after surgery (ERAS) can reduce the postoperative complications in elderly patients with gastric cancer as well. Further prospective randomized controlled trials about elderly gastric cancer should be carried out in the future, which can provide advanced evidences for treatment. PMID- 27215515 TI - [Integrative management of operation, perioperative rehabilitation and postoperative adjuvant chemotherapy in elderly patients with colorectal carcinoma]. AB - With the aging of the Chinese population, it seems obvious that the number of elderly patients with the disease of colorectal carcinoma grows significantly. Meanwhile, no evidence-based practical guideline for the treatment of colorectal carcinoma are available in this particular age group. Therefore, the concept of integrative management has been brought up by the Colorectal Cancer Center of the Second Affiliated Hospital of Zhejiang University, which combines the processes of surgery, perioperative rehabilitation and adjuvant chemotherapy together. In this way, the cooperation and complementarity between different clinical departments could cooperate and complete tasks together to integrate the treatment processes into a cohesive one. To achieve the goal of integrative management, the project is divided into horizontal and vertical aspects. The horizontal integration means the cooperation between different clinical departments, which is also known as multi-discipline treatment (MDT). The vertical integration reflects the completeness of the entire treatment under the goal of consistency, strictness and job separation, which could also be explained as the clinical pathway. Furthermore, this review stresses on the integrative strategy of both clinical and biochemical indexes rehabilitation, as well as the operation and postoperative adjuvant chemotherapy which has been put in execution several years by the Colorectal Cancer Center of the Second Affiliated Hospital of Zhejiang University. PMID- 27215516 TI - [Application of radiotherapy in perioperative comprehensive treatment for the elderly with rectal cancer]. AB - Considered that most of the phase II or III clinical trials contain less elderly patients or only contain those who had good health status, these results might not be applied in those elderly patients with some complex status. The patients of 70 years old or more usually have complications or worse organ function, thus the standard treatment for them becomes a gray zone. In rectal cancer patients, the rate of elderly patients receiving standard chemoradiotherapy (CRT) is obviously lower than that of the younger ones. More and more retrospective studies found that the prognosis of the elderly (>=70) who received neo-adjuvant or adjuvant CRT was better than that of those who received surgery or radiotherapy only, and the outcome of the above-mentioned elderly was similar to those of other phase III trial or younger patients with good tolerance. In addition, some studies revealed patients with good status, less or slight complications had a better prognosis. The advance of radiation therapy, such as Image-guided Radiation Therapy (IGRT), Intensity-modulated Radiation Therapy (IMRT), Stereotactic Body Radiation Therapy (SBRT), brachytherapy and particle therapy, will benefit the elderly cancer patients. We think that treatments recommended to the elderly will become more personalized. PMID- 27215518 TI - [Clinicopathologic characteristics and prognostic factors of gastric cancer in the elderly patients over 75 years]. AB - OBJECTIVE: To investigate the features of clinicopathology and prognosis of gastric cancer in elderly patients over 75 years old. METHODS: A total of 193 elderly gastric cancer patients(>=75 years old) were treated in the Tumour Hospital of Harbin Medical University from January 2007 to December 2010, accounting for 5.6%, 6.5%, 6.9%, 7.9% of gastric cancer patients in each year from 2007 to 2010, respectively. Among them, 99(51.3%) patients received radical operations (radical group), 35(18.1%) patients received palliative operations (palliative group), 11(5.7%) patients received simple gastrojejunal anastomosis or gastrostomosis (anastomosis and stomy group), and 48(24.9%) patients received non-operation treatments such as chemotherapy, biology or immunology and so on (non-operation group). Clinicopathological and follow-up data of these 193 elderly patients were retrospectively analyzed. Survival time was compared among different treatment groups by Log-rank test and risk factors affecting the survival time of patients undergoing radical operation were analyzed by multivariate regression analysis. RESULTS: The median age of these 193 elderly gastric cancer patients was 79 (75-98) years old. There were 140(72.5%) males and 53(27.5%) females. Among them, 79(40.9%) patients were complicated with anemia, 71(36.8%) with hypoproteinemia, 19(9.8%) had comorbid diabetes mellitus, 21(10.9%) had comorbid pneumonia, 54(28.0%) had history of smoking and alcohol, 14(7.3%) had genetic family history of cancer. The median overall survival time was 27.9 months. The median survival time was 38.2 months in the radical group, 17.4 months in the palliative group, 7.7 months in the anastomosis and stomy group, and 10.1 months in the non-operation group respectively, and the difference was statistically significant(P=0.000). The univariate analysis of survival time in radical group revealed that depth of invation(T stage, P=0.046), lymph node metastasis (N stage, P=0.000), tumor diameter (P=0.049), TNM staging (P=0.004), and CEA level (P=0.029) were associated with survival time. Gender, age, Borrmann type, tumor differentiation, surgical procedures, CA199 level anemia and hypoalbuminemia were not associated with the survival time(all P>0.05). Multivariate analysis revealed that lymph node metastasis was the independent prognostic factor associated with shorter survival time in the elderly patients who underwent radical resection[N1 stage: P=0.005, OR=3.481, 95% CI:1.468-8.254; N2 stage: P=0.006, OR=2.848, 95% CI:1.341-6.050; N3 stage: P=0.000, OR=4.798, 95% CI:2.207-10.432]. CONCLUSIONS: In gastric cancer patients, more and more elderly patients are being diagnosed. Radical resection can prolong their postoperative survival time, but if lymph node metastasis is present, the risk of shorter postoperative survival time elevates. PMID- 27215517 TI - [Analysis of clinicopathological features and risk factors for postoperative complications in the elderly gastric cancer patients]. AB - OBJECTIVE: To investigate the clinicopathological features and postoperative short-term complications in the elderly gastric cancer patients. METHODS: Clinical data of 270 elderly patients with gastric cancer who underwent gastrectomy in Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine between July 2012 and June 2014 were analyzed retrospectively. Among 270 patients, 220 were 70 to 79 years old( old group) and 50 were >=80 years old(oldest group). The clinicopathological features were compared between the two groups. Perioperative factors were analyzed to determine if they are associated with postoperative complications. Multivariate logistic regression model was performed. RESULTS: Before operation, most elderly patients (n=161, 59.6%) had 2 or more than 2 comorbidities, including hypertension (n=154, 57.0%), anaemia (n=126, 46.7%), diabetes (n=53, 19.6%), arhythmia (n=52, 19.3%), cardiovascular disease(n=33, 12.2%), and chronic pulmonary disease(n=28, 10.4%). Elderly gastric cancers were more likely to locate at the lower third of the stomach (n=116, 43.0%). The pathological type was mainly the poorly differentiated carcinoma (n=152, 56.3%), and stage III was more common in TNM staging(n=138, 51.1%). As compared to the old group, the oldest group had more preoperative comorbid diseases(P=0.048), more previous surgery(P=0.029), more preoperative transfusion (P=0.019), more combined cholecystectomy (P=0.007) and feeding jejunostomy (P=0.037), but less tumor invasion of nerves(P=0.045). No significant differences in other clinicopathological parameters were found between the two groups (all P>0.05). A total of 121 (44.8%) patients presented postoperative complications, including severe complication in 30 cases(11.1%) and death in 4 cases(1.5%). Forty-seven patients(17.4%) presented operation associated complications, including infection in 28 cases(10.4%) and leakage in 21 cases(7.8%). One hundred and seven(39.6%) patients presented non-operation associated complications, including pneumonia in 48 cases(17.8%), hypertension in 23 cases(8.5%), and arhythmia in 17 cases(6.3%). Postoperative morbidities of Clavien-Dindo class II complication and non-operation-associated complication were higher in the oldest group compared with old group(P<0.05), while other postoperative complications were compared between the two groups, only urinary tract infection was significantly different(P<0.05). Univariate analysis showed that postoperative complications were significantly associated with age(chi(2)=7.308, P=0.007), number of comorbid diseases (chi(2)=10.872, P=0.001), cardiovascular disease (chi(2)=9.412, P=0.002), hypertension (chi(2)=4.934, P=0.026) and preoperative transfusion (chi(2)=3.911, P=0.048). Multivariate analysis showed that only the number of comorbid diseases was an independent risk factor for postoperative complications(OR=2.810, 95% CI: 1.710 to 4.616, P=0.000). CONCLUSION: Non-operation-associated postoperative complications are more likely to occur in the elderly patients due to more comorbid diseases. Perioperative intensive care should be carried out for the elderly gastric cancer patients with comorbid diseases in order to improve surgical safety and efficacy. PMID- 27215519 TI - [Prognostic value of preoperative neutrophil-to-lymphocyte ratio in the elderly patients over 75 years old with gastric cancer]. AB - OBJECTIVE: To investigate the clinical implication of preoperative neutrophil-to lymphocyte ratio (NLR), and association of NLR with the prognosis of the elderly patients over 75 years old with primary gastric cancer. METHODS: Clinical data of 160 patients (>=75 years) with gastric cancer undergoing gastrectomy in Department of Gastrointestinal Surgery, the Tumour Hsopital of Harbin Medical University form January 2007 to December 2010 were retrospectively analyzed. Preoperative neutrophil and lymphocyte count was measured and NLR was calculated. The cut-off value of NLR to predict the survival was obtained from the receiver operating characteristic(ROC) curve. Patients were divided into two groups based on cut-off value. Clinicopathological features were compared between two groups using Chi-square test or Fisher exact test. Cox proportional hazard model was used to analyze risk factors associated with survival. RESULTS: The cut-off value of NLR was 1.83 with 0.709 of sensitivity and 0.562 of specificity. A total of 54 patients with NLR<1.83 belonged to NLR-0 group, and 106 patients with NLR>=1.83 belonged to NLR-1 group. As compared to NLR-0 group, patients in NLR-1 group had significantly higher proportion in maximum tumor size >= 50 mm [66.0%(70/106) vs. 42.6%(23/54), P=0.004], serosal invasion [75.5%(80/106) vs. 57.4%(31/54), P=0.029], positive lymph node metastasis [83.0% (88/106) vs. 55.6%(30/54), P=0.001] and TNM stage III( [79.2%(84/106) vs. 61.1%(33/54), P=0.013]. The median survival of NLR-0 and NLR-1 group was 1 209 days and 587 days respectively, with significant difference(P=0.001). Multivariate analysis showed that NLR>=1.83(HR=0.530, 95% CI: 0.332 to 0.846, P=0.008), serosal invasion (HR=0.570, 95% CI: 0.332 to 0.979, P=0.042), and lymph node metastasis(HR=0.475, 95% CI: 0.462 to 1.685, P=0.033) were independent risk factors of poor prognosis(all P<0.05). CONCLUSION: Preoperative higher NLR value in the elderly patients over 75 years old with primary gastric cancer indicates larger tumor size, severe serous invasion, more lymph node metastasis, later TNM staging, and poorer prognosis. PMID- 27215520 TI - [Efficacy comparison of laparoscopic versus open distal gastrectomy with D2 lymph dissection for advanced gastric cancer]. AB - OBJECTIVE: To evaluate the long-term clinical outcomes between laparoscopic and open distal gastrectomy with D2 lymph dissection for advanced gastric cancer. METHODS: Clinical data of 377 cases of laparoscopic distal gastrectomy and 301 cases of open distal gastrectomy with D2 lymph dissection at the Southwest Hospital, the Third Military Medical University from January 2004 to June 2010 were retrospectively analyzed. Patients were followed up until September 2015. Surgical outcomes, postoperative complications and long-term survival were compared between the two groups. RESULTS: Compared with conventional open group, laparoscopic group was associated with lower intraoperative blood loss [(125+/ 89) ml vs. (290+/-161) ml, t=-15.942, P=0.000], shorter time to oral intake [(2.9+/-0.7) days vs. (4.1+/-1.6) days, t=-12.120, P=0.000], quicker bowel function retum[(2.7+/-1.4) days vs. (3.6+/-1.6) days, t=-7.804, P=0.000], shorter postoperative hospital stay [(7.7+/-3.6) days vs. (10.1+/-4.1) days, t=-8.107, P=0.000]. In addition, there were no significant differences in the operative time[(207+/-57) minutes vs. (202+/-43) minutes, P>0.05], number of retrieved lymph nodes(33+/-13 vs. 31+/-15, P>0.05), resection margin length(P>0.05) between two groups. The postoperative complication morbidity in laparoscopic group was significantly lower than that in open group[7.2%(22/377) vs. 12.6%(38/301), chi(2)=5.762, P=0.016]. Within perioperative period, 7 patients underwent operation again due to complication and 1 case died of peritoneal bleeding in laparoscopic group; 6 patients underwent re-operation and 2 cases died of peritoneal infection with hepatic failure and lung infection with respiratory failure. During the median follow-up of 86 months (range from 3-140 months), relapse occurred in 171(45.4%) patients and 183(48.5%, among them, 156 cases died of primary disease) patients died in laparoscopic group; relapse occurred in 140(46.5%) patients and 151(50.2%, among them, 127 cases died of primary disease) patients died in open group. The difference in overall 5-year survival rate between two groups was not statistically significant (51.5% vs. 49.8%, chi(2)=0.142, P=0.706). No significant difference was seen in 5-year disease-free survival rate (49.1% vs. 47.8%, chi(2)=0.062, P=0.803). Stratified analysis based on TNM stage also showed no significant difference in 5-year overall or disease free survival rate(both P>0.05). CONCLUSION: Laparoscopic distal gastrectomy with D2 lymph dissection for advanced gastric cancer has better short-term efficacy and similar long-tern efficacy as compared to open surgery. PMID- 27215521 TI - [Predictive value of log odds of positive lymph nodes for the prognosis of patients with node-negative squamous cell carcinoma of the thoracic esophagus after radical esophagectomy]. AB - OBJECTIVE: To investigate the log odds of positive lymph nodes(LODDS) on the prognosis of patients with node-negative squamous cell carcinoma of the thoracic esophagus after radical esophagectomy. METHODS: Clinical data of 136 patients with node-negative squamous cell carcinoma of the thoracic esophagus after radical esophagectomy from January 2005 to January 2009 were retrospectively analyzed. LODDS was estimated using the calculation: log(pnod+0.5)/(tnod pnod+0.5), in which pnod indicates the number of positive lymph nodes and tnod indicates the total number of lymph nodes retrieved. The best cut-off value for LODDS was identified by using the receiver operating characteristic (ROC) curve. Drawing of survival curves was employed with the Kaplan-Meier estimator, and survival rate was analyzed using Log-rank test. The Cox proportional hazard model was used to identify independent factors associated with prognosis. RESULTS: A total of 136 patients, including 112 males and 24 females, seventy-nine patients were 65 years or older(range 27-92 years), and were included in the present study. Among them, the most cancer site was the middle third of the thoracic esophagus(115 cases), followed by the lower third(13 cases), and the upper third(8 cases). There were 70 patients with tumor diameter <=3.5 cm and 66 patients with tumor diameter >3.5 cm. There were 32 patients with stage pT1-2, and 104 with stage pT3-4. The number of patients in TNM classification I, II and III was 14, 85 and 37, respectively. All the patients received radical esophagectomy with primary tumor resection and lymph node dissection. The median follow-up time was 44.2 months(range, 4.4-98.4 months). Five-year overall survival rate was 43.2%, and the median total survival time was 48 months. ROC analysis showed that the appropriate cut-off value of LODDS was -1.2. There were 99 patients with LODDS<=-1.2(LODDS1 stage), 37 patients with LODDS >-1.2(LODDS2 stage), the median survival time and 5-year survival rate were 56.5 months and 48.3% in patients with LODDS1 stage and 30.0 months and 29.7% in patients with LODDS 2 stage, respectively, with significant difference(chi(2)=4.980, P=0.026). Multivariate analyses showed that recurrence(HR=0.627, 95% CI:0.395 to 0.996; P=0.048) and LODDS >-1.2(HR=1.853; 95% CI:1.155 to 2.974; P=0.011) were the independent factors affecting the prognosis of patients. CONCLUSIONS: For patients with node-negative squamous cell carcinoma of the thoracic esophagus after radical esophagectomy, LODDS stage has a unique prediction for prognosis, and patients with LODDS less than -1.2 (cut-off value) have a better prognosis. PMID- 27215522 TI - [Study of introperitoneal hyperthermic perfusion chemotherapy combined with systemic neoadjuvent chemotherapy in treatment of gastric cancer patients with peritoneal carcinomatosis]. AB - OBJECTIVE: The aim of this study is to discuss the curative effect of introperitoneal hyperthermic perfusion chemotherapy(IHPC) combined with systemic neoadjuvant chemotherapy on the gastric cancer patients with peritoneal carcinomatosis. METHODS: Sixty-four patients with gastric cancer and peritoneal carcinomatosis who were hospitalized in the Department of Gastrointestinal Surgery of First Hospital of Jilin University from December 2006 to December 2013. After peritoneal carcinomatosis was confirmed during laparoscopic exploration, FOLFOX6 (oxaliplatin and calcium folinate and 5-Fu) was performed for systemic chemotherapy. One course was 14 days and a complete treatment includes four courses. At the same time, patients underwent peritoneal catheter insertion and received IHPC(5-Fu 1 500 mg/m(2) and Cisplatin 35 mg/m(2) were added into 0.9% NaCl solution 2 000 ml, the infusion velocity was 35-45 ml/min, infusion time was 45-60 minutes, the temperature was controlled to 41 degrees C). A comprehensive evaluation was taken after the fourth course of treatment before operation. Further surgical therapy was performed according to the assessment result. RESULTS: Sixty-four patients received IHPC combined with systemic chemotherapy. Thirty-two patients(50.0%) had partial response, 18(28.1%) stable disease, and 14(21.9%) progressive disease after chemotherapy. No severe complications or death occurred during the neoadjuvant chemotherapy. Thirty-two patients(50.0%) received radical resection, 10(15.6%) palliative operation, and another 22 patients(37.4%) didn't comply with inclusion criteria of operation. Patients receiving operation had a median survival time of 678 days, which was significantly longer than patients without operation, with a median survival time of 251(chi(2)=23.34, P=0.02). CONCLUSIONS: IHPC combined with systemic chemotherapy is an effective therapeutic method for gastric cancer patients with peritoneal carcinomatosis in terms of reducing preoperative tumor load and achieving radical resection. PMID- 27215523 TI - [Comparative study of three-dimensional and two-dimensional laparoscopic-assisted D2 radical gastrectomy in short-term efficacy]. AB - OBJECTIVE: To evaluate the advantage and short-term efficacy of three-dimensional (3D) laparoscopic-assisted D2 radical gastrectomy for gastric cancer. METHODS: Clinical data of 116 gastric cancer patients who underwent laparoscopic-assisted D2 radical gastrectomy in our department from January 2014 to August 2015 were analyzed retrospectively. Among 116 patients, 56 received 3D and 60 received two dimensional(2D) technique respectively. All the surgeries were performed by the same team. The operative parameters, short-term efficacy and hospital expense were compared between the two groups. RESULTS: There were no significant differences between the two groups in baseline data(all P>0.05). All the operations were performed successfully without conversion. Compared with 2D group, 3D group had shorter operative time [(186.2+/-22.8) minutes vs. (198.1+/ 26.4) minutes, t=2.589, P=0.011], less intraoperative blood loss [(73.6+/-28.5) ml vs. (88.1+/-32.3)ml, t=2.555, P=0.012]. Whereas no significant differences in dissected lymph nodes(36.5+/-6.6 vs. 34.5+/-5.4, P=0.073), time to first flatus[(3.1+/-1.5) days vs. (3.3+/-1.8) days, P=0.729], length of hospital stay[(11.7+/-2.9) days vs. (12.6+/-3.1) days, P=0.088], incidence of postoperative complications [8.9%(5/56) vs. 11.7%(7/60), P=0.628] and hospitalization cost [(8.6+/-1.4)*10(4) yuan vs. (8.1+/-1.2)*10(4) yuan, P=0.055] were found between two groups. CONCLUSION: Three-dimensional laparoscopic assisted D2 radical gastrectomy may be advantageous over two-dimensional laparoscopic-assisted D2 radical gastrectomy. PMID- 27215524 TI - [Long-term survival of total laparoscopic radical distal gastrectomy with delta shaped anastomosis]. AB - OBJECTIVE: To compare the long-term survival of total laparoscopic radical distal gastrectomy (TLDG) with delta-shaped anastomosis and laparoscopic assisted radical distal gastrectomy (LADG) with tubular anastomosis. METHODS: The study retrospectively analyzed the clinical and pathologic data of 160 distal gastric cancer patients who underwent laparoscopic radical distal gastrectomy with Billroth I anastomosis at the First Affiliated Hospital of Chongqing Medical University from December 2012 to March 2015. All the patients were definitively diagnosed as primary gastric carcinoma before operation, and no evidences of invasion to adjacent organs, distant metastasis or enlarged fused lymph nodes around important vessels were discovered by image tests. Eighty-six patients underwent TLDG with delta-shaped anastomosis (delta-shaped anastomosis group, DSG) and 74 patients underwent LADG with tubular anastomosis (tubular anastomosis group, TAG) in two surgery teams who had different experience of gastroduodenostomy. All the patients agreed the operation and signed informed consent. All patients followed until October 2015 when the final cumulative survival rate was counted. Survival was analyzed by Kaplan-Meier method. RESULTS: The baseline data were comparable and operations were successfully completed. Postoperative follow-up time of DSG was 7-32 months, follow-up rate was 91%(78/86), and 11 of whom died of the gastric cancer. The cumulative survival rate by the end of the follow-up was 82.8%. Postoperative follow-up time of TAG was 7-33 months, follow-up rate was 95%(70/74), 7 of whom died of the gastric cancer. The cumulative survival rate by the end of the follow-up was 81.7%. The intergroup difference of cumulative survival rate was not significant(chi(2)=1.210, P=0.271). No stage I patient died of gastric cancer in both groups. The cumulative survival rate by the end of the follow-up of stage II was 87.2% vs. 93.3%(DAG vs. TAG, chi(2)=0.426, P=0.514) ,and in stage III was 65.3% vs. 37.6%(DAG vs. TAG, chi(2)=0.718, P=0.397), and the differences were not significant. CONCLUSION: The TLDG with delta-shaped anastomosis and LADG with tubular anastomosis have similar long-term survival for distal gastric cancer treatment. PMID- 27215525 TI - [Laparoscopic gastrectomy for gastric stump cancer: analysis of 7 cases]. AB - OBJECTIVE: To evaluate the safety and feasibility of laparoscopic gastrectomy for gastric stump cancer. METHODS: Clinical and follow-up data of 7 patients who underwent laparoscopic gastrectomy for gastric stump cancer in our department from January 2008 to July 2015 were analyzed retrospectively. RESULTS: There were 5 male and 2 female patients, with a mean age of (62.1+/-10.7) years. Initial gastrectomy was performed for gastric cancer in 3 patients and peptic ulceration in 4. The initial surgery was B-II( gastrojejunostomy in 6 patients and Roux-en-Y gastrojejunostomy in 1. Duration between primary gastrectomy and occurrence of gastric stump cancer was ranged from 6-30 years for peptic ulceration, and from 11-15 years for gastric cancer. During the operation, adhesiolysis and exploration to locate the tumor were performed. Following total remnant gastrectomy and lymphadenectomy, intracorporeal anastomosis was accomplished by Roux-en-Y reconstruction. The methods of intracorporeal esophagojejunostomy were end-to-side approach using a circular stapler in 1 patient, side-to-side approach using an endoscopic linear staple in 2 patients, and hand-sewn technique in 4 patients. The operation time was (247.1+/-17.5) minutes and the intraoperative blood loss was (100.0+/-30.8) ml without transfusion. The number of retrieved lymph node was 19.1+/-4.8. The first flatus time, diet resumption time, postoperative hospital stay were (3.3+/-1.5) days, (3.7+/-0.8) days, (9.4+/-2.6) days, respectively. One patient experienced gastrointestinal bleeding that was managed conservatively and ultimately cured. Seven patients were followed up till January 2016. After follow-up from 6 to 38 months, 1 patient died of peritoneal metastasis 17 months after surgery, and 1 patient died of Alzheimer's disease 19 months after surgery. The other 5 patients were still alive without metastasis or recurrence. CONCLUSION: Laparoscopic gastrectomy for gastric stump cancer is feasible and safe. PMID- 27215526 TI - [Clinical value of the narrow-band imaging combined with endoscopic submucosal dissection for gastric high grade intraepithelial neoplasia]. AB - OBJECTIVE: To determine the feasibility, safety and short-time efficacy of narrow band imaging (NBI) combined with endoscopic submucosal dissection (ESD) for treating gastric high grade intraepithelial neoplasia (HGIN). METHODS: Clinical data of 78 patients with gastric HGIN diagnosed by gastroscope and pathology undergoing NBI combined with ESD at Wuxi No.2 People's Hospital and Zhongshan Hospital of Fudan University from January 2014 to December 2015 were retrospectively analyzed. Their clinicopathological and follow-up data were analyzed. RESULTS: There were 47 males and 31 females aged from 38 to 85 years old. Preoperative NBI showed that lesions of all the 78(100%) patients had clear resection margin, and 91%(71/78) lesions had abundant vessels in the central depression area. One case was converted to open abdominal operation due to intra operational perforation, 77(98.7%) gastric HGIN lesions were successfully dissected under ESD, including 74 cases(94.9%) of en bloc dissection, and other 3 cases with severe adhesion of submucosa whose lesion wound after ESD was treated with argon plasma coagulation(APC). The mean maximum diameter of the lesion size was (1.2+/-0.8) cm. The average operation time was(48+/-21) minutes. Delayed hemorrhage occurred in 5 cases(6.4%) who were also treated successfully by endoscopic hemostasis. Postoperational pathology revealed en bloc dissection rate was 91.0%(71/78), positive rate of resection margin was 3.8%(3/78), and healing dissection rate was 89.7%(70/78). Thirty-two lesions (41.0%) remained the diagnosis as HGIN, 6 lesions(7.7%) were diagnosed as low grade intraepithelial neoplasia, and 40 lesions (51.3%) were diagnosed as adenocarcinoma. Fifty-seven cases were followed up for 12 months, 21 cases were followed up for 6 months, and there was no recurrence in those 3 patients with positive margin. Two cases (2.6%) relapsed and were diagnosed as adenocarcinoma by repeat pathology examination. CONCLUSION: NBI combined with ESD for diagnosis and treatment of gastric HGIN is safe and effective, and can achieve en bloc complete resection of the lesions with a low complication rate. PMID- 27215527 TI - [Analysis of the factors in the disease-free interval of metachronous pulmonary metastasis from rectal cancer]. AB - OBJECTIVE: To investigate the factors in the disease-free interval (DFI) of metachronous pulmonary metastasis from rectal cancer. METHODS: Clinical data of 92 patients with metachronous pulmonary metastasis from rectal cancer in the Department of Colorectal Surgery at the Changhai Hospital of the Second Military Medical University from January 2001 to December 2013 were analyzed retrospectively. Univariate and multivariate analysis were performed to find the factors affecting disease-free interval of metachronous pulmonary metastasis from rectal cancer using Log-rank test and Cox proportional hazards model, respectively. RESULTS: The median age of all the cases was 61 (range, 26-81) years. Of the 92 cases, 59 were males and 33 were females. Thirty-six cases were confirmed to have <5 cm distance from lower margin to dentate line. Forty-four cases were examined to have 5 MUg/L carcinoembryonic antigen(CEA) level. Of these cases reviewed pathologically, 69 cases were adenocarcinoma, 23 were mucinous adenocarcinoma; 19 cases had stage T1-2 lesions, 73 had stage T3-4 lesions; 43 cases had stage N0 metastasis, 49 had stage N1-2 metastasis. Thirty cases received preoperative radiotherapy, 63 cases received postoperative chemotherapy. The median follow up time of all the cases was 62(range, 3-140) months. The DFI of all the cases was (25.9+/-21.0) months. Univariate Log-rank test indicated that the factors associated with the disease-free interval of metachronous pulmonary metastasis of rectal cancer were location of the tumor(chi(2)=4.496, P=0.034), preoperative CEA level (chi(2)=5.553, P=0.018), T stage (chi(2)=5.796, P=0.016), N stage (chi(2)=6.780, P=0.009), preoperative neoadjuvant radiotherapy (chi(2)=11.718, P=0.001) and postoperative adjuvant chemotherapy (chi(2)=9.214, P=0.002). A shorter distance from lower margin to dentate line(<5 cm), a lower preoperative CEA level(<5 MUg/L), advanced T stage lesions(T3-4), advanced N stage metastasis(N1-2), no use of preoperative radiotherapy and use of postoperative chemotherapy were associated with shorter DFI of patients with metachronous pulmonary metastasis from rectal cancer. Multivariate analysis showed that N stage(OR=0.525, 95% CI: 0.309-0.891, P=0.017), location of the tumor (OR=1.770, 95% CI:1.115-2.812, P=0.016) and preoperative neoadjuvant radiotherapy (OR=1.976, 95% CI:1.228-3.401, P=0.006) were the independent risk factors associated with the disease-free interval of metachronous pulmonary metastasis from rectal cancer. CONCLUSIONS: Advanced N stage, low location of the tumor and no use of preoperative neoadjuvant radiotherapy are risk factors of shorter disease-free interval of metachronous pulmonary metastasis from rectal cancer. PMID- 27215528 TI - [Efficacy observation of partial stapled transanal rectal resection combined with Bresler procedure in the treatment of rectocele and internal rectal intussusception]. AB - OBJECTIVE: To evaluate the efficacy of partial stapled transanal rectal resection (part-STARR) combined with Bresler procedure in the treatment of obstructed defecation syndrome (ODS) associated with rectocele and internal rectal intussusception(IRI), and compare with STARR. METHODS: A randomized controlled study from January 2013 to December 2014 was undertaken. Sixty female patients with ODS caused by rectocele and IRI were prospectively enrolled and randomly divided into trial group (29 cases) receiving part-STARR combined with Bresler procedure, and control group (31 cases) undergoing STARR only. For patients in trial group, two thirds of posterior rectal wall were stapled with STARR methods and one third of anterior with Bresler procedure, while for those in control group, only STARR was performed. Intra-operational status, postoperative complications, Wexner constipation score and patient satisfaction 3 months and 6 months after operation, and rectocele defecography 6 months after operation were compared between the two groups. RESULTS: The average operation time of trial group was longer than that of control group [(31.2+/-5.4) minutes vs. (28.7+/ 4.0) minutes, t=2.127, P=0.038]. There were no significant differences in intra operative blood loss, postoperative hospital stay and complications(pain, postoperative bleeding, rectovaginal fistula, feeling of tenesmus and swelling) between the two methods(all P>0.05). There were no significant differences in the Wexner score of constipation between the two groups before operation and 3 months after operation (6.72+/-1.19 vs. 7.32+/-1.25, t=-1.896, P=0.063), while the Wexner score of trial group was significantly lower 6 months after operation (6.90+/-1.42 vs. 7.74+/-1.26, t=-2.463, P=0.018). Patient satisfaction between two groups was not significantly different 3 months after operation(chi(2)=5.743, P=0.125), while trial group had better satisfaction 6 months after operation[93.1%(27/29) vs. 67.7%(21/31), chi(2)=8.247, P=0.041]. There was no difference in depth of rectocele on defecography between the two groups before operation, while rectocele was significantly improved 6 months after operation [(0.7+/-0.2) cm vs. (0.9+/-0.2) cm, t=2.527, P=0.014]. CONCLUSION: Partial STARR combined with Bresler procedure in the treatment of ODS associated with rectocele and IRI has better efficacy than STARR only. PMID- 27215529 TI - [Impact of depression and anxiety assessment performed in gastrointestinal cancer patients on postoperative depression and anxiety symptom and mental health service visit]. AB - OBJECTIVE: To investigate the impact of depression and anxiety assessment performed in gastrointestinal cancer patients on postoperative depression and anxiety symptom and mental health service visit. METHODS: A total of 254 gastrointestinal cancer patients who underwent surgical procedure were assigned into assessment group (n=121) and control group (n=133). Depression and anxiety assessment were performed with PHQ-9 and GAD-7 in assessment group on admission, discharge and at 3-month follow-up while in control group only at 3-month follow up. The point prevalence of depression and anxiety were evaluated in assessment group with established cut-off reported by ASCO defining depression as a PHQ-9 score no less than 8 and anxiety as a GAD-7 score no less than 5. PHQ-9 and GAD-7 scores at 3-month follow-up were compared using Mann-Whitney U test. RESULTS: According to the PHQ-9 and GAD-7 score, the prevalence of depression was 28.9%(35/121) and anxiety was 37.2%(45/121) in assessment group, and depression was found in 9.9%(12/121) with comorbid anxiety. During the 3-month follow-up, the PHQ-9 and GAD-7 score in assessment group (6.02+/-4.67 and 4.19+/-3.95) were both lower than those in control group (8.83+/-6.63 and 6.41+/-5.80) with statistically significant differences (all P<0.05). Patients in assessment group were more likely to seek for help in mental health service than those in control group [10.7%(13/121) vs. 3.0%(4/133), chi(2)=9.726, P=0.014] in 3-month follow-up after surgery. CONCLUSIONS: The prevalence of depression and anxiety is high in gastrointestinal cancer patients. Depression and anxiety assessment routinely performed for gastrointestinal cancer patients can enhance utilization of mental health service and reduce postoperative depression and anxiety symptom thus potentially improve quality of life. PMID- 27215530 TI - [Onodera prognostic nutrition index predicts nutrition risk in gastrointestinal elective operation patients]. AB - OBJECTIVE: To evaluate the clinical effectiveness of Onodera prognostic nutrition index (OPNI) in the predictive value of nutrition risk. METHODS: In a prospective cohort study from July 2014 to June 2015 in the Department of General Surgery of the Ninth People's Hospital of Chongqing, NRS2002 and OPNI were conducted in 200 patients undergoing gastrointestinal elective operation. OPNI was calculated with serum albumin (Alb) and peripheral lymphocyte (TLC) [OPNI=Alb(10(9)/L)+5*TLC(10(9)/L)]. By using the results of NRS2002 as the golden standard for diagnosis of nutrition risk (A NRS2002 score>=3 was deemed as nutritional risk and a nutritional care plan should be initiated. A NRS2002 score <3 was deemed as no nutritional risk), the effectiveness of OPNI was evaluated by the receiver operator characteristic(ROC) curve. The sensitivity, specificity, positive and negative predictive values, Youden indexes and area under ROC curve(AUC) of different diagnostic cut-off points of OPNI were analyzed to determine the optimal operating point (OOP). Kappa test was used to estimate the consistency of different cut-off points for OPNI with NRS2002 in defining nutrition risk. RESULTS: A total of 103 patients were of NRS2002 >=3 group, and 97 of NRS2002 <3 group. The overall OPNI was 45.4+/-7.4. When OOP was 45.8, the AUC of OPNI was 0.914 (95% CI: 0.873 to 0.954); the sensitivity, specificity, Youden indexes were 85.4%, 85.6%, 0.711; the positive predictive value and negative predictive value were 85.3% and 83.7%, respectively. According to this OOP, the subjects were divided into the OPNI >=45.8 group(n=102) and OPNI <45.8 group (n=98). Compared with OPNI >=45.8 group, OPNI <45.8 group were older [(66.5+/-12.1)years vs. (57.0+/-15.3) years, t=-4.905, P=0.000], and had lower BMI[(20.4+/-3.0) kg/m(2) vs. (21.7+/-3.0) kg/m(2), t=3.069, P=0.002], lower albumin[(34.7+/-4.7)10(9)/L vs.(43.6+/-3.4)10(9)/L, t=15.542, P=0.000] and lower TLC[(1.0+/-0.5)10(9)/L vs.(1.6+/-0.7)10(9)/L, t=7.254, P=0.000], respectively. Kappa test indicated that when using OPNI=45.8, the diagnostic value of OPNI on nutrition risk was consistence with NRS2002(Kappa=0.691, P=0.000). CONCLUSIONS: OPNI can be used as a relatively simple and reliable method for clinical screening and assessment of nutrition risk. PMID- 27215531 TI - [Application of spectral CT in the differentiation of stage T3 and T4a gastric carcinoma]. AB - OBJECTIVE: To investigate the application value of spectral CT in the differentiation of stage T3 and T4a gastric carcinoma. METHODS: Data of 62 gastric cancer patients of stage T3 and T4a undergoing abdominal spectral CT examination in the First Affiliated Hospital of Zhengzhou University from December 2013 to December 2014 were collected retrospectively. There were 38 male and 24 female patients, with age of 33 to 77(58.6+/-10.4) years old. Abdominal double-phase enhanced scanning in gemstone spectral imaging mode was used to measure Iodine concentration (IC, 100 MUg/ml) and water concentration(WC, 100 MUg/ml) of perigastric fat tissue adjacent to the lesion during arterial phase(AP) and venous phase(VP), and normalized iodine concentration (nIC) was calculated respectively(nIC=IC/IC of aorta on the same slice). IC, WC, nIC of arterial phase and venous phase between stage T3 and T4a lesions were compared with double independent sample t test and compared with pathology. The diagnostic efficacy was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: During arterial phase in stage T4a cases, IC (100 MUg/ml) was 5.19+/-0.81 and nIC was -0.05+/-0.01, which was significantly higher than -3.44+/ 1.54 (P=0.000) and -0.03+/-0.01 (P=0.000) in stage T3 cases. During venous phase in T4a cases, IC (100 MUg/ml) was -3.78+/-0.94 and nIC was -0.04+/-0.01, which was significantly higher than -1.62+/-1.43 (P=0.000) and -0.02+/-0.02 (P=0.000) in stage T3 cases. As compared to arterial phase, IC and nIC of stage T4a and T3 of venous phase were more significantly different (all P<0.05). WC of stage T4a during arterial and venous phase was 955.72+/-15.68 and 949.86+/-17.36 respectively, while WC of stage T3 during arterial and venous phase was 947.77+/ 18.43 and 942.46+/-18.53 respectively. There were no significant differences in WC between two stage cases during arterial and venous phase (P=0.106, P=0.143). ROC analysis showed that area under the ROC of IC and nIC during arterial phase was 0.829 and 0.867 respectively, and cut-off value of nIC was -0.039 for differentiation of stage T3 and T4a with corresponding 83.3% of sensitivity and 75.0% of specificity; area under the ROC of IC and nIC during venous phase was 0.873 and 0.905 respectively, and cut-off value of nIC was -0.031 for differentiation of stage T3 and T4a with corresponding 81.0% of sensitivity and 85.0% of specificity. CONCLUSIONS: Abdominal spectral CT scan is useful in the differentiation of stage T3 and T4a gastric carcinoma. The IC of perigastric fat tissue is significantly higher in stage T4a gastric carcinoma compared to stage T3 gastric carcinoma. Higher diagnostic efficacy can be obtained when taking 0.031 as the cut-off value of nIC during venous phase. PMID- 27215532 TI - [Expression of KIF18A in gastric cancer and its association with prognosis]. AB - OBJECTIVE: To explore the expression of KIF18A gene protein in gastric cancer tissues and its association with the prognosis of patients. METHODS: Twenty fresh paired gastric cancer specimens and adjacent normal mucosa(at least 5 cm from the edge of tumor) from 20 gastric cancer patients undergoing operation in Department of General Surgery at the First Affiliated Hosptial of Anhui Medical University between March 2015 and July 2015 were collected. Real-time PCR was used to examine KIF18A mRNA expression in above specimens. Meanwhile, paraffin embedded cancer tissue samples from 129 gastric cancer patients undergoing operation and 23 samples of randomly selected normal gastric tissue(adjacent non-cancer tissue) were collected to establish the microarray. Immunohistochemistry method was applied to detect the KIF18A protein expression in the microarray after confirmation by pathologists. Association of KIF18A expression with clinicopathological features in gastric cancer patients was evaluated. Cox proportional hazard model was used to identify prognostic risk factors. RESULTS: Among 20 fresh paired gastric cancer specimens, mRNA expression of KIF18A in 16 specimens was obviously lower than that in adjacent normal tissues. The positive rate of KIF18A protein expression in gastric cancer tissues was significantly lower than that in normal gastric tissues in microarray[45.0%(58/129) vs. 69.6%(16/23), P=0.041]. KIF18A protein expression was significantly associated with invasion depth (P=0.008) and TNM staging (P=0.032). The median overall survival of all the 129 patients was 44.0(95% CI: 39.78-49.24) months. The three year survival rates of patients with high and low KIF18A expression were 67.2% and 36.6% respectively(P=0.020). Cox regression analysis showed that KIF18A expression was an independent protective factor of the prognosis of gastric cancer patients (HR=0.570, 95% CI:0.335 to 0.970). CONCLUSIONS: KIF18A expression is down-regulated in gastric cancer tissue, which may play a critical role in gastric cancer carcinogenesis. Lower expression of KIF18A is associated with poor prognosis of gastric cancer patients. KIF18A may be a potential prognostic marker of gastric cancer. PMID- 27215533 TI - [Clinical and prognostic features of surgical treatment in gastric cancer in aged patients]. AB - The incidence of gastric cancer in the elderly is increasing because of increased life expectancy and improved medical care. Gastric cancer in the elderly is characterized by specific clinicopathological features, including a male predominance gender tendency, more comorbid diseases, more advanced clinical stage, distinct histopathological findings, absence of family history, etc. The incidence of surgery-related post-operative complication shows no significant difference between elderly and non-elderly patients. However, the incidence of non-surgery-related complications is relatively higher in elderly patients. Although the overall survival rate of elderly patients is lower, the disease specific survival rate of elderly patients is comparable with non-elderly patients. Therefore, surgery is still an effective way to improve the prognosis of elderly gastric cancer patients, and care should be taken while dealing with the comorbid diseases in elderly gastric cancer patients to improve the survival. PMID- 27215534 TI - Particulate systems based on pectin/chitosan association for the delivery of manuka honey components and platelet lysate in chronic skin ulcers. AB - The aim of the present work was the development of a powder formulation for the delivery of manuka honey (MH) bioactive components and platelet lysate (PL) in chronic skin ulcers. In particular pectin (PEC)/chitosan (CS) particles were prepared by ionotropic gelation in the presence of calcium chloride and subsequently characterized for particle size, hydration properties and mechanical resistance. Different experimental conditions (calcium chloride and CS concentrations; rest time in the cationic solution) were considered in order to obtain particles characterized by optimal size, hydration properties and mechanical resistance. Two different fractions of MH were examined: one (Fr1), rich in methylglyoxal and the other (Fr2), rich in polyphenols. Particles were loaded with Fr1, fraction able to enhance in vitro proliferation of human fibroblasts, and with PL. The presence of CS in Fr1-loaded particles produced an improvement in cell proliferation. Moreover, PL loading into particles did not affect the biological activity of the hemoderivative. In vivo efficacy of PL- and Fr1-loaded particles was evaluated on a rat wound model. Both treatments markedly increased wound healing to the same extent. PMID- 27215535 TI - Hot-melt extruded filaments based on pharmaceutical grade polymers for 3D printing by fused deposition modeling. AB - Fused deposition modeling (FDM) is a 3D printing technique based on the deposition of successive layers of thermoplastic materials following their softening/melting. Such a technique holds huge potential for the manufacturing of pharmaceutical products and is currently under extensive investigation. Challenges in this field are mainly related to the paucity of adequate filaments composed of pharmaceutical grade materials, which are needed for feeding the FDM equipment. Accordingly, a number of polymers of common use in pharmaceutical formulation were evaluated as starting materials for fabrication via hot melt extrusion of filaments suitable for FDM processes. By using a twin-screw extruder, filaments based on insoluble (ethylcellulose, Eudragit((r)) RL), promptly soluble (polyethylene oxide, Kollicoat((r)) IR), enteric soluble (Eudragit((r)) L, hydroxypropyl methylcellulose acetate succinate) and swellable/erodible (hydrophilic cellulose derivatives, polyvinyl alcohol, Soluplus((r))) polymers were successfully produced, and the possibility of employing them for printing 600MUm thick disks was demonstrated. The behavior of disks as barriers when in contact with aqueous fluids was shown consistent with the functional application of the relevant polymeric components. The produced filaments were thus considered potentially suitable for printing capsules and coating layers for immediate or modified release, and, when loaded with active ingredients, any type of dosage forms. PMID- 27215536 TI - Mechanisms linking electrical alternans and clinical ventricular arrhythmia in human heart failure. AB - BACKGROUND: Mechanisms of ventricular tachycardia (VT) and ventricular fibrillation (VF) in patients with heart failure (HF) are undefined. OBJECTIVE: The purpose of this study was to elucidate VT/VF mechanisms in HF by using a computational-clinical approach. METHODS: In 53 patients with HF and 18 control patients, we established the relationship between low-amplitude action potential voltage alternans (APV-ALT) during ventricular pacing at near-resting heart rates and VT/VF on long-term follow-up. Mechanisms underlying the transition of APV-ALT to VT/VF, which cannot be ascertained in patients, were dissected with multiscale human ventricular models based on human electrophysiological and magnetic resonance imaging data (control and HF). RESULTS: For patients with APV-ALT k score >1.7, complex action potential duration (APD) oscillations (>=2.3% of mean APD), rather than APD alternans, most accurately predicted VT/VF during long-term follow-up (+82%; -90% predictive values). In the failing human ventricular models, abnormal sarcoplasmic reticulum (SR) calcium handling caused APV-ALT (>1 mV) during pacing with a cycle length of 550 ms, which transitioned into large magnitude (>100 ms) discordant repolarization time alternans (RT-ALT) at faster rates. This initiated VT/VF (cycle length <400 ms) by steepening apicobasal repolarization (189 ms/mm) until unidirectional conduction block and reentry. Complex APD oscillations resulted from nonstationary discordant RT-ALT. Restoring SR calcium to control levels was antiarrhythmic by terminating electrical alternans. CONCLUSION: APV-ALT and complex APD oscillations at near-resting heart rates in patients with HF are linked to arrhythmogenic discordant RT-ALT. This may enable novel physiologically tailored, bioengineered indices to improve VT/VF risk stratification, where SR calcium handling and spatial apicobasal repolarization are potential therapeutic targets. PMID- 27215537 TI - Correlation of Bone Mineral Parameters with Anthropometric Measurements and the Effect of Glucocorticoids on Bone Mineral Parameters in Congenital Adrenal Hyperplasia: Correspondence. PMID- 27215538 TI - Correlation of Bone Mineral Parameters with Anthropometric Measurements and the Effect of Glucocorticoids on Bone Mineral Parameters in Congenital Adrenal Hyperplasia: Authors' Reply. PMID- 27215539 TI - Profile and Risk Factor Analysis of Unintentional Injuries in Children. AB - OBJECTIVE: To study the profile and various risk factors associated with unintentional injuries in children. METHODS: The study is a cross sectional analysis of data collected from 351 children presenting with unintentional injury to a tertiary care hospital in Navi Mumbai, India. Data were collected about variables based on Haddon Phase Factor Matrix - host, environment and agent factors. Proportions for categorical variables across various groups were compared using Chi square test or Fisher's exact test. Logistic regression model was used to evaluate the factors. RESULTS: Falls (36 %) were the most common injuries followed by bites (23 %). Majority of children were school going children (38 %) followed by preschool children (29 %). Forty-seven percent were from lower socioeconomic class. Commonest place of injury was home (48 %) and the commonest time was evening (49 %). Though there was male predominance in injuries, the difference across gender did not vary significantly (p = 0.15). Poisonings were significantly more common in infants and toddlers and in rural population (p < 0.001); kerosene being the commonest agent. Rural population is at more risk of bites compared to urban (p < 0.001); dog bites being the commonest followed by scorpion bites. Foreign bodies were significantly more common in upper and middle socioeconomic class and bites, in lower socioeconomic class (p < 0.005). Injuries from rural area and lower socioeconomic class were more serious, requiring hospitalization; they were also more likely to present late to the hospital (p < 0.05). CONCLUSIONS: Profile of injuries varies widely as per the variations in agent, host and environmental factors. Socio environmental, economic conditions and infancy-toddler age groups are predisposing risk factors for bites and poisoning. Although rural areas and lower socioeconomic class population are more vulnerable to serious types of injuries, they still lack essential basic medical care. PMID- 27215540 TI - Transcriptomic and proteomic analyses of core metabolism in Clostridium termitidis CT1112 during growth on alpha-cellulose, xylan, cellobiose and xylose. AB - BACKGROUND: Clostridium termitidis CT1112 is an anaerobic, Gram-positive, mesophilic, spore-forming, cellulolytic bacterium, originally isolated from the gut of a wood feeding termite Nasusitermes lujae. It has the ability to hydrolyze both cellulose and hemicellulose, and ferment the degradation products to acetate, formate, ethanol, lactate, H2, and CO2. It is therefore ges in gene and gene product expression during growth of C. termitidis on cellobiose, xylose, xylan, and alpha-cellulose. RESULTS: Correlation of transcriptome and proteome data with growth and fermentation profiles identified putative carbon-catabolism pathways in C. termitidis. The majority of the proteins associated with central metabolism were detected in high abundance. While major differences were not observed in gene and gene-product expression for enzymes associated with metabolic pathways under the different substrate conditions, xylulokinase and xylose isomerase of the pentose phosphate pathway were found to be highly up regulated on five carbon sugars compared to hexoses. In addition, genes and gene products associated with a variety of cellulosome and non-cellulosome associated CAZymes were found to be differentially expressed. Specifically, genes for cellulosomal enzymes and components were highly expressed on alpha-cellulose, while xylanases and glucosidases were up-regulated on 5 carbon sugars with respect to cellobiose. Chitinase and cellobiophosphorylases were the predominant CAZymes expressed on cellobiose. In addition to growth on xylan, the simultaneous consumption of two important lignocellulose constituents, cellobiose and xylose was also demonstrated. CONCLUSION: There are little changes in core-metabolic pathways under the different carbon sources compared. The most significant differences were found to be associated with the CAZymes, as well as specific up regulation of some key components of the pentose phosphate pathway in the presence of xylose and xylan. This study has enhanced our understanding of the physiology and metabolism of C. termitidis, and provides a foundation for future studies on metabolic engineering to optimize biofuel production from natural biomass. PMID- 27215542 TI - [12]aneN3 Modified Tetraphenylethene Molecules as High-Performance Sensing, Condensing, and Delivering Agents toward DNAs. AB - Four [12]aneN3 modified tetraphenylethene (TPE) compounds with different numbers of polyamine units and structure configurations, namely 1, 2, 3, and 4, were designed and synthesized. All compounds showed strong aggregation-induced emission (AIE) features. Compounds 2 and 4 showed significant emission enhancement after the addition of ssDNAs and dsDNAs of different lengths as well as calf thymus DNA (ctDNA). Compounds 1 and 3 showed very poor fluorescent responses toward DNAs. Gel electrophoresis demonstrated the abilities of 1-4 to condense DNA effectively. Complete retardation of plasmid DNA can be achieved at a concentration of 25 MUM (1), 8 MUM (for 2 and 3) and 4 MUM (4). Experiments including fluorescent contrastive titrations, scanning electron microscopy, dynamic laser scattering, EB displacement, and gel electrophoresis demonstrated that the four compounds were able to integrate with DNA through electrostatic interactions and supramolecular stacking. A vicinal configuration around TPE (2) and more triazole-[12]aneN3 recognition sites (4) evidently enhanced the sensing capability toward oligonucleotides, and the TPE unit played an important role in the plasmid DNA condensation process because of its strong binding. With the advantages of low cytotoxicity, effective DNA sensing, and DNA condensing properties, compound 4 was successfully applied as a nonviral DNA vector and fluorescent tracer for label-free gene delivery, which is the first example of a nonviral gene vector with AIE activity. PMID- 27215541 TI - Nasopharyngeal pneumococcal carriage rates among HIV-infected adults following widespread pediatric use of conjugate pneumococcal vaccine-13. AB - BACKGROUND: Nasopharyngeal pneumococcal carriage rates among HIV-infected adults has not been described since conjugate pneumococcal vaccine-13 (PCV13) was added to the universal infant and childhood vaccination schedule in 2010. METHODS: HIV infected adults presenting for routine health care visits to the Designated AIDS Center in Syracuse, NY between December 2013 and June 2015 were eligible for enrollment. Demographic, medical, and social history were recorded after obtaining informed consent. Nasopharyngeal samples were collected and cultured for the presence of Streptococcus pneumoniae using standard microbiologic techniques. Antibiotic susceptibility testing was performed using E-test->. RESULTS: 707 nasopharyngeal samples were collected from 414 HIV-infected adults. 18 samples were culture positive for S. pneumoniae; 1 (6%) isolate was of vaccine type, 9 (50%) were non-vaccine types, and 8 (44%) were non-typeable. The 18 isolates were recovered from 15 different patients (4% of those enrolled). Three patients were culture positive for pneumococcus isolated from 2 consecutive samples, with non-typeable pneumococci identified consecutively from 2 patients and serotype 35B identified consecutively from 1 patient. The most commonly identified non-vaccine serotypes were 35B and 15B/C. Identified pneumococci were penicillin and cefotaxime susceptible. CONCLUSION: Four percent of HIV-infected adults in our study population were colonized with S. pneumoniae. The non-vaccine serotypes 35B and 15B/C predominated. PMID- 27215543 TI - The International Headache Society: The history of its founding. PMID- 27215544 TI - Paranasal sinus opacification in headache sufferers: A population-based imaging study (the HUNT study-MRI). AB - Background The association between headache and paranasal sinus disease is still unclear. Because of symptom overlap, the two conditions are not easily studied on the basis of symptoms alone. The aim of the present study was to investigate whether paranasal sinus opacification on magnetic resonance imaging (MRI) was associated with migraine, tension-type headache (TTH) or unclassified headache. Methods This was a cross-sectional study of 844 randomly selected participants (442 women, age range 50-65 years, mean age 57.7 years). Based on 14 headache questions, participants were allocated to four mutually exclusive groups: migraine, TTH, unclassified headache or headache free. On MRI, opacifications as mucosal thickening, polyps/retention cysts and fluid in the five paired sinuses were measured and recorded if >=1 mm. For each participant, opacification thickness was summed for each sinus and, in addition, a total sum of all sinuses was calculated. Opacification in each sinus was compared between headache-free participants and the headache groups using non-parametric tests, and the total sum was compared by logistical regression. Results No significant association was found between paranasal sinus opacification and headache in general, nor when headache was differentiated into migraine, TTH and unclassified headache. This was also true in separate analyses of mucosal thickening and fluid and of opacification from each paranasal sinus. Conclusion Migraine, TTH and unclassified headache were found not to be associated with an increased degree of paranasal sinus opacification at MRI. PMID- 27215545 TI - Comment on "Paranasal sinus opacification in headache sufferers: A population based imaging study (the HUNT study-MRI)". PMID- 27215546 TI - A metagenomic comparison of endemic viruses from broiler chickens with runting stunting syndrome and from normal birds. AB - Runting-stunting syndrome (RSS) in broiler chickens is an enteric disease that causes significant economic losses to poultry producers worldwide due to elevated feed conversion ratios, decreased body weight during growth, and excessive culling. Of specific interest are the viral agents associated with RSS which have been difficult to fully characterize to date. Past research into the aetiology of RSS has implicated a wide variety of RNA and DNA viruses however, to date, no individual virus has been identified as the main agent of RSS and the current opinion is that it may be caused by a community of viruses, collectively known as the virome. This paper attempts to characterize the viral pathogens associated with 2-3-week-old RSS-affected and unaffected broiler chickens using next generation sequencing and comparative metagenomics. Analysis of the viromes identified a total of 20 DNA and RNA viral families, along with 2 unidentified categories, comprised of 31 distinct viral genera and 7 unclassified genera. The most abundant viral families identified in this study were the Astroviridae, Caliciviridae, Picornaviridae, Parvoviridae, Coronaviridae, Siphoviridae, and Myoviridae. This study has identified historically significant viruses associated with the disease such as chicken astrovirus, avian nephritis virus, chicken parvovirus, and chicken calicivirus along with relatively novel viruses such as chicken megrivirus and sicinivirus 1 and will help expand the knowledge related to enteric disease in broiler chickens, provide insights into the viral constituents of a healthy avian gut, and identify a variety of enteric viruses and viral communities appropriate for further study. PMID- 27215547 TI - Total synthesis, biosynthesis and biological profiles of clavine alkaloids. AB - This review highlights noteworthy synthetic and biological aspects of the clavine subfamily of ergot alkaloids. Recent biosynthetic insights have laid the groundwork for a better understanding of the diverse biological pathways leading to these indole derivatives. Ergot alkaloids were among the first fungal-derived natural products identified, inspiring pharmaceutical applications in CNS disorders, migraine, infective diseases, and cancer. Pergolide, for example, is a semi-synthetic clavine alkaloid that has been used to treat Parkinson's disease. Synthetic activities have been particularly valuable to facilitate access to rare members of the Clavine family and empower medicinal chemistry research. Improved molecular target identification tools and a better understanding of signaling pathways can now be deployed to further extend the biological and medical utility of Clavine alkaloids. PMID- 27215548 TI - Responses of Leaky Integrate-and-Fire Neurons to a Plurality of Stimuli in Their Receptive Fields. AB - A fundamental question concerning the way the visual world is represented in our brain is how a cortical cell responds when its classical receptive field contains a plurality of stimuli. Two opposing models have been proposed. In the response averaging model, the neuron responds with a weighted average of all individual stimuli. By contrast, in the probability-mixing model, the cell responds to a plurality of stimuli as if only one of the stimuli were present. Here we apply the probability-mixing and the response-averaging model to leaky integrate-and fire neurons, to describe neuronal behavior based on observed spike trains. We first estimate the parameters of either model using numerical methods, and then test which model is most likely to have generated the observed data. Results show that the parameters can be successfully estimated and the two models are distinguishable using model selection. PMID- 27215549 TI - Commentary on 'Haemodynamic Performance of Low strength Below knee Graduated Elastic Compression Stockings in Health, Venous Disease, and Lymphedema'. PMID- 27215550 TI - Short-term change of carotid intima-media thickness after treatment of hyperglycemia in patients with diabetes: a cross-sectional study. AB - BACKGROUND: The carotid artery intima-media thickness (CIMT) has been used as a predictor of cardiovascular events, but it remains unclear whether CIMT can change over the short term. We evaluated changes of CIMT in patients with diabetes during admission to hospital for 2 weeks. METHODS: A total of 279 inpatients with diabetes aged 61 +/- 14 years were recruited. They were on treatment with insulin and/or oral agents, excluding drugs that influence the fluid balance and hemodynamics. CIMT was measured on the day after admission and on the day before discharge, and the association of DeltaCIMT (calculated by subtracting the baseline value from that on the day before discharge) with clinical factors was evaluated. RESULTS: Based on the reported annual increase of CIMT (0.04 mm/year), the patients were divided into three groups, in which CIMT increased [I: DeltaCIMT >= 0.04 mm, n = 64, DeltaCIMT = 0.077 +/- 0.048 (mean +/- SD)], CIMT decreased (D: DeltaCIMT <= -0.04 mm, n = 51, DeltaCIMT = -0.090 +/- 0.086), or CIMT was unchanged (N: -0.04 mm < DeltaCIMT < 0.04 mm, n = 164, DeltaCIMT = 0.002 +/- 0.022). Binary logistic regression analysis showed that baseline CIMT and hemoglobin (Hb) were positively correlated, while Hb on the day before discharge was negatively correlated, with a decrease of CIMT. In contrast, baseline HbA1c and Hb were negatively correlated, while Hb on the day before discharge was positively correlated, with an increase of CIMT. CONCLUSIONS: CIMT may show plasticity in patients with diabetes and can change even after short term treatment of hyperglycemia for 2 weeks. PMID- 27215551 TI - Transarterial chemoembolization of hepatocellular carcinoma in a rat model: the effect of additional injection of survivin siRNA to the treatment protocol. AB - BACKGROUND: Transarterial chemoembolization is one of the most widely accepted interventional treatment options for treatment of hepatocellular carcinoma. Still there is a lack of a standard protocol regarding the injected chemotherapeutics. Survivin is an inhibitor of Apoptosis protein that functions to inhibit apoptosis, promote proliferation, and enhance invasion. Survivin is selectively up-regulated in many human tumors. Small interfering RNA (siRNA) can trigger an RNA interference response in mammalian cells and induce strong inhibition of specific gene expression including Survivin. The aim of the study is to assess the effectiveness of the additional injection of Survivin siRNA to the routine protocol of Transarterial Chemoembolization (TACE) for the treatment of hepatocellular carcinoma in a rat model. METHODS: The study was performed on 20 male ACI rats. On day 0 a solid Morris Hepatoma 3924A was subcapsullary implanted in the liver. On day 12 MRI measurement of the initial tumor volume (V1) was performed. TACE was performed on day 13. The rats were divided into 2 groups; Group (A, n = 10) in which 0.1 mg mitomycin, 0.1 ml lipiodol and 5.0 mg degradable starch microspheres were injected in addition 2.5 nmol survivin siRNA were injected. The same agents were injected in Group (B,=10) without Survivin siRNA. MRI was repeated on day 25 to assess the tumor volume (V2). The tumor growth ratio (V2/V1) was calculated. Western blot and immunohistochemical analysis were performed. RESULTS: For group A the mean tumor growth ratio (V2/V1) was 1.1313 +/- 0.1381, and was 3.1911 +/- 0.1393 in group B. A statistically significant difference between both groups was observed regarding the inhibition of tumor growth (P < 0.0001) where Group A showed more inhibition compared to Group B. Similarly immunohistochemical analysis showed significantly lower (p < 0.002) VEGF staining in group A compared to group B. Western Blot analysis showed a similar difference in VEGF expression (P < 0.0001). CONCLUSION: The additional injection of Survivin siRNA to the routine TACE protocol increased the inhibition of the hepatocellular carcinoma growth in a rat animal model compared to regular TACE protocol. PMID- 27215552 TI - Urinary Proteomics Yield Pathological Insights for Ureteropelvic Junction Obstruction. AB - Prenatal hydronephrosis is a common condition that may spontaneously resolve after birth. However, this condition can result in renal damage and requires surgical correction in a number of cases. Preventing renal damage is paramount, but existing diagnostic technology is invasive, exposes infants to radiation, is costly, and is often indeterminate. A better understanding of the pathophysiology of renal obstruction as reflected in the urinary proteome may provide new insights into the disease that could potentially alter the clinical management of hydronephrosis. We performed a quantitative proteomics study of urine that was surgically obtained from eight clinically significant, unilaterally obstructed infants versus eight healthy controls, with the goal of identifying quantitatively varying proteins and the biological networks associated with them. Notably, urine was obtained from both the obstructed kidney and the bladder. Over 1100 proteins were identified, and a total of 76 quantitatively varying proteins were identified. Proteins involved in oxidative stress, inflammation, and renal disease pathways showed the most significant abundance differences. This study gives a deeper understanding of the critical proteomic changes associated with renal obstruction and represents the deepest proteomic profile of renal obstruction to date. PMID- 27215553 TI - Systematic Errors in Peptide and Protein Identification and Quantification by Modified Peptides. AB - The principle of shotgun proteomics is to use peptide mass spectra in order to identify corresponding sequences in a protein database. The quality of peptide and protein identification and quantification critically depends on the sensitivity and specificity of this assignment process. Many peptides in proteomic samples carry biochemical modifications, and a large fraction of unassigned spectra arise from modified peptides. Spectra derived from modified peptides can erroneously be assigned to wrong amino acid sequences. However, the impact of this problem on proteomic data has not yet been investigated systematically. Here we use combinations of different database searches to show that modified peptides can be responsible for 20-50% of false positive identifications in deep proteomic data sets. These false positive hits are particularly problematic as they have significantly higher scores and higher intensities than other false positive matches. Furthermore, these wrong peptide assignments lead to hundreds of false protein identifications and systematic biases in protein quantification. We devise a "cleaned search" strategy to address this problem and show that this considerably improves the sensitivity and specificity of proteomic data. In summary, we show that modified peptides cause systematic errors in peptide and protein identification and quantification and should therefore be considered to further improve the quality of proteomic data annotation. PMID- 27215554 TI - Adalimumab-Receiving Ulcerative Colitis Patient Suffered Latent Tuberculosis Reactivation Despite Correct Chemoprophylaxis and was Successfully Treated while on Anti-Tumour Necrosis Factor Therapy. PMID- 27215555 TI - Prognostic implications of sarcomatoid and rhabdoid differentiation in patients with grade 4 renal cell carcinoma. AB - OBJECTIVE: Sarcomatoid and rhabdoid differentiation are associated with poor outcomes in renal cell carcinoma (RCC). We examined the impact of differentiation on cancer-specific survival (CSS) in surgically treated patients with grade 4 RCC. MATERIALS AND METHODS: Using our institutional database of 1176 nephrectomies from 2005 to 2013, we identified patients with grade 4 RCC or any grade and the presence of sarcomatoid or rhabdoid differentiation. We divided the cohort based on differentiation: no differentiation, rhabdoid only, sarcomatoid only, and sarcomatoid and rhabdoid. CSS was analyzed using the Kaplan-Meier method and Cox proportional hazards modeling. RESULTS: Of 264 patients with grade 4 RCC, 159 (60.2 %) exhibited differentiation, including 45 (28.3 %) with rhabdoid only, 87 (54.7 %) with sarcomatoid only, and 27 (16.9 %) with rhabdoid and sarcomatoid. Sarcomatoid differentiation, either alone or with rhabdoid differentiation, was associated with worse median CSS than no differentiation (1.1 vs. 3.3 years, p < 0.01, and 0.9 vs. 3.3 years, p < 0.01, respectively). In patients with non-metastatic (HR 1.95, 95 % CI 1.19-3.19, p = 0.008) and metastatic (HR 2.22, 95 % CI 1.45-3.41, p < 0.001) RCC, sarcomatoid differentiation was associated with an increased risk of cancer-specific death. On multivariable analysis, sarcomatoid differentiation was an independent predictor of RCC death in patients with non-metastatic (HR 1.72, 95 % CI 1.04 2.84, p = 0.03) and metastatic (HR 1.74, 95 % CI 1.05-2.90, p = 0.03) disease. Rhabdoid differentiation alone was not associated with worse CSS (p = 0.55). CONCLUSIONS: In grade 4 RCC, sarcomatoid differentiation is associated with increased mortality risk across all stages of disease. Rhabdoid differentiation is not associated with additional mortality risk. PMID- 27215556 TI - Determinants of thirst distress in patients on hemodialysis. AB - PURPOSE: Thirst sensation can induce nonadherence with fluid restriction in patients on hemodialysis (HD) and may lead to large interdialytic weight gain (IWG). This study aimed to evaluate thirst distress and its determinants and to explore fluid management strategies used by patients on HD. METHODS: A cross sectional study was conducted in a sample of 203 patients who were followed in three HD centers in Turkey, from January 2015 to June 2015. Data were collected by a personal information form, the Thirst Distress Scale (TDS) and the Visual Analogue Scale (VAS) for thirst and xerostomia. Data analysis was performed using descriptive statistics, Student's t test, the one-way analysis of variance, Pearson's correlation coefficients, and linear regression analysis. RESULTS: The mean TDS score was 20.71 +/- 8.34, which is a higher than moderate level of thirst distress. The significant determinants of thirst distress of the patients were the VAS thirst score (unstandardized beta = 1.73, p < 0.001), the VAS xerostomia score (unstandardized beta = 0.42, p < 0.001), and the IWG values (unstandardized beta = 1.20, p = 0.003), after controlling for specific variables. The most common strategies used to reduce fluid intake or relieve thirst were avoiding salty foods (70.9 %), limiting salt on food (70.9 %), and spacing liquids over the entire day (57.6 %). CONCLUSIONS: Patients with higher levels of thirst and xerostomia and those with a high IWG were more likely to have higher thirst distress. A greater understanding of thirst distress and its related factors could contribute to more effective interventions that improve health and well-being in patients on HD. PMID- 27215558 TI - Improving long term outcomes in urea cycle disorders-report from the Urea Cycle Disorders Consortium. AB - The Urea Cycle Disorders Consortium (UCDC) has conducted, beginning in 2006, a longitudinal study (LS) of eight enzyme deficiencies/transporter defects associated with the urea cycle. These include N-acetylglutamate synthase deficiency (NAGSD); Carbamyl phosphate synthetase 1 deficiency (CPS1D); Ornithine transcarbamylase deficiency (OTCD); Argininosuccinate synthetase deficiency (ASSD) (Citrullinemia); Argininosuccinate lyase deficiency (ASLD) (Argininosuccinic aciduria); Arginase deficiency (ARGD, Argininemia); Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome (or mitochondrial ornithine transporter 1 deficiency [ORNT1D]); and Citrullinemia type II (mitochondrial aspartate/glutamate carrier deficiency [CITRIN]). There were 678 UCD patients enrolled in 14 sites in the U.S., Canada, and Europe at the writing of this paper. This review summarizes findings of the consortium related to outcome, focusing primarily on neuroimaging findings and neurocognitive function. Neuroimaging studies in late onset OTCD offered evidence that brain injury caused by biochemical dysregulation may impact functional neuroanatomy serving working memory processes, an important component of executive function and regulation. Additionally, there were alteration in white mater microstructure and functional connectivity at rest. Intellectual deficits in OTCD and other urea cycle disorders (UCD) vary. However, when neuropsychological deficits occur, they tend to be more prominent in motor/performance areas on both intelligence tests and other measures. In some disorders, adults performed significantly less well than younger patients. Further longitudinal follow-up will reveal whether this is due to declines throughout life or to improvements in diagnostics (especially newborn screening) and treatments in the younger generation of patients. PMID- 27215557 TI - Klotho, the Holy Grail of the kidney: from salt sensitivity to chronic kidney disease. AB - The Klotho gene displays an extremely shortened life span with loss of function missense mutations leading to premature multiple organ failure, thus resembling human premature aging syndromes. The transmembrane form of Klotho protein functions as an obligatory co-receptor for FGF23. Klotho and FGF23 are crucial components for the regulation of vitamin D metabolism and subsequently blood phosphate levels. The secreted Klotho protein has multiple regulatory functions, including effects on electrolyte homeostasis, on growth factor pathways as well as on oxidative stress, which are currently the object of extensive research. Klotho protein deficiency is observed in many experimental and clinical disease models. Genetic polymorphisms such as the G-395A polymorphism in the promoter region of the Klotho gene have been associated with the development of essential hypertension. The kidneys are the primary site of Klotho production, and renal Klotho is decreased in CKD, followed by a reduction in plasma Klotho. Klotho deficiency has been both associated with progression of CKD as well as with its cardinal systemic manifestations, including cardiovascular disease. Thus, Klotho has been suggested both as a risk biomarker for early detection of CKD and additionally as a potential therapeutic tool in the future. PMID- 27215559 TI - Gender Differences among Smokers Living with HIV. AB - Tobacco use has emerged as a leading cause of death among persons living with HIV (PLWH) who smoke cigarettes. In contrast to the general population where smoking prevalence in men exceeds that in women, large surveys have shown similar smoking rates among male and female PLWH. There are important behavioral and biological differences between male and female smokers, but little is known about the relationships between tobacco use and gender in PLWH. Herein, the authors present a detailed examination of gender differences in smokers living with HIV (N = 267; 54% male, 46% female) recruited in 2 tobacco treatment trials. The authors found higher rates of heavy smoking and other substance use in men. Women were more likely to have used pharmacotherapy during quit attempts. Asthma rates were markedly higher in female smokers. There were no significant differences in a range of psychobehavioral domains or in cessation rates between male and female smokers living with HIV. PMID- 27215560 TI - 23-Valent Pneumococcal Polysaccharide Vaccine Uptake in the United States Air Force HIV Program. AB - Streptococcus pneumoniae infection is a predominant cause of bacterial infection in HIV-infected individuals. However, reported rates of pneumococcal vaccination with 23-valent polysaccharide vaccine (PPV23) are variable. We evaluated uptake of PPV23 in patients diagnosed with HIV between 1996 and 2012 (n = 507) in the United States Air Force, a centralized HIV program with free access to care including vaccines and medications. A total of 411 (81.1%) patients received at least 1 PPV23 dose. The PPV23 vaccination within 1 year of diagnosis was greater for those diagnosed between 2004 and 2012 (n = 184, 86%) compared with 1996 to 2003 (n = 104, 56.5%; P < .001). For those with >=6 years of follow-up, receipt of a second recommended PPV23 dose was greater for those diagnosed between 1996 and 2003 (n = 52, 57.8%) compared with 2004 to 2012 (n = 9, 28.1%; P = .004). Although first PPV23 vaccination was high in recent years, process improvement efforts are underway to overcome barriers and improve uptake of pneumococcal vaccines in our program. PMID- 27215562 TI - Cell Block Preparation versus Liquid-Based Thin-Layer Cervical Cytology: A Comparative Study Evaluating Human Papillomavirus Testing by Hybrid Capture 2/Cervista, in situ Hybridization and p16 Immunohistochemistry. AB - OBJECTIVE: Cell block (CB) preparations from residual liquid-based Pap samples have been shown to be of diagnostic value. In this study we evaluated human papillomavirus (HPV) in situ hybridization (ISH) and p16 immunohistochemistry (IHC) on CB preparations and compared the results with the primary diagnosis and standard HPV tests. DESIGN: In total, 197 HE-stained CB slides prepared from CBs from residual Pap samples (152 ASCUS, 2 ASC-H, 32 LGSIL, 4 HGSIL, 1 AGUS and 6 normal) were analyzed. Hybrid Capture-2 (HC-2)/Cervista testing and HPV ISH and p16 IHC were performed on the CB samples. The test performance characteristics were compared with HPV and p16 assay performances. RESULTS: The cellular architecture was well maintained in CBs with excellent consistency. HPV ISH testing had an excellent concordance with the HC-2/Cervista methods (85%) with high sensitivity (82.6%; 95% CI 75.9, 89.4) and specificity (89.3%). Of all the p16 tests, 38% were positive (60 out of 159 samples). The overall concordance between p16 and HC-2/Cervista (64%), or between p16 and ISH (68%), was lower than the concordance between ISH and HC-2/Cervista (85%). CONCLUSIONS: HPV ISH and p16 IHC testing is feasible, cost effective and practical. A combination of the two tests would ultimately improve diagnostic accuracy, leading to better therapeutic decisions. PMID- 27215561 TI - Efficacy of a Single, Brief Alcohol Reduction Intervention among Men and Women Living with HIV/AIDS and Using Alcohol in Kampala, Uganda: A Randomized Trial. AB - We evaluated the efficacy of a brief motivational intervention (MI) counseling in reducing alcohol consumption among persons living with HIV/AIDS in Kampala, Uganda. Persons living with HIV/AIDS with Alcohol Use Disorders Identification Tool (AUDIT) score >=3 points were randomized to either standardized positive prevention counseling alone or in combination with alcohol brief MI counseling. The mean change in AUDIT-C scores over 6 months was compared by treatment arm. The mean (standard deviation [SD]) AUDIT-C scores were 6.3 (2.3) and 6.8 (2.3) for control and MI arms ( P = .1) at baseline, respectively, and change in mean AUDIT-C score was not statistically different between arms over the 6 months ( P = .8). However, there was a statistically significant decrease in mean AUDIT-C score (-1.10; 95% confidence interval: -2.19 to -0.02, P = .046) among women in the MI arm. There was a nondifferential reduction in alcohol consumption overall, but MI appeared effective among women only. Studies with more than 1 counseling session and evaluation of gender differences in treatment response are needed. PMID- 27215563 TI - Concurrent chemoradiotherapy plus adjuvant chemotherapy versus concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma : A matched pair multicenter analysis of outcomes. AB - PURPOSE: The benefit of adjuvant chemotherapy (AC) in locoregionally advanced nasopharyngeal carcinoma (NPC) is controversial. This study compared concurrent chemoradiotherapy plus AC (CCRT/AC) with CCRT. METHODS: Pair-matched analysis based on eight clinicopathological features of 244 patients treated with platinum based CCRT/AC or CCRT alone was performed. Survival outcomes were assessed using the Kaplan-Meier method and log-rank test. Toxicities and response rates were compared using Fisher's exact test. RESULTS: Four-year overall survival, progression-free survival, distant failure-free survival, and locoregional failure-free survival were 72 %, 61 %, 71 %, and 81 %, respectively, for the CCRT arm, compared to 74 % (hazard ratio, HR 0.89; 95 % confidence interval, CI 0.64 1.23; P = 0.474), 62 % (HR 0.91, 95 % CI 0.68-1.20, P = 0.489), 73 % (HR 0.84, 95 % CI 0.59-1.18, P = 0.316), and 84 % (HR 0.84, 95 % CI 0.52-1.24, P = 0.323), respectively, for the CCRT/AC arm. Cox multivariate regression analysis demonstrated AC was not an independent prognostic factor. Overall, there was a higher incidence of grade 3-4 toxicities in the CCRT/AC arm. The most common grade 3-4 adverse events in the CCRT/AC arm were vomiting (27 %), nausea (43 %), leukopenia/neutropenia (23 %), thrombocytopenia (8.8 %), and anemia (6.2 %). CONCLUSION: Addition of AC to CCRT increased toxicities but did not improve survival in locoregionally advanced NPC. PMID- 27215564 TI - A Case of SLC29A3 Spectrum Disorder-Unresponsive to Multiple Immunomodulatory Therapies. PMID- 27215565 TI - Artery-First Distal Pancreatectomy. AB - Artery-first pancreatectomy is a technique to ligate the feeding artery before the division of the pancreas with intents to reduce the blood loss and to perform more oncologic resection; for example, the splenic artery (SA) is ligated first for artery-first distal pancreatectomy (DP). Potential merits of artery-first DP include early determination of resectability in the setting of pancreatic cancer with possible involvement of SA and/or celiac artery. However, due to difficulties in exposing the origin of SA, especially in open surgery, artery first DP has been rarely performed. Through the experience of laparoscopic DP, we have developed a technique of artery-first DP by the 'Tora-no-Ana' approach, which consists of posterior dissection of the pancreatic body thorough a division of the ligament of Treitz. A hanging maneuver of the pancreatic parenchyma with SA and vein is another key for a successful artery-first DP. By the hanging maneuver, the origin of SA is well visualized and clearly identified either by open, laparoscopic or robotic approach so that oncologic resection can be achieved. In conclusion, artery-first DP is safe and feasible if the surgical principals by the Tora-no-Ana approach and hanging maneuver of the pancreatic body are adhered. PMID- 27215566 TI - Effects of Walnut Consumption on Colon Carcinogenesis and Microbial Community Structure. AB - Walnuts are composed of a complex array of biologically active constituents with individual cancer-protective properties. Here, we assessed the potential benefit of whole walnut consumption in a mouse tumor bioassay using azoxymethane. In study 1, a modest reduction (1.3-fold) in tumor numbers was observed in mice fed a standard diet (AIN-76A) containing 9.4% walnuts (15% of total fat). In study 2, the effects of walnut supplementation was tested in the Total Western Diet (TWD). There was a significant reduction (2.3-fold; P < 0.02) in tumor numbers in male mice fed TWD containing 7% walnuts (10.5% of total fat). Higher concentrations of walnuts lacked inhibitory effects, particularly in female mice, indicating there may be optimal levels of dietary walnut intake for cancer prevention. Since components of the Mediterranean diet have been shown to affect the gut microbiome, the effects of walnuts were therefore tested in fecal samples using 16S rRNA gene sequencing. Carcinogen treatment reduced the diversity and richness of the gut microbiome, especially in male mice, which exhibited lower variability and greater sensitivity to environmental changes. Analysis of individual operational taxonomic units (OTU) identified specific groups of bacteria associated with carcinogen exposure, walnut consumption, and/or both variables. Correlation analysis also identified specific OTU clades that were strongly associated with the presence and number of tumors. Taken together, our results indicate that walnuts afford partial protection to the colon against a potent carcinogenic insult, and this may be due, in part, to walnut-induced changes to the gut microbiome. Cancer Prev Res; 9(8); 692-703. (c)2016 AACR. PMID- 27215567 TI - Extensive horizontal gene transfers between plant pathogenic fungi. AB - BACKGROUND: Horizontal gene transfer (HGT) plays an important role in the adaptation of lineages to changing environments. The extent of this process in eukaryotes, however, remains controversial. The most well-known and dramatic form of HGT represents intracellular gene transfer from endosymbionts to the host nuclear genome. Such episodes of transfer typically involve hundreds of genes and are thought to be possible only in the case of endosymbiosis. RESULTS: Using a conservative phylogenomic approach, we analyzed genomic data from the fungal pathogen Magnaporthiopsis incrustans in the order Magnaporthales and identified two instances of exclusive sharing of HGT-derived gene markers between Magnaporthales and another lineage of plant-pathogenic fungi in the genus Colletotrichum. Surprisingly, inspection of these data demonstrated that HGT is far more widespread than anticipated, with more than 90 genes (including 33 highly supported candidates) being putatively transferred between Magnaporthales and Colletotrichum. These gene transfers are often physically linked in the genome and show more than two-fold functional enrichment in carbohydrate activating enzymes associated with plant cell wall degradation. CONCLUSIONS: Our work provides a novel perspective on the scale of HGT between eukaryotes. These results challenge the notion that recognized HGT plays a minor role in the evolution of fungal lineages, and in the case we describe, is likely implicated in the evolution of plant pathogenesis. More generally, we suggest that the expanding database of closely related eukaryotic genomes and the application of novel analytic methods will further underline the significant impact of foreign gene acquisition across the tree of life. Major lifestyle transitions such as those accompanying the origin of extremophily or pathogenesis are expected to be ideal candidates for studying the mode and tempo of HGT. PMID- 27215568 TI - Health Care Utilization and Direct Medical Costs of Tennis Elbow: A Population Based Study. AB - BACKGROUND: Tennis elbow is commonly encountered by physicians, yet little is known about the cost of treating this condition. HYPOTHESIS: The largest cost associated with treating tennis elbow is procedural intervention. STUDY DESIGN: Descriptive epidemiology study. LEVEL OF EVIDENCE: Level 4. METHODS: This retrospective population-based study reviewed patients who were treated for new onset tennis elbow between January 1, 2003 and December 31, 2012. All patients were followed up through their medical and administrative records to identify health care encounters and interventions for tennis elbow. Unit costs for each health service/procedure were adjusted to nationally representative unit costs in 2013 inflation-adjusted dollars. RESULTS: In a cohort of 931 patients who had 2 or more clinical encounters for new-onset lateral epicondylosis during a 12-month period after initial diagnosis, 62% received a median of 3 physical therapy sessions (cost, $100/session) and 40% received a median of 1 steroid injection (cost, $82/injection). Only 4% of patients received surgical intervention with mean costs of $4000. The mean (median) total direct medical cost of services related to lateral epicondylosis for the entire cohort was $660 ($402) per patient over the 1-year period after diagnosis. Patients who continued to be treated conservatively between 6 and 12 months after diagnosis incurred relatively low median costs of $168 per patient. CONCLUSION: In this cohort, a second encounter with a physician for tennis elbow was a strong predictor of increased treatment cost due to a higher likelihood of specialist referral, use of physical therapy, or treatment with steroid injection. CLINICAL RELEVANCE: The majority of direct medical spending on tennis elbow occurs within the first 6 months of treatment, and relatively little expense occurs between 6 and 12 months after diagnosis unless a patient undergoes surgical intervention. PMID- 27215569 TI - Worrying about wasting GP time as a barrier to help-seeking: a community-based, qualitative study. AB - BACKGROUND: Worrying about wasting GP time is frequently cited as a barrier to help-seeking for cancer symptoms. AIM: To explore the circumstances under which individuals feel that they are wasting GP time. DESIGN AND SETTING: Community based, qualitative interview studies that took place in London, the South East and the North West of England. METHOD: Interviewees (n = 62) were recruited from a sample (n = 2042) of adults aged >=50 years, who completed a 'health survey' that included a list of cancer 'alarm' symptoms. Individuals who reported symptoms at baseline that were still present at the 3-month follow-up (n = 271), and who had also consented to be contacted (n = 215), constituted the pool of people invited for interview. Analyses focused on accounts of worrying about wasting GP time. RESULTS: Participants were worried about wasting GP time when time constraints were visible, while dismissive interactions with their GP induced a worry of unnecessary help-seeking. Many felt that symptoms that were not persistent, worsening, or life-threatening did not warrant GP attention. Additionally, patients considered it time-wasting when they perceived attention from nurses or pharmacists to be sufficient, or when appointment structures (for example, 'one issue per visit') were not adhered to. Close relationships with GPs eased worries about time-wasting, while some patients saw GPs as fulfilling a service financed by taxpayers. CONCLUSION: Worrying about wasting GP time is a complex barrier to help-seeking. GP time and resource scarcity, symptom gravity, appointment etiquette, and previous GP interactions contribute to increasing worries. Friendly GP relationships, economic reasoning, and a focus on the GP's responsibilities as a medical professional reduce this worry. PMID- 27215570 TI - Patients with cancer and change of general practice: a Danish population-based cohort study. AB - BACKGROUND: General practice plays an important role in the cancer care pathway. Patient dissatisfaction with the diagnostic process may be expressed by changing to another general practice. AIM: To compare the frequency of change of practice (COP) in patients with cancer (n = 150 216) with a matched cancer-free control cohort (n = 1 502 114) and to analyse associations with cancer type and patient characteristics. DESIGN AND SETTING: A population-based matched cohort study using historical and prospectively collected data from Danish nationwide registers. METHOD: COP was defined as a change of practice list, unrelated to change of address or reorganisation of the practice. Data were analysed monthly in the year before and after a cancer diagnosis. RESULTS: More patients with cancer than controls changed general practice (4.1% versus 2.6%) from 7 months before and until 12 months after diagnosis. The COP rate varied by cancer type (rectal cancer served as reference). Before the diagnosis, COP was most often seen among patients with ovarian cancer (risk ratio [RR] 1.51, 95% confidence interval [CI] = 1.10 to 2.08) and multiple myeloma (RR 1.89, 95% CI = 1.34 to 2.67). After the diagnosis, COP was most frequent among patients with brain cancer (RR 1.38, 95% CI = 1.05 to 1.82) and ovarian cancer (RR 1.51, 95% CI = 1.21 to 1.88). CONCLUSION: Patients with cancer changed general practice more frequently than the cancer-free controls. COP variations between cancer types may be attributed to lack of diagnostic timeliness due to clinical complexity of the diagnosis and the role of the GP in the diagnostic process. PMID- 27215571 TI - Using alternatives to face-to-face consultations: a survey of prevalence and attitudes in general practice. AB - BACKGROUND: The ubiquitous use of communication technologies has led to an expectation that a similar approach should extend to health care. Despite considerable rhetoric about the need for general practices to offer alternatives to face-to-face consultations, such as telephone, email, and internet video consultations, the extent to which such technologies are actually used at present is unclear. AIM: The aim of the survey was to identify the frequency and range of ways in which general practices are providing (or planning) alternatives to face to-face consultations. DESIGN AND SETTING: A postal survey of practices around Bristol, Oxford, Lothian, the Highlands, and the Western Isles of Scotland. METHOD: A postal questionnaire survey was sent to each of the GPs and practice managers of 421 practices between January and May 2015. RESULTS: A response was received from 319/421 practices (76%). Although the majority of the practices reported that they were conducting telephone consultations frequently (n = 211/318, 66%), fewer were implementing email consultations (n = 18/318, 6%), and most (n = 169/318, 53%) had no plans to introduce this. None were currently using internet video, and 86% (n = 273/318) had no plans to introduce internet video consultations. These findings were repeated in the reported use of alternatives to face-to-face consultations at an individual GP level. Optional free text responses were completed by 28% of responders, and offered an explanation for the (often perceived) barriers and incentives for implementation. CONCLUSION: Despite policy pressure to introduce consultations by email and internet video, there is a general reluctance among GPs to implement alternatives to face-to-face consultations. This identifies a substantial gap between rhetoric and reality in terms of the likelihood of certain alternatives (email, video) changing practice in the near future. PMID- 27215573 TI - Early visual experience influences behavioral lateralization in the guppy. AB - Individual differences in lateralization of cognitive functions characterize both humans and non-human species. Genetic factors can account for only a fraction of the variance observed and the source of individual variation in laterality remains in large part elusive. Various environmental factors have been suggested to modulate the development of lateralization, including asymmetrical stimulation of the sensory system during ontogeny. In this study, we raised newborn guppies in an asymmetric environment to test the hypothesis that early left-right asymmetries in visual input may affect the development of cerebral asymmetries. Each fish was raised in an impoverished environment but could voluntarily observe a complex scene in a nearby compartment containing a group of conspecifics. Using asymmetric structures, we allowed some subjects to observe the complex scene with the right eye, others with the left eye, and control fish with both eyes. Among asymmetrically stimulated fish, the mirror test revealed eye dominance congruent with the direction of asymmetric stimulation, while controls showed no left-right laterality bias. Interestingly, asymmetric exposure to social stimuli also affected another aspect of visual lateralization-eye preference for scrutinizing a potential predator-but did not influence a measure of motor asymmetry. As the natural environment of guppies is fundamentally asymmetrical, we suggest that unequal left-right stimulation is a common occurrence in developing guppies and may represent a primary source of individual variation in lateralization as well as an efficient mechanism for producing laterality phenotypes that are adapted to local environmental conditions. PMID- 27215572 TI - Barriers to medication adherence for the secondary prevention of stroke: a qualitative interview study in primary care. AB - BACKGROUND: Medications are highly effective at reducing risk of recurrent stroke, but success is influenced by adherence to treatment. Among survivors of stroke and transient ischaemic attack (TIA), adherence to medication is known to be suboptimal. AIM: To identify and report barriers to medication adherence for the secondary prevention of stroke/TIA. DESIGN AND SETTING: A qualitative interview study was conducted within general practice surgeries in the East of England, UK. METHOD: Patients were approached by letter and invited to take part in a qualitative research study. Semi-structured interviews were undertaken with survivors of stroke, caregivers, and GPs to explore their perspectives and views around secondary prevention and perceived barriers to medication adherence. Key themes were identified using a grounded theory approach. Verbatim quotes describing the themes are presented here. RESULTS: In total, 28 survivors of stroke, including 14 accompanying caregivers and five GPs, were interviewed. Two key themes were identified. Patient level barriers included ability to self-care, the importance people attach to a stroke event, and knowledge of stroke and medication. Medication level barriers included beliefs about medication and beliefs about how pills work, medication routines, changing medications, and regimen complexity and burden of treatment. CONCLUSION: Patients who have had a stroke are faced with multiple barriers to taking secondary prevention medications in UK general practice. This research suggests that a collaborative approach between caregivers, survivors, and healthcare professionals is needed to address these barriers and facilitate medication-taking behaviour. PMID- 27215574 TI - Coping with a changing soundscape: avoidance, adjustments and adaptations. AB - Since the industrial age, background anthropogenic noise has become a pervasive feature of many habitable environments. This relatively recent environmental feature can be particularly challenging for organisms that use acoustic forms of communication due to its propensity for masking and decreasing the potential acoustic space of signals. Furthermore, anthropogenic noise may affect biological processes including animal interactions, physiological and behavioural responses to stimuli and cognitive development. However, animals' cognitive abilities may enable them to cope with high levels of anthropogenic noise through learning, the employment of acoustic and behavioural flexibility as well as the use of multi modal sensory systems. We are only just beginning to understand how neural structures, endocrine systems and behaviour are mechanistically linked in these scenarios, providing us with information we can use to mitigate deleterious effects of pervasive noise on wildlife, along with highlighting the remarkable adaptability of animals to an increasingly anthropogenic world. In this review, I will focus mainly on birds, due to the amount of literature on the topic, and survey recent advancements made in two main spheres: (1) how anthropogenic noise affects cognitive processes and (2) how cognition enables animals to cope with increasingly noisy environments. I will be highlighting current gaps in our knowledge, such as how noise might impact behavioural traits such as predation, as well as how noise causes physical damage to neurotransmitters and affects stress levels, in order to direct future studies on this topic. PMID- 27215575 TI - The effects of incubation temperature on the development of the cortical forebrain in a lizard. AB - The embryos of egg-laying species are exposed to variable thermal regimes, which can influence not only the resultant hatchling's morphology (e.g., size, sex) and performance (e.g., locomotor speed), but also its cognitive performance (learning ability). To clarify the proximate basis for this latter effect, we incubated eggs of the scincid lizard Bassiana duperreyi under simulated 'hot' and 'cold' natural nest temperatures to examine the effect of incubation temperature on the structure of the telencephalon region of the forebrain. Hatchlings from low temperature incubation had larger telencephalons (both in absolute terms and relative to body size) and larger neurons in their medial cortices, whereas the medial cortices of hatchlings from high-temperature incubation had fewer neurons overall, but greater neuronal density, and more neurons in certain areas. These temperature-induced differences in B. duperreyi forebrain development are consistent with (and may explain) the disparities in learning ability between hatchlings from our two incubation treatments. The phenotypic plasticity of lizard telencephalon anatomy in response to incubation temperature presents exciting opportunities for studies on the evolutionary and developmental determinants of intelligence in vertebrates, but also offers a cautionary tale. Global climate changes, wrought by anthropogenic activities, may directly modify brain structure in reptiles. PMID- 27215577 TI - Erratum to: Solid-State Quantitative 1H and 31P MRI of Cortical Bone in Humans. PMID- 27215576 TI - Contemporary management of fibrolamellar hepatocellular carcinoma: diagnosis, treatment, outcome, prognostic factors, and recent developments. AB - Fibrolamellar hepatocellular carcinoma (FL-HCC) is a malignant liver tumor which is thought to be a variant of conventional hepatocellular carcinoma (HCC). It accounts for a small proportion of HCC cases and occurs in a distinctly different group of patients which are young and usually not in the setting of chronic liver disease. The diagnosis of FL-HCC requires the integration of clinical information, imaging studies, and histology. In terms of the treatment options, the only potentially curative treatment option for patients who have resectable disease is surgery either liver resection (LR) or liver transplantation (LT). When performed in a context of aggressive therapy, long-term outcomes after surgery, particularly liver resection for FL-HCC, were favorable. The clinical outcome of patients with unresectable disease is suboptimal with median survival of less than 12 months. The aim of this review is to update the available evidence on diagnosis, treatment options, outcome predictors, and recent developments of patients with this rare disease and to provide a summarized overview of the available literature. PMID- 27215578 TI - Workforce characteristics of privately practicing nurse practitioners in Australia: Results from a national survey. AB - PURPOSE: Australian private practice nurse practitioner (PPNP) services have grown since legislative changes in 2010 enabled eligible nurse practitioners (NPs) to access reimbursement for care delivered through the Medicare Benefits Schedule (MBS) and Pharmaceutical Benefits Scheme (PBS). This article provides data from a national survey on the workforce characteristics of PPNPs in Australia. METHOD: PPNPs in Australia were invited to complete an electronic survey. Quantitative data were analyzed using descriptive statistics and qualitative data using thematic analysis. There were 73 completed surveys. CONCLUSIONS: One of the intentions of expanding access to MBS and PBS for patients treated by NPs was to increase patients' access to health care through greater flexibility in the healthcare workforce. The results of this survey confirm that the workforce characteristics of PPNPs provide a potentially untapped resource to meet current primary healthcare demand. IMPLICATIONS FOR PRACTICE: The findings of this study allow us to understand the characteristics of PPNP services, which are significant for workforce planning. The focus of PPNP practice is toward primary health care with PPNPs working predominantly in general practice settings. The largest age group of PPNPs is over 50 years and means a proportion will be retiring in the next 15 years. PMID- 27215579 TI - The hnRNP family: insights into their role in health and disease. AB - Heterogeneous nuclear ribonucleoproteins (hnRNPs) represent a large family of RNA binding proteins (RBPs) that contribute to multiple aspects of nucleic acid metabolism including alternative splicing, mRNA stabilization, and transcriptional and translational regulation. Many hnRNPs share general features, but differ in domain composition and functional properties. This review will discuss the current knowledge about the different hnRNP family members, focusing on their structural and functional divergence. Additionally, we will highlight their involvement in neurodegenerative diseases and cancer, and the potential to develop RNA-based therapies. PMID- 27215581 TI - SLICER: inferring branched, nonlinear cellular trajectories from single cell RNA seq data. AB - Single cell experiments provide an unprecedented opportunity to reconstruct a sequence of changes in a biological process from individual "snapshots" of cells. However, nonlinear gene expression changes, genes unrelated to the process, and the possibility of branching trajectories make this a challenging problem. We develop SLICER (Selective Locally Linear Inference of Cellular Expression Relationships) to address these challenges. SLICER can infer highly nonlinear trajectories, select genes without prior knowledge of the process, and automatically determine the location and number of branches and loops. SLICER recovers the ordering of points along simulated trajectories more accurately than existing methods. We demonstrate the effectiveness of SLICER on previously published data from mouse lung cells and neural stem cells. PMID- 27215580 TI - Febuxostat exerts dose-dependent renoprotection in rats with cisplatin-induced acute renal injury. AB - The aim of the present study was to investigate possible renoprotective effects of febuxostat, a highly potent xanthine oxidase inhibitor, against cisplatin (CIS)-induced acute kidney injury in rats. Male Sprague Dawley rats were randomly assigned into four groups of six rats each, as follows: normal control; CIS, received a single intraperitoneal injection of CIS (7.5 mg/kg); [febuxostat 10 + CIS] and [febuxostat 15 + CIS], received febuxostat (10 and 15 mg/kg/day, respectively, orally) for 14 days, starting 7 days before CIS injection. At the end of experiment, 24-h urine output was collected and serum was separated for biochemical assessments. Kidney tissue homogenate was prepared for determination of oxidative stress-related parameters, nitric oxide (NO), and tumor necrosis factor-alpha (TNF-alpha). Moreover, histological alterations of kidney tissues were evaluated. Serum creatinine, blood urea, and urinary total protein were significantly elevated, while serum albumin and creatinine clearance were significantly reduced, in CIS-intoxicated rats, indicating depressed renal function. CIS administration also elicited renal oxidative stress, evidenced by increased malondialdehyde content and depleted levels of reduced glutathione and superoxide dismutase activity. Moreover, enhancement of renal levels of the pro inflammatory TNF-alpha indicated renal inflammation. CIS-administered rats also showed increased serum lactate dehydrogenase activity and reduced renal NO bioavailability. Febuxostat dose-dependently improved or restored these changes to near-normal (e.g., mean +/- SD of serum creatinine levels in control, CIS, [febuxostat 10 + CIS] and [febuxostat 15 + CIS] groups were 0.78 +/- 0.19, 3.28 +/- 2.0 (P < 0.01 versus control group), 1.03 +/- 0.36 (P < 0.01 versus CIS group), and 0.93 +/- 0.21 (P < 0.01 versus CIS group) mg/dl, respectively, and blood urea levels for the different groups were 36.80 +/- 4.36, 236.10 +/- 89.19 (P < 0.0001 versus control group), 114.50 +/- 78.63 (P < 0.05 versus CIS group), and 60.91 +/- 14.30 (P < 0.001 versus CIS group) mg/dl, respectively). Histological analysis of renal tissues also demonstrated that febuxostat offered a dose-dependent renoprotection. The present study suggests that antioxidant, anti-inflammatory, and cytoprotective mechanisms potentially mediate the renoprotective effects of febuxostat in CIS-administered rats, presenting febuxostat as a promising combinatorial strategy for cancer patients undergoing CIS chemotherapy. PMID- 27215582 TI - Assessment of ventriculo-vascular properties in repaired coarctation using cardiac magnetic resonance-derived aortic, left atrial and left ventricular strain. AB - OBJECTIVES: In patients with repaired coarctation of aorta (CoA), we assessed ventriculo-vascular characteristics using CMR-derived aortic area strain (AAS), left atrial (LA) and left ventricular (LV) longitudinal and circumferential strain (LS, CS). METHODS: Seventy-five subjects including 50 with repaired CoA divided into hypertensive (n = 25), normotensive (n = 25) and 25 controls were studied. AAS was measured at 3 levels: ascending aorta, proximal descending and descending aorta. LA and LV LS were measured using CMR-feature tracking. LA and LV end-diastolic volumes, ejection fraction (EF) and mass were measured. RESULTS: Mean patient age was 19.7 +/- 6.7 and controls 23 +/- 15 (years). All strains (LA, LV, ascending and descending aortic) were lower in CoA subgroups compared to controls except the AAS at diaphragm, which was not different. Comparisons between hypertensive and normotensive CoA showed no differences in LV mass, LV volumetric indices, and LA and LV strain indices; however, ascending AAS was lower in hypertensive subgroup (p = 0.02). Ascending AAS was correlated with LV mass (r = -0.4, p = 0.005), LVEF (r = -0.4, p = 0.004), systolic blood pressure (r = -0.5, p = 0.0001) and LVLS (r = 0.5, p = 0.001). CONCLUSIONS: Ascending AAS correlated with LV mass, EF and LVLS. In hypertensive CoA, ascending AAS was reduced compared to normotensive CoA and controls, indicating vascular remodelling differences influenced by ongoing hypertension. KEY POINTS: * Impaired arterial strain is a measure of increased stiffness in arteries * Ascending aorta strain correlates with left ventricular mass and longitudinal strain * Ascending aorta strain is significantly lower in hypertensive coarctation patients * Hypertension may be a consequence of vascular pathology persisting despite repair. PMID- 27215583 TI - Selection by mating competitiveness improves the performance of Anastrepha ludens males of the genetic sexing strain Tapachula-7. AB - The sexual performance of Anastrepha ludens males of the Tapachula-7 genetic sexing strain, produced via selection based on mating success, was compared with that of males produced without selection in competition with wild males. Mating competition, development time, survival, mass-rearing quality parameters and pheromone production were compared. The results showed that selection based on mating competitiveness significantly improved the sexual performance of offspring. Development time, survival of larvae, pupae and adults, and weights of larvae and pupae increased with each selection cycle. Differences in the relative quantity of the pheromone compounds (Z)-3-nonenol and anastrephin were observed when comparing the parental males with the F4 and wild males. The implications of this colony management method on the sterile insect technique are discussed. PMID- 27215586 TI - Cumulative Muscle Protein Synthesis and Protein Intake Requirements. AB - Muscle protein synthesis (MPS) fluctuates widely over the course of a day and is influenced by many factors. The time course of MPS responses to exercise and the influence of training and nutrition can only be pieced together from several different investigations and methods, many of which create unnatural experimental conditions. Measurements of cumulative MPS, the sum synthesis over an extended period, using deuterium oxide have been shown to accurately reflect muscle responses and may allow investigations of the response to exercise, total protein intake requirements, and interaction with protein timing in free-living experimental conditions; these factors have yet to be carefully integrated. Such studies could include clinical and athletic populations to integrate nutritional and exercise recommendations and help guide their revisions to optimize the skeletal muscle function that is so important to overall health. PMID- 27215588 TI - The transition from evolutionary stability to branching: A catastrophic evolutionary shift. AB - Evolutionary branching-resident-mutant coexistence under disruptive selection-is one of the main contributions of Adaptive Dynamics (AD), the mathematical framework introduced by S.A.H. Geritz, J.A.J. Metz, and coauthors to model the long-term evolution of coevolving multi-species communities. It has been shown to be the basic mechanism for sympatric and parapatric speciation, despite the essential asexual nature of AD. After 20 years from its introduction, we unfold the transition from evolutionary stability (ESS) to branching, along with gradual change in environmental, control, or exploitation parameters. The transition is a catastrophic evolutionary shift, the branching dynamics driving the system to a nonlocal evolutionary attractor that is viable before the transition, but unreachable from the ESS. Weak evolutionary stability hence qualifies as an early warning signal for branching and a testable measure of the community's resilience against biodiversity. We clarify a controversial theoretical question about the smoothness of the mutant invasion fitness at incipient branching. While a supposed nonsmoothness at third order long prevented the analysis of the ESS branching transition, we argue that smoothness is generally expected and derive a local canonical model in terms of the geometry of the invasion fitness before branching. Any generic AD model undergoing the transition qualitatively behaves like our canonical model. PMID- 27215589 TI - Electrocardiographic features of sudden unexpected death in epilepsy. AB - Sudden unexpected death in epilepsy (SUDEP) is the most common cause of epilepsy related mortality. We hypothesized that electrocardiography (ECG) features may distinguish SUDEP cases from living subjects with epilepsy. Using a matched case control design, we compared ECG studies of 12 consecutive cases of SUDEP over 10 years and 22 epilepsy controls matched for age, sex, epilepsy type (focal, generalized, or unknown/mixed type), concomitant antiepileptic, and psychotropic drug classes. Conduction intervals and prevalence of abnormal ventricular conduction diagnosis (QRS >=110 msec), abnormal ventricular conduction pattern (QRS <110 msec, morphology of incomplete right or left bundle branch block or intraventricular conduction delay), early repolarization, and features of inherited cardiac channelopathies were assessed. Abnormal ventricular conduction diagnosis and pattern distinguished SUDEP cases from matched controls. Abnormal ventricular conduction diagnosis was present in two cases and no controls. Abnormal ventricular conduction pattern was more common in cases than controls (58% vs. 18%, p = 0.04). Early repolarization was similarly prevalent in cases and controls, but the overall prevalence exceeded that of published community based cohorts. PMID- 27215591 TI - Clinical Community Psychology: Reflections on the Decades Following Swampscott. AB - The Swampscott report was foundational, but in some ways reflected divisions within community psychology that have continued into the present. Community psychologists trained in the 1970s and, especially, the 1980s confronted a period where the original focus of community mental health began to have less influence in the mental health field due to a variety of public policies, and the growth of third party payments as a significant source of health care funding. Programs that engaged communities and provided a base for prevention interventions were greatly curtailed because of changes in federal legislation and limited opportunities for state and local funding, although prevention interventions found growing interest from research funders. Clinical and community psychologists who trained in this period increasingly looked to a variety of areas outside of mental health. Consequently, the field of community psychology has become more applied and less academic, with increased attention to advocacy, theory, and global perspectives. The sweep of these changes and their implications for the future of the field are discussed here. PMID- 27215590 TI - Classification of patients with low back-related leg pain: a systematic review. AB - BACKGROUND: The identification of clinically relevant subgroups of low back pain (LBP) is considered the number one LBP research priority in primary care. One subgroup of LBP patients are those with back related leg pain. Leg pain frequently accompanies LBP and is associated with increased levels of disability and higher health costs than simple low back pain. Distinguishing between different types of low back-related leg pain (LBLP) is important for clinical management and research applications, but there is currently no clear agreement on how to define and identify LBLP due to nerve root involvement. The aim of this systematic review was to identify, describe and appraise papers that classify or subgroup populations with LBLP, and summarise how leg pain due to nerve root involvement is described and diagnosed in the various systems. METHODS: The search strategy involved nine electronic databases including Medline and Embase, reference lists of eligible studies and relevant reviews. Selected papers were appraised independently by two reviewers using a standardised scoring tool. RESULTS: Of 13,358 initial potential eligible citations, 50 relevant papers were identified that reported on 22 classification systems. Papers were grouped according to purpose and criteria of the classification systems. Five themes emerged: (i) clinical features (ii) pathoanatomy (iii) treatment-based approach (iv) screening tools and prediction rules and (v) pain mechanisms. Three of the twenty two systems focused specifically on LBLP populations. Systems that scored highest following quality appraisal were ones where authors generally included statistical methods to develop their classifications, and supporting work had been published on the systems' validity, reliability and generalisability. There was lack of consistency in how LBLP due to nerve root involvement was described and diagnosed within the systems. CONCLUSION: Numerous classification systems exist that include patients with leg pain, a minority of them focus specifically on distinguishing between different presentations of leg pain. Further work is needed to identify clinically meaningful subgroups of LBLP patients, ideally based on large primary care cohort populations and using recommended methods for classification system development. PMID- 27215587 TI - Sources and Functions of Extracellular Small RNAs in Human Circulation. AB - Various biotypes of endogenous small RNAs (sRNAs) have been detected in human circulation, including microRNAs, transfer RNAs, ribosomal RNA, and yRNA fragments. These extracellular sRNAs (ex-sRNAs) are packaged and secreted by many different cell types. Ex-sRNAs exhibit differences in abundance in several disease states and have, therefore, been proposed for use as effective biomarkers. Furthermore, exosome-borne ex-sRNAs have been reported to elicit physiological responses in acceptor cells. Exogenous ex-sRNAs derived from diet (most prominently from plants) and microorganisms have also been reported in human blood. Essential issues that remain to be conclusively addressed concern the (a) presence and sources of exogenous ex-sRNAs in human bodily fluids, (b) detection and measurement of ex-sRNAs in human circulation, (c) selectivity of ex sRNA export and import, (d) sensitivity and specificity of ex-sRNA delivery to cellular targets, and (e) cell-, tissue-, organ-, and organism-wide impacts of ex sRNA-mediated cell-to-cell communication. We survey the present state of knowledge of most of these issues in this review. PMID- 27215592 TI - Prehospital Medical Planning for the 2015 Philadelphia Papal Visit. AB - In September 2015 Philadelphia hosted the World Meeting of Families, which culminated with a two day visit by Pope Francis. Emergency medical services (EMS) planning for the event was a complex process that involved the cooperation of municipal, state, and federal agencies, as well as many private organizations. Because the visit was designated as a National Security Special Event, Philadelphia had to balance the priorities of the United States Secret Service and other law enforcement agencies to keep the Pope and visitors safe with the medical needs of visitors and the ongoing needs of the city. Planning had to consider the impact of security on EMS operations, the anticipated crowd size and demographics, and how many patient encounters were likely. Other considerations were the weather, the number of additional medical providers and ambulances that would be needed for the event, where they would come from, and how these resources would be best deployed. The event had a regional impact, as the Pope visited several areas of the city and adjacent suburbs over his two day visit. Vehicular traffic and public transportation were heavily affected. Area hospitals increased their staffing in anticipation of higher patient censuses. This made it difficult to find sufficient volunteers in the immediate Philadelphia area to work at medical tents at the event venues. The city's extensive planning efforts, combined with some good luck, overcame these many challenges. The World Meeting of Families and Papal visit were viewed as a success for the attendees and the city. Philadelphia's experience may be beneficial for other cities hosting such events in the future. PMID- 27215593 TI - A new symmetrodont mammal (Trechnotheria: Zhangheotheriidae) from the Early Cretaceous of China and trechnotherian character evolution. AB - We report the discovery of Anebodon luoi, a new genus and species of zhangheotheriid symmetrodont mammal from the Lujiatun site of the Lower Cretaceous Yixian Formation, China. The fossil is represented by an associated partial skull and dentaries with a nearly complete dentition, and with a dental formula of I4/3 C1/1 P5/4 M3/4. This new taxon lacks the high molar count typical of derived symmetrodonts, differing from the well-represented zhangheotheriids Zhangheotherium and Maotherium in having a postcanine dental formula that resembles more primitive tinodontid symmetrodonts on the one hand, and sister taxa to therians such as Peramus on the other. Upper and lower distal premolars are strongly molariform and are captured undergoing replacement, clarifying positional homology among related taxa. We also describe the rostrum and, for the first time in a symmetrodont, much of the orbital mosaic. Importantly, our new taxon occupies a basal position within the Zhangheotheriidae and permits discussion of trechnotherian character evolution, ultimately shedding additional light on the evolution of therians. PMID- 27215594 TI - The "Pillow" Technique for Thumb Carpometacarpal Joint Arthritis: Cohort Study With 10- to 15-Year Follow-Up. AB - PURPOSE: Arthritis of the carpometacarpal joint of the thumb is common, and there are many studies regarding its treatment. We investigated the long-term outcome of interposition arthroplasty with a fascia lata allograft (pillow technique), without ligament reconstruction, to treat thumb carpometacarpal arthritis. The technique consisted of complete trapeziectomy, use of alloplastic tensor fascia lata, and K-wire immobilization for 5 weeks. METHODS: The outcomes of 31 thumbs in 24 female patients were measured at a mean follow-up of 12.5 years (range, 10 15 years). RESULTS: Grip strength, key pinch, pulp-to-pulp pinch, tripod pinch, and range of motion were all improved. The Disabilities of the Arm, Shoulder, and Hand median score, which was only measured postoperatively, was an average of 5 (range, 0-52.6). No extrusion of the graft material was noted, and no revisions were performed. CONCLUSIONS: Our results indicate that a fascia lata allograft can be used as an interposition material in thumb carpometacarpal arthroplasty. This technique provides pain relief and satisfactory function at an average of 12.5 years after surgery. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 27215595 TI - The Pharmacological Treatment of Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: Inhaled corticosteroids (ICS) are markedly less effective against chronic obstructive pulmonary disease (COPD) than against asthma, and also have worse side effects. Whether ICS should be used to treat COPD is currently a matter of debate. METHODS: This review is based on pertinent articles retrieved by a selective search in PubMed and the Excerpta Medica Database (EMBASE) carried out in May 2015. We analyzed clinical trials of ICS for the treatment of COPD with a duration of at least one year, along with meta-analyses and COPD guidelines. RESULTS: ICS lower the frequency and severity of COPD exacerbations in comparison to monotherapy with a long-acting beta2-agonist, but have no effect on mortality. Compared to placebo, ICS monotherapy lessens the decline of forced expiratory volume in one second (FEV1) over one year by merely 5.80 mL (statistically insignificant; 95% confidence interval: [-0.28; 11.88]) and only marginally improve quality of life. ICS use in patients with COPD increases the risk of pneumonia. A combination of ICS with a long-acting bronchodilator improves FEV1 by 133 mL [105; 161] and lowers the frequency of severe exacerbations by 39% . The frequency of exacerbations is lowered mainly in patients who have many exacerbations; thus, ICS treatment is suitable only for patients with grade III or IV COPD. CONCLUSION: ICS monotherapy has no clinically useful effect on pulmonary function in COPD. The main form of drug treatment for COPD is with broncho - dilators, either alone or in combination with ICS. ICS can be given to patients with grade III or IV COPD to make exacerbations less frequent. Patients with an asthma-COPD overlap syndrome (ACOS) can benefit from ICS treatment. PMID- 27215596 TI - Clonal Hematopoiesis of Indeterminate Potential. AB - BACKGROUND: Patients with cytopenia are increasingly undergoing molecular genetic tests of periperal blood or bone marrow for diagnostic purposes. These tests can detect genetic mutations that do not have any morphological correlate in hematologic neoplasia such as myelo - dysplastic syndrome (MDS). A new entity was recently defined to lessen the risk of incorrect diagnoses of MDS. This new entity is a potential precursor of myeloid diseases, analogously to monoclonal gammopathy of undetermined significance as a potential precursor of multiple myeloma. METHODS: This review is based on pertinent articles retrieved by a selective search in PubMed employing the terms "clonal hematopoiesis," "acute myeloid leukemia," and "myelodysplastic syndrome." RESULTS: Clonal hematopoiesis of indeterminate potential (CHIP) is a new entity in which somatic mutations are found in cells of the blood or bone marrow, but no other criteria for hematologic neoplasia are met. Its prevalence rises with age and is roughly 10% among persons aged 70 to 80. It is estimated that, in Germany, about 2.75 million people are affected. The most common mutation is on the DNMT3A gene, followed by TET2 and ASXL1. The rate of transformation to a hematological neoplasia is 0.5-1% per year, and thus about 13 times higher than the incidence of such neoplasias in general. If CHIP is discovered incidentally in a patient with a normal blood count, a complete blood count with differential should be repeated three months later and then at annual intervals. CONCLUSION: CHIP must be included in the differential diagnosis of peripheral blood cytopenia. This new entity can help us understand the clinical significance of clonal hematopoiesis. PMID- 27215597 TI - The Prevalence of Visual Impairment in Retirement Home Residents. AB - BACKGROUND: Elderly persons often have eye diseases causing either reversible or irreversible visual loss. The prevalence of such problems among retirement home residents is unknown. METHODS: 203 residents of retirement homes in and around Wurzburg, Germany, were examined. Clinical histories were taken, including information on prior ophthalmological care, and ophthalmological examinations were performed, including visual acuity, slit-lamp examination of the anterior segment of the eye, fundoscopy (with optical coherence tomography), and measurement of the intraocular pressure. RESULTS: 119 women and 84 men aged 55 to 101 were examined in 6 retirement homes. 44 (21.7% ) had ophthalmological findings that required acute treatment. The most common diagnoses in the anterior segment of the eye were keratoconjunctivitis sicca (160; 78.8% ), cataract (88; 43.3% ), secondary cataract (15; 7.4% ), glaucoma (33; 12.3% ), and eyelid malpositions (25; 12.3% ). In the fundus, 45 residents (22.2% ) had dry age related macular degeneration (AMD), 7 (3.4% ) had fresh wet AMD, and 7 (3.4% ) had epiretinal gliosis. 81 (39.9% ) could give no information about earlier ophthalmologic examinations, and 42 (20.7% ) had not been to an ophthalmologist for at least 5 years. After correction of refractive errors, their mean decimal visual acuity improved from 0.25 to 0.33. CONCLUSION: The retirement home residents that we examined were not receiving adequate ophthalmological care; in particular, some of them had irreversible eye diseases that were not being treated. The ophthalmological care of retirement home residents needs to be improved through better collaboration of all types of personnel taking care of them. PMID- 27215598 TI - On Pathogenesis. PMID- 27215599 TI - In Reply. PMID- 27215600 TI - Erratum to: Use of Modeling and Simulation Tools for Understanding the Impact of Formulation on the Absorption of a Low Solubility Compound: Ciprofloxacin. PMID- 27215601 TI - A Novel Physiology-Based Mathematical Model to Estimate Red Blood Cell Lifespan in Different Human Age Groups. AB - Direct measurement of red blood cell (RBC) survival in humans has improved from the original accurate but limited differential agglutination technique to the current reliable, safe, and accurate biotin method. Despite this, all of these methods are time consuming and require blood sampling over several months to determine the RBC lifespan. For situations in which RBC survival information must be obtained quickly, these methods are not suitable. With the exception of adults and infants, RBC survival has not been extensively investigated in other age groups. To address this need, we developed a novel, physiology-based mathematical model that quickly estimates RBC lifespan in healthy individuals at any age. The model is based on the assumption that the total number of RBC recirculations during the lifespan of each RBC (denoted by N max) is relatively constant for all age groups. The model was initially validated using the data from our prior infant and adult biotin-labeled red blood cell studies and then extended to the other age groups. The model generated the following estimated RBC lifespans in 2 year-old, 5-year-old, 8-year-old, and 10-year-old children: 62, 74, 82, and 86 days, respectively. We speculate that this model has useful clinical applications. For example, HbA1c testing is not reliable in identifying children with diabetes because HbA1c is directly affected by RBC lifespan. Because our model can estimate RBC lifespan in children at any age, corrections to HbA1c values based on the model-generated RBC lifespan could improve diabetes diagnosis as well as therapy in children. PMID- 27215602 TI - Isolation and detection of microRNA from the egg of chickens. AB - BACKGROUND: The egg is a vital part of the chicken developmental process and an important protein source for humans. Despite the chicken egg being a subject of intense research little attention has been given to the role of microRNAs within the egg. FINDINGS: We report a method for the reproducible and reliable isolation of miRNA from the albumen and yolk of chicken eggs. We also report the detection via real-time PCR of a number of miRNAs from both of these biological fluids. CONCLUSIONS: These findings provide an interesting look into the chicken egg and raise questions as to the role that miRNAs maybe playing in the chicken egg. This method of detecting miRNAs in chicken eggs will allow researchers to investigate the presence of an additional level of epigenetic programming in chick development previously unknown and also how this impacts the nutritional value of eggs for human consumption. PMID- 27215603 TI - Comparison of the time-to-indexing in PubMed between biomedical journals according to impact factor, discipline, and focus. AB - BACKGROUND: Practicing evidence-based medicine requires health care professionals to efficiently retrieve relevant and current literature. OBJECTIVE: The purpose of this study was to compare the time interval between PubMed entry and indexing with Medical Subject Headings (MeSH) between biomedical journals with varying impact factors, focus areas, and health care discipline representation. METHODS: This was a cross-sectional study of articles entered into PubMed database between January 1 and December 31, 2012. The primary endpoint was the number of days between PubMed entry and indexing with MeSH terms. RESULTS: A total of 7906 articles were reviewed across 18 journals. In the first comparison, the time-to indexing was 177 +/- 100 days, 111 +/- 69 days, and 23 +/- 40 days for articles published in journals with impact factors of 2.0-2.5, 4.5-6.5, and >25, respectively (P <= 0.001). In the second comparison, the time-to-indexing was 111 +/- 69 days for general medicine versus 170 +/- 74 days for specialty journals (P <= 0.001). In the third comparison, the overall time-to-indexing was 177 +/- 100 days, 234 +/- 107 days, and 163 +/- 58 days for medicine, nursing, and pharmacy journals, respectively (P <= 0.001). CONCLUSIONS: Study results identified a significant delay between entry of articles into the PubMed database and time-to indexing with MeSH terms across journals of varying impact factor, discipline, and focus. Results suggest that there may be factors that influence the priority by which articles are indexed with MeSH terms. Future research should focus on determining those journal characteristics and any impact of this delay on clinical practice. PMID- 27215604 TI - Spectral domain optical coherence tomography and B-scan ultrasonography in the evaluation of retinal tears in acute, incomplete posterior vitreous detachment. AB - BACKGROUND: The purpose of this study was to evaluate the extension and traction effects of posterior vitreous detachment (PVD) complicated with retinal tears using spectral domain optical coherence tomography (OCT) and B-scan ultrasonography. METHODS: Complete ophthalmological examination, B-scan ultrasonography and spectral domain OCT were performed in patients with acute PVD and retinal tears. Vitreous detachment was classified as complete or incomplete, based on extent of posterior pole or peripheral vitreous detachment. Retinal tear location and persistent traction on the retinal flap was evaluated with B-scan ultrasonography and OCT. Categorical data were evaluated with Fisher's exact test. Statistical significance was considered as P < 0.05. RESULTS: Twenty-six eyes of 25 patients were assessed. Four eyes (15 %) presented complete PVD with detachment at the posterior pole and periphery. 22 eyes (85 %) presented incomplete PVD with detachment in the periphery. Twenty eyes presented retinal tears in the superior quadrants with respect to only 6 in the inferior quadrants (p = 0.006). There was a higher incidence of retinal tears in the pre with respect to post-equatorial areas (19 vs 7 eyes, p = 0.019). B-scan ultrasonography and OCT revealed persistent traction on the retinal tear flap in 19 and 15 eyes, respectively. CONCLUSIONS: In acute PVD, retinal tears are prevalently associated with peripheral vitreous detachment. The impact of complete or incomplete PVD can be of clinical value when evaluating patients with retinal tears. PMID- 27215605 TI - Long noncoding NONRATT021972 siRNA normalized abnormal sympathetic activity mediated by the upregulation of P2X7 receptor in superior cervical ganglia after myocardial ischemia. AB - Previous studies showed that the upregulation of the P2X7 receptor in cervical sympathetic ganglia was involved in myocardial ischemic (MI) injury. The dysregulated expression of long noncoding RNAs (lncRNAs) participates in the onset and progression of many pathological conditions. The aim of this study was to investigate the effects of a small interfering RNA (siRNA) against the NONRATT021972 lncRNA on the abnormal changes of cardiac function mediated by the up-regulation of the P2X7 receptor in the superior cervical ganglia (SCG) after myocardial ischemia. When the MI rats were treated with NONRATT021972 siRNA, their increased systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), low-frequency (LF) power, and LF/HF ratio were reduced to normal levels. However, the decreased high-frequency (HF) power was increased. GAP43 and tyrosine hydroxylase (TH) are markers of nerve sprouting and sympathetic nerve fibers, respectively. We found that the TH/GAP43 value was significantly increased in the MI group. However, it was reduced after the MI rats were treated with NONRATT021972 siRNA. The serum norepinephrine (NE) and epinephrine (EPI) concentrations were decreased in the MI rats that were treated with NONRATT021972 siRNA. Meanwhile, the increased P2X7 mRNA and protein levels and the increased p ERK1/2 expression in the SCG were also reduced. NONRATT021972 siRNA treatment inhibited the P2X7 agonist BzATP-activated currents in HEK293 cells transfected with pEGFP-P2X7. Our findings suggest that NONRATT021972 siRNA could decrease the upregulation of the P2X7 receptor and improve the abnormal changes in cardiac function after myocardial ischemia. PMID- 27215606 TI - A role for septin 2 in Drp1-mediated mitochondrial fission. AB - Mitochondria are essential eukaryotic organelles often forming intricate networks. The overall network morphology is determined by mitochondrial fusion and fission. Among the multiple mechanisms that appear to regulate mitochondrial fission, the ER and actin have recently been shown to play an important role by mediating mitochondrial constriction and promoting the action of a key fission factor, the dynamin-like protein Drp1. Here, we report that the cytoskeletal component septin 2 is involved in Drp1-dependent mitochondrial fission in mammalian cells. Septin 2 localizes to a subset of mitochondrial constrictions and directly binds Drp1, as shown by immunoprecipitation of the endogenous proteins and by pulldown assays with recombinant proteins. Depletion of septin 2 reduces Drp1 recruitment to mitochondria and results in hyperfused mitochondria and delayed FCCP-induced fission. Strikingly, septin depletion also affects mitochondrial morphology in Caenorhabditis elegans, strongly suggesting that the role of septins in mitochondrial dynamics is evolutionarily conserved. PMID- 27215607 TI - Identification of Maturation-Specific Proteins by Single-Cell Proteomics of Human Oocytes. AB - Oocytes undergo a range of complex processes via oogenesis, maturation, fertilization, and early embryonic development, eventually giving rise to a fully functioning organism. To understand proteome composition and diversity during maturation of human oocytes, here we have addressed crucial aspects of oocyte collection and proteome analysis, resulting in the first proteome and secretome maps of human oocytes. Starting from 100 oocytes collected via a novel serum-free hanging drop culture system, we identified 2,154 proteins, whose function indicate that oocytes are largely resting cells with a proteome that is tailored for homeostasis, cellular attachment, and interaction with its environment via secretory factors. In addition, we have identified 158 oocyte-enriched proteins (such as ECAT1, PIWIL3, NLRP7)(1) not observed in high-coverage proteomics studies of other human cell lines or tissues. Exploiting SP3, a novel technology for proteomic sample preparation using magnetic beads, we scaled down proteome analysis to single cells. Despite the low protein content of only ~100 ng per cell, we consistently identified ~450 proteins from individual oocytes. When comparing individual oocytes at the germinal vesicle (GV) and metaphase II (MII) stage, we found that the Tudor and KH domain-containing protein (TDRKH) is preferentially expressed in immature oocytes, while Wee2, PCNA, and DNMT1 were enriched in mature cells, collectively indicating that maintenance of genome integrity is crucial during oocyte maturation. This study demonstrates that an innovative proteomics workflow facilitates analysis of single human oocytes to investigate human oocyte biology and preimplantation development. The approach presented here paves the way for quantitative proteomics in other quantity limited tissues and cell types. Data associated with this study are available via ProteomeXchange with identifier PXD004142. PMID- 27215608 TI - Type-Specific Identification of Genital Human Papillomavirus Infection in Women with Cytological Abnormality. AB - OBJECTIVES: To estimate the frequency of human papillomavirus (HPV) infection and the genotype distribution of HPV among women with a Pap smear showing atypical squamous cells of undetermined significance (ASC-US) attending the Program for the Detection and Control of Cervical Cancer in Bogota, Colombia. STUDY DESIGN: Cervical samples from 200 women with an ASC-US Pap smear were analyzed for the presence of HPV DNA and genotype distribution using a commercial molecular technique (Linear Array(r); Roche Molecular Systems, USA). RESULTS: HPV infection was found in 140 women (70%). High-risk HPV types were present in 46.4% of the samples; 16.4% showed a low-risk HPV type, and 37.1% showed both. Of the positive samples, 42.9% were infected with a single viral genotype, whereas 57.1% exhibited multiple HPV infections. The most common HPV genotypes were HPV 16, 53, and 52 with a prevalence of 26.4, 16.4, and 13.6%, respectively. CONCLUSION: The epidemiological characterization of HPV infections described in this study might guide actions for epidemiological surveillance to strengthen the program in Bogota and to develop appropriate HPV vaccination programs. PMID- 27215609 TI - A Review of Techniques for Closure of the Pancreatic Remnant following Distal Pancreatectomy. AB - The prevalence of pancreatic diseases needing surgical intervention is continuously rising. Distal pancreatectomy is performed in the case of pathologies affecting the left side of the pancreas. More and more sophisticated surgical techniques have appeared and an increasing number of published articles discuss the possibilities for closure of the pancreatic remnant. However, the optimum solution is still under debate, as none of the examined techniques have been proven superior in reducing the incidence of the most common surgical complication, the formation of a postoperative pancreatic fistula (PF). Fistula rates have been stationary at 20-30% in the past decades despite the apparent advancement of medicine. This review presents a survey of the relevant articles examining different closure strategies and risk factors to reduce fistula formation rate. International medical publication database search and assessment was carried out to include the findings of studies investigating the efficacy of pancreatic remnant closure techniques to gain a clearer view on the complexity of pancreas fistulas. Emphasis is on indications for surgery, risk factors for postoperative fistula formation and strategies to seal the pancreatic remnant to avoid leakage. Findings suggest that careful patient selection, meticulous surgical techniques are equally important to reduce fistula rates. Ideal closure of the pancreatic remnant is still to be developed, as none of the widespread techniques (hand-sewn suture or staple closure) proved to be statistically significantly superior. Additional closure and covering methods (seromuscular patch, falciform ligament patch, pancreatico-enteric anastomosis, reinforced staplers, fibrin glue etc.) can have profitable effect but strong evidences are yet to come due to small case numbers. The recent introduction of standardized classification of PFs and future prospective randomized trials are more likely to be susceptible to determine if any of the standard or experimental closure techniques is more beneficial than the others. PMID- 27215610 TI - An inhibitor of the Keap1-Nrf2 protein-protein interaction protects NCM460 colonic cells and alleviates experimental colitis. AB - Ulcerative colitis (UC) is a chronic relapsing-remitting form of inflammatory bowel disease (IBD) that increases the risk of colorectal cancer, the third most common malignancy in humans. Oxidative stress is a risk factor for the development of UC. The Keap1-Nrf2-ARE pathway is one of the most important defensive mechanisms against oxidative and/or electrophilic stresses. In this study, we identified CPUY192018 as a potent small-molecule inhibitor of the Keap1 Nrf2 PPI, investigated the cyto-protective effects of CPUY192018 on the NCM460 colonic cells and evaluated whether treatment with the inhibitor of the Keap1 Nrf2 PPI exerts protection on an established experimental model of UC induced by dextran sodium sulfate (DSS). Our study clearly demonstrated that CPUY192018 had a cytoprotective effect against DSS in both NCM460 cells and mouse colon via the activation of Nrf2 signaling. These results suggested that activation of Nrf2 by directly inhibiting the Keap1-Nrf2 PPI may be beneficial as a treatment for UC. PMID- 27215611 TI - Independent validation of the prognostic capacity of the ISUP prostate cancer grade grouping system for radiation treated patients with long-term follow-up. AB - BACKGROUND: There has been a recent proposal to change the grading system of prostate cancer into a five-tier grade grouping system. The prognostic impact of this has been demonstrated in regards only to biochemical recurrence-free survival (bRFS) with short follow-up (3 years). METHODS: Between 1990 and 2013, 847 consecutive men were treated with definitive external beam radiation therapy at a single academic center. To validate the new grade grouping system, bRFS, distant metastases-free survival (DMFS) and prostate cancer-specific survival (PCSS) were calculated. Adjusted Kaplan-Meier and multivariable Cox regression analyses were performed to assess the independent impact of the new grade grouping system. Discriminatory analyses were performed to compare the commonly used three-tier Gleason score system (6, 7 and 8-10) to the new system. RESULTS: The median follow-up of our cohort was 88 months. The 5-grade groups independently validated differing risks of bRFS (group 1 as reference; adjusted hazard ratio (aHR) 1.35, 2.16, 1.79 and 3.84 for groups 2-5, respectively). Furthermore, a clear stratification was demonstrated for DMFS (aHR 2.03, 3.18, 3.62 and 13.77 for groups 2-5, respectively) and PCSS (aHR 3.00, 5.32, 6.02 and 39.02 for groups 2-5, respectively). The 5-grade group system had improved prognostic discrimination for all end points compared with the commonly used three-tiered system (that is, Gleason score 6, 7 and 8-10). CONCLUSIONS: In a large independent radiotherapy cohort with long-term follow-up, we have validated the bRFS benefit of the proposed five-tier grade grouping system. Furthermore, we have demonstrated that the system is highly prognostic for DMFS and PCSS. Grade group 5 had markedly worse outcomes for all end points, and future work is necessary to improve outcomes in these patients. PMID- 27215612 TI - Attitudes to incorporating genomic risk assessments into population screening programs: the importance of purpose, context and deliberation. AB - BACKGROUND: The use of an overall risk assessment based on genomic information is consistent with precision medicine. Despite the enthusiasm, there is a need for public engagement on the appropriate use of such emerging technologies in order to frame meaningful evaluations of utility, including the practical implementation and acceptability issues that might emerge. Doing so requires the involvement of the end users of these services, including patients, and sections of the public who are the target group for population based screening. In the present study we sought to explore public attitudes to the potential integration of personal genomic profiling within existing population screening programs; and to explore the evolution of these attitudes as part of a deliberative process. METHODS: We conducted a mixed methods study presented in the format of a deliberative workshop. Participants were drawn from communities in Ottawa, Ontario (ON) and St John's, Newfoundland and Labrador (NL), Canada. Individuals were approached to take part in a workshop on the incorporation of genomic risk profiling for either colorectal cancer screening (CRC), or newborn screening for type 1 diabetes mellitus (T1DM). RESULTS: A total of N = 148 (N = 65 ON, N = 83 NL) participants provided data for analysis. Participants in both groups were supportive of public funding for genomic risk profiling, although participants in the T1DM groups expressed more guarded positive attitudes than participants in the CRC groups. These views were stable throughout the workshop (CRC, p = 0.15, T1DM, p =0.39). Participants were less positive about individual testing, with a significant decrease in support over the course of the workshop (CRC p = 0.02, T1DM, p = 0.003). Common concerns related to access to test results by third parties. CONCLUSIONS: The findings of this study suggest that members of the target populations for potential genomic profiling tests (designed for screening or risk prediction purposes) can engage in meaningful deliberation about their general acceptability and personal utility. Evaluations of whether a test would be personally useful may depend on the experience of the participants in personal health decision making, the purpose of the test, and the availability of interventions to reduce disease risk. PMID- 27215614 TI - Basic psychological needs and neurophysiological responsiveness to decisional conflict: an event-related potential study of integrative self processes. AB - Fulfillment of the basic psychological needs for competence, relatedness, and autonomy is believed to facilitate people's integrative tendencies to process psychological conflicts and develop a coherent sense of self. The present study therefore used event-related potentials (ERPs) to examine the relation between need fulfillment and the amplitude of conflict negativity (CN), a neurophysiological measure of conflict during personal decision making. Participants completed a decision-making task in which they made a series of forced choices according to their personal preferences. Three types of decision making situations were created on the basis of participants' unique preference ratings, which were obtained prior to ERP recording: low-conflict situations (choosing between an attractive and an unattractive option), high-conflict approach-approach situations (choosing between two similarly attractive options), and high-conflict avoidance-avoidance situations (choosing between two similarly unattractive options). As expected, CN amplitudes were larger in high- relative to low-conflict situations, and source localization analyses suggested that the anterior cingulate cortex was the generating structure of the CN. Most importantly, people reporting higher need fulfillment exhibited larger CN amplitudes in avoidance-avoidance situations relative to low-conflict situations; to a lesser extent, they also exhibited larger CN amplitudes in approach-approach situations relative to low-conflict situations. By contrast, people reporting lower need fulfillment exhibited CN amplitudes that poorly discriminated the three decision situations. These results suggest that need fulfillment may promote self-coherent functioning by increasing people's receptivity to and processing of events that challenge their abilities to make efficient, self congruent choices. PMID- 27215615 TI - Increasing access to eye care ... there's an app for that. Peek: smartphone technology for eye health. PMID- 27215616 TI - Using Mendelian randomization to investigate a possible causal relationship between adiposity and increased bone mineral density at different skeletal sites in children. AB - BACKGROUND: Lean mass is positively associated with bone mineral density (BMD). However, the relationship between adiposity and BMD is more controversial. In particular, it is unclear if the observational association between the two reflects a causal effect of fat mass on BMD. Previous Mendelian randomization (MR) studies using variants in the FTO and MC4R genes as genetic instruments for adiposity have suggested that fat mass does indeed causally influence BMD. However, it is possible that these genetic variants pleiotropically influence lean mass and affect BMD through pathways independent of adiposity, invalidating one of the core assumptions of MR and complicating interpretation of the analysis. METHODS: To investigate whether adiposity causally affects BMD, we investigated the relationship between fat mass and BMD at the skull (SK), upper limbs (UL) and lower limbs (LL), spine (SP) and pelvis (PE), using 32 body mass index (BMI)-associated SNPs, including a variant near ADCY3 that was strongly associated with fat but not lean mass in our sample. Dual-energy X-ray absorptiometry (DXA) scans and genetic data were available for 5221 subjects (mean age 9.9 years) from the Avon Longitudinal Study of Parents and Children. We performed a series of MR analyses involving single BMI-associated SNPs and allelic scores of these SNPs. We used new extensions of the MR method including MR Egger regression and multivariable MR, which are more robust to possible confounding effects due to horizontal pleiotropy and, in the case of multivariable MR, specifically account for the effect of lean mass in the analysis. Bidirectional Mendelian randomization analysis was also performed to examine whether BMD causally affected BMI and adiposity. RESULTS: Observationally, fat mass was strongly positively related to BMD at all sites, but more weakly at the skull. Instrumental variables (IV) analyses using an allelic score of BMI SNPs suggested that fat mass was causally related to LL-BMD, UL-BMD, SP-BMD and PE-BMD but not SK-BMD. Multivariable MR, Egger regression and IV analyses involving the ADCY3 variant suggested a positive causal effect of adiposity on all sites except the skull, and that an effect was present even after taking lean mass into account. Finally, IV analyses using BMD allelic scores showed no evidence of reverse causality between BMD and fat mass. CONCLUSIONS: Our results suggest that adiposity is causally related to increased BMD at all sites except the skull, perhaps reflecting positive effects of loading on bone formation at weighted but not unweighted sites. In contrast, we found no evidence for BMD causally affecting BMI or measures of adiposity. Our results illustrate how MR can be used profitably to investigate clinical questions relevant to osteoporosis. PMID- 27215617 TI - Maternal underweight and obesity and risk of orofacial clefts in a large international consortium of population-based studies. AB - Background: Evidence on association of maternal pre-pregnancy weight with risk of orofacial clefts is inconsistent. Methods: Six large case-control studies of orofacial clefts from Northern Europe and the USA were included in analyses pooling individual-level data. Cases included 4943 mothers of children with orofacial clefts (cleft lip only: 1135, cleft palate with cleft lip: 2081, cleft palate only: 1727) and controls included 10 592 mothers of unaffected children. Association of orofacial cleft risk with pre-pregnancy maternal weight classified by level of body mass index (BMI, kg/m 2 ) was evaluated using logistic regression adjusting for multiple covariates. Results: Cleft palate, both alone and with cleft lip (CP+/-CL), was associated with maternal class II+ pre pregnancy obesity (>= 35)compared with normal weight [adjusted odds ratio (aOR) = 1.36; 95% confidence interval (CI) = 1.16, 1.58]. CP+/-CL was marginally associated with maternal underweight (aOR = 1.16; 95% CI = 0.98, 1.36). Cleft lip alone was not associated with BMI. Conclusions: In this largest population-based study to date, we found an increased risk of cleft palate, with or without cleft lip, in class II+ obese mothers compared with normal-weight mothers; underweight mothers may also have an increased risk, but this requires further study. These results also suggest that extremes of weight may have a specific effect on palatal development. PMID- 27215619 TI - Effects of Transcranial Magnetic Stimulation on Body Perception: No Evidence for Specificity of the Right Temporo-Parietal Junction. AB - Previous data suggest that the right temporo-parietal junction (rTPJ) may have a specific role in abnormal body perception (ABP), including out-of-body experience. We tested this hypothesis with inhibitory (1 Hz) and excitatory (15 Hz) repetitive transcranial magnetic stimulation (rTMS) of the rTPJ and a control site (CS, 5 cm posterior to the rTPJ along the lateral sulcus direction in Brodmann area 19R) in 35 healthy adults. ABP frequency was higher with 1 Hz than with 15 Hz rTMS but unaffected by the rTMS site (rTPJ/CS). Response to an own body transformation task were delayed with 1 Hz compared to 15 Hz rTMS but also unaffected by rTMS site. ABP from rTMS at both sites induced electroencephalographic power decrease in all frequencies at left anterior and central cortical sites. Our data suggest that inhibitory rTMS can lead to ABP. However, the rTPJ may not play a specific role in this process. PMID- 27215618 TI - Nitric oxide in paediatric respiratory disorders: novel interventions to address associated vascular phenomena? AB - Nitric oxide (NO) has a significant role in modulating the respiratory system and is being exploited therapeutically. Neonatal respiratory failure can affect around 2% of all live births and is responsible for over one third of all neonatal mortality. Current treatment method with inhaled NO (iNO) has demonstrated great benefits to patients with persistent pulmonary hypertension, bronchopulmonary dysplasia and neonatal respiratory distress syndrome. However, it is not without its drawbacks, which include the need for patients to be attached to mechanical ventilators. Notably, there is also a lack of identification of subgroups amongst abovementioned patients, and homogeneity in powered studies associated with iNO, which is one of the limitations. There are significant developments in drug delivery methods and there is a need to look at alternative or supplementary methods of NO delivery that could reduce current concerns. The addition of NO-independent activators and stimulators, or drugs such as prostaglandins to work in synergy with NO donors might be beneficial. It is of interest to consider such delivery methods within the respiratory system, where controlled release of NO can be introduced whilst minimizing the production of harmful byproducts. This article reviews current therapeutic application of iNO and the state-of-the-art technology methods for sustained delivery of NO that may be adapted and developed to address respiratory disorders. We envisage this perspective would prompt active investigation of such systems for their potential clinical benefit. PMID- 27215620 TI - Molecular analysis of Crimean-Congo hemorrhagic fever virus and Rickettsia in Hyalomma marginatum ticks removed from patients (Spain) and birds (Spain and Morocco), 2009-2015. AB - Crimean-Congo hemorrhagic fever virus (CCHFV) was detected in Spain in 2010. The presence of CCHFV in Hyalomma marginatum ticks from migratory birds passing through Morocco during the spring migration strengthened the hypothesis of the arrival of infected ticks transported by birds to the Iberian Peninsula. Furthermore, Hyalomma species are vectors of bacterial infections such as spotted fever rickettsioses. CCHFV and Rickettsia were screened in Hyalomma ticks from Spain attached to patients (n=12) and birds (n=149). In addition, Rickettsia was investigated in 52 Hyalomma ticks from Morocco (previously reported as CCHFV infected). No sample collected in Spain showed an infection with CCHFV. Two ticks removed from patients (16.7%), as well as 47 (31.5%) and 4 (7.7%) from birds, collected in Spain and Morocco respectively, were infected with Rickettsia aeschlimannii. Rickettsia sibirica subsp. mongolitimonae was also found in 2 ticks from birds collected in Spain (1.3%). The risk of CCHFV-infected ticks attached to migratory birds to reach the North of Spain is low. This study corroborates the presence of R. aeschlimannii in Spain and Morocco, and supports that H. marginatum can be a potential vector of R. sibirica subsp. mongolitimonae in the Iberian Peninsula. PMID- 27215621 TI - Revised and extended norms for a picture naming test sensitive to category dissociations. AB - This study presents revised and extended norms for a picture naming test [Laiacona et al. (Arch Neurol Psicol Psichiatr 54:209-248, 1993)], based on 80 Snodgrass and Vanderwart (J Exp Psychol Human Learn Mem 6:174-215, 1980) pictures, devised to detect a categorical dissociation in the naming of items between biological and man-made categories. This survey is based on data from 215 healthy Italian participants. Since males are more frequently reported to have a disproportionate impairment of biological categories, norms have also been separately calculated for males and females and for the two categories of man made objects and biological entities. Besides providing new normative values based on the Equivalent Scores approach, this study reappraises the interaction between categorical dissociations and sex in the normal population, and discusses some methodological aspects concerning the use of statistical norms. PMID- 27215622 TI - Upregulation of miR-183 expression and its clinical significance in human brain glioma. AB - Glioma is the most common type of primary malignant tumor in the central nervous system (CNS) with a high incidence and a high mortality rate, as well as an extremely low 5-year survival rate. As a class of small non-coding RNAs, microRNAs (miRNAs) may be closely involved in carcinogenesis and might also be connected with glioma diagnosis and prognosis. In this study, we aimed at investigating the expression level of microRNA-183 (miR-183) in 105 cases of glioma tissues of four World Health Organization (WHO) grades and 10 cases of normal brain tissues and its potential predictive and prognostic values in glioma. We found that the expression levels of miR-183 were significantly higher in glioma tissues than that in normal brain tissues, and also higher in high grade gliomas (WHO grade III and IV) compared with low-grade gliomas (WHO grade I and II). The miR-183 expression level was classified as low or high according to the median value. High expression of miR-183 was found to significantly correlate with larger tumor size, higher WHO grade, and worse Karnofsky performance score (KPS). Kaplan-Meier survival analysis showed that patients with high miR-183 expression had worse overall survival (OS) and progression-free survival (PFS) than patients with low miR-183 expression. Moreover, univariate and multivariate analyses indicated that miR-183 expression level was an independent prognostic parameter of a patient's OS and PFS. In conclusion, our study indicated that miR 183 was upregulated in glioma, and that it may be used as a potential biomarker of poor prognosis in patients with glioma. PMID- 27215623 TI - Influence of four polymorphisms in ABCA1 and PTGS2 genes on risk of Alzheimer's disease: a meta-analysis. AB - We preformed this meta-analysis to investigate the influence of ABCA1 (ATP binding cassette sub-family A member 1) rs2422493 (C-477T), rs1800977 (C-14T), rs2066718 (V771M), and PTGS2 (Prostaglandin-endoperoxide synthase 2) rs20417 (G 765C) polymorphisms on the risk of Alzheimer's disease (AD). Seventeen eligible case-control studies were acquired from PubMed, Embase, Alzgene, Chinese National Knowledge Infrastructure and Wanfang databases. The pooled odds ratios (ORs) with 95 % confidence intervals (95 % CI) were calculated to evaluate the association under five genetic models. Combined data indicated that ABCA1 rs2422493 polymorphism was statistically significant associated with increasing AD risk in three genetic models (allelic T vs C: OR = 1.12, 95 % CI: 1.01-1.24; homozygous TT vs CC: OR = 1.26, 95 % CI: 1.03-1.55; and recessive TT vs TC + CC: OR = 1.33, 95 % CI: 1.12-1.58) while no association was found between two other ABCA1 polymorphisms and AD susceptibility. Nevertheless, a further risk-stratification analysis showed that ApoE-epsilon4 carriers with any ABCA1 polymorphism suffered a much higher probability to be AD patients. Meanwhile, PTGS2 rs20417 polymorphism was linked to decreasing AD risk with a P < 0.0001 in five genetic models (e.g., allelic C vs G: OR = 0.59, 95 % CI: 0.50-0.70; homozygous CC vs GG: OR = 0.31, 95 % CI: 0.18-0.52; and heterozygous CG vs GG: OR = 0.64, 95 % CI: 0.52-0.78). In summary, our meta-analysis results showed that ABCA1 rs2422493 polymorphism was a risk factor for AD while PTGS2 rs20417 variant showed a protective effect on AD risk. In addition, ABCA1 rs2066718 and rs1800977 polymorphisms might not contribute to AD susceptibility in general population, but they should play a role on AD development when interacted with ApoE-epsilon4. PMID- 27215624 TI - [Food Allergy and Intolerance : Distinction, Definitions and Delimitation]. AB - Immunologically mediated hypersensitivity to foods is defined as food allergy, mainly due to immunglobulins of class E (IgE) triggering immediate reactions (type I hypersensitivity) with possible involvement of mucosa, skin, airways, intestinal tract, and the vascular system. Primary food allergy is based on (early) IgE sensitization against animal (e. g., cow's milk, hen's eggs) or plant proteins (e. g. peanut, hazelnut or wheat). In the case of secondary food allergies, IgE against pollen proteins (e. g., birch) reacts to structurally related food proteins (with cross-reactions to stone and pit fruits). Non immunological food intolerance reactions are mostly based on carbohydrate malassimilation (e. g., lactose intolerance, fructose malabsorption) and are rarely due to pseudo-allergies (e. g., flavors, dyes, preservatives) primarily in patients with chronic urticaria. Common intestinal symptoms are mainly due to functional disorders (e. g., irritable bowel disease), rarely because of inflammatory intestinal diseases (e. g., celiac disease). Histamine intolerance, gluten hypersensitivity, and so-called food type III hypersensitivities are controversial diagnoses. The aforementioned disease entities/models are of variable importance for the affected individuals, the public health system, and society in general. PMID- 27215625 TI - [Children and adolescents after child abuse and neglect: Do they receive appropriate treatment?]. AB - BACKGROUND: Child abuse and neglect (CAN) is a risk factor for the development of psychiatric disorders. Untreated, disorders can sustain into adulthood. OBJECTIVES: This study compares rates of psychiatric disorders to mental health care utilization in victims of CAN. METHODS: From three regions in Germany, 322 children and adolescents aged between 4 and 17 and a non-abusive caregiver were assessed for the child's history of CAN, mental health and mental health care utilization via semi-structured interviews. RESULTS: Approximately two thirds of the participants (present state 64.29 %; lifetime 69.57 %) suffered from a psychiatric disorder classifiable with ICD-10. Posttraumatic stress disorder (25.16 %), conduct disorders (21.34 %) and attention and hyperactivity disorders (16.15 %) were most frequently diagnosed. Merely 19.88 % were using mental health care at the time of the assessment. CONCLUSIONS: The provision of mental health care for victims of CAN is insufficient. To improve access to appropriate services for this vulnerable clientele, cooperation between psychiatrists and psychotherapists and the child welfare system is essential. The implementation and dissemination of evidence-based diagnostic methods and treatments must be further advanced. PMID- 27215626 TI - Physical activity surveillance in the European Union: reliability and validity of the European Health Interview Survey-Physical Activity Questionnaire (EHIS-PAQ). AB - BACKGROUND: The current study examined the reliability and validity of the European Health Interview Survey-Physical Activity Questionnaire (EHIS-PAQ), a novel questionnaire for the surveillance of physical activity (PA) during work, transportation, leisure time, sports, health-enhancing and muscle-strengthening activities over a typical week. METHODS: Reliability was assessed by administering the 8-item questionnaire twice to a population-based sample of 123 participants aged 15-79 years at a 30-day interval. Concurrent (inter-method) validity was examined in 140 participants by comparisons with self-report (International Physical Activity Questionnaire-Long Form (IPAQ-LF), 7-day Physical Activity Record (PAR), and objective criterion measures (GT3X+ accelerometer, physical work capacity at 75% (PWC(75%)) from submaximal cycle ergometer test, hand grip strength). RESULTS: The EHIS-PAQ showed acceptable reliability, with a median intraclass correlation coefficient across PA domains of 0.55 (range 0.43-0.73). Compared to the GT3X+ (counts/minutes/day), the EHIS PAQ underestimated moderate-to-vigorous PA (median difference -11.7, p-value = 0.054). Spearman correlation coefficients (rho) for validity were moderate-to strong (rho's > 0.41) for work-related PA (IPAQ = 0.64, GT3X + =0.43, grip strength = 0.48), transportation-related PA (IPAQ = 0.62, GT3X + =0.43), walking (IPAQ = 0.58), and health-enhancing PA (IPAQ = 0.58, PAR = 0.64, GT3X + =0.44, PWC(75%) = 0.48), and fair-to-poor (rho's < 0.41) for moderate-to-vigorous aerobic recreational and muscle-strengthening PA. CONCLUSIONS: The EHIS-PAQ showed good evidence for reliability and validity for the measurement of PA levels at work, during transportation and health-enhancing PA. PMID- 27215627 TI - Spreading Depression in Primary and Secondary Headache Disorders. AB - PURPOSE OF REVIEW: Spreading depression (SD) is a wave of simultaneous and near complete depolarization of virtually all cells in brain tissue associated with a transient "depression" of all spontaneous or evoked electrical activity in the brain. SD is widely accepted as the pathophysiological event underlying migraine aura and may play a role in headache pathogenesis in secondary headache disorders such as ischemic stroke, subarachnoid or intracerebral hemorrhage, traumatic brain injury, and epilepsy. Here, we provide an overview of the pathogenic mechanisms and propose plausible hypotheses on the involvement of SD in primary and secondary headache disorders. RECENT FINDINGS: SD can activate downstream trigeminovascular nociceptive pathways to explain the cephalgia in migraine, and possibly in secondary headache disorders as well. In healthy, well-nourished tissue (such as migraine), the intense transmembrane ionic shifts, the cell swelling, and the metabolic and hemodynamic responses associated with SD do not cause tissue injury; however, when SD occurs in metabolically compromised tissue (e.g., in ischemic stroke, intracranial hemorrhage, or traumatic brain injury), it can lead to irreversible depolarization, injury, and neuronal death. Recent non-invasive technologies to detect SDs in human brain injury may aid in the investigation of SD in headache disorders in which invasive recordings are not possible. SD explains migraine aura and progression of neurological deficits associated with other neurological disorders. Studying the nature of SD in headache disorders might provide pathophysiological insights for disease and lead to targeted therapies in the era of precision medicine. PMID- 27215628 TI - Stress and Primary Headache: Review of the Research and Clinical Management. AB - This review begins with a discussion of the nature of stress and then presents the functional model of primary headache as a framework for conceptualizing the complex relationship between stress and headaches. Research is reviewed on stress as a trigger of headaches and how stress can play a role in the developmental and psychosocial context of headaches. Clinical management of headaches from a stress perspective is considered both at the level of trials of behavioral interventions that broadly fit into the stress management category and the additional strategies that might be useful for individual cases based on the research demonstrating associations between stress and headaches. The review concludes by suggesting that although some researchers have questioned whether stress can trigger headaches, overall, the literature is still supportive of such a link. Advances in methodology are discussed, the recent emphasis on protective factors is welcomed, and directions for future research suggested. PMID- 27215629 TI - Sideline Neurological Evaluation: a Detailed Approach to the Sideline, In-Game Neurological Assessment of Contact Sport Athletes. AB - Contact sport holds inherent risk of traumatic injury to participant athletes. Neurologic injury, from trauma, portends significant potential for morbidity and mortality. The in-game sideline presents a challenging setting for injury evaluation. Athletic trainers and team physicians should understand general principles of the neurologic evaluation and apply a systematic approach that allows an organized evaluation of and differential diagnosis of neurologic injury. Athlete welfare demands an immediate, accurate diagnosis followed by targeted management. Management provides appropriate referral, timely treatment, and appropriate return-to-play decision. Management begins with recognition. PMID- 27215631 TI - Climbing the Ladder: Experience with Developing a Large Group Genetic Counselor Career Ladder at Children's National Health System. AB - Children's National Health System (CNHS) is a not-for-profit pediatric hospital that employs around twenty genetic counselors in a range of specialties, including clinical pediatric, neurology, fetal medicine, research, and laboratory. CNHS lacked a structured system of advancement for their genetic counselors; therefore, a formal career ladder was proposed by the genetic counselors based on years of experience, responsibility, and job performance. This career ladder utilized monetary, academic, and seniority incentives to encourage advancement and continue employment at CNHS. The creation and ultimate approval of the career ladder required direct input from genetic counselors, Department Chairs, and Human Resource personnel. The establishment of a genetic counselor career ladder at CNHS will hopefully benefit the profession of genetic counselors as a whole and allow other facilities to create and maintain their own career ladder to meet the needs of the growing, competitive, field of genetic counseling. PMID- 27215633 TI - Impact of bevacizumab containing first line chemotherapy on recurrent disease in epithelial ovarian cancer: A case-control study. AB - OBJECTIVE: To evaluate the timing and pattern of relapse, and duration of response to second line chemotherapy in advanced ovarian cancer (AOC) patients treated with first line carboplatin-paclitaxel chemotherapy with or without bevacizumab. PATIENTS AND METHODS: This is a case-control study including 222 AOC patients. Seventy-four women treated with first line carboplatin-paclitaxel bevacizumab chemotherapy (Cases) were matched based on laparoscopic predictive index value, and residual tumor at first surgery with 148 AOC patients treated with carboplatin-paclitaxel. Distribution of pattern of relapse, and response to second line chemotherapy was compared between the two groups. Time to Progression (TTP) for second line chemotherapy was also analyzed for study purpose. RESULTS: Median platinum-free interval (PFI) was 16months (range 2-65) in Cases, compared with 9months (1-83) in Controls (p-value=0.001). Twenty patients (51.3%) among Cases showed recurrence in multiple anatomic sites, compared with 31 (31.9%) in the Control group (p-value=0.035). Peritoneal recurrence occurred as diffuse in 30 Cases (96.8%), and 60 Controls (82.2%; p-value=0.046). Secondary cytoreductive surgery (SCS) was successfully completed in 53.5% of Controls compared to 10.0% of Cases (p-value=0.016). In women with fully platinum-sensitive relapse, response rate to second line chemotherapy was 85.2% in Controls, compared to 38.4% in Cases (p-value=0.002). Finally, Cases showed a shorter TTP, compared to Controls (5months vs 8months; p-value=0.041). CONCLUSIONS: Incorporation of bevacizumab into upfront regimens prolongs PFI in AOC patients, but is associated with wider presentation of relapse, lower rate of complete SCS, and shorter TTP to second line chemotherapy in women with platinum-sensitive disease. PMID- 27215634 TI - Combination of body mass-based resistance training and high-intensity walking can improve both muscle size and VO2 peak in untrained older women. AB - AIM: Here, we aimed to compare the effect of a combination of body mass-based resistance exercise and moderate-intensity (55% peak oxygen uptake [ VO2 peak]) walking or high-intensity (75% VO2 peak) walking on muscle size and VO2 peak in untrained older women. METHODS: A total of 12 untrained older women (mean age 60 +/- 2 years) were randomly assigned to either a moderate-intensity aerobic training group (n = 6) or high-intensity aerobic training group (n = 6). Both groups carried out body-mass based (lower body) resistance exercises (2 sets of 10 repetitions) on 3 days/week for 8 weeks. Between these exercises, the participants in the moderate-intensity aerobic training group walked at a previously determined speed equivalent to 55% VO2 peak, whereas those in the high intensity aerobic training group walked at a speed equivalent to 75% VO2 peak. RESULTS: Muscle thickness of the anterior aspect of the thigh and maximal isokinetic knee extension strength significantly increased in both groups (P < 0.01); these relative changes were negatively correlated with the absolute muscle thickness of the anterior aspect of the thigh value and the relative value of maximal knee strength to body mass at pre-intervention, respectively. A significant group * time interaction was noted for VO2 peak (P < 0.05), which increased only in the high-intensity aerobic training group. CONCLUSIONS: Body mass-based resistance training significantly induced muscle hypertrophy in untrained older women. In particular, lower muscle thickness before intervention was associated with greater training-induced growth. Furthermore, VO2 peak can be increased by combined circuit training involving low-load resistance exercise and walking, particularly when a relatively high intensity of walking is maintained. Geriatr Gerontol Int 2017; 17: 779-784. PMID- 27215635 TI - Reproductive investment is connected to innate immunity in a long-lived animal. AB - Life-history theory predicts that organisms optimize their resource allocation strategy to maximize lifetime reproductive success. Individuals can flexibly reallocate resources depending on their life-history stage, and environmental and physiological factors, which lead to variable life-history strategies even within species. Physiological trade-offs between immunity and reproduction are particularly relevant for long-lived species that need to balance current reproduction against future survival and reproduction, but their underlying mechanisms are poorly understood. A major unresolved issue is whether the first line innate immune function is suppressed by reproductive investment. In this paper, we tested if reproductive investment is associated with the suppression of innate immunity, and how this potential trade-off is resolved depending on physiological state and residual reproductive value. We used long-lived capital breeding female eiders (Somateria mollissima) as a model. We showed that the innate immune response, measured by plasma bacteria-killing capacity (BKC), was negatively associated with increasing reproductive investment, i.e., with increasing clutch size and advancing incubation stage. Females in a better physiological state, as indexed by low heterophil-to-lymphocyte (H/L) ratios, showed higher BKC during early incubation, but this capacity decreased as incubation progressed, whereas females in poorer state showed low BKC capacity throughout incubation. Although plasma BKC generally declined with increasing H/L ratios, this decrease was most pronounced in young females. Our results demonstrate that reproductive investment can suppress constitutive first-line immune defence in a long-lived bird, but the degree of immunosuppression depends on physiological state and age. PMID- 27215636 TI - Component, group and demographic Allee effects in a cooperatively breeding bird species, the Arabian babbler (Turdoides squamiceps). AB - In population dynamics, inverse density dependence can be manifested by individual fitness traits (component Allee effects), and population-level traits (demographic Allee effects). Cooperatively breeding species are an excellent model for investigating the relative importance of Allee effects, because there is a disproportionately larger benefit to an individual of being part of a large group. As a consequence, larger groups have greater performance than small groups, known as the group Allee effect. Although small populations of cooperative breeders may be prone to all levels of Allee effects, empirical evidence for the existence of a demographic Allee effects is scarce. To determine the extent to which Allee effects are present in a cooperatively breeding species, we used a comprehensive 35-year life history database for cooperatively breeding Arabian babblers (Turdoides squamiceps). Firstly, we confirmed the existence of a component Allee effect by showing that breeding individuals in large groups receive greater benefits than those in small groups; second, we confirmed the existence of group Allee effect by showing that larger groups survive longer. And thirdly, we identified a demographic Allee effect by showing that per capita population growth rate is positively affected by population density. Finally, we found that emigration and immigration rates, although dependent on group size, do not buffer against component and group-level Allee effects becoming a demographic Allee effect. Our finding of the existence of all three levels of Allee effects in a cooperative breeder may have important implications for future research and conservation decisions. PMID- 27215637 TI - Mother knows the best mould: an essential role for non-wood dietary components in the life cycle of a saproxylic scarab beetle. AB - Beetles living in tree hollows can feed on a wealth of substrates-e.g. the rotten wood surrounding the cavity, leaf humus falling into the hole, and larval frass accumulating in the cavity. In this paper, we examine the role of these main substrates in Finnish tree hollows in the female preference and larval growth of the hermit beetle Osmoderma barnabita. We rear larvae on diets consisting of wood material (as affected by brown-rot), leaf humus, and larval frass, in varying proportions. To pinpoint the effects of microbes, we contrast larval growth on sterilized versus unsterilized larval frass, and on pure mycelia of the cavity creating fungus Laetiporus sulphureus. Finally, to relate larval performance to female preference, we examine female choice among the three main substrates used in the larval rearings. We found that the presence of one substrate modifies the influence of another, with larval growth and survival being highest on pure leaf humus. Microbes came with both positive and negative impacts on larval performance, as larvae grew quicker on unsterilized than on sterilized larval frass, but were also struck by higher mortality. On pure fungal mycelia, larvae neither grew nor survived. Female preference reflected larval performance, with leaf humus being preferred over other resources. Overall, our study suggests that organisms inhabiting tree holes may be dependent on subsidies entering the cavity from outside, and that ovipositing females may specifically respond to the presence of such subsidies. Thus, the quality of a microhabitat may depend on what enters it from outside. PMID- 27215638 TI - Redox-dependent interactions between reduced/oxidized cytochrome c and cytochrome c oxidase evaluated by in-situ electrochemical surface plasmon resonance. AB - The interactions between the redox couple of cytochrome c (Cyt c) and cytochrome c oxidase (COX) were investigated at a mimic redox-modulated interface by using an electrochemical surface plasmon resonance (EC-SPR) system. Although early studies of the binding between COX and Cyt c have been conducted using several techniques in homogeneous solutions, a problem still inherent is that ferro cytochrome c (Cyt c red), the reduced form of Cyt c, can be easily oxidized into ferri-cytochrome c (Cyt c ox) and adversely impact the accuracy and reproducibility of the binding measurements. In order to realize reliable redox dependent binding tests, here the Cyt c red is quantitatively electro-generated from Cyt c ox by in situ cathodic polarization in a flow cell. Then the kinetic and dissociation constants of the bindings between COX and Cyt c red/Cyt c ox can be evaluated accurately. In this study, the values of association/dissociation rate constants (k a, k d) for both COX/Cyt c red and COX/Cyt c ox were obtained. The dissociation constants, K D, were finally calculated as 3.33 * 10(-8) mol . L(-1) for COX/Cyt c red and 4.25 * 10(-5) mol . L(-1) for COX/Cyt c ox, respectively. In-situ EC-SPR is promising for better mimicking the in vivo condition that COX is embedded in the inner mitochondrial membrane and Cyt c acts as an electron shuttle in the mobile phase. It is an effective method for the investigation of redox-dependent biomolecular interactions. Graphical Abstract Schematic representation of the experimental designs using EC-SPR system. (a) the Au-Cys-COX SPR chip with SAM layers. (b) redox-modulated Cyt c and its binding onto pre-immobilized COX. PMID- 27215639 TI - Quantification of 11 thyroid hormones and associated metabolites in blood using isotope-dilution liquid chromatography tandem mass spectrometry. AB - This paper describes a novel analytical methodology for the simultaneous determination of absolute and total concentrations of 11 native thyroid hormones and associated metabolites, viz. thyroxine (T4), 3,3', 5-triiodothyronine (T3), 3,3', 5'-triiodothyronine (rT3), 3,5-diiodothyronine (3,5-T2), 3,3'- diiodothyronine (3,3'-T2), 3-iodothyronine (T1), thyronine (T0), 3 iodothyronamine (T1AM), tetraiodothyroacetic acid (Tetrac), triiodothyroacetic acid (Triac), and diiodothyroacetic acid (Diac), in 50-MUL of plasma or serum. The method was optimized using four isotopic labeled surrogate and internal standards in combination with solid-phase extraction and LC-MS/MS. The methodology was further evaluated using amphibian plasma and serum with matrix matched calibration applied for quantification. Method detection limits are 3.5 pg T4, 1.5 pg T3, 2.9 pg rT3, 1.7 pg 3,3'-T2, 2.3 pg 3,5-T2, and between 0.3 and 7.5 pg for the remaining six metabolites in 50 MUL aliquots of blood sera or plasma. Accuracies and repeatabilities for all analytes were between 88 and 103 % and 1.31 and 17.2 %, respectively. Finally, we applied the method on adult frog (Xenopus laevis) plasma and tadpole (Rana (Lithobates) catesbeiana) serum. We observed up to seven different thyroid hormones and associated metabolites in tadpole serum. This method will enable researchers to improve the assessment of thyroid homeostasis and endocrine disruption in animals and humans. Graphical Abstract Quantification of 11 thyroid hormones and metabolites from 50 MUL plasma or serum using protein denaturation in combination with solid-phase extraction followed by LC-MS/MS. PMID- 27215640 TI - Duplication of FOXP2 binding sites within CNTNAP2 gene in a girl with neurodevelopmental delay. PMID- 27215641 TI - Exome sequencing reveals a nebulin nonsense mutation in a dog model of nemaline myopathy. AB - Nemaline myopathy (NM) is a congenital muscle disorder associated with muscle weakness, hypotonia, and rod bodies in the skeletal muscle fibers. Mutations in 10 genes have been implicated in human NM, but spontaneous cases in dogs have not been genetically characterized. We identified a novel recessive myopathy in a family of line-bred American bulldogs (ABDs); rod bodies in muscle biopsies established this as NM. Using SNP profiles from the nuclear family, we evaluated inheritance patterns at candidate loci and prioritized TNNT1 and NEB for further investigation. Whole exome sequencing of the dam, two affected littermates, and an unaffected littermate revealed a nonsense mutation in NEB (g.52734272 C>A, S8042X). Whole tissue gel electrophoresis and western blots confirmed a lack of full-length NEB in affected tissues, suggesting nonsense-mediated decay. The pathogenic variant was absent from 120 dogs of 24 other breeds and 100 unrelated ABDs, suggesting that it occurred recently and may be private to the family. This study presents the first molecularly characterized large animal model of NM, which could provide new opportunities for therapeutic approaches. PMID- 27215642 TI - Cellular ageing mechanisms in osteoarthritis. AB - Age is the strongest independent risk factor for the development of osteoarthritis (OA) and for many years this was assumed to be due to repetitive microtrauma of the joint surface over time, the so-called 'wear and tear' arthritis. As our understanding of OA pathogenesis has become more refined, it has changed our appreciation of the role of ageing on disease. Cartilage breakdown in disease is not a passive process but one involving induction and activation of specific matrix-degrading enzymes; chondrocytes are exquisitely sensitive to changes in the mechanical, inflammatory and metabolic environment of the joint; cartilage is continuously adapting to these changes by altering its matrix. Ageing influences all of these processes. In this review, we will discuss how ageing affects tissue structure, joint use and the cellular metabolism. We describe what is known about pathways implicated in ageing in other model systems and discuss the potential value of targeting these pathways in OA. PMID- 27215644 TI - Developing a framework of service convenience in health care: An exploratory study for a primary care provider. AB - From retail health clinics and online appointment scheduling to (mobile) kiosks that enable patient check-in and automate the collection of copays and open balances, convenience has become an important topic in the health care sector over the last few years. While service convenience has also gained much interest in academia, one common limitation is that authors have adopted a "goods centered" perspective focusing primarily on retail settings. Results of this exploratory study reveal that health care service convenience encompasses seven different dimensions: decision, access, scheduling, registration and check-in, transaction, care delivery, and postconsultation convenience. Implications and future research suggestions are discussed. PMID- 27215646 TI - Study of Male Sex Hormone Levels in Male Egyptian Children with Beta-Thalassemia: Correlation with Iron load. AB - BACKGROUND: Beta thalassemia is an inherited hemoglobin disorder resulting in chronic hemolytic anemia. RBCs hemolysis and repeated blood transfusions are the major causes of secondary iron overload which leads to deposition of iron in different endocrine glands. Delayed puberty and hypogonadism are the most obvious clinical consequences of iron overload. The aim of this study was to evaluate male sex hormone levels in male children with beta- thalassemia major in correlation with iron overload. MATERIAL AND METHODS: The present study was conducted on 60 male children with beta- thalassemia major with serum ferritin of more than 1000 ng/ml with their age ranging from 11-18 years and mean age value of 14.16+/-2.48 (Group I) and 60 male children with beta- thalassemia major of matched age with no iron overload (Group II). For all children in both groups the following were done: Complete blood count, Hb electrophoresis, serum ferritin, serum iron, TIBC, serum testosterone levels and assessment of testicular volume by ultrasound and Orchidometer. RESULTS: Serum iron and ferritin were significantly higher while TIBC, serum testosterone levels and testicular volume were significantly lower in Group I than Group II (Mean serum iron was 221.70 +/- 46.76 in group I versus 122.45 +/- 14.32 in group II with p value of 0.001, mean serum ferritin was 2595.06 +/- 903.43 in group I versus 373.75 +/- 6.82 in group II with p value of 0.001, mean serum TIBC was 210.93 +/- 18.17 in group I versus 311.40 +/- 13.57 in group II with p value of 0.001, mean serum testosterone was 1.01+/-1.61 in group I versus 2.73+/-2.66 in group II with p value of 0.006, mean testicular volume was 4.45+/- 4.92 in group I versus 8.66+/-7.08 in group II with p value of 0.016). There was significant negative correlation between serum ferritin and serum testosterone and between serum ferritin and testicular volume in studied patients in group I (r = -0.457 and p value = 0.011 for correlation between ferritin and testosterone and r = -0.908 and p value = 0.001 for correlation between ferritin and testicular volume). CONCLUSION: Male sex hormone and testicular volume were significantly lower in thalassemic patients with iron overload, significant negative correlation and serum ferritin. RECOMMENDATIONS: Regular follow up for thalassemia patients for early detection of iron overload with regular assessment of puberty as thalassemic patients are vulnerable to develop hypogonadism and may require sex hormone replacement therapy. PMID- 27215643 TI - Ageing in relation to skeletal muscle dysfunction: redox homoeostasis to regulation of gene expression. AB - Ageing is associated with a progressive loss of skeletal muscle mass, quality and function-sarcopenia, associated with reduced independence and quality of life in older generations. A better understanding of the mechanisms, both genetic and epigenetic, underlying this process would help develop therapeutic interventions to prevent, slow down or reverse muscle wasting associated with ageing. Currently, exercise is the only known effective intervention to delay the progression of sarcopenia. The cellular responses that occur in muscle fibres following exercise provide valuable clues to the molecular mechanisms regulating muscle homoeostasis and potentially the progression of sarcopenia. Redox signalling, as a result of endogenous generation of ROS/RNS in response to muscle contractions, has been identified as a crucial regulator for the adaptive responses to exercise, highlighting the redox environment as a potentially core therapeutic approach to maintain muscle homoeostasis during ageing. Further novel and attractive candidates include the manipulation of microRNA expression. MicroRNAs are potent gene regulators involved in the control of healthy and disease-associated biological processes and their therapeutic potential has been researched in the context of various disorders, including ageing-associated muscle wasting. Finally, we discuss the impact of the circadian clock on the regulation of gene expression in skeletal muscle and whether disruption of the peripheral muscle clock affects sarcopenia and altered responses to exercise. Interventions that include modifying altered redox signalling with age and incorporating genetic mechanisms such as circadian- and microRNA-based gene regulation, may offer potential effective treatments against age-associated sarcopenia. PMID- 27215647 TI - Are biosimilars patentable? AB - INTRODUCTION: This paper explores whether, and under what circumstances, a biosimilar approved in the United States under the Biologics Price Competition and Innovation Act (hereafter 'BPCIA') can be patented. The possibility that a biosimilar product could have meaningful patent protection arises from specific requirements for biosimilarity under the BPCIA, which account for the fact that manufacturing processes of biologics are inherently imprecise. The requirements for biosimilar approval may provide sufficient leeway to a biosimilar applicant to patent structural or formulation differences that provide non-clinical but business-relevant advantages over the reference molecule, such as improved shelf life or ease of manufacture, without compromising clinical biosimilarity. AREAS COVERED: Examination of the BPCIA and related Acts, Food and Drug Administration (FDA) guidance papers, case law, patent database searching, and relevant scholarly articles. EXPERT OPINION: Legislative and regulatory requirements for the approval of a biosimilar under the BPCIA are focused on clinical results and allow a degree of leeway for differences to exist between a biosimilar's structure and non-clinical components and those of the biosimilar's reference molecule. This leeway can be exploited to provide the biosimilar with potentially patentable business-relevant advantages over its reference product while maintaining clinical biosimilarity to the reference product. PMID- 27215645 TI - A natural frameshift mutation in Campanula EIL2 correlates with ethylene insensitivity in flowers. AB - BACKGROUND: The phytohormone ethylene plays a central role in development and senescence of climacteric flowers. In ornamental plant production, ethylene sensitive plants are usually protected against negative effects of ethylene by application of chemical inhibitors. In Campanula, flowers are sensitive to even minute concentrations of ethylene. RESULTS: Monitoring flower longevity in three Campanula species revealed C. portenschlagiana (Cp) as ethylene sensitive, C. formanekiana (Cf) with intermediate sensitivity and C. medium (Cm) as ethylene insensitive. We identified key elements in ethylene signal transduction, specifically in Ethylene Response Sensor 2 (ERS2), Constitutive Triple Response 1 (CTR1) and Ethylene Insensitive 3- Like 1 and 2 (EIL1 and EIL2) homologous. Transcripts of ERS2, CTR1 and EIL1 were constitutively expressed in all species both throughout flower development and in response to ethylene. In contrast, EIL2 was found only in Cf and Cm. We identified a natural mutation in Cmeil2 causing a frameshift which resulted in difference in expression levels of EIL2, with more than 100-fold change between Cf and Cm in young flowers. CONCLUSIONS: This study shows that the naturally occurring 7 bp frameshift discovered in Cmeil2, a key gene in the ethylene signaling pathway, correlates with ethylene insensitivity in flowers. We suggest that transfer of the eil2 mutation to other plant species will provide a novel tool to engineer ethylene insensitive flowers. PMID- 27215648 TI - The atrial T wave: The elusive electrocardiographic wave exposed by a case of shifting atrial pacemaker. AB - The atrial T wave (Ta wave) is the body surface manifestation of atrial repolarisation and, unlike the P wave (atrial depolarisation), is little recognised. We report the case of a patient with shifting pacemaker which clearly demonstrates the effect of the Ta wave on ST segment and T wave. A simple conceptual model is used to explain the observed phenomenon. The case serves as a reminder of this often forgotten ECG wave and its potential effects on other ECG features. PMID- 27215649 TI - A case of reversible third-degree AV block due to Lyme carditis. AB - The most common manifestation of Lyme carditis is a varying degree of atrioventricular (AV) conduction block. This case describes a 45-year-old male with third-degree AV block due to Lyme carditis. Treatment with intravenous antibiotics resulted in complete normalization of AV conduction, thereby averting permanent pacemaker implantation. PMID- 27215652 TI - Toward a Better Drug for Gastroparesis: The Problem With a Moving Target. PMID- 27215653 TI - How to Select a Mentor as a Trainee and Junior Faculty. PMID- 27215654 TI - Detectable Drug Levels in Infants Exposed to Biologics: So What? PMID- 27215655 TI - The Dawning of a New Editorial Board for Gastroenterology. PMID- 27215657 TI - Good News-Bad News: Current Status of GI Cancers. PMID- 27215656 TI - Rectal Indomethacin Reduces Pancreatitis in High- and Low-Risk Patients Undergoing Endoscopic Retrograde Cholangiopancreatography. AB - BACKGROUND & AIMS: Rectal indomethacin reduces the risk of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). Most studies of its efficacy included high-risk cohorts and excluded low-risk patients, including those with malignant biliary obstruction. We investigated the potential of rectal indomethacin to prevent post-ERCP pancreatitis (PEP) in a variety of patients. METHODS: We performed a retrospective cohort study of 4017 patients who underwent ERCP at the Hospital of the University of Pennsylvania, from 2009 and 2015, including 823 patients with malignant biliary obstruction. After June 2012, with a few exceptions, patients received indomethacin after their procedure. We collected data from patients' records on demographic and clinical features, procedures, and development of PEP. PEP was defined by consensus criteria. Multivariable logistic regression was used to determine adjusted odds ratios (ORs) for the association between indomethacin and PEP. RESULTS: Rectal indomethacin reduced the odds of PEP by 65% (OR, 0.35; 95% confidence interval [CI], 0.24-0.51; P < .001) and moderate-to-severe PEP by 83% (OR, 0.17; 95% CI, 0.09-0.32; P < .001). In patients with malignant obstruction, rectal indomethacin reduced the risk of PEP by 64% (OR, 0.36; 95% CI, 0.17-0.75; P < .001) and moderate-to-severe PEP by 80% (OR, 0.20; 95% CI, 0.07-0.63; P < .001). Among patients with malignant obstruction, rectal indomethacin provided the greatest benefit to patients with pancreatic adenocarcinoma: 2.31% of these patients who received rectal indomethacin developed PEP vs 7.53% who did not receive rectal indomethacin (P < .001) and 0.59% of these patients who received rectal indomethacin developed moderate-to-severe PEP vs 4.32% who did not receive rectal indomethacin (P = .001). CONCLUSIONS: In a large retrospective cohort study of patients undergoing ERCP that included low-risk patients and patients with malignant biliary obstruction, rectal indomethacin was associated with a significant decrease in the absolute rate and severity of pancreatitis. PMID- 27215658 TI - 2015 James W. Freston Single Topic Conference: A Renaissance in the Understanding and Management of Irritable Bowel Syndrome. PMID- 27215659 TI - The Toronto Helicobacter pylori Consensus in Context. PMID- 27215661 TI - First Do No Harm: Is It Safe to Use Immunosuppressants in Inflammatory Bowel Disease Patients With Prior Cancer? PMID- 27215660 TI - YAP1 and TAZ Control Pancreatic Cancer Initiation in Mice by Direct Up-regulation of JAK-STAT3 Signaling. AB - BACKGROUND & AIMS: Pancreatitis is the most important risk factor for pancreatic ductal adenocarcinoma (PDAC). Pancreatitis predisposes to PDAC because it induces a process of acinar cell reprogramming known as acinar-to-ductal metaplasia (ADM) a precursor of pancreatic intraepithelial neoplasia lesions that can progress to PDAC. Mutations in KRAS are found at the earliest stages of pancreatic tumorigenesis, and it appears to be a gatekeeper to cancer progression. We investigated how mutations in KRAS cooperate with pancreatitis to promote pancreatic cancer progression in mice. METHODS: We generated mice carrying conditional alleles of Yap1 and Taz and disrupted Yap1 and Taz using a Cre-lox recombination strategy in adult mouse pancreatic acinar cells (Yap1fl/fl;Tazfl/fl;Ela1-CreERT2). We crossed these mice with LSL-KrasG12D mice, which express a constitutively active form of KRAS after Cre recombination. Pancreatic tumor initiation and progression were analyzed after chemically induced pancreatitis. We analyzed pancreatic tissues from patients with pancreatitis or PDAC by immunohistochemistry. RESULTS: Oncogenic activation of KRAS in normal, untransformed acinar cells in the pancreatic tissues of mice resulted in increased levels of pancreatitis-induced ADM. Expression of the constitutive active form of KRAS in this system led to activation of the transcriptional regulators YAP1 and TAZ; their function was required for pancreatitis-induced ADM in mice. The JAK-STAT3 pathway was a downstream effector of KRAS signaling via YAP1 and TAZ. YAP1 and TAZ directly mediated transcriptional activation of several genes in the JAK-STAT3 signaling pathway; this could be a mechanism by which acinar cells that express activated KRAS become susceptible to inflammation. CONCLUSIONS: We identified a mechanism by which oncogenic KRAS facilitates ADM and thereby generates the cells that initiate neoplastic progression. This process involves activation of YAP1 and TAZ in acinar cells, which up-regulate JAK-STAT3 signaling to promote development of PDAC in mice. PMID- 27215662 TI - The effect of host nutritional quality on multiple components of Trichogramma brassicae fitness. AB - For parasitoids, the host represents the sole source of nutrients for the developing immature. Subsequently, host quality is an important factor affecting immature development and the resulting fitness of the emerging parasitoid, with impacts on fecundity, longevity and offspring sex ratio. Host age is an integral component of host quality and a key factor in host selection by the female parasitoid. The current study aimed to investigate the effect of decreasing host quality (determined by increasing host age) on adult life history traits (size, wing loading, longevity, and fecundity) and nutritional reserves (protein, lipid and glycogen concentrations) of the parasitoid Trichogramma brassicae. Higher quality hosts resulted in the production of larger offspring with increased resource reserves and enhanced mobility. One-day-old eggs contained significantly more protein and triglyceride than 25- and 45-day-old eggs. Quality of host and fitness of reared wasps decreased due to host aging. Parasitoids reared on 1-day old hosts were larger, with greater fecundity and longevity, a reduced wind loading index, and produced a higher proportion of female offspring when compared with those reared on 25- and 45-day-old hosts. In addition, wasps reared on 1-day old hosts contained higher energy resources, as determined by triglyceride, glycogen and protein reserves, which are essential to successful offspring production. One-day-old hosts can therefore be considered as the best age for producing wasps with greater fitness, since they contain the highest amount of protein, glycogen, and triglyceride. This has implications for the mass rearing of T. brassicae and enhancing the efficacy of this biological control agent. PMID- 27215663 TI - The fragment molecular orbital method combined with density-functional tight binding and the polarizable continuum model. AB - The energy and its analytic gradient are formulated for the fragment molecular orbital (FMO) method combined with density-functional tight-binding (DFTB) and the polarizable continuum model (PCM). The accuracy is demonstrated in comparison with unfragmented calculations and numerical gradients. The instability in the description of proteins using density functional theory (DFT) and DFTB is analyzed for both unfragmented and FMO methods. The cause of the instability is shown to be charged residues, and the problem is particularly severe in the gas phase when long-range functionals are not used. Adding solvent effects considerably increases the gap between occupied and virtual orbitals and stabilizes convergence. The pair interaction energies calculated using FMO-DFT and FMO-DFTB in solution are shown to correlate, whereas the latter method is 4840 times faster than the former for a protein consisting of 1961 atoms. The structures of five proteins (containing up to 3578 atoms) optimized using FMO DFTB/PCM agree reasonably well with experiment. PMID- 27215664 TI - Second harmonic generation imaging reveals a distinct organization of collagen fibrils in locations associated with cartilage growth. AB - PURPOSE: The articular-epiphyseal cartilage complex (AECC) is responsible for the expansion of the bone ends and serves the function of the articular cartilage in juvenile mammals. Bundles of collagen fibrils surrounding cells were in the literature observed more frequently near the articular surface of the AECC. The articular surface, the perichondrium, and cartilage canals are interfaces where appositional growth of the AECC has been demonstrated. The current study aimed to evaluate the potential of second harmonic generation (SHG) to locate the collagen fibril bundles near the articular surface and to examine whether a comparable collagen fibril organization could be observed near the other interfaces of the AECC. MATERIALS AND METHODS: The study included the femoral condyle of four piglets aged 82-141 days. The forward and backward scattered SHG, and their ratio, was analyzed across the AECC using objectives with different numerical aperture. Two-photon-excited fluorescence was used to visualize cells. RESULTS: A similar pattern of collagen fibril organization was observed near the articular surface, around cartilage canals, and adjacent to the perichondrium. The pattern consisted of a higher ratio of forward to backward scattered SHG that increased relative to the surrounding matrix at lower numerical aperture. This was interpreted to reflect collagen fibril bundles in the territorial matrix of cells in these areas. CONCLUSIONS: The observed arrangement of collagen fibrils was suggested to be related to the presumed different growth activity in these areas and indicated that SHG may be used as an indirect and label-free marker for cartilage matrix growth. PMID- 27215665 TI - The impact of major trauma centre implementation on the pathways and outcome of traumatic intracranial extradural haematoma in a regional centre. AB - INTRODUCTION: A new trauma care system with regional major trauma centres (MTC) was implemented on 1st April 2012 across England. We aimed to assess whether this has affected the referral pathways and mortality of patients undergoing emergency craniotomy for extradural haematoma (EDH), where clinical outcome is correlated with the time to intervention. MATERIALS AND METHODS: This was a retrospective cohort comparison study. All patients who had undergone evacuation of EDH from January 2011 to December 2013 were identified. Only those in whom a decision for emergency craniotomy had been made at the time of referral to the on-call neurosurgeon were included. The CRASH predicted risk of mortality was calculated for individual patients. Mortality was assessed at 14 days in order to compute standardised mortality ratios (SMR). RESULTS: Overall, 65 patients underwent EDH evacuation during the study period (21 pre-MTC and 44 post-MTC). Of those, 43 emergency procedures according to the aforementioned definition were included for further analysis (13 pre-MTC, 30 post-MTC). The mean CRASH predicted risk of mortality was 0.21 for the pre-MTC cohort (95% CI: 0.07-0.34) and 0.094 for the post-MTC cohort (95% CI: 0.039-0.15; p = 0.052). There was no significant difference in the rate of secondary transfers before and after MTC implementation (9/13 vs. 23/30, p = 0.71). The mean interval from referral to operation was 198 min for the pre-MTC cohort (95% CI: 123-273) and 201 min for the post-MTC cohort (95% CI: 141-262; p = 0.95). The SMR was 0.37 for the pre-MTC cohort (95% CI: 0.02-1.81; 1 death) and 0.71 for the post-MTC cohort (95% CI: 0.12-2.34; 2 deaths). CONCLUSIONS: MTC implementation has not affected the time to operation or the mortality following EDH evacuation. PMID- 27215666 TI - Willing but Not Able: Patient and Provider Receptiveness to Addressing Intimate Partner Violence in Johannesburg Antenatal Clinics. AB - Intimate partner violence (IPV) during pregnancy is associated with maternal and infant health. However, in South Africa, where 20% to 35% of pregnant women report experiencing IPV, antenatal care rarely addresses violence. Little research has explored how clinic staff, community members, or pregnant women themselves view IPV. We conducted formative, qualitative research with 48 participants in urban Johannesburg. Focus group discussions with pregnant women (n = 13) alongside qualitative interviews with health providers (n = 10), managers and researchers (n = 10), non-governmental organizations (n = 6), community leaders (n = 4), and pregnant abused women (n = 5) explored the context of IPV and health care response. Data were analyzed using a team approach to thematic coding in NVivo 10. We found that pregnant women in the urban Johannesburg setting experience multiple forms of IPV, but tend not to disclose violence to antenatal care providers. Providers are alert to physical injuries or severe outcomes from IPV, but miss subtler cues, such as emotional distress or signs of poor mental health. Providers are uncertain how to respond to IPV, and noted few existing tools, training, or referral systems. Nevertheless, providers were supportive of addressing IPV, as they noted this as a common condition in this setting. Providers and managers considered the safety and well-being of mother and infant to be a strong rationale for the identification of IPV. Pregnant women were receptive to being asked about violence in a kind and confidential way. Understaffing, insufficient training, and poorly developed referral systems were noted as important health system problems to address in future interventions. South African patients and providers are receptive to the identification of and response to IPV in antenatal care, but require tools and training to be able to safely address violence in the health care setting. Future interventions should consider the urban South African antenatal clinic a supportive, if under-resourced, entry point for improving the health of pregnant women experiencing violence. PMID- 27215667 TI - Sex Offending and the Transition From Adolescence to Adulthood: A Cross-Lagged Analysis of General Offending and Sexual Assault in College Males. AB - The purpose of this study was to determine the direction of the general offending sexual assault relationship in young males transitioning from late adolescence to early adulthood. It was predicted that the path leading from general offending to sexual assault would be significant and the path leading from sexual assault to general offending would be non-significant. This hypothesis was tested in a convenience sample of 851 male college students using three waves of data. Four cross-lagged correlations were compared after controlling for race, relationship status, blame attributions, and precursors for each predicted variable. Consistent with the hypothesis, both general offending leading to sexual assault pathways were statistically significant and both sexual assault leading to general offending pathways were not non-significant. Supplemental analyses revealed that more than half the specific non-sexual offenses contributing to the general offending score were capable of predicting general offending, indicating that the non-significant sexual assault pathways were not simply a function of the more limited size or scope of the sexual assault measure. The fact that general offending predicted sexual assault but not vice versa suggests that adult onset sexual assault may be an extension of prior non-sexual offending. PMID- 27215668 TI - [Not Available]. PMID- 27215669 TI - Effect of cow age on the in vitro developmental competence of oocytes obtained after FSH stimulation and coasting treatments. AB - The use of oocytes obtained from younger donors for IVF followed by embryo transfer represents an opportunity to accelerate genetic gain by reducing generation time. In this study, we investigated the relationship between donor age and the in vitro developmental competence of oocytes obtained from Holstein females (aged 5-18 months) after FSH stimulation and coasting. The follicle size patterns showed a significantly higher total number of small follicles (5-6 mm) from donors aged 5 to 10 months and a higher total number of medium-sized follicles (7-10 mm) in donors aged 6 to 7 months. Our analysis also revealed that the total number of follicles was significantly higher (P < 0.05) in donors aged 5 to 8 months and tended to be higher (P = 0.053) in nine-month-old donors. However, oocytes obtained from donors aged 5 to 10 months yielded fewer embryos reaching the morula and blastocyst stages. In summary, our results demonstrate that a higher number of oocytes can be obtained from younger animals but lower developmental competence negates this gain. PMID- 27215670 TI - First characterization of extremely halophilic 2-deoxy-D-ribose-5-phosphate aldolase. AB - 2-Deoxy-d-ribose-5-phosphate aldolase (DERA) catalyzes the aldol reaction between two aldehydes and is thought to be a potential biocatalyst for the production of a variety of stereo-specific materials. A gene encoding DERA from the extreme halophilic archaeon, Haloarcula japonica, was overexpressed in Escherichia coli. The gene product was successfully purified, using procedures based on the protein's halophilicity, and characterized. The expressed enzyme was stable in a buffer containing 2 M NaCl and exhibited high thermostability, retaining more than 90% of its activity after heating at 70 degrees C for 10 min. The enzyme was also tolerant to high concentrations of organic solvents, such as acetonitrile and dimethylsulfoxide. Moreover, H. japonica DERA was highly resistant to a high concentration of acetaldehyde and retained about 35% of its initial activity after 5-h' exposure to 300 mM acetaldehyde at 25 degrees C, the conditions under which E. coli DERA is completely inactivated. The enzyme exhibited much higher activity at 25 degrees C than the previously characterized hyperthermophilic DERAs (Sakuraba et al., 2007). Our results suggest that the extremely halophilic DERA has high potential to serve as a biocatalyst in organic syntheses. This is the first description of the biochemical characterization of a halophilic DERA. PMID- 27215671 TI - Production and immunogenicity of Actinobacillus pleuropneumoniae ApxIIA protein in transgenic rice callus. AB - Actinobacillus pleuropneumoniae is a major etiological agent that is responsible for swine pleuropneumonia, a highly contagious respiratory infection that causes severe economic losses in the swine production industry. ApxIIA is one of the virulence factors in A. pleuropneumoniae and has been considered as a candidate for developing a vaccine against the bacterial infection. A gene encoding an ApxIIA fragment (amino acids 439-801) was modified based on a plant-optimized codon and constructed into a plant expression vector under the control of a promoter and the 3' UTR of the rice amylase 3D gene. The plant expression vector was introduced into rice embryogenic callus (Oryza sativa L. cv. Dongjin) via particle bombardment-mediated transformation. The integration and transcription of the ApxIIA439-801 gene were confirmed by using genomic DNA PCR amplification and Northern blot analysis, respectively. The synthesis of ApxIIA439-801 antigen protein in transgenic rice callus was confirmed by western blot analysis. The concentration of antigen protein in lyophilized samples of transgenic rice callus was 250 MUg/g. Immunizing mice with protein extracts from transgenic plants intranasally elicited secretory IgA. These results demonstrate the feasibility of using a transgenic plant to elicit immune responses against A. pleuropneumoniae. PMID- 27215673 TI - Growing the North American Society for Pediatric and Adolescent Gynecology-Thirty Years in the Making. PMID- 27215672 TI - Dynamic changes in neural circuitry during adolescence are associated with persistent attenuation of fear memories. AB - Fear can be highly adaptive in promoting survival, yet it can also be detrimental when it persists long after a threat has passed. Flexibility of the fear response may be most advantageous during adolescence when animals are prone to explore novel, potentially threatening environments. Two opposing adolescent fear-related behaviours-diminished extinction of cued fear and suppressed expression of contextual fear-may serve this purpose, but the neural basis underlying these changes is unknown. Using microprisms to image prefrontal cortical spine maturation across development, we identify dynamic BLA-hippocampal-mPFC circuit reorganization associated with these behavioural shifts. Exploiting this sensitive period of neural development, we modified existing behavioural interventions in an age-specific manner to attenuate adolescent fear memories persistently into adulthood. These findings identify novel strategies that leverage dynamic neurodevelopmental changes during adolescence with the potential to extinguish pathological fears implicated in anxiety and stress-related disorders. PMID- 27215674 TI - Evaluation of medication-assisted treatment of opioid dependence-The physicians' perspective. AB - BACKGROUND: There is controversy about which outcome parameters should be employed to assess substance use treatment. Subjective measures of medication assisted treatment (MAT) of opioid dependence are increasingly important. However, while patients' perspectives have been examined, the caregivers' views remain largely unknown. Here, we explore how physicians evaluate MAT, and which predictors are most relevant. METHODS: We conducted a retrospective cohort study of all MAT episodes with oral opioid agonists in the canton of Zurich between 1998 and 2013 using a case register. Termination forms of the register include a physician-completed assessment on the course of the treatment episode. Mixed model analysis was applied to determine relevant predictors. RESULTS: The analysis was based on 17,234 episodes from 7432 patients. Mean global assessment of the course of MAT was 'moderate'. The most important predictors for treatment evaluation by physicians were treatment break off as reason for termination (p<0.0001), psychological improvement throughout treatment (p<0.0001), wish for abstinence from the substitute (p<0.0001), social integration index at termination (p<0.0001), and social (p<0.0001) as well as medical (p<0.0001) improvement. The negative association of treatment break off with MAT assessment was more pronounced in semi-rural than urban areas (p<0.0001). CONCLUSION: Predictors relating to the well-being and functioning of the patient as well as the reasons underlying treatment termination appear to be more important for the treating physician's evaluation of medication-assisted treatment episodes than on going substance use. Coming off the opioid medication plays a central role, independent of ongoing illicit substance use. PMID- 27215675 TI - What do cells actually want? AB - Genome-scale models require an objective function representing what an organism strives for. A method has been developed to infer this fundamental biological function from data.Please see related Research article: www.dx.doi.org/10.1186/s13059-016-0968-2. PMID- 27215676 TI - Base-catalyzed controllable reaction of 3-ylideneoxindoles with O-Boc hydroxycarbamates for the synthesis of amidoacrylates and spiroaziridine oxindoles. AB - A base-catalyzed divergent reaction of 3-ylideneoxindoles with O-Boc hydroxycarbamates has been developed to provide efficient access to various amidoacrylates and spiroaziridine oxindoles with generally high yields, which should be potentially useful in drug discovery. PMID- 27215678 TI - Epigenetic regulation of skeletal muscle metabolism. AB - Normal skeletal muscle metabolism is essential for whole body metabolic homoeostasis and disruptions in muscle metabolism are associated with a number of chronic diseases. Transcriptional control of metabolic enzyme expression is a major regulatory mechanism for muscle metabolic processes. Substantial evidence is emerging that highlights the importance of epigenetic mechanisms in this process. This review will examine the importance of epigenetics in the regulation of muscle metabolism, with a particular emphasis on DNA methylation and histone acetylation as epigenetic control points. The emerging cross-talk between metabolism and epigenetics in the context of health and disease will also be examined. The concept of inheritance of skeletal muscle metabolic phenotypes will be discussed, in addition to emerging epigenetic therapies that could be used to alter muscle metabolism in chronic disease states. PMID- 27215677 TI - COPD and stroke: are systemic inflammation and oxidative stress the missing links? AB - Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation and loss of lung function, and is currently the third largest cause of death in the world. It is now well established that cardiovascular related comorbidities such as stroke contribute to morbidity and mortality in COPD. The mechanisms linking COPD and stroke remain to be fully defined but are likely to be interconnected. The association between COPD and stroke may be largely dependent on shared risk factors such as aging and smoking, or the association of COPD with traditional stroke risk factors. In addition, we propose that COPD-related systemic inflammation and oxidative stress may play important roles by promoting cerebral vascular dysfunction and platelet hyperactivity. In this review, we briefly discuss the pathogenesis of COPD, acute exacerbations of COPD (AECOPD) and cardiovascular comorbidities associated with COPD, in particular stroke. We also highlight and discuss the potential mechanisms underpinning the link between COPD and stroke, with a particular focus on the roles of systemic inflammation and oxidative stress. PMID- 27215679 TI - Sex hormone therapy and progression of cardiovascular disease in menopausal women. AB - One of the most controversial health decisions facing women is deciding upon the use of hormonal treatments for symptoms of menopause. This brief review focuses on the historical context of use of menopausal hormone treatments (MHT), summarizes results of major observational, primary and secondary prevention studies of MHT and cardiovascular (CV) outcomes, provides evidence for how sex steroids modulate CV function and identifies challenges for future research. As medicine enters an era of personalization of treatment options, additional research into sex differences in the aetiology of CV diseases will lead to better risk identification for CV disease in women and identify whether a woman might receive CV benefit from specific formulations and doses of MHT. PMID- 27215680 TI - Prevalence of Cerebral Palsy among 8-Year-Old Children in 2010 and Preliminary Evidence of Trends in Its Relationship to Low Birthweight. AB - BACKGROUND: The public health objective for cerebral palsy (CP) in the United States is to reduce the percentage of children with CP who were born low birthweight (LBW, <2500 g) by 10% between 2006 and 2020. This study reports the prevalence of CP in a constant surveillance area for the years 2006, 2008, and 2010 and describes initial progress towards the CP public health objective. METHODS: Data on children with CP at age 8 years were ascertained by the Autism and Developmental Disabilities Monitoring (ADDM) Network, a population-based surveillance system that monitored CP in four areas of the United States. RESULTS: CP prevalence in 2010 was 2.9 per 1000 [95% confidence interval (CI) 2.6, 3.2], down from 3.5 (95% CI 3.2, 3.9) in the same surveillance area in 2006. Among CP cases with no documented postneonatal aetiology, 49.1% (95% CI 42.9, 55.2) were born LBW in 2010 compared with 54.3% (95% CI 48.4, 60.1) in 2006. In 2010, 28.1% (95% CI 22.9, 30.4) were born very low birthweight (VLBW, <1500 g) compared with 35.4% (95% CI 30.0, 41.2) in 2006. The relative risks for associations between CP and both LBW and VLBW also declined, though not significantly, during the study period. CONCLUSIONS: Declines in the associations between CP and LBW categories may have contributed to declines during the study period in both the prevalence of CP and the percentage of children with CP who were born LBW or VLBW. Ongoing monitoring of these trends is warranted. PMID- 27215681 TI - Patterns in medicinal plant knowledge and use in a Maroon village in Suriname. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Traditional medicine plays an important role in the primary health care practices of Maroons living in the interior of Suriname. Large numbers of medicinal plants are employed to maintain general health and cure illnesses. Little is known, however, on how knowledge of herbal medicine varies within the community and whether plant use remains important when modern health care becomes available. AIM OF THE STUDY: To document the diversity in medicinal plant knowledge and use in a remote Saramaccan Maroon community and to assess the importance of medicinal plants vis a vis locally available modern healthcare. We hypothesized that ailments which could be treated by the village health center would be less salient in herbal medicine reports. METHODS: During three months fieldwork in the Saramaccan village of Pikin Slee, ethnobotanical data were collected by means of participant observations, voucher collections and 27 semi-structured interviews and informal discussions with 20 respondents. To test whether knowledge of medicinal plant species was kept within families, we performed a Detrended Correspondence Analysis. RESULTS: In total, 110 medicinal plant species were recorded, with 302 health use reports and 72 uses, mostly related to general health concerns (42%), diseases of the digestive system (10%), musculoskeletal system and fever (each 7%). Bathing was the most important mode of application. Most health use reports related to cure (58%) and health promotion (39%), while disease prevention played a minor role. Traditional medicine not only treated cultural illnesses, but also health concerns that could be treated with locally available modern medicines. Knowledge of medicinal plant species is not strictly kept within families, but also shared with friends. Certain recipes and applications, however, may be specific family knowledge. CONCLUSION: Medicinal plants play a very important role in the daily lives of the Pikin Slee villagers. Plant use reflects actual health concerns, but as modern medicines are available for most of these concerns, the use of herbal medicines seems to be a deep rooted cultural preference, especially when concerned with cultural illnesses and health promotion. Locally provided healthcare could be enriched if traditional knowledge, illness concepts, and medicinal plant uses could fit into a larger, community-oriented framework. PMID- 27215682 TI - The effect of methanol rhizome extract of Nymphaea lotus Linn. (Nymphaeaceae) in animal models of diarrhoea. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Nymphaea lotus, which is widely distributed throughout tropical Africa, enjoys a number of ethnomedical uses in Nigeria. Traditionally, the rhizomes of N. lotus are used to cure diarrhoea. AIM OF STUDY: This study aims to evaluate the antidiarrhoeal activity of the methanol rhizome extract of N. lotus plant in laboratory animals. MATERIALS AND METHODS: The extract was screened for activity against castor oil-induced diarrhoea and magnesium sulphate-induced diarrhoea as well as effect on gastric transit time in mice. The effect of methanol rhizome extract of Nymphaea lotus on the perfused isolated tissue preparation was also determined. RESULTS: For castor oil-induced diarrhoea, the extract at doses of 200, 400 and 800mg/kg produced significant reduction in the frequency of diarrhoea (at p<0.001, p<0.001 and p<0.01 respectively). The extract at 800mg/kg produced a significant delay in onset of diarrhoea (p<0.05) comparable to loperamide (3mg/kg). The frequency of magnesium sulphate-induced diarrhoea was also significantly reduced in the groups treated with 200, 400 and 800mg/kg of the extract at p<0.001, p<0.001 and p<0.01 respectively. At doses of 200mg/kg and 400mg/kg, the protection produced was comparable to loperamide, 3mg/kg. All treated groups produced significant reduction in the transit of charcoal meal along the intestinal tract at p<0.001. The extract at low concentration (4*10(-4)-6.4*10(-2)mg/ml) had contractile effect on the tone of contraction of the rabbit jejunum while at higher concentrations (8*10(-2)-512*10(-2)mg/ml) produced significant reduction in the tone and rate of spontaneous contraction of rabbit jejunum. The extract at lower concentrations (4*10(-4)-2*10(-2)mg/ml) has no effect on contraction of the guinea pig ileum while higher concentrations (4*10(-2)-512*10(-2)mg/ml) produced significant relaxant activity on guinea pig ileum. CONCLUSION: This study has shown that the methanol rhizome extract of N. lotus has antidiarrhoeal properties thus justifying its use by the local population for this purpose. PMID- 27215683 TI - Sulfate conjugation of daphnetin by the human cytosolic sulfotransferases. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In Turkey, daphnetin-containing Daphne oleoides is used as a folk medicine for treating rheumatic pain and lumbago. A daphnetin containing traditional Chinese medicine tablet, named Zushima-Pian, is available in China for treating rheumatoid arthritis. The present study aimed to investigate the metabolism of daphnetin through sulfation in cultured human cells and to identify the human cytosolic sulfotransferase(s) (SULT(s)) that is(are) capable of mediating the sulfation of daphnetin. MATERIALS AND METHODS: Cultured HepG2 human hepatoma cells and Caco-2 human colon carcinoma cells were labeled with [(35)S]sulfate in the presence of different concentrations of daphnetin. Thirteen known human SULTs, previously expressed and purified, as well as cytosols of human kidney, liver, lung, and small intestine, were examined for daphnetin-sulfating activity using an established sulfotransferase assay. RESULTS: [(35)S]sulfated daphnetin was found to be generated and released by HepG2 cells and Caco-2 cells labeled with [(35)S] sulfate in the presence of daphnetin. Among the 13 known human SULTs, SULT1A1, SULT1A2, SULT1A3, SULT1B1, and SULT1C4 displayed significant sulfating activity toward daphnetin. Of the four human organ samples later tested, small intestine and liver cytosols displayed considerably higher daphnetin-sulfating activity than those of lung and kidney. CONCLUSION: The results derived from the present study showed unequivocally that daphnetin could be sulfated in cultured human cells and by purified human SULT enzymes as well as human organ cytosols. The information obtained provided a basis for further studies on the metabolism of daphnetin through sulfation in vivo. PMID- 27215684 TI - Reducing hypoxia and inflammation during invasive pulmonary aspergillosis by targeting the Interleukin-1 receptor. AB - Hypoxia as a result of pulmonary tissue damage due to unresolved inflammation during invasive pulmonary aspergillosis (IPA) is associated with a poor outcome. Aspergillus fumigatus can exploit the hypoxic microenvironment in the lung, but the inflammatory response required for fungal clearance can become severely disregulated as a result of hypoxia. Since severe inflammation can be detrimental to the host, we investigated whether targeting the interleukin IL-1 pathway could reduce inflammation and tissue hypoxia, improving the outcome of IPA. The interplay between hypoxia and inflammation was investigated by in vivo imaging of hypoxia and measurement of cytokines in the lungs in a model of corticosteroid immunocompromised and in Cxcr2 deficient mice. Severe hypoxia was observed following Aspergillus infection in both models and correlated with development of pulmonary inflammation and expression of hypoxia specific transcripts. Treatment with IL-1 receptor antagonist reduced hypoxia and slightly, but significantly reduced mortality in immunosuppressed mice, but was unable to reduce hypoxia in Cxcr2(-/-) mice. Our data provides evidence that the inflammatory response during invasive pulmonary aspergillosis, and in particular the IL-1 axis, drives the development of hypoxia. Targeting the inflammatory IL-1 response could be used as a potential immunomodulatory therapy to improve the outcome of aspergillosis. PMID- 27215685 TI - Coronary Heart Disease, Diabetes, and Sexuality in Men. AB - Erectile dysfunction (ED) has been well recognized as a marker of increased cardiovascular risk for more than 15 years, especially in younger men. Early detection of ED represents an opportunity to intervene to decrease the risk of future cardiovascular events and limit the progression of ED severity. Evidence suggests there is a window of opportunity of 3 to 5 years from the onset of ED to subsequent cardiovascular events. This opportunity is usually missed if the onus is placed on the patient to seek care for his sexual problems. Unfortunately, these clear messages have not been incorporated into routine cardiovascular care. The reasons for these disparities within specialties are discussed in this article, in addition to management algorithms. Lifestyle modification is usually recommended as the first-line treatment to correct ED and lessen cardiovascular risk, but evidence suggests that this might be effective only in men without established cardiovascular comorbidities. In men with type 2 diabetes mellitus and established cardiovascular disease, lifestyle modification alone is unlikely to be effective. Cardiovascular medications are often associated with sexual dysfunction but changes in medication are more likely to be beneficial in men with milder recent-onset ED. A balanced view must be taken related to medication adverse events, taking into account optimal management of established cardiovascular disease. Testosterone deficiency has been associated with different metabolic disorders, especially metabolic syndrome and type 2 diabetes mellitus. Testosterone deficiency syndrome has been associated with an independent burden on sexual function globally and increased cardiovascular and all-cause mortality. Testosterone replacement therapy has been shown to improve multiple aspects of sexual function and, in some studies, has been associated with a decrease in mortality, especially in men with type 2 diabetes mellitus. Recent studies have suggested that phosphodiesterase type 5 inhibitors, the first line medications to treat ED, could decrease cardiovascular and all-cause mortality, through multiple mechanisms, predominantly related to improved endothelial function. PMID- 27215686 TI - Evidence-Based Management Guidelines on Peyronie's Disease. AB - INTRODUCTION: Despite recent advances in our knowledge and treatment strategies in Peyronie's Disease (PD), much remained unknown about this disease. AIM: To provide a clinical framework and key guideline statements to assist clinicians in an evidence-based management of PD. METHODS: A systematic literature search was conducted to identify published literature relevant to PD. The search included all relevant articles published up to June 2015, including preclinical studies and published guidelines. References used in the text were assessed according to their level of evidence, and guideline recommendations were graded based on the Oxford Centre for Evidence-Based Medicine Levels of Evidence. Owing to the paucity of larger series and randomized placebo-controlled trials with regard to surgical intervention, guideline statements are provided as clinical principle or expert opinion. MAIN OUTCOME MEASURES: This literature was discussed at a panel meeting, and selected articles with the highest evidence available were used to create consensus guideline statements for the Fourth International Consultation on Sexual Medicine guidelines on PD. RESULTS: In addition to existing Third International Consultation on Sexual Medicine guidelines on PD, seven new summary recommendations were created. CONCLUSION: A greater understanding of the scientific basis of PD is greatly needed to address our understanding of the pathophysiology, clinical epidemiology, psychosocial, and diagnostic assessment as well as treatment strategies. PMID- 27215687 TI - Editorial Comment on "Erectile and Ejaculatory Function Preserved With Convective Water Vapor Energy Treatment of Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia: Randomized Controlled Study". PMID- 27215688 TI - Response and Rebuttal to Editorial Commentary on "Erectile and Ejaculatory Function Preserved With Convective Water Vapor Energy Treatment of Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia: Randomized Controlled Study". PMID- 27215689 TI - Assessment of Sexual Function in Infertile Women in a Gynecological Care Setting. AB - INTRODUCTION: Infertility has a high prevalence worldwide. There is also a high prevalence of sexual problems, mainly in gynecological care settings, but many women are unlikely to discuss sexual problems with their physicians. AIMS: To verify how second-year gynecology residents (SGRs) assess the sexual function of infertile women who are undergoing assisted reproductive techniques (ART) at a single infertility tertiary care center in Brazil. MAIN OUTCOME MEASURES: Medical records of patients. METHODS: This retrospective cohort study evaluated all medical records of women who underwent in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) between January 2011 and December 2012 at a fertility clinic of the Hospital das Clinicas of Ribeirao Preto Medical School, University of Sao Paulo. RESULTS: A total of 616 women underwent ART during the study period. The mean patient age was 34.5 +/- 4.4 years, mean weight was 65.6 +/- 12.4 kg, mean height was 163 +/- 0.6 cm, and mean body mass index (BMI) was 24.8 +/- 4.3 kg/m(2). We classified the methods that medical residents used to assess the sexual frequency of these women as a numerical method, by categorization, or none (no assessment). A total of 26.7% (n = 166) of the SGRs did not assess female sexual function and 26.2% (n = 163) made assessments using categorization. SGRs who used a numerical method rather than categorization to classify the sexual frequency of their female patients were more likely to record answers to other questions on sexual desire, arousal, and orgasm. CONCLUSION: SGRs typically do not assess female sexual function in infertile couples. There was considerable heterogeneity among SGRs in their assessment of coital frequency and female sexual function. PMID- 27215690 TI - Differences in Pelvic Morphology Between Women With and Without Provoked Vestibulodynia. AB - OBJECTIVE: Pelvic morphology has been suggested to reflect increased tone and reduced strength of the pelvic floor muscles (PFMs) in women with provoked vestibulodynia (PVD) compared to healthy controls. We aimed to determine whether there are differences in pelvic morphology in the resting state, on maximum voluntary contraction (MVC), or on maximum effort Valsalva maneuver (MVM) between women with and without PVD. METHODS: While imaged using ultrasound, 38 women with PVD and 39 controls relaxed their PFMs, performed 3 MVCs and performed 3 MVMs. Levator plate length (LPL), levator plate angle (LPA), and anorectal angle (ARA) were determined at rest, at MVC and at MVM. The displacement of the bladder neck (BN) on MVC and on MVM was also determined. Two-way ANCOVAs were used to evaluate the main effects of group and task, the interaction between group and task, and the effect of resting morphology on LPL, LPA, and ARA. A 2-way repeated-measures ANOVA was used to determine whether the groups differed in terms of BN displacement during the tasks. RESULTS: Women with PVD had smaller LPLs and LPAs than controls across all tasks. The significant group differences in LPL and LPA at MVC and MVM were no longer significant once the resting values were included as covariates in the models. Bladder neck displacement differed between the groups at MVM but not at MVC. CONCLUSION: Women with PVD display shorter LPL sand smaller LPAs than controls but their behavior does not differ when MVC and MVMs are performed. Our results do not support the hypothesis that women with PVD demonstrate abnormalities in PFM contractility on MVC or compliance on MVM. PMID- 27215691 TI - Management of Distal & Proximal Penile Prosthesis Crossover. AB - The Surgical Techniques Section is sponsored in part by Coloplast. PMID- 27215692 TI - A compact light-sheet microscope for the study of the mammalian central nervous system. AB - Investigation of the transient processes integral to neuronal function demands rapid and high-resolution imaging techniques over a large field of view, which cannot be achieved with conventional scanning microscopes. Here we describe a compact light sheet fluorescence microscope, featuring a 45 degrees inverted geometry and an integrated photolysis laser, that is optimized for applications in neuroscience, in particular fast imaging of sub-neuronal structures in mammalian brain slices. We demonstrate the utility of this design for three dimensional morphological reconstruction, activation of a single synapse with localized photolysis, and fast imaging of neuronal Ca(2+) signalling across a large field of view. The developed system opens up a host of novel applications for the neuroscience community. PMID- 27215693 TI - Patients' Preference for Integrating Homoeopathy Services within the Secondary Health Care Settings in India: The Part 3 (PPIH-3) Study. AB - Indian patients' preference for integrated homoeopathy services remains underresearched. Two earlier surveys revealed favorable attitude toward and satisfaction from integrated services. The objectives of this study were to examine knowledge, attitudes, and practice of homoeopathy and to evaluate preference toward its integration into secondary-level health care. A cross sectional survey was conducted during May to October 2015 among 659 adult patients visiting randomly selected secondary-level conventional health care setups in Kolkata, Mumbai, Kottayam, and New Delhi (India) using a self administered 24-item questionnaire in 4 local vernaculars (Bengali, Marathi, Malayalam, and Hindi). Knowledge and practice scores were compromised; attitude scores toward integration and legal regulation were high. Respondents were uncertain regarding side effects of homoeopathy and concurrent use and interactions with conventional medicines. A total of 82.40% (95% confidence interval = 79.23, 85.19) of the participants were in favor of integrating homoeopathy services. Preference was significantly higher in Delhi and lower in Kottayam. Probable strategic measures for further development of integrated models are discussed. PMID- 27215694 TI - Improved Performance of Organic Light-Emitting Field-Effect Transistors by Interfacial Modification of Hole-Transport Layer/Emission Layer: Incorporating Organic Heterojunctions. AB - Organic heterojunctions (OHJs) consisting of a strong electron acceptor 1,4,5,8,9,11-hexaazatriphenylene hexacarbonitrile (HAT-CN) and an electron donor N,N'-di(naphthalene-1-yl)-N,N'-diphenyl-benzidine (NPB) were demonstrated for the first time that they can be implemented as effective modification layers between hole transport layer (HTL) and emission layer in the heterostructured organic light-emitting field effect transistors (OLEFETs). The influence of both HAT CN/NPB junction (npJ) and NPB/HAT-CN junction (pnJ) on the optoelectronic performance of OLEFETs were conscientiously investigated. It is found that both the transport ability of holes and the injection ability of holes into emissive layer can be dramatically improved via the charge transfer of the OHJs and that between HAT-CN and the HTL. Consequently, OLEFETs with pnJ present optimal performance of an external quantum efficiency (EQE) of 3.3% at brightness of 2630 cdm(-2) and the ones with npJs show an EQE of 4.7% at brightness of 4620 cdm(-2). By further utilizing npn OHJs of HAT-CN/NPB/HAT-CN, superior optoelectronic performance with an EQE of 4.7% at brightness of 8350 cdm(-2) and on/off ratio of 1 * 10(5) is obtained. The results demonstrate the great practicality of implementing OHJs as effective modification layers in heterostructured OLEFETs. PMID- 27215695 TI - Within-subject covariation between depression- and anxiety-related affect. AB - Studies find a strong positive relationship between the affective components of anxiety and depression. However, most research thus far has examined the between person correlations among these constructs, while ignoring how changes in these two types of affect covary over time within a person. Within-person correlations could differ meaningfully from how anxiety- and depression-related affect relate across individuals. Further, individuals may differ in terms of how highly these constructs covary over time. The current study aimed to (1) compare between- and within-person correlations between anxious and depressive affect, (2) examine lagged effects between anxious and depressive affect over time, (3) test whether individuals differ in their within-person correlations between these two types of affect, and (4) examine whether the mean level of affective intensity moderated these individual differences. These questions were explored using college undergraduates (N = 50) who rated their depression- and anxiety- related affect six times a day for two weeks. A higher average correlation was observed between anxious and depressive affect in between-person compared to within-person analyses. Significant bidirectional lagged effects were observed between these constructs. Individuals with higher average levels of anxious affect experienced stronger within-person correlations between anxious and depressive affect. PMID- 27215696 TI - Usefulness of the SF-36 Health Survey in screening for depressive and anxiety disorders in rheumatoid arthritis. AB - BACKGROUND: This study aimed to assess the accuracy of the Short-Form Health Survey (SF-36) mental health subscale (MH) and mental component summary (MCS) scores in identifying the presence of probable major depressive or anxiety disorder in patients with rheumatoid arthritis. METHODS: SF-36 data were collected in 100 hospital outpatients with rheumatoid arthritis. MH and MCS scores were compared against depression and anxiety data collected using validated measures as part of routine clinical practice. Sensitivity and specificity of the SF-36 were established using receiver operating characteristic (ROC) curve analysis, and area under the curve (AUC) compared the performance of the SF-36 components with the 9-item Patient Health Questionnaire (PHQ9) for depression and the 7-item Generalised Anxiety Disorder (GAD7) questionnaire for anxiety. RESULTS: The MH with a threshold of <=52 had sensitivity and specificity of 81.0 and 71.4 % respectively to detect anxiety, correctly classifying 73.5 % of patients with probable anxiety disorder. A threshold of <=56 had sensitivity and specificity of 92.6 and 73.2 % respectively to detect depression, correctly classifying 78.6 % of patients, and the same threshold could also be used to detect either depression or anxiety with a sensitivity of 87.9 %, specificity of 76.9 % and accuracy of 80.6 %. The MCS with a threshold of <=35 had sensitivity and specificity of 85.7 and 81.9 % respectively to detect anxiety, correctly classifying 82.8 % of patients with probable anxiety disorder. A threshold of <=40 had sensitivity and specificity of 92.3 and 70.2 % respectively to detect depression, correctly classifying 76.3 % of patients. A threshold of <=38 could be used to detect either depression or anxiety with a sensitivity of 87.5 %, specificity of 80.3 % and accuracy of 82.8 %. CONCLUSION: This analysis may increase the utility of a widely-used questionnaire. Overall, optimal use of the SF-36 for screening for mental disorder may be through using the MCS with a threshold of <=38 to identify the presence of either depression or anxiety. PMID- 27215697 TI - Cytokine expression in three chicken host systems infected with H9N2 influenza viruses with different pathogenicities. AB - SD/818 and SD/196 are H9N2 influenza virus strains isolated from chickens from the same farm at different times that exhibited similar genetic evolution. However, strain SD/818 exhibited higher pathogenicity in chickens than strain SD/196 and other H9N2 influenza virus epidemic strains from China. The expression of cytokines is an important host defence mechanism following viral infection and their intensity is a major determinant of viral pathogenicity. To elucidate the mechanism underlying the increased pathogenicity of strain SD/818 from the host's perspective, viral replication and cytokine expression were dynamically studied using real-time quantitative reverse transcription PCR in chickens infected with strain SD/818 compared with chickens infected with strain SD/196 in this study. The results showed that the replication of strain SD/818 and the expressions of IL-1beta, IL-6, TNF-alpha, IFN-alpha and IFN-beta induced by strain SD/818 were higher than those induced by strain SD/196 in the chicken host system. Expression of these cytokines in chickens coincided with or followed virus replication. These results suggested that high-level viral replication and pro-inflammatory cytokine expression (but not decreased type I IFN expression) were associated with the higher pathogenicity of strain SD/818 in chickens. PMID- 27215699 TI - Ivabradine, a novel medication for treatment of heart failure with reduced ejection fraction. AB - PURPOSE: To critically evaluate current literature, review pharmacology, and discuss clinical role of ivabradine for patients with heart failure (HF) with reduced ejection fraction. DATA SOURCES: A PubMed search was conducted using the search terms ivabradine and HF. All human studies analyzing the use of ivabradine in patients with HF with reduced ejection fraction and prescribing information were evaluated. CONCLUSIONS: Greater benefit was seen in the prespecified subgroup with heart rate (HR) > 70 beats per minute (bpm) in the BEAUTIFUL study. Therefore, SHIFT examined the effect of ivabradine on patients with higher resting HR, lower ejection fraction, who had been hospitalized for HF within the previous year. A significant difference was found in the composite primary endpoint of cardiovascular death and hospitalizations for worsening HF in patients with HF and left ventricular systolic dysfunction, driven primarily by reduction in hospitalizations for worsening HF. The most common adverse effect was bradycardia. IMPLICATIONS FOR PRACTICE: Ivabradine is a safe and effective medication for HR reduction to reduce hospitalizations in patients with stable, symptomatic HF (ejection fraction < 35%), in sinus rhythm, and HR > 70 bpm. PMID- 27215700 TI - Status epilepticus in scrub typhus. AB - Scrub typhus is an emerging infection, and there is little information about status epilepticus (SE) in scrub typhus. We report the clinical spectrum and outcome of SE in scrub typhus. In a 3-year prospective hospital-based observational study, all scrub typhus patients with SE were included. Scrub typhus was diagnosed by immunochromatography assay. SE was defined if convulsions lasted longer than 5 min. The patients' demographic, clinical, computed tomography (CT), magnetic resonance imaging (MRI), and electroencephalography (EEG) findings were noted. Response to antiepileptic drugs (AEDs) and outcome at 1 month and 1 year were recorded. Between 2012 and 2014, there were 66 patients with scrub typhus admitted with central nervous system (CNS) involvement, 10 (15.2%) of whom had SE (generalized convulsions in 5, secondary generalized in one). The median age of the patients was 34 (range 18-71) years and seven were female. The duration of SE ranged between 10 min and 48 h. SE responded to one AED in five patients, two AEDs in three patients, and more than two AEDs in two patients. Cranial MRI findings were normal. All patients recovered completely with doxycycline by 1 month and AED was withdrawn by 8 months in all. Although 15% patients with scrub typhus may have SE, they have good outcome. PMID- 27215701 TI - Automated PGP9.5 immunofluorescence staining: a valuable tool in the assessment of small fiber neuropathy? AB - BACKGROUND: In this study we explored the possibility of automating the PGP9.5 immunofluorescence staining assay for the diagnosis of small fiber neuropathy using skin punch biopsies. The laboratory developed test (LDT) was subjected to a validation strategy as required by good laboratory practice guidelines and compared to the well-established gold standard method approved by the European Federation of Neurological Societies (EFNS). To facilitate automation, the use of thinner sections. (16 um) was evaluated. Biopsies from previously published studies were used. The aim was to evaluate the diagnostic performance of the LDT compared to the gold standard. We focused on technical aspects to reach high quality standardization of the PGP9.5 assay and finally evaluate its potential for use in large scale batch testing. RESULTS: We first studied linear nerve fiber densities in skin of healthy volunteers to establish reference ranges, and compared our LDT using the modifications to the EFNS counting rule to the gold standard in visualizing and quantifying the epidermal nerve fiber network. As the LDT requires the use of 16 um tissue sections, a higher incidence of intra epidermal nerve fiber fragments and a lower incidence of secondary branches were detected. Nevertheless, the LDT showed excellent concordance with the gold standard method. Next, the diagnostic performance and yield of the LDT were explored and challenged to the gold standard using skin punch biopsies of capsaicin treated subjects, and patients with diabetic polyneuropathy. The LDT reached good agreement with the gold standard in identifying small fiber neuropathy. The reduction of section thickness from 50 to 16 um resulted in a significantly lower visualization of the three-dimensional epidermal nerve fiber network, as expected. However, the diagnostic performance of the LDT was adequate as characterized by a sensitivity and specificity of 80 and 64 %, respectively. CONCLUSIONS: This study, designed as a proof of principle, indicated that the LDT is an accurate, robust and automated assay, which adequately and reliably identifies patients presenting with small fiber neuropathy, and therefore has potential for use in large scale clinical studies. PMID- 27215702 TI - Solid nano-in-nanoparticles for potential delivery of siRNA. AB - siRNA-based therapeutics possess great potential to treat a wide variety of genetic disorders. However, they suffer from low cellular uptake and short half lives in blood circulation; issues that remain to be addressed. This work is, to the best of our knowledge, the first to report the production of solid nano-in nanoparticles, termed double nano carriers (DNCs) by means of the innovative technology of nano spray drying. DNCs (with a median size of 580-770nm) were produced by spraying at low temperatures (50 degrees C) to prevent damage to heat sensitive biomacromolecules like siRNA. DNCs consisting of Poly (d,l-lactide-co glycolide) used as a wall material, encapsulating 20% human serum albumin primary nanoparticles (PNPs) loaded with siRNA, were obtained as a dry nanoparticulate powder with smooth spherical surfaces and a unique inner morphology. Incubation of pegylated or non-pegylated DNCs under sink conditions at 37 degrees C, elicited a controlled release profile of the siRNA for up to 12 or 24h, respectively, with a minimal burst effect. Prolonged incubation of pegylated DNCs loaded with active siRNA (anti EGFR) in an A549 epithelial cell culture monolayer did not induce any apparent cytotoxicity. A slow degradation of the internalized DNCs by the cells was also observed resulting in the progressive release of the siRNA for up to 6days, as corroborated by laser confocal microscopy. The structural integrity and silencing activity of the double encapsulated siRNA were fully preserved, as demonstrated by HPLC, gel electrophoresis, and potent RNAi activity of siRNA extracted from DNCs. These results demonstrate the potential use of DNCs as a nano drug delivery system for systemic administration and controlled release of siRNA and potentially other sensitive bioactive macromolecules. PMID- 27215703 TI - Surface Plasmon Enhanced Photocatalysis of Au/Pt-decorated TiO2 Nanopillar Arrays. AB - The low quantum yields and lack of visible light utilization hinder the practical application of TiO2 in high-performance photocatalysis. Herein, we present a design of TiO2 nanopillar arrays (NPAs) decorated with both Au and Pt nanoparticles (NPs) directly synthesized through successive ion layer adsorption and reaction (SILAR) at room temperature. Au/Pt NPs with sizes of ~4 nm are well dispersed on the TiO2 NPAs as evidenced by electron microscopic analyses. The present design of Au/Pt co-decoration on the TiO2 NPAs shows much higher visible and ultraviolet (UV) light absorption response, which leads to remarkably enhanced photocatalytic activities on both the dye degradation and photoelectrochemical (PEC) performance. Its photocatalytic reaction efficiency is 21 and 13 times higher than that of pure TiO2 sample under UV-vis and visible light, respectively. This great enhancement can be attributed to the synergy of electron-sink function of Pt and surface plasmon resonance (SPR) of Au NPs, which significantly improves charge separation of photoexcited TiO2. Our studies demonstrate that through rational design of composite nanostructures one can harvest visible light through the SPR effect to enhance the photocatalytic activities initiated by UV-light, and thus realize more effectively utilization of the whole solar spectrum for energy conversion. PMID- 27215704 TI - What timing of vaccination is potentially dangerous for children younger than 2 years? AB - Vaccine-preventable diseases still occur although measured coverage rates at 2 y of age are high. The occurrence of these diseases may be explained in part by untimely, that is, late vaccination. Our objective was to identify potentially dangerous vaccination delays for each dose of each vaccine in children younger than 2 y. A 3-round Delphi process was conducted by e-mail. We recruited 37 French experts in vaccines for children: 16 from the Infovac-France group and 21 from the French study group for pediatric infectious diseases. Items were generated by a literature review for the 10 vaccine doses recommended before 2 y of age. Item reduction in round 1 and 2 and any consensus in round 3 used a 70% consensus cutoff. The mean participation rate was 79%. Delays that should not be exceeded were identified for all vaccine doses. The 70% consensus was reached for 6 of the 10 vaccine doses: 15 d after the recommended date for the first 2 doses of the diphtheria-tetanus-acellular pertussis-inactivated polio vaccine/Haemophilus influenzae b vaccine and for the second dose of the pneumococcal conjugate vaccine, 1 month for the meningococcal C vaccine and for the first dose of the measles-mumps-rubella vaccine, and 11 y of age for completion of the hepatitis B vaccination. This Delphi process identified potentially dangerous vaccination delays for children to the age of 2 y. These can be used as new indicators in further studies of vaccine effectiveness and can help to improve the quality of vaccine protection in children. PMID- 27215707 TI - Retained Percutaneous Endoscopic Gastrostomy Causing Small Bowel Obstruction in Inguinal Hernia. PMID- 27215706 TI - Neuroinvasive influenza virus A(H5N8) in fattening ducks, Hungary, 2015. AB - Highly pathogenic avian influenza (HPAI) A virus H5N8 was detected in far east Asian countries during 2014 and emerged in late 2014 in European countries. Hungary reported a HPAI A(H5N8) outbreak during late winter of 2015 at a Pekin duck fattening facility. Epidemiologic monitoring was extended to holdings in neighboring areas and nearby habitats used by wild birds but failed to identify the source of infection. In addition to respiratory symptoms, the affected birds showed lethargy and neuronal signs, including torticollis. Consistent with this finding, influenza A virus antigen was detected in large quantity in the brain. Molecular analysis of the identified strain showed very close genetic relationship (and >99% nucleotide sequence identity) with co-circulating HPAI A(H5N8) strains. A number of unique or rarely detected amino acid changes was detected in the HA (T220I, R512G), the M2 (I39M), the NA (T211I), the NS1 (P85T), and the PB2 (I261V) proteins of the Hungarian strain. Further studies are needed to demonstrate whether any of these mutations can be linked to neuroinvasiveness and neurovirulence in ducks. PMID- 27215705 TI - Overcoming barriers to effective immunotherapy: MDSCs, TAMs, and Tregs as mediators of the immunosuppressive microenvironment in head and neck cancer. AB - A significant subset of head and neck cancers display a T-cell inflamed phenotype, suggesting that patients with these tumors should respond to therapeutic approaches aimed at strengthening anti-tumor immune responses. A major barrier to the development of an effective anti-tumor immune response, at baseline or in response to immunotherapy, is the development of an immunosuppressive tumor microenvironment. Several well described mechanisms of effector immune cell suppression in the head and neck cancer microenvironment are discussed here, along with updates on current trials designed to translate what we have learned from pre-clinical and correlative clinical studies into improved responses in patients with head and neck cancer following immune activating therapies. PMID- 27215708 TI - Operative versus Nonoperative Management of Multiple Rib Fractures. PMID- 27215709 TI - Inflammatory Pseudotumor of the Breast. PMID- 27215710 TI - A Novel Technique to Retrieve a Misdeployed Aortic Endograft within a Dislodged Iliac Stent. PMID- 27215711 TI - Traumatic Rupture of Extra-adrenal Pheochromocytoma. PMID- 27215712 TI - Trends in Elderly Trauma Revisited: Has Management of Elders with Blunt Traumatic Injury Improved? PMID- 27215713 TI - Micronutrient and Metabolic Status in Morbidly Obese Patients Undergoing Bariatric Surgery in a University Bariatric Program. PMID- 27215714 TI - Frank Netter: A Man of Art and Science. AB - Medical illustrations are highly used by medical professionals for various reasons. They have facilitated learning for many centuries and allowed a detailed analysis of subjects. Complex information on anatomy, histology, physiology, and even surgical procedures can be transformed by illustrations into a clear and accurate source that words could never fully describe. The idea that art can be used to enhance the study of science has been emphasized by many medical illustrators. One person who will always be remembered for his artwork in the modern era is Frank H. Netter. The New York native, born in 1906, is one of the era's most well-known medical illustrators. Almost all medical professionals, at one point or another, have come across one of his numerous artistic sketches during their career. Although best known for his Atlas of Human Anatomy, some of Netter's other projects include the CIBA Collection of Medical Illustrations, the "Transparent Women," and the Clinical Symposia series. Medicine lost an educator and an artist in 1991; however, his collection of illustrations remains as his lasting gift to the field. PMID- 27215715 TI - Financial Benefits of a Hepatopancreaticobiliary Program. AB - Financial implications of developing a hepatopancreaticobiliary (HPB) center have not been considered. We undertook this study to determine hospital income associated with a new HPB center and to gauge the opportunity cost associated with such a center. Operations included were based on the HPB fellowship curriculum and the six most commonly undertaken general surgery operations. The income with "core" HPB operations (n = 93) and the six most frequently undertaken general surgery operations (n = 583) at one hospital from June 2012 to June 2013 were determined. Patients were not screened based on the ability to pay. Data are reported as mean +/- standard deviation. Per operation, hospital income with HPB operations and general surgery operations were $15,583.20 +/- $45,909.41 and $5,162.22 +/- $33,679.10 (P < 0.005), respectively. Accordingly, net incomes of $1,449,238.04 (n = 93) and $3,009,572.78 (n = 583) were observed. Although general surgery operations are ubiquitous, HPB centers are uncommonly pursued at most hospitals, in part due to the patient volumes necessary to meet the expertise required. A "core" HPB operation produces triple the net income of a general surgery operation. Accordingly, significant financial benefit is achievable with the development of an HPB center when adequate volume is realized. PMID- 27215716 TI - Duodenal Neuroendocrine Tumors: Location Matters! AB - Duodenal neuroendocrine tumors (NETs) are rare. Historically, when feasible a less aggressive surgical approach is considered. The aim of this study was to identify factors associated with prognosis and the necessity for more aggressive surgical procedures. All patients who underwent surgery for duodenal NETs between September 2005 and June 2014 were identified retrospectively. Data collected included clinical presentation, operative findings, and histopathological data. Eighteen patients underwent surgical management for duodenal NETs. Two patients underwent transduodenal excision (11%), two patients had partial duodenal resection (11%), two patients had antrectomy including 1st part of duodenum (D1) resection (33%), and eight underwent pancreaticoduodenectomy [PD (44%)]. On analysis, 2nd part of duodenum (D2) location was the most common site of duodenal NETs (n = 9, 50%). The odds of having a PD were 10 times higher when the lesion was in D2 location. The odds of having a positive lymph node are nine times higher when the lesion is in D2 region. The odds of having a positive lymph node are three times higher when lesion is greater than T1. D2 location of NETs is associated with higher odds of lymph node positivity and need for more extensive procedures like PD. PMID- 27215717 TI - An Imaging Diagnostic Protocol in Children with Clinically Suspected Acute Appendicitis. AB - The objective of the present study is to evaluate a new diagnostic strategy using clinical findings followed by ultrasound (US) and, in selected cases, MRI. This study included 166 children presenting signs and symptoms suggesting acute appendicitis. Cases classified as suggesting appendicitis according to clinical exams had to be referred to surgery, whereas the other cases were discharged. Unclear cases were evaluated using US. If the US results were considered inconclusive, patients underwent MRI. Of the 166 patients, 78 (47%) had acute appendicitis and 88 (53%) had other diseases. The strategy under study had a sensitivity of 96 per cent, specificity of 100 per cent, positive predictive value of 100 per cent, negative predictive value of 97 per cent, and accuracy of 98 per cent. Eight patients remained undiagnosed and underwent MRI. After MRI two girls presented normal appendixes and were discharged. One girl had an enlarged appendix on MRI and appendicitis could have been confirmed by surgery. In the other five patients, no other sign of the disease was detected by MRI such as an inflammatory mass, free fluid or an abscess in the right iliac fossa. All of them were discharged after clinical observation. In the vast majority of cases the correct diagnosis was reached by clinical and US examinations. When clinical assessment and US findings were inconclusive, MRI was useful to detect normal and abnormal appendixes and valuable to rule out other abdominal pathologies that mimic appendicitis. PMID- 27215718 TI - Decision-Making in Breast Cancer Surgery: Where Do Patients Go for Information? AB - Patient decision-making regarding breast cancer surgery is multifactorial, and patients derive information on surgical treatment options from a variety of sources which may have an impact on choice of surgery. We investigated the role of different information sources in patient decision-making regarding breast cancer surgery. Two hundred and sixty-eight patients with breast cancer, eligible for breast-conserving therapy were surveyed in the immediate preoperative period, and clinical data were also collected. This survey evaluated the scope and features of patient-driven research regarding their ultimate choice of surgical treatment. The two most common sources of information used by patients were written material from surgeons (199/268-74%) and the Internet (184/268-69%). There was a trend for women who chose bilateral mastectomy to use the Internet more frequently than those choosing unilateral mastectomy (P = 0.056). Number of surgeons consulted, genetic testing, and MRI were significant predictors of patient choice of mastectomy over breast-conserving therapy. Multivariate analysis showed that the number of surgeons consulted (P < 0.001) and genetic testing (P < 0.001) were independent predictors of choosing mastectomy, whereas MRI was not. In conclusions, understanding factors driving patient decision making may promote more effective education for patients requiring breast cancer surgery. PMID- 27215719 TI - The Prevalence of Oral Flora in the Biofilm Microbiota of the Endotracheal Tube. AB - The endotracheal tube (ETT) is recognized as an independent factor for infection in intubated patients. The presence of biofilm contributes to the development of pneumonia. Standard culturing techniques are inadequate to detect many of the bacteria present in a biofilm. Delineation of the microbiota in the ETT is needed to further understand infections in ventilated patients. A prospective, observational study was performed at a university, Level I trauma center. Twenty ETT were collected at extubation. Bioluminal accretions were removed and quantified. DNA was extracted and 16S ribosomal RNA gene analysis performed using the Human Oral Microbe Identification Microarray. Twenty ETT were evaluated. Mean age was 47.5 years (19-82). Five were smokers. Mean ventilator days was 3.6 +/- 3.1. Mean intensive care unit days was 7.8 +/- 6.3. In those ETT, 87 different bacterial species were identified. Mean number of bacterial species identified was 16 +/- 9 (3-35). There was no relationship between duration of intubation and number of species (P = 0.5). Nonsmokers had a greater variety of bacteria than smokers (P = 0.03). Patients with pneumonia did not have a greater variety of bacteria (P = 0.14). Parvimonas micra presence was associated with reintubation (P = 0.01). The most common species in smokers were different from nonsmokers. There is a wide variety of bacteria present in an ETT, many of which cannot be cultured by standard means. Variation is not correlated to duration of intubation or accretion volume. Studies to evaluate these bacteria and their interaction with the biofilm may further delineate factors in development of infections. PMID- 27215720 TI - High-Volume Hospitals with High-Volume and Low-Volume Surgeons: Is There a "Field Effect" for Pancreaticoduodenectomy? AB - Since the Leapfrog Group established hospital volume criteria for pancreaticoduodenectomy (PD), the importance of surgeon volume versus hospital volume in obtaining superior outcomes has been debated. This study was undertaken to determine whether low-volume surgeons attain the same outcomes after PD as high-volume surgeons at high-volume hospitals. PDs undertaken from 2010 to 2012 were obtained from the Florida Agency for Health Care Administration. High-volume hospitals were identified. Surgeon volumes within were determined; postoperative length of stay (LOS), in-hospital mortality, discharge status, and hospital charges were examined relative to surgeon volume. Six high-volume hospitals were identified. Each hospital had at least one surgeon undertaking >= 12 PDs per year and at least one surgeon undertaking < 12 PDs per year. Within these six hospitals, there were 10 "high-volume" surgeons undertaking 714 PDs over the three-year period (average of 24 PDs per surgeon per year), and 33 "low-volume" surgeons undertaking 225 PDs over the three-year period (average of two PDs per surgeon per year). For all surgeons, the frequency with which surgeons undertook PD did not predict LOS, in-hospital mortality, discharge status, or hospital charges. At the six high-volume hospitals examined from 2010 to 2012, low-volume surgeons undertaking PD did not have different patient outcomes from their high volume counterparts with respect to patient LOS, in-hospital mortality, patient discharge status, or hospital charges. Although the discussion of volume for complex operations has shifted toward surgeon volume, hospital volume must remain part of the discussion as there seems to be a hospital "field effect." PMID- 27215721 TI - Small Bowel Perforations by Metallic Grill Brush Bristles: Clinical Presentations and Opportunity for Prevention. AB - Increasing reports on the incidental ingestion of metallic bristles from barbeque grill cleaning brushes have been reported. We sought to describe the clinical presentation and grilling habits of patients presenting after ingesting metallic bristles in an attempt to identify risk factors. We performed a chart review of six patients with documented enteric injury from metallic bristles. Subjects were contacted and administered a survey focused on the events surrounding the bristle ingestion. We arranged for in-home visits to inspect the grill and grill brush whenever possible. Of the six subjects identified, three (50%) were male, five (83%) were white, and they ranged in age from 18 to 65 years (mean 42.5). All complained of abdominal pain. All bristles were identified by CT scan. Three patients underwent laparoscopic enterorrhaphy, and two underwent laparotomy. The remaining patients did not require intervention. None had replaced their grill brush in at least two years. Surgeon's awareness of this unusual injury is important to identify and manage this problem. Alternative methods to clean the grill should be sought and grill brushes should be replaced at least every two years. PMID- 27215722 TI - CT Scan Mapping of Splenic Flexure in Relation to Spleen and its Clinical Implications. AB - Splenic flexure mobilization is a challenging step during left colon resection. The maneuver places the spleen at risk for injury. To minimize this risk, we conducted this study for CT scan mapping of splenic flexure in relation to the spleen. One hundred and sixty CT scans of abdomen were reviewed. The level of the splenic flexure was determined in relation to hilum and lower pole of spleen. These levels were compared with patient demographics. Statistical analysis was performed using Fisher's exact test. The splenic flexure was above the hilum of the spleen in 95 patients (67.86%), at the splenic hilum level in 11 patents (7.88%), between the hilum and lower pole of the spleen in 12 (8.57%), at the lower pole of the spleen in 15 (10.7%) patients and 7 (5%) patients has a splenic flexure that lied below the lower pole of the spleen. Patient demographics showed no statistical significance in regard to splenic flexure location. Splenic flexure lies above the hilum of the spleen in majority of patients. This should be considered as part of operative strategies for left colon resection. PMID- 27215723 TI - Laparoscopic Adrenalectomy for Adrenal Cancer-A Systematic Review. AB - Laparoscopic adrenalectomy is increasingly employed for removal of adrenal masses. As adrenal tumors increase in size, however, their malignant potential likewise increases, raising concerns for the use of laparoscopy for removal of large adrenal malignancies. We present a systematic review of the use of laparoscopic adrenalectomy of large malignant tumors. A PubMed search was undertaken and two independent reviewers reviewed the manuscripts and a methodological index for nonrandomized studies score was determined. Manuscripts with scores greater than eight were included. The primary end points were rate of cancer recurrence, rate of conversion to open, complications, and surgical technique. Our initial search produced 412 manuscripts. After abstract review, 44 manuscripts were scored, of which 19 manuscripts were used. A total of 2183 tumors were removed, of which 517 were malignant. Average follow-up time was 38.7 months. The recurrence rate was 12.9 per cent. The rate of conversion was 3.6 per cent. The main techniques used were transabdominal and retroperitoneal. No significant differences in rate of recurrence or complications were seen when compared with open. Laparoscopic adrenalectomy may be performed for large and malignant tumors; however, most manuscripts on this subject lack significant scientific rigor and follow-up. PMID- 27215724 TI - Not All Abdomens Are the Same: A Comparison of Damage Control Surgery for Intra abdominal Sepsis versus Trauma. AB - Damage control surgery (DCS) was developed to manage exsanguinating trauma patients, but is increasingly applied to the management of peritoneal sepsis and abdominal catastrophes. Few manuscripts compare the outcomes of these surgeries on disparate patient populations. A multi-institutional three group propensity score matched case cohort study comparing penetrating trauma (PT-DCS), blunt trauma (BT-DCS), and intraperitoneal sepsis (IPS-DCS) was performed comparing patients treated with DSC between 2008 and 2013. Propensity scoring was performed using demographic and presenting physiologic data. Four hundred and twelve patients were treated with DCS across two institutions. Propensity matching for age, gender, and initial Acute Physiology and Chronic Health Evaluation II score 80 identified 80 patients per group for comparison. Rate of primary fascial closure was lowest in the IPS-DCS group, and highest in the penetrating trauma DCS group. Intra-abdominal complication rates were highest in the IPS-DCS group. IPS-DCS had increased time to definitive closure compared with the other two groups (RR 1.8; 1.3-2.2; P < 0.03). Mortality at 90 days was highest in the IPS DCS group and patients whose definitive closure was delayed >eight days were more than twice the risk of death at 90 days across all groups. (RR 2.15; 1.2-3.5; P < 0.002). Expected outcomes after the use of DCS for trauma and emergency general surgery are quite different. Despite this difference, prompt abdominal closure at the earliest possible opportunity afforded the best outcome in patients managed via DCS. PMID- 27215725 TI - What Factors Predict Hospital Readmission after Colorectal Surgery? AB - Readmissions pose a significant hardship for patients and constitute a major quality and financial concern for hospitals. We sought to define risk factors associated with hospital readmission after colorectal surgery at a tertiary care hospital. We evaluated readmission among all patients who underwent a colorectal surgical procedure between July 16, 2007 and June 30, 2011. In a cohort of 4879 operative encounters, 492 (10%) were readmitted to the hospital within 30 days of discharge. Procedures with highest readmissions included stoma creation (22%), ileoanal pouch surgery (22%), and total proctocolectomy (30%). In multivariate analysis, the following variables were associated with risk of readmission: postoperative complication, use of anxiolytics, high comorbidity score, patient setting, alcohol use, and stoma creation. Surgeon of record was not associated with readmission. In conclusion, several patient, procedural, and postoperative factors were associated with an increased risk of readmission. Considerably high rates of readmission were noted after stoma creation, ileoanal pouch procedures, and proctocolectomy. Surgeon of record was not associated with risk of readmission, indicating little value to this metric as a physician-specific indicator of quality. PMID- 27215726 TI - Tranexamic Acid Use in United States Trauma Centers: A National Survey. AB - Tranexamic acid (TXA) is an antifibrinolytic agent that is listed as an essential medication by the World Health Organization for traumatic hemorrhage. We determined United States-based surgeons' familiarity with TXA and their use of TXA. An online survey was sent to the 1291 attending surgeon members of a national trauma organization. The survey was organized into three general parts: respondent demographics, perceptions of TXA, and experience with TXA. The survey was completed by 35 per cent of members. TXA was available at 89.1 per cent of centers. Experience with TXA was variable: 38.0 per cent use regularly, 24.9 per cent use it 1 to 2 times per year, 12.3 per cent use it rarely, and 24.7 per cent had never used it. Among surgeons who had used TXA, 77.1 per cent noted that TXA had reduced bleeding, but 22.9 per cent indicated that it had not. Reasons for not routinely using TXA included uncertain clinical benefit (47.7%) and unfamiliarity (31.5%). Finally, 90.5 per cent of respondents indicated that are looking toward national organizations to develop practice guidelines. TXA is widely available in civilian United States trauma centers. Although a majority of surveyed surgeons had used TXA, only 38 per cent use TXA regularly for significant traumatic hemorrhage; principal reasons for this are uncertainty regarding clinical benefit and unfamiliarity with the drug. National guidelines are sought. PMID- 27215727 TI - Institutional Improvement in Weight Loss after Laparoscopic Sleeve Gastrectomy. AB - Laparoscopic sleeve gastrectomy (LSG) is a recent addition to the bariatric surgery armamentarium. It has been demonstrated to be an efficacious stand-alone bariatric procedure in regard to weight loss. This study evaluates the progress of our initial experience with LSG. Retrospective review of prospective data from 2008 to 2010. Compared data between our first operative year of experience with LSG (2008) and our third year of experience (2010). Data compared for up to three years postoperatively. End points were percentage of excess body weight loss (%EWL) and percentage of excess body mass index loss (%EBL). Institutional improvement in %EWL and %EBL rates as our collective experience increased with LSG. Mean increase in %EWL of 14 per cent and mean increase of %EBL of 22 per cent. In our first year performing LSG the institutional weight loss was <50 per cent EWL, which is often cited as a benchmark level for "success" after bariatric surgery. By our third year of experience with LSG we achieved an institutional weight loss >50 per cent EWL. Institutional improvement in weight loss results with LSG as the collective experience increased. Several factors could have contributed to this observation to include a surgical mentorship program and the institution of formal nutritional education. This study demonstrates that institutional experience is a significant factor in weight loss results with LSG. PMID- 27215728 TI - Late Biliary Complications after Pancreaticoduodenectomy. AB - Since morbidity of pancreaticoduodenectomy (PD) has been improved, concerns about late complications have raised. We present a review of long-term biliary complications after PD attended at our institution. The data of 86 patients operated on from January 2001 to May 2014 were examined and incidence of late biliary complications was recorded. The preoperative features of the patients, timing of symptoms appearance, results of diagnostic imaging test, and the management strategies were analyzed. Late biliary complications occurred in 14 patients (16.3%). The median time to diagnosis was 9.50 months. The preoperative peak bilirubin level, need for preoperative drainage and intraoperative blood loss were not significantly different for patients with long-term biliary events. Eight patients (57.14%) developed true biliary strictures. Three of them (37.5%) had experienced a postoperative biliary leak (P < 0.0005) and resulted in benign strictures. The remaining five patients revealed tumor recurrence. Six patients had no biliary obstruction and cholangitis could only be explained through afferent-limb stasis. Late biliary strictures appear predominantly in the first postoperative year and develop more likely if a bile leak occurred in the postoperative period. However, biliary strictures are not always responsible for late biliary symptoms and afferent limb stasis may also be included in the differential diagnosis. PMID- 27215729 TI - Discharge Destination after Elective Femoropopliteal Bypass in Patients without Critical Ischemia. AB - Femoropopliteal bypass (FPB) remains a widely accepted treatment option for symptomatic leg ischemia, even in patients without features of critical limb ischemia (CLI). These patients are revascularized to improve symptoms of exertional limb pain and the goal of such treatment is to increase their ability to ambulate within the community. Therefore, the anticipated initial discharge disposition for a patient without CLI undergoing FPB is back to their home. This study examined the disposition at initial discharge of such patients. Data from the 2012 National Surgical Quality Improvement Program registry was queried for all elective FPB performed in patients without CLI. Analysis was limited to patients surviving to initial discharge who were living independently at home before surgery. Initial disposition was defined as to HOME or to a FACILITY (either rehabilitation or skilled nursing); these constituting the study groups. Univariate analysis and multivariable logistic regression were performed to identify patient risk factors for failure to discharge to home. In-hospital and postoperative events were also recorded and compared. Significance was defined at P <= 0.05. In National Surgical Quality Improvement Program 2012, 1060 cases of elective FPB in patients without CLI were found. The mean+/- SD age of the population was 65 +/- 9 years; 359 (34%) of patients were female; 198 (19%) had a reported race other than white; and most (893, 84%) had hypertension. 60 (6%) patients failed to discharge to home (26 to rehabilitation, 34 to skilled nursing). On univariate analysis, age (FACILITY 68 +/- 11 years vs HOME 65 +/- 9 years, P = 0.009), female gender (55% vs 37%, P < 0.001), nonwhite race (30% vs 18%, P = 0.007), and a history of diabetes (48% vs 33%, P = 0.01), dialysis (5% vs 1.3%, P = 0.02) congestive heart failure (5% vs 1.1%, P = 0.01), or a stroke (cerebrovascular accident, 5% vs 2.6%, P = 0.01) were found to predict failure to discharge to home. On multivariate analysis, female gender [odds ratio (OR) = 2.4, 95% confidence interval = 1.4-4.1, P = 0.002], and a history of congestive heart failure (OR = 4.7, 1.2-18, 0.03] or cerebrovascular accident (OR = 3.4, 1.9 9.4, 0.02) independently predicted failure to discharge to home. FACILITY patients had higher rates of infectious complications (8.3% vs 1.4%, P < 0.001), myocardial infarction (3.3% vs 0.8%, P = 0.05), operative transfusion (22% vs 5.8%, P < 0.001), and unplanned reoperation (17% vs 2.4%, P < 0.001) during their initial hospitalization. Elective FPB results in a low but not negligible failure of initial return to the community in patients without CLI. Female gender and serious comorbidities predict initial discharge to a facility, which is associated with a complicated hospital course. Careful patient selection is important to achieve good outcomes in this population and furthermore study into the specific preoperative functional and socioeconomic factors predicting failure of early return to the community is warranted. PMID- 27215730 TI - Impact of a Quality Improvement Intervention to Increase Brief Alcohol and Drug Interventions on a Level I Trauma Service. AB - Screening and brief intervention (SBI) decreases alcohol use and related consequences among trauma patients. Although SBI is required in Level I and II trauma centers, implementation often is difficult. This study used the Plan-Do Study-Act approach to identify and implement measures to increase the number of patients receiving SBI at a Level I trauma center. A multidisciplinary Quality Improvement Committee with representation from the Trauma Service and SBI Team met monthly during 2011. Stepwise interventions included identifying a resident "champion" responsible for screening, brief intervention, and referral to treatment, including an SBI report at monthly trauma conferences, and incorporating SBI into the trauma order set. Outcomes measures were number of patients screened, patients screening positive, and the number of patients receiving SBI. At baseline, 170 of 362 patients (47%) were screened, 68/170 (40%) had positive screens, and 30/68 (44% of those with positive screens) received SBI services. Quarter 2 saw increases in patients screened-275/437 (63%), patients screening positive (106/275; 39%) and those receiving SBI (60/106; 57%). Increases culminated in Quarter 4 with screening 401/466 (86%; P < 0.001) patients, 208/401 (52%; P < 0.001) patients screening positive, and 114 patients (55%; P = 0.296) receiving services. Use of similar quality improvement measures nationwide could improve rates of provision of this important service. PMID- 27215731 TI - The possible role of air pollution in the link between ADHD and obesity. PMID- 27215732 TI - Scaling-Up Youth-Led Social Justice Efforts through an Online School-Based Social Network. AB - The exploration of social networking sites (SNS) in promoting social change efforts offers great potential within the field of community psychology. Online communities on SNS provide opportunities for bridging across groups, thus fostering the exchange of novel ideas and practices. Currently, there have only been limited efforts to examine SNS within the context of youth-led efforts. To explore the potential of SNS to facilitate the diffusion of social justice efforts between distinct youth groups, we linked three school-based youth-led participatory action research projects involving 54 high school students through a SNS. This study offers an innovative methodological approach and framework, utilizing social network analysis and strategic sampling of key student informants to investigate what individual behaviors and online network features predict student adoption of social change efforts. Findings highlight prospective facilitators and barriers to diffusion processes within a youth-led online network, as well as key constructs that may inform future research. We conclude by providing suggestions for scholars and practitioners interested in examining how SNS can be used to enhance the diffusion of social justice strategies, youth led engagement efforts, and large-scale civic organizing. PMID- 27215733 TI - How and for whom does web-based acceptance and commitment therapy work? Mediation and moderation analyses of web-based ACT for depressive symptoms. AB - BACKGROUND: Acceptance and Commitment Therapy (ACT) has been demonstrated to be effective in reducing depressive symptoms. However, little is known how and for whom therapeutic change occurs, specifically in web-based interventions. This study focuses on the mediators, moderators and predictors of change during a web based ACT intervention. METHODS: Data from 236 adults from the general population with mild to moderate depressive symptoms, randomized to either web-based ACT (n = 82) or one of two control conditions (web-based Expressive Writing (EW; n = 67) and a waiting list (n = 87)), were analysed. Single and multiple mediation analyses, and exploratory linear regression analyses were performed using PROCESS and linear regression analyses, to examine mediators, moderators and predictors on pre- to post- and follow-up treatment change of depressive symptoms. RESULTS: The treatment effect of ACT versus the waiting list was mediated by psychological flexibility and two mindfulness facets. The treatment effect of ACT versus EW was not significantly mediated. The moderator analyses demonstrated that the effects of web-based ACT did not vary according to baseline patient characteristics when compared to both control groups. However, higher baseline depressive symptoms and positive mental health and lower baseline anxiety were identified as predictors of outcome across all conditions. Similar results are found for follow-up. CONCLUSIONS: The findings of this study corroborate the evidence that psychological flexibility and mindfulness are distinct process mechanisms that mediate the effects of web-based ACT intervention. The results indicate that there are no restrictions to the allocation of web-based ACT intervention and that web-based ACT can work for different subpopulations. TRIAL REGISTRATION: Netherlands Trial Register NTR2736 . Registered 6 February 2011. PMID- 27215734 TI - The anti-tubercular drug delamanid as a potential oral treatment for visceral leishmaniasis. AB - There is an urgent requirement for safe, oral and cost-effective drugs for the treatment of visceral leishmaniasis (VL). We report that delamanid (OPC-67683), an approved drug for multi-drug resistant tuberculosis, is a potent inhibitor of Leishmania donovani both in vitro and in vivo. Twice-daily oral dosing of delamanid at 30 mg kg(-1) for 5 days resulted in sterile cures in a mouse model of VL. Treatment with lower doses revealed a U-shaped (hormetic) dose-response curve with greater parasite suppression at 1 mg kg(-1) than at 3 mg kg(-1) (5 or 10 day dosing). Dosing delamanid for 10 days confirmed the hormetic dose-response and improved the efficacy at all doses investigated. Mechanistic studies reveal that delamanid is rapidly metabolised by parasites via an enzyme, distinct from the nitroreductase that activates fexinidazole. Delamanid has the potential to be repurposed as a much-needed oral therapy for VL. PMID- 27215736 TI - Proceedings of the World Molecular Imaging Congress 2015, Honolulu, Hawaii, September 2-5, 2015: General Abstracts. PMID- 27215735 TI - Extended-release acetylsalicylic acid for secondary prevention of stroke and cardiovascular events. AB - INTRODUCTION: Aspirin has been the bedrock of antiplatelet treatment strategies for the secondary prevention of recurrent cardiovascular and cerebrovascular events for the last 3 decades. The limitations of standard aspirin therapy include bleeding, gastrotoxicity, and loss of antiplatelet effect over a 24-hour period in selected high-risk patients. An extended-release (ER) aspirin formulation, Durlaza(r) (New Haven Pharmaceuticals, Inc., North Haven, CT), has been developed to address some of the latter limitations and may provide an alternative to standard aspirin in the secondary prevention of cardiovascular disease. AREAS COVERED: We searched articles describing the use aspirin for secondary prevention of stroke and cardiovascular events in PubMed published until May 2016. This is a comprehensive review which describes active- and placebo-controlled clinical trials, overview of American and European recommendations, controversies surrounding standard aspirin use, and a description of pharmacodynamics of standard and extended release aspirin formulations. Expert commentary: Available data indicates an increased bleeding risk with the use of standard aspirin therapy in conjunction with potent P2Y12 receptor blockers, and/or oral anticoagulants. Trials evaluating the efficacy of replacing aspirin with a low-dose oral anticoagulant in patients with stable cardiovascular disease or acute coronary syndrome are ongoing. Future studies are warranted to determine if the use of ER-ASA formulation may obviate safety concerns surrounding standard aspirin therapy. PMID- 27215738 TI - PEG-assisted reconstruction of the cervical spinal cord in rats: effects on motor conduction at 1 h. PMID- 27215737 TI - Cultured pericytes from human brain show phenotypic and functional differences associated with differential CD90 expression. AB - The human brain is a highly vascular organ in which the blood-brain barrier (BBB) tightly regulates molecules entering the brain. Pericytes are an integral cell type of the BBB, regulating vascular integrity, neuroinflammation, angiogenesis and wound repair. Despite their importance, identifying pericytes amongst other perivascular cell types and deciphering their specific role in the neurovasculature remains a challenge. Using primary adult human brain cultures and fluorescent-activated cell sorting, we identified two CD73(+)CD45(-) mesenchymal populations that showed either high or low CD90 expression. CD90 is known to be present on neurons in the brain and peripheral blood vessels. We found in the human brain, that CD90 immunostaining localised to the neurovasculature and often associated with pericytes. In vitro, CD90(+) cells exhibited higher basal proliferation, lower expression of markers alphaSMA and CD140b, produced less extracellular matrix (ECM) proteins, and exhibited lesser pro-inflammatory responses when compared to the CD90(-) population. Thus, CD90 distinguishes two interrelated, yet functionally distinct pericyte populations in the adult human brain that may have discrete roles in neurovascular function, immune response and scar formation. PMID- 27215739 TI - A surprisingly poor correlation between in vitro and in vivo testing of biomaterials for bone regeneration: results of a multicentre analysis. AB - New regenerative materials and approaches need to be assessed through reliable and comparable methods for rapid translation to the clinic. There is a considerable need for proven in vitro assays that are able to reduce the burden on animal testing, by allowing assessment of biomaterial utility predictive of the results currently obtained through in vivo studies. The purpose of this multicentre review was to investigate the correlation between existing in vitro results with in vivo outcomes observed for a range of biomaterials. Members from the European consortium BioDesign, comprising 8 universities in a European multicentre study, provided data from 36 in vivo studies and 47 in vitro assays testing 93 different biomaterials. The outcomes of the in vitro and in vivo experiments were scored according to commonly recognised measures of success relevant to each experiment. The correlation of in vitro with in vivo scores for each assay alone and in combination was assessed. A surprisingly poor correlation between in vitro and in vivo assessments of biomaterials was revealed indicating a clear need for further development of relevant in vitro assays. There was no significant overall correlation between in vitro and in vivo outcome. The mean in vitro scores revealed a trend of covariance to in vivo score with 58 %. The inadequacies of the current in vitro assessments highlighted here further stress the need for the development of novel approaches to in vitro biomaterial testing and validated pre-clinical pipelines. PMID- 27215740 TI - Osteocyte differentiation and the formation of an interconnected cellular network in vitro. AB - Extracellular matrix (ECM) stiffness and cell density can regulate osteoblast differentiation in two dimensional environments. However, it is not yet known how osteoblast-osteocyte differentiation is regulated within a 3D ECM environment, akin to that existing in vivo. In this study we test the hypothesis that osteocyte differentiation is regulated by a 3D cell environment, ECM stiffness and cell density. We encapsulated MC3T3-E1 pre-osteoblastic cells at varied cell densities (0.25, 1 and 2 * 106 cells/mL) within microbial transglutaminase (mtgase) gelatin hydrogels of low (0.58 kPa) and high (1.47 kPa) matrix stiffnesses. Cellular morphology was characterised from phalloidin-FITC and 4',6 diamidino-2-phenylindole (DAPI) dilactate staining. In particular, the expression of cell dendrites, which are phenotypic of osteocyte differentiation, were identified. Immunofluorescent staining for the osteocytes specific protein DMP-1 was conducted. Biochemical analyses were performed to determine cell number, alkaline phosphatase activity and mineralisation at 2.5 hours, 3, 21 and 56 days. We found that osteocyte differentiation and the formation of an interconnected network between dendritic cells was significantly increased within low stiffness 3D matrices, compared to cells within high stiffness matrices, at high cell densities. Moreover we saw that this network was interconnected, expressed DMP-1 and also connected with osteoblast-like cells at the matrix surface. This study shows for the first time the role of the 3D physical nature of the ECM and cell density for regulating osteocyte differentiation and the formation of the osteocyte network in vitro. Future studies could apply this method to develop 3D tissue engineered constructs with an osteocyte network in place. PMID- 27215741 TI - Low-magnitude high-frequency vibration enhanced mesenchymal stem cell recruitment in osteoporotic fracture healing through the SDF-1/CXCR4 pathway. AB - Low-magnitude high-frequency vibration (LMHFV) has been proven to promote osteoporotic fracture healing. Mechanical stimulation was reported to enhance SDF 1/CXCR4 signalling in mesenchymal stem cells (MSCs). We hypothesised that LMHFV promoted osteoporotic fracture healing by enhancing MSC migration through the SDF 1/CXCR4 pathway. 152 ovariectomised SD-rats received closed femoral fracture in groups of vibration+MSC (VMG) (20 min/d, 5 d/week), vibration+MSC+AMD3100 (VMAG; AMD, a CXCR4 inhibitor) (1 mg/kg/d, intraperitoneal), MSC (MG) (1 * 106 MSC, intracardiac) or control (CG) for a treatment duration of 2, 4 or 8 weeks. MSC migration was evaluated by ex-vivo green fluorescent protein signal in the callus; and fracture healing was examined by weekly radiographs, endpoint computed-tomography and mechanical test. At week-2 and week-4, ex-vivo callus GFP intensity of VMG was significantly higher than other groups (p < 0.05). From week 2 to week-3, both callus width and callus area in VMG were significantly larger; and from week-7 to week-8, smaller than other groups (p < 0.05). At week-8, high density bone volume fraction, bone volume fraction, bone mineral density and stiffness in VMG were significantly higher than other 3 groups (p < 0.05). This study demonstrated that LMHFV promoted MSC migration and fracture healing in osteoporotic rats. This effect was attenuated by CXCR4 inhibitor, providing strong evidence that SDF-1-mediated MSC migration was one of the important mechanisms through which LMHFV enhanced fracture healing. PMID- 27215742 TI - Intermittent exotropia with a positive Bielschowsky head-tilt test. AB - AIMS: To investigate the clinical features of patients with intermittent exotropia (IXT) with and without positive Bielschowsky head-tilt test (BHTT), but without superior oblique palsy. METHODS: We retrospectively reviewed the charts of 118 patients with IXT. Patients were divided into two groups according to positive or negative BHTT. Associated risk factors for positive BHTT in patients with IXT were analysed. The changes in the BHTT result after surgery were also analysed. RESULTS: Fifty patients showed a positive BHTT, and 68 patients showed a negative BHTT. There were significant differences between the groups with regard to the elapsed time from the onset of IXT, the angle of distance exodeviation, inferior oblique muscle overaction, vertical deviation at the primary position, suppression and stereoacuity (all for p<0.05). Risk factors for a positive BHTT among patients with IXT were the elapsed period since the onset of IXT (OR, 1.034; 95% CI 1.008 to 1.061, p=0.011), angle of distance exodeviation (OR, 1.087; 95% CI 1.015 to 1.165, p=0.017) and near stereoacuity (OR, 1.006; 95% CI 1.001 to 1.011, p=0.029). Horizontal muscle surgery alone, without cyclovertical muscle surgery, resulted in a significant decrease in the number of patients with positive BHTT (p<0.01). CONCLUSIONS: A positive BHTT was seen in patients with IXT with larger angle exodeviations, longer elapsed time periods since the onset of IXT and worse stereoacuity. The positive BHTT could be eliminated using horizontal muscle surgery only, without complementary inferior oblique muscle weakening surgery. PMID- 27215743 TI - Clinical implications of serum IgG4 levels in patients with IgG4-related ophthalmic disease. AB - AIMS: The present study aimed to investigate the clinical implications of serum IgG4 levels in patients with IgG4-related ophthalmic disease (ROD). METHODS: The medical records of 31 patients who met the diagnostic criteria for IgG4-ROD were retrospectively reviewed. Twenty-five patients whose serum IgG4 levels could be identified were included. Clinical manifestations and serum IgG4 levels before and after corticosteroid treatment were obtained. Factors associated with relapse were evaluated by comparing the features of patients with disease relapse with those of patients without relapse. RESULTS: Twenty-four patients were 'definite' and one was 'probable' for IgG4-ROD according to the diagnostic criteria. Serum IgG4 levels were higher in patients with systemic involvement (p=0.046). All patients improved clinically after corticosteroid treatment. Serum IgG4 levels decreased after steroid treatment (p=0.005) and normalised in nine patients. In cases of relapse, serum IgG4 levels increased along with the aggravation of symptoms (p=0.047). Serum IgG4 levels that were still elevated (>=135 mg/dL) after steroid treatment (p=0.034) and cessation of steroid treatment during disease remission (p=0.043) were predictive factors for IgG4-ROD relapse. CONCLUSIONS: Serum IgG4 level can be considered an adjunctive marker for treatment response in IgG4-ROD. Patients with serum IgG4 levels that remain elevated after steroid treatment should be carefully observed for relapse. A continuing maintenance dose of oral steroid is recommended to prevent relapse, even when clinical remission is achieved. PMID- 27215744 TI - Five-year visual acuity outcomes and injection patterns in patients with pro-re nata treatments for AMD, DME, RVO and myopic CNV. AB - BACKGROUND: Anti vascular endothelial growth factor (VEGF) therapy is an established treatment for various retinal diseases. Long-term data on injection frequencies and visual acuity (VA), however, are still rare. METHODS: Five-year analysis of real-life VA developments and injection patterns from 2072 patients (2577 eyes; 33 187 injections) with chronically active disease undergoing pro-re nata treatment for age-related macular degeneration (AMD), diabetic macular oedema (DME), retinal vein occlusion (RVO) and myopic choroidal neovascularisation (CNV). RESULTS: Maximum mean VA gain in year 1 was+5.2 letters in AMD, +6.2 in DME, +10 in RVO and+7.2 in myopic CNV. Over 5 years, however, VA in patients with AMD declined. By year 5, 34% of patients with AMD had experienced VA loss of >15 letters, 56% had remained stable and 10% had gained >15 letters. Long-term VA developments in DME and RVO were more favourable with 81% of DME and 79% of patients with RVO gaining or maintaining vision at 5 years. In AMD, median injection frequency was six in year 1 and between four and five in consecutive years. In DME and RVO, median injection frequency was six in year 1 but lower compared with AMD in consecutive years. Injection frequency in DME was weakly associated with patient age (rs=0.1; p=0.03). CONCLUSIONS: In AMD, the initial VA gain was not maintained long term despite higher injection numbers compared with DME, RVO and myopic CNV. The presented real-world data provide a peer-group-based estimate of VA developments and injection frequencies for counselling patients undergoing long-term anti-VEGF therapy. PMID- 27215746 TI - Are There Indications for Total Pancreatectomy in 2016? AB - An elective total pancreatectomy (TP) was first performed by Eugene Rockey of Portland, Oregon, in 1942. In the 1960s and 1970s, TP was the routine resection for pancreatic cancer in many centers because of fear of a leaking pancreatojejunostomy and multicentricity of the disease but the result used to be dreadful (in today's perspective). However, more recently, postoperative mortality and morbidity after pancreatic resections have improved due to better anastomotic technique and pre-, peri- and postoperative care. Today, TP - despite being a more extensive operation - can be offered with about the same operation risk as that of a Whipple procedure. Also, major improvements in the control of diabetes have been seen and there is actually an ongoing discussion on the actual severity of the diabetic state after TP. Also, the development of modern pancreatic enzyme preparations with sufficient control of endocrine and exocrine pancreatic insufficiency provides options for overcoming the postoperative problems following TP. Due to the improved results, there are today different - and more specific - indications than before for TP: malignant tumors growing from the pancreatic head into the left pancreas, pancreatic head cancer where it is not possible to secure a tumor-free resection margin with extended resection or with dubious changes in the pancreatic main duct at frozen section, recurrent malignancy in the pancreatic remnant, at cancer surgery with resection of the celiac trunk, rescue pancreatectomy after a leaking pancreatojejunostomy with sepsis or bleeding after a Whipple-type first resection, multifocal intraductal papillary mucinous neoplasm with potentially malignant foci present in all parts of the gland, multiple metastases of renal cell carcinoma and melanoma without any residual tumor outside the pancreatic gland (possibly also other specified but uncommon metastatic tumors with a potential for cure by pancreatectomy), multifocal neuroendocrine tumors including multiple endocrine neoplasia and hereditary pancreatic cancer with a high grade of cancer penetration risk for the bearers. PMID- 27215747 TI - Erratum. PMID- 27215748 TI - The relevance of gender in the care of hip fracture patients. AB - As in many conditions, gender interplays with other social structures of inequality to impact upon women's and men's health and healthcare. This narrative review examines knowledge about sex, gender and hip fracture and suggests ways of highlighting the influence of gender in hip fracture healthcare. These will be considered in relation to two areas. Firstly the multifactorial dimension of hip fractures which identifies ethnicity, marital status, lifestyle, co-morbidities, environment in relation to falls and osteoporosis as important factors influencing the experience of hip fracture. Secondly the importance of acknowledging gender as a key element within research and management of care. Implications for practice are that we need a raised awareness of gender when we assess and care for patients, to ask critical questions about the gender bias in the evidence we use and reflect on how services and care practices may be biased towards gendered assumptions. PMID- 27215749 TI - The effect of aclidinium bromide on daily respiratory symptoms of COPD, measured using the Evaluating Respiratory Symptoms in COPD (E-RS: COPD) diary: pooled analysis of two 6-month Phase III studies. AB - BACKGROUND: Reducing the severity of respiratory symptoms is a key goal in the treatment of chronic obstructive pulmonary disease (COPD). We evaluated the effect of aclidinium bromide 400 MUg twice daily (BID) on respiratory symptoms, assessed using the Evaluating Respiratory Symptoms in COPD (E-RS(TM): COPD) scale (formerly EXACT-RS). METHODS: Data were pooled from the aclidinium 400 MUg BID and placebo arms of two 24-week, double-blind, randomized Phase III studies evaluating aclidinium monotherapy (ATTAIN) or combination therapy (AUGMENT COPD I) in patients with moderate to severe airflow obstruction. Patients were stratified by Global initiative for chronic Obstructive Lung Disease (GOLD) Groups A-D. Change from baseline in E-RS scores, proportion of responders (patients achieving pre-defined improvements in E-RS scores), and net benefit (patients who improved minus patients who worsened) were analyzed. RESULTS: Of 1210 patients, 1167 had data available for GOLD classification. Mean (standard deviation) age was 63.2 (8.6) years, 60.7 % were male, and mean post bronchodilator forced expiratory volume in 1 s was 54.4 % predicted. Compared with placebo, aclidinium 400 MUg BID significantly improved RS-Total (2.38 units vs 0.79 units, p < 0.001) and domain scores (all p < 0.001) at Week 24, and doubled the likelihood of being an RS-Total score responder (p < 0.05), irrespective of GOLD group. The net benefit for RS-Total (Overall: 56.9 % vs 19.4 %; A + C: 65.7 % vs 6.3 %; B + D: 56.0 % vs 20.8 %, for aclidinium 400 MUg BID and placebo respectively; all p < 0.05) and domain scores (all p < 0.05) was significantly greater with aclidinium compared with placebo, in both GOLD Groups A + C and B + D. CONCLUSIONS: Aclidinium 400 MUg BID significantly improved respiratory symptoms regardless of the patients' level of symptoms at baseline. Net treatment benefit was similar in patients with low or high levels of symptoms. TRIAL REGISTRATION: ATTAIN (ClinicalTrials.gov identifier: NCT01001494 ) and AUGMENT COPD I (ClinicalTrials.gov identifier: NCT01437397 ). PMID- 27215750 TI - What is the context of contextual cueing? AB - People have a powerful ability to extract regularities from noisy environments and to utilize this knowledge to assist in visual search. Extensive research has shown that this ability, termed contextual cueing (CC), is robust and ubiquitous, but it is still unclear what exactly is the context that is being leaned. Researchers have typically focused on how people learn spatial configuration regularities and have hence used simplified, meaningless search stimuli. Here, observers performed visual search tasks using images of real-world objects. The results revealed that, contrary to past findings, the repetition of either arbitrary spatial information or identity information was not sufficient to produce context learning. Instead, learning was found only when both types of information were repeated together. These results were further replicated in hybrid search tasks, in which subjects looked for multiple target templates. Together, these data suggest that CC is more limited than typically assumed, yet this learning is highly robust. PMID- 27215752 TI - Nanoionic devices enabling a multitude of new features. AB - In recent years, interesting nanoscale phenomena caused by physical or chemical effects due to local ion transfers near heterointerfaces using ionic conductors have been discovered, and the so-called "nanoionic devices" (which apply new functionalities gained by exploiting those phenomena) are being proposed. Up until now, nanoionic devices with unique functions that have been unattainable with conventional semiconductor devices have been developed. These devices include brain-type devices, completely solid-state electric-double-layer transistors, multi-functional on-demand-type devices, superconducting elements capable of modulating transition temperature, and so on. As for research and development on nanodevices for next-generation information and communication technologies, expected developments of these devices in the field of solid-state ionics are introduced based on the results of our research. PMID- 27215751 TI - Prevalence of previously undiagnosed abdominal aortic aneurysms in the area of Como: the ComoCuore "looking for AAA" ultrasonography screening. AB - The prognosis for abdominal aortic aneurysm (AAA) rupture is poor. Long-term follow-up of population-based randomized trials has demonstrated that ultrasound (US) screening for abdominal aortic aneurysms (AAAs) measuring 3 cm or greater decreases AAA-related mortality rates and is cost-effective. We though to prospectively perform during a 26-month period a limited US examination of the infrarenal aorta in volunteers of both gender aged 60-85 years without history of AAA living in the area of Como, Italy. From September 2010 to November 2013 ComoCuore, a no-profit nongovernmental association, enrolled 1555 people (aged 68.8 +/- 6.8 years; 48.6 % males). Clinical data and a US imaging of the aorta were collected for each participant. AAA was found in 22 volunteers (1.4 %) mainly males (2.5 % in males vs. 0.4 % in females p = 0.005). Overall, the prevalence of cardiovascular risk factors was higher in patients with vs. without AAA (mean 2.9 +/- 3.0 vs. 1.4 +/- 1.0 respectively, p < 0.0001). Independent predictors of AAA on multivariate analysis were age (OR 1.14, 1.06-1.22; p < 0.0001), male gender (OR 8.23, 1.79-37.91; p = 0.007), and both current (OR 4.98, 1.57-15.79; p = 0.007) and previous smoking (OR 2.76, 1.12-8.94; p = 0.03). Our study confirms the feasibility of one time US screening for AAA in a large cohort of asymptomatic people. Independent predictors of AAA were male sex, older age and a history of smoking. Accordingly to recent data the prevalence of AAA seems to be declining, maybe due to a reduction of smoking in Italy. PMID- 27215755 TI - [Psoriasis]. PMID- 27215753 TI - Stimulatory Effect of Balanced Deep-Sea Water Containing Chitosan Oligosaccharides on Glucose Uptake in C2C12 Myotubes. AB - Deep-sea water (DSW) and chitosan oligosaccharides (COS) have recently drawn much attention because of their potential medical and pharmaceutical applications. Balanced DSW (BDSW) was prepared by mixing DSW mineral extracts and desalinated water. This study investigated the effects of BDSW, COS, and BDSW containing COS on glucose uptake and their mode of action in mature C2C12 myotubes. BDSW and COS increased glucose uptake in a dose-dependent manner. BDSW containing COS synergistically increased glucose uptake; this was dependent on the activation of insulin receptor substrate 1 and protein kinase C in insulin-dependent signaling pathways as well as liver kinase B1, AMP-activated protein kinase, and mammalian target of rapamycin in insulin-independent signaling pathways. Quantitative real time polymerase chain reaction revealed that the expressions of the following genes related to glucose uptake were elevated: glucose transporter 4 (GLUT4), insulin-responsive aminopeptidase, and vesicle-associated membrane protein 2 for abundant proteins of GLUT4 storage vesicles (GSVs); syntaxin 4 and soluble N ethylmaleimide-sensitive factor attachment protein 23 for trafficking between the plasma membrane and GSVs; and syntaxin 6 and syntaxin 16 for trafficking between GSVs and the trans-Golgi network. Taken together, these results suggest BDSW containing COS has a greater stimulatory effect on glucose uptake than BDSW or COS alone. Moreover, this effect is mediated by the stimulation of diverse signaling pathways via the activation of main signaling molecules related to GSV trafficking. PMID- 27215754 TI - [Psoriasis in special localizations]. AB - A large proportion of patients with plaque psoriasis suffer from psoriatic lesions of the scalp, nails, and intertrigines. These locations can also be soley or predominantly affected. Scalp psoriasis, nail psoriasis, and inverse psoriasis are often perceived as particularly stigmatizing. Involvement of these parts of the body is associated with an increased risk of psoriatic arthritis. Location specific features must be considered when choosing treatment. Evidence for topical therapy of scalp psoriasis with steroids and combinations of steroids and vitamin D analogues is high. These agents are regarded as safe and effective treatments of first choice. Efficacy of TNF antagonists and apremilast is well documented for refractory scalp psoriasis. Nail psoriasis often responds insufficiently to topical therapy. Several effective systemic medications including methotrexate and TNF antagonists are available for treatment of severe forms. Controlled trials for treatment of inverse psoriasis are scarce. Topical steroids, vitamin D analogues, dithranol, and off-label calcineurin inhibitors are used in clinical practice. This review provides a survey on the clinical presentation and current evidence for treatment of psoriasis in challenging locations. PMID- 27215757 TI - Understanding Experiences of Diabetes Medications Among African Americans Living With Type 2 Diabetes. AB - African American (AA) adults are disproportionally affected by type 2 diabetes and are diagnosed at an earlier age, but are less adherent to diabetes medications compared with the general population. This qualitative study sought to describe the experiences of taking diabetes medications among midlife AA men and women with type 2 diabetes and to identify factors that influence these experiences. Fifteen AAs completed semistructured interviews. Using the Roy adaptation model, thematic analysis coded for both adaptive and ineffective experiences. Adaptive experiences included self-confidence in one's ability to control diabetes, a belief in the value of diabetes medication, assuming responsibility for one's health, developing a routine for taking medication, and positive relationships with the care team. Ineffective experiences for medication taking included: feeling powerless over diabetes, self-blame, and fear. One's self-concept as a person with diabetes, as well as assuming the role of "medication taker," were prominent themes. PMID- 27215758 TI - The influence of marital status on the use of breast, cervical, and colorectal cancer screening. AB - PURPOSE: To examine the impact of marital status on the use of screening for breast, cervical, and colorectal cancer. METHODS: We relied on 2012 Behavioral Risk Factor Surveillance System Survey age-appropriate screening cohorts. Appropriate screening for breast, cervical, and colorectal cancer was determined according to United States Preventive Services Task Force recommendations in effect at the time of the 2012 survey. Complex samples logistic regression models were performed to examine the effect of marital status on cancer screening. RESULTS: Overall, 81.6, 83.9, and 68.9% of married participants underwent breast, cervical, and colorectal cancer, respectively, relative to 74.2, 75.1, and 60.9% for divorced/widowed/separated, individuals, and 74.7, 78.7, and 53.4% for never married individuals. Marital status (married vs. never married) was an independent predictor of screening for all cancers examined: breast cancer, odds ratio (OR): 1.42 (95% confidence interval [CI]: 1.25-1.61); cervical cancer, OR: 1.29 (95% CI: 1.16-1.43); colorectal cancer, OR: 1.63 (95% CI: 1.51-1.77). Gender specific subgroup analyses for colorectal cancer suggests that marital status may exert a greater effect in men, relative to women (married men: OR 1.75, 95% CI: 1.56-1.96; married women: OR: 1.52, 95% CI: 1.35-1.70). CONCLUSION: Being married is associated with increased utilization of breast, cervical, and colorectal cancer screening. The influence of marital status was greater in men relative to women eligible for colorectal cancer screening. Our results emphasize the importance of social determinants of health-seeking behaviors. PMID- 27215759 TI - Alexithymia in Chronic Pain Disorders. AB - This review proposes a critical discussion of the recent studies investigating the presence of alexithymia in patients suffering from different chronic pain (CP) conditions. The term CP refers to pain that persists or progresses over time, while alexithymia is an affective dysregulation, largely observed in psychosomatic diseases. Overall, the examined studies showed a high prevalence of alexithymia, especially difficulties in identifying feelings, in all the different CP conditions considered. However, the association between alexithymia and pain intensity was not always clear and in some studies this relationship appeared to be mediated by negative effect, especially depression. The role of alexithymia in CP should be clarified by future studies, paying particular attention to two aspects: the use of additional measures, in addition to the Toronto Alexithymia Scale, to assess alexithymia, and the analysis of the potential differences in the evolution of different CP conditions with reference to the presence or absence of alexithymia. PMID- 27215760 TI - Chagas cardiomyopathy: The potential effect of benznidazole treatment on diastolic dysfunction and cardiac damage in dogs chronically infected with Trypanosoma cruzi. AB - Cardiac involvement represents the main cause of mortality among patients with Chagas disease, and the relevance of trypanocidal treatment to improving diastolic dysfunction is still doubtful. In the present study, we used a canine model infected with the benznidazole-sensitive Berenice-78 Trypanosoma cruzi strain to verify the efficacy of an etiologic treatment in reducing the parasite load and ameliorating cardiac muscle tissue damage and left ventricular diastolic dysfunction in the chronic phase of the infection. The effect of the treatment on reducing the parasite load was monitored by blood PCR and blood culture assays, and the effect of the treatment on the outcome of heart tissue damage and on diastolic function was evaluated by histopathology and echo Doppler cardiogram. The benefit of the benznidazole-treatment in reducing the parasite burden was demonstrated by a marked decrease in positive blood culture and PCR assay results until 30days post-treatment. At this time, the PCR and blood culture assays yielded negative results for 82% of the treated animals, compared with only 36% of the untreated dogs. However, a progressive increase in the parasite load could be detected in the peripheral blood for one year post-treatment, as evidenced by a progressive increase in positive results for both the PCR and the blood culture assays at follow-up. The parasite load reduction induced by treatment was compatible with the lower degree of tissue damage among animals euthanized in the first month after treatment and with the increased cardiac damage after this period, reaching levels similar to those in untreated animals at the one-year follow-up. The two infected groups also presented similar, significantly smaller values for early tissue septal velocity (E' SIV) than the non-infected dogs did at this later time. Moreover, in the treated animals, an increase in the E/E' septal tissue filling pressure ratio was observed when compared with basal values as well as with values in non-infected dogs. These findings strongly suggest that the temporary reduction in the parasite load that was induced by benznidazole treatment was not able to prevent myocardial lesions and diastolic dysfunction for long after treatment. PMID- 27215761 TI - Paediatric early warning systems (PEWS) in the ED. PMID- 27215762 TI - In response to 'Top 10 lessons from the Glasgow major incidents'. PMID- 27215763 TI - The benefit/risk ratio challenge in clinical research, and the case of HIV cure: an introduction. AB - This piece introduces the JME symposium 'The benefit/risk ratio challenge in clinical research, and the case of HIV cure.' PMID- 27215764 TI - Snakes and ladders: state interventions and the place of liberty in public health policy. AB - In this paper I outline and explore some problems in the way that the Nuffield Council of Bioethics' report Public Health: Ethical Issues (2007) presents its 'Intervention Ladder'. They see the metaphor of a ladder both as capturing key normative priorities and as making a real and important contribution to ethical policymaking in public health. In this paper I argue that the intervention ladder is not a useful model for thinking about policy decisions, that it is likely to produce poor decisions and that it is incompatible with the report's stated approach to relevant public health policy values. PMID- 27215765 TI - Coparenting after marital dissolution and children's mental health: a systematic review. AB - OBJECTIVE: Research has shown that coparenting is a vital family mechanism in predicting mental health in children and adolescents. Considering the increasing prevalence of marital dissolution in Western societies, the objective of this systematic review was to summarize the key results of empirical studies that tested the association between mental health of children and coparenting after marital dissolution. DATA SOURCE: The studies were obtained from three databases (PsycInfo, PubMed, and Web of Knowledge), published between January 2000 and October 2014. The titles, abstracts, and key words of the generated citations were independently reviewed by two investigators to consensually select the articles that met the inclusion criteria. Articles that used psychometrically valid tools to measure at least one mental health indicator and at least one dimension of coparenting in samples with divorced parents were included in the review. DATA SYNTHESIS: Of the 933 screened articles, 11 met the inclusion criteria. Significant positive associations were found between coparental conflict and behavioral problems and symptoms of anxiety, depression, and somatization. Significant positive associations were also found between other specific dimensions of coparenting (coparental support, cooperation, and agreement), overall mental health, self-esteem, and academic performance. CONCLUSIONS: The integrated analysis of these studies suggests that coparenting is a key mechanism within the family system for the prediction of child mental health after marital dissolution, and thus, it is recommended that pediatricians, psychologists, and other health professionals consider coparenting as a psychosocial variable for children's mental health assessment and diagnosis. PMID- 27215767 TI - Non-invasive mechanical ventilation in elderly patients: A narrative review. AB - The treatment of acute respiratory failure with non-invasive ventilation (NIV) as a first-line therapy is increasingly common in intensive care units. The reduced invasiveness of NIV leads to better outcomes than endotracheal intubation in carefully selected groups of patients. Furthermore, the use of NIV as a palliative treatment for respiratory failure and dyspnea has become increasingly common. NIV also has an impact on the use of "do not intubate" orders. In the present narrative review, we explore the use and outcome of NIV in elderly patients. To accomplish this, we reviewed the most recent available medical literature. Geriatr Gerontol Int 2017; 17: 689-696. PMID- 27215766 TI - Coping with Pain in the Face of Healthcare Injustice in Patients with Sickle Cell Disease. AB - To evaluate the pain coping strategies of patients with sickle cell disease (SCD) who experience healthcare injustice from either physicians or nurses during medical visits for pain management. It is unknown how patients' coping with pain relates to their experiences of healthcare injustice from physicians or nurses. This descriptive comparative study included adult outpatients with SCD who completed the PAINReportIt(r), Healthcare Justice Questionnaire(c), and Coping Strategies Questionnaire-SCD. Data were analyzed using independent t tests. Frequent coping strategies of patients who experienced healthcare justice from physicians were praying-hoping and from nurses were praying-hoping, calming self statements, diverting attention, and increasing behavioral activity. In contrast, frequent coping strategies of patients who experienced healthcare injustice from physicians were catastrophizing and isolation and from nurses were isolation. Patients who experienced healthcare justice used different sets of pain coping strategies than those who experienced healthcare injustice during medical visits for pain management. PMID- 27215768 TI - Racial/Ethnic Differences in Predictors of Mental Health Treatment in Persons with Comorbid Diabetes and Depression. AB - Diabetes and depression are two of the most frequently diagnosed health conditions in the United States and often co-occur. The present study examines racial/ethnic differences in predictors of mental health service use among a national sample of African Americans, Hispanics, and non-Hispanic Whites with a self-reported diabetes and depression diagnosis. Multiple logistic regression was used to analyze a cross-sectional sample (N = 3377) of the 2012 National Health Interview Survey (NHIS), a nationally representative, cross-sectional survey. African Americans were less likely to have visited a mental health professional in the last 12 months (odds ratio [OR] = .634, confidence interval [CI] [0.429, 0.911]). Significant odds ratios also uncovered results for the "never married" (OR = 1.737, CI [1.322, 2.281]) category. Also for the entire sample, being 55 years or older (OR = .352, CI [0.234, 0.533]) was found to be strongly associated with mental health service use for individuals with diabetes. Being unemployed or not in the labor force increased the odds of mental health service use in persons with diabetes and depression, whereas having less than a high school diploma or Graduate Equivalency Diploma decreased odds of visits (OR = .611, CI [0.394, 0.945]) as did not having health insurance (OR = .540, CI [0.365, 0.800]). Racial/ethnic variation in mental health service utilization exists among persons with self-reported diabetes and depression. Due to the challenges associated with comorbid depression and diabetes, as well as the impact depression can have on diabetes self-management, it is imperative that more strategies for managing both depression and diabetes be explored. PMID- 27215769 TI - Effects of lifestyle and physical exercise on impaired glucose tolerance in middle-aged men. AB - BACKGROUND: The rapid lifestyle changes in China correlate with alarming rise of diabetes mellitus (DM) and its comorbidities such as cardiovascular disease. Impaired glucose intolerance (IGT) is one of the risk factors associated with DM onset. We investigated the relation between lifestyle such as meat and carbohydrate intake, smoking and alcohol and physical exercise on IGT in 349 middle-aged (age range 41 to 59 years) Chinese men with no history of DM or any related treatments. METHODS: After being assessed for glucose tolerance, study participants were classified into the IGT (N.=172) and NGT (N.=177) group. Using a questionnaire they were assessed for daily meat and carbohydrate intake, smoking and alcohol drinking habits and physical exercise. Associations were analyzed with a single-factor ANOVA and regression and controlled for body mass index (BMI). RESULTS: Significant differences between IGT and NGT groups were found for high appetite intake (>400 g/day: 91.9% vs. 41.8%, respectively, P<0.01), high meat intake (>100 g/day: 62.2% vs. 40.7%, P<0.01), frequent smoking (20 cigarettes/day during more than 2 years: 51.2% vs. 9.05%, P<0.01) and frequent physical exercise (>= 3 times/week: 15.1% vs. 65.5%, respectively, P<0.01). CONCLUSIONS: Our study found that high carbohydrate and meat intake, frequent smoking and low physical exercise associate with IGT in middle-aged men. Further studies are needed to assess whether diminishing or eliminating these risk factors could reverse IGT in middle age, both in men and women. PMID- 27215770 TI - Diabetes education program with emphasis on physical exercise in subjects with type 2 diabetes: a community-based quasi-experimental study. AB - BACKGROUND: Diabetes mellitus (DM) requires permanent multidisciplinary treatment. This study investigated the effects of an educational program with emphasis on physical exercise on biological health markers of subjects with type 2 DM (T2DM). METHODS: This was a quasi-experimental study with subjects who attended a diabetes education program over one year. At the beginning, middle and end of the annual cycle, glycated hemoglobin (HbA1c), lipid profile and anthropometry were measured. The program offered two hours of educational and exercise interventions twice a week. Before and after each session capillary blood glucose (BG) was measured. Statistical analysis used Pearson's chi2, paired t, ANOVA-RM and MANOVA tests to compare results with significance levels set at P<0.05. RESULTS: Data of 103 subjects (73% women) were analyzed. Mean age was 64.1+/-10.8 years and 23% of participants were on insulin therapy. As an acute effect mean BG decreased significantly (P<0.001) from 157.5+/-61.5 mg/dL to 128.5+/-47.5 mg/dL after the intervention sessions, also resulting in increased prevalence of normoglycemic BG (from 44.0% to 68.6%). Chronic effects of participation in the program could be perceived through significant reduction (P<0.05) from beginning to end of the study of mean BG (from 144.8+/-5.0 mg/dL to 135.3+/-3.1 mg/dL), HbA1c (from 7.3+/-1.3% to 7.1+/-1.0%) and triglycerides (from 177.9+/-121.3 mg/dL to 150.5+/-130.9 mg/dL). There were no significant changes in anthropometric variables. CONCLUSIONS: A diabetes education program with emphasis on supervised physical exercise improved triglycerides and glycemic control in subjects with T2DM. PMID- 27215771 TI - Agility and change of direction in soccer: differences according to the player ages. AB - BACKGROUND: The goal of this study was to compare the changes of direction speed (CODS) and reactive agility (RA) in soccer players of different ages, in order to optimize the best training of these skills. METHODS: One hundred eighty-seven players, divided into bi-annual age-groups, U12, U14, U16 and U18, performed two tests: Y-Agility Test, carried out in planned and reactive mode (Y-PLAN and Y REAC) and Illinois for Change of Direction Test (ICODT). Difference between Y REAC minus Y-PLAN represents the index of reactivity (REAC-INDEX). RESULTS: MANOVA showed significant differences among groups (F3,182=14.591; P<0.01; eta2p=0.244). Y-PLAN showed significant differences only between U12 and the other groups (P<0.01). ICODT results were significantly different between the groups U12 and U14 and the other groups (P<0.01). Significant Pearson's correlations between Y-TEST and ICODT, for the three categories of young players (0.398 P<0.05; 0.615 P<0.01; 0.608 P<0.01 respectively), were found, whereas no significant correlation was found in U18 group. CONCLUSIONS: The best performance of Y-PLAN and ICODT, through age, depends on physical skill level, whereas the best RA results depend on technique and experience that help the players to use anticipatory skill. The high correlations between CODS and RA performances, differently than adult athletes, suggest that an effective work program for young players may include RA and CODS training at the same time. PMID- 27215772 TI - Introducing a new entity: underwater 12-lead exercise ECG. PMID- 27215773 TI - Suitability of the alkalistable carbonic anhydrase from a polyextremophilic bacterium Aeribacillus pallidus TSHB1 in biomimetic carbon sequestration. AB - Carbonic anhydrase (CA) was produced from the polyextremophilic (halotolerant, moderately thermophilic and alkaliphilic) bacterium Aeribacillus pallidus TSHB1 isolated from water and sediment samples of Choti Anhoni hot spring of Pipariya, Madhya Pradesh (India), is being reported to be suitable for carbon sequestration. Growth and CA production were inhibited at higher CO2 concentration (5-10 %). Under optimized culture variables (tryptone 0.8 %, yeast extract 0.08 %, glucose 1 %, micronutrient solution 1 %, inoculums size 1.10 %, agitation 200 at pH 8, and temperature 55 degrees C), 3.7-fold higher CA production was attained than that under unoptimized conditions. The zymogram analysis of the partially purified CA revealed an activity band corresponding to 32 kDa. The enzyme is stable in the pH range between 8.0 and 11.0 with T 1/2 of 40, 15, and 8 min at 60, 70, and 80 degrees C, respectively. The CA of A. pallidus displayed a marked enhancement in the rate of CaCO3 precipitation from aqueous CO2. The CA-aided formation of CaCO3 was 42.5 mg mg(-1) protein. Scanning electron microscopy revealed the formation of rhomboid calcite crystals. This is the first report on the production and applicability of CA from the polyextremophilic A. pallidus in carbon sequestration. PMID- 27215774 TI - Does load uncertainty affect adaptation to catch training? AB - Catching relies on anticipatory and compensatory control processes. Load uncertainty increases anticipatory and compensatory neuromotor effort in catching. This experiment tested the effect of load uncertainty in plyometric catch/throw training on elbow flexion reaction time (RT), movement time (MT) and peak torque, as well as the distribution of anticipatory and compensatory neuromotor effort in catching. We expected load uncertainty training to be superior to traditional training for improving elbow flexion MT and peak torque, as well as for reallocating neuromotor effort from compensatory to anticipatory control in catching. Three groups of men (mean age = 21), load knowledge training (K) (n = 14), load uncertainty training (U) (n = 13) and control (C) (n = 14), participated. Groups K and U trained three times/week for 6 weeks using single arm catch/throw exercises with 0.45-4.08 kg balls. Sets involved 16 repetitions of four different ball masses presented randomly. Group K had knowledge of ball mass on every repetition, whereas group U never did. Change scores were analyzed using Kruskal-Wallis tests and follow-up Wilcoxon rank-sum tests. Group K improved both RT and MT (by 6.2 and 12 %, respectively), whereas group U did not. Both groups K and U improved peak eccentric elbow flexion torque. Group K reallocated neuromotor effort from compensatory to anticipatory processes in the biceps, triceps and the all muscle average, whereas group U did so in the triceps only. In sum, plyometric catch/throw training caused a reallocation of neuromotor effort from compensatory to anticipatory control in catching. However, load uncertainty training did not amplify this effect and in fact appeared to inhibit the reallocation of neuromotor effort from compensatory to anticipatory control. PMID- 27215776 TI - Ventilatory Responses to Hypercarbia in Infants of Mothers Who Smoke and Misuse Substances. AB - The ventilatory response of infants of mothers who smoke and misuse substances and controls to carbon dioxide was assessed at 6-12 weeks and the perinatal period. Infants of mothers who smoke and misuse substances had a dampened response at the peak age of sudden infant death syndrome, greater than in the perinatal period. PMID- 27215775 TI - Exploring the relationship between boredom proneness and self-control in traumatic brain injury (TBI). AB - Characterized as an agitated state in which the individual is motivated to engage in their environment but all attempts to do so fail to satisfy, boredom represents a disengaged attentional state that is associated with negative affect and poor self-control. There have been anecdotal reports of increased levels of boredom post-traumatic brain injury (TBI). For the first time, we provide objective evidence that TBI patients do indeed experience higher levels of boredom proneness. Hierarchical regression analyses showed that the presence and severity of head injury were a significant positive predictor of levels of boredom proneness and a negative predictor of self-control. As with healthy controls, TBI patients showed a strong negative correlation between boredom proneness and self-control-those with lower levels of self-control exhibited higher levels of boredom proneness. This was despite the fact that our TBI patients reported higher overall levels of self-control (probably concomitant with their older mean age). The TBI patients also showed strong positive correlations between boredom proneness and measures of physical aggression and anger. Together, this suggests that patients with TBI may be more susceptible to increased levels of boredom proneness and other negative affective states that arise as a consequence of failures of self-control. PMID- 27215777 TI - Thrombocytopenia Pitfalls: Misdiagnosing Type 2B von Willebrand Disease as Ethylenediaminetetraacetic Acid-Dependent Pseudothrombocytopenia. PMID- 27215778 TI - Fine Motor Differences and Prenatal Serotonin Reuptake Inhibitors Exposure. AB - OBJECTIVE: To examine fine motor differences between preschoolers with prenatal exposure to serotonin reuptake inhibitor (SRI) and children of mothers with major depressive disorder. STUDY DESIGN: A subset of children (N = 40) from a larger study on the effects of prenatal SRI and untreated major depressive disorder participated in a kinematic task of visual motor and fine motor functions at ages 4-5 years: exposure to SRI (n = 15), untreated major depressive disorder exposure (n = 10), and the control group (n = 15). The task was to reach and secure a peg, then drop it in a small hole near the start position in the light condition with full visibility or in the glow condition in which a phosphorescent peg glows in the dark. Movement-tracking software measured the positioning of the moving hand and fingers. RESULTS: In the glow condition, the group exposed to SRIs had a greater proportion of maximum aperture than the group with major depressive disorder, and the group exposed to SRIs was slower than the group with major depressive disorder to drop the peg into the hole. In the glow condition, the trajectory of the group exposed to SRI was less straight than the group with major depressive disorder, and the group with major depressive disorder had a straighter trajectory than the control group. CONCLUSION: This study provides evidence that preschool aged children with prenatal SRI exposure have poorer fine motor and visual-motor control compared with those with prenatal untreated major depressive disorder. PMID- 27215779 TI - Paracetamol Accelerates Closure of the Ductus Arteriosus after Premature Birth: A Randomized Trial. AB - OBJECTIVE: To study the biologic effect of paracetamol, an inhibitor of prostaglandin synthase, on early closure of ductus arteriosus, and to evaluate possible adverse effects associated with the drug. STUDY DESIGN: In a controlled, double-blind, phase I-II trial, very low gestational age (<32 weeks) infants requiring intensive care were randomly assigned to intravenous paracetamol or placebo (0.45% NaCl). A loading dose of 20 mg/kg was given within 24 hours of birth, followed by 7.5 mg/kg every 6 hours for 4 days. Daily cardiac ultrasound examinations of ductal calibers were performed before the first dose, and until 1 day after the last dose. The main outcome was a decrease in the ductal caliber without side effects. RESULTS: Of 63 screened infants, 48 were randomized: 23 were assigned to paracetamol and 25 to placebo. Before the intervention, their ductal calibers were similar. During the intervention, the ductus closed faster in the paracetamol group (hazard ratio 0.49, 95% CI 0.25-0.97, P = .016). The mean (95% CI) postnatal ages for ductal closure were 177 hours (31.1-324) for the paracetamol-treated vs 338 hours (118-557) for controls (P = .045). Paracetamol serum levels were within the therapeutic range, and no adverse effects were evident. CONCLUSIONS: Prophylactic paracetamol induced early closure of the ductus arteriosus without detectable side effects. Further trials are required to determine whether intravenous paracetamol may safely prevent symptomatic patent ductus arteriosus. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01938261; European Clinical Trials Database: EudraCT 2013-008142-33. PMID- 27215780 TI - Neonatal Lumbosacral Ulceration Masking Lumbosacral and Intraspinal Hemangiomas Associated with Occult Spinal Dysraphism. PMID- 27215781 TI - Cannabinoid receptor 2 (CB2) agonists and antagonists: a patent update. AB - INTRODUCTION: Modulation of the CB2 receptor is an interesting approach for pain and inflammation, arthritis, addictions, neuroprotection, and cancer, among other possible therapeutic applications, and is devoid of central side effects. AREAS COVERED: This review highlights the novel scaffolds for CB2 ligands and the diverse therapeutic applications for CB2 modulators disclosed in patents published since 2012. EXPERT OPINION: Structural diversity of CB2 modulator scaffolds characterized the patent literature. Several CB2 agonists reached clinical Phase II for pain management and inflammation. Other therapeutic applications need to be explored such as neuroprotection and/or neurodegeneration. PMID- 27215782 TI - Determining the functional role of waterborne amino acid uptake in hagfish nutrition: a constitutive pathway when fasting or a supplementary pathway when feeding? AB - Hagfish are unique among aquatic "vertebrates" in their ability to absorb amino acids directly from the water via skin and gill epithelia, but it is unknown whether this phenomenon extends beyond a few studied substrates; what effect fed state has on absorption; and what functional role this may play in hagfish nutrition. Using in vivo and in vitro transport assays, uptake and tissue distribution of the waterborne amino acids L-alanine, L-lysine, and L phenylalanine were examined as a function of fed state. All three amino acids were shown to be taken up from the water (lysine and phenylalanine for the first time). Following immersion in radiolabelled solutions for 24 h, phenylalanine was the amino acid that accumulated at the highest levels in almost all tissues, with the highest accumulation noted in red blood cells and bile, followed by gill and liver. In general, tissues of fed hagfish displayed a significantly reduced phenylalanine accumulation compared to tissues of hagfish fasted for 3 weeks. An in vitro assay showed that phenylalanine was transported across the skin at the highest rate, with the uptake of lysine occurring at the lowest rate. Feeding status had no significant effect on in vitro transport. These data indicate that dissolved organic nutrients are a significant source of nutrition to hagfish, and may be relatively more important during periods of fasting than during periods of feeding when immersed in decaying carcasses. PMID- 27215783 TI - Characterization of a small outbreak of Salmonella enterica serovar Infantis that harbour CTX-M-65 in Ecuador. PMID- 27215784 TI - The differential frequency of Lineage(-)CRTH2(-)CD45(+)NKp44(-)CD117( )CD127(+)ILC subset in the inflamed terminal ileum of patients with Crohn's disease. AB - Deregulation of various components of the immune system has been reported in the inflamed gut of Crohn's disease (CD) patients. Innate lymphoid cells (ILCs) are novel innate effector lymphocytes which can rapidly respond to danger signals, from invading pathogens or tissue damage, to maintain homeostasis, especially along the mucosal surfaces. The purpose of this study is to compare composition of the intestinal ILCs subsets of CD patients with differential inflammatory conditions of the terminal ileum, which are marked by distinct histological appearances and mucosal profiles of cytokines. We observed alterations in the frequency of Lineage(-)CRTH2(-)CD45(+)NKp44(-)CD117(-)CD127(+)ILC subset in the inflamed terminal ileum. PMID- 27215786 TI - Wineries Evaluation of Costs and Benefits of Sustainability Certification Program: The Case of Terra Vitis in France. AB - BACKGROUND: The current paper analyses the evaluation of the costs and benefits of French wineries (N=69) participating in the sustainability program Terra Vitis, a widespread environmental certification scheme within the French wine industry. METHOD: An online questionnaire was sent to all Terra Vitis participants, in order to analyse the evaluation of economic costs and benefits (together with environmental benefits) as perceived by wineries. RESULTS: Our findings reveal that older participants in the scheme (over 5 years), firms with higher export share (>40% of annual turnover) and cooperative wineries tend to be keener to assign a positive evaluation to the benefits/costs ratio in both the vineyard and the winery. CONCLUSION: In the context of increasing concerns regarding the economic and environmental performance of the French agricultural sector, such findings and also the patent research could be useful for policy makers and entrepreneurs in defining mainstream normative and corporate strategies. PMID- 27215785 TI - Transcriptomic network analyses of leaf dehydration responses identify highly connected ABA and ethylene signaling hubs in three grapevine species differing in drought tolerance. AB - BACKGROUND: Grapevine is a major food crop that is affected by global climate change. Consistent with field studies, dehydration assays of grapevine leaves can reveal valuable information of the plant's response at physiological, transcript, and protein levels. There are well-known differences in grapevine rootstocks responses to dehydration. We used time-series transcriptomic approaches combined with network analyses to elucidate and identify important physiological processes and network hubs that responded to dehydration in three different grapevine species differing in their drought tolerance. RESULTS: Transcriptomic analyses of the leaves of Cabernet Sauvignon, Riparia Gloire, and Ramsey were evaluated at different times during a 24-h controlled dehydration. Analysis of variance (ANOVA) revealed that approximately 11,000 transcripts changed significantly with respect to the genotype x treatment interaction term and approximately 6000 transcripts changed significantly according to the genotype x treatment x time interaction term indicating massive differential changes in gene expression over time. Standard analyses determined substantial effects on the transcript abundance of genes involved in the metabolism and signaling of two known plant stress hormones, abscisic acid (ABA) and ethylene. ABA and ethylene signaling maps were constructed and revealed specific changes in transcript abundance that were associated with the known drought tolerance of the genotypes including genes such as VviABI5, VviABF2, VviACS2, and VviWRKY22. Weighted-gene coexpression network analysis (WGCNA) confirmed these results. In particular, WGCNA identified 30 different modules, some of which had highly enriched gene ontology (GO) categories for photosynthesis, phenylpropanoid metabolism, ABA and ethylene signaling. The ABA signaling transcription factors, VviABI5 and VviABF2, were highly connected hubs in two modules, one being enriched in gaseous transport and the other in ethylene signaling. VviABI5 was distinctly correlated with an early response and high expression for the drought tolerant Ramsey and with little response from the drought sensitive Riparia Gloire. These ABA signaling transcription factors were highly connected to VviSnRK1 and other gene hubs associated with sugar, ethylene and ABA signaling. CONCLUSION: A leaf dehydration assay provided transcriptomic evidence for differential leaf responses to dehydration between genotypes differing in their drought tolerance. WGCNA proved to be a powerful network analysis approach; it identified 30 distinct modules (networks) with highly enriched GO categories and enabled the identification of gene hubs in these modules. Some of these genes were highly connected hubs in both the ABA and ethylene signaling pathways, supporting the hypothesis that there is substantial crosstalk between the two hormone pathways. This study identifies solid gene candidates for future investigations of drought tolerance in grapevine. PMID- 27215787 TI - A Type I Signal Peptidase Is Required for Pilus Assembly in the Gram-Positive, Biofilm-Forming Bacterium Actinomyces oris. AB - The Gram-positive bacterium Actinomyces oris, a key colonizer in the development of oral biofilms, contains 18 LPXTG motif-containing proteins, including fimbrillins that constitute two fimbrial types critical for adherence, biofilm formation, and polymicrobial interactions. Export of these protein precursors, which harbor a signal peptide, is thought to be mediated by the Sec machine and require cleavage of the signal peptide by type I signal peptidases (SPases). Like many Gram-positive bacteria, A. oris expresses two SPases, named LepB1 and LepB2. The latter has been linked to suppression of lethal "glyco-stress," caused by membrane accumulation of the LPXTG motif-containing glycoprotein GspA when the housekeeping sortase srtA is genetically disrupted. Consistent with this finding, we show here that a mutant lacking lepB2 and srtA was unable to produce high levels of glycosylated GspA and hence was viable. However, deletion of neither lepB1 nor lepB2 abrogated the signal peptide cleavage and glycosylation of GspA, indicating redundancy of SPases for GspA. In contrast, the lepB2 deletion mutant failed to assemble the wild-type levels of type 1 and 2 fimbriae, which are built by the shaft fimbrillins FimP and FimA, respectively; this phenotype was attributed to aberrant cleavage of the fimbrillin signal peptides. Furthermore, the lepB2 mutants, including the catalytically inactive S101A and K169A variants, exhibited significant defects in polymicrobial interactions and biofilm formation. Conversely, lepB1 was dispensable for the aforementioned processes. These results support the idea that LepB2 is specifically utilized for processing of fimbrial proteins, thus providing an experimental model with which to study the basis of type I SPase specificity. IMPORTANCE: Sec-mediated translocation of bacterial protein precursors across the cytoplasmic membrane involves cleavage of their signal peptide by a signal peptidase (SPase). Like many Gram-positive bacteria, A. oris expresses two SPases, LepB1 and LepB2. The latter is a genetic suppressor of lethal "glyco-stress" caused by membrane accumulation of glycosylated GspA when the housekeeping sortase srtA is genetically disrupted. We show here that LepB1 and LepB2 are capable of processing GspA, whereas only LepB2 is required for cleavage of fimbrial signal peptides. This is the first example of a type I SPase dedicated to LPXTG motif-containing fimbrial proteins. Thus, A. oris provides an experimental model with which to investigate the specificity mechanism of type I SPases. PMID- 27215788 TI - Absence of the cbb3 Terminal Oxidase Reveals an Active Oxygen-Dependent Cyclase Involved in Bacteriochlorophyll Biosynthesis in Rhodobacter sphaeroides. AB - The characteristic green color associated with chlorophyll pigments results from the formation of an isocyclic fifth ring on the tetrapyrrole macrocycle during the biosynthesis of these important molecules. This reaction is catalyzed by two unrelated cyclase enzymes employing different chemistries. Oxygenic phototrophs such as plants and cyanobacteria utilize an oxygen-dependent enzyme, the major component of which is a diiron protein named AcsF, while BchE, an oxygen sensitive [4Fe-4S] cluster protein, dominates in phototrophs inhabiting anoxic environments, such as the purple phototrophic bacterium Rhodobacter sphaeroides We identify a potential acsF in this organism and assay for activity of the encoded protein in a strain lacking bchE under various aeration regimes. Initially, cells lacking bchE did not demonstrate AcsF activity under any condition tested. However, on removal of a gene encoding a subunit of the cbb3 type respiratory terminal oxidase, cells cultured under regimes ranging from oxic to micro-oxic exhibited cyclase activity, confirming the activity of the oxygen dependent enzyme in this model organism. Potential reasons for the utilization of an oxygen-dependent enzyme in anoxygenic phototrophs are discussed. IMPORTANCE: The formation of the E ring of bacteriochlorophyll pigments is the least well characterized step in their biosynthesis, remaining enigmatic for over 60 years. Two unrelated enzymes catalyze this cyclization step; O2-dependent and O2 independent forms dominate in oxygenic and anoxygenic phototrophs, respectively. We uncover the activity of an O2-dependent enzyme in the anoxygenic purple phototrophic bacterium Rhodobacter sphaeroides, initially by inactivation of the high-affinity terminal respiratory oxidase, cytochrome cbb3 We propose that the O2-dependent form allows for the biosynthesis of a low level of bacteriochlorophyll under oxic conditions, so that a rapid initiation of photosynthetic processes is possible for this bacterium upon a reduction of oxygen tension. PMID- 27215789 TI - Cyanobacterial RNA Helicase CrhR Localizes to the Thylakoid Membrane Region and Cosediments with Degradosome and Polysome Complexes in Synechocystis sp. Strain PCC 6803. AB - The cyanobacterium Synechocystis sp. strain PCC 6803 encodes a single DEAD box RNA helicase, CrhR, whose expression is tightly autoregulated in response to cold stress. Subcellular localization and proteomic analysis results indicate that CrhR localizes to both the cytoplasmic and thylakoid membrane regions and cosediments with polysome and RNA degradosome components. Evidence is presented that either functional RNA helicase activity or a C-terminal localization signal was required for polysome but not thylakoid membrane localization. Polysome fractionation and runoff translation analysis results indicate that CrhR associates with actively translating polysomes. The data implicate a role for CrhR in translation or RNA degradation in the thylakoid region related to thylakoid biogenesis or stability, a role that is enhanced at low temperature. Furthermore, CrhR cosedimentation with polysome and RNA degradosome complexes links alteration of RNA secondary structure with a potential translation-RNA degradation complex in Synechocystis IMPORTANCE: The interaction between mRNA translation and degradation is a major determinant controlling gene expression. Regulation of RNA function by alteration of secondary structure by RNA helicases performs crucial roles, not only in both of these processes but also in all aspects of RNA metabolism. Here, we provide evidence that the cyanobacterial RNA helicase CrhR localizes to both the cytoplasmic and thylakoid membrane regions and cosediments with actively translating polysomes and RNA degradosome components. These findings link RNA helicase alteration of RNA secondary structure with translation and RNA degradation in prokaryotic systems and contribute to the data supporting the idea of the existence of a macromolecular machine catalyzing these reactions in prokaryotic systems, an association hitherto recognized only in archaea and eukarya. PMID- 27215790 TI - YodL and YisK Possess Shape-Modifying Activities That Are Suppressed by Mutations in Bacillus subtilis mreB and mbl. AB - Many bacteria utilize actin-like proteins to direct peptidoglycan (PG) synthesis. MreB and MreB-like proteins are thought to act as scaffolds, guiding the localization and activity of key PG-synthesizing proteins during cell elongation. Despite their critical role in viability and cell shape maintenance, very little is known about how the activity of MreB family proteins is regulated. Using a Bacillus subtilis misexpression screen, we identified two genes, yodL and yisK, that when misexpressed lead to loss of cell width control and cell lysis. Expression analysis suggested that yodL and yisK are previously uncharacterized Spo0A-regulated genes, and consistent with these observations, a DeltayodL DeltayisK mutant exhibited reduced sporulation efficiency. Suppressors resistant to YodL's killing activity occurred primarily in mreB mutants and resulted in amino acid substitutions at the interface between MreB and the highly conserved morphogenic protein RodZ, whereas suppressors resistant to YisK occurred primarily in mbl mutants and mapped to Mbl's predicted ATP-binding pocket. YodL's shape-altering activity appears to require MreB, as a DeltamreB mutant was resistant to the effects of YodL but not YisK. Similarly, YisK appears to require Mbl, as a Deltambl mutant was resistant to the cell-widening effects of YisK but not of YodL. Collectively, our results suggest that YodL and YisK likely modulate MreB and Mbl activity, possibly during the early stages of sporulation. IMPORTANCE: The peptidoglycan (PG) component of the cell envelope confers structural rigidity to bacteria and protects them from osmotic pressure. MreB and MreB-like proteins are thought to act as scaffolds for PG synthesis and are essential in bacteria exhibiting nonpolar growth. Despite the critical role of MreB-like proteins, we lack mechanistic insight into how their activities are regulated. Here, we describe the discovery of two B. subtilis proteins, YodL and YisK, which modulate MreB and Mbl activities. Our data suggest that YodL specifically targets MreB, whereas YisK targets Mbl. The apparent specificities with which YodL and YisK are able to differentially target MreB and Mbl make them potentially powerful tools for probing the mechanics of cytoskeletal function in bacteria. PMID- 27215791 TI - Magnified endoscopic observation of early colorectal cancer by linked color imaging with crystal violet staining (with video). AB - BACKGROUND AND AIMS: Many reports have shown the usefulness of magnification endoscopy with crystal violet (CV) staining for delineating the pit pattern in the diagnosis of colorectal carcinoma. However, the diagnostic accuracy of this method is not adequate for assessing the depth of invasion of early stage cancers. The novel technology of linked color imaging (LCI) combined with CV staining is expected to improve the accuracy of determining the depth of invasion. METHODS: We studied 3 patients with early stage colorectal cancer who were referred to our hospital. After CV spraying, high-magnification endoscopy was conducted by using the LCI mode. Efficacy of this modality was evaluated by comparing the preoperative diagnostic endoscopic images with posttreatment histopathologic findings. RESULTS: In 2 cases of rectal cancer, although conventional endoscopic examination could not exclude the possibility of submucosal cancer, use of the LCI mode with CV staining confirmed mucosal cancer. Eventually, EMR was conducted and achieved curative resection. In 1 case of sigmoid colon cancer, both conventional and CV magnification endoscopy suggested submucosal cancer. However, mucosal cancer was diagnosed by the novel method, and EMR achieved curative resection. CONCLUSIONS: LCI high-magnification endoscopy combined with CV staining provides images close to histopathologic findings and is expected to improve the accuracy of endoscopic diagnosis of the depth of invasion for early stage colorectal cancer. PMID- 27215792 TI - Microfluidic Exosome Analysis toward Liquid Biopsy for Cancer. AB - Assessment of a tumor's molecular makeup using biofluid samples, known as liquid biopsy, is a prominent research topic in precision medicine for cancer, due to its noninvasive property allowing repeat sampling for monitoring molecular changes of tumors over time. Circulating exosomes recently have been recognized as promising tumor surrogates because they deliver enriched biomarkers, such as proteins, RNAs, and DNA. However, purification and characterization of these exosomes are technically challenging. Microfluidic lab-on-a-chip technology effectively addresses these challenges owing to its inherent advantages in integration and automation of multiple functional modules, enhancing sensing performance, and expediting analysis processes. In this article, we review the state-of-the-art development of microfluidic technologies for exosome isolation and molecular characterization with emphasis on their applications toward liquid biopsy-based analysis of cancer. Finally, we share our perspectives on current challenges and future directions of microfluidic exosome analysis. PMID- 27215793 TI - Supratentorial extraventricular WHO grade III (anaplastic) ependymoma 17 years after total removal of WHO grade II ependymoma of the fourth ventricle. AB - We report a WHO grade III ependymoma of the supratentorial interhemispheric fissure and grew to form a large mass with anaplastic transformation without local recurrence 17 years after the total removal of a fourth ventricular WHO grade II ependymoma. We emphasize the necessity of long-term follow-up, even in benign ependymomas. PMID- 27215794 TI - Flight behaviour and dispersal of Rhynchophorus ferrugineus (Coleoptera: Dryophthoridae) adults using mark-release-recapture method. AB - The flight ability and patterns of an insect influence its spread, and the study of its behaviour can be used to improve the strategies to control the pest. Regarding Rhynchophorus ferrugineus (Olivier) (Coleoptera: Dryophthoridae), one of the worst threats to palm trees worldwide, laboratory experiments have been conducted to analyze their flight potential. However, these data must be complemented with tests that allow us to know its flight behaviour and dispersal patterns under field conditions. Two mark-release-recapture experiments were conducted in areas with R. ferrugineus infestations. In the first, the effects of weevil sex, temperature, solar radiation, and relative humidity, on the take-off and flight mobility of adults were analyzed. The second experiment aimed to determine the maximum flight distance covered by adults in field. The take-off rate for R. ferrugineus males was significantly greater than for females, and was positively influenced by temperature (optimum take-off around 25 degrees C) and solar radiation, both factors being highly correlated. Female weevil recaptures were significantly higher, especially as temperatures increased (optimum recapture around 21 degrees C). Dispersal distances of weevil adults increased when temperatures rose, and while this insect tended to fly short distances (<500 m), it was able to cover up to 7 km. The dispersal of R. ferrugineus adults mainly occurred during the first 7 days after their release, and when relative humidity increased, their dispersal time was reduced. The results obtained will permit a more effective implementation of certain measures used to control R. ferrugineus, such as olfactory trapping or intensive surveillance around pest outbreaks. PMID- 27215795 TI - Decoupling of large-scale brain networks supports the consolidation of durable episodic memories. AB - At a large scale, the human brain is organized into modules of interconnected regions, some of which play opposing roles in supporting cognition. In particular, the Default-Mode Network (DMN) has been linked to operations on internal representations, while task-positive networks are recruited during interactions with the external world. Here, we test the hypothesis that the generation of durable long-term memories depends on optimal recruitment of such antagonistic large-scale networks. As long-term memory consolidation is a process ongoing for days and weeks after an experience, we propose that individuals characterized by strong decoupling of the DMN and task-positive networks at rest operate in a mode beneficial for the long-term stabilization of episodic memories. To capture network connectivity unaffected by transient task demands and representative of brain behavior outside an experimental setting, 87 participants were scanned during rest before performing an associative encoding task. To link individual resting-state functional connectivity patterns to time dependent memory consolidation processes, participants were given an unannounced memory test, either after a brief interval or after a retention period of ~6 weeks. We found that participants with a resting state characterized by high synchronicity in a DMN-centered network system and low synchronicity between task positive networks showed superior recollection weeks after encoding. These relationships were not observed for information probed only hours after encoding. Furthermore, the two network systems were found to be anticorrelated. Our results suggest that this memory-relevant antagonism between DMN and task-positive networks is maintained through complex regulatory interactions between the systems. PMID- 27215796 TI - Dielectric characteristics of fast Li ion conducting garnet-type Li5+2xLa3Nb2 xYxO12 (x = 0.25, 0.5 and 0.75). AB - Here, we report the dielectric characteristics of Li-stuffed garnet-type Li5+2xLa3Nb2-xYxO12 (x = 0.25, 0.5 and 0.75) in the temperature range about -53 to 50 degrees C using AC impedance spectroscopy. All the investigated Li-stuffed garnet compounds were prepared, under the same condition, using conventional solid-state reaction at elevated temperature in air. The Nyquist plots show mainly bulk contribution to the total Li(+) ion conductivity for Li5.5La3Nb1.75Y0.25O12 (Li5.5-Nb) and Li6La3Nb1.5Y0.5O12 (Li6-Nb), while both bulk and grain-boundary effects are visible in the case of Li6.5La3Nb1.25Y0.75O12 (Li6.5-Nb) phase at ~-22 degrees C. Non-Debye relaxation process was observed in the modulus AC impedance plots. The dielectric loss tangent of Li5+2xLa3Nb2 xYxO12 are compared with that of the corresponding Ta analogue, Li5+2xLa3Ta2 xYxO12 and showed a decrease in peak intensity for the Nb-based garnet samples which may be attributed to a slight increase in their Li(+) ion conductivity. The relative dielectric constant values were also found to be higher for the Ta member (>60 for Li5+2xLa3Ta2-xYxO12) than that of the corresponding Nb analogue (~50 for Li5+2xLa3Nb2-xYxO12) at below room temperature. A long-range order Li(+) ion migration pathway with relaxation time (tau0) 10(-18)-10(-15) s and an activation energy of 0.59-0.40 eV was observed for the investigated Li5+2xLa3Nb2 xYxO12 garnets and is comparable to that of the corresponding Ta-based Li5+2xLa3Ta2-xYxO12 garnets. PMID- 27215797 TI - The role of hepatitis E virus infection in adult Americans with acute liver failure. AB - : Acute hepatitis E virus (HEV) infection is a leading cause of acute liver failure (ALF) in many developing countries, yet rarely identified in Western countries. Given that antibody testing for HEV infection is not routinely obtained, we hypothesized that HEV-related ALF might be present and unrecognized in North American ALF patients. Serum samples of 681 adults enrolled in the U.S. Acute Liver Failure Study Group were tested for anti-HEV immunoglobulin (Ig) M and anti-HEV IgG levels. Subjects with a detectable anti-HEV IgM also underwent testing for HEV RNA. Mean patient age was 41.8 years, 32.9% were male, and ALF etiologies included acetaminophen (APAP) hepatotoxicity (29%), indeterminate ALF (23%), idiosyncratic drug-induced liver injury DILI (22%), acute hepatitis B virus infection (12%), autoimmune hepatitis (12%), and pregnancy-related ALF (2%). Three men ages 36, 39, and 70 demonstrated repeatedly detectable anti-HEV IgM, but all were HEV-RNA negative and had other putative diagnoses. The latter 2 subjects died within 3 and 11 days of enrollment whereas the 36-year-old underwent emergency liver transplantation on study day 2. At admission, 294 (43.4%) of the ALF patients were anti-HEV IgG positive with the seroprevalence being highest in those from the Midwest (50%) and lowest in those from the Southeast (28%). Anti-HEV IgG+ subjects were significantly older, less likely to have APAP overdose, and had a lower overall 3-week survival compared to anti-HEV IgG- subjects (63% vs. 70%; P = 0.018). CONCLUSION: Acute HEV infection is very rare in adult Americans with ALF (i.e., 0.4%) and could not be implicated in any indeterminate, autoimmune, or pregnancy-related ALF cases. Past exposure to HEV with detectable anti-HEV IgG was significantly more common in the ALF patients compared to the general U.S. POPULATION: (Hepatology 2016;64:1870-1880). PMID- 27215799 TI - Erratum to: A benchmark for RNA-seq quantification pipelines. PMID- 27215798 TI - Functional development of mechanosensitive hair cells in stem cell-derived organoids parallels native vestibular hair cells. AB - Inner ear sensory epithelia contain mechanosensitive hair cells that transmit information to the brain through innervation with bipolar neurons. Mammalian hair cells do not regenerate and are limited in number. Here we investigate the potential to generate mechanosensitive hair cells from mouse embryonic stem cells in a three-dimensional (3D) culture system. The system faithfully recapitulates mouse inner ear induction followed by self-guided development into organoids that morphologically resemble inner ear vestibular organs. We find that organoid hair cells acquire mechanosensitivity equivalent to functionally mature hair cells in postnatal mice. The organoid hair cells also progress through a similar dynamic developmental pattern of ion channel expression, reminiscent of two subtypes of native vestibular hair cells. We conclude that our 3D culture system can generate large numbers of fully functional sensory cells which could be used to investigate mechanisms of inner ear development and disease as well as regenerative mechanisms for inner ear repair. PMID- 27215800 TI - Periodontal ligament stem/progenitor cells with protein-releasing scaffolds for cementum formation and integration on dentin surface. AB - : Purpose/Aim: Cementogenesis is a critical step in periodontal tissue regeneration given the essential role of cementum in anchoring teeth to the alveolar bone. This study is designed to achieve integrated cementum formation on the root surfaces of human teeth using growth factor-releasing scaffolds with periodontal ligament stem/progenitor cells (PDLSCs). MATERIALS AND METHODS: Human PDLSCs were sorted by CD146 expression, and characterized using CFU-F assay and induced multi-lineage differentiation. Polycaprolactone scaffolds were fabricated using 3D printing, embedded with poly(lactic-co-glycolic acids) (PLGA) microspheres encapsulating connective tissue growth factor (CTGF), bone morphogenetic protein-2 (BMP-2), or bone morphogenetic protein-7 (BMP-7). After removing cementum on human tooth roots, PDLSC-seeded scaffolds were placed on the exposed dentin surface. After 6-week culture with cementogenic/osteogenic medium, cementum formation and integration were evaluated by histomorphometric analysis, immunofluorescence, and qRT-PCR. RESULTS: Periodontal ligament (PDL) cells sorted by CD146 and single-cell clones show a superior clonogenecity and multipotency as compared with heterogeneous populations. After 6 weeks, all the growth factor delivered groups showed resurfacing of dentin with a newly formed cementum-like layer as compared with control. BMP-2 and BMP-7 showed de novo formation of tissue layers significantly thicker than all the other groups, whereas CTGF and BMP-7 resulted in significantly improved integration on the dentin surface. The de novo mineralized tissue layer seen in BMP-7-treated samples expressed cementum matrix protein 1 (CEMP1). Consistently, BMP-7 showed a significant increase in CEMP1 mRNA expression. CONCLUSION: Our findings represent important progress in stem cell-based cementum regeneration as an essential part of periodontium regeneration. PMID- 27215801 TI - [A small spleen]. PMID- 27215802 TI - A diphenyl diselenide-supplemented diet and swimming exercise promote neuroprotection, reduced cell apoptosis and glial cell activation in the hypothalamus of old rats. AB - Aging is a process characterized by deterioration of the homeostasis of various physiological systems; although being a process under influence of multiple factors, the mechanisms involved in aging are not well understood. Here we investigated the effect of a (PhSe)2-supplemented diet (1ppm, 4weeks) and swimming exercise (1% of body weight, 20min per day, 4weeks) on proteins related to glial cells activation, apoptosis and neuroprotection in the hypothalamus of old male Wistar rats (27month-old). Old rats had activation of astrocytes and microglia which was demonstrated by the increase in the levels of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba-1) in hypothalamus. A decrease of B-cell lymphoma 2 (Bcl-2) and procaspase-3 levels as well as an increase of the cleaved PARP/full length PARP ratio (poly (ADP-ribose) polymerase, PARP) and the pJNK/JNK ratio (c-Jun N-terminal kinase, JNK) were observed. The levels of mature brain-derived neurotrophic factor (mBDNF), the pAkt/Akt ratio (also known as protein kinase B) and NeuN (neuronal nuclei), a neuron marker, were decreased in the hypothalamus of old rats. Old rats that received a (PhSe)2-supplemented diet and performed swimming exercise had the hypothalamic levels of Iba-1 and GFAP decreased. The combined treatment also increased the levels of Bcl-2 and procaspase-3 and decreased the ratios of cleaved PARP/full length PARP and pJNK/JNK in old rats. The levels of mBDNF and NeuN, but not the pAkt/Akt ratio, were increased by combined treatment. In conclusion, a (PhSe)2-supplemented diet and swimming exercise promoted neuroprotection in the hypothalamus of old rats, reducing apoptosis and glial cell activation. PMID- 27215803 TI - Serial Echocardiographic Assessment of Left Ventricular Filling Pressure and Remodeling among ST-Segment Elevation Myocardial Infarction Patients Treated by Primary Percutaneous Intervention. AB - BACKGROUND: Acute myocardial infarction and remodeling of the left ventricle is associated with significant changes in systolic and diastolic echocardiographic derived indices. The investigators have tried to determine whether persistence of increased ratio of transmitral flow velocity (E) to early mitral annulus velocity (e'), signifying increased cardiac filling pressure, is associated with left ventricular (LV) remodeling and increased chamber size among patients presenting with ST-segment elevation myocardial infarction, who underwent successful reperfusion with primary percutaneous coronary intervention. METHODS: Fifty-two patients (76% men; mean age, 61 +/- 10 years) with first ST-segment elevation myocardial infarctions who underwent primary percutaneous coronary intervention were retrospectively studied. Echocardiography was performed at baseline (days 1 3) and after 178 +/- 62 days. Patients were stratified according to E/septal e' ratio >15 and <=15 in both examinations. All patients received optimal medical therapy according to guidelines and local practice. RESULTS: Patients with maintained or worsened E/septal e' ratios to >15 demonstrated on the second examination worse LV ejection fractions (mean, 45 +/- 12% vs 52 +/- 8%; P = .03) and higher indexed LV end-diastolic volumes (mean, 81.3 +/- 22.9 vs 69.2 +/- 13.4 mL/m(2); P = .01) and end-systolic volumes (mean, 33.0 +/- 12.2 vs 23.7 +/- 13.4 mL/m(2); P = .02) compared with the first examination, representing LV remodeling. Patients with E/septal e' ratios > 15 on the second examination demonstrated a positive correlation between the change in E/septal e' ratio and the change in indexed LV end-diastolic volume (linear R(2) = 0.344, P = .03). CONCLUSIONS: Among patients with ST-segment elevation myocardial infarctions undergoing primary percutaneous coronary intervention, early and persistent elevation of the E/septal e' ratio may be associated with LV remodeling. PMID- 27215804 TI - Controlling Octahedral Rotations in a Perovskite via Strain Doping. AB - The perovskite unit cell is the fundamental building block of many functional materials. The manipulation of this crystal structure is known to be of central importance to controlling many technologically promising phenomena related to superconductivity, multiferroicity, mangetoresistivity, and photovoltaics. The broad range of properties that this structure can exhibit is in part due to the centrally coordinated octahedra bond flexibility, which allows for a multitude of distortions from the ideal highly symmetric structure. However, continuous and fine manipulation of these distortions has never been possible. Here, we show that controlled insertion of He atoms into an epitaxial perovskite film can be used to finely tune the lattice symmetry by modifying the local distortions, i.e., octahedral bonding angle and length. Orthorhombic SrRuO3 films coherently grown on SrTiO3 substrates are used as a model system. Implanted He atoms are confirmed to induce out-of-plane strain, which provides the ability to controllably shift the bulk-like orthorhombically distorted phase to a tetragonal structure by shifting the oxygen octahedra rotation pattern. These results demonstrate that He implantation offers an entirely new pathway to strain engineering of perovskite-based complex oxide thin films, useful for creating new functionalities or properties in perovskite materials. PMID- 27215807 TI - Synthesis of 3-Substituted Aryl[4,5]isothiazoles through an All-Heteroatom Wittig Equivalent Process. AB - Extending the previous use of tert-butyl sulfoxide as the sulfinyl source, intramolecular sulfinylation of sulfonamides was successfully performed. The resulting sulfinimides were not isolated and instead were believed to go through an all-heteroatom Wittig-equivalent process to eventually afford aryl[4,5]isothiazoles in high yields. PMID- 27215808 TI - Studies towards the synthesis of tedanolide C. Construction of the C13-epi C1-C15 fragment. AB - The preparation of an advanced intermediate on route towards the synthesis of tedanolide C is reported here. It is based on the coupling of two fragments of similar size and complexity, which in turn are prepared by highly stereoselective substrate-controlled titanium-mediated aldol reactions from chiral ketones. PMID- 27215809 TI - A Randomized Controlled Study of Mineral Trioxide Aggregate and Super Ethoxybenzoic Acid as Root-end Filling Materials in Endodontic Microsurgery: Long term Outcomes. AB - INTRODUCTION: The purpose of the present study was to evaluate the long-term clinical outcome of endodontic microsurgery when mineral trioxide aggregate (MTA) and super ethoxybenzoic acid (Super EBA; Harry J. Bosworth, Skokie, IL) were used as root-end filling materials. Additionally, this study aimed to compare the clinical outcome of endodontic microsurgery at the 1-year follow-up with that at the 4-year follow-up. METHODS: Two hundred sixty teeth were randomly assigned to either the MTA or Super EBA group in equal numbers using the minimization method. Endodontic microsurgery was performed according to the Yonsei protocol. The previous study of 192 teeth examined at the 1-year follow-up revealed a success rate of 95.6% for MTA and 93.1% for Super EBA. Patients were recalled 4 years after surgery, and treated teeth were classified as successes or failures with Molven's criteria. The Pearson chi-square test and the McNemar test were conducted to analyze and compare the success rates. RESULTS: A total of 182 teeth were examined at the 4-year follow-up. The success rate was 91.6% for MTA and 89.9% for Super EBA. Statistical analysis of the success rate did not show any significant difference between the 2 materials (P = .8). The overall success rate at the 4-year follow-up was 89.5%, which was slightly lower compared with 94.3% at the 1-year follow-up. However, there was no significant difference between the follow-up periods (P = .063). CONCLUSIONS: This study identified no significant difference in the 4-year success rates of MTA and Super EBA as root-end filling materials in endodontic microsurgery. Additionally, compared with short-term outcomes, long-term follow-up outcomes were not significantly different. PMID- 27215810 TI - Removal of Root Canal Fillings in Curved Canals Using Either Reciprocating Single or Rotary Multi-instrument Systems and a Supplementary Step with the XP-Endo Finisher. AB - INTRODUCTION: This study compared the efficacy of a reciprocating single instrument system and a rotary multi-instrument system followed by a supplementary approach with a finishing instrument in removing the filling material from curved canals during retreatment. METHODS: Forty mesial canals from extracted mandibular molars were instrumented and filled. Then, each mesial canal was retreated by using either Reciproc (VDW, Munich, Germany) or Mtwo (VDW) instruments, alternating the technique used per canal from root to root. The working time was recorded, and the percentage of removed filling volume was assessed by means of micro-computed tomography imaging before and after retreatment. Canals still showing filling material remnants were subjected to an adjunctive approach with the XP-Endo Finisher (FKG Dentaire, La Chaux-de-Fonds, Switzerland), and another microCT scan was taken. Data were statistically analyzed with a significance level of 5%. RESULTS: The percentage of filling material removed with Mtwo instruments (96%) was significantly higher than Reciproc (89%) (P < .05), both used up to a final instrument size of 40. Mtwo required less time to remove the filling material than Reciproc (P < .05). Intragroup analysis in the Reciproc group showed that the R40 instrument removed significantly more filling material than R25 (P < .05). The supplementary approach with the XP-Endo Finisher was effective in significantly enhancing the removal of filling material (P < .05). CONCLUSIONS: The rotary multiple instrument system was more effective and faster than the reciprocating single instrument approach in removing previous root canal fillings. As for the Reciproc group, it was observed that the larger instrument promoted significantly better results. The adjunctive finishing instrument XP-Endo Finisher significantly improved filling material removal. PMID- 27215811 TI - Inapparent Streptococcus agalactiae infection in adult/commercial tilapia. AB - We report on inapparent infections in adult/commercial tilapia in major tilapia fish farms in Guangdong. A total of 146 suspected isolates were confirmed to be S. agalactiae using an API 20 Strep system and specific PCR amplification. All isolates were identified as serotype Ia using multiplex serotyping PCR. An MLST assay showed single alleles of adhP (10), atr (2), glcK (2), glnA (1), pheS (1), sdhA (3) and tkt (2), and this profile was designated 'unique ST 7'. The analysis of virulence genes resulted in 10 clusters, of which dltr-bca-sodA-spb1-cfb-bac (62, 42.47%) was the predominant virulence gene profile. The PFGE analysis of S. agalactiae yielded 6 distinct PFGE types (A, B, C, D, F and G), of which Pattern C (103) was the predominant type, accounting for approximately 70.55% (103/146) of the total S. agalactiae strains. Therefore, unlike what has been found in juvenile tilapia, in which PFGE pattern D/F is the major prevalent pattern, we found that pattern C was the major prevalent pattern in inapparent infected adult/commercial tilapia in Guangdong, China. In conclusion, we close a gap in the current understanding of S. agalactiae epidemiology and propose that researchers should be alert for inapparent S. agalactiae infections in adult/commercial tilapia to prevent a potential threat to food safety. PMID- 27215812 TI - Nanotubes from Oxide-Based Misfit Family: The Case of Calcium Cobalt Oxide. AB - Misfit layered compounds (MLCs) have generated significant interest in recent years as potential thermoelectric materials. MLC nanotubes could reveal behavior that is entirely different from the bulk material. Recently, new chemical strategies were exploited for the synthesis of nanotubular forms of chalcogenide based MLCs, which are promising candidates for thermoelectric materials. However, analogous synthesis of oxide-based MLC nanotubes has not been demonstrated until now. Here, we report a chemical strategy for synthesis of cobalt-oxide-based misfit nanotubes. A combination of high-resolution (scanning) transmission electron microscopy (including image simulations), spatially resolved electron energy-loss spectroscopy, electron diffraction, and density functional theory (DFT) calculations is used to discover the formation of a phase within these nanotubes that differs significantly from bulk calcium cobaltite MLCs. Furthermore, DFT calculations show that this phase is semiconducting with a band gap in excess of 1 eV, unlike bulk calcium cobaltite MLCs, which are known to be metallic. Through systematic experiments, we propose a formation mechanism for these nanotubes that could also apply more generally to realizing other oxide based MLC nanotubes. PMID- 27215814 TI - Vibrational Heat Transport in Molecular Junctions. AB - We review studies of vibrational energy transfer in a molecular junction geometry, consisting of a molecule bridging two heat reservoirs, solids or large chemical compounds. This setup is of interest for applications in molecular electronics, thermoelectrics, and nanophononics, and for addressing basic questions in the theory of classical and quantum transport. Calculations show that system size, disorder, structure, dimensionality, internal anharmonicities, contact interaction, and quantum coherent effects are factors that combine to determine the predominant mechanism (ballistic/diffusive), effectiveness (poor/good), and functionality (linear/nonlinear) of thermal conduction at the nanoscale. We review recent experiments and relevant calculations of quantum heat transfer in molecular junctions. We recount the Landauer approach, appropriate for the study of elastic (harmonic) phononic transport, and outline techniques that incorporate molecular anharmonicities. Theoretical methods are described along with examples illustrating the challenge of reaching control over vibrational heat conduction in molecules. PMID- 27215813 TI - Muscle myeloid type I interferon gene expression may predict therapeutic responses to rituximab in myositis patients. AB - OBJECTIVE: To identify muscle gene expression patterns that predict rituximab responses and assess the effects of rituximab on muscle gene expression in PM and DM. METHODS: In an attempt to understand the molecular mechanism of response and non-response to rituximab therapy, we performed Affymetrix gene expression array analyses on muscle biopsy specimens taken before and after rituximab therapy from eight PM and two DM patients in the Rituximab in Myositis study. We also analysed selected muscle-infiltrating cell phenotypes in these biopsies by immunohistochemical staining. Partek and Ingenuity pathway analyses assessed the gene pathways and networks. RESULTS: Myeloid type I IFN signature genes were expressed at higher levels at baseline in the skeletal muscle of rituximab responders than in non-responders, whereas classic non-myeloid IFN signature genes were expressed at higher levels in non-responders at baseline. Also, rituximab responders have a greater reduction of the myeloid and non-myeloid type I IFN signatures than non-responders. The decrease in the type I IFN signature following administration of rituximab may be associated with the decreases in muscle-infiltrating CD19(+) B cells and CD68(+) macrophages in responders. CONCLUSION: Our findings suggest that high levels of myeloid type I IFN gene expression in skeletal muscle predict responses to rituximab in PM/DM and that rituximab responders also have a greater decrease in the expression of these genes. These data add further evidence to recent studies defining the type I IFN signature as both a predictor of therapeutic responses and a biomarker of myositis disease activity. PMID- 27215815 TI - Charge Transfer Dynamics from Photoexcited Semiconductor Quantum Dots. AB - Understanding photoinduced charge transfer from nanomaterials is essential to the many applications of these materials. This review summarizes recent progress in understanding charge transfer from quantum dots (QDs), an ideal model system for investigating fundamental charge transfer properties of low-dimensional quantum confined nanomaterials. We first discuss charge transfer from QDs to weakly coupled acceptors within the framework of Marcus nonadiabatic electron transfer (ET) theory, focusing on the dependence of ET rates on reorganization energy, electronic coupling, and driving force. Because of the strong electron-hole interaction, we show that ET from QDs should be described by the Auger-assisted ET model, which is significantly different from ET between molecules or from bulk semiconductor electrodes. For strongly quantum-confined QDs on semiconductor surfaces, the coupling can fall within the strong coupling limit, in which case the donor-acceptor interaction and ET properties can be described by the Newns Anderson model of chemisorption. We also briefly discuss recent progress in controlling charge transfer properties in quantum-confined nanoheterostructures through wavefunction engineering and multiple exciton dissociation. Finally, we identify a few key areas for further research. PMID- 27215817 TI - Characterizing Localized Surface Plasmons Using Electron Energy-Loss Spectroscopy. AB - Electron energy-loss spectroscopy (EELS) offers a window to view nanoscale properties and processes. When performed in a scanning transmission electron microscope, EELS can simultaneously render images of nanoscale objects with subnanometer spatial resolution and correlate them with spectroscopic information at a spectral resolution of ~10-100 meV. Consequently, EELS is a near-perfect tool for understanding the optical and electronic properties of individual plasmonic metal nanoparticles and few-nanoparticle assemblies, which are significant in a wide range of fields. This review presents an overview of basic plasmonics and EELS theory and highlights several recent noteworthy experiments involving the interrogation of plasmonic metal nanoparticle systems using electron beams. PMID- 27215818 TI - Understanding the Surface Hopping View of Electronic Transitions and Decoherence. AB - We present a current, up-to-date review of the surface hopping methodology for solving nonadiabatic problems, 25 years after Tully published the fewest switches surface hopping algorithm. After reviewing the original motivation for and failures of the algorithm, we give a detailed examination of modern advances, focusing on both theoretical and practical issues. We highlight how one can partially derive surface hopping from the Schrodinger equation in the adiabatic basis, how one can change basis within the surface hopping algorithm, and how one should understand and apply the notions of decoherence and wavepacket bifurcation. The question of time reversibility and detailed balance is also examined at length. Recent applications to photoexcited conjugated polymers are discussed briefly. PMID- 27215816 TI - Molecular Shape and the Hydrophobic Effect. AB - This review focuses on papers published since 2000 on the topic of the properties of solutes in water. More specifically, it evaluates the state of the art of our understanding of the complex relationship between the shape of a hydrophobe and the hydrophobic effect. To highlight this, we present a selection of references covering both empirical and molecular dynamics studies of small (molecular-scale) solutes. These include empirical studies of small molecules, synthetic hosts, crystalline monolayers, and proteins, as well as in silico investigations of entities such as idealized hard and soft spheres, small solutes, hydrophobic plates, artificial concavity, molecular hosts, carbon nanotubes and spheres, and proteins. PMID- 27215819 TI - Biophysical Insights from Temperature-Dependent Single-Molecule Forster Resonance Energy Transfer. AB - Single-molecule fluorescence microscopy techniques can be used in combination with micrometer length-scale temperature control and Forster resonance energy transfer (FRET) in order to gain detailed information about fundamental biophysical phenomena. In particular, this combination of techniques has helped foster the development of remarkable quantitative tools for studying both time- and temperature-dependent structural kinetics of biopolymers. Over the past decade, multiple research efforts have successfully incorporated precise spatial and temporal control of temperature into single-molecule FRET (smFRET)-based experiments, which have uncovered critical thermodynamic information on a wide range of biological systems such as conformational dynamics of nucleic acids. This review provides an overview of various temperature-dependent smFRET approaches from our laboratory and others, highlighting efforts in which such methods have been successfully applied to studies of single-molecule nucleic acid folding. PMID- 27215820 TI - Measuring the Hydrodynamic Size of Nanoparticles Using Fluctuation Correlation Spectroscopy. AB - Fluctuation correlation spectroscopy (FCS) is a well-established analytical technique traditionally used to monitor molecular diffusion in dilute solutions, the dynamics of chemical reactions, and molecular processes inside living cells. In this review, we present the recent use of FCS for measuring the size of colloidal nanoparticles in solution. We review the theoretical basis and experimental implementation of this technique and its advantages and limitations. In particular, we show examples of the use of FCS to measure the size of gold nanoparticles, monitor the rotational dynamics of gold nanorods, and investigate the formation of protein coronas on nanoparticles. PMID- 27215821 TI - Water-Mediated Hydrophobic Interactions. AB - Hydrophobic interactions are driven by the combined influence of the direct attraction between oily solutes and an additional water-mediated interaction whose magnitude (and sign) depends sensitively on both solute size and attraction. The resulting delicate balance can lead to a slightly repulsive water mediated interaction that drives oily molecules apart rather than pushing them together and thus opposes their direct (van der Waals) attraction for each other. As a consequence, competing solute size-dependent crossovers weaken hydrophobic interactions sufficiently that they are only expected to significantly exceed random thermal energy fluctuations for processes that bury more than ~1 nm(2) of water-exposed area. PMID- 27215823 TI - Liquid Cell Transmission Electron Microscopy. AB - Liquid cell transmission electron microscopy (TEM) has attracted significant interest in recent years. With nanofabricated liquid cells, it has been possible to image through liquids using TEM with subnanometer resolution, and many previously unseen materials dynamics have been revealed. Liquid cell TEM has been applied to many areas of research, ranging from chemistry to physics, materials science, and biology. So far, topics of study include nanoparticle growth and assembly, electrochemical deposition and lithiation for batteries, tracking and manipulation of nanoparticles, catalysis, and imaging of biological materials. In this article, we first review the development of liquid cell TEM and then highlight progress in various areas of research. In the study of nanoparticle growth, the electron beam can serve both as the illumination source for imaging and as the input energy for reactions. However, many other research topics require the control of electron beam effects to minimize electron beam damage. We discuss efforts to understand electron beam-liquid matter interactions. Finally, we provide a perspective on future challenges and opportunities in liquid cell TEM. PMID- 27215822 TI - Fundamental Properties of One-Dimensional Zinc Oxide Nanomaterials and Implementations in Various Detection Modes of Enhanced Biosensing. AB - Recent bioapplications of one-dimensional (1D) zinc oxide (ZnO) nanomaterials, despite the short development period, have shown promising signs as new sensors and assay platforms offering exquisite biomolecular sensitivity and selectivity. The incorporation of 1D ZnO nanomaterials has proven beneficial to various modes of biodetection owing to their inherent properties. The more widely explored electrochemical and electrical approaches tend to capitalize on the reduced physical dimensionality, yielding a high surface-to-volume ratio, as well as on the electrical properties of ZnO. The newer development of the use of 1D ZnO nanomaterials in fluorescence-based biodetection exploits the innate optical property of their high anisotropy. This review considers stimulating research advances made to identify and understand fundamental properties of 1D ZnO nanomaterials, and examines various biosensing modes utilizing them, while focusing on the unique optical properties of individual and ensembles of 1D ZnO nanomaterials specifically pertaining to their bio-optical applications in simple and complex fluorescence assays. PMID- 27215824 TI - The electrochemical behaviour of TTF in Li-O2 batteries using a TEGDME-based electrolyte. AB - The electrochemical behaviour of tetrathiafulvalene (TTF), a redox mediator proposed to improve the recharge kinetics of Li-O2 batteries, was investigated via synchrotron and lab X-ray diffraction. Using the LiFePO4 anode, TTF causes chemical lithiation of the FePO4 phase. TTF is also found to be unstable during discharge/charge cycles. PMID- 27215826 TI - Corrigendum. AB - Effects of a supportive educational nursing care programme on fatigue and quality of life in patients with heart failure: a randomised controlled trialEuropean Journal of Cardiovascular Nursing 2016; 15: 157-167. PMID- 27215825 TI - Subjective health complaints, functional ability, fear avoidance beliefs, and days on sickness benefits after work rehabilitation - a mediation model. AB - BACKGROUND: Long-term sick leave and withdrawal from working life is a concern in western countries. In Norway, comprehensive inpatient work rehabilitation may be offered to sick listed individuals at risk of long-term absence from work. Knowledge about prognostic factors for work outcomes after long-term sick leave and work rehabilitation is still limited. The aim of this study was to test a mediation model for various hypothesized biopsychosocial predictors of continued sick leave after inpatient work rehabilitation. METHODS: One thousand one hundred fifty-five participants on long-term sick leave from eight different work rehabilitation clinics answered comprehensive questionnaires at arrival to the clinic, and were followed with official register data on sickness benefits for 3 years. Structural equation models were conducted, with days on sickness benefits after work rehabilitation as the outcome. RESULTS: Fear avoidance beliefs for work mediated the relation between both musculoskeletal complaints and education on days on sickness benefits after work rehabilitation. The relation between musculoskeletal complaints and fear avoidance beliefs for work was furthermore fully mediated by poor physical function. Previous sick leave had a strong independent effect on continued sick leave after work rehabilitation. Fear avoidance beliefs for work did not mediate the small effect of pseudoneurological complaints on continued sick leave. Poor coping/interaction ability was neither related to continued sick leave nor fear avoidance beliefs for work. CONCLUSIONS: The mediation model was partly supported by the data, and provides some possible new insight into how fear avoidance beliefs for work and functional ability may intervene with subjective health complaints and days on sickness benefits after work rehabilitation. PMID- 27215827 TI - The association between benzodiazepines and influenza-like illness-related pneumonia and mortality: a survival analysis using UK Primary Care data. AB - PURPOSE: Bacterial superinfections, including pneumonia, are frequent complications of influenza-like illness (ILI). Clinical and laboratory evidence suggests that benzodiazepines and Z-drugs may influence susceptibility to infections and mortality. We investigated whether benzodiazepines and zopiclone modify the occurrence of ILI-related pneumonia and mortality. METHODS: We obtained data on 804 051 ILI patients from a comprehensive primary care database, the Clinical Practice Research Datalink. The follow-up period started from the diagnosis of ILI for 30 days. Pneumonia and deaths occurring within the 30-day follow-up period were considered as potentially 'ILI related'. Exposure to benzodiazepines and zopiclone was determined in the period preceding a diagnosis of ILI with current use defined as a prescription for benzodiazepines in the month prior to ILI diagnosis. Cox regression was used for the analyses. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) are presented. RESULTS: Influenza-like illness-related pneumonia and mortality were noted in 1117 and 707 ILI patients, respectively. Current exposure to benzodiazepines was associated with increased occurrence of both ILI-related pneumonia and mortality (ILI related pneumonia adjusted HR 4.24, 95%CI [2.27, 7.95]; ILI-related mortality adjusted HR 20.69, 95%CI [15.54, 27.54]). A similar increase in ILI-related mortality but not pneumonia was observed with current zopiclone use (ILI-related mortality adjusted HR 10.86, 95%CI [6.93, 17.02]; ILI-related pneumonia adjusted HR 1.97, 95%CI [0.63, 6.12]). CONCLUSION: Benzodiazepines may increase the likelihood of pneumonia and mortality related to ILI. A cautionary approach to prescribing benzodiazepine is suggested in people known to be at increased risk of pneumonia or mortality. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27215828 TI - Facilitators and barriers to NCD prevention in Pakistanis-invincibility or inevitability: a qualitative research study. AB - BACKGROUND: Non-communicable diseases (NCD) are the leading causes of death globally. In Pakistan, they are among the top ten causes of mortality, especially in the productive age group (30-69 years). Evidence suggests that health perceptions and beliefs strongly influence the health behavior of an individual. We performed focus group interviews to delineate the same so as to design the user interface of a non-invasive stroke risk monitoring device. METHODS: It was a qualitative study, designed to explore how health perceptions and beliefs influence behavior for NCD prevention. Four focus group discussions (FGD) were conducted with 30 stable participants who had diabetes mellitus, ischemic heart disease, blood pressure, and stroke. The data was collected using a semi structured interview guide designed to explore participants' perceptions of their illnesses, self-management behaviors and factors affecting them. The interviews were transcribed and content analysis was done using steps of content analysis by Morse and Niehaus [10]. RESULTS: Medication adherence, self-monitoring of blood sugars and blood pressures, and medical help seeking were the commonly performed self-management behaviors by the participants. Personal experience of illness, familial inheritance of disease, education and fear of premature death when life responsibilities were unfulfilled, emerged as strong facilitators of self management behaviors. A sense of personal invincibility, Fatalism or inevitability, lack of personal threat realization, limited knowledge, inadequate health education, health care and financial constraints appeared as key barriers to the self-management of chronic disease in participants. CONCLUSIONS: Behavioural interventional messaging will have to engender a sense of personal vulnerability and yet empower self-efficacy solutions at the individual level to deal with both invincibility and inevitability barriers to adoption of healthy behavior. PMID- 27215829 TI - Purification and characterization of chitinase showing antifungal and biodegradation properties obtained from Streptomyces anulatus CS242. AB - In an effort to identify a microbial enzyme that can be useful as a fungicide and biodegradation agent of chitinous wastes, a chitinase (Chi242) was purified from the culture supernatant of Streptomyces anulatus CS242 utilizing powder of shrimp shell wastes as a sole carbon source. It was purified employing ammonium sulfate precipitation and gel permeation chromatography techniques. The molecular weight of the purified chitinase was ~38 kDa by SDS-PAGE. The N-terminal amino acid sequence (A-P-G-A-P-G-T-G-A-L) showed close similarity to those of other Streptomyes chitinases. The purified enzyme displayed optimal activity at pH 6.0 and 50 degrees C respectively. It showed substantial thermal stability for 2 h at 30-60 degrees C, and exhibited broad pH stability in the range 5.0-13.0 for 48 h at 4 degrees C. Scanning electron microscopy confirmed the ability of this enzyme to adsorb onto solid shrimp bio-waste and to degrade chitin microfibers. Chi242 could proficiently convert colloidal chitin to N-acetyl glucosamine (GlcNAc) and N-acetyl chitobiose (GlcNAc)2 signifying that this enzyme is suitable for bioconversion of chitin waste. In addition, it exerted an effective antifungal activity towards fungal pathogen signifying its role as a biocontrol agent. Thus, a single microbial cell of Streptomyces anulatus CS242 justified its dual role. PMID- 27215831 TI - Comparison of amino and epoxy functionalized SBA-15 used for carbonic anhydrase immobilization. AB - Two functionalized SBA-15 [amine-functionalized SBA-15 (AFS) and epoxy functionalized SBA-15 (GFS)] with different types of functional groups were synthesized by a hydrothermal process and post functionalized with 3 aminopropyltriethoxysilane (APTES) and 3-glycidyloxypropyltrimethoxysilane (GPTMS), respectively. They were used for the immobilization of carbonic anhydrase (CA). The physicochemical properties of the functionalized SBA-15 were characterized by X-ray powder diffraction (XRD), N2 adsorption-desorption, (13)C, (29)Si solid-state nuclear magnetic resonance (NMR) spectroscopy, and scanning electron microscopy (SEM). Before and after CA was immobilized on AFS and GFS, the effects of temperature and pH value on the enzyme activity, storage stability, and reusability were investigated using para-nitrophenyl acetate (p NPA) assay. CA/GFS showed a better performance with respect to storage stability and reusability than CA/AFS. Moreover, the amount of CaCO3 precipitated over CA/AFS was less than that precipitated over CA/GFS, which was almost equal to that precipitated over the free CA. The results indicate that the epoxy group is a more suitable functional group for covalent bonding with CA than the amino group, and GFS is a promising support for CA immobilization. PMID- 27215832 TI - Improvement of enantioselectivity of the B-type halohydrin hydrogen-halide-lyase from Corynebacterium sp. N-1074. AB - Halohydrin hydrogen-halide-lyase (H-Lyase) is a bacterial enzyme involved in the degradation of halohydrins. This enzyme catalyzes the intramolecular nucleophilic displacement of a halogen by a vicinal hydroxyl group in halohydrins, producing the corresponding epoxides. The H-Lyases have been classified into A, B and C subtypes based on amino acid sequence similarities. These enzymes have attracted much attention as industrial catalysts in the synthesis of chiral chemicals from prochiral halohydrins. In the present study, we constructed mutants of B-type H Lyase from Corynebacterium sp. N-1074 (HheB) displaying higher enantioselectivity by structure-based site-directed mutagenesis and random mutagenesis. A triple mutant of HheB exhibited 98.5% enantioselectivity, the highest ever reported, toward (R)-4-chloro-3-hydroxy-butyronitrile production, with the yield reaching approximately two-fold that of the wild-type enzyme. We discuss the structural basis of the high enantioselectivity and productivity of the mutant by comparing the crystal structures of the mutant HheB and the wild-type enzyme in complex with or without the substrate analogue. PMID- 27215833 TI - Comparison of electrochemical and microbiological characterization of microbial fuel cells equipped with SPEEK and Nafion membrane electrode assemblies. AB - Microbial fuel cells equipped with SPEEK-MEA (SPEEK-MFC) and Nafion-MEA (Nafion MFC) were constructed with organic waste as electron donor and lake sediment as inoculum and were then evaluated comprehensively by electrochemical and microbial analyses. The proton conductivity of SPEEK was several hundreds-fold lower than that of Nafion 117, whereas the oxygen mass and diffusion transfer coefficients of SPEEK were 10-fold lower than those of Nafion 117. It was difficult to predict which was better membrane for MFC based on the feature of membrane. Analyses of polarization curves indicated that the potential of electricity production was similar in both MFCs, as the SPEEK-MFC produced 50-80% of the practical current density generated by the Nafion-MFC. Chronopotentiometry analyses indicated that the Nafion-MEA kept the performance longer than the SPEEK-MEA for long period, whereas performance of both anodes improved on time. Multidimensional scaling analyses based on DGGE profiles revealed the anolytic and biofilm communities of the SPEEK-MFC had developed differently from those of the Nafion-MFC. Clone library analyses indicated that Geobacter spp. represented 6.3% of the biofilm bacterial community in the Nafion-MFC but not detected in the SPEEK-MFC. Interestingly, the clone closely related to Acetobacterium malicum strain HAAP-1, belonging to the homoacetogens, became dominant in both anolytic and biofilm communities of the SPEEK-MFC. It was suggested that the lower proton conductivity of SPEEK-MEA allowed the bacteria closely related to strain HAAP-1 to be dominant specifically in SPEEK-MFC. These results indicated that Nafion-MFC ranked with SPEEK-MFC and that MEAs had strong selective pressure for electricity-producing bacterial community. PMID- 27215830 TI - The underlying neurobiology of key functional domains in young people with mood and anxiety disorders: a systematic review. AB - BACKGROUND: Mood and anxiety disorders are leading causes of disability and mortality, due largely to their onset during adolescence and young adulthood and broader impact on functioning. Key factors that are associated with disability and these disorders in young people are social and economic participation (e.g. education, employment), physical health, suicide and self-harm behaviours, and alcohol and substance use. A better understanding of the objective markers (i.e. neurobiological parameters) associated with these factors is important for the development of effective early interventions that reduce the impact of disability and illness persistence. METHODS: We systematically reviewed the literature for neurobiological parameters (i.e. neuropsychology, neuroimaging, sleep-wake and circadian biology, neurophysiology and metabolic measures) associated with functional domains in young people (12 to 30 years) with mood and/or anxiety disorders. RESULTS: Of the one hundred and thirty-four studies selected, 7.6 % investigated social and economic participation, 2.1 % physical health, 15.3 % suicide and self-harm behaviours, 6.9 % alcohol and substance use, whereas the majority (68.1 %) focussed on clinical syndrome. CONCLUSIONS: Despite the predominance of studies that solely examine the clinical syndrome of young people the literature also provides evidence of distinct associations among objective measures (indexing various aspects of brain circuitry) and other functional domains. We suggest that a shift in focus towards characterising the mechanisms that underlie and/or mediate multiple functional domains will optimise personalised interventions and improve illness trajectories. PMID- 27215834 TI - Clinical Nomogram for Predicting Survival of Esophageal Cancer Patients after Esophagectomy. AB - The aim of this study was to construct an effective clinical nomogram for predicting the survival of esophageal cancer patients after esophagectomy. We identified esophageal cancer patients (n = 4,281) who underwent esophagectomy between 1988 and 2007 from the Surveillance, Epidemiology, and End Results (SEER) 18 registries database. Clinically significant parameters for survival were used to construct a nomogram based on Cox regression analyses. The model was validated using bootstrap resampling and a Chinese cohort (n = 145). A total of 4,109 patients from the SEER database were included for analysis. The multivariate analyses showed that the factors of age, race, histology, tumor site, tumor size, grade and depth of invasion, and the numbers of metastases and retrieved nodes were independent prognostic factors. All of these factors were selected into the nomogram. The nomogram showed a clear prognostic superiority over the seventh AJCC-TNM classification (C-index: SEER cohort, 0.716 vs 0.693, respectively; P < 0.01; Chinese cohort, 0.699 vs 0.680, respectively; P < 0.01). Calibration of the nomogram predicted the probabilities of 3- and 5-year survival, which corresponded closely with the actual survival rates. This novel prognostic model may improve clinicians' abilities to predict individualized survival and to make treatment recommendations. PMID- 27215835 TI - Food cravings in pregnancy: Preliminary evidence for a role in excess gestational weight gain. AB - Currently, more than 50% of American women gain an excessive amount of weight during pregnancy as per guidelines established by the Institute of Medicine and American Congress of Obstetrics and Gynecology. This excess gestational weight gain (GWG) is associated with health complications in both mothers and children. This study sought to examine the hypothesized causal role of cravings in excess GWG. Pregnant women were recruited from a local hospital (n = 40) and via posts on pregnancy-related websites (n = 43). Weight (current and pregravid) and height data were collected to calculate body mass index (BMI) and recommended versus excess GWG. Participants completed the Food Craving Inventory (FCI), which quantifies "frequency" of cravings for specific foods and the likelihood of "giving in" to these cravings. Overweight/obesity prior to pregnancy was reported by 40.5%-57.9% of participants. At the time of survey completion, 19.5% of online and 31.6% of hospital respondents had gained more than the recommended amount of weight for their stage of gestation. All women had experienced and given in to at least one craving, with cravings for "sweets" and "fast foods" being most common. Craving "frequency" accounted for a substantial portion of variance in excess GWG (25.0% in the online sample and 32.0% in respondents recruited at the hospital). Frequency of "giving in" to cravings accounted for 35.0% of the variance in excess GWG in the online sample only. Findings suggest that both craving frequency and consumption of craved foods may increase risk of excess GWG, providing support for the development of interventions targeting cravings in pregnancy as potentially modifiable determinants of energy intake. PMID- 27215836 TI - Investigating the effects of caffeine on executive functions using traditional Stroop and a new ecologically-valid virtual reality task, the Jansari assessment of Executive Functions (JEF((c))). AB - OBJECTIVE: Caffeine has been shown to have effects on certain areas of cognition, but in executive functioning the research is limited and also inconsistent. One reason could be the need for a more sensitive measure to detect the effects of caffeine on executive function. This study used a new non-immersive virtual reality assessment of executive functions known as JEF((c)) (the Jansari Assessment of Executive Function) alongside the 'classic' Stroop Colour-Word task to assess the effects of a normal dose of caffeinated coffee on executive function. METHOD: Using a double-blind, counterbalanced within participants procedure 43 participants were administered either a caffeinated or decaffeinated coffee and completed the 'JEF((c))' and Stroop tasks, as well as a subjective mood scale and blood pressure pre- and post condition on two separate occasions a week apart. JEF((c)) yields measures for eight separate aspects of executive functions, in addition to a total average score. RESULTS: Findings indicate that performance was significantly improved on the planning, creative thinking, event , time- and action-based prospective memory, as well as total JEF((c)) score following caffeinated coffee relative to the decaffeinated coffee. The caffeinated beverage significantly decreased reaction times on the Stroop task, but there was no effect on Stroop interference. CONCLUSION: The results provide further support for the effects of a caffeinated beverage on cognitive functioning. In particular, it has demonstrated the ability of JEF((c)) to detect the effects of caffeine across a number of executive functioning constructs, which weren't shown in the Stroop task, suggesting executive functioning improvements as a result of a 'typical' dose of caffeine may only be detected by the use of more real-world, ecologically valid tasks. PMID- 27215837 TI - Appetitive traits and relationships with BMI in adults: Development of the Adult Eating Behaviour Questionnaire. AB - The Child Eating Behaviour Questionnaire (CEBQ) is a validated parent-report measure of appetitive traits associated with weight in childhood. There is currently no matched measure for use in adults. The aim of this study was to adapt the CEBQ into a self-report Adult Eating Behaviour Questionnaire (AEBQ) to explore whether the associations between appetitive traits and BMI observed in children are present in adults. Two adult samples were recruited one year apart from an online survey panel in 2013 (n = 708) and 2014 (n = 954). Both samples completed the AEBQ and self-reported their weight and height. Principal component analysis (PCA) was used to derive 35 items for the AEBQ in Sample 1 and confirmatory factor analysis (CFA) was used to replicate the factor structure in Sample 2. Reliability of the AEBQ was assessed using Cronbach's alpha and a two week test-retest in a sub-sample of 93 participants. Correlations between appetitive traits measured by the AEBQ and BMI were calculated. PCA and CFA results showed the AEBQ to be a reliable questionnaire (Cronbach's alpha > 0.70) measuring 8 appetitive traits similar to the CEBQ [Hunger (H), Food Responsiveness (FR), Emotional Over-Eating (EOE), Enjoyment of Food (EF), Satiety Responsiveness (SR), Emotional Under-eating (EUE), Food Fussiness (FF) and Slowness in Eating (SE)]. Associations with BMI showed FR, EF (p < 0.05) and EOE (p < 0.01) were positively associated and SR, EUE and SE (p < 0.01) were negatively associated. Overall, the AEBQ appears to be a reliable measure of appetitive traits in adults which translates well from the validated child measure. Adults with a higher BMI had higher scores for 'food approach' traits (FR, EOE and EF) and lower scores for 'food avoidance' traits (SR, EUE and SE). PMID- 27215838 TI - Food attitudes and well-being: The role of culture. AB - Previous cross-cultural studies have found differences in food attitudes. For example, Americans are more concerned about weight gain than people from France and India. This study aimed to add on the literature on cross-cultural differences in food attitudes by comparing Euro-Americans with Costa Ricans on three different food attitudes: concern about gaining weight, food negativity, and the belief in the link between diet and health. This study also analyzes the implications of food attitudes on well-being. Specifically, within and across cultures, analyses were done to test the relationship between food attitudes and both anxiety and depression. Results showed that Costa Ricans are significantly less concerned about weight and less food negative than Euro-Americans. In further analyses an interaction was revealed, in which Costa Ricans that are high on weight concern but low on food negativity show lower levels of depression, compared to Euro-Americans. Results and implications for further research are discussed. PMID- 27215839 TI - Social cognitions about food choice in children aged five to eight years: Feasibility and predictive validity of an age appropriate measurement. AB - There are currently no instruments available to measure social cognitions towards food choice in children. This study aimed to test the feasibility and predictive validity of a novel measurement tool to assess food-related social cognitions. Sixty-eight children, five to eight years old, were asked to sort cards with photographs of four fruit and four sweet/savoury snacks as a mean to measure attitudes, subjective norms, perceived behavioural control (PBC), and intention. Subsequently, food choice (dependent variable) was assessed using a laboratory food choice task in which children could gain access to sweet and savoury or fruit items, or a combination. All participants completed the tasks successfully, demonstrating feasibility of the procedure. The order in which the cards were sorted for each construct differed sufficiently and correlations between constructs were in line with previous studies. Measures of PBC, intention, attitude, and subjective norm from the mother, but not from teachers or friends, correlated significantly with subsequent food choice. It is possible to measure food-related social cognitions in children aged five to eight and these measures were predictive of observed behaviour. The new instrument can contribute to our understanding of psychological determinants of food choice in young children. PMID- 27215840 TI - Effectiveness of Taste Lessons with and without additional experiential learning activities on children's willingness to taste vegetables. AB - This study assessed the effectiveness of the Dutch school programme Taste Lessons with and without additional experiential learning activities on children's willingness to taste unfamiliar vegetables. Thirty-three primary schools (877 children in grades 6-7 with a mean age of 10.3 years) participated in Taste Lessons Vegetable Menu (TLVM, lessons and extra activities), Taste Lessons (TL, lessons), or a control group. A baseline and follow-up measurement was used to assess for each child: number of four familiar and four unfamiliar vegetables tasted, quantity tasted, choice of vegetable of which to eat more, and number of vegetables willing to taste again later. Furthermore, children filled out a questionnaire on daily vegetable intake and food neophobia. Multilevel and Cox regression analyses were conducted to compare changes in the outcome measures between the three study groups. No significant intervention effects were found on willingness to taste unfamiliar vegetables. Neither were effects found on familiar vegetables, except for number of familiar vegetables tasted (p < 0.05). Furthermore, no significant intervention effects were found on daily vegetable consumption and food neophobia. These results indicate that more intensive school based nutrition education activities are needed to increase children's willingness to taste unfamiliar vegetables and increase their vegetable intake. PMID- 27215852 TI - Repeat revascularization: Percutaneous coronary intervention after coronary artery bypass graft surgery. AB - Repeat myocardial revascularization procedures are markedly different from de novo interventions, with increased procedural risk and technical-demanding complexity. However the number of patients previously treated with coronary artery bypass graft (CABG) that need a repeat revascularization due to graft failure is increasing consistently. Late graft failure, usually caused by saphenous vein grafts (SVG) attrition, is certainly not uncommon. However PCI on degenerated SVG presents higher complication rate and worse clinical outcome compared with native arteries interventions. In acute graft failure setting, PCI represents a valuable option to treat postoperative myocardial infarction. PMID- 27215841 TI - Optical electrophysiology for probing function and pharmacology of voltage-gated ion channels. AB - Voltage-gated ion channels mediate electrical dynamics in excitable tissues and are an important class of drug targets. Channels can gate in sub-millisecond timescales, show complex manifolds of conformational states, and often show state dependent pharmacology. Mechanistic studies of ion channels typically involve sophisticated voltage-clamp protocols applied through manual or automated electrophysiology. Here, we develop all-optical electrophysiology techniques to study activity-dependent modulation of ion channels, in a format compatible with high-throughput screening. Using optical electrophysiology, we recapitulate many voltage-clamp protocols and apply to Nav1.7, a channel implicated in pain. Optical measurements reveal that a sustained depolarization strongly potentiates the inhibitory effect of PF-04856264, a Nav1.7-specific blocker. In a pilot screen, we stratify a library of 320 FDA-approved compounds by binding mechanism and kinetics, and find close concordance with patch clamp measurements. Optical electrophysiology provides a favorable tradeoff between throughput and information content for studies of NaV channels, and possibly other voltage-gated channels. PMID- 27215853 TI - Telomere-associated aging disorders. AB - Telomeres are dynamic nucleoprotein-DNA structures that cap and protect linear chromosome ends. Several monogenic inherited diseases that display features of human premature aging correlate with shortened telomeres, and are referred to collectively as telomeropathies. These disorders have overlapping symptoms and a common underlying mechanism of telomere dysfunction, but also exhibit variable symptoms and age of onset, suggesting they fall along a spectrum of disorders. Primary telomeropathies are caused by defects in the telomere maintenance machinery, whereas secondary telomeropathies have some overlapping symptoms with primary telomeropathies, but are generally caused by mutations in DNA repair proteins that contribute to telomere preservation. Here we review both the primary and secondary telomeropathies, discuss potential mechanisms for tissue specificity and age of onset, and highlight outstanding questions in the field and future directions toward elucidating disease etiology and developing therapeutic strategies. PMID- 27215854 TI - School Substance Use Norms and Racial Composition Moderate Parental and Peer Influences on Adolescent Substance Use. AB - Parental and peer influences on adolescent substance use have been well demonstrated. However, limited research has examined how parental and peer influences vary across school contexts. This study used a multilevel approach to examine the effects of school substance use norms and school racial composition in predicting adolescent substance use (a composite measure of alcohol, tobacco, and marijuana use) and in moderating parental and peer influences on adolescent substance use. A total of 14,346 adolescents from 34 schools in a mid-western county completed surveys electronically at school. Analyses were conducted using hierarchical linear modeling. Results indicated that school-level disapproval against substance use and percentage of minority students at school were negatively associated with adolescent substance use. School-level disapproval moderated the association between peer substance use and adolescent substance use, with the association being stronger when school-level disapproval was lower. School racial composition moderated the influence of parental disapproval and peer substance use on adolescent substance use. Specifically, both the association between parental disapproval and adolescent substance use and the association between peer substance use and adolescent substance use were weaker for adolescents who attended schools with higher percentages of minority students. Findings highlighted the importance of considering the role of school contexts, in conjunction with parental and peer influences, in understanding adolescent substance use. PMID- 27215856 TI - Ulnar nerve entrapment at elbow in obstructive sleep apnea patients: a randomized controlled trial. AB - PURPOSE: Obstructive sleep apnea (OSA) is a highly prevalent disease. For diagnostic and therapeutic purposes, OSA has been divided into several subgroups. Positional OSA (POSA), the most frequent subgroup (56 %), is described as overall apnea hypopnea index (AHI) >=5 and supine AHI at least twice as high when compared to non-supine AHI. We aimed to investigate the frequency of ulnar nerve entrapment neuropathy at the elbow (UNEE) in OSA patients without clinical signs and symptoms of ulnar neuropathy and intended to find if sleeping position in OSA had an impact on UNEE development. METHODS: Fifty POSA, 48 non-positional OSA (NPOSA) patients, and 45 healthy controls without diabetes mellitus, hypothyroidism, rheumatic diseases, and cervical radiculopathy underwent nerve conduction studies. RESULTS: We found that UNEE was highly frequent in OSA patients (42.9 %) and significantly more frequent in moderate to severe POSA patients than mild POSA patients (65.4 vs. 33.3 %, p < 0.05). Furthermore, when compared to non-positional ones, UNEE was significantly more frequent in moderate to severe POSA patients (65.4 vs. 36.4 %, p < 0.05). CONCLUSIONS: Our results showed that the severity of OSA in positional patients was correlated with increased frequency of UNEE. OSA patients should be informed about the predisposition of UNEE and questioned for the symptoms in periodical controls. POSA patients should be alerted about the additional effect of sleeping position on UNEE and the necessity of OSA treatment should be emphasized. PMID- 27215858 TI - Army Medical Department at War: Lessons Learned. PMID- 27215857 TI - Inter-examiner agreement of the systematic physical examination in patients with obstructive sleep disorders. AB - PURPOSE: The goal of this study was to investigate the agreement between examiners who were or were not trained in the physical examination of the upper airway (UA) and the craniofacial skeleton of individuals with obstructive sleep disorders (OSD). METHOD: A systematic assessment of the UA and craniofacial skeleton was performed on 55 individuals with OSD. The participants were consecutively assessed by three otorhinolaryngologists who specialized in sleep medicine for at least 1 year (trained examiners) and two doctors who were attending a residency program in otorhinolaryngology (untrained examiners). RESULTS: When analyzing all of the parameters assessed, the concordance was better in the trained group (k = 0.694, which is considered "good") compared to the untrained group (k = 0.475, "fair") (p < 0.001). The inter-examiner agreement was also better in the trained compared to the untrained group, as follows: craniofacial (k = 0.643 vs. 0.349), nasal (k = 0.657 vs. 0.614), and pharyngeal (k = 0.729 vs. 0.276) abnormalities (p < 0.05). CONCLUSION: The overall concordance of the physical examination of the UA and craniofacial skeleton was "good" among the trained specialists and "fair" among examiners without appropriate training, despite its subjectivity. PMID- 27215859 TI - Planning for Organizational Success: Hope is Not a Method. AB - The foundational requirement for US Army Medical Department (AMEDD) organizational success on the battlefield is proper planning in accordance with Army doctrinal and tactical guidance. The same can be said for every type of AMEDD garrison-based organization. Commanders and leaders of AMEDD garrison-based organizations must be familiar with and rehearsed in the military decision making process, and use it to their advantage in support of the Warfighter and his or her family. PMID- 27215855 TI - Delta inulin-derived adjuvants that elicit Th1 phenotype following vaccination reduces respiratory syncytial virus lung titers without a reduction in lung immunopathology. AB - Respiratory syncytial virus (RSV) is a significant cause of lower respiratory tract infections resulting in bronchiolitis and even mortality in the elderly and young children/infants. Despite the impact of this virus on human health, no licensed vaccine exists. Unlike many other viral infections, RSV infection or vaccination does not induce durable protective antibodies in humans. In order to elicit high titer, neutralizing antibodies against RSV, we investigated the use of the adjuvant AdvaxTM, a novel polysaccharide adjuvant based on delta inulin microparticles, to enhance antibody titers following vaccination. BALB/c mice were vaccinated intramuscularly with live RSV as a vaccine antigen in combination with one of two formulations of AdvaxTM. Advax-1 was comprised of the standard delta inulin adjuvant and Advax-2 was formulated delta inulin plus CpG oligodendronucleotides (ODNs). An additional group of mice were either mock vaccinated, immunized with vaccine only, or administered vaccine plus Imject Alum. Following 3 vaccinations, mice had neutralizing antibody titers that correlated with reduction in viral titers in the lungs. Advax-1 significantly enhanced serum RSV-specific IgG1 levels at week 6 indicative of a Th2 response, similar to titers in mice administered vaccine plus Imject Alum. In contrast, mice vaccinated with vaccine plus Advax-2 had predominately IgG2a titers indicative of a Th1 response that was maintained during the entire study. Interestingly, regardless of which AdvaxTM adjuvant was used, the neutralizing titers were similar between groups, but the viral lung titers were significantly lower (~10E+3pfu/g) in mice administered vaccine with either AdvaxTM adjuvant compared to mice administered adjuvants only. The lung pathology in vaccinated mice with AdvaxTM was similar to Imject Alum. Overall, RSV vaccine formulated with AdvaxTM had high neutralizing antibody titers with low lung viral titers, but exacerbated lung pathology compared to unvaccinated mice. PMID- 27215860 TI - Data-driven Casualty Estimation and Disease Nonbattle Injury/Battle Injury Rates in Recent Campaigns. AB - To ensure Soldiers are properly equipped and mission capable to perform full spectrum operations, Army medical planners use disease nonbattle injury (DNBI) and battle injury (BI) admission rates in the Total Army Analysis process to support medical deployment and force structure planning for deployed settings. For more than a decade, as the proponent for the DNBI/BI methodology and admission rates, the Statistical Analysis Cell (previously Statistical Analysis Branch, Center for Army Medical Department Strategic Studies) has provided Army medical planners with DNBI/BI rates based upon actual data from recent operations. This article presents the data-driven methodology and casualty estimation rates developed by the Statistical Analysis Cell and accredited for use by 2 Army Surgeon Generals, displays the top 5 principal International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM) diagnoses for DNBI/BI in Operation Iraqi Freedom/Operation New Dawn (OIF/OND), and discusses trends in DNBI rates in OIF/OND during the stabilization period. Our methodology uses 95th percentile daily admission rates as a planning factor to ensure that 95% of days in theater are supported by adequate staff and medical equipment. We also present our DNBI/BI estimation methodology for non-Army populations treated at Role 3 US Army medical treatment facilities. PMID- 27215861 TI - Surveillance of Disease and Nonbattle Injuries During US Army Operations in Afghanistan and Iraq. AB - Disease and nonbattle injury (DNBI) are the leading causes of morbidity during wars and military operations. However, adequate medical data were never before available to service public health centers to conduct DNBI surveillance during deployments. This article describes the process, results and lessons learned from centralized DNBI surveillance by the US Army Center for Health Promotion and Preventive Medicine, predecessor of the US Army Public Health Command, during operations in Afghanistan and Iraq (2001-2013).The surveillance relied primarily on medical evacuation records and in-theater hospitalization records. Medical evacuation rates (per 1,000 person-years) for DNBI were higher (Afghanistan: 56.7; Iraq: 40.2) than battle injury rates (Afghanistan: 12.0; Iraq: 7.7). In Afghanistan and Iraq, respectively, the leading diagnostic categories for medical evacuations were nonbattle injury (31% and 34%), battle injury (20% and 16%), and behavioral health (12% and 10%). Leading causes of medically evacuated nonbattle injuries were sports/physical training (22% and 24%), falls (23% and 26%) and military vehicle accidents (8% and 11%). This surveillance demonstrated the feasibility, utility, and benefits of centralized DNBI surveillance during military operations. PMID- 27215862 TI - Dismounted Complex Blast Injuries Including Invasive Fungal Infections. AB - Large blast injuries during dismounted operations in southwest Afghanistan causing major limb amputations and perineal injuries associated with large blood volume resuscitation were associated with invasive fungal, primarily mold, infections. This article outlines the interventions undertaken to mitigate excess morbidity and mortality associated with invasive fungal infection. These interventions include defining the problem and associated risk with systemically collected and analyzed information, developing improved protective body armor for the thigh and perineal region, standardizing management through clinical practice guidelines that outlined risk, diagnostic and treatment recommendations with enhanced discussions on the weekly Theater Combat Casualty Care Conference that includes personnel from the combat zone, Germany, and the United States. The article concludes by explaining the key way forward with regarding an inner-war approach to sustained knowledge and skills. PMID- 27215863 TI - Battlefield Tourniquets: Lessons Learned in Moving Current Care Toward Best Care in an Army Medical Department at War. AB - Bleeding prevention and control by tourniquet use by out-of-hospital caregivers is a major breakthrough in military medicine of current wars. The present review documents developments in tourniquet practices since 2001 among the US military services for aid in improving doctrine, policy, and especially care in wars to come. Tourniquets are an adjunct for resuscitation in self-care and buddy aid and today are issued to all military servicepersons who deploy into a combat zone. In the US Army, virtually every Soldier is trained in first aid tourniquet use; since 2009 they are instructed early and often to use them early and often. Despite substantial knowledge gains among the services in tourniquet use and resulting improvements in casualty survival, current evidence shows persistent difficulties in achieving best care with tourniquet use for individual trauma patients. Nevertheless, contemporary tourniquet use incorporates key lessons learned over the last 14 years of war that include: (1) tourniquet use reliably stops bleeding from limb wounds and prevents mortality in prehospital settings; and (2) brief tourniquet use appears to be safe. These 2 lessons have become so evident that civilian emergency medical systems have begun using them, albeit unevenly. Collection and interpretation of data of casualties with tourniquet use have showed that such intervention has lifesaving benefit through 2 mechanisms: control of both ongoing hemorrhage and shock severity. The next generation of interventions in bleeding control involves developing the skill sets, education, and standards of tourniquet users which may improve hemorrhage control in wars to come. PMID- 27215864 TI - Lessons Learned for the Resuscitation of Traumatic Hemorrhagic Shock. AB - The lessons learned regarding the resuscitation of traumatic hemorrhagic shock are numerous and come from a better understanding of the epidemiology, pathophysiology, and experience in this population over 10-plus years of combat operations. We have now come to better understand that the greatest benefit in survival can come from improved treatment of hemorrhage in the prehospital phase of care. We have learned that there is an endogenous coagulopathy that occurs with severe traumatic injury secondary to oxygen debt and that classic resuscitation strategies for severe bleeding based on crystalloid or colloid solutions exacerbate coagulopathy and shock for those with life-threatening hemorrhage. We have relearned that a whole blood-based resuscitation strategy, or one that at least recapitulates the functionality of whole blood, may reduce death from hemorrhage and reduce the risks of excessive crystalloid administration which include acute lung injury, abdominal compartment syndrome, cerebral edema, and anasarca. Appreciation of the importance of shock and coagulopathy management underlies the emphasis on early hemostatic resuscitation. Most importantly, we have learned that there is still much more to understand regarding the epidemiology, pathophysiology, and the resuscitation strategies required to improve outcomes for casualties with hemorrhagic shock. PMID- 27215865 TI - Theater Blood Support in the Prehospital Setting. AB - The Army Blood Program (ABP) is charged with the responsibility of supporting the Warfighter on the battlefield, in addition to meeting garrison hospital blood requirements on a daily basis. Blood support concepts developed in response to Operation Iraqi Freedom/Operation Enduring Freedom combat operations are the cornerstone to maintaining current capabilities and shaping future endeavors.. The ABP is actively engaged with research, advanced development of blood products and medical technology to improve blood safety and efficacy for both our conventional and operational forces. The feasibility of frozen/deglycerolized red blood cell use in theater has been demonstrated. The use of Blood Group A plasma in the place of Blood Group AB plasma has been successful. Placement of cryoprecipitate at Role 2 medical facilities and the placement of blood products on MEDEVAC (Vampire Program missions) have proven invaluable in moving transfusion therapy closer to the point of Injury. The improved patient outcomes from earlier transfusion of blood products has driven the requirement for far forward blood support. Now (more than ever), there are products and processes in place to meet the requirements for blood use in the prehospital setting. PMID- 27215866 TI - Shaping the Flight Paramedic Program. AB - Over the past 14 years of conflict, the Department of Defense medical community has made significant strides in patient care. As the conflicts developed, many sources identified a critical gap in en route care, specifically the need for critical care trained personnel for point of injury and intrahospital transfers, as well as improved outcomes for patients who received care from critical care trained providers. As stopgap measures were implemented, the US Army instituted the Critical Care Flight Paramedic Program in order to meet this need of life saving critical care transport. Execution of both an institutional training model as well as a home station training option allows for increased numbers of personnel trained, as well as flexibility for National Guard and Army Reserve units to keep personnel in their area. The Critical Care Flight Paramedic Program's educational outcomes have been exceptional, with National Registry Paramedic pass rates well above the national average. As the program develops, recertification and sustainment of knowledge and skills will be challenges, and novel approaches and flexibility will become critical for continued success. PMID- 27215867 TI - US Army Physical Therapist Roles and Contributions in Operations Enduring Freedom and Iraqi Freedom. AB - Musculoskeletal injuries are a leading cause of health care utilization, medical evacuation, and disability. US Army physical therapists (PTs) have served as physician extenders for the management of nonsurgical neuromusculoskeletal injuries since the Vietnam conflict. The roles and evidence supporting US Army physical therapy continue to evolve. This article discusses the different levels of care and roles of US Army PTs, the contributions and evidence regarding US Army physical therapy, and physical therapy lessons learned during Operations Enduring Freedom and Iraqi Freedom. Since 2001, US Army PTs and enlisted physical therapy technicians have provided care from Levels 1 to 5 and assignments have expanded to special operations and brigade combat teams. Evidence suggests US Army PTs serving both in referral and direct access roles provided safe and definitive care that maximized readiness while reducing evacuation. Key physical therapy lessons learned include: (1) a continued focus on a Soldier sports medicine forward care model, (2) a need for injury risk assessment, physical performance screenings, and reconditioning programs that optimize readiness, and (3) continued support for physical therapy structure, training, and research that maximizes Soldier readiness and health. PMID- 27215868 TI - The Role of Army Nurse Practitioners Supporting Wars in Iraq and Afghanistan. AB - Family nurse practitioners are an essential member of the military medical team. They were incorporated into the Army medical system almost as soon as there was an academic program to develop the role in primary care settings. The role for nurse practitioners during deployment has not been as clear. Even though they have been around for 50 years, the specific role nurse practitioners provide is still evolving. This article explores the incorporation of nurse practitioners into Army medicine with a focus on deployed medicine. Nurse practitioners have been shown to be very versatile providers with the requisite skill sets to meet the demands of the combat environment and are able to substitute for other medical assets that are critically short due to sustained conflict. Clarifying the value a nurse practitioner brings to medical care in the combat environment is essential to insure all assets are being employed to provide the best medical care to the US fighting force. PMID- 27215869 TI - Advances in Anesthesia Delivery in the Deployed Setting. AB - Lessons learned over the past decade and a half of combat casualty management has brought about numerous advances in trauma anesthesia practice. In the post Vietnam era, deployable anesthesia equipment centered on the capability to provide a balanced anesthetic technique, utilizing a combination of volatile gas and intravenous anesthetic adjuncts. The evolution of the modern battlefield has forced anesthesia providers across the military to adapt to mission requirements that often dictate a surgical capability that is more rapidly mobile and less reliant on logistical support. Institutional medical equipment development has focused on fielding a lighter, more mobile volatile gas delivery method. Despite numerous advances in anesthetic gas delivery, many veteran anesthesia providers have come to recognize the value of alternative anesthetic techniques in the deployed setting. One of the most appealing advances in combat anesthesia practice is the emergence of total intravenous anesthetics (TIVA) for trauma management and resuscitation. Although there have been numerous developments in anesthetic equipment for use in the deployed setting, TIVA has many advantages over volatile gas administration. Future research, development, and education should focus on TIVA and the ability to provide this as an alternative safe anesthetic for patients in austere environments. It is imperative to retain the lessons we have learned in order to adapt more effectively in future conflicts. This accumulation of knowledge must inform future innovative solutions to the challenges of casualty management in a deployed setting. PMID- 27215870 TI - Roles of Occupational Therapists in Theater, Past and Present. AB - The impetus to deploy occupational therapy (OT) assets into theaters of operation lies in the occupational therapist's ability to evaluate the effect of physical and/or behavioral symptoms on functional performance and effectively develop individualized interventions. Occupational therapy utilization has been robust during 14 years of continuous deployments in Iraq and Afghanistan. Occupational therapy's indoctrinated role in combat is solely with the combat and operational stress control missions, however, the skills and capabilities of this profession have demonstrated efficacy in other specializations, including concussion care. The effectiveness of OT interventions is demonstrated with improved return to duty (RTD) rates for casualties suffering with combat and operational stress reactions where OT was a major component of a restoration and reconditioning program. As well, postconcussion RTD rates have been linked to the broad skill sets inherent in OT that allow casualties to remain in theater from the point of injury to complete recovery and RTD. PMID- 27215871 TI - Wounded, Ill, and Injured Challenges. AB - The Washington Post articles of February 2007 led to a close examination of the care provided Wounded Warriors at Walter Reed Army Medical Center. Subsequent reports by the President's Commission, Independent Review Group, and Defense Health Board all recommended ways to improve care. Joint Task Force National Capital Region Medical was established to implement the recommended improvements in Warrior care, and the recommendations of the Base Realignment and Closure Commission to close Walter Reed and realign the staff into a new Walter Reed National Military Medical Center and Fort Belvoir Community Hospital. It accomplished these tasks, maintained existing wounded, ill, and injured care, and safely transferred patients during the height of the fighting season in Afghanistan. It successfully accomplished its mission through engaged leadership, establishing an appropriate environment for Warrior care, careful management of casualty flow, and robust communication with all parties affected by the changes. The lessons learned in Warrior care should be considered when planning future military medical operations. PMID- 27215872 TI - Rehabilitation of the Combat Casualty: Lessons Learned from Past and Current Conflicts. AB - The field of rehabilitation is deeply rooted in military medicine, especially in promoting the restoration of function and community reintegration of injured service members returning from war. Since military operations began in Iraq and Afghanistan over a decade ago, rehabilitative care programs have been integral in supporting the Military Healthcare System in providing high quality comprehensive care for combat casualties and their families, particularly those with complex blast injuries resulting in conditions such as amputation and other limb dysfunction, traumatic brain injury, and spinal cord injury. Fundamental to a successful rehabilitation program is the coordination of interdisciplinary care that not only crosses multiple medical specialties and disciplines, but also promotes ongoing education, research, quality improvement and readiness. This brief article is intended to highlight some of the most important lessons learned from current and past conflicts in delivering the highest quality rehabilitative care to our nation's heroes. PMID- 27215873 TI - Battlefield Documentation of Tactical Combat Casualty Care in Afghanistan. AB - Performance improvement is reliant on information and data, as you cannot improve what you do not measure. The US military went to war in 2001 without an integrated trauma care system to collect and analyze combat casualty care data. By 2006, the conflict in Afghanistan began appreciating the capture and consolidation of hospital care documentation into the Department of Defense Trauma Registry. In contrast, a paucity of documentation has existed for prehospital or tactical combat casualty care (TCCC). Using the 75th Ranger casualty documentation model established in 2005, the Joint Trauma System developed a casualty data collection system for prehospital care using the TCCC Card, the TCCC After Action Report (AAR), and the Prehospital Trauma Registry. In 2013, this system was mandated for use by US forces in Afghanistan. The Joint Trauma System also created and deployed a prehospital team to be an integral part of the Joint Theater Trauma System in Afghanistan. This prehospital team provided prehospital training and facilitated prehospital data capture. Described and analyzed in this report are prehospital data captured in Afghanistan from 2013 to 2014 using the TCCC Card and the TCCC AAR. PMID- 27215874 TI - Traumatic Brain Injury Clinical Recommendations: Impact on Care and Lessons Learned. AB - Over 330,000 service members have been diagnosed with traumatic brain injury (TBI) since 2000. The Defense and Veterans Brain Injury Center (DVBIC) is uniquely positioned to identify knowledge gaps and disseminate information related to TBI to assist service members, clinical providers, and military families. The DVBIC utilizes a standardized process based on Institutes of Medicine and World Health Organization recommendations for the development of evidenced-based clinical guidelines. This presentation provided an overview of the need and process for developing TBI-specific clinical recommendations (CRs) related to diagnosis and treatment issues, and the lessons learned throughout their development. The development of CRs provides evidence-based, standardized guidance for symptom management and treatment recommendations following TBI. Included within the DVBIC process are site-specific adjustments that address the needs and requirements of our military stakeholders, including the operational challenges of the deployed setting. The identification of the need for TBI diagnosis and treatment guidelines within the Military Health System and the consideration of military service-specific and Department of Defense policy are integrated within an evidenced-based, systematic CR development process. PMID- 27215875 TI - Acute and Chronic Pain on the Battlefield: Lessons Learned from Point of Injury to the United States. AB - Historically, war tends to accelerate innovation within military medicine. In this article, the authors argue this truism has recurred in the case of acute and chronic pain management for combatants in the global war on terrorism (GWOT). Advances in regional anesthesia techniques and multimodal acute pain care are highlighted in light of the typical weapons, injuries, and comorbid conditions of the modern combat era. Reported success of providing chronic pain care in the war theater during GWOT is discussed in the context of operational requirements for current and future wars. A description is provided of the Pain Management Task Force (PMTF) and Pain Campaign Plan which was initiated during GWOT. The PMTF effort enhanced pain education and clinical pain care through leadership and organizational changes, which created broader access to pain treatments for patients and more standardized treatment capabilities across the enterprise. PMID- 27215876 TI - Leveraging Trauma Lessons from War to Win in a Complex Global Environment. AB - The US military has made great strides in combat casualty care since 2001. As the Army concludes combat operations in Iraq and Afghanistan, it faces new operational challenges in trauma care. The military medical community must stay ahead of the curve through sustaining current investments in combat casualty care research. This article describes lessons learned at war from a Joint Trauma System perspective in order to place in context how we should proceed in order to provide optimal care for our Warfighters in the future. PMID- 27215877 TI - Infection Prevention in the Deployed Environment. AB - Up to 50% of combat injured patients from recent conflicts have suffered infectious complications, predominantly with multidrug-resistant (MDR) bacteria acquired nosocomially in the chain of tactical combat casualty care. These bacteria have ranged from MDR Acinetobacter baumannii-calcoaceticus associated with Operation Iraqi Freedom (OIF), to extended spectrum beta-lactamase producing Enterobacteriaceae from operations in Afghanistan. Experience from interventions at Level III facilities demonstrate that basic infection control (IC) procedures, such as improvements in hand hygiene, use of ventilator associated pneumonia bundles, and antimicrobial stewardship, can improve outcomes even in austere environments. While some systematic interventions have been implemented to mitigate this risk, including development of the Deployed Infection Control Course, the Multidrug-Resistance Surveillance Network, and the Trauma Infectious Disease Outcomes Study, ongoing vulnerabilities remain. Deployed microbiology capabilities should be strengthened, theater-level IC standard operating procedures should be implemented, and a joint, theater-level expert IC consultant should be appointed to be responsible for directing IC activities from Levels I to IV. PMID- 27215878 TI - Medical Logistics Lessons Observed During Operations Enduring Freedom and Iraqi Freedom. AB - Medical Logistics (MEDLOG) is a function of the Army's integrated System for Health that provides the medical products and specialized logistics services required to deliver health protection and care under all operational conditions. In unified land operations, MEDLOG is an inherent function of Health Service Support (HSS), which also includes casualty care and medical evacuation. This paper focuses on a few key lessons observed during Operations Enduring Freedom and Iraqi Freedom with direct implications for the support of HSS in future operations as envisioned in the Army Operating Concept and the Joint Concept for Health Services. It also examines a few key enablers that helped mitigate these challenges that are not yet fully acknowledged in Army Medical Department doctrine, policy, and planning. PMID- 27215879 TI - Planning Staff and Space Capacity Requirements during Wartime. AB - Determining staff and space requirements for military medical centers can be challenging. Changing patient populations change the caseload requirements. Deployment and assignment rotations change the experience and education of clinicians and support staff, thereby changing the caseload capacity of a facility. During wartime, planning becomes increasingly more complex. What will the patient mix and caseload volume be by location? What type of clinicians will be available and when? How many beds are needed at each facility to meet caseload demand and match clinician supply? As soon as these factors are known, operations are likely to change and planning factors quickly become inaccurate. Soon, more beds or staff are needed in certain locations to meet caseload demand while other locations retain underutilized staff, waiting for additional caseload fluctuations. This type of complexity challenges the best commanders. As in so many other industries, supply and demand principles apply to military health, but very little is stable about military health capacity planning. Planning analysts build complex statistical forecasting models to predict caseload based on historical patterns. These capacity planning techniques work best in stable repeatable processes where caseload and staffing resources remain constant over a long period of time. Variability must be simplified to predict complex operations. This is counterintuitive to the majority of capacity planners who believe more data drives better answers. When the best predictor of future needs is not historical patterns, traditional capacity planning does not work. Rather, simplified estimation techniques coupled with frequent calibration adjustments to account for environmental changes will create the most accurate and most useful capacity planning and management system. The method presented in this article outlines the capacity planning approach used to actively manage hospital staff and space during Operations Iraqi Freedom and Enduring Freedom. PMID- 27215880 TI - Military Sleep Management: An Operational Imperative. AB - Sleep is critical for military operational readiness but is commonly disregarded during operational planning. The start of combat operations with Operation Iraqi Freedom saw a dramatic rise in diagnosis rates of clinically significant sleep disorders among officers and enlisted. This coincided with a parallel rise in behavioral health disorders. In this article, the etiology of sleep problems and sleep disorders in our military population is reviewed, and guidance is provided for improving sleep health in our military population. It is our view that appropriate sleep planning and management affords military units and commanders a near-term tactical advantage in terms of maintaining alertness, a midterm tactical advantage of decreasing susceptibility to sleep and behavioral health disorders, and a long-term strategic advantage with increased readiness and resiliency of their Soldiers. PMID- 27215881 TI - Evolution of Military Combat Eye Protection. AB - Appreciation for combat eye protection steadily increased following World War II. Products derived from experiences in World War I, World War II, Korea, Vietnam, and the Iran/Iraq war drove technical improvements throughout the 1980s and 1990s. Dismal wear compliance prior to 2004 indicates Soldiers and their leaders did not appreciate these improvements and found little value in the bulky, ugly, and uncomfortable products. In 2003, the 10th Mountain Division requested enhanced eye protection. Program Executive Office Soldier, the optometry consultant to the Army Surgeon General, members of the Tri-Service Vision Conservation and Readiness Program, and other subject matter experts selected and tested commercial off-the-shelf eye protection against military ballistic impact standards. Optical devices that met ballistic standards formed the first Authorized Protective Eyewear List and were fielded beginning in 2004. Wear compliance rose dramatically for the stylish protective eyewear, reaching 85% to 95% and eye injuries decreased across the Department of Defense even as the incidence of attacks in Iraq increased. Researchers continue to evaluate new materials and designs to increase the capabilities, features and level of protection of future ballistic eyewear. PMID- 27215882 TI - The US Army Medical Department Email Teleconsultation Program. AB - The US Army Surgeon General authorized the formation of an email based teleconsultation program in 2004 to support deployed healthcare providers in Iraq and Afghanistan. The program, which began its 12th year of operation in April 2015, was originally viewed as a temporary solution until a robust system was fielded. Although future of the program as a going concern has not been determined, there is the possibility it could be incorprated into the critical care consultation program managed at an Army Medical Center. PMID- 27215883 TI - Cardiovascular Complaints Among Military Members During Operation Enduring Freedom. AB - During Operation Enduring Freedom, the US military began deploying a dedicated theater cardiology consultant to Afghanistan in an effort to increase rates of return to duty in service members with cardiovascular complaints. This study was designed to categorize these complaints and determine the effect on both aeromedical evacuation and return to duty rates during a 2.5 year observation period. A total of 1,495 service members were evaluated, with 43% presenting due to chest pain followed by arrhythmias/palpitations (24.5%) and syncope (13.5%). Eighty-five percent of individuals returned to duty, most commonly with complaints of noncardiac chest pain, palpitations, or abnormal electrocardiograms. Fifteen percent were evacuated out of theater, most often with acute coronary syndrome, pulmonary embolus, or ventricular tachycardia. The forward-deployed theater cardiology consultant is vital in the disposition of military members by effectively parsing out life threatening cardiovascular conditions versus low risk diagnoses that can safely return to duty. PMID- 27215884 TI - Pediatric Wartime Injuries in Afghanistan and Iraq: What Have We Learned? AB - The majority of the documented experience in pediatric trauma care during the past decade of conflict is from the inpatient Role 3 mission. Pediatric patients (defined as 14 years of age or less) accounted for 5% to 10% of combat admissions. Care for these patients was resource intensive and mortality rates significantly higher than those seen in pediatric hospitals in the United States. The largest documented experience to date with explosive injuries and massive transfusions in children were reported from this conflict. Improvements in logistic and personnel support was seen throughout the decade of conflict, however long-term outcomes and clinical practice guidelines to direct future care for these children are lacking. PMID- 27215885 TI - Role of Human Health Care Providers and Medical Treatment Facilities in Military Working Dog Care and Accessibility Difficulties with Military Working Dog Blood Products. AB - The use of military working dogs (MWDs) in support of military operations has increased dramatically over recent years, as they have proven to be our most reliable deterrent to improvised explosive devices. Healthcare delivery for MWDs in combat presents unique challenges and requires extensive collaboration between veterinarians and human health care providers (HCPs). A successful example is the incorporation of MWD emergency care for nonveterinary HCPs into the Joint Trauma System Clinical Practice Guidelines, which has proven to be a helpful product. Additional challenges that need further solutions include MWDs as patients in human medical treatment facilities (MTFs) and the procurement of appropriate canine blood components in an operational environment. It is often necessary for MWDs to be treated as patients in human MTFs, however, there is no Department of Defense guidance to support this activity. Access to MWD blood products is limited to collection of fresh whole blood in the operational setting. Similar to humans, specific blood component therapy, such as fresh frozen plasma, is often indicated for sick or injured MWDs. Currently there is no formal system in place to deliver any blood products for MWDs or to facilitate collection in theater. PMID- 27215886 TI - Select Public Health and Communicable Disease Lessons Learned During Operations Iraqi Freedom and Enduring Freedom. AB - History has taught us that the threat of communicable diseases to operational readiness should not be underestimated. The unique operational challenges of a decade at war in Southwest Asia have left us with many new lessons about prevention and mitigation of disease. The successes of military immunization programs demonstrated the successful application of military science to modern combat. Historic maladies such as tuberculosis and malaria continue to challenge our Army health leadership while new challenges with diseases like Q fever and rabies led to questions about our preparedness. These conflicts also brought awareness of issues about the broader deployed community, and the often unique risks that arise when US service members interact more frequently with foreign militaries, local nationals, and third country nationals. Application of these lessons to predeployment training and integration into leadership decision-making will improve our ability to maintain force readiness in future conflicts and adapt Army policy to current evidence and intelligence. PMID- 27215887 TI - Deployment Exposures and Long-term Health Risks: The Shadow of War. AB - The victory in Operations Desert Shield/Desert Storm has been "shadowed" by long term health concerns among returning troops. During Operations Iraqi Freedom, New Dawn, and Enduring Freedom, the Department of the Army and Department of Defense implemented recommendations of the Institute of Medicine relating to environmental exposure assessment, hazard response, documentation of exposures, and risk assessment using environmental sampling data to evaluate potential health risks among deployed troops. Recommendations regarding risk communication proved more difficult to implement, however. Exposure to particulate matter and airborne hazards including burn pit emissions and chemical warfare agents have received attention from service members, the media, and in some cases, Congress. A combination of lack of clear and consistent messages, imperfect and sometimes seemingly contradictory science, and strong perceptions suggest that questions related to these exposures and their potential long-term health effects will persist. PMID- 27215888 TI - Deployment-related Respiratory Issues. AB - Military deployment to Southwest Asia since 2003 in support of Operations Enduring Freedom/Iraqi Freedom/New Dawn has presented unique challenges from a pulmonary perspective. Various airborne hazards in the deployed environment include suspended geologic dusts, burn pit smoke, vehicle exhaust emissions, industrial air pollution, and isolated exposure incidents. These exposures may give rise to both acute respiratory symptoms and in some instances development of chronic lung disease. While increased respiratory symptoms during deployment are well documented, there is limited data on whether inhalation of airborne particulate matter is causally related to an increase in either common or unique pulmonary diseases. While disease processes such as acute eosinophilic pneumonia and exacerbation of preexisting asthma have been adequately documented, there is significant controversy surrounding the potential effects of deployment exposures and development of rare pulmonary disorders such as constrictive bronchiolitis. The role of smoking and related disorders has yet to be defined. This article presents the current evidence for deployment-related respiratory symptoms and ongoing Department of Defense studies. Further, it also provides general recommendations for evaluating pulmonary health in the deployed military population. PMID- 27215889 TI - Impact of North Atlantic Treaty Organization Policies and Procedures on Combined Medical Operations: Food and Water Safety and Veterinary Support. AB - Effective multilateral military operations such as those conducted by the North Atlantic Treaty Organization (NATO) require close cooperation and standardization between member nations to ensure interoperability. Failure to standardize policies, procedures, and doctrine prior to the commencement of military operations will result in critical interoperability gaps, which jeopardize the health of NATO forces and mission success. To prevent these gaps from occurring, US forces must be actively involved with NATO standardization efforts such as the Committee of the Chiefs of Medical Services to ensure US interests are properly represented when NATO standards are developed and US doctrine and procedures will meet the established NATO requirements. PMID- 27215890 TI - Water for Warfighters in Iraq and Afghanistan: A Summary of Lessons Learned. AB - The Army is the Department of Defense executive agent for land-based field water supplies. The Army Corps of Engineers, Army Quartermaster Corps, and Army Medical Department coordinate to provide the necessary support to obtain, treat, disinfect, certify, distribute, and monitor drinking water during deployments. This collaboration is necessary to ensure that an adequate quantity of acceptable quality drinking water is available for deployed personnel at all base camps and in all operations. Important lessons were learned from the beginning of operations in Iraq in 2003 continuing throughout 2 wars. These included lessons about the employment and management of bottled water during deployments, the quality and potential usefulness of "wastewater" from the reverse osmosis water purifiers, the usefulness and acceptability of military packaged water, and our lack of preparedness to readily address the drinking water needs of small squad and platoon-sized operations lasting more than a few days. The lessons we learned have and will continue to enhance our ability to readily meet Warfighters' requirements for that most critical of supplies--sustaining a supply of safe, aesthetically pleasing drinking water. PMID- 27215891 TI - Surgical and Resuscitation Capabilities for the "Next War" Based on Lessons Learned From "This War". AB - The Army gleaned many lessons regarding the provision of medical care to casualties during the past 14 years of combat. Using these lessons learned in the Joint Capabilities and Integration Development process and through the analysis of an integrated process action team, the Army recently approved 3 changes to medical organizations that are intended to provide trauma management farther forward on the battlefield. These changes include the substitution of an emergency medicine trained physician and emergency medicine physician assistant (PA) in lieu of a general medical officer and primary care PA within the brigade combat team; reorganization of the forward surgical team into a forward surgical and resuscitative team; and the modularization of the traditional 248 bed combat support hospital. The Army anticipates that these changes related to personnel, organizations, doctrine, and materiel will enable Army medicine to provide enhanced trauma management closer to the point of a combatant's injury. These modifications are projected to begin in fiscal year 2016. PMID- 27215892 TI - Predeployment Medical Training for Providers. AB - Following the attacks of September 11, 2001, the United States became simultaneously engaged in military conflicts in 2 theaters of operation. At that time there was no organized program to train medical providers assigned to deployable Role 1 or Role 2 aid stations. To fill this gap, the Tactical Combat Medical Care (TCMC) course was developed and instituted at Fort Sam Houston, Texas, in 2004 to provide the training platform for providers in preparation for assignment to and deployment with combat units. The TCMC course has become the standard for prehospital wartime care training. All military healthcare providers (physicians, physician assistants, nurses, combat medics) requiring training to supplement their basic medical education and facility-based experiences are eligible to attend this course. PMID- 27215893 TI - Lessons Learned: Employment and Tactical Use of The Combat Medic During Stability Support Operations. AB - It is the intent of this article to define the strategy by which Combat Medics have been employed in contemporary stability operations and counterinsurgency conflicts. This article describes the advances in training based on Tactical Combat Casualty Care and how training evolved into an evidence-based model. Training platforms evolved with shifts in mission requirements, new technology, improved medical techniques, and changing protocols. The last portion of this article details recommendations in doctrine, materiel, and training that could enable optimal sustainment standards while retaining operational capability across a wide variety of combat and peace operations. Lessons learned and changes adapted for Medics that are addressed: (1) advances in training and employment of the Combat Medic necessitated by tactics and strategy of current conflicts, (2) Combat Medic regulatory requirements and centralized, just-in-time training, and (3) changes in sustainment training driven by certification requirements and use of medical simulation training centers. PMID- 27215894 TI - Army Medical Department at War: Healthcare in a Complex World. PMID- 27215895 TI - Comparison of allergenic extracts from different origins: the value of the FDA's bioequivalent allergy unit (BAU). AB - INTRODUCTION: Allergy immunotherapy (AIT) is the only disease-modifying intervention for the treatment of allergic diseases. The clinical effectiveness of AIT is clearly dose-dependent, so it is important that clinicians can assess and compare the potency of the various products available. However, this is not possible in practice, because manufacturers use different methods to determine potency. Therefore, a clear need exists for adoption of a 'gold-standard' measure of allergenicity. The bioequivalent allergy unit (BAU) is thus far the only allergen unit approved by a regulatory agency (the US Food and Drug Administration), with European regulatory authorities yet to adopt a common unit. AREAS COVERED: Using PubMed, we performed a review of the literature on measures of allergen extract potency, use of the BAU, and BAU assessment for grass pollen tablets. Expert commentary: There is an obvious benefit to allergists and patients for having a single, comparable unit across products, and we strongly support the adoption of a single, 'gold-standard' unit of measurement for all products. Use of the BAU allows a clear comparison of the potency of allergen products from different manufacturers, and enables better understanding of the potential reasons for any differences in administration and dosing protocols between these products. PMID- 27215897 TI - Revisiting kinetic boundary conditions at the surface of fuel droplet hydrocarbons: An atomistic computational fluid dynamics simulation. AB - The role of boundary conditions at the interface for both Boltzmann equation and the set of Navier-Stokes equations have been suggested to be important for studying of multiphase flows such as evaporation/condensation process which doesn't always obey the equilibrium conditions. Here we present aspects of transition-state theory (TST) alongside with kinetic gas theory (KGT) relevant to the study of quasi-equilibrium interfacial phenomena and the equilibrium gas phase processes, respectively. A two-state mathematical model for long-chain hydrocarbons which have multi-structural specifications is introduced to clarify how kinetics and thermodynamics affect evaporation/condensation process at the surface of fuel droplet, liquid and gas phases and then show how experimental observations for a number of n-alkane may be reproduced using a hybrid framework TST and KGT with physically reasonable parameters controlling the interface, gas and liquid phases. The importance of internal activation dynamics at the surface of n-alkane droplets is established during the evaporation/condensation process. PMID- 27215898 TI - Elucidating the Origin of the Attractive Force among Hydrophilic Macroions. AB - Coarse-grained simulation approach is applied to provide a general understanding of various soluble, hydrophilic macroionic solutions, especially the strong attractions among the like-charged soluble macroions and the consequent spontaneous, reversible formation of blackberry structures with tunable sizes. This model captures essential molecular details of the macroions and their interactions in polar solvents. Results using this model provide consistent conclusions to the experimental observations, from the nature of the attractive force among macroions (counterion-mediated attraction), to the blackberry formation mechanism. The conclusions can be applied to various macroionic solutions from inorganic molecular clusters to dendrimers and biomacromolecules. PMID- 27215900 TI - Is It Time to Expand the Role of Total Pancreatectomy for IPMN? AB - Intraductal papillary mucinous neoplasms (IPMN) are cystic precursors to pancreatic cancer believed to arise within a widespread neoplastic field defect. The tendency for some patients to present with multifocal disease and/or develop additional lesions over time argues in favor of a field defect and complicates surgical management decisions. Surgery usually consists of partial pancreatic resection, which leaves behind a pancreatic remnant at risk for recurrent disease and progression to cancer. As an alternative, total pancreatectomy (TP) provides the most complete oncologic resection, but postoperative morbidity and quality of life (QoL) issues have generally limited its use to only the highest risk patients. Significant progress has been made in the management of the post-TP apancreatic state and studies now show less morbidity with acceptable QoL comparable to type 1 diabetic and post-pancreaticoduodenectomy patients. These improvements do not yet justify the routine use of TP, but they have opened the door for expansion to additional subsets of non-invasive IPMN. Here, we have identified several groups of patients that we believe would benefit from TP over partial resection based on the most current literature. PMID- 27215899 TI - Versatile molybdenum disulfide based antibacterial composites for in vitro enhanced sterilization and in vivo focal infection therapy. AB - Biologically, MoS2-based nanostructures have been intensely applied for the photothermal therapy of cancer, but rarely for antibacterial uses. In this contribution, a multifunctional chitosan (CS) functionalized magnetic MoS2 (abbreviated to CFM) was constructed to nonspecifically combat bacterial infection by integrating bacterial conjugation and enrichment, and NIR-triggered photothermal sterilization. Owing to the abundant introduced amino groups, the CFM complex offers a significantly enhanced conjugation efficiency without obvious specificity towards both Gram-positive and -negative bacteria compared to amino-free magnetic MoS2. The magnetic properties of CFM obtained from iron oxide facilitate the enrichment of a CFM-bacteria conjugate, improving the photothermal efficiency of CFM as a photothermal antibacterial agent. Specifically, after being trapped together with bacteria cells, CFM shows an enhanced in vitro photothermal sterilization ability. In vivo S. aureus-induced abscess treatment studies show faster healing when CFM is used as subcutaneous nano-localized heating sources with the assistance of an external magnet to concentrate the CFM bacteria conjugate. This work establishes an innovative solution and a novel antimicrobial agent for combating bacterial infections without the use of antibiotics, which may open a new area of application and research for MoS2-based nanostructures. PMID- 27215901 TI - Glyceraldehyde-3-phosphate dehydrogenase: Aggregation mechanisms and impact on amyloid neurodegenerative diseases. AB - The review analyses data on specific features of aggregation of glyceraldehyde-3 phosphate dehydrogenase (GAPDH) and possible role of this enzyme in the development of neurodegenerative diseases. Different post-translational modifications of the enzyme are considered: oxidation, nitrosylation, and S glutathionylation of the active site sulfhydryl groups, as well as phosphorylation, glycation and homocysteinylation of other amino acid residues. Modification of the sulfhydryl groups of the enzyme inhibits the enzymatic activity of GAPDH, resulting in slowdown of glycolysis, and may lead to the dissociation of the cofactor NAD from the active site of the enzyme. The resulting apo-GAPDH (without NAD) is less stable and prone to dissociation, denaturation, and subsequent aggregation. These processes could play a crucial role in the translocation of GAPDH subunits from the cytoplasm into the nucleus, which is linked to the induction of apoptosis. Phosphorylation and glycation of GAPDH are presumably involved in the regulation of protein-protein interactions and intracellular localization of the enzyme. Besides, glycation by dicarbonyl compounds and aldehydes may directly inhibit glycolysis. Homocysteinylation of GAPDH may stabilize aggregates of the enzyme by additional disulfide bonding. All types of post-translational modifications affect aggregation of GAPDH. A special attention is given to the role of chaperones in the amyloidogenic transformation of proteins and to confirmation of the hypothesis on blocking of the chaperones by misfolded protein forms. The denatured GAPDH forms were shown to interact directly with amyloidogenic proteins (alpha-synuclein and amyloid-beta peptide) and to play a crucial role in blocking of chaperone system. PMID- 27215902 TI - Melatonin Regulates Daily Variations in Electric Behavior Arousal in Two Species of Weakly Electric Fish with Different Social Structures. AB - Timing is crucial for social interactions. Animal behavior is synchronized with biotic and abiotic environment variables ensuring that the activity phase of conspecifics occurs during the same period of the day. As biological rhythms are embedded in the complex integrative control of the brain, it is fundamental to explore its interaction with environmental and social factors. This approach will unravel the link between external stimuli carrying information on environmental cycles and the neural commands for behavior, including social behavior, associated with precise phases of those cycles. Arousal in the solitary Gymnotus omarorum and in the gregarious Brachyhypopomus gauderio is characterized by a nocturnal increase in the basal discharge rate of electric behavior, which is mild and transient in G. omarorum and large and persistent in B. gauderio. In this study, we show that the major integrator of social behavior, AVT (arginine vasotocin), is not involved in the nocturnal increase of electric behavior basal rate in isolated animals of either species. On the other hand, endogenous melatonin, the major modulator of the circadian system, is responsible for the nocturnal increase in electric behavior in isolated individuals of both species. PMID- 27215904 TI - Top 10 List for the Cardiovascular Care of Older Adults. PMID- 27215903 TI - Investigating the role of MRGPRC11 and capsaicin-sensitive afferent nerves in the anti-influenza effects exerted by SLIGRL-amide in murine airways. AB - BACKGROUND: The hexapeptide SLIGRL-amide activates protease-activated receptor-2 (PAR-2) and mas-related G protein-coupled receptor C11 (MRGPRC11), both of which are known to be expressed on populations of sensory nerves. SLIGRL-amide has recently been reported to inhibit influenza A (IAV) infection in mice independently of PAR-2 activation, however the explicit roles of MRGPRC11 and sensory nerves in this process are unknown. Thus, the principal aim of this study was to determine whether SLIGRL-amide-induced inhibition of influenza infection is mediated by MRGPRC11 and/or by capsaicin-sensitive sensory nerves. METHODS: The inhibitory effect of SLIGRL-amide on IAV infection observed in control mice in vivo was compared to effects produced in mice that did not express MRGPRC11 (mrgpr-cluster? (-/-) mice) or had impaired sensory nerve function (induced by chronic pre-treatment with capsaicin). Complementary mechanistic studies using both in vivo and ex vivo approaches investigated whether the anti-IAV activity of SLIGRL-amide was (1) mimicked by either activators of MRGPRC11 (BAM8-22) or by activators (acute capsaicin) or selected mediators (substance P, CGRP) of sensory nerve function, or (2) suppressed by inhibitors of sensory nerve function (e.g. NK1 receptor antagonists). RESULTS: SLIGRL-amide and BAM8-22 dose-dependently inhibited IAV infection in mrgpr-cluster? (-/-) mice that do not express MRGPRC11. In addition, SLIGRL-amide and BAM8-22 each inhibited IAV infection in capsaicin-pre-treated mice that lack functional sensory nerves. Furthermore, the anti-IAV activity of SLIGRL-amide was not mimicked by the sensory neuropeptides substance P or CGRP, nor blocked by either NK1 (L-703,606, RP67580) and CGRP receptor (CGRP8-37) antagonists. Direct stimulation of airway sensory nerves through acute exposure to the TRPV1 activator capsaicin also failed to mimic SLIGRL-amide-induced inhibition of IAV infectivity. The anti-IAV activity of SLIGRL-amide was mimicked by the purinoceptor agonist ATP, a direct activator of mucus secretion from airway epithelial cells. Additionally, both SLIGRL-amide and ATP stimulated mucus secretion and inhibited IAV infectivity in mouse isolated tracheal segments. CONCLUSIONS: SLIGRL-amide inhibits IAV infection independently of MRGPRC11 and independently of capsaicin-sensitive, neuropeptide-releasing sensory nerves, and its secretory action on epithelial cells warrants further investigation. PMID- 27215905 TI - Prevalence and Significance of Unrecognized Renal Dysfunction in Patients with Stroke. AB - BACKGROUND: Unrecognized renal dysfunction, defined as an estimated glomerular filtration rate <60 mL/min/1.73 m(2) in the presence of normal serum creatinine levels, is a common comorbidity among patients with various cardiovascular conditions. The current study was aimed to evaluate the prevalence and clinical significance of unrecognized renal dysfunction in patients with acute stroke. METHODS: The cohort consisted of patients with acute stroke included in the prospective National Acute Stroke ISraeli (NASIS) registry. Unrecognized renal insufficiency was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m(2) in the presence of serum creatinine <=1.2 mg/dL. The 2 primary outcomes were in-hospital mortality and the composite of in-hospital mortality or severe disability at hospital discharge. RESULTS: Of the 7900 patients with stroke included in the study, 5571 (70.5%) had normal renal function, 1510 (19.1%) had recognized renal insufficiency, and 819 (10.4%) had unrecognized renal insufficiency. Mortality rates were higher in patients with recognized and unrecognized renal insufficiency compared with patients with normal renal function (9.9%, 9.1%, and 4.4%, respectively, P < .0001). Adjusted odds ratios (ORs) for in-hospital mortality were higher for patients with renal dysfunction recognized (OR, 2.1; 95% confidence interval [CI], 1.6-2.7; P < .001) or unrecognized (OR, 1.6; 95% CI, 1.1-2.2; P = .006) compared with patients with normal renal function. Likewise, adjusted ORs for the composite of in-hospital mortality or severe disability at hospital discharge were higher for patients with renal dysfunction recognized (OR, 1.3; 95% CI, 1.1-1.5; P = .004) or unrecognized (OR, 1.2; 95% CI, 1.01-1.5; P = .04). CONCLUSIONS: Unrecognized renal insufficiency is common among patients with acute stroke and is associated with adverse short-term outcomes. PMID- 27215906 TI - A Picture's Worth: Giant Cell Arteritis. PMID- 27215907 TI - Middle East Respiratory Syndrome Interpreted: Human Herpesvirus 6B Pneumonia. PMID- 27215908 TI - Unmasking a Hidden Cause of Persistent Facial Ulceration: The Relevancy of a Neurologic Examination. PMID- 27215909 TI - Free health care for under-fives, expectant and recent mothers? Evaluating the impact of Sierra Leone's free health care initiative. AB - This study evaluates the impact of Sierra Leone's 2010 Free Health Care Initiative (FHCI). It uses two nationally representative surveys to identify the impact of the policy on utilisation of maternal care services by pregnant women and recent mothers as well as the impact on curative health care services and out of-pocket payments for consultation and prescription in children under the age of 5 years. A Regression Discontinuity Design (RDD) is applied in the case of young children and a before-after estimation approach, adjusted for time trends in the case of expectant and recent mothers. Our results suggest that children affected by the FHCI have a lower probability of incurring any health expenditure in public, non-governmental and missionary health facilities. However, a proportion of eligible children are observed to incur some health expenditure in participating facilities with no impact of the policy on the level of out-of pocket health expenditure. Similarly, no impact is observed with the utilisation of services in these facilities. Utilisation of informal care is observed to be higher among non-eligible children while in expectant and recent mothers, we find substantial but possibly transient increases in the use of key maternal health care services in public facilities following the implementation of the FHCI. The diminishing impact on utilisation mirrors experience in other countries that have implemented free health care initiatives and demonstrates the need for greater domestic and international efforts to ensure that resources are sufficient to meet increasing demand and monitor the long run impact of these policies. PMID- 27215910 TI - Further Psychometric Evaluation of the Child Disgust Scale. AB - This study evaluated the psychometric properties of the Child Disgust Scale (CDS) among 457 youth (ages 8-17, M = 14.77 +/- 1.98 years) initiating residential treatment for obsessive-compulsive disorder and anxiety disorders. Confirmatory factor analysis supported a bifactor model with two distinct factors of Disgust Avoidance and Disgust Affect, in addition to an overall General Disgust factor. Strong internal consistency was observed for the CDS total and factor scores. In addition, CDS scores demonstrated generally modest and positive correlations with child-reported obsessive-compulsive and anxiety symptoms, weaker correlations with parent-reported anxiety and child-rated impairment, and non-significant correlations with parent-rated impairment. Findings suggest that the CDS displays strong psychometric properties and is developmentally appropriate for use in pediatric clinical populations with obsessive-compulsive and anxiety disorders. PMID- 27215911 TI - Brain arteriovenous malformations: implications of CEACAM1-positive inflammatory cells and sex on hemorrhage. AB - Brain arteriovenous malformations (bAVMs) are severe conditions which, upon rupture, cause debilitating neurological deficits and even death. The exact cellular and molecular mechanisms associated with bAVM rupture are currently unclear. The objective of this study was to explore the potential role of CEA related cell adhesion molecule-1 (CEACAM1) in bAVM pathophysiology. Expression and localization of CEACAM1 were assessed immunohistochemically in tissue microarrays from bAVM patients (n = 60). The association of CEACAM1 with clinical parameters was analyzed with Spearman's rank correlation coefficient and chi square test. The predictive value of CEACAM1 was tested using logistic regression analysis. CEACAM1 was highly expressed in tissue-infiltrating neutrophil granulocytes. High levels of CEACAM1-positive cells were associated with bAVM rupture (hemorrhage), but not with arteriovenous malformation (AVM) size, preoperative embolization, or seizure. This association was significant (p = 0.029, chi-square) in male but not in female patients, and high CEACAM1-positive immune infiltration showed predictive significance for hemorrhage in male bAVM patients only (OR = 6.50, 95 % CI 1.09-38.63, p = 0.040). Within the ruptured bAVM group, patients with a short hemorrhage to surgery (HTS) time interval had higher levels of CEACAM1 immune infiltration than patients with long HTS. This decrease in the levels of CEACAM1 immune infiltration between the HTS short and HTS long groups was, however, significant only in female patients (p = 0.022, chi square). Our findings substantiate the role of inflammation in the pathophysiology of bAVM and suggest the presence of sexual dimorphism in this disease. PMID- 27215912 TI - Atypical pituitary adenomas: clinical characteristics and role of ki-67 and p53 in prognostic and therapeutic evaluation. A series of 50 patients. AB - The aim of the study was to assess incidence rate, hormonal activity, and local invasiveness and evaluate outcomes of so-diagnosed atypical pituitary adenomas that underwent endoscopic endonasal surgery at the Division of Neurosurgery of Universita degli Studi di Napoli Federico II. According to the 2004 WHO classification, atypical pituitary adenomas are defined by an invasive growth, Ki 67/MIB-1 proliferative index greater than 3 %, high p53 immunoreactivity, and increased mitotic activity. A retrospective analysis of a series of 434 pituitary adenomas that underwent endoscopic endonasal surgery at our department between March 2007 and February 2013 was performed. Fifty adenomas (11.5 %) met the criteria of diagnosis of atypical lesions; 10 (21.6 %) of the 50 patients were recurrent tumors with a previous transsphenoidal surgery. Forty-one (82 %) were macroadenomas, and 21/50 (42 %) showed a clear invasion of the cavernous sinus. Histotype of atypical adenomas figured out to be nonfunctioning in 23 cases (46 %), PRL secreting in 10 cases (20 %), ACTH secreting and GH secreting each apart in 8 patients (16 %), and in a single case a GH/PRL secreting adenoma (2 %). The Ki-67 labeling index ranged from 3.5 to 22.5 % (mean 5.6 %). Tumor recurrence was observed in six cases (12 %) after a mean time of 18 months (range 9-24 months). Mean follow-up was 36.5 months (range 2-80 months). Atypical pituitary adenomas account for ca. 10 % of all pituitary adenomas; these lesions have peculiar features. It should be considered that a strong immunopositivity of p53 and higher Ki-67 LI could predict an increased risk of tumor recurrence, but more studies and larger series are expected to confirm and enlarge the diagnostic and therapeutic management process of these lesions. PMID- 27215914 TI - Effect of S/N Ratio on the Removal of Hydrogen Sulfide from Biogas in Anoxic Bioreactors. AB - Both biogas desulfurization and wastewater denitrification can be achieved simultaneously, when nitrate/nitrite is used as the electron acceptor for H2S oxidation. The main objective of this study was to investigate the influence of the molar ratio of sulfide/nitrate (S/N) on biogas desulfurization performance in a biotrickling filter (BTF) and a biobubble column (BBC). The results show that with the decrease of the S/N ratios from 3.6 to 0.7, the removal efficiencies of H2S increased from about 66 to 100 %, while the removal of nitrate decreased from 100 to 70 % in the two bioreactors. The BTF has a better and more stable desulfurization performance than the BBC does, which could be attributed to their different gas-liquid contacting modes. With the increase of the S/N ratios from 1.0 to 2.5 in the BTFs, the removal of H2S in biogas was affected slightly, while the percentages of the produced sulfate decreased evidently. In addition, different supplying methods of nitrate wastewater, i.e., intermittent and continuous, did not affect the removal of H2S significantly, while the intermittent addition of nitrate wastewater increased the percentages of sulfate and denitrification performance. PMID- 27215915 TI - Effect of Plant Growth Promoting Bacteria Associated with Halophytic Weed (Psoralea corylifolia L) on Germination and Seedling Growth of Wheat Under Saline Conditions. AB - Halotolerant bacteria associated with Psoralea corylifolia L., a luxuriantly growing annual weed in salinity-affected semi-arid regions of western Maharashtra, India were evaluated for their plant growth-promoting activity in wheat. A total of 79 bacteria associated with different parts viz., root, shoot and nodule endophytes, rhizosphere, rhizoplane, and leaf epiphytes, were isolated and grouped based on their habitat. Twelve bacteria isolated for their potential in plant growth promotion were further selected for in vitro studies. Molecular identification showed the presence of the genera Bacillus, Pantoea, Marinobacterium, Acinetobacter, Enterobacter, Pseudomonas, Rhizobium, and Sinorhizobium (LC027447-53; LC027455; LC027457, LC027459, and LC128410). The phylogenetic studies along with carbon source utilization profiles using the Biolog(r) indicated the presence of novel species and the in planta studies revealed promising results under salinity stress. Whereas the nodule endophytes had minute plant growth-promoting (PGP) activity, the cell free culture filtrates of these strains enhanced seed germination of wheat (Triticum aestivum L). The maximum vigor index was monitored in isolate Y7 (Enterobacter sp strain NIASMVII). Indole acetic acid (IAA) production by the isolates ranged between 0.22 and 25.58 MUg mL-1. This signifies the need of exploration of their individual metabolites for developing next-generation bio-inoculants through co inoculation with other compatible microbes. This study has potential in utilization of the weed-associated microbiome in terms of alleviation of salinity stress in crop plants. PMID- 27215913 TI - State-of-art in surgical treatment of dissecting posterior circulation intracranial aneurysms. AB - Vertebrobasilar (VB) intracranial dissecting aneurysms (IDAs) pose difficult therapeutic issues and are especially among the most difficult to manage surgically. There are, however, some cases where selective aneurysm obliteration by endovascular approach is impossible or is associated with an unacceptable risk of morbidity. This is particularly true when the aneurysm is dissecting, giant, or has a large neck. In such cases, surgical treatment may be the only alternative. Optimal management of these lesions is therefore challenging and treatment decisions have to be made on a case-by-case basis. Ideal treatment should be a complete surgical excision of the lesion; however, this procedure might only be possible after distal and proximal vessel wall occlusion which might not be tolerated by the patient depending on the location of the aneurysm. Therefore, formulation of recommendations concerning the surgical strategy remains still difficult due to inconsistency of surgical outcomes. The literature describing surgical strategy of VB IDAs is varying in quality and content, and many studies deal with only a few patients. In the presented review, the authors summarize the current knowledge on the incidence, pathogenesis, clinical presentation, and diagnostic procedures with special emphasis on surgical treatment of IDAs in posterior circulation. PMID- 27215916 TI - Feminine hygiene practices among female patients and nurses in Lebanon. AB - BACKGROUND: Inappropriate feminine hygiene practices are related to vulvovaginitis. We investigated the prevalence of personal hygiene habits among Lebanese women as well as their awareness of adequate practices. METHODS: Consists of a cross-sectional observational study. Female patients and nurses at Hotel-Dieu de France University Hospital in Beirut- Lebanon filled a questionnaire about their intimate hygiene habits and knowledge of proper practices. RESULTS: The study included 249 women. 21.3 % of the 136 nurses and 38.9 % of the 113 patients reported a history of vulvovaginitis. The majority of women took an intimate bath at least twice daily. 14 % of nurses and 17 % of patients douched.20. Seven percent of the nurses and 43.4 % of the patients used wet wipes. 1.5 % of nurses and 4.4 % of patients used feminine deodorant sprays. There was a significant lack of awareness mainly among patients about suitable hygiene practices as well for their adverse effects. CONCLUSION: Education provided by nurses, and other healthcare providers is essential to promote reproductive health among Lebanese women. PMID- 27215917 TI - Cholinergic enhancement increases regional cerebral blood flow to the posterior cingulate cortex in mild Alzheimer's disease. AB - AIM: The brain region that shows reductions in regional cerebral blood flow (rCBF) earliest is the posterior cingulate cortex (PCC), which is thought to have a relationship with cognitive function. We made a hypothesis that the PCC hypoperfusion is a result of cholinergic dysfunction and can be restored by cholinergic enhancement. This present longitudinal study aimed to detect the restoration of PCC rCBF in response to donepezil, an acetylcholine esterase inhibitor. METHODS: We evaluated rCBF changes in the PCC, precuneus and anterior cingulate cortex using perfusion single-photon emission computed tomography (SPECT), statistical analysis and region of interest analysis, prospectively. We allocated 36 patients with mild AD to either the responder or non-responder groups based on changes in Mini-Mental State Examination scores. The patients were followed up for 18 months. RESULTS: The PCC rCBF significantly increased in responders after 6 months of donepezil therapy. Statistical maps at baseline showed a typical decreased pattern of mild AD and obvious rCBF restoration in the bilateral PCC at 6 months in responders. Changes in Mini-Mental State Examination scores and the AD assessment scale cognitive scores significantly correlated with rCBF changes in the PCC of responders. CONCLUSIONS: Cholinergic enhancement restored PCC rCBF under the three conditions of mild AD, responders and short follow-up interval, and that increase correlated with improved cognitive function. These findings support our hypothesis that PCC rCBF reflects cholinergic function in AD patients. Geriatr Gerontol Int 2017; 17: 951-958. PMID- 27215918 TI - Walk them or no leg to stand on! Diagnostic delay of neurologic conditions in young children. AB - Diagnosis of low incidence neurological conditions can be a challenge in paediatric emergency medicine. Neurological examination in young children can be very difficult, and medical staff may not previously have encountered conditions like acute demyelinating encephalomyelitis. We propose that the simple process of walking a child (provided they were previously ambulant) is the crucial step in the neurological examination. We present three cases to demonstrate this important part of the examination. PMID- 27215919 TI - Associations between compulsive buying and substance dependence/abuse, major depressive episodes, and generalized anxiety disorder among men and women. AB - The objective of this study was to examine the associations between compulsive buying and substance dependence/abuse, major depressive episodes, and generalized anxiety disorder at the mean age of 43. Participants came from a community-based random sample of residents in 2 New York counties in 1975 (N = 548). The participants were followed from adolescence to early midlife. The mean age of participants at the most recent interview was 43.0 (standard deviation = 2.8). Of the participants, 55% were females. Over 90% of the participants were Caucasian. The prevalence of substance dependence/abuse, major depressive episodes, and generalized anxiety disorder (during the past 5 years before the interviews) was 6.6, 13.7, and 11.5%, respectively. Logistic regression analyses showed that compulsive buying was significantly associated with substance dependence/abuse (adjusted odds ratio = 1.60), major depressive episodes (adjusted odds ratio = 1.70), and generalized anxiety disorder (adjusted odds ratio = 1.63), despite controlling for substance dependence/abuse, major depressive episodes, and generalized anxiety disorder, respectively, at the mean age of 37, and demographic factors. Since the study sample is limited to predominantly Caucasian participants (over 90%) with a close association to a small geographic area, the findings may not be generalizable to racial/ethnic minority groups or individuals living in other parts of the country. Nevertheless, it is important that clinicians treating substance dependence/abuse, major depressive episodes, and generalized anxiety disorder consider the role of compulsive buying. PMID- 27215920 TI - Plasma acylated and plasma unacylated ghrelin: useful new biomarkers in patients with neuroendocrine tumors? AB - To date, the value of fasting plasma acylated ghrelin (AG) and unacylated ghrelin (UAG) as potential novel biomarkers in patients with neuroendocrine tumors (NETs) is unknown. The aims of this study are to (i) compare fasting AG and UAG levels between nonobese, nondiabetic NET patients (N=28) and age- (+/-3 years) and sex matched nonobese, nondiabetic controls (N=28); and (ii) study the relationship between AG, UAG, and AG/UAG ratios and biochemical (chromogranin-A (CgA) and neuron-specific enolase (NSE) levels) and clinical parameters (age at diagnosis, sex, primary tumor location, carcinoid syndrome, ENETS TNM classification, Ki-67 proliferation index, grading, prior incomplete surgery) in NET patients. Fasting venous blood samples (N=56) were collected and directly stabilized with 4-(2 aminoethyl) benzenesulfonyl fluoride hydrochloride after withdrawal. Plasma AG and UAG levels were determined by ELISA. Expression of ghrelin was examined in tumor tissue by immunohistochemistry. There were no significant differences between NET patients and controls in AG (median: 62.5 pg/mL, IQR: 33.1-112.8 vs median: 57.2pg/mL, IQR: 26.7-128.3, P=0.66) and UAG in levels (median: 76.6pg/mL, IQR: 35.23-121.7 vs median: 64.9, IQR: 27.5-93.1, P=0.44). No significant correlations were found between AG, UAG, and AG/UAG ratios versus biochemical and clinical parameters in NET patients with the exception of age at diagnosis (AG: rho= -0.47, P=0.012; AG/UAG ratio: rho= -0.50, P=0.007) and baseline chromogranin A levels (AG/UAG ratio: rho= -0.44, P=0.019). In our view, fasting plasma acylated and unacylated ghrelin appear to have no value as diagnostic biomarkers in the clinical follow-up of patients with NETs. PMID- 27215921 TI - Opening (and Swallowing) A Can of Worms to Treat My Crohn's Disease. AB - Editor's Note: This article discusses the experience, ingenuity, and determination of Sean Ahrens, a young patient with Crohn's disease who took it upon himself to treat his longstanding, symptomatic Crohn's disease with pig whipworm eggs. Reading this story will make some of you uncomfortable. You might question whether this work belongs in a medical journal or sends the wrong message to readers. However, we recognize that this topic is controversial and that N=1 reports cannot and should not change practice. The purpose of this story is not to encourage the use of pig whipworm or to demonstrate its efficacy (or lack thereof). We firmly believe that patients are uniquely qualified to provide insights into how they view their illnesses, weigh risks and benefits, and ultimately achieve self-efficacy. Stories like this are important for us to acknowledge and understand, even if they do not change our practice. PMID- 27215922 TI - Measurement of Inflammation in Eosinophilic Esophagitis Using an Eosinophil Peroxidase Assay. AB - OBJECTIVES: We describe a simple, quick method to measure an eosinophil granule protein, eosinophil peroxidase (EPO), as a marker of eosinophil activity, in eosinophilic esophagitis (EoE). METHODS: Esophageal mucosal brushings initially were collected from 36 patients with active EoE (n=13), resolved EoE (n=13), and controls (n=10) before endoscopic biopsy collection; the brushes were frozen at 80 oC until assayed. EPO on the brush was measured in a colorimetric assay visually and by spectrophotometric absorbance measurements (at 492 nm), and was compared with peak eosinophil counts in esophageal biopsy specimens. The assay was calibrated with known EPO concentrations; as EPO increased in the assay, the color changed from light yellow to dark brown. RESULTS: Mucosal brush specimens from active EoE yielded orange to dark brown colors with absorbance measurements > 1.1 U; in contrast, control and resolved EoE brush specimens yielded a light to dark yellow color with absorbance measurements < 1.1. We then corroborated the results at the bedside (real time) in 16 additional patients. EPO on the brush was measured directly in < 1 h in the assay visually and by absorbance at 492 nm. Absorbance units strongly correlated with peak eosinophil counts both with the frozen brush (rs=0.79, P<0.0001) and with the bedside (rs=0.86, P<0.00017) approaches. CONCLUSIONS: The results support the use of this rapid method to detect and monitor EoE disease activity. Moreover, because eosinophils infiltrate and degranulate in the esophagus in EoE in a patchy manner, this method may be more accurate than current practice by testing for an eosinophil constituent from both intact and degranulated cells, and by sampling large portions of the esophageal lumen rather than small biopsy specimens that may not be representative of eosinophil involvement. PMID- 27215923 TI - Risk of Autoimmunity in EoE and Families: A Population-Based Cohort Study. AB - OBJECTIVES: Recent genome-wide association studies have suggested possible genetic associations between eosinophilic esophagitis (EoE) and genes associated with autoimmunity. No studies to date have looked at potential genetic association of EoE with specific autoimmune diseases by evaluating such diagnoses within family members. Investigate the risk of specific autoimmune disease within EoE probands and their extended family members. METHODS: The Utah Population Database offers a unique opportunity to link medical records from over 85% of Utah's population to genealogy records representing Utah. We searched for associations of specific autoimmune diseases in probands diagnosed with EoE and their extended family members (e.g., first cousins). Comparisons were made to age and sex-matched controls and their respective families at a 5:1 ratio. RESULTS: Excess risk for multiple autoimmune conditions was detected in subjects with a diagnosis of EoE. Celiac, Crohn's, ulcerative colitis (UC), rheumatoid arthritis, IgA deficiency, CVID, multiple sclerosis (MS), and Hashimoto's thyroiditis were found at increased risk in first-degree relatives of EoE subjects. UC, systemic sclerosis, and MS had nominally significant associations within second-degree family members of EoE subjects; and, in reverse analysis, probands and their families with the above three conditions were at an increased risk for EoE suggesting shared genetic factors with EoE. CONCLUSIONS: Patients with EoE have an increased risk of multiple autoimmune diseases. Possible shared genetic etiologies were observed between EoE and UC, systemic sclerosis, and MS. Practitioners should be aware of these comorbid associations and query all EoE patients and family members for symptoms of these diseases. PMID- 27215925 TI - Comparing the performance of FOCE and different expectation-maximization methods in handling complex population physiologically-based pharmacokinetic models. AB - For the purpose of population pharmacometric modeling, a variety of mathematic algorithms are implemented in major modeling software packages to facilitate the maximum likelihood modeling, such as FO, FOCE, Laplace, ITS and EM. These methods are all designed to estimate the set of parameters that maximize the joint likelihood of observations in a given problem. While FOCE is still currently the most widely used method in population modeling, EM methods are getting more popular as the current-generation methods of choice because of their robustness with more complex models and sparse data structures. There are several versions of EM method implementation that are available in public modeling software packages. Although there have been several studies and reviews comparing the performance of different methods in handling relatively simple models, there has not been a dedicated study to compare different versions of EM algorithms in solving complex PBPK models. This study took everolimus as a model drug and simulated PK data based on published results. Three most popular EM methods (SAEM, IMP and QRPEM) and FOCE (as a benchmark reference) were evaluated for their estimation accuracy and converging speed when solving models of increased complexity. Both sparse and rich sampling data structure were tested. We concluded that FOCE was superior to EM methods for simple structured models. For more complex models and/ or sparse data, EM methods are much more robust. While the estimation accuracy was very close across EM methods, the general ranking of speed (fastest to slowest) was: QRPEM, IMP and SAEM. IMP gave the most realistic estimation of parameter standard errors, while under- and over- estimation of standard errors were observed in SAEM and QRPEM methods. PMID- 27215924 TI - Recurrence of Clostridium difficile Infection in Patients with Inflammatory Bowel Disease: The RECIDIVISM Study. AB - OBJECTIVES: Recurrent Clostridium difficile infection (rCDI) contributes to a significant burden of disease in patients with inflammatory bowel disease (IBD). In this study, we seek to identify risk factors for rCDI in a population of IBD patients at the Mount Sinai Hospital IBD Centre. METHODS: In this retrospective cohort study, IBD patients with rCDI diagnosed between 2010 and 2013 were identified and compared with IBD patients with single-episode CDI. Multivariate regression was used to identify predictors of rCDI in IBD. Outcome analysis was performed for hospitalizations due to CDI, colectomy, and CDI-attributable mortality. RESULTS: A total of 503 patients were included, 110 (22%) of whom had IBD (49% CD, 51% ulcerative colitis). Recurrent CDI occurred in 32% of IBD patients compared with 24% of non-IBD patients (P<0.01). IBD patients with rCDI were more likely than those without rCDI to report recent antibiotic therapy (42.9 vs. 30.7%, P<0.01), 5-aminosalicylic acid (5-ASA) use (51.5 vs. 30.7%, P<0.001), steroid use (51.4 vs. 33.3%, P<0.001), and biologic therapy (48.6 vs. 40.0%, P<0.01). Infliximab (34.3 vs. 17.3%, P<0.01) but not adalimumab was associated with more rCDI events. Using a Cox model of predictors of rCDI in IBD, significant predictors included non-ileal Crohn's disease (hazard ratio (HR) 2.85, 95% confidence interval (CI) 1.30-6.30) and the use of 5-ASA (HR 2.15, 95% CI 1.11-4.18). CONCLUSIONS: Compared with the general population, IBD patients are 33% more likely to experience rCDI. Within the IBD cohort, exposure to certain drug classes (antibiotics, 5-ASA, steroids, certain biologics) and non ileal Crohn's disease were found to be the predictors of rCDI. PMID- 27215926 TI - Severe pneumonia by Mycoplasma as an adverse event of everolimus therapy in patients with tuberous sclerosis complex. AB - BACKGROUND: Epilepsy is one of the most common symptoms in Tuberous Sclerosis Complex (TSC), appearing mainly in the first year of life and often resistant to therapy. Several studies have demonstrated the effectiveness of everolimus but its safety in children has not yet been well reported. We present two cases of severe pneumonia caused by Mycoplasma in two children receiving everolimus for epilepsy secondary to TSC. STUDY CASES: Both patients were admitted to the PICU for severe pneumonia with pleural effusion. One of them needed support with high concentration of oxygen and broad spectrum antibiotics and the other developed a septic shock with acute respiratory distress needing mechanical ventilation, vasoactive drugs, pleural drainage and broad-spectrum antibiotics. Everolimus was discontinued and in both patients Mycoplasma pneumoniae was identified by PCR. Both patients were discharged without sequelae. CONCLUSION: Everolimus therapy for epilepsy in the context of TCS could be associated, as in these two cases, with severe bacterial infection by Mycoplasma. PMID- 27215928 TI - External model validation of binary clinical risk prediction models in cardiovascular and thoracic surgery. AB - Clinical risk-prediction models serve an important role in healthcare. They are used for clinical decision-making and measuring the performance of healthcare providers. To establish confidence in a model, external model validation is imperative. When designing such an external model validation study, thought must be given to patient selection, risk factor and outcome definitions, missing data, and the transparent reporting of the analysis. In addition, there are a number of statistical methods available for external model validation. Execution of a rigorous external validation study rests in proper study design, application of suitable statistical methods, and transparent reporting. PMID- 27215927 TI - Learning curves for transapical transcatheter aortic valve replacement in the PARTNER-I trial: Technical performance, success, and safety. AB - OBJECTIVES: Introduction of hybrid techniques, such as transapical transcatheter aortic valve replacement (TA-TAVR), requires skills that a heart team must master to achieve technical efficiency: the technical performance learning curve. To date, the learning curve for TA-TAVR remains unknown. We therefore evaluated the rate at which technical performance improved, assessed change in occurrence of adverse events in relation to technical performance, and determined whether adverse events after TA-TAVR were linked to acquiring technical performance efficiency (the learning curve). METHODS: From April 2007 to February 2012, 1100 patients, average age 85.0 +/- 6.4 years, underwent TA-TAVR in the PARTNER-I trial. Learning curves were defined by institution-specific patient sequence number using nonlinear mixed modeling. RESULTS: Mean procedure time decreased from 131 to 116 minutes within 30 cases (P = .06) and device success increased to 90% by case 45 (P = .0007). Within 30 days, 354 patients experienced a major adverse event (stroke in 29, death in 96), with possibly decreased complications over time (P ~ .08). Although longer procedure time was associated with more adverse events (P < .0001), these events were associated with change in patient risk profile, not the technical performance learning curve (P = .8). CONCLUSIONS: The learning curve for TA-TAVR was 30 to 45 procedures performed, and technical efficiency was achieved without compromising patient safety. Although fewer patients are now undergoing TAVR via nontransfemoral access, understanding TA TAVR learning curves and their relationship with outcomes is important as the field moves toward next-generation devices, such as those to replace the mitral valve, delivered via the left ventricular apex. PMID- 27215929 TI - Treatment of pediatric hyperkalemia with sodium polystyrene sulfonate. AB - OBJECTIVE: To describe the safety and efficacy of sodium polystyrene sulfonate (SPS) in pediatric patients with acute hyperkalemia. METHODS: A retrospective chart review of all patients less than 18 years of age administered SPS for acute hyperkalemia at Texas Children's Hospital between 2011 and 2014. RESULTS: Our cohort consisted of 156 patients (mean age 6.8 +/- 6.1 years). The peak mean potassium concentration observed was 6.5 +/- 0.77 mmol/l prior to administration of SPS. The mean SPS dose was 0.64 +/- 0.32 g/kg. The majority (91 %) of the SPS doses were given orally. The nadir mean potassium concentration in the 48 h post SPS was 4.7 +/- 1.2 mEq/l, which occurred at 16.7 +/- 14.7 h post-dose. In the 48 h following SPS administration, 68 (43 %) patients required at least one additional intervention after SPS dose. Patients who required an additional intervention after initial SPS dose differed significantly in weight, baseline serum potassium, and were more likely to have received SPS treatment via the rectal route. A gastrointestinal adverse event was documented in 24 (15 %) patients. CONCLUSIONS: SPS was used effectively and safely in the majority of patients in this report. However, it may not be appropriate as a first single line agent in patients with severe acute hyperkalemia who require a greater than 25 % reduction in serum potassium levels or those at a high risk for cardiac arrhythmias. PMID- 27215930 TI - High Serum Insulin-Like Growth Factor-Binding Protein 1 (IGFBP-1) is Associated with High Fracture Risk Independent of Insulin-Like Growth Factor 1 (IGF-I). AB - High serum levels of IGFBP-1 are related both to low body mass index (BMI) and to low insulin-like growth factor 1 (IGF-I), which both in turn are related to low bone mineral density (BMD) and to increased fracture risk. However, we have found no previous prospective studies on IGFBP-1 and fracture risk. Despite its name, IGFBP-1 is not only just a binding protein but also has its own IGF-independent effects, e.g., stimulating osteoclast differentiation. IGFBP-1 might have an IGF related and/or an IGF-independent association to fracture risk. This is a population-based prospective cohort study with a ten-year follow-up of 351 women aged 69-79 at inclusion. Fracture and mortality data were collected from national health care registers. IGFBP-1 had a positive linear relation to the risk of both hip fractures and "major osteoporotic fractures" including fractures of the hip, spine, shoulder, and wrist. The age-adjusted hazard ratio (HR) for a hip fracture was 1.46 (95 % CI 1.08-1.99) for one SD increase in IGFBP-1. The corresponding age-adjusted HR for major osteoporotic fractures was 1.33 (95 % CI 1.05-1.69). The relation between IGFBP-1 and fracture risk was not confounded by either IGF-I or BMI. Femoral neck BMD, however, mediated 56 % of the total "effect" of IGFBP-1 on hip fracture risk. In conclusion, IGFBP-1 had a positive linear relation to fracture risk, partly mediated by BMD but not related to IGF-I or BMD. This implies that IGFBP-1 might be an important factor in bone turnover and that further studies on this would be valuable. PMID- 27215931 TI - Accelerated Brain DCE-MRI Using Iterative Reconstruction With Total Generalized Variation Penalty for Quantitative Pharmacokinetic Analysis: A Feasibility Study. AB - PURPOSE: To investigate the feasibility of using undersampled k-space data and an iterative image reconstruction method with total generalized variation penalty in the quantitative pharmacokinetic analysis for clinical brain dynamic contrast enhanced magnetic resonance imaging. METHODS: Eight brain dynamic contrast enhanced magnetic resonance imaging scans were retrospectively studied. Two k space sparse sampling strategies were designed to achieve a simulated image acquisition acceleration factor of 4. They are (1) a golden ratio-optimized 32 ray radial sampling profile and (2) a Cartesian-based random sampling profile with spatiotemporal-regularized sampling density constraints. The undersampled data were reconstructed to yield images using the investigated reconstruction technique. In quantitative pharmacokinetic analysis on a voxel-by-voxel basis, the rate constant Ktrans in the extended Tofts model and blood flow FB and blood volume VB from the 2-compartment exchange model were analyzed. Finally, the quantitative pharmacokinetic parameters calculated from the undersampled data were compared with the corresponding calculated values from the fully sampled data. To quantify each parameter's accuracy calculated using the undersampled data, error in volume mean, total relative error, and cross-correlation were calculated. RESULTS: The pharmacokinetic parameter maps generated from the undersampled data appeared comparable to the ones generated from the original full sampling data. Within the region of interest, most derived error in volume mean values in the region of interest was about 5% or lower, and the average error in volume mean of all parameter maps generated through either sampling strategy was about 3.54%. The average total relative error value of all parameter maps in region of interest was about 0.115, and the average cross-correlation of all parameter maps in region of interest was about 0.962. All investigated pharmacokinetic parameters had no significant differences between the result from original data and the reduced sampling data. CONCLUSION: With sparsely sampled k space data in simulation of accelerated acquisition by a factor of 4, the investigated dynamic contrast-enhanced magnetic resonance imaging pharmacokinetic parameters can accurately estimate the total generalized variation-based iterative image reconstruction method for reliable clinical application. PMID- 27215932 TI - Application of Metal Implant 16-Bit Imaging: New Technique in Radiotherapy. AB - OBJECTIVE: This study aimed to evaluate the computed tomography number and the variation of dose distribution based on 12-bit, 16-bit, and revised 16-bit images while the metal bars were inserted. METHODS: The phantoms containing stainless steel, titanium alloy, and aluminum bar were scanned with computed tomography. These images were reconstructed with 12-bit and 16-bit imaging technologies. The "cupping artifacts" computed tomography value of the metal object revised by Matlab software was called the revised 16-bit image. The computed tomography values of these metal materials were analyzed. Two radiotherapy treatment plans were designed using the treatment plan system: (1) gantry was of 0 degrees irradiation field and (2) gantry was of 90 degrees and 270 degrees for 2 opposed irradiation fields. The dose profile and dose-volume histogram of a structure of interest were analyzed in various images. The analysis was based on the radiotherapy plan differences between 3 different imaging techniques (12-bit imaging, 16-bit imaging, and revised 16-bit imaging technologies). RESULTS: For low-density metal object (computed tomography value <3071 Hounsfield unit, HU), the radiotherapy plan results were consistent based on 3 different imaging techniques. For high-density metal object (computed tomography value >3071 HU), the difference in radiotherapy plan results was obvious. The dose of 12-bit was 15.9% higher than revised 16-bit on average for the downstream of titanium rod. For stainless steel, this number reached up to 42.7%. CONCLUSION: A 16-bit imaging technology of metal implants can distinguish the computed tomography value of different metal materials. Furthermore, the revised 16-bit imaging technology can improve the dose computational accuracy of radiotherapy plan with high-density metal implants. PMID- 27215933 TI - The molecular and clinical features of dengue during outbreak in Jambi, Indonesia in 2015. AB - Dengue is hyperendemic in Indonesia. In 2015, reported cases of dengue fever doubled those of 2014 in the Jambi municipality of Sumatra. We examined viral aetiology and its relationship with disease outcome in Jambi. Dengue-suspected patients' sera were collected and NS1 detection and IgM/IgG serology were performed. Dengue virus (DENV) serotyping was performed using real-time RT-PCR. Envelope genes were sequenced to determine the genotypes of DENV. Clinical, haematologic, and demographic data were recorded. Of 210 dengue-suspected patients, 107 were confirmed. The disease manifested as Dengue Fever (62%), Dengue Haemorrhagic Fever (36%), and Dengue Shock Syndrome (2%). The serotypes of 94 DENV were determined. All DENV serotypes were detected with DENV-1 as the predominant serotype (66%). Genotypically, the DENV-1 viruses belong to Genotype I, DENV-2 was of Cosmopolitan genotype, DENV-3 as Genotype I, and DENV-4 belonged to Genotype II. Comparison with historical data revealed serotype predominance switched from DENV-3 to DENV-1, and the replacement of Genotype IV of DENV-1 with Genotype I. In summary, DENV-1 predominated during the 2015 dengue outbreak in Jambi. The full spectrum of dengue disease occurred and was characterized by a switch in predominant serotypes. PMID- 27215934 TI - The stress response is attenuated during inclement weather in parental, but not in pre-parental, Lapland longspurs (Calcarius lapponicus) breeding in the Low Arctic. AB - Birds breeding at high latitudes can be faced with extreme weather events throughout the breeding season. In response to environmental perturbations, vertebrates activate the hypothalamic-pituitary-adrenal (HPA) axis and synthesize corticosterone, which promotes changes in behavior and physiology to help the animal survive. The parental care hypothesis suggests that the HPA axis activity should be downregulated during the parental stage of breeding to prevent nest abandonment. However, it is unknown what happens to HPA axis activity in response to severe weather at the transition from the pre-parental to parental stages of breeding. We sampled baseline corticosterone levels and the time course of corticosterone elevation over 60min of restraint stress and assessed body condition and fat stores in Lapland longspurs (Calcarius lapponicus) breeding in the Low Arctic in the presence and absence of snowstorms. The results showed that during the pre-parental stage, HPA axis activity was up-regulated in response to snowstorms, with corticosterone levels continuing to increase through 60min of restraint. However, once birds were parental, HPA axis activity was unaffected by snowstorms and levels peaked at 10min. Fat levels and body condition did not change in response to snowstorms but fat levels declined in males during the pre parental stage. These data suggest that the parental care hypothesis can be applied to severe storm events; parental birds restrained the activity of the HPA axis, likely to focus on the reproductive effort that is already underway, while pre-parental birds greatly upregulated HPA axis activity in response to snowstorms to maximize self-preservation. PMID- 27215935 TI - Likelihood of ACL graft rupture: not meeting six clinical discharge criteria before return to sport is associated with a four times greater risk of rupture. AB - BACKGROUND: The decision as to whether or not an athlete is ready to return to sport (RTS) after ACL reconstruction is difficult as the commonly used RTS criteria have not been validated. PURPOSE: To evaluate whether a set of objective discharge criteria, including muscle strength and functional tests, are associated with risk of ACL graft rupture after RTS. MATERIALS AND METHODS: 158 male professional athletes who underwent an ACL reconstruction and returned to their previous professional level of sport were included. Before players returned to sport they underwent a battery of discharge tests (isokinetic strength testing at 60 degrees , 180 degrees and 300 degrees /s, a running t test, single hop, triple hop and triple crossover hop tests). Athletes were monitored for ACL re ruptures once they returned to sport (median follow-up 646 days, range 1-2060). RESULTS: Of the 158 athletes, 26 (16.5%) sustained an ACL graft rupture an average of 105 days after RTS. Two factors were associated with increased risk of ACL graft rupture: (1) not meeting all six of the discharge criteria before returning to team training (HR 4.1, 95% CI 1.9 to 9.2, p<=0.001); and (2) decreased hamstring to quadriceps ratio of the involved leg at 60 degrees /s (HR 10.6 per 10% difference, 95% CI 10.2 to 11, p=0.005). CONCLUSIONS: Athletes who did not meet the discharge criteria before returning to professional sport had a four times greater risk of sustaining an ACL graft rupture compared with those who met all six RTS criteria. In addition, hamstring to quadriceps strength ratio deficits were associated with an increased risk of an ACL graft rupture. PMID- 27215936 TI - From management to prevention: the new cure for sports concussion. PMID- 27215937 TI - Improve your health and fitness in 'Just 6 weeks'. PMID- 27215939 TI - Cranioplasty: morbidity and failure. AB - OBJECTIVE: Cranioplasty is a technically straightforward procedure; however, it is becoming increasingly apparent that it is associated with relatively high morbidity and a significant failure rate due to either infection or autologous bone flap resorption. The aim of this study was to determine which factors influenced the incidence of cranioplasty complications and failure. METHODS: A retrospective analysis was undertaken of all patients who had a cranioplasty at the two major trauma hospitals in Western Australia between the start of 2004 and the middle of 2015. RESULTS: Five hundred and twelve had a cranioplasty after craniectomy for a variety of different indications. Sixty-three patients developed a postoperative intracranial collection following cranioplasty (12.3%, 95% confidence interval [CI] 9.7-15.4), however only 19 required surgical evacuation. One hundred and twenty-one patients had seizures following cranioplasty (23.6%, 95% CI 20.2-27.5) Nine patients died within six months following cranioplasty. Forty-two patients (8.2%, 95% CI 6.1-10.9) developed cranioplasty infection that necessitated removal of the implant. However a change in clinical management of these patients had led to no infections for the past three years. Amongst 330 patients who had autologous cranioplasty, clinically significant bone resorption occurred in 69 patients (20.9%, 95% CI 16.9-25.6). CONCLUSION: One key finding in this study is the reduction in infection rate that can occur when a single senior clinician performs the procedure and there is strict adherence to aseptic technique. This may result in a significant reduction in morbidity. PMID- 27215938 TI - Drought-responsive WRKY transcription factor genes TaWRKY1 and TaWRKY33 from wheat confer drought and/or heat resistance in Arabidopsis. AB - BACKGROUND: Drought stress is one of the major causes of crop loss. WRKY transcription factors, as one of the largest transcription factor families, play important roles in regulation of many plant processes, including drought stress response. However, far less information is available on drought-responsive WRKY genes in wheat (Triticum aestivum L.), one of the three staple food crops. RESULTS: Forty eight putative drought-induced WRKY genes were identified from a comparison between de novo transcriptome sequencing data of wheat without or with drought treatment. TaWRKY1 and TaWRKY33 from WRKY Groups III and II, respectively, were selected for further investigation. Subcellular localization assays revealed that TaWRKY1 and TaWRKY33 were localized in the nuclei in wheat mesophyll protoplasts. Various abiotic stress-related cis-acting elements were observed in the promoters of TaWRKY1 and TaWRKY33. Quantitative real-time PCR (qRT-PCR) analysis showed that TaWRKY1 was slightly up-regulated by high temperature and abscisic acid (ABA), and down-regulated by low-temperature. TaWRKY33 was involved in high responses to high-temperature, low-temperature, ABA and jasmonic acid methylester (MeJA). Overexpression of TaWRKY1 and TaWRKY33 activated several stress-related downstream genes, increased germination rates, and promoted root growth in Arabidopsis under various stresses. TaWRKY33 transgenic Arabidopsis lines showed lower rates of water loss than TaWRKY1 transgenic Arabidopsis lines and wild type plants during dehydration. Most importantly, TaWRKY33 transgenic lines exhibited enhanced tolerance to heat stress. CONCLUSIONS: The functional roles highlight the importance of WRKYs in stress response. PMID- 27215940 TI - Molecular cloning and expression of the vitellogenin gene and its correlation with ovarian development in an invasive pest Octodonta nipae on two host plants. AB - There is an ongoing relationship between host plants and herbivores. The nutrient substances and secondary compounds found in the host plant can not only impact the growth and development process of herbivores, but, more importantly, may also affect their survival and reproductive fitness. Vitellogenesis is the core process of reproductive regulation and is generally considered as a reliable indicator for evaluating the degree of ovarian development in females. Vitellogenin (Vg) plays a critical role in the synthesis and secretion of yolk protein. In this study, the full-length cDNA of the Vg gene in an alien invasive species, the nipa palm hispid beetle Octodonta nipae Maulik (Coleoptera: Chrysomelidae) (OnVg) was cloned and, the effect of host plant on the OnVg expression level and ovarian development was investigated. The results revealed that the OnVg was highly and exclusively expressed in adult females, but barely detectable in larvae, pupae and adult males. The relative expression level of OnVg and egg hatchability were much higher in females fed on Phoenix canariensis (their preferred host) than those fed on Phoenix roebelenii. A positive correlation relationship between OnVg expression and egg hatchability was also detected. Additionally, the anatomy of the female reproductive system showed that the ovaries of individuals fed on P. canariensis were considerably more developed than in females fed on P. roebelenii. The results may be applicable to many pest management situations through reproductive disturbance by alternating host plant species or varieties or by reproductive regulation through vitellogenesis mediated by specific endocrine hormones. PMID- 27215941 TI - Drug Design based on Protein Structure Network. AB - Although structure-based drug design (SBDD) has become an indispensable tool in drug discovery for a long time, it continues to pose major challenges to date. With the advancement of "omics" techniques, systems biology has enriched SBDD into a new era, called polypharmacology, in which multi-targets drug or drug combination is designed to fight complex diseases. As a preliminary tool in systems biology, protein structure networks (PSNs) treat a protein as a set of residues linked by edges corresponding to the intramolecular interactions existing in folded structures between the residues. The PSN offers a computationally efficient tool to study the structure and function of proteins, and thus may facilitate structure-based drug design. Herein, we provide an overview of recent advances in PSNs, from predicting functionally important residues, to charactering protein-protein interactions and allosteric communication paths. Furthermore, we discuss potential pharmacological applications of PSN concepts and tools, and highlight the application to two families of drug targets, GPCRs and Hsp90. Although the application of PSNs as a framework for computer-aided drug discovery has been limited to date, we put forward the potential utility value in the near future and propose the PSNs could also serve as a new tool for polypharmacology research. PMID- 27215942 TI - Molecular evidence of hybrid zones of Cedrela (Meliaceae) in the Yungas of Northwestern Argentina. AB - In the Yungas of Northwestern Argentina, three endangered species of Cedrela (C. angustifolia, C. saltensis, and C. balansae) follow altitudinal gradients of distribution with contact zones between them. We sampled 210 individuals from 20 populations that spanned most of Cedrela's geographical range in the Yungas, and used Amplified Fragment Length Polymorphism (AFLP) markers and DNA sequences of the nuclear Internal Transcribed Spacer (ITS) to investigate hybrid zones. Data analyses employed an array of complementary methods, including principal coordinate analyses, Bayesian clustering analyses, maximum likelihood tree building, and network techniques. Both nuclear molecular systems - AFLP and ITS - provided insights into the evolutionary history of Cedrela in the Yungas in a congruent manner. We uncovered strong support for the occurrence of natural hybridization between C. balansae and C. saltensis. Additionally, we identified hybrid zones in areas of sympatry (at both the Calilegua National Park and the San Andres farm) and in transition zones from 820 to 1100meters above sea level (localities of Pintascayo and Acambuco). There was no evidence for hybridization of either C. balansae or C. saltensis with C. angustifolia. The role of hybrid populations in conservation and use of genetic resources in the Yungas were discussed. PMID- 27215943 TI - Theory of reactions at electrified interfaces. AB - Interfacial reaction and transport processes are a decisive factor for the overall performance of electrochemical systems. However, existing models rely on phenomenological descriptions of charged interfaces, which yields no deeper insights. We present a generic theory to describe charge and electron transfer reactions at charged interfaces, which is applicable to different electrochemical systems, like fuel cells or batteries with liquid or solid electrolytes. In the present work, our general theory is adopted to the electrochemical double layer at the interface between a solid electrode and a liquid electrolyte. The model allows to describe the intercalation reaction in Li-ion insertion batteries as a two-step process, consisting of a first desolvation and adsorption and a second actual insertion step. It becomes apparent that a charging of the double layer acts as the necessary driving force for the charge transfer across the interface. PMID- 27215944 TI - Domain topology and domain switching kinetics in a hybrid improper ferroelectric. AB - Charged polar interfaces such as charged ferroelectric walls or heterostructured interfaces of ZnO/(Zn,Mg)O and LaAlO3/SrTiO3, across which the normal component of electric polarization changes suddenly, can host large two-dimensional conduction. Charged ferroelectric walls, which are energetically unfavourable in general, were found to be mysteriously abundant in hybrid improper ferroelectric (Ca,Sr)3Ti2O7 crystals. From the exploration of antiphase boundaries in bilayer perovskites, here we discover that each of four polarization-direction states is degenerate with two antiphase domains, and these eight structural variants form a Z4 * Z2 domain structure with Z3 vortices and five distinct types of domain walls, whose topology is directly relevant to the presence of abundant charged walls. We also discover a zipper-like nature of antiphase boundaries, which are the reversible creation/annihilation centres of pairs of two types of ferroelectric walls (and also Z3-vortex pairs) in 90 degrees and 180 degrees polarization switching. Our results demonstrate the unexpectedly rich nature of hybrid improper ferroelectricity. PMID- 27215945 TI - The New Generation of Thai Fathers: Breadwinners Involved in Parenting. AB - Becoming a father for the first time might cause great changes in a man's identity and lifestyle. Teenage fathers must strive to balance two competing roles: the teenage role and the father role. The current study design followed grounded theory methodology to gain a deeper understanding of how Thai teenage fathers reason about becoming and being a father from a gender equality perspective. Participants were selected from a heterogeneous group of fathers until saturation was reached ( n = 25). Most of the fathers were cohabiting with their partner in an extended family. An interview guide was developed, a pilot study was undertaken, and interviews were performed on two different occasions: once during the second trimester of pregnancy and again when the baby was 5 to 6 months old. The core category, "Male breadwinners involved in parenting," encompassed persons making the transition from being solely a teenager to being a teenage father. Most of the fathers accepted the unintended pregnancy and took on the expected breadwinning responsibility of a father. They prepared for fatherhood and changed their lifestyle. Their families provided support. Nevertheless, the fathers sought to avoid further unplanned parenthood by learning about family planning. The teenage fathers emphasized breadwinning first, then involved himself in the child and the housework. These findings provide an increased understanding of Thai teenage fathers. PMID- 27215946 TI - Zika virus infection, a new public health challenge. PMID- 27215947 TI - Mitochondrial damage and ageing using skin as a model organ. AB - Ageing describes the progressive functional decline of an organism over time, leading to an increase in susceptibility to age-related diseases and eventually to death, and it is a phenomenon observed across a wide range of organisms. Despite a vast repertoire of ageing studies performed over the past century, the exact causes of ageing remain unknown. For over 50 years it has been speculated that mitochondria play a key role in the ageing process, due mainly to correlative data showing an increase in mitochondrial dysfunction, mitochondrial DNA (mtDNA) damage, and reactive oxygen species (ROS) with age. However, the exact role of the mitochondria in the ageing process remains unknown. The skin is often used to study human ageing, due to its easy accessibility, and the observation that the ageing process is able to be accelerated in this organ via environmental insults, such as ultra violet radiation (UVR). This provides a useful tool to investigate the mechanisms regulating ageing and, in particular, the role of the mitochondria. Observations from dermatological and photoageing studies can provide useful insights into chronological ageing of the skin and other organs such as the brain and liver. Moreover, a wide range of diseases are associated with ageing; therefore, understanding the cause of the ageing process as well as regulatory mechanisms involved could provide potentially advantageous therapeutic targets for the prevention or treatment of such diseases. PMID- 27215948 TI - Improved interoceptive awareness in chronic low back pain: a comparison of Back school versus Feldenkrais method. AB - PURPOSE: To determine the efficacy of the Feldenkrais method for relieving pain in patients with chronic low back pain (CLBP) and the improvement of interoceptive awareness. METHOD: This study was designed as a single-blind randomized controlled trial. Fifty-three patients with a diagnosis of CLBP for at least 3 months were randomly allocated to the Feldenkrais (mean age 61.21 +/- 11.53 years) or Back School group (mean age 60.70 +/- 11.72 years). Pain was assessed using the visual analog scale (VAS) and McGill Pain Questionnaire (MPQ), disability was evaluated with the Waddel Disability Index, quality of life was measured with the Short Form-36 Health Survey (SF-36), and mind-body interactions were studied using the Multidimensional Assessment of Interoceptive Awareness Questionnaire (MAIA). Data were collected at baseline, at the end of treatment, and at the 3-month follow-up. RESULTS: The two groups were matched at baseline for all the computed parameters. At the end of treatment (Tend), there were no significant differences between groups regarding chronic pain reduction (p = 0.290); VAS and MAIA-N sub scores correlated at Tend (R = 0.296, p = 0.037). By the Friedman analysis, both groups experienced significant changes in pain (p < 0.001) and disability (p < 0.001) along the investigated period. CONCLUSIONS: The Feldenkrais method has comparable efficacy as Back School in CLBP. Implications for rehabilitation The Feldenkrais method is a mind-body therapy that is based on awareness through movement lessons, which are verbally guided explorations of movement that are conducted by a physiotherapist who is experienced and trained in this method. It aims to increase self-awareness, expand a person's repertoire of movements, and to promote increased functioning in contexts in which the entire body cooperates in the execution of movements. Interoceptive awareness, which improves with rehabilitation, has a complex function in the perception of chronic pain and should be investigated further in future research. The efficacy of the Feldenkrais method is comparable with that of BS for nonspecific chronic low back pain. The physician can recommend a body-mind rehabilitation approach, such as the Feldenkrais method, or an educational and rehabilitation program, such as BS, to the patient, based on his individual needs. The 2 rehabilitation approaches are equally as effective in improving interoceptive awareness. PMID- 27215950 TI - Noninvasive evaluation of radiation-enhanced glioma cells invasiveness by ultra high-field (1)H-MRS in vitro. AB - INTRODUCTION: Glioma is the most common type of the primary CNS tumor. Radiotherapy is an important treatment measure after surgery. However, its highly invasive character is the main reason of postoperative recurrence. The aim of the study was to probe the correlation between the invasion ability and the metabolite characteristics of glioma cells at the cellular level after irradiation by using 14.7T high-resolution nuclear proton magnetic resonance spectroscopy ((1)H-MRS). METHODS: To determine the matrix metalloproteinase-2 (MMP-2) activity and metabolite ratios of glioma cells after irradiation with different doses of X-rays, U87 and C6 glioma cells were exposed to X-ray irradiation of 0, 1, 5, 10, and 15Gy. After 20h, the perchloric acid (PCA) extraction method was used to evaluate water-soluble metabolites [choline (Cho), creatine (Cr), and N-acetylaspartate (NAA)], and (1)H-MRS patterns and changes in metabolite ratios were observed in vitro by 14.7T high resolution (1)H-MRS. Matrigel invasion assays and gelatin zymography were performed to test the invasion ability of U87 and C6 glioma cells. RESULTS: Good MR spectra were obtained from PCA method extracts of U87 and C6 glioma cells. Both radiation induced MMP-2 activity and the Cho/Cr and Cho/NAA ratios increased after irradiation, and their increase occurred in a dose-dependent manner. The MMP-2 activity and the Cho/Cr and Cho/NAA ratios of glioma cells increased after irradiation up to 10Gy and decreased thereafter. In particular, the Cho/NAA ratio of U87 cells increased from 3.55+/-0.06 (0Gy) to 9.13+/-0.30 (10Gy) and then declined to 5.94+/-0.15 (15Gy). Furthermore, the invasion ability of glioma cells had a strong positive correlation with the Cho/Cr and Cho/NAA ratios. Both the Cho/Cr ratio and the Cho/NAA ratio of U87 glioma cells were highly positively correlated with the number of invading cells in the Matrigel invasion assay. The Pearson's correlation coefficient (r) values of U87 cells were 0.89 (Cho/Cr ratio versus invasion ability) and 0.91 (Cho/NAA ratio versus invasion ability) (P<0.01). C6 cells exhibited similar changes to those of U87 cells. CONCLUSIONS: In vitro high-resolution (1)H-MRS is useful for detecting glioma invasiveness at the cellular level. PMID- 27215949 TI - Efficacy and mechanisms of behavioral therapy components for insomnia coexisting with chronic obstructive pulmonary disease: study protocol for a randomized controlled trial. AB - BACKGROUND: Difficulty falling asleep, staying asleep or poor-quality sleep (insomnia) is common in people with chronic obstructive pulmonary disease (COPD). Insomnia is related to greater mortality and morbidity, with four times the risk of mortality for sleep times below 300 min. However, insomnia medications are used with caution in COPD due to their potential adverse effects. While cognitive behavioral therapy for insomnia (CBT-I) is effective for people with primary insomnia and people with other chronic illnesses, the efficacy and mechanisms of action of such a therapy are yet unclear in people with both insomnia and COPD. The purpose of this study is to rigorously test the efficacy of two components of insomnia therapy - CBT-I and COPD education (COPD-ED) - in people with coexisting insomnia and COPD, and to identify mechanisms responsible for therapy outcomes. The rationale for the proposed study is that once the efficacy and mechanisms of CBT-I and COPD-ED are known, new and innovative approaches for insomnia coexisting with COPD can be developed to non-pharmacologically minimize insomnia and fatigue, thereby leading to longer, higher-quality and more productive lives for people with COPD, and reduced societal cost due to the effects of insomnia. METHODS: We are conducting a randomized, controlled, parallel-group (N = 35 each group) comparison of CBT-I, COPD-ED and non-COPD, non-sleep health education Attention Control (AC) using a highly efficient four-group design. Arm 1 comprises 6 weekly sessions of CBT-I + AC; Arm 2 = 6 weekly sessions of COPD-ED + AC; Arm 3 = 6 weekly sessions of CBT-I + COPD-ED; and Arm 4 = 6 weekly sessions of AC. This design will allow completion of the following specific aims: (1) to determine the efficacy of individual treatment components, CBT-I and COPD-ED, on insomnia and fatigue, (2) to define the mechanistic contributors to the outcomes after CBT-I and COPD-ED. DISCUSSION: The research is innovative because it represents a new and substantive departure from the usual insomnia therapy, namely by testing traditional CBT-I with education to enhance outcomes. The work proposed in aims 1 and 2 will provide systematic evidence of the efficacy and mechanisms of components of a novel approach to insomnia comorbid with COPD. Such results are highly likely to provide new approaches for preventive and therapeutic interventions for insomnia and fatigue in COPD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01973647 . Registered on 22 October 2013. PMID- 27215951 TI - Superiority of the extracellular volume fraction over the myocardial T1 value for the assessment of myocardial fibrosis in patients with non-ischemic cardiomyopathy. AB - PURPOSE: This study aimed to assess the efficacies of the myocardial T1 value and the extracellular volume fraction (ECV) for determining the severity of myocardial fibrosis in patients with non-ischemic cardiomyopathy. MATERIALS AND METHODS: Myocardial fibrosis is considered the most important indicator of cardiac damage associated with non-ischemic cardiomyopathy. Recently, modified Look-Locker inversion recovery imaging (MOLLI) has been used for T1 mapping and measurement of the ECV for the assessment of myocardial fibrosis. The present study included 22 patients (mean age, 61.5+/-12.7; 21 male) with non-ischemic heart failure. Motion corrected myocardial T1 mapping was automatically performed using a MOLLI sequence, and the ECV was estimated from the pre- and post-contrast blood and myocardial T1 values corrected for the hematocrit level. All endomyocardial biopsy specimens were obtained from the inferoposterior left ventricular wall. The percentage of myocardial fibrosis (%F) was determined after Elastica Masson-Goldner staining as follows: (fibrosis area/[fibrosis area+myocardial area])*100. RESULTS: No correlation was noted between the %F and the pre- (r=0.290, p=0.191) or post-contrast T1 values (r=-0.190, p=0.398); however, a significant correlation was noted between the %F and ECV (r=0.750, p<0.001). CONCLUSIONS: In this study, the ECV reflected the extent of myocardial fibrosis, but the pre- and post-contrast T1 values did not. The ECV may be used to estimate the severity of myocardial fibrosis in patients with non-ischemic cardiomyopathy. PMID- 27215952 TI - Are oral nutritional supplements more effective than dietary advice in malnourished care home residents? PMID- 27215953 TI - Skin lesion image segmentation using Delaunay Triangulation for melanoma detection. AB - Developing automatic diagnostic tools for the early detection of skin cancer lesions in dermoscopic images can help to reduce melanoma-induced mortality. Image segmentation is a key step in the automated skin lesion diagnosis pipeline. In this paper, a fast and fully-automatic algorithm for skin lesion segmentation in dermoscopic images is presented. Delaunay Triangulation is used to extract a binary mask of the lesion region, without the need of any training stage. A quantitative experimental evaluation has been conducted on a publicly available database, by taking into account six well-known state-of-the-art segmentation methods for comparison. The results of the experimental analysis demonstrate that the proposed approach is highly accurate when dealing with benign lesions, while the segmentation accuracy significantly decreases when melanoma images are processed. This behavior led us to consider geometrical and color features extracted from the binary masks generated by our algorithm for classification, achieving promising results for melanoma detection. PMID- 27215955 TI - Effect of Ions and Ionic Strength on Surface Plasmon Absorption of Single Gold Nanowires. AB - The local temperature change from a single optically excited gold nanowire, lithographically prepared on Al0.94Ga0.06N embedded with Er(3+) ions, is measured in air, pure water, and various concentrations of aqueous solutions of ionic solutes of NaCl, Na2SO4, and MgSO4. The absorption cross section of the nanowire under pure water (2.25 * 10(-14) m(2)) and different solution ionic strength is measured from the slopes of temperature change versus laser intensity plots. Addition of charges into the solution decreases the amount of heat generated during optical excitation of the gold nanostructures because the absorption cross section of the gold nanowire is attenuated. A Langmuir-type behavior of the absorption cross section with ionic strength is observed that is identified with an increase in the occupancy of screened interfacial charges. The absorption cross section of the nanowire decreases with ionic strength until a saturation value of 9 * 10(-15) m(2), where saturation in the occupancy of screened interfacial charge occurs. Dynamic measurements of temperature for a single gold nanowire immersed in a microchannel flow cell show a sharp and fast temperature drop for the flow of ionic solution compared to the pure (deionized) water, suggesting that the technique can be developed as a sensor probe to detect the presence of ions in solution. PMID- 27215954 TI - Investigating causality in the association between 25(OH)D and schizophrenia. AB - Vitamin D deficiency is associated with increased risk of schizophrenia. However, it is not known whether this association is causal or what the direction of causality is. We performed two sample bidirectional Mendelian randomization analysis using single nucleotide polymorphisms (SNPs) robustly associated with serum 25(OH)D to investigate the causal effect of 25(OH)D on risk of schizophrenia, and SNPs robustly associated with schizophrenia to investigate the causal effect of schizophrenia on 25(OH)D. We used summary data from genome-wide association studies and meta-analyses of schizophrenia and 25(OH)D to obtain betas and standard errors for the SNP-exposure and SNP-outcome associations. These were combined using inverse variance weighted fixed effects meta-analyses. In 34,241 schizophrenia cases and 45,604 controls, there was no clear evidence for a causal effect of 25(OH)D on schizophrenia risk. The odds ratio for schizophrenia per 10% increase in 25(OH)D conferred by the four 25(OH)D increasing SNPs was 0.992 (95% CI: 0.969 to 1.015). In up to 16,125 individuals with measured serum 25(OH)D, there was no clear evidence that genetic risk for schizophrenia causally lowers serum 25(OH)D. These findings suggest that associations between schizophrenia and serum 25(OH)D may not be causal. Therefore, vitamin D supplementation may not prevent schizophrenia. PMID- 27215956 TI - Phylogenetic niche conservatism explains an inverse latitudinal diversity gradient in freshwater arthropods. AB - The underlying mechanisms responsible for the general increase in species richness from temperate regions to the tropics remain equivocal. Many hypotheses have been proposed to explain this astonishing pattern but additional empirical studies are needed to shed light on the drivers at work. Here we reconstruct the evolutionary history of the cosmopolitan diving beetle subfamily Colymbetinae, the majority of which are found in the Northern hemisphere, hence exhibiting an inversed latitudinal diversity gradient. We reconstructed a dated phylogeny using 12 genes, to investigate the biogeographical history and diversification dynamics in the Colymbetinae. We aimed to identify the role that phylogenetic niche conservatism plays in the inversed diversification pattern seen in this group. Our results suggest that Colymbetinae originated in temperate climates, which supports the hypothesis that their distribution is the result of an ancestral adaptation to temperate environmental conditions rather than tropical origins, and that temperate niche conservatism can generate and/or maintain inverse latitudinal diversity gradients. PMID- 27215958 TI - The effect of hydrostatic pressure on staurosporine-induced neural differentiation in mouse bone marrow-derived mesenchymal stem cells. AB - In this study, the role of hydrostatic pressure on staurosporine-induced neural differentiation in mouse bone marrow mesenchymal stem cells were investigated. The cells were cultured in treatment medium containing 100 nM of staurosporine for 4 hours; then the cells were affected by hydrostatic pressure (0, 25,50, 100 mmHg). The percentage of cell viability by trypan blue staining and the percentage of cell death by Hoechst/PI differential staining were assessed. We obtained the total neurite length. Expression of beta-tubulin III and GFAP (Glial fibrillary acidic protein) proteins were also analyzed by immunocytochemistry. The percentage of cell viability in treatments decreased relative to the increase in hydrostatic pressure and time (p Keywords: bone marrow mesenchymal stem cell, hydrostatic pressure, immunocytochemistry, neural differentiation, neurite length, cell differentiation. PMID- 27215957 TI - Telocytes (interstitial Cajal-like cells) in human Fallopian tubes. AB - BACKGROUND: Telocytes represent a relatively newly discovered population of cells found within the various tissues and organs, including Fallopian tubes. It is presumed that telocytes could serve as a sensor of hormone levels or regulate activity of muscle peristaltic movement. METHODS: Tissue sections from anatomically different parts of Fallopian tubes of 48 women (age 48.8+/-9.1) were stained for the expression of five different antigens: c-kit (CD117), CD34, vimentin, podoplanin (D2-40) and Dog-1. RESULTS: Telocytes form a network associated with the smooth muscle cells. From the mentioned antibodies, only anti c-kit (CD117) seems to be relatively selective specific to the telocytes, others react also with numerous other cells and tissue structures. Our results when using antibodies against podoplanin and Dog-1 are in dissonance with recent literature - with regards to our results, they are not suitable for detection of telocytes. CONCLUSION: Methods of immunohistochemistry are suitable for identification of telocytes in Fallopian tubes. C-kit (CD117) antigens are useful for routine identification of telocytes in histological sections. This antigen can be combined with CD34 or vimentin in cases of double staining immunohistochemistry. PMID- 27215959 TI - New data on harmful effects of trans-fatty acids. AB - Various margarines containing trans-fatty acids were marketed as being healthier because of the absence of cholesterol, suggesting to use margarine instead of butter. Fifteen years ago, research documented the grave health risk of trans fats (T-fat). US FDA in 2015 finalized its decision that T-fat is not safe and set a three-year time limit for complete removal of T-fat from all foods. The greatest danger from T-fat lies in its capacity to distort the cell membranes. The primary health risk identified for T-fat consumption is an elevated risk of coronary heart disease. T-fats have an adverse effect on the brain and nervous system. T-fat from the diet is incorporated into brain cell membranes and alter the ability of neurons to communicate. This can diminish mental performance. Relationship between T-fat intake and depression risk was observed. There is growing evidence for a possible role of T-fat in the development of Alzheimer's disease and cognitive decline with age. PMID- 27215960 TI - Practices and thinking of laboratory detection in the aid to West Africa to fight against Ebola. AB - BACKGROUND: The outbreak of Ebola virus disease in West Africa has brought great disaster to the people's health in affected countries. China dispatched first group of public health experts and medical staff to Sierra Leone in September 2014 to fight Ebola. METHODS: To systematically collect huge amount of primary data, and to make analysis, draw conclusions and lessons in terms of six aspects, respectively as training before departure, local disease information, track of epidemic situation, transformation of temporary laboratory, detection of Ebola virus samples as well as assessment through single blind test. RESULTS: 1) Our team has launched preparatory works in advance before going to Sierra Leone. 2) Malaria is the country's severest infectious disease. 3) Observation centers were overcrowded with large number of suspected cases being inspected, implying high risk of nosocomial infection. 4) A BSL-II laboratory with 3 work areas and 2 buffer areas was built, achieving several major functions within 6 days. 5) Confirmed by South African Raqqa laboratory, our detection accuracy reached 100%. 6) At one week before return, the daily average sample amount of our team reached 66 cases and our detection capability was equivalent to that of USA. CONCLUSIONS: Successful experience from fighting against Ebola in Sierra Leone could be summarized as: 1) Optimized processes and scientific security measures are prerequisite to improving the detection ability. 2) The close collaboration between laboratory and observation center has created a new model of China's foreign aid. 3) Comprehensive information investigation and training lay a solid foundation for the successful completion of tasks. PMID- 27215961 TI - Interleukin 10 and transforming growth factor beta 1 gene polymorphisms in juvenile idiopathic arthritis. AB - OBJECTIVES: The aim of this study is to identify the associations between interleukin 10 (IL-10) and transforming growth factor beta 1 (TGF-beta1) gene polymorphisms and individual susceptibility to juvenile idiopathic arthritis (JIA) in a group of Iranian patients. BACKGROUND: Cytokine genes, including IL-10 and TGF-beta1, are known to play important roles in the pathogenesis of JIA. METHODS: Using polymerase chain reaction with sequence-specific primers method, the frequency of alleles, genotypes and haplotypes of IL-10 (positions -1082, 819, -592) and TGF-beta1 (codon 10, codon 25) single-nucleotide polymorphisms (SNPs) were investigated in 55 patients with JIA as a case group and compared with 140 healthy unrelated controls. RESULTS: The G allele was significantly less frequent at TGF-beta1 codon 25 in patients with JIA than in the controls (p < 0.01). The frequency of CT genotype at TGF-beta1 codon 10 was found to be higher in healthy individuals in comparison with that in patients group (p = 0.04). We observed no differences in the frequency of alleles, genotypes and haplotypes of IL-10 gene between the groups of patients and controls. CONCLUSIONS: Considering the low frequency of existence of TGF-beta1 G allele at codon 25 as well as TGF beta1 CT genotype at codon 10 in patients with JIA, it seems that these cytokine gene polymorphisms could play role as the protective factors against JIA. PMID- 27215962 TI - Freund's complete adjuvant effect on BALB/c mice: an insight into inflammation and oxidative stress after immunity challenge. AB - Freund's complete adjuvant (FCA) is a mean used for improving immunization efficacy in experiments and veterinary medicine. Despite high efficacy, it is not used in human vaccination due to number of adverse effects. Arthritis can be an example of a typical adverse consequence. In this work, we decided to investigate the link between oxidative stress and inflammation in animals exposed to FCA. BALB/c mice received either saline or FCA in doses 10-50 ul and were euthanized from one to three days after infection. Interleukins (IL) IL-2, IL-4 and tumor necrosis factor alpha (TNF-alpha) were determined in plasma. Ferric reducing antioxidant power (FRAP), malondialdehyde by thiobarbituric acid reactive substances assay (TBARS), reduced glutathione (GSH) and caspase-3 were measured in livers, muscles and other organs. We determined significant effect of FCA on TBARS and GSH in the livers. Beside this, TBARS were altered in muscles as well. Inflammation was confirmed by increased level of TNF-alpha. Taking the results into account, we infer that the harmful effect of FCA is mediated not only by inflammation but also by oxidative. This should be considered when pathological consequences of FCA are scored. PMID- 27215963 TI - Construction of a Hep-2 cell line stably transfected with Livin shRNA. AB - OBJECTIVE: The aim of this study was to construct a eukaryotic expression plasmid with a short hairpin RNA (shRNA) targeting Livin in order to obtain a stably transfected Hep-2 cell line with a reduced expression of Livin. METHODS: The shRNA targeting Livin mRNA was designed, and a shRNA plasmid and a negative control plasmid were constructed. After amplification in E. coli, restriction endonuclease digestion and sequence confirmation, the plasmids were transfected into Hep-2 cells using Lipofectamine 2000. The stably transfected cell line was screened using G418, and inhibition of Livin mRNA and protein levels were detected using real-time PCR and western blotting, respectively. RESULTS: pGenesil-Livin-shRNA eukaryotic expression plasmid was successfully constructed and identified by sequencing. Green fluorescent protein (GFP) expression was observed in Hep-2 cells transfected with shRNA plasmids by fluorescence microscopy. The expression levels of Livin mRNA and protein decreased significantly in Hep-2 cells transfected with the shRNA recombinant plasmid. The mRNA level was reduced by 47.17 %, and the protein level was reduced by 34.25 %. CONCLUSION: The shRNA eukaryotic expression plasmid targeting Livin was successfully constructed, which could significantly inhibit the expression of Livin in laryngeal cancer Hep-2 cells. This provides a basis for future research on the function of Livin in Hep-2 cells, and gene therapy for laryngeal cancer. PMID- 27215964 TI - The effects of caffeic acid phenethyl ester on streptozotocin-induced diabetic liver injury. AB - The aim of the present study was to clarify the role of oxidative stress in streptozotocin induced liver injury and the possible protective effect of caffeic acid phenethyl ester (CAPE) using histological and biochemical parameters. 32 male Wistar rats were divided into 4 groups as follows: Group 1: Control animals, Group 2: Control animals given CAPE Group 3: STZ-induced diabetic animals (DM group), Group 4: STZ-induced diabetic rats given CAPE (DM+CAPE group). All the injections started on the same day of single-dose STZ injection and continued for 20 days. At the end of this period, livers were removed and processed for routine histological procedures. Biochemical parameters and morphological changes were examined. In DM group, blood glucose levels were significantly increased compared with the control group. Significant increases in tissue malondialdehyde (MDA) level and decreases in superoxide dismutase (SOD) and total glutathione (GSH) activities were detected in DM group. Administration of CAPE significantly reduced these values. STZ-induced histopathological alterations including inflammatory cell infiltration around portal triad, congestion, loss of glycogen in the hepatocytes. Additionally, degenerative cellular alterations, such as numerous vacuolizations including myelinic figure formation, pyknotic nuclei with peripheral localization of heterochromatin condensation and mitochondrial elongation were observed in cytoplasm of hepatocytes. CAPE significantly reduced these histopathological changes. Our results indicate that CAPE should be considered in the prevention of oxidative stress in diabetic liver. PMID- 27215965 TI - Delineating the antigenotoxic and anticytotoxic potentials of 4-methylimidazole against ethyl methanesulfonate toxicity in bone marrow cell of swiss albino mice. AB - 4-Methylimidazole (4-MEI) is mostly used in beverages and coloring food, dark beers and common brands of cola drinks, which may contain more than 100 MUg of this compound per 12-ounce serving. This study was aimed to investigate the antigenotoxic and anticytotoxic effects of 4-MEI (100, 130 and 160 mg/kg) against ethyl methanesulfonate (240 mg/kg) using chromosome aberrations (CAs) and Mitotic index (MI) tests in bone marrow cells of Swiss Albino Mice at 12 h and 24 h treatment periods. So, the t-test was used for the statistical analysis.In this research, 4-MEI at all concentrations for 12 h treatment period reduced chromosomal aberrations and at 130 and 160 mg/kg concentrations for 24 h treatment period increased chromosomal aberrations induced by EMS (240 mg/kg), but th ese reductions and increases were not significant. Also, intraperitoneal injection of 4-MEI at doses of 100, 130 and 160 mg/kg combined with EMS (240 mg/kg) showed that the mitotic index was decreased at 100 and 130 mg/kg for 12h and 130 mg/kg for 24 h treatment periods, when compared to positive sample (EMS), but did not show any statistically difference from the EMS treated group. It can be concluded that 4-MEI might not be antigenotoxic and protective effects in bone marrow cells of Swiss Albino Mice, because 4-MEI could not reduce the chromosomal aberrations induced by EMS. PMID- 27215966 TI - Investigation of histopathological effects after intra-arterial sugammadex injection in an experimental animal model. AB - PURPOSE: Intra-arterial injection of medications are related to mortality and morbidity. It was aimed to investigate the histopathological effects caused by two different intra-arterial doses of sugammadex, a new selective relaxant binding agent used to reverse the effects of steroidal systemic muscle relaxants used in surgeries carried out under general anesthesia. METHODS: A total of 15 rabbits were randomly divided into 3 groups. The control group was given 1 mL saline bolus into the central artery of the ear. The other two groups (Group Sgdx2 and group Sgdx16) were given 2 and 16 mg/kg sugammadex, respectively, intra arterially. RESULTS: In control group, histopathological evaluation was in normal limits. The cross-sections belonging to Group Sgdx2 did not have any significant pathological change compared with control group (p > 0.05). Edema and single-cell necrosis were significantly higher in Group Sgdx16 when compared to control group (p < 0.05). In comparison to Group Sgdx2, single-cell necrosis was significantly higher in Group Sgdx16 (p < 0.05). CONCLUSION: Being broadly used in anesthesia, sugammadex should be administered with care because when given by intra-arterial route it may cause tissue damage and tissue loss and the patients' arteries should be carefully checked. PMID- 27215967 TI - Orbital phlegmona from upper eyelid chalazion. PMID- 27215969 TI - Plant Diseases and Management Approaches in Organic Farming Systems. AB - Organic agriculture has expanded worldwide. Numerous papers were published in the past 20 years comparing plant diseases in organic and conventional crops. Root diseases are generally less severe owing to greater soil health, whereas some foliar diseases can be problematic in organic agriculture. The soil microbial community and nitrogen availability play an important role in disease development and yield. Recently, the focus has shifted to optimizing organic crop production by improving plant nutrition, weed control, and plant health. Crop-loss assessment relating productivity to all yield-forming and -reducing factors would benefit organic production and sustainability evaluation. PMID- 27215968 TI - Influence of glycemic index and glycemic load of the diet on the risk of overweight and adiposity in childhood. AB - OBJECTIVE: To investigate the association between the glycemic index and the glycemic load of the diet with the risk of overweight and high adiposity in children with 5 years of age. METHODS: Cross-sectional study nested in a cohort of 232 children born and living in Diamantina (MG, Brazil). Parents and/or guardians provided the food intake data, using a semiquantitative food frequency questionnaire, past history and socioeconomic conditions. Anthropometric and fatness data were collected from the children. The dietary glycemic index and the glycemic load were calculated from the food intake. The glycemic index and glycemic load effect on overweight and adiposity in children was assessed by the Poisson regression (p<0.05). RESULTS: The prevalence of overweight by body mass index was 17.3%, and high adiposity was observed in 3.4% and 6.9% by triceps skinfold and subscapular skinfold, respectively. No difference was reported between the mean body mass index, triceps skinfold and subscapular skinfold according to the glycemic index and glycemic load tertiles; however, the overweight group presented a higher carbohydrate intake (p=0.04). No association was found between glycemic index and glycemic load with overweight and adiposity among the children assessed. CONCLUSIONS: The glycemic index and glycemic load of the diet were not identified as risk factors for overweight and adiposity in this cross-sectional study. PMID- 27215970 TI - Cladosporium fulvum Effectors: Weapons in the Arms Race with Tomato. AB - In this review, I recount my personal history. My drive to study host-pathogen interactions was to find alternatives for agrochemicals, which was triggered after reading the book "Silent Spring" by Rachel Carson. I reflect on my research at the Laboratory of Phytopathology at Wageningen University, where I have worked for my entire career on the interaction between Cladosporium fulvum and tomato, and related gene-for-gene pathosystems. I describe different methods used to identify and sequence avirulence (Avr) genes from the pathogen and resistance (R) genes from the host. The major genes involved in classical gene-for-gene interactions have now been identified, and breeders can produce plants with multiple R genes providing durable and environmentally safe protection against pathogens. In some cases, this might require the use of genetically modified plants when R genes cannot be introduced by classical breeding. PMID- 27215971 TI - Root Border Cells and Their Role in Plant Defense. AB - Root border cells separate from plant root tips and disperse into the soil environment. In most species, each root tip can produce thousands of metabolically active cells daily, with specialized patterns of gene expression. Their function has been an enduring mystery. Recent studies suggest that border cells operate in a manner similar to mammalian neutrophils: Both cell types export a complex of extracellular DNA (exDNA) and antimicrobial proteins that neutralize threats by trapping pathogens and thereby preventing invasion of host tissues. Extracellular DNases (exDNases) of pathogens promote virulence and systemic spread of the microbes. In plants, adding DNase I to root tips eliminates border cell extracellular traps and abolishes root tip resistance to infection. Mutation of genes encoding exDNase activity in plant-pathogenic bacteria (Ralstonia solanacearum) and fungi (Cochliobolus heterostrophus) results in reduced virulence. The study of exDNase activities in plant pathogens may yield new targets for disease control. PMID- 27215973 TI - Asymmetric synthesis of crambescin A-C carboxylic acids and their inhibitory activity on voltage-gated sodium channels. AB - Synthesis of both enantiomers of crambescin B carboxylic acid is described. A cis enyne starting material was epoxidized under the conditions of Katsuki asymmetric epoxidation to give 95% ee of the epoxide, which was transformed to crambescin B carboxylic acid via bromocation-triggered cascade cyclization as the key step. Enantiomerically pure crambescin A and C carboxylic acids were also synthesized from the product of the cascade reaction. Structure-activity relationship (SAR) studies against voltage-gated sodium channel (VGSC) inhibition using those synthetic compounds revealed that the natural enantiomer of crambescin B carboxylic acid was most active and comparable to tetrodotoxin, and the unalkylated cyclic guanidinium structure is indispensible, while the carboxylate moiety is not important. The absolute stereochemistry of crambescin A was determined by a comparison of the methyl ester derived from natural crambescin A with that derived from the stereochemically defined crambescin A carboxylic acid synthesized in this study. PMID- 27215972 TI - Management of atypical femoral fracture: a scoping review and comprehensive algorithm. AB - BACKGROUND: Atypical femoral fractures (AFF) are a rare type of femoral stress fracture recently described, potentially associated with prolonged bisphosphonate therapy. Evidence-based recommendations regarding diagnosis and management of these fractures are scarce. The purpose of this study is to propose an algorithm for the diagnosis and management of AFF. METHODS: We performed a PubMed search of the last ten years using the keywords "atypical femoral fractures" and identified further articles through an evaluation of the publications cited in these articles. Relevant studies were included by agreement between researchers, depending on their specialization. Pertinent points of debate were discussed based on the available literature, allowing for consensus regarding the proposed management algorithm. RESULTS: Using a systematic approach we performed a scoping review that included a total of 137 articles. CONCLUSIONS: A practical guide for diagnosis and management of AFF based on the current concepts is proposed. In spite of the impressive large volume of published literature available since AFF were initially identified, the level of evidence is mostly poor, in particular regarding treatment choice. Therefore, further studies are required. PMID- 27215974 TI - The Relationship between Co-rumination and Internalizing Problems: A Systematic Review and Meta-analysis. AB - : Co-rumination refers to the process of engaging in repeated discussion of personal problems in dyadic relationships. The current systematic review and meta analysis provided an evaluation of the relationship between co-rumination and internalizing problems in children, adolescents and young adults, along with an investigation of potential moderator variables. Studies were eligible for inclusion if they quantitatively assessed the relationship between co-rumination and depression, anxiety and/or internalizing problems using validated measures. An electronic search was conducted in PsycINFO, PsycARTICLES, Medline, Scopus and the Cochrane Library database of systematic reviews for studies published since 2002. In addition, unpublished studies were located by contacting authors in the field and by online searches of dissertation databases. Thirty-eight studies were deemed eligible for inclusion comprising a total of 12 829 community-based participants. A random-effects model was employed in the analysis, and effect sizes were obtained exclusively from cross-sectional data. Small to moderate effect sizes were found across four outcomes representing internalizing problems (mean corrected correlation range 0.14 to 0.26), with no significant variability across these variables. Female participants were found to score significantly higher on measures of co-rumination compared with males (d = -0.55). Moderator analyses revealed mixed findings. No significant effects were found for age, gender or publication status. A significant effect was found for co-rumination questionnaire version used (p = 0.05), and a marginal effect found for co rumination partner (same-sex best friend versus other confidants; p = 0.08). These findings indicate that co-rumination may have a modest but significant association with internalizing problems. The implications of these findings and directions for further research are discussed. Copyright (c) 2016 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Co-rumination has maladaptive (repetitive, unproductive discussion of problems) components, but also shows an association with friendship satisfaction. The current review found that co-rumination has small-moderate association with depression and anxiety. Practitioners should be aware of the way in which people discuss affective distress with others. PMID- 27215975 TI - A One-Day-Old Girl With Neutropenia. PMID- 27215976 TI - Effects on health-related quality of life in patients treated with lurasidone for bipolar depression: results from two placebo controlled bipolar depression trials. AB - BACKGROUND: Depressive symptoms associated with bipolar disorder negatively impact health-related quality of life (HRQoL). The efficacy of lurasidone in reducing depressive symptoms has been previously demonstrated. The objective of this study was to examine the direct and indirect effect (mediated through improvement in depression symptoms) of lurasidone in improving patient HRQoL. METHODS: A secondary analysis of data was conducted of two 6-week, double-blind, placebo-controlled trials assessing the effect of lurasidone (lurasidone monotherapy [20-60 mg/day or 80-120 mg/day]; lurasidone adjunctive to lithium or valproate [20-120 mg/day]) in patients with bipolar depression. Patient HRQoL was measured using the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q SF). Depression symptoms were measured using the Montgomery-Asberg Depression Rating Scale (MADRS). Analysis of covariance (ANCOVA) was used to estimate the effect of lurasidone on improvement in the Q-LES-Q SF percentage maximum score from baseline to 6 weeks. Path analysis was used to evaluate the total effect (beta1), as well as the indirect (beta2*beta3) and direct (beta4) effect of lurasidone on Q-LES-Q SF change through improvements in MADRS. RESULTS: A total of 340 and 485 patients from the monotherapy and adjunctive therapy, respectively, were included in the analysis. At 6-weeks, ANCOVA analyses demonstrated that lurasidone provided significant improvement in adjusted mean Q LES-Q SF scores in comparison to placebo for monotherapy (22.9 and 22.7 vs. 15.2, both p < 0.01) and adjunctive therapy (23.1 vs. 17.9, p = 0.01). Path analyses indicated that lurasidone treatment predicted MADRS improvement (monotherapy: beta2 = -0.44, p < 0.001; adjunctive therapy: beta2 = -0.34, p = 0.003), which subsequently predicted improvement in Q-LES-Q SF (monotherapy: beta3 = -0.73, p < 0.001; adjunctive therapy: beta3 = -0.75, p < 0.001); however, the effect of lurasidone on improvement in Q-LES-Q SF was largely mediated by change in MADRS (monotherapy: beta4 = 0.11, p = 0.13; adjunctive therapy: beta4 = 0.02, p = 0.77). CONCLUSIONS: Lurasidone as a monotherapy and adjunctive to lithium or valproate is an effective treatment for improving HRQoL in patients with bipolar depression. However, improvement in HRQoL was not independent of improvement in depression, indicating that the effect of lurasidone on improving patient HRQoL may act through a reduction in depressive symptoms associated with bipolar disorder. TRIAL REGISTRATION: Clinicaltrials.gov identifiers: NCT00868699 and NCT00868452 (both registered March 23, 2009). PMID- 27215977 TI - miRNA-dependent target regulation: functional characterization of single nucleotide polymorphisms identified in genome-wide association studies of Alzheimer's disease. AB - BACKGROUND: A growing body of evidence suggests that microRNAs (miRNAs) are involved in Alzheimer's disease (AD) and that some disease-associated genetic variants are located within miRNA binding sites. In the present study, we sought to characterize functional polymorphisms in miRNA target sites within the loci defined in earlier genome-wide association studies (GWAS). The main objectives of this study were to (1) facilitate the identification of the gene or genes responsible for the GWAS signal within a locus of interest and (2) determine how functional polymorphisms might be involved in the AD process (e.g., by affecting miRNA-mediated variations in gene expression). METHODS: Stringent in silico analyses were developed to select potential polymorphisms susceptible to impairment of miRNA-mediated repression, and subsequent functional assays were performed in HeLa and HEK293 cells. RESULTS: Two polymorphisms were identified and further analyzed in vitro. The AD-associated rs7143400-T allele (located in 3' untranslated region [3'-UTR] of FERMT2) cotransfected with miR-4504 resulted in lower protein levels relative to the rs7143400-G allele cotransfected with the same miRNA. The AD-associated rs9909-C allele in the 3'-UTR of NUP160 abolished the miR-1185-1-3p-regulated expression observed for the rs9909-G allele. CONCLUSIONS: When considered in conjunction with the findings of previous association studies, our results suggest that decreased expression of FERMT2 might be a risk factor in the etiopathology of AD, whereas increased expression of NUP160 might protect against the disease. Our data therefore provide new insights into AD by highlighting two new proteins putatively involved in the disease process. PMID- 27215978 TI - A genomic screen for long noncoding RNA genes epigenetically silenced by aberrant DNA methylation in colorectal cancer. AB - Long noncoding RNAs (lncRNAs) have emerged as key components in multiple cellular processes, although their physiological and pathological functions are not fully understood. To identify cancer-related lncRNAs, we screened for those that are epigenetically silenced in colorectal cancer (CRC). Through a genome-wide analysis of histone modifications in CRC cells, we found that the transcription start sites (TSSs) of 1,027 lncRNA genes acquired trimethylation of histone H3 lysine 4 (H3K4me3) after DNA demethylation. Integrative analysis of chromatin signatures and the DNA methylome revealed that the promoter CpG islands (CGIs) of 66 lncRNA genes contained cancer-specific methylation. By validating the expression and methylation of lncRNA genes in CRC cells, we ultimately identified 20 lncRNAs, including ZNF582-AS1, as targets of epigenetic silencing in CRC. ZNF582-AS1 is frequently methylated in CRC cell lines (87.5%), primary CRCs (77.2%), colorectal adenomas (44.7%) and advanced adenomas (87.8%), suggesting that this methylation is an early event during colorectal tumorigenesis. Methylation of ZNF582-AS1 is associated with poor survival of CRC patients, and ectopic expression of ZNF582-AS1 suppressed colony formation by CRC cells. Our findings offer insight into the association between epigenetic alterations and lncRNA dysregulation in cancer and suggest that ZNF582-AS1 may be a novel tumor suppressive lncRNA. PMID- 27215979 TI - Periodontal diseases and risk of oral cancer in Southern India: Results from the HeNCe Life study. AB - Some studies suggest that periodontal diseases increase the risk of oral cancer, but contradictory results also exist. Inadequate control of confounders, including life course exposures, may have influenced prior findings. We estimate the extent to which high levels of periodontal diseases, measured by gingival inflammation and recession, are associated with oral cancer risk using a comprehensive subset of potential confounders and applying a stringent adjustment approach. In a hospital-based case-control study, incident oral cancer cases (N = 350) were recruited from two major referral hospitals in Kerala, South India, from 2008 to 2012. Controls (N = 371), frequency-matched by age and sex, were recruited from clinics at the same hospitals. Structured interviews collected information on several domains of exposure via a detailed life course questionnaire. Periodontal diseases, as measured by gingival inflammation and gingival recession, were evaluated visually by qualified dentists following a detailed protocol. The relationship between periodontal diseases and oral cancer risk was assessed by unconditional logistic regression using a stringent empirical selection of potential confounders corresponding to a 1% change-in estimates. Generalized gingival recession was significantly associated with oral cancer risk (Odds Ratio = 1.83, 95% Confidence Interval: 1.10-3.04). No significant association was observed between gingival inflammation and oral cancer. Our findings support the hypothesis that high levels of periodontal diseases increase the risk of oral cancer. PMID- 27215980 TI - Neurotransmissional, structural, and conduction velocity changes in cerebral ganglions of Lumbricus terrestris on exposure to acrylamide. AB - Acrylamide (ACR), an environmental toxin though being investigated for decades, remains an enigma with respect to its mechanism/site of actions. We aim to explicate the changes in cerebral ganglions and giant fibers along with the behavior of worms on ACR intoxication (3.5-17.5 mg/mL of medium/7 days). Neurotransmitter analysis revealed increased levels of excitatory glutamate and inhibitory gamma amino butyrate with reduced levels of dopamine, serotonin, melatonin, and epinephrine (p < 0.001). Scanning electron microscopy showed architectural changes in cerebral ganglions at 3.5 mg/mL/ACR. The learning behavior as evidenced by Pavlovian and maze tests was also altered well at 3.5 mg/mL of ACR. Electrophysiological assessment showed a reduction in conduction velocity of the medial and lateral giant nerve fibers. We speculate that the observed dose/time-dependent changes in neurotransmission, neurosecretion, and conduction velocity on ACR intoxication at 17.5 mg/ml, possibly, could be due to its effect on nerve fibers governing motor functions. The bioaccumulation factor in the range of 0.38-0.99 mg/g of ACR causes a detrimental impact on giant fibers affecting behavior of worm. The observations made using the simple invertebrate model implicate that the cerebral ganglionic variations in the worms may be useful to appreciate the pathology of the neurological diseases which involve motor neuron dysfunction, esp where the availability of brain samples from the victims are scarce. PMID- 27215981 TI - Effect of progressive drought stress on growth, leaf gas exchange, and antioxidant production in two maize cultivars. AB - Drought stress is one of the major environmental factors responsible for reduction in crop productivity. In the present study, responses of two maize cultivars (Rung Nong 35 and Dong Dan 80) were examined to explicate the growth, yield, leaf gas exchange, leaf water contents, osmolyte accumulation, membrane lipid peroxidation, and antioxidant activity under progressive drought stress. Maize cultivars were subjected to varying field capacities (FC) viz., well watered (80 % FC) and drought-stressed (35 % FC) at 45 days after sowing. The effects of drought stress were analyzed at 5, 10, 15, 20, ad 25 days after drought stress (DAS) imposition. Under prolonged drought stress, Rung Nong 35 exhibited higher reduction in growth and yield as compared to Dong Dan 80. Maize cultivar Dong Dan 80 showed higher leaf relative water content (RWC), free proline, and total carbohydrate accumulation than Run Nong 35. Malondialdehyde (MDA) and superoxide anion were increased with prolongation of drought stress, with higher rates in cultivar Run Nong 35 than cultivar Dong Dan 80. Higher production of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) and glutathione reductase (GR) resulted in improved growth and yield in Dong Dan 80. Overall, the cultivar Dong Dan 80 was better able to resist the detrimental effects of progressive drought stress as indicated by better growth and yield due to higher antioxidant enzymes, reduced lipid peroxidation, better accumulation of osmolytes, and maintenance of tissue water contents. PMID- 27215982 TI - Environmental evaluation of dredged sediment submitted to a solidification stabilization process using hydraulic binders. AB - PURPOSE: Dredging of sediments, a requirement for harbor maintenance, removes millions of tons of mineral wastes, contaminated at varying degrees with trace metals, from the water. In previous investigations, Cu and Zn have been identified as highly concentrated trace metals associated to sulfides, mineral phases sensitive to oxidation. In order to ensure their sustainable management, the solidification/stabilization (S/S) and/or the valorization of contaminated sediments as secondary raw materials is a way to be promoted. Indeed, their reuse as a substitute of sand in cemented mortar formulation would allow combining both treatment and valorization of such wastes. METHODS: In the present study, the environmental assessment of mortars formulated with raw and weathered marine sediments (in particular contaminated with Cu, Pb and Zn), compared to sand reference mortars, was conducted through two kinetic leaching tests: weathering cell tests (WCTs), in which mortars were crushed and leached twice a week, and a tank monolith leaching test (MLT), in which leaching was performed on monolithic mortars with increasing leachate renewal time. RESULTS: In both leaching tests, calcium and sulfur were released continuously from sediment mortars, showing the oxidation-neutralization processes of sulfides and carbonates. In the MLT, Cu was released by sediment mortars through diffusion, particularly by weathered mortars, at low concentrations during 60 days of the test duration. With the more aggressive WCT, Cu concentrations were higher at the beginning but became negligible after 7 days of testing. Pb was released through diffusion mechanisms until depletion in both tests, whereas Zn was particularly well immobilized in the cemented matrices. CONCLUSIONS: The S/S process applied using hydraulic binders proved to be efficient in the stabilization of Cu, Pb, and Zn highly presents in studied sediments, and further valorization in civilian engineering applications could be considered. PMID- 27215983 TI - Biodegradability of the anticancer drug etoposide and identification of the transformation products. AB - Etoposide susceptibility to microbiological breakdown was studied in a batch biotransformation system, in the presence or absence of artificial wastewater containing nutrients, salts and activated sludge at two concentration levels. The primary focus of the present study was to study etoposide transformation products by ultra-high performance liquid chromatography coupled to high-resolution hybrid quadrupole-Orbitrap tandem mass spectrometry (MS/MS). Data-dependent experiments combining full-scan MS data with product ion spectra were acquired to identify the molecular ions of etoposide transformation products, to propose the molecular formulae and to elucidate their chemical structures. Due to the complexity of the matrix, visual inspection of the chromatograms showed no clear differences between the controls and the treated samples. Therefore, the software package MZmine was used to facilitate the identification of the transformation products and speed up the data analysis. In total, we propose five transformation products; among them, four are described as etoposide transformation products for the first time. Even though the chemical structures of these new compounds cannot be confirmed due to the lack of standards, their molecular formulae can be used to target them in monitoring studies. PMID- 27215985 TI - Nitrogen oxides and ozone in Portugal: trends and ozone estimation in an urban and a rural site. AB - This study provides an analysis of the spatial distribution and trends of NO, NO2 and O3 concentrations in Portugal between 1995 and 2010. Furthermore, an estimation model for daily ozone concentrations was developed for an urban and a rural site. NO concentration showed a significant decreasing trend in most urban stations. A decreasing trend in NO2 is only observed in the stations with less influence from emissions of primary NO2. Several stations showed a significant upward trend in O3 as a result of the decrease in the NO/NO2 ratio. In the northern rural region, ozone showed a strong correlation with wind direction, highlighting the importance of long-range transport. In the urban site, most of the variance is explained by the NO2/NOX ratio. The results obtained by the ozone estimation model in the urban site fit 2013 observed data. In the rural site, the estimated ozone during extreme events agrees with observed concentration. PMID- 27215984 TI - Distribution, sources, and ecological risk assessment of polycyclic aromatic hydrocarbons in the water and suspended sediments from the middle and lower reaches of the Yangtze River, China. AB - Samples were collected from the middle and lower reaches of the Yangtze River, China, to study the concentrations, distributions, and compositions of 16 US-EPA priority polycyclic aromatic hydrocarbons (PAHs) in water and suspended particulate matter (SPM). We also evaluated sources of the PAHs and their potential toxicity. Total concentrations of the PAHs (SigmaPAHs) in water ranged from 17.33 to 77.12 ng L(-1), and in SPM, the levels ranged from 595.91 to 2473.74 ng g(-1). Total concentrations of seven carcinogenic PAHs (SigmaCPAHs) ranged from 7.63 to 13.02 ng L(-1) in water and 276.55 to 1216.89 ng g(-1) in SPM. PAH levels in water samples were relatively low, and those in the lower reaches were higher than in the middle reaches. SPM samples had higher levels of PAHs, especially in the lower reaches and in Dongting Lake and Poyang Lake. Principal component analysis (PCA) with multiple linear regression analysis (MLR) was performed to quantitatively characterize the PAH sources. Two factors and their contributions were identified from water samples. Coal and wood combustion accounted for 74.1 % of the PAHs, and petroleum emissions explained 25.9 % of the PAHs. Three source factors were identified from SPM samples: these were vehicular emissions (46.3 % of PAHs), wood and coal combustion (40.4 % of PAHs), and petrogenic sources (13.3 %). Ecological risk assessment indicated that a moderate undesirable impact will be caused by PAHs, and some control measures and remedial actions should be conducted. PMID- 27215986 TI - Trace metals dynamics under contrasted land uses: contribution of statistical, isotopic, and EXAFS approaches. AB - Three sub-basins of the Seine River (France) under contrasted land uses (i.e., forested, agricultural, and urban) have been investigated in order to assess the origin and seasonal variation of trace metals, and evaluate their geochemical background and dynamics. Our results highlight a high anthropogenic impact on all elements for both the dissolved and particulate fractions. The main source for each element in the dissolved phase was determined and shows that transition and post-transition metals mainly originate from forested areas, while alkali and alkaline earth elements, metalloids, and halogens rather originate from agricultural land use. Conversely, for the particulate phase, most of the elements cannot be associated with a specific land use. Seasonal variation of elements was assessed according to the forested and agricultural land uses, and geochemical backgrounds were determined using average export rates, highlighting that the geochemical background for the forested land use is higher than the agricultural one for most of the elements. Finally, to confirm those results, Zn dynamics in the three characteristic sub-basins and between the different land uses was investigated using a combination of Zn speciation, Zn isotopic ratio, and Zn export rates. PMID- 27215987 TI - Photocatalytic degradation of an emerging pollutant by TiO2-coated glass rings: a kinetic study. AB - This work presents the photocatalytic degradation of the pharmaceutical drug clofibric acid in a fixed-bed reactor filled with TiO2-coated glass rings. Experiments were carried out under UV radiation. A kinetic model that takes into account radiation absorption by means of the local surface rate of photon absorption (LSRPA) has been developed. The LSRPA was obtained from the results of a radiation model. The Monte Carlo method was employed to solve the radiation model, where the interaction between photons and TiO2-coated rings was considered. Data from experiments carried out with rings with different numbers of catalyst coatings and different irradiation levels were used to estimate the parameters of the kinetic model. A satisfactory agreement was obtained between model simulations and experimental results. PMID- 27215988 TI - Influence of suspended particles on the emission of organophosphate flame retardant from insulation boards. AB - The influence of the presence of the so-called seed particles on the emission rate of Tris (1-chloroisopropyl) phosphate (TCIPP) from polyisocyanurate (PIR) insulation boards was investigated in this study. Two Field and Laboratory Emission Test cells (FLEC) were placed on the surface of the same PIR board and respectively supplied with clean air (reference FLEC) and air containing laboratory-generated soot particles (test FLEC). The behavior of the area specific emission rates (SER A ) over a time period of 10 days was studied by measuring the total (gas + particles) concentrations of TCIPP at the exhaust of each FLEC. The estimated SER A of TCIPP from the PIR board at the quasi-static equilibrium were found to be 0.82 MUg m(-2) h(-1) in the absence of seed particles, while the addition of soot particles led to SER A of 2.16 MUg m(-2) h( 1). This indicates an increase of the SER A of TCIPP from the PIR board with a factor of 3 in the presence of soot particles. The TCIPP partition coefficient to soot particles at the quasi-static equilibrium was 0.022 +/- 0.012 m(3) MUg(-1). In the next step, the influence of real-life particles on TCIPP emission rates was investigated by supplying the test FLEC with air from a professional kitchen where mainly frying and baking activities took place. Similar to the reference FLEC outcomes, SER A was also found to increase in this real-life experiment over a time period of 20 days by a factor 3 in the presence of particles generated during cooking activities. The median value of estimated particle-gas coefficient for this test was 0.062 +/- 0.037 m(3) MUg(-1). PMID- 27215989 TI - The fractionation and geochemical characteristics of rare earth elements measured in ambient size-resolved PM in an integrated iron and steelmaking industry zone. AB - Improved understanding of the fractionation and geochemical characteristic of rare earth elements (REEs) from steel plant emissions is important due to the unclear atmospheric signature of these elements and their adverse impact on human health and the environment. In this study, ambient particulate matter of different sizes was collected from one site in an integrated iron and steelmaking industrial zone (HG) and one urban background site with no direct industrial emissions (ZWY) during a 1-year sampling campaign in China. The total concentrations of REEs for TSP, PM10, and PM2.5 were 27.248, 14.989, 3.542 ng/m(3) in HG and 6.326, 5.274, 1.731 ng/m(3), respectively, in ZWY, which revealed the local influence of the steelmaking activities to the air quality. With respect to ZWY, the REEs in HG site are obviously fractionated in the coarser fraction, and LREEs account for more than 80 % of the total REE burden in all of the samples. Additionally, the REEs in HG and ZWY show a homogeneous trend with successively increased LREE/HREE ratios from the coarse particles to the fine particles. In our samples, La, Ce, Nd, and Sm are the most enriched rare earth elements, especially in the HG site. Moreover, ternary diagrams of LaCeSm indicate that the REEs in HG are potentially contributed by steelworks, carrier vehicles, coal combustion, and road dust re-suspension. PMID- 27215990 TI - Influence of permeability on nanoscale zero-valent iron particle transport in saturated homogeneous and heterogeneous porous media. AB - Nanoscale zero-valent iron (NZVI) particles can be used for in situ groundwater remediation. The spatial particle distribution plays a very important role in successful and efficient remediation, especially in heterogeneous systems. Initial sand permeability (k 0) influences on spatial particle distributions were investigated and quantified in homogeneous and heterogeneous systems within the presented study. Four homogeneously filled column experiments and a heterogeneously filled tank experiment, using different median sand grain diameters (d 50), were performed to determine if NZVI particles were transported into finer sand where contaminants could be trapped. More NZVI particle retention, less particle transport, and faster decrease in k were observed in the column studies using finer sands than in those using coarser sands, reflecting a function of k 0. In heterogeneous media, NZVI particles were initially transported and deposited in coarse sand areas. Increasing the retained NZVI mass (decreasing k in particle deposition areas) caused NZVI particles to also be transported into finer sand areas, forming an area with a relatively homogeneous particle distribution and converged k values despite the different grain sizes present. The deposited-particle surface area contribution to the increasing of the matrix surface area (theta) was one to two orders of magnitude higher for finer than coarser sand. The dependency of theta on d 50 presumably affects simulated k changes and NZVI distributions in numerical simulations of NZVI injections into heterogeneous aquifers. The results implied that NZVI can in principle also penetrate finer layers. PMID- 27215991 TI - Characteristics of Hospitalizations for Heart Failure with Preserved Ejection Fraction. AB - BACKGROUND: Hospitalizations for heart failure with preserved ejection fraction (HFpEF) are increasing. There are limited data examining national trends in patients hospitalized with HFpEF. METHODS: Using the Nationwide Inpatient Sample, we examined 5,046,879 hospitalizations with a diagnosis of acute heart failure in 2003-2012, stratifying hospitalizations by HFpEF and heart failure with reduced ejection fraction (HFrEF). Patient and hospital characteristics, in-hospital mortality, and length of stay were examined. RESULTS: Compared with HFrEF, those with HFpEF were older, more commonly female, and more likely to have hypertension, atrial fibrillation, chronic lung disease, chronic renal failure, and anemia. Over time, HFpEF comprised increasing proportions of men and patients aged >=75 years. In-hospital mortality rate for HFpEF decreased by 13%, largely due to improved survival in those aged >=65 years. Multivariable regression analyses showed that pulmonary circulation disorders, liver disease, and chronic renal failure were independent predictors of in-hospital mortality, whereas treatable diseases including hypertension, coronary artery disease, and diabetes were inversely associated. CONCLUSIONS: This study represents the largest cohort of patients hospitalized with HFpEF to date, yielding the following observations: number of hospitalizations for HFpEF was comparable with that of HFrEF; patients with HFpEF were most often women and elderly, with a high burden of comorbidities; outcomes appeared improved among a subset of patients; pulmonary hypertension, liver disease, and chronic renal failure were strongly associated with poor outcomes. PMID- 27215992 TI - Antivenom Costs Show Need for Education and Collaborative Efforts. PMID- 27215993 TI - The Reply. PMID- 27215994 TI - Pheidippides Redux Revisited. PMID- 27215995 TI - The Reply. PMID- 27215996 TI - Value of ST-Segment Elevation in Lead aVR for Predicting Severe Left Main or 3 Vessel Disease. PMID- 27215997 TI - The Reply. PMID- 27215998 TI - Electrocardiographic Diagnosis of Right Ventricular Infarction by Proximal Occlusion of a Very Dominant Right Coronary Artery. PMID- 27215999 TI - Periodic ventilation: Consequences for the bodily CO2 stores and gas exchange efficiency. AB - Using a mathematical model of CO2 transport, we investigated the underlying cause of why and to what extent periodic ventilation is less efficient for CO2 excretion/elimination compared to continuous/tidal ventilation leading to elevated CO2 stores unless mean alveolar minute ventilation () is elevated. The model predicts that the reduced efficiency of periodic ventilation is intrinsic to the sequential arrangement and differences in the relative storage capacities (product of size and CO2 capacitance coefficient) of the lungs, blood and tissues that leads to predominant blood and tissue storage during apnoeic periods. Consequently, overall CO2 transport becomes more prone to perfusion and diffusion limitation during periodic ventilation. At constant cardiac output (Q.) inefficiency will increase with the apnoeic duration (tap) concomitant with increasing blood and tissues CO2 storage and with the relative time spent apnoeic (tap/tcyc) due to increasing V.A/Q. mismatch. Conversely, temporal variation of Q. to better match V.A can reduce inefficiency radically. Thus such adjustment in blood flow is necessary for efficient CO2 elimination in periodic ventilation. PMID- 27216000 TI - The effect of cannabinoids on dinitrofluorobenzene-induced experimental asthma in mice. AB - Cannabinoids have anti-inflammatory effects and can produce bronchodilation in the airways. We have investigated the effects of cannabinoids on tracheal hyperreactivity and airway inflammation in dinitrofluorobenzene (DNFB)-induced experimental non-atopic asthma in mice. 5-hydroxytryptamine (5-HT)-induced contraction response was enhanced while carbachol- and electrical field stimulation-induced contractions, and isoprenaline-induced relaxation responses were remained unchanged in DNFB group. The increased 5-HT-induced contractions were inhibited by incubation with either atropine or tetrodotoxin. DNFB application resulted in increased macrophage number in the bronchoalveolar lavage fluid (BALF). In vivo ACEA (CB1 agonist) treatment prevented the increase in 5-HT contractions, while JWH133 (CB2 agonist) had no effect. However, neither ACEA nor JWH133 prevented the increase in macrophage number in BALF. In vitro ACEA incubation also inhibited the increase in 5-HT contraction in DNFB group. These results show that cannabinoid CB1 receptor agonist can prevent tracheal hyperreactivity to 5-HT in DNFB-induced non-atopic asthma in mice. PMID- 27216010 TI - Copper disrupts S-nitrosothiol signaling in activated BV2 microglia. AB - Microglia, the primary resident immune cells of the central nervous system (CNS), responds rapidly to pathogens and injury by secreting immune mediators including nitric oxide (NO). The reaction of NO with the anti-oxidant glutathione forms S nitrosoglutathione (GSNO), the major pool of biologic NO in the body. GSNO is degraded by GSNO reductase (GSNOR). Recently, we have shown that copper (Cu(I)) inhibits the release of NO in lipopolysaccharide (LPS)-stimulated BV2 microglia and induces BV2 microglia to acquire a mixed a profile with both pro- and anti inflammatory characteristics. Since GSNOR is the critical enzyme in GSNO metabolism, we sought to determine whether Cu(I) affects GSNOR activity and S nitrosothiol (SNO) accumulation in activated BV2 microglia. Our results show that GSNOR protein expression is reduced by Cu(I) treatment in LPS-stimulated BV2 microglia. Our results also show a decrease in S-nitrosothiol content despite a reduced GSNOR expression. This effect is most likely due to Cu(I) reacting with the central thiol of the SNO bond resulting in the degradation of SNO. A dose of 1 MUM Cu(I) did not affect SNO protein accumulation in LPS-stimulated BV2 microglia, however, a dose of 100 MUM Cu(I) inhibited SNO protein in accordance with inhibition of S-nitrosothiols. These data provide direct evidence that Cu(I) disrupts S-nitrosothiol homeostasis and NO metabolism, and, thus, provide new insights into the mechanisms involved in microglia-mediated-CNS disorders. PMID- 27216011 TI - Treatment of Locally Advanced Pancreatic Ductal Adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is increasingly common and a leading cause of cancer-related mortality. Surgery remains the only possibility for cure. Upwards of 40% of patients present with locally advanced PDAC (LA-PDAC), where management strategies continue to evolve. In this review, we highlight current trends in neoadjuvant chemotherapy, surgical resection, and other multimodality approaches for patients with LA-PDAC. Despite promising early results, additional work is needed to more accurately and appropriately tailor treatment for patients with LA-PDAC. PMID- 27216012 TI - Diabetes mellitus and pre-diabetes are frequently undiagnosed and underreported in patients referred for pancreatic surgery. A prospective observational study. AB - OBJECTIVE: Previous reports on the prevalence of diabetes in pancreatic cancer and chronic pancreatitis patients are based on inconsistent and equivocal criteria. The objective of this study is to prospectively assess with conclusive methods the preoperative glycaemic status of patients undergoing pancreatic surgery. We hypothesise that most of those patients are unaware of these disturbances in glycaemic status and that the prevalence is underestimated. METHODS: During the last 2 years, patients referred for pancreatic surgery and without history of diabetes underwent a prospective preoperative screening with an oral glucose tolerance test (OGTT) and determination of the glycated haemoglobin level (HbA1c). The American Diabetes Association's criteria for diabetes and pre-diabetes were used. Beta-cell function and insulin sensitivity were calculated using HOMA2 indices. Impact on surgical policy has been scored. RESULTS: 99 patients were screened, 25 had a history of diabetes. The other 74 underwent an OGTT and HbA1c determination. Only 29.7% (22/74) had a normal glucose metabolism, while 8.1% (6/74) had impaired fasting glucose, 21.6% (16/74) had impaired glucose tolerance, 6.7% (5/74) had a combination of both, and 33.8% (25/74) had undiagnosed diabetes. In 15.2% (15/99) of the patients, this preoperative assessment had an impact on surgical policy. CONCLUSIONS: 77.7% of patients referred for pancreatic surgery had some degree of (pre-)diabetes. In 70.3% of patients without a history of diabetes, these disturbances in glucose metabolism are a new finding. Physicians involved in pancreatic surgery should be aware of the frequently undiagnosed (pre-)diabetes and actively check for it. This prevalence is underestimated. PMID- 27216013 TI - Palaeolithic diet decreases fasting plasma leptin concentrations more than a diabetes diet in patients with type 2 diabetes: a randomised cross-over trial. AB - BACKGROUND: We have previously shown that a Palaeolithic diet consisting of the typical food groups that our ancestors ate during the Palaeolithic era, improves cardiovascular disease risk factors and glucose control compared to the currently recommended diabetes diet in patients with type 2 diabetes. To elucidate the mechanisms behind these effects, we evaluated fasting plasma concentrations of glucagon, insulin, incretins, ghrelin, C-peptide and adipokines from the same study. METHODS: In a randomised, open-label, cross-over study, 13 patients with type 2 diabetes were randomly assigned to eat a Palaeolithic diet based on lean meat, fish, fruits, vegetables, root vegetables, eggs and nuts, or a diabetes diet designed in accordance with current diabetes dietary guidelines during two consecutive 3-month periods. The patients were recruited from primary health-care units and included three women and 10 men [age (mean +/- SD) 64 +/- 6 years; BMI 30 +/- 7 kg/m(2); diabetes duration 8 +/- 5 years; glycated haemoglobin 6.6 +/- 0.6 % (57.3 +/- 6 mmol/mol)] with unaltered diabetes treatment and stable body weight for 3 months prior to the start of the study. Outcome variables included fasting plasma concentrations of leptin, adiponectin, adipsin, visfatin, resistin, glucagon, insulin, C-peptide, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1 and ghrelin. Dietary intake was evaluated by use of 4-day weighed food records. RESULTS: Seven participants started with the Palaeolithic diet and six with the diabetes diet. The Palaeolithic diet resulted in a large effect size (Cohen's d = -1.26) at lowering fasting plasma leptin levels compared to the diabetes diet [mean difference (95 % CI), -2.3 (-5.1 to 0.4) ng/ml, p = 0.023]. No statistically significant differences between the diets for the other variables, analysed in this study, were observed. CONCLUSIONS: Over a 3-month study period, a Palaeolithic diet resulted in reduced fasting plasma leptin levels, but did not change fasting levels of insulin, C peptide, glucagon, incretins, ghrelin and adipokines compared to the currently recommended diabetes diet. TRIAL REGISTRATION: ClinicalTrials.gov NCT00435240. PMID- 27216014 TI - Impact of recombinant Drosophila S2 cell population enrichment on expression of rabies virus glycoprotein. AB - Recombinant Drosophila S2 cells have been used for the expression of many proteins of medical interest. However, membrane-attached glycoproteins, which commonly exhibit lower expression levels compared to soluble proteins, may require special procedures in order to attain high levels of expression. In this study, two S2 cell population enrichment methods (antibiotic and immunomagnetic selection) were evaluated for their ability to enhance expression of the membrane anchored rabies virus glycoprotein (RVGP). Quantification of RVGP production and determination of its cDNA copy number in transformed cells showed that both enrichment methods increased RVGP expression without significantly affecting its gene copy number. More interestingly, RVGP mRNA levels measured after cycloheximide treatment were poorly correlated with glycoprotein levels. Both enrichment methods enhanced expression of RVGP by recombinant S2 cells, with the highest level of expression achieved using immunomagnetic selection. PMID- 27216015 TI - Patterning at the 10 nanometer length scale using a strongly segregating block copolymer thin film and vapor phase infiltration of inorganic precursors. AB - In this work, we demonstrate the use of self-assembled thin films of the cylinder forming block copolymer poly(4-tert-butylstyrene-block-2-vinylpyridine) to pattern high density features at the 10 nm length scale. This material's large interaction parameter facilitates pattern formation in single-digit nanometer dimensions. This block copolymer's accessible order-disorder transition temperature allows thermal annealing to drive the assembly of ordered 2 vinylpyridine cylinders that can be selectively complexed with the organometallic precursor trimethylaluminum. This unique chemistry converts organic 2 vinylpyridine cylinders into alumina nanowires with diameters ranging from 8 to 11 nm, depending on the copolymer molecular weight. Graphoepitaxy of this block copolymer aligns and registers sub-12 nm diameter nanowires to larger-scale rectangular, curved, and circular features patterned by optical lithography. The alumina nanowires function as a robust hard mask to withstand the conditions required for patterning the underlying silicon by plasma etching. We conclude with a discussion of some of the challenges that arise with using block copolymers for patterning at sub-10 nm feature sizes. PMID- 27216016 TI - Comparison of methods of steroid administration combined with tonsillectomy for IgA nephropathy patients. AB - BACKGROUND: IgA nephropathy (IgAN) is a chronic glomerular disease that causes end-stage renal disease in 20-40 % of patients within 20 years. The efficacy of tonsillectomy combined with steroid pulse (SP) administration (TSP) for clinical remission of IgAN has been reported. Particularly in Japan, TSP has been performed widely. However, the optimum method for steroid administration in TSP has not been established. METHODS: We retrospectively compared clinical remission in IgAN patients treated with tonsillectomy combined with two different steroid administration methods: (1) three courses of SP therapy and oral prednisolone administered on alternate days (group 3A; n = 25); and (2) one course of SP therapy and oral prednisolone administered on consecutive days (group 1C; n = 22). RESULTS: There was no significant difference in the clinical remission rates between the two groups at 12 (48.0 vs. 40.9 %, P = 0.77) and 24 months after starting treatment (68.0 vs. 72.7 %, P = 0.76) and at the final observation (76.0 vs. 81.8 %, P = 0.73). The mean period from starting treatment to remission of hematuria in group 3A was significantly shorter than that in group 1C (5.7 +/- 4.4 vs. 9.9 +/- 5.9 months, P = 0.03). Dyslipidemic patients treated for the first time with statin after the SP therapy were more present in group 3A at 24 months (P = 0.02). CONCLUSIONS: In IgAN patients, treatment of group 3A may be effective for inducing rapid remission of hematuria. Further studies are needed to establish an appropriate protocol for TSP. PMID- 27216017 TI - Mutation profile and treatment of Gitelman syndrome in Chinese patients. AB - BACKGROUND: Gitelman syndrome (GS) is a rare autosomal recessive disease caused by loss-of-function mutations in the SLC12A3 gene, and is characterized by hypokalemia and metabolic alkalosis. In this study, we aimed to study the genotype, phenotype, and treatment in 42 GS patients, the largest sample size so far in mainland China. METHOD: We retrospectively studied the clinical data and genetic characteristics of 42 patients diagnosed with GS in Peking Union Medical College Hospital from 2012 to 2015. Therapeutic efficacy of spironolactone and potassium supplements was also studied retrospectively. RESULTS: Eighty-one mutation alleles were found in 42 patients, and total of 52 distinctly different mutation alleles were identified, of which 15 were new mutation alleles. p.Asp486Asn was a hotspot in our series, with the allele frequency being 19.7 % (16/81), and was found in 13 patients (31.0 %). Treatment with spironolactone or potassium supplements alone significantly increased serum potassium concentration by 0.36 +/- 0.37 and 0.45 +/- 0.35 mmol/l, respectively (both P < 0.05), and combined therapy with spironolactone and potassium increased serum potassium concentration by 0.69 +/- 0.64 mmol/l (P < 0.05). CONCLUSIONS: 18.5 % (15/81) mutation sites identified in 42 Chinese GS patients are novel. p.Asp486Asn mutation is a hotspot, which is different from the reports from other countries. Spironolactone could moderately elevate serum potassium level, and spironolactone in combination with potassium supplements tended to be more effective. PMID- 27216018 TI - Hydromorphone for neuropathic pain in adults. AB - BACKGROUND: Opioid drugs, including hydromorphone, 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 hydromorphone, at any dose, and by any route of administration. Other opioids are considered in separate reviews.This review is part of an update of a previous review, Hydromorphone for acute and chronic pain that was withdrawn in 2013 because it needed updating and splitting to be more specific for different pain conditions. This review focuses only on neuropathic pain. OBJECTIVES: To assess the analgesic efficacy of hydromorphone 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), via the CRSO; MEDLINE via Ovid; and EMBASE via Ovid from inception to 17 November 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 hydromorphone (at any dose, by any route of administration, or in any formulation) 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. We assessed the quality of the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation). MAIN RESULTS: Searches identified seven publications relating to four studies. We excluded three studies. One post hoc (secondary) analysis of a study published in four reports assessed the efficacy of hydromorphone in neuropathic pain, satisfied our inclusion criteria, and was included in the review. The single included study had an enriched enrolment, randomised withdrawal design with 94 participants who were successfully switched from oral morphine to oral hydromorphone extended release (about 60% of those enrolled). These participants were then randomised to continuing hydromorphone for 12 weeks or tapering down the hydromorphone dose to placebo. The methodological quality of the study was generally good, but we judged the risk of bias for incomplete outcome data as unclear, and for study size as high.Since we identified only one study for inclusion, we were unable to carry out any analyses. The included study did not report any of our prespecified primary outcomes, which relate to the number of participants achieving moderate or substantial levels of pain relief. It did report a slightly larger increase in average pain intensity for placebo in the randomised withdrawal phase than for continuing with hydromorphone. It also reported the number of participants who withdrew due to lack of efficacy in the randomised withdrawal phase, which may be an indicator of efficacy. However, in addition to using an enriched enrolment, randomised withdrawal study design, there was an unusual choice of imputation methods for withdrawals (about 50% of participants); the evidence was of very low quality and inadequate to make a judgement on efficacy. Adverse events occurred in about half of participants with hydromorphone, the most common being constipation and nausea. A similar proportion of participants experienced adverse events with placebo, the most common being opioid withdrawal syndrome (very low quality evidence). Most adverse events were mild or moderate in intensity. One in eight participants withdrew while taking hydromorphone during the conversion and titration phase, despite participants being opioid-tolerant (very low quality evidence).We downgraded the quality of the evidence to very low because there was only one study with few participants, it did not report clinically useful efficacy outcomes, and it was a post hoc analysis. AUTHORS' CONCLUSIONS: There was insufficient evidence to support or refute the suggestion that hydromorphone has any efficacy in any neuropathic pain condition. PMID- 27216019 TI - Effects of consecutive monoculture of Pseudostellaria heterophylla on soil fungal community as determined by pyrosequencing. AB - Under consecutive monoculture, the biomass and quality of Pseudostellaria heterophylla declines significantly. In this study, a three-year field experiment was conducted to identify typical growth inhibition effects caused by extended monoculturing of P. heterophylla. Deep pyrosequencing was used to examine changes in the structure and composition of soil fungal community along a three-year gradient of monoculture. The results revealed a distinct separation between the newly planted plot and the two-year, three-year monocultured plots. The Shannon and Simpson diversity indices were significantly higher in the two-year and three year monoculture soils than in the newly planted soil. Consecutive monoculture of this plant led to a significant increase in relative abundance of Fusarium, Trichocladium and Myrothecium and Simplicillium, etc., but a significant decrease in the relative abundance of Penicillium. Quantitative PCR analysis confirmed a significant increase in Fusarium oxysporum, an agent known to cause wilt and rot disease of P. heterophylla. Furthermore, phenolic acid mixture at a ratio similar to that found in the rhizosphere could promote mycelial growth of pathogenic F. oxysporum. Overall, this study demonstrated that consecutive monoculture of P. heterophylla can alter the fungal community in the rhizosphere, including enrichment of host-specific pathogenic fungi at the expense of plant-beneficial fungi. PMID- 27216020 TI - Posterior fossa arachnoid cyst herniation through craniocervical junction. PMID- 27216021 TI - Accumulation and Depletion of Cadmium in the Blood, Milk, Hair, Feces, and Urine of Cows During and After Treatment. AB - The objective of this study was to assess the accumulation and depletion of cadmium in the blood, milk, hair, feces, and urine of Holstein cows during and after treatment. Three Holstein cows received daily oral cadmium administrations (as cadmium chloride) of 0.182 mg/kg body weight/day for 21 days followed by a 63 day withdrawal period. Blood, milk, hair, feces, and urine were collected during treatment and withdrawal periods. Cadmium concentrations were measured by inductively coupled plasma mass spectrometry (ICP-MS). Cadmium concentrations in blood (0.61-1.12 MUg/L), milk (0.39-1.04 MUg/L), and urine (0.41-2.05 MUg/L) were low. Comparatively, cadmium concentrations in feces were higher, especially on treatment day 14 (20.11 mg/kg dry matter). Fecal cadmium concentrations decreased to baseline levels (0.12 mg/kg dry matter) on withdrawal day 21. Hair cadmium concentrations increased with treatment, reaching the highest levels on withdrawal day 7 (24.33 MUg/kg). Most of the cadmium was excreted via the feces and very little was present in urine or milk. Cadmium residues were detected in blood and milk more than 63 days after cadmium withdrawal. Hair cadmium concentrations may reflect exposure to the metal. PMID- 27216022 TI - Role of Hydrogen Sulfide on Autophagy in Liver Injuries Induced by Selenium Deficiency in Chickens. AB - Selenium (Se) is an indispensable trace mineral that was associated with liver injuries in animal models. Hydrogen sulfide (H2S) is involved in many liver diseases, and autophagy can maintain liver homeostasis with a stress stimulation. However, little is known about the correlation between H2S and autophagy in the liver injury chicken models induced by Se deficiency. In this study, we aimed to investigate the correlation between H2S and autophagy in the liver injury chicken models. We randomly divided 120 1-day-old chickens into two equal groups. The control group was fed with complete food with a Se content of 0.15 mg/kg, and the Se-deficiency group (lab group) was fed with a Se-deficient diet with a Se content of 0.033 mg/kg. When the time comes to 15, 25, and 35 days, the chickens were sacrificed (20 each). The liver tissues were gathered and examined for pathological observations, the mRNA and protein levels of H2S synthases (CSE, CBS, and 3-MST) and the mRNA and protein levels of autophagy-related genes. The results showed that the expression of CSE, CBS, and 3-MST and H2S production were higher in the lab group than in the control group. Swellings, fractures, and vacuolizations were visible in the mitochondria cristae in the livers of the lab group and autophagosomes were found as well. In addition, the expression of autophagy-related genes (ATG5, LC3-I, LC3-II, Beclin1, and Dynein) was higher in the lab group than in the control group (p < 0.05) while TOR decreased significantly in the lab group (p < 0.05). The results showed that H2S and autophagy were involved in the liver injury chicken models, and H2S was correlated with autophagy. PMID- 27216023 TI - [Erratum to: Periprosthetic fractures following total hip and knee arthroplasty : Risk factors, epidemiological aspects, diagnostics and classification systems]. PMID- 27216024 TI - [Not Available]. PMID- 27216025 TI - Profiles of Student Perceptions of School Climate: Relations with Risk Behaviors and Academic Outcomes. AB - School climate has been linked to a variety of positive student outcomes, but there may be important within-school differences among students in their experiences of school climate. This study examined within-school heterogeneity among 47,631 high school student ratings of their school climate through multilevel latent class modeling. Student profiles across 323 schools were generated on the basis of multiple indicators of school climate: disciplinary structure, academic expectations, student willingness to seek help, respect for students, affective and cognitive engagement, prevalence of teasing and bullying, general victimization, bullying victimization, and bullying perpetration. Analyses identified four meaningfully different student profile types that were labeled positive climate, medium climate-low bullying, medium climate-high bullying, and negative climate. Contrasts among these profile types on external criteria revealed meaningful differences for race, grade-level, parent education level, educational aspirations, and frequency of risk behaviors. PMID- 27216027 TI - Long term results after cochlear implantation: Schooling and social insertion of teenagers and young adults. AB - INTRODUCTION: To analyse the long-term impact of cochlear implantation (CI) in deaf patients on perception and language, and on schooling and social insertion. METHOD: A total of 131 profoundly deaf patients that had unilateral CI, aged at follow up 16 to 26 years old and with 5 years minimum of follow up were included for the study. 84 of them had profound congenital deafness (Gc) and 47 had progressive deafness (Gp). In Gc, the mean age at CI was 5 years (3-16), the mean FU was 15 years. In Gp, the mean age at CI was 9 years (3-17 years), the mean FU was 11 years. The perceptive scores (open set sentences (OSS), word in open set sentences (WSS)), the intelligibility rate (SIR), the lexical scores (EVIP) were analysed and compared to the Schooling Status (SS) & Social Insertion (SSSI) (University/Working/Handicapped environment) and Classified as (Mainstream or Specialized). Both groups were compared. RESULTS: The mean results for Gc and Gp respectively were for the OSS score: 67.1% and 80.7% (P=0.009) and the SIR: 4.5 and 4.8 (P=0.049). EVIP scores were: in Gc, 56% of patients had normal or>=+1 SD; in Gp 72% of patients had normal or>=+1 SD. The SSSI: 63% in Gc and 83% in Gp were in Mainstream Schooling. Low level of EVIP scores were linked to Specialized environment in both groups (P=0.01, P=0.04). DISCUSSION: Long-term results show that differences have to be expected whether implanted children had congenital or progressive deafness. In both groups, strong correlations remain between perceptive results, lexical scores and the SSSI. CONCLUSION: On the long term the lexical level remains a relevant tool to assess the evolution of implantees. For those who do not reach a near to normal lexical level, impact on the schooling and the social insertion has to be expected. PMID- 27216026 TI - Herpes simplex encephalitis as a complication of neurosurgical procedures: report of 3 cases and review of the literature. AB - BACKGROUND: Herpes simplex virus (HSV) is the most common identified cause of focal encephalitis worldwide. However, postoperative HSV encephalitis (HSVE) is a rare complication of neurosurgical procedures and a significant clinical challenge METHOD: We describe 3 cases of postoperative HSVE and review all published reports. A total of 23 cases were identified. DISCUSSION: Clinical heterogeneity represents a diagnostic challenge in the postoperative setting. Cerebral magnetic resonance imaging showed typical findings in a minority of patients only, whereas HSV-specific polymerase chain reaction on the cerebrospinal fluid proved to be a valuable test. The postoperative viral pathophysiology remains a subject of debate. The rate of adverse outcome is high and early antiviral treatment seems to be a strong predictor of clinical outcome. CONCLUSION: We recommend early empirical treatment for any patient presenting with post-neurosurgical lymphocytic meningo-encephalitis, and prophylactic antiviral treatment for patients with a history of previous HSVE who will undergo a neurosurgical procedure. PMID- 27216028 TI - Channel catfish granzyme-like I is a highly specific serine protease with metase activity that is expressed by fish NK-like cells. AB - Here we present the extended cleavage specificity of catfish granzyme-like I, previously identified in fish NK-like cells. This protease has been characterised using substrate phage display and further validated by using a panel of recombinant substrates. A strict preference for Met in the P1 (cleavage) position, indicating metase specificity was observed. A screening of potential in vivo substrates was performed based on the derived P5-P3' consensus: Arg-Val-Thr Gly-Met(?)Ser-Leu-Val. Channel catfish caspase 6 was one very interesting potential target identified. This site was present in an adjacent position to the classic caspase activation site (Asp179 in human caspase 6). Cleavage of this site (hence potential activation) by the catfish granzyme-like I could reveal a novel mechanism of caspase 6 activation. This poses an interesting idea that the role of granzyme-like proteases in the activation of caspase dependent apoptosis mechanisms has been conserved for over 400 million years. PMID- 27216029 TI - A viral histone H4 suppresses insect insulin signal and delays host development. AB - Parasitization by an endoparasitoid wasp, Cotesia plutellae, alters host development of Plutella xylostella by extending larval period and preventing metamorphosis. Insulin signal plays a crucial role in mediating insect development and controlling blood sugar level in insects. In this study, three insulin-like peptide genes (PxILP1-3) were predicted from the genome of P. xylostella. However, only PxILP1 was confirmed to be expressed in P. xylostella. Starvation suppressed the expression level of PxILP1 and up-regulated plasma trehalose level. RNA interference against PxILP1 mimicked starvation effect and extended the larval period of P. xylostella. Parasitized larvae exhibited significantly lower levels of PxILP1 expression compared to nonparasitized larvae. Injection of wasp-symbiotic polydnavirus C. plutellae bracovirus (CpBV) also suppressed PxILP1 expression and extended the larval period. Injection of a viral segment (CpBV-S30) containing a viral histone H4 (CpBV-H4) also suppressed PxILP1 expression. Co-injection of CpBV-S30 and double-stranded RNA (dsCpBV-H4) specific to CpBV-H4 rescued the suppression of PxILP1 expression. Injection of CpBV-S30 significantly extended larval development. Co-injection of CpBV-S30 with dsCpBV-H4 rescued the delay of larval development. Injection of a bovine insulin to parasitized larvae prevented parasitoid development. These results indicate that parasitism of C. plutellae can down-regulate host insulin signaling with the help of parasitic factor CpBV-H4. PMID- 27216030 TI - Spiritual Struggle Among Patients Seeking Treatment for Chronic Headaches: Anger and Protest Behaviors Toward God. AB - This study examined anger and protest behaviors toward God among 80 US adults seeking treatment for chronic headaches (66 women, 14 men; 71 completed treatment). Measures were administered before and after an intensive 3-week outpatient treatment program. At both times, anger and protest toward God correlated with lower pain acceptance, more emotional distress, and greater perceived disability. However, when considered simultaneously, anger predicted sustained distress, whereas protest behaviors (e.g., complaining, questioning, arguing) predicted both reduced distress and an increased sense of meaning. These findings suggest the utility of distinguishing between anger toward God and behaviors suggesting assertiveness toward God. PMID- 27216031 TI - Reconnecting to Spirituality: Christian-Identified Adolescents and Emerging Adult Young Men's Journey from Diagnosis of HIV to Coping. AB - Spirituality is important to holistic health, yet little is known about its impact on young people with HIV. To address this knowledge deficit, a grounded theory study used semi-structured interviews of 20 Christian-identified adolescent and emerging adult gay males and one perinatally infected male. This study revealed that, to cope with HIV health issues, participants used a process of reconnecting with their spirituality. In order to successfully reconnect with their spirituality, study participants reported a need to re-embrace and re engage in spiritual practices, hold onto hope, believe they are normal, and commit to beliefs and practices despite rejection from the church. PMID- 27216032 TI - A methodological comparison of two European primary care databases and replication in a US claims database: inhaled long-acting beta-2-agonists and the risk of acute myocardial infarction. AB - PURPOSE: Results from observational studies on inhaled long-acting beta-2 agonists (LABA) and acute myocardial infarction (AMI) risk are conflicting, presumably due to variation in methodology. We aimed to evaluate the impact of applying a common study protocol on consistency of results in three databases. METHODS: In the primary analysis, we included patients from two GP databases (Dutch-Mondriaan, UK-CPRD GOLD) with a diagnosis of asthma and/or COPD and at least one inhaled LABA or a "non-LABA inhaled bronchodilator medication" (short acting beta-2-agonist or short-/long-acting muscarinic antagonist) prescription between 2002 and 2009. A claims database (USA-Clinformatics) was used for replication. LABA use was divided into current, recent (first 91 days following the end of a treatment episode), and past use (after more than 91 days following the end of a treatment episode). Adjusted hazard ratios (AMI-aHR) and 95 % confidence intervals (95 % CI) were estimated using time-dependent multivariable Cox regression models stratified by recorded diagnoses (asthma, COPD, or both asthma and COPD). RESULTS: For asthma or COPD patients, no statistically significant AMI-aHRs (age- and sex-adjusted) were found in the primary analysis. For patients with both diagnoses, a decreased AMI-aHR was found for current vs. recent LABA use in the CPRD GOLD (0.78; 95 % CI 0.68-0.90) and in Mondriaan (0.55; 95 % CI 0.28-1.08), too. The replication study yielded similar results. Adjusting for concomitant medication use and comorbidities, in addition to age and sex, had little impact on the results. CONCLUSIONS: By using a common protocol, we observed similar results in the primary analysis performed in two GP databases and in the replication study in a claims database. Regarding differences between databases, a common protocol facilitates interpreting results due to minimized methodological variations. However, results of multinational comparative observational studies might be affected by bias not fully addressed by a common protocol. PMID- 27216033 TI - [Arrhythmia in adults with congenital heart defects : Incidence, substrates, and mechanisms]. AB - Arrhythmia management is one of the main challenges in the treatment of adult patients with congenital heart disease (ACHD). Apart from heart failure, arrhythmias are mainly responsible for morbidity and mortality in these patients. Supraventricular tachycardia is more frequent than ventricular arrhythmias and is not only associated with debilitating symptoms, but is often as threatening as ventricular tachycardia. The incidence depends on the underlying defect, type, and time of repair. For the overall ACHD population the incidence of supraventricular tachycardia is up to 50 % and increases with age and time since surgery. Arrhythmia substrate relates to structural abnormalities due to the congenital defect and most importantly to the amount of incisions and material used for repair. In addition, poor hemodynamic conditions influence substrate through dilatation, hypertrophy, and fibrosis. Both supraventricular and ventricular arrhythmias are due to a macroreentrant mechanism in the vast majority of patients, but focal arrhythmias occasionally occur as well. PMID- 27216034 TI - Nanopore formation process in artificial cell membrane induced by plasma generated reactive oxygen species. AB - We investigated morphological change of an artificial lipid bilayer membrane induced by oxygen radicals which were generated by non-equilibrium atmospheric pressure plasma. Neutral oxygen species, O((3)Pj) and O2((1)Deltag), were irradiated of a supported lipid bilayer existing under a buffer solution at various conditions of dose time and distances, at which the dose amounts of the oxygen species were calculated quantitatively. Observation using an atomic force microscope and a fluorescence microscope revealed that dose of the neutral oxygen species generated nanopores with the diameter of 10-50 nm in a phospholipid bilayer, and finally destructed the bilayer structure. We found that protrusions appeared on the lipid bilayer surface prior to the formation of nanopores, and we attributed the protrusions to the precursor of the nanopores. We propose a mechanism of the pore formation induced by lipid oxidation on the basis of previous experimental and theoretical studies. PMID- 27216035 TI - Promoting the immunization neighborhood: Benefits and challenges of pharmacies as additional locations for HPV vaccination. PMID- 27216036 TI - Improvement of Insulin Injection Technique: Examination of Current Issues and Recommendations. AB - PURPOSE: Correct insulin injection technique is a crucial aspect of diabetes management. The purpose of this article is (1) to outline the medical literature, including patient-based studies and surveys, surrounding the type of issues and problems that patients encounter with injectable insulin therapy and the degree to which correct insulin technique is being applied and (2) to review the latest recommendations for insulin injection technique and discuss the key aspects that diabetes educators and other health care professionals should be communicating to their patients to ensure that injection technique is optimized. CONCLUSIONS: Examination of the literature and multiple patient surveys demonstrates that patients continue to have many issues with insulin injection technique, highlighting the pressing need for effective patient education. In addition, many patients are not using insulin pen devices correctly. Widespread lack of injection site rotation and reuse of needles have resulted in high rates of lipohypertrophy. Lipohypertrophy has in turn been associated with significantly increased levels of unexplained hypoglycemia and glycemic variability and significantly increased insulin costs. By providing clear, evidence-based consensus recommendations, initiatives such as the Forum for Injection Technique are helping to address these issues but will be successful only if concerted efforts in patient education and reeducation are made to ensure that these recommendations are implemented consistently. This should involve all stakeholders in insulin therapy-particularly diabetes educators, who are at the forefront of patient education. PMID- 27216037 TI - Molecular characterization of protein kinase C delta (PKCdelta)-Smac interactions. AB - BACKGROUND: Protein kinase C delta (PKCdelta) is known to be an important regulator of apoptosis, having mainly pro- but also anti-apoptotic effects depending on context. In a previous study, we found that PKCdelta interacts with the pro-apoptotic protein Smac. Smac facilitates apoptosis by suppressing inhibitor of apoptosis proteins (IAPs). We previously established that the PKCdelta-Smac complex dissociates during induction of apoptosis indicating a functional importance. Because the knowledge on the molecular determinants of the interaction is limited, we aimed at characterizing the interactions between PKCdelta and Smac. RESULTS: We found that PKCdelta binds directly to Smac through its regulatory domain. The interaction is enhanced by the PKC activator TPA and seems to be independent of PKCdelta catalytic activity since the PKC kinase inhibitor GF109203X did not inhibit the interaction. In addition, we found that C1 and C2 domains from several PKC isoforms have Smac-binding capacity. CONCLUSIONS: Our data demonstrate that the Smac-PKCdelta interaction is direct and that it is facilitated by an open conformation of PKCdelta. The binding is mediated via the PKCdelta regulatory domain and both the C1 and C2 domains have Smac-binding capacity. With this study we thereby provide molecular information on an interaction between two apoptosis-regulating proteins. PMID- 27216038 TI - Protons at the speed of sound: Predicting specific biological signaling from physics. AB - Local changes in pH are known to significantly alter the state and activity of proteins and enzymes. pH variations induced by pulses propagating along soft interfaces (e.g. membranes) would therefore constitute an important pillar towards a physical mechanism of biological signaling. Here we investigate the pH induced physical perturbation of a lipid interface and the physicochemical nature of the subsequent acoustic propagation. Pulses are stimulated by local acidification and propagate - in analogy to sound - at velocities controlled by the interface's compressibility. With transient local pH changes of 0.6 directly observed at the interface and velocities up to 1.4 m/s this represents hitherto the fastest protonic communication observed. Furthermore simultaneously propagating mechanical and electrical changes in the lipid interface are detected, exposing the thermodynamic nature of these pulses. Finally, these pulses are excitable only beyond a threshold for protonation, determined by the pKa of the lipid head groups. This protonation-transition plus the existence of an enzymatic pH-optimum offer a physical basis for intra- and intercellular signaling via sound waves at interfaces, where not molecular structure and mechano-enyzmatic couplings, but interface thermodynamics and thermodynamic transitions are the origin of the observations. PMID- 27216039 TI - Inhibition of CaMKIV relieves streptozotocin-induced diabetic neuropathic pain through regulation of HMGB1. AB - BACKGROUND: The pathogenesis of diabetic neuropathic pain is complicated and its underlying mechanisms remain unclear. Calmodulin-dependent protein kinases (CaMKs) IV (CaMKIV), one of CaMKs, regulates several transcription factors in pain mechanisms. High-mobility group box 1 (HMGB1) is a key mediator in diabetic neuropathic pain. This study aims to find the roles and mechanisms of CaMIV in diabetic neuropathic pain. METHODS: Diabetic animal models were constructed by injecting with streptozotocin (STZ) intraperitoneally. They were randomly divided into seven groups (n = 6 per group): Naive, Normal Saline, STZ, STZ + Sham, STZ + DMSO and STZ + KN93 (an inhibitor of CaMKIV) (50 MUg), STZ + KN93 (100 MUg), which received KN93 (50 or 100 MUg) intrathecally after the administration of STZ. Phospho-CaMKIV (pCaMKIV) and HMGB1 expression in rat dorsal root ganglion (DRG) and RAW264.7 cell line were measured by western blot. Distribution of pCaMKIV immune reactivity in different subpopulations of DRG neurons was measured by double-immunofluorescence staining. RESULTS: The pCaMKIV and HMGB1 in DRG significantly increased after STZ administration, and pCaMKIV can regulate the expression of HMGB1 based on both cellular and animal models. Pretreatment with CaMKIV inhibitor attenuated STZ-induced mechanical allodynia and thermal hyperalgesia, as well as reduced HMGB1 expression in the DRG. CONCLUSIONS: This study demonstrates that CaMKIV can relieve STZ-induced diabetic neuropathic pain. The mechanism of this function depended on the process: pCaMKIV localized in the nuclei of DRG neurons and regulated HMGB1 which was an important mediator of neuropathic pain. These findings reported CaMKIV may be a potential target or important node in relieving diabetic neuropathic pain. PMID- 27216040 TI - Role of intrahepatic B cells in non-alcoholic fatty liver disease by secreting pro-inflammatory cytokines and regulating intrahepatic T cells. AB - OBJECTIVE: To investigate the alterations and functions of intrahepatic B (IHB) cells in non-alcoholic fatty liver disease (NAFLD) model induced by high-fat diet (HFD). METHODS: C57BL/6 J mice were fed with HFD for 16 weeks to induce NAFLD. Flow cytometry was used to analyze lymphocytes from liver, spleen and peripheral blood mononuclear cells (PBMC). Real-time polymerase chain reaction and immunofluorescence stain were applied to investigate cytokine expression in the intrahepatic lymphocytes and IHB cells. CD4(+) intrahepatic T (IHT) cells and IHB cells were enriched by a magnetic-activated cell sorting method and cultured in vitro. The cytokines and immunoglobulin (Ig) levels in the plasma, cultural supernatants and liver homogenates were monitored with cytometric bead arrays or multiplex immunoassays. RESULTS: The percentage of IHB cells in CD45(+) cells was significantly higher in the NAFLD group than in the control group (P < 0.05). IHB cells expressed higher levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha in the NAFLD group, and produced higher levels of IL-6 and TNF-alpha under the stimulation of lipopolysaccharide (LPS) than the control group. IgG2a levels were higher in the plasma, liver homogenates and the culture supernatants of IHB cells after stimulated by LPS and anti-CD40/IgM in the NAFLD group than in the control group. Moreover, IHB cells enhanced the activation of CD4(+) IHT cells and promoted the differentiation into T helper (Th) 1 cells in the NAFLD group. CONCLUSION: IHB cells might be involved in NAFLD both by inducing the secretion of IL-6, TNF-alpha and IgG2a and by enhancing the activation of CD4(+) IHT cells and their differentiation into Th1 cells. PMID- 27216041 TI - Baseline of polycyclic aromatic hydrocarbons in the surface sediment and sea cucumbers (Holothuria leucospilota and Stichopus hermanni) in the northern parts of Persian Gulf. AB - Polycyclic aromatic hydrocarbons (PAHs) were determined in the surface sediments and in the sea cucumbers (Holothuria leucospilota and Stichopus hermanni) from around six Islands in the northern parts of Persian Gulf. The ranges of the average concentrations of PAHs in surface sediments, H. leucospilota and S. hermanni were 10.33-186.16ngg(-1) dw, 12.49-505.44ngg(-1) dw and 8.08-389.39ngg( 1) dw, respectively. The spatial distribution of PAHs reveals that pollutant concentration is relatively higher at the western parts of Persian Gulf. International sedimentary quality guidelines (TEL-PEL) indicated a low probability of harmful effects to benthic organisms. PAH source identification showed that the PAHs in the sediments come from pyrogenic and mixed origin. PMID- 27216042 TI - Assessment of perfluorooctanoic acid and perfluorooctane sulfonate in surface water - Tamil Nadu, India. AB - As an emerging class of environmentally persistent organic pollutants, perfluorinated compounds (PFCs), particularly perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS); have been universally found in the environment. Wastewater and untreated effluents are likely the major causes for the accumulation of PFCs in surface water. There are very few reports on the contamination of PFCs in the developing countries, particularly in India. This study reports the quantitative analysis of PFOA and PFOS in Noyyal, Cauvery, and also lakes in and around Chennai, using Ultra-Fast liquid chromatograph. The concentration of PFOA and PFOS ranged from 4 to 93ng/L and 3 to 29ng/L, respectively. The concentration of PFOS was below detectable limit in Cauvery River. A reliable concentration of PFOA was recorded at all sites of River Cauvery (5ng/L). The present study could be useful for the assessment of future monitoring programs of PFOA and PFOS in the surface water. PMID- 27216043 TI - Predicting pollutant concentrations in the water column during dredging operations: Implications for sediment quality criteria. AB - The development of new dredging techniques that can reduce, or at least predict, the environmental impacts, is in high demand by governments in developing countries. In the present work, a new methodology was developed, to evaluate the level of metals contamination (i.e. cadmium, lead and zinc) of the water column, during a dredging operation. This methodology was used to evaluate the impacts of the construction of a new maritime terminal in Sepetiba Bay, Brazil. The methodology quantifies the amount of resuspended sediments and calculates the expected contaminants concentrations in the water column. The results indicated that sediment quality criteria were not compatible with water quality criteria, because the dredging of contaminated sediments does not necessarily yield contaminated water. It is suggested that the use of sediment quality criteria for dredging operations might be abandoned, and the methodology presented in this study applied to assess dredging's environmental impacts, predicting water contamination levels. PMID- 27216044 TI - Variability in antioxidant/detoxification enzymes of Sinonovacula constricta exposed to benzo[a]pyrene and phenanthrene. AB - The purpose of this study was to investigate the toxic effects induced by benzo[a]pyrene and phenanthrene. For this purpose, a study was performed on the clam exposed to 0.0, 0.5, 4.5MUgL(-1) B(a)P and PHE for 15days using parameters of antioxidant defenses and oxidative stress. Antioxidant biomarkers including ethoxyresorufin-O-deethylase, glutathione S-transferase, superoxide dismutase, and glutathione and rylhydrocarbon hydroxylasein gills of Sinonovacula constricta, were analyzed after a 1-, 3-, 9- and 15-day exposure to seawater containing B(a)P and PHE. Integrated biomarker response was calculated by combining multiple biomarkers into a single value. The results showed that the activity of all antioxidant biomarkers was induced throughout the exposure period, and different patterns of variations were detected with exposure time. In addition, the study showed that the two concentrations used caused the activation of different general detoxification mechanisms, and the same concentration at different two PAH compounds induced different toxicity responses. PMID- 27216045 TI - Evaluation of mobile metals in sediments of Burullus Lagoon, Egypt. AB - The Burullus Lagoon north Nile Delta of Egypt is a UNESCO-protected area. Recently it has become a sediment sink which led to shrinking in its area and depth accompanying with increasing contaminant levels. In this study we attempt to explore the spatial distribution and their mobility of heavy metals (Zn, Cu, Ni, Cr and Pb) based on 21surface sediment samples recovered from Burullus lagoon basin and nine drains. The risk assessment code of the studied heavy metals can be arranged as Zn>Cu>Pb>Cr>Ni for all the samples collected from the lagoon basin and nine different drains. The heavy metals tend to accumulate in fine sediments and human activities promote the accumulation of contaminated sediments in water courses. PMID- 27216046 TI - Can PBDE natural formation and degradation processes interfere with the identification of anthropogenic trends and sources? Evidences from sediments of the Nador Lagoon (Morocco). AB - This paper presents the first results related to PBDE concentrations in sediments of the Nador Lagoon (N-E Morocco), an area endangered by different pollutant sources. Analyses were performed by HRGC-LRMS and confirmed by HRGC-HRMS on selected samples. Total surficial concentrations were 0.059-8.2ngg(-1). The maxima were found close to Nador City. Along the sedimentary records, the highest total concentrations (11 and 2.2ngg(-1)) were found at depths corresponding to times (1930s-1950s) when these chemicals were not yet produced. Dehydroxylation or demethoxylation of naturally occurring structural analogues of PBDEs under reducing conditions was suggested. BDE-47 dominated the congener compositions, while BDE-209, when present, could be detected only by HRGC-HRMS, proving that analytical degradation modified the original assemblage. Microbial anaerobic degradation could have changed congener compositions in sediments deposited from the 1970s to the 2000s. Current values are not harmful, but increasing trends call for constant monitoring. PMID- 27216047 TI - Calcitriol inhibits tumor necrosis factor alpha and macrophage inflammatory protein-2 during lipopolysaccharide-induced acute lung injury in mice. AB - Acute lung injury is a common complication of sepsis in intensive care unit patients with an extremely high mortality. The present study investigated the effects of calcitriol, the active form of vitamin D, on tumor necrosis factor alpha (TNF-alpha) and macrophage inflammatory protein-2 (MIP-2) in sepsis-induced acute lung injury. Mice were intraperitoneally (i.p.) injected with lipopolysaccharide (LPS, 1.0mg/kg) to establish the animal model of sepsis induced acute lung injury. Some mice were i.p. injected with calcitriol (1.0MUg/kg) before LPS injection. An obvious infiltration of inflammatory cells in the lungs was observed beginning at 1h after LPS injection. Correspondingly, TNF-alpha and MIP-2 in sera and lung homogenates were markedly elevated in LPS treated mice. Interestingly, calcitriol obviously alleviated LPS-induced infiltration of inflammatory cells in the lungs. Moreover, calcitriol markedly attenuated LPS-induced elevation of TNF-alpha and MIP-2 in sera and lung homogenates. Further analysis showed that calcitriol repressed LPS-induced p38 mitogen-activated protein kinase (MAPK) and protein kinase B (Akt) phosphorylation. In addition, calcitriol blocked LPS-induced nuclear translocation of nuclear factor kappa B (NF-kappaB) p65 and p50 subunit in the lungs. Taken together, these results suggest that calcitriol inhibits inflammatory cytokines production in LPS-induced acute lung injury. PMID- 27216048 TI - Antifungal Susceptibility Testing of Ascomycetous Yeasts Isolated from Animals. AB - Recent studies suggest that antifungal resistance in yeast isolates of veterinary origin may be an underdiagnosed threat. We tested a collection of 92 ascomycetous yeast isolates that were obtained in Spain from birds, mammals and insects for antifungal susceptibility. MICs to amphotericin B and azoles were low, and no resistant isolates were detected. Despite these results, and given the potential role of animals as reservoirs of resistant strains, continuous monitoring of antifungal susceptibility in the veterinary setting is recommended. PMID- 27216049 TI - In Vitro Synergism between Azithromycin or Terbinafine and Topical Antimicrobial Agents against Pythium insidiosum. AB - We describe here in vitro activity for the combination of azithromycin or terbinafine and benzalkonium, cetrimide, cetylpyridinium, mupirocin, triclosan, or potassium permanganate. With the exception of potassium permanganate, the remaining antimicrobial drugs were active and had an MIC90 between 2 and 32 MUg/ml. The greatest synergism was observed for the combination of terbinafine and cetrimide (71.4%). In vivo experimental evaluations will clarify the potential of these drugs for the topical treatment of lesions caused by Pythium insidiosum. PMID- 27216050 TI - Biochemical Characterization of the Active Anti-Hepatitis C Virus Metabolites of 2,6-Diaminopurine Ribonucleoside Prodrug Compared to Sofosbuvir and BMS-986094. AB - Ribonucleoside analog inhibitors (rNAI) target the hepatitis C virus (HCV) RNA dependent RNA polymerase nonstructural protein 5B (NS5B) and cause RNA chain termination. Here, we expand our studies on beta-d-2'-C-methyl-2,6-diaminopurine ribonucleotide (DAPN) phosphoramidate prodrug 1 (PD1) as a novel investigational inhibitor of HCV. DAPN-PD1 is metabolized intracellularly into two distinct bioactive nucleoside triphosphate (TP) analogs. The first metabolite, 2'-C-methyl GTP, is a well-characterized inhibitor of NS5B polymerase, whereas the second metabolite, 2'-C-methyl-DAPN-TP, behaves as an adenosine base analog. In vitro assays suggest that both metabolites are inhibitors of NS5B-mediated RNA polymerization. Additional factors, such as rNAI-TP incorporation efficiencies, intracellular rNAI-TP levels, and competition with natural ribonucleotides, were examined in order to further characterize the potential role of each nucleotide metabolite in vivo Finally, we found that although both 2'-C-methyl-GTP and 2'-C methyl-DAPN-TP were weak substrates for human mitochondrial RNA (mtRNA) polymerase (POLRMT) in vitro, DAPN-PD1 did not cause off-target inhibition of mtRNA transcription in Huh-7 cells. In contrast, administration of BMS-986094, which also generates 2'-C-methyl-GTP and previously has been associated with toxicity in humans, caused detectable inhibition of mtRNA transcription. Metabolism of BMS-986094 in Huh-7 cells leads to 87-fold higher levels of intracellular 2'-C-methyl-GTP than DAPN-PD1. Collectively, our data characterize DAPN-PD1 as a novel and potent antiviral agent that combines the delivery of two active metabolites. PMID- 27216051 TI - Imidazo[1,2-a]Pyridine-3-Carboxamides Are Active Antimicrobial Agents against Mycobacterium avium Infection In Vivo. AB - A panel of six imidazo[1,2-a]pyridine-3-carboxamides (IAPs) were shown to have low-micromolar activity against Mycobacterium avium strains. Compound ND-10885 (compound 2) showed significant activity in the lung, spleen, and liver in a mouse M. avium infection model. A combined regimen consisting of ND-10885 (compound 2) and rifampin was additive in its anti-M. avium activity in the lung. Our data indicate that IAPs represent a new class of antibiotics that are active against M. avium and could potentially serve as an effective addition to a combined treatment regimen. PMID- 27216052 TI - Individual or Combined Effects of Meropenem, Imipenem, Sulbactam, Colistin, and Tigecycline on Biofilm-Embedded Acinetobacter baumannii and Biofilm Architecture. AB - Acinetobacter baumannii biofilms are difficult to eradicate. We investigated the effects of meropenem (2 mg/liter), imipenem (2 mg/liter), sulbactam (4 mg/liter), colistin (2 mg/liter), and tigecycline (2 mg/liter), alone or in combination, on biofilm-embedded carbapenem-resistant and carbapenem-susceptible A. baumannii (CRAb and CSAb, respectively) cells, as well as on the architecture of the biofilms. A. baumannii ATCC 15151 (Ab15151) and its OXA-82-overproducing transformant, along with two clinical CSAb and two clinical CRAb isolates of differing clonalities, were used. The minimal bactericidal concentrations for biofilm-embedded cells of the six tested isolates were >50-fold those of their planktonic cells. When used individually, meropenem exhibited a higher killing effect than the other four antimicrobials on biofilm-embedded CSAb cells in the colony biofilm assay. For two clinical CRAb isolates, meropenem plus sulbactam or sulbactam plus tigecycline showed >100-fold the bactericidal effect exhibited by these agents used alone after 48 h of treatment. The effect of antimicrobials on the architecture of Ab15151 biofilm emitting green fluorescence was determined by confocal laser scanning microscopy using COMSTAT software. Significant decreases in the maximum biofilm thickness were observed after exposure to meropenem and imipenem. Meropenem plus sulbactam significantly decreased the biomass and mean thickness and increased the roughness coefficient of biofilms, but sulbactam plus tigecycline only decreased the maximum and mean biofilm thickness compared to any of these agents used alone. Meropenem was active against biofilm-embedded CSAb, whereas meropenem plus sulbactam exhibited synergism against biofilm-embedded CRAb and caused significantly more damage to the biofilm architecture than did any of the agents used alone. PMID- 27216053 TI - Cefazolin versus Nafcillin for Methicillin-Sensitive Staphylococcus aureus Bloodstream Infection in a California Tertiary Medical Center. AB - Recent observational studies have suggested possible reductions in mortality in patients receiving cefazolin versus antistaphylococcal penicillins. We examined 90-day mortality in patients receiving cefazolin compared to nafcillin for methicillin-susceptible Staphylococcus aureus (MSSA) bloodstream infection (BSI). We identified persons with MSSA BSI admitted to San Francisco General Hospital from January 2008 to July 2013 through a hospital-wide infection surveillance system and confirmed 90-day mortality using U.S. national vital registries. We included persons receiving cefazolin or nafcillin as the predominant intravenous antimicrobial agent; all participants received inpatient Infectious Diseases service consultation. We estimated the association between receipt of cefazolin and 90-day risk of death by multivariate logistic regression, including a propensity score for receiving cefazolin as the second predictor. Of 230 MSSA BSI cases, 30 received nafcillin and 70 received cefazolin as the predominant antimicrobial; 10 died within 90 days, 5 from each group. Unadjusted analysis showed substantial but not statistically significant reduced odds of death in those receiving cefazolin (odds ratio, 0.38; 95% confidence interval [CI], 0.10 to 1.44). Multivariate analysis with propensity scores found a similar adjusted odds ratio (0.40; 95% CI, 0.09 to 1.74; P = 0.22). We found a large reduction in 90-day mortality in those receiving cefazolin compared to nafcillin for MSSA BSI, but this finding was not statistically significant. The magnitude of effect seen in this and other studies justifies further study. PMID- 27216054 TI - Assessment of the In Vitro Activity of Ceftazidime-Avibactam against Multidrug Resistant Klebsiella spp. Collected in the INFORM Global Surveillance Study, 2012 to 2014. AB - Increasing resistance in Gram-negative bacilli, including Klebsiella spp., has reduced the utility of broad-spectrum cephalosporins. Avibactam, a novel non-beta lactam beta-lactamase inhibitor, protects beta-lactams from hydrolysis by Gram negative bacteria that produce extended-spectrum beta-lactamases (ESBLs) and serine carbapenemases, including Ambler class A and/or class C and some class D enzymes. In this analysis, we report the in vitro activity of ceftazidime avibactam and comparators against multidrug-resistant (MDR) Klebsiella spp. from the 2012-2014 INFORM surveillance study. Isolates collected from 176 sites were sent to a central laboratory for confirmatory identification and tested for susceptibility to ceftazidime-avibactam and comparator agents, including ceftazidime alone. A total of 2,821 of 10,998 (25.7%) Klebsiella species isolates were classified as MDR, based on resistance to three or more classes of antimicrobials. Among the MDR isolates, 99.4% had an ESBL screen-positive phenotype, and 27.4% were not susceptible to meropenem as an example of a carbapenem. Ceftazidime-avibactam was highly active against MDR isolates, including ESBL-positive and serine carbapenemase-producing isolates, with MIC50/90 values of 0.5/2 MUg/ml and 96.6% of all MDR isolates and ESBL-positive MDR isolates inhibited at the FDA breakpoint (MIC value of <=8 MUg/ml). Ceftazidime-avibactam did not inhibit isolates producing class B enzymes (metallo beta-lactamases) either alone or in combination with other enzymes. These in vitro results support the continued investigation of ceftazidime-avibactam for the treatment of MDR Klebsiella species infections. PMID- 27216055 TI - Thioridazine as Chemotherapy for Mycobacterium avium Complex Diseases. AB - Mycobacterium avium-intracellulare complex (MAC) causes an intractable intracellular infection that presents as chronic pulmonary disease. Currently, therapy consists of ethambutol and macrolides and takes several years to complete. The neuroleptic phenothiazine thioridazine kills mycobacteria by inhibiting the electron transport chain. In several experiments with bacterial populations of up to 10(12) CFU/ml, we failed to isolate any bacteria resistant to 3 times the MIC of thioridazine, suggesting the absence of resistant mutants at bacterial burdens severalfold higher than those encountered in patients. In the hollow-fiber model of intracellular MAC (HFS-MAC), thioridazine achieved an extracellular half-life of 16.8 h and an intracellular half-life of 19.7 h. Thioridazine concentrations were >28,000-fold higher inside infected macrophages than in the HFS-MAC central compartment (equivalent to plasma). Thioridazine maximal kill was 5.20 +/- 0.75 log10 CFU/ml on day 7 (r(2) = 0.96) and 7.19 +/- 0.31 log10 CFU/ml on day 14 (r(2) = 0.99), the highest seen with any drug in the system. Dose fractionation studies revealed that thioridazine efficacy and acquired drug resistance were driven by the peak concentation-to-MIC ratio, with a 50% effective concentration (EC50) of 2.78 +/- 0.44 for microbial killing. Acquired drug resistance was encountered by day 21 with suboptimal doses, demonstrating that fluctuating drug concentrations drive evolution faster than static concentrations in mutation frequency studies. However, the thioridazine EC50 changed 16.14-fold when the concentration of fetal bovine serum was changed from 0% to 50%, suggesting that intracellular potency could be heavily curtailed by protein binding. Efficacy in patients will depend on the balance between trapping of the drug in the pulmonary system and the massive intracellular concentrations versus very high protein binding of thioridazine. PMID- 27216056 TI - Virulence and Experimental Treatment of Trichoderma longibrachiatum, a Fungus Refractory to Treatment. AB - Different inocula of Trichoderma longibrachiatum were tested in a murine model, and only the highest one (1 * 10(7) CFU/animal) killed all of the mice at day 15 postinfection, with spleen and liver the most affected organs. The efficacies of amphotericin B deoxycholate, liposomal amphotericin B, voriconazole, and micafungin were evaluated in the same model, with very poor results. Our study demonstrated the low virulence but high resistance to antifungal compounds of this fungus. PMID- 27216057 TI - Pharmacokinetics and Safety of Tenofovir Alafenamide in HIV-Uninfected Subjects with Severe Renal Impairment. AB - Tenofovir alafenamide (TAF) is an oral prodrug of tenofovir (TFV) that has greater stability in plasma than TFV disoproxil fumarate (TDF) and circulates as intact TAF, resulting in the direct and higher lymphatic loading of and exposure to TFV diphosphate, the active moiety. Unlike TFV, TAF is minimally eliminated in urine. The pharmacokinetics (PK) of TAF and TFV in HIV-uninfected subjects with severe renal impairment and matched healthy controls were evaluated. Subjects with severe renal impairment (RI; estimated glomerular filtration rate [eGFR], 15 to 29 ml/min) and controls (eGFR, >=90 ml/min) matched for age, gender, and body mass index received a single dose of TAF at 25 mg. Blood and urine samples for TAF and TFV PK determinations were collected over 7 days postdosing, and subjects were followed up at 14 days. A total of 14 renally impaired subjects and 13 control subjects enrolled and completed the study. The TAF maximum observed concentration in plasma (Cmax) and the area under the concentration-versus-time curve (AUC) extrapolated to infinite time (AUCinf) were 79% and 92% higher, respectively, in subjects with severe RI than the controls, primarily due to higher absorption. The TFV Cmax and AUCinf were 2.8-fold and 5.7-fold higher, respectively, in subjects with severe RI than the controls. In subjects with severe RI, TAF at 25 mg provided a TFV AUC 10 to 40% lower than that from historical TDF-based TFV exposures in subjects with normal renal function. There were no discontinuations due to adverse events. In subjects with severe RI receiving TAF at 25 mg, TAF exposures were higher than those for the controls; these differences are unlikely to be clinically meaningful. TFV exposures were higher than those for the controls but lower than the exposures in nonrenally impaired subjects on TDF-based regimens. PMID- 27216058 TI - Detection of the mcr-1 Colistin Resistance Gene in Carbapenem-Resistant Enterobacteriaceae from Different Hospitals in China. AB - The spread of the plasmid-mediated colistin resistance gene, mcr-1, into carbapenem-resistant Enterobacteriaceae (CRE) clinical isolates poses a significant threat to global health. Here we report the identification of three mcr-1-harboring carbapenem-resistant Escherichia coli strains, collected from three patients in two provinces in China. Our results show that mcr-1-harboring CRE strains have started to spread in different hospitals in China. In addition, this report presents the first description of chromosomal integration of mcr-1 into a carbapenem-resistant E. coli strain. PMID- 27216059 TI - Phenotypic Screening In Vitro of Novel Aromatic Amidines against Trypanosoma cruzi. AB - The current treatment of Chagas disease (CD), based on nifurtimox and benznidazole (Bz), is unsatisfactory. In this context, we performed the phenotypic in vitro screening of novel mono- and diamidines and drug interaction assays with selected compounds. Ten novel amidines were tested for their activities against bloodstream trypomastigote (BT) and amastigote forms of Trypanosoma cruzi (Y and Tulahuen strains) and their toxicities for mammalian host cells (L929 cells and cardiac cells). Seven of 10 molecules were more active than Bz against BT, with the most active compound being the diamidine DB2267 (50% effective concentration [EC50] = 0.23 MUM; selectivity index = 417), which was 28 fold more active and about 3 times more selective than the standard drug. Five of the six monoamidines were also more active than Bz. The combination of DB2267 and DB2236 in fixed-ratio proportions showed an additive effect (sum of fractional inhibitory concentrations < 4) on BT. Interestingly, when intracellular forms were exposed to DB2267, its activity was dependent on the parasite strain, being effective (EC50 = 0.87 +/- 0.05 MUM) against a discrete typing unit (DTU) II strain (strain Y) but not against a representative DTU VI strain (strain Tulahuen) even when different vehicles (beta-cyclodextrin and dimethyl sulfoxide) were used. The intrinsic fluorescence of several diamidines allowed their uptake to be studied. Testing of the uptake of DB2236 (inactive) and DB2267 (active) by amastigotes of the Y strain showed that the two compounds were localized intracellularly in different compartments: DB2236 in the cytoplasm and DB2267 in the nucleus. Our present data encourage further studies regarding the activities of amidines and provide information which will help with the identification of novel agents for the treatment of CD. PMID- 27216060 TI - Differential Antimicrobial Susceptibilities of Granulicatella adiacens and Abiotrophia defectiva. AB - MICs of 25 Abiotrophia defectiva and 109 Granulicatella adiacens isolates were determined by broth microdilution. Using CLSI breakpoints, the susceptibilities of A. defectiva and G. adiacens isolates were, respectively, 24% and 34% to penicillin, 92% and 22% to ceftriaxone, 48% and 3% to cefepime, 72% and 87% to meropenem, 92% and 10% to cefotaxime, 100% and 97% to levofloxacin, 92% and 80% to clindamycin, and 24% and 50% to erythromycin. All isolates were susceptible to vancomycin. In the penicillin-susceptible subgroup, all A. defectiva isolates were susceptible to ceftriaxone; however, 62% of G. adiacens isolates were ceftriaxone nonsusceptible. PMID- 27216062 TI - Moxifloxacin Improves Treatment Outcomes in Patients with Ofloxacin-Resistant Multidrug-Resistant Tuberculosis. AB - It is unclear whether the use of moxifloxacin (MFX), a newer synthetic fluoroquinolone, results in better outcomes in patients with ofloxacin (OFX) resistant multidrug-resistant tuberculosis (MDR-TB). During the period from April 2006 to December 2013, a total of 2,511 patients with culture-confirmed tuberculosis (TB) were treated at a TB referral hospital in southern Taiwan. Of the 2,511 patients, 325 (12.9%) had MDR-TB, and of those 325 patients, 81 (24.9%) had OFX-resistant MDR-TB and were included in the study. Among the 81 patients with OFX-resistant MDR-TB, 50 (61.7%) were successfully treated and 31 (38.3%) had unfavorable outcomes, including treatment failure (n = 25; 30.9%), loss to follow-up (n = 2; 2.5%), and death (n = 4; 4.9%). Patients treated with MFX had a significantly higher rate of treatment success (77.3% versus 43.2%; odds ratio [OR] = 4.46, 95% confidence interval [CI] = 1.710 to 11.646, P = 0.002) than patients not treated with MFX, especially among those infected with MFX susceptible isolates (40.7%) or isolates with low-level resistance to MFX (28.4%). Multivariate logistic regression analysis showed that treatment with MFX (adjusted odds ratio = 6.54, 95% CI = 1.44 to 29.59, P = 0.015) was the only independent factor associated with treatment success. Mutation at codon 94 in the gyrA gene was the most frequent mutation (68.0%) associated with high-level MFX resistance. Multivariate Cox proportional hazards regression analysis showed that treatment with MFX was also an independent factor associated with early culture conversion (hazard ratio = 3.12, 95% CI = 1.48 to 6.54, P = 0.003). Our results show that a significant proportion of OFX-resistant MDR-TB isolates were susceptible or had low-level resistance to MFX, indicating that patients with OFX resistant MDR-TB benefit from treatment with MFX. PMID- 27216061 TI - The MisR Response Regulator Is Necessary for Intrinsic Cationic Antimicrobial Peptide and Aminoglycoside Resistance in Neisseria gonorrhoeae. AB - During infection, the sexually transmitted pathogen Neisseria gonorrhoeae (the gonococcus) encounters numerous host-derived antimicrobials, including cationic antimicrobial peptides (CAMPs) produced by epithelial and phagocytic cells. CAMPs have both direct and indirect killing mechanisms and help link the innate and adaptive immune responses during infection. Gonococcal CAMP resistance is likely important for avoidance of host nonoxidative killing systems expressed by polymorphonuclear granulocytes (e.g., neutrophils) and intracellular survival. Previously studied gonococcal CAMP resistance mechanisms include modification of lipid A with phosphoethanolamine by LptA and export of CAMPs by the MtrCDE efflux pump. In the related pathogen Neisseria meningitidis, a two-component regulatory system (2CRS) termed MisR-MisS has been shown to contribute to the capacity of the meningococcus to resist CAMP killing. We report that the gonococcal MisR response regulator but not the MisS sensor kinase is involved in constitutive and inducible CAMP resistance and is also required for intrinsic low-level resistance to aminoglycosides. The 4- to 8-fold increased susceptibility of misR-deficient gonococci to CAMPs and aminoglycosides was independent of phosphoethanolamine decoration of lipid A and the levels of the MtrCDE efflux pump and seemed to correlate with a general increase in membrane permeability. Transcriptional profiling and biochemical studies confirmed that expression of lptA and mtrCDE was not impacted by the loss of MisR. However, several genes encoding proteins involved in membrane integrity and redox control gave evidence of being MisR regulated. We propose that MisR modulates the levels of gonococcal susceptibility to antimicrobials by influencing the expression of genes involved in determining membrane integrity. PMID- 27216063 TI - Complete Nucleotide Sequence of an IncI2 Plasmid Coharboring blaCTX-M-55 and mcr 1. AB - We report the complete nucleotide sequence of a plasmid, pA31-12, carrying blaCTX M-55 and mcr-1 from a chicken Escherichia coli isolate. pA31-12 has an IncI2 replicon that displays extensive sequence similarity with pHN1122-1-borne blaCTX M-55 and pHNSHP45-borne mcr-1 Insertion sequences ISEcp1 and ISApl1 are responsible for the mobilization of blaCTX-M-55 and mcr-1, respectively. The colocalization of mcr-1 with an extended-spectrum beta-lactamase gene on a conjugative plasmid may accelerate the dissemination of both genes by coselection. PMID- 27216064 TI - Predicting Antibiotic Resistance in Urinary Tract Infection Patients with Prior Urine Cultures. AB - To improve antibiotic prescribing, we sought to establish the probability of a resistant organism in urine culture given a previous resistant culture in a setting endemic for multidrug-resistant (MDR) organisms. We performed a retrospective analysis of inpatients with paired positive urine cultures. We focused on ciprofloxacin-resistant (cipro(r)) Gram-negative bacteria, extended spectrum-beta-lactamase (ESBL)-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae (CRE), and carbapenem-resistant nonfermenters (CRNF). Comparisons were made between the frequency of each resistance phenotype following a previous culture with the same phenotype and the overall frequency of that phenotype, and odds ratios (ORs) were calculated. We performed a regression to assess the effects of other variables on the likelihood of a repeat resistant culture. A total of 4,409 patients (52.5% women; median age, 70 years) with 19,546 paired positive urine cultures were analyzed. The frequencies of cipro(r) bacteria, ESBL-producing Enterobacteriaceae, CRE, and CRNF among all cultures were 47.7%, 30.6%, 1.7%, and 2.6%, respectively. ORs for repeated resistance phenotypes were 1.87, 3.19, 48.25, and 19.02 for cipro(r) bacteria, ESBL producing Enterobacteriaceae, CRE, and CRNF, respectively (P < 0.001 for all). At 1 month, the frequencies of repeated resistance phenotypes were 77.4%, 66.4%, 57.1%, and 33.3% for cipro(r) bacteria, ESBL-producing Enterobacteriaceae, CRE, and CRNF, respectively. Increasing time between cultures and the presence of an intervening nonresistant culture significantly reduced the chances of a repeat resistant culture. Associations were statistically significant over the duration of follow-up (60 months) for CRE and for up to 6 months for all other pathogens. Knowledge of microbiology results in the six preceding months may assist with antibiotic stewardship and improve the appropriateness of empirical treatment for urinary tract infections (UTIs). PMID- 27216065 TI - Investigation of Elimination Rate, Persistent Subpopulation Removal, and Relapse Rates of Mycobacterium tuberculosis by Using Combinations of First-Line Drugs in a Modified Cornell Mouse Model. AB - Currently, the most effective tuberculosis control method involves case finding and 6 months of chemotherapy. There is a need to improve our understanding about drug interactions, combination activities, and the ability to remove persistent bacteria using the current regimens, particularly in relation to relapse. We aimed to investigate the therapeutic effects of three main components, rifampin (RMP), isoniazid (INH), and pyrazinamide (PZA), in current drug regimens using a modified version of the Cornell mouse model. We evaluated the posttreatment levels of persistent Mycobacterium tuberculosis in the organs of mice using culture filtrate derived from M. tuberculosis strain H37Rv. When RMP was combined with INH, PZA, or INH-PZA, significant additive activities were observed compared to each of the single-drug treatments. However, the combination of INH and PZA showed a less significant additive effect than either of the drugs used on their own. Apparent culture negativity of mouse organs was achieved at 14 weeks of treatment with RMP-INH, RMP-PZA, and RMP-INH-PZA, but not with INH-PZA, when conventional tests, namely, culture on solid agar and in liquid broth, indicated that the organs were negative for bacteria. The relapse rates for RMP-containing regimens were not significantly different from a 100% relapse rate at the numbers of mice examined in this study. In parallel, we examined the organs for the presence of culture filtrate-dependent persistent bacilli after 14 weeks of treatment. Culture filtrate treatment of the organs revealed persistent M. tuberculosis Modeling of mycobacterial elimination rates and evaluation of culture filtrate-dependent organisms showed promise as surrogate methods for efficient factorial evaluation of drug combinations in tuberculosis in mouse models and should be further evaluated against relapse. The presence of culture filtrate-dependent persistent M. tuberculosis is the likely cause of disease relapse in this modified Cornell mouse model. PMID- 27216066 TI - Binding of Daptomycin to Anionic Lipid Vesicles Is Reduced in the Presence of Lysyl-Phosphatidylglycerol. AB - The cytoplasmic membrane of Staphylococcus aureus contains ~20 mol% of the net cationic lipid lysyl-phosphatidylglycerol (LPG). Elevated fractions of LPG are associated with increased resistance to cationic antibiotics, including the lipopeptide daptomycin (DAP). Although the surface charge of the bacterial cytoplasmic membrane is altered by LPG, surface binding of DAP was found to be only moderately affected in anionic vesicles containing 20 mol% LPG. These results suggest that charge repulsion cannot fully explain LPG-mediated resistance to cationic peptides. PMID- 27216067 TI - Modeling Meropenem Treatment, Alone and in Combination with Daptomycin, for KPC Producing Klebsiella pneumoniae Strains with Unusually Low Carbapenem MICs. AB - Klebsiella pneumoniae strains producing K. pneumoniae carbapenemase (KPC) cause serious infections in debilitated and immunocompromised patients and are associated with prolonged hospital stays and increased mortality rates. Daptomycin is a lipopeptide used against Staphylococcus aureus infection and considered inactive against Gram-negative bacteria. We investigated the effectiveness of a daptomycin-meropenem combination by synergy kill curve and a pharmacokinetic/pharmacodynamic model. The combination may represent a novel therapeutic strategy against infections caused by KPC-producing K. pneumoniae strains. PMID- 27216068 TI - Frequency of BKC-1-Producing Klebsiella Species Isolates. AB - BKC-1 is a new class A serine carbapenemase that was recently identified in Klebsiella pneumoniae clinical isolates. The principal objective of this study was to evaluate the frequency of blaBKC-1 by testing a collection of Klebsiella isolates. Only 2 of 635 Klebsiella isolates (0.3%) carried blaBKC-1 The two BKC-1 producing isolates belonged to clonal complex 442 and possessed identical pulsed field gel electrophoresis patterns. The blaBKC-1 gene was inserted into a 10-kb plasmid that was identical to the previously reported plasmid, p60136. The BKC producing K. pneumoniae isolates presented also possessed other mechanisms for beta-lactam resistance, such as genes encoding extended-spectrum beta-lactamases and mutations in the genes ompK35 and ompK36, encoding the major porins. PMID- 27216069 TI - A Transposon Screen Identifies Genetic Determinants of Vibrio cholerae Resistance to High-Molecular-Weight Antibiotics. AB - Gram-negative bacteria are notoriously resistant to a variety of high-molecular weight antibiotics due to the limited permeability of their outer membrane (OM). The basis of OM barrier function and the genetic factors required for its maintenance remain incompletely understood. Here, we employed transposon insertion sequencing to identify genes required for Vibrio cholerae resistance to vancomycin and bacitracin, antibiotics that are thought to be too large to efficiently penetrate the OM. The screen yielded several genes whose protein products are predicted to participate in processes important for OM barrier functions and for biofilm formation. In addition, we identified a novel factor, designated vigA (for vancomycin inhibits growth), that has not previously been characterized or linked to outer membrane function. The vigA open reading frame (ORF) codes for an inner membrane protein, and in its absence, cells became highly sensitive to glycopeptide antibiotics (vancomycin and ramoplanin) and bacitracin but not to other large antibiotics or detergents. In contrast to wild type (WT) cells, the vigA mutant was stained with fluorescent vancomycin. These observations suggest that VigA specifically prevents the periplasmic accumulation of certain large antibiotics without exerting a general role in the maintenance of OM integrity. We also observed marked interspecies variability in the susceptibilities of Gram-negative pathogens to glycopeptides and bacitracin. Collectively, our findings suggest that the OM barrier is not absolute but rather depends on specific OM-antibiotic interactions. PMID- 27216070 TI - High Prevalence of Heterogeneously Glycopeptide-Intermediate Coagulase-Negative Staphylococci in Sternal Wounds. PMID- 27216071 TI - Spread of Plasmids Carrying Multiple GES Variants. AB - Five GES-producing Enterobacteriaceae isolates that displayed an extended spectrum beta-lactamase (ESBL) phenotype harbored two GES variants: GES-7 ESBL and GES-6 carbapenemase. In all isolates, the two GES alleles were located on the same integron that was inserted into an 80-kb IncM1 self-conjugative plasmid. Whole-genome sequencing suggested in vivo horizontal gene transfer of the plasmid along with clonal diffusion of Enterobacter cloacae To our knowledge, this is the first description in Europe of clustered Enterobacteriaceae isolates carrying two GES beta-lactamases, of which one has extended activity toward carbapenems. PMID- 27216072 TI - In Vivo Pharmacodynamic Target Assessment of Delafloxacin against Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae in a Murine Lung Infection Model. AB - Delafloxacin is a broad-spectrum anionic fluoroquinolone under development for the treatment of bacterial pneumonia. The goal of the study was to determine the pharmacokinetic/pharmacodynamic (PK/PD) targets in the murine lung infection model for Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae Four isolates of each species were utilized for in vivo studies: for S. aureus, one methicillin-susceptible and three methicillin-resistant isolates; S. pneumoniae, two penicillin-susceptible and two penicillin-resistant isolates; K. pneumoniae, one wild-type and three extended-spectrum beta-lactamase-producing isolates. MICs were determined using CLSI methods. A neutropenic murine lung infection model was utilized for all treatment studies, and drug dosing was by the subcutaneous route. Single-dose plasma pharmacokinetics was determined in the mouse model after administration of 2.5, 10, 40, and 160 mg/kg. For in vivo studies, 4-fold-increasing doses of delafloxacin (range, 0.03 to 160 mg/kg) were administered every 6 h (q6h) to infected mice. Treatment outcome was measured by determining organism burden in the lung (CFU counts) at the end of each experiment (24 h). The Hill equation for maximum effect (Emax) was used to model the dose-response data. The magnitude of the PK/PD index, the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC), associated with net stasis and 1-log kill endpoints was determined in the lung model for all isolates. MICs ranged from 0.004 to 1 mg/liter. Single dose PK parameter ranges include the following: for maximum concentration of drug in serum (Cmax), 2 to 70.7 mg/liter; AUC from 0 h to infinity (AUC0-infinity), 2.8 to 152 mg . h/liter; half-life (t1/2), 0.7 to 1 h. At the start of therapy mice had 6.3 +/- 0.09 log10 CFU/lung. In control mice the organism burden increased 2.1 +/- 0.44 log10 CFU/lung over the study period. There was a relatively steep dose-response relationship observed with escalating doses of delafloxacin. Maximal organism reductions ranged from 2 log10 to more than 4 log10 The median free-drug AUC/MIC magnitude associated with net stasis for each species group was 1.45, 0.56, and 40.3 for S. aureus, S. pneumoniae, and K. pneumoniae, respectively. AUC/MIC targets for the 1-log kill endpoint were 2- to 5-fold higher. Delafloxacin demonstrated in vitro and in vivo potency against a diverse group of pathogens, including those with phenotypic drug resistance to other classes. These results have potential relevance for clinical dose selection and evaluation of susceptibility breakpoints for delafloxacin for the treatment of lower respiratory tract infections involving these pathogens. PMID- 27216073 TI - New Regimen for Continuous Infusion of Vancomycin in Critically Ill Patients. AB - Despite the development of new agents with activity against Gram-positive bacteria, vancomycin remains one of the primary antibiotics for critically ill septic patients. Because sepsis can alter antimicrobial pharmacokinetics, the development of an appropriate dosing strategy to provide adequate concentrations is crucial. The aim of this study was to prospectively validate a new dosing regimen of vancomycin given by continuous infusion (CI) to septic patients. We included all adult septic patients admitted to a mixed intensive care unit (ICU) between January 2012 and May 2013, who were treated with a new vancomycin CI regimen consisting of a loading dose of 35 mg/kg of body weight given as a 4-h infusion, followed by a daily CI dose adapted to creatinine clearance (CrCL), as estimated by the Cockcroft-Gault formula (median dose, 2,112 [1,500 to 2,838] mg). Vancomycin concentrations were measured at the end of the loading dose (T1), at 12 h (T2), at 24 h (T3), and the day after the start of therapy (T4). Vancomycin concentrations of 20 to 30 mg/liter at T2, T3, and T4 were considered adequate. A total of 107 patients (72% male) were included. Median age, weight, and CrCL were 59 (interquartile range [IQR], 48 to 71) years, 75 (IQR, 65 to 85) kg, and 94 (IQR, 56 to 140) ml/min, respectively. Vancomycin concentrations were 44 (IQR, 37 to 49), 25 (IQR, 21 to 32), 22 (IQR, 19 to 28), and 26 (IQR, 22 to 29) mg/liter at T1, T2, T3, and T4, respectively. Concentrations were adequate in 56% (60/107) of patients at T2, in 54% (57/105) at T3, and in 73% (41/56) at T4. This vancomycin regimen permitted rapid attainment of target concentrations in serum for most patients. Concentrations were insufficient in only 16% of patients at 12 h of treatment. PMID- 27216074 TI - In Vitro Susceptibility of Global Surveillance Isolates of Pseudomonas aeruginosa to Ceftazidime-Avibactam (INFORM 2012 to 2014). AB - Broth microdilution antimicrobial susceptibility testing was performed for ceftazidime-avibactam and comparator agents against 7,062 clinical isolates of Pseudomonas aeruginosa collected from 2012 to 2014 in four geographic regions (Europe, Asia/South Pacific, Latin America, Middle East/Africa) as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance program. The majority of isolates were susceptible to ceftazidime avibactam, with the proportions susceptible differing marginally across the four regions (MIC90, 8 to 16 MUg/ml; 88.7 to 93.2% susceptible), in contrast to lower susceptibilities to the following comparator beta-lactam agents: ceftazidime (MIC90, 32 to 64 MUg/ml; 71.5 to 80.8% susceptible), meropenem (MIC90, >8 MUg/ml; 64.9 to 77.4% susceptible), and piperacillin-tazobactam (MIC90, >128 MUg/ml; 62.3 to 71.3% susceptible). Compared to the overall population, susceptibility to ceftazidime-avibactam of isolates that were nonsusceptible to ceftazidime (n = 1,627) was reduced to between 56.8% (Middle East/Africa; MIC90, 64 MUg/ml) and 68.9% (Asia/South Pacific; MIC90, 128 MUg/ml), but these percentages were higher than susceptibilities to other beta-lactam agents (0 to 44% susceptible, depending on region and agent; meropenem MIC90, >8 MUg/ml; 26.5 to 43.9% susceptible). For this subset of isolates, susceptibilities to amikacin (MIC90, >32 MUg/ml; 53.2 to 80.0% susceptible) and colistin (MIC90, 1 MUg/ml; 98.5 to 99.5% susceptible) were comparable to or higher than that of ceftazidime avibactam. A similar observation was made with isolates that were nonsusceptible to meropenem (n = 1,926), with susceptibility to ceftazidime-avibactam between 67.8% (Middle East/Africa; MIC90, 64 MUg/ml) and 74.2% (Europe; MIC90, 32 MUg/ml) but again with reduced susceptibility to comparators except for amikacin (MIC90, >32 MUg/ml; 56.8 to 78.7% susceptible) and colistin (MIC90, 1 MUg/ml; 98.9 to 99.3% susceptible). Of the 8% of isolates not susceptible to ceftazidime avibactam, the nonsusceptibility of half could be explained by their possession of genes encoding metallo-beta-lactamases. The data reported here are consistent with results from other country-specific and regional surveillance studies and show that ceftazidime-avibactam demonstrates in vitro activity against globally collected clinical isolates of P. aeruginosa, including isolates that are resistant to ceftazidime and meropenem. PMID- 27216075 TI - Changes in the Frequencies of beta-Lactamase Genes among Enterobacteriaceae Isolates in U.S. Hospitals, 2012 to 2014: Activity of Ceftazidime-Avibactam Tested against beta-Lactamase-Producing Isolates. AB - Among 15,588 Enterobacteriaceae isolates collected in 63 U.S. hospitals from 2012 to 2014, 2,129 (13.7%) displayed an extended-spectrum beta-lactamase (ESBL) phenotype. These rates were similar over time (13.2 to 13.9%); however, differences among Escherichia coli (12.7 and 15.1% in 2012 and 2014; P = 0.007) and Klebsiella pneumoniae (18.9 and 15.5% in 2012 and 2014; P = 0.006) were noted when comparing 2014 and 2012. Carbapenem-resistant Enterobacteriaceae (CRE) (2.3 and 1.8%) and carbapenem-resistant K. pneumoniae (6.8 and 5.1%; P = 0.003) rates were lower in 2014 than in 2012. Isolates carrying blaCTX-M-15-like genes were stable (42.1 to 42.4%), but a decrease among E. coli isolates (59.1 and 49.7%; P = 0.008) and an increase among K. pneumoniae isolates (32.7 and 41.2%; P = 0.022) in 2014 were observed. Isolates carrying blaKPC (304) decreased over the years (16.5 and 10.9%; P = 0.008), mainly due to the decrease in K. pneumoniae isolates harboring blaKPC (n = 285; 35.6 and 28.4%; P = 0.041) in hospitals in the Mid Atlantic and South Atlantic regions, where these isolates were highly prevalent during 2012 and 2013. Isolates carrying blaCMY-2-like and blaCTX-M-14-like genes increased (8.2 and 11.9% and 9.1 and 12.9%, respectively; P = 0.04 for both), and those producing blaSHV ESBL decreased (24.9 and 12.7%; P < 0.001) over the studied years, due to a decreased occurrence of the enzymes among K. pneumoniae isolates. Other enzymes were detected in smaller numbers of isolates, including four K. pneumoniae isolates carrying blaNDM-1 metallo-beta-lactamase (two in 2012 and two in 2014). Ceftazidime-avibactam, a recently approved beta-lactamase inhibitor combination, was very active against the ESBL phenotype isolates (MIC50/90, 0.12 and 1 MUg/ml; 99.7% susceptible) and CRE strains (MIC50/90, 0.5 and 2 MUg/ml; 98.5% susceptible) that displayed elevated MIC values for many comparator agents. In conclusion, significant changes were noted in the frequencies of isolates harboring various beta-lactamases among U.S. hospitals between 2012 and 2014 that will require continued monitoring. PMID- 27216076 TI - Simultaneous Determination of Eight beta-Lactam Antibiotics, Amoxicillin, Cefazolin, Cefepime, Cefotaxime, Ceftazidime, Cloxacillin, Oxacillin, and Piperacillin, in Human Plasma by Using Ultra-High-Performance Liquid Chromatography with Ultraviolet Detection. AB - A simple and rapid ultra-high-performance liquid chromatography (UHPLC) method using UV detection was developed for the simultaneous determination of eight beta lactam antibiotics in human plasma, including four penicillins, amoxicillin (AMX), cloxacillin (CLX), oxacillin (OXA), and piperacillin (PIP), and four cephalosporins, cefazolin (CFZ), cefepime (FEP), cefotaxime (CTX), and ceftazidime (CAZ). One hundred-microliter samples were spiked with thiopental as an internal standard, and proteins were precipitated by acetonitrile containing 0.1% formic acid. Separation was achieved on a pentafluorophenyl (PFP) column with a mobile phase composed of phosphoric acid (10 mM) and acetonitrile in gradient elution mode at a flow rate of 500 MUl/min. Detection was performed at 230 nm for AMX, CLX, OXA, and PIP and 260 nm for CFZ, FEP, CTX, and CAZ. The total analysis time did not exceed 13 min. The method was found to be linear at concentrations ranging from 2 to 100 mg/liter for each compound, and all validation parameters fulfilled international requirements. Between- and within run accuracy errors ranged from -5.2% to 11.4%, and precision was lower than 14.2%. This simple method requires small-volume samples and can easily be implemented in most clinical laboratories to promote the therapeutic drug monitoring of beta-lactam antibiotics. The simultaneous determination of several antibiotics considerably reduces the time to results for clinicians, which may improve treatment efficiency, especially in critically ill patients. PMID- 27216077 TI - Transcriptome Profiling of Antimicrobial Resistance in Pseudomonas aeruginosa. AB - Emerging resistance to antimicrobials and the lack of new antibiotic drug candidates underscore the need for optimization of current diagnostics and therapies to diminish the evolution and spread of multidrug resistance. As the antibiotic resistance status of a bacterial pathogen is defined by its genome, resistance profiling by applying next-generation sequencing (NGS) technologies may in the future accomplish pathogen identification, prompt initiation of targeted individualized treatment, and the implementation of optimized infection control measures. In this study, qualitative RNA sequencing was used to identify key genetic determinants of antibiotic resistance in 135 clinical Pseudomonas aeruginosa isolates from diverse geographic and infection site origins. By applying transcriptome-wide association studies, adaptive variations associated with resistance to the antibiotic classes fluoroquinolones, aminoglycosides, and beta-lactams were identified. Besides potential novel biomarkers with a direct correlation to resistance, global patterns of phenotype-associated gene expression and sequence variations were identified by predictive machine learning approaches. Our research serves to establish genotype-based molecular diagnostic tools for the identification of the current resistance profiles of bacterial pathogens and paves the way for faster diagnostics for more efficient, targeted treatment strategies to also mitigate the future potential for resistance evolution. PMID- 27216078 TI - Epigenetic reprogramming of fallopian tube fimbriae in BRCA mutation carriers defines early ovarian cancer evolution. AB - The exact timing and contribution of epigenetic reprogramming to carcinogenesis are unclear. Women harbouring BRCA1/2 mutations demonstrate a 30-40-fold increased risk of high-grade serous extra-uterine Mullerian cancers (HGSEMC), otherwise referred to as 'ovarian carcinomas', which frequently develop from fimbrial cells but not from the proximal portion of the fallopian tube. Here we compare the DNA methylome of the fimbrial and proximal ends of the fallopian tube in BRCA1/2 mutation carriers and non-carriers. We show that the number of CpGs displaying significant differences in methylation levels between fimbrial and proximal fallopian tube segments are threefold higher in BRCA mutation carriers than in controls, correlating with overexpression of activation-induced deaminase in their fimbrial epithelium. The differentially methylated CpGs accurately discriminate HGSEMCs from non-serous subtypes. Epigenetic reprogramming is an early pre-malignant event integral to BRCA1/2 mutation-driven carcinogenesis. Our findings may provide a basis for cancer-preventative strategies. PMID- 27216080 TI - Re: PI-RADS version 2: what you need to know. PMID- 27216079 TI - Feasibility of fluorescence energy transfer system for imaging the renoprotective effects of aliskiren in diabetic mice. AB - INTRODUCTION: We investigated the feasibility of using a fluorescence resonance energy transfer system to image enzymatic activity in order to evaluate the effects of aliskiren (a direct renin inhibitor) on diabetic nephropathy. MATERIALS AND METHODS: First, we induced diabetes in C57BL/6J mice using streptozotocin, then treated them with either aliskiren (25 mg/kg/day) or the angiotensin type 1 receptor blocker valsartan (15 mg/kg/day) for four weeks. Finally, we utilized renin fluorescence resonance energy transfer substrate to assess renin activity. RESULTS: Renin activity was much higher in the kidneys of diabetic mice compared to those of the non-diabetic control mice. While aliskiren inhibited this activity, valsartan did not. We noted that production of reactive oxygen species intensified and the bioavailability of nitric oxide diminished in the glomeruli of diabetic mice. Aliskiren and valsartan significantly ameliorated these effects. They suppressed glomerular production of reactive oxygen species and urinary albumin excretion. In fact, urinary albumin excretion in diabetic mice treated with aliskiren or valsartan was lower than that in untreated diabetic mice. Furthermore, aliskiren and valsartan significantly reduced glomerular permeability by maintaining the glomerular endothelial surface layer. CONCLUSION: Fluorescence resonance energy transfer could provide a new tool for evaluating tissue and plasma enzymatic activity. PMID- 27216081 TI - Easy-to-use clinical measures of walking ability in children and adolescents with cerebral palsy: a systematic review. AB - OBJECTIVE: The aims of this systematic review were to identify quick, simple and easy-to-use measures of walking ability currently used to assess children and adolescents with cerebral palsy (CP), and to evaluate the clinical utility and psychometric properties of these measures. DATA SOURCES: The PubMed, CINAHL, SPORTDiscus and MEDLINE databases were searched up to March 2015. REVIEW METHODS: Two independent reviewers rated the methodological quality of the identified measures using the COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) checklist. RESULTS: The 1-Minute Walk Test, Timed Up and Go Test, ABILOCO-Kids, Gillette Functional Assessment Questionnaire and Functional Mobility Scale were identified. Each measure can be carried out within 5 min with limited equipment, and does not require examiner training. There was "limited" to "strong" evidence on the reliability and validity of these measurements, whereas evidence on measurement error and responsiveness was limited. CONCLUSION: The identified measures in this systematic review may be considered for the clinical measurement of walking ability in children and adolescents with CP in a quick, simple and easy-to-use manner. However, there is overall a lack of evidence on the psychometric properties of these tools. The lack of evidence regarding measurement error and responsiveness might limit their value in measuring change over time. Implications for Rehabilitation The ABILOCO Kids, 1-Minute Walk Test, Timed Up and Go Test, Gillette Functional Assessment Questionnaire, Functional Mobility Scale can be performed within 5 min with limited equipment, and do not require examiner training for measuring of walking ability in children and adolescents with cerebral palsy. The clinicians should use these measurement tools carefully when assessing change over time as the available evidence on measurement error and responsiveness is limited. When clinicians use these measurement tools, the psychometric properties reported in this systematic review should be considered in the selection of tools and subsequent interpretation of results. PMID- 27216082 TI - Evidence from two independent backcross experiments supports genetic linkage of microsatellite Hcms8a20, but not other candidate loci, to a major ivermectin resistance locus in Haemonchus contortus. AB - Haemonchus contortus is the leading parasitic nematode species used to study anthelmintic drug resistance. A variety of candidate loci have been implicated as being associated with ivermectin resistance in this parasite but definitive evidence of their importance is still lacking. We have previously performed two independent serial backcross experiments to introgress ivermectin resistance loci from two H. contortus ivermectin-resistant strains - MHco4(WRS) and MHco10(CAVR) into the genetic background of the ivermectin-susceptible genome reference strain MHco3(ISE). We have interrogated a number of candidate ivermectin resistance loci in the resulting backcross populations and assessed the evidence for their genetic linkage to an ivermectin resistance locus. These include the microsatellite marker Hcms8a20 and six candidate genes Hco-glc-5, Hco-avr-14, Hco lgc-37 (previously designated Hco-hg-1), Hco-pgp-9 (previously designated Hco-pgp 1), Hco-pgp-2 and Hco-dyf-7. We have sampled the haplotype diversity of amplicon markers within, or adjacent to, each of these loci in the parental strains and fourth generation backcross populations to assess the evidence for haplotype introgression from the resistant parental strain into the genomic background of the susceptible parental strain in each backcross. The microsatellite Hcms8a20 locus showed strong evidence of such introgression in both independent backcrosses, suggesting it is linked to an important ivermectin resistance mutation in both the MHco4(WRS) and MHco10(CAVR) strains. In contrast, Hco-glc-5, Hco-avr-14, Hco-pgp-9 and Hco-dyf-7 showed no evidence of introgression in either backcross. Hco-lgc-37 and Hco-pgp-2 showed only weak evidence of introgression in the MHco3/4 backcross but not in the MHco3/10 backcross. Overall, these results suggest that microsatellite marker Hcms8a20, but not the other candidate genes tested, is linked to a major ivermectin resistance locus in the MHco4(WRS) and MHco10(CAVR) strains. This work also emphasises the need for genome-wide approaches to identify mutations responsible for the ivermectin resistance in this parasite. PMID- 27216083 TI - Relative Importance of Central and Peripheral Adiposities on Cardiometabolic Variables in Females: A Japanese Population-Based Study. AB - In epidemiological studies, there is little evidence regarding the relative impact of central adiposity and peripheral adiposity on cardiometabolic risk factors, especially in Asian populations. This study investigated associations between central-to-peripheral fat ratios and cardiometabolic variables using data from a population-based study of Japanese women. The source population was composed of 1800 women aged 50 yr or older at the 15th- to 16th-yr follow-up survey of the Japanese Population-Based Osteoporosis Cohort Study. This study analyzed cross-sectional data from 998 women for whom complete information about body fat variables according to dual-energy X-ray absorptiometry, cardiometabolic variables, and potential confounding factors was available. Both before and after adjusting for potential confounding factors, trunk-to-appendicular fat ratios showed significant (p < 0.05) correlations with brachial-ankle pulse wave velocity, serum lipids, and hemoglobin A1c levels. Relationships between fat ratios and cardiometabolic variables were independent of relationships between fat volumes (in whole body or in trunk) and cardiometabolic variables. Furthermore, relationships between trunk-to-appendicular fat ratios and cardiometabolic variables were observed among women in the lowest tertile of total body fat (brachial-ankle pulse wave velocity, beta = 0.08; high-density lipoprotein cholesterol, beta = -0.32; low-density lipoprotein cholesterol, beta = 0.15; and hemoglobin A1C, beta = 0.16; p < 0.05, respectively). Central adiposity is more related to cardiometabolic variables than peripheral adiposity. Information on central-to-peripheral fat ratios is particularly valuable for the evaluation of relatively thin Japanese women. PMID- 27216084 TI - Identification of a Vitis vinifera endo-beta-1,3-glucanase with antimicrobial activity against Plasmopara viticola. AB - Inducible plant defences against pathogens are stimulated by infections and comprise several classes of pathogenesis-related (PR) proteins. Endo-beta-1,3 glucanases (EGases) belong to the PR-2 class and their expression is induced by many pathogenic fungi and oomycetes, suggesting that EGases play a role in the hydrolysis of pathogen cell walls. However, reports of a direct effect of EGases on cell walls of plant pathogens are scarce. Here, we characterized three EGases from Vitis vinifera whose expression is induced during infection by Plasmopara viticola, the causal agent of downy mildew. Recombinant proteins were expressed in Escherichia coli. The enzymatic characteristics of these three enzymes were measured in vitro and in planta. A functional assay performed in vitro on germinated P. viticola spores revealed a strong anti-P. viticola activity for EGase3, which strikingly was that with the lowest in vitro catalytic efficiency. To our knowledge, this work shows, for the first time, the direct effect against downy mildew of EGases of the PR-2 family from Vitis. PMID- 27216085 TI - Informal caregivers' burden and stress in caring for stroke survivors with spatial neglect: an exploratory mixed-method study. AB - BACKGROUND: Spatial neglect prolongs stroke survivors' recovery to independence. However, little is known about the impact of spatial neglect on caregivers of stroke survivors. OBJECTIVE: To explore the factors associated with burden and stress among informal caregivers of stroke survivors with spatial neglect. METHODS: Following the previous study of 108 stroke survivors, we reached 24 stroke survivors' caregivers, and 20 caregivers (age: M+/-SD=56.9+/-12.7 years; 12 females) completed the study. 10 survivors had symptoms of spatial neglect, and 10 did not (i.e., SN+ or SN-, respectively) at the time when discharged from inpatient rehabilitation, which was 9.3+/-6.2 months before the present study. Via a semi-structured telephone interview, we assessed caregivers' burden and stress qualitatively and quantitatively. RESULTS: No difference was observed across caregiver groups in cognitive function, depressive mood, or community mobility. In comparison, caregivers of the SN+ group allocated more time to care, controlling for survivors' disability (adjusted effective size d = 1.80). Their self-perceived burden and stress were more severe than the other group (adjusted d = .99). Qualitative analysis indicated caregivers of the SN+ group were more likely to describe economic stressors and undesirable changes in career and vacation planning. While 80% of participants preferred their care recipients to receive additional motor or mobility therapy, caregivers of the SN+ group were more likely to suggest additional therapy for cognitive impairment. CONCLUSIONS: This exploratory study suggests that spatial neglect may heighten caregivers' burden and stress levels. Future studies with a large sample size are required. PMID- 27216086 TI - In vitro cell-based assays for evaluation of antioxidant potential of plant derived products. AB - Several plant-derived compounds have been screened by antioxidant assays, but many of these results are questionable, since they do not evaluate the pharmacologic parameters. In fact, the development of better antioxidants stills a great challenge. In vitro cell-based assays have been employed to assess the antioxidant effect of various compounds at subcellular level. Cell-based assays can also reveal compounds able to enhance the antioxidant pathways, but without direct radical scavenging action (which could not be detected by traditional assays). These methodologies are general of easy implementation and reproducible making them suitable for the early stages of drug discovery. Hydrogen peroxide, a nonradical derivative of oxygen, can be employed as an oxidative agent in these assays due its biochemical properties (presence of all biological systems, solubility) and capacity to induce cell death. Truthfully, if their limitations are understood (such as difference on cell metabolism when in in vitro conditions), these cell-based assays can provide useful information about the pathways involved in the protective effects of phytochemicals against cell death induced by oxidative stress, which can be exploited to develop new therapeutic approaches. PMID- 27216087 TI - Footprints in the Sand: Personal, Psychological, and Relational Profiles of Religious, Spiritual, and Atheist LGB Individuals. AB - The present study offers a comparison of the demographic features and lived experiences of lesbian, gay, and bisexual (LGB) individuals with religious, spiritual, or atheist (R/S/A) belief systems. In this sample of 212 participants, the relationship of participants' R/S/A beliefs to personal variables (e.g., age, gender, race), mental health variables (e.g., life satisfaction, psychological distress, internalized heterosexism, self-esteem), and relational variables (e.g., outness, connection to LGBTQ communities) were assessed. Correlational analyses indicated that level of R/S/A belief was unrelated to self-esteem, life satisfaction, or psychological distress; however, greater religious belief was correlated positively and significantly with internalized heterosexism and outness as LGB. To test the interactions of R/S/A beliefs and categorical variables of interest (e.g., race), log-linear analyses with follow-up chi-square tests were conducted. Findings suggested more similarities than differences for LGB people across R/S/A systems of belief. Limitations and implications for future research are discussed. PMID- 27216088 TI - The Potential for Infrastructure Benefits and the Responsiveness Requirement. PMID- 27216089 TI - Clinical Trials Infrastructure as a Quality Improvement Intervention in Low- and Middle-Income Countries. AB - Mounting evidence suggests that participation in clinical trials confers neither advantage nor disadvantage on those enrolled. Narrow focus on the question of a "trial effect," however, distracts from a broader mechanism by which patients may benefit from ongoing clinical research. We hypothesize that the existence of clinical trials infrastructure-the organizational culture, systems, and expertise that develop as a product of sustained participation in cooperative clinical trials research-may function as a quality improvement lever, improving the quality of care and outcomes of all patients within an institution or region independent of their individual participation in trials. We further contend that this "infrastructure effect" can yield particular benefits for patients in low- and middle-income countries (LMICs). The hypothesis of an infrastructure effect as a quality improvement intervention, if correct, justifies enhanced research capacity in LMIC as a pillar of health system development. PMID- 27216090 TI - The Infrastructure Effect: Scientific Conjecture or Wishful Thinking? PMID- 27216091 TI - If Research Is a Pillar of Health System Development, Why Only Focus on Clinical Trials? PMID- 27216092 TI - Never Look a Gift Horse in the Mouth? Four Reasons Not to Blur the Line Between Research and Care in Low- and Middle-Income Countries. PMID- 27216093 TI - "Reasonable Availability" Criterion Remains Salient. PMID- 27216094 TI - The Good Example: Potential of Clinical Research to Expand Quality Care in Low- and Middle-Income Countries. PMID- 27216095 TI - Clinical Trials Cannot Substitute for Health System Strengthening Initiatives or Specifically Designed Health Policy and Systems Research. PMID- 27216096 TI - Broadening the "Infrastructure Effect": Lessons from the Early Development of Research Ethics in Eastern Europe. PMID- 27216097 TI - Not Just "Study Drugs" for the Rich: Stimulants as Moral Tools for Creating Opportunities for Socially Disadvantaged Students. AB - An argument in the cognitive enhancement literature is that using stimulants in populations of healthy but socially disadvantaged individuals mistakenly attributes pathology to nonpathological individuals who experience social inequalities. As the argument goes, using stimulants as cognitive-enhancing drugs to solve the social problem of poorly educated students in inadequate schools misattributes the problem as an individual medical problem, when it is really a collective sociopolitical problem. I challenge this argument on the grounds that not all types of enhancement have to be explained in medical terms, but rather at least one conception of enhancement can be explained in social terms-opportunity maintenance. Therefore, I propose that as a moral requirement we ought to explore whether stimulants could be a means of remedying underprivileged children's experiences of social inequalities that are borne from inadequate schools for the sake of increasing their chances for opportunities and well-being. PMID- 27216098 TI - Cognitive Enhancement in Healthy Children Will Not Close the Achievement Gap in Education. PMID- 27216099 TI - Pharmacists Can't Administer Opportunity: The Role of Neuroenhancers in Educational Inequalities. PMID- 27216100 TI - Hindering Abilities or Maintaining Opportunities? Using Medical Resources for Social Deficits. PMID- 27216101 TI - Securing Opportunities for the Disadvantaged, or Medicalization Through the Back Door? PMID- 27216102 TI - Using Stimulants to Tackle Social Disadvantages: Interesting in Theory, Problematic in Practice. PMID- 27216103 TI - A Rawlsian Version of the Opportunity Maintenance Thesis. PMID- 27216104 TI - Promoting Stimulants to Increase Educational Equality: Some Concerns. PMID- 27216105 TI - Self-Pathologizing and the Perception of Necessity: Two Major Risks of Providing Stimulants to Educationally Underprivileged Students. PMID- 27216109 TI - Response to Open Peer Commentaries on "Not Just 'Study Drugs' for The Rich: Stimulants as Moral Tools for Creating Opportunities for Socially Disadvantaged Students". PMID- 27216110 TI - Updated Clinical Practice Guidelines on Heart Failure: An International Alignment. PMID- 27216111 TI - 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. PMID- 27216113 TI - Nanoscience and Nanotechnology around the World. PMID- 27216115 TI - Prospects for Thermal Atomic Layer Etching Using Sequential, Self-Limiting Fluorination and Ligand-Exchange Reactions. AB - Thermal atomic layer etching (ALE) of Al2O3 and HfO2 using sequential, self limiting fluorination and ligand-exchange reactions was recently demonstrated using HF and tin acetylacetonate (Sn(acac)2) as the reactants. This new thermal pathway for ALE represents the reverse of atomic layer deposition (ALD) and should lead to isotropic etching. Atomic layer deposition and ALE can together define the atomic layer growth and removal steps required for advanced semiconductor fabrication. The thermal ALE of many materials should be possible using fluorination and ligand-exchange reactions. The chemical details of ligand exchange can lead to selective ALE between various materials. Thermal ALE could produce conformal etching in high-aspect-ratio structures. Thermal ALE could also yield ultrasmooth thin films based on deposit/etch-back methods. Enhancement of ALE rates and possible anisotropic ALE could be achieved using radicals or ions together with thermal ALE. PMID- 27216116 TI - Coping with the metabolic stress of leaving home. AB - Detachment from extracellular matrix causes metabolic defects that transformed cells must overcome in order to survive and proliferate outside of their normal niche. A recent report from Jiang et al. published in Nature describes how cancer cells grown in suspension utilize reductive carboxylation of glutamine to transfer reducing power from the cytosol to mitochondria to detoxify reactive oxygen species and promote anchorage-independent growth and survival. PMID- 27216112 TI - Digital Cognitive Behavioural Therapy for Insomnia versus sleep hygiene education: the impact of improved sleep on functional health, quality of life and psychological well-being. Study protocol for a randomised controlled trial. AB - BACKGROUND: Previous research has demonstrated that digital CBT (dCBT), delivered via the Internet, is a scalable and effective intervention for treating insomnia in otherwise healthy adults and leads to significant improvements in primary outcomes relating to sleep. The majority of people with insomnia, however, seek help because of the functional impact and daytime consequences of poor sleep, not because of sleep discontinuity per se. Although some secondary analyses suggest that dCBT may have wider health benefits, no adequately powered study has investigated these as a primary endpoint. This study specifically aims to investigate the impact of dCBT for insomnia upon health and well-being, and will investigate sleep-related changes as mediating factors. METHODS/DESIGN: We propose a pragmatic, parallel-group, randomised controlled trial of 1000 community participants meeting criteria for insomnia disorder. In the DIALS trial (Digital Insomnia therapy to Assist your Life as well as your Sleep), participants will be randomised to dCBT delivered using web and/or mobile channels (in addition to treatment as usual (TAU)) or to sleep hygiene education (SHE), comprising a website plus a downloadable booklet (in addition to TAU). Online assessments will take place at 0 (baseline), 4 (mid-treatment), 8 (post treatment), and 24 (follow-up) weeks. At week 25 all participants allocated to SHE will be offered dCBT, at which point the controlled element of the trial will be complete. Naturalistic follow-up will be invited at weeks 36 and 48. Primary outcomes are functional health and well-being at 8 weeks. Secondary outcomes are mood, fatigue, sleepiness, cognitive function, productivity and social functioning. All main analyses will be carried out at the end of the final controlled follow-up assessments and will be based on the intention-to-treat principle. Further analyses will determine whether observed changes in functional health and well-being are mediated by changes in sleep. The trial is funded by Big Health Ltd. DISCUSSION: This study will be the first large-scale, specifically designed investigation of the health and well-being benefits of CBT for insomnia, and the first examination of the association between CBT-mediated sleep improvement and health status. TRIAL REGISTRATION: ISRCTN60530898 . PMID- 27216117 TI - Implementation and validation of a combined MRI-CT-based cervical cancer brachytherapy program using existing infrastructure. AB - PURPOSE: To describe the implementation of an MRI-CT-based cervical cancer brachytherapy (BT) program using existing infrastructure. To evaluate its impact on treatment planning. METHODS AND MATERIALS: A step-wise method was used to design and implement three-dimensional-based planning. Prospective risk analysis was used to create a process map and planning protocol. To evaluate the program, charts of cervical cancer patients treated curatively between January 2013 and December 2014, with at least one MRI during BT planning, were reviewed. Dosimetric comparisons were made between prescription point used and that of the traditional Point A and between MRI-planned treatments and CT-planned treatments. They were evaluated for differences between plans as well as adherence to Groupe Europeen de Curietherapie-European Society for Radiotherapy & Oncology (GEC ESTRO) recommendations for high-risk clinical target volume coverage and organs at-risk constraints. RESULTS: Implementation of the MRI-CT planning program occurred using existing infrastructure. Key to the implementation was communication between departments and the use of a process map to document the workflow. Eighty percent of treatments were prescribed to a point other than Point A, there were no major differences between the MRI-planned and CT-planned (with MRI guidance) treatments, and GEC-ESTRO recommendations were met for target coverage and organs at risk dose constraints. CONCLUSIONS: It was feasible to implement an MRI-CT-based cervical cancer BT planning program using existing infrastructure and that resulting plans meet GEC-ESTRO recommendations. PMID- 27216118 TI - Monte Carlo dose calculations for high-dose-rate brachytherapy using GPU accelerated processing. AB - PURPOSE: Current clinical brachytherapy dose calculations are typically based on the Association of American Physicists in Medicine Task Group report 43 (TG-43) guidelines, which approximate patient geometry as an infinitely large water phantom. This ignores patient and applicator geometries and heterogeneities, causing dosimetric errors. Although Monte Carlo (MC) dose calculation is commonly recognized as the most accurate method, its associated long computational time is a major bottleneck for routine clinical applications. This article presents our recent developments of a fast MC dose calculation package for high-dose-rate (HDR) brachytherapy, gBMC, built on a graphics processing unit (GPU) platform. METHODS AND MATERIALS: gBMC-simulated photon transport in voxelized geometry with physics in (192)Ir HDR brachytherapy energy range considered. A phase-space file was used as a source model. GPU-based parallel computation was used to simultaneously transport multiple photons, one on a GPU thread. We validated gBMC by comparing the dose calculation results in water with that computed TG-43. We also studied heterogeneous phantom cases and a patient case and compared gBMC results with Acuros BV results. RESULTS: Radial dose function in water calculated by gBMC showed <0.6% relative difference from that of the TG-43 data. Difference in anisotropy function was <1%. In two heterogeneous slab phantoms and one shielded cylinder applicator case, average dose discrepancy between gBMC and Acuros BV was <0.87%. For a tandem and ovoid patient case, good agreement between gBMC and Acruos BV results was observed in both isodose lines and dose-volume histograms. In terms of the efficiency, it took ~47.5 seconds for gBMC to reach 0.15% statistical uncertainty within the 5% isodose line for the patient case. CONCLUSIONS: The accuracy and efficiency of a new GPU-based MC dose calculation package, gBMC, for HDR brachytherapy make it attractive for clinical applications. PMID- 27216119 TI - Quantitative Proteomics Analysis of Tissue Interstitial Fluid for Identification of Novel Serum Candidate Diagnostic Marker for Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is the fifth most common malignant cancer in the world. The sensitivity of alpha-fetoprotein (AFP) is still inadequate for HCC diagnosis. Tissue interstitial fluid (TIF), as the liquid microenvironment of cancer cells, was used for biomarker discovery in this study. Paired tumor and nontumor TIF samples from 6 HBV-HCC patients were analyzed by a proteomic technique named iTRAQ (isobaric tag for relative and absolute quantitation). Totally, 241 up-regulated proteins (ratio >= 1.3, p < 0.05) and 288 down regulated proteins (ratio <= -1.3, p < 0.05) in tumor TIF were identified. Interestingly, proteins in S100 family were found remarkably up-regulated in tumor TIF. One dramatically up-regulated protein S100A9 (ratio = 19) was further validated by ELISA in sera from liver cirrhosis (LC, HCC high risk population) and HCC patients (n = 47 for each group). The level of this protein was significantly elevated in HCC sera compared with LC (p < 0.0001). The area under the curve of this protein to distinguish HCC from LC was 0.83, with sensitivity of 91% (higher than AFP) and specificity of 66%. This result demonstrated the potential of S100A9 as a candidate HCC diagnostic biomarker. And TIF was a kind of promising material to identify candidate tumor biomarkers that could be detected in serum. PMID- 27216120 TI - Endovascular treatment using woven stents for ruptured vertebral artery dissecting aneurysm induced by varicella zoster virus: case report. AB - Subarachnoid hemorrhage with ruptured cerebral artery dissection caused by varicella zoster (VZ) vasculopathy is rare. We report a rare case of vertebral artery (VA) dissection induced by VZ virus, successfully treated with stent assisted coil embolization and systemic anti viral medication, on six month follow-up cerebral angiography with the review of literatures. PMID- 27216121 TI - Genetic differentiation of Liparus glabrirostris (Curculionidae: Molytinae) populations from the fragmented habitats of the Alps and Carpathian Mountains. AB - Populations of Liparus glabrirostris (Curculionidae: Molytinae), a weevil inhabiting higher altitudes of Central Europe, were sampled from 24 localities in the Alps and Carpathian Mountains, and the geographical structuring of genetic variation was analyzed. Comparison of the concatenated mitochondrial cytochrome oxidase subunit I and subunit II sequences revealed consistent genetic divergence between the populations of L. glabrirostris from different mountain ranges. In phylogenetic analysis using maximum parsimony and median-joining networks, concatenated mitochondrial haplotypes from the Alps and Carpathians clustered as separate lineages, with high bootstrap support. Substantial genetic distances determined between the separated groups ranged from 2.6 to 3.0%, with divergence estimated to have initiated approximately 0.85-0.98 million years ago. The nuclear elongation factor 1alpha gene was additionally amplified and haplotype analysis showed very low evolutionary divergence (0.2%), with separate clustering as well. The observed divergence suggests that the populations have been isolated for a long time, as a consequence of environmental changes resulting in varying fragmentation of habitats in the Alps and Carpathians, interrupting genetic exchange events and altering the genetic structure of L. glabrirostris populations. On the other hand, comparison of morphological characteristics showed no differences to confirm genetically well differentiated groups of populations. A polymerase chain reaction and restriction fragment length polymorphism-based method was therefore developed to discriminate between the Alpine and Carpathian lineages. PMID- 27216122 TI - Corrigendum to "Analysis of main constituents and mechanisms underlying antidepressant-like effects of Xiaochaihutang in mice" [J. Ethnopharmacol. 175 (2015) 48-57]. PMID- 27216123 TI - Evidence for Improving Preparation, Recruitment, and Retention of Nurse Faculty: Findings From EIN-Funded Studies. PMID- 27216124 TI - Pathways to the PhD in Nursing: An Analysis of Similarities and Differences. AB - New educational pathways are needed to increase the number of doctor of philosophy (PhD)-prepared nurses. To address this need, an early-entry PhD option designed to engage students in PhD coursework and research during the undergraduate nursing major was developed at the University of Wisconsin-Madison. An evaluation comparing the early-entry option with two more conventional entry points was conducted. Three groups (N = 84) comprised the sample: (a) early-entry students admitted as undergraduates or immediately upon graduation (N = 29), (b) mid-entry students with baccalaureate degrees and at least 1 year of work experience (N = 27), and (c) delayed-entry students with master's degrees and 1 or more years of work experience (N = 28). Qualitative and quantitative data were collected from the 3 groups of students who were admitted from 2002 to 2011. The sources of data were transcriptions of individual interviews and reviews of existing data. Seventy-seven percent of the sample participated in the individual interviews. The database review included all students who matriculated into the PhD program. Common themes among the 3 groups included a need for educational funding, the importance of a faculty mentor, and concern about preparation for the teaching role and the academic work environment. The groups were also comparable in terms of research productivity during doctoral study and postgraduation employment. Differences were found on measures of diversity, program progression, and perceptions of clinical competence. The findings provide needed data for the development and expansion of educational pathways to the PhD in nursing. PMID- 27216125 TI - Hiring Intentions of Directors of Nursing Programs Related to DNP- and PhD Prepared Faculty and Roles of Faculty. AB - This study surveyed administrators of associate degree in nursing (ADN) and bachelor of science in nursing (BSN) programs across the United States to identify hiring intentions and describe the roles and responsibilities of DNP- and PhD-prepared faculty members. The final sample included 253 ADN and 229 BSN programs. ADN programs were neither intentionally hiring nor looking to hire doctorally prepared nurse faculty. Deans and directors of BSN programs reported an average of 3 openings for the next academic year, 2 projected for new PhD prepared faculty and 1 for a faculty member with a DNP. Schools have made varying decisions regarding the type of appointment (tenure or nontenure track) for DNP prepared faculty members. Challenges that DNP-prepared faculty members encountered in meeting the role and promotion expectations in their schools focused predominantly on scholarship. PMID- 27216126 TI - Assessment of the Impact of Teaching Demands on Research Productivity Among Doctoral Nursing Program Faculty. AB - This article reports the findings of a study that examined the research and scholarship productivity of doctorally prepared nursing faculty teaching and mentoring doctoral students and the conflicting demands on them to maintain programs of research and scholarship. The specific aims were to (a) examine the research productivity and scholarship of faculty members teaching in doctoral programs and mentoring doctoral students to examine the perceived effectiveness of existing institutional mechanisms to support scholarship, (b) explore institutional features and personal practices used by doctoral program faculty to develop and maintain research and scholarship productivity, and (c) analyze predictors of scholarship productivity. Data were collected via an on-line researcher-developed survey that examined doctoral faculty roles/responsibilities and their relationship to their scholarly productivity, overall research productivity, and institutional features and personal practices to support research/scholarship activities. Survey respondents reported spending a large amount of time engaged in research-related activities with 58.9% (n = 326) spending anywhere from 6 to 20 hours per week conducting research, writing research-based papers, giving presentations, grant writing, or conducting evidence-based improvement projects. Scholar productivity among the respondents was robust. Personal practices that most strongly supported faculty members' scholarship productivity were the belief that engaging in scholarship made them better teachers and the personal gratification in experiencing doctoral students' successes. A multiple regression analysis conducted to determine predictors of productivity indicated that the strongest predictor was the average number of hours spent on research/scholarship-related activities, followed by time bought out from teaching and other responsibilities of the faculty role for research. PMID- 27216127 TI - Identifying Barriers and Facilitators to Nurse Faculty Careers for PhD Nursing Students. AB - The shortage of doctorally educated nurses pursuing faculty careers is a major concern regarding the development of the nurse faculty workforce. This cross sectional study aims to identify barriers and facilitators to academic careers for doctoral (PhD) nursing students. A total of 1,500 PhD students were randomly selected from nursing schools across the country to participate in our survey, and a 62.8% response rate was achieved. The study found that 72% of respondents planned to pursue faculty careers after graduating. Students with postgraduation plans for academic careers, nonacademic careers, and undecided careers showed distinct profiles of demographic and academic characteristics. They also perceived facilitators and barriers to faculty careers differently. The most influential facilitators were interest in teaching and an appreciation of the impact of nursing research on patient care, and the most considered barriers were poor financial compensation and a negative perception of academia. Minority students were more likely than White students to have plans for academic careers. Various experiences during doctoral education appeared to have a positive impact on students' decisions to pursue academic careers. PMID- 27216128 TI - Exploring the Pursuit of Doctoral Education by Nurses Seeking or Intending to Stay in Faculty Roles. AB - The purpose of this study was to describe the factors influencing the pursuit and completion of doctoral education by nurses intending to seek or retain faculty roles. Traditionally, doctoral education evolved to focus on the preparation of nurses to conduct scientific research, primarily through the doctor of philosophy programs. Most recently, the doctor of nursing practice degree emerged and was designed for advanced practice nurses to be clinical leaders who translate research into practice and policy. Nurses who pursue doctoral education in order to assume or maintain faculty roles must choose between these degrees if they desire a doctorate within the discipline; however, factors influencing their decisions and the intended outcomes of their choice are not clear. During this study, 548 nurses (current students or recent graduates of doctoral programs) completed a comprehensive survey to generate critical evidence about the factors influencing the choices made. Principal findings are related to the issues of time, money, and program selection. These findings can be used to develop strategies to increase enrollment and, therefore, the number of doctorally prepared faculty who are specifically prepared to excel as nursing faculty. PMID- 27216129 TI - Creating Nursing's New Academic Spaces: Making Dreams Come True. AB - After a description of the approval process for new construction, this article examines the design-bid-build delivery method because it is the most traditional, by defining and exploring each of the major construction phases: programming, cost estimates, preliminary design, schematic design, design development, construction drawings, bidding/negotiation, construction and, finally, move-in, and occupancy. Viewpoints of key players are examined to understand how the nursing dean in partnership with the architect shepherd nursing's dream into reality. Using a recent building project as an exemplar, Dr. Bavier shares her work as dean, and Mr. Bavier, as an architect specializing in education facilities, shares his planning and design experiences on several academic facilities. The outcome is information and guidance for deans to use their collaboration with the architect and other team members to assure a custom tailored nursing education facility. PMID- 27216130 TI - Utilizing Team Debate to Increase Student Abilities for Mentoring and Critical Appraisal of Global Health Care in Doctor of Nursing Practice Programs. AB - Although graduates of doctor of nursing practice (DNP) programs are expected to demonstrate competence in advanced clinical scholarship, mentoring, and leadership, little is published about how team debate on a global health care topic supports DNP student learning and skill development. PURPOSE: This article reports on an illuminative evaluation of DNP student learning experiences of team debate in the context of a 2-week international school program in Ireland. METHOD: A focused illuminative evaluation approach involving a cohort of seven DNP students, who had participated in an international school team debate, was used. Data were collected using a Web-based qualitative questionnaire designed to elicit in-depth reflective accounts of DNP students' learning experiences. RESULTS: Content analysis revealed that team debate on a global health care topic enhanced learning in relation to fostering critical thinking and critical appraisal skills; encouraging teamwork; providing opportunities for mentoring, relationship building, and socialization into profession; and, from the DNP student perspective, increasing knowledge and global understanding of health care. CONCLUSION: This evaluation provides insights for nurse educators into the benefits of introducing team debate as a group activity to enhancing scholarly inquiry and mentoring skills of DNP students. Further research to evaluate team debate in other nurse education programs is needed. PMID- 27216131 TI - Impact of Advocacy Initiatives on Nurses' Motivation to Sustain Momentum in Public Policy Advocacy. AB - The purpose of this study is to elicit insight from the public policy leaders of 2 regional professional nursing organizations on key qualities of their current advocacy initiatives that motivate nurses to sustain momentum in public policy advocacy beyond a single episode. The goal is to inform quality improvement in the development of future advocacy initiatives to increase sustained engagement of nurses. METHODS: Social cognitive theory was used as the rationale for this qualitative, descriptive study. A purposive convenience sample of executive leadership and board committee members from 2 regional professional nursing organizations were recruited to complete an initial Web-based electronic survey, followed by separate semistructured interview focus groups. One organization was composed primarily of advanced practice registered nurses, and the other group composed of diverse, multispecialty nursing members with varied educational levels. RESULTS: Nine themes emerged, categorized as facilitators or challenges to the positive impact of advocacy initiatives on nurses' motivation. CONCLUSION: Highlighting and marketing facilitators to the positive impact of advocacy initiatives on nurses' motivation to sustain momentum in public policy advocacy, while designing and testing new initiatives that address the challenges, may increase the number of nurses who sustain engagement in the policy advocacy process. PMID- 27216132 TI - "Nursing Students Assaulted": Considering Student Safety in Community-Focused Experiences. AB - Community nursing experiences for undergraduate students have progressed beyond community-based home visits to a wide array of community-focused experiences in neighborhood-based centers, clinics, shelters, and schools. Our Bachelor of Science in Nursing program chose to use sites situated within neighborhoods close to campus in order to promote student and faculty engagement in the local community. These neighborhood sites provide opportunities for students to deliver nursing services to underserved and vulnerable populations experiencing poverty and health disparities. Some of these neighborhoods are designated as high crime areas that may potentially increase the risk of harm to students and faculty. There is a need to acknowledge the risk to personal safety and to proactively create policies and guidelines to reduce potential harm to students engaged in community-focused experiences. When a group of baccalaureate nursing students was assaulted while walking to a neighborhood clinic, the faculty was challenged as how to respond given the lack of policies and guidelines. Through our experience, we share strategies to promote personal safety for students and recommend transparency by administrators regarding potential safety risks to students engaged in community-focused fieldwork activities. PMID- 27216133 TI - Diversity of burial rates in convergent settings decreased as Earth aged. AB - The evolution and the growth of the continental crust is inextricably linked to the evolution of Earth's geodynamic processes. The detrital zircon record within the continental crust, as well as the isotopic composition of this crust, indicates that the amount of juvenile felsic material decreased with time and that in geologically recent times, the generation of new crust is balanced by recycling of the crust back into the mantle within subduction zones. However it cannot always have been so; yet the nature of the crust and the processes of crustal reworking in the Precambrian Earth are not well constrained. Here we use both detrital zircon ages and metamorphic pressure-temperature-time (P-T-t) information from metasedimentary units deposited in proposed convergent settings from Archaean, Proterozoic and Phanerozoic terrains to characterize the evolution of minimum estimates of burial rate (km.Ma(-1)) as a function of the age of the rocks. The demonstrated decrease in burial rate correlates positively with a progressive decrease in the production of juvenile felsic crust in the Archaean and Proterozoic. Burial rates are also more diverse in the Archaean than in modern times. We interpret these features to reflect a progressive decrease in the diversity of tectonic processes from Archaean to present, coupled with the emergence of the uniquely Phanerozoic modern-style collision. PMID- 27216134 TI - Short Communication: The Impact of Switching from Atripla to Darunavir/Ritonavir Monotherapy on Neurocognition, Quality of Life, and Sleep: Results from a Randomized Controlled Study. AB - We investigated whether a treatment switch from Atripla(r) (tenofovir, emtricitabine, and efavirenz) to DRV/r monotherapy may improve neuropsychological performance, health-related quality of life, and sleep function. Virologically suppressed subjects and asymptomatic on Atripla for >=6 months were randomized 1:1 to continue Atripla or switch to boosted darunavir (DRV/r) 800/100 mg once daily for 48 weeks. Neurocognitive tests, the International HIV Dementia Scale (IHDS), Medical Outcomes Study HIV Health Survey (MOS-HIV), EQ-5D-3L, and the Hospital Anxiety and Depression Scale (HADS) were completed at baseline and at week 48. Sleep function was evaluated at week 48. Twenty-six patients on DRV/r and 31 on Atripla completed the 48-week study. No significant difference in the change in scores from week 0 to week 48 between the two arms was observed in neurocognitive outcomes, IHDS, health outcomes (EQ-5D-3L and QOL), and HADS score. By contrast, the HADS score and sleep quality were both significantly better in the DRV/r arm. In conclusion, switching to DRV/r monotherapy did not affect neurocognitive function or quality of life but improved anxiety, and sleep quality was significantly better than in continued Atripla. PMID- 27216135 TI - Ligand K-edge XAS, DFT, and TDDFT analysis of pincer linker variations in Rh(i) PNP complexes: reactivity insights from electronic structure. AB - Here we report P K-edge, Cl K-edge, and Rh L3-edge X-ray absorption spectroscopy (XAS) data for Rh[C5H3N-2,6-(XP(t)Bu2)2]Cl, where X = O ((tBu)PONOP; ) or CH2 ((tBu)PNP; ). Solid-state XAS data for and were compared to density functional theory (DFT) and time-dependent density functional theory (TDDFT) calculations to identify how changing the PNP pincer linker from O to CH2 affected electronic structure and bonding at Rh(i). Pronounced differences in XAS peak intensities and energies were observed. The P K-edge XAS data revealed a large increase in Rh 4dx(2)-y(2) and P 3p orbital-mixing (Rh-P sigma*) in compared to , and pronounced transition energy variations reflected marked differences in orbital energies and compositions. By comparison, the Cl K-edge XAS data revealed only subtle differences in Rh-Cl covalency, although larger splitting between the Rh-Cl pi* and sigma* transitions was observed in . Analysis of the occupied MOs from DFT (HOMO, HOMO-1, HOMO-2, and HOMO-3) and comparison to the unoccupied MOs involved in XAS revealed a relatively uniform energy increase (ca. 0.3-0.5 eV) for all five 4d-derived molecular orbitals in Rh((tBu)PNP)Cl () compared to Rh((tBu)PONOP)Cl (). The energy shift was relatively invariant with respect to differences in orbital symmetry, bonding type (sigma or pi), and orbital mixing, which suggested that the increase could be attributed to electrostatic effects. The change in d-orbital energies are consistent with known reactivity differences of Rh((tBu)PONOP)(+) and Rh((tBu)PNP)(+) towards CO, H2, and CH2Cl2, and are explained here by considering how d-orbital energies affect covalent L -> M sigma bonding and M -> L pi backbonding. PMID- 27216136 TI - Prognosis and survival analysis of paraquat poisoned patients based on improved HPLC-UV method. AB - Paraquat (PQ) has caused deaths of numerous people around the world. In order to assess the lethal plasma concentration, the patients who acquired acute PQ intoxication were analyzed by plasma concentration monitoring. The plasma PQ concentrations were determined by high performance liquid chromatography (HPLC) which used 5-bromopyrimidine as internal standard and trichloroacetic acid methanol (1:9) as protein precipitant. The liver, kidney and coagulation function were determined by automatic biochemical analyzer. According to plasma PQ concentration, 90 patients were divided into four groups: trace PQ group (<50ng/mL), low PQ group (<1000ng/mL), medium PQ group (1000-5000ng/mL) and high PQ group (>5000ng/mL). The clinical data from the four groups was statistically analyzed. The results showed the developed HPLC methods exhibited a high degree of accuracy and good linearity within 50-25000ng/mL (R=0.9998). The Spearman's correlation analysis showed PQ concentration had a strong relationship to total bilirubin, direct bilirubin, aspartic transaminase, urea nitrogen, prothrombin time, prothrombin activity, and international normalized ratio (P<0.01). The cured or survival PQ poisoned patients among the trace PQ group, the low PQ group, the medium PQ group, and the high PQ group were 19/19 (100%), 19/21 (90.47%), 11/25 (44.0%), and 0/25 (0%) respectively. The mean hospital days were (10.37+/-8.04), (18.76+/-12.06), (16.76+/-14.44), and (4.04+/-5.41) days respectively. The Cox regression analysis indicated that plasma PQ concentration was highly related to prognosis (P<0.05). In conclusion, no patient presenting with a PQ concentration over 5000ng/mL survived. The plasma PQ level is related to liver, kidney and coagulation function, which can be used as an important clinical index to judge the prognosis of PQ poisoned patients. CHEMICAL COMPOUNDS: Paraquat (PubChem CID: 15938), 5-bromopyrimidine (PubChem CID: 78344), acetonitrile (PubChem CID: 6342), sodium dihydrogen phosphate (PubChem CID: 23672064), sodium heptanesulfonate (PubChem CID: 23672332), methylprednisolone (PubChem CID: 6741), cyclophosphamide (PubChem CID: 2907). PMID- 27216137 TI - Dose-ranging study of salmeterol using a novel fluticasone propionate/salmeterol multidose dry powder inhaler in patients with persistent asthma. AB - BACKGROUND: New inhalation devices with improved lung delivery may allow the use of lower salmeterol doses for treatment of asthma. OBJECTIVE: To determine the dose of salmeterol administered from a novel fluticasone propionate/salmeterol (FS) inhalation-driven, multidose dry powder inhaler (MDPI), which provides comparable efficacy and safety to FS dry powder inhaler (DPI). METHODS: This double-blind, six-period crossover, dose-ranging study randomized 72 patients (ages >=12 years; with persistent asthma and predose maximum forced expiratory volume in 1 second [FEV1] of 40-85% of the predicted normal) to treatment sequences (one dose per treatment), which consisted of FS MDPI 100/6.25, 100/12.5, 100/25, 100/50 MUg; fluticasone propionate (Fp) MDPI 100 MUg; and open label FS DPI 100/50 MUg. The primary efficacy variable was the baseline-adjusted FEV1 area under the curve over 12 hours after the dose (AUC0-12). Pharmacokinetics and tolerability were also assessed. RESULTS: FEV1 AUC0-12 was significantly higher with all FS MDPI doses and FS DPI versus Fp MDPI (p < 0.0001), and with FS MDPI 100/50 MUg versus FS DPI (least squares [LS] mean, 57.88 mL; p = 0.0017). FEV1 AUC0-12 trended toward higher efficacy with FS MDPI 100/25 MUg (LS mean, 34.14 mL; p = 0.0624) and was comparable with FS MDPI 100/12.5 MUg (LS mean, 3.42 mL; p = 0.8503) versus FS DPI. Salmeterol area under the plasma concentration-versus-time curve from time 0 to the time of the last measurable concentration (AUC0-t) for FS MDPI 100/12.5 MUg and 100/25 MUg was lower versus FS DPI 100/50 MUg; AUC0-t for FS MDPI 100/50 MUg was higher than FS DPI 100/50 MUg. All FS MDPI doses were generally well tolerated. CONCLUSION: All FS MDPI doses produced greater efficacy versus Fp MDPI. FS MDPI 100/12.5 MUg demonstrated similar efficacy to FS DPI 100/50 MUg with less salmeterol exposure. Clinicaltrials.gov NCT02139644, NCT02175771, and NCT02141854. PMID- 27216138 TI - On the vagal cardiac nerves, with special reference to the early evolution of the head-trunk interface. AB - The vagus nerve, or the tenth cranial nerve, innervates the heart in addition to other visceral organs, including the posterior visceral arches. In amniotes, the anterior and posterior cardiac branches arise from the branchial and intestinal portions of the vagus nerve to innervate the arterial and venous poles of the heart, respectively. The evolution of this innervation pattern has yet to be elucidated, due mainly to the lack of morphological data on the vagus in basal vertebrates. To investigate this topic, we observed the vagus nerves of the lamprey (Lethenteron japonicum), elephant shark (Callorhinchus milii), and mouse (Mus musculus), focusing on the embryonic patterns of the vagal branches in the venous pole. In the lamprey, no vagus branch was found in the venous pole throughout development, whereas the arterial pole was innervated by a branch from the branchial portion. In contrast, the vagus innervated the arterial and venous poles in the mouse and elephant shark. Based on the morphological patterns of these branches, the venous vagal branches of the mouse and elephant shark appear to belong to the intestinal part of the vagus, implying that the cardiac nerve pattern is conserved among crown gnathostomes. Furthermore, we found a topographical shift of the structures adjacent to the venous pole (i.e., the hypoglossal nerve and pronephros) between the extant gnathostomes and lamprey. Phylogenetically, the lamprey morphology is likely to be the ancestral condition for vertebrates, suggesting that the evolution of the venous branch occurred early in the gnathostome lineage, in parallel with the remodeling of the head trunk interfacial domain during the acquisition of the neck. J. Morphol. 277:1146 1158, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27216140 TI - Salt--too much or too little? PMID- 27216139 TI - Associations of urinary sodium excretion with cardiovascular events in individuals with and without hypertension: a pooled analysis of data from four studies. AB - BACKGROUND: Several studies reported a U-shaped association between urinary sodium excretion and cardiovascular disease events and mortality. Whether these associations vary between those individuals with and without hypertension is uncertain. We aimed to explore whether the association between sodium intake and cardiovascular disease events and all-cause mortality is modified by hypertension status. METHODS: In this pooled analysis, we studied 133,118 individuals (63,559 with hypertension and 69,559 without hypertension), median age of 55 years (IQR 45-63), from 49 countries in four large prospective studies and estimated 24-h urinary sodium excretion (as group-level measure of intake). We related this to the composite outcome of death and major cardiovascular disease events over a median of 4.2 years (IQR 3.0-5.0) and blood pressure. FINDINGS: Increased sodium intake was associated with greater increases in systolic blood pressure in individuals with hypertension (2.08 mm Hg change per g sodium increase) compared with individuals without hypertension (1.22 mm Hg change per g; pinteraction<0.0001). In those individuals with hypertension (6835 events), sodium excretion of 7 g/day or more (7060 [11%] of population with hypertension: hazard ratio [HR] 1.23 [95% CI 1.11-1.37]; p<0.0001) and less than 3 g/day (7006 [11%] of population with hypertension: 1.34 [1.23-1.47]; p<0.0001) were both associated with increased risk compared with sodium excretion of 4-5 g/day (reference 25% of the population with hypertension). In those individuals without hypertension (3021 events), compared with 4-5 g/day (18,508 [27%] of the population without hypertension), higher sodium excretion was not associated with risk of the primary composite outcome (>= 7 g/day in 6271 [9%] of the population without hypertension; HR 0.90 [95% CI 0.76-1.08]; p=0.2547), whereas an excretion of less than 3 g/day was associated with a significantly increased risk (7547 [11%] of the population without hypertension; HR 1.26 [95% CI 1.10-1.45]; p=0.0009). INTERPRETATION: Compared with moderate sodium intake, high sodium intake is associated with an increased risk of cardiovascular events and death in hypertensive populations (no association in normotensive population), while the association of low sodium intake with increased risk of cardiovascular events and death is observed in those with or without hypertension. These data suggest that lowering sodium intake is best targeted at populations with hypertension who consume high sodium diets. FUNDING: Full funding sources listed at end of paper (see Acknowledgments). PMID- 27216141 TI - Assuaging death anxiety in older overseas-born Australians of culturally and linguistically diverse backgrounds hospitalised for end-of-life care. AB - BACKGROUND: Death anxiety is a known phenomenon in older people of culturally and linguistically diverse backgrounds (CALD) hospitalised for end-of-life (EOL) care . Little is known about how nurses assuage death anxiety in this population. AIMS: To investigate strategies used by nurses to assuage death anxiety and facilitate a good death in older CALD Australians hospitalised for EOL care. METHODS: Advanced as a qualitative descriptive inquiry, a purposeful sample of 22 nurses was recruited from four Victorian healthcare services. Interviews were transcribed verbatim and analysed using thematic analysis processes. FINDINGS: Nurses used three key strategies: recognising death anxiety; delineating its dimensions; and initiating conventional nursingcaring behaviours to help contain it. Contrary to expectations, cultural similarities rather than differences were found in the strategies used. CONCLUSIONS: Nursing strategies for recognising, delineating, and managing death anxiety in older CALD people hospitalised at the EOL is an important component of quality EOL care. PMID- 27216142 TI - Cellular thermal shift and clickable chemical probe assays for the determination of drug-target engagement in live cells. AB - Proof of drug-target engagement in physiologically-relevant contexts is a key pillar of successful therapeutic target validation. We developed two orthogonal technologies, the cellular thermal shift assay (CETSA) and a covalent chemical probe reporter approach (harnessing sulfonyl fluoride tyrosine labeling and subsequent click chemistry) to measure the occupancy of the mRNA-decapping scavenger enzyme DcpS by a small molecule inhibitor in live cells. Enzyme affinity determined using isothermal dose response fingerprinting (ITDRFCETSA) and the concentration required to occupy 50% of the enzyme (OC50) using the chemical probe reporter assay were very similar. In this case, the chemical probe method worked well due to the long offset kinetics of the reversible inhibitor (determined using a fluorescent dye-tagged probe). This work suggests that CETSA could become the first choice assay to determine in-cell target engagement due to its simplicity. PMID- 27216143 TI - Phenotypic Characterization of a Leishmania donovani Cyclophilin 40 Null Mutant. AB - Protozoan parasites of the genus Leishmania adapt to their arthropod and vertebrate hosts through the development of defined life cycle stages. Stage differentiation is triggered by environmental stress factors and has been linked to parasite chaperone activities. Using a null mutant approach we previously revealed important, nonredundant functions of the cochaperone cyclophilin 40 in L. donovani-infected macrophages. Here, we characterized in more detail the virulence defect of cyp40-/- null mutants. In vitro viability assays, infection tests using macrophages, and mixed infection experiments ruled out a defect of cyp40-/- parasites in resistance to oxidative and hydrolytic stresses encountered inside the host cell phagolysosome. Investigation of the CyP40-dependent proteome by quantitative 2D-DiGE analysis revealed up regulation of various stress proteins in the null mutant, presumably a response to compensate for the lack of CyP40. Applying transmission electron microscopy we showed accumulation of vesicular structures in the flagellar pocket of cyp40-/- parasites that we related to a significant increase in exosome production, a phenomenon previously linked to the parasite stress response. Together these data suggest that cyp40-/- parasites experience important intrinsic homeostatic stress that likely abrogates parasite viability during intracellular infection. PMID- 27216144 TI - Total knee arthroplasty using trochlear groove as guide for position of femoral component in severe knee osteoarthritis. AB - BACKGROUND: Apart from transepicondylar axis, the native femoral sulcus was also reported to be used as a guide for the femoral component position in total knee arthroplasty (TKA). However, it was not shown in patients with severe knee osteoarthritis. This study was conducted to compare the position of trochlear groove in patients with and without osteoarthritis, and to assess whether trochlear groove could be used as a guide for position of femoral component in TKA for severe knee osteoarthritis. METHODS: Total 50 severe knee osteoarthritis patients (Kellgren Lawrence grade 3 or 4) who underwent TKA were included. Meanwhile, 50 patients who underwent arthroscopic surgery without osteoarthritis were included as control. The distance from trochlear groove to the midpoint of a virtual anterior condyle osteotomy line (parallel to the posterior condyle line) (a-b) was recorded by radiological and surgical measurements. Midpoint of transepicondylar axis and trochlear groove were used as guide for placing prosthesis model in TKA, respectively. No-thumb test was performed to assess the patellar tracking. The position of femoral component was finally performed using trochlear groove as guide in TKA. RESULTS: Value of "a-b" was significantly different between osteoarthritic and control knees (P = 0.008). During the placement of prosthesis model, similar patellar tracking was detected between using midpoint of transepicondylar axis and trochlear groove as guide (P > 0.05). After placing femoral component using trochlear groove as guide, most patients obtained good patellofemoral congruence with pneumatic tourniquet inflated (n = 43) or deflated (n = 5), and good patellofemoral congruence was also obtained by lateral patellar retinaculum release in two patients. CONCLUSION: Despite the shifting of trochlear groove caused by severe knee osteoarthritis, trochlear groove can be used as a guide for position of femoral component, with equivalent patellar tracking compared with transepicondylar axis. PMID- 27216145 TI - Ectodomain Architecture Affects Sequence and Functional Evolution of Vertebrate Toll-like Receptors. AB - Toll-like receptors (TLRs) are crucial components of innate immunity that specifically recognize diverse pathogen-associated molecular patterns from pathogens. The continuous hydrogen-bond network (asparagine ladder) formed among the asparagine residues on the concave surfaces of neighboring leucine-rich repeat modules assists in stabilizing the overall shape of TLR ectodomains responsible for ligand recognition. Analysis of 28 types of vertebrate TLRs showed that their ectodomains possessed three types of architectures: a single domain architecture with an intact asparagine ladder, a three-domain architecture with the ladder interrupted in the middle, and a trans-three-domain architecture with the ladder broken in both termini. Based on a phylogenetic analysis, the three vertebrate TLR architectures arose during early evolution. The 1428 vertebrate TLRs can be divided into eight families based on sequence and structural differences. TLRs ligand specificities are affected by their ectodomain architectures. Three-domain TLRs bind hydrophobic ligands, whereas single-domain and trans-three-domain TLRs mainly recognize hydrophilic ligands. Analysis of 39 vertebrate genomes suggested that the number of single-domain TLR genes in terrestrial vertebrate genomes decreased by half compared to aquatic vertebrate genomes. Single-domain TLR genes underwent stronger purifying selective pressures than three-domain TLR genes in mammals. Overall, ectodomain architecture influences the sequence and functional evolution of vertebrate TLRs. PMID- 27216146 TI - Vitronectin and dermcidin serum levels predict the metastatic progression of AJCC I-II early-stage melanoma. AB - Like many cancers, an early diagnosis of melanoma is fundamental to ensure a good prognosis, although an important proportion of stage I-II patients may still develop metastasis during follow-up. The aim of this work was to discover serum biomarkers in patients diagnosed with primary melanoma that identify those at a high risk of developing metastasis during the follow-up period. Proteomic and mass spectrophotometry analysis was performed on serum obtained from patients who developed metastasis during the first years after surgery for primary tumors and compared with that from patients who remained disease-free for more than 10 years after surgery. Five proteins were selected for validation as prognostic factors in 348 melanoma patients and 100 controls by ELISA: serum amyloid A and clusterin; immune system proteins; the cell adhesion molecules plakoglobin and vitronectin and the antimicrobial protein dermcidin. Compared to healthy controls, melanoma patients have high serum levels of these proteins at the moment of melanoma diagnosis, although the specific values were not related to the histopathological stage of the tumors. However, an analysis based on classification together with multivariate statistics showed that tumor stage, vitronectin and dermcidin levels were associated with the metastatic progression of patients with early-stage melanoma. Although melanoma patients have increased serum dermcidin levels, the REPTree classifier showed that levels of dermcidin <2.98 MUg/ml predict metastasis in AJCC stage II patients. These data suggest that vitronectin and dermcidin are potent biomarkers of prognosis, which may help to improve the personalized medical care of melanoma patients and their survival. PMID- 27216147 TI - Comparative Leaf and Root Transcriptomic Analysis of two Rice Japonica Cultivars Reveals Major Differences in the Root Early Response to Osmotic Stress. AB - BACKGROUND: Rice (Oryza sativa L.) is one of the most important crops cultivated in both tropical and temperate regions and is characterized by a low water-use efficiency and a high sensitivity to a water deficit, with yield reductions occurring at lower stress levels compared to most other crops. To identify genes and pathways involved in the tolerant response to dehydration, a powerful approach consists in the genome-wide analysis of stress-induced expression changes by comparing drought-tolerant and drought-sensitive genotypes. RESULTS: The physiological response to osmotic stress of 17 japonica rice genotypes was evaluated. A clear differentiation of the most tolerant and the most sensitive phenotypes was evident, especially after 24 and 48 h of treatment. Two genotypes, which were characterized by a contrasting response (tolerance/sensitivity) to the imposed stress, were selected. A parallel transcriptomic analysis was performed on roots and leaves of these two genotypes at 3 and 24 h of stress treatment. RNA Sequencing data showed that the tolerant genotype Eurosis and the sensitive genotype Loto mainly differed in the early response to osmotic stress in roots. In particular, the tolerant genotype was characterized by a prompt regulation of genes related to chromatin, cytoskeleton and transmembrane transporters. Moreover, a differential expression of transcription factor-encoding genes, genes involved in hormone-mediate signalling and genes involved in the biosynthesis of lignin was observed between the two genotypes. CONCLUSIONS: Our results provide a transcriptomic characterization of the osmotic stress response in rice and identify several genes that may be important players in the tolerant response. PMID- 27216149 TI - Corrections. PMID- 27216148 TI - Inhibition of Ovarian Tumor Growth by Targeting the HU177 Cryptic Collagen Epitope. AB - Evidence suggests that stromal cells play critical roles in tumor growth. Uncovering new mechanisms that control stromal cell behavior and their accumulation within tumors may lead to development of more effective treatments. We provide evidence that the HU177 cryptic collagen epitope is selectively generated within human ovarian carcinomas and this collagen epitope plays a role in SKOV-3 ovarian tumor growth in vivo. The ability of the HU177 epitope to regulate SKOV-3 tumor growth depends in part on its ability to modulate stromal cell behavior because targeting this epitope inhibited angiogenesis and, surprisingly, the accumulation of alpha-smooth muscle actin-expressing stromal cells. Integrin alpha10beta1 can serve as a receptor for the HU177 epitope in alpha-smooth muscle actin-expressing stromal cells and subsequently regulates Erk dependent migration. These findings are consistent with a mechanism by which the generation of the HU177 collagen epitope provides a previously unrecognized alpha10beta1 ligand that selectively governs angiogenesis and the accumulation of stromal cells, which in turn secrete protumorigenic factors that contribute to ovarian tumor growth. Our findings provide a new mechanistic understanding into the roles by which the HU177 epitope regulates ovarian tumor growth and provide new insight into the clinical results from a phase 1 human clinical study of the monoclonal antibody D93/TRC093 in patients with advanced malignant tumors. PMID- 27216150 TI - Angiopoietin-1 receptor Tie2 distinguishes multipotent differentiation capability in bovine coccygeal nucleus pulposus cells. AB - BACKGROUND: The intervertebral disc (IVD) has limited self-healing potential and disc repair strategies require an appropriate cell source such as progenitor cells that could regenerate the damaged cells and tissues. The objective of this study was to identify nucleus pulposus-derived progenitor cells (NPPC) and examine their potential in regenerative medicine in vitro. METHODS: Nucleus pulposus cells (NPC) were obtained from 1-year-old bovine coccygeal discs by enzymatic digestion and were sorted for the angiopoietin-1 receptor Tie2. The obtained Tie2- and Tie2+ fractions of cells were differentiated into osteogenic, adipogenic, and chondrogenic lineages in vitro. Colony-forming units were prepared from both cell populations and the colonies formed were analyzed and quantified after 8 days of culture. In order to improve the preservation of the Tie2+ phenotype of NPPC in monolayer cultures, we tested a selection of growth factors known to have stimulating effects, cocultured NPPC with IVD tissue, and exposed them to hypoxic conditions (2 % O2). RESULTS: After 3 weeks of differentiation culture, only the NPC that were positive for Tie2 were able to differentiate into osteocytes, adipocytes, and chondrocytes as characterized by calcium deposition (p < 0.0001), fat droplet formation (p < 0.0001), and glycosaminoglycan content (p = 0.0095 vs. Tie2- NPC), respectively. Sorted Tie2- and Tie2+ subpopulations of cells both formed colonies; however, the colonies formed from Tie2+ cells were spheroid in shape, whereas those from Tie2- cells were spread and fibroblastic. In addition, Tie2+ cells formed more colonies in 3D culture (p = 0.011) than Tie2- cells. During expansion, a fast decline in the fraction of Tie2+ cells was observed (p < 0.0001), which was partially reversed by low oxygen concentration (p = 0.0068) and supplementation of the culture with fibroblast growth factor 2 (FGF2) (p < 0.0001). CONCLUSIONS: Our results showed that the bovine nucleus pulposus contains NPPC that are Tie2+. These cells fulfilled formally progenitor criteria that were maintained in subsequent monolayer culture for up to 7 days by addition of FGF2 or hypoxic conditions. We propose that the nucleus pulposus represents a niche of precursor cells for regeneration of the IVD. PMID- 27216151 TI - The German version of the Perceived Stress Scale - psychometric characteristics in a representative German community sample. AB - BACKGROUND: The Perceived Stress Scale Cohen (J Health Soc Behav 24:385-96, 1983) is a widely and well-established self-report scale measuring perceived stress. However, the German version of the PSS-10 has not yet been validated. Thus, the purposes of this representative study were to psychometrically evaluate the PSS 10, and to provide norm values for the German population. METHODS: The PSS-10 and standardized scales of depression, anxiety, fatigue, procrastination and life satisfaction were administered to a representative, randomly selected German community sample consisting of 1315 females and 1148 male participants in the age range from 14 to 90 years. RESULTS: The results demonstrated a good internal consistency and construct validity. Perceived stress was consistently associated with depression, anxiety, fatigue, procrastination and reduced life satisfaction. Confirmatory factor analysis revealed a bi-dimensional structure with two related latent factors. Regarding demographic variables, women reported a higher level of stress than men. Perceived stress decreased with higher education, income and employment status. Older and married participants felt less stressed than younger and unmarried participants. CONCLUSION: The PSS-10 is a reliable, valid and economic instrument for assessing perceived stress. As psychological stress is associated with an increased risk of diseases, identifying subpopulations with higher levels of stress is essential. Due to the dependency of the perceived stress level on demographic variables, particularly age and sex, differentiated norm values are needed, which are provided in this paper. PMID- 27216152 TI - Peculiarities of the interaction of the restriction endonuclease BspD6I with DNA containing its recognition site. AB - BACKGROUND: Nicking endonucleases are enzymes that recognize specific sites in double-stranded DNA and cleave only one strand at a predetermined position. These enzymes are involved in DNA replication and repair; they can also function as subunits of bacterial heterodimeric restriction endonucleases. One example of such a proteins is the restriction endonuclease BspD6I (R.BspD6I) from Bacillus species strain D6, which consists of the large subunit - nicking endonuclease BspD6I (Nt.BspD6I), and the small subunit (ss.BspD6I). Nt.BspD6I can function independently. Similar enzymes are now widely used in numerous biotechnological applications. The aim of this study was to investigate the fundamental properties of two subunits of R.BspD6I and their interdependence in the course of R.BspD6I activity. METHODS: The binding and hydrolysis of DNA duplexes by R.BspD6I are primary analyzed by gel electrophoresis. To elucidate the difference between Nt.BspD6I interaction with the substrate and product of hydrolysis, the thickness shear mode acoustic method is used. RESULTS AND CONCLUSIONS: The thermodynamic and kinetic parameters of the Nt.BspD6I interaction with DNA are determined. For the first time we demonstrated that Nt.BspD6I bends the DNA during complex formation. Nt.BspD6I is able to form complexes with the product nicked in the top strand and ss.BspD6I cleaves the bottom strand of the DNA consecutively. Furthermore, the influence of dA methylation in the R.BspD6I recognition site on ss.BspD6I activity is analyzed. GENERAL SIGNIFICANCE: The obtained results provide evidence that Nt.BspD6I coordinates the activity of R.BspD6I by strictly coupling of the bottom strand cleavage by ss.BspD6I to the top strand cleavage. PMID- 27216153 TI - CITED2 Modulates Breast Cancer Metastatic Ability through Effects on IKKalpha. AB - Previously, we identified the transcriptional coactivator CITED2 as a potential facilitator of bone metastasis using a murine mammary cancer model. Extending these studies to human breast cancer, it was observed that CITED2 mRNA expression was significantly elevated in patient specimens of metastatic breast cancer relative to primary tumors, with highest levels in metastasis to bone relative to non-bone sites. To further evaluate CITED2 functions in breast cancer metastasis, CITED2 expression was stably reduced in the human breast cancer cell lines MDA-MB 231 and MDA-MB-468, which are metastatic in animal models. While CITED2 knockdown had no effect on cell proliferation, cell migration and invasion were significantly reduced, as was the establishment of metastasis following intracardiac administration in athymic nude mice. To explore the mechanism behind these effects, gene expression following CITED2 knockdown in MDA-MB-231 cells by cDNA microarray was performed. As confirmed at the mRNA and protein levels in both MDA-MB-231 and MDA-MB-468 cells, expression of the NF-kappaB regulator IKKalpha was significantly reduced, along with several NF-kappaB targets with known roles in metastasis (OPN, MMP9, uPA, SPARC, IL11, and IL1beta). Furthermore, ChIP assay revealed recruitment of CITED2 to the promoter of IKKalpha, indicating a direct role in regulating its expression. Consistent with reduced IKKalpha expression, CITED2 knockdown inhibited both canonical and noncanonical NF-kappaB signaling. Finally, restoration of IKKalpha expression following CITED2 knockdown in MDA-MB-231 and MDA-MB-468 cells rescued their invasive ability. Collectively, these data demonstrate that CITED2 modulates metastatic ability in human breast cancer cells, at least in part, through the regulation of IKKalpha. IMPLICATIONS: The current study highlights the role of CITED2 in facilitating breast cancer metastasis, partly via regulation of IKKalpha. Mol Cancer Res; 14(8); 730-9. (c)2016 AACR. PMID- 27216154 TI - JNK1 Inhibition Attenuates Hypoxia-Induced Autophagy and Sensitizes to Chemotherapy. AB - Inhibition of hypoxia-induced stress signaling through JNK potentiates the effects of oxaliplatin. The JNK pathway plays a role in both autophagy and apoptosis; therefore, it was determined how much of the effect of JNK inhibition on oxaliplatin sensitivity is dependent on its effect on autophagy. We studied the impact of JNK isoform downregulation in the HT29 colon adenocarcinoma cell line on hypoxia- and oxaliplatin-induced responses. Electron microscopic analyses demonstrated that both oxaliplatin- and hypoxia-induced formations of autophagosomes were reduced significantly in HT29 cells treated with the JNK inhibitor SP600125. The role of specific JNK isoforms was defined using HT29 derived cell lines stably expressing dominant-negative constructs for JNK1 and JNK2 (HTJ1.3 and HTJ2.2, respectively). These cell lines demonstrated that functional JNK1 is required for hypoxia-induced autophagy and that JNK2 does not substitute for it. Inhibition of autophagy in HTJ1.3 cells also coincided with enhancement of intrinsic apoptosis. Analysis of Bcl2-family proteins revealed hyperphosphorylation of Bcl-XL in the HTJ1.3 cell line, but this did not lead to the expected dissociation from Beclin 1. Consistent with this, knockdown of Bcl XL in HT29 cells did not significantly affect the induction of autophagy, but abrogated hypoxic resistance to oxaliplatin due to the faster and more robust activation of apoptosis. IMPLICATIONS: These data suggest that balance between autophagy and apoptosis is shifted toward apoptosis by downregulation of JNK1, contributing to oxaliplatin sensitization. These findings further support the investigation of JNK inhibition in colorectal cancer treatment. Mol Cancer Res; 14(8); 753-63. (c)2016 AACR. PMID- 27216155 TI - A Novel EGFR Extracellular Domain Mutant, EGFRDelta768, Possesses Distinct Biological and Biochemical Properties in Neuroblastoma. AB - EGFR is a popular therapeutic target for many cancers. EGFR inhibitors have been tested in children with refractory neuroblastoma. Interestingly, partial response or stable disease was observed in a few neuroblastoma patients. As EGFR mutations are biomarkers for response to anti-EGFR drugs, primary neuroblastoma tumors and cell lines were screened for mutations. A novel EGFR extracellular domain deletion mutant, EGFRDelta768, was discovered and the biologic and biochemical properties of this mutant were characterized and compared with wild-type and EGFRvIII receptors. EGFRDelta768 was found to be constitutively active and localized to the cell surface. Its expression conferred resistance to etoposide and drove proliferation as well as invasion of cancer cells. While EGFRDelta768 had similarity to EGFRvIII, its biologic and biochemical properties were distinctly different from both the EGFRvIII and wild-type receptors. Even though erlotinib inhibited EGFRDelta768, its effect on the mutant was not as strong as that on wild-type EGFR and EGFRvIII. In addition, downstream signaling of EGFRDelta768 was different from that of the wild-type receptor. In conclusion, this is the first study to demonstrate that neuroblastoma express not only EGFRvIII, but also a novel EGFR extracellular domain deletion mutant, EGFRDelta768. The EGFRDelta768 also possesses distinct biologic and biochemical properties which might have therapeutic implications for neuroblastoma as well as other tumors expressing this novel mutant. IMPLICATIONS: Neuroblastoma expressed a novel EGFR mutant which possesses distinct biologic and biochemical properties that might have therapeutic implications. Mol Cancer Res; 14(8); 740-52. (c)2016 AACR. PMID- 27216156 TI - Hypothalamic-pituitary-adrenal axis hyperactivity is associated with decreased brain-derived neurotrophic factor in female suicide attempters. AB - INTRODUCTION: Both decreased levels of brain-derived neurotrophic factor (BDNF) and hypothalamic-pituitary-adrenal (HPA) axis dysregulation may be involved in the pathophysiology of suicidal behaviour, as well as cognitive symptoms of depression. Pre-clinical and clinical studies have shown interactions between HPA axis activity and BDNF, but this has not been studied in a clinical cohort of suicidal subjects. The purpose of this study was, therefore, to investigate associations between HPA-axis activity and BDNF in suicide attempters. Furthermore, this study examined the relationship between the HPA-axis, BDNF, and cognitive symptoms in suicidal patients. Since previous data indicate gender related differences in BDNF and the HPA axis, males and females were examined separately. METHOD: Seventy-five recent suicide attempters (n = 41 females; n = 34 males) were enrolled in the study. The Dexamethasone Suppression Test (DST) was performed and BDNF in plasma were analysed. Patients were evaluated with the Comprehensive Psychopathological Rating Scale (CPRS) from which items 'Concentration difficulties' and 'Failing memory' were extracted. RESULTS: Only among females, DST non-suppressors had significantly lower BDNF compared to DST suppressors (p = 0.022), and there was a significant correlation between post-DST serum cortisol at 8 a.m. and BDNF (rs = -0.437, p = 0.003). Concentration difficulties correlated significantly with post-DST cortisol in all patients (rs = 0.256, p = 0.035), in females (rs = 0.396, p = 0.015), and with BDNF in females (rs = -0.372, p = 0.020). CONCLUSION: The findings suggest an inverse relationship between the HPA-axis and BDNF in female suicide attempters. Moreover, concentration difficulties may be associated with low BDNF and DST non suppression in female suicide attempters. PMID- 27216157 TI - An exploratory approach demonstrating immune skewing and a loss of coordination among cytokines in plasma and saliva of Veterans with combat-related PTSD. AB - Studies have suggested PTSD to be associated with an inflammatory state, although few studies have examined the balances between stimulatory and inhibitory immune mediators in PTSD. An exploratory approach was taken to assess the immune imbalances between Th1 stimulatory, inflammatory and inhibitory mediators associated with PTSD. This approach focused on a tightly-controlled and relatively homogeneous population of Veterans, all with similar levels of combat exposure in the Afghanistan and Iraq wars, but some testing negative and others testing positive for PTSD. Although the sample size was small (6 controls and 7 with PTSD) and a limitation of this study, the results showed significant imbalances in immune cytokines favoring a Th1 and inflammatory state, with reduced levels of inhibitory cytokines in Veterans with PTSD. This was particularly prominent in the saliva of PTSD subjects compared to in their plasma. PMID- 27216158 TI - Telomere attrition in beta and alpha cells with age. AB - We have reported telomere attrition in beta and alpha cells of the pancreas in elderly patients with type 2 diabetes, but it has not been explored how the telomere lengths of these islet cells change according to age in normal subjects. To examine the telomere lengths of beta and alpha cells in individuals without diabetes across a wide range of ages, we conducted measurement of the telomere lengths of human pancreatic beta and alpha cells obtained from 104 autopsied subjects without diabetes ranging in age from 0 to 100 years. As an index of telomere lengths, the normalized telomere-centromere ratio (NTCR) was determined for beta (NTCRbeta) and alpha (NTCRalpha) cells by quantitative fluorescence in situ hybridization (Q-FISH). We found NTCRbeta and NTCRalpha showed almost the same levels and both decreased according to age (p < 0.001 for both). NTCRs decreased more rapidly with age and were more widely distributed (p = 0.036 for NTCRbeta, p < 0.001 for NTCRalpha) in subjects under 18 years of age than in subjects over 18 years. There was a positive correlation between NTCRbeta and NTCRalpha only among adult subjects (p < 0.001). In conclusion, the telomeres of beta and alpha cells become shortened with normal aging process. PMID- 27216159 TI - Environmental pollutants and child health-A review of recent concerns. AB - In recent years, many new studies have evaluated associations between environmental pollutants and child health. This review aims to provide a broad summary of this literature, comparing the state of epidemiological evidence for the effects of a wide range of environmental contaminants (air pollutants, heavy metals, organochlorine compounds, perfluoroalkyl substances, polybrominated diphenyl ethers, pesticides, phthalates and bisphenol A) on child health outcomes. The review addresses effects on foetal growth and prematurity, neurodevelopment, respiratory and immune health, and childhood growth and obesity. Findings of recent prospective studies and meta-analyses have corroborated previous good evidence, often at lower exposure levels, for effects on foetal growth of air pollution and polychlorinated biphenyls (PCBs), for neurotoxic effects of lead, methylmercury, PCBs and organophosphate pesticides, and for respiratory health effects of air pollution. Moderate evidence has emerged for a potential role of environmental pollutants in attention deficit hyperactivity disorder and autism (lead, PCBs, air pollution), respiratory and immune health (dichlorodiphenyldichloroethylene - DDE - and PCBs), and obesity (DDE). In addition, there is now moderate evidence that certain chemicals of relatively recent concern may be associated with adverse child health outcomes, specifically perfluorooctanoate and foetal growth, and polybrominated diphenyl ethers and neurodevelopment. For other chemicals of recent concern, such as phthalates and bisphenol A, the literature is characterised by large inconsistencies preventing strong conclusions. In conclusion, since most of the recent literature evaluates common exposures in the general population, and not particularly high exposure situations, this accumulating body of evidence suggests that the unborn and young child require more protection than is currently provided. Large, coordinated research efforts are needed to improve understanding of long-term effects of complex chemical mixtures. PMID- 27216160 TI - Ablation Strategies for Locally Advanced Pancreatic Cancer. AB - With the advent of novel and somewhat effective chemotherapy against pancreas cancer, several groups developed a new interest on locally advanced pancreatic cancer (LAPC). Unresectable tumors constitute up to 80% of pancreatic cancer (PC) at the time of diagnosis and are associated with a 5-year overall survival of less than 5%. To control those tumors locally, with perhaps improved patients survival, significant advances were made over the last 2 decades in the development of ablation methods including cryoablation, radiofrequency ablation, microwave ablation, high intensity focused ultrasound and irreversible electroporation (IRE). Many suggested a call for caution for possible severe or lethal complications in using such techniques on the pancreas. Most fears were on the heating or freezing of the pancreas, while non-thermal ablation (IRE) could offer safer approaches. The multimodal therapies along with high-resolution imaging guidance have created some enthusiasm toward ablation for LAPC. The impact of ablation techniques on primarily non-resectable PC remains, however, unclear. PMID- 27216161 TI - Heterogeneity of a Constitutional Complex Chromosomal Rearrangement in 2q. AB - Complex chromosome rearrangements (CCRs) are unusual structural chromosome alterations found in humans, and to date only a few have been characterized molecularly. New mechanisms, such as chromothripsis, have been proposed to explain the presence of the CCRs in cancer cells and in patients with congenital disorders and/or mental retardation. The aim of the present study was the molecular characterization of a constitutional CCR in a girl with multiple congenital disorders and intellectual disability in order to determine the genotype-phenotype relation and to clarify whether the CCR could have been caused by chromosomal catastrophic events. The present CCR was characterized by G banding, high-resolution CGH, multiplex ligation-dependent probe amplification and subtelomeric 2q-FISH analyses. Preliminary results indicate that the de novo CCR is unbalanced showing a 2q37.3 deletion and 2q34q37.2 partial trisomy. Our patient shows some of the typical traits and intellectual disability described in patients with 2q37 deletion and also in carriers of 2q34q37.2 partial trisomy; thus, the clinical disorders could be explained by additional effects of both chromosome alterations (deletions and duplications). A posterior, sequential FISH study using BAC probes revealed the unexpected presence of at least 17 different reorganizations affecting 2q34q37.2, suggesting the existence of chromosome instability in this region. The present CCR is the first case described in the literature of heterogeneity of unbalanced CCRs affecting a small region of 2q, indicating that the mechanisms involved in constitutional chromosome rearrangement may be more complex than previously thought. PMID- 27216162 TI - Identification, characterization and molecular adaptation of class I redox systems for the production of hydroxylated diterpenoids. AB - BACKGROUND: De novo production of multi-hydroxylated diterpenoids is challenging due to the lack of efficient redox systems. RESULTS: In this study a new reductase/ferredoxin system from Streptomyces afghaniensis (AfR.Afx) was identified, which allowed the Escherichia coli-based production of the trihydroxylated diterpene cyclooctatin, a potent inhibitor of human lysophospholipase. This production system provides a 43-fold increase in cyclooctatin yield (15 mg/L) compared to the native producer. AfR.Afx is superior in activating the cylcooctatin-specific class I P450s CotB3/CotB4 compared to the conventional Pseudomonas putida derived PdR.Pdx model. To enhance the activity of the PdR.Pdx system, the molecular basis for these activity differences, was examined by molecular engineering. CONCLUSION: We demonstrate that redox system engineering can boost and harmonize the catalytic efficiency of class I hydroxylase enzyme cascades. Enhancing CotB3/CotB4 activities also provided for identification of CotB3 substrate promiscuity and sinularcasbane D production, a functionalized diterpenoid originally isolated from the soft coral Sinularia sp. PMID- 27216163 TI - Prevalence of Renal Impairment and Associated Conditions Among HCV-Infected Persons in the Chronic Hepatitis Cohort Study (CHeCS). AB - BACKGROUND: Guidelines for the treatment of HCV-infected persons were updated in August 2015 with new recommendations for patients with renal impairment. Treatment is imperative for patients with severe, renal-associated extrahepatic manifestations of HCV infection. AIMS: We sought to describe the prevalence of these conditions among current HCV-infected patients in a population-based prospective, observational cohort study at four large US health systems. METHODS: Data from cohort patients with chronic HCV infection during 2012 were analyzed for the period from 2006 to 2013. We determined the prevalence of mild to moderately impaired renal function defined as having the most recent estimated glomerular filtration rate [eGFR] <= 80 ml/min/1.73 m(2), with severe impairment defined as eGFR < 30 ml/min/1.73 m(2), based on the treatment guidelines. Prevalence of extrahepatic conditions was ascertained using ICD9-codes. RESULTS: Among 5772 persons, the prevalence of eGFR <= 80 was 33 % and eGFR < 30 was 2 %, including among patients with hepatic fibrosis. Diagnosed extrahepatic renal manifestations were rare: vasculitis- 0.2 %, nephrotic syndrome- 0.3 %, and cryoglobulinemia- 0.9 %. CONCLUSIONS: While the prevalence of severe renal impairment and diagnosed extrahepatic manifestations was low, mild-to-moderate renal impairment was common in HCV patients, including those with advanced liver fibrosis for whom the need for treatment is urgent. PMID- 27216164 TI - Far-field optical nanothermometry using individual sub-50 nm upconverting nanoparticles. AB - We demonstrate far-field optical thermometry using individual NaYF4 nanoparticles doped with 2% Er(3+) and 20% Yb(3+). Isolated 20 * 20 * 40 nm(3) particles were identified using only far-field optical imaging, confirmed by subsequent scanning electron microscopy. The luminescence thermometry response for five such single particles was characterized for temperatures from 300 K to 400 K. A standard Arrhenius model widely used for larger particles can still be accurately applied to these sub-50 nm particles, with good particle-to-particle uniformity (response coefficients exhibited standard deviations below 5%). With its spatial resolution on the order of 50 nm when imaging a single particle, far below the diffraction limit, this technique has potential applications for both fundamental thermal measurements and nanoscale metrology in industrial applications. PMID- 27216165 TI - Design and Synthesis of Potent in Vitro and in Vivo Anticancer Agents Based on 1 (3',4',5'-Trimethoxyphenyl)-2-Aryl-1H-Imidazole. AB - A novel series of tubulin polymerization inhibitors, based on the 1-(3',4',5' trimethoxyphenyl)-2-aryl-1H-imidazole scaffold and designed as cis-restricted combretastatin A-4 analogues, was synthesized with the goal of evaluating the effects of various patterns of substitution on the phenyl at the 2-position of the imidazole ring on biological activity. A chloro and ethoxy group at the meta- and para-positions, respectively, produced the most active compound in the series (4o), with IC50 values of 0.4-3.8 nM against a panel of seven cancer cell lines. Except in HL-60 cells, 4o had greater antiproliferative than CA-4, indicating that the 3'-chloro-4'-ethoxyphenyl moiety was a good surrogate for the CA-4 B ring. Experiments carried out in a mouse syngenic model demonstrated high antitumor activity of 4o, which significantly reduced the tumor mass at a dose thirty times lower than that required for CA-4P, which was used as a reference compound. Altogether, our findings suggest that 4o is a promising anticancer drug candidate that warrants further preclinical evaluation. PMID- 27216166 TI - The Role of Age-Related Declines in Subcortical Auditory Processing in Speech Perception in Noise. AB - Older adults, even those without hearing impairment, often experience increased difficulties understanding speech in the presence of background noise. This study examined the role of age-related declines in subcortical auditory processing in the perception of speech in different types of background noise. Participants included normal-hearing young (19 - 29 years) and older (60 - 72 years) adults. Normal hearing was defined as pure-tone thresholds of 25 dB HL or better at octave frequencies from 0.25 to 4 kHz in both ears and at 6 kHz in at least one ear. Speech reception thresholds (SRTs) to sentences were measured in steady state (SS) and 10-Hz amplitude-modulated (AM) speech-shaped noise, as well as two talker babble. In addition, click-evoked auditory brainstem responses (ABRs) and envelope following responses (EFRs) in response to the vowel /alpha/ in quiet, SS, and AM noise were measured. Of primary interest was the relationship between the SRTs and EFRs. SRTs were significantly higher (i.e., worse) by about 1.5 dB for older adults in two-talker babble but not in AM and SS noise. In addition, the EFRs of the older adults were less robust compared to the younger participants in quiet, AM, and SS noise. Both young and older adults showed a "neural masking release," indicated by a more robust EFR at the trough compared to the peak of the AM masker. The amount of neural masking release did not differ between the two age groups. Variability in SRTs was best accounted for by audiometric thresholds (pure-tone average across 0.5-4 kHz) and not by the EFR in quiet or noise. Aging is thus associated with a degradation of the EFR, both in quiet and noise. However, these declines in subcortical neural speech encoding are not necessarily associated with impaired perception of speech in noise, as measured by the SRT, in normal-hearing older adults. PMID- 27216167 TI - Gynecological cancer alarm symptoms: is contact with specialist care associated with lifestyle and socioeconomic status? A population-based study. AB - INTRODUCTION: The aim of this study was to determine the proportion of patients who were referred to specialist care after reporting gynecological cancer alarm symptoms to their general practitioner. We sought to investigate whether contact with specialist care was associated with lifestyle factors or socioeconomic status. MATERIAL AND METHODS: Nationwide population-based prospective cohort study in Denmark, based on a random sample of 51 090 women aged 20 years or older from the general population. A web-based questionnaire regarding gynecological alarm symptoms and lifestyle was distributed to the invited individuals. Data about contact with specialist care were obtained from the National Patient Register and the National Health Insurance Service Registry, whereas information about socioeconomic status was collected from Statistics Denmark. Main outcome measures were percentages of patients having contact with specialist care and odds ratios (ORs) for associations between specialist care contact, lifestyle factors and socioeconomic status. RESULTS: The study included 25 866 nonpregnant women; 2957 reported the onset of at least one gynecological cancer alarm symptom, and 683 of these (23.1%) reported symptoms to their general practitioner. The proportion of individuals having contact with specialist care ranged from 39.3% (pain during intercourse) to 47.8% (bleeding during intercourse). Individuals with higher educational level had significantly higher odds of contact with a specialist (OR 1.86, 95% CI 1.17-2.95). CONCLUSIONS: Educational level influences contact with specialist care among patients with gynecological cancer alarm symptoms. Future studies should investigate inequalities in access to the secondary healthcare system. PMID- 27216168 TI - Bonfire red titles. PMID- 27216169 TI - Addressing the role of medical students using community mobilization and social media in the Ebola response. AB - Health professions education in the 21st century should incorporate both community mobilization and social media strategies. First, community mobilization facilitates change by educating community members with evidence-based, high quality and up-to-date health information and empowering their active participation in target health initiatives. Second, advancements in technology and globalization foster the development of innovative communication technologies used as a key tool in the 'roll out' of community health initiatives during epidemics such as Ebola virus disease. In August 2014, medical students of Sierra Leone and Guinea used these dual health promotional strategies in the Kick Ebola Out campaign to educate community members about transmission of the Ebola virus and preventive measures, as well as to reduce perceptions related to stigma or fear of disease transmission. In this report, we describe how medical students, who are trained in basic and clinical sciences, evidence-based practices, and social determinants of health, can serve as human resources for health and facilitate dynamic communication strategies to educate and empower both medical students and community members for local or national health initiatives. PMID- 27216170 TI - Raising awareness of cognitive biases during diagnostic reasoning. AB - INTRODUCTION: Bias in diagnostic reasoning can potentially lead to severe consequences. We explored how to design an experiential learning workshop in a general practice clerkship to raise awareness on bias. METHOD: A group of 12 students was split into two groups. Both groups 'diagnosed' two patients in two case studies. Only one group, without them knowing, were given a case including salient distracting features. The whole group discussed the influence of these distractors. In the second round all students had salient distracting features in their case descriptions but only one group had a debiasing tool, a checklist to reconsider their first diagnosis, which they discussed in the final large group discussion. RESULTS: Students were misled by salient distracting features and thus experienced how one small difference in a case description may lead to a different diagnosis, due to bias. The debiasing tool was regarded with scepticism. Afterwards, students indicated that, thanks to experiencing bias themselves, they felt better equipped to recognize the risk of bias. CONCLUSIONS: An experiential learning approach with case studies containing salient distracting features seems to be a viable method to learn about bias in a general practice clerkship. PMID- 27216171 TI - Establishing a scholarly culture requires a conceptual framework for leveraging change. PMID- 27216172 TI - Comparative Structural Dynamics of tRNA(Phe) with Respect to Hinge Region Methylated Guanosine: A Computational Approach. AB - Transfer RNAs (tRNAs) contain various uniquely modified nucleosides thought to be useful for maintaining the structural stability of tRNAs. However, their significance for upholding the tRNA structure has not been investigated in detail at the atomic level. In this study, molecular dynamic simulations have been performed to assess the effects of methylated nucleic acid bases, N (2) methylguanosine (m(2)G) and N (2)-N (2)-dimethylguanosine (m 2 (2) G) at position 26, i.e., the hinge region of E. coli tRNA(Phe) on its structure and dynamics. The results revealed that tRNA(Phe) having unmodified guanosine in the hinge region (G26) shows structural rearrangement in the core of the molecule, resulting in lack of base stacking interactions, U-turn feature of the anticodon loop, and TPsiC loop. We show that in the presence of the unmodified guanosine, the overall fold of tRNA(Phe) is essentially not the same as that of m(2)G26 and m 2 (2) G26 containing tRNA(Phe). This structural rearrangement arises due to intrinsic factors associated with the weak hydrogen-bonding patterns observed in the base triples of the tRNA(Phe) molecule. The m(2)G26 and m 2 (2) G26 containing tRNA(Phe) retain proper three-dimensional fold through tertiary interactions. Single-point energy and molecular electrostatics potential calculation studies confirmed the structural significance of tRNAs containing m(2)G26 and m 2 (2) G26 compared to tRNA with normal G26, showing that the mono methylated (m(2)G26) and dimethylated (m 2 (2) G26) modifications are required to provide structural stability not only in the hinge region but also in the other parts of tRNA(Phe). Thus, the present study allows us to better understand the effects of modified nucleosides and ionic environment on tRNA folding. PMID- 27216173 TI - Taking a Stand: The Next 50 Years of Community Psychology. AB - On the occasion of the 50th anniversary of community psychology, the author looks backwards in community psychology literature and to each side in other allied disciplines to suggest three fundamental issues that are in need of critical reflection and re-evaluation as we move toward the next 50 plus years of our field. These fundamental issues are: Defining community psychology, Doing community psychology, and Perfecting community psychology. PMID- 27216174 TI - Sexual selection leads to a tenfold difference in reproductive success of alternative reproductive tactics in male Atlantic salmon. AB - The precocious maturation of some male Atlantic salmon (Salmo salar L.) has become a textbook example of alternative mating tactics, but the only estimates of reproductive success available so far are either the collective contribution of precocious males to reproduction in the wild or individual reproductive success in oversimplified experimental conditions. Using genetic parentage analysis on anadromous and precocious potential spawners and their offspring, we quantified components of individual reproductive success of both tactics in a natural population. On average, precocious males produced 2.24 (variance 67.62) offspring, against 27.17 (3080) for anadromous males. For both tactics, most of the variance in reproductive success was due to mating success, with 83% of precocious males having no mate, against 50% for anadromous males. Body size increased reproductive success of anadromous males and tended to decrease precocious males' reproductive success. Although these results do not solve the coexistence of alternative reproductive tactics (ARTs) in Atlantic salmon, their inclusion in comprehensive models of lifetime reproductive success should shed light on the evolution of precocious maturation in Atlantic salmon and its effect on the selection of phenotypic traits. PMID- 27216175 TI - Sex allocation and secondary sex ratio in Cuban boa (Chilabothrus angulifer): mother's body size affects the ratio between sons and daughters. AB - Secondary sex ratios of animals with genetically determined sex may considerably deviate from equality. These deviations may be attributed to several proximate and ultimate factors. Sex ratio theory explains some of them as strategic decisions of mothers improving their fitness by selective investment in sons or daughters, e.g. local resource competition hypothesis (LRC) suggests that philopatric females tend to produce litters with male-biased sex ratios to avoid future competition with their daughters. Until now, only little attention has been paid to examine predictions of sex ratio theory in snakes possessing genetic sex determination and exhibiting large variance in allocation of maternal investment. Cuban boa is an endemic viviparous snake producing large-bodied newborns (~200 g). Extremely high maternal investment in each offspring increases importance of sex allocation. In a captive colony, we collected breeding records of 42 mothers, 62 litters and 306 newborns and examined secondary sex ratios (SR) and sexual size dimorphism (SSD) of newborns. None of the examined morphometric traits of neonates appeared sexually dimorphic. The sex ratio was slightly male biased (174 males versus 132 females) and litter sex ratio significantly decreased with female snout-vent length. We interpret this relationship as an additional support for LRC as competition between mothers and daughters increases with similarity of body sizes between competing snakes. PMID- 27216177 TI - FAP Promotes Immunosuppression by Cancer-Associated Fibroblasts in the Tumor Microenvironment via STAT3-CCL2 Signaling. AB - Cancer-associated fibroblasts (CAF) are components of the tumor microenvironment whose contributions to malignant progression are not fully understood. Here, we show that the fibroblast activation protein (FAP) triggers induction of a CAF subset with an inflammatory phenotype directed by STAT3 activation and inflammation-associated expression signature marked by CCL2 upregulation. Enforcing FAP expression in normal fibroblasts was sufficient to endow them with an inflammatory phenotype similar to FAP(+)CAFs. We identified FAP as a persistent activator of fibroblastic STAT3 through a uPAR-dependent FAK-Src-JAK2 signaling pathway. In a murine liver tumor model, we found that FAP(+)CAFs were a major source of CCL2 and that fibroblastic STAT3-CCL2 signaling in this setting promoted tumor growth by enhancing recruitment of myeloid-derived suppressor cells (MDSC). The CCL2 receptor CCR2 was expressed on circulating MDSCs in tumor bearing subjects and FAP(+)CAF-mediated tumor promotion and MDSC recruitment was abrogated in Ccr2-deficient mice. Clinically, we observed a positive correlation between stromal expression of FAP, p-STAT3, and CCL2 in human intrahepatic cholangiocarcinoma, a highly aggressive liver cancer with dense desmoplastic stroma, where elevated levels of stromal FAP predicted a poor survival outcome. Taken together, our results showed how FAP-STAT3-CCL2 signaling in CAFs was sufficient to program an inflammatory component of the tumor microenvironment, which may have particular significance in desmoplasia-associated cancers. Cancer Res; 76(14); 4124-35. (c)2016 AACR. PMID- 27216178 TI - The Tumor-Associated Glycosyltransferase ST6Gal-I Regulates Stem Cell Transcription Factors and Confers a Cancer Stem Cell Phenotype. AB - The glycosyltransferase ST6Gal-I, which adds alpha2-6-linked sialic acids to substrate glycoproteins, has been implicated in carcinogenesis; however, the nature of its pathogenic role remains poorly understood. Here we show that ST6Gal I is upregulated in ovarian and pancreatic carcinomas, enriched in metastatic tumors, and associated with reduced patient survival. Notably, ST6Gal-I upregulation in cancer cells conferred hallmark cancer stem-like cell (CSC) characteristics. Modulating ST6Gal-I expression in pancreatic and ovarian cancer cells directly altered CSC spheroid growth, and clonal variants with high ST6Gal I activity preferentially survived in CSC culture. Primary ovarian cancer cells from patient ascites or solid tumors sorted for alpha2-6 sialylation grew as spheroids, while cells lacking alpha2-6 sialylation remained as single cells and lost viability. ST6Gal-I also promoted resistance to gemcitabine and enabled the formation of stably resistant colonies. Gemcitabine treatment of patient-derived xenograft tumors enriched for ST6Gal-I-expressing cells relative to pair-matched untreated tumors. ST6Gal-I also augmented tumor-initiating potential. In limiting dilution assays, subcutaneous tumor formation was inhibited by ST6Gal-I knockdown, whereas in a chemically induced tumor initiation model, mice with conditional ST6Gal-I overexpression exhibited enhanced tumorigenesis. Finally, we found that ST6Gal-I induced expression of the key tumor-promoting transcription factors, Sox9 and Slug. Collectively, this work highlighted a previously unrecognized role for a specific glycosyltransferase in driving a CSC state. Cancer Res; 76(13); 3978-88. (c)2016 AACR. PMID- 27216176 TI - Safety out of control: dopamine and defence. AB - We enjoy a sophisticated understanding of how animals learn to predict appetitive outcomes and direct their behaviour accordingly. This encompasses well-defined learning algorithms and details of how these might be implemented in the brain. Dopamine has played an important part in this unfolding story, appearing to embody a learning signal for predicting rewards and stamping in useful actions, while also being a modulator of behavioural vigour. By contrast, although choosing correct actions and executing them vigorously in the face of adversity is at least as important, our understanding of learning and behaviour in aversive settings is less well developed. We examine aversive processing through the medium of the role of dopamine and targets such as D2 receptors in the striatum. We consider critical factors such as the degree of control that an animal believes it exerts over key aspects of its environment, the distinction between 'better' and 'good' actual or predicted future states, and the potential requirement for a particular form of opponent to dopamine to ensure proper calibration of state values. PMID- 27216179 TI - Three-Dimensional Breast Cancer Models Mimic Hallmarks of Size-Induced Tumor Progression. AB - Tumor size is strongly correlated with breast cancer metastasis and patient survival. Increased tumor size contributes to hypoxic and metabolic gradients in the solid tumor and to an aggressive tumor phenotype. Thus, it is important to develop three-dimensional (3D) breast tumor models that recapitulate size-induced microenvironmental changes and, consequently, natural tumor progression in real time without the use of artificial culture conditions or gene manipulations. Here, we developed size-controlled multicellular aggregates ("microtumors") of subtype-specific breast cancer cells by using non-adhesive polyethylene glycol dimethacrylate hydrogel microwells of defined sizes (150-600 MUm). These 3D microtumor models faithfully represent size-induced microenvironmental changes, such as hypoxic gradients, cellular heterogeneity, and spatial distribution of necrotic/proliferating cells. These microtumors acquire hallmarks of tumor progression in the same cell lines within 6 days. Of note, large microtumors of hormone receptor-positive cells exhibited an aggressive phenotype characterized by collective cell migration and upregulation of mesenchymal markers at mRNA and protein level, which was not observed in small microtumors. Interestingly, triple negative breast cancer (TNBC) cell lines did not show size-dependent upregulation of mesenchymal markers. In conclusion, size-controlled microtumor models successfully recapitulated clinically observed positive association between tumor size and aggressive phenotype in hormone receptor-positive breast cancer while maintaining clinically proven poor correlation of tumor size with aggressive phenotype in TNBC. Such clinically relevant 3D models generated under controlled experimental conditions can serve as precise preclinical models to study mechanisms involved in breast tumor progression as well as antitumor drug effects as a function of tumor progression. Cancer Res; 76(13); 3732-43. (c)2016 AACR. PMID- 27216181 TI - Noninvasive In Vivo Imaging and Biologic Characterization of Thyroid Tumors by ImmunoPET Targeting of Galectin-3. AB - The high prevalence of thyroid nodules in the adult population and the relatively low incidence of thyroid cancer make the preoperative identification of malignant lesions challenging. The beta-galactoside-binding protein galectin-3 is widely expressed in well-differentiated thyroid carcinomas, but not in normal thyrocytes and benign thyroid nodules. This molecule offers a candidate biomarker to improve thyroid cancer diagnosis. Here we report the development of an immunoPET approach for noninvasive imaging of thyroid cancer. The method employs a (89)Zr-labeled mAb to galectin-3, which shows high specificity and binding affinity in vitro Reliable and specific immunoPET imaging was obtained of thyroid cancer in vivo in murine xenograft models of human thyroid cancer. Our findings provide a method to improve the clinical management of patients with thyroid nodules while reducing unnecessary surgery and social costs. Cancer Res; 76(12); 3583-92. (c)2016 AACR. PMID- 27216182 TI - Copy Number Alterations in Enzyme-Coding and Cancer-Causing Genes Reprogram Tumor Metabolism. AB - Somatic copy number alterations frequently occur in the cancer genome affecting not only oncogenic or tumor suppressive genes, but also passenger and potential codriver genes. An intrinsic feature resulting from such genomic perturbations is the deregulation in the metabolism of tumor cells. In this study, we have shown that metabolic and cancer-causing genes are unexpectedly often proximally positioned in the chromosome and share loci with coaltered copy numbers across multiple cancers (19 cancer types from The Cancer Genome Atlas). We have developed an analysis pipeline, Identification of Metabolic Cancer Genes (iMetCG), to infer the functional impact on metabolic remodeling from such coamplifications and codeletions and delineate genes driving cancer metabolism from those that are neutral. Using our identified metabolic genes, we were able to classify tumors based on their tissue and developmental origins. These metabolic genes were similar to known cancer genes in terms of their network connectivity, isoform frequency, and evolutionary features. We further validated these identified metabolic genes by (i) using gene essentiality data from several tumor cell lines, (ii) showing that these identified metabolic genes are strong indicators for patient survival, and (iii) observing a significant overlap between our identified metabolic genes and known cancer-metabolic genes. Our analyses revealed a hitherto unknown generic mechanism for large-scale metabolic reprogramming in cancer cells based on linear gene proximities between cancer causing and -metabolic genes. We have identified 119 new metabolic cancer genes likely to be involved in rewiring cancer cell metabolism. Cancer Res; 76(14); 4058-67. (c)2016 AACR. PMID- 27216180 TI - Antagonizing Integrin beta3 Increases Immunosuppression in Cancer. AB - Integrin beta3 is critical for tumor invasion, neoangiogenesis, and inflammation, making it a promising cancer target. However, preclinical and clinical data of integrin beta3 antagonists have demonstrated no benefit or worse outcomes. We hypothesized that integrin beta3 could affect tumor immunity and evaluated tumors in mice with deletion of integrin beta3 in macrophage lineage cells (beta3KOM). beta3KOM mice had increased melanoma and breast cancer growth with increased tumor-promoting M2 macrophages and decreased CD8(+) T cells. Integrin beta3 antagonist, cilengitide, also enhanced tumor growth and increased M2 function. We uncovered a negative feedback loop in M2 myeloid cells, wherein integrin beta3 signaling favored STAT1 activation, an M1-polarizing signal, and suppressed M2 polarizing STAT6 activation. Finally, disruption of CD8(+) T cells, macrophages, or macrophage integrin beta3 signaling blocked the tumor-promoting effects of integrin beta3 antagonism. These results suggest that effects of integrin beta3 therapies on immune cells should be considered to improve outcomes. Cancer Res; 76(12); 3484-95. (c)2016 AACR. PMID- 27216183 TI - Novel beta-HPV49 Transgenic Mouse Model of Upper Digestive Tract Cancer. AB - The beta genus of human papillomaviruses (beta-HPV) includes approximately 50 different viral types that are subdivided into five species (beta-1 through beta 5). Nonmelanoma cancers may involve some beta-1 and beta-2 HPV types, but the biology of most beta-HPV types and their possible connections to human disease are still little characterized. In this study, we studied the effects of beta-3 type HPV49 in a novel transgenic (Tg) mouse model, using a cytokeratin K14 promoter to drive expression of the E6 and E7 genes from this virus in the basal skin epidermis and the mucosal epithelia of the digestive tract (K14 HPV49 E6/E7 Tg mice). Viral oncogene expression only marginally increased cellular proliferation in the epidermis of Tg animals, compared with wild-type littermates, and we observed no spontaneous tumor formation during their entire lifespan. However, we found that K14 HPV49 E6/E7-Tg mice were highly susceptible to upper digestive tract carcinogenesis upon initiation with 4-nitroquinoline 1 oxide (4NQO). This was a selective effect, as the same mice did not exhibit any skin lesions after chronic UV irradiation. Opposite results were observed in an analogous Tg model expressing the beta-2 HPV38 E6 and E7 oncogenes at the same anatomic sites. While these mice were highly susceptible to UV-induced skin carcinogenesis, as previously shown, they were little affected by 4NQO treatment. Overall, our findings highlight important differences in the biologic properties of certain beta-type HPV that affect their impact on carcinogenesis in an anatomic site-specific manner. Cancer Res; 76(14); 4216-25. (c)2016 AACR. PMID- 27216184 TI - Circulating Omentin as a Novel Biomarker for Colorectal Cancer Risk: Data from the EPIC-Potsdam Cohort Study. AB - Omentin is a novel biomarker shown to exert metabolic, inflammatory, and immune related properties and thereby could be implicated in the risk of colorectal cancer. So far, the association between omentin and colorectal cancer risk has not been evaluated in prospective cohort studies. We investigated the association between prediagnostic plasma omentin concentrations and risk of colorectal cancer in a case-cohort comprising 251 incident colorectal cancer cases diagnosed over a mean follow-up time of 10.4 years and 2,295 persons who remained free of cancer in the European Prospective Investigation into Cancer and Nutrition-Potsdam study. Hazard ratios as a measure of relative risk (RR) and 95% confidence intervals (CI) were computed using a Prentice-modified Cox regression. In a multivariable model adjusted for age, sex, education, dietary and lifestyle factors, body mass index (BMI), and waist circumference, higher omentin concentrations were associated with a higher colorectal cancer risk (RRcontinuously per doubling of omentin concentrations = 1.98; 95% CI, 1.45 2.73). Additional adjustment for metabolic biomarkers, including glycated hemoglobin, high-density lipoprotein cholesterol, and C-reactive protein, did not alter the results. In stratified analyses, the positive association between omentin and colorectal cancer risk was retained in participants with BMI < 30 (RRcontinuously per doubling of omentin concentrations = 2.26; 95% CI, 1.57 3.27), whereas among participants with BMI >= 30 no association was revealed (RRcontinuously per doubling of omentin concentrations = 1.07; 95% CI, 0.63-1.83; Pinteraction = 0.005). These novel findings provide the first lines of evidence for an independent association between prediagnostic omentin concentrations and colorectal cancer risk and suggest a potential interaction with the adiposity state of the individual. Cancer Res; 76(13); 3862-71. (c)2016 AACR. PMID- 27216185 TI - Adipocyte Exosomes Promote Melanoma Aggressiveness through Fatty Acid Oxidation: A Novel Mechanism Linking Obesity and Cancer. AB - Malignant progression results from a dynamic cross-talk between stromal and cancer cells. Recent evidence suggests that this cross-talk is mediated to a significant extent by exosomes, nanovesicles secreted by most cell types and which allow the transfer of proteins, lipids, and nucleic acids between cells. Adipocytes are a major component of several tumor microenvironments, including that of invasive melanoma, where cells have migrated to the adipocyte-rich hypodermic layer of the skin. We show that adipocytes secrete exosomes in abundance, which are then taken up by tumor cells, leading to increased migration and invasion. Using mass spectrometry, we analyzed the proteome of adipocyte exosomes. Interestingly, these vesicles carry proteins implicated in fatty acid oxidation (FAO), a feature highly specific to adipocyte exosomes. We further show that, in the presence of adipocyte exosomes, FAO is increased in melanoma cells. Inhibition of this metabolic pathway completely abrogates the exosome-mediated increase in migration. Moreover, in obese mice and humans, both the number of exosomes secreted by adipocytes as well as their effect on FAO-dependent cell migration are amplified. These observations might in part explain why obese melanoma patients have a poorer prognosis than their nonobese counterparts. Cancer Res; 76(14); 4051-7. (c)2016 AACR. PMID- 27216186 TI - Multiregion Whole-Exome Sequencing Uncovers the Genetic Evolution and Mutational Heterogeneity of Early-Stage Metastatic Melanoma. AB - Cancer genome sequencing has shed light on the underlying genetic aberrations that drive tumorigenesis. However, current sequencing-based strategies, which focus on a single tumor biopsy, fail to take into account intratumoral heterogeneity. To address this challenge and elucidate the evolutionary history of melanoma, we performed whole-exome and transcriptome sequencing of 41 multiple melanoma biopsies from eight individual tumors. This approach revealed heterogeneous somatic mutations in the range of 3%-38% in individual tumors. Known mutations in melanoma drivers BRAF and NRAS were always ubiquitous events. Using RNA sequencing, we found that the majority of mutations were not expressed or were expressed at very low levels, and preferential expression of a particular mutated allele did not occur frequently. In addition, we found that the proportion of ultraviolet B (UVB) radiation-induced C>T transitions differed significantly (P < 0.001) between early and late mutation acquisition, suggesting that different mutational processes operate during the evolution of metastatic melanoma. Finally, clinical history reports revealed that patients harboring a high degree of mutational heterogeneity were associated with more aggressive disease progression. In conclusion, our multiregion tumor-sequencing approach highlights the genetic evolution and non-UVB mutational signatures associated with melanoma development and progression, and may provide a more comprehensive perspective of patient outcome. Cancer Res; 76(16); 4765-74. (c)2016 AACR. PMID- 27216187 TI - Mitochondria-Targeted Analogues of Metformin Exhibit Enhanced Antiproliferative and Radiosensitizing Effects in Pancreatic Cancer Cells. AB - Metformin (Met) is an approved antidiabetic drug currently being explored for repurposing in cancer treatment based on recent evidence of its apparent chemopreventive properties. Met is weakly cationic and targets the mitochondria to induce cytotoxic effects in tumor cells, albeit not very effectively. We hypothesized that increasing its mitochondria-targeting potential by attaching a positively charged lipophilic substituent would enhance the antitumor activity of Met. In pursuit of this question, we synthesized a set of mitochondria-targeted Met analogues (Mito-Mets) with varying alkyl chain lengths containing a triphenylphosphonium cation (TPP(+)). In particular, the analogue Mito-Met10, synthesized by attaching TPP(+) to Met via a 10-carbon aliphatic side chain, was nearly 1,000 times more efficacious than Met at inhibiting cell proliferation in pancreatic ductal adenocarcinoma (PDAC). Notably, in PDAC cells, Mito-Met10 potently inhibited mitochondrial complex I, stimulating superoxide and AMPK activation, but had no effect in nontransformed control cells. Moreover, Mito Met10 potently triggered G1 cell-cycle phase arrest in PDAC cells, enhanced their radiosensitivity, and more potently abrogated PDAC growth in preclinical mouse models, compared with Met. Collectively, our findings show how improving the mitochondrial targeting of Met enhances its anticancer activities, including aggressive cancers like PDAC in great need of more effective therapeutic options. Cancer Res; 76(13); 3904-15. (c)2016 AACR. PMID- 27216188 TI - Histone Deacetylase Inhibition in Prostate Cancer Triggers miR-320-Mediated Suppression of the Androgen Receptor. AB - Targeting androgen receptor (AR) by pharmacologic intervention is one of the effective approaches for treatment of malignant prostate cancers. Histone deacetylase (HDAC) alters the epigenetic status of tumor-associated genes, including those for miRNAs (miRNA), and affects the behavior of cancers. Here, we examined the molecular effects of a HDAC inhibitor, OBP-801, on AR expression and tumor cell growth in prostate cancers. Treatment with OBP-801 efficiently suppressed cell growth of three prostate cancer lines (22Rv1, VCaP, and LNCaP), together with AR downregulation, regardless of their hormone sensitivity. Intriguingly, this effect by OBP-801 was not due to decreased transcriptional activity of the AR gene, but due to posttranscriptional regulation, namely by miRNA-mediated suppression. Among the upregulated miRNAs after OBP-801 treatment in the three prostate cancer cell lines, miR-320a, whose expression was significantly correlated with prognosis of prostate cancers (P = 0.0185), was the most closely associated with AR expression. An miR-320a mimic suppressed AR protein expression together with growth suppression, while anti-miR-320a oligonucleotide significantly abrogated the growth suppression by OBP-801 treatment. FISH analysis revealed that miR-320a was highly expressed in human normal prostate luminal cells, but was rarely expressed in prostate cancer cells. In an AR-dependent prostate tumorigenic rat model, OBP-801 treatment profoundly increased miR-320a expression and repressed prostate tumorigenesis. Our data demonstrated that OBP-801 effectively suppressed AR activity via epigenetic upregulation of miR-320a, which resulted in tumor cell growth suppression of prostate cancers. OBP-801 may be a potent AR-targeting therapeutic reagent in AR positive prostate cancer regardless of androgen dependency. Cancer Res; 76(14); 4192-204. (c)2016 AACR. PMID- 27216189 TI - YAP Mediates Tumorigenesis in Neurofibromatosis Type 2 by Promoting Cell Survival and Proliferation through a COX-2-EGFR Signaling Axis. AB - The Hippo-YAP pathway has emerged as a major driver of tumorigenesis in many human cancers. YAP is a transcriptional coactivator and while details of YAP regulation are quickly emerging, it remains unknown what downstream targets are critical for the oncogenic functions of YAP. To determine the mechanisms involved and to identify disease-relevant targets, we examined the role of YAP in neurofibromatosis type 2 (NF2) using cell and animal models. We found that YAP function is required for NF2-null Schwann cell survival, proliferation, and tumor growth in vivo Moreover, YAP promotes transcription of several targets including PTGS2, which codes for COX-2, a key enzyme in prostaglandin biosynthesis, and AREG, which codes for the EGFR ligand, amphiregulin. Both AREG and prostaglandin E2 converge to activate signaling through EGFR. Importantly, treatment with the COX-2 inhibitor celecoxib significantly inhibited the growth of NF2-null Schwann cells and tumor growth in a mouse model of NF2. Cancer Res; 76(12); 3507-19. (c)2016 AACR. PMID- 27216190 TI - Dicer Elicits Paclitaxel Chemosensitization and Suppresses Cancer Stemness in Breast Cancer by Repressing AXL. AB - Paclitaxel is a standard-of-care chemotherapy for breast cancer, despite the increasing recognition of its poor effectiveness in the treatment of patients with advanced disease. Here, we report that adenovirus-type 5 E1A-mediated elevation of the miRNA-processing enzyme Dicer is sufficient to enhance paclitaxel sensitization and reduce cancer stem-like cell properties in this setting. Elevating Dicer expression increased levels of the AXL kinase targeting miRNA miR-494, thereby repressing AXL expression to increase paclitaxel sensitivity. We found that Dicer expression was regulated at the transcription level by E1A, through activation of an MAPK14/CEBPalpha pathway. Our findings define a mechanism of E1A-mediated chemosensitization for paclitaxel, which is based upon the suppression of breast cancer stem-like cells, with potential implications for the diagnosis and treatment of breast cancer patients. Cancer Res; 76(13); 3916-28. (c)2016 AACR. PMID- 27216191 TI - LIM Kinase Inhibitor Pyr1 Reduces the Growth and Metastatic Load of Breast Cancers. AB - LIM kinases (LIMK) are emerging targets for cancer therapy, and they function as network hubs to coordinate actin and microtubule dynamics. When LIMKs are inhibited, actin microfilaments are disorganized and microtubules are stabilized. Owing to their stabilizing effect on microtubules, LIMK inhibitors may provide a therapeutic strategy to treat taxane-resistant cancers. In this study, we investigated the effect of LIMK inhibition on breast tumor development and on paclitaxel-resistant tumors, using a novel selective LIMK inhibitor termed Pyr1. Treatment of breast cancer cells, including paclitaxel-resistant cells, blocked their invasion and proliferation in vitro and their growth in vivo in tumor xenograft assays. The tumor-invasive properties of Pyr1 were investigated in vivo by intravital microscopy of tumor xenografts. A striking change of cell morphology was observed with a rounded phenotype arising in a subpopulation of cells, while other cells remained elongated. Notably, although Pyr1 decreased the motility of elongated cells, it increased the motility of rounded cells in the tumor. Pyr1 administration prevented the growth of metastasis but not their spread. Overall, our results provided a preclinical proof of concept concerning how a small-molecule inhibitor of LIMK may offer a strategy to treat taxane resistant breast tumors and metastases. Cancer Res; 76(12); 3541-52. (c)2016 AACR. PMID- 27216192 TI - S-nitrosylation of the Mitochondrial Chaperone TRAP1 Sensitizes Hepatocellular Carcinoma Cells to Inhibitors of Succinate Dehydrogenase. AB - S-nitrosoglutathione reductase (GSNOR) represents the best-documented denitrosylase implicated in regulating the levels of proteins posttranslationally modified by nitric oxide on cysteine residues by S-nitrosylation. GSNOR controls a diverse array of physiologic functions, including cellular growth and differentiation, inflammation, and metabolism. Chromosomal deletion of GSNOR results in pathologic protein S-nitrosylation that is implicated in human hepatocellular carcinoma (HCC). Here we identify a metabolic hallmark of aberrant S-nitrosylation in HCC and exploit it for therapeutic gain. We find that hepatocyte GSNOR deficiency is characterized by mitochondrial alteration and by marked increases in succinate dehydrogenase (SDH) levels and activity. We find that this depends on the selective S-nitrosylation of Cys(501) in the mitochondrial chaperone TRAP1, which mediates its degradation. As a result, GSNOR deficient cells and tumors are highly sensitive to SDH inhibition, namely to alpha-tocopheryl succinate, an SDH-targeting molecule that induced RIP1/PARP1 mediated necroptosis and inhibited tumor growth. Our work provides a specific molecular signature of aberrant S-nitrosylation in HCC, a novel molecular target in SDH, and a first-in-class therapy to treat the disease. Cancer Res; 76(14); 4170-82. (c)2016 AACR. PMID- 27216193 TI - A Novel Bispecific Antibody Targeting EGFR and cMet Is Effective against EGFR Inhibitor-Resistant Lung Tumors. AB - Non-small cell lung cancers (NSCLC) with activating EGFR mutations become resistant to tyrosine kinase inhibitors (TKI), often through second-site mutations in EGFR (T790M) and/or activation of the cMet pathway. We engineered a bispecific EGFR-cMet antibody (JNJ-61186372) with multiple mechanisms of action to inhibit primary/secondary EGFR mutations and the cMet pathway. JNJ-61186372 blocked ligand-induced phosphorylation of EGFR and cMet and inhibited phospho-ERK and phospho-AKT more potently than the combination of single receptor-binding antibodies. In NSCLC tumor models driven by EGFR and/or cMet, JNJ-61186372 treatment resulted in tumor regression through inhibition of signaling/receptor downmodulation and Fc-driven effector interactions. Complete and durable regression of human lung xenograft tumors was observed with the combination of JNJ-61186372 and a third-generation EGFR TKI. Interestingly, treatment of cynomolgus monkeys with JNJ-61186372 resulted in no major toxicities, including absence of skin rash observed with other EGFR-directed agents. These results highlight the differentiated potential of JNJ-61186372 to inhibit the spectrum of mutations driving EGFR TKI resistance in NSCLC. Cancer Res; 76(13); 3942-53. (c)2016 AACR. PMID- 27216194 TI - Genomic Landscape Established by Allelic Imbalance in the Cancerization Field of a Normal Appearing Airway. AB - Visually normal cells adjacent to, and extending from, tumors of the lung may carry molecular alterations characteristics of the tumor itself, an effect referred to as airway field of cancerization. This airway field has been postulated as a model for early events in lung cancer pathogenesis. Yet the genomic landscape of somatically acquired molecular alterations in airway epithelia of lung cancer patients has remained unknown. To begin to fill this void, we sought to comprehensively characterize the genomic architecture of chromosomal alterations inducing allelic imbalance (AI) in the airway field of the most common type of lung tumors, non-small cell lung cancer (NSCLC). To do so, we conducted a genome-wide survey of multiple spatially distributed normal appearing airways, multiregion tumor specimens, and uninvolved normal tissues or blood from 45 patients with early-stage NSCLC. We detected alterations in airway epithelia from 22 patients, with an increased frequency in NSCLCs of squamous histology. Our data also indicated a spatial gradient of AI in samples at closer proximity to the NSCLC. Chromosome 9 displayed the highest levels of AI and comprised recurrent independent events. Furthermore, the airway field AI included oncogenic gains and tumor suppressor losses in known NSCLC drivers. Our results demonstrate that genome-wide AI is common in the airway field of cancerization, providing insights into early events in the pathogenesis of NSCLC that may comprise targets for early treatment and chemoprevention. Cancer Res; 76(13); 3676-83. (c)2016 AACR. PMID- 27216195 TI - Clonotypic Diversification of Intratumoral T Cells Following Sipuleucel-T Treatment in Prostate Cancer Subjects. AB - Sipuleucel-T is an autologous cellular therapy for asymptomatic, or minimally symptomatic, metastatic castrate-resistant prostate cancer, designed to stimulate an immune response against prostate cancer. In a recent clinical trial (NCT00715104), we found that neoadjuvant sipuleucel-T increased the number of activated T cells within the tumor microenvironment. The current analysis examined whether sipuleucel-T altered adaptive T-cell responses by expanding pre existing T cells or by recruiting new T cells to prostate tissue. Next-generation sequencing of the T-cell receptor (TCR) genes from blood or prostate tissue was used to quantitate and track T-cell clonotypes in these treated subjects with prostate cancer. At baseline, there was a significantly greater diversity of circulating TCR sequences in subjects with prostate cancer compared with healthy donors. Among healthy donors, circulating TCR sequence diversity remained unchanged over the same time interval. In contrast, sipuleucel-T treatment reduced circulating TCR sequence diversity versus baseline as measured by the Shannon index. Interestingly, sipuleucel-T treatment resulted in greater TCR sequence diversity in resected prostate tissue in sipuleucel-T-treated subjects versus tissue of nonsipuleucel-T-treated subjects with prostate cancer. Furthermore, sipuleucel-T increased TCR sequence commonality between blood and resected prostate tissue in treated versus untreated subjects with prostate cancer. The broadening of the TCR repertoire within the prostate tissue supports the hypothesis that sipuleucel-T treatment facilitates the recruitment of T cells into the prostate. Our results highlight the importance of assessing T-cell response to immunotherapy both in the periphery and in tumor tissue. Cancer Res; 76(13); 3711-8. (c)2016 AACR. PMID- 27216196 TI - Rho GTPase Transcriptome Analysis Reveals Oncogenic Roles for Rho GTPase Activating Proteins in Basal-like Breast Cancers. AB - The basal-like breast cancer (BLBC) subtype accounts for a disproportionately high percentage of overall breast cancer mortality. The current therapeutic options for BLBC need improvement; hence, elucidating signaling pathways that drive BLBC growth may identify novel targets for the development of effective therapies. Rho GTPases have previously been implicated in promoting tumor cell proliferation and metastasis. These proteins are inactivated by Rho-selective GTPase-activating proteins (RhoGAP), which have generally been presumed to act as tumor suppressors. Surprisingly, RNA-Seq analysis of the Rho GTPase signaling transcriptome revealed high expression of several RhoGAP genes in BLBC tumors, raising the possibility that these genes may be oncogenic. To evaluate this, we examined the roles of two of these RhoGAPs, ArhGAP11A (also known as MP-GAP) and RacGAP1 (also known as MgcRacGAP), in promoting BLBC. Both proteins were highly expressed in human BLBC cell lines, and knockdown of either gene resulted in significant defects in the proliferation of these cells. Knockdown of ArhGAP11A caused CDKN1B/p27-mediated arrest in the G1 phase of the cell cycle, whereas depletion of RacGAP1 inhibited growth through the combined effects of cytokinesis failure, CDKN1A/p21-mediated RB1 inhibition, and the onset of senescence. Random migration was suppressed or enhanced by the knockdown of ArhGAP11A or RacGAP1, respectively. Cell spreading and levels of GTP-bound RhoA were increased upon depletion of either RhoGAP. We have established that, via the suppression of RhoA, ArhGAP11A and RacGAP1 are both critical drivers of BLBC growth, and propose that RhoGAPs can act as oncogenes in cancer. Cancer Res; 76(13); 3826-37. (c)2016 AACR. PMID- 27216197 TI - STAT3/IRF1 Pathway Activation Sensitizes Cervical Cancer Cells to Chemotherapeutic Drugs. AB - Neoadjuvant radio/chemotherapy regimens can markedly improve cervical cancer outcome in a subset of patients, while other patients show poor responses, but may encounter severe adverse effects. Thus, there is a strong need for predictive biomarkers to improve clinical management of cervical cancer patients. STAT3 is considered as a critical antiapoptotic factor in various malignancies. We therefore investigated STAT3 activation during cervical carcinogenesis and its impact on the response of cervical cancer cells to chemotherapeutic drugs. Tyr705 phosphorylated STAT3 increased from low-grade cervical intraepithelial neoplasia (CIN1) to precancerous CIN3 lesions. Notably, pTyr705-STAT3 activation significantly declined from CIN3 to invasive cancer, also when compared in the same clinical biopsy. pTyr705-STAT3 was also low or absent in cultured human cervical cancer cell lines, consistent with the in vivo expression data. Unexpectedly, IL6-type cytokine signaling inducing STAT3 activation rendered cervical cancer cells significantly more susceptible to chemotherapeutic drugs, that is, cisplatin or etoposide. This chemosensitization was STAT3-dependent and we identified IFN regulatory factor-1 (IRF1) as the STAT3-inducible mediator required for cell death enhancement. In line with these data, pTyr705-STAT3 significantly correlated with nuclear IRF1 expression in cervical cancer in vivo Importantly, high IRF1 expression in pretreatment cervical cancer biopsy cells was associated with a significantly better response to neoadjuvant radio/chemotherapy of the patients. In summary, our study has identified a key role of the STAT3/IRF1 pathway for chemosensitization in cervical cancer. Our results suggest that pretherapeutic IRF1 expression should be evaluated as a novel predictive biomarker for neoadjuvant radio/chemotherapy responses. Cancer Res; 76(13); 3872-83. (c)2016 AACR. PMID- 27216198 TI - Early Epigenetic Downregulation of microRNA-192 Expression Promotes Pancreatic Cancer Progression. AB - Pancreatic ductal adenocarcinoma (PDAC) is characterized by very early metastasis, suggesting the hypothesis that metastasis-associated changes may occur prior to actual tumor formation. In this study, we identified miR-192 as an epigenetically regulated suppressor gene with predictive value in this disease. miR-192 was downregulated by promoter methylation in both PDAC and chronic pancreatitis, the latter of which is a major risk factor for the development of PDAC. Functional studies in vitro and in vivo in mouse models of PDAC showed that overexpression of miR-192 was sufficient to reduce cell proliferation and invasion. Mechanistic analyses correlated changes in miR-192 promoter methylation and expression with epithelial-mesenchymal transition. Cell proliferation and invasion were linked to altered expression of the miR-192 target gene SERPINE1 that is encoding the protein plasminogen activator inhibitor-1 (PAI-1), an established regulator of these properties in PDAC cells. Notably, our data suggested that invasive capacity was altered even before neoplastic transformation occurred, as triggered by miR-192 downregulation. Overall, our results highlighted a role for miR-192 in explaining the early metastatic behavior of PDAC and suggested its relevance as a target to develop for early diagnostics and therapy. Cancer Res; 76(14); 4149-59. (c)2016 AACR. PMID- 27216199 TI - A Longitudinal Test of the Parent-Adolescent Family Functioning Discrepancy Hypothesis: A Trend toward Increased HIV Risk Behaviors Among Immigrant Hispanic Adolescents. AB - Parent-adolescent discrepancies in family functioning play an important role in HIV risk behaviors among adolescents, yet longitudinal research with recent immigrant Hispanic families remains limited. This study tested the effects of trajectories of parent-adolescent family functioning discrepancies on HIV risk behaviors among recent-immigrant Hispanic adolescents. Additionally, we examined whether and to what extent trajectories of parent-adolescent family functioning discrepancies vary as a function of gender. We assessed family functioning of 302 Hispanic adolescents (47 % female) and their parent (70 % female) at six time points over a three-year period and computed latent discrepancy scores between parent and adolescent reports at each timepoint. Additionally, adolescents completed measures of sexual risk behaviors and alcohol use. We conducted a confirmatory factor analysis to determine the feasibility of collapsing parent and adolescent reported family functioning indicators onto a single latent discrepancy variable, tested model invariance over time, and conducted growth mixture modeling (GMM). GMM yielded a three-class solution for discrepancies: High-Increasing, High-Stable, and Low-Stable. Relative to the Low-Stable class, parent-adolescent dyads in the High-Increasing and High-Stable classes were at greater risk for adolescents reporting sexual debut at time 6. Additionally, the High-Stable class was at greater risk, relative to the Low-Stable class, in terms of adolescent lifetime alcohol use at 30 months post-baseline. Multiple group GMM indicated that trajectories of parent-adolescent family functioning trajectories did not vary by gender. Implications for future research and practice are discussed. PMID- 27216200 TI - The Mobility of Youth in the Justice System: Implications for Recidivism. AB - Both residential mobility and community disadvantage have been shown to be associated with negative outcomes for adolescents generally and juvenile offenders specifically. The current study examines the effects of moving among a large sample (n = 13,096) of previously adjudicated youth (31.6 % female, 41.2 % Black, 16.5 % Hispanic). Additionally, we examine whether moving upward to a more affluent neighborhood, moving downward to an area of greater disadvantage, or moving laterally to a similar neighborhood tempers the effects of residential mobility. We use a combination of analytical techniques, including propensity score matching to untangle the effects of mobility sans pre-existing conditions between movers and non-movers. Results show relocation increases recidivism, irrespective of the direction of the move with regard to socioeconomic context. Moving upward has the most detrimental impact for adjudicated male adolescents, while downward relocations evidenced the largest effect for female youth. Implications for policy and future research needs are discussed. PMID- 27216202 TI - Letter from the editor. PMID- 27216201 TI - The Role of Sleep in the Relationship Between Victimization and Externalizing Problems in Adolescents. AB - Victimization is linked to externalizing outcomes in adolescents and recent theorizing suggests that sleep plays a role in this relationship; however, there is little evidence examining sleep as a mediator. This study examines associations between victimization experiences and changes in aggression, delinquency, and drug use. Data were obtained from three waves of a school-based study with middle-school youth (n = 785; 55 % female; 20 % African American; M = 12.32, SD = .51 years at T1), and path analyses were used to test the key hypotheses. Analyses controlling for major life events, demographic factors, and school site revealed that victimization indirectly affected delinquency and drug use, but not aggression, through its relationship with sleep problems. Further, the effects of sleep problems on drug use were specific to females. These data suggest that intervening to address sleep problems resulting from victimization may serve to reduce some forms of externalizing behavior. PMID- 27216203 TI - Human Vaccines & Immunotherapeutics: News. PMID- 27216204 TI - A preliminary study of the neuroanatomical correlates of primary writing tremor: role of cerebellum. AB - INTRODUCTION: To explore the neuroanatomical correlates of primary writing tremor (PWT) and the role of cerebellum, using advanced structural neuroimaging. Till date, there are no studies exploring the gray and white matter changes using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) in PWT. METHODS: Ten male patients with PWT were evaluated clinically and with magnetic resonance imaging. VBM and DTI images of patients were compared with that of 10 healthy male subjects. Spatially unbiased infra-tentorial template (SUIT) analysis was done to investigate the alterations of cerebellar gray matter. Region-of-interest analysis was performed on regions observed to be significantly different on DTI analysis. RESULTS: The mean duration of illness and mean age of the patients were 3.5 +/- 1.9 and 51.7 +/- 8.6 years, respectively. On VBM analysis, the cluster of gray matter atrophy was found in bilateral cerebellar areas of culmen and left declive, right superior and medial frontal gyrus, bilateral middle frontal gyrus, bilateral anterior cingulate gyrus, and bilateral parahippocampal gyrus. DTI showed significantly reduced fractional anisotrophy of the anterior thalamic radiation, cingulum, and inferior fronto-occipital fasciculus in PWT patients compared to controls. The axial diffusivity, mean diffusivity, and radial diffusivity maps did not reveal any significant differences. On SUIT analysis, significant atrophy was found in right uvula and semilunar lobule in patients with PWT compared to controls. CONCLUSIONS: Our study found that patients with PWT had predominant gray matter atrophy in parts of cerebellum and frontal lobe along with white matter changes of the cingulum and frontal lobe connections. PMID- 27216205 TI - Non-ischemic cerebral enhancing lesions secondary to endovascular aneurysm therapy: nickel allergy or foreign body reaction? Case series and review of the literature. AB - INTRODUCTION: Delayed onset of non-ischemic cerebral enhancing (NICE) lesions is a rare complication of intracranial aneurysms' endovascular therapy (EVT). The purpose of this study is to report this rare complication and its potential pathophysiology in a single-center case series and review the relevant literature. METHODS: After retrospective review of all patients managed by EVT at our institution from January 1, 2012 to December 31, 2014, 2 out of 374 patients (0.5 %) with such a complication were identified. Skin patch testing was performed with all endovascular devices used in the two patients and with the European baseline series, including nickel. All previously published cases in the English literature were reviewed based on exhaustive PubMed and Embase research. RESULTS: Patient no. 1 developed NICE lesions 1 month after balloon-assisted coiling of a ruptured anterior communicating artery aneurysm. Patient no. 2 developed NICE lesions 12 months (the longest delay reported to date for such a complication) after the treatment of a right carotid-ophthalmic aneurysm by loose coiling and flow diversion. Patient no. 2 demonstrated nickel skin reactivity, but none of the two patients presented allergic reaction to the devices used during interventions. CONCLUSIONS: Based on our observations and review of the literature, we hypothesize that delayed non-ischemic cerebral enhancing lesions after EVT are more likely related to foreign body emboli rather than nickel allergy. The two presented cases demonstrate the potential for recurrence and prolonged fluctuation of NICE lesions, warranting long-term follow-up for all patients presenting this complication. PMID- 27216206 TI - Low-dose spinal-epidural anesthesia for Cesarean section in a parturient with uncontrolled hyperthyroidism and thyrotoxic heart disease. AB - A 29-year-old woman at 34 weeks' gestation with uncontrolled hyperthyroidism and thyrotoxic heart disease was admitted to urgency Cesarean section. After preoperative sedation and good communication, low-dose spinal anesthesia (7.5 mg 0.5 % bupivacaine) combined with epidural anesthesia (6 ml 2 % lidocaine) was performed through L3-4 inter-vertebral. Opioids were given intravenously to the mother for sedation after delivery of the baby. Satisfactory anesthesia and sedation was provided during surgery. The mother and the neonate were safe and no special complication was found after surgery. Our case demonstrated that low-dose spinal anesthesia combined with epidural anesthesia with intravenous opioids can provide satisfactory anesthesia and sedation, and reduce the risk of heart failure and thyroid storm. PMID- 27216208 TI - Erratum to: Arthroscopic lateral acromion resection (ALAR) optimizes rotator cuff tear relevant scapula parameters. PMID- 27216207 TI - [Prehypertension in young patients]. PMID- 27216209 TI - RAC-tagging: Recombineering And Cas9-assisted targeting for protein tagging and conditional analyses. AB - A fluent method for gene targeting to establish protein tagged and ligand inducible conditional loss-of-function alleles is described. We couple new recombineering applications for one-step cloning of gRNA oligonucleotides and rapid generation of short-arm (~1 kb) targeting constructs with the power of Cas9 assisted targeting to establish protein tagged alleles in embryonic stem cells at high efficiency. RAC (Recombineering And Cas9)-tagging with Venus, BirM, APEX2 and the auxin degron is facilitated by a recombineering-ready plasmid series that permits the reuse of gene-specific reagents to insert different tags. Here we focus on protein tagging with the auxin degron because it is a ligand-regulated loss-of-function strategy that is rapid and reversible. Furthermore it includes the additional challenge of biallelic targeting. Despite high frequencies of monoallelic RAC-targeting, we found that simultaneous biallelic targeting benefits from long-arm (>4 kb) targeting constructs. Consequently an updated recombineering pipeline for fluent generation of long arm targeting constructs is also presented. PMID- 27216210 TI - The evolution of the molecular response to stress and its relevance to trauma and stressor-related disorders. AB - The experience of "stress", in its broadest meaning, is an inevitable part of life. All living creatures have evolved multiple mechanisms to deal with such threats and challenges and to avoid damage to the organism that may be incurred from these stress responses. Trauma and stressor-related disorders are psychiatric conditions that are caused specifically by the experience of stress, though depression, anxiety and some other disorders may also be unleashed by stress. Stress, however, is not a mandatory criterion of these diagnoses. This article focuses on the evolution of the neurochemicals involved in the response to stress and the systems in which they function. This includes the skin and gut, and the immune system. Evidence suggests that responses to stress are evolutionarily highly conserved, have wider involvement than the hypothalamic pituitary adrenal stress axis alone, and that excessive stress responses can produce stressor-related disorders in both humans and animals. PMID- 27216211 TI - Behavioral tagging: A novel model for studying long-term memory. AB - New information acquired by our brain is stored in the form of two types of memories: short term memory (STM) and long term memory (LTM). Initially, Synaptic and Capture hypothesis has been proposed to describe the synaptic changes that occur during memory formation. However, recently Behavioral Tagging hypothesis was proposed that relies on the setting of a learning tag and the synthesis of plasticity related proteins (PRPs). Behavioral Tagging has its roots in Synaptic and Capture hypothesis. It seeks to explain that how a learning tag produced as a result of weak training can be paired up with PRPs (formed as a result of novelty) and can lead to long lasting memories. We have focused on describing behavioral paradigms that have been used for establishing the model of "Behavioral Tagging" and the molecules which qualify for potential PRP candidature. PMID- 27216212 TI - Toward a systems-oriented approach to the role of the extended amygdala in adaptive responding. AB - Research into the structure and function of the basal forebrain macrostructure called the extended amygdala (EA) has recently seen considerable growth. This paper reviews that work, with the objectives of identifying underlying themes and developing a common goal towards which investigators of EA function might work. The paper begins with a brief review of the structure and the ontological and phylogenetic origins of the EA. It continues with a review of research into the role of the EA in both aversive and appetitive states, noting that these two seemingly disparate avenues of research converge on the concept of reinforcement either negative or positive - of adaptive responding. These reviews lead to a proposal as to where the EA may fit in the organization of the basal forebrain, and an invitation to investigators to place their findings in a unifying conceptual framework of the EA as a collection of neural ensembles that mediate adaptive responding. PMID- 27216214 TI - Prevalence and risk factors of chronic obstructive pulmonary diseases in a Hlai community in Hainan Island of China. AB - OBJECTIVES: We investigated prevalence and risk factors of chronic obstructive pulmonary disease (COPD) in a population of Hlai (the Li) ethnicity, a major minority, in Qicha Town, Changjiang County, Hainan Province, PRC, during 2014. METHODS: All residents at the age of 40 years or older were interviewed with standardized questionnaires. Spirometry was performed to measure the possible airflow limitation. According to the GOLD criteria, post bronchodilator FEV1/FVC < 70% was defined as COPD. Case-control study was used to screen the risk factors by analyzing COPD group (212 cases) and non-COPD control group (236 cases). Single factor analysis and multiple factor logistic regression analysis were used as statistical methods. RESULTS: The prevalence of COPD in the residents at the age of 40 years or older of Hlai community was 5.07% (286/5637) (95% CI = 0.045 0.057). In the logistic regression analysis, the COPD prevalence was 5.07% (147/2901) in men and 5.08% (139/2736) in women, respectively, with odds ratio (OR) 1.003, 95% CI 0.790-1.272 and P > 0.05, suggesting that the sex did not affect the COPD prevalence in the investigated samples, but age (OR = 1.096), expectoration (OR = 87.917), locomotor activity limitation (OR = 3.908) and frequency of respiration (OR = 2.512) were risk factors and associated with the development of COPD. Notably, although the tobacco smoker in male and female COPD patients were 48.6% (54/111) and 4.0% (4/101), respectively, passive smokers in female with COPD were 45.6% (46/101). CONCLUSION: In the Hlai population aged >=40 years, the COPD prevalence was 5.07%. Smoking, age, expectoration, locomotor activity limitation and frequency of respiration were risk factors of COPD in Hlai ethnicity. PMID- 27216213 TI - Generalized CNS arousal: An elementary force within the vertebrate nervous system. AB - Why do animals and humans do anything at all? Arousal is the most powerful and essential function of the brain, a continuous function that accounts for the ability of animals and humans to respond to stimuli in the environment by producing muscular responses. Following decades of psychological, neurophysiological and molecular investigations, generalized CNS arousal can now be analyzed using approaches usually applied to physical systems. The concept of "criticality" is a state that illustrates an advantage for arousal systems poised near a phase transition. This property provides speed and sensitivity and facilitates the transition of the system into different brain states, especially as the brain crosses a phase transition from less aroused to more aroused states. In summary, concepts derived from applied mathematics of physical systems will now find their application in this area of neuroscience, the neurobiology of CNS arousal. PMID- 27216215 TI - FVIII-binding IgG modulates FVIII half-life in patients with severe and moderate hemophilia A without inhibitors. AB - The substantial variability in pharmacokinetic parameters in hemophilia patients A poses a challenge for optimal treatment with factor VIII (FVIII) products. We investigated the effect of FVIII-specific immunoglobulin G (IgG) on FVIII half life in a cohort of 42 adult patients with severe and moderate hemophilia A without inhibitors. Fifteen (35.7%) of 42 patients tested positive for FVIII binding IgG with titers >=1:20 in the initial antibody screen, 9 of these 15 patients had FVIII-specific antibodies with titers >=1:40, mostly low-to-moderate affinity IgG1 and IgG3, and 1 had high-affinity IgG4 and later developed low titer FVIII inhibitors. His brother with low-to-moderate-affinity IgG1 and IgG3 also later developed low-titer FVIII inhibitors. The presence of FVIII-specific IgG subclass titer >=1:40 antibodies was significantly associated with shorter FVIII half-life (median, 7.8 hours [interquartile range, 6.6-9.2 hours]) vs 10.4 hours [interquartile range, 8.9-13.8 hours]); the regression coefficient adjusted for log age and log von Willebrand factor (VWF) antigen was -0.32 (P = .004), accounting for 16.9% of the observed variability of FVIII half-life in our cohort. Our data indicate a significant contribution of non-neutralizing FVIII specific IgG to FVIII half-life reduction in hemophilia A patients. Thus, screening for FVIII-specific IgG could be beneficial in tailoring FVIII prophylactic regimens. PMID- 27216216 TI - Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. AB - The efficacy and favorable safety profile of daratumumab monotherapy in multiple myeloma (MM) was previously reported. Here, we present an updated pooled analysis of 148 patients treated with daratumumab 16 mg/kg. Data were combined from part 2 of a first-in-human phase 1/2 study of patients who relapsed after or were refractory to >=2 prior therapies and a phase 2 study of patients previously treated with >=3 prior lines of therapy (including a proteasome inhibitor [PI] and an immunomodulatory drug [IMiD]) or were double refractory. Among the pooled population, patients received a median of 5 prior lines of therapy (range, 2 to 14 prior lines of therapy), and 86.5% were double refractory to a PI and an IMiD. Overall response rate was 31.1%, including 13 very good partial responses, 4 complete responses, and 3 stringent complete responses. The median duration of response was 7.6 months (95% confidence interval [CI], 5.6 to not evaluable [NE]). The median progression-free survival (PFS) and overall survival (OS) were 4.0 months (95% CI, 2.8-5.6 months) and 20.1 months (95% CI, 16.6 months to NE), respectively. When stratified by responders vs stable disease/minimal response vs progressive disease/NE, median PFS was 15.0 months (95% CI, 7.4 months to NE) vs 3.0 months (95% CI, 2.8-3.7 months) vs 0.9 months (95% CI, 0.9-1.0 months), respectively, and median OS was NE (95% CI, NE to NE) vs 18.5 months (95% CI, 15.1-22.4 months) vs 3.7 months (95% CI, 1.7-7.6 months), respectively. No new safety signals were identified. In this pooled data set, daratumumab 16 mg/kg monotherapy demonstrated rapid, deep, and durable responses, with a clinical benefit that extended to patients with stable disease or better. PMID- 27216218 TI - LNK mutations in familial myeloproliferative neoplasms. PMID- 27216217 TI - Treosulfan-based conditioning for allogeneic HSCT in children with chronic granulomatous disease: a multicenter experience. AB - Chronic granulomatous disease (CGD) can be cured by allogeneic hemopoietic stem cell transplantation (HSCT). Complications include graft failure, graft-versus host disease (GVHD), infection, and transplant-related mortality; therefore, reduced-intensity conditioning regimens are being used to improve outcomes. In this retrospective study, the aim was to determine the outcome of treosulfan based conditioning in HSCT for pediatric patients with CGD. The following data were collected: risk features pre-HSCT, additional conditioning agents, donor type and stem cell source, toxicity, engraftment, GVHD, chimerism, viral reactivation, post-HSCT complications, length of follow-up, and outcome. Seventy patients (median age, 107 months; interquartile range [IQR], 46-232 months) from 16 centers worldwide were transplanted between 2006 and 2015. Ninety-one percent had high-risk features. Fifty-seven HLA-matched donors, 12 HLA-mismatched donors, and 1 CD3(+)TCR alphabeta/CD19 depleted parental haploidentical transplants were performed. No major toxicity was reported. Median times to neutrophil and platelet engraftment were 17 (IQR, 15-35) and 16 (IQR, 13-50) days. At a median follow-up of 34 months (IQR, 13-102 months), the overall survival was 91.4%, and event-free survival was 81.4%. The cumulative incidence of acute grade III-IV GVHD was 12%. Nine patients developed chronic GVHD. When split cell chimerism was available, 95% or more myeloid donor chimerism was documented in 80% of surviving patients. Secondary graft failure occurred in 12% of patients. Treosulfan containing conditioning regimens can be used safely in HSCT for children with CGD and high-risk clinical features, achieving excellent survival with high myeloid chimerism. Further studies are needed to compare with other regimens and evaluate the long-term outcome, particularly on fertility. PMID- 27216219 TI - Cytomegalovirus replication reduces the relapse incidence in patients with acute myeloid leukemia. PMID- 27216220 TI - A comparative study of time-specific oxidative stress after acute myocardial infarction in patients with and without diabetes mellitus. AB - BACKGROUND: Oxidative stress is involved in the initiation and progression of atherosclerosis, and hyperglycemia is known to increase oxidative stress, which injures the endothelium and accelerates atherosclerosis. To clarify the relation between oxidative stress, diabetes mellitus (DM), and acute myocardial infarction (AMI), we evaluated and compared time-specific oxidative stress after AMI in patients with and without DM by simple measurement of derivatives of reactive oxygen metabolites (d-ROMs) levels as indices of reactive oxygen species production. METHODS: Sixty-eight AMI patients were enrolled (34 non-DM patients and 34 DM patients). Using the FRAS4 free radical analytical system, we measured d-ROMs levels in each patient at two time points: 1 and 2 weeks after AMI onset. RESULTS: d-ROM levels decreased significantly between week 1 and week 2 (from 475.4 +/- 119.4 U.CARR to 367.7 +/- 87.9 U.CARR, p < 0.001) in the non-DM patients but did not change in the DM patients (from 463.1 +/- 109.3 U.CARR to 461.7 +/- 126.8 U.CARR, p = 0.819). Moreover, significant correlation was found in the total patient group between d-ROMs levels at 1 week and N-terminal prohormone of brain natriuretic peptide (r = 0.376, p = 0.041) and between d-ROM levels at 2 weeks and 2-hour oral glucose tolerance test glucose levels (r = 0.434, p < 0.001). CONCLUSIONS: Exposure to oxidative stress is greater in AMI patients with DM than AMI patients without DM. Our study results suggest that it is the continuous hyperglycemia that increases oxidative stress in these patients, causing endothelial dysfunction and accelerating atherosclerosis. However, long-term follow up study is needed to assess whether the increased oxidative stress affects patient outcomes. PMID- 27216221 TI - [Anti-tumor necrosis factor drug therapy: The usefulness of monitoring drug levels and anti-drug antibodies in clinical practice]. PMID- 27216222 TI - Broadening the Conceptualization of Participation of Persons With Physical Disabilities: A Configurative Review and Recommendations. AB - Within the context of physical disability, participation has typically been conceptualized in terms of one's performance of different roles and activities. This perspective, however, ignores the meanings and satisfactions that a person derives from participating. Without an accepted conceptualization of participation that accounts for people's subjective perceptions and experiences, it is challenging for decision-makers and service providers to design meaningful participation-enhancing services, programs, and policies. Accordingly, our objectives were (1) to conduct a review of definitions and conceptualizations of participation that extend beyond performance and capture people's subjective experiences of participating and (2) to identify key experiential aspects of participation that can be used as a basis for conceptualizing and operationalizing the concept more broadly. The project involved a systematic, configurative review of relevant literature. Ten relevant articles were identified. Information on characteristics associated with experiential aspects of participation was extracted and subjected to a thematic analysis. The following 6 themes emerged: autonomy, belongingness, challenge, engagement, mastery, and meaning. Drawing on these findings, it is recommended that the individual's subjective perceptions of autonomy, belongingness, challenge, engagement, mastery, and meaning associated with participating be incorporated into conceptualizations and operationalizations of the participation construct. This recommendation provides a starting point for clinicians, researchers, and policymakers to conceptualize and measure the participation concept more consistently and more broadly. PMID- 27216223 TI - Independent, Community-Based Aerobic Exercise Training for People With Moderate to-Severe Traumatic Brain Injury. AB - OBJECTIVE: To determine whether people with moderate-to-severe traumatic brain injury (TBI) can adhere to a minimally supervised, community-based, vigorous aerobic exercise program. DESIGN: Prospective trial. SETTING: Young Men's Christian Association (YMCA) facilities. PARTICIPANTS: Community-dwelling volunteers (N=10; 8 men, 2 women; age range, 22-49y) 6 to 15 months after moderate-to-severe TBI. INTERVENTION: Participants received memberships to local YMCAs and brief orientations to exercise. They were then asked to independently complete >=12 weeks of >=3 training sessions per week, performed at 65% to 85% of maximum heart rate for >=30 minutes per session. Participants could self-select exercise modality, provided they met intensity and duration targets. Programmable heart rate monitors captured session intensity and duration. MAIN OUTCOME MEASURES: Independence with equipment and facility use and compliance with training goals (session frequency, duration, intensity, total weeks of training). RESULTS: All participants achieved independence with equipment and facility use. All met at least 2 of 4 training goals; half met all 4 goals. Participants averaged (+/-SD) 3.3+/-0.7 sessions per week for 13 weeks (range, 6-24). Average +/- SD session duration was 62+/-23 minutes, of which 51+/-22 minutes occurred at or above individuals' heart rate training targets. CONCLUSIONS: People in recovery from moderate-to-severe TBI can, with minimal guidance, perform vigorous, community-based exercise. This suggests that decentralized exercise may be logistically and economically sustainable after TBI, expanding its potential therapeutic utility and rendering longer-duration exercise studies more feasible. PMID- 27216224 TI - Effects of Respiratory Muscle Training on Respiratory Function, Respiratory Muscle Strength, and Exercise Tolerance in Patients Poststroke: A Systematic Review With Meta-Analysis. AB - OBJECTIVE: To examine the effects of respiratory muscle training on respiratory function, respiratory muscle strength, and exercise tolerance in patients poststroke. DATA SOURCES: We searched MEDLINE, Cochrane Library, Embase, SciELO, Physiotherapy Evidence Database (PEDro), and CINAHL (from the earliest date available to November 2015) for trials. STUDY SELECTION: Randomized controlled trials (RCTs) that examined the effects of respiratory muscle training versus nonrespiratory muscle training in patients poststroke. Two reviewers selected studies independently. DATA EXTRACTION: Extracted data from the published RCTs. Study quality was evaluated using the PEDro Scale. Weighted mean differences (WMDs), standard mean differences (SMDs), and 95% confidence intervals (CIs) were calculated. DATA SYNTHESIS: Eight studies met the study criteria. Respiratory muscle training improved maximal inspiratory pressure WMDs (7.5; 95% CI, 2.7 12.4), forced vital capacity SMDs (2.0; 95% CI, 0.6-3.4), forced expiratory volume at 1 second SMDs (1.2; 95% CI, 0.6-1.9), and exercise tolerance SMDs (0.7; 95% CI, 0.2-1.2). No serious adverse events were reported. CONCLUSIONS: Respiratory muscle training should be considered an effective method of improving respiratory function, inspiratory muscle strength, and exercise tolerance in patients poststroke. Further research is needed to determine optimum dosages and duration of effect. PMID- 27216225 TI - Rehabilitation in Multiple Sclerosis: A Systematic Review of Systematic Reviews. AB - OBJECTIVES: To systematically evaluate existing evidence from published systematic reviews of clinical trials for the effectiveness of rehabilitation for improving function and participation in persons with multiple sclerosis (MS). DATA SOURCES: A literature search was conducted using medical and health science electronic databases (MEDLINE, EMBASE, CINAHL, PubMed, Cochrane Library) up to January 31, 2016. STUDY SELECTION: Two reviewers independently applied inclusion criteria to select potential systematic reviews assessing the effectiveness of organized rehabilitation for persons with MS. Data were summarized for type of interventions, type of study designs included, outcome domains, method of data synthesis, and findings. DATA EXTRACTION: Data were extracted by 2 reviewers independently for methodological quality using the Assessment of Multiple Systematic Reviews. Quality of evidence was critically appraised with the Grades of Recommendation, Assessment, Development, and Evaluation. DATA SYNTHESIS: Thirty-nine systematic reviews (one with 2 reports) evaluated best evidence to date. There is "strong" evidence for physical therapy for improved activity and participation, and for exercise-based educational programs for the reduction of patient-reported fatigue. There is "moderate" evidence for multidisciplinary rehabilitation for longer-term gains at the levels of activity (disability) and participation, for cognitive-behavior therapy for the treatment of depression, and for information-provision interventions for improved patient knowledge. There is "limited" evidence for better patient outcomes using psychological and symptom management programs (fatigue, spasticity). For other rehabilitation interventions, the evidence is inconclusive because of limited methodologically robust studies. CONCLUSIONS: Despite the range of rehabilitative treatments available for MS, there is a lack of high-quality evidence for many modalities. Further research is needed for effective rehabilitation approaches with appropriate study design, outcome measurement, type and intensity of modalities, and cost-effectiveness of these interventions. PMID- 27216226 TI - Takayasu arteritis presenting with malignant hypertension; a rare manifestation of a rare disease: a case report and review of the literature. AB - Takayasu arteritis (TA) is a chronic inflammatory and obliterative disease of large vessels, which mainly affects the aorta and its major branches. TA can lead to renal failure and renovascular hypertension in 60% of patients; it is rare in children aged <10 years and, more rarely, it presents with malignant hypertension in the paediatric age group. Here we present a case of 9-year-old boy with TA who presented with malignant hypertension and required surgical intervention to control the blood pressure. Subsequently, his medications were titrated using 24 h ambulatory blood pressure monitoring (ABPM) and is doing well on follow-up. PMID- 27216228 TI - Editorial Commentary: Atherogenesis. PMID- 27216229 TI - Photodissociation UV-Vis Spectra of Cold Protonated Azobenzene and 4 (Dimethylamino)azobenzene and Their Benzenediazonium Cation Fragment. AB - Gas phase photodissociation electronic spectra of protonated azobenzene (ABH(+)) and 4-(dimethylamino)azobenzene (dmaABH(+)) were measured in a cryogenically cooled ion trap at temperatures of a few tens of Kelvin. Experimental results were complemented with electronic structure calculations in the ground state at the MP2/cc-pVDZ level of theory, and in the low lying excited states using the RI CC2 method. Calculated energies revealed that only the trans isomers of the azonium molecular ions (protonation site on the azo group) will likely exist in the trap at the temperatures achieved in the experiment. The first transition of trans-ABH(+) is pi* <- pi, and the absorption band in the spectrum appears strongly red-shifted from that of the neutral molecule. The calculations showed that upon excitation the quasi-planar ground state (S0) transforms into a chairlike excited state (S1) by twisting the CNNC dihedral angle about 96 degrees . A 41 cm(-1) active vibrational progression found in the ABH(+) spectrum may be associated with the twisting of the azo bond. Conversely, the electronic spectrum of dmaABH(+) exhibits a steep and unstructured S1 <- S0 absorption corresponding to a less distorted S1 state. The next two quasi-degenerate bands in the ABH(+) spectrum evidence sharper onsets and a charge transfer character. Using a second fragmentation laser and an additional He cooling pulse in the trap, it was possible to measure the UV spectrum of cold benzenediazonium fragments. PMID- 27216227 TI - A voltage-dependent chloride channel fine-tunes photosynthesis in plants. AB - In natural habitats, plants frequently experience rapid changes in the intensity of sunlight. To cope with these changes and maximize growth, plants adjust photosynthetic light utilization in electron transport and photoprotective mechanisms. This involves a proton motive force (PMF) across the thylakoid membrane, postulated to be affected by unknown anion (Cl(-)) channels. Here we report that a bestrophin-like protein from Arabidopsis thaliana functions as a voltage-dependent Cl(-) channel in electrophysiological experiments. AtVCCN1 localizes to the thylakoid membrane, and fine-tunes PMF by anion influx into the lumen during illumination, adjusting electron transport and the photoprotective mechanisms. The activity of AtVCCN1 accelerates the activation of photoprotective mechanisms on sudden shifts to high light. Our results reveal that AtVCCN1, a member of a conserved anion channel family, acts as an early component in the rapid adjustment of photosynthesis in variable light environments. PMID- 27216230 TI - More than just dancing: experiences of people with Parkinson's disease in a therapeutic dance program. AB - PURPOSE: To understand why individuals with Parkinson's disease (PD) participate in a community-based therapeutic dance program and to explore its influence on perceived physical, social and emotional well-being of participants. METHODS: A qualitative descriptive design was employed using one-on-one semi-structured interviews. Individuals with PD who participated in the Dancing with Parkinson's program were recruited from two locations. Interviews were audio-recorded, transcribed, de-identified and then placed into NVivo 10 software for analysis. A content analysis approach was used with an inductive analysis method to generate a coding scheme. Group discussion facilitated development of overarching themes. RESULTS: Ten participants' responses revealed that the dance program allows for self-improvement and regaining identity through disease self-management. Positive influences of socialization arose through the class, decreasing isolation and improving quality of life. Participants communicate through music and dance to enhance connection with others. CONCLUSIONS: Dancing with Parkinson's classes allow for re-development of the social self, which can increase sense of enjoyment in life. Dance programs provide opportunities for social interaction, non-verbal communication and self-improvement, reestablishing self-identity and a sense of usefulness. This study provides unique insight into the experience of participating in a dance program from the perspective of individuals with PD. Implications for rehabilitation Dance is emerging as a strategy to address the physical and psychosocial effects of Parkinson's disease (PD), but little is known regarding participants' perceptions of community-based therapeutic dance programs for PD. This study found that Dancing with Parkinson's (DWP) facilitated an improvement in social participation, resulting in decreased isolation and improved quality of life. Participation in the DWP program can facilitate a positive change in perspective and attitude toward a PD diagnosis, thereby increasing feelings of self-efficacy and improving self-management of the disease. Participants of this study emphasized the multifaceted benefits of DWP, suggesting that it has great potential for addressing not only the physical challenges, but also the cognitive and emotional challenges associated with PD. PMID- 27216231 TI - Variability in prevalence of Cymatocarpus solearis (Trematoda, Brachycoeliidae) in Caribbean spiny lobsters Panulirus argus (Decapoda: Palinuridae) from Bahia de la Ascension (Mexico). AB - Cymatocarpus solearis, a brachycoeliid trematode that parasitizes sea turtles, uses spiny lobsters Panulirus argus as second intermediate hosts. We examined variability in infection by C. solearis in Bahia de la Ascension, Mexico, a tropical bay with a highly productive fishery for P. argus that is based on the extensive use of casitas (large artificial shelters), which can harbor multiple juveniles and adults of this gregarious lobster species. We sampled 3956 lobsters from 466 casitas distributed over three bay zones within two closed seasons and one fishing season. In these lobsters (9.5-115.2mm carapace length, CL), the average infection prevalence was 11.7% but the probability of infection increased significantly with size. Prevalence varied with season but was consistently higher in one zone than in the other two zones. Infection with C. solearis was negatively related with clinical infection with Panulirus argus Virus 1 (PaV1). We also sampled 405 lobsters from the commercial catch obtained throughout the bay at the onset of the fishing season. In these relatively larger lobsters (70.3 168.0mm CL), average prevalence of C. solearis was higher (23.5%) but was not affected by lobster size or sex. Encysted metacercariae occurred in both abdominal and cephalothoracic muscles. The effects of C. solearis on phenotypic traits of P. argus that may potentially impact the host population dynamics and fisheries remain to be investigated. PMID- 27216232 TI - Anesthesia and anesthetic action mechanism of essential oils of Aloysia triphylla and Cymbopogon flexuosus in silver catfish (Rhamdia quelen). AB - OBJECTIVES: To document the time for anesthesia induction and recovery using different concentrations of essential oils (EOs) of Cymbopogon flexuosus and Aloysia triphylla in silver catfish (Rhamdia quelen), and to determine whether the mechanism of action of either EO involves the benzodiazepine (BDZ) site of the GABAA receptor. STUDY DESIGN: Experimental study. ANIMALS: A total of 144 silver catfish, length 7.5 +/- 1.1 cm, weighing 3.95 +/- 0.85 g. METHODS: Essential oils were evaluated at concentrations of 25, 150 and 300 MUL L-1, and also ethanol alone (seven groups, n = 6 per group). Induction of sedation or anesthesia and recovery were assessed. In a further six groups (n = 6 per group), fish were exposed to both EOs (25, 150 or 300 MUL L-1) with diazepam 150 MUm, and also diazepam (10 MUm) alone. Flumazenil (5 or 10 MUm) was added to the recovery water of fish exposed to diazepam (150 MUm) or both EOs (150 and 300 MUL L-1) (total of 10 groups = 60 fish). RESULTS: Both EOs induced anesthesia at concentrations of 150 and 300 MUL L-1, and sedation at 25 MUL L-1. There was no significant difference between EOs for reaching deep anesthesia; there was a significantly longer recovery time for the EO of C. flexuosus. The addition of diazepam (150 MUm) resulted in faster induction of anesthesia with both EOs, with no significant change in recovery times. Flumazenil (10 MUm) reversed the diazepam-induced anesthesia, but not the anesthesia induced by EOs. CONCLUSIONS AND CLINICAL RELEVANCE: The EO of C. flexuosus induced effective sedation (25 MUL L-1) and anesthesia (150 and 300 MUL L-1) without short-term mortality. The modulation of the BDZ site of the GABAA receptor in the anesthetic action mechanism of both EOs was not demonstrated. PMID- 27216234 TI - How LGBT College Students Perceive and Engage the Campus Religious and Spiritual Climate. AB - The purpose of this study was to compare how students of diverse sexual orientations and gender identities perceive the campus religious and spiritual climate and engage in interfaith and spiritual activities during college. Using data from a national study of 13,776 students at 52 institutions that took part in the Campus Religious and Spiritual Climate Survey, results indicate significant variations in perceptions and engagement by sexual orientation and gender identity. In addition, worldview identity shapes the relationships between sexual orientation and gender identity and perceptions of and engagement on campus. PMID- 27216233 TI - Risk factors and preventive strategies for post-operative pancreatic fistula after pancreatic surgery: a comprehensive review. AB - BACKGROUND: Pancreas surgery has developed into a fairly safe procedure in terms of mortality, but is still hampered by considerable morbidity. Among the most frequent and dreaded complications are the development of a post-operative pancreatic fistula (POPF). The prediction and prevention of POPF remains an area of debate with several questions yet to be firmly addressed with solid answers. METHODS: A systematic review of systematic reviews/meta-analyses and randomized trials in the English literature (PubMed/MEDLINE, Cochrane library, EMBASE) covering January 2005 to December 2015 on risk factors and preventive strategies for POPF. RESULTS: A total of 49 systematic reviews and meta-analyses over the past decade discussed patient, surgeon, pancreatic disease and intraoperative related factors of POPF. Non-modifiable factors (age, BMI, comorbidity) and pathology (histotype, gland texture, duct size) that indicates surgery are associated with POPF risk. Consideration of anastomotic technique and use of somatostatin-analogs may slightly modify the risk of fistula. Sealant products appear to have no effect. Perioperative bleeding and transfusion enhance risk, but is modifiable by focus on technique and training. Drains may not prevent fistulae, but may help in early detection. Early drain-amylase may aid in detection. Predictive scores lack uniform validation, but may have a role in patient information if reliable pre-operative risk factors can be obtained. CONCLUSIONS: Development of POPF occurs through several demonstrated risk factors. Anastomotic technique and use of somatostatin-analogs may slightly decrease risk. Drains may aid in early detection of leaks, but do not prevent POPF. PMID- 27216235 TI - Exploring Anti-inflammatory Potential of Thiazolidinone Derivatives of Benzenesulfonamide via Synthesis, Molecular Docking and Biological Evaluation. AB - BACKGROUND: The present study reports the synthesis and biological evaluation of thiazolidinone derivatives bearing benzenesulfonamide investigated for cyclooxygenase-2 (COX-2) inhibitory activity and in vivo anti-inflammatory activity. METHODS: The synthesis of 4-(4-oxo-2-substituted-1,3-thiazolidin-3-yl) benzenesulfonamide derivatives were carried out by conventional synthesis, involves the one-pot condensation reaction of sulfanilamide. The synthesized compounds were evaluated against COX-1 and human recombinant COX-2 by using colorimetric enzyme assay kit and in-vivo study was carried out by carageenan induced rat paw edema method. RESULTS: Five derivatives 3a, 3b, 3f, 3g, and 3j showed pronounced COX-2 percentage inhibition (55.76, 61.75, 46.54, 43.32, and 49.77% respectively). Structure activity relationship suggested that the compound with a 4-hydroxy group on phenyl ring leads to more selective inhibition of COX-2 than celecoxib, which is supported by molecular docking study. In silico ADME properties showed that compound 3a, 3b, 3f, 3g, and 3j complies Lipinski's rule of five and show no violation. Molecular docking study divulged the binding interactions of thiazolidinone derivatives into the active site of COX-2 and thereby helps to design the potent inhibitors. CONCLUSION: The overall studies inferred that compound 3b rendered it as a good leadcandidate for the further development of more potent anti-inflammatory agent. PMID- 27216236 TI - Air quality co-benefits of subnational carbon policies. AB - To mitigate climate change, governments ranging from city to multi-national have adopted greenhouse gas (GHG) emissions reduction targets. While the location of GHG reductions does not affect their climate benefits, it can impact human health benefits associated with co-emitted pollutants. Here, an advanced modeling framework is used to explore how subnational level GHG targets influence air pollutant co-benefits from ground level ozone and fine particulate matter. Two carbon policy scenarios are analyzed, each reducing the same total amount of GHG emissions in the Northeast US: an economy-wide Cap and Trade (CAT) program reducing emissions from all sectors of the economy, and a Clean Energy Standard (CES) reducing emissions from the electricity sector only. Results suggest that a regional CES policy will cost about 10 times more than a CAT policy. Despite having the same regional targets in the Northeast, carbon leakage to non-capped regions varies between policies. Consequently, a regional CAT policy will result in national carbon reductions that are over six times greater than the carbon reduced by the CES in 2030. Monetized regional human health benefits of the CAT and CES policies are 844% and 185% of the costs of each policy, respectively. Benefits for both policies are thus estimated to exceed their costs in the Northeast US. The estimated value of human health co-benefits associated with air pollution reductions for the CES scenario is two times that of the CAT scenario. IMPLICATIONS: In this research, an advanced modeling framework is used to determine the potential impacts of regional carbon policies on air pollution co benefits associated with ground level ozone and fine particulate matter. Study results show that spatially heterogeneous GHG policies have the potential to create areas of air pollution dis-benefit. It is also shown that monetized human health benefits within the area covered by policy may be larger than the model estimated cost of the policy. These findings are of particular interest both as U.S. states work to develop plans to meet state-level carbon emissions reduction targets set by the EPA through the Clean Power Plan, and in the absence of comprehensive national carbon policy. PMID- 27216237 TI - Microbiome of HIV-infected people. AB - Consistent interactions between the gut microbiome and adaptive immunity recently led several research groups to evaluate modifications of human gut microbiota composition during HIV infection. Herein we propose to review the shifts reported in infected individuals, as their correlation to disease progression. Though the gut microbiota is consistently altered in HIV individuals, the literature reveals several discrepancies, such as changes in microbial diversity associated with HIV status, taxa modified in infected subjects or influence of ART on gut flora restoration. Similarly, mechanisms involved in interactions between gut bacteria and immunity are to date poorly elucidated, emphasizing the importance of understanding how microbes can promote HIV replication. Further research is needed to propose adjuvant therapeutics dedicated to controlling disease progression through gut microbiome restoration. PMID- 27216238 TI - Evaluation of antimicrobial activity of glycerol monolaurate nanocapsules against American foulbrood disease agent and toxicity on bees. AB - The American Foulbrood Disease (AFB) is a fatal larval bee infection. The etiologic agent is the bacterium Paenibacillus larvae. The treatment involves incineration of all contaminated materials, leading to high losses. The Glycerol Monolaurate (GML) is a known antimicrobial potential compound, however its use is reduced due to its low solubility in water and high melting point. The nanoencapsulation of some drugs offers several advantages like improved stability and solubility in water. The present study aimed to evaluate the antimicrobial activity against P. larvae and the toxicity in bees of GML nanoparticles. The nanocapsules were produced and presented mean diameter of 210 nm, polydispersity index of 0.044, and zeta potential of -23.4 mV demonstrating the acceptable values to predict a stable system. The microdilution assay showed that it is necessary 142 and 285 MUg/mL of GML nanocapsules to obtain a bacteriostatic and bactericidal effect respectively. The time-kill curve showed the controlled release of compound, exterminating the microorganism after 24 h. The GML nanocapsules were able to kill the spore form of Paenibacillus larvae while the GML do not cause any effect. The assay in bees showed that the GML has a high toxicity while the GML nanoparticles showed a decrease on toxic effects. Concluding, the formulation shows positive results in the action to combat AFB besides not causing damage to bees. PMID- 27216239 TI - Serum bactericidal assay for the evaluation of typhoid vaccine using a semi automated colony-counting method. AB - Typhoid fever, mainly caused by Salmonella enterica serovar Typhi (S. Typhi), is a life-threatening disease, mostly in developing countries. Enzyme-linked immunosorbent assay (ELISA) is widely used to quantify antibodies against S. Typhi in serum but does not provide information about functional antibody titers. Although the serum bactericidal assay (SBA) using an agar plate is often used to measure functional antibody titers against various bacterial pathogens in clinical specimens, it has rarely been used for typhoid vaccines because it is time-consuming and labor-intensive. In the present study, we established an improved SBA against S. Typhi using a semi-automated colony-counting system with a square agar plate harboring 24 samples. The semi-automated SBA efficiently measured bactericidal titers of sera from individuals immunized with S. Typhi Vi polysaccharide vaccines. The assay specifically responded to S. Typhi Ty2 but not to other irrelevant enteric bacteria including Vibrio cholerae and Shigella flexneri. Baby rabbit complement was more appropriate source for the SBA against S. Typhi than complements from adult rabbit, guinea pig, and human. We also examined the correlation between SBA and ELISA for measuring antibody responses against S. Typhi using pre- and post-vaccination sera from 18 human volunteers. The SBA titer showed a good correlation with anti-Vi IgG quantity in the serum as determined by Spearman correlation coefficient of 0.737 (P < 0.001). Taken together, the semi-automated SBA might be efficient, accurate, sensitive, and specific enough to measure functional antibody titers against S. Typhi in sera from human subjects immunized with typhoid vaccines. PMID- 27216241 TI - Estimation and Correction of the Blood Volume Variations of Dried Blood Spots Using a Postcolumn Infused-Internal Standard Strategy with LC-Electrospray Ionization-MS. AB - Dried blood spots (DBSs) have had a long history in disease screening in newborns but have gained attention in recent years in the medical care of adults because of the growing importance of personalized medicine. DBSs have several advantages, such as easy transportation, cost-effectiveness, and minimally invasive biological sampling. There are two strategies to process DBS samples. One method takes a fixed diameter of subsample, and another requires the extraction of the whole spot. The whole-spot extraction method is less affected by hematocrit caused errors, but it requires calibration of the blood volume. We propose a novel strategy using a postcolumn infused-internal standard (PCI-IS) method with liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS) for estimating and correcting blood volume variations on the DBS cards. By using PCI IS to measure the extent of ion suppression in the first ion suppression zone in the chromatogram, the blood volume on the DBS cards can be calculated and further calibrated. We used reference blood samples with different volumes (5 to 25 MUL) to construct a calibration curve between the blood volume and the extent of ion suppression. The calibration curve was used to estimate the blood volume on the DBS cards collected from 6 volunteers, with 5 designated volumes from each volunteer. The estimation accuracy of the PCI-IS method was between 74.5% and 120.3%. The validated PCI-IS method was used to estimate and calibrate blood volume variation and also to quantify the voriconazole concentration for 26 patients undergoing voriconazole therapy. A high correlation was found for the quantification results between the DBS samples and the conventionally used plasma samples (r = 0.97). The PCI-IS method was demonstrated to be a simple and accurate method for estimating and calibrating the blood volume variation on DBS cards, which greatly facilitates using the DBS method for therapeutic drug monitoring (TDM) for improving the efficacy and safety of drug therapy. PMID- 27216240 TI - Chinese herbal medicine Tangshen Formula treatment of patients with type 2 diabetic kidney disease with macroalbuminuria: study protocol for a randomized controlled trial. AB - BACKGROUND: Diabetic kidney disease (DKD) is one of the most common microvascular complications of diabetes mellitus and the main cause of end-stage renal disease. Present medications for DKD are not entirely satisfactory. Preliminary studies indicate that the Chinese herbal formula Tangshen Formula (TSF) appears to decrease the proteinuria and improve the estimated glomerular filtration rate (eGFR) in DKD patients. METHODS/DESIGN: This trial is a five-center, randomized, double-blind, placebo-controlled study. DKD patients with a 24-h urinary protein (24 h UP) level between 0.5 and 3.5 g and serum creatinine < 265 MUmol/L (3 mg/dl) will be included. A sample size of 144 participants will be randomly distributed into the treatment group (TSF plus irbesartan) and the control group (placebo plus irbesartan) at a ratio of 1:1. The study duration will be 50 weeks, comprising a 2-week run-in period, 24 weeks of intervention, and 24 weeks of follow-up. The primary endpoint will be the 24 h UP. Secondary endpoints will be an evaluation of renal function, management of blood lipids, improvement in traditional Chinese medicine symptoms, and safety assessments. Adverse events will also be evaluated. DISCUSSION: This study will provide evidence for the effectiveness and safety of TSF compared to placebo in treating DKD patients with macroalbuminuria. TRIAL REGISTRATION: Chinese Clinical Trials Registry, ChiCTR TRC-13003566 . Registered 9 August 2013. PMID- 27216242 TI - Adjunctive ivabradine in combination with amiodarone: A novel therapy for pediatric congenital junctional ectopic tachycardia. AB - BACKGROUND: Treatment of congenital junctional ectopic tachycardia (JET) is often challenging. In the majority of patients affected, a combination of >=2 antiarrhythmic drugs is required for JET control. OBJECTIVE: The purpose of this study was to assess the efficacy and safety of adjunctive ivabradine therapy for pediatric congenital JET. METHODS: Since January 2015, 5 consecutive patients aged 10 days to 3.5 years (median 8 weeks) were treated with adjunctive ivabradine for congenital JET. All patients had previously undergone antiarrhythmic therapy with unsatisfactory control of JET. Ivabradine was administered orally at an initial dosage of 0.05-0.1 mg/kg/d divided into 2 single doses and was increased up to 0.28 mg/kg/d if necessary. RESULTS: In all 5 patients, ivabradine proved to be successful in controlling JET. Complete suppression of JET and conversion into sinus rhythm were achieved in 4 of 5 patients. The remaining patient had effective heart rate control with persistent slow JET. Mean heart rate was reduced by 31% compared to pre-ivabradine (P = .03) as assessed by 24-hour Holter monitoring. Echocardiography revealed improvement of left ventricular function in all 3 patients with previously impaired left ventricular function. No significant side effects of ivabradine were encountered during median follow-up of 135 days (range 37-203 days). CONCLUSION: In our group of patients with congenital JET, adjunctive treatment with ivabradine resulted in effective and safe rhythm/heart rate control and therefore may be recommended early in the course of this rare inborn tachyarrhythmia. PMID- 27216243 TI - A 36-year-old woman with shortness of breath. PMID- 27216244 TI - Variations of the accessory nerve: anatomical study including previously undocumented findings-expanding our misunderstanding of this nerve. AB - INTRODUCTION: The anatomy of the accessory nerve has been well described but continued new clinical and anatomical findings exemplify our lack of a full understanding of the course of this nerve. Therefore, this study aimed to expand on our knowledge of the course of the 11th cranial nerve via anatomical dissections. METHODS: Fifty-six cadavers (112 sides) underwent dissection of the accessory nerve from its cranial and spinal origins to its emergence into the posterior cervical triangle. Immunohistochemistry was performed when appropriate. RESULTS: Our findings included two cases (1.8%) where the nerve was duplicated, one intracranially and one extracranially. One accessory nerve (0.9%) was found to enter its own dural compartment within the jugular foramen. The majority of sides (80%) were found to have a cranial root of the accessory nerve. Thirty-one sides (28%) had connections to cervical dorsal roots medially and three sides (2.7%) laterally. Medial connections were most common with the C1 nerve. Medial components of these dorsal root connections were all sensory in nature. However, lateral components were motor on two sides (1.8%). Nerves traveled anterior to the internal jugular vein on 88% of sides. One (0.9%) left side nerve joined an interneural anastomosis between the dorsal rootlets. Macroganglia were found on the spinal part of the intracranial nerve on 13% of sides. The lesser occipital nerve arose directly from the accessory nerve on two sides (1.8%) and communicated with the accessory nerve on 5.4% of sides. One side (0.9%) was found to communicate with the facial nerve with both nerves innervating the sternocleidomastoid muscle. CONCLUSIONS: Additional anatomical knowledge of the variants of the accessory nerve may benefit patient care when this nerve is pathologically involved. PMID- 27216245 TI - Ground beetle assemblages across a habitat gradient in a stream watershed during 16 years of observation. AB - Most studies on riverine ground beetle assemblages last 1-2 years, and studies on carabids from lowland stream ecosystems are rare. In 1999, a 16-year study was launched to gain insight into the structure and diversity of carabid assemblages in a cross-section of four habitats located beside a 5 m wide stream: Meadow (wet meadow), Clumps (meadow scattered with birch and willow clumps farther from the river), Birch (birch stand), and Pine (pine stand located the farthest from the stream). The total number of 14, 216 individuals representing 118 carabid species were collected. Eleven functional carabid groups have been analysed. Principal response curve analysis showed significant differences existing during the whole study period among carabid assemblages from the four habitats. Generalised Linear Mixed Models analysis revealed a dependence of Chao2 estimator performance on temperature and ground water level, whereas life traits of carabids depended solely on the latter factor, affecting species composition (i.e., proportions of autumn and spring breeders, large and small zoophages, hemizoophages, forest, generalists and open area species, wingless species, hygrophilous, mesophilous and xerophilous species). The lower the ground water level, the higher was the proportion of late-successional species. Both Chao2 value and the proportion of late-successional species were growing with the increasing distance from the stream, peaking in the Pine habitat. Early-successional fauna dominated in streamside assemblages. IndVal analysis identified 1-9 characteristic species for each habitat type, mostly non-recurrent during the study period. Thus, species composition of riverine carabid assemblages should be studied for longer periods than 1-2 years to avoid accidental observations. PMID- 27216247 TI - Health Services in Boarding School: An Oasis of Care, Counseling, and Comfort. AB - Adolescents who attend high school as preparatory boarding students are growing up and learning to care for themselves in a very different set of circumstances than those who live at home with their families. Although this choice may present myriad opportunities for personal growth and academic advantages, nurturance and support from caring adults is necessary to foster health and well-being. Our model of a collaborative relationship between nursing and counseling in providing health services to the adolescents in our care at St. Mark's School is designed to effectively meet this challenge. While it is true that a very small percentage of adolescents attend preparatory boarding schools in the United States, this article is an attempt to present our working model for consideration by other school nurses and counselors in our field of practice, especially since there is a lack of professionally relevant current literature for reference. PMID- 27216246 TI - Evidence supporting the conceptual framework of cancer chemoprevention in canines. AB - As with human beings, dogs suffer from the consequences of cancer. We investigated the potential of a formulation comprised of resveratrol, ellagic acid, genistein, curcumin and quercetin to modulate biomarkers indicative of disease prevention. Dog biscuits were evaluated for palatability and ability to deliver the chemopreventive agents. The extent of endogenous DNA damage in peripheral blood lymphocytes from dogs given the dietary supplement or placebo showed no change. However, H2O2-inducible DNA damage was significantly decreased after consumption of the supplement. The expression of 11 of 84 genes related to oxidative stress was altered. Hematological parameters remained in the reference range. The concept of chemoprevention for the explicit benefit of the canine is compelling since dogs are an important part of our culture. Our results establish a proof-of-principle and provide a framework for improving the health and well being of "man's best friend". PMID- 27216248 TI - Physical Conditions and Special Needs as Risk Factors of Peer Victimization Among School Children in Taiwan. AB - Students with physical symptoms and diseases may be at an increased risk of peer victimization. This study examined the associations of several medical conditions (obesity, asthma, allergy, epilepsy, and diabetes) with experience of physical, verbal, and relational victimization among children. A sample of 6,233 fourth grade students from 314 elementary schools in Taiwan was recruited for the analysis. The mean age of the sample was 10.5, with an even distribution of gender (50.3% male and 49.7% female). Children with asthma, allergy, and epilepsy reported higher frequencies of peer victimization. Those who took daily medications or received treatment were also at a higher risk of being victimized. Diabetes and obesity were not found to be associated with peer victimization. The findings highlighted that children with physical conditions suffer maltreatment from peers. Sensitivity training should be provided to school health professionals, so they can evaluate the risk of victimization among students with special needs during assessment. PMID- 27216249 TI - Regulatory mechanisms of immune tolerance in type 1 diabetes and their failures. AB - In this brief review we propose to discuss salient data showing the importance of immune regulatory mechanisms, and in particular of Treg, for the control of pathogenic anti-beta-cell response in autoimmune diabetes. Disease progression that culminates with the massive destruction of insulin-secreting beta-cells and advent of hyperglycemia and glycosuria tightly correlates with a functional deficit in immune regulation. Better dissection of the cellular and molecular mechanisms through which the immune system normally sustains tolerance to "self", and which become defective when autoimmune aggression is overt, is the only direct and robust way to learn how to harness these effectively, so as to restore immune tolerance in patients with insulin-dependent type 1 diabetes. No doubt that regulatory T cells are a privileged mechanism underlying this self-tolerance in the periphery. The discovery of the key role of the transcription factor FoxP3, represented the cornerstone leading to the great advances in the field we are witnessing today. Type 1 diabetes is certainly one of the prototypic T cell mediated autoimmune diseases where immune regulatory mechanisms relying on specialized subsets of T cells have been the most thoroughly analyzed from the fundamental point of view and also largely exploited in a translational therapeutic perspective. PMID- 27216250 TI - The study on facial soft tissue thickness using Han population in Xinjiang. AB - Facial profile is an important aspect in physical anthropology, forensic science, and cosmetic research. Thus, facial soft tissue measurement technology plays a significant role in facial restoration. A considerable amount of work has investigated facial soft tissue thickness, which significantly varies according to gender, age, and race. However, only few studies have considered the nutritional status of the investigated individuals. Moreover, no sufficient research among Chinese ethnic groups, particularly Xinjiang population in China, is currently available. Hence, the current study investigated the adaptability of facial soft tissue to the underlying hard tissue among young adults of Han population in Xinjiang, China; the analysis was performed on the basis of gender, skeletal class, and body mass index (BMI). Measurements were obtained from the lateral cephalometric radiographs of 256 adults aged 18-26 years old. Differences in soft tissue thickness were observed between genders and among skeletal classes. With regard to gender, significant differences in soft tissue thickness were found at rhinion, glabella, subnasale, stomion, labrale superius, pogonion, and gnathion among different BMI groups. Thus, nutritional status should be considered when reconstructing an individual's facial profile. Results showed that the thinnest and thickest craniofacial soft tissues existed in rhinion and lip regions, respectively. Overall, this research provides valuable data for forensic facial reconstruction and identification of young adults in Xinjiang, China. PMID- 27216251 TI - Female urinary incontinence and wellbeing: results from a multi-national survey. AB - BACKGROUND: Previous research has shown that the severity of symptoms of urinary incontinence impacts on quality of life and wellbeing. The aim of this article is to investigate the relationship between female urinary incontinence and mental wellbeing. This involved analyses comparing those with UI and those without to determine whether any differences in wellbeing were modified by demographic factors, specific wellbeing domain, or exercise and frequency of sex. Following this, further analyses compared sub-groups of those with UI (based on the impact of the UI) to determine which characteristics were important in influencing wellbeing. METHODS: An internet survey of women with UI, aged between 45 and 60 years, has been previously reported and this article reports secondary analyses of that data. A sample from 4 countries: the UK, France, Germany and the USA. Two thousand four hundred three women completed the survey, 1203 with UI and 1200 who did not report UI. The main outcome measures were the scores from the Warwick Edinburgh Mental Wellbeing Scale (WEMWBS). RESULTS: The results showed that lower wellbeing is observed in UI. This effect is observed in all aspects of wellbeing and most sub-groups of UI sufferers. Lifestyle influences wellbeing and those with UI who exercise less frequently or have sex infrequently are especially likely to report lower wellbeing. Wellbeing decreases as a function of the indirect measures of severity of UI and reductions in HRQol. Again, these changes reflect all aspects of wellbeing measured by WEMWBS. CONCLUSIONS: The results show that women with UI, aged 45-60 years, report lower wellbeing. This effect was not modified by demographic factors and was apparent in most of the domains measured by the WEMWBS. The reduced wellbeing was related to the impact of the UI on behaviour, embarrassment associated with it, and frequency of leakage. PMID- 27216252 TI - Spider web and silk performance landscapes across nutrient space. AB - Predators have been shown to alter their foraging as a regulatory response to recent feeding history, but it remains unknown whether trap building predators modulate their traps similarly as a regulatory strategy. Here we fed the orb web spider Nephila pilipes either live crickets, dead crickets with webs stimulated by flies, or dead crickets without web stimulation, over 21 days to enforce spiders to differentially extract nutrients from a single prey source. In addition to the nutrients extracted we measured web architectures, silk tensile properties, silk amino acid compositions, and web tension after each feeding round. We then plotted web and silk "performance landscapes" across nutrient space. The landscapes had multiple peaks and troughs for each web and silk performance parameter. The findings suggest that N. pilipes plastically adjusts the chemical and physical properties of their web and silk in accordance with its nutritional history. Our study expands the application of the geometric framework foraging model to include a type of predatory trap. Whether it can be applied to other predatory traps requires further testing. PMID- 27216253 TI - Real-World Analysis of Medical Costs and Healthcare Resource Utilization in Elderly Women with HR+/HER2- Metastatic Breast Cancer Receiving Everolimus-Based Therapy or Chemotherapy. AB - INTRODUCTION: The objective of this study was to analyze medical costs and healthcare resource utilization (HRU) associated with everolimus-based therapy or chemotherapy among elderly women with hormone-receptor-positive, human-epidermal growth-factor-receptor-2-negative (HR+/HER2-) metastatic breast cancer (mBC). METHODS: Elderly women (>=65 years) with HR+/HER2- mBC who failed a non-steroidal aromatase-inhibitor and subsequently began a new line of treatment with everolimus-based therapy or chemotherapy for mBC (index therapy) during July 20, 2012 to March 31, 2014 were identified from two large commercial claims databases. All-cause, BC-, and adverse event (AE)-related medical costs (2014 USD), and all-cause and AE-related HRU per patient per month (PPPM) were compared between patients treated with everolimus-based therapy and chemotherapy across their first four lines of therapy for mBC. Adjusted costs and HRU differences were estimated by pooling all lines and using multivariable models adjusted for differences in patient characteristics. RESULTS: In total, 925 elderly patients (mean age approximately 73 years) with HR+/HER2- mBC met the inclusion criteria; 230 received everolimus-based therapy (240 lines) and 737 received chemotherapy (939 lines). Compared with chemotherapy, everolimus-based therapy was associated with significantly lower total all-cause PPPM medical services costs (adjusted mean difference: $4007), driven by lower inpatient ($1994) and outpatient ($1402) costs; lower BC-related medical services costs ($3129), driven by both BC-related inpatient ($1883) and outpatient costs ($913); and lower AE-related medical services costs ($1873; all P < 0.01). Additionally, compared to patients treated with chemotherapy, patients treated with everolimus-based therapy had fewer all cause outpatient visits (adjusted incidence rate ratio = 0.69), BC-related outpatient visits (0.66), other-medical-service visits (0.65), and AE-related HRU (0.59), which was driven by significantly fewer AE-related outpatient visits (0.56; all P < 0.01). Subgroup analyses comparing medical costs of everolimus based therapy with capecitabine monotherapy showed consistent results overall. CONCLUSION: This retrospective claims database analysis of elderly women with HR+/HER2- mBC in the United States showed that everolimus-based therapy was associated with significantly lower all-cause, BC-related, and AE-related medical services costs and less use of healthcare resources compared with chemotherapy. FUNDING: Novartis. PMID- 27216254 TI - miRiaD: A Text Mining Tool for Detecting Associations of microRNAs with Diseases. AB - BACKGROUND: MicroRNAs are increasingly being appreciated as critical players in human diseases, and questions concerning the role of microRNAs arise in many areas of biomedical research. There are several manually curated databases of microRNA-disease associations gathered from the biomedical literature; however, it is difficult for curators of these databases to keep up with the explosion of publications in the microRNA-disease field. Moreover, automated literature mining tools that assist manual curation of microRNA-disease associations currently capture only one microRNA property (expression) in the context of one disease (cancer). Thus, there is a clear need to develop more sophisticated automated literature mining tools that capture a variety of microRNA properties and relations in the context of multiple diseases to provide researchers with fast access to the most recent published information and to streamline and accelerate manual curation. METHODS: We have developed miRiaD (microRNAs in association with Disease), a text-mining tool that automatically extracts associations between microRNAs and diseases from the literature. These associations are often not directly linked, and the intermediate relations are often highly informative for the biomedical researcher. Thus, miRiaD extracts the miR-disease pairs together with an explanation for their association. We also developed a procedure that assigns scores to sentences, marking their informativeness, based on the microRNA disease relation observed within the sentence. RESULTS: miRiaD was applied to the entire Medline corpus, identifying 8301 PMIDs with miR-disease associations. These abstracts and the miR-disease associations are available for browsing at http://biotm.cis.udel.edu/miRiaD . We evaluated the recall and precision of miRiaD with respect to information of high interest to public microRNA-disease database curators (expression and target gene associations), obtaining a recall of 88.46-90.78. When we expanded the evaluation to include sentences with a wide range of microRNA-disease information that may be of interest to biomedical researchers, miRiaD also performed very well with a F-score of 89.4. The informativeness ranking of sentences was evaluated in terms of nDCG (0.977) and correlation metrics (0.678-0.727) when compared to an annotator's ranked list. CONCLUSIONS: miRiaD, a high performance system that can capture a wide variety of microRNA-disease related information, extends beyond the scope of existing microRNA-disease resources. It can be incorporated into manual curation pipelines and serve as a resource for biomedical researchers interested in the role of microRNAs in disease. In our ongoing work we are developing an improved miRiaD web interface that will facilitate complex queries about microRNA-disease relationships, such as "In what diseases does microRNA regulation of apoptosis play a role?" or "Is there overlap in the sets of genes targeted by microRNAs in different types of dementia?"." PMID- 27216255 TI - Schistosoma mansoni and soil-transmitted helminths among preschool-aged children in Chuahit, Dembia district, Northwest Ethiopia: prevalence, intensity of infection and associated risk factors. AB - BACKGROUND: Intestinal schistosomiasis and soil-transmitted helminthiasis are the major public health problems globally. Compared with any other age group, pre school aged children and school-aged children are the most exposed. There are few studies showing the burden of intestinal schistosomiasis, and soil-transmitted helminthiasis among pre-school aged children in Ethiopia. Hence, this study aimed to assess the prevalence of schistosoma mansoni and soil-transmitted helminths and associated risk factors among preschool aged children of Chuahit and surrounding Kebeles, Northwest Ethiopia. METHODS: A community based cross sectional study was conducted from February 2 to March 27 2015. Four hundred one preschool-aged children were included in the study by using two stage cluster sampling technique. Pretested structured questionnaire was employed to collected data via face-to-face interview technique. A single stool specimen was collected, and a portion of the sample was processed by Kato Katz method. RESULTS: Of the total children, 141 (35.2 %) harbored one or more intestinal helminthes. Schistosoma mansoni was found in 45 (11.2 %) of preschool age children. Ascaris lumbricoides was the predominant isolate, 77 (19.2 %) followed by S. mansoni, 45 (11.2 %). The least parasites isolated were Tania species, 2 (0.5 %). After adjusting for other variables, being mothers who did not have the habit of washing hands after toilet (AOR = 7.3, 95%CI: 2.97-17.95), being occupationally housewife mothers (AOR = 8.9, 95%CI: 2.27-25.4), using protected spring water as a main family source of water (AOR = 3.9, 95%CI: 1.2-12.3) and child habit of not wearing shoe (AOR = 1.91, 95%CI: 1.01-3.64) were significantly associated with high prevalence of soil-transmitted helminthiasis among preschool-age children in Chuahit. CONCLUSION: The current study showed that relatively higher level of STH and S. mansoni among preschool-aged children in Chuahit. This finding calls for a need of public health education, promotion of women education and provision of safe water to reduce the burden of soil-transmitted intestinal helminthiasis and schistosomiaisis. PMID- 27216256 TI - Heike Folsch: Peeling back the layers. PMID- 27216257 TI - Division of labor in the growth cone by DSCR1. AB - Local protein synthesis directs growth cone turning of nascent axons, but mechanisms governing this process within compact, largely autonomous microenvironments remain poorly understood. In this issue, Wang et al. (2016. J. Cell Biol http://dx.doi.org/10.1083/jcb.201510107) demonstrate that the calcineurin regulator Down syndrome critical region 1 protein modulates both basal neurite outgrowth and growth cone turning. PMID- 27216258 TI - Extracellular chloride signals collagen IV network assembly during basement membrane formation. AB - Basement membranes are defining features of the cellular microenvironment; however, little is known regarding their assembly outside cells. We report that extracellular Cl(-) ions signal the assembly of collagen IV networks outside cells by triggering a conformational switch within collagen IV noncollagenous 1 (NC1) domains. Depletion of Cl(-) in cell culture perturbed collagen IV networks, disrupted matrix architecture, and repositioned basement membrane proteins. Phylogenetic evidence indicates this conformational switch is a fundamental mechanism of collagen IV network assembly throughout Metazoa. Using recombinant triple helical protomers, we prove that NC1 domains direct both protomer and network assembly and show in Drosophila that NC1 architecture is critical for incorporation into basement membranes. These discoveries provide an atomic-level understanding of the dynamic interactions between extracellular Cl(-) and collagen IV assembly outside cells, a critical step in the assembly and organization of basement membranes that enable tissue architecture and function. Moreover, this provides a mechanistic framework for understanding the molecular pathobiology of NC1 domains. PMID- 27216259 TI - Enhancing antibody folding and secretion by tailoring the Saccharomyces cerevisiae endoplasmic reticulum. AB - BACKGROUND: The yeast Saccharomyces cerevisiae provides intriguing possibilities for synthetic biology and bioprocess applications, but its use is still constrained by cellular characteristics that limit the product yields. Considering the production of advanced biopharmaceuticals, a major hindrance lies in the yeast endoplasmic reticulum (ER), as it is not equipped for efficient and large scale folding of complex proteins, such as human antibodies. RESULTS: Following the example of professional secretory cells, we show that inducing an ER expansion in yeast by deleting the lipid-regulator gene OPI1 can improve the secretion capacity of full-length antibodies up to fourfold. Based on wild-type and ER-enlarged yeast strains, we conducted a screening of a folding factor overexpression library to identify proteins and their expression levels that enhance the secretion of antibodies. Out of six genes tested, addition of the peptidyl-prolyl isomerase CPR5 provided the most beneficial effect on specific product yield while PDI1, ERO1, KAR2, LHS1 and SIL1 had a mild or even negative effect to antibody secretion efficiency. Combining genes for ER enhancement did not induce any significant additional effect compared to addition of just one element. By combining the Deltaopi1 strain, with the enlarged ER, with CPR5 overexpression, we were able to boost the specific antibody product yield by a factor of 10 relative to the non-engineered strain. CONCLUSIONS: Engineering protein folding in vivo is a major task for biopharmaceuticals production in yeast and needs to be optimized at several levels. By rational strain design and high-throughput screening applications we were able to increase the specific secreted antibody yields of S. cerevisiae up to 10-fold, providing a promising strain for further process optimization and platform development for antibody production. PMID- 27216260 TI - Confronting the HIV, Tuberculosis, Addiction, and Incarceration Syndemic in Southeast Asia: Lessons Learned from Malaysia. AB - Throughout Southeast Asia, repressive drug laws have resulted in high rates of imprisonment in people who inject drugs (PWID) and people living with HIV (PLH), greatly magnifying the harm associated with HIV, tuberculosis, and addiction. We review findings from Malaysia's largest prison to describe the negative synergistic effects of HIV, tuberculosis, addiction, and incarceration that contribute to a 'perfect storm' of events challenging public and personal health and offer insights into innovative strategies to control these converging epidemics. The majority of PLH who are imprisoned in Malaysia are opioid dependent PWID. Although promoted by official policy, evidence-based addiction treatment is largely unavailable, contributing to rapid relapse and/or overdose after release. Similarly, HIV treatment in prisons and compulsory drug treatment centers is sometimes inadequate or absent. The prevalence of active tuberculosis is high, particularly in PLH, and over 80 % of prisoners and prison personnel are latently infected. Mandatory HIV testing and subsequent segregation of HIV infected prisoners increases the likelihood of tuberculosis acquisition and progression to active disease, amplifying the reservoir of infection for other prisoners. We discuss strategies to control these intersecting epidemics including screening linked to standardized treatment protocols for all three conditions, and effective transitional programs for released prisoners. For example, recently introduced evidence-based interventions in prisons like antiretroviral therapy (ART) to treat HIV, isoniazid preventive therapy to treat latent tuberculosis infection, and methadone maintenance to treat opioid dependence, have markedly improved clinical care and reduced morbidity and mortality. Since introduction of these interventions in September 2012, all-cause and HIV-related mortality have decreased by 50.0 % and 75.7 %, respectively. We discuss the further deployment of these interventions in Malaysian prisons. PMID- 27216262 TI - Performance of DSM-5 Persistent Complex Bereavement Disorder Criteria in a Community Sample of Bereaved Military Family Members. AB - OBJECTIVE: The purpose of this article was to examine the accuracy of DSM-5 proposed criteria for persistent complex bereavement disorder in identifying putative cases of clinically impairing grief and in excluding nonclinical cases. Performance of criteria sets for prolonged grief disorder and complicated grief were similarly assessed. METHOD: Participants were family members of U.S. military service members who died of any cause since September 11, 2001 (N=1,732). Putative clinical and nonclinical samples were derived from this community sample using cutoff scores from the Inventory of Complicated Grief and the Work and Social Adjustment Scale. Items from a self-report grief measure (Complicated Grief Questionnaire) were matched to DSM-5 persistent complex bereavement disorder, prolonged grief disorder, and complicated grief criteria. Endorsed items were used to identify cases. RESULTS: Criteria sets varied in their ability to identify clinical cases. DSM-5 persistent complex bereavement disorder criteria identified 53%, prolonged grief disorder criteria identified 59%, and complicated grief criteria identified more than 90% of putative clinical cases. All criteria sets accurately excluded virtually all nonclinical grief cases and accurately excluded depression in the absence of clinical grief. CONCLUSIONS: The DSM-5 persistent complex bereavement disorder criteria accurately exclude nonclinical, normative grief, but also exclude nearly half of clinical cases, whereas complicated grief criteria exclude nonclinical cases while identifying more than 90% of clinical cases. The authors conclude that significant modification is needed to improve case identification by DSM-5 persistent complex bereavement disorder diagnostic criteria. Complicated grief criteria are superior in accurately identifying clinically impairing grief. PMID- 27216261 TI - Prenatal Nicotine Exposure and Risk of Schizophrenia Among Offspring in a National Birth Cohort. AB - OBJECTIVE: Cigarette smoking during pregnancy is a major public health problem leading to adverse health outcomes and neurodevelopmental abnormalities among offspring. Its prevalence in the United States and Europe is 12%-25%. This study examined the relationship between prenatal nicotine exposure (cotinine level) in archived maternal sera and schizophrenia in offspring from a national birth cohort. METHOD: The authors conducted a population-based nested case-control study of all live births in Finland from 1983 to 1998. Cases of schizophrenia in offspring (N=977) were identified from a national registry and matched 1:1 to controls on date of birth, sex, and residence. Maternal serum cotinine levels were prospectively measured, using quantitative immunoassay, from early- to mid gestation serum specimens archived in a national biobank. RESULTS: A higher maternal cotinine level, measured as a continuous variable, was associated with an increased odds of schizophrenia (odds ratio=3.41, 95% confidence interval, 1.86-6.24). Categorically defined heavy maternal nicotine exposure was related to a 38% increased odds of schizophrenia. These findings were not accounted for by maternal age, maternal or parental psychiatric disorders, socioeconomic status, and other covariates. There was no clear evidence that weight for gestational age mediated the associations. CONCLUSIONS: To the authors' knowledge, this is the first study of the relationship between a maternal smoking biomarker and schizophrenia. It provides the most definitive evidence to date that smoking during pregnancy is associated with schizophrenia. If replicated, these findings suggest that preventing smoking during pregnancy may decrease the incidence of schizophrenia. PMID- 27216269 TI - IASGO News. PMID- 27216263 TI - Bioavailability of polycyclic aromatic hydrocarbons (PAHs) to short-neck clam (Paphia undulata) from sediment matrices in mudflat ecosystem of the west coast of Peninsular Malaysia. AB - The bioaccumulation and bioavailability of polycyclic aromatic hydrocarbons (PAHs) were characterized in sediment and Paphia undulata (short-neck clam) from six mudflat areas in the west coasts of Peninsular Malaysia. The concentrations of total PAHs varied from 357.1 to 6257.1 and 179.9 +/- 7.6 to 1657.5 +/- 53.9 ng g -1 dry weight in sediment and short-neck clam samples, respectively. PAHs can be classified as moderate to very high level of pollution in sediments and moderate to high level of pollution in short-neck clams. The diagnostic ratios of individual PAHs and principal component analysis indicate both petrogenic and pyrogenic sources with significant dominance of pyrogenic source. The first PAHs biota-sediment accumulation factors and relative biota-sediment accumulation factors data for short-neck clam were obtained in this study, indicating a preferential accumulation of lower molecular weight PAHs. Evaluation of PAH levels in sediments and short-neck clams indicates that short-neck clam could be introduced as a good biomonitor in mudflats. The results also demonstrated that under environmental conditions, the sedimentary load of hydrocarbons appears to be one of the factors controlling their bioavailability to biota. PMID- 27216270 TI - Ternary borides Nb7Fe3B8 and Ta7Fe3B8 with Kagome-type iron framework. AB - Two new ternary borides TM7Fe3B8 (TM = Nb, Ta) were synthesized by high temperature thermal treatment of samples obtained by arc-melting. This new type of structure with space group P6/mmm, comprises TM slabs containing isolated planar hexagonal [B6] rings and iron centered TM columns in a Kagome type of arrangement. Chemical bonding analysis in Nb7Fe3B8 by means of the electron localizability approach reveals two-center interactions forming the Kagome net of Fe and embedded B, while weaker multicenter bonding present between this net and Nb atoms. Magnetic susceptibility measurements reveal antiferromagnetic order below TN = 240 K for Nb7Fe3B8 and TN = 265 K for Ta7Fe3B8. Small remnant magnetization below 0.01MUB per f.u. is observed in the antiferromagnetic state. The bulk nature of the magnetic transistions was confirmed by the hyperfine splitting of the Mossbauer spectra, the sizable anomalies in the specific heat capacity, and the kinks in the resistivity curves. The high-field paramagnetic susceptibilities fitted by the Curie-Weiss law show effective paramagnetic moments MUeff~ 3.1MUB/Fe in both compounds. The temperature dependence of the electrical resistivity also reveals metallic character of both compounds. Density functional calculations corroborate the metallic behaviour of both compounds and demonstrate the formation of a sizable local magnetic moment on the Fe-sites. They indicate the presence of both antiferro- and ferrromagnetic interactions. PMID- 27216271 TI - Antimicrobial Susceptibility among European Gram-Negative and Gram-Positive Isolates Collected as Part of the Tigecycline Evaluation and Surveillance Trial (2004-2014). AB - BACKGROUND: European centers (n = 226) involved in the Tigecycline Evaluation and Surveillance Trial (TEST, 2004-2014) submitted data and bacterial isolates. METHODS: Minimal inhibitory concentrations and susceptibility were determined using Clinical and Laboratory Standards Institute methods and European Committee on Antimicrobial Susceptibility Testing breakpoints. RESULTS: The rates of the following resistant pathogens increased from 2004 to 2014: extended-spectrum beta lactamase (ESBL)-positive Escherichia coli (from 8.9 to 16.9%), multidrug resistant Acinetobacter baumannii complex (from 15.4 to 48.5%), and ESBL-positive Klebsiella pneumoniae (from 17.2 to 23.7%). The rate of methicillin-resistant Staphylococcus aureus was 27.5% in 2004 and 28.9% in 2014. Resistance to the carbapenems (imipenem and meropenem) was 37.4 and 14.5% for A. baumannii complex and Pseudomonas aeruginosa, respectively. Carbapenem resistance was <=4.3% among the Enterobacteriaceae and 0.2% against Streptococcus pneumoniae. The resistance to tigecycline ranged between 7.4% against ESBL-producing K. pneumoniae and 0.0% against S. aureus. CONCLUSIONS: The carbapenems and tigecycline were active against Enterobacteriaceae. Agents with activity against A. baumannii complex and P. aeruginosa are limited. The carbapenems, tigecycline, linezolid, and vancomycin were active against Gram-positive organisms. PMID- 27216272 TI - Improving outcomes in total knee arthroplasty-do navigation or customized implants have a role? AB - Modern total knee arthroplasty is effective at treating the pain and disability associated with osteoarthritis. The number of total knee replacements done in the USA continues to increase. Despite the great care taken during all of these procedures, some patients remain dissatisfied with their outcome. While this dissatisfaction is likely multifactorial, malalignment of the prosthetic components is a major cause of postoperative complications. A neutral mechanical axis plus or minus 3 degrees is felt to have a positive impact on the survivorship of the prosthesis. Conventional instrumentation has been shown to have a significant number of total knee replacements that lie well outside a neutral coronal alignment. With that in mind, significant effort has been placed into the development of technology to improve the overall alignment of the prosthesis. In order to reduce the number of outliers, several companies have developed cost-effective systems to aid the surgeon in achieving a more predictably aligned prosthesis in all three planes. We will review the literature that is available regarding several of these tools to examine if navigation or custom guides improve outcomes in total knee arthroplasty. Our review supports that while both navigation and custom implants guides seem to be a cost effective way to achieve a predictable mechanical alignment of a total knee prosthesis therefore reducing the number of outliers, the cost may be increased operative times with no perceived difference in patient satisfaction with navigation custom guides. PMID- 27216273 TI - What motivates men to choose nursing as a profession? A systematic review of qualitative studies. AB - AIM: This systematic review was conducted to provide a deeper understanding of male nurses' motivations for choosing nursing as a profession. METHODS: A systematic literature review of qualitative data was conducted. CINAHL, Pubmed, PsychINFO, Pubmesh, and Embase were searched from January 1970 to December 2013. Qualitative studies which described male nurses' motivations for choosing nursing were selected. DATA COLLECTION AND ANALYSIS: Relevant data were extracted from the included papers and were coded and then synthesised under four main themes. RESULTS: Four main themes were identified which described male nurses' motivations for choosing nursing; 'Early exposure to nursing and other health care professionals', 'Choosing nursing as a profession by chance', 'Choosing nursing because of extrinsic motivating factors', and 'Choosing nursing because of intrinsic motivating factors'. CONCLUSIONS: To help encourage more men to enter and remain in nursing, recruitment and retention strategies need to focus on addressing the gender stereotypes associated with the nursing profession. PMID- 27216274 TI - First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non inferiority trial. AB - BACKGROUND: Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab is the standard therapy for physically fit patients with advanced chronic lymphocytic leukaemia. This international phase 3 study compared the efficacy and tolerance of the standard therapy with a potentially less toxic combination consisting of bendamustine and rituximab. METHODS: Treatment-naive fit patients with chronic lymphocytic leukaemia (aged 33-81 years) without del(17p) were enrolled after undergoing a central screening process. Patients were randomly assigned (1:1) with a computer-generated randomisation list using randomly permuted blocks with a block size of eight and were stratified according to participating country and Binet stage. Patients were allocated to receive six cycles of intravenous fludarabine (25 mg/m(2) per day) and cyclophosphamide (250 mg/m(2) per day) for the first 3 days or to intravenous bendamustine (90 mg/m(2) per day) for the first 2 days of each cycle. Rituximab 375 mg/m(2) was given intravenously in both groups on day 0 of cycle 1 and subsequently was given at 500 mg/m(2) during the next five cycles on day 1. The primary endpoint was progression-free survival with the objective to assess non-inferiority of bendamustine and rituximab to the standard therapy. We aimed to show that the 2 year progression-free survival with bendamustine and rituximab was not 67.5% or less with a corresponding non-inferiority margin of 1.388 for the hazard ratio (HR) based on the 90.4% CI. The final analysis was done by intention to treat. The study is registered with ClinicalTrials.gov, number NCT%2000769522. FINDINGS: 688 patients were recruited between Oct 2, 2008, and July 11, 2011, of which 564 patients who met inclusion criteria were randomly assigned. 561 patients were included in the intention-to-treat population: 282 patients in the fludarabine, cyclophosphamide, and rituximab group and 279 in the bendamustine and rituximab group. After a median observation time of 37.1 months (IQR 31.0-45.5) median progression-free survival was 41.7 months (95% CI 34.9-45.3) with bendamustine and rituximab and 55.2 months (95% CI not evaluable) with fludarabine, cyclophosphamide, and rituximab (HR 1.643, 90.4% CI 1.308-2.064). As the upper limit of the 90.4% CI was greater than 1.388 the null hypothesis for the corresponding non-inferiority hypothesis was not rejected. Severe neutropenia and infections were more frequently observed with fludarabine, cyclophosphamide, and rituximab (235 [84%] of 279 vs 164 [59%] of 278, and 109 [39%] vs 69 [25%], respectively) during the study. The increased frequency of infectious complications with fludarabine, cyclophosphamide, and rituximab was more pronounced in patients older than 65 years. INTERPRETATION: The combination of fludarabine, cyclophosphamide, and rituximab remains the standard front-line therapy in fit patients with chronic lymphocytic leukaemia, but bendamustine and rituximab is associated with less toxic effects. FUNDING: Roche Pharma AG, Mundipharma, German Federal Ministry of Education and Research. PMID- 27216275 TI - Choosing frontline chemoimmunotherapy for CLL. PMID- 27216276 TI - Cooperative organocatalysis of Mukaiyama-type aldol reactions by thioureas and nitro compounds. AB - A unique organocatalytic system for Mukaiyama-type aldol reactions based on the cooperative action of nitro compounds and thioureas has been identified. This system is compatible with a wide range of substrates and does not require low temperatures, inert atmospheres, or an aqueous workup. A catalytic mechanism based on nitro group-mediated silyl cation transfer has been proposed. PMID- 27216277 TI - Enhanced Mechanical Performance of Bio-Inspired Hybrid Structures Utilising Topological Interlocking Geometry. AB - Structural composites inspired by nacre have emerged as prime exemplars for guiding materials design of fracture-resistant, rigid hybrid materials. The intricate microstructure of nacre, which combines a hard majority phase with a small fraction of a soft phase, achieves superior mechanical properties compared to its constituents and has generated much interest. However, replicating the hierarchical microstructure of nacre is very challenging, not to mention improving it. In this article, we propose to alter the geometry of the hard building blocks by introducing the concept of topological interlocking. This design principle has previously been shown to provide an inherently brittle material with a remarkable flexural compliance. We now demonstrate that by combining the basic architecture of nacre with topological interlocking of discrete hard building blocks, hybrid materials of a new type can be produced. By adding a soft phase at the interfaces between topologically interlocked blocks in a single-build additive manufacturing process, further improvement of mechanical properties is achieved. The design of these fabricated hybrid structures has been guided by computational work elucidating the effect of various geometries. To our knowledge, this is the first reported study that combines the advantages of nacre inspired structures with the benefits of topological interlocking. PMID- 27216278 TI - H3 histamine receptor antagonist pitolisant reverses some subchronic disturbances induced by olanzapine in mice. AB - The use of atypical antipsychotic drugs like olanzapine is associated with side effects such as sedation and depression-like symptoms, especially during the initial period of the use. It is believed that the occurrence of these undesirable effectsis mainly the result of the histamine H1receptors blockade by olanzapine. In addition, use of olanzapine increases the level of triglycerides in the blood, which correlates with growing obesity. The aim of this study was to investigate the influence of pitolisant - H3 histamine antagonist - on subchronic olanzapine-induced depresion-like symptoms, sedation and hypertriglicerydemia. Forced swim test was conducted to determinate depressive-like effect of olanzapine and antidepressive-like activity during the co-administered pitolisant. The test was performed after the first and fifteenth day of the treatment of the mice. The spontaneous activity of the mice was measured on the fourteenth day of the treatment with a special, innovative RFID-system (Radio frequency identification system) - TraffiCage (TSE-Systems, Germany). Triglyceride levels were determined on the sixteenth day of the experiment after 15 cycles of drug administration. Daily olanzapine treatment (4 mg/kg b.w., i.p., d.p.d) for 15 days significantly induces sedation (p < 0.05) and prolongs immobility time in forced swim tests (FST) in mice (p < 0.05); and also elevates the level of triglycerides (p < 0.05). Administration of pitolisant (10 mg/kg b.w., i.p.) subsequentto olanzapine normalizes these adverse effects. This study presents a promising alternative for counteracting some behavioral changes and metabolic disturbances which occur in the early period of treatment with antipsychotic drugs. PMID- 27216279 TI - A clickable glutathione approach for identification of protein glutathionylation in response to glucose metabolism. AB - Glucose metabolism and mitochondrial function are closely interconnected with cellular redox-homeostasis. Although glucose starvation, which mimics ischemic conditions or insufficient vascularization, is known to perturb redox homeostasis, global and individual protein glutathionylation in response to glucose metabolism or mitochondrial activity remains largely unknown. In this report, we use our clickable glutathione approach, which forms clickable glutathione (azido-glutathione) by using a mutant of glutathione synthetase (GS M4), for detection and identification of protein glutathionylation in response to glucose starvation. We found that protein glutathionylation is readily induced in HEK293 cells in response to low glucose concentrations when mitochondrial reactive oxygen species (ROS) are elevated in cells, and glucose is the major determinant for inducing reversible glutathionylation. Proteomic and biochemical analysis identified over 1300 proteins, including SMYD2, PP2Calpha, and catalase. We further showed that PP2Calpha is glutathionylated at C314 in a C-terminal domain, and PP2Calpha C314 glutathionylation disrupts the interaction with mGluR3, an important glutamate receptor associated with synaptic plasticity. PMID- 27216280 TI - Management of headache and associated factors among undergraduate medicine and health science students of University of Gondar, North West Ethiopia. AB - BACKGROUND: The headache disorders, namely, migraine and tension type headache and the associated analgesic consumption is badly underestimated and thus makes a major current public health problem. The objective of this study was to determine the prevalence of migraine and tension type headaches and the associated management options used among undergraduate students of College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia. METHOD: Institution based cross sectional study was conducted among 720 students in May, 2014. Pretested and structured self-administered questionnaires were used as data collecting tool followed by short interview to diagnose the type of headache based on the International Headache Society diagnostic criteria. SPSS version 20 was also used to analyse the data descriptively as well as inferentially using logistic regression models to investigate factors associated with presence of headache and analgesic use. RESULT: The prevalence of lifetime headache and headache in the last 12 months was 81.11 and 67.22 %, respectively. Migraine and tension type headache were having 94 (13.06 %) and 481 (66.81 %) prevalence, respectively. Prevalence of life time headache was significant among females, students with family history of headache and lack of adequate vacation time. Similarly, lifetime prevalence of analgesic use for headache was 72.45 % and it had statistical association with sex, age, type of headache, lack of adequate vacation time and family history of headache. Majority of the students, migraineurs (54.65 %) and the tension type headache sufferers (66.17 %) commonly used paracetamol. CONCLUSION: High prevalence without adequate medical care seeking behaviour and the associated significant analgesic consumption necessitate the designing of all rounded strategies to improve the quality of life of individuals with such neurologic disorders. PMID- 27216281 TI - Both systemic and local lipopolysaccharide (LPS) burden are associated with knee OA severity and inflammation. AB - OBJECTIVE: The microbiome is recognized as a new frontier in medicine with connections to a variety of diseases. We aimed to evaluate the association of lipopolysaccharide (LPS), a key pro-inflammatory product of the microbiome, with severity of inflammation, symptoms and radiographic abnormalities of knee osteoarthritis (OA). DESIGN: LPS was measured using a recombinant Factor C (rFC) assay, carefully optimized for systemic and synovial fluid (SF) analyses. LPS binding protein (LBP) was tested in both serum and SF of 25 patients (31 knees) from the Etarfolatide cohort for association with OA phenotypic outcomes. Models were adjusted for age, gender and body mass index. RESULTS: Based on LPS spike and-recovery, both serum and SF dilutions of 0.1% were required to achieve recovery rates of at least 75% in all test specimens. Low coefficients of variation (CVs) (<10%) were achieved with both serum and SF dilutions <0.2%. Serum LPS and LBP were associated with the abundance of activated macrophages in the knee joint capsule and synovium. SF LPS and LBP were associated with the abundance of activated macrophages in the synovium. Serum LPS, LBP and SF LPS were associated with knee osteophyte severity. SF LPS was positively associated with knee joint space narrowing (JSN) severity and total WOMAC score. SF LBP was positively associated with self-reported knee pain score. CONCLUSION: These data strongly support a role for LPS in the pathogenesis and severity of structural abnormalities and symptoms of knee OA. PMID- 27216283 TI - The cell cycle-related genes as biomarkers for schizophrenia. AB - BACKGROUND: Recent studies suggest that genomic abnormalities such as single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) may elevate the risk of schizophrenia. Such genomic abnormalities often occur during chromosomal DNA replication in the S phase of cell cycle. In addition, several studies showed that abnormal expressions of several cell cycle-related genes are associated with schizophrenia. Therefore, here we compared mRNA expression levels of cell cycle related genes in peripheral blood cells between patients with schizophrenia and healthy controls. METHOD: mRNA expression levels of cell cycle-related genes in peripheral blood cells from patients with schizophrenia and healthy controls were measured with quantitative reverse transcription polymerase chain reaction (Q-RT PCR). The discovery, replication and intervention studies with Q-RT-PCR were performed as follows: discovery (40 cases and 20 controls), replication (82 cases and 74 controls) and intervention (22 cases and 18 controls). RESULT: Nine genes were identified in the discovery and replication stages as schizophrenia associated genes. Moreover, the combination of mRNA expression levels of CDK4, MCM7 and POLD4 was identified as a potential biomarker for schizophrenia with multivariate logistic regression analysis. The intervention stage revealed that the mRNA expression levels of these three genes were significantly decreased in the acute state of schizophrenia, and CDK4 was significantly recovered in the remission state of schizophrenia. CONCLUSION: The combination of mRNA expression levels of three cell cycle-related genes such as CDK4, MCM7 and POLD4 is expected to be a candidate for useful biomarkers for schizophrenia. Especially, the mRNA expression changes of CDK4 may be potential as both trait and state markers for schizophrenia. PMID- 27216282 TI - Pharmacologically distinct pramipexole-mediated akinesia vs. risk-taking in a rat model of Parkinson's disease. AB - Pramipexole and ropinirole are dopamine agonists that are efficacious in treating motor disturbances of neuropathologies, e.g., Parkinson's disease and restless legs syndrome. A significant portion of treated patients develop impulsive/compulsive behaviors. Current treatment is dose reduction or switching to an alternative dopamine replacement, both of which can undermine the motor benefits. Needed is a preclinical model that can assist in identifying adjunct treatments to dopamine agonist therapy that reduce impulsive/compulsive behaviors without interfering with motor benefits of the dopamine agonist. Toward that objective, the current study implemented a rat model of Parkinson's disease to behaviorally profile chronically administered pramipexole. This was accomplished with male Sprague-Dawley rats wherein (i) 6-hydroxydopamine-induced lesions of the dorsolateral striatum produced Parkinson's disease-like akinesia, measured in the forelimbs, (ii) intracranial self-stimulation-mediated probability discounting indicated impulsivity/risk-taking, and (iii) two doses of pramipexole were continuously administered for 14-28days via osmotic minipumps to mirror the chronic, stable exposure achieved with extended release formulations. The atypical antidepressant, mirtazapine, is known to reduce behaviors associated with drug addiction in rats; thus, we demonstrated model utility here by determining the effects of mirtazapine on pramipexole-induced motor improvements versus probability discounting. We observed that forelimb akinesia subsequent to striatal lesions was attenuated by both pramipexole doses tested (0.3 and 1.2mg/kg/day) within 4h of pump implant dispensing 0.3mg/kg/day and 1h by 1.2mg/kg/day. By contrast, 12-14days of infusion with 0.3mg/kg/day did not alter discounting, but increases were obtained with 1.2mg/kg/day pramipexole, with 67% of 1.2mg/kg/day-treated rats meeting categorical criteria for 'high risk-taking'. Insertion of a second minipump delivering mirtazapine did not alter motor function during 14days of co-administration with pramipexole, but was sufficient to attenuate risk-taking. These outcomes revealed distinct probability discounting and anti-akinesia profiles for pramipexole, indicating that pharmacotherapy, (e.g., mirtazapine treatments), can be developed that reduce risk-taking while leaving motor benefits intact. PMID- 27216285 TI - Stale and flaccid policy impedes the productive potential of ageing populations. PMID- 27216284 TI - Chronic Pruritus in the Absence of Skin Disease: Pathophysiology, Diagnosis and Treatment. AB - Chronic pruritus arises not only from dermatoses, but also, in up to half of cases, from extracutaneous origins. A multitude of systemic, neurological, psychiatric, and somatoform conditions are associated with pruritus in the absence of skin disease. Moreover, pruritus is a frequently observed side effect of many drugs. It is therefore difficult for physicians to make a correct diagnosis. Chronic pruritus patients frequently present to the dermatologist with skin lesions secondary to a long-lasting scratching behavior, such as lichenification and prurigo nodularis. A structured clinical history and physical examination are essential in order to evaluate the pruritus, along with systematic, medical history-adapted laboratory and radiological tests carried out according to the differential diagnosis. For therapeutic reasons, a symptomatic therapy should be promptly initiated parallel to the diagnostic procedures. Once the underlying factor(s) leading to the pruritus are identified, a targeted therapy should be implemented. Importantly, the treatment of accompanying disorders such as sleep disturbances or mental symptoms should be taken into consideration. Even after successful treatment of the underlying cause, pruritus may persist, likely due to chronicity processes including peripheral and central sensitization or impaired inhibition at spinal level. A vast arsenal of topical and systemic agents targeting these pathophysiological mechanisms has been used to deter further chronicity. The therapeutic options currently available are, however, still insufficient for many patients. Thus, future studies aiming to unveil the complex mechanisms underlying chronic pruritus and develop new therapeutic agents are urgently needed. PMID- 27216286 TI - Nursing care at its finest: a personal experience. PMID- 27216287 TI - The race against antimicrobial resistance. PMID- 27216289 TI - Letter to the Editor. PMID- 27216290 TI - Ontogenetic allometry constrains cranial shape of the head-first burrowing worm lizard Cynisca leucura (Squamata: Amphisbaenidae). AB - Amphisbaenians are fossorial, predominantly limbless squamate reptiles with distinct cranial shapes corresponding to specific burrowing behaviors. Due to their cryptic lifestyles and the scarcity of museum specimens, little is known of their intraspecific variation, particularly regarding cranial osteology. This represents a critical lack of information, because the majority of morphological investigations of squamate relationships are based on cranial characters. We investigated cranial variation in the West African Coast Worm Lizard Cynisca leucura, a round-headed member of the Amphisbaenidae. Using geometric morphometric analyses of three-dimensional computed tomographic scans, we found that cranial osteology of C. leucura is highly conserved, with the majority of shape changes occurring during growth as the cranium becomes more slender and elongate, accompanied by increasing interdigitation among the dermal roofing bones. Elements of the ventral portion of the cranium remain loosely connected in adults, possibly as a protective mechanism against repeated compression and torsion during burrow excavation. Intraspecific variation was strongly correlated with size change from juveniles to adults, indicating a dominant role of ontogenetic allometry in determining cranial shape. We found no evidence of sexual dimorphism, either during growth or among adults. Given the fossorial habits of C. leucura, we hypothesize that cranial allometry is under strong stabilizing selection to maintain adequate proportions for head-first digging, thereby constraining the ability of individuals to respond to differing selection pressures, including sexual selection and variation in diet or microhabitat. For species in which digging imposes less mechanical stress (e.g., in softer sand), allometric associations during growth may be weakened, allowing changes to the ontogenetic trajectory and subsequent morphological traits. Such developmental dissociation between size and shape, known as heterochrony, may also be implicit in the evolution of the other amphisbaenian cranial shapes (shovel, spade, and keel), which may themselves be functionally adapted for their respective burrowing techniques. J. Morphol. 277:1159-1167, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27216291 TI - An ultra-thin, un-doped NiO hole transporting layer of highly efficient (16.4%) organic-inorganic hybrid perovskite solar cells. AB - NiO is a wide band gap p-type oxide semiconductor and has potential for applications in solar energy conversion as a hole-transporting layer (HTL). It also has good optical transparency and high chemical stability, and the capability of aligning the band edges to the perovskite (CH3NH3PbI3) layers. Ultra-thin and un-doped NiO films with much less absorption loss were prepared by atomic layer deposition (ALD) with highly precise control over thickness without any pinholes. Thin enough (5-7.5 nm in thickness) NiO films with the thickness of few time the Debye length (LD = 1-2 nm for NiO) show enough conductivities achieved by overlapping space charge regions. The inverted planar perovskite solar cells with NiO films as HTLs exhibited the highest energy conversion efficiency of 16.40% with high open circuit voltage (1.04 V) and fill factor (0.72) with negligible current-voltage hysteresis. PMID- 27216292 TI - Transcriptome Analysis Reveals Distinct Gene Expression Profiles in Eosinophilic and Noneosinophilic Chronic Rhinosinusitis with Nasal Polyps. AB - Chronic rhinosinusitis with nasal polyps (CRSwNP), one of the most prevalent chronic diseases, is characterized by persistent inflammation of sinonasal mucosa. However, the pathogenesis of CRSwNP remains unclear. Here, we performed next-generation RNA sequencing and a comprehensive bioinformatics analyses to characterize the transcriptome profiles, including mRNAs and long noncoding RNAs (lncRNAs), in patients with eosinophilic and noneosinophilic CRSwNP. A total of 1917 novel lncRNAs and 280 known lncRNAs were identified. We showed eosinophilic CRSwNP (ECRSwNP) and noneosinophilic CRSwNP (non-ECRSwNP) display distinct transcriptome profiles. We identified crucial pathways, including inflammatory, immune response and extracellular microenvironment, connected to the pathogenetic mechanism of CRSwNP. We also discovered key lncRNAs differentially expressed, including lncRNA XLOC_010280, which regulates CCL18 and eosinophilic inflammation. The qRT-PCR and in situ RNA hybridization results verified the key differentially expressed genes. The feature of distinct transcriptomes between ECRSwNP and non-ECRSwNP suggests the necessity to develop specific biomarkers and personalized therapeutic strategies. Our findings lay a solid foundation for subsequent functional studies of mRNAs and lncRNAs as diagnostic and therapeutic targets in CRSwNP by providing a candidate reservoir. PMID- 27216294 TI - A short-term high fat diet increases exposure to midazolam and omeprazole in healthy subjects. AB - OBJECTIVES: Knowledge of factors contributing to variation in drug metabolism is of vital importance to optimize drug treatment. This study assesses the effects of a short-term hypercaloric high fat diet on metabolism of five oral drugs, which are each specific for a single P450 isoform: midazolam (CYP3A4), omeprazole (CYP2C19), metoprolol (CYP2D6), S-warfarin (CYP2C9) and caffeine (CYP1A2). METHODS: In 9 healthy volunteers, pharmacokinetics of the five drugs were assessed after an overnight fast at two separate occasions: after a regular diet and after 3 days of a hypercaloric high fat diet (i.e. regular diet supplemented with 500 mL cream [1715 kcal, 35% fat]). Pharmacokinetic parameters (mean [SEM]) were estimated by non-compartmental analysis. RESULTS: The high fat diet increased exposure to midazolam by 19% from 24.7 (2.6) to 29.5 (3.6) ng ml-1h-1 (p=0.04) and exposure to omeprazole by 31% from 726 (104) to 951 (168) ng ml-1h-1 (p=0.05). Exposure to metoprolol, caffeine and S-warfarin was not affected by the high fat diet. CONCLUSION: A short-term hypercaloric high fat diet increases exposure to midazolam and omeprazole, possibly reflecting modulation of CYP3A4 and CYP2C19. PMID- 27216293 TI - JAG1-Mediated Notch Signaling Regulates Secretory Cell Differentiation of the Human Airway Epithelium. AB - Basal cells (BC) are the stem/progenitor cells of the human airway epithelium capable of differentiating into secretory and ciliated cells. Notch signaling activation increases BC differentiation into secretory cells, but the role of individual Notch ligands in regulating this process in the human airway epithelium is largely unknown. The objective of this study was to define the role of the Notch ligand JAG1 in regulating human BC differentiation. JAG1 over expression in BC increased secretory cell differentiation, with no effect on ciliated cell differentiation. Conversely, knockdown of JAG1 decreased expression of secretory cell genes. These data demonstrate JAG1-mediated Notch signaling regulates differentiation of BC into secretory cells. PMID- 27216295 TI - Genome Editing: From Drosophila to Non-Model Insects and Beyond. AB - Insect is the largest group of animals on land. Many insect species inflict economical and health losses to humans. Yet many more benefit us by helping to maintain balances in our ecosystem. The benefits that insects offer remain largely untapped, justifying our continuing efforts to develop tools to better understand their biology and to better manage their activities. Here we focus on reviewing the progresses made in the development of genome engineering tools for model insects. Instead of detailed descriptions of the molecular mechanisms underlying each technical advance, we focus our discussion on the logistics for implementing similar tools in non-model insects. Since none of the tools were developed specific for insects, similar approaches can be applied to other non model organisms. PMID- 27216298 TI - XI National Congress: Portuguese Neuroradiology Society (SPNR) : XI Congresso Nacional de Neurorradiologia. Aveiro. October 23-25(th), 2015. PMID- 27216296 TI - A Zebrafish Model of 5q-Syndrome Using CRISPR/Cas9 Targeting RPS14 Reveals a p53 Independent and p53-Dependent Mechanism of Erythroid Failure. AB - 5q-syndrome is a distinct form of myelodysplastic syndrome (MDS) where a deletion on chromosome 5 is the underlying cause. MDS is characterized by bone marrow failures, including macrocytic anemia. Genetic mapping and studies using various models support the notion that ribosomal protein S14 (RPS14) is the candidate gene for the erythroid failure. Targeted disruption of RPS14 causes an increase in p53 activity and p53-mediated apoptosis, similar to what is observed with other ribosomal proteins. However, due to the higher risk for cancer development in patients with ribosome deficiency, targeting the p53 pathway is not a viable treatment option. To better understand the pathology of RPS14 deficiency in 5q deletion, we generated a zebrafish model harboring a mutation in the RPS14 gene. This model mirrors the anemic phenotype seen in 5q-syndrome. Moreover, the anemia is due to a late-stage erythropoietic defect, where the erythropoietic defect is initially p53-independent and then becomes p53-dependent. Finally, we demonstrate the versatility of this model to test various pharmacological agents, such as RAP 011, L-leucine, and dexamethasone in order to identify molecules that can reverse the anemic phenotype. PMID- 27216297 TI - A centrifugal direct recombinase polymerase amplification (direct-RPA) microdevice for multiplex and real-time identification of food poisoning bacteria. AB - In this study, we developed a centrifugal direct recombinase polymerase amplification (direct-RPA) microdevice for multiplex and real-time identification of food poisoning bacteria contaminated milk samples. The microdevice was designed to contain identical triplicate functional units and each unit has four reaction chambers, thereby making it possible to perform twelve direct-RPA reactions simultaneously. The integrated microdevice consisted of two layers: RPA reagents were injected in the top layer, while spiked milk samples with food poisoning bacteria were loaded into sample reservoirs in the bottom layer. For multiplex bacterial detection, the target gene-specific primers and probes were dried in each reaction chamber. The introduced samples and reagents could be equally aliquoted and dispensed into each reaction chamber by centrifugal force, and then the multiplex direct-RPA reaction was executed. The target genes of bacteria spiked in milk could be amplified at 39 degrees C without a DNA extraction step by using the direct-RPA cocktails, which were a combination of a direct PCR buffer and RPA enzymes. As the target gene amplification proceeded, the increased fluorescence signals coming from the reaction chambers were recorded in real-time at an interval of 2 min. The entire process, including the sample distribution, the direct-RPA reaction, and the real-time analysis, was accomplished with a custom-made portable genetic analyzer and a miniaturized optical detector. Monoplex, duplex, and triplex food poisoning bacteria (Salmonella enterica, Escherichia coli O157:H7, and Vibrio parahaemolyticus) detection was successfully performed with a detection sensitivity of 4 cells per 3.2 MUL of milk samples within 30 min. By implementing the direct-PRA on the miniaturized centrifugal microsystem, the on-site food poisoning bacteria analysis would be feasible with high speed, sensitivity, and multiplicity. PMID- 27216300 TI - Assessment of Surgery Residents' Interpersonal Communication Skills: Validation Evidence for the Communication Assessment Tool in a Simulation Environment. AB - OBJECTIVES: Although development of trainees' competency in interpersonal communication is essential to high-quality patient-centered surgical care, nontechnical skills present assessment challenges for residency program directors. The Communication Assessment Tool (CAT) demonstrated internal reliability and content validity for general surgery residents, though the tool has not yet been applied in simulation. The study provides validation evidence for using the CAT to assess surgical residents' interpersonal communication skills in simulation scenarios. DESIGN: Simulations of delivering bad news were completed by 21 general surgery residents during a mandatory communication curriculum. Upon completion of the 10-minute scenario, standardized participants (SPs) assessed performance using the 14-item CAT rating scale and individually provided feedback to residents. Discrete communication behaviors were recorded on video review by a trained blinded observer. The traits emotional intelligence questionnaire short form (TEIQue-SF) was completed by the residents 6 months later. SP-CAT ratings are evaluated with respect to learner characteristics, observed behaviors, and TEIQue results. SETTING: Surgical simulation center in a 900-bed tertiary care hospital. PARTICIPANTS: General surgery residents were targeted learners. Trauma survivors network volunteers served as SPs, acting as a family member of a patient who developed an intracerebral hemorrhage following a small bowel procedure. RESULTS: Discrete communication behaviors were reliably assessed by the observer (interrater reliability with trainer: 89% agreement, kappa = 0.77). SP-CAT ratings ranged from 34 to 61. Higher SP-CAT ratings were correlated with positive communication behaviors (Spearman rho = 0.42, p = 0.056). Total TEIQue was positively related to SP-CAT ratings (rho = 0.42, p = 0.061). The TEIQue emotionality factor was strongly correlated with SP-CAT ratings (rho = 0.52, p = 0.016). CONCLUSIONS: The CAT demonstrates content validity in a simulation environment with former patients acting as SPs. This study provides validation evidence relating the SP-CAT to discrete observations of communication behaviors by a trained, reliable observer as well as residents' self-reported emotional intelligence traits. PMID- 27216301 TI - National Orthopedic Residency Attrition: Who Is At Risk? AB - BACKGROUND: National U.S. orthopedic resident attrition rates have been historically low, but no literature exists as to the characteristics of those who leave nor the circumstance of the departure. We aimed to determine factors that may place a resident at higher risk for attrition. Additionally, we planned to determine whether the 2003-work hour restriction affected attrition rate. MATERIALS AND METHODS: All orthopedic surgery residency program directors in the United States were surveyed on demographic data for their current resident class, the number of residents who left the program, as well as demographic description for each of the residents who left their program from 1998 to 2013. Exclusion criteria included military programs and those younger than 3 years. All data were deidentified and compared to the Accreditation Council for Graduate Medical Education Data Resource book to protect against sample error in respondents. RESULTS: Of 146 programs included, the overall response rate was 54% of residency directors, representing 51% of orthopedic residents. The respondent demographic make-up of 13.7% female, and average program size of 22.3 residents, compared similarly to the Accreditation Council for Graduate Medical Education national average of 13% female and 23-resident program size. Compared to all respondents, residents who left their program were more likely to be female (27%, p = 0.0018), single (51%, p = 0.0028), and without children (80%, p = 0.0018). There was no statistical difference based on minority status or 2003-instituted work hour restriction. Of those who left, 45% transferred to another specialty, 34% were dismissed, 14% voluntarily withdrew or cited personal reasons, and 6% transferred to another orthopedic program. The most common specialties to transfer into were radiology (30%), emergency medicine (25%), and anesthesia (18%). CONCLUSIONS: Orthopedic residents who are female, single, or without children are statistically more likely to undergo attrition. Consideration could be given to targeted mentoring of these resident groups. PMID- 27216302 TI - A novel device for intraoperative cauterization of bleeding points in endoscopic sinus surgery. AB - Hemostasis is a critical point in endoscopic sinus and skull base surgery. A variety of techniques are presently available for reducing intraoperative bleeding; however, several limitations of the classical instruments should be stated. For example, reaching bleeding points in an anatomically angled site with straightforward bipolar devices could be quite difficult. With the aim of solving this problem, we developed a simple system using a standard curved suction tube, a rubber catheter and a monopolar system. This device provides an integrated suction function and is able to reach all paranasal and skull base areas, making it extremely useful in gaining precise access to the site of bleeding while providing excellent endoscopic vision. The described monopolar suction tube has proven to be a valid instrument for intraoperative hemostasis in endoscopic procedures; moreover, it does not add any further cost, making it applicable in particular healthcare settings, such as those in developing countries. PMID- 27216303 TI - Randomized study comparing inflammatory response after tonsillectomy versus tonsillotomy. AB - : To determine if there was a difference in the inflammatory reaction after tonsil surgery with "traditional" techniques (tonsillectomy and adenoidectomy or TA) compared to partial intracapsular tonsillectomy and adenoidectomy (PITA). DESIGN: Randomized, double-blind study. SETTING: tertiary care academic hospital. Children under the age of 16 years with a diagnosis of obstructive sleep disordered breathing were randomly allocated into three study groups: TA with electrocautery (n = 34), PITA with CO2 laser (n = 30) and PITA with debrider (n = 28). All of the children underwent adenoidectomy with a current at the same surgical procedure. MAIN OUTCOME MEASURE: c-reactive protein level (CRP) was the primary endpoint. In addition, the following were assessed: white blood cells (WBC), neutrophils (NEU), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). Pre- and post-procedure measurements were compared between the groups. Parents filled out a questionnaire daily during the first postoperative week assessing pain, swallowing and snoring. CRP levels ascended higher in the PITA groups after surgery (p = 0.023), WBC and NEU showed the same pattern, IL-6 levels were higher in PITA group and there was no difference in TNF-alpha levels between the two types of procedures. Postoperative pain and postoperative hemorrhage were significantly lower in the PITA groups as compared to the TA group (p = 0.01 and 0.048). PITA in comparison to TA is associated with lower morbidity; however, the inflammatory response does not differ significantly in the first 24 h after surgery. Additional long-term studies assessing efficacy of PITA are warranted. LEVEL OF EVIDENCE: Level 1, prospective randomized controlled trial. PMID- 27216304 TI - A New Class of Antibody-Drug Conjugates with Potent DNA Alkylating Activity. AB - The promise of tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADC) has now been realized, evidenced by the approval of two ADCs, both of which incorporate highly cytotoxic tubulin-interacting agents, for cancer therapy. An ongoing challenge remains in identifying potent agents with alternative mechanisms of cell killing that can provide ADCs with high therapeutic indices and favorable tolerability. Here, we describe the development of a new class of potent DNA alkylating agents that meets these objectives. Through chemical design, we changed the mechanism of action of our novel DNA cross-linking agent to a monofunctional DNA alkylator. This modification, coupled with linker optimization, generated ADCs that were well tolerated in mice and demonstrated robust antitumor activity in multiple tumor models at doses 1.5% to 3.5% of maximally tolerated levels. These properties underscore the considerable potential of these purpose-created, unique DNA interacting conjugates for broadening the clinical application of ADC technology. Mol Cancer Ther; 15(8); 1870-8. (c)2016 AACR. PMID- 27216305 TI - Susceptibility to human cancer: From the perspective of a pathologist. AB - The etiologies of human cancer can only be discerned when the genetic clustering of cancer occurs within a family or when cancer occurs endemically in a particular environment. The possible approaches to solving the nature/nurture problem, especially for human carcinogenesis, posit a fascinating challenge for pathologists. This perspective review presents some examples of how clues to human cancer etiologies and/or susceptibilities reside in the realm of pathology practice. These examples using various omics techniques including adductomics, which I would like to highlight in this article, show that the currently available concepts and methods in human pathology can open a path toward the brave new world of a post-genomic era of medicine for young pathologists, whether their original intention was toward the pursuit of diagnostic or investigative knowledge. PMID- 27216306 TI - [Benign colonic metaplasia of the umbilicus]. PMID- 27216307 TI - [Role of in vivo and ex vivo confocal microscopy and of optical coherence tomography as aids in the diagnosis of molluscum contagiosum]. PMID- 27216308 TI - [Excision of a subungual exostosis associated with a fibrokeratoma of the proximal nail matrix of the thumb (part II)]. PMID- 27216311 TI - A quantitative structure-property relationship (QSPR) study of singlet oxygen generation by pteridines. AB - The QSPR method is used in photochemistry for the prediction of the absorption wavelength, fluorescence intensity, photolysis quantum yield, etc. However, to our knowledge, no attempts have been made to use the quantum yield of singlet oxygen ((1)O2) generation (PhiDelta) as an analyzed parameter in a QSPR study. We performed QSPR analysis of 29 pteridine compounds (including pterin and flavin sensitizers) for their ability to produce singlet oxygen in aqueous (D2O) solutions. Pteridines are ubiquitously present in living systems (mostly as coenzymes), possess high photochemical activity and have multiple applications as photosensitizers. Our goal was to develop a QSPR model for the fast virtual screening and prediction of the (1)O2 generation quantum yield of pteridines. Quantum-chemical descriptors were calculated using the AM1 semi-empirical method. The ability of pteridines to generate singlet oxygen was found to be significantly correlated with the HOMO orbital energy (R(2) = 0.806) and electronegativity (R(2) = 0.840). The best QSPR model obtained using electronegativity, dipole density and electrostatic charge of the N3 atom of the pteridine system allows us to predict PhiDelta of pterin and flavin photosensitizers. The model possesses high internal stability (q(2) = 0.881), as well as high predicting ability for the external dataset (pred_R(2) = 0.873). More QSPR analysis is needed for the prediction of PhiDelta of pteridines and other groups of sensitizers in aqueous as well as in non-polar solutions. PMID- 27216309 TI - The type of the functional cardiovascular response to upright posture is associated with arterial stiffness: a cross-sectional study in 470 volunteers. AB - BACKGROUND: In a cross-sectional study we examined whether the haemodynamic response to upright posture could be divided into different functional phenotypes, and whether the observed phenotypes were associated with known determinants of cardiovascular risk. METHODS: Volunteers (n = 470) without medication with cardiovascular effects were examined using radial pulse wave analysis, whole-body impedance cardiography, and heart rate variability analysis. Based on the passive head-up tilt induced changes in systemic vascular resistance and cardiac output, the principal determinants of blood pressure, a cluster analysis was performed. RESULTS: The haemodynamic response could be clustered into 3 categories: upright increase in vascular resistance and decrease in cardiac output were greatest in the first (+45 % and -27 %, respectively), smallest in the second (+2 % and -2 %, respectively), and intermediate (+22 % and -13 %, respectively) in the third group. These groups were named as 'constrictor' (n = 109), 'sustainer' (n = 222), and 'intermediate' (n = 139) phenotypes, respectively. The sustainers were characterized by male predominance, higher body mass index, blood pressure, and also by higher pulse wave velocity, an index of large arterial stiffness, than the other groups (p < 0.01 for all). Heart rate variability analysis showed higher supine and upright low frequency/high frequency (LF/HF) ratio in the sustainers than constrictors, indicating increased sympathovagal balance. Upright LF/HF ratio was also higher in the sustainer than intermediate group. In multivariate analysis, independent explanatory factors for higher pulse wave velocity were the sustainer (p < 0.022) and intermediate phenotypes (p < 0.046), age (p < 0.001), body mass index (p < 0.001), and hypertension (p < 0.001). CONCLUSIONS: The response to upright posture could be clustered to 3 functional phenotypes. The sustainer phenotype, with smallest upright decrease in cardiac output and highest sympathovagal balance, was independently associated with increased large arterial stiffness. These results indicate an association of the functional haemodynamic phenotype with an acknowledged marker of cardiovascular risk. TRIAL REGISTRATION: ClinicalTrials.gov NCT01742702. PMID- 27216310 TI - Motile properties of the bi-directional kinesin-5 Cin8 are affected by phosphorylation in its motor domain. AB - The Saccharomyces cerevisiae kinesin-5 Cin8 performs essential mitotic functions in spindle assembly and anaphase B spindle elongation. Recent work has shown that Cin8 is a bi-directional motor which moves towards the minus-end of microtubules (MTs) under high ionic strength (IS) conditions and changes directionality in low IS conditions and when bound between anti-parallel microtubules. Previous work from our laboratory has also indicated that Cin8 is differentially phosphorylated during late anaphase at cyclin-dependent kinase 1 (Cdk1)-specific sites located in its motor domain. In vivo, such phosphorylation causes Cin8 detachment from spindles and reduces the spindle elongation rate, while maintaining proper spindle morphology. To study the effect of phosphorylation on Cin8 motor function, we examined in vitro motile properties of wild type Cin8, as well as its phosphorylation using phospho-deficient and phospho-mimic variants, in a single molecule fluorescence motility assay. Analysis was performed on whole cell extracts and on purified Cin8 samples. We found that addition of negative charges in the phospho-mimic mutant weakened the MT-motor interaction, increased motor velocity and promoted minus-end-directed motility. These results indicate that phosphorylation in the catalytic domain of Cin8 regulates its motor function. PMID- 27216312 TI - Validation of the Simbionix PROcedure Rehearsal Studio sizing module: A comparison of software for endovascular aneurysm repair sizing and planning. AB - An important determinant of successful endovascular aortic aneurysm repair is proper sizing of the dimensions of the aortic-iliac vessels. The goal of the present study was to determine the concurrent validity, a method for comparison of test scores, for EVAR sizing and planning of the recently introduced Simbionix PROcedure Rehearsal Studio (PRORS). Seven vascular specialists analyzed anonymized computed tomography angiography scans of 70 patients with an infrarenal aneurysm of the abdominal aorta, using three different sizing software packages Simbionix PRORS (Simbionix USA Corp., Cleveland, OH, USA), 3mensio (Pie Medical Imaging BV, Maastricht, The Netherlands), and TeraRecon (Aquarius, Foster City, CA, USA). The following measurements were included in the protocol: diameter 1 mm below the most distal main renal artery, diameter 15 mm below the lowest renal artery, maximum aneurysm diameter, and length from the most distal renal artery to the left iliac artery bifurcation. Averaged over the locations, the intraclass correlation coefficient is 0.83 for Simbionix versus 3mensio, 0.81 for Simbionix versus TeraRecon, and 0.86 for 3mensio versus TeraRecon. It can be concluded that the Simbionix sizing software is as precise as two other validated and commercially available software packages. PMID- 27216313 TI - "Corrupt" dietary guidelines must be rewritten to tackle obesity and diabetes, report warns. PMID- 27216314 TI - Relationships among pain intensity, pain-related distress, and psychological distress in pre-surgical total knee arthroplasty patients: a secondary analysis. AB - The current study aimed to examine the relationships between movement and resting pain intensity, pain-related distress, and psychological distress in participants scheduled for total knee arthroplasty (TKA). This study examined the impact of anxiety, depression, and pain catastrophizing on the relationship between pain intensity and pain-related distress. Data analyzed for the current study (N = 346) were collected at baseline as part of a larger Randomized Controlled Trial investigating the efficacy of TENS for TKA (TANK Study). Participants provided demographic information, pain intensity and pain-related distress, and completed validated measures of depression, anxiety, and pain catastrophizing. Only 58% of the sample reported resting pain >0 while 92% of the sample reported movement pain >0. Both movement and resting pain intensity correlated significantly with distress (rs = .86, p < .01 and .79, p < .01, respectively). About three quarters to two thirds of the sample (78% for resting pain and 65% for movement pain) reported different pain intensity and pain-related distress. Both pain intensity and pain-related distress demonstrated significant relationships with anxiety, depression, and catastrophizing. Of participants reporting pain, those reporting higher anxiety reported higher levels of distress compared to pain intensity. These findings suggest that anxious patients may be particularly distressed by movement pain preceding TKA. Future research is needed to investigate the utility of brief psychological interventions for pre-surgical TKA patients. PMID- 27216315 TI - Membrane phase characteristics control NA-CATH activity. AB - Our studies presented in this report focus on the behavior of NA-CATH, an alpha helical cathelicidin antimicrobial peptide, originally discovered in the Naja atra snake. It has demonstrated high potency against gram-positive and gram negative bacteria with minimal hemolysis. Here we examine the kinetics, behaviors and potential mechanisms of the peptide in the presence of membrane liposome, modeling Escherichia coli, whose membrane exhibits distinct lipid phases. To understand NA-CATH interactions, the role of lipid phases is critical. We test three different lipid compositions to detangle the effect of phase on NA-CATH's activity using a series of leakage experiments. From these studies, we observe that NA-CATH changes from membrane disruption to pore-based lysing, depending on phases and lipid composition. This behavior also plays a major role in its kinetics. PMID- 27216316 TI - On the dynamics of molecular self-assembly and the structural analysis of bilayer membranes using coarse-grained molecular dynamics simulations. AB - We present a molecular dynamics simulation study of the self-assembly of coarse grained lipid molecules from unbiased random initial configurations. Our lipid model is based on a well-tried CG polymer model with an additional potential that mimics the hydrophobic properties of lipid tails. We find that several stages of self-organization of lipid clusters are involved in the dynamics of bilayer formation and that the resulting equilibrium structures sensitively depend on the strength of hydrophobic interactions hc of the lipid tails and on temperature T. The obtained stable lipid membranes are quantitatively analyzed with respect to their local structure and their degree of order. At equilibrium, we obtain self stabilizing bilayer membrane structures that exhibit a bending stiffness kappaB and compression modulus KC comparable to experimental measurements under physiological conditions. We present a phase diagram of our lipid model which covers a sol-gel transition, a liquid (or gel-like) phase including stable bilayer structures and vesicle formation, as well as a quasi-crystalline phase. We also determine the exact conditions for temperature T and degree of hydrophobicity hc for stable bilayer formation including closed vesicles. PMID- 27216317 TI - Indoor radon measurements in south west England explained by topsoil and stream sediment geochemistry, airborne gamma-ray spectroscopy and geology. AB - Predictive mapping of indoor radon potential often requires the use of additional datasets. A range of geological, geochemical and geophysical data may be considered, either individually or in combination. The present work is an evaluation of how much of the indoor radon variation in south west England can be explained by four different datasets: a) the geology (G), b) the airborne gamma ray spectroscopy (AGR), c) the geochemistry of topsoil (TSG) and d) the geochemistry of stream sediments (SSG). The study area was chosen since it provides a large (197,464) indoor radon dataset in association with the above information. Geology provides information on the distribution of the materials that may contribute to radon release while the latter three items provide more direct observations on the distributions of the radionuclide elements uranium (U), thorium (Th) and potassium (K). In addition, (c) and (d) provide multi element assessments of geochemistry which are also included in this study. The effectiveness of datasets for predicting the existing indoor radon data is assessed through the level (the higher the better) of explained variation (% of variance or ANOVA) obtained from the tested models. A multiple linear regression using a compositional data (CODA) approach is carried out to obtain the required measure of determination for each analysis. Results show that, amongst the four tested datasets, the soil geochemistry (TSG, i.e. including all the available 41 elements, 10 major - Al, Ca, Fe, K, Mg, Mn, Na, P, Si, Ti - plus 31 trace) provides the highest explained variation of indoor radon (about 40%); more than double the value provided by U alone (ca. 15%), or the sub composition U, Th, K (ca. 16%) from the same TSG data. The remaining three datasets provide values ranging from about 27% to 32.5%. The enhanced prediction of the AGR model relative to the U, Th, K in soils suggests that the AGR signal captures more than just the U, Th and K content in the soil. The best result is obtained by including the soil geochemistry with geology and AGR (TSG + G + AGR, ca. 47%). However, adding G and AGR to the TSG model only slightly improves the prediction (ca. +7%), suggesting that the geochemistry of soils already contain most of the information given by geology and airborne datasets together, at least with regard to the explanation of indoor radon. From the present analysis performed in the SW of England, it may be concluded that each one of the four datasets is likely to be useful for radon mapping purposes, whether alone or in combination with others. The present work also suggest that the complete soil geochemistry dataset (TSG) is more effective for indoor radon modelling than using just the U (+Th, K) concentration in soil. PMID- 27216318 TI - Syphilis, a curable cause of acute polyarthritis. PMID- 27216320 TI - Arabidopsis Farms Colletotrichum tofieldiae for Phosphate Uptake. PMID- 27216319 TI - SUVH2 and SUVH9 Couple Two Essential Steps for Transcriptional Gene Silencing in Arabidopsis. AB - In Arabidopsis, an RNA-directed DNA methylation pathway (RdDM) is responsible for de novo establishment of DNA methylation and contributes to transcriptional gene silencing. Recently, the microrchidia (MORC)-type ATPases were shown to play essential roles in enforcing transcriptional gene silencing of a subset of genes and transposons by regulating the formation of higher-order chromatin architecture. However, how MORC proteins cooperate with the RdDM pathway components to regulate gene expression remains largely unclear. In this study, SUVH9 and MORC6 were identified from a screening of suppressors of idm1, which is a mutant defective in active DNA demethylation. SUVH9 and MORC6 are required for silencing of two reporter genes and some endogenous genes without enhancing DNA methylation levels. SUVH9, one of SU(VAR)3-9 homologs involved in RdDM, directly interacts with MORC6 and its two close homologs, MORC1 and MORC2. Similar to MORC6, SUVH9 and its homolog SUVH2 are required for heterochromatin condensation and formation of 3D chromatin architecture at SDC and Solo-LTR loci. We propose that SUVH2 and SUVH9 bind to the methylated DNA and facilitate the recruitment of a chromatin-remodeling complex to the target loci in association with MORC proteins. PMID- 27216321 TI - A 47-year-old woman with hypercapnia and altered mental status. AB - Permissive hypercapnia is a commonly used ventilator strategy in attempt to improve refractory hypoxemia. The rationale of such practice is based on the assumption that hypercapnia, although associated with altered mental status, is well tolerated. Here, we report a case in which the altered mental status caused by hypercapnia is underlined by a life-threatening mechanism. The case indicates the severity of hypercapnia may have been mistakenly overlooked in the past. PMID- 27216322 TI - Alternative Knowledges and the Future of Community Psychology: Provocations from an American Indian Healing Tradition. AB - In the early years of this globalized century, alternative health knowledges and wellness traditions circulate faster and farther than ever before. To the degree that community psychologists seek collaboration with cultural minority and other marginalized populations in support of their collective wellbeing, such knowledges and traditions are likely to warrant attention, engagement, and support. My purpose in this article is to trace an epistemological quandary that community psychologists are ideally poised to consider at the interface of hegemonic and subjugated knowing with respect to advances in community wellbeing. To this end, I describe an American Indian knowledge tradition, its association with specific indigenous healing practices, its differentiation from therapeutic knowledge within disciplinary psychology, and the broader challenge posed by alternative health knowledges for community psychologists. PMID- 27216323 TI - [Spirituality of children and adolescents - a neglected dimension in child and adolescent psychiatry and psychotherapy?]. PMID- 27216324 TI - [Prevention and prognosis of highly expressive violence among young people - a difficult challenge]. PMID- 27216325 TI - [School shootings by adult outsiders - psychiatric aspects and risk markers]. AB - Objective: Three cases of rampage killings at German schools by adult outsiders were identified and analyzed. The cases took place between 1913 and 1983. To what extent do psychiatric aspects play a role and are there risk factors that can be identified und used for prevention? Method: For the identification of risk factors the warning behavior typology was utilized which covers eight behavioral factors. Results: Severe mental problems were found in all three cases. The factors of the warning behavior typology were present in different relevance: Pathway (100 %), Fixation (100 %), Identification (33 %), novel aggression (33 %), energy burst (33 %), Leakage (66 %), last resort (66 %), directly communicated threat (0 %). Conclusions: The prevention of such cases seems to be most promising installing a regional and interdisciplinary threat management model. The field of threat management offers a scientific frame with evidence based tools and methods. PMID- 27216326 TI - [The NETWASS prevention model for early identification and assessment of adolescents in psychosocial crisis]. AB - The research-based NETWASS prevention model aims to enable school staff to identify students experiencing a psychosocial crisis that could lead to severe targeted school violence and to initiate appropriate support measures. A detailed analysis of the adolescent psychosocial crisis is conducted at an early stage by evaluating possible warning behaviors, crisis symptoms, a student's individual and social background, and resources. The model was implemented in 98 schools. During the project duration of seven months staff from 59 schools reported 99 cases of a student's psychosocial crisis. Three experts conducted a content analysis of the reported qualitative data focusing on crisis symptoms of the students as well as the initiated measures. Results show a broad spectrum of risk factors, whereas aggressive behavior of students was reported most frequently. On the basis of theoretical assumptions, the reported cases were divided into three distinct risk groups. A total of eight high-risk cases were observed and reported by the school staff. The school staff mostly reacted to the student crisis by initiating resource-orientated measures, the expertise of child and youth therapists was mostly requested for the high risk cases. By describing the impact of cases and choice of measures undertaken, the study aims to give an overview of incidents schools as well as clinical psychologists and therapists are confronted with. PMID- 27216327 TI - [Leaking: Frequency and correlates of announcements and threats of homicidal violence reported by Berlin schools between 1996 and 2007]. AB - Threats and announcements of homicidal violence at schools may have massive consequences like evacuations, police searches, criminal investigations, or loss of the sense of security by students, teachers, and parents. However, there is a lack of systematic studies about that phenomenon. The present article would like to contribute to closing the research gap. It presents results about the frequency and structure of threats and announcements of homicidal violence in schools in Berlin. The study is based on an official dataset from school administration reports of violent acts in Berlin schools which has been studied within the Berlin Leaking-Projekt. The sample consists of 427 threats and announcements of homicidal violence between 1996 and 2007. The study is an exceptional analysis of the phenomenon: it presents crosscutting results about frequency and characteristics of threats and the threatening students as well as results of a longitudinal analysis about the development of threats and announcements. Results show a rate of 0,3 threats and announcements per 1 000 student and year. During the observation time span a steady increase of threats and announcements - year by year, influenced by imitation effects after school shootings - has been observed. PMID- 27216328 TI - [Pilot study on the effectiveness of a multimodal group treatment for children with oppositional defiant disorder in clinical primary care]. AB - Aim: Pilot study on the effectiveness of a multimodal group treatment for children with oppositional defiant disorder in clinical primary care. Objective: Oppositional defiant disorder (ODD) is a frequent disorder in children and a common cause for referral to child psychiatric services. ODD consists of irritability, headstrongness and hurtful behaviours. The aim of the pilot study was to assess the effectiveness of combined cognitive-behavioural group interventions - the Baghira group training for the children and the Positive Parenting Program Triple P - in an outpatient child psychiatric service. Method: 42 children with ODD who attended the combined interventions were compared to 26 untreated probands in a waiting list control group. Externalizing problem behaviour, aggression and delinquency were assessed at treatment begin, treatment end and at the 6-month follow-up with questionnaires for the children, parents and teachers. Results: In comparison to the waiting list control group in the treatment group parent-reported externalizing problems decreased significantly between pre- and posttreatment assessment. A trend to significance was found for the decrease of teacher reported delinquency. Medium effect sizes were found and all effects were stable at follow-up. Conclusions: In this pilot study the combined interventions have shown to be effective in clinical primary care for the treatment of ODD and beneficial for the children and their families. For the assessment of the specific effectiveness of the Baghira group training further and larger studies are required. PMID- 27216329 TI - Effectiveness of the Prevention Program for Externalizing Problem Behavior (PEP) in Preschoolers with Severe and No or Mild ADHD Symptoms. AB - Objective: The prevention program for externalizing problem behavior (PEP), developed for parents and teachers of preschool children, showed the effectiveness of both modules (PEP-PA and PEP-TE) under routine care conditions in two separate studies. This secondary analysis examined the effects of both modules on preschool children with severe attention deficit/hyperactivity disorder (ADHD) symptoms compared with children with no or mild ADHD symptoms. Methods: In the within-subject control group, design changes in child symptoms and problem behavior in specific situations at home and school during the waiting period were compared with changes during the intervention period (3 months each). Results: For children with severe ADHD, parent training reduced specific problem situations at home (HSQ-D[please provide full name here]), and teacher training showed significant effects on oppositional-aggressive behavior as well as the total problem score of the Caregiver Teacher Report Form (C-TRF). Children with no or mild ADHD benefited from parent training on the HSQ-D score, oppositional aggressive behavior and the total problem score of the Child Behavior Checklist (CBCL), while teacher training had significant effects on all outcomes assessed. Conclusion: Our results suggest that parent training reduces mainly specific behavior problems at home in children with severe ADHD symptoms and with no/mild ADHD symptoms, while teacher training reduces ADHD symptoms and ODD[please provide full name here] symptoms including specific behavior problems in the kindergarten in children with no/mild ADHD symptoms. However, in children with severe ADHD only overall problems and ODD symptoms were significantly reduced by teacher Training. PMID- 27216330 TI - [Moving from a price system to a budget system]. PMID- 27216334 TI - Erratum to: 'Early versus late initiation of renal replacement therapy in critically ill patients with acute kidney injury (The ELAIN-Trial): study protocol for a randomized controlled trial'. PMID- 27216335 TI - A new oxidative stress marker for thiol-disulphide homeostasis in seasonal allergic rhinitis. AB - BACKGROUND: Reactive oxygen species has a crucial role in the pathogenesis of many diseases. Reactive oxygen species has been effectively documented in patients with asthma, but very little research has been reported in subjects with allergic rhinitis. OBJECTIVES: To investigate thiol (SH)-disulfide (SS) homeostasis, a new oxidative stress marker present in patients with seasonal allergic rhinitis (SAR). METHODS: A total of 64 subjects, including 32 patients with SAR and 32 healthy controls, were included in the study. We measured the SH levels as a marker of antioxidant protection and SS as a marker related to oxidant stress. Sera specimens were taken from patients with SAR during exacerbation and during asymptomatic time periods. In addition, sera samples from the control group were also obtained during the pollen season to compare with those from patients with SAR. RESULTS: In patients with SAR, during exacerbation periods, SH, SS, % SS/SH, % SS to total SH (TT), and % SH/TT were significantly different (p < 0.05) than in patients with SAR during asymptomatic periods. Although SS was significantly higher in patents with SAR during exacerbation periods, SH was significantly higher in patients with SAR during asymptomatic periods. Patients with SAR during asymptomatic periods and the control group did not significantly differ (p > 0.05) regarding SH, SS, TT, % SS/SH, % SS/TT, and % SH/TT. CONCLUSION: SAR is a disorder that elevates systemic oxidative stress and reduces antioxidant enzyme activities. Our results shed light on the etiopathogenesis of the disease and can help develop new therapeutic approaches. PMID- 27216336 TI - Chronic rhinosinusitis, endothelial dysfunction, and atherosclerosis. AB - BACKGROUND: Chronic inflammation is associated with accelerated atherosclerosis, endothelial dysfunction (ED), and cardiovascular diseases. Because chronic rhinosinusitis (CRS) is an inflammatory disease, it may be associated with the development of ED and accelerated atherosclerosis. OBJECTIVE: To investigate the relationship between CRS and carotid intima-media thickness (CIMT), flow-mediated dilation (FMD) of the brachial artery, and microalbuminuria. MATERIALS AND METHODS: This cross-sectional study included 38 patients with CRS and 29 healthy controls. In addition to measuring spot urine albumin-creatinine ratios, FMD of the brachial artery and CIMT were assessed noninvasively. RESULTS: Patients with CRS had lower FMD scores (p = 0.031), higher CIMT scores (p = 0.005), and a higher urinary albumin-creatinine ratio (p = 0.036) compared with healthy controls. In a multivariate analysis, CIMT and FMD were independently associated with the presence of CRS. However, the relationship between urinary albumin and creatinine, and the presence of CRS was no longer observed. CONCLUSIONS: CRS is associated with ED and atherosclerosis, as indicated by decreased FMD and increased CIMT in patients with CRS. Further studies are necessary to identify the exact pathophysiologic mechanisms responsible for our findings. PMID- 27216337 TI - Protective effects of melatonin and selenium against apoptosis of olfactory sensory neurons: A rat model study. AB - BACKGROUND: Selenium plays a role in the prevention of oxidative damage and has been linked to regulatory functions in cell growth, apoptosis, cell survival, and cytotoxicity. Melatonin has an antioxidant effect, which protects against a number of free radical species. Given its antioxidant properties, melatonin has been widely known to inhibit neuronal apoptosis. We examined the cytoprotective effects of melatonin and selenium in rat olfactory sensory neurons after rhinosinusitis by immunohistochemical evaluation of olfactory bulb mucosa. METHODS: Rhinosinusitis was induced bilaterally in 24 animals. Twenty-four rats were randomly divided into three equal groups. The melatonin group was treated with intraperitoneal (i.p.) melatonin and ampicillin-sulbactam, the selenium group was treated with i.p. selenium and ampicillin-sulbactam, the antibiotic group was treated with i.p. ampicillin-sulbactam; all three groups were treated for 10 days. After a period of 10 days of treatment, the animals were killed for immunohistochemical analyses. All olfactory bulb mucosae were removed immediately. RESULTS: No histochemical differences were found in the three groups. Terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick end labeling-positive cells were detected in each group. In the antibiotic group, the appearance of apoptotic cells was higher, whereas the number of apoptotic cells significantly decreased in the melatonin group. When compared with the selenium group, fewer terminal deoxynucleotidyl transferase 2' deoxyuridine 5'-triphosphate nick end labeling-positive cells were observed in the melatonin group, which was not significant. In the antibiotic group, the cytoplasmic active caspase-3 and Bax immunostaining in the olfactory epithelium and glandular cells of stroma were higher when compared with the immunostaining in melatonin and selenium groups. Active caspase-3 and Bax immunostaining in the subepithelial stroma was dramatically reduced in the melatonin group. In contrast, the staining intensity and the number of Bcl-2 immunopositive cells were significantly increased in the melatonin group. In the selenium group, Bax and active caspase-3 were moderately immunopositive in the epithelium and subepithelial stroma. However, Bcl-2 immunostaining was more pronounced in the olfactory epithelium and some stromal cells. CONCLUSION: Our results indicated the possibility that the supplementation of melatonin and selenium, two antioxidant agents for the treatments in the rhinosinusitis rat model, might be reduced or prevent anosmia. PMID- 27216338 TI - Asthma in ear, nose, and throat primary care patients with chronic rhinosinusitis with nasal polyps. AB - BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common inflammatory disorder associated with asthma. This association is well described in patients with CRSwNP undergoing endoscopic sinus surgery (ESS); however, some patients are never referred for surgery, and the frequency of asthma in this group is largely unknown. OBJECTIVE: To determine the frequency of asthma in patients with CRSwNP treated in a primary care (PC) setting who have never been referred for surgery and to compare this with ESS patients. METHODS: Fifty-seven patients with CRSwNP who had never undergone ESS were prospectively recruited from nine PC ear, nose, and throat clinics in the Copenhagen area. CRSwNP was diagnosed according to the European Position Paper on Chronic Rhinosinusitis and Nasal Polyps; severity was assessed by using a visual analog scale. Allergy, lung function, and asthma tests (reversibility to beta2-agonist, peak expiratory flow variability, and mannitol challenge) were performed. Findings were compared with our previously published data from patients with CRSwNP referred for surgery. RESULTS: Asthma was diagnosed in 25 patients (44%) based on respiratory symptoms and a positive asthma test; of these, 12 (48%) had undiagnosed asthma prior to study onset. Furthermore, when using the same methods, we found a lower frequency of asthma in PC patients compared with ESS patients (44% versus 65%, p = 0.04). CONCLUSION: A high prevalence of asthma in PC patients with CRSwNP was found. Frequently, asthma was undiagnosed. However, asthma was significantly less prevalent in PC patients compared with patients referred for ESS. The frequent concomitance of asthma, i.e., united airways disease, in PC patients calls for closer collaboration between ear, nose, and throat specialists, and asthma specialists. PMID- 27216339 TI - Prevalence and allergen of allergic rhinitis in Korean children. AB - BACKGROUND: In recent decades, the amount of data about allergic rhinitis (AR) in Korean National Health Insurance Service has increased. OBJECTIVE: To investigate the prevalence and quality of sensitized allergens of AR in Korean children and adolescents. METHODS: This study obtained the results of the Korean International Study of Asthma and Allergies in Childhood questionnaires and the skin-prick test (SPT) results of 14,356 students who participated in a health screening from 2010 to 2014. AR was defined as one with current symptoms of AR with at least one or more positive results of an SPT with inhalant allergens. RESULTS: The prevalence of AR in children was 20.8%. Positive rates of the allergen group were 87.3% for house-dust mites, 37.0% for pollen, 12.4% for mold, and 8.4% for pets. The common allergens in descending order were Dermatophagoides pteronyssinus, Dermatophagoides farinae, Betula, Humulus, Alnus, and Alternaria. As the children became older, pollen-sensitization rates tended to increase (p value for trends, <0.001). In metropolitan and middle inland areas, weed pollen was the most common pollen. The rates of tree-pollen sensitization were the highest at the seaside and in the southern inland. The most common comorbid allergic diseases associated with AR were pollen allergy and allergic conjunctivitis at 37.0% and 34.5%, respectively. CONCLUSIONS: This was the first study conducted in Korea to investigate the prevalence of AR in the general population by using both questionnaires and SPTs. The allergens used for the SPTs were chosen based on the common allergens in this study, and this current pollen data will contribute to establish the cause of increasing AR prevalence in Korea. PMID- 27216340 TI - Prevalence of rhinitis and associated factors in schoolchildren who live in the Amazon islands. AB - BACKGROUND: The prevalence of rhinitis has been reported to be higher in urban areas. OBJECTIVE: To determine the prevalence of rhinitis in schoolchildren who lived on two islands in the Brazilian Amazon, including a rural island and an urban island, and to identify the associated risk factors. METHODS: Four hundred children (200 per island) were evaluated by using the International Study of Asthma and Allergy in Childhood standard written questionnaire (rhinitis module). A convenience sample for both islands was selected based on the age group of the study (5-8 years). The children were assessed for potential risk factors (complementary written questionnaire) identified by logistic regression. RESULTS: The prevalence of active rhinitis was significantly higher in the children who lived on Outeiro Island compared with Combu Island (34.5% versus 18.0%, respectively). The associated risk factors for rhinitis symptoms on Combu Island included parental history of rhinitis (odds ratio [OR] 9.4 [95% confidence interval {CI}, 2.1-41.4]) and delivery by caesarean-section (OR 5.2 [95% CI, 1.2 21.9]), and for Outeiro Island included parental history of rhinitis (OR 4.5 [95% CI, 1.7-11.2]) and of asthma (OR 3.8 [95% CI, 1.5-9.8]), nocturnal cough in the previous year (OR 5.8 [95% CI, 2.1-16.0]), breast-feeding (>=6 months) (OR 9.6 [95% CI, 1.1-82.1]), moisture (OR 2.4 [95% CI, 0.9-6.4]), and consumption of fruit juice more than two times a week (OR 4.3 [95% CI, 1.2-15.0]). CONCLUSION: The different risk factors identified for rhinitis on each island indicated the role of the urban environment in the development of the disease. PMID- 27216341 TI - Skin diseases of the nose. AB - OBJECTIVES: The goal of this study was to review the main lesion types of the nasal skin and appropriate treatment strategies rather than to present a comprehensive list of all diseases that affect the skin that can involve the nose. METHODS: We reviewed the main nasal skin lesion types and available treatment strategies. Nasal skin lesions were classified as benign, premalignant, or malignant. RESULTS: Benign lesions of the nose include nonmalignant tumoral lesions (i.e., freckles, comedo, adenoma sebaceum [Pringle disease], hydrocystoma, fibrous papules, sebaceous hyperplasia, and rhinophyma), autoimmune and inflammatory conditions (i.e., pemphigus, sarcoidosis, systemic lupus erythematosus, facial eosinophilic granuloma, rosacea, herpes zoster infection, leishmaniasis, and leprosy), and vascular lesions (i.e., telangiectasis, hemangioma, and spider nevus). Premalignant lesions are actinic keratosis and keratoacanthoma; and malignant tumors are melanoma, basal cell carcinoma, and squamous cell carcinoma. Regardless of whether or not they are malignant, all facial lesions can yield significant cosmetic discomfort that should be evaluated carefully before commencing any curative or corrective intervention. In general, benign lesions are treated with dermabrasive modalities, such as trichloroacetic acid, phenol, salicylate, and laser ablation. Electrocautery, cryosurgery, and surgical excision are also used, although these methods may result in scar formation, which can sometimes be more problematic than the original lesion itself. CONCLUSION: Any disease that affects the skin, especially those diseases that are triggered by ultraviolet exposure, can involve the face and nose. Cosmetic defects due both to the lesion itself and the intervention must be discussed with the patient, preferably in the presence of a first-degree relative, before commencement of treatment. As a result of heterogeneity of skin lesions of the nose, appropriate education of general practitioners as well as otorhinolaryngologists is mandatory. PMID- 27216342 TI - Electrocauterization and no packing may be comparable with nasal packing for postoperative hemorrhage after endoscopic sinus surgery. AB - BACKGROUND: Nasal packing is commonly performed after functional endoscopic sinus surgery (FESS). However, nasal packing is associated with higher cost (owing to the cost of packing materials), patient discomfort, delayed wound healing, and concern about toxic shock syndrome. Some surgeons have been performing FESS without packing, but there are few studies that show its safety. OBJECTIVE: The purpose of this study was to evaluate the safety of electrocauterization and no packing. METHODS: A total of 490 patients who underwent bilateral FESS for chronic rhinosinusitis were included in this retrospective study, 242 in the nasal packing group and 248 in the electrocauterization and no-packing group. Electrocauterization was performed by using a suction coagulator. Rates of immediate (first 24 hours after surgery) and delayed postoperative bleeding were compared. Patient characteristics, including concomitant disease and medication history, and Lund-Mackay computed tomography score were also assessed Results: There were no significant differences in age; sex; Lund-Mackay score; use of anticoagulant drugs; or prevalence of hypertension, diabetes, or asthma between the two groups. In the electrocauterization and no-packing group, there were fewer patients with allergic rhinitis and more smokers. Primary bleeding did not occur in the nasal packing group, but 11 patients (4.4%) had delayed bleeding. Primary bleeding occurred in four patients (1.7%) in the electrocauterization and no-packing group, and five patients (2.1%) had delayed bleeding. There were no significant differences in primary (p = 0.058) and secondary bleeding (p = 0.142) between the two groups. All bleeding was minor and easily controlled. Multivariate logistic regression analysis ruled out significant correlation between no packing and postoperative bleeding. CONCLUSION: This study provided evidence that, in terms of postoperative hemorrhage, the safety of the electrocauterization and no-packing technique after FESS was comparable with that of nasal packing. PMID- 27216343 TI - Endoscopic repair of bilateral choanal atresia, starting with vomer resection: Evaluation study. AB - BACKGROUND: Choanal atresia is the most common inborn nasal anomaly, and its definitive treatment is surgical to achieve proper bilateral nasal patency. Four main surgical approaches were used for repair: transantral, transpalatal, transseptal, and transnasal. The transnasal endoscopic approach is the most widely accepted nowadays. In this study, we aimed to evaluate the long-term results of a transnasal endoscopic repair of congenital choanal atresia started with resection of the posterior portion of the vomer and was completed without the use of stents in a large series of patients. METHODS: Twenty-five patients (age range, 3-15 days) with bilateral congenital choanal atresia had surgery by using stentless endoscopic transnasal repair by starting with resection of the vomer bone. Postoperative control included office fiberoptic nasal endoscopy. RESULTS: During the follow-up period of 15-66 months (mean [standard deviation], 35.76 +/- 16.8 months), 18 patients (72%) had a wide choana with adequate nasal breathing; Six patients (24%) had narrowing of the choana (<50%), still with adequate and satisfactory airway without feeding difficulties, and one patient (4%) developed restenosis (>50%) after 7 months, which necessitated repeated surgery. One patient (the fourth case) developed a palatal defect, which healed conservatively. No other complications were detected. CONCLUSION: The described technique proved to be effective and easier, with good long-term satisfactory results in a large series of patients. This technique allows early use of both nasal passages for simultaneous endoscope and instrument insertion to excise both atretic plates without the use of stents or flaps. PMID- 27216344 TI - Immunorhinology and rhinosinusitis: Where are we heading? PMID- 27216345 TI - A systematic review of the sinonasal microbiome in chronic rhinosinusitis. AB - BACKGROUND: The interaction between the host and microorganisms in chronic rhinosinusitis (CRS) is poorly understood and is a growing area of interest. More recently, methodologies have been developed to assess the microbiome without the use of culture by analyzing the bacterial 16S ribosomal RNA gene. We reviewed the microbiome literature to better understand the role of microbes in CRS. METHODS: Systematic review of studies that used the 16S ribosomal RNA gene deep sequencing. RESULTS: Nine publications met the search criteria. Eight studies evaluated the microbiome in controls (total, 83 subjects; range, 3-28 per study), whereas six of the studies included patients with CRS (total, 121 patients; range, 7-43 per study). Various sequencing techniques, primers, sample sites, and extraction methods were used. Of the articles that specified the number of taxa in controls, an average of 1587 taxa were identified (range, 911-2330). Significant heterogeneity was noted among the studies; however, Firmicutes, Actinobacteria, and Bacteroides phyla were identified in every sample of control patients and patients with CRS. Three of the studies showed enrichment to some degree of Staphylococcus aureus in patients with CRS. The total bacterial burden in CRS was similar to the controls. One study demonstrated a decrease in diversity, whereas other studies did not show any changes in CRS when compared with controls. CONCLUSION: Although there are common phyla present in both control patients and patients with CRS, no consistent enrichment of any particular taxon was identified. Our findings indicated that there was no clear single causative microbe in CRS. More studies are needed to better understand the significance of the host interaction with the microbiome and the role it plays in CRS. PMID- 27216346 TI - HMGB1-TLR4 signaling contributes to the secretion of interleukin 6 and interleukin 8 by nasal epithelial cells. AB - BACKGROUND: Alarmins play important roles in the pathogenesis of inflammatory and autoimmune diseases. However, the role of the alarmin protein high-mobility group box 1 (HMGB1) in upper airway inflammation is unclear. OBJECTIVE: To determine if HMGB1 is present in the nasal mucosa and, if so, to elucidate its role in upper airway inflammation. METHODS: Nasal secretions were collected from a total of 32 patients with chronic rhinosinusitis with nasal polyp, allergic rhinitis, and control subjects. The concentration of HMGB1 in nasal secretions and its tissue and cellular localization were examined by enzyme immunoassays and immunofluorescent staining of nasal polyps and cultured nasal epithelial cells. We then examined whether nasal epithelial cells secrete HMGB1 after inflammatory stimulation by tumor necrosis factor (TNF) alpha. The effects of HMGB1 on the production and secretion of interleukin (IL) 6 and IL-8 were also examined in cultured nasal epithelial cells. RESULTS: Significantly higher concentrations of HMGB1 were found in nasal secretions from patients with chronic rhinosinusitis with nasal polyp or allergic rhinitis compared with the control subjects. HMGB1 expression was localized in the nuclei of epithelial cells and other constitutive cells in nasal polyps and in the nuclei of cultured nasal epithelial cells. TNF alpha stimulated the production and secretion of HMGB1 by cultured nasal epithelial cells. HMGB1 stimulated the production and secretion of IL-6 and IL-8 by cultured nasal epithelial cells, and anti-toll-like receptor 4 blocking antibody significantly inhibited HMGB1-induced secretion of IL-6 and IL-8. CONCLUSIONS: Nasal secretions contain substantial amounts of HMGB1. TNF-alpha stimulates the production of HMGB1, which, in turn, upregulates the production and secretion of IL-6 and IL-8 by nasal epithelial cells via toll-like receptor 4, which indicated that HMGB1 plays an important role in the pathogenesis of upper airway inflammation. PMID- 27216347 TI - Decreased expression of E-cadherin and ZO-1 in the nasal mucosa of patients with allergic rhinitis: Altered regulation of E-cadherin by IL-4, IL-5, and TNF-alpha. AB - BACKGROUND: Allergic rhinitis is a chronic nasal inflammatory disease mediated by an immunoglobulin E mediated process to environmental allergens. Although atopy is a potent predisposing risk factor for allergic rhinitis, local tissue susceptibilities are inevitable for disease expression. The nasal epithelium maintains tissue homeostasis by providing a physical barrier controlled by epithelial junctional proteins. However, the expression of epithelial junctional proteins has not been studied in patients with allergic rhinitis. We sought to elucidate the expression and the regulation of epithelial junctional proteins in the nasal epithelium of patients with allergic rhinitis. METHODS: The expression of E-cadherin and zonula occludens (ZO) 1 in epithelium of turbinate was measured by using real-time polymerase chain reaction, Western blot, and immunohistochemical assays, and was compared between control subjects and patients with allergic rhinitis. In addition, the expression levels of E-cadherin and ZO-1 were determined in cultured epithelial cell treated with interleukin (IL) 4, IL-5, tumor necrosis factor (TNF) alpha, and interferon gamma. RESULTS: The expression and the immunoreactivity of E-cadherin and ZO-1 were decreased in the nasal epithelium of patients with allergic rhinitis. Interestingly, the stimulation of cultured epithelial cells with IL-4, IL-5, and TNF-alpha resulted in downregulation of E-cadherin expression only in cultured epithelial cells of patients with allergic rhinitis, whereas E-cadherin expression in cultured epithelial cells of controls was not affected by stimulation with the same panel of cytokines. CONCLUSION: Decreased expression of epithelial junctional proteins was found in patients with allergic rhinitis. The disruption of epithelial integrity by IL-4, IL-5, and TNF-alpha in vitro indicated a possible role for these cytokines in the pathogenesis of patients with allergic rhinitis. PMID- 27216348 TI - Investigation of asthma comorbidity in children with different severities of allergic rhinitis. AB - BACKGROUND: Allergic rhinitis (AR) and asthma comorbidity is widely seen. However, the effects of AR on asthma are more likely to be studied in the literature. OBJECTIVE: To investigate the prevalence of asthma in children with AR who are followed-up and to evaluate the effect of asthma on the severity of AR. METHODS: A total of 509 children with AR who were followed-up in the pediatric allergy-immunology department between January 2012 and December 2013 were enrolled in the study. Asthma and AR are diagnosed by using the Global Initiative for Asthma and the Allergic Rhinitis and its Impact on Asthma, respectively. The patients were categorized into two groups according to the presence of asthma. The two groups were compared according to sociodemographic characteristics, clinical features, and laboratory findings. Skin-prick test results, serum immunoglobulin E levels, and the percentage of eosinophils of the patients were evaluated. RESULTS: A total of 299 of the patients were boys (58.7%) the mean age was 7.2 +/- 3.5 years (range, 1.5-18 years). Patients with moderate-severe persistent rhinitis (40.5% of all patients) were the most common rhinitis subgroup. Mild intermittent rhinitis was diagnosed in 17.7%, mild persistent rhinitis in 11.2%, and moderate-severe intermittent rhinitis in 30.6% of the patients. Two hundred seventy-one children with AR (53.2%) also had concomitant asthma. The patients were categorized into two groups: AR-asthma comorbidity group (group I) and AR-only group (group II). There was no significant difference between these two groups when compared with the sex, age, familial atopy, exposure to smoke, and severity of AR (p > 0.05). The duration of illness, immunoglobulin E levels, number of positive sensitivity, sensitivity to house-dust mites, sensitivity to cockroaches, and polysensitization were significantly higher in the AR-asthma comorbidity group (p < 0.05). CONCLUSION: This study showed that asthma comorbidity had no effect on the severity of AR. However, it was also shown that the majority of children with AR had asthma comorbidity. For these purposes, the presence of asthma should be investigated in children with AR, independent of severity. PMID- 27216349 TI - Two-dimensional assessment of the nasal valve area cannot predict minimum cross sectional area or airflow resistance. AB - BACKGROUND: Clinicians who manage nasal obstruction often comment on the shape and size of the nasal valve (NV) area. However, correlation of the symptoms of obstruction, nasal airflow dynamics, and the endoscopic appearance of the anatomic cross-sectional area of the NV is poorly understood. Endoscopic imaging and calculation of the NV area is investigated as a tool for either clinical or research use. OBJECTIVE: To describe and evaluate a two-dimensional measurement of the minimum cross-sectional area (MCA) of the NV by using endoscopic imaging. METHODS: A cross-sectional study of patients with symptoms of nasal obstruction who were undergoing nasal assessment was performed. The NV was measured with digital imaging taken from the endoscopy. Adobe Photoshop was used to calculate the digital MCA of the NV based on pixel count and a reference marker placed in the image field. Airway parameters were assessed by using a nasal obstruction visual analog scale, nasal airway resistance via rhinomanometry, and acoustic rhinometry derived MCA (acoustic MCA). Correlation of the digital MCA and airway parameters was made and interobserver correlation of the MCA measures was calculated. RESULTS: Thirty-three nasal airways were assessed: mean (standard deviation) digital MCA (0.28 +/- 0.13 cm(2)) and mean (standard deviation) acoustic MCA (0.51 +/- 0.15 cm(2)). Correlation of the digital MCA with visual analog scale was poor (Pearson r = 0.10, p = 0.56). Similar finding between digital and acoustic MCA was poor (Pearson r = 0.50, p = 0.56, respectively) despite a moderately strong interobserver correlation for the digital MCA (Pearson r = 0.79, p < 0.001). CONCLUSION: Qualitative endoscopic assessment of the NV may help clinicians predict NV dysfunction but simple two-dimensional measures seemed to be of limited value in accurately assessing the three dimensional NV quantitatively. PMID- 27216350 TI - Does oxymetazoline increase the efficacy of nasal steroids in treating nasal polyposis? AB - BACKGROUND: Although nasal steroids are the mainstay treatments in nasal polyposis, up to one-half of patients do not respond and need surgical treatment. This study aimed to evaluate whether oxymetazoline administration produces any additive effect on nasal steroid therapy and whether rebound congestion develops after oxymetazoline treatment. METHODS: Sixty-eight patients with nasal polyposis were randomly assigned in a 1:1 ratio to receive either oxymetazoline plus mometasone furoate nasal spray (MFNS) or placebo plus MFNS, 2 sprays per nostril twice daily, with an interval of 5 minutes between each medication for 4 weeks. All the patients were then treated with MFNS, 2 sprays per nostril twice daily for 2 weeks. The nasal symptoms score, peak inspiratory flow index, nasal mucociliary clearance time (NMCCT), and total nasal polyps score were used to evaluate treatment outcomes. An intention-to-treat analysis was performed, and a worst case sensitivity analysis was applied to missing cases. RESULTS: Thirty four patients were allocated to the oxymetazoline-MFNS group, and 34 to the placebo-MFNS group. One patient in each group was lost to last-visit follow-up. At 4 weeks after beginning treatment, the oxymetazoline-MFNS group showed significantly greater improvement in blocked nose, hyposmia, peak flow, NMCCT, and total nasal polyps score than the placebo-MFNS group. During the nasal steroid phase, both groups showed continuing improvement in all outcome variables. However, the oxymetazoline-MFNS group still showed significantly greater improvement in blocked nose, hyposmia, NMCCT, and total nasal polyps score, but not peak flow, than the placebo-MFNS group at the end of the study. CONCLUSION: The use of nasal steroids with oxymetazoline was more effective over 6 weeks than nasal steroids alone in improving blocked nose, hyposmia, nasal mucociliary clearance, and polyp size in treatment of nasal polyposis. There was no evidence of rebound congestion after 4 weeks of oxymetazoline treatment. PMID- 27216351 TI - Semi-depot house-dust mite allergen extract for Chinese with allergic rhinitis and asthma. AB - BACKGROUND: Real-world data of the subcutaneous immunotherapy (SCIT) with semi depot house-dust mite (HDM) allergen extract (a HDM allergen extract that contains a 50%-50% mixture of Dermatophagoides pteronyssinus and Dermatophagoides farina) for allergic rhinitis and asthma was unavailable in China until recently. AIM: To investigate the effectiveness and safety of a HDM-SCIT for allergic rhinitis and asthma in Chinese patients. METHODS: A multicenter, single-arm, open label, self-controlled study. Chinese patients with allergic rhinitis or allergic asthma and with a history of symptoms from HDM exposure were included and received allergen-specific immunotherapy for 1 year by subcutaneous injection of HDM-SCIT. The primary outcome measure was the percentage of patients with an improvement in symptom severity assessed at 12 months after initiation of the treatment. The occurrence of adverse events and compliance of treatment were also evaluated. RESULTS: A total of 272 outpatients were included for effectiveness analysis. The subject-evaluated improvement rate in the visual analog scale (VAS) was 76.1% and 71.3% at 6 and 12 months, respectively; corresponding values for investigator-evaluated VAS were 77.9% and 71.7%, respectively (p < 0.0001). Symptom score changes were -2.43 and -3.79 at 6 and 12 months, respectively (both p < 0.0001); the VAS improvement rate and symptom score change did not differ significantly between children and adolescents and/or adults. Good injection schedule adherence was found in 98.8% of the patients. No study drug-related serious adverse events or serious systemic allergic reactions occurred. CONCLUSION: HDM-SCIT was safe and effective in the treatment of allergic rhinitis and asthma in a Chinese population, with good compliance. PMID- 27216352 TI - Attention-deficit/hyperactivity disorder-related symptoms improved with allergic rhinitis treatment in children. AB - BACKGROUND: Increased prevalence of attention-deficit/hyperactivity disorder (ADHD) in children with allergic rhinitis (AR) has been reported. Our previous study showed that children with untreated AR had higher ADHD scores than did the controls. OBJECTIVE: This prospective follow-up study aimed to investigate whether elevated ADHD scores in children with AR could be decreased by AR treatment. METHODS: Sixty-eight children with AR (age range, 6-14 years) and who were drug naive were enrolled and evaluated by AR symptom score, ADHD symptom scores, and computerized continuous performance test, before and after AR therapy, which included nonpharmacologic intervention, oral antihistamines, and topical steroids. Thirty-one age-matched controls and 13 children with pure ADHD were also enrolled for comparison. The relationship between the AR and ADHD score change was analyzed by a partial correlation test, and univariate and multivariate linear regression models were applied to investigate possible predictors for the improvement of ADHD scores by AR treatment. RESULTS: AR symptom scores in children with AR decreased significantly after treatment (p < 0.001), and their ADHD scores also decreased significantly (p < 0.001). An improved AR symptom score was positively correlated with improved detectability (rp = 0.617, p = 0.001) and commission error (rp = 0.511, p = 0.011). Significant predictors for the improvement of ADHD scores included age, AR drugs, AR subtypes, and multiple atopic diseases (ps < 0.05). CONCLUSION: Higher ADHD scores in children with AR compared with healthy controls decreased significantly with AR treatment. For children with AR and borderline ADHD symptoms, who do not meet full ADHD diagnostic criteria, we recommend initially treating their AR and monitoring improvement of ADHD symptoms. PMID- 27216353 TI - Intranasal corticosteroid therapy in the treatment of obstructive sleep apnea: A meta-analysis of randomized controlled trials. AB - AIM: To assess the efficacy of intranasal corticosteroid therapy in the treatment of obstructive sleep apnea (OSA) based on current evidence. METHODS: A number of medical literature data bases: PubMed, Cochrane Library, Scopus, and CINAHL, were searched comprehensively to identify randomized controlled trials (RCT) that reported on the efficacy of intranasal corticosteroid therapy for OSA. The selected studies were subjected to a meta-analysis and a risk-of-bias assessment. RESULTS: Seven RCTs met our eligibility criteria, five of these were included in our meta-analysis. The results indicated that intranasal corticosteroid therapy has a better effect in decreasing the apnea-hypopnea index compared with those participants who received placebo (standard mean difference 0.95 [95% confidence interval, -1.42 to -0.47]) (n = 221, I(2) = 62%). CONCLUSION: Our study results showed that patients who received intranasal corticosteroid therapy had a significant improvement in OSA. However, this evidence was limited by the potential risk of bias and heterogeneity of the selected RCTs. PMID- 27216354 TI - The effects of a cold pack on postoperative turbinate and/or septal bleeding and pain. AB - BACKGROUND: The objective of this study is to evaluate the effects of a cold pack in postoperative turbinate and/or septal surgery in terms of postoperative bleeding control, pain management, and patient preference for or against application of a cold pack. METHODS: A randomized controlled trial was done at the Department of Otolaryngology, King Chulalongkorn Memorial Hospital, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. Ninety-nine adult subjects intending to have turbinate and/or septal surgery were consecutively enrolled in this study. Intervention was randomized into two groups. Postoperative bleeding was collected by paper tissue and weighed to determine amount and/or volume of blood loss. Postoperative pain was measured by using the visual analog scale. Patient preference for or against the use of a cold pack was also assessed. RESULTS: The mean (standard deviation) postoperative bleeding in the cold pack group was 1.31 +/- 1.50 g compared with 1.81 +/- 1.89 g in the control group. The mean difference was 0.50 g (95% confidence interval, -0.19 to 1.19 g; p = 0.15). The mean (standard deviation) postoperative visual analog scale pain score in the cold pack group was 2.40 +/- 2.32 compared with 3.33 +/- 2.83 in the control group. The mean difference was 0.94 (95% confidence interval, -0.11 to 1.99; p = 0.79). Most of the subjects preferred using a cold pack (78.7%) to not using a cold pack (21.3%) (p < 0.001). CONCLUSION: A cold pack after turbinate and/or septal surgery had no benefit in terms of postoperative bleeding or postoperative pain. PMID- 27216355 TI - Comparative techniques of medial rectus muscle retraction for endoscopic exposure of the medial intraconal space. AB - OBJECTIVE: The medial rectus muscle (MRM) is the medial boundary to the intraconal space of the orbit, and retraction of the MRM is oftentimes necessary for endoscopic removal of intraconal tumors, e.g., orbital hemangioma. We evaluated each of the reported methods of MRM retraction for endoscopic orbital surgery and quantified the degree of intraconal exposure conferred by each method. METHODS: Eight orbits from four cadaver heads were dissected. In each orbit, medial orbital decompression was performed and the MRM was retracted by using four previously described techniques: (1) external MRM retraction at the globe insertion point by using vessel loop (external group), (2) transseptal MRM retraction by using vessel loop (transseptal group), (3) transchoanal retraction of the MRM by using vessel loop (choanal group), and (4) transseptal four-handed technique by using double ball retraction by a second surgeon (transseptal double ball group). The length, height, and area of exposure of the medial intraconal space were quantified and compared. RESULTS: The average +/- standard deviation (SD) anterior-posterior exposures for the external group, transseptal group, and transseptal double ball group were 17.51 +/- 3.39 mm, 16.59 +/- 4.16 mm, and 18.0 +/- 15.25 mm, respectively. The choanal group provided significantly less exposure (12.39 +/- 3.44 mm, p = 0.049) than the other groups. The average +/- SD vertical exposures for the transseptal group, choanal group, and transseptal double ball group were 12.53 +/- 4.38 mm, 13.05 +/- 5.86 mm, and 13.57 +/- 3.74 mm, respectively. The external group provided significantly less exposure (4.51 +/- 1.56 mm, p = 0.0072) than the other groups. The transseptal and transseptal double ball groups provided the greatest total access by surface area (58.88 +/- 26.96 mm(2) and 62.94 +/- 34.74 mm(2), respectively) compared with the external and choanal groups (34.82 +/- 23.37 mm(2) and 43.10 +/- 23.68 mm(2), respectively). Although the transseptal trajectory of MRM retraction was optimal, the difference in total area of exposure between the static vessel loop retraction and the dynamic, four-handed technique with double ball instrument retraction was not significant. Of note, the exposure provided by the choanal technique required the surgeon to work both above and below the muscle. CONCLUSION: Retraction of the MRM toward the choanae provided the least length of exposure, and external retraction exposed the least height and total area. Transseptal MRM retraction was most favorable and provided the largest endoscopic corridor to the medial intraconal space. A four-handed approach for endoscopic intraconal surgery of the orbit may offer advantages in dynamic adjustments in retraction. PMID- 27216356 TI - The nasofrontal beak: A consistent landmark for superior septectomy during Draf III drill out. AB - INTRODUCTION: Cerebrospinal fluid (CSF) leak occurs in 1-11% of endoscopic Draf III, or endoscopic modified Lothrop, procedures. CSF leak can occur during surgery during a superior nasal septectomy. This study investigated whether the posterior edge of the nasofrontal beak (NFB) at the level of the internal frontal ostium is a safe landmark to use to avoid skull base injury when beginning the superior septectomy. METHODS: Preoperative computed tomography maxillofacial scans were reviewed from 100 patients from the University of Pennsylvania sinus surgery data base. The narrowest anteroposterior distance between the posterior edge of the NFB and the anterior aspect of the olfactory fossa (OF) at the level of the internal frontal ostium was measured in each patient. Measurements were taken in the midline and to the left and right of midline. Six fresh cadaver heads were also dissected to evaluate these relationships. RESULTS: On computed tomography analysis, the NFB was anterior to the OF on the left and right of the midline in 100% of the patients, with mean distances of 6.04 and 6.41 mm, respectively. The NFB was anterior to the OF in the midline in 98% of patients, with a mean distance of 9.02 mm. In all six cadavers, the posterior edge of the NFB was anterior to the OF in the midline and to the left and right of midline at the level of the internal frontal ostia. CONCLUSIONS: During Draf III, the posterior edge of the NFB was a reliable landmark for avoiding iatrogenic CSF leak during the superior septectomy. PMID- 27216357 TI - The impact of surgical trainee participation on sinus surgery outcomes. PMID- 27216358 TI - Compulsive foreign language syndrome: A clinical observation not a mystery. PMID- 27216359 TI - Using principal component analysis to capture individual differences within a unified neuropsychological model of chronic post-stroke aphasia: Revealing the unique neural correlates of speech fluency, phonology and semantics. AB - Individual differences in the performance profiles of neuropsychologically impaired patients are pervasive yet there is still no resolution on the best way to model and account for the variation in their behavioural impairments and the associated neural correlates. To date, researchers have generally taken one of three different approaches: a single-case study methodology in which each case is considered separately; a case-series design in which all individual patients from a small coherent group are examined and directly compared; or, group studies, in which a sample of cases are investigated as one group with the assumption that they are drawn from a homogenous category and that performance differences are of no interest. In recent research, we have developed a complementary alternative through the use of principal component analysis (PCA) of individual data from large patient cohorts. This data-driven approach not only generates a single unified model for the group as a whole (expressed in terms of the emergent principal components) but is also able to capture the individual differences between patients (in terms of their relative positions along the principal behavioural axes). We demonstrate the use of this approach by considering speech fluency, phonology and semantics in aphasia diagnosis and classification, as well as their unique neural correlates. PCA of the behavioural data from 31 patients with chronic post-stroke aphasia resulted in four statistically-independent behavioural components reflecting phonological, semantic, executive-cognitive and fluency abilities. Even after accounting for lesion volume, entering the four behavioural components simultaneously into a voxel-based correlational methodology (VBCM) analysis revealed that speech fluency (speech quanta) was uniquely correlated with left motor cortex and underlying white matter (including the anterior section of the arcuate fasciculus and the frontal aslant tract), phonological skills with regions in the superior temporal gyrus and pars opercularis, and semantics with the anterior temporal stem. PMID- 27216360 TI - Essential structural elements in tRNA(Pro) for EF-P-mediated alleviation of translation stalling. AB - The ribosome stalls on translation of polyproline sequences due to inefficient peptide bond formation between consecutive prolines. The translation factor EF-P is able to alleviate this stalling by accelerating Pro-Pro formation. However, the mechanism by which EF-P recognizes the stalled complexes and accelerates peptide bond formation is not known. Here, we use genetic code reprogramming through a flexible in-vitro translation (FIT) system to investigate how mutations in tRNA(Pro) affect EF-P function. We show that the 9-nt D-loop closed by the stable D-stem sequence in tRNA(Pro) is a crucial recognition determinant for EF P. Such D-arm structures are shared only among the tRNA(Pro) isoacceptors and tRNA(fMet) in Escherichia coli, and the D-arm of tRNA(fMet) is essential for EF-P induced acceleration of fMet-puromycin formation. Thus, the activity of EF-P is controlled by recognition elements in the tRNA D-arm. PMID- 27216361 TI - Neutrophil elastase in amniotic fluid as a predictor of preterm birth after emergent cervical cerclage. AB - INTRODUCTION: The aim of this study was to investigate neutrophil elastase (NE) in amniotic fluid as a potential marker for predicting pregnancy continuation. MATERIAL AND METHODS: We enrolled 34 pregnant women with bulging fetal membrane during the second trimester who underwent emergent cerclage after confirming the absence of intrauterine infection (amniotic fluid glucose >=15 mg/dL). Amniotic fluid NE levels were compared between women who completed and did not complete 30, 34, and 36 weeks of gestation, and the optimal cut-off value for predicting pregnancy continuation was estimated. Moreover, the differences in the duration of continued pregnancy were compared between women with NE levels above and below the optimal cut-off value. RESULTS: The optimal cut-off value for NE in amniotic fluid that predicted pregnancy continuation beyond 30, 34, and 36 weeks of gestation was 180 ng/mL; this cut-off value had a sensitivity, specificity, positive predictive value, and negative predictive value of 84.0, 77.8, 91.3, and 63.7% beyond 30 weeks of gestation; 87.5, 80.0, 91.5, and 72.3% beyond 34 weeks of gestation; and 85.0, 71.4, 80.9, and 76.9% beyond 36 weeks of gestation, respectively. The duration of continued pregnancy from emergent cerclage to delivery was significantly longer in women with amniotic fluid NE <180 ng/mL (95.1 +/- 5.4 days) than in women with amniotic fluid NE >=180 ng/mL (44.8 +/- 14.3 days). CONCLUSION: The NE levels in amniotic fluid may serve as a useful marker for predicting the duration of continued pregnancy after cervical cerclage. PMID- 27216362 TI - What Aspects of Quality of Life Are Important From Palliative Care Patients' Perspectives? A Systematic Review of Qualitative Research. AB - CONTEXT: Despite the availability of numerous tools professing to measure quality of life (QOL) in the palliative care setting, no single instrument includes all patient-valued domains. OBJECTIVES: To identify which aspects of QOL are important from palliative care patients' perspectives, aiding coverage, and content validity evaluation of available tools. METHODS: A systematic review and synthesis of qualitative research was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. ASSIA, CINAHL, Cochrane library, Embase, Medline, PsycINFO, and PubMed were searched from database inception to December 31, 2015. Published, peer-reviewed, English language articles reporting primary qualitative data investigating QOL domains in adults with a progressive, life-limiting illness were included. Studies a priori exploring a chosen aspect of QOL were not included. Articles scoring <=2 on reporting quality were excluded. Framework synthesis was used to identify key themes across the studies. RESULTS: Overall, 3589 articles were screened and 24 studies were included. Eight important aspects of QOL were identified: physical; personal autonomy; emotional; social; spiritual; cognitive; healthcare; and preparatory. All but one study discussed spiritual aspects, whereas only six studies mentioned cognitive aspects. CONCLUSION: A broad range of domains are important to the QOL of people with life-limiting illnesses receiving palliation. Refinement of measures is needed to help ensure services address issues valued by patients such as preparation for death and aspects of health care provision, elements which are seldom included in currently available preference-based measures used to inform value for money decisions in palliative care. PMID- 27216363 TI - Toward Safer Transitions: A Curriculum to Teach and Assess Hospital-to-Hospice Handoffs. AB - CONTEXT: Patient handoffs are an increasingly emphasized skill in medical and nursing education, and handoff education is required by the Accreditation Council for Graduate Medical Education. Traditional handoff tools lack content that is unique to hospice and palliative medicine. OBJECTIVES: The objective of the study was to develop a comprehensive curriculum to teach and assess patient handoffs in hospice and palliative medicine fellowships. METHODS: Eight hospice physicians, nurse practitioners, and nurses were interviewed to determine core content for a hospital-to-hospice handoff. This content was used to create a verbal handoff template and direct observation assessment tool, which were reviewed by the same hospice providers for content validity. The handoff template was taught to two groups of palliative medicine fellows and one group of internal medicine residents using an interactive didactic and role play, and feedback was obtained to further refine the curriculum. RESULTS: After refinement, the complete handoff curriculum (verbal handoff template, didactic with role play, assessment by faculty using direct observation tool) was successfully integrated into a hospice and palliative medicine fellowship, satisfying Accreditation Council for Graduate Medical Education requirements related to transitions in care. CONCLUSION: The hospital-to-hospice handoff is a unique opportunity to teach patient safety in a palliative medicine context. PMID- 27216364 TI - Ste20-like kinase, SLK, activates the heat shock factor 1 - Hsp70 pathway. AB - Expression and activation of SLK increases during renal ischemia-reperfusion injury. When highly expressed, SLK signals via c-Jun N-terminal kinase and p38 to induce apoptosis, and it exacerbates apoptosis induced by ischemia-reperfusion injury. Overexpression of SLK in glomerular epithelial cells (GECs)/podocytes in vivo induces injury and proteinuria. In response to various stresses, cells enhance expression of chaperones or heat shock proteins (e.g. Hsp70), which are involved in the folding and maturation of newly synthesized proteins, and can refold denatured or misfolded proteins. We address the interaction of SLK with the heat shock factor 1 (HSF1)-Hsp70 pathway. Increased expression of SLK in GECs (following transfection) induced HSF1 transcriptional activity. Moreover, HSF1 transcriptional activity was increased by in vitro ischemia-reperfusion injury (chemical anoxia/recovery) and heat shock, and in both instances was amplified further by SLK overexpression. HSF1 binds to promoters of target genes, such as Hsp70 and induces their transcription. By analogy to HSF1, SLK stimulated Hsp70 expression. Hsp70 was also enhanced by anoxia/recovery and was further amplified by SLK overexpression. Induction of HSF1 and Hsp70 was dependent on the kinase activity of SLK, and was mediated via polo-like kinase-1. Transfection of constitutively active HSF1 enhanced Hsp70 expression and inhibited SLK-induced apoptosis. Conversely, the proapoptotic action of SLK was augmented by HSF1 shRNA, or the Hsp70 inhibitor, pifithrin-MU. In conclusion, increased expression/activity of SLK activates the HSF1-Hsp70 pathway. Hsp70 attenuates the primary proapoptotic effect of SLK. Modulation of chaperone expression may potentially be harnessed as cytoprotective therapy in renal cell injury. PMID- 27216365 TI - Oxidative and nitrosative signalling in pulmonary arterial hypertension - Implications for development of novel therapies. AB - Pulmonary arterial hypertension (PAH) is a syndrome characterised by an increase in pulmonary vascular resistance. This results in elevated resting pulmonary artery pressure and leads to progressive right ventricular (RV) failure, secondary to increased afterload. Although initially thought to be a disease driven primarily by endothelial dysfunction with a resultant vasoconstrictor versus vasodilator imbalance, it has become increasingly apparent that the rise in pulmonary vascular resistance that causes RV failure is also attributable to pulmonary vascular remodelling. This inflammatory, hyper-proliferative and anti apoptotic phenotype is accompanied by a metabolic switch from physiological mitochondrial oxidative phosphorylation to aerobic glycolysis. The molecular pathways triggering this cellular metabolic shift have been the subject of extensive investigation, as their discovery will inevitably lead to new therapeutic targets. Reactive oxygen/nitrogen species (ROS/RNS) including hydrogen peroxide, superoxide and peroxynitrite are second messenger molecules that are involved in functional oxidative and nitrosative modification of proteins. Dysregulation of oxidative signalling caused by an excess of ROS and RNS relative to antioxidants has been heavily implicated in the underlying pathophysiology of PAH and likely participates in this metabolic reprogramming. This review will focus on the role of oxidative signalling and redox reactions to the molecular pathology of PAH. In addition, promising novel therapeutic agents targeting these pathways will be discussed. PMID- 27216366 TI - Is high hypnotizability a necessary diathesis for pathological dissociation? AB - During the 19th century, high hypnotizability was considered to be a form of psychopathology that was inseparable from hysteria. Today, hypnotizability is considered to be a normal trait that has no meaningful relationship with psychopathology. Psychiatric patients generally manifest medium to low hypnotizability. Nevertheless, several psychiatric diagnoses are marked by an unexpectedly large proportion of patients with high hypnotizability. This is especially true of the diagnostic categories that were subsumed by the 19th century concept of hysteria: dissociative identity disorder, somatization disorder, and complex conversion disorders. These hysteria-related modern diagnoses are also highly dissociative. A review and analysis of the literature regarding the relationship between hypnotizability and dissociation indicates that high hypnotizability is almost certainly a necessary diathesis for the development of a severe dissociative disorder. Such a diathesis has significant implications for (a) the psychiatric nosologies of the American Psychiatric Association and the World Health Organization, (b) the hypnosis field, and (c) the etiology and construct validity of dissociative identity disorder and other severe dissociative disorders. Specifically, the dissociative disorders (excepting depersonalization disorder, which is not classified as a dissociative disorder by the World Health Organization) are manifestations of hypnotic pathology. PMID- 27216367 TI - 3-O-methyldopa levels in newborns: Result of newborn screening for aromatic l amino-acid decarboxylase deficiency. AB - BACKGROUND: The diagnosis of aromatic l-amino-acid decarboxylase (AADC) deficiency is often delayed because a cerebrospinal fluid analysis is required to detect a neurotransmitter deficiency. We here demonstrated that an elevated concentration of l-dopa metabolite 3-O-methyldopa (3-OMD) in dried blood spots could be integrated into newborn screening program to precisely predict AADC deficiency. METHODS: After obtaining parental consent, an additional spot was punched from newborn filter paper, eluted, cleaned, and analyzed by tandem mass spectrometry. Newborns with a 3-OMD concentration exceeding 500ng/mL were referred for confirmatory testing. RESULTS: From September 2013 to December 2015, 127,987 newborns were screened for AADC deficiency. The mean 3-OMD concentration in these newborns was 88.08ng/mL (SD=27.74ng/mL). Four newborns exhibited an elevated 3-OMD concentration (range, 939-3241ng/mL). All four newborns were confirmed to carry two pathologic DDC mutations, indicating an incidence of AADC deficiency of 1:32,000. During the follow-up period, three patients developed typical symptoms of AADC deficiency. Among 16 newborns with mildly elevated 3-OMD levels, six were heterozygous for the DDC IVS6+4A>T mutation. CONCLUSION: Newborn screening of AADC deficiency was achieved with a 100% positive-predictive rate. An association for gestational age could be further elucidated. PMID- 27216368 TI - Towards rational drug treatment of Lesch-Nyhan disease. AB - Lesch-Nyhan disease (LND) is a rare X-chromosomal purine metabolism disorder. LND is characterized by self-injurious behavior (SIB) for which there is no drug treatment. This commentary places a recent clinical study by Khasnavis et al. (Mol. Genetic. Metab., in press) on drug treatment of SIB into a broader context. Although the study by Khasnavis et al. was no break-through in terms of "positive" results, nonetheless, it presents an excellent model of how clinical studies in general and clinical studies on rare diseases should be conducted. PMID- 27216369 TI - Plasma bupivacaine concentrations following orbital injections in cats. AB - OBJECTIVE: To determine plasma bupivacaine concentrations after retrobulbar or peribulbar injection of bupivacaine in cats. STUDY DESIGN: Randomized, crossover, experimental trial with a 2 week washout period. ANIMALS: Six adult healthy cats, aged 1-2 years, weighing 4.6 +/- 0.7 kg. METHODS: Cats were sedated by intramuscular injection of dexmedetomidine (36-56 MUg kg-1) and were administered a retrobulbar injection of bupivacaine (0.75 mL, 0.5%; 3.75 mg) and iopamidol (0.25 mL), or a peribulbar injection of bupivacaine (1.5 mL, 0.5%; 7.5 mg), iopamidol (0.5 mL) and 0.9% saline (1 mL) via a dorsomedial approach. Blood (2 mL) was collected before and at 5, 10, 15, 22, 30, 45, 60, 120, 240 and 480 minutes after bupivacaine injection. Atipamezole was administered approximately 30 minutes after bupivacaine injection. Plasma bupivacaine and 3 hydroxybupivacaine concentrations were determined using liquid chromatography mass spectrometry. Bupivacaine maximum plasma concentration (Cmax) and time to Cmax (Tmax) were determined from the data. RESULTS: The bupivacaine median (range) Cmax and Tmax were 1.4 (0.9-2.5) MUg mL-1 and 17 (4-60) minutes, and 1.7 (1.0-2.4) MUg mL-1, and 28 (8-49) minutes, for retrobulbar and peribulbar injections, respectively. In both treatments the 3-hydroxybupivacaine peak concentration was 0.05-0.21 MUg mL-1. CONCLUSIONS AND CLINICAL RELEVANCE: In healthy cats, at doses up to 2 mg kg-1, bupivacaine peak plasma concentrations were approximately half that reported to cause arrhythmias or convulsive electroencephalogram (EEG) activity in cats, and about one-sixth of that required to produce hypotension. PMID- 27216370 TI - Fucoidan improves bioactivity and vasculogenic potential of mesenchymal stem cells in murine hind limb ischemia associated with chronic kidney disease. AB - Chronic kidney disease (CKD) is a significant risk factor for cardiovascular and peripheral vascular disease. Although mesenchymal stem cell (MSC)-based therapy is a promising strategy for treatment of ischemic diseases associated with CKD, the associated pathophysiological conditions lead to low survival and proliferation of transplanted MSCs. To address these limitations, we investigated the effects of fucoidan, a sulfated polysaccharide, on the bioactivity of adipose tissue-derived MSCs and the potential of fucoidan-treated MSCs to improve neovascularization in ischemic tissues of CKD mice. Treatment of MSCs with fucoidan increased their proliferative potential and the expression of cell cycle associated proteins, such as cyclin E, cyclin dependent kinase (CDK) 2, cyclin D1, and CDK4, via focal adhesion kinase and the phosphatidylinositol-4,5 bisphosphate 3-kinase-Akt axis. Moreover, fucoidan enhanced the immunomodulatory activity of MSCs through the ERK-IDO-1 signal cascade. Fucoidan was found to augment the proliferation, incorporation, and endothelial differentiation of transplanted MSCs at ischemic sites in CKD mice hind limbs. In addition, transplantation of fucoidan-treated MSCs enhanced the ratio of blood flow and limb salvage in CKD mice with hind limb ischemia. To our knowledge, our findings are the first to reveal that fucoidan enhances the bioactivity of MSCs and improves their neovascularization in ischemic injured tissues of CKD. In conclusion, fucoidan-treated MSCs may provide an important pathway toward therapeutic neovascularization in patients with CKD. PMID- 27216371 TI - Online and Offline Conversations About Alcohol: Comparing the Effects of Familiar and Unfamiliar Discussion Partners. AB - Although research has demonstrated that interpersonal communication about alcohol influences drinking behaviors, this notion has mainly been examined in offline contexts with familiar conversation partners. The present study investigated how communication mode and familiarity influence conversational valence (i.e., how negatively or positively people talk) and binge drinking norms. During a 2 (offline vs. online communication) * 2 (unfamiliar vs. familiar conversation partner) lab experiment, participants (N = 76) were exposed to an anti-binge drinking campaign, after which they discussed binge drinking and the campaign. Binge drinking norms were measured 1 week before and directly after the discussion. Results revealed that conversations between unfamiliar conversation partners were positive about the campaign, especially in offline settings, subsequently leading to healthier binge drinking norms. We recommend that researchers further investigate the influence of communication mode and familiarity on discussion effects, and we suggest that health promotion attempts might benefit from eliciting conversations about anti-binge drinking campaigns between unfamiliar persons. PMID- 27216372 TI - The effect of a task-specific locomotor training strategy on gait stability in patients with cerebellar disease: a feasibility study. AB - PURPOSE: There is a lack of evidence-based recommendations for the physiotherapeutic intervention specifically for locomotor training in patients with cerebellar ataxia. The purpose of this study is to determine the feasibility and effect of a more specific rehabilitation strategy that aims to improve gait quality in patients with cerebellar ataxia. METHODS: Nineteen patients with degenerative cerebellar ataxia were recruited to participate in the study. The patients participated in a 12-week locomotor training program, two times per week for 1.5 h per session (a total of 24 training sessions). The treatment approach emphasized the relearning of proper gait movement strategies through intensive practice that enhances the patient's perception and control of the essential components of normal gait movement. RESULTS: A quantitative analysis of step-by step gait performance indicated that postural sway during locomotion was reduced, and the gait movement pattern became more consistent after the 12-week locomotor training program. These improvements in gait stability persisted over the 3-month period following intervention. CONCLUSION: This study provides preliminary evidence that learning-based rehabilitation strategies targeting disease-specific locomotion symptoms may be helpful for reducing ataxic gait and improving motor control during walking in patients with cerebellar dysfunction. Implications for rehabilitation Physiotherapeutic interventions that aim to promote gait stability in cerebellar patients need to create a specific learning context that improve disease-related gait deficits. It is desirable to use explicit instructions to facilitate the conscious awareness and control of body center and posture. As patients reacquire the fundamental gait ability, providing training experience with various locomotor tasks that facilitate the transfer of learning may be helpful to increase generalizability of locomotor intervention. PMID- 27216373 TI - Capillary Liquid Chromatography Mass Spectrometry Analysis of Intact Monolayer Protected Gold Clusters in Complex Mixtures. AB - In some respects, large noble-metal clusters protected by thiolate ligands behave as giant molecules of definite composition and structure; however, their rigorous analysis continues to be quite challenging. Analysis of complex mixtures of intact monolayer-protected clusters (MPCs) by liquid chromatography mass spectrometry (LC-MS) could provide quantitative identification of the various components present. This advance is critical for biomedical and toxicological research, as well as in fundamental studies that rely on the identification of selected compositions. This work expands upon the separate LC and MS results previously achieved, by interfacing the capillary liquid chromatograph directly to the electrospray source of the mass spectrometer, in order to provide an extremely sensitive, quantitative, and rapid means to characterize MPCs and their derivatives far beyond that of earlier reports. Here, we show that nonaqueous reversed-phase chromatography can be coupled to mass-spectrometry detection to resolve complex mixtures in minute (~100 ng) samples of gold MPCs, of molecular masses up to ~40 kDa, and with single-species sensitivity easily demonstrated for components on the level of sub-10 ng or picomole (1 pmol). PMID- 27216375 TI - Intima-media thickness remodelling in hypertensive subjects with long-term well controlled blood pressure levels. AB - Aim of this study was to evaluate in a long follow-up the carotid artery remodelling in a cohort of young hypertensive subjects having good blood pressure (BP) control. We studied 20 grade I hypertensives (HT) by assessing the B-mode ultrasound of mean carotid intima-media thickness (mean-IMT) and maximum IMT (M MAX) in each carotid artery segment (common, bulb, internal), bilaterally. We compared their ultrasound measurements with those recorded 5 and 10 years earlier. While the first 5-year follow-up was observational, in the second 5-year follow-up, lifestyle modifications and/or pharmacological therapy were started to obtain well-controlled BP levels. Office BP was measured at the time of the ultrasound studies and every 6 months during the follow-up. BP levels were: 10 years 144/91 mmHg, 5 years 143/90 mmHg and 129 +/- 79 mmHg at the time of the study. In the first 5-year observational follow-up, both mean-IMT and M-MAX increased (Delta 0.116 and Delta 0.165 mm, respectively, p < 0.0005). In the 5 year intervention follow-up, characterized by well-controlled BP, mean-IMT slightly but significantly increased (Delta 0.084 mm, p = 0.004), whereas M-MAX remained stable (Delta 0.026 mm). In our HT, well-controlled BP levels were able to prevent pro-atherogenic remodelling (expressed by M-MAX). Conversely, good BP control slightly decreased but did not stop the progression in mean-IMT, which is likely to reflect some hypertrophy of the arterial media layer. PMID- 27216374 TI - Interaction of single and multi wall carbon nanotubes with the biological systems: tau protein and PC12 cells as targets. AB - Subtle changes in the structure of nanoparticles influence their surface tension and corresponding interaction with cells and proteins. Here, the interaction of the single wall carbon nanotube (SWCNT) and multiwall carbon nanotube (MWCNT) with different surface tension with tau protein was evaluated using a variety of techniques including far and near circular dichroism, fluorescence spectroscopy, dynamic light scattering, Zeta potential, and TEM evaluation. Also the cytotoxicity of SWCNT and MWCNT on the PC12 cell line as a model of nervous system cell line was investigated by the MTT, LDH, acridine orange/ethidium bromide staining, flow cytometry, caspase 3 activity, cell and membrane potential assays. It was observed that SWCNT induced more structural changes of tau protein relative to MWCNT/tau protein interaction. It was also revealed that SWCNT and MWCNT impaired the viability and complexity of PC12 cells in different modes of cytotoxicity. Analysis of cellular outcomes indicated that MWCNT in comparison with SWCNT resulted in induction of necrotic modes of cell death, whereas apoptotic modes of cell death were activated in SWCNT-incubated cells. Together these findings suggest that surface tension may be used to determine how nanoparticle structure affects neurotoxicity and protein conformational changes. PMID- 27216376 TI - Associated disease risk from the introduced generalist pathogen Sphaerothecum destruens: management and policy implications. AB - The rosette agent Sphaerothecum destruens is a novel pathogen, which is currently believed to have been introduced into Europe along with the introduction of the invasive fish topmouth gudgeon Pseudorasbora parva (Temminck & Schlegel, 1846). Its close association with P. parva and its wide host species range and associated host mortalities, highlight this parasite as a potential source of disease emergence in European fish species. Here, using a meta-analysis of the reported S. destruens prevalence across all reported susceptible hosts species; we calculated host-specificity providing support that S. destruens is a true generalist. We have applied all the available information on S. destruens and host-range to an established framework for risk-assessing non-native parasites to evaluate the risks posed by S. destruens and discuss the next steps to manage and prevent disease emergence of this generalist parasite. PMID- 27216377 TI - Spontaneous Bilateral Cervical Internal Carotid and Vertebral Artery Dissection in a Japanese Patient without Collagen Vascular Disease with Special Reference to Single-Nucleotide Polymorphisms. AB - Spontaneous cervical artery dissection (sCAD) is a major cause of ischemic stroke in young adults. Frequently, sCAD involves multiple neck arteries, accounting for 13%-28% of the total sCAD cases. However, little is known about factors related to multiple sCAD. In this case, a 52-year-old man was admitted due to headache without aura. There was a personal history of migraine with aura and a family history of similar symptoms. The patient's younger brother had a left vertebral artery (VA) dissecting aneurysm and underwent endovascular occlusion of his parent artery at the age of 48. Magnetic resonance imaging of our admitted patient showed hyperintensities in the right internal carotid artery (ICA) without acute infarction, and magnetic resonance angiography revealed a narrowing of the right ICA. Angiography was then performed, which showed a trace of dissection of the left ICA and both VAs as well as the right ICA. The patient did not fulfill any major criteria of collagen vascular disease such as Ehlers-Danlos syndrome type IV or Loeys-Dietz syndrome. The data in our patient are quite similar to those reported in patients with single-nucleotide polymorphism (SNP) of PHACTR1. Obtaining the patient's informed consent, we analyzed a common SNP variation in the rs9349379[G] allele (PHACTR1), which has been reported to be associated with a lower risk of sCAD. PMID- 27216378 TI - A New Risk Index for Predicting Outcomes among Patients Undergoing Carotid Endarterectomy in Large Administrative Data Sets. AB - BACKGROUND: We developed and validated a new index to provide risk adjustment and to predict in-hospital patient mortality and other outcomes in patients undergoing carotid endarterectomy (CEA). METHODS: The primary endpoint was occurrence of stroke, cardiac complications, or death during hospitalization for CEA derived from the Nationwide Inpatient Sample. Multivariate logistic regression was performed to identify the effect of clinical and demographic factors on occurrence of the primary endpoint. Data from 2005 to 2006 (study period 1) were used to derive risk index score whereas data from 2007 to 2009 (study period 2) were used for validation of the risk index. RESULTS: A total of 120,633 patients with mean age in years [ +/-SD] of 71.1[ +/-9.5] (42.4% women) underwent CEA during the derivation period. The rate of occurrence of composite endpoint during study period 1 was 3.1%. Predictors of the composite endpoint were (odds ratio [OR], P value) as follows: age 70 years or older (1.15, .013 assigned 1 point), atrial fibrillation (3.18, <.0001 assigned 3 points), Congestive Heart Failure (CHF) (1.81, <.0001 assigned 2 points), cigarette smoking (1.64, <.0001 assigned 2 points), symptomatic status (1.87, <.001 assigned 2 points), and chronic renal failure (1.64, <.0001 assigned 2 points). When applied to the validation cohort (n = 71,222), patients with scores 0-1 (OR 1.6, 95% confidence interval [CI] 1.5-1.8), scores 2-3 (OR 4.0, 95% CI 3.8-4.3), scores 4-5 (OR 7.5, 95% CI 6.8-8.2), and scores greater than 5 (OR 10.9, 95% CI 9.8-12.2) had composite rates of endpoint. The receiver operating characteristic curve of the risk index was 68.5% [+/-SE 0.5%]. CONCLUSION: New risk index will assist in risk adjustment for analyses of outcomes in large administrative data sets for comparative studies involving patients undergoing CEA. PMID- 27216379 TI - "True" Accessory Anterior Cerebral Artery: A Newly Reported Anterior Cerebral Arterial Anomaly and a Proposal for Its Classification. AB - If we use the same naming policy of middle cerebral arterial anomalies, then accessory anterior cerebral arteries (ACAs) should be applied for ACA anomalies originating from the ACA. We experienced such a rare ACA anomaly, which we referred to as true accessory ACA. PMID- 27216380 TI - Hot topics in the diagnosis and management of skin and soft-tissue infections. AB - Eighteen hot topics regarding the diagnosis and management of skin and soft tissue infections (SSTIs) were selected and reviewed by members of the SSTI Working Group of the International Society of Chemotherapy (ISC). Despite the large amount of literature available on the issue selected, there are still many unknowns with regard to many of them and further studies are required to answer these challenging issues that face clinicians on a daily basis. PMID- 27216381 TI - Novel cruzipain inhibitors for the chemotherapy of chronic Chagas disease. AB - Despite current efforts worldwide to develop new medications against Chagas disease, only two drugs are available, nifurtimox and benznidazole. Both drugs require prolonged treatment and have multiple side effects and limited efficacy on adult patients chronically infected with Trypanosoma cruzi. Recently, computer guided drug repositioning led to the discovery of the trypanocidal effects of clofazimine and benidipine. These compounds showed inhibitory effects on cruzipain, the major cysteine protease of T. cruzi, of different parasite stages and in a murine model of acute Chagas disease. The aim of this work was to determine the efficacy of these novel cruzipain inhibitors when administered in a murine model of chronic Chagas disease. Benidipine and clofazimine were able to reduce the parasite burden in cardiac and skeletal muscles of chronically infected mice compared with untreated mice as well as diminish the inflammatory process in these tissues. Further studies should be performed to study the synergism with benznidazole and nifurtimox in view of combined therapies. PMID- 27216382 TI - Early detection of metallo-beta-lactamase NDM-1- and OXA-23 carbapenemase producing Acinetobacter baumannii in Libyan hospitals. AB - Acinetobacter baumannii is an opportunistic pathogen causing various nosocomial infections. The aim of this study was to characterise the molecular support of carbapenem-resistant A. baumannii clinical isolates recovered from two Libyan hospitals. Bacterial isolates were identified by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF/MS). Antibiotic susceptibility testing was performed using disk diffusion and Etest methods, and carbapenem resistance determinants were studied by PCR amplification and sequencing. Multilocus sequence typing (MLST) was performed for typing of the isolates. All 36 imipenem-resistant isolates tested were identified as A. baumannii. The blaOXA-23 gene was detected in 29 strains (80.6%). The metallo beta-lactamase blaNDM-1 gene was detected in eight isolates (22.2%), showing dissemination of multidrug-resistant (MDR) A. baumannii in Tripoli Medical Center and Burn and Plastic Surgery Hospital in Libya, including one isolate that co expressed the blaOXA-23 gene. MLST revealed several sequence types (STs). Imipenem-resistant A. baumannii ST2 was the predominant clone (16/36; 44.4%). This study shows that NDM-1 and OXA-23 contribute to antibiotic resistance in Libyan hospitals and represents the first incidence of the association of these two carbapenemases in an autochthonous MDR A. baumannii isolated from patients in Libya, indicating that there is a longstanding infection control problem in these hospitals. PMID- 27216383 TI - In vitro activity of artemisone and artemisinin derivatives against extracellular and intracellular Helicobacter pylori. AB - The in vitro activity of the new artemisinin derivative artemisone as well as other molecules of the same class against Helicobacter pylori and their effects when combined with standard antibiotics were evaluated. Since H. pylori can be internalised into gastric epithelial cells, the effects of artemisinin, dihydroartemisinin and artemisone against intracellular H. pylori were also investigated. Bacteriostatic [minimum inhibitory concentration (MIC)] and bactericidal [minimum bactericidal concentration (MBC)] activities were assessed against 24 clinical strains of H. pylori with different antibiotics susceptibilities. Artemisone showed MIC50 and MIC90 values of 0.25 mg/L and 0.5 mg/L, respectively, and an MBC50 value of 0.5 mg/L. Artemisone was synergistic with amoxicillin in 60% of strains, with clarithromycin in 40% and with metronidazole in 20%. There was no interaction between artemisone and omeprazole or bismuth citrate. Against intracellular H. pylori, only dihydroartemisinin at 2* MIC caused a 1 log10 CFU decrease after 18 h and 24 h of incubation. This is the first demonstration in vitro of the activity of artemisinin derivatives against intracellular H. pylori and indicates that artemisone has the potential to be efficacious for the treatment of H. pylori infection, especially in combination with antibiotics. PMID- 27216384 TI - Clinical isolates of uropathogenic Escherichia coli ST131 producing NDM-7 metallo beta-lactamase in China. AB - Here we report five cases of NDM-7-producing Escherichia coli from patients with bacteriuria in a teaching hospital in mainland China. Two isolates belonged to sequence type 131 (ST131), simultaneously carrying blaCTX-M-15, blaSHV-11, blaTEM 1 and qnrS1. The blaNDM-7 gene was located on a conjugative IncX3-type plasmid bearing blaTEM-1 and qnrS1. These findings indicate the spread of NDM-7 metallo beta-lactamase in a highly resistant and virulent E. coli sequence type in China. PMID- 27216385 TI - Clostridium difficile infection following systemic antibiotic administration in randomised controlled trials: a systematic review and meta-analysis. AB - Antibiotics have been the most important risk factor for Clostridium difficile infection (CDI). However, only data from non-randomised studies have been reviewed. We sought to evaluate the risk for development of CDI associated with the major antibiotic classes by analysing data from randomised controlled trials (RCTs). The PubMed, Cochrane and Scopus databases were searched and the references of selected RCTs were also hand-searched. Eligible studies should have compared only one antibiotic versus another administered systemically. Inclusion of studies comparing combinations of antibiotics was allowed only if the second antibiotic was the same or from the same class or if it was administered in a subset of the enrolled patients who were equally distributed in the two arms. Only a minority of the selected RCTs (79/1332; 5.9%) reported CDI episodes. Carbapenems were associated with more CDI episodes than fluoroquinolones [risk ratio (RR) = 2.44, 95% confidence interval (CI) 1.32-4.49] and cephalosporins (RR = 2.24, 95% CI 1.46-3.42), but not penicillins (RR = 2.53, 95% CI 0.87-7.41). Cephalosporins were associated with more CDIs than penicillins (RR = 2.36, 95% CI 1.32-4.23) and fluoroquinolones (RR = 2.84, 95% CI 1.60-5.06). There was no difference in CDI frequency between fluoroquinolones and penicillins (RR = 1.34, 95% CI 0.55-3.25). Finally, clindamycin was associated with more CDI episodes than cephalosporins and penicillins (RR = 3.92, 95% CI 1.15-13.43). In conclusion, data from RCTs showed that clindamycin and carbapenems were associated with more CDIs than other antibiotics. PMID- 27216386 TI - Influence of contralateral acoustic hearing on adult bimodal outcomes after cochlear implantation. AB - OBJECTIVE: To examine post-implantation benefit and time taken to acclimate to the cochlear implant for adult candidates with more hearing in the contralateral non-implanted ear than has been previously considered within local candidacy guidelines. DESIGN: Prospective, within-subject experimental design. STUDY SAMPLE: Forty postlingual hearing-impaired adult subjects with a contralateral ear word score in quiet ranging from 27% to 100% (median 67%). RESULTS: Post implantation improvement of 2.4 dB and 4.0 dB was observed on a sentence in coincident babble test at presentation levels of 65 and 55 dB SPL respectively, and a 2.1 dB benefit in spatial release from masking (SRM) advantage observed when the noise location favoured the implanted side. Significant post-operative group mean change of between 2.1 and 3.0 was observed on the sub-scales of the speech, spatial, and qualities (SSQ) questionnaire. Degree of post-implantation speech reception threshold (SRT) benefit on the coincident babble test and on perception of soft speech and sounds in the environment was greater for subjects with less contralateral hearing. The degree of contralateral acoustic hearing did not affect time taken to acclimate to the device. CONCLUSIONS: The findings from this study support cochlear implantation for candidates with substantial acoustic hearing in the contralateral ear, and provide guidance regarding post implantation expectations. PMID- 27216387 TI - Novel ZnO:Al contacts to CdZnTe for X- and gamma-ray detectors. AB - CdZnTe (CZT) has made a significant impact as a material for room-temperature nuclear-radiation detectors due to its potential impact in applications related to nonproliferation, homeland security, medical imaging, and gamma-ray telescopes. In all such applications, common metals, such as gold, platinum and indium, have been used as electrodes for fabricating the detectors. Because of the large mismatch in the thermal-expansion coefficient between the metal contacts and CZT, the contacts can undergo stress and mechanical degradation, which is the main cause for device instability over the long term. Here, we report for the first time on our use of Al-doped ZnO as the preferred electrode for such detectors. The material was selected because of its better contact properties compared to those of the metals commonly used today. Comparisons were conducted for the detector properties using different contacts, and improvements in the performances of ZnO:Al-coated detectors are described in this paper. These studies show that Al:ZnO contacts to CZT radiation detectors offer the potential of becoming a transformative replacement for the common metallic contacts due to the dramatic improvements in the performance of detectors and improved long-term stability. PMID- 27216388 TI - A review on development of analytical methods to determine monitorable drugs in serum and urine by micellar liquid chromatography using direct injection. AB - Therapeutic drug monitoring is a common practice in clinical studies. It requires the quantification of drugs in biological fluids. Micellar liquid chromatography (MLC), a well-established branch of Reverse Phase-High Performance Liquid Chromatography (RP-HPLC), has been proven by many researchers as a useful tool for the analysis of these matrices. This review presents several analytical methods, taken from the literature, devoted to the determination of several monitorable drugs in serum and urine by micellar liquid chromatography. The studied groups are: anticonvulsants, antiarrhythmics, tricyclic antidepressants, selective serotonin reuptake inhibitors, analgesics and bronchodilators. We detail the optimization strategy of the sample preparation and the main chromatographic conditions, such as the type of column, mobile phase composition (surfactant, organic solvent and pH), and detection. The finally selected experimental parameters, the validation, and some applications have also been described. In addition, their performances and advantages have been discussed. The main ones were the possibility of direct injection, and the efficient chromatographic elution, in spite of the complexity of the biological fluids. For each substance, the measured concentrations were accurate and precise at their respective therapeutic range. It was found that the MLC-procedures are fast, simple, inexpensive, ecofriendly, safe, selective, enough sensitive and reliable. Therefore, they represent an excellent alternative for the determination of drugs in serum and urine for monitoring purposes. PMID- 27216389 TI - Towards a semiquantitative non invasive characterisation of Tyrian purple dye composition: Convergence of UV-Visible reflectance spectroscopy and fast-high temperature-high performance liquid chromatography with photodiode array detection. AB - In this paper, partial least square (PLS) regression is innovatively applied for a semi-quantitative non invasive study of the most precious dye of Antiquity: Tyrian purple. This original approach for the study of organic dyes in the cultural heritage field, is based on the correlation of spectrophotometric (UV Visible) and chromatographic (Fast-HT-HPLC-PDA) data from an extensive set of textiles prepared with different snail species according to historical recipes. A cross-validated PLS model, based on the quantity of 6,6'-dibromoindigotin, displays an excellent correlation factor (R(2)Y = 0.987) between values determined by chromatography and those predicted from reflectance spectra. This indicates that the spectral features of Tyrian purple on textile fibre is strictly related to the amount of this indigoid component whose content may be non invasively predicted from reflectance spectrum. The studied correlation also highlights that, independently of the dyeing method and nature of the textile fibre used, the relative content of 6,6'-dibromindigotin may be used as a parameter to distinguish samples prepared with Hexaplex trunculus L. snails from those prepared with further mollusc species. To validate this model, archaeological textile fragments dating from the Roman period were successfully examined. The results achieved open an absolutely new way in Tyrian purple analysis in cultural heritage by non invasive spectroscopic techniques attesting their convergence with HPLC and giving them a semi-quantitative value. PMID- 27216390 TI - Ferrocene-functionalized graphene electrode for biosensing applications. AB - A novel ferrocene-functionalized reduced graphene oxide (rGO)-based electrode is proposed. It was fabricated by the drop casting of ferrocene-functionalized graphene onto polyester substrate as the working electrode integrated within screen-printed reference and counter electrodes. The ferrocene-functionalized rGO has been fully characterized using FTIR, XPS, contact angle measurements, SEM and TEM microscopy, and cyclic voltammetry. The XPS and EDX analysis showed the presence of Fe element related to the introduced ferrocene groups, which is confirmed by a clear CV signal at ca. 0.25 V vs. Ag/AgCl (0.1 KCl). Mediated redox catalysis of H2O2 and bio-functionalization with glucose oxidase for glucose detection were achieved by the bioelectrode providing a proof for potential biosensing applications. PMID- 27216391 TI - Amyloid-beta peptides time-dependent structural modifications: AFM and voltammetric characterization. AB - The human amyloid beta (Abeta) peptides, Abeta1-40 and Abeta1-42, structural modifications, from soluble monomers to fully formed fibrils through intermediate structures, were investigated, and the results were compared with those obtained for the inverse Abeta40-1 and Abeta42-1, mutant Abeta1-40Phe(10) and Abeta1 40Nle(35), and rat Abeta1-40Rat peptide sequences. The aggregation was followed at a slow rate, in chloride free media and room temperature, and revealed to be a sequence-structure process, dependent on the physicochemical properties of each Abeta peptide isoforms, and occurring at different rates and by different pathways. The fibrilization process was investigated by atomic force microscopy (AFM), via changes in the adsorption morphology from: (i) initially random coiled structures of ~0.6 nm height, corresponding to the Abeta peptide monomers in random coil or in alpha-helix conformations, to (ii) aggregates and protofibrils of 1.5-6.0 nm height and (iii) two types of fibrils, corresponding to the Abeta peptide in a beta-sheet configuration. The reactivity of the carbon electrode surface was considered. The hydrophobic surface induced rapid changes of the Abeta peptide conformations, and differences between the adsorbed fibrils, formed at the carbon surface (beaded, thin, <2.0 nm height) or in solution (long, smooth, thick, >2.0 nm height), were detected. Differential pulse voltammetry showed that, according to their primary structure, the Abeta peptides undergo oxidation in one or two steps, the first step corresponding to the tyrosine amino acids oxidation, and the second one to the histidine and methionine amino acids oxidation. The fibrilization process was electrochemically detected via the decrease of the Abeta peptide oxidation peak currents that occurred in a time dependent manner. PMID- 27216392 TI - A new strategy for label-free electrochemical immunoassay based on "gate-effect" of beta-cyclodextrin modified electrode. AB - A novel label-free electrochemical immunoassay was developed for prostate specific antigen (PSA) detection via using beta-cyclodextrin (beta-CD) assembled layer created gates for the electron transfer of probe. To construct the sensor, a gold electrode was self-assembled with monoclonal anti-PSA antibody labeled 6 mercapto-beta-cyclodextrin. Interspaces among beta-CD molecules in the layer were automatically formed on gold electrode, which act as the channel of the electron transfer of [Fe(CN)6](3-/4-) probe. When PSA bind with anti-PSA, it can block these channels on the electrode surface due to their steric hindrance effect, resulting in the decrease in redox current of the probe. Through such a gate controlled effect, ultra trace amount of PSA may make the currents change greatly after the immunoreaction, which enhanced the signal-to-noise ratio to achieve the amplification effect. By evaluating the logarithm of PSA concentrations, the immunosensor had a good linear response to the current changes with a detection limit of 0.3 pg/mL (S/N = 3) when PSA concentration ranged from 1.0 pg/mL to 1.0 ng/mL. The label-free immunosensor exhibited satisfactory performances in sensitivity, repeatability as well as specificity. PMID- 27216393 TI - Halloysite nanotubes-titanium dioxide as a solid-phase microextraction coating combined with negative corona discharge-ion mobility spectrometry for the determination of parathion. AB - Halloysite nanotubes-titanium dioxide (HNTs-TiO2) as a biocompatible environmentally friendly solid-phase microextraction (SPME) fiber coating was prepared. HNTs-TiO2 was chemically coated on the surface of a fused-silica fiber using a sol-gel process. Parathion as an organophosphorus pesticide was selected as a model compound to investigate the extraction efficiency of the fiber. The extracted analyte was detected by negative corona discharge-ion mobility spectrometer (NCD-IMS). The effective parameters on the extraction efficiency, such as salt effect, extraction temperature and extraction time were investigated and optimized. The extraction efficiency of HNTs-TiO2 fiber was compared with bare-silica (sol-gel based coating without HNTs-TiO2), HNTs, carbon nanotubes and commercial SPME fibers (PA, PDMS, and PDMS-DVB). The HNTs-TiO2 fiber showed highest extraction efficiency among the studied fibers. The intra- and inter-day relative standard deviations were found to be 4.3 and 6.3%, respectively. The limit of detection and limit of quantification values were 0.03 and 0.1 MUg L( 1), respectively. The dynamic range of the method was in the range of 0.1-25 MUg L(-1). The spiking recoveries were between 85 (+/-9) and 97 (+/-6). The SPME-HNTs TiO2 combined with NCD-IMS was successfully applied for the determination of parathion in apple, strawberry, celery and water samples. PMID- 27216394 TI - Stir bar sorptive-dispersive microextraction mediated by magnetic nanoparticles nylon 6 composite for the extraction of hydrophilic organic compounds in aqueous media. AB - A new and sensitive analytical method based on the recently developed approach termed stir bar-sorptive dispersive microextraction (SBSDME) using a magnetic CoFe2O4@SiO2-nylon 6 composite as sorbent material is presented for the extraction of hydrophilic organic compounds. The simultaneous determination of four hydrophilic UV filters in environmental water samples has been chosen as a model analytical application due to the increasing awareness regarding the occurrence of sunscreen residuals in natural waters. The developed SBSDME approach combines the principles and benefits of stir bar sorptive extraction (SBSE) and dispersive solid phase extraction (DSPE) but allows for lower extraction time and easier post-extraction treatment. Moreover, most importantly, it enables the use of new magnetic materials that affords higher versatility and can be tailored to the needs of the analysis. The main experimental parameters involved in the SBSDME process (i.e. composite amount, extraction time, pH, ionic strength, desorption solvent and desorption time) were evaluated to provide the best enrichment factors. Under the optimized conditions, the method was successfully validated showing good linearity, enrichment factors between 105 and 145 depending on the analyte, limits of detection and quantification in the low ng mL(-1) range (1.6-2.9 ng mL(-1) and 5.4-9.6 ng mL(-1), respectively) and good intra- and inter-day repeatability (RSD < 13%). The developed method was applied to the analysis of water samples of different origin (sea, river and swimming pool). Relative recovery values ranged between 90 and 115%, thus showing that the matrices under consideration do not affect the extraction process. PMID- 27216395 TI - Quantification of 1-hydroxypyrene in undiluted human urine samples using magnetic solid-phase extraction coupled with internal extractive electrospray ionization mass spectrometry. AB - Polycyclic aromatic hydrocarbons (PAHs) are a group of ubiquitous environmental contaminants raising worldwide concerns due to their carcinogenic effects. In this study, 1-hydroxypyrene (1-OHP, the most widely used biomarker of internal dose of PAHs exposure) in undiluted human urine samples (10 mL) was selectively enriched by polypyrrole-coated Fe3O4 magnetite nanocomposites (termed as Fe3O4@Ppy, 1 mg) and then directly eluted by the electrospraying solvent (acetone/benzene/acetic acid (v/v/v, 90/10/1); 100 uL) biased with -3.5 kV to produce the deprotonated 1-OHP anions for mass spectrometric analysis. The method established here significantly improved the current performance for detection of urinary 1-OHP, providing the speed for a single sample analysis within 4 min, the limits of detection (LOD) of 0.0001 MUg L(-1), the linear response range of 0.001 5.000 MUg L(-1) (R(2) = 0.9994), recovery rates of 90.6-96.1%, and relative standard deviation (RSD, n = 6) values between 2.9% and 8.0%. Human samples including raw human urine collected from 10 healthy volunteers (5 smokers and 5 nonsmokers) and 7 lung cancer patients have been successfully analyzed, showing that magnetic solid-phase extraction (MSPE) coupled with internal extractive electrospray ionization mass spectrometry (iEESI-MS) is an alternative strategy for high throughput quantitative detection of urinary 1-OHP for health risk assessment of PAHs exposure. PMID- 27216396 TI - Near infrared spectroscopic imaging assessment of cartilage composition: Validation with mid infrared imaging spectroscopy. AB - Disease or injury to articular cartilage results in loss of extracellular matrix components which can lead to the development of osteoarthritis (OA). To better understand the process of disease development, there is a need for evaluation of changes in cartilage composition without the requirement of extensive sample preparation. Near infrared (NIR) spectroscopy is a chemical investigative technique based on molecular vibrations that is increasingly used as an assessment tool for studying cartilage composition. However, the assignment of specific molecular vibrations to absorbance bands in the NIR spectrum of cartilage, which arise from overtones and combinations of primary absorbances in the mid infrared (MIR) spectral region, has been challenging. In contrast, MIR spectroscopic assessment of cartilage is well-established, with many studies validating the assignment of specific bands present in MIR spectra to specific molecular vibrations. In the current study, NIR imaging spectroscopic data were obtained for compositional analysis of tissues that served as an in vitro model of OA. MIR spectroscopic data obtained from the identical tissue regions were used as the gold-standard for collagen and proteoglycan (PG) content. MIR spectroscopy in transmittance mode typically requires a much shorter pathlength through the sample (<=10 microns thick) compared to NIR spectroscopy (millimeters). Thus, this study first addressed the linearity of small absorbance bands in the MIR region with increasing tissue thickness, suitable for obtaining a signal in both the MIR and NIR regions. It was found that the linearity of specific, small MIR absorbance bands attributable to the collagen and PG components of cartilage (at 1336 and 856 cm(-1), respectively) are maintained through a thickness of 60 MUm, which was also suitable for NIR data collection. MIR and NIR spectral data were then collected from 60 MUm thick samples of cartilage degraded with chondroitinase ABC as a model of OA. Partial least squares (PLS) regression using NIR spectra as input predicted the MIR-determined compositional parameters of PG/collagen within 6% of actual values. These results indicate that NIR spectral data can be used to assess molecular changes that occur with cartilage degradation, and further, the data provide a foundation for future clinical studies where NIR fiber optic probes can be used to assess the progression of cartilage degradation. PMID- 27216397 TI - Synergy between Printex nano-carbons and silver nanoparticles for sensitive estimation of antioxidant activity. AB - We report on the synthesis, characterization and applications of a Printex L6 carbon-silver hybrid nanomaterial (PC-Ag), which was obtained using a polyol method. In addition, we also highlight the use of Printex L6 nano-carbon as a much cheaper alternative to the use of carbon nanotubes and graphene. The silver nanoparticles (AgNP) were prepared directly on the surface of the Printex 6L carbon "nanocarbon" material using ethylene glycol as the reducing agent. The hybrid nanomaterial was characterized by High-angle annular dark-field transmission electron microscopy (HAADF-TEM), energy-dispersive X-ray spectroscopy (EDX), selected area electron diffraction (SAED), Raman spectroscopy and cyclic voltammetry. Optimized electrocatalytic activity on glassy carbon electrode was reached for the architecture GC/PC-Ag, the silver nanoparticles with size ranging between 1 and 2 nm were well-distributed throughout the hybrid material. The synergy between PC nano-carbons and AgNPs was verified by detection of gallic acid (GA) at a low applied potential (0.091 V vs. Ag/AgCl). GA detection was performed in a concentration range between 5.0 * 10(-7) and 8.5 * 10(-6) mol L(-1), with a detection limit of 6.63 * 10(-8) mol L(-1) (66.3 nmol L( 1)), which is considerably lower than similar devices. The approach for fabricating the reproducible GC/PC-Ag electrodes is entirely generic and may be explored for other types of (bio)sensors and devices. PMID- 27216398 TI - Fluorescent oligomer as a chemosensor for the label-free detection of Fe(3+) and dopamine with selectivity and sensitivity. AB - In this article, a sensitive and selective turn-off fluorescence chemosensor, Tyloxapol (one kind of water soluble oligomer), was developed for the label-free detection of Fe(3+) ions in aqueous solution. Fluorescence (FL) experiments demonstrated that Tyloxapol was a sensitive and selective fluorescence sensor for the detection of Fe(3+) directly in water over a wide range of metal cations including Na(+), K(+), Ag(+), Hg(2+), Cd(2+), Co(2+), Cu(2+), Cr(3+), Mn(2+), Ba(2+), Zn(2+), Ni(2+), Mg(2+), Ca(2+), and Pb(2+). Moreover, the fluorescence intensity of Tyloxapol has shown a linear response to Fe(3+) in the concentration range of 0-100 MUmol L(-1) with a detection limit of 2.2 MUmol L(-1) in aqueous solution. Next, based on a competition mechanism, another turn-on sensing application of the Tyloxapol/Fe(3+) platform to probe dopamine (DA) against various other biological molecules such as other neurotransmitters or amino acids (norepinephrine bitartrate, acetylcholine chloride, alanine, valine, phenylalanine, tyrosine, leucine, glycine, histidine) were also investigated. It is expected that our strategy may offer a new approach for developing simple, cost-effective, rapid and sensitive sensors in biological and environmental applications. PMID- 27216399 TI - Fluorescent carbon nanoparticles: A low-temperature trypsin-assisted preparation and Fe(3+) sensing. AB - In recent years, extensive researches are focused on the fluorescent carbon nanoparticles (CNPs) due to their excellent photochemical, biocompatible and water-soluble properties. However, these synthesis methods are generally suffered from tedious processes. In this paper, fluorescent carbon nanoparticles are synthesized by a facile, one-pot, low-temperature method with trypsin and dopamine as precursors. The synthesis process avoids any heating operation and organic solvent, which provides a "green" and effective preparation route. The obtained CNPs exhibit excellent water-solubility, salt-tolerance and photostability. Based on the synergistic action of the inner filter effect and static quenching mechanism, the CNPs are exploited as a "turn-off" fluorescence sensor for sensitive and selective detection of Fe(3+) ions. The probe shows a wide linear range from 0.1 to 500 MUM, with a limit of detection of 30 nM. Furthermore, the as-fabricated fluorescent sensing system is successfully applied to the analysis of Fe(3+) in biological samples such as human urine and serum samples with satisfactory recoveries (92.8-113.3%). PMID- 27216401 TI - A fatal combination of situs inversus, pregnancy and cardiac arrest treated with an automated external defibrillator. PMID- 27216400 TI - Reference intervals for thyroid stimulating hormone and free thyroxine derived from neonates undergoing routine screening for congenital hypothyroidism at a university teaching hospital in Nairobi, Kenya: a cross sectional study. AB - BACKGROUND: In order to accurately interpret neonatal thyroid function tests (TFTs), it is necessary to have population specific reference intervals (RIs) as there is significant variation across different populations possibly due to genetic, environmental or analytical issues. Despite the importance of RIs, globally there are very few publications on RIs for neonatal TFTs primarily due to ethical and technical issues surrounding recruitment of neonates for a prospective study. To the best of our knowledge, this is the first report from Africa on neonatal RIs for TFTs. METHODS: We used hospital based data largely derived from neonates attending the wellness clinic at the Aga Khan University Hospital Nairobi (AKUHN) where screening for congenital hypothyroidism is routinely done. Specifically we derived age and gender stratified RIs for free thyroxine (fT4) and thyroid stimulating hormone (TSH) which had been analyzed on a Roche e601 analyzer from 2011 to 2013. Determination of reference intervals was done using a non-parametric method. RESULTS: A total of 1639 and 1329 non duplicate TSH and fT4 values respectively were used to derive RIs. There was a decline in TSH and fT4 levels with increase in age. Compared to the Roche RIs, the derived RIs for TSH in neonates aged 0-6 days and those aged 7-30 days had lower upper limits and narrower RIs. The fT4 lower limits for neonates less than 7 days and those aged 7-30 days were higher than those proposed by Roche. There was a significant difference in TSH RIs between male and female neonates aged less than 15 days. No gender differences were seen for all other age stratifications for both TSH and fT4. Appropriate age and gender specific RIs were subsequently determined. CONCLUSION: The AKUHN derived RIs for fT4 and TSH revealed similar age related trends to what has been published. However, the differences seen in upper and lower limits across different age stratifications when compared to the Roche RIs highlight the need for population specific RIs for TFTs especially when setting up a screening programme for congenital hypothyroidism. We subsequently recommend the adoption of the derived RIs by the AKUHN laboratory and hope that the RIs obtained can serve as a reference for the African population. PMID- 27216402 TI - A fatal combination of situs inversus, pregnancy and cardiac arrest treated with an automated external defibrillator. PMID- 27216403 TI - Inadvertent complication of the Senning procedure. PMID- 27216404 TI - Piscine orthoreovirus can infect and shed through the intestine in experimentally challenged Atlantic salmon (Salmo salar L.). AB - Piscine orthoreovirus (PRV) is a ubiquitous virus in Norwegian salmon farms associated with the disease heart and skeletal muscle inflammation (HSMI). Experimental challenge has shown that the virus replicates in circulating red blood cells of Atlantic salmon prior to infecting heart myocytes. The infection route from water to blood is however still unknown. The related mammalian orthoreovirus primarily infects the lungs and gastrointestinal (GI) tract and is proposed to spread mainly through the faecal-oral route. To investigate the role of the salmonid GI tract in PRV-infection, oral and anal administration of virus was compared to intraperitoneal (i.p.) injection. When administered anally, PRV was transferred to blood 4 days post challenge (dpc) and levels peaked at 42 dpc, similar to i.p. injected fish. PRV was detected in heart and faeces with corresponding kinetics, and inflammatory heart lesions consistent with HSMI were observed from 49 dpc. The orally intubated group showed slower virus kinetics in both blood and heart, and no signs of HSMI. Compared to the oral and i.p. administration routes, leakage of virus inoculate by anal intubation was minor and challenge was restricted to the mid- and distal intestine. These findings show that anal intubation is an efficacious method for PRV delivery to the GI tract and demonstrates that PRV can establish infection through the intestine with the potential for transmission via faeces. PMID- 27216405 TI - Undocumented migrant women in Denmark have inadequate access to pregnancy screening and have a higher prevalence Hepatitis B virus infection compared to documented migrants in Denmark: a prevalence study. AB - BACKGROUND: Pregnant residents of Denmark are tested by their GP for current infections with Hepatitis B virus (HBV), HIV and syphilis through the Danish pregnancy screening programme to identify infections and initiate interventions to prevent mother-to-child transmission. Documented migrants (DM) have access to this screening but undocumented migrants (UM) do not, instead relying on ad-hoc care from clinics run by non-governmental organisations. We aimed to assess screening frequency in UM and to compare prevalence of infection in UM with DM. METHODS: We obtained individual-level information on HBV, HIV and syphilis testing frequency and results for pregnant women attending three clinics specialising in care for UM between August 2011 and August 2014. We obtained aggregate data on the prevalence of the three infections for documented migrants from the Danish pregnancy screening programme and birth register between January 2011 and January 2014. Planned abortions were excluded from the study. We described demographic features of pregnant UM and estimated the screening frequency for HIV, HBV and syphilis. We compared prevalence of current infections in UM and DM by calculating standardised prevalence ratios (SPR). RESULTS: The three UM clinics registered 219 pregnancies qualifying for screening. Overall 43, 58 and 60 % of pregnant UM had a test result recorded for HBV, Syphilis and HIV respectively, compared to >99 % in the general Danish population including DM. The prevalence of HBV was higher in UM than in DM (SPR: 2.4; 95 % CI: 1.1-5.3). The SPR of 2 (95 % CI: 0.5-8.0) for HIV was not statistically significant, potentially due to small sample size of UM. None of the pregnant UM tested positive for Syphilis. CONCLUSIONS: Pregnant UM have a poorer chance of being tested for HIV, HBV and syphilis, despite having a higher prevalence of HBV than DM. We recommend giving systematic access to routine pregnancy screening to all UM to prevent mother-to-child transmission and to address the observed health care inequity. PMID- 27216406 TI - Corticosteroids or Not for Postoperative Nausea: A Double-Blinded Randomized Study. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) is common after general anaesthesia, and corticosteroids are used in many protocols for enhanced recovery after surgery (ERAS). However, surgical techniques are developing, and ERAS protocols need to be reevaluated from time to time. PATIENTS AND METHOD: In this study, we compared the effects of oral vs. parenteral corticosteroid administration on postoperative nausea. Elective Roux-y-gastric bypass (RYGB) patients were randomly assigned to either 8 mg betamethasone orally (n = 50) or parentally (n = 25) or as controls (n = 25), in a double-blind design. PONV risk factors were noted. All patients had the same anaesthetic technique. Data were collected at baseline, on arrival to the recovery room (RR) and at five more time points during the first 24 h. Nausea and tiredness were patient assessed using visual analogue scales; rescue drug consumption was recorded. RESULTS: Operation time was 30-40 min. Neither demographics nor risk factors for nausea differed between groups. Neither peak values for nor total amount of nausea differed between groups. The number of supplemental injections was the same for all groups. COMMENTS: In a setting of modern laparoscopic RYGB, the value of betamethasone in preventing PONV seems to be limited. ERAS protocols may need re evaluation. PMID- 27216407 TI - Should We Use the Model for End-Stage Liver Disease (MELD) to Predict Mortality After Colorectal Surgery? AB - We sought to determine the accuracy of the Model for End-Stage Liver Disease and the Mayo Clinic Postoperative Mortality Risk in Patients with Cirrhosis Calculator in patients with ascites who underwent colorectal surgery. The National Surgical Quality Improvement Program database was queried for patients with ascites who underwent a major colorectal operation. Predicted 90-day mortality rate based on the Model for End-Stage Liver Disease and 30-day mortality based on the Mayo Clinic Postoperative Mortality Risk in Patients with Cirrhosis Calculator were compared with observed 30-day mortality. The cohort contained 3137 patients with ascites who underwent a colorectal operation. The Model for End-Stage Liver Disease predicted that 252 (8 %) of patients with ascites undergoing colorectal operations would die within 90 days postoperatively, yet we observed 821 deaths (26 % mortality) within 30 days after surgery (p < 0.001). The Mayo Clinic Postoperative Mortality Risk in Patients with Cirrhosis Calculator predicted that 491 (16.6 % mortality) of patients with ascites undergoing colorectal operations would die within 30 days postoperatively, yet we observed 707 (23.9 % mortality) at 30 days (p < 0.01). We concluded that the current risk prediction models significantly under predict mortality in patients with ascites who underwent colorectal surgery. PMID- 27216408 TI - Oral artemisinin monotherapy removal from the private sector in Eastern Myanmar between 2012 and 2014. AB - BACKGROUND: In 2012 the Artemisinin Monotherapy Therapy Replacement (AMTR) project was implemented in Eastern Myanmar to increase access to subsidized, quality-assured artemisinin combination therapy (ACT) and to remove oral artemisinin monotherapy (AMT) from the private sector. The aim of this paper is to examine changes over time in the private sector anti-malarial landscape and to illustrate the value of complementary interventions in the context of a national ACT subsidy. METHODS: Three rounds of cross-sectional malaria medicine outlet surveys were conducted, in 2012, 2013 and 2014. Project intervention areas were selected from the Myanmar Artemisinin Resistance Containment (MARC) area. Provider detailing was implemented in these selected areas. Comparison areas were selected outside of this catchment area, from townships in close proximity to the MARC framework. Within each domain, multi-staged sampling was used to select areas for the survey. Outlets with the potential to sell or distribute anti malarials in the private sector were screened for eligibility. RESULTS: The total number of outlets approached for an interview was as follows in the intervention and comparison areas, respectively: 2012, N = 2046 and 1612; 2013, N = 1636 and 1884; 2014, N = 2939 and 2941. The percentage of pharmacies, general retailers and mobile providers (classed as 'priority outlets') with oral AMT in stock on the day of the survey decreased over time in the intervention areas (2012 = 68 %; 2013 = 48 %; 2014 = 10 %). Conversely, quality-assured ACT availability increased among these outlets (2012 = 4 %; 2013 = 62 %; 2014 = 79 %). Relative oral AMT market share among priority outlets also decreased over time (2012 = 44 %; 2013 = 18 %; 2014 = 14 %), while market share of quality-assured ACT increased (2012 = 3 %; 2013 = 59 %; 2014 = 51 %). Among priority outlets in the comparison area, similar trends were observed, though changes over time were less substantial compared to the intervention area. Other outlet types (community health workers and health facilities) performed relatively well over time though modest improvements were also observed. CONCLUSION: The findings point to the successful design and implementation of a strategy to rapidly remove oral AMT from pharmacies, general retailers and mobile providers and to replace its use with quality-assured ACT. The evidence also highlights the importance of supporting interventions in the context of a high-level subsidy. PMID- 27216409 TI - [Erratum to: Ductal adenocarcinoma and unusual differential diagnosis]. PMID- 27216410 TI - [Tumor-like lesions of bone]. AB - Historically, tumor-like lesions of bone were defined as non-neoplastic bone lesions. Today, however, some of them are considered real neoplasms. They are among the most frequent bone lesions. They usually grow slowly, but occasionally they grow rapidly. Many of them can be diagnosed by plain films alone; in others, CT and MRI yield additional features for a correct diagnosis. Some lesions do not need treatment; others should be resected, and some may even recur. Non-ossifying fibroma, juvenile and aneurysmal bone cysts, fibrous and osteofibrous dysplasia and eosinophilic granuloma are presented. PMID- 27216411 TI - The 51st Congress of the European Society for Surgical Research. May 25-28, 2016, Prague, Czech Republic: Abstracts. PMID- 27216412 TI - A 1,2,3-dithiazolyl-o-naphthoquinone: a neutral radical with isolable cation and anion oxidation states. AB - Under aprotic conditions, the reaction of 4-amino-1,2-naphthoquinone with excess S2Cl2 generates 4,5-dioxo-naphtho[1,2-d][1,2,3]dithiazol-2-ium chloride in a typical Herz condensation. By contrast, prior literature reports an imine (NH) product, 4,5-dioxo-1H-naphtho[1,2-d][1,2,3]dithiazole, for the same reaction performed in acetic acid. Herein, the cation product is isolated with four different counter-anions (Cl(-), GaCl4(-), FeCl4(-) and OTf(-)). Reduction of the cation generates a neutral radical 1,2,3-dithiazolyl-o-naphthoquinone, with potential ligand properties. Further reduction generates a closed shell anion, isolated as a water-stable Li(+) complex and exhibiting O,O-bidentate chelation. The hydroxy (OH) isomer of the original imine (NH) product is reported, and this can be readily deprotonated and acylated (OAc). All species are structurally characterized. Solution redox behaviour and EPR are discussed where appropriate. PMID- 27216413 TI - Aspartame intake is associated with greater glucose intolerance in individuals with obesity. AB - This study examined whether sucrose, fructose, aspartame, and saccharin influences the association between obesity and glucose tolerance in 2856 adults from the NHANES III survey. Aspartame intake significantly influenced the association between body mass index (BMI) and glucose tolerance (interaction: P = 0.004), wherein only those reporting aspartame intake had a steeper positive association between BMI and glucose tolerance than those reporting no aspartame intake. Therefore, consumption of aspartame is associated with greater obesity related impairments in glucose tolerance. PMID- 27216414 TI - Targeted Therapy and Checkpoint Immunotherapy Combinations for the Treatment of Cancer. AB - Many advances in the treatment of cancer have been driven by the development of targeted therapies that inhibit oncogenic signaling pathways and tumor-associated angiogenesis, as well as by the recent development of therapies that activate a patient's immune system to unleash antitumor immunity. Some targeted therapies can have effects on host immune responses, in addition to their effects on tumor biology. These immune-modulating effects, such as increasing tumor antigenicity or promoting intratumoral T cell infiltration, provide a rationale for combining these targeted therapies with immunotherapies. Here, we discuss the immune modulating effects of targeted therapies against the MAPK and VEGF signaling pathways, and how they may synergize with immunomodulatory antibodies that target PD1/PDL1 and CTLA4. We critically examine the rationale in support of these combinations in light of the current understanding of the underlying mechanisms of action of these therapies. We also discuss the available preclinical and clinical data for these combination approaches and their implications regarding mechanisms of action. Insights from these studies provide a framework for considering additional combinations of targeted therapies and immunotherapies for the treatment of cancer. PMID- 27216415 TI - Multi-component self-assembled anti-tumor nano-vaccines based on MUC1 glycopeptides. AB - Novel multi-component self-assembled nano-vaccines containing both Pam3CSK4 and CpG were developed for the first time. These multi-component vaccines could effectively activate the macrophages in vitro and elicit strong antibody immune responses and anti-tumor immune responses in vivo. PMID- 27216416 TI - A survey of views and opinions of health professionals managing thirst in chronic heart failure. AB - BACKGROUND: Thirst is a common and burdensome symptom of chronic heart failure (CHF) which affects adherence to self-care practices specifically fluid restriction. Despite this, there is no standard clinical practice for managing the symptom of thirst. AIMS AND OBJECTIVES: The aim is to identify the current strategies recommended by health professionals to help relieve thirst in CHF patients and their perceived usefulness of these strategies. METHODS: A survey was distributed to attendees of the 8th Annual Scientific Meeting of Australasian Cardiovascular Nursing College. RESULTS: There were 42 of 70 respondents to the survey. The majority (33 of 40; 82.5%) had recommended various strategies to alleviate thirst. The most recommended strategy was ice chips (36 of 38; 94.7%). Overall, the respondents reported 'some use' in all of the strategies. CONCLUSION: Information from this survey may help in the incorporation of thirst relieving strategies into evidence-based guidelines; further improving the quality of care of patients. PMID- 27216417 TI - Pancreatic Surgery: Past, Present, and Future. PMID- 27216418 TI - A study of the influence of ethnicity on serology and clinical features in lupus. AB - OBJECTIVE: The objective of this study was to review the links between ethnicity, serology and clinical expression in systemic lupus erythematosus (SLE) in a single cohort that was followed over a 36-year period. PATIENTS AND METHODS: Patients with SLE treated at the University College London Hospitals (UCLHs) between January 1978 and December 2013 formed the cohort. We assessed the demographic, clinical and serological data. Standard methods were used for laboratory testing. The Student t test and Mann-Whitney U test were used for the continuous variables; the Fisher's exact test was used for the categorical variables. RESULTS: We studied 624 SLE patients: There were 571 women (91.5%), with a mean age at diagnosis of 29.0 +/- 6.5 years; and 53 men (8.5%), with a mean age at diagnosis of 29.4 +/- 15.3 years. Ethnically, 369 of the patients were European, 100 were Afro-Caribbean, 77 were East Asian, 56 were South Asian and 21 were of mixed ethnicity. The East Asian patients developed the disease at a younger age than the other ethnic groups (p < 0.0001). The Afro-Caribbean patients were less frequently associated with the presence of rash and photosensitivity, and the non-European patients were more likely to have alopecia and renal involvement. The South Asian patients were significantly associated with musculoskeletal and neurological involvement, serositis, Sicca syndrome and hematological features. The Afro-Caribbean patients had the highest prevalence of anti-Smith, anti-RNP, anti-Ro and anti-La antibodies. Anti-IgG anticardiolipin (aCL) antibodies were significantly associated with the non-East Asian groups; and hypocomplementemia was common in the East Asians. Rash, alopecia, mouth ulcers, serositis, neurological, joint and renal involvement were significantly associated with the presence of anti-Smith and anti-RNP antibodies in the Afro Caribbean group. We also observed an association of joint involvement and the presence of anti-Ro and anti-La antibodies in this group. CONCLUSIONS: The East Asian patients developed their SLE disease at a younger age than the other ethnic groups. Cutaneous involvement was more frequent in those who were not Afro Caribbean. Serositis, joint and neurological involvement were more frequently diagnosed in the South Asian patients. Anti-ENA antibodies were frequently associated with the Afro-Caribbean patients. PMID- 27216419 TI - Elevated procalcitonin levels in a severe lupus flare without infection. PMID- 27216420 TI - Formation of Magnetic Anisotropy by Lithography. AB - Artificial interface anisotropy is demonstrated in alternating Co/Pt and Co/Pd stripe patterns, providing a means of forming magnetic anisotropy using lithography. In-plane hysteresis loops measured along two principal directions are explained in depth by two competing shape and interface anisotropies, thus confirming the formation of interface anisotropy at the Co/Pt and Co/Pd interfaces of the stripe patterns. The measured interface anisotropy energies, which are in the range of 0.2-0.3 erg/cm(2) for both stripes, are smaller than those observed in conventional multilayers, indicating a decrease in smoothness of the interfaces when formed by lithography. The demonstration of interface anisotropy in the Co/Pt and Co/Pd stripe patterns is of significant practical importance, because this setup makes it possible to form anisotropy using lithography and to modulate its strength by controlling the pattern width. Furthermore, this makes it possible to form more complex interface anisotropy by fabricating two-dimensional patterns. These artificial anisotropies are expected to open up new device applications such as multilevel bits using in-plane magnetoresistive thin-film structures. PMID- 27216421 TI - Erratum to: Network-driven plasma proteomics expose molecular changes in the Alzheimer's brain. PMID- 27216422 TI - Gibberellin stimulates regrowth after defoliation of sheepgrass (Leymus chinensis) by regulating expression of fructan-related genes. AB - Gibberellins (GAs) affect forage growth and development; however, it is largely unknown how GAs regulate the metabolism of fructan (an important polysaccharide reserve in many cereals) and the regrowth of forage plants after defoliation. To explore the mechanism of the responses of defoliated sheepgrass [Leymus chinensis (Trin.) Tzvel] to GA, we sprayed defoliated sheepgrass with GA3 and/or paclobutrazol (PAC; an inhibitor of GA biosynthesis) and analyzed the growth characteristics, carbohydrate contents, and transcript levels of genes related to GA metabolism, GA signal transduction, and fructan metabolism. The results showed that spraying exogenous GA3 onto defoliated sheepgrass promoted leaf and internode elongation, while spraying with PAC inhibited leaf and internode elongation, compared with the control. Spraying GA3 onto defoliated sheepgrass also altered the fructan content by extending the period of fructan utilization. At the transcriptional level, exogenous GA3 increased the transcript levels of genes related to GA metabolism in the sheath. Taken together, our results suggest that exogenous GA3 stimulates the regrowth of defoliated sheepgrass regrowth by regulating GA and fructan-related genes, and by promoting endogenous GA synthesis, fructan metabolism, and signaling. PMID- 27216423 TI - Arabidopsis ATAF1 enhances the tolerance to salt stress and ABA in transgenic rice. AB - NAC (NAM, ATAF1/2, CUC2) transcription factors are plant-specific and have diverse functions in many plant developmental processes and responses to stress. In our previous study, we found that the expression of ATAF1, an Arabidopsis NAC gene, was obviously induced by high-salinity and abscisic acid (ABA). The overexpression of ATAF1 in Arabidopsis increased plant sensitivity to ABA and salt. To investigate whether ATAF1 affects the sensitivity of monocotyledon plant to salt and ABA, ATAF1 transgenic rice were generated. Transgenic rice exhibited significantly improved salt tolerance and insensitivity to ABA. The results of real-time PCR showed that ATAF1 overexpression in rice elevated the transcription of OsLEA3, OsSalT1 and OsPM1, which are stress-associated genes. Our results indicate that ATAF1 plays an important role in response to salt stress and may be utilized to improve the salt tolerance of rice. PMID- 27216424 TI - Screening dietary flavonoids for the reversal of P-glycoprotein-mediated multidrug resistance in cancer. AB - P-Glycoprotein (P-gp) serves as a therapeutic target for the development of inhibitors to overcome multidrug resistance in cancer cells. Although various screening procedures have been practiced so far to develop first three generations of P-gp inhibitors, their toxicity and drug interaction profiles are still a matter of concern. To address the above important problem of developing safe and effective P-gp inhibitors, we have made systematic computational and experimental studies on the interaction of natural phytochemicals with human P gp. Molecular docking and QSAR studies were carried out for 40 dietary phytochemicals in the drug-binding site of the transmembrane domains (TMDs) of P gp. Dietary flavonoids exhibit better interactions with homology modeled human P gp. Based on the computational analysis, selected flavonoids were tested for their inhibitory potential against P-gp transport function in drug resistant cell lines using calcein-AM and rhodamine 123 efflux assays. It has been found that quercetin and rutin were the highly desirable flavonoids for the inhibition of P gp transport function and they significantly reduced resistance in cytotoxicity assays to paclitaxel in P-gp overexpressing MDR cell lines. Hence, quercetin and rutin may be considered as potential chemosensitizing agents to overcome multidrug resistance in cancer. PMID- 27216425 TI - Crosstalk between AhR and wnt/beta-catenin signal pathways in the cardiac developmental toxicity of PM2.5 in zebrafish embryos. AB - Recent studies have shown an association between congenital heart defects and air fine particle matter (PM2.5), but the molecular mechanisms remain elusive. It is well known that a number of organic compounds in PM2.5 can act as AhR agonists, and activation of AhR can antagonize Wnt/beta-catenin signaling. Therefore, we hypothesized that PM2.5 could activate AhR and then repress the expression of wnt/beta-catenin targeted genes essential for cardiogenesis, resulting in heart defects. To test this hypothesis, we investigated the effects of extractable organic matter (EOM) from PM2.5 on AhR and Wnt/beta-catenin signal pathways in zebrafish embryos. We confirmed that EOM could cause malformations in the heart and decreased heart rate in zebrafish embryos at 72hpf, and found that the EOM induced heart defects were rescued in embryos co-exposed with EOM plus AhR antagonist CH223191 or beta-catenin agonist CHIR99021. We further found that EOM had increased the expression levels of AhR targeted genes (Cyp1a1, Cyp1b1 and Ahrra) and reduced the mRNA levels of beta-catenin targeted genes (axin2, nkx2.5 and sox9b). The mRNA expression level of Rspo2, a beta-catenin upstream gene, was also decreased in embryos exposed to EOM. Supplementation with CH223191 or CHIR99021 attenuated most of the EOM-induced expression changes of genes involved in both AhR and wnt/beta-catenin signal pathways. However, the mRNA expression level of AhR inhibitor Ahrrb, which did not change by EOM treatment alone, was increased in embryos co-exposed to EOM plus CH223191 or CHIR99021. We conclude that the activation of AhR by EOM from PM2.5 might repress wnt/beta-catenin signaling, leading to heart defects in zebrafish embryos. Furthermore, our results indicate that the cardiac developmental toxicity of PM2.5 might be prevented by targeting AhR or wnt/beta-catenin signaling. PMID- 27216426 TI - Influence of exposure time on toxicity-An overview. AB - Data on toxicity of chemicals is usually reported as the LD50, or LC50, with the exposure time from experimental testing in the laboratory reported. But the exposure time is not considered to be a quantifiable variable which can be used to evaluate its importance in expressed toxicity, often described in general terms such as acute, chronic and so on. For the last hundred years Habers Rule has been successfully used to extrapolate from reported exposure times to other exposure times which may be needed for setting standards, health risk assessments and other applications. But it has limitations particularly in environmental applications where exposure levels are low and exposure times are relatively long. The Reduced Life Expectancy (RLE) model overcomes these problems and can be utilised under all exposure conditions. It can be expressed as ln(LT50)=-a (LC50)(nu)+b where the constants nu, a and b can be evaluated by fitting the model to experimental data on the LC50, and corresponding LT50, together with the Normal Life Expectancy (NLE) of the organism being considered as a data point when the LC50 is zero. The constant, nu, at a value of unity gives a linear relationship and where nu<1 the relationship has a concave shape. In our extensive evaluations of the RLE model for fish, invertebrates and mammals involving 115 data sets and with a wide range of organic and inorganic toxicants the RLE model gave correlation coefficients of >0.8 with 107 sets of data. The RLE model can be used to extrapolate from a limited data set on exposure times and corresponding LT50 values to any exposure time and corresponding LT50 value. The discrepancy between Haber's Rule and RLE model increases as the exposure time increases. PMID- 27216427 TI - Application of the Price-Volume Approach in Cases of Innovative Drugs Where Value Based Pricing is Inadequate: Description of Real Experiences in Italy. AB - Several cases of expensive drugs designed for large patient populations (e.g. sofosbuvir) have raised a complex question in terms of drug pricing. Even assuming value-based pricing, the treatment with these drugs of all eligible patients would have an immense budgetary impact, which is unsustainable also for the richest countries. This raises the need to reduce the prices of these agents in comparison with those suggested by the value-based approach and to devise new pricing methods that can achieve this goal. The present study discusses in detail the following two methods: (i) The approach based on setting nation-wide budget thresholds for individual innovative agents in which a fixed proportion of the historical pharmaceutical expenditure represents the maximum budget attributable to an innovative treatment; (ii) The approach based on nation-wide price-volume agreements in which drug prices are progressively reduced as more patients receive the treatment. The first approach has been developed in the USA by the Institute for Clinical and Economic Review and has been applied to PCSK9 inhibitors (alirocumab and evolocumab). The second approach has been designed for the Italian market and has found a systematic application to manage the price of ranibizumab, sofosbuvir, and PCSK9 inhibitors. While, in the past, price-volume agreements have been applied only on an empirical basis (i.e. in the absence of any quantitative theoretical rule), more recently some explicit mathematical models have been described. The performance of these models is now being evaluated on the basis of the real-world experiences conducted in some European countries, especially Italy. PMID- 27216428 TI - Attitudes of Patients and Prescribing Clinicians to Polypharmacy and Medication Withdrawal in Heart Failure. PMID- 27216429 TI - CD20-Mimotope Peptide Active Immunotherapy in Systemic Lupus Erythematosus and a Reappraisal of Vaccination Strategies in Rheumatic Diseases. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune disease in which any organs can be potential targets of autoimmune aggression. Although the pathogenic auto-antibodies have been well characterized, the role of B cells goes far beyond that of antibodies production, and B cell-targeted therapy may be an interesting therapeutic approach. The anti-CD20 monoclonal antibody rituximab has been successfully used to control the most severe form of SLE, and even if two controlled clinical trials failed to demonstrate its superiority compared to conventional immunosuppressants, off-label use of rituximab is still commonly adopted in clinical practice in SLE nephritis resistant to immunosuppressants. Different protocols have stipulated heterogeneous dosages but all of them included repeated injections of the drug, exposing the patient to the risk of adverse reactions and to tachyphylaxis (loss of the therapeutic effect). Stimulation of the host's immune system to develop a CD20 antigen-specific immune response by means of CD20-mimotope molecules may offer an approach that can overcome these drawbacks. This study provides a critical overview of vaccination therapy in rheumatic diseases and reports the design of a vaccination strategy in (New Zealand Black/New Zealand White) F1 SLE-prone mice using CD20-mimotope peptides. By week 47, this vaccine induces a B- cell depletion by 74 % (cell number, mean +/- SD, 0.57 +/- 0.38) as compared to week 29 (2.19 +/- 0.55) (p = 0.005) and prolongs survival in peptide-treated mice (median, 46.71 weeks; 95 % CI, 39.78-53.64) as compared to the control group (median 39.85; 95 % CI, 37.41 42.30) (Kaplan-Meier p = 0.002), although no differences between the peptide group and control group were detected in terms of proteinuria and auto-antibodies titers. These data indicate the feasibility of this approach, and the mouse model described here may be useful to optimize vaccination protocol and to define the mechanism(s) underlying B- cell depletion. PMID- 27216432 TI - Shock-wave lithotripsy: variance within UK practice. AB - The objectives of this study are to determine the current treatment policies of UK shock-wave lithotripsy centres. Fixed-site lithotripter centres in the UK were identified via the national Therapeutic Interventions for Stones of the Ureter (TISU) study (n = 25). Questionnaires were completed regarding current SWL protocols for each centre, including management of anticoagulation, use of antibiotics and analgesia, urine testing, pacemakers, and arterial aneurysms. Data were collected regarding service delivery. Responses were obtained for 21 centres. Most centres use the Storz Modulith (85.7 %). Wide variation was observed in clinical contraindications to SWL, with 47.6 % centres performing SWL in patients with an abdominal aortic aneurysm, 66.7 % performing SWL in patients with a pacemaker, and 66.7 % of centres not performing SWL in asymptomatic patients with a urine dipstick positive for nitrites and leucocytes. The management of anticoagulation pre- and post-SWL showed wide variation, with the omission of anticoagulation ranging from 0 to 10 days pre-SWL. Seventeen distinct analgesia regimens were reported and prophylactic antibiotics are routinely administered in 25.0 % of centres. Tamsulosin is prescribed to all patients in 20.0 % of centres and a further 15.0 % of centres routinely prescribe tamsulosin post-SWL of ureteric stones. The included centres undertake SWL a median of 4 days per week and treat a median of six patients per list. Emergency SWL is unavailable in 30.0 % of centres. This observational real-life study has identified a significant disparity in the delivery of SWL throughout the UK, despite high numbers of patients with renal and ureteric stones being treated with this modality. Further studies should address the key areas of controversy, including an assessment of technical training, and facilitate the development of national guidelines to ensure a high level of standardized care for SWL patients. PMID- 27216433 TI - Neuroscience-based nomenclature (jNbN) to replace traditional terminology of psychotropic medications. PMID- 27216430 TI - The Role of STAT Signaling Pathways in the Pathogenesis of Systemic Lupus Erythematosus. AB - Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder with a broad spectrum of clinical presentations and association with multiple immunological abnormalities. Recent research of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway-revealed aberrant STAT signaling in inflammatory conditions and autoimmune diseases including SLE. STAT proteins are major components in interferon (IFN)-dependent gene expression and are responsible for signal transduction of over 50 cytokines, hormones, and growth factors regulating key cellular processes such as survival, proliferation, and differentiation. This review summarizes the present evidence from experimental animal models and patients with SLE for the involvement of STAT pathways in the pathogenesis of SLE underlining the role of different members of the STAT family. Genome-wide association studies provided evidence that variations in STAT4 gene are linked to the development of SLE in humans. First integration with genome-wide epigenomics data suggests that control of CD4+ T cell differentiation in which STATs play a major role may be an important component of the genetic contribution to disease susceptibility. Increased transcript and total protein STAT1 levels were described both in SLE T and B cells suggestive of the priming mechanisms that augment STAT1 signaling responses to IFN. STAT3 has a crucial role in Th17 differentiation, T follicular helper, and B cells, and STAT3 inhibition could represent a possible future therapeutic target in SLE. STAT5B appears to act as a critical modulator of human Treg development and function. While the imbalance between phosphorylated STAT5 and STAT3 in human SLE T cells was implicated in dysregulated IL-10 expression, Treg specific deletion of STAT3 in mouse model even enhanced Th17-mediated inflammation. Finally, we present also a comprehensive analysis of studies investigating STAT signaling responses in conventional and regulatory subsets of SLE T and B cells and possible implications of STAT inhibition for clinical therapy. PMID- 27216434 TI - An open letter concerning do-it-yourself users of transcranial direct current stimulation. PMID- 27216435 TI - Phospholipid: diacylglycerol acyltransferase contributes to the conversion of membrane lipids into triacylglycerol in Myrmecia incisa during the nitrogen starvation stress. AB - In addition to the Kennedy pathway for de novo biosynthesis, triacylglycerol (TAG), the most important stock for microalgae-based biodiesel production, can be synthesized by phospholipid: diacylglycerol acyltransferase (PDAT) that transfers an acyl group from phospholipids (PLs) to diacylglycerol (DAG). This study presents a novel gene that encodes PDAT from the green microalga Myrmecia incisa Reisigl H4301 (designated MiPDAT ). MiPDAT is localized on the plasma membrane (PM) via the agroinfiltration of tobacco leaves with a green fluorescent protein fused construct. MiPDAT synthesizes TAG based on functional complementary experiments in the mutant yeast strain H1246 and the membrane lipid phosphatidylcholine (PC) is preferentially used as substrates as revealed by in vitro enzyme activity assay. The gradually increased transcription levels of MiPDAT in M. incisa during the cultivation under nitrogen starvation conditions is proposed to be responsible for the decrease and increase of the PC and TAG levels, respectively, as detected by liquid chromatography-mass spectrometry after 4 d of nitrogen starvation. In addition, the mechanism by which MiPDAT in this microalga uses PC to yield TAG is discussed. Accordingly, it is concluded that this PM-located PDAT contributes to the conversion of membrane lipids into TAG in M. incisa during the nitrogen starvation stress. PMID- 27216436 TI - Simultaneous cathodoluminescence and electron microscopy cytometry of cellular vesicles labeled with fluorescent nanodiamonds. AB - Light and Transmission Electron Microscopies (LM and TEM) hold potential in bioimaging owing to the advantages of fast imaging of multiple cells with LM and ultrastructure resolution offered by TEM. Integrated or correlated LM and TEM are the current approaches to combine the advantages of both techniques. Here we propose an alternative in which the electron beam of a scanning TEM (STEM) is used to excite concomitantly the luminescence of nanoparticle labels (a process known as cathodoluminescence, CL), and image the cell ultrastructure. This CL STEM imaging allows obtaining luminescence spectra and imaging ultrastructure simultaneously. We present a proof of principle experiment, showing the potential of this technique in image cytometry of cell vesicular components. To label the vesicles we used fluorescent diamond nanocrystals (nanodiamonds, NDs) of size ~150 nm coated with different cationic polymers, known to trigger different internalization pathways. Each polymer was associated with a type of ND with a different emission spectrum. With CL-STEM, for each individual vesicle, we were able to measure (i) their size with nanometric resolution, (ii) their content in different ND labels, and realize intracellular component cytometry. In contrast to the recently reported organelle flow cytometry technique that requires cell sonication, CL-STEM-based image cytometry preserves the cell integrity and provides a much higher resolution in size. Although this novel approach is still limited by a low throughput, the automatization of data acquisition and image analysis, combined with improved intracellular targeting, should facilitate applications in cell biology at the subcellular level. PMID- 27216437 TI - Recurrent pulseless electrical activity in a patient with coronary vasospasm and supravalvular aortic stenosis: a case report. AB - BACKGROUND: Pulseless electrical activity cardiac arrest is associated with poor outcomes and the identification of potentially reversible reasons for cardiac arrest is fundamental. CASE PRESENTATION: We describe the case of a 46-year-old male with the rare coincidental finding of supravalvular aortic stenosis and coronary vasospasm leading to recurrent pulseless electrical activity cardiac arrest. Extracorporeal life support was successfully applied for hemodynamic stabilization. Supravalvular aorticstenosis underwent surgical repair. The patient survived five time resuscitation and was discharged after full neurological recovery. CONCLUSIONS: Coronary vasospasm and supravalvular aortic stenosis are rare but potentially reversible causes of pulseless electrical activity cardiac arrest. Extracorporeal life support allows accurate diagnostic and possibly therapy even of uncommon reasons for cardiac arrest. PMID- 27216438 TI - NAT2 polymorphisms and risk for Parkinson's disease: a systematic review and meta analysis. AB - INTRODUCTION: Several studies suggested a possible association between certain polymorphisms in the N-acetyl-transferase 2 (NAT2) gene (which encodes a very important enzyme involved in xenobiotic metabolism) and the risk for Parkinson's disease (PD). As the results of studies on this issue are controversial, we conducted a systematic review and a meta-analysis of eligible studies on this putative association. AREAS COVERED: The authors revised the relationship between NAT2 polymorphisms and the risk of developing PD using several databases, and performed a meta-analysis using the software Meta-Disc1.1.1. In addition heterogeneity between studies was analyzed. A description of studies regarding gene-gene interactions and gene-environmental interactions involving NAT2 polymorphisms is also made. EXPERT OPINION: Despite several recent meta-analyses showing an association between several polymorphisms in genes related with detoxification mechanisms such as cytochrome P4502D6 (CYP2D6), and glutathione transferases M1 and T1 (GSTM1, and GSTT1), data on NAT2 gene polymorphisms obtained from the current meta-analysis do not support a major association with PD risk, except in Asian populations. However, data from many studies are incomplete and therefore insufficient data exists to draw definitive conclusions. Several studies suggesting gene-gene and gene-environmental factors involving NAT2 gene in PD risk await confirmation. PMID- 27216439 TI - Efficient analysis of large datasets and sex bias with ADMIXTURE. AB - BACKGROUND: A number of large genomic datasets are being generated for studies of human ancestry and diseases. The ADMIXTURE program is commonly used to infer individual ancestry from genomic data. RESULTS: We describe two improvements to the ADMIXTURE software. The first enables ADMIXTURE to infer ancestry for a new set of individuals using cluster allele frequencies from a reference set of individuals. Using data from the 1000 Genomes Project, we show that this allows ADMIXTURE to infer ancestry for 10,920 individuals in a few hours (a 5 * speedup). This mode also allows ADMIXTURE to correctly estimate individual ancestry and allele frequencies from a set of related individuals. The second modification allows ADMIXTURE to correctly handle X-chromosome (and other haploid) data from both males and females. We demonstrate increased power to detect sex-biased admixture in African-American individuals from the 1000 Genomes project using this extension. CONCLUSIONS: These modifications make ADMIXTURE more efficient and versatile, allowing users to extract more information from large genomic datasets. PMID- 27216440 TI - Extensive study of potential harmful elements (Ag, As, Hg, Sb, and Se) in surface sediments of the Bohai Sea, China: Sources and environmental risks. AB - This study analyzed 405 surface sediment samples, obtained from across the Bohai Sea, for concentrations of five potentially harmful elements (Ag, As, Hg, Sb, and Se) and several ancillary parameters (Al, Fe, Mn, total organic carbon (TOC), and grain size). Statistically, the spatial distributions of these elements were correlated positively with Al, Fe, TOC, and grain size, indicating natural sources for these elements or common accumulation mechanisms. The assessment of potential environmental risk with empirical sediment quality guidelines showed that a significant proportion of the samples had As and Sb concentrations that exceeded the effects range low (ERL) or T20 values in the Bohai Sea, indicating the potential for adverse biological effects. However, the assessment results differed when using evaluation methods that considered background values. Based on the geoaccumulation index (Igeo), Hg and Ag were found to have the highest percentages (35% and 60%, respectively) in samples that were moderately contaminated. The estimated contamination degree (Cd) suggested higher contamination levels for the entire area, with 69% of the samples being moderately contaminated. Generally, except for some local hotspots, such as Jinzhou Bay, the contamination levels of these elements in the Bohai Sea were established as slight to moderate. Samples from the Jinzhou Bay area had concentrations that were 10-100 times higher than in the rest of the Bohai Sea, indicating severe contamination. PMID- 27216441 TI - Impact of disability and chronic conditions on health. AB - BACKGROUND: Today one in five Americans have a disability and nearly half of Americans experiences a chronic condition. Whether disability results from or is a risk factor for chronic conditions, the combined effects of disability and chronic conditions warrants further investigation. OBJECTIVES: Examine the added impact of chronic conditions among those with and without disability on self reported health status and behaviors. METHODS: 2009 Behavioral Risk Factor Surveillance System (BRFSS) data were analyzed to examine the association of disability with unhealthy behaviors and poor health stratified by number of self reported chronic conditions (0, 1, or 2+). Linear and logistic regression models accounting for the complex survey weights were used. RESULTS: Participants with disability were 6 times more likely to report fair/poor self-rated health, reported 9 more unhealthy days in a month and 6 more days in a month when poor health kept them from usual activities, were 4 times more likely to be dissatisfied with life, had greater odds of being a current smoker, and were less likely to be physically active. Presence of chronic conditions in addition to disability was associated, in a dose-response manner, with poor health status and unhealthy behaviors. CONCLUSIONS: People living with both chronic diseases and disability are at substantially increased risks for poor health status and unhealthy behaviors, further affecting effective management of their chronic conditions. Multi-level interventions in primary care and in the community that address social and environmental barriers that hinder adults with disability from adopting more healthy lifestyles and improving health are needed. PMID- 27216442 TI - Closure of community pharmacies in deprived areas will increase GP consultations, says report. PMID- 27216443 TI - Correction: Cucurbit[7]uril inclusion complexation as a supramolecular strategy for color stabilization of anthocyanin model compounds. AB - Correction for 'Cucurbit[7]uril inclusion complexation as a supramolecular strategy for color stabilization of anthocyanin model compounds' by Barbara Held, et al., Photochem. Photobiol. Sci., 2016, DOI: 10.1039/c6pp00060f. PMID- 27216444 TI - Substituted N-aminothioglycolurils containing thiosemicarbazone moiety and their cytotoxic activity in vitro. AB - A library of hybrid molecules bearing thioglycoluril and (hetero)aromatic aldehyde thiosemicarbazone moieties was synthesized via a tandem hydrazone formation-ring contraction reaction of 5,7-dialkyl-3-thioxoperhydroimidazo[4,5-e] 1,2,4-triazin-6-ones with (hetero)aromatic aldehydes. All synthesized compounds were tested for their cytotoxic activity against rhabdomyosarcoma, A549, and MS human cancer cell lines by MTT-assay. Among the derivatives, (E)-4 benzylideneamino-1,3-dimethyl-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-one 1f was found to have the most marked antiproliferative activity toward the tested cell lines (1f: IC[Formula: see text] 23.7, and 6.4 [Formula: see text]M, respectively). The IC[Formula: see text] value of thioglycoluril 1f against normal human embryonic kidney cells HEK293 was 72.5 [Formula: see text]M, which appeared to be 3-11-fold higher than IC[Formula: see text] values of 1f against human cancer cells. PMID- 27216445 TI - Active site fingerprinting and pharmacophore screening strategies for the identification of dual inhibitors of protein kinase C (RhoKappaCbeta) and poly (ADP-ribose) polymerase-1 (PARP-1). AB - Current clinical studies have revealed that diabetic complications are multifactorial disorders that target two or more pathways. The majority of drugs in clinical trial target aldose reductase and protein kinase C ([Formula: see text]), while recent studies disclosed a significant role played by poly (ADP ribose) polymerase-1 (PARP-1). In light of this, the current study was aimed to identify novel dual inhibitors of [Formula: see text] and PARP-1 using a pharmaco informatics methodology. Pharmacophore-based 3D QSAR models for these two targets were generated using HypoGen and used to screen three commercially available chemical databases to identify dual inhibitors of [Formula: see text] and PARP-1. Overall, 18 hits were obtained from the screening process; the hits were filtered based on their drug-like properties and predicted binding affinities (docking analysis). Important amino acid residues were predicted by developing a fingerprint of the active site using alanine-scanning mutagenesis and molecular dynamics. The stability of the complexes (18 hits with both proteins) and their final binding orientations were investigated using molecular dynamics simulations. Thus, novel hits have been predicted to have good binding affinities for [Formula: see text] and PARP-1 proteins, which could be further investigated for in vitro/in vivo activity. PMID- 27216446 TI - Characterization of an epimastigote-stage-specific hemoglobin receptor of Trypanosoma congolense. AB - BACKGROUND: Since Trypanosoma spp. lack a complete heme synthesis pathway, the parasites are totally dependent on their host for heme throughout all of the stages of their life-cycle. We herein report the identification and characterization of a T. congolense epimastigote form (EMF)-specific hemoglobin (Hb) receptor. The gene was initially reported to encode a T. congolense haptoglobin (Hp)-Hb complex receptor (TcHpHbR) based on its similarity to a gene encoding a T. brucei Hp-Hb complex receptor (TbHpHbR). METHODS: Trypanosoma congolense IL3000 was used in this study. A TcHpHbR gene was PCR amplified from the parasite genome. The recombinant protein was used as an immunogen to raise antibodies for immunofluorescence assay and immunoblotting. Hemoglobin uptake by the parasite was examined by using Alexa 488 labelled Hb and visualized by confocal laser scanning microscopy. The qualitative and quantitative interaction between TcHpHbR and its ligand were measured using a surface plasmon resonance assay. RESULTS: We found that, unlike TbHpHbR, TcHpHbR was exclusively expressed in the EMF stage at RNA and protein levels. The recombinant TcHpHbR (rTcHpHbR) was co-precipitated with free-Hb in a GST-pull down assay. Surface plasmon resonance revealed that rTcHpHbR binds free-Hb with high affinity (dissociation constant (K d) = 2.1*10(-8) M) but free-Hp with low affinity (K d = 2.2*10(-7) M). Furthermore, Alexa 488-labelled-Hb was only taken up by the EMF and co localized with tomato lectin, which is a marker of endocytic compartments (flagellar pocket and lysosome). CONCLUSION: We conclude that the T. congolense EMF takes up free-Hb via TcHpHbR, a receptor which is specific to this developmental stage. We therefore propose renaming TcHpHbR as T. congolense EMF specific Hb receptor (TcEpHbR). PMID- 27216447 TI - Tepidibacillus infernus sp. nov., a moderately thermophilic, selenate- and arsenate-respiring hydrolytic bacterium isolated from a gold mine, and emended description of the genus Tepidibacillus. AB - A novel aerotolerant anaerobic, moderately thermophilic, organotrophic bacterium, strain MBL-TLPT, was isolated from a sample of microbial mat, developed under the flow of subsurface water in TauTona gold mine, South Africa. Cells of the new isolate were flagellated, spore-forming rods, 0.25-0.5 um in width and 3-15 um in length. Strain MBL-TLPT grew in the temperature range from 25 to 58 degrees C, pH range from 5.6 to 8.8 and at NaCl concentration from 0 to 85 g l-1. The isolate was able to ferment yeast extract and mono-, oligo- and polysaccharides, including starch and xanthan gum. The G+C content of the DNA was 35 mol%. Phylogenetic analysis of 16S rRNA gene sequences of strain MBL-TLPT and relatives showed its affiliation to the genus Tepidibacillus. Tepidibacillus fermentans STGHT was its closest relative (97.1 % identity of 16S rRNA gene sequences). Based on phylogenetic analysis and the physiological properties of the novel isolate, we propose a novel species, Tepidibacillus infernus sp. nov., with MBL TLPT(=DSM 28123T=VKM V-2949T) as the type strain. PMID- 27216448 TI - Rapid and Efficient One-Pot Synthesis of 3,4-Dihydroquinoxalin-2-Amine Derivatives Catalyzed by Co3O4@SiO2 Core-Shell Nanoparticles Under Ultrasound Irradiation. AB - In this research, a general synthetic method for the synthesis of 3,4- dihydroquinoxalin-2-amine derivatives was developed using Co3O4@SiO2 nanoparticles under ultrasonic irradiation. Firstly by a simple and green process, Co3O4;@SiO2 nanoparticles were prepared via sonication, and then these nanoparticles were used as an efficient catalyst for the synthesis of 3,4- dihydroquinoxalin-2-amines via three-component reactions of ophenylenediamines (OPDA), diverse ketones and various isocyanides in ethanol under ultrasound irradiation. The combinatorial synthesis was attained for this procedure with applying ultrasound irradiation while making use of ethanol as green ambient. The present approach offers several advantages such as high yields, environmentally benign, simple work-up, excellent yield of products and short reaction times. The nanomagnetic catalyst could be readily recovered using a simple external magnet and reused several times without any significant loss in activity. The catalyst was fully characterized by FT-IR, FE-SEM, XRD, EDX, VSM and TEM analysis. PMID- 27216449 TI - Diagnosis value of serum soluble B7-H4 expression in non-small cell lung cancer. AB - INTRODUCTION: B7-H4, a member of the inhibitory B7 family, can restrain T cell proliferation, activation, cytokine secretion, and may be involved in immune evasion in cancer patients. OBJECTIVES: This aim of the study was to determine the expression level of soluble B7-H4 (sB7-H4) in circulation and to subsequently evaluate the clinical significance of circulating sB7-H4 in patients with non small cell lung cancer (NSCLC). METHODS: Serum specimens from 128 patients with NSCLC, 100 healthy volunteers (HV), and 80 patients with benign lung diseases (BLD) were collected. The concentrations of sB7-H4 were measured by sandwich enzyme-linked immunosorbent assay. RESULTS: Serum sB7-H4 levels in patients with NSCLC were significantly higher than those in patients with BLD (P < 0.05), or those in HV (P < 0.05). Using a cutoff of 27.8 ng/mL, the sensitivity and specificity of sB7-H4 in differentiating between patients with NSCLC and patients with BLD, and between patients with NSCLC and HV was, 46.9% and 92.5%, and 54.7% and 95.0%, respectively. An area under the curve (AUC) for NSCLC resulting from sB7-H4 (0.863), which was significantly better than any other tumour markers tested including CA125 (0.763), and CEA (0.775). CONCLUSION: In conclusion, assessment of serum sB7-H4 levels could be considered as a diagnostic biomarker for NSCLC. PMID- 27216450 TI - Surface complex of ZnTMPyP4 metalloporphyrin with double-stranded Poly(A) Poly(U). AB - This communication presents synthesis and spectral characterization of metalloporphyrin [Zn(X)TMPyP4] (TMPyP4 is 5,10,15,20-tetrakis (N-methylpyridinium 4-yl)porphyrin), and studies its binding onto anionic surface sites of synthetic double stranded polynucleotide Poly(A)-Poly(U). [Zn(X)TMPyP4] binding with Poly(A)-Poly(U) was monitored by UV-Vis absorbance spectroscopy, two fluorescence spectroscopies and 1H NMR in a working aqueous medium of 0.15M ionic strength, pH7.0 and at 25 degrees C. The evidence provided by spectroscopic measurements and multivariate data analysis suggests the use of this metalloporphyrin as a probe for investigation of the polynucleotide surface. In contrast to TMPyP4 intercalation, an outside adsorption of [Zn(X)TMPyP4] induces an attenuation of luminescence intensity and has little influence on the shape of luminescence band. Special attention was paid to the quantitative description of the interaction between neighboring ligands on the Poly(A)-Poly(U) surface. The intrinsic binding constant to an isolated binding site lgKin 5.8+/-0.1, the cooperativity parameter omega 1.8+/-0.2, and number of monomers occupied by a ligand n=2 (25 degrees C; pH7.0) were calculated based upon the recently proposed non-linear least-squares fitting procedure. The discovered cooperativity of binding of [Zn(X)TMPyP4] metalloporphyrin to Poly(A)-Poly(U) is significantly lower as compared to free porphyrin TMPyP4, reflecting minimal mutual influence between the nearest neighboring ligands bound with functional PO4(-) groups of the polynucleotide surface. PMID- 27216451 TI - Revised stability constant, spectroscopic properties and binding mode of Zn(II) to FluoZin-3, the most common zinc probe in life sciences. AB - 2-[2-[2-[2-[bis(carboxylatomethyl)amino]-5-methoxyphenoxy]ethoxy]-4-(2,7-difluoro 3-oxido-6-oxo-4a,9a-dihydroxanthen-9-yl)anilino]acetate (FluoZin-3) is used very broadly in life sciences as intra- and extracellular Zn(II) sensor selective for Zn(II) over Co(II), Ca(II) and Mg(II) ions at their physiological concentrations. It has been used for determination of relative and absolute levels of exchangeable Zn(II) in cells and extracellular fluids. Despite its popularity, the knowledge of its acid/base and Zn(II) coordination abilities and of its spectroscopic properties remained very limited. Also the published conditional dissociation constant ((C)Kd) values at pH7.4 are slightly discrepant, (15nM or 8.9nM). In this work we determined the (C)Kd for Zn(II) complexation by FluoZin-3 at pH7.4 with nitrilotriacetic acid (NTA) as competitor using two independent methods: fluorimetry and UV-Vis spectroscopy. For the first time, we investigated FluoZin-3 alone and complexed with Zn(II) in the wide range of pH, determining the total of eight pKa values from fluorescence spectra and from various regions of UV-Vis spectra. The validated values of (C)Kd (9.1+/-0.4nM; -log (C)Kd=8.04) and of the absolute (pH-independent) stability constant log betaZnL (8.16+/-0.05) were provided by fluorescence spectroscopy experiments performed at 1MUM concentrations. Our experiments demonstrated that both of aminocarboxylate moieties of FluoZin-3 bind the Zn(II) ion synergistically. PMID- 27216452 TI - Strong infrared photoluminescence in highly porous layers of large faceted Si crystalline nanoparticles. AB - Almost all physical processes in solids are influenced by phonons, but their effect is frequently overlooked. In this paper, we investigate the photoluminescence of large silicon nanoparticles (approximately 100 nm size, synthesized by chemical vapor deposition) in the visible to the infrared detection range. We find that upon increasing laser irradiance, an enormous photoluminescence emission band appears in the infrared. Its intensity exhibits a superlinear power dependence, increasing over four orders of magnitude in the investigated pump power range. Particles of different sizes as well as different shapes in porous layers are investigated. The results are discussed taking into account the efficient generation of phonons under high-power pumping, and the reduced capability, porosity dependent, of the silicon nanoparticles to exchange energy with each other and with the substrate. Our findings are relevant for heat management strategies in silicon. PMID- 27216453 TI - Prioritizing the Local in an Era of Globalization: A Proposal for Decentering Community Psychology. AB - In this article, I outline a proposal for decentering the field of United States based community psychology. Transnational migrations, border crossings, and proliferating neoliberal trade and global media characterize the contemporary moment we live in. These movements challenge any monolithic disciplinary narrative of community psychology. Drawing from liberation psychology and women of Color feminisms, I argue that decentering the field involves engendering more reciprocal, nonhierarchical relations between the core and peripheries of knowledge production. Specifically, I consider the decentering project in two related realms-content and agents of knowledge production. The first issue concerns the kind of research and theorizing we engage in, the issues or topics we investigate, and the subject populations we work with. The second issue pertains to the agents who engage in the aforementioned processes, exercising epistemic power, that is the authority to construct what is considered legitimate and valid knowledge. I conclude with the implications of the decentering project for a multistranded community psychology that is responsive to the cartographies of contemporary struggles. PMID- 27216454 TI - Occurrence predictors of the temporal interictal epileptic discharges in epilepsy patients with extratemporal lesions: A prospective cohort study. AB - OBJECTIVE: Electrical kindling models of epilepsy suggest that medial temporal structures are more prone to be irritated. The aim of this study is to investigate the occurrence rate of temporal interictal epileptic discharges (TIEDs) in the epilepsy patients with extratemporal lesions (ETLs), and to determine the predictive factors for TIEDs in this cohort. METHODS: Totally 221 patients were admitted for presurgical evaluation, and focal ETL were found in all of them by MRI examination. The occurrence rates of TIEDs in several groups with different brain lobe locations, durations; of epilepsy, seizure frequencies, and onset ages stages were assessed. We also evaluated the surgical outcome of; resection in this cohort. RESULTS: The total occurrence rate of TIEDs in this cohort was 29.9%. The occurrence rate of TIEDs in the patients with longer durations (>5 or 10 years) was significantly higher than those with shorter duration (<1 year). These; patients with lower seizure frequency (<1 seizure/month) had a significantly decreased incidence of TIEDs; compared with those with higher frequency (>1 seizure/month or week). In the terms of the brain lobe locations; and age at onset, there were no differences between the groups. Furthermore, there were no differences in terms of the surgical outcomes between the patients with TIEDs and other patients in this series. CONCLUSIONS: TIEDs were frequently recorded in these patients with ETLs, and the predictive factors for TIEDs included the epilepsy duration and seizure frequency. SIGNIFICANCE: This study is instrumental for the presurgical EEG interpretationand the counseling of these ETLs patients considered for epilepsy surgery. PMID- 27216455 TI - Correspondence to: Surgical management of cervico-mediastinal goiters: Our experience and review of literature. PMID- 27216456 TI - Lipid droplet proteins, Lds1p, Lds2p, and Rrt8p, are implicated in membrane protein transport associated with ergosterol. AB - Lipid droplets (LDs) are ubiquitous organelles, enclosed in a monolayer of phospholipid, which store excess fatty acids as neutral lipids such as triacylglycerol and sterol esters. Previous studies have revealed that LDs contain many proteins with various functions required for lipid metabolism and vesicular trafficking. Among them, Lds (Lipid Droplet in Sporulation) proteins, Lds1p and Lds2p, are reportedly induced and localized to LDs during yeast sporulation, but their cellular function has not been clarified. Here we show that the Lds proteins, Lds1p, Lds2p and Rrt8p, are expressed and localized at LDs in vegetative cells, being required for proper localization of plasma membrane proteins. We found that deletion of Lds genes led to mis-sorting of Wsc1p, a cell wall stress sensor, from the plasma membrane to the vacuole. We also demonstrated that lack of these proteins partially suppressed the growth defect and mis sorting of the high-affinity tryptophan transporter Tat2p, induced by impairment of ergosterol biosynthesis. Furthermore, we identified Sec39p/Dsl3p, a component of the DSL1 tethering complex that mediates the interaction with COPI vesicles, as a binding partner for Lds2p. These results suggest a possible role of Lds proteins in maintenance of membrane lipid homeostasis and accompanying membrane protein transport. PMID- 27216457 TI - Enterovirus 71 induces anti-viral stress granule-like structures in RD cells. AB - Stress granules (SGs) are dynamic cytoplasmic granules formed in response to a variety of stresses, including viral infection. Several viruses can modulate the formation of SG with different effects, but the relationship between SG formation and EV71 infection is poorly understood. In this study, we report that EV71 inhibits canonical SGs formation in infected cells and induces the formation of novel RNA granules that were distinguished from canonical SGs in composition and morphology, which we termed 'SG like structures'. Our results also demonstrated that EV71 triggered formation of SG-like structures is dependent on PKR and eIF2alpha phosphorylation and requires ongoing cellular mRNA synthesis. Finally, we found that SG-like structures are antiviral RNA granules that promote cellular apoptosis and suppress EV71 propagation. Taken together, our findings explain the formation mechanism of SG-like structures induced by EV71 and shed light on virus host interaction and molecular mechanism underlying EV71 pathogenesis. PMID- 27216458 TI - beta-Hydroxybutyrate elevation as a compensatory response against oxidative stress in cardiomyocytes. AB - Recent studies have shown that the ketone body beta-hydroxybutyrate (betaOHB) acts not only as a carrier of energy but also as a signaling molecule that has a role in diverse cellular functions. Circulating levels of ketone bodies have been previously reported to be increased in patients with congestive heart failure (HF). In this study, we investigated regulatory mechanism and pathophysiological role of betaOHB in HF. First, we revealed that betaOHB level was elevated in failing hearts, but not in blood, using pressure-overloaded mice. We also measured cellular betaOHB levels in both cardiomyocytes and non-cardiomyocytes stimulated with or without H2O2 and revealed that increased myocardial betaOHB was derived from cardiomyocytes but not non-cardiomyocytes under pathological states. Next, we sought to elucidate the mechanisms of myocardial betaOHB elevation and its implication under pathological states. The gene and protein expression levels of CoA transferase (SCOT), a key enzyme involved in ketone body oxidation, was decreased in failing hearts. In cardiomyocytes, H2O2 stimulation caused betaOHB accumulation concomitantly with SCOT downregulation, implying that the accumulation of myocardial betaOHB occurs because of the decline in its utilization. Finally, we checked the effects of betaOHB on cardiomyocytes under oxidative stress. We found that betaOHB induced FOXO3a, an oxidative stress resistance gene, and its target enzyme, SOD2 and catalase. Consequently, betaOHB attenuated reactive oxygen species production and alleviated apoptosis induced by oxidative stress. It has been reported that hyperadrenergic state in HF boost lipolysis and result in elevation of circulating free fatty acids, which can lead hepatic ketogenesis for energy metabolism alteration. The present findings suggest that the accumulation of betaOHB also occurs as a compensatory response against oxidative stress in failing hearts. PMID- 27216459 TI - Down-regulation of SIRT3 promotes ovarian carcinoma metastasis. AB - Distant metastasis and local recurrence are still the major causes for failure of treatment in patients with ovarian carcinoma (OC), making it urgent to further elicit the molecular mechanisms of OC metastasis. Sirtuin-3 (SIRT3), a member of the NAD(+)-dependent Class III histone deacetylases, may function as different role depending on the cell-type and tumor-type. However, the function and mechanism of SIRT3 has been not explored in OC metastasis. Here, we found that SIRT3 was significantly down-regulated in the metastatic tissues and highly metastatic cell line of ovarian cancer. In addition, knockdown of SIRT3 enhanced the migration and invasion in vitro and the liver metastasis in vivo of ovarian cancer cell. By contrast, ectopic overexpression of SIRT3 dramatically suppressed cancer cell metastatic capability. Mechanistically, SIRT3 inhibits epithelial-to mesenchymal transition (EMT) by down-regulating Twist in ovarian cancer cells. Furthermore, an interaction between SIRT3 and Twist was detected. In conclusion, our results demonstrated that SIRT3 plays a crucial suppressive role in the metastasis of ovarian cancer by down-regulating Twist, and that this novel SIRT3/Twist axis may be valuable to develop new strategies for treating OC patients with metastasis. PMID- 27216460 TI - Inhibition of lectin-like oxidized low-density lipoprotein receptor-1 reduces cardiac fibroblast proliferation by suppressing GATA Binding Protein 4. AB - Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and GATA Binding Protein 4 (GATA4) are important for the growth of cardiac fibroblasts (CFs). When deregulated, LOX-1 and GATA4 can cause cardiac remodeling. In the present study, we found novel evidence that GATA4 was required for the LOX-1 regulation of CF proliferation. The inhibition of LOX-1 by RNA interference LOX-1 lentivirus resulted in the loss of PI3K/Akt activation and GATA4 protein expression. The overexpression of LOX-1 by lentivirus rescued CF proliferation, PI3K/Akt activation, and GATA4 protein expression. Moreover, GATA4 overexpression enhanced CF proliferation with LOX-1 inhibition. We also found that the inhibition of PI3K/Akt activation by LY294002, a PI3K inhibitor, reduced cell proliferation and protein level of GATA4. In summary, GATA4 may play an important role in the LOX-1 and PI3K/Akt regulation of CF proliferation. PMID- 27216461 TI - microRNA-150 inhibits the formation of macrophage foam cells through targeting adiponectin receptor 2. AB - Transformation of macrophages into foam cells plays a critical role in the pathogenesis of atherosclerosis. The aim of this study was to determine the expression and biological roles of microRNA (miR)-150 in the formation of macrophage foam cells and to identify its functional target(s). Exposure to 50 MUg/ml oxidized low-density lipoprotein (oxLDL) led to a significant upregulation of miR-150 in THP-1 macrophages. Overexpression of miR-150 inhibited oxLDL induced lipid accumulation in THP-1 macrophages, while knockdown of miR-150 enhanced lipid accumulation. apoA-I- and HDL-mediated cholesterol efflux was increased by 66% and 43%, respectively, in miR-150-overexpressing macrophages relative to control cells. In contrast, downregulation of miR-150 significantly reduced cholesterol efflux from oxLDL-laden macrophages. Bioinformatic analysis and luciferase reporter assay revealed adiponectin receptor 2 (AdipoR2) as a direct target of miR-150. Small interfering RNA-mediated downregulation of AdipoR2 phenocopied the effects of miR-150 overexpression, reducing lipid accumulation and facilitating cholesterol efflux in oxLDL-treated THP-1 macrophages. Knockdown of AdipoR2 induced the expression of proliferator activated receptor gamma (PPARgamma), liver X receptor alpha (LXRalpha), ABCA1, and ABCG1. Moreover, pharmacological inhibition of PPARgamma or LXRalpha impaired AdipoR2 silencing-induced upregulation of ABCA1 and ABCG1. Taken together, our results indicate that miR-150 can attenuate oxLDL-induced lipid accumulation in macrophages via promotion of cholesterol efflux. The suppressive effects of miR 150 on macrophage foam cell formation are mediated through targeting of AdipoR2. Delivery of miR-150 may represent a potential approach to prevent macrophage foam cell formation in atherosclerosis. PMID- 27216462 TI - Leda-1/Pianp is targeted to the basolateral plasma membrane by a distinct intracellular juxtamembrane region and modulates barrier properties and E Cadherin processing. AB - Leda-1/Pianp is a type-I transmembrane protein which is sorted to the basolateral membrane domain of polarized epithelial cells. Here, we investigated trafficking mechanisms and functions of Leda-1/Pianp in MDCK and MCF-7 cells. Basolateral sorting and posttranslational modifications depended on the intracellular juxtamembrane region. Functionally, Leda-1/Pianp increased the transepithelial electrical resistance generated by a polarized cell sheet. Furthermore, resistance to junctional destabilization by tumor cells was enhanced by Leda 1/Pianp indicating increased stability and tightness of intercellular junctions. While Claudin 1 and 4 expression and activities of small GTPases were not affected, gamma-Secretase-mediated cleavage of E-Cadherin was attenuated by Leda 1/Pianp. Regulation of proteolytic processing is thus a molecular mechanism by which Leda-1/Pianp can affect junctional integrity and function. PMID- 27216463 TI - H(+)/peptide transporter (PEPT2) is expressed in human epidermal keratinocytes and is involved in skin oligopeptide transport. AB - Peptide transporter 2 (PEPT2) is a member of the proton-coupled oligopeptide transporter family, which mediates the cellular uptake of oligopeptides and peptide-like drugs. Although PEPT2 is expressed in many tissues, its expression in epidermal keratinocytes remains unclear. We investigated PEPT2 expression profile and functional activity in keratinocytes. We confirmed PEPT2 mRNA expression in three keratinocyte lines (normal human epidermal keratinocytes (NHEKs), immortalized keratinocytes, and malignant keratinocytes) by reverse transcription-polymerase chain reaction (RT-PCR) and quantitative real-time RT PCR. In contrast to PEPT1, PEPT2 expression in the three keratinocytes was similar or higher than that in HepG2 cells, used as PEPT2-positive cells. Immunolocalization analysis using human skin showed epidermal PEPT2 localization. We studied keratinocyte transport function by measuring the oligopeptide content using liquid chromatography/tandem mass spectrometry. Glycylsarcosine uptake in NHEKs was pH-dependent, suggesting that keratinocytes could absorb small peptides in the presence of an inward H(+) gradient. We also performed a skin-permeability test of several oligopeptides using skin substitute, suggesting that di- and tripeptides pass actively through the epidermis. In conclusion, PEPT2 is expressed in keratinocytes and involved in skin oligopeptide uptake. PMID- 27216464 TI - The correlation of inflammatory markers and plasma vaspin levels in patients with diabetic nephropathy. AB - Vaspin, a recently identified adipokine, is a visceral adipose tissue-derived serine protease inhibitor that may have insulin sensitizing effect on adipose tissue. Herein, we measured vaspin level in patients with different stages of diabetic nephropathy (DNP), and investigated the correlation of the vaspin level with other inflammatory parameters. 106 adult type 2 diabetic patients with no known chronic inflammatory disease were included and grouped according to the stage of DNP: Albuminuria <30 mg/day and estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73m(2) (Group-1); albuminuria 30-300 mg/day and eGFR >60 mL/min/1.73m(2) (Group-2); albuminuria >300 mL/min and eGFR <60 mL/min/1.73m(2) (Group-3). Demographic, clinical and laboratory data were recorded as well as vaspin, high sensitivity C-reactive protein (hsCRP), interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha levels. There were 38, 35 and 33 patients in Group 1, 2 and 3, respectively. Groups were similar regarding age and gender. Vaspin level did not differ between groups. When all the groups were considered, vaspin was positively correlated with IL-6 level (r = 0.215, p = 0.041). No correlation of vaspin was found with IL-1, TNF-alpha and hsCRP levels (p = 0.580, r = 0.054; p = 0.463, r = 0.072; p = 0.812, r = 0.025, respectively). Vaspin levels of the patients with GFR >=60 mL/min/1.73m(2) was less than that of patients with GFR <60 mL/min/1.73m(2) (p = 0.03). Age and IL-6 were found to be the major determinants of vaspin level with linear regression analysis. In patients with DNP, vaspin level does not change within the early stages of DNP; while it is higher in patients with decreased GFR, which may be related with increasing inflammation regardless of the stage of the kidney disease. PMID- 27216466 TI - An Outbreak of Norovirus Infection from Shellfish Soup Due to Unforeseen Insufficient Heating During Preparation. AB - Norovirus causes large outbreaks involving all age groups and are considered the most common cause of infectious foodborne diseases worldwide. The aim of this study was to describe a norovirus outbreak connected to insufficient heat treatment during preparation of a shellfish soup in serving portions, during a company Christmas celebration in Norway, December 2013. A questionnaire sent to the employees, showed that 67 % (n = 43) of the celebration participants, reported gastrointestinal symptoms including stomach pain, vomiting, diarrhoea and light fever in the period between 24 and 48 h post celebration. Several dishes were served, including shellfish soup made with carpet shell clams (Tapes rhomboides) in porcelain cups. Consuming this soup, was the only significant risk factor for infection. Norovirus GI and GII were detected in the remaining raw shellfish. To mimic the time and temperature obtained during bivalve soup preparation, raw chopped shellfish tissue and raw cepa onion were added in porcelain cups tempered to 20 degrees C. To each of these cups, boiling soup base was added. The temperature in the shellfish tissue was continuously recorded, and showed a maximum of 49 degrees C in the period between 3 and 7 min after adding the boiling soup base. After 1 h the temperature was 30 degrees C. This time and temperature combination was obviously not sufficient for inactivation of norovirus present in the shellfish tissue. In conclusion, the heat-absorbing capacity of cold ingredients, utensils and table wear porcelain should not be underestimated during food production. Consumers who want to avoid eating raw shellfish, should not assume that the shellfish tissue in preparation as described in our study is adequately heat treated. PMID- 27216465 TI - Conservation of uORF repressiveness and sequence features in mouse, human and zebrafish. AB - Upstream open reading frames (uORFs) are ubiquitous repressive genetic elements in vertebrate mRNAs. While much is known about the regulation of individual genes by their uORFs, the range of uORF-mediated translational repression in vertebrate genomes is largely unexplored. Moreover, it is unclear whether the repressive effects of uORFs are conserved across species. To address these questions, we analyse transcript sequences and ribosome profiling data from human, mouse and zebrafish. We find that uORFs are depleted near coding sequences (CDSes) and have initiation contexts that diminish their translation. Linear modelling reveals that sequence features at both uORFs and CDSes modulate the translation of CDSes. Moreover, the ratio of translation over 5' leaders and CDSes is conserved between human and mouse, and correlates with the number of uORFs. These observations suggest that the prevalence of vertebrate uORFs may be explained by their conserved role in repressing CDS translation. PMID- 27216467 TI - SWIFT-Review: a text-mining workbench for systematic review. AB - BACKGROUND: There is growing interest in using machine learning approaches to priority rank studies and reduce human burden in screening literature when conducting systematic reviews. In addition, identifying addressable questions during the problem formulation phase of systematic review can be challenging, especially for topics having a large literature base. Here, we assess the performance of the SWIFT-Review priority ranking algorithm for identifying studies relevant to a given research question. We also explore the use of SWIFT Review during problem formulation to identify, categorize, and visualize research areas that are data rich/data poor within a large literature corpus. METHODS: Twenty case studies, including 15 public data sets, representing a range of complexity and size, were used to assess the priority ranking performance of SWIFT-Review. For each study, seed sets of manually annotated included and excluded titles and abstracts were used for machine training. The remaining references were then ranked for relevance using an algorithm that considers term frequency and latent Dirichlet allocation (LDA) topic modeling. This ranking was evaluated with respect to (1) the number of studies screened in order to identify 95 % of known relevant studies and (2) the "Work Saved over Sampling" (WSS) performance metric. To assess SWIFT-Review for use in problem formulation, PubMed literature search results for 171 chemicals implicated as EDCs were uploaded into SWIFT-Review (264,588 studies) and categorized based on evidence stream and health outcome. Patterns of search results were surveyed and visualized using a variety of interactive graphics. RESULTS: Compared with the reported performance of other tools using the same datasets, the SWIFT-Review ranking procedure obtained the highest scores on 11 out of 15 of the public datasets. Overall, these results suggest that using machine learning to triage documents for screening has the potential to save, on average, more than 50 % of the screening effort ordinarily required when using un-ordered document lists. In addition, the tagging and annotation capabilities of SWIFT-Review can be useful during the activities of scoping and problem formulation. CONCLUSIONS: Text-mining and machine learning software such as SWIFT-Review can be valuable tools to reduce the human screening burden and assist in problem formulation. PMID- 27216468 TI - [Reflexive analysis of home hospitalization in the elderly]. PMID- 27216469 TI - Why factor XI deficiency is a clinical concern. AB - INTRODUCTION: Inherited fXI deficiency has been an enigma since its discovery in 1953. The variable and relatively mild symptoms in patients with even the most severe form of the disorder seem out of step with the marked abnormalities in standard clotting assays. Indeed, the contribution of factor XI to hemostasis in an individual is not adequately assessed by techniques available in modern clinical laboratories. AREAS COVERED: We discuss clinical studies, genetic/genomic analyses, and advances in laboratory medicine that are reshaping our views on the role of factor XI in pathologic coagulation. We review how the disorder associated with factor XI deficiency has contributed to changes in blood coagulation models, and discuss the complex genetics of the deficiency state and its relationship to bleeding. Finally, we cover new laboratory approaches that may distinguish deficient patients who are prone to bleeding from those without such predisposition. Expert commentary: Advances in understanding the biology of factor XI have led to modifications in treatment of factor XI-deficient patients. Factor replacement is used more judiciously, and alternative approaches are gaining favor. In the future, better laboratory tests may allow us to target therapy to those patients who would benefit most. PMID- 27216470 TI - Toxicity of tannic acid-modified silver nanoparticles in keratinocytes: potential for immunomodulatory applications. AB - Hydrolyzable tannins are known to exhibit anti-inflammatory activity, which can be used in combination with silver nanoparticles (AgNPs) for dermal uses. In this study, we investigated the effects of tannic acid-modified 13, 33, 46nm and unmodified 10-65nm AgNPs using the human-derived keratinocyte HaCaT and VK2-E6/E7 cell lines in the form of stationary and spheroids cultures. After exposition to tannic acid-modified AgNPs, VK2-E6/E7 cells showed higher toxicity, increased production of reactive oxygen species (ROS) and activity of JNK stress kinase, while HaCaT cell line demonstrated less ROS production and activation of ERK kinase. AgNPs internalization was detected both in the superficial and internal layers of spheroids prepared from both cell lines. Tannic acid modified AgNPs sized above 30nm did not induce DNA breaks in comet assay performed in both cell lines. Tannic acid-modified but not unmodified AgNPs down-regulated TNF-alpha and LPS-triggered production of IL-8 in VK2-E6/E7 but not in HaCaT cells. In summary, tannic acid-modified AgNPs sized above 30nm show good toxicological profile both in vitro and possess immunomodulatory properties useful for potential dermal applications in humans. PMID- 27216471 TI - Cytotoxicity of carteolol to human corneal epithelial cells by inducing apoptosis via triggering the Bcl-2 family protein-mediated mitochondrial pro-apoptotic pathway. AB - Carteolol is a frequently used nonselective beta-adrenoceptor antagonist for glaucoma and ocular hypertension treatment, and its repeated/prolonged usage might be cytotoxic to the cornea, especially the outmost human corneal epithelium (HCEP). The aim of the present study was to characterize the cytotoxicity of carteolol to HCEP and its underlying cellular and molecular mechanisms using an in vitro model of HCEP cells. After HCEP cells were treated with carteolol at concentrations varying from 2% to 0.015625%, the cytotoxicity, apoptosis-inducing effect and pro-apoptotic pathway was investigated, respectively. Our results showed that carteolol at concentrations above 0.03125% induced time- and dose dependent growth retardation, cytopathic morphological changes and viability decline of HCEP cells. Moreover, carteolol induced G1 phase arrest, plasma membrane permeability elevation, phosphatidylserine externalization, DNA fragmentation, and apoptotic body formation of HCEP cells. Furthermore, carteolol also induced activation of caspase-9 and -3, disruption of mitochondrial transmembrane potential, up-regulation the cytoplasmic amount of cytochrome c and apoptosis-inducing factor, and up-regulation of pro-apoptotic Bax and Bad, down regulation of anti-apoptotic Bcl-2 and Bcl-xL. In conclusion, carteolol above 1/64 of its clinical therapeutic dosage has a time- and dose-dependent cytotoxicity to HCEP cells, which is achieved by inducing apoptosis via triggering Bcl-2 family protein-mediated mitochondrial pro-apoptotic pathway. PMID- 27216472 TI - Officimalonic acids A-H, lanostane triterpenes from the fruiting bodies of Fomes officinalis. AB - Phytochemical investigation of the methanolic extract of the fruiting bodies of Fomes officinalis led to the isolation of eight 24-methyl-lanostane triterpenes named officimalonic acids A-H, along with one known lanostane triterpene. Their structures were elucidated based on the analysis of spectroscopic data, single crystal X-ray diffraction, and electronic circular dichroism. Officimalonic acid A represents a previously unknown triterpene type with a 24-methyl-7(8 -> 9)abeo lanostane skeleton, and all of the compounds possessed a malonate half-ester moiety at C-3. Anti-inflammatory assay revealed that officimalonic acids D, E, G, H, and fomitopsin A showed potent inhibitory effects (IC50 = 5.1-8.9 MUM) on nitric oxide production in lipopolysaccharide-induced RAW264.7 cells. Officimalonic acids E, G, H showed moderate cytotoxicity against H460, HepG2 and BGC-823 human cell lines. PMID- 27216473 TI - Impact of fetal gender on the risk of preterm birth, a national cohort study. AB - INTRODUCTION: Fetal gender is associated with preterm birth; however, a proper subdivision by onset of labor and corresponding neonatal outcome by week of gestation is lacking. MATERIAL AND METHODS: Data from the Netherlands Perinatal Registry (1999-2010) were used to calculate relative risk ratios for gender by week of gestation and gender-related risk on adverse neonatal outcomes using a moving average technique. White European women with an alive fetus at onset of labor were included. Adverse neonatal outcomes were defined as neonatal mortality and a composite of neonatal morbidity. Onset of labor was categorized as spontaneous onset with intact membranes, premature rupture of membranes, and induction or elective cesarean section. RESULTS: The study population comprised 1 736 615 singleton deliveries (25(+0) -42(+6) weeks). Male fetuses were at increased risk of spontaneous preterm birth with intact membranes compared with a female fetus with a peak between 27 and 31 weeks [relative risk (RR) 1.5; 95% CI 1.4-1.6]. Male fetuses were also at increased risk of preterm premature rupture of membranes between 27 and 37 weeks (RR 1.2; 95% CI 1.16-1.23). No gender effect was seen for medically indicated preterm birth. No significant differences were seen for neonatal mortality. Males were at significantly increased risk of composite neonatal morbidity from 29 weeks onwards (RR 1.3; 95% CI 1.3-1.4). CONCLUSIONS: Male fetal gender is a relevant risk factor for spontaneous preterm birth, both for intact membranes and for preterm premature rupture of membranes in white European women. In addition, male infants are at increased risk of neonatal morbidity. PMID- 27216474 TI - Understanding Decision-Making in Specialized Domestic Violence Courts: Can Contemporary Theoretical Frameworks Help Guide These Decisions? AB - This study fills a gap in the literature by exploring the utility of contemporary courtroom theoretical frameworks-uncertainty avoidance, causal attribution, and focal concerns-for explaining decision-making in specialized domestic violence courts. Using data from two specialized domestic violence courts, this study explores the predictors of prosecutorial and judicial decision-making and the extent to which these factors are congruent with theoretical frameworks often used in studies of court processing. Findings suggest that these theoretical frameworks only partially help explain decision-making in the courts under study. A discussion of the findings and implications for future research is provided. PMID- 27216475 TI - Adult Pornography and Violence Against Women in the Heartland: Results From a Rural Southeast Ohio Study. AB - Many rural parts of the United States are now "pornified." There is growing quantitative evidence revealing that rural women are at higher risk of being victimized by intimate violence than their urban and suburban counterparts. In depth interviews with 55 rural southeast Ohio women who wanted to leave, were trying to leave, or were in the process of leaving, or who have left their male marital/cohabiting partners reveal that pornography is a major component of the problem of rural woman abuse. The main objective of this article is twofold: (a) to present the results of our qualitative study, and (b) to suggest future directions in theoretical and empirical work. PMID- 27216476 TI - Predicting Bystander Efficacy and Willingness to Intervene in College Men and Women: The Role of Exposure to Varying Levels of Violence in Pornography. AB - Students from two research universities completed items measuring the frequency of their using different kinds of pornography, and measures of their willingness and intent to intervene to help a bystander who might be experiencing sexual violence. Hierarchical logistic regressions showed that for men, violent/degrading pornography use, but not explicit but non-degrading pornography use, was significantly associated with reduced bystander willingness to intervene, but not associated with bystander efficacy. Women did not show the same impact of violent/degrading pornography use on the two bystander intervention variables. Results suggest violence/degrading pornography may contribute to a culture of acceptance of violence against women. PMID- 27216477 TI - Fermi-Surface Topological Phase Transition and Horizontal Order-Parameter Nodes in CaFe2As2 Under Pressure. AB - Iron-based compounds (IBS) display a surprising variety of superconducting properties that seems to arise from the strong sensitivity of these systems to tiny details of the lattice structure. In this respect, systems that become superconducting under pressure, like CaFe2As2, are of particular interest. Here we report on the first directional point-contact Andreev-reflection spectroscopy (PCARS) measurements on CaFe2As2 crystals under quasi-hydrostatic pressure, and on the interpretation of the results using a 3D model for Andreev reflection combined with ab-initio calculations of the Fermi surface (within the density functional theory) and of the order parameter symmetry (within a random-phase approximation approach in a ten-orbital model). The almost perfect agreement between PCARS results at different pressures and theoretical predictions highlights the intimate connection between the changes in the lattice structure, a topological transition in the holelike Fermi surface sheet, and the emergence on the same sheet of an order parameter with a horizontal node line. PMID- 27216478 TI - Efficacy of Ophthalmic Viscosurgical Devices in Preventing Temperature Rise at the Corneal Endothelium during Phacoemulsification. AB - PURPOSE: To investigate temperature alterations in the aqueous humor and the corneal endothelium during phacoemulsification, and to evaluate the effect of ophthalmic viscosurgical devices in preventing a temperature rise at the corneal endothelium during phacoemulsification. METHODS: Temperatures of the aqueous humor and corneal endothelium were measured using two temperature probes set in the anterior chamber during ultrasound oscillation in porcine eyes, with or without ophthalmic viscosurgical devices. RESULTS: Without an ophthalmic viscosurgical device, temperatures in both the aqueous humor and the corneal endothelium rapidly rose during the ultrasound oscillation, while with an ophthalmic viscosurgical device, the temperature elevation of the corneal endothelium site was suppressed compared with the aqueous humor. CONCLUSION: Surgeons need to be especially aware of ophthalmic viscosurgical device retention during phacoemulsification, because it can protect the corneal endothelium from heat generated during this procedure. PMID- 27216479 TI - Efficacy of an aluminium triformate mouthrinse during the maintenance phase in periodontal patients: a pilot double blind randomized placebo-controlled clinical trial. AB - BACKGROUND: The aim of this prospective placebo-controlled pilot study was to evaluate short-term effects of a mouthrinse containing aluminium triformate (ATF) on gingival inflammation and plaque formation in periodontal patients who are in the maintenance phase. ATF has styptic (astringent) and anti-inflammatory effects. METHODS: Forty non-smoking periodontal patients with modified sulcus bleeding index (MSBI) >=40 % were randomly divided into two groups. The participants received a masked mouthrinse (ATF or placebo) and were instructed with the rinsing protocol of 3 daily rinses during 30 s for 7 days. One blinded investigator (CE) performed all clinical examinations. The primary outcome was reduction in gingival inflammation as measured by MSBI. The secondary outcomes were reduction of the amount of plaque as measured by plaque index (PI) and approximal plaque index (API) and the occurrence of side effects. The patients were evaluated at the start and the end of the rinsing period, including the compliance of the patients. RESULTS: MSBI was reduced in both groups compared to baseline, but the ATF group showed significantly more reduction in MSBI compared to the placebo group (ATF: 17.6 %, placebo: 7.6 %, p = 0.035). ATF and placebo had no effects on dental plaque. Patients reported ATF mouthrinse not to have side effects other than oral sensation, whereas compliance of the patients was good. Almost all patients in the ATF group reported reduction of gum bleeding after 1 week of rinsing with ATF. CONCLUSIONS: This short-term pilot clinical trial is a firm basis to design a long-term controlled clinical trial to show whether ATF helps to inhibit further periodontal breakdown in maintenance patients with high MSBI. TRIAL REGISTRATION: This trial was registered in the WHO International Clinical Trials Registry Platform as DRKS00007672 , date of registration: 21/01/2015. PMID- 27216480 TI - Characteristics Associated with Patient-Centered Medical Home Capability in Health Centers: A Cross-Sectional Analysis. AB - BACKGROUND: The patient-centered medical home (PCMH) model is being implemented in health centers (HCs) that provide comprehensive primary care to vulnerable populations. OBJECTIVE: To identify characteristics associated with HCs' PCMH capability. DESIGN: Cross-sectional analysis of a national dataset of Federally Qualified Health Centers (FQHCs) in 2009. Data for PCMH capability, HC, patient, neighborhood, and regional characteristics were combined from multiple sources. PARTICIPANTS: A total of 706 (70 %) of 1014 FQHCs from the Health Resources and Services Administration Community Health Center Program, representing all 50 states and the District of Columbia. MAIN MEASURES: PCMH capability was scored via the Commonwealth Fund National Survey of FQHCs through the Safety Net Medical Home Scale (0 [worst] to 100 [best]). HC, patient, neighborhood, and regional characteristics (all analyzed at the HC level) were measured from the Commonwealth survey, Uniform Data System, American Community Survey, American Medical Association physician data, and National Academy for State Health Policy data. KEY RESULTS: Independent correlates of high PCMH capability included having an electronic health record (EHR) (11.7-point [95 % confidence interval, CI 10.2 13.3]), more types of financial performance incentives (0.7-point [95 % CI 0.2 1.1] higher total score per one additional type, maximum possible = 10), more types of hospital-HC affiliations (1.6-point [95 % CI 1.1-2.1] higher total score per one additional type, maximum possible = 6), and location in certain US census divisions. Among HCs with an EHR, location in a state with state-supported PCMH initiatives and PCMH payments was associated with high PCMH capability (2.8 point, 95 % CI 0.2-5.5). Other characteristics had small effect size based on the measure unit (e.g. 0.04-point [95 % CI 0-0.08] lower total score per one percentage point more minority patients), but the effects could be practically large at the extremes. CONCLUSIONS: EHR adoption likely played a role in HCs' improvement in PCMH capability. Factors that appear to hold promise for supporting PCMH capability include a greater number of types of financial performance incentives, more types of hospital-HC affiliations, and state-level support and payment for PCMH activities. PMID- 27216481 TI - Capsule Commentary on Schapira et al., Inadequate Systems to Support Breast and Cervical Cancer Screening in Primary Care Practice. PMID- 27216482 TI - Capsule Commentary on Phibbs et. al., At-Home versus In-Clinic INR Monitoring: A Cost-Utility Analysis from The Home INR Study (THINRS). PMID- 27216483 TI - Young women's life experiences and perceptions of sexual and reproductive health in rural KwaZulu-Natal South Africa. AB - Women in South Africa bear a disproportionate burden of the HIV epidemic. Female controlled HIV prevention methods offer promising interventions to reduce this burden but cannot be effectively employed without a better understanding of young women's perceptions of their sexual and reproductive health. This study examines social, environmental and cultural factors contributing to young women's perceptions of, and experiences with, sexual and reproductive health to identify the challenges of engaging adolescent girls in HIV prevention. Twenty-five 15-19 year-old women were interviewed using semi-structured in-depth interview questions to discover their life context, future goals and relationships with men, and to understand how these factors influence their sexual and reproductive health decisions and outcomes. A thematic analysis of interview findings indicates that although participants are aware of the risks posed by engaging in risky sexual behaviour, life context shapes their perceptions and prioritisation of their health, which presents a barrier to achieving healthy behaviours and positive health outcomes. These findings may influence future research into how young women's health perceptions influence their sexual health behaviours, and how they utilise sexual and reproductive health services in a clinical setting. This has implications for introducing forms of female-controlled HIV prevention for this population. PMID- 27216484 TI - A significant association between deltamethrin resistance, Plasmodium falciparum infection and the Vgsc-1014S resistance mutation in Anopheles gambiae highlights the epidemiological importance of resistance markers. AB - BACKGROUND: The success of malaria vector control is threatened by widespread pyrethroid insecticide resistance. However, the extent to which insecticide resistance impacts transmission is unclear. The objective of this study was to examine the association between the DDT/pyrethroid knockdown resistance mutation Vgsc-1014S, commonly termed kdr, and infection with Plasmodium falciparum sporozoites in Anopheles gambiae. METHODS: WHO standard methods were used to characterize susceptibility of wild female mosquitoes to 0.05 % deltamethrin. PCR based molecular diagnostics were used to identify mosquitoes to species and to genotype at the Vgsc-L1014S locus. ELISAs were used to detect the presence of P. falciparum sporozoites and for blood meal identification. RESULTS: Anopheles mosquitoes were resistant to deltamethrin with mortality rates of 77.7 % [95 % CI 74.9-80.3 %]. Of 545 mosquitoes genotyped 96.5 % were A. gambiae s.s. and 3.5 % were Anopheles arabiensis. The Vgsc-1014S mutation was detected in both species. Both species were predominantly anthropophagic. In A. gambiae s.s., Vgsc-L1014S genotype was significantly associated with deltamethrin resistance (chi2 = 11.2; p < 0.001). The P. falciparum sporozoite infection rate was 4.2 %. There was a significant association between the presence of sporozoites and Vgsc-L1014S genotype in A. gambiae s.s. (chi2 = 4.94; p = 0.026). CONCLUSIONS: One marker, Vgsc-1014S, was associated with insecticide resistance and P. falciparum infection in wild-caught mixed aged populations of A. gambiae s.s. thereby showing how resistance may directly impact transmission. PMID- 27216485 TI - Global survey of the omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid in the blood stream of healthy adults. AB - Studies reporting blood levels of the omega-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were systematically identified in order to create a global map identifying countries and regions with different blood levels. Included studies were those of healthy adults, published in 1980 or later. A total of 298 studies met all inclusion criteria. Studies reported fatty acids in various blood fractions including plasma total lipids (33%), plasma phospholipid (32%), erythrocytes (32%) and whole blood (3.0%). Fatty acid data from each blood fraction were converted to relative weight percentages (wt.%) and then assigned to one of four discrete ranges (high, moderate, low, very low) corresponding to wt.% EPA+DHA in erythrocyte equivalents. Regions with high EPA+DHA blood levels (>8%) included the Sea of Japan, Scandinavia, and areas with indigenous populations or populations not fully adapted to Westernized food habits. Very low blood levels (<=4%) were observed in North America, Central and South America, Europe, the Middle East, Southeast Asia, and Africa. The present review reveals considerable variability in blood levels of EPA+DHA and the very low to low range of blood EPA+DHA for most of the world may increase global risk for chronic disease. PMID- 27216486 TI - Disinhibition of the extracellular-signal-regulated kinase restores the amplification of circadian rhythms by lithium in cells from bipolar disorder patients. AB - Bipolar disorder (BD) is characterized by depression, mania, and circadian rhythm abnormalities. Lithium, a treatment for BD stabilizes mood and increases circadian rhythm amplitude. However, in fibroblasts grown from BD patients, lithium has weak effects on rhythm amplitude compared to healthy controls. To understand the mechanism by which lithium differentially affects rhythm amplitude in BD cells, we investigated the extracellular-signal-regulated kinase (ERK) and related signaling molecules linked to BD and circadian rhythms. In fibroblasts from BD patients, controls and mice, we assessed the contribution of the ERK pathway to lithium-induced circadian rhythm amplification. Protein analyses revealed low phospho-ERK1/2 (p-ERK) content in fibroblasts from BD patients vs. CONTROLS: Pharmacological inhibition of ERK1/2 by PD98059 attenuated the rhythm amplification effect of lithium, while inhibition of two related kinases, c-Jun N terminal kinase (JNK), and P38 did not. Knockdown of the transcription factors CREB and EGR-1, downstream effectors of ERK1/2, reduced baseline rhythm amplitude, but did not alter rhythm amplification by lithium. In contrast, ELK-1 knockdown amplified rhythms, an effect that was not increased further by the addition of lithium, suggesting this transcription factor may regulate the effect of lithium on amplitude. Augmentation of ERK1/2 signaling through DUSP6 knockdown sensitized NIH3T3 cells to rhythm amplification by lithium. In BD fibroblasts, DUSP6 knockdown reversed the BD rhythm phenotype, restoring the ability of lithium to increase amplitude in these cells. We conclude that the inability of lithium to regulate circadian rhythms in BD may reflect reduced ERK activity, and signaling through ELK-1. PMID- 27216487 TI - Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. AB - The present study investigated interactions between the novel psychoactive tryptamines DiPT, 4-OH-DiPT, 4-OH-MET, 5-MeO-AMT, and 5-MeO-MiPT at monoamine receptors and transporters compared with the classic hallucinogens lysergic acid diethylamide (LSD), psilocin, N,N-dimethyltryptamine (DMT), and mescaline. We investigated binding affinities at human monoamine receptors and determined functional serotonin (5-hydroxytryptamine [5-HT]) 5-HT2A and 5-HT2B receptor activation. Binding at and the inhibition of human monoamine uptake transporters and transporter-mediated monoamine release were also determined. All of the novel tryptamines interacted with 5-HT2A receptors and were partial or full 5-HT2A agonists. Binding affinity to the 5-HT2A receptor was lower for all of the tryptamines, including psilocin and DMT, compared with LSD and correlated with the reported psychoactive doses in humans. Several tryptamines, including psilocin, DMT, DiPT, 4-OH-DiPT, and 4-OH-MET, interacted with the serotonin transporter and partially the norepinephrine transporter, similar to 3,4 methylenedioxymethamphetamine but in contrast to LSD and mescaline. LSD but not the tryptamines interacted with adrenergic and dopaminergic receptors. In conclusion, the receptor interaction profiles of the tryptamines predict hallucinogenic effects that are similar to classic serotonergic hallucinogens but also MDMA-like psychoactive properties. PMID- 27216488 TI - Evaluation of anti-acne property of purified bee venom serum in humans. AB - OBJECTIVE: Acne vulgaris is a chronic dermatologic disease with four factors involved in the development of lesions. Treatments need to address as many of these underlying factors as possible in order to reduce acne lesions. As such, purified bee venom (PBVTM ) serum is an attractive therapeutic option for acne, but little data exist on the efficacy of this treatment strategy. METHODS: In this prospective, noncomparative study, 30 subjects having mild-to-moderate acne vulgaris were enrolled and treated with PBVTM serum twice daily for a period of 6 weeks. Clinical evaluation of lesions by expert visual grading and image analysis were made at weeks 0 (baseline), 3, and 6. RESULTS: The average visual acne grade of all volunteers significantly improved with the PBVTM serum treatment at weeks 3 (P < 0.05) and 6 (P < 0.001) when compared with the baseline grade at week 0. In addition, there was a mean percent improvement of 8.6% and 52.3% in acne grade observed after 3 and 6 weeks of PBVTM serum use, with 20% and 77% of the subjects showing improvement, respectively, when compared with baseline. Moreover, the subjects showed improvement in open comedones, closed comedones, papules, pustules, and nodules after 3 and 6 weeks of PBVTM serum use. CONCLUSION: Six weeks of treatment with PBVTM serum was found to be effective in the treatment of mild-to-moderate acne vulgaris, with no incidence of serious side effects or irritation. PMID- 27216489 TI - A Single-Level Tunnel Model to Account for Electrical Transport through Single Molecule- and Self-Assembled Monolayer-based Junctions. AB - We present a theoretical analysis aimed at understanding electrical conduction in molecular tunnel junctions. We focus on discussing the validity of coherent versus incoherent theoretical formulations for single-level tunneling to explain experimental results obtained under a wide range of experimental conditions, including measurements in individual molecules connecting the leads of electromigrated single-electron transistors and junctions of self-assembled monolayers (SAM) of molecules sandwiched between two macroscopic contacts. We show that the restriction of transport through a single level in solid state junctions (no solvent) makes coherent and incoherent tunneling formalisms indistinguishable when only one level participates in transport. Similar to Marcus relaxation processes in wet electrochemistry, the thermal broadening of the Fermi distribution describing the electronic occupation energies in the electrodes accounts for the exponential dependence of the tunneling current on temperature. We demonstrate that a single-level tunnel model satisfactorily explains experimental results obtained in three different molecular junctions (both single-molecule and SAM-based) formed by ferrocene-based molecules. Among other things, we use the model to map the electrostatic potential profile in EGaIn-based SAM junctions in which the ferrocene unit is placed at different positions within the molecule, and we find that electrical screening gives rise to a strongly non-linear profile across the junction. PMID- 27216491 TI - Haplotype Study in Argentinean Variegate Porphyria Patients. AB - BACKGROUND/AIMS: The porphyrias are genetically heterogeneous diseases, and each mutation is exclusive to one or two families. Among the mutations responsible for variegate porphyria in our country, c.1042_1043insT stands out, since it was described only in Argentina and is present in about 40% of genetically diagnosed families. Thus, we hypothesized the possible existence of a common ancestor for the mutation in our population. METHODS: We conducted a study based on microsatellite (short tandem repeats) haplotypes. RESULTS: We found a common haplotype in all of the patients carrying the common mutation. The age of the mutation was estimated to be about 375 years. CONCLUSION: There is a recent founder effect in our population for this particular genetic alteration in variegate porphyria. PMID- 27216490 TI - The health gains and cost savings of dietary salt reduction interventions, with equity and age distributional aspects. AB - BACKGROUND: A "diet high in sodium" is the second most important dietary risk factor for health loss identified in the Global Burden of Disease Study 2013. We therefore aimed to model health gains and costs (savings) of salt reduction interventions related to salt substitution and maximum levels in bread, including by ethnicity and age. We also ranked these four interventions compared to eight other modelled interventions. METHODS: A Markov macro-simulation model was used to estimate QALYs gained and net health system costs for four dietary sodium reduction interventions, discounted at 3 % per annum. The setting was New Zealand (NZ) (2.3 million adults, aged 35+ years) which has detailed individual-level administrative cost data. RESULTS: The health gain was greatest for an intervention where most (59 %) of the sodium in processed foods was replaced by potassium and magnesium salts. This intervention gained 294,000 QALYs over the remaining lifetime of the cohort (95 % UI: 238,000 to 359,000; 0.13 QALY per 35+ year old). Such salt substitution also produced the highest net cost-savings of NZ$ 1.5 billion (US$ 1.0 billion) (95 % UI: NZ$ 1.1 to 2.0 billion). All interventions generated relatively larger per capita QALYs for men vs women and for the indigenous Maori population vs non-Maori (e.g., 0.16 vs 0.12 QALYs per adult for the 59 % salt substitution intervention). Of relevance to workforce productivity, in the first 10 years post-intervention, 22 % of the QALY gain was among those aged <65 years (and 37 % for those aged <70). CONCLUSIONS: The benefits are consistent with the international literature, with large health gains and cost savings possible from some, but not all, sodium reduction interventions. Health gain appears likely to occur among working-age adults and all interventions contributed to reducing health inequalities. PMID- 27216493 TI - Confocal Bioluminescence Imaging for Living Tissues with a Caged Substrate of Luciferin. AB - Fluorescence imaging can elucidate morphological organization and coordinal networks, but its background luminescence degrades the image contrast. Our confocal bioluminescence imaging system uses a luciferase caged substrate, with light passing through multipinhole arrays, causing bioluminescence at a focal plane. After a charge-coupled device camera captures luminescence, the imaging system acquires confocal images of multilayered cells with depth information, supporting quantitative analysis of spatial cellular localization in living tissues. PMID- 27216492 TI - Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials. AB - AIMS/HYPOTHESIS: Delayed-release metformin (Metformin DR) was developed to maximise gut-based mechanisms of metformin action by targeting the drug to the ileum. Metformin DR was evaluated in two studies. Study 1 compared the bioavailability and effects on circulating glucose and gut hormones (glucagon like peptide-1, peptide YY) of Metformin DR dosed twice-daily to twice-daily immediate-release metformin (Metformin IR). Study 2 compared the bioavailability and glycaemic effects of Metformin DR dosages of 1,000 mg once-daily in the morning, 1,000 mg once-daily in the evening, and 500 mg twice-daily. METHODS: Study 1 was a blinded, randomised, crossover study (three * 5 day treatment periods) of twice-daily 500 mg or 1,000 mg Metformin DR vs twice-daily 1,000 mg Metformin IR in 24 participants with type 2 diabetes conducted at two study sites (Celerion Inc.; Tempe, AZ, and Lincoln, NE, USA). Plasma glucose and gut hormones were assessed over 10.25 h at the start and end of each treatment period; plasma metformin was measured over 11 h at the end of each treatment period. Study 2 was a non-blinded, randomised, crossover study (three * 7 day treatment periods) of 1,000 mg Metformin DR once-daily in the morning, 1,000 mg Metformin DR once-daily in the evening, or 500 mg Metformin DR twice-daily in 26 participants with type 2 diabetes performed at a single study site (Celerion, Tempe, AZ). Plasma glucose was assessed over 24 h at the start and end of each treatment period, and plasma metformin was measured over 30 h at the end of each treatment period. Both studies implemented centrally generated computer-based randomisation using a 1:1:1 allocation ratio. RESULTS: A total of 24 randomised participants were included in study 1; of these, 19 completed the study and were included in the evaluable population. In the evaluable population, all treatments produced similar significant reductions in fasting glucose (median reduction range, -0.67 to -0.81 mmol/l across treatments) and postprandial glucose (Day 5 to baseline AUC0-t ratio = 0.9 for all three treatments) and increases in gut hormones (Day 5 to baseline AUC0-t ratio range: 1.6-1.9 for GLP-1 and 1.4-1.5 for PYY) despite an almost 60% reduction in systemic metformin exposure for 500 mg Metformin DR compared with Metformin IR. A total of 26 randomised participants were included in study 2: 24 had at least one dose of study medication and at least one post dose pharmacokinetic/pharmacodynamic assessment and were included in the pharmacokinetic/pharmacodynamic intent-to-treat analysis; and 12 completed all treatment periods and were included in the evaluable population. In the evaluable population, Metformin DR administered once-daily in the morning had 28% (90% CI 16%, -39%) lower bioavailability (least squares mean ratio of metformin AUC0-24) compared with either once-daily in the evening or twice-daily, although the glucose-lowering effects were maintained. In both studies, adverse events were primarily gastrointestinal in nature, and indicated similar or improved tolerability for Metformin DR vs Metformin IR; there were no clinically meaningful differences in vital signs, physical examinations or laboratory values. CONCLUSIONS/INTERPRETATION: Dissociation of gut hormone release and glucose lowering from plasma metformin exposure provides strong supportive evidence for a distal small intestine-mediated mechanism of action. Directly targeting the ileum with Metformin DR once-daily in the morning may provide maximal metformin efficacy with lower doses and substantially reduce plasma exposure. Metformin DR may minimise the risk of lactic acidosis in those at increased risk from metformin therapy, such as individuals with renal impairment. TRIAL REGISTRATION: Clinicaltrials.gov NCT01677299, NCT01804842 FUNDING: : This study was funded by Elcelyx Therapeutics Inc. PMID- 27216494 TI - Effect of diet composition on growth performance, hepatic metabolism and antioxidant activities in Siberian sturgeon (Acipenser baerii, Brandt, 1869) submitted to starvation and refeeding. AB - Many fish species undergo natural starvation periods. Adaptation to starvation is possible through the activation of behavioral, biochemical and physiological mechanisms. Knowledge of the effect of dietary nutrients on the intermediary metabolism during starvation and refeeding can be useful to improve fish health and optimize aquaculture production. To analyze the effect of dietary nutrients on liver metabolism of Siberian sturgeon (Acipenser baerii) submitted to starvation and refeeding, four isoenergetic diets differing in nutrient composition were designed: LP-St (38 % protein, 12 % lipid, 36 % carbohydrate), HP-St (44 % protein, 10 % lipid, 30 % carbohydrate), LP-L (38 % protein, 18 % lipid, 25 % carbohydrate) and HP-L (44 % protein, 16 % lipid, 22 % carbohydrate). Four groups of fish were fed 3 weeks to satiety with the corresponding diet, starved for 2 weeks and then refeed 5 weeks to satiety on the same diet. Starvation mobilized the hepatic lipid store to a greater extent than glycogen. Starvation increased superoxide dismutase activity irrespective of the diet, while low protein diets (LP-St and LP-L) increased catalase activity. The oxidative damage decreased after 5 weeks of refeeding. Refeeding the starved fish on the HP-St diet promoted the greatest growth performance. In addition to reporting for the first time the effect of diet composition on growth, liver composition and antioxidant activities in Siberian sturgeon submitted to starvation and refeeding, our findings suggest that refeeding on HP-St diet stimulated the use of dietary carbohydrates and allowed a protein sparing effect in Siberian sturgeon. PMID- 27216495 TI - Fat deposition pattern and mechanism in response to dietary lipid levels in grass carp, Ctenopharyngodon idellus. AB - This study aimed to evaluate the fat deposition pattern and lipid metabolic strategies of grass carp in response to dietary lipid levels. Five isonitrogenous diets (260 g kg-1 crude protein) containing five dietary lipid levels (0, 20, 40, 60, 80 g kg-1) were fed to quadruplicate groups of 15 fish with initial weight 200 g, for 8 weeks. The best growth performance and feed utilization was observed in fish fed with lipid level at 40 g kg-1. MFI and adipose tissue lipid content increased with increasing dietary lipid level up to 40 g kg-1, and higher lipid level in diet made no sense. Fish adapted to high lipid intake through integrated regulating mechanisms in several related tissues to maintain lipid homeostasis. In the present study, grass carp firstly increased PPARgamma and CPT1 expressions in adipose tissue to elevate adipocyte differentiation and lipolysis to adapt to high lipid intake above 40 g kg-1. In liver, fish elevated hepatic lipid uptake but depressed biosynthesis of hepatic FAs, resulted in no difference in HSI and liver lipid content among the groups. Only in muscle, fish showed a significant fat deposition when the lipid intake above 40 g kg-1. The excess lipid, derived from enhanced serum TC and TG contents, was more likely to induce deposition in muscle rather than lipid uptake by adipose tissue in grass carp fed with high dietary lipid, indicating the muscle of grass carp might be the main responding organ to high lipid intake. PMID- 27216496 TI - Recognition and Importance of New Definitions of Peripancreatic Fluid Collections in Managing Patients with Acute Pancreatitis. AB - Our understanding of the etiopathogenesis of acute pancreatitis has matured tremendously in the last 3 decades. Advanced cross-sectional imaging with 3 dimensional techniques along with use of intravenous contrast to image the presence or absence of organ tissue perfusion has allowed early recognition of necrotizing pancreatitis. With this knowledge, the old terms to describe what used to be called 'peri-pancreatic fluid collections' we now recognize are no longer accurate nor appropriate. The 2013 revised Atlanta Classification has introduced a new, accurate, objective classification of acute pancreatitis and terminology for the natural history of all forms of acute pancreatitis that is easy to use and will help in both the description of the disease and its appropriate treatment. This review will describe these pancreatic and peri pancreatic collections with added insight into their natural history. PMID- 27216498 TI - A qualitative study of older people's experience of living with neurogenic claudication to inform the development of a physiotherapy intervention. AB - PURPOSE: The aim of this study was to explore older people's experiences of living with neurogenic claudication (NC), their preferences for physiotherapy treatment provision and associated outcomes in order to inform an intervention to be tested in a clinical trial. METHOD: Patients with a diagnosis of NC and/or lumbar spinal stenosis were recruited through a UK NHS tertiary care center. Semi structured interviews and self-report questionnaires were used to obtain data. A thematic analysis was conducted. RESULTS: 15 participants were recruited; half were classed as frail older adults. Pain and the threat of pain was a prominent feature of participants' experience of NC. This led to a loss of engagement in meaningful activities and sense of self. Discourses of ageing influenced experiences as well as treatment preferences, particularly the acceptability of walking aids. A combination of one-to-one and group setting for treatment was preferred. Outcome preferences related to re-engagement in meaningful activities and pain reduction. Limitations relate to generalisability of the findings for NC patients not under physiotherapy treatment. CONCLUSION: We have obtained important findings about older people's experiences of living with NC and preferences for physiotherapy treatment and outcomes. These will be incorporated into an evidence-based intervention and evaluated in a randomized controlled trial. Implications for rehabilitation Older people living with NC want to get back to meaningful activities and learn how to live with the threat of pain. Allied health professionals (AHPs) should be sensitive to the complex and ambiguous ways in which older people live with ageing and age-related decline. AHPs are in a position to support patients' successful transition to the use of walking aids thereby reducing stigmatizing effects and increasing activity. AHPs should consider a mixture of one-to-one and group classes to enable rehabilitation for older NC patients. PMID- 27216497 TI - Enrichment of extracellular vesicles from tissues of the central nervous system by PROSPR. AB - BACKGROUND: Extracellular vesicles (EVs) act as key mediators of intercellular communication and are secreted and taken up by all cell types in the central nervous system (CNS). While detailed study of EV-based signaling is likely to significantly advance our understanding of human neurobiology, the technical challenges of isolating EVs from CNS tissues have limited their characterization using 'omics' technologies. We therefore developed a new Protein Organic Solvent Precipitation (PROSPR) method that can efficiently isolate the EV repertoire from human biological samples. RESULTS: In the current report, we present a novel experimental workflow that outlines the process of sample extraction and enrichment of CNS-derived EVs using PROSPR. Subsequent LC-MS/MS-based proteomic profiling of EVs enriched from brain homogenates successfully identified 86 of the top 100 exosomal markers. Proteomic profiling of PROSPR-enriched CNS EVs indicated that > 75 % of the proteins identified matched previously reported exosomal and microvesicle cargoes, while also expanded the known human EV associated proteome with 685 novel identifications. Similarly, lipidomic characterization of enriched CNS vesicles not only identified previously reported EV-specific lipid families (PS, SM, lysoPC, lysoPE) but also uncovered novel lipid isoforms not previously detected in human EVs. Finally, dedicated flow cytometry of PROSPR-CNS-EVs revealed that ~80 % of total microparticles observed were exosomes ranging in diameter from <=100 nm to 300 nm. CONCLUSIONS: These data demonstrate that the optimized use of PROSPR represents an easy-to-perform and inexpensive method of enriching EVs from human CNS tissues for detailed characterization by 'omics' technologies. We predict that widespread use of the methodology described herein will greatly accelerate the study of EVs biology in neuroscience. PMID- 27216499 TI - Rapid bench identification of methicillin-sensitive and methicillin-resistant Staphylococcus aureus: A multicenter comparative evaluation of Alere PBP2a Culture Colony Test (Alere) Versus Slidex MRSA detection (bioMerieux). AB - Using 30 clinical isolates of Staphylococcus aureus representative of the most prevalent clones circulating in France, the performance of the AlereTM PBP2a Culture Colony Test (CCT) and the Slidex((r)) MRSA detection kit (SMD) were compared in 5 different labs. CCT demonstrated better performance and was easier to conduct in routine. PMID- 27216500 TI - Functional Antagonism of Human CD40 Achieved by Targeting a Unique Species Specific Epitope. AB - Current clinical anti-CD40 biologic agents include both antagonist molecules for the treatment of autoimmune diseases and agonist molecules for immuno-oncology, yet the relationship between CD40 epitope and these opposing biological outcomes is not well defined. This report describes the identification of potent antagonist domain antibodies (dAbs) that bind to a novel human CD40-specific epitope that is divergent in the CD40 of nonhuman primates. A similarly selected anti-cynomolgus CD40 dAb recognizing the homologous epitope is also a potent antagonist. Mutagenesis, biochemical, and X-ray crystallography studies demonstrate that the epitope is distinct from that of CD40 agonists. Both the human-specific and cynomolgus-specific molecules remain pure antagonists even when formatted as bivalent Fc-fusion proteins, making this an attractive therapeutic format for targeting hCD40 in autoimmune indications. PMID- 27216502 TI - Possible mechanism of host manipulation resulting from a diel behaviour pattern of eye-dwelling parasites? AB - Parasitic infection often results in alterations to the host's phenotype, and may modify selection pressures for host populations. Elucidating the mechanisms underlying these changes is essential to understand the evolution of host parasite interactions. A variety of mechanisms may result in changes in the host's behavioural phenotype, ranging from simple by-products of infection to chemicals directly released by the parasite to alter behaviour. Another possibility may involve parasites freely moving to certain sites within tissues, at specific times of the day to induce behavioural changes in the host. We tested the hypothesis that parasites shift to certain sites within the host by quantifying the location and activity of the trematode Tylodelphys sp., whose mobile metacercarial stages remain unencysted in the eyes of the second intermediate fish host, the common bully (Gobiomorphus cotidianus). This parasite's definitive host is a piscivorous bird feeding exclusively during daytime. Ocular obstruction and metacercarial activity were assessed within the sedated host's eye at three time points 24 h-1 period, using video captured via an ophthalmoscope. Although observed metacercarial activity did not change between time periods, ocular obstruction was significantly reduced at night. Increased visual obstruction specifically during the foraging time of the parasite's definitive host strongly suggests that the parasite's activity pattern is adaptive. PMID- 27216501 TI - The Structure-Specific Recognition Protein 1 Associates with Lens Epithelium Derived Growth Factor Proteins and Modulates HIV-1 Replication. AB - The lens epithelium-derived growth factor p75 (LEDGF/p75) is a chromatin-bound protein essential for efficient lentiviral integration. Genome-wide studies have located LEDGF/p75 inside actively transcribed genes where it mediates lentiviral integration. Although its role in HIV-1 integration is clearly established, the role of LEDGF/p75-associated proteins in HIV-1 infection remains unexplored. Using protein-protein interaction assays, we demonstrated that LEDGF/p75 complexes with a chromatin-remodeling complex facilitates chromatin transcription (FACT), a heterodimer of the structure-specific recognition protein 1 (SSRP1) and the human homolog of suppressor of Ty 16 (hSpt16). Detailed analysis of the interaction of LEDGF/p75 with the FACT complex indicates that LEDGF/p75 interacts with SSRP1 in an hSpt16-independent manner that requires the PWWP domain of LEDGF proteins and the HMG domain of SSRP1. Functional characterizations demonstrate a LEDGF/p75-independent role of SSRP1 in the regulation of HIV-1 replication. shRNA mediated partial knockdown of SSRP1 reduces HIV-1 infection, but not Murine Leukemia Virus, in human CD4(+) T cells. Similarly, SSRP1 knockdown affects infection by HIV-1-derived viruses that express genes from the viral LTR but not from an internal immediate-early CMV promoter, suggesting a role of SSRP1 in LTR driven gene expression but not in viral DNA integration. Together, our data demonstrate for the first time the association of LEDGF proteins with the FACT complex and give further support to a role of SSRP1 in HIV-1 infection. PMID- 27216503 TI - Resolution of severe pulmonary arterial hypertension complicating adult-onset Still's disease. PMID- 27216504 TI - Desensitization strategies in adult heart transplantation-Will persistence pay off? AB - Strategies are needed to enable successful heart transplantation in highly sensitized patients. Immunologic challenges from sensitization to human leukocyte antigen (HLA) reduce access to compatible donors, extend waiting times to transplant, and increase the risks of antibody-mediated rejection and cardiac allograft vasculopathy after transplant. The prime goal of desensitization is to increase access to transplantation through expansion of the donor organ pool. Existing therapies are directed at key components of the humoral immune response with newer biologically based regimens able to target plasma cells as the source of antibody production, as well as complement activation that has a central role in antibody-mediated injury. Despite the emergence of early promising results for these agents, a significant knowledge gap remains with the current data for desensitization, extrapolated mostly from non-heart solid-organ transplants and small observational studies. Notably, no approach has demonstrated significant and sustainable reductions in HLA antibody pre-transplant, and the ideal desensitization strategy remains elusive. In addition, clinical tools to evaluate the humoral response and efficacy of therapy are limited, focusing almost exclusively on HLA antibody detection. Importantly, desensitization is associated with significant costs and potential risks, and overall long-term outcomes and cost-effectiveness have not been sufficiently evaluated. Investigation is ongoing into the development of a clinically effective desensitization strategy in heart transplantation. PMID- 27216505 TI - At the nexus of fire, water and society. AB - The societal risks of water scarcity and water-quality impairment have received considerable attention, evidenced by recent analyses of these topics by the 2030 Water Resources Group, the United Nations and the World Economic Forum. What are the effects of fire on the predicted water scarcity and declines in water quality? Drinking water supplies for humans, the emphasis of this exploration, are derived from several land cover types, including forests, grasslands and peatlands, which are vulnerable to fire. In the last two decades, fires have affected the water supply catchments of Denver (CO) and other southwestern US cities, and four major Australian cities including Sydney, Canberra, Adelaide and Melbourne. In the same time period, several, though not all, national, regional and global water assessments have included fire in evaluations of the risks that affect water supplies. The objective of this discussion is to explore the nexus of fire, water and society with the hope that a more explicit understanding of fire effects on water supplies will encourage the incorporation of fire into future assessments of water supplies, into the pyrogeography conceptual framework and into planning efforts directed at water resiliency.This article is part of the themed issue 'The interaction of fire and mankind'. PMID- 27216506 TI - The pyrohealth transition: how combustion emissions have shaped health through human history. AB - Air pollution from landscape fires, domestic fires and fossil fuel combustion is recognized as the single most important global environmental risk factor for human mortality and is associated with a global burden of disease almost as large as that of tobacco smoking. The shift from a reliance on biomass to fossil fuels for powering economies, broadly described as the pyric transition, frames key patterns in human fire usage and landscape fire activity. These have produced distinct patters of human exposure to air pollution associated with the Agricultural and Industrial Revolutions and post-industrial the Earth global system-wide changes increasingly known as the Anthropocene. Changes in patterns of human fertility, mortality and morbidity associated with economic development have been previously described in terms of demographic, epidemiological and nutrition transitions, yet these frameworks have not explicitly considered the direct consequences of combustion emissions for human health. To address this gap, we propose a pyrohealth transition and use data from the Global Burden of Disease (GBD) collaboration to compare direct mortality impacts of emissions from landscape fires, domestic fires, fossil fuel combustion and the global epidemic of tobacco smoking. Improving human health and reducing the environmental impacts on the Earth system will require a considerable reduction in biomass and fossil fuel combustion.This article is part of the themed issue 'The interaction of fire and mankind'. PMID- 27216507 TI - Community owned solutions for fire management in tropical ecosystems: case studies from Indigenous communities of South America. AB - Fire plays an increasingly significant role in tropical forest and savanna ecosystems, contributing to greenhouse gas emissions and impacting on biodiversity. Emerging research shows the potential role of Indigenous land-use practices for controlling deforestation and reducing CO2 emissions. Analysis of satellite imagery suggests that Indigenous lands have the lowest incidence of wildfires, significantly contributing to maintaining carbon stocks and enhancing biodiversity. Yet acknowledgement of Indigenous peoples' role in fire management and control is limited, and in many cases dismissed, especially in policy-making circles. In this paper, we review existing data on Indigenous fire management and impact, focusing on examples from tropical forest and savanna ecosystems in Venezuela, Brazil and Guyana. We highlight how the complexities of community owned solutions for fire management are being lost as well as undermined by continued efforts on fire suppression and firefighting, and emerging approaches to incorporate Indigenous fire management into market- and incentive-based mechanisms for climate change mitigation. Our aim is to build a case for supporting Indigenous fire practices within all scales of decision-making by strengthening Indigenous knowledge systems to ensure more effective and sustainable fire management.This article is part of the themed issue 'The interaction of fire and mankind'. PMID- 27216508 TI - In the line of fire: the peatlands of Southeast Asia. AB - Peatlands are a significant component of the global carbon (C) cycle, yet despite their role as a long-term C sink throughout the Holocene, they are increasingly vulnerable to destabilization. Nowhere is this shift from sink to source happening more rapidly than in Southeast Asia, and nowhere else are the combined pressures of land-use change and fire on peatland ecosystem C dynamics more evident nor the consequences more apparent. This review focuses on the peatlands of this region, tracing the link between deforestation and drainage and accelerating C emissions arising from peat mineralization and fire. It focuses on the implications of the recent increase in fire occurrence for air quality, human health, ecosystem resilience and the global C cycle. The scale and controls on peat-driven C emissions are addressed, noting that although fires cause large, temporary peaks in C flux to the atmosphere, year-round emissions from peat mineralization are of a similar magnitude. The review concludes by advocating land management options to reduce future fire risk as part of wider peatland management strategies, while also proposing that this region's peat fire dynamic could become increasingly relevant to northern peatlands in a warming world.This article is part of the themed issue 'The interaction of fire and mankind'. PMID- 27216510 TI - Increasing western US forest wildfire activity: sensitivity to changes in the timing of spring. AB - Prior work shows western US forest wildfire activity increased abruptly in the mid-1980s. Large forest wildfires and areas burned in them have continued to increase over recent decades, with most of the increase in lightning-ignited fires. Northern US Rockies forests dominated early increases in wildfire activity, and still contributed 50% of the increase in large fires over the last decade. However, the percentage growth in wildfire activity in Pacific northwestern and southwestern US forests has rapidly increased over the last two decades. Wildfire numbers and burned area are also increasing in non-forest vegetation types. Wildfire activity appears strongly associated with warming and earlier spring snowmelt. Analysis of the drivers of forest wildfire sensitivity to changes in the timing of spring demonstrates that forests at elevations where the historical mean snow-free season ranged between two and four months, with relatively high cumulative warm-season actual evapotranspiration, have been most affected. Increases in large wildfires associated with earlier spring snowmelt scale exponentially with changes in moisture deficit, and moisture deficit changes can explain most of the spatial variability in forest wildfire regime response to the timing of spring.This article is part of the themed issue 'The interaction of fire and mankind'. PMID- 27216509 TI - Global combustion: the connection between fossil fuel and biomass burning emissions (1997-2010). AB - Humans use combustion for heating and cooking, managing lands, and, more recently, for fuelling the industrial economy. As a shift to fossil-fuel-based energy occurs, we expect that anthropogenic biomass burning in open landscapes will decline as it becomes less fundamental to energy acquisition and livelihoods. Using global data on both fossil fuel and biomass burning emissions, we tested this relationship over a 14 year period (1997-2010). The global average annual carbon emissions from biomass burning during this time were 2.2 Pg C per year (+/-0.3 s.d.), approximately one-third of fossil fuel emissions over the same period (7.3 Pg C, +/-0.8 s.d.). There was a significant inverse relationship between average annual fossil fuel and biomass burning emissions. Fossil fuel emissions explained 8% of the variation in biomass burning emissions at a global scale, but this varied substantially by land cover. For example, fossil fuel burning explained 31% of the variation in biomass burning in woody savannas, but was a non-significant predictor for evergreen needleleaf forests. In the land covers most dominated by human use, croplands and urban areas, fossil fuel emissions were more than 30- and 500-fold greater than biomass burning emissions. This relationship suggests that combustion practices may be shifting from open landscape burning to contained combustion for industrial purposes, and highlights the need to take into account how humans appropriate combustion in global modelling of contemporary fire. Industrialized combustion is not only an important driver of atmospheric change, but also an important driver of landscape change through companion declines in human-started fires.This article is part of the themed issue 'The interaction of fire and mankind'. PMID- 27216511 TI - Wildfire policy and management in England: an evolving response from Fire and Rescue Services, forestry and cross-sector groups. AB - Severe wildfires are an intermittent problem in England. The paper presents the first analysis of wildfire policy, showing its halting evolution over two decades. First efforts to coordinate wildfire management came from local fire operation groups, where stakeholders such as fire services, land owners and amenity groups shared knowledge and equipment to tackle the problem. A variety of structures and informal management solutions emerged in response to local needs. Knowledge of wildfire accumulated within regional and national wildfire forums and academic networks. Only later did the need for central emergency planning and the response to climate change produce a national policy response. Fire statistics have allowed wildfires to be spatially evidenced on a national scale only since 2009. National awareness of wildfire was spurred by the 2011 fire season, and the high-impact Swinley Forest fire, which threatened critical infrastructure and communities within 50 miles of London. Severe wildfire was included in the National Risk Register for the first time in 2013. Cross-sector approaches to wildfire proved difficult as government responsibility is fragmented along the hazard chain. Stakeholders such as the Forestry Commission pioneered good practice in adaptive land management to build fire resilience into UK forests. The grass-roots evolution of participatory solutions has also been a key enabling process. A coordinated policy is now needed to identify best practice and to promote understanding of the role of fire in the ecosystem.This article is part of a themed issue 'The interaction of fire and mankind'. PMID- 27216513 TI - People, El Nino southern oscillation and fire in Australia: fire regimes and climate controls in hummock grasslands. AB - While evidence mounts that indigenous burning has a significant role in shaping pyrodiversity, the processes explaining its variation across local and external biophysical systems remain limited. This is especially the case with studies of climate-fire interactions, which only recognize an effect of humans on the fire regime when they act independently of climate. In this paper, we test the hypothesis that an anthropogenic fire regime (fire incidence, size and extent) does not covary with climate. In the lightning regime, positive El Nino southern oscillation (ENSO) values increase lightning fire incidence, whereas La Nina (and associated increases in prior rainfall) increase fire size. ENSO has the opposite effect in the Martu regime, decreasing ignitions in El Nino conditions without affecting fire size. Anthropogenic ignition rates covary positively with high antecedent rainfall, whereas fire size varies only with high temperatures and unpredictable winds, which may reduce control over fire spread. However, total area burned is similarly predicted by antecedent rainfall in both regimes, but is driven by increases in fire size in the lightning regime, and fire number in the anthropogenic regime. We conclude that anthropogenic regimes covary with climatic variation, but detecting the human-climate-fire interaction requires multiple measures of both fire regime and climate.This article is part of the themed issue 'The interaction of fire and mankind'. PMID- 27216512 TI - The role of fire in UK peatland and moorland management: the need for informed, unbiased debate. AB - Fire has been used for centuries to generate and manage some of the UK's cultural landscapes. Despite its complex role in the ecology of UK peatlands and moorlands, there has been a trend of simplifying the narrative around burning to present it as an only ecologically damaging practice. That fire modifies peatland characteristics at a range of scales is clearly understood. Whether these changes are perceived as positive or negative depends upon how trade-offs are made between ecosystem services and the spatial and temporal scales of concern. Here we explore the complex interactions and trade-offs in peatland fire management, evaluating the benefits and costs of managed fire as they are currently understood. We highlight the need for (i) distinguishing between the impacts of fires occurring with differing severity and frequency, and (ii) improved characterization of ecosystem health that incorporates the response and recovery of peatlands to fire. We also explore how recent research has been contextualized within both scientific publications and the wider media and how this can influence non-specialist perceptions. We emphasize the need for an informed, unbiased debate on fire as an ecological management tool that is separated from other aspects of moorland management and from political and economic opinions.This article is part of the themed issue 'The interaction of fire and mankind'. PMID- 27216514 TI - Using community archetypes to better understand differential community adaptation to wildfire risk. AB - One of the immediate challenges of wildfire management concerns threats to human safety and property in residential areas adjacent to non-cultivated vegetation. One approach for relieving this problem is to increase human community 'adaptiveness' to deal with the risk and reality of fire in a variety of landscapes. The challenge in creating 'fire-adapted communities' (FACs) is the great diversity in character and make-up of populations at risk from wildfire. This paper outlines a recently developed categorization scheme for Wildland-Urban Interface (WUI) communities based on a larger conceptual approach for understanding how social diversity is likely to influence the creation of FACs. The WUI categorization scheme situates four community archetypes on a continuum that recognizes dynamic change in human community functioning. We use results from the WUI classification scheme to outline key characteristics associated with each archetype and results from recent case studies to demonstrate the diversity across WUI communities. Differences among key characteristics of local social context will likely result in the need for different adaptation strategies to wildfire. While the WUI archetypes described here may not be broadly applicable to other parts of the world, we argue that the conceptual approach and strategies for systematically documenting local influences on wildfire adaptation have potential for broad application.This article is part of the themed issue 'The interaction of fire and mankind'. PMID- 27216515 TI - Global trends in wildfire and its impacts: perceptions versus realities in a changing world. AB - Wildfire has been an important process affecting the Earth's surface and atmosphere for over 350 million years and human societies have coexisted with fire since their emergence. Yet many consider wildfire as an accelerating problem, with widely held perceptions both in the media and scientific papers of increasing fire occurrence, severity and resulting losses. However, important exceptions aside, the quantitative evidence available does not support these perceived overall trends. Instead, global area burned appears to have overall declined over past decades, and there is increasing evidence that there is less fire in the global landscape today than centuries ago. Regarding fire severity, limited data are available. For the western USA, they indicate little change overall, and also that area burned at high severity has overall declined compared to pre-European settlement. Direct fatalities from fire and economic losses also show no clear trends over the past three decades. Trends in indirect impacts, such as health problems from smoke or disruption to social functioning, remain insufficiently quantified to be examined. Global predictions for increased fire under a warming climate highlight the already urgent need for a more sustainable coexistence with fire. The data evaluation presented here aims to contribute to this by reducing misconceptions and facilitating a more informed understanding of the realities of global fire.This article is part of themed issue 'The interaction of fire and mankind'. PMID- 27216516 TI - Managing the human component of fire regimes: lessons from Africa. AB - Human impacts on fire regimes accumulated slowly with the evolution of modern humans able to ignite fires and manipulate landscapes. Today, myriad voices aim to influence fire in grassy ecosystems to different ends, and this is complicated by a colonial past focused on suppressing fire and preventing human ignitions. Here, I review available evidence on the impacts of people on various fire characteristics such as the number and size of fires, fire intensity, fire frequency and seasonality of fire in African grassy ecosystems, with the intention of focusing the debate and identifying areas of uncertainty. Humans alter seasonal patterns of fire in grassy systems but tend to decrease total fire emissions: livestock have replaced fire as the dominant consumer in many parts of Africa, and fragmented landscapes reduce area burned. Humans alter the season and time of day when fires occur, with important implications for fire intensity, tree-grass dynamics and greenhouse gas (GHG) emissions. Late season fires are more common when fire is banned or illegal: these later fires are far more intense but emit fewer GHGs. The types of fires which preserve human livelihoods and biodiversity are not always aligned with the goal of reducing GHG concentrations. Current fire management challenges therefore involve balancing the needs of a large rural population against national and global perspectives on the desirability of different types of fire, but this cannot happen unless the interests of all parties are equally represented. In the future, Africa is expected to urbanize and land use to intensify, which will imply different trajectories for the continent's fire regimes.This article is part of the themed issue 'The interaction of fire and mankind. PMID- 27216517 TI - Living on a flammable planet: interdisciplinary, cross-scalar and varied cultural lessons, prospects and challenges. AB - Living with fire is a challenge for human communities because they are influenced by socio-economic, political, ecological and climatic processes at various spatial and temporal scales. Over the course of 2 days, the authors discussed how communities could live with fire challenges at local, national and transnational scales. Exploiting our diverse, international and interdisciplinary expertise, we outline generalizable properties of fire-adaptive communities in varied settings where cultural knowledge of fire is rich and diverse. At the national scale, we discussed policy and management challenges for countries that have diminishing fire knowledge, but for whom global climate change will bring new fire problems. Finally, we assessed major fire challenges that transcend national political boundaries, including the health burden of smoke plumes and the climate consequences of wildfires. It is clear that to best address the broad range of fire problems, a holistic wildfire scholarship must develop common agreement in working terms and build across disciplines. We must also communicate our understanding of fire and its importance to the media, politicians and the general public.This article is part of the themed issue 'The interaction of fire and mankind'. PMID- 27216518 TI - The interaction of fire and mankind. PMID- 27216519 TI - The interaction of fire and mankind: Introduction. AB - Fire has been an important part of the Earth system for over 350 Myr. Humans evolved in this fiery world and are the only animals to have used and controlled fire. The interaction of mankind with fire is a complex one, with both positive and negative aspects. Humans have long used fire for heating, cooking, landscape management and agriculture, as well as for pyrotechnologies and in industrial processes over more recent centuries. Many landscapes need fire but population expansion into wildland areas creates a tension between different interest groups. Extinguishing wildfires may not always be the correct solution. A combination of factors, including the problem of invasive plants, landscape change, climate change, population growth, human health, economic, social and cultural attitudes that may be transnational make a re-evaluation of fire and mankind necessary. The Royal Society meeting on Fire and mankind was held to address these issues and the results of these deliberations are published in this volume.This article is part of the themed issue 'The interaction of fire and mankind'. PMID- 27216520 TI - The influence of leaf morphology on litter flammability and its utility for interpreting palaeofire. AB - Studies of palaeofire rely on quantifying the abundance of fossil charcoals in sediments to estimate changes in fire activity. However, gaining an understanding of the behaviour of palaeofires is also essential if we are to determine the palaeoecological impact of wildfires. Here, I use experimental approaches to explore relationships between litter fire behaviour and leaf traits that are observable in the fossil record. Fire calorimetry was used to assess the flammability of 15 species of conifer litter and indicated that leaf morphology related to litter bulk density and fuel load that determined the duration of burning and the total energy released. These data were applied to a fossil case study that couples estimates of palaeolitter fire behaviour to charcoal-based estimates of fire activity and observations of palaeoecological changes. The case study reveals that significant changes in fire activity and behaviour likely fed back to determine ecosystem composition. This work highlights that we can recognize and measure plant traits in the fossil record that relate to fire behaviour and therefore that further research is warranted towards estimating palaeofire behaviour as it can enhance our ability to interpret the palaeoecological impact of palaeofires throughout Earth's long evolutionary history.This article is part of the themed issue 'The interaction of fire and mankind'. PMID- 27216521 TI - The discovery of fire by humans: a long and convoluted process. AB - Numbers of animal species react to the natural phenomenon of fire, but only humans have learnt to control it and to make it at will. Natural fires caused overwhelmingly by lightning are highly evident on many landscapes. Birds such as hawks, and some other predators, are alert to opportunities to catch animals including invertebrates disturbed by such fires and similar benefits are likely to underlie the first human involvements with fires. Early hominins would undoubtedly have been aware of such fires, as are savanna chimpanzees in the present. Rather than as an event, the discovery of fire use may be seen as a set of processes happening over the long term. Eventually, fire became embedded in human behaviour, so that it is involved in almost all advanced technologies. Fire has also influenced human biology, assisting in providing the high-quality diet which has fuelled the increase in brain size through the Pleistocene. Direct evidence of early fire in archaeology remains rare, but from 1.5 Ma onward surprising numbers of sites preserve some evidence of burnt material. By the Middle Pleistocene, recognizable hearths demonstrate a social and economic focus on many sites. The evidence of archaeological sites has to be evaluated against postulates of biological models such as the 'cooking hypothesis' or the 'social brain', and questions of social cooperation and the origins of language. Although much remains to be worked out, it is plain that fire control has had a major impact in the course of human evolution.This article is part of the themed issue 'The interaction of fire and mankind'. PMID- 27216522 TI - Fire, climate and vegetation linkages in the Bolivian Chiquitano seasonally dry tropical forest. AB - South American seasonally dry tropical forests (SDTFs) are critically endangered, with only a small proportion of their original distribution remaining. This paper presents a 12 000 year reconstruction of climate change, fire and vegetation dynamics in the Bolivian Chiquitano SDTF, based upon pollen and charcoal analysis, to examine the resilience of this ecosystem to drought and fire. Our analysis demonstrates a complex relationship between climate, fire and floristic composition over multi-millennial time scales, and reveals that moisture variability is the dominant control upon community turnover in this ecosystem. Maximum drought during the Early Holocene, consistent with regional drought reconstructions, correlates with a period of significant fire activity between 8000 and 7000 cal yr BP which resulted in a decrease in SDTF diversity. As fire activity declined but severe regional droughts persisted through the Middle Holocene, SDTFs, including Anadenanthera and Astronium, became firmly established in the Bolivian lowlands. The trend of decreasing fire activity during the last two millennia promotes the idea among forest ecologists that SDTFs are threatened by fire. Our analysis shows that the Chiquitano seasonally dry biome has been more resilient to Holocene changes in climate and fire regime than previously assumed, but raises questions over whether this resilience will continue in the future under increased temperatures and drought coupled with a higher frequency anthropogenic fire regime.This article is part of the themed issue 'The interaction of fire and mankind'. PMID- 27216523 TI - Fire in the mind: changing understandings of fire in Western civilization. AB - For most of human history, fire has been a pervasive presence in human life, and so also in human thought. This essay examines the ways in which fire has functioned intellectually in Western civilization as mythology, as religion, as natural philosophy and as modern science. The great phase change occurred with the development of industrial combustion; fire faded from quotidian life, which also removed it from the world of informing ideas. Beginning with the discovery of oxygen, fire as an organizing concept fragmented into various subdisciplines of natural science and forestry. The Anthropocene, however, may revive the intellectual role of fire as an informing idea or at least a narrative conceit.This article is part of the themed issue 'The interaction of fire and mankind'. PMID- 27216524 TI - Fire history on the California Channel Islands spanning human arrival in the Americas. AB - Recent studies have suggested that the first arrival of humans in the Americas during the end of the last Ice Age is associated with marked anthropogenic influences on landscape; in particular, with the use of fire which, would have given even small populations the ability to have broad impacts on the landscape. Understanding the impact of these early people is complicated by the dramatic changes in climate occurring with the shift from glacial to interglacial conditions. Despite these difficulties, we here attempt to test the extent of anthropogenic influence using the California Channel Islands as a smaller, landscape-scale test bed. These islands are famous for the discovery of the 'Arlington Springs Man', which are some of the earliest human remains in the Americas. A unifying sedimentary charcoal record is presented from Arlington Canyon, Santa Rosa Island, based on over 20 detailed sedimentary sections from eight key localities. Radiocarbon dating was based on thin, fragile, long fragments of charcoal in order to avoid the 'inbuilt' age problem. Radiocarbon dating of 49 such fragments has allowed inferences regarding the fire and landscape history of the Canyon ca 19-11 ka BP. A significant period of charcoal deposition is identified approximately 14-12.5 ka BP and bears remarkable closeness to an estimated age range of the first human arrival on the islands.This article is part of the themed issue 'The interaction of fire and mankind'. PMID- 27216525 TI - Multiscale perspectives of fire, climate and humans in western North America and the Jemez Mountains, USA. AB - Interannual climate variations have been important drivers of wildfire occurrence in ponderosa pine forests across western North America for at least 400 years, but at finer scales of mountain ranges and landscapes human land uses sometimes over-rode climate influences. We reconstruct and analyse effects of high human population densities in forests of the Jemez Mountains, New Mexico from ca 1300 CE to Present. Prior to the 1680 Pueblo Revolt, human land uses reduced the occurrence of widespread fires while simultaneously adding more ignitions resulting in many small-extent fires. During the 18th and 19th centuries, wet/dry oscillations and their effects on fuels dynamics controlled widespread fire occurrence. In the late 19th century, intensive livestock grazing disrupted fuels continuity and fire spread and then active fire suppression maintained the absence of widespread surface fires during most of the 20th century. The abundance and continuity of fuels is the most important controlling variable in fire regimes of these semi-arid forests. Reduction of widespread fires owing to reduction of fuel continuity emerges as a hallmark of extensive human impacts on past forests and fire regimes.This article is part of the themed issue 'The interaction of fire and mankind'. PMID- 27216526 TI - Pyrodiversity is the coupling of biodiversity and fire regimes in food webs. AB - Fire positively and negatively affects food webs across all trophic levels and guilds and influences a range of ecological processes that reinforce fire regimes, such as nutrient cycling and soil development, plant regeneration and growth, plant community assembly and dynamics, herbivory and predation. Thus we argue that rather than merely describing spatio-temporal patterns of fire regimes, pyrodiversity must be understood in terms of feedbacks between fire regimes, biodiversity and ecological processes. Humans shape pyrodiversity both directly, by manipulating the intensity, severity, frequency and extent of fires, and indirectly, by influencing the abundance and distribution of various trophic guilds through hunting and husbandry of animals, and introduction and cultivation of plant species. Conceptualizing landscape fire as deeply embedded in food webs suggests that the restoration of degraded ecosystems requires the simultaneous careful management of fire regimes and native and invasive plants and animals, and may include introducing new vertebrates to compensate for extinctions that occurred in the recent and more distant past.This article is part of the themed issue 'The interaction of fire and mankind'. PMID- 27216527 TI - The deforestation story: testing for anthropogenic origins of Africa's flammable grassy biomes. AB - Africa has the most extensive C4 grassy biomes of any continent. They are highly flammable accounting for greater than 70% of the world's burnt area. Much of Africa's savannas and grasslands occur in climates warm enough and wet enough to support closed forests. The combination of open grassy systems and the frequent fires they support have long been interpreted as anthropogenic artefacts caused by humans igniting frequent fires. True grasslands, it was believed, would be restricted to climates too dry or too cold to support closed woody vegetation. The idea that higher-rainfall savannas are anthropogenic and that fires are of human origin has led to initiatives to 'reforest' Africa's open grassy systems paid for by carbon credits under the assumption that the net effect of converting these system to forests would sequester carbon, reduce greenhouse gases and mitigate global warming. This paper reviews evidence for the antiquity of African grassy ecosystems and for the fires that they sustain. Africa's grassy biomes and the fires that maintain them are ancient and there is no support for the idea that humans caused large-scale deforestation. Indicators of old-growth grasslands are described. These can help distinguish secondary grasslands suitable for reforestation from ancient grasslands that should not be afforested.This article is part of the themed issue 'The interaction of fire and mankind'. PMID- 27216528 TI - Fire effects on soils: the human dimension. AB - Soils are among the most valuable non-renewable resources on the Earth. They support natural vegetation and human agro-ecosystems, represent the largest terrestrial organic carbon stock, and act as stores and filters for water. Mankind has impacted on soils from its early days in many different ways, with burning being the first human perturbation at landscape scales. Fire has long been used as a tool to fertilize soils and control plant growth, but it can also substantially change vegetation, enhance soil erosion and even cause desertification of previously productive areas. Indeed fire is now regarded by some as the seventh soil-forming factor. Here we explore the effects of fire on soils as influenced by human interference. Human-induced fires have shaped our landscape for thousands of years and they are currently the most common fires in many parts of the world. We first give an overview of fire effect on soils and then focus specifically on (i) how traditional land-use practices involving fire, such as slash-and-burn or vegetation clearing, have affected and still are affecting soils; (ii) the effects of more modern uses of fire, such as fuel reduction or ecological burns, on soils; and (iii) the ongoing and potential future effects on soils of the complex interactions between human-induced land cover changes, climate warming and fire dynamics.This article is part of the themed issue 'The interaction of fire and mankind'. PMID- 27216529 TI - Coxiella burnetii Genotypes in Iberian Wildlife. AB - To investigate if Coxiella burnetii, the causative agent of Q fever, genotypes circulating in wildlife are associated with those infecting livestock and humans, multiple-locus variable number tandem-repeat analysis (MLVA-6-marker) was carried out over C. burnetii obtained from red deer (Cervus elaphus), Eurasian wild boar (Sus scrofa), European wild rabbit (Oryctolagus cuniculus), black rat (Rattus rattus), and wood mouse (Apodemus sylvaticus). MLVA typing was performed by using six variable loci in C. burnetii: Ms23, Ms24, Ms27, Ms28, Ms33, and Ms34. The C. burnetii cooperative database from MLVABank 5.0 was employed to compare genotypes found in this study with 344 isolates of diverse origin. Twenty-two genotypes from wildlife and two genotypes from domestic goats were identified. Some MLVA genotypes identified in wildlife or in farmed game clustered with genotypes of human Q fever clinical cases, supporting the idea that humans and wildlife share C. burnetii genotypes. The major part of genotypes identified in coexisting red deer and rabbits clustered according to their host of origin, suggesting host specificity for particular C. burnetii genotypes. These findings provide important insights to understand the epidemiology of C. burnetii at the wildlife livestock-human interface. PMID- 27216530 TI - Variations in Bacterial Community in a Temperate Lake Associated with an Agricultural Watershed. AB - Terrestrially derived carbon and nutrients are washed into lakes, providing nutritional drivers for both microbial heterotrophy and phototrophy. Changes in the quantity and diversity of carbon and nutrients exported from watersheds in response to alterations in long-term land use have led to a need for evaluation of the linkage between watershed-exported carbon and nutrients and bacterial community structure in watershed associated lakes. To learn more about these interactions, we investigated Muskrat Lake in Michigan, which has a well-defined moderately sized watershed dominated by agriculture. We measured the water chemistry, characterized the dissolved organic carbon, and determined the structure of the bacterial communities at the inlet and center of this lake (five depths per site) over the summer and fall of 2008. The lake had temporal and rain event-based fluctuations in water chemistry, as well as temporal and rain event dependent shifts in bacterial communities as measured by terminal restriction fragment length polymorphism. Agricultural watershed inputs were observed in the lake during and after rain events. Terminal restriction fragment length polymorphism and 454 pyrosequencing of the bacterial communities indicated that there were differences over time and that the dominant phylotypes shifted between summer and late fall. Some populations (e.g., Polynucleobacter and Mycobacterium) increased during fall, while others (e.g., Gemmatimonas) diminished. Redundancy and partitioning analyses showed that water chemistry is highly correlated with variations in the bacterial community of the lake, which explained 34 % of the variations in the bacterial community. Dissolved organic carbon had the greatest effects on variations in the Muskrat Lake bacterial community (2 %). The results of this study provide information that will enable a better understanding of the interaction between the bacterial community of lakes and changes in chemical properties as a result of nutrient importation from the surrounding watershed. PMID- 27216532 TI - Erratum to: Dogs, cats, parasites, and humans in Brazil: opening the black box. PMID- 27216531 TI - Comparison of non-parametric methods for ungrouping coarsely aggregated data. AB - BACKGROUND: Histograms are a common tool to estimate densities non parametrically. They are extensively encountered in health sciences to summarize data in a compact format. Examples are age-specific distributions of death or onset of diseases grouped in 5-years age classes with an open-ended age group at the highest ages. When histogram intervals are too coarse, information is lost and comparison between histograms with different boundaries is arduous. In these cases it is useful to estimate detailed distributions from grouped data. METHODS: From an extensive literature search we identify five methods for ungrouping count data. We compare the performance of two spline interpolation methods, two kernel density estimators and a penalized composite link model first via a simulation study and then with empirical data obtained from the NORDCAN Database. All methods analyzed can be used to estimate differently shaped distributions; can handle unequal interval length; and allow stretches of 0 counts. RESULTS: The methods show similar performance when the grouping scheme is relatively narrow, i.e. 5-years age classes. With coarser age intervals, i.e. in the presence of open-ended age groups, the penalized composite link model performs the best. CONCLUSION: We give an overview and test different methods to estimate detailed distributions from grouped count data. Health researchers can benefit from these versatile methods, which are ready for use in the statistical software R. We recommend using the penalized composite link model when data are grouped in wide age classes. PMID- 27216533 TI - The perils of motherhood at age 14. PMID- 27216534 TI - The c.-190 C>A transversion in promoter region of protamine1 gene as a genetic risk factor for idiopathic oligozoospermia. AB - The genome condensation in the sperm head is resulted with replacing of histones by protamines during spermatogenesis. It is reported that defects in the protamine 1 (PRM1) and/or 2 (PRM2) genes cause male infertility. Located on chromosome 16 (16p13.2) these genes contain numerous unstudied single nucleotide polymorphisms. This study aimed to investigate the association of c.-190 C>A and g.298 G>C transversions that respectively occur in PRM1 and PRM2 genes with idiopathic oligozoospermia. In a case-control study, we collected blood samples from 130 idiopathic oligozoospermia and 130 fertile men. Detection of c.-190 C>A and g.298 G>C polymorphisms performed by direct sequencing and PCR-RFLP methods respectively. An in silico analysis was performed by ASSP, NetGene 2, and PNImodeler online web servers. Our data revealed that g.298 G>C transversion in PRM2 was not associated with oligozoospermia (P > 0.05). Whereas, -190CA and 190AA genotypes in PRM1 gene were associated significantly with increased risk of oligozoospermia (P = 0.0017 and 0.0103, respectively). Also carriers of A allele (CA+AA) for PRM1 c.-190 C>A were at a high risk for oligozoospermia (OR 3.2440, 95 % CI 1.8060-5.8270, P = 0.0001). Further, in silico analysis revealed that c. 190 C>A transversion may alter transcription factor interactions with the promoter region of PRM1. The results revealed that the c.-190 C>A transversion may involve in the susceptibility for oligozoospermia and could be represented as a noninvasive molecular marker for genetic diagnosis of idiopathic oligozoospermia. PMID- 27216535 TI - Molecular identification of Kiss/GPR54 and function analysis with mRNA expression profiles exposure to 17alpha-ethinylestradiol in rare minnow Gobiocypris rarus. AB - 17alpha-ethinylestradiol (EE2) is a widely existed endocrine disrupting chemical in water environment. Kisspeptins act as indispensable regulators through GPR54 in the hypothalamic-pituitary-gonadal (HPG) axis. This study aimed to provide further understanding of the effect of EE2 on HPG axis. Molecular cloning and tissue distribution of kiss genes and GPR54s were performed in Gobiocypris rarus. The mRNA expression profiles of kiss1, kiss2, GPR54s and GnRHs were detected in G. rarus brain and/or gonad following 3- and 6-days EE2 (1, 5, 25 and 125 ng/L) exposure. Results showed that kiss genes and GPR54s were highly expressed in brain and gonad. Both kiss1 and kiss2 were increased in female brain and suppressed in male brain following EE2 exposure. GnRHs were inhibited in a concentration-dependent manner in male brain following 3-days EE2 exposure. In gonad, GPR54b was almost suppressed in all of EE2 concentrations. The present findings suggest that EE2 impacts the genes expression of Kiss/GPR54-GnRH system in G. rarus, thereby probably disturbing the neuroendocrine homeostasis. PMID- 27216536 TI - Alternative splicing generates novel Fads3 transcript in mice. AB - Fads3 is the third member of the fatty acid desaturase gene cluster; with at least eight evolutionarily conserved alternative transcripts (AT), having no clearly established function as are known for FADS2 and FADS1. Here we present identification of a novel Fads3 transcript in mice (Fads3AT9), characterize Fads3AT9 expression in mouse tissues and evaluate correlations with metabolite profiles. Total RNA obtained from mouse tissues is reverse-transcribed into cDNA and used as template for PCR reactions. Tissue fatty acids were extracted and quantified by gas chromatography. Sequencing analysis revealed complete absence of exon 2 resulting in an open reading frame of 1239 bp, encoding a putative protein of 412 aa with loss of 37 aa compared to classical Fads3 (Fads3CS). FADS3AT9 retains all the conserved regions characteristic of front end desaturase (cytochrome b5 domain and three histidine repeats). Both Fads3CS and Fads3AT9 are ubiquitously expressed in 11 mouse tissues. Fads3AT9 abundance was greater than Fads3CS in pancreas, liver, spleen, brown adipose tissue and thymus. Fads3CS expression is low in pancreas while Fads3AT9 is over ten-fold greater abundance. The eicosanoid precursor fatty acid 20:4n - 6, the immediate desaturation product of the Fads1 coded Delta5-desaturase, was highest in pancreas where Fads3CS is low. Changes in expression patterns and fatty acid profiles suggest that Fads3AT9 may play a role in the regulation and/or biosynthesis of long chain polyunsaturated fatty acids from precursors. PMID- 27216537 TI - Effects of prenatal Poly I:C exposure on global histone deacetylase (HDAC) and DNA methyltransferase (DNMT) activity in the mouse brain. AB - The aim of our study was to investigate the brain-specific epigenetic effects on global enzymatic histone deacetylase (HDAC) and DNA methyltransferase (DNMT) activity after prenatal exposure to maternal immune challenge by polyinosinic:polycytidylic acid (Poly I:C) at gestational day (GD) 17 in C57BL/6JRccHsd mouse offspring. Pregnant mice were randomly divided into 2 groups, receiving either 5 mg/kg Poly I:C or phosphate buffered saline (PBS) intravenously at GD 17. Subsequently, the effects on whole brain enzymatic HDAC and DNMT activity and the protein levels of various HDAC isoforms were assessed in the offspring. Overall, a significant sex * treatment interaction effect was observed after prenatal exposure to maternal immune challenge by Poly I:C, indicative of increased global HDAC activity particularly in female offspring from mothers injected with Poly I:C when compared to controls. Results on the levels of specific HDAC isoforms suggested that neither differences in the levels of HDAC1, HDAC2, HDAC3, HDAC4 or HDAC6 could explain the increased global HDAC activity observed in female Poly I:C offspring. In conclusion, we show that Poly I:C administration to pregnant mice alters global brain HDAC, but not DNMT activity in adult offspring, whereas it is still unclear which specific HDAC(s) mediate(s) this effect. These results indicate the necessity for further research on the epigenetic effects of Poly I:C. PMID- 27216538 TI - Cribrihabitans pelagius sp. nov., a marine alphaproteobacterium isolated from seawater. AB - A Gram-stain-negative, strictly aerobic, cream-coloured, motile, chemoheterotrophic, rod-shaped bacterium, designated strain KMU-32T, was isolated from seawater at Najeong Beach in Korea. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that the novel isolate was affiliated with the family Rhodobacteraceae of the class Alphaproteobacteria and that it showed highest sequence similarity (98.2 %) to Cribrihabitans neustonicus CC-AMHB-3T. The DNA DNA relatedness value between strain KMU-32T and C. neustonicus CC-AMHB-3T was 48.5 +/- 4 %. The DNA G+C content of strain KMU-32T was determined to be 63.7 mol%. Ubiquinone 10 (Q-10) was the sole respiratory quinone. The predominant cellular fatty acid was C18 : 1omega7c. Strain KMU-32T had diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, an unidentified aminolipid and an unidentified lipid as polar lipids. From the distinct phylogenetic position and combination of genotypic and phenotypic characteristics, strain KMU-32T is considered to represent a novel species of the genus Cribrihabitans, for which the name Cribrihabitans pelagius sp. nov. is proposed. The type strain is KMU-32T (= KCTC 42981T = NBRC 111834T). PMID- 27216539 TI - Phytoremediation potential of transplanted bare-root seedlings of trees for lead/zinc and copper mine tailings. AB - Selecting plant species that can overcome unfavorable conditions and increase the recovery of degraded mined lands remains a challenge. A pot experiment was conducted to evaluate the feasibility of using transplanted tree seedlings for the phytoremediation of lead/zinc and copper mine tailings. One-year-old bare root of woody species (Rhus chinensis Mill, Quercus acutissima Carruth, Liquidambar formosana Hance, Vitex trifolia Linn. var. simplicifolia Cham, Lespedeza cuneata and Amorpha fruticosa Linn) were transplanted into pots with mine tailings and tested as potential metal-tolerant plants. Seedling survival, plant growth, root trait, nutrient uptake, and metal accumulation and translocation were assessed. The six species grew in both tailings and showed different tolerance level. A. fruticosa was highly tolerant of Zn, Pb and Cu, and grew normally in both tailings. Metal concentrations were higher in the roots than in the shoots of the six species. All of the species had low bioconcentration and translocation factor values. However, R. chinensis and L. formosana had significantly higher translocation factor values for Pb (0.88) and Zn (1.78) than the other species. The nitrogen-fixing species, A. fruticosa, had the highest tolerance and biomass production, implying that it has great potential in the phytoremediation of tailing areas in southern China. PMID- 27216540 TI - Evaluation of the utility of popliteal lymph node examination in a cyclophosphamide model of immunotoxicity in the rat. AB - The objective of this study was to characterize the variability of rat lymphoid organ weights and morphology following treatment with a known immunotoxicant, with a focus on the usefulness of evaluating popliteal lymph node weight and histology. Cyclophosphamide was administered to male Sprague-Dawley rats by oral gavage at doses of 2, 7 or 12 mg/kg/day for 10 consecutive days. Left and right popliteal lymph nodes (PLN), spleen and thymus were collected at necropsy, weighed, fixed and processed for histopathology. Femoral bone marrow was also collected, fixed and processed for histology. Organ weight variability was greater for PLN than for either spleen or thymus in control animals. There was a significant but weak correlation between paired left and right PLN weights (p < 0.005; r(2) = 0.2774). Significant treatment-related decreases in lymphoid organ weights were observed in spleen and thymus at >= 7 mg/kg/day (p < 0.01), whereas in PLN a significant decrease (p < 0.05) was noted only at 12 mg/kg/day. The inclusion of PLN did not enhance the sensitivity of detection of systemic treatment-related changes in lymphoid organs in a rat cyclophosphamide model. PMID- 27216541 TI - Structural, electrochemical and photophysical properties of an exocyclic di ruthenium complex and its application as a photosensitizer. AB - The reaction of cis-bis(2,2'-bipyridine)dichlororuthenium(ii) hydrate with a conformationally mobile bipyridyl macrocycle afforded [(bpy)2Ru(MU L)Ru(bpy)2]Cl4.6H2O, a bridged di-Ru complex. Single crystal X-ray diffraction showed the macrocyclic ligand adopting a bowl-like structure with the exo coordinated Ru(ii) centers separated by 7.29 A. Photophysical characterization showed that the complex absorbs in the visible region (lambdamax = 451 nm) with an emission maximum at 610 nm (tau = 706 ns, PhiPL = 0.021). Electrochemical studies indicate the di-Ru complex undergoes three one-electron reversible reductions and a reversible one-electron oxidation process. This electrochemical reversibility is a key characteristic for its use as an electron transfer agents. The complex was evaluated as a photocatalyst for the electronically mismatched Diels-Alder reaction of isoprene and trans-anethole using visible light. It afforded the expected product in good conversion (69%) and selectivity (dr > 10 : 1) at low loadings (0.5-5.0 mol%) and the sensitizer/catalyst was readily recycled. These results suggest that the bipyridyl macrocycle could be widely applied as a bridging ligand for the generation of chromophore-catalyst assemblies. PMID- 27216542 TI - Implementing a patient blood management program in Norway: Where to start? AB - Norway has recently established a working group to implement a national patient blood management (PBM) program. Although benchmarking regarding blood usage is challenging in Norway due to legal barriers, a survey was sent to different hospitals to identify possible areas to be prioritized in the first phase of the PBM program. Among them, optimizing the patient's hemoglobin level before elective surgery and implementing electronic check-lists for the indication of transfusion when ordering blood products are two measures that may have a considerable impact on blood usage. The results of the survey also showed that patients may receive a red blood cell transfusion at hemoglobin levels that are higher than those internationally recommended. Since there are no national guidelines for the use of blood products, agreement regarding hemoglobin thresholds is essential to reduce variation in transfusion practice. To achieve these goals, the transfusion specialist plays a key role in promoting the principles behind the PBM concept at the local hospital. PMID- 27216543 TI - An update on laboratory measurements of Dabigatran: Smart specific and calibrated dedicated assays for measuring anti-IIa activity in plasma. AB - Use of Direct Oral Anticoagulants (DOACs) is continuously increasing for clinical application. The first product released was Dabigatran, which was proposed for many preventive and curative applications, especially for prevention of stroke in patients with non-valvular atrial fibrillation. Although measurement of Dabigatran Anti-IIa activity in plasma is not requested on a routine basis, in some situations its measurement is clinically useful. Especially, before an emergency surgery in treated patients, where its presence at high concentrations, which will expose the patient at an increased bleeding risk, has to be excluded. Hence, smart, specific, rapid and accurate quantitative assays are warranted as an essential required. HemoclotTM Thrombin Inhibitors and Biophen(r) DTI were specifically designed for these applications, and can be used on all automated instruments with a standard range protocol for measuring concentrations at peak, or with a low range protocol for testing residual concentrations. Both functional assays have a good correlation with the reference LC-MS/MS method, and concentrations measured are similar. Performances of these assays and interferences of various substances or drugs are discussed. Some differences in variations of clotting times are observed between mechanical or optical clot detection instruments, which could be explained by the fibrin clot structure, altered by direct Factor Xa inhibitors, and more especially Rivaroxaban. Both clotting and chromogenic assays offer a safe and accurate quantitative measurement of Dabigatran in plasma in all situations where this determination is requested. In short this manuscript provides an in depth update on current opinions on laboratory aspects of measuring Dabigatran concentrations in plasma, when required. PMID- 27216544 TI - Donor lymphocyte infusion after allogeneic stem cell transplantation. AB - Allogeneic stem cell transplantation (allo-SCT) is considered the cornerstone in the treatment of several malignant and not malignant hematological diseases. However, relapse of hematological disease after allo-SCT is considered the most challenging point in the field. The risk can be reduced through optimal patients, donor and disease selection before allo-SCT, but harnessing donor immune system is an appealing way to treat or avoid disease relapse. Donor lymphocyte infusion (DLI) is a simple and effective therapy after allo-SCT. In this paper, the efficacy of DLI will be analyzed in different hematological diseases, focusing also on their therapeutic or pre-emptive use. PMID- 27216545 TI - Pleural fluid CEA. PMID- 27216546 TI - Innovations and Improvements in Pharmacokinetic Models Based on Physiology. AB - BACKGROUND: Accompanied by significant improvements of modeling techniques and computational methods in medical sciences, the last thirty years saw the flourishing of pharmacokinetic models for applications in the pharmacometric field. In particular, physiologically based pharmacokinetic (PBPK) models, grounded on a mechanistic foundation, have been applied to explore a multiplicity of aspects with possible applications in patient care and new drugs development, as in the case of siRNA therapies. METHOD: This article summarizes the features we recently introduced in PBPK modeling within a threeyear research project funded by Italian Research Ministry. Four major points are detailed: (i) the mathematical formulation of the model, which allows modulating its complexity as a function of the administration route and active principle; (ii) a dedicated parameter of the PBPK model quantifies the drugprotein binding, which affects the active principle distribution; (iii) the gall bladder compartment and the bile enterohepatic circulation process; (iv) the coupling of the pharmacokinetic and pharmacodynamic models to produce an overall understanding of the drug effects on mammalian body. RESULTS: The proposed model is applied to two separate endovenous (remifentanil) and oral (sorafenib) drug administrations. The resulting PBPK simulations are consistent with the literature experimental data. Blood concentration predictability is confirmed in multiple reference subjects. Furthermore, in case of sorafenib administration in mice, it is possible to evaluate the drug concentration in the liver and reproduce the effects of the enterohepatic circulation. Finally, a preliminary application of the coupling of the pharmacokinetic/pharmacodynamic models is presented and discussed. PMID- 27216547 TI - Survival of a very low-birthweight infant with Potter sequence on long-term hemodialysis. AB - Recent advances in neonatal cardiorespiratory management and neonatal renal replacement therapy have led to occasional reports of favorable short-term and long-term outcomes for Potter sequence, once thought to be fatal. The present patient was a girl born at a gestational age of 34 weeks 4 days with a birthweight of 1398 g. She was diagnosed with Potter sequence complicated by pulmonary hypoplasia due to left renal agenesis and small right kidney. Hemodialysis was started because anuria persisted even after persistent pulmonary hypertension receded and cardiorespiratory status improved. Peritoneal dialysis during the clinical course failed to achieve stability because of pericatheter leakage and frequent obstruction of the peritoneal dialysis catheter; in the meantime, hemodialysis was also performed. Once bodyweight passed 3.5 kg, peritoneal dialysis became more feasible with stability; the patient was discharged at 9 months and at the time of writing was on peritoneal dialysis at home, and renal transplantation was planned. PMID- 27216549 TI - Dynamic resolution of 2-cyclohexylidene acetaldehydes through organocatalytic dienamine [4+2] cycloaddition. AB - Organocatalytic formed dienamines are shown to be involved in dynamic resolution of 2-cyclohexylidene acetaldehydes. By reaction of racemic 2-cyclohexylidene acetaldehydes with benzoquinones in the presence of a diarylprolinol-silyl ether catalyst, tricyclic products are formed in good to high yield and excellent enantioselectivity, while the diastereoselectivity depends on the substituent in the 2-cyclohexylidene acetaldehydes. Studies based on experimental observations and DFT-calculations point to a dynamic thermodynamic resolution-directed pathway. Some transformations of the optically active products are also presented. PMID- 27216548 TI - Whole genome analysis of halotolerant and alkalotolerant plant growth-promoting rhizobacterium Klebsiella sp. D5A. AB - This research undertook the systematic analysis of the Klebsiella sp. D5A genome and identification of genes that contribute to plant growth-promoting (PGP) traits, especially genes related to salt tolerance and wide pH adaptability. The genome sequence of isolate D5A was obtained using an Illumina HiSeq 2000 sequencing system with average coverages of 174.7* and 200.1* using the paired end and mate-pair sequencing, respectively. Predicted and annotated gene sequences were analyzed for similarity with the Kyoto Encyclopedia of Genes and Genomes (KEGG) enzyme database followed by assignment of each gene into the KEGG pathway charts. The results show that the Klebsiella sp. D5A genome has a total of 5,540,009 bp with 57.15% G + C content. PGP conferring genes such as indole-3 acetic acid (IAA) biosynthesis, phosphate solubilization, siderophore production, acetoin and 2,3-butanediol synthesis, and N2 fixation were determined. Moreover, genes putatively responsible for resistance to high salinity including glycine betaine synthesis, trehalose synthesis and a number of osmoregulation receptors and transport systems were also observed in the D5A genome together with numerous genes that contribute to pH homeostasis. These genes reveal the genetic adaptation of D5A to versatile environmental conditions and the effectiveness of the isolate to serve as a plant growth stimulator. PMID- 27216550 TI - Association Between Aerobic Exercise and Rosiglitazone Avoided the NAFLD and Liver Inflammation Exacerbated in PPAR-alpha Knockout Mice. AB - Nonalcoholic fatty liver disease (NAFLD) is one of the main liver diseases today, and may progress to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Some studies have shown the beneficial effects of aerobic exercise on reversing NAFLD. To verify whether chronic aerobic exercise improves the insulin resistance, liver inflammation, and steatohepatitis caused by a high fat diet (HF) and whether PPARalpha is involved in these actions. C57BL6 wild type (WT) and PPAR-alpha knockout (KO) mice were fed with a standard diet (SD) or HF during 12 weeks; the HF mice were trained on a treadmill during the last 8 weeks. Serum glucose and insulin tolerances, serum levels of aspartate aminotransferase, hepatic content of triacylglycerol, cytokines, gene expression, and protein expression were evaluated in all animals. Chronic exposure to HF diet increased triacylglycerol accumulation in the liver, leading to NAFLD, increased aminotransferase in the serum, increased peripheral insulin resistance, and higher adiposity index. Exercise reduced all these parameters in both animal genotypes. The liver lipid accumulation was not associated with inflammation; trained KO mice, however, presented a huge inflammatory response that was probably caused by a decrease in PPAR-gamma expression. We conclude that exercise improved the damage caused by a HF independently of PPARalpha, apparently by a peripheral fatty acid oxidation in the skeletal muscle. We also found that the absence of PPARalpha together with exercise leads to a decrease in PPAR-gamma and a huge inflammatory response. J. Cell. Physiol. 232: 1008-1019, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27216551 TI - A novel frameshift mutation of DDHD1 in a Japanese patient with autosomal recessive spastic paraplegia. AB - Spastic paraplegia (SPG) type 28 is an autosomal recessive SPG caused by mutations in the DDHD1 gene. We examined a Japanese 54-years-old male patient with autosomal recessive SPG. His parents were consanguineous. He needed a wheelchair for transfer due to spastic paraplegia. There was a history of operations for bilateral hallux valgus, thoracic ossification of the yellow ligament, bilateral carpal tunnel syndrome, bilateral ankle contracture, and lumbar spinal canal stenosis. He noticed gait disturbance at age 14. He used a cane for walking in his 40s. On neurological examination, he showed hyperreflexia, spasticity, and weakness in the lower extremities and bilateral Babinski reflexes. Urinary dysfunctions and impaired vibration sense in the lower limbs were observed. By exome sequencing analysis using Agilent SureSelect and Illumina MiSeq, we identified 17,248 homozygous nucleotide variants in the patient. Through the examination of 48 candidate genes known to be responsible for autosomal recessive SPG, we identified a novel homozygous 4-bp deletion, c.914_917delGTAA, p.Ser305Ilefs*2 in exon2 of the DDHD1 gene encoding phosphatidic acid-preferring phospholipase A1 (PA-PLA1). The mutation is expected to cause a frameshift generating a premature stop codon 3-bp downstream from the deletion. In consequence, the DDHD domain that is known to be critical for PLA1 activity is completely depleted in the mutated DDHD1 protein, predicted to be a functionally null mutation of the DDHD1 gene. By Sanger sequencing, we confirmed that both parents are heterozygous for the mutation. This variation was not detected in 474 Japanese control subjects as well as the data of the 1,000G Project. We conclude that the novel mutation in DDHD1 is the causative variant for the SPG28 patient that is the first record of the disease in Japanese population. PMID- 27216552 TI - Colloidal synthesis of Cu-ZnO and Cu@CuNi-ZnO hybrid nanocrystals with controlled morphologies and multifunctional properties. AB - Metal-semiconductor hybrid nanocrystals have received extensive attention owing to their multiple functionalities which can find wide technological applications. The utilization of low-cost non-noble metals to construct novel metal semiconductor hybrid nanocrystals is important and meaningful for their large scale applications. In this study, a facile solution approach is developed for the synthesis of Cu-ZnO hybrid nanocrystals with well-controlled morphologies, including nanomultipods, core-shell nanoparticles, nanopyramids and core-shell nanowires. In the synthetic strategy, Cu nanocrystals formed in situ serve as seeds for the heterogeneous nucleation and growth of ZnO, and it eventually forms various Cu-ZnO hetero-nanostructures under different reaction conditions. These hybrid nanocrystals possess well-defined and stable heterostructure junctions. The ultraviolet-visible-near infrared spectra reveal morphology-dependent surface plasmon resonance absorption of Cu and the band gap absorption of ZnO. Furthermore, we construct a novel Cu@CuNi-ZnO ternary hetero-nanostructure by incorporating the magnetic metal Ni into the pre-synthesized colloidal Cu nanocrystals. Such hybrid nanocrystals possess a magnetic Cu-Ni intermediate layer between the ZnO shell and the Cu core, and exhibit ferromagnetic/superparamagnetic properties which expand their functionalities. Finally, enhanced photocatalytic activities are observed in the as-prepared non noble metal-ZnO hybrid nanocrystals. This study not only provides an economical way to prepare high-quality morphology-controlled Cu-ZnO hybrid nanocrystals for potential applications in the fields of photocatalysis and photovoltaic devices, but also opens up new opportunities in designing ternary non-noble metal semiconductor hybrid nanocrystals with multifunctionalities. PMID- 27216553 TI - Effects of dietary addition of heat-killed Mycobacterium phlei on growth performance, immune status and anti-oxidative capacity in early weaned piglets. AB - The contradiction between high susceptibility of early weaned piglets to enteric pathogens and rigid restriction of antibiotic use in the diet is still prominent in the livestock production industry. To address this issue, the study was designed to replace dietary antibiotics partly or completely by an immunostimulant, namely heat-killed Mycobacterium phlei (M. phlei). Piglets (n = 192) were randomly assigned to one of the four groups: (1) basal diet (Group A), (2) basal diet + a mixture of antibiotics (80 mg/kg diet, Group B), (3) basal diet + a mixture of antibiotics (same as in Group B, but 40 mg/kg diet) + heat killed M. phlei (1.5 g/kg diet) (Group C) and (4) basal diet + heat-killed M. phlei (3 g/kg diet) (Group D). All piglets received the respective diets from days 21 to 51 of age and were weaned at the age of 28 d. Compared with the Control (Group A), in all other groups the average daily gain, average daily feed intake, small intestinal villus height:crypt depth ratio and protein levels of occludin and ZO-1 in the jejunal mucosa were increased. A decreased incidence of diarrhoea in conjunction with an increased sIgA concentration in the intestinal mucosa and serum IL-12 and IFN-gamma concentrations was found in groups supplemented with heat-killed M. phlei (Groups C and D), but not in Group B. Groups C and D also showed decreased IL-2 concentrations in the intestinal mucosa with lower TLR4 and phosphor-IkappaB protein levels. The antioxidant capacity was reinforced in Groups C and D, as evidenced by the reduction in malondialdehyde and enhanced activities of antioxidant enzymes in serum. These data indicate that heat-killed M. phlei is a promising alternative to antibiotic use for early weaned piglets via induction of protective immune responses. PMID- 27216554 TI - Effect of high fibre diets formulated with different fibrous ingredients on performance, nutrient digestibility and faecal microbiota of weaned piglets. AB - The aim of the experiment on 180 weaned piglets (8.9 kg body weight) was to investigate the influence of high fibre diets formulated with different fibrous ingredients on performance, nutrient digestibility, diarrhoea incidence and numbers of faecal microbiota. The dietary treatments included a Control diet and five high fibre diets formulated with different fibre sources including wheat bran, soybean hulls, naked oat hulls, palm kernel expeller and bamboo fibre. The high fibre diets averaged 14.6% neutral detergent fibre with different non-starch polysaccharides (NSP) components and were fed ad libitum for 28 d. Faecal samples were collected during the last 3 d of the experiment and the apparent total tract digestibility of nutrients and fibre components were determined. Pigs fed the Control and wheat bran diets had a higher (p <= 0.05) average daily gain (ADG) than pigs fed the palm kernel expeller and bamboo meal diets. The reduced ADG for pigs appeared to be related to reductions in the digestibility of gross energy and dry matter, respectively. The feed-to-gain ratio was significantly higher (p <= 0.05) for pigs fed the fibre diets. The digestibility of NSP components was different among the treatments. The diarrhoea incidence was not affected by treatments. The abundance of faecal bifidobacteria was significantly higher (p <= 0.05) for pigs fed the wheat bran diet than for pigs fed the bamboo meal diet. It was concluded that the diets formulated with different fibre sources when fed to weaned piglets have different effects on pig performance, nutrient digestibility and numbers of faecal microbiota. The wheat bran diet rich in arabinoxylans enabled a better performance than the other tested diets with fibre addition. PMID- 27216555 TI - The effects of inulin, dried Jerusalem artichoke tuber and a multispecies probiotic preparation on microbiota ecology and immune status of the large intestine in young pigs. AB - The study aimed at determining the effect of two types of prebiotics and a multispecies probiotic on microbiota activity and composition, as well as mucosal immunity in the large intestine of young pigs. In total 48 piglets were divided into 6 groups (n = 8), which received from day 10 of life probiotic unsupplemented (PU) or probiotic-supplemented (PS) diets. Probiotics were added at 0.5 g/kg diet and contained: Lactococcus lactis, Carnobacterium divergens, Lactobacillus casei, Lactobacillus plantarum and Saccharomyces cerevisiae. The PU and PS diets were formulated without prebiotic addition (control) or with addition of 2% of inulin from chicory root (IN) or 4% of dried Jerusalem artichoke tubers (DJA). After 40 days of feeding, digesta and tissue samples were taken from the caecum and three sections of the colon for analyses of microbiota activity and composition, secretory immunoglobulin A (sIgA) and intraepithelial lymphocytes (IEL). IN diets decreased the caecal digesta pH and beta-glucosidase activity but increased propionic, valeric and total short chain fatty acid (SCFA) concentrations compared to control diets. Feeding DJA diets increased caecal valeric acid level, decreased the concentration of isoacids in the colon, reduced beta-glucosidase and beta-glucuronidase activity in the middle colon and increased Bifidobacterium spp. populations in the proximal and distal colon. PS diets increased the caecal acetic acid and total SCFA level, and Clostridium spp. populations in the distal colon. Neither probiotic nor prebiotics affected sIgA level or IEL number in the large intestine. In conclusion, DJA modified the microbiota ecology in the large intestine of young pigs to a greater extent than IN and the applied probiotic did not enhance effects of prebiotics. PMID- 27216556 TI - Nitrogen supply in cattle coupled with appropriate supply of utilisable crude protein at the duodenum, a precursor to metabolisable protein. AB - The overall objective of this study was to calculate the amount of nitrogen (N) that cattle feed must contain in order to utilise the potential supply of utilisable crude protein at the duodenum provided by their energy intake without incurring a negative N balance, that is, without having to break down body protein. For this purpose, the literature was screened for measurements of net degradation and renal excretion of urea as well as N balances (N intake, faecal N and urinary N) in ruminants (cattle, sheep and goats) fed diets with varying N concentrations. Irreversible loss of N from the body urea pool increased with increasing N intake, but net degradation of urea as a proportion of irreversible loss decreased concurrently. Faecal N appeared not to be influenced by N intake and exceeded 11 g/kg dry matter intake (DMI) only in 7% of the data sets available. Urinary non-urea-N rarely exceeded 4 g/kg DMI and appeared independent of N intake. Urinary urea-N showed a clear dependence of N intake, and it is concluded that 1 g N/kg DMI is sufficient for compensating inevitable N losses in the form of urinary urea. In conclusion, ruminant rations should contain the following N concentrations (per kg DM) to account for obligatory losses: 11 g for compensating losses as faecal N, 4 g for compensating losses as urinary non-urea N and 1 g for compensating inevitable losses as urinary urea-N. The derived recommendations should be helpful for limiting N excretion where this is desirable for ecological reasons. PMID- 27216557 TI - Effect of dietary vegetable oils on the fatty acid profile of plasma lipoproteins in dairy cows. AB - The aim of this study was to elucidate the effect of dietary supplementation of soybean oil (SO) and hydrogenated palm oil (HPO) on the transport of fatty acids (FA) within plasma lipoproteins in lactating and non-lactating cows. Three lactating and three non-lactating Holstein cows were used in two different 3 * 3 Latin square experiments that included three periods of 21 d. Dietary treatments for lactating cows consisted of a basal diet (control; no fat supplement) and fat supplemented diets containing SO (500 g/d per cow) or HPO (500 g/d per cow). For non-lactating cows, dietary treatments consisted of a basal diet (control; no fat supplement) and fat-supplemented diets containing SO (170 g/d per cow) or HPO (170 g/d per cow). Compared with the control and SO diet, HPO addition increased (p < 0.05) the concentration of C16:0, C18:0, C18:2cis-9,12, C18:3cis-9,12,15 and total saturated and polyunsaturated FA in the plasma of lactating cows. In non lactating cows, the SO addition increased the plasma concentration of C18:1trans 11. In lactating cows, concentrations of C16:0, C18:0 and total saturated FA were increased (p < 0.05) by HPO addition in the high-density lipoprotein (HDL). Total saturated FA were increased (p < 0.05) by HPO in very-low-density lipoprotein (VLDL). In non-lactating cows, the concentration of C18:0 was increased (p < 0.05) by HPO in HDL, whereas C18:1trans-11 was increased (p < 0.05) by SO in the low-density lipoprotein. Overall, it was found that distribution and transport of FA within the bovine plasma lipoproteins may be influenced by chain length and degree of unsaturation of dietary lipids. Also, the distribution of individual FA isomers such as C18:1trans-11 and C18:2cis-9,trans-11 may vary depending on the physiological state of the cow (lactating or non-lactating), and are increased in plasma (lactating cows) and the HDL (non-lactating cows) when cows are fed SO. PMID- 27216558 TI - Highly conductive side chain block copolymer anion exchange membranes. AB - Block copolymers based on poly(styrene) having pendent trimethyl styrenylbutyl ammonium (with four carbon ring-ionic group alkyl linkers) or benzyltrimethyl ammonium groups with a methylene bridge between the ring and ionic group were synthesized by reversible addition-fragmentation radical (RAFT) polymerization as anion exchange membranes (AEMs). The C4 side chain polymer showed a 17% increase in Cl(-) conductivity of 33.7 mS cm(-1) compared to the benzyltrimethyl ammonium sample (28.9 mS cm(-1)) under the same conditions (IEC = 3.20 meq. g(-1), hydration number, lambda = ~7.0, cast from DMF/1-propanol (v/v = 3 : 1), relative humidity = 95%). As confirmed by small angle X-ray scattering (SAXS), the side chain block copolymers with tethered ammonium cations showed well-defined lamellar morphologies and a significant reduction in interdomain spacing compared to benzyltrimethyl ammonium containing block copolymers. The chemical stabilities of the block copolymers were evaluated under severe, accelerated conditions, and degradation was observed by (1)H NMR. The block copolymer with C4 side chain trimethyl styrenylbutyl ammonium motifs displayed slightly improved stability compared to that of a benzyltrimethyl ammonium-based AEM at 80 degrees C in 1 M NaOD aqueous solution for 30 days. PMID- 27216559 TI - 'Jumping to conclusions' data-gathering bias in psychosis and other psychiatric disorders - Two meta-analyses of comparisons between patients and healthy individuals. AB - There has been an increase in attention to studying shared mechanisms underlying psychiatric disorders. The 'Jumping to conclusions' (JTC(1)) bias, a tendency to make decisions with certainty based on insufficient information, has been reported in patients with psychosis, and process-based treatment protocols targeting this bias have recently been developed. This review aimed to investigate to what extent the JTC bias, measured by various tasks, is associated with psychotic disorders and other psychiatric disorders using a meta-analytic approach. We examined 6864 articles published between 1990 and 2015, and meta analysed 46 studies. The first meta-analysis included 40 effect sizes comparing patients with schizophrenia spectrum or other psychotic disorders and healthy controls. There was a hastier data-gathering style in patients with psychosis than healthy individuals, with a moderate aggregated effect size. The second meta analysis included 18 effect sizes comparing patients with non-psychotic disorders and healthy controls. There was marked heterogeneity in effect sizes and evidence for publication bias. After removal of outliers, the aggregated effect size for JTC was not statistically significant. A planned subgroup analysis showed no significant effect of JTC in depression. Other diagnostic subgroups yielded small non-significant results. Therefore, our findings do not support the suggestion that JTC is a transdiagnostic phenomenon beyond psychosis. PMID- 27216560 TI - [Chronic fatigue syndrome in adolescents]. PMID- 27216561 TI - Effects of Extracurricular Participation on the Internalizing Problems and Intrapersonal Strengths of Youth in a System of Care. AB - Although extracurricular participation has been linked to positive youth outcomes in the general population, no research to date has examined benefits for youth diagnosed with mental health challenges. Youth in systems of care (SOCs) receive a variety of services and supports that could help them capitalize on this potential for positive development, such as access to flexible funding to support recreational interests. However, research has not examined the degree to which the increased community involvement (e.g., extracurricular participation) sought in SOCs contributes to improved outcomes. This study addresses these gaps by investigating the relationships between both average and increased extracurricular participation frequency and breadth and internalizing problems and intrapersonal strengths among SOC youth. Findings revealed that, on average, higher frequency of youth participation was associated with higher intrapersonal strengths and lower internalizing problems. Increases in participation frequency were also associated with increased strengths and decreased internalizing problems. These findings suggest that efforts to implement supports for increasing extracurricular participation of SOC youth could improve their psychosocial outcomes beyond the benefits yielded via formal services. Taken together, these results provide support for advocacy efforts to integrate youth with mental health challenges into existing extracurriculars and to create new extracurricular opportunities. PMID- 27216563 TI - Comparing laryngoscopy devices: Devices, settings, clinicians - And outcomes. PMID- 27216562 TI - Genetically engineered pre-microRNA-34a prodrug suppresses orthotopic osteosarcoma xenograft tumor growth via the induction of apoptosis and cell cycle arrest. AB - Osteosarcoma (OS) is the most common primary malignant bone tumor in children, and microRNA-34a (miR-34a) replacement therapy represents a new treatment strategy. This study was to define the effectiveness and safety profiles of a novel bioengineered miR-34a prodrug in orthotopic OS xenograft tumor mouse model. Highly purified pre-miR-34a prodrug significantly inhibited the proliferation of human 143B and MG-63 cells in a dose dependent manner and to much greater degrees than controls, which was attributed to induction of apoptosis and G2 cell cycle arrest. Inhibition of OS cell growth and invasion were associated with release of high levels of mature miR-34a from pre-miR-34a prodrug and consequently reduction of protein levels of many miR-34a target genes including SIRT1, BCL2, c-MET, and CDK6. Furthermore, intravenous administration of in vivo-jetPEI formulated miR 34a prodrug significantly reduced OS tumor growth in orthotopic xenograft mouse models. In addition, mouse blood chemistry profiles indicated that therapeutic doses of bioengineered miR-34a prodrug were well tolerated in these animals. The results demonstrated that bioengineered miR-34a prodrug was effective to control OS tumor growth which involved the induction of apoptosis and cell cycle arrest, supporting the development of bioengineered RNAs as a novel class of large molecule therapeutic agents. PMID- 27216564 TI - Do subfertile women adjust their habits when trying to conceive? AB - AIM: The aim of this study was to investigate lifestyle habits and lifestyle adjustments among subfertile women trying to conceive. MATERIALS AND METHODS: Women (n = 747) were recruited consecutively at their first visit to fertility clinics in mid-Sweden. Participants completed a questionnaire. Data were analyzed using logistic regression, t tests, and chi-square tests. RESULTS: The response rate was 62% (n = 466). Mean duration of infertility was 1.9 years. During this time 13.2% used tobacco daily, 13.6% drank more than three cups of coffee per day, and 11.6% consumed more than two glasses of alcohol weekly. In this sample, 23.9% of the women were overweight (body mass index, BMI 25-29.9 kg/m(2)), and 12.5% were obese (BMI >=30 kg/m(2)). Obese women exercised more and changed to healthy diets more frequently than normal-weight women (odds ratio 7.43; 95% confidence interval 3.7-14.9). Six out of ten women (n = 266) took folic acid when they started trying to conceive, but 11% stopped taking folic acid after some time. Taking folic acid was associated with a higher level of education (p < 0.001). CONCLUSIONS: Among subfertile women, one-third were overweight or obese, and some had other lifestyle factors with known adverse effects on fertility such as use of tobacco. Overweight and obese women adjusted their habits but did not reduce their body mass index. Women of fertile age would benefit from preconception counseling, and the treatment of infertility should routinely offer interventions for lifestyle changes. PMID- 27216566 TI - The danger model: questioning an unconvincing theory. PMID- 27216565 TI - Research Resources for Nuclear Receptor Signaling Pathways. AB - Nuclear receptor (NR) signaling pathways impact cellular function in a broad variety of tissues in both normal physiology and disease states. The complex tissue-specific biology of these pathways is an enduring impediment to the development of clinical NR small-molecule modulators that combine therapeutically desirable effects in specific target tissues with suppression of off-target effects in other tissues. Supporting the important primary research in this area is a variety of web-based resources that assist researchers in gaining an appreciation of the molecular determinants of the pharmacology of a NR pathway in a given tissue. In this study, selected representative examples of these tools are reviewed, along with discussions on how current and future generations of tools might optimally adapt to the future of NR signaling research. PMID- 27216567 TI - Pulmonary tuberculosis: Resistance pattern to first line anti-tuberculosis drugs in the Coimbra District, 2000-2011. PMID- 27216568 TI - Asthma prevalence in Portuguese preschool children: The latest scientific evidence. PMID- 27216569 TI - Natural Inhibitors of HMG-CoA Reductase-An Insilico Approach Through Molecular Docking and Simulation Studies. AB - Plant products have always been considered for many important metabolic disorders due to its abundant medicinal properties. Alarming adverse effects of overuse of statins has been reported for patients with dyslipidemia. This study was aimed to identify compounds with potent anti-dyslipidemic property from selected plants and analyze them for their efficiency in binding with HMG-CoA reductase, a key enzyme in lipid metabolism. The docking studies indicate rutin as the best compound that can inhibit HMG-CoA reductase as it had strong binding affinity to the enzyme. The molecular dynamics simulation studies confirmed the stability of the HMG-CoA reductase-rutin complex. RMSD, RMSF, Rg, H-bond results indicated that the HMG-CoA reductase-rutin complex is highly stable. Presently, statins are not preferred for individuals with pre-existing liver disease. Our study identified rutin as a promising lead compound which could be further developed into an anti-dyslipidemic molecule. Our results will be a good starting point for future experimental and clinical studies and if the results from such studies match international standards plant derived rutin might emerge as a good alternative to statins. J. Cell. Biochem. 118: 52-57, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27216570 TI - Dose-dependent effects of levetiracetam after hypoxia and hypothermia in the neonatal mouse brain. AB - Perinatal asphyxia to the developing brain remains a major cause of morbidity. Hypothermia is currently the only established neuroprotective treatment available for term born infants with hypoxic-ischemic encephalopathy, saving one in seven to eight infants from developing severe neurological deficits. Therefore, additional treatments with clinically applicable drugs are indispensable. This study investigates a potential additive neuroprotective effect of levetiracetam combined with hypothermia after hypoxia-induced brain injury in neonatal mice. 9 day-old C57BL/6-mice (P9) were subjected either to acute hypoxia or room-air. After 90min of systemic hypoxia (6% O2), pups were randomized into six groups: 1) vehicle, 2) low-dose levetiracetam (LEV), 3) high-dose LEV, 4) hypothermia (HT), 5) HT combined with low-dose LEV and 6) HT combined with high-dose LEV. Pro apoptotic factors, neuronal structures, and myelination were analysed by histology and on protein level at appropriate time points. On P28 to P37 long term outcome was assessed by neurobehavioral testing. Hypothermia confers acute and long-term neuroprotection by reducing apoptosis and preservation of myelinating oligodendrocytes and neurons in a model of acute hypoxia in the neonatal mouse brain. Low-dose LEV caused no adverse effects after neonatal hypoxic brain damage treated with hypothermia whereas administration of high-dose LEV alone or in combination with hypothermia increased neuronal apoptosis after hypoxic brain injury. LEV in low- dosage had no additive neuroprotective effect following acute hypoxic brain injury. PMID- 27216571 TI - Brain-machine interface facilitated neurorehabilitation via spinal stimulation after spinal cord injury: Recent progress and future perspectives. AB - Restoration of motor function is one of the highest priorities in individuals afflicted with spinal cord injury (SCI). The application of brain-machine interfaces (BMIs) to neuroprostheses provides an innovative approach to treat patients with sensorimotor impairments. A BMI decodes motor intent from cortical signals to control external devices such as a computer cursor or a robotic arm. Recent BMI systems can now use these motor intent signals to directly activate paretic muscles or to modulate the spinal cord in a way that reengage dormant neuromuscular systems below the level of injury. In this perspective, we review the progress made in the development of brain-machine-spinal-cord interfaces (BMSCIs) and highlight their potential for neurorehabilitation after SCI. The advancement and application of these neuroprostheses goes beyond improved motor control. The use of BMSCI may combine repetitive physical training along with intent-driven neuromodulation to promote neurorehabilitation by facilitating activity-dependent plasticity. Strong evidence suggests that proper timing of volitional neuromodulation facilitates long-term potentiation in the neuronal circuits that can promote permanent functional recovery in SCI subjects. However, the effectiveness of these implantable neuroprostheses must take into account the fact that there will be continuous changes in the interface between the signals of intent and the actual trigger to initiate the motor action. PMID- 27216572 TI - Should Risk Adjustment for Surgical Outcomes Reporting Include Sociodemographic Status? A Study of Coronary Artery Bypass Grafting in California. AB - BACKGROUND: Public reporting of surgical outcomes must adjust for patient risk. However, whether patient sociodemographic status (SDS) should be included is debatable. Our objective was to empirically compare risk-adjustment models and hospital ratings with or without SDS factors for patients undergoing coronary artery bypass grafting. STUDY DESIGN: This is a retrospective analysis of the California Coronary Artery Bypass Grafting Outcomes Reporting Program, 2011-2012. Outcomes included 30-day or in-hospital mortality, perioperative stroke, and 30 day readmission. Sociodemographic status factors included race, language, insurance, ZIP code-based median income, and percent that were a college graduate. The c-statistic and goodness-of-fit were compared between models with and without SDS factors. Differences in hospital performance rating when adjusting for SDS were also compared. RESULTS: None of the SDS factors predicted mortality. Income, education, and language had no impact on any outcomes. Insurance predicted stroke (MediCal vs private insurance, odds ratio [OR] = 1.91; 95% CI, 1.11-3.31; p = 0.020) and readmissions (Medicare vs private insurance, OR = 1.36; 95% CI, 1.16-1.61; p < 0.001; MediCal vs private insurance, OR = 1.56; 95% CI, 1.26-1.94; p < 0.001). Race also predicted stroke (Asian vs white, OR = 2.26; p < 0.001). Adding SDS factors improved the c-statistic in readmission only (0.652 vs 0.645; p = 0.008). Goodness-of-fit worsened when adding SDS factors to mortality models, but was no different in stroke or readmissions. Hospital performance rating only changed in readmissions; of 124 hospitals, only 1 hospital moved from "better" to "average" when adjusting for SDS. CONCLUSIONS: Adjusting for insurance improves statistical models when analyzing readmissions after coronary artery bypass grafting, but does not impact hospital performance ratings substantially. Deciding whether SDS should be included in a patient's risk profile depends on valid measurements of SDS and requires a nuanced approach to assessing how these variables improve risk-adjusted models. PMID- 27216573 TI - KCNQ channel openers reverse depressive symptoms via an active resilience mechanism. AB - Less than half of patients suffering from major depressive disorder, a leading cause of disability worldwide, achieve remission with current antidepressants, making it imperative to develop more effective treatment. A new therapeutic direction is emerging from the increased understanding of natural resilience as an active stress-coping process. It is known that potassium (K(+)) channels in the ventral tegmental area (VTA) are an active mediator of resilience. However, no druggable targets have been identified to potentiate active resilience mechanisms. In the chronic social defeat stress model of depression, we report that KCNQ-type K(+) channel openers, including FDA-approved drug retigabine (ezogabine), show antidepressant efficacy. We demonstrate that overexpression of KCNQ channels in the VTA dopaminergic neurons and either local infusion or systemic administration of retigabine normalized neuronal hyperactivity and depressive behaviours. These findings identify KCNQ as a target for conceptually novel antidepressants that function through the potentiation of active resilience mechanisms. PMID- 27216574 TI - Quantitation and pharmacokinetic modeling of therapeutic antibody quality attributes in human studies. AB - A thorough understanding of drug metabolism and disposition can aid in the assessment of efficacy and safety. However, analytical methods used in pharmacokinetics (PK) studies of protein therapeutics are usually based on ELISA, and therefore can provide a limited perspective on the quality of the drug in concentration measurements. Individual post-translational modifications (PTMs) of protein therapeutics are rarely considered for PK analysis, partly because it is technically difficult to recover and quantify individual protein variants from biological fluids. Meanwhile, PTMs may be directly linked to variations in drug efficacy and safety, and therefore understanding of clearance and metabolism of biopharmaceutical protein variants during clinical studies is an important consideration. To address such challenges, we developed an affinity-purification procedure followed by peptide mapping with mass spectrometric detection, which can profile multiple quality attributes of therapeutic antibodies recovered from patient sera. The obtained data enable quantitative modeling, which allows for simulation of the PK of different individual PTMs or attribute levels in vivo and thus facilitate the assessment of quality attributes impact in vivo. Such information can contribute to the product quality attribute risk assessment during manufacturing process development and inform appropriate process control strategy. PMID- 27216575 TI - Fast generation of three-qubit Greenberger-Horne-Zeilinger state based on the Lewis-Riesenfeld invariants in coupled cavities. AB - In this paper, we propose an efficient scheme to fast generate three-qubit Greenberger-Horne-Zeilinger (GHZ) state by constructing shortcuts to adiabatic passage (STAP) based on the "Lewis-Riesenfeld (LR) invariants" in spatially separated cavities connected by optical fibers. Numerical simulations illustrate that the scheme is not only fast, but robust against the decoherence caused by atomic spontaneous emission, cavity losses and the fiber photon leakages. This might be useful to realize fast and noise-resistant quantum information processing for multi-qubit systems. PMID- 27216576 TI - [Prospective study in 2 hospitals]. AB - OBJECTIVES: The purpose of this study is to know the incidence rate of medication reconciliation at admission and discharge in patients of La Rioja and to improve the patient safety on medication reconciliation. MATERIAL AND METHODS: An observational prospective study, part of the Joint Action PaSQ, Work Package 5, European Union Network for Patient Safety and Quality of Care. The study has taken into account the definitions of the Institute for Safe Medication Practices. Any unintended discrepancy in medication between chronic treatment and the treatment prescribed in the hospital was considered as a reconciliation error. RESULTS: A total of 750 patients were included, 9 (1.2%) of whom showed at least one discrepancy. The patients had a total of 3,156 mediations registered: 2,313 prescriptions (73.4%) showed no differences, while 821 prescriptions (26%) were intended discrepancies and 21 prescriptions (0.6%) unintended discrepancies were considered by the physician as reconciliation errors. A percentage of 1.2 of the patients, which represents 0.6% of the medicines (one in 166 medications registered) had reconciliation errors during their hospital stay. CONCLUSIONS: A proceeding has been implemented by means of the physician doing the medication reconciliation and reviewing it with the help of a medication reconciliation form. The medication reconciliation is a priority strategic objective to improve the safety of patients. PMID- 27216578 TI - The ICF (International Classification of Functioning, Disability and Health) developed by the WHO for measuring function in hemophilia. AB - INTRODUCTION: Assessment of the disease in people with hemophilia (PWH) must include an analysis of functioning. Researchers have done a lot of work over the last two decades in developing disease specific assessment tools in hemophilia - some of them based on the ICF (International Classification of Functioning, Disability and Health). AREAS COVERED: This article is a narrative review of the ICF developed by the World Health Organization (WHO) in the context of hemophilia. Expert commentary: The WFH has developed a website with a 'compendium of assessment tools' based on the ICF. The ICF developed by the WHO makes it possible to propose an approach that prioritizes capacities over difficulties. This article is intended to motivate physicians who treat PWH to incorporate the ICF into their assessments. A generalized use of the ICF will provide a common communication context. The ICF developed by the WHO should be used in hemophilia. PMID- 27216577 TI - The Associations between Peripheral Artery Disease and Physical Outcome Measures in Men and Women with Chronic Kidney Disease. AB - BACKGROUND: Peripheral artery disease (PAD) is highly prevalent and associated with significant morbidity and mortality, but sex-based differences are incompletely understood. We sought to define the associations between PAD and physical outcome measures and to determine if these associations differed by sex in the Chronic Renal Insufficiency Cohort. METHODS: Among 3,543 participants, we assessed the cross-sectional relationship between PAD severity defined by ankle brachial index; and (1) physical activity (metabolic equivalent [MET]-hr/wk), (2) walking pace (slow versus medium and/or fast), and (3) physical function (12-item Short Form Health Survey [SF-12]) at baseline. RESULTS: In a multivariable linear regression model, PAD severity was not associated with physical activity defined by total MET-hr per wk in men or women (P = 0.432). However, PAD severity was significantly associated with walking activity (P = 0.037), although this relationship did not differ by sex (P = 0.130). Similarly, PAD severity was significantly associated with walking pace (P < 0.001), although this relationship did not differ by sex (P = 0.086). In contrast, there was an independent association between PAD severity and SF-12 (P = 0.018), with a significant interaction by sex (P < 0.001). CONCLUSIONS: These data suggest that tools used to evaluate the functional consequences of PAD should focus on walking activity and walking pace, as well as physical function, where sex-specific associations should be accounted for. PMID- 27216579 TI - Impact of maternal education level on risk of low Apgar score. AB - OBJECTIVE: To investigate the association between 5-min Apgar score and socio economic characteristics of pregnant women, particularly education level. STUDY DESIGN: Population-based cross-sectional study. METHODS: This study used hospital records of live term singleton births in Brazil from 2004 to 2009, obtained from the Ministry of Health National Information System. Crude and adjusted odds ratios (ORs) were used to estimate the risk of a low 5-min Apgar score (<=6) associated with maternal education level, maternal age, marital status, primiparity, number of prenatal visits and mode of delivery (vaginal/caesarean section). RESULTS: Nearly 12 million records were analysed. Births from mothers with 0, 1-3, 4-7 and 8-11 years of education resulted in crude ORs for low 5-min Apgar score of 3.1, 2.2, 1.8 and 1.3, respectively (reference: >=12 years of education). The crude OR for mothers aged >=41 years (reference 21-34 years) was 1.4, but no risk was detected for those with >=12 years of education and those who gave birth by caesarean section (OR 1.0 [95% confidence interval 0.9-1.2]). Generally, the risk of a low 5-min Apgar score was found to increase as maternal age moved away from 21 to 34 years (OR 1.1-1.7), and for mothers with the same characteristics, the risk of a low 5-min Apgar score was found to decrease markedly as education level increased (adjusted OR decreased from 2.6 to 1.2). CONCLUSION: Maternal education level is clearly associated with the risk of a low 5-min Apgar score. PMID- 27216580 TI - Subjective Numeracy and the Influence of Order and Amount of Audible Information on Perceived Medication Value. AB - BACKGROUND: Order and amount of information influence patients' risk perceptions, but most studies have evaluated patients' reactions to written materials. The objective of this study was to examine the effect of 4 communication strategies, varying in their order and/or amount of information, on judgments related to an audible description of a new medication and among patients who varied in subjective numeracy. METHODS: We created 5 versions of a hypothetical scenario describing a new medication. The versions were composed to elucidate whether order and/or amount of the information describing benefits and adverse events influenced how subjects valued a new medication. After listening to a randomly assigned version, perceived medication value was measured by asking subjects to choose one of the following statements: the risks outweigh the benefits, the risks and benefits are equally balanced, or the benefits outweigh the risks. RESULTS: Of the 432 patients contacted, 389 participated in the study. Listening to a brief description of benefits followed by an extended description of adverse events resulted in a greater likelihood of perceiving that the medication's benefits outweighed the risks compared with 1) presenting the extended adverse events description before the benefits, 2) giving a greater amount of information related to benefits, and 3) sandwiching the adverse events between benefits. These associations were only observed among subjects with average or higher subjective numeracy. CONCLUSION: If confirmed in future studies, our results suggest that, for patients with average or better subjective numeracy, perceived medication value is highest when a brief presentation of benefits is followed by an extended description of adverse events. PMID- 27216581 TI - Side Effect Perceptions and Their Impact on Treatment Decisions in Women. AB - BACKGROUND: Side effects prompt some patients to forego otherwise-beneficial therapies. This study explored which characteristics make side effects particularly aversive. METHODS: We used a psychometric approach, originating from research on risk perception, to identify the factors (or components) underlying side effect perceptions. Women ( N = 149) aged 40 to 74 years were recruited from a patient registry to complete an online experiment. Participants were presented with hypothetical scenarios in which an effective and necessary medication conferred a small risk of a single side effect (e.g., nausea, dizziness). They rated a broad range of side effects on several characteristics (e.g., embarrassing, treatable). In addition, we collected 4 measures of aversiveness for each side effect: choosing to take the medication, willingness to pay to avoid the side effect (WTP), negative affective attitude associated with the side effect, and how each side effect ranks among others in terms of undesirability. A principal components analysis (PCA) was used to identify the components underlying side effect perceptions. Then, for each aversiveness measure separately, regression analyses were used to determine which components predicted differences in aversiveness among the side effects. RESULTS: The PCA revealed 4 components underlying side effect perceptions: affective challenge (e.g., frightening), social challenge (e.g., disfiguring), physical challenge (e.g., painful), and familiarity (e.g., common). Side effects perceived as affectively and physically challenging elicited the highest levels of aversiveness across all 4 measures. CONCLUSIONS: Understanding what side effect characteristics are most aversive may inform interventions to improve medical decisions and facilitate the translation of novel biomedical therapies into clinical practice. PMID- 27216582 TI - Underestimation of Variance of Predicted Health Utilities Derived from Multiattribute Utility Instruments. AB - BACKGROUND: Parameter uncertainty in value sets of multiattribute utility-based instruments (MAUIs) has received little attention previously. This false precision leads to underestimation of the uncertainty of the results of cost effectiveness analyses. The aim of this study is to examine the use of multiple imputation as a method to account for this uncertainty of MAUI scoring algorithms. METHOD: We fitted a Bayesian model with random effects for respondents and health states to the data from the original US EQ-5D-3L valuation study, thereby estimating the uncertainty in the EQ-5D-3L scoring algorithm. We applied these results to EQ-5D-3L data from the Commonwealth Fund (CWF) Survey for Sick Adults ( n = 3958), comparing the standard error of the estimated mean utility in the CWF population using the predictive distribution from the Bayesian mixed-effect model (i.e., incorporating parameter uncertainty in the value set) with the standard error of the estimated mean utilities based on multiple imputation and the standard error using the conventional approach of using MAUI (i.e., ignoring uncertainty in the value set). RESULT: The mean utility in the CWF population based on the predictive distribution of the Bayesian model was 0.827 with a standard error (SE) of 0.011. When utilities were derived using the conventional approach, the estimated mean utility was 0.827 with an SE of 0.003, which is only 25% of the SE based on the full predictive distribution of the mixed-effect model. Using multiple imputation with 20 imputed sets, the mean utility was 0.828 with an SE of 0.011, which is similar to the SE based on the full predictive distribution. CONCLUSION: Ignoring uncertainty of the predicted health utilities derived from MAUIs could lead to substantial underestimation of the variance of mean utilities. Multiple imputation corrects for this underestimation so that the results of cost-effectiveness analyses using MAUIs can report the correct degree of uncertainty. PMID- 27216583 TI - 5-year efficacy of entecavir in Indian patients with chronic hepatitis B. AB - BACKGROUND: Entecavir, a drug with high potency and genetic barrier against hepatitis B virus, was believed to become very effective in reducing the hepatitis B burden in India. Long-term studies on its treatment outcome are scarce. METHODS: One hundred and six chronic hepatitis B (CHB) patients (17 cirrhotics of Child class A/B) who received entecavir therapy (0.5/1 mg/day) in a prospective open-label study from January 2010 to September 2015 were included in the analysis. Strict drug compliance was ensured. At least 1-year follow up was mandatory. Patients were followed up for HBV DNA negativity, e antigen seroconversion and hepatic events. Subgroup analysis for HBV DNA negativity was done for age (below and above 60 years), sex, HBV DNA level, e antigen status, cirrhosis and prior other modes of therapy. RESULTS: One (0.94 %) patient had primary drug resistance. Mean follow up was 2.5 (1 to 5) years. Overall HBV DNA negativity was 89 % to 98 % at 1 to 5 years and e antigen seroconversion rate 18.2 % at 5 years. ALT normalization paralleled HBV DNA negativity. No flare, decompensation, hepatocellular cancer or adverse reaction to drug was observed. Most achieved HBV DNA negativity after 6 months of therapy with lower response in those with high HBV DNA level, cirrhosis and prior therapy at baseline but only up to 1 year. Relapse was universal after stoppage of therapy. None lost HBsAg. CONCLUSION: Entecavir will need to be continued indefinitely in Indian patients with CHB. PMID- 27216584 TI - Pre-admission interventions to improve outcome after elective surgery-protocol for a systematic review. AB - BACKGROUND: Poor physical health and fitness increases the risk of death and complications after major elective surgery. Pre-admission interventions to improve patients' health and fitness (referred to as prehabilitation) may reduce postoperative complications, decrease the length of hospital stay and facilitate the patient's recovery. We will conduct a systematic review of RCTs to examine the effectiveness of different types of prehabilitation interventions in improving the surgical outcomes of patients undergoing elective surgery. METHODS: This review will be conducted and reported according to the Cochrane and PRISMA reporting guidelines. MEDLINE, EMBASE, CENTRAL, CINAHL, PsycINFO, ISI Web of Science and clinical trial registers will be searched for any intervention administered before any elective surgery (including physical activity, nutritional, educational, psychological, clinical or multicomponent), which aims to improve postoperative outcomes. Reference lists of included studies will be searched, and grey literature including conference proceedings, theses, dissertations and preoperative assessment protocols will be examined. Study quality will be assessed using Cochrane's risk of bias tool, and meta-analyses for trials that use similar interventions and report similar outcomes will be undertaken where possible. DISCUSSION: This systematic review will determine whether different types of interventions administered before elective surgery are effective in improving postoperative outcomes. It will also determine which components or combinations of components would form the most effective prehabilitation intervention. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015019191. PMID- 27216585 TI - QSAR Accelerated Discovery of Potent Ice Recrystallization Inhibitors. AB - Ice recrystallization is the main contributor to cell damage and death during the cryopreservation of cells and tissues. Over the past five years, many small carbohydrate-based molecules were identified as ice recrystallization inhibitors and several were shown to reduce cryoinjury during the cryopreservation of red blood cells (RBCs) and hematopoietic stems cells (HSCs). Unfortunately, clear structure-activity relationships have not been identified impeding the rational design of future compounds possessing ice recrystallization inhibition (IRI) activity. A set of 124 previously synthesized compounds with known IRI activities were used to calibrate 3D-QSAR classification models using GRid INdependent Descriptors (GRIND) derived from DFT level quantum mechanical calculations. Partial least squares (PLS) model was calibrated with 70% of the data set which successfully identified 80% of the IRI active compounds with a precision of 0.8. This model exhibited good performance in screening the remaining 30% of the data set with 70% of active additives successfully recovered with a precision of ~0.7 and specificity of 0.8. The model was further applied to screen a new library of aryl-alditol molecules which were then experimentally synthesized and tested with a success rate of 82%. Presented is the first computer-aided high-throughput experimental screening for novel IRI active compounds. PMID- 27216586 TI - Association between Genetic Polymorphisms of the Beta Adrenergic Receptor and Diurnal Intraocular Pressure in Chinese Volunteers and Glaucoma Patients. AB - PURPOSE: To evaluate the relationship between genetic polymorphisms of the beta adrenergic receptor (ADR) and diurnal intraocular pressure (IOP) in Chinese healthy volunteers, normal tension glaucoma (NTG) patients, and primary open angle glaucoma (POAG) patients. METHODS: Fifty healthy volunteers (control group), 55 untreated NTG patients, and 55 untreated POAG patients were recruited. IOP of both eyes was measured at 3-hour intervals from 0600 to 2400 hours. For control group, IOP data from the eye with better mean deviation (MD) of visual field was used for statistical analysis. For glaucoma patients, IOP data from the eye with a greater visual field defect was used for statistical analysis. Genetic polymorphisms of ADR were determined by direct DNA sequencing. The relationship between IOP and genetic polymorphisms was statistically analyzed. RESULTS: R16G (A/G), L84L (G/A), and R175R (C/A) in beta2-ADR showed significantly different allele in the three groups (p = 0.005, p = 0.045, and p = 0.045, respectively). For the POAG group, C/C of R389G (C/G) in beta1-ADR had a significantly lower diurnal mean IOP (p < 0.001), peak IOP (p = 0.010), trough IOP (p < 0.001), and larger IOP range (p = 0.047) than G carriers; C/C of R389G (C/G) in beta1-ADR and G carriers had parallel diurnal IOP curves but significantly different diurnal IOP levels (p = 0.001); C/C of Q27E (C/G) in beta2-ADR had a significantly higher diurnal mean IOP (p = 0.045) than G carriers; G/G of L84L (G/A) in beta2-ADR had a significantly higher diurnal mean IOP (p = 0.044) than A carriers; C/C of R175R (C/A) in beta2-ADR had a significantly higher diurnal mean IOP (p = 0.044) than A carriers; T/T of W64R (T/C) in beta3-ADR had a significantly smaller IOP range (p = 0.001) than C carriers. CONCLUSION: Certain polymorphisms of beta2-ADR showed significantly different genotype frequencies in healthy volunteers untreated NTG patients, and POAG patients. Polymorphisms of the beta-ADR gene may alter the untreated IOP level of POAG patients. PMID- 27216587 TI - [Trauma and resilience among children 3 to 6 years old in three neighborhoods of Port-au-Prince after the 2010 earthquake in Haiti]. AB - : The paper describes an action research for indicative assessment of psychological problems of young children following the 2010 earthquake in Haiti, and the interest of using the Creole version of the questionnaire PSYCa 3-6. The survey took place in Port-au-Prince, and the evaluators were trained to a proper standardized administration of the questionnaire. BACKGROUND: The mental health needs of young children in natural disaster contexts often remain unaddressed. The lack of a rapid and simple tool for screening combined with few mental health professionals available to accurately diagnose and provide appropriate care mean that young children remain without care. Here, we present the results of psychological screening of young children aged 3 to 6 using the questionnaire PSYCa 3-6. METHODS: This study was conducted in Port-au-Prince, Haiti. The scale was translated into Haitian Creole using corroboration of independent translations and submitted twice to the parents at home, at the end of 2011 and again at the beginning of 2013. At the first stage 166 children 3 to 6 years old were included 49 of whom were included at the second stage. The results and diagnostic properties were assessed comparing the PSYCa 3-6 to the Clinical Global Impression Severity Scale as the gold standard. RESULTS: Boys were more prone to psychological disturbances than girls. The size and position among the siblings increased the score of psychological disturbance. The neighborhood and the perception of environmental violence had a significant impact on the score of psychological disturbance. The significant improvement in scores between the two examinations showed moderate resiliency whose main factors seemed to be the social support received by the family, the rapid return to school, faith and religious practice. PMID- 27216588 TI - Catatonic syndrome: From detection to therapy. AB - INTRODUCTION: Catatonia is a psychomotor syndrome which can include motor, mental, behavioral and vegetative symptoms. Exclusively associated with schizophrenia until the 1970s, catatonia still remains an under-diagnosed syndrome with significant morbidity and mortality. LITERATURE FINDINGS: As a result of its different forms and developments, catatonic syndrome can be associated with many organic and psychiatric etiologies and confused with a variety of diagnoses. In addition to its organic complications, malignant catatonia can also be extremely severe. Several diagnostic scales are described, those of Bush and Peralta being the most widely used. Despite the recent development of the DSM-5, we can regret the lack of progress in the international classifications concerning both the recognition of the etiological diversity of this syndrome and in the clinical and therapeutic approaches to it. The diagnosis is based solely on clinical data, and needs to be completed by information from paraclinical settings, particularly with respect to detecting organic etiology. The first-line treatment is still based on the use of certain benzodiazepines or benzodiazepine-like agents such as lorazepam, diazepam and zolpidem. If the first or second line fails, or in case of malignant catatonia, electroconvulsive therapy is recommended. For the periodic form, no large-sample study has been performed on long-term treatment. A few case reports suggest the use of lithium in periodic catatonia, specifically to prevent recurrent episodes or at least to extend the inter-episode intervals. Other studies are in favor of the use of benzodiazepines, with disagreement between gradual discontinuation and long-term treatment. Concerning the management of catatonia in patients with schizophrenia, for whom first-line benzodiazepines are often insufficient, certain atypical antipsychotics such as clozapine or quetiapine appear efficient. These data are also applicable to children and adolescents. CONCLUSION: Often neglected by practitioners, catatonic syndrome remains a common entity of which it is important to be aware, especially in case of rapid installation of the symptoms. Diagnostic scales should be used and a lorazepam test should be performed to avoid delaying the diagnosis. Second-line therapy requires further study. This concerns in particular diazepam, anti-NMDA (N-methyl-D-aspartate) and rTMS (repetitive transcranial magnetic stimulation). Some specificities of catatonia, such as the periodic form and cases in patients with schizophrenia, also require further evaluations. PMID- 27216589 TI - [Autobiographical memory and self-disorders in schizophrenia]. AB - OBJECTIVES: Disorders of self in schizophrenia have been considered as the core feature of the illness since its early clinical description. However, until recently, the understanding of these disorders referred mostly to philosophical considerations. The aim of this work is to examine how the various aspects of autobiographical memory deficits may be considered as possible cognitive mechanisms accounting for self-disorders in patients. METHODS: We performed a theoretical review of the literature on autobiographical memory studies in schizophrenia. Our approach of cognitive psychopathology was grounded in the model of the Self-Memory System put forward by Conway (2005), which posits reciprocal relationships between autobiographical memory and the self. This model stresses the distinction between the working-self and the autobiographical memory knowledge base. The latter contains all autobiographical information stored in our life and is organized according to the specificity of this information. The role of the working-self is to maintain the coherence of the self and to control the access to autobiographical memories and corresponding memory details. The working-self supports an experiential or phenomenological dimension of the self, especially when a highly detailed autobiographical memory is retrieved, and a past event is re-experienced by the rememberer. The working-self also entails a conceptual part, the conceptual self, which contains self-knowledge and self images. RESULTS: Our review showed that autobiographical memories of patients with schizophrenia are less specific and contain fewer phenomenological details than those of healthy participants. Patients also have difficulty assessing the subjective temporal distance of past events, and their ability to re-experience unique past personal events is affected as shown by a reduced conscious recollection and a smaller frequency of Field visual perspective during recall of autobiographical memories. This global alteration of all phenomenological characteristics of autobiographical memories strongly suggests an alteration of the phenomenological dimension of the self in schizophrenia. Since some of these alterations are also found in patients when they plan for future personal events, the ability to mentally travel in time is reduced in patients and reflects an impaired sense of self across time. The literature also shows that self-images are more passive, less coherent and less stable in time in patients compared to healthy participants. These results point to an alteration of the conceptual dimension of the self in schizophrenia. This may be partly explained by a weaker connection between the self and autobiographical memory and by other alterations of autobiographical memories closely linked to the self. In fact, the reminiscence bump is disorganized in patients and comprises poorly detailed memories. Memories grounding self-images are less organized and weakly connected to self-images. Finally, patients have an impaired ability to give a meaning to or to draw lessons from self-defining memories of their life. CONCLUSION: Based on these results, we discuss current and future therapeutic interventions including both cognitive remediation methods and cognitive psychotherapy applied to autobiographical memory. These methods appear relevant to help patients improve both the sense of self associatied with their autobiographical memory retrieval and the coherence and stability of the self. PMID- 27216590 TI - [Insight and psychiatric dangerousness: A review of the literature]. AB - INTRODUCTION: Violence committed by individuals with severe mental illness has become an increasing focus of concern among clinicians, policy makers, and the general public, often as the result of tragic events. Research has shown in the past two decades an increased risk of violence among patients with mental disorder. Nevertheless, of those suffering from mental illness, perpetrators of other directed violence form a minority subgroup. The means by which there is this association between mental illness and violence has remained controversial. Factors such as positive psychotic symptoms, medication non-adherence, alcohol or psychoactive substance abuse and antisocial personality were found to be predictive of violence. Overall, literature provides support to the assertion that violent behavior of mentally ill patients is a heterogeneous phenomenon that is driven by multiple inter-related and independent factors. Furthermore, psychiatrists are often asked to predict an individual's future dangerousness, in a medical or a legal context. In the process of risk assessment of dangerousness, more focus has been placed on dynamic risk factor. In this context, lack of insight has established itself both as a part of violence risk models and as a clinical item in structured approaches to measure dangerousness. However, few studies have tested these associations. The main purpose of this paper is to review the literature concerning the relationship between insight and dangerousness and discuss the contributions of the insight in the assessment of dangerousness in patients with mental illness. We included twenty studies that evaluated the association between insight and variable such as physical or verbal violence, aggressiveness, hostility or sexual aggression. RESULTS: According to the findings of this review, the strength and specific nature of this relationship remain unclear due to considerable methodological and conceptual shortcomings, including heterogeneity in the definition and assessment of violence, a minority of prospective studies and the lack of systematic consideration of possible confounding variables. However, the ability of the patient to perceive their illness is an important element to be considered in assessing the dangerousness both medically and legally. Higher belief flexibility and lower confidentiality of individual judgment, which reflect greater cognitive insight, may be associated with a lower incidence of violence, in particular in schizophrenia by decreasing the degree of confidence related to psychotic symptoms. CONCLUSION: In the growing efforts to reduce stigma associated with mental illness, it is important to identify a subgroup of patients at risk of violence and provide them with targeted treatment. In this sense, it seems important in the future to continue in this field of research to determine if the lack of insight is a covariate of a worsened condition or a specific violence risk factor per se. PMID- 27216591 TI - [Restorative Justice: Neither care nor repression? The case study of Louis, a multi-recidivist, neither "dangerous" nor "sick"]. AB - OBJECTIVES: The proposed criminological hypothesis is that the restorative justice approach would allow offenders to recognize the victims with more empathic feelings, assuming a decreasing effect on the needs and risks of recidivism (Griffiths and Murdoch, 2007). Authors of aggravated robbery raise several psychological issues (i.e. incomprehension of the causes of their act, euphemistic labelling and moral disengagement, lack of empathy) that the restorative program proposes to work through scriptwriting of personal histories, better comprehension of the conflict in the past and exchanges focused on the personal and social consequences of the acts (emotional chain). The aim of the process is to encourage persons weakened by their social and delinquent situations to elaborate, plan and realize new personal goals. METHODOLOGY: With the collaboration of the service de l'application des peines de Tours (service for the execution of sentences), the service penitentiaire d'insertion et de probation 37 (probation and social reintegration service) and the service d'aide aux victimes d'infractions penales (association for victims of crime) of the French department 37, centre, the program PARIS attempted an implementation and evaluation of the relational or restorative justice process in the context of non custodial sentences and in particular in the cases of aggravated theft (art. 311 1 to 311-16 of the French penal code). Its particularity was to touch the three spheres of victimization: (1) financial, (2) physical and (3) psychological prejudices. After the admission of the participants, a preliminary (psycho)criminological diagnosis served to evaluate the suitability for the perpetrator and the victim to be confronted in following settings. In this context we met Louis, a recidivist of aggravated thefts but causing minimal harm and punished with minimal sentences. He presented no mental illness but showed severe existential problems involved in his delinquent behaviour. His delinquent acts presented similarities marked by auto-punitive tendencies. For example, he remained on site until being arrested and joked with the police. RESULTS: The case Louis revealed what neither the care nor repression succeeded to reach, namely the quality of the relationship which can in itself confine or on the contrary repair. Relational Justice, by seeking neither to "suppress" nor to "care", allows the participants to reconstruct and understand the other with empathy, and strengthened the protective factors. Mediation as a method or purpose held a prominent place in the reconstruction process of the participants as it allowed us to act on both the "frame" (scenario of the problem-situation) and the "drama" ((non)-effectiveness of cognitive strategies and experienced emotions) of the original problem-situation. So the restorative program was an alternative to the socio-judicial measures inducing potential therapeutic effects on the future path of the participant. CONCLUSION: If the question of the relevance of direct, or perhaps better indirect, confrontations between the author and the victim still remains the (psycho-)criminological diagnosis of the penal couple's - author and victim - relationship investigates the psychosocial and delinquent process in terms of motivation. A satisfaction survey at the end of the program helps to analyse the future prospects of the participants. Based on dynamic and structured methods, the PARIS relational Justice program offers a Third Way between care and punishment: restoration of existential and relational links. PMID- 27216592 TI - Lithium and suicide prevention. PMID- 27216593 TI - [Ethical principles in electronvulsivotherapy]. AB - ECT or electroconvulsive therapy (ECT) is a therapeutic technique invented in 1935 but which was really developed after World War II and then spreading widely until the mid 1960s. The source of this technique, and some forms of stigma including films, have participated widely to make it suspect from a moral point of view. The ethical principles that support the establishment of a treatment by ECT are those relating to any action in psychiatry and are based on the one hand on the founding principles of bioethics: autonomy, beneficence, non-malfeasance, and justice, and on the other hand on the information on the technical and consent to this type of care. PMID- 27216594 TI - [Infants' attachment security in a vulnerable French sample]. AB - INTRODUCTION: Attachment is a long lasting emotional link established between infants and their caregivers. The quality of early relationships allows infants to safely explore their environment and contribute to the establishment of a broad range of social skills. Several intervention programs targeting infant attachment have been implemented in different contexts, showing diverse degrees of efficacy. OBJECTIVE: The present paper describes, for the first time, children's attachment quality distributions in a French multi-risk population, with a preventive intervention, usual or reinforced. METHOD: In the CAPEDP study (Parenting and Attachment in Early Childhood: reducing mental health disorder risks and promoting resilience), a sub-sample of 117 women was recruited to assess the effects of this home-visiting program on children's attachment security. With that intent, the Strange Situation Paradigm was used when infants were between 12 and 16 months of age. RESULTS: In the intervention group, 63% (n=41) of the infants were coded as secure, while 15% (n=10) of them were coded as insecure-avoidant and 22% (n=14) as insecure-ambivalent/resistant. 56% (n=29) of control group infants (usual care) were coded as secure, while 27% (n=14) were coded as insecure-avoidant and 17% (n=9) as insecure-ambivalent/resistant. Even if the percentage of children with a secure attachment in the reinforced intervention group was higher than that of the control group, this difference did not reach the threshold of significance [Chi2 (2)=2.40, P=0.30]. DISCUSSION: Intervention group distributions were closer to normative samples, and these distributions show the clinical impact of our program. In general, preventive interventions focused on attachment quality have moderate effects but, in our case, several factors might have contributed to lower the statistical impact of the program. Firstly, the control group cannot be considered has having received zero intervention for two reasons: (a) the French usual perinatal health system (Maternal and Infant Protection System) is particularly generous and (b) the effect of this usual system might have been increased by the project intensive assessment protocol (6 visits during 28 months). Secondly, it is possible that the full effect of the intervention had not yet been detected because, when a child's attachment was assessed, only two thirds of the intervention visits had been performed (29 of 44 visits). A "sleeper effect" is still possible: we hope that a more clear result will be seen when children are assessed again, at 48 months, in our follow-up study (CAPEDP-A II). By clarifying the mechanisms involved in the development of a secure attachment, our study aims to contribute and refine the development of early preventive intervention strategies in high perinatal and psychosocial vulnerability contexts. PMID- 27216595 TI - Does baclofen have antidepressant qualities? PMID- 27216596 TI - [Adjustment disorder and DSM-5: A review]. AB - INTRODUCTION: This paper exposes the complexity and discrete characteristic of the adjustment disorder with reference to its clinical and scientific diagnosis. Even though the disorder occurs in frequent clinical circumstances after important life events, such as mobbing, burn-out, unemployment, divorce or separation, pregnancy denial, surgical operation or cancer, the adjustment disorder is often not considered in the diagnosis since better known disorders with similar symptoms prevail, such as major depression and anxiety disorder. Ten years ago, Bottero had already noticed that the adjustment disorder diagnosis remained rather uncommon with reference to patients he was working with while Langlois assimilated this disorder with an invisible diagnosis. METHODOLOGY: In order to maximize the data collection, we used the article review below and challenged their surveys and results: National Center for Biotechnology Information (NBCI - Pubmed) for international articles and Cairn.info for French literature. Moreover, we targeted the following keywords on the search engine and used articles, which had been published from 1 February 1975 to 31 January 2015: "adjustment", "adjustment disorder" and the French translation "trouble de l'adaptation". RESULTS: One hundred and ninety-one articles matched our search criteria. However, after a closer analysis, solely 105 articles were selected as being of interest. Many articles were excluded since they were related to non psychiatric fields induced by the term "adaptation". Indeed, the number of corresponding articles found for the adjustment disorder literally pointed-out the lack of existing literature on that topic in comparison to more known disorders such as anxiety disorder (2661 articles) or major depression (5481 articles). This represents up to 50 times more articles in comparison to the number of articles we found on adjustment disorder and up to 20 times more articles for the eating disorder (1994), although the prevalence is not significantly higher than for the adjustment disorder. According to their relevance and their content, we have split the articles into seven subcategories: 1. General description: most scientific articles generally describe the adjustment disorder as being a transition diagnosis, which is ambiguous, marginal and difficult to detect. The findings claim that only a few studies have been conducted on the adjustment disorder despite a high prevalence in the general population and in the clinical field. 2. CLASSIFICATION: the DSM-5 defined the adjustment disorder as a set of different outcomes and syndromes induced by stress after a difficult life event. While the link to other disorders has not been mentioned, the diagnosis of this disorder is no longer excluded or perceived as a secondary diagnosis. The DSM-5 faced criticism from three points of view: the operationalization of the concept of stress, the differential diagnosis and the description. 3. Prevalence: different samples have shown a significantly high prevalence of the adjustment disorder within the population. In addition to the psychiatric pain induced by difficult life events we need to emphasize the fact that 12.5 to 19.4 percent of the patients faced heavy and severe pathologies and depended on clinical care and treatment. 4. Etiology, comorbidity or associated symptomatology: the literature identified the tendency to commit suicide and stressful life events as being two fundamental characteristics of adjustment disorder. The third one is the personality profile. 5. DIFFERENTIAL DIAGNOSIS: that motivates researchers to focus on the adjustment disorder: the differentiation approach as to the major depression. Indeed, the aetiology, the symptomatology and the treatment differ from the adjustment disorder. 6. ASSESSMENT: very recently, Dutch researchers have developed and validated the Diagnostic Interview Adjustment Disorder (DIAD). 7. TREATMENT: in 2014, no data or meta-analysis recommended drug treatment in addition to therapy. In fact, several authors have demonstrated the ineffectiveness of drug therapy. The literature suggests a psychotherapeutic approach to treat adjustment disorder. CONCLUSION: Emotional reactions triggered by life events are responsible for full therapy agendas and for the rush in emergency rooms and hospitals. The reflex when faced with crying, insomnia or suicidal thoughts to give a diagnostic of major depressive disorder s is generally accepted by everyone. The elevated risk to commit suicide and the approved success of remission or healing through treatment (psychotherapy) are two major reasons why several studies promote the importance and the need to identify the adjustment disorder of our patients. PMID- 27216597 TI - Original Research: Potential of urinary nephrin as a biomarker reflecting podocyte dysfunction in various kidney disease models. AB - Urinary nephrin is a potential non-invasive biomarker of disease. To date, however, most studies of urinary nephrin have been conducted in animal models of diabetic nephropathy, and correlations between urinary nephrin-to-creatinine ratio and other parameters have yet to be evaluated in animal models or patients of kidney disease with podocyte dysfunction. We hypothesized that urinary nephrin to-creatinine ratio can be up-regulated and is negatively correlated with renal nephrin mRNA levels in animal models of kidney disease, and that increased urinary nephrin-to-creatinine ratio levels are attenuated following administration of glucocorticoids. In the present study, renal nephrin mRNA, urinary nephrin-to-creatinine ratio, urinary protein-to-creatinine ratio, and creatinine clearance ratio were measured in animal models of adriamycin nephropathy, puromycin aminonucleoside nephropathy, anti-glomerular basement membrane glomerulonephritis, and 5/6 nephrectomy. The effects of prednisolone on urinary nephrin-to-creatinine ratio and other parameters in puromycin aminonucleoside (single injection) nephropathy rats were also investigated. In all models tested, urinary nephrin-to-creatinine ratio and urinary protein-to creatinine ratio increased, while renal nephrin mRNA and creatinine clearance ratio decreased. Urinary nephrin-to-creatinine ratio exhibited a significant negative correlation with renal nephrin mRNA in almost all models, as well as a significant positive correlation with urinary protein-to-creatinine ratio and a significant negative correlation with creatinine clearance ratio. Urinary protein to-creatinine ratio exhibited a significant negative correlation with renal nephrin mRNA. Following the administration of prednisolone to puromycin aminonucleoside (single injection) nephropathy rats, urinary nephrin-to creatinine ratio was significantly suppressed and exhibited a significant positive correlation with urinary protein-to-creatinine ratio. In addition, the decrease in number of glomerular Wilms tumor antigen-1-positive cells was attenuated, and urinary nephrin-to-creatinine ratio exhibited a significant negative correlation in these cells. In conclusion, these results suggest that urinary nephrin-to-creatinine ratio level is a useful and reliable biomarker for predicting the amelioration of podocyte dysfunction by candidate drugs in various kidney disease models with podocyte dysfunction. This suggestion will also be validated in a clinical setting in future studies. PMID- 27216599 TI - Original Research: Porcine model for observing changes due to ischemia/reperfusion injury secondary to intra-abdominal endovascular balloon occlusion. AB - Compared with conventional aortic cross-clamping, endovascular balloon occlusion (EBO) is a valuable strategy in unstable ruptured abdominal aorta aneurysm patients; however, it is unclear how long the balloon may remain safely inflated. Using a porcine model, we evaluated the influence of different EBO time periods on intra-abdominal pressure (IAP) and the association between various pathophysiologic indicators and reperfusion time. Twelve healthy three-month-old domestic piglets were subjected to ischemia/reperfusion injury using EBO within the abdominal aorta. Animals were grouped as A, B, and C based on 30, 60, or 120 min of ischemic time, respectively. Changes in IAP, hemodynamic data, respiratory and renal function, and histology after reperfusion were compared with baseline measurements. All pigs gradually developed intra-abdominal hypertension after ischemia/reperfusion injury. IAP increased significantly after 4 h of reperfusion in all three groups (all P < 0.001) with maximal IAP reaching > 22 mmHg in 10 pigs. However, no significant intergroup differences were found. Cardiac output remained stable, but mixed venous oxygen saturation decreased significantly at 4 h after reperfusion (P < 0.05). The pH decreased significantly at 10 min in all three groups (all P < 0.001). Histological changes in the small intestine, lung, and kidney occurred secondary to aortic ischemia; however, no significant differences were noted between groups (P > 0.05). EBO within the abdominal aorta induced ischemia/reperfusion injury which led to intra-abdominal hypertension, pathological changes within multiple organs, and decreased mixed venous oxygen saturation after only 30 min of abdominal aortic ischemia. PMID- 27216600 TI - The combination of Artemisia princeps Pamp, Leonurus japonicas Houtt, and Gardenia jasminoides Ellis fruit attenuates the exacerbation of energy, lipid, and glucose by increasing hepatic PGC-1alpha expression in estrogen-deficient rats. AB - BACKGROUND: Artemisia princeps Pamp (APP), Leonurus japonicas Houtt (LJH), and Gardenia jasminoides Ellis fruit (GJE) have been traditionally used in East Asia to treat women's diseases related to reproductive system. They may attenuate the deterioration of energy, lipid, glucose and bone metabolism by estrogen deficiency. The present study explored the combination of APP, LJH, and GJE to overcome the symptoms of estrogen deficiency and the mechanism was explored. METHODS: Ovariectomized (OVX) rats were divided into five groups and fed high-fat diets supplemented with 2 % dextrin (control), 2 % APP, 2 % APP + LJH (15:5), APP + LJH + GJE (10:5:5) or 17beta-estradiol (30 MUg/kg bw/day) for 8 weeks. After 8 weeks of their consumption, energy, lipid, glucose and bone metabolisms were investigated and hepatic insulin signaling and fatty acid metabolism were determined. RESULTS: APP + LJH + GJE, but not APP itself, improved energy metabolism and attenuated a decrease in energy expenditure by the same amount as estrogen. Moreover, APP + LJH + GJE reduced visceral fat and intramuscular fat and increased lean body mass measured by DEXA by as much as the positive-control. APP itself suppressed increased LDL cholesterol and triglyceride levels in OVX rats and APP + LJH + GJE alleviated dyslipidemia in OVX rats. Overnight-fasted serum insulin levels and HOMA-IR were reduced in the descending order of APP, APP + LJH, APP + LJH + GJE, positive-control in OVX rats. APP and APP + LJH elevated insulin secretion in the 1st part of OGTT to decrease serum glucose levels while APP + LJH + GJE reduced serum glucose levels without increasing serum insulin levels during OGTT. APP + LJH + GJE decreased insulin resistance during ITT in OVX rats more than the positive-control. The APP + LJH + GJE group exhibited increased hepatic peroxisomal proliferator-activated receptor-gamma coactivator 1alpha expression, which increased the number of genes involved in fatty acid oxidation and decreased fatty acid synthesis. Hepatic insulin signaling (pAkt and pGSK-1beta) was also potentiated to reduce phosphoenolpyruvate carboxykinase proteins. CONCLUSION: The combination of APP + LJH + GJE attenuated various menopausal symptoms in OVX rats. Thus, it may have potential as a therapeutic agent for the treatment of postmenopausal symptoms. PMID- 27216598 TI - Wake me when it's over - Bacterial toxin-antitoxin proteins and induced dormancy. AB - Toxin-antitoxin systems are encoded by bacteria and archaea to enable an immediate response to environmental stresses, including antibiotics and the host immune response. During normal conditions, the antitoxin components prevent toxins from interfering with metabolism and arresting growth; however, toxin activation enables microbes to remain dormant through unfavorable conditions that might continue over millions of years. Intense investigations have revealed a multitude of mechanisms for both regulation and activation of toxin-antitoxin systems, which are abundant in pathogenic microorganisms. This minireview provides an overview of the current knowledge regarding type II toxin-antitoxin systems along with their clinical and environmental implications. PMID- 27216601 TI - Self-Assembled Superparamagnetic Iron Oxide Nanoclusters for Universal Cell Labeling and MRI. AB - Superparamagnetic iron oxide (SPIO) nanoparticles have been widely used in a variety of biomedical applications, especially as contrast agents for magnetic resonance imaging (MRI) and cell labeling. In this study, SPIO nanoparticles were stabilized with amphiphilic low molecular weight polyethylenimine (PEI) in an aqueous phase to form monodispersed nanocomposites with a controlled clustering structure. The iron-based nanoclusters with a size of 115.3 +/- 40.23 nm showed excellent performance on cellular uptake and cell labeling in different types of cells, moreover, which could be tracked by MRI with high sensitivity. The SPIO nanoclusters presented negligible cytotoxicity in various types of cells as detected using MTS, LDH, and flow cytometry assays. Significantly, we found that ferritin protein played an essential role in protecting stress from SPIO nanoclusters. Taken together, the self-assembly of SPIO nanoclusters with good magnetic properties provides a safe and efficient method for universal cell labeling with noninvasive MRI monitoring capability. PMID- 27216602 TI - Growth of Hydrothermally Derived CdS-Based Nanostructures with Various Crystal Features and Photoactivated Properties. AB - CdS crystallites with rod- and flower-like architectures were synthesized using a facile hydrothermal growth method. The hexagonal crystal structure of CdS dominated the growth mechanisms of the rod- and flower-like crystallites under specific growth conditions, as indicated by structural analyses. The flower-like CdS crystallites had a higher crystal defect density and lower optical band gap value compared with the rod-like CdS crystallites. The substantial differences in microstructures and optical properties between the rod- and flower-like CdS crystallites revealed that the flower-like CdS crystallites exhibited superior photoactivity, and this performance could be further enhanced through appropriate thermal annealing in ambient air. A postannealing procedure conducted in ambient air oxidized the surfaces of the flower-like CdS crystallites and formed a CdO phase. The formation of heterointerfaces between the CdS and CdO phases mainly contributed to the improved photoactivity of the synthesized flower-like CdS crystallites. PMID- 27216603 TI - Hybrid solar cell on a carbon fiber. AB - In this work, a method to assemble nanoscale hybrid solar cells in the form of a brush of radially oriented CdS nanowire crystals around a single carbon fiber is demonstrated for the first time. A solar cell was assembled on a carbon fiber with a diameter of ~5-10 MUm which served as a core electrode; inorganic CdS nanowire crystals and organic dye or polymer layers were successively deposited on the carbon fiber as active components resulting in a core-shell photovoltaic structure. Polymer, dye-sensitized, and inverted solar cells have been prepared and compared with their analogues made on the flat indium-tin oxide electrode. PMID- 27216604 TI - Recent Progress Towards Quantum Dot Solar Cells with Enhanced Optical Absorption. AB - Quantum dot solar cells, as a promising candidate for the next generation solar cell technology, have received tremendous attention in the last 10 years. Some recent developments in epitaxy growth and device structures have opened up new avenues for practical quantum dot solar cells. Unfortunately, the performance of quantum dot solar cells is often plagued by marginal photon absorption. In this review, we focus on the recent progress made in enhancing optical absorption in quantum dot solar cells, including optimization of quantum dot growth, improving the solar cells structure, and engineering light trapping techniques. PMID- 27216605 TI - Knowledge and awareness of malaria and mosquito biting behaviour in selected sites within Morogoro and Dodoma regions Tanzania. AB - BACKGROUND: In Tanzania there has been a downward trend in malaria prevalence partly due to use of insecticide-treated bed nets for protection against Anopheles mosquitoes. However, residual malaria transmission attributed to early biting behaviour of malaria vectors is being reported. Knowledge of mosquito feeding behaviour is key to improvements in control approaches. The present study aimed to assess knowledge and awareness on malaria and malaria vectors in Morogoro and Dodoma regions of Tanzania. METHODS: A cross sectional study was undertaken in selected sites in Morogoro and Dodoma Tanzania. A structured questionnaire was administered to 218 randomly selected households from each of which the head or second in/charge and the most senior primary school child were interviewed. RESULTS: A total of 400 participants of whom 56 % were females, were recruited into the study. Their ages ranged between nine and 58 years. Among the participants, 70.7 % had primary school education and the rest attained secondary school (16.8 %), university/college (4.0 %) and not attended school at all (8.5 %). Fifteen per cent of the participants were employed, while 45.5 % were self employed and 39.5 % were studying. Overall, 58.5 % of respondents were knowledgeable of malaria and its vector. However, 78.8 % were not aware that early mosquito bites can transmit malaria and 86.5 % said that only midnight biting mosquito bite was responsible for malaria transmission. The majority (66 %) of respondents visited a health facility on observing malaria symptoms while 15.8 % took anti-malaria drugs without medical consultation. CONCLUSION: This study has shown that Anopheles is well known as the night-biting vector of malaria. The majority of participants were not aware of changed biting behaviour of malaria-transmitting mosquitoes and that early outdoor mosquito bite is a risk of malaria transmission. School children have shown a better understanding of malaria and its vector. Therefore, more awareness of Anopheles feeding behaviour is needed. PMID- 27216606 TI - Food Web Structure Shapes the Morphology of Teleost Fish Brains. AB - Previous work showed that teleost fish brain size correlates with the flexible exploitation of habitats and predation abilities in an aquatic food web. Since it is unclear how regional brain changes contribute to these relationships, we quantitatively examined the effects of common food web attributes on the size of five brain regions in teleost fish at both within-species (plasticity or natural variation) and between-species (evolution) scales. Our results indicate that brain morphology is influenced by habitat use and trophic position, but not by the degree of littoral-pelagic habitat coupling, despite the fact that the total brain size was previously shown to increase with habitat coupling in Lake Huron. Intriguingly, the results revealed two potential evolutionary trade-offs: (i) relative olfactory bulb size increased, while relative optic tectum size decreased, across a trophic position gradient, and (ii) the telencephalon was relatively larger in fish using more littoral-based carbon, while the cerebellum was relatively larger in fish using more pelagic-based carbon. Additionally, evidence for a within-species effect on the telencephalon was found, where it increased in size with trophic position. Collectively, these results suggest that food web structure has fundamentally contributed to the shaping of teleost brain morphology. PMID- 27216607 TI - Cohort studies and the development of psychopathology: commentary on the Great Smoky Mountain Study. PMID- 27216608 TI - 3D Human Adipose-Derived Stem Cell Clusters as a Model for In Vitro Fibrosis. AB - Excessive extracellular matrix (ECM) deposition is a cause of progressive fibrosis, which ultimately leads to progressive organ dysfunction. The lack of an in vitro fibrosis model and in vitro drug screening tools limits the development of effective antifibrotic drugs. The profibrotic cytokine transforming growth factor-beta1 (TGF-beta1), which is secreted by a variety of cells under continuous hypoxic condition, correlates strongly with tissue fibrosis and is largely responsible for the observed increases in ECM deposition in fibrotic diseases. In this study, we established an in vitro fibrosis model in which human adipose-derived stem cells (hASCs) secrete TGF-beta1 by engineering three dimensional cell masses (3DCMs) of hASCs on a maltose-binding protein-basic fibroblast growth factor (MBP-FGF2)-immobilized substrate. We found that the hypoxic microenvironment created in the interior of 3DCMs during the early stages of culture leads to activation and synthesis of TGF-beta1. The gene expression of fibrosis-related molecules such as TGF-beta1, alpha-smooth muscle actin (alphaSMA), and collagen type I was upregulated in 3DCMs. As culture time increased, overexpression of TGF-beta1 led to differentiation of hASCs into activated myofibroblasts, which accumulate excessive collagen type I and are characterized by alphaSMA expression. Furthermore, immunofluorescence data verified the increase in collagen type I synthesis in alphaSMA-positive cells. Scanning electron microscopy revealed rigid and compact 3DCMs, probably due to accumulation of ECM components and cross-linking of these components. The advantage of this TGF-beta1-mediated 3D in vitro fibrosis model is that it opens up new avenues to understand the common mechanism of fibrosis, which will then facilitate the development of broadly effective antifibrotic compounds and the screening of existing antifibrotic agents. To the best of our knowledge, this is the first proper biomimetic 3D in vitro fibrosis model to be developed. PMID- 27216609 TI - Role of C-Reactive Protein Assessment as Early Predictor of Surgical Site Infections Development after Pancreaticoduodenectomy. AB - BACKGROUND: Surgical site infections (SSIs) are extremely common in pancreatic surgery and explain its considerable morbidity and mortality, even in tertiary centers. Early detection of these complications, with the help of laboratory assays, improve clinical outcome. The aim of the present study is to evaluate C reactive protein (CRP) diagnostic accuracy as early predictor of SSIs after pancreaticoduodenectomy (PD). METHODOLOGY: We considered 251 consecutive PD. We prospectively recorded preoperative clinical and anthropometric data, intraoperative details and the postoperative outcome. In the first pool of consecutive patients (n = 150), we analyzed CRP levels from postoperative day 1 to 7 and investigated the prediction of SSIs. We then validated the diagnostic accuracy on the following 101 consecutive cases. RESULTS: At multivariate analysis, high BMI and preoperative biliary stenting appeared to be independently associated with SSIs and organ-space SSI development. The CRP cutoff of 17.27 mg/dl on postoperative day 3 (78% sensitivity, 79% specificity) and of 14.72 mg/dl on postoperative day 4 (87% sensitivity, 82% specificity) was in a position to predict the course of 78.2 and 80.2% of patients, respectively. CONCLUSIONS: CRP on postoperative days 3 and 4 seems able to predict postoperative course, selecting patients deserving intensification of diagnostic assessment; patients not satisfying these conditions could be reasonably directed toward early discharge. PMID- 27216610 TI - Bronchodilator response not a significant marker of poor asthma control. PMID- 27216611 TI - Sustaining critical care: using evidence-based simulation to evaluate ICU management policies. AB - Intensive Care Units (ICU) are costly yet critical hospital departments that should be available to care for patients needing highly specialized critical care. Shortage of ICU beds in many regions of the world and the constant fire fighting to make these beds available through various ICU management policies motivated this study. The paper discusses the application of a generic system dynamics model of emergency patient flow in a typical hospital, populated with empirical evidence found in the medical and hospital administration literature, to explore the dynamics of intended and unintended consequences of such ICU management policies under a natural disaster crisis scenario. ICU management policies that can be implemented by a single hospital on short notice, namely premature transfer from ICU, boarding in ward, and general ward admission control, along with their possible combinations, are modeled and their impact on managerial and health outcome measures are investigated. The main insight out of the study is that the general ward admission control policy outperforms the rest of ICU management policies under such crisis scenarios with regards to reducing total mortality, which is counter intuitive for hospital administrators as this policy is not very effective at alleviating the symptoms of the problem, namely high ED and ICU occupancy rates that are closely monitored by hospital management particularly in times of crisis. A multivariate sensitivity analysis on parameters with diverse range of values in the literature found the superiority of the general ward admission control to hold true in every scenario. PMID- 27216612 TI - Everolimus improves neuropsychiatric symptoms in a patient with tuberous sclerosis carrying a novel TSC2 mutation. AB - Tuberous sclerosis complex (TSC) is a neurocutaneous disorder characterized by multiple symptoms including neuropsychological deficits such as seizures, intellectual disability, and autism. TSC is inherited in an autosomal dominant pattern and is caused by mutations in either the TSC1 or TSC2 genes, which enhance activation of the mammalian target of rapamycin (mTOR) signaling pathway. Recent studies have suggested that mTOR inhibitors such as rapamycin can reverse TSC-associated deficits in rodent models of TSC. In addition, clinical trials are ongoing to test the efficacy of mTOR inhibitors toward the psychiatric symptoms associated with TSC. Here, we report a case study of a Korean patient with TSC, who exhibited multiple symptoms including frequent seizures, intellectual disability, language delays, and social problems. We performed whole exome sequencing and identified a novel small deletion mutation in TSC2. Expressing the novel deletion mutant in HEK293T cells significantly increased mTOR pathway activation. Furthermore, everolimus treatment showed not only reduction in SEGA size, but dramatically improved behavioral deficits including autism related behaviors in the patient. In summary, we identified a novel small deletion mutation in TSC2 associated with severe TSC in a Korean family that enhances the activation of mTOR signaling in vitro. Everolimus treatment improved behavioral deficits in the patient. PMID- 27216614 TI - Evaluation of technological properties of Enterococcus faecium CECT 8849, a strain isolated from human milk, for the dairy industry. AB - In this work, a variety of biochemical properties of Enterococcus faecium CECT 8849, which had been isolated from breast milk, were analyzed. Its acidifying capacity and proteolytic activity were low but, in contrast, remarkable peptidase and esterase activities were observed. Ethanol and 3-hydroxy-2-butanone were the most abundant volatile compounds found in experimental model cheese manufactured with E. faecium CECT 8849. This strain inhibited the growth of several Listeria monocytogenes and Listeria innocua strains in vitro. Enterocin A and B structural genes were detected in E. faecium CECT 8849. Model fermented milk and cheeses were manufactured from milk inoculated or not with L. innocua CECT 8848 (2.5-3 log10 colony forming units mL(-1)) using E. faecium CECT 8849 or Lactococcus lactis ESI 153 as starter cultures. Although E. faecium CECT 8849 controlled Listeria growth in both dairy models, it led to lower reduction in Listeria counts when compared with L. lactis ESI 153. PMID- 27216613 TI - Optimising Inhaled Pharmacotherapy for Elderly Patients with Chronic Obstructive Pulmonary Disease: The Importance of Delivery Devices. AB - Chronic obstructive pulmonary disease (COPD) is common in older people. Inhaled medications are the mainstay of pharmacological treatment of COPD, and are typically administered by handheld inhalers, such as pressurised metered-dose inhalers and dry powder inhalers, or by nebulisers. For each of the three major categories of aerosol delivery devices, several new inhalers have recently been launched, each with their own particularities, advantages and disadvantages. Consequently, broader availability of new drug-device combinations will increase prescription opportunities. Despite this, however, there is limited guidance available in published guidelines on the choice of inhalers, and still less consideration is given to elderly patients with COPD. The aim of this article is to provide a guide for healthcare professionals on device selection and factors to be considered for effective inhaled drug delivery in elderly COPD patients, including device factors (device type and complexity of use), patient factors (inspiratory capabilities, manual dexterity and hand strength, cognitive ability, co-morbidities) and considerations for healthcare professionals (proper education of patients in device use). PMID- 27216615 TI - A Novel Association of the Suppressor of Cytokine Signaling 1 (SOCS1) Gene Polymorphisms in Ischemic Stroke Patients. AB - Ischemic stroke is a common neurological disease and a leading cause of permanent disability in many countries. Recent studies provide evidence on the role of the suppressor of the cytokine signaling 1 (SOCS1) gene in the development and progression of atherosclerotic lesions. However, few studies have assessed the association between single nucleotide polymorphisms (SNPs) on SOCS1 gene and ischemic stroke. Therefore, the present study aimed to investigate the role of SOCS1 polymorphism in ischemic stroke risk in a northern Chinese Han population. We examined 475 patients with ischemic stroke and 486 normal controls. Three SNPs (rs243327, rs243330, and rs33932899) of SOCS1 gene were determined for TaqMan genotyping assays. We also classified these case samples in depth by complications with hypertension or diabetes and by ischemic stroke subtypes. When adjusting models by multiple factor analysis by logistic regression, then calculated 10,000 permutations were performed for each model to correct the multiple test. Under additive model, the rs243327 was associated with ischemic stroke with hypertension (p = 0.047). Under heterozygous model, the rs33932899 and rs243330 were significantly associated with ischemic stroke subtypes by atherosclerosis (p = 0.038, p = 0.048, respectively). In summary, our data demonstrated for the first time that the polymorphisms of the SOCS1 gene are associated with the risk of ischemic stroke in a northern Chinese Han population, suggesting that SOCS1 gene polymorphisms may play an important role in the pathogenesis of ischemic stroke. PMID- 27216616 TI - Cochrane plain language summaries are highly heterogeneous with low adherence to the standards. AB - BACKGROUND: The aim of this study was to analyze whether Cochrane plain language summaries (PLSs) adhere to the Standards for the reporting of Plain Language Summaries in new Cochrane Intervention Reviews (PLEACS). METHODS: A systematic analysis of adherence to the measurable PLEACS items was performed for Cochrane PLSs published from March 2013 to the end of January 2015. Duplicate independent data extraction was performed. An adherence score was calculated for each PLS and for the Cochrane Review Groups (CRGs) that published them. RESULTS: Of the 1738 analyzed PLSs, not a single one adhered fully to the measured PLEACS items. The highest adherence was found for absence of details of the search strategy (99 % adherence), and the lowest adherence for an item mandating to address quality according to the GRADE system (0.7 % adherence). Overall adherence percentage of PLSs reporting reviews with included studies was 57 %. Different CRGs had a wide range of adherence scores. CONCLUSIONS: Cochrane plain language summaries are highly heterogeneous with a low adherence to the PLEACS standards. Therefore, there is much room for improving the content and consistency of the PLS. A standardization of PLSs is necessary to ensure delivery of proper and consistent information for consumers. PMID- 27216617 TI - Seasonal profile of metal accumulation in the acanthocephalan Pomphorhynchus laevis: a valuable tool to study infection dynamics and implications for metal monitoring. AB - BACKGROUND: A large number of studies demonstrated that acanthocephalans exhibit a high metal accumulation potential and thus can be used as sensitive accumulation indicators. However, similar to free-living bioindicators, a seasonal variation in metal concentrations in parasites might occur. Accordingly, the influence of seasonality has to be elucidated if parasites should be applied as sentinels. METHODS: In order to assess a possible seasonal profile of element concentrations, the concentrations of As, Cd, Co, Cu, Fe, Mn, Mo, Ni, Pb, V and Zn in the acanthocephalan Pomphorhynchus laevis and in its host barbel (Barbus barbus) were analysed in a seasonal manner (spring, summer and autumn) using inductively coupled plasma mass spectrometry (ICP-MS). RESULTS: Five elements (As, Cd, Cu, Pb and Zn) were detected in significantly higher concentrations in the parasites compared to host muscle, intestine and liver. Their levels in P. laevis showed a clear seasonal pattern, while the concentrations in the fish tissues remained similar during the year. The highest concentrations in the parasites were found in autumn, followed by spring and summer. Evidence from the literature suggests that this profile coincides with the seasonality of acanthocephalan transmission, as their annual concentration profile reflected the mean individual weight pattern during the year. Parasite infrapopulations in autumn consisted mainly of young worms which are characterised by an accelerated metabolism and a higher surface to volume ratio resulting in higher element concentrations when compared to older worms which are assumed to slow down their metabolism and additionally excrete metals with their eggs. CONCLUSIONS: Based on the available data from the present study and literature, a model is suggested, which visualises the accumulation kinetic of several elements under natural conditions. According to the element accumulation data the lifespan of P. laevis in barbel was roughly estimated to range between six and eight months. PMID- 27216618 TI - Simvastatin Attenuates Neuropathic Pain by Inhibiting the RhoA/LIMK/Cofilin Pathway. AB - Neuropathic pain occurs due to deleterious changes in the nervous system caused by a lesion or dysfunction. Currently, neuropathic pain management is unsatisfactory and remains a challenge in clinical practice. Studies have suggested that actin cytoskeleton remodeling may be associated with neural plasticity and may involve a nociceptive mechanism. Here, we found that the RhoA/LIM kinase (LIMK)/cofilin pathway, which regulates actin dynamics, was activated after chronic constriction injury (CCI) of the sciatic nerve. Treatments that reduced RhoA/LIMK/cofilin pathway activity, including simvastatin, the Rho kinase inhibitor Y-27632, and the synthetic peptide Tat-S3, attenuated actin filament disruption in the dorsal root ganglion and CCI-induced neuropathic pain. Over-activation of the cytoskeleton caused by RhoA/LIMK/cofilin pathway activation may produce a scaffold for the trafficking of nociceptive signaling factors, leading to chronic neuropathic pain. Here, we found that simvastatin significantly decreased the ratio of membrane/cytosolic RhoA, which was significantly increased after CCI, by inhibiting the RhoA/LIMK/cofilin pathway. This effect was highly dependent on the function of the cytoskeleton as a scaffold for signal trafficking. We conclude that simvastatin attenuated neuropathic pain in rats subjected to CCI by inhibiting actin-mediated intracellular trafficking to suppress RhoA/LIMK/cofilin pathway activity. PMID- 27216619 TI - Apelin-13 Impaires Acquisition but Not Consolidation or Expression of Contextual Fear in Rats. AB - Apelin-13, as an endogenous neuropeptide, is the ligand for the G-protein-coupled receptor, APJ, which has recently been demonstrated to be involved in the process that contributes to learning and memory. Previous studies showed that apelin may be required for certain forms of learning and memory. Up to date, the role of apelin in fear memory has not been explored. In the present study, we tested the effects of apelin-13 (1.0, 2.0 and 4.0 ug/rat) on contextual fear conditioning (experiment 1), consolidation (experiment 2) and expression (experiment 3) in rats. A well established fear conditioning protocol was used, which contained three training phases: habituation, fear conditioning and test. Apelin-13 was i.c.v injected 10 min before conditioning (experiment 1), immediately after conditioning (experiment 2) or 10 min before testing (experiment 3). The values of percent freezing were used to measure fear. We found that only 2.0 ug apelin 13 administrations produced a decrease freezing in experiment 1. The most effective dose of apelin-13 (2.0 ug) was selected, but it had no effect on freezing in experiment 2 and 3. Furthermore, the decreased freezing in experiment 1 was not attributed to the deficits of locomotor activity and foot-shock sensitivity. These results, for the first time, indicated that apelin-13 impaired fear acquisition but not fear consolidation or expression. PMID- 27216620 TI - Blue Light Action on Mitochondria Leads to Cell Death by Necroptosis. AB - Blue light impinging on the many mitochondria associated with retinal ganglion cells (RGCs) in situ has the potential of eliciting necroptosis through an action on RIP1/RIP3 to stimulate RGC death in diseases like glaucoma and diabetic retinopathy. Cells in culture die when exposed to blue light. The death process is mitochondria-dependent and is known to involve a decrease in the production of ATP, a generation of ROS, the activation of poly-(ADP-ribose) polymerase, the stimulation of apoptosis-inducing factor (AIF) as well as the up-regulation of heme-oxygenase-1 (HO-1). Our present results show that blue light-induced activation of AIF is not directly linked with the stimulation of RIP1/RIP3. Down regulation of RIP1/RIP3 did not influence AIF. AIF activation therefore appears to enhance the rate of necroptosis by a direct action on DNA breakdown, the end stage of necroptosis. This implies that silencing of AIF mRNA may provide a degree of protection to blue light insult. Also, necrostatin-1 attenuated an increased turnover of HO-1 mRNA caused by blue light to suggest an indirect inhibition of necroptosis, caused by the action of necrostatin-1 on RIP1/RIP3 to reduce oxidative stress. This is supported by the finding that gene silencing of RIP1 and RIP3 has no effect on HO-1. We therefore conclude that inhibitors of RIP kinase might be more specific than necrostatin-1 as a neuroprotective agent to blunt solely necroptosis caused by blue light. PMID- 27216621 TI - Margaret McCartney: Fighting for the NHS's moral life. PMID- 27216623 TI - A Glutathione (GSH)-Responsive Near-Infrared (NIR) Theranostic Prodrug for Cancer Therapy and Imaging. AB - To reduce the side effects of chemotherapy, nontoxic prodrugs activated by the tumor microenvironment are urgently required for use in cancer treatment. In this work, we developed prodrug 4 for tumor-targeting treatment and imaging of the anticancer drug release in vivo. Taking advantage of the high glutathione (GSH) concentration in cancer cells, the disulfide bond in prodrug 4 was cleaved, resulting in the release of an active anticancer drug and a near-infrared (NIR) fluorescence dye turn-on. Furthermore, contrast to the free anticancer drug, the prodrug exhibited higher cytotoxicity to hepatoma cells than that to normal HL 7702 cells. Thus, prodrug 4 is a promising platform for specific tumor activatable drug delivery system, because of its favorable features of in situ and in vivo monitoring of the drug release and therapeutic efficacy. PMID- 27216622 TI - Do novel genes drive morphological novelty? An investigation of the nematosomes in the sea anemone Nematostella vectensis. AB - BACKGROUND: The evolution of novel genes is thought to be a critical component of morphological innovation but few studies have explicitly examined the contribution of novel genes to the evolution of novel tissues. Nematosomes, the free-floating cellular masses that circulate through the body cavity of the sea anemone Nematostella vectensis, are the defining apomorphy of the genus Nematostella and are a useful model for understanding the evolution of novel tissues. Although many hypotheses have been proposed, the function of nematosomes is unknown. To gain insight into their putative function and to test hypotheses about the role of lineage-specific genes in the evolution of novel structures, we have re-examined the cellular and molecular biology of nematosomes. RESULTS: Using behavioral assays, we demonstrate that nematosomes are capable of immobilizing live brine shrimp (Artemia salina) by discharging their abundant cnidocytes. Additionally, the ability of nematosomes to engulf fluorescently labeled bacteria (E. coli) reveals the presence of phagocytes in this tissue. Using RNA-Seq, we show that the gene expression profile of nematosomes is distinct from that of the tentacles and the mesenteries (their tissue of origin) and, further, that nematosomes (a Nematostella-specific tissue) are enriched in Nematostella-specific genes. CONCLUSIONS: Despite the small number of cell types they contain, nematosomes are distinct among tissues, both functionally and molecularly. We provide the first evidence that nematosomes comprise part of the innate immune system in N. vectensis, and suggest that this tissue is potentially an important place to look for genes associated with pathogen stress. Finally, we demonstrate that Nematostella-specific genes comprise a significant proportion of the differentially expressed genes in all three of the tissues we examined and may play an important role in novel cell functions. PMID- 27216624 TI - Synthesis and DNA-binding study of imidazole linked thiazolidinone derivatives. AB - A novel series of imidazole-linked thiazolidinone hybrid molecules were designed and synthesized through a feasible synthetic protocol. The molecules were characterized with Fourier transform infrared (FT-IR), 1 H nuclear magnetic resonance (NMR), 13 C NMR and high-resolution mass spectrometry (HRMS) techniques. In vitro susceptibility tests against Gram-positive (S. aureus and B. subtilis) and Gram-negative bacteria (E. coli and P. aeruginosa) gave highly promising results. The most active molecule (3e) gave a minimal inhibitory concentration (MIC) value of 3.125 MUg/mL which is on par with the reference drug streptomycin. Structure-activity relationships revealed activity enhancement by nitro and chloro groups when they occupied meta position of the arylidene ring in 2-((3-(imidazol-1-yl)propyl)amino)-5-benzylidenethiazolidin-4-ones. DNA-binding study of the most potent molecule 3e with salmon milt DNA (sm-DNA) under simulated physiological pH was probed with UV-visible absorption, fluorescence quenching, gel electrophoresis and molecular docking techniques. These studies established that compound 3e has a strong affinity towards DNA and binds at DNA minor groove with a binding constant (Kb ) 0.18 * 102 L mol-1 . Molecular docking simulations predicted strong affinity of 3e towards DNA with a binding affinity (DeltaG) -8.5 kcal/mol. Van der Waals forces, hydrogen bonding and hydrophobic interactions were predicted as the main forces of interaction. The molecule 3e exhibited specific affinity towards adenine-thiamine base pairs. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27216625 TI - Event-related EEG power modulations and phase connectivity indicate the focus of attention in an auditory own name paradigm. AB - Estimating cognitive abilities in patients suffering from Disorders of Consciousness remains challenging. One cognitive task to address this issue is the so-called own name paradigm, in which subjects are presented with first names including the own name. In the active condition, a specific target name has to be silently counted. We recorded EEG during this task in 24 healthy controls, 8 patients suffering from Unresponsive Wakefulness Syndrome (UWS) and 7 minimally conscious (MCS) patients. EEG was analysed with respect to amplitude as well as phase modulations and connectivity. Results showed that general reactivity in the delta, theta and alpha frequency (event-related de-synchronisation, ERS/ERD, and phase locking between trials and electrodes) toward auditory stimulation was higher in controls than in patients. In controls, delta ERS and lower alpha ERD indexed the focus of attention in both conditions, late theta ERS only in the active condition. Additionally, phase locking between trials and delta phase connectivity was highest for own names in the passive and targets in the active condition. In patients, clear stimulus-specific differences could not be detected. However, MCS patients could reliably be differentiated from UWS patients based on their general event-related delta and theta increase independent of the type of stimulus. In conclusion, the EEG signature of the active own name paradigm revealed instruction-following in healthy participants. On the other hand, DOC patients did not show clear stimulus-specific processing. General reactivity toward any auditory input, however, allowed for a reliable differentiation between MCS and UWS patients. PMID- 27216626 TI - Objective characterization of daily living transitions in patients with Parkinson's disease using a single body-fixed sensor. AB - Body-fixed sensors (BFS), e.g., accelerometers worn for several days, can be used to augment the traditional clinical assessment. Long-term recordings obtained with BFS have been applied to study tremor, postural control, freezing of gait, turning abilities, motor response fluctuations and fall risk among older adults and patients with Parkinson's disease (PD). We aimed to test whether BFS-derived measures of transitions differ between patients with PD and healthy controls, and to evaluate whether there are differences among patients with mild PD, compared to more severe patients, and to controls. We also explored the added value of the metrics extracted from the sensor as compared to traditional testing in the lab. Ninety-nine patients with PD and 38 healthy older adults (HOA) participated in this study and wore a body-fixed sensor for 3 days. Walk-to-sit (n = 3286) and Sit-to-walk (n = 2858) transitions were analyzed and a machine learning algorithm was applied to distinguish between the groups. Significant differences in transitions were observed between PD patients and HOA, between mild and severe PD, and between mild PD and HOA, both in temporal and distribution features. The machine learning algorithm discriminated patients from HOA (accuracy = 92.3 %), mild from severe patients (accuracy = 89.8 %), and mild patients from HOA (accuracy = 85.9 %). These initial results suggest that body-fixed sensor-derived metrics of everyday transitions can characterize disease severity and differentiate mild PD patients from healthy older adults. Perhaps this approach can help with the integration of BFS into clinical care and the tracking of disease progression and the response to therapy. PMID- 27216628 TI - Sickeningly Sweet: Does Sugar Cause Type 2 Diabetes? Yes. PMID- 27216627 TI - Educational differences in dietary intake and compliance with dietary recommendations in a Swiss adult population. AB - OBJECTIVES: This study assessed the impact of education on diet and compliance with the national recommendations. METHODS: The study included 4338 adult participants of the Colaus study, a cross-sectional, population-based study conducted between 2009 and 2012 in Lausanne (Switzerland). Education was categorized as primary, apprenticeship, secondary, and tertiary. RESULTS: Men with primary vs. tertiary education had a lower intake of monounsaturated fatty acids (29.4 vs. 30.9 g/day), iron (11.4 vs. 11.8 mg/day), vitamin A (758.2 vs. 904.2 retinol equivalents/day), and vitamin D (2.3 vs. 3.0 MUg/day). Women with primary vs. tertiary education had a lower intake of monounsaturated fatty acids (25.5 vs. 27.4 g/day), fiber (15.6 vs. 17.2 g/day) and iron (9.8 vs. 10.3 mg/day). Men with primary vs. tertiary education had a better compliance with protein recommendations [odds ratio (95 % CI): 2.31 (1.37; 3.90)], while women with primary vs. tertiary education had a better compliance with vitamin A recommendations [odds ratio 1.74 (1.15; 2.65)]. CONCLUSIONS: Overall, our results do not confirm a unidirectional association between education and diet, and question the approach of targeted interventions alone in selected educational groups to prevent chronic diseases. PMID- 27216629 TI - Genomic evidence that Vibrio inhibens is a heterotypic synonym of Vibrio jasicida. AB - Vibrio inhibens is a marine bacterium species of the genus Vibrio (Vibrionaceae, Gammaproteobacteria). The species has been shown to be closely related to members of the genus Vibrio in the so-called Harveyi clade. The clade includes at least 11 closely related species with similar physiological and biochemical properties. Due to these similarities, species of the Harveyi clade are difficult to characterize taxonomically. Previously phenotypic and genotypic properties of the V. inhibens type strain were compared with six species of the Harveyi clade, resulting in the possibility that V. inhibens could be a synonym of a previously described species. In this study, the taxonomic status of V. inhibens was analyzed using genomic approaches. The whole-genome sequence of the type strain of V. inhibens, CECT 7692T, was obtained and analyzed. Calculations of average nucleotide identity with the blast algorithm (ANIb) showed that CECT 7692T has an ANIb of 97.5 % or higher to five strains of Vibrio. jasicida, including the type strain, but an ANIb lower than 93.5 % to other members of the Harveyi clade Vibrio. Phylogenetic analysis based on nucleotide sequences of 133 protein-coding genes showed a close evolutionary relationship of CECT 7692T to V. jasicida. Based on these results, Vibrio inhibens is proposed to be a later heterotypic synonym of V. jasicida. PMID- 27216630 TI - Slowdown of growth controls cellular differentiation. AB - How can changes in growth rate affect the regulatory networks behavior and the outcomes of cellular differentiation? We address this question by focusing on starvation response in sporulating Bacillus subtilis We show that the activity of sporulation master regulator Spo0A increases with decreasing cellular growth rate. Using a mathematical model of the phosphorelay-the network controlling Spo0A-we predict that this increase in Spo0A activity can be explained by the phosphorelay protein accumulation and lengthening of the period between chromosomal replication events caused by growth slowdown. As a result, only cells growing slower than a certain rate reach threshold Spo0A activity necessary for sporulation. This growth threshold model accurately predicts cell fates and explains the distribution of sporulation deferral times. We confirm our predictions experimentally and show that the concentration rather than activity of phosphorelay proteins is affected by the growth slowdown. We conclude that sensing the growth rates enables cells to indirectly detect starvation without the need for evaluating specific stress signals. PMID- 27216631 TI - Co-culture model consisting of human brain microvascular endothelial and peripheral blood mononuclear cells. AB - BACKGROUND: Numerous systems exist to model the blood-brain barrier (BBB) with the goal of understanding the regulation of passage into the central nervous system (CNS) and the potential impact of selected insults on BBB function. These models typically focus on the intrinsic cellular properties of the BBB, yet studies of peripheral cell migration are often excluded due to technical restraints. NEW METHOD: This method allows for the study of in vitro cellular transmigration following exposure to any treatment of interest through optimization of co-culture conditions for the human brain microvascular endothelial cells (BMEC) cell line, hCMEC/D3, and primary human peripheral blood mononuclear cells (PBMCs). RESULTS: hCMEC/D3 cells form functionally confluent monolayers on collagen coated polytetrafluoroethylene (PTFE) transwell inserts, as assessed by microscopy and tracer molecule (FITC-dextran (FITC-D)) exclusion. Two components of complete hCMEC/D3 media, EBM-2 base-media and hydrocortisone (HC), were determined to be cytotoxic to PBMCs. By combining the remaining components of complete hCMEC/D3 media with complete PBMC media a resulting co culture media was established for use in hCMEC/D3-PBMC co-culture functional assays. COMPARISON WITH EXISTING METHODS: Through this method, issues of extensive differences in culture media conditions are resolved allowing for treatments and functional assays to be conducted on the two cell populations co cultured simultaneously. CONCLUSION: Described here is an in vitro co-culture model of the BBB, consisting of the hCMEC/D3 cell line and primary human PBMCs. The co-culture media will now allow for the study of exposure to potential insults to BBB function over prolonged time courses. PMID- 27216632 TI - Indirect effects of TiO2 nanoparticle on neuron-glial cell interactions. AB - Although, titanium dioxide nanoparticles (TiO2NPs) are nanomaterials commonly used in consumer products, little is known about their hazardous effects, especially on central nervous systems. To examine this issue, ALT astrocyte-like, BV-2 microglia and differentiated N2a neuroblastoma cells were exposed to 6 nm of 100% anatase TiO2NPs. A lipopolysaccharide (LPS) was pre-treated to activate glial cells before NP treatment for mimicking NP exposure under brain injury. We found that ALT and BV-2 cells took up more NPs than N2a cells and caused lower cell viability. TiO2NPs induced IL-1beta in the three cell lines and IL-6 in N2a. LPS-activated BV-2 took up more TiO2NPs than normal BV-2 and released more intra/extracellular reactive oxygen species (ROS), IL-1beta, IL-6 and MCP-1 than did activated BV-2. Involvement of clathrin- and caveolae-dependent endocytosis in ALT and clathrin-dependent endocytosis and phagocytosis in BV-2 both had a slow NP translocation rate to lysosome, which may cause slow ROS production (after 24 h). Although TiO2NPs did not directly cause N2a viability loss, by indirect NP exposure to the bottom chamber of LPS-activated BV-2 in the Transwell system, they caused late apoptosis and loss of cell viability in the upper N2a chamber due to H2O2 and/or TNF-alpha release from BV-2. However, none of the adverse effects in N2a or BV-2 cells was observed when TiO2NPs were exposed to ALT-N2a or ALT-BV-2 co-culture. These results demonstrate that neuron damage can result from TiO2NP-mediated ROS and/or cytokines release from microglia, but not from astrocytes. PMID- 27216633 TI - Discovery of potent adenosine A2a antagonists as potential anti-Parkinson disease agents. Non-linear QSAR analyses integrated with pharmacophore modeling. AB - Adenosine A2A receptor antagonists are of great interest in the treatment for Parkinson's disease. In this study, we combined extensive pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis to explore the structural requirements for potent Adenosine A2A antagonists. Genetic function algorithm (GFA) joined with k nearest neighbor (kNN) analyses were applied to build predictive QSAR models. Successful pharmacophores were complemented with exclusion spheres to improve their receiver operating characteristic curve (ROC) profiles. Best QSAR models and their associated pharmacophore hypotheses were validated by identification of several novel Adenosine A2A antagonist leads retrieved from the National Cancer Institute (NCI) structural database. The most potent hit illustrated IC50 value of 545.7 nM. PMID- 27216634 TI - Establishing equivalence of a Chinese version of the stroke specific quality of life measure for stroke survivors. AB - INTRODUCTION: The Stroke Specific Quality of Life Scale is a stroke-specific measure of health-related quality of life. However, there has been no Chinese (Hong Kong) version of the scale. METHODS: A descriptive study was conducted to examine the reliability, validity and factor structure of the translated version (SSQOL-C) among stroke survivors. Participants completed SSQOL-C, and the Chinese versions of the Medical Outcomes Study Short-Form Health Survey (SF-36), Stroke Self-Efficacy Questionnaire (SSEQ-C) and Frenchay Activities Index (FAI). Thirty of these participants completed the same questionnaires after 4 weeks. RESULTS: A total of 135 stroke survivors (mean age 58.90 +/- 9.75) were recruited. SSQOL-C had good internal consistency with Cronbach's alphas for each domain ranging from 0.63 to 0.90. Most domains had moderate to high correlations with similar dimensions of SF-36, SSEQ-C, FAI and Barthel ADL Index total scores (Spearman's rho: 0.40-0.77, p < 0.01), suggesting acceptable convergent validity. Principal component analyses suggested an 11-factor model in contrast to the 12-factor model for the original scale with six new factors emerging and five original factors retained. DISCUSSION: The results suggest SSQOL-C is a reliable and valid tool for measuring Chinese stroke survivors' health-related quality of life. More studies are needed to confirm the 11-factor model of the scale. Implications for rehabilitation The translated Chinese version of the Stroke Specific Quality of Life Scale is a reliable and valid tool for measuring Chinese stroke survivors' health-related quality of life. An 11-factor model in contrast to the 12-factor model for the original scale with six new factors emerging and five original factors retained. PMID- 27216635 TI - Neural effects of social environmental stress - an activation likelihood estimation meta-analysis. AB - BACKGROUND: Social environmental stress, including childhood abuse and deprivation, is associated with increased rates of psychiatric disorders such as schizophrenia and depression. However, the neural mechanisms mediating risk are not completely understood. Functional magnetic resonance imaging (MRI) studies have reported effects of social environmental stress on a variety of brain regions, but interpretation of results is complicated by the variety of environmental risk factors examined and different methods employed. METHOD: We examined brain regions consistently showing differences in blood oxygen level dependent (BOLD) response in individuals exposed to higher levels of environmental stress by performing a coordinate-based meta-analysis on 54 functional MRI studies using activation likelihood estimation (ALE), including an overall sample of 3044 participants. We performed separate ALE analyses on studies examining adults (mean age ?18 years) and children/adolescents (mean age <18 years) and a contrast analysis comparing the two types of study. RESULTS: Across both adult and children/adolescent studies, ALE meta-analysis revealed several clusters in which differences in BOLD response were associated with social environmental stress across multiple studies. These clusters incorporated several brain regions, among which the right amygdala was most frequently implicated. CONCLUSIONS: These findings suggest that a variety of social environmental stressors is associated with differences in the BOLD response of specific brain regions such as the right amygdala in both children/adolescents and adults. What remains unknown is whether these environmental stressors have differential effects on treatment response in these brain regions. PMID- 27216636 TI - Do We Know Where We Stand? Neighborhood Relative Income, Subjective Social Status, and Health. AB - Bridging research on relative income and subjective social status (SSS), this study examines how neighborhood relative income is related to ones' SSS, and in turn, physical and mental health. Using a survey sample of 1807 U.S. adults, we find that neighborhood median income significantly moderates the relationship between household income and self-reported physical and mental health. Low-income individuals living in high-income neighborhoods (i.e., relative disadvantage) report better physical and mental health than low-income individuals living in low-income neighborhoods. In addition, high-income individuals living in low income neighborhoods (i.e., relative advantage) report higher SSS (relative to neighbors), whereas low-income individuals living in high-income neighborhoods (i.e., relative disadvantage) also report higher SSS. We draw from social comparison theory to interpret these results positing that downward comparisons may serve an evaluative function while upward comparisons may result in affiliation with better-off others. Finally, we demonstrate that SSS explains the relationship between neighborhood relative income and health outcomes, providing empirical support for the underlying influence of perceived social position. PMID- 27216637 TI - Evaluation of the irritancy and hypersensitivity potential following topical application of didecyldimethylammonium chloride. AB - Didecyldimethylammonium chloride (DDAC) is a dialkyl-quaternary ammonium compound that is used in numerous products for its bactericidal, virucidal and fungicidal properties. There have been clinical reports of immediate and delayed hypersensitivity reactions in exposed individuals; however, the sensitization potential of DDAC has not been thoroughly investigated. The purpose of these studies was to evaluate the irritancy and sensitization potential of DDAC following dermal exposure in a murine model. DDAC induced significant irritancy (0.5 and 1%), evaluated by ear swelling in female Balb/c mice. Initial evaluation of the sensitization potential was conducted using the local lymph node assay (LLNA) at concentrations ranging from 0.0625-1%. A concentration-dependent increase in lymphocyte proliferation was observed with a calculated EC3 value of 0.17%. Dermal exposure to DDAC did not induce increased production of IgE as evaluated by phenotypic analysis of draining lymph node B-cells (IgE (+) B220(+)) and measurement of total serum IgE levels. Additional phenotypic analyses revealed significant and dose-responsive increases in the absolute number of B cells, CD4 (+) T-cells, CD8 (+) T-cells and dendritic cells in the draining lymph nodes, along with significant increases in the percentage of B-cells (0.25% and 1% DDAC) at Day 10 following 4 days of dermal exposure. There was also a significant and dose-responsive increase in the number of activated CD44 (+) CD4 (+) and CD8 (+) T-cells and CD86 (+) B-cells and dendritic cells following exposure to all concentrations of DDAC. These results demonstrate the potential for development of irritation and hypersensitivity responses to DDAC following dermal exposure and raise concerns about the use of this chemical and other quaternary ammonium compounds that may elicit similar effects. PMID- 27216638 TI - Challenges in developing drugs for pediatric CNS disorders: A focus on psychopharmacology. AB - Many psychiatric and behavioral disorders manifest in childhood (attention deficit hyperactivity disorder, obsessive compulsive disorder, anxiety, depression, schizophrenia, autism spectrum disorder, etc.) and the opportunity for intervening early may attenuate full development of the disorder and lessen long term disability. Yet, pediatric drug approvals for CNS indications are limited, and pediatric testing generally occurs only after establishing adult efficacy, more as an afterthought rather than with the initial goal of developing the medication for a pediatric CNS indication. With pharmaceutical companies decreasing funding of their neuroscience research divisions overall, the prospects for moving promising investigational drugs forward into pediatrics will only decline. The goal of this review is to highlight important challenges around pediatric drug development for psychiatric disorders, specifically during clinical development, and to present opportunities for filling these gaps, using new strategies for de-risking investigational drugs in new clinical trial designs/models. We will first present the current trends in pediatric drug efficacy testing in academic research and in industry trials, we will then discuss the regulatory landscape of pediatric drug testing, including policies intended to support and encourage more testing. Obstacles that remain will then be presented, followed by new designs, funding opportunities and considerations for testing investigational drugs safely. PMID- 27216639 TI - Improving dynamic phytoplankton reserve-utilization models with an indirect proxy for internal nitrogen. AB - Ecologists have often used indirect proxies to represent variables that are difficult or impossible to measure directly. In phytoplankton, the internal concentration of the most limiting nutrient in a cell determines its growth rate. However, directly measuring the concentration of nutrients within cells is inaccurate, expensive, destructive, and time-consuming, substantially impairing our ability to model growth rates in nutrient-limited phytoplankton populations. The red chlorophyll autofluorescence (hereafter "red fluorescence") signal emitted by a cell is highly correlated with nitrogen quota in nitrogen-limited phytoplankton species. The aim of this study was to evaluate the reliability of including flow cytometric red fluorescence as a proxy for internal nitrogen status to model phytoplankton growth rates. To this end, we used the classic Quota model and designed three approaches to calibrate its model parameters to data: where empirical observations on cell internal nitrogen quota were used to fit the model ("Nitrogen-Quota approach"), where quota dynamics were inferred only from changes in medium nutrient depletion and population density ("Virtual Quota approach"), or where red fluorescence emission of a cell was used as an indirect proxy for its internal nitrogen quota ("Fluorescence-Quota approach"). Two separate analyses were carried out. In the first analysis, stochastic model simulations were parameterized from published empirical relationships and used to generate dynamics of phytoplankton communities reared under nitrogen-limited conditions. Quota models were fitted to the dynamics of each simulated species with the three different approaches and the performance of each model was compared. In the second analysis, we fit Quota models to laboratory time-series and we calculate the ability of each calibration approach to describe the observed trajectories of internal nitrogen quota in the culture. Results from both analyses concluded that the Fluorescence-Quota approach including per-cell red fluorescence as a proxy of internal nitrogen substantially improved the ability of Quota models to describe phytoplankton dynamics, while still accounting for the biologically important process of cell nitrogen storage. More broadly, many population models in ecology implicitly recognize the importance of accounting for storage mechanisms to describe the dynamics of individual organisms. Hence, the approach documented here with phytoplankton dynamics may also be useful for evaluating the potential of indirect proxies in other ecological systems. PMID- 27216640 TI - Development of a population of cancer cells: Observation and modeling by a Mixed Spatial Evolutionary Games approach. AB - Living cells, like whole living organisms during evolution, communicate with their neighbors, interact with the environment, divide, change their phenotypes, and eventually die. The development of specific ways of communication (through signaling molecules and receptors) allows some cellular subpopulations to survive better, to coordinate their physiological status, and during embryonal development to create tissues and organs or in some conditions to become tumors. Populations of cells cultured in vitro interact similarly, also competing for space and nutrients and stimulating each other to better survive or to die. The results of these intercellular interactions of different types seem to be good examples of biological evolutionary games, and have been the subjects of simulations by the methods of evolutionary game theory where individual cells are treated as players. Here we present examples of intercellular contacts in a population of living human cancer HeLa cells cultured in vitro and propose an evolutionary game theory approach to model the development of such populations. We propose a new technique termed Mixed Spatial Evolutionary Games (MSEG) which are played on multiple lattices corresponding to the possible cellular phenotypes which gives the possibility of simulating and investigating the effects of heterogeneity at the cellular level in addition to the population level. Analyses performed with MSEG suggested different ways in which cellular populations develop in the case of cells communicating directly and through factors released to the environment. PMID- 27216641 TI - A cost-effective method to get insight into the peritoneal dialysate effluent proteome. AB - : Protein depletion with acetonitrile and protein equalization with dithiothreitol have been assessed with success as proteomics tools for getting insight into the peritoneal dialysate effluent proteome. The methods proposed are cost-effective, fast and easy of handling, and they match the criteria of analytical minimalism: low sample volume and low reagent consumption. Using two dimensional gel electrophoresis and peptide mass fingerprinting, a total of 72 unique proteins were identified. Acetonitrile depletes de PDE proteome from high abundance proteins, such as albumin, and enriches the sample in apolipo-like proteins. Dithiothreitol equalizes the PDE proteome by diminishing the levels of albumin and enriching the extract in immunoglobulin-like proteins. The annotation per gene ontology term reveals the same biological paths being affected for patients undergoing peritoneal dialysis, namely that the largest number of proteins lost through peritoneal dialysate are extracellular proteins involved in regulation processes through binding. SIGNIFICANCE: Renal failure is a growing problem worldwide, and particularly in Europe where the population is getting older. Up-to-date there is a focus of interest in peritoneal dialysis (PD), as it provides a better quality of life and autonomy of the patients than other renal replacement therapies such as haemodialysis. However, PD can only be used during a short period of years, as the peritoneum lost its permeability through time. Therefore to make a breakthrough in PD and consequently contribute to better healthcare system it is urgent to find a group of biomarkers of peritoneum degradation. Here we report on two cost-effective methods for protein depletion in peritoneal dialysate effluent (PDE). The use of ACN and DTT over PDE to deplete high abundant proteins or to equalize the concentration of proteins, respectively, performs well and with similar protein profiles than when the same chemicals are used in human plasma samples. ACN depletes de PDE proteome from large proteins, such as albumin, and enriches the sample in apolipoproteins. DTT equalizes the PDE proteome by diminishing the levels of large proteins such as albumin and enriching the extract in immunoglobulins. Although the number and type of proteins identified are different, the annotation per gene ontology term reveals the same biological paths being affected for patients undergoing peritoneal dialysate. Thus, the largest number of proteins lost through peritoneal dialysate belongs to the group of extracellular proteins involved in regulation processes through binding. As for the searching of biomarkers, DTT seems to be the most promising of the two methods because acts as an equalizer and it allows interrogating more proteins in the same sample. PMID- 27216643 TI - Screening for target toxins of the antiophidic protein DM64 through a gel-based interactomics approach. AB - : DM64 is a glycosylated protein with antivenom activity isolated from the serum of the opossum Didelphis aurita. It binds non-covalently to myotoxins I (Asp49) and II (Lys49) from Bothrops asper venom and inhibits their myotoxic effect. In this study, an affinity column with immobilized DM64 as bait was used to fish potential target toxins. All ten isolated myotoxins tested were able to effectively bind to the DM64 column. To better access the specificity of the inhibitor, crude venoms from Bothrops (8 species), Crotalus (2 species) and Naja naja atra were submitted to the affinity purification. Venom fractions bound and nonbound to the DM64 column were analyzed by two-dimensional gel electrophoresis and MALDI-TOF/TOF MS. Although venom fractions bound to the column were mainly composed of basic PLA2, a few spots corresponding to acidic PLA2 were also observed. Some unexpected protein spots were also identified: C-type lectins and CRISP may represent putative new targets for DM64, whereas the presence of serine peptidases in the venom bound fraction is likely a consequence of nonspecific binding to the column matrix. The present results contribute to better delineate the inhibitory potential of DM64, providing a framework for the development of more specific antivenom therapies. BIOLOGICAL SIGNIFICANCE: Local tissue damage induced by myotoxic PLA2 remains a serious consequence of snake envenomation, since it is only partially neutralized by traditional antivenom serotherapy. Myotoxin inhibition by highly specific molecules offers great promise in the treatment of snakebites, a health problem largely neglected by governments and pharmaceutical industries. Bioactive compounds such as DM64 can represent a valuable source of scaffolds for drug development in this area. The present study has systematically profiled the binding specificity of DM64 toward a variety of snake venom toxin classes and therefore can lead to a better understanding of the structure-function relationship of this important antivenom protein. PMID- 27216644 TI - Transcriptomic and proteomic analyses provide new insights into the regulation mechanism of low-temperature-induced leafy head formation in Chinese cabbage. AB - In Chinese cabbage, leafy head-related traits are directly related to the cabbage yield and marketability, which are often primarily concerned target for breeders. Although intensive studies has been on head formation in Chinese cabbage in the past decade, very scanty information is available on mechanism involved in the head formation under the influence of low temperature at transcriptome and proteome perspective. In this study, quantitative expression profiling based on RNA-Seq transcriptome and iTRAQ proteome were combined to investigate this trait for a global picture of the molecular dynamics. Total of 2931 transcripts and 365 proteins were identified with significantly changed level in abundance from heading and non-heading Chinese cabbage. Related analyses including function annotations, hierarchical categories, as well as the correlation from transcript to-proteins were performed. The results indicated that the leafy head formation of Chinese cabbage has involved a complex regulatory pattern. The correlated genes that were mapped to the pathway of plant hormone signal transduction suggested that the head formation might be an integrated result of various plant hormones. Our combined analysis will provide a comprehensive approach to understanding the regulation mechanism of leafy head formation in Chinese cabbage. BIOLOGICAL SIGNIFICANCE: This study revealed the direct relation of leafy-heading traits with the yield of the plant. A comprehensive investigation was done by integrating quantitative expression profiling analysis of transcriptome and proteomic to provide crucial information for further research on the molecular mechanism involved in head formation in Chinese cabbage. The correlation of transcript-to-protein in abundance may afford some necessary information of involvement of post-transcriptional factors influencing leafy head formation in Chinese cabbage. PMID- 27216642 TI - Oncogenic KIT mutations in different exons lead to specific changes in melanocyte phospho-proteome. AB - Mutations in the proto-oncogene c-KIT (KIT) are found in several cancers, and the site of these mutations differs markedly between cancer types. We used site directed mutagenesis to induce KIT(559), KIT(642) and KIT(816) mutations in primary human melanocytes (PHM) and we investigated the impact of each mutation on KIT function. We studied canonical KIT-signaling pathways by immunoblotting, and we used stable isotope labeling by amino acids in cell culture (SILAC) and kinase prediction models to identify kinases differently activated in respective mutants. We validated our results with the analysis of phosphorylation levels of selected substrates for each kinase. We concluded that CK1 epsilon and delta are more active in cell clones harboring KIT(559) and KIT(642) mutations, whereas PAK4 is more active in clones with KIT(816) mutation. Our findings might help to develop further therapeutic options for tumors with specific KIT mutations in different domains. BIOLOGICAL SIGNIFICANCE: Different types of cancers harbor mutations in the oncogene KIT. The use of small molecules inhibitors directly targeting KIT had a limited success in the treatment of patients with KIT mutant cancers. Our study describes specific phospho-proteome changes due to different KIT mutations, and provides targets of further therapeutic options. PMID- 27216645 TI - Induction of wheat straw delignification by Trametes species. AB - Wheat straw is the major crop residue in European countries which makes it the most promising material for bioconversion into biofuels. However, cellulose and hemicellulose are protected with lignin, so delignification is an inevitable phase in lignocellulose processing. The organisms predominantly responsible for its degradation are white-rot fungi and among them Trametes species represent promising degraders due to a well-developed ligninolytic enzyme system. Although numerous studies have confirmed that low molecular weight compounds can induce the production and activity of ligninolytic enzymes it is not clear how this reflects on the extent of delignification. The aim of the study was to assess the capacity of p-anisidine and veratryl alcohol to induce the production and activity of Mn-oxidizing peroxidases and laccases, and wheat straw delignification by six Trametes species. Significant inter- and intraspecific variations in activity and features of these enzymes were found, as well as differences in the potential of lignocellulose degradation in the presence or absence of inducers. Differences in the catalytic properties of synthesized enzyme isoforms strongly affected lignin degradation. Apart from enhanced lignin degradation, the addition of p-anisidine could significantly improve the selectivity of wheat straw ligninolysis, which was especially evident for T. hirsuta strains. PMID- 27216646 TI - Pulmonary veins stenosis after catheter ablation of atrial fibrillation as the cause of haemoptysis: three cases and a literature review. AB - BACKGROUND: Haemoptysis is a common clinical symptom with a complicated aetiology. Patients usually visit pulmonologists initially and are misdiagnosed due to physician ignorance regarding the rare causes of haemoptysis. METHODS: We report three cases of haemoptysis due to pulmonary vein stenosis accompanied by catheter ablation for atrial fibrillation and review the related literature. RESULTS: The three patients presented haemoptysis and they all had the history of catheter ablation. They received kinds of non-invasive and invasive diagnostic and therapeutic procedures. Finally they were confirmed to have pulmonary vein stenosis by either pulmonary angiography or thorax computed tomography three dimensional reconstructions. CONCLUSIONS: Haemoptysis could be caused by pulmonary vein stenosis secondary to catheter ablation for atrial fibrillation. Doctors should be aware of this rare aetiology. PMID- 27216647 TI - Eating School Lunch Is Associated with Higher Diet Quality among Elementary School Students. AB - BACKGROUND: Few studies have assessed the dietary quality of children who eat meals from home compared with school meals according to the 2010 Dietary Guidelines for Americans. OBJECTIVE: The objective of this study was to examine diet quality for elementary school students in relation to source of breakfast and lunch (whether school meal or from an outside source). DESIGN: An observational study was conducted of students in 43 schools in San Diego, CA, during the 2011-2012 school year. PARTICIPANTS/SETTING: Fourth- and fifth-grade students (N=3,944) completed a diary-assisted 24-hour food recall. MAIN OUTCOME MEASURES: The Healthy Eating Index-2010 (HEI-2010) scores of children who ate breakfast and lunch at school were compared with the HEI-2010 scores of children who obtained their meals from home and a combination of both school and home. STATISTICAL ANALYSIS: Analysis of variance, chi2 test, and generalized estimating equation models adjusted for age, sex, race/ethnicity, grade, language, and school level clustering were performed. RESULTS: School lunch eaters had a higher mean+/-standard deviation overall diet quality score (HEI-2010=49.0+/-11.3) compared with students who ate a lunch obtained from home (46.1+/-12.2; P=0.02). There was no difference in overall diet quality score by breakfast groups. Students who ate school breakfast had higher total fruit (P=0.01) and whole fruit (P=0.0008) scores compared with students who only ate breakfast obtained from home. Students who ate school foods had higher scores for dairy (P=0.007 for breakfast and P<0.0001 for lunch) and for empty calories from solid fats and added sugars (P=0.01 for breakfast and P=0.007 for lunch). CONCLUSIONS: Eating school lunch was associated with higher overall diet quality compared with obtaining lunch from home. Future studies are needed that assess the influence of the Healthy Hunger-Free Kids Act on children's diet quality. PMID- 27216648 TI - Nano-SPRi Aptasensor for the Detection of Progesterone in Buffer. AB - Progesterone is a steroid hormone that plays a central role in the female reproductive processes such as ovulation and pregnancy with possible effects on other organs as well. The measurement of progesterone levels in bodily fluids can assist in early pregnancy diagnosis and can provide insight for other reproductive functions. In this work, the detection of progesterone was examined by integrating novel aptamer development with a nanoEnhanced surface plasmon resonance imaging sensor. First, we developed X-aptamers and selected them for binding to progesterone. Then, we took advantage of the multi-array feature of SPRi to develop an optimized biosensor capable of simultaneously screening the 9 X-aptamers developed to determine the binding capabilities of each aptamer. The sensor surface design conditions were further optimized for the sandwich assay, which employed nanoEnhancers (NIR-streptavidin coated quantum dots) for ultrasensitive detection of progesterone molecules. The assay designed was examined over a concentration range of 1.575 ng/mL to 126 MUg/mL resulting in a limit of detection (LOD) of 1.575 ng/mL (5 nM) in phosphate buffer. PMID- 27216649 TI - Development of a multi-residue analysis of diclofenac and some transformation products in bivalves using QuEChERS extraction and liquid chromatography-tandem mass spectrometry. Application to samples from mesocosm studies. AB - Pharmaceuticals are ubiquitously present in the aquatic environment, mainly due to insufficient removal in wastewater treatment plants. Although these compounds are often found at trace levels in waters, long-term exposure can have negative impacts on biotic communities due to their inherent biological activity. The non steroidal anti-inflammatory drug diclofenac (DCF) is one of the most frequently detected human pharmaceuticals in water and has recently been included in the "watch" list of the European Union. However little data are available on the detection of this substance and its transformation products in aquatic organisms. In this context, an analytical methodology has been developed to quantify traces of DCF along with its biotic and abiotic transformation products in a wild species of bivalve, the zebra mussel Dreissena polymorpha. A modified QuEChERS extraction was implemented on a small quantity of soft bivalve tissue (100mg). This was followed by liquid chromatography coupled to tandem-mass spectrometry (LC-MS/MS) with electrospray ionization in positive mode (ESI+). Whole analytical method was validated on spiked real samples, with regard to linearity (from 1 to 50 or 100ng/g depending on the target compounds, R(2)>0.99), intra-day precision (relative standard deviation (RSD)<18%), inter-day precision (RSD <25%), (recoveries 78-117%), and limits of detection and of quantification (both inferior or equal to 1ng/g). The optimized method was successfully applied to organisms collected from mesocosm experiments. Bioconcentration factors comprised between 4 and 13 were observed for DCF in the zebra mussels. To the best of our knowledge, the product 2-indolone was for the first time detected in bivalves, with levels up to 6ng/g. PMID- 27216650 TI - Glutathione modified screen-printed carbon nanofiber electrode for the voltammetric determination of metal ions in natural samples. AB - This work reports the development of a glutathione modified electrode via electrografting on a screen-printed carbon nanofiber substrate (GSH-SPCNFE). GSH SPCNFE was compared to a classical screen-printed carbon electrode modified with glutathione (GSH-SPCE) for the simultaneous voltammetric determination of Cd(II) and Pb(II). Their electrochemical characterization and analytical performance suggest that SPCNFE could be a much better support for GSH immobilization. The applicability of GSH-SPCNFE for the determination of low concentration levels of Pb(II) and Cd(II) ions in environmental samples was successfully tested in a certified wastewater reference material by means of stripping voltammetry with a very high reproducibility and good trueness. PMID- 27216651 TI - One-pot aqueous synthesis of gadolinium doped CdTe quantum dots with dual imaging modalities. AB - A facile one-pot strategy has been developed for the aqueous synthesis of Gd doped CdTe (Gd:CdTe) QDs as fluorescence and magnetic resonance imaging dual modal agent. The prepared Gd:CdTe QDs showed narrow size distribution and the average size was less than 5nm. The amount of Gd(3+) dopant in Gd:CdTe QDs significantly affected the optical properties of obtained QDs. The highest PL QY for the prepared Gd:CdTe QDs was up to 42.5%. The QDs showed the weak toxicity and significant enhancement in MRI signal. The specific relaxivity value (r1) was determined to be 4.22mM(-1)s(-1). These properties make the prepared Gd:CdTe QDs be an effective dual-modal imaging agent and have great potential applications in biomedical field. PMID- 27216652 TI - Determination of Sb(III) using an ex-situ bismuth screen-printed carbon electrode by adsorptive stripping voltammetry. AB - The determination of Sb(III) on an ex-situ bismuth screen-printed carbon electrode (ex-situ BiSPCE) by means of adsorptive stripping voltammetry (AdSV) using quercetin-5'-sulfonic acid as chelating agent was optimized. The effect of different experimental parameters such pH, ligand concentration (CQSA), accumulation potential (Eacc) and accumulation time (tacc) were studied to obtain a wide linear range, the highest sensitivity and the lowest detection limit. Ex situ BiSPCE was analytically compared with a sputtered bismuth screen-printed electrode (BispSPE) under optimal conditions. The obtained analytical parameters suggest that ex-situ BiSPCE behaves much better than BispSPE and the first was selected for this study. Optimal parameters were pH=4.6; CQSA=10.0 to 20.0*10( 6)molL(-1); Eacc=-0.5V and tacc=60s. Peak area is proportional to Sb(III) concentration up to 100.0MUgL(-1) (tacc 60s) and 45.0MUgL(-1) (tacc 120s) range, with detection limits of 1.2MUgL(-)(1) (tacc 60s) and 0.8MUgL(-1) (tacc 120s). The relative standard deviation for a Sb(III) solution (20.0MUgL(-1)) was 3.9% for ten successive assays. Thus, the effect of various interfering metal ions was studied and the methodology was validated using a spiked groundwater reference material with very satisfactory results. PMID- 27216653 TI - Characterization of soil organic matter with different degrees of humification using evolved gas analysis-mass spectrometry. AB - Evolved gas analysis-mass spectrometry (EGA-MS) provides a direct connection between the pyrolyzer and mass spectrometer through a deactivated capillary tube, and provides both a thermal profile relating to the differential thermogravimetric curve of the sample and a mass spectrum of evolved gas from the sample. In this study, EGA-MS was performed to obtain thermal profiles and identify the pyrolysis products of 12 humic acids (HAs) with different degrees of humification extracted from 5 Andisols, 3 Entisols, and 3 Inceptisols, as well as soil samples. All HAs were thermally decomposed gradually over a wide temperature range (100-700 degrees C), and the EGA curves showed four peaks and shoulders at around 250, 350, 450, and 550 degrees C. The peaks at around 550 degrees C were observed for the Andisol HAs only. Carboxyl groups, carbohydrates, and short chain alkanes and alkenes of the HAs and bulk soil samples evolved at a relatively low-temperature region (200-300 degrees C). On the other hand, aromatics including benzenes and lignin derivatives evolved at a relatively high temperature region (300-600 degrees C). While the shapes of the EGA curves were different between the soils and extracted HAs, the major components of the evolved gas and the pyrolysis behavior of the constituents in the HAs and soil samples were similar. The amount of evolved gas from the Andisol HAs, which mainly consisted of CO2, was very low in comparison to that from the Entisol and Inceptisol HAs. The amount of evolved gas and the molecular weight of the pyrolysis products decreased as humification progressed, but the proportion of CO2 in the total area of the EGA curves increased. The results demonstrated that humification reduces the proportion of volatile components and increases the amount of carboxyl groups. As a result, the molecular structure of HAs is found to be mainly composed of non-volatile components and carboxyl groups. Since EGA MS can provide information about the chemical structure and pyrolysis characteristics of a small sample without pretreatment, it is a useful tool for soil organic matter research. PMID- 27216654 TI - Preconcentration and determination of vanadium and molybdenum in milk, vegetables and foodstuffs by ultrasonic-thermostatic-assisted cloud point extraction coupled to flame atomic absorption spectrometry. AB - A new ultrasonic-thermostatic-assisted cloud point extraction procedure (UTA-CPE) was developed for preconcentration at the trace levels of vanadium (V) and molybdenum (Mo) in milk, vegetables and foodstuffs prior to determination via flame atomic absorption spectrometry (FAAS). The method is based on the ion association of stable anionic oxalate complexes of V(V) and Mo(VI) with [9 (diethylamino)benzo[a]phenoxazin-5-ylidene]azanium; sulfate (Nile blue A) at pH 4.5, and then extraction of the formed ion-association complexes into micellar phase of polyoxyethylene(7.5)nonylphenyl ether (PONPE 7.5). The UTA-CPE is greatly simplified and accelerated compared to traditional cloud point extraction (CPE). The analytical parameters optimized are solution pH, the concentrations of complexing reagents (oxalate and Nile blue A), the PONPE 7.5 concentration, electrolyte concentration, sample volume, temperature and ultrasonic power. Under the optimum conditions, the calibration curves for Mo(VI) and V(V) are obtained in the concentration range of 3-340ugL(-1) and 5-250ugL(-1) with high sensitivity enhancement factors (EFs) of 145 and 115, respectively. The limits of detection (LODs) for Mo(VI) and V(V) are 0.86 and 1.55ugL(-1), respectively. The proposed method demonstrated good performances such as relative standard deviations (as RSD %) (<=3.5%) and spiked recoveries (95.7-102.3%). The accuracy of the method was assessed by analysis of two standard reference materials (SRMs) and recoveries of spiked solutions. The method was successfully applied into the determination of trace amounts of Mo(VI) and V(V) in milk, vegetables and foodstuffs with satisfactory results. PMID- 27216655 TI - Quantitative determination based on the differences between spectra-temperature relationships. AB - In the Near-infrared (NIR) spectral measurement it is not always possible to keep the experimental conditions constant. The fluctuations in external variables, such as temperature, will result in a nonlinear shift and a broadening of the spectral bands. In this study, the temperature-induced spectral variation coefficient (TSVC) was obtained by using loading space standardization (LSS). The relationship between TSVC and normalized squared temperature was quantitatively analyzed and applied to the quantitative determination of the compositions in mixtures. NIR spectra of peanut-soy-corn oil mixtures measured at seven temperatures were analyzed. It was found that, the relationship between TSVC and normalized squared temperature can be established by using LSS. Furthermore, the quantitative determination of the compositions in a mixture can be achieved by using the difference between the relationships, i.e., the slope of the relationship. The calibration curves between slope and composition volume are found to be reliable with the correlation coefficients (R(2)) as high as 0.9992. Quantitative determination by the calibration curves were also validated. Therefore, the method can be an effective tool for investigating the effect of temperature and quantitatively analysis. PMID- 27216656 TI - An evaluation of the impact of urban air pollution on paint dosimeters by tracking changes in the lipid MALDI-TOF mass spectra profile. AB - We evaluated the impact of urban air pollution on egg yolk tempera paint dosimeters (binary mixture samples made with historic artist's blue, red and white pigments) by tracking changes over time in their lipid matrix-assisted laser desorption ionization time-of-flight mass spectra (MALDI-TOF-MS) profiles. We studied triacylglycerols (TGs), phospholipids (PLs) and their oxidation by products from paint dosimeters that had been exposed outdoors for six months to the polluted atmosphere in the city center of Granada (Spain). Four types of chickens' eggs were also analyzed to find out whether their lipid mass spectra (lipid fingerprints) varied significantly. The ultimate goal of this research is to provide a precise analytical protocol to show whether the changes in the egg yolk identified in paint dosimeters are due to pigment-binder interactions. The Bligh-Dyer (BD) method was optimized for the extraction of the lipids. This innovative procedure included a washing-step prior to the mass spectrometric analysis, which proved crucial for obtaining higher quality lipid fingerprints. A novel interpretation of the results is proposed by applying the BD method, which suggests that transesterification processes occurred in the lipid fractions that were catalyzed by the pigments in the paint dosimeters. In blank dosimeters specific ions produced by oxidative cleavage of PLs and/or TGs may be used as markers of the presence of egg yolk binders. The composition and structure of the specific lipid compounds are also tentatively proposed. In aged dosimeters the intact content of the TGs and PLs decreased; however, we propose that short-chain oxidative products arising from TGs and PLs are present in all the samples, except for the white lead based dosimeter. We end with a new explanation as to why this dosimeter behaves differently from the others. PMID- 27216657 TI - High fluorescence S, N co-doped carbon dots as an ultra-sensitive fluorescent probe for the determination of uric acid. AB - Sulfur, nitrogen co-doped carbon dots (S, N co-doped C-dots) as highly selective fluorescent probe for uric acid (UA) detection were designed. The S, N co-doped C dots with high quantum yield of 73.1% were prepared by hydrothermal method. It was found that the fluorescence of S, N co-doped C-dots was quenched apparently by hydroxyl radicals from Fenton reaction between H2O2 and Fe(2+). The production of H2O2 originated from the oxidization of UA by uricase. Therefore, an optical biosensor was developed for the detection of UA based on Fenton reaction and enzymatic reaction. Under the optimized conditions, two linear relationships between the ratio of fluorescence quenching of the C-dots and UA concentration were found in the range of 0.08-10uM and 10-50uM, respectively. The detection limit was down to 0.07uM. Moreover, the proposed biosensor was successfully applied to the detection of uric acid in human serum samples. PMID- 27216658 TI - A versatile method for analysis of saliva, plasma and urine for total thiols using HPLC with UV detection. AB - A simple and rapid HPLC method using 2-chloro-1-methyllepidinium tetrafluoroborate (CMLT) as a derivatization reagent was developed for simultaneous determination of homocysteine (Hcy), glutathione (GSH), gamma glutamylcysteine (gamma-GluCys), cysteinylglycine (CysGly), N-acetylcysteine (NACys) and cysteine (Cys) in human saliva, plasma and urine. Separation of the analytes was achieved in just 7min using an HPLC, followed by UV detection at 355nm. Chromatographic separation was accomplished on Aeris PEPTIDE XB-C18 (150mm*4.6mm, 3.6um) column from Phenomenex with a gradient elution: 0-4.0min, 7 30% B; 4.0-5.5min, 30-7% B; 5.5-7.5min, 7% B; (A: B, v/v); (A) 0.5% CH3COOH and (B) EtOH. Mobile phase was delivered at a flow rate 1.0mLmin(-1). Linearity in detector response for total thiols was observed over the range of 0.1-20MUmolL( 1) for Hcy, GSH and gamma-GluCys, 0.25-50MUmolL(-1) for NACys and CysGly and 5 300 for Cys. The LOQ values for Hcy, GSH, gamma-GluCys, NACys, CysGly and Cys were 0.05, 0.05, 0.10, 0.06, 0.12 and 0.08MUmolL(-1), respectively. The method was successfully implemented to analysis of the samples donated by 15 apparently healthy volunteers and 10 patients. PMID- 27216659 TI - Fast and efficient proteolysis by reusable pepsin-encapsulated magnetic sol-gel material for mass spectrometry-based proteomics applications. AB - Hydrophobic silicon-based material having magnetic properties was fairly synthesized by a classical sol-gel approach. Pepsin enzyme was encapsulated in the sol-gel material and the enzyme activity was evaluated in consequence of the digestion of some common proteins such as alpha- and beta-casein, cytochrome c, myoglobin, and bovine serum albumin (BSA) both in a single protein batch and in the protein mixture. The optimum digestion time of the studied proteins using pepsin-encapsulated magnetic sol-gel material was found to be 20min. To produce the magnetic sol-gel material for convenient and easy proteomics applications, Fe3O4 was doped inside sol-gel material during the gelation step. It was observed that the activity of encapsulated pepsin was not affected by the amount of Fe3O4. Poly(ethylene glycol) was also inserted in sol-gel bulk to obtain suitable roughness and increase the hydrophilicity of the material surface to let protein molecules reach to the sol-gel material easily. The digestion of the protein mixture and non-fat bovine milk was performed with the pepsin-encapsulated magnetic sol-gel material and the digested solutions were analyzed using SDS PAGE, MALDI-TOF-MS and LC-MS/MS for the protein identification. Reusability of the pepsin-encapsulated sol-gel material was examined and it was determined that they could be used at least 20 times. Finally, IgG digestions with a fast incubation time period were carried out using pepsin-encapsulated sol-gel material for generation of (Fab)2 product to evaluate the kinetic performance of the material. PMID- 27216660 TI - Derivatization reaction-based surface-enhanced Raman scattering (SERS) for detection of trace acetone. AB - A facile method was developed for determination of trace volatile acetone by coupling a derivatization reaction to surface-enhanced Raman scattering (SERS). With iodide modified Ag nanoparticles (Ag IMNPs) as the SERS substrate, acetone without obvious Raman signal could be converted to SERS-sensitive species via a chemical derivatization reaction with 2,4-dinitrophenylhydrazine (2,4-DNPH). In addition, acetone can be effectively separated from liquid phase with a purge sampling device and then any serious interference from sample matrices can be significantly reduced. The optimal conditions for the derivatization reaction and the SERS analysis were investigated in detail, and the selectivity and reproducibility of this method were also evaluated. Under the optimal conditions, the limit of detection (LOD) for acetone was 5mgL(-1) or 0.09mM (3sigma). The relative standard deviation (RSD) for 80mgL(-1) acetone (n=9) was 1.7%. This method was successfully used for the determination of acetone in artificial urine and human urine samples with spiked recoveries ranging from 92% to 110%. The present method is convenient, sensitive, selective, reliable and suitable for analysis of trace acetone, and it could have a promising clinical application in early diabetes diagnosis. PMID- 27216661 TI - Volatile methylsiloxanes in personal care products - Using QuEChERS as a "green" analytical approach. AB - Organosiloxanes, namely volatile methylsiloxanes (VMSs) are one of the most relevant classes of ingredients incorporated in personal care products (PCPs), such as creams and lotions, bath soaps and hair care products. Their use has caused concern among the scientific community due to their potential toxic behaviour to human health and environment. This manuscript reports the first application of QuEChERS ("Quick, Easy, Cheap, Effective, Rugged and Safe") extraction followed by gas chromatography - mass spectrometry analysis to determine VMSs in cosmetics and personal care products. Eight VMSs, four linear (L2-L5) and four cyclic (D3-D6) were investigated in 36 samples. The validated method was able to remove the interfering matrix components, conducting to high recovery percentages (74-104%) and low relative standard deviations (<18%). A linear behaviour was observed in the range of 0.005-2.50mgL(-1) (correlation coefficient, R(2)>0.996) and limits of detection ranged from 0.17ngg(-1) (L2) to 3.75ngg(-1) (L5). Matrix effects were also investigated for all analysed compounds and matrices and showed not to be significant. Global uncertainty of the proposed methodology was also estimated using a bottom-up approach being between 5% and 35% (on average). Finally, the method was satisfactorily applied to the analysis of 36 personal care products. As expected, results showed the existence of VMSs in all analysed samples in concentrations up to 754ugg(-1). D4 and D5 were more frequently detected while body moisturizers, facial creams and shampoos showed the highest levels of VMSs. PMID- 27216662 TI - Laser induced breakdown spectroscopy for the discrimination of Candida strains. AB - The present study reports the evaluation of Laser Induced Breakdown Spectroscopy (LIBS) and Neural Networks (NN) for the discrimination of different strains of various species of Candida. This genus of yeast was selected due to its medical relevance as it is commonly found in cases of fungal infection in humans. Twenty one strains belonging to seven species of Candida were included in the study. Scanning Electron Microscopy with Energy-Dispersive X-ray Spectroscopy (SEM-EDS) was employed as a complementary technique to provide information about elemental composition of Candida cells. The use of LIBS spectra in combination with optimized NN models provided reliable discrimination among the distinct Candida strains with a high spectral correlation index for the samples analyzed, without any false positive or false negative. Therefore, this study indicates that LIBS NN based methodology has the potential to be used as fast fungal identification or even diagnostic method. PMID- 27216663 TI - Quantitative determinations and imaging in different structures of buried human bones from the XVIII-XIXth centuries by energy dispersive X-ray fluorescence - Postmortem evaluation. AB - In this work, a non-commercial triaxial geometry energy dispersive X-ray Fluorescence (EDXRF) setup and a benchtop u-XRF system were used to identify postmortem contamination in buried bones. For two of the individuals, unusually high concentrations of Cu and Pb, but also Zn (in one individual) were observed. The pigments of the burial shroud coverings have been identified as the source of contamination. Accurate and precise quantitative results were obtained by nondestructive process using fundamental parameters method taking into account the matrix absorption effects. A total of 30 bones from 13 individuals, buried between the mid-XVIIIth to early XIXth centuries, were analyzed to study the elemental composition and elemental distribution. The bones were collected from a church in Almada (Portugal), called Ermida do Espirito Santo, located near the Tagus River and at the sea neighbourhood. The triaxial geometry setup was used to quantify Ca, Fe, Cu, Zn, Br, Sr and Pb of powder pressed bone pellets (n=9 for each bone). Cluster analysis was performed considering the elemental concentrations for the different bones. There was a clear association between some bones regarding Fe, Cu, Zn, Br and Pb content but not a categorization between cortical and trabecular bones. The elemental distribution of Cu, Zn and Pb were assessed by the benchtop MU-analysis, the M4 Tornado, based on a polycapillary system which provides multi-elemental 2D maps. The results showed that contamination was mostly on the surface of the bone confirming that it was related to the burial shroud covering the individuals. PMID- 27216664 TI - Prediction of olive oil sensory descriptors using instrumental data fusion and partial least squares (PLS) regression. AB - Headspace-Mass Spectrometry (HS-MS), Fourier Transform Mid-Infrared spectroscopy (FT-MIR) and UV-Visible spectrophotometry (UV-vis) instrumental responses have been combined to predict virgin olive oil sensory descriptors. 343 olive oil samples analyzed during four consecutive harvests (2010-2014) were used to build multivariate calibration models using partial least squares (PLS) regression. The reference values of the sensory attributes were provided by expert assessors from an official taste panel. The instrumental data were modeled individually and also using data fusion approaches. The use of fused data with both low- and mid-level of abstraction improved PLS predictions for all the olive oil descriptors. The best PLS models were obtained for two positive attributes (fruity and bitter) and two defective descriptors (fusty and musty), all of them using data fusion of MS and MIR spectral fingerprints. Although good predictions were not obtained for some sensory descriptors, the results are encouraging, specially considering that the legal categorization of virgin olive oils only requires the determination of fruity and defective descriptors. PMID- 27216665 TI - Qualitative and quantitative spectro-chemical analysis of dates using UV-pulsed laser induced breakdown spectroscopy and inductively coupled plasma mass spectrometry. AB - Laser Induced Breakdown Spectroscopy (LIBS) is demonstrated for the spectral analysis of nutritional and toxic elements present in several varieties of date fruit samples available in the Saudi Arabia market. The method analyzes the optical emission of a test sample when subjected to pulsed laser ablation. In this demonstration, our primary focus is on calcium (Ca) and magnesium (Mg), as nutritional elements, and on chromium (Cr), as a toxic element. The local thermodynamic equilibrium (LTE) condition was confirmed prior to the elemental characterization of date samples to ensure accuracy of the LIBS analysis. This was achieved by measuring parameters associated with the plasma, such as the electron temperature and the electron number density. These plasma parameters aid interpretation of processes such as ionization, dissociation, and excitation occurring in the plasma plume formed by ablating the date palm sample. The minimum detection limit was established from calibration curves that involved plotting the LIBS signal intensity as a function of standard date samples with known concentrations. The concentration of Ca and Mg detected in different varieties of date samples was between 187 and 515 and 35-196mgL(-1) respectively, while Cr concentration measured between 1.72 and 7.76mgL(-1). In order to optimize our LIBS system, we have studied how the LIBS signal intensity depends on the incident laser energy and the delay time. In order to validate our LIBS analysis results, standard techniques such as inductively coupled plasma mass spectrometry (ICP-MS) were also applied on an identical (duplicate) date samples as those used for the LIBS analysis. The LIBS results exhibit remarkable agreement with those obtained from the ICP-MS analysis. In addition, the finger print wavelengths of other elements present in date samples were also identified and are reported here, which has not been previously reported, to the best of our knowledge. PMID- 27216666 TI - Experimental variability and data pre-processing as factors affecting the discrimination power of some chemometric approaches (PCA, CA and a new algorithm based on linear regression) applied to (+/-)ESI/MS and RPLC/UV data: Application on green tea extracts. AB - The influence of the experimental variability (instrumental repeatability, instrumental intermediate precision and sample preparation variability) and data pre-processing (normalization, peak alignment, background subtraction) on the discrimination power of multivariate data analysis methods (Principal Component Analysis -PCA- and Cluster Analysis -CA-) as well as a new algorithm based on linear regression was studied. Data used in the study were obtained through positive or negative ion monitoring electrospray mass spectrometry (+/-ESI/MS) and reversed phase liquid chromatography/UV spectrometric detection (RPLC/UV) applied to green tea extracts. Extractions in ethanol and heated water infusion were used as sample preparation procedures. The multivariate methods were directly applied to mass spectra and chromatograms, involving strictly a holistic comparison of shapes, without assignment of any structural identity to compounds. An alternative data interpretation based on linear regression analysis mutually applied to data series is also discussed. Slopes, intercepts and correlation coefficients produced by the linear regression analysis applied on pairs of very large experimental data series successfully retain information resulting from high frequency instrumental acquisition rates, obviously better defining the profiles being compared. Consequently, each type of sample or comparison between samples produces in the Cartesian space an ellipsoidal volume defined by the normal variation intervals of the slope, intercept and correlation coefficient. Distances between volumes graphically illustrates (dis)similarities between compared data. The instrumental intermediate precision had the major effect on the discrimination power of the multivariate data analysis methods. Mass spectra produced through ionization from liquid state in atmospheric pressure conditions of bulk complex mixtures resulting from extracted materials of natural origins provided an excellent data basis for multivariate analysis methods, equivalent to data resulting from chromatographic separations. The alternative evaluation of very large data series based on linear regression analysis produced information equivalent to results obtained through application of PCA an CA. PMID- 27216667 TI - Water monitoring by optofluidic Raman spectroscopy for in situ applications. AB - The feasibility of water monitoring by Raman spectroscopy with a portable optofluidic system for in-situ applications has been successfully demonstrated. In the proposed approach, the sample under analysis is injected into a capillary nozzle in order to produce a liquid jet that acts as an optical waveguide. This jet waveguide provides an effective strategy to excite and collect the Raman signals arising from water contaminants due to the high refractive index difference between air and water. The proposed approach avoids any necessity of liquid container or flow cell and removes any background signal coming from the sample container commonly affects Raman measurements. Furthermore, this absence is a significant advantage for in situ measurements where fouling problems can be relevant and cleaning procedures are troublesome. The extreme simplicity and efficiency of the optical scheme adopted in our approach result in highly sensitive and rapid measurements that have been performed on different representative water pollutants. The experimental results demonstrate the high potentiality of our device in water quality monitoring and analysis. In particular, nitrate and sulfate are detected below the maximum contamination level allowed for drinking water, whereas a limit of detection of 40mg/l has been found for benzene. PMID- 27216668 TI - Disposable sensor for electrochemical determination of chloride ions. AB - This work describes the development of a new, simple and inexpensive method for the determination of chloride ions, by using voltammetric disposable sensors. The sensor includes three screen printed electrodes: a working, an auxiliary (both carbon based paste electrodes), and a pseudo-reference Ag/AgCl paste based electrode. Since the presence of chloride ions in the solution modifies the equilibrium potential of Ag/AgCl electrode, the concentration of this analyte has been determined through the systematic shift of the voltammetric peak potential of a control species such as potassium ferricyanide, potassium ferrocyanide or ferrocenemethanol. These control species can be used in solution or mixed into the carbon paste of the working screen printed electrode. In order to characterize the developed methods, reproducibility, repeatability and detection limit of the sensors were calculated in each case. Reproducibility values below 3% (n=5) were obtained. When ferrocenemethanol was used as control species, the lowest quantity of chloride ions detected was 10.0mM. A comprehensive study of interfering ions was also carried out. These sensors were successfully applied to determine the chloride content in sea water and in a commercial saline solution sample. PMID- 27216669 TI - Chemically modified carbon paste and membrane sensors for the determination of benzethonium chloride and some anionic surfactants (SLES, SDS, and LABSA): Characterization using SEM and AFM. AB - Chemically modified carbon-paste (CMCP) and membrane- sensors based on incorporating benzothonium-tetraphenylborate (BT-TPB) were constructed for the analysis of benzethonium chloride, and some other surfactants such as sodium lauryl ether sulphate (SLES), sodium dodecyl sulphate (SDS), and linear alkylbenzene sulphonic acid (LABSA). All sensors showed good sensitivity and reverse wide linearity over a concentration range of 5.97*10(-7) to 1.00*10(-3) and 5.96*10(-7) to 3.03*10(-3)molL(-1) with limit of detection of 3.92*10(-7)and 3.40*10(-7)molL(-1) for membrane and chemically modified carbon paste sensors, respectively, with respect to benzethonium chloride (BT.Cl). They could be used over a wide pH range of 2.0-10.0. The thermal coefficients of membrane and CMCP sensors are 5.40*10(-4), 1.17*10(-4)V/ degrees C, respectively. The sensors indicated a wide selectivity over different inorganic cations. The effect of soaking on the surface morphology of the membrane sensor was studied using EDX SEM and AFM techniques. The response time was <10s The freshly prepared, exhausted membrane, and CMCP sensors were successfully applied for the potentiometric determination of the pure BT.Cl solution. They were also used for the determination of its pharmaceutical formulation Dermoplast((r)) antibacterial spray (20% benzocaine+0.2% benzethonium chloride) with recovery values ranging from 97.54+/-1.70 to 101.25+/-1.12 and from 96.32+/-2.49 to 101.23+/-2.15%. The second goal of these sensors is the potentiometric determination of different surfactants such as SLES, SDS, and LABSA with good recovery values using BT.Cl as a titrant in their pure forms, and in samples containing one of them (shampoo, Touri((r)) dishwashing liquid, and waste water). The statistical analysis of the obtained data was studied. PMID- 27216670 TI - Ultra-sensitive "turn-on" detection method for Hg(2+) based on mispairing biosensor and emulsion PCR. AB - Sensor-based detection methods have inspired the idea that chemical or physical signals could be converted to nucleic acid signals to be quantitatively detected using a combination of appropriate detection tools. To achieve ultra-sensitive and absolute quantitative detection of mercury ion (Hg(2+)), we have combined a mispairing biosensor for Hg(2+) and emulsion PCR. The parameters that might influence the biosensor step, such as the duration of isothermal amplification and the concentration of the sensor oligonucleotide, have been firstly optimized in our study to achieve the most efficient biosensor detection. The evaluation results of secondary structures between the biosensors with different number of T Hg-T structures achieved by Circular Dichroism have indicated that the secondary hairpin structure would be varied according to the change of number of T-Hg-T structures, which could influence the quantitative detection results. Further optimization of number of T-Hg-T within the biosensor sequences showed that 5 T Hg-T structures could generate the most efficient amplification. After the above optimizations, the emulsion PCR has been employed to achieve the absolute quantitation of nucleic acid signals. The final results have shown that the limit of quantitation (LOQ) in our study was as low as 40fmol, and the limit of detection (LOD) was 10fmol. The practical detection tests showed that the quantitative results were stable and accurate for all substrates. In conclusion, by combining a mispairing biosensor with emulsion PCR, we developed a flexible and stable quantitative "turn-on" detection method with ultra-sensitivity that can detect trace amounts Hg(2+) within different substrates. PMID- 27216671 TI - A novel and cost-effective method for the determination of fifteen polycyclic aromatic hydrocarbons in low volume rainwater samples. AB - A novel single-step method was developed for the determination of 15 polycyclic aromatic hydrocarbons (PAHs) at ultratrace levels in rainwater by on-line in-tube solid-phase microextraction (IT-SPME) coupled to high-performance liquid chromatography-photodiode array-fluorescence detection. This paper is focused on a study of the IT-SPME coupling and optimization, its application to rainwater and other environmental waters and the stability of PAH rainwater solutions. In order to solve the different extractive behavior of PAHs, several IT-SPME parameters were optimized, with the type and percentage of organic modifier playing a decisive role. In the kinetic study on stability of PAH solutions, the organic modifier has proven to be effective as a preservative, avoiding the loss of the higher-molecular weight PAHs. The proposed method presents a wide interval of linearity (10-1500ngL(-1)) and a good relative standard deviation between 3.4% and 14.6% for the PAHs analyzed. Detection and quantification limits between 2.3 and 28ngL(-1) and 5.7 and 65ngL(-1) were obtained respectively, taking into account the values of the procedure blanks. Recoveries for different kinds of real water samples were within the range of 72-110%. Low and medium-molecular weight PAHs predominate in daily and monthly rainwater samples analyzed. In comparison with other methods reported, the proposed method achieves a significant reduction of the sample volume, the organic solvent consumption and time of sample treatment, allowing a cost-effective analysis of environmental waters. The method is especially suitable for samples from the precipitation events of low intensity or short duration for which sample volume is limiting. PMID- 27216672 TI - Application of the PASSIL technique for the passive sampling of exemplary polar contaminants (pharmaceuticals and phenolic derivatives) from water. AB - Ionic liquids (ILs) are one of the very promising media for the passive sampling of organic contaminants in water. These compounds offer a wide range of interactions with various analytes and give possibilities to control analyte properties by altering their structures, but most of all, possess a high polarity independent of the water solubility. Recently, some ILs were successfully applied as the receiving phase in the passive sampling of polyaromatic hydrocarbons, and this approach was acronymized to PASSIL. In this paper, we aimed to verify the applicability of the PASSIL technique for the selective extraction and enrichment of polar and semi-polar compounds from aqueous environments. The test kit of analytes comprised selected pharmaceuticals and phenol-type compounds, while the applied ILs were alkylimidazolium- and alkylphosphonium entities with a variety of anions. The 14-day-long experiments were performed in static and semi-static no-renewal systems. The kinetics of the uptake process, the analyte extraction efficiency and the sampling rates for all analytes were determined. One of the tested ionic liquids [P666-14][N(CN)2] presented very promising properties both as a stable medium between polyethersulfone (PES) membranes as well as a highly effective extraction phase. The uptake kinetics of the analytes and the determined sampling rates confirm the better and faster efficiency of PASSIL extraction when compared to commercially available passive samplers. Additionally, some selectivity was observed during analyte extraction, which results from the specific interaction between the IL and analytes, but not from the lipophilicity or ionization state of the analytes. These very promising findings make the PASSIL approach a very promising and competitive analytical tool for the extraction of environmental contaminants over a wide polarity range. PMID- 27216673 TI - Chromatic analysis by monitoring unmodified silver nanoparticles reduction on double layer microfluidic paper-based analytical devices for selective and sensitive determination of mercury(II). AB - This study demonstrates chromatic analysis based on a simple red green blue (RGB) color model for sensitive and selective determination of mercury(II). The analysis was performed by monitoring the color change of a microfluidic Paper based Analytical Device (uPAD). The device was fabricated by using alkyl ketene dimer (AKD)-inkjet printing and doped with unmodified silver nanoparticles (AgNPs) which were disintegrated when being exposed to mercury(II). The color intensity was detected by using an apparatus consisting of a digital camera and a homemade light box generating constant light intensity. A progressive increase in color intensity of the tested area on the uPAD (3.0mm) was observed with increasing mercury(II) concentration. The developed system enabled quantification of mercury(II) at low concentration with the detection limit of 0.001mgL(-1) (3 SD blank/slope of the calibration curve) and small sample volume uptake (2uL). The linearity range of the calibration curve in this technique was demonstrated from 0.05 to 7mgL(-1) (r(2)=0.998) with good precision (RSD less than 4.1%). Greater selectivity towards mercury(II) compared with potential interference ions was also observed. Furthermore, the percentage recoveries of spiked water samples were in an acceptable range which was in agreement with the values obtained from the conventional method utilizing cold vapor atomic absorption spectrometer (CVAAS). The proposed technique allows a rapid, simple, sensitive and selective analysis of trace mercury(II) in water samples. PMID- 27216674 TI - Multicomponent blood lipid analysis by means of near infrared spectroscopy, in geese. AB - This study provides accurate near infrared (NIR) spectroscopic models on some laboratory determined clinicochemical parameters (i.e. total lipid (5.57+/-1.95 g/l), triglyceride (2.59+/-1.36 mmol/l), total cholesterol (3.81+/-0.68 mmol/l), high density lipoprotein (HDL) cholesterol (2.45+/-0.58 mmol/l)) of blood serum samples of fattened geese. To increase the performance of multivariate chemometrics, samples significantly deviating from the regression models implying laboratory error were excluded from the final calibration datasets. Reference data of excluded samples having outlier spectra in principal component analysis were not marked as false. Samples deviating from the regression models but having non outlier spectra in PCA were identified as having false reference constituent values. Based on the NIR selection methods, 5% of the reference measurement data were rated as doubtful. The achieved models reached R(2) of 0.864, 0.966, 0.850, 0.793, and RMSE of 0.639 g/l, 0.232 mmol/l, 0.210 mmol/l, 0.241 mmol/l for total lipid, triglyceride, total cholesterol and HDL cholesterol, respectively, during independent validation. Classical analytical techniques focus on single constituents and often require chemicals, time-consuming measurements, and experienced technicians. NIR technique provides a quick, cost effective, non hazardous alternative method for analysis of several constituents based on one single spectrum of each sample, and it also offers the possibility for looking at the laboratory reference data critically. Evaluation of reference data to identify and exclude falsely analyzed samples can provide warning feedback to the reference laboratory, especially in the case of analyses where laboratory methods are not perfectly suited to the subjected material and there is an increased chance of laboratory error. PMID- 27216675 TI - Suicide inactivation of covalent peroxidase-mimicking DNAzyme with hydrogen peroxide and its protection by a reductant substrate. AB - Recently a covalent peroxidase-mimicking DNAzyme (cPMDNAzyme) with the improved catalytic activity was prepared. Here we demonstrate that hydrogen peroxide, the oxidant substrate of cPMDNAzyme is an inactivating agent of this catalyst. Presence of the reductant substrate, 2,2'-azino-bis(3-ethylbenthothiazoline-6 sulfonic acid (ABTS) prevents the inactivation of cPMDNAzyme. The experimental conditions (pH-optimum, concentrations of ABTS and H2O2) for the determination of cPMDNAzyme activity were optimized that allows a construction of the colorimetric cPMDNAzyme-based biosensors and assays with improved sensitivity. PMID- 27216676 TI - A preconcentration method for analysis of neonicotinoids in honey samples by ionic liquid-based cold-induced aggregation microextraction. AB - A preconcentration approach based on ionic liquid-based cold-induced aggregation microextraction for determination of neonicotinoid insecticide residues in honey samples before high-performance liquid chromatographic analysis has been developed. Room temperature ionic liquid [C4MIM][PF6] (extraction solvent) and SDS (emulsifier) was used for extraction of the target analytes. The parameters affecting the extraction efficiency were optimized. The optimum microextraction conditions were 200uL room temperature ionic liquids [C4MIM][PF6] containing 0.05molL(-1) SDS, 0.75g sodium carbonate, vortex agitation speed of 1800rpm for 30s and centrifugation at 3500rpm for 10min. Under optimum conditions, the high enrichment factors of 200 could be obtained, leading to low limit of detection (0.01ugL(-1) for all analytes) with the relative standard deviations lower than 2.68% and 5.38% for retention time and peak area, respectively. Good recoveries for the spiked target neonicotinoids at three different concentrations of honey samples were obtained in 86-100% and relative standard deviations were lower than 8.1%. The results demonstrated that the proposed method can be used as an alternative powerful method for the simultaneous determination of the studied insecticides in real honey samples. PMID- 27216677 TI - A feasibility study for producing an egg matrix candidate reference material for the polyether ionophore salinomycin. AB - The aim of this work was to study the feasibility of producing an egg matrix candidate reference material for salinomycin. Preservation techniques investigated were freeze-drying and spray drying dehydration. Homogeneity and stability studies of the produced batches were conducted according to ISO Guides 34 and 35. The results showed that all produced batches were homogeneous and both freeze-drying and spray drying techniques were suitable for matrix dehydrating, ensuring the material stability. In order to preserve the material integrity, it must be transported within the temperature range of -20 up to 25 degrees C. The results constitute an important step towards the development of an egg matrix reference material for salinomycin is possible. PMID- 27216678 TI - Redistribution of fluorescent molecules at the solid/liquid interface with total internal reflection illumination. AB - Many intriguing physical and chemical processes commonly take place at the solid/liquid interface. Total internal reflection illumination, together with single molecule spectroscopy, provides a robust platform for the selective exploration of kinetic processes close the interface. With these techniques, it was observed that the distribution of Rhodamine B molecules close to a solid/liquid interface could be regulated in a photo-induced route. The laser induced repulsion force at this interface is enough to compromise the Brownian diffusion of single molecules in a range of several hundred nanometers normal to the solid/liquid interface. This observation is fundamentally and practically interesting because moderate laser intensity is enough to initiate this repulsion effect. Therefore, it might display extensive applications in the development of photo-modulation technique with high throughput capability. PMID- 27216679 TI - Detection and mapping of trace explosives on surfaces under ambient conditions using multiphoton electron extraction spectroscopy (MEES). AB - Multiphoton electron extraction spectroscopy (MEES) is an analytical method in which UV laser pulses are utilized for extracting electrons from solid surfaces in multiphoton processes under ambient conditions. Counting the emitted electrons as a function of laser wavelength results in detailed spectral features, which can be used for material identification. The method has been applied to detection of trace explosives on a variety of surfaces. Detection was possible on dusty swabs spiked with explosives and also in the standard dry-transfer contamination procedure. Plastic explosives could also be detected. The analytical limits of detection (LODs) are in the sub pmole range, which indicates that MEES is one of the most sensitive detection methods for solid surface under ambient conditions. Scanning the surface with the laser allows for its imaging, such that explosives (as well as other materials) can be located. The imaging mode is also useful in forensic applications, such as detection of explosives in human fingerprints. PMID- 27216680 TI - DNAzyme-based biosensor for Cu(2+) ion by combining hybridization chain reaction with fluorescence resonance energy transfer technique. AB - A novel signal amplification strategy based on Cu(2+)-dependent DNAzyme was developed for sensing Cu(2+) ion by combining hybridization chain reaction (HCR) with fluorescence resonance energy transfer (FRET) technique. In the presence of Cu(2+) ion, the substrate strands of Cu(2+)-dependent DNAzyme immobilized on magnetic beads were specifically cleaved and released. The released strands initiated the HCR process of hairpin H1 and H2 labeled with FAM as the donor and TAMRA as the acceptor, respectively. Long nicked dsDNA structures were self assembled to bring the donor and the acceptor in close proximity, resulting in a FRET process. The relative ratio of fluorescent intensities of the acceptor and donor was used to quantitatively detect Cu(2+) ion with a limit of detection of 0.5nmolL(-1). This proposed biosensor was applied to detect Cu(2+) ion in tap water with satisfactory results. PMID- 27216681 TI - Dual immunosensor based on methylene blue-electroadsorbed graphene oxide for rapid detection of the influenza A virus antigen. AB - Rapid detection of influenza viral infections in poultry facilities is advantageous in several aspects such as environmental/personal safety, food security, and socio-economy. Herein, we report the development of an electrochemical-based dual-sensor platform composed of methylene blue electroadsorbed graphene oxide nanostructures modified with monoclonal antibodies against the HA proteins of H5N1 and H1N1. Bio-functional layers comprised of chitosan and protein-A molecules were implemented at the interface of the sensor element and antibodies, which synergistically enriched the bio-activity of immobilized antibodies for the immune complex formation. The differential pulse voltammetric signals resulted from the developed immunosensor platform exhibited a good correlation (R(2)=0.9978 for H1N1 and R(2)=0.9997 for H5N1) for the wide range of target concentrations 25-500pM). Chronoamperometric study also revealed the amplified current sensitivity of the immunoelectrodes even at the picomolar level. The proposed immunosensor design not only provides rapid analytical response time (<1min) but simplicity in fabrication and instrumentation, which paves an attractive platform for on-farm monitoring of viral infections. PMID- 27216682 TI - Biosensor based on electrospun blended chitosan-poly (vinyl alcohol) nanofibrous enzymatically sensitized membranes for pirimiphos-methyl detection in olive oil. AB - An ultra-sensitive electrochemical biosensor was successfully developed for rapid detection of pirimiphos-methyl in olive oil, based of genetically-engineered acetylcholinesterase (AChE) immobilization into electrospun chitosan/poly (vinyl alcohol) blend nanofibers. Due to their unique properties such as spatial structure, high porosity, and large surface area, the use of nanofibers allowed improving the biosensor response by two folds. The developed biosensor showed a good performance for detecting pirimiphos-methyl, with a limit of detection of 0.2nM, a concentration much lower than the maximum residue limit allowed set by international regulations (164nM). The biosensor was used for the detection of pirimiphos-methyl in olive oil samples after a simple liquid-liquid extraction, and the recovery rates were close to 100%. PMID- 27216683 TI - Cascade enzymatic catalysis in poly(acrylic acid) brushes-nanospherical silica for glucose detection. AB - The ultrasensitive monitoring of glucose with a fast and accurate method is significant in potential therapeutics and optimizes protein biosynthesis. Incorporation of enzyme into matrix is considered as promising candidates for constructing highly sensitive glucose-responsive systems. In this study, three dimensional poly(acrylic acid) brushes-nanospherical silica (PAA-nano silica) with high amplification capability and stability were used to covalently immobilize bienzymes for cascade enzymatic catalysis. The major advantages of PAA nano silica-bienzyme co-incorporation is that the enzymes are proximity distribution, and such close confinement both minimized the diffusion of intermediates among the enzymes in the consecutive reaction and improve the utilization efficiency of enzymes, thereby enhancing the overall reaction efficiency and specificity. Thus, this present bienzymatic biosensor shows robust signal amplification and ultrasensitivity of glucose-responsive properties with a detection limit of 0.04MUM. PMID- 27216684 TI - Dumbbell-shaped metallothionein-templated silver nanoclusters with applications in cell imaging and Hg(2+) sensing. AB - Metallothionein (MT) is a cysteine-rich, low-molecular-weight protein, which adopts a unique dumbbell-shaped structure with a stable C-terminal alpha-domain and a reactive N-terminal beta-domain. The specific configuration serves as a unique scaffold for the synthesis of ultra-small fluorescent metal nanoclusters (NCs). For the first time, MT-templated Ag NCs (MT-Ag NCs) with excellent antioxidant capacity and superior biocompatibility were facilely synthesized. The NCs were thoroughly characterized by various techniques. Zn(2+) in the beta domain was preferentially replaced by Ag(+), which was then reduced by NaBH4 to yield Ag NCs, while Zn(2+) in the alpha-domain was intactly tetrahedrally coordinated through thiolate ligands in MT. Fluorescent imaging of HeLa cells was achieved by attaching folic acid (FA) to MT-Ag NCs. Due to the strong binding capacity toward the thiolate ligands in the alpha-domain, Hg(2+) was assayed via quenching the fluorescence of Ag NCs by an energy transfer process. The methodology described herein may be extended to the synthesis of other metal NCs with potential applications in biosensing and cell imaging. PMID- 27216685 TI - Classification of biodiesel and fuel blends using gas chromatography - differential mobility spectrometry with cluster analysis and isolation of C18:3 me by dual ion filtering. AB - Fatty acid alkyl esters (FAAEs) were determined at 10-100mg/L in biodiesel and blends with petrodiesel without sample pre-treatment using gas chromatography with a tandem differential mobility detector. Selectivity was provided through chromatographic separations and atmospheric pressure chemical ionization reactions in the detector with mobility characterization of gas ions. Limits of detection were ~0.5ng with an average of 2.98% RSD for peak area precision, <=1.3% RSD for retention time precision, and <=9.2% RSD for compensation voltage precision. Biodiesel blends were classified using principal component analysis (PCA) and hierarchical cluster analysis (HCA). Unsupervised cluster analysis captured 52.72% of variance in a single PC while supervised analysis captured 71.64% of variance using Fisher ratio feature selection. Test set predictions showed successful clustering according to source or feedstock when regressed onto the training set model. Detection of the regulated substance methyl linolenate (C18:3 me) was achieved in 6-10s with a 1m long capillary column using dual ion filtering in the tandem differential mobility detector. PMID- 27216686 TI - Recent approaches to improving selectivity and sensitivity of enzyme-based biosensors for organophosphorus pesticides: A review. AB - Pesticide determination has attracted great attention due to the fact that they exhibit high acute toxicity and can cause long-term damage to the environment and human lives even at trace levels. Although classical analytical methods (including gas chromatography, high performance liquid chromatography, capillary electrophoresis and mass spectrometry) have been effectively used for analysis of pesticides in contaminated samples, they present certain limitations such as time consuming sample preparation, complexity, and the requirement of expensive instrumentation and highly skilled personnel. For these reasons, there is an expanding need for analytical methods able to provide simple, rapid, sensitive, selective, low cost and reliable detection of pesticides at trace levels. Over the past decades, acetylcholinesterase (AChE) biosensors have emerged as simple, rapid and ultra-sensitive tools for toxicity detection of pesticides in the environment and food. These biosensors have the potential to complement or replace the classical analytical methods by simplifying or eliminating sample preparation and making field-testing easier and faster with significant decrease in cost per analysis. With the recent engineering of more sensitive AChE enzymes, the development of more reliable immobilization matrices and the progress in the area of microelectronics, AChE biosensors could become competitive for multi analyte screening and soon be used for the development of portable instrumentation for rapid toxicity testing of samples. The enzymes organophosphorus hydrolase (OPH) and organophosphorus acid anhydrolase (OPAA) have also shown considerable potential in OP biosensor applications and they have been used for direct detection of OPs. This review presents the recent advances in the fabrication of enzyme biosensors for organophosphorus pesticides (OPs) and their possible applications for toxicity monitoring of organophosphorus pesticide residues in real samples. The focus will be on the different strategies for the biosensor construction, the analytical performance of the biosensors and the advantages and disadvantages of these biosensor methods. The recent works done to improve the analytical performance, sensitivity and selectivity of these biosensors will also be discussed. PMID- 27216687 TI - A FRET based aptasensor coupled with non-enzymatic signal amplification for mercury (II) ion detection. AB - In this work, the idea of incorporating a non-enzymatic signal amplification with a regular aptasensor was tested. In this proof of principle, the sensor was designed for the detection of mercury (II) ions (Hg(2+)) based on the Forster Resonance Energy Transfer (FRET), and the catalyzed hairpin assembly (CHA) technique that was used as the signal amplification method. This sensor comprised a mercury aptamer-catalyst complex (Apt-C) and two types of hairpin DNA: H1 labeled with fluorescein and H2 labeled with tetramethylrhodamine. In the presence of Hg(2+), two facing thymine bases in the mercury aptamer strand were coordinated with one mercury ion. This caused the release of the catalyst for the catalyzed hairpin assembly (CHA) reaction that turned H1 and H2 hairpins into H1 H2 hybrids. FRET was then used to report the hairpin-duplex transformation. The sensor showed excellent specificity towards Hg(2+) over other possible interfering cations present at even a 100 fold greater concentrations. It had a linear range of 10.0-200.0nM, and a good detection limit of 7.03+/-0.18nM, which is lower than the regulatory mercury limit for drinking water (10nM or 2ppb). The sensor was used to detect spiked Hg(2+) in nine real surface water samples collected from three different areas. Acceptable recoveries and small standard deviations indicated that the sensor was practically applicable, and the proposed idea to incorporate a CHA amplification in a regular aptasensor was not only feasible but beneficial. The same principles can be applied to develop sensors for various different targets. PMID- 27216688 TI - Evaluation of flow injection-solution cathode glow discharge-atomic emission spectrometry for the determination of major elements in brines. AB - A new method for the determination of major metal elements in high salinity brines was developed by solution cathode glow discharge (SCGD) with flow injection analysis (FIA). The matrix interferences of major cations and anions in brines have been evaluated. It was found that high concentration of Na(+) and K(+) could interfere each other, K(+) at a concentration of 400mgL(-1) enhanced the signal intensity of Na(+) more than 20%. The effect of the anions was observed and it was noted that the signal intensity of both Ca(2+) and Mg(2+) were suppressed significantly when the SO4(2-) reached 100mgL(-1). It was demonstrated that some low molecular weight organic substances such as formic acid, glycerol and ascorbic acid could eliminate interference of SO4(2-) even with volume percentages of 0.5%. Under the optimized condition, the proposed FIA SCGD can determine K, Na, Ca and Mg with the limits of detection of 0.49 (K), 0.14 (Na), 11 (Ca) and 5.5 (Mg) ngmL(-1). The proposed method has been successfully applied to the analysis of 5 salt lake samples and compared with those obtained with inductively coupled plasma atomic emission spectrometry (ICP AES). The advantages of small size, low energy consumption, good stability and repeatability indicated that the SCGD is promising for the determination of major ions in brine samples. PMID- 27216689 TI - 3D-printed polylactic acid supports for enhanced ionization efficiency in desorption electrospray mass spectrometry analysis of liquid and gel samples. AB - The potential of 3D printing technology was here exploited to prepare tailored polylactic acid (PLA) supports for desorption electrospray ionization (DESI) experiments. PLA rough solid supports presenting wells of different shape (i.e. cylindrical, cubic and hemispherical cavities) were designed to accommodate samples of different physical state. The potentials of such supports in terms of sample loading capacity, sensitivity, signal stability were tested by analysing a peptide (i.e. insulin) and an aminoglycoside antibiotic (i.e. gentamicin sulphate) from solution and a chitosan-based gel. The results obtained were compared with those obtained by using a traditional polytetrafluoroethylene (PTFE) support and discussed. By using PLA support on the flat side, signal intensity improved almost twice with respect to PTFE support, whereas with spherical wells a five times improved signal sensitivity and good stability (RSD<6%) were obtained for the analysis of two model molecules. Limits of detection were in the 3-10nM range and linearity was demonstrated for both analytes in the 0.05-0.5MUM range for semi-quantitative or quantitative purposes. The use of a well and the set-up of optimal source parameters allowed the analysis of samples in a gel state with good precision (RSD<10%) and accuracy (86+/-6-102+/-9%), otherwise difficult to analyse on a flat smooth surface. These findings are of great interest and stimulus to exploit the advantages of 3D printing technology for the development of devices for a DESI source, presenting different shapes or configuration as a function of the sample types. PMID- 27216690 TI - Electrocatalytic oxidation of nitrite using metal-free nitrogen-doped reduced graphene oxide nanosheets for sensitive detection. AB - Nitrite can become poisonous to animals and human beings as it can lead to generation of carcinogenic N-nitrosamines. Metal-free nitrogen-doped reduced graphene oxide (NrGO) exhibited a good electrocatalytic activity toward oxidation of nitrite with the relatively low oxidation potential of 0.68V (v.s. saturated calomel electrode), thus, a facile electrochemical sensor based on metal-free NrGO was fabricated for sensitive detection of nitrite for the first time. The novel sensor showed a wide linear concentration range from 0.5 to 5000MUM and a low detection limit of 0.2MUM at the signal-to-noise ratio of 3 with good selectivity, stability, and reproducibility. This fabricated sensor was used for the determination of nitrite in pickled garlic and river water. These results demonstrate that the facile metal-free NrGO-modified electrochemical sensor has promising applications for the determination of nitrite in food and environment. PMID- 27216692 TI - Facilitated wavelength selection and model development for rapid determination of the purity of organic spelt (Triticum spelta L.) flour using spectral imaging. AB - Based on a new approach for wavelength selection, a multispectral real-time imaging system was proposed for the staple food industry to determine the fidelity of organic spelt flour (OSF) from three categories of adulterants including rye flour (RF), organic wheat flour (OWF) and spelt flour (SF). Calibration models were first built by partial least squares discriminant analysis (PLSDA) and partial least squares regression (PLSR) with spectral pretreatment for multivariate analysis of hyperspectral image in the spectral range of 900-1700nm. Instead of qualifying certain groups of characteristic wavelengths for RF, OWF, SF and OSF separately, a set of mutual wavelengths (1145, 1192, 1222, 1349, 1359, 1396, 1541, and 1567nm) was chosen by first derivative and mean centring iteration algorithm (FMCIA) for all investigated flour samples. Then these selected feature wavelengths were utilized in PLSDA, PLSR and multiple linear regression (MLR) models to devise multispectral imaging system. Better performances for both qualitative discrimination of OSF and quantitative measure of adulterants were emerged in simplified PLSDA and PLSR models, with mean determination coefficients in cross validation (R(2)CV) of 0.958 and in prediction (R(2)P) of 0.957, respectively. To visualize the adulterants in OSF samples, the distribution maps were drawn by computing the spectral response of each pixel on corresponding spectral images at specific frequencies using a quantitative identification function. The results reveal that spectral imaging integrated with multivariate analysis has good potential for rapidly evaluating the purity of organic spelt flour. PMID- 27216691 TI - In situ analysis of lipid oxidation in oilseed-based food products using near infrared spectroscopy and chemometrics: The sunflower kernel paste (tahini) example. AB - A new near-infrared (NIR) spectroscopic method was developed for the analytical measurement of lipid oxidation in sunflower kernel paste (tahini), which was chosen as an example of a complex oilseed-based food product. The NIR spectra of sunflower tahini were acquired for the extracted fat phase (EFP) and for the intact sunflower tahini (IST) samples during controlled storage. The best peroxide value (PV) calibration models were considered suitable for quality control (ratio of performance of deviation [RPD]>5). The best PV partial least squares (PLS) model result for EFP (RPD 6.36) was obtained when using standard normal variate (SNV) and the Savitzky-Golay first derivative in the 1140-1184nm, 1388-1440nm and 2026-2194nm regions. In the case of IST spectra, the best PV models (RPD 5.23) were obtained when either multiple scattering correction (MSC) or SNV were followed by the Savitzky-Golay second derivative for the 1148-1180nm and 2064-2132nm regions. There were poor correlations between the NIR-predicted values and the reference data of the p-anisidine value (pAV) for both EFP and IST. Overall, the results obtained showed that NIR spectroscopy is an appropriate analytical tool for monitoring sunflower paste PV in situ. Due to the nonexistence of the extraction step, it demonstrates a unique and substantial advantage over presently known methods. Based on these results it is strongly recommended that, when using NIR PLS models to assess lipid oxidation in situ in similar oilseed-based food products (e.g., sesame tahini, hazelnut and cocoa liquor used for chocolate production, peanut butter, hazelnut, almond, pistachio spreads), suitable calibration sets containing samples of different particle sizes and stored at different temperatures be selected. PMID- 27216693 TI - Analysis of high-purity germanium dioxide by ETV-ICP-AES with preliminary concentration of trace elements. AB - The paper presents a combined technique of germanium dioxide analysis by inductively coupled plasma atomic emission spectrometry (ICP-AES) with preconcentration of trace elements by distilling off matrix and electrothermal (ETV) introduction of the trace elements concentrate into the ICP. Evaluation of metrological characteristics of the developed technique of high-purity germanium dioxide analysis was performed. The limits of detection (LODs) for 25 trace elements ranged from 0.05 to 20ng/g. The accuracy of proposed technique is confirmed by "added-found" ("or spiking") experiment and comparing the results of ETV-ICP-AES and ICP-AES analysis of high purity germanium dioxide samples. PMID- 27216694 TI - The role of leadership perception as a mediator between managers' self-monitoring and subordinate attitudes. AB - Although the role of social cognition in leadership perception has been emphasized frequently in recent years, research using this approach in an organizational context is rare. This study investigated subordinates' perceptions of their managers as leaders (that is, to what extent they perceive their manager as a leader) as a potential mediating factor explaining the relationship between managers' self-monitoring and their subordinates' attitudes toward their organizations. The study was carried out with middle-level managers (N = 64) and their subordinates (N = 210) from various business organizations in Turkey. Results indicate that subordinates' leadership perceptions of their managers mediate the relationship between managers' self-monitoring and their subordinates' affective and normative organizational commitment. These results provide insight into some of the antecedents and outcomes of leadership perception. PMID- 27216695 TI - All models are wrong, but some are useful: a comment on Ogden (2016). PMID- 27216696 TI - Reconstitution of synaptic Ion channels from rodent and human brain in Xenopus oocytes: a biochemical and electrophysiological characterization. AB - Disruption in the expression and function of synaptic proteins, and ion channels in particular, is critical in the pathophysiology of human neuropsychiatric and neurodegenerative diseases. However, very little is known regarding the functional and pharmacological properties of native synaptic human ion channels, and their potential changes in pathological conditions. Recently, an electrophysiological technique has been enabled for studying the functional and pharmacological properties of ion channels present in crude membrane preparation obtained from post-mortem frozen brains. We here extend these studies by showing that human synaptic ion channels also can be studied in this way. Synaptosomes purified from different regions of rodent and human brain (control and Alzheimer's) were characterized biochemically for enrichment of synaptic proteins, and expression of ion channel subunits. The same synaptosomes were also reconstituted in Xenopus oocytes, in which the functional and pharmacological properties of the native synaptic ion channels were characterized using the voltage clamp technique. We show that we can detect GABA, (RS)-alpha-Amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid, and NMDA receptors, and modulate them pharmacologically with selective agonists, antagonists, and allosteric modulators. Furthermore, changes in ion channel expression and function were detected in synaptic membranes from Alzheimer's brains. Our present results demonstrate the possibility to investigate synaptic ion channels from healthy and pathological brains. This method of synaptosomes preparation and injection into oocytes is a significant improvement over the earlier method. It opens the way to directly testing, on native ion channels, the effects of novel drugs aimed at modulating important classes of synaptic targets. Disruption in the expression and function of synaptic ion channels is critical in the pathophysiology of human neurodegenerative diseases. We here show that synaptosomes purified from rodent and human frozen brain (control and Alzheimer disease) can be studied both biochemically and functionally. This method opens the way to directly testing the effects of novel drugs on native ion channels. PMID- 27216697 TI - The defect-induced localization in many positions of the quantum random walk. AB - We study the localization of probability distribution in a discrete quantum random walk on an infinite chain. With a phase defect introduced in any position of the quantum random walk (QRW), we have found that the localization of the probability distribution in the QRW emerges. Different localized behaviors of the probability distribution in the QRW are presented when the defect occupies different positions. Given that the coefficients of the localized stationary eigenstates relies on the coin operator, we reveal that when the defect occupies different positions, the amplitude of localized probability distribution in the QRW exhibits a non-trivial dependence on the coin operator. PMID- 27216698 TI - The impact of sport on health status, psychological well-being and physical performance of adults with haemophilia. AB - BACKGROUND: There is increasing recognition that sport is important for individuals with haemophilia; however, there remains a paucity of data of the importance of this in adults, many of whom already have joint pathology related to childhood bleeds and treatment access. This multicentre, cross-sectional study presents the impact of sport on health-related quality of life (HRQoL), physical performance and clinical outcomes in adults with haemophilia. RESULTS: Fifty adults aged 35.12+/-14.7 with mild (n = 12), moderate (n = 10), or severe (n = 28) haemophilia A (70%) or B (30%) from four haemophilia centres across the United Kingdom participated in the study. A total of 64% were overweight/obese according to their BMI; median orthopaedic joint scores using the WFH Orthopaedic Joint Score (OJS) were 6 (range 0-48). On a VAS pain scale (range of 0-10), patients reported mean score of 5.66 +/- 2.4. 36% of participants reported not doing any sport, mainly due to their physical condition. However, 64% of participants reported undertaking sporting activity including contact sports, mostly twice per week in average 4 h week(-1) . Participating in sport did not have a statistically significant impact on HRQoL; except in the domain 'sport and leisure' of the Haem-A-QoL. Patients doing more sport reported significantly better HRQoL than those doing less sport (P < 0.005). Those doing sport for more than 4 h week(-1) had a significantly better physical performance than patients doing less sport (assessed with Hep-Test-Q). Encouraging physical activity and sport in older patients with haemophilia may have a direct impact on their HRQoL; thus, education about sport activity should be incorporated into routine haemophilia care. PMID- 27216699 TI - Zn, Cd, S and trace metal bioaccumulation in willow (Salix spp.) cultivars grown hydroponically. AB - Willows (Salix spp.) can be used to phytoremediate soils contaminated by Zn and Cd under certain conditions. In this study, the ability of 14 Salix cultivars to concentrate Cd, Zn and S in leaves was measured in hydroponic culture with 10 and 200 uM Cd and Zn, respectively, in the nutrient medium. The cultivars showed a wide range of biomass yields, tolerance to metals, and foliar concentrations of Zn and Cd, with some cultivars accumulating up to 1000 mg kg(-1) Zn, 70 mg kg(-1) Cd and 10,000 mg kg(-1) S with only mild phytotoxicity symptoms attributable to excess Zn. Cultivars with higher foliar Zn concentrations tended to have higher foliar Cd concentrations as well, and competition between Zn and Cd for uptake was observed. Exposure of Salix cultivars to Cd and Zn did not affect foliar concentrations of secondary metabolites such as polyphenols, but trace metal concentrations in leaves were significantly reduced (Fe and Cu) or increased (Mn) by exposure to excess Zn and Cd. Sulfur-XANES spectroscopy showed foliar S to be predominantly in highly oxidized (sulfate plus sulfonate) and reduced (thiol) forms, with oxidized S more prevalent in willows with the highest total S content. PMID- 27216700 TI - Advances in the development of complexes that contain a group 13 element chalcogen multiple bond. AB - Inorganic group 13 element (M) chalcogenides (E) based on the general formular M2E3 are ubiquitous in synthesis, catalysis and material science. The parent ME fragment which aggregates to form three dimensional networks in the condensed phase can be expected to exhibit multiple bond character between the elements. Low temperature matrix isolation techniques are required to investigate the nature of this elusive species. An alternate approach for respective studies is the synthesis of electron-precise molecular complexes that contain the ME entity and for which isolation at ambient temperature is possible. This is realized by kinetic stabilization with bulky ligands and thermodynamic stabilization using electron donor, as well as acceptor groups attached to the ME functionality (i.e. donor-acceptor stabilization). In this article we revise the literature on complex compounds that exhibit a bonding interaction between a group 13 element atom and a chalcogen atom that is reasonably to be interpreted in terms of a double- or triple bond. PMID- 27216701 TI - MicroRNA Control of p53. AB - Tumor suppressor p53 plays a central role in tumor suppression. As a transcription factor, p53 mainly exerts its tumor suppressive function through transcriptional regulation of many target genes. To maintain the proper function of p53, p53 protein level and activity are exquisitely controlled by a group of positive and negative regulators in cells. Thus, p53, its regulators, and regulated genes form a complicated p53 signaling network. microRNAs (miRNAs) are a group of endogenous small non-coding RNA molecules. miRNAs play an important role in regulation of gene expression by blocking translational protein synthesis and/or degrading target mRNAs. Recent studies have demonstrated that p53 and its network are regulated by miRNAs at multiple levels. Some miRNAs regulate the level and function of p53 through directly targeting p53, whereas some other miRNAs target regulators of p53, such as MDM2 and MDM4, to indirectly regulate the activity and function of p53. On the other hand, p53 also regulates the transcriptional expression and the biogenesis of a group of miRNAs, which contributes to the tumor suppressive function of p53. p53 is the most frequently mutated gene in human cancer. Many tumor-associated mutant p53, which have "gain of-function" activities in tumorigenesis independently of wild type p53, can regulate the expression of different miRNAs and modulate the biogenesis of specific miRNAs to promote tumorigenesis. These findings have demonstrated that miRNAs are important regulators and mediators of p53 and its signaling pathway, which highlights a pivotal role of miRNAs in the p53 network and cancer. J. Cell. Biochem. 118: 7-14, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27216702 TI - Increased in vivo effector function of human IgG4 isotype antibodies through afucosylation. AB - For some antibodies intended for use as human therapeutics, reduced effector function is desired to avoid toxicities that might be associated with depletion of target cells. Since effector function(s), including antibody-dependent cell mediated cytotoxicity (ADCC), require the Fc portion to be glycosylated, reduced ADCC activity antibodies can be obtained through aglycosylation of the human IgG1 isotype. An alternative is to switch to an IgG4 isotype in which the glycosylated antibody is known to have reduced effector function relative to glycosylated IgG1 antibody. ADCC activity of glycosylated IgG1 antibodies is sensitive to the fucosylation status of the Fc glycan, with both in vitro and in vivo ADCC activity increased upon fucose removal ("afucosylation"). The effect of afucosylation on activity of IgG4 antibodies is less well characterized, but it has been shown to increase the in vitro ADCC activity of an anti-CD20 antibody. Here, we show that both in vitro and in vivo activity of anti-CD20 IgG4 isotype antibodies is increased via afucosylation. Using blends of material made in Chinese hamster ovary (CHO) and Fut8KO-CHO cells, we show that ADCC activity of an IgG4 version of an anti-human CD20 antibody is directly proportional to the fucose content. In mice transgenic for human FcgammaRIIIa, afucosylation of an IgG4 anti-mouse CD20 antibody increases the B cell depletion activity to a level approaching that of the mIgG2a antibody. PMID- 27216704 TI - Eu/Tb codoped spindle-shaped fluorinated hydroxyapatite nanoparticles for dual color cell imaging. AB - Lanthanide doped fluorinated hydroxyapatite (FAp) nanoparticles are promising cell imaging nanomaterials but they are excited at wavelengths which do not match the light sources usually found in a commercial confocal laser scanning microscope (CLSM). In this work, we have successfully prepared spindle-shaped Eu/Tb codoped FAp nanoparticles by a hydrothermal method. Compared with single Eu doped FAp, Eu/Tb codoped FAp can be excited by a 488 nm laser, and exhibit both green and red light emission. By changing the amounts of Eu and Tb peaks, the emission in the green region (500-580 nm) can be decreased to the benefit of the emission in the red region (580-720 nm), thus reaching a balanced dual color emission. Using MC3T3-E1 cells co-cultured with Eu/Tb codoped FAp nanoparticles, it is observed that the nanoparticles are cytocompatible even at a concentration as high as 800 MUg ml(-1). The Eu/Tb codoped FAp nanoparticles are located in the cytoplasm and can be monitored by dual color-green and red imaging with a single excitation light at 488 nm. At a concentration of 200 MUg ml(-1), the cytoplasm is saturated in 8 hours, and Eu/Tb codoped FAp nanoparticles retain their fluorescence for at least 3 days. The cytocompatible Eu/Tb codoped FAp nanoparticles with unique dual color emission will be of great use for cell and tissue imaging. PMID- 27216703 TI - Photo-induced halide redistribution in organic-inorganic perovskite films. AB - Organic-inorganic perovskites such as CH3NH3PbI3 are promising materials for a variety of optoelectronic applications, with certified power conversion efficiencies in solar cells already exceeding 21%. Nevertheless, state-of-the-art films still contain performance-limiting non-radiative recombination sites and exhibit a range of complex dynamic phenomena under illumination that remain poorly understood. Here we use a unique combination of confocal photoluminescence (PL) microscopy and chemical imaging to correlate the local changes in photophysics with composition in CH3NH3PbI3 films under illumination. We demonstrate that the photo-induced 'brightening' of the perovskite PL can be attributed to an order-of-magnitude reduction in trap state density. By imaging the same regions with time-of-flight secondary-ion-mass spectrometry, we correlate this photobrightening with a net migration of iodine. Our work provides visual evidence for photo-induced halide migration in triiodide perovskites and reveals the complex interplay between charge carrier populations, electronic traps and mobile halides that collectively impact optoelectronic performance. PMID- 27216705 TI - Novel insights into iron regulation and requirement in marine medaka Oryzias melastigma. AB - Iron (Fe) is an essential trace element for marine fish. However, our knowledge of Fe requirements at different development stages of marine fish is still limited. Here, we reported the efficient Fe absorption strategies adopted by larval fish under different dietary Fe supplementary levels (i.e., 0-640 mg/kg). Biokinetically, the larval fish controlled their dietary Fe assimilation efficiency (AE, 1.6-18.5%), and enhanced their waterborne Fe uptake (ca. 2.5 fold change of uptake rate constant) once the dietary Fe was deficient (i.e., 27.4 mg Fe/kg feed). Transcriptionally, the expression of hepcidin1 (hep1; Fe regulator; i.e., 2.3-15.7 fold change) in larval fish was positively correlated with the Fe supplementary levels. Comparatively, the female adult fish were poor in assimilating the added Fe source (i.e., ferric form) with similar life sustainable levels of Fe (i.e., 0.046-0.12 MUg/g/d assimilated for Fe supplementary levels of 27.4, 162 and 657 mg Fe/kg feed). The overall feeding experiments suggested that dietary net Fe flux sufficient for the normal growth of larval medaka was 0.71-1.75 MUg/g/d (i.e., 83.9 mg Fe/kg feed), consistent with the modeled value (i.e., 1.09-2.16 MUg/g/d). In female adults, the estimated essential net Fe flux was 0.88-0.90 MUg/g/d. PMID- 27216706 TI - Metal-insulator-metal waveguides for particle trapping and separation. AB - Optical particle trapping and separation are essential techniques in the fields of biology and chemistry. In many applications, it is important to identify passive separation techniques that only rely on intrinsic forces in a system with a fixed device geometry. We present a dual-waveguide sorter that utilizes the loss of metal-insulator-metal (MIM) waveguides for completely passive particle trapping and separation and is created using a unique angle sidewall deposition process. Our experiments show that an inner Au-Si3N4-Au waveguide is able to trap particles within the propagation distance of its dominant modes and release the particles into an outer Au-H2O-Au waveguide. The outer waveguide then propels the particles and separates them by size. The separation results are accurately modeled by a first-principles, analytical model. PMID- 27216707 TI - Can EGFR-Tyrosine Kinase Inhibitors (TKI) Alone Without Talc Pleurodesis Prevent Recurrence of Malignant Pleural Effusion (MPE) in Lung Adenocarcinoma. AB - BACKGROUND AND OBJECTIVE: Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKIs) are effective against lung adenocarcinoma. However, limited data is available assessing the effectiveness of EGFR-TKI use in preventing re-accumulation of MPE. To our knowledge, there is no literature on comparison of talc pleurodesis with EGFR-TKIs alone on re-accumulation of MPE in Asian population. We investigated if EGFR-TKI therapy for advanced lung adenocarcinoma with malignant pleural effusion (MPE) is also successful in preventing pleural fluid re-accumulation following initial drainage. METHODS: An observational cohort study of patients with lung adenocarcinoma and MPE in the year 2012 was conducted. RESULTS: 70 patients presented with MPE from lung adenocarcinoma. Fifty six underwent EGFR mutation testing of which 39 (69.6%) had activating EGFR mutation and 34 (87.1%) received TKI. 20 were managed by pleural fluid drainage only whereas 14 underwent talc pleurodesis following pleural fluid drainage. Time taken for the pleural effusion to re-accumulate in those with and without pleurodesis was 9.9 vs. 11.7 months, p=0.59 respectively. More patients (n=10, 25.6%) with activating EGFR mutation presented with complete opacification (white-out) of the hemithorax compared to none without activating EGFR mutation (p=0.02). CONCLUSION: In TKI eligible patients, early talc pleurodesis may not confer additional benefit in preventing re-accumulation of pleural effusion and may be reserved for non-adenocarcinoma histology, or EGFR negative adenocarcinoma. Complete opacification of the hemithorax on presentation may serve as an early radiographic signal of positive EGFR mutation status. PMID- 27216709 TI - Does the North American Society for Pediatric and Adolescent Gynecology Short Curriculum Increase Resident Knowledge in Pediatric and Adolescent Gynecology? AB - STUDY OBJECTIVE: To determine if the North American Society for Pediatric and Adolescent Gynecology (NASPAG) Short Curriculum improves self-reported knowledge in pediatric and adolescent gynecology (PAG) among obstetrics and gynecology (Ob/Gyn) residents, at programs without PAG-trained faculty. DESIGN: Prospective, cross-sectional exposure to the NASPAG short curriculum with a follow-up questionnaire. SETTING: Ob/Gyn residency training programs without PAG faculty. PARTICIPANTS: Ob/Gyn residents in training from February 2015 to June 2015. INTERVENTIONS: Exposure to the NASPAG Short Curriculum. MAIN OUTCOME MEASURES: Improvement in self-perceived knowledge after completion of curriculum. RESULTS: Two hundred twenty-seven residents met inclusion criteria; 34 completed the study (15% response). Less than 50% of residents reported adequate knowledge in the areas of prepubertal vaginal bleeding, vulvovaginitis, precocious and delayed puberty, Home environment, Education and Employment, Eating, peer-related Activities, Drugs, Sexuality, Suicide/depression, Safety from injury and violence (HEEADSSS) interview, pelvic pain, and bleeding management in teens with developmental delay. After completion of the curriculum, self-reported knowledge improved in 8 of 10 learning objectives, with no significant improvement in bleeding disorders or Mullerian anomalies. There was no association between pretest knowledge and level of residency training, type of residency program, previous exposure to PAG lectures, and previous exposure to patients with PAG complaints. CONCLUSION: Significant deficiencies exist regarding self-reported knowledge of core PAG topics among Ob/Gyn residents at programs without PAG trained faculty. Use of the NASPAG Short Curriculum by residents without access to PAG-trained faculty resulted in improved self-reported knowledge in PAG. PMID- 27216708 TI - MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism. AB - Mitochondria are ancient organelles that are thought to have emerged from once free-living alpha-proto-bacteria. As such, they still possess several bacterial like qualities, including a semi-autonomous genetic system, complete with an independent genome and a unique genetic code. The bacterial-like circular mitochondrial DNA (mtDNA) has been described to encode 37 genes, including 22 tRNAs, 2 rRNAs, and 13 mRNAs. Two additional peptides reported to originate from the mtDNA, namely humanin (Hashimoto et al., 2001; Ikone et al., 2003; Guo et al., 2003) [1-3] and MOTS-c (mitochondrial ORF of the twelve S c) (Lee et al., 2015) [4], indicate a larger mitochondrial genetic repertoire (Shokolenko and Alexeyev, 2015) [5]. These mitochondrial-derived peptides (MDPs) have profound and distinct biological activities and provide a paradigm-shifting concept of active mitochondrial-encoded signals that act at the cellular and organismal level (i.e. mitochondrial hormone) (da Cunha et al., 2015; Quiros et al., 2016) [6,7]. Considering that mitochondria are the single most important metabolic organelle, it is not surprising that these MDPs have metabolic actions. MOTS-c has been shown to target the skeletal muscle and enhance glucose metabolism. As such, MOTS-c has implications in the regulation of obesity, diabetes, exercise, and longevity, representing an entirely novel mitochondrial signaling mechanism to regulate metabolism within and between cells. PMID- 27216710 TI - Influence of Sources of Information and Parental Attitudes on Human Papillomavirus Vaccine Uptake among Adolescents. AB - STUDY OBJECTIVE: The purpose of this study was to: 1) describe parental sources of information about human papillomavirus (HPV) vaccination for adolescents, 2) understand how parental sources of information about HPV vaccine are associated with adolescent HPV vaccine uptake, and 3) understand if the relationship between a greater number of HPV-related information sources and HPV vaccine uptake among adolescents is mediated by parental attitudes. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS: We conducted a 3-arm randomized controlled trial in middle and high schools in eastern Georgia from 2011 to 2013. As part of the trial, we surveyed parents during the final year to understand their sources of information about HPV vaccine for their adolescent. Data were collected from 360 parents via phone and online surveys. MAIN OUTCOME MEASURES: Parents responded to a survey that asked them to identify demographic information, parental HPV attitudes, sources of information about HPV vaccination, and HPV vaccine uptake. RESULTS: Most of the sample was African American (74%; n = 267) and 53% of parents (n = 192) reported that their adolescent received at least 1 HPV vaccine dose. The top sources of information about HPV vaccine reported by parents were a doctor or medical professional (80%; n = 287) and television (64%; n = 232). A mediation analysis showed sources of information about HPV vaccine are associated with parental attitudes, and parental attitudes about HPV vaccine are associated with vaccine uptake among adolescents. CONCLUSION: These findings highlight the importance of HPV sources of information on parental attitudes. PMID- 27216711 TI - Ehapp2: Estimate haplotype frequencies from pooled sequencing data with prior database information. AB - To reduce the cost of large-scale re-sequencing, multiple individuals are pooled together and sequenced called pooled sequencing. Pooled sequencing could provide a cost-effective alternative to sequencing individuals separately. To facilitate the application of pooled sequencing in haplotype-based diseases association analysis, the critical procedure is to accurately estimate haplotype frequencies from pooled samples. Here we present Ehapp2 for estimating haplotype frequencies from pooled sequencing data by utilizing a database which provides prior information of known haplotypes. We first translate the problem of estimating frequency for each haplotype into finding a sparse solution for a system of linear equations, where the NNREG algorithm is employed to achieve the solution. Simulation experiments reveal that Ehapp2 is robust to sequencing errors and able to estimate the frequencies of haplotypes with less than 3% average relative difference for pooled sequencing of mixture of real Drosophila haplotypes with 50* total coverage even when the sequencing error rate is as high as 0.05. Owing to the strategy that proportions for local haplotypes spanning multiple SNPs are accurately calculated first, Ehapp2 retains excellent estimation for recombinant haplotypes resulting from chromosomal crossover. Comparisons with present methods reveal that Ehapp2 is state-of-the-art for many sequencing study designs and more suitable for current massive parallel sequencing. PMID- 27216712 TI - B7H6-derived peptides trigger TNF-alpha-dependent immunostimulatory activity of lymphocytic NK92-MI cells. AB - The rise of biologics that can stimulate immune responses towards the eradication of tumors has led to the evolution of cancer-based immunotherapy. Representatively, B7H6 has been recently identified as a protein ligand on tumor cells that binds specifically to the NKp30 receptor and triggers NK cell-derived cytokine production, which ultimately leads to tumor cell lysis and death. In an effort to develop effective immunotherapy approaches, the rational design of a novel class of immunostimulatory peptides (IPs) derived from the binding interface of B7H6:NKp30 is described in this study. The IPs comprised the B7H6 active site sequence for NKp30 binding and immunostimulatory activity. An aminohexanoic acid linker was also introduced at the N-terminus of the peptides for FITC-labeling by Fmoc-solid phase peptide synthesis. The peptides were characterized by LCMS to confirm identities and purities >95%. The secondary structures of the peptides were examined by CD spectroscopy in H2 O, PBS and a H2 O:TFE mixture which demonstrated versatile peptide structures which transitioned from random coil (H2 O) to alpha-helical (PBS) and turn-type (H2 O:TFE) conformations. Their biological properties were then evaluated by flow cytometry, enzyme-linked immunosorbent assays (ELISAs), and cell death assays. The occupancy of the synthetic peptides to a human NK cell line demonstrated comparable binding relative to the natural NKp30 ligand, B7H6, and the human anti-NKp30 monoclonal antibody (mAb), in a concentration dependent manner. A competitive binding assay between the human anti-NKp30 mAb or B7H6, and the synthetic peptides, demonstrated partial displacement of the ligands upon anti-NKp30 mAb treatment, suggesting NKp30 receptor specificities by the synthetic peptides. Moreover, the immunostimulatory activity of B7H6 was demonstrated by the secretion of the pro inflammatory cytokines tumor necrosis factor-alfa (TNF-alpha) and interferon gamma (IFN-gamma) by the human NK cell line. The immunostimulatory effects of IPs on the NK cells was assessed by the production of TNF-alpha alone as IFN-gamma was undetectable. In a cell death assay, the IPs were found to be nontoxic, without any observable evidence of early or late stage apoptosis within the NK92 MI cells. Taking these findings together, this novel class of synthetic peptides may prove to be a promising lead in the development of a peptide-based immunotherapy approach, especially against B7H6 expressing tumors. (c) 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 658-672, 2016. PMID- 27216713 TI - Repeated sugammadex reversal of muscle relaxation during lumbar spine surgery with intraoperative neurophysiological multimodal monitoring. AB - Intraoperative neurophysiological monitoring during spine surgery is usually acomplished avoiding muscle relaxants. A case of intraoperative sugammadex partial reversal of the neuromuscular blockade allowing adequate monitoring during spine surgery is presented. A 38 year-old man was scheduled for discectomy and vertebral arthrodesis throughout anterior and posterior approaches. Anesthesia consisted of total intravenous anesthesia plus rocuronium. Intraoperatively monitoring was needed, and the muscle relaxant reverted twice with low dose sugammadex in order to obtain adequate responses. The doses of sugammadex used were conservatively selected (0.1mg/kg boluses increases, total dose needed 0.4mg/kg). Both motor evoqued potentials, and electromyographic responses were deemed adequate by the neurophysiologist. If muscle relaxation was needed in the context described, this approach could be useful to prevent neurological sequelae. This is the first study using very low dose sugammadex to reverse rocuronium intraoperatively and to re-establish the neuromuscular blockade. PMID- 27216714 TI - Arbuscular mycorrhizal symbiosis affects the grain proteome of Zea mays: a field study. AB - Maize is one of the most important crops worldwide and is strongly dependent on arbuscular mycorrhiza (AM) fungi, organisms that form a mutualistic association with land plants. In maize, AM symbiosis enhances spike dry weight, spike length, spike circumference, and the dry weight and dimensions of the grain. Notwithstanding its ubiquitous nature, the detailed relationship between AM fungal colonization and plant development is not completely understood. To facilitate a better understanding of the effects of AM fungi on plants, the work reported here assessed the effects of a consortium of AM fungi on the kernel proteome of maize, cultivated in open-field conditions. To our knowledge, this is the first report of the modulation of a plant seed proteome following AM fungal inoculation in the field. Here, it was found that AM fungi modify the maize seed proteome by up-regulating enzymes involved in energetic metabolism, embryo development, nucleotide metabolism, seed storage and stress responses. PMID- 27216715 TI - Characterizing the Retinal Function of Psammomys obesus: A Diurnal Rodent Model to Study Human Retinal Function. AB - PURPOSE: To compare the retinal function of a diurnal murid rodent, Psammomys obesus, with that of Wistar albino rat and human subjects. MATERIALS AND METHODS: Adult Psammomys obesus were captured and transferred to the animal facilities where they were maintained at 25 degrees C with standard light/dark cycles and natural halophilic plants, rich in water and mineral salts. Standard full-field photopic and scotopic electroretinograms were obtained. RESULTS: The right eye of all animals displayed well detectable and reproducible scotopic and photopic electroretinogram (ERG) responses. Results were compared with those obtained from human subjects and Wistar rats. ERG measurement showed that the amplitudes of scotopic responses in Psammomys obesus are quite similar to those of human subjects. The amplitude of the photopic a-wave was comparable to that of humans and six times higher than that of the albino rat. The amplitudes of photopic b wave, photopic oscillatory potentials (OPs), and 30 Hz flicker were all markedly larger in Psammomys obesus compared to those obtained from human subjects and Wistar rats. Furthermore, like the human photopic ERG, the photopic ERG of Psammomys obesus also includes prominent post b-wave components (i.e. i- and d waves) while the ERG of Wistar rats does not. CONCLUSIONS: Our results suggest that the retinal function of Psammomys obesus, especially the cone-mediated function, shares several features with that of human subjects. We believe that Psammomys obesus represents an interesting alternative to study the structure and function of the normal and diseased retina in a human-like rodent model of retinal function. PMID- 27216716 TI - Cancer Awareness in Aotearoa New Zealand (CAANZ), 2001 and 2015: Study Protocols. AB - Population cancer awareness is of interest worldwide, as efforts are made to reduce cancer incidence via changes in risk and protective behaviours. To date, few studies have described changes in awareness over time, despite significant investment in raising awareness about various cancer types and risk behaviours. This paper describes the Cancer Awareness in Aotearoa New Zealand (CAANZ) survey, a cross-sectional telephone survey of adult New Zealanders conducted in 2014/2015 (CAANZ15, n = 1064) and its comparison with a similar 2001 study (CAANZ01, n = 438). Both aimed to describe current cancer awareness among a national sample of New Zealand (NZ) adults, with additional aims for CAANZ15 being to explore emerging issues in information provision and supportive care. Follow-up studies are challenged by changes in communication technologies and, in turn, potential issues in sampling. However, given the value of information about changing awareness, pragmatic steps were taken in CAANZ15 to maximise the response rate and comparability of the surveys. A response rate of 64 % was achieved for both samples. When compared to the adult NZ population, the CAANZ15 sample tended to be older, of higher socioeconomic status and under-representative of people with Pacific, Asian or, to a lesser extent, Maori (the indigenous population of NZ) ethnicity. To compensate for possible disproportionate age-by-ethnicity (Maori/non-Maori) groups in the sample, poststratification weighting was adopted. While caution will need to be exercised in drawing conclusions from comparisons made between these two cohorts, the dearth of such studies means that insights gained should be useful for guiding reflection on future cancer control directions and the generation of new hypotheses. PMID- 27216717 TI - The roles of the outdoors and occupants in contributing to a potential pan microbiome of the built environment: a review. AB - Recent high-throughput sequencing technology has led to an expansion of knowledge regarding the microbial communities (microbiome) across various built environments (BEs). The microbiome of the BE is dependent upon building factors and conditions that govern how outdoor microbes enter and persist in the BE. Additionally, occupants are crucial in shaping the microbiome of the BE by releasing human-associated microorganisms and resuspending microbes on floors and surfaces. Therefore, both the outdoors and occupants act as major sources of microorganisms found in the BE. However, most characterizations of the microbiome of the BE have been conducted in the Western world. Notably, outdoor locations and population groups present geographical variations in outdoor and human microbiomes, respectively. Given the influences of the outdoor and human microbiomes on BE microbiology, and the geographical variations in outdoor and human microbiomes, it is likely that the microbiomes of BEs also vary by location. The summation of microbiomes between BEs contribute to a potential BE pan-microbiome, which will both consist of microbes that are ubiquitous in indoor environments around the world, and microbes that appear to be endemic to particular geographical locations. Importantly, the BE pan-microbiome can potentially question the global application of our current views on indoor microbiology. In this review, we first provide an assessment on the roles of building and occupant properties on shaping the microbiome of the BE. This is then followed by a description of geographical variations in the microbiomes of the outdoors and humans, the two main sources of microbes in BEs. We present evidence of differences in microbiomes of BEs around the world, demonstrating the existence of a global pan-microbiome of the BE that is larger than the microbiome of any single indoor environment. Finally, we discuss the significance of understanding the BE pan-microbiome and identifying universal and location specific relationships between building and occupant characteristics and indoor microbiology. This review highlights the much needed efforts towards determining the pan-microbiome of the BE, thereby identifying general and location-specific links between the microbial communities of the outdoors, human, and BE ecosystems, ultimately improving the health, comfort, and productivity of occupants around the world. PMID- 27216718 TI - Germinated brown rice ameliorates obesity in high-fat diet induced obese rats. AB - BACKGROUND: Germinated brown rice (GBR) is a novel functional food that is high in fiber and bioactive compounds with health-promoting properties. This study aims to evaluate anti-obesity effects of GBR in obese rats fed high-fat diet (HFD). METHODS: Male Sprague-Dawley rats were fed HFD for 8 weeks to induce obesity. The rats were then administrated with GBR where the source of dietary carbohydrate of HFD was replaced by either 25 % GBR, 50 % GBR or 100 % GBR for another 8 weeks. Changes in anthropometry, dietary status, biochemical parameters and histopathology of liver and adipose tissue were measured. RESULTS: Rats fed with HFD were showed elevation in body weight gain and in white adipose tissue mass compared with rats consumed commercial diet. The GBR administration in 50 % GBR and 100 % GBR were significantly decreased body weight gains and food intakes as well as improved lipid profiles in obese rats. In addition, the administration of GBR had reduced adiposity by showing declination in white adipose tissue mass, adipocytes size and leptin level concomitantly with a higher ratio of fat excretion into feces. Micro- and macrovesicular steatosis were evidently attenuated in obese rats fed GBR. CONCLUSION: These findings demonstrated that GBR exhibited anti-obesity effects through suppression of body weight gain and food intake, improvement of lipid profiles and reduction of leptin level and white adipose tissue mass in obese rats fed HFD. PMID- 27216720 TI - Streptococcus bovis/S. equinus complex septicemia in a group of calves following intramuscular vaccination. AB - Organisms previously classified as Streptococcus bovis (i.e., the S. bovis/S. equinus complex) are common in cattle feces, but may also act as opportunistic pathogens. In the current work, Streptococcus infantarius subsp. coli, a member of this complex, was associated of a cluster of calves that died within hours of injection with a modified live viral vaccine. Within 12 h of vaccination of 46 calves at a cow/calf operation, 4 calves had died, 3 calves were ill, and 1 unvaccinated cow was dead. Autopsies were performed on the cow, 2 dead calves, and 1 affected surviving calf, which was euthanized ~24 h after vaccine administration. The animals had similar gross anatomic and microscopic lesions, including subcutaneous and intramuscular dark hemorrhage on the caudal neck, multiorgan ecchymosis and petechiation, and alveolitis to interstitial pneumonia. Gram-positive cocci were in the vasculature of the lung and skeletal muscle, and S. infantarius subsp. coli was cultured from tissues and from the vaccines used on affected animals, but not in vials used on unaffected animals. Together, these findings suggest death caused by streptococcal septicemia and toxemia as a result of contamination. PMID- 27216719 TI - Decrease in tick bite consultations and stabilization of early Lyme borreliosis in the Netherlands in 2014 after 15 years of continuous increase. AB - BACKGROUND: Nationwide surveys have shown a threefold increase in general practitioner (GP) consultations for tick bites and early Lyme borreliosis from 1994 to 2009 in the Netherlands. We now report an update on 2014, with identical methods as for the preceding GP surveys. METHODS: To all GPs in the Netherlands, a postal questionnaire was sent inquiring about the number of consultations for tick bites and erythema migrans diagnoses (most common manifestation of early Lyme borreliosis) in 2014, and the size of their practice populations. RESULTS: Contrasting to the previously rising incidence of consultations for tick bites between 1994 and 2009, the incidence decreased in 2014 to 488 consultations for tick bites per 100,000 inhabitants, i.e., 82,000 patients nationwide. This survey revealed a first sign of stabilization of the previously rising trend in GP diagnosed erythema migrans, with 140 diagnoses per 100,000 inhabitants of the Netherlands. This equals about 23,500 annual diagnoses of erythema migrans nationwide in 2014. CONCLUSIONS: In contrast to the constantly rising incidence of GP consultations for tick bites and erythema migrans diagnoses in the Netherlands between 1994 and 2009, the current survey of 2014 showed a first sign of stabilization of erythema migrans diagnoses and a decreased incidence for tick bite consultations. PMID- 27216721 TI - Kir7.1 immunoreactivity in canine choroid plexus tumors. AB - Choroid plexus neoplasms are uncommon brain tumors in dogs. Choroid plexus carcinomas often spread diffusely throughout the ventricular system and subarachnoid space and, in aggressive forms, can mimic histologic patterns of other carcinomas, including being embedded in a desmoplastic reaction. Although choroid plexus tumors (CPTs) heterogeneously express pan-cytokeratin, little is known about other markers to identify choroid plexus and their associated tumors. Kir7.1, an inward-rectifier potassium channel, is reported to have high diagnostic utility in human neuropathology to distinguish CPTs from other primary brain tumors and cerebral metastases. To determine Kir7.1 expression in the dog brain, we analyzed the immunoreactivity of Kir7.1 in normal brain, gliomas, ependymomas, CPTs, meningiomas, and carcinomas. In normal brain tissue, the immunostaining was restricted to the choroid plexus where there was robust membrane immunoreactivity along the apical border of the cells with less intense cytoplasmic staining. Similar strong immunoreactivity was detected in 12 of 12 CPTs, whereas 5 of 5 gliomas, 4 of 5 ependymomas, 5 of 5 meningiomas, and 5 of 6 carcinomas had no immunoreactivity. One ependymoma and 1 nasal carcinoma with squamous metaplasia were up to 75% immunopositive, with moderate cytoplasmic and membranous immunoreactivity, but lacking the robust apical immunoreactivity pattern. Analysis for immunoreactivity in a tissue microarray failed to yield any other locations in which immunoreactivity was detected. These results, including the distinctive pattern of immunostaining in CPTs, suggest that Kir7.1 is an excellent marker for CPTs in the dog. PMID- 27216722 TI - Choroid plexus papilloma in a beluga whale (Delphinapterus leucas). AB - We report herein a choroid plexus papilloma in a beluga whale (Delphinapterus leucas). This case was positive for choroid plexus tumor marker Kir7.1 on immunohistochemistry. These results and the high conservation of Kir7.1 across species at the amino acid sequence level strongly suggest that antibodies directed against Kir7.1 not only can be employed for the diagnosis of choroid plexus tumors in cetaceans, but are also likely to be diagnostically useful in other animal species. PMID- 27216723 TI - Development of an equine coronavirus-specific enzyme-linked immunosorbent assay to determine serologic responses in naturally infected horses. AB - Equine coronavirus (EqCoV) infection has been documented in most reports through quantitative qPCR analysis of feces and viral genome sequencing. Although qPCR is used to detect antigen during the acute disease phase, there is no equine specific antibody test available to study EqCoV seroprevalence in various horse populations. We developed an enzyme-linked immunosorbent assay (ELISA) targeting antibodies to the spike (S) protein of EqCoV and validated its use, using acute and convalescent sera from 83 adult horses involved in 6 outbreaks. The EqCoV S protein-based ELISA was able to reliably detect antibodies to EqCoV in naturally infected horses. The greatest seroconversion rate was observed in horses with clinical signs compatible with EqCoV infection and EqCoV qPCR detection in feces. The EqCoV S protein-based ELISA could be used effectively for seroepidemiologic studies in order to better characterize the overall infection rate of EqCoV in various horse populations. PMID- 27216725 TI - Polarised press reporting about HIV prevention: Social representations of pre exposure prophylaxis in the UK press. AB - Pre-exposure prophylaxis is a novel biomedical HIV prevention option for individuals at high risk of HIV acquisition. Although pre-exposure prophylaxis has yielded encouraging results in various clinical trials, opponents argue that pre-exposure prophylaxis poses a number of risks to human health and to sexually transmitted infection prevention efforts. Using qualitative thematic analysis and social representation theory, this article explores coverage of pre-exposure prophylaxis in the UK print media between 2008 and 2015 in order to chart the emerging social representations of this novel HIV prevention strategy. The analysis revealed two competing social representations of pre-exposure prophylaxis: (1) as a positive development in the 'battle' against HIV (the hope representation) and (2) as a medical, social and psychological setback in this battle, particularly for gay/bisexual men (the risk representation). These social representations map onto the themes of pre-exposure prophylaxis as a superlatively positive development; pre-exposure prophylaxis as a weapon in the battle against HIV/AIDS; and risk, uncertainty and fear in relation to pre exposure prophylaxis. The hope representation focuses on taking (individual and collective) responsibility, while the risk representation focuses on attributing (individual and collective) blame. The implications for policy and practice are discussed. PMID- 27216724 TI - Molecular identification of Salmonella enterica subsp. enterica serovar Gallinarum biovars Gallinarum and Pullorum by a duplex PCR assay. AB - Salmonella enterica subsp. enterica serovar Gallinarum biovar Gallinarum (S Gallinarum) and biovar Pullorum (S Pullorum) are 2 poultry pathogens that cause major economic losses to the poultry industry worldwide. Control of both diseases mainly relies on the adoption of biosecurity programs, and success is dependent on accurate and fast detection. Based on this concept, we developed a duplex PCR assay, targeting 2 chromosomal sequences, which allowed us to precisely identify and differentiate S Gallinarum and S Pullorum field strains. This assay was validated by testing genomic DNA from 40 S Gallinarum and 29 S Pullorum field strains, 87 other Salmonella serovars, and 7 non-Salmonella strains. The serovar identifier region (SIR) primers produced a fragment only in S Gallinarum and S Pullorum strains, whereas the fragment from the ratA coding sequence, which was previously demonstrated to differentiate the 2 biovars, was also amplified from other Salmonella serovars. Our results showed that the combination of both SIR and ratA amplifications could be used to identify as well as to differentiate colonies of S Gallinarum and S Pullorum reliably. Thus, we believe this methodology can be a useful ancillary tool for routine veterinary diagnostic laboratories by providing rapid, accurate results. PMID- 27216726 TI - Schwann Cells Migration on Patterned Polydimethylsiloxane Microgrooved Surface. AB - Schwann cells (SCs) aid in nerve repair in the peripheral nervous system, and their ability to migrate into the injury site is critical for nerve regeneration after injury. The majority of studies on SC behavior have focused on SC alignment through contact guidance, rather than migration. The few studies on SC migration primarily investigated the migration of individual cells over several hours with time-lapse microscopy. However, during neural tissue repair, SCs do not migrate as single cells but as a population of cells over physiologically relevant time and length scales. Thus from a practical perspective, there is a need to understand the migration of large populations of SC and the collective guidance cues from the surrounding environment in designing optimal transplantable scaffolds. This study investigates a large population of migrating SCs over a period of 2 weeks on patterned polydimethylsiloxane (PDMS) microgrooved channels of different sizes. Two methods were used to quantify the migration velocity of a large cell population that minimized the confounding effect due to cell proliferation: one based on a leading edge velocity and a second based on a binary velocity. Both approaches showed that the SC population migrated the fastest on the smallest sized microgrooved channels. The insights provided in this study could inform on future designs of transplantable scaffolds for peripheral nerve regeneration. PMID- 27216727 TI - A new dawn for buried garbage? An investigation of the marketability of previously disposed shredder waste. AB - This paper examines the market potential of disposed shredder waste, a resource that is increasingly emphasized as a future mine. A framework with gate requirements of various outlets was developed and contrasted with a pilot project focusing on excavated waste from a shredder landfill, sorted in an advanced recycling facility. Only the smallest fraction by percentage had an outlet, the metals (8%), which were sold according to a lower quality class. The other fractions (92%) were not accepted for incineration, as construction materials or even for re-deposition. Previous studies have shown similar lack of marketability. This means that even if one fraction can be recovered, the outlet of the other material is often unpredictable, resulting in a waste disposal problem, which easily prevents a landfill mining project altogether. This calls for marketability and usability of deposited waste to become a central issue for landfill mining research. The paper concludes by discussing how concerned actors can enhance the marketability, for example by pre-treating the disposed waste to acclimatize it to existing sorting methods. However, for concerned actors to become interested in approaching unconventional resources such as deposited waste, greater regulatory flexibility is needed in which, for example, re deposition could be allowed as long as the environmental benefits of the projects outweigh the disadvantages. PMID- 27216728 TI - Solid-state drawing of post-consumer isotactic poly(propylene): Effect of melt filtration and carbon black on structural and mechanical properties. AB - Post-consumer plastic waste obtained via mechanical recycling is usually applied in thick-walled products, because of the low mechanical strength due to the presence of contaminants. In fact, sorted post-consumer isotactic poly(propylene) (i-PP) can be considered as a blend of 95% i-PP and 5% poly(ethylene), with traces of poly(ethylene terephthalate) (PET). By applying a treatment such as solid-state drawing (SSD) after melt extrusion, the polymer chains can be oriented in one direction, thereby improving the stiffness and tensile strength. In this research, molecular processes such as crystal break-up and chain orientation of these complex blends were monitored as a function of draw ratio. The melt filter mesh size - used to exclude rigid PET particles - and the addition of carbon black (CB) - often added for coloration in the recycling industry - were varied to investigate their influence on the SSD process. This research shows that despite the blend complexity, the molecular processes during SSD compare to virgin i-PP and that similar draw ratios can be obtained (lambdamax=20), albeit at reduced stiffness and strength as a result of the foreign polymers present in post-consumer i-PP. It is observed that the process stability improves with decreasing mesh size and that higher draw ratios can be obtained. The addition of carbon black, which resides in the dispersed PE phase, also stabilizes the SSD process. Compared to isotropic post-consumer i-PP, the stiffness can be improved by a factor 10 to over 11GPa, while the tensile strength can be improved by a factor 15-385MPa, which is approx. 70% of the maximum tensile strength achieved for virgin i-PP. PMID- 27216729 TI - Physico-chemical characterisation of material fractions in residual and source segregated household waste in Denmark. AB - Physico-chemical waste composition data are paramount for the assessment and planning of waste management systems. However, the applicability of data is limited by the regional, temporal and technical scope of waste characterisation studies. As Danish and European legislation aims for higher recycling rates evaluation of source-segregation and recycling chains gain importance. This paper provides a consistent up-to-date dataset for 74 physico-chemical parameters in 49 material fractions from residual and 24 material fractions from source-segregated Danish household waste. Significant differences in the physico-chemical properties of residual and source-segregated waste fractions were found for many parameters related to organic matter, but also for elements of environmental concern. Considerable differences in potentially toxic metal concentrations between the individual recyclable fractions within one material type were observed. This indicates that careful planning and performance evaluation of recycling schemes are important to ensure a high quality of collected recyclables. Rare earth elements (REE) were quantified in all waste fractions analysed, with the highest concentrations of REE found in fractions with high content of mineral raw materials, soil materials and dust. The observed REE concentrations represent the background concentration level in non-hazardous waste materials that may serve as a reference point for future investigations related to hazardous waste management. The detailed dataset provided here can be used for assessments of waste management solutions in Denmark and for the evaluation of the quality of recyclable materials in waste. PMID- 27216730 TI - Immobilization of antimony in waste-to-energy bottom ash by addition of calcium and iron containing additives. AB - The leaching of Sb from waste-to-energy (WtE) bottom ash (BA) often exceeds the Dutch limit value of 0.32mgkg(-1) for recycling of BA in open construction applications. From the immobilization mechanisms described in the literature, it could be concluded that both Ca and Fe play an important role in the immobilization of Sb in WtE BA. Therefore, Ca and Fe containing compounds were added to the samples of the sand fraction of WtE BA, which in contrast to the granulate fraction is not recyclable to date, and the effect on the Sb leaching was studied by means of batch leaching tests. Results showed that addition of 0.5 and 2.5% CaO, 5% CaCl2, 2.5% Fe2(SO4)3 and 1% FeCl3 decreased the Sb leaching from 0.62+/-0.02mgkgDM(-1) to 0.20+/-0.02, 0.083+/-0.044, 0.25+/-0.01, 0.27+/ 0.002 and 0.29+/-0.02mgkgDM(-1), respectively. Due to the increase in pH from 11.41 to 12.53 when 2.5% CaO was added, Pb and Zn leaching increased and exceeded the respective leaching limits. Addition of 5% CaCO3 had almost no effect on the Sb leaching, as evidenced by the resulting 0.53mgkgDM(-1) leaching concentration. This paper shows a complementary enhancement of the effect of Ca and Fe, by comparing the aforementioned Sb leaching results with those of WtE BA with combined addition of 2.5% CaO or 5% CaCl2 with 2.5% Fe2(SO4)3 or 1% FeCl3. These lab scale results suggest that formation of romeites with a high Ca content and formation of iron antimonate (tripuhyite) with a very low solubility are the main immobilization mechanisms of Sb in WtE BA. Besides the pure compounds and their mixtures, also addition of 10% of two Ca and Fe containing residues of the steel industry, hereafter referred to as R1 and R2, was effective in decreasing the Sb leaching from WtE BA below the Dutch limit value for reuse in open construction applications. To evaluate the long term effect of the additives, pilot plots of WtE BA with 10% of R1 and 5% and 10% of R2 were built and samples were submitted to leaching tests at regular intervals over time. The Sb leaching from untreated WtE BA was just below or above the Dutch limit value. The Sb leaching from the pilot plots of BA with additives first remained stable around 0.13mgkg(-1) but had a tendency to slightly increase after 6months, indicating the need for further research on the effect of weathering, and more specifically of carbonation, on Sb leaching from WtE BA. PMID- 27216731 TI - Fecal Calprotectin, Elastase, and Alpha-1-Antitrypsin Levels After Roux-en-Y Gastric Bypass; Calprotectin Is Significantly Elevated in the Majority of Patients. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) causes several alterations in gastrointestinal function. We hypothesized that levels of three commonly used fecal tests change after RYGB. METHODS: Fecal levels of calprotectin, elastase, and alpha-1-antitrypsin were determined in 122 patients without signs of gastrointestinal disease 1 to 2 years after RYGB. Medians, distribution of values, and the percentage of patients with levels above or below reference values were determined. RESULTS: Median fecal calprotectin level was 163.5 (<30 1587) MUg/g; in 87 % of patients, it was above the reference value (<50 MUg/g). Median fecal elastase level was 444 (<15-647) MUg/g; 13 % was below the reference value (>200 MUg/g). Median fecal alpha-1-antitrypsin level was 0.51 (<0.20-2.20) mg/g, comparable to the reference values. CONCLUSIONS: Fecal calprotectin levels are significantly higher than the reference value in most patients after RYGB. Fecal elastase is significantly lower. This might indicate that the validity of fecal calprotectin testing is impaired after RYGB and the specificity for fecal elastase is decreased. Clinical awareness of altered fecal markers after RYGB is essential to prevent unnecessary diagnostic tests, such as colonoscopy. Fecal alpha-1-antitrypsin is not influenced by RYGB. PMID- 27216732 TI - Traffic Crash Risks in Morbidly Obese Drivers Before and After Weight Loss Surgery. AB - Morbidly obese drivers have a higher risk of road crashes because of associated conditions such as obstructive sleep apnea. We assessed whether weight loss surgery has an impact on subsequent road crash risks in morbidly obese drivers. Our longitudinal self-matched cohort analyses suggest that road crash risks are three times higher in morbidly obese drivers than the population norm. Yet, weight loss surgery yields no significant reductions in crash risks. We found similar results in patients not previously diagnosed with sleep disorders, suggesting the need to clarify the relationship of obesity with road crash risk. PMID- 27216733 TI - Intraabdominal Trocar-Free Vacuum Liver Retractor for Laparoscopic Sleeve Gastrectomy (Video). AB - PURPOSE: Retraction of the liver is essential in laparoscopic sleeve gastrectomy. Recently, a new internal liver retractor, the LiVac(r) device, has been introduced. The current video report (run-time 7:26 min) seeks to demonstrate the efficacy and safety of the LiVac(r) trocar-free liver retractor in laparoscopic sleeve gastrectomy. MATERIALS AND METHODS: The LiVac(r) retractor is inserted besides an abdominal trocar and uses the vacuum system of the operating room without the need for specific devices. The liver is retracted without the need of an assistant or extra trocars. RESULTS: The present case is a laparoscopic sleeve gastrectomy in a 30-year-old woman with morbid obesity (BMI 45.3 kg/m(2)). The LiVac(r) retractor provided an excellent view of the operative field. No problems or device-related complications occured during the procedure. CONCLUSIONS: The LiVac liver retractor was easy to applicate in the presented case and provided a good exposure of the operative field. PMID- 27216735 TI - Effects of Hyperbaric Oxygen Therapy on Inflammasome Signaling after Traumatic Brain Injury. AB - OBJECTIVE: Neuroinflammation plays an important role in secondary tissue damage after traumatic brain injury (TBI). Recently, the inflammasome-mediated inflammatory pathway has been observed in the inflammatory response of TBI. In this study, we investigated the influence of hyperbaric oxygen therapy (HBOT) on inflammasome activation after TBI. METHODS: The experimental mice were randomly divided into 4 groups as follows: sham-operated normobaric air (21% O2 at one absolute atmosphere), HBOT only, TBI + normobaric air and TBI + HBOT. Following the evaluation of motor deficits and brain edema, the expression of inflammasome components and effectors was measured by qRT-PCR and Western blotting. Moreover, alterations in IL-1beta, IL-18 and high-mobility group box 1 (HMGB1) were calculated by enzyme-linked immunosorbent assay at each time point after injury. RESULTS: HBOT improved motor score and reduced brain edema. Furthermore, it suppressed protein expression of inflammasome components and reduced the levels of IL-1beta and IL-18, accompanied by the reduction of HMGB1 in brain tissues and serum. CONCLUSION: These results suggest that HBOT may alleviate the inflammatory response after TBI by inhibiting the activation of inflammasome signaling. PMID- 27216734 TI - The epidemiology of residual Plasmodium falciparum malaria transmission and infection burden in an African city with high coverage of multiple vector control measures. AB - BACKGROUND: In the Tanzanian city of Dar es Salaam, high coverage of long-lasting insecticidal nets (LLINs), larvicide application (LA) and mosquito-proofed housing, was complemented with improved access to artemisinin-based combination therapy and rapid diagnostic tests by the end of 2012. METHODS: Three rounds of city-wide, cluster-sampled cross-sectional surveys of malaria parasite infection status, spanning 2010 to 2012, were complemented by two series of high resolution, longitudinal surveys of vector density. RESULTS: Larvicide application using a granule formulation of Bacillus thuringiensis var. israelensis (Bti) had no effect upon either vector density (P = 0.820) or infection prevalence (P = 0.325) when managed by a private-sector contractor. Infection prevalence rebounded back to 13.8 % in 2010, compared with <2 % at the end of a previous Bti LA evaluation in 2008. Following transition to management by the Ministry of Health and Social Welfare (MoHSW), LA consistently reduced vector densities, first using the same Bti granule in early 2011 [odds ratio (OR) (95 % confidence interval (CI)) = 0.31 (0.14, 0.71), P = 0.0053] and then a pre diluted aqueous suspension formulation from mid 2011 onwards [OR (95 % CI) = 0.15 (0.07, 0.30), P ? 0.000001]. While LA by MoHSW with the granule formulation was associated with reduced infection prevalence [OR (95 % CI) = 0.26 (0.12, 0.56), P = 0.00040], subsequent liquid suspension use, following a mass distribution to achieve universal coverage of LLINs that reduced vector density [OR (95 % CI) = 0.72 (0.51, 1.01), P = 0.057] and prevalence [OR (95 % CI) = 0.80 (0.69, 0.91), P = 0.0013], was not associated with further prevalence reduction (P = 0.836). Sleeping inside houses with complete window screens only reduced infection risk [OR (95 % CI) = 0.71 (0.62, 0.82), P = 0.0000036] if the evenings and mornings were also spent indoors. Furthermore, infection risk was only associated with local vector density [OR (95 % CI) = 6.99 (1.12, 43.7) at one vector mosquito per trap per night, P = 0.037] among the minority (14 %) of households lacking screening. Despite attenuation of malaria transmission and immunity, 88 % of infected residents experienced no recent fever, only 0.4 % of these afebrile cases had been treated for malaria, and prevalence remained high (9.9 %) at the end of the study. CONCLUSIONS: While existing vector control interventions have dramatically attenuated malaria transmission in Dar es Salaam, further scale-up and additional measures to protect against mosquito bites outdoors are desirable. Accelerated elimination of chronic human infections persisting at high prevalence will require active, population-wide campaigns with curative drugs. PMID- 27216736 TI - A Preliminary Estimate of Total Petroleum Hydrocarbons in Water and Some Commercially Important Fish Species in the Amba Estuary, West Coast of India. AB - Amba Estuary, which receives effluent from several industries including a petrochemical complex, opens to the southern limits of the Mumbai Harbor. The study was conducted to find out the level of Total Petroleum Hydrocarbons (TPHs) in water and their bioconcentration in ten commercially important fishes from Amba Estuary during different months. In water high concentration of TPHs (39.7 MUg/L) was obtained during December (middle of estuary) and minimum value (7.2 MUg/L) was observed in September (lower estuarine). The maximum concentration of TPHs was found to be in Trichiurus savala (3.2 ug/g) during December and minimum in Boleophthalmus sp (0.4 ug/g) during May. Irrespective of the monthly variations, TPHs accumulation in all the species was considerably lower than hazardous levels. Although there was no statistical significance between TPHs and total length/weight, the T. savala recording maximum concentration during all months and it can be used as indicator of hydrocarbon pollution in this region. PMID- 27216737 TI - VanA-Type MRSA (VRSA) Emerged in Surface Waters. AB - Due to the widespread occurrence of mecA-encoded methicillin resistance in Staphylococcus aureus (MRSA), treatment of staphylococcal infections is shifted to glycopeptide antibiotics like vancomycin and teicoplanin. The selective pressure of glycopeptides has eventually led to the emergence of staphylococci with increased resistance. Of great concern is vanA-encoded high level vancomycin and teicoplanin resistance in MRSA (VRSA). Therefore, this study aimed at investigating the occurrence of VRSA in surface waters. Out of 290, two staphylococcal isolates identified as MRSA Al11, Ba01, and one as MRS Co11 through 16S rRNA sequencing, also displayed high level resistance towards vancomycin and teicoplanin. These staphylococcal isolates were found to harbor vanA gene with sequence similarities of 99 %-100 % to the vanA gene extracted from vancomycin- and teicoplanin-resistant enterococcal (VRE) surface water isolates of Enterococcus faecalis Cr07, E07, Pb06 and E. faecium E330. High level glycopeptide resistance rendering protein encoded by the vanA gene, D-alanine-D lactate ligase found in VRE, was also shown to be present in all vanA-type staphylococcal isolates through western blot. Current study elucidated that surface waters provide high potential for enterococcal vanA gene being transferred to MRSA, so called VRSA, and require special scientific consideration. PMID- 27216738 TI - Minimally Invasive Surgery for Pancreatic Disease - Current Status. AB - Laparoscopic procedures have advanced to represent the new gold standard in many surgical fields. Although application in pancreatic surgery is hampered by the friable nature of the gland and the difficulty of its exposure, advanced technology and surgeons' experience are leading to an expansion of minimally invasive pancreatic surgery. Addressing the whole range of main operative procedures, this review analyzes the literature data so far to give an overview about the current status of minimally invasive pancreatic surgery, its indications and limitations. In acute pancreatitis, a step-up approach from percutaneous drainage to retroperitoneoscopic necrosectomy seems beneficial. Transgastric necrosectomy also preserves the retroperitoneal compartment in contrast to the laparoscopic approach, which has widely been abandoned. In tumor pathology, laparoscopic access is adequate for small benign lesions in the pancreatic tail and body. Oncological outcome shows to be at least equal to the open procedure. Concerning laparoscopic pancreaticoduodenectomy, there is no evidence for a patients' benefit currently although several studies prove that it can be done. PMID- 27216739 TI - Biological Discourses on Human Races and Scientific Racism in Brazil (1832-1911). AB - This paper analyzes biological and scientific discourses about the racial composition of the Brazilian population, between 1832 and 1911. The first of these dates represents Darwin's first arrival in the South-American country during his voyage on H.M.S. Beagle. The study ends in 1911, with the celebration of the First universal Races congress in London, where the Brazilian physical anthropologist J.B. Lacerda predicted the complete extinction of black Brazilians by the year 2012. Contemporary European and North-American racial theories had a profound influence in Brazilian scientific debates on race and miscegenation. These debates also reflected a wider political and cultural concern, shared by most Brazilian scholars, about the future of the Nation. With few known exceptions, Brazilian evolutionists, medical doctors, physical anthropologists, and naturalists, considered that the racial composition of the population was a handicap to the commonly shared nationalistic goal of creating a modern and progressive Brazilian Republic. PMID- 27216740 TI - Magnetic nanotherapeutics for dysregulated synaptic plasticity during neuroAIDS and drug abuse. AB - The human immunodeficiency virus (HIV) is a neurotropic virus. It induces neurotoxicity and subsequent brain pathologies in different brain cells. Addiction to recreational drugs remarkably affects the initiation of HIV infections and expedites the progression of acquired immunodeficiency syndrome (AIDS) associated neuropathogenesis. Symptoms of HIV-associated neurocognitive disorders (HAND) are noticed in many AIDS patients. At least 50 % of HIV diagnosed cases show one or other kind of neuropathological signs or symptoms during different stages of disease progression. In the same line, mild to severe neurological alterations are seen in at least 80 % autopsies of AIDS patients. Neurological illnesses weaken the connections between neurons causing significant altercations in synaptic plasticity. Synaptic plasticity alterations during HIV infection and recreational drug abuse are mediated by complex cellular phenomena involving changes in gene expression and subsequent loss of dendritic and spine morphology and physiology. New treatment strategies with ability to deliver drugs across blood-brain barrier (BBB) are being intensively investigated. In this context, magnetic nanoparticles (MNPs) based nanoformulations have shown significant potential for target specificity, drug delivery, drug release, and bioavailability of desired amount of drugs in non-invasive brain targeting. MNPs based potential therapies to promote neuronal plasticity during HIV infection and recreational drug abuse are being developed. PMID- 27216741 TI - Local Control Modality and Outcome for Ewing Sarcoma of the Femur: A Report From the Children's Oncology Group. AB - BACKGROUND: The choice of a local control (LC) modality for Ewing sarcoma (EWS) of the femur is controversial. This study aimed to determine the effect of LC modality on tumor LC and patient outcomes. METHODS: The study reviewed the treatment and outcomes for 115 patients who had EWS of the femur treated with similar chemotherapy in three cooperative group trials. Patient outcomes were analyzed according to the LC modality using the log-rank test and the cumulative incidence of local or distant failure using competing risks regression. RESULTS: The median age of the patients was 13 years. The most common tumor location was the proximal femur followed by the mid femur. For 55 patients with available data, the tumor was larger than 8 cm in 29 patients and 8 cm or smaller in 26 patients. For 84 patients (73 %), surgery only was performed, whereas 17 patients (15 %) had surgery plus radiation, and 14 patients (12 %) had radiation only. The 5-year event-free survival (EFS) rate was 65 % (95 % confidence interval [CI], 55 73 %), and the 5-year overall survival (OS) rate was 70 % (95 % CI, 61-78 %). Patient outcomes did not differ significantly according to tumor location within the femur (proximal, mid or distal) or tumor size (<8 vs >=8 cm). The findings showed no statistically significant differences in EFS, OS, cumulative incidence of local failure, or cumulative incidence of distant failure according to LC modality (surgery, surgery plus radiation, or radiation). CONCLUSIONS: The LC modality did not significantly affect disease outcome for EWS of the femur. Further study of treatment complications and functional outcome may help to define the optimal LC modality. PMID- 27216742 TI - Nomograms for Predicting Axillary Response to Neoadjuvant Chemotherapy in Clinically Node-Positive Patients with Breast Cancer. AB - BACKGROUND: Many patients with clinically node-positive breast cancer receive neoadjuvant chemotherapy (NAC). Recent trials suggest the potential for limiting axillary surgery in patients who convert to pathologically node-negative disease. The authors developed a nomogram to predict axillary response to NAC in patients with cN1 disease that can assist clinicians in treatment planning. METHODS: Patients with cT1-4N1M0 breast cancer who received NAC and underwent axillary lymph node dissection from 2001 through 2013 were identified (n = 584). Uni- and multivariate logistic regression analyses were performed to determine factors predictive of nodal conversion. A nomogram to predict the likelihood of nodal pathologic complete response (pCR) was constructed based on clinicopathologic variables and validated using an external dataset. RESULTS: Axillary pCR was achieved for 217 patients (37 %). Patients presenting with high nuclear grade [grade 3 vs. 1, odds ratio (OR) 13.4], human epidermal growth factor receptor 2 positive (OR 4.7), estrogen receptor (ER)-negative (OR 3.5), or progesterone receptor-negative (OR 4.3) tumors were more likely to achieve nodal pCR. These factors, together with clinically relevant factors including presence of multifocal/centric disease, clinical T stage, and extent of nodal disease seen on regional nodal ultrasound at diagnosis were used to create nomograms predicting nodal conversion. The discrimination of the nomogram using ER+ status (>1 % staining) versus ER- status [area under the curve (AUC) 78 %] was improved slightly using the percentage of ER staining (AUC 78.7 %). Both nomograms were validated using an external cohort. CONCLUSION: Nomograms incorporating routine clinicopathologic parameters can predict axillary pCR in node-positive patients receiving NAC and may help to inform treatment decisions. PMID- 27216743 TI - Early Gastric Cancer: Trends in Incidence, Management, and Survival in a Well Defined French Population. AB - BACKGROUND: Little is known about the epidemiology of early gastric cancer (EGC) in Western countries. The aim of this study was to analyze trends in the incidence, management, and survival of EGC in a well-defined population over a 30 year period. METHODS: Data were obtained from the population-based cancer Registry of Burgundy (France). Incidence rates were calculated by sex, age, and 10 year period of diagnosis. Net survival rates were calculated and a multivariate relative survival analysis performed. RESULTS: EGC represented 6.7 % of gastric cancer diagnosed between 1982 and 2011. Age-standardized incidence rates were higher in men (0.79/100,000) than in women (0.40/100,000). Between the periods 1982-1991 and 2002-2011, it decreased from 0.97 to 0.53 per 100,000 in men and from 0.44 to 0.30 per 100,000 in women. Overall, 19 % of the tumors were limited to the mucosa, 69 % to the submucosa, and 15 % invaded lymph nodes. Node invasion and male sex were the only significant prognostic factors. Five-year net survival was 50 % in node-positive patients and 85 % in node-negative patients (p < 0.001). In multivariate analysis, the relative risk of death in men compared to women was 2.3 and was 10.4 in patients with positive nodes compared to patients with negative nodes. CONCLUSIONS: EGCs are rare in France. The prognosis is favorable, except for node-positive cancers, which may benefit from the recently developed adjuvant chemotherapy for gastric cancer. PMID- 27216744 TI - Multimodality imaging of fibromuscular dysplasia. AB - OBJECTIVE: Fibromuscular dysplasia (FMD) is an uncommon non-inflammatory and non atherosclerotic cause of arterial disease that may result in stenosis, tortuosity, aneurysm, or dissection. The clinical presentation depends on the vascular bed involved and ranges from asymptomatic to multisystem disease and end organ ischemia. The purpose of this article is to review the role of imaging in patients with FMD with an emphasis on renal FMD. The relevant epidemiology, histopathology, imaging techniques, and interpretation of images will be discussed. CONCLUSION: Renal artery FMD requires a high index of suspicion for accurate and prompt diagnosis and implementation of appropriate therapy. The treatment will vary based on clinical presentation and distribution of involvement. Noninvasive imaging with duplex ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI) are reasonable alternatives for the depiction of FMD in comparison to catheter-directed angiography (CA). Patients with FMD are often treated by multispecialty practice including the interventional radiologist. PMID- 27216745 TI - MicroRNA in late lung development and bronchopulmonary dysplasia: the need to demonstrate causality. AB - MicroRNA are emerging as powerful regulators of cell differentiation and tissue and organ development. Several microRNA have been described to play a role in branching morphogenesis, a key step in early lung development. However, considerably less attention has been paid to microRNA as regulators of the process of secondary septation, which drives lung alveolarization during late lung development. Secondary septation is severely perturbed in bronchopulmonary dysplasia (BPD), a common complication of preterm birth characterized by blunted alveolarization. A number of studies to date have reported microRNA microarray screens in animal models of BPD; however, only two studies have attempted to demonstrate causality. Although the expression of miR-150 was altered in experimental BPD, a miR-150(-/-) knockout mouse did not exhibit appreciable protection in a BPD animal model. Similarly, while the expression of miR-489 in the lung was reduced in clinical and experimental BPD, antagomiR and over expression approaches could not validate a role for miR-489 in the impaired alveolarization associated with experimental BPD. This mini-review aims to highlight microRNA that have been revealed by multiple microarray studies to be potential causal players in normal and pathological alveolarization. Additionally, the challenges faced in attempting to demonstrate a causal role for microRNA in lung alveolarization are discussed. These include the tremendous variability in the animal models employed, and the limitations and advantages offered by the available tools, including antagomiRs and approaches for the validation of a specific microRNA-mRNA interaction during lung alveolarization. PMID- 27216746 TI - Elevated variant density around SV breakpoints in germline lineage lends support to error-prone replication hypothesis. AB - Copy number variants (CNVs) are a class of structural variants that may involve complex genomic rearrangements (CGRs) and are hypothesized to have additional mutations around their breakpoints. Understanding the mechanisms underlying CNV formation is fundamental for understanding the repair and mutation mechanisms in cells, thereby shedding light on evolution, genomic disorders, cancer, and complex human traits. In this study, we used data from the 1000 Genomes Project to analyze hundreds of loci harboring heterozygous germline deletions in the subjects NA12878 and NA19240. By utilizing synthetic long-read data (longer than 2 kbp) in combination with high coverage short-read data and, in parallel, by comparing with parental genomes, we interrogated the phasing of these deletions with the flanking tens of thousands of heterozygous SNPs and indels. We found that the density of SNPs/indels flanking the breakpoints of deletions (in-phase variants) is approximately twice as high as the corresponding density for the variants on the haplotype without deletion (out-of-phase variants). This fold change was even larger for the subset of deletions with signatures of replication based mechanism of formation. The allele frequency (AF) spectrum for deletions is enriched for rare events; and the AF spectrum for in-phase SNPs is shifted toward this deletion spectrum, thus offering evidence consistent with the concomitance of the in-phase SNPs/indels with the deletion events. These findings therefore lend support to the hypothesis that the mutational mechanisms underlying CNV formation are error prone. Our results could also be relevant for resolving mutation-rate discrepancies in human and to explain kataegis. PMID- 27216747 TI - Luminescence enhancement of (Sr1-x Mx )2 SiO4 :Eu2+ phosphors with M (Ca2+ /Zn2+ ) partial substitution for white light-emitting diodes. AB - Eu2+ -doped Sr2 SiO4 phosphor with Ca2+ /Zn2+ substitution, (Sr1-x Mx )2 SiO4 :Eu2+ (M = Ca, Zn), was prepared using a high-temperature solid-state reaction method. The structure and luminescence properties of Ca2+ /Zn2+ partially substituted Sr2 SiO4 :Eu2+ phosphors were investigated in detail. With Ca2+ or Zn2+ added to the silicate host, the crystal phase could be transformed between the alpha-form and the beta-form of the Sr2 SiO4 structure. Under UV excitation at 367 nm, all samples exhibit a broad band emission from 420 to 680 nm due to the 4f6 5d1 -> 4f7 transition of Eu2+ ions. The broad emission band consists of two peaks at 482 and 547 nm, which correspond to Eu2+ ions occupying the ten-fold oxygen-coordinated Sr.(I) site and the nine-fold oxygen-coordinated Sr.(II) site, respectively. The luminescence properties, including the intensity and lifetime of Sr2 SiO4 :Eu2+ phosphors, improved remarkably on Ca2+ /Zn2+ addition, and promote its application in white light-emitting diodes. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27216748 TI - Massive hemoptysis due to primary mucoepidermoid carcinoma of the lung in a 12 year-old. PMID- 27216749 TI - Artefactual incised wounds due to postmortem predation by the Sri Lankan water monitor (kabaragoya). AB - Monitor lizards are large reptilian animals mostly seen around water based habitats. Sri Lanka has an endemic water monitor lizard called the kabaragoya (Varanus salvator salvator) which is perhaps the most common large animal scavenger in the country. Scavenging by the kabaragoya can result in postmortem incised injuries which are caused by their sharp pointed claws as they grip or crawl over a dead body. The author presents four cases where these claw marks raised significant medicolegal issues. In one case of a young female they mimicked defense injuries that might be seen in a person that was killed with heavy sharp weapon trauma to the head. In another case, claw marks on the face raised homicidal allegations in an immersion death following intoxication. In a case of suicidal drowning these injuries simulated self-inflicted cuts. The fourth case shows how claw marks complicated the investigation of a dismembered upper limb. Kabaragoya claw marks are mostly seen in decomposed and macerated bodies recovered from water. Injuries are mostly superficial and limited to skin and soft tissues. Bony injuries are not seen. Awareness of the creature's scavenging habits and careful analysis of the appearance and distribution of the injuries is essential to differentiate claw marks from sharp weapon trauma. PMID- 27216750 TI - Validating the generic quality of life tool "QOL10" in a substance use disorder treatment cohort exposes a unique social construct. AB - BACKGROUND: Generic quality of life (QoL) instruments provide important measures of self-reported wellbeing that can be compared across healthy and clinical populations. The aim of this analysis is to validate the ten-item QoL instrument "QOL10", as well as to confirm the validity of the embedded "QOL5" questionnaire and single-item "QOL1" in measuring overall QoL among adults in a substance use disorder treatment study. METHODS: We used exploratory factor analysis and measured internal and convergent validity of the QOL10 against the gold standard measure of the WHOQOL-BREF, in a subsample of 107 participants in a substance use disorder treatment study. RESULTS: The QOL10 displayed internal and convergent validity to the gold standard measure. Factor analysis revealed a two-factor structure that can be interpreted as "social QoL", containing items about relationships and social functioning, and "global QoL", comprised of items about health, working ability, self-evaluation, and an overall QoL estimation. CONCLUSIONS: The QOL10 provides clinically useful and valid measures of social related QoL and global QoL via two subscales. Interestingly, the QOL10's social QoL measure, from the current sample, had little relationship to the analyzed groups previously reported to have differential global QoL: social QoL appears to be not only conceptually distinct from global QoL, but also to be less influenced by typical substance- and treatment-specific factors. PMID- 27216751 TI - Assessing the Nutrition Literacy of Parents and Its Relationship With Child Diet Quality. AB - OBJECTIVE: To estimate the reliability and validity of the Nutrition Literacy Assessment Instrument for Parents (NLit-P) and to investigate relationships among parental nutrition literacy, parental and child body mass index, and child diet quality (Healthy Eating Index). METHODS: Cross-sectional study of 101 parent child dyads that collected measures of socioeconomic status, nutrition literacy, 2 24-hour child diet recalls, and body mass index. Reliability of NLit-P was assessed by confirmatory factor analysis. Pearson correlation and multiple linear regression were used. RESULTS: Fair to substantial reliability was seen across 5 NLit-P domains, whereas Pearson correlations support concurrent validity for the NLit-P related to child diet quality and parental income, age, and educational attainment (P < .001). For every 1% increase in NLit-P, there was a 0.51 increase in child Healthy Eating Index (multivariate coefficient, 0.174; P < .001). CONCLUSIONS AND IMPLICATIONS: The NLit-P demonstrates potential for measuring parental nutrition literacy, which may be an important educational target for improving child diet quality. PMID- 27216752 TI - Evaluation of the diagnostic potential of urinary N-Acetyltyramine-O,beta glucuronide (NATOG) as diagnostic biomarker for Onchocerca volvulus infection. AB - BACKGROUND: Onchocerciasis, also known as river blindness is one of the neglected tropical diseases affecting millions of people, mainly in sub-Saharan Africa and is caused by the filarial nematode Onchocerca volvulus. Efforts to eliminate this disease are ongoing and are based on mass drug administration programs with the microfilaricide ivermectin. In order to monitor the efficacy of these programs, there is an unmet need for diagnostic tools capable of identifying infected patients. We have investigated the diagnostic potential of urinary N acetyltyramine-O,beta-glucuronide (NATOG), which is a promising O. volvulus specific biomarker previously identified by urine metabolome analysis. METHODS: A liquid chromatography tandem mass spectrometry (LC-MS/MS) method was used to assess the stability characteristics of NATOG and to evaluate the levels of NATOG in study samples. An LC-fluorescence method was also developed. RESULTS: Stability characteristics of NATOG were investigated and shown to be ideally suited for use in tropical settings. Also, an easy and more accessible method based on liquid chromatography coupled to fluorescence detection was developed and shown to have the necessary sensitivity (limit of quantification 1 MUM). Furthermore, we have evaluated the levels of NATOG in a population of 98 nodule positive individuals from Ghana with no or low levels of microfilaria in the skin and compared them with the levels observed in different control groups (endemic controls (n = 50), non-endemic controls (n = 18) and lymphatic filariasis (n = 51). Only a few (5 %) of nodule-positive individuals showed an increased level (> 10 MUM) of NATOG and there was no statistical difference between the nodule positive individuals and the control groups (P > 0.05). CONCLUSIONS: Results of the present study indicate the limited potential of NATOG as a diagnostic biomarker for O. volvulus infection in amicrofilaridermic individuals. PMID- 27216754 TI - Cholesterol in the rod outer segment: A complex role in a "simple" system. AB - The rod outer segment (ROS) of retinal photoreceptor cells consists of disk membranes surrounded by the plasma membrane. It is a relatively uncomplicated system in which to investigate cholesterol distribution and its functional consequences in biologically relevant membranes. The light sensitive protein, rhodopsin is the major protein in both membranes, but the lipid compositions are significantly different in the disk and plasma membranes. Cholesterol is high in the ROS plasma membrane. Disk membranes are synthesized at the base of the ROS and are also high in cholesterol. However, cholesterol is rapidly depleted as the disks are apically displaced. During this apical displacement the disk phospholipid fatty acyl chains become progressively more unsaturated, which creates an environment unfavorable to cholesterol. Membrane cholesterol has functional consequences. The high cholesterol found in the plasma membrane and in newly synthesized disks inhibits the activation of rhodopsin. As disks are apically displaced and cholesterol is depleted rhodopsin becomes more responsive to light. This effect of cholesterol on rhodopsin activation has been shown in both native and reconstituted membranes. The modulation of activity can be at least partially explained by the effect of cholesterol on bulk lipid properties. Cholesterol decreases the partial free volume of the hydrocarbon region of the bilayer and thereby inhibits rhodopsin conformational changes required for activation. However, cholesterol binds to rhodopsin and may directly affect the protein also. Furthermore, cholesterol stabilizes rhodopsin to thermal denaturation. The membrane must provide an environment that allows rhodopsin conformational changes required for activation while also stabilizing the protein to thermal denaturation. Cholesterol thus plays a complex role in modulating the activity and stability of rhodopsin, which have implications for other G-protein coupled receptors. PMID- 27216753 TI - The Vitamin E Analog Gamma-Tocotrienol (GT3) Suppresses Radiation-Induced Cytogenetic Damage. AB - PURPOSE: Ionizing radiation (IR) generates reactive oxygen species (ROS), which cause DNA double-strand breaks (DSBs) that are responsible for cytogenetic alterations. Because antioxidants are potent ROS scavengers, we determined whether the vitamin E isoform gamma-tocotrienol (GT3), a radio-protective multifunctional dietary antioxidant, can suppress IR-induced cytogenetic damage. METHODS: We measured DSB formation in irradiated primary human umbilical vein endothelial cells (HUVECs) by quantifying the formation of gamma-H2AX foci. Chromosomal aberrations (CAs) were analyzed in irradiated HUVECs and in the bone marrow cells of irradiated mice by conventional and fluorescence-based chromosome painting techniques. Gene expression was measured in HUVECs with quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). RESULTS: GT3 pretreatment reduced DSB formation in HUVECS, and also decreased CAs in HUVECs and mouse bone marrow cells after irradiation. Moreover, GT3 increased expression of the DNA-repair gene RAD50 and attenuated radiation-induced RAD50 suppression. CONCLUSIONS: GT3 attenuates radiation-induced cytogenetic damage, possibly by affecting RAD50 expression. GT3 should be explored as a therapeutic to reduce the risk of developing genetic diseases after radiation exposure. PMID- 27216756 TI - Tandem cervical/intracranial internal carotid artery occlusion due to cardiac myxoma treated successfully with mechanical endovascular thrombectomy. PMID- 27216755 TI - De novo transcriptome analysis in radish (Raphanus sativus L.) and identification of critical genes involved in bolting and flowering. AB - BACKGROUND: The appropriate timing of bolting and flowering is pivotal for reproductive success in Brassicaceae crops including radish (Raphanus sativus L.). Although several flowering regulatory pathways had been described in some plant species, no study on genetic networks of bolting and flowering regulation was performed in radish. In this study, to generate dataset of radish unigene sequences for large-scale gene discovery and functional pathway identification, a cDNA library from mixed radish leaves at different developmental stages was subjected to high-throughput RNA sequencing (RNA-seq). RESULTS: A total of 54.64 million clean reads and 111,167 contigs representing 53,642 unigenes were obtained from the radish leaf transcriptome. Among these, 50,385 unigenes were successfully annotated by BLAST searching against the public protein databases. Functional classification and annotation indicated that 42,903 and 15,382 unique sequences were assigned to 55 GO terms and 25 COG categories, respectively. KEGG pathway analysis revealed that 25,973 unigenes were classified into 128 functional pathways, among which 24 candidate genes related to plant circadian rhythm were identified. Moreover, 142 potential bolting and flowering-related genes involved in various flowering pathways were identified. In addition, seven critical bolting and flowering-related genes were isolated and profiled by T-A cloning and RT-qPCR analysis. Finally, a schematic network model of bolting and flowering regulation and pathways was put forward in radish. CONCLUSIONS: This study is the first report on systematic identification of bolting and flowering related genes based on transcriptome sequencing and assembly in radish. These results could provide a foundation for further investigating bolting and flowering regulatory networks in radish, and facilitate dissecting molecular genetic mechanisms underlying bolting and flowering in Brassicaceae vegetable crops. PMID- 27216757 TI - Hydrocephalus in vein of Galen malformation. Another paradigm shift in neurosurgery. PMID- 27216758 TI - Effectiveness of seasonal trivalent influenza vaccination against hospital attended acute respiratory infections in pregnant women: A retrospective cohort study. AB - BACKGROUND: Pregnant women are at risk of serious influenza infection. Although previous studies indicate maternal influenza vaccination can prevent hospitalisation in young infants, there is limited evidence of the effect in mothers. METHODS: A cohort of 34,701 pregnant women delivering between 1 April 2012 and 31 December 2013 was created using birth records. Principal diagnosis codes from hospital emergency department (ED) and inpatient records were used to identify episodes of acute respiratory illness (ARI) during the 2012 and 2013 southern hemisphere influenza seasons. Cox regression models were used to calculate adjusted hazard ratios (aHRs) by maternal vaccination status, controlling for Indigenous status, socioeconomic level, medical conditions, and week of delivery. RESULTS: 3,007 (8.7%) women received a seasonal influenza vaccine during pregnancy. Vaccinated women were less likely to visit an ED during pregnancy for an ARI (9.7 visits per 10,000 person-days vs. 35.5 visits per 10,000 person-days; aHR: 0.19, 95% CI: 0.05-0.68). Vaccinated women were also less likely to be hospitalised with an ARI compared to unvaccinated women (16.2 hospitalisations per 10,000 person-days vs. 34.0 hospitalisations per 10,000 person-days; aHR: 0.35, 95% CI: 0.13-0.97). CONCLUSIONS: Influenza vaccination during pregnancy was associated with significantly fewer hospital attendances for ARI in pregnant women. PMID- 27216759 TI - Zika vaccine misconceptions: A social media analysis. PMID- 27216760 TI - Risk of solid organ transplant rejection following vaccination with seasonal trivalent inactivated influenza vaccines in England: A self-controlled case series. AB - BACKGROUND: Annual seasonal influenza vaccination is recommended for transplant recipients. No formal pharmacoepidemiology study has been published on the association between solid organ transplant (SOT) rejection and vaccination with seasonal trivalent inactivated influenza vaccines (TIIVs). METHODS: The risk of SOT (liver, kidney, lung, heart or pancreas) rejection after TIIV vaccination was assessed using a self-controlled case-series method (NCT01715792). SOT recipients in England with transplant rejection were selected from the Clinical Practice Research Datalink and linked Hospital Episode Statistics inpatient data. The study period (September 2006 to August 2009) encompassed three consecutive influenza seasons. We calculated the relative incidence (RI) of SOT rejection between the 30- and 60-day post-vaccination risk periods and the control periods (any follow-up period excluding risk periods), using a Poisson regression model. RESULTS: In seasons 2006/07, 2007/08, 2008/09 and pooled seasons, 132, 136, 168 and 375 subjects, respectively, experienced at least one transplant rejection; approximately half (45%-51%) of these subjects had received a TIIV. For season 2006/07, the RI of rejection of any organ, adjusted for time since transplantation, was 0.74 (95% CI: 0.24-2.28) and 0.58 (95% CI: 0.24-1.38) during the 30-day and 60-day risk periods, respectively. Corresponding RIs for season 2007/08 were 1.21 (95% CI: 0.55-2.64) and 1.31 (95% CI: 0.69-2.48); for season 2008/09, 0.99 (95% CI: 0.43-2.28) and 0.64 (95% CI: 0.31-1.33); and for pooled seasons 1.01 (95% CI: 0.58-1.76) and 0.88 (95% CI: 0.56-1.38). The results of a separate analysis of kidney rejections and analyses that took into account additional potential confounders were consistent with those of the main analyses, with 95% CIs including 1 and upper limits below 3. CONCLUSION: This study provides reassuring evidence of the safety profile of TIIVs in SOT recipients, thus supporting current recommendations to vaccinate this risk group annually. PMID- 27216761 TI - Report of the Cent Gardes HIV Vaccines Conference. Part 1: The antibody response; Fondation Merieux Conference Center, Veyrier-du-Lac, France, 25-27 October 2015. AB - The 2015 Cent Gardes Conference on HIV vaccines took place on October 25-27 at the Merieux Foundation Conference Center in Veyrier du Lac, near Annecy, France. The meeting reviewed progress in the development of HIV vaccines and identified new directions of future research. The field has advanced incrementally over the past year but major progress will require additional information from new clinical trials. In this article, we review the presentations on humoral immune responses to HIV, and highlight the difficulty of eliciting broadly neutralizing antibodies by vaccination. Advances in cellular immunity for HIV prevention will be reviewed separately, in a following article. PMID- 27216762 TI - Outer retinal deformity detected by optical coherence tomography in eyes with foveal hypoplasia. AB - PURPOSE: To investigate the relationship between vision and foveal maturity, especially in foveal hypoplasia exhibiting severe structural immaturity. METHODS: This retrospective observational case series included 42 eyes of 23 patients (mean age, 7.0 +/- 5.0 years; 9 patients with foveal hypoplasia as an isolated entity and 14 patients with aniridia). A complete ophthalmic examination included measurement of best-corrected visual acuity (BCVA) and spectral-domain optical coherence tomography (SD-OCT). The sensory retina, ganglion cell complex (GCC), and outer retinal layers, including Henle's fiber layer (HFL), were measured and analyzed. RESULTS: Using SD-OCT images, eyes were classified as having a differentiated (6 eyes), diffuse (19 eyes), or no HFL (17 eyes), based on the appearance of the HFL around the foveal region. The logMAR BCVA was significantly worse (p < 0.0001) in eyes with diffuse HFL and those with no HFL than in those with differentiated HFL. Outer retinal thickness (outer plexiform layer + HFL + outer nuclear layer) was less (p = 0.0051) in eyes with no HFL than in those with differentiated HFL. The logMAR BCVA, GCC thickness, and outer retinal thickness in eyes with foveal hypoplasia with aniridia were significantly worse (p = 0.0083), thicker (p = 0.0039), and thinner (p = 0.0001), respectively, than in eyes with foveal hypoplasia as an isolated entity. CONCLUSIONS: In eyes with foveal hypoplasia with severe structural immaturity, diffuse HFL or no HFL was associated with worse vision. There was greater foveal immaturity in eyes with foveal hypoplasia with aniridia compared with foveal hypoplasia as an isolated entity. PMID- 27216763 TI - Recent progress on targeting the alphavbeta1 integrin for the treatment of tissue fibrosis. PMID- 27216764 TI - Obama calls on Congress to fully fund Zika response. PMID- 27216765 TI - Field Reports: Yes, They Will Add to the Prehospital and Disaster Knowledge Base. AB - Fattah S , Rehn M , Wisborg T . Field reports: yes, they will add to the prehospital and disaster knowledge base. Prehosp Disaster Med. 2016;31(4):461 461. PMID- 27216766 TI - Using Community Partnerships to Better Understand the Barriers to Using an Evidence-Based, Parent-Mediated Intervention for Autism Spectrum Disorder in a Medicaid System. AB - Service use disparities have been noted to impede under-resourced families' ability to access high-quality services for their child with autism spectrum disorder (ASD). These disparities are particularly relevant for parent-mediated interventions and may suggest a lack of fit between these interventions and the needs of under-resourced community settings. This study used Roger's Diffusion of Innovations theory to guide community partnerships aimed at understanding the perceived compatibility, complexity, and relative advantage of using an evidence based, parent-mediated intervention (Project ImPACT) within a Medicaid system. Three focus groups were conducted with 16 Medicaid-eligible parents, and three focus groups were conducted with 16 ASD providers operating within a Medicaid system. Across all groups, parents and providers reported general interest in using Project ImPACT. However, primary themes emerged regarding the need to (a) reduce the complexity of written materials; (b) allow for a more flexible program delivery; (c) ensure a strong parent-therapist alliance; (d) involve the extended family; and (e) help families practice the intervention within their preexisting routines. Results are discussed as they relate to the design and fit of evidence based, parent-mediated interventions for under-resourced community settings. PMID- 27216767 TI - Allohahella marinimesophila gen. nov., sp. nov., isolated from seawater and reclassification of Hahella antarctica as Allohahella antarctica comb. nov. AB - A Gram-stain-negative, non-endospore-forming, strictly aerobic, irregular rod shaped bacterium without flagellum, designated strain H94T, was isolated by the high-throughput cultivation method from seawater of an amphioxus breeding zone in the coastal region of Qingdao, China. Growth was observed at 4-37 degrees C (optimum 28 degrees C), at pH 6.0-10.0 (optimum pH 7.0) and in the presence of 1 12 % (w/v) NaCl (optimum 1-2 %). The predominant cellular fatty acids were C18 : 1omega9c, C16 : 0 and C16 : 1omega9c. The polar lipids comprised phosphatidylethanolamine, phosphatidylglycerol and an unidentified phosphoglycolipid. The major respiratory quinone was ubiquinone-9 (Q-9). The genomic DNA G+C content of strain H94T was 56.2 mol%. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain H94T shared the highest similarity (95.9 %) with Hahella antarctica NBRC 102683T, and exhibited 92.9 % and 92.1 % similarity with the two other recognized Hahella species, Hahella chejuensis KCTC 2396T and Hahella ganghwensis DSM 17046T, respectively. The phylogenetic position revealed that strain H94T formed a stable distinct lineage cluster together with Hahella antarctica NBRC 102683T and this result was further confirmed by multilocus sequence analysis based on housekeeping genes gyrB and rpoB. On the basis of the polyphasic taxonomic analyses, strain H94T is considered to represent a novel species in a new genus, for which the name Allohahellamarinimesophila gen. nov., sp. nov. is proposed. The type strain of Allohahellamarinimesophila is H94T (=CGMCC 1.10800T=JCM 17555T). It is also proposed that Hahella antarctica should be reclassified within the genus Allohahella as Allohahella antarctica comb. nov. (type strain NBRC 102683T=IMCC 3113T=KCCM 42675T). The type species of the genus Allohahella is Allohahella antarctica comb. nov. PMID- 27216768 TI - Enhanced immune response to foot-and-mouth disease vaccine by oral administration of ginseng stem-leaf saponins. AB - Vaccination is an important approach to the control of foot-and-mouth disease (FMD). This study evaluated the effect of oral administration of ginseng stem leaf saponins (GSLS) on the immune response to FMD vaccine and the gut mucosal immunity in mice. In experiment 1, mice were orally administered GSLS or not treated as a control. The animals were then immunized twice with FMD vaccine. Blood was sampled weekly within five weeks after the boost immunization for measurement of serum IgG and the isotypes. In experiment 2, mice were orally administrated GSLS or not treated as a control. After that, splenocytes were prepared from sacrificed mice for lymphocyte proliferation assay and intestinal tissues were sampled for immunohistochemistry and histological examination. The results showed that oral administration of GSLS significantly enhanced serum IgG and the isotype responses to FMD vaccine as well as the number of intestinal intraepithelial lymphocytes (IELs) and immunoglobulin A (IgA)+ cells. Therefore, GSLS may be a potent oral adjuvant and deserve further study to improve vaccination in susceptible animals. PMID- 27216770 TI - Sharing Clinical Trial Data. PMID- 27216769 TI - Quantification of 2-methylcitric acid in dried blood spots improves newborn screening for propionic and methylmalonic acidemias. AB - Background Newborn screening for propionic acidemia and methylmalonic acidurias using the marker propionylcarnitine (C3) is neither sensitive nor specific. Using C3 to acetylcarnitine (C3/C2) ratio, together with conservative C3 cut-offs, can improve screening sensitivity, but the false positive rate remains high. Incorporating the marker 2-methylcitric acid has been suggested, to improve the positive predictive value for these disorders without compromising the sensitivity. Methods Between July 2011 and December 2012 at the Newborn Screening Ontario laboratory, all neonatal dried blood spot samples that were reported as screen positive for propionic acidemia or methylmalonic acidurias based on elevated C3 and C3/C2 ratio were analyzed for 2-methylcitric acid, using liquid chromatography tandem mass spectrometry. Results Of 222,420 samples screened, 103 were positive for methylmalonic acidurias or propionic acidemia using C3 and C3/C2 ratio as markers. There were nine true positives: propionic acidemia (n = 3), Cobalamin (Cbl) A (n=1), and Cbl C (n = 5). Among false positives there were 72 neonates not affected, 20 with maternal B12 deficiency, and two incidental finding (transcobalamin II and unclassified Cbl defect). 2-Methylcitric acid was analyzed in all 103 samples and ranged between 0.1 and 89.4 umol/l (reference range 0.04-0.36). Only 14 samples exceeded the set 2-methylcitric acid cut-off of 1.0 umol/l, including the samples from all nine true positives. Conclusion By including 2-methylcitric acid in the screening algorithm, the positive predictive value of our primary and secondary screening targets improved from 8.7 to 64.3%. This would have eliminated 89 unnecessary referrals while maintaining 100% sensitivity. PMID- 27216771 TI - Patient factors associated with non-attendance at colonoscopy after a positive screening faecal occult blood test. AB - Background Screening participants with abnormal faecal occult blood test results who do not attend further testing are at high risk of colorectal cancer, yet little is known about their reasons for non-attendance. Methods We conducted a medical record review of 170 patients from two English Bowel Cancer Screening Programme centres who had abnormal guaiac faecal occult blood test screening tests between November 2011 and April 2013 but did not undergo colonoscopy. Using information from patient records, we coded and categorized reasons for non attendance. Results Of the 170 patients, 82 were eligible for review, of whom 66 had at least one recorded reason for lack of colonoscopy follow-up. Reasons fell into seven main categories: (i) other commitments, (ii) unwillingness to have the test, (iii) a feeling that the faecal occult blood test result was a false positive, (iv) another health issue taking priority, (v) failing to complete bowel preparation, (vi) practical barriers (e.g. lack of transport), and (vii) having had or planning colonoscopy elsewhere. The most common single reasons were unwillingness to have a colonoscopy and being away. Conclusions We identify a range of apparent reasons for colonoscopy non-attendance after a positive faecal occult blood test screening. Education regarding the interpretation of guaiac faecal occult blood test findings, offer of alternative confirmatory test options, and flexibility in the timing or location of subsequent testing might decrease non-attendance of diagnostic testing following positive faecal occult blood test. PMID- 27216772 TI - Chronic intermittent hypobaric hypoxia antagonizes renal vascular hypertension by enhancement of vasorelaxation via activating BKCa. AB - AIM: The purpose of the present study was to explore anti-hypertensive effect of chronic intermittent hypobaric hypoxia (CIHH) in renovascular hypertension (RVH) rats, as well as the role of large-conductance calcium-activated potassium channel (BKCa) in anti-hypertensive effect of CIHH. MAIN METHODS: Male adult age- and body weight-matched Sprague-Dawley rats were divided into SHAM, CIHH, RVH and RVH+CIHH groups. Hypertension was induced by two-kidney-1-clip method (2K1C) in RVH rats. CIHH rats were exposed to 28-days hypobaric hypoxia simulating 5000m altitude, 6h daily. SHAM rats got an operation without 2K1C, and RVH+CIHH rats received CIHH treatment after 2K1C. The endothelium-dependent vasorelaxation induced by acetylcholine (ACh), BKCa currents in smooth muscle cells (VSMCs) of mesenteric arteries and the protein expression of BKCa in mesenteric arteries was examined. KEY FINDINGS: The systolic arterial blood pressure (SAP) in RVH rats was higher than that in SHAM rats and CIHH treatment significantly decreased SAP in RVH rats. The enhanced vasorelaxation of mesenteric artery in CIHH-treated RVH rats was cancelled by BKCa blocker IBTX. The vasorelaxation induced by BKCa activator was reduced in RVH rats and the decreased vasorelaxation was improved by CIHH treatment. The beta1 subunit of BKCa in mesenteric artery was upregulated and BKCa current in VSMCs was increased in CIHH-treated RVH rats compared with RVH rats. SIGNIFICANCE: In conclusion, CIHH treatment enhances the relaxation of mesenteric artery through activation of BKCavia up-regulating beta1 subunit of BKCa, which might be one of mechanisms for anti-hypertensive effect of CIHH in RVH rats. PMID- 27216773 TI - Epigenetic therapy as a novel approach for GFI136N-associated murine/human AML. AB - Epigenetic changes can contribute to development of acute myeloid leukemia (AML), a malignant disease of the bone marrow. A single-nucleotide polymorphism of transcription factor growth factor independence 1 (GFI1) generates a protein with an asparagine at position 36 (GFI1(36N)) instead of a serine at position 36 (GFI1(36S)), which is associated with de novo AML in humans. However, how GFI1(36N) predisposes to AML is poorly understood. To explore the mechanism, we used knock-in mouse strains expressing GFI1(36N) or GFI1(36S). Presence of GFI1(36N) shortened the latency and increased the incidence of AML in different murine models of myelodysplastic syndrome/AML. On a molecular level, GFI1(36N) induced genomewide epigenetic changes, leading to expression of AML-associated genes. On a therapeutic level, use of histone acetyltransferase inhibitors specifically impeded growth of GFI1(36N)-expressing human and murine AML cells in vitro and in vivo. These results establish, as a proof of principle, how epigenetic changes in GFI1(36N)-induced AML can be targeted. PMID- 27216775 TI - Recent Advances in Defining the Genetic Basis of Rheumatoid Arthritis. AB - Rheumatoid arthritis (RA) is the most common inflammatory arthritis and exhibits genetic overlap with other autoimmune and inflammatory disorders. Although predominant associations with the HLA-DRB1 locus have been known for decades, recent data have revealed additional insight into the likely causative variants within HLA-DRB1 as well as within other HLA loci that contribute to disease risk. In addition, more than 100 common variants in non-HLA loci have been implicated in disease susceptibility. Genetic factors are involved not only in the development of RA, but also with various disease subphenotypes, including production and circulating levels of autoantibodies and joint destruction. The major current challenge is to integrate these new data into a precise understanding of disease pathogenesis, including the critical cell types and molecular networks involved as well as interactions with environmental factors. We predict that delineating the functional effects of genetic variants is likely to drive new diagnostic and therapeutic approaches to the disease. PMID- 27216774 TI - Polycomb PRC2 complex mediates epigenetic silencing of a critical osteogenic master regulator in the hippocampus. AB - During hippocampal neuron differentiation, the expression of critical inducers of non-neuronal cell lineages must be efficiently silenced. Runx2 transcription factor is the master regulator of mesenchymal cells responsible for intramembranous osteoblast differentiation and formation of the craniofacial bone tissue that surrounds and protects the central nervous system (CNS) in mammalian embryos. The molecular mechanisms that mediate silencing of the Runx2 gene and its downstream target osteogenic-related genes in neuronal cells have not been explored. Here, we assess the epigenetic mechanisms that mediate silencing of osteoblast-specific genes in CNS neurons. In particular, we address the contribution of histone epigenetic marks and histone modifiers on the silencing of the Runx2/p57 bone-related isoform in rat hippocampal tissues at embryonic to adult stages. Our results indicate enrichment of repressive chromatin histone marks and of the Polycomb PRC2 complex at the Runx2/p57 promoter region. Knockdown of PRC2 H3K27-methyltransferases Ezh2 and Ezh1, or forced expression of the Trithorax/COMPASS subunit Wdr5 activates Runx2/p57 mRNA expression in both immature and mature hippocampal cells. Together these results indicate that complementary epigenetic mechanisms progressively and efficiently silence critical osteoblastic genes during hippocampal neuron differentiation. PMID- 27216777 TI - Genomic Analysis of the Emergence, Evolution, and Spread of Human Respiratory RNA Viruses. AB - The emergence and reemergence of rapidly evolving RNA viruses-particularly those responsible for respiratory diseases, such as influenza viruses and coronaviruses pose a significant threat to global health, including the potential of major pandemics. Importantly, recent advances in high-throughput genome sequencing enable researchers to reveal the genomic diversity of these viral pathogens at much lower cost and with much greater precision than they could before. In particular, the genome sequence data generated allow inferences to be made on the molecular basis of viral emergence, evolution, and spread in human populations in real time. In this review, we introduce recent computational methods that analyze viral genomic data, particularly in combination with metadata such as sampling time, geographic location, and virulence. We then outline the insights these analyses have provided into the fundamental patterns and processes of evolution and emergence in human respiratory RNA viruses, as well as the major challenges in such genomic analyses. PMID- 27216776 TI - CRISPR/Cas9 for Human Genome Engineering and Disease Research. AB - The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated 9 (Cas9) system, a versatile RNA-guided DNA targeting platform, has been revolutionizing our ability to modify, manipulate, and visualize the human genome, which greatly advances both biological research and therapeutics development. Here, we review the current development of CRISPR/Cas9 technologies for gene editing, transcription regulation, genome imaging, and epigenetic modification. We discuss the broad application of this system to the study of functional genomics, especially genome-wide genetic screening, and to therapeutics development, including establishing disease models, correcting defective genetic mutations, and treating diseases. PMID- 27216778 TI - Developmental Origins of Common Disease: Epigenetic Contributions to Obesity. AB - The perinatal period is a window of susceptibility for later life disease. Recent epigenetic findings are beginning to increase our understanding of the molecular mechanisms that may contribute to the programming of obesity. This review summarizes recent evidence that supports the role of epigenetically mediated early life programming in the later onset of obesity. Establishing such links between environmental exposures and modifiable molecular changes ultimately holds promise to inform interventional efforts toward alleviating the environmentally mediated onset of obesity. PMID- 27216779 TI - QwikMD - Integrative Molecular Dynamics Toolkit for Novices and Experts. AB - The proper functioning of biomolecules in living cells requires them to assume particular structures and to undergo conformational changes. Both biomolecular structure and motion can be studied using a wide variety of techniques, but none offers the level of detail as do molecular dynamics (MD) simulations. Integrating two widely used modeling programs, namely NAMD and VMD, we have created a robust, user-friendly software, QwikMD, which enables novices and experts alike to address biomedically relevant questions, where often only molecular dynamics simulations can provide answers. Performing both simple and advanced MD simulations interactively, QwikMD automates as many steps as necessary for preparing, carrying out, and analyzing simulations while checking for common errors and enabling reproducibility. QwikMD meets also the needs of experts in the field, increasing the efficiency and quality of their work by carrying out tedious or repetitive tasks while enabling easy control of every step. Whether carrying out simulations within the live view mode on a small laptop or performing complex and large simulations on supercomputers or Cloud computers, QwikMD uses the same steps and user interface. QwikMD is freely available by download on group and personal computers. It is also available on the cloud at Amazon Web Services. PMID- 27216780 TI - Asymmetric dimethylarginine and related metabolites in exhaled breath condensate of children with cystic fibrosis. AB - INTRODUCTION: Asymmetric dimethylarginine (ADMA) competitively inhibits nitric oxide synthase (NOS). Its levels in specimens from murine models and asthmatic patients are related to inflammation and oxidative stress. Patients with cystic fibrosis(CF) reportedly have higher arginase activity, lower NO production and NOS expression than healthy controls. OBJECTIVE: The objective was to assess the role of ADMA and related metabolites as disease biomarkers in exhaled breath condensate (EBC) of pediatric CF patients, compared with age-matched healthy controls (HC). METHODS: A longitudinal design was conceived and 34 CF patients (21 stable, 13 at the onset of exacerbation) and 16 HC were enrolled. All CF patients underwent clinical examination, spirometry and EBC collection at enrolment; the same tests were performed also after an antibiotic course in those patients with exacerbation. Metabolites levels in EBC were measured with an ultra performance liquid chromatography and tandem mass spectrometry technique. RESULTS: All CF patients had ADMA levels (expressed as ratio to tyrosine) similar to those in HC (median 0.0112, IQR 0.0103-0.0120 and median 0.0114, IQR 0.0090 0.0128, respectively; P = 0.983), while a significant increase in the citrulline/tyrosine ratio was found in CF patients (median 0.6419, IQR 0.5738 0.6899 in CF vs median 0.4176, IQR 0.2986-0.5082 in HC; P = 0.00003). No differences in ADMA levels emerged between stable patients and those with exacerbation. CONCLUSION: ADMA and related aminoacids were measured simultaneously for the first time in EBC from CF patients. Higher citrulline/tyrosine ratios were found in CF children with normal ADMA levels, suggesting a dysregulated ADMA metabolism in these patients. PMID- 27216782 TI - Corrigendum. PMID- 27216781 TI - 34th European Society for Paediatric Infectious Diseases annual meeting. PMID- 27216789 TI - Anisotropic metal growth on phospholipid nanodiscs via lipid bilayer expansion. AB - Self-assembling biomolecules provide attractive templates for the preparation of metallic nanostructures. However, the intuitive transfer of the "outer shape" of the assembled macromolecules to the final metallic particle depends on the intermolecular forces among the biomolecules which compete with interactions between template molecules and the metal during metallization. The shape of the bio-template may thus be more dynamic than generally assumed. Here, we have studied the metallization of phospholipid nanodiscs which are discoidal particles of ~10 nm diameter containing a lipid bilayer ~5 nm thick. Using negatively charged lipids, electrostatic adsorption of amine-coated Au nanoparticles was achieved and followed by electroless gold deposition. Whereas Au nanoparticle adsorption preserves the shape of the bio-template, metallization proceeds via invasion of Au into the hydrophobic core of the nanodisc. Thereby, the lipidic phase induces a lateral growth that increases the diameter but not the original thickness of the template. Infrared spectroscopy reveals lipid expansion and suggests the existence of internal gaps in the metallized nanodiscs, which is confirmed by surface-enhanced Raman scattering from the encapsulated lipids. Interference of metallic growth with non-covalent interactions can thus become itself a shape-determining factor in the metallization of particularly soft and structurally anisotropic biomaterials. PMID- 27216790 TI - How do different humanness measures relate? Confronting the attribution of secondary emotions, human uniqueness, and human nature traits. AB - The present research examines the relationship between the infrahumanization approach and the two-dimensional model of humanness: an issue that has received very little empirical attention. In Study 1, we created three unknown groups (Humanized, Animalized, and Mechanized) granting/denying them Human Nature (HN) and Human Uniqueness (HU) traits. The attribution of primary/secondary emotions was measured. As expected, participants attributed more secondary emotions to the humanized compared to dehumanized groups. Importantly, both animalized and mechanized groups were attributed similar amounts of secondary emotions. In Study 2, the groups were described in terms of their capacity to express secondary emotions. We measured the attribution of HN/HU traits. Results showed that the infrahumanized group was denied both HU/HN traits. The results highlight the importance of considering the common aspects of both approaches in understanding processes of dehumanization. PMID- 27216791 TI - Exploring linguistic correlates of social anxiety in romantic stories. AB - The current study used computerized linguistic analysis of stories about either going on a date or taking a walk down a street to examine linguistic correlates of social anxiety in a sample of undergraduate students. In general, linguistic analysis revealed associations of social anxiety with several linguistic variables, including negative emotion, affect, and anxiety words. Participants higher in social anxiety wrote fewer affect words. The relationship between social anxiety and anxiety words depended on gender, whereas the relationship between social anxiety and negative emotion words depended on both gender and the nature of primes (supraliminal vs. subliminal) received. Overall, our findings highlight the potential utility and benefits of using linguistic analysis as another source of information about how individuals higher in social anxiety process romantic stimuli. PMID- 27216792 TI - Drug Interactions with Angiotensin Receptor Blockers: Role of Human Cytochromes P450. AB - BACKGROUND: Angiotensin receptor blockers (ARBs) are the most recent class of agents for the treatment of hypertension. However, ARBs may cause a low incidence of headache, upper respiratory infection, back pain, muscle cramps, fatigue, dizziness, and many other side effects. In some cases, such toxicity is associated with pharmacokinetic alterations. METHODS: The cytochrome P450 (CYP) enzyme system plays an important role in a lot of clinically important pharmacokinetic drug interactions. To identify relevant studies on drug-drug and food-drug pharmacokinetic interactions with the ARBs, a literature search of Google Scholar was performed from January 1994 to June 2015, with the following keywords: 'losartan', 'valsartan,' 'candesartan,' 'irbesartan,' 'telmisartan,' 'eprosartan,' 'olmesartan,' and 'azilsartan', combined with the keyword 'pharmacokinetic interactions' and 'CYP'. RESULTS: Based on the literatures published, it has been demonstrated that pharmacokinetic interactions of losartan with other agents are mainly via CYP2C9- and CYP3A4-mediated, the role played by CYP enzyme system in the metabolism of valsartan, candesartan, irbesartan, and azilsartan appears modest, and cytochrome P450 system has no influence on the metabolism of telmisartan, eprosartan, olmesartan. Therefore, according to these pharmacokinetic findings, no dosage adjustment is recommended when eprosartan, telmisartan and olmesartan are combined with other pharmacological agents in patients with hypertension. CONCLUSION: This review summarize the available data on cytochrome P450 - related drug-drug interactions reported in the literature for the eight ARBs. Knowledge of the pharmacokinetic properties of the ARBs should allow the avoidance of the majority of drug interactions without compromising therapeutic benefits. PMID- 27216793 TI - Paediatric brainstem: A comprehensive review of pathologies on MR imaging. AB - The brainstem is a midline structure formed by the midbrain, pons and medulla and is a home for various vital neurological centres of the human body. A diverse spectrum of disease entities can involve the brainstem, which includes infections, metabolic disorders, demyelination, vascular conditions, neurodegenerative disorders and tumours. Brainstem involvement can be primary or secondary, i.e., as part of systemic disorders. Due to the overlapping clinical presentation and symptomatology, imaging plays a decisive role in the detection, localisation and characterisation of brainstem pathologies. Magnetic resonance imaging (MRI) is the modality of choice and the use of advanced MR techniques such as diffusion-weighted imaging and spectroscopy can be especially helpful in providing a tenable diagnoses. This article is a compilation of the MR imaging manifestations of a spectrum of common and uncommon brainstem pathologies that can be encountered in the paediatric age group. Teaching Points * The paediatric brainstem can be afflicted by many pathologies that may overlap clinico radiologically. * MRI is the best modality for the localisation and diagnosis of brainstem pathologies. * Diffusion-weighted imaging is useful in the diagnosis of vascular and metabolic disorders. * Occasionally, demyelination and neoplasms can be indistinguishable on imaging. PMID- 27216794 TI - Antiviral and virucidal activities of Duabanga grandiflora leaf extract against Pseudorabies virus in vitro. AB - BACKGROUND: Duabanga grandiflora or known in Malaysia as Berembang Bukit, Megawasih, or Pedada Bukit, is a native plant of the Southeast Asian countries. In this study, the anti-viral properties of D. grandiflora were investigated. METHODS: The D. grandiflora leaf extracts were obtained with ethyl acetate, hexane, and ethanol as solvents and labelled 37 leaf ethyl acetate (37 L EA), 37 leaf hexane (37 L H), 37 leaf ethanol (37 L ET), respectively. The cytotoxicity of the extracts on Vero cells were determined by the 3-(4,5-Diamethylthiazol-2 yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay. RESULTS: Among extracts, 37 L EA was most cytotoxic to Vero cells, followed by 37 L H and 37 L ET, with CC50 of 218, 833, and >1000 MUg/mL, respectively. The cytopathic effect (CPE) and plaque reduction, inhibition, and virucidal assays and the selective index (SI) were employed to determine the effect of the extracts on infectivity and replication of pseudorabies virus (PrV) in Vero cells. The D. grandiflora leaf extracts showed dose-dependent antiviral activities, with higher activities at high doses. The 37 L ET and 37 L EA showed anti-viral effects through plaque formation and viral replication inhibitions, and virucidal property. The SI of the 37 L ET and 37 L EA by the viral replication inhibition assay was 8.3 and 1.9, respectively, and by the CPE reduction assay, 6.7 and 2.9, respectively. CONCLUSION: Ethanol is the best solvent for the preparation of D. grandiflora leaf extract as an antiviral agent. PMID- 27216795 TI - Body Image Satisfaction Among Blacks. AB - Satisfaction with body image is a factor related to health outcomes. The purpose of this study is to examine the relationship between body image satisfaction and body size perception in an urban, Black community sample in New Orleans, Louisiana. Only 42.2% of respondents were satisfied with their body image and 44.1% correctly perceived their body size. Most respondents chose an ideal image in the normal body mass index range with over half choosing an ideal image smaller than their actual size. Misperception was greatest among the heaviest respondents. Females, those who overestimated their size, those with an education beyond high school, and those who were active in order to lose weight were less likely to be satisfied ( p < .001). Those who were active but not trying to lose weight were more likely to be satisfied ( p < .001). This suggests that perception of and satisfaction with body size may play a role in health behavior decisions. PMID- 27216796 TI - Prophylactic antibiotic treatment in severe acute ischemic stroke: the Antimicrobial chemopRrophylaxis for Ischemic STrokE In MaceDonIa-Thrace Study (ARISTEIDIS). AB - Infections represent a leading cause of mortality in patients with acute ischemic stroke, but it is unclear whether prophylactic antibiotic treatment improves the outcome. We aimed to evaluate the effects of this treatment on infection incidence and short-term mortality. This was a pragmatic, prospective multicenter real-world analysis of previously independent consecutive patients with acute ischemic stroke who were >18 years, and who had at admission National Institutes of Health Stroke Scale (NIHSS) >11. Patients with infection at admission or during the preceding month, with axillary temperature at admission >37 degrees C, with chronic inflammatory diseases or under treatment with corticosteroids were excluded from the study. Among 110 patients (44.5 % males, 80.2 +/- 6.8 years), 31 (28.2 %) received prophylactic antibiotic treatment, mostly cefuroxime (n = 21). Prophylactic antibiotic treatment was administered to 51.4 % of patients who developed infection, and to 16.4 % of patients who did not (p < 0.001). Independent predictors of infection were NIHSS at admission [relative risk (RR) 1.16, 95 % confidence interval (CI) 1.08-1.26, p < 0.001] and prophylactic antibiotic treatment (RR 5.84, 95 % CI 2.03-16.79, p < 0.001). The proportion of patients who received prophylactic antibiotic treatment did not differ between patients who died during hospitalization and those discharged, or between patients who died during hospitalization or during follow-up and those who were alive 3 months after discharge. Prophylactic administration of antibiotics in patients with severe acute ischemic stroke is associated with an increased risk of infection during hospitalization, and does not affect short term mortality risk. PMID- 27216797 TI - Portal vein thrombosis in patients with cirrhosis: underdiagnosis and undertreatment? PMID- 27216798 TI - Considerations in Applying a New Stent Retriever in Pediatric Endovascular Cerebral Thrombectomy for Acute Ischemic Stroke. AB - Acute ischemic stroke (AIS) in children has been difficult to diagnose, treat and study, due to atypical clinical presentation, imaging challenges and the rarity of large-vessel embolic occlusion as the etiology of acute neurological change in children. With endovascular thrombectomy showing success in randomized trials of adult AIS, the technique is increasingly being extrapolated to pediatric stroke. However, there is little evidence regarding the safety or efficacy of applying in children these devices developed and tested in adults. There is concern about a vessel-to-device size mismatch that may result in a different complication and benefit profile than typically seen. We report on the successful application in pediatric stroke of a newer-generation, smaller stent retriever, designed to be delivered through relatively smaller and more navigable microcatheters than the prior generation of this device. PMID- 27216799 TI - Pediatric sepsis and septic shock management in resource-limited settings. PMID- 27216800 TI - Laparoscopic Distal Pancreatectomy for Pancreatic Tumors: Does Size Matter? AB - BACKGROUND: Laparoscopic distal pancreatectomy (LDP) for large pancreatic tumors may require prolonged dissection, and this could be associated with increased operative time and intraoperative complications. METHODS: From a total cohort of 190 consecutive patients undergoing LDP, 18 patients were found to have pancreatic tumors >5 cm and were included in the retrospective study of prospectively collected data. Three techniques were used to approach the splenic vessels: the superior pancreatic, the inferior supracolic and post-pancreatic transection. RESULTS: Of these 18 patients, 13 were women and 5 were men, the median age was 68 years and their median tumor size 7 cm. Exocrine pancreatic malignancy was diagnosed in 8 patients, 6 patients had neuroendocrine pancreatic tumors and 4 patients cystic neoplasm. The median number of resected nodes was 14. R1 resections for exocrine pancreatic malignancies were found in 50% of patients. Morbidity (grade >II) was found in 16.6% of patients and 30 days mortality in 1 patient. Overall median survival was 50 months and 29 months for patients with exocrine pancreatic malignancies. CONCLUSIONS: LDP for large tumors, while technically demanding, is possible without additional morbidity and did not compromise short- and long-term oncological outcomes. PMID- 27216801 TI - The bovine milk microbiota: insights and perspectives from -omics studies. AB - Recent significant progress in culture-independent techniques, together with the parallel development of -omics technologies and data analysis capabilities, have led to a new perception of the milk microbiota as a complex microbial community with great diversity and multifaceted biological roles, living in an environment that was until recently believed to be sterile. In this review, we summarize and discuss the latest findings on the milk microbiota in dairy cows, with a focus on the role it plays in bovine physiology and health. Following an introduction on microbial communities and the importance of their study, we present an overview of the -omics methods currently available for their characterization, and outline the potential offered by a systems biology approach encompassing metatranscriptomics, metaproteomics, and metametabolomics. Then, we review the recent discoveries on the dairy cow milk microbiome enabled by the application of -omics approaches. Learning from studies in humans and in the mouse model, and after a description of the endogenous route hypothesis, we discuss the role of the milk microbiota in the physiology and health of both the mother and the offspring, and report how it can be changed by farming practices and during infection. In conclusion, we shortly outline the impact of the milk microbiota on the quality of milk and of dairy products. PMID- 27216802 TI - Soluble Levels of Receptor for Advanced Glycation Endproducts (RAGE) and Progression of Atherosclerosis in Individuals Infected with Human Immunodeficiency Virus: ACTG NWCS 332. AB - Identification of biomarkers and/or mediators of cardiovascular disease (CVD) associated with HIV infection would be of diagnostic and therapeutic value. As soluble receptor for advanced glycation endproducts (sRAGE) and endogenous secretory (esRAGE) have been implicated in vascular complications in other settings, we investigated whether either soluble form of RAGE was associated with changes in carotid intima-media thickness (CIMT) in HIV-infected patients and HIV uninfected controls. We found no differences in sRAGE, esRAGE, or CIMT among groups at study entry, or in yearly rates of change in sRAGE, esRAGE, or CIMT by HIV-serostatus (all p > 0.10). However, yearly rates of change in sRAGE (p = 0.07) and esRAGE (p < 0.001) were higher in those taking protease inhibitors, and lower baseline esRAGE levels (p = 0.06) were associated with increased odds of CIMT progression in HIV-infected individuals. Although esRAGE was not altered by HIV-serostatus (p = 0.17), its inverse relationship with CIMT progression in HIV infected patients suggests a possible role as a mediator of CVD in HIV-infected persons. PMID- 27216803 TI - Review: the Multiple Roles of Monocytic Microparticles. AB - Monocytic microparticles (mMP) are microparticles derived from human monocytes either under in vivo or in vitro conditions. The size of mMP is between 0.1 and 1.0 MUm. Apart from the size range, mMPs are also identified based on phosphatidylserine and CD14 expression on their surface, though this is not always the case. Monocytic MP are critical players in inflammation, endothelial cell function, and blood coagulation. They exhibit dual function by either helping the progression of such conditions or limiting it, depending on certain factors. Furthermore, the numbers of mMP are elevated in some autoimmune diseases, infectious diseases, and metabolic disorders. However, it is unknown whether mMP play an active role in these diseases or are simply biomarkers. The mechanism of mMP modulation is yet to be identified. In this review, we highlight the mechanism of mMP formation and the roles that they play in inflammation, blood coagulation, and different disease settings. PMID- 27216804 TI - Moderate traumatic brain injury, acute phase course and deviations in physiological variables: an observational study. AB - BACKGROUND: Patients with moderate traumatic brain injury (TBI) are a heterogeneous group with great variability in clinical course. Guidelines for monitoring and level of care in the acute phase are lacking. The main aim of this observational study was to describe injury severity and the acute phase course during the first three days post-injury in a cohort of patients with moderate TBI. Deviations from defined parameters in selected physiological variables were also studied, based on guidelines for severe TBI during the same period. METHODS: During a 5-year period (2004-2009), 119 patients >=16 years (median age 47 years, range 16-92) with moderate TBI according to the Head Injury Severity Scale were admitted to a Norwegian level 1 trauma centre. Injury-related and acute phase data were collected prospectively. Deviations in six physiological variables were collected retrospectively. RESULTS: Eighty-six percent of the patients had intracranial pathology on CT scan and 61 % had extracranial injuries. Eighty-four percent of all patients were admitted to intensive care units (ICUs) the first day, and 51 % stayed in ICUs >=3 days. Patients staying in ICUs >=3 days had lower median Glasgow Coma Scale score; 12 (range 9-15) versus 13 (range 9-15, P = 0.003) and more often extracranial injuries (77 % versus 42 %, P = 0.001) than patients staying in ICU 0-2 days. Most patients staying in ICUs >=3 days had at least one episode of hypotension (53 %), hypoxia (57 %), hyperthermia (59 %), anaemia (56 %) and hyperglycaemia (65 %), and the proportion of anaemia related to number of measurements was high (33 %). CONCLUSION: Most of the moderate TBI patients stayed in an ICU the first day, and half of them stayed in ICUs >=3 days due to not only intracranial, but also extracranial injuries. Deviations in physiological variables were often seen in this latter group of patients. Lack of guidelines for patients with moderate TBI may leave these deviations uncorrected. We propose that in future research of moderate TBI, patients might be differentiated with regard to their need for monitoring and level of care the first few days post-injury. This could contribute to improvement of acute phase management. PMID- 27216805 TI - Factors influencing adults' immunization practices: a pilot survey study of a diverse, urban community in central Ohio. AB - BACKGROUND: Adult vaccination rates in the United States are well below recommendations with disparities in race, ethnicity, and education level resulting in even lower rates for these populations. This study aimed to identify the barriers to and perceptions of immunizations in adults in an urban, underserved, multicultural community. Understanding the factors that influence adults' decisions to receive routinely recommended vaccines will aid health care providers and public health officials to design programs to improve vaccination rates. METHODS: This cross-sectional, survey-based study was conducted in January 2014 in Columbus, Ohio. Participants were recruited from four urban federally qualified health centers and four grocery stores affiliated with those clinics. The survey gathered self-reported receipt of immunizations, knowledge about indications for immunizations, and factors influencing decisions to receive an immunization. Data was analyzed in 2014. Descriptive statistics were generated for all survey items and Chi-Square or Fisher's Exact tests were used as appropriate to test for associations between demographic characteristics and factors influencing immunization decisions. RESULTS: The top five factors likely to affect the decision to receive an immunization among the 304 respondents were: "doctor's recommendation" (80.6 %), "knowing why I should get a vaccine" (78.2 %), "knowing which vaccines I need" (75.5 %), cost (54.2 %), and "concern about getting sick if I get a vaccine" (54.0 %). Significant differences in factors influencing the immunization decision exist among respondents based on ethnicity and education level. For those participants with self-identified diabetes, heart disease, or asthma, less than half were aware that certain immunizations could reduce the risk of complications associated with their disease(s). CONCLUSIONS: Data from this study may inform and shape patient education programs conducted in clinics, retailers, and communities, as well as advocacy efforts for adult immunizations. Results from this study suggest that patients would respond to programs for promoting vaccine uptake if they focused on benefits and indications for vaccines. The results also highlighted the need for education regarding immunizations for patients with chronic diseases and special indications. The differences in perceptions found between groups can be used to create targeted interventions based on the needs of those patient populations. PMID- 27216806 TI - Efficacy of Prophylactic Mesh in End-Colostomy Construction: A Systematic Review and Meta-analysis of Randomized Controlled Trials. AB - BACKGROUND: Parastomal hernia is a very common complication after colostomy, especially end-colostomy. It is unclear whether prophylactic placement of mesh at the time of stoma formation could prevent parastomal hernia formation after surgery for rectal cancer. A systematic review and meta-analysis were conducted to evaluate the efficacy of prophylactic mesh in end-colostomy construction. METHODS: PubMed, Embase, and the Cochrane Library were searched, covering records entered from their inception to September 2015. Randomized controlled trials (RCTs) comparing stoma with mesh to stoma without mesh after surgery for rectal cancer were included. The primary outcome was the incidence of parastomal hernia. Pooled risk ratios (RR) with 95 % confidence intervals (CI) were obtained using random effects models. RESULTS: Six RCTs containing 309 patients were included. Parastomal hernia occurred in 24.4 % (38 of 156) of patients with mesh and 50.3 % (77 of 153) of patients without mesh. Meta-analysis showed a lower incidence of parastomal hernia (RR, 0.42; 95 % CI 0.22-0.82) and reoperation related to parastomal hernia (RR, 0.23; 95 % CI 0.06-0.89) in patients with mesh. Stoma related morbidity was similar between mesh group and non-mesh group (RR, 0.65; 95 % CI 0.33-1.30). CONCLUSIONS: Prophylactic placement of a mesh at the time of a stoma formation seems to be associated with a significant reduction in the incidence of parastomal hernia and reoperation related to parastomal hernia after surgery for rectal cancer, but not the rate of stoma-related morbidity. However, the results should be interpreted with caution because of the heterogeneity among the studies. PMID- 27216807 TI - Ultrasound-Guided Placement of Central Venous Port Systems via the Right Internal Jugular Vein: Are Chest X-Ray and/or Fluoroscopy Needed to Confirm the Correct Placement of the Device? AB - BACKGROUND: Percutaneous central venous port (CVP) placement using ultrasound guidance (USG) via right internal jugular vein is described as a safe and effective procedure. The aim of this study is to determine whether intraoperative fluoroscopy (IF) and/or postoperative chest X-ray (CXR) are required to confirm the correct position of the catheter. METHODS: Between January 2012 and December 2014, 302 adult patients underwent elective CVP system placement under USG. The standard venous access site was the right internal jugular vein. The length of catheter was calculated based on the height of the patient. IF was always performed to confirm US findings. RESULTS: 176 patients were men and 126 were women and average height was 176.2 cm (range 154-193 cm). The average length of the catheter was 16.4 cm (range 14-18). Catheter malposition and pneumothorax were observed in 4 (1.3 %) and 3 (1 %) patients, respectively. IF confirmed the correct position of the catheter in all cases. Catheter misplacement (4 cases) was previously identified and corrected on USG. Our rates of pneumothorax are in accordance with those of the literature (0.5-3 %). CONCLUSION: Ultrasonography has resulted in improved safety and effectiveness of port system implantation. The routine use of CXR and IF should be considered unnecessary. PMID- 27216808 TI - Prehospital Blood Transfusions in Non-Trauma Patients. AB - INTRODUCTION: Despite advances in trauma care, hemorrhage continues to be the leading cause of preventable mortality in trauma. The evidence to support its use in non-trauma patients is limited. We aim to report our experience with prehospital blood product transfusion. We hypothesize that it is safe, appropriately utilized, and that our protocol, which was designed for trauma patients, is adaptable to fit the needs of non-trauma patients. METHODS: Patients transfused with blood products, packed red blood cells (pRBCs) or plasma, in the prehospital environment between 2002 and 2014 were included. Trauma patients were compared to non-trauma patients using descriptive statistics. RESULTS: A total of 857 patients (n = 549 trauma and n = 308 non-trauma) were transfused with pRBCs (76 %, n = 654, mean 1.6 +/- 1.1 units en route), plasma (53 %, n = 455, mean 1.7 +/- 0.7 unit), or both (29 %, n = 252) during ground (12 %) or air (84 %) critical care transport. Mean age was 60.8 +/- 21.6 years with 60.1 % (n = 515) males. Subsequently, in-hospital blood transfusions were performed in 80 % of patients, operations in 44 %, and endoscopy in 31 %. Five percent (n = 41) of patients did not require any of these interventions. Thirty-day mortality rate was 18 %, and one patient (<0.01 %) had a transfusion reaction. The majority of patients were non-trauma (n = 549, 64 %). Of the non-trauma patients, 219 (40 %) were surgical, 193 (35 %) gastrointestinal bleeds, and 137 (25 %) medical. CONCLUSION: Both non-trauma and trauma patients require blood products for life threatening hemorrhage and the majority required further interventions. Further research on the benefits of transfusion among non-trauma patients is warranted. PMID- 27216809 TI - Gastric Outlet Obstruction After Esophagectomy: Retrospective Analysis of the Effectiveness and Safety of Postoperative Endoscopic Pyloric Dilatation. AB - BACKGROUND AND AIMS: Delayed gastric emptying after esophagectomy with gastric replacement can pose a significant postoperative problem, often leading to aspiration and pneumonia. The present study analyzes retrospectively the effectiveness of endoscopic pyloric dilatation for post-surgical gastric outlet obstruction. METHODS: Between March 2006 and March 2010, 403 patients underwent a transthoracic en-bloc esophagectomy and reconstruction with a gastric tube and intrathoracic esophagogastrostomy. In patients with postoperative symptoms of an outlet dysfunction and the confirmation by endoscopy, pyloric dilatations were performed without preference with either 20- or 30-mm balloons. RESULTS: A total of 89 balloon dilatations of the pylorus after esophagectomy were performed in 60 (15.6 %) patients. In 21 (35 %) patients, a second dilatation of the pylorus was performed. 55 (61.8 %) dilatations were performed with a 30-mm balloon and 34 (38.2 %) with a 20-mm balloon. The total redilatation rate for the 30-mm balloon was 20 % (n = 11) and 52.9 % (n = 18) for the 20-mm balloon (p < 0.001). All dilatations were performed without any complications. CONCLUSIONS: Pylorus spasm contributes to delayed gastric emptying leading to postoperative complications after esophagectomy. Endoscopic pyloric dilatation after esophagectomy is a safe procedure for treatment of gastric outlet obstruction. The use of a 30-mm balloon has the same safety profile but a 2.5 lower redilatation rate compared to the 20 mm balloon. Thus, the use of 20-mm balloons has been abandoned in our clinic. PMID- 27216810 TI - Epidemiology and outcome of sepsis in adult patients with Streptococcus pneumoniae infection in a Norwegian county 1993-2011: an observational study. AB - BACKGROUND: Invasive pneumococcal disease (IPD) is responsible for significant mortality and morbidity worldwide. There are however few longitudinal studies on the changes in case fatality rate of IPD in recent years. We carried out a prospective observational study of patients with IPD in Nord Trondelag county in Norway from 1993 to 2011 to study the clinical variables and disease outcome. The main outcome was all-cause mortality after 30 and 90 days. METHODS: Patients with positive blood cultures were registered prospectively by the microbiology laboratory and clinical variables were registered retrospectively from patients' hospital records. The severity of sepsis was assigned according to the 2001 International Sepsis Definition Conference criteria. The association between mortality and predictive factors was studied using a logistic regression model. RESULTS: The total number of patients was 414 with mean age of 67 years and 53 % were male. Comorbidity was assessed by the Charlson Comorbidity Index (CCI). A CCI-score of 0 was registered in 144 patients (34.8 %), whereas 190 had a score of 1-2 (45.9 %) and 80 (19.3 %) had a score >=3. 68.8 % of the patients received appropriate antibiotics within the first 6 h. The 30-day mortality risk increased by age and was 3-fold higher for patients aged >=80 years (24.9, 95 % CI 16.4 33.4 %) compared to patients aged <70 (8.0, 95 % CI 3.5-12.4 %). 110 patients, (26.6 %) had severe sepsis and 37 (8.9 %) had septic shock. The 30 day all-cause mortality risk for those with sepsis without organ failure was 5.4 % (95 % CI 2.7 8.0 %), 20.2 % (95 % CI 13.5-27.4 %) for those with severe sepsis and 35.0 % (95 % CI 21.6-49.0 %) for those with septic shock. The mortality risk did not differ between the first and the second halves of the study period with a 30-day mortality risk of 13.5 % (95 % CI 7.9-19.2 %) for 1993-2002 versus 11.8 % (95 % CI 8.2-15.3 %) for 2003-2011. CONCLUSION: IPD carries a high mortality despite early and appropriate antibiotics in most cases. We found no substantial decrease in case fatality rate during the study period of 18 years. Older age and higher severity of disease were important risk factors for death in IPD. PMID- 27216811 TI - Heterogeneity of Human Aging and Its Assessment. AB - Understanding the heterogeneity in health of older adults is a compelling question in the biology of aging. We analyzed the performance of five measures of health heterogeneity, judging them by their ability to predict mortality. Using clinical and biomarker data on 1,013 participants of the Canadian Study of Health and Aging who were followed for up to 6 years, we calculated two indices of biological age using the Klemera and Doubal method, which controversially includes using chronological age as a "biomarker," and three frailty indices (FIs) that do not include chronological age: a standard clinical FI, an FI from standard laboratory blood tests and blood pressure, and their combination (FI combined). Predictive validity was tested using Cox proportional hazards analysis and discriminative ability by the area under the receiver-operating characteristic curves. All five measures showed moderate performance that was improved by combining measures to evaluate larger numbers of items. The greatest addition in explanatory power came from the FI-combined that showed the best mortality prediction in an age-adjusted model. More extensive comparisons across different databases are required, but these results do not support including chronological age as a biomarker. PMID- 27216812 TI - Molecular identification of different trypanosome species and subspecies in tsetse flies of northern Nigeria. AB - BACKGROUND: Animal African Trypanosomiasis (AAT) is caused by several species of trypanosomes including Trypanosoma congolense, T. vivax, T. godfreyi, T. simiae and T. brucei. Two of the subspecies of T. brucei also cause Human African Trypanosomiasis. Although some of them can be mechanically transmitted by biting flies; these trypanosomes are all transmitted by tsetse flies which are the cyclical vectors of Trypanosoma congolense, T. godfreyi, T. simiae and T. brucei. We present here the first report assessing the prevalence of trypanosomes in tsetse flies in Nigeria using molecular tools. METHODS: 488 tsetse flies of three species, Glossina palpalis palpalis, G. tachinoides and G. morsitans submorsitans were collected from Wuya, Niger State and Yankari National Park, Bauchi State in 2012. Trypanosomes were detected and identified using an ITS1 PCR assay on DNA purified from the 'head plus proboscis' (H + P) and abdomen (ABD) parts of each fly. RESULTS: T. vivax and T. congolense Savannah were the major parasites detected. Trypanosomes prevalence was 7.1 % in G. p. palpalis, 11.9 % in G. tachinoides and 13.5 % in G. m. submorsitans. Prevalences of T. congolense Savannah ranged from 2.5 to 6.7 % and of T. vivax were approximately 4.5 %. Trypanosoma congolense Forest, T. godfreyi and T. simiae were also detected in the site of Yankari. The main biological and ecological determinants of trypanosome prevalence were the fly sex, with more trypanosomes found in females than males, and the site, with T. congolense subspp. being more abundant in Yankari than in Wuya. As expected, the trypanosome species diversity was higher in Yankari National Park than in the more agricultural site of Wuya where vertebrate host species diversity is lower. CONCLUSIONS: Our results show that T. congolense Savannah and T. vivax are the main species of parasite potentially causing AAT in the two study sites and that Yankari National Park is a potential reservoir of trypanosomes both in terms of parasite abundance and species diversity. PMID- 27216813 TI - Let the substrate flow, not the enzyme: Practical immobilization of d-amino acid oxidase in a glass microreactor for effective biocatalytic conversions. AB - Exploiting enzymes for chemical synthesis in flow microreactors necessitates their reuse for multiple rounds of conversion. To achieve this goal, immobilizing the enzymes on microchannel walls is a promising approach, but practical methods for it are lacking. Using fusion to a silica-binding module to engineer enzyme adsorption to glass surfaces, we show convenient immobilization of d-amino acid oxidase on borosilicate microchannel plates. In confocal laser scanning microscopy, channel walls appeared uniformly coated with target protein. The immobilized enzyme activity was in the range expected for monolayer coverage of the plain surface with oxidase (2.37 * 10(-5) nmol/mm(2) ). Surface attachment of the enzyme was completely stable under flow. The operational half-life of the immobilized oxidase (25 degrees C, pH 8.0; soluble catalase added) was 40 h. Enzymatic oxidation of d-Met into alpha-keto-gamma-(methylthio)butyric acid was characterized in single-pass and recycle reactor configurations, employing in line measurement of dissolved O2 , and off-line determination of the keto-acid product. Reaction-diffusion time-scale analysis for different flow conditions showed that the heterogeneously catalyzed reaction was always slower than diffusion of O2 to the solid surface (DaII <= 0.3). Potential of the microreactor for intensifying O2 -dependent biotransformations restricted by mass transfer in conventional reactors is thus revealed. Biotechnol. Bioeng. 2016;113: 2342-2349. (c) 2016 Wiley Periodicals, Inc. PMID- 27216814 TI - Comparative analysis of the pteridophyte Adiantum MFT ortholog reveals the specificity of combined FT/MFT C and N terminal interaction with FD for the regulation of the downstream gene AP1. AB - To study the evolution of phosphatidylethanolamine-binding protein (PEBP) gene families in non-flowering plants, we performed a functional analysis of the PEBP gene AcMFT of the MFT clade in the pteridophyte Adiantum capillus-veneris. The expression of AcMFT was regulated by photoperiod similar to that for FT under both long day and short day conditions. Ectopic expression of AcMFT in Arabidopsis promotes the floral transition and partially complements the late flowering defect in transgenic Arabidopsis ft-1 mutants, suggesting that AcMFT functions similarly to FT in flowering plants. Interestingly, a similar partial compensation of the ft-1 late flowering phenotype was observed in Arabidopsis ectopically expressing only exon 4 of the C terminus of AcMFT and FT. This result indicated that the fourth exon of AcMFT and FT plays a similar and important role in promoting flowering. Further analysis indicated that exons 1-3 in the N terminus specifically enhanced the function of FT exon 4 in controlling flowering in Arabidopsis. Protein pull-down assays indicated that Arabidopsis FD proteins interact with full-length FT and AcMFT, as well as peptides encoded by 1-3 exon fragments or the 4th exon alone. Furthermore, similar FRET efficiencies for FT-FD and AcMFT-FD heterodimer in nucleus were observed. These results indicated that FD could form the similar complex with FT and AcMFT. Further analysis indicated that the expression of AP1, a gene downstream of FT, was up-regulated more strongly by FT than AcMFT in transgenic Arabidopsis. Our results revealed that AcMFT from a non-flowering plant could interact with FD to regulate the floral transition and that this function was reduced due to the weakened ability of AcMFT-FD to activate the downstream gene AP1. PMID- 27216815 TI - Modulating the Cascade architecture of a minimal Type I-F CRISPR-Cas system. AB - Shewanella putrefaciens CN-32 contains a single Type I-Fv CRISPR-Cas system which confers adaptive immunity against bacteriophage infection. Three Cas proteins (Cas6f, Cas7fv, Cas5fv) and mature CRISPR RNAs were shown to be required for the assembly of an interference complex termed Cascade. The Cas protein-CRISPR RNA interaction sites within this complex were identified via mass spectrometry. Additional Cas proteins, commonly described as large and small subunits, that are present in all other investigated Cascade structures, were not detected. We introduced this minimal Type I system in Escherichia coli and show that it provides heterologous protection against lambda phage. The absence of a large subunit suggests that the length of the crRNA might not be fixed and recombinant Cascade complexes with drastically shortened and elongated crRNAs were engineered. Size-exclusion chromatography and small-angle X-ray scattering analyses revealed that the number of Cas7fv backbone subunits is adjusted in these shortened and extended Cascade variants. Larger Cascade complexes can still confer immunity against lambda phage infection in E. coli Minimized Type I CRISPR Cas systems expand our understanding of the evolution of Cascade assembly and diversity. Their adjustable crRNA length opens the possibility for customizing target DNA specificity. PMID- 27216816 TI - mCSM-AB: a web server for predicting antibody-antigen affinity changes upon mutation with graph-based signatures. AB - Computational methods have traditionally struggled to predict the effect of mutations in antibody-antigen complexes on binding affinity. This has limited their usefulness during antibody engineering and development, and their ability to predict biologically relevant escape mutations. Here we present mCSM-AB, a user-friendly web server for accurately predicting antibody-antigen affinity changes upon mutation which relies on graph-based signatures. We show that mCSM AB performs better than comparable methods that have been previously used for antibody engineering. mCSM-AB web server is available at http://structure.bioc.cam.ac.uk/mcsm_ab. PMID- 27216818 TI - A contrastive analysis of laser heating between the human and guinea pig cochlea by numerical simulations. AB - BACKGROUND: The photo-thermal effect has been hypothesised to be one of the most possible biophysical mechanisms for laser-cochlea stimulation. However, there is a lack of studies to date for direct assessing laser heating in humans due to the large body of evidence required to demonstrate safety and efficacy. Instead, the majority focus on animals like the guinea pig, from which a number of valuable results have been gained. However, in light of the increasing need to improve laser safety, it has became necessary to find out whether studies on animals can shed light on safe laser parameters in the human cochlea. Hence, we conducted this contrastive analysis of laser heating between the human and guinea pig cochlea with the aim of assisting further investigations in this field. METHODS: In this work, a 3D symmetrical model was adopted to simplify the spiraled cochlea. With attention focused on the effect of heat conduction, the time dependent heat equation was solved using finite element method with the COMSOL Script. In the simulations, cochleae with different sizes and various boundary thermal conditions were utilized. RESULTS: Laser heating in both cochleae has a similar trend. In the first stage, or at the beginning of the laser heating, both cochleae increased their temperatures rapidly. In the second stage in which the laser heating reached a quasi-steady stage, the peak temperatures began to rise slowly as more laser pulses were applied. However, three differences of the laser heating were observed. The first is regarding the temperature rise. The results show that laser heating in guinea pig is higher than that in human under the same laser parameters. The second difference is the fluctuation of temperature rise at the center of the modiolus. There is a larger fluctuation of temperature rise in the guinea pig cochlea, compared with that in the human cochlea. The third one is the time for reaching a steady thermal state. The results show that the guinea pig cochlea takes longer time to reach a steady thermal state than the human cochlea. Those differences are mainly attributed to the distinctive thermal boundaries and the various sizes of the two cochleae. CONCLUSIONS: This study finds that the laser heating in the guinea pig cochlea is higher than that in the human cochlea under the condition of the same laser parameters. However, laser stimulation still displays a high spatial selectivity in both cochleae despite the effects of heat conduction. The results indicate that experimental studies on the guinea pig could appropriately be an alternative model for the sake of laser safety. PMID- 27216817 TI - Dysregulated signaling hubs of liver lipid metabolism reveal hepatocellular carcinoma pathogenesis. AB - Hepatocellular carcinoma (HCC) has a high mortality rate and early detection of HCC is crucial for the application of effective treatment strategies. HCC is typically caused by either viral hepatitis infection or by fatty liver disease. To diagnose and treat HCC it is necessary to elucidate the underlying molecular mechanisms. As a major cause for development of HCC is fatty liver disease, we here investigated anomalies in regulation of lipid metabolism in the liver. We applied a tailored network-based approach to identify signaling hubs associated with regulation of this part of metabolism. Using transcriptomics data of HCC patients, we identified significant dysregulated expressions of lipid-regulated genes, across many different lipid metabolic pathways. Our findings, however, show that viral hepatitis causes HCC by a distinct mechanism, less likely involving lipid anomalies. Based on our analysis we suggest signaling hub genes governing overall catabolic or anabolic pathways, as novel drug targets for treatment of HCC that involves lipid anomalies. PMID- 27216819 TI - Acute and short-term effects of caloric restriction on metabolic profile and brain activation in obese, postmenopausal women. AB - OBJECTIVE: Early anthropometric and metabolic changes during a caloric-restricted diet in obese postmenopausal women and correlations between these factors with activity in brain areas involved in processing of visual food related stimuli were investigated. SUBJECTS AND METHODS: An 8-week prospective intervention study of 18 healthy postmenopausal women, with a body mass index of 30-35 kg m-2. The first 2 weeks subjects were on an isocaloric diet and 4 weeks on a 1000 kcal restricted diet followed by 2 weeks on an isocaloric diet. Anthropometric and laboratory analyses were performed weekly during the isocaloric diet and three times a week during the caloric-restricted diet. Functional magnetic resonance imaging scans were obtained before and after the caloric restriction in four separate sessions (fasting or sated). Generalized Estimating Equations analysis was used for data analysis. RESULTS: A mean weight loss of 4.2+/-0.5 kg (4.8%) and a 4.2+/-0.4 cm decline in waist circumference were achieved. In the first week of caloric restriction, triglyceride, leptin, resistin and adiponectin levels as well as systolic blood pressure decreased and insulin-like growth factor-binding protein 1 levels increased. During and after weight loss, a significant increase in ghrelin levels was observed. Before weight loss, increased activation of the right amygdala was seen in response to food stimuli, and free fatty acids and glucose correlated with activity in various areas involved in food reward processing. After weight loss, fasting ghrelin and sated leptin levels correlated with activity in these areas. CONCLUSIONS: Already in the first week of caloric restriction in obese postmenopausal women, various favourable metabolic changes occur before clinically relevant weight loss is achieved. Activity in the amygdala region and correlations of metabolic factors with activity in brain areas involved in food reward processing differ substantially before and after weight loss. PMID- 27216820 TI - Adiponectin mediates the additive effects of combining daily exercise with caloric restriction for treatment of non-alcoholic fatty liver. AB - BACKGROUND/OBJECTIVES: Little is known regarding whether or not combining daily exercise (EX) with caloric restriction (CR) additionally alleviates non-alcoholic fatty liver disease (NAFLD). The study investigated the effect of the combination of EX and CR on NAFLD and its underlying mechanisms in high-fat diet (HFD) induced obese mice. METHODS: C57BL/6 mice (N=50) were fed a standard chow (SC; n=10) or HFD (n=40) for 24 weeks. After 16 weeks, the HFD mice were further assigned to one of the following groups for the remaining 8 weeks: the first group of mice (HFD; n=10) remained to HFD, the second group of mice (HFD-EX; n=10) remained to HFD while subjected to EX, the third group of mice (HFD-CR; n=10) switched their diet from HFD to SC and the fourth group of mice (HFD-EX+CR; n=10) switched their diet from HFD to SC while simultaneously being subjected to EX. RESULTS: HFD resulted in obesity, impaired glucose tolerance, hypercholesterolemia and histology-based hepatic steatosis in conjunction with hypoadiponectinemia and downregulation of hepatic adiponectin receptors. However, EX or CR alleviated the fatty liver and its metabolic complications significantly. Compared with EX or CR alone, the combination of EX and CR resulted in further alleviations of NAFLD-associated conditions. The additive benefits of the combined treatment were associated with greater elevations of adiponectin and its hepatic receptors, in conjunction with greater expression of their downstream targets involved in fatty acid oxidation, de novo lipogenesis and anti-inflammation. CONCLUSIONS: The current findings provide experimental evidence in favor of the combination of EX and CR as a superior strategy for NAFLD treatment than EX or CR alone. PMID- 27216821 TI - Differential effects of BDNF and neurotrophin 4 (NT4) on endocytic sorting of TrkB receptors. AB - Neurotrophins are a family of growth factors playing key roles in the survival, development, and function of neurons. The neurotrophins brain-derived neurotrophic factor (BDNF) and NT4 both bind to and activate TrkB receptors, however, they mediate distinct neuronal functions. The molecular mechanism of how TrkB activation by BDNF and NT4 leads to diverse outcomes is unknown. Here, we report that BDNF and NT4 lead to differential endocytic sorting of TrkB receptors resulting in diverse biological functions in cultured cortical neurons. Fluorescent microscopy and surface biotinylation experiments showed that both neurotrophins stimulate internalization of TrkB with similar kinetics. Exposure to BDNF for 2-3 h reduced the surface pool of TrkB receptors to half, whereas a longer treatment (4-5 h) with NT4 was necessary to achieve a similar level of down-regulation. Although BDNF and NT4 induced TrkB phosphorylation with similar intensities, BDNF induced more rapid ubiquitination and degradation of TrkB than NT4. Interestingly, TrkB receptor ubiquitination by these ligands have substantially different pH sensitivities, resulting in varying degrees of receptor ubiquitination at lower pH levels. Consequently, NT4 was capable of maintaining longer sustained downstream signaling activation that correlated with reduced TrkB ubiquitination at endosomal pH. Thus, by leading to altered endocytic trafficking itineraries for TrkB receptors, BDNF and NT4 elicit differential TrkB signaling in terms of duration, intensity, and specificity, which may contribute to their functional differences in vivo. The neurotrophins, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4), both bind to and activate TrkB receptors, however, they mediate distinct neuronal functions. Here, we propose that BDNF and NT4 lead to differential endocytic sorting of TrkB receptors resulting in diverse biological functions. BDNF induces more rapid ubiquitination and degradation of TrkB than NT4. Consequently, NT4 is capable of maintaining more sustained signaling downstream of TrkB receptors. PMID- 27216822 TI - RNA-seq analysis of virR and revR mutants of Clostridium perfringens. AB - BACKGROUND: Clostridium perfringens causes toxin-mediated diseases, including gas gangrene (clostridial myonecrosis) and food poisoning in humans. The production of the toxins implicated in gas gangrene, alpha-toxin and perfringolysin O, is regulated by the VirSR two-component regulatory system. In addition, RevR, an orphan response regulator, has been shown to affect virulence in the mouse myonecrosis model. RevR positively regulates the expression of genes that encode hydrolytic enzymes, including hyaluronidases and sialidases. RESULTS: To further characterize the VirSR and RevR regulatory networks, comparative transcriptomic analysis was carried out with strand-specific RNA-seq on C. perfringens strain JIR325 and its isogenic virR and revR regulatory mutants. Using the edgeR analysis package, 206 genes in the virR mutant and 67 genes in the revR mutant were found to be differentially expressed. Comparative analysis revealed that VirR acts as a global negative regulator, whilst RevR acts as a global positive regulator. Therefore, about 95 % of the differentially expressed genes were up regulated in the virR mutant, whereas 81 % of the differentially expressed genes were down-regulated in the revR mutant. Importantly, we identified 23 genes that were regulated by both VirR and RevR, 18 of these genes, which included the sporulation-specific spoIVA, sigG and sigF genes, were regulated positively and negatively by RevR and VirR, respectively. Furthermore, analysis of the mapped RNA-seq reads visualized as depth of coverage plots showed that there were 93 previously unannotated transcripts in intergenic regions. These transcripts potentially encode small RNA molecules. CONCLUSION: In conclusion, using strand specific RNA-seq analysis, this study has identified differentially expressed chromosomal and pCP13 native plasmid-encoded genes, antisense transcripts, and transcripts within intergenic regions that are controlled by the VirSR or RevR regulatory systems. PMID- 27216824 TI - Rapid Fabrication of a Cell-Seeded Collagen Gel-Based Tubular Construct that Withstands Arterial Pressure : Rapid Fabrication of a Gel-Based Media Equivalent. AB - Based on plastically compressed cell-seeded collagen gels, we fabricated a small diameter tubular construct that withstands arterial pressure without prolonged culture in vitro. Specifically, to mimic the microstructure of vascular media, the cell-seeded collagen gel was uniaxially stretched prior to plastic compression to align collagen fibers and hence cells in the gel. The resulting gel sheet was then wrapped around a custom-made multi-layered braided tube to form aligned tubular constructs whereas the gel sheet prepared similarly but without uniaxial stretching formed control constructs. With the braided tube, fluid in the gel construct was further removed by vacuum suction aiming to consolidate the concentric layers of the construct. The construct was finally treated with transglutaminase. Both SEM and histology confirmed the absence of gaps in the wall of the construct. Particularly, cells in the wall of the aligned tubular construct were circumferentially aligned. The enzyme-mediated crosslinking increased burst pressure of both the constructs significantly; the extent of the increase of burst pressure for the aligned tubular construct was greater than that for the control counterpart. Increasing crosslinking left the compliance of the aligned tubular construct unchanged but reduced that of the control construct. Cells remained viable in transglutaminase-treated plastically compressed gels after 6 days in culture. This study demonstrated that by combining stretch-induced fiber alignment, plastic compression, and enzyme mediated crosslinking, a cell-seeded collagen gel-based tubular construct with potential to be used as vascular media can be made within 3 days. PMID- 27216823 TI - The primate pedunculopontine nucleus region: towards a dual role in locomotion and waking state. AB - The mesencephalic reticular formation (MRF) mainly composed by the pedunculopontine and the cuneiform nuclei is involved in the control of several fundamental brain functions such as locomotion, rapid eye movement sleep and waking state. On the one hand, the role of MRF neurons in locomotion has been investigated for decades in different animal models, including in behaving nonhuman primate (NHP) using extracellular recordings. On the other hand, MRF neurons involved in the control of waking state have been consistently shown to constitute the cholinergic component of the reticular ascending system. However, a dual control of the locomotion and waking state by the same groups of neurons in NHP has never been demonstrated in NHP. Here, using microelectrode recordings in behaving NHP, we recorded 38 neurons in the MRF that were followed during transition between wakefulness (TWS) and sleep, i.e., until the emergence of sleep episodes characterized by typical cortical slow wave activity (SWA). We found that the MRF neurons, mainly located in the pedunculopontine nucleus region, modulated their activity during TWS with a decrease in firing rate during SWA. Of interest, we could follow some MRF neurons from locomotion to SWA and found that they also modulated their firing rate during locomotion and TWS. These new findings confirm the role of MRF neurons in both functions. They suggest that the MRF is an integration center that potentially allows to fine tune waking state and locomotor signals in order to establish an efficient locomotion. PMID- 27216825 TI - Only women report increase in pain threshold following fatiguing contractions of the upper extremity. AB - PURPOSE: The perception of pain in response to a noxious stimulus can be markedly reduced following an acute bout of exercise [exercise-induced hypoalgesia (EIH)]. Sex differences in EIH frequently occur after exercise but may be confounded by the sex differences in muscle fatigue. The purpose was to determine if sex differences in pain relief occur after an exercise protocol when muscle fatigue is similar for both young and older men and women. METHODS: Pain perception of 33 men (15 young) and 31 women (19 young) was measured using a pressure pain stimulus on the left index finger before and after maximal velocity concentric contractions of knee extensors or elbow flexors (separate days). During the 2-min pressure pain test, participants verbally indicated the onset of pain (pain threshold) and reported pain intensity (0-10) every 20 s. RESULTS: Only women experienced an increase in pain threshold (30 +/- 27 to 41 +/- 32 s) following elbow flexor exercise (trial * sex: p = 0.03). Neither men nor women experienced an increase in pain threshold following knee extensor exercise, and pain ratings were unchanged after exercise with either limb (p > 0.05). The pain response to exercise was similar in young and older adults (trial * age: p > 0.05), despite older adults demonstrating greater fatigability than young adults for the elbow flexor and knee extensor exercise tasks. CONCLUSIONS: Under controlled conditions where muscle fatigue is similar, sex differences in EIH occur in young and older adults that is site specific (upper extremity). Only women experience EIH following acute single limb high-velocity contractions. PMID- 27216826 TI - Loss of Nrf2 abrogates the protective effect of Keap1 downregulation in a preclinical model of cutaneous squamous cell carcinoma. AB - Cutaneous squamous cell carcinomas (cSCC) are the most common and highly mutated human malignancies, challenging identification of driver mutations and targeted therapies. Transcription factor NF-E2 p45-related factor 2 (Nrf2) orchestrates a cytoprotective inducible program, which counteracts the damaging effects of solar UV radiation, the main etiological factor in cSCC development. Downregulation of Kelch-like ECH-associated protein 1 (Keap1), a Cullin-3/Rbx1 ubiquitin ligase substrate adaptor protein, which mediates the ubiquitination and proteasomal degradation of Nrf2, has a strong protective effect in a preclinical model of cSCC. However, in addition to Nrf2, Keap1 affects ubiquitination of other proteins in the carcinogenesis process, including proteins involved in inflammation and DNA damage repair. Here, we generated Keap1(flox/flox) SKH-1 hairless mice in which Nrf2 is disrupted (Keap1(flox/flox)/Nrf2(-/-)) and subjected them chronically to solar-simulated UV radiation. We found that the incidence, multiplicity and burden of cSCC that form in Keap1(flox/flox)/Nrf2(-/ ) mice are much greater than in their Keap1(flox/flox)/Nrf2(+/+) counterparts, establishing Nrf2 activation as the protection mediator. Our findings further imply that inhibition of Nrf2 globally, a strategy proposed for cancer treatment, is unlikely to be beneficial. PMID- 27216827 TI - Rituximab and protection from vaccine preventable diseases: applying the evidence to pediatric patients. AB - INTRODUCTION: This article analyses and highlights the challenge of immunization and preventing vaccine preventable diseases in pediatric patients on rituximab. Rituximab is a chimeric anti-CD 20 monoclonal antibody that is an immunosuppressant affecting both cellular and humoral immunity. Children and adolescents on rituximab are at increased risk of infection and vaccine preventable diseases, and require additional strategies to optimize and maximize their protection against such illnesses. Areas covered: This article provides a comprehensive MEDLINE and Pubmed review of existing literature regarding vaccine immunogenicity and safety in patients on rituximab, and assists in providing an evidence base to develop immunization guidelines. Of particular note, the use of live-attenuated vaccines and optimum timing of vaccines post rituximab is considered and discussed. Expert commentary: The increasing use of rituximab in a variety of novel areas within pediatrics must be accompanied by informed discussion around mitigating the risks. These include immunosuppression, and potential susceptibility to infection. Optimizing vaccine status by establishing adequate antibody titers prior to commencement remains the best preventative strategy. PMID- 27216828 TI - Factors influencing emergency nurses' ethical problems during the outbreak of MERS-CoV. AB - BACKGROUND: Whenever there has been a worldwide contagious disease outbreak, there have been reports of infection and death of healthcare workers. Particularly because emergency nurses have contact with patients on the front line, they experience ethical problems in nursing while struggling with infectious diseases in an unfavorable environment. OBJECTIVE: The objective of this study was to explore emergency nurses' ethical problems and to identify factors influencing these problems during the outbreak of Middle East respiratory syndrome-coronavirus in Korea. DESIGN AND SAMPLE: For this cross-sectional study, a questionnaire survey was conducted with emergency nurses working in six hospitals selected through convenience sampling from the hospitals designated for Middle East respiratory syndrome-coronavirus patients in the capital area. METHODS: Data were collected from 169 emergency nurses in Korea during August 2015. Ethical considerations: This research was approved by the Institutional Review Board of G University in Korea. RESULTS: The findings of this study suggest that during the Middle East respiratory syndrome-coronavirus outbreak, emergency nurses experienced ethical problems tied to a mind-set of avoiding patients. Three factors were found to influence emergency nurses' ethical problems (in order of influence): cognition of social stigmatization, level of agreement with infection control measures, and perceived risk. CONCLUSION: Through this study, we obtained information on emergency nurses' ethical problems during the Middle East respiratory syndrome-coronavirus outbreak and identified the factors that influence them. As found in this study, nurses' ethical problems were influenced most by cognitions of social stigmatization. Accordingly, to support nurses confidently care for people during future health disasters, it is most urgent to promote appropriate public consciousness that encourages healthcare workers. PMID- 27216829 TI - Contributions of host cellular trafficking and organization to the outcomes of plant-pathogen interactions. AB - In recent years it has become increasingly apparent that dynamic changes in protein localization, membrane trafficking pathways, and cellular organization play a major role in determining the outcome of interactions between plants and pathogenic microorganisms. Plants have evolved sophisticated perception systems to recognize the presence of potentially pathogenic microorganisms via the detection of non-self or modified-self elicitor molecules, pathogen virulence factors, or the activities of such virulence factors. Dynamic changes to host cellular organization and membrane trafficking pathways play pivotal roles in detection and signaling by plant immune receptors and are vital for the execution of spatially targeted defense responses to thwart invasion by potential pathogens. Conversely, from the perspective of the pathogen, the ability to manipulate plant cellular organization and trafficking processes to establish infection structures and deliver virulence factors is a major determinant of pathogen success. This review summarizes selected topics that illustrate how dynamic changes in host cellular trafficking and organization shape the outcomes of diverse plant-pathogen interactions and addresses ways in which our rapidly expanding knowledge of the cell biological processes that contribute to immunity or infection may influence efforts to improve plant disease resistance. PMID- 27216830 TI - Neuroendocrine tumors of the pancreas: Degree of cystic component predicts prognosis. AB - BACKGROUND: Although most pancreatic neuroendocrine tumors are solid, approximately 10% are cystic. Some studies have suggested that cystic pancreatic neuroendocrine tumors are associated with a more favorable prognosis. METHODS: A retrospective review of all patients with pancreatic neuroendocrine tumors who underwent operative resection between 1999 and 2014 at a single academic medical center was performed. Based on cross-sectional imaging performed before operation, pancreatic neuroendocrine tumors were classified according to the size of the cystic component relative to the total tumor size: purely cystic (100%), mostly cystic (>=50%), mostly solid (<50%), and purely solid (0%). Clinicopathologic characteristics and recurrence-free survival were assessed between groups. RESULTS: In the study, 214 patients met inclusion criteria: 8 with purely cystic tumors, 7 with mostly cystic tumors, 15 with mostly solid tumors, and 184 with purely solid tumors. The groups differed in terms of tumor size (1.5 +/- 0.5, 3.0 +/- 1.7, 3.7 +/- 2.6, and 4.0 +/- 3.5 cm), lymph node positivity (0%, 0%, 26.7%, and 34.2%), intermediate or high grade (0%, 16.7%, 20.0%, and 31.0%), synchronous liver metastases (0%, 14.3%, 20.0%, and 26.6%) and need for pancreaticoduodenectomy (0%, 0%, 6.7%, and 25.0%), respectively. No cases of purely cystic pancreatic neuroendocrine tumors were associated with synchronous liver or lymph node metastasis, intermediate/high grade, recurrence, or death due to disease. Among patients presenting without metastatic disease, 10 year recurrence-free survival was 100% in patients with purely and mostly cystic tumors versus 53.0% in patients with purely and mostly solid tumors; however, this difference did not reach statistical significance. CONCLUSION: Pancreatic neuroendocrine tumors demonstrate a spectrum of biologic behavior with an increasing cystic component being associated with more favorable clinicopathologic features and prognosis. Purely cystic pancreatic neuroendocrine tumors may represent 1 subset that can be safely observed without immediate resection. PMID- 27216831 TI - Splenic artery pseudoaneurysm penetrating to the stomach. PMID- 27216832 TI - Reply: Tailored approach to cystic liver hydatidosis is mandatory. PMID- 27216833 TI - Canada's courts and government disagree on assisted dying as deadline looms. PMID- 27216834 TI - Serial neuropsychological assessment of an adolescent girl after suffering a sudden out-of-hospital-cardiac-arrest following recreational inhalant use. AB - Sudden out-of-hospital-cardiac-arrest (OHCA) following recreational inhalant use is well documented in the literature. The present case study reports the long term neuropsychological sequelae of a 14-year-old girl who suffered an OHCA secondary to recreational butane gas inhalation. The patient was assessed on day 13 as an inpatient, and again at 3- and 12-month outpatient follow-ups. Acutely the patient demonstrated significant impairment on tasks associated with verbal and non-verbal memory and executive functioning. Re-testing at 3-months post acute state suggested improved executive and non-verbal functions while showing continued deficits in verbal memory. At 12-months she was cognitively performing at levels expected for her age. This case is reported for its rarity in successfully being able to track the patient's clinical course from hospital discharge to the successful reintegration back into school and community settings. PMID- 27216835 TI - Optimal dosing of intravenous ketamine for procedural sedation in children in the ED-a randomized controlled trial. AB - OBJECTIVE: The objective of the study is to compare need for redosing, sedation efficacy, duration, and adverse events between 3 commonly administered doses of parenteral ketamine in the emergency department (ED). METHODS: We conducted a prospective, double-blind, randomized controlled trial on a convenience sample of children 3 to 18years who received intravenous ketamine for procedural sedation. Children from each age group (3-6, 7-12, and 13-18years) were assigned in equal numbers to 3 dosing groups (1, 1.5, and 2mg/kg) using random permuted blocks. The primary outcome measure was need for ketamine redosing to ensure adequate sedation. Secondary outcome measures were sedation efficacy, sedation duration, and sedation-related adverse events. RESULTS: A total of 171 children were enrolled of whom 125 (1mg/kg, 50; 1.5mg/kg, 35; 2mg/kg, 40) received the randomized dose and were analyzed. The need for ketamine redosing was higher in the 1mg/kg group (8/50; 16.0% vs 1/35; 2.9% vs 2/40; 5.0%). There was no significant difference in the median Ramsay sedation scores (5.5 [interquartile range {IQR}, 4-6] vs 6 [IQR, 4-6] vs 6 [IQR, 5-6]), FACES-R score (0 [IQR, 0-4] vs 0 [IQR, 0-0] vs 0 [IQR, 0-0]), sedation duration in minutes (23 [IQR, 19-38] vs 24.5 [IQR, 17.5-34.5] vs 23 [IQR, 19-29]), and adverse events (10.0% vs 14.3% vs 10.0%) between the 3 dosing groups. Physician satisfaction was lower in the 1mg/kg group (79.6% vs 94.1% vs 97.3%). CONCLUSIONS: Adequate sedation was achieved with all 3 doses of ketamine. Higher doses did not increase the risk of adverse events or prolong sedation. Ketamine administered at 1.5 or 2.0mg/kg intravenous required less redosing and resulted in greater physician satisfaction. PMID- 27216836 TI - When ultrasound approach is worse, something is suspicious.... PMID- 27216837 TI - Environmental toxicology without chemistry and publications without discourse: Linked impediments to better science. PMID- 27216838 TI - Comment on ET&C perspectives, November 2015-A holistic view. AB - In response to a recent collection of perspectives published in Environmental Toxicology and Chemistry, the authors argue that there is little value in revisiting and rehashing the well-documented issues around toxicity metrics, competing statistical paradigms, legitimacy of theoretical constructs for species sensitivity distributions, and a number of other unresolved (and perhaps unresolvable) attendant statistical issues that have occupied journal space for more than 30 yr. This is not to say that these matters are unimportant-they are; however, the discussion on these topics is mature, with very few new insights being offered. To move forward on some of these seemingly intractable issues, the authors suggest the ecotoxicological community would be better served by the formation of a subdiscipline of "statistical ecotoxicology," where professional statisticians and ecotoxicologists work in unison. As it currently stands, statistical developments in ecotoxicology are not necessarily undertaken or peer reviewed by professional statisticians, a situation that has no doubt contributed to the lack of real progress on important recommendations such as the phasing out of no-observed-effect concentrations. Environ Toxicol Chem 2016;35:1337-1339. (c) 2016 SETAC. PMID- 27216839 TI - Solution NMR studies on Helicobacter pylori proteins for antibiotic target discovery. AB - INTRODUCTION: Helicobacter pylori (H. pylori) is a well-known widespread pathogenic bacterium that survives in the extremely acidic conditions of the human gastric mucosa. The global prevalence of H. pylori-resistant antibiotics has become an emerging issue in the 21st century and has necessitated the development of novel antibiotic drugs. Many efforts have aimed to discover antibiotic target proteins of H. pylori based on its genome of more than 1600 genes. AREAS COVERED: This article highlights NMR spectroscopy as a valuable tool for determining the structure and dynamics of potential antibiotic-targeted proteins of H. pylori and evaluating their modes of interaction with native or synthetic binding partners. The residue-specific information on binding in solution provides a structural basis to identify and optimize lead compounds. EXPERT OPINION: NMR spectroscopy is a powerful method for obtaining details of biomolecular interactions with a broad range of binding affinities. This strength facilitates the identification of the binding interface of the encounter complex that plays an integral role in a variety of biological functions. This low affinity complex is difficult to crystallize, which impedes structure determination using X-ray crystallography. Additionally, the relative binding affinities can be predicted from the type of spectral change upon binding. High resolution NMR spectroscopy in combination with advanced computer simulation would provide more confidence in complex structures. The application of NMR to studies of the H. pylori protein could contribute to the development of these targeted novel antibiotics. PMID- 27216840 TI - Spontaneous Coronary Artery Dissection. AB - Spontaneous coronary artery dissection is an important etiology of nonatherosclerotic acute coronary syndrome, myocardial infarction, and sudden death. Innovations in the catheterization laboratory including optical coherence tomography and intravascular ultrasound have enhanced the ability to visualize intimal disruption and intramural hematoma associated with SCAD. Formerly considered "rare," these technological advances and heightened awareness suggest that SCAD is more prevalent than prior estimates. SCAD is associated with female sex, young age, extreme emotional stress, or extreme exertion, pregnancy, and fibromuscular dysplasia. The clinical characteristics and management strategies of SCAD patients are different than for atherosclerotic heart disease and deserve specific consideration. This review will highlight recent discoveries about SCAD as well as describe current efforts to elucidate remaining gaps in knowledge. PMID- 27216841 TI - Ocular Pseudoexfoliation Syndrome Linkage to Cardiovascular Disease. AB - PURPOSE OF REVIEW: Pseudoexfoliation syndrome (PEX) is a common cause of open angle glaucoma that is characterized by stress-induced elastic microfibrillopathy related to an accumulation of matrix metalloproteinases. The accumulation of matrix metalloproteinases increases deposition of protein substance within ocular structures and other organs including the heart. Many studies have associated the presence of cardiovascular disease with pseudoexfoliation syndrome, but much debate exists between studies in terms of significant relationships. The following meta-analysis aims to relate pseudoexfoliation syndrome with certain cardiovascular events and disorders. A thorough literature review was performed to acquire information concerning PEX patients with certain cardiovascular disorders. Diseases considered included myocardial infarction, ischemic heart disease, angina, congestive heart failure, cardiomyopathy, aortic aneurysm, hypertension, and homocystinuria. Patients without evidence of pseudoexfoliation disease were the controls of our study. Multiple forest plots were created to compile and analyze collected data for statistical comparison. RECENT FINDINGS: From a literature review, 18 studies were selected for our analysis. Cardiovascular disorders that had a statistically significant association (within a 95 % confidence interval) with PEX included ischemic heart disease, aortic aneurysms, and homocystinuria. The association between ischemic heart disease and PEX was statistically significant (p = 0.045). Myocardial infarction, chronic ischemic heart disease, angina, and hypertension did not show a correlation of relationship with the presence of pseudoexfoliation. Patients with PEX are prone to present with ischemic heart disease in addition to abdominal aortic aneurysms and homocystinuria. Patients that present with PEX should be screened for these detrimental cardiovascular disorders. PMID- 27216843 TI - Coronary Artery Imaging with Transthoracic Doppler Echocardiography. AB - Coronary artery imaging with transthoracic Doppler echocardiography is a simple and useful technique to diagnose significant coronary artery stenosis. The visualization of mosaic flow in the proximal left coronary artery provides a direct indication of the presence of significant stenosis at the corresponding site during routine echocardiography. Coronary flow velocity reserve (CFVR) has a high diagnostic accuracy and feasibility in detecting the presence of functionally significant coronary stenosis in the left anterior descending coronary artery (LAD) and in the right coronary artery. The measurement of CFVR in the LAD also provides prognostic information in patients with intermediate coronary stenosis. This review summarizes the utility of transthoracic coronary artery imaging. PMID- 27216842 TI - Role of Echocardiography in the Evaluation of Left Ventricular Assist Devices: the Importance of Emerging Technologies. AB - The role of left ventricular assist devices (LVAD) in patients with end-stage heart failure is well known, both as a temporary treatment before transplantation and as destination therapy, in a scenario of a relative shortage of donors to satisfy the increasing requests for transplantation. The increased population of LVAD patients needs careful imaging assessment before, during, and after LVAD implantation; echocardiography is the best tool for their evaluation and is considered the diagnostic technique of choice for the assessment before, during, and after device implantation. Although the conventional echocardiographic assessment is quite effective in evaluating the main critical issues, the role of new technologies like three-dimensional echocardiography and myocardial deformation measurements is still not properly clarified. In this review, we aim to provide an overview of the main elements that should be considered in the assessment of these patients, underlining the role that could be played by new techniques to improve the diagnostic and prognostic effectiveness of echocardiography in this setting. PMID- 27216844 TI - Multisite Pacing for Cardiac Resynchronization Therapy: Promise and Pitfalls. AB - Cardiac resynchronization therapy (CRT) reduces the morbidity and mortality of patients with symptomatic heart failure and intraventricular conduction delay. However, its clinical outcomes are non-uniform and up to one third of treated patients are subsequently classified as non-responders. Multisite pacing (MSP), i.e. stimulating the myocardium from multiple locations, has emerged as a potential therapeutic option in patients requiring CRT. The rationale for MSP is based on the hypothesis that increasing the pacing locations in the left ventricle results in a more physiologic and coordinated myocardial systole. MSP can be achieved by additional leads in the right or left ventricle but this can lead to high battery drain and more frequent generator replacements. Multipolar left ventricular leads can deliver pacing at multiple sites, and therefore, a single lead can be used for MSP. However, the optimal programming settings and the outcomes of this approach remain yet to be determined. PMID- 27216845 TI - Future Lipid-Altering Therapeutic Options Targeting Residual Cardiovascular Risk. AB - Low-density lipoproteins (LDL) play a causal role in the development of atherosclerosis, and reduction of LDL cholesterol with a statin is a cornerstone in prevention of cardiovascular disease. However, it remains an unmet need to reduce the residual risk on maximally tolerated statin alone or in combination with other drugs such as ezetimibe. Among the new LDL-lowering therapies, PCSK9 inhibitors appear the most promising class. Genetic studies suggest that triglyceride-rich lipoproteins are associated with cardiovascular risk and several promising triglyceride-lowering therapies are at various stages of development. At the opposite end, high-density lipoprotein (HDL) cholesterol seems to not be causally associated with cardiovascular risk, and thus far, trials designed to reduce cardiovascular risk by mainly raising HDL cholesterol levels have been disappointing. Nevertheless, new drugs targeting HDL are still in development. This review describes the new drugs reducing LDL, apolipoprotein(a), and triglyceride-rich lipoproteins, and the strategies to modulate HDL metabolism. PMID- 27216846 TI - How Well Can We Control Dyslipidemias Through Lifestyle Modifications? AB - The role for lifestyle modifications to correct dyslipidemia(s) is reviewed. Dietary composition is crucial. Replacing saturated fat with MUFA or n-6 PUFA lowers plasma low-density lipoproteins (LDL) cholesterol and ameliorates the LDL/HDL ratio. Replacing saturated fat with carbohydrates has diverging effects due to the heterogeneity of carbohydrate foods. Diets rich in refined carbohydrates increase fasting and postprandial triglycerides, whereas the consumption of fiber-rich, low GI foods lowers LDL cholesterol with no detrimental effects on triglycerides. The role of polyphenols is debated: available evidence suggests a lowering effect of polyphenol-rich foods on postprandial triglycerides. As for functional foods, health claims on a cholesterol lowering effect of psyllium, beta-glucans and phytosterols are accepted by regulatory agencies. The importance of alcohol intake, weight reduction, and physical activity is discussed. In conclusion, there is evidence that lifestyle affects plasma lipid. A multifactorial approach including multiple changes with additive effects is the best option. This may also ensure feasibility and durability. The traditional Mediterranean way of life can represent a useful model. PMID- 27216848 TI - Responsiveness and Minimally Important Difference of the 6-Minute Stepper Test in Patients with Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: The validity and reproducibility of the 6-minute stepper test (6MST) have already been demonstrated in patients with chronic obstructive pulmonary disease (COPD). OBJECTIVES: The aim of this study was to evaluate the responsiveness of the 6MST to pulmonary rehabilitation (PR) in patients with COPD, to determine a minimal important difference (MID) for the 6MST, and to compare the 6MST and the 6-minute walk test (6MWT). METHODS: Sixty-two patients with COPD were included in a prospective experimental study. Participants underwent a 3-week inpatient PR program. The primary outcome was the change in the number of steps during the 6MST measured before and after PR. The secondary outcome included the change in the 6-minute walking distance (6MWD) pulse oximetry, heart rate, dyspnea, and leg discomfort during the tests measured before and after PR. MID was determined by anchor-based and distribution approaches. RESULTS: After PR, we observed a significant increase in the number of steps during the 6MST (22.5 steps; 95% CI 13.8-31.3; p < 0.0001) and in the 6MWD (26.6 m; 95% CI 17.6-35.5; p < 0.0001). The 6MST and 6MWT were improved by 10.1 and 6.5%, respectively. The number of steps during the 6MST was significantly correlated with the 6MWD before (r = 0.72; p < 0.0001) and after PR (r = 0.66; p < 0.0001). MID was estimated to be around 20 steps. CONCLUSION: The 6MST appears to be as responsive as the 6MWT in assessing functional improvement during PR in patients with COPD. The 6MST is a low-cost assessment and requires limited space. PMID- 27216847 TI - Triglyceride-Rich Lipoproteins and Remnants: Targets for Therapy? AB - It is now evident that elevated circulating levels of triglycerides in the non fasting state, a marker for triglyceride (TG)-rich remnant particles, are associated with increased risk of premature cardiovascular disease (CVD). Recent findings from basic and clinical studies have begun to elucidate the mechanisms that contribute to the atherogenicity of these apoB-containing particles. Here, we review current knowledge of the formation, intravascular remodelling and catabolism of TG-rich lipoproteins and highlight (i) the pivotal players involved in this process, including lipoprotein lipase, glycosylphosphatidylinositol HDL binding protein 1 (GPIHBP1), apolipoprotein (apo) C-II, apoC-III, angiopoietin like protein (ANGPTL) 3, 4 and 8, apoA-V and cholesteryl ester transfer protein; (ii) key determinants of triglyceride (TG) levels and notably rates of production of very-low-density lipoprotein 1 (VLDL1) particles; and (iii) the mechanisms which underlie the atherogenicity of remnant particles. Finally, we emphasise the polygenic nature of moderate hypertriglyceridemia and briefly discuss modalities for its clinical management. Several new therapeutic strategies to attenuate hypertriglyceridemia have appeared recently, among which those targeted to apoC III appear to hold considerable promise. PMID- 27216849 TI - Is the flexion strength really increased after tenodesis for tendinopathy of the long head of the biceps? PMID- 27216850 TI - Minimally Invasive Pancreatic Resection: Is It Really the Future? AB - The introduction and widespread application of minimally invasive surgery has been one of the most important innovations that radically changed the practice of surgery during the last few decades. The application to pancreatic surgery of minimally invasive approach has only recently emerged: both laparoscopic distal pancreatectomy (LDP) and laparoscopic pancreaticoduodenectomy (LPD) can be competently performed. LDP and LPD are advocated to improved perioperative outcomes, including decreased blood loss, shorter length of stay, reduced postoperative pain and expedited time to functional recovery. However, the indication to minimally invasive approach for pancreatic surgery is often benign or low-grade malignant pathologies. In this review, we summarize the current data on minimally invasive pancreatic surgery, focusing on indication, perioperative and oncological outcomes. PMID- 27216851 TI - N-acetylcysteine supplementation reduces oxidative stress for cytosine arabinoside in rat model. AB - Cytosine arabinoside (ARA-C) is a pyrimidine analog that may cause keratoconjunctivitis when used in high doses. The underlying mechanism may be the increased amounts of reactive oxygen radicals that may damage the DNA synthesis of corneal and conjunctival epithelial cells. Topical corticosteroids are one of the prophylactic treatments for keratoconjunctivitis induced by ARA-C. Forty Wistar-type albino rats were included in this study the rats were divided into four groups. The first group (Group 1) received only ARA-C, the second group (Group 2) received ARA-C and N-acetylcysteine (NAC), the third group (Group 3) received only NAC and the fourth group (Group 4) was the control group. The total oxidant status (TOS), the total antioxidant capacity and the oxidative stress index (OSI) measurements of the cornea and the conjunctiva were evaluated in these four groups. The mean TOS and OSI value was the highest in Group 1 and the lowest in Group 3. The differences in TOS and OSI values were statistically significant between Group 1 and Group 2. There are decreases in TOS and OSI values in rats which received ARA-C with NAC administration. NAC may have a protective effect on ARA-C-induced keratoconjunctivitis. PMID- 27216852 TI - Occurrence of intraocular air bubbles during intravitreal injections for retinopathy of prematurity. AB - This study aims to present five cases with retinopathy of prematurity (ROP) who were found to have intraocular air bubbles after intravitreal injection (IVI) treatment. The medical records of 148 infants who underwent IVI for ROP were retrospectively reviewed and the ones who demonstrated post-injection intraocular air bubble formation were recruited. Of the 148 patients (31 babies received ranibizumab, 20 babies received aflibercept, 97 babies received bevacizumab), five were found to have intraocular air bubbles right after the IVI. Two infants received intravitreal ranibizumab and three received intravitreal bevacizumab injections. Although intraocular pressure increased temporarily, no intraocular sterile or infective reactions were observed in the postoperative period. The air bubble was found to resorb spontaneously within 72 h. The occurrence rate of the intravitreal air bubbles in our series was 3.37 % despite previously not been reported in the literature. Due to the intravitreal air injection risk, it is important to be more careful while preparing the intravitreal medication before treatment in premature babies. PMID- 27216853 TI - Complicating Counterspaces: Intersectionality and the Michigan Womyn's Music Festival. AB - The counterspaces framework articulated by Case and Hunter (2012), follows from community psychology's long-standing interest in the potential for settings to promote well-being and liberatory responses to oppression. This framework proposes that certain settings (i.e., "counterspaces") facilitate a specific set of processes that promote the well-being of marginalized groups. We argue that an intersectional analysis is crucial to understand whether and how counterspaces achieve these goals. We draw from literature on safe spaces and present a case study of the Michigan Womyn's Music Festival (Michfest) to illustrate the value of an intersectional analysis and explore how these processes operate. Based on 20 in-person interviews, 23 responses to an online survey, and ethnographic field notes, we show how Michfest was characterized by a particular intersection of identities at the setting level, and intersectional diversity complicated experiences at the individual level. Moreover, intersectional identities provided opportunities for dialogue and change at the setting level, including the creation of counterspaces within counterspaces. Overall, we demonstrate the need to attend to intersectionality in counterspaces, and more broadly in how we conceptualize settings in community psychology. PMID- 27216854 TI - Effect of Medicago sativa L. and compost on organic and inorganic pollutant removal from a mixed contaminated soil and risk assessment using ecotoxicological tests. AB - Several Gentle Remediation Options (GRO), e.g., plant-based options (phytoremediation), singly and combined with soil amendments, can be simultaneously efficient for degrading organic pollutants and either stabilizing or extracting trace elements (TEs). Here, a 5-month greenhouse trial was performed to test the efficiency of Medicago sativa L., singly and combined with a compost addition (30% w/w), to treat soils contaminated by petroleum hydrocarbons (PHC), Co and Pb collected at an auto scrap yard. After 5 months, total soil Pb significantly decreased in the compost-amended soil planted with M. sativa, but not total soil Co. Compost incorporation into the soil promoted PHC degradation, M. sativa growth and survival, and shoot Pb concentrations [3.8 mg kg(-1) dry weight (DW)]. Residual risk assessment after the phytoremediation trial showed a positive effect of compost amendment on plant growth and earthworm development. The O2 uptake by soil microorganisms was lower in the compost amended soil, suggesting a decrease in microbial activity. This study underlined the benefits of the phytoremediation option based on M. sativa cultivation and compost amendment for remediating PHC- and Pb-contaminated soils. PMID- 27216856 TI - Development of a Large Animal Long-Term Intervertebral Disc Organ Culture Model That Includes the Bony Vertebrae for Ex Vivo Studies. AB - Intervertebral disc (IVD) degeneration is a common cause of low back pain. Testing potential therapeutics in the regeneration of the disc requires the use of model systems. Although several animal models have been developed to investigate IVD degeneration, they are technically challenging to prepare, expensive, present with limitations when performing biomechanical studies on the disc, and are impractical in large-scale screening of novel anabolic and scaffolding agents. An IVD organ culture system offers an inexpensive alternative. In the current paradigm, the bony endplates are removed to allow for nutrient diffusion and maintenance of disc cell viability. Although this is an excellent system for testing biologics, it results in concave cartilage endplates and, as such, requires special platens for loading purposes in a bioreactor as flat ones can overload the annular disc region leading to improper loading. Furthermore, the absence of bone makes it unsuitable for applying complex cyclic loading, a topic of interest in the study of chronic progressive degeneration, as multiaxial loading is more representative of daily forces encountered by the IVD. We have developed and validated a novel long-term IVD organ culture model that retains vertebral bone and is easy to prepare. Our model is ideal for testing potential drugs and alternate-based therapies, in addition to investigating the long-term effects of loading paradigms on disc degeneration and repair. PMID- 27216855 TI - From "traction bronchiectasis" to honeycombing in idiopathic pulmonary fibrosis: A spectrum of bronchiolar remodeling also in radiology? AB - BACKGROUND: The diagnostic and prognostic impact of traction bronchiectasis on high resolution CT scan (HRCT) in patients suspected to have idiopathic pulmonary fibrosis (IPF) is increasing significantly. MAIN BODY: Recent data demonstrated that cysts in honeycombing areas are covered by epithelium expressing bronchiolar markers. In IPF bronchiolization is the final consequence of a variety of pathogenic events starting from alveolar stem cell exhaustion, and ending in a abnormal/dysplastic proliferation of bronchiolar epithelium. CT scan features of traction bronchiectasis and honeycombing should be interpreted under the light of these new pathogenetic and morphologic considerations. SHORT CONCLUSION: We suggest that in IPF subjects traction bronchiectasis and honeycombing -now defined as distinct entities on HRCT scan- are actually diverse aspects of a continuous spectrum of lung remodeling. PMID- 27216858 TI - Abstracts presented at the 19th Japanese Research Society of Clinical Anatomy on November 14th 2015 at The University of Tokyo, Tokyo, Japan. PMID- 27216857 TI - Development and validation of the Shy Bladder and Bowel Scale (SBBS). AB - Currently research exploring paruresis and parcopresis, anxiety relating to urinating and having bowel motions in public respectively is limited. While there are several validated measures of paruresis, no valid measure assessing parcopresis is currently available. The present study investigates the development and validation of the Shy Bladder and Bowel Scale (SBBS) which assesses both paruresis and parcopresis. Two participant groups were utilised to validate this scale, a student psychology cohort (n = 387) and a public cohort (n = 334). An eight-item two-factor model was identified in the psychology cohort and confirmed in the public cohort. The two-factor SBBS was found to be a valid and reliable measure of paruresis and parcopresis. Paruresis and parcopresis related concerns were associated with social anxiety in both cohorts. Subscales for both paruresis and parcopresis (i.e. difficulty, interference and distress) were positively correlated, suggesting individuals are likely to report similar levels of concerns across both conditions. Further, individuals self-identifying with either paruresis or parcopresis reported significantly higher scores on the respective SBBS subscales than non-identifying paruresis and parcopresis individuals. The SBBS also demonstrated strong test-retest reliability in a small sample of adults (n = 13). Overall, the developed scale provides clinicians and researchers with a valuable tool to evaluate both paruresis and parcopresis. PMID- 27216859 TI - Multi-facetted impulsivity following nigral degeneration and dopamine replacement therapy. AB - Impulse control disorders (ICDs) are debilitating side effects of dopamine replacement therapy (DRT) in Parkinson's disease (PD) that severely affect the quality of life of patients. While DRT, the pattern and extent of neurodegeneration, and prodromic factors of vulnerability (e.g. impulsivity) have all been hypothesized to play a role in the development of ICDs, their respective, and potentially interacting, contributions remain to be established. High impulsive (HI), Intermediate (Int) or low impulsive (LI) rats were identified based on their performance in both a differential reinforcement of low rate of responding (DRL) and a fixed consecutive number (FCN) schedules, that operationalize two independent facets of impulsivity, waiting and action inhibition (motor impulsivity). We investigated whether high impulsivity trait influenced the progressive development of a parkinsonian state induced by viral mediated overexpression of alpha-synuclein, and whether impulsivity trait and nigrostriatal neurodegeneration independently or jointly influenced the effects of DRT on impulse control. alpha-synuclein-induced nigrostriatal neurodegeneration increased both waiting and motor impulsivity. The D2/D3 dopamine receptor agonist pramipexole exacerbated motor impulsivity more than waiting. However, the pramipexole-induced increase in waiting impulsivity observed in both sham and lesioned rats, was more pronounced in HI lesioned rats, which displayed a restricted alpha-synuclein-induced dopaminergic neurodegeneration. Thus, a PD-like nigrostriatal lesion increases both motor and waiting impulsivity, but its interaction with a pre-existing impulsivity trait, which, at the cellular level, confers resilience to dopaminergic neurodegeneration, worsens the detrimental effects of D2/D3 dopamine receptor agonists on inhibitory control. PMID- 27216860 TI - Neutrophil-to-lymphocyte count ratio is associated with perforated appendicitis in elderly patients of emergency department. AB - PURPOSE: The diagnostic value of the neutrophil-to-lymphocyte count ratio (NLR) and the Appendicitis Inflammatory Response (AIR) score for identifying acute appendicitis (AA) perforation in elderly patients in the emergency department (ED) were evaluated. METHODS: A total of 103 patients who were admitted for appendectomy for AA via the ED between January 2012 and December 2014 were reviewed retrospectively. Patients aged 65 and over were included. Patient age, sex, comorbidities, body temperature, clinical findings and initial laboratory results including white blood cell (WBC) count, NLR, serum levels of CRP and total bilirubin (TB) in the ED were assessed, and the AIR score was calculated. RESULTS: Perforation due to AA was identified in 58 (56.3 %) elderly patients. Median WBC count, neutrophil count, CRP and TB were significantly higher in the perforated group compared to the non-perforated group (p = 0.005, p = 0.001, p = 0.004 and p = 0.012) in the ED. The NLR was significantly different in the two groups (perforated vs non-perforated group, 9.5 vs 5.1, p < 0.001). The area under the curve value of NLR was 0.755 (95 % CI 0.660-0.834), and the cutoff value was 5.6 (sensitivity 78.0 % and specificity 65.9 %). In multivariate logistic analysis, NLR > 5.6 [odds ratio (OR) 6.794, p = 0.001] was significant independent factor for AA perforation in elderly patients. The AIR score risk probability did not differ between the two groups of elderly patients (p = 0.094). Twenty-five (42.4 %) patients in the perforated group and five (11.4 %) patients in the non-perforated group were classified as high probability by the modified AIR score including the NLR value (p = 0.001). CONCLUSION: We suggest that the initial NLR in the elderly patient is the most powerful predictive factor for the diagnosis of AA perforation in the ED. PMID- 27216861 TI - Diabetes Risk and Disease Management in Later Life: A National Longitudinal Study of the Role of Marital Quality. AB - OBJECTIVES: We assess the association between marital quality and both the risk of developing diabetes and the management of diabetes after its onset in later life. METHOD: We use data from the first two waves of the National Social Life, Health, and Aging Project to estimate regression models with lagged dependent variables. The sample includes 1,228 married respondents, among whom 389 were diabetic. Those with either a reported diagnosis or with HbA1c >= 6.5% are identified diabetic. We categorize diabetic respondents into three groups: controlled, undiagnosed, and uncontrolled diabetes. We conduct factor analysis to construct positive and negative marital quality scales. RESULTS: For women, an increase in positive marital quality between Waves 1 and 2 is related to a lower risk of being diabetic at Wave 2, net of diabetes status at Wave 1; surprisingly, for men, an increase in negative marital quality between Waves 1 and 2 is related to both a lower risk of being diabetic at Wave 2 and a higher chance of controlling diabetes at Wave 2 after its onset. DISCUSSION: Our results challenge the traditional assumption that negative marital quality is always detrimental to health and encourage family scholars to distinguish different sources and types of negative marital quality. PMID- 27216862 TI - Protein tyrosine phosphatase SHP-1: resurgence as new drug target for human autoimmune disorders. AB - Recognition of self-antigen and its destruction by the immune system is the hallmark of autoimmune diseases. During the developmental stages, immune cells are introduced to the self-antigen, for which tolerance develops. The inflammatory insults that break the immune tolerance provoke immune system against self-antigen, progressively leading to autoimmune diseases. SH2 domain containing protein tyrosine phosphatase (PTP), SHP-1, was identified as hematopoietic cell-specific PTP that regulates immune function from developing immune tolerance to mediating cell signaling post-immunoreceptor activation. The extensive research on SHP-1-deficient mice elucidated the diversified role of SHP 1 in immune regulation, and inflammatory process and related disorders such as cancer, autoimmunity, and neurodegenerative diseases. The present review focalizes upon the implication of SHP-1 in the pathogenesis of autoimmune disorders, such as allergic asthma, neutrophilic dermatosis, atopic dermatitis, rheumatoid arthritis, and multiple sclerosis, so as to lay the background in pursuance of developing therapeutic strategies targeting SHP-1. Also, new SHP-1 molecular targets have been suggested like SIRP-alpha, PIPKIgamma, and RIP-1 that may prove to be the focal point for the development of therapeutic strategies. PMID- 27216863 TI - Combined immunodeficiency in a patient with mosaic monosomy 21. AB - Monosomy 21 is an extremely rare genetic disorder presenting with a wide array of symptoms. Recurrent infections, some life threatening, have been reported in several monosomy 21 patients and attributed to an, as of yet, undefined immunodeficiency. Here we report on a 3-year-old boy with mosaic monosomy 21 who presented with clinical and laboratory evidence of immunodeficiency. Despite suffering from infections highly suggestive of a cell-mediated immune defect, the patient's T cells displayed normal counts, subsets and proliferation capability. T cell receptor repertoire was diverse, and de novo T cell production was intact. Consistent with earlier case reports, our patient displayed mildly low B cell counts with hypogammaglobulinemia. B cell subsets demonstrated mainly naive and marginal zone B cells that have not undergone class switch. Subsequently, IgG, IgA and IgE levels were near absent, whereas IgM level was normal. De novo B cell production and B cell receptor diversity were normal. Together, these results are indicative of a defect in immunoglobulin class switching as the principal cause of immunodeficiency in monosomy 21. A better understanding of the immunodeficiency in this syndrome will enable targeted treatment and prevention of infections in order to prevent morbidity and mortality in these patients. PMID- 27216864 TI - A balancing act in cardiac hypertrophy. PMID- 27216865 TI - Pulmonary hypertension begets pulmonary hypertension: mutually reinforcing roles for haemodynamics, inflammation, and cancer-like phenotypes. PMID- 27216866 TI - Is stress response a new link between adipose tissue and atherogenesis? The role of HSPs/HSF1. PMID- 27216867 TI - EphrinB2/EphB4 pathway in postnatal angiogenesis: a potential therapeutic target for ischemic cardiovascular disease. AB - Ischemic cardiovascular disease remains one of the leading causes of morbidity and mortality in the world. Proangiogenic therapy appears to be a promising and feasible strategy for the patients with ischemic cardiovascular disease, but the results of preclinical and clinical trials are limited due to the complicated mechanisms of angiogenesis. Facilitating the formation of functional vessels is important in rescuing the ischemic cardiomyocytes. EphrinB2/EphB4, a novel pathway in angiogenesis, plays a critical role in both microvascular growth and neovascular maturation. Hence, investigating the mechanisms of EphrinB2/EphB4 pathway in angiogenesis may contribute to the development of novel therapeutics for ischemic cardiovascular disease. Previous reviews mainly focused on the role of EphrinB2/EphB4 pathway in embryo vascular development, but their role in postnatal angiogenesis in ischemic heart disease has not been fully illustrated. Here, we summarized the current knowledge of EphrinB2/EphB4 in angiogenesis and their interaction with other angiogenic pathways in ischemic cardiovascular disease. PMID- 27216868 TI - New [(eta(5)-C5H5)Ru(N-N)(PPh3)][PF6] compounds: colon anticancer activity and GLUT-mediated cellular uptake of carbohydrate-appended complexes. AB - Eight ruthenium(ii) compounds of the general formula [(eta(5)-C5H5)Ru(N N)(PPh3)][PF6] were rationally designed, exhibiting high cytotoxicity against HCT116 human colon cancer cells, with IC50 between 14.56 and 1.56 MUM; importantly, compounds 5Ru and 6Ru are the first reported ruthenium glycoconjugates exploiting glucose transporters, widely overexpressed in cancer, for cellular uptake. PMID- 27216869 TI - Patients with abdominal aortic aneurysm have a high prevalence of popliteal artery aneurysms. AB - Patients with abdominal aortic aneurysms (AAA) are more prone to develop popliteal artery aneurysms (PAA), but the prevalence is not well known. Our aim was to investigate the prevalence of PAA in patients with AAA, and to determine whether a certain risk factor profile is more commonly found in patients with concurrent aneurysms. All AAA patients (ICD code I71.3, I71.4) attending the outpatient clinic at the Karolinska University Hospital between 2011 and 2013 were included in the study cohort (n=465); 48% (225) had been subjected to an ultrasound or computed tomography scan of their popliteal arteries. In these patients, three definitions of PAA were considered (? 10.5, ? 12, ? 15 mm), although the overall analysis is based on PAA ? 12 mm. The mean age was 70.7 years (SD 7.5), 89% were men, and the mean AAA diameter was 47 mm (SD 14). The prevalence of PAA was 19% (n=43) by definition ? 12 mm, and 11% (n=25) with 15 mm. Claudication was more frequently found in AAA patients with PAA than patients without PAA. Sensitivity between clinical examination and radiology was 26%, and the specificity for clinical examination was 90%. In conclusion, owing to the high prevalence of PAA in AAA patients, described by us and others, the low cost and risks associated with ultrasound and the poor sensitivity at clinical examination, all women and men with AAA should undergo one radiological examination of their popliteal arteries. PMID- 27216871 TI - Thyroid hormone-dependent formation of a subcortical band heterotopia (SBH) in the neonatal brain is not exacerbated under conditions of low dietary iron (FeD). AB - Thyroid hormones (TH) are critical for brain development and insufficiencies can lead to structural abnormalities in specific brain regions. Administration of the goitrogen propylthiouracil (PTU) reduces TH production by inhibiting thyroperoxidase (TPO), an enzyme that oxidizes iodide for the synthesis of TH. TPO activity is iron (Fe)-dependent and dietary iron deficiency (FeD) also reduces circulating levels of TH. We have previously shown that modest degrees of TH insufficiency induced in pregnant rat dams alters the expression of TH responsive genes in the cortex and hippocampus of the neonate, and results in the formation of a subcortical band heterotopia (SBH) in the corpus callosum (Royland et al., 2008, Bastian et al., 2014, Gilbert et al., 2014). The present experiment investigated if FeD alone was sufficient to induce a SBH or if FeD would augment SBH formation at lower doses of PTU. One set of pregnant rats was administered 0, 1, 3, or 10ppm of PTU via drinking water starting on gestational day (GD) 6. FeD was induced in a 2nd set of dams beginning on GD2. A third set of dams received the FeD diet from GD2 paired with either 1ppm or 3ppm PTU beginning on GD6. All treatments continued until the time of sacrifice. On PN18, one female pup from each litter was sacrificed and the brain examined for SBH. We observed lower maternal, PN2 and PN18 pup serum T4 in response to PTU. FeD reduced serum T4 in pups on PN16, but did not affect serum T4 in dams or PN2 pups. Neither did FeD in combination with PTU alter T4 levels in dams on PN18 or pups on PN2 compared to PTU treatment alone. By PN16, however more severe T4 reductions were observed in pups when FeD was combined with PTU. SBH increased with increasing dosage of PTU, but counter to our hypothesis, no SBH was detected in the offspring of FeD dams. As such, T4 levels in dams and newborn pups rather than older neonates appear to be a better predictor SBH associated with TH insufficiency. These data indirectly support previous work indicating prenatal TH insufficiency but not postnatal TH insufficiency in offspring is required for SBH formation. PMID- 27216870 TI - Traditional graft preparation decreases physiologic responses, diminishes viscoelasticity, and reduces cellular viability of the conduit: A porcine saphenous vein model. AB - Traditional methods of intraoperative human saphenous vein preparation for use as bypass grafts can be deleterious to the conduit. The purpose of this study was to characterize acute graft preparation injury, and to mitigate this harm via an improved preparation technique. Porcine saphenous veins were surgically harvested (unprepared controls, UnP) and prepared using traditional (TraP) and improved preparations (ImP). The TraP used unregulated radial distension, marking with a surgical skin marker and preservation in heparinized normal saline. ImP used pressure-regulated distension, brilliant blue FCF-based pen marking and preservation in heparinized Plasma-Lyte A. Rings from each preparation were suspended in a muscle bath for characterization of physiologic responses to vasoactive agents and viscoelasticity. Cellular viability was assessed using the methyl thiazolyl tetrazolium (MTT) assay and the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay for apoptosis. Contractile responses to potassium chloride (110 mM) and phenylephrine (10 uM), and endothelial-dependent and independent vasodilatory responses to carbachol (0.5 uM) and sodium nitroprusside (1 uM), respectively, were decreased in TraP tissues compared to both UnP and ImP tissues (p ? 0.05). TraP tissues demonstrated diminished viscoelasticity relative to UnP and ImP tissues (p ? 0.05), and reduced cellular viability relative to UnP control (p ? 0.01) by the MTT assay. On the TUNEL assay, TraP tissues demonstrated a greater degree of apoptosis relative to UnP and ImP tissues (p ? 0.01). In conclusion, an improved preparation technique prevents vascular graft smooth muscle and endothelial injury observed in tissues prepared using a traditional approach. PMID- 27216872 TI - Co-exposure to fish oil or folic acid does not reverse effects in the progeny induced by maternal exposure to fluoxetine. PMID- 27216873 TI - Is an ecological school-based nutrition intervention effective to improve adolescents' nutrition-related knowledge, attitudes and behaviour in rural areas of China? AB - PURPOSE: The purpose of this article is to examine the effect of a school-based nutrition intervention using an ecological approach to improve adolescents' nutrition-related knowledge, attitudes and behaviour in rural China. METHODS: A cluster-randomised intervention trial design was employed. Two middle schools were randomly selected and assigned to the school that was conducting a holistic school-based intervention using health-promoting school (HPS) framework, 'HPS School', or to the 'Control School' in Mi Yun County, Beijing. From each school we randomly selected 65 seventh-grade students to participate in the study. Their nutrition-related knowledge, attitudes and behaviour were measured by pre- and post-intervention surveys with the same instrument. The nutrition intervention lasted for six months. RESULTS: Adolescents in the intervention school were more likely to know the nutrition knowledge items, with an odds ratio (OR) ranging from 1.86 (95% confidence interval (CI): 1.11-3.09) to 6.34 (95% CI: 3.83-10.47); more likely to think nutrition is very important to health, developing healthy dietary habits is very important, and that expired foods should be thrown away, with ORs of 3.03 (95% CI: 1.60-5.76), 2.76 (95% CI: 1.66-4.59) and 2.35 (95% CI: 1.33-4.17) respectively, and more likely to consume no soft drinks, desserts or fried food, and to eat vegetables every day of the last week, with ORs of 1.99 (95% CI: 1.31-3.04), 3.96 (95% CI: 2.43-6.46), 3.63 (95% CI: 2.26-5.85), and 2.51 (95% CI: 1.41-4.48) respectively, as compared with those in the control school after interventions. CONCLUSIONS: Our intervention using the HPS framework, an ecological approach, was an appropriate model to promote nutrition among adolescents in rural China and its use should be advocated in future school-based nutrition promotion programmes for adolescents. PMID- 27216874 TI - Outcomes of a Behavioral Intervention to Increase Condom Use and Reduce HIV Risk Among Urban African American Young Adults. AB - African Americans comprise nearly half of people in the United States living with the human immunodeficiency virus (HIV) but compose one tenth of the population. Infection rate among young African American adults is 11 times that of Whites. The Color It Real Program was a seven-session, weekly administered, age-specific, and culturally tailored intervention designed to provide HIV education and address behavioral motivations (risk awareness, decisional balance exercises, partner negotiation, and attitudes) associated with HIV risk among African Americans ages 18 to 24 years in Atlanta, Georgia. Effectiveness was assessed through a quasi-experimental study design that consisted of intervention (n = 88) and control (n = 52) groups completing a 45-item survey. When controlling for gender and education, repeated measures analysis of variance revealed that the intervention group had significant increases in HIV transmission knowledge (F = 4.84, p = .0305), condom use, and intentions to use condoms (F = 4.38, p = .0385). Risky sexual behavior means did not significantly differ between groups (F = 1.44, p = .2331). Results indicate the value of culturally tailored educational strategies toward improved HIV knowledge and adoption of risk reduction strategies. Future studies investigating the differential impact of programs by gender and sexual orientation are also critical. Continued innovation and tailoring of risk reduction strategies for minority young adults will contribute to reducing HIV incidence and prevalence over the life course. PMID- 27216875 TI - Process Evaluation of Making HEPA Policy Practice: A Group Randomized Trial. AB - This study examines the link between implementation of Strategies to Enhance Practice (STEPs) and outcomes. Twenty after-school programs (ASPs) participated in an intervention to increase children's accumulation of 30 minutes/day of moderate to vigorous physical activity (MVPA) and quality of snacks served during program time. Outcomes were measured via accelerometer (MVPA) and direct observation (snacks). STEPs implementation data were collected via document review and direct observation. Based on implementation data, ASPs were divided into high/low implementers. Differences between high/low implementers' change in percentage of boys accumulating 30 minutes/day of MVPA were observed. There was no difference between high/low implementers for girls. Days fruits and/or vegetables and water were served increased in the high/low implementation groups, while desserts and sugar-sweetened beverages decreased. Effect sizes (ES) for the difference in changes between the high and low group ranged from low (ES = 0.16) to high (ES = 0.97). Higher levels of implementation led to increased MVPA for boys, whereas girls MVPA benefited from the intervention regardless of high/low implementation. ESs of the difference between high/low implementers indicate that increased implementation of STEPs increases days healthier snacks are served. Programs in the high-implementation group implemented a variety of STEPs strategies, suggesting local adoption/adaptation is key to implementation. PMID- 27216876 TI - Statewide Dissemination of Sesame Street Resources for Families Affected by Incarceration. AB - The number of children with an incarcerated parent has increased nearly 80% in the past 20 years. Despite the growing need, few educational resources exist to promote the emotional health of young children with incarcerated parents. To address this need, Sesame Street recently released developmentally appropriate, multimedia resources, and piloted the dissemination of those resources in 10 states. The current study describes the process used in one pilot state to disseminate the resources; documents the reach of those dissemination efforts, including the number of resource kits distributed, number of community-based and clinical providers reached, and location of providers across the state; and examines providers' impressions of the utility of the resources and their perspectives on how the resources support children and families affected by incarceration. This study has important implications for translating research evidence for community providers and practitioners who aim to promote the emotional health of young children affected by incarceration. PMID- 27216877 TI - Pharmacology of Ischemia-Reperfusion. Translational Research Considerations. AB - Ischemia-reperfusion (IRI) is a complex physiopathological mechanism involving a large number of metabolic processes that can eventually lead to cell apoptosis and ultimately tissue necrosis. Treatment approaches intended to reduce or palliate the effects of IRI are varied, and are aimed basically at: inhibiting cell apoptosis and the complement system in the inflammatory process deriving from IRI, modulating calcium levels, maintaining mitochondrial membrane integrity, reducing the oxidative effects of IRI and levels of inflammatory cytokines, or minimizing the action of macrophages, neutrophils, and other cell types. This study involved an extensive, up-to-date review of the bibliography on the currently most widely used active products in the treatment and prevention of IRI, and their mechanisms of action, in an aim to obtain an overview of current and potential future treatments for this pathological process. The importance of IRI is clearly reflected by the large number of studies published year after year, and by the variety of pathophysiological processes involved in this major vascular problem. A quick study of the evolution of IRI-related publications in PubMed shows that in a single month in 2014, 263 articles were published, compared to 806 articles in the entire 1990. PMID- 27216878 TI - Involvement of Auxin and Brassinosteroid in Dwarfism of Autotetraploid Apple (Malus * domestica). AB - The plant height is an important trait in fruit tree. However, the molecular mechanism on dwarfism is still poorly understood. We found that colchicine induced autotetraploid apple plants (Malus * domestica) exhibited a dwarf phenotype. The vertical length of cortical parenchyma cells was shorter in autotetraploids than in diploids, by observing paraffin sections. Hormone levels of indoleacetic acid (IAA) and brassinosteroid (BR) were significantly decreased in 3- and 5-year-old autotetraploid plants. Digital gene expression (DGE) analysis showed that the differentially expressed genes were mainly involved in IAA and BR pathways. microRNA390 was significantly upregulated according to microarray analysis. Exogenous application of IAA and BR promoted stem elongation of both apple plants grown in medium. The results show that dwarfing in autotetraploid apple plants is most likely regulated by IAA and BR. The dwarf phenotype of autotetraploid apple plants could be due to accumulation of miR390 after genome doubling, leading to upregulation of apple trans-acting short interfering RNA 3 (MdTAS3) expression, which in turn downregulates the expression of MdARF3. Overall, this leads to partial interruption of the IAA and BR signal transduction pathway. Our study provides important insights into the molecular mechanisms underlying dwarfism in autopolyploid apple plants. PMID- 27216879 TI - Eviscerated Corneas as Tissue Source for Ex Vivo Expansion of Limbal Epithelial Cells on Platelet-Rich Plasma Gels. AB - : Purpose/Aim of the study: To assess if corneal epithelium can be cultured ex vivo from corneas eviscerated due to irretrievable trauma, according to a cell culture method that made use of autologous platelet-rich plasma (A-PRP) as culture substrate. To compare corneal epithelium cultured ex vivo from corneas eviscerated following trauma using A-PRP combined with Dulbecco's modified Eagles medium (DMEM), versus DMEM alone. MATERIALS AND METHODS: This was a laboratory case-controlled study of human corneal cells cultured in a mixture of A-PRP and DMEM, versus DMEM alone from six eviscerated corneas. A 100 explants were created, of which 50 explants were plated on A-PRP-gel construct combined with DMEM and 50 controls were placed in serum-free DMEM alone. Donor patients received systemic antibiotics prior to evisceration. RESULTS: Confluent epithelium in monolayers could be cultured when donor limbal biopsies were placed in a mixture of A-PRP culture medium and DMEM. No growth was observed when corneas were placed in serum-free DMEM medium only (p < 0.05). No bacterial infection was observed in cultures. CONCLUSIONS: This study demonstrated that A PRP is a viable and effective alternative to bovine serum for the ex vivo expansion of limbal epithelial cells. It also shows that eviscerated corneas are a viable source of donor tissue for this purpose in South Africa where access to tissue banks is limited. PMID- 27216880 TI - Targeted nanobubbles in low-frequency ultrasound-mediated gene transfection and growth inhibition of hepatocellular carcinoma cells. AB - The use of SonoVue combined with ultrasound exposure increases the transfection efficiency of short interfering RNA (siRNA). The objective of this study was to prepare targeted nanobubbles (TNB) conjugated with NET-1 siRNA and an antibody GPC3 to direct nanobubbles to hepatocellular carcinoma cells. SMMC-7721 human hepatocellular carcinoma cells were treated with six different groups. The transfection efficiency and cellular apoptosis were measured by flow cytometry. The protein and messenger RNA (mRNA) expression were measured by Western blot and quantitative real-time PCR, respectively. The migration and invasion potential of the cells were determined by Transwell analysis. The results show that US-guided siRNA-TNB transfection effectively enhanced gene silencing. In summary, siRNA-TNB may be an effective delivery vector to mediate highly effective RNA interference in tumor treatment. PMID- 27216882 TI - Evidence of pathogenicity of a mutation in 3' untranslated region causing mild haemophilia A. AB - INTRODUCTION: Despite the high mutation detection rate, in a small group of haemophilia A patients, using current screening methods, no causal mutation in F8 can be detected. In such cases, the causal mutation might be in the non-coding sequences of F8. AIM: Rarely, mutations in non-coding sequences reveal a pivotal role. Here, we analysed a mild haemophilia A patient harbouring a mutation in the 3' untranslated region (UTR) of F8 and elucidated the molecular mechanism leading to haemophilia phenotype. METHODS: To find the causal mutation, the complete F8 genomic region was analysed by next generation sequencing. The effect of the identified alteration on F8 expression was evaluated in silico and analysed for the splicing effect at mRNA level. Moreover, in vitro studies using a luciferase reporter system were performed to functionally analyse the mutation. RESULTS: We identified an alteration in the 3' UTR (c.*56G>T) as the only change in F8 gene. Pedigree analysis showed a segregation pattern for three affected members for the presumptive mutation. Moreover, the variant was predicted in silico to create a new donor splice site, which was also detected at mRNA level, resulting in a 159 bp deletion in 3' UTR of F8. Finally, the variant showed reduced expression of the gene reporter firefly luciferase in cell line expression analysis. CONCLUSION: Our results advocate the patient specific c.*56G>T base change in the 3' UTR to be a disease-associated mutation leading to alternative splicing explaining the mild haemophilia A phenotype. PMID- 27216883 TI - Size-dependent adhesion energy of shape-selected Pd and Pt nanoparticles. AB - Thermodynamically stable shape-selected Pt and Pd nanoparticles (NPs) were synthesized via inverse micelle encapsulation and a subsequent thermal treatment in vacuum above 1000 degrees C. The majority of the Pd NPs imaged via scanning tunneling microscopy (STM) had a truncated octahedron shape with (111) top and interfacial facets, while the Pt NPs were found to adopt a variety of shapes. For NPs of identical shape for both material systems, the NP-support adhesion energy calculated based on STM data was found to be size-dependent, with large NPs (e.g. ~6 nm) having lower adhesion energies than smaller NPs (e.g. ~1 nm). This phenomenon was rationalized based on support-induced strain that for larger NPs favors the formation of lattice dislocations at the interface rather than a lattice distortion that may propagate through the smaller NPs. In addition, identically prepared Pt NPs of the same shape were found to display a lower adhesion energy compared to Pd NPs. While in both cases, a transition from a lattice distortion to interface dislocations is expected to occur with increasing NP size, the higher elastic energy in Pt leads to a lower transition size, which in turn lowers the adhesion energy of Pt NPs compared to Pd. PMID- 27216881 TI - Dietary magnesium and copper affect survival time and neuroinflammation in chronic wasting disease. AB - Chronic wasting disease (CWD), the only known wildlife prion disease, affects deer, elk and moose. The disease is an ongoing and expanding problem in both wild and captive North American cervid populations and is difficult to control in part due to the extreme environmental persistence of prions, which can transmit disease years after initial contamination. The role of exogenous factors in CWD transmission and progression is largely unexplored. In an effort to understand the influence of environmental and dietary constituents on CWD, we collected and analyzed water and soil samples from CWD-negative and positive captive cervid facilities, as well as from wild CWD-endozootic areas. Our analysis revealed that, when compared with CWD-positive sites, CWD-negative sites had a significantly higher concentration of magnesium, and a higher magnesium/copper (Mg/Cu) ratio in the water than that from CWD-positive sites. When cevidized transgenic mice were fed a custom diet devoid of Mg and Cu and drinking water with varied Mg/Cu ratios, we found that higher Mg/Cu ratio resulted in significantly longer survival times after intracerebral CWD inoculation. We also detected reduced levels of inflammatory cytokine gene expression in mice fed a modified diet with a higher Mg/Cu ratio compared to those on a standard rodent diet. These findings indicate a role for dietary Mg and Cu in CWD pathogenesis through modulating inflammation in the brain. PMID- 27216884 TI - Liver transplantation for children with acute liver failure associated with secondary hemophagocytic lymphohistiocytosis. AB - Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening systemic disease, characterized by overwhelming stimulation of the immune system and categorized as primary or secondary types. Occasionally, acute liver failure (ALF) may dominate the clinical presentation. Given the systemic nature of HLH and risk of recurrence, HLH is considered by many a contraindication to liver transplantation (LT). The aim of this study is to review our single-center experience with LT in children with secondary HLH and ALF (HLH-ALF). This is a cross-sectional, retrospective study of children with secondary HLH-ALF that underwent LT in 2005-2014. Of 246 LTs, 9 patients (3 males; median age, 5 years; range, 0.7-15.4 years) underwent LT for secondary HLH-ALF. Disease progression was rapid with median 14 days (range, 6-27 days) between first symptoms and LT. Low fibrinogen/high triglycerides, elevated ferritin, hemophagocytosis on liver biopsy, and soluble interleukin 2 receptor levels were the most commonly fulfilled diagnostic criteria; HLH genetic studies were negative in all patients. Immunosuppressive therapy after LT included corticosteroids adjusted to HLH treatment protocol and tacrolimus. Thymoglobulin (n = 5), etoposide (n = 4), and alemtuzumab (n = 2) were used in cases of recurrence. Five (56%) patients experienced HLH recurrence, 1 requiring repeat LT, and 3 died. Overall graft and patient survival were 60% and 67%, respectively. Six patients are alive and well at a median of 24 months (range, 15-72 months) after transplantation. In conclusion, LT can be beneficial in selected patients with secondary HLH-ALF and can restore good health in an otherwise lethal condition. Liver Transplantation 22 1245-1253 2016 AASLD. PMID- 27216885 TI - UK guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults 2016 (print summary - Full guidelines available at http://dx.doi.org/10.1016/j.bjps.2016.01.034). PMID- 27216886 TI - Microvascular disease and risk of cardiovascular events among individuals with type 2 diabetes: a population-level cohort study. AB - BACKGROUND: Diabetes confers a two times excess risk of cardiovascular disease, yet predicting individual risk remains challenging. The effect of total microvascular disease burden on cardiovascular disease risk among individuals with diabetes is unknown. METHODS: A population-based cohort of patients with type 2 diabetes from the UK Clinical Practice Research Datalink was studied (n=49 027). We used multivariable Cox models to estimate hazard ratios (HRs) for the primary outcome (the time to first major cardiovascular event, which was a composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal ischaemic stroke) associated with cumulative burden of retinopathy, nephropathy, and peripheral neuropathy among individuals with no history of cardiovascular disease at baseline. FINDINGS: During a median follow-up of 5.5 years, 2822 (5.8%) individuals experienced a primary outcome. After adjustment for established risk factors, significant associations were observed for the primary outcome individually for retinopathy (HR 1.39, 95% CI 1.09-1.76), peripheral neuropathy (1.40, 1.19-1.66), and nephropathy (1.35, 1.15-1.58). For individuals with one, two, or three microvascular disease states versus none, the multivariable-adjusted HRs for the primary outcome were 1.32 (95% CI 1.16-1.50), 1.62 (1.42-1.85), and 1.99 (1.70-2.34), respectively. For the primary outcome, measures of risk discrimination showed significant improvement when microvascular disease burden was added to models. In the overall cohort, the net reclassification index for USA and UK guideline risk strata were 0.036 (95% CI 0.017-0.055, p<0.0001) and 0.038 (0.013-0.060, p<0.0001), respectively. INTERPRETATION: The cumulative burden of microvascular disease significantly affects the risk of future cardiovascular disease among individuals with type 2 diabetes. Given the prevalence of diabetes globally, further work to understand the mechanisms behind this association and strategies to mitigate this excess risk are warranted. FUNDING: Circulation Foundation. PMID- 27216887 TI - Diabetic microvascular complications as simple indicators of risk for cardiovascular outcomes and heart failure. PMID- 27216890 TI - French drug agency was not wrong to allow deadly trial, review says. PMID- 27216889 TI - Structure-based site-directed photo-crosslinking analyses of multimeric cell adhesive interactions of voltage-gated sodium channel beta subunits. AB - The beta1, beta2, and beta4 subunits of voltage-gated sodium channels reportedly function as cell adhesion molecules. The present crystallographic analysis of the beta4 extracellular domain revealed an antiparallel arrangement of the beta4 molecules in the crystal lattice. The interface between the two antiparallel beta4 molecules is asymmetric, and results in a multimeric assembly. Structure based mutagenesis and site-directed photo-crosslinking analyses of the beta4 mediated cell-cell adhesion revealed that the interface between the antiparallel beta4 molecules corresponds to that in the trans homophilic interaction for the multimeric assembly of beta4 in cell-cell adhesion. This trans interaction mode is also employed in the beta1-mediated cell-cell adhesion. Moreover, the beta1 gene mutations associated with generalized epilepsy with febrile seizures plus (GEFS+) impaired the beta1-mediated cell-cell adhesion, which should underlie the GEFS+ pathogenesis. Thus, the structural basis for the beta-subunit-mediated cell cell adhesion has been established. PMID- 27216888 TI - In vivo epidermal migration requires focal adhesion targeting of ACF7. AB - Turnover of focal adhesions allows cell retraction, which is essential for cell migration. The mammalian spectraplakin protein, ACF7 (Actin-Crosslinking Factor 7), promotes focal adhesion dynamics by targeting of microtubule plus ends towards focal adhesions. However, it remains unclear how the activity of ACF7 is regulated spatiotemporally to achieve focal adhesion-specific guidance of microtubule. To explore the potential mechanisms, we resolve the crystal structure of ACF7's NT (amino-terminal) domain, which mediates F-actin interactions. Structural analysis leads to identification of a key tyrosine residue at the calponin homology (CH) domain of ACF7, whose phosphorylation by Src/FAK (focal adhesion kinase) complex is essential for F-actin binding of ACF7. Using skin epidermis as a model system, we further demonstrate that the phosphorylation of ACF7 plays an indispensable role in focal adhesion dynamics and epidermal migration in vitro and in vivo. Together, our findings provide critical insights into the molecular mechanisms underlying coordinated cytoskeletal dynamics during cell movement. PMID- 27216891 TI - GCN5 modulates osteogenic differentiation of periodontal ligament stem cells through DKK1 acetylation in inflammatory microenvironment. AB - Periodontal ligament stem cells (PDLSCs) from periodontitis patients showed defective osteogenic differentiation. However, the mechanism of impaired osteogenic differentiation of PDLSCs in inflammatory microenvironments is still unclear. In this study, we found that inflammation in the microenvironment resulted in downregulation of histone acetyltransferase GCN5 expression and lack of GCN5 caused decreased osteogenic differentiation of PDLSCs. Previous study showed activated Wnt/beta-cateinin pathway of PDLSCs resulted in defective osteogenic differentiation. Here we found knockdown of GCN5 decreased the expression of DKK1, an inhibitor of Wnt/beta-cateinin pathway, thus activated Wnt/beta-catenin pathway of PDLSCs. Mechanistically, GCN5 regulated DKK1 expression by acetylation of Histone H3 lysine 9 (H3K9) and Histone H3 lysine 14 (H3K14) at its promoter region. Interestingly, we found that in vivo injection of aspirin rescued the periodontitis of rats through inhibiting inflammation and upregulating GCN5 expression. Furthermore, aspirin treatment of PDLSCs upregulated GCN5 expression and increased osteogenic differentiation of PDLSCs. In conclusion, GCN5 plays a protective role in periodontitis through acetylation of DKK1 and applying drugs targeting GCN5, such as aspirin, could be a new approach for periodontitis treatment. PMID- 27216892 TI - Preparedness of Finnish Emergency Medical Services for Chemical Emergencies. AB - Introduction The preparedness level of Finnish Emergency Medical Services (EMS) for treating chemical emergencies is unknown. The aim of this study was to survey the preparedness level of EMS systems for managing and handling mass-casualty chemical incidents in the prehospital phase in Finland. Hypothesis The study hypothesis was that university hospital districts would have better clinical capability to treat patients than would central hospital districts in terms of the number of patients treated in the field within one hour after dispatching as well as patients transported to hospital within one hour or two hours after dispatching. METHODS: This cross-sectional study was conducted as a Webropol (Wuppertal, Germany) survey. All hospital districts (n=20) in continental Finland were asked about their EMS preparedness level in terms of capability of treating and transporting chemically affected patients in the field. Their capability for decontamination of affected patients in the field was also inquired. RESULTS: University hospital district-based EMS systems had at least 20% better absolute clinical capacity than central hospital-based EMS systems for treating chemically affected patients concerning all treatments inquired about, except the capacity for non-invasive ventilation (NIV)/continuous positive airway pressure (CPAP) treatment in the field. Overall, there was a good level of preparedness for treating chemical accident patients with supplemental oxygen, bronchodilators, and inhaled corticosteroids. Preparedness for providing antidote therapy in cases of cyanide gas exposure was, in general, low. The variation among the hospital districts was remarkable. Only nine of 15 central hospital district EMS had a mobile decontamination unit available, whereas four of five university hospital districts had one. CONCLUSION: Emergency Medical Services capacity in Finland for treating chemically affected patients in the field needs to be improved, especially in terms of antidote therapy. Mobile decontamination units should be available in all hospital districts. Jama TJ , Kuisma MJ . Preparedness of Finnish Emergency Medical Services for chemical emergencies. Prehosp Disaster Med. 2016;31(4):392-396. PMID- 27216893 TI - Draft genome sequence of Bradyrhizobium sp. strain BR 3262, an effective microsymbiont recommended for cowpea inoculation in Brazil. AB - The strain BR 3262 was isolated from nodule of cowpea (Vigna unguiculata L. Walp) growing in soil of the Atlantic Forest area in Brazil and it is reported as an efficient nitrogen fixing bacterium associated to cowpea. Firstly, this strain was assigned as Bradyrhizobium elkanii, however, recently a more detailed genetic and molecular characterization has indicated it could be a Bradyrhizobium pachyrhizi species. We report here the draft genome sequence of B. pachyrhizi strain BR 3262, an elite bacterium used as inoculant for cowpea. The whole genome with 116 scaffolds, 8,965,178bp and 63.8% of C+G content for BR 3262 was obtained using Illumina MiSeq sequencing technology. Annotation was added by the RAST prokaryotic genome annotation service and shown 8369 coding sequences, 52 RNAs genes, classified in 504 subsystems. PMID- 27216894 TI - Estradiol-induced neurogenesis in the female accessory olfactory bulb is required for the learning of the male odor. AB - Odors processed by the main and accessory olfactory bulbs (MOB, AOB) are important for sexual behavior. Interestingly, both structures continue to receive new neurons during adulthood. A role for olfactory neurogenesis in sexual behavior in female mice has recently been shown and gonadal hormones such as estradiol can modulate adult neurogenesis. Therefore, we wanted to determine the role of estradiol in learning the odors of sexual partners and in the adult neurogenesis of female aromatase knockout mice (ArKO), unable to produce estradiol. Female wild-type (WT) and ArKO mice were exposed to male odors during 7 days, and olfactory preferences, cell proliferation, cell survival and functional involvement of newborn neurons were analyzed, using BrdU injections, in combination with a marker of cell activation (Zif268) and neuronal fate (doublecortin, NeuN). Behavioral tasks indicated that both WT and ArKO females were able to discriminate between the odors of two different males, but ArKO mice failed to learn the familiar male odor. Proliferation of newborn cells was reduced in ArKO mice only in the dentate gyrus of the hippocampus. Olfactory exposure decreased cell survival in the AOB in WT females, suggesting a role for estradiol in a structure involved in sexual behavior. Finally, newborn neurons do not seem to be functionally involved in the AOB of ArKO mice compared with WT, when females were exposed to the odor of a familiar male, suggesting that estradiol-induced neurogenesis in the AOB is required for the learning of the male odor in female mice. Aromatase knockout mice (ArKO) presented deficits in olfactory preferences without affecting their olfactory discrimination abilities, and showed no functional involvement of newborn neurons in the accessory olfactory bulb (AOB) in response to the odor of a familiar male. These results suggest that estradiol-induced neurogenesis in the female AOB is required for the learning of the male odor. PMID- 27216896 TI - Reliable quantification of rhinovirus species C using real-time PCR. AB - BACKGROUND: Rhinovirus C (RV-C) is an important respiratory pathogen of children, but little is known about its contribution to disease severity, though viral load appears to be important. Difficulty in RV-C cultivation and target sequence variation has precluded the development of a PCR based quantification method. OBJECTIVE: The aim of this study was to develop and validate reverse transcription quantitative PCR (RT-qPCR) assays for a broad range of circulating RV-C genotypes in nasopharyngeal aspirates (NPAs). STUDY DESIGN: Four assays were designed to quantify a 296bp region located within the 5' untranslated region (UTR) of RV-C types. These assays were based on in silico analysis of available RV-C sequences. Probes were designed to provide 100% homology to the corresponding RV-C genotypes. RESULTS: The linear dynamic range of each of the four assays spanned eight orders of magnitude (10(4)-10(11) copies/mL). The limit of detection for assays 1-4 was estimated to be 1147 copies/mL, 765 copies/mL, 1138 copies/mL and 1470 copies/mL respectively. Each assay demonstrated a strong linear relationship (r(2)=>0.995) and amplification efficiency greater than 95%. Repeatability and reproducibility of the method were shown to be high, with coefficients of variations lower than 8% and 15% respectively. PMID- 27216895 TI - Immunogenetic Pathogenesis of Celiac Disease and Non-celiac Gluten Sensitivity. AB - Celiac disease is the most common oral intolerance in Western countries. It results from an immune response towards gluten proteins from certain cereals in genetically predisposed individuals (HLA-DQ2 and/or HLA-DQ8). Its pathogenesis involves the adaptive (HLA molecules, transglutaminase 2, dendritic cells, and CD4(+) T-cells) and the innate immunity with an IL-15-mediated response elicited in the intraepithelial compartment. At present, the only treatment is a permanent strict gluten-free diet (GFD). Multidisciplinary studies have provided a deeper insight of the genetic and immunological factors and their interaction with the microbiota in the pathogenesis of the disease. Similarly, a better understanding of the composition of the toxic gluten peptides has improved the ways to detect them in food and drinks and how to monitor GFD compliance via non-invasive approaches. This review, therefore, addresses the major findings obtained in the last few years including the re-discovery of non-celiac gluten sensitivity. PMID- 27216897 TI - Does Biology Transcend the Symptom-based Boundaries of Psychosis? AB - Psychotic disorders, as defined by clinical features alone, overlap considerably in terms of symptoms, familial patterns, risk genes, outcome, and treatment response. As a result, numerous neurobiological measurements fail to distinguish patients with the most prevalent classic psychotic syndromes. Statistical methods applied to such biological measurements in large numbers of patients with psychosis yield novel categories that cut across traditional diagnostic boundaries. Such new classification approaches within psychosis hopefully represent an opportunity to transcend clinical phenomenologically defined syndromes in psychiatry with neurobiologically defined diseases that can advance drug discovery and support precision medicine approaches in psychiatry. PMID- 27216898 TI - Are We Really Impacting Duration of Untreated Psychosis and Does It Matter?: Longitudinal Perspectives on Early Intervention from the Irish Public Health Services. AB - Although early intervention in psychosis is clinically intuitive and theoretically feasible, the reality is that over recent decades the evidence base to support it has not advanced as much as might have been anticipated. Material benefits of early intervention in established psychosis have not been universally demonstrated and much uncertainty continues to surround the field of treatment in the prodromal phase. Undoubtedly methodological differences between studies are relevant and better understanding of different treatment models and the effectiveness of their constituent parts may yield the most benefit, particularly from a public health perspective. PMID- 27216899 TI - The Case for Adjunctive Monoclonal Antibody Immunotherapy in Schizophrenia. AB - This article presents the case in favor of clinical trials of adjunctive monoclonal antibody immunotherapy in schizophrenia. Evidence for prenatal and premorbid immune risk factors for the development of schizophrenia in the offspring is highlighted. Then key evidence for immune dysfunction in patients with schizophrenia is considered. Next, previous trials of adjunctive anti inflammatory or other immunotherapy in schizophrenia are discussed. Then evidence for psychosis as a side effect of immunotherapy for other disorders is discussed. Also presented is preliminary evidence for adjunctive monoclonal antibody immunotherapy in psychiatric disorders. Finally, important considerations in the design and implementation of clinical trials of adjunctive monoclonal antibody immunotherapy in schizophrenia are discussed. PMID- 27216900 TI - Redefining Medication Adherence in the Treatment of Schizophrenia: How Current Approaches to Adherence Lead to Misinformation and Threaten Therapeutic Relationships. AB - Medication adherence is as much of a problem today as it was 50 years ago. A major barrier to progress is that the definition emphasizes obedience to medication recommendations rather than shared outcome goals. As a result, schizophrenia patients are keenly aware of the social risks of disclosing nonadherence. Nondisclosure leads to misinformation, which in turn leads to serious errors in medication decisions. Another consequence is that adherence struggles may harm the therapeutic relationship. When nonadherence is inevitable, the strategy should shift to the use of harm reduction strategies that aim to preserve the therapeutic relationship while mitigating risks. PMID- 27216901 TI - Update on New and Emerging Treatments for Schizophrenia. AB - Although there has been more than 50 years of development, there remains a great need for better antipsychotic medications. This article looks at the recent advances in treatment of schizophrenia. New hypotheses have been suggested that may replace or complement the dopamine hypotheses. The article explores the different novel drugs that impact some of the key neurotransmitter systems currently. Phosphodiesterase 10A inhibitors and alpha-7 neuronal nicotinic acetylcholine receptor modulators constitute the majority. The marketing of these medications eventually may result in change about how schizophrenia is treated. PMID- 27216902 TI - Treatment-Resistant Schizophrenia. AB - Although treatment-resistant schizophrenia (TRS) was described 50 years ago and has a gold standard treatment with clozapine based on well-defined criteria, there is still a matter of great interest and controversy. In terms of the underlying mechanisms of the development of TRS, progress has been made for the elucidation of the neurochemical mechanisms. Structural neuroimaging studies have shown that patients with TRS have significant reduction of the prefrontal cortex volume when compared with non- TRS. This article updates and enhances our previous review with new evidence mainly derived from new studies, clinical trials, systematic reviews, and meta-analyses. PMID- 27216903 TI - Transcending Psychosis: The Complexity of Comorbidity in Schizophrenia. AB - Schizophrenic illness encompasses diverse clinical phenomena and consists of unclear underlying pathogeneses. For the past century, the comorbidities in schizophrenia have drawn persistent interest and debate due to its high prevalence rate and a need for better management. However, its clinical and biological diversity continue to challenge both the practicing clinicians and researchers. Emerging clinical and research evidence in the past decade suggest a distinct biopsychosocial pathogenesis and unique clinical attributes in some comorbid disorders in patients with schizophrenia. In addition, current evidence also supports improved outcomes with specific assessment and treatment of these subgroup of schizophrenia. The recent changes in DSV-5 and shift in the NIMH focus towards the real world clinical practice and research provide increased impetus to explore the pathogeneses and treatment of schizophrenia with comorbid disorders. PMID- 27216904 TI - Detecting and Managing Adverse Effects of Antipsychotic Medications: Current State of Play. AB - Antipsychotics are some of the most frequently prescribed medications not only for psychotic disorders and symptoms but also for a wide range of on-label and off-label indications. Because second-generation antipsychotics have largely replaced first-generation antipsychotics as first-line options due to their substantially decreased risk of extrapyramidal side effects, attention has shifted to other clinically concerning adverse events associated with antipsychotic therapy. The focus of this article is to update the nonextrapyramidal side effects associated with second-generation antipsychotics. Issues surrounding diagnosis and monitoring as well as clinical management are addressed. PMID- 27216905 TI - Recovery in Schizophrenia: What Consumers Know and Do Not Know. AB - The recovery model has permeated mental health systems by leading to the development of new psychiatric interventions and services and the reconfiguration of traditional ones. There is growing evidence that these interventions and services confer benefits in clinical and recovery-oriented outcomes. Despite the seeming adoption of recovery by policy makers, the transformation of mental health systems into recovery-oriented systems has been fraught with challenges. PMID- 27216906 TI - What Does Mental Health Parity Really Mean for the Care of People with Serious Mental Illness? AB - Parity of mental health and substance abuse insurance benefits with medical care benefits, as well as parity in their management, are major ongoing concerns for adults with serious mental illness (SMI). The Mental Health Parity and Addiction Equity Act of 2008 guaranteed this parity of benefits and management in large private insurance plans and privately managed state Medicaid plans, but only if the benefits were offered at all. The Patient Protection and Affordable Care Act of 2010 extended parity to all persons receiving insurance through the state health insurance marketplaces, through the state Medicaid Expansions, and through new individual and small group plans. This article presents an analysis of how accessible parity has become for adults with SMI at both the system and personal levels several years after these legislative changes have been implemented. PMID- 27216907 TI - What's Hot in Schizophrenia Research? AB - Schizophrenia is a heterogeneous psychiatric illness for which the cause or causes are presently unknown. There is increasing evidence from multiple levels of research suggesting that inflammation may play an important role in the development and persistence of psychosis and cognitive impairment in a proportion of people with schizophrenia. This overview of recent literature focuses on studies of neuroinflammation that are considered to be of increasing interest in schizophrenia research and are poised to have an impact on the cause, diagnosis, and potential treatment of at least some forms or subtypes of schizophrenia. PMID- 27216908 TI - Converging Perspectives on Schizophrenia. PMID- 27216909 TI - A Review of the Ultrasound Assessment of Diaphragmatic Function in Clinical Practice. AB - Ultrasonography is the only non-invasive, non-ionizing imaging technique widely available to directly assess diaphragmatic function. Two different sonographic approaches permit the assessment of muscle thickening in the zone of apposition and excursion of the dome of the diaphragm. Thanks to the new hand-held ultrasound instruments, the morphology and function of the diaphragm can be assessed in different settings, such as outpatient clinic, pulmonary function test laboratory, hospital department and intensive care unit, and under different conditions. Despite the existence of different acoustic views and several codified approaches, a comprehensive sonographic examination has never been standardized for clinical use. In this review, we summarize the clinical indications, methods and perspectives of the technique in adults. PMID- 27216910 TI - Combinatorial evolution of phosphotriesterase toward a robust malathion degrader by hierarchical iteration mutagenesis. AB - Malathion is one of the most widely used organophosphorus pesticides in the United States and developing countries. Herein, we enhanced the degradation rate of malathion starting with a phosphotriesterase PoOPHM2 while also considering thermostability. In the first step, iterative saturation mutagenesis at residues lining the binding pocket (CASTing) was employed to optimize the enzyme active site for substrate binding and activity. Hot spots for enhancing activity were then discovered through epPCR-based random mutagenesis, and these beneficial mutations were then recombined by DNA shuffling. Finally, guided by in silico energy calculations (FoldX), thermostability of the variant was improved. The mutations extend from the core region to the enzyme surface during the evolutionary pathway. After screening <9,000 mutants, the best variant PoOPHM9 showed 25-fold higher activity than wild-type PoOPHM2 , with a thermostability (T50 (15) ) of 67.6 degrees C. Thus, PoOPHM9 appears to be an efficient and robust candidate for malathion detoxification. Biotechnol. Bioeng. 2016;113: 2350 2357. (c) 2016 Wiley Periodicals, Inc. PMID- 27216911 TI - Critical roles of adenosine A2A receptor in regulating the balance of Treg/Th17 cells in allergic asthma. AB - INTRODUCTION: Deficiency of Treg cells and hyperactivity of Th17 cells together are involved in the immunological pathogenesis of asthma. The adenosine A2A receptor (A2AR) plays a critical role in the increased Foxp3 expression of Treg cells and the decreased Th17 generation. OBJECTIVE: The study aimed to investigate A2AR expression in peripheral blood and its regulatory effect on balance of Treg/Th17 cells in asthma. METHODS: Thirty-one patients with chronic persistent asthma were recruited and divided into 18 intermittent to mild asthma patients, 13 moderate to severe asthma patients. A2AR, Foxp3, and ROR-gammat mRNA expression levels in peripheral blood mononuclear cells (PBMCs) were measured by quantitative polymerase chain reaction (qPCR). TGF-beta, IL-17, and IgE in plasma were detected with enzyme-linked immunosorbent assay (ELISA). Forty-two BALB/c mice were randomly, equally assigned to control group, ovalbumin (OVA) group and OVA + CGS (CGS21680, A2AR agonist) group. The infiltration of lung inflammation cells were evaluated by HE, A2AR, Foxp3, and ROR-gammat mRNA in lung tissues measured by qPCR, TGF-beta, IL-17, and IgE in plasma measured with ELISA, and IL 17 and TGF-beta protein in lung tissues analyzed with immunohistochemical. RESULTS: Our results showed that expression A2AR mRNA in PBMCs was associated with asthma severity. Foxp3 mRNA, TGF-beta, and FEV1%pred positively correlated with A2AR mRNA in asthma. ROR-gammat mRNA and IL-17 negatively correlated with A2AR mRNA in asthma. CGS could promote Foxp3 mRNA expression, TGF-beta, and improve lung function while inhibit ROR-gammat mRNA expression, IL-17, and the infiltration of lung inflammation cells. CONCLUSION: A2AR could regulate the balance of Treg/Th17 cells in asthma. PMID- 27216913 TI - Seq and You Will Find. AB - The human genome sequence is freely available, nearly complete and is providing a foundation of research opportunities that are overturning our current understanding of human biology. The advent of next generation sequencing has revolutionized the way we can interrogate the genome and its transcriptional products and how we analyze, diagnose, monitor and even treat human disease. Personal genetic profiles are increasing dramatically in medical value as researchers accumulate more and more knowledge about the interaction between genetic and environmental factors that contribute to the onset of common disorders. As the cost of sequencing plummets, whole genome sequencing of individuals is becoming a reality and the field of personalized genomic medicine is rapidly developing. Now there is great need for accurate annotation of all functionally important sequences in the human genome and the variations within them that contribute to health and disease. The vast majority of our genome gives rise to RNA transcripts. This extraordinarily versatile molecule not only encodes protein information but also has great structural dynamics and plasticity, capacity for DNA/RNA/protein interactions and catalytic activity. It is a key regulator of biological networks with clear links to human disease and a more comprehensive understanding of its function is needed to maximise its use in medical practice. This review focuses on the complexity of our genome and the impact of sequencing technologies in understanding its many products and functions in health and disease. PMID- 27216912 TI - Whole exome sequencing links dental tumor to an autosomal-dominant mutation in ANO5 gene associated with gnathodiaphyseal dysplasia and muscle dystrophies. AB - Tumors of the jaws may represent different human disorders and frequently associate with pathologic bone fractures. In this report, we analyzed two affected siblings from a family of Russian origin, with a history of dental tumors of the jaws, in correspondence to original clinical diagnosis of cementoma consistent with gigantiform cementoma (GC, OMIM: 137575). Whole exome sequencing revealed the heterozygous missense mutation c.1067G > A (p.Cys356Tyr) in ANO5 gene in these patients. To date, autosomal-dominant mutations have been described in the ANO5 gene for gnathodiaphyseal dysplasia (GDD, OMIM: 166260), and multiple recessive mutations have been described in the gene for muscle dystrophies (OMIM: 613319, 611307); the same amino acid (Cys) at the position 356 is mutated in GDD. These genetic data and similar clinical phenotypes demonstrate that the GC and GDD likely represent the same type of bone pathology. Our data illustrate the significance of mutations in single amino-acid position for particular bone tissue pathology. Modifying role of genetic variations in another gene on the severity of the monogenic trait pathology is also suggested. Finally, we propose the model explaining the tissue-specific manifestation of clinically distant bone and muscle diseases linked to mutations in one gene. PMID- 27216914 TI - Tet-On Systems For Doxycycline-inducible Gene Expression. AB - The tetracycline-controlled Tet-Off and Tet-On gene expression systems are used to regulate the activity of genes in eukaryotic cells in diverse settings, varying from basic biological research to biotechnology and gene therapy applications. These systems are based on regulatory elements that control the activity of the tetracycline-resistance operon in bacteria. The Tet-Off system allows silencing of gene expression by administration of tetracycline (Tc) or tetracycline-derivatives like doxycycline (dox), whereas the Tet-On system allows activation of gene expression by dox. Since the initial design and construction of the original Tet-system, these bacterium-derived systems have been significantly improved for their function in eukaryotic cells. We here review how a dox-controlled HIV-1 variant was designed and used to greatly improve the activity and dox-sensitivity of the rtTA transcriptional activator component of the Tet-On system. These optimized rtTA variants require less dox for activation, which will reduce side effects and allow gene control in tissues where a relatively low dox level can be reached, such as the brain. PMID- 27216916 TI - Structural language, pragmatic communication, behavior, and social competence in children adopted internationally: A pilot study. AB - The objectives of this study were to examine the association of structural language and pragmatic communication with behavior problems and social competence in girls adopted internationally. Participants included girls between 6-12 years of age who were internationally adopted from China (n = 32) and Eastern-Europe (n = 25) and a control group of never-adopted girls (n = 25). Children completed the Wechsler Abbreviated Scale of Intelligence. Parents completed the Child Communication Checklist- second edition, the Child Behavior Checklist, and the Home and Community Social Behavior Scales. Compared to the controls, parents in the Eastern European group reported more problems with social competence, externalizing behaviors, structural language, and pragmatic communication. The Chinese group evidenced more internalizing problems. Using generalized linear regression, interaction terms were examined to determine if the associations of pragmatic communication and structural language with behavior problems and social competence varied across groups. Controlling for general intellectual functioning, poorer pragmatic communication was associated with more externalizing problems and poorer social competence. In the Chinese group, poorer pragmatic communication was associated with more internalizing problems. Post adoption weaknesses in pragmatic communication are associated with behavior problems and social competence. Internationally adopted children may benefit from interventions that target pragmatic communication. PMID- 27216915 TI - Albumin nanostructures as advanced drug delivery systems. AB - INTRODUCTION: One of the biggest impacts that the nanotechnology has made on medicine and biology, has been in the area of drug delivery systems (DDSs). Many drugs suffer from serious problems concerning insolubility, instability in biological environments, poor uptake into cells and tissues, sub-optimal selectivity for targets and unwanted side effects. Nanocarriers can be designed as DDSs to overcome many of these drawbacks. One of the most versatile building blocks to prepare these nanocarriers is the ubiquitous, readily available and inexpensive protein, serum albumin. Areas covered: This review covers the use of different types of albumin (human, bovine, rat, and chicken egg) to prepare nanoparticle and microparticle-based structures to bind drugs. Various methods have been used to modify the albumin structure. A range of targeting ligands can be attached to the albumin that can be recognized by specific cell receptors that are expressed on target cells or tissues. Expert opinion: The particular advantages of albumin used in DDSs include ready availability, ease of chemical modification, good biocompatibility, and low immunogenicity. The regulatory approvals that have been received for several albumin-based therapeutic agents suggest that this approach will continue to be successfully explored. PMID- 27216917 TI - Role of neuroinflammation and sex hormones in war-related PTSD. AB - The susceptibility to develop posttraumatic stress disorder (PTSD) is greatly influenced by both innate and environmental risk factors. One of these factors is gender, with women showing higher incidence of trauma-related mental health disorders than their male counterparts. The evidence so far links these differences in susceptibility or resilience to trauma to the neuroprotective actions of sex hormones in reducing neuroinflammation after severe stress exposure. In this review, we discuss the impact of war-related trauma on the incidence of PTSD in civilian and military populations as well as differences associated to gender in the incidence and recovery from PTSD. In addition, the mutually influencing role of inflammation, genetic, and sex hormones in modulating the consequences derived from exposure to traumatic events are discussed in light of current evidence. PMID- 27216918 TI - In vivo response to polypropylene following implantation in animal models: a review of biocompatibility. AB - INTRODUCTION AND HYPOTHESIS: Polypropylene is a material that is commonly used to treat pelvic floor conditions such as pelvic organ prolapse (POP) and stress urinary incontinence (SUI). Owing to the nature of complications experienced by some patients implanted with either incontinence or prolapse meshes, the biocompatibility of polypropylene has recently been questioned. This literature review considers the in vivo response to polypropylene following implantation in animal models. The specific areas explored in this review are material selection, impact of anatomical location, and the structure, weight and size of polypropylene mesh types. METHODS: All relevant abstracts from original articles investigating the host response of mesh in vivo were reviewed. Papers were obtained and categorised into various mesh material types: polypropylene, polypropylene composites, and other synthetic and biologically derived mesh. RESULTS: Polypropylene mesh fared well in comparison with other material types in terms of host response. It was found that a lightweight, large-pore mesh is the most appropriate structure. CONCLUSION: The evidence reviewed shows that polypropylene evokes a less inflammatory or similar host response when compared with other materials used in mesh devices. PMID- 27216919 TI - Myocardial fragmentation associated with disruption of the Z-band in hypertrophic cardiomyopathy in Noonan syndrome. AB - A 13-year-old female with Noonan syndrome had been diagnosed with hypertrophic cardiomyopathy, and she died of heart failure at the age of 25 years. Light microscopic and electron microscopic examination of her biopsied myocardium and autopsy heart showed myocardial fragmentation associated with Z-band disruption as well as myocardial hypertrophy and disarray with interstitial fibrosis. Myocardial fragmentation associated with Z-band disruption may be related to the progression of cardiac dysfunction. PMID- 27216920 TI - Corrigendum: An integrative approach to investigate the respective roles of single-nucleotide variants and copy-number variants in Attention Deficit/Hyperactivity Disorder. PMID- 27216921 TI - Association between in vitro fertilization outcomes and inherited thrombophilias: a meta-analysis. AB - PURPOSE: The aim of this study was to determine whether in vitro fertilization (IVF) outcomes are associated with inherited thrombophilias. METHODS: Several databases including PubMed, Embase, and Cochrane Library were retrieved up to 12 January 2016. The quality of the included studies was assessed by two authors. The associations of the following mutations in inherited thrombophilias and IVF outcomes were explored: factor V Leiden (FVL), prothrombin gene G20210A mutation (PGM), 5,10-methylentetrahydrofolate reductase (MTHFR) C677T, MTHFR (A1298C) and activated protein C resistance (APCR). The main outcome measures included CPR and implantation rate (IR). The relative risk (RR) and its 95 % confidence interval (CI) were calculated for effect index. Heterogeneity test was evaluated by Chi square based on Q statistic and I (2) statistics. RESULTS: A total of seven articles published between 2007 and 2015 with the ages of subjects between 30.9 and 36.2 were included. For subgroups analysis of CPR or IR, there were no significant differences in MTHFR (C377T), MTHFR (A1298C), FVL, PGM, and FVL/PGM mutation were found between the mutation group and control group (P > 0. 05). CONCLUSIONS: IVF outcomes are not associated with FVL, PGM, MTHFR (C677T), MTHFR (A1298C), and APCR mutation in inherited thrombophilias. PMID- 27216922 TI - Impact of Neurosurgery Medical Student Research Grants on Neurosurgery Residency Choice. AB - BACKGROUND: Recent decades have seen a rapid expansion of involvement of medical students in biomedical research during medical school training. Research within medical school has been shown to influence medical students with regard to medical knowledge, career development, and residency specialty choice. The objective of this study was to evaluate the impact of neurosurgery medical student research grants on neurosurgery residency choice and provide an insight on the demographics of grant awardees. METHODS: In this retrospective study, a search of award recipients was performed using data available on the American Association of Neurological Surgeons, Congress of Neurological Surgeons, and Neurosurgery Research and Education Foundation websites. Searched years included the first cycle of American Association of Neurological Surgeons/Neurosurgery Research and Education Foundation (2007) and Council of State Neurosurgical Societies/Congress of Neurological Surgeons (2008-2009) grant awards until the 2015-2016 cycle, which is the latest award cycle to date. RESULTS: The initial search yielded 163 research grants that were awarded to 158 students between the years of 2007 and 2016. Among the 163 grant recipients, 126 (77.3%) were men. Among the 88 recipients who entered postgraduate residency programs, 51% (45 of 88) matched into neurosurgery residency. When considering both neurosurgery and neurology residency programs, the percentage increased to 59.1% (52 of 88). CONCLUSIONS: Neurosurgery grants for medical students are highly successful in producing future neurosurgeons with >50% of grant recipients matched into neurosurgery. Women are underrepresented in neurosurgery grants and neurosurgery residency programs. This situation can be improved by providing insight about the field early in medical school, perhaps through increased use of neurosurgery medical student grants. PMID- 27216923 TI - Three-Dimensional Versus Two-Dimensional Neuroendoscopy: A Preclinical Laboratory Study. AB - BACKGROUND: Use of traditional two-dimensional (2-D) neuroendoscopy is limited by lack of depth perception. The advent of next-generation three-dimensional (3-D) endoscopes potentially compensates for this limitation. The aim of this study was to objectively compare the 2 modalities in a controlled laboratory environment. METHODS: Using 2-D and 3-D endoscopes, 8 participants performed simple and complex motor tasks. Participants were divided into 3 groups: novice (n = 3), beginner (n = 4), and expert (n = 1), based on prior neuroendoscopy training. Efficiency of completing simple motor tasks in an allocated time and time to complete complex motor tasks were recorded for both visualization methods with demerits for inaccuracy. RESULTS: Inaccuracy was reduced with increasing experience in the use of the 3-D endoscope for simple motor tasks such as spiral drawing (P = 0.04), but there was no statistical difference in completion time for complex motor tasks pertaining to depth perception among the groups (P > 0.05) or within groups for simple or complex tasks. To assess the impact on the learning curve, we analyzed the performance improvement in use of the other endoscope based on which endoscope each participant used first. There was marked improvement in accuracy and efficiency of 2-D scope use in the "3-D first" group for performing simple motor tasks such as dotted-line drawing (P = 0.002), but no benefit was observed for complex motor tasks. CONCLUSIONS: Our data do not support the superiority of the 3-D endoscope over its conventional 2-D congener, although its use may shorten the learning curve associated with neuroendoscopy, regardless of subjects' prior experience with neuroendoscopy. PMID- 27216924 TI - Efficacy of Transsacral Instrumentation for High-Grade Spondylolisthesis at L5 S1: A Systematic Review of the Literature. AB - BACKGROUND: High-grade L5-S1 spondylolisthesis is challenging to treat, and there is no standard recommended operative technique. The authors performed a systematic review of the literature evaluating the efficacy and safety of modern transsacral instrumentation techniques for high-grade L5-S1 spondylolisthesis. METHODS: A systematic PubMed search adherent to PRISMA guidelines included relevant clinical studies reporting transsacral instrumentation for high-grade L5 S1 spondylolisthesis in adult humans from 1980 onward. Available data regarding clinical and radiographic outcomes for individual patients were abstracted. RESULTS: Nine of 311 studies were eligible for detailed review. They reported on 38 patients (mean 33.1 years; range 18-66 years) treated with transsacral instrumentation. Transsacral cages (6 articles, n = 23), screws (2 articles, n = 12) and rods (1 article, n = 3) were used. Posterior (86.8%) and combined anteroposterior approaches were used, both with (55.2%) and without decompression, partial reduction (23.7%), posterior pedicle screw fixation (94.7%), and adjacent level inter-body fusion (42.1%). Four patients had 6 perioperative complications (15.8%). Mean follow-up time was 30.1 months (range 2 58 months; n = 37). All patients had adequate fusion on follow-up imaging (n = 34) and no progression of slip (n = 32). All patients had improvement in pain (n = 32) and at least average function postoperatively (94.7%; n = 33/35). CONCLUSION: Operative techniques for managing high-grade L5-S1 spondylolisthesis are evolving. In our systematic review, modern transsacral instrumentation resulted in good clinical outcome and fusion rates, and acceptable complication rates. Risks and benefits should be individualized for each patient. Transsacral instrumentation is a viable and effective treatment option for this pathology. PMID- 27216925 TI - Economic Analysis of Deep Brain Stimulation in Parkinson Disease: Systematic Review of the Literature. AB - BACKGROUND: Parkinson disease (PD) is a chronic multifaceted neurodegenerative disorder of adult onset that affects quality of life and places a burden on patients, caregivers, and society. In early disease, dopaminergic therapy improves motor symptoms, but as the disease progresses, symptoms tend to increase in frequency and severity, even with best medical treatment (BMT). Deep brain stimulation (DBS) becomes an option for certain patients, but cost becomes an important issue. OBJECTIVE: We performed a systematic review of the literature of economic studies of the use of DBS in patients with PD, including costs studies or economic evaluations expressed as cost per improvement in quality life, decrease in dose of pharmacological treatments, and the decrease of caregiver burden. METHODS: We reviewed the following databases: Medline/PubMed, Embase, Cochrane Database of Systematic Reviews, LILACS, Cochrane Central Register of Controlled Trials, WHO International Clinical Trials Registry Platform ICTRP portal and ClinicalTrials.gov from 1980 to 2015. Costs have been converted or adjusted to 2016 US dollars (US$). RESULTS: Nine studies were identified. The average cost of DBS for a patient with PD in 5 years is US$186,244. The quality adjusted life year was higher in DBS compared with BMT after at least 2 years of treatment, with an average incremental cost utility ratio of US$41,932 per additional quality-adjusted life year gained. Costs in the first year are higher with DBS because of direct costs related to the surgical procedure, the device, and the more frequent controls. Studies show better results with a longer time horizon (up to 5 years). CONCLUSION: DBS is a cost-effective intervention for patients with advanced PD, but it has a high initial cost compared with BMT. However, DBS reduces pharmacologic treatment costs and should also reduce direct, indirect, and social costs of PD on the long term. PMID- 27216926 TI - Whatever? The effect of social exclusion on adopting persuasive messages. AB - The aversive state of social exclusion can result in a broad range of cognitive deficits. Being unable or unmotivated to process relevant information, we assumed that social exclusion would also affect the success of persuasive attempts. We hypothesized that socially excluded people would adopt attitudes regardless of persuasion quality. In three studies using different manipulations of social exclusion and persuasion, we showed that participants who were socially excluded adopted persuasive messages regardless of argument quality. In contrast, this undifferentiated response was not shown by socially included participants who were more persuaded by high- compared to low-quality arguments. In Study 3, we moreover revealed that this pattern could only be replicated in reliable situations-that is, when the communicator appeared credible. These findings support the assumption that social exclusion can lead to reduced processing of information. PMID- 27216927 TI - Zucchini shoestring virus: a distinct potyvirus in the papaya ringspot virus cluster. AB - Zucchini shoestring virus (ZSSV) has been proposed to be a putative potyvirus in the papaya ringspot virus (PRSV) cluster, based on the sequence similarity of its coat protein to those of related potyviruses. ZSSV has been associated with the outbreak of a damaging disease of baby marrow (Cucurbita pepo L.) that had been observed throughout the province of KwaZulu-Natal, in the Republic of South Africa (RSA). We report the genome sequence of ZSSV, determined by next generation sequencing of total RNA extracted from an infected baby marrow (Cucurbita pepo L.). The ZSSV genome is 10,295 nucleotides long excluding the poly(A) tail and displays a typical potyvirus organization. Algerian watermelon mosaic virus (AWMV; EU410442.1) was identified as the closest relative of ZSSV, sharing the highest nucleotide sequence identity of 65.68%. The nucleotide and amino acid sequence identity values for each protein support the differentiation of ZSSV as a member of a distinct species in the genus Potyvirus. This taxonomic position was also confirmed using the Pairwise Sequence Comparison online tool from the National Center for Biotechnology Information. Phylogenetic analysis of the polyprotein coding sequence of ZSSV grouped ZSSV together with AWMV and Moroccan watermelon mosaic virus, but in different clusters. ZSSV is the second cucurbit-infecting virus in the PRSV cluster present in RSA. PMID- 27216928 TI - Complete genome sequence of Piry vesiculovirus. AB - Piry virus (PIRYV) is a rhabdovirus (genus Vesiculovirus) and is described as a possible human pathogen, originally isolated from a Philander opossum trapped in Para State, Northern Brazil. This study describes the complete full coding sequence and the genetic characterization of PIRYV. The genome sequence reveals that PIRYV has a typical vesiculovirus-like organization, encoding the five genes typical of the genus. Phylogenetic analysis confirmed that PIRYV is most closely related to Perinet virus and clustered in the same clade as Chandipura and Isfahan vesiculoviruses. PMID- 27216930 TI - Corynebacterium guangdongense sp. nov., isolated from a contaminated plate. AB - A novel Gram-reaction-positive, non-motile and facultatively anaerobic bacterium, designated strain S01T, was isolated from a nutrient agar plate kept on a laboratory clean bench at Guangdong Institute of Microbiology, PR China, which was contaminated from an unknown source. Strain S01T was found to be catalase positive and oxidase-negative. Similarity searches revealed that the strain shared the highest 16S rRNA gene similarity with Corynebacterium humireducens MFC 5T (95.9 %). However, phylogenetic analysis based on the 16S rRNA gene sequences showed that strain S01T was closely related to Corynebacteriumdoosanense JCM 17317T (94.8 %) and Corynebacterium maris JCM 17018T (94.8 %). The major fatty acids were C18:1omega9c, C16:0, 10-methyl C18:0 and C18:0. The respiratory quinones predominantly consisted of MK-8(H2), with small amounts of MK-8 and MK 9(H2). Polar lipids contained phosphatidylglycerol, diphosphatidylglycerol, phosphatidylinositol, an unidentified aminolipid, two unidentified glycolipids and two unidentified lipids. Mycolic acids were present. The cell-wall peptidoglycan contained meso-diaminopimelic acid and the major cell-wall sugars were galactose, arabinose and glucose. The genomic DNA G+C content of strain S01T was 70.7+/-0.1 mol%. The results of phenotypic, phylogenetic and chemotaxonomic analyses indicated that strain S01T represents a novel species of the genus Corynebacterium, for which the name Corynebacterium guangdongense sp. nov. is proposed. The type strain is S01T (=GDMCC 1.1022T=CCTCC AB 2015423T=KCTC 39608T). PMID- 27216931 TI - Effects of Early Bedside Cycle Exercise on Intracranial Pressure and Systemic Hemodynamics in Critically Ill Patients in a Neurointensive Care Unit. AB - BACKGROUND: Physiotherapy is an important part of treatment after severe brain injuries and stroke, but its effect on intracranial and systemic hemodynamics is minimally investigated. Therefore, the aim of this study was to assess the effects of an early bedside cycle exercise on intracranial and systemic hemodynamics in critically ill patients when admitted to a neurointensive care unit (NICU). METHODS: Twenty critically ill patients suffering from brain injuries or stroke were included in this study performed in the NICU at Sahlgrenska University Hospital. One early implemented exercise session was performed using a bedside cycle ergometer for 20 min. Intracranial and hemodynamic variables were measured two times before, three times during, and two times after the bedside cycling exercise. Analyzed variables were intracranial pressure (ICP), cerebral perfusion pressure (CPP), mean arterial blood pressure (MAP), heart rate (HR), peripheral oxygen saturation (SpO2), cardiac output (CO), stroke volume (SV), and stroke volume variation (SVV). The cycling intervention was conducted within 7 +/- 5 days after admission to the NICU. RESULTS: Cycle exercise increased MAP (p = 0.029) and SV (p = 0.003) significantly. After exercise CO, SV, MAP, and CPP decreased significantly, while no changes in HR, SVV, SpO2, or ICP were noted when compared to values obtained during exercise. There were no differences in data obtained before versus after exercise. CONCLUSION: Early implemented exercise with a bedside cycle ergometer, for patients with severe brain injuries or stroke when admitted to a NICU, is considered to be a clinically safe procedure. PMID- 27216929 TI - Taxonomy of the order Mononegavirales: update 2016. AB - In 2016, the order Mononegavirales was emended through the addition of two new families (Mymonaviridae and Sunviridae), the elevation of the paramyxoviral subfamily Pneumovirinae to family status (Pneumoviridae), the addition of five free-floating genera (Anphevirus, Arlivirus, Chengtivirus, Crustavirus, and Wastrivirus), and several other changes at the genus and species levels. This article presents the updated taxonomy of the order Mononegavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV). PMID- 27216932 TI - An autoethnographic exploration of the use of goal oriented feedback to enhance brief clinical teaching encounters. AB - Supervision in the outpatient context is increasingly in the form of single day interactions between students and preceptors. This creates difficulties for effective feedback, which often depends on a strong relationship of trust between preceptor and student. Building on feedback theories focusing on the relational and dialogic aspects of feedback, this study explored the use of goal-oriented feedback in brief encounters with learners. This study used autoethnography to explore one preceptor's feedback interactions over an eight-month period both in the ambulatory setting and on the wards. Data included written narrative reflections on feedback interactions with twenty-three learners informed by discussions with colleagues and repeated reading of feedback literature. Thematic and narrative analyses of data were performed iteratively. Data analysis emphasized four recurrent themes. (1) Goal discussions were most effective when initiated early and integrated throughout the learning experience. (2) Both learner and preceptor goals were multiple and varied, and feedback needed to reflect this complexity. (3) Negotiation or co-construction of goals was important when considering the focus of feedback discussions in order to create safer, more effective interactions. (4) Goal oriented interactions offer potential benefits to the learner and preceptor. Goal oriented feedback promotes dialogue as it requires both preceptor and learner to acknowledge and negotiate learning goals throughout their interaction. In doing so, feedback becomes an explicit component of the preceptor-learner relationship. This enhances feedback interactions even in relatively brief encounters, and may begin an early educational alliance that can be elaborated with longer interactions. PMID- 27216933 TI - Craniofacial shape transition across the house mouse hybrid zone: implications for the genetic architecture and evolution of between-species differences. AB - Craniofacial shape differences between taxa have often been linked to environmental adaptation, e.g., new food sources, or have been studied in the context of domestication. Evidence for the genetic basis of such phenotypic differences to date suggests that between-species as well as between-population variation has an oligogenic basis, i.e., few loci of large effect explain most of the variation. In mice, it has been shown that within-population craniofacial variation has a highly polygenic basis, but there are no data regarding the genetic basis of between-species differences in natural populations. Here, we address this question using a phenotype-focused approach. Using 3D geometric morphometrics, we phenotyped a panel of mice derived from a natural hybrid zone between Mus musculus domesticus and Mus mus musculus and quantify the transition of craniofacial shape along the hybridization gradient. We find a continuous shape transition along the hybridization gradient and unaltered developmental stability associated with hybridization. This suggests that the morphospace between the two subspecies is continuous despite reproductive isolation and strong barriers to gene flow. We show that quantitative changes in overall genome composition generate quantitative changes in craniofacial shape; this supports a highly polygenic basis for between-species craniofacial differences in the house mouse. We discuss our findings in the context of oligogenic versus polygenic models of the genetic architecture of morphological traits. PMID- 27216934 TI - The tell-tale thigh. AB - A body of a 91-year-old donor underwent whole-body CT scanning before being transferred for use in an anatomical dissection course. Metallic objects were detected in the thigh muscles, extensive bone abnormalities were found in the left femur and the diaphysis of the left femur was 50% wider than that of the right diaphysis. History revealed that the body donor had been seriously wounded at the end of World War II by a rocket explosion. His multiple fractures and lesions had not been surgically treated either in an Austrian military hospital or in a French prisoner of war camp. The patient suffered for almost 70 years from this violation of the Geneva Conventions. In the light of current armed conflicts, the present case is an example of how one injustice can result in severe, lifelong medical consequences. It also shows that the history behind a wounded thigh can have an enormous impact on teaching ethics to today's medical students. PMID- 27216935 TI - Hypoglycemia due to monoclonal anti-insulin antibody in a patient with multiple myeloma. PMID- 27216936 TI - The Radical-Pair Mechanism of Magnetoreception. AB - Although it has been known for almost half a century that migratory birds can detect the direction of the Earth's magnetic field, the primary sensory mechanism behind this remarkable feat is still unclear. The leading hypothesis centers on radical pairs-magnetically sensitive chemical intermediates formed by photoexcitation of cryptochrome proteins in the retina. Our primary aim here is to explain the chemical and physical aspects of the radical-pair mechanism to biologists and the biological and chemical aspects to physicists. In doing so, we review the current state of knowledge on magnetoreception mechanisms. We dare to hope that this tutorial will stimulate new interdisciplinary experimental and theoretical work that will shed much-needed additional light on this fascinating problem in sensory biology. PMID- 27216937 TI - Faecal microbiota profiles as diagnostic biomarkers in primary sclerosing cholangitis. PMID- 27216938 TI - Proteomic analysis of ascending colon biopsies from a paediatric inflammatory bowel disease inception cohort identifies protein biomarkers that differentiate Crohn's disease from UC. AB - OBJECTIVE: Accurate differentiation between Crohn's disease (CD) and UC is important to ensure early and appropriate therapeutic intervention. We sought to identify proteins that enable differentiation between CD and UC in children with new onset IBD. DESIGN: Mucosal biopsies were obtained from children undergoing baseline diagnostic endoscopy prior to therapeutic interventions. Using a super stable isotope labeling with amino acids in cell culture (SILAC)-based approach, the proteomes of 99 paediatric control and biopsies of patients with CD and UC were compared. Multivariate analysis of a subset of these (n=50) was applied to identify novel biomarkers, which were validated in a second subset (n=49). RESULTS: In the discovery cohort, a panel of five proteins was sufficient to distinguish control from IBD-affected tissue biopsies with an AUC of 1.0 (95% CI 0.99 to 1.0); a second panel of 12 proteins segregated inflamed CD from UC within an AUC of 0.95 (95% CI 0.86 to 1.0). Application of the two panels to the validation cohort resulted in accurate classification of 95.9% (IBD from control) and 80% (CD from UC) of patients. 116 proteins were identified to have correlation with the severity of disease, four of which were components of the two panels, including visfatin and metallothionein-2. CONCLUSIONS: This study has identified two panels of candidate biomarkers for the diagnosis of IBD and the differentiation of IBD subtypes to guide appropriate therapeutic interventions in paediatric patients. PMID- 27216939 TI - Adaptation and validation of the "tolerability and quality of life" (TOOL) questionnaire in Chinese bipolar patients. AB - BACKGROUND: It is well known that the antipsychotic drugs impact the health related quality of life (HRQoL) of the bipolar patients. The side effects had been assessed only from the doctors' perspective and neglected the patients' subjective feeling. The aim of the study is to validate the specific instrument "tolerability and quality of life" (TOOL) into Chinese to describe and grade the impact of antipsychotic drugs on HRQoL from patients' view. METHODS: A psychometric study was conducted with euthymic bipolar disorder patients (N = 105) under antipsychotic treatment. The psychometric properties of the TOOL, including internal consistency, retest reliability, concurrent validity, content validity, discriminative validity, item analysis, confirmatory factor analysis and feasibility, were analyzed. RESULTS: The internal consistency and intraclass correlation coefficient (ICC) were adequate (Cronbach's alpha = 0.80 and ICC = 0.81). A confirmatory factor analysis (CFA) validated the one-factor model. Significant Spearman's rank correlations between the TOOL and both Bref QoL.BD (Brief version of Quality of Life in Bipolar Disorder) (r = -0.33, P < 0.01) and UKU (Udvalg for Kliniske Undersogelser side effects scale) (r = 0.13, P < 0.05) were found. LIMITATIONS: Small sample size and no specific self-report instrument in Chinese to evaluate the criterion validity. CONCLUSIONS: TOOL appears to be a reliable and valid measure to assess the impact of adverse events of antipsychotic drugs on HRQoL from the patients' perspective. PMID- 27216940 TI - Validation study of a Chinese version of Partners in Health in Hong Kong (C-PIH HK). AB - BACKGROUND: The Partners in Health (PIH) scale is a measure designed to assess the generic knowledge, attitudes, behaviors, and impacts of self-management. A cross-cultural adaptation of the PIH for use in Hong Kong was evaluated in this study. This paper reports the validity and reliability of the Chinese version of PIH (C-PIH[HK]). METHOD: A 12-item PIH was translated using forward-backward translation technique and reviewed by individuals with chronic diseases and health professionals. A total of 209 individuals with chronic diseases completed the scale. The construct validity, internal consistency, and test-retest reliability were evaluated in two waves. RESULTS: The findings in Wave 1 (n = 73) provided acceptable psychometric properties of the C-PIH(HK) but supported the adaptation of question 5 to improve the cultural relevance, validity, and reliability of the scale. An adapted version of C-PIH(HK) was evaluated in Wave 2. The findings in Wave 2 (n = 136) demonstrated good construct validity and internal consistency of C-PIH(HK). A principal component analysis with Oblimin rotation yielded a 3-factor solution, and the Cronbach's alphas of the subscales ranged from 0.773 to 0.845. Participants were asked whether they perceived the self-management workshops they attended and education provided by health professionals as useful or not. The results showed that the C-PIH(HK) was able to discriminate those who agreed and those who disagreed related to the usefulness of individual health education (p < 0.0001 in all subscales) and workshops (p < 0.001 in the knowledge subscale) as hypothesized. The test-retest reliability was high (ICC = 0.818). CONCLUSION: A culturally adapted version of PIH for use in Hong Kong was evaluated. The study supported good construct validity, discriminate validity, internal consistency, and test-retest reliability of the C PIH(HK). PMID- 27216941 TI - CSF Abeta1-42 - an excellent but complicated Alzheimer's biomarker - a route to standardisation. AB - The 42 amino acid form of amyloid beta (Abeta1-42) in cerebrospinal fluid (CSF) has been widely accepted as a central biomarker for Alzheimer's disease. Several immunoassays for CSF Abeta1-42 are commercially available, but can suffer from between laboratory and batch-to-batch variability as well as lack of standardisation across assays. As a consequence, no general cut-off values have been established for a specific context of use (e.g., clinical diagnostics) and selection of individuals for enrolment in clinical trials (patient stratification) remains challenging. The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) has initiated a working group for CSF proteins (WG-CSF) to facilitate standardisation of CSF Abeta1-42 measurement results. The efforts of the IFCC WG-CSF include the development of certified reference materials (CRMs) and reference measurement procedures (RMPs) for key biomarkers. Two candidate RMPs for quantification of Abeta1-42 in CSF based on liquid chromatography tandem mass spectrometry have been developed and tested in two ring trials. Furthermore, two commutability studies including native CSF pools, artificial CSF and spiked materials have been completed. On the basis of these studies, human CSF pools containing only endogenous Abeta1-42 at three concentrations were selected as the format for future CRMs that are now being processed. PMID- 27216942 TI - Controversies in the Diagnosis of Subarachnoid Hemorrhage. AB - BACKGROUND: Headache is a common chief complaint in emergency departments, accounting for 2% of visits, and subarachnoid hemorrhage (SAH) is a life threating cause of headache. This deadly disease is most commonly due to aneurysmal rupture. Various approaches exist for diagnosis, with recent studies evaluating these approaches. A great deal of controversy exists about the optimal diagnosis strategy for SAH. OBJECTIVE: This article in the Best Clinical Practice Series seeks to educate emergency physicians on the recent literature in the diagnosis of SAH and provide an evidence-based approach. DISCUSSION: Various diagnostic strategies exist, including use of noncontrast head computed tomography (CT) alone, CT/lumbar puncture (LP) in combination, CT/CT angiography, and magnetic resonance imaging/magnetic resonance angiography. The use of clinical decision rules has also been espoused, and several contemporary studies have evaluated cerebrospinal fluid results of red blood cell count and xanthochromia in the diagnosis of SAH. Recent literature supports that a negative head CT done within 6 h of headache onset places the patient at a < 1% risk for SAH. With the complex literature, a shared decision-making model should be followed with options, risks, and benefits discussed with the patient. CONCLUSIONS: Literature support exists for all of the diagnostic strategies. The American College of Emergency Physicians Clinical Policy supports CT and LP for definitive diagnosis. Risk stratification and a shared decision-making model with the patient should be followed, and a negative head CT within 6 h of headache onset places patient at a risk of < 1% for having SAH. PMID- 27216944 TI - Pointing Device Performance in Steering Tasks. AB - Use of touch-screen-based interactions is growing rapidly. Hence, knowing the maneuvering efficacy of touch screens relative to other pointing devices is of great importance in the context of graphical user interfaces. Movement time, accuracy, and user preferences of four pointing device settings were evaluated on a computer with 14 participants aged 20.1 +/- 3.13 years. It was found that, depending on the difficulty of the task, the optimal settings differ for ballistic and visual control tasks. With a touch screen, resting the arm increased movement time for steering tasks. When both performance and comfort are considered, whether to use a mouse or a touch screen for person-computer interaction depends on the steering difficulty. Hence, a input device should be chosen based on the application, and should be optimized to match the graphical user interface. PMID- 27216943 TI - A novel polysaccharide from Sargassum integerrimum induces apoptosis in A549 cells and prevents angiogensis in vitro and in vivo. AB - Many polysaccharides isolated from plants have exhibited promising antitumor activities. The aim of this study is to investigate the antitumor activity of the novel polysaccharide named SPS from Sargassum integerrimum, elucidate the underlying anticancer mechanism in a human lung cancer cell line A549, and evaluate its anti-angiogenic activity both in vitro and in vivo. The results show that SPS significantly reduces A549 cells viability in a dose- and time-dependent manner via MTT method. Flow cytometry analysis indicates that SPS could induce cell apoptosis, the loss of mitochondrial membrane potential (MMP), generation of reactive oxygen species (ROS) and G2/M phase cell cycle arrest of A549 cells. Up regulation of the expressions of P53 and Bax, down-regulation of the expression of Bcl-2, and activation of cleaved caspase-3, caspase-9 and PARP are also detected by western blotting after the treatment of SPS. In addition, SPS inhibits the proliferation, migration and cord formation of human umbilical vein endothelial cells (HUVECs) in vitro, and prevents the vascular development of zebrafish embryos in vivo. Altogether, our data prove the anticancer and anti angiogenesis properties of SPS, and provide further insights into the potential pharmacological application of SPS as antitumor and anti-angiogenic agent against lung cancer. PMID- 27216945 TI - Bifactor Modeling of the Behavior Rating Inventory of Executive Function (BRIEF) in a Chilean Sample. AB - The Behavior Rating Inventory of Executive Functions evaluates executive functioning through the observation of students' performance in real contexts. Most psychometric studies of the scale have only tested the first-order structure, despite the hierarchical configuration of its theoretical model. A bifactor model was conducted on a normative sample of 5- to 18-year-old Chileans (M age = 11.3 years, SD = 3.7) to test a hierarchical structure of three first order factors and an independent second-order factor. Bifactor analyses showed best fit for the proposed hierarchical structure. Findings supported a method to evaluate executive functioning models that provides a general global factor score that may complement existing indices and thus help clinicians to make better inferences. PMID- 27216946 TI - Doctors raise concerns about India's draft bill to regulate life support withdrawal. PMID- 27216947 TI - Clinical Effectiveness of Liraglutide vs Sitagliptin on Glycemic Control and Body Weight in Patients with Type 2 Diabetes: A Retrospective Assessment in Sweden. AB - INTRODUCTION: The aim of the present study was to use real-world data from Swedish primary-care and national registries to understand clinical outcomes in patients with Type 2 diabetes (T2D) treated with liraglutide in clinical practice, and to compare with data from those treated with sitagliptin. METHODS: This was a non-interventional, retrospective study conducted between February 2014 and September 2014 using T2D patient data from Swedish primary-care centers and national healthcare registries. The primary objective was to assess the effectiveness of liraglutide in control of glycemia and body weight in clinical practice (stage 1). The secondary objective was to compare the clinical effectiveness of liraglutide with sitagliptin on glycemic control and body weight in clinical practice in a propensity-score-matched population (stage 2). RESULTS: In stage 1 (n = 402), 39.4% of patients treated with liraglutide achieved >=1.0% (10.9 mmol/mol) reduction in glycated hemoglobin (HbA1c) after 180 days of treatment and 54.9% achieved the target HbA1c of <7.0% (53.0 mmol/mol). Moreover, compared with baseline, 22.5% of patients treated with liraglutide achieved both >=1.0% reduction in HbA1c and >=3.0% reduction in body weight. In stage 2, a significantly greater proportion of patients receiving liraglutide (n = 180) than sitagliptin (n = 208) achieved >=1.0% reduction in HbA1c [52.9% vs 33.5%, respectively (P = 0.0002)]. Mean body-weight loss was also significantly greater in patients receiving liraglutide vs sitagliptin [-3.5 vs -1.3 kg, respectively (P < 0.0001)]. CONCLUSION: This study provides real-world evidence from Sweden corroborating previous clinical trials that demonstrate greater efficacy of liraglutide over sitagliptin on glycemic control and body-weight reduction in patients with T2D. FUNDING: Novo Nordisk A/S. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02077946. PMID- 27216949 TI - Lanthanide Germanate Cluster Organic Frameworks Based on {Ln8Ge12} Clusters: From One-Dimensional Chains to Two-Dimensional Layers and Three-Dimensional Frameworks. AB - Under hydrothermal conditions, six series of novel lanthanide (Ln) organogermanates (LnGs) [Ln8Ge12(MU3-O)24E12(H2O)16].14H2O (Ln(3+) = Pr(3+), 1; Nd(3+), 2; Sm(3+), 3; Eu(3+), 4; Gd(3+), 5; one-dimensional (1-D) LnG cluster organic chain (LnGCOC)), {[Nd8Ge12(MU3-O)24E12(H2O)10](MU2-H2O)2[Nd8Ge12(MU3 O)24E12(H2O)16]}.18H2O (6, two-dimensional (2-D) planar LnG cluster organic layer (LnGCOL)), {[Ln2GeE(HO)2O(H2O)(CH3COO)2(CO3)]2[Ln8Ge12E12(MU3-O)24(H2O)10]}.6H2O (Ln(3+) = Pr(3+), 7; Nd(3+), 8; 2-D wave-shaped LnGCOL), [TbGeE(HO)2O(H2O)(pca)]2[Tb8Ge12E12(MU3-O)24(H2O)8].10H2O (9, three-dimensional (3-D) LnG cluster organic framework (LnGCOF)), {([Nd(pza)2(H2O)2]2[Nd8Ge12E12(MU3 O)24(H2O)12])([Nd(pza)2]2[Nd8Ge12E12(Hpza)2(MU3-O)24(H2O)10])}.4OH.14H2O (10, 3-D LnGCOF), {[Nd8Ge12E12(MU3-O)24(H2O)10][Nd(pca)(pda)(H2O)]2}.12H2O (11, 3-D LnGCOF) and {[Nd8Ge12E12(MU3-O)24(H2O)10][Nd(pza)(pda)(H2O)]2}.12H2O (12, 3-D LnGCOF) (Hpca = 2-picolinic acid, H2pda = 2,6-pyridinedicarboxylic acid, Hpza = 2 pyrazinecarboxylic acid) were prepared by introducing the second auxiliary ligands into the organogermanate-lanthanide-oxide reaction system. The obtainment of these LnGs realized the utilization of the second auxiliary ligands inducing the assembly from 1-D LnGCOCs to 2-D LnGCOLs and 3-D LnGCOFs based on LnG cluster (LnGC) {Ln8Ge12E12(MU3-O)24(H2O)16}({Ln8Ge12}) units and Ln-organic complexes or organic ligand connectors. It should be noted that the well-organized structural constructions of 1-12 can be visualized as the gradual replacement of active water sites located at equatorial and polar positions on the hypothetical [Ln8Ge12(MU3-O)24E12(H2O)18] LnGC core with oxygen or nitrogen atoms from organic ligands. The solid-state luminescent properties of 2, 3, 4, 6, and 8-12 have been investigated at room temperature. PMID- 27216948 TI - Metabolic Dysfunction in Heart Failure: Diagnostic, Prognostic, and Pathophysiologic Insights From Metabolomic Profiling. AB - Metabolic impairment is an intrinsic component of heart failure (HF) pathophysiology. Although initially conceived as a myocardial defect, metabolic dysfunction is now recognized as a systemic process with complex interplay between the myocardium and peripheral tissues and organs. Specifically, HF associated metabolic dysfunction includes alterations in substrate utilization, insulin resistance, defects in energy production, and imbalanced anabolic catabolic signaling leading to cachexia. Each of these metabolic abnormalities is associated with significant morbidity and mortality in patients with HF; however, their detection and therapeutic management remains challenging. Given the difficulty in obtaining human cardiac tissue for research purposes, peripheral blood metabolomic profiling, a well-established approach for characterizing small molecule metabolite intermediates from canonical biochemical pathways, may be a useful technology for dissecting biomarkers and mechanisms of metabolic impairment in HF. In this review, metabolic abnormalities in HF will be discussed with particular emphasis on the application of metabolomic profiling to detecting, risk stratifying, and identifying novel targets for metabolic therapy in this heterogeneous population. PMID- 27216950 TI - Neonatal metabolic acidosis at birth: In search of a reliable marker. AB - OBJECTIVE: A newborn may present acidemia on the umbilical artery blood which can result from respiratory acidosis or metabolic acidosis or be of mixed origin. Currently, in the absence of a satisfactory definition, the challenge is to determine the most accurate marker for metabolic acidosis, which can be deleterious for the neonate. METHODS: We reviewed the methodological and physiological aspects of the perinatal literature to search for the best marker of NMA. RESULTS: Base deficit and pH have been criticized as the standard criteria to predict outcome. The proposed threshold of pathogenicity is not based on convincing studies. The algorithms of various blood gas analyzers differ and do not take into account the specific neonatal acid-base profile. CONCLUSION: Birth-related neonatal eucapnic pH is described as the most pertinent marker of NMA at birth. The various means of calculating this value and the level below which it seems to play a possible pathogenic role are presented. PMID- 27216951 TI - [Methotrexate in ectopic pregnancy is almost allowed!]. PMID- 27216952 TI - [Management of uterine myomas during pregnancy]. AB - OBJECTIVE: To assess the impact of myomas on pregnancy and discuss the role of myomectomy during cesarean section. METHODS: Databases PubMed, Medline and Cochrane were searched until 30 June 2015. RESULTS: The most commonly reported obstetric complications relative to fibroids are: increased rate of spontaneous miscarriage in women with submucosal or intramural fibroids, pain, placentation disorders and malpresentation. A higher cesarean section rate is found among pregnant women with fibroids. The most common postpartum complication is postpartum haemorrhage. For years, risk of haemorrhage led caregivers not to practice myomectomy during cesarean section. Current data are rather reassuring. No study shows significant hemorrhage differences between myomectomy during cesarean section and cesarean section alone or myomectomy alone. The long-term morbidity of myomectomy during cesarean section is not enough studied but does not appear higher than expected for fertility and complications during pregnancy. Therefore, myomectomy during cesarean section is not currently recommended by learned societies. CONCLUSION: Women with fibroids is a common obstetric situation. Complications are rare. Myomectomy during cesarean section seems to be not associated with higher short-term maternal morbidity. But studies with a longer-term follow-up of patients are necessary. PMID- 27216953 TI - [Biermer disease miming HELLP syndrome]. PMID- 27216954 TI - [Endoscopic 3D latissimus dorsi flap harvesting for immediate breast reconstruction]. PMID- 27216955 TI - [Interpretation of umbilical cord pH at birth: The trap of hypercapnia]. PMID- 27216956 TI - [Psychology and sexology are essential, from diagnosis to comprehensive care of endometriosis]. AB - Endometriosis, defined by the presence of endometrial tissue outside the uterine cavity, is a common but often under diagnosed pathology. The clinical manifestations are varied (chronic pelvic pain, urinary or gastrointestinal symptoms) and can sometimes be very frustrated, delaying the diagnosis. This delay in diagnosis can be a high source of stress responsible for an important psychological impact in these patients, having a sense of misunderstanding and neglect of the medical profession. This climate of stress and anxiety can cause alteration of behavior including sexual disorders. In addition, endometriosis can be revealed as part of an infertility evaluation, and the patient and the couple can already be affected by this situation. The clinical and psychological impact of endometriosis inevitably leads to an impairment of patient's quality of life and sexuality. The objective of this article is to show the psychological consequences of endometriosis and its impact on sexuality, in order to highlight this essential aspect for a comprehensive care of patients. PMID- 27216957 TI - Methotrexate treatment for ectopic pregnancy after assisted reproductive technology: A case-control study. AB - OBJECTIVES: Ectopic pregnancy (EP) occurs in 2% to 5.6% of pregnancies achieved by assisted reproductive technology (ART). EP treatment options include medical treatment by uses of methotrexate (MTX) systemic injection. The objective of this study was to compare MTX treatment effectiveness for EP occurring spontaneously or following ART. METHODS: A case-control study performed in the department of obstetrics and gynecology at a tertiary health care center in France. Twenty EP achieved by ART (ART group) and 60 spontaneous EP (SEP group) received MTX treatment between January 2002 and May 2012. The main outcome measures were MTX treatment failure rates, number of MTX injections administered and recovery time. RESULTS: MTX treatment failure rates observed in ART and SEP groups were similar (3/20 [15%] versus 10/60 [17%]: OR=0.88 [0.22-3.58]). Mean duration of recovery time in patients with successful MTX treatment did not differ between ART and SEP groups (33+/-14 days versus 28+/-13 days, P=0.39). A second MTX injection was required more frequently in ART group than in SEP group (10/20 [50%] versus 10/60 [17%]: OR=5 [1.65-15.15]). CONCLUSIONS: It is concluded that MTX treatment is equally effective for spontaneous EP and EP achieved by ART, two injections of MTX being more frequently required in case of ART. PMID- 27216958 TI - [Are ultrasound measurements of the cervical length and fetal head-perineum distance predictive of delivery outcome in post-term pregnancies?]. AB - OBJECTIVE: Post-term pregnancy is frequently associated with higher fetal and maternal morbidity and mortality. Its management essentially depends on clinical cervical characteristics as evaluated by the Bishop score (BS). However, BS is poorly predictive of the delivery outcome. We sought to demonstrate that ultrasound measurement of cervical length and evaluation of fetal height could predict the outcome in post-term pregnancies. METHODS: A prospective single center study was undertaken between the 21st of January and the 1st of June 2013. Fetal height was measured using a transperineal technique and cervical length was evaluated by a vaginal ultrasound on patients consulting and their term date. C section rates were considered to be the primary judgment criteria. RESULTS: A total of 136 patients were included. C-section rates in this population was 19%. Fetal height and cervical length were not different between the C-section group and the vaginal delivery group. CONCLUSION: Our study demonstrates that ultrasound measurement of cervical length and fetal height do not show better results than BS in predicting the outcome of post-term pregnancy. Combining these ultrasound measurements has already been suggested in other studies and promising results have been shown. More studies are necessary to further these results. PMID- 27216959 TI - Deep infiltrating endometriosis: Should rectal and vaginal opacification be systematically used in MR imaging? AB - OBJECTIVES: To evaluate the interest of rectal and vaginal filling in vaginal and recto-sigmoid endometriosis with MR imaging. To compare the results between a senior and a junior radiologist review. METHODS: Sixty-seven patients with clinically suspected deep infiltrating endometriosis were included in our MRI protocol consisting of repeated T2-weigthed sequences (axial and sagittal) before and after rectal and vaginal marking with ultrasonography gel. Vaginal and recto sigmoid endometriosis lesions were analyzed before and after opacification. The inter-reader agreement between senior and junior scores was studied. RESULTS: Concerning vaginal and muscularis and beyond colonic involvement, no significant difference (P=0.32) was observed and the inter-reader agreement was excellent (K=0.96 and 0.97 respectively). Concerning serosa colonic lesions, a significant difference was observed (P=0.01) and the inter-reader agreement was poor (K=0). CONCLUSIONS: Rectal and vaginal filling in endometriosis staging with MRI is not necessary no matter the reader experiment. PMID- 27216960 TI - [Pap smear for mass screening: Results of an African experiment]. AB - OBJECTIVES: To assess the impact of smear test in the fight against cervix uteri cancer in Senegal. METHODS: This was a descriptive cross-sectional study of 1836 Pap smears performed in patients over 15 years during several screening campaigns in Senegal conducted between June 2010 and June 2012. We analyzed epidemiological data, pathological smears, and the proposed management. RESULTS: In 69% of cases, the women were less than 45 years old. They were mostly multiparous and did not use contraceptive methods before. The smears were interpreted in 91.4% (n=1661) and were pathological in 5.2% of cases. They revealed mainly atypical squamous cells of undetermined significance, squamous intraepithelial low-grade lesions, and squamous intraepithelial high-grade lesions, respectively in 2.5% (n=46), 1.7% (n=30) and 1% (n=19) of cases. Multiparity, early marriages were the main risk factors. Patients with pathological smars had colposcopy with cryotherapy (23 cases), and colposcopy and biopsy (13 cases). A hysterectomy was performed in 4 cases. CONCLUSION: The pathological smear rate found in this study confirms the interest to continue cervical cancer screening with this practice. Strengthening of its geographical and financial access through a national prevention program will effectively help to lower cases of cervical cancer. PMID- 27216962 TI - Nutrition has a pervasive impact on cardiac microRNA expression in isogenic mice. AB - The complex interaction between obesity, Western-style diets, and cardiovascular disease is of increasing interest, with a growing number of children being born to obese parents with poor lifestyle choices. These offspring have themselves an increased susceptibility to obesity and subsequent cardiovascular disease in adult life, which may be 'programmed' by their intrauterine environment. Cardiac microRNAs (miRNAs) are affected by multiple disease states, and have also been shown to be capable of exerting a hormone-like control on whole body metabolism. Here we sought to determine the effect of prenatal exposure to maternal obesity and/or postnatal exposure to a Western diet on miRNA expression in the heart. Unbiased small RNA sequencing was carried out on cardiac tissue from young adult mice born to lean or obese mothers; offspring were weaned onto either a low-fat control diet or a high-fat Western-style diet. We found 8 cardiac miRNAs that were significantly altered in response to maternal obesity, but only when the offspring were challenged postnatally with the Western diet. In contrast, postnatal exposure to the diet alone induced significant changes to the expression of a much larger number of miRNAs (33 in offspring of lean and 46 in offspring of obese). Many of the affected miRNAs have previously been implicated in various cardiac pathologies. The pervasive cardiac miRNA changes induced by a Western diet suggest that an individual's lifestyle choices outweigh the impact of any programming effects by maternal obesity on miRNA-related cardiac health. PMID- 27216961 TI - TRIM31 promotes Atg5/Atg7-independent autophagy in intestinal cells. AB - Autophagy is responsible for the bulk degradation of cytosolic constituents and plays an essential role in the intestinal epithelium by controlling beneficial host-bacterial relationships. Atg5 and Atg7 are thought to be critical for autophagy. However, Atg5- or Atg7-deficient cells still form autophagosomes and autolysosomes, and are capable of removing proteins or bacteria. Here, we report that human TRIM31 (tripartite motif), an intestine-specific protein localized in mitochondria, is essential for promoting lipopolysaccharide-induced Atg5/Atg7 independent autophagy. TRIM31 directly interacts with phosphatidylethanolamine in a palmitoylation-dependent manner, leading to induction of autolysosome formation. Depletion of endogenous TRIM31 significantly increases the number of intestinal epithelial cells containing invasive bacteria. Crohn's disease patients display TRIM31 downregulation. Human cytomegalovirus-infected intestinal cells show a decrease in TRIM31 expression as well as a significant increase in bacterial load, reversible by the introduction of wild-type TRIM31. We provide insight into an alternative autophagy pathway that protects against intestinal pathogenic bacterial infection. PMID- 27216963 TI - Identification of chilling-responsive microRNAs and their targets in vegetable soybean (Glycine max L.). AB - Chilling stress is a major factor limiting the yield and quality of vegetable soybean (Glycine max L.) on a global scale. In the present study, systematic identification and functional analysis of miRNAs under chilling stress were carried out to clarify the molecular mechanism of chilling resistance. Two independent small RNA libraries from leaves of soybean were constructed and sequenced with the high-throughput Illumina Solexa system. A total of 434 known miRNAs and 3 novel miRNAs were identified. Thirty-five miRNAs were verified by qRT-PCR analysis. Furthermore, their gene targets were identified via high throughput degradome sequencing. A total of 898 transcripts were targeted by 54 miRNA families attributed to five categories. More importantly, we identified 51 miRNAs differentially expressed between chilling stress and control conditions. The targets of these miRNAs were enriched in oxidation-reduction, signal transduction, and metabolic process functional categories. Our qRT-PCR analysis confirmed a negative relationship among the miRNAs and their targets under chilling stress. Our work thus provides comprehensive molecular evidence supporting the involvement of miRNAs in chilling-stress responses in vegetable soybean. PMID- 27216965 TI - Malignant hyperechoic breast lesions at ultrasound: A pictorial essay. AB - Malignant breast lesions are typically hypoechoic at sonography. However, a small subgroup of hyperechoic malignant breast lesions is encountered in clinical practice. We present a pictorial essay of a number of different hyperechoic breast malignancies with mammographic, sonographic and histopathologic correlation. Suspicious sonographic features in a hyperechoic lesion include inhomogeneity in echogenic pattern, an irregular margin, posterior acoustic shadowing and internal vascularity. A hyperechoic lesion at ultrasound does not discount the need to undertake histological assessment of a mammographically suspicious lesion. PMID- 27216966 TI - The endocrine disruptors among the environmental risk factors for stillbirth. AB - Persistent organic pollutants have been lately taken into consideration for their adverse effects, as possible stillbirth contributors; stillbirth can be in fact considered the most dramatic pregnancy complication. Congenital abnormalities account for few stillbirths and many related disorders are potentially modifiable or often coexist, such as maternal infections, non-communicable diseases, lifestyle factors and maternal age. Causal pathways for stillbirth frequently involve impaired placental function, either with fetal growth restriction or preterm labour. For this reason, many current efforts are focusing on the study of endocrine disruptor (ED) placental transfer, to better understand the in utero exposure dynamics. In this regard, our research group has investigated, by gas chromatography-mass spectrometry, the EDs presence in brain samples of 24 stillbirths, collected over a 3-year period (2012-2014), coming from the Northeast Italy, a notorious area devoted to apple cultivation. Surprisingly, organochlorine pesticides (OCPs), well-known EDs, have been detected in 11 samples. Apart from the noteworthy evidence of pesticides' bio-persistence, this finding implies a redefinition of the placental barrier concept: not a real safety system, but a time-deferral mechanism of absorption. The term 'placental barrier' in fact refers to a 4-membrane structure, made up by two epithelial layers, which exactly lining the chorionic villi, and by two endothelial layers, belonging to the feeding vessels for the fetus. It is an effective barrier only for a low administration of water-soluble substances, which encounter obstacle to cross four instead of two membranes. High doses of water-soluble compounds can reach appreciable concentration in the fetal blood, and the lipid-soluble chemicals, such as EDs, are able to pass the placental barrier, through a simple mechanism of passive diffusion, even in minimal concentrations. After crossing the placental barrier, it is emerged from our results that they can also pass through the still immature blood-brain barrier of the fetus. PMID- 27216967 TI - Placing ecosystem services at the heart of urban water systems management. AB - Current approaches have failed to deliver a truly integrated management of the different elements of the urban water system, such as freshwater ecosystems, drinking water treatment plants, distribution networks, sewer systems and wastewater treatment plants. Because the different parts of urban water have not been well integrated, poor decisions have been made for society in general, leading to the misuse of water resources, the degradation of freshwater ecosystems and increased overall treatment costs. Some attempts to solve environmental issues have adopted the ecosystem services concept in a more integrated approach, however this has rarely strayed far away from pure policy, and has made little impact in on-the-ground operational matters. Here, we present an improved decision-making framework to integrate the management of urban water systems. This framework uses the ecosystem service concept in a practical way to make a better use of both financial and water resources, while continuing to preserve the environment. PMID- 27216968 TI - Biomarker analysis of liver cells exposed to surfactant-wrapped and oxidized multi-walled carbon nanotubes (MWCNTs). AB - Carbon nanotubes (CNTs) have great potential in industrial, consumer, and mechanical applications, based partly on their unique structural, optical and electronic properties. CNTs are commonly oxidized or treated with surfactants to facilitate aqueous solution processing, and these CNT surface modifications also increase possible human and ecological exposures to nanoparticle-contaminated waters. To determine the exposure outcomes of oxidized and surfactant-wrapped multiwalled carbon nanotubes (MWCNTs) on biochemical processes, metabolomics based profiling of human liver cells (C3A) was utilized. Cells were exposed to 0, 10, or 100ng/mL of MWCNTs for 24 and 48h; MWCNT particle size distribution, charge, and aggregation were monitored concurrently during exposures. Following MWCNT exposure, cellular metabolites were extracted, lyophilized, and buffered for (1)H NMR analysis. Acquired spectra were subjected to both multivariate and univariate analysis to determine the consequences of nanotube exposure on the metabolite profile of C3A cells. Resulting scores plots illustrated temporal and dose-dependent metabolite responses to all MWCNTs tested. Loadings plots coupled with t-test filtered spectra identified metabolites of interest. XPS analysis revealed the presence of hydroxyl and carboxyl functionalities on both MWCNTs surfaces. Metal content analysis by ICP-AES indicated that the total mass concentration of the potentially toxic impurities in the exposure experiments were extremely low (i.e. [Ni]<=2*10(-10)g/mL). Preliminary data suggested that MWCNT exposure causes perturbations in biochemical processes involved in cellular oxidation as well as fluxes in amino acid metabolism and fatty acid synthesis. Dose-response trajectories were apparent and spectral peaks related to both dose and MWCNT dispersion methodologies were determined. Correlations of the significant changes in metabolites will help to identify potential biomarkers associated with carbonaceous nanoparticle exposure. PMID- 27216969 TI - Generalized concentration addition approach for predicting mixture toxicity. AB - A new mathematical model for analyzing data and predicting the effect of mixtures of toxic substances is presented as a generalized form of the concentration addition model. The proposed method, the generalized concentration addition (GCA) model, can be applied to mixtures with arbitrary strengths of interactions (synergistic or antagonistic). It requires mixture effect data for least 1 exposure concentration of the mixture in which fractions of all components and concentration-response functions for each component are known. The GCA model evaluates the interaction between components by introducing a novel response function, which is independent of the response functions for each individual components, to describe the effect of addition between different components. The GCA method was applied to published mixture toxicity data, and it was found to fit the mixture effect better than both the concentration addition model and the independent action model, the implication being that the proposed approach is widely applicable. Environ Toxicol Chem 2017;36:265-275. (c) 2016 SETAC. PMID- 27216970 TI - Entanglement convertibility by sweeping through the quantum phases of the alternating bonds XXZ chain. AB - We study the entanglement structure and the topological edge states of the ground state of the spin-1/2 XXZ model with bond alternation. We employ parity-density matrix renormalization group with periodic boundary conditions. The finite-size scaling of Renyi entropies S2 and Sinfinity are used to construct the phase diagram of the system. The phase diagram displays three possible phases: Haldane type (an example of symmetry protected topological ordered phases), Classical Dimer and Neel phases, the latter bounded by two continuous quantum phase transitions. The entanglement and non-locality in the ground state are studied and quantified by the entanglement convertibility. We found that, at small spatial scales, the ground state is not convertible within the topological Haldane dimer phase. The phenomenology we observe can be described in terms of correlations between edge states. We found that the entanglement spectrum also exhibits a distinctive response in the topological phase: the effective rank of the reduced density matrix displays a specifically large "susceptibility" in the topological phase. These findings support the idea that although the topological order in the ground state cannot be detected by local inspection, the ground state response at local scale can tell the topological phases apart from the non topological phases. PMID- 27216971 TI - The Promise of Direct-to-Consumer Telehealth for Disaster Response and Recovery. AB - Telehealth has great promise to improve and even revolutionize emergency response and recovery. Yet telehealth in general, and direct-to-consumer (DTC) telehealth in particular, are underutilized in disasters. Direct-to-consumer telehealth services allow patients to request virtual visits with health care providers, in real-time, via phone or video conferencing (online video or mobile phone applications). Although DTC services for routine primary care are growing rapidly, there is no published literature on the potential application of DTC telehealth to disaster response and recovery because these services are so new. This report presents several potential uses of DTC telehealth across multiple disaster phases (acute response, subacute response, and recovery) while noting the logistical, legal, and policy challenges that must be addressed to allow for expanded use. Uscher-Pines L , Fischer S , Chari R . The promise of direct-to consumer telehealth for disaster response and recovery. Prehosp Disaster Med. 2016;31(4):454-456. PMID- 27216972 TI - Rice bran proteins and their hydrolysates modulate cholesterol metabolism in mice on hypercholesterolemic diets. AB - The hypolipidemic properties of defatted rice bran protein (DRBP), fresh rice bran protein (FRBP), DRBP hydrolysates (DRBPH), and FRBP hydrolysates (FRBPH) were determined in mice on high fat diets for four weeks. Very low-density lipoprotein cholesterol (VLDL-C), low-density lipoprotein cholesterol (LDL-C) contents, and the hepatic total cholesterol content were reduced while fecal total cholesterol and total bile acid (TBA) contents were increased in the FRBPH diet group. The expression levels of hepatic genes for cholesterol biosynthesis HMG-CoAR and SREBP-2 were lowest in the FRBPH diet group. The mRNA level of HMG CoAR was significantly positively correlated with the hepatic TG content (r = 0.82, P < 0.05). The mRNA levels of genes related to bile acid biosynthesis and cholesterol efflux, CYP7A1, ABCA1, and PPARgamma were up-regulated in all test groups. The results suggest that FRBPH regulates cholesterol metabolism in mice fed the high fat and cholesterol diet by increasing fecal steroid excretion and expression levels of genes related to bile acid synthesis and cholesterol efflux, and the down-regulation of the expression levels of genes related to cholesterol biosynthesis. PMID- 27216973 TI - Epidemiology of endometriosis and its comorbidities. AB - Genetic profile, inflammation, hormonal activity, menstrual cyclicity, organochlorine burden, prostaglandin metabolism and immunological factors have been suggested to play a role in the establishment and development of endometriosis. From the epidemiological perspective, several risk factors have been studied to suggest or support the different aetiological hypotheses. Social class and family history apart, the factors most consistently associated with endometriosis are early age at menarche and long and heavy menstrual cycles. These menstrual characteristics (together with nulliparity) reflect increased exposure to menstruation. The other main risk factors are pigmentary traits and sun habits, alcohol intake, use of oral contraceptives, and environmental factors such as exposure to polychlorinated biphenyls and dioxin. All of these factors support a potential role of hormonal mileau and inflammation in the pathogenesis of endometriosis. There is a clear association between endometriosis and gastrointestinal and immunological diseases, ovarian cancer and other gynaecological cancers, and thyroid cancer. PMID- 27216974 TI - Autistic traits and attention to speech: Evidence from typically developing individuals. AB - Individuals with autism spectrum disorder have a preference for attending to non speech stimuli over speech stimuli. We are interested in whether non-speech preference is only a feature of diagnosed individuals, and whether we can we test implicit preference experimentally. In typically developed individuals, serial recall is disrupted more by speech stimuli than by non-speech stimuli. Since behaviour of individuals with autistic traits resembles that of individuals with autism, we have used serial recall to test whether autistic traits influence task performance during irrelevant speech sounds. The errors made on the serial recall task during speech or non-speech sounds were counted as a measure of speech or non-speech preference in relation to no sound condition. We replicated the serial order effect and found the speech to be more disruptive than the non-speech sounds, but were unable to find any associations between the autism quotient scores and the non-speech sounds. Our results may indicate a learnt behavioural response to speech sounds. PMID- 27216976 TI - Recurrent episodes of periorbital edema in an elderly woman. PMID- 27216975 TI - Identification and functional analysis of two novel connexin 50 mutations associated with autosome dominant congenital cataracts. AB - Autosomal dominant congenital cataracts (ADCC) are clinically and genetically heterogeneous diseases. The present study recruited two Chinese families with bilateral nuclear cataract or zonular pulverulent phenotype. Direct sequencing of candidate genes identified two novel missense mutations of Cx50, Cx50P59A (c.175C > G) and Cx50R76H (c.227G > A), both co-segregated well with all affected individuals. Bioinformatics analysis predicted deleterious for both mutations. Functional and cellular behaviors of wild type and mutant Cx50 examined by stably transfecting recombinant systems revealed similar protein expression levels. Protein distribution pattern by fluorescence microscopy showed that Cx50R76H localized at appositional membranes forming gap junctions with enormous cytoplasmic protein accumulation, whereas the Cx50P59A mutation was found inefficient at forming detectable plaques. Cell growth test by MTT assay showed that induction of Cx50P59A decreased cell viability. Our study constitutes the first report that the Cx50P59A and Cx50R76H mutations are associated with ADCC and expands the mutation spectrum of Cx50 in association with congenital cataracts. The genetic, cellular, and functional data suggest that the altered intercellular communication governed by mutated Cx50 proteins may act as the molecular mechanism underlying ADCC, which further confirms the role of Cx50 in the maintenance of human lens transparency. PMID- 27216977 TI - Novel effects of sphingosylphosphorylcholine on invasion of breast cancer: Involvement of matrix metalloproteinase-3 secretion leading to WNT activation. AB - Sphingosylphosphorylcholine (SPC) participates in several cellular processes including metastasis. SPC induces keratin reorganization and regulates the viscoelasticity of metastatic cancer cells including PANC-1 cancer cells leading to enhanced migration and invasion. The role of SPC and the relevant mechanism in invasion of breast cell are as yet unknown. SPC dose-dependently induces invasion of breast cancer cells or breast immortalized cells. Reverse transcription polymerase chain reaction and Western blot analyses of MCF10A and ZR-75-1 cells indicated that SPC induces expression and secretion of matrix metalloproteinase-3 (MMP3). From online KMPLOT, relapse free survival is high in patients having low MMP3 expressed basal breast cancer (n=581, p=0.032). UK370106 (MMP3 inhibitor) or gene silencing of MMP3 markedly inhibited the SPC-induced invasion of MCF10A cells. An extracellular signal-regulated kinase (ERK) inhibitor, PD98059, significantly suppressed the secretion and the gelatinolytic activity of MMP3, and invasion in MCF10A cells. Over-expression of ERK1 and ERK2 promoted both the expression and secretion of MMP3. In contrast, gene silencing of ERK1 and ERK2 attenuated the secretion of MMP3 in MCF10A cells. The effects of SPC-induced MMP3 secretion on beta-catenin and TCF/lymphoid enhancer factor (LEF) promoter activity were examined since MMP3 indirectly activates canonical Wnt signaling. SPC induced translocation of beta-catenin to nucleus and increased TCF/LEF promoter activity. These events were suppressed by UK370106 or PD98059. Wnt inhibitor, FH535 inhibited SPC-induced MMP3 secretion and invasion. Taken together, these results suggest that SPC induces MMP3 expression and secretion via ERK leading to Wnt activation. PMID- 27216978 TI - Impact of Dyrk1A level on alcohol metabolism. AB - Alcoholic liver diseases arise from complex phenotypes involving many genetic factors. It is quite common to find hyperhomocysteinemia in chronic alcoholic liver diseases, mainly due to deregulation of hepatic homocysteine metabolism. Dyrk1A, involved in homocysteine metabolism at different crossroads, is decreased in liver of hyperhomocysteinemic mice. Here, we hypothesized that Dyrk1A contributes to alcohol-induced hepatic impairment in mice. Control, hyperhomocysteinemic and mice overexpressing Dyrk1A were fed using a Lieber DeCarli liquid diet with or without ethanol (5% v/v ethanol) for one month, and liver histological examination and liver biochemical function tests were performed. Plasma alanine aminotransferase and homocysteine levels were significantly decreased in mice overexpressing Dyrk1A compared to control mice with or without alcohol administration. On the contrary, the mean plasma alanine aminotransferase and homocysteine levels were significantly higher in hyperhomocysteinemic mice than that of control mice after alcohol administration. Paraoxonase 1 and CYP2E1, two phase I xenobiotic metabolizing enzymes, were found increased in the three groups of mice after alcohol administration. However, NQO1, a phase II enzyme, was only found increased in hyperhomocysteinemic mice after alcohol exposure, suggesting a greater effect of alcohol in liver of hyperhomocysteinemic mice. We observed positive correlations between hepatic alcohol dehydrogenase activity, Dyrk1A and ADH4 protein levels. Importantly, a deleterious effect of alcohol consumption on hepatic Dyrk1A protein level was found. Our study reveals on the one hand a role of Dyrk1A in ethanol metabolism and on the other hand a deleterious effect of alcohol administration on hepatic Dyrk1A level. PMID- 27216980 TI - Cytokine-induced killer cells interact with tumor lysate-pulsed dendritic cells via CCR5 signaling. AB - The antitumor activity of cytokine-induced killer (CIK) cells can be increased by co-culturing them with tumor lysate-pulsed dendritic cells (tDCs); this phenomenon has been studied mainly at the population level. Using time-lapse imaging, we examined how CIK cells gather information from tDCs at the single cell level. tDCs highly expressed CCL5, which bound CCR5 expressed on CIK cells. tDCs strongly induced migration of Ccr5(+/+) CIK cells, but not that of Ccr5(-/-) CIK cells or Ccr5(+/+) CIK cells treated with the CCR5 antagonist Maraviroc. Individual tDCs contacted Ccr5(+/+) CIK cells more frequently and lengthily than with Ccr5(-/-) CIK cells. Consequently, tDCs increased the antitumor activity of Ccr5(+/+) CIK cells in vitro and in vivo, but did not increase that of Ccr5(-/-) CIK cells. Taken together, our data provide insight into the mechanism of CIK cell activation by tDCs at the single-cell level. PMID- 27216979 TI - Antitumor effect of FGFR inhibitors on a novel cholangiocarcinoma patient derived xenograft mouse model endogenously expressing an FGFR2-CCDC6 fusion protein. AB - Cholangiocarcinoma is a highly lethal cancer with limited therapeutic options. Recent genomic analysis of cholangiocarcinoma has revealed the presence of fibroblast growth factor receptor 2 (FGFR2) fusion proteins in up to 13% of intrahepatic cholangiocarcinoma (iCCA). FGFR fusions have been identified as a novel oncogenic and druggable target in a number of cancers. In this study, we established a novel cholangiocarcinoma patient derived xenograft (PDX) mouse model bearing an FGFR2-CCDC6 fusion protein from a metastatic lung nodule of an iCCA patient. Using this PDX model, we confirmed the ability of the FGFR inhibitors, ponatinib, dovitinib and BGJ398, to modulate FGFR signaling, inhibit cell proliferation and induce cell apoptosis in cholangiocarcinoma tumors harboring FGFR2 fusions. In addition, BGJ398 appeared to be superior in potency to ponatinib and dovitinib in this model. Our findings provide a strong rationale for the investigation of FGFR inhibitors, particularly BGJ398, as a therapeutic option for cholangiocarcinoma patients harboring FGFR2 fusions. PMID- 27216981 TI - Aquaporin 9 is down-regulated in hepatocellular carcinoma and its over-expression suppresses hepatoma cell invasion through inhibiting epithelial-to-mesenchymal transition. AB - Aquaporin 9 (AQP9) is the main aquaglyceroporin in the liver. Few studies have been performed regarding the role of AQP9 in hepatocellular carcinoma (HCC). Here, we report the expression and function of AQP9 in HCC tissues and cell lines. We found that AQP9 mRNA and protein levels were down-regulated in HCC tissues and human hepatoma cell lines compared to the para-cancer normal liver tissues and normal hepatocyte line, respectively. In a human HCC SMMC-7721 cell line, over-expression of AQP9 suppressed cell invasion in vitro and xenograft tumor growth in vivo. AQP9 over-expression increased the expression of E-cadherin and decreased the expression of N-cadherin in SMMC-7721 cells and xenografted tumors, which was correlated with decreased levels of phosphoinositide 3-kinase (PI3K) and p-Akt. Conversely, using siRNA to knock down AQP9 over-expression could reverse the phenotype caused by AQP9 over-expression. Our findings suggest that AQP9 is down-regulated in hepatocellular carcinoma and its over-expression suppresses hepatoma cell invasion through inhibiting epithelial-to-mesenchymal transition. PMID- 27216983 TI - Implicit theories of smoking and association with current smoking status. AB - Implicit theories of smoking refer to people's beliefs about whether smoking behavior is something that is changeable (incremental belief) or fixed (entity belief). This study examines implicit theories of smoking and its association with smoking behavior in a nationally representative sample of US adults using data from the Health Information National Trends Survey. The current results show that implicit theories of smoking are associated with smoking. Among former smokers, 90 percent endorsed an incremental belief about smoking compared to 70 percent of current smokers. Our study provides initial evidence for the role of implicit theories of smoking as a psychological factor associated with smoking behavior. PMID- 27216982 TI - Cancer-associated fibroblasts promote hepatocellular carcinoma metastasis through chemokine-activated hedgehog and TGF-beta pathways. AB - Fibroblasts are rich in the surrounding microenvironment of hepatocellular carcinoma (HCC) because most HCCs occur in fibrotic or cirrhotic livers. However, the role of cancer-associated fibroblasts (CAFs) in HCC metastasis remains obscure. Here, we reported that CAFs promote the migration and invasion of HCC cells in vitro and facilitate the HCC metastasis to the bone, brain and lung in NOD/SCID mice. The RayBio human chemokine antibody array revealed that CAFs secret higher levels of CCL2, CCL5, CCL7 and CXCL16 than peri-tumor fibroblasts. CCL2 and CCL5 increase the migration but not the invasion of HCC cells, while CCL7 and CXCL16 promote both migration and invasion of HCC cells. Moreover, CCL2 and CCL5 stimulate the activation of the hedgehog (Hh) pathway, while CCL7 and CXCL16 enhance the activity of the transforming growth factor-beta (TGF-beta) pathway in HCC cells. The neutralizing antibodies of chemokines notably attenuate the effect of CAFs on HCC metastasis and compromised the activation of Hh and TGF beta pathways in HCC cells. In summary, CAF-secreted CCL2, CCL5, CCL7 and CXCL16 promote HCC metastasis through the coordinate activation of Hh and TGF-beta pathways in HCC cells. PMID- 27216984 TI - A pilot randomised test of a self-affirmation implementation intention intervention to reduce dietary salt intake. AB - Self-affirmation may reduce defensive processing towards health messages. We tested the effects of a self-affirmation implementation intentional intervention with regard to salt risk message acceptance, estimates of daily-recommended intake and self-reported intake. Participants ( n = 65) who consumed over 6 g/day of salt were randomised into three conditions: self-affirmation, self-affirming implementation intention and control. Participants attended the laboratory and completed a 2-week follow-up. There was no effect of the condition on message acceptance, salt estimation and 2-week salt intake. Across conditions, 2-week salt intake was reduced. We found no evidence for either intervention with regard to salt risk message acceptance and behaviour change. PMID- 27216986 TI - The Electrostatic Screening Length in Concentrated Electrolytes Increases with Concentration. AB - According to classical electrolyte theories interactions in dilute (low ion density) electrolytes decay exponentially with distance, with the Debye screening length the characteristic length scale. This decay length decreases monotonically with increasing ion concentration due to effective screening of charges over short distances. Thus, within the Debye model no long-range forces are expected in concentrated electrolytes. Here we reveal, using experimental detection of the interaction between two planar charged surfaces across a wide range of electrolytes, that beyond the dilute (Debye-Huckel) regime the screening length increases with increasing concentration. The screening lengths for all electrolytes studied-including aqueous NaCl solutions, ionic liquids diluted with propylene carbonate, and pure ionic liquids-collapse onto a single curve when scaled by the dielectric constant. This nonmonotonic variation of the screening length with concentration, and its generality across ionic liquids and aqueous salt solutions, demonstrates an important characteristic of concentrated electrolytes of substantial relevance from biology to energy storage. PMID- 27216985 TI - Megalencephaly-capillary malformation polymicrogyria: A review and complex pediatric case report. AB - Megalencephaly-Capillary Malformation Polymicrogyria (M-CAP) is a rare genetic disorder characterized by a spectrum of anomalies including macrocephaly and neurovascular malformations. Although developmental delays have been identified, research is devoid of neuropsychological data. This case report presents the neuropsychological profile of a 7-year-old, identified with M-CAP. Neuropsychological evaluation was completed subsequent to medical diagnosis. Reports from both parents and teachers included cognitive regression; specifically in the recall of learned material, reading, and information sequencing. Direct testing revealed a WISC-IV GAI at <1st percentile, a diverse range of scores across the battery, and a splinter skill strength of average to above on visual memory tests. Performance included below grade level reading and writing, reduced adaptive functioning, and reported executive dysfunction. Her strong visual memory skills were recommended as a medium to enhance learning. Neurocognitive deficits revealed diverse, multisystem and multifocal impairments. The neuropsychological evaluation also showed significant decline from the previous evaluation and prompted a neurologic consult and corrective surgical procedure. PMID- 27216987 TI - N(6)-Methyladenosine Methyltransferases and Demethylases: New Regulators of Stem Cell Pluripotency and Differentiation. AB - The discovery of mammalian N(6)-methyladenosine (m(6)A) methyltransferases and demethylases has enriched our knowledge of the dynamic regulation of the most prevalent posttranscriptional RNA modification, m(6)A methylation. This reversible methylation process of adding and removing m(6)A marks on RNA has been shown to have broad biological functions in fine tuning cellular processes and gene expression. Recent studies have revealed a critical role for the currently known m(6)A methyltransferases and demethylases in regulating the pluripotency and differentiation of stem cells. These data establish a novel dimension in epigenetic regulation at the RNA level to affect mammalian cell fate. PMID- 27216988 TI - The nucleo-junctional interplay of the cellular prion protein: A new partner in cancer-related signaling pathways? AB - The cellular prion protein PrP(c) plays important roles in proliferation, cell death and survival, differentiation and adhesion. The participation of PrP(c) in tumor growth and metastasis was pointed out, but the underlying mechanisms were not deciphered completely. In the constantly renewing intestinal epithelium, our group demonstrated a dual localization of PrP(c), which is targeted to cell-cell junctions in interaction with Src kinase and desmosomal proteins in differentiated enterocytes, but is predominantly nuclear in dividing cells. While the role of PrP(c) in the dynamics of intercellular junctions was confirmed in other biological systems, we unraveled its function in the nucleus only recently. We identified several nuclear PrP(c) partners, which comprise gamma-catenin, one of its desmosomal partners, beta-catenin and TCF7L2, the main effectors of the canonical Wnt pathway, and YAP, one effector of the Hippo pathway. PrP(c) up regulates the activity of the beta-catenin/TCF7L2 complex and its invalidation impairs the proliferation of intestinal progenitors. We discuss how PrP(c) could participate to oncogenic processes through its interaction with Wnt and Hippo pathway effectors, which are controlled by cell-cell junctions and Src family kinases and dysregulated during tumorigenesis. This highlights new potential mechanisms that connect PrP(c) expression and subcellular redistribution to cancer. PMID- 27216989 TI - A transfectant RK13 cell line permissive to classical caprine scrapie prion propagation. AB - To assess scrapie infectivity associated with caprine-origin tissues, bioassay can be performed using kids, lambs or transgenic mice expressing caprine or ovine prion (PRNP) alleles, but the incubation periods are fairly long. Although several classical ovine scrapie prion permissive cell lines with the ability to detect brain-derived scrapie prion have been available, no classical caprine scrapie permissive cell line is currently available. Therefore, the aims of this study were to generate a rabbit kidney epithelial cell line (RK13) stably expressing caprine wild-type PRNP (cpRK13) and then to assess permissiveness of cpRK13 cells to classical caprine scrapie prion propagation. The cpRK13 and plasmid control RK13 (pcRK13) cells were incubated with brain-derived classical caprine scrapie inocula prepared from goats or ovinized transgenic mice (Tg338, express ovine VRQ allele) infected with caprine scrapie. Significant PrP(Sc) accumulation, which is indicative of scrapie prion propagation, was detected by TSE ELISA and immunohistochemistry in cpRK13 cells inoculated with classical caprine scrapie inocula. Western blot analysis revealed the typical proteinase K resistant 3 PrP(res) isoforms in the caprine scrapie prion inoculated cpRK13 cell lysate. Importantly, PrP(Sc) accumulation was not detected in similarly inoculated pcRK13 cells, whether by TSE ELISA, immunohistochemistry, or western blot. These findings suggest that caprine scrapie prions can be propagated in cpRK13 cells, thus this cell line may be a useful tool for the assessment of classical caprine prions in the brain tissues of goats. PMID- 27216990 TI - Comparison of Aqueous Humor Nitric Oxide Levels After Different Corneal Collagen Cross-Linking Methods. AB - PURPOSE: Nitric oxide production can cause either apoptotic or necrotic cell death through oxidative stress. We aimed to investigate the nitrite oxide metabolites (NOx) and nitrite levels in the aqueous humor of rabbit eyes after different methods of corneal collagen cross-linking (CXL). MATERIALS AND METHODS: Twenty-four eyes of 12 adult New Zealand rabbits were used. They were assigned into four groups, each including six eyes. Group 1 (control) consisted of eyes with no treatment. Group 2 received UV-A power setting at 3 mW/cm2 for 30 minutes of continuous exposure and named as standard CXL group. Group 3 received UV-A power setting at 30 mW/cm2 for 3 minutes of continuous exposure and named as accelerated CXL (A-CXL) group. Group 4 received UV-A power setting at 30 mW/cm2 for 6 minutes of pulsed exposure (1 sec on, 1 sec off) and named as pulse-light accelerated CXL (PLA-CXL). Aqueous humors were aspirated from anterior chamber with a 27G needle after 1 hour UV-A exposure. NOx and nitrite levels were measured Results: The nitrite levels in aqueous humor were significantly increased in Group 2 and Group 3 when compared with Group 1 (p = 0.000, p = 0.036, respectively). When treatment modalities were compared with each other, high nitrite level in Group 2 was statistically significant when compared with Group 4 (p = 0.019). NOx levels were higher in Group 2 when compared with Group 1 (p = 0.006). CONCLUSIONS: Numerous studies investigated the physiological and pathophysiological roles of NO. NO is considered one of the most important molecule for ocular health. According to NOx level in aqueous humor, it seems that PLA-CXL is the safest method due to the similar results with control group. PMID- 27216991 TI - Synthesis of meta-substituted [(18)F]3-fluoro-4-aminopyridine via direct radiofluorination of pyridine N-oxides. AB - Due to their electron-rich aromatic structure, nucleophilic (radio)fluorination of pyridines is challenging, especially at the meta position. In this paper, we describe the first example of direct fluorination of a pyridine N-oxide to produce a meta fluorinated pyridine. Specifically, fluorination of 3-bromo-4 nitropyridine N-oxide produced in several minutes 3-fluoro-4-nitropyridine N oxide in moderate yield at room temperature. This intermediate compound was later converted to 3-fluoro-4-aminopyridine easily by catalytic hydrogenation. Furthermore, this approach was successfully applied for labeling with fluorine 18. The use of pyridine N-oxides for the preparation of fluoropyridines is unprecedented in the chemical literature and has the potential to offer a new way for the synthesis of these important structures in pharmaceuticals and radiopharmaceuticals. PMID- 27216992 TI - Predictors of non-adherence to prescribed prophylactic clotting-factor treatment regimens among adolescent and young adults with a bleeding disorder. AB - INTRODUCTION: Adherence to clotting-factor treatment regimens, especially among adolescents and young adults (AYAs), is under-researched. AIM: We determined factors associated with better adherence to prophylaxis. METHODS: From April through December 2012, a convenience sample of AYA (aged 13-25 years) persons with haemophilia or von Willebrand disease (VWD) completed an online survey that assessed adherence to prescribed prophylactic treatment regimens [Validated Haemophilia Regimen Treatment Adherence Scale (VERITAS)-Pro]. Logistic regression analysis assessed demographic and clinical factors related to non-adherence (VERITAS-Pro>=57). RESULTS: Seventy-three prophylactically treating AYAs participated. Of which, 88%, 8% and 4% had haemophilia A, B and VWD respectively. Almost all (90%) had severe disease and 58% had never developed an inhibitor. Most were aged 13-17 years (56%), white (78%), non-Hispanic (88%), never married (94%) and had some type of health insurance (96%). Median VERITAS-Pro score was 48 (range = 25-78) and 22 (30%) participants were non-adherent to prophylaxis (VERITAS-Pro>=57). Final logistic regression modelling suggested that, compared to those aged 13-17 years, participants aged 18-25 years were 6.2 (95% CI: 1.8 21.0; P < 0.01) times more likely to be non-adherent. Compared to respondents whose mother had at least a Bachelor's degree, respondents whose mother did not were 3.8 (95% CI: 1.0-14.3; P = 0.05) times more likely to be non-adherent. CONCLUSIONS: Results suggest that adherence efforts should be especially targeted to young adults as they transition from adolescence (i.e. parental supervision) and assume primary responsibility for their bleeding disorder care. Healthcare providers should be mindful of AYAs whose mothers have less formal education and ensure that adequate time and resources are dedicated to family adherence education. PMID- 27216993 TI - On the Mechanism of Copper(I)-Catalyzed Azide-Alkyne Cycloaddition. AB - The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction regiospecifically produces 1,4-disubstituted-1,2,3-triazole molecules. This heterocycle formation chemistry has high tolerance to reaction conditions and substrate structures. Therefore, it has been practiced not only within, but also far beyond the area of heterocyclic chemistry. Herein, the mechanistic understanding of CuAAC is summarized, with a particular emphasis on the significance of copper/azide interactions. Our analysis concludes that the formation of the azide/copper(I) acetylide complex in the early stage of the reaction dictates the reaction rate. The subsequent triazole ring-formation step is fast and consequently possibly kinetically invisible. Therefore, structures of substrates and copper catalysts, as well as other reaction variables that are conducive to the formation of the copper/alkyne/azide ternary complex predisposed for cycloaddition would result in highly efficient CuAAC reactions. Specifically, terminal alkynes with relatively low pKa values and an inclination to engage in pi-backbonding with copper(I), azides with ancillary copper-binding ligands (aka chelating azides), and copper catalysts that resist aggregation, balance redox activity with Lewis acidity, and allow for dinuclear cooperative catalysis are favored in CuAAC reactions. Brief discussions on the mechanistic aspects of internal alkyne-involved CuAAC reactions are also included, based on the relatively limited data that are available at this point. PMID- 27216994 TI - Biochemical and electrophysiological characterization of N-glycans on NMDA receptor subunits. AB - In mammals, excitatory synapses contain two major types of ionotropic glutamate receptors: alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and N-methyl-d-aspartate receptors (NMDARs). Both receptor types are comprised of several subunits that are post-translationally modified by N-glycosylation. However, the precise N-glycans that are attached to these receptor types are largely unknown. Here, we used biochemistry to confirm that native NMDARs are extensively N-glycosylated; moreover, we found that the NMDAR GluN2B subunit differs from GluN1 subunits with respect to endoglycosidase H sensitivity. Next, we used a complete panel of lectins to determine the glycan composition of NMDARs in both cerebellar tissue and cultured cerebellar granule cells. Our experiments identified 23 lectins that pulled down both the GluN1 and GluN2B NMDAR subunits. We then performed an electrophysiological analysis using representative lectins and found that pre-incubating cerebellar granule cells with the AAL, WGA, or ConA alters the receptor's biophysical properties; this lectin-mediated effect was eliminated when the cells were deglycosylated with peptide-N-glycosidase F. Similar lectin-mediated effects were observed using HEK293 cells that express recombinant GluN1/GluN2B receptors. Finally, using mutant recombinant GluN subunits expressed in HEK293 cells, we found that 11 out of 12 predicted N glycosylation sites in GluN1 and 7 out of 7 N-glycosylation sites in GluN2B are occupied by N-glycans. These data provide new insight into the role that N glycosylation plays in regulating the function of NMDA receptors in the central nervous system. All animal experiments were performed in accordance with relevant institutional ethics guidelines and regulations with respect to protecting animal welfare. We examined the N-glycan composition of NMDA receptors (NMDARs) using deglycosylating enzymes, lectin-based biochemistry, and electrophysiology. Our results revealed that cerebellar NMDARs associate with 23 different lectins that have unique specificities for glycan structures. Furthermore, we found that 11 out of 12 predicted N-glycosylation sites in GluN1 and 7 out of 7 N-glycosylation sites in GluN2B are occupied by N-glycans. These data shed light on the glycan composition of NMDARs, revealing potential targets for the development of novel therapeutic approaches. PMID- 27216995 TI - Impact of elvitegravir on human adipocytes: Alterations in differentiation, gene expression and release of adipokines and cytokines. AB - Elvitegravir is a recently developed integrase inhibitor used for antiretroviral treatment of HIV infection. Secondary effects, including disturbances in lipid metabolism and, ultimately, in adipose tissue distribution and function, are common concerns associated with antiretroviral treatments. Here, we provide the first study of the effects of elvitegravir (in comparison with efavirenz, a non nucleoside analog inhibitor of reverse transcriptase; and raltegravir, another integrase inhibitor) on human adipocyte differentiation, gene expression and secretion of adipokines and cytokines. Elvitegravir impaired adipogenesis and adipocyte metabolism in human SGBS adipocytes in a concentration-dependent manner (delaying acquisition of adipocyte morphology and reducing the expression of adipogenesis marker genes such as PPARgamma, glucose transporter GLUT4, lipoprotein lipase, and the adipokines adiponectin and leptin). Compared with efavirenz, the effects of elvitegravir were similar but tended to occur at higher concentrations than those elicited by efavirenz, or were somewhat less intense than those caused by efavirenz at similar concentration. Elvitegravir tended to cause a more moderate induction of pro-inflammatory cytokines than efavirenz. Efavirenz induced a marked concentration-dependent increase in interleukin-8 expression and release whereas elvitregravir had little effect. Raltegravir had totally neutral actions of adipogenesis, adipocyte metabolism-related gene expression and release of adipokines and cytokines. In conclusion, elvitegravir alters adipocyte differentiation and function and promotes induction of pro inflammatory cytokines similarly to efavirenz, but several effects were less intense. Further assessment of lipid metabolism and adipose tissue function in patients administered elvitegravir-based regimes is advisable considering that totally neutral effects of elvitegravir on lipid homeostasis cannot be anticipated from the current study in vitro. PMID- 27216996 TI - Effects of tai chi exercise on bone health in perimenopausal and postmenopausal women: a systematic review and meta-analysis. AB - Tai chi exercise may have positive effects on bone health in perimenopausal and postmenopausal women. This systematic review is the first to summarize evidence to clarify the efficacy of tai chi exercise in bone health. The benefits of tai chi exercise on bone health remain unclear; further studies are needed. Emerging randomized controlled trials (RCTs) exploring the efficacy of tai chi exercise on bone health among older women, but yielded inconclusive results. Our objective is to conduct a systematic review to evaluate evidence from RCTs to clarify the efficacy of tai chi exercise on bone mineral density (BMD), and bone turnover markers (BTM) in perimenopausal and postmenopausal women. Six electronic databases were searched, and reference lists of systematic reviews and identified studies from the search strategy were also screened. We included all RCTs that investigate tai chi exercise for bone health in perimenopausal and postmenopausal women. Data selection, extraction, and evaluation of risk of bias were performed independently by two reviewers. Ten trials detailed in 11 articles were included. Six of the 11 studies reported positive outcomes on bone health. Results of our meta-analysis showed a significant effect of tai chi exercise on BMD change at the spine compared with no treatment in perimenopausal and postmenopausal women. When tai chi exercise combined with a calcium supplement was compared with the calcium supplement alone, the result of BMD change at the spine showed no significant effect. Because the measurable effect observed was minimal, and due to the low quality of methodology of the studies, we conclude that the result is of limited reliability. Tai chi exercise may have benefits on bone health in perimenopausal and postmenopausal women, but the evidence is sometimes weak, poor, and inconsistent. Consequently, only limited conclusions can be drawn regarding the efficacy of tai chi exercise on bone health. Further well designed studies with low risk of bias are needed. PMID- 27216998 TI - Caged xanthones: Potent inhibitors of global predominant MRSA USA300. AB - Total of 22 caged xanthones were subjected to susceptibility testing of global epidemic MRSA USA300. Natural morellic acid showed the strongest potency (MIC of 12.5MUM). However, its potent toxicity diminishes MRSA therapeutic potential. We synthetically modified natural morellic acid to yield 13 derivatives (3a-3m). Synthetically modified 3b retained strong potency in MRSA growth inhibition, yet the toxicity was 20-fold less than natural morellic acid, permitting the possibility of using caged xanthones for MRSA therapeutic. PMID- 27216997 TI - Low serum intact parathyroid hormone level is an independent risk factor for overall mortality and major adverse cardiac and cerebrovascular events in incident dialysis patients. AB - Abnormal bone dynamics is a major risk factor for cardiovascular disease in patients with chronic kidney disease. The level of serum intact parathyroid hormone (iPTH) is widely used as a bone dynamic marker. We investigated the effect of the mean level of serum iPTH on overall mortality and cardiovascular outcomes in incident dialysis patients. PURPOSE: Chronic kidney disease-mineral bone disorder (CKD-MBD) is a major risk factor for cardiovascular disease (CVD) in patients with end-stage renal disease (ESRD). CKD-MBD is classified as low- or high-turnover bone disease according to the bone dynamics; both are related to vascular calcification in ESRD. To evaluate the prognostic value of abnormal serum parathyroid hormone (PTH) levels on ESRD patients, we investigated the effects of time-averaged serum intact PTH (TA-iPTH) levels on overall mortality and major adverse cardiac and cerebrovascular events (MACCEs) in incident dialysis patients. METHODS: Four hundred thirteen patients who started dialysis between January 2009 and September 2013 at Yonsei University Health System were enrolled. The patients were divided into three groups according to TA-iPTH levels during the 12 months after the initiation of dialysis: group 1, <65 pg/ml; group 2, 65-300 pg/ml; and group 3, >300 pg/ml. Cox regression analyses were performed to determine the prognostic value of TA-iPTH for overall mortality and MACCEs. RESULTS: The mean age of the patients was 57 +/- 15 years, and 222 patients (54 %) were men. During the median follow-up of 40.8 +/- 29.3 months, 49 patients (12 %) died, and MACCEs occurred in 55 patients (13 %). The multivariate Cox regression analyses demonstrated that a low TA-iPTH level was an independent risk factor for both overall mortality (group 2 as reference; group 1: hazard ratio (HR) = 2.06, 95 % confidence interval (CI) = 1.11-3.83, P = 0.023) and MACCEs (HR = 1.82, 95 % CI = 1.04-3.20, P = 0.036) in incident dialysis patients after adjustment for confounding factors. CONCLUSION: Low serum TA-iPTH is a useful clinical marker of both overall mortality and MACCEs in patients undergoing incident dialysis, mediated by vascular calcification. PMID- 27216999 TI - Protective effect of novel substituted nicotine hydrazide analogues against hypoxic brain injury in neonatal rats via inhibition of caspase. AB - In hypoxic-ischemic injury of the brain of neonates, the level of caspase-3 was found to be aberrantly activated. Its overexpression leads to the alteration of cytoskeleton protein fodrin and loss of DNA repair enzyme which ultimately results in neurological impairment and disability. Concerning this, the present study was intended to develop novel nicotine hydrazide analogues as caspase inhibitors via efficient synthetic route. These compounds were subsequently tested for inhibitory activity against caspase-3 and -7 where they exhibit highly potent activity against caspase-3 revealing compound 5k as most potent inhibitor (IC50=19.4+/-2.5MUM). In Western blot analysis, 5k considerably inhibits the overexpression of caspase-3. The aryl nicotinate of compound 5k, as indicated by molecular docking was found to engage His121 and critical enzyme thiols, i.e., Cys163 of caspase-3 for its potent activity. Moreover, histopathological examination of brain tissues and hippocampus neurons showed that compound 5k considerably improves the brain injury and exert neuroprotective effects in hypoxic-ischemic (HI). In brain homogenate, 5k significantly improves the activity of MDA, SOD, GSH-Px, CAT and T-AOC to exert its beneficial effect against oxidative stress induced by HI injury. PMID- 27217000 TI - Preventive effect of a novel diosgenin derivative on arterial and venous thrombosis in vivo. AB - Current therapy for blood vessel thrombosis has the risk of leading to gastrointestinal bleeding and thrombocytopenia. We previously reported that a new derivative of diosgenin, compound 5, had significant anti-inflammatory activity superior to that of aspirin, prolonged bleeding time, and inhibited platelet aggregation in vitro. In the present study, we investigated the in vivo efficacy and safety of compound 5 using the ferric chloride (FeCl3)-induced arterial and venous thrombosis models in rats as well as its toxicity in mice. Compared with the control rats, those treated with compound 5 showed significantly less adenosine diphosphate (ADP)-induced platelet aggregation and a prolonged activated partial thromboplastin time mediated by the specific regulation of factor VIII. Furthermore, compound 5 significantly reduced the average length and weight of thrombi in both arteries and veins. These findings were similar to those of aspirin at the same dose. The safety evaluation revealed a much lower risk of bleeding and lesser gastric mucosal damage with compound 5 than with the same dose of aspirin. An oral dose of up to 575.5mg/kg showed no toxicity in mice. In conclusion, consistent with our in vitro findings, compound 5 exhibited an in vivo antithrombotic activity that was comparable to aspirin mainly by reducing platelet aggregation and regulating factor VIII, but with fewer side effects. PMID- 27217001 TI - Synthesis and anti-proliferative activity of fluoro-substituted chalcones. AB - A series of novel fluoro-substituted chalcone derivatives have been synthesized. All synthesized compounds were characterized by (1)H nuclear magnetic resonance (NMR), (13)C NMR, and elemental analysis. Their anti-proliferative activities were evaluated against five cancer cells lines, namely, A549, A498, HeLa, A375, and HepG2 using the MTT method. Most of the compounds showed moderate to high activity with IC50 values in the range of 0.029-0.729MUM. Of all the synthesized compounds, 10 and 19 exhibited the most potent anti-proliferative activities against cancer cells, and 10 was identified as the most promising compound. PMID- 27217002 TI - Discovery of novel 7-azaindoles as PDK1 inhibitors. AB - A combined screening strategy using HTS together with focused kinase library and virtual screening led to the identification of diverse chemical series as PDK1 inhibitors. We focused our medicinal chemistry efforts on 7-azaindoles with low micromolar IC50s (e.g., 16: IC50=1.1MUM) in the biochemical PDK1 assay. Our structure-guided optimization efforts considered also PDK1 X-ray structures with weaker binding fragments and resulted in 7-azaindoles with significantly improved biochemical PDK1 potency in the two-digit nanomolar range. However, the most potent analogues only showed moderate activities in a cellular mechanistic assay (42: IC50=2.3MUM) together with either low microsomal stability or low permeability. The described structure-activity relationship together with PDK1 X ray structures and early ADME data provided the basis for our subsequent hit-to lead program. PMID- 27217003 TI - New anti-inflammatory sterols from a gorgonian Pinnigorgia sp. AB - Chemical investigation on the EtOAc-soluble fraction from the MeOH/DCM extract of a gorgonian Pinnigorgia sp. afforded two new sterols, 11-acetoxy-24S-methyl 3beta,5alpha,6alpha-trihydroxy-9,11-secocholest-7-en-9-one (1) and 5beta,6beta epoxy-(22E,24R)-ergosta-8,22-diene-3beta,7beta-diol (2). The structures of sterols 1 and 2 were elucidated on the basis of spectroscopic analysis and by comparison of their spectroscopic data with those of related analogues. Both 1 and 2 were shown to significantly inhibit the accumulation of the pro inflammatory iNOS and COX-2 protein in LPS-stimulated RAW264.7 macrophage cells. PMID- 27217004 TI - Stimuli-responsive magnetic nanoparticles for tumor-targeted bimodal imaging and photodynamic/hyperthermia combination therapy. AB - Despite magnetic nanoparticles having shown great potential in cancer treatment, tremendous challenges related to diagnostic sensitivity and treatment efficacy for clinical application remain. Herein, we designed optimized multifunctional magnetite nanoparticles (AHP@MNPs), composed of Fe3O4 nanoparticles and photosensitizer conjugated hyaluronic acid (AHP), to achieve enhanced tumor diagnosis and therapy. Fe3O4 nanoparticles (MNPs) were synthesized by a facile hydrolysis method. MNPs have higher biocompatibility, controllable particle sizes, and desirable magnetic properties. The fabricated AHP@MNPs have enhanced water solubility (average size: 108.13 +/- 1.08 nm), heat generation properties, and singlet oxygen generation properties upon magnetic and laser irradiation. The AHP@MNPs can target tumors via CD44 receptor-mediated endocytosis, which have enhanced tumor therapeutic effects through photodynamic/hyperthermia-combined treatment without any drugs. We successfully detected tumors implanted in mice via magnetic resonance imaging and optical imaging. Furthermore, we demonstrated the photodynamic/hyperthermia-combined therapeutic efficacy of AHP@MNPs with synergistically enhanced efficacy against cancer. PMID- 27217005 TI - Can repurposing of existing drugs provide more effective therapies for invasive fungal infections? PMID- 27217006 TI - Surgical Approaches to the Nasal Cavity and Sinuses. AB - The nasal cavity and sinuses may be exposed primarily via a dorsal or ventral surgical approach. Surgical planning involves the use of advanced imaging, such as computed tomography or MRI. Surgical treatment of lesions of the nasal cavity usually is limited to benign lesions or can also be used in combination with adjunctive therapy, such as radiation therapy. Extreme caution must be exercised with a dorsal approach to the nasal cavity to avoid complications of inadvertent penetration into the brain case. Gentle tissue handling and careful closure of the mucoperiosteum must be exercised following a ventral approach to minimize the risk of oronasal fistula formation. PMID- 27217007 TI - Ear, Nose, and Throat Conditions: Purpose and Acknowledgment. PMID- 27217008 TI - The role of facial canal diameter in the pathogenesis and grade of Bell's palsy: a study by high resolution computed tomography. AB - INTRODUCTION: The exact etiology of Bell's palsy still remains obscure. The only authenticated finding is inflammation and edema of the facial nerve leading to entrapment inside the facial canal. OBJECTIVE: To identify if there is any relationship between the grade of Bell's palsy and diameter of the facial canal, and also to study any possible anatomic predisposition of facial canal for Bell's palsy including parts which have not been studied before. METHODS: Medical records and temporal computed tomography scans of 34 patients with Bell's palsy were utilized in this retrospective clinical study. Diameters of both facial canals (affected and unaffected) of each patient were measured at labyrinthine segment, geniculate ganglion, tympanic segment, second genu, mastoid segment and stylomastoid foramen. The House-Brackmann (HB) scale of each patient at presentation and 3 months after the treatment was evaluated from their medical records. The paired samples t-test and Wilcoxon signed-rank test were used for comparison of width between the affected side and unaffected side. The Wilcoxon signed-rank test was also used for evaluation of relationship between the diameter of facial canal and the grade of the Bell's palsy. Significant differences were established at a level of p=0.05 (IBM SPSS Statistics for Windows, Version 21.0.; Armonk, NY, IBM Corp). RESULTS: Thirty-four patients - 16 females, 18 males; mean age+/-Standard Deviation, 40.3+/-21.3 - with Bell's palsy were included in the study. According to the HB facial nerve grading system; 8 patients were grade V, 6 were grade IV, 11 were grade III, 8 were grade II and 1 patient was grade I. The mean width at the labyrinthine segment of the facial canal in the affected temporal bone was significantly smaller than the equivalent in the unaffected temporal bone (p=0.00). There was no significant difference between the affected and unaffected temporal bones at the geniculate ganglion (p=0.87), tympanic segment (p=0.66), second genu (p=0.62), mastoid segment (p=0.67) and stylomastoid foramen (p=0.16). We did not find any relationship between the HB grade and the facial canal diameter at the level of labyrinthine segment (p=0.41), tympanic segment (p=0.12), mastoid segment (p=0.14), geniculate ganglion (p=0.13) and stylomastoid foramen (p=0.44), while we found significant relationship at the level of second genu (p=0.02). CONCLUSION: We found the diameter of labyrinthine segment of facial canal as an anatomic risk factor for Bell's palsy. We also found significant relationship between the HB grade and FC diameter at the level of second genu. Future studies (MRI-CT combined or 3D modeling) are needed to promote this possible relevance especially at second genu. Thus, in the future it may be possible to selectively decompress particular segments in high grade BP patients. PMID- 27217010 TI - [Dosing Schedules and Outcomes in Patients Treated with First-Line Sunitinib for Advanced Renal Cell Carcinoma]. AB - The objective of this study was to determine whether alternative sunitinib schedules (AS) could prolong survival of patients with advanced renal cell carcinoma (RCC) compared to the traditional 4-weeks-on/2- weeks-off schedule (TS). Between August 2008 and December 2014, 58 patients with advanced RCC were treated with sunitinib. We retrospectively reviewed the records of the patients who received first-line sunitinib. The progression-free survival, overall survival, relative dose intensity and toxicity in the AS and TS groups were compared. A total of 38 patients were included in the analysis. AS was used for 22 patients who started to receive sunitinib beginning in December 2012. For these patients, sunitinib was administered with a 2-weeks-on/1-week-off, 2-weeks on/2-weeks-off or 2-weeks-on/3-weeks-off schedule according to the adverse events and clinical characteristics of each patient. The median progression-free survival was 5 months (95% CI: 3-7) for TS compared to 12 months (95% CI: 7-17) for AS (p=0.0020). The median overall survival was 17 months (95% CI: 10-20) for TS compared to 57 months (95% CI: 25-57) for AS (p=0.0006). There was no significant difference between the TS and AS groups (64% versus 71%). The incidence of Grade >=3 thrombocytopenia in the AS group was smaller than that in the TS group (44% versus 27%). Treatment with sunitinib using AS may provide a better outcome than that with TS. Prospective, randomized trials should be conducted to confirm this speculation. PMID- 27217009 TI - Prevalence of dizziness in the population of Minas Gerais, Brazil, and its association with demographic and socioeconomic characteristics and health status. AB - INTRODUCTION: The state of Minas Gerais, Brazil has no data on the prevalence of dizziness in the population and this information can be fundamental as the basis of public health policies, promotion, prevention and rehabilitation campaigns. OBJECTIVE: Investigate the prevalence of the symptom of dizziness in the population of Minas Gerais according to Sample Survey of Households, as well as describe the profile of interviewed individuals and the association between dizziness and socioeconomic, demographic features and health status. METHODS: This was a cross-sectional observational study that analyzed individuals with dizziness symptom reported in the previous month. The data entered in the Sample Survey of Households of 2011 were analyzed. An independent statistical association was determined between the selected variables and dizziness through multivariate analysis. RESULTS: Dizziness was the third major complaint among individuals who mentioned any health problems in the previous month, with an estimated population of 209,025 individuals and reported by 6.7% of symptomatic ones, with higher prevalence values only reported for the symptoms of fever and headache. Among individuals who reported dizziness, 94% were adults or elderly (p<=0.001) and 63% were females (p=0.003). A statistically significant association (p<0.001) was observed between the response variable and the variables: self-perceived health, hypertension, heart disease, diabetes, depression, seeking or requiring medical or health care in the previous month and private health care plan or insurance. Among individuals with dizziness, 84.2% sought or required medical or health care and 80.1% did not have a private health plan or insurance in the assessed period. CONCLUSION: The dizziness symptom was highly prevalent in the population of Minas Gerais during the assessed month of the investigation. Dizziness was prevalent in adults and the elderly and showed a statistical association with socioeconomic and demographic characteristics, as well as the assessed health status. PMID- 27217011 TI - [Have Case Loads of Radical Surgery for Prostate Cancer Been Concentrated in Hospitals with Robotic Equipment ?--Analyses with Questionnaire Survey and Diagnostic Procedure Combination (DPC) Data]. AB - We investigated whether installation of robot-assisted surgical equipment in hospitals resulted in concentration of the case loads of radical prostatectomy. We selected 11 areas with populations of around 1 million or more where there were one or more hospitals with robotic equipment and 4 or more without it. In addition, annual changes of case loads for prostatectomy over 4 years from 2010 to 2013 were clearly determined in these areas. The case loads were determined based on the results of a questionnaire survey for the hospitals with robots and on the Diagnostic Procedures Combination data provided by the Ministry of Health, Labor and Wealth for those without such equipment. The concentration of the case loads was principally defined as when hospitals with robots had more predominant proportion of cases than those without them in the comparison between case loads prior to instillation of robots (or in the initial year of the study) and those in the final years. The 11 selected areas included 44 hospitals with robots and 156 without them. Concentration of case loads was found in 5 areas. In 4 areas, installation of robots did not have a specific relation to the distribution pattern s of case loads in hospitals with or without the equipment. The remaining 2 areas tended to have a weak but not definite concentration of case loads. In the areas in which installation did not influence case loads the further analysis revealed that their case loads had already been concentrated in the initial year (2010) of the study. Although the current results were found in a single department of the hospital, robotic installation may result in concentration of prostatectomy case loads for such hospitals in some areas. The current results are intriguing when we consider the future roles of acute care hospitals and beds in our country where the number of aged patients having chronic diseases will increase. In conclusion, installation of robotic equipment may result in concentration of prostatectomy case loads in some areas. PMID- 27217012 TI - [Two Cases of Oncocytic Papillary Renal Cell Carcinoma]. AB - Oncocytic papillary renal cell carcinoma isa variant of papillary renal cell carcinoma (PRCC). We herein report two cases treated with retroperitoneoscopic partial nephrectomy. Histologically, tumor cells of both cases exhibit round and regular nuclei with CK7 positive areas in the cytoplasm typical of TYPE1 PRCC and eosinophilic granular cytoplasm with E-cadherin positive areas in the cytoplasmic membrane, which indicates TYPE2 PRCC. Out of 46 cases reported in the literature, only one died of disease, which reveals its low malignant potential. PMID- 27217013 TI - [Laparoscopic Nephrectomy in Infant with Diamond Blackfan Syndrome]. AB - An 8-month-old girl with Diamond Blackfan syndrome and idiopathic neutropenia needed steroid therapy for anemia, but the left multicystic dysplastic kidney was often infected. We performed laparoscopic nephrectomy for infection control without any complications. Neutrocytes increased and the infection decreased after nephrectomy even with steroid therapy. Finally, she underwent bone marrow transplantation, as the anemia was not responding to steroid therapy. PMID- 27217014 TI - [Possible Diagnosis of Segmental Ureteritis Due to an IgG4-Related Disease that Improved with Steroid Therapy]. AB - A 70-year-old woman was referred to our department after being diagnosed with right hydronephrosis on the basis of computed tomography (CT). CT and magnetic resonance imaging results indicated circumferential wall thickening in the right middle ureter. A retrograde pyelogram revealed an approximately 20 mm stricture in the right middle ureter, and urine cytology results were pseudo-positive. Ureteroscopy was performed due to suspicion of a malignant tumor of the urinary tract, but no malignant lesions were found. Biopsy results showed only the pathology of nonspecific ureteritis, and a diagnosis could not be made even with immunostaining. The patient's blood IgG4 levels were high (317 mg/dl). Based on the diagnostic criteria, the patient was given a possible diagnosis of an IgG4 related disease and treated by the placement ofa ureteral stent and administration of steroid therapy. After starting treatment, blood IgG4 levels decreased and the imaging findings showed improvement. The ureteral stent was removed in the 12th week, and steroid administration was discontinued in the 14th week. No recurrence has since been noted. PMID- 27217015 TI - [A Case of Inflammatory Myofibroblastic Tumor of Urinary Bladder]. AB - A 61-year-old man presenting with voiding pain was diagnosed with a bladder tumor by ultrasound in another hospital, and was subsequently referred to our hospital. Cystoscopy showed a nodular tumor and surrounding edematous mucosa in the right wall of the bladder. Initially, we suspected bladder invasion of gastrointestinal malignancy, but abdominal computed tomography, magnetic resonance imaging, and a series of tumor marker tests revealed no abonormalities. We performed transurethral resection of the bladder tumor under the clinical diagnosis of a submucosal tumor originating from the bladder wall. Histopathological examination revealed spindle cell proliferation, which was positively stained with anti anaplastic lymphoma kinase (ALK) antibody. Based on the findings, the diagnosis of an inflammatory myofibroblastic tumor (IMT) was made. Therefore, we performed partial cystectomy to reduce the risk of local recurrence. The pathological diagnosis was IMT, and the surgical margins were negative. Bladder IMT is a rare disease, and surgical resection is the only recommended treatment. In the literature, if completely resected, the prognosis of patients with bladder IMT is excellent. Also, in the present case, no recurrence has been detected for over 6 months. PMID- 27217016 TI - [A Case of Spindle Cell Lipoma in the Inguinal Region]. AB - A 68-year-old man presented to our hospital for the first time because of a left inguinal mass that had been gradually enlarging over the past 20 years. At the initial visit, a 10*5 cm, soft, movable mass was detected in the left inguinal region. Magnetic resonance imaging revealed a smoothly shaped, internally heterogeneous tumor, with suppressed areas on a fat-suppressed image. In addition, the tumor showed partial enhancement with gadolinium and it did not continue into the spermatic cord. We performed excision of mass. During surgery, we observed that the tumor was well circumscribed and located on an aponeurosis of the external abdominal oblique muscle; therefore, we inferred it occurred from the subcutaneous tissue. The excised tumor was smoothly shaped and contained yellow and white nodes. On histopathological examination, the tumor was identified as a spindle cell lipoma. PMID- 27217017 TI - In vitro analysis of essential binding sites on the promoter of the Serratia marcescens spn operon with the quorum-sensing receptor SpnR. AB - The N-acylhomoserine lactone (AHL) receptor SpnR is a LuxR family protein that acts as a negative regulator of AHL-dependent quorum sensing (QS). SpnR binds to DNA in Serratia marcescens AS-1 via the spn box; however, the binding affinity of SpnR with the nucleotides on the spn box has not yet been investigated. In this study, we used an spn-box-modified sensor electrode, and quartz crystal microbalance analysis demonstrated a drastic reduction of the uptake of SpnR. The nucleotides G5 and C16 at the AHL-receptor complex-binding site are conserved in Gram-negative bacteria, including the lux box in Vibrio fischeri, the tra box in Agrobacterium tumefaciens, and the spn box in S. marcescens. Indeed, the affinity of SpnR to DNA was reduced to 8% by G5C substitution of the spn box. The affinity of SpnR tagged with maltose-binding protein to the immobilized gene promoter was reduced in the order of C16G and G5C substitutions, which corresponded with previous reports on the lux box. These results suggest that formation of hydrogen bonds at amino acid residues containing guanine at position 5 on a lux-box-like promoter universally contributes to the stability of the receptor complex, whose interaction initiates a sequential QS process in the LuxR family. Biotechnol. Bioeng. 2016;113: 2513-2517. (c) 2016 Wiley Periodicals, Inc. PMID- 27217018 TI - Leaf epidermis images for robust identification of plants. AB - This paper proposes a methodology for plant analysis and identification based on extracting texture features from microscopic images of leaf epidermis. All the experiments were carried out using 32 plant species with 309 epidermal samples captured by an optical microscope coupled to a digital camera. The results of the computational methods using texture features were compared to the conventional approach, where quantitative measurements of stomatal traits (density, length and width) were manually obtained. Epidermis image classification using texture has achieved a success rate of over 96%, while success rate was around 60% for quantitative measurements taken manually. Furthermore, we verified the robustness of our method accounting for natural phenotypic plasticity of stomata, analysing samples from the same species grown in different environments. Texture methods were robust even when considering phenotypic plasticity of stomatal traits with a decrease of 20% in the success rate, as quantitative measurements proved to be fully sensitive with a decrease of 77%. Results from the comparison between the computational approach and the conventional quantitative measurements lead us to discover how computational systems are advantageous and promising in terms of solving problems related to Botany, such as species identification. PMID- 27217019 TI - Metformin attenuates fluctuating glucose-induced endothelial dysfunction through enhancing GTPCH1-mediated eNOS recoupling and inhibiting NADPH oxidase. AB - AIMS: The aim of this study was to investigate whether and how metformin ameliorated endothelial dysfunction induced by fluctuating glucose (FG) in human umbilical vein endothelial cells (HUVECs). METHODS: HUVECs, which were exposed to FG to induce endothelial dysfunction, were incubated with nitric oxide synthase (NOS) inhibitor N-nitro-l-arginine-methyl ester (l-NAME), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin, metformin and/or adenosine monophosphate-activated protein kinase (AMPK) inhibitor compound C. The oxidative stress and endothelial NOS (eNOS) coupling were evaluated. RESULTS: FG induced endothelial dysfunction as indicated by increased reactive oxygen species (ROS) generation and decreased nitric oxide (NO) production. Although FG increased eNOS phosphorylation, uncoupled eNOS was evidenced by downregulated guanosine 5'-triphosphate cyclohydrolase 1 (GTPCH1) and tetrahydrobiopterin (BH4) levels. FG also upregulated the level of p47-phox, a subunit of NADPH oxidase. Similar to l-NAME and apocynin, metformin ameliorated the FG-induced endothelial dysfunction by decreasing ROS generation. Furthermore, metformin recoupled eNOS through upregulating GTPCH1 and BH4 levels, and attenuated the upregulation of p47-phox in FG-treated HUVECs. Addition of compound C abolished the above effects of metformin. CONCLUSION: Metformin improves the FG-induced endothelial dysfunction in HUVECs. The protective effect of metformin may be mediated through activation of GTPCH1-mediated eNOS recoupling and inhibition of NADPH oxidase via an AMPK-dependent pathway. PMID- 27217020 TI - Screening for type 2 diabetes mellitus in overweight and obese subjects made easy by the FINDRISC score. AB - AIM: To evaluate the use of the FINDRISC score in an overweight and obese population to predict glucose status. METHODS: In 651 overweight/obese subjects (M/F: 193/458, age 43+/-13 y, BMI 38.2+/-6.1kg/m(2)) glucose status was tested using OGTT and HbA1c. Furthermore, the FINDRISC questionnaire and CT visceral fat (VAT) and subcutaneous fat (SAT) were examined. RESULTS: Exactly 50.4% were found to have prediabetes and 11.1% were newly diagnosed with type 2 diabetes (T2DM) (M/F=22.2/8.8%). Subjects without T2DM had a FINDRISC score of 11+/-3, those with pre-DM 13+/-4, and subjects with de novo T2DM 15+/-5. The aROC of the FINDRISC for detecting T2DM was 0.76 (95% CI 0.72-0.82), with 13 as cutoff point. The FINDRISC score correlated with VAT (r=0.34, p<0.001) and VAT/SAT ratio (r=0.39, p<0.001). The aROC of the FINDRISC to detect excess VAT was 0.79 (95%CI 0.72 0.84). CONCLUSIONS: In a large group of overweight and obese subjects, 50.4% were found to have pre-DM and 11.1% were newly diagnosed with T2DM. The FINDRISC score increased with worsening of glucose tolerance status and proved to be an independent predictor of T2DM status, as did HOMA-B, HOMA-S and VAT. The FINDRISC can also function as a good tool to predict visceral obesity. PMID- 27217022 TI - Classes of antihypertensive agents and mortality in hypertensive patients with type 2 diabetes-Network meta-analysis of randomized trials. AB - AIMS: The aim of this study was to evaluate the effects of antihypertensive drug classes in mortality in patients with type 2 diabetes. METHODS: MEDLINE, EMBASE, Clinical Trials and Cochrane Library were searched for randomized trials comparing thiazides, beta-blockers, calcium channel blockers (CCBs), angiotensin converting inhibitors (ACEi) and angiotensin-receptor blockers (ARBs), alone or in combination for hypertension treatment in patients with type 2 diabetes. Outcomes were overall and cardiovascular mortality. Network meta-analysis was used to obtain pooled effect estimate. RESULTS: A total of 27 studies, comprising 49,418 participants, 5647 total and 1306 cardiovascular deaths were included. No differences in total or cardiovascular mortality were observed with isolated antihypertensive drug classes compared to each other or placebo. The ACEi and CCB combination showed evidence of reduction in cardiovascular mortality comparing to placebo [median HR, 95% credibility intervals: 0.16, 0.01-0.82], betablockers (0.20, 0.02-0.98), CCBs (0.21, 0.02-0.97) and ARBs (0.18, 0.02-0.91). In included trials, this combination was the treatment that most consistently achieved both lower systolic and diastolic end of study blood pressure. CONCLUSIONS: There is no benefit of a single antihypertensive class in reduction of mortality in hypertensive patients with type 2 diabetes. Reduction of cardiovascular mortality observed in patients treated with ACEi and CCB combination may be related to lower blood pressure levels. PMID- 27217021 TI - Do traditional cardiovascular risk factors solely explain intima-media thickening in youth with type 1 diabetes? AB - AIMS: The aim of this study was to assess age-specific carotid intima-media thickness (cIMT) in children and adolescents with type 1 diabetes and to investigate associations between cIMT, age, classical cardiovascular disease (CVD) and other risk factors. METHODS: This study included a cross-sectional analysis of cIMT in 178 patients with type 1 diabetes and 208 healthy controls across age categories. In patients, the impact of gender, socio-economic status, ethnicity, current and historical body mass index, blood pressure, hemoglobin A1c, high-density lipoprotein, and low-density lipoprotein cholesterol on cIMT was studied in a retrospective follow-up cohort study. RESULTS: Median cIMT was equally greater in patients versus controls across all age categories (P<=0.03). Regression models in patients confirmed a lack of association between cIMT and classical CVD risk factors. CONCLUSIONS: Children and adolescents with type 1 diabetes showed greater cIMT than controls in all age categories. Increased cIMT did not seem to be consistently associated with classical adult CVD risk factors, adding to the current debate in pediatrics about the impact on classical CVD risk factors to the development of subclinical atherosclerosis in type 1 diabetes. Future studies are warranted to determine if cIMT could assist in predicting macrovascular complications of type 1 diabetes. PMID- 27217023 TI - Diabetes distress from the patient's perspective: Qualitative themes and treatment regimen differences among adults with type 2 diabetes. AB - AIMS: To explore diabetes distress in a sample of adults with type 2 diabetes, treated and not treated with insulin. METHODS: Six focus groups were conducted with 32 adults with type 2 diabetes, divided by treatment regimen (insulin treated N=15; 67% female; 60% black; 46% Hispanic; M age 54; M HbA1c 73mmol/mol (8.8%); non-insulin-treated N=17; 53% female; 65% black; 13% Hispanic; M age 58; M HbA1c 55mmol/mol (7.2%)). A coding team transcribed and analyzed interviews to describe themes. Themes were then compared between groups and with existing diabetes distress measures. RESULTS: Participants in both groups described a range of sources of diabetes distress, including lack of support/understanding from others, difficulties communicating with providers, and distress from the burden of lifestyle changes. Insulin-treated participants described significant emotional distress related to the burden of their insulin regimen. They were more likely to report physical burden related to diabetes; to describe feeling depressed as a result of diabetes; and to express distress related to challenges with glycemic control. Non-insulin-treated participants were more likely to discuss the burden of comorbid medical illnesses. CONCLUSIONS: Our data generate hypotheses for further study into the emotional burdens of diabetes for insulin treated adults with type 2 diabetes and are in line with quantitative research documenting increased diabetes-related distress among insulin-treated individuals. Data describe needs, currently unmet by most models of care, for comprehensive assessment and tailored management of diabetes-related distress. PMID- 27217030 TI - Apixaban for periprocedural anticoagulation during catheter ablation of atrial fibrillation: a systematic review and meta-analysis of 1691 patients. AB - PURPOSE: Apixaban, a direct factor Xa inhibitor recently approved for thromboembolic prophylaxis in patients with nonvalvular atrial fibrillation (AF), is increasingly used in patients undergoing catheter ablation of AF. However, large randomized studies supporting its use in the ablation context are still lacking. We undertook the present meta-analysis to assess the impact of apixaban in terms of thromboembolic and bleeding events in patients undergoing AF ablation as compared to warfarin. METHODS: MEDLINE/PubMed, Cochrane Library, and references reporting AF ablation and apixaban were screened and studies included if matching inclusion and exclusion criteria. RESULTS: One randomized and five nonrandomized studies were included in the analysis. Patients enrolled were 1691 patients (668 on apixaban and 1023 on warfarin). There was no heterogeneity in all the outcome comparisons. No deaths were reported. We did not observe any difference between apixaban and warfarin with respect to thromboembolic events (OR = 1.10, 95 % CI 0.24-5.16), major bleedings (OR = 1.56, 95 % CI 0.59-4.13), cardiac tamponade (OR 1.69, 95 % CI 0.52-5.54), minor bleedings (OR 0.96, 95 % CI 0.58-1.59), and the composite endpoint of death, thromboembolic events, and bleedings (OR 1.03, 95 % CI 0.65-1.64). CONCLUSIONS: The rates of death, thromboembolic events, major bleedings including cardiac tamponade, and minor bleedings in patients on apixaban undergoing AF ablation are very low and similar to that seen in patients treated with uninterrupted warfarin. Although primary driven by nonrandomized studies, these results support apixaban as periprocedural anticoagulation during AF ablation procedures. PMID- 27217031 TI - Long-time "real-life" performance of the subcutaneous ICD in patients with electrical heart disease or idiopathic ventricular fibrillation. AB - BACKGROUNDS: The totally subcutaneous implantable defibrillator (S-ICD) has been designed as a new alternative to conventional implantable defibrillators. This system is especially attractive for young patients. However, long-term experience is not yet available. To address the question whether the S-ICD system is safe and feasible for young patients with electrical heart disease or idiopathic ventricular fibrillation (VF), the data of a standard of care prospective single center S-ICD registry were evaluated. METHODS: In the present study, 24 patients (age 34.2 +/- 11.5 years) with electrical heart disease or idiopathic VF received an S-ICD for primary (n = 8) or secondary prevention (n = 16). The mean follow-up duration was 29.6 +/- 15.1 months. RESULTS: Ventricular arrhythmias were adequately detected in four patients (17 %). In three patients (13 %) oversensing was noticed and led to at least one inappropriate shock in two patients (8 %). Further adverse events included surgical revision due to a mobile pulse generator as well as explantation of one system and switch to a transvenous ICD system due to several ineffective shocks. CONCLUSIONS: The results of the present study suggest that S-ICD therapy may be an attractive alternative in young patients with electrical heart disease or idiopathic VF. However, episodes of oversensing as well as ineffective shocks may occur. PMID- 27217033 TI - Planomonospora corallina sp. nov., isolated from soil. AB - A novel actinomycete strain, A-T 11038T, was isolated from bamboo rhizospheric soil collected in Thailand. Based on a polyphasic approach, the novel strain was characterized as a member of the genus Planomonospora, which developed cylindrical to clavate sporangia containing a single motile spore on aerial mycelium. The 16S rRNA gene sequence and phylogenetic analysis indicated that strain A-T 11038T was closely related to Planomonospora sphaerica JCM 9374T (98.82 %), P.lanomonospora parontospora subsp. parontospora NBRC 13880T and P.parontospora subsp. antibiotica JCM 3094T (98.54 %), Planomonospora alba JCM 9373T (98.41 %) and Planomonospora venezuelensis JCM 3167T (97.51 %). The DNA-DNA relatedness values that distinguished strain A-T 11038T from the most closely related species were below 45 %. The novel strain contained meso-diaminopimelic acid in cell-wall hydrolysates, and rhamnose, ribose, madurose and glucose in whole-cell hydrolysates. The predominant menaquinone was MK-9(H2). The diagnostic phospholipids were diphosphatidylglycerol, phosphatidylmethylethanolamine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol mannosides, phosphatidylinositol and aminophosphoglycolipids. The predominant cellular fatty acids were unsaturated fatty acids C17 : 1 and C16 : 1 and saturated fatty acid C16 : 0. The G+C content of the genomic DNA was 73.5 mol%. Following the evidence obtained using a polyphasic approach, the novel strain is proposed as a representative of a novel species to be named Planomonospora corallina sp. nov. The type strain is A-T 11038T (=BCC 67829T=TBRC 4489T=NBRC 110609T). PMID- 27217032 TI - A systematic review of the clinical survival of zirconia implants. AB - OBJECTIVES: The aim of this review was to evaluate the clinical success and survival rates of zirconia ceramic implants after at least 1 year of function and to assess if there is sufficient evidence to justify using them as alternatives to titanium implants. MATERIALS AND METHODS: An electronic search in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Clinical Trials (CENTRAL) databases was performed in April 2015 by two independent examiners to retrieve clinical studies focusing on the survival rate of zirconia implants after at least 1 year of function. Implant survival was estimated using the overall proportion reported in the studies with a Clopper-Pearson 95 % confidence interval (random effect model with a Der-Simonian Laird estimate). RESULTS: Fourteen articles were selected out of the 1519 titles initially screened. The overall survival rate of zirconia one- and two-piece implants was calculated at 92 % (95 % CI 87-95) after 1 year of function. The survival of implants at 1 year for the selected studies revealed considerable heterogeneity. CONCLUSIONS: In spite of the unavailability of sufficient long-term evidence to justify using zirconia oral implants, zirconia ceramics could potentially be the alternative to titanium for a non-metallic implant solution. However, further clinical studies are required to establish long-term results, and to determine the risk of technical and biological complications. Additional randomized controlled clinical trials examining two-piece zirconia implant systems are also required to assess their survival and success rates in comparison with titanium as well as one-piece zirconia implants. CLINICAL RELEVANCE: Zirconia implants provide a potential alternative to titanium ones. However, clinicians must be aware of the lack of knowledge regarding long-term outcomes and specific reasons for failure. PMID- 27217034 TI - Erratum to: Developing Mentoring Competency: Does a One Session Training Workshop Have Impact? PMID- 27217035 TI - Bridging Cultural Psychiatry and Global Mental Health: A Resident-Led Initiative. PMID- 27217036 TI - Neoadjuvant Imatinib in Locally Advanced Gastrointestinal stromal Tumours, Will Kit Mutation Analysis Be a Pathfinder? AB - INTRODUCTION: Longer duration of neoadjuvant (NA) imatinib (IM) used for locally advanced (LA) gastrointestinal stromal tumours (GIST) is not based on biology of the tumour reflected by kit mutation analysis. MATERIAL AND METHODS: LA or locally recurrent (LR) GIST treated with NA IM from May 2008 to March 2015 from a prospective database were included in the analysis. Archived formalin-fixed paraffin-embedded tissues (FFPE) were used for testing KIT exons 9, 11, 13 and 17 by PCR. RESULTS: One hundred twenty-five patients with LA or LR GIST were treated with NA IM. Forty-five patients (36 %) had undergone c-kit mutation testing. Exon 11 was seen in 25 patients (55.5 %), 3 with exon 9 (6.7 %) and 2 with exon 13 (4.4 %). Twelve were wild type (26.6 %) and 3 (6.7 %) were declared uninterpretable. Response rate (RR) for the exon 11 mutants was higher than the non-exon 11 mutant group (84 vs. 40 %, p = 0.01). Disease stabilization rate (DSR) rates were also higher in the exon 11 subgroup than non-exon 11 group (92 vs. 75 %). Eighty-four per cent exon 11 and 75 % non-exon 11 mutants were surgical candidates. Patients undergoing surgery had significantly improved event free survival (EFS) (p < 0.001) compared to patients not undergoing surgery, with the same trend seen in OS (p = 0.021). Patients with a SD on response to NA IM had a lower EFS (p = 0.076) and OS compared to patients achieving CR/PR. There were no differences between the various exon variants in terms of outcomes and responses CONCLUSION: Upfront evaluation of kit mutation status may help us in delineating separate treatment strategies for potentially biologically different tumours and assessing the correct timing of surgery for this subset of GIST. PMID- 27217037 TI - Structural Equation Modeling Test of an Integrated Model of Spanish Youth's Condom Use. AB - Heterosexual transmission represents 26 % of newly diagnosed infection in Spanish youth. Behavioral change models have emphasized the influence of multiple variables to predict condom use behavior. The aim of this study is to examine how those variables are organized and which theory explains the condom use behavior better. A sample of 424 young heterosexuals (M age = 20.62; SD = 2.16) filled out a battery of self-report questionnaires for assessing AIDS-related variables, personality traits and clinical variables (general, sexuality-related and health related). A structural model was specified that included perceived pleasure and condom use self-efficacy as predictive variables. Depression and sexual compulsivity indirectly influence behavior. The final model accounted for 65.9 % of the variance in behavior. These results highlight the importance of cognitive and emotional variables as predictors of behavior (ex. expectations of pleasure and self-efficacy beliefs). This is important information for designing effective psychological interventions. PMID- 27217038 TI - Robot-assisted surgery versus conventional laparoscopic surgery for endometrial cancer: a systematic review and meta-analysis. AB - PURPOSE: To compare perioperative outcomes between robot-assisted surgery (RAS) and conventional laparoscopic surgery (CLS) for the treatment of endometrial cancer by conducting a meta-analysis. METHODS: We searched the Cochrane Central Register of Controlled Trials, PubMed, and EMBASE up to January 8, 2016. Studies clearly documenting a comparison between RAS and CLS for patients with endometrial cancer were included. The perioperative outcomes of interest included intraoperative visceral injuries, postoperative complications, operation time, estimated blood loss (EBL), blood transfusion, total lymph nodes harvested (TLNH), conversion to laparotomy, and length of hospital stay. The weighted mean difference (WMD) and odds ratio (OR) were pooled with either a fixed-effects or a random-effects model. RESULTS: A total of 19 studies were included in the analysis, involving 3056 patients. The pooled analysis showed that RAS was associated with lower EBL (WMD -77.65; 95 % confidence interval [CI] -105.58 to 49.72), lower conversion rate (OR 0.29; 95 % CI 0.18-0.46), and shorter hospital stay (WMD -0.48; 95 % CI -0.70 to -0.26) compared to CLS. The incidence of intraoperative visceral injuries, operation time, transfusion rate, and TLNH showed no significant differences between RAS and CLS. CONCLUSIONS: RAS is a feasible and effective surgical approach that may be superior to CLS for the treatment of endometrial cancer, with lower EBL and lower conversion rate. Further prospective randomized trials are required to validate our findings. PMID- 27217043 TI - Renal function in atrial fibrillation patients switched from warfarin to a direct oral anticoagulant. AB - All available direct oral anticoagulants (DOACs) are at least partially eliminated by the kidneys. These agents are increasingly being used as alternatives to warfarin for stroke prevention in patients with atrial fibrillation. The aim of this study was to identify changes in renal function and associated DOAC dosing implications in a multicenter cohort of atrial fibrillation patients switched from warfarin to DOAC treatment. We included all patients in the Michigan Anticoagulation Quality Improvement Initiative cohort who switched from warfarin to a DOAC with atrial fibrillation as their anticoagulant indication between 2009 and 2014, and who had at least two creatinine values. Compliance with FDA-recommended dosing based on renal function was assessed. Of the 189 patients switched from warfarin to a DOAC, 34 (18.0 %) had a baseline creatinine clearance <50 mL/min and 23 (12.2 %) experienced important fluctuations in renal function. Of these 23 patients, 6 (26.1 %) should have impacted the DOAC dosing, but only 1 patient actually received an appropriate dose adjustment. Additionally, 15 (7.9 %) of patients on DOACs had a dose change performed, but only one patient demonstrated a change in renal function to justify the dose adjustment. Most atrial fibrillation patients who switched from warfarin to a DOAC had stable renal function. However, the majority of patients who had a change in renal function did not receive the indicated dose change. As the use of DOACs expands, monitoring of renal function and appropriate dose adjustments are critical. PMID- 27217044 TI - Developing more effective, non-neurotoxic, methotrexate-based therapy in infants with brain tumors. PMID- 27217045 TI - Reply to Prof Ian J. Cohen. PMID- 27217046 TI - Therapeutic drug monitoring of 5-fluorouracil. AB - PURPOSE: For over 50 years, 5-FU has played a critical role in the systemic chemotherapy of cancer patients. 5-FU serves as the main backbone of combination chemotherapy for patients with colorectal cancer in both the adjuvant and metastatic disease settings. Herein, we review the current status of 5-FU therapeutic drug monitoring (TDM) and discuss its potential role in the clinical practice setting. METHOD: PubMed and abstracts from the American Society of Clinical Oncology were searched up through September 2015 for clinical data relating to 5-FU TDM. RESULTS: 5-FU dosing has been typically determined by using body surface area (BSA). However, it is now well established that BSA-based 5-FU dosing is correlated with a wide variation of 5-FU systemic exposure. Pharmacokinetic (PK) studies of 5-FU systemic exposure have shown a wide range of interpatient variation of 5-FU plasma drug levels. Over the past 30 years, increasing efforts have been placed on optimizing 5-FU dosing with the main goals of increasing antitumor efficacy while reducing drug-associated toxicity. There is growing evidence to show that 5-FU dosing based on plasma 5-FU drug level is feasible and that 5-FU TDM can improve clinical outcomes by improving efficacy of 5-FU-based combination regimens and reducing toxicities. CONCLUSION: Dose adjustment of 5-FU is feasible, and PK-based dosing can significantly improve clinical outcomes by reducing toxicities and improving efficacy. PMID- 27217047 TI - Effects of CYP3A5 polymorphism on the pharmacokinetics of a once-daily modified release tacrolimus formulation and acute kidney injury in hematopoietic stem cell transplantation. AB - BACKGROUND: Tacrolimus is metabolized by cytochrome P450 (CYP) 3A4 and 3A5. We investigated the influence of CYP3A5 polymorphism and concurrent use of azole antifungal agents (AZ) on the pharmacokinetics of a once-daily modified-release tacrolimus formulation (Tac-QD) in patients after hematopoietic stem cell transplantation (HSCT). DESIGN AND METHODS: Twenty-four patients receiving allogeneic HSCT were enrolled. Genotyping for CYP3A5*3 was done by a PCR restriction fragment length polymorphism method. Trough blood concentrations (C0) of tacrolimus were measured by chemiluminescence magnetic microparticle immunoassay. Continuous infusion of tacrolimus was administered from the day before transplantation and was switched to Tac-QD after adequate oral intake. RESULTS: Thirteen patients had a CYP3A5*3/*3 genotype, and 11 patients had a CYP3A5*1/*1 or *1/*3 genotype. No significant difference was observed in daily dosages and the C0 of tacrolimus between the two genotype groups without AZ. However, in patients who were co-administered AZ, the C0 values of tacrolimus were higher in patients with the CYP3A5*3/*3 allele than with the CYP3A5*1 allele (P = 0.034), although daily doses of Tac-QD in patients with CYP3A5*3/*3 were significantly lower than those with the CYP3A5*1 allele (P = 0.041). The cumulative incidence of acute kidney injury was higher in patients with the CYP3A5*3/*3 than with the CYP3A5*1 allele when AZ was co-administered. The decrement for daily dosage of Tac-QD was significantly greater in patients expressing the CYP3A5*3/*3 than the CYP3A5*1 allele. CONCLUSIONS: CYP3A5 genotyping may be useful for safe and effective immunosuppressive therapy with Tac-QD in HSCT patients in whom the use of AZ is anticipated. PMID- 27217048 TI - Pectus excavatum severity underestimated due to lack of objective measures in radiological reports. AB - During a routine physical examination, the degree of pectus excavatum (PE) is not always appreciated as the external appearance does not always reflect the severity of the deformity. In the patient in this case report, the severity had been underestimated for 33 years. The physicians, having requested standard two view chest radiographs, had relied solely on the radiological reports, where the PE had been ambiguously described as 'moderate' or 'substantial'. In patients where PE has been observed, it is essential that an objective numeric measure of severity, using the Haller index, is included in radiological reports. PMID- 27217049 TI - Rickettsia conorii is a potent complement activator in vivo and combined inhibition of complement and CD14 is required for attenuation of the cytokine response ex vivo. AB - Mediterranean spotted fever caused by Rickettsia conorii is a potentially lethal disease characterized by vascular inflammation affecting multiple organs. Studies of R. conorii so far have focused on activation of inflammatory cells and their release of inflammatory cytokines, but complement activation has not been investigated in R. conorii-infected patients. Here, we performed a comprehensive analysis of complement activation markers and the soluble cross-talking co receptor CD14 (sCD14) in plasma from R. conorii-infected patients. The clinical data were supplemented with ex vivo experiments where the cytokine response was characterized in human whole blood stimulated with R. conorii. Complement activation markers at the level of C3 (C3bc, C3bBbP) and terminal pathway activation (sC5b-9), as well as sCD14, were markedly elevated (p <0.01 for all), and closely correlated (p <0.05 for all), in patients at admission compared with healthy matched controls. All tested markers were significantly reduced to baseline values at time of follow up. Rickettsia conorii incubated in human whole blood was shown to trigger complement activation accompanied by release of the inflammatory cytokines interleukin-1beta (IL-1beta), IL-6, IL-8 and tumour necrosis factor. Whereas inhibition of either C3 or CD14 had only a minor effect on released cytokines, combined inhibition of C3 and CD14 resulted in significant reduction, virtually to baseline levels, of the four cytokines (p <0.05 for all). Our data show that complement is markedly activated upon R. conorii infection and complement activation is, together with CD14, responsible for a major part of the cytokine response induced by R. conorii in human whole blood. PMID- 27217050 TI - Measuring patient activation: The utility of the Patient Activation Measure within a UK context-Results from four exemplar studies and potential future applications. AB - OBJECTIVE: Patient activation can be measured using the Patient Activation Measure (PAM) developed by Hibbard et al., however, little is known about the uses of the PAM in research and in practice. This study aims to explore its differing utility in four UK exemplar sites. METHODS: Data from four exemplars in a range of health settings with people living with long-term conditions (i.e. stroke or COPD) were evaluated. PAM scores were described and explored in relation to clinical and sociodemographic variables and outcome measures. RESULTS: PAM scores illustrated that most with COPD or stroke reported PAM levels of 3 or 4, indicating that they are engaging, but may need help to sustain their scores. The exemplars illustrate the utility of, and potential issues involved in, using PAM as a process/outcome measure to predict activation and the effectiveness of interventions, and as a tool to inform tailoring of targeted interventions. CONCLUSIONS: The PAM tool has been shown to be useful as an outcome measure, a screening tool to tailor education, or a quality indicator for delivery of care. PRACTICE IMPLICATIONS: However good demographic and patient history are needed to substantiate PAM scores. Further work is needed to monitor PAM prospectively. PMID- 27217051 TI - Clinical-pharmacogenetic predictive models for MTX discontinuation due to adverse events in rheumatoid arthritis. AB - We describe a novel approach to investigate and evaluate combined effect of a large number of clinical and pharmacogenetic factors on treatment outcome. We have used this approach to investigate predictors of methotrexate (MTX)-induced adverse events (AEs) leading to treatment discontinuation in rheumatoid arthritis (RA) patients. In total, 333 RA patients were genotyped for 34 polymorphisms in MTX transporters, folate and adenosine pathways. The effect of clinical and pharmacogenetic factors was assessed with penalized regression in the cause specific Cox proportional hazards model. The predictive capacity was evaluated with the area under time-dependent receiver operating characteristic curve where cross-validation was applied. SLC19A1, ABCG2, ADORA3 and TYMS were associated with discontinuation because of AEs in clinical-pharmacogenetic model. Cross validation showed that both clinical-pharmacogenetic model and nongenetic model had worthless predictive ability for MTX discontinuation because of AEs. These models could be further improved, either with additional polymorphisms or with epigenetic predictors. PMID- 27217052 TI - Thiopurine S-methyltransferase testing for averting drug toxicity: a meta analysis of diagnostic test accuracy. AB - Thiopurine S-methyltransferase (TPMT) deficiency increases the risk of serious adverse events in persons receiving thiopurines. The objective was to synthesize reported sensitivity and specificity of TPMT phenotyping and genotyping using a latent class hierarchical summary receiver operating characteristic meta analysis. In 27 studies, pooled sensitivity and specificity of phenotyping for deficient individuals was 75.9% (95% credible interval (CrI), 58.3-87.0%) and 98.9% (96.3-100%), respectively. For genotype tests evaluating TPMT*2 and TPMT*3, sensitivity and specificity was 90.4% (79.1-99.4%) and 100.0% (99.9-100%), respectively. For individuals with deficient or intermediate activity, phenotype sensitivity and specificity was 91.3% (86.4-95.5%) and 92.6% (86.5-96.6%), respectively. For genotype tests evaluating TPMT*2 and TPMT*3, sensitivity and specificity was 88.9% (81.6-97.5%) and 99.2% (98.4-99.9%), respectively. Genotyping has higher sensitivity as long as TPMT*2 and TPMT*3 are tested. Both approaches display high specificity. Latent class meta-analysis is a useful method for synthesizing diagnostic test performance data for clinical practice guidelines.The Pharmacogenomics Journal advance online publication, 24 May 2016; doi:10.1038/tpj.2016.37. PMID- 27217053 TI - The safety of Sino-implant (II) for women with medical conditions or other characteristics: a systematic review. AB - OBJECTIVES: This study aims to systematically review evidence published on the safety of Sino-implant (II) [SI (II)] among women with medical conditions or characteristics identified by the World Health Organization for eligibility for contraceptive use. STUDY DESIGN: We searched PubMed, WEIPU, CNKI and Wanfang to identify all relevant evidence published in peer-reviewed journals from 1991 through 2014 regarding the safety of SI (II). We considered studies among women with medical conditions or other characteristics, such as age and parity, as direct evidence and studies among healthy women or a general population of women as indirect evidence. RESULTS: We identified 108 articles of which 9 met our inclusion criteria. Among women with medical conditions, no evidence was identified for the outcomes of interest, including serious adverse events or outcomes related to medical conditions. Among healthy women, evidence regarding efficacy of SI (II) for women weighing >=70 kg was conflicting; one study showed an increased pregnancy rate and another showed no relationship. Women with menorrhagia did not experience worsened symptoms and may benefit from SI (II) use. Healthy women using SI (II) were no more likely than users of other methods to gain weight, develop elevated blood pressure, have abnormal liver or bone density tests or develop ovarian cysts or uterine myomas. CONCLUSIONS: Evidence among healthy women suggests SI (II) is safe and had health outcomes similar to those of other levonorgestrel implants. Studies were limited and conflicting regarding efficacy for women >=70 kg. All included studies were conducted in China, limiting generalizability. PMID- 27217054 TI - Sepsis: pathophysiology and clinical management. AB - Sepsis, severe sepsis, and septic shock represent increasingly severe systemic inflammatory responses to infection. Sepsis is common in the aging population, and it disproportionately affects patients with cancer and underlying immunosuppression. In its most severe form, sepsis causes multiple organ dysfunction that can produce a state of chronic critical illness characterized by severe immune dysfunction and catabolism. Much has been learnt about the pathogenesis of sepsis at the molecular, cell, and intact organ level. Despite uncertainties in hemodynamic management and several treatments that have failed in clinical trials, investigational therapies increasingly target sepsis induced organ and immune dysfunction. Outcomes in sepsis have greatly improved overall, probably because of an enhanced focus on early diagnosis and fluid resuscitation, the rapid delivery of effective antibiotics, and other improvements in supportive care for critically ill patients. These improvements include lung protective ventilation, more judicious use of blood products, and strategies to reduce nosocomial infections. PMID- 27217055 TI - Association Between Sedentary Lifestyle and Diastolic Dysfunction Among Outpatients With Normal Left Ventricular Systolic Function Presenting to a Tertiary Referral Center in the Middle East. AB - BACKGROUND: Sedentary lifestyle has become prevalent in our community. Recent data showed controversy on the effect of regular exercise on left ventricular compliance and myocardial relaxation. HYPOTHESIS: We sought to assess whether physical inactivity is an independent predictor of diastolic dysfunction in or community, after adjustment for several covariates. METHODS: Consecutive outpatients presenting to the echocardiography laboratory between July 2013 and June 2014 were prospectively enrolled. Clinical variables were collected prospectively at enrollment. Patients were considered physically active if they exercised regularly >=3* a week, >=30 minutes each time. The primary endpoint was presence of diastolic dysfunction. RESULTS: The final cohort included 1356 patients (mean age [SD] 52.9 [17.4] years, 51.3% female). Compared with physically active patients, the 1009 (74.4%) physically inactive patients were older, more often female, and had more comorbidities and worse diastolic function (51.3% vs 38.3%; P < 0.001). On univariate analysis, physical inactivity was associated with 70% increased odds of having diastolic dysfunction (odds ratio: 1.70, 95% confidence interval: 1.32-2.18, P < 0.001). There was significant interaction between physical activity and left ventricular mass index (LVMI; P = 0.026). On multivariate analysis, patients who were physically inactive and had LVMI >= median had significantly higher odds of having diastolic dysfunction (odds ratio: 2.82, 95% confidence interval: 1.58-5.05, P < 0.001). CONCLUSIONS: In a large, prospectively enrolled cohort from a single tertiary center in the Middle East, physically inactive patients with increased LVMI had 2- to 3-fold increased odds of having diastolic dysfunction after multivariate adjustment. PMID- 27217056 TI - Response to Statin Use and Aneurysm Risk in Patients With Bicuspid Aortic Valve Disease. PMID- 27217057 TI - Author's Reply. PMID- 27217058 TI - Best practices for metabolite quantification in drug development: updated recommendation from the European Bioanalysis Forum. AB - Metabolite quantification and profiling continues to grow in importance in today's drug development. The guidance provided by the 2008 FDA Metabolites in Safety Testing Guidance and the subsequent ICH M3(R2) Guidance (2009) has led to a more streamlined process to assess metabolite exposures in preclinical and clinical studies in industry. In addition, the European Bioanalysis Forum (EBF) identified an opportunity to refine the strategies on metabolite quantification considering the experience to date with their recommendation paper on the subject dating from 2010 and integrating the recent discussions on the tiered approach to bioanalytical method validation with focus on metabolite quantification. The current manuscript summarizes the discussion and recommendations from a recent EBF Focus Workshop into an updated recommendation for metabolite quantification in drug development. PMID- 27217059 TI - Screening for cardiac and respiratory problems in elite sport - compare and contrast. PMID- 27217060 TI - Identification of an activation site in Bak and mitochondrial Bax triggered by antibodies. AB - During apoptosis, Bak and Bax are activated by BH3-only proteins binding to the alpha2-alpha5 hydrophobic groove; Bax is also activated via a rear pocket. Here we report that antibodies can directly activate Bak and mitochondrial Bax by binding to the alpha1-alpha2 loop. A monoclonal antibody (clone 7D10) binds close to alpha1 in non-activated Bak to induce conformational change, oligomerization, and cytochrome c release. Anti-FLAG antibodies also activate Bak containing a FLAG epitope close to alpha1. An antibody (clone 3C10) to the Bax alpha1-alpha2 loop activates mitochondrial Bax, but blocks translocation of cytosolic Bax. Tethers within Bak show that 7D10 binding directly extricates alpha1; a structural model of the 7D10 Fab bound to Bak reveals the formation of a cavity under alpha1. Our identification of the alpha1-alpha2 loop as an activation site in Bak paves the way to develop intrabodies or small molecules that directly and selectively regulate these proteins. PMID- 27217064 TI - The rise of Chinese ophthalmology and eye research. PMID- 27217062 TI - Iron(II) Initiation of Lipid and Protein Oxidation in Pork: The Role of Oxymyoglobin. AB - Iron(II), added as FeSO4.7H2O, was found to increase the rate of oxygen depletion as detected electrochemically in a pork homogenate from Longissimus dorsi through an initial increase in metmyoglobin formation from oxymyoglobin and followed by formation of primary and secondary lipid oxidation products and protein oxidation as detected as thiol depletion in myofibrillar proteins. Without added iron(II), under the same conditions at 37 degrees C, oxygen consumption corresponded solely to the slow oxymyoglobin autoxidation. Long-lived myofibrillar protein radicals as detected by ESR spectroscopy in the presence of iron(II) were formed subsequently to oxymyoglobin oxidation, and their level was increased by lipid oxidation when oxygen was completely depleted. Similarly, the time profile for formation of lipid peroxide indicated that oxymyoglobin oxidation initiates both protein oxidation and lipid oxidation. PMID- 27217061 TI - Composition and function of the pediatric colonic mucosal microbiome in untreated patients with ulcerative colitis. AB - Inflammatory bowel diseases (IBD) are chronic intestinal inflammatory disorders characterized by a complex disruption of the physiologic interaction between the host immune system and intestinal microbes precipitated by environmental factors. Numerous observations indicate the altered composition and function of the intestinal microbiome of patients with ulcerative colitis (UC), a subtype of IBD. The accuracy of these results may be limited by confounding factors, such as concurrent medication use. To address these limitations, we examined the colonic mucosal microbiome of pediatric patients with UC prior to initiating treatment. Based on bacterial 16S rRNA gene sequencing, we identified a significant decrease in the phylum Verrucomicrobia in patients with UC. At the genus level, we observed a significant decrease in the short chain fatty acid producer Roseburia. Despite these compositional changes, we did not identify inferred gene content differences between the UC and control groups. To determine if microbial taxa may be associated with clinical outcomes, we retrospectively assessed the clinical course of the UC patients. Despite similar metrics of OTU richness and diversity, multiple OTU differences were observed between patients who responded to therapy and those who did not. Our observations regarding the mucosal microbiome and the associations with differential clinical outcomes support the contributions of gut microbes to disease onset and modulation. PMID- 27217065 TI - Fighting blinding fundus diseases: China on the way! PMID- 27217067 TI - Cardiopulmonary adaptation to short-term high altitude exposure in adult Fontan patients. AB - OBJECTIVE: High altitude-related hypoxia induces pulmonary vasoconstriction. In Fontan patients without a contractile subpulmonary ventricle, an increase in pulmonary artery pressure is expected to decrease circulatory output and reduce exercise capacity. This study investigates the direct effects of short-term high altitude exposure on pulmonary blood flow (PBF) and exercise capacity in Fontan patients. METHODS: 16 adult Fontan patients (mean age 28+/-7 years, 56% female) and 14 matched controls underwent cardiopulmonary exercise testing with measurement of PBF with a gas rebreathing system at 540 m (low altitude) and at 3454 m (high altitude) within 12 weeks. RESULTS: PBF at rest and at exercise was higher in controls than in Fontan patients, both at low and high altitude. PBF increased twofold in Fontan patients and 2.8-fold in the control group during submaximal exercise, with no significant difference between low and high altitude (p=0.290). A reduction in peak oxygen uptake at high compared with low altitude was observed in Fontan patients (22.8+/-5.1 and 20.5+/-3.8 mL/min/kg, p<0.001) and the control group (35.0+/-7.4 and 29.1+/-6.5 mL/min/kg, p<0.001). The reduction in exercise capacity was less pronounced in Fontan patients compared with controls (9+/-12% vs 17+/-8%, p=0.005). No major adverse clinical event was observed. CONCLUSIONS: Short-term high altitude exposure has no negative impact on PBF and exercise capacity in Fontan patients when compared with controls, and was clinically well tolerated. TRIAL REGISTRATION NUMBER: NCT02237274: Results. PMID- 27217068 TI - Cardiovascular events and all-cause mortality with insulin versus glucagon-like peptide-1 analogue in type 2 diabetes. AB - OBJECTIVES: To analyse time to cardiovascular events and mortality in patients with type 2 diabetes (T2D) who received treatment intensification with insulin or a glucagon-like peptide-1 (GLP-1ar) analogue following dual therapy failure with metformin (MET) and sulphonylurea (SU). METHODS: A retrospective cohort study was conducted in 2003 patients who were newly treated with a GLP-1ar or insulin following dual therapy (MET+SU) failure between 2006 and 2014. Data were sourced from The Health Improvement Network database. Risks of major adverse cardiovascular events (MACE) (non-fatal myocardial infarction, non-fatal stroke and all-cause mortality) were compared between MET+SU+insulin (N=1584) versus MET+SU+GLP-1ar (N=419). Follow-up was for 5 years (6614 person-years). Propensity score matching analysis and Cox proportional hazard models were employed. RESULTS: Mean age was 52.8+/-14.1 years. Overall, the number of MACE was 231 vs 11 for patients who added insulin versus GLP-1ar, respectively (44.5 vs 7.7 per 1000-person-years adjusted HR (aHR): 0.27; 95% CI 0.14 to 0.53; p<0.0001). Insulin was associated with significant increase in weight compared with GLP-1ar (1.78 vs -3.93 kg; p<0.0001) but haemoglobin A1c reduction was similar between both treatment groups (-1.29 vs -0.98; p=0.156). In a subgroup analysis of obese patients (body mass index >30 kg/m(2)) there were 84 vs 11 composite outcomes (38.6 vs 8.1 per 1000 person-years; aHR: 0.31; 95% CI 0.16 to 0.61; p=0.001) in the insulin and GLP-1ar groups, respectively. CONCLUSIONS: In this cohort of obese people with T2DM, intensification of dual oral therapy by adding GLP-1ar analogue is associated with a lower MACE outcome in routine clinical practice, compared with adding insulin therapy as the third glucose-lowering agent. PMID- 27217069 TI - Evidence for widespread infection of African bats with Crimean-Congo hemorrhagic fever-like viruses. AB - Crimean Congo hemorrhagic fever virus (CCHFV) is a highly virulent tick-borne pathogen that causes hemorrhagic fever in humans. The geographic range of human CCHF cases largely reflects the presence of ticks. However, highly similar CCHFV lineages occur in geographically distant regions. Tick-infested migratory birds have been suggested, but not confirmed, to contribute to the dispersal. Bats have recently been shown to carry nairoviruses distinct from CCHFV. In order to assess the presence of CCHFV in a wide range of bat species over a wide geographic range, we analyzed 1,135 sera from 16 different bat species collected in Congo, Gabon, Ghana, Germany, and Panama. Using a CCHFV glycoprotein-based indirect immunofluorescence test (IIFT), we identified reactive antibodies in 10.0% (114/1,135) of tested bats, pertaining to 12/16 tested species. Depending on the species, 3.6%-42.9% of cave-dwelling bats and 0.6%-7.1% of foliage-living bats were seropositive (two-tailed t-test, p = 0.0447 cave versus foliage). 11/30 IIFT reactive sera from 10 different African bat species had neutralizing activity in a virus-like particle assay. Neutralization of full CCHFV was confirmed in 5 of 7 sera. Widespread infection of cave-dwelling bats may indicate a role for bats in the life cycle and geographic dispersal of CCHFV. PMID- 27217071 TI - In situ-forming click-crosslinked gelatin based hydrogels for 3D culture of thymic epithelial cells. AB - Hydrogels prepared from naturally derived gelatin can provide a suitable environment for cell attachment and growth, making them favourable materials in tissue engineering. However, physically crosslinked gelatin hydrogels are not stable under physiological conditions while chemical crosslinking of gelatin by radical polymerization may be harmful to cells. In this study, we attached the norbornene functional group to gelatin, which was subsequently crosslinked with a polyethylene glycol (PEG) linker via the nitrile oxide-norbornene click reaction. The rapid crosslinking process allows the hydrogel to be formed within minutes of mixing the polymer solutions under physiological conditions, allowing the gels to be used as injectable materials. The hydrogels properties including mechanical strength, swelling and degradation, can be tuned by changing either the ratio of the reacting groups or the total concentration of the polymer precursors. Murine embryonic fibroblastic cells cultured in soft gels (2 wt% of gelatin and 1 wt% of PEG linker) demonstrated high cell viability as well as similar phenotypic profiles (PDGFRalpha and MTS15) to Matrigel cultures over 5 days. Thymic epithelial cell and fibroblast co-cultures produced epithelial colonies in these gels following 7 days incubation. These studies demonstrate that gelatin based hydrogels, prepared using "click" crosslinking, provide a robust cell culture platform with retained benefits of the gelatin material, and are therefore suitable for use in various tissue engineering applications. PMID- 27217070 TI - Racial disparities in the risk of Stevens-Johnson Syndrome and toxic epidermal necrolysis as urate-lowering drug adverse events in the United States. AB - OBJECTIVES: HLA-B*5801 allele carriage (a strong determinant of allopurinol hypersensitivity syndrome) varies substantially among races, which may lead to racial disparities in the risk of Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) in the context of urate-lowering drug adverse events (ULDAEs). We examined this hypothesis in a large, racially diverse, and generalizable setting. METHODS: Using a database representative of US hospitalizations (2009-2013), we investigated the racial distribution of hospitalized SJS/TEN (principal discharge diagnosis) as ULDAEs (ICD-9-CM Classification of External Causes). Our reference groups included the US Census population, US allopurinol users, and ULDAE hospitalizations without SJS/TEN. RESULTS: We identified 606 cases hospitalized for SJS/TEN as ULDAEs (mean age = 68 years; 44% male), among which there was an overrepresentation of Asians (27%) and Blacks (26%), and an underrepresentation of Whites (29%) and Hispanics (% too low-to-report), compared with the US Census population (5%, 12%, 67%, and 15%, respectively). The hospitalization rate ratios for SJS/TEN among Asians, Blacks, and Whites were 11.9, 5.0, and 1.0 (referent), respectively. These associations persisted using other national referents. According to the NHANES 2009-2012, allopurinol constituted 96.8% of urate-lowering drug use, followed by probenecid (2.1%). CONCLUSIONS: These national data indicate that Asians and Blacks have a substantially higher risk of SJS/TEN as ULDAEs than Whites (or Hispanics), correlating well with corresponding frequencies of HLA-B*5801 in the US population (i.e., 7.4%, 4%, 1%, and 1%, respectively). Given its market dominance and established association with SJS/TEN, our findings support the use of vigilance in these minorities when considering allopurinol. PMID- 27217072 TI - Contrasting dynamics of fragile and non-fragile polyalcohols through the glass, and dynamical, transitions: A comparison of neutron scattering and dielectric relaxation data for sorbitol and glycerol. AB - BACKGROUND: Glycerol and sorbitol are glass-forming hydrogen-bonded systems characterized by intriguing properties which make these systems very interesting also from the applications point of view. The goal of this work is to relate the hydrogen-bonded features, relaxation dynamics, glass transition properties and fragility of these systems, in particular to seek insight into their very different liquid fragilities. METHODS: The comparison between glycerol and sorbitol is carried out by collecting the elastic incoherent neutron scattering (EINS) intensity as a function of temperature and of the instrumental energy resolution. RESULTS: Intensity data vs temperature and resolution are analyzed in terms of thermal restraint and Resolution Elastic Neutron Scattering (RENS) approaches. CONCLUSIONS: The number of OH groups, which are related to the connecting sites, is a significant parameter both in the glass transition and in the dynamical transition. On the other hand, the disordered nature of sorbitol is confirmed by the existence of different relaxation processes. GENERAL SIGNIFICANCE: From the applications point of view, glycerol and sorbitol have remarkable bioprotectant properties which make these systems useful in different technological and industrial fields. Furthermore, polyols are rich in glassforming liquid phenomenology and highly deserving of study in their own right. The comparison of EINS and calorimetric data on glycerol and sorbitol helps provide a connection between structural relaxation, dynamical transition, glass transition, and fragility. The evaluation of the inflection point in the elastic intensity behavior as a function of temperature and instrumental energy resolution provides a confirmation of the validity of the RENS approach. This article is part of a Special Issue entitled "Science for Life" Guest Editor: Dr. Austen Angell, Dr. Salvatore Magazu and Dr. Federica Migliardo. PMID- 27217073 TI - Effects of coating spherical iron oxide nanoparticles. AB - We investigate the effect of several coatings applied in biomedical applications to iron oxide nanoparticles on the size, structure and composition of the particles. The four structural techniques employed - TEM, DLS, VSM, SAXS and EXAFS - show no significant effects of the coatings on the spherical shape of the bare nanoparticles, the average sizes or the local order around the Fe atoms. The NPs coated with hydroxylmethylene bisphosphonate or catechol have a lower proportion of magnetite than the bare and citrated ones, raising the question whether the former are responsible for increasing the valence state of the oxide on the NP surfaces and lowering the overall proportion of magnetite in the particles. VSM measurements show that these two coatings lead to a slightly higher saturation magnetization than the citrate. This article is part of a Special Issue entitled "Science for Life" Guest Editor: Dr. Austen Angell, Dr. Salvatore Magazu and Dr. Federica Migliardo. PMID- 27217074 TI - Estimation of elimination half-lives of organic chemicals in humans using gradient boosting machine. AB - BACKGROUND: Elimination half-life is an important pharmacokinetic parameter that determines exposure duration to approach steady state of drugs and regulates drug administration. The experimental evaluation of half-life is time-consuming and costly. Thus, it is attractive to build an accurate prediction model for half life. METHODS: In this study, several machine learning methods, including gradient boosting machine (GBM), support vector regressions (RBF-SVR and Linear SVR), local lazy regression (LLR), SA, SR, and GP, were employed to build high quality prediction models. Two strategies of building consensus models were explored to improve the accuracy of prediction. Moreover, the applicability domains (ADs) of the models were determined by using the distance-based threshold. RESULTS: Among seven individual models, GBM showed the best performance (R(2)=0.820 and RMSE=0.555 for the test set), and Linear-SVR produced the inferior prediction accuracy (R(2)=0.738 and RMSE=0.672). The use of distance based ADs effectively determined the scope of QSAR models. However, the consensus models by combing the individual models could not improve the prediction performance. Some essential descriptors relevant to half-life were identified and analyzed. CONCLUSIONS: An accurate prediction model for elimination half-life was built by GBM, which was superior to the reference model (R(2)=0.723 and RMSE=0.698). GENERAL SIGNIFICANCE: Encouraged by the promising results, we expect that the GBM model for elimination half-life would have potential applications for the early pharmacokinetic evaluations, and provide guidance for designing drug candidates with favorable in vivo exposure profile. This article is part of a Special Issue entitled "System Genetics" Guest Editor: Dr. Yudong Cai and Dr. Tao Huang. PMID- 27217075 TI - Using BEEHAVE to explore pesticide protection goals for European honeybee (Apis melifera L.) worker losses at different forage qualities. AB - Losses of honeybee colonies are intensely debated and although honeybees suffer multiple stressors, the main focus has been on pesticides. As a result, the European Food Safety Authority (EFSA) revised the guidance for pesticide risk assessment for honeybees. The European Food Safety Authority reported a protection goal of negligible effect at 7% of colony size and then used the Khoury honeybee colony model to set trigger values for forager losses. However, the Khoury model is very simplistic and simulates colonies in an idealized state. In the present study, the authors demonstrate how a more realistic published honeybee model, BEEHAVE, with a few simple changes, can be used to explore pesticide risks. The results show that forage availability interacts with pesticide-induced worker losses, and colony resilience increases with forage quality. Adding alternative unexposed forage to the landscape also substantially mitigates the effects of pesticide exposure. The results indicate that EFSA's reported protection goal of 7% of colony size and triggers for daily worker losses are overly conservative. The authors conclude that forage availability is critical for colony resilience and that with adequate forage the colonies are resilient to even high levels of worker losses. However, the authors recommend setting protection goals using suboptimal forage conditions to ensure conservatism and for such suboptimal forage, a total of 20% reduction in colony size was safe. Environ Toxicol Chem 2017;36:254-264. (c) 2016 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC. PMID- 27217077 TI - Prevalence of Unique Pediatric Pathologies Encountered by Paramedic Students Across Age Groups. AB - Introduction Traditionally, Emergency Medical Services (EMS) educators have divided the pediatric population into age groups to assist in targeting their clinical and didactic curriculum. Currently, the accrediting body for paramedic training programs requires student exposure to pediatric patients based entirely on age without specifying exposure to specific pathologies within each age stratification. Identifying which pathologies are most common within the different pediatric age groups would allow educators to design curriculum targeting the most prevalent pathologies in each age group and incorporating the physiologic and psychological developmental milestones commonly seen at that age. Hypothesis It was hypothesized that there are unique clusterings of pathologies, represented by paramedic student primary impressions, that are found in different age groups which can be used to target provider education. METHODS: This is a retrospective review of prospectively collected data documented by paramedic students in the Fisdap (Field Internship Student Data Acquisition Project; Saint Paul, Minnesota USA) database over a one-year period. For the purposes of this study, pediatric patients were defined arbitrarily as those between the ages of 0 16 years. All paramedic student primary impressions recorded in Fisdap for patients aged 0-16 years were abstracted. Primary impression by age was calculated and graphed. The frequency of primary impression was then assessed for significance of trend by age with an alpha <=.05 considered significant. RESULTS: The following primary impressions showed clinically and statistically significant variability in prevalence among different pediatric age groups: respiratory distress, medical-other, abdominal pain, seizure, overdose/poisoning, behavioral, and cardiac. In patients less than 13 years old, respiratory and other-medical were the most common two primary impressions and both decreased with age. In patients 5-16 years old, the prevalence of abdominal pain and behavioral/psych increased. Bimodal distributions for overdose were seen with one spike in the toddler and another in the adolescent population. Seizures were most common in the age group associated with febrile seizure. Sepsis was seen most often in the youngest patients and its prevalence decreased with age. CONCLUSION: There are statistically significant variations in the frequency of paramedic student primary impressions as a function of age in the pediatric population. Emphasizing paramedic student exposure to the most common pathologies encountered in each age group, in the context of the psychological and physiological milestones of each age, may improve paramedic student pediatric practice. Ernest EV , Brazelton TB , Carhart ED , Studnek JR , Tritt PL , Philip GA , Burnett AM . Prevalence of unique pediatric pathologies encountered by paramedic students across age groups. Prehosp Disaster Med. 2016; 31(4):386-391. PMID- 27217078 TI - The formation and breakdown of structured clots from whole milk during gastric digestion. AB - The behaviour of milk fat globules in the coagula of unheated and heated (90 degrees C for 20 min) whole milk during gastric digestion was investigated using a human gastric simulator. Structured protein clots were formed by a coagulation process that was driven by the action of the milk-clotting enzyme, pepsin, on the protein fraction of the whole milk. The fat globules in the milk appeared to be embedded in the clots as they formed. After clot formation, the different structures of the clots formed with unheated and heated whole milk led to different rates of protein hydrolysis by pepsin and resulted in the release of fat globules from the clots into the digesta; the release of fat globules was faster in the clots from the heated whole milk. Comparison of the rates of fat globule release from the clots and the rates of the reduction in fat-free matter in the clots showed that the release of fat globules from the clots from both unheated and heated milk was linearly dependent on the breakdown of the protein in the clots. Coalescence of fat globules appeared to occur in the gastric digesta and also within the protein. PMID- 27217076 TI - Next-generation proteasome inhibitor MLN9708 sensitizes breast cancer cells to doxorubicin-induced apoptosis. AB - Doxorubicin (Dox), one of the most effective chemotherapy drug for cancer treatment, is limited by its severe side effects and chemoresistance. Dox induces DNA damage and leads to significant proteomic changes in the cancer cells, which makes the ubiquitin-proteasome system a potential target to enhance the efficacy of Dox therapy. The unsuccessful clinical trials of proteasome inhibitor PS-341 (bortezomib) in solid tumors led to the invention of MLN9708 (ixazomib), an orally bioavailable next-generation proteasome inhibitor with improved pharmacokinetic and pharmacodynamic features. In this preclinical study, we used eight human breast cancer cell lines, which represent the major molecular subtypes of breast cancer, to validate the cytotoxic effects of MLN9708, alone and in combination with Dox. We found that MLN9708 had cytotoxic effects, induced autophagy and MKP-1 expression, and enhanced Dox-induced apoptosis in these cell lines. MLN9708 also enhanced Dox-induced JNK and p38 phosphorylation and inhibited Dox-induced IkappaBalpha degradation. Our in vitro results suggest that MLN9708 has antitumor effects in breast cancer and can sensitize breast cancer cells to Dox treatment. This promising combination may be an effective and feasible therapeutic option for treating breast cancer and warrants clinical validation. PMID- 27217079 TI - Screening of chelating ligands to enhance mercury accumulation from historically mercury-contaminated soils for phytoextraction. AB - Screening of optimal chelating ligands which not only have high capacities to enhance plant uptake of mercury (Hg) from soil but also can decrease bioavailable Hg concentration in soil is necessary to establish a viable chemically-assisted phytoextraction. Therefore, Brassica juncea was exposed to historically Hg contaminated soil (total Hg, 90 mg kg-1) to investigate the efficiency of seven chelating agents [ammonium thiosulphate, sodium thiosulphate, ammonium sulfate, ammonium chloride, sodium nitrate, ethylenediaminetetraacetic acid (EDTA), and sodium sulfite] at enhancing Hg phytoextraction; the leaching of bioavailable Hg caused by these chelating agents was also investigated. The Hg concentration in control (treated with double-distilled water) plant tissues was below 1 mg kg-1. The remarkably higher Hg concentration was found in plants receiving ammonium thiosulphate and sodium sulfite treatments. The bioaccumulation factors and translocation factors of ammonium thiosulphate and sodium sulfite treatments were significantly higher than those of the other treatments. The more efficient uptake of Hg by plants upon treatment with ammonium thiosulphate and sodium sulfite compared to the other treatments might be explained by the formation of special Hg-thiosulphate complexes that could be preferentially taken up by the roots and transported in plant tissues. The application of sulfite significantly increased bioavailable Hg concentration in soil compared with that in initial soil and control soil, whereas ammonium thiosulphate significantly decreased bioavailable Hg concentration. The apparent decrease of bioavailable Hg in ammonium thiosulphate-treated soil compared with that in sodium sulfite-treated soil might be attributable to the unstable Hg-thiosulphate complexes formed between thiosulphate and Hg; they could react to produce less bioavailable Hg in the soil. The results of this study indicate that ammonium thiosulphate may be an optimal chelating ligand for phytoextraction due to its great potential to enhance Hg accumulation in plants while decreasing bioavailable Hg concentration in the soil. PMID- 27217080 TI - Near-instant automatic access to visually presented words in the human neocortex: neuromagnetic evidence. AB - Rapid and efficient processing of external information by the brain is vital to survival in a highly dynamic environment. The key channel humans use to exchange information is language, but the neural underpinnings of its processing are still not fully understood. We investigated the spatio-temporal dynamics of neural access to word representations in the brain by scrutinising the brain's activity elicited in response to psycholinguistically, visually and phonologically matched groups of familiar words and meaningless pseudowords. Stimuli were briefly presented on the visual-field periphery to experimental participants whose attention was occupied with a non-linguistic visual feature-detection task. The neural activation elicited by these unattended orthographic stimuli was recorded using multi-channel whole-head magnetoencephalography, and the timecourse of lexically-specific neuromagnetic responses was assessed in sensor space as well as at the level of cortical sources, estimated using individual MR-based distributed source reconstruction. Our results demonstrate a neocortical signature of automatic near-instant access to word representations in the brain: activity in the perisylvian language network characterised by specific activation enhancement for familiar words, starting as early as ~70 ms after the onset of unattended word stimuli and underpinned by temporal and inferior-frontal cortices. PMID- 27217081 TI - Oil lenses on the air-water surface and the validity of Neumann's rule. AB - Many studies have focused on the mechanisms of oil spreading over the air-water surface, oil lens formation, and lens dynamics: Franklin et al.(1774), Rayleigh (1890), Neumann and Wangerin (1894), Hardy (1912), Lyons (1930), Langmuir (1933), Miller (1941), Zisman (1941), Pujado and Scriven (1972), Seeto et al. (1983), and Takamura et al. (2012). Despite all of these studies, the phenomenon of the oil lens's air-water surface equilibrium is still under discussion. Here, we highlight an accurate method to study the oil lens's three-phase-contact angle by reflected light interferometry, using both common (CRLI) and differential reflected light interferometry (DRLI) to verify Neumann's rule (the vectorial sum of the three tensions is zero). For non-spreading oils, the validity of Neumann's rule is confirmed for small lenses when the role of the oil film tension around the lens's meniscus is taken into consideration. Neumann's rule was also validated when the monolayer surface pressure isotherm was taken into consideration for oil spreading on the air-water surface. The periodic monolayer surface pressure oscillation of the oil phase monolayer created by the air evaporating biphilic oil was monitored with time. The monolayer's surface pressure periodic oscillation was attributed to the instability of the aqueous film covering the oil drop phase. The knowledge gained from this study will benefit the fundamental understanding of the oil lens's air-water surface equilibrium and oil spill mechanisms, thereby promoting better methods for the prevention and clean-up of oil spills. PMID- 27217082 TI - Electrokinetics of the silica and aqueous electrolyte solution interface: Viscoelectric effects. AB - The manipulation of biomolecules, fluid and ionic current in a new breed of integrated nanofluidic devices requires a quantitative understanding of electrokinetics at the silica/water interface. The conventional capacitor-based electrokinetic Electric Double Layer (EDL) models for this interface have some known shortcomings, as evidenced by a lack of consistency within the literature for the (i) equilibrium constants of surface silanol groups, (ii) Stern layer capacitance, (iii) zeta (zeta) potential measured by various electrokinetic methods, and (iv) surface conductivity. In this study, we consider how the experimentally observable viscoelectric effect - that is, the increase of the local viscosity due to the polarisation of polar solvents - affects electrokinetcs at the silica/water interface. Specifically we consider how a model that considers viscoelectric effects (the VE model) performs against two conventional electrokinetic models, namely the Gouy-Chapman (GC) and Basic Stern capacitance (BS) models, in predicting four fundamental electrokinetic phenomena: electrophoresis, electroosmosis, streaming current and streaming potential. It is found that at moderate to high salt concentrations (>5*10(-3)M) predictions from the VE model are in quantitative agreement with experimental electrokinetic measurements when the sole additional adjustable parameter, the viscoelectric coefficient, is set equal to a value given by a previous independent measurement. In contrast neither the GS nor BS models is able to reproduce all experimental data over the same concentration range using a single, robust set of parameters. Significantly, we also show that the streaming current and potential in the moderate to high surface charge range are insensitive to surface charge behaviour (including capacitances) when viscoelectric effects are considered, in difference to models that do not consider these effects. This strongly questions the validity of using pressure based electrokinetic experiments to measure surface charge characteristics within this experimentally relevant high pH and moderate to high salt concentration range. At low salt concentrations (<5*10(-3)M) we find that there is a lack of consistency in previously measured channel conductivities conducted under similar solution conditions (pH, salt concentration), preventing a conclusive assessment of any model suitability in this regime. PMID- 27217083 TI - Design and stability study of an oral solution of amlodipine besylate for pediatric patients. AB - INTRODUCTION: Amlodipine is an antihypertensive agent recommended for the management of hypertension in children and adolescents. The commercially available tablets of 5 and 10mg do not provide the necessary flexibility in dosing needed for treating children. Our goal was to develop a pediatric oral solution of amlodipine, using a robust manufacturing process suitable for ex tempora and larger scale production. METHODS: The parameters API and preservative content, related substances, appearance and pH were studied under four different storage conditions. Samples were analyzed up to 12months. Microbiological quality was studied in an 18-week in-use test based on a two-times daily dosing schedule. RESULTS: The stability of the formulation was influenced by storage conditions and composition. A formulation containing amlodipine besylate, sucrose syrup and methyl paraben remained physically stable for 12months at 4 degrees C with no loss of amlodipine content. Related substances increased during the study but remained below 0.5%. In-use stability was proven up to 18weeks. DISCUSSION: Storage under refrigerated conditions was necessary to prevent precipitation and to obtain an acceptable shelf-life. In conclusion, we have developed and validated an amlodipine oral solution, suitable for the pediatric population. This liquid formulation is preferred over manipulated commercial dosage forms or non-standardized extemporaneously compounded formulations. PMID- 27217085 TI - Promoting Adult Pertussis Vaccination in the Workplace. PMID- 27217084 TI - Promoting Adult Pertussis Vaccination in the Workplace. AB - Vaccines are an important disease prevention strategy among individuals of all age groups. Despite the success of vaccinations in preventing communicable diseases, adults, in particular, often have sub-optimal vaccination rates. Consequently, some vaccine-preventable diseases, such as pertussis, are still on the rise in the United States despite the availability of the Tdap vaccine. As most adults can be found in the workplace, occupational and environmental health nurses are in a unique position to encourage employers to promote adequate Tdap vaccination among their employees. As specific resources regarding Tdap vaccination are lacking, the Pertussis Prevention Toolkit was developed to help occupational health nurses promote Tdap vaccination in the workplace. PMID- 27217086 TI - Perturbation of genome integrity to fight pathogenic microorganisms. AB - BACKGROUND: Resistance against antibiotics is unfortunately still a major biomedical challenge for a wide range of pathogens responsible for potentially fatal diseases. SCOPE OF REVIEW: In this study, we aim at providing a critical assessment of the recent advances in design and use of drugs targeting genome integrity by perturbation of thymidylate biosynthesis. MAJOR CONCLUSION: We find that research efforts from several independent laboratories resulted in chemically highly distinct classes of inhibitors of key enzymes within the routes of thymidylate biosynthesis. The present article covers numerous studies describing perturbation of this metabolic pathway in some of the most challenging pathogens like Mycobacterium tuberculosis, Plasmodium falciparum, and Staphylococcus aureus. GENERAL SIGNIFICANCE: Our comparative analysis allows a thorough summary of the current approaches to target thymidylate biosynthesis enzymes and also include an outlook suggesting novel ways of inhibitory strategies. This article is part of a Special Issue entitled "Science for Life" Guest Editor: Dr. Austen Angell, Dr. Salvatore Magazu and Dr. Federica Migliardo. PMID- 27217087 TI - Air pollution particles and iron homeostasis. AB - BACKGROUND: The mechanism underlying biological effects, including pro inflammatory outcomes, of particles deposited in the lung has not been defined. MAJOR CONCLUSIONS: A disruption in iron homeostasis follows exposure of cells to all particulate matter including air pollution particles. Following endocytosis, functional groups at the surface of retained particle complex iron available in the cell. In response to a reduction in concentrations of requisite iron, a functional deficiency can result intracellularly. Superoxide production by the cell exposed to a particle increases ferrireduction which facilitates import of iron with the objective being the reversal of the metal deficiency. Failure to resolve the functional iron deficiency following cell exposure to particles activates kinases and transcription factors resulting in a release of inflammatory mediators and inflammation. Tissue injury is the end product of this disruption in iron homeostasis initiated by the particle exposure. Elevation of available iron to the cell precludes deficiency of the metal and either diminishes or eliminates biological effects. GENERAL SIGNIFICANCE: Recognition of the pathway for biological effects after particle exposure to involve a functional deficiency of iron suggests novel therapies such as metal supplementation (e.g. inhaled and oral). In addition, the demonstration of a shared mechanism of biological effects allows understanding the common clinical, physiological, and pathological presentation following exposure to disparate particles. This article is part of a Special Issue entitled Air Pollution, edited by Wenjun Ding, Andrew J. Ghio and Weidong Wu. PMID- 27217088 TI - An Examination of the Topology and Measurement of the Alexithymia Construct Using Network Analysis. AB - There is some ongoing controversy surrounding the definition and measurement of the alexithymia construct. Whereas most researchers describe 4 components comprising the construct (difficulty identifying feelings, difficulty describing feelings, restricted fantasizing, and externally oriented thinking), some include a 5th component, which is defined as "reduced experiencing of emotional feelings." This study examined the topology and measurement of alexithymia using the method of network analysis with data from a heterogeneous multilanguage sample (N = 1,696) that had completed the Bermond-Vorst Alexithymia Questionnaire (BVAQ; Vorst & Bermond, 2001 ). The BVAQ includes an Emotionalizing subscale for assessing the purported 5th component; we compared the network analyses conducted both with and without the Emotionalizing items. The results revealed strong associations between Emotionalizing and Analyzing (externally oriented thinking) items, but Emotionalizing items had almost as many negative as positive connections with items assessing the other components of the construct. A comparison of communities identified by modularity analyses of the 2 networks failed to support emotionalizing as a distinct component of the construct. In addition, network metrics revealed that Fantasizing items were particularly weak within both networks, suggesting that reduced fantasizing might be a peripheral component of the alexithymia construct. Implications for the measurement and treatment of alexithymia are discussed. PMID- 27217089 TI - Anti-inflammatory and Wound Healing Activities of Aloe vera, Honey and Milk Ointment on Second-Degree Burns in Rats. AB - The aim of the present study was morphological and morphometric investigation of burn healing impacts of an honey, milk, and Aloe vera (HMA) ointment on experimentally induced second-degree burns, to approve the medicinal basis of its use in Iranian traditional medicine. A total of 21 male Albino rats weighing 200 to 300 g were divided into 3 groups of 7, including (1) control group, (2) positive control group, and (3) the treatment group that were treated with eucerin, silver sulfadiazine 3% and HMA ointment 5% respectively.After anesthetizing, the second-degree burns (1 cm(2) areas) were made on the back of the animals using a digital controlled hot plaque, and each group was treated topically, based on the time scheduled. Then, skin punch biopsies were obtained on the 1st, 14th, and 28th days of post-burn induction; processed; and stained using hematoxylin and eosin and Masson's trichrome methods. The results showed that HMA ointment induces cell proliferation, increasing the wound closure rate, blood vessel counts, and collagen fiber density in treated animals. It also reduced the wound secretions, inflammation, and scar formation. According to the obtained morphological, morphometric results, we concluded that the traditional HMA ointment, which is rich in therapeutic biomaterials and minerals, has multiple healing effects on burn wounds in rats. PMID- 27217090 TI - The Adipose Mesenchymal Stem Cell Secretome Inhibits Inflammatory Responses of Microglia: Evidence for an Involvement of Sphingosine-1-Phosphate Signalling. AB - Central nervous system (CNS) inflammation is primarily driven by microglial cells which secrete proinflammatory cytokines and undergo proliferation upon activation, as it occurs in neurodegenerative diseases. Uncontrolled or prolonged CNS inflammation is potentially harmful and can result in cellular damage. Recently, many studies have focused on human adipose tissue as an attractive source of cytokines with immunosuppressive properties that potentially modulate inflammation. Our study aimed to evaluate if different methods of human tissue collection could affect adipose mesenchymal stem cell (ADSC)-derived cytokine secretion and investigate the effects of ADSC secretome in modulating microglia activation and the possible implication of sphingosine-1-phosphate (S1P) in these effects. Our results demonstrate that the conditioned medium (CM) of ADSCs isolated by two different processing methods (lipoaspirate and Lipogems) significantly inhibited the lipopolysaccharide (LPS)-induced effects on microglia activation, including microglial expression of CD68, cytokine secretion, proliferation, and migration. Pulse studies with radiolabeled sphingosine demonstrated that LPS treatment of resting microglia induced a significant increase of both cellular and extracellular S1P. Moreover, and of relevance, FTY720, a functional antagonist of S1P receptor, inhibited the multiple LPS induced proinflammatory effects on microglia, and S1P suppressed the anti inflammatory effect of ADSC-CM. This suggests that LPS-mediated microglial activation is countered by ADSC-CM through the modulation of sphingosine kinase/S1P signalling. PMID- 27217091 TI - The components of rice and watermelon root exudates and their effects on pathogenic fungus and watermelon defense. AB - Watermelon (Citrullus lanatus) is susceptible to wilt disease caused by the fungus Fusarium oxysporum f. sp niveum (FON). Intercropping management of watermelon/aerobic rice (Oryza sativa) alleviates watermelon wilt disease, because some unidentified component(s) in rice root exudates suppress FON sporulation and spore germination. Here, we show that the phenolic acid p coumaric acid is present in rice root exudates only, and it inhibits FON spore germination and sporulation. We found that exogenously applied p-coumaric acid up regulated the expression of ClPR3 in roots, as well as increased chitinase activity in leaves. Furthermore, exogenously applied p-coumaric acid increased beta-1,3-glucanase activity in watermelon roots. By contrast, we found that ferulic acid was secreted by watermelon roots, but not by rice roots, and that it stimulated spore germination and sporulation of FON. Exogenous application of ferulic acid down-regulated ClPR3 expression and inhibited chitinase activity in watermelon leaves. Salicylic acid was detected in both watermelon and rice root exudates, which stimulated FON spore germination at low concentrations and suppressed spore germination at high concentrations. Exogenously applied salicylic acid did not alter ClPR3 expression, but did increase chitinase and beta-1,3-glucanase activities in watermelon leaves. Together, our results show that the root exudates of phenolic acids were different between rice and watermelon, which lead to their special ecological roles on pathogenic fungus and watermelon defense. PMID- 27217092 TI - The Role of Pyruvate in Protecting 661W Photoreceptor-Like Cells Against Light Induced Cell Death. AB - PURPOSE: Light is a requirement for the function of photoreceptors in visual processing. However, prolonged light exposure can be toxic to photoreceptors, leading to increased reactive oxygen species (ROS), lipid peroxidation, and photoreceptor cell death. We used the 661W mouse cone photoreceptor-like cell line to study the effects of pyruvate in protecting these cells from light induced toxicity. METHODS: 661W cells were exposed to 15,000 lux continuous bright light for 5 hours and incubated in Dulbecco's modified eagle medium (DMEM) with various concentrations of pyruvate. Following light damage, cells were assessed for changes in morphology, cell toxicity, viability, and ROS production. Mitochondrial respiration and anaerobic glycolysis were also assessed using a Seahorse Xfe96 extracellular flux analyzer. RESULTS: We found that cell death caused by light damage in 661W cells was dramatically reduced in the presence of pyruvate. Cells with pyruvate-supplemented media also showed attenuation of oxidative stress and maintained normal levels of ATP. We also found that alterations in the concentrations of pyruvate had no effect on mitochondrial respiration or glycolysis in light-damaged cells. CONCLUSIONS: Taken together, the results show that pyruvate is protective against light damage but does not alter the metabolic output of the cells, indicating an alternative role for pyruvate in reducing oxidative stress. Thus, sodium pyruvate is a possible candidate for the treatment against the oxidative stress component of retinal degenerations. PMID- 27217093 TI - Development of an Interdisciplinary Team Communication Framework and Quality Metrics for Home-Based Medical Care Practices. AB - BACKGROUND: The unique needs of homebound adults receiving home-based medical care (HBMC) (ie, home-based primary care and home-based palliative care services) are ideally provided by interdisciplinary care teams (IDTs) that provide coordinated care. The composition of team members from an array of organizations and the unique dimension of providing care in the home present specific challenges to timely access and communication of patient care information. The objective of this work was to develop a conceptual framework and corresponding quality indicators (QIs) that assess how IDT members for HBMC practices access and communicate key patient information with each other. METHODS: A systematic review of peer-reviewed and gray literature was performed to inform a framework for care coordination in the home and the development of candidate QIs to assess processes by which all IDT members optimally access and use patient information. A technical expert panel (TEP) participated in a modified Delphi process to assess the validity and feasibility of each QI and to identify which would be most suitable for testing in the field. RESULTS: Thematic analysis of literature revealed 4 process themes for how HBMC practices might engage in high-quality care coordination: using electronic medical records, conducting interdisciplinary team meetings, sharing standardized patient assessments, and communicating via secure e-messaging. Based on these themes, 9 candidate QIs were developed to reflect these processes. Three candidate QIs were assessed by the TEP as valid and feasible to measure in an HBMC practice setting. These indicators focused on use of IDT meetings, standardized patient assessments, and secure e-messaging. CONCLUSION: Translating the complex issue of care coordination into QIs will improve care delivered to vulnerable home-limited adults who receive HBMC. Guided by the literature, we developed a framework to reflect optimal care coordination in the home setting and identified 3 candidate QIs to field-test in HBMC practices. PMID- 27217094 TI - What Should the Optimal Systolic Blood Pressure Goal Be in Treating Older Persons with Hypertension? PMID- 27217095 TI - Cloudy, Foul-Smelling Urine Not a Criteria for Diagnosis of Urinary Tract Infection in Older Adults. PMID- 27217096 TI - Loneliness in Nursing Homes. PMID- 27217098 TI - ERRATUM. PMID- 27217097 TI - Experience of a new high-purity factor X concentrate in subjects with hereditary factor X deficiency undergoing surgery. AB - INTRODUCTION: Maintaining haemostasis in surgery is challenging for hereditary rare bleeding disorders in which multi-coagulation-factor concentrates are the only therapeutic option. Hereditary factor X (FX) deficiency affects 1:500 000 to 1:1 000 000 individuals, and no specific replacement FX concentrate has been available. A high-purity, plasma-derived FX concentrate (pdFX) has been developed for patients with hereditary FX deficiency. AIM: Our objective was to assess the safety and efficacy of pdFX in subjects with FX deficiency undergoing surgery. METHODS: Subjects with hereditary mild-to-severe FX deficiency (basal plasma FX activity [FX:C] <20 IU dL(-1) ) undergoing surgery received pdFX preoperatively to raise FX:C to 70-90 IU dL(-1) and postoperatively to maintain levels >50 IU dL(-1) until the subject was no longer at risk of bleeding due to surgery. Efficacy of pdFX was assessed by blood loss during surgery, requirement for blood transfusion, postoperative bleeding from the surgical or other sites, and changes in haemoglobin levels. Safety was assessed by adverse events (AEs), development of inhibitors, and clinically significant changes in laboratory parameters. RESULTS: Five subjects (aged 14-59 years) underwent seven surgical procedures (four major and three minor). Treatment duration was 1-15 days. For each procedure, pdFX treatment was assessed as "excellent" in preventing bleeding and achieving haemostasis. No blood transfusions were required, no AEs related to pdFX were observed, and no clinically significant trends were found in any laboratory parameters. CONCLUSION: These data demonstrate that pdFX is safe and effective as replacement therapy in five subjects with mild-to-severe FX deficiency undergoing surgery on seven occasions. PMID- 27217099 TI - The scaffold protein calcium/calmodulin-dependent serine protein kinase controls ATP release in sensory ganglia upon P2X3 receptor activation and is part of an ATP keeper complex. AB - P2X3 receptors, gated by extracellular ATP, are expressed by sensory neurons and are involved in peripheral nociception and pain sensitization. The ability of P2X3 receptors to transduce extracellular stimuli into neuronal signals critically depends on the dynamic molecular partnership with the calcium/calmodulin-dependent serine protein kinase (CASK). The present work used trigeminal sensory neurons to study the impact that activation of P2X3 receptors (evoked by the agonist alpha,beta-meATP) has on the release of endogenous ATP and how CASK modulates this phenomenon. P2X3 receptor function was followed by ATP efflux via Pannexin1 (Panx1) hemichannels, a mechanism that was blocked by the P2X3 receptor antagonist A-317491, and by P2X3 silencing. ATP efflux was enhanced by nerve growth factor, a treatment known to potentiate P2X3 receptor function. Basal ATP efflux was not controlled by CASK, and carbenoxolone or Pannexin silencing reduced ATP release upon P2X3 receptor function. CASK-controlled ATP efflux followed P2X3 receptor activity, but not depolarization-evoked ATP release. Molecular biology experiments showed that CASK was essential for the transactivation of Panx1 upon P2X3 receptor activation. These data suggest that P2X3 receptor function controls a new type of feed-forward purinergic signaling on surrounding cells, with consequences at peripheral and spinal cord level. Thus, P2X3 receptor-mediated ATP efflux may be considered for the future development of pharmacological strategies aimed at containing neuronal sensitization. P2X3 receptors are involved in sensory transduction and associate to CASK. We have studied in primary sensory neurons the molecular mechanisms downstream P2X3 receptor activation, namely ATP release and partnership with CASK or Panx1. Our data suggest that CASK and P2X3 receptors are part of an ATP keeper complex, with important feed-forward consequences at peripheral and central level. PMID- 27217100 TI - The role of anxiety in vulnerability for self-injurious behaviour: studies in a rodent model. AB - Self-injurious behaviour (SIB) is a debilitating characteristic that is highly prevalent in autism and other neurodevelopmental disorders. Pathological anxiety is also common, and there are reports of comorbid anxiety and self-injury in some children. We have investigated potential interactions between anxiety and self injury, using a rat model of pemoline-induced self-biting. In one experiment, rats were pre-screened for trait anxiety by measuring expression of anxiety related behaviour on the elevated plus maze and open field emergence test. The rats were then treated with pemoline once daily for ten days, and vulnerability for pemoline-induced self-injury was evaluated. This revealed modest correlations between innate levels of anxiety-related behaviour in the open field test (time in the start box, and latency to enter the open field), and vulnerability for pemoline-induced self-biting (total duration of self-injurious oral contact, and total size of tissue injury). Measures in the elevated plus maze were not significantly correlated with vulnerability for pemoline-induced self-injury. In a second experiment, rats were treated with the beta-carboline FG 7142 twice daily, during 5days of treatment with pemoline. The rats that were treated with this anxiogenic drug exhibited greater duration of self-injurious oral contact, and larger injuries than vehicle-treated controls did. Overall, these results suggest that anxiety may contribute to the etiology and/or expression of self injurious behaviour, and indicate that further research is warranted. PMID- 27217101 TI - Risky choice and brain CRF after adolescent ethanol vapor exposure and social stress in adulthood. AB - Adolescent ethanol exposure increases risky choice and alters corticotropin releasing factor (CRF) systems in adulthood. The impact of stress on risky choice after adolescent intermittent ethanol (AIE) exposure is not known. We investigated time-specific effects of AIE vapor exposure during early adolescence on risky choice after stress or no stress in adulthood. Male Wistar rats were exposed to air or AIE vapor on postnatal days 28-42 (adolescence) and were exposed to 10days of social defeat or no stress on postnatal days 172-181 (adulthood). Risky choice was assessed in the probability discounting task under baseline conditions and after days 1 and 10 of social defeat. CRF and CRF receptor 1 (CRFR1) mRNA levels were assessed in the prefrontal cortex (PFC) and the central nucleus of the amygdala (CeA) 24h post-stress to evaluate persistent effects of stress on the brain. AIE exposure had no effect on risky choice either at baseline or after social defeat. Additionally, neither acute nor chronic social defeat affected risky choice in air-exposed rats. In the PFC, chronic social defeat selectively decreased CRF mRNA levels in air-exposed rats and increased CRFR1 mRNA levels in all rats. AIE exposure increased CRF mRNA levels in the CeA with no effect of social stress. Our results indicate no effect of ethanol exposure via vapor during early adolescence on risky choice, while our previous findings indicated that AIE exposure via gavage affected risky choice. Both AIE exposure and social defeat altered CRF and CRFR1 mRNA levels in the brain. PMID- 27217102 TI - Microbial modulation of behavior and stress responses in zebrafish larvae. AB - The influence of the microbiota on behavior and stress responses is poorly understood. Zebrafish larvae have unique characteristics that are advantageous for neuroimmune research, however, they are currently underutilized for such studies. Here, we used germ-free zebrafish to determine the effects of the microbiota on behavior and stress testing. The absence of a microbiota dramatically altered locomotor and anxiety-related behavior. Additionally, characteristic responses to an acute stressor were also obliterated in larvae lacking exposure to microbes. Lastly, treatment with the probiotic Lactobacillus plantarum was sufficient to attenuate anxiety-related behavior in conventionally raised zebrafish larvae. These results underscore the importance of the microbiota in communicating to the CNS via the microbiome-gut-brain axis and set a foundation for using zebrafish larvae for neuroimmune research. PMID- 27217103 TI - Over-expression of the GluN2B subunit in the forebrain facilitates the acquisition of morphine-related positive and aversive memory in rats. AB - GluN2B-containing N-methyl-d-aspartate (NMDA) receptors in the brain are known to have an important role in drug-associated learning and memory. Selective blockage of GluN2B-containing NMDA receptors (GluN2B-NMDARs) has been shown to impair morphine-induced conditioned place preference (CPP) without affecting natural reward-induced CPP. In the present study, GluN2B transgenic rats with over expressed GluN2B-subunits in the forebrain were used to assess the susceptibility to CPP induced by morphine and natural rewards as well as to naloxone-induced conditioned place aversion (CPA). The results showed that GluN2B transgenic rats exhibited a relatively higher susceptibility to morphine-induced CPP and naloxone induced CPA than their wild-type littermates did, while they retained the similar sensitivity as wild-type rats to CPP induced by natural reinforcers (food and sucrose). These findings suggest that increased level of GluN2B-NMDARs in forebrain facilitates formation of drug-related memory, but not that associated with natural rewards. GluN2B-NMDARs might be a potential target for the treatment of drug abuse. PMID- 27217104 TI - Cobalamin's (Vitamin B12) Surprising Function as a Photoreceptor. AB - Cobalamin (Vitamin B12) is an adenosyl- or methyl-donating cofactor for many enzymes, yet many proteins with unknown or nonenzymatic function also contain B12 binding domains. Recent studies show that light excitation energy can promote covalent linkage of B12 to transcription factors with this linkage, affecting gene expression. Thus, B12 now has a newly described regulatory function. Here, our bioinformatics analysis reveals other transcription factors, photoreceptors, kinases, and oxygen sensors that harbor a B12-binding domain that could also regulate activity in response to light absorption. PMID- 27217105 TI - The matter of motivation: Striatal resting-state connectivity is dissociable between grit and growth mindset. AB - The current study utilized resting-state functional magnetic resonance imaging (fMRI) to examine how two important non-cognitive skills, grit and growth mindset, are associated with cortico-striatal networks important for learning. Whole-brain seed-to-voxel connectivity was examined for dorsal and ventral striatal seeds. While both grit and growth mindset were associated with functional connectivity between ventral striatal and bilateral prefrontal networks thought to be important for cognitive-behavioral control. There were also clear dissociations between the neural correlates of the two constructs. Grit, the long-term perseverance towards a goal or set of goals, was associated with ventral striatal networks including connectivity to regions such as the medial prefrontal and rostral anterior cingulate cortices implicated in perseverance, delay and receipt of reward. Growth mindset, the belief that effort can improve talents, notably intelligence, was associated with both ventral and dorsal striatal connectivity with regions thought to be important for error monitoring, such as dorsal anterior cingulate cortex. Our findings may help construct neurocognitive models of these non-cognitive skills and have critical implications for character education. Such education is a key component of social and emotional learning, ensuring that children can rise to challenges in the classroom and in life. PMID- 27217106 TI - Does inhibitory control training transfer?: behavioral and neural effects on an untrained emotion regulation task. AB - Inhibitory control (IC) is a critical neurocognitive skill for successfully navigating challenges across domains. Several studies have attempted to use training to improve neurocognitive skills such as IC, but few have found that training generalizes to performance on non-trained tasks. We used functional magnetic resonance imaging (fMRI) to investigate the effect of IC training on a related but untrained emotion regulation (ER) task with the goal of clarifying how training alters brain function and why its effects typically do not transfer across tasks. We suggest hypotheses for training-related changes in activation relevant to transfer effects: the strength model and several plausible alternatives (shifting priorities, stimulus-response automaticity, scaffolding). Sixty participants completed three weeks of IC training and underwent fMRI scanning before and after. The training produced pre- to post-training changes in neural activation during the ER task in the absence of behavioral changes. Specifically, individuals in the training group demonstrated reduced activation during ER in the left inferior frontal gyrus and supramarginal gyrus, key regions in the IC neural network. This result is less consistent with the strength model and more consistent with a motivational account. Implications for future work aiming to further pinpoint mechanisms of training transfer are discussed. PMID- 27217107 TI - Conditioned social dominance threat: observation of others' social dominance biases threat learning. AB - Social groups are organized along dominance hierarchies, which determine how we respond to threats posed by dominant and subordinate others. The persuasive impact of these dominance threats on mental and physical well-being has been well described but it is unknown how dominance rank of others bias our experience and learning in the first place. We introduce a model of conditioned social dominance threat in humans, where the presence of a dominant other is paired with an aversive event. Participants first learned about the dominance rank of others by observing their dyadic confrontations. During subsequent fear learning, the dominant and subordinate others were equally predictive of an aversive consequence (mild electric shock) to the participant. In three separate experiments, we show that participants' eye-blink startle responses and amygdala reactivity adaptively tracked dominance of others during observation of confrontation. Importantly, during fear learning dominant vs subordinate others elicited stronger and more persistent learned threat responses as measured by physiological arousal and amygdala activity. Our results characterize the neural basis of learning through observing conflicts between others, and how this affects subsequent learning through direct, personal experiences. PMID- 27217108 TI - Motivational incentives lead to a strong increase in lateral prefrontal activity after self-control exertion. AB - Self-control is key to success in life. Initial acts of self-control temporarily impair subsequent self-control performance. Why such self-control failures occur is unclear, with prominent models postulating a loss of a limited resource vs a loss of motivation, respectively. Here, we used functional magnetic resonance imaging to identify the neural correlates of motivation-induced benefits on self control. Participants initially exerted or did not exert self-control. In a subsequent Stroop task, participants performed worse after exerting self-control, but not if they were motivated to perform well by monetary incentives. On the neural level, having exerted self-control resulted in decreased activation in the left inferior frontal gyrus. Increasing motivation resulted in a particularly strong activation of this area specifically after exerting self-control. Thus, after self-control exertion participants showed more prefrontal neural activity without improving performance beyond baseline level. These findings suggest that impaired performance after self-control exertion may not exclusively be due to a loss of motivation. PMID- 27217109 TI - Performance monitoring during a minimal group manipulation. AB - The on-going (self-)monitoring of our behaviour is inextricably intertwined with the surrounding social context. In this study, we investigated whether a minimal group paradigm assigning individuals to arbitrary group categories is powerful enough to induce changes in behavioural, psychophysiological and event-related potential correlates of performance monitoring. Following arbitrary group assignment based on ostensible task performance and a group identification task, 22 volunteers performed a flanker-task during both in-group and out-group contexts, while electroencephalography was performed. More errors were committed in the out-group compared with the in-group context. Error-related negativity amplitudes were larger for in-group compared with out-group errors. However, subsequent processing reflected in late Pe amplitudes and stimulus-driven conflict reflected in N2 amplitudes were not affected by the group context. Heart rate deceleration (during both correct and incorrect trials) tended to be more pronounced during the out-group compared with the in-group context. This surprising observation was corroborated by subjective ratings of performance satisfaction, in which participants reported higher satisfaction with their out group performance. This study identified specific stimulus evaluation processes to be affected by a minimal group manipulation and demonstrated thereby transient top-down effects of a social context manipulation on performance monitoring. PMID- 27217110 TI - Self-enhancement among Westerners and Easterners: a cultural neuroscience approach. AB - We adopted a cultural neuroscience approach to the investigation of self enhancement. Western and Eastern participants made self-referent judgments on positive and negative traits while we recorded their electroencephalography signals. At the judgmental level, we assessed trait endorsement (judgments of traits self-descriptiveness) and reaction times (speed of such judgments). Participants endorsed more positive traits as self-descriptive and more negative traits as non-self-descriptive, although the magnitude of this effect (level of self-positivity) was higher in the Western than Eastern sample. Moreover, all participants responded faster to positive self-descriptive traits and to negative non-self-descriptive traits, indicating that the self-enhancement motive is equally potent across cultures. At the neurophysiological level, we assessed N170 and LPP. Negative traits elicited larger N170 among Easterners, indicating initial allocation of attentional resources to the processing of negative information. However, negative compared to positive self-descriptive traits elicited a larger LPP, whereas negative and positive non-self-descriptive traits did not differ in the LPP they elicited. This pattern generalized across samples, pointing to a pancultural physiological correlate of the self-enhancement motive. PMID- 27217111 TI - Neural connectivity during reward expectation dissociates psychopathic criminals from non-criminal individuals with high impulsive/antisocial psychopathic traits. AB - Criminal behaviour poses a big challenge for society. A thorough understanding of the neurobiological mechanisms underlying criminality could optimize its prevention and management. Specifically,elucidating the neural mechanisms underpinning reward expectation might be pivotal to understanding criminal behaviour. So far no study has assessed reward expectation and its mechanisms in a criminal sample. To fill this gap, we assessed reward expectation in incarcerated, psychopathic criminals. We compared this group to two groups of non criminal individuals: one with high levels and another with low levels of impulsive/antisocial traits. Functional magnetic resonance imaging was used to quantify neural responses to reward expectancy. Psychophysiological interaction analyses were performed to examine differences in functional connectivity patterns of reward-related regions. The data suggest that overt criminality is characterized, not by abnormal reward expectation per se, but rather by enhanced communication between reward-related striatal regions and frontal brain regions. We establish that incarcerated psychopathic criminals can be dissociated from non criminal individuals with comparable impulsive/antisocial personality tendencies based on the degree to which reward-related brain regions interact with brain regions that control behaviour. The present results help us understand why some people act according to their impulsive/antisocial personality while others are able to behave adaptively despite reward-related urges. PMID- 27217112 TI - Targeting modulates audiences' brain and behavioral responses to safe sex video ads. AB - Video ads promoting condom use are a key component of media campaigns to stem the HIV epidemic. Recent neuroimaging studies in the context of smoking cessation, point to personal relevance as one of the key variables that determine the effectiveness of public health messages. While minority men who have sex with men (MSM) are at the highest risk of HIV infection, most safe-sex ads feature predominantly Caucasian actors in heterosexual scenarios. We compared brain respons of 45 African American MSM to safe sex ads that were matched (i.e. 'Targeted') to participants' sexual orientation and race, and 'Untargeted' ads that were un matched for these characteristics. Ad recall, perceived 'convincingness' and attitudes towards condom use were also assessed. We found that Targeted ads were better remembered than the Untargeted ads but perceived as equally convincing. Targeted ads engaged brain regions involved in self referential processing and memory, including the amygdala, hippocampus, temporal and medial prefrontal cortices (MPFC) and the precuneus. Connectivity between MPFC and precuneus and middle temporal gyrus was stronger when viewing Targeted ads. Our results suggest that targeting may increase cognitive processing of safe sex ads and justify further prospective studies linking brain response to media public health interventions and clinical outcomes. PMID- 27217113 TI - Emotion regulation changes the duration of the BOLD response to emotional stimuli. AB - Emotion regulation theories posit that strategies like reappraisal should impact both the intensity and duration of emotional responses. However, research on reappraisal to date has examined almost exclusively its effect on the intensity of responses while failing to examine its effect on the duration of responses. To address this, we used inverse logit functions to estimate the height and duration of hemodynamic responses to negative pictures when individuals with recent life stress were instructed to use reappraisal either to decrease their negative emotion or to increase their positive emotion (relative to unregulated viewing of negative pictures). Several emotion-generative regions such as the amygdala, thalamus and midbrain exhibited decreases in duration of activation, even when controlling for differences in height of activation. In addition, whereas the amygdala exhibited both decreased activation height and duration when participants reappraised to decrease their negative emotion, it only exhibited decreased duration when participants reappraised to increase their positive emotion. These results indicate that emotion regulation alters the temporal dynamics of emotional responding and that models of reappraisal should accommodate whether reappraisal influences the height of activation, duration of activation or both, which may change based on the goal of the reappraisal strategy being used. PMID- 27217114 TI - From painkiller to empathy killer: acetaminophen (paracetamol) reduces empathy for pain. AB - Simulation theories of empathy hypothesize that empathizing with others' pain shares some common psychological computations with the processing of one's own pain. Support for this perspective has largely relied on functional neuroimaging evidence of an overlap between activations during the experience of physical pain and empathy for other people's pain. Here, we extend the functional overlap perspective to the neurochemical level and test whether a common physical painkiller, acetaminophen (paracetamol), can reduce empathy for another's pain. In two double-blind placebo-controlled experiments, participants rated perceived pain, personal distress and empathic concern in response to reading scenarios about another's physical or social pain, witnessing ostracism in the lab, or visualizing another study participant receiving painful noise blasts. As hypothesized, acetaminophen reduced empathy in response to others' pain. Acetaminophen also reduced the unpleasantness of noise blasts delivered to the participant, which mediated acetaminophen's effects on empathy. Together, these findings suggest that the physical painkiller acetaminophen reduces empathy for pain and provide a new perspective on the neurochemical bases of empathy. Because empathy regulates prosocial and antisocial behavior, these drug-induced reductions in empathy raise concerns about the broader social side effects of acetaminophen, which is taken by almost a quarter of adults in the United States each week. PMID- 27217115 TI - Disentangling the roles of arousal and amygdala activation in emotional declarative memory. AB - A large body of evidence in animals and humans implicates the amygdala in promoting memory for arousing experiences. Although the amygdala can trigger threat-related noradrenergic-sympathetic arousal, in humans amygdala activation and noradrenergic-sympathetic arousal do not always concur. This raises the question how these two processes play a role in enhancing emotional declarative memory. This study was designed to disentangle these processes in a combined subsequent-memory/fear-conditioning paradigm with neutral items belonging to two conceptual categories as conditioned stimuli. Functional MRI, skin conductance (index of sympathetic activity), and pupil dilation (indirect index of central noradrenergic activity) were acquired throughout procedures. Recognition memory for individual items was tested 24 h later. We found that pupil dilation and skin conductance responses were higher on CS+ (associated with a shock) compared with CS- trials, irrespective of later memory for those items. By contrast, amygdala activity was only higher for CS+ items that were later confidently remembered compared with CS+ items that were later forgotten. Thus, amygdala activity and not noradrenergic-sympathetic arousal, predicted enhanced declarative item memory. This dissociation is in line with animal models stating that the amygdala integrates arousal-related neuromodulatory changes to alter mnemonic processes elsewhere in the brain. PMID- 27217116 TI - Independent component processes underlying emotions during natural music listening. AB - The aim of this study was to investigate the brain processes underlying emotions during natural music listening. To address this, we recorded high-density electroencephalography (EEG) from 22 subjects while presenting a set of individually matched whole musical excerpts varying in valence and arousal. Independent component analysis was applied to decompose the EEG data into functionally distinct brain processes. A k-means cluster analysis calculated on the basis of a combination of spatial (scalp topography and dipole location mapped onto the Montreal Neurological Institute brain template) and functional (spectra) characteristics revealed 10 clusters referring to brain areas typically involved in music and emotion processing, namely in the proximity of thalamic limbic and orbitofrontal regions as well as at frontal, fronto-parietal, parietal, parieto-occipital, temporo-occipital and occipital areas. This analysis revealed that arousal was associated with a suppression of power in the alpha frequency range. On the other hand, valence was associated with an increase in theta frequency power in response to excerpts inducing happiness compared to sadness. These findings are partly compatible with the model proposed by Heller, arguing that the frontal lobe is involved in modulating valenced experiences (the left frontal hemisphere for positive emotions) whereas the right parieto-temporal region contributes to the emotional arousal. PMID- 27217117 TI - Neural decoding of discriminative auditory object features depends on their socio affective valence. AB - Human voices consist of specific patterns of acoustic features that are considerably enhanced during affective vocalizations. These acoustic features are presumably used by listeners to accurately discriminate between acoustically or emotionally similar vocalizations. Here we used high-field 7T functional magnetic resonance imaging in human listeners together with a so-called experimental 'feature elimination approach' to investigate neural decoding of three important voice features of two affective valence categories (i.e. aggressive and joyful vocalizations). We found a valence-dependent sensitivity to vocal pitch (f0) dynamics and to spectral high-frequency cues already at the level of the auditory thalamus. Furthermore, pitch dynamics and harmonics-to-noise ratio (HNR) showed overlapping, but again valence-dependent sensitivity in tonotopic cortical fields during the neural decoding of aggressive and joyful vocalizations, respectively. For joyful vocalizations we also revealed sensitivity in the inferior frontal cortex (IFC) to the HNR and pitch dynamics. The data thus indicate that several auditory regions were sensitive to multiple, rather than single, discriminative voice features. Furthermore, some regions partly showed a valence-dependent hypersensitivity to certain features, such as pitch dynamic sensitivity in core auditory regions and in the IFC for aggressive vocalizations, and sensitivity to high-frequency cues in auditory belt and parabelt regions for joyful vocalizations. PMID- 27217118 TI - Neural dissociations between meaningful and mere inconsistency in impression updating. AB - Recent neuroimaging work has identified a network of regions that work in concert to update impressions of other people, particularly in response to inconsistent behavior. However, the specific functional contributions of these regions to the updating process remain unclear. Using fMRI, we tested whether increases in activity triggered by inconsistent behavior reflect changes in the stored representations of other people in response to behavioral inconsistency, or merely a response to the inconsistency itself. Participants encountered a series of individuals whose behavior either changed in an attributionally meaningful fashion or was merely inconsistent with the immediately preceding behavior. We observed that left ventrolateral prefrontal cortex (vlPFC) and left inferior frontal gyrus (IFG) were preferentially recruited in response to unexpected, immoral behavior, whereas a separate set of regions (including dorsal anterior cingulate cortex, posterior cingulate cortex and temporoparietal junction/inferior parietal lobule) was preferentially recruited in response to more mundane inconsistencies in behavior. These results shed light on the distributed systems supporting impression updating. Specifically, while many regions supporting updating may primarily respond to moment-to-moment changes in behavior, a subset of regions (e.g. vlPFC and IFG) may contribute to updating person representations in response to trait-relevant changes in behavior. PMID- 27217121 TI - Synergistically enhanced activity of graphene quantum dots/graphene hydrogel composites: a novel all-carbon hybrid electrocatalyst for metal/air batteries. AB - Primary zinc/air batteries could be the next generation of energy storage devices because of their high power density and high safety. Graphene quantum dots nested in the graphene hydrogel have been proposed as excellent all-carbon hybrid oxygen reduction reaction (ORR) catalysts, indicative of their great potential in primary zinc/air batteries. PMID- 27217120 TI - Women are better at seeing faces where there are none: an ERP study of face pareidolia. AB - Event-related potentials (ERPs) were recorded in 26 right-handed students while they detected pictures of animals intermixed with those of familiar objects, faces and faces-in-things (FITs). The face-specific N170 ERP component over the right hemisphere was larger in response to faces and FITs than to objects. The vertex positive potential (VPP) showed a difference in FIT encoding processes between males and females at frontal sites; while for men, the FIT stimuli elicited a VPP of intermediate amplitude (between that for faces and objects), for women, there was no difference in VPP responses to faces or FITs, suggesting a marked anthropomorphization of objects in women. SwLORETA source reconstructions carried out to estimate the intracortical generators of ERPs in the 150-190 ms time window showed how, in the female brain, FIT perception was associated with the activation of brain areas involved in the affective processing of faces (right STS, BA22; posterior cingulate cortex, BA22; and orbitofrontal cortex, BA10) in addition to regions linked to shape processing (left cuneus, BA18/30). Conversely, in the men, the activation of occipito/parietal regions was prevalent, with a considerably smaller activation of BA10. The data suggest that the female brain is more inclined to anthropomorphize perfectly real objects compared to the male brain. PMID- 27217119 TI - Socioeconomic disadvantages and neural sensitivity to infant cry: role of maternal distress. AB - Socioeconomic disadvantage such as poverty can increase distress levels, which may further make low-income mothers more vulnerable to difficulties in the transition to parenthood. However, little is known about the neurobiological processes by which poverty and maternal distress are associated with risks for adaptations to motherhood. Thus, the current study examined the associations between income and neural responses to infant cry sounds among first-time new mothers (N = 28) during the early postpartum period. Lower income was associated with reduced responses to infant cry in the medial prefrontal gyrus (involved in evaluating emotional values of stimuli), middle prefrontal gyrus (involved in affective regulation) and superior temporal gyrus (involved in sensory information processing). When examining the role of maternal distress, we found a mediating role of perceived stress, but not depressive symptoms, in the links between income and prefrontal responses to infant cry. Reduced neural responses to infant cry in the right middle frontal gyrus and superior temporal gyrus were further associated with less positive perceptions of parenting. The results demonstrate that perceived stress associated with socioeconomic disadvantages may contribute to reduced neural responses to infant cry, which is further associated with less positive perceptions of motherhood. PMID- 27217123 TI - Man With Pigmentation on Left Flank. PMID- 27217122 TI - Managing coexistent cataract and glaucoma with iStent. AB - The iStent is an intraocular implant that resides within Schlemm canal and allows for direct bypass of the trabecular meshwork by aqueous fluid. It is one of several procedures termed microinvasive glaucoma surgery. The prominence of microinvasive glaucoma surgery is growing because of its role in lowering intraocular pressure in mild to moderate glaucoma combined with its favorable safety profile. With transcleral glaucoma filtering surgery, there is an increased potential for significant complications including hypotony, suprachoroidal hemorrhage, and long-term risk of endophthalmitis. In comparison, the iStent minimizes this risk and has been shown to be similar to cataract surgery in terms of associated complications. As will be discussed, multiple publications have addressed both the safety and efficacy of the implant. This review additionally presents an overview of implantation technique as well as what to expect postoperatively. Looking forward, the second-generation models may ease implantation and the use of multiple stents may potentially play a role in more advanced disease. PMID- 27217124 TI - Persistent Fever and Ankle Pain in a Child. PMID- 27217125 TI - Correction. PMID- 27217126 TI - Computed Tomography Angiography of the Head Is a Reasonable Next Test After a Negative Noncontrast Head Computed Tomography Result in the Emergency Department Evaluation of Subarachnoid Hemorrhage. PMID- 27217127 TI - Tried and True and Still the Best: Lumbar Puncture, Not Computed Tomography Angiogram, for the Diagnosis of Subarachnoid Hemorrhage. PMID- 27217128 TI - The Basketball Diaries. PMID- 27217129 TI - Sex, Drugs, Hepatitis C, and an Urban Emergency Department: Answers to the January 2016 Journal Club Questions. PMID- 27217130 TI - Female Infant With Toe Swelling. PMID- 27217131 TI - Young Male With Oral Swelling. PMID- 27217132 TI - Sickle Cell Crisis and You: A How-to Guide. PMID- 27217133 TI - Observation Units as Substitutes for Hospitalization or Home Discharge. PMID- 27217134 TI - In reply. PMID- 27217135 TI - Multicenter Evaluation of a 0-Hour/1-Hour Algorithm in the Diagnosis of Myocardial Infarction With High-Sensitivity Cardiac Troponin T. PMID- 27217136 TI - In reply. PMID- 27217137 TI - In reply. PMID- 27217138 TI - Laryngospasm With Apparent Aspiration During Sedation With Nitrous Oxide. PMID- 27217139 TI - Woman With Facial Trauma. PMID- 27217140 TI - Young Man With Bilateral Arm Pain. PMID- 27217141 TI - Man With Acute Eye Lesion. PMID- 27217142 TI - Elderly Female With Swelling of the Right Breast. PMID- 27217143 TI - Improved production of N-acetylglucosamine in Saccharomyces cerevisiae by reducing glycolytic flux. AB - Glucosamine and its derivatives are utilized in the food and biomedical industries. However, current production relies on hydrolysis of natural sources, making it difficult to maintain quality and eliminate allergenic risk. Therefore, microbial production with aid of metabolic engineering is required. We previously demonstrated production of N-acetylglucosamine (GlcNAc) in Saccharomyces cerevisiae by overexpressing an allosteric regulation-free Gfa1p mutant and the haloacid dehalogenase-like phosphatase YqaB. In this study, we further improved GlcNAc production by reducing glycolytic flux. Eukaryotic phosphofructokinase 1 (PFK-1) is allosterically activated by fructose 2,6-bisphosphate (F26BP). Disruption of PFK-2, which synthesizes F26BP, resulted in a slight decrease of GlcNAc production and no significant change of glucose consumption and ethanol production. However, when galactose was used as a sole carbon source to the strain without PFK-2, GlcNAc production was significantly increased and ethanol production was reduced, suggesting that further reduction of glycolytic flux can be used to further improve GlcNAc production. The methodology used in this study can be applied to improve production of carbohydrate derivatives in S. cerevisiae. Biotechnol. Bioeng. Biotechnol. Bioeng. 2016;113: 2524-2528. (c) 2016 Wiley Periodicals, Inc. PMID- 27217144 TI - Reduced expression of APC-1B but not APC-1A by the deletion of promoter 1B is responsible for familial adenomatous polyposis. AB - Germline mutations in the tumor suppressor gene APC are associated with familial adenomatous polyposis (FAP). Here we applied whole-genome sequencing (WGS) to the DNA of a sporadic FAP patient in which we did not find any pathological APC mutations by direct sequencing. WGS identified a promoter deletion of approximately 10 kb encompassing promoter 1B and exon1B of APC. Additional allele specific expression analysis by deep cDNA sequencing revealed that the deletion reduced the expression of the mutated APC allele to as low as 11.2% in the total APC transcripts, suggesting that the residual mutant transcripts were driven by other promoter(s). Furthermore, cap analysis of gene expression (CAGE) demonstrated that the deleted promoter 1B region is responsible for the great majority of APC transcription in many tissues except the brain. The deletion decreased the transcripts of APC-1B to 39-45% in the patient compared to the healthy controls, but it did not decrease those of APC-1A. Different deletions including promoter 1B have been reported in FAP patients. Taken together, our results strengthen the evidence that analysis of structural variations in promoter 1B should be considered for the FAP patients whose pathological mutations are not identified by conventional direct sequencing. PMID- 27217145 TI - Conditional ablation of neuroligin-1 in CA1 pyramidal neurons blocks LTP by a cell-autonomous NMDA receptor-independent mechanism. AB - Neuroligins are postsynaptic cell-adhesion molecules implicated in autism and other neuropsychiatric disorders. Despite extensive work, the role of neuroligins in synapse function and plasticity, especially N-methyl-d-aspartate (NMDA) receptor (NMDAR)-dependent long-term potentiation (LTP), remains unclear. To establish which synaptic functions unequivocally require neuroligins, we analyzed single and triple conditional knockout (cKO) mice for all three major neuroligin isoforms (NL1-NL3). We inactivated neuroligins by stereotactic viral expression of Cre-recombinase in hippocampal CA1 region pyramidal neurons at postnatal day 0 (P0) or day 21 (P21) and measured synaptic function, synaptic plasticity and spine numbers in acute hippocampal slices 2-3 weeks later. Surprisingly, we find that ablation of neuroligins in newborn or juvenile mice only modestly impaired basal synaptic function in hippocampus and caused no alteration in postsynaptic spine numbers. However, triple cKO of NL1-NL3 or single cKO of NL1 impaired NMDAR mediated excitatory postsynaptic currents and abolished NMDAR-dependent LTP. Strikingly, the NL1 cKO also abolished LTP elicited by activation of L-type Ca2+ channels during blockade of NMDARs. These findings demonstrate that neuroligins are generally not essential for synapse formation in CA1 pyramidal neurons but shape synaptic properties and that NL1 specifically is required for LTP induced by postsynaptic Ca2+-elevations, a function which may contribute to the pathophysiological role of neuroligins in brain disorders. PMID- 27217146 TI - Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: evidence from voxel-based meta-analysis. AB - Finding robust brain substrates of mood disorders is an important target for research. The degree to which major depression (MDD) and bipolar disorder (BD) are associated with common and/or distinct patterns of volumetric changes is nevertheless unclear. Furthermore, the extant literature is heterogeneous with respect to the nature of these changes. We report a meta-analysis of voxel-based morphometry (VBM) studies in MDD and BD. We identified studies published up to January 2015 that compared grey matter in MDD (50 data sets including 4101 individuals) and BD (36 data sets including 2407 individuals) using whole-brain VBM. We used statistical maps from the studies included where available and reported peak coordinates otherwise. Group comparisons and conjunction analyses identified regions in which the disorders showed common and distinct patterns of volumetric alteration. Both disorders were associated with lower grey-matter volume relative to healthy individuals in a number of areas. Conjunction analysis showed smaller volumes in both disorders in clusters in the dorsomedial and ventromedial prefrontal cortex, including the anterior cingulate cortex and bilateral insula. Group comparisons indicated that findings of smaller grey matter volumes relative to controls in the right dorsolateral prefrontal cortex and left hippocampus, along with cerebellar, temporal and parietal regions were more substantial in major depression. These results suggest that MDD and BD are characterised by both common and distinct patterns of grey-matter volume changes. This combination of differences and similarities has the potential to inform the development of diagnostic biomarkers for these conditions. PMID- 27217147 TI - Exome sequencing for bipolar disorder points to roles of de novo loss-of-function and protein-altering mutations. AB - Although numerous genetic studies have been conducted for bipolar disorder (BD), its genetic architecture remains elusive. Here we perform, to the best of our knowledge, the first trio-based exome sequencing study for BD to investigate potential roles of de novo mutations in the disease etiology. We identified 71 de novo point mutations and one de novo copy-number mutation in 79 BD probands. Among the genes hit by de novo loss-of-function (LOF; nonsense, splice site or frameshift) or protein-altering (LOF, missense and inframe indel) mutations, we found significant enrichment of genes highly intolerant (first percentile of intolerant genes assessed by Residual Variation Intolerance Score) to protein altering variants in general population, an observation that is also reported in autism and schizophrenia. When we performed a joint analysis using the data of schizoaffective disorder in published studies, we found global enrichment of de novo LOF and protein-altering mutations in the combined group of bipolar I and schizoaffective disorders. Considering relationship between de novo mutations and clinical phenotypes, we observed significantly earlier disease onset among the BD probands with de novo protein-altering mutations when compared with non-carriers. Gene ontology enrichment analysis of genes hit by de novo protein-altering mutations in bipolar I and schizoaffective disorders did not identify any significant enrichment. These results of exploratory analyses collectively point to the roles of de novo LOF and protein-altering mutations in the etiology of bipolar disorder and warrant further large-scale studies. PMID- 27217149 TI - Arc expression identifies the lateral amygdala fear memory trace. PMID- 27217150 TI - An epigenetic mechanism links socioeconomic status to changes in depression related brain function in high-risk adolescents. AB - Identifying biological mechanisms through which the experience of adversity emerges as individual risk for mental illness is an important step toward developing strategies for personalized treatment and, ultimately, prevention. Preclinical studies have identified epigenetic modification of gene expression as one such mechanism. Recent clinical studies have suggested that epigenetic modification, particularly methylation of gene regulatory regions, also acts to shape human brain function associated with risk for mental illness. However, it is not yet clear whether differential gene methylation as a function of adversity contributes to the emergence of individual risk for mental illness. Using prospective longitudinal epigenetic, neuroimaging and behavioral data from 132 adolescents, we demonstrate that changes in gene methylation associated with lower socioeconomic status (SES) predict changes in risk-related brain function. Specifically, we find that lower SES during adolescence is associated with an increase in methylation of the proximal promoter of the serotonin transporter gene, which predicts greater increases in threat-related amygdala reactivity. We subsequently demonstrate that greater increases in amygdala reactivity moderate the association between a positive family history for depression and the later manifestation of depressive symptoms. These initial results suggest a specific biological mechanism through which adversity contributes to altered brain function, which in turn moderates the emergence of general liability as individual risk for mental illness. If replicated, this prospective pathway may represent a novel target biomarker for intervention and prevention among high risk individuals. PMID- 27217148 TI - Retrieving fear memories, as time goes by.... AB - Research in fear conditioning has provided a comprehensive picture of the neuronal circuit underlying the formation of fear memories. In contrast, our understanding of the retrieval of fear memories is much more limited. This disparity may stem from the fact that fear memories are not rigid, but reorganize over time. To bring some clarity and raise awareness about the time-dependent dynamics of retrieval circuits, we review current evidence on the neuronal circuitry participating in fear memory retrieval at both early and late time points following auditory fear conditioning. We focus on the temporal recruitment of the paraventricular nucleus of the thalamus (PVT) for the retrieval and maintenance of fear memories. Finally, we speculate as to why retrieval circuits change with time, and consider the functional strategy of recruiting structures not previously considered as part of the retrieval circuit. PMID- 27217151 TI - Mood, stress and longevity: convergence on ANK3. AB - Antidepressants have been shown to improve longevity in C. elegans. It is plausible that orthologs of genes involved in mood regulation and stress response are involved in such an effect. We sought to understand the underlying biology. First, we analyzed the transcriptome from worms treated with the antidepressant mianserin, previously identified in a large-scale unbiased drug screen as promoting increased lifespan in worms. We identified the most robust treatment related changes in gene expression, and identified the corresponding human orthologs. Our analysis uncovered a series of genes and biological pathways that may be at the interface between antidepressant effects and longevity, notably pathways involved in drug metabolism/degradation (nicotine and melatonin). Second, we examined which of these genes overlap with genes which may be involved in depressive symptoms in an aging non-psychiatric human population (n=3577), discovered using a genome-wide association study (GWAS) approach in a design with extremes of distribution of phenotype. Third, we used a convergent functional genomics (CFG) approach to prioritize these genes for relevance to mood disorders and stress. The top gene identified was ANK3. To validate our findings, we conducted genetic and gene-expression studies, in C. elegans and in humans. We studied C. elegans inactivating mutants for ANK3/unc-44, and show that they survive longer than wild-type, particularly in older worms, independently of mianserin treatment. We also show that some ANK3/unc-44 expression is necessary for the effects of mianserin on prolonging lifespan and survival in the face of oxidative stress, particularly in younger worms. Wild-type ANK3/unc-44 increases in expression with age in C. elegans, and is maintained at lower youthful levels by mianserin treatment. These lower levels may be optimal in terms of longevity, offering a favorable balance between sufficient oxidative stress resistance in younger worms and survival effects in older worms. Thus, ANK3/unc-44 may represent an example of antagonistic pleiotropy, in which low-expression level in young animals are beneficial, but the age-associated increase becomes detrimental. Inactivating mutations in ANK3/unc-44 reverse this effect and cause detrimental effects in young animals (sensitivity to oxidative stress) and beneficial effect in old animals (increased survival). In humans, we studied if the most significant single nucleotide polymorphism (SNP) for depressive symptoms in ANK3 from our GWAS has a relationship to lifespan, and show a trend towards longer lifespan in individuals with the risk allele for depressive symptoms in men (odds ratio (OR) 1.41, P=0.031) but not in women (OR 1.08, P=0.33). We also examined whether ANK3, by itself or in a panel with other top CFG-prioritized genes, acts as a blood gene-expression biomarker for biological age, in two independent cohorts, one of live psychiatric patients (n=737), and one of suicide completers from the coroner's office (n=45). We show significantly lower levels of ANK3 expression in chronologically younger individuals than in middle age individuals, with a diminution of that effect in suicide completers, who presumably have been exposed to more severe and acute negative mood and stress. Of note, ANK3 was previously reported to be overexpressed in fibroblasts from patients with Hutchinson-Gilford progeria syndrome, a form of accelerated aging. Taken together, these studies uncover ANK3 and other genes in our dataset as biological links between mood, stress and longevity/aging, that may be biomarkers as well as targets for preventive or therapeutic interventions. Drug repurposing bioinformatics analyses identified the relatively innocuous omega-3 fatty acid DHA (docosahexaenoic acid), piracetam, quercetin, vitamin D and resveratrol as potential longevity promoting compounds, along with a series of existing drugs, such as estrogen-like compounds, antidiabetics and sirolimus/rapamycin. Intriguingly, some of our top candidate genes for mood and stress-modulated longevity were changed in expression in opposite direction in previous studies in the Alzheimer disease. Additionally, a whole series of others were changed in expression in opposite direction in our previous studies on suicide, suggesting the possibility of a "life switch" actively controlled by mood and stress. PMID- 27217153 TI - Epigenetic profiling of ADHD symptoms trajectories: a prospective, methylome-wide study. AB - Attention-deficit/hyperactivity disorder (ADHD) is a prevalent developmental disorder, associated with a range of long-term impairments. Variation in DNA methylation, an epigenetic mechanism, is implicated in both neurobiological functioning and psychiatric health. However, the potential role of DNA methylation in ADHD symptoms is currently unclear. In this study, we examined data from the Avon Longitudinal Study of Parents and Children (ALSPAC) specifically the subsample forming the Accessible Resource for Integrated Epigenomics Studies (ARIES)-that includes (1) peripheral measures of DNA methylation (Illumina 450k) at birth (n=817, 49% male) and age 7 (n=892, 50% male) and (2) trajectories of ADHD symptoms (7-15 years). We first employed a genome-wide analysis to test whether DNA methylation at birth associates with later ADHD trajectories; and then followed up at age 7 to investigate the stability of associations across early childhood. We found that DNA methylation at birth differentiated ADHD trajectories across multiple genomic locations, including probes annotated to SKI (involved in neural tube development), ZNF544 (previously implicated in ADHD), ST3GAL3 (linked to intellectual disability) and PEX2 (related to perixosomal processes). None of these probes maintained an association with ADHD trajectories at age 7. Findings lend novel insights into the epigenetic landscape of ADHD symptoms, highlighting the potential importance of DNA methylation variation in genes related to neurodevelopmental and peroxisomal processes that play a key role in the maturation and stability of cortical circuits. PMID- 27217152 TI - Attention-deficit hyperactivity disorder in adults: A systematic review and meta analysis of genetic, pharmacogenetic and biochemical studies. AB - The adult form of attention-deficit/hyperactivity disorder has a prevalence of up to 5% and is the most severe long-term outcome of this common disorder. Family studies in clinical samples as well as twin studies suggest a familial liability and consequently different genes were investigated in association studies. Pharmacotherapy with methylphenidate (MPH) seems to be the first-line treatment of choice in adults with attention-deficit hyperactive disorder (ADHD) and some studies were conducted on the genes influencing the response to this drug. Finally some peripheral biomarkers were identified in ADHD adult patients. We believe this work is the first systematic review and meta-analysis of candidate gene association studies, pharmacogenetic and biochemical (metabolomics) studies performed in adults with ADHD to identify potential genetic, predictive and peripheral markers linked specifically to ADHD in adults. After screening 5129 records, we selected 87 studies of which 61 were available for candidate gene association studies, 5 for pharmacogenetics and 21 for biochemical studies. Of these, 15 genetic, 2 pharmacogenetic and 6 biochemical studies were included in the meta-analyses. We obtained an association between adult ADHD and the gene BAIAP2 (brain-specific angiogenesis inhibitor 1-associated protein 2), even after Bonferroni correction, with any heterogeneity in effect size and no publication bias. If we did not apply the Bonferroni correction, a trend was found for the carriers allele 9R of dopamine transporter SLC6A3 40 bp variable tandem repeat polymorphism (VNTR) and for 6/6 homozygotes of SLC6A3 30 bp VNTR. Negative results were obtained for the 9-6 haplotype, the dopamine receptor DRD4 48 bp VNTR, and the enzyme COMT SNP rs4680. Concerning pharmacogenetic studies, no association was found for the SLC6A3 40 bp and response to MPH with only two studies selected. For the metabolomics studies, no differences between ADHD adults and controls were found for salivary cortisol, whereas lower serum docosahexaenoic acid (DHA) levels were found in ADHD adults. This last association was significant even after Bonferroni correction and in absence of heterogeneity. Other polyunsaturated fatty acids (PUFAs) such as AA (arachidonic acid), EPA (eicosapentaenoic acid) and DyLA (dihomogammalinolenic acid) levels were not different between patients and controls. No publication biases were observed for these markers. Genes linked to dopaminergic, serotoninergic and noradrenergic signaling, metabolism (DBH, TPH1, TPH2, DDC, MAOA, MAOB, BCHE and TH), neurodevelopment (BDNF and others), the SNARE system and other forty genes/proteins related to different pathways were not meta-analyzed due to insufficient data. In conclusion, we found that there were not enough genetic, pharmacogenetic and biochemical studies of ADHD in adults and that more investigations are needed. Moreover we confirmed a significant role of BAIAP2 and DHA in the etiology of ADHD exclusively in adults. Future research should be focused on the replication of these findings and to assess their specificity for ADHD. PMID- 27217154 TI - Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation. AB - Immune abnormalities have been described in some individuals with autism spectrum disorders (ASDs) as well as their family members. However, few studies have directly investigated the role of prenatal cytokine and chemokine profiles on neurodevelopmental outcomes in humans. In the current study, we characterized mid gestational serum profiles of 22 cytokines and chemokines in mothers of children with ASD (N=415), developmental delay (DD) without ASD (N=188), and general population (GP) controls (N=428) using a bead-based multiplex technology. The ASD group was further divided into those with intellectual disabilities (developmental/cognitive and adaptive composite score<70) (ASD+ID, N=184) and those without (composite score?70) (ASD-noID, N=201). Levels of cytokines and chemokines were compared between groups using multivariate logistic regression analyses, adjusting for maternal age, ethnicity, birth country and weight, as well as infant gender, birth year and birth month. Mothers of children with ASD+ID had significantly elevated mid-gestational levels of numerous cytokines and chemokines, such as granulocyte macrophage colony-stimulating factor, interferon-gamma, interleukin-1alpha (IL-1alpha) and IL-6, compared with mothers of children with either ASD-noID, those with DD, or GP controls. Conversely, mothers of children with either ASD-noID or with DD had significantly lower levels of the chemokines IL-8 and monocyte chemotactic protein-1 compared with mothers of GP controls. This observed immunologic distinction between mothers of children with ASD+ID from mothers of children with ASD-noID or DD suggests that the intellectual disability associated with ASD might be etiologically distinct from DD without ASD. These findings contribute to the ongoing efforts toward identification of early biological markers specific to subphenotypes of ASD. PMID- 27217155 TI - Breast-Milk Iodine Concentrations, Iodine Status, and Thyroid Function of Breastfed Infants Aged 2-4 Months and Their Mothers Residing in a South African Township. AB - OBJECTIVE: Lactating women and their infants are susceptible to iodine deficiency and iodine excess. In South Africa, no data exist on the iodine status and thyroid function of these vulnerable groups. METHODS: In a cross-sectional study, urinary iodine concentrations (UIC), thyroid function, and breast-milk iodine concentrations (BMIC) were assessed in 100 lactating women from a South African township and their 2-4-month-old breastfed infants. Potential predictors of UIC, thyroid function, and BMIC, including household salt iodine concentrations (SIC) and maternal sodium excretion, were also investigated. RESULTS: The median (25th 75th percentile) UIC was 373 (202-627) MUg/L in infants and 118 (67-179) MUg/L in mothers. Median household SIC was 44 (27-63) ppm. Household SIC and maternal urinary sodium excretion predicted UIC of lactating mothers. Median BMIC was 179 (126-269) MUg/L. Age of infants, SIC, and maternal UIC predicted BMIC. In turn, infant age and BMIC predicted UIC of infants. Forty-two percent of SIC values were within the South African recommended salt iodine fortification level at production of 35-65 ppm, whilst 21% of SIC were >65 ppm. Thyroid-stimulating hormone, total thyroxine, and thyroglobulin concentrations in the dried whole blood spot specimens from the infants were 1.3 (0.8-1.9) mU/L, 128+/-33 mmol/L, and 77.1 (56.3-105.7) MUg/L, respectively, and did not correlate with infant UIC or BMIC. CONCLUSION: Our results suggest that the salt fortification program in South Africa provides adequate iodine to lactating women and indirectly to their infants via breast milk. However, monitoring of salt iodine content of the mandatory salt iodization program in South Africa is important to avoid over iodization of salt. PMID- 27217156 TI - Child labour in low- and middle-income countries and its consequences for mental health: a systematic literature review of epidemiologic studies. AB - In low- and middle-income countries, large numbers of children are involved in work. Whilst studies have shown that child labour may be harmful to children's physical health, little is known about child labour's effects on mental health. It is important to understand the relationship between work and mental health problems during childhood, and identify possible risk factors for poorer mental health. A systematic literature review was conducted. Published papers in any language that compared the mental health of children (<18 years) who had been exposed to work with those who had not been exposed to work were included. Twelve published observational studies on the association between child labour and general psychopathology, internalising and externalising problems were identified. Child labour was found to be strongly associated with poor mental health outcomes in seven studies. More significant associations were found between child labour and internalising problems than externalising problems. The burden of poor mental health as a result of child labour is significant given the numbers of children in work. Risk factors for poorer mental health were involvement in domestic labour, younger age, and greater intensity of work, which could be due to the potential of child labour to cause isolation, low self esteem, and perception of an external locus of control. The risk factors suggested by this review will have implications for policy makers. Additional research is needed in low-income countries, risk factors and also into the potential psychological benefits of low levels of work. PMID- 27217157 TI - Streptomyces canalis sp. nov., an actinomycete isolated from an alkali-removing canal. AB - A novel actinomycete strain, designated TRM 46794-61T, was isolated from an alkali-removing canal in 14th Farms of Xinjiang Production and Construction Corps, north-west China. The isolate contained ll-diaminopimelic acid as the diagnostic diamino acid. The whole-cell sugar patterns of the isolate contained ribose, mannose and glucose. The polar lipids were diphosphatidylglycerol, phosphatidylmethylethanolamine, phosphatidylethanolamine, phosphatidylcholine, phosphatidylinositol, phosphatidylinositol mannoside and two unidentified phospholipids. The predominant menaquinones were MK-9(H2), MK-9(H4), MK-9(H6) and MK-9(H8). The major fatty acids were iso-C16 : 0, anteiso-C17 : 0 and anteiso-C15 : 0. The G+C content of the DNA was 70.4 mol%. Phylogenetic analysis showed that strain TRM 46794-61T had a 16S rRNA gene sequence similarity of 97.6 % with the most closely related species with a validly published name, Streptomyces aidingensis TRM 46012T, and it could be distinguished from all species in the genus Streptomyces based on data from this polyphasic taxonomic study. However, DNA-DNA hybridization studies between strain TRM 46794-61T and S.aidingensis TRM 46012T showed only 45.4 % relatedness. On the basis of these data, strain TRM 46794-61T should be designated as a representative of a novel species of the genus Streptomyces, for which the name Streptomyces canalis sp. nov. is proposed. The type strain is TRM 46794-61T (=CCTCC AA 2015006T=KCTC 39568T). PMID- 27217158 TI - Treatment protocol with pulse and oral steroids for IgA Nephropathy after kidney transplantation. AB - BACKGROUND: No specific treatment for IgA nephropathy (IgAN) after kidney transplantation is currently available. METHODS: We conducted a retrospective single-center study on 29 patients with biopsy-proven de novo and recurrent IgAN after kidney transplantation, divided into two groups. Group 1 (n = 16) received intravenous methylprednisolone 500 mg per day for three consecutive days at the beginning of months 1, 3 and 5, plus oral prednisone 0.5 mg/kg every other day for 6 months. The control group (n = 13, Group 2) received supportive therapies. RESULTS: The two groups were comparable for serum creatinine (sCr) and proteinuria at the time of renal biopsy, but differed significantly at the end of follow-up. sCr was 1.8 +/- 0.4 mg/dl in Group 1 vs. 2.7 +/- 0.9 in Group 2 (p = 0.002), and proteinuria was 0.9 g/day in Group 1 vs. 1.9 in Group 2 (p = 0.04). The composite outcome of death-censored graft loss or doubling of sCr displayed 2 events in Group 1 (12.5 % of the entire group) and 5 events in Group 2 (38.5 % of the entire group), p = 0.19, odds ratio (OR) 4.4 [95 % confidence interval (CI) 0.7-27.8]. CONCLUSIONS: In the absence of therapeutic guidelines for de novo or recurrent IgAN after kidney transplantation, our study reports that therapy with pulse and oral steroids for 6 months is associated with an improved renal function. Nevertheless, further randomized controlled studies in larger patient cohorts are necessary to establish the gold standard treatment. PMID- 27217159 TI - Inverse Expression Levels of EphrinA3 and EphrinA5 Contribute to Dopaminergic Differentiation of Human SH-SY5Y Cells. AB - Two key principles underlying successful cellular therapies for Parkinson's disease (PD) are appropriate differentiation of dopaminergic (DA) neurons from transplanted cells and precise axon growth. EphrinAs, a subclass of ephrins, act as axon guidance molecules and are highly expressed in DA brain regions. Existing evidences indicate that they act as either repulsion or attraction signals to guide axon growth. This study investigated whether ephrinAs are involved in DA neuron differentiation. Data from miRCURYTM LNA mRNAs/microRNAs microarrays and quantitative real-time polymerase chain reaction (qRT-PCR) showed upregulated ephrinA3 mRNA (EFNA3) and downregulated ephrinA5 mRNA (EFNA5) during DA neuron differentiation. In addition, hsa-miR-4271 was downregulated, which could influence EFNA3 translation. Furthermore, immunofluorescence (IF) and western blotting confirmed the mRNA results and showed increased ephrinA3 and decreased ephrinA5 protein levels in differentiating DA neurons. Taken together, our results indicate that inverse expression levels of ephrinA3 and ephrinA5, which are possibly influenced by microRNAs, contribute to DA neuron differentiation by guiding axon growth. PMID- 27217160 TI - Drugs affecting glycosaminoglycan metabolism. AB - Glycosaminoglycans (GAGs) are charged polysaccharides ubiquitously present at the cell surface and in the extracellular matrix. GAGs are crucial for cellular homeostasis, and their metabolism is altered during pathological processes. However, little consideration has been given to the regulation of the GAG milieu through pharmacological interventions. In this review, we provide a classification of small molecules affecting GAG metabolism based on their mechanism of action. Furthermore, we present evidence to show that clinically approved drugs affect GAG metabolism and that this could contribute to their therapeutic benefit. PMID- 27217162 TI - Determination of free and conjugated forms of endocrine-disrupting chemicals in human biological fluids by GC-MS. AB - BACKGROUND: Humans are exposed to hazardous substances including endocrine disrupting chemicals (EDCs). These compounds have been associated with some diseases such as cancer and ascribed adverse effects on life-essential organs. RESULTS: The method, which allows the determination of both free and conjugated forms of EDCs, involves the liquid-liquid extraction from the sample with ethyl acetate, followed by its preconcentration and clean-up by SPE in a continuous system for the subsequent determination by GC-MS. The proposed method affords very low LODs and RSD. CONCLUSION: This allowed its successful application to the determination of EDCs in human urine, blood and breast milk. The most frequently founded were methylparaben, ethylparaben, bisphenol A and triclosan. PMID- 27217161 TI - The cardiac-restricted protein ADP-ribosylhydrolase-like 1 is essential for heart chamber outgrowth and acts on muscle actin filament assembly. AB - Adprhl1, a member of the ADP-ribosylhydrolase protein family, is expressed exclusively in the developing heart of all vertebrates. In the amphibian Xenopus laevis, distribution of its mRNA is biased towards actively growing chamber myocardium. Morpholino oligonucleotide-mediated knockdown of all Adprhl1 variants inhibits striated myofibril assembly and prevents outgrowth of the ventricle. The resulting ventricles retain normal electrical conduction and express markers of chamber muscle differentiation but are functionally inert. Using a cardiac specific Gal4 binary expression system, we show that the abundance of Adprhl1 protein in tadpole hearts is tightly controlled through a negative regulatory mechanism targeting the 5'-coding sequence of Xenopus adprhl1. Over-expression of full length (40kDa) Adprhl1 variants modified to escape such repression, also disrupts cardiac myofibrillogenesis. Disarrayed myofibrils persist that show extensive branching, with sarcomere division occurring at the actin-Z-disc boundary. Ultimately, Adprhl1-positive cells contain thin actin threads, connected to numerous circular branch points. Recombinant Adprhl1 can localize to stripes adjacent to the Z-disc, suggesting a direct role for Adprhl1 in modifying Z-disc and actin dynamics as heart chambers grow. Modelling the structure of Adprhl1 suggests this cardiac-specific protein is a pseudoenzyme, lacking key residues necessary for ADP-ribosylhydrolase catalytic activity. PMID- 27217163 TI - An inter-laboratory cross-validation study for the determination of perampanel in human plasma by liquid chromatography assays. AB - For sample assay to support global clinical studies of perampanel, a novel AMPA receptor antagonist, six chromatographic assay methods in human plasma were developed and fully validated at each laboratory using liquid chromatography with tandem mass spectrometry (LC-MS/MS) or LC with fluorescence detection (LC-FL). In this study, samples fortified with known perampanel concentrations were assayed at six laboratories to find whether assay data are comparable. Perampanel was extracted by protein precipitation or liquid-liquid extraction, chromatographed on a reverse-phase column then detected by MS/MS or FL to achieve the limit of quantification of 0.25 or 1 ng/mL. Cross-validation samples at four concentrations prepared at a central laboratory were determined at six laboratories and the mean accuracy at each concentration was within +/-15% except the low concentration at one laboratory (relative error -17.4%), suggesting that plasma concentrations of perampanel in clinical trials can be compared across laboratories. PMID- 27217164 TI - Preface : Potential applications of pathogen genomics. PMID- 27217165 TI - Introduction : Potential applications of pathogen genomics. PMID- 27217166 TI - Novel technologies applied to the nucleotide sequencing and comparative sequence analysis of the genomes of infectious agents in veterinary medicine. AB - Next-generation sequencing (NGS), also referred to as deep, high-throughput or massively parallel sequencing, is a powerful new tool that can be used for the complex diagnosis and intensive monitoring of infectious disease in veterinary medicine. NGS technologies are also being increasingly used to study the aetiology, genomics, evolution and epidemiology of infectious disease, as well as host-pathogen interactions and other aspects of infection biology. This review briefly summarises recent progress and achievements in this field by first introducing a range of novel techniques and then presenting examples of NGS applications in veterinary infection biology. Various work steps and processes for sampling and sample preparation, sequence analysis and comparative genomics, and improving the accuracy of genomic prediction are discussed, as are bioinformatics requirements. Examples of sequencing-based applications and comparative genomics in veterinary medicine are then provided. This review is based on novel references selected from the literature and on experiences of the World Organisation for Animal Health (OIE) Collaborating Centre for the Biotechnology-based Diagnosis of Infectious Diseases in Veterinary Medicine, Uppsala, Sweden. PMID- 27217167 TI - Standard finishing categories for high-throughput sequencing of viral genomes. AB - Viral genome sequencing has become the cornerstone of almost all aspects of virology. In particular, high-throughput, next-generation viral genome sequencing has become an integral part of molecular epidemiological investigations into outbreaks of viral disease, such as the recent outbreaks of Middle Eastern respiratory syndrome, Ebola virus disease and Zika virus infection. Multiple institutes have acquired the expertise and necessary infrastructure to perform such investigations, as evidenced by the accumulation of thousands of novel viral sequences over progressively shorter time periods. The authors recently proposed a nomenclature comprised of five high-throughput sequencing standard categories to describe the quality of determined viral genome sequences. These five categories (standard draft, high quality, coding complete, complete and finished) cover all levels of viral genome finishing and can be applied to sequences determined by any technology platform or assembly technique. PMID- 27217168 TI - High-throughput sequencing and vaccine design. AB - Next-generation sequencing (NGS) technologies have reshaped genome research. The resulting increase in sequencing depth and resolution has led to an unprecedented level of genomic detail and thus an increasing awareness of the complexity of animal, human and pathogen genomes. This has resulted in new approaches to vaccine research. On the one hand, the increase in genome complexity challenges our ability to study and understand pathogen biology and pathogen-host interactions. On the other hand, the increase in genomic data also provides key information for developing and designing improved vaccines against pathogens that were previously extremely difficult to deal with, such as rapidly mutating RNA viruses or bacteria that have complex interactions with the host immune system. This review describes how the broad application of NGS technologies to genome research is affecting vaccine research. It focuses on implications for the field of viral genomics, and includes recent animal and human studies. PMID- 27217169 TI - Next-generation sequencing workflows in veterinary infection biology: towards validation and quality assurance. AB - Recent advancements in DNA sequencing methodologies and sequence data analysis have revolutionised research in many areas of biology and medicine, including veterinary infection biology. New technology is poised to bridge the gap between the research and diagnostic laboratory. This paper defines the potential diagnostic value and purposes of next-generation sequencing (NGS) applications in veterinary infection biology and explores their compatibility with the existing validation principles and methods of the World Organisation for Animal Health. Critical parameters for validation and quality control (quality metrics) are suggested, with reference to established validation and quality assurance guidelines for NGS-based methods of diagnosing human heritable diseases. Although most currently described NGS applications in veterinary infection biology are not primary diagnostic tests that directly result in control measures, this critical reflection on the advantages and remaining challenges of NGS technology should stimulate discussion on its diagnostic value and on the potential to validate NGS methods and monitor their diagnostic performance. PMID- 27217170 TI - Metagenomic approaches to identifying infectious agents. AB - Since the advent of next-generation sequencing (NGS) technologies, the untargeted screening of samples from outbreaks for pathogen identification using metagenomics has become technically and economically feasible. However, various aspects need to be considered in order to exploit the full potential of NGS for virus discovery. Here, the authors summarise those aspects of the main steps that have a significant impact, from sample selection through sample handling and processing, as well as sequencing and finally data analysis, with a special emphasis on existing pitfalls. PMID- 27217171 TI - Using genomics to identify novel antimicrobials. AB - There is a critical need in animal agriculture to develop novel antimicrobials and alternative strategies that will help to reduce the use of antibiotics and address the challenges of antimicrobial resistance. High-throughput gene expression analysis is providing new tools that are enabling the discovery of host-derived antimicrobial peptides. Examples of gene-encoded natural antibiotics that have gained attention include antimicrobial peptides such as human granulysin and its multi-species homolog, namely NK-lysin, which provide a protective response against a broad range of microbes and are a principal component of innate immunity in vertebrates. Both granulysin and NK-lysin are localised in cytolytic granules in natural killer and cytotoxic T lymphocytes. Host-derived NK-lysins that were first described in mammals are also found in avian species, and they have been shown to have antimicrobial activities that could potentially be used to control important poultry pathogens. Morphological alterations observed following chicken NK-lysin binding to Eimeria sporozoites and Escherichia coli membranes indicate damage and disruption of cell membranes, suggesting that NK-lysin kills pathogenic protozoans and bacteria by direct interaction. Genotype analysis revealed that chicken NK-lysin peptides derived from certain alleles were more effective at killing pathogens than those derived from others, which could potentially affect susceptibility to diseases. Although the host-derived antimicrobial peptides described in this paper may not, by themselves, be able to replace the antibiotics currently used in animal production, their use as specific treatments based on their known mechanisms of action is showing promising results. PMID- 27217172 TI - Animal genomics and infectious disease resistance in poultry. AB - Avian pathogens are responsible for major costs to society, both in terms of huge economic losses to the poultry industry and their implications for human health. The health and welfare of millions of birds is under continued threat from many infectious diseases, some of which are increasing in virulence and thus becoming harder to control, such as Marek's disease virus and avian influenza viruses. The current era in animal genomics has seen huge developments in both technologies and resources, which means that researchers have never been in a better position to investigate the genetics of disease resistance and determine the underlying genes/mutations which make birds susceptible or resistant to infection. Avian genomics has reached a point where the biological mechanisms of infectious diseases can be investigated and understood in poultry and other avian species. Knowledge of genes conferring disease resistance can be used in selective breeding programmes or to develop vaccines which help to control the effects of these pathogens, which have such a major impact on birds and humans alike. PMID- 27217173 TI - Transgenic animals resistant to infectious diseases. AB - The list of transgenic animals developed to test ways of producing livestock resistant to infectious disease continues to grow. Although the basic techniques for generating transgenic animals have not changed very much in the ten years since they were last reviewed for the World Organisation for Animal Health, one recent fundamental technological advance stands to revolutionise genome engineering. The advent of technically simple and efficient site-specific gene targeting has profound implications for genetically modifying livestock species. PMID- 27217174 TI - Viruses within animal genomes. AB - Viruses and their hosts can co-evolve to reach a fragile equilibrium that allows the survival of both. An excess of pathogenicity in the absence of a reservoir would be detrimental to virus survival. A significant proportion of all animal genomes has been shaped by the insertion of viruses that subsequently became 'fossilised'. Most endogenous viruses have lost the capacity to replicate via an infectious cycle and now replicate passively. The insertion of endogenous viruses has contributed to the evolution of animal genomes, for example in the reproductive biology of mammals. However, spontaneous viral integration still occasionally occurs in a number of virus-host systems. This constitutes a potential risk to host survival but also provides an opportunity for diversification and evolution. PMID- 27217175 TI - Using genomics for surveillance of veterinary infectious agents. AB - Factors such as globalisation, climate change and agricultural intensification can increase the risk of microbial emergence. As a result, there is a growing need for flexible laboratory-based surveillance tools to rapidly identify, characterise and monitor global (re-)emerging diseases. Although many tools are available, novel sequencing technologies have launched a new era in pathogen surveillance. Here, the authors review the potential applications of high throughput genomic technologies for the surveillance of veterinary pathogens. They focus on the two types of surveillance that will benefit most from these new tools: hazard-specific surveillance (pathogen identification and typing) and early-warning surveillance (pathogen discovery). The paper reviews how the resulting sequencing data can be used to improve diagnosis and concludes by highlighting the major challenges that hinder the routine use of this technology in the veterinary field. PMID- 27217176 TI - Animal genomics in natural reservoirs of infectious diseases. AB - Natural virus reservoirs such as wild bats, birds, rodents and non-human primates are generally non-model organisms that have, until recently, presented limited opportunities for in-depth study. Next-generation sequencing provides a way to partially circumvent this limitation, since the methods required for data acquisition and analysis are largely species-independent. Comparative genomics and other 'omics' provide new opportunities to study the structure and function of various biological systems of wild species that are otherwise out of reach. Genomes of natural reservoir hosts can help to identify dominant pathways of virus-host interaction and to reveal differences between susceptible and resistant organisms, populations and species. This is of great scientific interest and may also provide a resource for the rational design of treatments for viral diseases in humans and livestock. In this way, we will 'learn from nature' and one day apply this knowledge to create disease-resistant livestock or develop novel therapeutic and prevention strategies. Reservoir host genomics will also open up possibilities for developing novel vaccines for wildlife, aid in the development of new diagnostic platforms, and have broad implications for developmental and evolutionary biology. In this review, the authors focus on natural reservoir hosts of viral pathogens, although most of the discussion points should be equally applicable to natural reservoirs of pathogenic bacteria, fungi or other parasites. PMID- 27217177 TI - Genomics and outbreaks: foot and mouth disease. AB - Foot and mouth disease virus (FMDV) is an animal pathogen of global economic significance. Identifying the sources of outbreaks plays an important role in disease control; however, this can be confounded by the ease with which FMDV can spread via movement of infected livestock and animal products, aerosols or fomites, e.g. contaminated persons and objects. As sequencing technologies have advanced, this review highlights the uses of viral genomic data in helping to understand the global distribution and transboundary movements of FMDV, and the role that these approaches have played in control and surveillance programmes. The recent application of next-generation sequencing platforms to address important epidemiological and evolutionary challenges is discussed with particular reference to the advent of 'omics' technologies. PMID- 27217178 TI - Genomics and zoonotic infections: Middle East respiratory syndrome. AB - The emergence of Middle East respiratory syndrome (MERS) and the discovery of MERS coronavirus (MERS-CoV) in 2012 suggests that another SARS-like epidemic is occurring. Unlike the severe acute respiratory syndrome (SARS) epidemic, which rapidly disappeared in less than one year, MERS has persisted for over three years. More than 1,600 cases of MERS have been reported worldwide, and the disease carries a worryingly high fatality rate of >30%. A total of 182 MERS-CoV genomes have been sequenced, including 94 from humans and 88 from dromedary camels. The 182 genomes all share >99% identity, indicating minimal variation among MERS-CoV genomes. MERS-CoV is a lineage C Betacoronavirus (betaCoV). MERS CoV genomes can be roughly divided into two clades: clade A, which contains only a few strains, and clade B, to which most strains belong. In contrast to ORF1ab and structural proteins, the putative proteins encoded by ORF3, ORF4a, ORF4b, ORF5 and ORF8b in the MERS-CoV genome do not share homology with any known host or virus protein, other than those of its closely related lineage C betaCoVs. Human and dromedary viral genomes have intermingled, indicating that multiple camel-to-human transmission events have occurred. The multiple origins of MERS CoV suggest that the virus has been resident in dromedaries for many years. This is consistent with the detection of anti-MERS-CoV antibodies in dromedary camels as early as the 1980s. PMID- 27217179 TI - New perspectives from genomic analyses of bacterial infectious agents. AB - Recent advances in the technologies for genomic sequencing and systems for handling and processing sequencing data have transformed bacterial genomics into a near-routine approach for both small- and large-scale investigations of infectious agents. Nonetheless, the application of genomics - especially largerscale studies - to animal infectious agents lags behind its application to human pathogens, despite the growing importance of many animal species as food sources. Assiduously conducted genomic studies offer major benefits, not merely by providing a detailed understanding of infectious agents but also through the exploitation of such findings to enable more accurate diagnosis, high-resolution typing and the development of improved interventions. The use of genomics for these and other purposes is likely to grow in future years and it must be anticipated that investigation and characterisation of important animal infectious agents will also gain considerable benefits. Using mainly animal pathogens as examples - including several infectious agents listed by the World Organisation for Animal Health - this paper provides a concise summary of some recent purposes and developments in bacterial genomics analysis. PMID- 27217180 TI - The genomics of mycobacteria. AB - The species Mycobacterium bovis and Mycobacterium avium subspecies paratuberculosis are the causal agents, respectively, of tuberculosis and paratuberculosis in animals. Both mycobacteria, especially M. bovis, are also important to public health because they can infect humans. In recent years, this and the impact of tuberculosis and paratuberculosis on animal production have led to significant advances in knowledge about both pathogens and their host interactions. This article describes the contribution of genomics and functional genomics to studies of the evolution, virulence, epidemiology and diagnosis of both these pathogenic mycobacteria. PMID- 27217181 TI - Use of genomics to track bovine tuberculosis transmission. AB - The control of any infectious disease of livestock is made more difficult by the presence of a wildlife reservoir, as the reservoir is often poorly observed and difficult to manage. This problem is particularly acute for bovine tuberculosis (bTB) because the long duration of infection and low levels of infectiousness make tracing the sources of infection difficult. For over 30 years, the process of contact tracing has been aided by the exploitation of molecular markers in the pathogen, but this has largely only been capable of characterising broad associations between large communities of similar types. However, the recent advent of mass high-throughput 'whole-genome' sequencing (WGS) has revolutionised forensic epidemiology for other diseases, and now it has the potential to do so for bTB. In this review, the authors consider the historical context of WGS use and look at what prior molecular techniques have already achieved. They outline the key approaches to interpreting WGS data and consider both the role of advanced analytical techniques that exploit the evolutionary and epidemiological properties of the system and the problems associated with quantifying the role of hidden reservoirs of disease. Finally, they consider the particular difficulties associated with developing this technology for routine diagnostics and its potential for mass use. PMID- 27217182 TI - Diagnosis of vibriosis in the era of genomics: lessons from invertebrates. AB - Global changes linked to increases in temperature and ocean acidification, but also to more direct anthropogenic influences such as aquaculture, have caused a worldwide increase in the reports of Vibrio-associated illnesses affecting humans and also animals such as shrimp and molluscs. Investigation of the emergence of Vibrio pathogenesis events requires the analysis of microbial evolution at the gene, genome and population levels, in order to identify genomic modifications linked to increased virulence, resistance and/or prevalence, or to recent host shift. From a more applied point of view, the elucidation of virulence mechanisms is a prerequisite to devising prophylactic methods to fight infectious agents. In comparison with human pathogens, fairly little is known about the requirements for virulence in vibrios pathogenic to animals. However, the advent of genome sequencing, especially next-generation technologies, the possibility of genetically manipulating most of the Vibrio strains, and the recent availability of standardised animals for experimental infections have now compensated for the considerable delay in advancement of the knowledge of non-model pathogens such as Vibrio and have led to new scientific questions. PMID- 27217183 TI - Bioinformatics tools for analysing viral genomic data. AB - The field of viral genomics and bioinformatics is experiencing a strong resurgence due to high-throughput sequencing (HTS) technology, which enables the rapid and cost-effective sequencing and subsequent assembly of large numbers of viral genomes. In addition, the unprecedented power of HTS technologies has enabled the analysis of intra-host viral diversity and quasispecies dynamics in relation to important biological questions on viral transmission, vaccine resistance and host jumping. HTS also enables the rapid identification of both known and potentially new viruses from field and clinical samples, thus adding new tools to the fields of viral discovery and metagenomics. Bioinformatics has been central to the rise of HTS applications because new algorithms and software tools are continually needed to process and analyse the large, complex datasets generated in this rapidly evolving area. In this paper, the authors give a brief overview of the main bioinformatics tools available for viral genomic research, with a particular emphasis on HTS technologies and their main applications. They summarise the major steps in various HTS analyses, starting with quality control of raw reads and encompassing activities ranging from consensus and de novo genome assembly to variant calling and metagenomics, as well as RNA sequencing. PMID- 27217184 TI - Using genomics data to reconstruct transmission trees during disease outbreaks. AB - Genetic sequence data from pathogens present a novel means to investigate the spread of infectious disease between infected hosts or infected premises, complementing traditional contact-tracing approaches, and much recent work has gone into developing methods for this purpose. The objective is to recover the epidemic transmission tree, which identifies who infected whom. This paper reviews the various approaches that have been taken. The first step is to define a measure of difference between sequences, which must be done while taking into account such factors as recombination and convergent evolution. Three broad categories of method exist, of increasing complexity: those that assume no withinhost genetic diversity or mutation, those that assume no within-host diversity but allow mutation, and those that allow both. Until recently, the assumption was usually made that every host in the epidemic could be identified, but this is now being relaxed, and some methods are intended for sparsely sampled data, concentrating on the identification of pairs of sequences that are likely to be the result of direct transmission rather than inferring the complete transmission tree. Many of the procedures described here are available to researchers as free software. PMID- 27217186 TI - Seeing the bigger picture. PMID- 27217185 TI - Clinical analysis of bacterial strain profiles isolated from urinary tract infections: A 30-year study. AB - OBJECTIVES: We analyzed bacterial strains isolated from urine samples of patients with urinary tract infections (UTI) at Okayama University Hospital over a 30-year period to characterize trends in species and antimicrobial susceptibilities. METHODS: Clinical isolates were collected from in- and out-patients with pyuria and bacteriuria who were treated between 1984 and 2014 (one episode per patient and plural isolates were counted in polymicrobial infection). We examined these isolates to identify pathogens and tested for antimicrobial susceptibility. RESULTS: Isolates from complicated UTI over a 30-year period revealed Pseudomonas aeruginosa (P. aeruginosa) was the most frequently isolated in the first decade (1984-1994), MRSA in the second decade (1995-2004), and Escherichia coli (E. coli) in the latest decade (2005-2014). In uncomplicated UTI examined over 20 years, E. coli was the most frequently isolated species accounting for 47-94% of isolates. Fluoroquinolone (FQs)-insusceptible E. coli were first isolated in 1994 and increased to about 35% in 2013 in patients with complicated UTI. CONCLUSIONS: Complicated UTI involving P. aeruginosa and MRSA decreased over the last 10 years. Our data suggest that several factors such as shorter hospitalizations, shorter indwelling catheter use, and appropriate antimicrobial use has decreased colonization of P. aeruginosa and MRSA with relative increases in isolation of E. coli including FQs-insusceptible strains. We must continue our surveillance of antimicrobial-resistant bacteria isolated from urine samples and evaluate antibiograms, since their persistence in the urinary tract would be problematic. PMID- 27217187 TI - Tissue engineering: Signals from within. PMID- 27217188 TI - Tissue engineering: Scalable vascularized implants. PMID- 27217189 TI - Exciton-polariton condensates: Exciton-mediated superconductivity. PMID- 27217190 TI - Material Witness: Engines of imagination. PMID- 27217192 TI - RAGE-ligand axis: A new biomarker in multiple sclerosis, time for multicentre validation study! PMID- 27217191 TI - Impact of HPV vaccination on anogenital warts and respiratory papillomatosis. AB - Human papillomavirus (HPV), the most common sexually transmitted infection in the US and worldwide, can cause cancers, anogenital warts (AGW), and recurrent respiratory papillomatosis (RRP) in men, women, and children. Global incidence of AGW ranges from 160-289 cases per 100,000 person-years and peaks in young men and women in the third decade of life. RRP has an estimated incidence of 3 per 1 million person-years in children. Pre-licensure trial efficacy, modeling and time trend ecological studies have shown a significant short-term impact of 4vHPV vaccine. In girls aged 15-19 years, a previously published meta-analysis indicated that genital warts decreased significantly by 31%; stratified analysis revealed more substantial reductions in populations with high (>=50 %) vs. low (<50 % ) vaccination coverage (61% vs. 14%). Longer-term monitoring will reveal whether this impact continues under 9vHPV programs, and whether current declines in AGW are mirrored by declines in RRP. PMID- 27217193 TI - Urachal-sigmoid fistula managed by laparoscopic assisted high anterior resection, primary anastomosis and en bloc resection of the urachal cyst and involved bladder. AB - Sigmoid-urachal fistula is exceedingly rare in adults and only a few cases have been reported in the world literature. We present the case of a 54-year-old man with symptomatic sigmoid-urachal fistula managed successfully with a laparoscopic assisted high anterior resection, primary anastomosis and an en bloc resection of the urachal cyst and the involved cuff of bladder. PMID- 27217194 TI - The analysis of the influence of fractal structure of stimuli on fractal dynamics in fixational eye movements and EEG signal. AB - One of the major challenges in vision research is to analyze the effect of visual stimuli on human vision. However, no relationship has been yet discovered between the structure of the visual stimulus, and the structure of fixational eye movements. This study reveals the plasticity of human fixational eye movements in relation to the 'complex' visual stimulus. We demonstrated that the fractal temporal structure of visual dynamics shifts towards the fractal dynamics of the visual stimulus (image). The results showed that images with higher complexity (higher fractality) cause fixational eye movements with lower fractality. Considering the brain, as the main part of nervous system that is engaged in eye movements, we analyzed the governed Electroencephalogram (EEG) signal during fixation. We have found out that there is a coupling between fractality of image, EEG and fixational eye movements. The capability observed in this research can be further investigated and applied for treatment of different vision disorders. PMID- 27217196 TI - A sustained quality improvement program reduces nephrotoxic medication-associated acute kidney injury. AB - Exposure to nephrotoxic medication is among the most common causes of acute kidney injury (AKI) in hospitalized patients. Here we conducted a prospective quality improvement project implementing a systematic Electronic Health Record screening and decision support process (trigger) in our quaternary pediatric inpatient hospital. Eligible patients were noncritically ill hospitalized children receiving an intravenous aminoglycoside for more than 3 days or more than 3 nephrotoxins simultaneously (exposure) from September 2011 through March 2015. Pharmacists recommended daily serum creatinine monitoring in exposed patients after appearance on the trigger report and AKI was defined by the Kidney Disease Improving Global Outcomes AKI criteria. A total of 1749 patients accounted for 2358 separate hospital admissions during which a total of 3243 episodes of nephrotoxin exposure were identified with 170 patients (9.7%) experiencing 2 or more exposures. A total of 575 individual AKI episodes occurred over the 43-month study period. Overall, the exposure rate decreased by 38% (11.63-7.24 exposures/1000 patient days), and the AKI rate decreased by 64% (2.96 1.06 episodes/1000 patient days). Assuming initial baseline exposure rates would have persisted without our project implementation, we estimate 633 exposures and 398 AKI episodes were avoided. Thus, systematic surveillance for nephrotoxic medication exposure and near real-time AKI risk can lead to sustained reductions in avoidable harm. These interventions and outcomes are translatable to other pediatric and nonpediatric hospitalized settings. PMID- 27217195 TI - Prevention of apoptosis averts glomerular tubular disconnection and podocyte loss in proteinuric kidney disease. AB - There is a great need for treatment that arrests progression of chronic kidney disease. Increased albumin in urine leads to apoptosis and fibrosis of podocytes and tubular cells and is a major cause of functional deterioration. There have been many attempts to target fibrosis, but because of the lack of appropriate agents, few have targeted apoptosis. Our group has described an ouabain-activated Na,K-ATPase/IP3R signalosome, which protects from apoptosis. Here we show that albumin uptake in primary rat renal epithelial cells is accompanied by a time- and dose-dependent mitochondrial accumulation of the apoptotic factor Bax, down regulation of the antiapoptotic factor Bcl-xL and mitochondrial membrane depolarization. Ouabain opposes these effects and protects from apoptosis in albumin-exposed proximal tubule cells and podocytes. The efficacy of ouabain as an antiapoptotic and kidney-protective therapeutic tool was then tested in rats with passive Heymann nephritis, a model of proteinuric chronic kidney disease. Chronic ouabain treatment preserved renal function, protected from renal cortical apoptosis, up-regulated Bax, down-regulated Bcl-xL, and rescued from glomerular tubular disconnection and podocyte loss. Thus we have identified a novel clinically feasible therapeutic tool, which has the potential to protect from apoptosis and rescue from loss of functional tissue in chronic proteinuric kidney disease. PMID- 27217197 TI - Challenging the dogma of mitochondrial reactive oxygen species overproduction in diabetic kidney disease. AB - The paradigm that high glucose drives overproduction of superoxide from mitochondria as a unifying theory to explain end organ damage in diabetes complications has been tightly held for more than a decade. With the recent development of techniques and probes to measure the production of distinct reactive oxygen species (ROS) in vivo, this widely held dogma is now being challenged with the emerging view that specific ROS moieties are essential for the function of specific intracellular signaling pathways and represent normal mitochondrial function. This review will provide a balanced overview of the dual nature of ROS, detailing current evidence for ROS overproduction in diabetic kidney disease, with a focus on cell types and sources of ROS. The technical aspects of measurement of mitochondrial ROS, both in isolated mitochondria and emerging in vivo methods will be discussed. The counterargument, that mitochondrial ROS production is reduced in diabetic complications, is consistent with a growing recognition that stimulation of mitochondrial biogenesis and oxidative phosphorylation activity reduces inflammation and fibrosis. It is clear that there is an urgent need to fully characterize ROS production paying particular attention to spatiotemporal aspects and to factor in the relevance of ROS in the regulation of cellular signaling in the pathogenesis of diabetic kidney disease. With improved tools and real-time imaging capacity, a greater understanding of the complex role of ROS will be able to guide novel therapeutic regimens. PMID- 27217198 TI - Is nephrology specialty at risk? AB - Interest in nephrology as a career choice has been steadily waning among internal medicine residents. This decline is reflected in a significant increment in unfilled fellowship training spots for several years. Interventional nephrology can help to reinvigorate an interest in nephrology as a whole. PMID- 27217201 TI - Unique 1D Co3O4 crystallized nanofibers with (220) oriented facets as high performance lithium ion battery anode material. AB - A novel one-step hydrothermal and calcination strategy was developed to synthesize the unique 1D oriented Co3O4 crystal nanofibers with (220) facets on the carbon matrix derived from the natural, abundant and low cost wool fibers acting as both carbon precursor and template reagent. The resultant W2@Co3O4 nanocomposite exhibited very high specific capacity and favorable high-rate capability when used as anode material of lithium ion battery. The high reversible Li(+) ion storage capacity of 986 mAh g(-1) was obtained at 100 mA g( 1) after 150 cycles, higher than the theoretical capacity of Co3O4 (890 mAh g( 1)). Even at the higher current density of 1 A g(-1), the electrode could still deliver a remarkable discharge capacity of 720 mAh g(-1) over 150 cycles. PMID- 27217202 TI - Measurement of the dimensions of food insecurity in developed countries: a systematic literature review. AB - OBJECTIVE: Food insecurity is a salient health issue comprised of four dimensions - food access, availability, utilization and stability over time. The aim of the present study was to conduct a systematic literature review to identify all multi item tools that measure food insecurity and explore which of the dimensions they assess. DESIGN: Five databases were searched (CENTRAL, CINAHL plus, EMBASE, MEDLINE, TRIP) for studies published in English since 1999. Inclusion criteria included human studies using multi-item tools to measure food security and studies conducted in developed countries. Manuscripts describing the US Department of Agriculture Food Security Survey Module, that measures 'food access', were excluded due to wide acceptance of the validity and reliability of this instrument. Two authors extracted data and assessed the quality of the included studies. Data were summarized against the dimensions of food insecurity. SETTING: A systematic review of the literature. SUBJECTS: The majority of tools were developed in the USA and had been used in different age groups and cultures. RESULTS: Eight multi-item tools were identified. All of the tools assessed the 'food access' dimension and two partially assessed the dimensions 'food utilization' and 'stability over time', respectively. 'Food availability' was not assessed by existing tools. CONCLUSIONS: Current tools available for measuring food insecurity are subjective, limited in scope, with a majority assessing only one dimension of food insecurity (access). To more accurately assess the true burden of food insecurity, tools should be adapted or developed to assess all four dimensions of food insecurity. PMID- 27217203 TI - 3D-printing of transparent bio-microfluidic devices in PEG-DA. AB - The vast majority of microfluidic systems are molded in poly(dimethylsiloxane) (PDMS) by soft lithography due to the favorable properties of PDMS: biocompatible, elastomeric, transparent, gas-permeable, inexpensive, and copyright-free. However, PDMS molding involves tedious manual labor, which makes PDMS devices prone to assembly failures and difficult to disseminate to research and clinical settings. Furthermore, the fabrication procedures limit the 3D complexity of the devices to layered designs. Stereolithography (SL), a form of 3D-printing, has recently attracted attention as a way to customize the fabrication of biomedical devices due to its automated, assembly-free 3D fabrication, rapidly decreasing costs, and fast-improving resolution and throughput. However, existing SL resins are not biocompatible and patterning transparent resins at high resolution remains difficult. Here we report procedures for the preparation and patterning of a transparent resin based on low MW poly(ethylene glycol) diacrylate (MW 250) (PEG-DA-250). The 3D-printed devices are highly transparent and cells can be cultured on PEG-DA-250 prints for several days. This biocompatible SL resin and printing process solves some of the main drawbacks of 3D-printed microfluidic devices: biocompatibility and transparency. In addition, it should also enable the production of non-microfluidic biomedical devices. PMID- 27217205 TI - Occupational therapy students rating the social profile of their educational group: do they agree? AB - BACKGROUND: During the curriculum, occupational therapy students learn to administer a range of assessment procedures. Interrater agreement between occupational therapy students' ratings of group functioning has not yet been examined. AIMS: To examine the interrater agreement within groups of students' ratings using the Social Profile. METHODS AND MATERIALS: The Social Profile assesses the social interaction behaviours in activity groups, and 35 students completed the measure. Two methods of obtaining an overall Social Profile score were explored. Intraclass correlation coefficients (ICC) were calculated to assess the level of agreement within groups of raters. RESULTS: Social interaction in the study groups occurred more frequently within the basic cooperative level. There was substantial agreement within groups of raters on this level, whereas there was low to moderate agreement on the other four levels. The weighted method of obtaining an overall Social Profile score showed higher ICC than the simpler method. CONCLUSION AND SIGNIFICANCE: It appears to be easier to reach high interrater agreement when considering frequently occurring behaviours in a group. The weighted method of obtaining an overall Social Profile score showed the best ICC results and should preferably be used in future studies where an overall measure is sought. PMID- 27217204 TI - Predictors of Excisional Volume Loss in Partial Nephrectomy: Is There Still Room for Improvement? AB - Since volume loss is the most important modifiable determinant of long-term renal function after partial nephrectomy, there is great interest in ways to reduce the loss of healthy parenchyma. We retrospectively reviewed 880 partial nephrectomies to identify predictors of excisional volume loss (EVL), based on pathologic assessment. After stepwise variable selection, we assessed age, sex, solitary kidney status, tumor size, endophytic property, estimated blood loss, surgical approach, and surgeon volume for association with EVL using multiple regression. Male sex (p<0.01), larger tumors (p<0.01), endophytic tumors (p=0.01), open approach (p<0.01), increased bleeding (p<0.01), and higher surgeon volume (p<0.01) were independently associated with greater EVL. Approach strongly influenced EVL with open surgery having 7.8 cm(3) more EVL than robotic surgery. Negative surgical margins (95.7% vs 94.1%, p=0.32) did not differ between open and robotic approaches, respectively. EVL is associated with patient, tumor, and especially provider factors, suggesting that volume preservation may be improved with surgical optimization. Lack of percent volume loss data, which precluded assessment of EVL's impact on long-term renal function, is a limitation. PATIENT SUMMARY: We found that surgical approach affects the quantity of healthy kidney removed during cancer surgery, suggesting that there is room for further surgical improvement. PMID- 27217206 TI - Inappropriate cadherin switching in the mouse epiblast compromises proper signaling between the epiblast and the extraembryonic ectoderm during gastrulation. AB - Cadherin switching from E-cadherin (E-cad) to N-cadherin (N-cad) is a key step of the epithelial-mesenchymal transition (EMT) processes that occurs during gastrulation and cancer progression. We investigate whether cadherins actively participate in progression of EMT by crosstalk to signaling pathways. We apply ectopic cadherin switching before the onset of mouse gastrulation. Mutants with an induced E-cad to N-cad switch (Ncadki) die around E8.5. Severe morphological changes including a small epiblast, a rounded shape, an enlarged extra-embryonic compartment and lack of the amnion, combined with a massive cell detachment from the ectodermal layer are detected. In contrast to epiblast-specific E-cad depletion, gastrulation is initiated in Ncadki embryos, but patterning of the germ-layers is abnormal. An overall reduction in BMP signaling, expansion of Nodal and Eomes domains, combined with reduced Wnt3a expression at the primitive streak is observed. Our results show that in addition to cadherin-dependent adhesion, proper embryonic development requires E-cad mediated signaling function to facilitate a feedback loop that stabilizes Bmp4 and Bmp2 expression in the extraembryonic ectoderm and sustained downstream activity in the epiblast. Moreover, for proper morphogenesis a fine-tuned spatio-temporal control of cadherin switching is required during EMT at gastrulation to avoid premature cell detachment and migration. PMID- 27217207 TI - Comparison of Noninvasively and Invasively Managed Patients, With or Without Revascularization in Non-ST Elevation Myocardial Infarction (from the Acute Coronary Syndrome Israeli Survey). AB - Patients with non-ST elevation myocardial infarction who are managed noninvasively at presentation or are catheterized but without revascularization represent a heterogeneous and understudied population. We evaluated the clinical characteristics, management strategies, and outcomes of patients with non-ST elevation myocardial infarction (NSTEMI) who were enrolled in the prospective biannual Acute Coronary Syndrome Israeli Surveys from 2004 to 2013. Patients were divided into 3 groups: no catheterization (no angio), catheterization with revascularization (angio-revascularized), and catheterization without revascularization (angio-nonrevascularized) groups. The study included 3,198 patients with NSTEMI. Coronary angiography was performed in 2,525 (79%) during the index hospitalization, of whom 1899 (59%) underwent revascularization. Evidence-based therapies were administered during the index hospitalization at a significantly higher rate to those in the angio-revascularized group compared with the other 2 groups. Multivariate analysis showed that compared with those in the angio-revascularized and angio-nonrevascularized groups, patients in the no angio group experienced a significantly higher risk for 1-year mortality (hazard ratio 2.04 [p <=0.0001] and 1.21 [p = 0.01], respectively). The risk associated with no revascularized was consistent in each risk subset analyzed, including an older age, and increased creatinine levels. In conclusion, our data, from a large real-world contemporary experience, suggest that patients with NSTEMI who do not undergo coronary revascularization during the index hospitalization represent a greater risk and undertreated group with increased risk for long-term mortality. PMID- 27217208 TI - Management of Patients Aged >=85 Years With ST-Elevation Myocardial Infarction. AB - Guidelines mandate urgent revascularization in patients presenting with ST elevation myocardial infarction (STEMI) irrespective of age. Whether this strategy is optimal in patients aged >=85 years remains uncertain. We aimed to assess the clinical characteristics and outcomes of patients aged >=85 years with STEMI stratified by their management strategy. We analyzed baseline clinical characteristics of 101 consecutive patients aged >=85 years who presented with STEMI to a tertiary Australian hospital. Patients were stratified based on whether they underwent invasive management with urgent coronary angiography +/- percutaneous coronary intervention or conservative management. Our primary outcome was long-term mortality. Independent predictors of conservative management and long-term mortality were assessed by multivariate logistic regression and Cox proportional hazard modeling respectively. Of the 101 patients included, 45 underwent invasive management. Independent predictors of having conservative management were older age, anterior STEMI, and cognitive impairment (all p <0.01). Patients managed invasively had lower in-hospital (13.3% vs 32.1%, p = 0.03), 30-day (13.3% vs 37.5%, p <0.01), 12-month (22.2% vs 57.1%, p <0.01), and long-term (40.0% vs 75.0%, p <0.01) mortality. Invasive management was an independent predictor of lower long-term mortality (hazard ratio 0.29, 95% CI 0.11 to 0.76, p <0.01). In conclusion, patients aged >=85 years with STEMI who were older, had cognitive impairment or presented with anterior ST-elevation were more likely to be managed conservatively. Those who underwent invasive management had reasonable short- and long-term outcomes. PMID- 27217209 TI - Human induced pluripotent stem cell-derived fiber-shaped cardiac tissue on a chip. AB - We propose a method for the production of a fiber-shaped three-dimensional (3D) cellular construct of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) for the quantification of the contractile force. By culturing the cardiomyocytes in a patterned hydrogel structure with fixed edges, we succeeded in fabricating hiPS-CM fibers with aligned cardiomyocytes. The fiber generated contractile force along the fiber direction due to the hiPS-CM alignment, and we were able to measure its contractile force accurately. Furthermore, to demonstrate the drug reactivity of hiPS-CM fibers, the changes in the contractile frequency and force following treatment with isoproterenol and propranolol were observed. We believe that hiPS-CM fibers will be a useful tool for pharmacokinetic analyses during drug development. PMID- 27217210 TI - Matrix Biologists in Action. PMID- 27217211 TI - Early GABAergic transmission defects in the external globus pallidus and rest/activity rhythm alteration in a mouse model of Huntington's disease. AB - Huntington's disease (HD) is characterized by progressive motor symptoms preceded by cognitive deficits and is regarded as a disorder that primarily affects the basal ganglia. The external globus pallidus (GPe) has a central role in the basal ganglia, projects directly to the cortex, and is majorly modulated by GABA. To gain a better understanding of the time course of HD progression and gain insight into the underlying mechanisms, we analyzed GABAergic neurotransmission in the GPe of the R6/1 mouse model at purportedly asymptomatic and symptomatic stages (i.e., 2 and 6months). Western blot and quantitative polymerase chain reaction (PCR) analyses revealed alterations in the GPe of male R6/1 mice compared with wild-type littermates. Expression of proteins involved in pre- and post-synaptic GABAergic compartments as well as synapse number were severely decreased at 2 and 6months. At both ages, patch-clamp electrophysiological recordings showed a decrease of spontaneous and miniature inhibitory post-synaptic currents (IPSCs) suggesting that HD mutation has an early effect on the GABA signaling in the brain. Therefore, we performed continuous locomotor activity recordings from 2 to 4months of age. Actigraphy analyses revealed rest/activity fragmentation alterations that parallel GABAergic system impairment at 2months, while the locomotor deficit is evident only at 3months in R6/1 mice. Our results reveal early deficits in HD and support growing evidence for a critical role played by the GPe in physiological and pathophysiological states. We suggest that actimetry may be used as a non-invasive tool to monitor early disease progression. PMID- 27217212 TI - White matter and task-switching in young adults: A Diffusion Tensor Imaging study. AB - The capacity to flexibly switch between different task rules has been previously associated with distributed fronto-parietal networks, predominantly in the left hemisphere for phasic switching sub-processes, and in the right hemisphere for more tonic aspects of task-switching, such as rule maintenance and management. It is thus likely that the white matter (WM) connectivity between these regions is critical in sustaining the flexibility required by task-switching. This study examined the relationship between WM microstructure in young adults and task switching performance in different paradigms: classical shape-color, spatial and grammatical tasks. The main results showed an association between WM integrity in anterior portions of the corpus callosum (genu and body) and a sustained measure of task-switching performance. In particular, a higher fractional anisotropy and a lower radial diffusivity in these WM regions were associated with smaller mixing costs both in the spatial task-switching paradigm and in the shape-color one, as confirmed by a conjunction analysis. No association was found with behavioral measures obtained in the grammatical task-switching paradigm. The switch costs, a measure of phasic switching processes, were not correlated with WM microstructure in any task. This study shows that a more efficient inter hemispheric connectivity within the frontal lobes favors sustained task-switching processes, especially with task contexts embedding non-verbal components. PMID- 27217213 TI - Partly segregated cortico-subcortical pathways support phonologic and semantic verbal fluency: A lesion study. AB - Verbal fluency refers to the ability to generate as many words as possible in a limited time interval, without repetition and according to either a phonologic (each word begins with a given letter) or a semantic rule (each word belongs to a given semantic category). While current literature suggests the involvement of left fronto-temporal structures in fluency tasks, whether the same or distinct brain areas are necessary for each type of fluency remains unclear. We tested the hypothesis for an involvement of partly segregated cortico-subcortical structures between phonologic and semantic fluency by examining with a voxel-based lesion symptom mapping approach the effects of brain lesions on fluency scores corrected for age and education level in a group of 191 unselected brain-damaged patients with a first left or right hemispheric lesion. There was a positive correlation between the scores to the two types of fluency, suggesting that common mechanisms underlie the word generation independent of the production rule. The lesion symptom mapping revealed that lesions to left basal ganglia impaired both types of fluency and that left superior temporal, supramarginal and rolandic operculum lesions selectively impaired phonologic fluency and left middle temporal lesions impaired semantic fluency. Our results corroborate current neurocognitive models of word retrieval and production, and refine the role of cortical-subcortical interaction in lexical search by highlighting the common executive role of basal ganglia in both types of verbal fluency and the preferential involvement of the ventral and dorsal language pathway in semantic and phonologic fluency, respectively. PMID- 27217214 TI - Activation of the adenosine A2A receptor attenuates experimental autoimmune encephalomyelitis and is associated with increased intracellular calcium levels. AB - Multiple sclerosis (MS) is a common autoimmune disease that inevitably causes inflammatory nerve demyelination. However, an effective approach to prevent its course is still lacking and urgently needed. Recently, the adenosine A2A receptor (A2AR) has emerged as a novel inflammation regulator. Manipulation of A2AR activity may suppress the MS process and protect against nerve damage. To test this hypothesis, we treated murine experimental autoimmune encephalomyelitis (EAE), a model for MS, with the selective A2AR agonist, CGS21680 (CGS). We evaluated the effects of CGS on the pathological features of EAE progression, including CNS cellular infiltration, inflammatory cytokine expression, lymphocyte proliferation, and cell surface markers. Treatment with CGS significantly suppressed specific lymphocyte proliferation, reduced infiltration of CD4(+) T lymphocytes, and attenuated the expression of inflammatory cytokines, which in turn inhibited the EAE progression. For the first time, we demonstrate that CGS can increase the intracellular calcium concentration ([Ca(2+)]i) in murine lymphocytes, which may be the mechanism underlying the suppressive effects of CGS induced A2AR activation on EAE progression. Our findings strongly suggest that A2AR is a potential therapeutic target for MS and provide insight into the mechanism of action of A2AR agonists, which may offer a therapeutic option for this disease. PMID- 27217215 TI - Inpatient Mortality Among Solid Organ Transplant Recipients Hospitalized for Sepsis and Severe Sepsis. AB - BACKGROUND: Solid organ transplant (SOT) recipients are at elevated risk of sepsis. The impact of SOT on outcomes following sepsis is unclear. METHODS: We performed a retrospective cohort study using data from University HealthSystem Consortium, a consortium of academic medical center affiliates. We examined the association between SOT and mortality among patients hospitalized with severe sepsis or explicitly coded sepsis in 2012-2014. We used International Classification of Diseases, Ninth Revision (ICD-9) codes to identify severe sepsis, explicitly coded sepsis, and SOT (kidney, liver, heart, lung, pancreas, or intestine transplants). We fit random-intercept logistic regression models to account for clustering by hospital. RESULTS: There were 903 816 severe sepsis hospitalizations (39 618 [4.4%] with SOT) and 410 623 sepsis hospitalizations (14 526 [3.9%] with SOT) in 250 hospitals. SOT recipients were younger and more likely to be insured by Medicare than those without SOT. Among hospitalizations for severe sepsis and sepsis, in-hospital mortality was lower among those with vs those without SOT (5.5% vs 9.4% for severe sepsis; 8.7% vs 12.7% for sepsis). After adjustment, the odds ratio for mortality comparing SOT patients vs non-SOT was 0.83 (95% confidence interval [CI], .79-.87) for severe sepsis and 0.78 (95% CI, .73-.84) for sepsis. Compared to non-SOT patients, kidney, liver, and co transplant (kidney-pancreas/kidney-liver) recipients demonstrated lower mortality. No association was present for heart transplant, and lung transplant was associated with higher mortality. CONCLUSIONS: Among patients hospitalized for severe sepsis or sepsis, those with SOT had lower inpatient mortality than those without SOT. Identifying the specific strategies employed for populations with improved mortality could inform best practices for sepsis among SOT and non SOT populations. PMID- 27217216 TI - Metaanalysis of the Performance of a Combined Treponemal and Nontreponemal Rapid Diagnostic Test for Syphilis and Yaws. AB - BACKGROUND: The human treponematoses are important causes of disease. Mother-to child transmission of syphilis remains a major cause of stillbirth and neonatal death. There are also almost 100 000 cases of endemic treponemal disease reported annually, predominantly yaws. Rapid diagnostic tests (RDTs) would improve access to screening for these diseases. Most RDTs cannot distinguish current and previous infection. The Dual Path Platform (DPP) Syphilis Screen & Confirm test includes both a treponemal (T1) and nontreponemal (T2) component and may improve the accuracy of diagnosis. METHODS: We conducted a metaanalysis of published and unpublished evaluations of the DPP-RDT for the diagnosis of syphilis and yaws. We calculated the sensitivity, specificity, and overall agreement of the test compared with reference laboratory tests. RESULTS: Nine evaluations, including 7267 tests, were included. Sensitivity was higher in patients with higher titer rapid plasma reagin (>=1:16) for both the T1 (98.2% vs 90.1%, P < .0001) and the T2 component (98.2% vs 80.6%, P < .0001). Overall agreement between the DPP test and reference serology was 85.2% (84.4%-86.1%). Agreement was highest for high titer active infection and lowest for past infection. CONCLUSIONS: The RDT has good sensitivity and specificity of the treponemal and nontreponemal components both in cases of suspected syphilis and yaws, although the sensitivity is decreased at lower antibody titers. PMID- 27217217 TI - Delayed Dosing of Oral Rotavirus Vaccine Demonstrates Decreased Risk of Rotavirus Gastroenteritis Associated With Serum Zinc: A Randomized Controlled Trial. AB - BACKGROUND: Rotavirus is the world's leading cause of childhood diarrheal death. Despite successes, oral rotavirus vaccines are less effective in developing countries. In an urban slum of Dhaka, we performed active diarrhea surveillance to evaluate monovalent G1P[8] rotavirus vaccine (RV1) efficacy and understand variables contributing to risk of rotavirus diarrhea (RVD). METHODS: We performed a randomized controlled trial of monovalent oral rotavirus vaccine (RV1). Seven hundred healthy infants received RV1 or no RV1 (1:1) using delayed dosing (10 and 17 weeks) and were followed for 1 year. Intensive diarrhea surveillance was performed. The primary outcome was >=1 episode of RVD. Nutritional, socioeconomic, and immunologic factors were assessed by logistic regression best subsets analysis for association with risk of RVD and interactions with vaccine arm. RESULTS: Incidence of all RVD was 38.3 cases per 100 person-years. Per protocol RV1 efficacy was 73.5% (95% confidence interval [CI], 45.8%-87.0%) against severe RVD and 51% (95% CI, 33.8%-63.7%) against all RVD. Serum zinc level (odds ratio [OR], 0.77; P = .002) and lack of rotavirus immunoglobulin A (IgA) seroconversion (OR, 1.95; P = .018) were associated with risk of RVD, independent of vaccination status. Water treatment and exclusive breastfeeding were of borderline significance. Factors not associated with RVD included height for age at 10 weeks, vitamin D, retinol binding protein, maternal education, household income, and sex. CONCLUSIONS: In an urban slum with high incidence of RVD, the efficacy of RV1 against severe RVD was higher than anticipated in the setting of delayed dosing. Lower serum zinc level and lack of IgA seroconversion were associated with increased risk of RVD independent of vaccination. CLINICAL TRIALS REGISTRATION: NCT01375647. PMID- 27217218 TI - Photochemical Modification of Single Crystalline GaN Film Using n-Alkene with Different Carbon Chain Lengths as Biolinker. AB - As a potential material for biosensing applications, gallium nitride (GaN) films have attracted remarkable attention. In order to construct GaN biosensors, a corresponding immobilization of biolinkers is of great importance in order to render a surface bioactive. In this work, two kinds of n-alkenes with different carbon chain lengths, namely allylamine protected with trifluoroacetamide (TFAAA) and 10-aminodec-1-ene protected with trifluoroacetamide (TFAAD), were used to photochemically functionalize single crystalline GaN films. The successful linkage of both TFAAA and TFAAD to the GaN films is confirmed by time-of-flight secondary ion mass spectrometry (ToF-SIMS) measurement. With increased UV illumination time, the intensity of the secondary ions corresponding to the linker molecules initially increases and subsequently decreases in both cases. Based on the SIMS measurements, the maximum coverage of TFAAA is achieved after 14 h of UV illumination, while only 2 h is required in the case of TFAAD to reach the situation of a fully covered GaN surface. This finding leads to the conclusion that the reaction rate of TFAAD is significantly higher compared to TFAAA. Measurements by atomic force microscopy (AFM) indicate that the coverage of GaN films by a TFAAA layer leads to an increased surface roughness. The atomic terraces, which are clearly observable for the pristine GaN films, disappear once the surface is fully covered by a TFAAA layer. Such TFAAA layers will feature a homogeneous surface topography even for reaction times of 24 h. In contrast to this, TFAAD shows strong cross-polymerization on the surface, this is confirmed by optical microscopy. These results demonstrate that TFAAA is a more suitable candidate as biolinker in context of the GaN surfaces due to its improved controllability. PMID- 27217221 TI - Themes in daily life of adolescents and young adults with congenital bleeding disorders: a qualitative study. PMID- 27217220 TI - Surgical management of oesophageal atresia. AB - There have been major advances in the surgery for oesophageal atresia (OA) and tracheo-oesophageal fistula(TOF) with survival now exceeding 90%. The standard open approach to OA and distal TOF has been well described and essentially unchanged for the last 60 years. Improved survival in recent decades is most attributable to advances in neonatal anaesthesia and perioperative care. Recent surgical advances include the use of thoracoscopic surgery for the repair of OA/TOF and in some centres isolated OA, thereby minimising the long term musculo skeletal morbidity associated with open surgery. The introduction of growth induction by external traction (Foker procedure) for the treatment of long-gap OA has provided an important tool enabling increased preservation of the native oesophagus. Despite this, long-gap OA still poses a number of challenges, and oesophageal replacement still may be required in some cases. PMID- 27217219 TI - Three-way junction conformation dictates self-association of phage packaging RNAs. AB - The packaging RNA (pRNA) found in the phi29 family of bacteriophage is an essential component of a powerful molecular motor used to package the phage's DNA genome into the capsid. The pRNA forms homomultimers mediated by intermolecular "kissing-loop" interactions, thus it is an example of the unusual phenomenon of a self-associating RNA that can form symmetric higher-order multimers. Previous research showed the pRNAs from phi29 family phages have diverse self-association properties and the kissing-loop interaction is not the sole structural element dictating multimerization. We found that a 3-way junction (3wj) within each pRNA, despite not making direct intermolecular contacts, plays important roles in stabilizing the intermolecular interactions and dictating the size of the multimer formed (dimer, trimer, etc.). Specifically, the 3wj in the pRNA from phage M2 appears to favor a different conformation compared to the 3wj in the phi29 pRNA, and the M2 junction facilitates formation of a higher-order multimer that is more thermostable. This behavior provides insights into the fundamental principles of RNA self-association, and additionally may be useful to engineer fine-tuned properties into pRNAs for nanotechnology. PMID- 27217222 TI - ISAC scholars mentorship program, the first season. PMID- 27217223 TI - Cytometric routes to single cell transcriptomics. PMID- 27217225 TI - A consensus-based tool for ranking the risk of blood-transmissible infections. AB - BACKGROUND: Emerging infectious diseases (EIDs) pose a threat to blood transfusion safety. Despite a lack of evidence, safety interventions may be required. However, what should decision makers base their decisions on? A model was developed that allows valuing the perceived risk of an EID for blood safety as derived from a group of experts. The model requires estimates of four disease characteristics and the accuracy of these estimates. STUDY DESIGN AND METHODS: Sixteen selected experts ranked 24 hypothetical diseases, each comprising a quantitative estimate of four characteristics: transfusion transmissibility, proportion of asymptomatic infectious phase, prevalence of infection, and disease impact. Each of the characteristics was expressed at one of six predefined levels with varying ranges of uncertainty. The model was derived using probabilistic inversion and was applied to value the perceived risk of most currently known EIDs relevant to blood transfusion. RESULTS: The model demonstrated that transmissibility and prevalence are the most important risk drivers. However, disease impact and likelihood of transmission during the asymptomatic phase of infection are more important when the disease characteristics are unknown. In the ranking of currently known EIDs, diseases that have been identified previously as posing a serious risk to blood transfusion appear at the top of the list. CONCLUSION: With the current model, the perceived risk of EIDs for transfusion safety can be determined for both known and unknown diseases, even when little information is available. Extension of the expert base, further model development and validation, and continuous updating of the model are recommended. PMID- 27217226 TI - G-Quadruplex ligands: Potent inhibitors of telomerase activity and cell proliferation in Plasmodium falciparum. AB - Telomeres are DNA and protein structures located at the ends of eukaryotic chromosomes. These structures maintain chromosomal stability by impeding chromosomal ends from being recognized and processed as fragmented DNA. They also support the complete replication of the genome by providing mechanisms that solve the end-replication problem. Telomeric DNA is formed of short, repeating, guanine rich sequences. The G-rich sequence extends towards the 3' end, forming a protruding single-stranded end that can acquire a conformation known as G quadruplex. The ligands stabilizing this structure are potent inhibitors of telomerase activity, a catalytic activity necessary to compensate for the loss of telomeric DNA that occurs in each round of replication. In the absence of telomerase, telomeres shorten after a given number of cell divisions, after which the cell enters a senescence state and finally dies. In the presence of telomerase activity, telomeres are preserved, and cells reach a state of indefinite replication or immortalization. This study analyzed the effect of two ligands of the G-quadruplex (TMPyP4 and Telomestatin) on the telomerase activity and cell proliferation of Plasmodium falciparum, given that this parasite has a high proliferation rate and an almost indefinite replication capacity. The effect of the ligands on telomerase activity was evaluated using the TRAP (Telomere Repeat Amplification Protocol) activity assay, which was performed in the presence of increasing concentrations of each ligand. In this study, TMPyP4 showed the highest inhibitory effect, reaching 50% inhibition at a 5MUM concentration. Regarding proliferation, both ligands drastically affected parasite growth, but Telomestatin had a stronger effect. After three days of treatment, parasite growth decreased by 90%. Thus, it is possible that this compound interferes with other vital pathways for the parasite beyond the elongation of telomeric DNA by telomerase. PMID- 27217227 TI - Effective atomic numbers (Zeff) of based calcium phosphate biomaterials: a comparative study. AB - This study determined the interaction of radiation parameters of four biomaterials as attenuators to measure the transmitted X-rays spectra, the mass attenuation coefficient and the effective atomic number by spectrometric system comprising the CdTe detector. The biomaterial BioOss(r) presented smaller mean energy than the other biomaterials. The MU/rho and Zeff of the biomaterials showed their dependence on photon energy. The data obtained from analytical methods of x-ray spectra, u/rho and Zeff, using biomaterials as attenuators, demonstrated that these materials could be used as substitutes for dentin, enamel and bone. Further, they are determinants for the characterization of the radiation in tissues or equivalent materials. PMID- 27217228 TI - Reproducibly creating hierarchical 3D carbon to study the effect of Si surface functionalization on the oxygen reduction reaction. AB - We report a new method to reproducibly fabricate functional 3D carbon structures directly on a current collector, e.g. stainless steel. The 3D carbon platform is formed by direct growth of upright arrays of carbon nanofiber bundles on a roughened surface of stainless steel via the seed-assisted approach. Each bundle consists of about 30 individual carbon nanofibers with a diameter of 18 nm on average. We have found that this new platform offers adequate structural integrity. As a result, no reduction of the surface area during downstream chemical functionalization was observed. With a fixed and reproducible 3D structure, the effect of the chemistry of the grafted species on the oxygen reduction reaction has been systematically investigated. This investigation reveals for the first time that non-conductive Si with an appropriate electronic structure distorts the carbon electronic structure and consequently enhances ORR electrocatalysis. The strong interface provides excellent electron connectivity according to electrochemical analysis. This highly reproducible and stable 3D platform can serve as a stepping-stone for the investigation of the effect of carbon surface functionalization on electrochemical reactions in general. PMID- 27217229 TI - The effect of Wolbachia on dengue outbreaks when dengue is repeatedly introduced. AB - Use of the Wolbachia bacterium is a proposed new strategy to reduce dengue transmission, which results in around 390 million individuals infected annually. In places with strong variations in climatic conditions such as temperature and rainfall, dengue epidemics generally occur only at a certain time of the year. Where dengue is not endemic, the time of year in which imported cases enter the population plays a crucial role in determining the likelihood of outbreak occurrence. We use a mathematical model to study the effects of Wolbachia on dengue transmission dynamics and dengue seasonality. We focus in regions where dengue is not endemic but can spread due to the presence of a dengue vector and the arrival of people with dengue on a regular basis. Our results show that the time-window in which outbreaks can occur is reduced in the presence of Wolbachia carrying Aedes aegypti mosquitoes by up to six weeks each year. We find that Wolbachia reduces overall case numbers by up to 80%. The strongest effect is obtained when the amplitude of the seasonal forcing is low (0.02-0.30). The benefits of Wolbachia also depend on the transmission rate, with the bacteria most effective at moderate transmission rates ranging between 0.08-0.12. Such rates are consistent with fitted estimates for Cairns, Australia. PMID- 27217230 TI - Stem cells from human exfoliated deciduous teeth differentiate toward neural cells in a medium dynamically cultured with Schwann cells in a series of polydimethylsiloxanes scaffolds. AB - OBJECTIVE: Schwann cells (SCs) are primary structural and functional cells in the peripheral nervous system. These cells play a crucial role in peripheral nerve regeneration by releasing neurotrophic factors. This study evaluated the neural differentiation potential effects of stem cells from human exfoliated deciduous teeth (SHEDs) in a rat Schwann cell (RSC) culture medium. APPROACH: SHEDs and RSCs were individually cultured on a polydimethylsiloxane (PDMS) scaffold, and the effects of the RSC medium on the SHEDs differentiation between static and dynamic cultures were compared. MAIN RESULTS: Results demonstrated that the SHED cells differentiated by the RSC cultured medium in the static culture formed neurospheres after 7 days at the earliest, and SHED cells formed neurospheres within 3 days in the dynamic culture. These results confirm that the RSC culture medium can induce neurospheres formation, the speed of formation and the number of neurospheres (19.16 folds high) in a dynamic culture was superior to the static culture for 3 days culture. The SHED-derived spheres were further incubated in the RSCs culture medium, these neurospheres continuously differentiated into neurons and neuroglial cells. Immunofluorescent staining and RT-PCR revealed nestin, beta-III tubulin, GFAP, and gamma-enolase of neural markers on the differentiated cells. SIGNIFICANCE: These results indicated that the RSC culture medium can induce the neural differentiation of SHED cells, and can be used as a new therapeutic tool to repair nerve damage. PMID- 27217231 TI - Women's experience of low back and/or pelvic pain (LBPP) during pregnancy. AB - OBJECTIVE: to explore the experiences of women suffering low back and/or pelvic pain during pregnancy. DESIGN: a qualitative design using focus groups. Each group was recorded with a digital audio recorder and analysed using the Newell and Burnard framework for thematic analysis. SETTING: an urban maternity hospital. PARTICIPANTS: a self-selecting sample of 14 women who had taken part in a pilot randomised controlled trial investigating reflexology for pregnancyrelated low back and / or pelvic pain. MEASUREMENTS AND FINDINGS: the group discussions were guided by a pre-determined schedule of questions designed to investigate women's experiences of pregnancyrelated low back and / or pelvic pain. Three main themes emerged: KEY CONCLUSIONS: low back and/ or pelvic pain affected women physically and emotionally during pregnancy. Their attitudes towards, and knowledge about the conditions differed. Women used a range of self help strategies for their symptoms and there was a general sense of dissatisfaction with routine advice and treatment, a finding supported by a growing body of research. IMPLICATIONS FOR PRACTICE: given that pregnancy-related low back and/ pelvic pain occur across the world, and affects the majority of pregnant women, heath care providers need to ensure that standard care provided is meeting women's needs. Health care professionals may require specific training in order to effectively provide individualised and evidence-based advice and support to pregnant women experiencing this pain. PMID- 27217233 TI - A survey on difficulties and desires of breast-feeding women in Wuhan, China. AB - OBJECTIVES: exclusive breast feeding in China is relatively low and no research has been conducted to explore the difficulties and desires of Chinese lactating mothers. Currently, Chinese women turn to massage therapists to increase breastmilk volume, implying that many breast-feeding women faced problems but had few support mechanisms.This study aimed to explore the difficulties and desires of Chinese breast-feeding women and to propose strategies for increasing the rate of exclusive breast feeding. METHODS: three hundred and seventy-five primiparous women were recruited from two randomized cluster communities in Wuhan following ethical approval. Face-to-face semistructured interviews were conducted with 76 of the participants to collect data on their infants' feeding status, duration of exclusive breast feeding, reasons for stopping, difficulties encountered, and sources of support for lactation. RESULTS: the breast feeding initiation rate was 93.6%, but exclusive breast feeding was only 6.2% at six months. The most frequently cited reason for giving up exclusive breast feeding was perceived breastmilk insufficiency. Women cited a desire for professional and individualised instruction from following resources: (1) lactation consultants in hospital and communities; (2) Qualified cuirushi; (3) breast feeding website;(4) Relatives, friends and peers;(5) Telephone hotline. CONCLUSIONS: to improve the rate and duration of exclusive breast feeding in China, effective and available resources must be available. Timely,professional and face-to-face lactation counselling such as lactation consultant, qualified cuirushin is needed. PMID- 27217232 TI - Opinions of professionals about integrating midwife- and obstetrician-led care in The Netherlands. AB - OBJECTIVE: the current division between midwife-led and obstetrician-led care creates fragmentation in maternity care in the Netherlands. This study aims to gain insight into the level of consensus among maternity care professionals about facilitators and barriers related to integration of midwife-led and obstetrician led care. Integration could result in more personal continuity of care for women who are referred during labour. This may lead to better birth experiences, fewer interventions and better outcomes for both mother and infant. DESIGN: a descriptive study using a questionnaire survey of 300 primary care midwives, 100 clinical midwives and 942 obstetricians. SETTING: the Netherlands in 2013. PARTICIPANTS: 131 (response 44%) primary care midwives, 51 (response 51%) clinical midwives and 242 (response 25%) obstetricians completed the questionnaire. FINDINGS: there was consensus about the clinical midwife caring for labouring women at moderate risk of complications. Although primary care midwives themselves were willing to expand their tasks there was no consensus among respondents on the tasks and responsibilities of the primary care midwife. Professionals agreed on the importance of good collaboration between professionals who should work together as a team. Respondents also agreed that there are conflicting interests related to the payment structure, which are a potential barrier for integrating maternity care. KEY CONCLUSIONS: this study shows that professionals are positive regarding an integrated maternity care system but primary care midwives, clinical midwives and obstetricians have different opinions about the specifications and implementation of this system. IMPLICATION FOR PRACTICE: our findings are in accordance with earlier research, showing that it is too early to design a blueprint for an integrated maternity care model in the Netherlands. To bring about change in the maternity care system, an implementation strategy should be chosen that accounts for differences in interests and opinions between professionals. PMID- 27217234 TI - Midwifing the notion of a 'good' birth: a philosophical analysis. AB - OBJECTIVE: to ponder afresh what makes a good birth experience in a listening manner. DESIGN: a hermeneutic approach that first explores the nature of how to listen to a story that is already familiar to us and then draws on Heidegger's notion of the fourfold to seek to capture how the components of a'good birth' come together within experience. SETTING: primary birthing centre, New Zealand PARTICIPANTS: the focus of this paper is the story of one participant. It was her second birth; her first birth involved a lot of medical intervention. She had planned to travel one hour to the tertiary birthing unit but in labour chose to stay at the Birth Centre. Her story seems to portray a 'very good birth'. FINDINGS: in talking of birth, the nature of a research approach is commonly to focus on one aspect: the place, the care givers, or the mode of care. In contrast, we took on the challenge of first listening to all that was involved in one woman's story. We came to see that what made her experience 'good' was'everything' gathered together in a coherent and supportive oneness. Heidegger's notion of the fourfold helped reveal that one cannot talk about one thing without at the same time talking about all the other things as well. Confidence was the thread that held the story together. KEY CONCLUSIONS: there is value in putting aside the fragmented approach of explicating birth to recognise the coming together of place, care, situation, and the mystery beyond explanation. Women grow a confidence in place when peers and community encourage the choice based on their own experience. Confidence of caregiver comes in relationship. Feeling confident within 'self' is part of the mystery. When confidence in the different dimensions holds together, birth is 'good'. IMPLICATIONS OR PRACTICE: one cannot simply build a new birthing unit and assume it will offer a good experience of birth. Experience is about so much more. Being mindful of the dimensions of confidence that need to be built up and sheltered is a quest for wise leaders. Protecting the pockets where we know 'good birth' already flourishes is essential. PMID- 27217235 TI - Supporting breast-feeding women from the perspective of the midwife: A systematic review of the literature. AB - INTRODUCTION: In 2003 the World Health Organization (WHO) recommended that infants should be fed exclusively with breast milk until the age of six months. However, breast feeding rates remain lower than recommended. The crucial period for breast feeding support is the first two weeks after birth. During this period breast feeding support from the midwife is needed. The aim of this paper is to gain an in-depth understanding of the role of midwives in their support of breast feeding women, from their own perspective. METHODS: Two researchers independently conducted a systematic and comprehensive literature search. Studies needed an empirical qualitative research design (1), had to focus on the role of the midwife in the support of the breast-feeding woman from the midwife's perspective (2), and had to be published between January 2005 and December 2014 (3) in order to be included. Language restrictions were English, Dutch, German and French. Eight qualitative research studies were included, using mainly focus group and in depth interview studies, which were reported in 11 papers representing 231 midwives and 24 maternity nurses. All but one study concerned midwives working in hospital settings. A critical appraisal was performed of each study. FINDINGS: Midwives value breast feeding education and breast feeding support as a significant part of their role as a postnatal midwife. However, the ways in which a midwife approaches and supports the breast-feeding woman vary. We distinguished two perspectives: 'the midwife as technical expert' and 'the midwife as a skilled companion'. The 'technical expert' midwife is mainly breast centred, focuses on techniques, uses the hands on approach and sees a woman as a novice. The 'skilled companion' midwife is woman centred, focuses on the mother - infant relationship and uses a hands off approach during the breast feeding support. The midwives working in a hospital setting face many barriers when performing breast feeding support, such as time restraints, which makes it difficult for them to carry out their preferred role as a 'skilled companion'. These barriers can influence the breast feeding support negatively. Supporting factors, such as evidence based breast feeding guidelines, have a positive influence on the breast feeding support. CONCLUSION: On the basis of findings of a synthesis of qualitative research studies, we conclude that the majority of the midwives provide breast feeding support as a technical expert and a minority as a skilled companion. Midwives prefer to be a skilled companion but face many barriers in their working contexts. PMID- 27217236 TI - A juxtaposition of birth and surgery: Providing skin-to-skin contact in the operating theatre and recovery. AB - OBJECTIVE: to provide insight into the facilitators and barriers of providing skin-to-skin contact in the operating theatre and recovery. DESIGN: ethnographic study utilising video recordings, field notes, focus groups and interviews. SETTING: a metropolitan public hospital in Sydney, Australia. PARTICIPANTS: 21 low-risk mothers having a repeat caesarean section, 26 support people, >125 staff members involved in their care and 43 staff members involved in focus groups/interviews. DATA COLLECTION AND ANALYSIS: collecting video footage and field notes for up two hours post caesarean section births, interviews at six weeks post partum and staff focus groups/interviews. Data was entered into NVivo10 and analysed using critical ethnographic techniques. FINDINGS: providing skin-to-skin contact in the operating theatre and recovery presents unique challenges due to the 'juxtaposition' of providing social and emotional care in an intrinsically medicalised setting. Staff members suggest that skin-to-skin contact in this environment can be improved by increasing staff and parent knowledge, writing and implementing a policy, addressing staffing issues, improving staff communication, addressing time constraints, adjusting the placement of equipment in the environment and making small changes to the way equipment is utilised. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: our findings show that skin-to-skin contact can be successfully implemented in the operating theatre and recovery room with staff members input into adjustments to existing care. PMID- 27217237 TI - Trends in birth choices after caesarean section in Japan: A national survey examining information and access to vaginal birth after caesarean. AB - OBJECTIVES: in the context of a rising caesarean section (CS) rate in Japan, the objectives of this study were; to investigate the national situation for women's birth options after primary CS; to explore characteristics of institutions accepting planned vaginal birth after caesarean (VBAC); to identify the timing and type of information given to women about their birth options by health professionals. DESIGN: a national census study using a self-administered postal survey of nursing managers within obstetric departments in Japanese hospitals and clinics was conducted. Data were analyzed to explore characteristics of institutions accepting or not accepting VBAC and information given to women about planned VBAC and planned repeat CS. SETTING: institutions included hospitals and clinics providing childbirth services throughout Japan. PARTICIPANTS: nursing managers from hospitals (n=303) and clinics (n=196) completed surveys about their institutional policies and practices around birth after CS. FINDINGS: only 154 (30.9%) of 499 institutions examined, accepted planned vaginal birth as an option for birth after CS. The success rate of VBAC was 77.0% in these institutions. Availability of transport services for institutional transfer and existence of a Maternal Fetal Intensive Care Unit (MFICU) were significantly associated with acceptance of VBAC (OR=5.39, p<0.001; OR=2.96, p=0.04). Information about options for birth method was mostly provided in the form of consent documents, and doctors were the sole provider of information about method of childbirth in 55.7% of institutions. Nursing managers described challenges in caring for women who strongly desire VBAC when women did not have access to information or if institutional policies conflicted with women's wishes. They recommended evidence based information for women regarding birth choices after CS and recognised the necessity of emotional support for women faced with decision dilemmas. KEY CONCLUSIONS: institutional policies and practices for birth after CS vary widely in Japan, with evidence of limited opportunities for women to make informed choices about planned VBAC. It was difficult for nurse managers to support women to choose VBAC when institutional policy conflicted with this choice and when women did not have consistent or balanced information. IMPLICATIONS FOR PRACTICE: strategies are needed to support women as well as pregnancy care providers to support women to consider VBAC as a possible birth option after CS and to expand the use of shared decision making in pregnancy care settings in Japan. PMID- 27217238 TI - Social support received by women with intellectual and developmental disabilities during pregnancy and childbirth: An exploratory qualitative study. AB - OBJECTIVE: this study aims to contribute to the development of a conceptual framework that will inform maternity care improvements for expectant mothers with intellectual and developmental disabilities (IDD) by exploring the structure, functions, and perceived quality of social support received by women with IDD during pregnancy and childbirth. DESIGN/SETTING: using a grounded theory approach, we conducted an exploratory study set in Ontario, Canada in 2015. PARTICIPANTS: the sample included four adult women with IDD who had given birth in the last five years. MEASUREMENTS: data were collected using semi-structured interviews. FINDINGS: the structure of social support received by women with IDD consisted of both formal and informal sources, but few or no friendships. Women with IDD reported high levels of informational and instrumental support and low levels of emotional support and social companionship. However, a high level of available support was not always perceived as beneficial. Emergent core categories suggest that social support is perceived as most effective when three conditions are met: (1) support is accessible, (2) support is provided by individuals expressing positive attitudes towards the pregnancy, and (3) autonomy is valued. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: our study confirms and identifies important gaps in the social support received by expectant mothers with IDD. Women with IDD currently lack accessible informational support, emotional support, and social companionship during pregnancy and childbirth. Additional findings regarding the structure and functions of social support are presented, and a preliminary conceptual framework of effective social support during pregnancy and childbirth, as perceived by women with IDD is also proposed. Findings suggest that increasing support accessibility should be a social and clinical priority; however, maternity care providers should be aware of stigmatizing attitudes and respect the autonomy of pregnant women with IDD as they prepare for motherhood. PMID- 27217239 TI - Coblation tonsillectomy under surgical microscopy: A retrospective study. AB - OBJECTIVE: A retrospective study to compare surgical parameters and postoperative pain in patients undergoing coblation tonsillectomy with or without microscopic guidance. METHODS: Data regarding duration of surgery and hospital stay, intraoperative blood loss, incidence of haemorrhage and postoperative pain scores were retrieved from the medical records of adult patients undergoing coblation tonsillectomy under direct vision or with microscopic guidance. RESULTS: The incidence of secondary haemorrhage (>24 h postoperatively) was significantly lower and the duration of hospital stay was significantly shorter in the microscope group (n = 92) than the direct vision group (n = 76). Pain scores both at rest and while swallowing reached <=3 (no significant impact on quality-of life) significantly faster in the microscope group than the direct vision group. CONCLUSIONS: Microscope-assisted coblation tonsillectomy decreases the duration of hospital stay and the incidence of postoperative secondary haemorrhage, and results in an early improvement in postoperative pain scores. PMID- 27217241 TI - Metabolic engineering of Escherichia coli to produce 2'-fucosyllactose via salvage pathway of guanosine 5'-diphosphate (GDP)-l-fucose. AB - 2'-Fucosyllactose (2-FL) is one of the key oligosaccharides in human milk. In the present study, the salvage guanosine 5'-diphosphate (GDP)-l-fucose biosynthetic pathway from fucose was employed in engineered Escherichia coli BL21star(DE3) for efficient production of 2-FL. Introduction of the fkp gene coding for fucokinase/GDP-l-fucose pyrophosphorylase (Fkp) from Bacteroides fragilis and the fucT2 gene encoding alpha-1,2-fucosyltransferase from Helicobacter pylori allows the engineered E. coli to produce 2-FL from fucose, lactose and glycerol. To enhance the lactose flux to 2-FL production, the attenuated, and deleted mutants of beta-galactosidase were employed. Moreover, the 2-FL yield and productivity were further improved by deletion of the fucI-fucK gene cluster coding for fucose isomerase (FucI) and fuculose kinase (FucK). Finally, fed-batch fermentation of engineered E. coli BL21star(DE3) deleting lacZ and fucI-fucK, and expressing fkp and fucT2 resulted in 23.1 g/L of extracellular concentration of 2-FL and 0.39 g/L/h productivity. Biotechnol. Bioeng. 2016;113: 2443-2452. (c) 2016 Wiley Periodicals, Inc. PMID- 27217240 TI - Role of Serum cartilage oligomeric matrix protein (COMP) in the diagnosis of rheumatoid arthritis (RA): A case-control study. AB - OBJECTIVE: To analyse the role of serum cartilage oligomeric matrix protein (COMP) levels in the differential diagnosis of rheumatoid arthritis (RA). METHODS: This case-control study analysed the clinical and laboratory characteristics of patients with RA and healthy control subjects. The diagnostic ability of COMP for RA was evaluated by comparing it with anti-cyclic citrullinated peptide antibody levels. The sensitivity, specificity, positive and negative predictive values were calculated. RESULTS: The study enrolled 82 patients with RA and 34 healthy control subjects. The serum COMP level was significantly higher in patients with RA compared with control subjects (mean +/- SD 29.51 +/- 9.21 ng/ml versus 17.85 +/- 5.55 ng/ml, respectively). The serum COMP level was significantly higher in patients with active RA compared with patients with RA in remission (mean +/- SD 33.08 +/- 8.80 ng/ml versus 24.94 +/- 7.65 ng/ml, respectively). The cut-off value for COMP to discriminate patients with RA from healthy individuals was 21.51 ng/ml (sensitivity 0.817, specificity 0.882, positive predictive value 0.944, negative predictive value 0.667, and accuracy 0.836). CONCLUSION: The serum COMP level has the potential to be used as a biological marker for differentiating between patients with RA and healthy individuals. PMID- 27217243 TI - Evidence for Absolute Moral Opposition to Genetically Modified Food in the United States. AB - Public opposition to genetic modification (GM) technology in the food domain is widespread (Frewer et al., 2013). In a survey of U.S. residents representative of the population on gender, age, and income, 64% opposed GM, and 71% of GM opponents (45% of the entire sample) were "absolutely" opposed-that is, they agreed that GM should be prohibited no matter the risks and benefits. "Absolutist" opponents were more disgust sensitive in general and more disgusted by the consumption of genetically modified food than were non-absolutist opponents or supporters. Furthermore, disgust predicted support for legal restrictions on genetically modified foods, even after controlling for explicit risk-benefit assessments. This research suggests that many opponents are evidence insensitive and will not be influenced by arguments about risks and benefits. PMID- 27217244 TI - No Absolutism Here: Harm Predicts Moral Judgment 30* Better Than Disgust Commentary on Scott, Inbar, & Rozin (2016). AB - Moral absolutism is the idea that people's moral judgments are insensitive to considerations of harm. Scott, Inbar, and Rozin (2016, this issue) claim that most moral opponents to genetically modified organisms are absolutely opposed motivated by disgust and not harm. Yet there is no evidence for moral absolutism in their data. Perceived risk/harm is the most significant predictor of moral judgments for "absolutists," accounting for 30 times more variance than disgust. Reanalyses suggest that disgust is not even a significant predictor of the moral judgments of absolutists once accounting for perceived harm and anger. Instead of revealing actual moral absolutism, Scott et al. find only empty absolutism: hypothetical, forecasted, self-reported moral absolutism. Strikingly, the moral judgments of so-called absolutists are somewhat more sensitive to consequentialist concerns than those of nonabsolutists. Mediation reanalyses reveal that moral judgments are most proximally predicted by harm and not disgust, consistent with dyadic morality. PMID- 27217242 TI - Integrated Microfluidic Isolation of Aptamers Using Electrophoretic Oligonucleotide Manipulation. AB - We present a microfluidic approach to integrated isolation of DNA aptamers via systematic evolution of ligands by exponential enrichment (SELEX). The approach employs a microbead-based protocol for the processes of affinity selection and amplification of target-binding oligonucleotides, and an electrophoretic DNA manipulation scheme for the coupling of these processes, which are required to occur in different buffers. This achieves the full microfluidic integration of SELEX, thereby enabling highly efficient isolation of aptamers in drastically reduced times and with minimized consumption of biological material. The approach as such also offers broad target applicability by allowing selection of aptamers with respect to targets that are either surface-immobilized or solution-borne, potentially allowing aptamers to be developed as readily available affinity reagents for a wide range of targets. We demonstrate the utility of this approach on two different procedures, respectively for isolating aptamers against a surface-immobilized protein (immunoglobulin E) and a solution-phase small molecule (bisboronic acid in the presence of glucose). In both cases aptamer candidates were isolated in three rounds of SELEX within a total process time of approximately 10 hours. PMID- 27217245 TI - Gray & Schein's (2016) Objections Are Theoretically and Statistically Faulty. PMID- 27217246 TI - The Relationship Between Deliberate Practice and Performance in Sports: A Meta Analysis. AB - Why are some people more skilled in complex domains than other people? According to one prominent view, individual differences in performance largely reflect individual differences in accumulated amount of deliberate practice. Here, we investigated the relationship between deliberate practice and performance in sports. Overall, deliberate practice accounted for 18% of the variance in sports performance. However, the contribution differed depending on skill level. Most important, deliberate practice accounted for only 1% of the variance in performance among elite-level performers. This finding is inconsistent with the claim that deliberate practice accounts for performance differences even among elite performers. Another major finding was that athletes who reached a high level of skill did not begin their sport earlier in childhood than lower skill athletes. This finding challenges the notion that higher skill performers tend to start in a sport at a younger age than lower skill performers. We conclude that to understand the underpinnings of expertise, researchers must investigate contributions of a broad range of factors, taking into account findings from diverse subdisciplines of psychology (e.g., cognitive psychology, personality psychology) and interdisciplinary areas of research (e.g., sports science). PMID- 27217247 TI - Summing Up Hours of Any Type of Practice Versus Identifying Optimal Practice Activities: Commentary on Macnamara, Moreau, & Hambrick (2016). AB - In their original article, Ericsson, Krampe, and Tesch-Romer (1993) reviewed the evidence concerning the conditions of optimal learning and found that individualized practice with training tasks (selected by a supervising teacher) with a clear performance goal and immediate informative feedback was associated with marked improvement. We found that this type of deliberate practice was prevalent when advanced musicians practice alone and found its accumulated duration related to attained music performance. In contrast, Macnamara, Moreau, and Hambrick's (2016, this issue) main meta-analysis examines the use of the term deliberate practice to refer to a much broader and less defined concept including virtually any type of sport-specific activity, such as group activities, watching games on television, and even play and competitions. Summing up every hour of any type of practice during an individual's career implies that the impact of all types of practice activity on performance is equal-an assumption that I show is inconsistent with the evidence. Future research should collect objective measures of representative performance with a longitudinal description of all the changes in different aspects of the performance so that any proximal conditions of deliberate practice related to effective improvements can be identified and analyzed experimentally. PMID- 27217248 TI - How Important Is Deliberate Practice? Reply to Ericsson (2016). AB - Ericsson and colleagues' view that individual differences in expertise can largely be accounted for by accumulated deliberate practice is not supported by the available empirical evidence. Extending earlier work (Macnamara, Hambrick, & Oswald, 2014), we found that deliberate practice accounted for a sizeable amount of variance in sports performance (18%), but it left a much larger amount unexplained. Ericsson's (2016, this issue) evaluation of our research is undercut by contradictions, omissions, and errors. We agree with Ericsson that future longitudinal research will deepen understanding of expertise, but our goal was to evaluate the importance of deliberate practice based on existing evidence. PMID- 27217249 TI - Homo Ignorans: Deliberately Choosing Not to Know. AB - Western history of thought abounds with claims that knowledge is valued and sought. Yet people often choose not to know. We call the conscious choice not to seek or use knowledge (or information) deliberate ignorance. Using examples from a wide range of domains, we demonstrate that deliberate ignorance has important functions. We systematize types of deliberate ignorance, describe their functions, discuss their normative desirability, and consider how they can be modeled. To date, psychologists have paid relatively little attention to the study of ignorance, let alone the deliberate kind. Yet the desire not to know is no anomaly. It is a choice to seek rather than reduce uncertainty whose reasons require nuanced cognitive and economic theories and whose consequences-for the individual and for society-require analyses of both actor and environment. PMID- 27217250 TI - Income Mobility Breeds Tolerance for Income Inequality: Cross-National and Experimental Evidence. AB - American politicians often justify income inequality by referencing the opportunities people have to move between economic stations. Though past research has shown associations between income mobility and resistance to wealth redistribution policies, no experimental work has tested whether perceptions of mobility influence tolerance for inequality. In this article, we present a cross national comparison showing that income mobility is associated with tolerance for inequality and experimental work demonstrating that perceptions of higher mobility directly affect attitudes toward inequality. We find support for both the prospect of upward mobility and the view that peoples' economic station is the product of their own efforts, as mediating mechanisms. PMID- 27217251 TI - A Vicious Cycle: A Social-Psychological Account of Extreme Racial Disparities in School Discipline. AB - Can social-psychological theory provide insight into the extreme racial disparities in school disciplinary action in the United States? Disciplinary problems carry enormous consequences for the quality of students' experience in school, opportunities to learn, and ultimate life outcomes. This burden falls disproportionately on students of color. Integrating research on stereotyping and on stigma, we theorized that bias and apprehension about bias can build on one another in school settings in a vicious cycle that undermines teacher-student relationships over time and exacerbates inequality. This approach is more comprehensive than accounts in which the predicaments of either teachers or students are considered alone rather than in tandem, it complements nonpsychological approaches, and it gives rise to novel implications for policy and intervention. It also extends prior research on bias and stigmatization to provide a model for understanding the social-psychological bases of inequality more generally. PMID- 27217252 TI - Scientific Psychology in the 18th Century: A Historical Rediscovery. AB - As early as 1783, the almost forgotten philosopher, metaphysicist, and psychologist Ferdinand Ueberwasser (1752-1812) designated himself "Professor fur empirische Psychologie und Logik" (professor of empirical psychology and logic) at the University of Munster, Germany. His position was initiated and supported by the minister and educational reformer Franz von Furstenberg (1729-1810), who considered psychology a core scientific discipline that should be taught at each school and university. At the end of the 18th century, then, psychology seems to have been on the verge of becoming an independent academic discipline, about 100 years before Wilhelm Wundt founded the discipline's first official laboratory. It seems surprising that Ueberwasser's writings-including a seminal textbook on empirical psychology-have been almost entirely overlooked in most historical accounts. We focus on this important founding moment of psychological science and on the circumstances that eventually brought this seminal development to a halt. PMID- 27217253 TI - Angry Birds, Angry Children, and Angry Meta-Analysts: A Reanalysis. AB - Ferguson's (2015a) meta-analysis assessed a very important and controversial topic about children's mental health and video games. In response to the concerns raised by researchers about the appropriateness of the meta-analytical methods used by Ferguson; we decided to reanalyze the data and discuss two major misconceptions about meta-analysis. We argue that partial correlations can (and should) be meta-analyzed instead of zero-order bivariate correlations if the predictors included in the partial correlation represent a similar construct. We also discuss the fallacy by which the conventional meta-analytical model assumes that the studies' effect sizes came into being according to the same random effect construct used by the analysis. Our replication results using partial correlations, standardized (valid and reliable) outcomes, and an improved meta analytical model (that does not assume a random effect is the mechanism of data generation) confirmed the main results of Ferguson's meta-analysis. There was a significant yet very small effect on aggressive behavior of exposure to both general, rp = 0.062, 95% CI [0.012, 0.112], and violent, rp = 0.055, 95% CI [0.019, 0.091], video games. A very small effect was seen on reduced prosocial behavior, but this was only in the general video game exposure category, rp = 0.072, 95% CI [0.045, 0.100]. PMID- 27217254 TI - Y haplotype variability in a population of SAO Paulo state, Brazil. PMID- 27217255 TI - Haplotype diversity of 13 RM Y-STRs in Chinese Han population and an update on the allele designation of DYF403S1. AB - Rapidly mutating Y-STRs (RM Y-STRs) have been paid much attention in recent years. The 13 RM Y-STRs have been proved to have substantially higher haplotype diversity and discrimination capacity than conventionally used Y-STRs, indicating the considerable power in paternal lineage differentiation. To investigate the haplotype diversity in Chinese Han population, we collected 252 unrelated male samples and tested the genotype of the 13 RM Y-STRs. Among 252 male individuals, a total of 250 haplotypes were observed in which only 2 haplotypes were shared by 2 males respectively. The haplotype diversity reached 0.999937 and the discrimination capacity was 99.21%, showing a great discrimination power in Chinese Han population. In addition, an update on the allele designation of DYF403S1 was proposed. PMID- 27217256 TI - Minor Depression: Is it Important? How Should it be Treated? PMID- 27217257 TI - The NS1 gene from bat-derived influenza-like virus H17N10 can be rescued in influenza A PR8 backbone. AB - Influenza A viruses have the potential to cause pandemics due to the introduction of novel subtypes against which human hosts have little or no preexisting immunity. Such viruses may result from reassortment between human and animal influenza viruses. Recently, new influenza-like viruses were identified in bats, raising the concern for a new reservoir of potentially harmful influenza viruses that could form reassortants with categorized human influenza A viruses. However, until now, it has not been possible to generate a recombinant reassortant virus containing a single functional gene or domain from H17N10 that could propagate. Here, we demonstrate that a recombinant A/Puerto Rico/8/1934 (H1N1) virus with NS1 gene from H17N10 influenza-like virus can be successfully rescued. We used luciferase reporter assays and quantitative reverse transcriptase PCR to show that the NS1 protein from H17N10 inhibited Sendai-virus (SeV)-induced activation of IFN-beta expression with an efficiency similar to NS1 from an H5N1 strain. Moreover, the crystal structure of the NS1 (H17N10) RNA-binding domain is also similar to that of other NS1s. These results demonstrate that H17N10 influenza like virus indeed contains functional genes that are compatible with categorized influenza A viruses. Although the chance of this particular event occurring in nature seems negligible, further research is needed to address the possibility of the natural formation of reassortants. PMID- 27217258 TI - Reforms of Retirement Policies: Three Common Paths in Aging in Japan and Korea. AB - Faced with an unparalleled rate of population aging, Japan and Korea have been reforming their retirement policies. To date, however, while the age of mandatory retirement has increased, employees continue to face significant decreases in compensation and other working conditions, typically at age 60 in Japan and age 55 in Korea. Three factors have contributed to shaping the path of the policy reforms in both the countries, including (1) the productivist welfare regimes, (2) the structure of the labor market for young workers, and (3) seniority-based wage and compensation systems. PMID- 27217259 TI - Association between Common Genetic Variants and Polycystic Ovary Syndrome Risk in a Chinese Han Population. AB - OBJECTIVE: Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting 5-7% of reproductive age women worldwide. The aim of our study was to explore the PCOS-related single nucleotide polymorphism (SNP) associations between common genetic variants and PCOS risk in a Han Chinese women population. METHODS: In this case-control study, 285 Chinese Han women aged 28.50+/-6.858 years with PCOS and 299 controls of a mean age of 32.66+/-7.018 years were compared. We selected recently published genome-wide association studies (GWAS) which identified several genetic loci in PCOS. All the SNPs were genotyped by Sequenom Mass-ARRAY technology. Associations between the gene and the risk of PCOS were tested using various genetic models by Statistical Package for the Social Sciences and Plink. RESULTS: We found that rs705702 in the RAB5B/SUOX was associated with PCOS (odds ratio=1.42; 95% confidence interval=1.08-1.87, p=0.011) and increased the PCOS risk. The genotypic model analysis also showed that rs705702 was associated with PCOS risk. CONCLUSION: Our results suggest that SNPs rs705702 in gene RAB5B/SUOX was associated with PCOS in Han Chinese women. PMID- 27217260 TI - [Continuous sedation until death. A French way for the end-of-life care?]. AB - Continuous sedation until death (CSUD) is a practice which has developed recently in several countries, appearing more acceptable than euthanasia and medically assisted suicide, since more close to a "natural death". The French parliament has just adopted a law which stipulates CSUD on request of the patient in a definite number of circumstances, especially in incurable diseases near to the terminal stage with suffering refractory to treatments. Thus France has adopted a unique international position for the end-of-life care. However several ethical problems raised by CSUD, which corresponds to a psycho-social death preceding the biological one, have been raised in the literature. The legitimacy of CSUD, especially if sedation is deep and not proportional to the degree of suffering, or if it is performed in case of a purely existential distress, is a matter of discussion. The primacy allocated to autonomy is questionable for the more vulnerable patients, who deserve mainly a social solidarity. The double-effect principle is replaced actually in CSUD by a co-intention both to relieve suffering and meanwhile eventually to hasten death, especially when stopping nutrition and hydration. CSUD is thus located in a grey zone between palliative care and euthanasia. PMID- 27217261 TI - [Painless outgrowth bones: Multiple exostosis diseases]. PMID- 27217262 TI - [Pathophysiology of preeclampsia]. AB - Preeclampsia is a hypertensive disease of pregnancy due to abnormal utero placental circulation. Hypoperfusion of the placenta and hypoxia/reoxygenation of the intervillous space are responsible of placental dysfunction. Trophoblastic factors are released in the maternal circulation and are responsible of the maternal endothelial dysfunction that characterize preeclampsia. Among those factors, the PlGF/sFlt-1 couple plays a major pathophysiologic role. PMID- 27217263 TI - Cardiac surgery, nosocomial infection, and the built environment. PMID- 27217264 TI - Advances in bioanalytical techniques to measure steroid hormones in serum. AB - Steroid hormones are measured clinically to determine if a patient has a pathological process occurring in the adrenal gland, or other hormone responsive organs. They are very similar in structure making them analytically challenging to measure. Additionally, these hormones have vast concentration differences in human serum adding to the measurement complexity. GC-MS was the gold standard methodology used to measure steroid hormones clinically, followed by radioimmunoassay, but that was replaced by immunoassay due to ease of use. LC MS/MS has now become a popular alternative owing to simplified sample preparation than for GC-MS and increased specificity and sensitivity over immunoassay. This review will discuss these methodologies and some new developments that could simplify and improve steroid hormone analysis in serum. PMID- 27217265 TI - Abrasion Plus Local Fibrin Sealant Instillation Produces Pleurodesis Similar to Pleurectomy in Rabbits. AB - BACKGROUND: Pleurodesis performed either by pleurectomy or pleural abrasion is recommended in the approach to primary spontaneous pneumothorax to avoid recurrence. However, the efficacy of parietal pleural abrasion in producing pleurodesis is questioned. This study aims to determine the efficacy of apical abrasion alone, abrasion plus fibrin sealant application, and pleurectomy in producing pleurodesis in rabbits. METHODS: Rabbits were subjected to video assisted thoracic surgery alone (control) or to video-assisted thoracic surgery with apical gauze abrasion, abrasion plus fibrin sealant instillation, or apical pleurectomy. Blood samples were collected preoperatively and 48 h and 28 days postoperatively to measure total leukocytes (white blood cell count), neutrophil counts, and serum interleukin (IL)-8 levels. After 28 days the animals were sacrificed for macroscopic evaluation of the degree of apical pleurodesis and microscopic evaluation of local pleural fibrosis and collagen deposition. RESULTS: White blood cell and neutrophil counts were similar in all groups, whereas the serum IL-8 level peaked at 48 h in all groups and decreased after 28 days, except in the pleurectomy group. After 28 days the abrasion plus fibrin sealant and pleurectomy groups had significantly more pleural adhesions, pleural fibrosis, and collagen deposition than the abrasion alone group, mainly due to thick mature fibers. CONCLUSIONS: Abrasion with local fibrin sealant instillation is as effective as pleurectomy in producing pleurodesis in rabbits. Apical pleurectomy elicits a more persistent elevation of serum IL-8 levels than apical abrasion alone or abrasion plus fibrin adhesive instillation. PMID- 27217267 TI - My Triumph Over Psychosis: A Journey From Schizophrenia and Homelessness to College Graduate. PMID- 27217268 TI - Experiences of a First-Episode Psychosis by a Psychology Graduate Student. PMID- 27217266 TI - A Randomized Trial to Test a Peer Mentor Intervention to Improve Outcomes in Persons Hospitalized With HIV Infection. AB - BACKGROUND: Few interventions have been shown to improve retention in human immunodeficiency virus (HIV) care, and none have targeted the hospitalized patient. Peer mentoring has not been rigorously tested. METHODS: We conducted a randomized, controlled clinical trial of a peer mentoring intervention. Eligible adults were hospitalized and were either newly diagnosed with HIV infection or out of care. The intervention included 2 in-person sessions with a volunteer peer mentor while hospitalized, followed by 5 phone calls in the 10 weeks after discharge. The control intervention provided didactic sessions on avoiding HIV transmission on the same schedule. The primary outcome was a composite of retention in care (completed HIV primary care visits within 30 days and between 31 and 180 days after discharge) and viral load (VL) improvement (>=1 log10 decline) 6 months after discharge. RESULTS: We enrolled 460 participants in 3 years; 417 were in the modified intent-to-treat analysis. The median age was 42 years; 74% were male; and 67% were non-Hispanic black. Baseline characteristics did not differ between the randomized groups. Twenty-eight percent of the participants in both arms met the primary outcome (P = .94). There were no differences in prespecified secondary outcomes, including retention in care and VL change. Post hoc analyses indicated interactions between the intervention and length of hospitalization and between the intervention and receipt of linkage services before discharge. CONCLUSIONS: Peer mentoring did not increase reengagement in outpatient HIV care among hospitalized, out-of-care persons. More intense and system-focused interventions warrant further study. CLINICAL TRIALS REGISTRATION: NCT01103856. PMID- 27217269 TI - Autism Tendencies and Psychosis Proneness Interactively Modulate Saliency Cost. AB - Atypical responses to salient information are a candidate endophenotype for both autism and psychosis spectrum disorders. The present study investigated the costs and benefits of such atypicalities for saliency-based selection in a large cohort of neurotypical adults in whom both autism and psychosis expressions were assessed. Two experiments found that autism tendencies and psychosis proneness interactively modulated the cost incurred in the presence of a task-irrelevant salient distractor. Specifically, expressions of autism and psychosis had opposing effects on responses to salient information such that the benefits associated with high expressions for autism offset costs associated with high expressions for psychosis. The opposing influences observed on saliency cost may be driven by distinct attentional mechanisms that are differentially affected by expressions for autism and psychosis. PMID- 27217273 TI - Health policy: The right to try is embodied in the right to die. PMID- 27217270 TI - Pharmacogenetic Associations of Antipsychotic Drug-Related Weight Gain: A Systematic Review and Meta-analysis. AB - Although weight gain is a serious but variable adverse effect of antipsychotics that has genetic underpinnings, a comprehensive meta-analysis of pharmacogenetics of antipsychotic-related weight gain is missing. In this review, random effects meta-analyses were conducted for dominant and recessive models on associations of specific single nucleotide polymorphisms (SNP) with prospectively assessed antipsychotic-related weight or body mass index (BMI) changes (primary outcome), or categorical increases in weight or BMI (>=7%; secondary outcome). Published studies, identified via systematic database search (last search: December 31, 2014), plus 3 additional cohorts, including 222 antipsychotic-naive youth, and 81 and 141 first-episode schizophrenia adults, each with patient-level data at 3 or 4 months treatment, were meta-analyzed. Altogether, 72 articles reporting on 46 non-duplicated samples (n = 6700, mean follow-up = 25.1wk) with 38 SNPs from 20 genes/genomic regions were meta-analyzed (for each meta-analysis, studies = 2-20, n = 81-2082). Eleven SNPs from 8 genes were significantly associated with weight or BMI change, and 4 SNPs from 2 genes were significantly associated with categorical weight or BMI increase. Combined, 13 SNPs from 9 genes (Adrenoceptor Alpha-2A [ADRA2A], Adrenoceptor Beta 3 [ADRB3], Brain-Derived Neurotrophic Factor [BDNF], Dopamine Receptor D2 [DRD2], Guanine Nucleotide Binding Protein [GNB3], 5 Hydroxytryptamine (Serotonin) Receptor 2C [HTR2C], Insulin-induced gene 2 [INSIG2], Melanocortin-4 Receptor [MC4R], and Synaptosomal-associated protein, 25kDa [SNAP25]) were significantly associated with antipsychotic-related weight gain (P-values < .05-.001). SNPs in ADRA2A, DRD2, HTR2C, and MC4R had the largest effect sizes (Hedges' g's = 0.30-0.80, ORs = 1.47-1.96). Less prior antipsychotic exposure (pediatric or first episode patients) and short follow-up (1-2 mo) were associated with larger effect sizes. Individual antipsychotics did not significantly moderate effect sizes. In conclusion, antipsychotic-related weight gain is polygenic and associated with specific genetic variants, especially in genes coding for antipsychotic pharmacodynamic targets. PMID- 27217271 TI - A Meta-analytic Review of Auditory Event-Related Potential Components as Endophenotypes for Schizophrenia: Perspectives From First-Degree Relatives. AB - INTRODUCTION: As endophenotypes bridge the gap between genetics and phenotypic disease expression, identifying reliable markers is important for fostering understanding of pathophysiology. The present aim was to conduct current meta analyses of 3 key auditory event-related potential (ERP) components that have been held as potential endophenotypes for schizophrenia: P50, P300 amplitude and latency, and mismatch negativity (MMN), reflective of sensory gating, attention and classification speed, and perceptual discrimination ability, respectively. In order to assess endophenotype viability, these components were examined in unaffected relatives of patients with schizophrenia and healthy controls. METHODS: Effect sizes (ES) were examined between relatives and controls for P50 suppression (10 studies, n = 360 relatives, 473 controls), P300 amplitude (20 studies, n = 868 relatives, 961 controls), P300 latency (17 studies, n = 674 relatives, 792 controls), and MMN (11 studies, n = 377 relatives, 552 controls). RESULTS: Reliable differences in P50 suppression (ES = 0.86, P < .001), P300 amplitude (ES = -0.52, P < .001), and P300 latency (ES = 0.44, P < .05) were found between unaffected relatives and controls. A trend was found between relatives and controls for MMN (ES = 0.21, P = 0.06), and the use of extraneous channels was found to be a significant moderator (P = 0.01). When MMN was analyzed using frontocentral channel Fz, a significant difference was found (ES = 0.26, P < 0.01). DISCUSSION: The results indicate that P50 suppression, P300 amplitude and P300 latency, and MMN may serve as viable endophenotypes for schizophrenia. PMID- 27217274 TI - Pancreatic cancer: Inflammatory index to predict survival. PMID- 27217276 TI - Haematological cancer: TOURMALINE - new gem unearthed in the MM treatment landscape. PMID- 27217278 TI - Biomechanical comparison of a novel engine-driven ridge spreader and conventional ridge splitting techniques. AB - OBJECTIVES: Ridge splitting techniques are used for horizontal ridge augmentation in implant dentistry. Recently, a novel engine-driven ridge splitting technique was introduced. This study compared the mechanical forces produced by conventional and engine-driven ridge splitting techniques in porcine mandibles. MATERIAL AND METHODS: In 33 pigs, mandibular premolar areas were selected for the ridge splitting procedures, designed as a randomized split-mouth study. The conventional group underwent a chisel-and-mallet procedure (control group, n = 20), and percussive impulse (Newton second, Ns) was measured using a sensor attached to the mallet. In the engine-driven ridge spreader group (test group, n = 23), a load cell was used to measure torque values (Newton centimeter, Ncm). Horizontal acceleration generated during procedures (control group, n = 10 and test group, n = 10) was compared between the groups. RESULTS: After ridge splitting, the alveolar crest width was significantly increased both in the control (1.23 +/- 0.45 mm) and test (0.98 +/- 0.41 mm) groups with no significant differences between the groups. The average impulse of the control group was 4.74 +/- 1.05 Ns. Torque generated by rotation in the test group was 9.07 +/- 2.15 Ncm. Horizontal acceleration was significantly less in the test group (0.82 +/- 1.05 g) than the control group (64.07 +/- 42.62 g) (P < 0.001). CONCLUSIONS: Narrow edentulous ridges can be expanded by novel engine-driven ridge spreaders. Within the limits of this study, the results suggested that an engine-driven ridge splitting technique may be less traumatic and less invasive than a conventional ridge splitting technique. PMID- 27217280 TI - Correction. PMID- 27217279 TI - Protocol for a systematic review of evaluation research for adults who have participated in the 'SMART recovery' mutual support programme. AB - INTRODUCTION: Self-Management and Recovery Training (SMART Recovery) offers an alternative to predominant 12-step approaches to mutual aid (eg, alcoholics anonymous). Although the principles (eg, self-efficacy) and therapeutic approaches (eg, motivational interviewing and cognitive behavioural therapy) of SMART Recovery are evidence based, further clarity regarding the direct evidence of its effectiveness as a mutual aid package is needed. Relative to methodologically rigorous reviews supporting the efficacy of 12-step approaches, to date, reviews of SMART Recovery have been descriptive. We aim to address this gap by providing a comprehensive overview of the evidence for SMART Recovery in adults with problematic alcohol, substance and/or behavioural addiction, including a commentary on outcomes assessed, potential mediators, feasibility (including economic outcomes) and a critical evaluation of the methods used. METHODS AND ANALYSIS: Methods are informed by the Cochrane Guidelines for Systematic Reviews and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement. 6 electronic peer-reviewed and 4 grey literature databases have been identified. Preliminary searches have been conducted for SMART Recovery literature (liberal inclusion criteria, not restricted to randomised controlled trials (RCTs), qualitative-only designs excluded). Eligible 'evaluation' articles will be assessed against standardised criteria and checked by an independent assessor. The searches will be re-run just before final analyses and further studies retrieved for inclusion. A narrative synthesis of the findings will be reported, structured around intervention type and content, population characteristics, and outcomes. Where possible, 'summary of findings' tables will be generated for each comparison. When data are available, we will calculate a risk ratio and its 95% CI (dichotomous outcomes) and/or effect size according to Cohen's formula (continuous outcomes) for the primary outcome of each trial. ETHICS AND DISSEMINATION: No ethical issues are foreseen. Findings will be disseminated widely to clinicians and researchers via journal publication and conference presentation(s). PROSPERO REGISTRATION NUMBER: CRD42015025574. PMID- 27217281 TI - Factors influencing communication and decision-making about life-sustaining technology during serious illness: a qualitative study. AB - OBJECTIVES: We aimed to identify factors influencing communication and decision making, and to learn how physicians and nurses view their roles in deciding about the use of life-sustaining technology for seriously ill hospitalised patients and their families. DESIGN: The qualitative study used Flanagan's critical incident technique to guide interpretive description of open-ended in-depth individual interviews. SETTING: Participants were recruited from the medical wards at 3 Canadian hospitals. PARTICIPANTS: Interviews were completed with 30 healthcare professionals (9 staff physicians, 9 residents and 12 nurses; aged 25-63 years; 73% female) involved in decisions about the care of seriously ill hospitalised patients and their families. MEASURES: Participants described encounters with patients and families in which communication and decision-making about life sustaining technology went particularly well and unwell (ie, critical incidents). We further explored their roles, context and challenges. Analysis proceeded using constant comparative methods to form themes independently and with the interprofessional research team. RESULTS: We identified several key factors that influenced communication and decision-making about life-sustaining technology. The overarching factor was how those involved in such communication and decision making (healthcare providers, patients and families) conceptualised the goals of medical practice. Additional key factors related to how preferences and decision making were shaped through relationships, particularly how people worked toward 'making sense of the situation', how physicians and nurses approached the inherent and systemic tensions in achieving consensus with families, and how physicians and nurses conducted professional work within teams. Participants described incidents in which these key factors interacted in dynamic and unpredictable ways to influence decision-making for any particular patient and family. CONCLUSIONS: A focus on more meaningful and productive dialogue with patients and families by (and between) each member of the healthcare team may improve decisions about life-sustaining technology. Work is needed to acknowledge and support the non-curative role of healthcare and build capacity for the interprofessional team to engage in effective decision-making discussions. PMID- 27217282 TI - Factors that shape the patient's hospital experience and satisfaction with lower limb arthroplasty: an exploratory thematic analysis. AB - OBJECTIVE: It is generally accepted that the patients' hospital experience can influence their overall satisfaction with the outcome of lower limb arthroplasty; however, little is known about the factors that shape the hospital experience. The aim of this study was to develop an understanding of what patients like and do not like about their hospital experience with a view to providing insight into where service improvements could have the potential to improve the patient experience and their satisfaction, and whether they would recommend the procedure. DESIGN: A mixed methods (quan-QUAL) approach. SETTING: Large regional teaching hospital. PARTICIPANTS: 216 patients who had completed a postoperative postal questionnaire at 12 months following total knee or total hip arthroplasty. OUTCOME MEASURES: Overall satisfaction with the outcome of surgery, whether to recommend the procedure to another and the rating of patient hospital experience. Free text comments on the best and worst aspects of their hospital stay were evaluated using qualitative thematic analysis. RESULTS: Overall, 77% of patients were satisfied with their surgery, 79% reported a good-excellent hospital experience and 85% would recommend the surgery to another. Qualitative analysis revealed clear themes relating to communication, pain relief and the process experience. Comments on positive aspects of the hospital experience were related to feeling well informed and consulted about their care. Comments on the worst aspects of care were related to being made to wait without explanation, moved to different wards and when they felt invisible to the healthcare staff caring for them. CONCLUSIONS: Positive patient experiences were closely linked to effective patient-health professional interactions and logistics of the hospital processes. Within arthroplasty services, the patient experience of healthcare could be enhanced by further attention to concepts of patient-centred care. Practical examples of this include more focus on developing staff-patient communication and the avoidance of 'boarding' procedures. PMID- 27217283 TI - Change in fasting plasma glucose and incident type 2 diabetes mellitus: results from a prospective cohort study. AB - OBJECTIVE: To investigate the association between changes in fasting plasma glucose (FPG) values and incident type 2 diabetes (T2D) in a cohort of the Iranian population. DESIGN: Prospective cohort study. SETTING: This study was conducted within the framework of the Tehran Lipid and Glucose Study (TLGS) to investigate the association between change in FPG between baseline examination (1999-2001) and the second visit (2002-2005) with incident T2D. PARTICIPANTS: A total of 3981 non-diabetic participants aged >=20 years. OUTCOME MEASURE: T2D was defined if the participant was using antidiabetic drugs or if FPG was >=7 mmol/L or if the 2 h post-challenge plasma glucose (2-hPCG) was >=11.1 mmol/L. RESULTS: During a median follow-up of 6.17 years, after the second examination, 288 new cases of T2D were identified. In a multivariate Cox proportional hazard analysis using age as timescale, we presented a simple model including FPG change (HR 1.19, 95% CI 1.07 to 1.33) and baseline waist circumference (WC) (HR 1.004, 95% CI 1.001 to 1.008) with a discriminative power (C-index) of 72%. Furthermore, we showed that the highest quartile of FPG change enhanced the T2D risk to 1.65 (95% CI 1.2 to 2.27) compared with the lowest quartile (p for trend=0.004).The independent risk of FPG change resisted further adjustment with 2-hPCG change. Adding the 2-hPCG change only slightly increased the discriminative power of the model including FPG change and baseline value of WC (0.73% vs 0.72%). After the study population had been limited to those with normal fasting glucose/normal glucose tolerance, FPG change remained an independent predictor (HR 1.57, 95% CI 1.31 to 1.88). CONCLUSIONS: Two measurements of FPG obtained about 3 years apart can help to identify populations at risk of incident T2D independently of important traditional risk factors and their changes, including 2-hPCG change. PMID- 27217284 TI - Comparison of the force applied on oral structures during intubation attempts by novice physicians between the Macintosh direct laryngoscope, Airway Scope and C MAC PM: a high-fidelity simulator-based study. AB - OBJECTIVE: We examined whether the use of Airway Scope (AWS) and C-MAC PM (C-MAC) decreased the force applied on oral structures during intubation attempts as compared with the force applied with the use of Macintosh direct laryngoscope (DL). DESIGN: Prospective cross-over study. PARTICIPANTS: A total of 35 novice physicians participated. INTERVENTIONS: We used 6 simulation scenarios based on the difficulty of intubation and intubation devices. OUTCOME MEASURES: Our primary outcome measures were the maximum force applied on the maxillary incisors and tongue during intubation attempts, measured by a high-fidelity simulator. RESULTS: The maximum force applied on maxillary incisors was higher with the use of the C-MAC than with the DL and AWS in the normal airway scenario (DL, 26 Newton (N); AWS, 18 N; C-MAC, 52 N; p<0.01) and the difficult airway scenario (DL, 42 N; AWS, 24 N; C-MAC, 68 N; p<0.01). In contrast, the maximum force applied on the tongue was higher with the use of the DL than with the AWS and C MAC in both airway scenarios (DL, 16 N; AWS, 1 N; C-MAC, 7 N; p<0.01 in the normal airway scenario; DL, 12 N; AWS, 4 N; C-MAC, 7 N; p<0.01 in the difficult airway scenario). CONCLUSIONS: The use of C-MAC, compared with the DL and AWS, was associated with the higher maximum force applied on maxillary incisors during intubation attempts. In contrast, the use of video laryngoscopes was associated with the lower force applied on the tongue in both airway scenarios, compared with the DL. Our study was a simulation-based study, and further research on living patients would be warranted. PMID- 27217285 TI - Examining the association between serum lactic dehydrogenase and all-cause mortality in patients with metabolic syndrome: a retrospective observational study. AB - OBJECTIVES: Emerging evidence indicates that elevated serum lactic dehydrogenase (LDH) levels are associated with increased cardiovascular mortality, but the mechanisms for this relationship remain uncertain. Since metabolic syndrome (MetS) is correlated with a higher risk of cardiovascular complications, we investigated the joint association between serum LDH levels and all-cause mortality in the US general population with MetS. DESIGN: Retrospective study. SETTING: The USA. PARTICIPANTS: A retrospective observational study of 3872 adults with MetS and 7516 adults without MetS in the National Health and Nutrition Examination Survey III was performed. MAIN OUTCOME MEASURES: Participants with and without MetS were both divided into 3 groups according to their serum LDH level. Multivariable Cox regression analyses and Kaplan-Meier survival probabilities were used to jointly relate all-cause, cardiovascular and cancer mortality risk to different serum LDH levels. RESULTS: For all-cause mortality in participants with MetS, multivariable adjusted HRs were 1.006 (95% CI 0.837 to 1.210; p=0.947) for serum LDH of 149-176 U/L compared with 65-149 U/L, and 1.273 (95% CI 1.049 to 1.547; p=0.015) for serum LDH of 176-668 U/L compared with 65-149 U/L. CONCLUSIONS: Results support a positive association between higher level of serum LDH and mortality from all causes in individuals with MetS. PMID- 27217286 TI - Quality measures for total ankle replacement, 30-day readmission and reoperation rates within 1 year of surgery: a data linkage study using the NJR data set. AB - OBJECTIVE: To report on the rate of 30-day readmission and the rate of additional or revision surgery within 12 months following total ankle replacement (TAR). DESIGN: A data-linkage study of the UK National Joint Registry (NJR) data and Hospital Episodes Statistics (HES) database. These two databases were linked in a deterministic fashion. HES episodes 12 months following the index procedure were isolated and analysed. Logistic regression was used to model predictors of reoperation and revision for primary ankle replacement. PARTICIPANTS: All patients who underwent primary and revision ankle replacements according to the NJR between February 2008 and February 2013. RESULTS: The rate of 30-day readmission following primary and revision ankle replacement was 2.2% and 1.3%, respectively. In the 12 months following primary and revision ankle replacements, the revision rate (where implants needed to be removed) was 1.2% with increased odds in those orthopaedic units preforming <20 ankle replacements per year and patients with a preoperative fixed equinus deformity. The reoperation other than revision (where implants were not removed) in the 12 months following primary and revision TARs was 6.6% and 9.3%, respectively. Rheumatoid arthritis, cemented prosthesis and high ASA grade significantly increased the odds of reoperation. CONCLUSIONS: TAR has a 30-day readmission rate of 2.2%, which is similar to that of knee replacement but lower than that of total hip replacement. 6.6% of patients undergoing primary TAR require a reoperation within 12 months of the index procedure. Early revision rates are significantly higher in low-volume centres. PMID- 27217287 TI - TOPS: Trial Of Prevention Strategies for low back pain in patients recently recovered from low back pain-study rationale and protocol. AB - INTRODUCTION: Low back pain (LBP) is the health condition that carries the greatest disability burden worldwide; however, there is only modest support for interventions to prevent LBP. The aim of this trial is to establish the effectiveness and cost-effectiveness of group-based exercise and educational classes compared with a minimal intervention control in preventing recurrence of LBP in people who have recently recovered from an episode of LBP. METHODS AND ANALYSIS: TOPS will be a pragmatic comparative effectiveness randomised clinical trial with a parallel economic evaluation combining three separate cohorts (TOPS Workers, TOPS Primary Care, TOPS Defence) with the same methodology. 1482 participants who have recently recovered from LBP will be randomised to either a comprehensive exercise and education programme or a minimal intervention control. Participants will be followed up for a minimum of 1 year. The primary outcome will be days till recurrence of LBP. Effectiveness will be assessed using survival analysis. Cost-effectiveness will be assessed from the societal perspective. ETHICS AND DISSEMINATION: This trial has been approved by the University of Sydney Human Research Ethics Committee (HREC) (ref: 2015/728) and prospectively registered with the Australian and New Zealand Clinical Trials Registry (ref: 12615000939594). We will also obtain ethics approval from the Australian Defence Force HREC. The results of this study will be submitted for publication in a prominent journal and widely publicised in the general media. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trial Registry (ANZCTR) 12615000939594. PMID- 27217288 TI - Reasons for non-participation in a primary care-based physical activity trial: a qualitative study. AB - OBJECTIVES: To explore reasons for non-participation in a primary care-based physical activity trial and understand how these may contribute to recruitment of non-representative research samples. We also aimed to elicit non-participants' own recommendations for enhancing trial uptake in primary care. DESIGN: Semistructured telephone interviews with non-participants to a randomised controlled trial of a very brief intervention for promoting physical activity conducted in primary care (the Very Brief Interventions trial), with thematic analysis of interview transcripts. SETTING: 5 general practice (GP) surgeries in the East of England, UK. PARTICIPANTS: Interviews were completed with 10 female and 6 male non-participants of white ethnicity and aged between 40 and 71 years. 13 of the 16 interviewees were either active or moderately active according to the GP Physical Activity Questionnaire (GPPAQ). RESULTS: Interviewees discussed a range of reasons for non-participation. These included beliefs surrounding the personal relevance of the trial based on preconceptions of intervention content. Many interviewees considered themselves either sufficiently active or too functionally limited to increase activity levels further, so rendering participation pointless in their view. Other identified barriers included a lack of free time, for trial participation and for increasing physical activity, and dissatisfaction with appointment scheduling systems in place at GP surgeries. Interviewees questioned the appropriateness of primary care as a context for delivering interventions to promote physical activity. In general, interviewees were positively disposed towards the idea of trial participation, especially if personal benefits are made salient, but suggested that interventions could be delivered in a different setting such as the internet. CONCLUSIONS: To increase participation in physical activity promotion trials conducted in primary care, the content of invitation materials and procedures for contacting potential participants require reconsideration. Specific recommendations include streamlining intervention materials and enhancing their relevance to the health concerns of invitees. TRIAL REGISTRATION NUMBER: ISRCTN72691150; Pre-results. PMID- 27217290 TI - Case Study Observational Research: A Framework for Conducting Case Study Research Where Observation Data Are the Focus. AB - Case study research is a comprehensive method that incorporates multiple sources of data to provide detailed accounts of complex research phenomena in real-life contexts. However, current models of case study research do not particularly distinguish the unique contribution observation data can make. Observation methods have the potential to reach beyond other methods that rely largely or solely on self-report. This article describes the distinctive characteristics of case study observational research, a modified form of Yin's 2014 model of case study research the authors used in a study exploring interprofessional collaboration in primary care. In this approach, observation data are positioned as the central component of the research design. Case study observational research offers a promising approach for researchers in a wide range of health care settings seeking more complete understandings of complex topics, where contextual influences are of primary concern. Future research is needed to refine and evaluate the approach. PMID- 27217291 TI - The Outcomes and Impact of a Post-Earthquake Rehabilitation Program in China: A Qualitative Study. AB - This study evaluated the outcomes and impact of a post-earthquake rehabilitation program in Sichuan, China. A case-study approach was adopted to conduct an in depth examination of the program. The results show that the program effectively enhanced the functional outcomes of earthquake survivors. However, the empowerment of earthquake survivors with disabilities requires further consideration, and the local community's ownership of the program must also be addressed. A combination of institution- and community-based approaches was advocated in developing the post-earthquake rehabilitation program to enhance its impact on the local community. PMID- 27217289 TI - A host cell membrane microdomain is a critical factor for organelle discharge by Toxoplasma gondii. AB - Host cell microdomains are involved in the attachment, entry, and replication of intracellular microbial pathogens. Entry into the host cell of Toxoplasma gondii and the subsequent survival of this protozoan parasite are tightly coupled with the proteins secreted from organelle called rhoptry. The rhoptry proteins are rapidly discharged into clusters of vesicles, called evacuoles, which are then delivered to parasitophorous vacuoles (PVs) or nucleus. In this study, we examined the roles of two host cell microdomain components, cholesterol and glycosylphosphatidylinositol (GPI), in evacuole formation. The acute depletion of cholesterol from the host cell plasma membrane blocked evacuole formation but not invasion. Whereas the lack of host cell GPI also altered evacuole formation but not invasion, instead inducing excess evacuole formation. The latter effect was not influenced by the evacuole-inhibiting effects of host cell cholesterol depletion, indicating the independent roles of host GPI and cholesterol in evacuole formation. In addition, the excess formation of evacuoles resulted in the enhanced recruitment of host mitochondria and endoplasmic reticulum to PVs, which in turn stimulated the growth of the parasite. PMID- 27217292 TI - WFITN ethics charter. PMID- 27217293 TI - Laparoscopically resected obturator nerve schwannoma: A case report. AB - Obturator nerve schwannomas are very rare. To date, only nine cases have been reported in the English-language literature; none of these were diagnosed preoperatively. A 68-year-old woman was admitted with left lower abdominal pain. CT and MRI revealed a mass 30 mm in diameter in the left obturator fossa, suggesting a retroperitoneal tumor. Because CT and MRI revealed clear continuity with the left obturator nerve, this case was diagnosed as an obturator nerve schwannoma. Tumor enucleation was performed by laparoscopy. On histopathological examination, this case was diagnosed as a benign obturator nerve schwannoma. Postoperatively, the patient developed weakness of the adductor muscle but recovered within 6 months with rehabilitation therapy. Preoperative diagnosis of obturator nerve schwannomas is quite difficult, but careful inspection of CT and MRI is important to identify the original nerve of schwannoma preoperatively. Accordingly, laparoscopic resection is a good treatment option. PMID- 27217294 TI - MUC1-C Stabilizes MCL-1 in the Oxidative Stress Response of Triple-Negative Breast Cancer Cells to BCL-2 Inhibitors. AB - Aberrant expression of myeloid cell leukemia-1 (MCL-1) is a major cause of drug resistance in triple-negative breast cancer (TNBC) cells. Mucin 1 (MUC1) is a heterodimeric oncoprotein that is aberrantly overexpressed in most TNBC. The present studies show that targeting the oncogenic MUC1 C-terminal subunit (MUC1 C) in TNBC cells with silencing or pharmacologic inhibition with GO-203 is associated with downregulation of MCL-1 levels. Targeting MUC1-C suppresses the MEK -> ERK and PI3K -> AKT pathways, and in turn destabilizes MCL-1. The small molecules ABT-737 and ABT-263 target BCL-2, BCL-XL and BCL-w, but not MCL-1. We show that treatment with ABT-737 increases reactive oxygen species and thereby MUC1-C expression. In this way, MUC1-C is upregulated in TNBC cells resistant to ABT-737 or ABT-263. We also demonstrate that MUC1-C is necessary for the resistance-associated increases in MCL-1 levels. Significantly, combining GO-203 with ABT-737 is synergistic in inhibiting survival of parental and drug resistant TNBC cells. These findings indicate that targeting MUC1-C is a potential strategy for reversing MCL-1-mediated resistance in TNBC. PMID- 27217295 TI - Inhibition of the Let-7 Family MicroRNAs Induces Cardioprotection Against Ischemia-Reperfusion Injury in Diabetic Rats. AB - BACKGROUND: The expression of the let-7 family microRNAs in the myocardium of streptozotocin-induced diabetic rats was measured, and the cardioprotection of inhibition of let-7 microRNAs against ischemia-reperfusion injury was investigated. METHODS: The diabetic rats and nondiabetic rats were subjected to 30 minutes of coronary artery occlusion followed by 120 minutes of reperfusion. The infarct size was determined by triphenyltetrazolium chloride staining. The expression of let-7 was measured by quantitative real-time polymerase chain reaction, and expressions of insulin receptor (InsR), insulin-like growth factor 1 receptor (IGF-1R), glucose transporter type 4 (GLUT4), and the phosphorylation states of Akt and the mammalian target of rapamycin (mTOR) were analyzed using Western blot. Inhibition of let-7 was performed by local transfection of lentivirus gene transfer vectors containing let-7 antimiR. RESULTS: Compared with nondiabetic rats, the expression of let-7 was enhanced in the myocardium of diabetic rats (p = 0.029), whereas expressions of InsR, IGF-1R, and GLUT4 were decreased after ischemia-reperfusion (p < 0.01). Local transfection of the let-7 antimiR markedly inhibited the expression of let-7 (p = 0.038) and improved expressions of InsR, IGF-1R, and GLUT4 in the myocardium of diabetic rats (p < 0.01). The infarct size of diabetic rats was much higher than that of nondiabetic rats (p < 0.0001). Transfection of the let-7 antimiR significantly reduced the infarct size of diabetic rats (p < 0.0001), and such an antiinfarct effect was abolished completely by pretreatment of Akt inhibitor LY294002 or mTOR inhibitor rapamycin. CONCLUSIONS: Inhibition of the let-7 family microRNAs improves glucose uptake and insulin resistance in the diabetic myocardium and induces cardioprotection against ischemia-reperfusion injury through Akt and mTOR pathways. PMID- 27217296 TI - Complex Esophageal Reconstruction Procedures Have Acceptable Outcomes Compared With Routine Esophagectomy. AB - BACKGROUND: Complex esophageal reconstruction (CER) is defined as restoring esophageal continuity in a previously operated field, using a nongastric conduit, or after esophageal diversion. This study compares the outcomes of CER with non CER (NCER), which uses an undisturbed stomach for reconstruction. METHODS: This single-institution retrospective cohort study compares 75 CERs with 75 NCERs from 1995 to 2014 that were matched for cancer versus benign disease. Distributions of demographic characteristics, comorbidities, and complications were compared between CER and NCER. Odds of mortality at 30 and 90 days were calculated with logistic regression. Overall survival was illustrated with Kaplan-Meier method and Cox proportional hazards regression. RESULTS: Although patients were similar in age, sex, and preoperative comorbidities, more non-white patients underwent CER (p = 0.04). Most NCER patients had adenocarcinoma (44%) or Barrett's high grade dysplasia (39%); most CER patients had other benign disease (44%) or squamous cell carcinoma (24%, p < 0.01). CER had statistically significantly higher rates of reoperation, pneumonia, infection, and gastrointestinal complications, and longer median length of stay than NCER. Odds of mortality for CER and NCER at 30 days (odds ratio [OR] 1.0, 95% CI: 0.1 to 16.3), 90 days (OR 2.6, 95% CI: 0.5 to 13.9) and overall (adjusted hazard ratio 1.56, 95% CI: 0.9 to 2.7) were not statistically significantly different. CONCLUSIONS: Compared with NCER, CER patients had higher rates of return to the operating room, more postoperative infections and gastrointestinal complications, and longer length of stay. However, 30-day, 90-day, and overall survival were similar. CER should be offered to patients with acceptable risks and anticipated long-term survival. PMID- 27217297 TI - Myocardial Revascularization for Patients With Diabetes: Coronary Artery Bypass Grafting or Percutaneous Coronary Intervention? AB - Patients affected by diabetes usually have extensive coronary artery disease. Coronary revascularization has a prominent role in the treatment of coronary artery disease in the expanding diabetic population. However, diabetic patients undergoing coronary artery bypass grafting or percutaneous coronary intervention experience worse outcomes than nondiabetic patients. Several studies comparing coronary artery bypass grafting vs percutaneous coronary intervention in subgroups of diabetic patients demonstrated a survival advantage and fewer repeat revascularization procedures with an initial surgical strategy. This review summarizes the current state of evidence comparing the effectiveness and safety of coronary artery bypass grafting and percutaneous coronary intervention in diabetic patients. PMID- 27217300 TI - Role of oxygen and DOM in sunlight induced photodegradation of organophosphorous flame retardants in river water. AB - The wide use of organophosphorous flame retardants (OPFR) and plasticizers causes a continuous release of large quantities into natural waters. One of the main contributors to micropollutants depletion in surface water is sunlight induced phototransformations. This study aims to elucidate whether alkyl, chloroalkyl and aryl organophosphorus flame retardants undergo phototransformations in river water. To perform the experiments, nine OPFR were subjected to natural sunlight, Xe lamp (simulated sunlight) and UV-C irradiations in ultra-pure Milli-Q water, Milli-Q water with humic acid and river water. Experiments demonstrated that OPFR achieve an important degree of photodegradation noticeable at long irradiation time, although direct photolysis did not account as the main photodegration mechanism. Results indicated that sunlight absorbing OPFR exhibited photosensitizing activity. The presence of azide in ultra- pure water inhibited some OPFR photodegration by singlet oxygen (1O2) scavenging, and the absence of dissolved oxygen significantly depleted most of OPFR removal. In the conditions studied, humic acid inhibited OPFR phototransformations, while river water enhanced their removal. Results from this study point out the need to further investigate the role of some OPFR as photosensitizers, which are important for fate and ecological risk assessment of flame retardants and other micropollutants in water. PMID- 27217298 TI - Impact of Human Mutant TGFbeta1/Fc Protein on Memory and Regulatory T Cell Homeostasis Following Lymphodepletion in Nonhuman Primates. AB - Transforming growth factor beta1 (TGFbeta1) plays a key role in T cell homeostasis and peripheral tolerance. We evaluated the influence of a novel human mutant TGFbeta1/Fc (human IgG4 Fc) fusion protein on memory CD4+ and CD8+ T cell (Tmem) responses in vitro and their recovery following antithymocyte globulin (ATG)-mediated lymphodepletion in monkeys. TGFbeta1/Fc induced Smad2/3 protein phosphorylation in rhesus and human peripheral blood mononuclear cells and augmented the suppressive effect of rapamycin on rhesus Tmem proliferation after either alloactivation or anti-CD3/CD28 stimulation. In combination with IL-2, the incidence of CD4+ CD25hi Foxp3hi regulatory T cells (Treg) and Treg:Th17 ratios were increased. In lymphodepleted monkeys, whole blood trough levels of infused TGFbeta1/Fc were maintained between 2 and 7 MUg/mL for 35 days. Following ATG administration, total T cell numbers were reduced markedly. In those given TGFbeta1/Fc infusion, CD8+ T cell recovery to predepletion levels was delayed compared to controls. Additionally, numbers of CD4+ CD25hi CD127lo Treg increased at 4-6 weeks after depletion but subsequently declined to predepletion levels by 12 weeks. In all monkeys, CD4+ CD25hi Foxp3hi Treg/CD4+ IL-17+ cell ratios were reduced, particularly after stopping TGFbeta1/Fc infusion. Thus, human TGFbeta1/Fc infusion may delay Tmem recovery following lymphodepletion in nonhuman primates. Combined (low-dose) IL-2 infusion may be required to improve the Treg:Th17 ratio following lymphodepletion. PMID- 27217299 TI - Promyelocytic leukemia protein isoform II inhibits infection by human adenovirus type 5 through effects on HSP70 and the interferon response. AB - Promyelocytic leukemia (PML) proteins have been implicated in antiviral responses but PML and associated proteins are also suggested to support virus replication. One isoform, PML-II, is required for efficient transcription of interferon and interferon-responsive genes. We therefore investigated the PML-II contribution to human adenovirus 5 (Ad5) infection, using shRNA-mediated knockdown. HelaDeltaII cells showed a 2-3-fold elevation in Ad5 yield, reflecting an increase in late gene expression. This increase was found to be due in part to the reduced innate immune response consequent upon PML-II depletion. However, the effect was minor because the viral E4 Orf3 protein targets and inactivates this PML-II function. The major benefit to Ad5 in HelaDeltaII cells was exerted via an increase in HSP70; depletion of HSP70 completely reversed this replicative advantage. Increased Ad5 late gene expression was not due either to the previously described inhibition of inflammatory responses by HSP70 or to effects of HSP70 on major late promoter or L4 promoter activity, but might be linked to an observed increase in E1B 55K, as this protein is known to be required for efficient late gene expression. The induction of HSP70 by PML-II removal was specific for the HSPA1B gene among the HSP70 gene family and thus was not the consequence of a general stress response. Taken together, these data show that PML-II, through its various actions, has an overall negative effect on the Ad5 lifecycle. PMID- 27217301 TI - Comparison of the toxicological impacts of carbamazepine and a mixture of its photodegradation products in Scrobicularia plana. AB - In the aquatic environment, pharmaceutical drugs are submitted to degradation processes, where photodegradation is one of the most important mechanisms affecting the fate, persistence and toxicity of the compounds. Carbamazepine, a widely used antiepileptic, is known to suffer photodegradation in water bodies and generate photoproducts, some of them with higher potential toxicity than the parent compound. Therefore, to evaluate the toxic effects of CBZ when combined with its photoproducts, an acute exposure (96h) with the edible clam Scrobicularia plana was performed using environmental concentrations of CBZ (0.00 9.00MUg/L) irradiated (and non-irradiated) with simulated solar radiation. The analysis of the irradiated CBZ solutions by mass spectrometry revealed the formation of 5 photoproducts, including acridine (a compound known to be carcinogenic). Oxidative stress results showed that the exposure to CBZ photoproducts did not increase the toxicity to clams, by comparison with the parent compound. Lipid peroxidation levels, catalase and superoxide dismutase activities were the most responsive parameters to these stressors and lipid peroxidation results appeared to show the presence of an antagonistic effect resulting from the mixture of CBZ and its photoproducts. PMID- 27217303 TI - Generation of stem cell-based bioartificial anterior cruciate ligament (ACL) grafts for effective ACL rupture repair. AB - In the present study, we combined stem cell technology with a non-absorbable biomaterial for the reconstruction of the ruptured ACL. Towards this purpose, multipotential stromal cells derived either from subcutaneous human adipose tissue (hAT-MSCs) or from induced pluripotent stem cells (iPSCs) generated from human foreskin fibroblasts (hiPSC-MSCs) were cultured on the biomaterial for 21days in vitro to generate a 3D bioartifical ACL graft. Stem cell differentiation towards bone and ligament at the ends and central part of the biomaterial was selectively induced using either BMP-2/FGF-2 or TGF-beta/FGF-2 combinations, respectively. The bioartificial ACL graft was subsequently implanted in a swine ACL rupture model in place of the surgically removed normal ACL. Four months post-implantation, the tissue engineered ACL graft generated an ACL-like tissue exhibiting morphological and biochemical characteristics resembling those of normal ACL. PMID- 27217304 TI - A p.(Glu809Lys) Mutation in the WFS1 Gene Associated with Wolfram-like Syndrome: A Case Report. AB - Wolfram-like syndrome (WFSL) is a rare autosomal dominant disease characterised by congenital progressive hearing loss, diabetes mellitus, and optic atrophy. The patient was a boy with the juvenile form of diabetes mellitus and findings which clinically matched the symptoms of Wolfram syndrome. At the age of 3 1/4 years, diabetes mellitus was diagnosed in this boy who also had severe psychomotor retardation, failure to thrive, a dysmorphic face with Peters anomaly type 3 (i.e. posterior central defect with stromal opacity of the cornea, adhering stripes of the iris, and cataract with corneolenticular adhesion), congenital glaucoma, megalocornea, severe hearing impairment, a one-sided deformity of the auricle with atresia of the bony and soft external auditory canal, non differentiable eardrum, missing os incus, hypothyreosis, and nephrocalcinosis. Molecular-genetic examinations revealed a de novo mutation p.(Glu809Lys) in the WFS1 gene. No mutations were detected in the biological parents. The mutation p.(Glu809Lys) in the WFS1 gene is associated with WFSL. PMID- 27217302 TI - Cold-inducible RNA-binding protein causes endothelial dysfunction via activation of Nlrp3 inflammasome. AB - Cold-inducible RNA-binding protein (CIRP) is a damage-associated molecular pattern (DAMP) molecule which stimulates proinflammatory cytokine release in hemorrhage and sepsis. Under these medical conditions, disruption of endothelial homeostasis and barrier integrity, typically induced by proinflammatory cytokines, is an important factor contributing to morbidity and mortality. However, the role of CIRP in causing endothelial dysfunction has not been investigated. In this study, we show that intravenous injection of recombinant murine CIRP (rmCIRP) in C57BL/6 mice causes lung injury, evidenced by vascular leakage, edema, increased leukocyte infiltration and cytokine production in the lung tissue. The CIRP-induced lung damage is accompanied with endothelial cell (EC) activation marked by upregulation of cell-surface adhesion molecules E selectin and ICAM-1. Using in vitro primary mouse lung vascular ECs (MLVECs), we demonstrate that rmCIRP treatment directly increases the ICAM-1 protein expression and activates NAD(P)H oxidase in MLVECs. Importantly, CIRP stimulates the assembly and activation of Nlrp3 inflammasome in MLVECs accompanied with caspase-1 activation, IL-1beta release and induction of proinflammatory cell death pyroptosis. Finally, our study demonstrates CIRP-induced EC pyroptosis in the lungs of C57BL/6 mice for the first time. Taken together, the released CIRP in shock can directly activate ECs and induce EC pyroptosis to cause lung injury. PMID- 27217305 TI - Advances in high frequency ultrasound separation of particulates from biomass. AB - In recent years the use of high frequency ultrasound standing waves (megasonics) for droplet or cell separation from biomass has emerged beyond the microfluidics scale into the litre to industrial scale applications. The principle for this separation technology relies on the differential positioning of individual droplets or particles across an ultrasonic standing wave field within the reactor and subsequent biomass material predisposition for separation via rapid droplet agglomeration or coalescence into larger entities. Large scale transducers have been characterised with sonochemiluminescence and hydrophones to enable better reactor designs. High frequency enhanced separation technology has been demonstrated at industrial scale for oil recovery in the palm oil industry and at litre scale to assist olive oil, coconut oil and milk fat separation. Other applications include algal cell dewatering and milk fat globule fractionation. Frequency selection depends on the material properties and structure in the biomass mixture. Higher frequencies (1 and 2MHz) have proven preferable for better separation of materials with smaller sized droplets such as milk fat globules. For palm oil and olive oil, separation has been demonstrated within the 400-600kHz region, which has high radical production, without detectable impact on product quality. PMID- 27217306 TI - Sonoelectrochemical one-pot synthesis of Pt - Carbon black nanocomposite PEMFC electrocatalyst. AB - Simultaneous electrocatalytic Pt-nanoparticle synthesis and decoration of Vulcan XC-72 carbon black substrate was achieved in a novel one-step-process, combining galvanostatic pulsed electrodeposition and pulsed ultrasonication with high power, low-frequency (20kHz) ultrasound. Aqueous chloroplatinic acid precursor baths, as well as carbon black suspensions in the former, were examined and decoration was proven by a combination of characterization methods, namely: dynamic light scattering, transmission electron microscopy, scanning electron microscopy with EDX-analysis and cyclic voltammetry. In particular, PVP was shown to have a beneficial stabilizing effect against free nanoparticle aggregation, ensuring narrow size distributions of the nanoparticles synthesized, but is also postulated to prevent the establishment of a strong metal-substrate interaction. Current pulse amplitude was identified as the most critical nanoparticle size determining parameters, while only small size particles, under 10nm, appeared to be attached to carbon black. PMID- 27217307 TI - New Opportunities. PMID- 27217308 TI - Universal Prevention Exposure as a Moderator of the Community Context: Findings from the PROSPER Project. AB - This study examined how participation in a universal family skills-building program may interact with community risks and resources to produce youth outcomes. Prior research has noted community-level variability in risk and protective factors, but thus far no study has examined the role that participation on a community-wide intervention may play in moderating the effects of community risks or resources. The study included 14 communities (seven in Iowa, seven in Pennsylvania) that implemented a family focused evidence-based program as part of the PROSPER project. Community level variables included both risk factors (percent of low income families, the availability of alcohol and tobacco, norms regarding adolescent substance use, incidence of drug-related crimes) and community resources (proactive school leadership, availability of youth-serving organizations, and student involvement in youth activities). The proximal youth and family outcomes included youth perceptions of their parents' management skills, parent-child activities, and family cohesion. Results indicated that the Strengthening Families Program:10-14 may have moderated the impact of the community risks and resources on community-level youth outcomes; risk levels meaningfully associated with community-level change in program participants, though these results varied somewhat by outcome. Generally, higher levels of resources also meaningfully associated with more positive change after participating in the family-focused intervention. These results suggest that the effect of some evidence-based programs may be even stronger in some communities than others; more research in this area is needed. PMID- 27217309 TI - Mapping the Social World of Classrooms: A Multi-Level, Multi-Reporter Approach to Social Processes and Behavioral Engagement. AB - Understanding the social context of classrooms has been a central goal of research focused on the promotion of academic development. Building on the current literature on classroom social settings and guided by a risk and protection framework, this study examines the unique and combined contribution of individual relationships and quality of classroom interactions on behavioral engagement among low-income Latino students in kindergarten to fifth grade (N = 111). Findings indicate that individual relationships with teachers and peers and classroom quality, each independently predicted behavioral engagement. Moreover, high-quality classrooms buffered the negative influence of students' difficulties in individual relationships on behavioral engagement. Findings illuminate the need to consider multiple layers of social classroom relationships and interactions and suggest the potential benefit of targeting classroom quality as a mechanism for improving behavioral engagement in urban elementary schools. PMID- 27217311 TI - The Functions and Longitudinal Outcomes of Adolescents' Naturally Occurring Mentorships. AB - Adolescence is a time during which positive adults outside the familial context may be most influential to development. A growing body of research on naturally occurring mentors has found favorable outcomes for youth who have these types of positive adult figures in their lives. Less is known, however, about how these naturally occurring mentors influence youths' development in the long-term. This study examines the long-term outcomes related to having a naturally occurring community mentor in adolescence. Results from longitudinal analyses of a nationally representative sample of adolescents revealed that having a mentor in adolescence was related to higher educational attainment, lower criminal activity, higher psychological well-being (i.e., optimism, self-efficacy, and lack of depressive symptoms), and greater romantic relationship satisfaction in adulthood. Additionally, a taxonomy of mentoring functions was created from qualitative responses and drawing upon the youth, work, and academic mentoring literature. This taxonomy aims to serve as a framework for understanding the functions of youth mentors to provide a foundation for future research. Implications of findings and future directions are considered. PMID- 27217310 TI - Reducing Binge Drinking in Adolescents through Implementation of the Strategic Prevention Framework. AB - The Strategic Prevention Framework (SPF) is a conceptual model that supports coalition-driven efforts to address underage drinking and related consequences. Although the SPF has been promoted by the U.S. Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Prevention and implemented in multiple U.S. states and territories, there is limited research on the SPF's effectiveness on improving targeted outcomes and associated influencing factors. The present quasi-experimental study examines the effects of SPF implementation on binge drinking and enforcement of existing underage drinking laws as an influencing factor. The intervention group encompassed 11 school districts that were implementing the SPF with local prevention coalitions across eight Kansas communities. The comparison group consisted of 14 school districts that were matched based on demographic variables. The intervention districts collectively facilitated 137 community-level changes, including new or modified programs, policies, and practices. SPF implementation supported significant improvements in binge drinking and enforcement outcomes over time (p < .001), although there were no significant differences in improvements between the intervention and matched comparison groups (p > .05). Overall, the findings provide a basis for guiding future research and community-based prevention practice in implementing and evaluating the SPF. PMID- 27217312 TI - Mentoring Relationship Closures in Big Brothers Big Sisters Community Mentoring Programs: Patterns and Associated Risk Factors. AB - Previous research suggests that early mentoring relationship (MR) closures may have harmful consequences for the health and well-being of youth participating in community-based mentoring programs. However, knowledge of the factors that lead some MRs to close early has been slow to emerge. This study examined patterns and correlates of early versus on-time MR closures among 569 youth participating in Big Brothers Big Sisters community mentoring programs. Thirty-four percent of youth experienced an early MR closure prior to the end of the program's 12 month period of commitment. The probability of closure was highest at 12 months into the MR. Early closures were positively associated with youth gender (girls), behavioral difficulties, and match determination difficulties. Early and on-time closures were associated with youth extrinsic motives for joining the program. Early MR closures were negatively associated with youth perceptions of parent emotional support, parent social support, high quality MR, weekly contact in MR, and parent support of the MR. Implications for programming are discussed. PMID- 27217313 TI - Character Development within Youth Development Programs: Exploring Multiple Dimensions of Activity Involvement. AB - We examined links among three dimensions of youth involvement (intensity, duration, and engagement) in Boy Scouts of America (BSA), an international out-of school time (OST) youth development program designed to promote moral and performance character in boys. Using data from 737 youth and their parents who participated in one of 40 BSA program sites (commonly referred to as "packs"), we first considered how individual- and pack-level measures of program involvement were differentially linked with character development. Next, we examined whether pack-level involvement characteristics moderate individual-level involvement characteristics, hypothesizing that highly involved packs would serve to further enhance the positive effects of high levels of individual involvement. Results indicated engagement was the strongest, most frequent predictor of increases in both moral and performance character. Although there were no direct effects of pack-level intensity, duration, or engagement, the effects of individual-level engagement were moderated by pack-level engagement, suggesting that the largest increases in moral and performance character occurred among highly engaged youth who were enrolled in highly engaged packs. These results highlight the need to examine multiple dimensions of OST program involvement simultaneously, and suggest that strengthening youth engagement in programming may provide a means for enhancing the positive effects of high-quality youth programming. PMID- 27217314 TI - Racial-ethnic Identity in Context: Examining Mediation of Neighborhood Factors on Children's Academic Adjustment. AB - Research consistently shows that neighborhood socio-demographic characteristics and residents' neighborhood perceptions matter for youth well-being, including a positive sense of racial-ethnic identity. Although elementary-school children are likely in the earlier phases of identity formation, the authors examined whether objective and subjective neighborhood characteristics are related to their racial ethnic identity and, in turn, their academic adjustment. A diverse sample (30.4% African American, 35.2% White, 12.3% Latino, & 22.0% Other) of 227 children in Grades 2 through 5 were surveyed in afterschool programs. Bivariate correlations showed that youth living in disadvantaged neighborhoods reported more barriers due to their race-ethnicity, but these barriers were not related to their sense of academic efficacy. Residing in a disadvantaged neighborhood was unrelated to youth's academic self-efficacy. However, path analyses showed that positive neighborhood perceptions were associated with a stronger sense of race-ethnicity (i.e., affirmation and belonging), which was in turn related to greater academic efficacy. These results suggest that neighborhood connection provides a source of affirmation and value for young children, helping them to understand who they are as part of a racial-ethnic group and helping to foster a sense of future achievement opportunities. This study provides additional evidence that along with other important proximal contexts (e.g., family, school), young children's neighborhood context is important for development. Results are discussed to highlight environmental influences on young children's awareness of race ethnicity and the implications of the combined impact of neighborhood and racial ethnic identity on psychosocial adjustment. PMID- 27217315 TI - Diverging Paths: Understanding Racial Differences in Civic Engagement Among White, African American, and Latina/o Adolescents Using Structural Equation Modeling. AB - There is increasing concern about the large civic engagement gap between Whites and Latina/o and African American youth. Some suggest this may be because traditional models and measures of civic engagement may not be as applicable for youth from historically marginalized groups. With an urban sample of middle and high school-age youth (n = 903, 52% female), we used structural equation modeling to identify differences in civic pathways between youth from different racial/ethnic backgrounds. We found significant differences between groups including much stronger relationships between exposure to democratic practices and civic self-efficacy and knowledge for African American and Latina/o youth than for White youth and a stronger relationship between civic knowledge and future civic engagement for Whites and Latina/os than for African Americans. These findings suggest that educators and researchers interested need to take into account the diversity of youths' racial experiences when examining youth civic development. PMID- 27217316 TI - Thriving Among African-American Adolescents: Religiosity, Religious Support, and Communalism. AB - While research has identified some positive factors in the lives of African American adolescents, there is limited, yet growing, empirical research examining how positive factors foster thriving for these youth. Using a positive youth development framework, we examined naturally occurring factors that promote thriving among African-American adolescents. This cross-sectional study included 152 youth who were surveyed at five Black churches in a large Midwestern city. Using MPlus, the structural regression model results revealed support for a model that demonstrated religiosity, religious support, and communalism are significantly and directly related to thriving among African-American adolescents. Implications for theory, research and practice are discussed. Moving from a deficit lens to a strengths-based approach can facilitate understanding of developmental processes and provide a foundation for supporting and enhancing positive outcomes among African-American adolescents. PMID- 27217317 TI - Thriving and Adapting: Resilience, Sense of Community, and Syndemics among Young Black Gay and Bisexual Men. AB - We examined resilience associated with the avoidance of psychosocial health conditions (i.e., syndemics) that increase vulnerability for HIV among young Black gay and bisexual men. We used analytic induction to compare a sample of 23 men who showed no evidence of syndemic conditions to a sample of 23 men who experienced syndemic conditions. The men who avoided syndemics reported supportive relationships with people who helped them to develop a strong sense of identity, provided them with opportunities to give back to their communities, and promoted positive norms about health. In contrast, the men experiencing syndemic conditions described numerous instances of trauma and oppression that infringed upon their desire to form positive relationships. Among these men, experiences of oppression were associated with shame, identity incongruence, social isolation, relational disconnection, mistrust of men, and expectations of further marginalization. We examined participants' experiences through the framework of the psychosocial sense of community. Results of this study provide evidence for using strength-based intervention strategies to prevent syndemic conditions. Findings suggest that to attenuate socio-structural barriers to health and comorbid psychosocial health concerns, interventions must address young men's social isolation and promote positive identity and sense of community. PMID- 27217318 TI - Profiles of Resilience and Psychosocial Outcomes among Young Black Gay and Bisexual Men. AB - Young Black gay/bisexual men (YBGBM) are affected by contextual stressors-namely syndemic conditions and minority stress-that threaten their health and well being. Resilience is a process through which YBGBM achieve positive psychosocial outcomes in the face of adverse conditions. Self-efficacy, hardiness and adaptive coping, and social support may be important resilience factors for YBGBM. This study explores different profiles of these resilience factors in 228 YBGBM in New York City and compares profiles on psychological distress, mental health, and other psychosocial factors. Four profiles of resilience were identified: (a) Low self-efficacy and hardiness/adaptive coping (23.5%); (b) Low peer and parental support (21.2%); (c) High peer support, low father support (34.5%); and (d) High father and mother support, self-efficacy, and hardiness/adaptive coping (20.8%). YBGBM in profile 1 scored markedly higher on distress (d = .74) and lower on mental health functioning (d = .93) compared to men in the other profiles. Results suggest that self-efficacy and hardiness/adaptive coping may play a more important role in protecting YBGBM from risks compared to social support and should be targeted in interventions. The findings show that resilience is a multidimensional construct and support the notion that there are different patterns of resilience among YBGBM. PMID- 27217319 TI - Dominant Cultural Narratives, Racism, and Resistance in the Workplace: A Study of the Experiences of Young Black Canadians. AB - Although many studies have examined lived experiences of racism and resistance in various contexts, relatively little research has examined such experiences among Black youth within the workplace-particularly in the Canadian context. In this study I use qualitative analyses of narrative interviews with 24 Black Canadian youth and young adults (aged 16-35) to examine the impact of dominant cultural narratives on lived experiences of workplace racism and resistance. Findings are presented using theatrical games as a central conceptual metaphor, suggesting that: (a) dominant cultural narratives have a major impact on relational dynamics of oppression in the workplace; (b) identity performance is a critical strategy for negotiating dominant cultural narratives in the workplace; and (c) panopticism (the internalized gaze) is a significant aspect of internalized oppression. Implications for future research and action are discussed. PMID- 27217320 TI - Social Change: Toward an Informed and Critical Understanding of Social Justice and the Capabilities Approach in Community Psychology. AB - Community psychology has long been concerned with social justice. However, deployments of this term are often vague and undertheorized. To address this weakness in the field's knowledge body we explored John Rawls's theory of social justice and Amartya Sen's economic theory of the capabilities approach and evaluated each for its applicability to community psychology theory, research, and action. Our unpacking of the philosophical and political underpinnings of Rawlsian theory of social justice resulted in identifying characteristics that limit the theory's utility in community psychology, particularly in its implications for action. Our analysis of the capability approach proposed by Amartya Sen revealed a framework that operationalizes social justice in both research and action, and we elaborate on this point. Going beyond benefits to community psychology in adopting the capabilities approach, we posit a bi directional relationship and discuss how community psychology might also contribute to the capabilities approach. We conclude by suggesting that community psychology could benefit from a manifesto or proclamation that provides a historical background of social justice and critiques the focus on the economic, sociological, and philosophical theories that inform present-day conceptualizations (and lack thereof) of social justice for community psychology. PMID- 27217321 TI - Exploration of Mechanisms behind Changes after Participation in a Parenting Intervention: A Qualitative Study in a Low-Resource Setting. AB - Parenting interventions are effective for preventing psychological difficulties in children. However, their active ingredients have not been comprehensively explored. How do they work? What are the mechanisms operating behind changes? In 2012, a randomized controlled trial of a parenting intervention was conducted in low-resource communities of Panama. Effects on child behavioral difficulties, parental stress, and parenting practices were large in the short and long term. This was an ideal opportunity to explore potential mechanisms operating behind effects found in this low-resource setting. Twenty-five parents were interviewed. Data were analyzed through an inductive semantic thematic analysis. Three themes emerged from the data: (a) psychological mechanisms behind changes, (b) behavioral changes in parent, and (c) changes in the children. Parents described that the intervention triggered changes in emotion regulation, self-efficacy, and problem solving. Parents also reported behavioral changes such as praising their children more often, who in turn seemed more responsible and better at following instructions. The study offers participant-driven insight into potential pathways of change after participation in this parenting intervention, pathways that are often overlooked in quantitative studies. Future studies should further explore these pathways, through mediator and moderator analyses, and determine how much is shared across interventions and across different cultural settings. PMID- 27217322 TI - Accumulation of Risk and Promotive Factors Among Young Children in US Military Families. AB - In the families of the new cohort of war veterans now entering the civilian population in the United States are over two million young children (Cozza, Haskins & Lerner, 2013; Institute of Medicine, 2013). Several noteworthy studies have shown that children exposed to separation from a parent due to combat related deployment are at elevated risk for a variety of negative consequences (Lester & Flake, 2013). Cozza et al. (2013) argue that existing studies of military children focus too much on the stresses or deficits they experience, failing to give sufficient attention to their strengths, the strengths of their families, or the supports around them. In the current study we focus on risk and promotive factors in the lives of children aged 0-10 in military families. We examine the likelihood of negative outcomes as functions of additive, cumulative, and interactive relationships between risk and promotive factors and children's outcomes. Risk factors, particularly parental depression, community poverty, and cumulative risk, were more strongly associated with children's outcomes than promotive factors. There was, however, a significant risk-protective relationship between accumulations of risk and promotive factors, consistent with promotive conditions operating in a protective fashion under conditions of elevated risk. PMID- 27217323 TI - The Willingness of Military Members to Seek Help: The Role of Social Involvement and Social Responsibility. AB - Anchored in the social organization theory of action and change, we use data from a large sample of active-duty Air Force members to examine the direct and indirect influence of social involvement and social responsibility on willingness to seek help in times of need via trust in formal systems and informal supports. Group comparisons are conducted between junior male, junior female, senior male, and senior female service members. The key mediational path in the model for all groups is the connection between social involvement and willingness to seek help via trust in formal systems. These results can inform both unit- and community level interventions intended to increase the likelihood that active-duty AF members will seek help in times of need. PMID- 27217324 TI - Disclosing Sexual Assault Within Social Networks: A Mixed-Method Investigation. AB - Most survivors of sexual assault disclose their experiences within their social networks, and these disclosure decisions can have important implications for their entry into formal systems and well-being, but no research has directly examined these networks as a strategy to understand disclosure decisions. Using a mixed-method approach that combined survey data, social network analysis, and interview data, we investigate whom, among potential informal responders in the social networks of college students who have experienced sexual assault, survivors contact regarding their assault, and how survivors narrate the role of networks in their decisions about whom to contact. Quantitative results suggest that characteristics of survivors, their social networks, and members of these networks are associated with disclosure decisions. Using data from social network analysis, we identified that survivors tended to disclose to a smaller proportion of their network when many network members had relationships with each other or when the network had more subgroups. Our qualitative analysis helps to contextualize these findings. PMID- 27217325 TI - Psychological-Mindedness and American Indian Historical Trauma: Interviews with Service Providers from a Great Plains Reservation. AB - The concept of historical trauma (HT) was developed to explain clinical distress among descendants of Jewish Holocaust survivors and has since been ascribed new meanings to account for suffering in diverse contexts. In American Indian (AI) communities, the concept of AI HT has been tailored and promoted as an expanded notion of trauma that combines psychological injury with historical oppression to causally connect experiences with Euro-American colonization to contemporary behavioral health disparities. However, rather than clinical formulations emphasizing psychological injury, a focused content analysis of interviews with 23 AI health and human service providers (SPs) on a Great Plains reservation demonstrated strong preferences for socio-cultural accounts of oppression. Reflective of a local worldview associated with minimal psychological-mindedness, this study illustrates how cultural assumptions embedded within health discourses like HT can conflict with diverse cultural forms and promote "psychologized" perspectives on suffering that may limit attention to social, economic, and political determinants of health. PMID- 27217326 TI - Diversity and Community Can Coexist. AB - We examine the (in)compatibility of diversity and sense of community by means of agent-based models based on the well-known Schelling model of residential segregation and Axelrod model of cultural dissemination. We find that diversity and highly clustered social networks, on the assumptions of social tie formation based on spatial proximity and homophily, are incompatible when agent features are immutable, and this holds even for multiple independent features. We include both mutable and immutable features into a model that integrates Schelling and Axelrod models, and we find that even for multiple independent features, diversity and highly clustered social networks can be incompatible on the assumptions of social tie formation based on spatial proximity and homophily. However, this incompatibility breaks down when cultural diversity can be sufficiently large, at which point diversity and clustering need not be negatively correlated. This implies that segregation based on immutable characteristics such as race can possibly be overcome by sufficient similarity on mutable characteristics based on culture, which are subject to a process of social influence, provided a sufficiently large "scope of cultural possibilities" exists. PMID- 27217327 TI - Policy Statement on the Incarceration of Undocumented Migrant Families: Society for Community Research and Action Division 27 of the American Psychological Association. PMID- 27217328 TI - A miniature shock wave driven micro-jet injector for needle-free vaccine/drug delivery. AB - This article presents a miniature shock wave driven micro-jet generator to deliver liquid drugs into human skin, to a controlled depth, with minimal invasion. The device can release the vaccine/drug to the depth of dermal blood vessels, without breaching much of the microcirculation system of dermis. The drug delivery technique is needle-free, which can reduce pain, trauma, and contamination besides minimal dosage and systemic exposure. The device can also be used to deliver liquid or colloidal drugs into soft tissues in human. The mechanical analyses of the device were carried out by analyzing the strength of the impulse of the shock wave, measuring the velocity of the generated jet and capturing the pressure exerted by the jet on the target. The penetrating ability of the jet was investigated by delivering it into sample of human skin and gelatin slabs. Theoretical analyses were carried out on the physics of the delivery and the predicted results had a close agreement with the experimental observations. The development can offer an important cost-effective solution to needle-free health care worldwide. Biotechnol. Bioeng. 2016;113: 2507-2512. (c) 2016 Wiley Periodicals, Inc. PMID- 27217329 TI - Factor VIII assay variability in postinfusion samples containing full length and B-domain deleted FVIII. AB - INTRODUCTION: Although the variability in factor VIII (FVIII):C measurement is well recognized, this has not been widely reported for post-FVIII infusion samples. AIM/METHODS: Three samples from haemophilia A patients were distributed in a UK National External Quality Assessment Scheme survey, each after treatment with either ReFacto AF, Kogenate FS or Advate. Fifty-two UK haemophilia centres performed FVIII assays using one-stage (n = 46) and chromogenic (n = 10) assays. Centres calibrated assays with the local plasma standard and with ReFacto AF laboratory standard for the ReFacto AF sample. RESULTS/CONCLUSIONS: Chromogenic assays gave significantly higher results than one-stage assays (P < 0.0001, 32% difference) in the post-Kogenate sample but not in the post-ReFacto AF (11% higher by chromogenic assay, ns) or post-Advate samples (3% lower by chromogenic, ns) when assays were calibrated with plasma standards. Twenty centres used all Instrumentation Laboratory (IL)-activated partial thromboplastin time reagents (Synthasil)/IL deficient plasma/reference plasma) in the one-stage assay and 15 used all Siemens reagents (Actin FS/Siemens deficient plasma/reference plasma); this made a significant difference to results post-ReFacto AF (41% higher by IL reagents, P < 0.0001) and Advate (39% higher by IL reagents, P < 0.0001), but not Kogenate (7% higher by IL, ns) when calibrated with plasma standards. Differences between results obtained with different one-stage assay reagents for monitoring Advate have implications for dosing patients. Furthermore, there was considerable inter-laboratory variation as indicated by CVs in the range 15-26% for chromogenic assay and 12-19% for one-stage assay results. This study suggests that external quality assessment schemes should offer participation in post-FVIII infusion schemes where haemophilic patients are monitored. PMID- 27217330 TI - Mice lacking Programmed cell death-1 show a role for CD8(+) T cells in long-term immunity against blood-stage malaria. AB - Even after years of experiencing malaria, caused by infection with Plasmodium species, individuals still have incomplete immunity and develop low-density parasitemia on re-infection. Previous studies using the P. chabaudi (Pch) mouse model to understand the reason for chronic malaria, found that mice with a deletion of programmed cell death-1 (PD-1KO) generate sterile immunity unlike wild type (WT) mice. Here we investigated if the mechanism underlying this defect during acute immunity also impacts on long-term immunity. We infected WT and PD 1KO mice with Pch-malaria and measured protection as well as immune responses against re-infections, 15 or 20 weeks after the original infection had cleared. WT mice showed approximately 1% parasitemia compared to sterile immunity in PD 1KO mice on re-infection. An examination of the mechanisms of immunity behind this long-term protection in PD-1KO mice showed a key role for parasite-specific CD8(+) T cells even when CD4(+) T cells and B cells responded to re-infection. These studies indicate that long-term CD8(+) T cell-meditated protection requires consideration for future malaria vaccine design, as part of a multi-cell type response. PMID- 27217331 TI - Effects of G6PD activity inhibition on the viability, ROS generation and mechanical properties of cervical cancer cells. AB - Glucose-6-phosphate dehydrogenase (G6PD) deficiency has been revealed to be involved in the efficacy to anti-cancer therapy but the mechanism remains unclear. We aimed to investigate the anti-cancer mechanism of G6PD deficiency. In our study, dehydroepiandrosterone (DHEA) and shRNA technology were used for inhibiting the activity of G6PD of cervical cancer cells. Peak Force QNM Atomic Force Microscopy was used to assess the changes of topography and biomechanical properties of cells and detect the effects on living cells in a natural aqueous environment. Flow cytometry was used to detect the apoptosis and reactive oxygen species (ROS) generation. Scanning electron microscopy was used to observe cell morphology. Moreover, a laser scanning confocal microscope was used to observe the alterations in cytoskeleton to explore the involved mechanism. When G6PD was inhibited by DHEA or RNA interference, the abnormal Young's modulus and increased roughness of cell membrane were observed in HeLa cells, as well as the idioblasts. Simultaneously, G6PD deficiency resulted in decreased HeLa cells migration and proliferation ability but increased ROS generation inducing apoptosis. What's more, the inhibition of G6PD activity caused the disorganization of microfilaments and microtubules of cytoskeletons and cell shrinkage. Our results indicated the anti-cervix cancer mechanism of G6PD deficiency may be involved with the decreased cancer cells migration and proliferation ability as a result of abnormal reorganization of cell cytoskeleton and abnormal biomechanical properties caused by the increased ROS. Suppression of G6PD may be a promising strategy in developing novel therapeutic methods for cervical cancer. PMID- 27217332 TI - Patients with proximal junctional kyphosis after stopping at thoracolumbar junction have lower muscularity, fatty degeneration at the thoracolumbar area. AB - BACKGROUND CONTEXT: There are several reports regarding pathogeneses and risk factors for proximal junctional kyphosis (PJK) in adult spinal deformity surgery. However, the relationship between thoracolumbar muscle condition and PJK has not been investigated yet. PURPOSE: We aimed to elucidate the thoracolumbar muscle conditions on the incidence of PJK in adult patients with spinal deformity treated by long instrumented spinal fusion surgery stopping at thoracolumbar junction with a minimum 2-year follow-up (F/U). STUDY DESIGN: This is a retrospective review of prospective database. PATIENT SAMPLE: A total of 44 cases of patients having multilevel spinal instrumented fusion stopping at thoracolumbar junction for adult spinal deformity in two academic institutions from 2004 to 2012 were enrolled in this study. OUTCOME MEASURES: For clinical outcomes, the Scoliosis Research Society questionnaire-22r (SRS-22r) was used preoperatively and at ultimate F/U. METHODS: Inclusion criteria were age >20 and minimum five vertebrae fused from T9 upper instrumented vertebra (UIV) to any lower instrumented vertebra. Radiographic assessment included pelvic parameters, Cobb measurements in the coronal-sagittal plane, and measurements of the thoracolumbar muscularity (cross-sectional area of muscle-vertebral body ratio*100) and fatty degeneration (signal intensity of muscle-subcutaneous fat ratio*100). RESULTS: The prevalence of PJK was 38.6%. Age at surgery, gender, fusions extending to the sacrum, levels fused, combined anterior-posterior surgery, and a UIV level were not significantly different between PJK and non-PJK groups. Lower bone mineral density (BMD; T-score: -2.5 vs. -1.3, p=.003) and lower muscularity and higher fatty degeneration at the level of T10 to L2 (131.8 vs. 159.0, p<.01; 59.0 vs. 44.0, p<.001, respectively) were identified risk factors for PJK. Radiographic parameters demonstrated a higher postoperative lumbar lordosis (LL) change (43.8 vs. 29.3, p<.001) and a larger sagittal vertical axis (SVA) change with surgery (8.4 cm vs. 4.8 cm, p=.01) in those with PJK. Although SRS postop pain scores were inferior in PJK group (3.3 vs. 4.1, p<.05), there were no significant differences in the average scores between the groups (3.5 vs. 3.3, p<.05). CONCLUSIONS: Patients with PJK had lower thoracolumbar muscularity and higher fatty degeneration than patients without PJK before surgery. Our data suggest that osteoporosis, large corrections in LL and SVA with surgery, and lower muscularity and higher fatty degeneration at the thoracolumbar area can lead to PJK. PMID- 27217333 TI - Arsenic silences hepatic PDK4 expression through activation of histone H3K9 methylatransferase G9a. AB - It is well established that increased liver cancer incidence is strongly associated with epigenetic silencing of tumor suppressor genes; the latter is contributed by the environmental exposure to arsenic. Pyruvate dehydrogenase kinase 4 (PDK4) is a mitochondrial protein that regulates the TCA cycle. However, the epigenetic mechanisms mediated by arsenic to control PDK4 expression remain elusive. In the present study, we showed that histone methyltransferase G9a- and Suv39H-mediated histone H3 lysine 9 (H3K9) methylations contributed to PDK4 silencing in hepatic cells. The PDK4 expression was induced by G9a inhibitor BRD4770 (BRD) and Suv39H inhibitor Chaetocin (CHA). In contrast, arsenic exposure decreased PDK4 expression by inducing G9a and increasing H3K9 di- and tri methylations levels (H3K9me2/3). In addition, arsenic exposure antagonizes the effect of BRD by enhancing the enrichment of H3K9me2/3 in the PKD4 promoter. Moreover, knockdown of G9a using siRNA induced PDK4 expression in HCC cells. Furthermore, arsenic decreased hepatic PDK4 expression as well as diminished the induction of PDK4 by BRD in mouse liver and hepatocytes. Overall, the results suggest that arsenic causes aberrant repressive histone modification to silence PDK4 in both HCC cells and in mouse liver. PMID- 27217334 TI - The surgical approach to near-total small bowel infarction in a patient with massive portomesenteric thrombosis. Case report. AB - AIM: To describe an acute portomesenteric venous thrombosis, with massive small bowel infarction, which is managed with small bowel resection, primary anastomosis, and open abdomen management (OAM). CASE REPORT: A 76-year-old male patient was admitted to the surgical ward, complaining spread abdominal pain. Contrast Enhanced Computed Tomography (CECT) diagnosed massive bowel ischemia, caused by portomesenteric thrombosis. He had negative coagulation tests for thrombophilia, while he presented concomitant risk factors (cancer, previous venous thrombosis, obesity). Surgery was performed, including open abdomen management, and the patient was discharged one month after surgery. No recurrences of portal thrombosis were found in one-year follow-up. DISCUSSION: Mesenteric venous thrombosis (MVT) diagnosis could be difficult to establish and it often presented itself late with peritonitis. Currently, CECT scanning is considered the gold standard for MVT, because it identifies not only filling defects in the portomesenteric system, but also possible complications, such as bowel ischemia. Standard initial treatment of MVT included heparin anticoagulation alone or in combination with surgery. When peritoneal signs initially are present, immediate surgery is indicated. During laparotomy, assessment of bowel viability and of the border between ischemia and vivid bowel could be more difficult to define. A planned "second-look" operation remains the gold standard for final bowel viability assessment. CONCLUSIONS: OAM strategy could possibly play an important role, also in case of resection for bowel ischemia, in improving survival in critically patients with increased risks of complications of re- anaesthesia and re-laparotomy. KEY WORDS: Acute Mesenteric Ischemia, Open Abdomen, Portal vein, Venous Thrombosis. PMID- 27217335 TI - Testicular torsion-detorsion and potential therapeutic treatments: A possible role for ischemic postconditioning. AB - Testicular torsion is a common urological emergency among adolescent boys and young men. Rotation of the testis and twisting of the spermatic cord rapidly leads to ischemia, resulting in a loss of germ cells. Thus, prompt diagnosis and urgent surgical intervention are required, but the subsequent release of the torsion induces reperfusion injury, which causes further damage to the ischemic testis. Testicular torsion-detorsion (ischemia-reperfusion) injury triggers the generation of reactive oxygen species, pro-inflammatory cytokines, neutrophil recruitment, lipid peroxidation, anoxia and apoptosis, which carry a significant risk of subsequent infertility. Previously, the effects of numerous pharmacological agents and treatments have been evaluated to prevent testicular ischemia-reperfusion injury in animal models. We propose a new treatment, especially postconditioning, to prevent adverse effects of ischemia-reperfusion injury after testicular torsion-detorsion. PMID- 27217336 TI - Functional definition of BirA suggests a biotin utilization pathway in the zoonotic pathogen Streptococcus suis. AB - Biotin protein ligase is universal in three domains of life. The paradigm version of BPL is the Escherichia coli BirA that is also a repressor for the biotin biosynthesis pathway. Streptococcus suis, a leading bacterial agent for swine diseases, seems to be an increasingly-important opportunistic human pathogen. Unlike the scenario in E. coli, S. suis lacks the de novo biotin biosynthesis pathway. In contrast, it retains a bioY, a biotin transporter-encoding gene, indicating an alternative survival strategy for S. suis to scavenge biotin from its inhabiting niche. Here we report functional definition of S. suis birA homologue. The in vivo functions of the birA paralogue with only 23.6% identity to the counterpart of E. coli, was judged by its ability to complement the conditional lethal mutants of E. coli birA. The recombinant BirA protein of S. suis was overexpressed in E. coli, purified to homogeneity and verified with MS. Both cellulose TLC and MALDI-TOFF-MS assays demonstrated that the S. suis BirA protein catalyzed the biotinylation reaction of its acceptor biotin carboxyl carrier protein. EMSA assays confirmed binding of the bioY gene to the S. suis BirA. The data defined the first example of the bifunctional BirA ligase/repressor in Streptococcus. PMID- 27217338 TI - Estimating changing contexts in schizophrenia. AB - SEE STEPHAN ET AL DOI101093/AWW120 FOR A SCIENTIFIC COMMENTARY ON THIS WORK: Real world information is often abstract, dynamic and imprecise. Deciding if changes represent random fluctuations, or alterations in underlying contexts involve challenging probability estimations. Dysfunction may contribute to erroneous beliefs, such as delusions. Here we examined brain function during inferences about context change from noisy information. We examined cortical-subcortical circuitry engaging anterior and dorsolateral prefrontal cortex, and midbrain. We hypothesized that schizophrenia-related deficits in prefrontal function might overestimate context change probabilities, and that this more chaotic worldview may subsequently gain familiarity and be over-reinforced, with implications for delusions. We then examined these opposing information processing biases against less expected versus familiar information patterns in relation to genetic risk for schizophrenia in unaffected siblings. In one experiment, 17 patients with schizophrenia and 24 normal control subjects were presented in 3 T magnetic resonance imaging with numerical information varying noisily about a context integer, which occasionally shifted up or down. Subjects were to indicate when the inferred numerical context had changed. We fitted Bayesian models to estimate probabilities associated with change inferences. Dynamic causal models examined cortical-subcortical circuitry interactions at context change inference, and at subsequent reduced uncertainty. In a second experiment, genetic risk for schizophrenia associated with similar cortical-subcortical findings were explored in an independent sample of 36 normal control subjects and 35 unaffected siblings during processing of intuitive number sequences along the number line, or during the inverse, less familiar, sequence. In the first experiment, reduced Bayesian models fitting subject behaviour suggest that patients with schizophrenia overestimated context change probabilities. Here, patients engaged anterior prefrontal cortex relatively less than healthy controls, in part driven by reduced effective connectivity from dorsolateral prefrontal cortex to anterior prefrontal cortex. In processing subsequent information indicating reduced uncertainty of their predictions, patients engaged relatively increased mid-brain activation, driven in part by increased dorsolateral prefrontal cortex to midbrain connectivity. These dissociable reduced and exaggerated prefrontal and subcortical circuit functions were accentuated in patients with delusions. In the second experiment, analogous dissociable reduced anterior prefrontal cortex and exaggerated midbrain engagement occurred in unaffected siblings when processing less expected versus more familiar number sequences. In conclusion, patients overestimated ambiguous context change probabilities with relatively reduced anterior frontal engagement. Subsequent reduced uncertainty about contextual state appeared over-reinforced, potentially contributing to confirmation bias and a cascade of aberrant belief processing about a more chaotic world relevant to delusions. These opposing cortical-subcortical effects relate in part to genetic risk for schizophrenia, with analogous imbalances in neural processing of less expected versus familiar information patterns. PMID- 27217337 TI - RNA- and protein-mediated control of Listeria monocytogenes virulence gene expression. AB - The model opportunistic pathogen Listeria monocytogenes has been the object of extensive research, aiming at understanding its ability to colonize diverse environmental niches and animal hosts. Bacterial transcriptomes in various conditions reflect this efficient adaptability. We review here our current knowledge of the mechanisms allowing L. monocytogenes to respond to environmental changes and trigger pathogenicity, with a special focus on RNA-mediated control of gene expression. We highlight how these studies have brought novel concepts in prokaryotic gene regulation, such as the 'excludon' where the 5'-UTR of a messenger also acts as an antisense regulator of an operon transcribed in opposite orientation, or the notion that riboswitches can regulate non-coding RNAs to integrate complex metabolic stimuli into regulatory networks. Overall, the Listeria model exemplifies that fine RNA tuners act together with master regulatory proteins to orchestrate appropriate transcriptional programmes. PMID- 27217341 TI - Inverted U-Shaped Relation Between the Risk of Sudden Cardiac Death and Maximal Left Ventricular Wall Thickness in Hypertrophic Cardiomyopathy. AB - BACKGROUND: Hypertrophic cardiomyopathy is associated with sudden cardiac death (SCD). Some studies have shown an association between risk of sudden death and left ventricular maximal wall thickness (MWT), but there are few data in patients with extreme hypertrophy. The aim of this study was to determine the relation between MWT and the risk of SCD. METHODS AND RESULTS: This is a multicenter, retrospective, longitudinal cohort study of 3673 adult (>=16 years) patients, previously used to develop and validate a risk prediction model for SCD (HCM Risk SCD [hypertrophic cardiomyopathy risk-SCD]). There was an inverted U-shaped relation between MWT and the estimated 5-year risk of SCD. In patients with MWT>=35 mm (n=47; mean age, 33 years; 81% men), there was a single SCD end point (annual rate, 0.2%; 95% confidence interval, 0.03-1.60) and 3 additional cardiovascular events during a median follow-up of 9.5 years. Compared with patients with MWT<=14 mm, those with MWT>=35 mm did not have a higher risk for SCD (hazard ratio, 0.22; 95% confidence interval, 0.03-1.65), cardiovascular death (hazard ratio, 0.66; 95% confidence interval, 0.26-1.67), or all-cause mortality (hazard ratio, 0.73; 95% confidence interval, 0.32-1.69). CONCLUSIONS: The risk of SCD has a complex, nonlinear relationship to MWT. The pathophysiological mechanisms behind this observation require further study but implantable cardioverter defibrillator implantation should not be guided solely on the severity of left ventricular hypertrophy. PMID- 27217339 TI - Genetic and phenotypic characterization of complex hereditary spastic paraplegia. AB - The hereditary spastic paraplegias are a heterogeneous group of degenerative disorders that are clinically classified as either pure with predominant lower limb spasticity, or complex where spastic paraplegia is complicated with additional neurological features, and are inherited in autosomal dominant, autosomal recessive or X-linked patterns. Genetic defects have been identified in over 40 different genes, with more than 70 loci in total. Complex recessive spastic paraplegias have in the past been frequently associated with mutations in SPG11 (spatacsin), ZFYVE26/SPG15, SPG7 (paraplegin) and a handful of other rare genes, but many cases remain genetically undefined. The overlap with other neurodegenerative disorders has been implied in a small number of reports, but not in larger disease series. This deficiency has been largely due to the lack of suitable high throughput techniques to investigate the genetic basis of disease, but the recent availability of next generation sequencing can facilitate the identification of disease-causing mutations even in extremely heterogeneous disorders. We investigated a series of 97 index cases with complex spastic paraplegia referred to a tertiary referral neurology centre in London for diagnosis or management. The mean age of onset was 16 years (range 3 to 39). The SPG11 gene was first analysed, revealing homozygous or compound heterozygous mutations in 30/97 (30.9%) of probands, the largest SPG11 series reported to date, and by far the most common cause of complex spastic paraplegia in the UK, with severe and progressive clinical features and other neurological manifestations, linked with magnetic resonance imaging defects. Given the high frequency of SPG11 mutations, we studied the autophagic response to starvation in eight affected SPG11 cases and control fibroblast cell lines, but in our restricted study we did not observe correlations between disease status and autophagic or lysosomal markers. In the remaining cases, next generation sequencing was carried out revealing variants in a number of other known complex spastic paraplegia genes, including five in SPG7 (5/97), four in FA2H (also known as SPG35) (4/97) and two in ZFYVE26/SPG15 Variants were identified in genes usually associated with pure spastic paraplegia and also in the Parkinson's disease-associated gene ATP13A2, neuronal ceroid lipofuscinosis gene TPP1 and the hereditary motor and sensory neuropathy DNMT1 gene, highlighting the genetic heterogeneity of spastic paraplegia. No plausible genetic cause was identified in 51% of probands, likely indicating the existence of as yet unidentified genes. PMID- 27217342 TI - Sudden Infant Death: QT or Not QT? That Is No Longer the Question. PMID- 27217343 TI - Unusual Atrioventricular Reentry Tachycardia in Congenitally Corrected Transposition of Great Arteries: A Novel Site for Catheter Ablation. PMID- 27217344 TI - A Human Pluripotent Stem Cell Model of Facioscapulohumeral Muscular Dystrophy Affected Skeletal Muscles. AB - : Facioscapulohumeral muscular dystrophy (FSHD) represents a major unmet clinical need arising from the progressive weakness and atrophy of skeletal muscles. The dearth of adequate experimental models has severely hampered our understanding of the disease. To date, no treatment is available for FSHD. Human embryonic stem cells (hESCs) potentially represent a renewable source of skeletal muscle cells (SkMCs) and provide an alternative to invasive patient biopsies. We developed a scalable monolayer system to differentiate hESCs into mature SkMCs within 26 days, without cell sorting or genetic manipulation. Here we show that SkMCs derived from FSHD1-affected hESC lines exclusively express the FSHD pathogenic marker double homeobox 4 and exhibit some of the defects reported in FSHD. FSHD1 myotubes are thinner when compared with unaffected and Becker muscular dystrophy myotubes, and differentially regulate genes involved in cell cycle control, oxidative stress response, and cell adhesion. This cellular model will be a powerful tool for studying FSHD and will ultimately assist in the development of effective treatments for muscular dystrophies. SIGNIFICANCE: This work describes an efficient and highly scalable monolayer system to differentiate human pluripotent stem cells (hPSCs) into skeletal muscle cells (SkMCs) and demonstrates disease-specific phenotypes in SkMCs derived from both embryonic and induced hPSCs affected with facioscapulohumeral muscular dystrophy. This study represents the first human stem cell-based cellular model for a muscular dystrophy that is suitable for high-throughput screening and drug development. PMID- 27217345 TI - Adipose Mesenchymal Stromal Cell-Based Therapy for Severe Osteoarthritis of the Knee: A Phase I Dose-Escalation Trial. AB - : Osteoarthritis (OA) is the most widespread musculoskeletal disorder in adults. It leads to cartilage damage associated with subchondral bone changes and synovial inflammation, causing pain and disability. The present study aimed at evaluating the safety of a dose-escalation protocol of intra-articular injected adipose-derived stromal cells (ASCs) in patients with knee OA, as well as clinical efficacy as secondary endpoint. A bicentric, uncontrolled, open phase I clinical trial was conducted in France and Germany with regulatory agency approval for ASC expansion procedure in both countries. From April 2012 to December 2013, 18 consecutive patients with symptomatic and severe knee OA were treated with a single intra-articular injection of autologous ASCs. The study design consisted of three consecutive cohorts (six patients each) with dose escalation: low dose (2 * 10(6) cells), medium dose (10 * 10(6)), and high dose (50 * 10(6)). The primary outcome parameter was safety evaluated by recording adverse events throughout the trial, and secondary parameters were pain and function subscales of the Western Ontario and McMaster Universities Arthritis Index. After 6 months of follow-up, the procedure was found to be safe, and no serious adverse events were reported. Four patients experienced transient knee joint pain and swelling after local injection. Interestingly, patients treated with low-dose ASCs experienced significant improvements in pain levels and function compared with baseline. Our data suggest that the intra-articular injection of ASCs is a safe therapeutic alternative to treat severe knee OA patients. A placebo-controlled double-blind phase IIb study is being initiated to assess clinical and structural efficacy. SIGNIFICANCE: Although this phase I study included a limited number of patients without a placebo arm, it showed that local injection of autologous adipose-derived stem cells was safe and well tolerated in patients with knee osteoarthritis. This study also provides encouraging preliminary evidence of efficacy. Larger and controlled long-term studies are now mandatory to confirm whether this new strategy of cell therapy can improve pain and induce structural benefit in osteoarthritis. PMID- 27217347 TI - Extensively drug-resistant Acinetobacter baumannii outbreak cross-transmitted in an intensive care unit and respiratory intensive care unit. AB - BACKGROUND: Extensively drug-resistant Acinetobacter baumannii (XDRAB) is a great threat in intensive care units (ICUs). The aim of this study was to describe an XDRAB outbreak which was cross-transmitted in the ICU and respiratory intensive care unit (RICU) in a tertiary care hospital from January-March 2013. METHODS: Patient and environmental surveillances were performed. Isolates were tested for antimicrobial susceptibility. Genotypes were analyzed by multilocus sequence typing (MLST). A series of enhanced strategies were implemented to control the outbreak. RESULTS: A total of 11 patients were infected by XDRAB strains during this outbreak. Three patients in the ICU were found positive for XDRAB at the onset of the outbreak. Thereafter, infections were detected in 6 patients in the RICU, followed by reappearance of this strain in the ICU in 2 patients. All A baumannii strains isolated from patients and the environment were extensively drug resistant. MLST revealed them as ST368. After 3 rounds of environmental screening and cleaning, the laminar flow system connecting the ICU and RICU was found as the source of transmission. Successful control of this outbreak was achieved through multifaceted intervention measures. CONCLUSIONS: This study suggested the importance of thorough surveillance and disinfection of the environment, including concealed devices, in preventing the transmission of an outbreak. PMID- 27217346 TI - Concise Review: Pancreatic Cancer and Bone Marrow-Derived Stem Cells. AB - Pancreatic adenocarcinoma remains one of the most challenging diseases of modern gastroenterology, and, even though considerable effort has been put into understanding its pathogenesis, the exact molecular mechanisms underlying the development and/or systemic progression of this malignancy still remain unclear. Recently, much attention has been paid to the potential role of bone marrow derived stem cells (BMSCs) in this malignancy. Hence, herein, we comprehensively review the most recent discoveries and current achievements and concepts in this field. Specifically, we discuss the significance of identifying pancreatic cancer stem cells and novel therapeutic approaches involving molecular interference of their metabolism. We also describe advances in the current understanding of the biochemical and molecular mechanisms responsible for BMSC mobilization during pancreatic cancer development and systemic spread. Finally, we summarize experimental, translational, and/or clinical evidence regarding the contribution of bone marrow-derived mesenchymal stem cells, endothelial progenitor cells, hematopoietic stem/progenitor cells, and pancreatic stellate cells in pancreatic cancer development/progression. We also present their potential therapeutic value for the treatment of this deadly malignancy in humans. SIGNIFICANCE: Different bone marrow-derived stem cell populations contribute to the development and/or progression of pancreatic cancer, and they might also be a promising "weapon" that can be used for anticancer treatments in humans. Even though the exact role of these stem cells in pancreatic cancer development and/or progression in humans still remains unclear, this concept continues to drive a completely novel scientific avenue in pancreatic cancer research and gives rise to innovative ideas regarding novel therapeutic modalities that can be safely offered to patients. PMID- 27217348 TI - Dissemination of human adenoviruses and rotavirus species A on fomites of hospital pediatric units. AB - Rotavirus A and human adenovirus dissemination were demonstrated both in a pediatric ward and in a neonatal intensive care unit (NICU) of the same pediatric hospital. Virus detection from fomites samples were higher in the pediatric ward (42.3% [137 out of 324]) than in the NICU (4.5% [7 out of 156]), revealing that cleaning processes used in our NICU are effective in reducing viral contamination, suggesting human adenovirus as a potential biomarker of contamination of hospital fomites. PMID- 27217349 TI - Detection of blaSPM-1, blaKPC, blaTEM and blaCTX-M genes in isolates of Pseudomonas aeruginosa, Acinetobacter spp. and Klebsiella spp. from cancer patients with healthcare-associated infections. AB - Pseudomonas aeruginosa, Acinetobacter spp. and Klebsiella spp. are three of the pathogens most frequently involved in infections of cancer patients, and the production of beta -lactamases is a major mechanism of resistance due to its wide diversity of existing enzymes. Therefore, the aim of the present study was to investigate the microbiological profile and data related to patients and infections, and to search for beta -lactamase genes in bacterial isolates from hospitalized cancer patients in a hospital in Recife, Pernambuco, Brazil. A total of 169 isolates were recovered between 2012 and 2014, of which 58 were P. aeruginosa, 36 were Acinetobacter spp. and 75 were Klebsiella spp. A high percentage of carbapenem resistance was observed in P. aeruginosa and Acinetobacter spp. Among the carbapenem-resistant bacteria, the blaSPM-1 gene was detected in P. aeruginosa (35.5 %) and Acinetobacter spp. (3.8 %), while blaKPC was detected in P. aeruginosa (25.8 %) only. Among the third- and fourth generation cephalosporin-resistant strains, in Klebsiella spp. we detected the genes blaTEM (30.6 %), blaCTX-M (58.3 %) and blaKPC (5.6 %), and in Acinetobacter spp. only blaTEM (25.9 %). This the first report of an Acinetobacter baumannii blaSPM-1 gene carrier that has been isolated in Brazil. The most frequent cancer types were bowel tumour [14.8 %; 95 % confidence interval (CI95 %) 9.8-21.1 %], breast cancer (13.6 %; CI95 % 8.8-19.7 %) and prostate cancer (11.2%; CI95 % 6.9 17.0 %). These results therefore provide knowledge of susceptibility profile and resistance mechanisms and thus can contribute to the strategic formulation of hospital infection control plans and the rational use of antimicrobials, reducing mortality from infection levels in cancer patients. PMID- 27217350 TI - Measurement of atomic electric fields and charge densities from average momentum transfers using scanning transmission electron microscopy. AB - This study sheds light on the prerequisites, possibilities, limitations and interpretation of high-resolution differential phase contrast (DPC) imaging in scanning transmission electron microscopy (STEM). We draw particular attention to the well-established DPC technique based on segmented annular detectors and its relation to recent developments based on pixelated detectors. These employ the expectation value of the momentum transfer as a reliable measure of the angular deflection of the STEM beam induced by an electric field in the specimen. The influence of scattering and propagation of electrons within the specimen is initially discussed separately and then treated in terms of a two-state channeling theory. A detailed simulation study of GaN is presented as a function of specimen thickness and bonding. It is found that bonding effects are rather detectable implicitly, e.g., by characteristics of the momentum flux in areas between the atoms than by directly mapping electric fields and charge densities. For strontium titanate, experimental charge densities are compared with simulations and discussed with respect to experimental artifacts such as scan noise. Finally, we consider practical issues such as figures of merit for spatial and momentum resolution, minimum electron dose, and the mapping of larger-scale, built-in electric fields by virtue of data averaged over a crystal unit cell. We find that the latter is possible for crystals with an inversion center. Concerning the optimal detector design, this study indicates that a sampling of 5mrad per pixel is sufficient in typical applications, corresponding to approximately 10*10 available pixels. PMID- 27217351 TI - Modeling the long-term kinetics of Salmonella survival on dry pet food. AB - Due to multiple outbreaks and large-scale product recalls, Salmonella has emerged as a priority pathogen in dry pet food and treats. However, little data are available to quantify risks posed by these classes of products to both pets and their owners. Specifically, the kinetics of Salmonella survival on complex pet food matrices are not available. This study measured the long-term kinetics of Salmonella survival on a dry pet food under storage conditions commonly encountered during production, retail, and in households (aw < 0.60, 23 degrees C). A Salmonella enterica cocktail of 12 strains isolated from dry pet foods and treats was used to inoculate commercial dry dog food. Salmonella was enumerated on non-selective (BHI) and selective (XLD and BS) media. Results at 570 days indicated an initial relatively rapid decline (up to 54 days), followed by a much slower extended decline phase. The Weibull model provided a satisfactory fit for time series of Log-transformed Salmonella counts from all three media (delta: mean 4.65 day/Log (CFU/g); p: mean 0.364 on BHI). This study provides a survival model that can be applied in quantitative risk assessment models. PMID- 27217352 TI - Differences in inactivation of Escherichia coli O157:H7 strains in ground beef following repeated high pressure processing treatments and cold storage. AB - High pressure processing (HPP) is a safe non-thermal processing method to effectively improve food safety. In this study, HPP treatment followed by cold storage was investigated to reduce Escherichia coli O157:H7 in ground beef. Experiments were conducted using ground beef contaminated with six E. coli O157:H7 strains one at a time or as a cocktail. Control and inoculated ground beef samples were HPP at 25 degrees C, 35 degrees C, and 45 degrees C, at 400 MPa and pre-determined number of pressure cycles totaling a holding time of 15 min. Optimum HPP parameters were 25 degrees C, 400 MPa at five pressure cycles of 3 min each which achieved a 5-log reduction of E. coli O157:H7 in ground beef. Storing HPP processed ground beef at 4 degrees C or -20 degrees C further decreased (P < 0.05) the E. coli O157:H7 population. An effective HPP treatment (5-log reduction) was developed that could be used post-processing to reduce the risk associated with E. coli O157:H7 contamination in ground beef. PMID- 27217353 TI - Hepatitis E virus genotype 3 in mussels (Mytilus galloprovinciallis), Spain. AB - Coastal waters can become contaminated with both human waste from sewage treatment plants and runoff following manure application. Thus, shellfish produced close to land can bioaccumulate enteric viruses of human and animal origin, including zoonotic hepatitis E virus that infect both human and swine. The goal of this study was to evaluate the presence of HEV in shellfish from Galicia (NW Spain), a densely populated region with a strong tradition of swine farming, and one of the most important regions in the world for mussel production. We tested 81 mussel batches by RT-qPCR followed by conventional broad spectrum nested RT-PCR and phylogenetic analysis. We have obtained 12 positive samples by RT-qPCR (14.81%) with HEV contamination levels ranging from 6.7 * 10(1) to 8.6 * 10(4) RNA copies/g digestive tissue. Phylogenetic analysis based on a 330 nt region of the ORF 1 showed that all sequenced isolates belonged to the zoonotic genotype 3 subgenotype e, being closely related to strains of human and swine origin. Results show that shellfish may be a potential route for HEV transmission to humans. PMID- 27217354 TI - Lactococcus lactis and Lactobacillus sakei as bio-protective culture to eliminate Leuconostoc mesenteroides spoilage and improve the shelf life and sensorial characteristics of commercial cooked bacon. AB - Cooked bacon is a typical Italian meat product. After production, cooked bacon is stored at 4 +/- 2 degrees C. During storage, the microorganisms that survived pasteurisation can grow and produce spoilage. For the first time, we studied the cause of the deterioration in spoiled cooked bacon compared to unspoiled samples. Moreover, the use of bio-protective cultures to improve the quality of the product and eliminate the risk of spoilage was tested. The results show that Leuconostoc mesenteroides is responsible for spoilage and produces a greening colour of the meat, slime and various compounds that result from the fermentation of sugars and the degradation of nitrogen compounds. Finally, Lactococcus lactis spp. lactis and Lactobacillus sakei were able to reduce the risk of Leuconostoc mesenteroides spoilage. PMID- 27217355 TI - Growth of Campylobacter incubated aerobically in fumarate-pyruvate media or media supplemented with dairy, meat, or soy extracts and peptones. AB - The ability of Campylobacter to grow aerobically in media supplemented with fumarate-pyruvate or with dairy, meat, or soy extracts or peptones was examined. Optical densities (OD) of Campylobacter cultured in basal media, media supplemented with fumarate-pyruvate or with 1.0, 2.5, 5.0, or 7.5% beef extract was measured. Growth was also compared in media supplemented with other extracts or peptones. Finally, cfu/mL of Campylobacter recovered from basal media or media supplemented with fumarate-pyruvate, casamino acids, beef extract, soytone, or beef extract and soytone was determined. Results indicated that OD of cultures grown in media supplemented with fumarate-pyruvate or with 5.0 or 7.5% beef extract were higher than OD of isolates grown in basal media or media supplemented with lower concentrations of beef extract. Highest OD were produced by isolates grown in media supplemented with beef extract, peptone from meat, polypeptone, proteose peptone, or soytone. Also, more cfu/mL were recovered from media with fumarate-pyruvate, beef extract, soytone, or beef extract-soytone than from basal media or media with casamino acids. Findings indicate that media supplemented with organic acids, vitamins, and minerals and media supplemented with extracts or peptones containing these metabolites can support aerobic growth of Campylobacter. PMID- 27217356 TI - Suitability of different Escherichia coli enumeration techniques to assess the microbial quality of different irrigation water sources. AB - The use of fecal indicators such as Escherichia coli has been proposed as a potential tool to characterize microbial contamination of irrigation water. Recently, not only the type of microbial indicator but also the methodologies used for enumeration have been called into question. The goal of this study was to assess the microbial quality of different water sources for irrigation of zucchini plants by using E. coli as an indicator of fecal contamination and the occurrence of foodborne pathogens. Three water sources were evaluated including reclaimed secondary treated water (RW-2), reclaimed tertiary UV-C treated water (RW-3) and surface water (SW). The suitability of two E. coli quantification techniques (plate count and qPCR) was examined for irrigation water and fresh produce. E. coli levels using qPCR assay were significantly higher than that obtained by plate count in all samples of irrigation water and fresh produce. The microbial quality of water samples from RW-2 was well predicted by qPCR, as the presence of foodborne pathogens were positively correlated with high E. coli levels. However, differences in the water characteristics influenced the suitability of qPCR as a tool to predict potential contamination in irrigation water. No significant differences were obtained between the number of cells of E. coli from RW-2 and RW-3, probably due to the fact that qPCR assay cannot distinguish between viable and dead cells. These results indicated that the selection of the most suitable technique for enumeration of indicator microorganisms able to predict potential presence of fecal contamination might be influenced by the water characteristics. PMID- 27217357 TI - Prevalence, antimicrobial susceptibility and molecular typing of Methicillin Resistant Staphylococcus aureus (MRSA) in bulk tank milk from southern Italy. AB - This paper assesses the prevalence of MRSA in bulk tank milk (BTM) samples from southern Italy, and the relationship between the Coagulase Positive Staphylococci count (CPS) and MRSA prevalence. Of 486 BTM samples tested, 12 samples (2.5%) resulted positive for the presence of MRSA. Great genetic diversity was found among the isolates: ST1/t127 and t174/IVa, ST5/t688/V, ST8/t unknown/IVa/V, ST45/t015/IVa, ST71/t524/V, ST88/t786/Iva, ST398/t011 and t899/IVa/V and ST2781/t1730/V. All isolates were pvl-negative and icaA positive. The majority of strains (58%) carried the ses (sec, seh, seg, seo, sem and sen) genes. All tested strains resulted susceptible to amikacin, cephalotin, cloramphenicol, gentamycin, trimethoprim - sulfamethoxazole, tobramycin and vancomycin, and variably resistant to ampicillin, oxacillin and tetracycline. No statistical association between the CPS count and MRSA detection was found in the MRSA-positive samples. Although some of the spa-types and STs detected in our survey are known to cause human infections, raw milk from Italian herds in the considered area is not a common source of MRSA. Nonetheless, it is necessary to assess the risk of foodborne infection and the risk related to the handling of milk. PMID- 27217358 TI - Validation of a predictive model coupling gas transfer and microbial growth in fresh food packed under modified atmosphere. AB - Predicting microbial safety of fresh products in modified atmosphere packaging implies to take into account the dynamic of O2, CO2 and N2 exchanges in the system and its effect on microbial growth. In this paper a mechanistic model coupling gas transfer and predictive microbiology was validated using dedicated challenge-tests performed on poultry meat, fresh salmon and processed cheese, inoculated with either Listeria monocytogenes or Pseudomonas fluorescens and packed in commercially used packaging materials (tray + lid films). The model succeeded in predicting the relative variation of O2, CO2 and N2 partial pressure in headspace and the growth of the studied microorganisms without any parameter identification. This work highlighted that the respiration of the targeted microorganism itself and/or that of the naturally present microflora could not be neglected in most of the cases, and could, in the particular case of aerobic microbes contribute to limit the growth by removing all residual O2 in the package. This work also confirmed the low sensitivity of L. monocytogenes toward CO2 while that of P. fluorescens permitted to efficiently prevent its growth by choosing the right combination of packaging gas permeability value and initial % of CO2 initially flushed in the pack. PMID- 27217359 TI - A new cause of spoilage in goose sausages. AB - The aim of this work was to determine the microorganisms present and to investigate their metabolites that cause spoilage of many goose sausages produced in Friuli, a northeast region of Italy. The defect was observed by sensorial analysis using the "needle probing" technique; the spoiled sausages were unsafe and not marketable. Despite the addition of starter, the microorganisms, particularly enterococci and Enterobacteriaceae, grew during ripening and produced a large amount of biogenic amines; therefore, these sausages represented a risk to consumers. The production of those compounds was confirmed in vitro. Furthermore, a second cause of spoilage was attributed to moulds that grew during ripening; the fungi grew between the meat and casing, producing a large amount of total volatile nitrogen, and consequently an ammonia smell was present either in the ripening area or in the sausages. This is the first description of this type of defect in goose sausages. PMID- 27217360 TI - Minimal inhibitory concentrations of undissociated lactic, acetic, citric and propionic acid for Listeria monocytogenes under conditions relevant to cheese. AB - Minimal inhibitory concentrations (MICs) of undissociated lactic acid were determined for six different Listeria monocytogenes strains at 30 degrees C and in a pH range of 4.2-5.8. Small increments in pH and acid concentrations were used to accurately establish the growth/no growth limits of L. monocytogenes for these acids. The MICs of undissociated lactic acid in the pH range of 5.2-5.8 were generally higher than at pH 4.6 for the different L. monocytogenes strains. The average MIC of undissociated lactic acid was 5.0 (SD 1.5) mM in the pH range 5.2-5.6, which is relevant to Gouda cheese. Significant differences in MICs of undissociated lactic acid were found between strains of L. monocytogenes at a given pH, with a maximum observed level of 9.0 mM. Variations in MICs were mostly due to strain variation. In the pH range 5.2-5.6, the MICs of undissociated lactic acid were not significantly different at 12 degrees C and 30 degrees C. The average MICs of undissociated acetic acid, citric acid, and propionic acid were 19.0 (SD 6.5) mM, 3.8 (SD 0.9) mM, and 11.0 (SD 6.3) mM, respectively, for the six L. monocytogenes strains tested in the pH range 5.2-5.6. Variations in MICs of these organic acids for L. monocytogenes were also mostly due to strain variation. The generated data contribute to improved predictions of growth/no growth of L. monocytogenes in cheese and other foods containing these organic acids. PMID- 27217361 TI - Assessment of the contribution of cocoa-derived strains of Acetobacter ghanensis and Acetobacter senegalensis to the cocoa bean fermentation process through a genomic approach. AB - Acetobacter ghanensis LMG 23848(T) and Acetobacter senegalensis 108B are acetic acid bacteria that originate from a spontaneous cocoa bean heap fermentation process and that have been characterised as strains with interesting functionalities through metabolic and kinetic studies. As there is currently little genetic information available for these species, whole-genome sequencing of A. ghanensis LMG 23848(T) and A. senegalensis 108B and subsequent data analysis was performed. This approach not only revealed characteristics such as the metabolic potential and genomic architecture, but also allowed to indicate the genetic adaptations related to the cocoa bean fermentation process. Indeed, evidence was found that both species possessed the genetic ability to be involved in citrate assimilation and displayed adaptations in their respiratory chain that might improve their competitiveness during the cocoa bean fermentation process. In contrast, other properties such as the dependence on glycerol or mannitol and lactate as energy sources or a less efficient acid stress response may explain their low competitiveness. The presence of a gene coding for a proton translocating transhydrogenase in A. ghanensis LMG 23848(T) and the genes involved in two aromatic compound degradation pathways in A. senegalensis 108B indicate that these strains have an extended functionality compared to Acetobacter species isolated from other ecosystems. PMID- 27217362 TI - Genes associated to lactose metabolism illustrate the high diversity of Carnobacterium maltaromaticum. AB - The dairy population of Carnobacterium maltaromaticum is characterized by a high diversity suggesting a high diversity of the genetic traits linked to the dairy process. As lactose is the main carbon source in milk, the genetics of lactose metabolism was investigated in this LAB. Comparative genomic analysis revealed that the species C. maltaromaticum exhibits genes related to the Leloir and the tagatose-6-phosphate (Tagatose-6P) pathways. More precisely, strains can bear genes related to one or both pathways and several strains apparently do not contain homologs related to these pathways. Analysis at the population scale revealed that the Tagatose-6P and the Leloir encoding genes are disseminated in multiple phylogenetic lineages of C. maltaromaticum: genes of the Tagatose-6P pathway are present in the lineages I, II and III, and genes of the Leloir pathway are present in the lineages I, III and IV. These data suggest that these genes evolved thanks to horizontal transfer, genetic duplication and translocation. We hypothesize that the lac and gal genes evolved in C. maltaromaticum according to a complex scenario that mirrors the high population diversity. PMID- 27217363 TI - The effect of locust bean gum (LBG)-based edible coatings carrying biocontrol yeasts against Penicillium digitatum and Penicillium italicum causal agents of postharvest decay of mandarin fruit. AB - Strains belonging to Wickerhamomyces anomalus, Metschnikowia pulcherrima and Aureobasidium pullulans species were tested in vitro as biocontrol agents (BCAs) against the post-harvest pathogenic molds Penicillium digitatum and Penicillium italicum. Moreover, studies aimed at screening the antifungal activity of selected yeast strains in vivo conditions against P. digitatum and P. italicum, and investigated the efficacy of a polysaccharidic matrix, locust bean gum (LBG), enriched with the tested BCAs, in controlling postharvest decays in artificially inoculated mandarins. The population dynamics of BCAs on wounds and the magnitude of peroxidase (POD) and superoxide dismutase (SOD) in fruit tissues were also investigated after treatments of mandarins with antagonistic yeasts. W. anomalus BS91, M. pulcherrima MPR3 and A. pullulans PI1 provided excellent control of postharvest decays caused by P. digitatum and P. italicum on mandarins, both when the yeasts were used alone and in combination with LBG, which enhanced the yeast cell viability over time. Finally, the increased activity of POD and lower decrease in SOD activity in response to BCAs application in mandarin fruits confirmed their involvement in the biocontrol mechanism. PMID- 27217364 TI - Physio-chemical, microbiological properties of tempoyak and molecular characterisation of lactic acid bacteria isolated from tempoyak. AB - This study aims to determine physio-chemical properties of tempoyak, characterise the various indigenous species of lactic acid bacteria (LAB) present at different stages of fermentation and also to determine the survival of selected foodborne pathogens in tempoyak. The predominant microorganisms present in tempoyak were LAB (8.88-10.42 log CFU/g). Fructobacillus durionis and Lactobacillus plantarum were the dominant members of LAB. Other LAB species detected for the first time in tempoyak were a fructophilic strain of Lactobacillus fructivorans, Leuconostoc dextranicum, Lactobacillus collinoides and Lactobacillus paracasei. Heterofermentative Leuconostoc mesenteroides and F. durionis were predominant in the initial stage of fermentation, and as fermentation proceeded, F. durionis remained predominant, but towards the end of fermentation, homofermentative Lb. plantarum became the predominant species. Lactic, acetic and propionic acids were present in concentrations ranging from 0.30 to 9.65, 0.51 to 7.14 and 3.90 to 7.31 mg/g, respectively. Genotyping showed a high degree of diversity among F. durionis and Lb. plantarum isolates, suggesting different sources of LAB. All tested Lb. plantarum and F. durionis (except for one isolate) isolates were multidrug resistant. Salmonella spp., Listeria monocytogenes and Staphylococcus aureus were not detected. However, survival study showed that these pathogens could survive up to 8-12 days. The results aiming at improving the quality and safety of tempoyak. PMID- 27217365 TI - Staphylococcus aureus isolated from handmade sweets: Biofilm formation, enterotoxigenicity and antimicrobial resistance. AB - Staphylococcus aureus is the second most important pathogen involved in foodborne outbreaks in Brazil. Because of their widespread distribution and biofilm forming ability, handmade sweets are easily contaminated with S. aureus. The aim of this study was to isolate and identify coagulase-positive staphylococci (CPS) from handmade sweets produced in Pelotas City/Brazil. The virulence potential was checked by evaluating the presence of the staphylococcal enterotoxin genes, icaA and icaD genes, the biofilm forming potential and antimicrobial resistance of the isolates. It was find just S. aureus among the CPS isolates. All the S. aureus isolates had biofilm forming ability on stainless steel and more than half of them on polystyrene surfaces. The majority of the isolates carried the icaA (66.6%) and icaD (58.4%) genes and some of them had the genes encoding enterotoxins A (33.4%) and B (16.6%). Furthermore, the majority of the isolates (83%) were resistant to at least one of the tested antimicrobials and multidrug resistance was observed in 8.4% of the isolates. The isolates had virulence potential, and half of them were enterotoxigenic. In addition, the ability of all the isolates to produce biofilms highlights the danger posed by these potentially virulent microorganisms persisting in food manufacturing environments. PMID- 27217366 TI - Toxoplasma gondii detection and viability assays in ham legs and shoulders from experimentally infected pigs. AB - Epidemiological studies of toxoplasmosis show that infection in humans is mainly caused by the consumption of raw, undercooked or cured meat. Cured "Serrano" ham is a typical pork product from the Mediterranean area, highly valued for its flavour. The "Serrano" ham is prepared from pork meat and undergoes a process known as curing and a subsequent fermentation without thermal or smoking treatments. The viability of Toxoplasma gondii in hams and shoulders from experimentally infected pigs that have been subject to different curing processes has been studied in order to evaluate the best method to completely eliminate the viable protozoa. The different treatments include, i) freezing the legs and shoulders below -20 degrees C for 3 days before salting with marine salt, ii) salting the meat with marine salt and nitrites, iii) salting only with marine salt (traditional process) and iv) salting with marine salt and then freezing at 20 degrees C for 3 days after the curing period. The ham leg samples were cured for 7 months and the shoulder samples for 5 months. The presence of T. gondii in the different treatments was studied by a "magnetic-capture" method for the isolation of T. gondii DNA and a quantitative real-time PCR to estimate the T. gondii burden in the ham legs and shoulders. The infectivity capacity of T. gondii in positive samples was assayed by bioassays in mice and some physicochemical parameters, such as pH, water activity (aw) and salt content, were evaluated at the end of the curing time. In all the cases where the samples were frozen the T. gondii infectivity was eliminated. In samples in which the meat was salted in marine salt plus nitrites, the parasite viability remained for longer than in the traditional salting process. The methods described here could be useful for producers to guarantee the safety of their products. PMID- 27217367 TI - Inactivation of Listeria monocytogenes, Salmonella spp. and Escherichia coli O157:H7 on cantaloupes by octenidine dihydrochloride. AB - The efficacy of a new generation disinfectant, octenidine dihydrochloride (OH), as wash and coating treatments for reducing Listeria monocytogenes (LM), Salmonella spp. (SAL), and Escherichia coli O157:H7 (EC) on cantaloupe was investigated. Cantaloupe rind plugs inoculated separately with the three bacterial species (~8 log CFU/cm(2)) were washed for 1, 3, 5 min at 25 degrees C in water, or chlorine (200 ppm), ethanol (1%), OH (0.01, 0.05, 0.1%) and surviving populations were measured after treatment. Additionally, inoculated cantaloupe rind plugs were coated with 2% chitosan or chitosan containing OH (0.01, 0.05, 0.1%) and sampled for surviving pathogens. Subsequently, the antimicrobial efficacy of OH wash and coating (0.1, 0.2%) on whole cantaloupes was determined. All OH wash reduced LM, SAL, and EC on cantaloupe rinds by > 5 log CFU/cm(2) by 2 min, and reduced populations to undetectable levels (below 2 log CFU/cm(2)) by 5 min (P < 0.05). Similarly, OH coating on cantaloupe rinds reduced the pathogens by 3-5 log /cm(2) (P < 0.05). Washing and coating whole cantaloupes with OH reduced the three pathogens by at least 5 log and 2 log CFU/cm(2), respectively (P < 0.05). Results suggest that OH could be used as antimicrobial wash and coating to reduce LM, SAL, and EC on cantaloupes. PMID- 27217368 TI - Effects of Citrox and chitosan on the survival of Escherichia coli O157:H7 and Salmonella enterica in vacuum-packaged turkey meat. AB - In this study, we examined the antimicrobial effects of citrus extract (Citrox((r))) and chitosan on lactic acid bacteria (LAB) and the pathogens Escherichia coli O157:H7 and Salmonella enterica on turkey meat during storage under vacuum packaging (VP) at 4 and 10 degrees C. We also examined the effects of Citrox and chitosan on pathogen contamination in tryptic soy broth (TSB). Chitosan alone or in combination with Citrox inhibited the growth of endogenous LAB in turkey meat, whereas citrus extract did not cause a major reduction in bacterial density. Citrus extract combined with chitosan yielded the lowest mesophilic total viable counts (TVCs), irrespective of temperature, showing major declines in all treated turkey samples from days 0-21 of storage. The shelf-lives of untreated, Citrox-treated, and chitosan and Citrox/chitosan-treated samples (as determined by TVC and sensory data) were 13, 17, and >21 days, respectively, at 4 degrees C for VP turkey. The addition of Citrox was more effective against S. enterica than E. coli in turkey, causing reductions of >0.5 and 2 log cfu/g at 4 and 10 degrees C, respectively, after 21 days of storage. Interestingly, the addition of chitosan had a significant inhibitory effect on E. coli at 4 degrees C and S. enterica at 10 degrees C as compared with the control (inoculated samples) resulting in dramatic reductions in E. coli (2 log) and S. enterica (5 log) cell counts on day 21. Of all the treatments examined, citrus extract in combination with chitosan showed an additive inhibitory effect against both pathogens, reducing E. coli and S. enterica populations, by approximately 2.7 or 4.5 and 2.2 or 5.6 log cfu/g, respectively, at 4 and 10 degrees C on day 21 of storage. PMID- 27217369 TI - Occurrence and behavior of Bacillus cereus in naturally contaminated ricotta salata cheese during refrigerated storage. AB - The present study shows the fate of Bacillus cereus in refrigerated ricotta salata cheese during shelf-life. 144 ricotta salata cheese belonging to nine naturally contaminated batches were stored refrigerated and analyzed at 24 h, 30, 60 and 90 days of storage. Total bacterial count, B. cereus spores and vegetative forms, intrinsic properties and composition were determined. The presence of spores was sporadic while the prevalence and the level of B. cereus vegetative cells decreased respectively from 83.3 % to 4.65 +/- 0.74 cfu g(-1) at the beginning of the observation period to 33.3 % and 1.99 +/- 0.55 cfu g(-1) after 90 days. No information is currently available on the fate of B. cereus in ricotta salata. The production process of ricotta salata includes steps such as whey heating followed by slow cooling of clots, which expose to the risk of spore germination and successive growth to levels compatible with toxins production. The prolonged refrigerated storage was not favorable to sporulation, explaining the successive death of vegetative cells. The present study demonstrate the potential risk of food poisoning as consequence of pre-formed emetic toxins in ricotta salata. Food safety of ricotta salata relies on the rapid refrigeration of the product during critical phases for cereulide production. PMID- 27217370 TI - Heat resistance of Salmonella enterica is increased by pre-adaptation to peanut oil or sub-lethal heat exposure. AB - Cross-protection represents a considerable challenge in the food industry where hurdled interventions are often employed to reduce Salmonella contamination. The heat resistance of Salmonella strains from five serotypes (i.e., Typhimurium, Enteritidis, Tennessee, Thompson and Hartford) at 70 degrees C was determined by measurement of viable cell populations before and after adaptation to two common stresses employed in low-water activity food processing, desiccation and sub lethal heat treatment. Survival of Salmonella at 70 degrees C significantly increased (p < 0.05) following the six-day incubation in peanut oil (aw 0.52 +/- 0.00) and/or the exposure to a sub-lethal heat treatment at 45 degrees C for 3 min. Quantitative PCR revealed upregulation of two desiccation stress-related genes, fadA and otsB, following the peanut oil incubation, whereas heat treatment induced upregulation of a heat-resistance gene, dnaK. Invasion gene invA and alternative sigma factor rpoE were downregulated following either of the treatments. Interestingly, different Salmonella strains yielded different transcriptional profiles. The strain-specific resistance phenotypes and transcriptional profiles provided further insights into the mechanisms employed to tolerate desiccation and heat stresses in the food industry. PMID- 27217371 TI - Corrigendum to "Development of a predictive model for the growth kinetics of aerobic microbial population on pomegranate marinated chicken breast fillets under isothermal and dynamic temperature conditions" [Food Microbiol. 55 (2016) 25-31]. PMID- 27217372 TI - Haploidentical transplantation in children with unmanipulated peripheral blood stem cell graft: The need to look beyond post-transplantation cyclophosphamide in younger children. AB - Haploidentical transplantation with PTCY following marrow or PBSC graft has been associated with low incidence of GVHD in adults with similar data lacking in children. We report on the outcome of 25 patients <20 yr of age (median age 12 yr), undergoing a haploidentical PBSC transplantation for both malignant and non malignant disorders. Engraftment was prompt and sustained. Cumulative incidences of acute GVHD and chronic GVHD were 40.3% and 16.7%, respectively. On subgroup analysis, it was evident that acute GVHD developed in 80% of patients <10 yr compared to only 13.3% in those between 10 and 20 yr [log-rank p = 0.001], despite similar graft composition with significantly higher NRM (60% vs. 0%; p = 0.001). The FFS was 63.5%; (79% in >10 yr and 40% in <10 yr, p = 0.01). Our data suggest that PTCY-based haploidentical PBSC transplantation is feasible in older children, but results in early and severe alloreactivity in younger children. These findings, despite being counterintuitive, could be explained by the variable metabolism of CY and oral mycophenolate in younger children indicating that PTCY-based approach as used in adults might not be adequate for younger children. PMID- 27217373 TI - Fusion of Boar Sperm with Nanoliposomes Prepared from Synthetic Phospholipids. AB - Liposomes are artificial membrane vesicles that can be used to test and model the functions and interactions of various biological membranes, or as a carrier system to deliver biologically active substances into the cells, or to incorporate lipids into the plasma membrane of target cells to modify membrane structure-function relationships. Sperm plasma membrane undergoes lipid modification during maturation in epididymis and during capacitation in the female reproductive tract to facilitate fertilization. Natural variation in the amounts and composition of lipids in the sperm plasma membrane may also contribute to the species-specific sperm sensitivities to handling and storage conditions. Boar sperm are notoriously susceptible to membrane damage and are resistant to compositional alteration by artificial liposomes. This study used flow cytometry to demonstrate stable incorporation of nanoliposomes prepared from a complex mixture of various phospholipids (phosphatidylcholine : phosphatidylethanolamine : sphingomyelin : phosphatidylserine : phosphatidylinositol) with high fusion efficiency. Over 90% of sperm rapidly took up fluorescently labelled liposomes and retained the lipids for at least 60 min, in a significant time- and concentration-dependent manner. This unique fusion efficacy could be used to alter sperm plasma membrane composition and hence membrane-based functional responses. PMID- 27217374 TI - Disrupting Y-Box-Binding Protein 1 Function Using OSU-03012 Prevents Endometriosis Progression in In Vitro and In Vivo Models. AB - The objective of the present study was to test the ability of OSU-03012 (2-amino N-[4-[5-phenanthren-2-yl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]acetamide), a novel and potent celecoxib-derivative, to impair endometriosis progression in in vitro and in vivo models based on its ability to indirectly block Y-box-binding protein 1 (YB-1) function. 12Z human endometriotic epithelial cells and sexually mature female C57BL/6J mice were treated with OSU-03012. Cellular proliferation was quantified by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromid assay. Expression of YB-1 and phosphorylated YB-1 in 12Z cells and endometriotic lesions was evaluated by Western blotting and immunohistochemistry (IHC). The IHC for proliferating cell nuclear antigen was performed. OSU-03012 treatment resulted in decreased YB-1 and its phosphorylated form in both in vitro and in vivo models. Endometriotic lesion size was significantly reduced in OSU-03012 treated mice (27.6 +/- 4.0 mm3) compared to those from the control group (50.5 +/ 6.9 mm3, P < .0001). A significant reduction in endometriotic epithelial cell proliferation was observed in endometriotic lesions exposed to OSU-03012 treatment ( P = .0346). In conclusion, targeting YB-1 via OSU-03012 showed a potent antiproliferative effect on endometriotic epithelial cells in vitro and in a mouse model of disease. PMID- 27217375 TI - Intrauterine Candida albicans Infection Causes Systemic Fetal Candidiasis With Progressive Cardiac Dysfunction in a Sheep Model of Early Pregnancy. AB - INTRODUCTION: Several recent studies have identified a potential role for intrauterine Candida albicans in adverse pregnancy outcomes, including preterm birth. There is, however, a limited understanding of the impact of intrauterine candida infection on fetal well-being in early pregnancy. Using a sheep model of early pregnancy, the aims of this study were to determine (1) the ability of experimentally induced intrauterine C albicans to infect the fetus and (2) whether C albicans exposure in early pregnancy is associated with alterations in fetal cardiac function, as measured by spectral tissue Doppler imaging analysis of fetal cardiac function. METHODS: Merino ewes carrying singleton pregnancies at 89 days' gestation (term is ~150 days) received C albicans (n = 8) via ultrasound guided intra-amniotic injection. Saline-exposed fetuses served as controls (n = 6). Spectral tissue Doppler imaging echocardiography and amniotic fluid collection were performed at baseline and 24 and 72 hours after intrauterine C albicans injection. Fetal tissues were collected at postmortem for analysis of infection and inflammation. RESULTS: Relative to saline control, intrauterine C albicans infection resulted in pronounced increases in amniotic fluid tumor necrosis factor alpha (TNF-alpha; P < .05) and cytokine/chemokine messenger RNA (interleukin [IL] 1beta, IL-6, TNF-alpha, and monocyte chemoattractant protein 1; P < .05) in the fetal myocardium, lung, skin, and liver at 72 and 96 hours postinfection. Spectral tissue Doppler imaging showed diastolic dysfunction at 24 hours and severe biventricular diastolic dysfunction 72 hours postinfection. CONCLUSION: Intrauterine C albicans infection in a sheep model of early pregnancy causes systemic fetal candidiasis, which is associated with a robust systemic inflammatory response and progressive cardiac dysfunction detectable by spectral tissue Doppler imaging. PMID- 27217376 TI - Nectin-3 Is Increased in the Cell Junctions of the Uterine Epithelium at Implantation. AB - Uterine luminal epithelial cells (UECs) undergo the plasma membrane transformation in the transition to receptivity. This involves transient alterations in the apical junctional complex (AJC) including increases to the depth and complexity of the tight junction, loss of the adherens junction, and a decrease in the number of desmosomes along the lateral cell membranes. Nectin-3 is key protein involved in the structure and function of the AJC. This study, used immunofluorescence, Western blotting, colocalization, and coimmunoprecipitation analyses, to investigate whether nectin-3 was present in the rat uterus and was regulated by hormones and the blastocyst during early pregnancy. The results showed that nectin-3 was present in UECs as 3 molecular weight protein isoforms (80 kDa, 60 kDa, and 32 kDa). At the time of fertilization (day 1 of pregnancy), nectin-3 was localized basally, but at the time of implantation, (day 6 of pregnancy) when UECs were receptive, nectin-3 increased in the cellular junctions. When UECs returned to the nonreceptive state (day 9 of pregnancy), nectin-3 redistributed back to the cell cytoplasm. This study also showed that nectin-3 localization at the cell junctions was likely to be controlled by progesterone; however, neither ovarian hormones nor the blastocyst regulated protein abundance. This study further showed that while nectin-3 localized to the tight junction at the time of implantation, it did not interact with occludin or l-afadin. These results suggest that at the time of implantation, nectin-3 may contribute to the formation of the tight junction in a protein complex independent from occludin and l-afadin. PMID- 27217377 TI - Influence of Septal Thickness on the Clinical Outcome After Alcohol Septal Alation in Hypertrophic Cardiomyopathy. AB - BACKGROUND: We assessed the influence of interventricular septal thickness (IVSd) on the clinical outcome and survival after alcohol septal ablation (ASA) in patient with hypertrophic cardiomyopathy. METHODS AND RESULTS: We analyzed 531 patients with hypertrophic cardiomyopathy (age: 56+/-14 years, men 55%) treated with ASA. Survival status was obtained 7.9+/-4.0 years after ASA. Baseline IVSd was inversely associated with survival (hazard ratio [HR] for 1 mm increment, 1.13; confidence interval, 1.05-1.21; P<0.001) after adjustment for age, sex, body mass index, and ASA-performing center. Compared with patients with baseline IVSd <20 mm, patients with baseline IVSd >=25 mm had reduced survival (HR, 5.0; CI, 2.1-12), whereas patients with baseline IVSd 20 to 24 mm had similar survival (HR, 1.4; CI, 0.7-2.8). Baseline IVSd was not correlated with New York Heart Association class, Canadian Cardiology Society class, or syncope. Clinical outcome was assessed 0.6+/-0.6 years after ASA. IVSd was not related to left ventricular outflow tract gradient reduction at rest (P=0.883) or during Valsalva maneuver (P=0.885). The proportion of patients in New York Heart Association class 3 to 4 was reduced from 86% to 10%; in Canadian Cardiology Society class 3 to 4 from 26% to 2%; and with syncope from 25% to 2%. There were no correlations between baseline IVSd and New York Heart Association class (P=0.067), Canadian Cardiology Society class (P=0.106), or syncope (P=0.426) after ASA. CONCLUSIONS: ASA had equal effects on left ventricular outflow tract gradients and symptoms throughout the spectrum of septal hypertrophy. Severe septal hypertrophy before ASA remained a marker of reduced survival after ASA with a 5-fold increased risk of all-cause mortality in patients with baseline IVSd >25 mm compared with patients with baseline IVSd <20 mm. PMID- 27217379 TI - Dramatic 2015 excess mortality in Italy: a 9.1% increase that needs to be explained. PMID- 27217378 TI - Early sex work initiation and condom use among alcohol-using female sex workers in Mombasa, Kenya: a cross-sectional analysis. AB - OBJECTIVES: Early initiation of sex work is prevalent among female sex workers (FSWs) worldwide. The objectives of this study were to investigate if early initiation of sex work was associated with: (1) consistent condom use, (2) condom negotiation self-efficacy or (3) condom use norms among alcohol-using FSWs in Mombasa, Kenya. METHODS: In-person interviews were conducted with 816 FSWs in Mombasa, Kenya. Sample participants were: recruited from HIV prevention drop-in centres, 18 years or older and moderate risk drinkers. Early initiation was defined as first engaging in sex work at 17 years or younger. Logistic regression modelled outcomes as a function of early initiation, adjusting for drop-in centre, years in sex work, supporting others and HIV status. RESULTS: FSWs who initiated sex work early were significantly less likely to report consistent condom use with paying sex partners compared with those who initiated sex work in adulthood. There was no significant difference between groups in consistent condom use with non-paying sex partners. FSWs who initiated sex work early endorsed less condom negotiation self-efficacy with paying sex partners compared with FSWs who did not initiate sex work early. CONCLUSIONS: Findings highlight a need for early intervention for at-risk youth and adolescent FSWs, particularly in relation to HIV sexual risk behaviours. Evidence-based interventions for adolescent FSWs or adult FSWs who began sex work in adolescence should be developed, implemented and evaluated. PMID- 27217380 TI - Activation of the ATF6 branch of the unfolded protein response in neurons improves stroke outcome. AB - Impaired function of the endoplasmic reticulum (ER stress) is a hallmark of many human diseases including stroke. To restore ER function in stressed cells, the unfolded protein response (UPR) is induced, which activates 3 ER stress sensor proteins including activating transcription factor 6 (ATF6). ATF6 is then cleaved by proteases to form the short-form ATF6 (sATF6), a transcription factor. To determine the extent to which activation of the ATF6 UPR branch defines the fate and function of neurons after stroke, we generated a conditional and tamoxifen inducible sATF6 knock-in mouse. To express sATF6 in forebrain neurons, we crossed our sATF6 knock-in mouse line with Emx1-Cre mice to generate ATF6-KI mice. After the ATF6 branch was activated in ATF6-KI mice with tamoxifen, mice were subjected to transient middle cerebral artery occlusion. Forced activation of the ATF6 UPR branch reduced infarct volume and improved functional outcome at 24 h after stroke. Increased autophagic activity at early reperfusion time after stroke may contribute to the ATF6-mediated neuroprotection. We concluded that the ATF6 UPR branch is crucial to ischemic stroke outcome. Therefore, boosting UPR pro survival pathways may be a promising therapeutic strategy for stroke. PMID- 27217381 TI - Evidence that adenosine contributes to Leao's spreading depression in vivo. AB - Leao's spreading depression of cortical activity is a propagating silencing of neuronal activity resulting from spreading depolarization (SD). We evaluated the contributions of action potential (AP) failure and adenosine A1 receptor (A1R) activation to the depression of evoked and spontaneous electrocorticographic (ECoG) activity after SD in vivo, in anesthetized mice. We compared depression with SD-induced effects on AP-dependent transmission, and synaptic potentials in the transcallosal and thalamocortical pathways. After SD, APs recovered rapidly, within 1-2 min, as demonstrated by evoked activity in distant projection targets. Evoked corticocortical postsynaptic potentials recovered next, within ~5 min. Spontaneous ECoG and evoked thalamocortical postsynaptic potentials recovered together, after ~10-15 min. The duration of ECoG depression was shortened 20% by systemic (10 mg/kg) or focal (30 uM) administration of A1R competitive antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). ECoG depression was also shortened by focal application of exogenous adenosine deaminase (ADA; 100 U/mL), and conversely, was prolonged 50% by the non-competitive ADA inhibitor deoxycoformycin (DCF; 100 uM). We concluded that while initial depolarization block is brief, adenosine A1R activation, in part, contributes to the persistent secondary phase of Leao's cortical spreading depression. PMID- 27217382 TI - Nivolumab Doubles Survival for Patients with HNSCC. AB - In patients with head and neck squamous cell carcinoma refractory to platinum based chemotherapy, those treated with nivolumab had a 30% reduction in the risk of death compared with those assigned to receive one of three single-agent chemotherapies, according to a recent phase III trial. In addition, 1-year survival among nivolumab recipients was double that of those who received a chemotherapeutic, the current standard of care. PMID- 27217384 TI - Photo Quiz: An 8-Year-Old Boy with Meningoencephalitis. PMID- 27217383 TI - Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non-Small Cell Lung Cancer, and Other Solid Tumors. AB - We evaluated the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of abemaciclib, an orally bioavailable inhibitor of cyclin dependent kinases (CDK) 4 and 6, in a multicenter study including phase I dose escalation followed by tumor-specific cohorts for breast cancer, non-small cell lung cancer (NSCLC), glioblastoma, melanoma, and colorectal cancer. A total of 225 patients were enrolled: 33 in dose escalation and 192 in tumor-specific cohorts. Dose-limiting toxicity was grade 3 fatigue. The maximum tolerated dose was 200 mg every 12 hours. The most common possibly related treatment-emergent adverse events involved fatigue and the gastrointestinal, renal, or hematopoietic systems. Plasma concentrations increased with dose, and pharmacodynamic effects were observed in proliferating keratinocytes and tumors. Radiographic responses were achieved in previously treated patients with breast cancer, NSCLC, and melanoma. For hormone receptor-positive breast cancer, the overall response rate was 31%; moreover, 61% of patients achieved either response or stable disease lasting >=6 months. SIGNIFICANCE: Abemaciclib represents the first selective inhibitor of CDK4 and CDK6 with a safety profile allowing continuous dosing to achieve sustained target inhibition. This first-in-human experience demonstrates single-agent activity for patients with advanced breast cancer, NSCLC, and other solid tumors. Cancer Discov; 6(7); 740-53. (c)2016 AACR.See related commentary by Lim et al., p. 697This article is highlighted in the In This Issue feature, p. 681. PMID- 27217385 TI - The Brief Case: Safe To Go Back in the Water? Vibrio parahaemolyticus Wound Infection Associated with Brackish Water. PMID- 27217386 TI - Correction for van Tonder et al., Genomics Reveals the Worldwide Distribution of Multidrug-Resistant Serotype 6E Pneumococci. PMID- 27217387 TI - Correction for Adler et al., Prevalence, Risk Factors, and Transmission Dynamics of Extended-Spectrum-beta-Lactamase-Producing Enterobacteriaceae: a National Survey of Cattle Farms in Israel in 2013. PMID- 27217388 TI - Closing the Brief Case: Safe To Go Back in the Water? Vibrio parahaemolyticus Wound Infection Associated with Brackish Water. PMID- 27217389 TI - Answer to June 2016 Photo Quiz. PMID- 27217391 TI - Chronic kidney disease in low- and middle-income countries. AB - Most of the global burden of chronic kidney disease (CKD) is occurring in low- and middle-income countries (LMICs). As a result of rapid urbanization in LMICs, a growing number of populations are exposed to numerous environmental toxins, high infectious disease burdens and increasing rates of noncommunicable diseases. For CKD, this portends a high prevalence related to numerous etiologies, and it presents unique challenges. A better understanding of the epidemiology of CKD in LMICs is urgently needed, but this must be coupled with strong public advocacy and broad, collaborative public health efforts that address environmental, communicable, and non-communicable risk factors. PMID- 27217392 TI - Pro: Meta-analysis: the case for. AB - With ever-accumulating medical evidence for treatment benefits and harms, it is vital that clinicians are able to access and use up-to-date, best evidence in specific clinical scenarios involving individual patients-the primary goal of evidence-based medicine. In this article, we propose that meta-analysis, when properly conducted and reported in the context of a rigorous systematic review, is an indispensable tool for synthesis and interpretation of clinical evidence for the purpose of informing clinical decision-making by clinicians, patients and health care policy makers. Meta-analysis provides many benefits, including enhanced precision and statistical power, greater transparency, identification of bias, exploration of heterogeneity of effects, enhanced generalizability, efficient integration of clinical knowledge, identification of evidence gaps, better informed future trial design and avoidance of unnecessary research duplication and potential patient harm. The overall standard, clinical value and reach of meta-analysis has been further enhanced by the development of standards for registration, conduct and reporting, as well as advanced meta-analytic techniques, such as network meta-analysis. Of course, meta-analysis can at times be limited by poor quality studies, trial heterogeneity, publication bias and non rigorous review and analysis, although through appraisal these issues are often able to be identified and explored, such that valuable clinical information can still be obtained. Consequently, meta-analysis is now the most highly cited form of research and is considered by many leading organizations to represent the highest level of clinical evidence. However, to maximize their considerable value, it is essential that all clinicians have the skills to critically appraise, carefully interpret and judiciously apply meta-analyses in their practice. PMID- 27217393 TI - Opponent's comments. PMID- 27217394 TI - Con: Meta-analysis: some key limitations and potential solutions. AB - Meta-analysis, a statistical combination of results of several trials to produce a summary effect, has been subject to criticism in the past, mainly for the reasons of poor quality of included studies, heterogeneity between studies meta analyzed and failing to address publication bias. These limitations can cause the results to be misleading, which is important if policy and practice decisions are based on systematic reviews and meta-analyses. We elaborate on these limitations and illustrate them with examples from the nephrology literature. Finally, we present some potential solutions, notably, education in meta-analysis for evidence producers and consumers as well as the use of individual patient data for meta-analyses. PMID- 27217395 TI - Opponent's comments. PMID- 27217396 TI - Moderator's view: Meta-analysis: the best knowledge but not always shining gold. AB - Meta-analysis has gained top status in medicine. Correctly so, well-performed meta-analysis is perceived as an unbeatable method for distilling first class medical knowledge. However, such a high status should in no way be considered as a guarantee that all information derived from meta-analyses is pure gold. Systematic reviews and meta-analyses not performed with due methodological attention abound and nephrology is not at all a protected territory. Herein I give concrete examples of meta-analyses published in major journals whose findings are not pure gold. PMID- 27217398 TI - Protective Roles of Endothelial AMP-Activated Protein Kinase Against Hypoxia Induced Pulmonary Hypertension in Mice. AB - RATIONALE: Endothelial AMP-activated protein kinase (AMPK) plays an important role for vascular homeostasis, and its role is impaired by vascular inflammation. However, the role of endothelial AMPK in the pathogenesis of pulmonary arterial hypertension (PAH) remains to be elucidated. OBJECTIVE: To determine the role of endothelial AMPK in the development of PAH. METHODS AND RESULTS: Immunostaining showed that endothelial AMPK is downregulated in the pulmonary arteries of patients with PAH and hypoxia mouse model of pulmonary hypertension (PH). To elucidate the role of endothelial AMPK in PH, we used endothelial-specific AMPK knockout mice (eAMPK(-/-)), which were exposed to hypoxia. Under normoxic condition, eAMPK(-/-) mice showed the normal morphology of pulmonary arteries compared with littermate controls (eAMPK(flox/flox)). In contrast, development of hypoxia-induced PH was accelerated in eAMPK(-/-) mice compared with controls. Furthermore, the exacerbation of PH in eAMPK(-/-) mice was accompanied by reduced endothelial function, upregulation of growth factors, and increased proliferation of pulmonary artery smooth muscle cells. Importantly, conditioned medium from endothelial cells promoted pulmonary artery smooth muscle cell proliferation, which was further enhanced by the treatment with AMPK inhibitor. Serum levels of inflammatory cytokines, including tumor necrosis factor-alpha and interferon gamma were significantly increased in patients with PAH compared with healthy controls. Consistently, endothelial AMPK and cell proliferation were significantly reduced by the treatment with serum from patients with PAH compared with controls. Importantly, long-term treatment with metformin, an AMPK activator, significantly attenuated hypoxia-induced PH in mice. CONCLUSIONS: These results indicate that endothelial AMPK is a novel therapeutic target for the treatment of PAH. PMID- 27217400 TI - Unlocking the Therapeutic Potential of Apelin. PMID- 27217399 TI - Constitutive Expression of a Dominant-Negative TGF-beta Type II Receptor in the Posterior Left Atrium Leads to Beneficial Remodeling of Atrial Fibrillation Substrate. AB - RATIONALE: Fibrosis is an important structural contributor to formation of atrial fibrillation (AF) substrate in heart failure. Transforming growth factor-beta (TGF-beta) signaling is thought to be intricately involved in creation of atrial fibrosis. OBJECTIVE: We hypothesized that gene-based expression of dominant negative type II TGF-beta receptor (TGF-beta-RII-DN) in the posterior left atrium in a canine heart failure model will sufficiently attenuate fibrosis-induced changes in atrial conduction and restitution to decrease AF. Because AF electrograms are thought to reflect AF substrate, we further hypothesized that TGF-beta-RII-DN would lead to increased fractionation and decreased organization of AF electrograms. METHODS AND RESULTS: Twenty-one dogs underwent injection+electroporation in the posterior left atrium of plasmid expressing a dominant-negative TGF-beta type II receptor (pUBc-TGFbeta-DN-RII; n=9) or control vector (pUBc-LacZ; n=12), followed by 3 to 4 weeks of right ventricular tachypacing (240 bpm). Compared with controls, dogs treated with pUBC-TGFbeta-DN RII demonstrated an attenuated increase in conduction inhomogeneity, flattening of restitution slope and decreased duration of induced AF, with AF electrograms being more fractionated and less organized in pUBc-TGFbeta-DN-RII versus pUBc LacZ dogs. Tissue analysis revealed a significant decrease in replacement/interstitial fibrosis, p-SMAD2/3 and p-ERK1/2. CONCLUSIONS: Targeted gene-based reduction of TGF-beta signaling in the posterior left atrium-with resulting decrease in replacement fibrosis-led to beneficial remodeling of both conduction and restitution characteristics of the posterior left atrium, translating into a decrease in AF and increased complexity of AF electrograms. In addition to providing mechanistic insights, this data may have important diagnostic and therapeutic implications for AF. PMID- 27217401 TI - Visit-to-Visit Variability in Blood Pressure Is Related to Late-Life Cognitive Decline. AB - The association between visit-to-visit variability of blood pressure (BP) and cognitive decline over time remains incompletely understood in a general population of older adults. We assessed the hypothesis that higher visit-to-visit variability in BP, but not mean BP, would be associated with faster decline in cognitive function among community-dwelling older adults. This prospective cohort study comprised 976 adults who had 3 or 4 visits with BP measurements as part of the China Health and Nutrition Survey from 1991, up to their first cognitive tests, and completed cognitive screening tests at >=2 visits in 1997, 2000, or 2004. Visit-to-visit BP variability was expressed as the SD, coefficient of variation, or as the variation independent of mean BP across visits conducted at a mean interval of 3.2 years. Mean (SD) age at the first cognitive test was 64 (6) years. Using multivariable-adjusted linear mixed-effects models, we found higher visit-to-visit variability in systolic BP, but not mean systolic BP, was associated with a faster decline of cognitive function (adjusted mean difference [95% confidence interval] for high versus low tertile of SD variability: standardized composite scores -0.038 standard units (SU)/y [-0.066 to -0.009] and verbal memory -0.041 SU/y [-0.075 to -0.008]). Higher visit-to-visit variability in diastolic BP was associated with a faster decline of cognitive function, independent of mean diastolic BP, among adults aged 55 to 64 years but not those >=65 years. Our results suggest that higher long-term BP visit-to-visit variability is associated with a faster rate of cognitive decline among older adults. PMID- 27217402 TI - Angiotensin-Converting Enzyme 2 Metabolizes and Partially Inactivates Pyr-Apelin 13 and Apelin-17: Physiological Effects in the Cardiovascular System. AB - Apelin peptides mediate beneficial effects on the cardiovascular system and are being targeted as potential new drugs. However, apelin peptides have extremely short biological half-lives, and improved understanding of apelin peptide metabolism may lead to the discovery of biologically stable analogues with therapeutic potential. We examined the ability of angiotensin-converting enzyme 2 (ACE2) to cleave and inactivate pyr-apelin 13 and apelin 17, the dominant apelin peptides. Computer-assisted modeling shows a conserved binding of pyr-apelin 13 and apelin 17 to the ACE2 catalytic site. In ACE2 knockout mice, hypotensive action of pyr-apelin 13 and apelin 17 was potentiated, with a corresponding greater elevation in plasma apelin levels. Similarly, pharmacological inhibition of ACE2 potentiated the vasodepressor action of apelin peptides. Biochemical analysis confirmed that recombinant human ACE2 can cleave pyr-apelin 13 and apelin 17 efficiently, and apelin peptides are degraded slower in ACE2-deficient plasma. The biological relevance of ACE2-mediated proteolytic processing of apelin peptides was further supported by the reduced potency of pyr-apelin 12 and apelin 16 on the activation of signaling pathways and nitric oxide production from endothelial cells. Importantly, although pyr-apelin 13 and apelin 17 rescued contractile function in a myocardial ischemia-reperfusion model, ACE2 cleavage products, pyr-apelin 12 and 16, were devoid of these cardioprotective effects. We designed and synthesized active apelin analogues that were resistant to ACE2 mediated degradation, thereby confirming that stable apelin analogues can be designed as potential drugs. We conclude that ACE2 represents a major negative regulator of apelin action in the vasculature and heart. PMID- 27217404 TI - G-Protein-Coupled Receptor MrgD Is a Receptor for Angiotensin-(1-7) Involving Adenylyl Cyclase, cAMP, and Phosphokinase A. AB - Angiotensin (Ang)-(1-7) has cardiovascular protective effects and is the opponent of the often detrimental Ang II within the renin-angiotensin system. Although it is well accepted that the G-protein-coupled receptor Mas is a receptor for the heptapeptide, the lack in knowing initial signaling molecules stimulated by Ang (1-7) prevented definitive characterization of ligand/receptor pharmacology as well as identification of further hypothesized receptors for the heptapeptide. The study aimed to identify a second messenger stimulated by Ang-(1-7) allowing confirmation as well as discovery of the heptapeptide's receptors. Ang-(1-7) elevates cAMP concentration in primary cells, such as endothelial or mesangial cells. Using cAMP as readout in receptor-transfected human embryonic kidney (HEK293) cells, we provided pharmacological proof that Mas is a functional receptor for Ang-(1-7). Moreover, we identified the G-protein-coupled receptor MrgD as a second receptor for Ang-(1-7). Consequently, the heptapeptide failed to increase cAMP concentration in primary mesangial cells with genetic deficiency in both Mas and MrgD Mice deficient in MrgD showed an impaired hemodynamic response after Ang-(1-7) administration. Furthermore, we excluded the Ang II type 2 receptor as a receptor for the heptapeptide but discovered that the Ang II type 2 blocker PD123319 can also block Mas and MrgD receptors. Our results lead to an expansion and partial revision of the renin-angiotensin system, by identifying a second receptor for Ang-(1-7), by excluding Ang II type 2 as a receptor for the heptapeptide, and by enforcing the revisit of such publications which concluded Ang II type 2 function by only using PD123319. PMID- 27217405 TI - Vascular Mineralocorticoid Receptors: Linking Risk Factors, Hypertension, and Heart Disease. PMID- 27217403 TI - Activation of Human T Cells in Hypertension: Studies of Humanized Mice and Hypertensive Humans. AB - Emerging evidence supports an important role for T cells in the genesis of hypertension. Because this work has predominantly been performed in experimental animals, we sought to determine whether human T cells are activated in hypertension. We used a humanized mouse model in which the murine immune system is replaced by the human immune system. Angiotensin II increased systolic pressure to 162 versus 116 mm Hg for sham-treated animals. Flow cytometry of thoracic lymph nodes, thoracic aorta, and kidney revealed increased infiltration of human leukocytes (CD45(+)) and T lymphocytes (CD3(+) and CD4(+)) in response to angiotensin II infusion. Interestingly, there was also an increase in the memory T cells (CD3(+)/CD45RO(+)) in the aortas and lymph nodes. Prevention of hypertension using hydralazine and hydrochlorothiazide prevented the accumulation of T cells in these tissues. Studies of isolated human T cells and monocytes indicated that angiotensin II had no direct effect on cytokine production by T cells or the ability of dendritic cells to drive T-cell proliferation. We also observed an increase in circulating interleukin-17A producing CD4(+) T cells and both CD4(+) and CD8(+) T cells that produce interferon-gamma in hypertensive compared with normotensive humans. Thus, human T cells become activated and invade critical end-organ tissues in response to hypertension in a humanized mouse model. This response likely reflects the hypertensive milieu encountered in vivo and is not a direct effect of the hormone angiotensin II. PMID- 27217406 TI - Blood Pressure-Related Outcomes in a Diabetic Population. PMID- 27217407 TI - Longitudinal Patterns of Blood Pressure, Incident Cardiovascular Events, and All Cause Mortality in Normotensive Diabetic People. AB - Lower blood pressure (BP) within the normotensive range has been suggested to be deleterious in diabetic people using antihypertensive drugs. We hypothesized that BP <120/80 mm Hg and BP trajectories may predict further risk of all-cause mortality or cardiovascular events in normotensive diabetic individuals. We included 3159 diabetic adults, free of hypertension, atherosclerotic cardiovascular diseases, or cancer in 2006 (baseline), from a community-based cohort including 101 510 participants. A total of 831 participants with BP <120/80 mm Hg and 2328 participants with BP of 120 to 139/80 to 89 mm Hg were included. BP and other clinical covariates were repeatedly measured every 2 years. During 7 years of follow-up, we documented 247 deaths and 177 cardiovascular events. Diabetic people with BP <120/80 mm Hg had a 46% increased risk of all-cause mortality (95% confidence interval, 10%-93%) compared with those with BP of 120 to 139/80 to 89 mm Hg at baseline. We then estimated the association between BP trajectories from 2006 to 2008 and adverse events among 2311 diabetic people who had both BP measures at 2006 and 2008. Relative to stable BP of 120 to 139/80 to 89 mm Hg, having persistently BP <120/80 mm Hg (hazard ratio: 2.35; 95% confidence interval, 1.10-5.01) or a spontaneous decrease in BP from 120 to 139/80 to 89 to <120/80 mm Hg (hazard ratio: 3.04; 95% confidence interval, 1.56-5.92) was significantly associated with an increased risk of all-cause mortality during 2008 to 2014. A rise in BP from 120 to 139/80 to 89 to >=140/90 mm Hg conferred a high risk of cardiovascular events (hazard ratio: 1.98; 95% confidence interval, 1.24-3.17). In normotensive diabetic people having a low BP or a decline in BP was both associated with an increased risk of all-cause mortality, whereas development of incident hypertension increased the risk of cardiovascular events. PMID- 27217408 TI - Will Exercise Advice Be Sufficient for Treatment of Young Adults With Prehypertension and Hypertension? A Systematic Review and Meta-Analysis. AB - Previous studies report benefits of exercise for blood pressure control in middle age and older adults, but longer-term effectiveness in younger adults is not well established. We performed a systematic review and meta-analysis of published randomized control trials with meta-regression of potential effect modifiers. An information specialist completed a comprehensive search of available data sources, including studies published up to June 2015. Authors applied strict inclusion and exclusion criteria to screen 9524 titles. Eligible studies recruited younger adults with a cardiovascular risk factor (with at least 25% of cohort aged 18-40 years); the intervention had a defined physical activity strategy and reported blood pressure as primary or secondary outcome. Meta analysis included 14 studies randomizing 3614 participants, mean age 42.2+/-6.3 (SD) years. At 3 to 6 months, exercise was associated with a reduction in systolic blood pressure of -4.40 mm Hg (95% confidence interval, -5.78 to -3.01) and in diastolic blood pressure of -4.17 mm Hg (95% confidence interval, -5.42 to -2.93). Intervention effect was not significantly influenced by baseline blood pressure, body weight, or subsequent weight loss. Observed intervention effect was lost after 12 months of follow-up with no reported benefit over control, mean difference in systolic blood pressure -1.02 mm Hg (95% confidence interval, -2.34 to 0.29), and in diastolic blood pressure -0.91 mm Hg (95% confidence interval, 1.85 to 0.02). Current exercise guidance provided to reduce blood pressure in younger adults is unlikely to benefit long-term cardiovascular risk. There is need for continued research to improve age-specific strategies and recommendations for hypertension prevention and management in young adults. PMID- 27217409 TI - Visit-to-Visit Blood Pressure Variability: An Insight Into the Mechanisms. PMID- 27217411 TI - Plasma Molecular Signatures in Hypertensive Patients With Renin-Angiotensin System Suppression: New Predictors of Renal Damage and De Novo Albuminuria Indicators. AB - Albuminuria is a risk factor strongly associated with cardiovascular disease, the first cause of death in the general population. It is well established that renin angiotensin system suppressors prevent the development of new-onset albuminuria in naif hypertensive patients and diminish its excretion, but we cannot forget the percentage of hypertensive patients who develop de novo albuminuria. Here, we applied multiple proteomic strategy with the purpose to elucidate specific molecular pathways involved in the pathogenesis and provide predictors and chronic organ damage indicators. Briefly, 1143 patients were followed up for a minimum period of 3 years. One hundred and twenty-nine hypertensive patients chronically renin-angiotensin system suppressed were recruited, classified in 3 different groups depending on their albuminuria levels (normoalbuminuria, de novo albuminuria, and sustained albuminuria), and investigated by multiple proteomic strategies. Our strategy allowed us to perform one of the deepest plasma proteomic analysis to date, which has shown 2 proteomic signatures: (1) with predictive value of de novo albuminuria and (2) sustained albuminuria indicator proteins. These proteins are involved in inflammation, immune as well as in the proteasome activation occurring in situations of endoplasmic reticulum stress. Furthermore, these results open the possibility of a future strategy based on anti-immune therapy to treat hypertension which could help to prevent the development of albuminuria and, hence, the progression of kidney damage. PMID- 27217410 TI - The Association Between Antihypertensive Medication Nonadherence and Visit-to Visit Variability of Blood Pressure: Findings From the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial. AB - Low adherence to antihypertensive medication has been hypothesized to increase visit-to-visit variability (VVV) of blood pressure (BP). We assessed the association between antihypertensive medication adherence and VVV of BP in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). VVV of BP was calculated using SD independent of mean, SD, and average real variability across study visits conducted 6 to 28 months after randomization. Participants who reported taking <80% of their antihypertensive medication at >=1 study visits were categorized as nonadherent. Participants were followed up for cardiovascular events and mortality after the assessment of adherence and VVV of BP. SD independent of mean of BP was higher for nonadherent (n=2912) versus adherent (n=16 878) participants; 11.4+/-4.9 versus 10.5+/-4.5 for systolic BP; 6.8+/-2.8 versus 6.2+/-2.6 for diastolic BP (each P<0.001). SD independent of mean of BP remained higher among nonadherent than among adherent participants after multivariable adjustment (0.8 [95% confidence interval, 0.7 1.0] higher for systolic BP and 0.4 [95% confidence interval, 0.3-0.5] higher for diastolic BP]. SD and average real variability of systolic BP and diastolic BP were also higher among nonadherent than among adherent participants. Adjustment for nonadherence did not explain the association of VVV of BP with higher fatal coronary heart disease or nonfatal myocardial infarction, stroke, heart failure, or mortality risk. In conclusion, improving medication adherence may lower VVV of BP. However, VVV of BP is associated with cardiovascular outcomes independent of medication adherence. PMID- 27217413 TI - Pilot Study of Blood Pressure in Girls With Turner Syndrome: An Awareness Gap, Clinical Associations, and New Hypotheses. AB - Cardiovascular disease is the major factor that reduces lifespan in Turner syndrome. High blood pressure (BP) is common in Turner syndrome and is the most easily treatable cardiovascular risk factor. We studied the prevalence of elevated screening systemic BP, awareness of the problem, and its clinical associations in a large group of girls attending the annual meeting of the Turner Syndrome Society of the United States. Among 168 girls aged 2 to 17 years, 42% had elevated screening BP (systolic and diastolic), yet only 8% reported a previous diagnosis of hypertension. History of aortic coarctation repair (17%) was positively associated with elevated systolic BP (52% versus 32%; P<0.05). Elevated systolic BP was positively associated with obesity (56% versus 31%; P<0.05). Because the prevalence of obesity in the studied population was similar to Center for Disease Control published data for obesity in all girls and the prevalence of increased BP is approximately twice that of the general population, the Turner syndrome phenotype/genotype probably includes an intrinsic risk for hypertension. Obesity and repaired aortic coarctation increase this risk further. There seems to be a BP awareness gap in girls with Turner syndrome. Because girls living with Turner syndrome are a sensitized population for hypertension, further study may provide clues to genetic factors leading to a better understanding of essential hypertension in the general population. PMID- 27217412 TI - Independent and Joint Effect of Brachial-Ankle Pulse Wave Velocity and Blood Pressure Control on Incident Stroke in Hypertensive Adults. AB - Pulse wave velocity (PWV) has been shown to influence the effects of antihypertensive drugs in the prevention of cardiovascular diseases. Data are limited on whether PWV is an independent predictor of stroke above and beyond hypertension control. This longitudinal analysis examined the independent and joint effect of brachial-ankle PWV (baPWV) with hypertension control on the risk of first stroke. This report included 3310 hypertensive adults, a subset of the China Stroke Primary Prevention Trial (CSPPT) with baseline measurements for baPWV. During a median follow-up of 4.5 years, 111 participants developed first stroke. The risk of stroke was higher among participants with baPWV in the highest quartile than among those in the lower quartiles (6.3% versus 2.4%; hazard ratio, 1.66; 95% confidence interval, 1.06-2.60). Similarly, the participants with inadequate hypertension control had a higher risk of stroke than those with adequate control (5.1% versus 1.8%; hazard ratio, 2.32; 95% confidence interval, 1.49-3.61). When baPWV and hypertension control were examined jointly, participants in the highest baPWV quartile and with inadequate hypertension control had the highest risk of stroke compared with their counterparts (7.5% versus 1.3%; hazard ratio, 3.57; 95% confidence interval, 1.88 6.77). There was a significant and independent effect of high baPWV on stroke as shown among participants with adequate hypertension control (4.2% versus 1.3%; hazard ratio, 2.29, 95% confidence interval, 1.09-4.81). In summary, among hypertensive patients, baPWV and hypertension control were found to independently and jointly affect the risk of first stroke. Participants with high baPWV and inadequate hypertension control had the highest risk of stroke compared with other groups. PMID- 27217415 TI - Psychometric Evaluation of the Spiritual Coping Strategies Scale Arabic Version for Saudi Nursing Students. AB - AIM: To evaluate the psychometric properties of the Spiritual Coping Strategies scale Arabic version (SCS-A) in a sample of nursing students in Saudi Arabia. METHOD: This study had a cross-sectional design with a convenience sample of 100 nursing students in Saudi Arabia. Using the SCS-A and the Muslim Religiosity Scale for data collection, data were analyzed to establish the reliability and validity of the SCS-A. FINDINGS: Good internal consistency reliability (Cronbach's alpha > .70) and stability reliability (intraclass correlation coefficient > .80) were observed. Two dominant factors were extracted from the scale items, the nonreligious coping strategies and religious coping strategies, which accounted for 35.5% and 32.7% of the variance, respectively. The religious coping subscale exhibited a strong positive correlation with the religious practices subscale of the Muslim Religious Involvement Scale (r = .45, p < .001) and total religiosity score (r = .48, p < .001) as well as a weak positive correlation with the intrinsic religious beliefs subscale (r = .25, p < .05). No significant relationship was found between nonreligious coping subscale and the Muslim Religious Involvement Scale. CONCLUSION: The SCS-A exhibited an acceptable validity and reliability, supporting its sound psychometric properties with respect to the responses from Saudi nursing students. PMID- 27217414 TI - Telling Tails: Very High Plasma Renin Levels Prompt the Diagnosis of Renal Artery Stenosis, Despite Initial Negative Imaging. PMID- 27217416 TI - An Opportunity for Healing and Holistic Care: Exploring the Roles of Health Care Providers Working Within Northern Canadian Aboriginal Communities. AB - PURPOSE: The purpose of this qualitative study was exploring what the roles and challenges of health care providers working within Northern Canadian Aboriginal communities are and what resources can help support or impede their efforts in working toward addressing health inequities within these communities. DESIGN: The qualitative research conducted was influenced by a postcolonial epistemology. The works of theorists Fanon on colonization and racial construction, Kristeva on semiotics and abjection, and Foucault on power/knowledge, governmentality, and biopower were used in providing a theoretical framework. METHODS: Critical discourse analysis of 25 semistructured interviews with health care providers was used to gain a better understanding of their roles and challenges while working within Northern Canadian Aboriginal communities. FINDINGS: Within this research study, three significant findings emerged from the data. First, the Aboriginal person's identity was constructed in relation to the health care provider's role of delivering essential health services. Second, health care providers were not treating the "ill" patient, but rather treating the patient for being "ill." Third, health care providers were treating the Aboriginal person for being "Aboriginal" by separating the patient from his or her identity. The treatment involved reforming the Aboriginal patient from the condition of being "Aboriginal." PMID- 27217417 TI - Calprotectin is a potential prognostic marker for polycystic ovary syndrome. AB - Background Calprotectin is an antimicrobial, calcium and zinc-binding heterocomplex protein and has been proposed as a marker to rule out inflammatory conditions. The aim of this study was to evaluate the role of calprotectin in the diagnosis of polycystic ovary syndrome and to investigate the association between calprotectin and insulin resistance. Methods A total of 41 females with polycystic ovary syndrome and 54 age-matched without polycystic ovary syndrome were eligible for the study. Serum concentration of calprotectin was determined using enzyme-linked immunosorbent assay. Clinical characteristics, hormone and metabolic parameters were evaluated in each subject. The predictive value of serum calprotectin was assessed using receiver operating characteristic curves. Correlations between the serum calprotectin concentrations and insulin resistance were examined using Spearman's correlation. Results We found that the serum calprotectin concentrations were significantly higher in polycystic ovary syndrome compared with the non-polycystic ovary syndrome group ( P < 0.001). The area under the receiver operating characteristic curve assay yielded a satisfactory result of 0.88 (95% confidence interval 0.81-0.95; P < 0.001). The optimum cut-off was 2.4 ug/mL with a 85.2% specificity and 75.6% sensitivity for polycystic ovary syndrome diagnosis. A significant positive correlation was found between the serum calprotectin and insulin resistance. Conclusions These results suggest that calprotectin might be a useful adjunct in the diagnosis of polycystic ovary syndrome, especially those with insulin resistance. PMID- 27217418 TI - Hepatic arterial damage after transarterial chemoembolization for the treatment of hepatocellular carcinoma: comparison of drug-eluting bead and conventional chemoembolization in a retrospective controlled study. AB - Background Transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) frequently causes feeding artery stenosis or occlusion that may interfere with repeated treatment. Purpose To investigate the incidence and predictors of hepatic arterial damage (HAD) after drug-eluting bead-TACE (DEB-TACE) in comparison with conventional TACE (Conv-TACE). Material and Methods We retrospectively analyzed 54 patients who underwent DEB-TACE for HCC as an initial treatment with follow-up angiography and 54 patients who underwent Conv-TACE using doxorubicin-lipiodol mixture and gelfoam particles for comparison. HAD was evaluated after a single session of TACE and graded as follows: grade I, no significant wall irregularity; grade II, overt stenosis; grade III, occlusion. Results The incidence of HAD was significantly higher in the DEB-TACE group than the Conv-TACE group when analyzed per branch (odds ratio [OR], 6.36; P < 0.001) and per patient (OR, 3.15; P = 0.005). For each HAD grade, the mean doxorubicin dose was greater in the DEB-TACE group than in the Conv-TACE group ( P < 0.001, P = 0.053, and P = 0.01 for grades I, II, and III, respectively). In multivariate analysis, risk factors of HAD included mean doxorubicin dose and selective embolization in the Conv-TACE group ( P = 0.03 and P < 0.001, respectively) and mean doxorubicin dose in the DEB-TACE group ( P = 0.004). Conclusion The incidence and grade of HAD were higher after DEB-TACE compared to Conv-TACE with doxorubicin dose as a possible risk factor. HAD was independent of overall survival in both groups. PMID- 27217419 TI - HtrA Is Important for Stress Resistance and Virulence in Haemophilus parasuis. AB - Haemophilus parasuis is an opportunistic pathogen that causes Glasser's disease in swine, with polyserositis, meningitis, and arthritis. The high-temperature requirement A (HtrA)-like protease, which is involved in protein quality control, has been reported to be a virulence factor in many pathogens. In this study, we showed that HtrA of H. parasuis (HpHtrA) exhibited both chaperone and protease activities. Finally, nickel import ATP-binding protein (NikE), periplasmic dipeptide transport protein (DppA), and outer membrane protein A (OmpA) were identified as proteolytic substrates for HpHtrA. The protease activity reached its maximum at 40 degrees C in a time-dependent manner. Disruption of the htrA gene from strain SC1401 affected tolerance to temperature stress and resistance to complement-mediated killing. Furthermore, increased autoagglutination and biofilm formation were detected in the htrA mutant. In addition, the htrA mutant was significantly attenuated in virulence in the murine model of infection. Together, these data demonstrate that HpHtrA plays an important role in the virulence of H. parasuis. PMID- 27217420 TI - Purification of Plasmodium Sporozoites Enhances Parasite-Specific CD8+ T Cell Responses. AB - Malaria infection caused by Plasmodium parasites continues to cause enormous morbidity and mortality in areas where it is endemic, and there is no licensed vaccine capable of inducing sterile protection. Hyperimmunization with attenuated whole sporozoites can induce sterile protective immune responses targeting preerythrocytic antigens. Most animal models of hyperimmunization rely on sporozoites dissected from mosquito salivary glands and injected without further purification. In BALB/c mice, repeated small doses of P. yoelii sporozoites progressively expand the population of sporozoite-specific CD8(+) T cells. In this study, large secondary doses of unpurified sporozoites unexpectedly led to contraction of sporozoite-specific CD8(+) T cell responses in sporozoite-primed mice. While sporozoite-primed CD8(+) T cells alternatively can be expanded by secondary exposure to Listeria monocytogenes expressing recombinant Plasmodium antigens, such expansion was potently inhibited by coinjection of large doses of unpurified sporozoites and by uninfected salivary glands alone. Purification of sporozoites away from mosquito salivary gland debris by density gradient centrifugation eliminated salivary gland-associated inhibition. Thus, the inhibitory effect appears to be due to exposure to uninfected mosquito salivary glands rather than sporozoites. To further assess the effect of salivary gland exposure on later sporozoite vaccinations, mice were immunized with uninfected salivary glands from a single mosquito. Compared to naive mice, salivary gland presensitization reduced subsequent liver burdens by 71%. These data show that a component(s) in mosquito salivary glands reduces liver infection, thereby limiting antigen dose and contributing to lower-magnitude T cell responses. These findings suggest that sporozoite immunogenicity studies be performed using purified sporozoites whenever feasible. PMID- 27217421 TI - Blastocystis Isolate B Exhibits Multiple Modes of Resistance against Antimicrobial Peptide LL-37. AB - Blastocystis is one of the most common eukaryotic organisms found in humans and many types of animals. Several reports have identified its role in gastrointestinal disorders, although its pathogenicity is yet to be clarified. Blastocystis is transmitted via the fecal-to-oral route and colonizes the large intestines. Epithelial cells lining the intestine secrete antimicrobial peptides (AMPs), including beta-defensins and cathelicidin, as a response to infection. This study explores the effects of host colonic antimicrobial peptides, particularly LL-37, a fragment of cathelicidin, on different Blastocystis subtypes. Blastocystis is composed of several subtypes that have genetic, metabolic, and biological differences. These subtypes also have various outcomes in terms of drug treatment and immune response. In this study, Blastocystis isolates from three different subtypes were found to induce intestinal epithelial cells to secrete LL-37. We also show that among the antimicrobial peptides tested, only LL-37 has broad activity on all the subtypes. LL-37 causes membrane disruption and causes Blastocystis to change shape. Blastocystis subtype 7 (ST7), however, showed relative resistance to LL-37. An isolate, ST7 isolate B (ST7-B), from this subtype releases proteases that can degrade the peptide. It also makes the environment acidic, which causes attenuation of LL-37 activity. The Blastocystis ST7-B isolate was also observed to have a thicker surface coat, which may protect the parasite from direct killing by LL-37. This study determined the effects of LL-37 on different Blastocystis isolates and indicates that AMPs have significant roles in Blastocystis infections. PMID- 27217423 TI - Symptoms, Quality of Life, and Daily Activities in People With Newly Diagnosed Solid Tumors Presenting to a Medical Oncologist. AB - INTRODUCTION: Symptom and Quality of Life (QOL) data are important patient reported outcomes. Early identification of these is critical for appropriate interventions. Data collection may be helped by modern information technology. AIM: This study examined symptoms and QOL in people with solid tumors at their first visit to a medical oncologist. We also evaluated the clinical utility of tablet computers (TC) to collect this data. METHODS: This was a prospective study of 105 consecutive patients in the cancer outpatient clinic of a tertiary level academic medical center. Symptom and QOL data was collected by TC with wireless database upload. RESULTS: One-third participants had moderate to severe pain; almost half clinically significant pain that interfered with daily activities. Tiredness, anxiety, and drowsiness were common (prevalence - 79%, 63% and 50% respectively). One-third of those who had items identified from the Edmonton System Assessment System also volunteered other symptoms, mostly gastrointestinal problems. Many of those affected also reported impaired Global Wellbeing and low Overall QOL. There was a 98% completion rate, which took on average ten minutes. Direct observation and informal feedback from patients and physicians regarding the acceptability of TC in this setting was uniformly positive. CONCLUSIONS: Amongst people with newly diagnosed solid tumors clinically important psychological and physical symptoms, QOL problems and difficulties with daily activities were commonly present in the 24-hour period and in the week before a first Medical Oncology visit. Symptom and QOL data collection by TC in busy outpatient clinics showed good clinical utility. PMID- 27217424 TI - Severe mitral regurgitation due to an extraordinary heart defect. AB - A previously non-described cause of mitral regurgitation is presented. An asymptomatic 50-year old male who was casually diagnosed of mitral valve Barlow's disease underwent cardiac surgery due to severe mitral regurgitation. In the operating theatre, a longitudinal fissure of 1.5-2.0 cm length, along the posterior mitral leaflet, was found responsible for the insufficiency. This defect had features of a potential congenital origin and it was successfully repaired with direct suture. Whether it is an atypical mitral cleft, a variation of Barlow's morphology spectrum or a new congenital heart defect remains unclear. PMID- 27217425 TI - Preventing violence in schizophrenia: Why do delusional familiarity disorders remain so unfamiliar? PMID- 27217422 TI - Distribution and Evolution of Yersinia Leucine-Rich Repeat Proteins. AB - Leucine-rich repeat (LRR) proteins are widely distributed in bacteria, playing important roles in various protein-protein interaction processes. In Yersinia, the well-characterized type III secreted effector YopM also belongs to the LRR protein family and is encoded by virulence plasmids. However, little has been known about other LRR members encoded by Yersinia genomes or their evolution. In this study, the Yersinia LRR proteins were comprehensively screened, categorized, and compared. The LRR proteins encoded by chromosomes (LRR1 proteins) appeared to be more similar to each other and different from those encoded by plasmids (LRR2 proteins) with regard to repeat-unit length, amino acid composition profile, and gene expression regulation circuits. LRR1 proteins were also different from LRR2 proteins in that the LRR1 proteins contained an E3 ligase domain (NEL domain) in the C-terminal region or an NEL domain-encoding nucleotide relic in flanking genomic sequences. The LRR1 protein-encoding genes (LRR1 genes) varied dramatically and were categorized into 4 subgroups (a to d), with the LRR1a to -c genes evolving from the same ancestor and LRR1d genes evolving from another ancestor. The consensus and ancestor repeat-unit sequences were inferred for different LRR1 protein subgroups by use of a maximum parsimony modeling strategy. Structural modeling disclosed very similar repeat-unit structures between LRR1 and LRR2 proteins despite the different unit lengths and amino acid compositions. Structural constraints may serve as the driving force to explain the observed mutations in the LRR regions. This study suggests that there may be functional variation and lays the foundation for future experiments investigating the functions of the chromosomally encoded LRR proteins of Yersinia. PMID- 27217426 TI - Nissen Fundoplication for Laryngopharyngeal Reflux After Patient Selection Using Dual pH, Full Column Impedance Testing: A Pilot Study. AB - OBJECTIVES: Prior studies demonstrate inconsistent diagnostic strategies for laryngopharyngeal reflux disease (LPR) patients who are offered laparoscopic Nissen fundoplication (Nissen). Superior symptom resolution outcomes are demonstrated in patients with accompanying typical gastroesophageal reflux (GERD) symptoms. This study aims to evaluate the efficacy of selecting patients with LPR complaints for Nissen using full column, dual pH impedance catheters (multichannel intraluminal impedance catheters [MII]). METHODS: All patients who underwent Nissen for management of LPR symptoms refractory to at least 3 months of twice daily (BID) proton pump inhibitor (PPI) therapy with reflux symptom index (RSI) of 13 or higher and who had demonstrable reflux on MII were included. Pre- and (minimum) 16 week post-Nissen RSI scores as well as LPR-specific complaints were collected. RESULTS: Eleven patients met criteria. Nine subjects (5 female, 4 male) had complete data. All 9 (100%) achieved improvement in RSI. The average pre-Nissen RSI was 31.7, and average post-Nissen RSI was 10 (P < .001). Six (67%) subjects dropped below an RSI of 13. Seven subjects (78%) had resolution of their primary LPR symptom, and 6 (67%) subjects had resolution of all LPR symptoms. CONCLUSIONS: Patients with LPR who are selected using dual pH and full column impedance are likely to demonstrate improvement in RSI following Nissen. PMID- 27217427 TI - Antiretroviral Therapy Initiation Following Policy Changes: Observations From China. AB - China's HIV/AIDS treatment policies have been evolving over the preceding decade. This study describes patterns of antiretroviral therapy (ART) initiation for a sample of people living with HIV/AIDS (PLHIV) in rural Anhui, China, where most PLHIV were infected via paid plasma donation during the 1990s. A total of 481 PLHIV who were receiving ART were included in our analyses. Times between HIV diagnosis and the initiation of ART were examined relative to the time points when major ART-related policies changed in China. More than half (53%) of PLHIV who had been diagnosed by 2003 received ART within 6 months, whereas 93% of PLHIV who had been diagnosed in 2010 or later received ART within 6 months. The study results provide additional support that the "Four Frees and One Care" policy in 2003 and the relaxation of ART eligibility in 2010 have facilitated the initiation of treatment for PLHIV in China. PMID- 27217428 TI - Passive Smoking and Risk of Colorectal Cancer: A Meta-analysis of Observational Studies. AB - We conducted this meta-analysis to explore the association between passive smoking and the risk of colorectal cancer. A literature search of online databases, including MEDLINE, EMBASE, the Cochrane Library, and Web of Science was performed up to June 30, 2015. A fixed-effects meta-analysis using Stata 12.0 was carried out to estimate the relative risks (RRs) and 95% confidence intervals (CIs) for the associations. Eleven articles, including 6 case-control studies and 6 cohort studies, were included in our analysis according to inclusion and exclusion criteria. The pooled RR of all studies showed a statistically significant association between passive smoking and colorectal cancer (RR = 1.14; 95% CI = 1.05-1.24). Results of subgroup analysis showed a positive association between passive smoking and rectal cancer ((RR = 1.33; 95% CI = 1.15-1.53) and that male passive smokers were at greater risks of colorectal cancer (RR = 1.73; 95% CI = 1.37-2.19) than females. Results suggested that passive smoking is associated with an increased risk of colorectal cancer. PMID- 27217429 TI - Meta-Analysis of the Association Between Whole and Refined Grain Consumption and Stroke Risk Based on Prospective Cohort Studies. AB - The association between whole and refined grain consumption and stroke risk remains unclear. A search using MEDLINE and EMBASE databases was performed through February 29, 2016. Seven prospective studies with a total of 446 451 subjects and 5892 stroke events were included. The summary relative risk (SRR) of stroke for the high versus low consumption was 0.95 (95% confidence interval [CI] = 0.83-1.14) for total grains, 0.92 (95% CI = 0.72-1.17) for whole grains, and 0.99 (95% CI = 0.84-1.16) for refined grains. Diets rich in whole grains were inversely associated with ischemic stroke risk (SRR = 0.75, 95% CI = 0.60-0.95). Our meta-analysis revealed that whole and refined grain consumption is not associated with total stroke risk; however, whole grain consumption is associated with reduced ischemic stroke risk. PMID- 27217430 TI - The German version of the Child Behavior Checklist 1.5-5 to identify children with a risk of autism spectrum disorder. AB - A long delay between the first registered symptoms of autism spectrum disorder and a final diagnosis has been reported. The reasons for this are the spare use of specialized autism instruments, missing clinical expertise, and the late referral to specialized centers in primary care. Previous studies recommending the Child Behavior Checklist 1.5-5 for screening have requested additional research. A total of 183 children aged 25-71 months participated in this study. The Child Behavior Checklist scales of 80 children with autism spectrum disorder were compared with 103 children diagnosed with other psychiatric disorders. In the logistic regression analysis, the Withdrawn and Pervasive Developmental Problems Child Behavior Checklist scales with a significant predictive value of risk for an autism spectrum disorder diagnosis were identified. The optimal cutoff points T = 64.5 on the Pervasive Developmental Problems scale (area under the curve = 0.781, sensitivity = 0.83, specificity = 0.60, positive predictive value = 0.62, negative predictive value = 0.82, odds ratio = 7) and T = 60.5 on the Withdrawn scale (area under the curve = 0.809, sensitivity = 0.88, specificity = 0.63, positive predictive value = 0.65, negative predictive value = 0.87, odds ratio = 12) were evaluated in the receiver operating characteristics analysis. The present study confirms the utility of the German version of the Child Behavior Checklist 1.5-5 as a level 1 screening tool to identify children with a risk of autism spectrum disorder; however, a risk of over-identifying should be considered. The Child Behavior Checklist 1.5-5 can complement the pediatric examination as a quick and cost-effective questionnaire. PMID- 27217431 TI - Requiem for Liberalizing Indications for Vena Caval Filters? PMID- 27217432 TI - Ivabradine: Role in the Chronic Heart Failure Armamentarium. AB - Ivabradine is approved to reduce hospitalizations for patients with symptomatic heart failure, reduced ejection fraction, and persistently elevated heart rate despite otherwise maximal medical therapy. However, the eligible patient population is a small fraction of those with heart failure overall. This review summarizes the major clinical evidence supporting the use of ivabradine, identifies and discusses areas of uncertainty from the clinical trial data, helps describe the population most likely to benefit, and attempts to place ivabradine within the multifaceted treatment scheme currently used for patients with heart failure and reduced ejection fraction. PMID- 27217433 TI - Access to Medications for Cardiovascular Diseases in Low- and Middle-Income Countries. AB - Cardiovascular diseases (CVD) represent the highest burden of disease globally. Medicines are a critical intervention used to prevent and treat CVD. This review describes access to medication for CVD from a health system perspective and strategies that have been used to promote access, including providing medicines at lower cost, improving medication supply, ensuring medicine quality, promoting appropriate use, and managing intellectual property issues. Using key evidence in published and gray literature and systematic reviews, we summarize advances in access to cardiovascular medicines using the 5 health system dimensions of access: availability, affordability, accessibility, acceptability, and quality of medicines. There are multiple barriers to access of CVD medicines, particularly in low- and middle-income countries. Low availability of CVD medicines has been reported in public and private healthcare facilities. When patients lack insurance and pay out of pocket to purchase medicines, medicines can be unaffordable. Accessibility and acceptability are low for medicines used in secondary prevention; increasing use is positively related to country income. Fixed-dose combinations have shown a positive effect on adherence and intermediate outcome measures such as blood pressure and cholesterol. We have a new opportunity to improve access to CVD medicines by using strategies such as efficient procurement of low-cost, quality-assured generic medicines, development of fixed-dose combination medicines, and promotion of adherence through insurance schemes that waive copayment for long-term medications. Monitoring progress at all levels, institutional, regional, national, and international, is vital to identifying gaps in access and implementing adequate policies. PMID- 27217434 TI - Considerations and Recommendations for the Introduction of Objective Performance Criteria for Transcatheter Aortic Heart Valve Device Approval. AB - In the United States, new surgical heart valves can be approved on the basis of objective performance criteria (OPC). In contrast, the US Food and Drug Administration traditionally requires stricter criteria for transcatheter heart valve (THV) approval, including randomized, clinical trials. Recent US Food and Drug Administration approval of new-generation THVs based on single-arm studies has generated interest in alternative study approaches for THV device approval. This review evaluates whether THV device approval could follow a pathway analogous to that of surgical heart valves by incorporating OPC and provides several considerations and recommendations. Factors to be taken into account in the construction of OPC include the maturity of THV technology, variability in transcatheter aortic valve replacement practice, end points included as OPC, follow-up terms for specific OPC, patient populations to which these OPC apply, and (statistical) methods for OPC development. We recommend that approval of THV devices in the United States for low- and intermediate-risk patients or for new indications should provisionally rely on data from randomized, clinical trials. However, it is recommended that formal OPC be applied for approval of new generation THVs for use in high- and extreme-risk patient populations. PMID- 27217435 TI - Individualizing Duration of Dual Antiplatelet Therapy After Acute Coronary Syndrome or Percutaneous Coronary Intervention. PMID- 27217436 TI - Severe Functional Tricuspid Stenosis Secondary to a Giant Saphenous Vein Bypass Graft Aneurysm. PMID- 27217437 TI - Letter by Picard and Ly Regarding Article, "Frequency and Predictors of Internal Mammary Artery Graft Failure and Subsequent Clinical Outcomes: Insights From the Project of Ex-Vivo Vein Graft Engineering via Transfection (PREVENT) IV Trial". PMID- 27217438 TI - Letter by Poullis and Pullan Regarding Article, "Frequency and Predictors of Internal Mammary Artery Graft Failure and Subsequent Clinical Outcomes: Insights From the Project of Ex-Vivo Vein Graft Engineering via Transfection (PREVENT) IV Trial". PMID- 27217439 TI - Response to Letters Regarding Article, "Frequency and Predictors of Internal Mammary Artery Graft Failure and Subsequent Clinical Outcomes: Insights From the Project of Ex-Vivo Vein Graft Engineering via Transfection (PREVENT) IV Trial". PMID- 27217440 TI - BRAF Status in Personalizing Treatment Approaches for Pediatric Gliomas. AB - PURPOSE: Alteration of the BRAF/MEK/MAPK pathway is the hallmark of pediatric low grade gliomas (PLGGs), and mTOR activation has been documented in the majority of these tumors. We investigated combinations of MEK1/2, BRAFV600E and mTOR inhibitors in gliomas carrying specific genetic alterations of the MAPK pathway. EXPERIMENTAL DESIGN: We used human glioma lines containing BRAFV600E (adult high grade: AM-38, DBTRG, PLGG: BT40), or wild-type BRAF (pediatric high-grade: SF188, SF9427, SF8628) and isogenic systems of KIAA1549:BRAF-expressing NIH/3T3 cells and BRAFV600E-expressing murine brain cells. Signaling inhibitors included everolimus (mTOR), PLX4720 (BRAFV600E), and AZD6244 (MEK1/2). Proliferation was determined using ATP-based assays. In vivo inhibitor activities were assessed in the BT40 PLGG xenograft model. RESULTS: In BRAFV600E cells, the three possible doublet combinations of AZD6244, everolimus, and PLX4720 exhibited significantly greater effects on cell viability. In BRAFWT cells, everolimus + AZD6244 was superior compared with respective monotherapies. Similar results were found using isogenic murine cells. In KIAA1549:BRAF cells, MEK1/2 inhibition reduced cell viability and S-phase content, effects that were modestly augmented by mTOR inhibition. In vivo experiments in the BRAFV600E pediatric xenograft model BT40 showed the greatest survival advantage in mice treated with AZD6244 + PLX4720 (P < 0.01). CONCLUSIONS: In BRAFV600E tumors, combination of AZD6244 + PLX4720 is superior to monotherapy and to other combinatorial approaches. In BRAFWT pediatric gliomas, everolimus + AZD6244 is superior to either agent alone. KIAA1549:BRAF-expressing tumors display marked sensitivity to MEK1/2 inhibition. Application of these results to PLGG treatment must be exercised with caution because the dearth of PLGG models necessitated only a single patient-derived PLGG (BT40) in this study. Clin Cancer Res; 22(21); 5312-21. (c)2016 AACR. PMID- 27217441 TI - Anti-EGFR Targeted Monoclonal Antibody Isotype Influences Antitumor Cellular Immunity in Head and Neck Cancer Patients. AB - PURPOSE: EGF receptor (EGFR) is highly overexpressed on several cancers and two targeted anti-EGFR antibodies which differ by isotype are FDA-approved for clinical use. Cetuximab (IgG1 isotype) inhibits downstream signaling of EGFR and activates antitumor, cellular immune mechanisms. As panitumumab (IgG2 isotype) may inhibit downstream EGFR signaling similar to cetuximab, it might also induce adaptive immunity. EXPERIMENTAL DESIGN: We measured in vitro activation of cellular components of the innate and adaptive immune systems. We also studied the in vivo activation of components of the adaptive immune system in patient specimens from two recent clinical trials using cetuximab or panitumumab. RESULTS: Both monoclonal antibodies (mAb) primarily activate natural killer (NK) cells, although cetuximab is significantly more potent than panitumumab. Cetuximab-activated neutrophils mediate antibody-dependent cellular cytotoxicity (ADCC) against head and neck squamous cell carcinomas (HNSCC) tumor cells, and interestingly, this effect was FcgammaRIIa- and FcgammaRIIIa genotype-dependent. Panitumumab may activate monocytes through CD32 (FcgammaRIIa); however, monocytes activated by either mAb are not able to mediate ADCC. Cetuximab enhanced dendritic cell (DC) maturation to a greater extent than panitumumab, which was associated with improved tumor antigen cross-presentation by cetuximab compared with panitumumab. This correlated with increased EGFR-specific cytotoxic CD8+ T cells in patients treated with cetuximab compared with those treated with panitumumab. CONCLUSIONS: Although panitumumab effectively inhibits EGFR signaling to a similar extent as cetuximab, it is less effective at triggering antitumor, cellular immune mechanisms which may be crucial for effective therapy of HNSCC. Clin Cancer Res; 22(21); 5229-37. (c)2016 AACR. PMID- 27217443 TI - Erratum for Alberti et al., Antimicrobial Susceptibilities of Abiotrophia defectiva, Granulicatella adiacens, and Granulicatella elegans. PMID- 27217442 TI - An Immunocompromised Child with Bloodstream Infection Caused by Two Escherichia coli Strains, One Harboring NDM-5 and the Other Harboring OXA-48-Like Carbapenemase. AB - We describe a 16-year-old neutropenic patient from the Middle East with bloodstream infection caused by two carbapenemase-producing Escherichia coli isolates that we characterized by whole-genome sequencing. While one displayed meropenem resistance and was blaNDM positive, the other demonstrated meropenem susceptibility yet harbored blaOXA181 (which encodes a blaOXA48-like enzyme). This report highlights the challenge of laboratory detection of blaOXA48-like enzymes and the clinical implications of genotypic resistance detection in carbapenemase-producing Enterobacteriaceae. PMID- 27217445 TI - High Concentration Capture Probes Enhance Massively Parallel Sequencing Assays. PMID- 27217446 TI - Randomized Phase II Evaluation of Bevacizumab Versus Bevacizumab Plus Fosbretabulin in Recurrent Ovarian, Tubal, or Peritoneal Carcinoma: An NRG Oncology/Gynecologic Oncology Group Study. AB - PURPOSE: The vascular disrupting agent fosbretabulin tromethamine selectively targets pre-existing tumor vasculature, which causes vascular shutdown and leads to cancer cell death and necrosis. Antiangiogenesis agents such as bevacizumab, a humanized antivascular endothelial growth factor monoclonal antibody, might prevent revascularization during and after treatment with a vascular disrupting agent. PATIENTS AND METHODS: Patients with recurrent or persistent epithelial ovarian, tubal, or peritoneal carcinoma, measurable or detectable disease, and three or fewer prior regimens were randomly assigned to bevacizumab (15 mg/kg intravenously once every 3 weeks) or the combination of bevacizumab (15 mg/kg) plus fosbretabulin (60 mg/m(2)) intravenously once every 3 weeks until disease progression or toxicity. Randomization was stratified by disease status (measurable v nonmeasurable), prior bevacizumab, and platinum-free interval. The primary end point was progression-free survival (PFS). The study was designed with 80% power for a one-sided alternative at a 10% level of significance to detect a reduction in the hazard by 37.5%. RESULTS: The study enrolled 107 patients. Median PFS was 4.8 months for bevacizumab and 7.3 months for bevacizumab plus fosbretabulin (hazard ratio, 0.69; 90% two-sided CI, 0.47 to 1.00; one-sided P = .05). The proportion responding (overall response rate) to bevacizumab was 28.2% among 39 patients with measurable disease and 35.7% among 42 patients treated with the combination. The relative probability of responding was 1.27 (90% CI, 0.74 to 2.17; one-sided P = .24). Adverse events greater than grade 3 were more common in the combination regimen than in bevacizumab only for hypertension (35% v 20%). There was one grade 3 thromboembolic event in the combination arm and one intestinal fistula in the bevacizumab only arm. CONCLUSION: On the basis of the PFS, overall response rate, and tolerability of these two antivascular therapies, further evaluation is warranted for this chemotherapy-free regimen. Fosbretabulin in combination with bevacizumab increases the risk of hypertension. PMID- 27217447 TI - Sticking to It: Improving Outcomes by Increasing Adherence. PMID- 27217448 TI - Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients Trial. AB - PURPOSE: We report the 5-year analysis from the phase III Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients (DASISION) trial, evaluating long-term efficacy and safety outcomes of patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with dasatinib or imatinib. PATIENTS AND METHODS: Patients with newly diagnosed CML-CP were randomly assigned to receive dasatinib 100 mg once daily (n = 259) or imatinib 400 mg once daily (n = 260). RESULTS: At the time of study closure, 61% and 63% of dasatinib- and imatinib-treated patients remained on initial therapy, respectively. Cumulative rates of major molecular response and molecular responses with a 4.0- or 4.5-log reduction in BCR-ABL1 transcripts from baseline by 5 years remained statistically significantly higher for dasatinib compared with imatinib. Rates for progression free and overall survival at 5 years remained high and similar across treatment arms. In patients who achieved BCR-ABL1 <= 10% at 3 months (dasatinib, 84%; imatinib, 64%), improvements in progression-free and overall survival and lower rates of transformation to accelerated/blast phase were reported compared with patients with BCR-ABL1 greater than 10% at 3 months. Transformation to accelerated/blast phase occurred in 5% and 7% of patients in the dasatinib and imatinib arms, respectively. Fifteen dasatinib-treated and 19 imatinib-treated patients had BCR-ABL1 mutations identified at discontinuation. There were no new or unexpected adverse events identified in either treatment arm, and pleural effusion was the only drug-related, nonhematologic adverse event reported more frequently with dasatinib (28% v 0.8% with imatinib). First occurrences of pleural effusion were reported with dasatinib, with the highest incidence in year 1. Arterial ischemic events were uncommon in both treatment arms. CONCLUSION: These final results from the DASISION trial continue to support dasatinib 100 mg once daily as a safe and effective first-line therapy for the long-term treatment of CML-CP. PMID- 27217450 TI - Prognostic Impact of the Combination of Recurrence Score and Quantitative Estrogen Receptor Expression (ESR1) on Predicting Late Distant Recurrence Risk in Estrogen Receptor-Positive Breast Cancer After 5 Years of Tamoxifen: Results From NRG Oncology/National Surgical Adjuvant Breast and Bowel Project B-28 and B-14. AB - PURPOSE: We determined the utility of the 21-Gene Recurrence Score (RS) in predicting late (> 5 years) distant recurrence (LDR) in stage I and II breast cancer within high and low-ESR1-expressing groups. PATIENTS AND METHODS: RS was assessed in chemotherapy/tamoxifen-treated, estrogen receptor (ER) -positive, node-positive National Surgical Adjuvant Breast and Bowel Project B-28 patients and tamoxifen-treated, ER-positive, node-negative B-14 patients. The association of the RS with risk of distant recurrence (DR) 0 to 5 years and those at risk > 5 years was assessed. An ESR1 expression cut point was optimized in B-28 and tested in B-14. RESULTS: Median follow-up was 11.2 years for B-28 and 13.9 years for B 14. Of 1,065 B-28 patients, 36% had low (< 18), 34% intermediate (18 to 30), and 30% high (>= 31) RS. Of 668 B-14 patients, 51% had low, 22% intermediate, and 27% high RS. Median ESR1 expression by reverse transcriptase polymerase chain reaction was: B-28, 9.7 normalized expression cycle threshold units (CT) and B 14, 10.7 CT. In B-28, RS was associated with DR 0 to 5 years (log-rank P < .001) and > 5 to 10 years (log-rank P = .02) regardless of ESR1 expression. An ESR1 expression cut point of 9.1 CT was identified in B-28. It was validated in B-14 patients for whom the RS was associated with DR in years 5 to 15: 6.8% (95% CI, 4.4% to 10.6%) versus 11.2% (95% CI, 6.2% to 19.9%) versus 16.4% (95% CI, 10.2% to 25.7%) for RS < 18, RS 18 to 30, and RS >= 31, respectively (log-rank P = .01). CONCLUSION: For LDR, RS is strongly prognostic in patients with higher quantitative ESR1. Risk of LDR is relatively low for patients with low RS. These results suggest the value of extended tamoxifen therapy merits evaluation in patients with intermediate and high RS with higher ESR1 expression at initial diagnosis. PMID- 27217449 TI - Randomized, Double-Blind, Phase III Trial of Enzastaurin Versus Placebo in Patients Achieving Remission After First-Line Therapy for High-Risk Diffuse Large B-Cell Lymphoma. AB - PURPOSE: To compare disease-free survival (DFS) after maintenance therapy with the selective protein kinase C beta (PKCbeta) inhibitor, enzastaurin, versus placebo in patients with diffuse large B-cell lymphoma (DLBCL) in complete remission and with a high risk of relapse after first-line therapy. PATIENTS AND METHODS: This multicenter, phase III, randomized, double-blind, placebo controlled trial enrolled patients who were at high risk of recurrence after rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Patients (N = 758) with stage II bulky or stage III to IV DLBCL, three or more International Prognostic Index risk factors at diagnosis, and a complete response or unconfirmed complete response after 6 to 8 cycles of R-CHOP were assigned 2:1 to receive oral enzastaurin 500 mg daily or placebo for 3 years or until disease progression or unacceptable toxicity. Primary end point was DFS 3 years after the last patient entered treatment. Correlative analyses of biomarkers, including cell of origin by immunohistochemistry and PKCbeta expression, with efficacy outcomes were exploratory objectives. RESULTS: After a median follow-up of 48 months, DFS hazard ratio for enzastaurin versus placebo was 0.92 (95% CI, 0.689 to 1.216; two-sided log-rank P = .541; 4-year DFS, 70% v 71%, respectively). Independent of treatment, no significant associations were observed between PKCbeta protein expression or cell of origin and DFS or overall survival. CONCLUSION: Enzastaurin did not significantly improve DFS in patients with high risk DLBCL after achieving complete response to R-CHOP. Achievement of a complete response may have abrogated the prognostic significance of cell of origin by immunohistochemistry. PMID- 27217452 TI - Appraising the Biological Evidence for and Against the Utility of GnRHa for Preservation of Fertility in Patients With Cancer. PMID- 27217451 TI - Exercise and Risk of Cardiovascular Events in Women With Nonmetastatic Breast Cancer. AB - PURPOSE: Cardiovascular disease (CVD) is a leading cause of death among women with nonmetastatic breast cancer. Whether exercise is associated with reductions in CVD risk in patients with breast cancer with an elevated CVD risk phenotype is not known. METHODS: Using a prospective design, women (n = 2,973; mean age, 57 years) diagnosed with nonmetastatic breast cancer participating in two registry based, regional cohort studies, completed a questionnaire that assessed leisure time recreational physical activity (metabolic equivalent task [MET]-h/wk). The primary end point was the first occurrence of any of the following: new diagnosis of coronary artery disease, heart failure, valve abnormality, arrhythmia, stroke, or CVD death, occurring after study enrollment. RESULTS: Median follow-up was 8.6 years (range, 0.2 to 14.8 years). In multivariable analysis, the incidence of cardiovascular events decreased across increasing total MET-h/wk categories (Ptrend < .001). Compared with < 2 MET-h/wk, the adjusted hazard ratio was 0.91 (95% CI, 0.76 to 1.09) for 2 to 10.9 MET-h/wk, 0.79 (95% CI, 0.66 to 0.96) for 11 to 24.5 MET-h/wk, and 0.65 (95% CI, 0.53 to 0.80) for >= 24.5 MET-h/wk. Similar trends were observed for the incidence of coronary artery disease and heart failure (P values < .05). Adherence to national exercise guidelines for adult patients with cancer (ie, >= 9 MET-h/wk) was associated with an adjusted 23% reduction in the risk of cardiovascular events in comparison with not meeting the guidelines (< 9 MET-h/wk; P < .001). The association with exercise did not differ according to age, CVD risk factors, menopausal status, or anticancer treatment. CONCLUSION: Exercise is associated with substantial, graded reductions in the incidence of cardiovascular events in women with nonmetastatic breast cancer. PMID- 27217453 TI - No Evidence for the Benefit of Gonadotropin-Releasing Hormone Agonist in Preserving Ovarian Function and Fertility in Lymphoma Survivors Treated With Chemotherapy: Final Long-Term Report of a Prospective Randomized Trial. AB - PURPOSE: We have reported previously that after 1-year follow up, gonadotropin releasing hormone agonist (GnRHa) did not prevent chemotherapy-induced premature ovarian failure (POF) in patients with lymphoma, but may provide protection of the ovarian reserve. Here, we report the final analysis of the cohort after 5 years of follow up. PATIENTS AND METHODS: A total of 129 patients with lymphoma were randomly assigned to receive either triptorelin plus norethisterone (GnRHa group) or norethisterone alone (control group) during chemotherapy. Ovarian function and fertility were reported after 2, 3, 4, and 5 to 7 years of follow up. The primary end point was POF, defined as at least one follicle-stimulating hormone value of > 40 IU/L after 2 years of follow up. RESULTS: Sixty-seven patients 26.21 +/- 0.64 years of age had available data after a median follow-up time of 5.33 years in the GnRHa group and 5.58 years in the control group (P = .452). Multivariate logistic regression analysis showed a significantly increased risk of POF in patients according to age (P = .047), the conditioning regimen for hematopoietic stem cell transplant (P = .002), and the cumulative dose of cyclophosphamide > 5 g/m(2) (P = .019), but not to the coadministration of GnRHa during chemotherapy (odds ratio, 0.702; P = .651). The ovarian reserve, evaluated using anti-Mullerian hormone and follicle-stimulating hormone levels, was similar in both groups. Fifty-three percent and 43% achieved pregnancy in the GnRHa and control groups, respectively (P = .467). CONCLUSION: To the best of our knowledge, this is the first long-term analysis confirming that GnRHa is not efficient in preventing chemotherapy-induced POF in young patients with lymphoma and did not influence future pregnancy rate. These results reopen the debate about the drug's benefit in that it should not be recommended as standard for fertility preservation in patients with lymphoma. PMID- 27217454 TI - Discussions of Life Expectancy and Changes in Illness Understanding in Patients With Advanced Cancer. AB - PURPOSE: Accurate illness understanding enables patients to make informed decisions. Evidence of the influence of prognostic discussions on the accuracy of illness understanding by patients would demonstrate the value of discussions. METHODS: Recent and past oncology provider-patient discussions about prognosis/life expectancy were examined for their association with changes in illness understanding by patients. Patients (N = 178) with advanced cancers refractory to prior chemotherapy whom oncologists expected to die within 6 months were interviewed before and after a visit in which cancer restaging scan results were discussed. Illness understanding scores were the sum of four indicator variables: patient terminal illness acknowledgment, recognition of incurable disease status, knowledge of the advanced stage of the disease, and expectation to live months as opposed to years. RESULTS: Before the restaging scan visit, nine (5%) of 178 patients had completely accurate illness understanding (ie, correctly answered each of the four illness understanding questions). Eighteen patients (10%) reported only recent discussions of prognosis/life expectancy with their oncologists; 68 (38%) reported only past discussions; 24 (13%) reported both recent and past discussions; and 68 (38%) reported that they never had discussions of prognosis/life expectancy with their oncologists. After adjustment for potential confounders (ie, education and race/ethnicity), analysis identified significant, positive changes in illness understanding scores for patients in groups that reported recent only (least-squares mean change score, 0.62; 95% CI, 0.23 to 1.01; P = .002) and both recent and past (least-squares mean change score, 0.37; 95% CI, 0.04 to 0.70; P = 0.028) discussions of prognosis/life expectancy with their oncologists. CONCLUSION: Patients with advanced cancer who report recent discussions of prognosis/life expectancy with their oncologists come to have a better understanding of the terminal nature of their illnesses. PMID- 27217456 TI - Journal Honors Lillian Smyth, MD, MB BCh BAO, MRCPI (Ireland), As Recipient of the 2016 Journal of Clinical Oncology Young Investigator Award. PMID- 27217455 TI - Treatment Adherence and Its Impact on Disease-Free Survival in the Breast International Group 1-98 Trial of Tamoxifen and Letrozole, Alone and in Sequence. AB - PURPOSE: To investigate adherence to endocrine treatment and its relationship with disease-free survival (DFS) in the Breast International Group (BIG) 1-98 clinical trial. METHODS: The BIG 1-98 trial is a double-blind trial that randomly assigned 6,193 postmenopausal women with hormone receptor-positive early breast cancer in the four-arm option to 5 years of tamoxifen (Tam), letrozole (Let), or the agents in sequence (Let-Tam, Tam-Let). This analysis included 6,144 women who received at least one dose of study treatment. Conditional landmark analyses and marginal structural Cox proportional hazards models were used to evaluate the relationship between DFS and treatment adherence (persistence [duration] and compliance with dosage). Competing risks regression was used to assess demographic, disease, and treatment characteristics of the women who stopped treatment early because of adverse events. RESULTS: Both aspects of low adherence (early cessation of letrozole and a compliance score of < 90%) were associated with reduced DFS (multivariable model hazard ratio, 1.45; 95% CI, 1.09 to 1.93; P = .01; and multivariable model hazard ratio, 1.61; 95% CI, 1.08 to 2.38; P = .02, respectively). Sequential treatments were associated with higher rates of nonpersistence (Tam-Let, 20.8%; Let-Tam, 20.3%; Tam 16.9%; Let 17.6%). Adverse events were the reason for most trial treatment early discontinuations (82.7%). Apart from sequential treatment assignment, reduced adherence was associated with older age, smoking, node negativity, or prior thromboembolic event. CONCLUSION: Both persistence and compliance are associated with DFS. Toxicity management and, for sequential treatments, patient and physician awareness, may improve adherence. PMID- 27217457 TI - Reply to B. Abderrahman and V. C. Jordan. PMID- 27217458 TI - Proceed With Caution: Concerns Related to Routine Internal Mammary Lymph Node Radiation for Node-Positive Breast Cancer. PMID- 27217460 TI - Internal Mammary Node Irradiation: Does One Treatment Fit All? PMID- 27217459 TI - Randomized, Prospective Evaluation Comparing Intensity of Lymphodepletion Before Adoptive Transfer of Tumor-Infiltrating Lymphocytes for Patients With Metastatic Melanoma. AB - PURPOSE: Adoptive cell transfer, the infusion of large numbers of activated autologous lymphocytes, can mediate objective tumor regression in a majority of patients with metastatic melanoma (52 of 93; 56%). Addition and intensification of total body irradiation (TBI) to the preparative lymphodepleting chemotherapy regimen in sequential trials improved objective partial and complete response (CR) rates. Here, we evaluated the importance of adding TBI to the adoptive transfer of tumor-infiltrating lymphocytes (TIL) in a randomized fashion. PATIENTS AND METHODS: A total of 101 patients with metastatic melanoma, including 76 patients with M1c disease, were randomly assigned to receive nonmyeloablative chemotherapy with or without 1,200 cGy TBI before transfer of tumor-infiltrating lymphcytes. Primary end points were CR rate (as defined by Response Evaluation Criteria in Solid Tumors v1.0) and overall survival (OS). Clinical and laboratory data were analyzed for correlates of response. RESULTS: CR rates were 24% in both groups (12 of 50 v 12 of 51), and OS was also similar (median OS, 38.2 v 36.6 months; hazard ratio, 1.11; 95% CI, 0.65 to 1.91; P = .71). Thrombotic microangiopathy was an adverse event unique to the TBI arm and occurred in 13 of 48 treated patients. With a median potential follow-up of 40.9 months, only one of 24 patients who achieved a CR recurred. CONCLUSION: Adoptive cell transfer can mediate durable complete regressions in 24% of patients with metastatic melanoma, with median survival > 3 years. Results were similar using chemotherapy preparative regimens with or without addition of TBI. PMID- 27217461 TI - Endocrine Therapy for Hormone Receptor-Positive Metastatic Breast Cancer: American Society of Clinical Oncology Guideline. AB - PURPOSE: To develop recommendations about endocrine therapy for women with hormone receptor (HR) -positive metastatic breast cancer (MBC). METHODS: The American Society of Clinical Oncology convened an Expert Panel to conduct a systematic review of evidence from 2008 through 2015 to create recommendations informed by that evidence. Outcomes of interest included sequencing of hormonal agents, hormonal agents compared with chemotherapy, targeted biologic therapy, and treatment of premenopausal women. This guideline puts forth recommendations for endocrine therapy as treatment for women with HR-positive MBC. RECOMMENDATIONS: Sequential hormone therapy is the preferential treatment for most women with HR-positive MBC. Except in cases of immediately life-threatening disease, hormone therapy, alone or in combination, should be used as initial treatment. Patients whose tumors express any level of hormone receptors should be offered hormone therapy. Treatment recommendations should be based on type of adjuvant treatment, disease-free interval, and organ function. Tumor markers should not be the sole criteria for determining tumor progression; use of additional biomarkers remains experimental. Assessment of menopausal status is critical; ovarian suppression or ablation should be included in premenopausal women. For postmenopausal women, aromatase inhibitors (AIs) are the preferred first-line endocrine therapy, with or without the cyclin-dependent kinase inhibitor palbociclib. As second-line therapy, fulvestrant should be administered at 500 mg with a loading schedule and may be administered with palbociclib. The mammalian target of rapamycin inhibitor everolimus may be administered with exemestane to postmenopausal women with MBC whose disease progresses while receiving nonsteroidal AIs. Among patients with HR-positive, human epidermal growth factor receptor 2-positive MBC, human epidermal growth factor receptor 2 targeted therapy plus an AI can be effective for those who are not chemotherapy candidates. PMID- 27217462 TI - Internal Mammary Node Irradiation in Breast Cancer: The Issue of Patient Selection. PMID- 27217463 TI - Estrogen Deprivation Therapy in Ovarian Cancer: An Opportunity. PMID- 27217464 TI - Reply to E. Avisar, H. Kuerer, L. Livi et al, and E. Hindie et al. PMID- 27217466 TI - Elective Nodal Irradiation in Breast Cancer: Time for Trials on the Basis of Tumor Biology. PMID- 27217465 TI - Biomarker Panel for Chronic Graft-Versus-Host Disease. AB - PURPOSE: To identify diagnostic and prognostic markers of chronic graft-versus host disease (cGVHD), the major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). PATIENTS AND METHODS: Using a quantitative proteomics approach, we compared pooled plasma samples obtained at matched time points after HCT (median, 103 days) from 35 patients with cGVHD and 18 without cGVHD (data are available via ProteomeXchange with identifier PXD002762). Of 105 proteins showing at least a 1.25-fold difference in expression, 22 were selected on the basis of involvement in relevant pathways and enzyme-linked immunosorbent assay availability. Chemokine (C-X-C motif) ligand 9 (CXCL9) and suppression of tumorigenicity 2 (ST2) also were measured on the basis of previously determined associations with GVHD. Concentrations of the four lead biomarkers were measured at or after diagnosis in plasma from two independent verification cohorts (n = 391) to determine their association with cGVHD. Their prognostic ability when measured at approximately day +100 after HCT was evaluated in plasma of a second verification cohort (n = 172). RESULTS: Of 24 proteins measured in the first verification cohort, nine proteins were associated with cGVHD, and only four (ST2, CXCL9, matrix metalloproteinase 3, and osteopontin) were necessary to compose a four-biomarker panel with an area under the receiver operating characteristic curve (AUC) of 0.89 and significant correlation with cGVHD diagnosis, cGVHD severity, and nonrelapse mortality. In a second verification cohort, this panel distinguished patients with cGVHD (AUC, 0.75), and finally, the panel measured at day +100 could predict cGVHD occurring within the next 3 months with an AUC of 0.67 and 0.79 without and with known clinical risk factors, respectively. CONCLUSION: We conclude that the biomarker panel measured at diagnosis or day +100 after HCT may allow patient stratification according to risk of cGVHD. PMID- 27217467 TI - Chikungunya virus-associated encephalitis: A cohort study on La Reunion Island, 2005-2009. PMID- 27217468 TI - No association of multiple sclerosis activity and progression with EBV or tobacco use in BENEFIT. PMID- 27217469 TI - Clinical Reasoning: Pneumocephalus and pneumorrhachis in a 67-year-old man. PMID- 27217470 TI - Emerging Subspecialties in Neurology: Neuro-ophthalmology. PMID- 27217471 TI - Human single-stranded DNA binding proteins: guardians of genome stability. AB - Single-stranded DNA-binding proteins (SSBs) are essential for maintaining the integrity of the genome in all organisms. All processes related to DNA, such as replication, excision, repair, and recombination, require the participation of SSBs whose oligonucleotide/oligosaccharide-binding (OB)-fold domain is responsible for the interaction with single-stranded DNA (ssDNA). For a long time, the heterotrimeric replication protein A (RPA) complex was believed to be the only nuclear SSB in eukaryotes to participate in ssDNA processing, while mitochondrial SSBs that are conserved with prokaryotic SSBs were shown to be essential for maintaining genome stability in eukaryotic mitochondria. In recent years, two new proteins, hSSB1 and hSSB2 (human SSBs 1/2), were identified and have better sequence similarity to bacterial and archaeal SSBs than RPA. This review summarizes the current understanding of these human SSBs in DNA damage repair and in cell-cycle checkpoint activation following DNA damage, as well as their relationships with cancer. PMID- 27217472 TI - Biological function and regulation of histone and non-histone lysine methylation in response to DNA damage. AB - DNA damage response (DDR) signaling network is initiated to protect cells from various exogenous and endogenous damage resources. Timely and accurate regulation of DDR proteins is required for distinct DNA damage repair pathways. Post translational modifications of histone and non-histone proteins play a vital role in the DDR factor foci formation and signaling pathway. Phosphorylation, ubiquitylation, SUMOylation, neddylation, poly(ADP-ribosyl)ation, acetylation, and methylation are all involved in the spatial-temporal regulation of DDR, among which phosphorylation and ubiquitylation are well studied. Studies in the past decade also revealed extensive roles of lysine methylation in response to DNA damage. Lysine methylation is finely regulated by plenty of lysine methyltransferases, lysine demethylases, and can be recognized by proteins with chromodomain, plant homeodomain, Tudor domain, malignant brain tumor domain, or proline-tryptophan-tryptophan-proline domain. In this review, we outline the dynamics and regulation of histone lysine methylation at canonical (H3K4, H3K9, H3K27, H3K36, H3K79, and H4K20) and non-canonical sites after DNA damage, and discuss their context-specific functions in DDR protein recruitment or extraction, chromatin environment establishment, and transcriptional regulation. We also present the emerging advances of lysine methylation in non-histone proteins during DDR. PMID- 27217473 TI - Non-homologous end joining: advances and frontiers. AB - DNA double-strand breaks (DSBs) are the most serious form of DNA damage. In human cells, non-homologous end joining (NHEJ) is the major pathway for the repair of DSBs. Different types of DSBs result in different subsets of NHEJ repair strategies. These variations in NHEJ repair strategies depend on numerous elements, such as the flexible recruitment of NHEJ-related proteins, the complexity of the DSB ends, and the spatial- and temporal-ordered formation of the multi-protein complex. On the one hand, current studies of DNA DSBs repair focus on the repair pathway choices between homologous recombination and classic or alternative NHEJ. On the other hand, increasing researches have also deepened the significance and dug into the cross-links between the NHEJ pathway and the area of genome organization and aging. Although remarkable progress has been made in elucidating the underlying principles during the past decades, the detailed mechanism of action in response to different types of DSBs remains largely unknown and needs further evaluation in the future study. PMID- 27217474 TI - DNA double-strand break repair: a tale of pathway choices. AB - Deoxyribonucleic acid double-strand breaks (DSBs) are cytotoxic lesions that must be repaired either through homologous recombination (HR) or non-homologous end joining (NHEJ) pathways. DSB repair is critical for genome integrity, cellular homeostasis and also constitutes the biological foundation for radiotherapy and the majority of chemotherapy. The choice between HR and NHEJ is a complex yet not completely understood process that will entail more future efforts. Herein we review our current understandings about how the choice is made over an antagonizing balance between p53-binding protein 1 and breast cancer 1 in the context of cell cycle stages, downstream effects, and distinct chromosomal histone marks. These exciting areas of research will surely bring more mechanistic insights about DSB repair and be utilized in the clinical settings. PMID- 27217476 TI - Role of the School Nurse in Providing School Health Services. AB - The American Academy of Pediatrics recognizes the important role school nurses play in promoting the optimal biopsychosocial health and well-being of school aged children in the school setting. Although the concept of a school nurse has existed for more than a century, uniformity among states and school districts regarding the role of a registered professional nurse in schools and the laws governing it are lacking. By understanding the benefits, roles, and responsibilities of school nurses working as a team with the school physician, as well as their contributions to school-aged children, pediatricians can collaborate with, support, and promote school nurses in their own communities, thus improving the health, wellness, and safety of children and adolescents. PMID- 27217475 TI - High-Intensity Sweeteners in Alternative Tobacco Products. AB - INTRODUCTION: Sweeteners in tobacco products may influence use initiation and reinforcement, with special appeal to adolescents. Recent analytical studies of smokeless tobacco products (snuff, snus, dissolvables) detected flavorants identical to those added to confectionary products such as hard candy and chewing gum. However, these studies did not determine the levels of sweeteners. The objective of the present study was to quantify added sweeteners in smokeless tobacco products, a dissolvable product, electronic cigarette liquids and to compare with sweetener levels in confectionary products. METHODS: Sweetener content of US-sourced smokeless tobacco, electronic cigarette liquid, and confectionary product samples was analyzed by liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS). RESULTS: All smokeless products contained synthetic high intensity sweeteners, with snus and dissolvables exceeding levels in confectionary products (as much as 25-fold). All snus samples contained sucralose and most also aspartame, but no saccharin. In contrast, all moist snuff samples contained saccharin. The dissolvable sample contained sucralose and sorbitol. Ethyl maltol was the most common sweet-associated component in electronic cigarette liquids. DISCUSSION: Sweetener content was dependent on product category, with saccharin in moist snuff, an older category, sucralose added at high levels to more recently introduced products (snus, dissolvable) and ethyl maltol in electronic cigarette liquid. The very high sweetener concentrations may be necessary for the consumer to tolerate the otherwise aversive flavors of tobacco ingredients. Regulation of sweetener levels in smokeless tobacco products may be an effective measure to modify product attractiveness, initiation and use patterns. IMPLICATIONS: Dissolvables, snus and electronic cigarettes have been promoted as risk-mitigation products due to their relatively low content of nitrosamines and other tobacco toxicants. This study is the first to quantify high intensity sweeteners in snus and dissolvable products. Snus and dissolvables contain the high intensity sweetener, sucralose, at levels higher than in confectionary products. The high sweetness of alternative tobacco products makes these products attractive to adolescents. Regulation of sweetener content in non-cigarette products is suggested as an efficient means to control product palatability and to reduce initiation in adolescents. PMID- 27217477 TI - Retrospective Cohort Study of Phototherapy and Childhood Cancer in Northern California. AB - OBJECTIVE: To investigate the association between neonatal phototherapy use and childhood cancer. METHODS: This retrospective cohort study included 499 621 children born at >=35 weeks' gestation from 1995 to 2011 in Kaiser Permanente Northern California hospitals, who survived to hospital discharge and were followed >=60 days. We obtained data on home and inpatient phototherapy, covariates, and cancer incidence from electronic records. We used propensity adjusted Cox and Poisson models to control for confounding and unequal follow-up times. RESULTS: There were 60 children with a diagnosis of cancer among 39 403 exposed to phototherapy (25 per 100 000 person-years), compared with 651 of 460 218 unexposed children (18 per 100 000 person-years; incidence rate ratio [IRR] 1.4; P = .01). Phototherapy was associated with increased rates of any leukemia (IRR 2.1; P = .0007), nonlymphocytic leukemia (IRR 4.0; P = .0004), and liver cancer (IRR 5.2; P = .04). With adjustment for a propensity score that incorporated bilirubin levels, chromosomal disorders, congenital anomalies, and other covariates, associations were no longer statistically significant: Adjusted hazard ratios (95% confidence intervals) were 1.0 (0.7-1.6) for any cancer, 1.6 (0.8-3.5) for any leukemia, 1.9 (0.6-6.9) for nonlymphocytic leukemia, and 1.4 (0.2-12) for liver cancer. Upper limits of 95% confidence intervals for adjusted 10-year excess risk were generally <0.1% but reached 4.4% for children with Down syndrome. CONCLUSIONS: Although phototherapy use was associated with increased cancer rates (particularly nonlymphocytic leukemia), control for confounding variables eliminated or attenuated the associations. Nonetheless, the possibility of even partial causality suggests that avoiding unnecessary phototherapy may be prudent. PMID- 27217478 TI - Neonatal Phototherapy and Infantile Cancer. AB - OBJECTIVE: To determine whether neonatal phototherapy is associated with cancer in the first year after birth. METHODS: We analyzed a data set from the California Office of Statewide Health Planning and Development that was created by linking birth certificates, death certificates, and hospital discharge abstracts up to age 1 year. Subjects were 5 144 849 infants born in California hospitals at >=35 weeks' gestation from 1998 to 2007. We used International Classification of Diseases, Ninth Revision codes to identify phototherapy at <15 days and discharge diagnoses of cancer at 61 to 365 days. We adjusted for potential confounding variables by using traditional and propensity-adjusted logistic regression models. RESULTS: Cancer was diagnosed in 58/178 017 infants with diagnosis codes for phototherapy and 1042/4 966 832 infants without such codes (32.6/100 000 vs 21.0/100 000; relative risk 1.6; 95% confidence interval [CI], 1.2-2.0, P = .002). In propensity-adjusted analyses, associations were seen between phototherapy and overall cancer (adjusted odds ratio [aOR] 1.4; 95% CI, 1.1-1.9), myeloid leukemia (aOR 2.6; 95% CI, 1.3-5.0), and kidney cancer (aOR 2.5; 95% CI, 1.2-5.1). The marginal propensity-adjusted absolute risk increase for cancer after phototherapy in the total population was 9.4/100 000 (number needed to harm of 10 638). Because of the higher baseline risk of cancer in infants with Down syndrome, the number needed to harm was 1285. CONCLUSIONS: Phototherapy may slightly increase the risk of cancer in infancy, although the absolute risk increase is small. This risk should be considered when making phototherapy treatment decisions, especially for infants with bilirubin levels below current treatment guidelines. PMID- 27217479 TI - Can Big Data Shed Light on the Origins of Pediatric Cancer? PMID- 27217480 TI - Statement of Endorsement: Corticosteroid Treatment of Duchenne Muscular Dystrophy. PMID- 27217481 TI - DNA CpG Methylation (5-Methylcytosine) and Its Derivative (5 Hydroxymethylcytosine) Alter Histone Posttranslational Modifications at the Pomc Promoter, Affecting the Impact of Perinatal Diet on Leanness and Obesity of the Offspring. AB - A maternal high-fat diet (HFD) alters the offspring's feeding regulation, leading to obesity. This phenomenon is partially mediated by aberrant expression of the hypothalamic anorexigenic neuropeptide proopiomelanocortin (POMC). Nevertheless, although some individual offspring suffer from morbid obesity, others escape the malprogramming. It is suggested that this difference is due to epigenetic programming. In this study, we report that in lean offspring of non-HFD-fed dams, essential promoter regions for Pomc expression were enriched with 5 hydroxymethylcytosine (5hmC) together with a reduction in the level of 5 methylcytosine (5mC). Moreover, 5hmC was negatively correlated whereas 5mC was positively correlated with body weight in offspring from both HFD- and control fed dams. We further found that Pomc expression in obese offspring is determined by a two-step epigenetic inhibitory mechanism in which CpG methylation is linked with histone posttranslational modifications. An increase in CpG methylation at the Poxmc promoter enables binding of methyl-binding domain 1 (MBD1) to 5mC, but not to its derivative 5hmC. MBD1 then interacts with SET domain bifurcated 1 methyltransferase to promote bimethylation on the histone 3 lysine 9 residue, reducing Pomc mRNA expression. These results suggest an epigenetic regulatory mechanism that affects obesity-prone or resilient traits. PMID- 27217482 TI - Connections Between the Gut Microbiome and Metabolic Hormones in Early Pregnancy in Overweight and Obese Women. AB - Overweight and obese women are at a higher risk for gestational diabetes mellitus. The gut microbiome could modulate metabolic health and may affect insulin resistance and lipid metabolism. The aim of this study was to reveal relationships between gut microbiome composition and circulating metabolic hormones in overweight and obese pregnant women at 16 weeks' gestation. Fecal microbiota profiles from overweight (n = 29) and obese (n = 41) pregnant women were assessed by 16S rRNA sequencing. Fasting metabolic hormone (insulin, C peptide, glucagon, incretin, and adipokine) concentrations were measured using multiplex ELISA. Metabolic hormone levels as well as microbiome profiles differed between overweight and obese women. Furthermore, changes in some metabolic hormone levels were correlated with alterations in the relative abundance of specific microbes. Adipokine levels were strongly correlated with Ruminococcaceae and Lachnospiraceae, which are dominant families in energy metabolism. Insulin was positively correlated with the genus Collinsella. Gastrointestinal polypeptide was positively correlated with the genus Coprococcus but negatively with family Ruminococcaceae This study shows novel relationships between gut microbiome composition and the metabolic hormonal environment in overweight and obese pregnant women at 16 weeks' gestation. These results suggest that manipulation of the gut microbiome composition may influence pregnancy metabolism. PMID- 27217483 TI - Gestational Diabetes Mellitus From Inactivation of Prolactin Receptor and MafB in Islet beta-Cells. AB - beta-Cell proliferation and expansion during pregnancy are crucial for maintaining euglycemia in response to increased metabolic demands placed on the mother. Prolactin and placental lactogen signal through the prolactin receptor (PRLR) and contribute to adaptive beta-cell responses in pregnancy; however, the in vivo requirement for PRLR signaling specifically in maternal beta-cell adaptations remains unknown. We generated a floxed allele of Prlr, allowing conditional loss of PRLR in beta-cells. In this study, we show that loss of PRLR signaling in beta-cells results in gestational diabetes mellitus (GDM), reduced beta-cell proliferation, and failure to expand beta-cell mass during pregnancy. Targeted PRLR loss in maternal beta-cells in vivo impaired expression of the transcription factor Foxm1, both G1/S and G2/M cyclins, tryptophan hydroxylase 1 (Tph1), and islet serotonin production, for which synthesis requires Tph1. This conditional system also revealed that PRLR signaling is required for the transient gestational expression of the transcription factor MafB within a subset of beta-cells during pregnancy. MafB deletion in maternal beta-cells also produced GDM, with inadequate beta-cell expansion accompanied by failure to induce PRLR-dependent target genes regulating beta-cell proliferation. These results unveil molecular roles for PRLR signaling in orchestrating the physiologic expansion of maternal beta-cells during pregnancy. PMID- 27217484 TI - Functional Brain Networks Are Altered in Type 2 Diabetes and Prediabetes: Signs for Compensation of Cognitive Decrements? The Maastricht Study. AB - Type 2 diabetes is associated with cognitive decrements, accelerated cognitive decline, and increased risk for dementia. Patients with the metabolic syndrome, a major risk factor for diabetes, may display comparable cognitive decrements as seen in type 2 diabetes. Currently, the impact of diabetes and prediabetes on cognition and the underlying organization of functional brain networks still remain to be elucidated. This study investigated whether functional brain networks are affected in type 2 diabetes and prediabetes. Forty-seven participants with diabetes, 47 participants with prediabetes, and 45 control participants underwent detailed cognitive testing and 3-Tesla resting state functional MRI. Graph theoretical network analysis was performed to investigate alterations in functional cerebral networks. Participants with diabetes displayed altered network measures, characterized by a higher normalized cluster coefficient and higher local efficiency, compared with control participants. The network measures of the participants with prediabetes fell between those with diabetes and control participants. Lower processing speed was associated with shorter path length and higher global efficiency. Participants with type 2 diabetes have altered functional brain networks. This alteration is already apparent in the prediabetic stage to a somewhat lower level, hinting at functional reorganization of the cerebral networks as a compensatory mechanism for cognitive decrements. PMID- 27217485 TI - Deficiency of Nuclear Factor-kappaB c-Rel Accelerates the Development of Autoimmune Diabetes in NOD Mice. AB - The nuclear factor-kappaB protein c-Rel plays a critical role in controlling autoimmunity. c-Rel-deficient mice are resistant to streptozotocin-induced diabetes, a drug-induced model of autoimmune diabetes. We generated c-Rel deficient NOD mice to examine the role of c-Rel in the development of spontaneous autoimmune diabetes. We found that both CD4(+) and CD8(+) T cells from c-Rel deficient NOD mice showed significantly decreased T-cell receptor-induced IL-2, IFN-gamma, and GM-CSF expression. Despite compromised T-cell function, c-Rel deficiency dramatically accelerated insulitis and hyperglycemia in NOD mice along with a substantial reduction in T-regulatory (Treg) cell numbers. Supplementation of isogenic c-Rel-competent Treg cells from prediabetic NOD mice reversed the accelerated diabetes development in c-Rel-deficient NOD mice. The results suggest that c-Rel-dependent Treg cell function is critical in suppressing early-onset autoimmune diabetogenesis in NOD mice. This study provides a novel natural system to study autoimmune diabetes pathogenesis and reveals a previously unknown c-Rel dependent mechanistic difference between chemically induced and spontaneous diabetogenesis. The study also reveals a unique protective role of c-Rel in autoimmune diabetes, which is distinct from other T-cell-dependent autoimmune diseases such as arthritis and experimental autoimmune encephalomyelitis, where c Rel promotes autoimmunity. PMID- 27217486 TI - Overexpressing IRS1 in Endothelial Cells Enhances Angioblast Differentiation and Wound Healing in Diabetes and Insulin Resistance. AB - The effect of enhancing insulin's actions in endothelial cells (ECs) to improve angiogenesis and wound healing was studied in obesity and diabetes. Insulin receptor substrate 1 (IRS1) was overexpressed in ECs using the VE-cadherin promoter to create ECIRS1 TG mice, which elevated pAkt activation and expressions of vascular endothelial growth factor (VEGF), Flk1, and VE-cadherin in ECs and granulation tissues (GTs) of full-thickness wounds. Open wound and epithelialization rates and angiogenesis significantly improved in normal mice and high fat (HF) diet-induced diabetic mice with hyperinsulinemia in ECIRS1 TG versus wild type (WT), but not in insulin-deficient diabetic mice. Increased angioblasts and EC numbers in GT of ECIRS1 mice were due to proliferation in situ rather than uptake. GT in HF-fed diabetic mice exhibited parallel decreases in insulin and VEGF-induced pAkt and EC numbers by >50% without changes in angioblasts versus WT mice, which were improved in ECIRS1 TG mice on normal chow or HF diet. Thus, HF-induced diabetes impaired angiogenesis by inhibiting insulin signaling in GT to decrease the differentiation of angioblasts to EC, which was normalized by enhancing insulin's action targeted to EC, a potential target to improve wound healing in diabetes and obesity. PMID- 27217488 TI - Hypothalamic Vitamin D Improves Glucose Homeostasis and Reduces Weight. AB - Despite clear associations between vitamin D deficiency and obesity and/or type 2 diabetes, a causal relationship is not established. Vitamin D receptors (VDRs) are found within multiple tissues, including the brain. Given the importance of the brain in controlling both glucose levels and body weight, we hypothesized that activation of central VDR links vitamin D to the regulation of glucose and energy homeostasis. Indeed, we found that small doses of active vitamin D, 1alpha,25-dihydroxyvitamin D3 (1,25D3) (calcitriol), into the third ventricle of the brain improved glucose tolerance and markedly increased hepatic insulin sensitivity, an effect that is dependent upon VDR within the paraventricular nucleus of the hypothalamus. In addition, chronic central administration of 1,25D3 dramatically decreased body weight by lowering food intake in obese rodents. Our data indicate that 1,25D3-mediated changes in food intake occur through action within the arcuate nucleus. We found that VDR colocalized with and activated key appetite-regulating neurons in the arcuate, namely proopiomelanocortin neurons. Together, these findings define a novel pathway for vitamin D regulation of metabolism with unique and divergent roles for central nervous system VDR signaling. Specifically, our data suggest that vitamin D regulates glucose homeostasis via the paraventricular nuclei and energy homeostasis via the arcuate nuclei. PMID- 27217487 TI - 4E-BP2/SH2B1/IRS2 Are Part of a Novel Feedback Loop That Controls beta-Cell Mass. AB - The mammalian target of rapamycin complex 1 (mTORC1) regulates several biological processes, although the key downstream mechanisms responsible for these effects are poorly defined. Using mice with deletion of eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2), we determine that this downstream target is a major regulator of glucose homeostasis and beta-cell mass, proliferation, and survival by increasing insulin receptor substrate 2 (IRS2) levels and identify a novel feedback mechanism by which mTORC1 signaling increases IRS2 levels. In this feedback loop, we show that 4E-BP2 deletion induces translation of the adaptor protein SH2B1 and promotes the formation of a complex with IRS2 and Janus kinase 2, preventing IRS2 ubiquitination. The changes in IRS2 levels result in increases in cell cycle progression, cell survival, and beta-cell mass by increasing Akt signaling and reducing p27 levels. Importantly, 4E-BP2 deletion confers resistance to cytokine treatment in vitro. Our data identify SH2B1 as a major regulator of IRS2 stability, demonstrate a novel feedback mechanism linking mTORC1 signaling with IRS2, and identify 4E-BP2 as a major regulator of proliferation and survival of beta-cells. PMID- 27217489 TI - Effects of gamma-Aminobutyric Acid A Receptor Activation on Counterregulatory Responses to Subsequent Exercise in Individuals With Type 1 Diabetes. AB - The effects of gamma-aminobutyric acid (GABA) A receptor activation on physiologic responses during next-day exercise in type 1 diabetes are unknown. To test the hypothesis that GABA A activation with the benzodiazepine alprazolam would blunt counterregulatory responses during subsequent exercise, 29 (15 male, 14 female) individuals with type 1 diabetes (HbA1c 7.8 +/- 1%) were studied during separate 2-day protocols. Day 1 consisted of morning and afternoon 2-h euglycemic or 2.9 mmol/L hypoglycemic clamps with or without 1 mg alprazolam given 30 min before each clamp. Day 2 consisted of a 90-min euglycemic cycling exercise at 50% VO2max Tritiated glucose was used to measure glucose kinetics. Despite equivalent day 2 insulin (93 +/- 6 pmol/L) and glucose levels (5.3 +/- 0.1 mmol/L), plasma epinephrine, norepinephrine, glucagon, cortisol, and growth hormone responses were similarly reduced after alprazolam or day 1 hypoglycemia compared with euglycemic control. Endogenous glucose production, lipolysis (glycerol, nonesterified fatty acid), and glycogenolysis (lactate) were also reduced during day 2 exercise after day 1 GABA A activation. We conclude that activation of GABA A receptors with alprazolam can result in widespread neuroendocrine, autonomic nervous system, and metabolic counterregulatory failure during subsequent submaximal exercise and may increase the risk of exercise associated hypoglycemia in individuals with type 1 diabetes. PMID- 27217490 TI - Difference in the Pharmacokinetics and Hepatic Metabolism of Antidiabetic Drugs in Zucker Diabetic Fatty and Sprague-Dawley Rats. AB - The Zucker diabetic fatty (ZDF) rat, an inbred strain of obese Zucker fatty rat, develops early onset of insulin resistance and displays hyperglycemia and hyperlipidemia. The phenotypic changes resemble human type 2 diabetes associated with obesity and therefore the strain is used as a pharmacological model for type 2 diabetes. The aim of the current study was to compare the pharmacokinetics and hepatic metabolism in male ZDF and Sprague-Dawley (SD) rats of five antidiabetic drugs that are known to be cleared via various mechanisms. Among the drugs examined, metformin, cleared through renal excretion, and rosiglitazone, metabolized by hepatic cytochrome P450 2C, did not exhibit differences in the plasma clearance in ZDF and SD rats. In contrast, glibenclamide, metabolized by hepatic CYP3A, canagliflozin, metabolized mainly by UDP-glucuronosyltransferases (UGT), and troglitazone, metabolized by sulfotransferase and UGT, exhibited significantly lower plasma clearance in ZDF than in SD rats after a single intravenous administration. To elucidate the mechanisms for the difference in the drug clearance, studies were performed to characterize the activity of hepatic drug-metabolizing enzymes using liver S9 fractions from the two strains. The results revealed that the activity for CYP3A and UGT was decreased in ZDF rats using the probe substrates, and decreased unbound intrinsic clearance in vitro for glibenclamide, canagliflozin, and troglitazone was consistent with lower plasma clearance in vivo. The difference in pharmacokinetics of these two strains may complicate pharmacokinetic/pharmacodynamic correlations, given that ZDF is used as a pharmacological model, and SD rat as the pharmacokinetics and toxicology strain. PMID- 27217493 TI - The Nitrification Inhibitor Methyl 3-(4-Hydroxyphenyl)Propionate Modulates Root Development by Interfering with Auxin Signaling via the NO/ROS Pathway. AB - Methyl 3-(4-hydroxyphenyl)propionate (MHPP) is a root exudate that functions as a nitrification inhibitor and as a modulator of the root system architecture (RSA) by inhibiting primary root (PR) elongation and promoting lateral root formation. However, the mechanism underlying MHPP-mediated modulation of the RSA remains unclear. Here, we report that MHPP inhibits PR elongation in Arabidopsis (Arabidopsis thaliana) by elevating the levels of auxin expression and signaling. MHPP induces an increase in auxin levels by up-regulating auxin biosynthesis, altering the expression of auxin carriers, and promoting the degradation of the auxin/indole-3-acetic acid family of transcriptional repressors. We found that MHPP-induced nitric oxide (NO) production promoted reactive oxygen species (ROS) accumulation in root tips. Suppressing the accumulation of NO or ROS alleviated the inhibitory effect of MHPP on PR elongation by weakening auxin responses and perception and by affecting meristematic cell division potential. Genetic analysis supported the phenotype described above. Taken together, our results indicate that MHPP modulates RSA remodeling via the NO/ROS-mediated auxin response pathway in Arabidopsis. Our study also revealed that MHPP significantly induced the accumulation of glucosinolates in roots, suggesting the diverse functions of MHPP in modulating plant growth, development, and stress tolerance in plants. PMID- 27217494 TI - The Cell Wall Arabinose-Deficient Arabidopsis thaliana Mutant murus5 Encodes a Defective Allele of REVERSIBLY GLYCOSYLATED POLYPEPTIDE2. AB - Traditional marker-based mapping and next-generation sequencing was used to determine that the Arabidopsis (Arabidopsis thaliana) low cell wall arabinose mutant murus5 (mur5) encodes a defective allele of REVERSIBLY GLYCOSYLATED POLYPEPTIDE2 (RGP2). Marker analysis of 13 F2 confirmed mutant progeny from a recombinant mapping population gave a rough map position on the upper arm of chromosome 5, and deep sequencing of DNA from these 13 lines gave five candidate genes with G->A (C->T) transitions predicted to result in amino acid changes. Of these five, only insertional mutant alleles of RGP2, a gene that encodes a UDP arabinose mutase that interconverts UDP-arabinopyranose and UDP-arabinofuranose, exhibited the low cell wall arabinose phenotype. The identities of mur5 and two SALK insertional alleles were confirmed by allelism tests and overexpression of wild-type RGP2 complementary DNA placed under the control of the 35S promoter in the three alleles. The mur5 mutation results in the conversion of cysteine-257 to tyrosine-257 within a conserved hydrophobic cluster predicted to be distal to the active site and essential for protein stability and possible heterodimerization with other isoforms of RGP. PMID- 27217495 TI - The Pseudomonas syringae Type III Effector HopG1 Induces Actin Remodeling to Promote Symptom Development and Susceptibility during Infection. AB - The plant cytoskeleton underpins the function of a multitude of cellular mechanisms, including those associated with developmental- and stress-associated signaling processes. In recent years, the actin cytoskeleton has been demonstrated to play a key role in plant immune signaling, including a recent demonstration that pathogens target actin filaments to block plant defense and immunity. Herein, we quantified spatial changes in host actin filament organization after infection with Pseudomonas syringae pv. tomato DC3000 (Pst DC3000), demonstrating that the type-III effector HopG1 is required for pathogen induced changes to actin filament architecture and host disease symptom development during infection. Using a suite of pathogen effector deletion constructs, coupled with high-resolution microscopy, we found that deletion of hopG1 from Pst DC3000 resulted in a reduction in actin bundling and a concomitant increase in the density of filament arrays in Arabidopsis, both of which correlate with host disease symptom development. As a mechanism underpinning this activity, we further show that the HopG1 effector interacts with an Arabidopsis mitochondrial-localized kinesin motor protein. Kinesin mutant plants show reduced disease symptoms after pathogen infection, which can be complemented by actin modifying agents. In total, our results support a model in which HopG1 induces changes in the organization of the actin cytoskeleton as part of its virulence function in promoting disease symptom development. PMID- 27217498 TI - Chronic Kidney Disease and Acute Myocardial Infarction: The Story After 1 Year. PMID- 27217497 TI - Chronic Kidney Disease and Health Status Outcomes Following Acute Myocardial Infarction. AB - BACKGROUND: The association between chronic kidney disease (CKD) and health status outcomes after acute myocardial infarction (AMI) is unknown. METHODS AND RESULTS: Patients were enrolled between 2005 and 2008 in the Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status (TRIUMPH) registry, a prospective multicenter observational study of AMI outcomes. The Seattle Angina Questionnaire and Short Form-12 were collected at baseline and at 1, 6, and 12 months following AMI. CKD was defined by an estimated glomerular filtration rate <60 mL/min, calculated during the AMI hospitalization. Linear repeated-measures models assessed the association between CKD and health status after AMI, accounting for the propensity to have follow-up heath status measures. Of 3617 patients, 576 (16%) had CKD and 3041 (84%) did not have CKD. Patients with CKD were older and had more comorbidity. Patients with CKD were more likely to have multivessel coronary disease and less likely to undergo revascularization. Among AMI survivors, patients with and without CKD had similar health-related quality of life (adjusted difference of 0.24, 95% CI -1.46 to 1.95), angina frequency (adjusted difference of 1.27, 95% CI -0.05 to 2.58), and mental health (adjusted difference of -0.07, 95% CI -0.90 to 0.75). In contrast, patients with CKD had lower physical health (adjusted difference -1.61, 95% CI -2.49 to -0.74), which was not clinically significant, compared with patients without CKD. CONCLUSIONS: Among AMI survivors, patients with CKD not only had more comorbidities but also, after adjusting for these patient differences, had similar health status compared with patients without CKD. Interventions aimed at improving health status after AMI should not focus on CKD status. PMID- 27217496 TI - A Laser Dissection-RNAseq Analysis Highlights the Activation of Cytokinin Pathways by Nod Factors in the Medicago truncatula Root Epidermis. AB - Nod factors (NFs) are lipochitooligosaccharidic signal molecules produced by rhizobia, which play a key role in the rhizobium-legume symbiotic interaction. In this study, we analyzed the gene expression reprogramming induced by purified NF (4 and 24 h of treatment) in the root epidermis of the model legume Medicago truncatula Tissue-specific transcriptome analysis was achieved by laser-capture microdissection coupled to high-depth RNA sequencing. The expression of 17,191 genes was detected in the epidermis, among which 1,070 were found to be regulated by NF addition, including previously characterized NF-induced marker genes. Many genes exhibited strong levels of transcriptional activation, sometimes only transiently at 4 h, indicating highly dynamic regulation. Expression reprogramming affected a variety of cellular processes, including perception, signaling, regulation of gene expression, as well as cell wall, cytoskeleton, transport, metabolism, and defense, with numerous NF-induced genes never identified before. Strikingly, early epidermal activation of cytokinin (CK) pathways was indicated, based on the induction of CK metabolic and signaling genes, including the CRE1 receptor essential to promote nodulation. These transcriptional activations were independently validated using promoter:beta glucuronidase fusions with the MtCRE1 CK receptor gene and a CK response reporter (TWO COMPONENT SIGNALING SENSOR NEW). A CK pretreatment reduced the NF induction of the EARLY NODULIN11 (ENOD11) symbiotic marker, while a CK-degrading enzyme (CYTOKININ OXIDASE/DEHYDROGENASE3) ectopically expressed in the root epidermis led to increased NF induction of ENOD11 and nodulation. Therefore, CK may play both positive and negative roles in M. truncatula nodulation. PMID- 27217499 TI - Acetaminophen Increases Aldosterone Secretion While Suppressing Cortisol and Androgens: A Possible Link to Increased Risk of Hypertension. AB - BACKGROUND: Acetaminophen (paracetamol) is a widely used analgesic and antipyretic drug. Potential side effects are of public health concern, and liver toxicity from acute overdose is well known. More recently, a regular use of acetaminophen has been associated with an increased risk of hypertension. METHODS: We investigated effects of acetaminophen on steroidogenesis as a possible mechanism for the hypertensive action by using the human adrenocortical cell line, H295R. Cells were treated with 0.1, 0.5, and 1mM of acetaminophen for 24 hours, and secretion of steroids and gene expression of key steps in the steroidogenesis were investigated. RESULTS: Progesterone and aldosterone secretion were increased dose dependently, while secretion of 17alpha-OH progesterone and cortisol as well as dehydroepiandrosterone and androstenedione was decreased. CYP17alpha-hydroxylase activity, assessed by the ratio 17alpha-OH progesterone/progesterone, and CYP17-lyase activity, assessed by the ratio androstenedione/17alpha-OH-progesterone, were both dose-dependently decreased by acetaminophen. No effects were revealed on cell viability. Treatment of cells with 0.5mM of acetaminophen did not cause any effects on the expression of 10 genes in the steroidogenic pathways. CONCLUSIONS: The pattern of steroid secretion caused by acetaminophen can be explained by inhibition of CYP17A1 enzyme activity. A decreased secretion of glucocorticoids and androgens, as demonstrated by acetaminophen, would, in an in vivo situation, induce adrenocorticotropic hormone release via negative feedback in the hypothalamic pituitary-adrenal axis and result in an upregulation of aldosterone secretion. Our results suggest a novel possible mechanism for acetaminophen-induced hypertension, which needs to be further elucidated in clinical investigations. PMID- 27217501 TI - Heart Rate Variability and Incident Stroke: The Atherosclerosis Risk in Communities Study. AB - BACKGROUND AND PURPOSE: Low heart rate variability (HRV), a marker of cardiac autonomic dysfunction, has been associated with increased all-cause and cardiovascular mortality. We examined the association between reduced HRV and incident stroke in a community-based cohort. METHODS: The Atherosclerosis Risk in Communities (ARIC) study measured HRV using 2-minute ECG readings in 12 550 middle-aged adults at baseline (1987-1989). HRV indices were calculated using the SD of RR intervals (SDNN), the mean of all normal RR intervals (meanNN), the root mean square of successive differences of successive RR intervals (RMSSD), low (LF) and high (HF) frequency power, and the LF/HF ratio. All HRV measures were categorized into quintiles. Incident stroke was adjudicated through 2011. Cox regression was used to estimate hazard ratios (HRs) with the lowest HRV quintile as the reference, with and without stratification by prevalent diabetes mellitus. RESULTS: Over a median follow-up of 22 years, 816 (6.5%) participants experienced incident stroke. After covariate adjustment, there was no strong evidence of association between HRV and stroke risk. In stratified analyses, the lowest HRV quintile was associated with higher stroke risk compared with the highest quintile for SDNN (HR, 2.0, 95% confidence interval, 1.1-4.0), RMSSD (HR, 1.7; 95% confidence interval, 0.9-3.2), LF (HR, 1.5; 95% confidence interval, 0.8 3.0), and HF (HR, 1.7; 95% confidence interval, 0.9-3.0) only among people with diabetes mellitus. CONCLUSIONS: Lower HRV was associated with higher risk of incident stroke among middle-aged adults with prevalent diabetes mellitus but not among people without diabetes mellitus. PMID- 27217502 TI - Picturing the Size and Site of Stroke With an Expanded National Institutes of Health Stroke Scale. AB - BACKGROUND AND PURPOSE: The National Institutes of Health Stroke Scale (NIHSS) includes minimal assessment of cognitive function, particularly in right hemisphere (RH) stroke. Descriptions of the Cookie Theft picture from the NIHSS allow analyses that (1) correlate with aphasia severity and (2) identify communication deficits in RH stroke. We hypothesized that analysis of the picture description contributes valuable information about volume and location of acute stroke. METHODS: We evaluated 67 patients with acute ischemic stroke (34 left hemisphere [LH]; 33 RH) with the NIHSS, analysis of the Cookie Theft picture, and magnetic resonance imaging, compared with 35 sex- and age-matched controls. We evaluated descriptions for total content units (CU), syllables, ratio of left:right CU, CU/minute, and percent interpretive CU, based on previous studies. Lesion volume and percent damage to regions of interest were measured on diffusion-weighted imaging. Multivariable linear regression identified variables associated with infarct volume, independently of NIHSS score, age and sex. RESULTS: Patients with RH and LH stroke differed from controls, but not from each other, on CU, syllables/CU, and CU/minute. Left:right CU was lower in RH compared with LH stroke. CU, syllables/CU, and NIHSS each correlated with lesion volume in LH and RH stroke. Lesion volume was best accounted by a model that included CU, syllables/CU, NIHSS, left:right CU, percent interpretive CU, and age, in LH and RH stroke. Each discourse variable and NIHSS score were associated with percent damage to different regions of interest, independently of lesion volume and age. CONCLUSIONS: Brief picture description analysis complements NIHSS scores in predicting stroke volume and location. PMID- 27217503 TI - Atrial Fibrillation Is Associated With a Worse 90-Day Outcome Than Other Cardioembolic Stroke Subtypes. AB - BACKGROUND AND PURPOSE: Patients with a cardioembolic stroke (CES) have worse outcomes than stroke patients with other causes of stroke. Among patients with CES, atrial fibrillation (AF) is a common comorbidity. Mounting data indicate that AF may be related to stroke pathogenesis beyond acute cerebral thromboembolism. We sought to determine whether AF represents an independent risk factor for stroke severity and outcome among patients with CES. METHODS: We retrospectively analyzed patients with acute hemispheric CES included in an academic medical center's stroke registry. CES was determined using the Causative Classification System of ischemic stroke. Multivariable logistic regression was used to determine whether AF was associated with 90-day outcome functional status. RESULTS: Our cohort included 140 patients. Of these, 52 had prevalent AF and 28 had incident AF diagnosed during their index hospitalization or within 90 days of hospital discharge. After adjustment for potential confounders or mediators, any AF (odds ratio, 2.51; 95% confidence interval, 1.03-6.33; P=0.049), infarct volume (odds ratio, 1.03; 95% confidence interval, 1.01-1.06; P=0.005), preadmission modified Rankin Scale score (odds ratio, 2.58; 95% confidence interval, 1.66-4.01; P<0.001), and admission National Institutes of Health Stroke Scale score (odds ratio, 1.17; 95% confidence interval, 1.08-1.28; P<0.001) remained associated with an unfavorable 90-day outcome (modified Rankin Scale score, 2-6). CONCLUSIONS: AF is associated with an unfavorable 90-day outcome among patients with a CES independent of established risk factors and initial stroke severity. This suggests that AF-specific mechanisms affect CES severity and functional status after CES. If confirmed in future studies, further investigation into the underlying pathophysiological mechanisms may provide novel avenues to AF detection and treatment. PMID- 27217504 TI - Detection and Predictive Value of Fractional Anisotropy Changes of the Corticospinal Tract in the Acute Phase of a Stroke. AB - BACKGROUND AND PURPOSE: A decrease in fractional anisotropy (FA) of the ipsilesional corticospinal tract (CST) distal to stroke lesions in the subacute (eg, 30 days) and chronic phase has been correlated with poor motor outcomes, but it is unclear whether FA values obtained within the acute stroke phase (here defined as 80 hours after onset) can predict later outcome. METHODS: Fifty-eight patients underwent an assessment of motor impairment in the acute phase and at 3 months using the upper extremity Fugl-Meyer assessment. FA values, obtained within 80 hours after stroke onset, were determined in 2 regions of interest: cerebral peduncle and a stretch of the CST caudal to each stroke lesion (nearest 5-slices). RESULTS: The FA laterality index for the cerebral peduncle-regions of interest was a poor predictor of 3-month outcome (R(2)=0.044; P=0.137), whereas the slope over the FA laterality index of the nearest-5-slices showed a relatively weak but significant prediction (R(2)=0.11; P=0.022) with the affected side having lower FA values. Initial upper extremity Fugl-Meyer (R(2)=0.69; P<0.001) and the weighted CST lesion load (R(2)=0.71; P<0.001) were strong predictors of 3-month outcome. In multivariate analyses, controlling for initial upper extremity Fugl-Meyer, weighted CST lesion load, and days-of-therapy, neither the FA laterality index of the cerebral peduncle nor the slope over the FA laterality index of the nearest-5-slices significantly contributed to the prediction of 86% of the variance in the upper extremity Fugl-Meyer at 3 months. CONCLUSIONS: FA reductions of the CST can be detected near the ischemic lesion in the acute stroke phase, but offer minimal predictive value to motor outcomes at 3 months. PMID- 27217505 TI - Echoing Plaque Activity of the Coronary and Intracranial Arteries in Patients With Stroke. AB - BACKGROUND AND PURPOSE: Atherosclerosis is a systemic disease, and both coronary and intracranial atherosclerosis are common in the elderly. Unlike coronary artery disease (CAD), intracranial atherosclerotic disease can cause intracranial atherosclerotic stroke by branch occlusive disease (B-type) and coronary-type rupture of plaque (C-type). We hypothesized that plaque characteristics of intracranial arteries are associated with those of coronary arteries. METHODS: Eighty-one patients with acute cerebral infarcts caused by intracranial atherosclerotic disease without history of CAD were analyzed. Asymptomatic CAD burden (number and degree of stenosis) and plaque characteristics (calcified, mixed, and noncalcified) were measured with multidetector computed tomography, whereas the asymptomatic intracranial atherosclerotic disease burden was measured using magnetic resonance angiography. The symptomatic intracranial artery was analyzed using high-resolution magnetic resonance imaging for vascular morphology (stenosis degree, remodeling index, and wall index) and plaque activation (enhancement pattern and volume). RESULTS: The asymptomatic CAD burden was correlated with the asymptomatic intracranial atherosclerotic disease burden. The overall CAD burden did not differ between B- and C-type intracranial atherosclerotic stroke. However, the prevalence of noncalcified coronary plaque was much higher in C-type intracranial atherosclerotic stroke and the presence of coronary noncalcified plaque was independently associated with C-type intracranial atherosclerotic stroke (odds ratio, 3.38; 95% confidence interval, 1.05-10.85; P=0.041). As the number of coronary noncalcified plaques increased, positive remodeling and plaque enhancement increased in the symptomatic intracranial artery on high-resolution magnetic resonance imaging. CONCLUSIONS: Plaques within the intracranial and coronary arteries behave in similar ways. Our results suggest the need to evaluate and treat other vascular trees in patients with vulnerable plaques within a single arterial system. PMID- 27217507 TI - Clinical Significance of Fluid-Attenuated Inversion Recovery Vascular Hyperintensities in Borderzone Infarcts. AB - BACKGROUND AND PURPOSE: Fluid-attenuated inversion recovery vascular hyperintensities (FVHs) are seen in some cases with cerebral hemodynamic impairment and collateral flow. Because the worst outcomes of patients with borderzone infarcts were mainly correlated with impaired hemodynamics, the presence of FVH might provide another clue for predicting the prognosis of patients with borderzone infarcts. METHODS: We reviewed 1377 consecutive patients with ischemic stroke. Cortical borderzone (CBZ) and internal borderzone infarcts were selected based on diffusion-weighted imaging. FVHs were defined as tubular- or serpentine-shaped hyperintensities in the subarachnoid space. We investigated the clinical significance of FVHs in borderzone-infarcted patients. RESULTS: Among 87 patients with borderzone infarcts, the presence of FVH was observed in 30 (34.5%). We identified 62 patients with CBZ infarcts and 25 patients with internal borderzone infarcts. In the cases with CBZ infarcts, the initial National Institutes of Health Stroke Scale scores and the portions of nonfavorable outcome at 3 months in the FVH(+) group were significantly higher than in the FVH(-) group (P<0.05 and P<0.001, respectively). Unlike the cases with CBZ infarcts, there were no significant differences of these clinical features between the FVH(+) group and the FVH(-) group in the patients with internal borderzone infarcts. CONCLUSIONS: The findings of FVH are associated with relatively severe clinical presentation and nonfavorable prognosis in patients with CBZ infarcts, but not in patients with internal borderzone infarcts. The presence of FVH may help to identify CBZ-infarcted patients who require close observation and hemodynamic control. PMID- 27217506 TI - Progressive Cortical Neuronal Damage and Chronic Hemodynamic Impairment in Atherosclerotic Major Cerebral Artery Disease. AB - BACKGROUND AND PURPOSE: Cross-sectional studies suggest that chronic hemodynamic impairment may cause selective cortical neuronal damage in patients with atherosclerotic internal carotid artery or middle cerebral artery occlusive disease. The purpose of this longitudinal study was to determine whether the progression of cortical neuronal damage, evaluated as a decrease in central benzodiazepine receptors (BZRs), is associated with hemodynamic impairment at baseline or hemodynamic deterioration during follow-up. METHODS: We evaluated the distribution of BZRs twice using positron emission tomography and (11)C flumazenil over time in 80 medically treated patients with atherosclerotic internal carotid artery or middle cerebral artery occlusive disease that had no ischemic episodes during follow-up. Using 3D stereotactic surface projections, we quantified abnormal decreases in the BZRs in the cerebral cortex within the middle cerebral artery distribution and correlated changes in the BZR index with the mean hemispheric values of hemodynamic parameters obtained from (15)O gas positron emission tomography. RESULTS: In the hemisphere affected by arterial disease, the BZR index in 40 patients (50%) was increased during follow-up (mean 26+/-20 months). In multivariable logistic regression analyses, increases in the BZR index were associated with the decreased cerebral blood flow at baseline and an increased oxygen extraction fraction during follow-up. Increases in the oxygen extraction fraction during follow-up were associated with a lack of statin use. CONCLUSIONS: In patients with atherosclerotic internal carotid artery or middle cerebral artery disease, the progression of cortical neuronal damage was associated with hemodynamic impairment at baseline and hemodynamic deterioration during follow-up. Statin use may be beneficial against hemodynamic deterioration and therefore neuroprotective. PMID- 27217508 TI - Outcome After Thrombectomy and Intravenous Thrombolysis in Patients With Acute Ischemic Stroke: A Prospective Observational Study. AB - BACKGROUND AND PURPOSE: In patients with ischemic stroke, randomized trials showed a better functional outcome after endovascular therapy with new-generation thrombectomy devices compared with medical treatment, including intravenous thrombolysis. However, effects on mortality and the generalizability of results to routine clinical practice are uncertain. METHODS: In a prospective observational register-based study patients with ischemic stroke treated either with thrombectomy, intravenous thrombolysis, or their combination were included. Primary outcome was the modified Rankin scale score (0 [no symptoms] to 6 [death]) at 3 months. Ordinal logistic regression was used to estimate the common odds ratio as treatment effects (shift analysis). Propensity score matching was applied to compare patients treated either with intravenous thrombolysis alone or with intravenous thrombolysis plus thrombectomy. RESULTS: Among 2650 recruited patients, 1543 received intravenous thrombolysis, 504 underwent thrombectomy, and 603 received intravenous thrombolysis in combination with thrombectomy. Later time-to-treatment was associated with worse outcomes among patients treated with thrombectomy plus thrombolysis. In 241 pairs of propensity score-matched patients with a proximal intracranial occlusion, thrombectomy plus thrombolysis was associated with improved functional outcome (common odds ratio, 1.84; 95% confidence interval, 1.32-2.57), and reduced mortality (15% versus 33%; P<0.0001) compared with intravenous thrombolysis alone. Results were similar in various sensitivity analyses accounting for missing outcome data and different analytic methods. CONCLUSIONS: Results from this large prospective registry show that also in routine clinical care thrombectomy plus thrombolysis compared with thrombolysis alone improved functional outcome and reduced mortality in patients with ischemic stroke. Earlier treatment was associated with better outcomes. PMID- 27217509 TI - Acute-Phase Blood Pressure Levels Correlate With a High Risk of Recurrent Strokes in Young-Onset Ischemic Stroke. AB - BACKGROUND AND PURPOSE: High blood pressure (BP) in acute stroke has been associated with a poor outcome; however, this has not been evaluated in young adults. METHODS: The relationship between BP and long-term outcome was assessed in 1004 consecutive young, first-ever ischemic stroke patients aged 15 to 49 years enrolled in the Helsinki Young Stroke Registry. BP parameters included systolic (SBP) and diastolic BP, pulse pressure, and mean arterial pressure at admission and 24 hours. The primary outcome measure was recurrent stroke in the long-term follow-up. Adjusted for demographics and preexisting comorbidities, Cox regression models were used to assess independent BP parameters associated with outcome. RESULTS: Of our patients (63% male), 393 patients (39%) had prestroke hypertension and 358 (36%) used antihypertensive treatment. The median follow-up period was 8.9 years (interquartile range 5.7-13.2). Patients with a recurrent stroke (n=142, 14%) had significantly higher admission SBP, diastolic BP, pulse pressure, and mean arterial pressure (P<0.001) and 24-h SBP, diastolic BP, and mean arterial pressure compared with patients without the recurrent stroke. Patients with SBP >=160 mm Hg compared with those with SBP <160 mm Hg had significantly more recurrent strokes (hazard ratio 3.3 [95% confidence interval, 2.05-4.55]; P<0.001) occurring earlier (13.9 years [13.0-14.6] versus 16.2 [15.8 16.6]; P<0.001) within the follow-up period. In multivariable analyses, higher admission SBP, diastolic BP, pulse pressure, and mean arterial pressure were independently associated with the risk of recurrent stroke, while the 24-hour BP levels were not. CONCLUSIONS: In young ischemic stroke patients, high acute phase BP levels are independently associated with a high risk of recurrent strokes. PMID- 27217510 TI - First-Ever Stroke and Transient Ischemic Attack Incidence and 30-Day Case Fatality Rates in a Population-Based Study in Argentina. AB - BACKGROUND AND PURPOSE: Epidemiological data about stroke are scarce in low- and middle-income Latin-American countries. We investigated annual incidence of first ever stroke and transient ischemic attack (TIA) and 30-day case-fatality rates in a population-based setting in Tandil, Argentina. METHODS: We prospectively identified all first-ever stroke and TIA cases from overlapping sources between January 5, 2013, and April 30, 2015, in Tandil, Argentina. We calculated crude and standardized incidence rates. We estimated 30-day case-fatality rates. RESULTS: We identified 334 first-ever strokes and 108 TIAs. Age-standardized incidence rate per 100 000 for Segi's World population was 76.5 (95% confidence interval [CI], 67.8-85.9) for first-ever stroke and 25.1 (95% CI, 20.2-30.7) for first-ever TIA, 56.1 (95% CI, 48.8-64.2) for ischemic stroke, 13.5 (95% CI, 9.9 17.9) for intracerebral hemorrhage, and 4.9 (95% CI, 2.7-8.1) for subarachnoid hemorrhage. Stroke incidence was slightly higher for men (87.8; 95% CI, 74.6 102.6) than for women (73.2; 95% CI, 61.7-86.1) when standardized for the Argentinean population. Thirty-day case-fatality rate was 14.7% (95% CI, 10.8 19.5) for ischemic stroke, 24.1% (95% CI, 14.2-36.6) for intracerebral hemorrhage, and 1.9% (95% CI, 0.4-5.8) for TIA. CONCLUSIONS: This study provides the first prospective population-based stroke and TIA incidence and case-fatality estimate in Argentina. First-ever stroke incidence was lower than that reported in previous Latin-American studies, but first-ever TIA incidence was higher. Thirty-day case-fatality rates were similar to those of other population-based Latin-American studies. PMID- 27217511 TI - Carotid Atherosclerosis and Stroke in Atrial Fibrillation: The Atherosclerosis Risk in Communities Study. AB - BACKGROUND AND PURPOSE: Whether consideration of carotid intima-media thickness (cIMT) and carotid plaque would improve risk prediction of ischemic stroke in persons with atrial fibrillation (AF) is unknown. The purpose of this study was to assess the improvement in risk prediction of stroke by adding cIMT and carotid plaque to the CHA2DS2-VASc (variables age, heart failure, hypertension, diabetes mellitus, myocardial infarction, and peripheral arterial disease) score. METHODS: We included participants from the Atherosclerosis Risk in Communities (ARIC) study (mean age, 63 years) who developed AF within 5 years after carotid measurement, were not on warfarin, and had no prior stroke at AF diagnosis. AF was ascertained from study ECGs and diagnosis codes, and stroke was physician adjudicated. Multivariable Cox models were used to assess association between carotid indices and ischemic stroke. Improvement in 10-year risk prediction of stroke was assessed by the C-statistic, net reclassification improvement, and relative integrated discrimination improvement. RESULTS: There were 81 (11.2%) stroke events that occurred among 724 participants with AF during a mean follow up of 8.5 years. Increased cIMT and presence of carotid plaque were significantly associated with increased stroke risk. The addition of cIMT+plaque to the CHA2DS2 VASc score marginally increased the C-statistic (95% confidence interval) from 0.685 (0.623-0.747) to 0.698 (0.638-0.759). The net reclassification improvement and integrated discrimination improvement for cIMT+plaque were 0.091 (95% confidence interval, 0.012-0.170) and 0.101 (95% confidence interval, 0.002 0.226), respectively. CONCLUSIONS: Increased cIMT and presence of carotid plaque are associated with increased risk of ischemic stroke in individuals with AF. Furthermore, they may improve risk prediction of stroke, over and above the CHA2DS2-VASc score. PMID- 27217512 TI - Letter by Choudhary et al Regarding Article, "Admission Hyperglycemia and Poor Outcomes in Cerebral Venous Thrombosis". PMID- 27217513 TI - Response to Letter Regarding Article, "Admission Hyperglycemia and Clinical Outcome in Cerebral Venous Thrombosis". PMID- 27217514 TI - Letter by Shao and Zhang Regarding Article, "Matrix Metalloprotease 3 Exacerbates Hemorrhagic Transformation and Worsens Functional Outcomes in Hyperglycemic Stroke". PMID- 27217515 TI - Response to Letter Regarding Article, "Matrix Metalloprotease 3 Exacerbates Hemorrhagic Transformation and Worsens Functional Outcomes in Hyperglycemic Stroke". PMID- 27217516 TI - Correction. PMID- 27217517 TI - A comparison of automated dispensing cabinet optimization methods. AB - PURPOSE: Results of a study comparing two methods of optimizing automated dispensing cabinets (ADCs) are reported. METHODS: Eight nonprofiled ADCs were optimized over six months. Optimization of each cabinet involved three steps: (1) removal of medications that had not been dispensed for at least 180 days, (2) movement of ADC stock to better suit end-user needs and available space, and (3) adjustment of par levels (desired on-hand inventory levels). The par levels of four ADCs (the Day Supply group) were adjusted according to average daily usage; the par levels of the other four ADCs (the Formula group) were adjusted using a standard inventory formula. The primary outcome was the vend:fill ratio, while secondary outcomes included total inventory, inventory cost, quantity of expired medications, and ADC stockout percentage. RESULTS: The total number of medications stocked in the eight machines was reduced from 1,273 in a designated two-month preoptimization period to 1,182 in a designated two-month postoptimization period, yielding a carrying cost savings of $44,981. The mean vend:fill ratios before and after optimization were 4.43 and 4.46, respectively. The vend:fill ratio for ADCs in the Formula group increased from 4.33 before optimization to 5.2 after optimization; in the Day Supply group, the ratio declined (from 4.52 to 3.90). The postoptimization interaction difference between the Formula and Day Supply groups was found to be significant (p = 0.0477). CONCLUSION: ADC optimization via a standard inventory formula had a positive impact on inventory costs, refills, vend:fill ratios, and stockout percentages. PMID- 27217518 TI - Ramucirumab: A vascular endothelial growth factor receptor-2 inhibitor with activity in several malignancies. AB - PURPOSE: The pharmacology, pharmacokinetics, safety, dosage and administration, current and potential roles in therapy, and cost considerations of ramucirumab are reviewed. SUMMARY: Ramucirumab is a recombinant monoclonal antibody that selectively inhibits vascular endothelial growth factor receptor-2. Ramucirumab has been approved for the treatment of gastric cancer, non-small-cell lung cancer (NSCLC), and metastatic colorectal cancer. Ramucirumab displays similar pharmacokinetics in patients with gastric cancer, NSCLC, and metastatic colorectal cancer. The most common adverse effects of any grade with ramucirumab monotherapy included fatigue, decreased appetite, abdominal pain, hypertension, anemia, hemorrhage, and diarrhea. For ramucirumab monotherapy in patients with gastric cancer, ramucirumab 8 mg/kg should be administered by i.v. infusion every two weeks. For combination therapy, ramucirumab should be administered at the same dose with weekly paclitaxel 80 mg/m(2) i.v. on days 1, 8, and 15 every 28 days. When treating NSCLC, the recommended ramucirumab dose is 10 mg/kg i.v. with docetaxel 75 mg/m(2) i.v. on day 1 every 21 days. For combination therapy with FOLFIRI (fluorouracil, leucovorin, and irinotecan) for metastatic colorectal cancer, ramucirumab 8 mg/kg should be administered by i.v. infusion every two weeks. The average wholesale prices of ramucirumab are $1224 and $6120 for the 100- and 500-mg single-dose vials, respectively. CONCLUSION: Ramucirumab has demonstrated benefit in a variety of cancers, supporting the role of antiangiogenic agents in the management of malignancies. However, the clinical benefit in certain malignancies may be offset by the high cost of ramucirumab and the duration of treatment. PMID- 27217519 TI - New combination antiviral for the treatment of hepatitis C. AB - PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, and safety of Viekira, as well as its place in hepatitis C virus (HCV) therapy, are reviewed. SUMMARY: Ombitasvir 25 mg-paritaprevir 150 mg-ritonavir 100 mg plus dasabuvir 250 mg (Viekira) is approved in the United States as a combination direct-acting antiviral agent for treatment-naive or treatment-experienced patients with HCV genotype 1 infection, including those with compensated cirrhosis. It is the first coformulated direct-acting antiviral that targets different stages of the virus's life cycle. Viekira is administered as an oral, interferon-free regimen. Phase III clinical trials demonstrated that Viekira administered with or without ribavirin can achieve sustained virological response rates of >=90%. These results are notable because they show that high virological cure rates can be achieved without peginterferon and ribavirin. Viekira is also effective for special patient populations, such as individuals coinfected with HIV, liver transplant recipients, and those with advanced renal disease. The most frequently reported adverse effects among patients associated with Viekira without ribavirin were nausea, pruritus, and insomnia. During clinical trials, the most common adverse effects among patients receiving Viekira with ribavirin were fatigue, nausea, pruritus, insomnia, and weakness. CONCLUSION: Viekira, the first coformulated direct-acting antiviral that targets different stages of the HCV life cycle, is an interferon-free treatment for HCV genotype 1 infection. It is associated with a virological cure rate of >=90% and treatment durations of 12 and 24 weeks. Viekira is also effective and safe for patients who have undergone liver transplantation, are coinfected with HIV, or have advanced kidney disease. PMID- 27217520 TI - Symptomatic accessory cardiac bronchus in an infant. PMID- 27217521 TI - Does UKLS strategy increase the yield of screen-detected lung cancers? A comparison with ITALUNG. PMID- 27217522 TI - Multivariate Analysis of the Risk Factors for First-Time Noncontact ACL Injury in High School and College Athletes: A Prospective Cohort Study With a Nested, Matched Case-Control Analysis. AB - BACKGROUND: Multivariate analysis that identifies the combination of risk factors associated with anterior cruciate ligament (ACL) trauma is important because it provides insight into whether a variable has a direct causal effect on risk or an indirect effect that is mediated by other variables. It can also reveal risk factors that might not be evident in univariate analyses; if a variable's effect is moderated by other variables, its association with risk may be apparent only after adjustment for the other variables. Most important, multivariate analyses can identify combinations of risk factors that are more predictive of risk than individual risk factors. HYPOTHESIS: A diverse combination of risk factors predispose athletes to first-time noncontact ACL injury, and these relationships are different for male and female athletes. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Athletes competing in organized sports at the high school and college levels participated in this study. Data from injured subjects (109 suffering an ACL injury) and matched controls (227 subjects) from the same athletic team were analyzed with multivariate conditional logistic regression to examine the effects of combinations of variables (demographic characteristics, joint laxity, lower extremity alignment, strength, and personality traits) on the risk of suffering their first ACL injury and to construct risk models. RESULTS: For male athletes, increases in anterior-posterior displacement of the tibia relative to the femur (knee laxity), posterior knee stiffness, navicular drop, and a decrease in standing quadriceps angle were jointly predictive of suffering an ACL injury. For female athletes the combined effects of having a parent who had suffered an ACL injury and increases in anterior-posterior knee laxity and body mass index were predictive of ACL injury. CONCLUSION: Multivariate models provided more information about ACL injury risk than individual risk factors. Both male and female risk models included increased anterior-posterior knee laxity as a predictor of ACL injury but were otherwise dissimilar. PMID- 27217523 TI - Clinical and Anatomic Predictors of Outcomes After the Latarjet Procedure for the Treatment of Anterior Glenohumeral Instability With Combined Glenoid and Humeral Bone Defects. AB - BACKGROUND: The Latarjet procedure for the treatment of recurrent anterior shoulder instability is highly successful, but reasons for failure are often unclear. Measurements of the "glenoid track" have not previously been evaluated as potential predictors of postoperative stability. HYPOTHESIS: There are clinical and anatomic characteristics, including the glenoid track, that are predictive of outcomes after the Latarjet procedure. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Patients who underwent the Latarjet procedure for anterior shoulder instability with glenoid bone loss before October 2012 were assessed for eligibility. Patient-reported subjective data that were prospectively collected and retrospectively reviewed included demographic information, patient satisfaction, pain measured on a visual analog scale (VAS), questions regarding instability, Single Assessment Numeric Evaluation (SANE) scores, American Shoulder and Elbow Surgeons (ASES) scores, Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) scores, and Short Form-12 Physical Component Summary (SF-12 PCS) scores. Anatomic measurements were performed of the coracoid size (surface area and width), width of the conjoined tendon and subscapularis tendon, estimated glenoid defect surface area, Hill-Sachs interval (HSI), and projected postoperative glenoid track engagement. Failure was defined as the necessity for revision stabilization or continued instability (dislocation or subjective subluxation) at a minimum of 2 years postoperatively. RESULTS: A total of 38 shoulders in 38 patients (33 men, 5 women) with a mean age of 26 years (range, 16-43 years) were included. The mean follow-up for 35 of 38 patients (92%) was 3.2 years (range, 2.0-7.9 years); 25 of 38 had undergone prior stabilization surgery, and 6 had workers' compensation claims. All mean subjective outcome scores significantly improved (P < .05), with a high median satisfaction score of 9 of 10. Eight patients had failures because of continued instability. Patients with moderate or higher preoperative pain scores (VAS >=3) had a negative correlation with postoperative SF-12 PCS scores (rho = 0.474, P = .022). Patients with outside-and-engaged (Out-E) or "off-track" lesions were 4.0 times more likely to experience postoperative instability (relative risk, 4.0; 95% CI, 1.32-12.2; P = .33). The width of patients' coracoid processes was also directly associated with postoperative stability (P = .014). Moreover, 50% (4/8) of failures demonstrated Out-E glenoid tracks (off-track lesions) versus 16% (4/25) of those without recurrent instability (P = .033). Five of 8 failures were considered as such because of subjective subluxation events, not frank dislocations. Four of the 6 patients with workers' compensation claims had failed results (P = .016). CONCLUSION: Workers' compensation claims were associated with continued instability, and patients with higher preoperative pain levels demonstrated lower SF-12 PCS scores postoperatively. The concept of the glenoid track may be predictive of stability after the Latarjet procedure and may be helpful in surgical decision making regarding the treatment of Hill-Sachs lesions at risk for persistent engagement. Although stability and patient satisfaction are high after the Latarjet procedure, subjective complaints of subluxation may be more common than previously estimated. PMID- 27217524 TI - Effect of Trochlear Dysplasia on Outcomes After Isolated Soft Tissue Stabilization for Patellar Instability. AB - BACKGROUND: Trochlear dysplasia is a well-described risk factor for patellofemoral instability. Despite its clear association with the incidence of patellar instability, it is unclear whether the presence of high-grade trochlear dysplasia influences clinical outcome after patellofemoral stabilization. PURPOSE: To determine whether isolated proximal soft tissue stabilization for patellofemoral instability is as successful in patients with high-grade dysplasia compared with low-grade or no dysplasia, as measured by disease-specific quality of-life and pain scores. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 277 patellofemoral stabilization procedures were performed during the study period. An isolated stabilization was performed in 233 patients, and 203 of these patients (87%) had adequate lateral radiographs and complete Banff Patella Instability Instrument (BPII) scores available for assessment. Of these, 152 patients underwent a medial patellofemoral ligament reconstruction (MPFL-R) and 51 patients received a medial patellofemoral ligament imbrication (MPFL-I). There were 21 patients with no trochlear dysplasia, 89 patients with low-grade dysplasia (Dejour type A), and 93 patients with high-grade dysplasia (Dejour types B-D). An independent-samples t test was used to determine the difference between the pre- and postoperative BPII scores. A Spearman rho correlation was calculated between 3 trochlear dysplasia groups and the BPII scores at a mean 24 months after patellofemoral stabilization. An independent samples t test was used to assess the influence of trochlear bump size on outcomes by stratifying data and assessing for a relationship to BPII scores. RESULTS: The independent-samples t test demonstrated statistically significant improvements in pre- to postoperative BPII scores for both groups. The MPFL-R group improved from a mean BPII score of 24.36 to 65.16 (P < .001), and the MPFL I group improved from a mean of 28.92 to 73.45 (P < .01). For the MPFL-R patient cohort, the Spearman rho correlation demonstrated a significant relationship between postoperative BPII scores and presence of a trochlear bump and degree of dysplasia (P <= .05). Overall, a trochlear bump of >=5 mm was associated with lower postoperative BPII scores (t(193) = 2.65, eta(2) = 0.04). CONCLUSION: This research has established a statistically significant correlation between trochlear dysplasia and disease-specific outcomes after MPFL-R surgery. Overall, there was evidence of significant improvement in disease-specific quality-of-life scores after patellofemoral stabilization surgery. This study is the largest cohort reported to date and therefore adds substantially to the evidence that trochlear dysplasia is a significant risk factor for and predictor of outcome among patients with patellofemoral instability. PMID- 27217525 TI - Platelet-Rich Plasma in a Murine Model: Leukocytes, Growth Factors, Flt-1, and Muscle Healing. AB - BACKGROUND: It is well known that platelet-rich plasma (PRP) preparations are not the same and that not all preparations include white blood cells, but the part that leukocytes play on the healing role of PRP is still unknown. PURPOSE: The primary aim of this study was to evaluate the influence of leukocytes in different PRP preparations with a special emphasis on growth factor concentrations. The secondary aim was to evaluate the influence of PRP on muscle healing. STUDY DESIGN: Controlled laboratory study. METHODS: Two PRP preparation procedures were evaluated. Blood fractions were stained with Rapid Panoptic, and growth factors (transforming growth factor beta 1 [TGF-beta1], vascular endothelial growth factor [VEGF], insulin-like growth factor [IGF], epidermal growth factor [EGF], hepatocyte growth factor [HGF], and platelet-derived growth factor [PDGF]) were quantified by enzyme-linked immunosorbent assay. Western blotting analysis was performed for Fms-related tyrosine kinase 1 (Flt-1). A muscle contusion injury was created and treated with PRP at different time points. RESULTS: Leukocytes were the main source of VEGF, and all other growth factors measured had a higher concentration in the preparations that included the buffy coat and consequently had a higher concentration of white blood cells. Flt 1 was also found in platelet-poor plasma (PPP). There were higher concentrations of PDGF and HGF in the preparations that encompassed the buffy coat. A PRP injection 7 days after the injury provided significantly increased exercise performance and decreased the fibrotic area when compared with other PRP-treated groups. CONCLUSION: VEGF is only present in PRP's buffy coat, while Flt-1 is present in PPP. A PRP injection 7 days after an injury resulted in improved exercise performance. CLINICAL RELEVANCE: The presence of Flt-1 in PRP provides yet another explanation for results described in the literature after a PRP injection. This information is relevant for selecting the best PRP for each type of injury. PMID- 27217526 TI - Investigating the European beech (Fagus sylvatica L.) leaf characteristics along the vertical canopy profile: leaf structure, photosynthetic capacity, light energy dissipation and photoprotection mechanisms. AB - Forest functionality and productivity are directly related to canopy light interception and can be affected by potential damage from high irradiance. However, the mechanisms by which leaves adapt to the variable light environments along the multilayer canopy profile are still poorly known. We explored the leaf morphophysiological and metabolic responses to the natural light gradient in a pure European beech (Fagus sylvatica L.) forest at three different canopy heights (top, middle and bottom). Structural adjustment through light-dependent modifications in leaf mass per area was the reason for most of the variations in photosynthetic capacity. The different leaf morphology along the canopy influenced nitrogen (N) partitioning, water- and photosynthetic N-use efficiency, chlorophyll (Chl) fluorescence and quali-quantitative contents of photosynthetic pigments. The Chl a to Chl b ratio and the pool of xanthophyll-cycle pigments (VAZ) increased at the highest irradiance, as well as lutein and beta-carotene. The total pool of ascorbate and phenols was higher in leaves of the top and middle canopy layers when compared with the bottom layer, where the ascorbate peroxidase was relatively more activated. The non-photochemical quenching was strongly and positively related to the VAZ/(Chl a + b) ratio, while Chl a/Chl b was related to the photochemical efficiency of photosystem II. Along the multilayer canopy profile, the high energy dissipation capacity of leaves was correlated to an elevated redox potential of antioxidants. The middle layer gave the most relevant contribution to leaf area index and carboxylation capacity of the canopy. In conclusion, a complex interplay among structural, physiological and biochemical traits drives the dynamic leaf acclimation to the natural gradients of variable light environments along the tree canopy profile. The relevant differences observed in leaf traits within the canopy positions of the beech forest should be considered for improving estimation of carbon fluxes in multilayer canopy models of temperate forests. PMID- 27217527 TI - Differences in ozone sensitivity among woody species are related to leaf morphology and antioxidant levels. AB - Ozone (O3) sensitivity varies greatly among plant species. Leaf traits such as stomatal conductance, antioxidant capacity and leaf morphology and anatomy may play important roles in controlling this variation, but the relative contributions of each trait remain elusive. In this study, we examined the differences in O3 sensitivity among 29 deciduous and evergreen woody species used for urban greening in China in an open-top chamber experiment. Elevated O3 caused visible injury and reductions in net photosynthesis, and these effects differed significantly among species. The deciduous species Sorbaria sorbifolia, Hibiscus syriacus and Fraxinus chinensis were the most sensitive, while evergreen species ranked among the most tolerant. O3 sensitivity was linked to both low leaf mass per area (LMA) and low leaf area-based antioxidant levels, but not to variation in leaf mass-based antioxidant levels or stomatal conductance. The well-known and easily measured leaf trait LMA thus represents a potentially useful metric for O3 risk assessment and for selecting appropriate species for urban greening in O3 polluted areas. PMID- 27217528 TI - Branch age and light conditions determine leaf-area-specific conductivity in current shoots of Scots pine. AB - Shoot size and other shoot properties more or less follow the availability of light, but there is also evidence that the topological position in a tree crown has an influence on shoot development. Whether the hydraulic properties of new shoots are more regulated by the light or the position affects the shoot acclimation to changing light conditions and thereby to changing evaporative demand. We investigated the leaf-area-specific conductivity (and its components sapwood-specific conductivity and Huber value) of the current-year shoots of Scots pine (Pinus sylvestris L.) in relation to light environment and topological position in three different tree classes. The light environment was quantified in terms of simulated transpiration and the topological position was quantified by parent branch age. Sample shoot measurements included length, basal and tip diameter, hydraulic conductivity of the shoot, tracheid area and density, and specific leaf area. In our results, the leaf-area-specific conductivity of new shoots declined with parent branch age and increased with simulated transpiration rate of the shoot. The relation to transpiration demand seemed more decisive, since it gave higher R(2) values than branch age and explained the differences between the tree classes. The trend of leaf-area-specific conductivity with simulated transpiration was closely related to Huber value, whereas the trend of leaf-area-specific conductivity with parent branch age was related to a similar trend in sapwood-specific conductivity. PMID- 27217529 TI - Freezing resistance in Patagonian woody shrubs: the role of cell wall elasticity and stem vessel size. AB - Freezing resistance through avoidance or tolerance of extracellular ice nucleation is important for plant survival in habitats with frequent subzero temperatures. However, the role of cell walls in leaf freezing resistance and the coordination between leaf and stem physiological processes under subzero temperatures are not well understood. We studied leaf and stem responses to freezing temperatures, leaf and stem supercooling, leaf bulk elastic modulus and stem xylem vessel size of six Patagonian shrub species from two sites (plateau and low elevation sites) with different elevation and minimum temperatures. Ice seeding was initiated in the stem and quickly spread to leaves, but two species from the plateau site had barriers against rapid spread of ice. Shrubs with xylem vessels smaller in diameter had greater stem supercooling capacity, i.e., ice nucleated at lower subzero temperatures. Only one species with the lowest ice nucleation temperature among all species studied exhibited freezing avoidance by substantial supercooling, while the rest were able to tolerate extracellular freezing from -11.3 to -20 degrees C. Leaves of species with more rigid cell walls (higher bulk elastic modulus) could survive freezing to lower subzero temperatures, suggesting that rigid cell walls potentially reduce the degree of physical injury to cell membranes during the extracellular freezing and/or thaw processes. In conclusion, our results reveal the temporal-spatial ice spreading pattern (from stem to leaves) in Patagonian shrubs, and indicate the role of xylem vessel size in determining supercooling capacity and the role of cell wall elasticity in determining leaf tolerance of extracellular ice formation. PMID- 27217530 TI - Individual traits as determinants of time to death under extreme drought in Pinus sylvestris L. AB - Plants exhibit a variety of drought responses involving multiple interacting traits and processes, which makes predictions of drought survival challenging. Careful evaluation of responses within species, where individuals share broadly similar drought resistance strategies, can provide insight into the relative importance of different traits and processes. We subjected Pinus sylvestris L. saplings to extreme drought (no watering) leading to death in a greenhouse to (i) determine the relative effect of predisposing factors and responses to drought on survival time, (ii) identify and rank the importance of key predictors of time to death and (iii) compare individual characteristics of dead and surviving trees sampled concurrently. Time until death varied over 3 months among individual trees (from 29 to 147 days). Survival time was best predicted (higher explained variance and impact on the median survival time) by variables related to carbon uptake and carbon/water economy before and during drought. Trees with higher concentrations of monosaccharides before the beginning of the drought treatment and with higher assimilation rates prior to and during the treatment survived longer (median survival time increased 25-70 days), even at the expense of higher water loss. Dead trees exhibited less than half the amount of nonstructural carbohydrates (NSCs) in branches, stem and relative to surviving trees sampled concurrently. Overall, our results indicate that the maintenance of carbon assimilation to prevent acute depletion of NSC content above some critical level appears to be the main factor explaining survival time of P. sylvestris trees under extreme drought. PMID- 27217531 TI - ERRATUM. PMID- 27217533 TI - Prospective cohort analysis of cellphone use and emotional and behavioural difficulties in children. AB - BACKGROUND: We previously reported associations between cellphone exposure and emotional and behavioural difficulties in children in the Danish National Birth Cohort using cross-sectional data. To overcome the limitations of cross-sectional analysis, we re-examined these associations with prospectively collected data. METHODS: Based on maternal reports, prenatal and postnatal cellphone exposures were assessed at age 7 years, and emotional and behavioural difficulties were assessed at 7 and 11 years with the Strengths and Difficulties Questionnaire. We used multivariable-adjusted logistic regression models to estimate ORs and 95% CIs relating prenatal exposure and age-7 cellphone use to emotional and behavioural difficulties at age 11 years. RESULTS: Children without emotional and behavioural difficulties at age 7 years, but who had cellphone exposures, had increased odds of emotional and behavioural difficulties at age 11 years, with an OR of 1.58 (95% CI 1.34 to 1.86) for children with both prenatal and age-7 cellphone exposures, 1.41 (95% CI 1.20 to 1.66) for prenatal exposure only, and 1.36 (95% CI 1.14 to 1.63) for age-7 use only. These results did not materially change when early adopters were excluded, or when children with emotional and behavioural difficulties at age 7 years were included in the analysis. CONCLUSIONS: Our findings are consistent with patterns seen in earlier studies, and suggest that both prenatal and postnatal exposures may be associated with increased risks of emotional and behavioural difficulties in children. PMID- 27217534 TI - Role of psychosocial work factors in the relation between becoming a caregiver and changes in health behaviour: results from the Whitehall II cohort study. AB - BACKGROUND: The present study tested the effects of becoming a caregiver combined with adverse working conditions on changes in health behaviours. METHODS: Participants were 5419 British civil servants from the Whitehall II cohort study who were not caregivers at baseline (phase 3, 1991-1994). Psychosocial work factors were assessed at baseline. Phase 4 questionnaire (1995-1996) was used to identify participants who became caregivers to an aged or disabled relative. Smoking, alcohol consumption and exercise were assessed at baseline and follow-up (phase 5, 1997-1999). RESULTS: Those who became caregivers were more likely to increase frequency of alcohol consumption, but only if they also reported low decision latitude at work (OR= 1.65, 95% CI 1.15 to 2.37 compared with non caregivers with average decision latitude), or belonged to low occupational social class (OR=2.38, 95% CI 1.17 to 4.78 compared with non-caregivers of high occupational social class). Caregivers were more likely to quit smoking if job demands were low (OR=2.92; 95% CI 1.07 to 7.92 compared with non-caregivers with low job demands), or if social support at work was high (OR=2.99, 95% CI 1.01 to 8.86 compared with caregivers with average social support). There was no effect of caregiving on reducing exercise below recommended number of hours per week, or on drinking above recommended number of units per week, regardless of working conditions. CONCLUSIONS: The findings underscore the importance of a well balanced work environment as a resource for people exposed to increased family demands. PMID- 27217535 TI - Effects of an air pollution personal alert system on health service usage in a high-risk general population: a quasi-experimental study using linked data. AB - BACKGROUND: There is no evidence to date on whether an intervention alerting people to high levels of pollution is effective in reducing health service utilisation. We evaluated alert accuracy and the effect of a targeted personal air pollution alert system, airAware, on emergency hospital admissions, emergency department attendances, general practitioner contacts and prescribed medications. METHODS: Quasi-experimental study describing accuracy of alerts compared with pollution triggers; and comparing relative changes in healthcare utilisation in the intervention group to those who did not sign-up. Participants were people diagnosed with asthma, chronic obstructive pulmonary disease (COPD) or coronary heart disease, resident in an industrial area of south Wales and registered patients at 1 of 4 general practices. Longitudinal anonymised record linked data were modelled for participants and non-participants, adjusting for differences between groups. RESULTS: During the 2-year intervention period alerts were correctly issued on 208 of 248 occasions; sensitivity was 83.9% (95% CI 78.8% to 87.9%) and specificity 99.5% (95% CI 99.3% to 99.6%). The intervention was associated with a 4-fold increase in admissions for respiratory conditions (incidence rate ratio (IRR) 3.97; 95% CI 1.59 to 9.93) and a near doubling of emergency department attendance (IRR=1.89; 95% CI 1.34 to 2.68). CONCLUSIONS: The intervention was associated with increased emergency admissions for respiratory conditions. While findings may be context specific, evidence from this evaluation questions the benefits of implementing near real-time personal pollution alert systems for high-risk individuals. PMID- 27217536 TI - Local antigen in nonlymphoid tissue promotes resident memory CD8+ T cell formation during viral infection. AB - Tissue-resident memory (Trm) CD8(+) T cells are functionally distinct from their circulating counterparts and are potent mediators of host protection against reinfection. Whether local recognition of antigen in nonlymphoid tissues during infection can impact the formation of Trm populations remains unresolved. Using skin infections with vaccinia virus (VacV)-expressing model antigens, we found that local antigen recognition had a profound impact on Trm formation. Activated CD8(+) T cells trafficked to VacV-infected skin in an inflammation-dependent, but antigen-independent, manner. However, after viral clearance, there was a subsequent ~50-fold increase in Trm formation when antigen was present in the tissue microenvironment. Secondary antigen stimulation in nonlymphoid tissue caused CD8(+) T cells to rapidly express CD69 and be retained at the site of infection. Finally, Trm CD8(+) T cells that formed during VacV infection in an antigen-dependent manner became potent stimulators of localized antigen-specific inflammatory responses in the skin. Thus, our studies indicate that the presence of antigen in the nonlymphoid tissue microenvironment plays a critical role in the formation of functional Trm CD8(+) T cell populations, a finding with relevance for both vaccine design and prevention of inflammatory disorders. PMID- 27217538 TI - Epstein-Barr virus nuclear protein EBNA3C directly induces expression of AID and somatic mutations in B cells. AB - Activation-induced cytidine deaminase (AID), the enzyme responsible for induction of sequence variation in immunoglobulins (Igs) during the process of somatic hypermutation (SHM) and also Ig class switching, can have a potent mutator phenotype in the development of lymphoma. Using various Epstein-Barr virus (EBV) recombinants, we provide definitive evidence that the viral nuclear protein EBNA3C is essential in EBV-infected primary B cells for the induction of AID mRNA and protein. Using lymphoblastoid cell lines (LCLs) established with EBV recombinants conditional for EBNA3C function, this was confirmed, and it was shown that transactivation of the AID gene (AICDA) is associated with EBNA3C binding to highly conserved regulatory elements located proximal to and upstream of the AICDA transcription start site. EBNA3C binding initiated epigenetic changes to chromatin at specific sites across the AICDA locus. Deep sequencing of cDNA corresponding to the IgH V-D-J region from the conditional LCL was used to formally show that SHM is activated by functional EBNA3C and induction of AID. These data, showing the direct targeting and induction of functional AID by EBNA3C, suggest a novel role for EBV in the etiology of B cell cancers, including endemic Burkitt lymphoma. PMID- 27217537 TI - Interferon-driven alterations of the host's amino acid metabolism in the pathogenesis of typhoid fever. AB - Enteric fever, caused by Salmonella enterica serovar Typhi, is an important public health problem in resource-limited settings and, despite decades of research, human responses to the infection are poorly understood. In 41 healthy adults experimentally infected with wild-type S. Typhi, we detected significant cytokine responses within 12 h of bacterial ingestion. These early responses did not correlate with subsequent clinical disease outcomes and likely indicate initial host-pathogen interactions in the gut mucosa. In participants developing enteric fever after oral infection, marked transcriptional and cytokine responses during acute disease reflected dominant type I/II interferon signatures, which were significantly associated with bacteremia. Using a murine and macrophage infection model, we validated the pivotal role of this response in the expression of proteins of the host tryptophan metabolism during Salmonella infection. Corresponding alterations in tryptophan catabolites with immunomodulatory properties in serum of participants with typhoid fever confirmed the activity of this pathway, and implicate a central role of host tryptophan metabolism in the pathogenesis of typhoid fever. PMID- 27217539 TI - Dynamic changes in Id3 and E-protein activity orchestrate germinal center and plasma cell development. AB - The generation of high-affinity antibodies requires germinal center (GC) development and differentiation of long-lived plasma cells in a multilayered process that is tightly controlled by the activity of multiple transcription factors. Here, we reveal a new layer of complexity by demonstrating that dynamic changes in Id3 and E-protein activity govern both GC and plasma cell differentiation. We show that down-regulation of Id3 in B cells is essential for releasing E2A and E2-2, which in a redundant manner are required for antigen induced B cell differentiation. We demonstrate that this pathway controls the expression of multiple key factors, including Blimp1, Xbp1, and CXCR4, and is therefore critical for establishing the transcriptional network that controls GC B cell and plasma cell differentiation. PMID- 27217540 TI - Oral health and risk of colorectal cancer: results from three cohort studies and a meta-analysis. AB - BACKGROUND: While studies have shown that poor oral health status may increase the risk of cancer, evidence of a specific association with the risk of colorectal cancer (CRC) is inconclusive. We evaluated the association between oral health and CRC risk using data from three large cohorts: the Shanghai Men's Health Study (SMHS), the Shanghai Women's Health Study (SWHS), and the Southern Community Cohort Study (SCCS), and carried out a meta-analysis of results from other relevant published studies. PATIENTS AND METHODS: This study applied a nested case-control study design and included 825 cases/3298 controls from the SMHS/SWHS and 238 cases/2258 controls from the SCCS. The association between oral health status (i.e. tooth loss/tooth decay) and CRC risk was assessed using conditional logistic regression models. A meta-analysis was carried out based on results from the present study and three published studies. RESULTS: We found that tooth loss was not associated with increased risk of CRC. ORs and respective 95% CIs associated with loss of 1-5, 6-10, and >10 teeth compared with those with full teeth are 0.87 (0.69-1.10), 0.93 (0.70-1.24), and 0.85 (0.66-1.11) among SMHS/SWHS participants; and 1.13 (0.72-1.79), 0.87 (0.52-1.43), and 1.00 (0.63 1.58) for those with loss of 1-4, 5-10, and >10 teeth among SCCS participants. Data regarding tooth decay were available in the SCCS, but were not associated with CRC risk. Meta-analysis confirmed the null association between tooth loss/periodontal disease and CRC risk (OR 1.05, 95% CI 0.86-1.29). CONCLUSION: In this analysis of three cohorts and a meta-analysis, we found no evidence supporting an association between oral health and CRC risk. PMID- 27217541 TI - Frequent PD-L1 expression in primary and metastatic penile squamous cell carcinoma: potential opportunities for immunotherapeutic approaches. AB - BACKGROUND: Despite aggressive multimodal therapy, locally advanced and/or metastatic penile squamous cell carcinoma (SqCC) is associated with significant morbidity and mortality, indicating a need for new therapeutic options. Given the emerging clinical utility of immunotherapeutics, we sought to assess the incidence and potential clinical significance of PD-L1 expression in penile SqCC. PATIENTS AND METHODS: Using an anti-PD-L1 primary antibody (clone 5H1), immunohistochemistry was carried out on whole tumor sections from 37 patients with penile SqCC treated at our institution between 2005 and 2013. PD-L1-positive tumors were defined as those with membranous staining in >=5% of tumor cells. Association between PD-L1 expression and clinicopathologic parameters was examined using Fisher's exact test. Correlation between PD-L1 expression in primary tumors and matched metastases was assessed using the Spearman rank correlation coefficient (rho). The difference in cancer-specific mortality between PD-L1-positive and -negative groups was examined using the log-rank test. RESULTS: Twenty-three (62.2%) of 37 primary tumors were positive for PD-L1 expression, and there was strong positive correlation of PD-L1 expression in primary and metastatic samples (rho = 0.72; 0.032 < P < 0.036). Primary tumor PD L1 expression was significantly associated with usual type histology (P = 0.040) and regional lymph node metastasis (P = 0.024), as well as decreased cancer specific survival (P = 0.011). CONCLUSIONS: The majority of primary penile SqCC tumors express PD-L1, which is associated with high-risk clinicopathologic features and poor clinical outcome. These data provide a rational basis for further investigation of anti-PD-1 and anti-PD-L1 immunotherapeutics in patients with advanced penile SqCC. PMID- 27217542 TI - PAN-EX: a pooled analysis of two trials of neoadjuvant chemotherapy followed by chemoradiotherapy in MRI-defined, locally advanced rectal cancer. AB - BACKGROUND: EXPERT and EXPERT-C were phase II clinical trials of neoadjuvant chemotherapy (NACT) followed by chemoradiotherapy (CRT) in high-risk, locally advanced rectal cancer (LARC). DESIGN: We pooled individual patient data from these trials. The primary objective was overall survival (OS) in the intention-to treat (ITT) population. Prognostic factors were also analysed. RESULTS: A total of 269 patients were included. Of these, 91.1% completed NACT, 88.1% completed CRT and 240 (89.2%) underwent curative surgery (R0/R1). After a median follow-up of 71.9 months, 5-year progression-free survival (PFS) and OS were 66.4% and 73.3%, respectively. In the group of R0/R1 resection patients, 5-year relapse free survival (RFS) and OS were 71.6% and 77.2%, respectively, with local recurrence occurring in 5.5% and distant metastases in 20.6% of cases. Significant prognostic factors after multivariate analyses included age, tumour grade and MRI extramural venous invasion (mrEMVI) at baseline, MRI tumour regression grade (mrTRG) after CRT, ypT stage after surgery and adherence to study treatment. mrTRG after NACT was associated with PFS (P = 0.002) and OS (P = 0.018) and appeared to stratify patients based on the incremental benefit from sequential CRT. Among the outcome measures considered, in the subgroup of R0/R1 resection patients, ypT and ypStage had the highest predictive accuracy for RFS (concordance index: 0.6238 and 0.6252, respectively) and OS (concordance index: 0.6094 and 0.6132, respectively). CONCLUSIONS: Administering NACT before CRT could be a potential strategy for high-risk LARC. In this setting, mrTRG after CRT is an independent prognostic factor, while mrTRG after NACT should be tested as a parameter for treatment selection in trials of NACT +/- CRT. ypT stage may be a valuable surrogate end point for future phase II trials investigating intensified neoadjuvant treatments in similar patient populations. PMID- 27217543 TI - How to report toxicity associated with targeted therapies? AB - BACKGROUND: In the era of personalized medicine, molecularly targeted therapies (MTT) have modified the outcome of some cancer types. The price of tumor control needs to be balanced with toxicity since these new therapies are administered continuously for several months or sometimes for several years. For cytotoxic drugs, the incidence of adverse event (AE) was traditionally reported as frequency and intensity. This simple measure is not sufficient to capture the recurrent nature and duration of AE. This paper presents two methods to better describe the toxicity burden across the time: prevalence and Q-TWiST. PATIENTS AND METHODS: Limitation of worst-grade method and advantages of prevalence and Q TWiST in the analysis of toxicity were illustrated using data from a phase II trial and a hypothetically simulated clinical trial. RESULTS: Prevalence integrates the recurrent nature of AE. Using prevalence, it is possible to obtain a time profile of AE. Q-TWiST method evaluates the weighted time spent in each health state and also considers the recurrent nature of side-effects in order to assess the 'risk-benefit' ratio of a treatment. When interpreting Q-TWiST results, it is necessary to take into account overall survival and progression free survival and to define a clinically relevant difference according to the setting. CONCLUSION: The two methods presented here capture different effects. They are helpful for physicians in their treatment choice (balance benefit risk), to counsel patients and to optimize supportive care. In order to ensure consistency and provide critical information required for medical decision making, it is important to encourage the use of alternative statistical methods in the analysis of toxicities associated with MTT. CLINICAL TRIAL: NCT00541008. PMID- 27217544 TI - Relationship between efficacy outcomes and weight gain during treatment of advanced, non-squamous, non-small-cell lung cancer patients. AB - BACKGROUND: Unintentional weight loss occurs among advanced non-small-cell lung cancer (NSCLC) patients and is associated with worse survival. Small studies have suggested that weight gain during treatment is associated with superior survival. PATIENTS AND METHODS: A retrospective analysis analyzed data from three international phase III studies comprising 2301 advanced, non-squamous NSCLC patients who received a platinum-based, first-line doublet, with or without bevacizumab and maintenance therapy. Body weight was recorded before and after treatment by each study's schedule. The relationship between weight gain and overall survival (OS) and progression-free survival (PFS) was assessed using log rank test and adjusted Cox modeling. Logistic regression assessed the association between baseline covariates and post-baseline weight gain. RESULTS: Four hundred and twenty-one (18.3%) patients had >5% weight gain after baseline. More than half of the weight gain cohort exhibited initial weight gain by 3 weeks. The median OS was 16.7 months versus 10.7 months for the >5% versus <=5% weight gain subgroup (n = 1880) (P < 0.001). PFS was 6.9 versus 4.8 months, respectively (P < 0.001). Differences in overall tumor response rate (50.8% versus 25.4%, respectively) and disease control rate (tumor response or stable disease) (91.5% versus 63.6%, respectively) were also significant (P < 0.001). The Cox modeling revealed the >5% subgroup had longer survival [hazard ratio (HR) = 0.54, 95% confidence interval (CI) 0.47-0.62; P < 0.001] than the <=5% subgroup after adjusting for baseline factors. Similar significant results were found for PFS (HR = 0.59, 95% CI 0.52-0.67; P < 0.001). Unadjusted logistic regression indicated a significant association between weight gain (>5% versus <=5%) and age, and BMI. CONCLUSIONS: Weight gain during treatment may be an early indicator of clinical benefit. If confirmed in prospective studies, monitoring weight change may provide important information regarding survival outcomes in NSCLC and may provide ideas for new therapeutic strategies. PMID- 27217545 TI - Salt stress response triggers activation of the jasmonate signaling pathway leading to inhibition of cell elongation in Arabidopsis primary root. AB - Salinity is a severe abiotic stress that affects irrigated croplands. Jasmonate (JA) is an essential hormone involved in plant defense against herbivory and in responses to abiotic stress. However, the relationship between the salt stress response and the JA pathway in Arabidopsis thaliana is not well understood at molecular and cellular levels. In this work we investigated the activation of JA signaling by NaCl and its effect on primary root growth. We found that JA responsive JAZ genes were up-regulated by salt stress in a COI1-dependent manner in the roots. Using a JA-Ile sensor we demonstrated that activation of JA signaling by salt stress occurs in the meristematic zone and stele of the differentiation zone and that this activation was dependent on JAR1 and proteasome functions. Another finding is that the elongation zone (EZ) and its cortical cells were significantly longer in JA-related mutants (AOS, COI1, JAZ3 and MYC2/3/4 genes) compared with wild-type plants under salt stress, revealing the participation of the canonical JA signaling pathway. Noteworthy, osmotic stress - a component of salt stress - inhibited cell elongation in the EZ in a COI1-dependent manner. We propose that salt stress triggers activation of the JA signaling pathway followed by inhibition of cell elongation in the EZ. We have shown that salt-inhibited root growth partially involves the jasmonate signaling pathway in Arabidopsis. PMID- 27217547 TI - Mechanisms and fitness implications of photomorphogenesis during chromatic acclimation in cyanobacteria. AB - Photosynthetic organisms absorb photons and convert light energy to chemical energy through the process of photosynthesis. Photosynthetic efficiency is tuned in response to the availability of light, carbon dioxide and nutrients to promote maximal levels of carbon fixation, while simultaneously limiting the potential for light-associated damage or phototoxicity. Given the central dependence on light for energy production, photosynthetic organisms possess abilities to tune their growth, development and metabolism to external light cues in the process of photomorphogenesis. Photosynthetic organisms perceive light intensity and distinct wavelengths or colors of light to promote organismal acclimation. Cyanobacteria are oxygenic photosynthetic prokaryotes that exhibit abilities to alter specific aspects of growth, including photosynthetic pigment composition and morphology, in responses to changes in available wavelengths and intensity of light. This form of photomorphogenesis is known as chromatic acclimation and has been widely studied. Recent insights into the photosensory photoreceptors found in cyanobacteria and developments in our understanding of the molecular mechanisms initiated by light sensing to affect the changes characteristic of chromatic acclimation are discussed. I consider cyanobacterial responses to light, the broad diversity of photoreceptors encoded by these organisms, specific mechanisms of photomorphogenesis, and associated fitness implications in chromatically acclimating cyanobacteria. PMID- 27217546 TI - Regulation, overexpression, and target gene identification of Potato Homeobox 15 (POTH15) - a class-I KNOX gene in potato. AB - Potato Homeobox 15 (POTH15) is a KNOX-I (Knotted1-like homeobox) family gene in potato that is orthologous to Shoot Meristemless (STM) in Arabidopsis. Despite numerous reports on KNOX genes from different species, studies in potato are limited. Here, we describe photoperiodic regulation of POTH15, its overexpression phenotype, and identification of its potential targets in potato (Solanum tuberosum ssp. andigena). qRT-PCR analysis showed a higher abundance of POTH15 mRNA in shoot tips and stolons under tuber-inducing short-day conditions. POTH15 promoter activity was detected in apical and axillary meristems, stolon tips, tuber eyes, and meristems of tuber sprouts, indicating its role in meristem maintenance and leaf development. POTH15 overexpression altered multiple morphological traits including leaf and stem development, leaflet number, and number of nodes and branches. In particular, the rachis of the leaf was completely reduced and leaves appeared as a bouquet of leaflets. Comparative transcriptomic analysis of 35S::GUS and two POTH15 overexpression lines identified more than 6000 differentially expressed genes, including 2014 common genes between the two overexpression lines. Functional analysis of these genes revealed their involvement in responses to hormones, biotic/abiotic stresses, transcription regulation, and signal transduction. qRT-PCR of selected candidate target genes validated their differential expression in both overexpression lines. Out of 200 randomly chosen POTH15 targets, 173 were found to have at least one tandem TGAC core motif, characteristic of KNOX interaction, within 3.0kb in the upstream sequence of the transcription start site. Overall, this study provides insights to the role of POTH15 in controlling diverse developmental processes in potato. PMID- 27217548 TI - HvPap-1 C1A protease actively participates in barley proteolysis mediated by abiotic stresses. AB - Protein breakdown and mobilization from old or stressed tissues to growing and sink organs are some of the metabolic features associated with abiotic/biotic stresses, essential for nutrient recycling. The massive degradation of proteins implies numerous proteolytic events in which cysteine-proteases are the most abundant key players. Analysing the role of barley C1A proteases in response to abiotic stresses is crucial due to their impact on plant growth and grain yield and quality. In this study, dark and nitrogen starvation treatments were selected to induce stress in barley. Results show that C1A proteases participate in the proteolytic processes triggered in leaves by both abiotic treatments, which strongly induce the expression of the HvPap-1 gene encoding a cathepsin F-like protease. Differences in biochemical parameters and C1A gene expression were found when comparing transgenic barley plants overexpressing or silencing the HvPap-1 gene and wild-type dark-treated leaves. These findings associated with morphological changes evidence a lifespan-delayed phenotype of HvPap-1 silenced lines. All these data elucidate on the role of this protease family in response to abiotic stresses and the potential of their biotechnological manipulation to control the timing of plant growth. PMID- 27217549 TI - The wheat Phs-A1 pre-harvest sprouting resistance locus delays the rate of seed dormancy loss and maps 0.3 cM distal to the PM19 genes in UK germplasm. AB - The precocious germination of cereal grains before harvest, also known as pre harvest sprouting, is an important source of yield and quality loss in cereal production. Pre-harvest sprouting is a complex grain defect and is becoming an increasing challenge due to changing climate patterns. Resistance to sprouting is multi-genic, although a significant proportion of the sprouting variation in modern wheat cultivars is controlled by a few major quantitative trait loci, including Phs-A1 in chromosome arm 4AL. Despite its importance, little is known about the physiological basis and the gene(s) underlying this important locus. In this study, we characterized Phs-A1 and show that it confers resistance to sprouting damage by affecting the rate of dormancy loss during dry seed after ripening. We show Phs-A1 to be effective even when seeds develop at low temperature (13 degrees C). Comparative analysis of syntenic Phs-A1 intervals in wheat and Brachypodium uncovered ten orthologous genes, including the Plasma Membrane 19 genes (PM19-A1 and PM19-A2) previously proposed as the main candidates for this locus. However, high-resolution fine-mapping in two bi parental UK mapping populations delimited Phs-A1 to an interval 0.3 cM distal to the PM19 genes. This study suggests the possibility that more than one causal gene underlies this major pre-harvest sprouting locus. The information and resources reported in this study will help test this hypothesis across a wider set of germplasm and will be of importance for breeding more sprouting resilient wheat varieties. PMID- 27217551 TI - Social networks and environmental outcomes. AB - Social networks can profoundly affect human behavior, which is the primary force driving environmental change. However, empirical evidence linking microlevel social interactions to large-scale environmental outcomes has remained scarce. Here, we leverage comprehensive data on information-sharing networks among large scale commercial tuna fishers to examine how social networks relate to shark bycatch, a global environmental issue. We demonstrate that the tendency for fishers to primarily share information within their ethnic group creates segregated networks that are strongly correlated with shark bycatch. However, some fishers share information across ethnic lines, and examinations of their bycatch rates show that network contacts are more strongly related to fishing behaviors than ethnicity. Our findings indicate that social networks are tied to actions that can directly impact marine ecosystems, and that biases toward within group ties may impede the diffusion of sustainable behaviors. Importantly, our analysis suggests that enhanced communication channels across segregated fisher groups could have prevented the incidental catch of over 46,000 sharks between 2008 and 2012 in a single commercial fishery. PMID- 27217550 TI - A single endoplasmic reticulum aminopeptidase-1 protein allotype is a strong risk factor for Behcet's disease in HLA-B*51 carriers. AB - INTRODUCTION: Endoplasmic reticulum aminopeptidase-1 (ERAP1) protein is highly polymorphic with numerous missense amino acid variants. We sought to determine the naturally occurring ERAP1 protein allotypes and their contribution to Behcet's disease. METHODS: Genotypes of all reported missense ERAP1 gene variants with 1000 Genomes Project EUR superpopulation frequency >1% were determined in 1900 Behcet's disease cases and 1779 controls from Turkey. ERAP1 protein allotypes and their contributions to Behcet's disease risk were determined by haplotype identification and disease association analyses. RESULTS: One ERAP1 protein allotype with five non-ancestral amino acids was recessively associated with disease (p=3.13*10-6, OR 2.55, 95% CI 1.70 to 3.82). The ERAP1 association was absent in individuals who lacked HLA-B*51. Individuals who carry HLA-B*51 and who are also homozygous for the haplotype had an increased disease odds compared with those with neither risk factor (p=4.80*10-20, OR 10.96, 95% CI 5.91 to 20.32). DISCUSSION: The Behcet's disease-associated ERAP1 protein allotype was previously shown to have poor peptide trimming activity. Combined with its requirement for HLA-B*51, these data suggest that a hypoactive ERAP1 allotype contributes to Behcet's disease risk by altering the peptides available for binding to HLA-B*51. PMID- 27217552 TI - QnAs with Partha Dasgupta. PMID- 27217554 TI - Correction for Bourzac, News Feature: Liquid sunlight. PMID- 27217555 TI - Correction to Supporting Information for Deng et al., Recruitment of the NineTeen Complex to the activated spliceosome requires AtPRMT5. PMID- 27217557 TI - Correction for Duin et al., Mode of action uncovered for the specific reduction of methane emissions from ruminants by the small molecule 3-nitrooxypropanol. PMID- 27217556 TI - Contextual sensitivity in scientific reproducibility. AB - In recent years, scientists have paid increasing attention to reproducibility. For example, the Reproducibility Project, a large-scale replication attempt of 100 studies published in top psychology journals found that only 39% could be unambiguously reproduced. There is a growing consensus among scientists that the lack of reproducibility in psychology and other fields stems from various methodological factors, including low statistical power, researcher's degrees of freedom, and an emphasis on publishing surprising positive results. However, there is a contentious debate about the extent to which failures to reproduce certain results might also reflect contextual differences (often termed "hidden moderators") between the original research and the replication attempt. Although psychologists have found extensive evidence that contextual factors alter behavior, some have argued that context is unlikely to influence the results of direct replications precisely because these studies use the same methods as those used in the original research. To help resolve this debate, we recoded the 100 original studies from the Reproducibility Project on the extent to which the research topic of each study was contextually sensitive. Results suggested that the contextual sensitivity of the research topic was associated with replication success, even after statistically adjusting for several methodological characteristics (e.g., statistical power, effect size). The association between contextual sensitivity and replication success did not differ across psychological subdisciplines. These results suggest that researchers, replicators, and consumers should be mindful of contextual factors that might influence a psychological process. We offer several guidelines for dealing with contextual sensitivity in reproducibility. PMID- 27217553 TI - Osmoregulatory inositol transporter SMIT1 modulates electrical activity by adjusting PI(4,5)P2 levels. AB - Myo-inositol is an important cellular osmolyte in autoregulation of cell volume and fluid balance, particularly for mammalian brain and kidney cells. We find it also regulates excitability. Myo-inositol is the precursor of phosphoinositides, key signaling lipids including phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. However, whether myo-inositol accumulation during osmoregulation affects signaling and excitability has not been fully explored. We found that overexpression of the Na(+)/myo-inositol cotransporter (SMIT1) and myo-inositol supplementation enlarged intracellular PI(4,5)P2 pools, modulated several PI(4,5)P2-dependent ion channels including KCNQ2/3 channels, and attenuated the action potential firing of superior cervical ganglion neurons. Further experiments using the rapamycin-recruitable phosphatase Sac1 to hydrolyze PI(4)P and the P4M probe to visualize PI(4)P suggested that PI(4)P levels increased after myo-inositol supplementation with SMIT1 expression. Elevated relative levels of PIP and PIP2 were directly confirmed using mass spectrometry. Inositol trisphosphate production and release of calcium from intracellular stores also were augmented after myo-inositol supplementation. Finally, we found that treatment with a hypertonic solution mimicked the effect we observed with SMIT1 overexpression, whereas silencing tonicity-responsive enhancer binding protein prevented these effects. These results show that ion channel function and cellular excitability are under regulation by several "physiological" manipulations that alter the PI(4,5)P2 setpoint. We demonstrate a previously unrecognized linkage between extracellular osmotic changes and the electrical properties of excitable cells. PMID- 27217558 TI - Nanospherical arabinogalactan proteins are a key component of the high-strength adhesive secreted by English ivy. AB - Over 130 y have passed since Charles Darwin first discovered that the adventitious roots of English ivy (Hedera helix) exude a yellowish mucilage that promotes the capacity of this plant to climb vertical surfaces. Unfortunately, little progress has been made in elucidating the adhesion mechanisms underlying this high-strength adhesive. In the previous studies, spherical nanoparticles were observed in the viscous exudate. Here we show that these nanoparticles are predominantly composed of arabinogalactan proteins (AGPs), a superfamily of hydroxyproline-rich glycoproteins present in the extracellular spaces of plant cells. The spheroidal shape of the AGP-rich ivy nanoparticles results in a low viscosity of the ivy adhesive, and thus a favorable wetting behavior on the surface of substrates. Meanwhile, calcium-driven electrostatic interactions among carboxyl groups of the AGPs and the pectic acids give rise to the cross-linking of the exuded adhesive substances, favor subsequent curing (hardening) via formation of an adhesive film, and eventually promote the generation of mechanical interlocking between the adventitious roots of English ivy and the surface of substrates. Inspired by these molecular events, a reconstructed ivy mimetic adhesive composite was developed by integrating purified AGP-rich ivy nanoparticles with pectic polysaccharides and calcium ions. Information gained from the subsequent tensile tests, in turn, substantiated the proposed adhesion mechanisms underlying the ivy-derived adhesive. Given that AGPs and pectic polysaccharides are also observed in bioadhesives exuded by other climbing plants, the adhesion mechanisms revealed by English ivy may forward the progress toward understanding the general principles underlying diverse botanic adhesives. PMID- 27217559 TI - Active dendrites regulate the impact of gliotransmission on rat hippocampal pyramidal neurons. AB - An important consequence of gliotransmission, a signaling mechanism that involves glial release of active transmitter molecules, is its manifestation as N-methyl-d aspartate receptor (NMDAR)-dependent slow inward currents in neurons. However, the intraneuronal spatial dynamics of these events or the role of active dendrites in regulating their amplitude and spatial spread have remained unexplored. Here, we used somatic and/or dendritic recordings from rat hippocampal pyramidal neurons and demonstrate that a majority of NMDAR-dependent spontaneous slow excitatory potentials (SEP) originate at dendritic locations and are significantly attenuated through their propagation across the neuronal arbor. We substantiated the astrocytic origin of SEPs through paired neuron-astrocyte recordings, where we found that specific infusion of inositol trisphosphate (InsP3) into either distal or proximal astrocytes enhanced the amplitude and frequency of neuronal SEPs. Importantly, SEPs recorded after InsP3 infusion into distal astrocytes exhibited significantly slower kinetics compared with those recorded after proximal infusion. Furthermore, using neuron-specific infusion of pharmacological agents and morphologically realistic conductance-based computational models, we demonstrate that dendritically expressed hyperpolarization-activated cyclic-nucleotide-gated (HCN) and transient potassium channels play critical roles in regulating the strength, kinetics, and compartmentalization of neuronal SEPs. Finally, through the application of subtype-specific receptor blockers during paired neuron-astrocyte recordings, we provide evidence that GluN2B- and GluN2D-containing NMDARs predominantly mediate perisomatic and dendritic SEPs, respectively. Our results unveil an important role for active dendrites in regulating the impact of gliotransmission on neurons and suggest astrocytes as a source of dendritic plateau potentials that have been implicated in localized plasticity and place cell formation. PMID- 27217560 TI - Extraordinary intelligence and the care of infants. AB - We present evidence that pressures for early childcare may have been one of the driving factors of human evolution. We show through an evolutionary model that runaway selection for high intelligence may occur when (i) altricial neonates require intelligent parents, (ii) intelligent parents must have large brains, and (iii) large brains necessitate having even more altricial offspring. We test a prediction of this account by showing across primate genera that the helplessness of infants is a particularly strong predictor of the adults' intelligence. We discuss related implications, including this account's ability to explain why human-level intelligence evolved specifically in mammals. This theory complements prior hypotheses that link human intelligence to social reasoning and reproductive pressures and explains how human intelligence may have become so distinctive compared with our closest evolutionary relatives. PMID- 27217561 TI - Spliceosomal intronogenesis. AB - The presence of intervening sequences, termed introns, is a defining characteristic of eukaryotic nuclear genomes. Once transcribed into pre-mRNA, these introns must be removed within the spliceosome before export of the processed mRNA to the cytoplasm, where it is translated into protein. Although intron loss has been demonstrated experimentally, several mysteries remain regarding the origin and propagation of introns. Indeed, documented evidence of gain of an intron has only been suggested by phylogenetic analyses. We report the use of a strategy that detects selected intron gain and loss events. We have experimentally verified, to our knowledge, the first demonstrations of intron transposition in any organism. From our screen, we detected two separate intron gain events characterized by the perfect transposition of a reporter intron into the yeast genes RPL8B and ADH2, respectively. We show that the newly acquired introns are able to be removed from their respective pre-mRNAs by the spliceosome. Additionally, the novel allele, RPL8Bint, is functional when overexpressed within the genome in a strain lacking the Rpl8 paralogue RPL8A, demonstrating that the gene targeted for intronogenesis is functional. PMID- 27217562 TI - Aurora kinase-induced phosphorylation excludes transcription factor RUNX from the chromatin to facilitate proper mitotic progression. AB - The Runt-related transcription factors (RUNX) are master regulators of development and major players in tumorigenesis. Interestingly, unlike most transcription factors, RUNX proteins are detected on the mitotic chromatin and apparatus, suggesting that they are functionally active in mitosis. Here, we identify key sites of RUNX phosphorylation in mitosis. We show that the phosphorylation of threonine 173 (T173) residue within the Runt domain of RUNX3 disrupts RUNX DNA binding activity during mitotic entry to facilitate the recruitment of RUNX proteins to mitotic structures. Moreover, knockdown of RUNX3 delays mitotic entry. RUNX3 phosphorylation is therefore a regulatory mechanism for mitotic entry. Cancer-associated mutations of RUNX3 T173 and its equivalent in RUNX1 further corroborate the role of RUNX phosphorylation in regulating proper mitotic progression and genomic integrity. PMID- 27217563 TI - Brain aerobic glycolysis and motor adaptation learning. AB - Ten percent to 15% of glucose used by the brain is metabolized nonoxidatively despite adequate tissue oxygenation, a process termed aerobic glycolysis (AG). Because of the known role of glycolysis in biosynthesis, we tested whether learning-induced synaptic plasticity would lead to regionally appropriate, learning-dependent changes in AG. Functional MRI (fMRI) before, during, and after performance of a visual-motor adaptation task demonstrated that left Brodmann area 44 (BA44) played a key role in adaptation, with learning-related changes to activity during the task and altered resting-state, functional connectivity after the task. PET scans before and after task performance indicated a sustained increase in AG in left BA 44 accompanied by decreased oxygen consumption. Intersubject variability in behavioral adaptation rate correlated strongly with changes in AG in this region, as well as functional connectivity, which is consistent with a role for AG in synaptic plasticity. PMID- 27217564 TI - Mobile phone data highlights the role of mass gatherings in the spreading of cholera outbreaks. AB - The spatiotemporal evolution of human mobility and the related fluctuations of population density are known to be key drivers of the dynamics of infectious disease outbreaks. These factors are particularly relevant in the case of mass gatherings, which may act as hotspots of disease transmission and spread. Understanding these dynamics, however, is usually limited by the lack of accurate data, especially in developing countries. Mobile phone call data provide a new, first-order source of information that allows the tracking of the evolution of mobility fluxes with high resolution in space and time. Here, we analyze a dataset of mobile phone records of ~150,000 users in Senegal to extract human mobility fluxes and directly incorporate them into a spatially explicit, dynamic epidemiological framework. Our model, which also takes into account other drivers of disease transmission such as rainfall, is applied to the 2005 cholera outbreak in Senegal, which totaled more than 30,000 reported cases. Our findings highlight the major influence that a mass gathering, which took place during the initial phase of the outbreak, had on the course of the epidemic. Such an effect could not be explained by classic, static approaches describing human mobility. Model results also show how concentrated efforts toward disease control in a transmission hotspot could have an important effect on the large-scale progression of an outbreak. PMID- 27217566 TI - Unacquainted callers can predict which citizens will vote over and above citizens' stated self-predictions. AB - People are regularly asked to report on their likelihoods of carrying out consequential future behaviors, including complying with medical advice, completing educational assignments, and voting in upcoming elections. Despite these stated self-predictions being notoriously unreliable, they are used to inform many strategic decisions. We report two studies examining stated self prediction about whether citizens will vote. We find that most self-predicted voters do not actually vote despite saying they will, and that campaign callers can discern which self-predicted voters will not actually vote. In study 1 (n = 4,463), self-predicted voters rated by callers as "100% likely to vote" were 2 times more likely to actually vote than those rated unlikely to vote. Study 2 (n = 3,064) replicated this finding and further demonstrated that callers' prediction accuracy was mediated by citizens' nonverbal signals of uncertainty and deception. Strangers can use nonverbal signals to improve predictions of follow through on self-reported intentions-an insight of potential value for politics, medicine, and education. PMID- 27217565 TI - Neonatal postcrania from Mezmaiskaya, Russia, and Le Moustier, France, and the development of Neandertal body form. AB - Neandertal and modern human adults differ in skeletal features of the cranium and postcranium, and it is clear that many of the cranial differences-although not all of them-are already present at the time of birth. We know less, however, about the developmental origins of the postcranial differences. Here, we address this deficiency with morphometric analyses of the postcrania of the two most complete Neandertal neonates-Mezmaiskaya 1 (from Russia) and Le Moustier 2 (from France)-and a recent human sample. We find that neonatal Neandertals already appear to possess the wide body, long pubis, and robust long bones of adult Neandertals. Taken together, current evidence indicates that skeletal differences between Neandertals and modern humans are largely established by the time of birth. PMID- 27217567 TI - Revealing a 5,000-y-old beer recipe in China. AB - The pottery vessels from the Mijiaya site reveal, to our knowledge, the first direct evidence of in situ beer making in China, based on the analyses of starch, phytolith, and chemical residues. Our data reveal a surprising beer recipe in which broomcorn millet (Panicum miliaceum), barley (Hordeum vulgare), Job's tears (Coix lacryma-jobi), and tubers were fermented together. The results indicate that people in China established advanced beer-brewing technology by using specialized tools and creating favorable fermentation conditions around 5,000 y ago. Our findings imply that early beer making may have motivated the initial translocation of barley from the Western Eurasia into the Central Plain of China before the crop became a part of agricultural subsistence in the region 3,000 y later. PMID- 27217569 TI - Enzymatically enhanced collisions on ultramicroelectrodes for specific and rapid detection of individual viruses. AB - We report the specific collision of a single murine cytomegalovirus (MCMV) on a platinum ultramicroelectrode (UME, radius of 1 MUm). Antibody directed against the viral surface protein glycoprotein B functionalized with glucose oxidase (GOx) allowed for specific detection of the virus in solution and a biological sample (urine). The oxidation of ferrocene methanol to ferrocenium methanol was carried out at the electrode surface, and the ferrocenium methanol acted as the cosubstrate to GOx to catalyze the oxidation of glucose to gluconolactone. In the presence of glucose, the incident collision of a GOx-covered virus onto the UME while ferrocene methanol was being oxidized produced stepwise increases in current as observed by amperometry. These current increases were observed due to the feedback loop of ferrocene methanol to the surface of the electrode after GOx reduces ferrocenium methanol back to ferrocene. Negative controls (i) without glucose, (ii) with an irrelevant virus (murine gammaherpesvirus 68), and (iii) without either virus do not display these current increases. Stepwise current decreases were observed for the prior two negative controls and no discrete events were observed for the latter. We further apply this method to the detection of MCMV in urine of infected mice. The method provides for a selective, rapid, and sensitive detection technique based on electrochemical collisions. PMID- 27217570 TI - Developmental cell death programs license cytotoxic cells to eliminate histocompatible partners. AB - In a primitive chordate model of natural chimerism, one chimeric partner is often eliminated in a process of allogeneic resorption. Here, we identify the cellular framework underlying loss of tolerance to one partner within a natural Botryllus schlosseri chimera. We show that the principal cell type mediating chimeric partner elimination is a cytotoxic morula cell (MC). Proinflammatory, developmental cell death programs render MCs cytotoxic and, in collaboration with activated phagocytes, eliminate chimeric partners during the "takeover" phase of blastogenic development. Among these genes, the proinflammatory cytokine IL-17 enhances cytotoxicity in allorecognition assays. Cellular transfer of FACS purified MCs from allogeneic donors into recipients shows that the resorption response can be adoptively acquired. Transfer of 1 * 10(5) allogeneic MCs eliminated 33 of 78 (42%) recipient primary buds and 20 of 76 (20.5%) adult parental adult organisms (zooids) by 14 d whereas transfer of allogeneic cell populations lacking MCs had only minimal effects on recipient colonies. Furthermore, reactivity of transferred cells coincided with the onset of developmental-regulated cell death programs and disproportionately affected developing tissues within a chimera. Among chimeric partner "losers," severe developmental defects were observed in asexually propagating tissues, reflecting a pathologic switch in gene expression in developmental programs. These studies provide evidence that elimination of one partner in a chimera is an immune cell based rejection that operates within histocompatible pairs and that maximal allogeneic responses involve the coordination of both phagocytic programs and the "arming" of cytotoxic cells. PMID- 27217568 TI - O-linked N-acetylglucosamine transferase (OGT) interacts with the histone chaperone HIRA complex and regulates nucleosome assembly and cellular senescence. AB - The histone chaperone HIRA complex, consisting of histone cell cycle regulator (HIRA), Ubinuclein1 (UBN1), and calcineurin binding protein 1 (CABIN1), deposits histone variant H3.3 to genic regions and regulates gene expression in various cellular processes, including cellular senescence. How HIRA-mediated nucleosome assembly of H3.3-H4 is regulated remains not well understood. Here, we show that O-linked N-acetylglucosamine (GlcNAc) transferase (OGT), an enzyme that catalyzes O-GlcNAcylation of serine or threonine residues, interacts with UBN1, modifies HIRA, and promotes nucleosome assembly of H3.3. Depletion of OGT or expression of the HIRA S231A O-GlcNAcylation-deficient mutant compromises formation of the HIRA H3.3 complex and H3.3 nucleosome assembly. Importantly, OGT depletion or expression of the HIRA S231A mutant delays premature cellular senescence in primary human fibroblasts, whereas overexpression of OGT accelerates senescence. Taken together, these results support a model in which OGT modifies HIRA to regulate HIRA-H3.3 complex formation and H3.3 nucleosome assembly and reveal the mechanism by which OGT functions in cellular senescence. PMID- 27217571 TI - Probabilistic population projections with migration uncertainty. AB - We produce probabilistic projections of population for all countries based on probabilistic projections of fertility, mortality, and migration. We compare our projections to those from the United Nations' Probabilistic Population Projections, which uses similar methods for fertility and mortality but deterministic migration projections. We find that uncertainty in migration projection is a substantial contributor to uncertainty in population projections for many countries. Prediction intervals for the populations of Northern America and Europe are over 70% wider, whereas prediction intervals for the populations of Africa, Asia, and the world as a whole are nearly unchanged. Out-of-sample validation shows that the model is reasonably well calibrated. PMID- 27217572 TI - Millennial-scale sustainability of the Chesapeake Bay Native American oyster fishery. AB - Estuaries around the world are in a state of decline following decades or more of overfishing, pollution, and climate change. Oysters (Ostreidae), ecosystem engineers in many estuaries, influence water quality, construct habitat, and provide food for humans and wildlife. In North America's Chesapeake Bay, once thriving eastern oyster (Crassostrea virginica) populations have declined dramatically, making their restoration and conservation extremely challenging. Here we present data on oyster size and human harvest from Chesapeake Bay archaeological sites spanning ~3,500 y of Native American, colonial, and historical occupation. We compare oysters from archaeological sites with Pleistocene oyster reefs that existed before human harvest, modern oyster reefs, and other records of human oyster harvest from around the world. Native American fisheries were focused on nearshore oysters and were likely harvested at a rate that was sustainable over centuries to millennia, despite changing Holocene climatic conditions and sea-level rise. These data document resilience in oyster populations under long-term Native American harvest, sea-level rise, and climate change; provide context for managing modern oyster fisheries in the Chesapeake Bay and elsewhere around the world; and demonstrate an interdisciplinary approach that can be applied broadly to other fisheries. PMID- 27217574 TI - Unfalsifiability of security claims. AB - There is an inherent asymmetry in computer security: Things can be declared insecure by observation, but not the reverse. There is no observation that allows us to declare an arbitrary system or technique secure. We show that this implies that claims of necessary conditions for security (and sufficient conditions for insecurity) are unfalsifiable. This in turn implies an asymmetry in self correction: Whereas the claim that countermeasures are sufficient is always subject to correction, the claim that they are necessary is not. Thus, the response to new information can only be to ratchet upward: Newly observed or speculated attack capabilities can argue a countermeasure in, but no possible observation argues one out. Further, when justifications are unfalsifiable, deciding the relative importance of defensive measures reduces to a subjective comparison of assumptions. Relying on such claims is the source of two problems: once we go wrong we stay wrong and errors accumulate, and we have no systematic way to rank or prioritize measures. PMID- 27217573 TI - Auxin-dependent compositional change in Mediator in ARF7- and ARF19-mediated transcription. AB - Mediator is a multiprotein complex that integrates the signals from transcription factors binding to the promoter and transmits them to achieve gene transcription. The subunits of Mediator complex reside in four modules: the head, middle, tail, and dissociable CDK8 kinase module (CKM). The head, middle, and tail modules form the core Mediator complex, and the association of CKM can modify the function of Mediator in transcription. Here, we show genetic and biochemical evidence that CKM-associated Mediator transmits auxin-dependent transcriptional repression in lateral root (LR) formation. The AUXIN/INDOLE 3-ACETIC ACID 14 (Aux/IAA14) transcriptional repressor inhibits the transcriptional activity of its binding partners AUXIN RESPONSE FACTOR 7 (ARF7) and ARF19 by making a complex with the CKM-associated Mediator. In addition, TOPLESS (TPL), a transcriptional corepressor, forms a bridge between IAA14 and the CKM component MED13 through the physical interaction. ChIP assays show that auxin induces the dissociation of MED13 but not the tail module component MED25 from the ARF7 binding region upstream of its target gene. These findings indicate that auxin-induced degradation of IAA14 changes the module composition of Mediator interacting with ARF7 and ARF19 in the upstream region of their target genes involved in LR formation. We suggest that this regulation leads to a quick switch of signal transmission from ARFs to target gene expression in response to auxin. PMID- 27217575 TI - Root exudates drive interspecific facilitation by enhancing nodulation and N2 fixation. AB - Plant diversity in experimental systems often enhances ecosystem productivity, but the mechanisms causing this overyielding are only partly understood. Intercropping faba beans (Vicia faba L.) and maize (Zea mays L.) result in overyielding and also, enhanced nodulation by faba beans. By using permeable and impermeable root barriers in a 2-y field experiment, we show that root-root interactions between faba bean and maize significantly increase both nodulation and symbiotic N2 fixation in intercropped faba bean. Furthermore, root exudates from maize promote faba bean nodulation, whereas root exudates from wheat and barley do not. Thus, a decline of soil nitrate concentrations caused by intercropped cereals is not the sole mechanism for maize promoting faba bean nodulation. Intercropped maize also caused a twofold increase in exudation of flavonoids (signaling compounds for rhizobia) in the systems. Roots of faba bean treated with maize root exudates exhibited an immediate 11-fold increase in the expression of chalcone-flavanone isomerase (involved in flavonoid synthesis) gene together with a significantly increased expression of genes mediating nodulation and auxin response. After 35 d, faba beans treated with maize root exudate continued to show up-regulation of key nodulation genes, such as early nodulin 93 (ENOD93), and promoted nitrogen fixation. Our results reveal a mechanism for how intercropped maize promotes nitrogen fixation of faba bean, where maize root exudates promote flavonoid synthesis in faba bean, increase nodulation, and stimulate nitrogen fixation after enhanced gene expression. These results indicate facilitative root-root interactions and provide a mechanism for a positive relationship between species diversity and ecosystem productivity. PMID- 27217577 TI - Are there prions in plants? PMID- 27217578 TI - Mother nurture and the social definition of neurodevelopment. PMID- 27217576 TI - beta1-subunit-induced structural rearrangements of the Ca2+- and voltage activated K+ (BK) channel. AB - Large-conductance Ca(2+)- and voltage-activated K(+) (BK) channels are involved in a large variety of physiological processes. Regulatory beta-subunits are one of the mechanisms responsible for creating BK channel diversity fundamental to the adequate function of many tissues. However, little is known about the structure of its voltage sensor domain. Here, we present the external architectural details of BK channels using lanthanide-based resonance energy transfer (LRET). We used a genetically encoded lanthanide-binding tag (LBT) to bind terbium as a LRET donor and a fluorophore-labeled iberiotoxin as the LRET acceptor for measurements of distances within the BK channel structure in a living cell. By introducing LBTs in the extracellular region of the alpha- or beta1-subunit, we determined (i) a basic extracellular map of the BK channel, (ii) beta1-subunit-induced rearrangements of the voltage sensor in alpha subunits, and (iii) the relative position of the beta1-subunit within the alpha/beta1-subunit complex. PMID- 27217579 TI - V3A takes over a job of MT+ after training on a visual task. PMID- 27217580 TI - Morphological Convergence Between an Allopolyploid and One of its Parental Species Correlates with Biased Gene Expression and DNA Loss. AB - The contribution of gene expression modulation to phenotypic evolution is of major importance to an understanding of the origin of divergent or convergent phenotypes during and following polyploid speciation. Here, we analyzed genome wide gene expression in 2 subspecies of the allotetraploid species, Senecio mohavensis A. Gray, and its diploid parents S. flavus (Decne.) Sch. Bip. and S. glaucus L. The tetraploid is morphologically much more similar to S. flavus, leading to earlier confusion over its taxonomic status. By means of an analysis of transcriptomes of all 3 species, we show that gene expression divergence between the parent species is relatively low (ca. 14% of loci), whereas there is significant unequal expression between ca. 20-25% of the parental homoeologues (gene copies) in the tetraploid. The majority of the expression bias in the tetraploid is in favor of S. flavus homoeologues (ca. 65% of the differentially expressed loci), and overall expression of this parental species subgenome is higher than that of the S. glaucus subgenome. To determine whether absence of expression of a particular S. glaucus homoeologue in the allotetraploid could be due to loss of DNA, we carried out a PCR-based assay and confirmed that in 3 out of 10 loci the S. glaucus homoeologue appeared absent. Our results suggest that biased gene expression is one cause of the allotetraploid S. mohavensis being more similar in morphology to one of its parent, S. flavus, and that such bias could result, in part, from loss of S. glaucus homoeologues at some loci in the allotetraploid. PMID- 27217581 TI - The outcome of antenatal ultrasound diagnosed anomalies of the kidney and urinary tract in a large Danish birth cohort. AB - OBJECTIVE: Antenatal ultrasound diagnosed anomalies of the kidney and urinary tract (AUDAKUT) are reported in 0.3%-5% on prenatal ultrasound (US) and 0.3%-4.5% on postnatal US. The anterior-posterior diameter of the renal pelvis (APD) is an essential measurement. Series with low threshold values of APD prenatally and postnatally will include healthy infants. It is important to avoid follow-up of such infants. INTERVENTIONS: In 2006, new Danish guidelines for AUDAKUT were introduced. AIM OF STUDY: Investigations of incidences and type of AUDAKUT based on Danish guidelines, including long-term follow-up. DESIGN: Cohort study. SETTING: Copenhagen University Hospital Hvidovre and Copenhagen University Hospital Rigshospitalet, Denmark. PATIENTS: Consecutive cases with AUDAKUT in the second and third trimesters, which were either terminated before 22 completed weeks of gestation or born in the 8-year period January 2006-December 2013. Patients were followed until June 2014. RESULTS: 50 193 live born children and 24 terminated fetuses (0.05%) were included. The prevalence of AUDAKUT was only 0.39% prenatally, 0.29% at first postnatal US and 0.22% at the end of follow-up, including terminated cases. The greater the prenatal and postnatal APD, the higher risk of febrile urinary tract infection (fUTI) and surgical intervention, and lower probability of resolution. 25% of the identified patients had fUTI and/or surgery. CONCLUSIONS: We recommend threshold values of APD at least 10 mm in the third trimester and in general at least 12 mm at first postnatal US for intensive follow-up. In this largest to date unselected birth cohort of AUDAKUT, the incidences of clinically significant AUDAKUT were in the lowest range of those previously published. PMID- 27217582 TI - Whole population integrated child health: moving beyond pathways. PMID- 27217583 TI - Pulmonary Th17 Antifungal Immunity Is Regulated by the Gut Microbiome. AB - Commensal microbiota are critical for the development of local immune responses. In this article, we show that gut microbiota can regulate CD4 T cell polarization during pulmonary fungal infections. Vancomycin drinking water significantly decreased lung Th17 cell numbers during acute infection, demonstrating that Gram positive commensals contribute to systemic inflammation. We next tested a role for RegIIIgamma, an IL-22-inducible antimicrobial protein with specificity for Gram-positive bacteria. Following infection, increased accumulation of Th17 cells in the lungs of RegIIIgamma(-/-) and Il22(-/-) mice was associated with intestinal segmented filamentous bacteria (SFB) colonization. Although gastrointestinal delivery of rRegIIIgamma decreased lung inflammatory gene expression and protected Il22(-/-) mice from weight loss during infection, it had no direct effect on SFB colonization, fungal clearance, or lung Th17 immunity. We further show that vancomycin only decreased lung IL-17 production in mice colonized with SFB. To determine the link between gut microbiota and lung immunity, serum-transfer experiments revealed that IL-1R ligands increase the accumulation of lung Th17 cells. These data suggest that intestinal microbiota, including SFB, can regulate pulmonary adaptive immune responses. PMID- 27217584 TI - IL-15 Trans-Signaling with the Superagonist RLI Promotes Effector/Memory CD8+ T Cell Responses and Enhances Antitumor Activity of PD-1 Antagonists. AB - Tumors with the help of the surrounding environment facilitate the immune suppression in patients, and immunotherapy can counteract this inhibition. Among immunotherapeutic strategies, the immunostimulatory cytokine IL-15 could represent a serious candidate for the reactivation of antitumor immunity. However, exogenous IL-15 may have a limited impact on patients with cancer due to its dependency on IL-15Ralpha frequently downregulated in cancer patients. In this work, we studied the antitumor activity of the IL-15 superagonist receptor linker-IL-15 (RLI), designed to bypass the need of endogenous IL-15Ralpha. RLI consists of human IL-15 covalently linked to the human IL-15Ralpha sushi(+) domain. In a mouse model of colorectal carcinoma, RLI as a stand-alone treatment could limit tumor outgrowth only when initiated at an early time of tumor development. At a later time, RLI was not effective, coinciding with the strong accumulation of terminally exhausted programmed cell death-1 (PD-1)(high) T cell Ig mucin-3(+) CD8(+) T cells, suggesting that RLI was not able to reactivate terminally exhausted CD8(+) T cells. Combination with PD-1 blocking Ab showed synergistic activity with RLI, but not with IL-15. RLI could induce a greater accumulation of memory CD8(+) T cells and a stronger effector function in comparison with IL-15. Ex vivo stimulation of tumor-infiltrated lymphocytes from 16 patients with renal cell carcinoma demonstrated 56% of a strong tumor infiltrated lymphocyte reactivation with the combination anti-PD-1/RLI compared with 43 and 6% with RLI or anti-PD-1, respectively. Altogether, this work provides evidence that the sushi-IL-15Ralpha/IL-15 fusion protein RLI enhances antitumor activity of anti-PD-1 treatment and is a promising approach to stimulate host immunity. PMID- 27217586 TI - Commentary on: Incidence and Risk Factors of Major Complications in Brachioplasty: Analysis of 2,294 Patients. PMID- 27217585 TI - CSF-1R-Dependent Lethal Hepatotoxicity When Agonistic CD40 Antibody Is Given before but Not after Chemotherapy. AB - Cancer immunotherapies are increasingly effective in the clinic, especially immune checkpoint blockade delivered to patients who have T cell-infiltrated tumors. Agonistic CD40 mAb promotes stromal degradation and, in combination with chemotherapy, drives T cell infiltration and de novo responses against tumors, rendering resistant tumors susceptible to current immunotherapies. Partnering anti-CD40 with different treatments is an attractive approach for the next phase of cancer immunotherapies, with a number of clinical trials using anti-CD40 combinations ongoing, but the optimal therapeutic regimens with anti-CD40 are not well understood. Pancreatic ductal adenocarcinoma (PDA) is classically resistant to immunotherapy and lacks baseline T cell infiltration. In this study, we used a tumor cell line derived from a genetically engineered mouse model of PDA to investigate alterations in the sequence of anti-CD40 and chemotherapy as an approach to enhance pharmacological delivery of chemotherapy. Unexpectedly, despite our previous studies showing anti-CD40 treatment after chemotherapy is safe in both mice and patients with PDA, we report in this article that anti-CD40 administration <3 d in advance of chemotherapy is lethal in more than half of treated C57BL/6 mice. Anti-CD40 treatment 2 or 3 d before chemotherapy resulted in significantly increased populations of both activated myeloid cells and macrophages and lethal hepatotoxicity. Liver damage was fully abrogated when macrophage activation was blocked using anti-CSF-1R mAb. These studies highlight the dual nature of CD40 in activating both macrophages and T cell responses, and the need for preclinical investigation of optimal anti-CD40 treatment regimens for safe design of clinical trials. PMID- 27217587 TI - Preoperative Risk Factors and Complication Rates of Thighplasty: Analysis of 1,493 Patients. AB - BACKGROUND: Despite a rise in thighplasties, outcomes and risk factors have not been well described. OBJECTIVES: This study investigated the incidence and risk factors of major complications following thighplasty in a large, prospective, multicenter database. It further evaluated the safety of combined procedures. METHODS: Patients undergoing thighplasty between 2008 and 2013 were identified within the CosmetAssure database (Birmingham, AL). The primary outcome was the occurrence of major complication(s) requiring emergency department visit, hospital admission, or reoperation within 30 days postoperatively. Age, gender, body mass index, smoking, diabetes, type of facility, and combination procedures were evaluated as risk factors. RESULTS: Among the 129,007 patients enrolled in CosmetAssure, 1493 (0.8%) underwent thighplasty. One thousand and eighty-eight (72.9%) thighplasties were combined with other procedures. Ninety-nine (6.6%) developed at least one complication. The most common complications were infection (2.7%), hematoma (2.1%), suspected venous thromboembolism (VTE) (1.1%), fluid overload (0.5%), and confirmed VTE (0.3%). Thighplasties performed in a hospital had higher complications (8.1%) than ambulatory surgical center (6.2%) and office based surgical suite (3.1%). When thighplasty was performed alone, smoking was an independent risk factor to develop at least one complication (RR = 9.51) and hematoma (RR = 13.48). Compared to thighplasty alone, complication rate did not increase with the addition of concomitant procedures (4.7% vs 7.4%, P = .079). CONCLUSION: Infection and hematoma are the most common major complications. In thighplasty alone, smoking is the only independent risk factor for overall complications and hematoma formation. The addition of concomitant cosmetic procedures does not increase complication rates. LEVEL OF EVIDENCE: 2 Risk. PMID- 27217588 TI - Incidence and Risk Factors of Major Complications in Brachioplasty: Analysis of 2,294 Patients. AB - BACKGROUND: Brachioplasty is a popular procedure to correct upper arm ptosis. However, current literature on complications and risk factors is scant and inconclusive. OBJECTIVES: Using a large, prospective, multicenter database, we report the incidence of major complications and risk factors in patients undergoing brachioplasty. METHODS: Patients who underwent brachioplasty between 2008 and 2013 were identified from the CosmetAssure (Birmingham, AL) database. The primary outcome was the occurrence of major complication(s), defined as complications requiring emergency room visit, hospital admission, or reoperation within 30 days of the procedure. Risk factors including age, gender, body mass index (BMI), smoking, diabetes, combined procedures, and type of surgical facility were evaluated using univariate and multivariate analysis. RESULTS: Within the 129,007 patients enrolled in CosmetAssure, 2294 (1.8%) underwent brachioplasty. Brachioplasty patients were more likely to be older than 50 years (50.1%), obese (36.3%), diabetic (5.5%), but less likely smokers (5.5%). Major complications occurred in 3.4% brachioplasties with infection (1.7%) and hematoma (1.1%) being most common. Combined procedures, performed in 66.8% cases, had a complication rate of 4.4%, in comparison to 1.3% for brachioplasties performed alone. Combined procedures (RR = 3.58), males (RR = 3.44), and BMI >= 30 kg/m(2) (RR = 1.92) were identified as independent risk factors for the occurrence of any complication. Combined procedures (RR = 12.42), and the male gender (RR = 8.89) increased the risk of hematoma formation. CONCLUSIONS: Complication rates from brachioplasty are much lower than previously reported. Hematoma and infection are the most common major complications. Combined procedures, male gender, and BMI >= 30 kg/m(2) are independent risk factors for complications. LEVEL OF EVIDENCE 2: Risk. PMID- 27217589 TI - Prostaglandin E2-Glyceryl Ester: In Vivo Evidence for a Distinct Pharmacological Identity from Intraocular Pressure Studies. AB - Prostaglandin E2 (PGE2)-2-glyceryl ester is a cyclo-oxygenase 2 product of the endocannabinoid 2-arachidonyl glycerol. It is claimed as pharmacologically novel, but this is complicated by rapid and irreversible isomerization to the 1(3) ester. For ocular studies, enzymatic hydrolysis of the ester moiety creates an additional complication. PG-glyceryl esters were stabilized to isomerization and hydrolysis by replacing the noncarbonyl O with NH, to form the serinolamide and propanediolamide as stable analogs of PG-2-glyceryl and PG-2-1(3) glyceryl esters, respectively. Intraocular pressure was measured in conscious dogs and conscious laser-induced ocular hypertensive monkeys. Pharmacological studies involved stable transfectants for each of the human recombinant prostanoid receptors and the isolated feline iris for prostamide activity. PGE2-serinolamide and PGE2- propanediolamide were essentially inactive at all receptors except the EP3 receptor (EC50, ~500 nM). This obliged elucidation of EP3 receptor involvement in the intraocular pressure response to these PGE2-glycyerl ester analogs. Since the EP3 receptor agonists sulprostone and GR 63799 did not lower monkey intraocular pressure, a role for EP3 receptors in mediating the effects of PGE2-serinolamide and PGE2-propanediolamide is not indicated. PGE2-glyceryl ester (0.01% and 0.1%) substantially lowered intraocular pressure in monkeys. PGE2 propanediolamide was more efficacious than PGE2-serinolamide in lowering intraocular pressure in monkey eyes, but both appeared equieffective in dog eyes. PGE2-serinolamide dose-dependently (0.01- 0.1%) lowered intraocular pressure in both species, but PGF2 alpha-serinolamide was inactive. In conclusion, stable PGE2-glyceryl ester analogs lowered intraocular pressure. These findings are consistent with the presence of a PGE2-glyceryl ester-specific recognition site in the eye. PMID- 27217591 TI - Pharmacological Effects of a Monoclonal Antibody against 6-Monoacetylmorphine upon Heroin-Induced Locomotor Activity and Pharmacokinetics in Mice. AB - Immunotherapy can provide a supplemental treatment strategy against heroin use on the principle of sequestering the active drug in the bloodstream, thereby reducing its distribution to the brain. Previous studies have shown that heroin's first metabolite, 6-monoacetylmorphine (6-MAM), is the main mediator of acute heroin effects. The objective of the present study was to characterize the pharmacological potential of a monoclonal antibody against 6-MAM (anti-6-MAM mAb) to counteract the heroin response. The individual contributions from heroin and 6 MAM to heroin effects were also examined by pretreating mice with anti-6-MAM mAb (10-100 mg/kg) prior to either heroin or 6-MAM injection (1.25-2.5 MUmol/kg). The opioid-induced behavioral response was assessed in a locomotor activity test, followed by opioid and antibody quantification in blood and brain tissue. Pretreatment with mAb caused a profound reduction of heroin- and 6-MAM-induced behavior, accompanied by correspondingly decreased levels of 6-MAM in brain tissue. mAb pretreatment was more efficient against 6-MAM injection than against heroin, leading to an almost complete blockade of 6-MAM-induced effects. mAb pretreatment was unable to block the immediate (5-minute) transport of active metabolites across the blood-brain barrier after heroin injection, indicating that heroin itself appears to enhance the immediate delivery of 6-MAM to the brain. The current study provides additional evidence that 6-MAM sequestration is crucial for counteracting the acute heroin response, and demonstrates the pharmacological potential of immunotherapy against heroin use. PMID- 27217590 TI - Peripheral Administration of a Long-Acting Peptide Oxytocin Receptor Agonist Inhibits Fear-Induced Freezing. AB - Oxytocin (OT) modulates the expression of social and emotional behaviors and consequently has been proposed as a pharmacologic treatment of psychiatric diseases, including autism spectrum disorders and schizophrenia; however, endogenous OT has a short half-life in plasma and poor permeability across the blood-brain barrier. Recent efforts have focused on the development of novel drug delivery methods to enhance brain penetration, but few efforts have aimed at improving its half-life. To explore the behavioral efficacy of an OT analog with enhanced plasma stability, we developed PF-06655075 (PF1), a novel non-brain penetrant OT receptor agonist with increased selectivity for the OT receptor and significantly increased pharmacokinetic stability. PF-06478939 was generated with only increased stability to disambiguate changes to selectivity versus stability. The efficacy of these compounds in evoking behavioral effects was tested in a conditioned fear paradigm. Both central and peripheral administration of PF1 inhibited freezing in response to a conditioned fear stimulus. Peripheral administration of PF1 resulted in a sustained level of plasma concentrations for greater than 20 hours but no detectable accumulation in brain tissue, suggesting that plasma or cerebrospinal fluid exposure was sufficient to evoke behavioral effects. Behavioral efficacy of peripherally administered OT receptor agonists on conditioned fear response opens the door to potential peripheral mechanisms in other behavioral paradigms, whether they are mediated by direct peripheral activation or feed-forward responses. Compound PF1 is freely available as a tool compound to further explore the role of peripheral OT in behavioral response. PMID- 27217592 TI - Manganese dioxide-modified carbon paste electrode for voltammetric determination of riboflavin. AB - A carbon paste electrode bulk was modified with MnO2 and investigated for use as an electrochemical sensor for riboflavin (vitamin B2) using differential pulse voltammetry (DPV). Riboflavin displays a well expressed oxidation peak at -0.15 V (versus Ag/AgCl) in solutions with a pH value of 2. Effects of pH value, pulse amplitude and pulse time were optimized by employing DPV. The signals obtained are linearly related to the concentrations of riboflavin in the range from 0.02 to 9 MUM. Other features include a 15 nM detection limit, and good reproducibility (+/-3 %) and repeatability (+/-2 %). Interferences by common compounds were tested, and the method was successfully applied to the determination of riboflavin in pharmaceutical formulations where is gave recoveries in the range from 95 to 97 %. Graphical abstractManganese(IV) oxide was used as a modifier for the carbon paste electrode (MnO2/CPE) for improving its performance toward riboflavin oxidation. Cyclic voltammetry and differential voltammetry were used for characterization and determination of riboflavin, respectively. PMID- 27217593 TI - alpha-Hemolysin nanopore studies reveal strong interactions between biogenic polyamines and DNA hairpins. AB - The alpha-hemolysin (alpha-HL) nanopore analyzes DNA as it is electrophoretically driven through the pore. The respective current vs. time (i-t) traces depends on the DNA sequence, its secondary structures, or on the physical conditions of the analysis. The current study describes analysis of a DNA hairpin with a 5' extension with the alpha-HL nanopore in the presence of the polyamines spermine (Spm), spermidine (Spd), and putrescine (Put). These studies identified a new i-t trace characteristic of the DNA-polyamine complex. Voltage-dependent studies determined that the hairpin-Spm complex formed with excess Spm was not unzipped and translocated through the pore even when the voltage was increased to 180 mV. The DNA hairpin sample was titrated with Spm, Spd, or Put that showed a dose dependent response in the characteristic event patterns for hairpins bound to Spm or Spd, but not for Put. Plots of the event types vs. count were used to calculate binding constants for the Spm or Spd hairpin interactions under these conditions. The titration also demonstrated that the event rate decreased ~10 fold when the Spm or Spd concentration was increased from 0 to 4 mM. These observations impose practical limitations on the ability to use Spm or Spd for DNA studies with the alpha-HL nanopore. PMID- 27217594 TI - General Strain Theory and Delinquency: Extending a Popular Explanation to American Indian Youth. AB - Despite evidence that American Indian adolescents are disproportionately involved in crime and delinquent behavior, there exists scant research exploring the correlates of crime among this group. We posit that Agnew's (1992) General Strain Theory (GST) is well suited to explain American Indian delinquent activity. Using the National Longitudinal Study of Adolescent Health, we examined a subsample of American Indian students-a study that represents, to the best of our knowledge, the initial published test of GST principles used to explain AI delinquent behavior. Overall, we find mixed support for the core principles of GST applying to AI delinquent behavior. We also found evidence that some of the personal and social resources identified by Agnew condition the strain-delinquent behavior relationship, albeit, sometimes in ways that are not entirely consistent with GST. PMID- 27217595 TI - Ecogeographical Variation in Skull Shape of South-American Canids: Abiotic or Biotic Processes? AB - Species morphological changes can be mutually influenced by environmental or biotic factors, such as competition. South American canids represent a quite recent radiation of taxa that evolved forms very disparate in phenotype, ecology and behaviour. Today, in the central part of South America there is one dominant large species (the maned wolf, Chrysocyon brachyurus) that directly influence sympatric smaller taxa via interspecific killing. Further south, three species of similar sized foxes (Lycalopex spp.) share the same habitats. Such unique combination of taxa and geographic distribution makes South American dogs an ideal group to test for the simultaneous impact of climate and competition on phenotypic variation. Using geometric morphometrics, we quantified skull size and shape of 431 specimens belonging to the eight extant South American canid species: Atelocynus microtis, Cerdocyon thous, Ch. brachyurus, Lycalopex culpaeus, L. griseus, L. gymnocercus, L. vetulus and Speothos venaticus. South American canids are significantly different in both skull size and shape. The hypercarnivorous bush dog is mostly distinct in shape from all the other taxa while a degree of overlap in shape-but not size-occurs between species of the genus Lycalopex. Both climate and competition impacts interspecific morphological variation. We identified climatic adaptations as the main driving force of diversification for the South American canids. Competition has a lower degree of impact on their skull morphology although it might have played a role in the past, when canid community was richer in morphotypes. PMID- 27217596 TI - Female Sexual Preferences Toward Conspecific and Hybrid Male Mating Calls in Two Species of Polygynous Deer, Cervus elaphus and C. nippon. AB - The behavioral processes at the basis of hybridization and introgression are understudied in terrestrial mammals. We use a unique model to test the role of sexual signals as a reproductive barrier to introgression by investigating behavioral responses to male sexual calls in estrous females of two naturally allopatric but reproductively compatible deer species, red deer and sika deer. Previous studies demonstrated asymmetries in acoustic species discrimination between these species: most but not all female red deer prefer conspecific over sika deer male calls while female sika deer exhibit no preference differences. Here, we extend this examination of acoustic species discrimination to the role of male sexual calls in introgression between parent species and hybrids. Using two-speaker playback experiments, we compared the preference responses of estrous female red and sika deer to male sexual calls from conspecifics versus red * sika hybrids. These playbacks simulate early secondary contact between previously allopatric species after hybridization has occurred. Based on previous conspecific versus heterospecific playbacks, we predicted that most female red deer would prefer conspecific calls while female sika deer would show no difference in their preference behaviors toward conspecific and hybrid calls. However, results show that previous asymmetries did not persist as neither species exhibited more preferences for conspecific over hybrid calls. Thus, vocal behavior is not likely to deter introgression between these species during the early stages of sympatry. On a wider scale, weak discrimination against hybrid sexual signals could substantially contribute to this important evolutionary process in mammals and other taxa. PMID- 27217597 TI - A Paradox of Genetic Variance in Epigamic Traits: Beyond "Good Genes" View of Sexual Selection. AB - Maintenance of genetic variance in secondary sexual traits, including bizarre ornaments and elaborated courtship displays, is a central problem of sexual selection theory. Despite theoretical arguments predicting that strong sexual selection leads to a depletion of additive genetic variance, traits associated with mating success show relatively high heritability. Here we argue that because of trade-offs associated with the production of costly epigamic traits, sexual selection is likely to lead to an increase, rather than a depletion, of genetic variance in those traits. Such trade-offs can also be expected to contribute to the maintenance of genetic variation in ecologically relevant traits with important implications for evolutionary processes, e.g. adaptation to novel environments or ecological speciation. However, if trade-offs are an important source of genetic variation in sexual traits, the magnitude of genetic variation may have little relevance for the possible genetic benefits of mate choice. PMID- 27217598 TI - Compartment-specific investigations of antioxidants and hydrogen peroxide in leaves of Arabidopsis thaliana during dark-induced senescence. AB - The aim of this study was to gain insight into the compartment-specific roles of ascorbate and glutathione in leaf senescence in Arabidopsis thaliana. The subcellular distribution of ascorbate, glutathione, and hydrogen peroxide (H2O2) was analyzed by transmission electron microscopy and correlated with the activity of antioxidative enzymes in wildtype plants and the ascorbate- and glutathione deficient mutants vtc2-1 and pad2-1, respectively. Both mutants showed earlier and stronger senescence than the wildtype indicating the importance of a functioning ascorbate and glutathione cycle in the induction and regulation of senescence. Glutathione levels dropped drastically and up to 93 % in all cell compartments of wildtype plants and the vtc2-1 mutant within the first day of dark-induced senescence while ascorbate contents remained unchanged until the very end. Glutathione contents in mitochondria of pad2-1 mutants decreased more slowly over the first 7 days than compared to the other plants indicating an important role of glutathione in mitochondria in this mutant during senescence. The strongest decrease (84 %) of glutathione contents in wildtype plants at this time point was found in mitochondria indicating an important role of mitochondria for the induction of senescence and cell death events. Due to the general decrease of the antioxidative capacity, a strong accumulation of H2O2 was observed in cell walls, plastids, and the cytosol in all plants. Activities of glutathione reductase, dehydroascorbate reductase and catalase were strongly reduced while ascorbate peroxidase and monodehydroascorbate reductase were increased. The initial rapid drop of glutathione levels seemed to be the trigger for senescence, while ascorbate appeared to be the key factor in regulating senescence through controlling H2O2 levels by the oxidation of reduced ascorbate to monodehydroascorbate and the subsequent reduction to ascorbate by monodehydroascorbate reductase. PMID- 27217600 TI - Nutritional Assessment in Critically Ill Patients. AB - BACKGROUND: Malnutrition is an important factor in the survival of critically ill patients. The purpose of the present study was to assess the nutritional status of patients in the intensive care unit (ICU) on the days of admission and discharge via a detailed nutritional assessment. METHODS: Totally, 125 patients were followed up from admission to discharge at 8ICUs in Shiraz, Iran. The patients' nutritional status was assessed using subjective global assessment (SGA), anthropometric measurements, biochemical indices, and body composition indicators. Diet prescription and intake was also evaluated. RESULTS: Malnutrition prevalence significantly increased on the day of discharge (58.62%) compared to the day of admission (28.8%) according to SGA (P<0.001). The patients' weight, mid-upper-arm circumference, mid-arm muscle circumference, triceps skinfold thickness, and calf circumference decreased significantly as well (P<0.001). Lean mass weight and body cell mass also decreased significantly (P<0.001). Biochemical indices showed no notable changes except for magnesium, which decreased significantly (P=0.013). A negative significant correlation was observed between malnutrition on discharge day and anthropometric measurements. Positive and significant correlations were observed between the number of days without enteral feeding, days delayed from ICU admission to the commencement of enteral feeding, and the length of ICU stay and malnutrition on discharge day. Energy and protein intakes were significantly less than the prescribed diet (26.26% and 26.48%, respectively). CONCLUSION: Malnutrition on discharge day increased in the patients in the ICU according to SGA. Anthropometric measurements were better predictors of the nutritional outcome of our critically ill patients than were biochemical tests. PMID- 27217599 TI - Variable Selection with Prior Information for Generalized Linear Models via the Prior LASSO Method. AB - LASSO is a popular statistical tool often used in conjunction with generalized linear models that can simultaneously select variables and estimate parameters. When there are many variables of interest, as in current biological and biomedical studies, the power of LASSO can be limited. Fortunately, so much biological and biomedical data have been collected and they may contain useful information about the importance of certain variables. This paper proposes an extension of LASSO, namely, prior LASSO (pLASSO), to incorporate that prior information into penalized generalized linear models. The goal is achieved by adding in the LASSO criterion function an additional measure of the discrepancy between the prior information and the model. For linear regression, the whole solution path of the pLASSO estimator can be found with a procedure similar to the Least Angle Regression (LARS). Asymptotic theories and simulation results show that pLASSO provides significant improvement over LASSO when the prior information is relatively accurate. When the prior information is less reliable, pLASSO shows great robustness to the misspecification. We illustrate the application of pLASSO using a real data set from a genome-wide association study. PMID- 27217601 TI - Effects of Arbutin on Radiation-Induced Micronuclei in Mice Bone Marrow Cells and Its Definite Dose Reduction Factor. AB - BACKGROUND: Interactions of free radicals from ionizing radiation with DNA can induce DNA damage and lead to mutagenesis and carsinogenesis. With respect to radiation damage to human, it is important to protect humans from side effects induced by ionizing radiation. In the present study, the effects of arbutin were investigated by using the micronucleus test for anti-clastogenic activity, to calculate the ratio of polychromatic erythrocyte to polychromatic erythrocyte plus normochromatic erythrocyte (PCE/PCE+NCE) in order to show cell proliferation activity. METHODS: Arbutin (50, 100, and 200 mg/kg) was intraperitoneally (ip)administered to NMRI mice two hours before gamma radiation at 2 and 4 gray (Gy). The frequency of micronuclei in 1000 PCEs (MnPCEs) and the ratio of PCE/PCE+NCE were calculated for each sample. Data were statistically evaluated using one-way ANOVA, Tukey HSD test, and t-test. RESULTS: The findings indicated that gamma radiation at 2 and 4 Gy extremely increased the frequencies of MnPCE (P<0.001) while reducing PCE/PCE+NCE (P<0.001) compared to the control group. All three doses of arbutin before irradiation significantly reduced the frequencies of MnPCEs and increased the ratio of PCE/PCE+NCE in mice bone marrow compared to the non-drug-treated irradiated control (P<0.001). All three doses of arbutin had no toxicity effect on bone marrow cells. The calculated dose reduction factor (DRF) showed DRF=1.93 for 2Gy and DRF=2.22 for 4 Gy. CONCLUSION: Our results demonstrated that arbutin gives significant protection to rat bone against the clastogenic and cytotoxic effects of gamma irradiation. PMID- 27217602 TI - Comparison of Auditory Perception in Cochlear Implanted Children with and without Additional Disabilities. AB - BACKGROUND: The number of children with cochlear implants who have other difficulties such as attention deficiency and cerebral palsy has increased dramatically. Despite the need for information on the results of cochlear implantation in this group, the available literature is extremely limited. We, therefore, sought to compare the levels of auditory perception in children with cochlear implants with and without additional disabilities. METHODS: A spondee test comprising 20 two-syllable words was performed. The data analysis was done using SPSS, version 19. RESULTS: Thirty-one children who had received cochlear implants 2 years previously and were at an average age of 7.5 years were compared via the spondee test. From the 31 children, 15 had one or more additional disabilities. The data analysis indicated that the mean score of auditory perception in this group was approximately 30 scores below that of the children with cochlear implants who had no additional disabilities. CONCLUSION: Although there was an improvement in the auditory perception of all the children with cochlear implants, there was a noticeable difference in the level of auditory perception between those with and without additional disabilities. Deafness and additional disabilities depended the children on lip reading alongside the auditory ways of communication. In addition, the level of auditory perception in the children with cochlear implants who had more than one additional disability was significantly less than that of the other children with cochlear implants who had one additional disability. PMID- 27217603 TI - Usage Pattern and Serum Level Measurement of Amikacin in the Internal Medicine Ward of the Largest Referral Hospital in the South of Iran: A Pharmacoepidemiological Study. AB - BACKGROUND: The inappropriate use of aminoglycosides has harmful effects such as the development of resistant pathogens and the incidence of nephrotoxicity and ototoxicity. Therefore, drug utilization evaluation of these drugs may improve their usage remarkably. The aim of this study was to assess the usage pattern of amikacin in an internal medicine ward. METHODS: This cross-sectional study was conducted in the Internal Medicine Ward of Nemazee Teaching Hospital, Shiraz, Iran, in 2011. The guideline for amikacin use was approved by the institutional Pharmacy and Therapeutics Committee, and the study criteria were developed to assess several parameters involved in amikacin therapy such as appropriateness of drug use, dosage, duration of therapy, toxicity monitoring, and serum concentration assay. Serum concentration was assayed using a Cobas Mira AutoAnalyzer. Clinical and paraclinical parameters such as glomerular filtration rate, culture, microbial sensitivity, white blood cell count, and fever were collected. RESULTS: Sixty-three patients were evaluated. Fifty-seven percent of the patients needed dose readjustment; however, it was not performed for 89% of them. Culture between 48 and 72 hours after amikacin administration was not controlled for 79% of the patients. In 19% of the patients, optimum therapeutic effect was not achieved. The mean+/-SD of the trough and peak concentrations was 7.63+/-5.4 MUg/mL and 15.67+/-7.79 MUg/mL, respectively. Forty-five percent of the trough and 38% of the peak levels were within the therapeutic range. The overall adherence of amikacin usage to the guideline was only 48%. CONCLUSION: To achieve appropriate treatment and prevent toxic effects, we recommend that pharmacokinetic dosing methods, amikacin guideline, and serum monitoring be considered. PMID- 27217604 TI - Anticonvulsant Effect of the Aqueous Extract and Essential Oil of Carum Carvi L. Seeds in a Pentylenetetrazol Model of Seizure in Mice. AB - BACKGROUND: Carum carvi L. (caraway), known as black zeera in Iran, has been indicated for the treatment of epilepsy in Iranian folk medicine. This study evaluated whether the aqueous extract and essential oil of caraway seeds have anticonvulsant effects in mice. METHODS: The anticonvulsant effects of the aqueous extract (200, 400, 800, 1600, and 3200 mg/kg, i.p.) and essential oil (25, 50, 100, 200, and 400 mg/kg, i.p.) of caraway were assessed using pentylenetetrazol (PTZ; 95 mg/kg i.p.) induced convulsions. Diazepam (3 mg/kg) was used as positive control. The latency time before the onset of myoclonic, clonic, and tonic convulsions and the percentage of mortality were recorded. In addition, the effect of caraway on neuromuscular coordination was evaluated using the rotarod performance test. RESULTS: The extract and essential oil dose dependently increased the latency time to the onset of myoclonic (ED50, 1257 and 62.2 mg/kg, respectively) and clonic (ED50, 929 and 42.3 mg/kg, respectively) seizures. The extract and essential oil of caraway prevented the animals from tonic seizure with ED50s of 2142.4 and 97.6 mg/kg, respectively. The extract and essential oil of caraway protected 28.6 and 71.4% of the animals from PTZ-induced death, respectively, and had no significant effect on neuromuscular coordination. CONCLUSION: This study showed that the aqueous extract and essential oil of caraway had anticonvulsant properties. However, the essential oil was more potent and effective than was the aqueous extract as an anticonvulsant. Additionally, the anticonvulsant effect of caraway was not due to a muscle relaxant activity. These findings support the acclaimed antiepileptic effect of caraway in folk medicine and propose its potential use in petit mal seizure in humans. PMID- 27217605 TI - Inter- and Intraspecific Variations of Leishmania Strains Isolated from Patients with Cutaneous and Visceral Leishmaniases in Fars Province, South of Iran. AB - BACKGROUND: Cutaneous and visceral leishmaniases are present in Fars Province in the south of Iran. The current study aimed to evaluate the inter- and intragenic diversities of Leishmania species isolated from patients with leishmaniasis in Fars Province, using PCR-based analyses and DNA sequencing of the N acetylglucosamine-1-phosphate transferase (nagt) gene. METHODS: Clinical samples were taken from the skin lesions of 120 individuals with clinical suspicion of cutaneous leishmaniasis (CL) referred to the major health centers of Shiraz. Along with microscopic examination, a part of each sample was used for in vitro cultivation. DNA was extracted from the cultured parasites and the nagt gene was PCR-amplified. For RFLP analysis, the PCR product of the nagt gene was digested with the Acc1 restriction enzyme. Moreover, the PCR products of 23 isolates were sequenced and analyzed, using MEGA5. RESULTS: From the 120 patients with clinical suspicion of CL, 110 (91.7%) cases were found to be positive by direct microscopy while 77 (64.1%) of the cultures were positive. Digestion of the PCR product with the Acc1 restriction enzyme detected L. major in 57 out of the 77 (74.1%) and L. tropica, in 20 out of the 77 (25.9%) cases with CL. Phylogenetic analysis grouped the Leishmania isolates into 3 main clades, representing L. major, L. infantum, and L. tropica, encompassing 2, 2, and 2 haplotypes, respectively. Within the clades, the L. tropica intraspecies divergence was more pronounced in L. major. CONCLUSION: The findings of this study demonstrated that the causative agent of CL in Fars Province was mainly L. majorz and that there was considerable heterogeneity between the Leishmania species and also within the L. major isolates. PMID- 27217606 TI - Effect of Aspirin on Spinal Cord Injury: An Experimental Study. AB - Aspirin is an anti-inflammatory drug, peroxyl radical scavenger, and antioxidant agent that inhibits phospholipases, nitric oxide synthetases, and cyclooxygenase enzymes. The existing literature contains no studies on the effects of various doses of aspirin on spinal cord injury (SCI). Therefore, we sought to investigate the putative effects of aspirin on experimental SCI. The weight-drop injury model was used to produce SCI in 100 albino Wistar rats. The animals were allocated to five groups: a control group, where the rats did not undergo any surgical or medical intervention except for anesthesia; a sham-treated group, where laminectomy was performed without SCI and no further therapy was administered; and three other groups, where the rats with SCI received low-dose aspirin [20 mg/kg], high-dose aspirin [80 mg/kg], and a vehicle, respectively. Half of the rats were sacrificed 24 hours later, and their spinal cords were excised for biochemical studies. The other rats were subjected to Basso, Beattie, and Bresnahan (BBB) locomotor rating scale scoring once a week for 6 consecutive weeks. Aspirin decreased lipid peroxidation following SCI as the mean (+/- standard error) catalase level was significantly higher in the high-dose aspirin group (46.10+/-12.01) than in the sham-treated group (16.07+/-2.42) and the vehicle-treated group (15.31+/-3.20) (P<0.05; P<0.05, respectively). Both of the groups treated with high-dose and low-dose aspirin demonstrated a higher mean BBB score than did the control group (P<0.001) and the sham-treated group (P<0.001). Our data provide evidence in support of the potential effects of aspirin in biochemical and neurobehavioral recovery after SCI. PMID- 27217607 TI - Dicer Gene Expression as a Prognostic Factor in Acute Lymphoblastic Leukemia and Chronic Lymphocytic Leukemia in Fars Province. AB - Alterations in the expression of microRNAs (miRNAs) have been proposed to play a role in the pathogenesis of acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). Dicer is one of the main regulators of miRNA biogenesis, and deregulation of its expression has been indicated as a possible cause of miRNA alterations observed in various cancers. Our aim was to analyze the expression of the Dicer protein and its relationship with ALL and CLL. This cross-sectional study was performed from 2010 to 2012 in Shahid Faghihi Hospital, Shiraz, Iran. In this study, 30 patients with CLL, 21 patients with ALL, 10 child healthy donors, and 19 adult healthy donors were recruited. The patients' samples were checked via flow cytometry, immunohistochemistry, and immunocytochemistry. The controls' samples were also examined in the hematology ward. Total RNA was extracted from the bone marrow and peripheral blood samples of the patients and controls. Then, reverse-transcription polymerase chain reaction was used to estimate the level of Dicer miRNA. The outcomes of the expression analysis of Dicer revealed statistically significant differences between the ALL patients/child healthy controls (mean+/-SD, 0.19+/-0.28 vs. 0.73+/-0.12; P<0.001) and the CLL patients/adult healthy controls (mean+/-SD, 0.24+/-0.25 vs. 0.41+/ 0.28; P=0.033). This is the first piece of evidence showing that the expression of the Dicer gene greatly decreased in the patients with ALL in comparison to the child controls. The expression of the Dicer gene was also downregulated in the patients with CLL compared to the adult controls. Given the above findings, the expression of Dicer may play an important role in the progression and prognosis of these diseases. PMID- 27217608 TI - Combined Effect of Trolox and EDTA on Frozen-Thawed Sperm Quality. AB - The freezing and thawing process not only is associated with serious damage to sperm such as damage to the plasma membrane and the acrosomal membrane but also changes the membrane permeability to some ions including calcium. Also, the generation of oxygen free radicals is increased during the freezing-thawing process. The purpose of this study was to evaluate of the effects of Trolox as an antioxidant and edetic acid (EDTA) as a calcium chelator on frozen-thawed (FT) sperm and compare these effects with those on fresh sperm. This study was done on these men of 25 healthy men, who referred to Shiraz Infertility Centerbetween2012 and2013. Normal samples were transferred to the ReproductivePhysiology Laboratory, Department of Physiology, Shiraz University of Medical Sciences, Shiraz. The samples were divided into two groups randomly: fresh and FT sperm groups. Each group was divided into five subgroups: control group, the solvent group (0.1%dimethyl sulfoxide [DMSO]), Trolox group (200MUM), EDTA group (1.1mM), and Trolox+EDTA group. The percentages of motility, viability, and acrosome reacted sperm were tested. The percentages of motility and viability in the FT sperm were lower than those in the fresh sperm. The progressive motility of the FT sperm was improved nonsignificantly with Trolox+EDTA. However, the effect of Trolox+EDTA on the progressive motility of the FT sperm was much more than that on the fresh sperm. The fewest acrosome-reacted sperm were observed in the EDTA containingFT sperm. Antioxidant supplementation or omission of extracellular calcium may partly improve motility and also reduce acrosomal damage in FT sperm. PMID- 27217609 TI - Familial Amyloid Polyneuropathy Type IV (FINNISH) with Rapid Clinical Progression in an Iranian Woman: A Case Report. AB - Familial amyloid polyneuropathy (FAP) type IV (FINNISH) is a rare clinical entity with challenging neuropathy and cosmetic deficits. Amyloidosis can affect peripheral sensory, motor, or autonomic nerves. Nerve lesions are induced by deposits of amyloid fibrils and treatment approaches for neuropathy are challenging. Involvement of cranial nerves and atrophy in facial muscles is a real concern in daily life of such patients. Currently, diagnosis of neuropathy can be made by electrodiagnostic studies and diagnosis of amyloidosis can be made by genetic testing or by detection of amyloid deposition in abdominal fat pad, rectal, or nerve biopsies. It is preferable to consider FAP as one of the differential diagnosis of a case presented with multiple cranial nerves symptoms. The authors present a case of familial amyloid polyneuropathy (FAP) type IV with severe involvement of multiple cranial nerves, peripheral limb neuropathy, and orthostatic hypotension. PMID- 27217610 TI - Acute Hemorrhagic Leukoencephalitis in Children: A Case Report. AB - Acute hemorrhagic leukoencephalitis (AHLE) is a rare demyelinating disease characterized by an acute rapidly progressive fulminant inflammation of the white matter. In this case report, we introduce a case of AHLE in children with an interesting and lengthy process and successful treatment. A previously healthy 13 year-old girl was admitted to the hospital because of fever and loss of consciousness. After 4 days, she was referred to our pediatric intensive care unit in Mashhad, Iran. On admission, she had right-sided parotiditis. With a diagnosis of AHLE, our patient was treated with methylprednisolone, intravenous immunoglobulin, acyclovir, and plasmapheresis. AHLE is a rare and severe demyelinating disease, the mortality and morbidity of which can be decreased by early detection and treatment with steroid therapy, intravenous immunoglobulin, acyclovir, and plasmapheresis. PMID- 27217611 TI - Report of a Case with Trisomy 9 Mosaicism. AB - Trisomy 9 is a rare chromosome disorder with high neonatal mortality. It is often seen in mosaic form. Most patients who survive are severely mentally retarded. The main features of this syndrome are "bulbous" nose, microphthalmia, dislocated limbs, and other anomalies of skeletal, cardiac, genitourinary, and central nervous system. Most patients have developmental and cognitive impairment. Patients with mosaicism survive longer than non-mosaics, but it was believed that the degree of mosaicism in lymphocytes or fibroblasts does not associate with survival or degree of impairment. In this report, we present a 2.5-year-old male case of mosaic trisomy 9, to show the wide range of clinical findings in this chromosome disorder. The patient had cardiac anomalies, inguinal hernia, and undescendent testes. He had low-set slightly malformed ears, deeply-set malformed eyes, small palpebral fissures, micrognathia, developmental delay and unilateral optic hypoplasia. The most prominent facial anomaly in this patient was eye anomalies. Cytogenetic analysis with G banding showed karyotype 47XY,+9 in 44% of peripheral lymphocytes examined (47XY,+9[22], 46XY[28]). His parents' karyotypes were normal. Moderate developmental delay, which was detected in this patient shows that the range of motor and cognitive impairment in this chromosomal disorder is quite broad. This fact should be considered in genetic counseling as well as prenatal diagnosis of this chromosomal disorder. PMID- 27217612 TI - Bears and berries: species-specific selective foraging on a patchily distributed food resource in a human-altered landscape. AB - ABSTRACT: When animals are faced with extraordinary energy-consuming events, like hibernation, finding abundant, energy-rich food resources becomes particularly important. The profitability of food resources can vary spatially, depending on occurrence, quality, and local abundance. Here, we used the brown bear (Ursus arctos) as a model species to quantify selective foraging on berries in different habitats during hyperphagia in autumn prior to hibernation. During the peak berry season in August and September, we sampled berry occurrence, abundance, and sugar content, a proxy for quality, at locations selected by bears for foraging and at random locations in the landscape. The factors determining selection of berries were species specific across the different habitats. Compared to random locations, bears selected locations with a higher probability of occurrence and higher abundance of bilberries (Vaccinium myrtillus) and a higher probability of occurrence, but not abundance, of lingonberries (Vaccinium vitis-idaea). Crowberries (Empetrum hermaphroditum) were least available and least used. Sugar content affected the selection of lingonberries, but not of bilberries. Abundance of bilberries at random locations decreased and abundance of lingonberries increased during fall, but bears did not adjust their foraging strategy by increasing selection for lingonberries. Forestry practices had a large effect on berry occurrence and abundance, and brown bears responded by foraging most selectively in mature forests and on clearcuts. This study shows that bears are successful in navigating human-shaped forest landscapes by using areas of higher than average berry abundance in a period when abundant food intake is particularly important to increase body mass prior to hibernation. SIGNIFICANCE STATEMENT: Food resources heterogeneity, caused by spatial and temporal variation of specific foods, poses a challenge to foragers, particularly when faced with extraordinary energy-demanding events, like hibernation. Brown bears in Sweden inhabit a landscape shaped by forestry practices. Bilberries and lingonberries, the bears' main food resources in autumn prior to hibernation, show different temporal and habitat-specific ripening patterns. We quantified the bears' selective foraging on these berry species on clearcuts, bogs, young, and mature forests compared to random locations. Despite a temporal decline of ripe bilberries, bears used locations with a greater occurrence and abundance of bilberries, but not lingonberries. We conclude that bears successfully navigated in this heavily human-shaped landscape by selectively foraging in high-return habitats for bilberries, but did not compensate for the decline in bilberries by eating more lingonberries. PMID- 27217613 TI - Yolk steroids in great tit Parus major eggs: variation and covariation between hormones and with environmental and parental factors. AB - ABSTRACT: Avian mothers can potentially alter the phenotypes of their offspring by varying the concentration of steroid hormones in their eggs. We explored variation in androstenedione (A4), testosterone (T), 5alpha-dihydrotestosterone (DHT), 17beta-estradiol (E2), and corticosterone (CORT) in the yolks of 12 free living great tit Parus major clutches. We analyzed variation and covariation in greater detail than previous studies, using models for variation with laying sequence that take into account variable clutch size and comparing correlations between pairs of hormones at the within- and between-clutch levels. We also investigated relationships between hormone levels and various environmental, life history, and parental traits. For three of the five steroids, we found no significant correlates, but based on individual statistical tests (a) DHT varied between clutches with male age (1 year old vs older); (b) DHT and CORT were negatively correlated within clutches with the average temperature on the day (DHT and CORT) or 3 days (DHT only) preceding laying; and (c) DHT in the last egg of the clutch relative to the clutch mean was positively correlated with the interval between clutch completion and the onset of incubation (incubation delay). Relationships with ambient temperature and incubation delay have not previously been reported for any yolk hormone in birds. Intriguingly, the three relationships for DHT are consistent with more DHT being transferred to eggs in situations that could be more energetically challenging for the female. More research is needed to determine the generality of the patterns we found and to understand their functional significance. SIGNIFICANCE STATEMENT: The yolks of birds' eggs contain steroid hormones produced by the mother which can affect the development and behavior of the resultant chicks. We analyzed five steroid hormones in the yolks of wild great tits and show for the first time that yolk hormone levels are related to ambient temperature in the day(s) just before laying and, in the last-laid egg, with the day it is laid relative to the onset of incubation, and that the concentrations of pairs of yolk hormones can vary with each other in a different way between and within clutches. These results contribute insights into the ways in which yolk hormones may adaptively modify the chicks or may reflect physiological processes occurring in the mother. PMID- 27217614 TI - Changes in vocal parameters with social context in humpback whales: considering the effect of bystanders. AB - ABSTRACT: Many theories and communication models developed from terrestrial studies focus on a simple dyadic exchange between a sender and receiver. During social interactions, the "frequency code" hypothesis suggests that frequency characteristics of vocal signals can simultaneously encode for static signaler attributes (size or sex) and dynamic information, such as motivation or emotional state. However, the additional presence of a bystander may result in a change of signaling behavior if the costs and benefits associated with the presence of this bystander are different from that of a simple dyad. In this study, two common humpback whale social calls ("wops" and "grumbles") were tested for differences related to group social behavior and the presence of bystanders. "Wop" parameters were stable with group social behavior, but were emitted at lower (14 dB) levels in the presence of a nearby singing whale compared to when a singing whale was not in the area. "Grumbles" were emitted at lower (30-39 Hz) fundamental frequencies in affiliative compared to non-affiliative groups and, in the presence of a nearby singing whale, were also emitted at lower (14 dB) levels. Vocal rates did not significantly change. The results suggest that, in humpbacks, the frequency in certain sound types relates to the social behavior of the vocalizing group, implying a frequency code system. The presence of a nearby audible bystander (a singing whale) had no effect on this frequency code, but by reducing their acoustic level, the signal-to-noise ratio at the singer would have been below 0, making it difficult for the singer to audibly detect the group. SIGNIFICANCE STATEMENT: The frequency, duration, and amplitude parameters of humpback whale social vocalizations were tested between different social contexts: group social behavior (affiliating versus non-affiliating), the presence of a nearby singing whale, and the presence of a nearby non-singing group. "Grumbles" (commonly heard low-frequency unmodulated sounds) frequencies were lower in affiliating groups compared to non-affiliating groups, suggesting a change in group motivation (such as levels of aggression). "Wop" (another common sound type) structure (frequency and duration) was similar in affiliating and non affiliating groups. In the presence of an audible bystander (a singing whale), both sound types were emitted at similar rates, but much lower amplitudes (14 dB), vastly reducing the detectability of these sounds by the singer. This suggests that these groups were acoustically avoiding the singing whale. They did not, however, acoustically respond to the presence of a nearby non-singing group. PMID- 27217615 TI - How Has Living with Intimate Partner Violence Affected the Work Situation? A Qualitative Study among Abused Women in Norway. AB - A qualitative study was conducted among 18 abused women from different parts of Norway to explore what paid work means for women exposed to partner violence and how living with an abusive partner affected their working life. Based on systematic text condensation analyses of their experiences as described in individual and focus group interviews, the study's findings reveal two major themes. The first is about recovery and survival, and the other about the spillover of problems caused by a violent partner into paid work. Work was important to the women, as it represented time off from violence, contact with others who cared for them, and maintenance of self-esteem and self-confidence. Having their own money provided security and strengthened the belief that they could manage on their own. The spillover of intimate partner violence problems appeared through feelings of fear, shame and guilt at work. PMID- 27217616 TI - 'Once upon a time ...': Orphanhood, childhood studies and the depoliticisation of childhood poverty in southern Africa. AB - Policy, interventions and research concerning southern African children remain dominated by a focus on AIDS-related orphanhood, although the association between orphanhood and disadvantage is highly questionable. I argue that the trope of the AIDS orphan serves a range of agendas, including for academic research. In particular, orphans represent the quintessential child-agent, celebrated in fairytales and fiction. Finally, I examine how this has led to a policy response education bursaries - that cannot adequately address childhood poverty in the region. PMID- 27217617 TI - Occupational Skills and Labour Market Progression of Married Immigrant Women in Canada. AB - We use the confidential files of the 1991-2006 Canadian Census, combined with information from O*NET on the skill requirements of jobs, to explore whether immigrant women behave as secondary workers, remaining marginally attached to the labour market and experiencing little career progression over time. Our results show that the current labour market patterns of female immigrants to Canada do not fit this profile, as previous studies found, but rather conform to patterns recently exhibited by married native women elsewhere, with rising participation and wage progression. At best, only relatively uneducated immigrant women in unskilled occupations may fit the profile of secondary workers, with slow skill mobility and low-status job-traps. Educated immigrant women, on the other hand, experience skill assimilation over time: a reduction in physical strength and an increase in analytical skills required in their jobs relative to those of natives. PMID- 27217618 TI - On the scenario of passive dosimeters in personnel monitoring: Relevance to diagnostic radiology and fluoroscopy-based interventional cardiology. PMID- 27217619 TI - Surface dose measurements and comparison of unflattened and flattened photon beams. AB - The purpose of this study was to evaluate the central axis dose in the build-up region and the surface dose of a 6 MV and 10 MV flattened photon beam (FB) and flattening filter free (FFF) therapeutic photon beam for different square field sizes (FSs) for a Varian Truebeam linear accelerator using parallel-plate ionization chamber and Gafchromic film. Knowledge of dosimetric characteristics in the build-up region and surface dose of the FFF is essential for clinical care. The dose measurements were also obtained empirically using two different commonly used dosimeters: a p-type photon semiconductor dosimeter and a cylindrical ionization chamber. Surface dose increased linearly with FS for both FB and FFF photon beams. The surface dose values of FFF were higher than the FB FSs. The measured surface dose clearly increases with increasing FS. The FFF beams have a modestly higher surface dose in the build-up region than the FB. The dependence of source to skin distance (SSD) is less significant in FFF beams when compared to the flattened beams at extended SSDs. PMID- 27217620 TI - Dosimetric differences in flattened and flattening filter-free beam treatment plans. AB - This study investigated the dosimetric differences in treatment plans from flattened and flattening filter-free (FFF) beams from the TrueBeam System. A total of 104 treatment plans with static (sliding window) intensity-modulated radiotherapy beams and volumetric-modulated arc therapy (VMAT) beams were generated for 15 patients involving three cancer sites. In general, the FFF beam provides similar target coverage as the flattened beam with improved dose sparing to organ-at-risk (OAR). Among all three cancer sites, the head and neck showed more important differences between the flattened beam and FFF beam. The maximum reduction of the FFF beam in the mean dose reached up to 2.82 Gy for larynx in head and neck case. Compared to the 6 MV flattened beam, the 10 MV FFF beam provided improved dose sparing to certain OARs, especially for VMAT cases. Thus, 10 MV FFF beam could be used to improve the treatment plan. PMID- 27217621 TI - An investigation of the dose distribution effect related with collimator angle in volumetric arc therapy of prostate cancer. AB - To investigate the dose-volume variations of planning target volume (PTV) and organ at risks (OARs) in eleven prostate cancer patients planned with single and double arc volumetric modulated arc therapy (VMAT) when varying collimator angle. Single and double arc VMAT treatment plans were created using Monaco5.0((r)) with collimator angle set to 0 degrees . All plans were normalized 7600 cGy dose to the 95% of clinical target volume (CTV) volume. The single arc VMAT plans were reoptimized with different collimator angles (0 degrees , 15 degrees , 30 degrees , 45 degrees , 60 degrees , 75 degrees , and 90 degrees ), and for double arc VMAT plans (0-0 degrees , 15 degrees -345, 30-330 degrees , 45-315 degrees , 60 300 degrees , 75-285 degrees , 90-270 degrees ) using the same optimization parameters. For the comparison the parameters of heterogeneity index (HI), dose volume histogram and minimum dose to the 95% of PTV volume (D95 PTV) calculated and analyzed. The best plans were verified using 2 dimensional ion chamber array IBA Matrixx((r)) and three-dimensional IBA Compass((r)) program. The comparison between calculation and measurement were made by the gamma-index (3%/3 mm) analysis. A higher D95 (PTV) were found for single arc VMAT with 15 degrees collimator angle. For double arc, VMAT with 60-300 degrees and 75-285 degrees collimator angles. However, lower rectum doses obtained for 75-285 degrees collimator angles. There was no significant dose difference, based on other OARs which are bladder and femur head. When we compared single and double arc VMAT's D95 (PTV), we determined 2.44% high coverage and lower HI with double arc VMAT. All plans passed the gamma-index (3%/3 mm) analysis with more than 97% of the points and we had an average gamma-index for CTV 0.36, for PTV 0.32 with double arc VMAT. These results were significant by Wilcoxon signed rank test statistically. The results show that dose coverage of target and OAR's doses also depend significantly on the collimator angles due to the geometry of target and OARs. Based on the results we have decided to plan prostate cancer patients in our clinic with double arc VMAT and 75 degrees -285 degrees collimator angles. PMID- 27217623 TI - Dosimetry of indigenously developed (192)Ir high-dose rate brachytherapy source: An EGSnrc Monte Carlo study. AB - Clinical application using high-dose rate (HDR) (192)Ir sources in remote afterloading technique is a well-established treatment method. In this direction, Board of Radiation and Isotope Technology (BRIT) and Bhabha Atomic Research Centre, India, jointly indigenously developed a remote afterloading machine and (192)Ir HDR source. The two-dimensional (2D) dose distribution and dosimetric parameters of the BRIT (192)Ir HDR source are generated using EGSnrc Monte Carlo code system in a 40 cm dia * 40 cm height cylindrical water phantom. The values of air-kerma strength and dose rate constant for BRIT (192)Ir HDR source are 9.894 * 10(-8) +/- 0.06% UBq(-1) and 1.112 +/- 0.11% cGyh(-1)U(-1), respectively. The values of radial dose function (gL(r)) of this source compare well with the corresponding values of BEBIG, Flexisource, and GammaMed 12i source models. This is because of identical active lengths of the sources (3.5 mm) and the comparable phantom dimensions. A comparison of gL(r) values of BRIT source with microSelectron-v1 show differences about 2% at r = 6 cm and up to 13% at r = 12 cm, which is due to differences in phantom dimensions involved in the calculations. The anisotropy function of BRIT (192)Ir HDR source is comparable with the corresponding values of microSelectron-v1 (classic) HDR source. PMID- 27217622 TI - Development of a deformable dosimetric phantom to verify dose accumulation algorithms for adaptive radiotherapy. AB - Adaptive radiotherapy may improve treatment outcomes for lung cancer patients. Because of the lack of an effective tool for quality assurance, this therapeutic modality is not yet accepted in clinic. The purpose of this study is to develop a deformable physical phantom for validation of dose accumulation algorithms in regions with heterogeneous mass. A three-dimensional (3D) deformable phantom was developed containing a tissue-equivalent tumor and heterogeneous sponge inserts. Thermoluminescent dosimeters (TLDs) were placed at multiple locations in the phantom each time before dose measurement. Doses were measured with the phantom in both the static and deformed cases. The deformation of the phantom was actuated by a motor driven piston. 4D computed tomography images were acquired to calculate 3D doses at each phase using Pinnacle and EGSnrc/DOSXYZnrc. These images were registered using two registration software packages: VelocityAI and Elastix. With the resultant displacement vector fields (DVFs), the calculated 3D doses were accumulated using a mass-and energy congruent mapping method and compared to those measured by the TLDs at four typical locations. In the static case, TLD measurements agreed with all the algorithms by 1.8% at the center of the tumor volume and by 4.0% in the penumbra. In the deformable case, the phantom's deformation was reproduced within 1.1 mm. For the 3D dose calculated by Pinnacle, the total dose accumulated with the Elastix DVF agreed well to the TLD measurements with their differences <2.5% at four measured locations. When the VelocityAI DVF was used, their difference increased up to 11.8%. For the 3D dose calculated by EGSnrc/DOSXYZnrc, the total doses accumulated with the two DVFs were within 5.7% of the TLD measurements which are slightly over the rate of 5% for clinical acceptance. The detector-embedded deformable phantom allows radiation dose to be measured in a dynamic environment, similar to deforming lung tissues, supporting the validation of dose mapping and accumulation operations in regions with heterogeneous mass, and dose distributions. PMID- 27217624 TI - Estimation of the effects of normal tissue sparing using equivalent uniform dose based optimization. AB - In this study, we intend to estimate the effects of normal tissue sparing between intensity modulated radiotherapy (IMRT) treatment plans generated with and without a dose volume (DV)-based physical cost function using equivalent uniform dose (EUD). Twenty prostate cancer patients were retrospectively selected for this study. For each patient, two IMRT plans were generated (i) EUD-based optimization with a DV-based physical cost function to control inhomogeneity (EUDWith DV) and (ii) EUD-based optimization without a DV-based physical cost function to allow inhomogeneity (EUDWithout DV). The generated plans were prescribed a dose of 72 Gy in 36 fractions to planning target volume (PTV). Mean dose, D30%, and D5% were evaluated for all organ at risk (OAR). Normal tissue complication probability was also calculated for all OARs using BioSuite software. The average volume of PTV for all patients was 103.02 +/- 27 cm(3). The PTV mean dose for EUDWith DV plans was 73.67 +/- 1.7 Gy, whereas for EUDWithout DV plans was 80.42 +/- 2.7 Gy. It was found that PTV volume receiving dose more than 115% of prescription dose was negligible in EUDWith DV plans, whereas it was 28% in EUDWithout DV plans. In almost all dosimetric parameters evaluated, dose to OARs in EUDWith DV plans was higher than in EUDWithout DV plans. Allowing inhomogeneous dose (EUDWithout DV) inside the target would achieve better normal tissue sparing compared to homogenous dose distribution (EUDWith DV). Hence, this inhomogeneous dose could be intentionally dumped on the high-risk volume to achieve high local control. Therefore, it was concluded that EUD optimized plans offer added advantage of less OAR dose as well as selectively boosting dose to gross tumor volume. PMID- 27217625 TI - Determination of optimal number of beams in direct machine parameter optimization based intensity modulated radiotherapy for head and neck cases. AB - This paper aims to introduce an algorithm called "sensitivity-based beam number selection (SBBNS)" for fully automated and case-specific determination of an optimal number of equispaced beams in intensity-modulated radiotherapy (IMRT). We tested the algorithm in five head and neck cases of varying complexity. We used direct machine parameter optimization method coupled with Auto Plan feature available in Pinnacle TPS (Version 9.10.0) for optimization. The Pearson correlation test shows a correlation of 0.88 between predicted and actual optimal number of beams, which indicates that SBBNS method is capable of predicting optimal number of beams for head and neck cases with reasonable accuracy. The major advantage of the algorithm is that it intrinsically takes into account various case- and machine-specific factors for the determination of optimal number. The study demonstrates that the algorithm can be effectively applied to IMRT scenarios to determine case specific and optimal number of beams for head and neck cases. PMID- 27217626 TI - Dosimetric and radiobiological comparison of CyberKnife M6TM InCise multileaf collimator over IRISTM variable collimator in prostate stereotactic body radiation therapy. AB - The impetus behind our study was to establish a quantitative comparison between the IRIS collimator and the InCise multileaf collimator (MLC) (Accuray Inc. Synnyvale, CA) for prostate stereotactic body radiation therapy (SBRT). Treatment plans for ten prostate cancer patients were performed on MultiPlanTM 5.1.2 treatment planning system utilizing MLC and IRIS for 36.25 Gy in five fractions. To reduce the magnitude of variations between cases, the planning tumor volume (PTV) was defined and outlined for treating prostate gland only, assuming no seminal vesicle or ex-capsule involvement. Evaluation indices of each plan include PTV coverage, conformity index (CI), Paddick's new CI, homogeneity index, and gradient index. Organ at risk (OAR) dose sparing was analyzed by the bladder wall Dmax and V37Gy, rectum Dmax and V36Gy. The radiobiological response was evaluated by tumor control probability and normal tissue complication probability based on equivalent uniform dose. The dose delivery efficiency was evaluated on the basis of planned monitor units (MUs) and the reported treatment time per fraction. Statistical significance was tested using the Wilcoxon signed rank test. The studies indicated that CyberKnife M6TM IRIS and InCiseTM MLC produce equivalent SBRT prostate treatment plans in terms of dosimetry, radiobiology, and OAR sparing, except that the MLC plans offer improvement of the dose fall-off gradient by 29% over IRIS. The main advantage of replacing the IRIS collimator with MLC is the improved efficiency, determined from the reduction of MUs by 42%, and a 36% faster delivery time. PMID- 27217627 TI - Dosimetric impact of setup errors in head and neck cancer patients treated by image-guided radiotherapy. AB - To assess and analyze the impact of setup uncertainties on target volume coverage and doses to organs at risk (OAR) in head and neck cancer (HNC) patients treated by image-guided radiotherapy (IGRT). Translational setup errors in 25 HNC patients were observed by kilovoltage cone beam computed tomography (kV CBCT). Two plans were generated. Plan one - the original plan which was the initially optimized and approved plan of the patient. All patients were treated according to their respective approved plans at a defined isocenter. Plan two - the plan sum which was the sum of all plans recalculated at a different isocenter according to setup errors in x, y, and z-direction. Plan sum was created to evaluate doses that would have been received by planning target volume (PTV) and OARs if setup errors were not corrected. These 2 plans were analyzed and compared in terms of target volume coverage and doses to OARs. A total 503 kV CBCT images were acquired for evaluation of setup errors in 25 HNC patients. The systematic (mean) and random errors (standard deviation) combined for 25 patients in x, y, and z directions were 0.15 cm, 0.21 cm, and 0.19 cm and 0.09 cm, 0.12 cm, and 0.09 cm, respectively. The study showed that there was a significant difference in PTV coverage between 2 plans. The doses to various OARs showed a nonsignificant increase in the plan sum. The correction of translational setup errors is essential for IGRT treatment in terms of delivery of planned optimal doses to target volume. PMID- 27217628 TI - Build-up material requirements in clinical dosimetry during total body irradiation treatments. AB - Total body irradiation (TBI) treatments are mainly used in a preparative regimen for hematopoietic stem cell (or bone marrow) transplantation. Our standard clinical regimen is a 12 Gy/6 fraction bi-daily technique using 6MV X-rays at a large extended source to surface distance (SSD). This work investigates and quantifies the dose build-up characteristics and thus the requirements for bolus used for in vivo dosimetry for TBI applications. Percentage dose build-up characteristics of photon beams have been investigated at large extended SSDs using ionization chambers and Gafchromic film. Open field measurements at different field sizes and with differing scatter conditions such as the introduction of standard Perspex scattering plates at different distances to the measurement point were made in an effort to determine the required bolus/build-up material required for accurate determination of applied dose. Percentage surface dose values measured for open fields at 300 cm SSD were found to range from 20% up to 65.5% for fields 5 cm * 5 cm to 40 cm * 40 cm, respectively. With the introduction of 1 cm Perspex scattering plates used in TBI treatments, the surface dose values increased up to 83-90% (93-97% at 1 mm depth), depending on the position of the Perspex scattering plate compared to the measurement point. Our work showed that at least 5 mm water equivalent bolus/scatter material should be placed over the EBT3 film for accurate dose assessment for TBI treatments. Results also show that a small but measurable decrease in measured dose occurred with 5 mm water equivalent thick bolus material of areas '3 cm(2). As such, we recommend that 3 cm * 3 cm * 5 mm bolus build-up is the smallest size that should be placed over EBT3 Gafchromic film when used for accurate in vivo dosimetry for TBI applications. PMID- 27217629 TI - Assessment of some image quality tests on a 128 slice computed tomography scanner using a Catphan700 phantom. PMID- 27217631 TI - Efficacy of desensitizing agents on postoperative sensitivity following an in office vital tooth bleaching: A randomized controlled clinical trial. AB - AIM: To assess and compare the incidence and intensity of experienced after an in office vital tooth bleaching in case of dental fluorosis using two different types of desensitizing agents, at different time periods. MATERIALS AND METHODS: Sixty-nine subjects with mild-to-moderate fluorosis were randomly divided into three groups of 23 each. Group I - control group (placebo), group II-potassium nitrate 5% and sodium monofluorophosphate 0.7% (Sensodent KF), and group III Casein Phosphopeptide-Amorphous Calcium Phosphate (CPP-ACP) (Tooth Mousse). In office vital tooth bleaching was done using 35% hydrogen peroxide liquid (Pola office) in two sessions. Desensitizing agent was applied for 10 min after each session. Postoperative sensitivity was recorded after 24 h and 7 days. The statistical analysis was done using chi-square test, analysis of variance (ANOVA), and post hoc Tukey's test. RESULTS: The experimental groups showed significantly less incidence and intensity of sensitivity compared to control group, whereas there was no difference between them. CONCLUSION: The desensitizing agents used in the study show effective reduction after an in office vital tooth bleaching. PMID- 27217630 TI - Advances in endodontics: Potential applications in clinical practice. AB - Contemporary endodontics has seen an unprecedented advance in technology and materials. This article aimed to review some of the challenges and advances in the following sections: (1) endodontic imaging, (2) root canal preparation, (3) root canal disinfection, (4) root canal filling, and (4) regenerative endodontic procedures (REPs). Jointly, these advances are aimed at improving the state of the art and science of root canal treatment. PMID- 27217632 TI - Effect of pH on physical properties of two endodontic biomaterials. AB - AIMS: To compare the surface microhardness, setting time, and elemental and topographic changes of mineral trioxide aggregate (MTA) and calcium-enriched mixture (CEM) in contact with acidic, neutral, and alkaline solutions. SUBJECTS AND METHODS: For evaluating 24-h and 28-day surface microhardness using Vickers test and initial setting time using Gillmore apparatus, glass molds were filled manually or ultrasonically, either with CEM or MTA and randomly immersed in solutions with acidic, neutral, and alkaline pH (5.4, 7.4, and 9.4, respectively). Topographic changes of the samples as well as energy dispersive X ray spectra were examined using the scanning electron microscopy. STATISTICAL ANALYSIS USED: Data were analyzed using the Kruskal-Wallis, Mann-Whitney, Wilcoxon, one- and two-way ANOVA, Tukey's post hoc, and t-tests. RESULTS: After 28 days, there was an increase in the microhardness for all samples (without statistical significance [P > 0.05]), except for the samples of CEM in acidic environment (P > 0.05). The setting time of MTA samples was statistically higher than CEM samples (P <= 0.001). The setting time of both biomaterials was significantly higher in acidic pH than other groups (P <= 0.005). Surface topography and elemental constituents of biomaterials were altered in different solutions. CONCLUSION: The surface microhardness, setting time, and elemental and topographic properties of MTA and CEM were affected by different solutions. CEM exhibited quicker setting time than MTA; however, acidic solution negatively influenced both of them. PMID- 27217633 TI - Evaluation of the dentinal wall adaptation ability of MTA Fillapex using stereo electron microscope. AB - BACKGROUND: An ideal root canal obturation requires a complete dentinal wall adaptation of sealer and Gutta-percha combinations without any gap formations. AIMS: The aim of the study was to evaluate the dentinal wall adaptation ability of MTA Fillapex root canal sealer using stereo electron microscope (SEM). METHODS: Twenty-four, single-rooted, human maxillary incisor teeth were used. All canals were prepared with a rotary nickel-titanium (Ni-Ti) instrument to a size F3 file. Teeth divided into two equal groups and one of the experimental groups was filled with AH Plus, and the other group was filled with MTA Fillapex using Gutta-percha single cone as a core material. The roots were prepared for SEM evaluation, and serial scanning electron photomicrographs were taken at *50, *100, *500, and *1000 magnifications. The gaps between the root canal sealer and canal walls were detected and measured in coronal, middle, and apical thirds. For each section, the highest value among the detected gap formations was recorded. STATISTICAL ANALYSIS: Mann-Whitney U-test, Freidman, and Wilcoxon tests were used. RESULTS: The statistical analysis showed no significant difference between two sealers in terms of gap formation (P > 0.05). CONCLUSIONS: MTA Fillapex has a similar dentinal wall adaptation ability as AH Plus does. PMID- 27217634 TI - Resistance to torsional failure and cyclic fatigue resistance of ProTaper Next, WaveOne, and Mtwo files in continuous and reciprocating motion: An in vitro study. AB - AIMS: The purpose of this study was to evaluate the resistance to torsional failure and cyclic fatigue resistance of ProTaper Next (PTN), WaveOne, and Mtwo files in continuous and reciprocating motion. SETTINGS AND DESIGN: Randomized control trial in a tertiary care setting. SUBJECTS AND METHODS: A total of 10 new size 25.06 taper PTN X2, 25.06 taper Mtwo files, and 25.08 taper WaveOne primary files each was selected. A custom fabricated cyclic fatigue testing device with a 70 degrees angle of curvature and 3 mm width; curvature starting at 6 mm from the tip was used. All instruments were rotated and reciprocated till fracture occurred and time till fracture of each instrument was recorded in seconds. For torsional failure testing 5 mm tip of each file was embedded in composite resin block and uniform torsional stresses (300 rpm, 2.0 Ncm) were applied repetitively by an endodontic motor with auto stop mode until file succumbed to torsional failure. Number of load applications leading to failure was recorded. STATISTICAL ANALYSIS USED: Data were analyzed using t-test for equality of means, Pearson correlation, and ANOVA test. RESULTS: All the files showed superior resistance to cyclic fatigue in reciprocating motion when compared with continuous rotation mode. WaveOne primary files displayed maximum resistance to cyclic fatigue both in continuous and reciprocating motion. WaveOne primary files also demonstrated maximum resistance to torsional failure followed by PTN with Mtwo files exhibiting least resistance. CONCLUSIONS: Operating files in reciprocating motion enhances their cyclic fatigue resistance. WaveOne files showed maximum resistance to cyclic fatigue and torsional failure due to their cross-sectional diameter coupled M-Wire technology. PMID- 27217635 TI - Effect of methods of evaluation on sealing ability of mineral trioxide aggregate apical plug. AB - AIM: The purpose of the study was to evaluate and compare the sealing ability of mineral trioxide aggregate (MTA) with three different methods. MATERIALS AND METHODS: Forty single canal teeth were decoronated, and root canals were enlarged to simulate immature apex. The samples were randomly divided into Group MD = MTA angelus mixed with distilled water and Group MC = MTA-angelus mixed with 2% chlorhexidine, and apical seal was recorded with glucose penetration method, fluid filtration method, and dye penetration methods and compared. RESULTS: The three methods of evaluation resulted differently. The glucose penetration method showed that MD sealed better than MC, but difference was statistically insignificant (P > 0.05). The fluid filtration method resulted that Group MC was statistically insignificant superior to Group MD (P > 0.05). The dye penetration method showed that Group MC sealed statistically better than Group MD. CONCLUSION: No correlation was found among the results obtained with the three methods of evaluation. Addition of chlorhexidine enhanced the sealing ability of MTA according to the fluid filtration test and dye leakage while according to the glucose penetration test, chlorhexidine did not enhance the sealing ability of MTA. This study showed that relying on the results of apical sealing by only method can be misleading. PMID- 27217636 TI - Comparative evaluation of apically extruded debris with V-Taper, ProTaper Next, and the Self-adjusting File systems. AB - BACKGROUND: Complete cleaning of the root canal is the goal for ensuring success in endodontics. Removal of debris plays an important role in achieving this goal. In spite of advancements in instrument design, apical extrusion of debris remains a source of inflammation in the periradicular region. AIM: To comparatively evaluate the amount of apically extruded debris with V-Taper, ProTaper Next, and the self-adjusting File (SAF) system. MATERIALS AND METHODS: Sixty-four extracted human mandibular teeth with straight root canals were taken. Access openings were done and working length determined. The samples were randomly divided into three groups: Group I - V-Taper files (n = 20), Group II - ProTaper Next (n = 20), Group III - SAF (n = 20). Biomechanical preparation was completed and the debris collected in vials to be quantitatively determined. The data obtained was statistically analyzed using ANOVA and post hoc Tukey's test. RESULTS: All the specimens showed apical debris extrusion. SAF showed significantly less debris extrusion compared to V-Taper and ProTaper Next (P < 0.001). Among Groups I and II, ProTaper Next showed lesser debris extrusion as compared to V-Taper, but it was not significant (P = 0.124). CONCLUSION: The SAF showed least amount of apical debris extrusion when compared to newer rotary endodontic instruments. This indicates that the incidence of inter-treatment flare-ups due to debris extrusion would be less with the SAF. PMID- 27217637 TI - Evaluation of dentinal tubule occlusion and depth of penetration of nano hydroxyapatite derived from chicken eggshell powder with and without addition of sodium fluoride: An in vitro study. AB - AIM: This in vitro study evaluated the degree of dentinal tubule occlusion and depth of penetration of nano-hydroxyapatite (nHAp) derived from chicken eggshell powder with and without the addition of 2% sodium fluoride (NaF) using scanning electron microscope (SEM) and confocal laser scanning microscope (CLSM). MATERIALS AND METHODS: nHAp was synthesized and characterized using X-ray diffraction and SEM-energy dispersive spectroscopy. Dentin discs were obtained from extracted teeth, pretreated with 17% ethylenediaminetetraacetic acid for 5 min and were divided into four groups based on the experimental agents as follows: Group 1: Untreated (control), Group 2: 2% NaF, Group 3: nHAp, Group 4: Combination of nHAp and 2% NaF. The treatment protocol was carried out for 7 days, after which the specimens were viewed under SEM and CLSM. STATISTICAL ANALYSIS USED: One-way ANOVA and Tukey's post hoc multiple comparison tests (P < 0.05). RESULTS: All the experimental agents occluded the dentinal tubules, but to varying degrees and depths. Specimens treated with the combination of nHAp and 2% NaF showed complete dentinal tubular occlusion and significantly greater depth of penetration than those treated with nHAp and 2% NaF alone. CONCLUSION: The combination of nHAp and 2% NaF was the most effective in occluding dentinal tubules. PMID- 27217638 TI - Comparison of apical debris extrusion of two rotary systems and one reciprocating system. AB - BACKGROUND: Postoperative inflammation and endodontic failure occur due to apical extrusion of debris. AIM: To evaluate the amount of apically extruded debris after preparation of straight root canals in extracted human teeth using three rotary systems. MATERIALS AND METHODS: Sixty single-rooted human teeth with single root canal and apical foramen were selected and randomly divided into three experimental groups (n = 20) according to the rotary system used: Group 1 - ProTaper, Group 2 - Revo-S, Group 3 - WaveOne. Apical enlargement was done up to size 40/0.06 for Groups 1 and 2 and 40/0.08 for Group 3. For debris collection, each tooth was held in a preweighed Eppendorf tube fixed inside a glass vial through rubber plug. After instrumentation, each tooth was separated from the Eppendorf tube and the debris adhering to the root surface was collected by washing the root with 1 mL of bi-distilled water and incubated at 70 degrees C for 5 days. The dry weight of extruded debris was weighed in an electronic balance. STATISTICAL ANALYSIS: The mean weights of extruded debris were statistically analyzed using GraphPad prism version 6 and the intergroup comparison was done using unpaired t-test. RESULTS: There was a statistically significant difference in the mean debris score among all the three groups - ProTaper (0.00065 g), Revo-S (0.00045 g) and WaveOne (0.00089 g). CONCLUSION: Revo-S system was associated with significantly less debris extrusion compared with ProTaper or WaveOne. PMID- 27217639 TI - Effect of storage media on fracture resistance of reattached tooth fragments using G-aenial Universal Flo. AB - BACKGROUND: Over a period of the past few years' episodes of dental trauma more commonly coronal fractures of anterior teeth are being increasingly reported in children. Fragment reattachment can be considered as a valid treatment option in such situations. However, ideal medium for storage of fragments before reattachment needs to be explored. AIM: To compare the fracture resistance of incisor tooth fragments stored in four storage media: Dry air, milk, coconut water, or egg white before reattaching them with G-aenial Universal Flo. MATERIALS AND METHODS: Forty-eight freshly extracted maxillary incisors were divided into four groups. Teeth were then sectioned, and fragments were stored in dry air (Group I), milk (Group II), coconut water (Group III), and egg white (Group IV). The fragments were reattached using simple reattachment technique and tested on the Universal Testing Machine. Statistical analysis was performed using one-way analysis of variance and post hoc Tukey's test. RESULTS: There was statistically significant difference (P < 0.05) in fracture resistance values between the groups. The highest fracture resistance value was demonstrated by Group II, whereas least fracture resistance values were observed in Group IV. CONCLUSION: Along with milk, coconut water being tested for the first time can be considered a viable alternative. PMID- 27217640 TI - The evaluation of interfaces between MTA and two types of GIC (conventional and resin modified) under an SEM: An in vitro study. AB - CONTEXT: Mineral trioxide aggregate (MTA) is a biocompatible repair material that is often used along with glass ionomer cement (GIC) in many clinical situations. AIMS: In this study, the interface of GIC and MTA was examined, and the effect of time on this interface was tested. MATERIALS AND METHODS: Forty 9-mm hollow cylindrical glass molds were filled with MTA and then according to the group either conventional GIC or resin-modified GIC (RMGIC) is filled immediately or after 45 min. The specimens were then sectioned, carbon coated, and examined using a scanning electron microscope (SEM) and the elemental analysis was done. STATISTICAL ANALYSIS: Observational study, no statistical analysis done. RESULTS: The SEM showed that both the groups underwent adhesive separation and gap formation at the interface. The specimens in which GIC was condensed over freshly mixed MTA (group IIA and group IIB) also showed cohesive separation in MTA; however, it was more in the GIC condensed after 45 min over MTA groups (group IA and group IB). The results were better for conventional GIC than RMGIC. CONCLUSIONS: GIC can be applied over freshly mixed MTA with minimal effects on the MTA, but this effect decreases with time. PMID- 27217641 TI - Evaluation of bleaching efficacy of 37.5% hydrogen peroxide on human teeth using different modes of activations: An in vitro study. AB - INTRODUCTION: The aim of this in vitro study is to evaluate the role of light and laser sources in the bleaching ability of 37.5% H2 O2 on extracted human teeth. MATERIALS AND METHODS: About 30 caries-free single-rooted maxillary central incisors were used for the study. Specimens were prepared by sectioning the crown portion of teeth mesiodistally, and labial surface was used for the study. Specimens were then immersed in coffee solution for staining. Color of each tooth was analyzed using Shadestar, a digital shademeter. Specimens were then divided into three groups of 10 each and were subjected to bleaching with 37.5% H2 O2, 37.5% H2 O2 + light activation, and 37.5% H2 O2 + laser activation, respectively. Postbleaching, the color was analyzed for all the specimens immediately and then after 1, 2, and 3 weeks intervals, respectively. RESULTS: All the statistical analyses were done using SPSS version 17. Intra- and inter-group comparisons were done with Friedman test and Kruskal-Wallis ANOVA, respectively. Statistical analysis concluded with a significant improvement in their shade values from baseline in all the three groups. Halogen light activation and laser-activated groups showed comparatively enhanced bleaching results over no-activation group, though the difference was not statistically significant. CONCLUSION: The results of the present study show that bleaching assisted with halogen light and laser showed increased lightness than nonlight activated group. Durability of bleaching results obtained postbleaching was maintained throughout the experimental trail period of 3 weeks for both halogen light and laser activation group, whereas no light activation group presented with shade rebound after 2 weeks postbleaching. PMID- 27217642 TI - Comparative evaluation of the effect of different crown ferrule designs on the fracture resistance of endodontically treated mandibular premolars restored with fiber posts, composite cores, and crowns: An ex-vivo study. AB - INTRODUCTION: In cases of severe hard tissue loss, 2 mm circumferential ferrule is difficult to achieve which leads to incorporation of different ferrule designs. AIM: To compare and evaluate the effect of different crown ferrule designs on the fracture resistance of mandibular premolars restored with fiber posts, composite cores, and crowns. MATERIALS AND METHODS: Fifty freshly extracted mandibular premolars were endodontically treated and divided into five groups: Group I - 2 mm circumferential ferrule above the cementoenamel junction (CEJ); Group II - 2 mm ferrule on the facial aspect above CEJ; Group III - 2 mm ferrule on the lingual aspect above CEJ; Group IV - 2 mm ferrule on the facial and lingual aspects above CEJ with interproximal concavities, and Group V - no ferrule (control group) and were later restored with fiber posts, composite cores, and crowns. Specimens were mounted on a universal testing machine, and compressive load was applied at a crosshead speed of 1 mm/min until fracture occurred. RESULTS: The results showed that circumferential ferrule produced the highest mean fracture resistance and the least fracture resistance was found in the control group. CONCLUSION: Circumferential ferrule increases the fracture resistance of endodontically treated teeth restored with bonded post, core, and crown. PMID- 27217644 TI - Histological response of human pulps capped with calcium hydroxide and a self etch adhesive containing an antibacterial component. AB - AIM: To compare human pulp tissue response following direct pulp capping with calcium hydroxide and a self-etch adhesive containing antibacterial component. MATERIALS AND METHODS: Sixty-six erupted sound premolars scheduled to be extracted for orthodontic reasons were selected from 17 human subjects. Pulp exposures were made. Direct pulp capping was then performed using calcium hydroxide and a self-etch adhesive containing antibacterial component in its primer. The teeth were then restored with composite resin. Two teeth were maintained intact as a control group. After 7 and 30 days, teeth were extracted and processed for light microscopic examination using a histological scoring system. The teeth were divided into four groups (N = 16) according to the pulp capping materials used and their days of extraction. The results were then statistically analyzed by Mann-Whitney U-test. RESULTS: After the 7-day observation period, the inflammatory reaction to the self-etch adhesive containing antibacterial component group was significantly less severe than that in the calcium hydroxide group (P < 0.05). After the 30-day observation period, the inflammatory reaction was slight in both groups, but specimens with dentin bridge formation in the self-etch adhesive group were significantly less common than those in the calcium hydroxide group (P < 0.05). PMID- 27217643 TI - Fracture resistance of endodontically treated single rooted premolars restored with Sharonlay: An in vitro study. AB - AIMS: The aim of this study is to compare in vitro the fracture resistance of the endodontically treated tooth restored with a novel design Sharonlay, with the two component restorative method, i.e., post with separate onlay, and onlay without post. SUBJECTS AND METHODS: 45 single-rooted mandibular second premolars were taken, and root canal treatment was performed. Teeth were then randomly divided into three groups (n = 15) based on the type of restoration given: Group I - metal onlay with cast post extension (Sharonlay), Group II - metal onlay with prefabricated metal post (Mani post system), Group III - metal onlay over endodontically treated tooth obturated with Gutta-percha (control group). Fracture resistance was checked using the Instron universal testing machine and the fracture patterns were analyzed. RESULTS: According to the values recorded, Group I showed maximum mean fracture resistance followed by Groups II and III. Statistically significant difference was found between Groups I and II and Groups I and III and statistically significant difference was found between Groups II and III. CONCLUSION: A single unit component Sharonlay, gives higher fracture resistance to a premolar as compared to (a) metal onlay with prefabricated metal post and (b) metal onlay over endodontically treated tooth. PMID- 27217645 TI - Management of large radicular cyst associated with amalgam particles in cystic lining. AB - The failure of amalgam retrofilling and presence of an associated cystic lesion makes surgical endodontic intervention inevitable. Amalgam retrofilling can also give rise to mucoperiosteal tattoo formation and allow incorporation of amalgam particles in the cystic lining. Such a finding has not yet been reported in the endodontic literature. This case report describes the successful endodontic management of a large radicular cyst associated with failed amalgam retrofilling, mucoperiosteal tattoo and amalgam particles dispersed in the epithelial cystic lining. All four mandibular incisors associated with the lesion presented with Weine Type II canal anatomy. The follow-up revealed clinical and radiographic signs of healing. PMID- 27217646 TI - Acute allergic angioedema of upper lip. AB - Mishaps can occur during dental procedures, some owing to inattention to detail and others are totally unpredictable. They usually include anaphylaxis or allergic reactions to materials used for restorative purposes or drugs such as local anesthetics. A patient reported to our department with moderate dental fluorosis, and the treatment was planned with indirect composite veneering. During the procedure while cementation acute allergic reaction occurred, the specific cause could not be identified after allergic testing. During the procedure while cementationacute allergic angioedema of upper lip. Anaphylaxis, urticaria, allergy, hereditary atopic eczema, cellulitis, cheilitis granulomatosa, and cheilitis glandularis. The patient was reassured and given prednisolone 10 mg and cetirizine 10 mg orally, once daily for 3 days after which the symptoms subsided. This paper will discuss the pathogenesis, classification, identification, and management of angioedema during dental procedures. PMID- 27217647 TI - Lichenoid reaction associated with silver amalgam restoration in a Bombay blood group patient: A case report. AB - The pathogenic relationship between the oral lichenoid reaction (OLR) and dental restorative materials has been confirmed many times. An OLR affecting oral mucosa in direct contact with an amalgam restoration represents a delayed, type IV, cell mediated immune response to mercury or one of the other constituents of the dental amalgam. Bombay blood group patients are more prone to this. A case of bilateral OLR is presented, which is present in relation to amalgam restoration. The lesion healed up after the replacement of restorations with an intermediate restorative material. The clinician should be aware of all the possible pathological etiologies of white lesions. If there is any doubt about the nature or management of a usual oral lesion, a referral to an appropriate specialist is mandatory. PMID- 27217648 TI - Mineral trioxide aggregate pulpotomy in autotransplanted immature mandibular third molar with a 4-year follow-up. AB - Autotransplantation is the surgical transposition of a tooth from its original site to another, replacing a lost or a compromised tooth by another tooth, usually the third molar in the same individual. This technique is considered a viable method due to its high success rate, well-grounded treatment option, provided the case selection and the procedure followed is within the acceptable limits. Autotransplantation is considered as an alternative approach of oral rehabilitations in a conservative manner mainly in young patients with compromised financial conditions to perform a high cost treatment. It is a fast way to recover function and aesthetic properties without interfering with the orofacial growth. This report describes a successful 4-year follow-up of a case of immediately performed mineral trioxide aggregate (MTA) pulpotomy in autotransplantated mandibular left immature third molar to replace the mandibular left first molar that was extracted due to extensive carious lesion. PMID- 27217649 TI - Management of external invasive cervical resorption of tooth with Biodentine: A case report. AB - Invasive cervical resorption (ICR) of a tooth is relatively uncommon and the etiology is not very clear. It is sometimes misdiagnosed and can lead to improper management or tooth loss. Correct diagnosis and proper management can result in a successful outcome. The treatment should aim toward the complete suppression of all resorbing tissues and the reconstruction of resorptive defect by the placement of a suitable filling material or some biological systems. One of the most significant developments of the past decade, i.e. the operating microscope used for surgical endodontics, helps the surgeon to assess pathological changes more precisely and to remove pathological lesions with far greater precision, thus minimizing tissue damage. The aim of this article was to show the management of maxillary left central incisor diagnosed with external ICR using Biodentine under dental operatory microscope (DOM). PMID- 27217650 TI - Atlantoaxial instability: Analyzing and reflecting on the Nature's reparative games. PMID- 27217651 TI - Interfacetal intra-articular spacers: Emergence of a concept. PMID- 27217652 TI - "Two-step" technique with OsiriXTM to evaluate feasibility of C2 pedicle for surgical fixation. AB - BACKGROUND: Surgical treatment of craniovertebral junction pathology has evolved considerably in recent decades with the implementation of short atlanto-axial fixation techniques, notwhithstanding increasing neurovascular risks. Also, there is strong evidence that fixation of C2 anatomical pedicle has the best biomechanical profile of the entire cervical spine. However, it is often difficult and misleading, to evaluate anatomical bony and vascular anomalies using the three orthogonal planes (axial, coronal, and sagittal) of CT. OBJECTIVES: The authors describe an innovative and simple technique to evaluate the feasibility of C2 pedicle for surgical screw fixation using preoperative planning with the free DICOM (Digital Imaging and Communications in Medicine) software OsiriXTM. MATERIALS AND METHODS: The authors report the applicatin of this novel technique in 5 cases (3 traumatic, 1 Os Odontoideum, and 1 complex congenital malformation) collected from our general case series of the Department in the last 5 years. RESULTS: In this proof of concept study, the pre-operative analysis with the two-step tecnique was detrimental for choosing the surgical tecnique. Detailed post-operative analysis confirmed correct position of C2 screws without cortical breach. There were no complications or mortality reported. CONCLUSION: This two-step technique is an easy and reliable way to determine the feasibility of C2 pedicle for surgical fixation. The detailed tridimensional radiological preoperative evaluation of craniovertebral junction anatomy is critical to the sucess and safety of this surgeries, and can avoid, to certain degree, expensive intra-operative tridimensional imaging facilities. PMID- 27217653 TI - Prediction of surgical outcome in compressive cervical myelopathy: A novel clinicoradiological prognostic score. AB - CONTEXT: Preoperative severity of myelopathy, age, and duration of symptoms have been shown to be highly predictive of the outcome in compressive cervical myelopathy (CCM). The role of radiological parameters is still controversial. AIMS: Define the prognostic factors in CCM and formulate a prognostic score to predict the outcome following surgery in CCM. SETTINGS AND DESIGN: Retrospective. MATERIALS AND METHODS: This study included 78 consecutive patients with CCM treated surgically. The modified Japanese Orthopaedic Association (mJOA) scale was used to quantify severity of myelopathy at admission and at 12-month follow up. The outcome was defined as good if the patient had mJOA score >=16 and poor if the score was <16. Age, sex, duration of symptoms, comorbidities, intrinsic hand muscle wasting (IHMW), diagnosis, surgical technique, Torg ratio, instability on dynamic radiographs, and magnetic resonance imaging (MRI) signal intensity changes were assessed. STATISTICS: Statistical Package for the Social Sciences (SPSS) (version 20.0) was used for statistical analysis. The association was assessed amongst variables using logistic regression analysis. Parameters having a statistically significant correlation with the outcome were included in formulating a prognostic score. RESULTS: Severity of myelopathy, IHMW, age, duration, diabetes, and instability on radiographs were predictive of the outcome with a P value <0.01. Genders, diagnosis, surgical procedure, Torg ratio, and intensity changes on MRI were not significantly related to the outcome. A 8-point scoring system was devised incorporating the significant clinicoradiological parameters, and it was found that nearly all patients (97.82%) with a score below 5 had good outcome and all patients (100%) with a score above 5 had poor outcome. The outcome is difficult to predict with a score of 5. CONCLUSIONS: Clinical parameters are better predictors of the outcome as compared to radiological findings, following surgery in CCM. A simple scoring system based on clinicoradiological parameters is suggested in this paper to predict the outcome following surgery in cases of CCM. PMID- 27217654 TI - Inequality in leg length is important for the understanding of the pathophysiology of lumbar disc herniation. AB - OBJECTIVE: Inequality in leg length may lead to to abnormal transmission of load across the endplates and degeneration lumbar spine and the disc space. There has been no study focusing on lumbar disc herniation (LDH) and leg length discrepancy. This subject was investigated in this study. MATERIALS AND METHODS: Consecutive adult patients with leg length discrepancy and low back pain (LBP) admitted to our department were respectivelly studied. RESULTS: A total number of 39 subjects (31 women and eight men) with leg length discrepancy and LBP and 43 (25 females and 18 males) patients with LBP as a control group were tested. Occurrence of disc herniation is statistically different between patients with hip dysplasia and control groups (P < 0.05). CONCLUSION: The results of this study showed a statistically significant association between leg length discrepancy and occurrence of LDH. The changes of spine anatomy with leg length discrepancy in hip dysplastic patients are of importance in understanding the nature of LDH. PMID- 27217655 TI - Cervical disc hernia operations through posterior laminoforaminotomy. AB - OBJECTIVE: The most common used technique for posterolateral cervical disc herniations is anterior approach. However, posterior cervical laminotoforaminomy can provide excellent results in appropriately selected patients with foraminal stenosis in either soft disc prolapse or cervical spondylosis. The purpose of this study was to present the clinical outcomes following posterior laminoforaminotomy in patients with radiculopathy. MATERIALS AND METHODS: We retrospectively evaluated 35 patients diagnosed with posterolateral cervical disc herniation and cervical spondylosis with foraminal stenosis causing radiculopathy operated by the posterior cervical keyhole laminoforaminotomy between the years 2010 and 2015. RESULTS: The file records and the radiographic images of the 35 patients were assessed retrospectively. The mean age was 46.4 years (range: 34-66 years). Of the patients, 19 were males and 16 were females. In all of the patients, the neurologic deficit observed was radiculopathy. The posterolaterally localized disc herniations and the osteophytic structures were on the left side in 18 cases and on the right in 17 cases. In 10 of the patients, the disc level was at C5-6, in 18 at C6-7, in 2 at C3-4, in 2 at C4-5, in 1 at C7-T1, in 1 patient at both C5-6 and C6-7, and in 1 at both C4-5 and C5-6. In 14 of these 35 patients, both osteophytic structures and protruded disc herniation were present. Intervertebral foramen stenosis was present in all of the patients with osteophytes. Postoperatively, in 31 patients the complaints were relieved completely and four patients had complaints of neck pain and paresthesia radiating to the arm (the success of operation was 88.5%). On control examinations, there was no finding of instability or cervical kyphosis. CONCLUSION: Posterior cervical laminoforaminotomy is an alternative appropriate choice in both cervical soft disc herniations and cervical stenosis. PMID- 27217656 TI - Syringomyelia secondary to "occult" dorsal arachnoid webs: Report of two cases with review of literature. AB - In a certain group of patients with syringomyelia, even with the advent of sophisticated magnetic resonance imaging (MRI), no associated abnormality or cerebrospinal fluid (CSF) block is easily identified. This type of syringomyelia is often termed idiopathic. Current literature has less than 10 reports of arachnoid webs to be the causative factor. We present our experience in the management of two cases of syringomyelia secondary to arachnoid webs. Both our patients presented with progressive neurological deterioration with MRI scans demonstrating cervical/thoracic syrinx without Chiari malformation or low-lying cord. There was no history of previous meningitis or trauma. Both patients underwent myelography that demonstrated dorsal flow block implying CSF obstruction. Cord displacement/change in caliber was also noted and this was not evident on MRI scans. Both patients underwent thoracic laminectomy. After opening the dura, thickened/abnormal arachnoid tissue was found that was resected thus widely communicating the dorsal subarachnoid space. Postoperatively at 6 months, both patients had significant symptomatic improvement with follow-up MRI scans demonstrating significant resolution of the syrinx. In patients with presumed idiopathic syringomyelia, imaging studies should be closely inspected for the presence of a transverse arachnoid web. We believe that all patients with idiopathic symptomatic syringomyelia should have MRI CSF flow studies and/or computed tomography (CT) myelography to identify such arachnoid abnormalities that are often underdiagnosed. Subsequent surgery should be directed at the establishment of normal CSF flow by laminectomy and excision of the offending arachnoid tissue. PMID- 27217657 TI - Primary intradural sacral epidermoid in a nondysraphic spine: Case report and review of literature. AB - The occurrence of epidermoids within the spinal canal is uncommon. Most of the reported spinal epidermoids (SEs) have been described in the thoracic or lumbar regions. They occur either following trauma or in the setting of coexistent spinal dysraphism. The authors describe an unusual case of a 28-year-old lady who presented with long-standing back pain and urinary incontinence. Magnetic resonance imaging (MRI) of her spine demonstrated a sacral SE without any coexistent spinal dysraphism. The diagnosis of an epidermoid was confirmed by histopathological examination following laminectomy and excision. To the authors' best knowledge, this is the third case of a sacral SE occurring in a non dysraphic spine. The case is discussed in the light of a relevant literature review. PMID- 27217658 TI - Atlantoaxial dislocation adjacent to kyphotic deformity in a case of adult Larsen syndrome. AB - Kyphotic deformity is often seen in Larsen syndrome. However, its progress in adults is not clear. The adjacent level compression in these patients adds to the difficulty regarding the level that needs to be operated. A 56-year-old male presented with neck pain and spastic quadriplegia. Radiology showed kyphotic deformity (sequelae of Larsen syndrome) with atlantoaxial dislocation. Cord compression was apparent at both levels but careful evaluation showed C1-2 level compression and some compression below the kyphotic deformity. The kyphotic spine was already fused and the canal diameter was adequate. The adjacent level C1-2 was fused and he improved dramatically. Correction of long-standing kyphotic deformity may not be necessary, as it unlikely to progress because of its tendency to fuse naturally. Rather, the adjacent levels are likely to compress the cord due to excessive stress. A proper clinical history and a thorough radiological examination help the surgeon to make an appropriate decision. PMID- 27217659 TI - Cervicomedullary intramedullary peripheral primitive neuroectodermal tumor with intratumoral bleed: Report of one case and review of literature. AB - Primitive neuroectodermal tumors (PNET) are highly malignant, yet relatively uncommon neoplasms of the central nervous system. Although a host of different parts of the nervous system can be affected, intramedullary location of PNET is extremely rare. Most reports on intramedullary PNET have reported central PNET (cPNET); peripheral PNET (pPNET) affecting intramedullary spinal location is extremely rare. Till now, seven such cases of intramedullary pPNET have been described in medical literature in English. Here, we report an 11-year-old boy with cervicomedullary junction intramedullary pPNET who presented with intratumoral bleed, wherein the clinical presentation and radiological features gave us no clue preoperatively about the underlying diagnosis. In this report, we additionally review certain salient aspects of this dreaded disease in light of the existing evidence. PMID- 27217660 TI - Congenital defects of C1 arches and odontoid process in a child with Down's syndrome: A case presentation. AB - We present the case of a 2-year-old child with Down's syndrome who presented to our unit with torticollis. Imaging studies revealed the rare occurrence of anterior and posterior C1 arch defects, absent odontoid process, and atlantoaxial subluxation. We managed her conservatively for 3 years without neurological deficits or worsening of atlantoaxial subluxation. We discuss the rare occurrences of anterior and posterior arch defects of the atlas, the radiological presentations of axis defects in patients, and the occurrence of atlantoaxial instability in patients with Down's syndrome. Management options with consideration to surgery in asymptomatic and symptomatic patients are also discussed. PMID- 27217661 TI - Late onset leptomeningeal and whole spine metastasis from supratentorial Glioblastoma multiforme: An uncommon manifestation of a common tumor. AB - Glioblastoma multiforme (GBM) is one of the most common and aggressive primary brain tumors, composing 12-20% of all the intracranial tumors in adults with a highly malignant course and average life expectancy of approximately 12-14 months following initial diagnosis. Leptomeningeal or intramedullary metastasis from primary GBM is a rare phenomenon with a poor prognosis. We present a rare case of GBM with late onset intramedullary, extramedullary, as well as leptomeningeal spinal metastasis. PMID- 27217662 TI - Stem cell therapy in spinal cord injury: Hollow promise or promising science? AB - Spinal cord injury (SCI) remains one of the most physically, psychologically and socially debilitating conditions worldwide. While rehabilitation measures may help limit disability to some extent, there is no effective primary treatment yet available. The efficacy of stem cells as a primary therapeutic option in spinal cord injury is currently an area under much scrutiny and debate. Several laboratory and some primary clinical studies into the use of bone marrow mesenchymal stem cells or embryonic stem cell-derived oligodentrocyte precursor cells have shown some promising results in terms of remyelination and regeneration of damaged spinal nerve tracts. More recently,laboratory and early clinical experiments into the use of Olfactory Ensheathing Cells, a type of glial cell derived from olfactory bulb and mucosa have provided some phenomenal preliminary evidence as to their neuroregenerative and neural bridging capacity. This report compares and evaluates some current research into selected forms of embryonic and mesenchymal stem cell therapy as well as olfactory ensheathing cell therapy in SCI, and also highlights some legal and ethical issues surrounding their use. While early results shows promise, more rigorous large scaleclinical trials are needed to shed light on the safety, efficacy and long term viability of stem cell and cellular transplant techniques in SCI. PMID- 27217663 TI - From the Desk of the Editor. PMID- 27217664 TI - Potential Prognostic Impact of Baseline CEA Level and Surgery of Primary Tumor Among Patients with Synchronous Stage IV Colorectal Cancer: A Large Population Based Study. AB - Prognostic role of surgical resection of the primary tumor and baseline CEA among patients with synchronous stage IV colorectal cancer (CRC) remains an area of debate. The objective of this study was to determine the prognostic value of baseline CEA and surgical resection of the primary among patients with synchronous stage IV CRC in the era of modern chemotherapy and biologic therapy. The Surveillance, Epidemiology and End Results Registry was searched to identify patients with synchronous stage IV CRC diagnosed between 2004 and 2009. Colorectal-cancer-specific survival (CCS) was estimated using the Kaplan-Meier product limit method. Cox models were fitted to assess the multivariable relationship of various patient and tumor characteristics and CCS. Three hundred thirty-three thousand, three hundred ninety nine patients were identified in the SEER registry. Median CCS among patients with their primary tumor removed was 21 M vs. 7 M (primary intact) respectively (p < 0.001). Median CCS among patients who had an elevated vs. non-elevated baseline CEA level was 14 M vs. 24 M respectively (p < 0.0001). By multivariable analysis, patients with an elevated baseline CEA had a 56 % increased risk of death from CRC compared to those with a non-elevated CEA level (HR = 1.56, 95%CI 1.47-1.65, p < 0.0001). Similarly patients who underwent surgical resection of the primary tumor had a 33 % decreased risk of death from CRC compared to those who did not (HR = 0.61, 95%CI 0.54-0.69, p < 0.0001). In our review of this large population SEER based study, an elevated baseline CEA level and surgical resection of the primary tumor among patients with synchronous stage IV CRC appeared to impact survival outcomes. Prospective validation of these results in a surgically unresectable patient population will be required. PMID- 27217665 TI - Radical Esophagectomy After Neoadjuvant Chemoradiation: Single Institutional Experience from Tertiary Cancer Centre in India. AB - Although preoperative chemoradiation has shown to improve surgical outcomes in both loco-regional control and long term survival; it has still not become the standard of care in many centers. There is reluctance in accepting preoperative chemoradiation primarily due to fear of increased perioperative morbidity/mortality or non-availability of infrastructure and expertise. We present a retrospective analysis of our results of radical esophagectomy after neoadjuvant chemoradiation. All patients who underwent Radical Esophagectomy from January 2009 to December 2013 by a single surgical team at our institute were included in the series (n = 118). Patients undergoing surgery after chemo radiation (group A = 66) were compared with those under going upfront surgery (group B = 52) in terms of patient variables (age, sex, comorbidities, tumor location, staging, histology) and postoperative surgical outcomes and complications using Chi square test. Overall and disease free survival was analyzed using Kaplan Meir curve. There was no difference in duration of surgery, postoperative stay and overall morbidity and mortality in both groups. Although group A patients had more of advanced cases clinically, but histopathology showed complete pathological response (pCR) in nearly 40 % patients and negative nodes (pN0) in 62.5 % patients. OS and DFS showed a trend towards better survival with preoperative chemoradiation. We conclude that radical esophagectomy after preoperative chemoradiation is feasible and safe in developing countries. Moreover pathological complete response correlates well with improved survival. Randomized control trials may be required to further substantiate the results. PMID- 27217666 TI - Multiple Bony Metastatic Lesions and Evaluation of Primary: Case Records of a Cancer Research Centre. AB - During 2012-13, we diagnosed 4 patients with extensive skeletal tuberculosis (TB) who were referred to us as cases of bony metastasis with unknown primary. Radiological investigations done outside favoured a diagnosis of disseminated malignancy. Positron emission tomography/computed tomography (PET/CT) scan performed in our institute for localization of primary lesion also suggested metastatic disease. There was no evidence of malignancy on histo-pathological examination (HPE) of the involved sites. The diagnosis of TB was established on characteristics HPE. This article highlights the diagnostic dilemma of PET/CT in cases of TB versus malignancy and the importance of HPE for reaching an accurate diagnosis. PMID- 27217667 TI - Submental Artery Island Flap in Patients who Have Received Prior Neck Irradiation. AB - Submental Artery Flap (SMAF) was first described in 1990 and has gained popularity ever since. However there has been relative paucity on information about the use of this flap in irradiated patients. Our aim was to explore the success of SMAF for reconstructing defects following oral cancer resection in this group of patients After prior approval from scientific and ethical committee, we performed a retrospective review of records of eleven patients who underwent SMAF reconstruction between March 2009 and September 2012. Seven patients (63 %) had undergone prior irradiation . The flap was viable in all the patients excepting for superficial epidermal loss in one patient who had undergone prior irradiation. There was major donor site complication in one, and recurrences in four patients, all in the irradiated group. SMAF may be used in patients with irradiated neck taking special precautions to avoid donor site morbidity. Previous neck irradiation may not affect flap viability. PMID- 27217668 TI - Pharyngocutaneous Fistula Incidence After PMMC Patch Pharnygoplasty for Post Laryngectomy Defect Reconstruction - Predictive Factors, Our Experience at KMIO. AB - To analyse pharyngocutaneous fistula, post Pectoralis major myocutaneous patch pharnygoplasty, and its association with various tumor, patient and treatment related factors. It is a retrospective study that included 48 patients who underwent laryngectomy and PMMC patch pharyngeal reconstruction from year 2009 to 2013. We studied the previously reported factors that could influence fistula formation such as age, gender, previous radiotherapy, previous tracheostomy, location of tumor, extent of tumor, tumor volume, tumor stage and surgical margins. Pharyngocutaneous fistula was observed in 13(27.1 %) cases. In 84.6 % (n = 11) patients, fistula closure was achieved by conservative measures. No statistically significant association was found between tumor location, extent and size. There was no association between history of previous tracheostomy and postoperative microscopic margin status. Patients with T4 disease showed increased association (36.7 %) compare to T3 stage (11 %) (p value-0.0362). Postoperatively 6 patients presented with dysphagia out of which 4 patients (66.7 %) had history of leak. It also showed significant increase in post operative stay and delay in oral feeding in fistula patients. There is still no consensus regarding the most significant risk factors, our data showed that, most disease and treatment related parameters were not predictive for fistula occurence. Prabably a larger number of patient cohart need to be analysed for additional information. PMID- 27217669 TI - Palliative Care Tailored Towards the Needs of the Poor in India. AB - Traditional approaches to palliative care may not meet the unique needs of poor cancer patients in developing countries. Cancer patients treated in India are often unable to make repeat visits to the hospital, pay for drugs, or understand and follow complex treatments. Many are from rural areas and may lack basic financial or social support. Our palliative care clinic has taken a series of innovative first steps towards meeting these unique needs, from providing treatment without complete diagnosis, accelerating through the World Health Organization (WHO) analgesic schedule, systematically simplifying prescriptions, and providing treatment free of charge. This paper describes these first steps, presents an initial evaluation of their impacts, and articulates a number of opportunities for additional improvements. PMID- 27217670 TI - Uterine Sarcoma: The Indian Scenario. AB - Uterine sarcomas are rare, highly malignant tumours comprising < 1 % of all gynaecologic malignancies. To evaluate clinical presentation, histolopathologic pattern and outcome of uterine sarcomas presenting to a tertiary referral centre over an 8 year period (2004-2012). All histologically proven uterine sarcomas were retrospectively analysed. Clinical presentation, histology, treatment and outcome were analysed. Mean age was 42 years. Predominant histopathology was endometrial stromal sarcoma (n = 13); 9 were low grade, carcinosarcoma (n = 8) and leiomyosarcoma (n = 2). Fourteen patients had Stage I disease, 3 Stage II, 4 Stage III and 2 were Stage IV at presentation. Patients with disease confined to uterus received no adjuvant treatment (61 %). Of these, 11 were endometrial stromal sarcoma (7 were low grade) and 3 were carcinosarcomas. Four patients received adjuvant EBRT following hysterectomy (17 %). Two patients who presented with metastases received palliative chemotherapy. Mean follow-up period was 46 months (0-86 months). Eleven patients (47 %) developed disease recurrence. Seven (30 %) had local recurrence, while 4 (17 %) developed pulmonary metastases. A total of eight patients died and all deaths were within 1 year of recurrence. The only prognostic factor that correlated with survival was the stage of disease at diagnosis. PMID- 27217671 TI - Colonoscopy in Colorectal Cancer Screening: Current Aspects. AB - Colonoscopy represents a very important diagnostic modality for screening for colorectal cancer, because it has the ability to both detect and effectively remove pro-malignant and malignant lesions. It is recommended by almost all international and national gastroenterology and cancer societies, as an initial screening modality or, following a positive fecal occult blood test, to be performed every 10 years in individuals of average risk starting from the age of 50. However, a significant problem is the so-called post-screening (interval) polyps and cancers found some years after the index colonoscopy. In order to reduce the rate of interval cancers it is extremely necessary to optimize the quality and effectiveness of colonoscopy. Bowel preparation is of paramount importance for both accurate diagnosis and subsequent treatment of lesions found on colonoscopy. The quality of bowel preparation could be significantly improved by splitting the dose regimens, a strategy that has been shown to be superior to single-dose regimen. A good endoscopic technique and optimal withdrawal time offering adequate time for inspection, would further optimize the rate of cecal intubation and the number of lesions detected. During the last years, sophisticated devices have been introduced that would further facilitate cecal intubation. The percentage of total colonoscopies is now super-passing the level of 95 % allowing the adenoma detection rate to be greater than the suggestive level of 25 % in men and 15 % in women. This review aims to provide the reader with the current knowledge concerning indications, usefulness, limitations and future perspectives of this probably most important screening technique for colorectal cancer available today. PMID- 27217672 TI - Need for Prophylactic Cholecystectomy in Silent Gall Stones in North India. AB - One of the criteria for recommending cholecystectomy for silent gall stones, is gall stones in regions with high incidence of gall bladder cancer. Both gall stones and gall bladder cancer are common in North India. All tertiary care centres in India report high rates of gall bladder cancer (GBC) incidence and poor treatment outcomes in the majority of cases due to advanced stage of presentation. Csendes of Chile has reported very high incidence of gallbladder cancer in Chile and Bolivia and advocated prophylactic cholecystectomy in asymptomatic patients. Incidence rate of gall bladder cancer in Indian males is equal to that of Chile, whereas in females, the rates are almost double the rates of Chile. Indians have also been found to have high concentrations of heavy metals in gall bladder wall, and antibodies to tumor suppressor genes. In India, gall bladder cancer is the commonest GI cancer in women and fourth commonest cancer overall in the female population. In view of the epidemiology and clinical scenario of gall bladder cancer and proven safety of laparoscopic cholecystectomy, there is a need to act before it is too late in the current rates of gall bladder cancer. This study looks at the evidence correlating gall stones and gall bladder cancer, in relation to India. There is pressing evidence today to justify a strategy of prophylactic cholecystectomy in silent gall stones in North India. Data for this study was selected through an internet based search for literature concerning gall stones and gall bladder cancer in India, and for prophylactic cholecystectomy. PMID- 27217673 TI - Rectovaginal Fistula with Anastomotic Stricture Post Anterior Resection - Sphincter Preservation, a Viable Option. AB - Rectovaginal fistula [RVF] is a devastating complication of anterior resection whose incidence worldwide is on a rise with widespread use of staplers for the rectal anastomosis. It is a special surgical challenge for the treating surgeon with limited suitable options available to treat this difficult situation. As there is no consensus on its management, most often patient ends up with permanent stoma and overall inferior quality of life. We are presenting a case of post anterior resection RVF which was treated with intersphincteric resection followed by hand sewn coloanal anastomosis. An intersphincteric resection avoids dissection in a previously violated rectovaginal plane and improves chances of sphincter preservation. A well vascularized colonic graft with hand sewn coloanal anastomoses well below the site of fistula and omental interposition further avoids the chances of recurrence of fistula. PMID- 27217674 TI - Malignant fibrous histiocytoma of maxillary sinus- a diagnostic challenge. AB - Malignant fibrous histiocytoma (MFH) is a malignant mesenchymal tumor uncommonly seen in head and neck region and even rarer in maxillary sinus with less than thirty cases reported in literature. Microscopic diagnosis at this rare site may be challenging because of the spectrum of features, which frequently overlap with other benign and malignant tumors. We herein report a case of malignant fibrous histiocytoma of the maxillary sinus in a 40-year-old man who presented with epistaxis. The initial biopsy appeared benign whereas histopathology of wide surgical excision was consistent with MFH. In view of the deep location, the diagnosis may be missed on a small biopsy, which can appear deceptive leading to diagnostic errors. This case report highlights the histopathological difficulties and pitfalls of this tumor at this rare site. PMID- 27217675 TI - Clear Cell Mypepithelial Carcinoma of the Base Tongue Managed by the Mandible Preserving Pull-Through Oropharyngectomy Approach. AB - Myoepithelial carcinoma (MC) is rare disease that comprises of only about 2 % of all salivary gland carcinomas and MC that focally or predominantly displays clear cell-type tumor cells are considered as CCMC. We recently got to treat a rare case of a base tongue clear cell myoepithelial carcinoma. (CCMC) Our patient, to the best of our knowledge is the second case of base tongue CCMC and the first with metastatic involvement of the cervical lymph nodes. We successfully managed the tumor using the "mandible preserving pull-through oropharyngectomy approach" Knowledge of the different surgical approaches and techniques is thus vital for better oncologic, functional and aesthetic outcomes following surgery for tumors especially in challenging sub sites like the oropharynx. PMID- 27217676 TI - Clavicle metastasis from carcinoma thyroid- an atypical skeletal event and a management dilemma. AB - Bone metastases is a well described event in the natural history of thyroid cancers and has the potential to severely impact the quality of life by causing pain, fractures and spinal cord compression. Follicular thyroid carcinomas have a greater propensity for distal metastasis than papillary and anaplastic thyroid carcinomas. The most common sites of skeletal metastasis among thyroid cancer patients are femur followed by humerus, pelvis, radius, and scapula. Clavicle metastasis at initial presentation is exceedingly rare. Although many studies have examined the various prognostic factors for patients with bony metastases from thyroid cancers, very few have actually evaluated the effects of surgical management. We present an unusual case of metastatic papillary carcinoma thyroid presenting with clavicle metastasis and review the role of surgical management of bone metastases. Clavicular resection as a part of the management of metastatic papillary carcinoma thyroid has, to the best of our knowledge never been reported before. PMID- 27217677 TI - A Rare Case of Cytokeratin-Positive Interstitial Reticulum Cell Sarcoma and Review of the Entity. AB - The tumors of dendritic/reticulum cells constitutes the rarest tumors affecting the lymphoid tissues. Among them tumors derived from fibroblastic reticular cells (FBRCs) are very rare, and those of cytokeratin (CK)-positive interstitial reticulum cells (CIRCs) origin are even more rare. These tumors can be easily misdiagnosed as tumors of other dendritic cells, myofibroblastic tumors or even metastatic poorly differentiated carcinomas. Less than twenty such cases have been reported in the literature till date. We present such a rare case of CIRC sarcoma in cervical lymph node of a 64-year-old man. PMID- 27217678 TI - Primary Melanoma of Infra Temporal Fossa: A Case Report. AB - This is the second case report in English literature of a primary non-cutaneous non mucosal melanoma (NCNM) originating from Infratemporal fossa (ITF). A 21 year woman who was previously treated for craniopharyngioma 14 years back with surgery and radiation, presented with left ITF swelling which after excision was histologically confirmed to be NCNM. She has been disease free till date. Therapeutic difficulties and diagnostic dilemmas in such a case are discussed. We propose the term of non cutaneous non mucosal melanoma (NCNM) for this rare entity. PMID- 27217679 TI - Biliary Ascariasis Mimicking Colonic Tumor Infiltration of the Biliary System. AB - Ascariasis is a common problem in developing countries with poor hygiene and sanitation. It is endemic in India and usually seen in the northern states. Biliary ascariasis is an uncommon cause of obstructive jaundice. We present a case of carcinoma of hepatic flexure of colon in which the patient developed biliary ascariasis and posed a diagnostic challenge as it mimicked tumor infiltration of the biliary system. PMID- 27217680 TI - Adenomatous Metaplasia Arising in a Horse-Shoe Kidney - A Rare Entity. AB - Urinary adenomatous metaplasia (nephrogenic adenomas) is uncommon, benign, apparently metaplastic response of the urothelium to chronic inflammation, trauma, surgery, urolithiasis, long-term indwelling urethral catheterization, and immunosuppressive therapy instillation. Gross or microscopic hematuria and some irritable urinary tract symptoms are often observed. A diagnosis is primarily based on the histopathological examination. We are reporting this case because adenomatous metaplasia is very rarely reported in the kidney especially in a horse shoe kidney with a large renal stone and these lesions could be mistakenly diagnosed as malignancy. In our knowledge this is the very first case of its kind. An awareness of this entity is critical to prevent over-diagnosis of cancer and to avoid unnecessary treatment. PMID- 27217681 TI - Giant Cell Tumor Bone in an Elderly Male- an Unusual Case Misdiagnosed on MRI as a Malignant Sarcoma. AB - Giant cell tumor (GCT) of the bone is a benign locally aggressive neoplasm which accounts for 3-8 % of all primary bone tumors. 60-70 % of the patients with giant cell tumor of the bone occur in the age group of 20-40 years. Patients older than 55 years of age very rarely develop GCT. Although many case series have been published on giant cell tumor of the bone, even on extensive search of literature, we found only a single series of 10 cases focusing exclusively on giant cell tumors in elderly. They observed that there was no difference in behavior of GCT in elderly and younger patients in terms of location of tumor, radiographic features and clinical course. We present a case of GCT of tibia in an elderly male without any evidence of malignant transformation or dedifferentiation, despite magnetic resonance imaging revealing features of a malignant lesion. PMID- 27217682 TI - Locally Advanced Askin's Tumour in a Child-a Rare Case Report and Review of the Literature. AB - Askin's tumor is a primitive neuroectodermal tumor (PNET) developing from the soft tissues of the chest wall and mainly occur in children and adolescents. The management approach is complex and requires a multidisciplinary team. We report a case of locally advanced Askin's tumour in a child because of its rarity and also to highlight the importance of keeping the possibility of PNET tumours in mind while dealing with cases of chest wall tumour in children. PMID- 27217683 TI - A Case of Rare Small Bowel Tumor in a Child and Review of Literature. PMID- 27217684 TI - Recurrent Low-Grade Fibromyxoid Sarcoma of the Neck: Report of a Case and Review of the Literature. AB - Low-grade fibromyxoid sarcoma (LGFMS) represents a rare, indolent, benign neoplasm that proliferates at various anatomical locations. Histologically, the tumor consists of bland, deceptively benign-appearing spindle cells in a whirling pattern, as well as myxoid and collagenized stroma. The current treatment includes surgical excision. The aim of this investigation was to analyze a rare clinical case of recurrent LGFMS of the neck. Relevant literature is briefly reviewed. An 81-year-old male was admitted with an enlarging painless nontender mass in the neck. The patient referred a past medical history of LGFMS. Magnetic Resonance Imaging (MRI) depicted a large, well-defined mass in the lower neck and supraclavicular area, extending till the left upper area of the anterior thoracic wall. Based on the imaging characteristics and the medical history, a wide surgical excision of a 5.6 * 6.6 * 3.3 cm area, in close proximity to the cervical vertebrae was performed. On microsopic examination, the tumor contained alternating fibrous and mixoid components, with mixed hypo- and hyper-cellular areas, minimal necrosis and negligible cellular pleomorphism or nuclear atypia. As LGFMS is a soft tissue malignancy, any recurrences are usually local; therefore treatment of choice is radical, wide margin surgical excision. Nevertheless, the ideal goal of large safety margin of healthy tissue might be unattainable if it requires resection of vital anatomic structures. Because LGFMS has a very low mitotic rate, neither chemotherapy nor radiotherapy is expected to have significant effect on long-term prognosis. PMID- 27217685 TI - Squamous Cell Carcinoma of Rectum: How to Treat? AB - Squamous cell carcinoma (SCC) of rectum is an uncommonly seen malignancy. It has been difficult to establish the precise etio-pathogenesis due to paucity of cases. For the same reason, the rigorous treatment protocol has not been defined. The available compendium of knowledge about this pathology is based on isolated case reports and case series. We report a case of SCC of rectum who was treated with chemo-radiotherapy. PMID- 27217686 TI - Pheochromocytoma of the Urinary Bladder - A Case Report of an Unusual Presentation. AB - Urinary bladder pheochromocytoma is rare. We report a case of bladder pheochromocytoma presenting with practically no obvious clinical symptoms in an adolescent who had undergone repair of mitral valve disease. PMID- 27217687 TI - Dumbbell Shaped Schwannoma of the Lateral Chest Wall masquandering as a soft tissue sarcoma. AB - Schwannomas are benign, slow growing nerve sheath tumours of Schwann cell origin. They predominantly are known to involve the head, neck and the flexor surfaces of the extremities, retroperitoneum and the posterior spinal roots. The chest wall is a relatively uncommon location for a schwannoma, the vast majority of which are intra-thoracic, which are usually located in the posterior mediastinum and bulge into the thoracic cavity. Schwannomas arising from the lateral chest wall are relatively uncommon (<5 %). Dumbbell shaped schwannomas of the lateral chest wall i.e. with an intra-thoracic and extra-thoracic component, is extraordinarily rare and to the best of our knowledge only one case has been reported prior. We report possibly the second case of a dumbbell shaped lateral chest wall schwannoma in a 33-year-old female patient which masquandered as a case of soft tissue sarcoma. PMID- 27217688 TI - Cannon Ball Metastases and Atrial Thrombus. AB - Cannon ball lesions and atrial thrombosis are seldom seen in clinical practice. A variety of infectious or non infectious conditions are associated with them. A meticulous search is required to delineate the exact etiology. PMID- 27217689 TI - Vaginal Neurilemmoma: Case Report with Brief Review. PMID- 27217690 TI - Squamous Cell Carcinoma Arising in Ovarian Teratoma: A Diagnostic Conundrum. PMID- 27217691 TI - Ileocaecal Lymphoma Presenting as Ileocolic Intussesception in a 7 Year Old Male. PMID- 27217692 TI - A Tribute to Dr. A. P. Majumadar. PMID- 27217693 TI - Current treatment of chronic hepatitis C in China: Dilemma and potential problems. AB - Major advances have been made in the treatment of chronic hepatitis C virus (HCV) infection with the advent of direct-acting antiviral agents (DAAs). China has the most cases of HCV infection worldwide, but none of the DAAs has been approved in mainland China so far, and interferon (IFN)-alpha-based treatment remains the standard of care. HCV patients without response or with contraindications to IFN based therapy have no alternative options. However, many patients buy DAAs, especially the generic forms of sofosbuvir, from other countries or areas. Under these circumstances, the use of these drugs may cause many predictable and unpredictable problems in ethics, law and medical practice. Given the obstacles of legal accessibility to DAAs and the potential problems of obtaining and using DAAs in China, the early launching of the DAAs in China or the legalization of buying drugs from areas outside China and using these drugs in China is an urgent issue and needs to be dealt with as soon as possible, in the interest of the patients. PMID- 27217694 TI - HER2 testing in gastric cancer: An update. AB - Human epidermal growth factor receptor 2 (HER2) overexpression is increasingly recognized as a frequent molecular abnormality in gastric and gastroesophageal cancer. With the recent introduction of HER2 molecular targeted therapy for patients with advanced gastric cancer, determination of HER2 status is crucial in order to select patients who may benefit from this treatment. This paper provides an update on our knowledge of HER2 in gastric and gastroesophageal cancer, including the prognostic relevance of HER2, the key differences between HER2 protein expression interpretation in breast and gastric cancer, the detection methods and the immunohistochemistry scoring system. PMID- 27217695 TI - Minimally invasive surgery for upper gastrointestinal cancer: Our experience and review of the literature. AB - Minimally invasive surgery (MIS) for upper gastrointestinal (GI) cancer, characterized by minimal access, has been increasingly performed worldwide. It not only results in better cosmetic outcomes, but also reduces intraoperative blood loss and postoperative pain, leading to faster recovery; however, endoscopically enhanced anatomy and improved hemostasis via positive intracorporeal pressure generated by CO2 insufflation have not contributed to reduction in early postoperative complications or improvement in long-term outcomes. Since 1995, we have been actively using MIS for operable patients with resectable upper GI cancer and have developed stable and robust methodology in conducting totally laparoscopic gastrectomy for advanced gastric cancer and prone thoracoscopic esophagectomy for esophageal cancer using novel technology including da Vinci Surgical System (DVSS). We have recently demonstrated that use of DVSS might reduce postoperative local complications including pancreatic fistula after gastrectomy and recurrent laryngeal nerve palsy after esophagectomy. In this article, we present the current status and future perspectives on MIS for gastric and esophageal cancer based on our experience and a review of the literature. PMID- 27217696 TI - Recent updates of precision therapy for gastric cancer: Towards optimal tailored management. AB - Signaling pathways of gastric carcinogenesis and gastric cancer progression are being avidly studied to seek optimal treatment of gastric cancer. Among them, hepatocyte growth factor (HGF)/c-MET, phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathways have been widely investigated. Their aberrant expression or mutation has been significantly associated with advanced stage or poor prognosis of gastric cancer. Recently, aberrations of immune checkpoints including programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) have been suggested as an important step in the formation of a microenvironment favorable for gastric cancer. Accomplishments in basic research have led to the development of novel agents targeting these signaling pathways. However, phase III studies of selective anti-HGF/c-MET antibodies and mTOR inhibitor failed to show significant benefits in terms of overall survival and progression-free survival. Few agents directly targeting STAT3 have been developed. However, this target is still critical issue in terms of chemoresistance, and SH2-containing protein tyrosine phosphatase 1 might be a significant link to effectively inhibit STAT3 activity. Inhibition of PD-1/PD-L1 showed durable efficacy in phase I studies, and phase III evaluation is warranted. Therapeutic strategy to concurrently inhibit multiple tyrosine kinases is a reasonable option, however, lapatinib needs to be further evaluated to identify good responders. Regorafenib has shown promising effectiveness in prolonging progression-free survival in a phase II study. In this topic highlight, we review the biologic roles and outcomes of clinical studies targeting these signaling pathways. PMID- 27217698 TI - Altered tryptophan hydroxylase 2 expression in enteric serotonergic nerves in Hirschsprung's-associated enterocolitis. AB - AIM: To determine if expression of colonic tryptophan hydroxylase-2 (TPH2), a surrogate marker of neuronal 5-hydroxytryptamine, is altered in Hirschsprung's associated enterocolitis. METHODS: Entire resected colonic specimens were collected at the time of pull-through operation in children with Hirschsprung's disease (HSCR, n = 12). Five of these patients had a history of pre-operative Hirschsprung's-associated enterocolitis (HAEC). Controls were collected at colostomy closure in children with anorectal malformation (n = 10). The distribution of expression of TPH2 was evaluated using immunofluorescence and confocal microscopy. Protein expression of TPH2 was quantified using western blot analysis in the deep smooth muscle layers. RESULTS: TPH2 was co-expressed in nitrergic and cholinergic ganglia in the myenteric and submucosal plexuses in ganglionic colon in HSCR and healthy controls. Co-expression was also seen in submucosal interstitial cells of Cajal and PDGFRalpha(+) cells. The density of TPH2 immuno-positive fibers decreased incrementally from ganglionic bowel to transition zone bowel to aganglionic bowel in the myenteric plexus. Expression of TPH2 was reduced in ganglionic bowel in those affected by pre-operative HAEC compared to those without HAEC and healthy controls. However, expression of TPH2 was similar or high compared to controls in the colons of children who had undergone diverting colostomy for medically refractory HAEC. CONCLUSION: Altered TPH2 expression in colonic serotonergic nerves of patients with HSCR complicated by HAEC may contribute to intestinal secretory and motor disturbances, including recurrent HAEC. PMID- 27217697 TI - Auto immune hepatitis. AB - To provide an update of the latest trends in epidemiology, clinical course, diagnostics, complications and treatment of auto immune hepatitis (AIH). A search of the MEDLINE database was performed using the search terms: "auto immune hepatitis", "clinical presentation", "symptoms", "signs", "diagnosis", "auto antibodies", "laboratory values", "serology", "histopathology", "histology", "genetics", "HLA genes", "non-HLA genes", "environment", "epidemiology", "prevalence", "incidence", "demographics", "complications", "HCC", "PBC", "PSC", "corticosteroid", "therapy", "treatment", "alternative treatment". English language full-text articles and abstracts were considered. Articles included reviews, meta-analysis, prospective retrospective studies. No publication date restrictions were applied. AIH is an immune meditated progressive inflammatory liver disease that predominantly affects middle-aged females but may affect people of all ages. The clinical spectrum of AIH is wide, ranging from absent or mild symptoms to fulminant hepatic failure. The aetiology of AIH is still unknown, but is believed to occur as the consequence of an aberrant immune response towards an un-known trigger in a genetically susceptible host. In the absence of a gold standard, diagnosis is based on the combination of clinical, biochemical and histopathological criteria. Immunosuppressive treatment has been the cornerstone of treatment since the earliest description of the disease in 1950 by Waldenstrom. Such treatment is often successful at inducing remission and generally leads to normal life expectancy. Nevertheless, there remain significant areas of unmet aetiological a clinical needs including fundamental insight in disease pathogenesis, optimal therapy, duration of treatment and treatment alternatives in those patients unresponsive to standard treatment regimens. PMID- 27217699 TI - Steatotic livers are susceptible to normothermic ischemia-reperfusion injury from mitochondrial Complex-I dysfunction. AB - AIM: To assess the effects of ischemic preconditioning (IPC, 10-min ischemia/10 min reperfusion) on steatotic liver mitochondrial function after normothermic ischemia-reperfusion injury (IRI). METHODS: Sixty male Sprague-Dawley rats were fed 8-wk with either control chow or high-fat/high-sucrose diet inducing > 60% mixed steatosis. Three groups (n = 10/group) for each dietary state were tested: (1) the IRI group underwent 60 min partial hepatic ischemia and 4 h reperfusion; (2) the IPC group underwent IPC prior to same standard IRI; and (3) sham underwent the same surgery without IRI or IPC. Hepatic mitochondrial function was analyzed by oxygraphs. Mitochondrial Complex-I, Complex-II enzyme activity, serum alanine aminotransferase (ALT), and histological injury were measured. RESULTS: Steatotic-IRI livers had a greater increase in ALT (2476 +/- 166 vs 1457 +/- 103 IU/L, P < 0.01) and histological injury following IRI compared to the lean liver group. Steatotic-IRI demonstrated lower Complex-I activity at baseline [78.4 +/- 2.5 vs 116.4 +/- 6.0 nmol/(min.mg protein), P < 0.001] and following IRI [28.0 +/ 6.2 vs 104.3 +/- 12.6 nmol/(min.mg protein), P < 0.001]. Steatotic-IRI also demonstrated impaired Complex-I function post-IRI compared to the lean liver IRI group. Complex-II activity was unaffected by hepatic steatosis or IRI. Lean liver mitochondrial function was unchanged following IRI. IPC normalized ALT and histological injury in steatotic livers but had no effect on overall steatotic liver mitochondrial function or individual mitochondrial complex enzyme activities. CONCLUSION: Warm IRI impairs steatotic liver Complex-I activity and function. The protective effects of IPC in steatotic livers may not be mediated through mitochondria. PMID- 27217700 TI - Contribution of mammalian target of rapamycin in the pathophysiology of cirrhotic cardiomyopathy. AB - AIM: To explore the role of mammalian target of rapamycin (mTOR) in the pathogenesis of cirrhotic cardiomyopathy and the potential of rapamycin to improve this pathologic condition. METHODS: Male albino Wistar rats weighing 100 120 g were treated with tetrachloride carbon (CCl4) for 8 wk to induce cirrhosis. Subsequently, animals were administered rapamycin (2 mg/kg per day). The QTc intervals were calculated in a 5-min electrocardiogram. Then, the left ventricular papillary muscles were isolated to examine inotropic responsiveness to beta-adrenergic stimulation using a standard organ bath equipped by Powerlab system. Phosphorylated-mTOR localization in left ventricles was immunohistochemically assessed, and ventricular tumor necrosis factor (TNF)-alpha was measured. Western blot was used to measure levels of ventricular phosphorylated-mTOR protein. RESULTS: Cirrhosis was confirmed by hematoxylin and eosin staining of liver tissues, visual observation of lethargy, weight loss, jaundice, brown urine, ascites, liver stiffness, and a significant increase of spleen weight (P < 0.001). A significant prolongation in QTc intervals occurred in cirrhotic rats exposed to CCl4 (P < 0.001), while this prolongation was decreased with rapamycin treatment (P < 0.01). CCl4-induced cirrhosis caused a significant decrease of contractile responsiveness to isoproterenol stimulation and a significant increase in cardiac TNF-alpha. These findings were correlated with data from western blot and immunohistochemical studies on phosphorylated mTOR expression in left ventricles. Phosphorylated-mTOR was significantly enhanced in cirrhotic rats, especially in the endothelium, compared to controls. Rapamycin treatment significantly increased contractile force and myocardial localization of phosphorylated-mTOR and decreased cardiac TNF-alpha concentration compared to cirrhotic rats with no treatment. CONCLUSION: In this study, we demonstrated a potential role for cardiac mTOR in the pathophysiology of cirrhotic cardiomyopathy. Rapamycin normalized the inotropic effect and altered phosphorylated-mTOR expression and myocardial localization in cirrhotic rats. PMID- 27217701 TI - Qinggan Huoxue Recipe suppresses epithelial-to-mesenchymal transition in alcoholic liver fibrosis through TGF-beta1/Smad signaling pathway. AB - AIM: To investigate the mechanism by which Qinggan Huoxue Recipe (QGHXR) inhibits epithelial-to-mesenchymal transition (EMT) in rats with alcoholic liver fibrosis (ALF). METHODS: A total of 75 male SD rats were used to induce ALF. Serum biochemical indicators, including alanine aminotransferase, aspartate aminotransferase, laminin and hyaluronidase, were measured. Liver histopathological changes were evaluated using hematoxylin-eosin and Sirius red staining. EMT was examined by analyzing the expression of the epithelial marker E cadherin and the mesenchymal markers vimentin and fibronectin using RT-PCR and Western blot. The inhibitory effect of QGHXR on EMT markers, as well as its effect on molecules associated with the transforming growth factor (TGF) beta1/Smad signaling pathway, including TGF-beta1, Smad3, snail, occludin, ZO-1 and claudin, was also examined. RESULTS: Compared with normal control rats, ALF rats exhibited a decrease in E-cadherin levels (mRNA: ALF 0.16 +/- 0.05 vs control 1.00 +/- 0.08; protein: ALF 0.09 +/- 0.05 vs control 0.70 +/- 0.17, P < 0.01) and an increase in vimentin and fibronectin levels (mRNA: 11.43 +/- 0.39 vs 1.00 +/- 0.19 and 9.91 +/- 0.34 vs 1.00 +/- 0.44, respectively, P < 0.01; protein: 1.13 +/- 0.42 vs 0.09 +/- 0.03 and 1.16 +/- 0.43 vs 0.09 +/- 0.00, respectively, P < 0.01). This indicates that EMT occurred in ALF rats. In addition, the TGF-beta1/Smad signaling pathway was activated in ALF rats, as evidenced by the increase in TGF-beta1 and snail levels (mRNA: 1.76 +/- 0.12 vs 1.00 +/- 0.05 and 6.98 +/- 0.41 vs 1.00 +/- 0.10, respectively, P < 0.01; protein: 1.43 +/- 0.05 vs 0.12 +/- 0.03 and 1.07 +/- 0.29 vs 0.07 +/- 0.02, respectively, P < 0.01) and the decrease in Smad3 levels (mRNA: 0.05 +/- 0.01 vs 1.00 +/- 0.12, P < 0.01; protein: 0.06 +/- 0.05 vs 0.89 +/- 0.12, P < 0.01). Furthermore, levels of the tight junction markers occludin, ZO-1 and claudin decreased in ALF rats compared with healthy control rats (mRNA: 0.60 +/- 0.09 vs 1.00 +/- 0.12, 0.11 +/- 0.00 vs 1.00 +/- 0.12 and 0.60 +/- 0.01 vs 1.00 +/- 0.08, respectively, P < 0.01; protein: 0.05 +/- 0.01 vs 0.87 +/- 0.40, 0.09 +/- 0.05 vs 0.89 +/- 0.18 and 0.04 +/- 0.03 vs 0.95 +/- 0.21, respectively, P < 0.01). In ALF rats treated with QGHXR, E-cadherin levels increased (mRNA: QGHXR 0.67 +/- 0.04 vs ALF model 0.16 +/- 0.05, P < 0.01; protein: QGHXR 0.66 +/- 0.21 vs ALF model 0.09 +/- 0.05, P < 0.01), and vimentin and fibronectin levels decreased (mRNA: 6.57 +/- 1.05 vs 11.43 +/- 0.39 and 1.45 +/- 1.51 vs 9.91 +/- 0.34, respectively, P < 0.01; protein: 0.09 +/- 0.03 vs 1.13 +/- 0.42 and 0.10 +/- 0.01 vs 1.16 +/- 0.43, respectively, P < 0.01). In addition, QGHXR inhibited the expression of TGF beta1 and increased the expression of Smad3 (mRNA: 1.03 +/- 0.11 vs 1.76 +/- 0.12, 0.70 +/- 0.10 vs 0.05 +/- 0.01, respectively, P < 0.05 and P < 0.01; protein: 0.12 +/- 0.03 vs 1.43 +/- 0.05 and 0.88 +/- 0.20 vs 0.06 +/- 0.05, respectively, P < 0.01). QGHXR treatment also reduced the levels of the EMT inducing transcription factor snail (mRNA: 2.28 +/- 0.33 vs 6.98 +/- 0.41, P < 0.01; protein: 0.08 +/- 0.02 vs 1.07 +/- 0.29, P < 0.01) and increased the occludin, ZO-1 and claudin levels (mRNA: 0.73 +/- 0.05 vs 0.60 +/- 0.09, 0.57 +/- 0.04 vs 0.11 +/- 0.00 and 0.68 +/- 0.03 vs 0.60 +/- 0.01, respectively, P < 0.01, P < 0.01 and P < 0.05; protein: 0.92 +/- 0.50 vs 0.05 +/- 0.01, 0.94 +/- 0.22 vs 0.09 +/- 0.05 and 0.94 +/- 0.29 vs 0.04 +/- 0.03, respectively, P < 0.01). The effects of QGR and HXR on the TGF-beta1/Smad signaling pathway were similar to that of QGHXR; however, the QGR- and HXR-induced changes in vimentin mRNA levels, the QGR-induced changes in fibronectin mRNA levels and the HXR-induced changes in snail and TGF-beta1 mRNA levels were not significant. CONCLUSION: Qinggan Huoxue Recipe inhibits EMT in ALF rats by modulating the TGF-beta1/Smad signaling pathway, suggesting that the mechanism underlying the amelioration of ALF induced by QGHXR is associated with this pathway. PMID- 27217702 TI - Laparoscopic colonic anastomosis using a degradable stent in a porcine model. AB - AIM: To explore the feasibility and safety of laparoscopic colonic anastomosis using a degradable stent in a porcine model. METHODS: Twenty Bama mini-pigs were randomly assigned to a stent group (n = 10) and control group (hand-sewn anastomosis, n = 10). The anastomotic completion and operation times were recorded, along with histological examination, postoperative general condition, complications, mortality, bursting pressure, and the average anastomotic circumference (AC). RESULTS: All pigs survived postoperatively except for one in the stent group that died from ileus at 11 wk postoperatively. The operation and anastomotic completion times of the stent group were significantly shorter than those of the control group (P = 0.004 and P = 0.001, respectively). There were no significant differences in bursting pressure between the groups (P = 0.751). No obvious difference was found between the AC and normal circumference in the stent group, but AC was significantly less than normal circumference in the control group (P = 0.047, P < 0.05). No intestinal leakage and luminal stenosis occurred in the stent group. Histological examination revealed that the stent group presented with lower general inflammation and better healing. CONCLUSION: Laparoscopic colonic anastomosis with a degradable stent is a simple, rapid, and safe procedure in this porcine model. PMID- 27217703 TI - Plasma long noncoding RNA expression profile identified by microarray in patients with Crohn's disease. AB - AIM: To investigate the expression pattern of plasma long noncoding RNAs (lncRNAs) in Chrohn's disease (CD) patients. METHODS: Microarray screening and qRT-PCR verification of lncRNAs and mRNAs were performed in CD and control subjects, followed by hierarchy clustering, GO and KEGG pathway analyses. Significantly dysregulated lncRNAs were categorized into subgroups of antisense lncRNAs, enhancer lncRNAs and lincRNAs. To predict the regulatory effect of lncRNAs on mRNAs, a CNC network analysis was performed and cross linked with significantly changed lncRNAs. The overlapping lncRNAs were randomly selected and verified by qRT-PCR in a larger cohort. RESULTS: Initially, there were 1211 up regulated and 777 down-regulated lncRNAs as well as 1020 up-regulated and 953 down-regulated mRNAs after microarray analysis; a heat map based on these results showed good categorization into the CD and control groups. GUSBP2 and AF113016 had the highest fold change of the up- and down-regulated lncRNAs, whereas TBC1D17 and CCL3L3 had the highest fold change of the up- and down-regulated mRNAs. Six (SNX1, CYFIP2, CD6, CMTM8, STAT4 and IGFBP7) of 10 mRNAs and 8 (NR_033913, NR_038218, NR_036512, NR_049759, NR_033951, NR_045408, NR_038377 and NR_039976) of 14 lncRNAs showed the same change trends on the microarray and qRT PCR results with statistical significance. Based on the qRT-PCR verified mRNAs, 1358 potential lncRNAs with 2697 positive correlations and 2287 negative correlations were predicted by the CNC network. CONCLUSION: The plasma lncRNAs profiles provide preliminary data for the non-invasive diagnosis of CD and a resource for further specific lncRNA-mRNA pathway exploration. PMID- 27217704 TI - Veterans health administration hepatitis B testing and treatment with anti-CD20 antibody administration. AB - AIM: To evaluate pretreatment hepatitis B virus (HBV) testing, vaccination, and antiviral treatment rates in Veterans Affairs patients receiving anti-CD20 Ab for quality improvement. METHODS: We performed a retrospective cohort study using a national repository of Veterans Health Administration (VHA) electronic health record data. We identified all patients receiving anti-CD20 Ab treatment (2002 2014). We ascertained patient demographics, laboratory results, HBV vaccination status (from vaccination records), pharmacy data, and vital status. The high risk period for HBV reactivation is during anti-CD20 Ab treatment and 12 mo follow up. Therefore, we analyzed those who were followed to death or for at least 12 mo after completing anti-CD20 Ab. Pretreatment serologic tests were used to categorize chronic HBV (hepatitis B surface antigen positive or HBsAg+), past HBV (HBsAg-, hepatitis B core antibody positive or HBcAb+), resolved HBV (HBsAg-, HBcAb+, hepatitis B surface antibody positive or HBsAb+), likely prior vaccination (isolated HBsAb+), HBV negative (HBsAg-, HBcAb-), or unknown. Acute hepatitis B was defined by the appearance of HBsAg+ in the high risk period in patients who were pretreatment HBV negative. We assessed HBV antiviral treatment and the incidence of hepatitis, liver failure, and death during the high risk period. Cumulative hepatitis, liver failure, and death after anti-CD20 Ab initiation were compared by HBV disease categories and differences compared using the chi(2) test. Mean time to hepatitis peak alanine aminotransferase, liver failure, and death relative to anti-CD20 Ab administration and follow-up were also compared by HBV disease group. RESULTS: Among 19304 VHA patients who received anti-CD20 Ab, 10224 (53%) had pretreatment HBsAg testing during the study period, with 49% and 43% tested for HBsAg and HBcAb, respectively within 6 mo pretreatment in 2014. Of those tested, 2% (167/10224) had chronic HBV, 4% (326/7903) past HBV, 5% (427/8110) resolved HBV, 8% (628/8110) likely prior HBV vaccination, and 76% (6022/7903) were HBV negative. In those with chronic HBV infection, <= 37% received HBV antiviral treatment during the high risk period while 21% to 23% of those with past or resolved HBV, respectively, received HBV antiviral treatment. During and 12 mo after anti-CD20 Ab, the rate of hepatitis was significantly greater in those HBV positive vs negative (P = 0.001). The mortality rate was 35%-40% in chronic or past hepatitis B and 26%-31% in hepatitis B negative. In those pretreatment HBV negative, 16 (0.3%) developed acute hepatitis B of 4947 tested during anti-CD20Ab treatment and follow-up. CONCLUSION: While HBV testing of Veterans has increased prior to anti-CD20 Ab, few HBV+ patients received HBV antivirals, suggesting electronic health record algorithms may enhance health outcomes. PMID- 27217705 TI - Contrast-enhanced ultrasound of histologically proven hepatic epithelioid hemangioendothelioma. AB - AIM: To analyze contrast-enhanced ultrasound (CEUS) features of histologically proven hepatic epithelioid hemangioendothelioma (HEHE) in comparison to other multilocular benign focal liver lesions (FLL). METHODS: Twenty-five patients with histologically proven HEHE and 45 patients with histologically proven multilocular benign FLL were retrospectively reviewed. Four radiologists assessed the CEUS enhancement pattern in consensus. RESULTS: HEHE manifested as a single (n = 3) or multinodular (n = 22) FLL. On CEUS, HEHE showed rim-like (18/25, 72%) or heterogeneous hyperenhancement (7/25, 28%) in the arterial phase and hypoenhancement (25/25, 100%) in the portal venous and late phases (PVLP), a sign of malignancy. Eighteen patients showed central unenhanced areas (18/25, 72%); in seven patients (7/25, 28%), more lesions were detected in the PVLP. In contrast, all patients with hemangioma and focal nodular hyperplasia showed hyperenhancement as the most distinctive feature (P < 0.01). CONCLUSION: CEUS allows for characterization of unequivocal FLL. By analyzing the hypoenhancement in the PVLP, CEUS can determine the malignant nature of HEHE. PMID- 27217706 TI - Lymph node dissection in esophageal carcinoma: Minimally invasive esophagectomy vs open surgery. AB - AIM: To compare lymph node dissection results of minimally invasive esophagectomy (MIE) and open surgery for esophageal squamous cell carcinoma. METHODS: We retrospectively reviewed data from patients who underwent MIE or open surgery for esophageal squamous cell carcinoma from January 2011 to September 2014. Number of lymph nodes resected, positive lymph node (pN+) rate, lymph node sampling (LNS) rate and lymph node metastatic (LNM) rate were evaluated. RESULTS: Among 447 patients included, 123 underwent MIE and 324 underwent open surgery. The number of lymph nodes resected did not significantly differ between the MIE and open surgery groups (21.1 +/- 4.3 vs 20.4 +/- 3.8, respectively, P = 0.0944). The pN+ rate of stage T3 esophageal squamous cell carcinoma in the open surgery group was higher than that in the MIE group (16.3% vs 11.4%, P = 0.031), but no differences was observed for stages T1 and T2 esophageal squamous cell carcinoma. The LNS rate at left para-recurrent laryngeal nerve (RLN) site was significantly higher for open surgery than for MIE (80.2% vs 43.9%, P < 0.001), but no differences were noted at other sites. The LNM rate at left para-RLN site in the open surgery group was significantly higher than that in the MIE group, regardless of pathologic T stage. CONCLUSION: For stages T1 and T2 esophageal squamous cell carcinoma, the lymph node dissection result after MIE was comparable to that achieved by open surgery. However, the efficacy of MIE in lymphadenectomy for stage T3 esophageal squamous cell carcinoma, particularly at left para-RLN site, remains to be improved. PMID- 27217707 TI - Chinese physicians' perceptions of fecal microbiota transplantation. AB - AIM: To explore Chinese physicians' perceptions towards fecal microbiota transplantation (FMT) and to provide information and an assessment of FMT development in China. METHODS: A self-administered questionnaire was developed according to the FMT practice guidelines and was distributed to physicians in hospitals via Internet Research Electronic Data Capture (REDcap) software and electronic mails to assess their attitudes toward and knowledge of FMT. The questionnaire included a brief introduction of FMT that was followed by 20 questions. The participants were required to respond voluntarily, under the condition of anonymity and without compensation. Except for the fill-in-the-blank questions, all of the other questions were required in the REDcap data collection systems, and the emailed questionnaires were completed based on eligibility. RESULTS: Up to December 9, 2014, 844 eligible questionnaires were received out of the 980 distributed questionnaires, with a response rate of 86.1%. Among the participants, 87.3% were from tertiary hospitals, and there were 647 (76.7%) gastroenterologists and 197 (23.3%) physicians in other departments (non gastroenterologists). Gastroenterologists' awareness of FMT prior to the survey was much higher than non-gastroenterologists' (54.3 vs 16.5%, P < 0.001); however, acceptance of FMT was not statistically different (92.4 vs 87.1%, P = 0.1603). Major concerns of FMT included the following: acceptability to patients (79.2%), absence of guidelines (56.9%), and administration and ethics (46.5%). On the basis of understanding, the FMT indications preferred by physicians were recurrent Clostridium difficile infection (86.7%), inflammatory bowel disease combined with Clostridium difficile infection (78.6%), refractory ulcerative colitis (70.9%), ulcerative colitis (65.4%), Crohn's disease (59.4%), chronic constipation (43.7%), irritable bowel syndrome (39.1%), obesity (28.1%) and type 2 diabetes (23.9%). For donor selection, the majority of physicians preferred individuals with a similar gut flora environment to the recipients. 76.6% of physicians chose lower gastrointestinal tract as the administration approach. 69.2% of physicians considered FMT a safe treatment. CONCLUSION: Chinese physicians have awareness and a high acceptance of FMT, especially gastroenterologists, which provides the grounds and conditions for the development of this novel treatment in China. Physicians' greatest concerns were patient acceptability and absence of guidelines. PMID- 27217708 TI - Hybrid, sequential and concomitant therapies for Helicobacter pylori eradication: A systematic review and meta-analysis. AB - AIM: To compare hybrid therapy (HT) with traditional sequential therapy (ST) and concomitant therapy (CT) for Helicobacter pylori (H. pylori) eradication. METHODS: We performed an electronic search of PubMed, Embase, and the CENTRAL database. Randomized controlled trials (RCTs) of HT were included in the meta analysis. The primary outcome was the eradication rate of H. pylori. The secondary outcomes included the compliance rate and adverse event rate. Effect estimates were pooled using the random-effects model. RESULTS: Twelve studies were included. Pooled results showed no significant differences in eradication rate between HT and ST in per-protocol (PP) analysis (RR = 1.03, 95%CI: 0.94 1.12, P = 0.59) or in intention-to-treat (ITT) analysis (RR = 1.00, 95%CI: 0.89 1.12, P = 0.94). HT and ST showed similarly high compliance rate (96% vs 98%, P = 0.55) and acceptable adverse event rate (30.3% vs 28.2%, P = 0.63). No significant results were seen in the eradication rate between HT and CT in PP analysis (RR = 1.01, 95%CI: 0.96-1.05, P = 0.76) or in ITT analysis (RR = 0.99, 95%CI: 0.95-1.03, P = 0.47). HT displayed a slightly higher compliance rate than CT (95.8% vs 93.2%, P < 0.05). The adverse event rates of HT and CT were similar (39.5% vs 44.2%, P = 0.24). CONCLUSION: Compared with ST or CT, HT yields a similar eradication rate, high compliance rate, and acceptable safety profiles. PMID- 27217709 TI - Endoscopic resection of sparganosis presenting as colon submucosal tumor: A case report. AB - Human sparganosis is a rare parasitic disease caused by infection with the tapeworm Sparganum, the migrating plerocercoid (second stage) larva of Spirometra species. Sparganosis usually involves subcutaneous tissues and/or muscles of various parts of the body, but involvement of other sites such as the brain, eye, peritoneopleural cavity, urinary track, scrotum, and abdominal viscera has also been documented. Infections caused by sparganum have a worldwide distribution but are most common in Southeast Asia such as China, Japan, and South Korea. Rectal sparganosis is an uncommon disease but should be considered in the differential diagnosis of unusual and suspicious rectal submucosal tumors. We report a case of rectal sparganosis presenting as rectal submucosal tumor. We performed endoscopic submucosal dissection of the rectal submucosal tumor. The sparganosis was confirmed based on the presence of calcospherules in the submucosal layer on histological examination. Moreover, the result of the immunoglobulin G antibody test for sparganosis was positive but became negative after endoscopic submucosal dissection. Though rare, rectal sparganosis should be considered in the differential diagnosis of rectal submucosal tumor-like lesions. This case suggests that physicians should make effort to exclude sparganosis through careful diagnostic approaches, including detailed history taking and serological tests for parasites. In this report, we aimed to highlight the clinical presentation of Sparganum infection as a rectal submucosal tumor. PMID- 27217710 TI - Successful management of adult lymphoma-associated intussusception by laparoscopic reduction and appendectomy. AB - Although primary gastrointestinal lymphoma is a rare malignancy, it can cause an intussusception in adults and can be a clinically challenging condition to manage. Intussusception could progress to life-threatening complications if left untreated or could delay chemotherapy if inappropriate surgical management is used. We report a 31-year-old man diagnosed with human immunodeficiency virus who was being treated with antiretroviral therapy. He presented with nausea, vomiting, poor appetite, and intermittent, cramping abdominal pain for over 1 wk. Abdominal computed tomography revealed a well-defined homogeneous mass in the mesenteric root region, together with a long segmental wall thickening in the ileum with ileocolic-type intussusception, which was suspected to be caused by a lymphoma. The intussusception was successfully laparoscopically reduced, and the tumor involvement of the appendix was confirmed by appendectomy with intraoperative frozen section. Systemic chemotherapy was immediately initiated after surgery without the need for bowel resection. PMID- 27217711 TI - von Willebrand factor antigen as a therapeutic target of portal hypertension in cirrhosis. AB - Increased thrombotic potential within the liver sinusoids due to local endothelial production of von Willebrand factor antigen macromolecules could represent an additional therapeutic target of portal hypertension in patients with cirrhosis. In this case, anti-inflammatory and antithrombotic drugs could modulate portal pressure by preventing the formation of intrahepatic platelet induced microthrombi. PMID- 27217713 TI - Computational Aspects of Optional Polya Tree. AB - Optional Polya tree (OPT) is a flexible nonparametric Bayesian prior for density estimation. Despite its merits, the computation for OPT inference is challenging. In this paper we present time complexity analysis for OPT inference and propose two algorithmic improvements. The first improvement, named limited-lookahead optional Polya tree (LL-OPT), aims at accelerating the computation for OPT inference. The second improvement modifies the output of OPT or LL-OPT and produces a continuous piecewise linear density estimate. We demonstrate the performance of these two improvements using simulated and real date examples. PMID- 27217712 TI - Psychometric Validation of the Insomnia Severity Index in Adults with Sickle Cell Disease. AB - BACKGROUND: The Insomnia Severity Index (ISI) is an instrument to evaluate insomnia symptoms. The psychometric properties have not been established in adults (18 years of age or older) with sickle cell disease (SCD). OBJECTIVE: Evaluate the reliability and validity of the ISI among adults with SCD. METHODS: Analysis included psychometric evaluation with exploratory factor analysis. RESULTS: Our 263 participants had a mean age of 35.6 years and primarily were female (54.8%) with HbSS genotype (69.2%). Almost 41% were classified as clinical insomnia cases (ISI >=14) using the traditional scoring approach. Two factors, Insomnia Symptoms and Insomnia Impact, emerged during factor analysis. Reliability of both factor-scales was good and each correlated with pain severity and depressive symptomatology (r = 0.38 to 0.66, p<.01). CONCLUSION: The ISI demonstrated construct validity and reliability for evaluating insomnia symptomatology among adults with SCD and can be used in research and clinical practice. PMID- 27217714 TI - Association of primary open-angle glaucoma with mitochondrial variants and haplogroups common in African Americans. AB - PURPOSE: To estimate the population frequencies of all common mitochondrial variants and ancestral haplogroups among 1,999 subjects recruited for the Primary Open-Angle African American Glaucoma Genetics (POAAGG) Study, including 1,217 primary open-angle glaucoma (POAG) cases and 782 controls, and to identify ancestral subpopulations and mitochondrial mutations as potential risk factors for POAG susceptibility. METHODS: Subject classification by characteristic glaucomatous optic nerve findings and corresponding visual field defects, as defined by enrolling glaucoma specialists, stereo disc photography, phlebotomy, extraction of total DNA from peripheral blood or saliva, DNA quantification and normalization, PCR amplification of whole mitochondrial genomes, Ion Torrent deep semiconductor DNA sequencing on DNA pools ("Pool-seq"), Sanger sequencing of 3,479 individual mitochondrial DNAs, and bioinformatic analysis. RESULTS: The distribution of common African haplogroups within the POAAGG study population was broadly similar to prior surveys of African Americans. However, the POAG case population was found to be enriched in L1c2 haplogroups, which are defined in part by missense mutations m.6150G>A (Val83Ile, odds ratio [OR] 1.8, p=0.01), m.6253C>T (Met117Thr, rs200165736, OR 1.6, p=0.04), and m.6480G>A (Val193Ile, rs199476128, OR 4.6, p=0.04) in the cytochrome c oxidase subunit 1 (MT-CO1) gene and by a variant, m.2220A>G (OR 2.0, p=0.01), in MT-RNR2, which encodes the mitochondrial ribosomal 16s RNA gene. L2 haplogroups were predicted to be overrepresented in the POAG case population by Pool-seq, and the difference was confirmed to be significant with Sanger sequencing, that targeted the L2 associated variants m.2416T>C (rs28358580, OR 1.2, p=0.02) and m.2332C>T (OR 1.2, p=.02) in MT-RNR2. Another variant within MT-RNR2, m.3010G>A (rs3928306), previously implicated in sensitivity to the optic neuropathy-associated antibiotic linezolid, and arising on D4 and J1 lineages, associated with Leber hereditary optic neuropathy (LHON) severity, was confirmed to be common (>5%) but was not significantly enriched in the POAG cases. Two variants linked to the composition of the gut microbiome, m.15784T>C (rs527236194, haplogroup L2a1) and m.16390G>A (rs41378955, L2 haplogroups), were also enriched in the case DNA pools. CONCLUSIONS: These results implicate African mtDNA haplogroups L1c2, L1c2b, and L2 as risk factors for POAG. Approximately one in four African Americans have these mitochondrial ancestries, which may contribute to their elevated glaucoma risk. These haplogroups are defined in part by ancestral variants in the MT-RNR2 and/or MT-CO1 genes, several of which have prior disease associations, such as MT-CO1 missense variants that have been implicated in prostate cancer. PMID- 27217715 TI - Gene expression changes in the retina following subretinal injection of human neural progenitor cells into a rodent model for retinal degeneration. AB - PURPOSE: Retinal degenerative diseases (RDDs) affect millions of people and are the leading cause of vision loss. Although treatment options for RDDs are limited, stem and progenitor cell-based therapies have great potential to halt or slow the progression of vision loss. Our previous studies have shown that a single subretinal injection of human forebrain derived neural progenitor cells (hNPCs) into the Royal College of Surgeons (RCS) retinal degenerate rat offers long-term preservation of photoreceptors and visual function. Furthermore, neural progenitor cells are currently in clinical trials for treating age-related macular degeneration; however, the molecular mechanisms of stem cell-based therapies are largely unknown. This is the first study to analyze gene expression changes in the retina of RCS rats following subretinal injection of hNPCs using high-throughput sequencing. METHODS: RNA-seq data of retinas from RCS rats injected with hNPCs (RCS(hNPCs)) were compared to sham surgery in RCS (RCS(sham)) and wild-type Long Evans (LE(sham)) rats. Differential gene expression patterns were determined with in silico analysis and confirmed with qRT-PCR. Function, biologic, cellular component, and pathway analyses were performed on differentially expressed genes and investigated with immunofluorescent staining experiments. RESULTS: Analysis of the gene expression data sets identified 1,215 genes that were differentially expressed between RCS(sham) and LE(sham) samples. Additionally, 283 genes were differentially expressed between the RCS(hNPCs) and RCS(sham) samples. Comparison of these two gene sets identified 68 genes with inverse expression (termed rescue genes), including Pdc, Rp1, and Cdc42ep5. Functional, biologic, and cellular component analyses indicate that the immune response is enhanced in RCS(sham). Pathway analysis of the differential expression gene sets identified three affected pathways in RCS(hNPCs), which all play roles in phagocytosis signaling. Immunofluorescent staining detected the increased presence of macrophages and microglia in RCS(sham) retinas, which decreased in RCS(hNPCs) retinas similar to the patterns detected in LE(sham). CONCLUSIONS: The results from this study provide evidence of the gene expression changes that occur following treatment with hNPCs in the degenerating retina. This information can be used in future studies to potentially enhance or predict responses to hNPC and other stem cell therapies for retinal degenerative diseases. PMID- 27217717 TI - Lack of association of the M129V polymorphism of the PRNP gene with pseudoexfoliation syndrome. AB - PURPOSE: In this study we aimed to evaluate the polymorphism at codon 129 (M129V) of the PRNP gene as a secondary risk factor for pseudoexfoliation syndrome (PEX). METHODS: Two hundred and seventy-five unrelated subjects, including 156 patients with PEX and 119 unrelated control subjects, were recruited from the University Hospital of Patras, Greece. All patients and controls were of Caucasian or European ancestry. The PRNP M129V (A/G) single-nucleotide polymorphism was genotyped by real-time polymerase chain reactions. Association of the polymorphism with PEX was assessed using the two-sided Pearson's chi-squared or Fisher's exact test. RESULT: No significant difference between patients and controls was observed in terms of frequencies of alleles and genotypes of the PRNP gene. CONCLUSION: Polymorphism at M129V of the PRNP gene was evaluated as a secondary risk factor for developing PEX. Our results suggest that this PRNP gene polymorphism is not associated with PEX. PMID- 27217718 TI - Macular edema in siliconized eyes. PMID- 27217716 TI - Mutation spectrum of the Norrie disease pseudoglioma (NDP) gene in Indian patients with FEVR. AB - PURPOSE: Mutations in the Norrie disease pseudoglioma (NDP; Xp11.3) gene have been involved in retinal blood vessel formation and neural differentiation and are implicated in familial exudative vitreoretinopathy (FEVR) cases. However, the role of the gene has not been explored in the Indian context. Thus, this study was designed to understand the involvement of NDP among Indian patients with FEVR. METHODS: The study cohort comprised 225 subjects, including unrelated patients with FEVR (n = 110) and ethnically matched healthy subjects (n = 115) recruited from a tertiary eye care center in India. The entire coding regions, intron-exon boundaries, along with the 5' and 3' untranslated regions of NDP were screened with resequencing following standard protocols. The spectrum of the observed variants was analyzed in conjunction with data available from other populations. RESULTS: Eight potentially pathogenic mutations (p.His4ArgfsX21, p.Asp23GlufsX9, p.Ile48ValfsX55, p.His50Asp, p.Ser57*, p.Gly113Asp, p.Arg121Gln, and p.Cys126Arg, including five novel ones), were observed in the coding region of the NDP gene in ten unrelated FEVR probands (9%). The novel changes were not observed in the control subjects and were unavailable in the dbSNP, ESP5400, NIEHS95, and ExAC databases. All probands with NDP mutations exhibited classical features of the disease as observed among patients with FEVR worldwide. CONCLUSIONS: This is perhaps the first study to demonstrate the involvement of NDP among patients with Indian FEVR that further expands its mutation spectrum. The data generated could have broad implications in genetic counseling, disease management, and early intervention for a better prognosis in FEVR. PMID- 27217719 TI - A nonrandomized, open-label study to evaluate the effect of nasal stimulation on tear production in subjects with dry eye disease. AB - BACKGROUND: Dry eye disease (DED), a chronic disorder affecting the tear film and lacrimal functional unit, is a widely prevalent condition associated with significant burden and unmet treatment needs. Since specific neural circuits play an important role in maintaining ocular surface health, microelectrical stimulation of these pathways could present a promising new approach to treating DED. This study evaluated the efficacy and safety of nasal electrical stimulation in patients with DED. METHODS: This prospective, open-label, single-arm, nonrandomized pilot study included 40 patients with mild to severe DED. After undergoing two screening visits, enrolled subjects were provided with a nasal stimulation device and instructed to use it at home four times daily (or more often as needed). Follow-up assessments were conducted up to day 180. The primary efficacy endpoint was the difference between unstimulated and stimulated tear production quantified by Schirmer scores. Additional efficacy endpoints included change from baseline in corneal and conjunctival staining, symptoms evaluated on a Visual Analog Scale, and Ocular Surface Disease Index scores. Safety parameters included adverse event (AE) rates, visual acuity, intraocular pressure, slit-lamp biomicroscopy, indirect ophthalmoscopy, and endoscopic nasal examinations. RESULTS: Mean stimulated Schirmer scores were significantly higher than the unstimulated scores at all visits, and corneal and conjunctival staining and symptom scores from baseline to day 180 were significantly reduced. No serious device-related AEs and nine nonserious AEs (three device-related) were reported. Intraocular pressure remained stable and most subjects showed little or no change in visual acuity at days 30 and 180. No significant findings from other clinical examinations were noted. CONCLUSION: Neurostimulation of the nasolacrimal pathway is a safe and effective means of increasing tear production and reducing symptoms of dry eye in patients with DED. PMID- 27217722 TI - Erratum: Efficacy and safety of different doses of a slow-release corticosteroid implant for macular edema [Corrigendum]. AB - [This corrects the article on p. 2527 in vol. 9.]. PMID- 27217721 TI - Efficacy and safety of different doses of a slow release corticosteroid implant for macular edema. PMID- 27217720 TI - Design, synthesis, and biological evaluation of 3-vinyl-quinoxalin-2(1H)-one derivatives as novel antitumor inhibitors of FGFR1. AB - FGFR1 is well known as a molecular target in anticancer drug design. TKI258 plays an important role in RTK inhibitors. Utilizing TKI258 as a lead compound that contains a quinazolinone nucleus, we synthesized four series of 3-vinyl quinoxalin-2(1H)-one derivatives, a total of 27 compounds. We further evaluated these compounds for FGFR1 inhibition ability as well as cytotoxicity against four cancer cell lines (H460, B16-F10, Hela229, and Hct116) in vitro. Some compounds displayed good-to-excellent potency against the four tested cancer cell lines compared with TKI258. Structure-activity relationship analyses indicated that small substituents at the side chain of the 3-vinyl-quinoxalin-2(1H)-one were more effective than large substituents. Lastly, we used molecular docking to obtain further insight into the interactions between the compounds and FGFR1. PMID- 27217723 TI - Simultaneous targeting of MyD88 and Nur77 as an effective approach for the treatment of inflammatory diseases. AB - Myeloid differentiation primary response protein 88 (MyD88) has long been considered a central player in the inflammatory pathway. Recent studies clearly suggest that it is an important therapeutic target in inflammation. On the other hand, a recent study on the interaction between the orphan nuclear receptor (Nur77) and p38alpha, leading to increased lipopolysaccharide-induced hyperinflammatory response, suggests this binary complex as a therapeutic target. In this study, we have designed inhibitors that can inhibit both MyD88 and Nur77 at the same time. Since both MyD88 and Nur77 are an integral part of the pathways involving lipopolysaccharide-induced activation of NF-kappaB-mediated inflammation, we tried to target both proteins with the same library in order to retrieve compounds having dual inhibitory properties. To perform this, we developed a homodimeric model of MyD88 and, along with the crystal structure of Nur77, screened a virtual library of compounds from the traditional Chinese medicine database containing ~61,000 compounds. We analyzed the resulting hits for their efficacy for dual binding and probed them for developing a common pharmacophore model that could be used as a prototype to screen compound libraries as well as to guide combinatorial library design to search for ideal dual-target inhibitors. Thus, our study explores the identification of novel leads having dual inhibiting effects due to binding to both MyD88 and Nur77 targets. PMID- 27217724 TI - Fimasartan for independent reduction of blood pressure variability in mild-to moderate hypertension. AB - BACKGROUND: The angiotensin receptor antagonist fimasartan lowered blood pressure (BP) in a previous large population study. The purpose of this study was to evaluate whether fimasartan treatment for 3 months affects clinical and home BP variability in addition to reducing BP. METHODS: The study enrolled 1,396 patients (mean age 56.2+/-10.0 years; males 53.6%) with mild-to-moderate hypertension who had a complete set of home BP measurements (morning and evening) and metabolic risk evaluation. During the 3 months of study, fimasartan alone was used to control BP at a daily dose of 30-120 mg. Clinical and home BP measurements were performed before and after the 3-month treatment. BP variability included beat-to-beat variability (clinical) and day-to-day variability (home). RESULTS: Fimasartan reduced BP after 3 months of treatment. The average reduction of clinical systolic BP (c-SBP) was 15.08+/-18.36 mmHg (P<0.0001), and the average reduction of morning home SBP (m-SBP) was 11.49+/ 19.33 mmHg (P<0.0001). Beat-to-beat variability as standard deviation (SD) of c SBP was reduced from 4.56+/-3.22 to 4.24+/-3.11 mmHg (P=0.0026). Day-to-day variability as SD of m-SBP was reduced from 7.92+/-6.74 to 6.95+/-4.97 mmHg (P<0.0001). Multiple regression analysis revealed an independent association between the change in the SD of c-SBP and the change in c-SBP (P=0.0268) and, similarly, between the change in the SD of m-SBP and the change in m-SBP (P=0.0258), after adjusting for age, sex, body mass index, and change in mean BP. CONCLUSION: This study indicated that 3 months of fimasartan treatment reduced day-to-day BP variability independent of BP reduction in patients with hypertension. PMID- 27217725 TI - Spirolactone provides protection from renal fibrosis by inhibiting the endothelial-mesenchymal transition in isoprenaline-induced heart failure in rats. AB - BACKGROUND: Fibrosis results in excessive accumulation of extracellular matrix proteins, collagen component alteration, and abnormalities in structure and is partly derived from a process called the endothelial-mesenchymal transition involving transforming growth factor beta (TGF-beta). We investigated whether spironolactone, an aldosterone receptor blocker, attenuated isoprenaline (Iso) induced heart failure in rats and also studied the mechanism for the same. METHODS: Sprague-Dawley rats were subcutaneously injected with Iso to induce heart failure, which promoted renal fibrosis; rats with spironolactone treatment were given a gavage of spironolactone (30 or 60 mg/kg/d, for 21 days). Cardiac function and fibrosis indices were measured. Pathological alterations and expression of Type I and III collagen, alpha-smooth muscle actin, cluster of differentiation-31, and TGF-beta were examined. RESULTS: In Iso-induced heart failure in rats, spironolactone significantly improved cardiac function and decreased myocardial fibrosis, reduced collagen fibrous proliferation in kidney, reduced expression of Type I and III collagen, increased the expression of cluster of differentiation-31, and decreased the expression of alpha-smooth muscle actin and TGF-beta. CONCLUSION: Spironolactone may prevent renal fibrosis by inhibiting the endothelial-mesenchymal transition. PMID- 27217726 TI - Treatment adherence to disease-modifying antirheumatic drugs in Chinese patients with rheumatoid arthritis. AB - OBJECTIVE: Nonadherence in rheumatoid arthritis (RA) patients using disease modifying antirheumatic drugs (DMARDs) may lead to joint damage and function loss. The aim of this cross-sectional study was to explore Chinese RA patients' adherence rates and investigate potential risk factors for nonadherence. METHODS: A total of 122 RA patients were recruited from the Affiliated Hospital of Nantong University from January 2014 to April 2015. Patients were asked to complete a set of standardized self-report questionnaires (Compliance Questionnaire on Rheumatology, Health Assessment Questionnaire, Short Form-36 questionnaire, 28 joint Disease Activity Score, Hospital Anxiety and Depression Scale, and Visual Analog Scale). Independent samples t-tests, chi-square analyses, and logistic regression modeling were used to analyze these data. RESULTS: Based on Compliance Questionnaire on Rheumatology, 38% of the patients adhered to DMARDs. Adherence was associated with education, income, depression, and the total number of DMARDs. Other demographic and clinical characteristics were not associated with adherence. Logistic regression models identified income, depression, and the total number of DMARDs as predictors of medication nonadherence. CONCLUSION: In this study, 62% of patients with RA were not adherent to their DMARD prescription. Education, income, depression, and the total number of DMARDs were associated with medication adherence, and income, depression, and the total number of DMARDs were independent predictors of medication adherence in patients with RA. These findings could help medical personnel develop helpful interventions to improve adherence in RA patients by paying more attention to the patients with these accompanying risk factors and, finally, improve RA patients' quality of life. PMID- 27217727 TI - Concordance between two methods in measuring treatment adherence in patients with type 2 diabetes. AB - OBJECTIVE: We analyzed the concordance between two methods for measuring treatment adherence (TA) and studied the determinants of TA in patients with type 2 diabetes mellitus. METHODS: We conducted a cross-sectional descriptive study in a primary care center, involving 320 diabetic patients. TA was measured using the Haynes-Sackett (H-S) adherence test during the patient interview and based on pharmacy refill data. TA was calculated globally and by drug groups (antihypertensive, lipid-lowering, and antidiabetic drugs). RESULTS: Poor TA as measured by the H-S test was observed in 11.2% of the patients. Based on pharmacy refill data, there was a poor global TA rate of 30.3%, which was 33.3%, 26.6%, and 34.2% for oral antidiabetic, antihypertensive, and lipid-lowering drugs, respectively. Concordance between the two methods was poor. There was no relationship between the degree of disease control and TA as measured by the H-S test. Good TA measured based on pharmacy refill data for antidiabetic and antihypertensive drugs was associated with lower glycosylated hemoglobin and diastolic blood pressure values, respectively. Patients with good global TA showed lower glycosylated hemoglobin, diastolic blood pressure, and low-density lipoprotein cholesterol values. The multivariate analysis found good oral antidiabetic adherence to be associated to free pharmacy service; good antihypertensive drug adherence to the existence of comorbidities; and good lipid lowering drug adherence to a history of ischemic heart disease, and a more experienced physician and/or female physician. CONCLUSION: Concordance between the two methods in assessing TA was low. Approximately one-third of the patients with type 2 diabetes mellitus presented poor TA in relation to antihypertensive, lipid-lowering, and antidiabetic medication. An improved TA was associated with a better control of the studied parameters. Comorbidities, such as ischemic heart disease and access to free pharmacy service, were identified as determinants of good TA. PMID- 27217728 TI - Naltrexone HCI/bupropion HCI for chronic weight management in obese adults: patient selection and perspectives. AB - Naltrexone, an opiate antagonist, and bupropion, a noradrenergic/dopaminergic antidepressant, have many effects on the reward systems of the brain. These medications impact eating behavior, presumably via their impact on food reward. However, only bupropion induces weight loss in obese individuals, while naltrexone does not have any appreciable effect. The combination of 32 mg of naltrexone and 360 mg of bupropion in a sustained-release combination pill form has been recently approved for obesity treatment. Studies have shown that the combination of these two medications is more effective in inducing weight loss, when combined with lifestyle intervention and calorie reduction, than each individual medicine alone. The naltrexone-bupropion combination, when combined with lifestyle intervention and modest calorie reduction, seems to be quite effective for 6-month and 1-year outcomes for clinically significant weight loss (over 5% of total body weight). These medications are not devoid of serious side effects, however, and careful patient selection can reduce dramatic complications and increase positive outcomes. This paper reviews existing weight loss clinical trials with bupropion and the bupropion-naltrexone combination. Additionally, the rationale for the suggested patient selection and clinical strategies for special patient populations are discussed. PMID- 27217729 TI - Fried frailty phenotype assessment components as applied to geriatric inpatients. AB - BACKGROUND: Management of geriatric patients would be simplified if a universally accepted definition of frailty for clinical use was defined. Among definitions of frailty, Fried frailty phenotype criteria constitute a common reference frame for many geriatric studies. However, this reference frame has been tested primarily in elderly patients presenting with relatively good health status. OBJECTIVE: The aim of this article was to assess the usefulness and limitations of Fried frailty phenotype criteria in geriatric inpatients, characterized by comorbidity and functional impairments, and to estimate the frailty phenotype prevalence in this group. PATIENTS AND METHODS: Five hundred consecutive patients of the university hospital subacute geriatric ward, aged 79.0+/-8.4 years (67% women and 33% men), participated in this cross-sectional study. Comprehensive geriatric assessment and Fried frailty phenotype component evaluation were performed in all patients. RESULTS: Multimorbidity (6.0+/-2.8 diseases) characterized our study group, with a wide range of clinical conditions and functional states (Barthel Index of Activities of Daily Living 72.2+/-28.2 and Mini-Mental State Examination 23.6+/ 7.1 scores). All five Fried frailty components were assessed in 65% of patients (95% confidence interval [CI] =60.8-69.2) (diagnostic group). One or more components were not feasible to be assessed in 35% of the remaining patients (nondiagnostic group) because of lack of past patient's body mass control and/or cognitive or physical impairment. Patients from the nondiagnostic group, as compared to patients from the diagnostic group, presented with more advanced age, higher prevalence of dementia, lower prevalence of hypertension, lower systolic and diastolic blood pressure, body mass index, Mini-Mental State Examination and Barthel Index of Activities of Daily Living. Despite diagnostic limitations, we found >=3 positive criteria (thus, frailty diagnosis) in 54.2% of the study group (95% CI =49.8-58.6), with prevalence from 31.7% in sexagenarians to 67.6% in nonagenarians. CONCLUSION: Fried frailty phenotype criteria seem useful for geriatric inpatient assessment, despite diagnostic limitations. High prevalence of frailty among geriatric inpatients suggests that evaluation for frailty should be considered a part of the comprehensive geriatric assessment. PMID- 27217730 TI - Validation of three tools for identifying painful new osteoporotic vertebral fractures in older Chinese men: bone mineral density, Osteoporosis Self Assessment Tool for Asians, and fracture risk assessment tool. AB - OBJECTIVE: This cross-sectional study compared three tools for predicting painful new osteoporotic vertebral fractures (PNOVFs) in older Chinese men: bone mineral density (BMD), the Osteoporosis Self-Assessment Tool for Asians (OSTA), and the World Health Organization fracture risk assessment tool (FRAX) (without BMD). METHODS: Men aged >=50 years were apportioned to a group for men with fractures who had undergone percutaneous vertebroplasty (n=111), or a control group of healthy men (n=385). Fractures were verified on X-ray and magnetic resonance imaging. BMD T-scores were determined by dual energy X-ray absorptiometry. Diagnosis of osteoporosis was determined by a BMD T-score of <=2.5 standard deviations below the average for a young adult at peak bone density at the femoral neck, total hip, or L1-L4. Demographic and clinical risk factor data were self-reported through a questionnaire. BMD, OSTA, and FRAX scores were assessed for identifying PNOVFs via receiver-operating characteristic (ROC) curves. Optimal cutoff points, sensitivity, specificity, and areas under the ROC curves (AUCs) were determined. RESULTS: Between the men with fractures and the control group, there were significant differences in BMD T-scores (at femoral neck, total hip, and L1-L4), and OSTA and FRAX scores. In those with fractures, only 53.15% satisfied the criteria for osteoporosis. Compared to BMD or OSTA, the FRAX score had the best predictive value for PNOVFs: the AUC of the FRAX score (cutoff =2.9%) was 0.738, and the sensitivity and specificity were 82% and 62%, respectively. CONCLUSION: FRAX may be a valuable tool for identifying PNOVFs in older Chinese men. PMID- 27217731 TI - Depression influences the quality of diabetes-related self-management activities in elderly patients with type 2 diabetes: a cross-sectional study. AB - PURPOSE: To evaluate the prevalence of depression and its impact on the quality of diabetes-related self-care activities in elderly patients with type 2 diabetes. PATIENTS AND METHODS: In this cross-sectional study, 184 patients with type 2 diabetes were enrolled. Depression was evaluated using Patient Health Questionnaire-9 while the quality of diabetes-related self-care activities was assessed using the Summary of Diabetes-Related Self Care Activities Questionnaire. RESULTS: In our study group, 53.3% of the patients had moderate depression, 17.9% had severe depression, and 28.8% had no depression symptoms. Patient's age (P=0.024), presence of diabetic neuropathy (P<0.001), and body mass index (P=0.037) proved to be independent and significant predictors for developing depression in patients with type 2 diabetes. The severity of depression was reverse correlated with the quality of self-care activities for all the studied components: global score (r=-0.305), diet intervention score (r= 0.297), exercise score (r=-0.388), glycemic monitoring score (r=-0.055), and feet care score (r=-0.180). The presence of severe depression was associated with an increased prevalence of diabetes complications such as diabetic neuropathy and chronic kidney disease. CONCLUSION: The prevalence of depression is higher in patients with type 2 diabetes compared to general population. Depression has a major negative impact on the quality of diabetes-related self-care activities and, being a treatable condition, proactive screening followed in case of a positive diagnosis by adequate treatment should be performed in all patients with diabetes. PMID- 27217732 TI - Canada acute coronary syndrome score was a stronger baseline predictor than age >=75 years of in-hospital mortality in acute coronary syndrome patients in western Romania. AB - BACKGROUND: Several risk scores were developed for acute coronary syndrome (ACS) patients, but their use is limited by their complexity. PURPOSE: The purpose of this study was to identify predictors at admission for in-hospital mortality in ACS patients in western Romania, using a simple risk-assessment tool - the new Canada acute coronary syndrome (C-ACS) risk score. PATIENTS AND METHODS: The baseline risk of patients admitted with ACS was retrospectively assessed using the C-ACS risk score. The score ranged from 0 to 4; 1 point was assigned for the presence of each of the following parameters: age >=75 years, Killip class >1, systolic blood pressure <100 mmHg, and heart rate >100 bpm. RESULTS: A total of 960 patients with ACS were included, 409 (43%) with ST-segment elevation myocardial infarction (STEMI) and 551 (57%) with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). The C-ACS score predicted in-hospital mortality in all ACS patients with a C-statistic of 0.95 (95% CI: 0.93-0.96), in STEMI patients with a C-statistic of 0.92 (95% confidence interval [CI]: 0.89-0.94), and in NSTE-ACS patients with a C-statistic of 0.97 (95% CI: 0.95-0.98). Of the 960 patients, 218 (22.7%) were aged >=75 years. The proportion of patients aged >=75 years was 21.7% in the STEMI subgroup and 23.4% in the NSTE-ACS subgroup (P>0.05). Age >=75 years was significantly associated with in-hospital mortality in ACS patients (odds ratio [OR]: 3.25, 95% CI: 1.24-8.25) and in the STEMI subgroup (OR >3.99, 95% CI: 1.28-12.44). Female sex was strongly associated with mortality in the NSTE-ACS subgroup (OR: 27.72, 95% CI: 1.83-39.99). CONCLUSION: We conclude that C-ACS score was the strongest predictor of in-hospital mortality in all ACS patients while age >=75 years predicted the mortality well in the STEMI subgroup. PMID- 27217735 TI - Immediate results and long-term cardiovascular outcomes of endovascular therapy in octogenarians and nonoctogenarians with peripheral arterial diseases. AB - PURPOSE: To investigate the clinical outcomes of endovascular therapy (EVT) in octogenarians and nonoctogenarians with peripheral arterial disease. METHODS: A retrospective analysis of 511 patients (654 affected legs) who underwent EVT between July 2005 and December 2013 was conducted in a prospectively maintained database. Immediate results and long-term vascular outcomes were analyzed and compared between octogenarians and nonoctogenarians. RESULTS: Octogenarians were more likely to be female and have atrial fibrillation (AF), whereas nonoctogenarians had higher rates of obesity, claudication, and medical comorbidities. There were no differences in the rates of EVT success, 30-day major adverse vascular events, and 6-month functional improvement between groups. Over the 10-year follow-up period, the rates of 3-year limb salvage, sustained clinical success, freedom from major cerebrovascular and cardiovascular events, and composite vascular events were similar between groups, but the survival rate was better in nonoctogenarians than in octogenarians (73% vs 63%, respectively, P=0.004). In Cox regression analysis, dependence on dialysis and AF were significant predictors of death (odds ratio [OR] 4.44 in dialyzed and 2.83 in AF patients), major cerebrovascular and cardiovascular events (OR 3.49 and 2.45), and composite vascular events (OR 3.14 and 2.25). CONCLUSION: EVT in octogenarians was feasible, without an increased risk of periprocedural complications. The rates of limb salvage, sustained clinical success, and long term vascular events were comparable between groups. Dialysis dependence and AF are independent predictors for poor prognosis in patients with peripheral arterial disease. However, these observations require further confirmation in larger scale studies. PMID- 27217734 TI - Correlation between vitamin D levels and apoptosis in geriatric patients infected with hepatitis C virus genotype 4. AB - BACKGROUND: Vitamin D levels play a pivotal role in most biological processes and differ according to age. A deficiency of vitamin D in chronic hepatitis C (CHC) patients has been shown to be linked with the severity of liver fibrosis, but little is known about the mechanism of this association. OBJECTIVE: In this study, we evaluate the potential interrelation between vitamin D levels, oxidative stress, and apoptosis, based on liver fibrosis in geriatric patients infected with hepatitis C virus (HCV) genotype 4. SUBJECTS AND METHODS: A total of 120 adult individuals aged 30-68 years were recruited in this study. Of these, 20 healthy subjects (15 men and five women) with a mean age of 48.3+/-6.1 years were selected as controls, and 100 patients with a mean age of 47.8+/-4.9 years with chronic HCV (CHC) who had undergone liver biopsy (80 men and 20 women) were included in this study. Based on liver radiographic (computed tomography, magnetic resonance imaging) and histological Metavir system analyses, the CHC patients were classified into three groups: asymptomatic CHC carriers (n=30), fibrosis (n=25), and cirrhosis (n=45). HCV RNA, HCV genotypes, inflammatory cytokines AFP and TNFalpha, 25-hydroxyvitamin D (25[OH]D) levels, apoptotic markers single-stranded DNA (ssDNA) and soluble Fas (sFas), and oxidative stress markers nitric oxide (NO) and total antioxidant capacity (TAC) were estimated by using molecular, immunoassay, and colorimetric techniques. RESULTS: Approximately 30% of the study population (n=30) were diagnosed as asymptomatic CHC carriers, and 70% of the study population (n=70) had severe fibrosis; these were classified into fibrosis and cirrhosis. There was a significant reduction in 25(OH)D levels and TAC activity, along with an increase in levels of NO, AFP, TNFalpha, ssDNA, and sFas in fibrosis and cirrhosis subjects compared with those of asymptomatic CHC carriers and health controls. The deficiency in 25(OH)D levels correlated positively with sFas, ssDNA, AFP, TNFalpha, NO, and TAC, and negatively with age, sex, liver function, body mass index, homeostatic model assessment - insulin resistance, HCV RNA, and viral load. Significant intercorrelation was reported between serum 25(OH)D concentrations and apoptotic and oxidative markers, which suggested progression of liver pathogenesis and fibrogenesis via oxidative and apoptotic mechanisms. CONCLUSION: The data showed that vitamin D status was significantly correlated with pathogenesis and fibrogenesis of the liver in geriatric patients infected with HCV genotype 4. The deficiency in 25(OH)D levels was shown to have a pivotal role in the pathogenesis of liver via apoptotic, oxidative stress, and inflammatory mechanistic pathways. The data point to adequate vitamin D levels being recommended for a good response to treatment strategies, especially in older CHC patients. PMID- 27217733 TI - Correlation between vitamin D levels and muscle fatigue risk factors based on physical activity in healthy older adults. AB - PURPOSE: The purpose of this study was to investigate the relationship of serum vitamin D levels with physical activity, obesity, muscle fatigue biomarkers, and total antioxidant capacity (TAC) in healthy older adults. METHODS: A total of 85 healthy older subjects aged 64-96 years were recruited in this study. Based on estimated energy expenditure scores, the participants were classified into three groups: inactive (n=25), moderate (n=20), and physically active (n=35). Serum 25(OH)D (25-hydroxy vitamin D) levels, metabolic syndrome parameters, TAC activity, muscle fatigue biomarkers (Ca, creatine kinase, lactic acid dehydrogenase, troponin I, hydroxyproline), physical activity, body fatness, and fatigue score (visual analog scale) were estimated using immunoassay techniques and prevalidated questionnaires, respectively. RESULTS: Physical activity was estimated in 64.6% of the participants. Males showed higher physical activity (42.5%) compared to females (26.25%). Compared to participants with lower activity, significant reduction in body mass index, waist circumference, hips, fasting blood sugar, triglycerides, total cholesterol, HDL-cholesterol, and LDL cholesterol were observed in moderate and physically active participants. Also, significant increase in the levels of serum 25(OH)D concentrations, calcium, and TAC activity along with reduction in the levels of muscle fatigue biomarkers: creatine kinase, lactic acid dehydrogenase, troponin I, hydroxyproline, and fatigue scores (visual analog scale) were reported in physically active participants compared to those of lower physical activity. In all participants, serum 25(OH)D concentrations correlated positively with Ca, TAC, physical activity scores, and negatively with body mass index, lipid profile, fatigue scores (visual analog scale), and muscle fatigue biomarkers. Stepwise regression analysis showed that serum 25(OH)D concentrations, physical activity, Ca, TAC, and demographic parameters explained approximately 61.4%-85.8% of reduction in both fatigue scores and muscle fatigue biomarkers with substantial improvement in muscle performance in healthy older adults. CONCLUSION: The data showed that considerable levels of 25(OH)D concentrations, calcium intake, and lower obesity positively correlated with the improvement in the muscle relief and performance of physically active participants. These results demonstrate that 25(OH)D concentrations and calcium might prevent muscle fatigue by regulation of the biosynthesis of creatine kinase, lactic acid dehydrogenase, troponin I, and hydroxyproline via a proposed antifree radical mechanism reported by higher TAC activity. It was suggested that vitamin D status could be reported as a marker of the improvement of muscle performance, especially in healthy older adults with lower physical activity. PMID- 27217736 TI - Is older adult care mediated by caregivers' cultural stereotypes? The role of competence and warmth attribution. AB - PURPOSE: The purpose of this study is to examine, from the stereotype content model (SCM) perspective, the role of the competence and warmth stereotypes of older adults held by professional caregivers. METHODS: A quasi-experimental design, ex post facto with observational analyses, was used in this study. The cultural view on competence and warmth was assessed in 100 caregivers working in a set of six residential geriatric care units (three of them organized following a person-centered care approach and the other three providing standard geriatric care). In order to assess caregivers' cultural stereotypical views, the SCM questionnaire was administered. To evaluate the role of caregivers' cultural stereotypes in their professional performance as well as in older adult functioning, two observational scales from the Sistema de Evaluacion de Residencias de Ancianos (assessment system for older adults residences)-RS (staff functioning and residents' functioning) were applied. RESULTS: Caregivers' cultural views of older adults (compared to young people) are characterized by low competence and high warmth, replicating the data obtained elsewhere from the SCM. Most importantly, the person-centered units predict better staff performance and better resident functioning than standard units. Moreover, cultural stereotyping of older adult competence moderates the effects of staff performance on resident functioning, in line with the findings of previous research. CONCLUSION: Our results underline the influence of caregivers' cultural stereotypes on the type of care, as well as on their professional behaviors and on older adult functioning. Caregivers' cultural stereotypes could be considered as a central issue in older adult care since they mediate the triangle of care: caregivers/older adults/type of care; therefore, much more attention should be paid to this psychosocial care component. PMID- 27217737 TI - Frailty and quality of life in elderly patients with acute coronary syndrome. AB - BACKGROUND: Frail elderly people are at risk of developing adverse health outcomes such as disability, hospitalization, and mortality. In recent years, the literature has drawn attention to the role of frailty syndrome (FS) in acute coronary syndrome (ACS). There are few studies regarding the relationship between two multidimensional variables such as FS and quality of life (QoL). OBJECTIVE: The aim of the study was to investigate the relationship between FS and early QoL of elderly patients with ACS (>=65 years old). METHODS: The study was conducted among 91 patients aged 65 years and over with ACS. The MacNew questionnaire was used to evaluate QoL and the Tilburg frailty indicator to evaluate frailty. RESULTS: FS was present in 82.4% of patients. The average Tilburg frailty indicator score was 7.43+/-2.57. A negative correlation between the global values of FS and QoL was shown (r=-0.549, P<0.05). The vulnerability factors that negatively affected early QoL were: FS, marital status, conservative therapy, and hypertension. In multivariate analysis, FS was found to be the independent predictor of worse QoL (beta +/- standard error -0.277+/-0.122, P=0.026). CONCLUSION: The presence of FS has a negative impact on early QoL in patients with ACS. The study suggests that in elderly patients with ACS, there is a need to identify frailty in order to implement additional therapeutic and nursing strategies in ACS. PMID- 27217738 TI - Clinical assessment tools identify functional deficits in fragility fracture patients. AB - PURPOSE: To identify inexpensive, noninvasive, portable, clinical assessment tools that can be used to assess functional performance measures that may put older patients at risk for falls such as balance, handgrip strength, and lumbopelvic control. PATIENTS AND METHODS: Twenty fragility fracture patients and 21 healthy control subjects were evaluated using clinical assessment tools (Nintendo Wii Balance Board [WBB], a handheld dynamometer, and an application for the Apple iPod Touch, the Level Belt) that measure functional performance during activity of daily living tasks. The main outcome measurements were balance (WBB), handgrip strength (handheld dynamometer), and lumbopelvic control (iPod Touch Level Belt), which were compared between fragility fracture patients and healthy controls. RESULTS: Fragility fracture patients had lower scores on the vertical component of the WBB Torso Twist task (P=0.042) and greater medial-lateral lumbopelvic sway during a 40 m walk (P=0.026) when compared to healthy controls. Unexpectedly, the fracture patients had significantly higher scores on the left leg (P=0.020) and total components (P=0.010) of the WBB Single Leg Stand task as well as less faults during the left Single Leg Stand task (P=0.003). CONCLUSION: The clinical assessment tools utilized in this study are relatively inexpensive and portable tools of performance measures capable of detecting differences in postural sway between fragility fracture patients and controls. PMID- 27217739 TI - Prognostic utility of the 2011 GOLD classification and other multidimensional tools in Asian COPD patients: a prospective cohort study. AB - BACKGROUND: How well the 2011 Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification prognosticates for Asian patients with COPD is unknown. OBJECTIVE: The authors aimed to study the predictive utility of the GOLD 2011 classification for exacerbations and mortality as compared with other multidimensional tools in an Asian population. METHODS: In all, 1,110 COPD patients were prospectively followed between March 2008 and March 2013. They were classified using the 2011 and 2007 GOLD guidelines, modified Medical Research Council score, St. George's Respiratory Questionnaire (SGRQ), and Body mass index, Obstruction, Dyspnea (BOD) index. Outcome measures were exacerbations and mortality. Multivariable survival analyses and receiver operating characteristic (ROC) curves were used to assess the different classification systems. RESULTS: Time-to-event analyses demonstrated earlier exacerbations in 2011's GOLD D when compared with GOLD A (hazard ratio [HR] 0.54, 95% confidence interval [CI]: 0.31 0.95, P=0.032) and GOLD B (HR 0.62, 95% CI: 0.45-0.85, P=0.003) and higher mortality when compared with GOLD A (HR 0.37, 95% CI: 0.16-0.88, P=0.025) and GOLD B (HR 0.46, 95% CI: 0.31-0.70, P<0.001). The areas under the ROC curve for GOLD 2011, GOLD 2007, modified Medical Research Council, St. George's Respiratory Questionnaire, and BOD index were 0.62, 0.59, 0.61, 0.60, and 0.61, respectively, for the prediction of exacerbations and 0.71, 0.70, 0.71, 0.71, and 0.72, respectively, for the prediction of mortality (ROC comparator, P>0.05). CONCLUSION: The 2011 GOLD classification predicts exacerbations and mortality moderately well in Asian COPD patients. Its prognostic utility is similar to that of other multidimensional systems. PMID- 27217740 TI - Prevalence of airflow limitation in subjects undergoing comprehensive health examination in Japan: Survey of Chronic Obstructive pulmonary disease Patients Epidemiology in Japan. AB - PURPOSE: There are still evidence gaps on the prevalence of airflow limitation in Japan. The purpose of this survey was to estimate the prevalence of airflow limitation among healthy subjects in Japan and to show what proportion of subjects with airflow limitation had been diagnosed with chronic obstructive pulmonary disease (COPD). SUBJECTS AND METHODS: This was an observational, cross sectional survey targeting multiple regions of Japan. Subjects aged 40 years or above who were undergoing comprehensive health examination were recruited from 14 centers in Japan. Airflow limitation was defined as having forced expiratory volume in 1 second/forced vital capacity less than 70%. RESULTS: In a total of 22,293 subjects, airflow limitation was most prevalent in subjects aged over 60 years (8.7%), but was also observed in subjects aged 50-59 years (3.1%) and 40-49 years (1.7%). Overall prevalence was 4.3%. Among subjects with smoking history (n=10,981), the prevalence of airflow limitation in each age group (12.8% in those aged over 60 years, 4.4% in those aged 50-59 years, and 2.2% in those aged 40-49 years) and overall prevalence (6.1%) were higher than that of total subjects. Of the smokers with airflow limitation, 9.4% had been diagnosed with COPD/emphysema and 27.3% with other respiratory diseases. CONCLUSION: Among smokers undergoing comprehensive health examination, prevalence of airflow limitation reached 12.8% in those aged over 60 years and airflow limitation was observed in subjects aged 40-59 years as well, though their prevalence was lower than that in subjects aged over 60 years. We demonstrated that a significant proportion of smokers with airflow limitation had not been diagnosed with COPD/emphysema, suggesting that some of them can be diagnosed with COPD or other respiratory diseases by a detailed examination after comprehensive health examination. Screening for subjects at risk of COPD by spirometry in comprehensive health examination starting at 40 years of age, followed by a detailed examination, may be an effective approach to increase the diagnosis of COPD. PMID- 27217741 TI - Health behaviors and their correlates among participants in the Continuing to Confront COPD International Patient Survey. AB - BACKGROUND AND AIMS: We used data from the Continuing to Confront COPD International Patient Survey to test the hypothesis that patients with COPD who report less engagement with their disease management are also more likely to report greater impact of the disease. METHODS: This was a population-based, cross sectional survey of 4,343 subjects aged >=40 years from 12 countries, fulfilling a case definition of COPD based on self-reported physician diagnosis or symptomatology. The impact of COPD was measured with COPD Assessment Test, modified Medical Research Council Dyspnea Scale, and hospital admissions and emergency department visits for COPD in the prior year. The 13-item Patient Activation Measure (PAM-13) instrument and the 8-item Morisky Medication Adherence Scale (MMAS-8) were used to measure patient disease engagement and medication adherence, respectively. RESULTS: Twenty-eight percent of subjects reported being either disengaged or struggling with their disease (low engagement: PAM-13 levels 1 and 2), and 35% reported poor adherence (MMAS-8 <6). In univariate analyses, lower PAM-13 and MMAS-8 scores were significantly associated with poorer COPD-specific health status, greater breathlessness and lower BMI (PAM-13 only), less satisfaction with their doctor's management of COPD, and more emergency department visits. In multivariate regression models, poor satisfaction with their doctor's management of COPD was significantly associated with both low PAM-13 and MMAS-8 scores; low PAM-13 scores were additionally independently associated with higher COPD Assessment Test and modified Medical Research Council scores and low BMI (underweight). CONCLUSION: Poor patient engagement and medication adherence are frequent and associated with worse COPD-specific health status, higher health care utilization, and lower satisfaction with health care providers. More research will be needed to better understand what factors can be modified to improve medication adherence and patient engagement. PMID- 27217742 TI - Impact of tiotropium + olodaterol on physical functioning in COPD: results of an open-label observational study. AB - BACKGROUND: Maintaining and improving physical functioning is key to mitigating the cycle of deconditioning associated with chronic obstructive pulmonary disease (COPD). We evaluated the impact of free combination of the long-acting anticholinergic tiotropium plus the long-acting beta2-agonist olodaterol on physical functioning in a real-world clinical setting. METHODS: In this open label noninterventional study, Global initiative for chronic Obstructive Lung Disease (GOLD) B-D patients with COPD aged >=40 years were treated for 4-6 weeks with either tiotropium 5 MUg + olodaterol 5 MUg (both via Respimat((r)) inhaler) or tiotropium 18 MUg (HandiHaler((r))) + olodaterol 5 MUg (Respimat((r))) once daily. Physical functioning was assessed by the self-reported 10-item Physical Functioning Questionnaire (PF-10). The primary end point was the percentage of patients achieving therapeutic success, defined as a 10-point increase in the PF 10 between baseline (visit 1) and weeks 4-6 (visit 2). Secondary end points included absolute PF-10 scores, Physicians' Global Evaluation, satisfaction with Respimat((r)) and adverse events. RESULTS: A total of 1,858 patients were treated: 1,298 (69.9%) with tiotropium 5 MUg + olodaterol 5 MUg and 560 (30.1%) with tiotropium 18 MUg + olodaterol 5 MUg. At study end, 1,683 (92.6%) and 1,556 patients (85.6%) continued using tiotropium and olodaterol, respectively; 48.9% (95% confidence interval: 46.5, 51.3) achieved the primary end point. Therapeutic success rates were significantly higher for maintenance-naive patients compared to those who had received prior therapy (59.1% vs 44.5%; P<0.0001), largely driven by maintenance-treatment-naive GOLD B (59.8%) and C (63.0%) patients. Absolute physical functioning scores increased from an average baseline of 44.0 (standard deviation: 25.2) to 54.2 (standard deviation: 26.9) at visit 2. Patients' general condition improved from baseline to visit 2, and patients were largely satisfied with the Respimat((r)) inhaler. Adverse events were reported by 7.5% of patients; the most common were respiratory in nature. CONCLUSION: Tiotropium + olodaterol improved physical functioning within 4-6 weeks in patients with moderate-to-very severe COPD. GOLD B and C patients with no prior maintenance treatment demonstrated the greatest benefit. PMID- 27217743 TI - Assisted ventilation in COPD - association between previous hospitalizations and mortality. AB - BACKGROUND: In general, previous studies have shown an association between prior exacerbations and mortality in COPD, but this association has not been demonstrated in the subpopulation of patients in need of assisted ventilation. We examined whether previous hospitalizations were independently associated with mortality among patients with COPD ventilated for the first time. PATIENTS AND METHODS: In the Danish National Patient Registry, we established a cohort of patients with COPD ventilated for the first time from 2003 to 2011 and previously medicated for obstructive airway diseases. We assessed the number of hospitalizations for COPD in the preceding year, age, sex, comorbidity, mode of ventilation, survival to discharge, and days to death beyond discharge. RESULTS: The cohort consisted of 6,656 patients of whom 66% had not been hospitalized for COPD in the previous year, 18% once, 8% twice, and 9% thrice or more. In-hospital mortality was 45%, and of the patients alive at discharge, 11% died within a month and 39% within a year. In multivariate models, adjusted for age, sex, mode of ventilation, and comorbidity, odds ratios for in-hospital death were 1.26 (95% confidence interval [CI]: 1.11-1.44), 1.43 (95% CI: 1.19-1.72), and 1.56 (95% CI: 1.30-1.87) with one, two, and three or more hospitalizations, respectively. Hazard ratios for death after discharge from hospital were 1.32 (95% CI: 1.19 1.46), 1.76 (95% CI: 1.52-2.02), and 2.07 (95% CI: 1.80-2.38) with one, two, and three or more hospitalizations, respectively. CONCLUSION: Preceding hospitalizations for COPD are associated with in-hospital mortality and after discharge in the subpopulation of patients with COPD with acute exacerbation treated with assisted ventilation for the first time. PMID- 27217744 TI - Matrix metalloproteinases-2/9-sensitive peptide-conjugated polymer micelles for site-specific release of drugs and enhancing tumor accumulation: preparation and in vitro and in vivo evaluation. AB - Since elevated expression of matrix metalloproteinase (MMP)-2 and MMP-9 is commonly observed in several malignant tumors, MMPs have been widely reported as key factors in the design of drug delivery systems. Several strategies have been proposed to develop MMPs-responsive nanoparticles to deliver chemotherapeutics to malignant solid tumors. A stimuli-responsive drug delivery system, which could be cleaved by MMPs, was proposed in this study. By inserting an MMP-2/9 cleavable oligopeptide GPVGLIGK-NH2 (GK8) as spacer between alpha-tocopherol succinate (alpha-TOS) and methoxy-polyethylene glycol molecular weight (MW 2000 Da) activated by N-hydroxysuccinimide (mPEG2K-NHS), mPEG2K-GK8-alpha-TOS (TGK) was synthesized as the primary ingredient for MMP-2/9-sensitive micelles composed of d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) and TGK (n:n =40:60, TGK micelles). mPEG2K-alpha-TOS (T2K) was similarly synthesized as nonsensitive control. The TGK micelles showed better stability than nonsensitive micelles composed of TPGS and T2K (n:n =40:60, T2K micelles) owing to the inserted peptide. Fluorescence resonance energy transfer results indicated that TGK micelles could be successfully cleaved by MMP-2/9. Effective drug release was demonstrated in the presence of collagenase type IV, a mixture of MMP-2 and MMP 9. Compared with nonsensitive micelles, docetaxel (DTX)-loaded TGK micelles showed a fold higher cellular uptake in HT1080 cells. While the half-maximal inhibitory concentration (IC50) of TGK and T2K micelles were similar (P>0.05) in MCF-7 cells (MMP-2/9 underexpression), the IC50 values of the aforementioned micelles were 0.064+/-0.006 and 0.122+/-0.009 MUg/mL, respectively, in HT1080 cells (MMP-2/9 overexpression). The MMP-2/9-sensitive micelles also demonstrated desired tumor targeting and accumulation ability in vivo. The results of in vivo antitumor effect evaluation indicate that TGK micelles are potent against solid tumors while maintaining minimum systemic toxicity compared with T2K micelles and DTX. PMID- 27217745 TI - Biomimetic synthesis of antimicrobial silver nanoparticles using in vitro propagated plantlets of a medicinally important endangered species: Phlomis bracteosa. AB - In vitro-derived cultures of plants offer a great potential for rapid biosynthesis of chemical-free antimicrobial silver nanoparticles (AgNPs) by enhancing their phytochemical reducing potential. Here, we developed an efficient protocol for in vitro micropropagation of a high-value endangered medicinal plant species, Phlomis bracteosa, in order to explore its biogenic potential in biomimetic synthesis of antimicrobial AgNPs. Murashige and Skoog medium supplemented with 2.0 mg/L thidiazuron was found to be more efficient in inducing optimum in vitro shoot regeneration (78%+/-4.09%), and 2.0 mg/L indole-3-butyric acid was used for maximum root induction (86%+/-4.457%). Antimicrobial AgNPs were successfully synthesized by using aqueous extract (rich in total phenolics and flavonoids content) of in vitro derived plantlets of P. bracteosa. Ultraviolet visible spectroscopy of synthesized AgNPs showed characteristic surface plasmon band in the range of 420-429 nm. The crystallinity, size, and shape of the AgNPs were characterized by X-ray diffraction and scanning electron microscopy. Face centered cubic AgNPs of almost uniform spherical size (22.41 nm) were synthesized within a short time (1 hour) at room temperature. Fourier-transform infrared spectroscopy revealed that the polyphenols were mainly responsible for reduction and capping of synthesized AgNPs. Energy dispersive X-ray analysis further endorsed the presence of elemental silver in synthesized AgNPs. These biosynthesized AgNPs displayed significantly higher bactericidal activity against multiple drug-resistant human pathogens. The present work highlighted the potent role of in vitro-derived plantlets of P. bracteosa for feasible biosynthesis of antimicrobial AgNPs, which can be used as nanomedicines in many biomedical applications. PMID- 27217746 TI - Synthesis, characterization, and evaluation of mPEG-SN38 and mPEG-PLA-SN38 micelles for cancer therapy. AB - 7-Ethyl-10-hydroxy camptothecin (SN38) is a potent topoisomerase inhibitor and a metabolite of irinotecan. Its clinical development has been hampered by its poor solubility. To address this problem, methoxy poly(ethylene glycol)-2000 (mPEG2K) SN38 and mPEG2K-poly(lactide) (PLA1.5K)-SN38 conjugates were prepared and then dispersed into an aqueous medium to form micelles. Physicochemical characteristics of SN38-polymer conjugate micelles, for example, micelle diameter, zeta potential, morphology, and drug content, were then evaluated. The results showed that the mean diameters of mPEG2K-SN38 and mPEG2K-PLA1.5K-SN38 micelles were ~130 and 20 nm, respectively. These two micelles had similar drug contents. mPEG2K-PLA1.5K-SN38 micelles were more homogeneous than mPEG2K-SN38 micelles. Moreover, in vitro drug release behavior of the micelles was studied by high performance liquid chromatography. SN38 release from mPEG2K-SN38 micelles was much faster than from mPEG2K-PLA1.5K-SN38 micelles. In vitro cytotoxicity, cellular uptake, and apoptosis assays of the SN38-polymer conjugate micelles were carried out on BEL-7402 human liver cancer cells. In vivo biodistribution and antitumor tumor efficacy studies were carried out in a nude mouse xenograft model derived from BEL-7402 cells. The results showed that mPEG2K-PLA1.5K-SN38 micelles were significantly more effective than mPEG2K-SN38 micelles in tumor inhibition, and the inhibitory effect of mPEG2K-PLA1.5K-SN38 micelles on tumor growth was significantly greater than that of mPEG2K-SN38 micelles (1,042 vs 1,837 mm) at 30 days. In conclusion, mPEG-PLA-SN38 is a promising anticancer agent that warrants further investigation. PMID- 27217747 TI - Development and evaluation of vitamin E d-alpha-tocopheryl polyethylene glycol 1000 succinate-mixed polymeric phospholipid micelles of berberine as an anticancer nanopharmaceutical. AB - Berberine (Brb) is an active alkaloid occurring in various common plant species, with well-recognized potential for cancer therapy. Brb not only augments the efficacy of antineoplastic chemotherapy and radiotherapy but also exhibits direct antimitotic and proapoptotic actions, along with distinct antiangiogenic and antimetastatic activities in a variety of tumors. Despite its low systemic toxicity, several pharmaceutical challenges limit the application of Brb in cancer therapy (ie, extremely low solubility and permeability, very poor pharmacokinetics (PKs), and oral bioavailability). Among lipid-based nanocarriers investigated recently for Brb, stealth amphiphilic micelles of polymeric phospholipid conjugates were studied here as a promising strategy to improve Brb delivery to tumors. Specifically, physicochemically stable micelles made of 1,2 distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (PEG-PE) mixed with d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) (PEG-succinate ester of vitamin E), in a 3:1 M ratio, increased Brb solubilization by 300%. Our PEG-PE/TPGS-mixed micelles firmly retained the incorporated Brb, displaying extended-release profile in simulated media, with up to 30-fold projected improvement in simulated PKs of Brb. Owing to the markedly better uptake of Brb-containing mixed micelles in vitro, our Brb-mixed micelles nanoformulation significantly amplified apoptosis and overall cytotoxic effectiveness against monolayer and spheroid cultures of human prostate carcinomas (16- to 18-fold lower half-maximal inhibitory concentration values in PC3 and LNPaC, respectively), compared to free Brb. Mixed PEG-PE/TPGS micelles represent a promising delivery platform for the sparingly soluble anticancer agent, Brb, encouraging further pharmaceutical development of this drug for cancer therapy. PMID- 27217748 TI - Oxidative stress response in neural stem cells exposed to different superparamagnetic iron oxide nanoparticles. AB - Biocompatibility, safety, and risk assessments of superparamagnetic iron oxide nanoparticles (SPIONs) are of the highest priority in researching their application in biomedicine. One improvement in the biological properties of SPIONs may be achieved by different functionalization and surface modifications. This study aims to investigate how a different surface functionalization of SPIONs - uncoated, coated with d-mannose, or coated with poly-l-lysine - affects biocompatibility. We sought to investigate murine neural stem cells (NSCs) as important model system for regenerative medicine. To reveal the possible mechanism of toxicity of SPIONs on NSCs, levels of reactive oxygen species, intracellular glutathione, mitochondrial membrane potential, cell-membrane potential, DNA damage, and activities of SOD and GPx were examined. Even in cases where reactive oxygen species levels were significantly lowered in NSCs exposed to SPIONs, we found depleted intracellular glutathione levels, altered activities of SOD and GPx, hyperpolarization of the mitochondrial membrane, dissipated cell membrane potential, and increased DNA damage, irrespective of the surface coating applied for SPION stabilization. Although surface coating should prevent the toxic effects of SPIONs, our results showed that all of the tested SPION types affected the NSCs similarly, indicating that mitochondrial homeostasis is their major cellular target. Despite the claimed biomedical benefits of SPIONs, the refined determination of their effects on various cellular functions presented in this work highlights the need for further safety evaluations. This investigation helps to fill the knowledge gaps on the criteria that should be considered in evaluating the biocompatibility and safety of novel nanoparticles. PMID- 27217749 TI - Initial study of sediment antagonism and characteristics of silver nanoparticle coated biliary stents in an experimental animal model. AB - OBJECTIVE: Plastic biliary stents used to relieve obstructive jaundice are frequently blocked by sediment, resulting in loss of drainage. We prepared stents coated with silver nanoparticles (AgNPs) and compared their ability to resist sedimentation with Teflon stents in a beagle model of obstructive jaundice. METHODS: AgNP-coated Teflon biliary stents were prepared by chemical oxidation reduction and evaluated in an obstructive jaundice model that was produced by ligation of common bile duct (CBD); animals were randomized to two equal groups for placement of AgNP-coated or Teflon control stents. Liver function and inflammatory index were found to be similar in the two groups, and the obstruction was relieved. Stents were removed 21 days after insertion and observed by scanning and transmission electron microscopy. The AgNP coating was analyzed by energy dispersive X-ray analysis (EDXA), and the composition of sediment was assayed by Fourier-transform infrared (FTIR) spectroscopy. RESULTS: Electron microscopy revealed a black, closely adherent AgNP stent coating, with thicknesses of 1.5-6 um. Sediment thickness and density were greater on Teflon than on AgNP-coated stents. EDXA confirmed the stability and integrity of the AgNP coating before and after in vivo animal experimentation. FTIR spectroscopy identified stent sediment components including bilirubin, cholesterol, bile acid, protein, calcium, and other substances. CONCLUSION: AgNP-coated biliary stents resisted sediment accumulation in this canine model of obstructive jaundice caused by ligation of the CBD. PMID- 27217750 TI - Effects of green-synthesized silver nanoparticles on lung cancer cells in vitro and grown as xenograft tumors in vivo. AB - Silver nanoparticles (AgNPs) have now been recognized as promising therapeutic molecules and are extending their use in cancer diagnosis and therapy. This study demonstrates for the first time the antitumor activity of green-synthesized AgNPs against lung cancer in vitro and in vivo. Cytotoxicity effect was explored on human lung cancer H1299 cells in vitro by MTT and trypan blue assays. Apoptosis was measured by morphological assessment, and nuclear factor-kappaB (NF-kappaB) transcriptional activity was determined by a luciferase reporter gene assay. The expressions of phosphorylated stat3, bcl-2, survivin, and caspase-3 were examined by Western blot analysis. AgNPs showed dose-dependent cytotoxicity and stimulation of apoptosis in H1299 cells. The effects on H1299 cells correlated well with the inhibition of NF-kappaB activity, a decrease in bcl-2, and an increase in caspase-3 and survivin expression. AgNPs significantly suppressed the H1299 tumor growth in a xenograft severe combined immunodeficient (SCID) mouse model. The results demonstrate the anticancer activities of AgNPs, suggesting that they may act as potential beneficial molecules in lung cancer chemoprevention and chemotherapy, especially for early-stage intervention. PMID- 27217751 TI - Phytogenic silver, gold, and bimetallic nanoparticles as novel antitubercular agents. AB - PURPOSE: Multi- and extensively drug-resistant tuberculosis (TB) is a global threat to human health. It requires immediate action to seek new antitubercular compounds and devise alternate strategies. Nanomaterials, in the present scenario, have opened new avenues in medicine, diagnosis, and therapeutics. In view of this, the current study aims to determine the efficacy of phytogenic metal nanoparticles to inhibit mycobacteria. METHODS: Silver (AgNPs), gold (AuNPs), and gold-silver bimetallic (Au-AgNPs) nanoparticles synthesized from medicinal plants, such as Barleria prionitis, Plumbago zeylanica, and Syzygium cumini, were tested against Mycobacterium tuberculosis and M. bovis BCG. In vitro and ex vivo macrophage infection model assays were designed to determine minimum inhibitory concentration (MIC) and half maximal inhibitory concentration of nanoparticles. Microscopic analyses were carried out to demonstrate intracellular uptake of nanoparticles in macrophages. Besides this, biocompatibility, specificity, and selectivity of nanoparticles were also established with respect to human cell lines. RESULTS: Au-AgNPs exhibited highest antitubercular activity, with MIC of <2.56 MUg/mL, followed by AgNPs. AuNPs did not show such activity at concentrations of up to 100 MUg/mL. In vitro and ex vivo macrophage infection model assays revealed the inhibition of both active and dormant stage mycobacteria on exposure to Au-AgNPs. These nanoparticles were capable of entering macrophage cells and exhibited up to 45% cytotoxicity at 30 MUg/mL (ten times MIC concentration) after 48 hours. Among these, Au-AgNPs synthesized from S. cumini were found to be more specific toward mycobacteria, with their selectivity index in the range of 94-108. CONCLUSION: This is the first study to report the antimycobacterial activity of AuNPs, AgNPs, and Au-AgNPs synthesized from medicinal plants. Among these, Au-AgNPs from S. cumini showed profound efficiency, specificity, and selectivity to kill mycobacteria. These should be investigated further to develop novel TB nanoantibiotics. PMID- 27217752 TI - Biosynthesis of silver nanoparticles by the fungus Arthroderma fulvum and its antifungal activity against genera of Candida, Aspergillus and Fusarium. AB - The objective of this study was to find one or more fungal strains that could be utilized to biosynthesize antifungal silver nanoparticles (AgNPs). Using morphological and molecular methods, Arthroderma fulvum was identified as the most effective fungal strain for synthesizing AgNPs. The UV-visible range showed a single peak at 420 nm, which corresponded to the surface plasmon absorbance of AgNPs. X-ray diffraction and transmission electron microscopy demonstrated that the biosynthesized AgNPs were crystalline in nature with an average diameter of 15.5+/-2.5 nm. Numerous factors could potentially affect the process of biosynthesis, and the main factors are discussed here. Optimization results showed that substrate concentration of 1.5 mM, alkaline pH, reaction temperature of 55 degrees C, and reaction time of 10 hours were the optimum conditions for AgNP biosynthesis. Biosynthesized AgNPs showed considerable activity against the tested fungal strains, including Candida spp., Aspergillus spp., and Fusarium spp., especially Candida spp. PMID- 27217753 TI - Diagnostic pitfalls in a young Romanian ranger with an acute psychotic episode. AB - The identification and distinction of the pathological conditions underlying acute psychosis are often challenging. We present the case of a 35-year-old ranger who had no history of acute or chronic infectious disease or any previous neuropsychiatric symptoms. He arrived at the Psychiatry Clinic and was admitted as an emergency case, displaying bizarre behavior, hallucinations, paranoid ideation, and delusional faults. These symptoms had first appeared 7 days earlier. An objective examination revealed abnormalities of behavior, anxiety, visual hallucinations, choreiform, and tic-like facial movements. After the administration of neuroleptic and antidepressant treatment, he showed an initial improvement, but on day 10 entered into a severe catatonic state with signs of meningeal irritation and was transferred to the intensive care unit. An electroencephalogram showed diffuse irritative changes, raising the possibility of encephalitis. Taking into consideration the overt occupational risk, Borrelia antibody tests were prescribed and highly positive immunoglobulin (Ig)M and IgG titers were obtained from serum, along with IgG and antibody index positivity in cerebrospinal fluid. In parallel, anti-N-methyl-D-aspartate receptor antibodies and a whole battery of other autoimmune encephalitis markers showed negative. A complex program of treatment was applied, including antibiotics, beginning with ceftazidime and ciprofloxacin - for suspected aspiration bronchopneumonia - and thereafter with ceftriaxone. A gradual improvement was noticed and the treatment continued at the Infectious Disease Clinic. Finally, the patient was discharged with a doxycycline, antidepressant, and anxiolytic maintenance treatment. On his first and second control (days 44 and 122 from the disease onset), the patient was stable with no major complaints, Borrelia seropositivity was confirmed both for IgM and IgG while the cerebrospinal fluid also showed reactivity for IgG on immunoblot. On the basis of the putative occupational risk, acute psychotic episode, and the success of antibiotic therapy, we registered this case as a late neuroborreliosis with atypical appearance. PMID- 27217754 TI - Factors affecting treatment adherence to atomoxetine in ADHD: a systematic review. AB - The purpose of this paper was to systematically review the literature related to research about the factors affecting treatment adherence and discontinuation of atomoxetine in pediatric, adolescent, and adult patients with attention deficit/hyperactivity disorder (ADHD). Medline was systematically searched using the following prespecified terms: "ADHD", "Adherence", "Compliance", "Discontinuation", and "Atomoxetine". We identified 31 articles that met all inclusion and exclusion criteria. The findings from this review indicate that persistence and adherence to atomoxetine treatment were generally high. Factors found to influence adherence and nonadherence to atomoxetine treatment in ADHD in this review include age, sex, the definition of response used, length of treatment, initial dose of treatment, comorbid conditions, and reimbursement. Tolerability was cited as an important reason for treatment discontinuation. More research is needed to understand those factors that can help to identify patients at risk for poor adherence and interventions that could improve treatment adherence early in the stage of this illness to secure a better long-term prognosis. PMID- 27217755 TI - Selecting score types for longitudinal evaluations: the responsiveness of the Comprehensive Developmental Inventory for Infants and Toddlers in children with developmental disabilities. AB - OBJECTIVE: The objective of this study was to examine the responsiveness of the Comprehensive Developmental Inventory for Infants and Toddlers (CDIIT) in children with developmental disabilities (DD). METHODS: The responsiveness of a measure is its ability to detect change over time, and it is fundamental to an outcome measure for detecting changes over time. We compared the responsiveness of four types of scores (ie, raw scores, developmental ages [DAs], percentile ranks [PRs], and developmental quotients [DQs]) in the five subtests of the CDIIT. The CDIIT was administrated three times at intervals of 3 months on 32 children with DD aged between 5 months and 64 months (mean =30.6, standard deviation [SD] =17.8). The CDIIT is a pediatric norm-referenced assessment commonly used for clinical diagnosis of developmental delays in five developmental areas: cognition, language, motor, social, and self-care skills. The responsiveness was analyzed using three methods: effect size, standardized response mean, and paired t-test. RESULTS: The effect size results showed that at the 3-month and 6-month follow-ups, responsiveness was small or moderate in the raw scores and DAs of most of the subtest scores of the CDIIT, but the level of responsiveness varied in the PRs and DQs. The standardized response mean results of the 3-month and 6-month follow-ups showed that most of the subtest scores of the CDIIT had respectively moderate and large responsiveness in raw scores and DAs, but the responsiveness varied (from no to large) in PRs and DQs. CONCLUSION: The findings generally support the use of the CDIIT as an outcome measure. We also suggest using the raw scores and DAs when using a norm-referenced pediatric developmental assessment to evaluate developmental changes and program effectiveness in children with DD. PMID- 27217756 TI - Absorbable scaphoid screw development: a comparative study on biomechanics. AB - BACKGROUND: The scaphoid is critical for maintaining the stability and movement of the wrist joints. This study aimed to develop a new internal fixator absorbable scaphoid screw (ASS) for fixation of the scaphoid waist after fracture and to test the biomechanical characteristics of ASS. MATERIALS AND METHODS: An ASS was prepared using polylactic acids and designed based on scaphoid measurements and anatomic features. Twenty fractured scaphoid waist specimens were randomly divided into experimental and control groups (n=10/group). Reduction and internal fixation of the scaphoid were achieved with either Kirschner wires (K-wires) or ASS. A moving target simulator was used to test palmar flexion and dorsal extension, with the range of testing (waist movement) set from 5 degrees of palmar flexion to 25 degrees of dorsal extension. Flexion and extension were repeated 2,000 times for each specimen. Fracture gap displacements were measured with a computerized tomography scanning. Scaphoid tensile and bending strengths were measured by using a hydraulic pressure biomechanical system. RESULTS: Prior to biomechanical fatigue testing, fracture gap displacements were 0.16+/-0.02 mm and 0.22+/-0.02 mm in the ASS and K-wire groups, respectively. After fatigue testing, fracture gap displacements in the ASS and the K-wire groups were 0.21+/-0.03 mm and 1.52+/-0.07 mm, respectively. The tensile strengths for the ASS and K-wire groups were 0.95+/-0.02 MPa and 0.63+/-0.02 MPa, respectively. CONCLUSION: Fixation using an ASS provided sufficient mechanical support for the scaphoid after fracture. PMID- 27217757 TI - Are neutrophil/lymphocyte ratio and platelet/lymphocyte ratio reliable parameters as prognostic indicators in malignant mesothelioma? AB - BACKGROUND: Malignant mesothelioma (MM) is an aggressive asbestos-related pleural tumor. The incidence is increasing with intensive use of asbestos in developing countries. We need an easily accessible, inexpensive, and reliable method for determining the low survival time prognosis of this tumor. The aim of our study was to investigate the viability of neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) as prognostic indicators in MM. PATIENTS AND METHODS: Thirty-six patients with MM, whose histopathologic diagnosis and follow up were performed by our clinic and whose complete archive data were accessible, were included in this retrospective study. The patients' histopathologic disease types and stages, complete blood count parameters at diagnosis, and survival were recorded. RESULTS: Eighteen of the patients with MM were male and the remaining 18 of them were female; the average follow-up period was 24.83+/-3.61 months. The PLR levels of the patients were statistically significant (P<0.05). The NLR and PLR area under the receiver operating characteristic curve values were 0.559 and 0.749, respectively (P=0.631 and P=0.044, respectively). CONCLUSION: PLR was a significant prognostic indicator of MM at diagnosis on complete blood count parameters; however, NLR was not a significant prognostic indicator. A large number of prospective studies are needed to prove the reliability of the parameters. PMID- 27217758 TI - Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios: are they useful for predicting gestational diabetes mellitus during pregnancy? AB - OBJECTIVE: We aimed to investigate whether the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) could be utilized to screen for gestational diabetes mellitus (GDM). SUBJECTS AND METHODS: NLR and PLR were assessed by retrospective analysis of 762 healthy and pregnant women with GDM. The patients were stratified into four groups, as follows: GDM (n=144), impaired glucose tolerance (n=76), only screen positive (n=238), and control (n=304). RESULTS: The leukocyte, neutrophil, and lymphocyte counts were significantly higher in the study groups compared with the control group (P=0.001; P<0.01). There were no statistically significant differences between the groups with respect to the NLR and PLR (P>0.05). CONCLUSION: We do not recommend that blood NLR and PLR can be used to screen for GDM. However, increase in the leukocyte count is an important marker for GDM as it provides evidence of subclinical inflammation. PMID- 27217759 TI - Comparative risk impact of edoxaban in the management of stroke and venous thromboembolism. AB - Edoxaban, a factor Xa inhibitor, was approved by the United States Food and Drug Administration in 2015 for stroke prevention in nonvalvular atrial fibrillation and treatment of venous thromboembolism. It is the fourth target-specific oral anticoagulant to be approved. Edoxaban is noninferior for efficacy compared to warfarin for both approved indications. Edoxaban is superior to warfarin for the first major or clinically relevant nonmajor bleeding event in venous thromboembolism and major bleeding in nonvalvular atrial fibrillation. Edoxaban is dosed once daily for both indications and requires dose adjustment for renal function. In patients with nonvalvular atrial fibrillation, use is not recommended in patients with a creatinine clearance greater than 95 mL/min due to reduced efficacy. Edoxaban offers a new therapeutic alternative to the currently available options in the market. PMID- 27217760 TI - Comparison of anterior decompression and fusion versus laminoplasty in the treatment of multilevel cervical ossification of the posterior longitudinal ligament: a systematic review and meta-analysis. AB - PURPOSE: A meta-analysis was conducted to evaluate the clinical outcomes, complications, reoperation rates, and late neurological deterioration between anterior decompression and fusion (ADF) and laminoplasty (LAMP) in the treatment of multilevel cervical ossification of the posterior longitudinal ligament (OPLL). METHODS: All related studies published up to August 2015 were acquired by searching PubMed and EMBASE. Exclusion criteria were case reports, revision surgeries, combined anterior and posterior surgeries, the other posterior approaches including laminectomy or laminectomy and instrumented fusion, non English studies, and studies with quality assessment scores of <7. The main end points including Japanese Orthopedic Association (JOA) score, recovery rate of JOA, cervical lordosis, complication rate, reoperation rate, and late neurological deterioration were analyzed. All available data was analyzed using RevMan 5.2.0 and Stata 12.0. RESULTS: A total of seven studies were included in the meta-analysis. The mean surgical level of ADF was 3.1, and the mean preoperative occupation ratios of ADF and LAMP group were 55.9% and 51.9%, respectively. No statistical difference was observed with regard to preoperative occupation ratio and preoperative JOA score. Although LAMP group had a higher preoperative cervical lordosis than ADF group (P<0.05, weighted mean difference [WMD] =-5.73, 95% confidence interval [CI] =-9.67--1.80), significantly decreased cervical lordosis was observed in LAMP group after operation. ADF group had higher postoperative JOA score (P<0.05, WMD =2.18, 95% CI =0.98-3.38) and neurological recovery rate (P<0.05, WMD =27.22, 95% CI =15.20-39.23). Furthermore, ADF group had a lower late neurological deterioration rate than the LAMP group (P<0.05, risk difference =0.16, 95% CI =0.04-0.73). The complication rates of both groups had no statistical difference. However, LAMP group had a significantly lower reoperation rate than ADF group. The reoperation rate of ADF group (20.5%) was almost six times that of LAMP group (3.5%). CONCLUSION: Our meta-analysis suggested that ADF was associated with better postoperative neurological function, neurological recovery rate, and less late neurological deterioration than LAMP in the treatment of multilevel cervical OPLL with a high mean occupation ratio. LAMP was associated with a decreased postoperative cervical lordosis, which might be a cause of late neurological deterioration. The complication rates of both groups showed no statistical difference. However, the reoperation rate was significantly higher in ADF group compared with LAMP group. Benefits and risks should be balanced when ADF or LAMP is selected. PMID- 27217761 TI - Effect of ketamine combined with butorphanol on emergence agitation of postoperative patients with gastric cancer. AB - BACKGROUND: This study aimed to investigate the effect of ketamine combined with butorphanol on emergence agitation (EA) in postoperative gastric cancer patients. MATERIALS AND METHODS: A total of 150 patients with gastric cancer were included and divided into group B (1 mg butorphanol before anesthesia induction, n=50), group K (1 mg/kg ketamine, n=50), and group C (1 mg butorphanol combined with 1 mg/kg ketamine, n=50). Mean arterial pressure (MAP) and heart rate (HR) at the end of operation, just before extubation (T0) and at 0 minute (T1), 5 minutes (T2), and 30 minutes (T3) after extubation were compared. Statistical analysis of recovery time, extubation time, time in postanesthesia care unit, and EA incidence and adverse reactions were performed. RESULTS: There were no differences among groups with respect to MAP and HR at T0 and T1 (P>0.05). Compared with patients in group C, significant reduction of MAP and HR were observed in groups K and B at T2 and T3 (P<0.05), while no differences were found between group K and group B (P>0.05). Recovery time, extubation time, time in postanesthesia care unit, and incidence of EA in group C were significantly less than those in groups K and B (P<0.05), but no differences were observed between group K and group B (P>0.05). Total incidence of adverse reactions were significantly increased in group K compared to those in groups C and B (P<0.05). CONCLUSION: Injection of ketamine combined with butorphanol before anesthesia induction was more effective than injection of ketamine or butorphanol separately in the prevention of EA. PMID- 27217763 TI - New treatment options for ALK+ advanced non-small-cell lung cancer: critical appraisal of ceritinib. AB - Rearrangements in ALK gene and EML4 gene were first described in 2007. This genomic aberration is found in about 2%-8% of non-small-cell lung cancer (NSCLC) patients. Crizotinib was the first ALK tyrosine kinase inhibitor licensed for the treatment of metastatic ALK-positive NSCLC based on a randomized Phase III trial. Despite the initial treatment response of crizotinib, disease progression inevitably develops after approximately 10 months of therapy. Different resistance mechanisms have recently been described. One relevant mechanism of resistance is the development of mutations in ALK. Novel ALK tyrosine kinase inhibitors have been developed to overcome these mutations. Ceritinib is an oral second-generation ALK inhibitor showing clinical activity not only in crizotinib resistant ALK-positive NSCLC but also in treatment-naive ALK-positive disease. In this paper, preclinical and clinical data of ceritinib are reviewed, and its role in the clinical setting is put into perspective. PMID- 27217762 TI - Emerging drugs for partial-onset epilepsy: a review of brivaracetam. AB - There are more than 12 new antiepileptic drugs approved in the last 2 decades. Even with these newer agents, seizure remission is still unachievable in around 30% of patients with partial-onset seizures (POS). Brivaracetam (BRV) is chemically related to levetiracetam (LEV) and possesses a strong binding affinity for the synaptic vesicle protein 2A tenfold above that of LEV, and other possible modes of antiepileptic actions. BRV is now under Phase III development for POS, but data from one Phase III trial also suggested its potential efficacy for primary generalized seizures. The purpose of this review is to provide updated information on the mechanisms of action of the available antiepileptic drugs, with a focus on BRV to assess its pharmacology, pharmacokinetics, clinical efficacy, safety, and tolerability in patients with uncontrolled POS. To date, six Phase IIb and III clinical trials have been performed to investigate the efficacy, safety, and tolerability of BRV as an adjunctive treatment for patients with POS. Generally, BRV was well tolerated and did not show significant difference in safety profile, compared to placebo. The efficacy outcomes of BRV, although not consistent across trials, did indicate that BRV was a promising add on therapy for patients with POS. In conclusion, the many favorable attributes of BRV, like its high oral efficacy, good tolerability, dosing regimen, and minimal drug interaction, make it a promising antiepileptic therapy for patients with uncontrolled partial-onset epilepsy. PMID- 27217764 TI - Information bias in health research: definition, pitfalls, and adjustment methods. AB - As with other fields, medical sciences are subject to different sources of bias. While understanding sources of bias is a key element for drawing valid conclusions, bias in health research continues to be a very sensitive issue that can affect the focus and outcome of investigations. Information bias, otherwise known as misclassification, is one of the most common sources of bias that affects the validity of health research. It originates from the approach that is utilized to obtain or confirm study measurements. This paper seeks to raise awareness of information bias in observational and experimental research study designs as well as to enrich discussions concerning bias problems. Specifying the types of bias can be essential to limit its effects and, the use of adjustment methods might serve to improve clinical evaluation and health care practice. PMID- 27217765 TI - Ectopic adrenocorticotropic hormone syndrome caused by neuroendocrine tumors of the thymus: 30-year experience with 16 patients at a single institute in the People's Republic of China. AB - BACKGROUND AND PURPOSE: Thymic neuroendocrine carcinomas (TNECs) are extremely uncommon. Certain cases of TNECs can produce the adrenocorticotropic hormone (ACTH) and cause ectopic ACTH syndrome (EAS). The current literature on this topic consists mainly of case reports, and therapeutic guidelines are lacking. The aim of this study was to discuss the diagnosis, surgical management, and prognosis of EAS caused by TNECs to improve clinical experience with this rare disease. METHODS: From June 1984 to June 2014, at the Peking Union Medical College Hospital, the surgical interventions and follow-up outcomes of 16 consecutive patients (eight men and eight women) with EAS caused by TNECs were retrospectively analyzed. RESULTS: The median age was 32.5 years (range: 13-47 years), and the median disease duration was 8.5 months (range: 1-150 months). All patients presented with clinical and biochemical evidence indicating a diagnosis of Cushing's syndrome. Contrast-enhanced thoracic computed tomography scans were critical to locating the ACTH-producing tumor and evaluating the feasibility of resection. All patients underwent surgery. One patient died of septicemia in the intensive care unit 2 weeks after surgery. No other morbidity or mortality occurred during the perioperative period. The median overall survival (OS) was 41 months (95% CI: 30.3-51.7 months), and the progression-free survival was 28 months (95% CI: 21.6-34.3 months). Both overall survival (P=0.002) and progression-free survival (P=0.030) improved significantly after complete resection. CONCLUSION: TNEC is an extremely aggressive disease that should be considered when treating patients with Cushing's syndrome due to ectopic ACTH secretion. In particular, all suspected patients should undergo contrast-enhanced thoracic computed tomography scans to facilitate early diagnosis. The current first-line treatment is surgical resection, and complete resection is a favorable prognostic factor. However, additional patients and a longer follow-up will be needed to determine the variables that are predictive of survival and to improve patient prognosis. PMID- 27217766 TI - Complete transthoracic resection of giant posterior mediastinal goiter: case report and review of surgical strategies. AB - Intrathoracic goiters generally occupy anterior mediastinum, rarely involving the posterior mediastinal space. Reported herein is a 54-year-old female with a giant posterior mediastinal mass that was successfully resected via right posterolateral thoracotomy. The final pathologic diagnosis was giant posterior mediastinal goiter. This patient has done well postoperatively, with no evidence of local recurrence at 12-month follow-up. Related surgical strategies in past publications are summarized. PMID- 27217768 TI - E-cadherin expression and prognosis of head and neck squamous cell carcinoma: evidence from 19 published investigations. AB - OBJECTIVE: The objective of this study was to review the published literature and investigate whether E-cadherin gene is a prognostic factor in head and neck squamous cell carcinoma by conducting a meta-analysis. METHODS: Studies were identified from the databases Embase, Medline, and Cochrane Library by using the keywords "E-cadherin gene" and "head and neck cancer". Overall survival (OS) and disease-free survival (DFS) were the primary outcome measurements. RESULTS: Our literature review identified 1,458 articles; 19 studies with a total number of 2,012 cases were eligible for inclusion in the meta-analysis. The hazard ratio (HR) for OS of patients with decreased expression of E-cadherin gene was 0.57 (95% CI =0.37, 0.89; P=0.000). However, statistical heterogeneity was unacceptably high (I (2)=74.5%, P=0.000). After sensitivity analysis, heterogeneity became acceptable, and the effect measure was still significant (I (2)=7.0%; HR =0.52; 95% CI =0.40, 0.66; P=0.000). The HR for DFS was 0.53 (95% CI =0.42, 0.67; P=0.000). CONCLUSION: This meta-analysis showed clear evidence that high E-cadherin gene expression is a positive prognostic factor of head and neck squamous cell carcinoma, resulting in better OS and DFS. However, this conclusion must be interpreted with caution due to a few limitations. PMID- 27217767 TI - Irreversible electroporation: state of the art. AB - The field of focal ablative therapy for the treatment of cancer is characterized by abundance of thermal ablative techniques that provide a minimally invasive treatment option in selected tumors. However, the unselective destruction inflicted by thermal ablation modalities can result in damage to vital structures in the vicinity of the tumor. Furthermore, the efficacy of thermal ablation intensity can be impaired due to thermal sink caused by large blood vessels in the proximity of the tumor. Irreversible electroporation (IRE) is a novel ablation modality based on the principle of electroporation or electropermeabilization, in which electric pulses are used to create nanoscale defects in the cell membrane. In theory, IRE has the potential of overcoming the aforementioned limitations of thermal ablation techniques. This review provides a description of the principle of IRE, combined with an overview of in vivo research performed to date in the liver, pancreas, kidney, and prostate. PMID- 27217769 TI - Serum biomarker panels for diagnosis of gastric cancer. AB - PURPOSE: Currently, serum biomarkers that are sufficiently sensitive and specific for early detection and risk classification of gastric adenocarcinomas are not known. In this study, ten serum markers were assessed using the Luminex system and enzyme-linked immunosorbent assay for the diagnosis of gastric cancer and analysis of the relation between prognosis and metastases. PATIENTS AND METHODS: A training set consisting of 228 gastric adenocarcinoma and 190 control samples was examined. A Luminex multiplex panel with nine biomarkers, consisting of three proteins discovered through our previous studies and six proteins previously reported to be cancer-associated, was constructed. One additional biomarker was detected using a commercial kit containing EDTA. Logistic regression, random forest (RF), and support vector machine (SVM) were used to identify the panel of discriminatory biomarkers in the training set. After selecting five proteins as candidate biomarkers, multivariate classification analyses were used to identify algorithms for diagnostic biomarker combinations. These algorithms were independently validated using a set of 57 gastric adenocarcinoma and 48 control samples. RESULTS: Serum pepsinogen I, serum pepsinogen II, A Disintegrin And Metalloproteinase domain-containing protein 8 (ADAM8), vascular endothelial growth factor (VEGF), and serum IgG to Helicobacter pylori were selected as classifiers in the three algorithms. These algorithms differentiated between the majority of gastric adenocarcinoma and control serum samples in the training/test set with high accuracy (RF 79.0%, SVM 83.8%, logistic regression 76.2%). These algorithms also differentiated the samples in the validation set (accuracy: RF 82.5%, SVM 86.1%, logistic regression 78.7%). CONCLUSION: A panel of combinatorial biomarkers comprising VEGF, ADAM8, IgG to H. pylori, serum pepsinogen I, and pepsinogen II were developed. The use of biomarkers is a less invasive method for the diagnosis of gastric adenocarcinoma. They may supplement clinical gastroscopic evaluation of symptomatic gastric cancer patients and enhance the diagnostic accuracy. PMID- 27217770 TI - Long noncoding RNA expression profile analysis of colorectal cancer and metastatic lymph node based on microarray data. AB - Long noncoding RNAs (lncRNAs) are emerging as an important part of biological progress in cancers, yet the aberrant lncRNAs implicated in colorectal cancer (CRC) with lymph node metastasis remain unknown. In this study, a total of 390 lncRNA transcripts and 508 mRNA transcripts were dysregulated in tumor tissues compared with paired metastatic lymph nodes. Functional prediction showed that lots of lncRNAs might be involved in biological pathways related to CRC metastasis by cis-regulation and trans-regulation of coexpressed genes. As a representative, ENST00000430471 was associated with cell proliferation and invasion of CRC cells. These results provided support for further investigations of the metastatic pathogenesis of CRC. PMID- 27217771 TI - Tandem mass spectrometry-based newborn screening strategy could be used to facilitate rapid and sensitive lung cancer diagnosis. AB - OBJECTIVE: Newborn screening (NBS) helps in the early detection of inborn errors of metabolism (IEM). The most effective NBS strategy prevailing in clinics is tandem mass spectrometry (MS/MS) analysis using dried blood spot (DBS) samples. Taking lung cancer (LC) as an example, this study tried to explore if this technique could be of any assistance for the discovery of tumor metabolite markers. MATERIALS AND METHODS: Twenty-six acylcarnitines and 23 amino acids, which are commonly used in IEM screening, were quantified using DBS samples from 222 LC patients, 118 benign lung disease (LD) patients, and 96 healthy volunteers (CONT). Forty-four calculated ratios based on the abovementioned metabolites were also included using MS/MS quantification results. RESULTS: This pilot study led to the findings of 65 significantly changed amino acids, acylcarnitines, and some of their ratios for the LC, LD, and CONT groups. Among the differential parameters, 12 items showed reverse changing trends between the LC and LD groups compared to the CONT group. Regression analysis demonstrated that six of them - Arg, Pro, C10:1, Arg/Orn, Cit/Arg, and C5-OH/C0 - could be used to diagnose LC with a sensitivity of 91.3% and a specificity of 92.7%. CONCLUSION: This study demonstrated the DBS-based MS/MS strategy was a promising tool for the discovery of tumor metabolite markers. Remarkably, this MS/MS analysis could be finished in several minutes, implying that it was a proper measure complementary to the traditional serum protein biomarker quantitation strategy for cancerous disease diagnosis and screening purposes. PMID- 27217772 TI - Predictive dosimetric parameters for gastrointestinal toxicity with hypofractioned radiotherapy in pancreatic adenocarcinoma. AB - To better guide the development and optimization of radiotherapy planning, to reduce the incidence of radiation reactions, and to improve the quality of life of the patients with pancreatic cancer using radiotherapy, we conducted this study to explore the dosimetric parameters that predict the risk of gastrointestinal (GI) toxicity with hypofractioned radiotherapy for pancreatic cancer. Between January 2014 and January 2015, the medical records of 68 patients with pancreatic cancer who underwent helical tomotherapy at the Air Force General Hospital were analyzed. The doses delivered to the planning target volume, clinical target volume, and gross tumor volume-internal gross tumor volume of the primary pancreatic lesions were 50, 60, and 70-80 Gy in 15-20 fractions, respectively. GI toxicity was scored according to version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events. The stomach and duodenum were contoured separately to determine the dose-volume histogram parameters. Univariate and multivariate analyses were adopted to identify clinical and physical risk factors associated with GI toxicity. The median follow up was 9 months (range: 4-16 months). Eighteen patients had grade II acute GI toxicity, one patient had grade III acute GI toxicity, 17 patients had grade II late GI toxicity, and one patient had grade III late GI toxicity. On univariate analysis, the volume, the average dose D mean, the maximum dose to 1, 3, 5, and 10 cm(3) of the stomach and duodenum (D1, D3, D5, and D10), and the relative volumes receiving 5-40 Gy (V5-V40), and the absolute volumes receiving 5-45 Gy (aV5-aV45) of the duodenum were significantly associated with grade II or higher GI toxicity (P<0.05). On multivariate analysis, aV45 of the duodenum was an independent predictor for grade II or higher GI toxicity (P=0.031). The receiver operating characteristic analysis also showed that an aV45 of 0.5 cm(3) was the optimal threshold to predict GI toxicity for the entire cohort. Our findings indicate that many dosimetric parameters of the duodenum correlate with grade II or higher GI toxicity. To reduce GI toxicity, the absolute volume of the irradiated duodenum should be reduced. PMID- 27217773 TI - Prognostic significance of miR-126 in various cancers: a meta-analysis. AB - OBJECTIVE: Recent studies have demonstrated that microRNA-126 (miR-126) might be a promising prognostic factor for cancer patients. This meta-analysis was conducted to assess the effectiveness of miR-126 as a prognostic biomarker for various cancers. METHODS: The search of studies was performed by using PubMed and Embase until January 22, 2016. Pooled hazard ratio (HR) with 95% confidence interval (CI) for patients' survival was calculated. A fixed-effect or random effects model was applied according to heterogeneity. The trim and fill method was used to adjust pooled HR. RESULTS: In all 17 articles comprising of 2,437 participants were included in this meta-analysis. The results indicated that a high level of miR-126 played a favorable role in the overall survival (HR 0.70, 95% CI: 0.62-0.79, random-effects model), with a heterogeneity measure index of I (2)=63.2% (P<0.01). Subgroup analyses showed that pooled HR was more significant in patients with digestive system cancers (HR 0.70, 95% CI: 0.59-0.83, fixed effects model) and respiratory system cancers (HR 0.71, 95% CI: 0.59-0.85, random effects model). Owing to publication bias, HR was adjusted to 0.59 (0.463-0.752, P<0.01) by the trim and fill method. CONCLUSION: miR-126 could be a promising biomarker for cancer prognosis prediction, especially in patients with digestive or respiratory system cancers. PMID- 27217774 TI - Haploidentical hematopoietic stem cell transplantation without total body irradiation for pediatric acute leukemia: a single-center experience. AB - Hematopoietic stem cell transplantation (HSCT) is a promising method for therapy of pediatric patients with acute leukemia. However, less availability of matched donors limited its wide application. Recently, haploidentical HSCT has become a great resource. Here, we have retrospectively reported our experience of 20 pediatric patients with acute leukemia who underwent haploidentical HSCT without total body irradiation (TBI) myeloablative regimen in our center from November 2007 to June 2014. All the patients attained successful HSCT engraftment in terms of myeloid and platelet recovery. Thirteen patients developed grade I-IV acute graft-versus-host disease (a-GVHD). The incidence of grade I-II a-GVHD, grade III IV a-GVHD, and chronic GVHD (c-GVHD) was 45%, 20%, and 25%, respectively. The mean myeloid and platelet recovery time was 13.20+/-2.41 and 19.10+/-8.37 days. The median follow-up time was 43.95+/-29.26 months. During the follow-up, three patients died. The overall survival (OS) rate was 85%. The present study indicated that haploidentical HSCT without TBI myeloablative regimen significantly improved the OS rate of pediatric patients with acute leukemia. PMID- 27217775 TI - Lead identification for the K-Ras protein: virtual screening and combinatorial fragment-based approaches. AB - OBJECTIVE: Kirsten rat sarcoma (K-Ras) protein is a member of Ras family belonging to the small guanosine triphosphatases superfamily. The members of this family share a conserved structure and biochemical properties, acting as binary molecular switches. The guanosine triphosphate-bound active K-Ras interacts with a range of effectors, resulting in the stimulation of downstream signaling pathways regulating cell proliferation, differentiation, and apoptosis. Efforts to target K-Ras have been unsuccessful until now, placing it among high-value molecules against which developing a therapy would have an enormous impact. K-Ras transduces signals when it binds to guanosine triphosphate by directly binding to downstream effector proteins, but in case of guanosine diphosphate-bound conformation, these interactions get disrupted. METHODS: In the present study, we targeted the nucleotide-binding site in the "on" and "off" state conformations of the K-Ras protein to find out suitable lead compounds. A structure-based virtual screening approach has been used to screen compounds from different databases, followed by a combinatorial fragment-based approach to design the apposite lead for the K-Ras protein. RESULTS: Interestingly, the designed compounds exhibit a binding preference for the "off" state over "on" state conformation of K-Ras protein. Moreover, the designed compounds' interactions are similar to guanosine diphosphate and, thus, could presumably act as a potential lead for K-Ras. The predicted drug-likeness properties of these compounds suggest that these compounds follow the Lipinski's rule of five and have tolerable absorption, distribution, metabolism, excretion and toxicity values. CONCLUSION: Thus, through the current study, we propose targeting only "off" state conformations as a promising strategy for the design of reversible inhibitors to pharmacologically inhibit distinct conformations of K-Ras protein. PMID- 27217776 TI - Correlation between pretreatment serum LDL-cholesterol levels and prognosis in nasopharyngeal carcinoma patients. AB - PURPOSE: To investigate the correlations between long-term survival outcomes in patients with nasopharyngeal carcinoma (NPC) and pretreatment serum low-density lipoprotein cholesterol (LDL-C) levels. PATIENTS AND METHODS: Between January 2008 and December 2011, 935 patients with newly diagnosed NPC who were treated with intensity-modulated radiation therapy were included in this retrospective clinical analysis. Patients were divided into two groups based on pretreatment LDL-C levels: normal LDL-C (<=3.64 mmol/L; n=816) and elevated LDL-C (>3.64 mmol/L; n=119). Associations between pretreatment LDL-C levels and treatment outcome were analyzed by univariate and multivariate analyses. RESULTS: The overall patient follow-up rate was 95.1%, and 726 patients received more than 5 years of follow-up. Five-year overall survival (OS), local control (LC), and distant metastasis-free survival (DMFS) rates of the entire patient population were 87.1%, 91.1%, and 87.2%, respectively. Rates of 5-year OS, LC, and DMFS for the elevated versus normal LDL-C groups were 77.0% vs 89.1% (P<0.001), 85.8% vs 91.9% (P=0.041), and 81.1% vs 88.1% (P=0.038), respectively. Compared with normal LDL-C levels, elevated LDL-C levels were identified as an independent prognostic factor of a poorer OS (hazard ratio [HR] =2.171; 95% confidence interval [CI] =1.424-3.309), LC rate (HR =1.762; 95% CI =1.021-3.942), and DMFS (HR =1.594; 95% CI =1.003-2.532). CONCLUSION: This study found that elevated pretreatment LDL-C levels are negative prognostic indicators of NPC. Elevated LDL-C levels may be useful indicators of locoregional control and distant metastasis in NPC patients. PMID- 27217777 TI - Screening of biomarkers for prediction of response to and prognosis after chemotherapy for breast cancers. AB - OBJECTIVE: To screen the biomarkers having the ability to predict prognosis after chemotherapy for breast cancers. METHODS: Three microarray data of breast cancer patients undergoing chemotherapy were collected from Gene Expression Omnibus database. After preprocessing, data in GSE41112 were analyzed using significance analysis of microarrays to screen the differentially expressed genes (DEGs). The DEGs were further analyzed by Differentially Coexpressed Genes and Links to construct a function module, the prognosis efficacy of which was verified by the other two datasets (GSE22226 and GSE58644) using Kaplan-Meier plots. The involved genes in function module were subjected to a univariate Cox regression analysis to confirm whether the expression of each prognostic gene was associated with survival. RESULTS: A total of 511 DEGs between breast cancer patients who received chemotherapy or not were obtained, consisting of 421 upregulated and 90 downregulated genes. Using the Differentially Coexpressed Genes and Links package, 1,244 differentially coexpressed genes (DCGs) were identified, among which 36 DCGs were regulated by the transcription factor complex NFY (NFYA, NFYB, NFYC). These 39 genes constructed a gene module to classify the samples in GSE22226 and GSE58644 into three subtypes and these subtypes exhibited significantly different survival rates. Furthermore, several genes of the 39 DCGs were shown to be significantly associated with good (such as CDC20) and poor (such as ARID4A) prognoses following chemotherapy. CONCLUSION: Our present study provided a serial of biomarkers for predicting the prognosis of chemotherapy or targets for development of alternative treatment (ie, CDC20 and ARID4A) in breast cancer patients. PMID- 27217778 TI - Delivery of a survivin promoter-driven antisense survivin-expressing plasmid DNA as a cancer therapeutic: a proof-of-concept study. AB - Survivin is a member of the inhibitor-of-apoptosis proteins family. It is overexpressed in many different cancer types but not in the differentiated normal tissue. In addition, overexpression of survivin promotes cancer cell survival and induces chemotherapeutic drug resistance, making it an attractive target for new anticancer interventions. Despite survivin being a promising molecular target for anticancer treatment, it is widely accepted that survivin is only a "semi druggable" target. Therefore, it is important to develop a new strategy to target survivin for anticancer treatment. In this study, we constructed a novel survivin promoter-driven full-length antisense survivin (pSur/AS-Sur) expression plasmid DNA. Promoter activity assay revealed that the activity of the survivin promoter of pSur/AS-Sur correlated with the endogenous expression of survivin at the transcriptional level in the transfected A549, MDA-MB-231, and PANC-1 cancer cells. Western blot analysis showed that liposomal delivery of pSur/AS-Sur successfully downregulated the expression of survivin in A549, MBA-MB-231, and PANC-1 cells in vitro. In addition, delivery of pSur/AS-Sur induced autophagy, caspase-dependent apoptosis, and caspase-independent apoptosis as indicated by the increased LC3B-II conversion, autophagosome formation, caspase-9/-3 and poly(ADP-ribose) polymerase-1 cleavage, and apoptosis-inducing factor nuclear translocation in A549, MBA-MB-231, and PANC-1 cells. Importantly, liposomal delivery of pSur/AS-Sur was also capable of decreasing the proliferation of the survivin/MDR1 coexpressing multidrug-resistant KB-TAX50 cancer cells and the estrogen receptor-positive tamoxifen-resistant MCF7-TamC3 cancer cells in vitro. In conclusion, the results of this study suggest that delivery of a survivin promoter-driven antisense survivin-expressing plasmid DNA is a promising way to target survivin and to treat survivin-expressing cancers in the future. PMID- 27217779 TI - High expression of Y-box-binding protein 1 correlates with poor prognosis and early recurrence in patients with small invasive lung adenocarcinoma. AB - BACKGROUND: Prognosis of small (<=2 cm) invasive lung adenocarcinoma remains poor, and identification of high-risk individuals from the patients after complete surgical resection of lung adenocarcinoma has become an urgent problem. YBX1 has been reported to be able to predict prognosis in many cancers (except lung adenocarcinoma) that are independent of TNM (tumor, nodes, metastases) staging, especially small invasive lung adenocarcinoma. Therefore, we examined the significance of YBX1 expression on prognosis and recurrence in patients with small invasive lung adenocarcinoma. MATERIAL AND METHODS: A total of 75 patients with small invasive lung adenocarcinoma after complete resection were enrolled from January 2008 to December 2010. Immunohistochemical staining was used to detect the expression of YBX1, and receiver operating characteristic curve analysis was performed to precisely assess the overall expression of YBX1. Meanwhile, primary lesions were identified based on the International Association for the Study of Lung Cancer, the American Thoracic Society, and the European Respiratory Society's classification of lung adenocarcinoma. The effect of different clinicopathological factors on patients' survival was examined. Furthermore, Western blot analysis was used to show the expression of YBX1 in vitro. RESULTS: Sensitivity and specificity of YBX1 for detecting small invasive lung adenocarcinoma from normal surrounding tissue were 66.7% and 74.7% (area under the receiver operating characteristic curve =0.731; P<0.001), respectively. High YBX1 expression was detected in 31 (41.3%) patients, and in A549, H322, Hcc827, and H1299 lung adenocarcinoma cells but not in HLF cells. In addition to sex, age, tumor size, TNM staging, pleural invasion, and lymph node metastasis, the expression of YBX1 was associated with the International Association for the Study of Lung Cancer, the American Thoracic Society, and the European Respiratory Society pathological grade risk (P=0.026) and differentiation (P=0.009). The patients with low YBX1 expression lived longer than those with high expression (5 year overall survival: 52.3% vs 79.0%; P=0.039) and showed fewer recurrences (P=0.024). In multivariate analyses, high YBX1 expression (odds ratio =2.737; 95% confidence interval: 1.058-7.082; P=0.038) was shown as an independent risk factor of overall survival but not of disease-free survival (odds ratio =1.696; 95% confidence interval: 0.616-4.673; P=0.307). CONCLUSION: YBX1 is an important predictor for the prognosis in patients with small invasive lung adenocarcinoma after complete resection. PMID- 27217780 TI - A Phase II prospective nonrandomized trial of magnetic resonance imaging-guided hematopoietic bone marrow-sparing radiotherapy for gastric cancer patients with concurrent chemotherapy. AB - PURPOSE: This study aimed to spare hematopoietical bone marrow (BM) identified by magnetic resonance (MR) radiation in order to alleviate acute hematologic toxicity (HT) for gastric cancer patients treated with postoperative chemoradiotherapy (CRT). METHODS: A prospective, open-label, single-arm Phase II study (Clinicaltrials.gov; NCT 01863420) was conducted in 25 patients with gastric cancer who were eligible for postoperative concurrent CRT. The MR images of vertebral body T8-L4 were fused with images of simulating computed tomography. Hematopoietical BM was contoured according to the MR and spared in radiotherapy plan. The CRT regimen consisted of daily capecitabine (1600 mg/m(2)/d) and 45 Gy of radiation at 1.8 Gy per day. Primary endpoints were grade >=3 HT that occurred within 2 months of initiation of CRT. The relationship between HT and dose-volume of BM was estimated by multivariable linear regression model. RESULTS: Twenty four patients (96%) had T3-4 disease and 22 (88%) had disease with node positive. The median age was 53 years (range, 28-73 years). Before concurrent CRT, adjuvant chemotherapy was administered with a mean cycle of 4.3+/-0.5. Only five patients (20%) developed grade 3-4 HT during treatment, among whom two (8.0%) patients experienced grade 3-4 leucopenia, two (8.0%) experienced neutropenia, and two (8.0%) experienced thrombocytopenia, respectively. None of the patients showed grade 3-4 anemia. Multivariable linear regression revealed increased BM-V5 (P=0.03) and BM-V20 (P=0.002) were found to be significantly associated with decreased white blood cells nadirs in multivariable regression; increased BM-V20 (P<0.001) with decreased absolute neutrophil count nadirs, increased BM-V30 (P=0.002) and volume of BM (P=0.001) with decreased platelet count nadirs. CONCLUSION: Irradiation of active BM identified by MR is associated with HTs. Techniques to limit low-dose radiation, especially V20, to BM could reduce HT in gastric cancer patients. PMID- 27217781 TI - HER2 induces cell proliferation and invasion of non-small-cell lung cancer by upregulating COX-2 expression via MEK/ERK signaling pathway. AB - HER2 positivity has been well studied in various cancers, but its importance in non-small-cell lung cancer (NSCLC) is still being explored. In this study, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to detect HER2 and COX-2 expression in NSCLC tissues. Then, pcDNA3.1 HER2 was used to overexpress HER2, while HER2 siRNA and COX-2 siRNA were used to silence HER2 and COX-2 expression. MTT assay and invasion assay were used to detect the effects of HER2 on cell proliferation and invasion. Our study revealed that HER2 and COX-2 expression were upregulated in NSCLC tissues and HER2 exhibited a significant positive correlation with the levels of COX-2 expression. Overexpression of HER2 evidently elevated COX-2 expression, while silencing of HER2 evidently decreased COX-2 expression. Furthermore, overexpressed HER2 induced the ERK phosphorylation, and this was abolished by the treatment with U0126, a pharmacological inhibitor of MEK, an upstream kinase of ERK. HER2 induced expression and promoter activity of COX-2 were also suppressed by U0126, suggesting that the MEK/ERK signaling pathway regulates COX-2 expression. In addition, HER2 induced activation of AKT signaling pathway, which was reversed by pretreatment with U0126 and COX-2 siRNA. MTT and invasion assays revealed that HER2 induced cell proliferation and invasion that were reversed by pretreatment with U0126 and COX-2 siRNA. In this study, our results demonstrated for the first time that HER2 elevated COX-2 expression through the activation of MEK/ERK pathway, which subsequently induced cell proliferation and invasion via AKT pathway in NSCLC tissues. PMID- 27217782 TI - Ruguo key genes and tumor driving factors identification of bladder cancer based on the RNA-seq profile. AB - AIM: This study aimed to select several signature genes associated with bladder cancer, thus to investigate the possible mechanism in bladder cancer. METHODS: The mRNA expression profile data of GSE31614, including ten bladder tissues and ten control samples, was downloaded from the Gene Expression Omnibus. The differentially expressed genes (DEGs) in bladder cancer samples compared with the control samples were screened using the Student's t-test method. Functional analysis for the DEGs was analyzed using the Database for Annotation, Visualization, and Integrated Discovery from the Gene Ontology database, followed by the transcription function annotation of DEGs from Tumor-Associated Gene database. Motifs of genes that had transcription functions in promoter region were analyzed using the Seqpos. RESULTS: A total of 1,571 upregulated and 1,507 downregulated DEGs in the bladder cancer samples were screened. ELF3 and MYBL2 involved in cell cycle and DNA replication were tumor suppressors. MEG3, APEX1, and EZH2 were related with the cell epigenetic regulation in bladder cancer. Moreover, HOXB9 and EN1 that have their own motif were the transcription factors. CONCLUSION: Our study has identified several key genes involved in bladder cancer. ELF3 and MYBL2 are tumor suppressers, HOXB9 and EN1 are the main regulators, while MEG3, APEX1, and EZH2 are driving factors for bladder cancer progression. PMID- 27217784 TI - Real-world hospital costs for nonchemotherapy drugs and nondrug care associated with platinum-based doublets in the first-line setting for advanced nonsquamous non-small-cell lung cancer in Chinese patients: a retrospective cohort study. AB - OBJECTIVE: The objective of this study was to compare hospital costs per treatment cycle (HCTC) for nonchemotherapy drugs and nondrug care associated with platinum-based doublets in the first-line setting for advanced nonsquamous non small-cell lung cancer (AdvNS-NSCLC) in Chinese patients. METHODS: Patients receiving platinum-based doublets in the first-line setting for AdvNS-NSCLC from 2010 to 2012 in two Chinese tertiary hospitals were identified to create the retrospective study cohort. Propensity score methods were used to create matched treatment groups for head-to-head comparisons on HCTC between pemetrexed-platinum and other platinum-based doublets. Multiple linear regression analyses were performed to rank studied platinum-based doublets for their associations with the log10 scale of HCTC for nonchemotherapy drugs and nondrug care. RESULTS: Propensity score methods created matched treatment groups for pemetrexed-platinum versus docetaxel-platinum (61 pairs), paclitaxel-platinum (39 pairs), gemcitabine platinum (93 pairs), and vinorelbine-platinum (73 pairs), respectively. Even though the log10 scale of HCTC for nonchemotherapy drugs and nondrug care associated with pemetrexed-platinum was ranked lowest in all patients (coefficient -0.174, P=0.015), which included patients experiencing any hematological adverse events (coefficient -0.199, P=0.013), neutropenia (coefficient -0.426, P=0.021), or leukopenia (coefficient -0.406, P=0.001), pemetrexed-platinum had the highest total HCTC (median difference from RMB 1,692 to RMB 7,400, P<0.001) among platinum-based doublets because of its higher drug acquisition costs (median difference from RMB 4,636 to RMB 7,332, P<0.001). CONCLUSION: Among Chinese patients receiving platinum-based doublets in the first line setting for AdvNS-NSCLC, the higher acquisition costs for nonplatinum cytotoxic drugs associated with pemetrexed-platinum could be partially offset by its significantly lower hospital costs for nonchemotherapy drugs and nondrug care. PMID- 27217785 TI - A burden of illness study for neuropathic pain in Europe. AB - PURPOSE: Neuropathic pain (NP) is often severe and represents a major humanistic and economic burden. This study aimed at providing insight on this burden across France, Germany, Italy, Spain, and the UK, considering direct and indirect costs, productivity loss, and humanistic impact on patients and their families. METHODS: Physician questionnaires provided data on patients presenting with NP covering demographics, sick leave and retirement, number of consultations, drug treatments, and surgical procedures. Patients provided further demographic and disease-related data and completed the Work Productivity and Activity Impairment (WPAI), the EuroQol 5-Dimension (EQ-5D), and the Brief Pain Inventory (BPI) questionnaires. All health-related direct unitary costs were collected from relevant country-specific sources and adjusted to 2012 prices (?) where necessary. A subgroup analysis of costs based on diabetic peripheral neuropathy (n=894), fibromyalgia (n=300), and low back pain (n=963) was performed. FINDINGS: About 413 physicians completed a total of 3,956 patient records forms. Total annual direct health-care costs per patient ranged from ?1,939 (Italy) to ?3,131 (Spain). Annual professional caregiver costs ranged from ?393 (France) to ?1,242 (UK), but this only represented a small proportion of total care because much care is provided by family or friends. Sick leave costs ranged from ?5,492 (UK) to ?7,098 (France), with 10%-32% patients prevented from working at some point by NP. Total cost (including direct and indirect costs) of NP per patient was ?10,313 in France (69% of the total cost), ?14,446 in Germany (78%), ?9,305 in Italy (69%), ?10,597 in Spain (67%), and ?9,685 in the UK (57%). Indirect costs (ie, sick leave) constituted the majority of costs in all five countries: ?7,098 in France, ?11,232 in Germany, ?6,382 in Italy, ?7,066 in Spain, and ?5,492 in the UK. In the subgroup analysis, total annual direct costs per patient were highest for neuropathic back pain and radiculopathy, and lowest for fibromyalgia. Mean WPAI score range was 34.4-56.1; BPI interference was 4.1-4.8; and EQ-5D was 0.57-0.74. The results suggest that a significant proportion of the patient's work time in the previous week was affected by NP, and these are relatively high compared with other diseases such as diabetes, respiratory conditions, and arthritis. IMPLICATIONS: Despite differences in practice between countries, these findings suggest a high opportunity cost for society in terms of lost work and productivity due to NP. The wider costs appear significantly higher to patients, carers/families, and society as a whole than to the health system alone. PMID- 27217783 TI - Stem cell technology in breast cancer: current status and potential applications. AB - Breast cancer, the leading cause of cancer among females, is supported by the presence of a rare subset of undifferentiated cells within the tumor, identified as breast cancer stem cells (BCSCs). BCSCs underlie the mechanisms of tumor initiation and sustenance and are implicated in the dissemination of the primary tumor to metastatic sites, as they have been found circulating in the blood of breast cancer patients. The discovery of BCSCs has generated a great amount of interest among the scientific community toward their isolation, molecular characterization, and therapeutic targeting. In this review, after summarizing the literature on molecular characterization of BCSCs and methodologies used for their isolation, we will focus on recent data supporting their molecular and functional heterogeneity. Additionally, following a synopsis of the latest approaches for BCSC targeting, we will specifically emphasize on the therapeutic use of naive or engineered normal stem cells in the treatment of breast cancer and present contradictory findings challenging their safety. PMID- 27217786 TI - Cost-effectiveness of bortezomib for multiple myeloma: a systematic review. AB - OBJECTIVES: To review published cost-effectiveness analyses (CEA) assessing bortezomib (BTZ) for multiple myeloma (MM) and explore possible bias affecting the cost-effectiveness of BTZ. METHODS: Literature was searched for published CEAs assessing BTZ or BTZ-containing regimens for MM from 2003 to 2015. The reported incremental cost-effectiveness ratios (ICER) were adjusted by 2014 country-specific gross domestic product per capita (GDPPC) to compare the cost effectiveness threshold of the World Health Organization (3 GDPPC per gained quality-adjusted life year [QALY]). RESULTS: A total of 17 published CEAs were included in this review. When compared to non-BTZ treatments, BTZ-containing regimens were cost-effective for induction treatment prior to stem cell transplantation (SCT) in Canada, Poland, and Germany (ICER per QALY: 0.9299-2.254 GDPPC). BTZ/melphalan/prednisolone (VMP) was cost-effective for previously untreated and SCT-ineligible MM patients when compared to melphalan plus prednisolone (MP), melphalan/prednisone/lenalidomide with lenalidomide maintenance, and cyclophosphamide/thalidomide/dexamethasone (CTD) (ICER per QALY: dominant to 2.374 GDPPC) in Canada, UK, and USA. BTZ was cost-effective for relapsed/refractory MM when compared to best supportive care (ICER per life year: 0.9317-1.8210 GDPPC) in the UK and the USA, thalidomide in USA (0.5178 GDPPC/LY), and dexamethasone (DEX) in four Nordic countries (?54,451-?81,560/QALY). However, the cost-effectiveness for VMP versus MP plus thalidomide (MPT) and continuous lenalidomide (LEN) plus low-dose DEX (RD) for previously untreated and SCT ineligible MM patients and BTZ versus LEN/DEX for relapsed/refractory MM patients could be unreliable because of the bias associated with model design and the indirect comparisons of treatment effects. CONCLUSION: Published CEAs suggested that BTZ or BTZ-containing regimens were cost-effective when compared to most non BTZ treatments for MM. However, the conflicting cost-effectiveness for VMP versus MPT for previously untreated and SCT-ineligible MM and BTZ versus LEN/DEX for relapsed/refractory MM needs more robust evidence for further clarification. PMID- 27217787 TI - Difficult-to-heal wounds of mixed arterial/venous and venous etiology: a cost effectiveness analysis of extracellular matrix. AB - IMPORTANCE: Difficult-to-heal wounds pose clinical and economic challenges, and cost-effective treatment options are needed. OBJECTIVE: The aim of this study is to determine the cost-effectiveness of extracellular matrix (ECM) relative to standard of care (SC) on wound closure for the treatment of mixed arterial/venous (A/V) or venous leg ulcers (VLUs). DESIGN SETTING AND PARTICIPANTS: A two-stage Markov model was used to predict the expected costs and outcomes of wound closure for ECM and SC. Outcome data used in the analysis were taken from an 8-week randomized clinical trial that directly compared ECM and SC. Patients were followed up for an additional 6 months to assess wound closure. Forty-eight patients completed the study; 25 for ECM and 23 for SC. SC was defined as a standard moist wound dressing. Transition probabilities for the Markov states were estimated from the clinical trial. MAIN OUTCOMES AND MEASURES: The economic outcome of interest was direct cost per closed-wound week. Resource utilization was based on the treatment regimen used in the clinical trial. Costs were derived from standard cost references. The payer's perspective was taken. RESULTS: ECM treated wounds closed, on average, after 5.4 weeks of treatment, compared with 8.3 weeks for SC wounds (P=0.02). Furthermore, complete wound closure was significantly higher in patients treated with ECM (P<0.05), with 20 wounds closed in the ECM group (80%) and 15 wounds closed in the SC group (65%). After 8 months, patients treated with ECM had substantially higher closed-wound weeks compared with SC (26.0 weeks versus 22.0 weeks, respectively). Expected direct costs per patient were $2,527 for ECM and $2,540 for SC (a cost savings of $13). CONCLUSION AND RELEVANCE: ECM yielded better clinical outcomes at a slightly lower cost in patients with mixed A/V and VLUs. ECM is an effective treatment for wound healing and should be considered for use in the management of mixed A/V and VLUs. PMID- 27217788 TI - Advances in the treatment of type 2 diabetes: impact of dulaglutide. AB - The purpose of this review is to provide a review of current data of the most recently approved glucagon-like peptide (GLP)-1-receptor agonist, dulaglutide, in the treatment of type 2 diabetes. To complete this, a PubMed search was performed to identify manuscripts published from 1947 to July 2015. The search terms "Trulicity", "dulaglutide", and "LY2189265" were utilized, and publications were included if they evaluated the pharmacology, pharmacokinetics, efficacy, safety, or patient-reported outcomes of dulaglutide. Dulaglutide is a GLP-1 receptor agonist that mimics endogenous GLP-1, the hormone produced in response to food intake. Modifications have been made to the molecule to delay breakdown and allow for once-weekly dosing. Dulaglutide has been studied as monotherapy and in combination with several agents, including metformin, glimepiride, pioglitazone, and insulin lispro. Dulaglutide has demonstrated superior efficacy compared to placebo, metformin, insulin glargine, sitagliptin, and twice-daily exenatide. It was found to be noninferior to liraglutide. The most common adverse effects in clinical studies were gastrointestinal-related adverse events, and patient satisfaction was high with the use of dulaglutide. Dulaglutide is an appealing option for the treatment of type 2 diabetes, based on its once-weekly dosing, A1c lowering comparable to liraglutide, weight reduction comparable to exenatide, and a similar adverse-effect profile to other GLP-1 receptor agonists. PMID- 27217789 TI - The effects of continuous application of sunscreen on photoaged skin in Japanese elderly people - the relationship with the usage. AB - Since photoaging of skin is caused by chronic sun exposure, it is well-recognized that regular sunscreen use can help prevent photoaging of skin in fair-skinned people. Therefore, application of sunscreen is recommended for the prevention of photoaging in many countries. However, the relationship between UV exposure and photoaging has rarely been investigated in clinical studies in Japan. In addition, there have been almost no long-term interventional studies in Japanese people. We have previously conducted a study where Japanese actinic keratosis patients were instructed to continuously apply sunscreen. The results indicated that long-term application of sunscreen is effective in suppressing actinic keratosis progression and generation. In the present study, we investigated the effects of sunscreen on photoaged skin in 14 elderly Japanese people. Skin conditions such as water content, transepidermal water loss, the number of spots, wrinkles, and skin color tone uniformity were measured and compared before and after the study. A statistically significant difference was observed only in skin surface hydration. There were large inter-individual differences in amount of sunscreen used throughout the study. The changes in the number of spots and skin color tone uniformity during the 18 months showed good correlation with amount of sunscreen being used. These results suggest an increase in the number of spots and deterioration in skin color tone uniformity in the 18-month non-sunscreen application period, and that such skin conditions improved with increasing use of sunscreen. In this study, we suggested an inhibitory effect on photoaging symptoms such as spots and skin color tone non-uniformity, by application of the appropriate amount of sunscreen over a long period of time in Japanese people, similar to Caucasians. PMID- 27217790 TI - Photoaging and the clinical utility of fractional laser. AB - The description of atomic structure by Niels Bohr set the basis for the emergence of quantum physics. Based on these fundamentals, Einstein published in 1917 a paper on the amplification of energy by Stimulated Emission of Radiation as part of his quantum theories. In 1955, Townes and Gordon turned Einstein's theories into practice, creating a coherent and amplified microwave device using ammonia gas in an optical medium. But it was at the beginning of the 1980s, that Anderson and Parrish published an article about the selective photothermolysis model which revolutionized clinical practice. The use of laser in photoaging began with CO2 (10,600 nm). In 1989, it was first used for resurfacing of a face with prominent photoaging. Ablative lasers have therefore had great popularity in the 1980s and 1990s, but prolonged postoperative time and significant risk of side effects have lowered the acceptance by patients. In 2004, the description of the fractionated radiation for the treatment of photoaging, by Mainstein, represented a great event. The stimulation of collagen occurred through fractional laser beams, which would reach the selected area while saving islands of sound skin. These islands accelerated the process of cicatrization of the treated tissue and shortened the postprocedure time. Furthermore, the fractionated radiation presented a smaller range of side effects, increasing the safety of the procedure. As mentioned earlier, as fractional lasers incise on the skin, they leave islands of healthy skin that accelerate recovery, while generating necrosis columns. Such necrosis columns remove damaged extracellular matrix material, allowing resettlement of fibroblasts. Such resettled fibroblasts, under the influence of a new tensile strength, restart to produce structures for extracellular matrix, such as collagen, elastin, and proteoglycans, in a more physiological way. Fractional lasers are considered by many dermatologists as the best choice in laser therapy for the treatment of photoaging. PMID- 27217791 TI - Essential phospholipids in fatty liver: a scientific update. AB - AIM: Although essential phospholipids (EPL) from soybean are often used in membrane-associated disorders and diseases, their high quality of purification and effects on prevalent liver diseases, especially on fatty liver diseases (FLDs) of different origin, are still widely unknown and a matter of continuous active research. The aim of this article is to review, discuss, and summarize the available results of EPL in the treatment of FLD. METHODS: Database research was carried out on Medline, Embase, Cochrane Library, country-specific journals, and follow-up literature citations for relevant hepatogastroenterological articles published between 1988 and 2014. We searched for and reviewed only those papers that indicated minimum extraction amount of 72% (3-sn-phosphatidyl)choline from soybean as being necessary to treat patients with a considerable amount of 1,2 dilinoleoylphosphatidylcholine as a key component in EPL. RESULTS: EPL has a well established mode of action, therapeutic effectiveness, and lack of toxicity, which ensures clinically relevant efficacy-to-safety ratio. It influences membrane- dependent cellular functions and shows anti-inflammatory, antioxidant, antifibrogenic, anti apoptotic, membrane-protective, and lipid-regulating effects. Due to its positive effects on membrane composition and functions, it accelerates the improvement or normalization of subjective symptoms; pathological, clinical, and biochemical findings; hepatic imaging; and liver histology. It is justified to administer EPL together with other therapeutic measurements in the liver. CONCLUSION: Pharmacological and clinical results confirm the efficacy of EPL in the treatment of FLD. PMID- 27217792 TI - The association between pro- and anti-inflammatory cytokine polymorphisms and periventricular leukomalacia in newborns with hypoxic-ischemic encephalopathy. AB - BACKGROUND: Periventricular leukomalacia (PVL) is a frequent consequence of hypoxic-ischemic injury. Functional cytokine gene variants that result in altered production of inflammatory (tumor necrosis factor-alpha [TNF-alpha] and interleukin-1beta [IL-1beta]) or anti-inflammatory (interleukin-10 [IL-10]) cytokines may modify disease processes, including PVL. OBJECTIVE: The aim of this study was to evaluate if there is a relationship between the two proinflammatory polymorphisms (TNF-alpha-1031T/C and IL-1beta-511C/T) and the anti-inflammatory polymorphism IL-10-1082G/A and PVL risk in Brazilian newborns with and without this injury. MATERIALS AND METHODS: A cross-sectional case-control study performed at the Neonatal Intensive Care Unit of the Children's Hospital and Maternity of the Sao Jose do Rio Preto Medical School (FAMERP). Fifty preterm and term newborns were examined as index cases and 50 term newborns as controls, of both sexes for both groups. DNA was extracted from peripheral blood leukocytes, and the sites that encompassed the three polymorphisms were amplified by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Gestational age ranged from 25 to 39 weeks, in the case group, and in the control group it ranged from 38 to 42.5 weeks (P<0.0001). Statistically significant association was found between TNF-alpha-1031T/C high expression genotype TC (odds ratio [OR], 2.495; 95% confidence interval [CI], 1.10-5.63; P=0.043) as well as between genotypes (TC + CC) (OR, 2.471; 95% CI, 1.10-5.55; P=0.044) and risk of PVL. Statistically significant association was found between IL-1beta-511C/T high expression genotypes (CT + TT) (OR, 23.120; 95% CI, 1.31-409.4; P=0.003) and risk of PVL. Statistically significant association between IL-10-1082G/A high expression genotype GG (OR, 0.07407; 95% CI, 0.02-0.34; P<0.0001) as well as between IL-10-1082G high expression allele (OR, 0.5098; 95% CI, 0.29-0.91; P=0,030) and PVL reduced risk was observed. There was a statistically significant association between TC/CT/GA genotype combination and the risk of PVL (OR, 6.469; 95% CI, 2.00-20.92; P=0.001). CONCLUSION: There is evidence of an association between the polymorphisms TNF-alpha-1031T/C, IL-1beta-511C/T, and IL-10-1082G/A and PVL risk in this Brazilian newborn population studied. PMID- 27217793 TI - Effective management of venous thromboembolism in the community: non-vitamin K antagonist oral anticoagulants. AB - Anticoagulation therapy is essential for the effective treatment and secondary prevention of venous thromboembolism (VTE). For many years, anticoagulation for acute VTE was limited to the use of initial parenteral heparin, overlapping with and followed by a vitamin K antagonist. Although highly effective, this regimen has several limitations and is particularly challenging when given in an ambulatory setting. Current treatment pathways for most patients with deep-vein thrombosis typically involve initial hospital or community-based ambulatory care with subsequent follow-up in a secondary care setting. With the introduction of non-vitamin K antagonist oral anticoagulants (NOACs) into routine clinical practice, it is now possible for the initial acute management of patients with deep-vein thrombosis to be undertaken by primary care. As hospital admissions associated with VTE become shorter, primary care will play an increasingly important role in the long-term management of these patients. Although the NOACs can potentially simplify patient management and improve clinical outcomes, primary care physicians may be less familiar with these new treatments compared with traditional therapy. To assist primary care physicians in further understanding the role of the NOACs, this article outlines the main differences between NOACs and traditional anticoagulation therapy and discusses the benefit risk profile of the different NOACs in the treatment and secondary prevention of recurrent VTE. Key considerations for the use of NOACs in the primary care setting are highlighted, including dose transition, risk assessment and follow up, duration of anticoagulant therapy, how to minimize bleeding risks, and the importance of patient education and counseling. PMID- 27217794 TI - Specific strength training compared with interdisciplinary counseling for girls with tension-type headache: a randomized controlled trial. AB - BACKGROUND: Childhood tension-type headache (TTH) is a prevalent and debilitating condition for the child and family. Low-cost nonpharmacological treatments are usually the first choice of professionals and parents. This study examined the outcomes of specific strength training for girls with TTH. METHODS: Forty-nine girls aged 9-18 years with TTH were randomized to patient education programs with 10 weeks of strength training and compared with those who were counseled by a nurse and physical therapist. Primary outcomes were headache frequency, intensity, and duration; secondary outcomes were neck-shoulder muscle strength, aerobic power, and pericranial tenderness, measured at baseline, after 10 weeks intervention, and at 12 weeks follow-up. Health-related quality of life (HRQOL) questionnaires were assessed at baseline and after 24 months. RESULTS: For both groups, headache frequency decreased significantly, P=0.001, as did duration, P=0.022, with no significant between-group differences. The odds of having headache on a random day decreased over the 22 weeks by 0.65 (0.50-0.84) (odds ratio [95% confidence interval]). For both groups, neck extension strength decreased significantly with a decrease in cervicothoracic extension/flexion ratio to 1.7, indicating a positive change in muscle balance. In the training group, shoulder strength increased $10% in 5/20 girls and predicted [Formula: see text] increased $15% for 4/20 girls. In the training group, 50% of girls with a headache reduction of $30% had an increase in [Formula: see text] >5%. For the counseling group, this was the case for 29%. A 24-month follow-up on HRQOL for the pooled sample revealed statistically significant improvements. Fifty-five percent of the girls reported little to none disability. CONCLUSION: The results indicate that both physical health and HRQOL can be influenced significantly by physical exercise and nurse counseling. More research is needed to examine the relationship between physical exercise, [Formula: see text], and TTH in girls. Thus, empowering patient education to promote maximum possible outcomes for all children needs more attention. PMID- 27217795 TI - Pharmacologic management of bone-related complications and bone metastases in postmenopausal women with hormone receptor-positive breast cancer. AB - There is a high risk for bone loss and skeletal-related events, including bone metastases, in postmenopausal women with hormone receptor-positive breast cancer. Both the disease itself and its therapeutic treatments can negatively impact bone, resulting in decreases in bone mineral density and increases in bone loss. These negative effects on the bone can significantly impact morbidity and mortality. Effective management and minimization of bone-related complications in postmenopausal women with hormone receptor-positive breast cancer remain essential. This review discusses the current understanding of molecular and biological mechanisms involved in bone turnover and metastases, increased risk for bone-related complications from breast cancer and breast cancer therapy, and current and emerging treatment strategies for managing bone metastases and bone turnover in postmenopausal women with hormone receptor-positive breast cancer. PMID- 27217796 TI - Multidisciplinary management for esophageal and gastric cancer. AB - The management of esophageal and gastric cancer is complex and involves multiple specialists in an effort to optimize patient outcomes. Utilizing a multidisciplinary team approach starting from the initial staging evaluation ensures that all members are in agreement with the plan of care. Treatment selection for esophageal and gastric cancer often involves a combination of chemotherapy, radiation, surgery, and palliative interventions (endoscopic and surgical), and direct communication between specialists in these fields is needed to ensure appropriate clinical decision making. At the University of Colorado, the Esophageal and Gastric Multidisciplinary Clinic was created to bring together all experts involved in treating these diseases at a weekly conference in order to provide patients with coordinated, individualized, and patient-centered care. This review details the essential elements and benefits of building a multidisciplinary program focused on treating esophageal and gastric cancer patients. PMID- 27217797 TI - Using existing questionnaires in latent class analysis: should we use summary scores or single items as input? A methodological study using a cohort of patients with low back pain. AB - BACKGROUND: Latent class analysis (LCA) is increasingly being used in health research, but optimal approaches to handling complex clinical data are unclear. One issue is that commonly used questionnaires are multidimensional, but expressed as summary scores. Using the example of low back pain (LBP), the aim of this study was to explore and descriptively compare the application of LCA when using questionnaire summary scores and when using single items to subgrouping of patients based on multidimensional data. MATERIALS AND METHODS: Baseline data from 928 LBP patients in an observational study were classified into four health domains (psychology, pain, activity, and participation) using the World Health Organization's International Classification of Functioning, Disability, and Health framework. LCA was performed within each health domain using the strategies of summary-score and single-item analyses. The resulting subgroups were descriptively compared using statistical measures and clinical interpretability. RESULTS: For each health domain, the preferred model solution ranged from five to seven subgroups for the summary-score strategy and seven to eight subgroups for the single-item strategy. There was considerable overlap between the results of the two strategies, indicating that they were reflecting the same underlying data structure. However, in three of the four health domains, the single-item strategy resulted in a more nuanced description, in terms of more subgroups and more distinct clinical characteristics. CONCLUSION: In these data, application of both the summary-score strategy and the single-item strategy in the LCA subgrouping resulted in clinically interpretable subgroups, but the single-item strategy generally revealed more distinguishing characteristics. These results 1) warrant further analyses in other data sets to determine the consistency of this finding, and 2) warrant investigation in longitudinal data to test whether the finer detail provided by the single-item strategy results in improved prediction of outcomes and treatment response. PMID- 27217798 TI - Sleep bruxism: challenges and restorative solutions. AB - Bruxism is a parafunctional activity related to clenching or grinding the teeth and tooth wear can be a consequence of sleep bruxism (SB). Management of severe tooth wear due to SB is a challenging situation because of the common reduced amount of remaining dental structure and loss of vertical dimension of occlusion. Rationale for the planning of oral rehabilitation of patients with SB presenting severe tooth wear should rely on evidence-based approaches; however, few studies have discussed properties of dental materials for SB rehabilitation and how to cosmetically manage severe tooth wear. This review aimed to provide an overview into bruxism cosmetic rehabilitation and how this can be implemented with good outcomes for the patient. PMID- 27217800 TI - The virgin land of quality management: a first measure of patient safety climate at the National Hospital of the Faroe Islands. AB - PURPOSE: The Faroe Islands are formally part of the Kingdom of Denmark, but the islands enjoy extensive autonomy as home ruled. In Denmark, extensive quality management initiatives have been implemented throughout hospitals, this was not the case in the Faroese Islands in 2013. The purpose of this study is to investigate the patient safety culture in the National Hospital of the Faroe Islands prior to implementation of quality management initiatives. METHODS: The Danish version of the Safety Attitudes Questionnaire (SAQ-DK) was distributed electronically to 557 staff members from five medical centers of the hospital, and one administrative unit. SAQ-DK has six cultural dimensions. The proportion of respondents with positive attitudes and mean scale scores were described, and comparison between medical specialties, and between clinical leaders and frontline staff was made using analysis of variance and chi-square test, respectively. RESULTS: The response rate was 65.8% (N=367). Job satisfaction was rated most favorable, and the perceived culture of the top management least favorable. Safety climate was the dimension with the greatest variability across the 28 units. The diagnostic center had the most favorable culture of all centers. More leaders than frontline staff had positive attitudes toward teamwork and safety climate, and working conditions, respectively. Also, the leaders perceived these dimensions more positive than the frontline staff, P<0.05. Among three management levels, the unit management was perceived most favorable and the top management least favorable. CONCLUSION: The management group is recommended to raise awareness of their role in supporting a safe and caring environment for patients and staff, moreover the leaders should ensure that every day work achieves its objectives; keeping the patients safe. Furthermore, following the development in patient safety culture over time is recommended. PMID- 27217799 TI - Abfraction lesions: etiology, diagnosis, and treatment options. AB - Abfraction is a type of noncarious cervical lesion (NCCL) characterized by loss of tooth tissues with different clinical appearances. Evidence supports that abfraction lesions, as any NCCLs, have a multifactorial etiology. Particularly, the cervical wear of abfraction can occur as a result of normal and abnormal tooth function and may also be accompanied by pathological wear, such as abrasion and erosion. The interaction between chemical, biological, and behavioral factors is critical and helps to explain why some individuals exhibit more than one type of cervical wear mechanism than others. In an era of personalized dentistry, patient risk factors for NCCLs must be identified and addressed before any treatment is performed. Marked variations exist in dental practice concerning the diagnosis and management of these lesions. The lack of understanding about the prognosis of these lesions with or without intervention may be a major contributor to variations in dentists' management decisions. This review focuses on the current knowledge and available treatment strategies for abfraction lesions. By recognizing that progressive changes in the cervical area of the tooth are part of a physiologically dynamic process that occurs with aging, premature and unnecessary intervention can be avoided. In cases of asymptomatic teeth, where tooth vitality and function are not compromised, abfraction lesions should be monitored for at least 6 months before any invasive procedure is planned. In cases of abfraction associated with gingival recession, a combined restorative-surgical approach may be performed. Restorative intervention and occlusal adjustment are not indicated as treatment options to prevent further tooth loss or progression of abfraction. The clinical decision to restore abfraction lesions may be based on the need to replace form and function or to relieve hypersensitivity of severely compromised teeth or for esthetic reasons. PMID- 27217801 TI - Knowledge of pregnant women on mother-to-child transmission of HIV, its prevention, and associated factors in Assosa town, Northwest Ethiopia. AB - INTRODUCTION: HIV/AIDS is a leading cause of death of children in sub-Saharan African countries. Almost all HIV-positive children acquire infection through mother-to-child transmission (MTCT) of HIV. Successful intervention toward prevention of mother-to-child transmission (PMTCT) and achieving the goal of eliminating the new HIV infection is highly dependent on everyone; especially, women of child-bearing age should have accurate and up-to-date knowledge about HIV transmission, risk of transmission to babies, and possible interventions. However, knowledge of MTCT of HIV, its prevention, and associated factors among women was not well studied in Benshangul Gumuz Region (Ethiopia). METHODS: A facility-based cross-sectional study was conducted involving 398 pregnant women who attended antenatal care services at governmental health institutions from February to March 2014 in Assosa town. Based on the flow of antenatal care attendants, the calculated sample size was proportionally allocated to the health facilities before data collection. Following this, systematic sampling method was used, and data were collected using an interviewer-administered questionnaire. Bivariate and multivariate binary logistic regression analysis was done using SPSS version 20 statistical packages. RESULT: A total of 386 pregnant women participated with a response rate of 97%, and 222 (57.5%) of them had full knowledge about the three critical modes of HIV transmission from mother to child, but only 67 (17.4%) knew the possible prevention methods. Knowledge on MTCT of HIV was positively associated with women who had sufficient knowledge on HIV/AIDS (adjusted odd ratio [AOR] =2.86, 95% confidence interval [CI] =1.54 5.32), women who had a favorable attitude to provider-initiated HIV counseling and testing (AOR =2.19, 95% CI =1.22-3.92), and women who did not expect any partner's reaction to positive HIV test result after testing (AOR =1.58, 95% CI =1.01-2.49). Correspondingly, knowledge on PMTCT of HIV was positively associated with women who had sufficient knowledge on HIV/AIDS (AOR =2.64, 95% CI =1.24 5.65), women who had favorable attitude toward provider's counseling and testing (AOR =4.27, 95% CI =1.95-9.34), and women who did not expect any partner's reaction to positive HIV test result after testing (AOR =3.56, 95% CI =1.58 8.01). CONCLUSION: Knowledge on MTCT and its prevention among women is low in the study area. We recommend more efforts to be exerted on improving women's knowledge of PMTCT of HIV. PMID- 27217802 TI - Hepatitis C in the Russian Federation: challenges and future directions. AB - Hepatitis C virus (HCV) infection is one of the most prevalent health problems in the world. Official registration of HCV infections in the Russian Federation started in 1994. Two clinical forms of infection - acute and chronic hepatitis C are registered separately. Moreover, the HCV national surveillance system also includes reports from laboratories on results from testing ~20 population risk groups for antibodies to HCV; approximately 15-16 million tests are performed annually. Modern epidemiological features of HCV infection in the Russian Federation are characterized by low incidence of the acute form of infection (acute HCV; one to two per 100,000) and a dramatic increase in chronic HCV (CHCV) cases. In 2013, the average nationwide rate of newly detected CHCV cases was 39.3/100,000. In the same year, the prevalence of CHCV demonstrating an accumulation of chronically infected patients in the country was much higher - 335.8/100,000. Four risk groups were identified as greatly affected by HCV, which were demonstrated by a high prevalence of antibodies to HCV: newborns from chronically infected women, persons from correctional facilities, patients with chronic liver diseases, and clients from clinics for sexually transmitted disease patients and drug users. It was found that several HCV genotypes circulated in different regions of the country; HCV1b had a prevalence of 55%-80% in almost every part of the country. However, in St Petersburg during the final decade of the last century and from 2001-2005, HCV3a subtype expanded circulation among young people due to increased intravenous drug addiction. Intravenous drug users were the major cause of a higher registration of double infection, with two different virus subtypes, and the appearance in Russia of new recombinant virus RF_2k/1b. It can be concluded that CHCV infection should be a focus of the health care system in Russia because serious epidemics of liver cirrhosis and hepatocellular carcinoma will be seen in the near future that will require urgent preventive and therapeutic measures. PMID- 27217803 TI - The effects of fabric for sleepwear and bedding on sleep at ambient temperatures of 17 degrees C and 22 degrees C. AB - The fibers used in clothing and bedding have different thermal properties. This study aimed to investigate the influences of textile fabrics on sleep under different ambient temperature (T a) conditions. Seventeen healthy young participants (ten males) underwent nine nights of polysomnography testing including an adaptation night. Participants were randomized to each of the three binary factors: sleepwear (cotton vs wool), bedding (polyester vs wool), and T a (17 degrees C vs 22 degrees C with relative humidity set at 60%). Skin temperature (T sk) and core temperature (T c) were monitored throughout the sleep period. Sleep onset latency (SOL) was significantly shortened when sleeping in wool with trends of increased total sleep time and sleep efficiency compared to cotton sleepwear. At 17 degrees C, the proportion of sleep stages 1 (%N1) and 3 (%N3) and rapid eye movement sleep was higher, but %N2 was lower than at 22 degrees C. Interaction effects (sleepwear * T a) showed a significantly shorter SOL for wool than cotton at 17 degrees C but lower %N3 for wool than cotton at 22 degrees C. A significantly lower %N2 but higher %N3 was observed for wool at 17 degrees C than at 22 degrees C. There was no bedding effect on sleep. Several temperature variables predicted the sleep findings in a stepwise multiple regression analysis and explained 67.8% of the variance in SOL and to a lesser degree the %N2 and %N3. These findings suggest that sleepwear played a contributory role to sleep outcomes and participants slept better at 17 degrees C than at 22 degrees C. PMID- 27217805 TI - Practical way of creating differential diagnoses through an expanded VITAMINSABCDEK mnemonic. AB - Having an organized, structured thinking process is critical in medicine. It is through this thinking process that enables one to go through the method of history-taking, which will eventually lead to making a definitive diagnosis and all other processes that follow. The use of mnemonic has been found to be useful for this purpose. The mnemonic VITAMINSABCDEK, is a convenient and practical way to assist in expanding the differential diagnoses and covers all possible causes of an illness. It is also easy to remember, as the vitamins whose letters are represented in this mnemonic cover the entire range of vitamins known. PMID- 27217804 TI - A novel implantable device for the treatment of obstructive sleep apnea: clinical safety and feasibility. AB - OBJECTIVE: Many cases of obstructive sleep apnea (OSA) involve collapse of the tongue base and soft palate during sleep, causing occlusion of the upper airway and leading to oxygen desaturation. Existing therapies can be effective, but they are plagued by patient adherence issues and the invasiveness of surgical approaches. A new, minimally invasive implant for OSA has been developed, which is elastic and contracts a few weeks after deployment, stabilizing the surrounding soft tissue. The device has had good outcomes in preclinical testing; this report describes the preliminary feasibility and safety of its implementation in humans. PATIENTS AND METHODS: A prospective, multicenter, single-arm feasibility study was conducted. Subjects were adults with moderate-to severe OSA who had previously failed or refused conventional continuous positive airway pressure treatment. Intraoperative feasibility data, postoperative pain, and safety information were collected for a 30-day postoperative period. RESULTS: Forty subjects participated (37 men, three women; average age of 46.1 years); each received two tongue-base implants and two soft-palate implants. Surgical procedure time averaged 43 minutes. Postsurgical pain resolved readily in most cases; at 30 days post implantation, <20% of subjects reported pain, which averaged less than two out of ten. Adverse events were generally the mild and expected sequelae of a surgical procedure with general anesthesia and intraoral manipulation. The device was well tolerated. Implant extrusions were reported with soft-palate implants (n=12), while tongue-base implants required few revisions (n=2). Quantitative and qualitative sleep effectiveness outcomes (including full-night polysomnographic and quality-of-life measures) will be presented in a subsequent report. CONCLUSION: Implantation of the device was feasible. Although a relatively high rate of extrusions occurred in the now discontinued palate implants, tongue-base implants were largely stable and well tolerated. The minimally invasive and maintenance-free implant may provide a new alternative to higher morbidity surgical procedures. PMID- 27217806 TI - Importance of incorporating teaching of feedback skills into medical curricula. PMID- 27217807 TI - Promotion of critical thinking in e-learning: a qualitative study on the experiences of instructors and students. AB - BACKGROUND: With the increasing popularity of e-learning programs, educational stakeholders are attempting to promote critical thinking in the virtual education system. This study aimed to explore the experiences of both the instructors and the students about critical thinking promotion within the virtual education system. METHODS: This qualitative study recruited the instructors and students from four academic disciplines provided by the Virtual School of Tehran University of Medical Sciences (Tehran, Iran). All programs were master's degree programs and utilized a blended (combination of e-learning and face to face) training. Semistructured interviews with the participants were used to collect data. RESULTS: The participants had a variety of experiences about how to promote critical thinking. These experiences were conceptualized in four main themes, namely, instructional design, educational leadership and management, local evidence, and belief systems. CONCLUSION: The present study clarified the factors affecting critical thinking promotion in e-learning. Not only the instructors but also the educational designers and leaders can benefit from our findings to improve the quality of virtual education programs and promote critical thinking. PMID- 27217808 TI - Pharmacotherapy for opioid dependence in jails and prisons: research review update and future directions. AB - PURPOSE: The World Health Organization recommends the initiation of opioid agonists prior to release from incarceration to prevent relapse or overdose. Many countries in the world employ these strategies. This paper considers the evidence to support these recommendations and the factors that have slowed their adoption in the US. METHODS: We reviewed randomized controlled trials (RCTs) and longitudinal/observational studies that examine participant outcomes associated with the initiation or continuation of opioid agonists (methadone, buprenorphine) or antagonists (naltrexone) during incarceration. Papers were identified through a literature search of PubMed with an examination of their references and were included if they reported outcomes for methadone, buprenorphine, or naltrexone continued during incarceration or initiated prior to release in a correctional institution. RESULTS: Fourteen studies were identified, including eight RCTs and six observational studies. One RCT found that patients treated with methadone who were continued on versus tapered off methadone during brief incarceration were more likely to return to treatment upon release. A second RCT found that the group starting methadone treatment in prison versus a waiting list was less likely to report using heroin and sharing syringes during incarceration. A third RCT found no differences in postrelease heroin use or reincarceration between individuals initiating treatment with methadone versus those initiating treatment with buprenorphine during relatively brief incarcerations. Findings from four additional RCTs indicate that starting opioid agonist treatment during incarceration versus after release was associated with higher rates of entry into community treatment and reduced heroin use. Finally, one pilot RCT showed that providing extended-release naltrexone prior to discharge resulted in significantly lower rates of opioid relapse compared to no medication. CONCLUSION: Reasons why uptake of these pharmacotherapies is limited in the US and relatively widespread in Europe are discussed. Recommendations for future research are outlined. PMID- 27217810 TI - A new method for discovering behavior patterns among animal movements. AB - Advanced satellite tracking technologies enable biologists to track animal movements at fine spatial and temporal scales. The resultant data present opportunities and challenges for understanding animal behavioral mechanisms. In this paper, we develop a new method to elucidate animal movement patterns from tracking data. Here, we propose the notion of continuous behavior patterns as a concise representation of popular migration routes and underlying sequential behaviors during migration. Each stage in the pattern is characterized in terms of space (i.e., the places traversed during movements) and time (i.e. the time spent in those places); that is, the behavioral state corresponding to a stage is inferred according to the spatiotemporal and sequential context. Hence, the pattern may be interpreted predictably. We develop a candidate generation and refinement framework to derive all continuous behavior patterns from raw trajectories. In the framework, we first define the representative spots to denote the underlying potential behavioral states that are extracted from individual trajectories according to the similarity of relaxed continuous locations in certain distinct time intervals. We determine the common behaviors of multiple individuals according to the spatiotemporal proximity of representative spots and apply a projection-based extension approach to generate candidate sequential behavior sequences as candidate patterns. Finally, the candidate generation procedure is combined with a refinement procedure to derive continuous behavior patterns. We apply an ordered processing strategy to accelerate candidate refinement. The proposed patterns and discovery framework are evaluated through conceptual experiments on both real GPS-tracking and large synthetic datasets. PMID- 27217809 TI - Progress toward pharmacotherapies for cannabis-use disorder: an evidence-based review. AB - Cannabis is the most widely used and variably regulated drug in the world, with increasing trends of use being reported in the US, Australia, Asia, and Africa. Evidence has shown a decrease in the age of commencement of cannabis use in some developed countries and a prolongation of risk of initiation to cannabis use beyond adolescence among more recent users. Cannabis use is associated with numerous health risks and long-term morbidity, as well as risk of developing cannabis-use disorders. Cannabis users infrequently seek professional treatment, and normally do so after a decade of use. Cannabis-use disorders are currently treated using a selection of psychosocial interventions. Severity of withdrawal is a factor that increases the risk of relapse, and is the target of pharmacotherapy studies. Currently, there is no approved pharmacotherapy for cannabis-use disorders. A number of approaches have been examined, and trials are continuing to find a safe and effective medication with little abuse liability. PMID- 27217811 TI - THE EFFECT OF MONOSIALOGANGLYOSIDE (GM-1) ADMINISTRATION IN SPINAL CORD INJURY. AB - OBJECTIVE: To evaluate the effect of monosialoganglioside (GM-1) in spinal cord trauma patients seen in our service who have not been treated with methylprednisolone. METHODS: Thirty patients with acute spinal cord trauma were randomly divided into two groups. In Group 1, patients received 200 mg GM-1 in the initial assessment and thereafter received 100 mg intravenous per day for 30 days and Group 2 (control) received saline. Patients were evaluated periodically (at 6 weeks, 6 months, one year and two years), using a standardized neurological assessment of the American Spinal Injury Association / International Spinal Cord Society. RESULTS: The comparative statistical analysis of motor indices, sensitive indices for pain and touch according to the standardization of ASIA / ISCOS showed that the assessments at 6 weeks, 6 months and 2 years, GM-Group 1 patients had higher rates than the control group regarding sensitivity to pain and touch, with no statistically significant difference from the motor index. CONCLUSION: The functional assessment showed improvement in the sensitive indices of patients treated with GM1 after post-traumatic spinal cord injury compared to patients who received placebo. Level of Evidence IV, Prospective Case Studies Series. PMID- 27217812 TI - PLATEAU-PATELLA ANGLE: AN OPTION FOR ASSESSING PATELLAR HEIGHT ON PROXIMAL TIBIA OSTEOTOMY. AB - OBJECTIVE: To compare the plateau-patella angle method to the methods already established for patellar height measurement in patients undergoing high tibial osteotomy. METHODS: This is a retrospective study of 13 patients undergoing medial opening tibial osteotomy. The patellar height was measured in pre and post operative radiographs by the methods from Insall-Salvati, Caton-Deschamps, Blackburne-Peel and patella-plateau angle, as well as the tibial slope and length of the patellar tendon. Measurements were performed by two knee surgeons at two different times. RESULTS: The mean age was 41.33 +/- 01.09 years old. The average rates of Caton-Deschamps, Blackburne-Peel, Insall-Salvati and plateau-patella angle were, respectively, 1.00; 0.89; 1.10; and 23.15 degrees preoperatively, and 0.89; 0.78; 1.11; and 20.46 degrees , postoperatively. The correlation of Caton-Deschamps, Blackburne-Pell, and Insall-Salvati indexes and plateau-patellar angle interobserver was 0.72 (p <0.001), 0:54 (p <0.001), 0.65 (p <0.001), and 0.67 (w <0.001), respectively. CONCLUSION: The plateau-patella angle method undergoes changes that are correlated with changes in tibial slope after osteotomy, unlike the classical methods. This fact may lead to overestimate the reduction of patellar height after osteotomy. Level of evidence IV. Case Series. PMID- 27217813 TI - EFFECT OF TRANEXAMIC ACID ON BLEEDING CONTROL IN TOTAL KNEE ARTHROPLASTY. AB - OBJECTIVES: To analyze the effectiveness of intravenous (IV) tranexamic acid (TA) in reducing blood loss in total knee arthroplasty (TKA). METHOD: The population sample was composed of patients with a diagnosis of primary knee osteoarthritis. The patients undergoing TKA were divided in two groups. Group A: comprised patients who used IV TA and B group, formed by patients who did not use TA in the intra or post-operative period. For descriptive analysis, quantitative variables were represented by mean and standard deviations when their distribution was normal and interquartile ranges and medians for non-normal variables. RESULTS: The mean age of patients was 68 years old, most of them were female and with involvement of the left knee. Postoperatively patients who had used IV TA showed less bleeding rate and less hemoglobin rate reduction. CONCLUSION: The use of IV TA in TKA reduces blood loss in peri- and postoperative periods. Regarding total blood loss reduction, hemoglobin rate and need for blood transfusions, IV TA should be used routinely during TKA since it has been shown to be safe with no increase in side effects as thromboembolic events. Level of Evidence III. Retrospective Comparative Study. PMID- 27217814 TI - KNEE SYNERGISM DURING GAIT REMAIN ALTERED ONE YEAR AFTER ACL RECONSTRUCTION. AB - OBJECTIVE: To compare the activation of the vastus lateralis (VL) and biceps femoris (BF) muscles during gait, as well VL/BF muscular co-contraction (MCC) between healthy (CG) and anterior cruciate ligament reconstructed (ACL-R) subjects. METHODS: Nineteen subjects, ten controls and nine ACL-R patients had a VL and BF electromyogram (EMG) captured to calculate the MCC ratio. A Principal Component (PC) Analysis was applied to reduce the dimensionality effect of each of the MCC, VL and BF curves for both healthy and ACL reconstructed groups. The PC scores were used to calculate the standard distance (SD). SD values were employed in order to compare each dependent variable (MCC, VL and BF) between the two groups using unpaired t-test. RESULTS: ACL-R group presented a lower VL activation at the beginning and at the end of the gait cycle, as compared to the control group. However, no difference was found for BF or VL/BF MCC. CONCLUSION: The gait analysis of ACL reconstructed patients demonstrated a persistent deficit in VL activation when compared to the control group, even one year after surgery. Level of Evidence III. Case Control Study. PMID- 27217815 TI - SERUM VALUES OF ALKALINE PHOSPHATASE AND LACTATE DEHYDROGENASE IN OSTEOSARCOMA. AB - OBJECTIVE: To study the relationship between the pre and post chemotherapy (CT) serum levels of alkaline phosphatase (AP) and lactate dehydrogenase (LDH), and the percentage of tumor necrosis (TN) found in specimens after the pre surgical CT in patients with osteosarcoma. METHODS: Series of cases with retrospective evaluation of patients diagnosed with osteosarcoma. Participants were divided into two groups according to serum values of both enzymes. The values of AP and LDH were obtained before and after preoperative CT. The percentage of tumor necrosis (TN) of surgical specimens of each patient was also included. RESULTS: One hundred and thirty seven medical records were included from 1990 to 2013. Both the AP as LDH decreased in the patients studied, being the higher in pre CT than post CT. The average LHD decrease was 795.12U/L and AP decrease was 437.40 U/L. The average TN was 34.10 %. There was no statistically significant correlation between the serums values and the percentage of tumoral necrosis. CONCLUSION: The serum levels values of AP and LDH are not good predictors for the chemotherapy-induced necrosis in patients with osteosarcoma. Level of Evidence IV, Case Series. PMID- 27217816 TI - EXTRA-ABDOMINAL DESMOID TUMOR: LOCAL RECURRENCE AND TREATMENT OPTIONS. AB - OBJECTIVE: To evaluate the rate of local recurrence of extra-abdominal desmoid tumor and compare the outcomes of surgical treatment and conservative treatment. METHODS: Twenty one patients (14 women and seven men), mean age 33.0+/-8.7 years old, with a diagnosis of desmoid tumor were evaluated. The mean follow-up period was 58.5+/-29.0 months. Fourteen cases involved the lower limbs, four cases involved the upper limbs, and three cases involved the trunk. The average tumor size was 12.7+/-7.5 cm. Of the 21 patients, 14 did not undergo previous treatment and seven patients relapsed before the initial evaluation. Surgical treatment was performed in 16 patients and conservative treatment was performed in five patients. RESULTS: Recurrence occurred in seven patients (33%) and six of them relapsed within the first 18 months. No significant difference was observed between conservative and surgical treatment. However, a significant difference was observed among patients undergoing wide resection and who experienced improved local control. CONCLUSION: The recurrence rate of desmoid tumor was 33.3%. There was no difference in recurrence between conservative and surgical treatment. In surgical treatment, wide margins showed better results for recurrence control. Level of Evidence III. Retrospective Observational Study. PMID- 27217817 TI - TUMORS OF THE PATELLA: THE EXPERIENCE OF INSTITUTE OF ORTHOPEDICS AND TRAUMATOLOGY AT UNIVERSITY OF SAO PAULO, BRAZIL. AB - OBJECTIVE: To obtain epidemiological data from the tumors of the patella diagnosed and treated at the Instituto de Ortopedia e Traumatologia do Hospital das Clinicas da Universidade de Sao Paulo (IOT-HC-FMUSP) between 1998 and 2015. METHODS: Series of cases with retrospective evaluation of patients diagnosed with tumors located in the patella. The data was obtained from the records and patients' charts at the Department of Pathology of IOT-HC-FMUSP. RESULTS: A total of 2220 medical records from patients with anatomopathological reports were included in the study. Only eight (0.3%) patients had patellar tumors. We found that six (75%) of these were benign, one (12.5%) was a pseudotumoral lesions and one (12.5%) was reported as malignant. Among benign tumors, the giant cell tumor (GCT) was the most frequently reported corresponding to 50% of the cases. Hemagioendothelioma was the only case of malignant tumor in this series. As for the pseudotumoral lesions, we found a brown tumor. CONCLUSION: From the data obtained retrospectively in a 17 year time frame, in a service that treats benign, malignant and pseudotumoral bone lesions, we conclude that our casuistry in patellar tumors is similar to that reported in scientific literature, where benign tumors are predominant in a 7:1 ratio over malignant tumors, being a rare location of appearance, with the GCT as the most common diagnosis . Level of Evidence IV, Case Series. PMID- 27217818 TI - PELVIC INJURY IN CHILDHOOD: WHAT IS ITS CURRENT IMPORTANCE? AB - OBJECTIVE: The purpose of this study was to assess the importance of pelvic fractures in childhood by analyzing epidemiological characteristics and associated injuries. METHODS: This is a retrospective study performed between 2002 and 2012 at two trauma referral centers in Sao Paulo. We identified 25 patients aged 16 years old or younger with pelvic fracture. RESULTS: The main mechanism of trauma was traffic accident (80%), followed by fall from height (16%). At hospital admission, 92% had traumatic brain injury and 40% had hemodynamic instability. Besides pelvic fractures, 56% of the children had other associated injuries (genitourinary, abdominal, vascular, chest and neurological), and 79% of them required operative treatment. According to the Torode and Zieg classification, the majority of cases were types III and IV. Seventy-two percent of all pelvic fractures were treated by surgery; 52% involved external fixation and 20% involved open reduction and internal fixation. CONCLUSIONS: The pelvic fractures in childhood can be considered a marker for injury severity, because the associated injuries usually are severe, needing operative treatment and leading to a high mortality rate (12%). Level of Evidence IV, Case Series. PMID- 27217819 TI - TREATMENT OF SCAPHOID NONUNION WITH OLECRANON BONE GRAFT AND COMPRESSION SCREW. AB - OBJECTIVE: To evaluate the outcome of olecranon bone graft and compression screw for the treatment of nonunion of the Lichtman type I scaphoid. METHOD: We evaluated 15 patients of 32 who underwent surgical treatment for nonunion of the Lichtman type I scaphoid with olecranon bone graft and screw compression. RESULTS: We obtained 100% consolidation in our sample. The mean flexion of the wrist on the affected side was 68 degrees and 75 degrees on the non-affected side. The average extension was 63 degrees and 72 degrees , respectively. The average grip strength was 35 kgf. This corresponds to 98% of the handgrip strength of the non-affected side, which was 37 kgf. The DASH score averaged 5 points. CONCLUSION: We believe that the use of bone graft obtained from the olecranon and secured with cannulated screw is a resolute technique for cases of linear nonunion of the Lichtmann type I scaphoid. It has the advantages of a new anesthesia for removal of the graft and the access is easy, providing a good exposure for removal and good aesthetic results. Level of evidence IV. Case series. PMID- 27217820 TI - APOPHYSEAL FRACTURE OR AVULSION OF THE GREATER TROCHANTER. AB - The apophyseal fracture or avulsion of the greater trochanter occurs in skeletally immature patients. It has at etiological factors indirect mechanisms (avulsion) and direct mechanisms (trauma on the trochanter), the latter being the most common. The clinical presentation is easily identified and a simple X- ray can confirm the diagnosis. Regardless of the treatment chosen, this pathology has a high correlation with osteonecrosis of the femoral head, even as a rare fact, however with innocent appearance, on this pathology. PMID- 27217822 TI - A randomized clinical trial of tailored interventions for health promotion and recidivism reduction among homeless parolees: outcomes and cost analysis. AB - OBJECTIVES: This study conducted a randomized controlled trial with 600 recently released homeless men exiting California jails and prisons. METHODS: The purpose of this study was to primarily ascertain how different levels of intensity in peer coaching and nurse-partnered intervention programs may impact reentry outcomes; specifically: (a) an intensive peer coach and nurse case managed (PC NCM) program; (b) an intermediate peer coaching (PC) program with brief nurse counseling; and (c) the usual care (UC) program involving limited peer coaching and brief nurse counseling. Secondary outcomes evaluated the operational cost of each program. RESULTS: When compared to baseline, all three groups made progress on key health-related outcomes during the 12-month intervention period; further, 84.5 % of all participants eligible for hepatitis A/B vaccination completed their vaccine series. The results of the detailed operational cost analysis suggest the least costly approach (i.e., UC), which accounted for only 2.11 % of the total project expenditure, was as effective in achieving comparable outcomes for this parolee population as the PC-NCM and PC approaches, which accounted for 53.98 % and 43.91 %, respectively, of the project budget. CONCLUSIONS: In this study, all three intervention strategies were found to be comparable in achieving a high rate of vaccine completion, which over time will likely produce tremendous savings to the public health system. PMID- 27217823 TI - Parallelizing Backpropagation Neural Network Using MapReduce and Cascading Model. AB - Artificial Neural Network (ANN) is a widely used algorithm in pattern recognition, classification, and prediction fields. Among a number of neural networks, backpropagation neural network (BPNN) has become the most famous one due to its remarkable function approximation ability. However, a standard BPNN frequently employs a large number of sum and sigmoid calculations, which may result in low efficiency in dealing with large volume of data. Therefore to parallelize BPNN using distributed computing technologies is an effective way to improve the algorithm performance in terms of efficiency. However, traditional parallelization may lead to accuracy loss. Although several complements have been done, it is still difficult to find out a compromise between efficiency and precision. This paper presents a parallelized BPNN based on MapReduce computing model which supplies advanced features including fault tolerance, data replication, and load balancing. And also to improve the algorithm performance in terms of precision, this paper creates a cascading model based classification approach, which helps to refine the classification results. The experimental results indicate that the presented parallelized BPNN is able to offer high efficiency whilst maintaining excellent precision in enabling large-scale machine learning. PMID- 27217824 TI - An Improved Genetic Fuzzy Logic Control Method to Reduce the Enlargement of Coal Floor Deformation in Shearer Memory Cutting Process. AB - In order to reduce the enlargement of coal floor deformation and the manual adjustment frequency of rocker arms, an improved approach through integration of improved genetic algorithm and fuzzy logic control (GFLC) method is proposed. The enlargement of coal floor deformation is analyzed and a model is built. Then, the framework of proposed approach is built. Moreover, the constituents of GA such as tangent function roulette wheel selection (Tan-RWS) selection, uniform crossover, and nonuniform mutation are employed to enhance the performance of GFLC. Finally, two simulation examples and an industrial application example are carried out and the results indicate that the proposed method is feasible and efficient. PMID- 27217825 TI - Spike Code Flow in Cultured Neuronal Networks. AB - We observed spike trains produced by one-shot electrical stimulation with 8 * 8 multielectrodes in cultured neuronal networks. Each electrode accepted spikes from several neurons. We extracted the short codes from spike trains and obtained a code spectrum with a nominal time accuracy of 1%. We then constructed code flow maps as movies of the electrode array to observe the code flow of "1101" and "1011," which are typical pseudorandom sequence such as that we often encountered in a literature and our experiments. They seemed to flow from one electrode to the neighboring one and maintained their shape to some extent. To quantify the flow, we calculated the "maximum cross-correlations" among neighboring electrodes, to find the direction of maximum flow of the codes with lengths less than 8. Normalized maximum cross-correlations were almost constant irrespective of code. Furthermore, if the spike trains were shuffled in interval orders or in electrodes, they became significantly small. Thus, the analysis suggested that local codes of approximately constant shape propagated and conveyed information across the network. Hence, the codes can serve as visible and trackable marks of propagating spike waves as well as evaluating information flow in the neuronal network. PMID- 27217826 TI - Detecting the Intention to Move Upper Limbs from Electroencephalographic Brain Signals. AB - Early decoding of motor states directly from the brain activity is essential to develop brain-machine interfaces (BMI) for natural motor control of neuroprosthetic devices. Hence, this study aimed to investigate the detection of movement information before the actual movement occurs. This information piece could be useful to provide early control signals to drive BMI-based rehabilitation and motor assisted devices, thus providing a natural and active rehabilitation therapy. In this work, electroencephalographic (EEG) brain signals from six healthy right-handed participants were recorded during self-initiated reaching movements of the upper limbs. The analysis of these EEG traces showed that significant event-related desynchronization is present before and during the execution of the movements, predominantly in the motor-related alpha and beta frequency bands and in electrodes placed above the motor cortex. This oscillatory brain activity was used to continuously detect the intention to move the limbs, that is, to identify the motor phase prior to the actual execution of the reaching movement. The results showed, first, significant classification between relax and movement intention and, second, significant detection of movement intention prior to the onset of the executed movement. On the basis of these results, detection of movement intention could be used in BMI settings to reduce the gap between mental motor processes and the actual movement performed by an assisted or rehabilitation robotic device. PMID- 27217827 TI - Progress in the Development of Nanotheranostic Systems. AB - This thematic issue includes both review and research articles and is intended to provide an overview on the recent progress in the development of nanostructure based therapeutic, diagnostic, and theranostic systems. PMID- 27217828 TI - Current and Future Theranostic Applications of the Lipid-Calcium-Phosphate Nanoparticle Platform. AB - Over the last four years, the Lipid-Calcium-Phosphate (LCP) nanoparticle platform has shown success in a wide range of treatment strategies, recently including theranostics. The high specific drug loading of radiometals into LCP, coupled with its ability to efficiently encapsulate many types of cytotoxic agents, allows a broad range of theranostic applications, many of which are yet unexplored. In addition to providing an overview of current medical imaging modalities, this review highlights the current theranostic applications for LCP using SPECT and PET, and discusses potential future uses of the platform by comparing it with both systemically and locally delivered clinical radiotherapy options as well as introducing its applications as an MRI contrast agent. Strengths and weaknesses of LCP and of nanoparticles in general are discussed, as well as caveats regarding the use of fluorescence to determine the accumulation or biodistribution of a probe. PMID- 27217829 TI - Dendritic Polymers for Theranostics. AB - Dendritic polymers are highly branched polymers with controllable structures, which possess a large population of terminal functional groups, low solution or melt viscosity, and good solubility. Their size, degree of branching and functionality can be adjusted and controlled through the synthetic procedures. These tunable structures correspond to application-related properties, such as biodegradability, biocompatibility, stimuli-responsiveness and self-assembly ability, which are the key points for theranostic applications, including chemotherapeutic theranostics, biotherapeutic theranostics, phototherapeutic theranostics, radiotherapeutic theranostics and combined therapeutic theranostics. Up to now, significant progress has been made for the dendritic polymers in solving some of the fundamental and technical questions toward their theranostic applications. In this review, we briefly summarize how to control the structures of dendritic polymers, the theranostics-related properties derived from their structures and their theranostics-related applications. PMID- 27217830 TI - Recent Progress in Light-Triggered Nanotheranostics for Cancer Treatment. AB - Treatments of high specificity are desirable for cancer therapy. Light-triggered nanotheranostics (LTN) mediated cancer therapy could be one such treatment, as they make it possible to visualize and treat the tumor specifically in a light controlled manner with a single injection. Because of their great potential in cancer therapy, many novel and powerful LTNs have been developed, and are mainly prepared from photosensitizers (PSs) ranging from small organic dyes such as porphyrin- and cyanine-based dyes, semiconducting polymers, to inorganic nanomaterials such as gold nanoparticles, transition metal chalcogenides, carbon nanotubes and graphene. Using LTNs and localized irradiation in combination, complete tumor ablation could be achieved in tumor-bearing animal models without causing significant toxicity. Given their great advances and promising future, we herein review LTNs that have been tested in vivo with a highlight on progress that has been made in the past a couple of years. The current challenges faced by these LTNs are also briefly discussed. PMID- 27217831 TI - Click Chemistry-Mediated Nanosensors for Biochemical Assays. AB - Click chemistry combined with functional nanoparticles have drawn increasing attention in biochemical assays because they are promising in developing biosensors with effective signal transformation/amplification and straightforward signal readout for clinical diagnostic assays. In this review, we focus on the latest advances of biochemical assays based on Cu (I)-catalyzed 1, 3-dipolar cycloaddition of azides and alkynes (CuAAC)-mediated nanosensors, as well as the functionalization of nanoprobes based on click chemistry. Nanoprobes including gold nanoparticles, quantum dots, magnetic nanoparticles and carbon nanomaterials are covered. We discuss the advantages of click chemistry-mediated nanosensors for biochemical assays, and give perspectives on the development of click chemistry-mediated approaches for clinical diagnosis and other biomedical applications. PMID- 27217833 TI - Safe and Immunocompatible Nanocarriers Cloaked in RBC Membranes for Drug Delivery to Treat Solid Tumors. AB - The therapeutic potential of nanoparticle-based drug carriers depends largely on their ability to evade the host immune system while delivering their cargo safely to the site of action. Of particular interest are simple strategies for the functionalization of nanoparticle surfaces that are both inherently safe and can also bestow immunoevasive properties, allowing for extended blood circulation times. Here, we evaluated a recently reported cell membrane-coated nanoparticle platform as a drug delivery vehicle for the treatment of a murine model of lymphoma. These biomimetic nanoparticles, consisting of a biodegradable polymeric material cloaked with natural red blood cell membrane, were shown to efficiently deliver a model chemotherapeutic, doxorubicin, to solid tumor sites for significantly increased tumor growth inhibition compared with conventional free drug treatment. Importantly, the nanoparticles also showed excellent immunocompatibility as well as an advantageous safety profile compared with the free drug, making them attractive for potential translation. This study demonstrates the promise of using a biomembrane-coating approach as the basis for the design of functional, safe, and immunocompatible nanocarriers for cancer drug delivery. PMID- 27217832 TI - Versatile Nanosystem-Based Cancer Theranostics: Design Inspiration and Predetermined Routing. AB - The relevance of personalized medicine, aimed at a more individualized drug therapy, has inspired research into nano-based concerted diagnosis and therapeutics (theranostics). As the intention is to "kill two birds with one stone", scientists have already described the emerging concept as a treasured tailor for the future of cancer therapy, wherein the main idea is to design "smart" nanosystems to concurrently discharge both therapeutic and diagnostic roles. These nanosystems are expected to offer a relatively clearer view of the ingenious cellular trafficking pathway, in-situ diagnosis, and therapeutic efficacy. We herein present a detailed review of versatile nanosystems, with prominent examples of recently developed intelligent delivery strategies which have gained attention in the field of theranostics. These nanotheranostics include various mechanisms programmed in novel platforms to enable predetermined delivery of cargo to specific sites, as well as techniques to overcome the notable challenges involved in the efficacy of theranostics. PMID- 27217834 TI - A Facile Approach to Functionalize Cell Membrane-Coated Nanoparticles. AB - Convenient strategies to provide cell membrane-coated nanoparticles (CM-NPs) with multi-functionalities beyond the natural function of cell membranes would dramatically expand the application of this emerging class of nanomaterials. We have developed a facile approach to functionalize CM-NPs by chemically modifying live cell membranes prior to CM-NP fabrication using a bifunctional linker, succinimidyl-[(N-maleimidopropionamido)-polyethyleneglycol] ester (NHS-PEG Maleimide). This method is particularly suitable to conjugate large bioactive molecules such as proteins on cell membranes as it establishes a strong anchorage and enable the control of linker length, a critical parameter for maximizing the function of anchored proteins. As a proof of concept, we show the conjugation of human recombinant hyaluronidase, PH20 (rHuPH20) on red blood cell (RBC) membranes and demonstrate that long linker (MW: 3400) is superior to short linker (MW: 425) for maintaining enzyme activity, while minimizing the changes to cell membranes. When the modified membranes were fabricated into RBC membrane-coated nanoparticles (RBCM-NPs), the conjugated rHuPH20 can assist NP diffusion more efficiently than free rHuPH20 in matrix-mimicking gels and the pericellular hyaluronic acid matrix of PC3 prostate cancer cells. After quenching the unreacted chemical groups with polyethylene glycol, we demonstrated that the rHuPH20 modification does not reduce the ultra-long blood circulation time of RBCM-NPs. Therefore, this surface engineering approach provides a platform to functionlize CM-NPs without sacrificing the natural function of cell membranes. PMID- 27217835 TI - Solid Tumor Therapy Using a Cannon and Pawn Combination Strategy. AB - Nanocarrier-based anti-tumor drugs hold great promise for reducing side effects and improving tumor-site drug retention in the treatment of solid tumors. However, therapeutic outcomes are still limited, primarily due to a lack of drug penetration within most tumor tissues. Herein, we propose a strategy using a nanocarrier-based combination of vascular disrupting agents (VDAs) and cytotoxic drugs for solid tumor therapy. Specifically, combretastatin A-4 (CA4) serves as a "cannon" by eradicating tumor cells at a distance from blood vessels; concomitantly, doxorubicin (DOX) serves as a "pawn" by killing tumor cells in close proximity to blood vessels. This "cannon and pawn" combination strategy acts without a need to penetrate every tumor cell and is expected to eliminate all tumor cells in a solid tumor. In a murine C26 colon tumor model, this strategy proved effective in eradicating greater than 94% of tumor cells and efficiently inhibited tumor growth with a weekly injection. In large solid tumor models (C26 and 4T1 tumors with volumes of approximately 250 mm(3)), this strategy also proved effective for inhibiting tumor growth. These results showing remarkable inhibition of tumor growth provide a valuable therapeutic choice for solid tumor therapy. PMID- 27217836 TI - Polydopamine Nanoparticles as a Versatile Molecular Loading Platform to Enable Imaging-guided Cancer Combination Therapy. AB - Cancer combination therapy to treat tumors with different therapeutic approaches can efficiently improve treatment efficacy and reduce side effects. Herein, we develop a theranostic nano-platform based on polydopamine (PDA) nanoparticles, which then are exploited as a versatile carrier to allow simultaneous loading of indocyanine green (ICG), doxorubicin (DOX) and manganese ions (PDA-ICG PEG/DOX(Mn)), to enable imaging-guided chemo & photothermal cancer therapy. In this system, ICG acts as a photothermal agent, which shows red-shifted near infrared (NIR) absorbance and enhanced photostability compared with free ICG. DOX, a model chemotherapy drug, is then loaded onto the surface of PDA-ICG-PEG with high efficiency. With Mn(2+) ions intrinsically chelated, PDA-ICG PEG/DOX(Mn) is able to offer contrast under T1-weighted magnetic resonance (MR) imaging. In a mouse tumor model, the MR imaging-guided combined chemo- & photothermal therapy achieves a remarkable synergistic therapeutic effect compared with the respective single treatment modality. This work demonstrates that PDA nanoparticles could serve as a versatile molecular loading platform for MR imaging guided combined chemo- & photothermal therapy with minimal side effects, showing great potential for cancer theranostics. PMID- 27217837 TI - Indocyanine Green-Loaded Polydopamine-Reduced Graphene Oxide Nanocomposites with Amplifying Photoacoustic and Photothermal Effects for Cancer Theranostics. AB - Photoacoustic (PA) imaging and photothermal therapy (PTT) as light-induced theranostic platforms have been attracted much attention in recent years. However, the development of highly efficient and integrated phototheranostic nanoagents for amplifying PA imaging and PTT treatments poses great challenges. Here, we report a novel phototheranostic nanoagent using indocyanine green-loaded polydopamine-reduced graphene oxide nanocomposites (ICG-PDA-rGO) with amplifying PA and PTT effects for cancer theranostics. The results demonstrate that the PDA layer coating on the surface of rGO could effectively absorb a large number of ICG molecules, quench ICG's fluorescence, and enhance the PDA-rGO's optical absorption at 780 nm. The obtained ICG-PDA-rGO exhibits stronger PTT effect and higher PA contrast than that of pure GO and PDA-rGO. After PA imaging-guided PTT treatments, the tumors in 4T1 breast subcutaneous and orthotopic mice models are suppressed completely and no treatment-induced toxicity being observed. It illustrates that the ICG-PDA-rGO nanocomposites constitute a new class of theranostic nanomedicine for amplifying PA imaging and PTT treatments. PMID- 27217838 TI - ATP-Responsive and Near-Infrared-Emissive Nanocarriers for Anticancer Drug Delivery and Real-Time Imaging. AB - Stimuli-responsive and imaging-guided drug delivery systems hold vast promise for enhancement of therapeutic efficacy. Here we report an adenosine-5'-triphosphate (ATP)-responsive and near-infrared (NIR)-emissive conjugated polymer-based nanocarrier for the controlled release of anticancer drugs and real-time imaging. We demonstrate that the conjugated polymeric nanocarriers functionalized with phenylboronic acid tags on surface as binding sites for ATP could be converted to the water-soluble conjugated polyelectrolytes in an ATP-rich environment, which promotes the disassembly of the drug carrier and subsequent release of the cargo. In vivo studies validate that this formulation exhibits promising capability for inhibition of tumor growth. We also evaluate the metabolism process by monitoring the fluorescence signal of the conjugated polymer through the in vivo NIR imaging. PMID- 27217841 TI - Epigenetic drugs: from chemistry via biology to medicine and back. PMID- 27217840 TI - Nanotechnology and cancer: improving real-time monitoring and staging of bladder cancer with multimodal mesoporous silica nanoparticles. AB - BACKGROUND: Despite being one of the most common cancers, bladder cancer is largely inefficiently and inaccurately staged and monitored. Current imaging methods detect cancer only when it has reached "visible" size and has significantly disrupted the structure of the organ. By that time, thousands of cells will have proliferated and perhaps metastasized. Repeated biopsies and scans are necessary to determine the effect of therapy on cancer growth. In this report, we describe a novel approach based on multimodal nanoparticle contrast agent technology and its application to a preclinical animal model of bladder cancer. The innovation relies on the engineering core of mesoporous silica with specific scanning contrast properties and surface modification that include fluorescence and magnetic resonance imaging (MRI) contrast. The overall dimensions of the nano-device are preset at 80-180 nm, depending on composition with a pore size of 2 nm. METHODS: To facilitate and expedite discoveries, we combined a well-known model of bladder cancer and our novel technology. We exposed nanoparticles to MB49 murine bladder cancer cells in vitro and found that 70 % of the cells were labeled by nanoparticles as measured by flow cytometry. The in vivo mouse model for bladder cancer is particularly well suited for T1- and T2-weighted MRI. RESULTS: Under our experimental conditions, we demonstrate that the nanoparticles considerably improve tumor definition in terms of volumetric, intensity and structural characteristics. Important bladder tumor parameters can be ascertained, non-invasively, repetitively, and with great accuracy. Furthermore, since the particles are not biodegradable, repetitive injection is not required. This feature allows follow-up diagnostic evaluations during cancer treatment. Changes in MRI signals show that in situ uptake of free particles has predilection to tumor cells relative to normal bladder epithelium. The particle distribution within the tumors was corroborated by fluorescent microscopy of sections of excised bladders. In addition, MRI imaging revealed fibrous finger-like projections into the tumors where particles insinuated themselves deeply. This morphological characteristic was confirmed by fluorescence microscopy. CONCLUSIONS: These findings may present new options for therapeutic intervention. Ultimately, the combination of real-time and repeated MRI evaluation of the tumors enhanced by nanoparticle contrast may have the potential for translation into human clinical studies for tumor staging, therapeutic monitoring, and drug delivery. PMID- 27217839 TI - Supramolecular Crafting of Self-Assembling Camptothecin Prodrugs with Enhanced Efficacy against Primary Cancer Cells. AB - Chemical modification of small molecule hydrophobic drugs is a clinically proven strategy to devise prodrugs with enhanced treatment efficacy. While this prodrug strategy improves the parent drug's water solubility and pharmacokinetic profile, it typically compromises the drug's potency against cancer cells due to the retarded drug release rate and reduced cellular uptake efficiency. Here we report on the supramolecular design of self-assembling prodrugs (SAPD) with much improved water solubility while maintaining high potency against cancer cells. We found that camptothecin (CPT) prodrugs created by conjugating two CPT molecules onto a hydrophilic segment can associate into filamentous nanostructures in water. Our results suggest that these SAPD exhibit much greater efficacy against primary brain cancer cells relative to that of irinotecan, a clinically used CPT prodrug. We believe these findings open a new avenue for rational design of supramolecular prodrugs for cancer treatment. PMID- 27217842 TI - Trauma Therapists' Clinical Applications, Training, and Personal Practice of Mindfulness and Meditation. AB - Mindfulness and meditation (MM) are increasingly used in trauma treatment, yet there is little research about therapist qualifications and clinical applications of these practices. We surveyed trauma therapists (N = 116) about their clinical uses, training, and personal practice of MM. Most respondents reported use of MM in trauma therapy, primarily MM-related imagery and breathing exercises and mindfulness in session or daily life. Almost a third used mindfulness-based stress reduction, mindfulness-based cognitive therapy, or mindfulness-based relapse prevention. Across all respondents, 66 % were trained by a mental health (MH) professional, 16 % were trained exclusively by a spiritual teacher, and 18 % received no training. On average, therapists used four types of MM. Less than half maintained a personal meditation practice and only 9 % reported practicing daily meditation. Therapists who were trained by a MH professional were more likely to integrate MM into trauma psychotherapy; those who were trained by a spiritual teacher were more likely to teach clients to use MM between sessions and reported more personal practice of MM. Results indicate divergence from standard recommendations for therapist personal practice and professional training in manualized uses; however, there is little guidance about requisite training and personal practice to support individualized uses of MM such as breathing exercises and imagery. Further research should address relationships of therapist training and personal practice to clinical outcomes in MM-informed trauma therapy. PMID- 27217843 TI - Attachment Security and Self-compassion Priming Increase the Likelihood that First-time Engagers in Mindfulness Meditation Will Continue with Mindfulness Training. AB - Mindfulness practice has many mental and physical health benefits but can be perceived as 'difficult' by some individuals. This perception can discourage compliance with mindfulness meditation training programs. The present research examined whether the activation of thoughts and feelings related to attachment security and self-compassion (through semantic priming) prior to a mindfulness meditation session might influence willingness to engage in future mindfulness training. We expected both of these primes to positively influence participants' willingness to continue with mindfulness training. We primed 117 meditation-naive individuals (84 female; mean age of 22.3 years, SD = 4.83) with either a self compassion, attachment security, or a neutral control prime prior to an introductory mindfulness exercise and measured their post-session willingness to engage in further training. Both experimental primes resulted in higher willingness to engage in further mindfulness training relative to the control condition. The self-compassion prime did so indirectly by increasing state mindfulness, while the attachment security prime had a direct effect. This study supports theoretical links between self-compassion and mindfulness and reveals a causal role for these factors in promoting willingness to engage in mindfulness training. Our findings have implications for improving compliance with mindfulness intervention programs. PMID- 27217844 TI - Zen meditation, Length of Telomeres, and the Role of Experiential Avoidance and Compassion. AB - Mindfulness refers to an awareness that emerges by intentionally focusing on the present experience in a nonjudgmental or evaluative manner. Evidence regarding its efficacy has been increasing exponentially, and recent research suggests that the practice of meditation is associated with longer leukocyte telomere length. However, the psychological mechanisms underlying this potential relationship are unknown. We examined the telomere lengths of a group of 20 Zen meditation experts and another 20 healthy matched comparison participants who had not previously meditated. We also measured multiple psychological variables related to meditation practice. Genomic DNA was extracted for telomere measurement using a Life Length proprietary program. High-throughput quantitative fluorescence in situ hybridization (HT-Q-FISH) was used to measure the telomere length distribution and the median telomere length (MTL). The meditators group had a longer MTL (p = 0.005) and a lower percentage of short telomeres in individual cells (p = 0.007) than those in the comparison group. To determine which of the psychological variables contributed more to telomere maintenance, two regression analyses were conducted. In the first model, which applied to the MTL, the following three factors were significant: age, absence of experiential avoidance, and Common Humanity subscale of the Self Compassion Scale. Similarly, in the model that examined the percentage of short telomeres, the same factors were significant: age, absence of experiential avoidance, and Common Humanity subscale of the Self Compassion Scale. Although limited by a small sample size, these results suggest that the absence of experiential avoidance of negative emotions and thoughts is integral to the connection between meditation and telomeres. PMID- 27217845 TI - Mindful Parenting Training in Child Psychiatric Settings: Heightened Parental Mindfulness Reduces Parents' and Children's Psychopathology. AB - Mindful parenting training is an application of mindfulness-based interventions that allows parents to perceive their children with unbiased and open attention without prejudgment and become more attentive and less reactive in their parenting. This study examined the effectiveness of mindful parenting training in a clinical setting on child and parental psychopathology and of mindfulness as a predictor of these outcomes. Seventy parents of 70 children (mean age = 8.7) who were referred to a mental health care clinic because of their children's psychopathology participated in an 8-week mindful parenting training. Parents completed questionnaires at pre-test, post-test and 8-week follow-up. A significant decrease was found in children's and parents' psychopathology and a significant increase in mindful parenting and in general mindful awareness. Improvement in general mindful awareness, but not mindful parenting, was found to predict a reduction in parental psychopathology, whereas improvement in mindful parenting, but not general mindful awareness, predicted the reduction of child psychopathology. This study adds to the emerging body of evidence indicating that mindful parenting training is effective for parents themselves and, indirectly, for their children suffering from psychopathology. As parents' increased mindful parenting, but not increased general mindfulness, is found to predict child psychopathology, mindful parenting training rather than general mindfulness training appears to be the training of choice. However, RCTs comparing mindful parenting to general mindfulness training and to parent management training are needed in order to shed more light on the effects of mindful parenting and mechanisms of change. PMID- 27217846 TI - Raising the bar for bladder cancer care. PMID- 27217847 TI - Go West: CUA annual meeting provides enriching education in a majestic setting. PMID- 27217848 TI - The many hats of a community urologist. PMID- 27217849 TI - Health advocacy in a competency-based curriculum: The emerging role of global surgery. PMID- 27217850 TI - First Canadian experience with robotic single-incision pyeloplasty: Comparison with multi-incision technique. AB - INTRODUCTION: We compared the outcomes of single-incision, robot-assisted laparoscopic pyeloplasty vs. multiple-incision pyeloplasty using the da Vinci robotic system. METHODS: We reviewed all consecutive robotic pyeloplasties by a single surgeon from January 2011 to August 2015. A total of 30 procedures were performed (16 single:14 multi-port). Two different single-port devices were compared: the GelPort (Applied Medical, Rancho Santa Margarita, CA) and the Intuitive single-site access port (Intuitive Surgical, Sunnyvale, CA). RESULTS: Patient demographics were similar between the two groups. Mean operating time was similar among the single and multi-port groups (225.2 min vs. 198.9 minutes [p=0.33]). There was no significant difference in length of hospital stay in either group (86.2 hr vs. 93.2 hr [p=0.76]). There was no difference in success rates or postoperative complications among groups. CONCLUSIONS: Single-port robotic pyeloplasty is non-inferior to multiple-incision robotic surgery in terms of operative times, hospitalization time, success rates, and complications. Verifying these results with larger cohorts is required prior to the wide adoption of this technique. Ongoing objective measurements of cosmesis and patient satisfaction are being evaluated. PMID- 27217851 TI - Robotic-assisted, single-site surgery: Having your surgical cake and eating it too! PMID- 27217853 TI - Mitigating pelvic recurrence and improving overall survival. PMID- 27217852 TI - Enumerating pelvic recurrence following radical cystectomy for bladder cancer: A Canadian multi-institutional study. AB - INTRODUCTION: We aimed to enumerate the rate of pelvic recurrence following radical cystectomy at university-affiliated hospitals in Canada. METHODS: Canadian, university-affiliated hospitals were invited to participate. They were asked to identify the first 10 consecutive patients undergoing radical cystectomy starting January 1, 2005, who had urothelial carcinoma stages pT3/T4 N0-2 M0. The first 10 consecutive cases starting January 1, 2005 who met these criteria were the patients submitted by that institution with information regarding tumour stage, age, number of nodes removed, and last known clinical status in regard to recurrence and patterns of failure. RESULTS: Of the 111 patients, 80% had pT3 and 20% pT4 disease, with 62% being node-negative, 14% pN1, and 27% pN2; 57% had 10 or more nodes removed. Cumulative incidence of pelvic relapse was 40% among the entire group. CONCLUSIONS: This review demonstrates a high rate of pelvic tumour recurrence following radical cystectomy for pT3/T4 urothelial cancer. PMID- 27217854 TI - Gravity-assisted drainage imaging in the assessment of pediatric hydronephrosis. AB - INTRODUCTION: As early detection of hydronephrosis increases, we require better methods of distinguishing between pediatric patients who require pyeloplasty vs. those with transient obstruction. Gravity-assisted drainage (GAD) as part of a standardized diuretic renography protocol has been suggested as a simple and safe method to differentiate patients. METHODS: Renal scans of 89 subjects with 121 hydronephrotic renal units between January 2004 and March 2007 were identified and analyzed. RESULTS: Of all renal units, 65% showed obstruction. GAD maneuver resulted in significant residual tracer drainage in eight renal units, moderate drainage in 12 renal units, and some improvement in 40 units after the GAD maneuver. Of the eight renal units with significant residual tracer drainage, only two proceeded to pyeloplasty. After pyeloplasty, nine children had improved time to half maximum (T(1/2) Max) and 13 were unchanged. CONCLUSIONS: Our study was limited due to its retrospective design and descriptive analyses, but includes a sufficient number of subjects to conclude that GAD as part of a diuretic renography protocol is an effective and simple technique that can help prevent unnecessary surgical procedures in pediatric patients. PMID- 27217855 TI - The challenges of diagnosing obstructive hydronephrosis in children. PMID- 27217856 TI - Efficacy, quality of life, and safety of cabazitaxel in Canadian metastatic castration-resistant prostate cancer patients treated or not with prior abiraterone. AB - INTRODUCTION: In the TROPIC study, cabazitaxel improved overall survival in abiraterone-naive metastatic castration-resistant prostate cancer (mCRPC) patients post-docetaxel. To evaluate cabazitaxel in routine clinical practice, an international, single-arm trial was conducted. Efficacy, safety, and quality of life (QoL) data were collected from Canadian patients enrolled. Overall survival and progression-free survival were not collected as part of this study. Importantly, prior abiraterone use was obtained and its impact on clinical parameters was examined. METHODS: Sixty-one patients from nine Canadian centres were enrolled, with prior abiraterone use known for 60 patients. Prostate specific antigen (PSA) response rate, safety, and impact on QoL life were analyzed as a function of prior abiraterone use. RESULTS: Overall, 92% of patients were ECOG 0/1, 88% had bone metastases, and 25% visceral metastases. Patients treated without prior abiraterone (NoPriorAbi) (n=35, 58%) and with prior abiraterone (PriorAbi) (n=25, 42%) had similar baseline characteristics, except for age and prior cumulative docetaxel dose. Median number of cabazitaxel cycles received was similar between groups (NoPriorAbi=6, PriorAbi=7), as was PSA response rate (NoPriorAbi=36.4%, PriorAbi=45.0%, p=0.54). Almost one-third (31%) of patients received prophylactic granulocyte colony-stimulating factors. Most frequent Grade 3/4 toxicities were neutropenia (14.8%); anemia, febrile neutropenia, fatigue (each at 9.8%); and diarrhea (8.2%). No treatment-related adverse event leading to death was observed. QoL and pain were improved with no difference seen between groups. Treatment discontinuation was mainly due to disease progression (45.9%) and adverse events (32.8%). CONCLUSIONS: In routine clinical practice, cabazitaxel's risk-benefit ratio in mCRPC patients previously treated with docetaxel seems to be maintained independent of prior abiraterone use. PMID- 27217857 TI - Assessing the utility of cabazitaxel in mCRPC. PMID- 27217858 TI - A simple prognostic model for overall survival in metastatic renal cell carcinoma. AB - INTRODUCTION: The primary purpose of this study was to develop a simpler prognostic model to predict overall survival for patients treated for metastatic renal cell carcinoma (mRCC) by examining variables shown in the literature to be associated with survival. METHODS: We conducted a retrospective analysis of patients treated for mRCC at two Canadian centres. All patients who started first line treatment were included in the analysis. A multivariate Cox proportional hazards regression model was constructed using a stepwise procedure. Patients were assigned to risk groups depending on how many of the three risk factors from the final multivariate model they had. RESULTS: There were three risk factors in the final multivariate model: hemoglobin, prior nephrectomy, and time from diagnosis to treatment. Patients in the high-risk group (two or three risk factors) had a median survival of 5.9 months, while those in the intermediate risk group (one risk factor) had a median survival of 16.2 months, and those in the low-risk group (no risk factors) had a median survival of 50.6 months. CONCLUSIONS: In multivariate analysis, shorter survival times were associated with hemoglobin below the lower limit of normal, absence of prior nephrectomy, and initiation of treatment within one year of diagnosis. PMID- 27217821 TI - Production of K[Formula: see text](892)[Formula: see text] and [Formula: see text](1020) in p-Pb collisions at [Formula: see text] = 5.02 TeV. AB - The production of K[Formula: see text](892)[Formula: see text] and [Formula: see text](1020) mesons has been measured in p-Pb collisions at [Formula: see text][Formula: see text] 5.02 TeV. K[Formula: see text] and [Formula: see text] are reconstructed via their decay into charged hadrons with the ALICE detector in the rapidity range [Formula: see text]. The transverse momentum spectra, measured as a function of the multiplicity, have a p[Formula: see text] range from 0 to 15 GeV/c for K[Formula: see text] and from 0.3 to 21 GeV/c for [Formula: see text]. Integrated yields, mean transverse momenta and particle ratios are reported and compared with results in pp collisions at [Formula: see text][Formula: see text] 7 TeV and Pb-Pb collisions at [Formula: see text][Formula: see text] 2.76 TeV. In Pb-Pb and p-Pb collisions, K[Formula: see text] and [Formula: see text] probe the hadronic phase of the system and contribute to the study of particle formation mechanisms by comparison with other identified hadrons. For this purpose, the mean transverse momenta and the differential proton-to-[Formula: see text] ratio are discussed as a function of the multiplicity of the event. The short-lived K[Formula: see text] is measured to investigate re-scattering effects, believed to be related to the size of the system and to the lifetime of the hadronic phase. PMID- 27217859 TI - Diagnosis, referral, and primary treatment decisions in newly diagnosed prostate cancer patients in a multidisciplinary diagnostic assessment program. AB - INTRODUCTION: We aimed to report on data from the multidisciplinary diagnostic assessment program (DAP) at the Gale and Graham Wright Prostate Centre (GGWPC) at North York General Hospital (NYGH). We assessed referral, diagnosis, and treatment decisions for newly diagnosed prostate cancer (PCa) patients as seen over time, risk stratification, and clinic type to establish a deeper understanding of current decision-making trends. METHODS: From June 2007 to April 2012, 1277 patients who were diagnosed with PCa at the GGWPC were included in this study. Data was collected and reviewed retrospectively using electronic patient records. RESULTS: 1031 of 1260 patients (81.8%) were seen in a multidisciplinary clinic (MDC). Over time, a decrease in low-risk (LR) diagnoses and an increase intermediate-risk (IR) diagnoses was observed (p<0.0001). With respect to overall treatment decisions 474 (37.1%) of patients received primary radiotherapy, 340 (26.6%) received surgical therapy, and 426 (33.4%) had conservative management; 57% of patients who were candidates for active surveillance were managed this way. No significant treatment trends were observed over time (p=0.8440). Significantly, different management decisions were made in those who attended the MDC compared to those who only saw a urologist (p<0.0001). CONCLUSIONS: In our DAP, the vast majority of patients presented with screen detected disease, but there was a gradual shift from low- to intermediate-risk disease over time. Timely multidisciplinary consultation was achievable in over 80% of patients and was associated with different management decisions. We recommend that all patients at risk for prostate cancer be worked up in a multi disciplinary DAP. PMID- 27217860 TI - Laparoscopic nephroureterectomy is associated with higher risk of adverse events compared to laparoscopic radical nephrectomy. AB - INTRODUCTION: Laparoscopic radical nephrectomy (LRN) and laparoscopic nephroureterectomy (LNU) are similar procedures and some surgeons may believe the perioperative risks are the same. The purpose of this study is to characterize and compare complications following LRN and LNU. METHODS: A historical cohort of patients who received either LRN or LNU between 2006 and 2012 was reviewed from the National Surgical Quality Improvement Program (NSQIP) database. Patient characteristics, surgical characteristics, and perioperative outcomes up to 30 days postoperatively were abstracted. Unadjusted and adjusted associations between procedure (LRN or LNU) and any adverse event were determined. RESULTS: During the study period, 4904 patients met study inclusion criteria; 4159 (84.8%) received a LRN while 745 (15.2%) received a LNU. Overall, 651 (13.3%) patients experienced at least one postoperative complication. LNU was associated with more complications than LRN (21% and 12%, respectively, p value <0.01). The most common complications were: bleeding requiring blood transfusion (9.0% LNU vs. 6.0% LRN), urinary tract infection (4.6% LNU vs. 1.5% LRN), wound infection (1.3% LNU vs. 1.8% LRN), and unplanned intubation (2.3% LNU vs. 0.9% LRN). After adjusting for potential confounders, LNU was associated with higher risk of any complication compared to LRN (relative risk [RR] 1.41, 95% confidence interval [CI] 1.16-1.72). Other variables independently associated with an increased risk of complications included: increasing patient age (RR 1.01, 95% CI 1.01-1.02), American Society of Anesthesiologists (ASA) classification >=3 (RR 1.34, 95% CI 1.10-1.63), higher preoperative creatinine (RR 1.11, 95% CI 1.06-1.17), >4 units of blood transfused within 72 hours before surgery (RR 1.93, 95% CI 1.29-2.86), and operative time >6 hours (RR 2.17, 95% CI 1.71-2.75). CONCLUSIONS: Postoperative complications within 30 days of surgery are common after LNU and LRN. Despite having technical similarities, LNU carries a significantly higher risk of developing short-term complications compared to LRN. This information should be considered when counseling patients prior to surgery. Notable limitations of this study included the lack of information on tumour stage and management of the distal ureter. PMID- 27217861 TI - CAPRA-S predicts outcome for adjuvant and salvage external beam radiotherapy after radical prostatectomy. AB - INTRODUCTION: We aimed to evaluate the predictive value of the Cancer of the Prostate Risk Assessment Postsurgical Score (CAPRA-S) for patients treated with radical prostatectomy followed by subsequent external beam radiotherapy (EBRT). METHODS: A total of 373 patients treated with EBRT between January 2000 and June 2015 were identified in the institutional database. Followup and complete CAPRA-S score were available for 334 (89.5%) patients. CAPRA-S scores were sorted into previously defined categories of low- (score 0-2), intermediate- (3-5), and high risk (6-12). Time to biochemical recurrence (BCR) was defined as prostate specific antigen (PSA) >0.20 ng/mL after EBRT. Survival analyses were performed using the Kaplan-Meier method and comparisons were made using the log-rank test. RESULTS: Overall median time from surgery to EBRT was 18 months (interquartile range [IQR] 8-36) and median followup since EBRT was 48 months (IQR 28-78). CAPRA S predicted time to BCR (<0.001), time to palliative androgen-deprivation therapy (ADT) (p=0.017), and a trend for significantly predicting overall survival (OS, p=0.058). On multivariate analysis, the CAPRA-S was predictive of time to BCR only (low-risk vs. intermediate-risk; hazard ratio [HR] 0.14, 95% confidence interval [CI] 0.043-0.48, p=0.001). The last PSA measurement before EBRT as a continuous and grouped variable proved highly significant in predicting all outcomes tested, including OS (p<=0.002). CONCLUSIONS: CAPRA-S predicts time to BCR and freedom from palliative ADT, and is borderline significant for OS. Together with the PSA before EBRT, CAPRA-S is a useful, predictive tool. The main limitation of this study is its retrospective design. PMID- 27217863 TI - The neutrophil-to-lymphocyte ratio in clinical practice. PMID- 27217862 TI - Anticholinergic use in children: Persistence and patterns of therapy. AB - INTRODUCTION: Overactive bladder (OAB) symptoms are complex and generally require long-term therapy. Nevertheless, it has been demonstrated that persistence rates of antimuscarinic drug use are low in adults. Better understanding of the treatment patterns of children treated with antimuscarinics could help to improve drug management. Our objective was to evaluate persistence rates of patients under 20 years of age on antimuscarinic therapy over a four-year period. METHODS: Patients having received a first-ever antimuscarinic drug prescription between April 2007 and March 2008 were identified using IMS Brogan's Public and Private Drug Plans database. Canadian drug claims data from Private Drug Plans, Regie de l'Assurance Maladie du Quebec, and Ontario Public Drug Plans were analyzed retrospectively. Patients were followed for four years to assess the prescribed drugs, the lines of treatment, and the duration of each treatment. RESULTS: Data were available for 374 patients. The most prescribed drug as a first-line therapy was oxybutynin (87.2%), followed by tolterodine LA (5.9%). Patients refilled their index prescriptions for an average of 429 days. Solifenacin had the highest mean duration of index therapy (765 days). The median number of antimuscarinics prescribed was one. At the end of the followup, 44 patients were still on therapy. Reasons for discontinuation of treatment were not available. CONCLUSIONS: Overall discontinuation rate of antimuscarinic therapy in children is comparable to what has been reported in adult patients with OAB. However, children seem to persist on the medication for a longer duration before adherence rates start declining. The low rate of persistence highlights the need to identify the reasons for discontinuation of therapy in children in order to obtain better persistence rates. PMID- 27217865 TI - [Not Available]. PMID- 27217864 TI - Author reply: The neutrophil-to-lymphocyte ratio in clinical practice. PMID- 27217866 TI - Percutaneous nephrolithotomy with one-shot dilation method: Is it safe in patients who had open surgery before? AB - INTRODUCTION: This study aimed to evaluate whether one-shot dilatation technique is as safe in patients with a history of open-stone surgery as it is in patients without previous open-stone surgery. METHODS: Between January 2007 and February 2015, 82 patients who underwent percutaneous nephrolithotomy (PNL) surgery with one-shot dilation technique who previously had open-stone surgery were retrospectively reviewed and evaluated (Group 1). Another 82 patients were selected randomly among patients who had PNL with one-shot dilation technique, but with no history of open renal surgery (Group 2). Age, gender, type of kidney stone, duration of surgery, radiation exposure time, and whether or not there was any bleeding requiring perioperative and postoperative transfusion were noted for each patient. RESULTS: The stone-free rates, operation and fluoroscopy time, and peroperative and postoperative complication rates were similar in both groups (p>0.05). CONCLUSIONS: Our experience indicated that PNL with one-shot dilation technique is a reliable method in patients with a history of open-stone surgery. PMID- 27217867 TI - [Bilateral breast tumefaction revealing acute leukemia (a report of a case)]. PMID- 27217868 TI - [Perceptions of Tunisian women based on the health beliefs model and their practices related to osteoporosis]. AB - INTRODUCTION: The aim of this study is to describe beliefs and practices of women related to health and osteoporosis in order to develop effective and targeted interventions for the prevention of this disease in the Tunisian context. METHODS: A descriptive cross-sectional study was conducted among 100 Tunisian women, aged 45 and older, who consult the basic health center in the suburban area of Sousse region (Tunisia). The collection of information was carried out with "osteoporosis health belief scale "developed by Kim and his colleagues validated and translated into Arabic in Tunisia and the questionnaire of "daily calcium inputs calculation" was developed by Patrice Fardellone. The interpretation of the results was based on the "Health Belief Model". RESULTS: Perception participants considered above average for the vulnerability of osteoporosis (58%). The advantages severity of their benefits of calcium intake and health motivation could be considered moderate moderated. However, the practical exposure to disease risks is relatively frequent and essentially related to socio-economic and cultural factors. CONCLUSION: The promotion programs should aim at creating a supportive physical and social environment for the adoption of safer behaviors and especially education must be targeted. PMID- 27217869 TI - [Evaluation of cardiac complications among chronic hemodialysis in Dakar]. AB - INTRODUCTION: Hemodialysis is the first extrarenal treatment method that allowed supporting patients in terminal chronic failure in Senegal since 1997. 25 years later, we conducted this study to determine the type and the prevalence of different cardiovascular complications and identify the main cardiovascular risk factors. METHODS: It is a retrospective study of 4 years. 38 patients treated at least 6 months in hemodialysis and cardiovascular explorations with a front chest x-ray, electrocardiogram and cardiac ultrasound. All patients who have not started hemodialysis, treated less than 6 months in hemodialysis, treaties in peritoneal dialysis or having raised cardiovascular explorations were excluded. For each selected patient, we collected data epidemiological, clinical, paraclinical and evolutionary aspects of cardiovascular complications. RESULTS: 38 patients were included in this study. The average age was 52 years +/- 12.85 and the sex ratio H/F of 1.53. Initial nephropathy was dominated by the nephroangiosclerose followed by diabetic nephropathy. Clinically the signs of appeal are marked by the effort dyspnea palpitations, chest pain and physically by the HTA, anemia. Cardiovascular complications were dominated by hypertrophy (LVH) left ventricular, rhythm type of arrhythmia disorders valvular leakage (mitral and tricuspid) and cerebral vascular accident (stroke). The average impact of LVH according the HTA is 81%, by sex of 78.26% for men and 60% for women. At the end of the study, 27 patients were pursuing hemodialysis and 11 had died 6 (54%) of cardiovascular cause. CONCLUSION: Hemodialysis is a common purification technique in Senegal and its complications remain especially dominated by abuses cardiovascular. PMID- 27217870 TI - Recurrent spontaneous pneumothorax in young woman: catamenial pneumothorax. PMID- 27217871 TI - Serological response to Epstein-Barr virus early antigen is associated with gastric cancer and human immunodeficiency virus infection in Zambian adults: a case-control study. AB - INTRODUCTION: Gastric cancer is one of the major causes of cancer related deaths, but data from sub-Saharan Africa are very scanty. The cancer genome atlas (TCGA) initiative confirmed Epstein-Barr virus (EBV) related cancer as a distinct subtype, and we set out to look for serological evidence of its role in a sub Saharan African patient group. METHODS: We used stored serum samples obtained from a gastric cancer case-control study conducted between 2010 and 2012 in Lusaka, Zambia. A total of 147 patients were included with 51 gastric adenocarcinoma cases and 96 age and sex matched controls. The presence of antibodies to EBV nuclear antigen-1 (EBNA-1) and early antigen (EA) was determined using commercially available ELISA kits. Data were analysed in STATA Stata Corp, College Station TX. RESULTS: Over 90% of all the samples analysed were positive for antibodies to EBNA-1. The presence of antibodies to EBV EA was significantly higher in gastric cancer cases than in controls, (OR 4.38; 95% CI 1.53-13.06, P = 0.0027), with an attributable risk of 23%. HIV infection was also associated with EBV EA seroprevalence (OR 10.97; 95% CI 2.26 -13.06, P = 0.001) but not EBNA-1 (OR 0.81; 95% CI 0.10 -38.75, P = 0.596). There was no association of EBV infection with age below 45 years, Helicobacter pylori infection, intestinal metaplasia, gastric atrophy or inflammation. CONCLUSION: We therefore conclude that EBV exposure is common among Zambian adults and that EBV EA seropositivity is associated with gastric cancer and HIV infection, but not premalignant lesions. PMID- 27217872 TI - Factors associated with road traffic injuries in Tanzania. AB - INTRODUCTION: Injuries represent a significant cause of morbidity and mortality worldwide and road traffic crashes accounts for a significant proportion of these injuries. Tanzania is among the countries with high rates of road traffic crashes. The aim of this study was to determine the pattern, associated factors and management of road traffic injury patients in Tanzania. METHODS: A cross sectional study of patients involved in motor traffic crashes and attended in six public hospitals of Tanzania mainland between April 2014 and September 2014. RESULTS: A total of 4675 road traffic injury patients were seen in studied hospitals, 76.6% were males. Majority (70.2%) were between 18 - 45 years age group. Motorcycles were the leading cause of road traffic crashes (53.4%), and drivers (38.3%) accounted for majority of victims. Fractures accounted for 34.1%, and injuries were severe in 2.2% as determined by the Kampala trauma score II (KTS II). Majorities 57.4% were admitted and 2.2% died at the casualty. Factors associated with mortality were; using police vehicles to hospital (P = 0.000), receiving medical attention within 2 to 10 hours after injury (P = 0.000), 18 - 45 years age group (P = 0.019), not using helmet (P = 0.007), severe injuries (P = 0.000) and sustaining multiple injury (P = 0.000). CONCLUSION: Road traffic Injuries in Tanzania are an important public health problem, predominantly in adult males, mostly due to motorcycle crashes. It is therefore important to reinforce preventive measures and pre-hospital emergency service is urgently needed. PMID- 27217873 TI - The Pan African Medical Journal 2015--A year in review. PMID- 27217874 TI - [Acute intestinal obstruction revealing enteropathy associated t-cell lymphoma, about a case]. AB - Enteropathy associated T-cell lymphoma (EATL) is a rare complication of celiac disease (CD). We report a case of EATL associated with CD revealed by acute intestinal obstruction. A North African woman of 38 years old with a history of infertility and chronic abdominal pain was admitted in emergency with acute intestinal obstruction. During the surgery, we found a tumor on the small intestine with mesenteric lymphadenopathy. Histology and immunohistochemistry of the specimen objectified a digestive T lymphoma CD3+ and immunological assessment of celiac disease was positive. The diagnosis of EATL was thus retained. Chemotherapy (CHOEP protocol) was established as well as gluten-free diet with a complete response to treatment. The EATL is a rare complication of CD that can be revealed by intestinal obstruction. The prognosis can be improved by early treatment involving surgery and chemotherapy. Its prevention requires early diagnosis of celiac and gluten-free diets. PMID- 27217876 TI - [Cutaneous larva migrans syndrome on a malformed foot (a case report)]. AB - Cutaneous larva migrans syndrome is a subcutaneous dermatitis caused by hookworms' larvae, originating from animals in parasitic impasse in humans. Transcutaneous infestation is favored by contact with contaminated soil. We report the case of a 15-month-old child, native of Guinea - Bissau, suffering from cutaneous larva migrans syndrome on a malformed foot. This malformation in the form of a syndactyly, associated with a tumefaction of the foot cause a delay in the standing position. Besides, the fact that the child never wears shoes because of the sick foot is another factor contributing to the patient's infestation by the larvae of the nematode. PMID- 27217875 TI - [Blood count results from hypertensive patients seen in laboratory of CHU-HJRB Antananarivo in 2013]. AB - INTRODUCTION: The blood count is a routine laboratory test prescribed to patients suffering from high blood pressure. This study aims to describe the results of blood count from hypertensive patients and to identify conditions associated. METHODS: This retrospective and descriptive study concerns the period from the 1st of December 2012 to 31 th of December 2013 in the laboratory of University Hospital Center CHU-HJRB of Antananarivo. All records of results from hypertensive patients who requested blood count have been exploited. RESULTS: Among 151 hypertensive patients, 91 (60.3%) had pathological blood counts. Of these, 64 (70.4%) showed one type of abnormality and 27 (29.6%) had multiple abnormalities. The anaemia (33.91%), the leukocytosis (33.04%), the polycythemia (10.43%) and the leukopenia (9.57%) are the most frequent. Among the multiple abnormalities, anaemia associated with leukocytosis is the most observed (29.6%). The microcytosis anaemia (41%) and the neutrophil polymorphonuclear leukocytosis are the most dominant (47.4%). Patients in nephrology (90%) and in endocrinology (81.3%) are the most concerned (p = 0,008). Hypertensive under 20 years old (100%) and women (61.5%) are the most affected (p > 0, 05). The seizures (100%), the edema of the lower limbs (100%) and diabetes (70%) are the signs and pathology most encountered. CONCLUSION: The blood count should be prescribed for all hypertensive patients to identify the affections that will be treated simultaneously with the high blood pressure. Thus, hypertensive patients will have a good follow-up and their life expectancy will be improved. PMID- 27217877 TI - A child that presents with an acute limp: Legg-Calve-Perthes disease. PMID- 27217878 TI - [Spontaneous hematoma of right angle of the transverse mesocolon: exceptional complication of anticoagulant therapy with vitamin K]. AB - Spontaneous hematoma of transverse mesocolon is a rare complication of anticoagulant treatment with vitamin K. We report the case of spontaneous hematoma of right angle of the transverse mesocolon associated with a hemoperitoneum in a 32-year-old patient treated by fluindione for pulmonary embolism. The diagnosis must be made urgently. The abdominal ultrasound and the scanning confirm the diagnosis. It is important to note that surgery is indicated only in the case of complications such as the risk of rupture of the hematoma. PMID- 27217879 TI - Advocating for efforts to protect African children, families, and communities from the threat of infectious diseases: report of the First International African Vaccinology Conference. AB - One means of improving healthcare workers' knowledge of and attitudes to vaccines is through running vaccine conferences which are accessible, affordable, and relevant to their everyday work. Various vaccinology conferences are held each year worldwide. These meetings focus heavily on basic science with much discussion about new developments in vaccines, and relatively little coverage of policy, advocacy, and communication issues. A negligible proportion of delegates at these conferences come from Africa, home to almost 40% of the global burden of vaccine-preventable diseases. To the best of our knowledge, no major vaccinology conference has ever been held on the African continent apart from World Health Organization (WHO) meetings. The content of the first International African Vaccinology Conference was planned to be different; to focus on the science, with a major part of discussions being on clinical, programmatic, policy, and advocacy issues. The conference was held in Cape Town, South Africa, from 8 to 11 November 2012. The theme of the conference was "Advocating for efforts to protect African children, families, and communities from the threat of infectious diseases". There were more than 550 registered participants from 55 countries (including 37 African countries). There were nine pre-conference workshops, ten plenary sessions, and 150 oral and poster presentations. The conference discussed the challenges to universal immunisation in Africa as well as the promotion of dialogue and communication on immunisation among all stakeholders. There was general acknowledgment that giant strides have been made in Africa since the global launch of the Expanded Programme on Immunisation in 1974. For example, there has been significant progress in introducing new and under-utilised vaccines; including hepatitis B, Haemophilus influenza type b, pneumococcal conjugate, rotavirus, meningococcal A conjugate, and human papillomavirus vaccines. In May 2012, African countries endorsed the Global Vaccine Action Plan at the World Health Assembly. However, more than six million children remain incompletely vaccinated in Africa leading to more than one million vaccine preventable deaths annually. In addition, there are persistent problems with leadership and planning, vaccine stock management, supply chain capacity and quality, provider-parent communication, and financial sustainability. The conference delegates agreed to move from talking to taking concrete actions around children's health, and to ensure that African governments commit to saving children's lives. They would advocate for lower costs of immunisation programmes in Africa, perhaps through bulk buying and improved administration of vaccine rollout through the New Partnership for Africa's Development. PMID- 27217880 TI - Tracheal rupture after misplacement of Sengstaken-Blakemore tube. PMID- 27217881 TI - Massive subcutaneous emphysema after traumatic pneumothorax. PMID- 27217882 TI - Intertrochanteric fracture non-unions with implant failure of the gamma nail. AB - Failure of internal fixation of intertrochanteric fracture is associated with delayed union or malunion resulting in persistent pain and diminished function. We report a rare case of implant failure of the gamma nail with intertrochanteric fracture non union treated by DCS plate screw and bone graft. PMID- 27217884 TI - The benefit of preventing exposure keratopathy in icu patient: a case report. PMID- 27217883 TI - [Epilepsy and acute seizures in childhood in sub-Saharan Africa: challenges and hopes]. AB - Epilepsy is a neurological disease common among children in sub-Saharan Africa (SSA). Although its exact prevalence in this population is unknown, it is probably similar to that found in the general population because of its early onset (60% starts before the age of 20 years) and the absence of bimodal distribution found in western countries. This review acknowledges the reality that current management of pediatric epilepsy in SSA is imperfect. To reverse this trend, the challenges are three fold: better education, improved therapeutics and more research. Doctors need to be trained in the practice of pediatric neurology and provided with working conditions that limit the brain drain. The resources necessary for the proper management of children with epilepsy in SSA need to be identified and provided (better availability of antiepileptic drugs, clear national guidelines, proper registration of traditional healers etc...). Finally, it is imperative that research be conducted to establish accurate incidence and prevalence figures for pediatric epilepsy, so that targeted control measures can be implemented. PMID- 27217885 TI - Peritoneal carcinomatosis, an unusual and only site of metastasis from lung adenocarcinoma. AB - Isolated peritoneal metastases of lung adenocarcinoma are very rare, even exceptional, occurring most often in the context of a multi-metastatic disease. This report presents a rare clinical case of isolated peritoneal metastasis from lung adenocarcinoma. We report a 56-year-old male who was monitored for lung adenocarcinoma whose evolution has been marked by an isolated metastatic recurrence in the peritoneum objectified by an abdominal-pelvic computed tomography (CT) and confirmed by a laparoscopy with abiopsy of the peritoneal nodules. The patient had received palliative chemotherapy with gemcitabine, cisplatin and bevacizumab. The evolution was marked by a progressive deterioration of the general condition and death two months after the third treatment cycle. Peritoneal carcinomatosis from lung adenocarcinoma is a very rare event, and is often associated with a poor prognosis. PMID- 27217886 TI - Fundus albipunctatus. PMID- 27217887 TI - Branding in children: a barbaric practice still exists in India. AB - Branding is an inhuman traditional practice most commonly employed to treat various disorders in neonates and children in certain community in India. Though stringent law exists to prevent such harmful practices, cases of branding is not uncommon in current era. PMID- 27217888 TI - Visual inspection with acetic acid and Lugol's iodine in cervical cancer screening at the general referral hospital Kayembe in Mbuji-Mayi, Democratic Republic of Congo. AB - INTRODUCTION: Cervical cancer is the leading cause of morbidity and mortality of women from cancer in the developing World. It is the primary cause of reduced life expectancy in Sub-Saharan countries such as Democratic Republic of Congo. The aim of this work was to determinate the socio-demographic profile of women with precancerous and cancerous lesions of the cervix, to determinate the frequency of VIA and VILI positive cases and to show the challenges that can be faced in managing patients with abnormalities in the city of Mbuji-Mayi in the Democratic Republic of Congo. METHODS: As part of its activities, the "Association de Lutte contre le Cancer du Col uterin" (ALCC) organized a community outreach followed by free voluntary testing for cervical cancer for two weeks (26(th)March to 10(th) April 2011) at the General Referral Hospital Kayembe in Mbuji-Mayi (Democratic Republic of Congo). RESULTS: A total of 229 women were examined. 38% of tests (VIA + VILI) were positive with 6 clinically suspected cases of invasive cancer at stage 1 (7% of cases). Nearly 70% of patients were still of childbearing age and had started their first sexual intercourse before 18 years of age and 86% of cases were multiparous. Given the material, financial and technical constraints, 75% of patients were placed in a monitoring program of 9 months to 1 year (= expectation and another test) while 11% of them were selected for a biopsy to be locally practiced and sent to the pathologist. Nearly 8% of the cases were candidates for hysterectomy. CONCLUSION: Given the difficulties encountered and the frequency of positive tests, we recommend another study with a larger sample, improved working conditions (mainly equipment) and the association of another test such as the Human Papilloma Virus (HPV) test. PMID- 27217889 TI - Microbial contamination of traditional liquid herbal medicinal products marketed in Mwanza city: magnitude and risk factors. AB - INTRODUCTION: The use of the traditional herbal medicinal products (THMPs) has been increasing worldwide due to the readily availability of raw materials and low cost compared to the synthetic industrial preparations. With this trend in mind, the safety and quality of THMPs need to be addressed so as to protect the community. The present study evaluated the magnitude and risk factors associated with microbial contamination of liquid THMPs marketed in Mwanza. METHODS: A cross sectional study was conducted in Mwanza city involving 59 participants from whom 109 liquid THMPs were collected and processed following the standard operating procedures. The data were analyzed using STATA software version 11. RESULTS: The median age (interquartile range) of participants was 35 (27-43) years, with males accounting for 36 (61%). Of 109 liquid THMPs collected, 89 (81.7%) were found to be contaminated; with predominant fecal coliforms being Klebsiella spp and Enterobacter spp. fortunately, no pathogenic bacteria like Salmonella spp and Shigella spp were isolated. There was a significant association of liquid THMPs contamination with low education level (p< 0.001), lack of formal training on THMPs (p = 0.023), lack of registration with the Ministry of Health (p = 0.001), lack of packaging of products (p < 0.001) and use of unboiled solvents during preparation of THMPs (p < 0.001). CONCLUSION: There is high contamination rate of liquid THMPs in Mwanza City which is attributable to individuals and system centered factors. Urgent measures to provide education to individuals involved in THMPs as well as setting up policies and regulations to reinforce THMPs safety is needed. PMID- 27217890 TI - Epidemiological and histopathological patterns of salivary gland tumors in Cameroon. AB - INTRODUCTION: Tumors of salivary glands are rare. According to Johns and Goldsmith in 1989, their annual incidence is less than 1/100000 without noteworthy geographical gap. But other authors suggest that their distribution may vary according to the race and geographical location. In Cameroon, existing studies give incomplete data. Hence, we underwent this study in order to draw the general profile of salivary gland tumors in Cameroon. METHODS: A retrospective study was carried out on the period spanning from January 2000 to December 2010 (11 years). It was done in nine Pathology services of different hospitals in Yaounde, Douala and Bamenda. We consulted the archive registers of those services, retaining any patient with salivary gland tumor, whatever the histological type or location. Information gathered was the year of diagnosis, the service, the age and sex, the site of the tumor (gland) the histological type and the benign/ malignant character. RESULTS: We recruited a total of 275 files. Women were 56% (154/275) and men 44% (121/275) of the sample. Fifty eight tumors were malignant (21.9%) while 217 were benign (78.1%). The overall mean age was 37.44 years, with extremes between 1 and 84 years. Pleomorphic adenoma (60.36%) was the most common benign tumor. Adenoid cystic carcinoma (31%), mucoepidermoid carcinoma (22.4%) and adenocarcinoma (19%) were the most common malignant tumors. Palate (66.7%), cheek (30%) and lips (3.3%) were the sites were the minor salivary glands were mostly involved. CONCLUSION: The differences with western world authors suggest a geographical variability of salivary gland tumors. PMID- 27217891 TI - The profile of patients with obstructive uropathy in Cameroon: case of the Douala General Hospital. AB - INTRODUCTION: Obstructive uropathy can lead to irreversible kidney damage. The etiology largely determined by the patient's age can be benign or malignant. This study aimed at determining the profile and outcome of patients with obstructive uropathy in Cameroon. METHODS: A cross sectional study carried out in the urology unit of the Douala General Hospital, including patients with a diagnosis of obstructive uropathy seen from January 2004 to December 2013. Clinical profile, treatment and outcome data were obtained from patients records. RESULTS: Of the 229 patients included 69% were men, mean age 50 +/-18 years. Associated comorbidities were hypertension, diabetes, and HIV. Mean haemoglobin 8,40+/ 2,4g/dl, mean GFR 10,3 +/-10ml/min, 94 (41%) patients needed emergency dialysis. Symptoms at presentation: asthenia (57%), anorexia (55%), loin pain (37%), vomiting (28%), oedema (20%), and anuria (15%). Urinary tract infection was present in 33 patients. Main aetiologies of obstruction: urolithiasis (35%), begnin prostatic hypertrophy (27%), prostatic cancer (12%), cervical cancer (16%), and congenital malformations (5%). Drainage was effective in 102 (45%) patients, 63 (28%) recovered completely, 91 (41%) were loss to follow up, 49 (22%) died and more women (p = 0.02). Mortality was associated with prostatic cancer (p = 0.000), cervical cancer (p = 0.004) and radiotherapy (p = 0.03). CONCLUSION: Patients with obstructive uropathy presented with significant impaired renal function. Main causes were urinary stones, prostatic hypertrophy, prostatic and cervical cancers. Renal recovery was poor, loss to follow up and mortality high. Specific strategies to target improvement in renal recovery and patient's survival are needed in this patient's group. PMID- 27217892 TI - [Tourniquets, a drama in the infant: about 3 cases]. AB - The time limit for the removal of a tourniquet is short; any delay in tourniquet deflation, especially if it exceeds the 3 hour limit, exposes to amputation hazards. Our objective was to report three cases of ischemic limb gangrene, caused by having forgotten to take a tourniquet off after a blood sampling, to inform healthcare professionals about the risk associated with that negligence. We encountered 3 cases of infants (2 three-month-old infants and 1 five-month-old infant), hospitalized in intensive care unit of Yalgado Ouedraogo University Hospital for upper-left limb swelling. Their medical history shows that there was a delay in tourniquet deflation after a blood sampling of 24 hours in two cases and of 48 hours in one case. Physical examination revealed a diffuse edema associated with upper limb gangrene spread to the mid-third of the upper arm, abolition of the ulnar and radial pulse as well as loss of sensation in the hand in 2 cases. In one case clinical signs were attenuated. The diagnosis of ischemic limb gangrene was confirmed in all cases. Laboratory examinations were normal. Two cases needed urgent trans-humeral amputation and one case needed debridement plus amputation of four fingers. The evolution was simple in all cases. Iatrogenic dry gangrene caused by a delay in tourniquet removal should never happen at hospitals. This can be guaranteed only by tightening up health management and by performing regular and accurate patient monitoring. PMID- 27217893 TI - Foodborne disease outbreak in a resource-limited setting: a tale of missed opportunities and implications for response. AB - INTRODUCTION: Foodborne diseases (FBD) have emerged as a major public health problem worldwide. Though the global burden of FBD is currently unknown, foodborne diarrhoeal diseases kill 1.9 million children globally every year. On 25th September 2014, health authorities in Eastern Region of Ghana were alerted of a suspected FBD outbreak involving patrons of a community food joint. We investigated to determine the magnitude, source and implement control and preventive measures. METHODS: A retrospective cohort study was conducted. We reviewed medical records for data on demographics and clinical features. A suspected foodborne disease was any person in the affected community with abdominal pain, vomiting and or diarrhea between 25(th) and 30(th) September 2014 and had eaten from the food joint. We conducted active case search, descriptive data analysis and calculated food specific attack rate ratios (ARR) and their corresponding 95% confidence intervals. RESULTS: Of 43 case-patients, 44.2% (19/43) were males; median age was 19 years (interquartile range: 17-24 years). Overall attack rate was 43.4% (43/99) with no fatality. Case counts rose sharply for four hours to a peak and fell to baseline levels after 12 hours. Compared to those who ate other food items, patrons who ate "waakye" and "shitor" were more likely to develop foodborne disease [ARR = 4.1 (95% CI = 1.09-15.63)]. Food samples and specimens from case-patients were unavailable for testing. Laboratory diagnostic capacity was also weak. CONCLUSION: A point source FBD outbreak linked to probable contaminated "waakye" and or "shitor" occurred. Missed opportunities for definitive diagnosis highlighted the need for strengthening local response capacity. PMID- 27217894 TI - Assessment of asthma control using asthma control test in chest clinics in Cameroon: a cross-sectional study. AB - INTRODUCTION: The goal of asthma treatment is to obtain and maintain a good control of symptoms. Investigating factors associated with inadequately control asthma could help in strategies to improve asthma control. This study aimed to determine the prevalence and factors associated with inadequately controlled asthma in asthma patients under chest specialist care. METHODS: A cross-sectional study was conducted from November 2012 to May 2013. Physician-diagnosed asthma patients aged 12 years and above were included. A questionnaire was used to collect demographic data, comorbidities, and medical history of asthma. Asthma control was assessed using the Asthma Control Test (ACT), with a score less than 20 for inadequately controlled asthma and a score greater or equal to 20 for controlled asthma. A multivariate analysis was used to identify factors associated with inadequately controlled asthma. RESULTS: Overall, 243 patients were included in this study. Asthma was controlled in 141 patients (58%) and inadequately controlled in 102 (42%). The mean duration of asthma was 8 years with an interquartile range of 4 and 18 years. Forty-three participants (17.7%) were not under any controller medication while the mean ACT score was 19.3 +/- 4.6. Independent associations were found between inadequately controlled asthma and female gender (OR 1.91; 95% CI 1.06-3.47) and obesity (OR 1.81; 1.01-3.27). CONCLUSION: Asthma remains poorly controlled in a large proportion of asthma patients under specialist care in Cameroon. Educational programs for asthma patients targeting women and based on weight loss for obese patients may help in improving the control of asthma. PMID- 27217895 TI - Hydroavacciniforme on a dark skin with mucosal involvement. PMID- 27217896 TI - An assessment of option B implementation for the prevention of mother to child transmission in Dschang, Cameroon: results from the DREAM (Drug Resource Enhancement against AIDS and Malnutrition) cohort. AB - INTRODUCTION: Scaling up of antiretroviral therapy (ART) to HIV+ pregnant women is crucial for the elimination of HIV infection in children. The aim of this study was to evaluate the feasibility and effectiveness of triple ART for Prevention of Mother-to Child Transmission (PMTCT) in Cameroon. METHODS: HIV positive pregnant women attending the DREAM Centre of Dschang, Cameroon for prenatal care were enrolled in a prospective cohort study, and received ART until the end of breastfeeding or indefinitely if their CD4 count was <350mm(3). Infants were evaluated for HIV infection at 1, 6 and 12 months of age. RESULTS: A total of 298 women were enrolled. Among them, 152 were already on established ART. Women were followed until 6 months after delivery with a retention rate of 92.6%. Eight women died. Those with a CD4 count <350 cells/mm(3) during pregnancy had the highest mortality risk (RR 2.53; 95% CL= 1.86-3.44). The HIV transmission rate was 1.2% at 12 months with an HIV free survival of 91%. In the proportional Cox regression analysis, the following factors were positively associated with infant mortality: maternal CD4< 350 cells/mm(3), no breastfeeding in the first 6 months of life, weight-for-age z score<-2. CONCLUSION: Results confirm the feasibility and effectiveness of the implementation of Option B, with very low rates of HIV MTC transmission, and potential benefits to the health of mothers and infants with earlier initiation of ART. Breastfeeding again demonstrates to be highly beneficial for the growth and survival of HIV exposed children. PMID- 27217898 TI - Obstructive sleep apnea presenting as pseudopheochromocytoma. AB - A 52-year-old female with a history of poorly controlled resistant hypertension was admitted to our hospital with severe hypertension. She had a history of fatigue and intermittent episodes of palpitations. Laboratory evaluation was significant for elevated 24-h urinary catecholamine levels (3,5 times the upper normal levels). This case was presenting with a clinical and biochemical picture indistinguishable from that of pheochromocytoma. However, neither computed tomography nor meta-iodo-benzyl-guanidine scintigraphy detected any catecholamine producing tumor in or outside the adrenal glands. Our patient was screened with full polysomnography because of heavy snoring, daytime somnolence and obesity. It revealed severe obstructive sleep apnea syndrome. After three months of continuous positive airway pressure therapy, the patient experienced resolution of his presenting symptoms, improved blood pressure control and normalization of his urinary catecholamine levels. This case highlights sleep disordered breathing as a potentially reversible cause of pseudo-pheochromocytoma. PMID- 27217897 TI - Knowledge and use of emergency contraception among students of public secondary schools in Ilorin, Nigeria. AB - INTRODUCTION: Unintended pregnancy and unsafe abortion pose a major reproductive health challenge to adolescents. Emergency contraception is safe and effective in preventing unplanned pregnancy. The objective of this study was to assess the student's knowledge and use of emergency contraception. METHODS: This cross sectional study was carried out in Ilorin, Nigeria, using multi-stage sampling method. Data was collected using pre-tested semi-structured self-administered questionnaire. Knowledge was scored and analysed. SPSS version 21.0 was used for data analysis. A p-value <0.05 was considered statistically significant. RESULTS: 27.8% of the respondents had good knowledge of emergency contraception. Majority of respondents (87.2%) had never used emergency contraception. Majority of those who had ever used emergency contraception (85.7%) used it incorrectly, using it more than 72 hours after sexual intercourse (p=0.928). CONCLUSION: Knowledge about Emergency contraception and prevalence of use were low. Contraceptive education should be introduced early in the school curriculum for adolescents. PMID- 27217899 TI - [Primary renal carcinoid metastasizing to distant sites 12 years after the initial diagnosis]. AB - Primary renal cancinoids are rare, with one hundred cases reported in the literature. Histologically, it is a well-differentiated tumor which shares a morphological pattern similar to that seen in carcinoids identified at other anatomic locations. We report a case of a 45-year-old man with primitive renal carcinoid, with diagnosis made after the detection of liver metastases. The tumour was peculiar given its tubulopapillary architecture, wrongly suggesting a diagnosis of papillary renal carcinoma. This diagnosis was revised 12 years after, following the appearance of other liver, bone and lung metastases. PMID- 27217900 TI - A review of the clinicopathologic characteristics of intestinal metaplasia in gastric mucosal biopsies. AB - INTRODUCTION: Although it is a well recognized premalignant lesion of the stomach, there is a dearth of information on the clinicopathologic features of gastric intestinal metaplasia in Nigerians. It is, therefore, necessary to study these features and their possible contribution to the development of gastric carcinoma in Nigerians. METHODS: All gastric biopsies with the histo-morphologic features of intestinal metaplasia diagnosed at the department of morbid anatomy and forensic medicine, Obafemi Awolowo university teaching hospitals complex, Ile Ife, Nigeria between January 2006 and December 2010 were used for the study. RESULTS: A total of 165 biopsies (21.3% of all gastric biopsies within the study period) with background chronic gastritis and intestinal metaplasia were reviewed. The mean age of patients with intestinal metaplasia was 50.3 years +/- 17 standard deviation (SD) while the ages of the patients ranged from 10-100 years. There were 83 males (50.3%) with a mean age of 48.1 +/- 18.2 SD years and 95% confidence interval (CI) of 44.1-52.1 years. There were, however, 82 females (49.6%) with a mean age of 52.5 (+/- 15.8 SD) years and a 95% CI of 49.0-56.0 years. There was no significant association between the histologic type of intestinal metaplasia and the patients' sex, age groups, severity of chronic gastritis, disease activity or degree of gastric glandular atrophy. CONCLUSION: There are no statistically significant differences in the clinicopathologic characteristics of the subtypes of intestinal metaplasia. In majority of patients, progression from intestinal metaplasia to gastric adenocarcinoma probably takes an average of about 7 years. PMID- 27217901 TI - [Peutz-Jeghers syndrome manifested as massive melaena at CHU-JRA Madagascar hospital: a case report]. AB - Peutz-Jeghers syndrome (SPJ) is characterized by intestinal hamartomatous polyps in association with mucocutaneous lentiginosis. Patients are exposed to mechanical and bleeding complications. It is a cancer predisposition syndrome. Our study highlights the diagnostic criteria for Peutz-Jeghers syndrome (SPJ), the complications and the therapeutic progresses in patient care. We report the case of a 32-year-old male presenting with a massive melaena. It was hospitalized in the surgical intensive care unit with hypovolemic shock difficult to control. This required surgical intervention to stop bleeding. We found a hamartomatous polyps in the small intestine which caused bleeding. Peutz Jeghers Syndrome was diagnosed on the basis of labial lentigines during childhood. Clinical and paraclinical explorations did not reveal the presence of cancer. In Madagascar, this disease is still poorly understood. In the literature, the diagnosis of Peutz Jeghers syndrome is based on clinical findings or on the presence of complications such as haemorrhage, invagination or bowel obstruction. In our case, the disease was complicated by gastrointestinal bleeding with hypovolemic shock. Endoscopic polypectomy using double-balloon enteroscopy can reduce emergency small bowel surgery. Peutz-Jeghers syndrome is a rare disease. Despite this, it is important for clinicians to know it and to take it into consideration in case of gastrointestinal bleeding. PMID- 27217902 TI - [Primitive benign retrovesical schwannoma: an extremely rare tumor, a case report]. AB - Schwannoma is usually a benign tumor of nervous origin arising from Schwann sheath cells. It is an extremely rare tumour because of its low incidence and its retrovescical localization. Histological and immunohistochemical examinations confirm the histological type as well as the benign or malignant origin of schwannoma. Because of the risk of recurrence and malignant transformation, excision must be complete. We report the case of a 39 years old patient, hospitalized for chronic pelvic pain accompanied by a sensation of heaviness, lower urinary tract irritation and urinary hesitancy. Diagnostic imaging (ultrasound, CT scan, MRI) of the pelvis showed a left-lateralized retrovescical mass with a thin wall, measuring 68x70x70 mm exerting mass effect on the bladder and the sigmoid. The surgical procedure, a midline laparotomy, allowed the removal of a well encapsulated retrovesical mass. Histological and immunohistochemical examinations concluded to a benign schwannoma. Recidivism and malignant transformation, although rare after surgery, impose postoperative clinical monitoring and annual CT scanning. PMID- 27217903 TI - [Perinatal morbidity and mortality in twin pregnancies in a Moroccan level-3 maternity ward]. AB - INTRODUCTION: Twin pregnancies are associated with a higher rate of perinatal morbidity and mortality than singleton pregnancies. The aim of the present study was to evaluate perinatal morbidity and mortality in twin pregnancies in a Moroccan level-3 maternity ward. METHODS: This is a comparative cross-sectional study of perinatal morbidity and mortality rates in newborn infants in twin pregnancies versus singleton pregnancies among women who gave birth at Souissi Maternity Hospital in Rabat from January 1 to February 28, 2014. RESULTS: There were 3297 births and, of these, 65 in twin pregnancies and 3167 in singleton pregnancies. Twin pregnancies were associated with higher rates of preeclampsia and eclampsia (P = 0.046), HELLP syndrome (P = 0.030), premature rupture of membranes (P < 0.001), malpresentation (P < 0.001), prematurity (P < 0.001), low birth weight in fullterm neonates (P < 0.001), respiratory distress at birth (P < 0.001), congenital malformations (P = 0.015), hospitalization in the neonatal period (P = 0.001), and perinatal mortality (P = 0.001) than singleton pregnancies. Monochorionic twins showed higher rates of low birth weight in fullterm pregnancies (P = 0.016) and of perinatal mortality (P = 0.017) than dichorionic twins. CONCLUSION: Twin pregnancies showed higher risk of perinatal morbidity and mortality than singleton pregnancies and were more exposed to prematurity. Monochorionic twin pregnancies showed a higher risk because of the significant exposure to low birth weight in fullterm babies. PMID- 27217904 TI - Sleep in space as a new medical frontier: the challenge of preserving normal sleep in the abnormal environment of space missions. AB - Space agencies such as the National Aeronautics and Space Administration of the United States, the Russian Federal Space Agency, the European Space Agency, the China National Space Administration, the Japan Aerospace Exploration Agency, and Indian Space Research Organization, although differing in their local political agendas, have a common interest in promoting all applied sciences that may facilitate man's adaptation to life beyond the earth. One of man's most important adaptations has been the evolutionary development of sleep cycles in response to the 24 hour rotation of the earth. Less well understood has been man's biological response to gravity. Before humans ventured into space, many questioned whether sleep was possible at all in microgravity environments. It is now known that, in fact, space travelers can sleep once they leave the pull of the earth's gravity, but that the sleep they do get is not completely refreshing and that the associated sleep disturbances can be elaborate and variable. According to astronauts' subjective reports, the duration of sleep is shorter than that on earth and there is an increased incidence of disturbed sleep. Objective sleep recordings carried out during various missions including the Skylab missions, space shuttle missions, and Mir missions all support the conclusion that, compared to sleep on earth, the duration in human sleep in space is shorter, averaging about six hours. In the new frontier of space exploration, one of the great practical problems to be solved relates to how man can preserve "normal" sleep in a very abnormal environment. The challenge of managing fatigue and sleep loss during space mission has critical importance for the mental efficiency and safety of the crew and ultimately for the success of the mission itself. Numerous "earthly" examples now show that crew fatigue on ships, trucks, and long-haul jetliners can lead to inadequate performance and sometimes fatal consequences, a reality which has caused many space agencies to take the issue of sleep seriously. PMID- 27217905 TI - Franz Kafka: An emblematic case of co-occurrence of sleep and psychiatryc disorders. PMID- 27217906 TI - Sleep disturbances and sexual function among men aged 45-75 years in an urban area of Iran. AB - BACKGROUND AND AIMS: Aging in men is associated with various physical and mental symptoms, including sleep problems and sexual dysfunction. The aim of this study was to determine the status of sleep disorders and sexual dysfunction in men aged 45-75 years in Ilam, Iran. MATERIALS AND METHODS: In this population-based cross sectional study, 390 men aged 45-75 years were selected by cluster randomization in Ilam-Iran. Data were collected using 0-100 brief sexual function inventory and the sleep disorder questionnaires. RESULTS: Totally, 34.6% of men complained about sleep disorders: 17.4% about falling asleep, 12.8% about frequent nocturnal awakenings, 12.8% about waking up in the early hours in the morning and problem in falling asleep again, and 24.9% about fatigue and tiredness despite getting enough sleep. There was a significant relationship between all aspects of sexual function and the common problems related to sleep (p<0.001). The older, unemployed, illiterate men, those with inadequate income, those affected by chronic diseases, and/or urinary incontinence had significantly inferior sexual function compared with the others. CONCLUSION: According to the high prevalence of sleep disorders in men as well as its association with sexual dysfunction, adopting health measures in this regard is necessary. PMID- 27217907 TI - Caffeine intake has no effect on sleep quality in community dwellers living in a rural Ecuadorian village (The Atahualpa Project). AB - More information is needed to better understand the effect of caffeine on sleep quality at the community level. In a population-based, cross-sectional study design, we aimed to assess the effect of caffeine intake on sleep quality by the use of a multivariate exposure-effect model, adjusted for relevant confounders. All Atahualpa residents aged >=40 years were identified during a door-to-door survey and interviewed with the Pittsburgh Sleep Quality Index (PSQI) and a structured instrument designed to estimate the daily amount of caffeine intake. An exposure-effect model was built using augmented inverse probability weighting taking into account variables that were associated with exposure (using a probit model) and variables that were associated with outcome (in a linear model). Out of 779 eligible individuals, 716 (92%) were included. Consumption of <100 mg/day of caffeine was recorded in 320 (45%) participants, from 100 to 200 mg/day in 299 (42%), and >200 mg/day in 97 (13%). Mean score in the PSQI was 4.5+/-2.2 points, with 203 (28%) individuals classified as poor sleepers (>=6 points). The exposure effect model, adjusted for variables associated with the exposure (symptoms of depression, total cholesterol blood levels and smoking) and the outcome (age, symptoms of depression, physical activity and fasting glucose levels), revealed no effect of caffeine intake in sleep quality (average exposure effect: 0.027, 95% C.I.: -0.284 to 0.338, p=0.866). This population-based study shows that caffeine intake has no effect on sleep quality in community-dwelling adults living in a rural village of Ecuador. PMID- 27217908 TI - Corrigendum to "Relationship between perceived sleep and polysomnography in older adult patients" [Sleep Sci. 8 (2015) 75-81]. AB - [This corrects the article DOI: 10.1016/j.slsci.2015.04.002.]. PMID- 27217909 TI - Sociodemographic factors influencing adherence to antenatal iron supplementation recommendations among pregnant women in Malawi: Analysis of data from the 2010 Malawi Demographic and Health Survey. AB - BACKGROUND AND AIM: Maternal morbidity and mortality statistics remain unacceptably high in Malawi. Prominent among the risk factors in the country is anaemia in pregnancy, which generally results from nutritional inadequacy (particularly iron deficiency) and malaria, among other factors. This warrants concerted efforts to increase iron intake among reproductive-age women. This study, among women in Malawi, examined factors determining intake of supplemental iron for at least 90 days during pregnancy. METHODS: A weighted sample of 10,750 women (46.7%), from the 23,020 respondents of the 2010 Malawi Demographic and Health Survey (MDHS), were utilized for the study. Univariate, bivariate, and regression techniques were employed. While univariate analysis revealed the percent distributions of all variables, bivariate analysis was used to examine the relationships between individual independent variables and adherence to iron supplementation. Chi-square tests of independence were conducted for categorical variables, with the significance level set at P < 0.05. Two binary logistic regression models were used to evaluate the net effect of independent variables on iron supplementation adherence. RESULTS: Thirty-seven percent of the women adhered to the iron supplementation recommendations during pregnancy. Multivariate analysis indicated that younger age, urban residence, higher education, higher wealth status, and attending antenatal care during the first trimester were significantly associated with increased odds of taking iron supplementation for 90 days or more during pregnancy (P < 0.01). CONCLUSIONS: The results indicate low adherence to the World Health Organization's iron supplementation recommendations among pregnant women in Malawi, and this contributes to negative health outcomes for both mothers and children. Focusing on education interventions that target populations with low rates of iron supplement intake, including campaigns to increase the number of women who attend antenatal care clinics in the first trimester, are recommended to increase adherence to iron supplementation recommendations. PMID- 27217911 TI - Urinary schistosomiasis among preschool children in Malengachanzi, Nkhotakota District, Malawi: Prevalence and risk factors. AB - AIM: This study was designed to determine the prevalence of and risk factors for schistosomiasis among a group of preschool children in Malawi. Schistosomiasis burden among preschoolers in Malawi is not well documented in the literature. METHODS: This study used field research (in the form of a snail survey), laboratory work (urinalysis and microscopy for parasite identification), and questionnaire-guided interviews to determine the prevalence of and risk factors for urinary schistosomiasis among children, aged between 6 and 60 months, in Malengachanzi, Nkhotakota District, Malawi. RESULTS: Urinary schistosomiasis prevalence among preschool children was 13%. Of the factors evaluated, only age (P = 0.027) was statistically significantly associated with urinary schistosomiasis risk. Four-year-old preschool children were five times more likely to contract urinary schistosomiasis than twoyear-old children (odds ratio [OR] = 5.255; 95% confidence interval [CI] = 1.014-27.237; P = 0.048). Increased contact with infested water among older children likely explains much of their increased risk. Infestation was evidenced by the presence of infected Bulinus globosus snails in the water contact points surveyed. Multiple regression analysis showed that visiting water contact sites daily (OR = 0.898, 95% CI = 0.185-4.350, P = 0.894), bathing in these sites (OR = 9.462, 95% CI = 0.036-0.00, P = 0.430) and lack of knowledge, among caregivers, regarding the causes of urinary schistosomiasis (OR = 0.235, 95% CI = 0.005-1.102, P = 0.066) posed statistically insignificant risk increases for preschoolers contracting urinary schistosomiasis. CONCLUSIONS: Urinary schistosomiasis was prevalent among preschool children in Malengachanzi, Nkhotakota District. Contact with infested water puts these children and the general population at risk of infection and reinfection. Inclusion of preschool children in treatment programmes should be considered imperative, along with safe treatment guidelines. To prevent infection, the population in the area should be provided with health education and safe alternative water sources. PMID- 27217910 TI - Assessment of non-standard HIV antiretroviral therapy regimens at Lighthouse Trust in Lilongwe, Malawi. AB - AIM: Lighthouse Trust in Lilongwe, Malawi serves approximately 25,000 patients with HIV antiretroviral therapy (ART) regimens standardized according to national treatment guidelines. However, as a referral centre for complex cases, Lighthouse Trust occasionally treats patients with non-standard ART regimens (NS-ART) that deviate from the treatment guidelines. We evaluated factors contributing to the use of NS-ART and whether patients could transition to standard regimens. METHODS: This was a cross-sectional study of all adult patients at Lighthouse Trust being treated with NS-ART as of February 2012. Patients were identified using the electronic data system. Medical charts were reviewed and descriptive statistics were obtained. RESULTS: One hundred six patients were initially found being treated with NS-ART, and 92 adult patients were confirmed to be on NS-ART after review. Mean patient age was 42.4 +/- 10.3 years, and 52 (57%) were female. Mean duration of treatment with the NS-ART being used at the time of data collection was 2.1 +/- 1.5 years. Eight patients (9%) were on modified first-line NS-ART and 84 (91%) were on modified second-line NS-ART, with 90 patients (98%) having multiple factors contributing to NS-ART use. Severe toxicity from one medication contributed in 28 cases (30%) and toxicity from multiple medications contributed in 46 cases (50%), while 22 patients (24%) were transitioned to NS ART following a stockout of their original medication. Following clinical review, 84 patients (91%) were transitioned to standard regimens, and eight (9%) were maintained on NS-ART because of incompatibility of their clinical features with the latest national guidelines. CONCLUSIONS: Primary factors contributing to NS ART use were medication toxicities and medication stockouts. Most patients were transitioned to standard regimens, although the need for NS-ART remains. PMID- 27217912 TI - Point-of-care lactate and creatinine analysis for sick obstetric patients at Queen Elizabeth Central Hospital in Blantyre, Malawi: A feasibility study. AB - BACKGROUND: To achieve good outcomes in critically ill obstetric patients, it is necessary to identify organ dysfunction rapidly so that life-saving interventions can be appropriately commenced. However, timely access to clinical chemistry results is problematic, even in referral institutions, in the sub-Saharan African region. Reliable point-of-care tests licensed for clinical use are now available for lactate and creatinine. AIM: We aimed to assess whether implementation of point-of-care testing for lactate and creatinine is feasible in the obstetric unit at the Queen Elizabeth Central Hospital (QECH) in Blantyre, Malawi, by obtaining the opinions of clinical staff on the use of these tests in practice. METHODS: During a two-month evaluation period nurse-midwives, medical interns, clinical officers, registrars, and consultants were given the opportunity to use StatStrip(r) and StatSensor(r) (Nova Biomedical, Waltham, USA) devices, for lactate and creatinine estimation, as part of their routine clinical practice in the obstetric unit. They were subsequently asked to complete a short questionnaire. RESULTS: Thirty-seven questionnaires were returned by participants: 22 from nurse-midwives and the remainder from clinicians. The mean satisfaction score for the devices was 7.6/10 amongst clinicians and 8.0/10 amongst nurse-midwives. The majority of participants stated that the obstetric high dependency unit (HDU) was the most suitable location for the devices. For lactate, 31 participants strongly agreed that testing should be continued and 24 strongly agreed that it would influence patient management. For creatinine, 29 strongly agreed that testing should be continued and 28 strongly agreed that it would influence their patient management. Twenty participants strongly agreed that they trust point-of-care devices. CONCLUSIONS: Point-of-care clinical chemistry testing was feasible, practical, and well received by staff, and was considered to have a useful role to play in the clinical care of sick obstetric patients at this referral centre. PMID- 27217913 TI - Risk perception and correlates of alcohol use among out-of-school youth in motor parks in Lagos State, Nigeria. AB - BACKGROUND AND AIM: The prevalence of alcohol use has increased globally. Out-of school youth are a vulnerable group who might have missed opportunities for learning healthy behaviours in a formal school environment. The purpose of this study was to determine the risk perception, pattern of use, and correlates of alcohol use among out-of-school youth in Lagos, Nigeria. METHODS: A cross sectional study was conducted among 380 out-of-school youth in motor parks in Lagos State, Nigeria, using interviewer administered questionnaires. RESULTS: The lifetime prevalence of alcohol use was 61.1%, while 55.5% were current drinkers. Beer (57.3%) was the most consumed type of alcohol, followed by distilled spirits (29.8%). Using the CAGE scoring system, more than half (57.8%) of the current drinkers had a drinking problem. Almost three quarters (70.1%) had experienced at least one episode of alcohol intoxication within the past month. A considerable number of current drinkers (63.5%) desired to reduce their alcohol intake or stop drinking, while 45.5% had made unsuccessful attempts to do so within the past year. Only 28.9% had received assistance to quit or reduce their drinking and of these less than half (39.3%) received assistance from a professional or healthcare worker. Males were more likely to be current drinkers and to have experienced episodes of alcohol intoxication. Parental and peer drinking were associated with alcohol use but not with intoxication. CONCLUSIONS: It is important to design specific programmes to reduce alcohol use among out-of-school youth in these settings. PMID- 27217914 TI - How IMF's loan freeze will affect health care in Malawi. PMID- 27217915 TI - Should haemoglobin A1C be used for diagnosis of diabetes mellitus in Malawi? PMID- 27217917 TI - "Mental health field has shown me that most healthcare workers focus on physical health and tend to ignore the mental health" Thengo Kavinya talks to Michael Udedi, Assistant Director of Clinical Services in the Ministry of Health. PMID- 27217916 TI - Uterine leiomyoma in a 19-year-old girl: Case report and literature review. PMID- 27217918 TI - Single Chain Antibodies Against gp55 of Human Cytomegalovirus (HCMV) for Prophylaxis and Treatment of HCMV Infections. AB - BACKGROUND: Immunotherapy is a promising prospective new treatment for cytomegalovirus (CMV) infections. Neutralizing effects have been reported using monoclonal antibodies. Recombinant single chain antibodies (scFvs) due to their advantages over monoclonal antibodies are potential alternatives and provide valuable clinical agents. OBJECTIVES: The aim of this study was to select specific single chain antibodies against gp55 of CMV and to evaluate their neutralizing effects. In the present study, we selected specific single chain antibodies against glycoprotein 55 (gp55) of CMV for their use in treatment and diagnosis. MATERIALS AND METHODS: Single chain antibodies specific against an epitope located in the C-terminal part of gp55 were selected from a phage antibody display library. After four rounds of panning, twenty clones were amplified by the polymerase chain reaction (PCR) and fingerprinted by MvaI restriction enzyme. The reactivities of the specific clones were tested by the enzyme-linked immunosorbent assay (ELISA) and the neutralizing effects were evaluated by the plaque reduction assay. RESULTS: Fingerprinting of selected clones revealed three specific single chain antibodies (scFv1, scFv2 and scFv3) with frequencies 25%, 20 and 20%. The clones produced positive ELISA with the corresponding peptide. The percentages of plaque reduction for scFv1, scFv2 and scFv3 were 23.7, 68.8 and 11.6, respectively. CONCLUSIONS: Gp55 of human CMV is considered as an important candidate for immunotherapy. In this study, we selected three specific clones against gp55. The scFvs reacted only with the corresponding peptide in a positive ELISA. The scFv2 with 68.8% neutralizing effect showed the potential to be considered for prophylaxis and treatment of CMV infections, especially in solid organ transplant recipients, for whom treatment of CMV is urgently needed. The scFv2 with neutralizing effect of 68.8%, has the potential to be considered for treatment of these patients. The specific scFv1 and scFv3 with lower neutralizing effects can be used for diagnostic purposes. PMID- 27217919 TI - In Vitro and in Vivo Antistaphylococcal Activity Determination of the New Recombinant Lysostaphin Protein. AB - BACKGROUND: Bacterial infection by antibiotic-resistant Staphylococcus aureus strains is a worldwide concern and the development of novel antistaphylococcal agents is acutely needed. Lysostaphin, an example of such novel agents, is a bacteriocin secreted by S. simulans to kill S. aureus through proteolysis of the Staphylococcus cell wall. OBJECTIVES: The aim of this study was to evaluate the in vitro and in vivo antistaphylococcal activity of recombinant lysostaphin. MATERIALS AND METHODS: The in vitro study of the recombinant lysostaphin activity against S. aureus was determined by turbidimetric assay. For in vivo investigation, two groups of rats were inoculated with 1.4 * 10(9) CFU S. aureus. Five days after the nasal instillation of S. aureus, treatment in one of the groups was performed with a single dose (200 MUg/dose) of recombinant lysostaphin formulated in Eucerin-based cream. RESULTS: Recombinant lysostaphin at 100 MUg/mL concentration showed a significant decrease of the optical density compared to the control samples. The in vivo study demonstrated that a single dose (200 MUg/dose) of recombinant lysostaphin cream significantly reduced nasal colonization in all the treated animals compared to the untreated ones. CONCLUSIONS: These results demonstrated that the recombinant lysostaphin produced in this study was able to kill nasal S. aureus in rats. It can be recommended for human clinical trial studies. PMID- 27217920 TI - Increasing Prevalence of Aminoglycoside-Resistant Enterococcus faecalis Isolates Due to the aac(6')-aph(2") Gene: A Therapeutic Problem in Kermanshah, Iran. AB - BACKGROUND: Enterococci are important pathogens in nosocomial infections. Various types of antibiotics, such as aminoglycosides, are used for treatment of these infections. Enterococci can acquire resistant traits, which can lead to therapeutic problems with aminoglycosides. OBJECTIVES: This study was designed to identify the prevalence of, and to compare, the aac(6')-aph(2") and aph(3)-IIIa genes and their antimicrobial resistance patterns among Enterococcus faecalis and E. faecium isolates from patients at Imam Reza hospital in Kermanshah in 2011 - 2012. PATIENTS AND METHODS: One hundred thirty-eight clinical specimens collected from different wards of Imam Reza hospital were identified to the species level by biochemical tests. Antimicrobial susceptibility tests against kanamycin, teicoplanin, streptomycin, imipenem, ciprofloxacin, and ampicillin were performed by the disk diffusion method. The minimum inhibitory concentrations of gentamicin, streptomycin, kanamycin, and amikacin were evaluated with the microbroth dilution method. The aminoglycoside resistance genes aac(6')-aph(2") and aph(3")-IIIa were analyzed with multiplex PCR. RESULTS: The prevalence of isolates was 33 (24.1%) for E. faecium and 63 (46%) for E. faecalis. Eighty-nine percent of the isolates were high-level gentamicin resistant (HLGR), and 32.8% of E. faecium isolates and 67.2% of E. faecalis isolates carried aac(6')-aph(2"). The prevalence of aph(3")-IIIa among the E. faecalis and E. faecium isolates was 22.7% and 77.3%, respectively. CONCLUSIONS: Remarkably increased incidence of aac(6')-aph(2") among HLGR isolates explains the relationship between this gene and the high level of resistance to aminoglycosides. As the resistant gene among enterococci can be transferred, the use of new-generation antibiotics is necessary. PMID- 27217921 TI - Analysis of DNA gyrA Gene Mutation in Clinical and Environmental Ciprofloxacin Resistant Isolates of Non-Tuberculous Mycobacteria Using Molecular Methods. AB - BACKGROUND: During the past several years, nontuberculous mycobacteria (NTM) have been reported as some of the most important agents of infection in immunocompromised patients. OBJECTIVES: The aim of this study was to evaluate the ciprofloxacin susceptibility of clinical and environmental NTM species isolated from Isfahan province, Iran, using the agar dilution method, and to perform an analysis of gyrA gene-related ciprofloxacin resistance. MATERIALS AND METHODS: A total of 41 clinical and environmental isolates of NTM were identified by conventional and multiplex PCR techniques. The isolates were separated out of water, blood, abscess, and bronchial samples. The susceptibility of the isolates to 1 ug/mL, 2 ug/mL and 4 ug/mL of ciprofloxacin concentrations was determined by the agar dilution method according to CLSI guidelines. A 120-bp area of the gyrA gene was amplified, and PCR-SSCP templates were defined using polyacrylamide gel electrophoresis. The 120-bp of gyrA amplicons with different PCR-SSCP patterns were sequenced. RESULTS: The frequency of the identified isolates was as follows: Mycobacterium fortuitum, 27 cases; M. gordonae, 10 cases; M. smegmatis, one case; M. conceptionense, one case; and M. abscessus, two cases. All isolates except for M. abscessus were sensitive to all three concentrations of ciprofloxacin. The PCR SSCP pattern of the gyrA gene of resistant M. abscessus isolates showed four different bands. The gyrA sequencing of resistant M. abscessus isolates showed 12 alterations in nucleotides compared to the M. abscessus ATCC 19977 resistant strain; however, the amino acid sequences were similar. CONCLUSIONS: This study demonstrated the specificity and sensitivity of the PCR-SSCP method for finding mutations in the gyrA gene. Due to the sensitivity of most isolates to ciprofloxacin, this antibiotic should be considered an appropriate drug for the treatment of related diseases. PMID- 27217922 TI - Construction of AAV-rat-IL4 and Evaluation of its Modulating Effect on Abeta (1 42)-Induced Proinflammatory Cytokines in Primary Microglia and the B92 Cell Line by Quantitative PCR Assay. AB - BACKGROUND: Interleukin-4 (IL-4), as the most prominent anti-inflammatory cytokine, plays an important role in modulating microglial activation and inflammatory responses in Alzheimer's disease (AD), a chronic inflammatory disorder. OBJECTIVES: The current study aimed to develop a new recombinant Adeno associated viral (rAAV) vector that delivers IL-4 and then assess the counterbalancing effect of the new construct along with recombinant IL-4 (rIL-4) protein in in-vitro models of AD. MATERIALS AND METHODS: The rAAV-IL4 was originally prepared and then employed along with rIL-4 protein to counter Amyloid beta (1-42)-induced proinflammatory cytokines in a primary microglia cell culture and the B92 rat microglia continuous cell line, using relative Real-Time PCR assay. RESULTS: Abeta (1-42) stimulated the production of the proinflammatory cytokines IL6, IL1beta, TNFalpha, and IL18 in both the primary microglia cell culture and the B92 cell line. Both the rAAV-IL4 construct and the rIL-4 protein were found to inhibit production of the most important Abeta (1-42)-induced proinflammatory cytokine mRNAs in the two types of cells with different patterns. CONCLUSIONS: It seems that the new construct can serve as an appropriate option in the modulation of Abeta-induced proinflammatory cytokine gene expression and microglia activation in patients affected by AD. PMID- 27217923 TI - Vision Examination Protocol for Archery Athletes Along With an Introduction to Sports Vision. AB - INTRODUCTION: Visual skills are one of the main pillars of intangible faculties of athletes that can influence their performance. Great number of vision tests used to assess the visual skills and it will be irrational to perform all vision tests for every sport. OBJECTIVES: The purpose of this protocol article is to present a relatively comprehensive battery of tests and assessments on static and dynamic aspects of sight which seems relevant to sports vision and introduce the most useful ones for archery. MATERIALS AND METHODS: Through extensive review of the literature, visual skills and respective tests were listed; such as 'visual acuity, 'contrast sensitivity', 'stereo-acuity', 'ocular alignment', and 'eye dominance'. Athletes were defined as "elite" and "non-elite" category based on their past performance. Dominance was considered for eye and hand; binocular or monocular aiming was planned to be recorded. Illumination condition was defined as to simulate the real archery condition to the extent possible. The full cycle of examinations and their order for each athlete was sketched (and estimated to take 40 minutes). Protocol was piloted in an eye hospital. Female and male archers aged 18 - 38 years who practiced compound and recurve archery with a history of more than 6 months were included. CONCLUSIONS: We managed to select and design a customized examination protocol for archery (a sight-intensive and aiming type of sports), serving skill assessment and research purposes. Our definition for elite and non-elite athletes can help to define sports talent and devise skill development methods as we compare the performance of these two groups. In our pilot, we identified 8 "archery figures" (by hand dominance, eye dominance and binocularity) and highlighted the concept "congruence" (dominant hand and eye in the same side) in archery performance. PMID- 27217924 TI - Parachute Jumping Induces More Sympathetic Activation Than Cortisol Secretion in First-Time Parachutists. AB - BACKGROUND: The word "stress" describes the status of the body affected by external or internal forces, or "stressors", threatening to alter its dynamic balance or homeostasis. The adaptive changes which occur in reply to stressors are either behavioral or physical. Once a given threshold is surpassed, a systemic reaction takes place involving the "stress system" in the brain together with its peripheral components, the hypothalamic-pituitary-adrenal axis and autonomic sympathetic. OBJECTIVES: Stress induces an activation of the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis. The purpose of this study was to investigate whether the SNS and the HPA axis would show parallel or divergent stress response patterns in a session of first parachute jump. PATIENTS AND METHODS: Activation of the SNS was evaluated by dosage of salivary alpha-amylase, galvanic skin responses, and heart rate in seven male novice parachutists. Activation of HPA axis was tested by dosage of cortisol. These variables were measured before and 1 minute and 90 minute after the jump. RESULTS: All variables reached a peak at 1 minute post-jump. Salivary alpha-amylase, galvanic skin responses and heart rate did not return to basal value at 90 minutes post-jump, while cortisol returned to basal value at 90 minutes post-jump. CONCLUSIONS: This evidence indicates that parachute jumping is accompanied by a dissociation of SNS and HPA response patterns in novice parachutists, showing a slower recovery in sympathetic activity than in cortisol secretion. PMID- 27217925 TI - Repeated Supramaximal Exercise-Induced Oxidative Stress: Effect of beta-Alanine Plus Creatine Supplementation. AB - BACKGROUND: Carnosine is a dipeptide formed from the beta-alanine and histidine amino acids and found in mainly in the brain and muscle, especially fast twitch muscle. Carnosine and creatine has an antioxidant effect and carnosine accounts for about 10% of the muscle's ability to buffer the H(+) ions produced by exercise. OBJECTIVES: The aim of the study was to investigate the effects of beta alanine and/or creatine supplementation on oxidant and antioxidant status during repeated Wingate tests (WTs). PATIENTS AND METHODS: Forty four sedentary males participated in the study. Participants performed three 30s WTs with 2 minutes rest between exercise bouts. After the first exercise session, the subjects were assigned to one of four groups: Placebo, Creatine, Beta-alanine and Beta-alanine plus creatine. Participants ingested twice per day for 22 consecutive days, then four times per day for the following 6 days. After the supplementation period the second exercise session was applied. Blood samples were taken before and immediately after the each exercise session for the analysis of oxidative stress and antioxidant markers. RESULTS: Malondialdehyde levels and superoxide dismutase activities were affected by neither supplementation nor exercise. During the pre supplementation session, protein carbonyl reduced and oxidized glutathione (GSH and GSSG) levels increased immediately after the exercise. However, during the post-supplementation session GSH and GSSG levels increased in beta-alanine and beta-alanine plus creatine groups immediately after the exercise compared to pre exercise. In addition, during the post-supplementation session total antioxidant capacity increased in beta-alanine group immediately after the exercise. CONCLUSIONS: Beta-alanine supplementation has limited antioxidant effect during the repeated WTs. PMID- 27217926 TI - Effect of Maximal Versus Supra-Maximal Exhausting Race on Lipid Peroxidation, Antioxidant Activity and Muscle-Damage Biomarkers in Long-Distance and Middle Distance Runners. AB - BACKGROUND: Exhausting physical exercise increases lipid peroxidation and causes important muscle damages. The human body tries to mitigate these adverse effects by mobilizing its antioxidant defenses. OBJECTIVES: This study aims to investigate the effect of a maximal versus supra-maximal race sustained until exhaustion on lipid peroxidation, antioxidant activity and muscle-damage biomarkers in trained (i.e. long-distance and middle-distance runners) and sedentary subjects. MATERIALS AND METHODS: The study has been carried out on 8 middle-distance runners (MDR), 9 long-distance runners (LDR), and 8 sedentary subjects (SS). Each subject has undergone two exhaustive running tests, the first one is an incremental event (VAMEVAL test), the second one is a constant supra maximal intensity test (limited-time test). Blood samples were collected at rest and immediately after each test. RESULTS: A significant increase in malondialdehyde (MDA) concentrations was observed in SS and MDR after the VAMEVAL test and in LDR after the Limited-Time test. A significant difference was also observed between LDR and the other two groups after the VAMEVAL test, and between LDR and MDR after the Limited-Time test. Significant modifications, notably, in myoglobin, CK, LDH, IL-6, TNF-alpha, and TAS were likewise noted but depending on the race-type and the sportive specialty. CONCLUSIONS: Maximal and supra-maximal races induce a significant increase in lipid peroxidation and cause non negligible inflammation and muscle damage. These effects were relatively related to the physical exercise type and the sportive specialty. PMID- 27217927 TI - Kinetic Post-match Fatigue in Professional and Youth Soccer Players During the Competitive Period. AB - BACKGROUND: No previous research has analysed kinetic fatigue of elite adult players and elite youth players during the competitive period. OBJECTIVES: The aim of the present study was to analyse kinetic post-match fatigue in professional and youth soccer players during the competitive period. MATERIALS AND METHODS: resting heart rate (HRrest), post-effort recovery heart rate (HRrecovery), rate of perceived exertion fatigue (RPEf), muscle soreness and blood samples with creatine kinase (CK) and resting lactate (La) from nine professional soccer players were measured immediately before, 24 hour and 48 hour after two official French first league matches (Ligue 1) whereas RPEf, HRrest, and 20m speed performance (speed-20 m) were measured in ten U-17 elite players immediately before, 24 hour and 48h after a friendly match. RESULTS: for professionals, a soccer match elevated all physiological markers during the next 24 hours (P < 0.05); only HRrecovery remained significantly different 48 hours after the match (P < 0.05) whereas there was no variation of HRrest, RPEf, and speed-20m, which were elevated until 24h and got back to reference values 48 hours after the match (P < 0.05) for the U17 players. Comparing the two groups, HRrest results remained lower all the time for professionals, and RPEf was lower for U-17, 24 hours after the match (P < 0.05). CONCLUSIONS: Independent of their level, professional soccer players, need 48 hours to recover after an official match. Professionals gain more fatigue than young players after a match, but recover as fast. Thus, they recover more efficiently especially due to a better physical condition and fitness training. It is expected that the results showed in the study help elite soccer and fitness coaches to manage the training load of the team according to the match. PMID- 27217928 TI - Management of In-Season Concurrent Rotator Cuff Tear With Shoulder Instability in Professional Contact Football Athletes; Respect the Career Goals! AB - INTRODUCTION: Professional sports injuries are usually all dealt with at one single operation to return the player to the sport after appropriate rehabilitation. We questioned the assumption that rotator cuff tears must be repaired concurrently with instability syndromes, and aimed to allow a professional rugby league player to achieve career goals by NOT correcting all pathology at one surgery. CASE PRESENTATION: A professional rugby league player presented with acute shoulder instability on a setting of a chronic full thickness rotator cuff tear. We performed an "in season" arthroscopic stabilization on an elite rugby league player, leaving a previously diagnosed large full thickness rotator cuff tear untreated. This allowed aggressive rehabilitation and return to contact competition at 12 weeks post-surgery. The player achieved a long held career goal of winning a premiership ring before undertaking rotator cuff repair at the end of the season. Latest follow up at seven years (still at elite level) demonstrated an asymptomatic shoulder. CONCLUSIONS: The assumption that all pathology found at surgical exploration requires correction to play at elite level is not universally correct. We postulate that whilst rotator cuff deficiency has severe long-term sequelae, it is shoulder instability alone that prevents high level contact sports participation. Career goal management is an important part of managing elite level athletes. We have demonstrated that by careful management of the specific pathology preventing participation can allow elite athletes to achieve career goals without compromising long-term health. PMID- 27217929 TI - A Prospective Analysis of the Injury Incidence of Young Male Professional Football Players on Artificial Turf. AB - BACKGROUND: The effects of synthetic surfaces on the risk of injuries is still debated in literature and the majority of published data seems to be contradictory. For such reasons the understanding of injury incidence on such surfaces, especially in youth sport, is fundamental for injury prevention. OBJECTIVES: The aim of this study was to prospectively report the epidemiology of injuries in young football players, playing on artificial turfs, during a one sports season. PATIENTS AND METHODS: 80 young male football players (age 16.1 +/- 3.7 years; height 174 +/- 6.6 cm; weight 64.2 +/- 6.3 kg) were enrolled in a prospective cohort study. The participants were then divided in two groups; the first included players age ranging from 17 to 19 (OP) whereas the second included players age ranging from 13 to 16 (YP). Injury incidence was recorded prospectively, according to the consensus statement for soccer. RESULTS: A total of 107 injuries (35 from the OP and 72 from the YP) were recorded during an exposure time of 83.760 hours (incidence 1.28/1000 per player hours); 22 during matches (incidence 2.84/1000 per player hours, 20.5%) and 85 during training (incidence 1.15/1000 per player hours, 79.5%). Thigh and groin were the most common injury locations (33.6% and 21.5%, respectively) while muscle injuries such as contractures and strains were the most common injury typologies (68.23%). No statistical differences between groups were displayed, except for the rate of severe injuries during matches, with the OP displaying slightly higher rates compared to the YP. Severe injuries accounted for 10.28% of the total injuries reported. The average time lost due to injuries was 14 days. Re-injuries accounted for 4.67% of all injuries sustained during the season. CONCLUSIONS: In professional youth soccer injury rates are reasonably low. Muscle injuries are the most common type of injuries while groin and thigh the most common locations. Artificial turf pitches don't seem to contribute to injury incidence in young football players. PMID- 27217930 TI - Effects of Complementary Creatine Monohydrate and Physical Training on Inflammatory and Endothelial Dysfunction Markers Among Heart Failure Patients. AB - BACKGROUND: Previous studies have reported endothelial dysfunction and inflammatory cytokine in heart failure patients (HF). OBJECTIVES: The purpose of this study was to determine the effects of creatine monohydrate and exercise on inflammatory and endothelial dysfunction markers among HF patients. PATIENTS AND METHODS: One hundred patients were prospectively randomized into two groups: Intervention group which received 5 grams/day creatine monohydrate and exercised for 8 weeks; and control group which did not receive any interventions. Interleukine-6 (IL-6), high sensitivity C reactive protein (hs-CRP), P-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) were measured at the start and end of the study for both groups. RESULTS: In total, 100 patients including 50 controls and 50 intervention group (54% male, mean EF of 34.2 +/- 10.5% and 52% male, mean EF of 35.6 +/- 12.7%, respectively) were analyzed. The serum levels of hs-CRP and IL-6 increased at the end of the study in the control group compared to the baseline, (7.5 +/- 1.5 mg/L vs. 6.9 +/- 1.3 mg/L, P < 0.05 and 3.0 +/- 0.75 ng/L vs. 2.55 +/- 0.9 ng/L, P < 0.05, respectively). However, compared to the baseline, the level of both markers decreased at the end of the study in the intervention group (6.3 +/- 1.6 mg/L vs.7.5 +/- 1.5 mg/L, P < 0.05 and 2.1 +/- 0.8 ng/L vs.2.5 +/- 0.5 ng/L, P < 0.05). Also, P-selectin and ICAM-1 levels increased at the end of study (56.9 +/- 1.8 ng/L vs. 51.9 +/- 1.5 ng/L, P < 0.05 and 368.1 +/- 25.4 ug/L vs. 353.1 +/- 10.4 ug/L, P < 0.05 respectively). Inversely, the levels of these markers decreased in the intervention group, at the end of study (49.7 +/- 1.9 ng/l vs. 51.4 +/- 2.1 ng/l, P < 0.05 and 342.7 +/- 16.5 ug/l vs. 350.4 +/- 14.7 ug/l, P < 0.05, respectively). VCAM-1 level was not decreased significantly at the end of the study in the intervention group (570.5 +/- 78.4 ug/L vs. 575.3 +/- 86.5 ug/L, P > 0.05). CONCLUSIONS: Combination of creatine monohydrate and exercise attenuated inflammation and endothelial dysfunction markers among heart failure patients. PMID- 27217931 TI - Regional Skin Temperature Response to Moderate Aerobic Exercise Measured by Infrared Thermography. AB - BACKGROUND: Infrared thermography (IRT) does not require contact with the skin, and it is a convenient, reliable and non-invasive technique that can be used for monitoring the skin temperature (TSK). OBJECTIVES: The aim of this study was to monitor the variations in the regional TSK during exercise on 28 regions of interest (ROIs) (forehead, face, chest, abdomen, back, lumbar, anterior and posterior neck, and posterior and anterior views of the right and left hands, forearms, upper arms, thighs, and legs) with IRT. PATIENTS AND METHODS: 12 physically active young males were monitored with IRT during the following three phases: a) 30 minutes before exercise b) while performing one hour of moderate intensity exercise on a treadmill at 60% of the VO2max, and c) 60 minutes after exercise. RESULTS: During pre-exercise, all TSK reached a steady-state (P <= 0.05), which ensured adequate thermal stabilisation. At the beginning of exercise, there was a significant reduction in the TSK in most ROIs after 10 minutes of activity, except for the lower limbs (legs and thighs). After one hour of recovery, in the anterior view of the hands and thighs and in the posterior view of the legs, there were significant increases in the TSK compared to pre exercise. CONCLUSIONS: There were significant distinctions in the skin temperature distribution during exercise according to the activity of the area under consideration during exercise, which may be important in the development of physiological models and heat flux analyses for different purposes. PMID- 27217932 TI - Outcome of Simultaneous Arthroscopic Anterior Cruciate Ligament and Posterior Cruciate Ligament Reconstruction With Hamstring Tendon Autograft: A Multicenter Prospective Study. AB - BACKGROUND: Multiligamentous injuries of knee are a complex problem in orthopaedics. Combined ACL-PCL injuries are uncommon, usually associated with knee dislocations. Extremity vascular status is essential because of possible arterio-venous compromise. These complex injuries require a systematic evaluation and treatment. Single setting simultaneous arthroscopic ACL and PCL reconstruction or a staged approach can be adopted to treat these cases. OBJECTIVES: To evaluate functional outcome of simultaneous arthroscopic ACL and PCL reconstruction with hamstring tendon autograft in multiligamentous knee injuries. PATIENTS AND METHODS: This prospective study was performed on 20 patients with combined ACL-PCL injuries who underwent simultaneous arthroscopic ACL-PCL reconstruction with hamstring tendon. Evaluation of functional outcome was by IKDC and Lysholm-Tegner scores. RESULTS: In 20 patients, mean age 34 years, return to full-time work and to full sports was 8 weeks and 6.2 months respectively. All patients had full range of motion except 2 patients with < 5 degrees flexion loss; 90% had negative Lachmann test; 95% had negative pivot shift and 10% patients had mild posterior drawer at 90 degrees (1+) at final follow up. Mean IKDC score was 90 (range 81 - 94); mean Tegner activity score was 7 and mean Lysholm knee score was 89. 85% returned to preinjury activity level and a 90% satisfaction rate. CONCLUSIONS: Simultaneous arthroscopic ACL and PCL reconstructions using hamstring tendon for combined ACL and PCL injuries is a clinically effective, safe, time saving and cost-effective procedure with better patient compliance and reproducible for a timely return of motion, strength, and function with favorable outcome. PMID- 27217933 TI - A Prospective Epidemiological Study of Injuries in Japanese National Tournament Level Badminton Players From Junior High School to University. AB - BACKGROUND: Injury prevention programs have recently been created for various sports. However, a longitudinal study on badminton injuries, as assessed by a team's dedicated medical staff, at the gymnasium has not been performed. OBJECTIVES: We aimed to perform the first such study to measure the injury incidence, severity and type as the first step in creating a badminton injury prevention program. PATIENTS AND METHODS: A prospective, longitudinal survey was conducted between April 2012 and March 2013 with 133 national tournament-level badminton players from junior high school to university in Japan with the teams' physical therapists at the gymnasium. Injury incidence was measured as the injury rate (IR) for every 1,000 hour (1000 hour) and IR for every 1,000 athlete exposures (1000 AE). Severity was classified in 5 levels by the number of days the athlete was absent from practice or matches. Injury types were categorized as trauma or overuse. RESULTS: Practice (IR) (1,000 hour) was significantly higher in female players than in male players; the rates increased with increasing age. IR (1,000 AE) was significantly higher in matches than in practice in both sexes of all ages, except for female junior high school students and injuries were most frequent for high school students in matches. The majority of the injuries were slight (83.8%); overuse injuries occurred approximately 3 times more than trauma. CONCLUSIONS: This is the first study in which medical staff assessed injuries in badminton, providing value through benchmark data. Injury prevention programs are particularly necessary for female university students in practice and high school students in matches. PMID- 27217934 TI - Comparison of the Effects of Resistance Exercise Orders on Number of Repetitions, Serum IGF-1, Testosterone and Cortisol Levels in Normal-Weight and Obese Men. AB - BACKGROUND: Exercise order affects repetition performance and acute hormonal responses to resistance training (RT) programs. OBJECTIVES: The purpose of this study was to compare the acute effects of two different resistance exercise orders (REO) on number of repetitions and serum Insulin-like Growth Factor-1 (IGF 1), testosterone and cortisol levels in normal-weight and obese men. MATERIALS AND METHODS: 25 untrained college-aged men were assigned to either obese (n = 11) or normal-weight (n = 15) groups. Subjects performed two REO protocols in 2 exercise groups. In the first group subjects began with large-muscle group and progressed to small-muscle group (Protocol A), while in the other group subjects performed the same exercise but in reverse sequence (Protocol B). Each activity was performed in 3 consecutive sets of 10 repetitions maximum to near fatigue. RESULTS: REOs did not affect number of repetitions in none of the groups. The average rating of perceived exertion was higher for protocol B in both groups. IGF-1 and testosterone increased immediately post exercise for both protocols and in both groups, however immediately post exercise increase in IGF-1 and testosterone were lower in obese group. Cortisol response to REO was weaker in obese group. CONCLUSIONS: Performing large muscle group exercises first in RE training and progressing to small muscle group produced greater anabolic hormonal response relative to reverse sequence in normal-weight young adult men. Anabolic hormonal response to REOs was blunted in the obese group. PMID- 27217935 TI - Injuries, Matches Missed and the Influence of Minimum Medical Standards in the A League Professional Football: A 5-Year Prospective Study. AB - BACKGROUND: Epidemiological data on the occurrence of time-loss injuries over several A-League seasons remains lacking, while the effect of the mandatory implementation of 'Minimum Medical Standards' as a part of the collective bargaining agreement (CBA) needs to be explored. OBJECTIVES: To explore the 5 year evolution of hamstring, groin, knee, ankle and total time-loss injuries among professional footballers in the A-League; to evaluate the consequences of these time-loss injuries in terms of total matches missed and costs incurred; and to explore whether the mandatory implementation of 'Minimum Medical Standards' in the A-League had led to a decrease in the occurrence of total time-loss injuries and total matches missed. PATIENTS AND METHODS: An observational prospective study has been carried out since 2008. Data were collected weekly during the seasons 2008 - 2009 to 2012 - 2013 through official match previews/reviews, official media releases, official websites and/or self-reports by players. Total and specific (hamstring, groin, knee and ankle) numbers of time-loss injuries and matches missed were obtained for each season and the related financial costs calculated. RESULTS: The total number of time-loss injuries and matches missed rose from 129 and 506 respectively in 2008 - 2009 to 202 and 1110 in 2010 - 2011. Following the introduction of 'Minimum Medical Standards', both categories decreased (significantly for matches missed). These time-loss injuries and matches missed led to high costs of up to AUD$ 37,317,029.29 (2012 - 2013 season). The same trend was found for knee injuries, while hamstring and ankle injuries remained almost the same. However, time-loss due to groin injuries increased despite the introduction of "Minimum Medical Standards". CONCLUSIONS: The introduction of "Minimum Medical Standards" in the A-League had a favorable effect on the number of total, hamstring, knee and ankle injuries and on the number of matches missed due to these injuries, but not on the number of groin injuries. The costs related to time-loss injuries and related matches missed remained high. PMID- 27217936 TI - The Prevalence of Cervical Human Papillomavirus Infection and the Most At-risk Genotypes Among Iranian Healthy Women: A Systematic Review and Meta-analysis. AB - BACKGROUND: One of the most common sexual-transmitted infections among women is human papillomavirus (HPV) infection which is associated with genital cancers. Different studies in Iran reported various prevalences, and combining their results could be important for health policy makers. This study aims to determine the total prevalence of HPV infection as well as its related genotypes, particularly HPV16 and HPV18 among Iranian healthy women. METHODS: Searching the Scientific Information Database, Iranmedex, Magiran, Irandoc, PubMed, Google Scholar, Scopus, and ScienceDirect databanks using relevant keywords and excluding duplicates and irrelevant evidence followed by applying exclusion criteria and quality assessment, eligible articles were selected. Standard error of the prevalence was calculated based on binomial distribution. Random effects model was used because of the high heterogeneity among the results. RESULTS: Of 14 studies entered into the systematic review, 24 pieces of evidence reported the HPV prevalence among 7655 healthy and noncancerous women in different Provinces of Iran. Total prevalence of HPV, 9.4% (95% confidence interval [CI]: 6.8-12.02); HPV16, 2.03% (95% CI: 1.3-2.8); HPV18, 1.7% (95% CI: 0.9-2.5); and other genotypes of HPV, 5.3% (95% CI: 3.6-6.9) were estimated. CONCLUSIONS: Our meta analysis showed that the total prevalence of HPV and its high-risk genotypes (16 and 18) among healthy noncancerous Iranian women was very high. PMID- 27217937 TI - The Direct Medical Costs of Outpatient Cares of Type 2 Diabetes in Iran: A Retrospective Study. AB - BACKGROUND: Diabetes mellitus is a chronic disease which many factors are involved and is developing considerably worldwide. Increasing aging population and obesity in the societies has improved the scale of the type 2 diabetes significantly. The aim of this study was to determine the direct medical costs of outpatient cares of diabetes in Iran. METHODS: Active patients of Isfahan Endocrinology and Metabolism Research Center (IEMRC) by the end of March 2011 were employed for data extraction. Type 2 diabetics were classified into 4 groups based on their therapeutic regimens. Type and frequency of health care services were extracted from the patients' profiles manually. The incidence of major diabetes complications were also examined from the subjects' profiles. The numbers of services used by the patients in different treatment groups were multiplied by the desired medical tariffs to calculate the direct medical costs. RESULTS: 2898 number of cases was reviewed in this study; 63.8 % women and 36.2% men. 4.3% of the patients were placed group I; 50.1% in group II, and 34.6% and 11% in groups III and IV respectively. The age distribution of the patients varied widely from 30 to 90 years; 5.8% between 30 and 39 years, 62.3% between 40 and 59, and 31.9% at 60 and over. Nephropathy (72.4%), and neuropathy (39%) were the most frequent adverse effect between the type 2 diabetics in Isfahan. The group III with spending $192.3 in total was absorbed the highest amount of the resources between the patients' groups. The average direct medical cost of outpatient cares of diabetics per year was 155.8 US $. CONCLUSIONS: The direct medical cost of diabetes management is progressed sharply in past years in Iran. Pharmaceutical expenditures was the main cost component of outpatient cares for diabetes. It is estimated that the Iranians directly spend approximately $4.05 milliard annually to manage 5.2 million diabetics in the country. PMID- 27217938 TI - Correlations Between Cutaneous Malignant Melanoma and Other Cancers: An Ecological Study in Forty European Countries. AB - BACKGROUND: The presence of noncutaneous neoplasms does not seem to increase the risk of cutaneous malignant melanoma; however, it seems to be associated with the development of other hematological, brain, breast, uterine, and prostatic neoplasms. An ecological transversal study was conducted to study the geographic association between cutaneous malignant melanoma and 24 localizations of cancer in forty European countries. METHODS: Cancer incidence rates were extracted from GLOBOCAN database of the International Agency for Research on Cancer. We analyzed the age-adjusted and gender-stratified incidence rates for different localizations of cancer in forty European countries and calculated their correlation using Pearson's correlation test. RESULTS: In males, significant correlations were found between cutaneous malignant melanoma with testicular cancer (r = 0.83 [95% confidence interval (CI): 0.68-0.89]), myeloma (r = 0.68 [95% CI: 0.46-0.81]), prostatic carcinoma (r = 0.66 [95% CI: 0.43-0.80]), and non Hodgkin lymphoma (NHL) (r = 0.63 [95% CI: 0.39-0.78]). In females, significant correlations were found between cutaneous malignant melanoma with breast cancer (r = 0.80 [95% CI: 0.64-0.88]), colorectal cancer (r = 0.72 [95% CI: 0.52-0.83]), and NHL (r = 0.71 [95% CI: 0.50-0.83]). CONCLUSIONS: These correlations call to conduct new studies about the epidemiology of cancer in general and cutaneous malignant melanoma risk factors in particular. PMID- 27217939 TI - Drought responses of three closely related Caragana species: implication for their vicarious distribution. AB - Drought is a major environmental constraint affecting growth and distribution of plants in the desert region of the Inner Mongolia plateau. Caragana microphylla, C. liouana, and C. korshinskii are phylogenetically close but distribute vicariously in Mongolia plateau. To gain a better understanding of the ecological differentiation between these three species, we examined the leaf gas exchange, growth, water use efficiency, biomass accumulation and allocation by subjecting their seedlings to low and high drought treatments in a glasshouse. Increasing drought stress had a significant effect on many aspects of seedling performance in all species, but the physiology and growth varied with species in response to drought. C. korshinskii exhibited lower sensitivity of photosynthetic rate and growth, lower specific leaf area, higher biomass allocation to roots, higher levels of water use efficiency to drought compared with the other two species. Only minor interspecific differences in growth performances were observed between C. liouana and C. microphylla. These results indicated that faster seedling growth rate and more efficient water use of C. korshinskii should confer increased drought tolerance and facilitate its establishment in more severe drought regions relative to C. liouana and C. microphylla. PMID- 27217940 TI - Butterfly oviposition preference is not related to larval performance on a polyploid herb. AB - The preference-performance hypothesis predicts that female insects maximize their fitness by utilizing host plants which are associated with high larval performance. Still, studies with several insect species have failed to find a positive correlation between oviposition preference and larval performance. In the present study, we experimentally investigated the relationship between oviposition preferences and larval performance in the butterfly Anthocharis cardamines. Preferences were assessed using both cage experiments and field data on the proportion of host plant individuals utilized in natural populations. Larval performance was experimentally investigated using larvae descending from 419 oviposition events by 21 females on plants from 51 populations of two ploidy types of the perennial herb Cardamine pratensis. Neither ploidy type nor population identity influenced egg survival or larval development, but increased plant inflorescence size resulted in a larger final larval size. There was no correlation between female oviposition preference and egg survival or larval development under controlled conditions. Moreover, variation in larval performance among populations under controlled conditions was not correlated with the proportion of host plants utilized in the field. Lastly, first instar larvae added to plants rejected for oviposition by butterfly females during the preference experiment performed equally well as larvae growing on plants chosen for oviposition. The lack of a correlation between larval performance and oviposition preference for A. cardamines under both experimental and natural settings suggests that female host choice does not maximize the fitness of the individual offspring. PMID- 27217941 TI - Effects of algal food quality on sexual reproduction of Daphnia magna. AB - The objective of our study was to investigate sexual reproduction of Daphnia magna associated with mating behaviors and hatching rates, according to different algal food sources. Since a diatom is known to contain more abundant long-chain poly unsaturated fatty acids (PUFAs), we hypothesized that the diatom-consuming D. magna would exhibit more successful reproduction rates. Upon the hypothesis, we designed three experiments using two algal species, a green alga (Chlorella vulgaris) and a diatom (Stephanodiscus hantzschii). From the results, we found that the mating frequency and copulation duration increased in the treatment with S. hantzschii, resulting in a significant increase of hatching rates of resting eggs. In the other two repetitive mating strategies (e.g., one female vs. multiple males, and one male vs. multiple females), we found that the hatching rates of resting eggs were greater in the S. hantzschii treatment. In addition to the mating strategy, male body size significantly increased in the diatom treatment, hence average diameter of penis was also statistically different among the treatments (greater diameter in the S. hantzschii treatment). To examine the effect of algal food quality, we estimated quantity of fatty acids in the two algal species. Our result showed that S. hantzschii had a higher proportion of long-chain PUFAs than C. vulgaris. Furthermore, a stable isotope analysis revealed that carbon and nitrogen originated from S. hantzschii were more assimilated to D. magna. In summary, our study manifested that diatom consumption of D. magna leads to more successful sexual reproduction. We then discussed how the diatom consumption of zooplankton influences food web dynamics in a freshwater ecosystem. PMID- 27217942 TI - Meta-analysis indicates that oxidative stress is both a constraint on and a cost of growth. AB - Oxidative stress (OS) as a proximate mechanism for life-history trade-offs is widespread in the literature. One such resource allocation trade-off involves growth rate, and theory suggests that OS might act as both a constraint on and a cost of growth, yet studies investigating this have produced conflicting results. Here, we use meta-analysis to investigate whether increased OS levels impact on growth (OS as a constraint on growth) and whether greater growth rates can increase OS (OS as a cost of growth). The role of OS as a constraint on growth was supported by the meta-analysis. Greater OS, in terms of either increased damage or reduced levels of antioxidants, was associated with reduced growth although the effect depended on the experimental manipulation used. Our results also support an oxidative cost of growth, at least in terms of increased oxidative damage, although faster growth was not associated with a change in antioxidant levels. These findings that OS can act as a constraint on growth support theoretical links between OS and animal life histories and provide evidence for a growth-self-maintenance trade-off. Furthermore, the apparent oxidative costs of growth imply individuals cannot alter this trade-off when faced with enhanced growth. We offer a starting platform for future research and recommend the use of oxidative damage biomarkers in nonlethal tissue to investigate the growth-OS relationship further. PMID- 27217944 TI - Sperm use economy of honeybee (Apis mellifera) queens. AB - The queens of eusocial ants, bees, and wasps only mate during a very brief period early in life to acquire and store a lifetime supply of sperm. As sperm cannot be replenished, queens have to be highly economic when using stored sperm to fertilize eggs, especially in species with large and long-lived colonies. However, queen fertility has not been studied in detail, so that we have little understanding of how economic sperm use is in different species, and whether queens are able to influence their sperm use. This is surprising given that sperm use is a key factor of eusocial life, as it determines the fecundity and longevity of queens and therefore colony fitness. We quantified the number of sperm that honeybee (Apis mellifera) queens use to fertilize eggs. We examined sperm use in naturally mated queens of different ages and in queens artificially inseminated with different volumes of semen. We found that queens are remarkably efficient and only use a median of 2 sperm per egg fertilization, with decreasing sperm use in older queens. The number of sperm in storage was always a significant predictor for the number of sperm used per fertilization, indicating that queens use a constant ratio of spermathecal fluid relative to total spermathecal volume of 2.364 * 10(-6) to fertilize eggs. This allowed us to calculate a lifetime fecundity for honeybee queens of around 1,500,000 fertilized eggs. Our data provide the first empirical evidence that honeybee queens do not manipulate sperm use, and fertilization failures in worker-destined eggs are therefore honest signals that workers can use to time queen replacement, which is crucial for colony performance and fitness. PMID- 27217943 TI - Genetic evidence for prevalence of alloparental care in a socially monogamous biparental cichlid fish, Perissodus microlepis, from Lake Tanganyika supports the "selfish shepherd effect" hypothesis. AB - Alloparental care - care for unrelated young - is rare in animals, and its ecological or evolutionary advantages or, alternative maladaptive nature, remain unclear. We investigate alloparental care in the socially monogamous cichlid fish Perissodus microlepis from Lake Tanganyika that exhibits bi-parental care. In a genetic parentage analysis, we discovered a surprisingly high percentage of alloparental care represented by brood mixing, extra-pair paternity and extra pair maternity in all broods that we investigated. The percentage of nondescendant juveniles of other parents, i.e., brood mixing, ranged from 5% to 57% (mean = 28%). The distribution of genetic parentage also suggests that this socially monogamous species has, in fact, polygamous mating system. The prevalence of genetically mixed broods can be best explained by two, not mutually exclusive hypotheses on farming-out and fostering behaviors. In the majority of broods, the sizes of the parents' own (descendant) offspring were significantly larger than those of the adopted (nondescendant) juveniles, supporting the 'selfish shepherd effect' hypothesis, i.e., that foster parents preferentially accept unrelated "smaller or not larger" young since this would tend to lower the predation risks for their own larger offspring. There was also a tendency for larger parents particularly mothers, more so than smaller parents, to care predominantly for their own offspring. Larger parents might be better at defending against cuckoldry and having foreign young dumped into their broods through farming-out behavior. This result might argue for maladaptive effects of allopatric care for the foster parents that only larger and possibly more experienced pairs can guard against. It needs to be determined why, apparently, the ability to recognize one's own young has not evolved in this species. PMID- 27217945 TI - Phylogenies and traits provide distinct insights about the historical and contemporary assembly of aquatic insect communities. AB - The assumption that traits and phylogenies can be used as proxies of species niche has faced criticisms. Evidence suggested that phylogenic relatedness is a weak proxy of trait similarity. Moreover, different processes can select different traits, giving opposing signals in null model analyses. To circumvent these criticisms, we separated traits of stream insects based on the concept of alpha and beta niches, which should give clues about assembling pressures expected to act independently of each other. We investigated the congruence between the phylogenetic structure and trait structure of communities using all available traits and all possible combinations of traits (4095 combinations). To account for hierarchical assembling processes, we analyzed patterns on two spatial scales with three pools of genera. Beta niche traits selected a priori - i.e., traits related to environmental variation (e.g., respiration type) - were consistently clustered on the smaller scale, suggesting environmental filtering, while alpha niche traits - i.e., traits related to resource use (e.g., trophic position) - did not display the expected overdispersion, suggesting a weak role of competition. Using all traits together provided random patterns and the analysis of all possible combinations of traits provided scenarios ranging from strong clustering to overdispersion. Communities were phylogenetically overdispersed, a pattern previously interpreted as phylogenetic limiting similarity. However, our results likely reflect the co-occurrence of ancient clades due to the stability of stream habitats along the evolutionary scale. We advise ecologists to avoid using combinations of all available traits but rather carefully traits based on the objective under consideration. Both trait and phylogenetic approaches should be kept in the ecologist toolbox, but phylogenetic distances should not be used as proxies of traits differences. Although the phylogenetic structure revealed processes operating at the evolutionary scale, only specific traits explained local processes operating in our communities. PMID- 27217947 TI - A Bayesian approach for temporally scaling climate for modeling ecological systems. AB - With climate change becoming more of concern, many ecologists are including climate variables in their system and statistical models. The Standardized Precipitation Evapotranspiration Index (SPEI) is a drought index that has potential advantages in modeling ecological response variables, including a flexible computation of the index over different timescales. However, little development has been made in terms of the choice of timescale for SPEI. We developed a Bayesian modeling approach for estimating the timescale for SPEI and demonstrated its use in modeling wetland hydrologic dynamics in two different eras (i.e., historical [pre-1970] and contemporary [post-2003]). Our goal was to determine whether differences in climate between the two eras could explain changes in the amount of water in wetlands. Our results showed that wetland water surface areas tended to be larger in wetter conditions, but also changed less in response to climate fluctuations in the contemporary era. We also found that the average timescale parameter was greater in the historical period, compared with the contemporary period. We were not able to determine whether this shift in timescale was due to a change in the timing of wet-dry periods or whether it was due to changes in the way wetlands responded to climate. Our results suggest that perhaps some interaction between climate and hydrologic response may be at work, and further analysis is needed to determine which has a stronger influence. Despite this, we suggest that our modeling approach enabled us to estimate the relevant timescale for SPEI and make inferences from those estimates. Likewise, our approach provides a mechanism for using prior information with future data to assess whether these patterns may continue over time. We suggest that ecologists consider using temporally scalable climate indices in conjunction with Bayesian analysis for assessing the role of climate in ecological systems. PMID- 27217946 TI - Intensity of space use reveals conditional sex-specific effects of prey and conspecific density on home range size. AB - Home range (HR) size variation is often linked to resource abundance, with sex differences expected to relate to sex-specific fitness consequences. However, studies generally fail to disentangle the effects of the two main drivers of HR size variation, food and conspecific density, and rarely consider how their relative influence change over spatiotemporal scales. We used location data from 77 Eurasian lynx (Lynx lynx) from a 16-year Scandinavian study to examine HR sizes variation relative to prey and conspecific density at different spatiotemporal scales. By varying the isopleth parameter (intensity of use) defining the HR, we show that sex-specific effects were conditional on the spatial scale considered. Males had larger HRs than females in all seasons. Females' total HR size declined as prey and conspecific density increased, whereas males' total HR was only affected by conspecific density. However, as the intensity of use within the HR increased (from 90% to 50% isopleth), the relationship between prey density and area showed opposing patterns for females and males; for females, the prey density effect was reduced, while for males, prey became increasingly important. Thus, prey influenced the size of key regions within male HRs, despite total HR size being independent of prey density. Males reduced their HR size during the mating season, likely to remain close to individual females in estrous. Females reduced their HR size postreproduction probably because of movement constrains imposed by dependent young. Our findings highlight the importance of simultaneously considering resources and intraspecific interactions as HR size determinants. We show that sex-specific demands influence the importance of prey and conspecific density on space use at different spatiotemporal scales. Thus, unless a gradient of space use intensity is examined, factors not related to total HR size might be disregarded despite their importance in determining size of key regions within the HR. PMID- 27217948 TI - Molecular identification of mosquitoes (Diptera: Culicidae) in southeastern Australia. AB - DNA barcoding is a modern species identification technique that can be used to distinguish morphologically similar species, and is particularly useful when using small amounts of starting material from partial specimens or from immature stages. In order to use DNA barcoding in a surveillance program, a database containing mosquito barcode sequences is required. This study obtained Cytochrome Oxidase I (COI) sequences for 113 morphologically identified specimens, representing 29 species, six tribes and 12 genera; 17 of these species have not been previously barcoded. Three of the 29 species ? Culex palpalis, Macleaya macmillani, and an unknown species originally identified as Tripteroides atripes ? were initially misidentified as they are difficult to separate morphologically, highlighting the utility of DNA barcoding. While most species grouped separately (reciprocally monophyletic), the Cx. pipiens subgroup could not be genetically separated using COI. The average conspecific and congeneric p-distance was 0.8% and 7.6%, respectively. In our study, we also demonstrate the utility of DNA barcoding in distinguishing exotics from endemic mosquitoes by identifying a single intercepted Stegomyia aegypti egg at an international airport. The use of DNA barcoding dramatically reduced the identification time required compared with rearing specimens through to adults, thereby demonstrating the value of this technique in biosecurity surveillance. The DNA barcodes produced by this study have been uploaded to the 'Mosquitoes of Australia-Victoria' project on the Barcode of Life Database (BOLD), which will serve as a resource for the Victorian Arbovirus Disease Control Program and other national and international mosquito surveillance programs. PMID- 27217950 TI - Populations of aspen (Populus tremuloides Michx.) with different evolutionary histories differ in their climate occupancy. AB - Quaking aspens (Populus tremuloides Michx.) are found in diverse habitats throughout North America. While the biogeography of aspens' distribution has been documented, the drivers of the phenotypic diversity of aspen are still being explored. In our study, we examined differences in climate between northern and southwestern populations of aspen, finding large-scale differences between the populations. Our results suggest that northern and southwestern populations live in distinct climates and support the inclusion of genetic and phenotypic data with species distribution modeling for predicting aspens' distribution. PMID- 27217949 TI - Using historical woodland creation to construct a long-term, large-scale natural experiment: the WrEN project. AB - Natural experiments have been proposed as a way of complementing manipulative experiments to improve ecological understanding and guide management. There is a pressing need for evidence from such studies to inform a shift to landscape-scale conservation, including the design of ecological networks. Although this shift has been widely embraced by conservation communities worldwide, the empirical evidence is limited and equivocal, and may be limiting effective conservation. We present principles for well-designed natural experiments to inform landscape scale conservation and outline how they are being applied in the WrEN project, which is studying the effects of 160 years of woodland creation on biodiversity in UK landscapes. We describe the study areas and outline the systematic process used to select suitable historical woodland creation sites based on key site- and landscape-scale variables - including size, age, and proximity to other woodland. We present the results of an analysis to explore variation in these variables across sites to test their suitability as a basis for a natural experiment. Our results confirm that this landscape satisfies the principles we have identified and provides an ideal study system for a long-term, large-scale natural experiment to explore how woodland biodiversity is affected by different site and landscape attributes. The WrEN sites are now being surveyed for a wide selection of species that are likely to respond differently to site- and landscape-scale attributes and at different spatial and temporal scales. The results from WrEN will help develop detailed recommendations to guide landscape-scale conservation, including the design of ecological networks. We also believe that the approach presented demonstrates the wider utility of well-designed natural experiments to improve our understanding of ecological systems and inform policy and practice. PMID- 27158449 TI - Possible repurposing of seasonal influenza vaccine for prevention of Zika virus infection. AB - The in silico analysis shows that the envelope glycoproteins E of Zika viruses (ZIKV) isolated in Asia, Africa and South and Central America encode highly conserved information determining their interacting profile and immunological properties. Previously it was shown that the same information is encoded in the primary structure of the hemagglutinin subunit 1 (HA1) from pdmH1N1 influenza A virus. This similarity suggests possible repurposing of the seasonal influenza vaccine containing pdmH1N1 component for prevention of the ZIKV infection. PMID- 27158450 TI - Surveillance, insecticide resistance and control of an invasive Aedes aegypti (Diptera: Culicidae) population in California. AB - The invasion and subsequent establishment in California of Aedes aegypti in 2013 has created new challenges for local mosquito abatement and vector control districts. Studies were undertaken to identify effective and economical strategies to monitor the abundance and spread of this mosquito species as well as for its control. Overall, BG Sentinel (BGS) traps were found to be the most sensitive trap type to measure abundance and spread into new locations. Autocidal Gravid-Ovitraps (AGO-B), when placed at a site for a week, performed equally to BGS in detecting the presence of female Ae. aegypti. Considering operational cost and our findings, we recommend use of BGS traps for surveillance in response to service requests especially in locations outside the known infestation area. We recommend AGO-Bs be placed at fixed sites, cleared and processed once a week to monitor mosquito abundance within a known infestation area. Long-term high density placements of AGO-Bs were found to show promise as an environmentally friendly trap-kill control strategy. California Ae. aegypti were found to be homozygous for the V1016I mutation in the voltage gated sodium channel gene, which is implicated to be involved in insecticide resistance. This strain originating from Clovis, California was resistant to some pyrethroids but not to deltamethrin in bottle bio-assays. Sentinel cage ultra-low-volume (ULV) trials using a new formulation of deltamethrin (DeltaGard(r)) demonstrated that it provided some control (average of 56% death in sentinel cages in a 91.4 m spray swath) after a single truck mounted aerial ULV application in residential areas. PMID- 27217953 TI - Ethiopic maternal care data mining: discovering the factors that affect postnatal care visit in Ethiopia. AB - BACKGROUND: Improving maternal health and reducing maternal mortality rate are key concerns. One of the eight millennium development goals adopted at the millennium summit, was to improve maternal health in Ethiopia. This leads towards discovering the factors that hinder postnatal care visit in Ethiopia. METHODS: In this research, knowledge discovery from data (KDD) was applied to identify the factors that hinder postnatal care visits in Ethiopia. Decision tree (using J48 algorithm) and rule induction (using JRip algorithm) techniques were applied on 6558 records of Ethiopian demographic and health survey data. To construct essential target dataset attributes exploratory data analysis with frequency diagram is performed, missing value was filled and noisy value was corrected. Also the data are preprocessed using business and data understanding with detail statistical summary. RESULT: J48 (93.97 % accuracy) and JRip (93.93 % accuracy) identifies places of delivery, assistance of health delivery professional, prenatal care health professional and age are the determinant factors. However, residence places also taken into consideration. CONCLUSIONS: In this study, encouraging results were obtained by employing both decision tree and rule induction techniques. The rules generated by J48 and JRip algorithms are much understandable to explain the outcome easily. Thus, the result obtained highly supportive to construct, evaluate and update advertising and promotional maternal health policies. It is better to create a generic model with more coverage in terms of economic, demographic, social and genetic factors so as to integrate the result with knowledge based system. PMID- 27217954 TI - The vasculature: a vessel for bone metastasis. AB - Emerging evidence indicates that the interactions between tumor cells and the bone microenvironment have a crucial role in the pathogenesis of bone metastasis and that they can influence tumor cell dissemination, quiescence and tumor growth in the bone. The vasculature is known to be critical for primary tumor growth, and anti-angiogenesis drugs are approved for the treatment of certain tumor types. The role of the vasculature in bone metastasis is less well known, but recent evidence shows that blood vessels in the bone are a key component of the local microenvironment for the tumor cells and contribute to the different consecutive phases of bone metastasis. A better insight in the importance of the vasculature for bone metastasis may help develop novel treatment modalities that either slow down tumor growth or, preferably, prevent or cure bone metastasis. PMID- 27217955 TI - Social, economic and environmental risk factors for acute lower respiratory infections among children under five years of age in Rwanda. AB - BACKGROUND: In low and middle-income countries, acute lower respiratory illness is responsible for roughly 1 in every 5 child deaths. Rwanda has made major health system improvements including its community health worker systems, and it is one of the few countries in Africa to meet the 2015 Millennium Development Goals, although prevalence of acute lower respiratory infections (4 %) is similar to other countries in sub-Saharan Africa. This study aims to assess social, economic, and environmental factors associated with acute lower respiratory infections among children under five to inform potential further improvements in the health system. METHODS: This is a cross-sectional study using data collected from women interviewed in the 2010 DHS about 8,484 surviving children under five. Based on a literature review, we defined 19 health, social, economic, and environmental potential risk factors, tested bivariate associations with acute lower respiratory infections, and advanced variables significant at the 0.1 confidence level to logistic regression modelling. We used manual backward stepwise regression to arrive at a final model. All analyses were performed in Stata v13 and adjusted for complex sample design. RESULTS: The following factors were independently associated with acute lower respiratory infections: child's age, anemia level, and receipt of Vitamin A; household toilet type and residence, and season of interview. In multivariate regression, being in the bottom ten percent of households (OR: 1.27, 95 % CI: 0.85-1.87) or being interviewed during the rainy season (OR: 1.61, 95 % CI: 1.24-2.09) was positively associated with acute lower respiratory infections, while urban residence (OR: 0.58, 95 % CI: 0.38-0.88) and being age 24-59 months versus 0-11 months (OR: 0.53, 95 % CI: 0.40 0.69) was negatively associated with acute lower respiratory infections. CONCLUSION: Potential areas for intervention including community campaigns about acute lower respiratory infections symptoms and treatment, and continued poverty reduction through rural electrification and modern stove distribution which may reduce use of dirty cooking fuel, improve living conditions, and reduce barriers to health care. PMID- 27217956 TI - Earlier infantile immune maturation is related to higher DTP vaccine responses in children. AB - There are large inter-individual variations in vaccine-specific antibody responses in children. We sought to investigate whether early-life environmental factors and/or adaptive immune maturation were related to diphtheria-tetanus pertussis (DTP) vaccine-specific antibody levels at 18 months of age. In the prospective FARMFLORA birth-cohort, including both farming and non-farming families, children were immunized with DTP vaccine at 3, 5 and 12 months of age. DTP vaccine-induced antibody levels were measured in plasma at 18 months of age. Infants' blood samples obtained at birth, 3-5 days, 4, 18 and 36 months and at 8 years of age were analyzed for total CD4(+) T- and B-cell counts, proportions of naive and memory T and B cells, and fractions of putative regulatory T cells by flow cytometry. Multivariate factor analysis was used to examine associations between immune variables and vaccine responses. The most apparent multivariate pattern was that higher anti-DTP antibody titers at 18 months of age were associated with lower infantile total counts of T and B cells in the blood. Furthermore, lower infantile total T- and B-cell blood counts were associated with higher proportions of circulating CD45RO(+) memory T cells and to lower proportions of alpha4beta7(+) naive T cells later in childhood. The multivariate findings were corroborated in univariate correlation analyses. Sex, delivery mode and dairy farm exposure were unrelated to the magnitude of DTP-specific antibody responses. Our results thus suggest that children with a more mature/activated infantile adaptive immunity respond with higher vaccine-induced anti-DTP antibody levels at 18 months of age. PMID- 27217957 TI - Targeting dendritic cells: a promising strategy to improve vaccine effectiveness. AB - Dendritic cell (DC) targeting is a novel strategy to enhance vaccination efficacy. This approach is based on the in situ delivery of antigen via antibodies that are specific for endocytic receptors expressed at the surface of DCs. Here we review the complexity of the DC subsets and the antigen presentation pathways that need to be considered in the settings of DC targeting. We also summarize current knowledge about antigen delivery to DCs via DEC-205, Clec9A and Clec12A, receptor targets that strongly enhance cellular and humoral immune responses. Finally, we discuss the intracellular trafficking criteria of the targeted receptors that may impact their effectiveness as DC targets. PMID- 27217958 TI - High intravascular tissue factor-but not extracellular microvesicles-in septic patients is associated with a high SAPS II score. AB - BACKGROUND: Sepsis is associated with coagulation abnormalities, and a high content of intravascular tissue factor (TF) may contribute to the development of multisystem organ failure. Circulating microvesicles (MVs) are increased during sepsis and characterized by their phosphatidylserine content. It is unclear whether MVs-as a part of the host response to the infection-are beneficial or rather contribute to systemic complications in sepsis. In the present prospective clinical pilot study, we investigated whether plasma TF and MVs are associated with the risk of multiple organ failure and mortality. METHODS: Thirty patients diagnosed with sepsis, severe sepsis, or septic shock were enrolled and classified as 19 survivors and 11 non-survivors. Blood samples were collected on the day of admission and then daily for up to 2 weeks. MVs and TF were quantified in plasma by ELISA. RESULTS: Non-survivors had significantly higher TF concentrations on day 3 compared to survivors. Logistic regression analysis revealed that patients with high amounts of TF had significantly increased risk for severity of disease, according to high Simplified Acute Physiology Score II (SAPS II) scores (odds ratio 18.7). In contrast, a higher content of phosphatidylserine-rich MVs were apparently associated with a lower risk for mortality and multiple organ failure, although this was only a trend and the odds ratios were not significant. CONCLUSIONS: This study showed that a high amount of TF in septic patients is significantly associated with increased risk for disease severity, according to a high SAPS II score. Quantification of total MVs in plasma, independent from their cell origin, might be indicative for the outcome of patients in sepsis. PMID- 27217959 TI - Predicting mortality in the intensive care unit: a comparison of the University Health Consortium expected probability of mortality and the Mortality Prediction Model III. AB - BACKGROUND: Quality benchmarks are increasingly being used to compare the delivery of healthcare, and may affect reimbursement in the future. The University Health Consortium (UHC) expected probability of mortality (EPM) is one such quality benchmark. Although the UHC EPM is used to compare quality across UHC members, it has not been prospectively validated in the critically ill. We aimed to define the performance characteristics of the UHC EPM in the critically ill and compare its ability to predict mortality with the Mortality Prediction Model III (MPM-III). METHODS: The first 100 consecutive adult patients discharged from the hospital (including deaths) each quarter from January 1, 2009 until September 30, 2011 that had an intensive care unit (ICU) stay were included. We assessed model discrimination, calibration, and overall performance, and compared the two models using Bland-Altman plots. RESULTS: Eight hundred ninety-one patients were included. Both the UHC EPM and the MPM-III had excellent performance (Brier score 0.05 and 0.06, respectively). The area under the curve was good for both models (UHC 0.90, MPM-III 0.87, p = 0.28). Goodness of fit was statistically significant for both models (UHC p = 0.002, MPM-III p = 0.0003), but improved with logit transformation (UHC p = 0.41; MPM-III p = 0.07). The Bland-Altman plot showed good agreement at extremes of mortality, but agreement diverged as mortality approached 50 %. CONCLUSIONS: The UHC EPM exhibited excellent overall performance, calibration, and discrimination, and performed similarly to the MPM-III. Correlation between the two models was poor due to divergence when mortality was maximally uncertain. PMID- 27217960 TI - A New Multi-Ingredient Recipe for the Treatment of Localized Advanced Periodontal Disease following the Surgical Removal of Impacted Wisdom Teeth. AB - Periodontal disease is a chronic inflammation of the tooth supporting structures. It leads to bone and attachment loss which is irreversible. Extraction of horizontally impacted lower third molar (L3M) teeth may result in localized periodontal pockets at the distal aspect of the adjacent lower second molars (L2M). We present a case of a 21-year-old male who suffered from a swelling and pain around his lower right second molar following surgical removal of a mesioangular impacted lower right third molar. We showed that oral hygiene measures, surgical access, mixture of autogenous and synthetic bone graft, and guided tissue regeneration (GTR) were enough to control the problem. PMID- 27217961 TI - A Rare Case of Spontaneous Pneumocephalus Associated with Nontraumatic Cerebrospinal Fluid Leak. AB - Introduction. Spontaneous nontraumatic pneumocephalus (PNC) and cerebrospinal fluid (CSF) leaks are both very uncommon conditions. We report a rare case of spontaneous pneumocephalus associated with CSF leak secondary to right sphenoid sinus bony defect without history of trauma. Case Description. 51-year-old Hispanic female with past medical history of hypertension and idiopathic intracranial hypertension (Pseudotumor Cerebri) presented to the emergency room complaining of headache and clear discharge from the right nostril. Physical examination was significant for right frontal sinus tenderness and clear discharge from right nostril. Computed Tomography (CT) scan of the brain showed moderate amount of extra-axial air within the right cerebral hemisphere indicative of pneumocephalus. CT scan of facial bones showed bony defect along the right sphenoid sinus with abnormal CSF collection. The patient was started on intravenous antibiotics for meningitis prophylaxis and subsequently underwent transsphenoidal repair of cerebrospinal fluid leak with abdominal fat graft. CSF rhinorrhea stopped completely after the surgery with near complete resolution of pneumocephalus before discharge. Conclusions. Early identification of pneumocephalus and surgical intervention can help decrease the morbidity and avoid possible complications. Idiopathic intracranial hypertension, although rare, can lead to CSF leak and pneumocepahlus. PMID- 27217962 TI - An Unusual Case of Asystole Occurring during Deep Brain Stimulation Surgery. AB - Background. Symptomatic bradycardia and hypotension in neurosurgery can produce severe consequences if not managed appropriately. The literature is scarce regarding its occurrence during deep brain stimulation (DBS) surgery. Case Presentation. A 67-year-old female presented for left DBS lead placement for essential tremors. During lead implantation, heart rate and blood pressure dropped rapidly; the patient became unresponsive and asystolic. Chest compressions were initiated and epinephrine was given. Within 30 seconds, the patient became hemodynamically stable and conscious. A head CT demonstrated no acute findings. After deliberation, a decision was made to complete the procedure. Assuming the etiology of the episode was the Bezold-Jarisch reflex (BJR), appropriate accommodations were made. The procedure was completed uneventfully. Conclusion. The episode was consistent with a manifestation of the BJR. The patient had a history of neurocardiogenic syncope and a relatively low volume state, factors prone to the BJR. Overall, lead implantation can still occur safely if preventive measures are employed. PMID- 27217963 TI - An Unusual Presentation of Right-Sided Sciatica with Foot Drop. AB - Rarely, sciatica is of extraspinal aetiology. By compressing the sciatic nerve, swelling of the short external rotators of the hip can cause sciatica. Uncommon anatomical relationships between the sciatic nerve and local muscles may potentiate this compressive effect. In this report, we describe the presentation of right sciatica and foot drop resulting from both extreme local constriction and unusual anatomical variation of the right sciatic nerve. PMID- 27217964 TI - Inferior Vena Cava Duplication: Incidental Case in a Young Woman. AB - A case of a double inferior vena cava (IVC) with retroaortic left renal vein, azygos continuation of the IVC, and presence of the hepatic portion of the IVC drained into the right renal vein is reported and the embryologic, clinical, and radiological significance is discussed. The diagnosis is suggested by multidetector computed tomography (MDCT), which reveals the aberrant vascular structures. Awareness of different congenital anomalies of IVC is necessary for radiologists to avoid diagnostic pitfalls and they should be remembered because they can influence several surgical interventions and endovascular procedures. PMID- 27217965 TI - Endodermal cyst in pineal region: Rare location. AB - BACKGROUND: Pineal tumors are very uncommon intracranial lesions, and endodermal cysts in this location are extremely rare. CASE DESCRIPTION: A 49-year-old right handed female presented with 3 weeks history of progressive dizziness and imbalance. Imaging studies showed 1.8 cm * 1.7 cm * 1.8 cm pineal lesion with small enhancing mural component displacing ventrally the quadrigeminal plate and narrowing of aqueduct of Sylvius without hydrocephalus. In addition, she was found with small interhemispheric lipoma, and small posterior falx possible meningioma. Cerebrospinal fluid markers obtained by lumbar puncture were all negative. She underwent tumor resection, and final pathology reported endodermal cyst. No new deficits were encountered, and her gait imbalance improved significantly by 3 months follow-up. CONCLUSIONS: With evidence of enlargement or symptomatic pineal lesions, surgical consideration is necessary. Among pineal lesions, endodermal cysts are extremely uncommon and although benign pathology, long-term follow-up is advised due to unknown chronic behavior. PMID- 27217967 TI - The possibility of seeding vestibular schwannomas through surgery: Limited experience with two cases. AB - BACKGROUND: We present two exceptional cases of possible tumor seeding in benign vestibular schwannoma (VS) patients occurring years after initial microsurgical resection. CASE DESCRIPTION: We retrospectively analyzed the surgical management, histology and documented the growth of new tumor occurrence in close vicinity of the original schwannomas by serial magnetic resonance imaging over a period of 10 years. None of the patients had stigmata of neurofibromatosis, making it a reasonable assumption that the second tumor was due to surgical seeding during the first surgery. Moreover, in the second case, a microsurgical re-exploration showed that the recurrent tumor did not show any adhesion or contact to the caudal cranial nerves as anticipated had this been a new cranial nerve schwannoma. CONCLUSIONS: Surgical seeding of VSs is a rare complication but can occur despite benign histology and generous irrigation during surgery. PMID- 27217966 TI - Socioeconomic status does not affect prognosis in patients with glioblastoma multiforme. AB - BACKGROUND: Glioblastoma multiforme (GBM) is an aggressive malignancy, but there is marked heterogeneity in survival time. Health care disparities have demonstrated significance in oncologic outcomes but have not been clearly examined in this patient population. We investigated the role of sociodemographic variables in the prognosis of adult patients diagnosed with GBM. METHODS: This retrospective analysis included patients with a histologically confirmed diagnosis of GBM, who underwent resection or biopsy at a single institution from 2000 to 2014. Socioeconomic status (SES) was determined by household income according to the US Census zip code tabulation areas and the US national poverty level. Multivariate Cox proportional hazards analysis calculated effects on patient survival. RESULTS: Thirty percent of 218 subjects were of low SES, 57% mid, and 13% high. Low SES patients tended to be male (62%), Caucasian (92%), unmarried (91%), have dependents (100%), and limited to high school education (55%). SES did not predict insurance or employment status. SES was associated with marital status and number of cohabitants (P < 0.0001) but not clinical trial enrollment. Multivariate analysis demonstrated no relationship between SES and survival. Shorter prognosis was associated with history of military service (hazard ratio [HR] 2.06, P = 0.0125), elderly patients (HR 1.70, P = 0.0158), and multifocal disease (HR 1.75, P = 0.0119). Longer prognosis was associated with gross total resection (HR 0.49, P = 0.0009), radiation therapy (HR 0.12, P < 0.0001), and temozolomide (HR 0.28, P < 0.0001). CONCLUSIONS: SES alone does not predict prognosis in patients with newly diagnosed GBM. Sociodemographic variables such as old age, military service record, and insurance type may have a prognostication role. PMID- 27217968 TI - Safety and efficacy of carmustine (BCNU) wafers for metastatic brain tumors. AB - BACKGROUND: Carmustine (BCNU) wafers (Gliadel) prolongs local disease control and progression-free survival (PFS) in patients with malignant gliomas. However, in metastatic brain tumors, there is a paucity of evidence in support of its safety and efficacy. The goal of this study was to assess the safety and efficacy of Gliadel wafers in patients with metastatic brain tumors. METHODS: We retrospectively reviewed the University of Washington experience with Gliadel wafers for metastatic brain tumors between 2000 and 2015. RESULTS: Gliadel wafers were used in 14 patients with metastatic brain tumors during the period reviewed. There were no postoperative seizures, strokes, or hemorrhages. There was one postoperative wound infection necessitating return to the operating room. The mean time to tumor progression (n = 7) and death (n = 5) after Gliadel wafer implantation was 2.5 and 2.9 years, respectively. Age was the only variable affecting PFS in patients receiving Gliadel wafers. Patients <53 years old (n = 7) had a PFS of 0.52 years, whereas patients >53 years old (n = 7) had a PFS of 4.29 years (P = 0.02). There was no significant difference in PFS in relation to presenting Karnofsky Performance Status (P = 0.26), number of brain metastasis (P = 0.82), tumor volume (P = 0.54), prior surgery (P = 0.57), or prior radiation (P = 0.41). There were no significant differences in the mean survival in relationship to any variable including age. CONCLUSIONS: BCNU wafers are a safe and a potentially efficacious adjunct to surgery and radiation for improving local disease control in metastatic brain tumors. Larger studies, however, are needed to examine overall efficacy and tumor specific efficacy. PMID- 27217969 TI - Commentary: Has pathology gone to the "birds" because we have just been "winging" it? PMID- 27217970 TI - Validation of break-apart and fusion MYC probes using a digital fluorescence in situ hybridization capture and imaging system. AB - INTRODUCTION: Detection of MYC translocations using fluorescence in situ hybridization (FISH) is important in the evaluation of lymphomas, in particular, Burkitt lymphoma and diffuse large B-cell lymphoma. Our aim was to validate a digital FISH capture and imaging system for the detection of MYC 8q24 translocations using LSI-MYC (a break-apart probe) and MYC 8;14 translocation using IGH-MYC (a fusion probe). MATERIALS AND METHODS: LSI-MYC probe was evaluated using tissue sections from 35 patients. IGH-MYC probe was evaluated using tissue sections from forty patients. Sections were processed for FISH and analyzed using traditional methods. FISH slides were then analyzed using the GenASIs capture and analysis system. RESULTS: Results for LSI-MYC had a high degree of correlation between traditional method of FISH analysis and digital FISH analysis. Results for IGH-MYC had a 100% concordance between traditional method of FISH analysis and digital FISH analysis. CONCLUSION: Annotated whole slide images of H and E and FISH sections can be digitally aligned, so that areas of tumor within a section can be matched and evaluated with a greater degree of accuracy. Images can be archived permanently, providing a means for examining the results retrospectively. Digital FISH imaging of the MYC translocations provides a better diagnostic tool compared to traditional methods for evaluating lymphomas. PMID- 27217971 TI - Removing defocused objects from single focal plane scans of cytological slides. AB - BACKGROUND: Virtual microscopy and automated processing of cytological slides are more challenging compared to histological slides. Since cytological slides exhibit a three-dimensional surface and the required microscope objectives with high resolution have a low depth of field, these cannot capture all objects of a single field of view in focus. One solution would be to scan multiple focal planes; however, the increase in processing time and storage requirements are often prohibitive for clinical routine. MATERIALS AND METHODS: In this paper, we show that it is a reasonable trade-off to scan a single focal plane and automatically reject defocused objects from the analysis. To this end, we have developed machine learning solutions for the automated identification of defocused objects. Our approach includes creating novel features, systematically optimizing their parameters, selecting adequate classifier algorithms, and identifying the correct decision boundary between focused and defocused objects. We validated our approach for computer-assisted DNA image cytometry. RESULTS AND CONCLUSIONS: We reach an overall sensitivity of 96.08% and a specificity of 99.63% for identifying defocused objects. Applied on ninety cytological slides, the developed classifiers automatically removed 2.50% of the objects acquired during scanning, which otherwise would have interfered the examination. Even if not all objects are acquired in focus, computer-assisted DNA image cytometry still identified more diagnostically or prognostically relevant objects compared to manual DNA image cytometry. At the same time, the workload for the expert is reduced dramatically. PMID- 27217972 TI - Exploring virtual reality technology and the Oculus Rift for the examination of digital pathology slides. AB - BACKGROUND: Digital slides obtained from whole slide imaging (WSI) platforms are typically viewed in two dimensions using desktop personal computer monitors or more recently on mobile devices. To the best of our knowledge, we are not aware of any studies viewing digital pathology slides in a virtual reality (VR) environment. VR technology enables users to be artificially immersed in and interact with a computer-simulated world. Oculus Rift is among the world's first consumer-targeted VR headsets, intended primarily for enhanced gaming. Our aim was to explore the use of the Oculus Rift for examining digital pathology slides in a VR environment. METHODS: An Oculus Rift Development Kit 2 (DK2) was connected to a 64-bit computer running Virtual Desktop software. Glass slides from twenty randomly selected lymph node cases (ten with benign and ten malignant diagnoses) were digitized using a WSI scanner. Three pathologists reviewed these digital slides on a 27-inch 5K display and with the Oculus Rift after a 2-week washout period. Recorded endpoints included concordance of final diagnoses and time required to examine slides. The pathologists also rated their ease of navigation, image quality, and diagnostic confidence for both modalities. RESULTS: There was 90% diagnostic concordance when reviewing WSI using a 5K display and Oculus Rift. The time required to examine digital pathology slides on the 5K display averaged 39 s (range 10-120 s), compared to 62 s with the Oculus Rift (range 15-270 s). All pathologists confirmed that digital pathology slides were easily viewable in a VR environment. The ratings for image quality and diagnostic confidence were higher when using the 5K display. CONCLUSION: Using the Oculus Rift DK2 to view and navigate pathology whole slide images in a virtual environment is feasible for diagnostic purposes. However, image resolution using the Oculus Rift device was limited. Interactive VR technologies such as the Oculus Rift are novel tools that may be of use in digital pathology. PMID- 27217973 TI - Digital pathology and anatomic pathology laboratory information system integration to support digital pathology sign-out. AB - BACKGROUND: The adoption of digital pathology offers benefits over labor intensive, time-consuming, and error-prone manual processes. However, because most workflow and laboratory transactions are centered around the anatomical pathology laboratory information system (APLIS), adoption of digital pathology ideally requires integration with the APLIS. A digital pathology system (DPS) integrated with the APLIS was recently implemented at our institution for diagnostic use. We demonstrate how such integration supports digital workflow to sign-out anatomical pathology cases. METHODS: Workflow begins when pathology cases get accessioned into the APLIS (CoPathPlus). Glass slides from these cases are then digitized (Omnyx VL120 scanner) and automatically uploaded into the DPS (Omnyx((r)) Integrated Digital Pathology (IDP) software v.1.3). The APLIS transmits case data to the DPS via a publishing web service. The DPS associates scanned images with the correct case using barcode labels on slides and information received from the APLIS. When pathologists remotely open a case in the DPS, additional information (e.g. gross pathology details, prior cases) gets retrieved from the APLIS through a query web service. RESULTS: Following validation of this integration, pathologists at our institution have signed out more than 1000 surgical pathology cases in a production environment. Integration between the APLIS and DPS enabled pathologists to review digital slides while simultaneously having access to pertinent case metadata. The introduction of a digital workflow eliminated costly manual tasks involving matching of glass slides and avoided delays waiting for glass slides to be delivered. CONCLUSION: Integrating the DPS and APLIS were instrumental for successfully implementing a digital solution at our institution for pathology sign-out. The integration streamlined our digital sign-out workflow, diminished the potential for human error related to matching slides, and improved the sign-out experience for pathologists. PMID- 27217974 TI - A real-time dashboard for managing pathology processes. AB - CONTEXT: The Eastern Ontario Regional Laboratory Association (EORLA) is a newly established association of all the laboratory and pathology departments of Eastern Ontario that currently includes facilities from eight hospitals. All surgical specimens for EORLA are processed in one central location, the Department of Pathology and Laboratory Medicine (DPLM) at The Ottawa Hospital (TOH), where the rapid growth and influx of surgical and cytology specimens has created many challenges in ensuring the timely processing of cases and reports. Although the entire process is maintained and tracked in a clinical information system, this system lacks pre-emptive warnings that can help management address issues as they arise. AIMS: Dashboard technology provides automated, real-time visual clues that could be used to alert management when a case or specimen is not being processed within predefined time frames. We describe the development of a dashboard helping pathology clinical management to make informed decisions on specimen allocation and tracking. METHODS: The dashboard was designed and developed in two phases, following a prototyping approach. The first prototype of the dashboard helped monitor and manage pathology processes at the DPLM. RESULTS: The use of this dashboard helped to uncover operational inefficiencies and contributed to an improvement of turn-around time within The Ottawa Hospital's DPML. It also allowed the discovery of additional requirements, leading to a second prototype that provides finer-grained, real-time information about individual cases and specimens. CONCLUSION: We successfully developed a dashboard that enables managers to address delays and bottlenecks in specimen allocation and tracking. This support ensures that pathology reports are provided within time frame standards required for high-quality patient care. Given the importance of rapid diagnostics for a number of diseases, the use of real-time dashboards within pathology departments could contribute to improving the quality of patient care beyond EORLA's. PMID- 27217975 TI - Pitfalls in the use of whole slide imaging for the diagnosis of central nervous system tumors: A pilot study in surgical neuropathology. AB - BACKGROUND: Whole slide imaging (WSI) finds increasingly higher value in everyday surgical pathology in addition to its well-established use for educational and research purposes. However, its diagnostic utility, especially in subspecialty settings such as neuropathology, is not fully validated. Neuropathology practice is unique with smaller overall tissue size and frequent need for high-power evaluation. In addition, tumor grade is an integral part of the initial diagnosis. The purpose of this study is to assess the feasibility of primary pathology diagnosis of surgical neuropathology specimens using WSI. MATERIALS AND METHODS: We reviewed consecutive surgical neuropathology cases diagnosed in our institution during a 2-month period and identified a single diagnostic slide, which was scanned at 40* magnification. Two neuropathologists who were blinded to the original diagnoses reviewed the whole slide image and rendered a diagnosis including tumor grade when applicable. They reviewed the single diagnostic slide after a wash-out period. Intra- and inter-observer discrepancies, as well as reasons for discrepancies, were evaluated. RESULTS: The concordance rates were 94.9% and 88% for two neuropathologists. Two critical issues leading to discrepancies were identified: (1) identification of mitoses and (2) recognition of nuclear details. CONCLUSIONS: Given the current study is exclusively for surgical neuropathology cases, an all-encompassing conclusion about the utility of WSI for diagnostic purposes may not be available. Nevertheless, pathologists should be aware of the potential pitfalls due to identification of mitotic figures and nuclear details. We recommend independent validation for each subspecialty of pathology to identify subspecialty-specific concerns, so they can be properly addressed. PMID- 27217976 TI - Evaluation of panoramic digital images using Panoptiq for frozen section diagnosis. AB - INTRODUCTION: Whole slide imaging (WSI) permits intraoperative consultations (frozen sections) to be performed remotely. However, WSI files are large and can be problematic if there are tissue artifacts (e.g., tissue folds) or when slides are scanned without multiplanes (Z-stacks) to permit focusing. The Panoptiq dynamic imaging system allows users to create their own digital files that combine low power panoramic digital images with regions of interest that can be imaged using high power Z-stacks. The aim of this study was to determine the utility of the Panoptiq dynamic imaging system for frozen section telepathology. MATERIALS AND METHODS: Twenty archival randomly selected genitourinary surgical pathology frozen sectional cases were evaluated using conventional light microscopy (glass slides), panoramic images, and whole slide images. To create panoramic images glass slides were digitized using a Prosilica GT camera (model GT1920C, Allied Vision Technologies) attached to an Olympus B * 45 microscope and Dell Precision Tower 810 computer (Dell). Panoptiq 3 version 3.1.2 software was used for image acquisition and Panoptiq View version 3.1.2 to view images (ViewsIQ, Richmond, BC, Canada). Image acquisition using Panoptiq software involved a pathology resident, who manually created digital maps (*4 objective) and then selected representative regions of interest to generate Z-stacks at higher magnification (*40 objective). Whole slide images were generated using an Aperio XT Scanscope (Leica) and viewed using ImageScope Software (Aperio ePathology, Leica). Three pathologists were asked to render diagnoses and rate image quality (1-10) and their diagnostic confidence (1-10) for each modality. RESULTS: The diagnostic concordance with glass slides was 98.3% for panoramic images and 100% for WSI. Panoptiq images were comparable to the glass slide viewing experience in terms of image quality and diagnostic confidence. Complaints regarding WSI included poor focus near tissue folds and air bubbles. Panoptiq permitted fine focusing of tissue folds and air bubbles. Issues with panoramic images included difficulty interpreting low-resolution *4 image maps and the presence of tiling artifacts. In some cases, Z-stacked areas of Panoptiq images were limited or not representative of diagnostic regions. The image file size of Panoptiq was more than 14 times smaller than that of WSI files. CONCLUSIONS: The Panoptiq imaging system is a novel tool that can be used for frozen section telepathology. Panoramic digital images were easy to generate and navigate, of relatively small file size, and offered a mechanism to overcome focusing problems commonly encountered with WSI of frozen sections. However, the acquisition of representative Panoptiq images was operator dependent with the individual creating files that may impact the final diagnosis. PMID- 27217977 TI - Sequential recruitment of Rab GTPases during early stages of phagocytosis. AB - The phagocytosis and destruction of pathogens and dead cells by macrophages is important for innate immunity and tissue maintenance. Multiple Rab family GTPases engage effector molecules to coordinate the early stages of phagocytosis, which include rapid changes in actin polymerization, membrane phospholipids, trafficking and the activation of receptors. Defining the spatiotemporal, sequential recruitment of these Rabs is critical for insights into how phagocytosis is initiated and coordinated. Here, we screened GFP-tagged Rabs expressed in fixed and live cells to identify and stratify those recruited to early phagocytic membranes at stages defined by phospholipid transitions. We propose a sequence of Rabs 35, 13, 8a, 8b, 27a, 10, and 31 that precedes and accompanies phagocytic cup closure, followed after closure by recruitment of endosomal Rabs 5a, 5b, 5c, 14, and 11. Reducing the expression of individual Rabs by siRNA knockdown, notably Rabs 35 and 13, disrupts phagocytosis prior to phagocytic cup closure, confirming a known role for Rab35 and revealing anew the involvement of Rab13. The results enhance our understanding of innate immune responses in macrophages by revealing the sequence of Rabs that initiates phagocytosis. PMID- 27217979 TI - Small GTPases in trafficking - a family approach: Introducing a rolling series focused on groups or families of small GTPases in trafficking. PMID- 27217978 TI - Degradation elements coincide with cofactor binding sites in a short-lived transcription factor. AB - Elaborate control of gene expression by transcription factors is common to all kingdoms of life. In eukaryotes, transcription factor abundance and activity are often regulated by targeted proteolysis via the ubiquitin-proteasome system (UPS). The yeast MATalpha2 (alpha2) cell type regulator has long served as a model for UPS-dependent transcription factor degradation. Proteolysis of alpha2 is complex: it involves at least 2 ubiquitylation pathways and multiple regions of alpha2 affect its degradation. Such complexity also exists for the degradation of other UPS substrates. Here I review alpha2 degradation, most notably our recent identification of 2 novel degradation elements within alpha2 that overlap corepressor binding sites. I discuss possible implications of these findings and consider how principles of alpha2 proteolysis may be relevant to the degradation of other UPS substrates. PMID- 27217980 TI - Fibroids and Infertility. AB - The precise impact of fibroids, which are the most common benign gynaecological tumours in women, on reproductive function and infertility is unknown. The need to treat submucosal fibroids is widely accepted, but fibroids in other locations and sizes continue to present a clinical conundrum. This article examines the mechanisms by which fibroids affect implantation and fertility, and stratifies their impact on basis of size, location and nature. It also explores the evidence base of the available treatment modalities in specific relation to improving fertility outcomes. Traditionally, a myomectomy has been advocated to treat fibroids for the reproductive population; however, as well as evaluating the benefits of surgery including endoscopic, this article explores alternative therapies including medical and radiological interventions. PMID- 27217981 TI - The Role of Complementary and Alternative Medicine for the Management of Fibroids and Associated Symptomatology. AB - This article discusses the role of complementary and alternative medicine (CAM) in the management of fibroids and associated symptomatology. Since there is such a paucity of direct research related to fibroids, conditions that are implicated in the causation of uterine fibroids and symptomatology that CAM treatments may or have been shown to make a difference are also considered. PMID- 27217982 TI - IL-6/STAT3 signaling in mice with dysfunctional type-2 ryanodine receptor. AB - Mice with genetically modified cardiac ryanodine receptor (Ryr2 (ADA/ADA) mice) are impaired in regulation by calmodulin, develop severe cardiac hypertrophy and die about 2 weeks after birth. We hypothesized that the interleukin 6 (IL 6)/signal transducer and activator of transcription-3 (STAT3) signaling pathway has a role in the development of the Ryr2 (ADA/ADA) cardiac hypertrophy phenotype, and determined cardiac function and protein levels of IL-6, phosphorylation levels of STAT3, and downstream targets c-Fos and c-Myc in wild type and RyR2 (ADA/ADA) mice, mice with a disrupted IL-6 gene, and mice treated with STAT3 inhibitor NSC74859. IL-6 protein levels were increased at postnatal day 1 but not day 10, whereas pSTAT3-Tyr705/STAT3 ratio and c-Fos and c-Myc protein levels increased in hearts of 10-day but not 1-day old Ryr2 (ADA/ADA) mice compared with wild type. Both STAT3 and pSTAT3-Tyr705 accumulated in the nuclear fraction of 10-day old Ryr2 (ADA/ADA) mice compared with wild type. Ryr2 (ADA /ADA) /IL-6(-/-) mice lived 1.5 times longer, had decreased heart to body weight ratio, and reduced c-Fos and c-Myc protein levels. The STAT3 inhibitor NSC74859 prolonged life span by 1.3-fold, decreased heart to body weight ratio, increased cardiac performance, and decreased pSTAT-Tyr705/STAT3 ratio and IL-6, c Fos and c-Myc protein levels of Ryr2 (ADA /ADA) mice. The results suggest that upregulation of IL-6 and STAT3 signaling contributes to cardiac hypertrophy and early death of mice with a dysfunctional ryanodine receptor. They further suggest that STAT3 inhibitors may be clinically useful agents in patients with altered Ca(2+) handling in the heart. PMID- 27217984 TI - Robot Assisted Stereotactic Laser Ablation for a Radiosurgery Resistant Hypothalamic Hamartoma. AB - Hypothalamic hamartomas (HH) are benign tumors that can cause significant morbidity in adults as a cause of epilepsy, particularly gelastic seizures. Open and endoscopic resections of HH offer good seizure control but have high rates of morbidity and are technically challenging. Stereotactic radiosurgery has been an alternative treatment; however, it results in comparably poor seizure control. Recently, in children, stereotactic laser ablation has shown promise as a surgical technique that can combine the best features of both of these approaches for the treatment of HH. Here we present the first reported use of a frameless robot-assisted stereotactic system to treat an HH. The patient had failed two previous Gamma Knife radiosurgery treatments. Post-procedure he had a stable, but unintentional weight loss of 20 kg and a transient episode of hemiparesis the night of the operation. At six months postoperatively the patient remained seizure free. Stereotactic laser ablation may represent a new standard in the treatment of HH in adults, especially in those who have failed radiosurgery. Further study is warranted in this population to determine efficacy and safety profiles. PMID- 27217983 TI - The Price of Perspective Taking: Child Depressive Symptoms Interact with Parental Empathy to Predict Immune Functioning in Parents. AB - Parental empathy is generally held as a positive characteristic; however, might there be contexts in which parental empathy is actually harmful? The present study examined whether adolescents' depressive symptoms might have immunologic costs for more empathic parents. One hundred forty three parents and their children completed self-report measures of empathy and depressive symptoms, respectively. One year later, production of four pro-inflammatory cytokines in parents' blood was measured in response to in vitro exposure to a bacterial product. Significant interactions across all inflammatory markers emerged, such that parents who were higher in empathy showed greater inflammatory cytokine production if their children also reported high levels of depressive symptoms, but lower cytokine production if their children reported low levels of symptoms. Less empathic parents showed the opposite pattern. These results provide support for the hypothesis that parents high in empathy may be especially sensitive physiologically to their children's psychopathologic symptoms. PMID- 27217986 TI - A new solution method for wheel/rail rolling contact. AB - To solve the problem of wheel/rail rolling contact of nonlinear steady-state curving, a three-dimensional transient finite element (FE) model is developed by the explicit software ANSYS/LS-DYNA. To improve the solving speed and efficiency, an explicit-explicit order solution method is put forward based on analysis of the features of implicit and explicit algorithm. The solution method was first applied to calculate the pre-loading of wheel/rail rolling contact with explicit algorithm, and then the results became the initial conditions in solving the dynamic process of wheel/rail rolling contact with explicit algorithm as well. Simultaneously, the common implicit-explicit order solution method is used to solve the FE model. Results show that the explicit-explicit order solution method has faster operation speed and higher efficiency than the implicit-explicit order solution method while the solution accuracy is almost the same. Hence, the explicit-explicit order solution method is more suitable for the wheel/rail rolling contact model with large scale and high nonlinearity. PMID- 27217985 TI - Portable Automated Oxygen Administration System for hypoxaemic patients. AB - Oxygen is a lifesaving medication that should be offered with an administration to a patient who suffers from oxygen deficiency to avoid toxic effects of excessive oxygen supplement as well as to minimize the exposure to hypoxaemia. This work aims to automate the process of administering oxygen delivery in order to extend the continuous oxygen administration process beyond the IC units, reduce the cost of oxygen administration in terms of well-trained health care providers and equipment, prolong the lifetime of oxygen supplement, and help in the process of weaning patient from oxygen. In this work, a prototype model for a Portable Automated Oxygen Delivery System that consists of two subsystems: an Oxygen Reader Subsystem and an Automated Adjustment Oxygen Delivery Subsystem, both communicating wirelessly, has been developed. The system promises significant benefits in improving the life quality of hypoxaemic patients as well as healthcare service for oxygen delivery administration. PMID- 27217987 TI - Modified bathroom scale and balance assessment: a comparison with clinical tests. AB - Frailty and detection of fall risk are major issues in preventive gerontology. A simple tool frequently used in daily life, a bathroom scale (balance quality tester: BQT), was modified to obtain information on the balance of 84 outpatients consulting at a geriatric clinic. The results computed from the BQT were compared to the values of three geriatric tests that are widely used either to detect a fall risk or frailty (timed get up and go: TUG; 10 m walking speed: WS; walking time: WT; one-leg stand: OS). The BQT calculates four parameters that are then scored and weighted, thus creating an overall indicator of balance quality. Raw data, partial scores and the global score were compared with the results of the three geriatric tests. The WT values had the highest correlation with BQT raw data (r = 0.55), while TUG (r = 0.53) and WS (r = 0.56) had the highest correlation with BQT partial scores. ROC curves for OS cut-off values (4 and 5 s) were produced, with the best results obtained for a 5 s cut-off, both with the partial scores combined using Fisher's combination (specificity 85 %: <0.11, sensitivity 85 %: >0.48), and with the empirical score (specificity 85 %: <7, sensitivity 85 %: >8). A BQT empirical score of less than seven can detect fall risk in a community dwelling population. PMID- 27217988 TI - A hybrid cuckoo search algorithm with Nelder Mead method for solving global optimization problems. AB - Cuckoo search algorithm is a promising metaheuristic population based method. It has been applied to solve many real life problems. In this paper, we propose a new cuckoo search algorithm by combining the cuckoo search algorithm with the Nelder-Mead method in order to solve the integer and minimax optimization problems. We call the proposed algorithm by hybrid cuckoo search and Nelder-Mead method (HCSNM). HCSNM starts the search by applying the standard cuckoo search for number of iterations then the best obtained solution is passing to the Nelder Mead algorithm as an intensification process in order to accelerate the search and overcome the slow convergence of the standard cuckoo search algorithm. The proposed algorithm is balancing between the global exploration of the Cuckoo search algorithm and the deep exploitation of the Nelder-Mead method. We test HCSNM algorithm on seven integer programming problems and ten minimax problems and compare against eight algorithms for solving integer programming problems and seven algorithms for solving minimax problems. The experiments results show the efficiency of the proposed algorithm and its ability to solve integer and minimax optimization problems in reasonable time. PMID- 27217989 TI - On the convergence of a high-accuracy compact conservative scheme for the modified regularized long-wave equation. AB - In this article, we develop a high-order efficient numerical scheme to solve the initial-boundary problem of the MRLW equation. The method is based on a combination between the requirement to have a discrete counterpart of the conservation of the physical "energy" of the system and finite difference method. The scheme consists of a fourth-order compact finite difference approximation in space and a version of the leap-frog scheme in time. The unique solvability of numerical solutions is shown. A priori estimate and fourth-order convergence of the finite difference approximate solution are discussed by using discrete energy method and some techniques of matrix theory. Numerical results are given to show the validity and the accuracy of the proposed method. PMID- 27217990 TI - Tissue plasminogen activator (tPA) attenuates propofol-induced apoptosis in developing hippocampal neurons. AB - BACKGROUND: We investigated the effect of propofol on the tissue plasminogen activator (tPA) release in developing hippocampal neurons, and explored the effects of exogenous tPA on the propofol-induced neuron apoptosis. METHODS: Primary hippocampal neurons isolated from neonatal Sprague-Dawley rats were exposed to propofol (20, 50, and 100 MUM) for 6 h either one time or three times. Finally, neurons were pretreated with exogenous tPA (5 ug/ml), followed by propofol exposure (100 MUM, 6 h). The neuron apoptosis was detected by terminal transferase deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) and the protein expression of cleaved caspase-3 (Cl-Csp3) was analyzed by western blot, the tPA in media was tested by enzyme-linked immunosorbent assay. RESULTS: Propofol exposure significantly increased the number of TUNEL-positive neurons and Cl-Csp3 expression in developing hippocampal neurons. Propofol decreased tPA level in the media of developing hippocampal neurons. The neuron appotosis induced by propofol was attenuated by pretreatment of tPA. CONCLUSION: Propofol exposure decreased tPA release in developing hippocampal neurons. The addition of tPA could partially reverse the apoptotic effect of propofol. PMID- 27217991 TI - Characterization of Newcastle disease virus isolates obtained from outbreak cases in commercial chickens and wild pigeons in Ethiopia. AB - Newcastle disease (ND), caused by virulent avian paramyxovirus type 1, is one of the most important diseases responsible for devastating outbreaks in poultry flocks in Ethiopia. However, the information about genetic characteristics of the Newcastle disease viruses (NDVs) circulating in commercial chickens and wild birds is scarce. In this study, we characterized isolates obtained from ND suspected outbreaks during 2012-2014 from poultry farms (n = 8) and wild pigeons (n = 4). The NDVs isolated from pathological specimens, through inoculation in embryonated chicken eggs, were characterized biologically by conventional intracerebral pathogenicity indices (ICPI), and genetically on the basis of Phylogenic analysis of partial F-gene sequences (260 bp) encompassing the cleavage site. The ICPI values of isolates from chickens ranged from 0.9 to 1.8; whereas, the ICPI of pigeon isolates was 1.4. All isolates contained multiple basic amino acids at the deduced cleavage site of fusion protein, which is a typical feature of virulent viruses. Phylogenic analysis of the partial cleavage site of F-gene (260 bp) indicated that all the sequences of viruses obtained from pigeons were identical and clustered within the genotype VIh while the sequences of viruses obtained from chickens were clustered together within the genotype VIf. The similarity between the viruses obtained from chickens and those obtained from pigeons ranged from 82.5 to 85.6 %. This suggests that different sub genotypes of genotype VI are circulating in chicken and wild pigeon population in Ethiopia. This warrants further study to understand the role of wild birds in the epidemiology of NDV in Ethiopia and as well highlights the importance of continuous surveillances both in wild birds and domestic poultry. PMID- 27217992 TI - Optimization of DNA extraction and PCR protocols for phylogenetic analysis in Schinopsis spp. and related Anacardiaceae. AB - The Anacardiaceae is an important and worldwide distributed family of ecological and socio-economic relevance. Notwithstanding that, molecular studies in this family are scarce and problematic because of the particularly high concentration of secondary metabolites-i.e. tannins and oleoresins-that are present in almost all tissues of the many members of the group, which complicate the purification and amplification of the DNA. The objective of this work was to improve an available DNA isolation method for Schinopsis spp. and other related Anacardiaceae, as well as the PCR protocols for DNA amplification of the chloroplast trnL-F, rps16 and ndhF and nuclear ITS-ETS fragments. The modifications proposed allowed the extraction of 70-120 ug of non-degraded genomic DNA per gram of dry tissue that resulted useful for PCR amplification. PCR reactions produced the expected fragments that could be directly sequenced. Sequence analyses of amplicons showed similarity with the corresponding Schinopsis accessions available at GenBank. The methodology presented here can be routinely applied for molecular studies of the group aimed to clarify not only aspects on the molecular biology but also the taxonomy and phylogeny of this fascinating group of vascular plants. PMID- 27217993 TI - Attitudes towards breast conservation in patients aged over 70 with breast cancer. AB - BACKGROUND: The majority of breast conserving surgery (BCS) is performed in younger women. There is little published information about the views of women aged over 70 regarding BCS. The aim of this study was to investigate the attitudes of this age group towards BCS, and factors which may influence their treatment decision-making. METHODS: A questionnaire was sent to all patients who were aged 70 or over at the time they had breast cancer surgery in NHS Lanarkshire between 1999 and 2013. This detailed surgical options and recommendations, timing of decision making, treatment expectations, psychological and cosmetic concerns and other factors which may have influenced any decision made e.g. travel for radiotherapy and potential side effects. RESULTS: Responses were received from 339 patients, 192 of whom had a mastectomy with the remaining undergoing BCS. In the mastectomy group 18 % (35) would have preferred to have BCS had it been an option, with 40 % (76) of group being happy to take neoadjuvant endocrine therapy to try and facilitate this. However, only 14 % (26) of patients would have considered neoadjuvant chemotherapy with the same aim. Almost half (82) of the mastectomy patients said that the risk of local recurrence following BCS was a factor which influenced their decision. CONCLUSION: BCS is something that patients aged over 70 are interested in considering in the same way as younger patients. More than a third of patients requiring mastectomy would be willing to take neoadjuvant endocrine therapy to attempt to downstage their tumour to facilitate BCS. PMID- 27217995 TI - Synchronous international scientific mobility in the space of affiliations: evidence from Russia. AB - The article presents a survey of Russian researchers' synchronous international scientific mobility as an element of the global system of scientific labor market. Synchronous international scientific mobility is a simultaneous holding of scientific positions in institutions located in different countries. The study explores bibliometric data from the Web of Science Core Collection and socio economic indicators for 56 countries. In order to examine international scientific mobility, we use a method of affiliations. The paper introduces a model of synchronous international scientific mobility. It enables to specify country's involvement in the international division of scientific labor. Synchronous international scientific mobility is a modern form of the international division of labor in science. It encompasses various forms of part time, temporary and remote employment of scientists. The analysis reveals the distribution of Russian authors in the space of affiliations, and directions of upward/downward international scientific mobility. The bibliometric characteristics of mobile authors are isomorphic to those of receiver country authors. Synchronous international scientific mobility of Russian authors is determined by differences in scientific impacts between receiver and donor countries. PMID- 27217994 TI - Conventional and modified hydrodistillation method for the extraction of glucosinolate hydrolytic products: a comparative account. AB - Eruca sativa is extensively used as raw and its oil is also used for cooking due to its exceptional flavour. The volatile nature of the hydrolytic products of glucosinolates makes the extraction difficult. The hydrodistillation method used previously yield very less amount of the extract as well as the absence of stirring in the round bottom flask causes burning of both the crushed seeds and the flask. To overcome these drawbacks, a method has been developed using magnetic stirrer and hot plate. The yield and composition of hydrolytic products in the extract with the modified method was increased along with an increase in the amount of major hydrolytic products as seen by GC-MS. This method thus has immense potential in pharmaceutical industries, due to the ease of extraction and isolation. PMID- 27217996 TI - Variation in aeolian environments recorded by the particle size distribution of lacustrine sediments in Ebinur Lake, northwest China. AB - Particle size analysis of lacustrine core sediments and atmospheric natural dust were conducted in the drainage area of Ebinur Lake in arid northwest China. Using a combination of (137)Cs and (210)Pb dating, a continuous record of aeolian transportation to the lake sediments and related factors over about the past 150 years was analyzed. Factor analysis revealed the particle-size distributions of riverine and aeolian sediments composed of the terrigenous materials of the lake deposits. Compared with the grain-size distributions of natural dust samples, the results showed that the coarser particle size fraction of lake sediments was mainly derived from the sediments that had experienced aeolian transport to the drainage surface, and the finer sediments came from hydraulic inputs. Then, the method of variations in particle-size standard deviation was used to extract the grain size intervals with the highest variability along a sedimentary sequence. The coarser grain-size populations dominated the variation patterns of the sedimentary sequence. During the last 150 years, strong intensity aeolian transportation occurred during three periods, 1915-1935, 1965-1975 and since the beginning of the 2000s. The climate was dry around 1910s-1930s in this region associated with the appropriate dynamic condition, which provided the enhanced source materials and wind power for the aeolian dust transport. Since 1950s, the climate controlled the foundation of aeolian dust transport, and the aeolian dust transport won't be increased under the humid climate. PMID- 27217997 TI - Spectrum of EGFR gene mutations and ALK rearrangements in lung cancer patients in Turkey. AB - The EGFR gene and ALK rearrangements are two genetic drivers of non-small cell lung cancer (NSCLC). The frequency of EGFR mutations and ALK rearrangement varies according to not only ethnicity but also gender, smoking status and the histological type of NSCLC. In the present study, we demonstrated the distribution of EGFR mutations in 132 NSCLC patients by using a pyrosequencing technique and the distribution of ALK rearrangements in 51 NSCLC patients by using fluorescent in situ hybridization technique in Turkey. Additionally, we compared the clinicopathological data of NSCLC patients with the mutation status of EGFR in their cancerous tissues. Both EGFR mutations and ALK rearrangements were identified in 19 (14.39 %) and 1 (1.96 %) patients, respectively. We found EGFR mutations in codon 861, 719 and 858 with the ratios of 10.52 % (2/19), 10.52 % (2/19) and 31.58 % (6/19), respectively, and deletion of exon 19 in 47.37 % (9/19) of the patients. We found the frequency of EGFR mutations to be significantly higher in female patients and nonsmokers (p = 0.043, p = 0.027, respectively). Consequently, we found EGFR mutations to be more frequent in female patients and nonsmokers. Future studies on larger patient groups would provide more accurate data to exhibit the relationship between EGFR mutations and ALK rearrangements and the clinicopathological status. PMID- 27217998 TI - Synthesis and characterization of multiwalled CNT-PAN based composite carbon nanofibers via electrospinning. AB - Electrospun fibrous membranes find place in diverse applications like sensors, filters, fuel cell membranes, scaffolds for tissue engineering, organic electronics etc. The objectives of present work are to electrospun polyacrylonitrile (PAN) nanofibers and PAN-CNT nanocomposite nanofibers and convert into carbon nanofiber and carbon-CNT composite nanofiber. The work was divided into two parts, development of nanofibers and composite nanofiber. The PAN nanofibers were produced from 9 wt% PAN solution by electrospinning technique. In another case PAN-CNT composite nanofibers were developed from different concentrations of MWCNTs (1-3 wt%) in 9 wt% PAN solution by electrospinning. Both types of nanofibers were undergone through oxidation, stabilization, carbonization and graphitization. At each stage of processing of carbon and carbon-CNT composite nanofibers were characterized by SEM, AFM, TGA and XRD. It was observed that diameter of nanofiber varies with processing parameters such as applied voltage tip to collector distance, flow rate of solution and polymer concentrations etc. while in case of PAN-CNT composite nanofiber diameter decreases with increasing concentration of CNT in PAN solution. Also with stabilization, carbonization and graphitization diameter of nanofiber decreases. SEM images shows that the minimum fiber diameter in case of 3 wt% of CNT solution because as viscosity increases it reduces the phase separation of PAN and solvent and as a consequence increases in the fiber diameter. AFM images shows that surface of film is irregular which give idea about mat type orientation of fibers. XRD results show that degree of graphitization increases on increasing CNT concentration because of additional stresses exerting on the nanofiber surface in the immediate vicinity of CNTs. TGA results shows wt loss decreases as CNT concentration increases in fibers. PMID- 27217999 TI - Erratum to: Flexible Ureterorenoscopy versus Extracorporeal Shock Wave Lithotripsy for the treatment of upper/middle calyx kidney stones of 10-20 mm: a retrospective analysis of 174 patients. AB - [This corrects the article DOI: 10.1186/2193-1801-3-557.]. PMID- 27218000 TI - Factors of land abandonment in mountainous Mediterranean areas: the case of Montenegrin settlements. AB - Land use changes have been investigated in the surroundings of 14 rural Montenegrin settlements in order to get specific information about trends in land abandonment since around 1950. Permanently, seasonally and less inhabited settlements with different geographic conditions were studied. This was done by interviewing local inhabitants, which enabled a holistic approach to reveal the underlying processes of land abandonment. According to the observed patterns of land use change, the study sites can be categorized into intensified, urbanized, extensified, overgrown and forested cases. The category of extensified settlements is characterized by a highly reduced agricultural management intensity, resulting in an increase in grasslands and fruit trees at the expense of cropland. This land use change is mainly related to emigrating and aging inhabitants, having less livestock. Such extensive land use is found in both permanently inhabited and abandoned villages. Only some studied settlements became largely overgrown by bushes and forest. The steep average slope gradients and a large distance to the nearest city are explanatory factors of such land abandonment. Land use intensification takes place in low-lying areas located nearby towns. PMID- 27218001 TI - Assessment of psychosocial factors and distress in women having adjuvant endocrine therapy for breast cancer: the relationship among emotional distress and patient and treatment-related factors. AB - PURPOSE: The aims of this study were to comprehensively describe the psychosocial and medical characteristics of women who initiated tamoxifen or aromatase inhibitors for breast cancer and to compare levels of emotional distress according to their medical (tumor demographics, treatment type, treatment duration) and psychosocial (self-esteem, perceived social support, sociodemographic) characteristics. METHODS: A total of 104 women currently receiving tamoxifen or aromatase inhibitors was recruited from outpatient clinics and they were asked to complete self-report questionnaires including the Rosenberg Self-Esteem Scale, the Multidimensional Scale of Perceived Social Support and the Hospital Anxiety and Depression Scale during their routine follow up. Psychosocial and medical characteristics of the patients were first described and subsequently the score of emotional distress was compared with these. RESULTS: The patients' mean age was 52.49 +/- 10.30 and they were being treated for an average of 24.3 months. Out of the patients' characteristics, educational and marital status, level of perceived social support and self-esteem were all significantly related with emotional distress. As for medical variables, the score of distress was relatively higher among patients in the first 2 years of their treatment than the patients who were in the second to fifth years of treatment, but this was not statistically significant. CONCLUSIONS: Given the results of this study, it appeared that patient variables, rather than the medical or treatment characteristics, were related with emotional distress in women undergoing endocrine treatment. For that reason it is critical that medical staff are aware of patient factors that relate to distress during a long period of adjuvant endocrine therapy. PMID- 27218002 TI - A high performance cost-effective digital complex correlator for an X-band polarimetry survey. AB - The detailed knowledge of the Milky Way radio emission is important to characterize galactic foregrounds masking extragalactic and cosmological signals. The update of the global sky models describing radio emissions over a very large spectral band requires high sensitivity experiments capable of observing large sky areas with long integration times. Here, we present the design of a new 10 GHz (X-band) polarimeter digital back-end to map the polarization components of the galactic synchrotron radiation field of the Northern Hemisphere sky. The design follows the digital processing trends in radio astronomy and implements a large bandwidth (1 GHz) digital complex cross-correlator to extract the Stokes parameters of the incoming synchrotron radiation field. The hardware constraints cover the implemented VLSI hardware description language code and the preliminary results. The implementation is based on the simultaneous digitized acquisition of the Cartesian components of the two linear receiver polarization channels. The design strategy involves a double data rate acquisition of the ADC interleaved parallel bus, and field programmable gate array device programming at the register transfer mode. The digital core of the back-end is capable of processing 32 Gbps and is built around an Altera field programmable gate array clocked at 250 MHz, 1 GSps analog to digital converters and a clock generator. The control of the field programmable gate array internal signal delays and a convenient use of its phase locked loops provide the timing requirements to achieve the target bandwidths and sensitivity. This solution is convenient for radio astronomy experiments requiring large bandwidth, high functionality, high volume availability and low cost. Of particular interest, this correlator was developed for the Galactic Emission Mapping project and is suitable for large sky area polarization continuum surveys. The solutions may also be adapted to be used at signal processing subsystem levels for large projects like the square kilometer array testbeds. PMID- 27218003 TI - Heavy metals in vegetables: screening health risks involved in cultivation along wastewater drain and irrigating with wastewater. AB - Irrigation of agricultural land with wastewater leads to continuous buildup of metals at these sites which gets accumulated in the vegetables and crops growing on these sites. Not just the crops irrigated with wastewater are hazardous, in present study, we have found that vegetables growing in vicinity of wastewater drain are also not safe for human consumption. The risk associated with consumption of vegetables was assessed by calculating hazard quotient and results revealed that the hazard quotient for leafy and tuberous vegetables was higher than the safe limits in all the sites irrespective of mode of irrigation. Spinach was the most hazardous among all as the hazard quotient with respect to cobalt and copper was highest in spinach. Uptake trend of metals in all vegetables: Iron > Cobalt > Copper > Cadmium > Lead. Cadmium, a potential carcinogen was found in concentrations higher than permissible limits in many vegetables from all sites. Highest level of cadmium (1.20 mg/kg) and copper (81.33 mg/kg) was reported in site which was in vicinity of waste water drain but irrigated with ground water. Concentration of copper and lead in vegetable samples from different sites exhibited no statistically significant difference with respect to different sites. PMID- 27218004 TI - Adomian decomposition sumudu transform method for solving a solid and porous fin with temperature dependent internal heat generation. AB - In this paper, Adomian decomposition sumudu transform method is introduced and used to solve the temperature distribution in a solid and porous fin with the temperature dependent internal heat generation for a fractional order energy balance equation. In this study, we assume heat generation as a variable of fin temperature for solid and porous fin and the heat transfer through porous media is simulated by using Darcy's model. The results are presented for the temperature distribution for the range of values of parameters appeared in the mathematical formulation and also compared with numerical solutions in order to verify the accuracy of the proposed method. It is found that the proposed method is in good agreement with direct numerical solution. PMID- 27218005 TI - An improved authenticated key agreement protocol for telecare medicine information system. AB - In telecare medicine information systems (TMIS), identity authentication of patients plays an important role and has been widely studied in the research field. Generally, it is realized by an authenticated key agreement protocol, and many such protocols were proposed in the literature. Recently, Zhang et al. pointed out that Islam et al.'s protocol suffers from the following security weaknesses: (1) Any legal but malicious patient can reveal other user's identity; (2) An attacker can launch off-line password guessing attack and the impersonation attack if the patient's identity is compromised. Zhang et al. also proposed an improved authenticated key agreement scheme with privacy protection for TMIS. However, in this paper, we point out that Zhang et al.'s scheme cannot resist off-line password guessing attack, and it fails to provide the revocation of lost/stolen smartcard. In order to overcome these weaknesses, we propose an improved protocol, the security and authentication of which can be proven using applied pi calculus based formal verification tool ProVerif. PMID- 27218006 TI - The existence of solutions of q-difference-differential equations. AB - By using the Nevanlinna theory of value distribution, we investigate the existence of solutions of some types of non-linear q-difference differential equations. In particular, we generalize the Rellich-Wittich-type theorem and Malmquist-type theorem about differential equations to the case of q-difference differential equations (system). PMID- 27218007 TI - On fixed points and convergence results of sequences generated by uniformly convergent and point-wisely convergent sequences of operators in Menger probabilistic metric spaces. AB - In the framework of complete probabilistic Menger metric spaces, this paper investigates some relevant properties of convergence of sequences built through sequences of operators which are either uniformly convergent to a strict k contractive operator, for some real constant k ? (0, 1), or which are strictly k contractive and point-wisely convergent to a limit operator. Those properties are also reformulated for the case when either the sequence of operators or its limit are strict [Formula: see text]-contractions. The definitions of strict (k and [Formula: see text]) contractions are given in the context of probabilistic metric spaces, namely in particular, for the considered probability density function. A numerical illustrative example is discussed. PMID- 27218008 TI - Interval oscillation criteria for second-order forced impulsive delay differential equations with damping term. AB - In this paper, we present some sufficient conditions for the oscillation of all solutions of a second order forced impulsive delay differential equation with damping term. Three factors-impulse, delay and damping that affect the interval qualitative properties of solutions of equations are taken into account together. The results obtained in this paper extend and generalize some of the the known results for forced impulsive differential equations. An example is provided to illustrate the main result. PMID- 27218009 TI - Retting and degumming of natural fibers by pectinolytic enzymes produced from Bacillus tequilensis SV11-UV37 using solid state fermentation. AB - The present study demonstrated the simultaneous production and optimization of pectinolytic enzymes (pectate lyase and polygalacturonase) under SSF from Bacillus tequilensis SV11-UV37 using wheat bran as a substrate, which is commercially viable and cost-effective. Optimization by one variable-at-a-time approach showed a maximum yield of pectate lyase (1371.25 U/gds) and polygalacturonase (85.45 U/gds) with wheat bran using 80 % (v/w) moisture, 0.7 mm particle size, 20 % (v/w) inoculum, 1 % (w/w) pectin at 37 degrees C, pH 6 and 72 h of incubation. In addition, optimization using central composite design achieved 1.6-fold improvement in both pectate lyase (1828.13 U/gds) and polygalacturonase (105.55 U/gds) yield at optimum levels of pectin (3 %, w/w), inoculum size (20 %, v/w) and moisture level (80 %, v/w). Further, Retting studies concluded that the enzyme mixture was efficient in separating the whole fiber from kenaf and part (>75 %) from sunn hemp. In degumming of sunn hemp fibers, amount of galacturonic acid released and percentage weight loss was higher in successive alkali and enzymatic treatment than their independent treatments. The scanning electron microscopic analysis also confirmed that alkali followed by enzymatic treatment effectively removed non-cellulosic gummy material from the fiber; hence, this enzyme mixture may find feasible applications in the fiber and textile industry. PMID- 27218010 TI - Evaluation of surface water quality indices and ecological risk assessment for heavy metals in scrap yard neighbourhood. AB - Pollution of surface water with heavy metals from industrial activities especially those from scrap yard has caused a major threat to human life exposing man to series of hazard, diseases, disability and consequently death. This study focuses on water quality indices of Owode-Onirin and Lafenwa scrap yard with respect to its physicochemical parameters and heavy metal concentrations by evaluating Heavy Metal Pollution Index (HPI), Metal Index (MI) and Potential Ecological Risk Index (PERI). Fifteen water samples were selected randomly from two locations by purposive sampling methods. Five heavy metals which includes Nickel (Ni), Zinc (Zn), Copper (Cu), Cadmium (Cd), Lead (Pb) were analyzed using Atomic Absorption Spectroscopy and standard analytical procedure were follow to ensure accuracy. One way analysis of variance was carried out to analyse the data. The concentrations of the heavy metals were significantly different between sampling locations. However, the mean concentrations of Cd (0.0121 mg/L) were found to be above the highest permissible value of Standard Organization of Nigeria standards for drinking water (SON 2007) and WHO (Guidelines for drinking water quality: incorporating 1st and 2nd Addlenda. World Health Organization, Geneva, 2004) for drinking water. Although Pb was present in two out of the fifteen water samples with a mean value of (0.0324 mg/L) which was also above the highest permissible value. The mean concentrations of Zn (0.2149 mg/L) and Cu (0.0341 mg/L) are found to be below the highest permissible value of the mentioned guideline while no trace of Ni was found in the water samples across the two sampling locations. The mean HPI 518.55 is far above the critical value of 100, indicates that selected water samples are critically polluted with heavy metals. MI revealed low quality water with mean value 4.83, suggests that the selected water is seriously affected with the present of heavy metal. The Hakanson PERI indicated that of the five heavy metals, the risk coefficient of Zn, Pb, Cu, and Ni had light levels of contamination while the level of Cd contamination posed the most serious potential ecological risk, with an index value between 14.1 and 234. The study concluded that order of magnitude to this five heavy metals contamination is Cd > Pb > Zn > Cu > Ni. PMID- 27218011 TI - Production of a microcapsule agent of chromate-reducing Lysinibacillus fusiformis ZC1 and its application in remediation of chromate-spiked soil. AB - Lysinibacillus fusiformis ZC1 is an efficient Cr(VI)-reducing bacterium that can transform the toxic and soluble chromate [Cr(VI)] form to the less toxic and precipitated chromite form [Cr(III)]. As such, this strain might be applicable for bioremediation of Cr(VI) in soil by reducing its bioavailability. The study objective was to prepare a microcapsule agent of strain ZC1 for bioremediation of Cr(VI)-contaminated soil. Using a single-factor orthogonal array design, the optimal fermentation medium was obtained and consisted of 6 g/L corn flour, 12 g/L soybean flour, 8 g/L NH4Cl and 6 g/L CaCl2. After enlarged fermentation, the cell and spore densities were 5.9 * 10(9) and 1.7 * 10(8) cfu/mL, respectively. The fermentation products were collected and embedded with 1 % gum arabic and 1 % sorbitol as the microcapsule carriers and were subsequently spray-dried. Strain ZC1 exhibited viable cell counts of (3.6 +/- 0.44) * 10(10) cfu/g dw after 50-day storage at room temperature. In simulated soil bioremediation experiments, 67 % of Cr(VI) was reduced in 5 days with the inoculation of this microcapsule agent, and the Cr(VI) concentration was below the soil Cr(VI) standard level. The results demonstrated that the microcapsule agent of strain ZC1 is efficient for bioremediation of Cr(VI)-contaminated soil. PMID- 27218012 TI - Extrahepatic Manifestations of Nonalcoholic Fatty Liver Disease. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide with an increased prevalence of metabolic, macro- and microvascular complications. The primary causes of mortality in NAFLD are cardiovascular disease (CVD), malignancy and liver disease. NAFLD is a multisystem disease that affects a variety of extra-hepatic organ systems. The main focus of this review is to summarize the reported extra-hepatic associations, which include CVD, chronic kidney disease, obstructive sleep apnea, osteoporosis, psoriasis, colorectal cancer, iron overload and various endocrinopathies (e.g. type 2 diabetes mellitus, thyroid dysfunction, and polycystic ovarian syndrome). Due to the systemic manifestations of NAFLD patients require a multidisciplinary assessment and may benefit from more rigorous surveillance and early treatment interventions to decrease mortality related to malignancy or cardiometabolic diseases. PMID- 27218013 TI - Getting to Zero: Tuberculosis Elimination in California. AB - This review of tuberculosis epidemiology is intended to provide a historical perspective on the public health approach to tuberculosis (TB) control in California. This historical context offers a lens through which to view current epidemiologic trends and insight into how new therapeutic tools can be applied. Since 1993, the year detailed case reporting was instituted, California has had a decrease in recent TB transmission as evidenced by a reduction in pediatric cases and an increased percentage of cases attributable to progression of latent infection to TB disease in the foreign-born population. Overall, there has been a dramatic decline in the annual TB case count, but the speed of the decline has slowed over the last several years. At the current pace and case count of 2137 in 2015, California will not achieve TB elimination (<1 TB case per one million population) for at least 100 years. There are an estimated 2.1 million persons in California with latent TB infection. Modeling suggests that LTBI detection and treatment are important in reaching TB elimination. For this reason, a coalition of stakeholders in California is exploring novel approaches to accelerate the case decline in order to prevent unnecessary disease and death. PMID- 27218016 TI - Microdesign using frictional, hooked, attachment mechanisms: a biomimetic study of natural attachment mechanisms-Part 3. AB - Part 1 completed the studies of five long-shafted, cellulose, frictional, hooked probabilistic fasteners. Part 2 identified three substructures prevalent in the natural world for probabilistic fasteners and detailed the collection of voxel dataclouds while measuring from the natural fluorescence of their composing chitin and cellulose under the laser illumination of a confocal microscope. In this part 3, consideration is given to the development of a behaviour-optimised bioinspired probabilistic attachment system that is thermodynamically inert due to attachment substructures, such as interlocking setae, that act as arrestors and temporary interlocking devices. The three devices of part 2 are considered for their relative merits, and one part is modelled for a rapid prototyping device. If one is considering the question of shape versus material, then it is at this stage that it is a very important issue since one is considering fundamental, simple shapes and the materials used to form them are of finite variety. Hence, the final design will hinge upon design for manufacture and component material qualities, in this case copper. PMID- 27218017 TI - Corrigendum to "Middle East Respiratory Syndrome Coronavirus Outbreak in the Republic of Korea, 2015" [Volume 6, Issue 4, August 2015, 269-278]. AB - [This corrects the article DOI: 10.1016/j.phrp.2015.08.006.]. PMID- 27218014 TI - Chlamydial Antibiotic Resistance and Treatment Failure in Veterinary and Human Medicine. AB - The Chlamydiaceae are widespread pathogens of both humans and animals. Chlamydia trachomatis infection causes blinding trachoma and reproductive complications in humans. Chlamydia pneumoniae causes human respiratory tract infections and atypical pneumonia. Chlamydia suis infection is associated with conjunctivitis, diarrhea, and failure to gain weight in domestic swine. Chlamydial infections in humans and domesticated animals are generally controlled by antibiotic treatment particularly macrolides (usually azithromycin) and tetracyclines (tetracycline and doxycycline). Tetracycline-containing feed has also been used to limit infections and promote growth in livestock populations, although its use has decreased because of growing concerns about antimicrobial resistance development. Because Sandoz and Rockey published an elegant review of chlamydial anti microbial resistance in 2010, we will review the following: (i) antibiotic resistance in C. suis, (ii) recent evidence for acquired resistance in human chlamydial infections, and (iii) recent non-genetic mechanisms of antibiotic resistance that may contribute to treatment failure. PMID- 27218018 TI - Comparative Anatomy and Facial Aging in the Animal Kingdom. PMID- 27218019 TI - Considerations for the Management of Medial Orbital Wall Blowout Fracture. AB - Recently, diagnoses of and operations for medial orbital blowout fracture have increased because of the development of imaging technology. In this article, the authors review the literature, and overview the accumulated knowledge about the orbital anatomy, fracture mechanisms, surgical approaches, reconstruction materials, and surgical methods. In terms of surgical approaches, transcaruncular, transcutaneous, and transnasal endoscopic approaches are discussed. Reconstruction methods including onlay covering, inlay implantation, and repositioning methods are also discussed. Consideration and understanding of these should lead to more optimal outcomes. PMID- 27218020 TI - Melatonin Protects Human Adipose-Derived Stem Cells from Oxidative Stress and Cell Death. AB - BACKGROUND: Adipose-derived stem cells (ASCs) have applications in regenerative medicine based on their therapeutic potential to repair and regenerate diseased and damaged tissue. They are commonly subject to oxidative stress during harvest and transplantation, which has detrimental effects on their subsequent viability. By functioning as an antioxidant against free radicals, melatonin may exert cytoprotective effects on ASCs. METHODS: We cultured human ASCs in the presence of varying dosages of hydrogen peroxide and/or melatonin for a period of 3 hours. Cell viability and apoptosis were determined with propidium iodide and Hoechst 33342 staining under fluorescence microscopy. RESULTS: Hydrogen peroxide (1-2.5 mM) treatment resulted in an incremental increase in cell death. 2 mM hydrogen peroxide was thereafter selected as the dose for co-treatment with melatonin. Melatonin alone had no adverse effects on ASCs. Co-treatment of ASCs with melatonin in the presence of hydrogen peroxide protected ASCs from cell death in a dose-dependent manner, and afforded maximal protection at 100 uM (n=4, one-way analysis of variance P<0.001). Melatonin co-treated ASCs displayed significantly fewer apoptotic cells, as demonstrated by condensed and fragmented nuclei under fluorescence microscopy. CONCLUSIONS: Melatonin possesses cytoprotective properties against oxidative stress in human ASCs and might be a useful adjunct in fat grafting and cell-assisted lipotransfer. PMID- 27218021 TI - Clinical Features and Management of a Median Cleft Lip. AB - BACKGROUND: Median cleft lip is a rare anomaly consisting of a midline vertical cleft through the upper lip. It can also involve the premaxillary bone, the nasal septum, and the central nervous system. In our current report, we present the clinical features of 6 patients with a median cleft lip and their surgical management according to the accompanying anomalies. METHODS: From December 2010 to January 2014, 6 patients with a median cleft lip were reviewed. Five of these cases underwent surgical correction; alveolar bone grafting was performed in a patient with a median alveolar cleft. The surgical technique included inverted-U excision of the upper lip and repair of the orbicularis oris muscle. The mean follow-up period was 20.4 months (range, 7.4-44.0 months). RESULTS: The study patients presented various anomalous features. Five patients received surgical correction, 4 with repair of the median cleft lip, and one with iliac bone grafting for median alveolar cleft. A patient with basal sphenoethmoidal meningocele was managed with transoral endoscopic surgery for repair of the meningocele. Successful surgical repair was achieved in all cases with no postoperative complications. CONCLUSIONS: Relatively mild forms of median cleft lip can be corrected with inverted-U excision with good aesthetic outcomes. In addition, there is a broad spectrum of clinical features and various anomalies, such as nasal deformity, alveolar cleft, and short upper frenulum, which require close evaluation. The timing of the operation should be decided considering the presence of other anomalies that can threaten patient survival. PMID- 27218022 TI - Outcomes of Primary Unilateral Cheiloplasty in Same-Day Surgical Settings. AB - BACKGROUND: Financial, clinical, and psychological considerations have made same day surgery an attractive option for a variety of procedures. This article aimed to analyse the postoperative results of same-day primary unilateral cleft nasolabial repair. METHODS: This study was performed from 2011 to 2014. Unilateral cleft lip patients fulfilling the inclusion criteria were preoperatively classified as mild, moderate, and severe. All patients underwent same-day surgery and were discharged after satisfying the appropriate clinical criteria, receiving thorough counselling, and the establishment of a means of communication by phone. Postoperative outcomes were assessed and stratified according to preoperative severity and the type of repair. RESULTS: A total of 423 primary unilateral cleft lip patients were included. Fisher's anatomical subunit approximation technique was the most common procedure, followed by Noordhoff's technique. The postoperative outcome was good in 89.8% of cases, fair in 9.9% of cases, and poor in 0.2% of cases. The complication rate was 1.18% (n=5), and no instances of mortality were observed. The average hospital stay was 7.5 hours, leading to a cost reduction of 19% in comparison with patients who stayed overnight for observation. CONCLUSIONS: Mild unilateral cleft lip was the most common deformity for which Fisher's anatomical subunit approximation technique was performed in most of the cases, with satisfactory postoperative outcomes. Refinements in the cleft rhinoplasty techniques over the course of the study improved the results regarding cleft nasal symmetry. Single-day primary unilateral cleft cheiloplasty was found to be a cost-effective procedure that did not pose an additional risk of complications. PMID- 27218023 TI - Postoperative Speech Outcomes and Complications in Submucous Cleft Palate Patients. AB - BACKGROUND: The postoperative speech outcomes of submucous cleft palate (SMCP) surgery are known to be poorer than those of other types of cleft palate. We attempted to objectively characterize the postoperative complications and speech outcomes of the surgical treatment of SMCP through a comparison with the outcomes of incomplete cleft palate (ICP). METHODS: This study included 53 SMCP patients and 285 ICP patients who underwent surgical repair from 1998 to 2015. The average age of the patients at the time of surgery was 3.9+/-1.9 years for the SMCP patients and 1.3+/-0.9 years for the ICP patients. A retrospective analysis was performed of the complications, the frequency of subsequent surgical correction for velopharyngeal dysfunction (VPD), and speech outcomes. RESULTS: In both the SMCP and ICP patients, no cases of respiratory difficulty, bleeding, or wound disruption were noted. Delayed wound healing and fistula occurred in 18.9% and 5.7% of the SMCP patients and in 14% and 3.2% of the ICP patients, respectively. However, no statistically significant difference in either delayed wound healing or fistula occurrence was observed between the two groups. The rate of surgical correction for VPD in the SMCP group was higher than in the ICP group. In the subset of 26 SMCP patients and 62 ICP patients who underwent speech evaluation, the median speech score value was 58.8 in the SMCP group and 66 in the ICP group, which was a statistically significant difference. CONCLUSIONS: SMCP and ICP were found to have similar complication rates, but SMCP had significantly worse speech outcomes. PMID- 27218024 TI - Management of the Sequelae of Severe Congenital Abdominal Wall Defects. AB - BACKGROUND: The survival rate of newborns with severe congenital abdominal wall defects has increased. After successfully addressing life-threatening complications, it is necessary to focus on the cosmetic and functional outcomes of the abdominal wall. METHODS: We performed a chart review of five cases treated in our institution. RESULTS: Five patients, ranging from seven to 18 years of age, underwent the following surgical approaches: simple approximation of the rectus abdominis fascia, the rectus abdominis sheath turnover flap, the placement of submuscular tissue expanders, mesh repair, or a combination of these techniques depending on the characteristics of each individual case. CONCLUSIONS: Patients with severe congenital abdominal wall defects require individualized surgical treatment to address both the aesthetic and functional issues related to the sequelae of their defects. PMID- 27218025 TI - Orofacial Soft Tissue Reconstruction with Locoregional Flaps in a Health Resource Depleted Environment: Experiences from Nigeria. AB - BACKGROUND: Reconstruction of orofacial soft tissue defects is often challenging due to functional and aesthetic demands. Despite advances in orofacial soft tissue defect reconstruction using free flaps, locoregional flaps still remain an important option, especially in health resource-depleted environments. This retrospective study highlights our experiences in oral and maxillofacial soft tissue reconstruction using locoregional flaps. METHODS: A twenty-three years retrospective analysis of all patients managed in our department was undertaken. Information was sourced from patients' case notes and operating theater records. Data was analyzed using SPSS ver. 16 (SPSS Inc.) and Microsoft Excel 2007 (Microsoft). RESULTS: A total of 77 patients underwent orofacial soft tissue defect reconstruction within the years reviewed. Males accounted for 55 (71.4%) cases and trauma was the main etiological factor in 45 (58.4%) of the patients treated. When sites of defect were considered, the lip, 27 (32.1%), was the most frequent site followed by the nose, 17 (20.2%). Forehead flap, 51 (59.3%), was the most commonly used flap. Complications noted were tumor recurrences at the recipient bed in 3 (3.9%) cases, tumor occurrence at the donor site in 1 (1.3%) case and postoperative infection in 11 (14.3%) cases. CONCLUSIONS: Locoregional flaps still have an important role in the rehabilitation of patients with orofacial soft tissue defects. They remain a vital tool in the armamentarium of the reconstructive surgeon, especially in health resource-depleted environments where advanced reconstructive techniques may not be feasible. PMID- 27218026 TI - The Onset and Duration of Action of 0.2% Lidocaine in a One-per-Mil Tumescent Solution for Hand Surgery. AB - BACKGROUND: One-per-mil tumescent solution, which contains 0.2% lidocaine with 1:1,000,000 epinephrine, has been reported to be clinically effective for hand surgery under local anesthesia. However, it was lacking in its basic pharmacokinetics profile in regard to the onset of action (OOA) and duration of action (DOA). METHODS: A randomized, double-blind study was conducted on 12 volunteers who met the inclusion criteria from October to November 2014. All volunteers had their right and left ring finger pulps injected with either one per-mil solution or 2% lidocaine. Semmes-Weinstein and two-point discrimination tests were used to test sensation. Visual analogue scale was recorded at the time when the finger lost its sensation and when it regained normal sensation to measure the OOA and DOA. The data were then analyzed with a paired t-test and a Wilcoxon signed-rank test. RESULTS: The OOA and DOA of 2% plain lidocaine were 1 minute and 99.67 minutes, respectively. Meanwhile, 0.2% lidocaine in a one-per mil tumescent solution showed an OOA of 5 minutes and a DOA of 186.83 minutes. The OOA of 0.2% lidocaine in a one-per-mil tumescent solution is statistically shorter than 2% plain lidocaine (P=0.04); while its DOA is statistically longer than 2% plain lidocaine (P<0.001). CONCLUSIONS: The 0.2% lidocaine in a one-per mil tumescent solution is statistically and clinically superior to 2% plain lidocaine in achieving longer duration of local anesthesia. PMID- 27218027 TI - A Legal Analysis of the Precedents of Medical Disputes in the Cosmetic Surgery Field. AB - BACKGROUND: Disputes regarding medical malpractice occur between practitioners and patients. As patients have become increasingly aware regarding medical care, an increase in the unexpected side effects of procedures has been observed, thereby leading to an increase in disputes regarding medical malpractice. In this study, we reviewed trends in precedents involving cosmetic surgery-related medical disputes, with the goal of helping to prevent unnecessary disputes in the future. METHODS: We conducted a search of the judgments made in South Korean courts between 2000 and 2013 that were related to the field of plastic surgery. A total of 54 judgments were analyzed, and the selected precedents were reviewed and classified according to the kind of negligence involved. RESULTS: The claim amounts ranged from under 8 million KRW (6,991 USD) to 750 million KRW (629,995 USD). The most common ratio of the judgment amount to the claim amount was 20% 30%. The judgments were classified according to the following categories: violation of the duty of explanation in 17 cases (29%), violation of the duty of care in 10 cases (17%), violation of both duties in 20 cases (35%), and no violation of duty in six cases (10%). CONCLUSIONS: Cosmetic surgery-related suits require different approaches than general malpractice suits. The Supreme Court requires plastic surgeons to determine the type, timing, methods, and scope of their treatments when considering possible results. Therefore, practitioners should be educated on their rights and responsibilities to enable them to cope with any possible medical dispute that may arise. PMID- 27218028 TI - A Rare Case of Pulmonary Epithelioid Hemangioendothelioma Presenting with Skin Metastasis. AB - Epithelioid hemangioendothelioma (EHE) is a well-differentiated and rare vascular tumor. Systemic metastases are uncommon. Herein, we present a patient with skin metastasis of pulmonary EHE (PEH) that was treated by wide excision. A 76-year old male was evaluated due to pulmonary thromboembolism and a solitary pulmonary nodule. A biopsy was performed and pathological examination of the mass confirmed EHE. No metastasis was observed. The patient returned to care approximately two years later due to a painful nodule in the right lower leg. A skin biopsy showed metastatic EHE from the lung. We used a safety margin of 1 cm based on clinical experience, because no prior case had been reported regarding the resection margin appropriate for primary cutaneous EHE and skin metastases of PEH. At four months after surgery, the patient recovered without complications or recurrence. Skin metastasis of PEH is extremely rare, and only two cases have been reported in the literature. In this case, we report a rare case of PEH with histologically diagnosed skin metastasis that was successfully treated by curative resection. It is expected that this case report will provide a helpful contribution to the extant data regarding PEH metastases. PMID- 27218029 TI - Fat Harvest Using a Closed-Suction Drain. AB - We propose a safe, simple, and novel method to harvest fat using a standard liposuction cannula and a Redivac or alternative closed-suction drain. The authors have used this technique for both 'dry' and 'wet' liposuction. This technique is both easy to perform and cost-effective whilst providing both a silent and relatively atraumatic fat harvest. The lower negative pressure compared with traditional harvesting systems likely preserves fat integrity for lipofilling. This method maximises resources already held within a hospital environment. PMID- 27218030 TI - Inconspicuous Nasoethmoidal Encephalocele Might Be Wrongly Diagnosed. PMID- 27218031 TI - Response To Dr. Tang Letter to Editor: Inconspicuous Nasoethmoidal Encephalocele Might Be Wrongly Diagnosed. PMID- 27218032 TI - Forehead Inclination in the Lateral Profile in Koreans. PMID- 27218033 TI - Sepsis Leading to Mortality after Augmentation Rhinoplasty with a Septal Extension Graft and Fat Grafting. PMID- 27218034 TI - Trichoblastic Carcinoma Arising from a Nevus Sebaceous. PMID- 27218035 TI - Bilateral Atypical Ductal Hyperplasia with Microcalcifications in a Patient with Gynecomastia. PMID- 27218036 TI - Acute Calcific Tendinitis in the Distal Interphalangeal Joint. PMID- 27218037 TI - Multiple Epidermal Cysts in the Volar Skin of the Thumb. PMID- 27218038 TI - An Evolutionary Understanding of Aging. PMID- 27218039 TI - External Fixation vs. Skeletal Traction for Treatment of Intertrochanteric Fractures in the Elderly. AB - BACKGROUND: Hip fractures are one of the causes of disability amongst elderly patients. External fixator and skeletal traction are two modes of treatment. OBJECTIVES: The aim of this study is to compare two different treatment modes for intertrochanteric fractures in elderly patients. PATIENTS AND METHODS: Sixty elderly patients with intertrochanteric fractures were randomized for treatment with either skeletal traction (Group A) or an external fixation (Group B). In this study patients at least 60 years of age, with AO/OTA A1 or A2 type fracture and intertrochanteric fracture as a result of minor trauma, were enrolled. RESULTS: Acceptable reduction was achieved in eight and 26 patients of group A and B, respectively. The mean duration of hospitalization in Group A and Group B was 14.3 +/- 1.1 and 2.2 +/- 0.6 days, respectively. Significant differences between the two groups were observed, regarding acceptable reduction and duration of hospitalization. Less pain was observed in group B, at five days and twelve months after surgery; the average HHS was 57 and 66, in group A and B, respectively (P > 0.05). CONCLUSIONS: Treatment with an external fixator is an effective treatment modality for intertrochanteric fractures in elderly high-risk patients. The advantages include rapid and simple application, insignificant blood loss, less radiation exposure, adequate fixation, pain reduction, early discharge from the hospital, low cost and more favorable functional outcome. PMID- 27218040 TI - Squat Winnowing: Cause of Meniscus Injuries in Non-Athletic Females. AB - BACKGROUND: Sports activities were thought to be the major cause of meniscus injury in both men and woman, but our observations of non-athletic females show that the cause of meniscus injury was unrelated to any type of sports activity. OBJECTIVES: This study revealed squat winnowing to be a major cause of meniscus injury in non-athletic females. PATIENTS AND METHODS: This retrospective study was conducted in a tertiary care orthopaedic hospital which caters to a population of 10 million people. We assessed 120 non-athletic females who had received treatment in our hospital over a period of 2 years. The most probable cause of knee injury, per initial patient history, was recorded for all non athletic females who presented clinical signs and symptoms of meniscus injury. The diagnoses were confirmed by relevant MRI and arthroscopy of patients' knees. All females who engaged in athletic activity and other females with unrelated, non-traumatic knee pathologies were excluded from the study. RESULTS: Through our study, we found that 42% (n = 50) of females suffered an injury during squat winnowing of rice, either at home or at work. Another 29% (n = 35) of females cited a history of slipping and spraining their knee as a cause of knee injury, while 19% (n = 16) of females suffered a knee injury during complex accidents such as a traffic accident. Finally, 13% (n = 16) of the females had no definite history of knee injury. CONCLUSIONS: Our observations add to the knowledge base of the various causes of meniscus tears; this study also revealed that socio cultural factors influence and contribute to the mechanism of various types of knee injury. PMID- 27218041 TI - Recurrent Dislocation of The Extensor Carpi Ulnaris Tendon in a Water-Polo Athlete. AB - INTRODUCTION: Dislocation/subluxation of the Extensor Carpi Ulnaris (ECU) tendon is a rare condition in the general population, but is a common problem among athletes that subject their wrists to forceful rotational movements. Pain and snapping sensation at the dorsoulnar aspect of the wrist especially during supination are the predominant symptoms that often necessitate surgical intervention. CASE PRESENTATION: We present a case of a professional water-polo athlete with recurrent ECU tendon dislocation, in whom a combination of direct repair of the tendon's subsheath and reinforcement with an extensor retinaculum graft led to definitive resolution of her symptoms and resulted in her uneventful return to high-level sport activities 4 months postoperatively. CONCLUSIONS: The treatment of symptomatic ECU instability is still controversial, especially for acute dislocations. Depending on the type of injury many surgical techniques have been proposed. Combination of direct repair of the tendon's subsheath and reinforcement with an extensor retinaculum graft is a reliable option. PMID- 27218042 TI - Efficacy of Intravenous Paracetamol Versus Intravenous Morphine in Acute Limb Trauma. AB - BACKGROUND: Efficient pain management is one of the most important components of care in the field of emergency medicine. OBJECTIVES: This study was conducted to compare intravenous paracetamol and intravenous morphine sulfate for acute pain reduction in patients with limb trauma. PATIENTS AND METHODS: In a randomized double-blinded clinical trial, all patients (aged 18 years and older) with acute limb trauma and a pain score of greater than 3/10 in the emergency department were recruited; they received either 1 g intravenous paracetamol or 0.1 mg/kg intravenous morphine sulfate over 15 minutes. The primary outcome was the pain score measured on a numerical rating scale at 0, 15 and 30 minutes after commencing drug administration. The requirement for rescue analgesia and the frequency of adverse reactions were also recorded. RESULTS: Sixty patients randomly received either IV paracetamol (n = 30) or IV morphine (n = 30). The mean reduction in numerical rating scale pain intensity scores at 30 minutes was 3.86 (+/- 1.61) for paracetamol, and 2.16 (+/- 1.39) for morphine. However, pain relief was significantly higher in the paracetamol group compared to the morphine group (P < 0.001). Four patients in the paracetamol group and 15 patients in the morphine group needed rescue analgesia and the difference was significant (P = 0.05). CONCLUSIONS: Intravenous paracetamol appears to provide better analgesia than intravenous morphine in acute limb trauma. Further larger studies are required. PMID- 27218043 TI - Effective Factors in Door-to-Needle Time for Streptokinase Administration in Patients With Acute Myocardial Infarction Admitted to the Emergency Department. AB - BACKGROUND: Cardiovascular incidents are a common cause of death around the world. Acute myocardial infarction (AMI) poses high risks for the patient due to plaque rupture or erosion along with a superimposed non-occlusive thrombus; therefore, timely treatment with antithrombotic agents plays a key role in reducing an AMI mortality rate. OBJECTIVES: The present study aimed to assess the time interval between the admission of AMI-suspected patients and treatment initiation. PATIENTS AND METHODS: This cross-sectional study was conducted on 110 patients admitted to the emergency department of Imam Hussein hospital in Tehran, Iran. Data were collected using checklists, completed by the patients' next of kin or the emergency staff. To analyze the data, student t- test and analysis of variance were used. RESULTS: In this study, 31 female and 79 male subjects were included, respectively. The mean time to receive the first dose of streptokinase was 66.39 minutes (73.74 minutes for females and 63.5 minutes for male patients), varying from 49.92 minutes in the morning to 69.78 minutes in the afternoon and 72.68 minutes during night shifts. CONCLUSIONS: The door-to-needle (DTN) time, in a standard setting, is recommended to be less than 30 minutes. According to the results of this study, the DTN time is comparatively two times longer in females and afternoon and night shifts. Different variables including emergency staff, physicians, patients' characteristics, and environmental/physical factors induced this difference. PMID- 27218044 TI - Missed Traumatic Thoracic Spondyloptosis With no Neurological Deficit: A Case Report and Literature Review. AB - INTRODUCTION: Traumatic thoracic spondyloptosis is caused by high energy trauma and is usually associated with severe neurological deficit. Cases presenting without any neurological deficit can be difficult to diagnose and manage. CASE PRESENTATION: We reported a four-week spondyloptosis of the ninth thoracic vertebra over the tenth thoracic vertebra, in a 20-year-old male without any neurological deficit. The patient had associated chest injuries. The spine injury was managed surgically with in-situ posterior instrumentation and fusion. The patient tolerated the operation well and postoperatively there was no neurological deterioration or surgical complication. CONCLUSIONS: Patients presenting with spondyloptosis with no neurological deficit can be managed with in-situ fusion via pedicle screws, especially when presenting late and with minimal kyphosis. PMID- 27218045 TI - Readability of Trauma-Related Patient Education Materials From the American Academy of Orthopaedic Surgeons. AB - CONTEXT: According to the american medical association (AMA) and the national institutes of health (NIH), the recommended readability of patient education materials should be no greater than a sixth-grade reading level. The online patient education information produced by the american academy of orthopaedic surgeons (AAOS) may be too complicated for some patients to understand. This study evaluated whether the AAOS's online trauma-related patient education materials meet recommended readability guidelines for medical information. EVIDENCE ACQUISITION: Ninety-nine articles from the "Broken Bones and Injuries" section of the AAOS-produced patient education website, orthoinfo.org, were analyzed for grade level readability using the Flesch-Kincaid formula, a widely used and validated tool to evaluate the text reading level. Results for each webpage were compared to the AMA/NIH recommended sixth-grade reading level and the average reading level of U.S. adults (eighth-grade). RESULTS: The mean (SD) grade level readability for all patient education articles was 8.8 (1.1). All but three of the articles had a readability score above the sixth-grade level. The readability of the articles exceeded this level by an average of 2.8 grade levels (95% confidence interval, 2.6 - 3.0; P < 0.0001). Furthermore, the average readability of the articles exceeded the average reading skill level of U.S. adults (eighth grade) by nearly an entire grade level (95% confidence interval, 0.6-1.0; P < 0.0001). CONCLUSIONS: The majority of the trauma-related articles from the AAOS patient education website have readability levels that may make comprehension difficult for a substantial portion of the patient population. PMID- 27218047 TI - Simultaneous, Isolated Traumatic Bilateral Patella Fractures. AB - INTRODUCTION: Isolated traumatic fractures of both Patellae, occurring at the same time, in an otherwise healthy person, are very rare. The Patella, as a subcutaneous and a cancellous bone, is vulnerable to injury. However, simultaneous injury to both Patellae without the involvement of any other bony injuries occurs infrequently, and only a few cases have been reported in the literature. CASE PRESENTATION: We report a rare case of isolated, traumatic bilateral Patella fracture with unusual fracture patterns and briefly review the literature. CONCLUSIONS: In simultaneous bilateral Patella fractures, good functional outcome can be expected following a stable surgical fixation and a structured rehabilitation regime. However, personality of the fracture determines salvage versus sacrifice of the Patella. PMID- 27218046 TI - Outcome of Radial Head Arthroplasty in Comminuted Radial Head Fractures: Short and Midterm Results. AB - BACKGROUND: Comminuted radial head fractures are often associated with secondary injuries and elbow instability. OBJECTIVES: The aim of this retrospective study was to evaluate how well the modular metallic radial head implant EVOLVE(r) prosthesis restores functional range of motion (ROM) and stability of the elbow in acute care. PATIENTS AND METHODS: Eighty-five patients with comminuted radial head fractures and associated injuries received treatment with an EVOLVE(r) prosthesis between May 2001 and November 2009. Seventy-five patients were available for follow-up. On average, patients were followed for 41.5 months (33.0: 4.0 - 93.0). Outcome assessment was done on the basis of pain, ROM, strength, radiographic findings, and functional rating scores such as Broberg and Morrey, the Mayo elbow performance index (MEPI), and disabilities of the arm, shoulder and hand (DASH). Our study is currently the largest analysis of clinical outcome of a modular radial head replacement in the literature. RESULTS: Overall, there were 2 (2.7%) Mason II fractures, 21 (28%) Mason III fractures, and 52 (69.3%) Mason IV fractures. Arbeitsgemeinschaft fur osteosynthesefragen (AO) classification was also determined. Of the 85 patients in our study, 75 were available for follow-up. Follow-up averaged 41.5 months (range, 4 - 93 months). Average scores for the cohort were as follows: Morrey, 85.7 (median 90.2; range 44.4 - 100); MEPI, 83.3 (85.0; 40.0 - 100); and DASH 26.1 points (22.5; 0.0 - 75.8). Mean flexion/extension in the affected joint was 125.7 degrees /16.5 degrees /0 degrees in comparison to the noninjured side 138.5 degrees /0 degrees /1.2 degrees . Mean pronation/supination was 70.5 degrees /0 degrees /67.1 degrees in comparison to the noninjured side 83.6 degrees /0 degrees /84.3 degrees . Handgrip strength of the injured compared to the non-injured arm was 78.8%. The following complications were also documented: 58 patients had periprosthetic radioluceny shown to be neither clinically significant nor relevant according to evaluated scores; 26 patients had moderate or severe periarticular ossification, and scored substantially worse according to MEPI and Morrey. Four patients required revisional surgery due to loosening of the prosthesis and chronic pain. In addition, one patient required a neurolysis of the ulnaris nerve, one developed a neobursa, and one had extensive swelling and blistering. The time interval between injury and treatment appeared to have an effect on results. Thirty-five patients were treated within the first 5 days after accident and showed better results than the 40 patients who were treated after 5 days. CONCLUSIONS: Comminuted radial head fractures with elbow instability can be treated well with a modular radial head prosthesis, which restores stability in acute treatment. The modular radial head arthroplasty used in this study showed promising findings in short to midterm results. PMID- 27218048 TI - A New Injury Severity Score for Predicting the Length of Hospital Stay in Multiple Trauma Patients. AB - BACKGROUND: Trauma is a leading cause of morbidity and mortality among individuals under 40 and is the third main cause for death throughout the world. OBJECTIVES: This study was designed to compare our modified injury scoring systems with the current injury severity score (ISS) from the viewpoint of its predictive value to estimate the duration of hospitalization in trauma patients. PATIENTS AND METHODS: This analytical cross-sectional study was performed at the general referral trauma center of Bandar-Abbas in southern Iran from March 2009 to March 2010. The study population consisted of all the trauma patients referred to the emergency department (ED). Demographic data, type and severity of injury, duration of admission, Glasgow coma scale (GCS), and revised trauma score (RTS) were recorded. The injury severity score (ISS) and NISS were calculated. The length of hospital stay was recorded during the patients follow-up and compared with ISS, NISS and modified injury scoring systems. RESULTS: Five hundred eleven patients (446 males (87.3%) and 65 females (12.7%)) were enrolled in the study. The mean age was 22 +/- 4.2 for males and 29.15 +/- 3.8 for females. The modified NISS had a relatively strong correlation with the length of hospitalization (r = 0.79). The formula below explains the length of hospitalization according to MNISS score. Duration of hospitalization was 0.415 + (2.991) MNISS. Duration of hospitalization had a strong correlation with MISS (r = 0.805, R2: 0.65). Duration of hospitalization was 0.113 + (7.915) MISS. CONCLUSIONS: This new suggested scale shows a better value to predict patients' length of hospital stay compared to ISS and NISS. However, future studies with larger sample sizes and more confounding factors such as prehospital procedures, intubation and other procedures during admission, should be designed to examine these scoring systems and confirm the results of our study. PMID- 27218049 TI - Recurrence in a Laparoscopically Repaired Traumatic Diaphragmatic Hernia: Case Report and Literature Review. AB - INTRODUCTION: Traumatic diaphragmatic hernia (TDH) develops infrequently following a traumatic diaphragmatic rupture (TDR). As TDR is frequently missed due to lack of sensitive and specific imaging modalities, a high index of suspicion for such injuries is essential, whether immediately posttraumatic, or even decades after the trauma. We describe a rare case of recurrence in a laparoscopically repaired TDH and review the current literature on the same. CASE PRESENTATION: A 23-year-old male with a history of primary laparoscopic repair of left-sided TDR two years ago presented with symptoms of acute large bowel obstruction. His chest X-ray showed a left-sided pleural effusion and a loop of the bowel in the left hemithorax, but no signs of free gas. An abdominal X-ray (AXR) demonstrated massively dilated large bowel with distension of the small bowel. At laparotomy, the obstructing lesion consisted of the large bowel with omentum herniated through the left hemidiaphragm, consistent with a left recurrent/chronic diaphragmatic hernia. The diaphragmatic defect was repaired with interrupted nylon. The patient made an uneventful recovery. CONCLUSIONS: Recurrence after repair of TDH is a less reported condition (with only two published articles) and little is known regarding the factors responsible for this. Laparoscopy is an excellent diagnostic tool, but currently management is probably best performed via an open technique using heavy non-absorbable suture material to prevent recurrence. Long term follow up of these patients should also be considered. PMID- 27218050 TI - Unusual Foreign Bone Fragment in Femoral Open Fracture. AB - INTRODUCTION: Femoral shaft fracture is one of the typical bone fractures due to high energy trauma and may occur as an open fracture. Some foreign materials may enter the fracture site such as sand, cloth particles and so on. CASE PRESENTATION: A 28-year-old motorcycle riding military member and his collaborator were received in the hospital because of multiple traumas due to a fall in a hollow during a surveillance mission. His collaborator died because of head trauma and multiple severe open fractures. When fixing the patients femoral fracture, a large femoral butterfly fragment was removed from the patient's thigh as a foreign segment. The patient's femur was fixed with a plate and screws. No femoral defect was detected during surgery or post-operative X-rays and CT scan. The removed segment was not a part of the patient's femur. CONCLUSIONS: Surgical and post-surgical findings showed that this segment was not related to the patient's femur. The foreign segment may have belonged to the other victim of this trauma. PMID- 27218052 TI - Nonsyndromic Isolated Temporal Bone Styloid Process Fracture. AB - INTRODUCTION: Fracture of the styloid process (SP) of the temporal bone is a rare traumatic injury in normal individuals who are not suffering from Eagle's syndrome. Diagnosis and management of this problem requires comprehensive knowledge about its signs and symptoms. This study aimed to present an isolated styloid process fracture in a nonsyndromic patient. CASE PRESENTATION: A 50-year old male patient was referred to our department with a complaint of sore throat. However, presentation of the problem resembled the symptoms of temporomandibular joint disorder (TMD). Fracture of the SP of the temporal bone was detected on the radiographs. Conservative treatment was undertaken for the patient. The symptoms diminished after about four months. CONCLUSIONS: Physicians should be aware of the signs and symptoms of different pain sources to prevent misdiagnosis and maltreatment. PMID- 27218051 TI - A Selective Corrective Exercise to Decrease Falling and Improve Functional Balance in Idiopathic Parkinson's Disease. AB - BACKGROUND: Posture instability and unsteady gait disorders in Parkinson's Disease (PD) usually contribute to fall-related fractures. Fall-related trauma in PD is the most common reason for injury. Despite providing modern care for PD patients (PP) in the recent years, anti-PD drugs have no effect on falling. There is an urgent need to administer exercise interventions to reduce falls and related injuries in the rehabilitation program of PP. OBJECTIVES: To explore the effect of a selective 10-week corrective exercise with an emphasis on gait training activities (GTA) on the number of falls (NOFs), fear of falling, functional balance, timed up and go (TUG) test among PD patients. PATIENTS AND METHODS: A purposeful sampling was performed on PP who had fallen or were at risk of falling in 2014. The study intervention consisted of a 10-week (3 sessions each week, each lasting 60 min) corrective exercise program. Participants were randomly allocated to control and two exercise groups; the exercise group with balance pad (EGBP) or exercise group with no balance pad (EGNBP). The analysis of variance (ANOVA) and paired t-test were used for comparison between the groups (P <= 0.05). RESULTS: Administrating a selective corrective exercise in exercise group with balance pad (EGBP) showed a significant difference in number of falls (NOF), Fall Efficacy Scale-international (FES-I), Berg balance scale (BBS) (and timed up and go) TUG (P = 0.001); while administrating the same exercise in exercise group with no balance pad (EGNBP) showed no significant difference in NOF (P = 0.225) and a significant difference in FES-I (P = 0.031), BBS (P = 0.047) and TUG (P = 0.012). The control group showed no significant difference in each of the dependent variables. CONCLUSIONS: Performing a selective corrective exercise on balance pad improves falling and functional balance in idiopathic PD. PMID- 27218053 TI - Comparison of Roll Stitch Technique and Core Suture Technique for Extensor Tendon Repair at the Metacarpophalangeal Joint level. AB - BACKGROUND: Proper suturing technique is needed to ensure good outcome in extensor tendon surgery. Different techniques have been reported for the repair of extensor tendon injuries at the level of the metacarpophalangeal joint (MCPJ). These reports were in vitro studies on cadaver models. Repair techniques must be clinically tested, to determine results. OBJECTIVES: The purpose of this in vivo study was to compare results of extensor tendon repair, using roll stitch and core suture techniques. PATIENTS AND METHODS: Forty two fingers, in 38 patients (aged 15- 45 years), with simple complete extensor tendon injuries in the MCPJ area, were identified and operated by a single surgeon. The patients were divided into two groups, according to the technique used for tendon repair. The first group consisted of 21 digits, in 19 patients, who were repaired with roll stitch technique, while the second group consisted of 21 digits, in 19 patients, who were repaired with core suture technique. The same splint and rehabilitation regimen (early passive range of motion) were given to all patients. The splints were removed at 6 weeks after surgery and range of motion of the operated fingers was measured and compared to uninjured hands, after 12 weeks. RESULTS: Five patients were lost to follow up or excluded from the study. There was no rupture of the repaired tendons in the groups. There was no statistically significant difference in mean MCPJ flexion, proximal interphalangeal joint (PIPJ) flexion, distal interphalangeal joint (DIPJ) flexion and total range of motion of the fingers, between the two groups. However, extension lag was significantly more common in the second group (11 of 19 digits) compared the first group (four of 17 digits). CONCLUSIONS: Roll stitch technique had superior outcome compared to the modified Kessler technique, when performed in the MCPJ area. LEVEL OF EVIDENCE: Therapeutic (Level III). PMID- 27218054 TI - Effect of Job Specialization on the Hospital Stay and Job Satisfaction of ED Nurses. AB - BACKGROUND: In recent decades, the increasing crowdedness of the emergency departments has posed various problems for patients and healthcare systems worldwide. These problems include prolonged hospital stay, patient dissatisfaction and nurse burnout or job dissatisfaction. OBJECTIVES: The aim of this study was to investigate the effect of emergency department (ED) nurses' job specialization on their job satisfaction and the length of patient stay in the ED. PATIENTS AND METHODS: This before-after quasi-experimental study was conducted from April to May 2014 at the Baqiyatallah Hospital, Tehran, Iran. Initially, 35 patients were recruited as controls and the length of their stay in the ED was measured in minutes via a chronometer; Moreover, nurses' job satisfaction was evaluated using the Mohrman-Cooke-Mohrman job satisfaction scale. Then, a job specialization intervention was developed based on the stabilization model. After that, 35 new patients were recruited to the treatment group and received specialized care services. Accordingly, the length of their stay in the ED was measured. Moreover, the same nurses' job satisfaction was re evaluated after the study. The study intervention lasted one month. Data were analyzed using the SPSS software version 20 and statistical tests such as the Kolmogrov-Smirnov, the paired and the independent t, and chi-square tests. RESULTS: There was a significant difference between the two groups of patients concerning the length of their stay in the ED (P < 0.001). Moreover, compared with the pretest readings, nurses had greater job satisfaction after the study (P < 0.001). CONCLUSIONS: The job specialization intervention can improve nurses' satisfaction and relieve the crowdedness of the EDs. PMID- 27218055 TI - Overview of Agents Used for Emergency Hemostasis. AB - CONTEXT: In today's modern world, despite the multiple advances made in the field of medicine, hemorrhagic shock is still the main cause of battlefield mortality and the second most prevalent cause of mortality in civilian trauma. Hemostatic agents can play a key role in establishing hemostasis in prehospital situations and preventing hemorrhage-associated death. In this respect, this article aims to review different aspects of known hemostatic agents. EVIDENCE ACQUISITION: A comprehensive search of the academic scientific databases for relevant keywords was conducted; relevant articles were compiled and assessed. RESULTS: Hemostatic agents can establish hemostasis by means of different mechanisms, including concentrating coagulation factors, adhesion to the tissues, in which traumatic hemorrhage occurred, and delivering procoagulant factors to the hemorrhage site. Presently, these hemostatics have been significantly improved with regard to efficacy and in adverse consequences, resulting from their use. Several hemostatic dressings have been developed to the degree that they have received FDA approval and are being used practically on the battlefield. In addition, there are currently several case reports on the use of such hemostatics in the hospital setting, in conditions where commonly known approaches fail to stop life threatening bleeding. CONCLUSIONS: The use of hemostatic dressings and agents is one of the main advancements achieved in recent decades. However, it can be claimed that the ideal hemostatic has not been recognized yet; therefore, this topic needs to be brought into focus and further addressed. PMID- 27218056 TI - Limitation of Mandibular Movement: A Rare Case Report of Unilateral Zygomatico Coronoid Interference. AB - INTRODUCTION: Zygomatico-coronoid interference is a rare type of mandibular extracapsular ankylosis. There is a lack of information on the treatment of these cases in the literature. Condylectomy and coronoidectomy are not always the best options for the treatment of limitations in mandibular movement. CASE PRESENTATION: A 51-year-old woman presented with mouth-opening limitation due to zygomatic bone displacement and interference with the coronoid process. The treatment plan was bilateral coronoidectomy through an intraoral approach and osteotomy of the right zygomatic arch through an extraoral incision. The patient was able to open her mouth to approximately 40 mm after surgery. The patient underwent physiotherapy during follow-up appointments. There was no relapse after three months of follow-up. CONCLUSIONS: This study shows that simultaneous arch osteotomy and coronoidectomy may be an appropriate treatment procedure for zygomatico-coronoid interference. PMID- 27218057 TI - Effects of Normobaric Hyperoxia in Traumatic Brain Injury: A Randomized Controlled Clinical Trial. AB - BACKGROUND: Traumatic brain injury (TBI) is one of the important causes of morbidity and mortality throughout the world, especially in young people. In recent years normobaric hyperoxia has become an important and useful step for recovery and improvement of outcome in TBI. OBJECTIVES: The purpose of this study was to evaluate the effects of normobaric hyperoxia on clinical neurological outcomes of patients with severe traumatic brain injuries. We used the Glasgow outcome scale (GOS), barthel index, and modified rankin scale (mRS) to measure the outcomes of patients with TBI. PATIENTS AND METHODS: Sixty-eight consecutive patients with severe TBI (mean Glasgow coma scale [GCS] score: 7.4) who met the inclusion criteria were entered in this randomized controlled clinical trial. The patients were randomized into two groups, as follows: 1) experimental: received 80% oxygen via mechanical ventilator in the first 6 hours of admission, 2) control: received 50% oxygen by mechanical ventilator in the first 6 hours of admission and then standard medical care. We measured the GOS, Barthel Index, and mRS at the time of discharge from hospital and reassessed these measurements at the 6-month follow-up after injury. RESULTS: According to our study, there were no significant sex or age differences between the two groups (P = 0.595 and 0.074). The number of days in the intensive care unit (ICU) in the control group and experimental group were 11.4 and 9.4 days, respectively (P = 0.28), while the numbers of days of general ward admission were 13.9 and 11.4 days (P = 0.137) respectively. The status of GOS at time of discharge were severe = 13 and 10, moderate = 16 and 19, and low = 5 and 5 in the control and experimental groups, respectively (P = 0.723); 6 months after injury, the scores were as follows: moderate = 16 and 9, low = 15 and 25, and severe = 3 and 0 (P = 0.024). The Barthel index scores in the control and experimental groups were 59.7 and 63.9 at time of discharge (P = 0.369) and 82.7 and 91.3 at 6 months after injury (P = 0.018), respectively. The mRS results were 2.6 and 2.3 at time of discharge (P = 0.320) and 1.6 and 0.7 at 6 months after injury (P = 0.006) for the control and experimental groups, respectively. CONCLUSIONS: According to the results of this study, oxygen therapy by mechanical ventilator in the first 6 hours after injury in patients with severe TBI can improve the final GOS, Barthel index, and mRS scores. It could also improve long-term outcomes and enhance rehabilitation and the quality of life. PMID- 27218058 TI - Efficacy of Pedicle Screw Fixation in Unstable Upper and Middle Thoracic Spine Fractures. AB - BACKGROUND: Treatment of unstable upper and middle thoracic spine fractures remains controversial. There is no consensus regarding optimal treatment. OBJECTIVES: In this study, we evaluated the efficacy of pedicular screw in the management of middle thoracic spine fractures to correct kyphosis and anterolisthesis and improve neurologic condition of patients. PATIENTS AND METHODS: Twenty-five patients with unstable T1-T10 fractures treated with pedicle screw fixation technique were studied. Neurologic situation, preoperative and postoperative radiographs were evaluated. Radiographic measurements included kyphotic deformity and anterolisthesis. An American Spinal Injury Association (ASIA) scale was used for neurologic classification of the patients. RESULTS: From a total of 25 patients, 21 cases were male and 4 were female. The mean age of the patients was 35.40 +/- 14.39 years. The mean degree of kyphosis improved from 27.04 +/- 7.33 degrees preoperatively to 15.96 +/- 5.76 degrees at final follow-up. The mean of anterolisthesis improved from 6.44 +/- 4.93 mm to 0.96 +/- 0.36 mm at final follow-up. Kyphosis (P = 0.0001), anterolisthesis (P = 0.0001) and neurological state (P = 0.01) improved significantly after operation. No cases of hardware failure, neurological deterioration and loss of correction were reported. CONCLUSIONS: Application of pedicular screw in unstable upper and middle thoracic spine fractures is an effective method that can correct kyphotic deformity and anterolisthesis and improve neurologic deficit. PMID- 27218059 TI - Physical and Mental Health of Patients Immediately After Discharge From Intensive Care Unit and 24 Hours Later. AB - BACKGROUND: Monitoring the health status of patients discharged from intensive care units is a crucial method of service evaluation. OBJECTIVES: This study aimed to assess the physical and mental health status of patients immediately after discharge from the ICU and 24 hours later. PATIENTS AND METHODS: This descriptive comparative study was conducted on 104 patients discharged from the ICUs of a referral trauma center in Shiraz, Southwest Iran. Physical parameters, including respiratory rate, need for supplemental oxygen, heart rate, blood pressure, and need for cardiac monitoring, were assessed. Hospital anxiety and depression scale (HADS) was used for mental health evaluation. The mental and physical status of patients were assessed before ICU discharge and 24 hours later; data were recorded in information forms and were analyzed using SPSS statistical software version 17. RESULTS: At the time of discharge, the respiratory rate of 28% of the participants was more than 24 minutes, and 95.2% received supplemental oxygen. However, after 24 hours these values decreased to 10% and 21.6%, respectively. The mean heart rate and systolic blood pressure were within the normal range at both time points. Additionally, 63% of the patients had anxiety scores above 11 at both time points, reflecting high anxiety. The number of patients who reported depression increased from 58.7% at ICU discharge to 69.6% after 24 hours. CONCLUSIONS: Despite the considerable improvement in most of the patients' physical condition in the first 24 hours after discharge from ICU, a significant number of them remain at risk for the development of adverse effects from this transition. The high prevalence of mental health disorders in these patients reveals the necessity to conduct follow-up consultations. PMID- 27218060 TI - Serum 25-Hydroxyvitamin D Levels in Pediatric Burn Patients. AB - BACKGROUND: Previous studies have implicated the important and active role of vitamin D in the immune system. OBJECTIVES: The aim of this study was to evaluate serum levels of 25-hydroxyvitamin D in children with burn injuries. MATERIALS AND METHODS: In this cross-sectional study, 118 patients with various degrees of burn injuries were enrolled. A checklist consisting of demographic data, total body surface area (TBSA) affected by burn, degree of burn, serum level of 25(OH)D, total protein, albumin, electrolytes, and parathyroid hormone was recorded for each patient. RESULTS: Sixty-eight (57.6%) males and 50 (42.4%) females with a mean age of 4.04 years (SD = 3.04) were evaluated. The mean level of 25(OH)D was 14.58 ng/mL (SD = 6.94). Levels of 25(OH)D in four (3.39%) cases were higher than 30 ng/mL, while 95 (81.35%) cases had levels lower than 20 ng/mL, and 19 (16.10%) cases had levels of 21 - 30 ng/mL. The level of 25(OH)D was below recommended levels in 96.61% of cases, while 81.34% had vitamin D deficiency and 16.1% had insufficiency. We found a significant correlation between vitamin 25(OH)D and total protein, albumin, and total and ionized calcium (P < 0.001). There was also a significant negative correlation between 25(OH)D and TBSA affected by burn (P = 0.001). CONCLUSIONS: The levels of 25(OH)D in children suffering from severe burns were low. Supplementation might be useful in patients with very low levels of serum vitamin D. PMID- 27218061 TI - A Prospective Study of Survival After In-Hospital Cardiopulmonary Resuscitation and its Related Factors. AB - BACKGROUND: Despite several studies, there is no agreement on factors that affect survival after in-hospital cardiopulmonary resuscitation (CPR). OBJECTIVES: This study aimed to evaluate the survival rate of in-hospital CPR and its related factors at Shahid Beheshti hospital in Kashan, Iran, in 2014. PATIENTS AND METHODS: A descriptive study was conducted on all cases of CPR performed in Kashan Shahid Beheshti hospital during a 6-month period in 2014. Through a consecutive sampling method, 250 cases of CPR were studied. A three-part researcher-made instrument was used. The outcome of CPR was documented as either survival to hospital discharge or unsuccessful (death of the patient). Chi-square test, t test, and logistic regression analysis were used to analyze the data. RESULTS: Of all CPR cases, 238 (95.2%) were unsuccessful and 12 (4.8%) survived to hospital discharge. Only 2.6% of patients who were resuscitated in medical units survived to hospital discharge, whereas this rate was 11.4% in the emergency department. Only 45 (18%) patients were defibrillated during resuscitation; in 11 patients, defibrillation was performed between 15 to 45 minutes after the initiation of CPR. The mean time from initiation of CPR to the first DC shock was 13.93 +/- 8.88 minutes. Moreover, the mean duration of CPR was 35.11 +/- 11.42 minutes. The survival rate was higher in the morning shift and lower during the time of shift change (9.4% vs. 0). The duration of CPR and speed of arrival of the CPR team were identified as factors that predicted the outcome of CPR. CONCLUSIONS: The survival rate after in-hospital CPR was very low. The duration of CPR and the time of initiating CPR effects patients' outcomes. These findings highlight the crucial role of an organized, skilled, well-established and timely CPR team. PMID- 27218062 TI - Bilateral Abducent Nerve Palsy After Neck Trauma: A Case Report. AB - INTRODUCTION: The abducent nucleus is located in the upper part of the rhomboid fossa beneath the fourth ventricle in the caudal portion of the pons. The abducent nerve courses from its nucleus, to innervate the lateral rectus muscle. This nerve has the longest subarachnoid course of all the cranial nerves, it is the cranial nerve most vulnerable to trauma. It has been reported that 1% to 2.7% of all head injuries are followed by unilateral abducent palsy, but bilateral abducent nerve palsy is extremely rare. CASE PRESENTATION: A 65-year-old woman presented to the emergency department following a motor vehicle accident. A neurological assessment showed the patient's Glascow coma scale (GCS) to be 15. She complained of double vision, and we found lateral gaze palsy in both eyes. A hangman fracture type IIA (C2 fracture with posterior ligamentous C1 - C2 distraction) was found on the cervical CT scan. A three-month follow-up of the patient showed complete recovery of the abducent nerve. CONCLUSIONS: Conservative treatment is usually recommended for traumatic bilateral abducent nerve palsy. Our patient recovered from this condition after three months without any remaining neurological deficit, a very rare outcome in a rare case. PMID- 27218063 TI - National Getaways for the Weary Trauma Surgeon; Part 6: Chal Nakhjir, a Living 7 Million-Year-Old Cave! PMID- 27218065 TI - University Students' Views Regarding Reasons for Drug Abuse Among Youths. PMID- 27218064 TI - Individual Factors of Social Acceptance in Patients Infected With Human Immunodeficiency Virus (HIV) at the Yazd Behavioral Consultation Center in Iran. AB - BACKGROUND: A considerable number of patients infected with HIV also have mental health problems. Individual psychotherapy is an effective way to treat these issues. Lack of social acceptance is a barrier to patients receiving proper medication and emotional/psychological support. OBJECTIVES: The purpose of this study was to examine the individual factors of social acceptance in patients infected with human immunodeficiency virus. PATIENTS AND METHODS: Fifty HIV infected patients who were registered in the Behavioral Consultation Center entered the study. Each of them filled out a questionnaire based on the Crown Marlow social acceptance scale. Their answers were evaluated according to the questionnaire key. RESULTS: Forty-five patients (90%) were male and five (10%) were female. Their ages ranged between 28 and 52 years old. Other variables researched in this study include patients' age, sex, education, occupation, place of living, marital status, family history of HIV, and family history of psychological disorders. Employed patients experienced more social acceptance than housewives and people who were unemployed or retired. CONCLUSIONS: This study showed that HIV-infected patients with jobs enjoy a great deal of acceptance from the people around them and a higher quality of life in general. It also led to suggestions for further study with the purpose of finding more effective solutions for HIV prevention and better strategies for dealing with psychological disorders. Such research could also help in providing an enhanced understanding of the potential psychological impact that AIDS has on patients in Iran. PMID- 27218066 TI - Comparative Study of the Activity of Brain Behavioral Systems in Methamphetamine and Opiate Dependents. AB - BACKGROUND: Substance dependency is a major problem for the general health of a society. Different approaches have investigated the substance dependency in order to explain it. Gray's reinforcement sensitivity theory (RST) is an advanced and important neuropsychological theory in this area. OBJECTIVES: The aim of this study was to compare three systems of the revised reinforcement sensitivity theory the behavioral activation system (r-BAS), the revised behavioral inhibition system (r-BIS), and the revised fight/flight/freezing system (r-FFFS) between patients dependent on methamphetamine and opiates, and a group of controls. PATIENTS AND METHODS: This research was a causal-comparative study that was conducted in the first six months of 2012. The population of the study was males of Mashhad city, who were dependent on methamphetamine or opiates, and ruling out psychotic disorders and prominent Axis II. Twenty-five people were selected by the convenient sampling method. Also, 25 non-dependent people from the patients' relatives were selected and matched for the variables of age, gender, and education to participate in this study. Participants were evaluated using a structured clinical interview (SCID) for DSM-IV, demographic questionnaire information, and a Jackson-5 questionnaire (2009). Data were analyzed by Chi-square, K-S, and independent t-test. RESULTS: The methamphetamine dependent group had a higher sensitivity in the r-BAS, r-BIS, and the r-Fight and r-Freezing systems compared to the control group (P < 0.05). However, there was no significant difference in r-Flight between the two groups (P > 0.05). "The scores of r-BIS were also significantly higher in the methamphetamine-dependent group than the opioid-dependent and control groups. For the r-Fight variable, the methamphetamine-dependent group was higher than the opioid-dependent group". CONCLUSIONS: The personality patterns of patients dependent on methamphetamines were different from the controls. These people have a high sensitivity to punishment cues, such as being compared in social conditions and a tendency for reinforcement and reward, because of their higher sensitivity in the behavioral inhibition and activation systems. PMID- 27218067 TI - Female Sexual Dysfunction Among the Wives of Opioid-Dependent Males in Iran. AB - BACKGROUND: Opiate abuse in males has significant effects on their sexual functions. In contrast, sexuality in females is a multidimensional issue that can strongly be affected by several factors in their partners. However, only a limited number of studies have assessed the role of males' opioid dependency in their female partners' sexual function. OBJECTIVES: The present study aimed to evaluate the effect of males' opioid dependency on their wives' sexual function compared to the sexual function of the females whose husbands were not opioid dependent. PATIENTS AND METHODS: This study included 340 women who were selected through convenience sampling and divided into a control (females whose husbands were not opioid dependent) and a case group (women whose husbands were opioid dependent). The data were collected through an interview according to the DSM-IV R criteria for female sexual dysfunctions by a senior female medical student who was one of the researchers. Finally, the data were entered into the SPSS statistical software (v. 15) and analyzed using the t-test and chi-square test. RESULTS: According to the results, the frequency of hypoactive sexual desire disorder and sexual aversion disorder in the control group was significantly higher than that of the case group (P < 0.05). CONCLUSIONS: The results showed that having an addicted husband could strongly affect some sexual domains in women. It could change the pattern of desire and motivation for sexual contact in females and alter their attitude toward the sexual relationship, thereby causing disturbances in the females' normal sexual function. PMID- 27218070 TI - RBO or Brazilian Orthopaedic Journal. PMID- 27218068 TI - The Relationship of Parental Mental Health and Dietary Pattern With Adolescent Mental Health. AB - BACKGROUND: Today, ensuring people's health and well-being has become a concern for societies. Health status results from an interaction of an individuals' various psychological, social, and physical aspects. OBJECTIVES: This study aims to investigate the relationship of parental mental health and dietary pattern with adolescent mental health. PATIENTS AND METHODS: In this study, 250 high school students in Shiraz were selected using random cluster sampling. The samples were analyzed using the Food Frequency Questionnaire (FFQ) and the General Health Questionnaire (GHQ-28). RESULTS: According to the findings, parental mental health explains 22% of the variance in children's mental health, so that in simultaneous regression, physical dimensions, anxiety, social functioning, and depression predicted 13%, 24%, 11%, and 24% of the variance of criterion variables, respectively. No significant relationship was observed between dietary pattern and adolescent mental health dimensions. There was a significant negative relationship only between depression and vegetable intake. Moreover, fruit (r = 0.15, P < 0.05) and vegetable (r = 0.16, P < 0.05) intake had a significant relationship with parental mental health dimensions. CONCLUSIONS: Parents' mental health and their psychological characteristics can be related to children's mental health and affect their dietary intake patterns. PMID- 27218069 TI - New therapeutic strategies for the treatment of male lower urinary tract symptoms. AB - Male lower urinary tract symptoms (LUTS) are prevalent in the general population, especially in those of advanced age, and are characterized by notable diversity in etiology and presentation, and have been proven to cause various degrees of impairment on quality of life. The prostate has traditionally been regarded as the core cause of male LUTS. As a result, medical treatment aims to provide symptomatic relief and effective management of progression of male LUTS due to benign prostatic enlargement. In this context, alpha1-blockers, phosphodiesterase 5 inhibitors, and 5alpha-reductase inhibitors have long been used as monotherapies or in combination treatment to control voiding LUTS. There is accumulating evidence, however, that highlights the role of the bladder in the pathogenesis of male LUTS. Current research interests have shifted to bladder disorders, and medical management is aimed at the bladder. Muscarinic receptor antagonists and the newly approved beta3-adrenergic agonist mirabegron aim to alleviate the most bothersome storage LUTS and thus improve quality of life. As voiding and storage LUTS frequently coexist, combination therapeutic strategies with alpha1-blockers and antimuscarinics or beta3-agonists have been introduced to manage symptoms effectively. Anti-inflammatory agents, vitamin D3-receptor analogs, and cannabinoids represent treatment modalities currently under investigation for use in LUTS patients. Furthermore, luteinizing hormone releasing hormone antagonists, transient receptor-potential channel blockers, purinergic neurotransmission antagonists, Rho-kinase inhibitors, and inhibitors of endothelin-converting enzymes could have therapeutic potential in LUTS management, but still remain in the experimental setting. This article reviews new strategies for the medical treatment of male LUTS, which are dictated by the potential role of the bladder and the risk of benign prostatic hyperplasia progression. Moreover, combination treatments and therapies currently under investigation are also presented. PMID- 27218071 TI - The role of pharmacotherapy in modifying the neurological status of patients with spinal and spinal cord injuries. AB - The aim here was to conduct a review of the literature on pharmacological therapies for modifying the neurological status of patients with spinal cord injuries. The PubMed database was searched for articles with the terms "spinal cord injury AND methylprednisolone/GM1/apoptosis inhibitor/calpain inhibitor/naloxone/tempol/tirilazad", in Portuguese or in English, published over the last five years. Older studies were included because of their historical importance. The pharmacological groups were divided according to their capacity to interfere with the physiopathological mechanisms of secondary injuries. Use of methylprednisolone needs to be carefully weighed up: other anti-inflammatory agents have shown benefits in humans or in animals. GM1 does not seem to have greater efficacy than methylprednisolone, but longer-term studies are needed. Many inhibitors of apoptosis have shown benefits in in vitro studies or in animals. Naloxone has not shown benefits. Tempol inhibits the main consequences of oxidation at the level of the spinal cord and other antioxidant drugs seem to have an effect superior to that of methylprednisolone. There is an urgent need to find new treatments that improve the neurological status of patients with spinal cord injuries. The benefits from treatment with methylprednisolone have been questioned, with concerns regarding its safety. Other drugs have been studied, and some of these may provide promising alternatives. Additional studies are needed in order to reach conclusions regarding the benefits of these agents in clinical practice. PMID- 27218072 TI - Postoperative infection in patients undergoing inspection of orthopedic damage due to external fixation. AB - OBJECTIVE: To conduct a retrospective analysis on cases undergoing inspection of orthopedic damage, at an orthopedic emergency service in a teaching hospital, with the aim of evaluating patients with postoperative infection after conversion to internal osteosynthesis. METHODS: This was a retrospective analysis covering the period from June 2012 to June 2013, on patients who underwent inspection of orthopedic damage due to external fixation and subsequently were converted to definitive osteosynthesis using a nail or plate. RESULTS: We found an infection rate of 13.3% in our sample and, furthermore, found that there had been technical errors in setting up the fixator in 60.4% of the cases. CONCLUSION: We found an infection rate that we considered high, along with inadequacies in constructing the external fixator. We emphasize that this procedure is not risk-free and that training for physicians who perform this procedure should be mandatory. PMID- 27218073 TI - Surgical treatment of avulsion fractures at the tibial insertion of the posterior cruciate ligament: functional result. AB - OBJECTIVE: To objectively and subjectively evaluate the functional result from before to after surgery among patients with a diagnosis of an isolated avulsion fracture of the posterior cruciate ligament who were treated surgically. METHOD: Five patients were evaluated by means of reviewing the medical files, applying the Lysholm questionnaire, physical examination and radiological examination. For the statistical analysis, a significance level of 0.10 and 95% confidence interval were used. RESULTS: According to the Lysholm criteria, all the patients were classified as poor (<64 points) before the operation and evolved to a mean of 96 points six months after the operation. We observed that 100% of the posterior drawer cases became negative, taking values less than 5 mm to be negative. CONCLUSION: Surgical methods with stable fixation for treating avulsion fractures at the tibial insertion of the posterior cruciate ligament produce acceptable functional results from the surgical and radiological points of view, with a significance level of 0.042. PMID- 27218074 TI - Length of preoperative hospital stay: a risk factor for reducing surgical infection in femoral fracture cases. AB - OBJECTIVE: To analyze infections of the surgical site among patients undergoing clean-wound surgery for correction of femoral fractures. METHODS: This was a historical cohort study developed in a large-sized hospital in Belo Horizonte. Data covering the period from July 2007 to July 2009 were gathered from the records in electronic medical files, relating to the characteristics of the patients, surgical procedures and surgical infections. The risk factors for infection were identified by means of statistical tests on bilateral hypotheses, taking the significance level to be 5%. Continuous variables were evaluated using Student's t test. Categorical variables were evaluated using the chi-square test, or Fisher's exact test, when necessary. For each factor under analysis, a point estimate and the 95% confidence interval for the relative risk were obtained. In the final stage of the study, multivariate logistic regression analysis was performed. RESULTS: 432 patients who underwent clean-wound surgery for correcting femoral fractures were included in this study. The rate of incidence of surgical site infections was 4.9% and the risk factors identified were the presence of stroke (odds ratio, OR = 5.0) and length of preoperative hospital stay greater than four days (OR = 3.3). CONCLUSION: To prevent surgical site infections in operations for treating femoral fractures, measures involving assessment of patients' clinical conditions by a multiprofessional team, reduction of the length of preoperative hospital stay and prevention of complications resulting from infections will be necessary. PMID- 27218075 TI - Rotator cuff injuries: current perspectives and trends for treatment and rehabilitation. AB - OBJECTIVE: To map out the approaches used by Brazilian orthopedists in treating complete tears of the rotator cuff. METHODS: A multiple-choice questionnaire was handed out to 232 orthopedists at the 45th Brazilian Congress of Orthopedics and Traumatology. Of these, 207 were returned but five were incomplete and were excluded. Thus, 202 questionnaires were used. RESULTS: Among the orthopedists who answered the questionnaires, around 60% were from the southeastern region and 46% were shoulder and elbow surgeons. There was a significant association (p < 0.05) between length of experience and number of rotator cuff repairs performed per year. There was also a significant association (p < 0.05) between shoulder specialty and the following variables: arthroscopic technique, use of anchors in a single-row configuration, mean time taken for an indication for surgery to be made in cases of traumatic and degenerative lesions, use of a specific protocol for postsurgical rehabilitation, return to sport and indication of irreparable injuries. CONCLUSIONS: Brazilian shoulder surgeons have well-established approaches toward treating rotator cuff injuries. Most of these approaches differ significantly from those of other specialties. This shows the importance of placing value on training in preparing shoulder specialists in this country. PMID- 27218076 TI - Evaluation of the results and complications of the Latarjet procedure for recurrent anterior dislocation of the shoulder. AB - OBJECTIVE: Evaluate the results and complications of Latarjet procedure in patients with anterior recurrent dislocation of the shoulder. METHODS: Fifty-one patients (52 shoulders) with anterior recurrent dislocation, surgically treated by Latarjet procedure, were analyzed retrospectively. The average follow-up time was 22 months, range 12-66 months; The age range was 15-59 years with a mean of 31; regarding sex, 42 (82.4%) patients were male and nine (17.6%) were female. The dominant side was affected in 29 (55.8%) shoulders. Regarding the etiology, 48 (92.3%) reported trauma and four (7.6%) had the first episode after a convulsion. RESULTS: The average elevation, lateral rotation and medial rotation of the operated shoulder were, respectively, 146 degrees (60-80 degrees ), 59 degrees (0-85 degrees ) and T8 (T5 gluteus), with statistical significance for decreased range of motion in all planes, compared with the other side. The scores of Rowe and UCLA were 90.6 and 31.4, respectively, in the postoperative period. Eleven shoulders (21.2%) had poor results: signs of instability (13.4%), non union (11.5%) and early loosening of the synthesis material (1.9%). There was a correlation between poor results and convulsive patients (p = 0.026). CONCLUSION: We conclude that the Latarjet procedure for correction of anterior recurrent dislocation leads to good and excellent results in 82.7% of cases. Complications are related to errors in technique. PMID- 27218077 TI - Evaluation of elbow flexion following free muscle transfer from the medial gastrocnemius or transfer from the latissimus dorsi, in cases of traumatic injury of the brachial plexus. AB - OBJECTIVE: To compare the gain in elbow flexion in patients with traumatic injury of the brachial plexus following muscle transfer from latissimus dorsi with the gain following free muscle transfer from the medial belly of the gastrocnemius. METHODS: This was a retrospective study in which the medical files of a convenience sample of 13 patients operated between 2000 and 2010 were reviewed. Group 1 comprised seven patients who underwent transfers from the gastrocnemius and group 2 (controls) comprised six patients who underwent transfers from the latissimus dorsi. The following functions were evaluated: (1) range of motion (ROM) of elbow flexion, in degrees, using manual goniometry and (2) grade of elbow flexion strength, using a muscle strength scale. Satisfactory results were defined as: (1) elbow flexion ROM >= 80 degrees and (2) elbow flexion strength >= M3. The Fisher exact and Kruskal-Wallis tests were used (p < 0.05). RESULTS: The patients' mean age was 32 years (range: 17-56) and 72% had been involved in motorcycle accidents. Elbow flexion strength >= M3 was observed in seven patients (100%) in group 1 and in five patients (83.3%) in group 2 (p = 0.462). None of the patients presented M5, and one patient (16.7%) in group 2 had a poor result (M2). Elbow flexion ROM with a gain >= 80 degrees (daily functions) was found in six patients (86%) in group 1 and in three patients (50%) in group 2 (p = 0.1). CONCLUSION: The patients in group 1 had greater gains in strength and ROM than did those in group 2, but without statistical significance. Thus, transfers from the gastrocnemius become a new surgical option, if other techniques cannot be used. PMID- 27218078 TI - Arthroplasty of the distal ulna distal in managing patients with post-traumatic disorders of the distal radioulnar joint: measurement of quality of life. AB - OBJECTIVE: To measure the quality of life and clinical-functional results from patients diagnosed with osteoarthrosis of the distal radioulnar joint who underwent surgical treatment using the technique of total arthroplasty of the ulna, with a total or partial Ascension((r)) prosthesis of the distal ulna. METHODS: Ten patients were evaluated after 12 months of follow-up subsequent to total or partial arthroplasty of the distal ulna. All of them presented post traumatic osteoarthrosis and/or chronic symptomatic instability of the distal radioulnar joint. The study was prospective. Seven patients had previously undergone wrist procedures (two cases with Darrach, three with Sauve-Kapandji and two with ligament reconstruction of the fibrocartilage complex) and three presented fractures of the distal ulna that evolved with pain, instability and osteoarthrosis of the distal radioulnar joint. The following were assessed: quality of life (DASH scale); percentage degree of palm grip strength (kgf) and pronosupination range of motion in relation to the unaffected side; pain (VAS); return to work; subjective evaluation of radiography; and complications. RESULTS: The patients presented a mean range of motion of 174.5 degrees (normal side: 180 degrees ). Quality of life was analyzed by applying the DASH questionnaire and the mean value found was 5.9. The mean pain score using the VAS was 2.3. The mean degree of palm grip strength (kgf) was 50.7, which represented 90.7% of the strength on the unaffected side. The complication rate was 10%: this patient presented slight dorsal instability of the ulna and persistent pain, and did not return to work. This patient is still being followed up in the outpatient clinic and occupational therapy sector, with little improvement. He does not wish to undergo a new procedure. The mean length of follow-up was 16.8 months, with a minimum of 10 and maximum of 36 months. CONCLUSION: This concept is subject to the test of time. Implantation of a prosthesis is a very interesting addition to the surgical arsenal for those who are specialists in hand surgery. Arthroplasty of the distal ulna is a safe and effective method with clinical-functional and quality-of-life improvements for patients and presents a low complication rate. PMID- 27218079 TI - Anatomical study on the innervation of the elbow capsule. AB - OBJECTIVES: To put forward an anatomical description of the innervation of the elbow capsule, illustrated through morphological analysis on dissections. METHODS: Thirty elbows from fresh fixed adult cadavers aged 32-74 years, of both sexes, were dissected. RESULTS: Among the dissected arms, we observed that the median nerve did not have any branches in two arms, while it had one branch in five arms, two branches in two arms, three branches in ten arms, four branches in nine arms and five branches in two arms. The radial nerve did not have any branches in two arms, while it had one branch in two arms, two branches in nine arms, three branches in ten arms, four branches in five arms and five branches in two arms. The ulnar nerve did not have any branches in three arms, while it had one branch in six arms, two branches in four arms, three branches in five arms, four branches in seven arms, five branches in four arms and six branches in one arm. CONCLUSIONS: We observed branches of the radial, ulnar and medial nerves in the elbow joint, and a close relationship between their capsular and motor branches. PMID- 27218080 TI - Intra and interobserver concordance between the different classifications used in Legg-Calve-Perthes disease. AB - OBJECTIVE: The aim of this study was to determine the intra and interobserver concordance rates of the Waldenstrom, Catterall and Herring classifications for Legg-Calve-Perthes disease. METHODS: One hundred radiographs of the pelvis in anteroposterior and Lauenstein views, from patients with this disease, were selected. The radiographs were classified by four physicians with different levels of experience who had previously been given guidance regarding the classifications used, in order to minimize any bias of interpretation. The radiographs were examined by the same observers at two different times in order to evaluate the intra and interobserver concordance. Reproducibility was assessed using the kappa index. RESULTS: The concordance analysis was stratified into levels (poor, slight, fair, moderate, good and excellent). The intraobserver analysis showed, for the Waldenstrom classification, moderate concordance for three examiners and fair for one; for Herring, excellent for one examiner and good for three; and for Catterall, good for all the examiners. The interobserver analysis showed: for the three classification systems, no situations of excellent concordance; for Waldenstrom, four situations of fair concordance, one moderate and one slight; for Herring, four situations of moderate concordance, one good and one fair; and for Catterall, four situations of moderate concordance and two fair. CONCLUSION: The classifications studied are the ones most used for guiding the treatment for Legg-Calve-Perthes disease, but the degree of intra and interobserver concordance is far from ideal. Complementary staging systems need to be taken into consideration, so that there can be greater certainty regarding the treatment. PMID- 27218081 TI - Migration and strains induced by different designs of force-closed stems for THA. AB - OBJECTIVES: Subtle differences in stem design can result in different mechanical responses of the total hip arthroplasty. Tests measuring migration of the stem relative to the femur, as well as the strains in the cement mantle and on the femur can detect different mechanical behavior between stems. METHODS: In this article, conical, double and triple tapered stems were implanted in composite femurs and subjected to static and cyclic loads. Stems differed mainly on taper angle, calcar radius and proximal stiffness. Stem migration and strains on the femur and in the cement mantle were achieved. RESULTS: Significant differences (p < 0.05) were noted in the permanent rotation between double and triple tapers, in the strains on the proximal medial femur between triple and both conical and double tapers, and in the strains on the lateral proximal femur between double tapers and both conical and triple tapers. CONCLUSION: The proposed mechanical tests were able to detect significant differences in the behavior of these resembling stems. Stem proximal stiffness and the calcar radius of the stem influence its rotational stability and the strain transmission to the femur. PMID- 27218082 TI - Characterization of hip and knee arthroplasties and factors associated with infection. AB - OBJECTIVE: To characterize arthroplasty procedures, calculate the surgical infection rate and identify related risk factors. METHODS: This was a retrospective cohort study. Data on operations performed between 2010 and 2012 were gathered from documental sources and were analyzed with the aid of statistical software, using Fisher's exact test, Student's t test and the nonparametric Mann-Whitney and Wilcoxon tests. RESULTS: 421 total arthroplasty procedures performed on 346 patients were analyzed, of which 208 were on the knee and 213 on the hip. It was found that 18 patients (4.3%) were infected. Among these, 15 (83.33%) were reoperated and 2 (15.74%) died. The prevalence of infection in primary total hip arthroplasty procedures was 3%; in primary total knee arthroplasty, 6.14%; and in revision of total knee arthroplasty, 3.45%. Staphylococcus aureus was prevalent. The length of the surgical procedure showed a tendency toward being a risk factor (p = 0.067). CONCLUSION: The prevalence of infection in cases of primary total knee arthroplasty was greater than in other cases. No statistically significant risk factors for infection were identified. PMID- 27218083 TI - Clinical-radiographic correlation of the femoral insertion point of the graft in reconstruction of the medial patellofemoral ligament. AB - OBJECTIVE: To analyze the radiographic positioning of the femoral tunnel and correlate this with the postoperative clinical results among patients undergoing reconstruction of the medial patellofemoral ligament (MPFL) alone. METHOD: This was a retrospective study in which 30 knees of 26 patients with recurrent dislocation of the patella that underwent MPFL reconstruction were evaluated. The femoral insertion point of the graft and the postoperative clinical condition were analyzed and correlated using the Kujala and Lysholm scales. RESULTS: 22 knees presented a femoral tunnel in the anatomical area (group A) and 8 outside of this location (group B). In group A, the mean score on the Kujala scale was 89.68 points and on the Lysholm scale was 92.45 points. In group B, the mean score on the Kujala scale was 84.75 points and on the Lysholm scale was 92 points. The difference between the means was not significant on either of the two scales. CONCLUSION: Correlation with the clinical results did not show any difference in relation to the positioning of the femoral insertion of the graft. PMID- 27218084 TI - Functional results from reconstruction of the anterior cruciate ligament using the central third of the patellar ligament and flexor tendons. AB - OBJECTIVES: To evaluate knee function in patients undergoing reconstruction of the anterior cruciate ligament (ACL) using the central third of the patellar ligament or the medial flexor tendons of the knee, i.e. quadruple ligaments from the semitendinosus and gracilis (ST-G), by means of the Knee Society Score (KSS) and the Lysholm scale. METHODS: This was a randomized prospective longitudinal study on 40 patients who underwent arthroscopic ACL reconstruction between September 2013 and August 2014. They comprised 37 males and three females, with ages ranging from 16 to 52 years. The patients were numbered randomly from 1 to 40: the even numbers underwent surgical correction using the ST-G tendons and the odd numbers, using the patellar tendon. Functional evaluations were made using the KSS and Lysholm scale, applied in the evening before the surgical procedure and six months after the operation. RESULTS: From the statistical analysis, it could be seen that the patients' functional capacity was significantly greater after the operation than before the operation. There was strong evidence that the two forms of therapy had similar results (p = >0.05), in all the comparisons. CONCLUSIONS: The results from the ACL reconstructions were similar with regard to functional recovery of the knee and improvement of quality of life, independent of the type of graft. It was not possible to identify the best method of surgical treatment. The surgeon's clinical and technical experience and the patient are the factors that determine the choice of graft type for use in ACL surgery. PMID- 27218085 TI - Diagnosis of knee injuries: comparison of the physical examination and magnetic resonance imaging with the findings from arthroscopy. AB - OBJECTIVES: To ascertain the sensitivity, specificity, accuracy and concordance of the physical examination (PE) and magnetic resonance imaging (MRI) in comparison with arthroscopy, in diagnosing knee injuries. METHODS: Prospective study on 72 patients, with evaluation and comparison of PE, MRI and arthroscopic findings, to determine the concordance, accuracy, sensitivity and specificity. RESULTS: PE showed sensitivity of 75.00%, specificity of 62.50% and accuracy of 69.44% for medial meniscal (MM) lesions, while it showed sensitivity of 47.82%, specificity of 93.87% and accuracy of 79.16% for lateral meniscal (LM) lesions. For anterior cruciate ligament (ACL) injuries, PE showed sensitivity of 88.67%, specificity of 94.73% and accuracy of 90.27%. For MM lesions, MRI showed sensitivity of 92.50%, specificity of 62.50% and accuracy of 69.44%, while for LM injuries, it showed sensitivity of 65.00%, specificity of 88.46% and accuracy of 81.94%. For ACL injuries, MRI showed sensitivity of 86.79%, specificity of 73.68% and accuracy of 83.33%. For ACL injuries, the best concordance was with PE, while for MM and LM lesions, it was with MRI (p < 0.001). CONCLUSIONS: Meniscal and ligament injuries can be diagnosed through careful physical examination, while requests for MRI are reserved for complex or doubtful cases. PE and MRI used together have high sensitivity for ACL and MM lesions, while for LM lesions the specificity is higher. Level of evidence II - Development of diagnostic criteria on consecutive patients (with universally applied reference "gold" standard). PMID- 27218086 TI - How to classify plantar plate injuries: parameters from history and physical examination. AB - OBJECTIVE: To find the best clinical parameters for defining and classifying the degree of plantar plate injuries. METHOD: Sixty-eight patients (100 metatarsophalangeal joints) were classified in accordance with the Arthroscopic Anatomical Classification for plantar plate injuries and were divided into five groups (0 to IV). Their medical files were reviewed and the incidence of each parameter for the respective group was correlated. These parameters were: use of high heels, sports, acute pain, local edema, Mulder's sign, widening of the interdigital space, pain in the head of the corresponding metatarsal, touching the ground, "drawer test", toe grip and toe deformities (in the sagittal, coronal and transversal planes). RESULTS: There were no statistically significant associations between the degree of injury and use of high-heel shoes, sports trauma, pain at the head of the metatarsal, Mulder's sign, deformity in pronation or displacement in the transversal and sagittal planes (although their combination, i.e. "cross toe", showed a statistically significant correlation). Positive correlations with the severity of the injuries were found in relation to initial acute pain, progressive widening of the interdigital space, loss of "touching the ground", positive results from the "drawer test" on the metatarsophalangeal joint, diminished grip strength and toe deformity in supination. CONCLUSIONS: The "drawer test" was seen to be the more reliable and precise tool for classifying the degree of plantar plate injury, followed by "touching the ground" and rotational deformities. It is possible to improve the precision of the diagnosis and the predictions of the anatomical classification for plantar plate injuries through combining the clinical history and data from the physical examination. PMID- 27218087 TI - Quantification of platelets obtained by different centrifugation protocols in SHR rats. AB - OBJECTIVE: To quantify the platelet concentration in the blood of SHR rats, by means of different centrifugation protocols, and to evaluate what the most effective method for obtaining platelets is. METHODS: We used 40 male rats of the isogenic SHR lineage. The animals were divided into three groups: control, using whole blood without centrifugation; single centrifugation, using whole blood subjected to a single centrifugation at 200 * g and 400 * g; and double centrifugation, using whole blood subjected one centrifugation at different rotations, followed by collection of whole plasma subjected to another centrifugation at different rotations: 200 * g + 200 * g; 200 * g + 400 * g; 200 * g + 800 * g; 400 * g + 400 * g; 400 * g + 800 * g. Samples of 3 ml of blood were drawn from each animal by means of cardiac puncture. The blood was stored in Vacutainer collection tubes containing 3.2% sodium citrate. The blood from the control group animals was analyzed without being subjected to centrifugation. After the blood from the other groups of animals had been subjected to centrifugation, the whole plasma was collected and subjected to platelet counting in the lower third of the sample. RESULTS: We obtained greatest platelet enrichment in the subgroup with two centrifugations comprising 400 * g for 10 min + 400 * g for 10 min, in which the mean platelet concentration was 11.30 times higher than that of the control group. CONCLUSION: It was possible to obtain a high platelet concentration using viable simple techniques, by means of centrifugation of whole blood and use of commonly used materials. The most effective method for obtaining platelet concentrate was found in samples subjected to two centrifugations. PMID- 27218088 TI - Fungal spondylodiscitis due to Candida albicans: an atypical case and review of the literature. AB - Spondylodiscitis due to Candida is a rare complication from hematogenic dissemination of infection caused by this fungus. We present an atypical case of spondylodiscitis caused by this germ that occurred after chest contusion and progressed with necrotizing fasciitis of the anterior region of the chest and osteomyelitis of the sternum. Through contiguity, it also affected the upper thoracic spine. The patient evolved with neurological alterations and recovered satisfactorily after appropriate treatment with surgical decompression of the spinal cord and specific antibiotic therapy. PMID- 27218089 TI - Avulsion fracture of the posterior cruciate ligament in an uncommon location associated with distal injury to the patellar ligament. AB - Avulsion fractures of the posterior cruciate ligament in unusual locations are rare injuries. We report the first case in the literature of an avulsion fracture of the posterior cruciate ligament associated with distal injury to the patellar ligament. The aim of this study was to present a novel case, the therapy used and the clinical follow-up. PMID- 27218090 TI - Formation of a pseudotumor in total hip arthroplasty using a tribological metal polyethylene pair. AB - The aim here was to report a case of a young adult patient who evolved with tumor formation in the left thigh, 14 years after revision surgery on hip arthroplasty. Davies in 2005 made the first description of this disease in patients undergoing metal-on-metal hip arthroplasty. Over the last decade, however, pseudotumors around metal-on-polyethylene surfaces have become more prevalent. Our patient presented with increased volume of the left thigh 8 years after hip arthroplasty revision surgery. Two years before the arising of the tumor in the thigh, a nodule in the inguinal region was investigated to rule out a malignant neoplastic process, but the results were inconclusive. The main preoperative complaints were pain, functional limitation and marked reduction in the range of motion of the left hip. Plain radiographs showed loosening of acetabular and femoral, and a large mass between the muscle planes was revealed through magnetic resonance imaging of the left thigh. The surgical procedure consisted of resection of the lesion and removal of the components through lateral approach. In respect of total hip arthroplasty, pseudotumors are benign neoplasms in which the bearing surface consists of metal-on-metal, but they can also occur in different tribological pairs, as presented in this case. PMID- 27218091 TI - Exposure to Cigarette Smoke Contributes to the Risk of Developing a Colorectal Adenoma, Doesn't It? Are Repeated Exposures to Such Smoke Dangerous? PMID- 27218092 TI - Impact of Microsatellite Instability in Signet-Ring Cell and Mucinous Components in Patients With Colorectal Carcinoma. PMID- 27218093 TI - Dose-Escalated Radiotherapy for the Treatment of Patients With Recurrent Colorectal Cancer. PMID- 27218094 TI - Role of Permacol Injection in the Treatment of Patients With Fecal Incontinence. PMID- 27218095 TI - Association Between Exposure to Environmental Tobacco Smoke at the Workplace and Risk for Developing a Colorectal Adenoma: A Cross-Sectional Study. AB - PURPOSE: A colorectal adenoma (CRA) is a well-defined precursor to colorectal cancer (CRC). Additionally, smoking is a potent risk factor for developing a CRA, as well as CRC. However, the association between exposure to environmental tobacco smoke (ETS) and the risk for developing a CRA has not yet been fully evaluated in epidemiologic studies. We performed a cross-sectional analysis on the association between exposure to ETS at the workplace and the risk for developing a CRA. METHODS: The study was conducted on subjects who had undergone a colonoscopy at a health promotion center from January 2012 to December 2012. After descriptive analyses, overall and subgroup analyses by smoking status were performed by using a multivariate logistic regression. RESULTS: Among the 1,129 participants, 300 (26.6%) were diagnosed as having CRAs. Exposure to ETS was found to be associated with CRAs in all subjects (fully adjusted odds ratio [OR], 1.95; 95% confidence interval [CI], 1.08-2.44; P = 0.001). In the subgroup analysis, exposure to ETS in former smokers increased the risk for developing a CRA (fully adjusted OR, 4.44; 95% CI, 2.07-9.51; P < 0.001). CONCLUSION: Exposure to occupational ETS at the workplace, independent of the other factors, was associated with increased risk for developing a CRA in all subjects and in former smokers. Further retrospective studies with large sample sizes may be necessary to clarify the causal effect of this relationship. PMID- 27218096 TI - Prognostic Impact of Microsatellite Instability in Colorectal Cancer Presenting With Mucinous, Signet-Ring, and Poorly Differentiated Cells. AB - PURPOSE: Mucinous cells (MUCs), signet-ring cells (SRCs), and poorly differentiated cells (PDCs) are uncommon histologic types and have been associated with advanced tumor stage and poor prognosis. However, MUCs, SRCs, and PDCs are commonly observed in cancers with high microsatellite instability (MSI), which have favorable outcomes compared with cancers with microsatellite stability (MSS). The purpose of this study was to evaluate the prognostic impact of high MSI in patients with sporadic colorectal cancer presenting with MUCs, SRCs, and/or PDCs. METHODS: Between January 2006 and December 2012, 176 with proven microsatellite status who also presented with MUCs, SRCs, and PDCs were selected for this study and were divided into 2 groups, high-MSI and MSS; their outcomes were analyzed. RESULTS: Of the 176 patients, 56 and 120, respectively, had high MSI and MSS cancers. High-MSI cancers had larger tumors, proximal tumor location, and a lower TNM stage. The recurrence rate was lower in the high-MSI group (13.7% vs. 35.4%, P = 0.006). Common patterns of distant metastasis for MUC, SRC, PDC cancers were peritoneal spread (46.9%) and hematogenous metastasis (46.4%). The 5 year CSS rates were 88.2% and 61.2% for patients with high-MSI and MSS cancers, respectively (P < 0.0001). In the multivariate analysis, except for stage-IV cancer, MSI status was an independent risk factor for cancer-specific survival (MSS: hazard ratio, 4.34; 95% confidence interval, 1.68-11.21). CONCLUSION: In patients with colorectal cancer presenting with MUCs, SRCs, and/or PDCs, those with high-MSI cancers had better outcomes. PMID- 27218098 TI - Safety and Efficacy of Permacol Injection in the Treatment of Fecal Incontinence. AB - PURPOSE: Permacol has been gaining popularity in recent times for the treatment of fecal incontinence (FI). This study aims to evaluate the safety and efficacy of anal submucosal Permacol injection in the treatment of FI. METHODS: All consecutive patients who underwent Permacol injection for FI over a 3-year period were included. Patients' data relating to obstetric history, anorectal/pelvic operations, type of FI, preoperative anorectal physiology results and follow-up details for outcome measures were collected. Preoperative and postoperative Cleveland Clinic Florida Incontinence Scores (CCFISs) were noted. Patients were surveyed by using a telephone questionnaire to assess the quality of life and other outcome measures. Data were analysed using SPSS ver.19.0. RESULTS: Thirty patients (28 females and 2 males) with a median age of 67 years were included in the study. Of those patients, 37%, 50%, and 13% were noted to have passive, mixed and urge FI, respectively. Six of the patients (20%) had repeat Permacol injections, 5 of whom had sustained responses to the first Permacol injection for a mean of 11 months. There was a significant improvement in the CCFIS from a baseline median of 12.5, mean 12.8 interquartile range [IQR], 6-20), to a median of 3.5, mean 4.8 (IQR, 0-20), P < 0.001. Of the patients surveyed by telephone 89% were satisfied with their overall experience and the improvement in their symptoms following Permacol injections. CONCLUSION: This study has demonstrated that Permacol injection for the treatment of FI is safe and effective and has no associated major complications. However, the results are not permanent; consequently, a significant proportion of the patients with an initial response may require repeat injections. PMID- 27218097 TI - Efficacy of Dose-Escalated Radiotherapy for Recurrent Colorectal Cancer. AB - PURPOSE: This study aimed to evaluate the effects of radiotherapy (RT) on progression-free survival (PFS) for patients with recurrent colorectal cancer. METHODS: We reviewed the records of 22 patients with recurrent colorectal cancer treated with RT between 2008 and 2014. The median radiation dose for recurrent disease was 57.6 Gy (range, 45-75.6 Gy). Patients were divided into 2 groups according to the type of RT: patients underwent RT without previous history of irradiation (n = 14) and those treated with secondary RT (reirradiation: n = 8) at the time of recurrence. RESULTS: The median follow-up period was 24.9 months (range, 4.5-66.6 months). Progression was observed in 14 patients (including 8 with loco-regional failure and 9 with distant metastases). Distant metastases were related to the RT dose (<70 Gy, P = 0.031). The 2-year loco-regional control (LRC), PFS, and overall survival (OS) rates were 74.6%, 45.1%, and 82.0%, respectively. The LRC rate was not different between the patients treated with RT for the first time and those treated with reirradiation (P = 0.101, 2-year LRC 79.5% vs. 41.7%). However, reirradiation was related to poor PFS (P = 0.022) and OS (P = 0.002). An escalated RT dose (>=70 Gy) was associated with a higher PFS (P = 0.014, 2-year PFS 63.5% vs. 20.8%). CONCLUSION: Salvage RT for locally recurrent colorectal cancer can be offered when surgery is impossible. Dose escalated RT shows a possible benefit in reducing the risk of progression. PMID- 27218099 TI - Incidentally Solitary, Synchronous, Metastatic Left Adrenal Mass From Colon Cancer. AB - The authors report the case of a 63-year-old man who underwent an open adrenalectomy for a synchronous, malignant, metastatic left adrenal tumor and a total colectomy for T3N0M1 (stage 4) primary, malignant colon cancer. Two polypoid lesions, one measuring 40 mm * 30 mm * 30 mm and the other measuring 20 mm * 10 mm * 10 mm, were found in the ascending colon and rectosigmoid (RS) junction, respectively, and a synchronous, malignant, left adrenal gland lesion measuring 70 mm * 50 mm * 30 mm was incidentally found on abdominal computed tomography scan. Histological examination revealed a metastatic, necrotic adenocarcinoma of the left adrenal mass, an adenocarcinoma of the cecal mass, and an adenomatous polyp (tubulovillous type) of the smallest polypoid lesion in RS junction that had invaded deeply into the submucosal layer. The patient recovered uneventfully, and his condition is now stable, with no evidence of local recurrence or metastatic disease, 2 years after the surgery. To the best of our knowledge, only 25 cases of an adrenalectomy for treating metastatic adrenal gland tumors have been reported to date; physicians should be aware of the possibility of this event. PMID- 27218100 TI - Xanthogranulomatous Appendicitis Mimicking Residual Burkitt's Lymphoma After Chemotherapy. AB - The case of a 23-year-old female treated with aggressive high-dose therapy for Burkitt's lymphoma is reported. A positron emission tomography and computed tomography scan after completion of chemotherapy revealed a residual hypermetabolic lesion in the right pelvic cavity. A pelvic magnetic resonance imaging scan showed circumferential wall thickening at the tip of the appendix. A laparoscopic exploration and appendectomy were performed, and a pathologic examination of the resected appendix revealed xanthogranulomatous appendicitis. This is a rare case of a xanthogranulomatous appendicitis mimicking remnant Burkitt's lymphoma after completion of chemotherapy. PMID- 27218102 TI - Glutathione Peroxidase Level in Patients with Vitiligo: A Meta-Analysis. AB - Abnormality of glutathione peroxidase (GPx) is involved in the etiology and pathogenesis of vitiligo. However, the results were controversial. Aim. The purpose of this meta-analysis is to compare the levels of GPx between vitiligo patients and healthy controls. Methods. Relevant published articles were searched according to eligibility criteria. A meta-analysis was conducted to pool estimates of the standardized mean difference (SMD) with 95% confidence interval (CI). Results. Twenty-three studies with a total of 1076 vitiligo patients and 770 healthy controls were included. The pooled meta-analysis showed that patients with vitiligo had equivalent levels of GPx with the healthy controls (SMD = 0.47, 95% CI: -1.03 to 0.08, and p = 0.095). Further subgroup analysis showed that the GPx levels of Asian patients or segmental vitiligo patients were, respectively, lower than those of healthy controls (Asian: SMD = -0.47, 95% CI: 1.08 to 0.14, and p = 0.001; segmental: SMD = -3.59, 95% CI: -6.38 to -0.80, and p = 0.012). Furthermore, the GPx levels in serum/plasma were significantly decreased in either stable or active vitiligo patients, comparing to healthy controls (stable: SMD = -2.01, 95% CI: -3.52 to -0.49, and p = 0.009; active: SMD = -2.34, 95% CI: -4.07 to -0.61, and p = 0.008). Conclusion. This meta-analysis showed a significant association between low GPx level and vitiligo. PMID- 27218101 TI - Nicotinamide Mononucleotide Adenylyl Transferase 2: A Promising Diagnostic and Therapeutic Target for Colorectal Cancer. AB - Colorectal cancer (CRC) is one of the most common cancers all over the world. It is essential to search for more effective diagnostic and therapeutic methods for CRC. Abnormal nicotinamide adenine dinucleotide (NAD) metabolism has been considered as a characteristic of cancer cells. In this study, nicotinamide mononucleotide adenylyl transferases (NMNATs) as well as p53-mediated cancer signaling pathways were investigated in patients with colorectal cancer. The CRC tissues and adjacent normal tissues were obtained from 95 untreated colorectal cancer patients and were stained for expression of nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) and p53. The survival rate was analyzed by the Kaplan-Meier method and the log-rank test. The multivariate Cox proportional hazard regression analysis was conducted as well. Our data demonstrated that expression of NMNAT2 and p53 was significantly higher in CRC tissues, while NMNAT2 expression is in correlation with the invasive depth of tumors and TNM stage. Significant positive correlation was found between the expression of NMNAT2 and the expression of p53. However, NMNAT2 expression was not a statistically significant prognostic factor for overall survival. In conclusion, our results indicated that NMNAT2 might participate in tumorigenesis of CRC in a p53-dependent manner and NMNAT2 expression might be a potential therapeutic target for CRC. PMID- 27218103 TI - A Comparison of Conventional Collagen Sponge and Collagen-Gelatin Sponge in Wound Healing. AB - The objective of this study was to compare the effectiveness of the collagen gelatin sponge (CGS) with that of the collagen sponge (CS) in dermis-like tissue regeneration. CGS, which achieves the sustained release of basic fibroblast growth factor (bFGF), is a promising material in wound healing. In the present study, we evaluated and compared CGSs and conventional CSs. We prepared 8 mm full thickness skin defects on the backs of rats. Either CGSs or CSs were impregnated with normal saline solution (NSS) or 7 MUg/cm(2) of bFGF solution and implanted into the defects. At 1 and 2 weeks after implantation, tissue specimens were obtained from the rats of each group (n = 3, total n = 24). The wound area, neoepithelial length, dermis-like tissue area, and the number and area of capillaries were evaluated at 1 and 2 weeks after implantation. There were no significant differences in the CGS without bFGF and CS groups. Significant improvements were observed in the neoepithelial length, the dermis-like tissue area, and the number of newly formed capillaries in the group of rats that received CGSs impregnated with bFGF. The effects on epithelialization, granulation, and vascularization of wound healing demonstrated that, as a scaffold, CGSs are equal or superior to conventional CSs. PMID- 27218104 TI - Mini Transsternal Approach to the Anterior High Thoracic Spine (T1-T4 Vertebrae). AB - Purpose. The anterior high thoracic spine is one of the most complex segments to be accessed surgically due to anatomical constraints and transitional characteristics. We describe in detail the mini transsternal approach to metastatic, infective, traumatic, and degenerative pathologies of T1 to T4 vertebral bodies. We analyse our surgical series, indications, and outcomes. Methods. Over a 5-year period 18 consecutive patients with thoracic myelopathy due to metastatic, infective, traumatic, and degenerative pathologies with T1 to T4 vertebral bodies involvement received a mini transsternal approach with intraoperative monitoring. Frankel scoring system was used to grade the neurological status. Results. Mean follow-up was 40 months. 78% patients improved in Frankel grade after surgery and 22% patients remained unchanged. Average operation time was 210 minutes. There were no intraoperative complications. One patient developed postoperative pneumonia successfully treated with antibiotics. Conclusion. The mini transsternal is a safe approach for infective, metastatic, traumatic, and degenerative lesions affecting the anterior high thoracic spine and the only one allowing an early and direct visualisation of the anterior theca. This approach overcomes the anatomical constraints of this region and provides adequate room for optimal reconstruction and preservation of spinal alignment in the cervicothoracic transition zone with good functional patient outcomes. PMID- 27218105 TI - MicroRNA Profiling in Patients with Upper Tract Urothelial Carcinoma Associated with Balkan Endemic Nephropathy. AB - Balkan endemic nephropathy (BEN) is a disease that affects people that live in the alluvial plains along the tributaries of the Danube River in the Balkan region. BEN is a chronic tubulointerstitial disease with a slow progression to terminal renal failure and has strong association with upper tract urothelial carcinoma (UTUC). There are several hypotheses about the etiology of BEN, but only the toxic effect of aristolochic acid has been confirmed as a risk factor in the occurrence of the disease. Aberrantly expressed miRNAs have been shown to be associated with many types of cancers. A number of studies have investigated the expression of microRNAs in urothelial carcinoma, mainly on urothelial bladder cancer, and only a few have included patients with UTUC. Here we present the first study of microRNA profiling in UTUC tissues from patients with BEN (BEN UTUC) and patients with UTUC from nonendemic Balkan regions (non-BEN-UTUC) in comparison to normal kidney tissues. We found 10 miRNAs that were differentially expressed in patients with BEN-UTUC and 15 miRNAs in patients with non-BEN-UTUC. miRNA signature determined in BEN-UTUC patients differs from the non-BEN-UTUC patients; only miR-205-5p was mutual in both groups. PMID- 27218106 TI - Antibacterial Efficacy of Calcium Hypochlorite with Vibringe Sonic Irrigation System on Enterococcus faecalis: An In Vitro Study. AB - Aim. The purpose of this study was to compare the in vitro efficacy of calcium hypochlorite (Ca[OCl]2) and sodium hypochlorite (NaOCl) associated with sonic (Vibringe) irrigation system in root canals which were contaminated with Enterococcus faecalis. Material and Methods. The root canals of 84 single-rooted premolars were enlarged up to a file 40, autoclaved, inoculated with Enterococcus faecalis, and incubated for 21 days. The samples were divided into 7 groups according to the irrigation protocol: G0: no treatment; G1: distilled water; G2: 2.5% NaOCl; G3: 2.5% Ca(OCl)2; G4: distilled water with sonic activation; G5: 2.5% NaOCl with sonic activation; and G6: 2.5% Ca(OCl)2 with sonic activation. Before and after decontamination procedures microbiological samples were collected and the colony-forming units were counted and the percentages of reduction were calculated. Results. Distilled water with syringe irrigation and sonic activation groups demonstrated poor antibacterial effect on Enterococcus faecalis compared to other experimental groups (p < 0.05). There was no statistically significant difference between syringe and sonic irrigation systems with Ca(OCl)2 and NaOCl. Conclusion. The antimicrobial property of Ca(OCl)2 has been investigated and compared with that of NaOCl. Both conventional syringe irrigation and sonic irrigation were found effective at removing E. faecalis from the root canal of extracted human teeth. PMID- 27218107 TI - Perceived Maternal Role Competence among the Mothers Attending Immunization Clinics of Dharan, Nepal. AB - BACKGROUND: Being a mother is considered by many women as their most important role in life. Women's perceptions of their abilities to manage the demands of parenting and the parenting skills they posses are reflected by perceived maternal role competence. The present study was carried out to assess the perceived maternal role competence and its associated factors among mothers. METHODS: A descriptive cross-sectional research study was carried out on 290 mothers of infant in four immunization clinics of Dharan, Nepal. Data were collected using a standardized predesigned, pretested questionnaire (Parent sense of competence scale, Rosenberg's self esteem scale, Maternity social support scale). The data were analyzed using descriptive and inferential statistics and multiple regression analysis at 0.05 level of significance. RESULTS: The mean score of the perceived maternal role competence obtained by mothers was 64.34+/ 7.90 and those of knowledge/skill and valuing/comfort subscale were 31+/-6.01 and 33+/-3.75, respectively. There was a significant association between perceived maternal role competence and factors as the age of the mother (P<0.001), educational status (P=0.015), occupation (P=0.001) and readiness for pregnancy (P=0.022). The study findings revealed a positive correlation between perceived maternal role competence and age at marriage (r=0.132, P=0.024), per capita income (r=0.118, P=0.045), self esteem (r=0.379, P<0.001), social support (r=0.272, P<0.001), and number of support persons (r=0.119, P=0.043). The results of the step wise multiple regression analysis revealed that the major predictor of perceived maternal role competence was self esteem. CONCLUSION: The factors associated with perceived maternal role competence were age, education, occupation, per capita income, self esteem, social support, and the number of support persons. PMID- 27218108 TI - Relationship between Family-Work and Work-Family Conflict with Organizational Commitment and Desertion Intention among Nurses and Paramedical Staff at Hospitals. AB - BACKGROUND: High turnover intention rate is one of the most common problems in healthcare organizations throughout the world. There are several factors that can potentially affect the individuals' turnover intention; they include factors such as work-family conflict, family-work conflict, and organizational commitment. The aim of this research was to determine the relationship between family-work and work-family conflicts and organizational commitment and turnover intention among nurses and paramedical staff at hospitals affiliated to Shiraz University of Medical Sciences (SUMS) and present a model using SEM. METHODS: This is a questionnaire based cross-sectional study among 400 nurses and paramedical staff of hospitals affiliated to SUMS using a random-proportional (quota) sampling method. Data collection was performed using four standard questionnaires. SPSS software was used for data analysis and SmartPLS software for modeling variables. RESULTS: Mean scores of work-family conflict and desertion intention were 2.6 and 2.77, respectively. There was a significant relationship between gender and family-work conflict (P=0.02). Family-work conflict was significantly higher in married participants (P=0.001). Based on the findings of this study, there was a significant positive relationship between work-family and family-work conflict (P=0.001). Also, work-family conflict had a significant inverse relationship with organizational commitment (P=0.001). An inverse relationship was seen between organizational commitment and turnover intentions (P=0.001). CONCLUSION: Thus, regarding the prominent and preventative role of organizational commitment in employees' desertion intentions, in order to prevent negative effects of staff desertion in health sector, attempts to make policies to increase people's organizational commitment must be considered by health system managers more than ever. PMID- 27218109 TI - The Effect of Aloe Vera Solution on Chemotherapy-Induced Stomatitis in Clients with Lymphoma and Leukemia: A Randomized Controlled Clinical Trial. AB - BACKGROUND: Stomatitis is the most common complication of chemotherapy. This study aimed to assess the effect of aloe vera solution on stomatitis and its pain intensity in patients undergoing chemotherapeutic procedures. METHODS: In this randomized controlled clinical trial, 64 patients with Acute Myeloid Leukemia and Acute Lymphocytic Leukemia undergoing chemotherapy were randomly divided into a control and an intervention group. The intervention group patients were asked to wash their mouths with 5 ml of aloe vera solution for two minutes three times a day for 14 days. The control group patients, however, used only the ordinary mouthwashes recommended in hematologic centers. The patients' mouths were examined by two assistants on days 1, 3, 5, 7, and 14. The intensity of stomatitis was recorded according to WHO stomatitis intensity checklists and pain was evaluated using Visual Analog Scale. The data were analyzed by SPSS statistical software, version 18. RESULTS: The results showed that aloe vera solution mouthwash significantly reduced the intensity of stomatitis and its pain in the intervention group compared to the control group. On the first day, no significant difference was found between the two groups regarding the mean intensity of stomatitis (P=0.178) and pain (P=0.154). However, a significant difference was observed between the two groups in this regard on other days (days 3-14: P=0.001 for stomatitis intensity, P=0.001 for pain). CONCLUSIONS: Aloe vera solution can improve the patients' nutritional status, reduce stomatitis and its pain intensity, and increase the patients' satisfaction. Trial Registration Number IRCT2014092819318N1. PMID- 27218110 TI - Effect of Roy's Adaptation Model-Guided Education on Coping Strategies of the Veterans with Lower Extremities Amputation: A Double-Blind Randomized Controlled Clinical Trial. AB - BACKGROUND: Any defect in the extremities of the body can affect different life aspects. The purpose of this study was to investigate the effect of Roy's adaptation model-guided education on coping strategies of the veterans with lower extremities amputation. METHODS: In a double-blind randomized controlled clinical trial, 60 veterans with lower extremities amputation referring to Kowsar Orthotics and Prosthetics Center of Veterans Clinic in Tehran, Iran were recruited using convenience method and randomly assigned to intervention and control groups in 2013-2014. Lazarus and Folkman coping strategies questionnaire was used to collect the data. After completing the questionnaires in both groups, maladaptive behaviours were determined in the intervention group and an education program based on Roy's adaptation model was implemented. After 2 months, both groups completed the questionnaires again. Data were analyzed using SPSS software. RESULTS: Independent T-test showed that the score of the dimensions of coping strategies did not have a statistically significant difference between the intervention and control groups in the pre-intervention stage (P>0.05). This test showed a statistically significant difference between the two groups in the post intervention stage in terms of the scores of different dimensions of coping strategies (P>0.05), except in dimensions of social support seeking and positive appraisal (P>0.05). CONCLUSION: The findings of this research indicated that the Roy's adaptation model-guided education improved the majority of coping strategies in veterans with lower extremities amputation. It is recommended that further interventions based on Roy's adaptation model should be performed to improve the coping of the veterans with lower extremities amputation. TRIAL REGISTRATION NUMBER: IRCT2014081118763N1. PMID- 27218111 TI - Comparison of the Temperament and Character of Patients Referred to Cosmetic Nasal Surgeon in Shiraz Hospitals, 2015. AB - BACKGROUND: Rhinoplasty is the most common cosmetic surgery which has been dramatically increasing in Iran. Currently, Iran is ranked the first in the world in rhinoplasty. In the present study, we aimed to assess the character and temperament traits of the applicants referred to rhinoplasty surgeons in Shiraz, southwest Iran in 2015. METHODS: In this cross-sectional study, we recruited 500 participants among rhinoplasty applicants for case and among students and clerks residing in Shiraz by convenience sampling method in 2015. The two groups were matched regarding the gender, age and educational level. Data were collected using a demographic questionnaire and temperament and character inventory to assess the four dimensions of temperament (including novelty seeking; harm avoidance; reward dependence; persistence) and the three dimensions of character (including self-directedness; cooperativeness; self-transcendence). Data were analyzed using SPSS software, version 20. Chi- square and t-test were used as appropriated. RESULTS: The mean+/-SD age of the participants was 27.43+/-6.6. The results showed a significant difference between the case and control groups with respect to the temperaments of novelty (9.47+/-2.80), harm avoidance (9.12+/ 3.3), persistence (2.69+/-1.04), the characters of cooperativeness (15.38+/ 4.02), and self-transcendence (9.48+/-3.41). CONCLUSION: Evaluating character and temperament traits in rhinoplasty applicants will be so helpful in identifying and predicting good candidates for such cosmetic surgery. Selecting the ideal patients can not only reduce the costs resulting from rhinoplasty imposed on families and society but also enhance the satisfaction of the patients and the surgeons. PMID- 27218112 TI - The Association of the Dietary Fat and Functional Ovarian Cysts in Women of Reproductive Age Referring to Three Hospitals in Mashhad, Iran, 2014. AB - BACKGROUND: Functional ovarian cysts (FOC) are one of the most common gynecological problems among women of reproductive age. Some studies have shown that diet may affect the function of the ovaries, so this study was performed to determine the association between the amount of dietary fat and functional ovarian cysts. METHODS: This case-control study was performed on 264 female patients (132 with cyst in the case group and 132 in the control group) aged 13 to 49. The case group had ovarian cyst with a size of less than 8 cm and the control group didn't have any ovarian cyst. Data were collected by questionnaires including a demographic questionnaire, and medical and midwifery characteristics questionnaire; the amount of fat in the diet was measured using food frequency questionnaire (FFQ). Data were analyzed using SPSS software. P<0.05 was considered significant. RESULTS: The mean of fat consumption in the case group was 119.84+/-103.09g and in the control group it was 109.90+/-54.66g. The result of data analysis showed that there was no statistically significant relationship between the amount of fat in the diet and FOC in confidence level of 95% (P=0.056). CONCLUSION: According to the findings of this study, the amount of fat consumption was higher in women with ovarian cysts; however, this difference was not statistically significant. In this regard, it is recommended that women of reproductive age should reduce their fat intake. PMID- 27218113 TI - Psychometric Properties of the Persian Version of Self-Transcendence Scale: Adolescent Version. AB - BACKGROUND: Given the greater tendency during adolescence toward risk-taking, identifying and measuring the factors affecting the adolescents' health is highly important to ensure the efficacy of health promoting interventions. One of these factors is self-transcendence. The aim of this study was to assess the psychometric features of the Self-Transcendence Scale (adolescents' version) in students in Tehran, the capital city of Iran. METHODS: This research was conducted in 2015. For this purpose, 1210 high school students were selected through the multistage cluster sampling method. After the backward-forward translation, the psychometric properties of the scale were examined through the assessment of the (face and construct) validity and reliability (internal consistency and stability) of the scale. The construct validity was assessed using two methods, factor analysis, and convergence of the scale with the Hopefulness Scale for Adolescents. RESULTS: The result of face validity was minor modifications in some words. The exploratory factor analysis resulted in the extraction of two dimensions, with explaining 52.79% of the variance collectively. In determining the convergent validity, the correlation between hopefulness score and self-transcendence score was r=0.47 (P<0.001). The internal consistency of the scale was determined using Cronbach's alpha of 0.82 for the whole scale and 0.75 and 0.70 for each of the sub-scales. The stability reliability was found to have an ICC of 0.86 and a confidence interval of 95%. CONCLUSION: The Persian version of the Adolescents' Self-Transcendence Scale showed an acceptable validity and reliability and can be used in the assessment of self-transcendence in Iranian adolescents. PMID- 27218114 TI - The Effects of Education on Spirituality through Virtual Social Media on the Spiritual Well-Being of the Public Health Students of Isfahan University of Medical Sciences in 2015. AB - BACKGROUND: The role and effects of people's spiritual well-being have received more attention in recent years. Knowing the factors related to spiritual well being, especially in students as the educated class and future builders of society, is too important. The aim of this study was to investigate the effectiveness of education on spirituality through social media in the spirituality well-being of public health students of Isfahan University of medical science. METHODS: A semi-experimental, pre-test, post-test study was conducted on 50 under- graduate public health students (3 men, 47 women; age range 18-30 years) of Isfahan University of Medical Sciences through convenience and purposive sampling. The educational content of spirituality education was used to promote and improve spiritual well-being, being sent by using one of the mobile phone applications. Using spiritual well-being questionnaire, the level of the individuals' spiritual well-being before and after the educational was evaluated. To analyze the data in this study, descriptive statistics and t-test were use SPSS software was used to analyze the data and the significance level was considered lower than 0.05%. RESULT: In total, 50 students including 3 men and 47women participated in the study. The mean age of the participants was 22.02+/-3.78. About 68% of the students were single and the remaining were married. The score of the participants' spiritual well-being was 96.5 before the intervention and it promoted to 103.3 after the intervention. The result of the analysis by t-test on the two groups showed that spirituality education can cause a significant increase in peoples' spiritual well-being (P<0.001). CONCLUSION: After the educational intervention, the level of people's spiritual well-being increased significantly. As a result, spirituality education causes conditions to improve the peoples' spiritual well-being. PMID- 27218115 TI - A Comparative Study of Perceived Social Support and Self-Efficacy among Women with Wanted and Unwanted Pregnancy. AB - BACKGROUND: Unwanted pregnancy induces adverse attitudes regarding pregnancy which is a natural event by increasing mental and socio-economic difficulties. Insufficient maternal care and low adjustment to parental role are known as consequences of unwanted pregnancy. Perceived social support and self-efficacy in pregnancy influence health related behaviors and may play a crucial role in adaptation to pregnancy; this study was conducted to examine and compare the self efficacy and social support among two groups of women with wanted and unwanted pregnancy. METHODS: This analytical descriptive research was conducted on 315 women referred to 13 health centers in the east and west of Ahvaz in 2011. Data were collected via random stratified sampling method through interview. The instrument of this study was a questionnaire in three distinct parts including demographic, modified Persian version of Vaux General social support (Chronbach's alpha =0.80) and Persian version of self-efficacy scale (Chronbach's alpha =0.80). Data were analyzed through independent t-test and ANOVA. A P<0.05 was considered significant. RESULTS: The mean age of the subjects was 25.8+/-5.6; unwanted pregnancy occurred in 135 women (42.2%). The mean scores of social support in the two given groups with wanted and unwanted pregnancy were 26.62+/ 4.16 and 22.28+/-7.57, respectively (P<0.001). Furthermore, the mean scores of self-efficacy for the wanted pregnancy group was 37.77+/-6.66 and for unwanted pregnancy group it was 31.03+/-6.31 (P<0.001). Women and their husbands' age, the number of male offspring in family and marriage years were significantly different in the two groups (P<0.05). CONCLUSION: This study showed that unwanted pregnant women are more likely to be exposed to low level of perceived social support and self-efficacy. Therefore more studies and interventions are recommended to be conducted to analyze the effect of family and friends' supports on unwanted pregnant women's perceived social support and self-efficacy and its adverse consequences. PMID- 27218116 TI - Home-based Palliative Care: A Strategy for Keeping Intensive Care Unit Beds Vacant. PMID- 27218117 TI - Leprous ganglionitis and myelitis. PMID- 27218119 TI - Human serum antibodies against EBV latent membrane protein 1 cross-react with alpha-synuclein. AB - OBJECTIVES: To identify the epitope on alpha-synuclein (alpha-syn) to which antibodies against the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) bind and to determine whether antibodies targeting this mimicry domain are present in human sera. METHODS: Reactivity of the alpha-syn-cross-reacting anti LMP1 monoclonal antibody CS1-4 to a synthetic peptide containing the putative mimicry domain was compared to those in which this domain was mutated and to murine and rat alpha-syn (which differ from human alpha-syn at this site) in Western blots. Using ELISA, sera from EBV+ (n = 4) and EBV- (n = 12) donors as well as those with infectious mononucleosis (IM; n = 120), and Hodgkin disease (HD; n = 33) were interrogated for antibody reactivity to synthetic peptides corresponding to regions of alpha-syn and LMP1 containing the mimicry domain. RESULTS: CS1-4 showed strong reactivity to wild-type human alpha-syn, but not to the mutant peptides or rodent alpha-syn. Control EBV- and EBV+ sera showed no reactivity to alpha-syn or LMP1 peptides. However, a significant proportion of IM and HD sera contained immunoglobulin M (IgM) (59% and 70%, in IM and HD, respectively), immunoglobulin G (IgG) (40% and 48%), and immunoglobulin A (IgA) (28% and 36%) antibodies to both peptides, as well as a significant correlation in the titers of IgM (rho = 0.606 and 0.664, for IM and HD, respectively), IgG (0.526 and 0.836), and IgA (0.569 and 0.728) antibodies targeting LMP1 and alpha syn peptides. CONCLUSIONS: Anti-EBV-LMP1 antibodies cross-reacting with a defined epitope in alpha-syn are present in human patients. These findings may have implications for the pathogenesis of synucleinopathies. PMID- 27218120 TI - Male tick bite: A rare cause of adult tick paralysis. PMID- 27218118 TI - Effective anti-Alzheimer Abeta therapy involves depletion of specific Abeta oligomer subtypes. AB - BACKGROUND: Recent studies have implicated specific assembly subtypes of beta amyloid (Abeta) peptide, specifically soluble oligomers (soAbeta) as disease relevant structures that may underlie memory loss in Alzheimer disease. Removing existing soluble and insoluble Abeta assemblies is thought to be essential for any attempt at stabilizing brain function and slowing cognitive decline in Alzheimer disease. IV immunoglobulin (IVIg) therapies have been shown to contain naturally occurring polyclonal antibodies that recognize conformational neoepitopes of soluble or insoluble Abeta assemblies including soAbeta. These naturally occurring polyclonal antibodies have been suggested to underlie the apparent clinical benefits of IVIg. However, direct evidence linking anti-Abeta antibodies to the clinical bioactivity of IVIg has been lacking. METHODS: Five month-old female Dutch APP E693Q mice were treated for 3 months with neat IVIg or with IVIg that had been affinity-depleted over immobilized Abeta conformers in 1 of 2 assembly states. Memory was assessed in a battery of tests followed by quantification of brain soAbeta levels using standard anti-soAbeta antibodies. RESULTS: We provide evidence that NU4-type soAbeta (NU4-soAbeta) assemblies accumulate in the brains of Dutch APP E693Q mice and are associated with defects in memory, even in the absence of insoluble Abeta plaques. Memory benefits were associated with depletion from APP E693Q mouse brain of NU4-soAbeta and A11 soAbeta but not OC-type fibrillar Abeta oligomers. CONCLUSIONS: We propose that targeting of specific soAbeta assembly subtypes may be an important consideration in the therapeutic and/or prophylactic benefit of anti-Abeta antibody drugs. PMID- 27218121 TI - The Phase Lag between Agonist-Induced Oscillatory Ca2+ and IP3 Signals Does Not Imply Causality (December 2015). AB - Activated phospholipase C (PLC*) generates 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) from phosphatidyl inositol (PIP2). The DAG remains in the plasma membrane and co-activates conventional protein kinase C (PKC) with Ca2+. We have developed a mathematical model for the activation of the Ca2+-dependent PKC and its negative feedback on phospholipase C (PLC) and coupled it to the De Young-Keizer model for IP3 mediated Ca2+ oscillations. The model describes the cascade of reactions for the translocation of PKC to plasma membrane, and simulates activation of Ca2+ and diacylglycerol (DAG) oscillations. The model demonstrates that oscillations in Ca2+ and DAG are possible with or without a positive Ca2+ feedback on phospholipase C consistent with experiment. In many experimental studies, the timing of the peaks of the Ca2+ and IP3 oscillations have been used to suggest causality, i.e. that the IP3 oscillations cause the Ca2+ oscillations. The model is used to explore this question. To this end, the positive and negative feedback between Ca2+ and IP3 production are modulated, resulting in changes to the phase lag between the peaks in [Ca2+]cyt and [IP]cyt. The model simulates a possible experimental protocol that can be used to differentiate whether or not the positive feedback of Ca2+ on PLC is needed for the oscillations. PMID- 27218122 TI - Mst1-mediated phosphorylation of Bcl-xL is required for myocardial reperfusion injury. AB - Mst1 is a central Ser-Thr kinase in the Hippo pathway, which promotes apoptosis and inhibits cell proliferation. We have shown previously that, in cardiomyocytes, oxidative stress activates Mst1 at mitochondria, where Mst1 phosphorylates Bcl-xL at Ser14, inducing dissociation of Bcl-xL from Bax and thereby promoting apoptosis. However, the functional significance of Ser14 phosphorylation of endogenous Bcl-xL in vivo remains elusive. We generated knockin (KI) mice in which Ser14 of Bcl-xL is replaced with Ala. KI mice were born at the expected Mendelian ratio, and adult KI mice exhibited normal cardiac morphology and function at baseline. However, KI mice were protected from myocardial ischemia/reperfusion (I/R) injury and exhibited reduced cardiomyocyte apoptosis. Although suppression of endogenous Mst1 also reduced I/R injury, there was no additive protective effect when Mst1 was inhibited in KI mice. The development of dilated cardiomyopathy induced by cardiac-specific overexpression of Mst1 was also ameliorated in KI mice. Lats2 and YAP, two other key components of the Hippo pathway, were not affected in KI mice. These results suggest that Ser14 phosphorylation of Bcl-xL plays an essential role in mediating both cardiomyocyte apoptosis and myocardial injury by acting as a key downstream mediator of Mst1 independently of the canonical Hippo pathway. PMID- 27218123 TI - Curly arrows meet electron density transfers in chemical reaction mechanisms: from electron localization function (ELF) analysis to valence-shell electron-pair repulsion (VSEPR) inspired interpretation. AB - Probing the electron density transfers during a chemical reaction can provide important insights, making possible to understand and control chemical reactions. This aim has required extensions of the relationships between the traditional chemical concepts and the quantum mechanical ones. The present work examines the detailed chemical insights that have been generated through 100 years of work worldwide on G. N. Lewis's ground breaking paper on The Atom and the Molecule (Lewis, G. N. The Atom and the Molecule, J. Am. Chem. Soc. 1916, 38, 762-785), with a focus on how the determination of reaction mechanisms can be reached applying the bonding evolution theory (BET), emphasizing how curly arrows meet electron density transfers in chemical reaction mechanisms and how the Lewis structure can be recovered. BET that combines the topological analysis of the electron localization function (ELF) and Thom's catastrophe theory (CT) provides a powerful tool providing insight into molecular mechanisms of chemical rearrangements. In agreement with physical laws and quantum theoretical insights, BET can be considered as an appropriate tool to tackle chemical reactivity with a wide range of possible applications. Likewise, the present approach retrieves the classical curly arrows used to describe the rearrangements of chemical bonds for a given reaction mechanism, providing detailed physical grounds for this type of representation. The ideas underlying the valence-shell-electron pair-repulsion (VSEPR) model applied to non-equilibrium geometries provide simple chemical explanations of density transfers. For a given geometry around a central atom, the arrangement of the electronic domain may comply or not with the VSEPR rules according with the valence shell population of the considered atom. A deformation yields arrangements which are either VSEPR defective (at least a domain is missing to match the VSEPR arrangement corresponding to the geometry of the ligands), VSEPR compliant or pseudo VSEPR when the position of bonding and non bonding domains are interchanged. VSEPR defective arrangements increase the electrophilic character of the site whereas the VSEPR compliant arrangements anticipate the formation of a new covalent bond. The frequencies of the normal modes which account for the reaction coordinate provide additional information on the succession of the density transfers. This simple model is shown to yield results in very good agreement with those obtained by BET. PMID- 27218124 TI - Dipole moments of trans- and cis-(4-methylcyclohexyl)methanol (4-MCHM): obtaining the right conformer for the right reason. AB - Accurate computational estimates of fundamental physical properties can be used as inputs in the myriad of extant models employed to predict toxicity, transport, and fate of contaminants. However, as molecular complexity of contaminants increases, it becomes increasingly difficult to determine the magnitude of the errors introduced by ignoring the 3D conformational space averaging within group additivity and semi-empirical approaches. The importance of considering 3D molecular structure is exemplified for the dipole moments of cis and trans isomers of (4-methylcyclohexyl)methanol (4-MCHM). When 10 000 gallons of 4-MCHM was spilled into the Elk River in January 2014, a lack of toxicological data and environmental partitioning coefficients hindered the immediate protection of human health and the local water supply in West Virginia, USA. Post-spill analysis of the contaminants suggested that the cis and trans isomers had observably different partitioning coefficients and solubility, and thus differing environmental fates. Obtaining high-quality dipole moments using ab initio quantum chemical methods for the isomeric pair was crucial in validating their experimental differences in solubility [Environ. Sci. Technol. Lett., 2015, 2, 127]. The use of first principles electronic structure theory is further explored here to obtain accurate conformer relative energies and dipole moments of cis- and trans-4-MCHM. Overall, the MP2 aug-cc-pVDZ level of theory affords the best balance between accuracy and computational cost. PMID- 27218125 TI - [Comment on "Individual Proton Pump Inhibitors and Outcomes in Patients With Coronary Artery Disease on Dual Antiplatelet Therapy: A Systematic Review"]. PMID- 27218126 TI - Hemophagocytic lymphohistiocytosis associated with visceral leishmaniasis. PMID- 27218127 TI - [Nursing Council wants federal nursing chamber]. PMID- 27218128 TI - [Chronic pain: national health insurance promotes national health goal]. PMID- 27218129 TI - [Nursing: family caregivers: family caregivers are not utilizing assistance]. PMID- 27218130 TI - [Constitutional complaint rejected]. PMID- 27218131 TI - [New ideas for persons with dementia]. PMID- 27218132 TI - [Health expenditures climb to 328 billion euro]. PMID- 27218133 TI - [Nursing professions - regulation]. PMID- 27218134 TI - Catalytic, Enantioselective Addition of Alkyl Radicals to Alkenes via Visible Light-Activated Photoredox Catalysis with a Chiral Rhodium Complex. AB - An efficient enantioselective addition of alkyl radicals, oxidatively generated from organotrifluoroborates, to acceptor-substituted alkenes is catalyzed by a bis-cyclometalated rhodium catalyst (4 mol %) under photoredox conditions. The practical method provides yields up to 97% with excellent enantioselectivities up to 99% ee and can be classified as a redox neutral, electron-transfer-catalyzed reaction. PMID- 27218135 TI - Investigation of the inhibitors of histone-lysine N-methyltransferase SETD2 for acute lymphoblastic leukaemia from traditional Chinese medicine. AB - Leukaemia is the leading cause of childhood malignancies. Recent research indicates that the SETD2 gene is associated with acute lymphoblastic leukaemia. This study aims to identify potential lead compounds from traditional Chinese medicine (TCM) using virtual screening for SET domain containing 2 (SETD2) protein against acute lymphoblastic leukaemia. Docking simulation was performed to determine potential candidates which obtain suitable docking poses in the binding domain of the SETD2 protein. We also performed molecular dynamics (MD) simulation to investigate the stability of docking poses of SETD2 protein complexes with the top three TCM candidates and a control. According to the results of docking and MD simulation, coniselin and coniferyl ferulate have high binding affinity and stable interactions with the SETD2 protein. Coniselin is isolated from the alcoholic extract of Comiselinum vaginatum Thell. Coniferyl ferulate can be isolated from Angelica sinensis, Poria cocos (Schw.) Wolf, and Notopterygium forbesii. Although S-adenosyl-L-homocysteine has more stable interactions with key residues in the binding domain than coniselin and coniferyl ferulate during MD simulation, the TCM compounds coniselin and coniferyl ferulate are still potential candidates as lead compounds for further study in the drug development process with the SETD2 protein against acute lymphoblastic leukaemia. PMID- 27218136 TI - Novel endoscopic multi-firing-clip applicator for endoscopic closure of large colonic perforations. AB - BACKGROUND: Existing endoclip closure devices have difficulty in closing large colonic perforation. We developed a novel endoscopic multi-firing-clip applicator (EMFCA) system to address these limitations, and report on its initial evaluation. MATERIAL AND METHODS: The functionality and efficacy of the prototype EMFCA equipped with re-openable clamp and preloaded with four clips were assessed using standardized 1.5 cm incisions created in ex-vivo porcine colonic segments. Endoscopic closure of the lacerations with two, three and four clips (n = five for each group) was followed by measurement of the leakage pressure of the three groups. Finite element analysis (FEA) was performed to validate the clip behavior and reliability during deployment. RESULTS: All 15 perforations were sealed without leakage until fully distended. The leakage pressures of colonic lacerations sealed with two, three, and four clips were 26.1 +/- 2.8 mmHg, 37.3 +/- 7.3 mmHg and 42.3 +/- 7.4 mmHg, respectively. The mean operation time to deploy one clip was 25.4 +/- 5.2 seconds. On FEA, the deformation of the shape of the clip matched that of the intended design, with each clip sustaining a maximum stress of 648.5 MPa without any material failure during deployment. CONCLUSIONS: These initial results confirm the efficacy of the EMFCA prototype system for endoscopic closure of colonic perforations. PMID- 27218137 TI - 3D Printing of Micropatterned Anion Exchange Membranes. AB - Micropatterned anion exchange membranes (AEMs) have been 3D printed via a photoinitiated free radical polymerization and quaternization process. The photocurable formulation, consisting of diurethane dimethacrylate (DUDA), poly(ethylene glycol) diacrylate (PEGDA), dipentaerythritol penta-/hexa- acrylate, and 4-vinylbenzyl chloride (VBC), was directly cured into patterned films using a custom 3D photolithographic printing process similar to stereolithography. Measurements of water uptake, permselectivity, and ionic resistance were conducted on the quaternized poly(DUDA-co-PEGDA-co-VBC) sample series to determine their suitability as ion exchange membranes. The water uptake of the polymers increased as the ion exchange capacity (IEC) increased due to greater quaternized VBC content. Samples with IEC values between 0.98 to 1.63 mequiv/g were synthesized by varying the VBC content from 15 to 25 wt %. The water uptake was sensitive to the PEGDA content in the network resulting in water uptake values ranging from 85 to 410 wt % by varying the PEGDA fractions from 0 to 60 wt %. The permselectivity of the AEM samples decreased from 0.91 (168 wt %, 1.63 mequiv/g) to 0.85 (410 wt %, 1.63 mequiv/g) with increasing water uptake and to 0.88 (162 wt %, 0.98 mequiv/g) with decreasing IEC. Permselectivity results were relatively consistent with the general understanding of the correlation between permselectivity, water uptake, and ion content of the membrane. Lastly, it was revealed that the ionic resistance of patterned membranes was lower than that of flat membranes with the same material volume or equivalent thickness. A parallel resistance model was used to explain the influence of patterning on the overall measured ionic resistance. This model may provide a way to maximize ion exchange membrane performance by optimizing surface patterns without chemical modification to the membrane. PMID- 27218138 TI - Physicochemical Changes and Glycation Reaction in Intermediate-Moisture Protein Sugar Foods with and without Addition of Resveratrol during Storage. AB - An intermediate-moisture food (IMF) model consisting of whey protein isolate and glucose and an IMF model fortified with resveratrol were used to study the effect of resveratrol on physicochemical changes and glycation of protein-sugar-rich foods during storage. The water activity (aw) of the storage was controlled at 0.75 or 0.56. The browning rate or hardness of fortified IMFs was significantly lower than that of IMFs after 45-day storage. The rate of Maillard reaction in the samples stored at aw 0.56 was higher than that of samples stored at aw 0.75. The fortified IMFs had lower levels of AGEs (advanced glycation end products), CML (N(epsilon)-(carboxymethyl)-l-lysine), and insoluble protein during storage. The inhibition capability of resveratrol against glycation was also confirmed by using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), liquid chromatography mass spectrometry (LC-MS), and Fourier transform infrared spectroscopy (FTIR) analysis to monitor glycated proteins and protein aggregation in the samples. The results of this study suggested that resveratrol could be used as an inhibitor to reduce the formation of undesirable AGEs and other Maillard reaction products in foods during storage. PMID- 27218139 TI - Apoptosis Inducing Factor Binding Protein PGAM5 Triggers Mitophagic Cell Death That Is Inhibited by the Ubiquitin Ligase Activity of X-Linked Inhibitor of Apoptosis. AB - Apoptosis inducing factor (AIF) plays a well-defined role in controlling cell death but is also a critical factor for maintaining mitochondrial energy homeostasis; how these dueling activities are balanced has remained largely elusive. To identify new AIF binding partners that may define the continuum of AIF cellular regulation, a biochemical screen was performed that identified the mitochondrial phosphoglycerate mutase 5 (PGAM5) as an AIF associated factor. AIF binds both the short and long isoforms of PGAM5 and can reduce the ability of PGAM5 to control antioxidant responses. Transient overexpression of either PGAM5 isoform triggers caspase activation and cell death, and while AIF could reduce this caspase activation neither AIF expression nor caspase activity is required for PGAM5-mediated death. PGAM5 toxicity morphologically and biochemically resembles mitophagic cell death and is inhibited by the AIF binding protein X linked inhibitor of apoptosis (XIAP) in a manner that depends on the ubiquitin ligase activity of XIAP. The phosphatase activity of PGAM5 was not required for cell death, and comparison of phosphatase activity between short and long PGAM5 isoforms suggested that only the long isoform is catalytically competent. This property correlated with an increased ability of PGAM5L to form dimers and/or higher order oligomers in intact cells compared to PGAM5S. Overall this study identifies an AIF/PGAM5/XIAP axis that can regulate PGAM5 activities related to the antioxidant response and mitophagy. PMID- 27218141 TI - Advancing the Scientific Foundation for Evidence-Based Practice in Clinical Child and Adolescent Psychology. AB - Evidence-based practice (EBP) has become a central focus in clinical child and adolescent psychology. As originally defined, EBP in psychology is the integration of the best available research evidence, patient characteristics, and clinical expertise. Although evidence-based perspectives have garnered widespread acceptance in recent years, there has also been some confusion and disagreement about the 3-part definition of EBP, particularly the role of research. In this article, we first provide a brief review of the development of EBP in clinical child and adolescent psychology. Next, we outline the following 4 points to help clarify the understanding of EBP: (a) knowledge should not be confused with epistemic processes, (b) research on clinician and client factors is needed for EBP, (c) research on assessment is needed for EBP, and (d) the 3-part conceptualization of EBP can serve as a useful framework to guide research. Based on these principles, we put forth a slightly revised conceptualization of EBP, in which the role of research is expanded and more clearly operationalized. Finally, based on our review of the literature, we offer illustrative examples of specific directions for future research to advance the evidence base for EBP in clinical child and adolescent psychology. PMID- 27218140 TI - Vitamin D deficiency and exercise-induced laryngospasm in young competitive rowers. AB - Exercise-induced dyspnea is common among adolescents and young adults and often originates from exercise-induced bronchoconstriction (EIB). Sometimes, dyspnea corresponds to exercise-induced laryngospasm (EILO), which is a paradoxical decrease in supraglottic/glottic area. Vitamin D deficiency, which occurs frequently at northern latitudes, might favor laryngospasm by impairing calcium transport and slowing striate muscle relaxation. The aim of this study was to evaluate whether vitamin D status has an influence on bronchial and laryngeal responses to exercise in young, healthy athletes. EIB and EILO were investigated during winter in 37 healthy competitive rowers (24 males; age range 13-25 years), using the eucapnic voluntary hyperventilation test (EVH). EIB was diagnosed when forced expiratory volume in the first second decreased by 10%, EILO when maximum mid-inspiratory flow (MIF50) decreased by 20%. Most athletes (86.5%) had vitamin D deficiency (below 30 ng/mL), 29 mild-moderate (78.4%) and 3 severe (8.1%). EVH showed EIB in 10 subjects (27%), EILO in 16 (43.2%), and combined EIB and EILO in 6 (16.2%). Athletes with EILO had lower vitamin D (19.1 ng/mL vs. 27.0 ng/mL, p < 0.001) and higher parathyroid hormone (30.5 pg/mL vs. 19.2 pg/mL, p = 0.006) levels. The degree of laryngoconstriction (post-EVH MIF50 as a percentage of pre EVH MIF50) was related directly with vitamin D levels (r = 0.51; p = 0.001) and inversely with parathyroid hormone levels (r = -0.53; p = 0.001). We conclude that vitamin D deficiency is common during winter in young athletes living above the 40th parallel north and favors laryngospasm during exercise, probably by disturbing calcium homeostasis. This effect may negatively influence athletic performance. PMID- 27218143 TI - Composition induced metal-insulator quantum phase transition in the Heusler type Fe2VAl. AB - We report the magnetism and transport properties of the Heusler compound Fe2+x V1 x Al at -0.10 ? x ? 0.20 under pressure and a magnetic field. A metal insulator quantum phase transition occurred at x ~ -0.05. Application of pressure or a magnetic field facilitated the emergence of finite zero-temperature conductivity sigma 0 around the critical point, which scaled approximately according to the power law (P - P c ) (gamma) . At x ? -0.05, a localized paramagnetic spin appeared, whereas above the ferromagnetic quantum critical point at x ~ 0.05, itinerant ferromagnetism was established. At the quantum critical points at x = -0.05 and 0.05, the resistivity and specific heat exhibited singularities characteristic of a Griffiths phase appearing as an inhomogeneous electronic state. PMID- 27218142 TI - The ginsenoside metabolite compound K exerts its anti-inflammatory activity by downregulating memory B cell in adjuvant-induced arthritis. AB - CONTEXT: Compound K (CK, 20-O-d-glucopyranosyl-20(S)-protopanaxadiol), a novel ginsenoside metabolite, is structurally a member of the dammarane-type triterpene saponins. Several studies have identified the anti-inflammatory activity of CK. Our previous study demonstrated that CK exerted its anti-inflammatory effect via inhibition of abnormal activation and differentiation of T cells. However, its mechanism of action on B cells remains unclear. OBJECTIVE: The objective of this study is to investigate the effect and underlying mechanisms of CK's effects on memory B cells in the setting of adjuvant-arthritis (AA). MATERIALS AND METHODS: Complete Freund's adjuvant was used to induce AA in rats. Rats were administered, either CK (10, 40, and 160 mg/kg), once daily for 15 d, or methotrexate (MTX; 0.5 mg/kg) once every 3 d, for a total of six times. To evaluate the anti inflammatory effect of CK, a global assessment and a swollen joint count of AA rats were performed every 3 d. Spleen index and histopathology were examined. Subsets of B cells including CD45R(+)IgM(+) (total B cells) and CD45R(+)CD27(+) (memory B cells) and expression of CD40 and CD40L were assayed by flow cytometry. RESULTS: Compared with the AA rats, global assessment scores and swollen joint counts were significantly lower in the treated groups received CK (40 and 160 mg/kg; p < 0.05 and p < 0.01, respectively). CK (40 and 160 mg/kg) decreased the spleen index (p < 0.01), and alleviated hyperplasia of lymph nodes (p < 0.05 and p < 0.01, respectively) and marginal zone (p < 0.05) in the spleen. In addition, CK (40 and 160 mg/kg) suppressed memory B cell subsets (p < 0.05), and suppressed CD40L expression on T cells and CD40 expression on B cells (p < 0.05 and p < 0.01, respectively). DISCUSSION AND CONCLUSION: This study demonstrated that CK downregulated memory B cells in AA rats, and this down-regulation may be T-cell dependent. PMID- 27218144 TI - Multiple effects of magnesium isoglycyrrhizinate on the disposition of docetaxel in docetaxel-induced liver injury. AB - 1. Magnesium isoglycyrrhizinate (MgIg) has been extensively used in treating liver injury which is the common adverse reaction of docetaxel (DOC). Due to the narrow therapeutic window, small changes in pharmacokinetic profiles can alter the toxicity and therapeutic efficacy of DOC significantly. The study aimed to explore the effects of MgIg on the disposition of DOC and the potential mechanism in DOC-induced liver injury. 2. Pharmacokinetics and tissues distribution behaviors showed that there was no significant difference between DOC group (DOCG) and MgIg + DOC group (MDOCG). The mRNA and protein levels of cytochrome P450 3A1 (CYP3A1) in liver, intestine, and kidney were significantly upregulated, and the P-glycoprotein (P-gp) was obviously downregulated in MDOCG when compared with DOCG. 3. Immunoglobulin M (IgM), CD8+ were upregulated in DOCG; while in MDOCG, IgM, CD8+ recovered to normal levels and complement C3; CD4+ were upregulated. 4. MgIg had no significant effects on the disposition of DOC in docetaxel-induced liver injury. Additional, potential drug-drug interaction may happen if MgIg co-administered with antitumor drugs which are the substrates of CYP3A4 or P-gp. Hepatoprotective mechanism of MgIg perhaps was through upregulation of C3, CD4+ and downregulation of IgM, CD8+. PMID- 27218145 TI - Coronary artery ectasia: new insights into pathophysiology, diagnosis, and treatment. AB - Coronary artery ectasia (CAE) is defined as a segment of the coronary artery that has a diameter of more than 1.5 times the normal adjacent segments. It was described many years ago, but many aspects of this phenomenon are still unknown. It can be found in 1.2-2% of patients referred for coronary angiography. Risk factors are similar to atherosclerosis, but not in all patients. Histology shows extensive destruction of the musculoelastic elements, with marked degradation of the medial collagen and elastin fibers with disruption of the internal and external elastic lamina. These patients have abnormal levels of matrix metalloproteinases and other related proteins. Yet, the actual etiology of CAE is still unknown. Advances in new and improved imaging modalities such as CT and magnetic resonance angiography enable easier and more accessible diagnosis and evaluation. Treatment is aimed mostly at common cardiovascular risk factors. In small series, CAE was associated with worse prognosis. Anticoagulation was never examined in large trials. Nitrates worsen the flow and should not be administered. Interventional treatments are also an option, but a challenging one. This review presents an update on the current knowledge on CAE. PMID- 27218146 TI - Associations between the Framingham Risk Score and coronary plaque characteristics as assessed by three-vessel optical coherence tomography. AB - OBJECTIVES: This study sought to explore the association between the Framingham Risk Score (FRS) and coronary plaque characteristics assessed by optical coherence tomography (OCT) imaging. BACKGROUND: Clinical prediction models are useful for identifying high-risk patients. However, coronary events often occur in individuals estimated to be at low risk. METHODS: A total of 254 patients with coronary artery disease who underwent three-vessel OCT were divided into tertiles according to FRS. Nonculprit plaque characteristics were compared among the three groups. RESULTS: A total of 663 plaques were analyzed. FRS was significantly associated with calcification [37% (low FRS) vs. 46% (intermediate FRS) vs. 70% (high FRS); P<0.001] and neovascularization [39% (low FRS) vs. 41% (intermediate FRS) vs. 56% (high FRS); P<0.001], but not with lipid-rich plaques or thin-cap fibroatheroma (TCFA). On multivariate analysis, FRS was an independent predictor of the presence of both calcification and neovascularization. There were no deaths, two acute myocardial infarctions, and 15 nontarget lesion revascularizations at the 1-year follow-up. The event rate increased progressively across FRS tertiles [2.4% (low FRS) vs. 7.1% (intermediate FRS) vs. 8.6% (high FRS); P=0.186]. The c-statistic for FRS to predict future clinical events was 0.628 (95% confidence interval, 0.500-0.757). The addition of both calcification and TCFA to FRS provided incremental prognostic value [c statistics: 0.761 (95% confidence interval, 0.631-0.890)]. CONCLUSION: The present study showed significant associations between FRS and the presence of coronary calcification and neovascularization in nonculprit plaques. The combination of FRS and OCT-detected calcifications and TCFA provides improved prognostic ability in identifying patients with known coronary artery disease who are at risk of recurrent events. PMID- 27218147 TI - Association of KALRN, ADIPOQ, and FTO gene polymorphism in type 2 diabetic patients with coronary artery disease: possible predisposing markers. AB - OBJECTIVES: Recently, several genes have been introduced as potential genetic markers for diabetes mellitus and coronary artery diseases (CAD). METHODS: In this case-control study, the associations of rs2241766 T/G of ADIPOQ, rs9289231 T/G of KALRN, and rs9939609 A/T of FTO polymorphisms with genetic susceptibility to CAD in type 2 diabetic (T2D) patients were investigated. A total of 224 T2D patients undergoing coronary angiography were randomly recruited into the study. Of the total diabetic patients, 152 were also diagnosed with CAD, whereas the rest were control participants. Genotyping of single-nucleotide polymorphisms was performed by high-resolution melting analysis. RESULTS: Genotype analysis showed that the minor allele (G) frequency of rs2241766 ADIPOQ was statistically significant in the CAD group compared with the control group [odds ratio (OR), 2.779; 95% confidence interval (CI), 1.403-5.504; P=0.003]. Also, it was found that the minor allele (G) frequency of rs9289231 KALRN was significantly associated with the risk of CAD (OR, 2.098; 95% CI, 1.096-4.017; P=0.025). In addition, no significant association was observed between the minor allele (A) of the FTO rs9939609 polymorphism and CAD (OR, 1.088; 95% CI, 0.578-2.015; P=0.788). It is speculated that the GG genotype and the G allele of the rs9289231 polymorphism of KALRN and the rs224766 polymorphism of ADIPOQ genes may be considered genetic risk factors for CAD in T2D patients and genetic variations of these genes may play a major role in the process of these disorders. CONCLUSION: Our case-control study in the Iranian population suggested a possible association between the mentioned single-nucleotide polymorphisms and CAD in T2D patients. However, further replication studies and comprehensive meta-analyses are required. PMID- 27218148 TI - Abnormal Mechanisms of Plasticity and Metaplasticity in Autism Spectrum Disorders and Fragile X Syndrome. AB - OBJECTIVES: Multiple lines of evidence from genetic linkage studies to animal models implicate aberrant cortical plasticity and metaplasticity in the pathophysiology of autism spectrum disorder (ASD) and fragile X syndrome (FXS). However, direct experimental evidence of these alterations in humans with these disorders is scarce. Transcranial magnetic stimulation (TMS) is a noninvasive tool for probing mechanisms of plasticity and metaplasticity in vivo, in humans. The aim of the current study was to examine mechanisms of plasticity and metaplasticity in humans with ASD and FXS. We employed a repetitive TMS protocol developed specifically to probe cortical plasticity, namely continuous theta burst stimulation (cTBS). METHODS: We applied a 40-second train of cTBS to primary motor cortex (M1) to healthy control participants and individuals with ASD or FXS, and we measured the cTBS-induced modulation in motor-evoked potentials (MEPs) in a contralateral intrinsic hand muscle. Each participant completed two sessions of the same protocol on two consecutive days. The degree of modulation in MEPs after cTBS on the first day was evaluated as a putative index of cortical plasticity. Examination of the changes in the effects of cTBS on the second day, as conditioned by the effects on the first day, provided an index of metaplasticity, or the propensity of a given cortical region to undergo plastic change based on its recent history. RESULTS: After a 40-second cTBS train, individuals with ASD show a significantly longer duration of suppression in MEP amplitude as compared with healthy controls, whereas individuals with FXS show a significantly shorter duration. After a second train of cTBS, 24 hours later, the ASD group was indistinguishable from the control group, and while in the FXS group MEPs were paradoxically facilitated by cTBS. CONCLUSION: These findings offer insights into the pathophysiology of ASD and FXS, specifically providing direct experimental evidence that humans with these disorders show distinct alterations in plasticity and metaplasticity, consistent with the findings in animal models. If confirmed in larger test-retest studies, repeated TMS measures of plasticity and metaplasticity may provide a valuable physiologic phenotype for ASD and FXS. PMID- 27218150 TI - Muscle satellite cell content and mRNA signaling in germ cell cancer patients - effects of chemotherapy and resistance training. PMID- 27218149 TI - FOXE3 contributes to Peters anomaly through transcriptional regulation of an autophagy-associated protein termed DNAJB1. AB - FOXE3 is a lens-specific transcription factor that has been associated with anterior segment ocular dysgenesis. To determine the transcriptional target(s) of FOXE3 that are indispensable for the anterior segment development, we examined the transcriptome and the proteome of cells expressing truncated FOXE3 responsible for Peters anomaly identified through linkage-coupled next-generation whole-exome sequencing. We found that DNAJB1, an autophagy-associated protein, was the only candidate exhibiting differential expression in both screens. We confirmed the candidacy of DNAJB1 through chromatin immunoprecipitation and luciferase assays while knockdown of DNAJB1 in human lens epithelial cells resulted in a mitotic arrest. Subsequently, we targeted dnajb1a in zebrafish through injection of a splice-blocking morpholino. The dnajb1a morphants exhibited underdeveloped cataractous lenses with persistent apoptotic nuclei. In conclusion, here we report DNAJB1 is a transcriptional target of FOXE3 in a novel pathway that is crucial for the development of the anterior segment of the eye. PMID- 27218151 TI - Dose-Dependent Changes in Auditory Sensory Gating in the Prefrontal Cortex of the Cynomolgus Monkey. AB - BACKGROUND Sensory gating, often described as the ability to filter out irrelevant information that is repeated in close temporal proximity, is essential for the selection, processing, and storage of more salient information. This study aimed to test the effect of sensory gating under anesthesia in the prefrontal cortex (PFC) of monkeys following injection of bromocriptine, haloperidol, and phencyclidine (PCP). MATERIAL AND METHODS We used an auditory evoked potential that can be elicited by sound to examine sensory gating during treatment with haloperidol, bromocriptine, and PCP in the PFC in the cynomolgus monkey. Scalp electrodes were located in the bilateral PFC and bilateral temporal, bilateral parietal, and occipital lobes. Administration of bromocriptine (0.313 mg/kg, 0.625 mg/kg, and 1.25 mg/kg), haloperidol (0.001 mg/kg, 0.01 mg/kg, and 0.05 mg/kg), and the N-methyl-D-aspartic acid receptor antagonist PCP (0.3 mg/kg) influenced sensory gating. RESULTS We demonstrated the following: (1) Administration of mid-dose bromocriptine disrupted sensory gating (N100) in the right temporal lobe, while neither low-dose nor high-dose bromocriptine impaired gating. (2) Low-dose haloperidol impaired gating in the right prefrontal cortex. Mid-dose haloperidol disrupted sensory gating in left occipital lobe. High-dose haloperidol had no obvious effect on sensory gating. (3) Gating was impaired by PCP in the left parietal lobe. CONCLUSIONS Our studies showed that information processing was regulated by the dopaminergic system, which might play an important role in the PFC. The dopaminergic system influenced sensory gating in a dose- and region-dependent pattern, which might modulate the different stages that receive further processing due to novel information. PMID- 27218197 TI - Carotenoid-to-Bacteriochlorophyll Energy Transfer in the LH1-RC Core Complex of a Bacteriochlorophyll b Containing Purple Photosynthetic Bacterium Blastochloris viridis. AB - Carotenoid-to-bacteriochlorophyll energy transfer has been widely investigated in bacteriochlorophyll (BChl) a-containing light harvesting complexes. Blastochloris viridis utilizes BChl b, whose absorption spectrum is more red-shifted than that of BChl a. This has implications on the efficiency and pathways of carotenoid-to BChl energy transfer in this organism. The carotenoids that comprise the light harvesting reaction center core complex (LH1-RC) of B. viridis are 1,2 dihydroneurosporene and 1,2-dihydrolycopene, which are derivatives of carotenoids found in the light harvesting complexes of several BChl a-containing purple photosynthetic bacteria. Steady-state and ultrafast time-resolved optical spectroscopic measurements were performed on the LH1-RC complex of B. viridis at room and cryogenic temperatures. The overall efficiency of carotenoid-to bacteriochlorophyll energy transfer obtained from steady-state absorption and fluorescence measurements were determined to be ~27% and ~36% for 1,2 dihydroneurosporene and 1,2-dihydrolycopene, respectively. These results were combined with global fitting and target analyses of the transient absorption data to elucidate the energetic pathways by which the carotenoids decay and transfer excitation energy to BChl b. 1,2-Dihydrolycopene transfers energy to BChl b via the S2 -> Qx channel with kET2 = (500 fs)(-1) while 1,2-dihydroneurosporene transfers energy via S1-> Qy (kET1 = (84 ps)(-1)) and S2 -> Qx (kET2 = (2.2 ps)( 1)) channels. PMID- 27218198 TI - Early impact of Medicare accountable care organizations on cancer surgery outcomes. AB - BACKGROUND: Accountable care organizations (ACOs) were established to improve care and outcomes for beneficiaries requiring highly coordinated, complex care. The objective of this study was to evaluate the association between hospital ACO participation and the outcomes of major surgical oncology procedures. METHODS: This was a retrospective cohort study of Medicare beneficiaries older than 65 years who were undergoing a major surgical resection for colorectal, bladder, esophageal, kidney, liver, ovarian, pancreatic, lung, or prostate cancer from 2011 through 2013. A difference-in-differences analysis was implemented to compare the postimplementation period (January 2013 through December 2013) with the baseline period (January 2011 through December 2012) to assess the impact of hospital ACO participation on 30-day mortality, complications, readmissions, and length of stay (LOS). RESULTS: Among 384,519 patients undergoing major cancer surgery at 106 ACO hospitals and 2561 control hospitals, this study found a 30 day mortality rate of 3.4%, a readmission rate of 12.5%, a complication rate of 43.8%, and a prolonged LOS rate of 10.0% in control hospitals and similar rates in ACO hospitals. Secular trends were noted, with reductions in perioperative adverse events in control hospitals between the baseline and postimplementation periods: mortality (percentage-point reduction, 0.1%; P = .19), readmissions (percentage-point reduction, 0.4%; P = .001), complications (percentage-point reduction, 1.0%; P < .001), and prolonged LOS (percentage-point reduction, 1.1%; P < .001). After accounting for these secular trends, this study identified no significant effect of hospital participation in an ACO on the frequency of perioperative outcomes (difference-in-differences estimator P values, .24-.72). CONCLUSIONS: Early hospital participation in the Medicare Shared Savings Program ACO program was not associated with greater reductions in adverse perioperative outcomes for patients undergoing major cancer surgery in comparison with control hospitals. Cancer 2016. (c) 2016 American Cancer Society. Cancer 2016;122:2739 2746. (c) 2016 American Cancer Society. PMID- 27218199 TI - Chemoselective Schwartz Reagent Mediated Reduction of Isocyanates to Formamides. AB - Addition of the in situ generated Schwartz reagent to widely available isocyanates constitutes a chemoselective, high-yielding, and versatile approach to the synthesis of variously functionalized formamides. Steric and electronic factors or the presence of sensitive functionalities (esters, nitro groups, nitriles, alkenes) do not compromise the potential of the method. Full preservation of the stereochemical information contained in the starting materials is observed. The use of formamides in the nucleophilic addition of organometallic reagents (Chida-Sato allylation, Charette-Huang addition to imidoyl triflate activated amides, Matteson homologation of boronic esters) is briefly investigated. PMID- 27218200 TI - Pneumothorax following shoulder arthroscopy under combined regional and general anaesthesia-A case report. AB - INTRODUCTION: Pneumothorax is a most rare intraoperative event but jeopardise safety. Risk factors for its occurrence should be acknowledged and it should be considered in cases of unexpected deterioration of oxygenation that not respond to standard management to improve oxygenation. PRESENTATION OF CASE: We describe a patient with mild obesity and recent shoulder trauma scheduled for elective arthroscopy under combined interscalene block and general anaesthesia in the beach chair position. The block was performed with ultrasound guidance in accordance with the departmental routines and before the induction of general anaesthesia. The patient experienced low saturation shortly after administration of general anaesthesia. A thoracic ultrasound was performed in order to rule out pneumothorax and recruitment manoeuvres was done based on the suspicion of atelectasis. Surgery was commenced under pressure controlled ventilation and saturation was kept around 90 at FiO2 1.0 after recruitment manoeuvres. An initial postoperative lung X-ray on the operating table showed subcutaneous emphysema but no pneumothorax. A postoperative CT-thorax, patient still intubated, showed an extensive pneumothorax that was treated with pulmonary drainage. Patient had subsequently an uncomplicated postoperative course. DISCUSSION: We can not state "whom to blame", the interscalene block, intubation and pressures assisted ventilation, recruitment manoeuvres, or surgery? In this paper we discuss possible causes that should raise the suspicion around pneumothorax in patients exhibiting unexpected low saturation perioperatively. CONCLUSION: Compromised oxygenation during surgery that not respond to recruitment should raise suspicion about pneumothorax. PMID- 27218201 TI - Elevated prothrombin time on routine preoperative laboratory results in a healthy infant undergoing craniosynostosis repair: Diagnosis and perioperative management of congenital factor VII deficiency. AB - INTRODUCTION: Congenital factor VII deficiency is a rare bleeding disorder with high phenotypic variability. It is critical that children with congenital Factor VII deficiency be identified early when high-risk surgery is planned. Cranial vault surgery is common for children with craniosynostosis, and these surgeries are associated with significant morbidity mostly secondary to the risk of massive blood loss. PRESENTATION OF CASE: A two-month old infant who presented for elective craniosynostosis repair was noted to have an elevated prothrombin time (PT) with a normal activated partial thromboplastin time (aPTT) on preoperative labs. The infant had no clinical history or reported family history of bleeding disorders, therefore a multidisciplinary decision was made to repeat the labs under general anesthesia and await the results prior to incision. The results confirmed the abnormal PT and the case was canceled. Hematologic workup during admission revealed factor VII deficiency. The patient underwent an uneventful endoscopic strip craniectomy with perioperative administration of recombinant Factor VIIa. DISCUSSION: Important considerations for perioperative laboratory evaluation and management in children with factor VII deficiency are discussed. Anesthetic and surgical management of the child with factor VII deficiency necessitates meticulous planning to prevent life threatening bleeding during the perioperative period. CONCLUSION: A thorough history and physical examination with a high clinical suspicion are vital in preventing hemorrhage during surgeries in children with coagulopathies. Abnormal preoperative lab values should always be confirmed and addressed before proceeding with high-risk surgery. A multidisciplinary discussion is essential to optimize the risk-benefit ratio during the perioperative period. PMID- 27218202 TI - A comparison of the caring behaviours of nursing students and registered nurses: implications for nursing education. AB - AIMS AND OBJECTIVES: To compare the respective views of nursing students and registered nurses on caring behaviours. BACKGROUND: Research has indicated that nursing includes not only technical skills and professional knowledge but also the expression of care. In addition to nursing care, nurses demonstrate the acts of supporting, negotiating, reinforcing and transforming. However, little research simultaneously investigates the caring behaviours of nursing students and registered nurses. DESIGN: A cross-sectional study was conducted. METHODS: A total of 657 subjects participated in this study. The research tool was a self administered structured questionnaire. Data were analysed using descriptive statistics, one-way analysis of variance, t-test and chi-square test. RESULTS: The results showed that the most important caring behaviour is 'knowing the patient', while the least is 'advocating for the patient', which includes caring behaviours to respect the patient's and family's best interests, and voicing for them, possibly because this behaviour is more difficult for nurses to practice in the Taiwanese culture. Moreover, there was no significant difference in the caring behaviours between nursing students and registered nurses. However, age was found to be a significant difference in the caring behaviours of nursing students and registered nurses. CONCLUSION: Caring behaviour is essential in clinical practice. Based on the results, this study suggested that role models should be provided to nursing students to develop proper caring behaviours. Nursing faculty can boost nursing students' interests in learning caring behaviours by incorporating diverse teaching strategies to enhance the effectiveness of caring behaviours. RELEVANCE TO CLINICAL PRACTICE: Much attention should be focused on education about awareness of caring behaviour for both nursing students and nursing staff. This study addressed that nursing administrators and faculty members should emphasise the importance of the essence of caring. Consequently, nursing curricula and training of nurses need to be concerned with implementing caring behaviour in clinical practice. PMID- 27218203 TI - Exploratory study on the prevalence of suicidal behavior, mental health, and social support in female street sex workers in Porto, Portugal. AB - We investigated suicidal behavior, mental health, and satisfaction with social support in 52 female street sex workers in Porto, Portugal, using the Suicidal Ideation Questionnaire, the Social Support Satisfaction Scale, and structured interviews. Almost half our interviewees (46.15%) reported high suicidal ideation and 44.2% had made at least one suicide attempt. Most had a mental health diagnosis, most commonly depression (88.2%). Social support and suicidal ideation were moderately negatively correlated. Further research is needed to improve understanding of suicidal behaviors in female sex workers and develop interventions to improve social support and reduce suicidal ideation and associated risk factors. PMID- 27218205 TI - Variation in properties of the sediment following electrokinetic treatments. AB - Many studies have reported variation in properties of the sediment within electrokinetic treatments (EKTs). However, we aim to reveal the variation in properties of the sediment following EKTs through laboratory experiments. We collected sewage-derived sediment from a littoral region, and passed it through a 2-mm sieve. We used a potentiostat to cause electrical current in EKT. We measured the sediment properties such as pH, redox potential (ORP), and hydrogen sulphide (H2S) concentration at the end of EKT and at 30 days following EKT. Results showed decreases in pH, increases in ORP, and decreases in H2S concentration at the end of EKT. Compared with the sediment without EKT, the decrease in ORP for the sediment within EKT was higher at 30 days following EKT. These suggest that anaerobic digestion of organic compounds occurs in the sediment following EKT, of which the oxidants produced by EKT serve as electron acceptors and organic compounds serve as electron donors. Furthermore, we found that EKT can remove H2S from the sediment and reduce H2S production in the sediment within EKT when compared to the case without EKT. These ensure that EKT can be used to remove H2S and control H2S production in the sediment. PMID- 27218204 TI - RNA as a fundamental component of interphase chromosomes: could repeats prove key? AB - Beginning with the precedent of XIST RNA as a 'chromosomal RNA' (cRNA), there is growing interest in the possibility that a diversity of non-coding RNAs may function in chromatin. We review findings which lead us to suggest that RNA is essentially a widespread component of interphase chromosomes. Further, RNA likely contributes to architecture and regulation, with repeat-rich 'junk' RNA in euchromatin (ecRNA) promoting a more open chromatin state. Thousands of low abundance nuclear RNAs have been reported, however it remains a challenge to determine which of these may function in chromatin. Recent findings indicate that repetitive sequences are enriched in chromosome-associated non-coding RNAs, and repeat-rich RNA shows unusual properties, including localization and stability, with similarities to XIST RNA. We suggest two frontiers in genome biology are emerging and may intersect: the broad contribution of RNA to interphase chromosomes and the distinctive properties of repeat-rich intronic or intergenic junk sequences that may play a role in chromosome structure and regulation. PMID- 27218206 TI - Medical mall founders' satisfaction and integrated management requirements. AB - Medical malls help provide integrated medical services and the effective and efficient independent management of multiple clinics, pharmacies and other medical facilities. Primary care in an aging society is a key issue worldwide and the establishment of a new model for primary care in Japanese medical malls is needed. Understanding the requirements of integrated management that contribute to the improvement of medical mall founders' satisfaction levels will help provide better services. We conducted a questionnaire survey targeting 1840 medical facilities nationwide; 351 facilities responded (19.1%). We performed comparative analyses on founders' satisfaction levels according to years in business, department/area, founder's relationship, decision-making system and presence/absence of liaison role. A total of 70% of medical malls in Japan have adjacent relationships with no liaison role in most cases; however, 60% of founders are satisfied. Integrated management requirements involve establishing the mall with peers from the same medical office unit or hospital, and establishing a system in which all founders can participate in decision-making (council system) or one where each general practitioner (GP) independently runs a clinic without communicating with others. The council system can ensure the capability of general practitioners to treat many primary care patients in the future. (c) 2016 The Authors. The International Journal of Health Planning and Management Published by John Wiley & Sons Ltd. PMID- 27218208 TI - Long-term clinical experience with darunavir (2007-2015) in a large cohort of HIV infected patients in Spain. AB - The clinical experience with the protease inhibitor darunavir/ritonavir (DRV/r) was retrospectively evaluated in a cohort of 173 HIV+ patients who initiated antiretroviral treatment including DRV/r (period 2007-2015). The 43.2% had a CD4 nadir <=100 cells/mm3 , 64.1% were treatment-experienced, and 36.5% had failed to >3 lines of antiretroviral therapy. Nonetheless, the rate of virological suppression (HIV-RNA <50 copies/ml) in naive patients was 63%, 66.7%, and 63.6% at 48, 96, and 144 weeks, respectively. The rate of virological suppression in treatment-experienced patients was 62.7%, 78.7%, and 79.1% at 48, 96, and 144 weeks, respectively. No differences were observed according to the immunovirological status neither dosage of DRV/r. Most of them (82.6%) maintained DRV/r treatment. Causes for DRV/r discontinuation were mainly gastrointestinal and cutaneous adverse events (10.5%), switch to simplification treatment strategies (3.5%) and virological failure (1.7%). These findings demonstrate the prolonged efficacy and tolerability of DRV/r even in multi-treated HIV+ patients with an unfavorable immunovirological status. J. Med. Virol. 88:2125-2131, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27218209 TI - The role of ascitic fluid viscosity in differentiating the nature of ascites and in the prediction of renal impairment and duration of ICU stay. AB - BACKGROUND AND AIM: Serum-ascites albumin gradient (SAAG) has been used in the classification of ascites for the last 20 years but it has some drawbacks. This study searches for possible correlations between ascitic fluid viscosity and the etiology of ascites, renal impairment, and length of ICU stay. MATERIALS AND METHODS: The study was conducted in Zagazig University Hospital, Egypt. It included 240 patients with ascites due to various causes. The patients were divided into two groups: the cirrhotic ascites group, which included 120 patients, and the noncirrhotic ascites group, which included 120 patients. Ascitic patients on medical management with diuretics, antibiotics, paracentesis, and infusion of plasma or albumin were excluded.The laboratory analysis included routine investigations to detect the cause of ascites as well as specific investigations such as ascitic fluid viscosity using a falling ball viscosimeter (microviscosimeter) at 37 degrees C. RESULTS: The mean ascitic viscosity of patients with SAAG at least 1.1 was 1.16+/-0.56, which was associated with serum creatinine 1.35+/-0.52 mg/dl and ICU stay of 3.3+/-1.2 days. In patients with SAAG less than 1.1 g/dl, the mean ascitic viscosity was 2.98+/-0.87, with serum creatinine 2.1+/-0.56 mg/dl and ICU stay of 7.1+/-1.3 days. Ascitic viscosity can discriminate ascites due to portal hypertension from those associated with nonportal hypertension at a cut-off value of 1.65; it can predict renal impairment in hepatic patients at a cut-off of 1.35 and long ICU stay at a cut off of 1.995 using receiver operating characteristic analysis. CONCLUSION: Ascitic viscosity measurement is rapid, inexpensive, and requires small sample volumes. Ascitic viscosity can discriminate ascites due to portal hypertension from those associated with nonportal hypertension at a cut-off value of 1.65. It can predict renal impairment in hepatic patients at a cut-off of 1.35 and long ICU stay at a cut-off of 1.995. PMID- 27218210 TI - Influence of Nanosegregation on the Surface Tension of Fluorinated Ionic Liquids. AB - We have investigated, both theoretically and experimentally, the balance between the presence of alkyl and perfluoroalkyl side chains on the surface organization and surface tension of fluorinated ionic liquids (FILs). A series of ionic liquids (ILs) composed of 1-alkyl-3-methylimidazolium cations ([CnC1im] with n = 2, 4, 6, 8, 10, or 12) combined with the perfluorobutanesulfonate anion was used. The surface tensions of the investigated liquid salts are considerably lower than those reported for non-fluorinated ionic liquids. The most surprising and striking feature is the identification, for the first time, of a minimum at n = 8 in the surface tension versus the length of the IL cation alkyl side chain. Supported by molecular dynamics (MD) simulations, it was found that this trend is a result of the competition between the two nonpolar domains (perfluorinated and aliphatic) pointing toward the gas-liquid interface, a phenomenon which occurs in ILs with perfluorinated anions. Furthermore, these ILs present the lowest surface entropy reported to date. PMID- 27218211 TI - Correlates of physical activity in people living with psychotic illness. AB - OBJECTIVE: In the light of the high prevalence of physical comorbidities in people with psychotic illness, there is a need to explore modifiable risk factors that may contribute to this disease burden. The benefits of physical activity to both physical and mental health have been well established. We aimed to examine the prevalence and correlates of physical activity in a national sample of adults living with psychotic illness. METHODS: Physical activity was assessed in 1801 people using the International Physical Activity Questionnaire. Participants were dichotomised into low and moderate-high physical activity groups and associations between physical activity and a range of sociodemographic, clinical and physical comorbidity variables were examined using logistic regression. RESULTS: More than half the participants were categorised in the moderate-high physical activity group with nearly half of the sample engaged in physical activity every day. There were significant associations between low physical activity and older age, unemployment, educational non-participation, antipsychotic medication use, social dysfunction, self-reported loneliness and obesity. However, there was no significant association between physical activity and sex, psychosis type, illness duration, physical comorbidity or negative symptoms. CONCLUSION: The findings from this study may inform future interventions designed to increase physical activity in people with psychotic illness. PMID- 27218213 TI - [Occupational Allergies to Trypsin and Chymotrypsin]. AB - Trypsin and chymotrypsin are proteolytic pancreatic enzymes that are secreted as the inactive precursors trypsinogen and chymotrypsinogen, respectively. They have several pharmacological as well as laboratory applications, especially in protein chemistry. Exposure to enzyme dusts has long been known to cause immediate occupational hypersensitivities of the airways. Also trypsin and chymotrypsin are potential inhalable sensitizers, and clear cases of specific airway sensitization caused by trypsin- and chymotrypsin-containing products have been reported by several studies. Positive skin prick and challenge tests as well as specific IgE antibodies have been described. These results and the clinical symptoms usually matched well, suggesting an immunological mechanism of action. Immediate urticarial reactions of the skin due to contact with these enzymes are possible, but there is no clear evidence of allergic cell-mediated delayed eczematous skin reactions. PMID- 27218212 TI - [The Role of Bronchoalveolar Lavage in the Diagnosis of Idiopathic Pulmonary Fibrosis: An Investigation of the Relevance of the Protein Content]. AB - Although bronchoalveolar lavage (BAL) is often used in the diagnosis of interstitial lung diseases (ILDs), its importance in investigating, in particular, idiopathic pulmonary fibrosis (IPF) is controversial. The cell distributions in the BAL are taken into account in the clinical routine, non cellular characteristics of the BAL play no role.Using mathematical modeling of data, the present work investigated the extent to which BAL features enable drawing conclusions about the underlying ILK or help exclude IPF. Included in the calculation are cellular findings of the BAL, in addition the protein and albumin content of the BAL, the nicotine history (pack years), and spirometry (FEV1, IVC).Using linear discriminant analysis and creating classification trees, the relevance of the characteristics of 806 patients with ILK was examined (183 IPF, 191 cryptogenic organizing pneumonia, 147 lung involvement in autoimmune disease, 97 respiratory bronchiolitis interstitial lung disease, 118 extrinsic allergic alveolitis, 41 lymphocytic interstitial pneumonia (LIP), 23 non-specific interstitial pneumonia (NSIP), 88 controls).There was a close positive relationship between protein levels and lymphocytes in the group as a whole. No such correlations were seen in IPF and NSIP. Albumin was closely correlated with the protein content in all groups.The lymphocytes are best suited to distinguish between different ILDs. Yet, a reliable calculation of the ILD is not possible on the basis of the investigated factors, the classification error ranged from 23.5 % (IPF) to 100 % (LIP, NSIP).Constellations that likely (> 99 %) speak against an IPF are lymphocytosis > 34 % or protein content > 347 mg/l. The same applies to the constellation: lymphocytes > 25 % together with protein > 250 mg/l.In ILD, BAL findings can narrow the diagnosis, but they are seldom diagnostic. BAL can make an important contribution to excluding of IPF. PMID- 27218214 TI - [Relevance of Outpatient, Equipment-based Exercise Training in Patients with Chronic Respiratory Diseases]. AB - Exercise training is one of the most important components in disease management for patients with chronic respiratory diseases. The clinically relevant benefits of endurance and strength training on dyspnea, exercise capacity and quality of life have been evaluated very well. However, there are some legal limitations by the German Working Group for Rehabilitation (BAR) concerning outpatient exercise training programs (beyond pulmonary rehabilitation): only group-based callisthenic training programs receive funding from health care insurances while professional equipment-based training programs are excluded despite their outstanding effectiveness.This review provides an overview on the methodology and the benefits of outpatient exercise training programs for patients with chronic respiratory diseases, and it critically discusses the organizational structures of these programs in Germany. PMID- 27218215 TI - Approach to the diagnosis of skeletal dysplasias: Experience at a center with limited resources. AB - PURPOSE: A fetus with skeletal disorder poses diagnostic challenges in a resource poor setting with limited management options. The objective of the study was to develop a step-by-step approach for the diagnosis of skeletal dysplasia in light of the limited resources available. METHODS: An algorithmic approach was used. The assessment for lethality was the first step, followed by the evaluation for fractures. In cases without evidence of fracture, severe constriction of thorax or associated polydactyly were searched for. In cases without severe thoracic constriction, the severity of micromelia was evaluated. After delivery, fetal examination was done to ascertain the etiology. RESULTS: During the 6-year period, 41 cases with shortened long bones were fully evaluated. Lethality was suspected in 30 cases. Fracture and beading were present in eight cases, and severe thoracic constriction with polydactyly was observed in seven cases. Mild micromelia was seen in 19 cases and severe micromelia in 7 cases. Among lethal skeletal dysplasias, thanatophoric dysplasia was most common (six cases). Among nonlethal skeletal dysplasias, achondroplasia was seen in eight cases. CONCLUSIONS: Lethality of skeletal dysplasia could be predicted on prenatal ultrasound with 100% accuracy. The step-by-step approach was helpful to characterize skeletal dysplasias. (c) 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:529-539, 2016. PMID- 27218216 TI - Elevated expression levels of serum insulin-like growth factor-1, tumor necrosis factor-alpha and vascular endothelial growth factor 165 might exacerbate type 2 diabetic nephropathy. AB - AIMS/INTRODUCTION: The present study aimed to determine the associations between expressions of insulin-like growth factor-1 (IGF-1), tumor necrosis factor-alpha (TNF-alpha) and vascular endothelial growth factor 165 (VEGF165 ) in serum, and occurrence and development of type 2 diabetic nephropathy (DN). MATERIALS AND METHODS: A total of 108 patients diagnosed as DN were randomly selected, including 50 patients in the microalbuminuria group, 44 patients in the macroalbuminuria group and 14 patients in the renal insufficiency group. Meanwhile, 97 healthy people were collected as a normal control group. Urinary albumin (UALB) and urine creatinine (Cr) of all participants were measured for 24 h, with their ratio (UALB/Cr) being calculated. Enzyme-linked immunosorbent assay was used to detect the serum concentrations of IGF-1, TNF-alpha and VEGF165 . RESULTS: The expressions of serum IGF-1, TNF-alpha and VEGF165 in the type 2 DN patients were significantly higher than those in the control group (all P < 0.05). The expressions of serum IGF-1, TNF-alpha and VEGF165 in the type 2 DN patients were positively correlated with UALB/Cr (all P < 0.05). As type 2 DN worsened, the expressions of serum IGF-1, TNF-alpha and VEGF165 increased, and type 2 DN severity had positive correlations with serum IGF-1, TNF-alpha and VEGF165 concentrations (all P < 0.05). There was a positive association between IGF-1 and TNF-alpha, IGF-1 and VEGF165 , and TNF-alpha and VEGF165 (all P < 0.05). Logistic regression analysis showed that IGF-1 and VEGF165 were associated with the progression of DN (both P < 0.05). CONCLUSIONS: Elevated expression levels of serum IGF-1, TNF-alpha and VEGF165 might exacerbate type 2 DN. PMID- 27218218 TI - Adolf Meyer's Influence on Curt Richter: Selection, Support, and Mentoring. AB - Adolph Meyer influenced Curt Richter from the time Richter became a graduate student in Psychology at Johns Hopkins in 1919 until Meyer retired in 1941. Meyer was on Richter's thesis committee. After Richter received his degree, Meyer selected him to replace J.B. Watson. During the next 20 years, Meyer gave Richter strong support in terms of equipment, laboratory space for animal research, and opportunities to teach medical students, attend clinical rounds, and do clinical research. It is less well known that Meyer also mentored Richter's scientific and professional development. Meyer's mentoring was so successful that Richter adopted the major scientific ideas of Meyer, especially psychobiology, distrust of theory, and respect for experiment. Thus, Meyer's ideas became the framework for Richter's famous research program that produced his major discoveries of behavior exerting homeostatic controls, psychoendocrinology, and biological clocks. PMID- 27218217 TI - Distance measurements between paramagnetic ligands bound to parallel stranded guanine quadruplexes. AB - Aside from a double helix, deoxyribonucleic acid (DNA) folds into non-canonical structures, one of which is the guanine quadruplex. Cationic porphyrins bind guanine quadruplexes, but the effects of ligand binding on the structure of guanine quadruplexes with more than four contiguous guanine quartets remains to be fully elucidated. Double electron-electron resonance (DEER) spectroscopy conducted at 9.5 GHz (X-band) using broadband, shaped inversion pulses was used to measure the distances between cationic copper porphyrins bound to model parallel-stranded guanine quadruplexes with increasing numbers of guanine quartets. A single Gaussian component was found to best model the time domain datasets, characteristic of a 2 : 1 binding stoichiometry between the porphyrins and each quadruplex. The measured Cu(2+)-Cu(2+) distances were found to be linearly proportional with the number of guanines. Rather unexpectedly, the ligand end-stacking distance was found to monotonically decreases the overall quadruplex length was extended, suggesting a conformational change in the quadruplex secondary structure dependent upon the number of successive guanine quartets. PMID- 27218219 TI - Comparing Self-stigma Between People With Different Mental Disorders in Taiwan. AB - Internalized stigma (or self-stigma), one of the most painful effects of stigma, causes people with mental health problems profound negative consequences, for example, psychological adversity, demoralization, and feelings of hopelessness. However, knowledge about self-stigma in people with different mental disorders is insufficient. We hypothesized that people with different psychiatric diagnoses have different levels of self-stigma. Through convenience sampling, we used the Internalized Stigma of Mental Illness Scale to compare people diagnosed with schizophrenia (n = 161), depressive disorder (n = 98), bipolar disorder (n = 43), and anxiety disorder (n = 45) in southern Taiwan. We found that people with schizophrenia (mean, 2.09-2.30) and those with bipolar disorder (mean, 2.16-2.38) had significantly higher levels of self-stigma, except for the Stigma Resistance, than did those with anxiety disorder (mean, 1.74-1.87). Our results suggest that clinicians should use different interventions to reduce self-stigma for populations with different psychiatric diagnoses. PMID- 27218220 TI - Perceived Discrimination in Patients With Psychiatric Disorder and Turkish Migration Background in Germany. AB - Perceived discrimination (PD) has a negative impact on the course of psychiatric disorders. We have investigated PD in inpatients with affective or anxiety disorder and Turkish migration background (TP) or native Germans (GP). Migration related, clinical, and sociodemographic data of n = 62 TP and n = 62 GP, matched for age, sex, and psychiatric diagnoses, were retrospectively analyzed. PD was assessed as one of 10 questions related to migration and acculturation (yes/no, severity 0-10). PD prevalence rates were compared between TP and GP; relationships of PD with other variables were analyzed using bivariate correlations and multiple regression analyses. A PD prevalence of 26% in TP and 1% in GP was found (odds ratio, 21.2 [2.7-165.8]). Migration background was the strongest predictor of PD in the total group. Within the TP sample, asylum seeking status and migration-related distress were significantly predictive of PD. In patients with psychiatric disorder in Germany, PD seems to be strongly related to migration-related distress. PMID- 27218221 TI - Preliminary Effectiveness and Sustainability of Group Aerobic Exercise Program in Patients with Schizophrenia. AB - The objective of this study was to examine the feasibility and sustained effect of a group aerobic exercise program in patients with schizophrenia. Twenty-four schizophrenic patients participated in a group-based individually tailored 90 minute outdoor cycling session per week for 3 months with intervention to enhance motivation. Physical health was evaluated by anthropometric measures, cardiorespiratory (CR) fitness, and blood tests. Mental health was assessed on self-esteem, interpersonal relationship, quality of life, and global function. Attrition rate for the exercise program was 8.3%. Exercise program significantly increased participant's self-esteem, positive relationship, global function, and quality of life. CR fitness significantly improved after 3 months. At the 9-month follow-up, 6 months after program completion, only in interpersonal relationship change the improved effects were maintained. These findings support the feasibility of group aerobic exercise program with high level of adherence and its long-term benefits in positive relationship change. PMID- 27218222 TI - Sound-Color Associations in Psychosis-Prone Individuals. AB - Synesthetic-pseudosynesthetic characteristics have been hypothesized to be a schizophrenia endophenotype, a developmental feature, and/or a symptom of psychosis. Few studies to date, however, have examined whether individuals at risk for psychosis have synesthetic symptoms. We examined the relationship between hue and pitch in high psychosis prone (HP; n = 30) and low psychosis prone individuals (LP; n = 31). Synesthesia was evaluated using self-report and two performance-based tasks. Results revealed that HP subjects experienced more synesthetic experiences than the LP only on the self-report measure. These results suggest that high psychotic prone patients report unusual experiences but are no more likely to exhibit synesthesia than LP individuals. HP individuals, however, were more likely to choose shorter wavelength colors than LP individuals on performance tasks. These results are consistent with the notion that psychosis vulnerability is associated with a preference to light wavelengths associated with increasing emotional valence and negative affect. PMID- 27218223 TI - Phthalimide-derived strigolactone mimics as germinating agents for seeds of parasitic weeds. AB - BACKGROUND: Broomrapes attack important crops, cause severe yield losses and are difficult to eliminate because their seed bank is virtually indestructible. In the absence of a host, the induction of seed germination leads to inevitable death due to nutrient starvation. Synthetic analogues of germination-inducing factors may constitute a cheap and feasible strategy to control the seed bank. These compounds should be easy and cheap to synthesise, as this will allow their mass production. The aim of this work is to obtain new synthethic germinating agents. RESULTS: Nineteen N-substituted phthalimides containing a butenolide ring and different substituents in the aromatic ring were synthesised. The synthesis started with commercially available phthalimides. The complete collection was assayed against the parasitic weeds Orobanche minor, O. cumana, Phelipanche ramosa and P. aegyptiaca, with the synthetic strigolactone analogue GR24 used as a positive control. These compounds offered low EC50 values: O. cumana 38.3 MUM, O. minor 3.77 MUM, P. aegyptiaca 1.35 MUM and P. ramosa 1.49 MUM. CONCLUSIONS: The synthesis was carried out in a few steps and provided the target compounds in good yields. The compounds tested showed great selectivity, and low EC50 values were obtained for structures that were simpler than GR24. (c) 2016 Society of Chemical Industry. PMID- 27218224 TI - The Nanoparticle Size Effect in Graphene Cutting: A "Pac-Man" Mechanism. AB - Metal-nanoparticle-catalyzed cutting is a promising way to produce graphene nanostructures with smooth and well-aligned edges. Using a multiscale simulation approach, we unambiguously identified a "Pac-Man" cutting mechanism, characterized by the metal nanoparticle "biting off" edge carbon atoms through a synergetic effect of multiple metal atoms. By comparing the reaction rates at different types of edge sites, we found that etching of an entire edge carbon row could be triggered by a single zigzag-site etching event, which explains the puzzling linear dependence of the overall carbon-atom etching rate on the nanoparticle surface area observed experimentally. With incorporation of the nanoparticle size effect, the mechanisms revealed herein open a new avenue to improve controllability in graphene cutting. PMID- 27218225 TI - Uropathogenic Escherichia coli causes fibrotic remodelling of the epididymis. AB - Despite antibiotic treatment, up to 40% of patients have impaired fertility after epididymitis due to serovars of Escherichia coli, a frequent pathogen. The reasons for infertility are unclear, but it may result from epididymal duct obstruction. To determine whether E. coli infection of the epididymis causes obstruction due to fibrosis, and to identify the key mediators, tissues from patients with epididymitis were assessed. Additionally, epididymitis was induced with uropathogenic E. coli (UPEC) or commensal serovars in wild-type and MyD88(-/ ) mice, which are relatively unresponsive to bacterial pathogens. Epididymal organ cultures were treated with activin A and bacteria and their histology and levels of cytokines and fibrosis markers were analysed. Patients with epididymitis showed severe fibrosis of the epididymal duct. In mice, UPEC infection also caused fibrosis and ductal obstruction in the cauda epididymis. Levels of mRNA for fibrotic markers (alpha-smooth muscle actin, fibronectin) and cytokines (activin A, TNFalpha, IL-1alpha, IL-1beta, IL-6) and total collagen levels were significantly elevated. This fibrotic response was blunted by the loss of MyD88. Activin A induced fibrosis in cultured epididymis, which was inhibited by the activin-binding protein follistatin. In summary, bacterial epididymitis causes fibrosis and obstruction. The milder tissue damage in Myd88( /-) UPEC epididymitis highlights the importance of the host response to infection in causing epididymal damage. Elevated levels of activin A in vivo and fibrotic remodelling elicited by activin A in vitro indicate that this cytokine is a potential target for supplementary treatment to antibiotic therapy. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 27218226 TI - Ultrastructural characterization of membranous torovirus replication factories. AB - Plus-stranded RNA viruses replicate in the cytosol of infected cells, in membrane bound replication complexes containing the replicase proteins, the viral RNA and host proteins. The formation of the replication and transcription complexes (RTCs) through the rearrangement of cellular membranes is currently being actively studied for viruses belonging to different viral families. In this work, we identified double-membrane vesicles (DMVs) in the cytoplasm of cells infected with the equine torovirus Berne virus (BEV), the prototype member of the Torovirus genus (Coronaviridae family, Nidovirales order). Using confocal microscopy and transmission electron microscopy, we observed a close relationship between the RTCs and the DMVs of BEV. The examination of BEV-infected cells revealed that the replicase proteins colocalize with each other and with newly synthesized RNA and are associated to the membrane rearrangement induced by BEV. However, the double-stranded RNA, an intermediate of viral replication, is exclusively limited to the interior of DMVs. Our results with BEV resemble those obtained with other related viruses in the Nidovirales order, thus providing new evidence to support the idea that nidoviruses share a common replicative structure based on the DMV arranged clusters. PMID- 27218228 TI - New Red-Emitting Tetrazine-Phenoxazine Fluorogenic Labels for Live-Cell Intracellular Bioorthogonal Labeling Schemes. AB - The synthesis of a set of tetrazine-bearing fluorogenic dyes suitable for intracellular labeling of proteins in live cells is presented. The red excitability and emission properties ensure minimal autofluorescence, while through-bond energy-transfer-based fluorogenicity reduces nonspecific background fluorescence of unreacted dyes. The tetrazine motif efficiently quenches fluorescence of the phenoxazine core, which can be selectively turned on chemically upon bioorthogonal inverse-electron-demand Diels-Alder reaction with proteins modified genetically with strained trans-cyclooctenes. PMID- 27218227 TI - Isolation and identification of anti-proliferative peptides from Spirulina platensis using three-step hydrolysis. AB - BACKGROUND: Spirulina platensis is an excellent source of proteins (>60%) that can be hydrolyzed into bioactive peptides. RESULTS: In this study, whole proteins of Spirulina platensis were extracted and hydrolyzed using three gastrointestinal endopeptidases (pepsin, trypsin and chymotrypsin). Subsequently, gel filtration chromatography was employed to separate hydrolysates, and four fractions (Tr1 Tr4) were obtained. Among them, Tr2 showed the strongest anti-proliferation activities on three cancer cells (MCF-7, HepG-2 and SGC-7901), with IC50 values of <31.25, 36.42 and 48.25 ug mL-1 , respectively. Furthermore, a new peptide, HVLSRAPR, was identified from fraction Tr1. This peptide exhibited strong inhibition on HT-29 cancer cells with an IC50 value of 99.88 ug mL-1 . CONCLUSION: Taken together, these peptides possessed anti-proliferation activities on cancer cells and low cytotoxicity on normal cells, suggesting that they might serve as a natural anticancer agent for nutraceutical and pharmaceutical industries. (c) 2016 Society of Chemical Industry. PMID- 27218229 TI - Alterations of voltage-dependent K(+) channels in the mesenteric artery during the early and chronic phases of diabetes. AB - This study investigated the alteration of voltage-dependent K(+) (Kv) channels in mesenteric arterial smooth muscle cells from control (Long-Evans Tokushima Otsuka [LETO]) and diabetic (Otsuka Long-Evans Tokushima Fatty [OLETF]) rats during the early and chronic phases of diabetes. We demonstrated alterations in the mesenteric Kv channels during the early and chronic phase of diabetes using the patch-clamp technique, the arterial tone measurement system, and RT-PCR in Long Evans Tokushima (LETO; for control) and Otsuka Long-Evans Tokushima Fatty (OLETF; for diabetes) type 2 diabetic model rats. In the early phase of diabetes, the amplitude of mesenteric Kv currents induced by depolarizing pulses was greater in OLETF rats than in LETO rats. The contractile response of the mesenteric artery induced by the Kv inhibitor, 4-aminopyridine (4-AP), was also greater in OLETF rats. The expression of most Kv subtypes- including Kv1.1, Kv1.2, Kv1.4, Kv1.5, Kv1.6, Kv2.1, Kv3.2, Kv4.1, Kv4.3, Kv5.1, Kv6.2, Kv8.1, Kv9.3, and Kv10.1-were increased in mesenteric arterial smooth muscle from OLETF rats compared with LETO rats. However, in the chronic phase of diabetes, the Kv current amplitude did not differ between LETO and OLETF rats. In addition, the 4-AP-induced contractile response of the mesenteric artery and the expression of Kv subtypes did not differ between the two groups. The increased Kv current amplitude and Kv channel related contractile response were attributable to the increase in Kv channel expression during the early phase of diabetes. The increased Kv current amplitude and Kv channel-related contractile response were reversed during the chronic phase of diabetes. PMID- 27218230 TI - Listeria monocytogenes septicemia in an immunocompromised dog. AB - An 11-year-old, male castrated, Boston Terrier was presented to the North Carolina State University College of Veterinary Medicine Small Animal Emergency Service with a 2-day history of progressive ataxia, left-sided head tilt, and anorexia. The dog had previously been diagnosed with chronic lymphoid leukemia and suspected immune-mediated destruction of his bone marrow precursor cells, possibly due to therapy with immunosuppressive dosages of prednisone and azathioprine. During the physical examination, abnormal findings included an increased body temperature and horizontal nystagmus. Diagnostic investigations included a computed tomography (CT) scan, which confirmed bilateral otitis media, and a blood culture, which was positive for Listeria monocytogenes serotype 4b (epidemic clone 1). Upon treatment with ampicillin/sulbactam, enrofloxacin, and minocycline, the dog became normothermic and the neurologic signs improved. L monocytogenes serotype 4b (epidemic clone 1) has been associated with outbreaks of human listeriosis originating from food contamination. Although rare case reports of Listeria spp. infection in dogs exist, an actual infection with the epidemic clone 1 strain has never before been reported in a dog. It should be included in the differential diagnoses in immunocompromised dogs with clinical signs of septicemia. PMID- 27218231 TI - The Use of NMR Metabolite Profiling and in vivo Hypoglycemic Assay for Comparison of Unfractionated Aqueous Leaf Extracts of Two Ocimum Species. AB - Ocimum basilicum and Ocimum gratissimum (Lamiaceae) are used to treat diabetes mellitus in Africa. In a previous work, we identified chicoric acid as a hypoglycemic substance in O. gratissimum. This study aims to compare the chemical metabolite profile and the hypoglycemic activity of unfractionated aqueous extracts from leaves of both Lamiaceae species. The metabolite composition of OB and OG decoctions (10% w/v) was analyzed using HPLC-DAD and NMR tools. Chicoric acid showed to be the major phenolic in both extracts, besides caftaric, caffeic, and rosmarinic acids; nevertheless, there is approximately three times more of this substance in OG. From 1D- and 2D-NMR analyses, 19 substances were identified in OB, while 12 in OG. The in vivo acute hypoglycemic activity of the extracts was assessed intraperitoneally in streptozotocin (STZ)-induced diabetic mice. The doses of 100 and 200 mg/kg of both extracts significantly reduced their glycemia, compared to controls (P < 0.05). OB was a little more effective than OG, despite the lower content of chicoric acid in OB. This result strongly suggests that components other than chicoric acid contribute to the hypoglycemic activity of the two extracts. Despite the abundance of caffeic and rosmarinic acids in OB, their hypoglycemic activity observed at 8.3 MUmol/kg was low. This is the first chemical profile of crude extracts from Ocimum species by NMR. Our findings confirmed the potential of both species in DM treatment in spite of marked differences in their chemical composition. However, long-term studies are necessary in order to identify the most promising of the two species for the development of an herbal medicine. PMID- 27218232 TI - Selective visual attention to emotional words: Early parallel frontal and visual activations followed by interactive effects in visual cortex. AB - Human brains spontaneously differentiate between various emotional and neutral stimuli, including written words whose emotional quality is symbolic. In the electroencephalogram (EEG), emotional-neutral processing differences are typically reflected in the early posterior negativity (EPN, 200-300 ms) and the late positive potential (LPP, 400-700 ms). These components are also enlarged by task-driven visual attention, supporting the assumption that emotional content naturally drives attention. Still, the spatio-temporal dynamics of interactions between emotional stimulus content and task-driven attention remain to be specified. Here, we examine this issue in visual word processing. Participants attended to negative, neutral, or positive nouns while high-density EEG was recorded. Emotional content and top-down attention both amplified the EPN component in parallel. On the LPP, by contrast, emotion and attention interacted: Explicit attention to emotional words led to a substantially larger amplitude increase than did explicit attention to neutral words. Source analysis revealed early parallel effects of emotion and attention in bilateral visual cortex and a later interaction of both in right visual cortex. Distinct effects of attention were found in inferior, middle and superior frontal, paracentral, and parietal areas, as well as in the anterior cingulate cortex (ACC). Results specify separate and shared mechanisms of emotion and attention at distinct processing stages. Hum Brain Mapp 37:3575-3587, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27218234 TI - Stenting of the Lateral Sinus in Idiopathic Intracranial Hypertension According to the Type of Stenosis. AB - BACKGROUND: Over the past decade, stenting of lateral sinus stenosis has been used to treat idiopathic intracranial hypertension. Two types of stenoses have been identified: extrinsic and intrinsic. OBJECTIVE: The aim of this study was to report the results of our use of this procedure to treat patients with extrinsic or intrinsic stenoses in idiopathic intracranial hypertension. METHODS: We retrospectively studied clinical, radiological, and manometric data from patients with idiopathic intracranial hypertension who were treated at our institution between January 2009 and January 2015 by stenting of the lateral sinus. RESULTS: Data were studied from 19 women and 2 men. Average body mass index was 29 kg/m 2 , and the median age at stenting was 33 years. Patients with extrinsic stenoses were younger than those with intrinsic stenoses. Transstenotic gradients measured with patients under general anesthesia were lower than those measured with patients under local anesthesia. In all cases, stenting was effective for papilledema and pulsatile tinnitus. Seventeen patients reporting headaches found that they disappeared completely after stenting. Two complications without long term effects were reported. CONCLUSION: Irrespective of the type of stenosis, stenting of lateral sinus stenoses is an effective treatment for intracranial hypertension symptoms. At our institution, this treatment has replaced draining of cerebrospinal fluid when treatment with acetazolamide has proved to be ineffective. PMID- 27218233 TI - Genome engineering tools for building cellular models of disease. AB - With the recent development of methods for genome editing of human pluripotent stem cells, study of the genetic basis of human diseases has been rapidly advancing. Genome-edited differentiated stem cells have provided new and more accurate insights into genomic underpinnings of diseases for which there have not been adequate treatments, and moving toward clinical application of genome editing holds great promise for acceleration of therapeutic translation. Here, we review recent advances in genome-editing technologies and their application to human biology in disease modeling and beyond. PMID- 27218235 TI - Ventriculoperitoneal Shunting for Glioblastoma: Risk Factors, Indications, and Efficacy. AB - BACKGROUND: Glioblastoma patients can develop hydrocephalus, either obstructive, typically at diagnosis as a result of mass effect, or communicating, usually later in the disease. OBJECTIVE: To characterize the indications and efficacy of ventriculoperitoneal (VP) shunting for patients with glioblastoma-associated hydrocephalus. METHODS: Retrospective review was conducted of 841 glioblastoma patients diagnosed from 2004 to 2014, 64 (8%) of whom underwent VP shunting for symptomatic hydrocephalus, to analyze symptoms and outcomes after shunting. Overall survival and postshunt survival were analyzed with Kaplan-Meier methods, with predictors evaluated by use of Cox proportional hazards. RESULTS: Of the 64 patients who underwent shunting, 42 (66%) had communicating hydrocephalus (CH) and 22 (34%) had obstructive hydrocephalus (OH). CH patients underwent more preshunt craniotomies than those with noncommunicating hydrocephalus, with a mean of 2.3 and 0.7 surgeries, respectively ( P < .001). Ventricular entry during craniotomy occurred in 52% of CH patients vs 59% of those with OH ( P = .8). After shunting, 61% of all patients achieved symptomatic improvement, which was not associated with hydrocephalus variant ( P > .99). Hydrocephalus symptom improvement rates were as follows: headache, 77%; lethargy, 61%; and altered cognition or memory, 54%. Symptomatic improvement was more likely in patients who were younger at shunt placement (hazard ratio, 0.96; P = .045). Symptomatic improvement, shorter time between glioblastoma diagnosis and shunt placement, and CH rather than OH led to improved postshunt survival (hazard ratio = 0.24-0.99; P = .01-.04). CONCLUSION: VP shunting improves symptoms in most glioblastoma patients with suspected CH or OH, specifically younger patients. Symptomatic improvement, shorter duration between glioblastoma diagnosis and shunt placement, and CH rather than OH improve postshunt survival. PMID- 27218236 TI - Molecular Basis for Differential Recognition of G-Quadruplex versus Double-Helix DNA by Bis-Phenanthroline Metal Complexes. AB - 1,10-Phenanthroline (Phen) derivatives are attractive ligands to provide metal complexes that are selective for different DNA secondary structures. Herein, we analyze the binding processes of two bis-Phen analogues and their Ni(II) complexes toward double-stranded DNA and telomeric G-quadruplex DNA by calorimetric and spectroscopic techniques. The free ligands can adapt to both DNA arrangements. Conversely, metal ion coordination produces an increase in ligand affinity for the tetrahelical structure, whereas it dramatically decreases binding to double-stranded DNA as a result of distinct binding modes on the two templates. In fact, Ni(II) complexes effectively stack on the G-quadruplex terminals, with an entropic loss counterbalanced by favorable enthalpy changes, whereas they cause a conformational reshaping of the double-helix form with a substantial decrease in the binding free energy. Consistently, no Ni(II) -DNA ionic pair has ever been identified. These results provide a rationale for the selective recognition of distinct DNA arrangements in view of targeted pharmacological applications. PMID- 27218237 TI - Situational drinking in private and public locations: A multilevel analysis of blood alcohol level in Finnish drinking occasions. AB - INTRODUCTION AND AIMS: The first aim was to estimate the extent to which the variation in alcohol use across specific drinking occasions arises from variation at the occasion level and from variation at the drinker level. The second aim was to identify characteristics of drinking situations that moderate or increase situational alcohol use beyond the influence of drinker-level characteristics. DESIGN AND METHODS: The general population aged 15-69 years in Finland was sampled randomly in 2008. The multilevel analysis was based on data from 1511 drinkers and 2933 drinking occasions that occurred in the 7 days before the interview. Alcohol use was operationalised as estimated blood alcohol level (BAL). Characteristics of drinking occasions included location, circumstance, company and timing. Drinker-level data included demographic and drinking pattern variables. RESULTS: Fifty-three percent of the variance in BAL was between occasions and 47% between respondents, for both women and men. With drinking patterns and demographic characteristics controlled for, the dominant characteristics of drinking occasions predisposing to greater intoxication were late-night drinking, across locations and for both genders. For private locations, predisposing characteristics included drinking on weekends for both genders and drinking with friends for men. DISCUSSION AND CONCLUSIONS: Situational and drinker levels are equally important in determining the BAL in drinking occasions; therefore, prevention efforts should be targeted at both risky individuals and risky drinking occasions. Occasions occurring late at night, often at home and with friends, are a central challenge for targeting preventive efforts related to situational drinking.[Mustonen H, Makela P, Lintonen T. Situational drinking in private and public locations: A multilevel analysis of blood alcohol level in Finnish drinking occasions. Drug Alcohol Rev 2016;35:772-784]. PMID- 27218238 TI - Improving outcomes in cancer diagnosis, prevention and control: barriers, facilitators and the need for health literacy in Ibadan Nigeria. AB - BACKGROUND: Cancers constitute a significant public health problem in Nigeria. Breast, cervix and prostate cancers are leading causes of cancer-related deaths. Changing diets, lifestyles, HIV/AIDS and macro-structural factors contribute to cancer morbidity and mortality. Poor health information linking cancer risk to individual behaviors, environmental pollutants and structural barriers undermine prevention/control efforts. Studies suggest increasing health literacy and empowering individuals to take preventive action will improve outcomes and mitigate impact on a weak health system. METHODS: We obtained qualitative data from 80 men, women, and young adults in 11 focus groups to assess beliefs, risk perceptions, preventive behaviors and perceptions of barriers and facilitators to cancer control in Ibadan, Nigeria and conducted thematic analysis. RESULTS: Participants demonstrated awareness of cancers and mentioned several risk factors related to individual behaviors and the environment. Nonetheless, myths and misconceptions as well as micro, meso and macro level barriers impede prevention and control efforts. CONCLUSION: Developing and implementing comprehensive context-relevant health literacy interventions in community settings are urgently needed.Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27218239 TI - Metastases to nasal cavity and paranasal sinuses. AB - The sinonasal cavities are rare locations for metastases. Metastases to these locations are usually solitary and produce similar symptoms to those of a primary sinonasal tumor. Nasal obstruction and epistaxis are the most frequent symptoms. The maxillary sinus is most frequently involved. The most common primary tumor sites to spread to this region originate in the kidney, breast, thyroid, and prostate, although any malignancy could potentially lead to a metastasis to the paranasal sinuses. The patient's prognosis is usually poor because of the fact that the sinonasal metastasis is usually associated with widespread disseminated disease. In the majority of patients, palliative therapy is the only possible treatment option. Nevertheless, whenever possible, surgical excision either alone or combined with radiotherapy may be useful for palliation of symptoms and, rarely, to achieve prolonged survival. This review considers the most interesting cases reported in the literature that presents metastases to the sinonasal cavities. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: 1847-1854, 2016. PMID- 27218240 TI - Risk factors and outcome of stroke in renal transplant recipients. AB - Stroke incidence is high in end-stage renal disease, and risk factors differ between the dialysis and general populations. However, risk factors and outcomes following renal transplantation remain unclear. We analyzed all adult patients with a functioning renal transplant from 01/01/2007 to 12/31/2012. Data were extracted from the electronic patient record. Variables associated with stroke were identified by survival analyses; demographic, clinical, and imaging and laboratory variables were assessed and case fatality determined. Follow-up was until 05/12/2013. A total of 956 patients were identified (median age 40.1 years, 59.9% male). Atrial fibrillation (AF) prevalence was 9.2%, and 38.2% received a transplant during follow-up. A total of 26 (2.7%) experienced a stroke during 4409 patient-years of follow-up (84.6% ischemic). Stroke incidence was 5.96/1000 patient-years. Factors associated with stroke on regression analysis were prior stroke, diabetes, age, systolic hypertension, and hemoglobin. Atrial fibrillation was associated with time to stroke (P<0.001). Warfarin did not associate with ischemic stroke risk in those with AF. Fatality was 19.2% at 7, 23.1% at 28, and 42.3% at 365 days after stroke. Patients with a functioning renal transplant have a high stroke incidence and case fatality. Unlike those on hemodialysis, risk factors are similar to the general population. We did not demonstrate benefit from warfarin use in those with AF. PMID- 27218241 TI - Hyperpolarization of Nitrogen-15 Schiff Bases by Reversible Exchange Catalysis with para-Hydrogen. AB - NMR with thermal polarization requires relatively concentrated samples, particularly for nuclei with low abundance and low gyromagnetic ratios, such as (15) N. We expand the substrate scope of SABRE, a recently introduced hyperpolarization method, to allow access to (15) N-enriched Schiff bases. These substrates show fractional (15) N polarization levels of up to 2 % while having only minimal (1) H enhancements. PMID- 27218242 TI - Fibrolamellar hepatocellular carcinoma in ascitic fluid: A case report with cytohistological correlation. AB - The fibrolamellar variant of hepatocellular carcinoma (FL-HCC) is distinguished from other hepatocellular carcinoma's (HCC) by its unique clinical and pathological features. Cytological features of this tumor on fine needle aspiration have been described earlier. We report a rare case of a 17-year-old African American male with metastatic FL-HCC, diagnosed by body fluid cytology. The patient presented with ascites and computed tomography (CT) scan revealed multiple omental masses and liver lesions. The fluid sample was obtained along with the omental biopsy and was found positive for metastatic fibrolamellar hepatocellular carcinoma. The fluid cytology showed atypical polygonal cells with enlarged nuclei, prominent nucleoli, and abundant granular cytoplasm. Cytomorphologic features of FL-HCC presenting in body fluids have been rarely described before. This case enriches the cytopathology literature by providing awareness of this tumor presenting as metastasis in body fluids, especially in young individuals with liver lesions. Presence of a concurrent biopsy specimen provided cytohistological correlation, as it remains the gold standard for the accuracy and reliability of cytological diagnoses. Diagn. Cytopathol. 2016;44:757 760. (c) 2016 Wiley Periodicals, Inc. PMID- 27218243 TI - Usefulness of daily surveillance blood cultures in allogeneic hematopoietic stem cell transplant recipients on steroids: a 1-year prospective study. AB - BACKGROUND: Bloodstream infections (BSI) are frequent and potentially severe complications in allogeneic hematopoietic stem cell transplant (AHSCT) recipients. In patients on steroids, surveillance blood cultures (SBCs) are routinely performed to detect asymptomatic BSI but their usefulness remains controversial. METHODS: We performed a 1-year, observational, prospective, single center study to assess the utility of daily SBCs in AHSCT recipients on steroids and a case-control study to identify risk factors associated with positive SBCs. All blood cultures (BCs) obtained from adults hospitalized in the HSCT unit were prospectively studied throughout 1 year. Characteristics, treatments, and outcome of patients were retrieved from medical charts. RESULTS: A total of 3594 BCs were obtained in 177 patients, including 1450 SBCs in 82 AHSCT recipients on steroids. In 33 patients, 103 SBCs (7%) were positive. Low-virulence bacteria were identified in 74% of episodes. When analyzing first episode of positive SBCs (28 patients), 6 (21%) true BSI were identified. CONCLUSIONS: Patients with positive SBCs were receiving antibiotic treatment less frequently at the time of SBCs (P < 0.001) and had more frequently BCs obtained through central venous access (P < 0.04) when compared to patients with negative SBCs. Daily SBCs in AHSCT recipients on steroids only rarely identify BSI and clear benefit for patients could not be demonstrated. PMID- 27218244 TI - Editorial Comment to Lower calyceal and renal pelvic stones in preschool children: A comparative study of mini-percutaneous nephrolithotomy versus extracorporeal shockwave lithotripsy. PMID- 27218246 TI - [You take one for me, i'll take one for you]. AB - No Abstract available. PMID- 27218247 TI - [Associated factors due to major bleeding in total hip replacement]. AB - MATERIAL AND METHODS: Total hip arthroplasty is a common procedure whose typical duration is greater than 90 minutes and is associated with substantial blood loss. It is usually performed in patients 60 years who have comorbidities. Knowing the factors associated with major bleeding in patients undergoing this procedure will allow us to identify patients who are at risk. We performed a retrospective study, according to a case-control model selecting patients for the primary outcome: major bleeding/not major bleeding. We included 142 patients treated with total hip arthroplasty, divided into 47 cases and 95 matched controls. RESULTS: The variables that showed a higher association to influence the presence of major bleeding was preoperative hemoglobin and hematocrit, BMI, operating time, as well as the use of blood transfusion increased the time of hospital stay. The preoperative hemoglobin value showed that the type of patient more associated with major bleeding had a hemoglobin 13 g/dl. We observed that 102 patients (71.8%) who underwent a blood transfusion had an increased length of stay (p 0.007). CONCLUSION: The presence of major bleeding is a frequent event. When knowing the factors associated with major bleeding, the surgical team can anticipate this event and modify it as possible. PMID- 27218248 TI - [Joint surface resection with a minimally invasive dorsal approach for arthrodesis of the distal interphalangeal joint]. AB - Degenerative joint disease of the distal interphalangeal joint of the fingers precedes its occurrence in all the remaining regions of the body and produces major disability. We describe a distal interphalangeal arthrodesis technique performed with minimally invasive surgery. Case etiology was varied and mean follow-up was 10 months. All cases healed and functional recovery started at postoperative week two. This is a reproducible technique that produces satisfactory results in the short and medium term. PMID- 27218245 TI - Rain-Shelter Cultivation Modifies Carbon Allocation in the Polyphenolic and Volatile Metabolism of Vitis vinifera L. Chardonnay Grapes. AB - This study investigated the effect of rain-shelter cultivation on the biosynthesis of flavonoids and volatiles in grapes, with an aim of determining whether rain-shelter application could help to improve the sensory attributes and quality of grapes. Vitis vinifera L. Chardonnay grapes, grown in the Huaizhuo basin region of northern China, were selected within two consecutive years. A rain-shelter roof was constructed using a colorless polyethylene (PE) film with a light transmittance of 80%. Results showed that rain-shelter treatment did not affect the accumulation of soluble solids during grape maturation. However, the allocation of assimilated carbon in phenolic and volatile biosynthetic pathways varied significantly, leading to alterations in polyphenolic and volatile profiles. The rain-shelter cultivation enhanced the concentration of flavan-3-ols via the flavonoid-3'5'-hydroxylase (F3'5'H) pathway, but reduced the level of flavonols and flavan-3-ols via the flavonoid-3'-hydroxylase (F3'H) pathway. In addition, the rain-shelter cultivation significantly enhanced the synthesis of fatty acid-derived volatiles, isoprene-derived terpenoids and amino acid-derived branched-chain aliphatics, but led to a decrease in the accumulation of isoprene derived norisoprenoids and amino acid-derived benzenoids. Principal component analysis revealed some key compounds that differentiated the grapes cultivated under open-field and rain-shelter conditions. Moreover, the effect of the rain shelter application on the accumulation of these compounds appeared to be vintage dependent. The alteration of their profiles caused by the rain-shelter treatment was significant in the vintage that received higher rainfall, which usually took place in the first rapid growth and veraison phases. PMID- 27218249 TI - [Extracorporeal shockwave terapy in sports and non-sports population. Preliminary results]. AB - BACKGROUND: Inflammatory and calcifying diseases of the soft tissues are disorders having significant economical and social repercussions. They can be treated with drugs or physical therapy, and if these fail, surgery used to be the last existing therapeutic step. In recent years, a non-surgical alternative is being used to treat them, the application of extracorporeal shock waves. This work aims to verify the capacity of this therapeutic technique to diminish pain and to define its application rules. METHOD: We treated 18 athletes and 12 patients from normal population with heel spurs, calcified and noncalcified tendonitis and plantar fasciitis. The results were evaluated with a visual analogical scale of pain and by echography, prior to treatment and after. RESULTS: The treatment was effective in 100% of the subjects. CONCLUSIONS: We conclude that once the medical therapeutic and the physical therapy measures are used up, treatment with shock waves is a good alternative to using surgery. PMID- 27218250 TI - [Bandi tibial tubercule osteotomy vs. artrhroscopy lavage in patelo femoral arthritis. 1 year follow-up]. AB - INTRODUCTION: Osteoarthritis is a degenerative joint disease that modifies the mechanical and biological properties of articular cartilage and subchondral bone, treatment is aimed at relieving pain, maintain joint and reduce disease progression function. The aim of this paper is to compare the surgical outcomes of the arthroscopic articular cleaning and Bandi procedure by using the WOMAC scale. METHODS: Cross-sectional study, functional outcome of treatment of patellofemoral ostheoarthritis by arthroscopic articular cleaning and Bandi procedure are compared. Variables were gender, age, affected side, surgical technique and preoperative and 12 months follow up WOMAC evaluation. We used descriptive statistics and t-test for mean difference in WOMAC between both groups of patients. RESULTS: n = 37 patients, the mean age was 53.48 (28-82), +/- 12.55 years; 11 (29.7%) males and 26 (70.3%) women, the affected side: 19 (51.35%) right and 18 (48.65%) left. SURGICAL TECHNIQUE: 45.9% arthroscopic articular cleaning and 54.1% Bandi procedure. Patients operated by both technics: Bandi and arthroscopic articular cleaning had improvement in pain, stiffness and physical function (p = 0.00); comparison of global WOMAC score for both techniques a year after showed no statistically significant differences (p = 0.78). CONCLUSION: Both techniques (Bandi and arthroscopic articular cleaning) offer good results at 365 days of surgery, however patients managed by arthroscopic articular cleaning have less pain compared with Bandi procedure. PMID- 27218251 TI - [Concordance between preoperatory diagnosis and arthroscopy findings of meniscal lesions associated to anterior cruciate ligament injury]. AB - INTRODUCTION: Ligament injuries of the knee joint are common during the second and third decades of life, clinical and radiological diagnosis presents difficulties since the surgical findings may differ significantly. The objective is to determine correlation between clinical-radiologic and arthroscopic diagnosis in patients with injury of the anterior cruciate ligament (ACL) and meniscal lesions. MATERIAL AND METHODS: Cross-sectional study held in 29 patients with ACL injury associated to meniscal lesions treated arthroscopically. Variables were age, gender, affected side, preoperative and postoperative diagnosis, type and location of meniscal injury; descriptive statistics and Cohen Kappa for concordance were used. RESULTS: There were 29 patients, 23 (79.3%) men and 6 (20.7%) women, mean age 39.04 (15-50) +/- 13.19 years; right side was affected in 69% and left in 31%; 19% had not meniscal lesion, 17.2% had injury in anterior horn, 10.3% in posterior horn and 6.9% in the body. The concordance between preoperative and artroscopic diagnosis was: Kappa 0.2; intraboservador was Kappa 1.0; between suspected meniscal injury and arthroscopic findings was: Kappa 0.2. CONCLUSIONS: The concordance between the clinical-radiological and arthroscopic diagnosis in patients with ACL injuries and meniscal injury associated is low, which has to be considered in the initial review and the arthroscopic treatment of patients. PMID- 27218252 TI - Hip resurfacing after iliofemoral distraction for type IV developmental dysplasia of the hip a case report. AB - Osteoarthritis secondary to developmental dysplasia of the hip is a surgical challenge because of the modified anatomy of the acetabulum which is deficient in its shape with poor bone quality, torsional deformities of the femur and the altered morphology of femoral head. Particularly in Crowe type III and IV, additional surgical challenges are present, such as limb-length discrepancy and adductor muscle contractures. This is a bilateral hip dysplasia case where bilateral hip replacement was indicated, on the left side with a resurfacing one and on the other side a two stage procedure using a iliofemoral external fixator to restore equal leg length with a lower risk of complications. This case report shows both the negative clinical outcome of the left and the excellent one of the right hip where the dysplasia was much more severe. Patient selection and implant positioning are crucial in determining long-term results. PMID- 27218253 TI - [Pelvic limb damage control following a complex foot injury. Case report]. AB - More than 20% of the tarsometatarsal joint injuries (Lisfranc injuries) occur during motor vehicle accidents. This kind of trauma is infrequent and in 50% of cases closed reduction is used. A 18 year-old male patient sustained a high energy trauma resulting in a Gustilo and Anderson III B open Lisfranc fracture dislocation of the left foot. Surgical debridement, open reduction and internal fixation, and immediate skin coverage were performed. The secondary complication rate may decrease with stringent treatment adherence and proper care of severe orthopedic injuries. Treatment of the latter, including bone and soft tissue injuries (skin, subcutaneous tissue, fascias, musculotendinous junctions, ligaments, periosteum, and neurovascular structures) should follow a multidisciplinary protocol: extensive debridement of nonviable tissue, eradication of infections, and tissue reconstruction or coverage. Thus, any orthopedic surgeon should possess basic knowledge of this protocol. Proper management, using the right technique in each case, and the right timing of treatment are of the utmost importance. PMID- 27218254 TI - Correction: Random-Effects, Fixed-Effects and the within-between Specification for Clustered Data in Observational Health Studies: A Simulation Study. AB - [This corrects the article DOI: 10.1371/journal.pone.0110257.]. PMID- 27218255 TI - Mapping Breakpoints of Complex Chromosome Rearrangements Involving a Partial Trisomy 15q23.1-q26.2 Revealed by Next Generation Sequencing and Conventional Techniques. AB - Complex chromosome rearrangements (CCRs), which are rather rare in the whole population, may be associated with aberrant phenotypes. Next-generation sequencing (NGS) and conventional techniques, could be used to reveal specific CCRs for better genetic counseling. We report the CCRs of a girl and her mother, which were identified using a combination of NGS and conventional techniques including G-banding, fluorescence in situ hybridization (FISH) and PCR. The girl demonstrated CCRs involving chromosomes 3 and 8, while the CCRs of her mother involved chromosomes 3, 5, 8, 11 and 15. HumanCytoSNP-12 Chip analysis identified a 35.4 Mb duplication on chromosome 15q21.3-q26.2 in the proband and a 1.6 Mb microdeletion at chromosome 15q21.3 in her mother. The proband inherited the rearranged chromosomes 3 and 8 from her mother, and the duplicated region on chromosome 15 of the proband was inherited from the mother. Approximately one hundred genes were identified in the 15q21.3-q26.2 duplicated region of the proband. In particular, TPM1, SMAD6, SMAD3, and HCN4 may be associated with her heart defects, and HEXA, KIF7, and IDH2 are responsible for her developmental and mental retardation. In addition, we suggest that a microdeletion on the 15q21.3 region of the mother, which involved TCF2, TCF12, ADMA10 and AQP9, might be associated with mental retardation. We delineate the precise structures of the derivative chromosomes, chromosome duplication origin and possible molecular mechanisms for aberrant phenotypes by combining NGS data with conventional techniques. PMID- 27218256 TI - Common Infections in Patients Prescribed Systemic Glucocorticoids in Primary Care: A Population-Based Cohort Study. AB - BACKGROUND: Little is known about the relative risk of common bacterial, viral, fungal, and parasitic infections in the general population of individuals exposed to systemic glucocorticoids, or about the impact of glucocorticoid exposure duration and predisposing factors on this risk. METHODS AND FINDINGS: The hazard ratios of various common infections were assessed in 275,072 adults prescribed glucocorticoids orally for >=15 d (women: 57.8%, median age: 63 [interquartile range 48-73] y) in comparison to those not prescribed glucocorticoids. For each infection, incidence rate ratios were calculated for five durations of exposure (ranging from 15-30 d to >12 mo), and risk factors were assessed. Data were extracted from The Health Improvement Network (THIN) primary care database. When compared to those with the same underlying disease but not exposed to glucocorticoids, the adjusted hazard ratios for infections with significantly higher risk in the glucocorticoid-exposed population ranged from 2.01 (95% CI 1.83-2.19; p < 0.001) for cutaneous cellulitis to 5.84 (95% CI 5.61-6.08; p < 0.001) for lower respiratory tract infection (LRTI). There was no difference in the risk of scabies, dermatophytosis and varicella. The relative increase in risk was stable over the durations of exposure, except for LRTI and local candidiasis, for which it was much higher during the first weeks of exposure. The risks of infection increased with age and were higher in those with diabetes, in those prescribed higher glucocorticoid doses, and in those with lower plasma albumin level. Most associations were also dependent on the underlying disease. A sensitivity analysis conducted on all individuals except those with asthma or chronic obstructive pulmonary disease produced similar results. Another sensitivity analysis assessing the impact of potential unmeasured confounders such as disease severity or concomitant prescription of chemotherapy suggested that it was unlikely that adjusting for these potential confounders would have radically changed the findings. Limitations of our study include the use of electronic medical records, which could have resulted in some degree of misclassification of the infectious outcomes; a possible reporting bias, as general practitioners could be more prone to record an infection in those exposed to glucocorticoids; and a low number of events for some outcomes such as scabies or varicella, which may have led to limited statistical power. CONCLUSIONS: The relative risk of LRTI and local candidiasis is very high during the first weeks of glucocorticoid exposure. Further studies are needed to assess whether low albumin level is a risk factor for infection by itself (e.g., by being associated with a higher free glucocorticoid fraction) or whether it reflects other underlying causes of general debilitation. PMID- 27218257 TI - Cystatin C and Risk of Diabetes and the Metabolic Syndrome - Biomarker and Genotype Association Analyses. AB - BACKGROUND: We recently reported a relationship between plasma levels of cystatin C and incidence of the metabolic syndrome (MetS) among the first 2,369 subjects who participated in the re-examination study of the population-based Malmo and Diet Cancer Cardiovascular cohort (MDC-CC-re-exam). In this study we aimed to replicate these results and also investigate if cystatin C was causally associated with MetS and diabetes. METHODS: We estimated the effect size of the strongest GWAS derived cystatin C SNP (major allele of rs13038305) on plasma cystatin C in the now completed MDC-CC-re-exam (n = 3,734) and thereafter examined the association between plasma cystatin C (403 cases of diabetes and 2665 controls) as well as rs13038305 (235 cases and 2425 controls) with incident diabetes. The association of rs13038305 and incident MetS (511 cases of MetS and 1980 controls) was similarly investigated in the whole MDC-CC-re-exam. We also attempted to replicate our previously shown association of cystatin C with incident MetS in subjects from the MDC-CC-re-exam (147 cases and 711 controls) that were not included in our previous report. RESULTS: In the entire MDC-CC-re exam, each copy of the major allele of rs13038305 was associated with approximately 0.30 standard deviation (SD) higher plasma concentration of cystatin C (beta = 0.33, p = 4.2E-28) in age and sex adjusted analysis. Cystatin C in plasma was not associated with incident diabetes after adjustment for known diabetes risk factors (OR per 1 SD increment 0.99 (0.86-1.13), p = 0.842). In the replication cohort of MDC-CC-re-exam, the OR (95% CI) for incident MetS in subjects belonging to quartiles 1, 2, 3 and 4 of plasma cystatin C levels was 1.00 (reference), 1.21 (0.70-2.07), 1.62 (0.95-2.78) and 1.72 (1.01-2.93) (ptrend = 0.026) in age and sex adjusted analysis. In the entire MDC-CC-re-exam the odds ratio for incident MetS and diabetes per copy of the major rs13038305 allele was 1.13, (0.95-1.34), p = 0.160 and 1.07, 95% CI 0.89-1.30, p = 0.478, respectively. CONCLUSION: We were able to replicate our previously shown association between high levels of cystatin C and increased risk of future development of MetS. However, a causal involvement of cystatin C in the etiology of MetS or diabetes seems unlikely since genetic elevation of plasma cystatin C was not significantly related to incidence of these diseases. PMID- 27218258 TI - Effect of Acute Effort on Isometric Strength and Body Balance: Trained vs. Untrained Paradigm. AB - Years of training in competitive sports leads to human body adaptation to a specific type of exercise. In judo bouts, maintaining hand grip on an opponent's clothes and postural balance is essential for the effective technical and tactical actions. This study compares changes after maximal anaerobic exercise among judo athletes and untrained subjects regarding 1) maximum isometric handgrip strength (HGSmax) and accuracy at the perceived 50% maximum handgrip force (1/2HGSmax) and 2) the balance of 13 judo athletes at national (n = 8) and international (n = 5) competitive levels and 19 untrained university students. The groups did not differ in age, body height, and weight. Body mass index (BMI) and body composition (JAWON) were evaluated. The Wingate Anaerobic Test (WAnT, Monark 875E) measured recommended anaerobic capacity indices. Hand grip strength (Takei dynamometer) and balance (biplate balance platform) were measured before warm-up (T1), before the WAnT test (T2), and after (T3). Parametric or non parametric tests were performed after verifying the variable distribution assumption. Judoists had higher BMI and fat-free mass index (FFMI) than the students. The athletes also showed higher relative total work and relative peak power and lower levels of lactic acid. The difference in judoists between HGSmax at T1 and HGSmax at T3 was statistically significant. Before warm-up (T1), athletes showed higher strength (more divergent from the calculated 1/2HGSmax value) compared to students. Substantial fatigue after the WAnT test significantly deteriorated the body stability indices, which were significantly better in judo athletes at all time points. The findings suggest specific body adaptations in judoists, especially for body composition, anaerobic energy system efficiency, and postural balance. These characteristics could be trained for specifically by judo athletes to meet the time-motion and anaerobic demands of contemporary bouts. PMID- 27218259 TI - Epidemiological, Clinical and Antiretroviral Susceptibility Characterization of Human Immunodeficiency Virus Subtypes B and Non-B in Pernambuco, Northeast Brazil. AB - BACKGROUND: HIV-1 diversity causes important differences in the virus' biological properties and their interactions with hosts, such as cell tropism, responses to antiretroviral therapy, drug-resistance, and disease progression. OBJECTIVES: We evaluated the interrelationship of phylogenetic inference with epidemiological and laboratory data for HIV-1 isolates circulating in Pernambuco, Northeast Region-Brazil. STUDY DESIGN: A total of 168 HIV-1 pol sequences were analysed, 64 were obtained from 2002-2003, and 104, from 2007-2009. Socio-demographic, clinical, and behavioural data were obtained from medical records. Laboratory testing enabled the determination of recent HIV-1 infections and co-infections with HBV, HCV, HTLV, or syphilis. Surveillance drug-resistance mutation analysis and antiretroviral susceptibility profiling were performed using HIV Drug Resistance Database. RESULTS: HIV-1 non-B was associated with female, lower education, lower viral loads, and higher T cell counts mean. Frequencies of co infection HIV-HBV, HIV-HCV, and HIV-syphilis were 27.8% (95% CI: 19.8-37.7), 1.04% (95% CI: 0.05-5.00) and 14.7% (95% CI: 8.6-23.0), respectively. Drug resistant mutations rate was 2.98% (95% CI: 1.10-6.47). HIV-HBV subtype B co infection was associated with men who have sex with men (MSM), higher education, higher viral loads and males. HIV-syphilis subtype non-B co-infection was associated with MSM status, lower T cell counts and males. CONCLUSIONS: Data showed the importance of molecular characterisations of the HIV-1 epidemic and its relation with epidemiological and clinical characteristics of the population, as well as its association with other infectious diseases, so they can effort to improve preventive measures for health services and more information about the progress and effects of the epidemic in Northeastern-Brazil. PMID- 27218260 TI - Potential Connectivity of Coldwater Black Coral Communities in the Northern Gulf of Mexico. AB - The black coral Leiopathes glaberrima is a foundation species of deep-sea benthic communities but little is known of the longevity of its larvae and the timing of spawning because it inhabits environments deeper than 50 m that are logistically challenging to observe. Here, the potential connectivity of L. glaberrima in the northern Gulf of Mexico was investigated using a genetic and a physical dispersal model. The genetic analysis focused on data collected at four sites distributed to the east and west of Mississippi Canyon, provided information integrated over many (~10,000) generations and revealed low but detectable realized connectivity. The physical dispersal model simulated the circulation in the northern Gulf at a 1km horizontal resolution with transport-tracking capabilities; virtual larvae were deployed 12 times over the course of 3 years and followed over intervals of 40 days. Connectivity between sites to the east and west of the canyon was hampered by the complex bathymetry, by differences in mean circulation to the east and west of the Mississippi Canyon, and by flow instabilities at scales of a few kilometers. Further, the interannual variability of the flow field surpassed seasonal changes. Together, these results suggest that a) dispersal among sites is limited, b) any recovery in the event of a large perturbation will depend on local larvae produced by surviving individuals, and c) a competency period longer than a month is required for the simulated potential connectivity to match the connectivity from multi-locus genetic data under the hypothesis that connectivity has not changed significantly over the past 10,000 generations. PMID- 27218261 TI - Relationship of mitral valve annulus plane and circumflex-right coronary artery plane: Implications for Transcatheter Mitral Valve Implantation. AB - AIM: Transcatheter mitral valve implantation (TMVI) is a novel technology for patients with severe mitral valve disease but at high surgical risk. Imaging guidance during the procedure is critical for successful device deployment. Identification of the mitral annular plane (MAP) with fluoroscopy during the procedure is limited by lack of clearly defined landmarks. We hypothesized that a plane defined by left circumflex-right coronary arteries (LCX-RCA) would have a consistent relationship to MAP. METHODS AND RESULTS: We studied 25 patients with gated cardiac computed tomography. We identified the MAP and the LCX-RCA plane in mid systole and diastole. The distance between the two planes in prespecified four points (anterior, posterior, medial, and lateral) in the apical 2 and 3 chamber views. Alignment of the planes was described by cranial/caudal angulation for both planes in RAO 30 degrees and LAO 90 degrees (lateral) angulation. Mean age was 81 +/- 9 years, 56% of patients had >=2+ mitral regurgitation. In mid systole, the distances between the LCX-RCA plane and the MAP in the four points were < 5 mm in 92% of patients. In mid diastole, distances were < 5 mm in 100% of patients. In mid systole, the correlation between the caudal/cranial orientations of the 2 planes was 0.85 and 0.80 in the LAO 90 degrees and RAO 30 degrees , respectively (P = <0.001). In mid diastole, this was 0.92 and 0.92 in the LAO 90 degrees and RAO 30 degrees , respectively (P = <0.001). CONCLUSION: LCX-RCA plane has a close and consistent relationship to the MAP and can be useful to guide TMVI. Accurate imaging of mitral valve annular plane during TMVI procedure is challenging. MAP guided by fluoroscopy might be crucial to guide successful prosthesis deployment. A plane defined by the left circumflex- right coronary arteries in the atrioventricular grove has a consistent relationship with MAP; this can be used aided by pre-procedural MDCT to guide TMVI procedure. (c) 2016 Wiley Periodicals, Inc. PMID- 27218262 TI - Burnout syndrome among medical students in Mexico: considerations about its measurement with the Maslach Burnout Inventory. PMID- 27218263 TI - The backroom in attacks on doctors. PMID- 27218264 TI - Dynamic Kinetic Resolution of Biaryl Lactones via a Chiral Bifunctional Amine Thiourea-Catalyzed Highly Atropo-enantioselective Transesterification. AB - A solution to the unmet synthetic challenge of achieving highly atropo enantioselective transesterification of Bringmann's lactones has been realized, employing a chiral bifunctional amine thiourea as promoter. The synergistic activation of the lactones and alcohols/phenols by the respective thiourea and amine groups is crucial for achieving the highly enantioselective, high-yielding dynamic kinetic resolution process. This protocol gives highly optically pure, axially chiral biaryl compounds with a broad substrate scope under mild reaction conditions. PMID- 27218265 TI - Virtual voices: social support and stigma in postnatal mental illness Internet forums. AB - Many women with postnatal mental illness do not get the treatment they need and this is often because stigma prevents disclosure. The purpose of this study was to explore online social support for postnatal mental illness, how women experience stigma and potential disadvantages of using Internet forums. Interviews were conducted with fifteen participants who had suffered postnatal mental illness and had used forums. Systematic thematic analysis identified common themes in relation to social support, stigma and disadvantages of using forums. Most women felt they benefited from visiting forums by developing a shared understanding and discourse about their illness. Findings suggest future research should investigate if women benefit from using online social support provided by forums, if use challenges stigma and further explore potential concerns about using forums. PMID- 27218266 TI - pKa prediction for acidic phosphorus-containing compounds using multiple linear regression with computational descriptors. AB - Ninety-six acidic phosphorus-containing molecules with pKa 1.88 to 6.26 were collected and divided into training and test sets by random sampling. Structural parameters were obtained by density functional theory calculation of the molecules. The relationship between the experimental pKa values and structural parameters was obtained by multiple linear regression fitting for the training set, and tested with the test set; the R(2) values were 0.974 and 0.966 for the training and test sets, respectively. This regression equation, which quantitatively describes the influence of structural parameters on pKa , and can be used to predict pKa values of similar structures, is significant for the design of new acidic phosphorus-containing extractants. (c) 2016 Wiley Periodicals, Inc. PMID- 27218267 TI - Structural and Biochemical Characterization of 6-Hydroxynicotinic Acid 3 Monooxygenase, A Novel Decarboxylative Hydroxylase Involved in Aerobic Nicotinate Degradation. PMID- 27218268 TI - Spillover of Marital Interactions and Parenting Stress in Families of Children With Autism Spectrum Disorder. AB - Few disorders appear to be more challenging for parents than autism spectrum disorder (ASD). Little is known about the extent to which parenting stress experienced by parents of children with ASD affects or is affected by marital quality. We examined daily spillover between level of parenting stress and marital interactions in a sample of 176 married couples (89.4% Caucasian, non Hispanic) who have a child with ASD (5-12 years of age, 85% male) via a 14-day daily diary approach. On each day of the daily diary, parents individually reported on 8 positive and 8 negative marital interactions and their level of parenting stress. Dyadic multilevel modeling analyses using hierarchical linear modeling were conducted to examine same-day and lagged-effect associations between number of positive and negative marital interactions and level of parenting stress. Having a day with a higher number of negative marital interactions was associated with a higher level of parenting stress for both mothers and fathers of children with ASD. Having a day with fewer positive marital interactions was associated with having a more stressful parenting day for mothers of children with ASD. Same-day spillover was moderated by parent gender and the functioning of the child with ASD. Spillover flowed bidirectionally for mothers of children with ASD. Helping parents of children with ASD find ways to engage in positive marital interactions on stressful parenting days and avoid having negative affect, tension, and behaviors stemming from negative marital interactions spill into parenting experiences are important intervention targets. PMID- 27218269 TI - Decreased Circulating Levels of Spexin in Obese Children. AB - CONTEXT: Spexin is a novel peptide that is implicated in obesity and related energy homeostasis in animals and adult humans. Little is known about its role in children. OBJECTIVE: The aim of the current study was to determine the potential role of Spexin in obese children and explore its relationships with various cardiometabolic risk factors. DESIGN AND PARTICIPANTS: This was a cross-sectional study composed of 69 children (51 obese and 18 normal weight; age 15.3 +/- 0.26 y). OUTCOME MEASURES: Spexin was measured using a specific enzyme-linked immunosorbent assay. Leptin, total and high-molecular-weight adiponectin, IL-6, high-sensitivity C-reactive protein, glucose, and insulin were also measured. Mann-Whitney U test, Pearson and Spearman rank correlations, logistic regression, and cluster analysis were used for the analysis and interpretation of the data. RESULTS: Spexin levels were significantly lower in obese vs normal-weight children, median(IQR) (0.33 ng/mL [0.27-0.44] vs 0.42 ng/mL [0.33-0.55]; P = .024), but did not correlate with other adipokines and/or insulin and glucose levels. Ordinal categorical variables of Spexin showed a strictly reverse association of obesity with the level of Spexin. Cluster analysis of Spexin and body mass index z score resulted in splitting the participants into normal-weight and obese-weight groups with high accuracy. CONCLUSIONS: Lower circulating levels of Spexin in obese children compared with their normal-weight counterparts and the ability to discriminate obese and normal-weight groups based on Spexin concentration enabled us to suggest a potential role for this novel peptide in childhood obesity. The clinical significance of these findings needs additional investigation. PMID- 27218270 TI - PCSK9 R46L Loss-of-Function Mutation Reduces Lipoprotein(a), LDL Cholesterol, and Risk of Aortic Valve Stenosis. AB - CONTEXT: Novel, low-density lipoprotein (LDL) cholesterol-lowering proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors also lower lipoprotein(a) levels, but the effect on aortic valve stenosis and myocardial infarction is unknown. OBJECTIVE: We tested the hypothesis that the PCSK9 R46L loss-of-function mutation is associated with lower levels of lipoprotein(a) and with reduced risk of aortic valve stenosis and myocardial infarction. DESIGN: We used two prospective cohort studies of the general population and one patient-based cohort. SETTING: Cohort studies selected at random individuals of Danish descent. PARTICIPANTS: We studied 103 083 individuals from the Copenhagen General Population Study, the Copenhagen City Heart Study, and the Copenhagen Ischemic Heart Disease Study. MAIN OUTCOME MEASURES: Lipoprotein(a), LDL cholesterol, and PCSK9 R46L genotype and diagnoses of aortic valve stenosis and myocardial infarction from national registries; lipoprotein(a) was measured from 49,617 individuals. RESULTS: Median (interquartile range) lipoprotein(a) levels were 10 (5-30) mg/dl for PCSK9 R46L noncarriers, 9 (4-32) mg/dl for heterozygotes, and 8 (4-42) mg/dl for homozygotes (trend P = .02). The corresponding values for LDL cholesterol levels were 124 (101-147) mg/dl, 104 (85-132) mg/dl, and 97 (85-128) mg/dl, respectively (trend P = 2 * 10(-52)). PCSK9 R46L carriers vs noncarriers had an age- and sex-adjusted odds ratio of 0.64 (95% confidence interval, 0.44 0.95) for aortic valve stenosis, 0.77 (0.65-0.92) for myocardial infarction, and 0.76 (0.64-0.89) for aortic valve stenosis or myocardial infarction. CONCLUSIONS: PCSK9 R46L carriers have lower levels of lipoprotein(a) and LDL cholesterol as well as reduced risk of aortic valve stenosis and myocardial infarction. This indirectly suggests that PCSK9 inhibitors may have a role in patients with aortic valve stenosis. PMID- 27218271 TI - The Association Between Air Pollution Exposure and Glucose and Lipids Levels. AB - CONTEXT: Evidence from recent decades supports a causal association between air pollution (particulate matter <10 MUm in diameter [PM10] and PM <2.5 MUm in diameter [PM2.5]) and oxidative stress, possibly involving impaired metabolism of glucose and lipids. OBJECTIVE: Using a satellite based model to assess PM exposure at 1-km spatial resolution, we examined the associations between PM and glucose, hemoglobin A1c (HbA1c), and lipids. DESIGN: Population-based retrospective cohort study of a 10-year period. SETTING: Members of the largest health care provider in Southern Israel. PARTICIPANTS: We included all serum glucose, HbA1c, and lipids tests of subjects with known cardiovascular diseases and risk factors. Subjects' glycemic status was defined as normal or diabetes. MAIN OUTCOME: Log-transformed glucose, HbA1c, and lipid values were explored by mixed models, with adjustment for personal and seasonal confounders. RESULTS: We assessed 73 117 subjects with over 600 000 samples. Three-month average concentration of PM10, but not 1- to 7-d exposure, was associated with increases of serum glucose, HbA1c, low-density lipoprotein and triglycerides, and decrease of high-density lipoprotein. The strongest associations were observed among subjects with diabetes (percent increase [95% confidence interval], for interquartile range increase of PM10 and PM2.5): 3.58% (1.03%; 6.20%) and 2.93% (0.35%; 5.59%) increase in HbA1c and 2.37% (2.11%; 2.63%) and 1.54% (1.26%; 1.83%) increase in low-density lipoprotein. Antidiabetic medications (other than insulin) attenuated the air pollution effect on serum glucose. CONCLUSIONS: Intermediate-term, but not short term, exposure to PM is associated with alterations in glucose, HbA1c, and lipids, especially among people with diabetes. PMID- 27218272 TI - Cushing in a Leaf: Endocrine Disruption From a Natural Remedy. AB - BACKGROUND: Information regarding the safety of herbal drugs is often not reported. We describe the case of a 65-year-old woman referred to us for a iatrogenic hypercortisolism, who denied any previous steroid consumption. She reported only a chronic application of a phytocosmetic cream, containing ethanol extract of the Cardiospermum halicacabum (CH) plant. Adrenal insufficiency occurred after the cream application was stopped. CH is used in traditional and Western medicine for its documented anti-inflammatory properties. Once the presence of synthetic glucocorticoids was ruled out in the phytocosmetic product, we investigated whether and how its chronic application could have caused the iatrogenic hypercortisolism. METHODS: Liquid chromatography high-resolution mass spectrometry (LC-HRMS) was performed to exclude the presence of known glucocorticoids in the cream. ELISA assay and Western blot analysis were employed to assess ACTH secretion and the glucocorticoid receptor expression respectively in murine ACTH-secreting pituitary adenoma cells AtT-20/D16v-F2, treated with dexamethasone, CH tincture, and mifepristone alone or in combination. To detect specific interaction of CH extract with the glucocorticoid receptor, we performed a dual-luciferase reporter assay in HEK293 cells. RESULTS: In AtT-20/D16v-F2 cells, CH extract showed to significantly reduce basal and CRH-induced ACTH secretion and the glucocorticoid receptor expression, similarly to dexamethasone; these effects were counteracted by mifepristone. In HEK293 cells, dexamethasone significantly induced luciferase activity after 24- and 36-hour treatment and CH tincture only after 36 hours; these effects were antagonized by mifepristone. CONCLUSIONS: CH extract displays a glucocorticoid-like activity, by means of a direct binding to the glucocorticoid receptor. PMID- 27218273 TI - Wnt Signaling Genes in Adipose Tissue and Skeletal Muscle of Humans With Different Degrees of Insulin Sensitivity. AB - CONTEXT: The beta-catenin-dependent Wnt signaling plays a role in adipogenesis, myogenesis, and glucose homeostasis. OBJECTIVE: The aim of this study was to assess adipose tissue and skeletal muscle expression of Wnt/beta-catenin signaling genes in a young healthy population according to insulin sensitivity and its regulation by hyperinsulinemia and free fatty acids. DESIGN: We examined 117 male volunteers. The participants were divided into subgroups of high-insulin sensitivity (IS) and low-IS on the basis of a 2-hour euglycemic clamp. In 20 subjects, the clamp was prolonged to 6 hours. After 1 week, another 6-hour clamp, with Intralipid/heparin infusion, was performed. Tissue biopsies were performed before each clamp and after 6-hour clamps. Additionally, we collected muscle biopsies from another group of 16 male subjects for cell cultures. Myotubes were treated with insulin separately and in combination with palmitate. RESULTS: We found decreased adipose tissue WNT10B, FZD1/8, LRP5, DVL2, CTNN1B, TCF7L2, and AXIN2 and increased muscle WNT10B, FZD1/8, LRP6, DVL1, GSK3B, CTNNB1, TCF7L2, AXIN2, MYC, and CCND1 expression in the low-IS group. Hyperinsulinemia resulted in a decrease in adipose tissue FZD4, LRP5/6, TCF7L2, and AXIN2 and an increase in muscle FZD1/8, DVL1/2/3, TCF7L2, AXIN2, and MYC expression. These changes disappeared after free fatty acid elevation. In myotubes, insulin increased the expression of FZD1, DVL2, CTNNB1, and TCF7L2, whereas palmitate abolished these effects. CONCLUSIONS: The association of beta-catenin-dependent Wnt signaling with insulin resistance is tissue specific. Observed changes might reflect a compensatory mechanism to increase muscle glucose uptake and to generate new fat cells in insulin-resistant conditions. PMID- 27218274 TI - Cardiometabolic Health in Obese Adolescents Is Related to Length of Obesity Exposure: A Pilot Study. AB - CONTEXT: Metabolically healthy obesity (MHO) is found in a subset of obese individuals. OBJECTIVE: This study sought to examine possible determinants of MHO related to the length of exposure to obesity, lifestyle factors, and dietary intake in adolescent boys. DESIGN: This was a cross-sectional Childhood Obesity Prevalence And Treatment study. Participants and Main Measures: Of 313 boys age 13.0-17.9 years with a body mass index (BMI) >= 97th percentile for age, two study cohorts were established based on two definitions of metabolically unhealthy obesity (MUO). Cohort 1 included 18 boys with at least three risk factors (hypertension, dyslipidemia, dysglycemia) who were matched for age, weight, height, and BMI with 18 boys with MHO. Cohort 2 included 35 boys with at least two risk factors who were compared with 31 boys with MHO. MHO was defined by the absence of cardiometabolic risk factors (excluding waist). Data on lifestyle factors and BMI growth trajectories were compared (MHO vs MUO). RESULTS: Boys with MUO (Cohort 1) presented with an earlier onset (4.3 vs 9.1 y; P = .005) and a longer duration of obesity (11.2 vs 6.4 y; P = .003) compared with those with MHO in both group comparisons using different MUO definitions. We found an overall trend toward higher BMI z scores (significant from 3-7 y; P < .001) in metabolically unhealthy compared with their healthy counterparts (Cohort 1). Boys with MHO had higher carbohydrate intake (P < .001). No additional determinants of MHO were observed. CONCLUSIONS: Increased cardiometabolic risk in boys is related to an earlier onset and a longer duration of obesity. PMID- 27218275 TI - Prediction of (19)F NMR Chemical Shifts in Labeled Proteins: Computational Protocol and Case Study. AB - The structural analysis of ligand complexation in biomolecular systems is important in the design of new medicinal therapeutic agents; however, monitoring subtle structural changes in a protein's microenvironment is a challenging and complex problem. In this regard, the use of protein-based (19)F NMR for screening low-molecular-weight molecules (i.e., fragments) can be an especially powerful tool to aid in drug design. Resonance assignment of the protein's (19)F NMR spectrum is necessary for structural analysis. Here, a quantum chemical method has been developed as an initial approach to facilitate the assignment of a fluorinated protein's (19)F NMR spectrum. The epigenetic "reader" domain of protein Brd4 was taken as a case study to assess the strengths and limitations of the method. The overall modeling protocol predicts chemical shifts for residues in rigid proteins with good accuracy; proper accounting for explicit solvation of fluorinated residues by water is critical. PMID- 27218276 TI - 5-Methylisoxazole-3-carboxamide-Directed Palladium-Catalyzed gamma-C(sp(3))-H Acetoxylation and Application to the Synthesis of gamma-Mercapto Amino Acids for Native Chemical Ligation. AB - Palladium-catalyzed acetoxylation of the primary gamma-C(sp(3))-H bonds in the amino acids Val, Thr, and Ile was achieved using a newly discovered 5 methylisoxazole-3-carboxamide directing group. The gamma-acetoxylated alpha-amino acid derivatives could be easily converted to gamma-mercapto amino acids, which are useful for native chemical ligation (NCL). The first application of NCL at isoleucine in the semisynthesis of a Xenopus histone H3 protein was also demonstrated. PMID- 27218277 TI - How Do I Diagnose and Treat Workers With Injuries From Hydrofluoric Acid? PMID- 27218278 TI - Burn Pit Emissions Exposure and Respiratory and Cardiovascular Conditions Among Airborne Hazards and Open Burn Pit Registry Participants. AB - OBJECTIVE: The aim of this study was to determine how burn pit emissions exposure is associated with the incidence of respiratory and cardiovascular conditions. METHODS: We examined the associations between assumed geographic and self reported burn pit emissions exposure and respiratory and cardiovascular outcomes in participants of the Airborne Hazards and Open Burn Pit Registry. RESULTS: We found significant dose-response associations for higher risk of self-reported emphysema, chronic bronchitis, or chronic obstructive pulmonary disease with increased days of deployment within 2 miles of selected burn pits (P-trend = 0.01) and self-reported burn pit smoke exposure (P-trend = 0.0005). CONCLUSIONS: We found associations between burn pit emissions exposure and higher incidence of post-deployment self-reported respiratory and cardiovascular conditions, but these findings should be interpreted with caution because the surrogate measurements of burn pit emissions exposure in this analysis may not reflect individual exposure levels. PMID- 27218279 TI - Characteristics of Cardiac Arrest Occurring in the Workplace: A Post Hoc Analysis of the Paris Area Fire Brigade Registry. AB - OBJECTIVES: The aim of this study was to describe the characteristics of out-of hospital cardiac arrest (OHCA) in different workplaces, their management, and the survival rate. METHODS: A post hoc analysis included all the OHCA cases that occurred at the workplace and were listed in the Fire Brigade of Paris database registry (2010 to 2014). Utstein-style variables, survival, and types of workplace were analyzed. RESULTS: The study included 298 OHCA cases, mostly young (44% between 18 and 50 years), male (86%), and nontraumatic (86%). Differences in the survival chain were found to be related to the types of work location: bystander cardiopulmonary resuscitation was performed in 0% to 55% of cases, and workplace-automated external defibrillators were used in 0% to 20% of cases. Long term survival without major incapacity was 0% to 23%. CONCLUSIONS: The characteristics of OHCA differ as a function of the type of workplace. PMID- 27218280 TI - Diurnal and Reactivity Measures of Cortisol in Response to Intensive Resilience and Tactical Training Among Special Forces Police. AB - Special Forces Police are called to the most dangerous situations that require skills and equipment beyond the training available to a patrol officer. We recruited a platoon of special forces (n = 18) and examined their basal and reactivity levels of cortisol in relation to occupational duties. Moreover, we measured the impact of a multiday program of intensive resilience and tactical training in improving cortisol responses to stressful situations. Participants were significantly more likely to exhibit basal cortisol levels higher than the civilian norms across all of the 5 days of intensive training. However, anticipatory cortisol, measured directly before exposure to critical incident scenarios, was significantly lower in Day 5 than in Day 1 of the training period. This study demonstrates that measuring cortisol is an objective method of examining training effects and possible long-term occupational health outcomes. PMID- 27218281 TI - Corrigendum. PMID- 27218282 TI - Excess Gestational Weight Gain in Pregnancy and the Role of Lifestyle Intervention. AB - With increasingly adverse lifestyles, young women in many countries have rapid weight gain and rising obesity. In keeping with this, most pregnant women exceed recommended gestational weight gain (GWG) and then retain weight postpartum. The consequences of excess GWG include maternal risks during pregnancy, neonatal risks and maternal obesity and chronic disease longer term, presenting a significant public health and economic burden worldwide. This article discusses the adverse maternal and infant risks with excess GWG apparent from observational studies, summarizes the existing guidelines for optimal GWG and highlights the need for further research to identify optimal GWG recommendations across the different ethnicities and weight ranges.We also review the evidence for lifestyle interventions in pregnancy to prevent excess GWG and highlighting the work underway to integrate large scale meta-analyses of individual patient data from lifestyle intervention studies to inform clinical practice beyond current observational data. Finally, we address the need to implement lifestyle interventions into routine pregnancy care to improve short and long term maternal health outcomes. PMID- 27218283 TI - Retrospective Studies: A Fresh Look. AB - PURPOSE: A first objective was to provide an overview of advantages and cautions around so-called retrospective clinical studies. A second objective was to provide guidelines for strong studies that can make a valid contribution to the clinical literature, whether these studies are prospective, retrospective, experimental, or observational. METHOD: Invited commentaries were solicited from statistical and study design experts. RESULTS: The strength of a clinical study does not lie so much with its point in time relative to data generation, as it lies with study design. In fact, quite surprisingly, data collected in the past can be modeled to create a prospective study, if appropriate. One distinctive strength of observational studies-which are sometimes but not always retrospective-is the ability to obtain a large corpus of data from medical databases rapidly, as sometimes warranted by pressing health care policy and practice issues. CONCLUSION: Retrospective studies, often considered inferior to prospective, randomized, and controlled clinical trials, can have strength and validity often not recognized in the hierarchy of clinical data. PMID- 27218284 TI - Chronic Mountain Sickness: Clinical Aspects, Etiology, Management, and Treatment. AB - Villafuerte, Francisco C., and Noemi Corante. Chronic mountain sickness: clinical aspects, etiology, management, and treatment. High Alt Med Biol. 17:61-69, 2016. Millions of people worldwide live at a high altitude, and a significant number are at risk of developing Chronic Mountain Sickness (CMS), a progressive incapacitating syndrome caused by lifelong exposure to hypoxia. CMS is characterized by severe symptomatic excessive erythrocytosis (EE; Hb >=19 g/dL for women and Hb >=21 g/dL for men) and accentuated hypoxemia, which are frequently associated with pulmonary hypertension. In advanced cases, the condition may evolve to cor pulmonale and congestive heart failure. Current knowledge indicates a genetic predisposition to develop CMS. However, there are important risk factors and comorbidities that may trigger and aggravate the condition. Thus, appropriate medical information on CMS is necessary to provide adequate diagnosis and healthcare to high-altitude inhabitants. After reviewing basic clinical aspects of CMS, including its definition, diagnosis, and common clinical findings, we discuss aspects of its etiology, and address its epidemiology, risk factors, and treatment. PMID- 27218285 TI - Evaluation of a novel natural drop for treatment of chronic rhinosinusitis without nasal polyps: a single blind randomized trial. AB - BACKGROUND: The present study investigated the effectiveness of a Pimpinella anisum-based herbal medicine for treating chronic rhinosinusitis (CRS) without polyps in comparison to fluticasone nasal spray, in a single-blinded randomized trial. METHODS: Patients with CRS without nasal polyps were randomly assigned into 2 treatment groups: individuals in the first group (n = 26) received 2 drops of a P. anisum-based herbal medicine (Sinupim) in each nostril every 12 hours, while those in the second group (n = 22) received 2 puffs of fluticasone nasal spray in each nostril every 12 hours. Both groups used their designated treatments for 4 weeks. Patients were evaluated by the 22-item Sino-Nasal Outcome Test (SNOT-22) at the start of the trial and after the completion of their treatment. RESULTS: Although both treatments were effective in reducing patients' symptoms, there were significantly better results in the Sinupim group based on the SNOT-22 evaluation. Mean changes in computed tomography (CT) scan scoring in Sinupim and fluticasone groups before and after treatment were 2.22 +/- 2.94 and 0.76 +/- 1.39, respectively, which was significant within both groups (p < 0.05). Postnasal drip and nasal obstruction were more significantly improved in the Sinupim group. CONCLUSION: A P. anisum-based herbal medicine may be an effective treatment for sinusitis without polyps. However, its wide acceptance needs further investigation. PMID- 27218286 TI - Idiopathic pulmonary fibrosis fibroblasts become resistant to Fas ligand dependent apoptosis via the alteration of decoy receptor 3. AB - Idiopathic pulmonary fibrosis (IPF) is an irreversible lethal lung disease with an unknown etiology. IPF patients' lung fibroblasts express inappropriately high Akt activity, protecting them in response to an apoptosis-inducing type I collagen matrix. FasL, a ligand for Fas, is known to be increased in the lung tissues of patients with IPF, implicated with the progression of IPF. Expression of Decoy Receptor3 (DcR3), which binds to FasL, thereby subsequently suppressing the FasL-Fas-dependent apoptotic pathway, is frequently altered in various human disease. However, the role of DcR3 in IPF fibroblasts in regulating their viability has not been examined. We found that enhanced DcR3 expression exists in the majority of IPF fibroblasts on collagen matrices, resulting in the protection of IPF fibroblasts from FasL-induced apoptosis. Abnormally high Akt activity suppresses GSK-3beta function, thereby accumulating the nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) in the nucleus, increasing DcR3 expression in IPF fibroblasts. This alteration protects IPF cells from FasL induced apoptosis on collagen. However, the inhibition of Akt or NFATc1 decreases DcR3 mRNA and protein levels, which sensitizes IPF fibroblasts to FasL-mediated apoptosis. Furthermore, enhanced DcR3 and NFATc1 expression is mainly present in myofibroblasts in the fibroblastic foci of lung tissues derived from IPF patients. Our results showed that when IPF cells interact with collagen matrix, aberrantly activated Akt increases DcR3 expression via GSK-3beta-NFATc1 and protects IPF cells from the FasL-dependent apoptotic pathway. These findings suggest that the inhibition of DcR3 function may be an effective approach for sensitizing IPF fibroblasts in response to FasL, limiting the progression of lung fibrosis. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 27218287 TI - Nanooctahedra Particles Assembled FeSe2 Microspheres Embedded into Sulfur-Doped Reduced Graphene Oxide Sheets As a Promising Anode for Sodium Ion Batteries. AB - Presently, considerable attention has been paid to the Fe-based dichalcogenides as anode materials for sodium ion batteries (SIBs) due to their abundant resources, chemical stability, and high theoretical capacity. In this paper, we make nanooctahedra particles assembled FeSe2 microspheres embedded into sulfur doped reduced graphene oxide sheets through a one-step hydrothermal reduction route, in which the reduction of graphene oxide, the doping of sulfur atoms, and the preparation of FeSe2/sulfur-doped reduced graphene oxide (FeSe2/SG) composites are realized at the same time. When serving as anodes for SIBs, the FeSe2/SG electrode can display superior electrochemical performances with a large reversible capacity of 447.5 mA h g(-1) at 0.5 A g(-1) and an excellent rate capability of 383.3 and 277.5 mA h g(-1) at the current density of 2.0 and 5.0 A g(-1), which could be attributed to the introduction of sulfur atoms into the reduced graphene oxide structure and the synergistic effect between microsphere like FeSe2 particles and sulfur-doped reduced graphene oxide sheets. PMID- 27218288 TI - Shielding Design for Adjacent, Underground Buildings of a Megavoltage Radiotherapy Facility. AB - In a radiotherapy facility, safety in areas next to the treatment room can be of concern when irradiating downward due to oblique x-ray transmission through the floor and/or walls, especially in areas immediately adjacent or underground. Even when there is no basement underneath, a usual conservative solution is to build a thick concrete slab as the base for the treatment room. Of course, this implies deeper soil excavation and higher associated costs. As a convenient alternative, the limiting walls can be buried a certain depth below floor level to shield oblique, downward irradiation. Besides, for space considerations, laminated barriers are usually employed, and some additional shielding to the floor may be required (L-shaped barriers). In this work, the author introduces an analytical method for calculating the required wall penetration below floor level or, alternatively, the additional floor shielding for L-shaped barriers, taking into account in either case the attenuation properties of the earth underneath the vault. Interestingly, the required penetration depth for a given wall barrier (primary or secondary), relative to a reference thickness, is only a function of basic attenuation data. Likewise, for a laminated, lead-concrete barrier, the required dimensions depend on the relative amount of lead used for the wall and on the corresponding attenuation data. The shielding design criteria developed in this work to protect underground nearby sites is conservative in nature, yet it yields optimal shield dimensions for wall footing and for wall-floor shielding, avoiding the need to construct oversized concrete slab floors. PMID- 27218289 TI - Indoor Gamma Dose Rates In Kuwait Using Handheld Gamma-ray Spectrometer. AB - A survey of indoor gamma dose rates was carried out in Kuwait using a NaI dosimeter/spectrometer. The measurements started from May 2013 until April 2015 and covered different locations within 200 dwellings: 158 halls, 26 rooms, 17 basements, and 43 kitchens (total of 244 locations). Alongside the dose rate measurements, gamma-ray spectra were also acquired to evaluate the relative contributions of K, Bi, and Tl and check the presence of Cs. The results show that the dose rates for all locations varied from 39.3 to 103.3 nSv h with a mean of 70.6 nSv h, indicating that the indoor dose rates are low and within the normal range. PMID- 27218290 TI - Decay Chain Deduction of Uranium Fission Products. AB - Delayed gamma spectrum is the fingerprint of uranium materials in arms control verification technology. The decay chain is simplified into basic state linear chain and excitation state linear chain to calculate and analyze the delayed gamma spectra of fission products. Formulas of the changing rule for nuclide number before and after zero-time are deduced. The C program for calculating the delayed gamma ray spectra data is constructed, and related experiments are conducted to verify this theory. Through analysis of the delayed gamma counts of several nuclides, the calculated results are found to be consistent with experimental values. PMID- 27218291 TI - 241Am INGROWTH AND ITS EFFECT ON INTERNAL DOSE. AB - Generally, plutonium has been manufactured to support commercial and military applications involving heat sources, weapons, and reactor fuel. This work focuses on three typical plutonium mixtures while observing the potential of Am ingrowth and its effect on internal dose. The term "ingrowth" is used to describe Am production due solely to the decay of Pu as part of a plutonium mixture, where it is initially absent or present in a smaller quantity. Dose calculation models do not account for Am ingrowth unless the Pu quantity is specified. This work suggested that Am ingrowth be considered in bioassay analysis when there is a potential of a 10% increase to the individual's committed effective dose. It was determined that plutonium fuel mixtures, initially absent of Am, would likely exceed 10% for typical reactor grade fuel aged less than 30 y; however, heat source grade and aged weapons grade fuel would normally fall below this threshold. Although this work addresses typical plutonium mixtures following separation, it may be extended to irradiated commercial uranium fuel and is expected to be a concern in the recycling of spent fuel. PMID- 27218292 TI - Methemoglobin-Based Biological Dose Assessment for Human Blood. AB - Methemoglobin is an oxidative form of hemoglobin in erythrocytes. The authors' aim was to develop a new biological dosimeter based on a methemoglobin assay. Methemoglobin in peripheral blood (of females or males) that was exposed to a Co source (0.20 Gy min) was quantified using an enzyme-linked immunosorbent assay. The dose range was 0.5-8.0 Gy. In a time-course experiment, the time points 0, 0.02, 1, 2, 3, 7, 15, 21, and 30 d after 4-Gy irradiation of heparinized peripheral blood were used. Methemoglobin levels in a lysed erythrocyte pellet from the irradiated blood of females and males increased with the increasing dose. Methemoglobin levels in female blood irradiated with gamma-doses more than 4 Gy were significantly higher than those in male samples at the same doses. Two dose-response relations were fitted to the straight line: one is with the correlation coefficient of 0.98 for females, and the other is with the correlation coefficient of 0.99 for males. The lower limit of dose assessment based on methemoglobin is about 1 Gy. Methemoglobin levels in blood as a result of auto-oxidation increase after 7-d storage at -20 degrees C. The upregulation of methemoglobin induced by gamma-radiation persists for ~3 d. The absorbed doses that were estimated using the two dose-response relations were close to the actual doses. The results suggest that methemoglobin can be used as a rapid and accurate biological dosimeter for early assessment of absorbed gamma-dose in human blood. PMID- 27218293 TI - Historical Patterns in the Types of Procedures Performed and Radiation Safety Practices Used in Nuclear Medicine From 1945-2009. AB - The authors evaluated historical patterns in the types of procedures performed in diagnostic and therapeutic nuclear medicine and the associated radiation safety practices used from 1945-2009 in a sample of U.S. radiologic technologists. In 2013-2014, 4,406 participants from the U.S. Radiologic Technologists (USRT) Study who previously reported working with medical radionuclides completed a detailed survey inquiring about the performance of 23 diagnostic and therapeutic radionuclide procedures and the use of radiation safety practices when performing radionuclide procedure-related tasks during five time periods: 1945-1964, 1965 1979, 1980-1989, 1990-1999, and 2000-2009. An overall increase in the proportion of technologists who performed specific diagnostic or therapeutic procedures was observed across the five time periods. Between 1945-1964 and 2000-2009, the median frequency of diagnostic procedures performed substantially increased (from 5 wk to 30 wk), attributable mainly to an increasing frequency of cardiac and non brain PET scans, while the median frequency of therapeutic procedures performed modestly decreased (from 4 mo to 3 mo). Also a notable increase was observed in the use of most radiation safety practices from 1945-1964 to 2000-2009 (e.g., use of lead-shielded vials during diagnostic radiopharmaceutical preparation increased from 56 to 96%), although lead apron use dramatically decreased (e.g., during diagnostic imaging procedures, from 81 to 7%). These data describe historical practices in nuclear medicine and can be used to support studies of health risks for nuclear medicine technologists. PMID- 27218294 TI - Radon Exposure and the Definition of Low Doses-The Problem of Spatial Dose Distribution. AB - Investigating the health effects of low doses of ionizing radiation is considered to be one of the most important fields in radiological protection research. Although the definition of low dose given by a dose range seems to be clear, it leaves some open questions. For example, the time frame and the target volume in which absorbed dose is measured have to be defined. While dose rate is considered in the current system of radiological protection, the same cancer risk is associated with all exposures, resulting in a given amount of energy absorbed by a single target cell or distributed among all the target cells of a given organ. However, the biological effects and so the health consequences of these extreme exposure scenarios are unlikely to be the same. Due to the heterogeneous deposition of radon progeny within the lungs, heterogeneous radiation exposure becomes a practical issue in radiological protection. While the macroscopic dose is still within the low dose range, local tissue doses on the order of Grays can be reached in the most exposed parts of the bronchial airways. It can be concluded that progress in low dose research needs not only low dose but also high dose experiments where small parts of a biological sample receive doses on the order of Grays, while the average dose over the whole sample remains low. A narrow interpretation of low dose research might exclude investigations with high relevance to radiological protection. Therefore, studies important to radiological protection should be performed in the frame of low dose research even if the applied doses do not fit in the dose range used for the definition of low doses. PMID- 27218295 TI - Vitamins A, C, and E May Reduce Intestinal 210Po Levels after Ingestion. AB - Damage to the gut mucosa is a probable contributory cause of death from ingested Po. Therefore, medical products are needed that can prevent, mitigate, and/or repair gastrointestinal (GI) damage caused by high-LET radiation emitted by Po. The present studies investigated the capacity of a diet highly enriched with vitamins A, C, and E (vitamin ACE) to protect against intestinal mucosal damage indicated by functional reductions in nutrient transport caused by orally ingested Po. Mice were gavaged with 0 or 18.5 kBq Po-citrate and fed a control or vitamin ACE-enriched diet (the latter beginning either 96 h before or immediately after gavage). Mouse intestines significantly retained Po on day 8 post-gavage. The concentration of Po in intestinal tissues was significantly (p<0.05) lower in all vitamin ACE groups compared to control. There were borderline significant Po induced reductions in intestinal absorption of D-fructose. The combination of vitamins A, C, and E may reduce Po incorporation in the intestines when given before, or enhance decorporation when provided after, Po gavage. PMID- 27218296 TI - Application of NCRP 156 Wound Model and ICRP 67 Systemic Plutonium Model for Analysis of Urine Data from Simulated Wounds in Nonhuman Primates. AB - The predictions of the wound model described in NCRP Report No. 156, coupled with the systemic model described in ICRP 67, were compared with the actual urinary excretion data and wound retention data from nonhuman primates injected intramuscularly or subcutaneously with Pu(IV) citrate. The results indicated that the early behavior of Pu(IV) citrate in wounds can be adequately described by the default retention parameters for moderately retained radionuclides suggested by the report. The urinary excretion rates after 200 d post intake could not be described well by the parameters of any of the default wound models because of the differences in the systemic handling of plutonium by humans compared to nonhuman primates. PMID- 27218300 TI - Mometasone furoate nasal spray for the treatment of asthma. AB - INTRODUCTION: Asthma is a common respiratory disease characterized by airway inflammation, bronchoconstriction and airway hyperresponsiveness and symptoms such as coughing, wheezing, shortness of breath and chest tightness. Allergic rhinitis is a common comorbidity in asthma and glucocorticoids are the key stone in the treatment of both diseases. Mometasone furoate is a potent synthetic steroid with a very high receptor affinity and a low bioavailability and shown to be superior compared to other inhaled corticosteroids. It is not clear whether the use of mometasone furoate nasal spray (MFNS) is associated with an improvement in asthma control. AREAS COVERED: This current paper reviews the current knowledge on the effect of mometasone furoate nasal spray in the treatment of asthma and includes clinical trials in which both subjective and objective outcomes are assessed. EXPERT OPINION: To date, only few clinical studies have investigated the effect of nasal steroids in the treatment of asthma. The studies investigating the effect of MFNS report contradicting results, although the most well-designed study to answer this question finds no improvement in asthma control. Thus, it seems unlikely that asthma guidelines will be influenced by the current knowledge on the effect of MFNS in the treatment of asthma. PMID- 27218301 TI - Simultaneous Turn and Step Task for Investigating Control Strategies in Healthy Young and Community Dwelling Older Adults. AB - A simultaneous turn and step motion is a vital component of many complex movements and may provide insight into age related balance and stability deficits during a weight transfer task. In this study, nine young adults and ten healthy, community dwelling older adults performed a simultaneous "turn and step" task from a quiet standing position under two self-selected speeds, self-paced and as quickly and efficiently as possible. Whole-body center of mass was estimated to investigate stability, segmental coordination, and variability. Older adults performed the task with greater variability, however they were unable to alter stability nor segmental coordination across the self-selected speeds; absence of this modulation portrays a trade-off between stability and manoeuvrability. An increase in variability with no observed directional differences suggests that the simultaneous turn and step task may be a sensitive discriminatory motor task helpful in elucidating the adoption of altered control strategies used by elderly populations. PMID- 27218302 TI - Bioreduction of Precious Metals by Microorganism: Efficient Gold@N-Doped Carbon Electrocatalysts for the Hydrogen Evolution Reaction. AB - The uptake of precious metals from electronic waste is of environmental significance and potential commercial value. A facile bioreductive synthesis is described for Au nanoparticles (ca. 20 nm) supported on N-doped carbon (Au@NC), which was derived from Au/Pycnoporus sanguineus cells. The interface and charge transport between Au and N-doped carbon were confirmed by HRTEM and XPS. Au@NC was employed as an electrocatalyst for the hydrogen evolution reaction (HER), exhibiting a small onset potential of -54.1 mV (vs. RHE), a Tafel slope of 76.8 mV dec(-1) , as well as robust stability in acidic medium. Au@NC is a multifunctional electrocatalyst, which demonstrates high catalytic activity in the oxygen reduction reaction (ORR), as evidenced by an onset potential of +0.97 V, excellent tolerance toward methanol, and long-term stability. This work exemplifies dual recovery of precious Au and fabrication of multifunctional electrocatalysts in an environmentally benign and application-oriented manner. PMID- 27218303 TI - Kinetics of Evaporation of Pinned Nanofluid Volatile Droplets at Subatmospheric Pressures. AB - We examine the effects of nanoparticle addition at low concentration on the evaporation kinetics of droplets in the constant radius mode. The evaporative behavior of deionized water and Al2O3 nanoparticle laden water on an aluminum substrate was observed at atmospheric and at different subatmospheric pressures. The two fluids exhibit the same evaporative behavior, independent of the droplet volume or the subatmospheric pressure. Moreover, the linear relationship between evaporation rate and droplet radius, initially proposed by Picknett and Bexon nearly four decades ago for droplets evaporating in the constant radius mode, is satisfied for both liquids. In addition, we have established a unified correlation solely function of fluid properties that extends this relationship to any subatmospheric pressure and fluid tested. We conclude that the addition of a small quantity of nanoparticles to the base fluid does not modify the kinetics of evaporation for pinned volatile droplets. PMID- 27218305 TI - Systematic review of cost-of-illness studies in hand eczema. AB - The individual burden of disease in hand eczema patients is considerable. However, little is known about the socio-economic impact of this disease. The aims of this review were to evaluate the literature on cost-of-illness in hand eczema, and to compose a checklist for future use. The literature was retrieved from the MEDLINE and EMBASE databases up to October 2015. Quality evaluation was based on seven relevant items in cost-of-illness studies. Cost data (direct and indirect) were extracted and converted into euros (2014 price level) by use of the Dutch Consumer Price Index. Six articles were included. The mean annual total cost per patient ranged from ?1311 [corrected] to ?9792 (direct cost per patient, ?521 to ?3722; [corrected] and indirect cost per patient, ?100 to ?6846). Occupational hand eczema patients showed indirect costs up to 70% of total costs, mainly because of absenteeism. A large diversity in hand eczema severity was found between studies. The socio-economic burden of hand eczema is considerable, especially for more severe and/or occupational hand eczema. Absenteeism from paid work leads to a high total cost-of-illness, although disregard of presenteeism often leads to underestimation of indirect costs. Differences in included cost components, the occupational status of patients and hand eczema severity make international comparison difficult. A checklist was added to standardize the approach to cost-of-illness studies in hand eczema. PMID- 27218306 TI - Representing object categories by connections: Evidence from a mutivariate connectivity pattern classification approach. AB - The representation of object categories is a classical question in cognitive neuroscience and compelling evidence has identified specific brain regions showing preferential activation to categories of evolutionary significance. However, the potential contributions to category processing by tuning the connectivity patterns are largely unknown. Adopting a continuous multicategory paradigm, we obtained whole-brain functional connectivity (FC) patterns of each of four categories (faces, scenes, animals and tools) in healthy human adults and applied multivariate connectivity pattern classification analyses. We found that the whole-brain FC patterns made high-accuracy predictions of which category was being viewed. The decoding was successful even after the contributions of regions showing classical category-selective activations were excluded. We further identified the discriminative network for each category, which span way beyond the classical category-selective regions. Together, these results reveal novel mechanisms about how categorical information is represented in large-scale FC patterns, with general implications for the interactive nature of distributed brain areas underlying high-level cognition. Hum Brain Mapp 37:3685-3697, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27218307 TI - Aspect ratio-related three-photon absorption and mechanism of alpha-FeOOH nanorods in the near-infrared. AB - Tuning a semiconductor nanomaterial with large three-photon absorption (3PA) cross section in the near infrared and investigating the relationship between the nanostructure and nonlinear optical properties is a challenging topic, which is of significance in potential applications. Here, we report the aspect ratio related 3PA response of alpha-FeOOH nanorods (NRs) in the near infrared. Large 3PA cross section at room temperature is achieved as high as ~10(-77) cm(6) s(2) photon(-2) when the distribution of photo-induced and intrinsic surface polarization charges of excitons to both ends of NRs is tuned through the aspect ratio, yielding total enhancement more than three times larger than that of NRs with 12.1 nm diameter. PMID- 27218304 TI - The pharmacokinetics and dosing of oral 4-methylumbelliferone for inhibition of hyaluronan synthesis in mice. AB - Recently, there has been considerable interest in using 4-methylumbelliferone (4 MU) to inhibit hyaluronan (HA) synthesis in mouse models of cancer, autoimmunity and a variety of other inflammatory disorders where HA has been implicated in disease pathogenesis. In order to facilitate future studies in this area, we have examined the dosing, treatment route, treatment duration and metabolism of 4-MU in both C57BL/6 and BALB/c mice. Mice fed chow containing 5% 4-MU, a dose calculated to deliver 250 mg/mouse/day, initially lose substantial weight but typically resume normal weight gain after 1 week. It also takes up to a week to see a reduction in serum HA in these animals, indicating that at least a 1-week loading period on the drug is required for most protocols. At steady state, more than 90% of the drug is present in plasma as the glucuronidated metabolite 4 methylumbelliferyl glucuronide (4-MUG), with the sulphated metabolite, 4 methylumbelliferyl sulphate (4-MUS) comprising most of the remainder. Chow containing 5% but not 0.65% 4-MU was effective at preventing disease in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis, as well as in the DORmO mouse model of autoimmune diabetes. While oral 4-MU was effective at preventing EAE, daily intraperitoneal injections of 4-MU were not. Factors potentially affecting 4-MU uptake and plasma concentrations in mice include its taste, short half-life and low bioavailability. These studies provide a practical resource for implementing oral 4-MU treatment protocols in mice. PMID- 27218308 TI - Zirconium-metalloporphyrin frameworks as a three-in-one platform possessing oxygen nanocage, electron media, and bonding site for electrochemiluminescence protein kinase activity assay. AB - A Zr-based metal-organic framework with zinc tetrakis(carboxyphenyl)-porphyrin (ZnTCPP) groups (MOF-525-Zn) was utilized to develop a novel electrochemiluminescence (ECL) biosensor for highly sensitive protein kinase activity assay. In this work, in terms of ECL measurements and cyclic voltammetry, the cathodic ECL behaviors of MOF-525-Zn in aqueous media were thoroughly investigated for the first time. The photoelectric active groups ZnTCPP on the MOF-525-Zn frameworks could promote the generation of singlet oxygen ((1)O2) via a series of electrochemical and chemical reactions, resulting in a strong and stable red irradiation at 634 nm. Additionally, the surfactant tetraoctylammonium bromide (TOAB) further facilitated dissolved oxygen to interact with the active sites ZnTCPP of MOF-525-Zn. Furthermore, the inorganic Zr-O clusters of MOF-525-Zn were simultaneously served as the recognition sites of phosphate groups. And then, an ultrasensitive ECL sensor was proposed for protein kinase A (PKA) activity detection with a linear range from 0.01 to 20 U mL(-1) and a sensitive detection limit of 0.005 U mL(-1). This biosensor can also be applied for quantitative kinase inhibitor screening. Finally, it exhibits good performance with high stability and acceptable fabrication reproducibility, which provide a valuable strategy for clinic diagnostics and therapeutics. PMID- 27218309 TI - The wise radialist's guide to optimal transfemoral access: Selection, performance, and troubleshooting. AB - Transradial access (TRA) has reduced vascular access-site complication (VASC) and bleeding rates in patients undergoing coronary angiography and intervention. A "radial-first" approach should be adopted and indications of TRA extended in order to maximize its beneficial effect. However, in certain clinical scenarios, transfemoral access (TFA) is a preferable or a mandatory route to successfully perform the procedure. Since the widespread adoption of TRA, a paradoxical increase in VASC rates has been observed in patients undergoing TFA, which might be attributed to a combination of increased risk profile of both the procedures and the patients, and a loss of skills in securing TFA by those who are now default radial operators. In the present article we provide recommendations on how to optimize patient selection for TRA and TFA, how to manage access site crossover, and how to perform state-of-the-art femoral artery puncture. (c) 2016 Wiley Periodicals, Inc. PMID- 27218408 TI - A 1,3-Capped Calix[4] Conjugate Possessing an Amine Moiety as an Anion Receptor: Reversible Anion Sensing Detected by Spectroscopy and Characterization of the Supramolecular Features by Microscopy. AB - A phenylenediamine-capped conjugate of calix[4]arene (Lamino ) was synthesized by reducing its precursor, Limino , with sodium borohydride in methanol. The Lamino sample binds to anions due to the more flexible and bent conformation of the capped aminophenolic binding core, compared to the precursor Limino . The Lamino sample showed selectivity towards H2 PO4 (-) by exhibiting a ratiometric increase in emission by about 11-fold with a detection limit of (1.2+/-0.2) MUm ((116+/ 20) ppb) over 15 anions studied, including other phosphates, such as P2 O7 (4-) , adenosine monophosphate (AMP(2-) ), adenosine diphosphate (ADP(2-) ), and adenosine triphosphate (ATP(2-) ). The Lamino sample shows an increase in the absorbance at lambda=315 nm in the presence of H2 PO4 (-) , CO3 (2-) , HCO3 (-) , CH3 CO2 (-) , and F(-) . The (1) H NMR spectroscopic titration of Lamino with H2 PO4 (-) , F(-) , and CH3 CO2 (-) showed major changes in the phenylene-capped and salicyl moieties, and thereby, confirming the aminophenolic region as the binding core. However, the binding strength of these anions followed the trend H2 PO4 (-) >F(-) ?CH3 CO2 (-) >HSO4 (-) . The heat changes observed by isothermal titration calorimetry support this trend. The Lamino sample showed reversible sensing towards H2 PO4 (-) and F(-) in the presence of Mg(2+) and Ca(2+) , respectively. NOESY studies of Lamino , in comparison with its anionic complexes, revealed that major conformational changes occurred in the capping region to facilitate the binding of anion. ESI-MS and the Job's method revealed 1:1 stoichiometry between Lamino and H2 PO4 (-) or F(-) . In the SEM micrographs of Lamino , the spherical particles are converted into spherical aggregates and further form large agglomerates and even branched sheets in the presence of anions, depending upon their binding strength. PMID- 27218409 TI - Investigating risky, distracting, and protective peer passenger effects in a dual process framework. AB - Prior studies indicated higher collision rates among young novice drivers with peer passengers. This driving simulator study provided a test for a dual process theory of risky driving by examining social rewards (peer passengers) and cognitive control (inhibitory control). The analyses included age (17-18 yrs, n=30; 21-24 yrs, n=20). Risky, distracting, and protective effects were classified by underlying driver error mechanisms. In the first drive, participants drove alone. In the second, participants drove with a peer passenger. Red-light running (violation) was more prevalent in the presence of peer passengers, which provided initial support for a dual process theory of risk driving. In a subgroup with low inhibitory control, speeding (violation) was more prevalent in the presence of peer passengers. Reduced lane-keeping variability reflected distracting effects. Nevertheless, possible protective effects for amber-light running and hazard handling (cognition and decision-making) were found in the drive with peer passengers. Avenues for further research and possible implications for targets of future driver training programs are discussed. PMID- 27218410 TI - Putrescine production by Lactococcus lactis subsp. cremoris CECT 8666 is reduced by NaCl via a decrease in bacterial growth and the repression of the genes involved in putrescine production. AB - The reduction of NaCl in food is a public health priority; high NaCl intakes have been associated with serious health problems. However, it is reported that reducing the NaCl content of cheeses may lead to an increase in the content of biogenic amines (BAs). The present work examines the effect of NaCl on the accumulation of putrescine (one of the BAs often detected at high concentration in cheese) in experimental Cabrales-like cheeses containing Lactococcus lactis subsp. cremoris CECT 8666, a dairy strain that catabolises agmatine to putrescine via the agmatine deiminase (AGDI) pathway. The genes responsible for this pathway are grouped in the AGDI cluster. This comprises a regulatory gene (aguR) (transcribed independently), followed by the catabolic genes that together form an operon (aguBDAC). Reducing the NaCl concentration of the cheese led to increased putrescine accumulation. In contrast, increasing the NaCl concentration of both pH-uncontrolled and pH-controlled (pH 6) cultures of L. lactis subsp. cremoris CECT 8666 significantly inhibited its growth and the production of putrescine. Such production appeared to be inhibited via a reduction in the transcription of the aguBDAC operon; no effect on the transcription of aguR was recorded. The present results suggest that low-sodium cheeses are at risk of accumulating higher concentrations of putrescine. PMID- 27218412 TI - RNAi as a management tool for the western corn rootworm, Diabrotica virgifera virgifera. AB - The western corn rootworm (WCR), Diabrotica virgifera virgifera, is the most important pest of corn in the US Corn Belt. Economic estimates indicate that costs of control and yield loss associated with WCR damage exceed $US 1 billion annually. Historically, corn rootworm management has been extremely difficult because of its ability to evolve resistance to both chemical insecticides and cultural control practices. Since 2003, the only novel commercialized developments in rootworm management have been transgenic plants expressing Bt insecticidal proteins. Four transgenic insecticidal proteins are currently registered for rootworm management, and field resistance to proteins from the Cry3 family highlights the importance of developing traits with new modes of action. One of the newest approaches for controlling rootworm pests involves RNA interference (RNAi). This review describes the current understanding of the RNAi mechanisms in WCR and the use of this technology for WCR management. Further, the review addresses ecological risk assessment of RNAi and insect resistance management of RNAi for corn rootworm. (c) 2016 Society of Chemical Industry. PMID- 27218411 TI - DNA methylation at stress-related genes is associated with exposure to early life institutionalization. AB - OBJECTIVES: Differences in DNA methylation have been associated with early life adversity, suggesting that alterations in methylation function as one pathway through which adverse early environments are biologically embedded. This study examined associations between exposure to institutional care, quantified as the proportion of time in institutional care at specified follow-up assessment ages, and DNA methylation status in two stress-related genes: FKBP5 and SLC6A4. MATERIALS AND METHODS: We analyzed data from the Bucharest Early Intervention Project, which is a prospective study in which children reared in institutional settings were randomly assigned (mean age 22 months) to either newly created foster care or care as usual (to remain in their current placement) and prospectively followed. A group of children from the same geographic area, with no history of institutionalized caregiving, were also recruited. DNA methylation status was determined in DNA extracted from buccal epithelial cells of children at age 12. RESULTS: An inverse association was identified such that more time spent in institutional care was associated with lower DNA methylation at specific CpG sites within both genes. DISCUSSION: These results suggest a lasting impact of early severe social deprivation on methylation patterns in these genes, and contribute to a growing literature linking early adversity and epigenetic variation in children. Am J Phys Anthropol 161:84-93, 2016.. (c) 2016 Wiley Periodicals, Inc. PMID- 27218414 TI - Ethane adsorption on aggregates of dahlia-like nanohorns: experiments and computer simulations. AB - This is a report on a study of the adsorption characteristics of ethane on aggregates of unopened dahlia-like carbon nanohorns. This sorbent presents two main groups of adsorption sites: the outside surface of individual nanohorns and deep, interstitial spaces between neighbouring nanohorns towards the interior of the aggregates. We have explored the equilibrium properties of the adsorbed ethane films by determining the adsorption isotherms and isosteric heat of adsorption. Computer simulations performed on different model structures indicate that the majority of ethane adsorption occurs on the outer region of the aggregates, near the ends of the nanohorns. We have also measured the kinetics of adsorption of ethane on this sorbent. The measurements and simulations were conducted along several isotherms spanning the range between 120 K and 220 K. PMID- 27218413 TI - Secondary EWSR1 gene abnormalities in SMARCB1-deficient tumors with 22q11-12 regional deletions: Potential pitfalls in interpreting EWSR1 FISH results. AB - SMARCB1 inactivation occurs in a variety of tumors, being caused by various genetic mechanisms. Since SMARCB1 and EWSR1 genes are located close to each other on chromosome 22, larger SMARCB1 deletions may encompass the EWSR1 locus. Herein, we report four cases with SMARCB1-deletions showing concurrent EWSR1 gene abnormalities by FISH, which lead initially to misinterpretations as EWSR1 rearranged tumors. Our study group included various morphologies: a poorly differentiated chordoma, an extrarenal rhabdoid tumor, a myoepithelial carcinoma, and a proximal-type epithelioid sarcoma. All cases showed loss of SMARCB1 (INI1) by immunohistochemistry (IHC) and displayed characteristic histologic features for the diagnoses. The SMARCB1 FISH revealed homozygous or heterozygous deletions in three and one case, respectively. The co-hybridized EWSR1 probes demonstrated either unbalanced split signals or heterozygous deletion in two cases each. The former suggested bona fide rearrangement, while the latter resembled an unbalanced translocation. However, all the FISH patterns were quite complex and distinct from the simple and uniform split signals seen in typical EWSR1 rearrangements. We conclude that in the context of 22q11-12 regional alterations present in SMARCB1-deleted tumors, simultaneous EWSR1 involvement may be misinterpreted as equivalent to EWSR1 rearrangement. A detailed clinicopathologic correlation and supplementing the EWSR1 FISH assay with complementary methodology is mandatory for correct diagnosis. (c) 2016 Wiley Periodicals, Inc. PMID- 27218415 TI - (-)-Epigallocatechin-3-gallate decreases colonic inflammation and permeability in a mouse model of colitis, but reduces macronutrient digestion and exacerbates weight loss. AB - SCOPE: (-)-Epigallocatechin-3-gallate (EGCG) has been reported to have putative health effects including the prevention of inflammation and obesity. Historically, polyphenols have been regarded as antinutritionals and while such effects may be beneficial in obese subjects, they may be deleterious in nutritionally compromised individuals. METHODS AND RESULTS: We examined the effect of EGCG in the dextran sulfate sodium (DSS)-treated mouse model of ulcerative colitis. Following induction of colitis, mice were treated with EGCG (3.2 mg/g) as the sole source of drinking fluid for 3 days. EGCG treatment mitigated DSS-induced colon shortening and spleen enlargement. EGCG also decreased colonic protein levels of IL-1beta, IL-6, and tumor necrosis factor alpha, as well as colonic lipid peroxides compared to DSS-treated controls. We observed that EGCG reduced DSS-induced gastrointestinal permeability. These beneficial effects were offset by enhanced body weight loss in EGCG-treated mice compared to DSS-treated controls. These effects were related to decreased protein and lipid digestion in EGCG-treated mice compared to DSS-treated controls. CONCLUSIONS: Our results suggest that although EGCG may exert anti-inflammatory effects, its ability to modulate macronutrient digestion may represent a dose limiting adverse effect that must be considered in the context of its use for treating inflammatory bowel disease. PMID- 27218416 TI - Epstein-Barr virus-associated leukemic lymphoma after allogeneic stem cell transplantation. AB - Leukemic Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative diseases (PTLD) following allogeneic hematopoietic stem cell transplantation are extremely rare. We can successfully treat an EBV-associated leukemic lymphoma patient with rituximab, cidofovir, and donor lymphocyte infusion (DLI). In the present case, EBV-specific T cells that were present in the peripheral blood before rituximab administration treatment rapidly increased after DLI in association with a decrease in the EBV-DNA load. PMID- 27218417 TI - Clinical outcomes in children with herpes simplex encephalitis receiving steroid therapy. AB - BACKGROUND: Herpes simplex virus encephalitis (HSE) is a significant cause of morbidity and mortality. Neurologic sequelae are common even after early initiation of acyclovir treatment. The host immune response during HSE can also lead to brain damage. There are an increasing number of reports favoring steroid use in HSE. OBJECTIVES: We aimed to compare the prognosis of children with HSE with and without steroid therapy. STUDY DESIGN: We retrospectively screened our hospital archive from 2009 to 2014 for patients diagnosed with HSE with a positive result for herpes simplex virus polymerase chain reaction in cerebrospinal fluid. Patients >=1 month and <=18 years at diagnosis were included in the study. Clinical outcomes in terms of cognitive function, motor function, electroencephalographic findings, seizure frequency, and radiologic findings were compared in patients who received adjuvant steroid therapy with those who did not. RESULTS: Six patients (1 boy, 5 girls; aged 4 months to 10 years) were included. Overall symptom duration before hospital admission was <=5days. Patients received acyclovir treatment for 21-28days. Three received steroid therapy early during the disease and three patients did not. No adverse effects related to steroids were observed. Follow-up duration was 6 months to 5 years. All patients had radiologic sequelae of encephalitis. Cognition, motor function, and seizure control were better in patients who received steroid therapy. CONCLUSIONS: Adjuvant steroid therapy seems to be effective in decreasing morbidity in children with HSE but the radiologic sequelae were the same in both groups. PMID- 27218418 TI - Efficacy of nonswallow nasogastric tube intubation: a randomised controlled trial. AB - AIMS AND OBJECTIVES: To prospectively identify the effect of the nonswallow procedure of nasogastric tube insertion. BACKGROUND: Nasogastric intubation is one of the most important and basic skills in treatment and nursing. Patients generally experience discomfort and encounter complications during this procedure. Thus, practitioners need a more convenient, effective, quicker and safer method to improve the performance of this procedure. DESIGN: This prospective randomised controlled trial was conducted from March to May 2014 in the four units of Gansun Province Hospital in Lanzhou, China. METHOD: A total of 80 participants were randomly assigned to an experimental group (n = 40) and a control group (n = 40). Participants in the experimental group underwent a nonswallow procedure for nasogastric tube insertion. RESULTS: There were statistically significant differences in nasogastric tube insertion between the study groups. A marked increase in the success rate at first intubation as well as a markedly reduced occurrence of nausea, tearing, mucosal injury and changes in vital signs (i.e. heart rate, breath, systolic pressure) were observed compared with the control group. No differences in the success rates at second and third intubation were observed between the groups. CONCLUSIONS: The nonswallow procedure of nasogastric tube intubation relieves discomfort and ensures the safety of patients. RELEVANCE TO CLINICAL PRACTICE: Patients subjected to nasogastric intubation are more likely to benefit from the nonswallow procedure when nasogastric tube insertion is performed. PMID- 27218419 TI - "Social Crimes": Understandings of HIV/AIDS as a Disease Among Grandparents Raising Grandchildren in Vietnam. AB - Grandparent caregivers are vital to the survival of grandchildren who are orphaned and who have been affected by HIV/AIDS. The purpose of this qualitative study was to understand the meaning of HIV as a disease among grandparents raising grandchildren orphaned by HIV/AIDS in northern Vietnam and to gain insight into how this understanding affected grandparents' relationships and health-seeking decisions. Results indicated that grandparents had knowledge deficits about the biomedical aspects of the disease and often hid their grandchildren's HIV status or preferred not to seek testing. Effective interventions must address stigma reduction, family relationships, and access to health care to increase testing and treatment of grandchildren. PMID- 27218420 TI - The child brain computes and utilizes internalized maternal choices. AB - As children grow, they gradually learn how to make decisions independently. However, decisions like choosing healthy but less-tasty foods can be challenging for children whose self-regulation and executive cognitive functions are still maturing. We propose a computational decision-making process in which children estimate their mother's choices for them as well as their individual food preferences. By employing functional magnetic resonance imaging during real food choices, we find that the ventromedial prefrontal cortex (vmPFC) encodes children's own preferences and the left dorsolateral prefrontal cortex (dlPFC) encodes the projected mom's choices for them at the time of children's choice. Also, the left dlPFC region shows an inhibitory functional connectivity with the vmPFC at the time of children's own choice. Our study suggests that in part, children utilize their perceived caregiver's choices when making choices for themselves, which may serve as an external regulator of decision-making, leading to optimal healthy decisions. PMID- 27218421 TI - Capnography standards for outside the operating room. AB - PURPOSE OF REVIEW: Standards for capnography inside operating theatres in high and middle-income countries are well recognized and implemented. This review examines recent standards and recommendations for the use of capnography outside the operating room and their rationale and development. RECENT FINDINGS: The landmark publication of the Royal College of Anaesthetists and Difficult Airway Society's National Audit Project 4 report provided compelling evidence of airway deaths and a significant patient harm occurring outside the operating room, particularly in ICUs and to a lesser extent in emergency departments. Up to 74% of these ICU deaths could have been prevented by capnography. This provided a serious wake up call for relevant clinicians. As a result, there have recently been new standards published for the use of capnography in these and other areas of the hospital. Waveform capnography can also reflect cardiac output, as the 2015 resuscitation guidelines emphasized. Work still needs to be done on implementing all of these new standards. SUMMARY: Established standards for using capnography within the operating theatre have significantly improved patient safety and it is hoped that the recent publication of new but similar capnography standards for application outside the operating theatre will do the same there. The reasons for the current low levels of implementation of some of these standards outside the operating room are worthy of further research. PMID- 27218422 TI - Measurement of morphological and physiological skin properties in aged care residents: a test-retest reliability pilot study. AB - This test-retest pilot study investigated the intra-rater reliability and reproducibility of non-invasive technologies to objectively quantify morphological (colour, thickness and elasticity) and physiological (transepidermal water loss (TEWL), hydration, sebum and pH) skin properties in an aged care population. Three consecutive measurements were taken from five anatomical skin sites, with the mean of each measurement calculated. The intra class correlation coefficient (ICC) and the standard error of measurement (SEM) were used to examine the intra-rater reliability and reproducibility of measurements. Non-invasive technologies in this study showed almost perfect reliability for ultrasound measurements of the subepidermal low echogenicity band (SLEB) (rho = 0.95-0.99) and skin thickness (rho = 0.95-0.99) across all sites. The ICC was substantial to almost perfect for pH (rho = 0.76-0.88) and viscoelasticity (rho = 0.67-0.91) across all sites. Hydration (rho = 0.53-0.85) and skin retraction (rho = 0.57-0.99) measurements ranged from moderate to almost perfect across all sites. TEWL and elasticity were substantial to almost perfect across four sites. Casual sebum levels and most colour parameters showed poor ICC. The use of non-invasive technologies in this study provided an objective and reliable means for quantifying ageing skin and may offer future studies a valuable option for assessing skin tear risk. PMID- 27218423 TI - A two-centre experience of transanal total mesorectal excision. AB - AIM: Transanal total mesorectal excision (TaTME) offers a promising alternative to the standard surgical abdominopelvic approach for rectal cancer. The aim of this study was to report a two-centre experience of this technique, focusing on the short-term and oncological outcome. METHOD: From May 2013 to May 2015, 40 selected patients with histologically proven rectal adenocarcinoma underwent TaTME in two institutions and were prospectively entered on an online international registry. RESULTS: Forty patients (80% men, mean body mass index 27.4 kg/m2 ) requiring TME underwent TaTME. Procedures included low anterior resection (n = 31), abdominoperineal excision (n = 7) and proctocolectomy (n = 2). A minimally invasive approach was attempted in all cases, with three conversions. The mean operation time was 368 min and 16 patients (40%) had a synchronous abdominal and transanal approach. There was no mortality and 16 postoperative complications occurred, of which 68.8% were minor. The median length of stay was 7.5 (3-92) days. A complete or near-complete TME specimen was delivered in 39 (97.5%) cases with a mean number of 20 lymph nodes harvested. R0 resection was achieved in 38 (95%) patients. After a median follow-up of 10.7 months, there were no local recurrences and six (15%) patients had developed distant metastases. CONCLUSION: TaTME appears to be feasible, safe and reproducible, without compromising the oncological principles of rectal cancer surgery. It is an attractive option for patients for whom laparoscopy is likely to be particularly difficult. These encouraging results should encourage larger studies with assessment of long-term function and the oncological outcome. PMID- 27218424 TI - Cadmium but not lead exposure affects Xenopus laevis fertilization and embryo cleavage. AB - Among the toxicological and ecotoxicological studies, few have investigated the effects on germ cells, gametes or embryos, while an impact at these stages will result in serious damage at a population level. Thus, it appeared essential to characterize consequences of environmental contaminant exposures at these stages. Therefore, we proposed to assess the effects of exposure to cadmium and lead ions, alone or in a binary mixture, on early stages of Xenopus laevis life cycle. Fertilization and cell division during segmentation were the studied endpoints. Cadmium ion exposures decreased in the fertilization rates in a concentration dependent manner, targeting mainly the oocytes. Exposure to this metal ions induced also delays or blockages in the embryonic development. For lead ion exposure, no such effect was observed. For the exposure to the mixture of the two metal ions, concerning the fertilization success, we observed results similar to those obtained with the highest cadmium ion concentration. PMID- 27218425 TI - Accumulation and detoxification dynamics of microcystin-LR and antioxidant responses in male red swamp crayfish Procambarus clarkii. AB - MC-LR is one of major microcystin isoforms with potent hepatotoxicity. In the present study, we aim to: 1) explore the dynamics of MC-LR accumulation and elimination in different tissues of male red swamp crayfish Procambarus clarkii; 2) reveal the mechanisms underlying hepatic antioxidation and detoxification. In the semi-static toxicity tests under the water temperature of 25+/-2 degrees C, P. clarkii were exposed to 0.1, 1, 10 and 100MUg/L MC-LR for 7days for accumulation and subsequently relocated to freshwater for another 7days to depurate MC-LR. MC-LR was measured in the hepatopancreas, intestine, abdominal muscle and gill by HPLC. The enzyme activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione S-transferase (GST), content of glutathione (GSH), and transcripts of Mn-sod, cat, gpx1, Mu-gst, heat shock protein90 (hsp90), hsp70 and hsp60 in hepatopancreas were detected. The results showed that P. clarkii accumulated more MC-LR in intestine, and less in abdominal muscle and gill during accumulation period and eliminated the toxin more quickly in gill and abdominal muscle, and comparatively slowly in intestine during depuration period. The fast increase of SOD and CAT activities at early stage, subsequent decrease at later stage of accumulation period and then fast increase during depuration period were partially consistent with the transcriptional changes of their respective genes. GPx was activated by longer MC LR exposure and gpx1 mRNA expression showed uncoordinated regulation pattern compared with its enzyme. Hsp genes were up-regulated when P. clarkii was exposed to MC-LR. PMID- 27218426 TI - Role of SULT-mediated sulfation in the biotransformation of 2-butoxyethanol and sorbitan monolaurate: A study using zebrafish SULTs. AB - 2-Butoxyethanol and sorbitan monolaurate are major components of oil dispersants that are applied in large quantities to control oil spill in the aquatic environment. An important question is whether aquatic animals are equipped with mechanisms for the detoxification of these oil dispersant compounds. The current study aimed to examine whether zebrafish cytosolic sulfotransferases (SULTs) are capable of sulfating 2-butoxyethanol and sorbitan monolaurate. A systematic analysis of 18 zebrafish SULTs revealed that SULT3 ST1 showed the strongest sulfating activity toward 2-butoxyethanol, while SULT1 ST3 displayed the strongest sulfating activity toward sorbitan monolaurate. The pH-dependence of these two SULTs in mediating the sulfation of 2-butoxyethanol or sorbitan monolaurate was examined. Taken together, these results implied that SULT mediated sulfation may function in the detoxification of these two oil dispersant compounds. PMID- 27218427 TI - A BOILED-Egg To Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules. AB - Apart from efficacy and toxicity, many drug development failures are imputable to poor pharmacokinetics and bioavailability. Gastrointestinal absorption and brain access are two pharmacokinetic behaviors crucial to estimate at various stages of the drug discovery processes. To this end, the Brain Or IntestinaL EstimateD permeation method (BOILED-Egg) is proposed as an accurate predictive model that works by computing the lipophilicity and polarity of small molecules. Concomitant predictions for both brain and intestinal permeation are obtained from the same two physicochemical descriptors and straightforwardly translated into molecular design, owing to the speed, accuracy, conceptual simplicity and clear graphical output of the model. The BOILED-Egg can be applied in a variety of settings, from the filtering of chemical libraries at the early steps of drug discovery, to the evaluation of drug candidates for development. PMID- 27218428 TI - Resilience of internal medicine house staff and its association with distress and empathy in an oncology setting. AB - CONTEXT: Resilience is a beneficial trait for resident physicians who are exposed to adversity through their work with patients. Inpatient hematology-oncology produces vicarious trauma for physicians in training. Physician distress and empathy influence patient care and may be associated with respectively lower and greater levels of resilience. METHODS: We collected measures of resilience (Connor-Davidson Resilience Scale), distress (Impact of Events Scale - Revised), and rotation-specific information (e.g., number of death encounters, death stress, and meaning) at the end of a routine hematology-oncology ward rotation. Empathy (Interpersonal Reactivity Index) was measured both before and after the rotation. RESULTS: Fifty-six out of 96 residents completed the study with an overall response rate of 58%. Resilience was negatively correlated with distress (r = -0.306, p = 0.023) but not with empathy (r = 0.172, p = 0.204) and nor with change in empathy over the course of the rotation (r = -0.122, p = 0.374). When separated by sex, male resilience was negatively correlated with distress (r = 0.389, p = 0.04), but female resilience was not. Resident distress levels were in a clinically significant (76%) or posttraumatic stress disorder range (17%), and resident empathy decreased during the rotation (p = 0.018). Resilience levels were similar in those who reported that death events were the most stressful experiences of the rotation and those who derived a sense of meaning from working with dying patients. CONCLUSIONS: Resident physicians experienced clinically relevant distress and a decrease in empathy. Resilient resident physicians were less likely to experience distress. This study provides evidence for the salutary effects of resilience on physician distress. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27218429 TI - Skin dose saving of the staff in 90Y/177Lu peptide receptor radionuclide therapy with the automatic dose dispenser. AB - OBJECTIVE: When handling Y-labelled and Lu-labelled radiopharmaceuticals, skin exposure is mainly due to beta-particles. This study aimed to investigate the equivalent dose saving of the staff when changing from an essentially manual radiolabelling procedure to an automatic dose dispenser (ADD). MATERIALS AND METHODS: The chemist and physician were asked to wear thermoluminescence dosimeters on their fingertips to evaluate the quantity of Hp(0.07) on the skin. Data collected were divided into two groups: before introducing ADD (no ADD) and after introducing ADD. RESULTS: For the chemist, the mean values (95th percentile) of Hp(0.07) for no ADD and ADD are 0.030 (0.099) and 0.019 (0.076) mSv/GBq, respectively, for Y, and 0.022 (0.037) and 0.007 (0.023) mSv/GBq, respectively, for Lu. The reduction for ADD was significant (t-test with P<0.05) for both isotopes. The relative differences before and after ADD collected for every finger were treated using the Wilcoxon test, proving a significantly higher reduction in extremity dose to each fingertip for Lu than for Y (P<0.05). For the medical staff, the mean values of Hp(0.07) (95th percentile) for no ADD and ADD are 0.021 (0.0762) and 0.0143 (0.0565) mSv/GBq, respectively, for Y, and 0.0011 (0.00196) and 0.0009 (0.00263) mSv/GBq, respectively, for Lu. The t-test provided a P-value less than 0.05 for both isotopes, making the difference between ADD and no ADD significant. CONCLUSION: ADD positively affects the dose saving of the chemist in handling both isotopes. For the medical staff not directly involved with the introduction of the ADD system, the analysis shows a learning curve of the workers over a 5-year period. Specific devices and procedures allow staff skin dose to be limited. PMID- 27218430 TI - Molecular biological correlation of fluorine-18 fluorodeoxyglucose uptake in esophageal squamous cell carcinoma. AB - OBJECTIVE: The aim of this study was to assess the relationship between fluorine 18 fluorodeoxyglucose (F-FDG) uptake and molecular biological markers in esophageal squamous cell carcinoma (ESCC) patients. METHODS: Our patient population included 51 patients who underwent F-FDG PET/computed tomography before surgery. Excised tumor tissue was analyzed immunohistochemically using monoclonal antibodies for glucose transporter-1 (GLUT-1), GLUT-3, CD34 [microvessel density (MVD) marker], CD68 (macrophage marker), and CD163 (tumor associated macrophage marker). The relationships among pathological factors [pathological T stage (p-T stage), pathological lymph node status (p-N status), pathological stage (p-stage), and pathological tumor length], the maximum standardized uptake value (SUVmax), and these molecular biological markers were evaluated using Spearman's rank test and the Kruskal-Wallis test. RESULTS: GLUT 1, GLUT-3, CD34, and CD163 significantly correlated with SUVmax (r=0.547, P<0.001 for GLUT-1; r=0.569, P<0.001 for GLUT-3; r=0.463, P=0.001 for CD34, r=0.455, P=0.001 for CD163), whereas SUVmax, GLUT-1, GLUT-3, CD34, and CD163 significantly correlated with p-T stage (r=0.552, P<0.001 for SUVmax, r=0.307, P=0.03 for GLUT 1, r=0.349, P=0.013 for GLUT-3, r=0.313, P=0.027 for CD34, r=0.526 for CD163, P<0.001), but not with p-N status. CD68 levels showed no significant correlation with SUVmax, p-T stage, p-stage, or p-N status. CONCLUSION: SUVmax, GLUT-1 expression, GLUT-3 expression, MVD, and TAMs show a relationship with the tumor stage and extent of ESCC. GLUT-1, GLUT-3, MVD, and TAMs are associated with the mechanism of F-FDG uptake in ESCC. PMID- 27218431 TI - Focal fluorine-18 fluorodeoxyglucose-avid parotid findings in patients with lung cancer: prevalence and characteristics. AB - OBJECTIVE: Correct interpretation of incidental tumors is important to plan an appropriate treatment. We assessed the incidence and imaging characteristics of fluorine-18 fluorodeoxyglucose (F-FDG)-avid focal parotid findings (FPFs) in patients with lung cancer. PATIENTS AND METHODS: FPFs in PET-computed tomography reports of cancer patients were searched. Those with known parotid malignancies, lymphoma, and diffuse F-FDG uptake in the entire parotid gland were not included in the analysis. RESULTS: FPFs were detected in 38/3120 cancer patients (1.23%), observed as a soft tissue mass with a mean diameter 1.6+/-0.5 cm (range 0.8-2.7 cm) and a mean maximum standardized uptake value of 7.7+/-3.7 (range 2.5-17.8). FPFs were observed in 23/604 (3.8%) patients with lung cancer, compared with 6/1366 (0.4%) with breast cancer and 5/842 (0.6%) with gastrointestinal malignancies. We assessed FPFs appearances in 23 patients with lung cancer (18 men, mean age 72.8+/-9.2); 20 (87%) were current or past smokers. There was no correlation between the stage or histopathological type of the lung cancer and the prevalence of parotid lesions. In four patients with histopathology, no malignancy was detected. For an additional 11 patients with available imaging and clinical follow-up (mean follow-up 15.5+/-13.5 months, range 3-42 months), FPFs were consistent with benign lesions. CONCLUSION: FPFs were more prevalent among patients with lung cancer than in patients with other malignancies. As F-FDG avidity was moderate to high, FPFs may mimic distant metastases. It is important to consider FPFs in the interpretation of a focal parotid lesion as misinterpretation may result in denial of appropriate therapy. PMID- 27218432 TI - Cultivation of Agaricus bisporus enriched with selenium, zinc and copper. AB - BACKGROUND: Agaricus bisporus (white button mushroom) is an important culinary and medicinal species of worldwide importance. The present study investigated for the first time whether it may be grown on substrates supplemented with Se alone or in combination with Cu and/or Zn (0.1-0.8 mmol L-1 ) to produce fruiting bodies of increased nutritional value. RESULTS: As found, substrate supplementation did not affect yielded biomass up to 0.6 mmol L-1 element concentrations regardless of the cultivation model. At 0.8 mmol L-1 Se + Cu and Se + Zn supplementation biomass comparable with controls still developed. The accumulation of trace elements in the fruiting bodies generally increased over the concentration gradient reaching its maximum at 0.6 mmol L-1 (for Se + Zn and Se + Cu + Zn) and 0.8 mmol L-1 (for Se and Se + Cu). The organic Se constituted the greatest share in total Se quota. As calculated, each 10 g of dried fruiting bodies of A. bisporus obtained from 0.6 or 0.8 mmol L-1 supplementation would represent 342-469% of the Recommended Daily Allowance (RDA) for Se, 43.4-48.5% for Cu and 5.2-5.8% for Zn. CONCLUSION: Considering inexpensive methods of A. bisporus cultivation, global popularity and use of this mushroom, its biofortification with Se, Cu and Zn could have a practical application in deficiency prevention and assisted treatment. (c) 2016 Society of Chemical Industry. PMID- 27218433 TI - Efficient programming of human mesenchymal stem cell-derived hepatocytes by epigenetic regulations. AB - BACKGROUND AND AIM: In view of its unique properties of detoxification and involvement of metabolic and biochemical functions, in vitro hepatocyte culture serves as a valuable material for drug screening and mechanistic analysis for pathology of liver diseases. The restriction of rapid de-differentiation and inaccessibility of human hepatocytes from routine clinical procedure, however, limits its use. METHODS: To address this issue, the effort to direct human mesenchymal stem cells (hMSCs) into hepatocytes using a modified protocol was proposed. With the additional treatment of histone deacetylase inhibitor (HDACi) and DNA methyltransferase inhibitor (DNMTi), in vitro hMSC-derived hepatocytes were cultivated and their hepatic characteristics were examined. RESULTS: By using a modified protocol, it was shown that Trichostatin A and 5-aza-2 deoxycitidine protected differentiating cells from death and could sufficiently trigger a wide range of liver-specific markers as well as liver functions including albumin production, glycogen storage, and urea cycle in hMSC-derived hepatocytes. The increased mRNA expression for hepatitis C virus (HCV) entry including CD81, Occludin, LDL receptor, and scavenger receptor class B type I in hMSC-derived hepatocytes was also detected, implying its potential to be utilized as an in vitro model to analyze dynamic HCV infection. CONCLUSIONS: The present study successfully established a protocol to direct hMSCs into hepatocyte-like cells suggesting the beneficial impact to apply HDACi and DNMTi as potent modulators for hMSCs to liver differentiation. PMID- 27218434 TI - Dietary vitamin C reduced mercury contents in the tissues of juvenile olive flounder (Paralichthys olivaceus) exposed with and without mercury. AB - A 2*3 factorial design was employed to evaluate the effects of dietary vitamin C (l-ascorblyl-2-monophosphate, C2MP) levels on growth and tissue mercury (Hg) accumulations in juvenile olive flounder, Paralichthys olivaceus. Six experimental diets with two levels of mercuric chloride (0 or 20mg HgCl2/kg diet) and three levels of vitamin C (0, 100, or 200mg C2MP/kg diet) were added to the basal diet. At the end of 6 weeks feeding trial, in presence or absence of dietary Hg, fish body weight gain, specific growth rate, feed efficiency, protein efficiency ratio and whole body lipid content were increased in a dose-dependent manner as dietary vitamin C level increased in the diets. Interestingly, fish fed 100 or 200mg C2MP/kg diets showed significant interactive effects on reducing Hg content in kidney tissue. These results revealed that dietary vitamin C as 100 or 200mg C2MP/kg diet had protective effect against Hg accumulation in juvenile olive flounder. PMID- 27218435 TI - Late-onset severe pneumonia after allogeneic hematopoietic stem cell transplantation: prognostic factors and treatments. AB - BACKGROUND: In this study, we aimed to evaluate the prognostic factors associated with and treatments for late-onset severe pneumonia (LOSP) in patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: Fifty consecutive patients who underwent non-T-cell-depleted allo-HSCT at the Peking University Institute of Hematology and met the criterion of LOSP after allo-HSCT were enrolled. RESULTS: The median time from allo-HSCT to the occurrence of LOSP was 231 (90-1487) days. Twenty-eight patients harbored 1 or more pathogens (infectious LOSP, I-LOSP), whereas 22 did not harbor any pathogens (non-infectious LOSP, NI-LOSP). The 100-day survival rate of LOSP patients was 31.1%. Patients smoking before allo-HSCT (0% vs. 35.4%, P = 0.002) and male gender (20.0% vs. 61.9%, P = 0.026) had lower 100-day survival rate. Patients with a lower bronchoalveolar lavage fluid (BALF) neutrophil percentage had higher 100-day survival rate relative to those with higher BALF neutrophil percentage (45.5% vs. 16.7%, P = 0.012). The 100-day survival rate of patients with I-LOSP was lower than that of patients with NI-LOSP (19.1% vs. 46.9%, P = 0.043). Patients given late (>=1 week after LOSP diagnosis) and low-dose methylprednisolone (MP) therapy (<=2 mg/kg/day) had the best 100-day survival rate. In the multivariate analysis, nonsmoking before allo-HSCT and late and low dose MP therapy were significantly associated with a better survival after LOSP. CONCLUSION: LOSP is a severe complication after allo-HSCT. The correct timing and corticosteroid dosage in the context of broad-spectrum antimicrobial therapy might further improve the outcomes of patients with LOSP. PMID- 27218436 TI - Validation of a novel saliva-based ELISA test for diagnosing tapeworm burden in horses. AB - BACKGROUND: Tapeworm infections pose a significant threat to equine health as they are associated with clinical cases of colic. Diagnosis of tapeworm burden using fecal egg counts (FECs) is unreliable, and, although a commercial serologic ELISA for anti-tapeworm antibodies is available, it requires a veterinarian to collect the blood sample. A reliable diagnostic test using an owner-accessible sample such as saliva could provide a cost-effective alternative for tapeworm testing in horses, and allow targeted deworming strategies. OBJECTIVES: The purpose of the study was to statistically validate a saliva tapeworm ELISA test and compare to a tapeworm-specific IgG(T) serologic ELISA. METHODS: Serum samples (139) and matched saliva samples (104) were collected from horses at a UK abattoir. The ileocecal junction and cecum were visually examined for tapeworms and any present were counted. Samples were analyzed using a serologic ELISA and the saliva tapeworm test. The test results were compared to tapeworm numbers and the various data sets were statistically analyzed. RESULTS: Saliva scores had strong positive correlations with both infection intensity (0.74) and serologic results (Spearman's rank coefficients; 0.74 and 0.86, respectively). The saliva tapeworm test was capable of identifying the presence of one or more tapeworms with 83% sensitivity and 85% specificity. Importantly, no high-burden (more than 20 tapeworms) horses were misdiagnosed. CONCLUSIONS: The saliva tapeworm test has statistical accuracy for detecting tapeworm burdens in horses with 83% sensitivity and 85% specificity, similar to those of the serologic ELISA (85% and 78%, respectively). PMID- 27218437 TI - Fetal myocardial deformation in maternal diabetes mellitus and obesity. AB - OBJECTIVE: Experimental evidence suggests that changes in the fetal myocardium result from intrauterine effects of maternal diabetes mellitus and obesity. The aim of this study was to assess fetal cardiac function using two-dimensional speckle-tracking echocardiography to determine the effects of maternal diabetes and obesity on the fetal myocardium. METHODS: Comparative cross-sectional evaluation of myocardial function in fetuses of mothers with diabetes mellitus (FDM) or obesity (FO) and normal gestational age-matched control fetuses (FC) was performed using two-dimensional speckle-tracking echocardiography at two centers. RESULTS: In total, 178 fetuses (82 FDM, 26 FO and 70 FC) met the enrolment criteria. Mean gestational age at assessment was similar among groups: 25.3 +/- 5.1 weeks for FDM, 25.0 +/- 4.6 weeks for FO and 25.1 +/- 4.9 weeks for FC. Mean maternal body mass index was significantly higher in FDM and FO groups compared with the FC group. Statistically significant differences in fetal cardiac function were detected between FDM and FC for global longitudinal strain (mean +/ SD, -21.4 +/- 6.5% vs -27.0 +/- 5.2%; P < 0.001), global circumferential strain (mean +/- SD, -22.6 +/- 6.5% vs -26.2 +/- 6.8%; P = 0.002), average longitudinal systolic strain rate (median, -1.4 (interquartile range (IQR), -1.7 to -1.1)/s vs -1.6 (IQR, -2.0 to -1.4)/s; P = 0.001) and average circumferential systolic strain rate (median, -1.4 (IQR, -1.9 to -1.1)/s vs -1.6 (IQR, -2.1 to -1.3)/s; P = 0.006). Cases of non-obese FDM also had abnormal strain parameters compared with FC. Global longitudinal strain (mean +/- SD, -21.1 +/- 7.5%) and average circumferential systolic strain rate (median, -1.3 (IQR, -1.8 to -1.1)/s) were significantly lower in FO compared with FC. CONCLUSIONS: Unfavorable changes occur in the fetal myocardium in response to both maternal diabetes mellitus and obesity. The long-term prognostic implications of these changes require further study. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 27218439 TI - Concept analysis and the building blocks of theory: misconceptions regarding theory development. AB - AIM: The purpose of this article is to discuss the attempts to justify concepts analysis as a way to construct theory - a notion often advocated in nursing. BACKGROUND: The notion that concepts are the building blocks or threads from which theory is constructed is often repeated. It can be found in many articles and well-known textbooks. However, this notion is seldom explained or defended. The notion of concepts as building blocks has also been questioned by several authors. However, most of these authors seem to agree to some degree that concepts are essential components from which theory is built. DESIGN: Discussion paper. DATA SOURCES: Literature was reviewed to synthesize and debate current knowledge. IMPLICATIONS FOR NURSING: Our point is that theory is not built by concepts analysis or clarification and we will show that this notion has its basis in some serious misunderstandings. We argue that concept analysis is not a part of sound scientific method and should be abandoned. CONCLUSION: The current methods of concept analysis in nursing have no foundation in philosophy of science or in language philosophy. The type of concept analysis performed in nursing is not a way to 'construct' theory. Rather, theories are formed by creative endeavour to propose a solution to a scientific and/or practical problem. The bottom line is that the current style and form of concept analysis in nursing should be abandoned in favour of methods in line with modern theory of science. PMID- 27218438 TI - Effect of seed sludge on nitrogen removal in a novel upflow microaerobic sludge reactor for treating piggery wastewater. AB - Anaerobic activated sludge (AnaS) and aerobic activated sludge (AerS) were used to start up a novel upflow microaerobic sludge reactor (UMSR), respectively, and the nitrogen removal in the two reactors were evaluated when treating low C/N ratio manure-free piggery wastewater with a COD/TN ration of about 0.85. With the same hydraulic retention time 8h and TN loading rate (NLR) 0.42kg/(m(3)d), the UMSR (R2) inoculated with AerS could reach its steady state earlier and obtained a better TN removal than that in the UMSR (R1) inoculated with AnaS. However, the accumulated AnaS made R1 show a better capability in bearing shock load and demonstrated an excellent NH4(+)-N and TN removal with a NLR as high as 1.07kg/(m(3)d). Microbial community structure of the accumulated AerS and AnaS were observable different. The decreased proportion of nitrifiers restricted the ammonium oxidation in R2, and resulting in a decrease in TN removal. PMID- 27218440 TI - Rapid quantification of low level polymorph content in a solid dose form using transmission Raman spectroscopy. AB - This proof of concept study demonstrates the application of transmission Raman spectroscopy (TRS) to the non-invasive and non-destructive quantification of low levels (0.62-1.32% w/w) of an active pharmaceutical ingredient's polymorphic forms in a pharmaceutical formulation. Partial least squares calibration models were validated with independent validation samples resulting in prediction RMSEP values of 0.03-0.05% w/w and a limit of detection of 0.1-0.2% w/w. The study further demonstrates the ability of TRS to quantify all tablet constituents in one single measurement. By analysis of degraded stability samples, sole transformation between polymorphic forms was observed while excipient levels remained constant. Additionally, a beam enhancer device was used to enhance laser coupling to the sample, which allowed comparable prediction performance at 60 times faster rates (0.2s) than in standard mode. PMID- 27218441 TI - Primary breast mucormycosis: FNAC diagnosis of a rare entity. AB - Mucormycosis is the common name given to several different diseases caused by fungi in the order of mucorales. The clinical hallmark of these opportunistic pathogens in invasive mucormycosis is tissue necrosis resulting from angioinvasion and subsequent thrombosis. Rarely the disease may affect immunocompetent individuals. In addition, the breast involvement in this disease is very rare. Herein, we describe a case of primary breast mucormycosis diagnosed on fine needle aspiration cytology (FNAC), in an immunocompetent young female, which is extremely rare. Diagn. Cytopathol. 2016;44:761-763. (c) 2016 Wiley Periodicals, Inc. PMID- 27218442 TI - Clinical guidelines for interstitial cystitis and hypersensitive bladder updated in 2015. AB - Clinical guidelines for interstitial cystitis and hypersensitive bladder have been updated as of 2015. The guidelines define interstitial cystitis by the presence of hypersensitive bladder symptoms (discomfort, pressure or pain in the bladder usually associated with urinary frequency and nocturia) and bladder pathology, after excluding other diseases explaining symptoms. Interstitial cystitis is further classified by bladder pathology; either Hunner type interstitial cystitis with Hunner lesions or non-Hunner type interstitial cystitis with mucosal bleeding after distension in the absence of Hunner lesions. Hypersensitive bladder refers to a condition, where hypersensitive bladder symptoms are present, but bladder pathology or other explainable diseases are unproven. Interstitial cystitis and hypersensitive bladder severely affect patients' quality of life as a result of disabling symptoms and/or comorbidities. Reported prevalence suggestive of these disorders varies greatly from 0.01% to >6%. Pathophysiology would be an interaction of multiple factors including urothelial dysfunction, inflammation, neural hyperactivity, exogenous substances and extrabladder disorders. Definite diagnosis of interstitial cystitis and hypersensitive bladder requires cystoscopy with or without hydrodistension. Most of the therapeutic options lack a high level of evidence, leaving a few as recommended therapeutic options. PMID- 27218443 TI - What information about donation after circulatory death is available on the Internet for potential donor families? AB - INTRODUCTION: The purpose of this study is to determine what information about donation after circulatory death (DCD) is available on the Internet and to document the common statements for and against DCD. METHODS: The search terms non heart-beating donor, donation after cardiac death, DCD, deceased donor, organ donation, and organ harvesting were entered into the four most-accessed English language Internet search engines. The top 10 webpages from each search (240 webpages) yielded 116 unique sites. Three reviewers reviewed each webpage and recorded statements for and against DCD as well as site type, tone, and mention of DCD. RESULTS: While 59 (50.9%) of the overall 116 sites included DCD information, only 10% of sites found with the term "organ donation" mentioned DCD at all. The sites that did include DCD were mostly (78%) of the type "medical journal" or "hospital or university webpage" and 89% of these had a positive or neutral tone. Nine positive and nine negative tropes were defined using the Grounded Theory Method. CONCLUSION: This study reveals the lack of information regarding DCD in organ donation webpages. Thoughtful responses to these statements should be considered in family discussions and in the design of future webpages. PMID- 26731112 TI - Is racecadotril effective for acute diarrhea in children? -First update. AB - This article updates the December 2015 Living FRISBEE (Living FRISBEE: Living FRIendly Summary of the Body of Evidence using Epistemonikos), based on the detection of two systematic reviews not identified in the previous version. Gastroenteritis or acute watery diarrhea is usually a self-limited disease, but it is still associated to substantial healthcare costs and remains a frequent demand for medical care. Racecadotril, an intestinal enkephalinase inhibitor, has been used as treatment because it would decrease the duration of acute diarrhea and fluid loss. However there is still no evidence supporting its routine use. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified five systematic reviews including nine randomized trials relevant for our question. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded racecadotril probably reduces the duration of acute diarrhea in pediatric patients, without increasing adverse effects. PMID- 27218446 TI - Police Officers Can Safely and Effectively Administer Intranasal Naloxone. AB - INTRODUCTION: Opioid overdose rates continue to rise at an alarming rate. One method used to combat this epidemic is the administration of naloxone by law enforcement. Many cities have implemented police naloxone administration programs, but there is a minimal amount of research examining this policy. The following study examines data over 18 months, after implementation of a police naloxone program in an urban setting. We describe the most common indications and outcomes of naloxone administration as well as examine the incidence of arrest, immediate detention, or voluntary transport to the hospital. In doing so, this study seeks to describe the clinical factors surrounding police use of naloxone, and the effects of police administration. METHODS: All police officer administrations were queried from April 2014 through September 2015 (n = 126). For each incident we collected the indication, response, and disposition of the patient that was recorded on a "sick-injured civilian" report that officers were required to complete after administration of naloxone. All of the relevant information was abstracted from this report into an electronic data collection form that was then input into SPSS for analysis. RESULTS: The most common indication for administration was unconscious/unresponsive (n = 117; 92.9%) followed by slowed breathing (n = 72; 57.1%), appeared blue (n = 63; 50.0%) and not breathing (n = 41; 32.5%). After administration of naloxone the majority of patients regained consciousness (n = 82; 65.1%) followed by began to breath (n = 71; 56.3%). However, in 17.5% (n = 22) of the cases "Nothing" happened when naloxone was administered. The majority of patients were transported voluntarily to the hospital (n = 122; 96.8%). Lastly, there was only one report where the patient became combative. CONCLUSION: Our study shows that police officers trained in naloxone administration can correctly recognize symptoms of opioid overdose, and can appropriately administer naloxone without significant adverse effects or outcomes. Furthermore, the administration of police naloxone does not result in a significant incidence of combativeness or need for scene escalations such as immediate detention. Further research is needed to investigate the impact of police naloxone; specifically, comparing outcomes of police delivery to EMS alone, as well as the impact on rural opioid overdoses. PMID- 27218445 TI - Selective Phosphorylation Inhibitor of Delta Protein Kinase C-Pyruvate Dehydrogenase Kinase Protein-Protein Interactions: Application for Myocardial Injury in Vivo. AB - Protein kinases regulate numerous cellular processes, including cell growth, metabolism, and cell death. Because the primary sequence and the three dimensional structure of many kinases are highly similar, the development of selective inhibitors for only one kinase is challenging. Furthermore, many protein kinases are pleiotropic, mediating diverse and sometimes even opposing functions by phosphorylating multiple protein substrates. Here, we set out to develop an inhibitor of a selective protein kinase phosphorylation of only one of its substrates. Focusing on the pleiotropic delta protein kinase C (deltaPKC), we used a rational approach to identify a distal docking site on deltaPKC for its substrate, pyruvate dehydrogenase kinase (PDK). We reasoned that an inhibitor of PDK's docking should selectively inhibit the phosphorylation of only PDK without affecting phosphorylation of the other deltaPKC substrates. Our approach identified a selective inhibitor of PDK docking to deltaPKC with an in vitro Kd of ~50 nM and reducing cardiac injury IC50 of ~5 nM. This inhibitor, which did not affect the phosphorylation of other deltaPKC substrates even at 1 MUM, demonstrated that PDK phosphorylation alone is critical for deltaPKC-mediated injury by heart attack. The approach we describe is likely applicable for the identification of other substrate-specific kinase inhibitors. PMID- 27218447 TI - Effective Postprandial Glucose Management in Pregnancy with Type 1 Diabetes. PMID- 27218448 TI - Volume-equated high- and low-repetition daily undulating programming strategies produce similar hypertrophy and strength adaptations. AB - The overarching aim of this study was to compare volume-equated high-repetition daily undulating periodization (DUPHR) versus a low-repetition daily undulating periodization (DUPLR) program for muscle performance. Sixteen college-aged (23 +/ 3 years) resistance-trained males were counterbalanced into 2 groups: (i) DUPHR (n = 8), with a weekly training order of 12 repetitions (Day 1), 10 repetitions (Day 2), and 8 repetitions (Day 3); and (ii) DUPLR (n = 8), with a weekly training order of 6 repetitions (Day 1), 4 repetitions (Day 2), and 2 repetitions (Day 3). Both groups trained 3 times/week for 8 weeks on nonconsecutive days, with pre- and post-training testing during weeks 1 and 8. Participants performed only squat and bench press exercises each session. Changes in one-repetition maximum (1RM) strength, muscle thickness (MT), and muscular endurance (ME) were assessed. Both groups significantly increased 1RM strength for both squat and bench press (p < 0.01), and no group differences existed (p > 0.05). Similarly, both groups experienced significant increases in chest, lateral quadriceps distal, and anterior quadriceps MT (p < 0.05), but no change was present in either group for lateral quadriceps mid MT (p < 0.05). No group differences were discovered for changes in MT (p > 0.05). ME did not significantly change in the squat or bench press for either group (p > 0.05); however, for squat ME, a moderate effect size was observed for DUPHR (0.57) versus a trivial effect size for DUPLR (0.17). Our findings suggest that in previously trained males, training volume is a significant contributor to strength and hypertrophy adaptations, which occur independently of specific repetition ranges. PMID- 27218449 TI - Multisensory integration in the developing tectum is constrained by the balance of excitation and inhibition. AB - Multisensory integration (MSI) is the process that allows the brain to bind together spatiotemporally congruent inputs from different sensory modalities to produce single salient representations. While the phenomenology of MSI in vertebrate brains is well described, relatively little is known about cellular and synaptic mechanisms underlying this phenomenon. Here we use an isolated brain preparation to describe cellular mechanisms underlying development of MSI between visual and mechanosensory inputs in the optic tectum of Xenopus tadpoles. We find MSI is highly dependent on the temporal interval between crossmodal stimulus pairs. Over a key developmental period, the temporal window for MSI significantly narrows and is selectively tuned to specific interstimulus intervals. These changes in MSI correlate with developmental increases in evoked synaptic inhibition, and inhibitory blockade reverses observed developmental changes in MSI. We propose a model in which development of recurrent inhibition mediates development of temporal aspects of MSI in the tectum. PMID- 27218450 TI - Gap junction networks in mushroom bodies participate in visual learning and memory in Drosophila. AB - Gap junctions are widely distributed in the brains across species and play essential roles in neural information processing. However, the role of gap junctions in insect cognition remains poorly understood. Using a flight simulator paradigm and genetic tools, we found that gap junctions are present in Drosophila Kenyon cells (KCs), the major neurons of the mushroom bodies (MBs), and showed that they play an important role in visual learning and memory. Using a dye coupling approach, we determined the distribution of gap junctions in KCs. Furthermore, we identified a single pair of MB output neurons (MBONs) that possess a gap junction connection to KCs, and provide strong evidence that this connection is also required for visual learning and memory. Together, our results reveal gap junction networks in KCs and the KC-MBON circuit, and bring new insight into the synaptic network underlying fly's visual learning and memory. PMID- 27218451 TI - Cytoplasmic NOTCH and membrane-derived beta-catenin link cell fate choice to epithelial-mesenchymal transition during myogenesis. AB - How cells in the embryo coordinate epithelial plasticity with cell fate decision in a fast changing cellular environment is largely unknown. In chick embryos, skeletal muscle formation is initiated by migrating Delta1-expressing neural crest cells that trigger NOTCH signaling and myogenesis in selected epithelial somite progenitor cells, which rapidly translocate into the nascent muscle to differentiate. Here, we uncovered at the heart of this response a signaling module encompassing NOTCH, GSK-3beta, SNAI1 and beta-catenin. Independent of its transcriptional function, NOTCH profoundly inhibits GSK-3beta activity. As a result SNAI1 is stabilized, triggering an epithelial to mesenchymal transition. This allows the recruitment of beta-catenin from the membrane, which acts as a transcriptional co-factor to activate myogenesis, independently of WNT ligand. Our results intimately associate the initiation of myogenesis to a change in cell adhesion and may reveal a general principle for coupling cell fate changes to EMT in many developmental and pathological processes. PMID- 27218452 TI - Long-range population dynamics of anatomically defined neocortical networks. AB - The coordination of activity across neocortical areas is essential for mammalian brain function. Understanding this process requires simultaneous functional measurements across the cortex. In order to dissociate direct cortico-cortical interactions from other sources of neuronal correlations, it is furthermore desirable to target cross-areal recordings to neuronal subpopulations that anatomically project between areas. Here, we combined anatomical tracers with a novel multi-area two-photon microscope to perform simultaneous calcium imaging across mouse primary (S1) and secondary (S2) somatosensory whisker cortex during texture discrimination behavior, specifically identifying feedforward and feedback neurons. We find that coordination of S1-S2 activity increases during motor behaviors such as goal-directed whisking and licking. This effect was not specific to identified feedforward and feedback neurons. However, these mutually projecting neurons especially participated in inter-areal coordination when motor behavior was paired with whisker-texture touches, suggesting that direct S1-S2 interactions are sensory-dependent. Our results demonstrate specific functional coordination of anatomically-identified projection neurons across sensory cortices. PMID- 27218453 TI - Cell-specific synaptic plasticity induced by network oscillations. AB - Gamma rhythms are known to contribute to the process of memory encoding. However, little is known about the underlying mechanisms at the molecular, cellular and network levels. Using local field potential recording in awake behaving mice and concomitant field potential and whole-cell recordings in slice preparations we found that gamma rhythms lead to activity-dependent modification of hippocampal networks, including alterations in sharp wave-ripple complexes. Network plasticity, expressed as long-lasting increases in sharp wave-associated synaptic currents, exhibits enhanced excitatory synaptic strength in pyramidal cells that is induced postsynaptically and depends on metabotropic glutamate receptor-5 activation. In sharp contrast, alteration of inhibitory synaptic strength is independent of postsynaptic activation and less pronounced. Further, we found a cell type-specific, directionally biased synaptic plasticity of two major types of GABAergic cells, parvalbumin- and cholecystokinin-expressing interneurons. Thus, we propose that gamma frequency oscillations represent a network state that introduces long-lasting synaptic plasticity in a cell-specific manner. PMID- 27218455 TI - Ab Initio Molecular Dynamics Simulations of an Excess Proton in a Triethylene Glycol-Water Solution: Solvation Structure, Mechanism, and Kinetics. AB - We investigate the solvation shell structures, the distribution of protonic defects, mechanistic details, kinetics, and dynamics of proton transfer for an excess proton in bulk water and for an excess proton in an aqueous solution of triethylene glycol (TEG) via Car-Parrinello molecular dynamics simulations. The PW91, PBE, and PBE with the Tkatchenko-Scheffler (TS) density-dependent dispersion functionals were used and compared for bulk water and the TEG-water mixtures. The excess proton is found to reside predominantly on water molecules but also resides on hydroxyl groups of TEG. The lifetimes associated with structural diffusion time scales of the protonated water were found to be on the order of ~1 ps. All three functionals studied support the presolvation requirement for structural diffusion. The highest level of theory shows a reduction in the free energy barrier for water-water proton transfer in TEG-water mixtures compared to bulk water. The effect of TEG shows no strong change in the kinetics for TEG-water mixtures compared to bulk water for this same level of theory. The excess proton displays burst-rest behavior in the presence of TEG, similar to that found in bulk water. We find that the TEG chain disrupts the hydrogen-bond network, causing the solvation shell around water to be populated by TEG chain groups instead of other waters, reducing the rigidity of the hydrogen-bond network. Methylene is a dominant hydrogen bond donor for the protonated water in hydrogen-bond networks associated with proton transfer and structural diffusion. This is consistent with previous studies that have found the hydronium ion to be amphiphilic in nature and to have higher proton mobility at oil-water interfaces. PMID- 27218456 TI - Combined multiplex loop-mediated isothermal amplification with lateral flow assay to detect sea and seb genes of enterotoxic Staphylococcus aureus. AB - Staphylococcal enterotoxins (SEs) are the most common cause of food poisoning worldwide and can induce symptoms, such as diarrhoea, vomiting and abdominal cramping. Thus, the aim of this study is to develop a multiplex loop-mediated isothermal amplification combined with a lateral flow assay (m-LAMP/LFA) to simultaneously detect the sea and seb genes of Staphylococcus aureus. The amplicons of the sea gene were labelled with digoxigenin (Dig) and biotin while those of seb gene were labelled with fluorescein isothiocyanate (FITC) and biotin. These amplicons were detected using a multiplex LFA with NeutrAvidin tagged gold nanoparticles as the detection reagent. After optimization, the detection limit of this assay was 10(2) CFU ml(-1) Staph. aureus, which was one tenth that of a multiplex PCR. This assay did not exhibit any cross-reactivity in detecting other enterotoxic Staph. aureus strains or other food pathogens. After 6 h of enrichment, this developed assay detected 1 CFU ml(-1) of Staph. aureus in milk, apple juice, cheese and rice. The developed m-LAMP/LFA method does not require expensive equipment and can be completely implemented within an 8-h workday. Therefore, this method can provide an effective means of quickly screening staphylococcal enterotoxin A- and/or staphylococcal enterotoxin B producing Staph. aureus in food samples. SIGNIFICANCE AND IMPACT OF THE STUDY: Staphylococcus aureus is one of the major foodborne pathogens worldwide, and its staphylococcal enterotoxin A and B are strongly associated with food poisoning. This work developed a multiplex loop-mediated isothermal amplification combined with a lateral flow assay (m-LAMP/LFA) to simultaneously detect the sea and seb genes of Staph. aureus in food samples. The assay has good specificity and sensitivity with ease-of-use features, making it ideal for on-site detection. PMID- 27218457 TI - Health Activism Targeting Corporations: A Critical Health Communication Perspective. AB - Health activists and health social movements have transformed medical treatment, promoted public health policies, and extended civil rights for people with illness and disability. This essay explores health activism that targets corporate-generated illness and risk in order to understand the unique communicative challenges involved in this area of contention. Arguing for greater critical engagement with policy, the article integrates policy research with social movements, subpolitics, and issue management literature. Drawing from activist discourse and multidisciplinary research, the article describes how a wide array of groups groups build visibility for corporate health effects, create the potential for networking and collaboration, and politicize health by attributing illness to corporate behaviors. The discussion articulates the implications of this activism for health communication theory, research, and practice. PMID- 27218454 TI - Comparative genomics explains the evolutionary success of reef-forming corals. AB - Transcriptome and genome data from twenty stony coral species and a selection of reference bilaterians were studied to elucidate coral evolutionary history. We identified genes that encode the proteins responsible for the precipitation and aggregation of the aragonite skeleton on which the organisms live, and revealed a network of environmental sensors that coordinate responses of the host animals to temperature, light, and pH. Furthermore, we describe a variety of stress-related pathways, including apoptotic pathways that allow the host animals to detoxify reactive oxygen and nitrogen species that are generated by their intracellular photosynthetic symbionts, and determine the fate of corals under environmental stress. Some of these genes arose through horizontal gene transfer and comprise at least 0.2% of the animal gene inventory. Our analysis elucidates the evolutionary strategies that have allowed symbiotic corals to adapt and thrive for hundreds of millions of years. PMID- 27218458 TI - Nitrous Oxide Production at a Fully Covered Wastewater Treatment Plant: Results of a Long-Term Online Monitoring Campaign. AB - The nitrous oxide emissions of the Viikinmaki wastewater treatment plant were measured in a 12 month online monitoring campaign. The measurements, which were conducted with a continuous gas analyzer, covered all of the unit operations of the advanced wastewater-treatment process. The relation between the nitrous oxide emissions and certain process parameters, such as the wastewater temperature, influent biological oxygen demand, and ammonium nitrogen load, was investigated by applying online data obtained from the process-control system at 1 min intervals. Although seasonal variations in the measured nitrous oxide emissions were remarkable, the measurement data indicated no clear relationship between these emissions and seasonal changes in the wastewater temperature. The diurnal variations of the nitrous oxide emissions did, however, strongly correlate with the alternation of the influent biological oxygen demand and ammonium nitrogen load to the aerated zones of the activated sludge process. Overall, the annual nitrous oxide emissions of 168 g/PE/year and the emission factor of 1.9% of the influent nitrogen load are in the high range of values reported in the literature but in very good agreement with the results of other long-term online monitoring campaigns implemented at full-scale wastewater-treatment plants. PMID- 27218459 TI - Two-Port Laparoscopic Cholecystectomy: 18 Patients Human Experience Using the Dynamic Laparoscopic NovaTract Retractor. AB - OBJECTIVE: The concept of reducing the number of transabdominal access ports has been criticized for violating basic tenets of traditional multiport laparoscopy. Potential benefits of reduced port surgery may include decreased pain, improved cosmesis, less hernia formation, and fewer wound complications. However, technical challenges associated with these access methods have not been adequately addressed by advancement in instrumentations. We describe our initial experience with the NovaTractTM Laparoscopic Dynamic Retractor. METHODS: A retrospective review of all patients who underwent two-port laparoscopic cholecystectomy between 2013 and 2014 using the NovaTract retractor was performed. The patients were equally divided into three groups (Group A, B, C) based on the order of case performed. RESULTS: Eighteen consecutive patients underwent successful two-port laparoscopic cholecystectomy for symptomatic cholelithiasis. Mean age was 39.9 years and mean body mass index was 28.1 kg/m(2) (range 21-39.4). Overall mean operative time was 65 minutes (range 42-105), with Group A of 70 minutes, Group B of 65 minutes, and Group C of 58 minutes (P = .58). All cases were completed laparoscopically using the retraction system, without a need for additional ports or open conversion. No intra- or postoperative complications were seen. All patients were discharged on the same day of surgery. No mortality found in this series. CONCLUSIONS: The NovaTract laparoscopic dynamic retractor is safe and easy to use, which is reflected by acceptable operative time for a laparoscopic cholecystectomy using only two ports. The system allows surgical approach to mimic the conventional laparoscopic techniques, while eliminating or reducing the number of retraction ports. PMID- 27218460 TI - Pharmacokinetic-Pharmacodynamic Correlation and Brain Penetration of sec Butylpropylacetamide, a New CNS Drug Possessing Unique Activity against Status Epilepticus. AB - sec-Butylpropylacetamide (SPD) is the amide derivative of valproic acid (VPA). SPD possess a wide-spectrum anticonvulsant profile better than that of VPA and blocks status epilepticus (SE) induced by pilocarpine and organophosphates. The activity of SPD on SE is better than that of benzodiazepines (BZDs) in terms of the ability to block SE when given 20-60 min after the beginning of a seizure. However, intraperitoneal (i.p.) administration to rats cannot be extrapolated to humans. Consequently, in the current study a comparative pharmacokinetic (PK) pharmacodynamic analysis of SPD was conducted following i.p., intramuscular (i.m.), and intravenous (i.v.) administrations to rats. SPD brain and plasma levels were quantified at various times after dosing following i.p. (60 mg/kg), i.v. (60 mg/kg), and i.m. administrations (120 mg/kg) to rats, and the major PK parameters of SPD were estimated. The antiseizure (SE) efficacies of SPD and its individual stereoisomers were assessed in the pilocarpine-induced BZD-resistant SE model following i.p. and i.m. administrations to rats at 30 min after seizure onset. The absolute bioavailabilities of SPD following i.p. and i.m. administrations were 76% (i.p.) and 96% (i.p.), and its clearance and half-life were 1.8-1.5 L h(-1) kg(-1) and 0.5-1.7 h, respectively. The SPD brain-to-plasma AUC ratios were 1.86 (i.v.), 2.31 (i.p.), and 0.77 (i.m.). Nevertheless, the ED50 values of SPD and its individual stereoisomers were almost identical in the rat pilocarpine-induced SE model following i.p. and i.m. administrations. In conclusion, in rats SPD is completely or almost completely absorbed after i.m. and i.p. administration and readily penetrates into the brain. Consequently, in spite of PK differences, the activities of SPD in the BZD-resistant SE model following i.m. and i.p. administrations are similar. PMID- 27218461 TI - [3 + 2]-Cycloadditions of Azomethine Imines and Ynolates. AB - A novel [3 + 2]-cycloaddition between azomethine imines and lithium ynolates is described to synthesize bicyclic pyrazolidinones. These bicyclic pyrazolidinones are versatile intermediates to form beta-amino acids and monocyclic pyrazolidinones. High diastereoselectivity and stereospecificity allow access to optically active products. PMID- 27218462 TI - Correction: Associations of ACE Gene Insertion/Deletion Polymorphism, ACE Activity, and ACE mRNA Expression with Hypertension in a Chinese Population. AB - [This corrects the article DOI: 10.1371/journal.pone.0075870.]. PMID- 27218463 TI - Epothilones Suppress Neointimal Thickening in the Rat Carotid Balloon-Injury Model by Inducing Vascular Smooth Muscle Cell Apoptosis through p53-Dependent Signaling Pathway. AB - Microtubule stabilizing agents (MTSA) are known to inhibit vascular smooth muscle cell (VSMC) proliferation and migration, and effectively reduce neointimal hyperplasia and restenosis. Epothilones (EPOs), non-taxane MTSA, have been found to be effective in the inhibition of VSMC proliferation and neointimal formation by cell cycle arrest. However, effect of EPOs on apoptosis in hyper-proliferated VSMCs as a possible way to reduce neointimal formation and its action mechanism related to VSMC viability has not been suited yet. Thus, the purposes of the present study was to investigate whether EPOs are able to inhibit neointimal formation by inducing apoptosis within the region of neointimal hyperplasia in balloon-injured rat carotid artery, as well as underlying action mechanism. Treatment of EPO-B and EPO-D significantly induced apoptotic cell death and mitotic catastrophe in hyper-proliferated VSMCs, resulting in cell growth inhibition. Further, EPOs significantly suppressed VSMC proliferation and induced apoptosis by activation of p53-dependent apoptotic signaling pathway, Bax/cytochrome c/caspase-3. We further demonstrated that the local treatment of carotid arteries with EPOs potently inhibited neointimal lesion formation by induction of apoptosis in rat carotid injury model. Our findings demonstrate a potent anti-neointimal hyperplasia property of EPOs by inducing p53-depedent apoptosis in hyper-proliferated VSMCs. PMID- 27218464 TI - Prediction and Quantification of Splice Events from RNA-Seq Data. AB - Analysis of splice variants from short read RNA-seq data remains a challenging problem. Here we present a novel method for the genome-guided prediction and quantification of splice events from RNA-seq data, which enables the analysis of unannotated and complex splice events. Splice junctions and exons are predicted from reads mapped to a reference genome and are assembled into a genome-wide splice graph. Splice events are identified recursively from the graph and are quantified locally based on reads extending across the start or end of each splice variant. We assess prediction accuracy based on simulated and real RNA-seq data, and illustrate how different read aligners (GSNAP, HISAT2, STAR, TopHat2) affect prediction results. We validate our approach for quantification based on simulated data, and compare local estimates of relative splice variant usage with those from other methods (MISO, Cufflinks) based on simulated and real RNA-seq data. In a proof-of-concept study of splice variants in 16 normal human tissues (Illumina Body Map 2.0) we identify 249 internal exons that belong to known genes but are not related to annotated exons. Using independent RNA samples from 14 matched normal human tissues, we validate 9/9 of these exons by RT-PCR and 216/249 by paired-end RNA-seq (2 x 250 bp). These results indicate that de novo prediction of splice variants remains beneficial even in well-studied systems. An implementation of our method is freely available as an R/Bioconductor package [Formula: see text]. PMID- 27218466 TI - Steroid-Based Therapy and Risk of Infectious Complications. AB - Lionel Rostaing and Paolo Malvezzi discuss the clinical implications of Laurence Fardet and colleagues' accompanying research study on infectious complications in patients receiving steroid treatment. PMID- 27218465 TI - Functional Assessment of Corticospinal System Excitability in Karate Athletes. AB - OBJECTIVES: To investigate the involvement of the primary motor cortex (M1) in the coordination performance of karate athletes through transcranial magnetic stimulation (TMS). METHODS: Thirteen right-handed male karate athletes (25.0+/ 5.0 years) and 13 matched non-athlete controls (26.7+/-6.2 years) were enrolled. A single-pulse TMS was applied using a figure-eight coil stimulator. Resting motor threshold (rMT) was determined. Surface electromyography was recorded from the first dorsal interosseous muscle. Motor evoked potential (MEP) latencies and amplitudes at rMT, 110%, and 120% of rMT were considered. Functional assessment of the coordination performance was assessed by in-phase (IP) and anti-phase (AP) homolateral hand and foot coordination tasks performed at 80, 120, and 180 bpm. RESULTS: Compared to controls, athletes showed lower rMT (p<0.01), shorter MEP latency (p<0.01) and higher MEP amplitude (p<0.01), with a significant correlation (r = 0.50, p<0.01) between rMT and MEP latency. Coordination decreased with increasing velocity, and better IP performances emerged compared to AP ones (p<0.001). In general, a high correlation between rMT and coordination tasks was found for both IP and AP conditions. CONCLUSION: With respect to controls, karate athletes present a higher corticospinal excitability indicating the presence of an activity-dependent alteration in the balance and interactions between inhibitory and facilitatory circuits determining the final output from the M1. Furthermore, the high correlation between corticospinal excitability and coordination performance could support sport-specific neurophysiological arrangements. PMID- 27218467 TI - Association between Daily Hydrogen Sulfide Exposure and Incidence of Emergency Hospital Visits: A Population-Based Study. AB - BACKGROUND: The adverse health effects of high concentrations of hydrogen sulfide (H2S) exposure are well known, though the possible effects of low concentrations have not been thoroughly studied. The aim was to study short-term associations between modelled ambient low-level concentrations of intermittent hydrogen sulfide (H2S) and emergency hospital visits with heart diseases (HD), respiratory diseases, and stroke as primary diagnosis. METHODS: The study is population based, using data from patient-, and population-registers from the only acute care institution in the Reykjavik capital area, between 1 January, 2007 and 30 June, 2014. The study population was individuals (>=18yr) living in the Reykjavik capital area. The H2S emission originates from a geothermal power plant in the vicinity. A model was used to estimate H2S exposure in different sections of the area. A generalized linear model assuming Poisson distribution was used to investigate the association between emergency hospital visits and H2S exposure. Distributed lag models were adjusted for seasonality, gender, age, traffic zones, and other relevant factors. Lag days from 0 to 4 were considered. RESULTS: The total number of emergency hospital visits was 32961 with a mean age of 70 years. In fully adjusted un-stratified models, H2S concentrations exceeding 7.00MUg/m3 were associated with increases in emergency hospital visits with HD as primary diagnosis at lag 0 risk ratio (RR): 1.067; 95% confidence interval (CI): 1.024 1.111, lag 2 RR: 1.049; 95%CI: 1.005-1.095, and lag 4 RR: 1.046; 95%CI: 1.004 1.089. Among males an association was found between H2S concentrations exceeding 7.00MUg/m3, and HD at lag 0 RR: 1.087; 95%CI: 1.032-1.146 and lag 4 RR: 1080; 95%CI: 1.025-1.138; and among those 73 years and older at lag 0 RR: 1.075; 95%CI: 1.014-1.140 and lag 3 RR: 1.072; 95%CI: 1.009-1.139. No associations were found with other diseases. CONCLUSIONS: The study showed an association between emergency hospital visits with HD as primary diagnosis and same day H2S concentrations exceeding 7.00MUg/m3, more pronounced among males and those 73 years and older than among females and younger individuals. PMID- 27218468 TI - Spreading Effect in Industrial Complex Network Based on Revised Structural Holes Theory. AB - This paper analyzed the spreading effect of industrial sectors with complex network model under perspective of econophysics. Input-output analysis, as an important research tool, focuses more on static analysis. However, the fundamental aim of industry analysis is to figure out how interaction between different industries makes impacts on economic development, which turns out to be a dynamic process. Thus, industrial complex network based on input-output tables from WIOD is proposed to be a bridge connecting accurate static quantitative analysis and comparable dynamic one. With application of revised structural holes theory, flow betweenness and random walk centrality were respectively chosen to evaluate industrial sectors' long-term and short-term spreading effect process in this paper. It shows that industries with higher flow betweenness or random walk centrality would bring about more intensive industrial spreading effect to the industrial chains they stands in, because value stream transmission of industrial sectors depends on how many products or services it can get from the other ones, and they are regarded as brokers with bigger information superiority and more intermediate interests. PMID- 27218470 TI - Donor Site Morbidity After Anterior Iliac Bone Graft Harvesting. AB - OBJECTIVES: The objective of this study was to evaluate donor site morbidity associated with anterior iliac crest bone graft harvesting for orthopaedic trauma reconstructions. DESIGN: Retrospective case series. SETTING: Level 1 trauma center. PATIENTS: Forty-Six consecutive patients who had undergone anterior iliac crest bone graft harvesting more than a 7-year period were reviewed. INTERVENTION: Grafts were taken by removing the inner table of the ilium from 2 cm posterior to the Anterior Superior Iliac Spine. The abductor insertion was left intact and the external contour of the ilium remained unaffected. MAIN OUTCOME MEASURE: Visual analog scale and modified Questionnaires. RESULTS: Thirty seven of the 46 patients were evaluated at average follow-up of 4.5 years after anterior iliac bone graft harvesting for nonunion or fusion for posttraumatic arthrosis. No patient complained of pain at final follow-up with all patients having a visual analog scale pain of 0 at final follow-up. Three patients reported some scar numbness, however, none complained of thigh numbness. Three patients, if they needed grafting in the future would seek alternative sources based on their remembrance of significant postoperative pain. CONCLUSIONS: Anterior inner table bone graft harvesting resulted in minimal morbidity and neither pain nor functional limitations at an average of 4.5 years. This technique has lower donor-site morbidity than previous reports of posterior graft sites. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 27218469 TI - Construction and Experimental Validation of a Petri Net Model of Wnt/beta-Catenin Signaling. AB - The Wnt/beta-catenin signaling pathway is important for multiple developmental processes and tissue maintenance in adults. Consequently, deregulated signaling is involved in a range of human diseases including cancer and developmental defects. A better understanding of the intricate regulatory mechanism and effect of physiological (active) and pathophysiological (hyperactive) WNT signaling is important for predicting treatment response and developing novel therapies. The constitutively expressed CTNNB1 (commonly and hereafter referred to as beta catenin) is degraded by a destruction complex, composed of amongst others AXIN1 and GSK3. The destruction complex is inhibited during active WNT signaling, leading to beta-catenin stabilization and induction of beta-catenin/TCF target genes. In this study we investigated the mechanism and effect of beta-catenin stabilization during active and hyperactive WNT signaling in a combined in silico and in vitro approach. We constructed a Petri net model of Wnt/beta-catenin signaling including main players from the plasma membrane (WNT ligands and receptors), cytoplasmic effectors and the downstream negative feedback target gene AXIN2. We validated that our model can be used to simulate both active (WNT stimulation) and hyperactive (GSK3 inhibition) signaling by comparing our simulation and experimental data. We used this experimentally validated model to get further insights into the effect of the negative feedback regulator AXIN2 upon WNT stimulation and observed an attenuated beta-catenin stabilization. We furthermore simulated the effect of APC inactivating mutations, yielding a stabilization of beta-catenin levels comparable to the Wnt-pathway activities observed in colorectal and breast cancer. Our model can be used for further investigation and viable predictions of the role of Wnt/beta-catenin signaling in oncogenesis and development. PMID- 27218471 TI - LCP Versus LISS in the Treatment of Open and Closed Distal Femur Fractures: Does it Make a Difference? AB - OBJECTIVES: We compared the postoperative complication rates between the less invasive stabilization system (LISS) plating and locking compression plate for open and closed distal femoral fracture fixation for superiority. DESIGN: Retrospective Review. SETTING: Multicenter. PARTICIPANTS: Patients identified through a hospital database who were treated for supracondylar femur fractures using LISS or LCP techniques between January 2005 and July 2010. INTERVENTION: Medical history, patient demographics, injury characteristics, presence of polytrauma, and surgical characteristics were collected for each patient. MAIN OUTCOME MEASUREMENTS: chi and logistic regression analysis was performed to compare postoperative infection and nonunion/reoperation regarding both plating techniques. RESULTS: Of 339 distal femoral fractures, 185 (54.6%) were repaired with a LISS plate and 154 (45.4%) were repaired with a LCP. Multivariate analysis revealed only open fractures to be a risk factor for nonunion (Odds ratio 2.42, P = 0.01) and infection (Odds ratio 3.47, P = 0.02), regardless of device used. No difference was seen between either plate type in infection, plate failure, or nonunion. CONCLUSIONS: Postoperative infection and nonunion rates are comparable between LISS and LCP for both open and closed distal femoral fracture fixation. As no difference was detected between plates, either may be used to treat distal femur fractures. Nonunion rate was higher than expected based on previous reports. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 27218473 TI - Corrigendum. PMID- 27218472 TI - Reaming Does Not Affect Functional Outcomes After Open and Closed Tibial Shaft Fractures: The Results of a Randomized Controlled Trial: Erratum. PMID- 27218474 TI - Large Area 2D and 3D Colloidal Photonic Crystals Fabricated by a Roll-to-Roll Langmuir-Blodgett Method. AB - We present our results on the fabrication of large area colloidal photonic crystals on flexible poly(ethylene terephthalate) (PET) film using a roll-to-roll Langmuir-Blodgett technique. Two-dimensional (2D) and three-dimensional (3D) colloidal photonic crystals from silica nanospheres (250 and 550 nm diameter) with a total area of up to 340 cm(2) have been fabricated in a continuous manner compatible with high volume manufacturing. In addition, the antireflective properties and structural integrity of the films have been enhanced via the use of a second roll-to-roll process, employing a slot-die coating of an optical adhesive over the photonic crystal films. Scanning electron microscopy images, atomic force microscopy images, and UV-vis optical transmission and reflection spectra of the fabricated photonic crystals are analyzed. This analysis confirms the high quality of the 2D and 3D photonic crystals fabricated by the roll-to roll LB technique. Potential device applications of the large area 2D and 3D colloidal photonic crystals on flexible PET film are briefly reviewed. PMID- 27218475 TI - A New Heterotrophic Cryptomonad: Hemiarma marina n. g., n. sp. AB - We report a new heterotrophic cryptomonad Hemiarma marina n. g., n. sp. that was collected from a seaweed sample from the Republic of Palau. In our molecular phylogenetic analyses using the small subunit ribosomal RNA gene, H. marina formed a clade with two marine environmental sequences, and the clade was placed as a sister lineage of the freshwater cryptomonad environmental clade CRY1. Alternatively, in the concatenated large and small subunit ribosomal RNA gene phylogeny, H. marina was placed as a sister lineage of Goniomonas. Light and electron microscopic observations showed that H. marina shares several ultrastructural features with cryptomonads, such as flattened mitochondrial cristae, a periplast cell covering, and ejectisomes that consist of two coiled ribbon structures. On the other hand, H. marina exhibited unique behaviors, such as attaching to substrates with its posterior flagellum and displaying a jumping motion. H. marina also had unique periplast arrangement and flagellar transitional region. On the basis of both molecular and morphological information, we concluded that H. marina should be treated as new genus and species of cryptomonads. PMID- 27218477 TI - Oral adaptation of the Trail Making Test: A practical review. AB - Despite being one of the most widely used measures in clinical neuropsychology, the Trail Making Test is highly reliant on intact vision and motor functioning. Given that these capacities are often compromised in patients requiring neuropsychological evaluation, various authors have proposed methods for adapting the Trail Making Test for oral administration. To date, a number of administration and score transformation methods have been proposed. We reviewed the existing literature on oral adaptation of the Trail Making Test in order to provide recommendations for practicing clinicians wishing to use the measure, and to highlight directions for future research. PMID- 27218476 TI - Effect of Intravenous Ethanol on Capsaicin-Induced Hyperalgesia in Human Subjects. AB - BACKGROUND: The objective of this study was to assess ethanol's (EtOH's) effects on capsaicin-induced hyperalgesia in healthy participants. Specifically, we investigated the change in area of capsaicin-induced hyperalgesia following 3 interventions: intravenous EtOH at 2 targeted breath alcohol concentrations (BrAC), or placebo. METHODS: Eighteen participants participated in 3 test days in a randomized order. Each test day, participants received an intradermal capsaicin injection on the volar surface of the forearm, followed by either infusion of high concentration EtOH (targeted BrAC = 0.100 g/dl), low concentration EtOH (targeted BrAC = 0.040 g/dl), or placebo. The area of hyperalgesia was determined by von Frey technique at 2 time points, prior to EtOH infusion, and again when target BrAC was reached. The primary outcome was the percent change in the area of capsaicin-induced hyperalgesia. Additional outcome measures included the visual analogue scale of mood states (VAS), which was administered at each time point. RESULTS: There was a marked 30% reduction in the area of capsaicin-induced hyperalgesia with infusion of a high concentration of EtOH (p < 0.05). Low concentration EtOH produced a 10% reduction in hyperalgesia area, although this finding did not reach significance. Further, participants reported significant feelings of euphoria and drowsiness at high concentrations of EtOH (p < 0.05), as measured by the VAS. CONCLUSIONS: In a human model examining pain phenomena related to central sensitization, this study is the first to demonstrate that capsaicin-induced hyperalgesia is markedly attenuated by EtOH. The capsaicin experimental pain paradigm employed provides a novel approach to evaluate EtOH's effects on pain processing. The antihyperalgesic effects of EtOH observed have important clinical implications for the converging fields of substance abuse and pain medicine and may inform why patients with chronic pain often report alcohol use as a form of self-medication. PMID- 27218478 TI - On the combination of c- and D-optimal designs: General approaches and applications in dose-response studies. AB - Dose-response modeling in areas such as toxicology is often conducted using a parametric approach. While estimation of parameters is usually one of the goals, often the main aim of the study is the estimation of quantities derived from the parameters, such as the ED50 dose. From the view of statistical optimal design theory such an objective corresponds to a c-optimal design criterion. Unfortunately, c-optimal designs often create practical problems, and furthermore commonly do not allow actual estimation of the parameters. It is therefore useful to consider alternative designs which show good c-performance, while still being applicable in practice and allowing reasonably good general parameter estimation. In effect, using optimal design terminology this means that a reasonable performance regarding the D-criterion is expected as well. In this article, we propose several approaches to the task of combining c- and D-efficient designs, such as using mixed information functions or setting minimum requirements regarding either c- or D-efficiency, and show how to algorithmically determine optimal designs in each case. We apply all approaches to a standard situation from toxicology, and obtain a much better balance between c- and D-performance. Next, we investigate how to adapt the designs to different parameter values. Finally, we show that the methodology used here is not just limited to the combination of c- and D-designs, but can also be used to handle more general constraint situations such as limits on the cost of an experiment. PMID- 27218479 TI - Reliability of the Knee Smartphone-Application Goniometer in the Acute Orthopedic Setting. AB - The standard goniometer (SG) is the most commonly used tool to assess range of motion (ROM) in patients with knee restrictions. Several medical applications have been designed to measure joint ROM. Little data are available on their reliability in the postoperative clinical setting. The purpose of this study was to assess whether a smartphone accelerometer-based knee goniometer application (App) is as reliable as the SG to measure knee ROM in clinical settings. A total of 60 subjects were included in this cross-sectional reliability trial. Overall, 20 healthy subjects (HS) and 20 acute postoperative patients (PO) underwent three active and three passive measurements in knee flexion and extension, using the SG and the smartphone knee goniometer App. To determine the fatigability of postoperative patients, a third group of 20 patients underwent a single active measurement in knee flexion and extension (PO1). Measurements were performed by three clinicians. For intraobserver reliability, mean intraclass correlation coefficient (ICC) values were higher for the App in all circumstances (overall mean SG 0.85, App 0.91), indicating an excellent correlation. For interobserver reliability, the highest ICC scores were in the PO1 group, with the App more consistent than the SG in all movements. Interobserver reliability was lower in the PO group versus PO1. Interobserver reliability was better for active ROM than for passive measurements. The overall concordance coefficient was very good to excellent with active measurements (range, 0.60-0.97). In conclusion, the App is a reliable tool for use in acute orthopedic care and offers better intra- and interobserver correlation scores for a single active measurement. PMID- 27218480 TI - Comparison between Closing-Wedge and Opening-Wedge High Tibial Osteotomy in Patients with Medial Knee Osteoarthritis: A Systematic Review and Meta-analysis. AB - Young active patients with medial knee osteoarthritis (OA) combined with varus leg alignment can be treated with high tibial osteotomy (HTO) to stop the progression of OA and avoid or postpone total knee arthroplasty (TKA). Closing wedge osteotomy (CWO) and opening-wedge osteotomy (OWO) are the most commonly used osteotomy techniques. The purpose of this study was to compare the clinical and radiologic outcomes and complications between OWO and CWO. We retrospectively evaluated 23 studies including 17 clinical trials from published databases from their inception to May 2015. We evaluated the clinical outcomes including operation time, visual analog scale (VAS), maximal flexion, and hospital for special surgery knee (HSS) score. The radiologic outcomes included patellar height measured by posterior tibial slope angle, hip-knee-ankle (HKA) angle, femorotibial (FT) axis, and limb length. Complications recorded included the incidence of deep vein thrombosis (DVT), common peroneal nerve injury, opposite cortical fracture, etc. There were no differences in most of the clinical outcomes except the operation time. OWO increased the posterior slope angle and limb length, decreased the patellar height, and provided higher accuracy of correction. CWO led to a higher incidence of opposite cortical fracture. PMID- 27218482 TI - Association between bone turnover markers, clinical variables, spinal syndesmophytes and bone mineral density in Mexican patients with ankylosing spondylitis. AB - OBJECTIVES: To compare bone turnover marker (BTM) levels and bone mineral density (BMD) between patients with ankylosing spondylitis (AS) and healthy controls (HC) and to evaluate, in AS, the association between BTM levels and clinical variables, spinal syndesmophytes, and BMD using multivariate analysis. METHOD: Seventy-eight AS patients were compared with 58 HC matched by gender. Spinal syndesmophytes in AS and other characteristics were assessed. C-terminal telopeptide fragments of type I collagen (CTX), bone-specific alkaline phosphatase (BAP), osteocalcin (OC) serum levels, and BMD of the lumbar spine, femoral neck, and forearm were evaluated. RESULTS: AS males and females had lower BAP levels than their respective HC (p < 0.001 and p = 0.001). AS patients with bridging syndesmophytes had higher OC levels than AS patients either with non bridging syndesmophytes (p = 0.001) or without spinal syndesmophytes (p < 0.001). OC and CTX levels correlated significantly with the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). In the multivariate linear regression adjusted by age, gender, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), BMD in the lumbar spine, and C-reactive protein (CRP), we observed an association between BAP levels and anti-tumour necrosis factor (anti-TNF) use (p = 0.05) whereas OC levels were associated with mSASSS (p < 0.001) and anti-TNF use (p = 0.05), and CTX levels were exclusively associated with mSASSS (p = 0.03). In the logistic regression analysis, only OC levels were associated with the presence of syndesmophytes in AS [odds ratio (OR) 2.42, 95% confidence interval (CI) 1.19 5.75]. CONCLUSIONS: We observed an increase in OC levels in AS patients with syndesmophytes. BTM levels were associated with the severity of spinal damage. Future longitudinal studies should evaluate whether these BTMs should be included as tools to determine the prognosis and progression of spinal damage. PMID- 27218484 TI - Are depot as effective as oral antipsychotics on first-episode psychosis? AB - Depot antipsychotics have been generally used in patients with chronic schizophrenia with adherence problems to oral therapy. However, it has been suggested they can be a good alternative in earlier stages too. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified three systematic reviews including two pertinent randomized trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded it is not clear whether there are differences between depot and oral antipsychotics in first-episode psychosis because the certainty of the available evidence is very low. PMID- 27218483 TI - Longitudinal improvement and stability of olfactory function in the evaluation of surgical management for chronic rhinosinusitis. AB - BACKGROUND: Abnormal olfaction is common with chronic rhinosinusitis (CRS) and associates with various measures of sinonasal inflammation. The Brief Smell Identification Test (BSIT) has demonstrated improvements in abnormal olfactory detection following endoscopic sinus surgery (ESS), but olfaction remains understudied using this instrument. Discerning longitudinal, postoperative durability in olfaction is critical for patient counseling. METHODS: Adult participants with medically recalcitrant CRS were prospectively enrolled into a multi-institutional cohort study and observed for 18 months after ESS. Olfaction was operationalized using BSIT scores collected at baseline, 6 months, 12 months, and 18 months postoperatively and compared using repeated measures analysis of variance (ANOVA). RESULTS: A total of 122 participants met inclusion criteria and were recruited between March 2011 and February 2014. Improvement in mean BSIT scores at 6-month follow-up were reported for all participants (p = 0.014) with greatest improvement in subjects with nasal polyposis (p = 0.001). No differences in mean BSIT scores were found between 6 months and 18 months overall; however, subjects with comorbid asthma (F(2) = 5.29; p = 0.010) and nasal polyposis (F(2) = 3.99; p = 0.033) reported significant mean worsening. Prevalence of abnormal olfaction decreased from 28% preoperatively to 17% at 6 months (p = 0.015), for all subjects, without significant change at 12 months (19%; p = 0.791) or at 18 months (21%; p = 0.581) postoperatively. CONCLUSION: Postoperative improvement in olfaction was reported 6 months after ESS using BSIT scores, with greatest improvements in patients undergoing polypectomy. Overall improvement persisted between 6 months and 18 months after ESS for most patient subgroups; however, dysosmia worsened after initial improvement in patients with asthma and nasal polyps, highlighting the need for further identification of prognostic factors associated with abnormal olfaction in CRS. PMID- 27218486 TI - The IgG1 B-cell receptor provides survival and proliferative signals analogue to the Igalpha but not the Igbeta co-receptor. AB - The function of the IgM B-cell receptor (BCR) is dependent on intact signaling of the co-receptors Igalpha and Igbeta, both of which contain a cytoplasmic tail bearing an immunoreceptor tyrosine-based activation motif. We have previously demonstrated that the cytoplasmic tail of the IgG1 BCR can partially compensate for the loss of the signaling moiety of Igalpha. Here, we show that unlike Igalpha, Igbeta signaling is indispensable for the development and function of IgG1-expressing B cells. Deletion of the cytoplasmic signaling tail of Igbeta compromised the survival and proliferation not only of IgM(+) B cells but also of IgG1-expressing B cells. In the absence of the signaling tail of Igbeta, the transcription levels of the antiapoptotic gene bcl-xl and the cell-cycle gene ccnd2 were reduced, consistent with the observed defects in survival and proliferation. These results demonstrate functional differences between Igalpha and Igbeta in the transduction of IgG1 BCR signal. PMID- 27218487 TI - Design and Synthesis of a Calcium-Sensitive Photocage. AB - Photolabile protecting groups (or "photocages") enable precise spatiotemporal control of chemical functionality and facilitate advanced biological experiments. Extant photocages exhibit a simple input-output relationship, however, where application of light elicits a photochemical reaction irrespective of the environment. Herein, we refine and extend the concept of photolabile groups, synthesizing the first Ca(2+) -sensitive photocage. This system functions as a chemical coincidence detector, releasing small molecules only in the presence of both light and elevated [Ca(2+) ]. Caging a fluorophore with this ion-sensitive moiety yields an "ion integrator" that permanently marks cells undergoing high Ca(2+) flux during an illumination-defined time period. Our general design concept demonstrates a new class of light-sensitive material for cellular imaging, sensing, and targeted molecular delivery. PMID- 27218485 TI - Contribution of peripheral and central chemoreceptors to sympatho-excitation in heart failure. AB - Chronic heart failure (CHF) is a major public health problem. Tonic hyper activation of sympathetic neural outflow is commonly observed in patients with CHF. Importantly, sympatho-excitation in CHF exacerbates its progression and is strongly related to poor prognosis and high mortality risk. Increases in both peripheral and central chemoreflex drive are considered markers of the severity of CHF. The principal peripheral chemoreceptors are the carotid bodies (CBs) and alteration in their function has been described in CHF. Mainly, during CHF the CB chemosensitivity is enhanced leading to increases in ventilation and sympathetic outflow. In addition to peripheral control of breathing, central chemoreceptors (CCs) are considered a dominant mechanism in ventilatory regulation. Potentiation of the ventilatory and sympathetic drive in response to CC activation has been shown in patients with CHF as well as in animal models. Therefore, improving understanding of the contribution of the peripheral and central chemoreflexes to augmented sympathetic discharge in CHF could help in developing new therapeutic approaches intended to attenuate the progression of CHF. Accordingly, the main focus of this review is to discuss recent evidence that peripheral and central chemoreflex function are altered in CHF and that they contribute to autonomic imbalance and progression of CHF. PMID- 27218591 TI - Women's Health across the Lifespan: A Continuing Education Theme Issue. PMID- 27218592 TI - Probiotics for Treatment and Prevention of Urogenital Infections in Women: A Systematic Review. AB - INTRODUCTION: Probiotics are a complementary and integrative therapy useful in the treatment and prevention of urogenital infections in women. This study extends the work of researchers who systematically investigated the scientific literature on probiotics to prevent or treat urogenital infections. METHODS: A systematic review was conducted to determine the efficacy of probiotics for prevention and/or treatment of urogenital infections in adult women from January 1, 2008, through June 30, 2015. We searched in CINAHL, MEDLINE, Cochrane Central Register of Controlled Trials, Web of Science, Dissertations and Theses, and Alt HealthWatch. After removing duplicates and studies that did not meet inclusion criteria, 20 studies were reviewed. All included at least one species of Lactobacillus probiotic as an intervention for treatment or prevention of urogenital infections. Data extracted included samples, settings, study designs, intervention types, reported outcomes, follow-up periods, and results. We evaluated all randomized controlled trials for risk of bias and made quality appraisals on all studies. RESULTS: Fourteen of the studies focused on bacterial vaginosis (BV), 3 on urinary tract infections (UTIs), 2 on vulvovaginal candidiasis, and one on human papillomavirus (HPV) as identified on Papanicolaou test. Studies were heterogeneous in terms of design, intervention, and outcomes. Four studies were of good quality, 9 of fair, and 7 poor. Probiotic interventions were effective for treatment and prevention of BV, prevention of recurrences of candidiasis and UTIs, and clearing HPV lesions. No study reported significant adverse events related to the probiotic intervention. DISCUSSION: The quality of the studies in this systematic review varied. Although clinical practice recommendations were limited by the strength of evidence, probiotic interventions were effective in treatment and prevention of urogenital infections as alternatives or co-treatments. More good quality research is needed to strengthen the body of evidence needed for application by clinicians. PMID- 27218594 TI - FROM COCHRANE DATABASE OF SYSTEMATIC REVIEWS (CDSR), ISSUE 12 (2015) and ISSUE 1 (2016). PMID- 27218593 TI - Preconception Care: Improving the Health of Women and Families. AB - Approximately 50% of the pregnancies in the United States are unintended. Most pregnancies are not diagnosed until after the period of organogenesis. Environmental exposures, chronic and acute illnesses, and ingestion of teratogens that can negatively affect the fetus may occur during these early weeks of pregnancy. Some chronic disease effects and lifestyle behaviors that affect the fetus can be adjusted prior to conception. Because of this, the health of a woman and her partner prior to pregnancy are of utmost importance. The Centers for Disease Control and Prevention and the Preconception Health and Health Care Initiative have established goals and evidence-based guidelines for preconception care. Preconception health care can be threaded into every visit with all women of reproductive age who are not pregnant. The guidelines focus on 3 main areas: screening, health promotion, and interventions. Screening is accomplished with women and couples via a thorough history and assessment of risks including a reproductive life plan; assessment of tobacco, alcohol and drug use; sexually transmitted infection (STI) testing and education; and assessment of environmental or teratogenic risk factors. Health promotion includes making sure the woman is current with regard to recommended vaccines, taking appropriate levels of folic acid, and maintaining a healthy weight and level of physical activity. The health care provider can intervene when indicated with management of chronic and acute illnesses, as well as provide assistance with tobacco, alcohol, and drug cessation as necessary. When a woman and her partner are healthy prior to pregnancy, unintended or planned, the woman and her fetus have a better chance at a healthy gestation and beyond. This article, via the use of case presentations, reviews how preconception health can be integrated into an office visit. PMID- 27218595 TI - Current Resources for Evidence-Based Practice, May/June 2016. PMID- 27218596 TI - FROM THE JOANNA BRIGGS INSTITUTE EVIDENCE-BASED PRACTICE DATABASE. PMID- 27218599 TI - Prognostic Importance of Diastolic Dysfunction in Relation to Post Procedural Aortic Insufficiency in Patients Undergoing Transcatheter Aortic Valve Replacement. AB - OBJECTIVES: We sought to examine whether baseline diastolic dysfunction (DD) is associated with increased mortality in patients who develop aortic insufficiency (AI) after transcatheter aortic valve replacement (TAVR). BACKGROUND: Significant post-TAVR AI is associated with increased mortality, likely secondary to adverse hemodynamics secondary to volume overload and decreased LV compliance from chronic pressure overload. However, the effect of baseline DD on outcomes of patients with post-TAVR AI has not been studied. METHODS: A total of 195 patients undergoing TAVR were included in the study. Patients with moderate-to-severe mitral stenosis, prior mitral valve replacement or atrial fibrillation were excluded. DD was classified at baseline by a 2-step approach as recommended by the American Society of Echocardiography while AI was evaluated 30 days post TAVR. Follow up data up to 2 years post-TAVR was used in survival analysis. RESULTS: Patients with severe baseline DD who developed >=mild post-TAVR AI had increased mortality compared to all other patients (HR = 3.89, CI: 1.76-8.6, P = 0.001), which remained significant after adjusting for post-TAVR AI, pre-TAVR AI, baseline mitral regurgitation, ejection fraction, pulmonary artery pressure, creatinine clearance and history of stroke. CONCLUSIONS: Even mild post-TAVR AI may have a negative impact on outcomes of patients with underlying severe DD. (c) 2016 Wiley Periodicals, Inc. PMID- 27218600 TI - Family involvement in emergency department discharge education for older people. AB - AIMS AND OBJECTIVES: To report findings concerning family involvement in emergency department discharge education for older people. BACKGROUND: The current trend of population ageing in Western countries has caused an increase in emergency department visits. Due to the continuing improvement in the mental and physical status of older people, they are frequently discharged home. Proper discharge education enables older people and their families to better understand how they can cope with the medical issue at home. Given the lack of research, we know relatively little about the significance of family involvement in older people's emergency department discharge education. DESIGN: A descriptive qualitative design was used. METHODS: Qualitative thematic interviews of seven older patients, five family members and fifteen nurses were conducted. Data were analysed using content analysis. RESULTS: Family involvement in discharge education was seen as turbulent. The experiences were twofold: family involvement was acknowledged, but there was also a feeling that family members were ostracised. Families were seen as a resource for nurses, but as obliged initiators of their own involvement. CONCLUSIONS: Our findings suggest that family members are not considered participants in emergency department care. For a family-friendly approach, actions should be taken on both individual and organisational levels. RELEVANCE TO CLINICAL PRACTICE: The findings support healthcare providers and organisation leaders in promoting family involvement in discharge education for older people. Families can be encouraged to be involved without feeling responsible for the interaction. PMID- 27218601 TI - Glucose induces delocalization of a flagellar biosynthesis protein from the flagellated pole. AB - To survive in a continuously changing environment, bacteria sense concentration gradients of attractants or repellents, and purposefully migrate until a more favourable habitat is encountered. While glucose is known as the most effective attractant, the flagellar biosynthesis and hence chemotactic motility has been known to be repressed by glucose in some bacteria. To date, the only known regulatory mechanism of the repression of flagellar synthesis by glucose is via downregulation of the cAMP level, as shown in a few members of the family Enterobacteriaceae. Here we show that, in Vibrio vulnificus, the glucose-mediated inhibition of flagellar motility operates by a completely different mechanism. In the presence of glucose, EIIA(Glc) is dephosphorylated and inhibits the polar localization of FapA (flagellar assembly protein A) by sequestering it from the flagellated pole. A loss or delocalization of FapA results in a complete failure of the flagellar biosynthesis and motility. However, when glucose is depleted, EIIA(Glc) is phosphorylated and releases FapA such that free FapA can be localized back to the pole and trigger flagellation. Together, these data provide new insight into a bacterial strategy to reach and stay in the glucose-rich area. PMID- 27218602 TI - The Influence of the Aquatic Environment on Gait Initiation: A Pilot Study. AB - Aquatic therapies are used to restore step initiation in people with locomotor disabilities. However, there is lack of evidence of underlining mechanisms of gait initiation in water. We investigated center of pressure (CoP), vertical and anterior-posterior impulse forces, and kinematics of the first step performed in water in comparison with overground walking. The peaks of anticipatory postural adjustment (APA) and the sections of CoP trajectories were longer in water than on land. Impulse forces were increased in water compared with land. Range of motion (ROM) of ankle joint increased in water while knee joint ROM did not change. We suggest that the aquatic environment may facilitate gait initiation training by allowing a longer step execution with greater stimuli and imposed resistance for the phases of gait initiation. PMID- 27218603 TI - New Trinuclear Complexes of Group 6, 8, and 9 Metals with a Triply Bridging Borylene Ligand. AB - Trinuclear complexes of group 6, 8, and 9 transition metals with a (MU3 -BH) ligand [(MU3 -BH)(Cp*Rh)2 (MU-CO)M'(CO)5 ], 3 and 4 (3: M'=Mo; 4: M'=W) and 5-8, [(Cp*Ru)3 (MU3 -CO)2 (MU3 -BH)(MU3 -E)(MU-H){M'(CO)3 }] (5: M'=Cr, E=CO; 6: M'=Mo, E=CO; 7: M'=Mo, E=BH; 8: M'=W, E=CO), have been synthesized from the reaction between nido-[(Cp*M)2 B3 H7 ] (nido-1: M=Rh; nido-2: M=RuH, Cp*=eta(5) C5 Me5 ) and [M'(CO)5 ?thf] (M'=Mo and W). Compounds 3 and 4 are isoelectronic and isostructural with [(MU3 -BH)(Cp*Co)2 (MU-CO)M'(CO)5 ], (M'=Cr, Mo and W) and [(MU3 -BH)(Cp*Co)2 (MU-CO)(MU-H)2 M''H(CO)3 ], (M''=Mn and Re). All compounds are composed of a bridging borylene ligand (B-H) that is effectively stabilized by a trinuclear framework. In contrast, the reaction of nido-1 with [Cr(CO)5 ?thf] gave [(Cp*Rh)2 Cr(CO)3 (MU-CO)(MU3 -BH)(B2 H4 )] (9). The geometry of 9 can be viewed as a condensed polyhedron composed of [Rh2 Cr(MU3 -BH)] and [Rh2 CrB2 ], a tetrahedral and a square pyramidal geometry, respectively. The bonding of 9 can be considered by using the polyhedral fusion formalism of Mingos. All compounds have been characterized by using different spectroscopic studies and the molecular structures were determined by using single-crystal X-ray diffraction analysis. PMID- 27218604 TI - A Historical Excursus on the Statistical Validation Parameters for QSAR Models: A Clarification Concerning Metrics and Terminology. AB - In the last years, external validation of QSAR models was the subject of intensive debate in the scientific literature. Different groups have proposed different metrics to find "the best" parameter to characterize the external predictivity of a QSAR model. This editorial summarizes the history of parameter development for the external QSAR model validation and suggests, once again, the concurrent use of several different metrics to assess the real predictive capability of QSAR models. PMID- 27218605 TI - Anger and guilt in treatment for chronic posttraumatic stress disorder. AB - BACKGROUND AND OBJECTIVES: Feelings of anger and guilt are important to consider when treating PTSD as they are related to higher PTSD severity and may be related to avoidance during treatment. Avoidance may impede emotional engagement, the process of connecting with distressing, fear-related emotions during imaginal exposure, which is considered an important mechanism for successful PTSD treatment in prolonged exposure (PE). Yet, little research has examined possible complications in achieving emotional engagement, such as anger and guilt. METHODS: The present study utilized data from 116 individuals with PTSD who received PE to investigate whether anger and guilt were associated with poorer emotional engagement, as captured by pre, peak, post, and mean subjective units of distress (SUDs), during the initial imaginal exposure, and whether anger and guilt predicted worse treatment outcome generally and as a result of lessened emotional engagement. RESULTS: Neither initial anger nor guilt hindered engagement nor predicted worse outcome. Contrary to hypotheses, higher guilt was predictive of greater anticipatory distress and slightly better PTSD outcome. The relationship between pre-treatment guilt cognitions and post-treatment PTSD severity was not mediated by engagement. LIMITATIONS: This study used a trauma specific measure of guilt and general measure for anger, however both are commonly used. In addition, this study examined emotional engagement during imaginal exposure to the exclusion of engagement with other therapy components, such as in vivo exposure. CONCLUSIONS: These findings help dispel concerns that those with higher anger and guilt will avoid emotionally engaging during the initial imaginal exposure due to feeling distressed by intense negative emotionality. PMID- 27218606 TI - Optimizing the use of intravenous magnesium sulfate for acute asthma treatment in children. AB - BACKGROUND: Asthma is the most common pediatric chronic disease and currently affects 7.1 million children in the United States. Many children experience acute asthma exacerbations. Many children also require hospitalization despite treatment in an emergency department with current standard therapy (corticosteroids, albuterol, and ipratropium). These hospitalizations may be avoided if effective adjunctive therapies can be developed to adequately treat severe exacerbations. METHODS: Publications were searched in the PubMed database using the following keywords: magnesium AND asthma AND children AND randomized controlled trial. A total of 30 publications were returned. References of relevant articles were also screened. We included publications of controlled randomized trials where intravenous magnesium sulfate was studied in children (age < 18 years) with acute asthma (n = 7). We excluded studies in adults or trials with other formulations of magnesium (e.g., nebulized). RESULTS: Previous studies have demonstrated that intravenous magnesium sulfate (IV MgSO4 ) significantly improves respiratory function and reduces hospitalization rate in children with moderate to severe asthma exacerbations. Current dosing regimens involve a short infusion of 25-75 mg/kg over 20 min (maximum 2-2.5 g/dose), though no studies have directly compared dosages for relative efficacy. Several studies suggest utilizing a peak plasma concentration of magnesium higher than 4 mg/dL as a surrogate of efficacy. This review summarizes the literature regarding the use of IV MgSO4 for the treatment of pediatric acute asthma. CONCLUSIONS: We suggest that optimized dosing regimens could be developed using a linked pharmacokinetic-pharmacodynamic modeling and simulation approach. We propose the factors that should be considered in future clinical trial design in order to better understand the use of IV MgSO4 in pediatric acute asthma. Pediatr Pulmonol. 2016;51:1414-1421. (c) 2016 Wiley Periodicals, Inc. PMID- 27218608 TI - Degradation of Flexible, ITO-Free Oligothiophene Organic Solar Cells. AB - We investigate the degradation of organic solar cells based on an oligothiophene (DCV5T-Me) small molecule donor and the acceptor C60. Two different flexible, transparent bottom electrode types are employed: a transparent metal electrode (TME) and silver nanowires (AgNWs). They exhibit high optical transparency up to 86% and a sheet resistance as low as 12Omega/?. Power conversion efficiencies of 7.0%, 5.7%, and 7.2% on TME, AgNWs, and indium tin oxide (ITO, reference) are reached, respectively. The solar cells are protected against moisture ingress utilizing a flexible alumina thin-film, exhibiting water vapor transmission rates down to 3 * 10(-5) g m(-2) day(-1) at 38 degrees C and 90% relative humidity (RH). Implementation of this ultrabarrier as top and bottom encapsulation enables fabrication of fully flexible devices. A decrease in PCE to 80% of initial values is observed after 1000 +/- 50 h on flexible, encapsulated TME but only 20 +/- 5 h on AgNWs in a climate of 38 degrees C/50% RH. Degradation in AgNW-based devices is attributed to electrode decomposition. PMID- 27218607 TI - Sulforaphane induces adipocyte browning and promotes glucose and lipid utilization. AB - SCOPE: Obesity is closely related to the imbalance of white adipose tissue storing excess calories, and brown adipose tissue dissipating energy to produce heat in mammals. Recent studies revealed that acquisition of brown characteristics by white adipocytes, termed "browning," may positively contribute to cellular bioenergetics and metabolism homeostasis. The goal was to investigate the putative effects of natural antioxidant sulforaphane (1-isothiocyanate-4 methyl-sulfonyl butane; SFN) on browning of white adipocytes. METHODS AND RESULTS: 3T3-L1 mature white adipocytes were treated with SFN for 48 h, and then the mitochondrial content, function, and energy utilization were assessed. SFN was found to induce 3T3-L1 adipocytes browning based on the increased mitochondrial content and activity of respiratory chain enzymes, whereas the mechanism involved the upregulation of nuclear factor E2-related factor 2/sirtuin1/peroxisome proliferator activated receptor gamma coactivator 1 alpha signaling. SFN enhanced uncoupling protein 1 expression, a marker for brown adipocyte, leading to the decrease in cellular ATP. SFN also enhanced glucose uptake and oxidative utilization, lipolysis, and fatty acid oxidation in 3T3-L1 adipocytes. CONCLUSION: SFN-induced browning of white adipocytes enhanced the utilization of cellular fuel, and application of SFN is a promising strategy to combat obesity and obesity-related metabolic disorder. PMID- 27218609 TI - Atomistic simulations of electrochemical metallization cells: mechanisms of ultra fast resistance switching in nanoscale devices. AB - We describe a new method that enables reactive molecular dynamics (MD) simulations of electrochemical processes and apply it to study electrochemical metallization cells (ECMs). The model, called EChemDID, extends the charge equilibration method to capture the effect of external electrochemical potential on partial atomic charges and describes its equilibration over connected metallic structures, on-the-fly, during the MD simulation. We use EChemDID to simulate resistance switching in nanoscale ECMs; these devices consist of an electroactive metal separated from an inactive electrode by an insulator and can be reversibly switched to a low-resistance state by the electrochemical formation of a conducting filament between electrodes. Our structures use Cu as the active electrode and SiO2 as the dielectric and have dimensions at the foreseen limit of scalability of the technology, with a dielectric thickness of approximately 1 nm. We explore the effect of device geometry on switching timescales and find that nanowires with an electroactive shell, where ions migrate towards a smaller inactive electrode core, result in faster switching than planar devices. We observe significant device-to-device variability in switching timescales and intermittent switching for these nanoscale devices. To characterize the evolution in the electronic structure of the dielectric as dissolved metallic ions switch the device, we perform density functional theory calculations on structures obtained from an EChemDID MD simulation. These results confirm the appearance of states around the Fermi energy as the metallic filament bridges the electrodes and show that the metallic ions and not defects in the dielectric contribute to the majority of those states. PMID- 27218611 TI - Symmetry conditions for type II multiferroicity in commensurate magnetic structures. AB - Type II multiferroics are magnetically ordered phases that exhibit ferroelectricity as a magnetic induced effect. We show that in single-k magnetic phases the presence in the paramagnetic phase of non-symmorphic symmetry combined with some specific type of magnetic propagation vector can be sufficient for the occurrence of this type of multiferroic behaviour. Other symmetry scenarios especially favourable for spin driven multiferroicity are also presented. We review and classify known type II multiferroics under this viewpoint. In addition, some other magnetic phases which due to their symmetry properties can exhibit type II multiferroicity are pointed out. PMID- 27218610 TI - Pornography consumption among adolescent girls in Sweden. AB - OBJECTIVES: The aims of this study were to describe patterns of pornography consumption, investigate differences between consumers and non-consumers of pornography regarding sexual experiences, health and lifestyle and determine associations between pornography consumption and sexual experiences, health and lifestyle among adolescent girls. The hypotheses were that adolescent girls categorised as pornography consumers would report sexual experiences to a greater extent, and a riskier lifestyle and poorer health, compared with non-consumers. METHODS: A classroom survey was conducted among 16-year-old girls (N = 393). RESULTS: One-third (30%) consumed pornography. In this group, almost half (43%) had fantasies about trying to copy sexual acts seen in pornography and 39% had tried to copy sexual activities seen in pornography. A higher proportion of pornography-consuming girls reported sexual experiences compared with peers. A third (30%) reported experience of anal sex compared with 15% among non-consuming peers (p = 0.001). Furthermore, peer-relationship problems (17% vs 9%; p = 0.015), use of alcohol (85% vs 69%; p = 0.001) and daily smoking (27% vs 14%; p = 0.002) were reported to a greater extent than in non-consuming peers. Pornography consumption, use of alcohol and daily smoking were associated with experience of casual sex. CONCLUSIONS: Pornography-consuming girls reported sexual experiences and a risky lifestyle to a greater extent compared with non-consuming girls. This indicates that pornography consumption may influence sexualisation and lifestyle. This is important to acknowledge when designing and implementing sexual health programmes for adolescents. PMID- 27218614 TI - A Rock on the Lukenia Hills: William R. Leigh. PMID- 27218615 TI - Reports of Obamacare's Demise Are Greatly Exaggerated. PMID- 27218624 TI - Development and Implementation of Expected Practices to Reduce Inappropriate Variations in Clinical Practice. PMID- 27218625 TI - A Stronger Treatment System for Opioid Use Disorders. PMID- 27218626 TI - A PIECE OF MY MIND. Black Lives. PMID- 27218627 TI - Dietary Salt, Kidney Disease, and Cardiovascular Health. PMID- 27218628 TI - Can Walkable Urban Design Play a Role in Reducing the Incidence of Obesity Related Conditions? PMID- 27218630 TI - Association of Neighborhood Walkability With Change in Overweight, Obesity, and Diabetes. AB - IMPORTANCE: Rates of obesity and diabetes have increased substantially in recent decades; however, the potential role of the built environment in mitigating these trends is unclear. OBJECTIVE: To examine whether walkable urban neighborhoods are associated with a slower increase in overweight, obesity, and diabetes than less walkable ones. DESIGN, SETTING, AND PARTICIPANTS: Time-series analysis (2001 2012) using annual provincial health care (N ~ 3 million per year) and biennial Canadian Community Health Survey (N ~ 5500 per cycle) data for adults (30-64 years) living in Southern Ontario cities. EXPOSURES: Neighborhood walkability derived from a validated index, with standardized scores ranging from 0 to 100, with higher scores indicating more walkability. Neighborhoods were ranked and classified into quintiles from lowest (quintile 1) to highest (quintile 5) walkability. MAIN OUTCOMES AND MEASURES: Annual prevalence of overweight, obesity, and diabetes incidence, adjusted for age, sex, area income, and ethnicity. RESULTS: Among the 8777 neighborhoods included in this study, the median walkability index was 16.8, ranging from 10.1 in quintile 1 to 35.2 in quintile 5. Resident characteristics were generally similar across neighborhoods; however, poverty rates were higher in high- vs low-walkability areas. In 2001, the adjusted prevalence of overweight and obesity was lower in quintile 5 vs quintile 1 (43.3% vs 53.5%; P < .001). Between 2001 and 2012, the prevalence increased in less walkable neighborhoods (absolute change, 5.4% [95% CI, 2.1% 8.8%] in quintile 1, 6.7% [95% CI, 2.3%-11.1%] in quintile 2, and 9.2% [95% CI, 6.2%-12.1%] in quintile 3). The prevalence of overweight and obesity did not significantly change in areas of higher walkability (2.8% [95% CI, -1.4% to 7.0%] in quintile 4 and 2.1% [95% CI, -1.4% to 5.5%] in quintile 5). In 2001, the adjusted diabetes incidence was lower in quintile 5 than other quintiles and declined by 2012 from 7.7 to 6.2 per 1000 persons in quintile 5 (absolute change, -1.5 [95% CI, -2.6 to -0.4]) and 8.7 to 7.6 in quintile 4 (absolute change, -1.1 [95% CI, -2.2 to -0.05]). In contrast, diabetes incidence did not change significantly in less walkable areas (change, -0.65 in quintile 1 [95% CI, -1.65 to 0.39], -0.5 in quintile 2 [95% CI, -1.5 to 0.5], and -0.9 in quintile 3 [95% CI, -1.9 to 0.02]). Rates of walking or cycling and public transit use were significantly higher and that of car use lower in quintile 5 vs quintile 1 at each time point, although daily walking and cycling frequencies increased only modestly from 2001 to 2011 in highly walkable areas. Leisure-time physical activity, diet, and smoking patterns did not vary by walkability (P > .05 for quintile 1 vs quintile 5 for each outcome) and were relatively stable over time. CONCLUSIONS AND RELEVANCE: In Ontario, Canada, higher neighborhood walkability was associated with decreased prevalence of overweight and obesity and decreased incidence of diabetes between 2001 and 2012. However, the ecologic nature of these findings and the lack of evidence that more walkable urban neighborhood design was associated with increased physical activity suggest that further research is necessary to assess whether the observed associations are causal. PMID- 27218631 TI - Tinnitus. PMID- 27218632 TI - Persistent Rash in a Patient Receiving Total Parenteral Nutrition. PMID- 27218629 TI - Sodium Excretion and the Risk of Cardiovascular Disease in Patients With Chronic Kidney Disease. AB - IMPORTANCE: Patients with chronic kidney disease (CKD) are at an increased risk of cardiovascular disease (CVD) compared with the general population. Prior studies have produced contradictory results on the association of dietary sodium intake with risk of CVD, and this relationship has not been investigated in patients with CKD. OBJECTIVE: To evaluate the association between urinary sodium excretion and clinical CVD events among patients with CKD. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study of patients with CKD from 7 locations in the United States enrolled in the Chronic Renal Insufficiency Cohort Study and followed up from May 2003 to March 2013. EXPOSURES: The cumulative mean of urinary sodium excretion from three 24-hour urinary measurements and calibrated to sex-specific mean 24-hour urinary creatinine excretion. MAIN OUTCOMES AND MEASURES: A composite of CVD events defined as congestive heart failure, stroke, or myocardial infarction. Events were reported every 6 months and confirmed by medical record adjudication. RESULTS: Among 3757 participants (mean age, 58 years; 45% women), 804 composite CVD events (575 heart failure, 305 myocardial infarction, and 148 stroke) occurred during a median 6.8 years of follow-up. From lowest (<2894 mg/24 hours) to highest (>=4548 mg/24 hours) quartile of calibrated sodium excretion, 174, 159, 198, and 273 composite CVD events occurred, and the cumulative incidence was 18.4%, 16.5%, 20.6%, and 29.8% at median follow-up. In addition, the cumulative incidence of CVD events in the highest quartile of calibrated sodium excretion compared with the lowest was 23.2% vs 13.3% for heart failure, 10.9% vs 7.8% for myocardial infarction, and 6.4% vs 2.7% for stroke at median follow-up. Hazard ratios of the highest quartile compared with the lowest quartile were 1.36 (95% CI, 1.09-1.70; P = .007) for composite CVD events, 1.34 (95% CI, 1.03-1.74; P = .03) for heart failure, and 1.81 (95% CI, 1.08-3.02; P = .02) for stroke after multivariable adjustment. Restricted cubic spline analyses of the association between sodium excretion and composite CVD provided no evidence of a nonlinear association (P = .11) and indicated a significant linear association (P < .001). CONCLUSIONS AND RELEVANCE: Among patients with CKD, higher urinary sodium excretion was associated with increased risk of CVD. PMID- 27218633 TI - Elevated Hemoglobin or Hematocrit Level. PMID- 27218634 TI - Treatment Indications for Antidepressants Prescribed in Primary Care in Quebec, Canada, 2006-2015. PMID- 27218635 TI - Risk of Anaphylaxis With Intravenous Iron Products. PMID- 27218636 TI - Risk of Anaphylaxis With Intravenous Iron Products. PMID- 27218637 TI - Intended vs Reported Scope of Practice. PMID- 27218638 TI - Intended vs Reported Scope of Practice--Reply. PMID- 27218639 TI - Pimping as a Practice in Medical Education. PMID- 27218640 TI - Pimping as a Practice in Medical Education. PMID- 27218641 TI - Pimping as a Practice in Medical Education. PMID- 27218642 TI - Pimping as a Practice in Medical Education--Reply. PMID- 27218643 TI - Incorrect Data. PMID- 27218644 TI - Incorrect Wording in Recommendations. PMID- 27218645 TI - Pimping as a Practice in Medical Education--Reply. PMID- 27218647 TI - Science and Practical Common Sense. PMID- 27218648 TI - JAMA PATIENT PAGE. Chronic Kidney Disease. PMID- 27218649 TI - The 5q deletion size in myeloid malignancies is correlated to additional chromosomal aberrations and to TP53 mutations. AB - Deletions in the long arm of chromosome 5 (del(5q)) are recurrent abnormalities in myeloid malignancies. We analyzed del(5q) and accompanying molecular mutations in MDS, MPN and MDS/MPN cases. A high del(5q) frequency was revealed in MDS (1869/11398 cases; 16%), followed by MDS/MPN (37/1107; 3%) and MPN (97/6373; 2%). To investigate potential associations of the del(5q) size with the respective phenotypes, we applied array CGH analyses in selected cohorts of 61 MDS, 22 MDS/MPN and 23 MPN cases. The size varied between 16 and 119 Mb with no differences between the entities. However, MPN and MDS/MPN cases with del(5q) sole showed a significantly smaller del(5q) than cases with additional aberrations. Sequence analysis of 27 genes revealed >=1 mutation in 91% of patients. The highest mutation frequencies in the total cohort were observed for TP53 (31%), JAK2 (23%) and DNMT3A (18%). The molecular mutation patterns in the del(5q) cohorts were different between the entities but resembled known patterns of cohorts not selected for del(5q). Further, TP53 mutations were significantly more frequent in cases with a larger deletion size (P = 0.003). The results suggest a correlation of large del(5q) with TP53 mutations and with additional chromosomal aberrations possibly contributing to more severe courses of these cases. (c) 2016 Wiley Periodicals, Inc. PMID- 27218651 TI - MHD Flow and Heat Transfer between Coaxial Rotating Stretchable Disks in a Thermally Stratified Medium. AB - This paper investigates the unsteady MHD flow of viscous fluid between two parallel rotating disks. Fluid fills the porous space. Energy equation has been constructed by taking Joule heating, thermal stratification and radiation effects into consideration. We convert system of partial differential equations into system of highly nonlinear ordinary differential equations after employing the suitable transformations. Convergent series solutions are obtained. Behavior of different involved parameters on velocity and temperature profiles is examined graphically. Numerical values of skin friction coefficient and Nusselt number are computed and inspected. It is found that tangential velocity profile is increasing function of rotational parameter. Fluid temperature reduces for increasing values of thermal stratification parameter. At upper disk heat transfer rate enhances for larger values of Eckert and Prandtl numbers. PMID- 27218650 TI - Opposing Regulation of the EGF Receptor: A Molecular Switch Controlling Cytomegalovirus Latency and Replication. AB - Herpesviruses persist indefinitely in their host through complex and poorly defined interactions that mediate latent, chronic or productive states of infection. Human cytomegalovirus (CMV or HCMV), a ubiquitous beta-herpesvirus, coordinates the expression of two viral genes, UL135 and UL138, which have opposing roles in regulating viral replication. UL135 promotes reactivation from latency and virus replication, in part, by overcoming replication-suppressive effects of UL138. The mechanism by which UL135 and UL138 oppose one another is not known. We identified viral and host proteins interacting with UL138 protein (pUL138) to begin to define the mechanisms by which pUL135 and pUL138 function. We show that pUL135 and pUL138 regulate the viral cycle by targeting that same receptor tyrosine kinase (RTK) epidermal growth factor receptor (EGFR). EGFR is a major homeostatic regulator involved in cellular proliferation, differentiation, and survival, making it an ideal target for viral manipulation during infection. pUL135 promotes internalization and turnover of EGFR from the cell surface, whereas pUL138 preserves surface expression and activation of EGFR. We show that activated EGFR is sequestered within the infection-induced, juxtanuclear viral assembly compartment and is unresponsive to stress. Intriguingly, these findings suggest that CMV insulates active EGFR in the cell and that pUL135 and pUL138 function to fine-tune EGFR levels at the cell surface to allow the infected cell to respond to extracellular cues. Consistent with the role of pUL135 in promoting replication, inhibition of EGFR or the downstream phosphoinositide 3-kinase (PI3K) favors reactivation from latency and replication. We propose a model whereby pUL135 and pUL138 together with EGFR comprise a molecular switch that regulates states of latency and replication in HCMV infection by regulating EGFR trafficking to fine tune EGFR signaling. PMID- 27218652 TI - The Effect of Seasonal Ambient Temperatures on Fire-Stimulated Germination of Species with Physiological Dormancy: A Case Study Using Boronia (Rutaceae). AB - Dormancy and germination requirements determine the timing and magnitude of seedling emergence, with important consequences for seedling survival and growth. Physiological dormancy is the most widespread form of dormancy in flowering plants, yet the seed ecology of species with this dormancy type is poorly understood in fire-prone vegetation. The role of seasonal temperatures as germination cues in these habitats is often overlooked due to a focus on direct fire cues such as heat shock and smoke, and little is known about the combined effects of multiple fire-related cues and environmental cues as these are seldom assessed in combination. We aimed to improve understanding of the germination requirements of species with physiological dormancy in fire-prone floras by investigating germination responses across members of the Rutaceae from south eastern Australia. We used a fully factorial experimental design to quantify the individual and combined effects of heat shock, smoke and seasonal ambient temperatures on germination of freshly dispersed seeds of seven species of Boronia, a large and difficult-to-germinate genus. Germination syndromes were highly variable but correlated with broad patterns in seed morphology and phylogenetic relationships between species. Seasonal temperatures influenced the rate and/or magnitude of germination responses in six species, and interacted with fire cues in complex ways. The combined effects of heat shock and smoke ranged from neutral to additive, synergistic, unitive or negative and varied with species, seasonal temperatures and duration of incubation. These responses could not be reliably predicted from the effect of the application of single cues. Based on these findings, fire season and fire intensity are predicted to affect both the magnitude and timing of seedling emergence in wild populations of species with physiological dormancy, with important implications for current fire management practices and for population persistence under climate change. PMID- 27218653 TI - Correction: Assembly and relaxation behaviours of phosphatidylethanolamine monolayers investigated by polarization and frequency resolved SFG-VS. AB - Correction for 'Assembly and relaxation behaviours of phosphatidylethanolamine monolayers investigated by polarization and frequency resolved SFG-VS' by Feng Wei et al., Phys. Chem. Chem. Phys., 2015, 17, 25114-25122. PMID- 27218654 TI - Deepwater Chondrichthyan Bycatch of the Eastern King Prawn Fishery in the Southern Great Barrier Reef, Australia. AB - The deepwater chondrichthyan fauna of the Great Barrier Reef is poorly known and life history information is required to enable their effective management as they are inherently vulnerable to exploitation. The chondrichthyan bycatch from the deepwater eastern king prawn fishery at the Swain Reefs in the southern Great Barrier Reef was examined to determine the species present and provide information on their life histories. In all, 1533 individuals were collected from 11 deepwater chondrichthyan species, with the Argus skate Dipturus polyommata, piked spurdog Squalus megalops and pale spotted catshark Asymbolus pallidus the most commonly caught. All but one species is endemic to Australia with five species restricted to waters offshore from Queensland. The extent of life history information available for each species varied but the life history traits across all species were characteristic of deep water chondrichthyans with relatively large length at maturity, small litters and low ovarian fecundity; all indicative of low biological productivity. However, variability among these traits and spatial and bathymetric distributions of the species suggests differing degrees of resilience to fishing pressure. To ensure the sustainability of these bycatch species, monitoring of their catches in the deepwater eastern king prawn fishery is recommended. PMID- 27218655 TI - Epidemiology and Reporting Characteristics of Systematic Reviews of Biomedical Research: A Cross-Sectional Study. AB - BACKGROUND: Systematic reviews (SRs) can help decision makers interpret the deluge of published biomedical literature. However, a SR may be of limited use if the methods used to conduct the SR are flawed, and reporting of the SR is incomplete. To our knowledge, since 2004 there has been no cross-sectional study of the prevalence, focus, and completeness of reporting of SRs across different specialties. Therefore, the aim of our study was to investigate the epidemiological and reporting characteristics of a more recent cross-section of SRs. METHODS AND FINDINGS: We searched MEDLINE to identify potentially eligible SRs indexed during the month of February 2014. Citations were screened using prespecified eligibility criteria. Epidemiological and reporting characteristics of a random sample of 300 SRs were extracted by one reviewer, with a 10% sample extracted in duplicate. We compared characteristics of Cochrane versus non Cochrane reviews, and the 2014 sample of SRs versus a 2004 sample of SRs. We identified 682 SRs, suggesting that more than 8,000 SRs are being indexed in MEDLINE annually, corresponding to a 3-fold increase over the last decade. The majority of SRs addressed a therapeutic question and were conducted by authors based in China, the UK, or the US; they included a median of 15 studies involving 2,072 participants. Meta-analysis was performed in 63% of SRs, mostly using standard pairwise methods. Study risk of bias/quality assessment was performed in 70% of SRs but was rarely incorporated into the analysis (16%). Few SRs (7%) searched sources of unpublished data, and the risk of publication bias was considered in less than half of SRs. Reporting quality was highly variable; at least a third of SRs did not report use of a SR protocol, eligibility criteria relating to publication status, years of coverage of the search, a full Boolean search logic for at least one database, methods for data extraction, methods for study risk of bias assessment, a primary outcome, an abstract conclusion that incorporated study limitations, or the funding source of the SR. Cochrane SRs, which accounted for 15% of the sample, had more complete reporting than all other types of SRs. Reporting has generally improved since 2004, but remains suboptimal for many characteristics. CONCLUSIONS: An increasing number of SRs are being published, and many are poorly conducted and reported. Strategies are needed to help reduce this avoidable waste in research. PMID- 27218656 TI - Synthesis of 6-Trichloromethylphenanthridines by Transition Metal-Free Radical Cyclization of 2-Isocyanobiphenyls. AB - An efficient method for the synthesis of 6-trichloromethylphenanthridines by benzoyl peroxide promoted cyclization reaction of 2-isocyanobiphenyls with carbon tetrachloride is developed. A radical pathway is proposed and evidenced for the reaction mechanism. This reaction tolerates a wide range of functional groups and the resulting 6-trichloromethylphenanthridines can be utilized as a useful synthetic precursor for corresponding 6-substituted phenanthridines. PMID- 27218657 TI - The use of varenicline to treat nicotine dependence among patients with cancer. AB - BACKGROUND: Continuing to smoke after a cancer diagnosis can adversely influence the prognosis for patients with cancer. However, remarkably few studies have carefully examined the use of first-line FDA-approved medications for nicotine dependence in patients with cancer. This study evaluated the feasibility, safety, and effect on cessation of varenicline for smoking cessation in patients with cancer. METHODS: Data from 132 treatment-seeking smokers who received 12 weeks of open-label varenicline and five brief behavioral counseling sessions were used to evaluate the feasibility, safety, and impact on cessation of varenicline. The effects of abstinence on cognitive function and affect were also explored. RESULTS: Of 459 patients screened, 306 were eligible for the study (66.7%) and 132 entered treatment (43.1%). Retention was 84.1% over 12 weeks. The rate of biochemically verified abstinence at week 12 was 40.2%. Expected side effects were reported (e.g. sleep problems, nausea), but there were no reports of elevated depressed mood, suicidal thoughts, or cardiovascular events. Abstinence was associated with improved cognitive function and reduced negative affect over time (p < 0.05). CONCLUSIONS: Although many patients with cancer who smoke did not enroll in treatment, the side effect profile of varenicline and its effect on short-term cessation converge with what is seen in the general population. Further, as with the general population, abstinence while taking varenicline may lead to improved cognitive function and reduced negative affect. The present data support the use of varenicline to help patients with cancer to quit smoking. PMID- 27218658 TI - High mortality in diabetic recipients of high KDPI deceased donor kidneys. AB - BACKGROUND: Deceased donor (DD) kidney quality is determined by calculating the Kidney Donor Profile Index (KDPI). Optimizing high KDPI (>=85%) DD transplant outcome is challenging. This retrospective study was performed to review our high KDPI DD transplant results to identify clinical practices that can improve future outcomes. METHODS: We retrospectively calculated the KDPI for 895 DD kidney recipients transplanted between 1/2002 and 11/2013. Age, race, body mass index (BMI), retransplantation, gender, diabetes (DM), dialysis time, and preexisting coronary artery disease (CAD) (previous myocardial infarction (MI), coronary artery bypass (CABG), or stenting) were determined for all recipients. RESULTS: About 29.7% (266/895) of transplants were from donors with a KDPI >=85%. By Cox regression older age, diabetes, female gender, and dialysis time >4 years correlated with shorter patient survival time. Diabetics with CAD who received a high KDPI donor kidney had a significantly increased risk of death (HR 4.33 (CI 1.82-10.30), P=.001) compared to low KDPI kidney recipients. The Kaplan-Meier survival curve for diabetic recipients of high KDPI kidneys was significantly worse if they had preexisting CAD (P<.001 by log-rank test). CONCLUSION: Patient survival using high KDPI donor kidneys may be improved by avoiding diabetic candidates with preexisting CAD. PMID- 27218659 TI - Nation Binding: How Public Service Broadcasting Mitigates Political Selective Exposure. AB - Recent research suggests that more and more citizens select news and information that is congruent with their existing political preferences. This increase in political selective exposure (PSE) has allegedly led to an increase in polarization. The vast majority of studies stem from the US case with a particular media and political system. We contend that there are good reasons to believe PSE is less prevalent in other systems. We test this using latent profile analysis with national survey data from the Netherlands (n = 2,833). We identify four types of media use profiles and indeed only find partial evidence of PSE. In particular, we find that public broadcasting news cross-cuts all cleavages. This research note offers an important antidote in what is considered a universal phenomenon. We do find, however, a relatively large segment of citizens opting out of news consumption despite the readily available news in today's media landscape. PMID- 27218660 TI - Epigenetic modifications: mechanisms of disease and biomarkers of food allergy. AB - The rise in IgE-mediated food allergy in recent times is the likely result of gene-environment interactions mediated via epigenetic pathways. As epigenetic modifications, including DNA methylation, are at the interface between the environment and the genome, they may be ideal biomarkers of modifiable disease pathways. High-throughput methylation profiling of immune cell subtypes or whole blood from patients allows the identification of disease specific epigenetic variants. If faithfully tracking with disease parameters, these 'signatures' may have clinical applications as biomarkers of disease or therapeutic response. Development of such tools will depend on a number of factors, including determining the most appropriate experimental approach, analysis methodology, patient groups, and informative target cells/tissues. Here we discuss these potential applications and their implications for food allergy practise. PMID- 27218661 TI - A powerful non-pharmacologic treatment for mania - virtually. PMID- 27218662 TI - Endoscopic treatment of Zenker's diverticulum with the stag beetle knife (sb knife) - feasibility and follow-up. AB - BACKGROUND AND AIMS: Flexible endoscopic treatment of symptomatic Zenker's diverticulum (ZD) is an established treatment option. This study reports the first large cohort of ZD patients treated with the stag beetle knife (sb knife, a new scissor-like device) regarding feasibility, safety, and sustainability of mucomyotomy using this technique. METHODS: From August 2013 to January 2016, n = 52 patients (pts) were treated at Klinikum Augsburg, a tertiary referral center, with the sb knife junior or standard. For stability and safety, the septum is fixed with a soft overtube before intervention. Symptoms were analyzed before and at 1 and 6 months past intervention using an extensive questionnaire of dysphagia, odynophagia, regurgitation, chronic cough, state of health, and complications. RESULTS: The mean size of ZD was 3 cm (1-5 cm). Forty-seven out of 52 (90.4%) patients received one treatment session. The mean procedure time was 32 min (18-60 min). In 10 procedures (17%), a clip was placed at the bottom of the resection line. No major complications (e.g., perforation, mediastinitis) occurred. Five patients (9.6%) required a second treatment after a mean of 7 months (3-13) due to symptomatic recurrence. One patient was lost to further follow-up after one month with no or rare complaints. One patient had a third treatment (1.9%) without complications. During a mean follow-up of 16 months (2 31), the dysphagia score improved from 2 (1-4) prior of treatment to 1 (0-4), odynophagia, regurgitation, and chronic cough were no longer reported in the asymptomatic patients at all. CONCLUSIONS: Flexible endoscopic treatment of ZD with the sb knife and overtube is effective, safe, and has lasting effects with a relatively low recurrence rate. PMID- 27218663 TI - Roles of FGFR in oral carcinogenesis. AB - Fibroblast growth factor receptors (FGFRs) play essential roles in organ development during the embryonic period, and regulate tissue repair in adults. Accumulating evidence suggests that alterations in FGFR signalling are involved in diverse types of cancer. In this review, we focus on aberrant regulation of FGFRs in pathogenesis of oral squamous cell carcinoma (OSCC), including altered expression and subcellular location, aberrant isoform splicing and mutations. We also provide an overview of oncogenic roles of each FGFR and its downstream signalling pathways in regulating OSCC cell proliferation and metastasis. Finally, we discuss potential application of FGFRs as anti-cancer targets in the preclinical environment and in clinical practice. PMID- 27218664 TI - Cell-free microRNAs in blood and other body fluids, as cancer biomarkers. AB - The discovery of cell-free microRNAs (miRNAs) in serum, plasma and other body fluids has yielded an invaluable potential source of non-invasive biomarkers for cancer and other non-malignant diseases. miRNAs in the blood and other body fluids are highly stable in biological samples and are resistant to environmental conditions, such as freezing, thawing or enzymatic degradation, which makes them convenient as potential biomarkers. In addition, they are more easily sampled than tissue miRNAs. Altered levels of cell-free miRNAs have been found in every type of cancer analysed, and increasing evidence indicates that they may participate in carcinogenesis by acting as cell-to-cell signalling molecules. This review summarizes the biological characteristics and mechanisms of release of cell-free miRNAs that make them promising candidates as non-invasive biomarkers of cancer. PMID- 27218665 TI - miR-375 controls porcine pancreatic stem cell fate by targeting 3 phosphoinositide-dependent protein kinase-1 (Pdk1). AB - OBJECTIVES: miR-375 is one of the highly expressed microRNAs (miRNAs) found in pancreatic islets of both humans and mice. In this study, we investigated functions of miRNA miR-375 in porcine pancreatic stem cells (PSC). MATERIALS AND METHODS: We transfected mimic and inhibitor of miR-375 in PSCs to measure functional roles of the microRNA and its effects on cell cycle proliferation and cell differentiation were determined. Luciferase assays were also performed to reveal the target gene of miR-375. RESULTS: Overexpression of miR-375 suppressed proliferation, promoted apoptosis and inhibited differentiation into islet-like cells. PDK1 was identified as being a target of miR-375. Furthermore, we found that overexpression of miR-375 inhibited activation of the PDK1-AKT signalling pathway. CONCLUSION: miR-375 directly targeted PDK1 in porcine PSCs, suppressing cell proliferation and differentiation into islet-like cells. PMID- 27218666 TI - Ex vivo sentinel lymph node mapping in colorectal cancer using a magnetic nanoparticle tracer to improve staging accuracy: a pilot study. AB - AIM: Nodal status is the most important prognostic factor in colorectal cancer (CRC). Small occult metastases may remain undetected on conventional histopathological examination, potentially resulting in undertreatment. Ex vivo sentinel lymph node mapping (SLNM) can be used to improve the accuracy of nodal staging, but the currently used tracers suffer from drawbacks, which hamper implementation of the technique in routine clinical practice. Magnetic tracers are the optimal size for sentinel lymph node (SLN) retention and allow objective quantitative selection of SLNs; they therefore have great potential for SLNM in CRC. The study evaluates the feasibility of ex vivo magnetic SLNM and compares the performance of this technique with blue dye SLNM. METHOD: Twenty-eight ex vivo SLNM procedures were performed in 27 histological node-negative patients with CRC using a magnetic tracer and blue dye. A magnetometer was used to select magnetic SLNs after formalin fixation of the CRC specimen. Both magnetic and blue SLNs were subjected to serial sectioning and immunohistochemical staining to reveal occult metastases. RESULTS: At least one SLN was successfully identified in 27/28 (96%) and 25/28 (89%) of the cases with the magnetic technique and blue dye. Isolated tumour cells were detected in 10 patients. This was predicted with 100% sensitivity and accuracy using the magnetic technique, and with 91% sensitivity and 96% accuracy using the blue dye technique. CONCLUSION: This study demonstrates that ex vivo magnetic SLNM is a feasible technique for use in routine clinical practice, improving nodal staging accuracy of CRC patients. PMID- 27218667 TI - Simulation-based evaluation of the performance of the F test in a linear multilevel model setting with sparseness at the level of the primary unit. AB - In a linear multilevel model, significance of all fixed effects can be determined using F tests under maximum likelihood (ML) or restricted maximum likelihood (REML). In this paper, we demonstrate that in the presence of primary unit sparseness, the performance of the F test under both REML and ML is rather poor. Using simulations based on the structure of a data example on ceftriaxone consumption in hospitalized children, we studied variability, type I error rate and power in scenarios with a varying number of secondary units within the primary units. In general, the variability in the estimates for the effect of the primary unit decreased as the number of secondary units increased. In the presence of singletons (i.e., only one secondary unit within a primary unit), REML consistently outperformed ML, although even under REML the performance of the F test was found inadequate. When modeling the primary unit as a random effect, the power was lower while the type I error rate was unstable. The options of dropping, regrouping, or splitting the singletons could solve either the problem of a high type I error rate or a low power, while worsening the other. The permutation test appeared to be a valid alternative as it outperformed the F test, especially under REML. We conclude that in the presence of singletons, one should be careful in using the F test to determine the significance of the fixed effects, and propose the permutation test (under REML) as an alternative. PMID- 27218668 TI - Screening for eating disorders in outpatient smoking cessation: Feasibility, pertinence, and acceptance of referral to specific treatment. AB - OBJECTIVE: To estimate (1) the feasibility and pertinence of implementing systematic screening for eating disorders (EDs) in outpatient smoking cessation (SC), and (2) the acceptance of a referral to ED-specific treatment. METHODS: Tobacco smokers (N = 203) who consecutively underwent the initial assessment of a SC program were screened for an ED. Screen-positive patients were administered the Mini International Neuropsychiatric Interview and received a referral to ED specific treatment using brief advice when identified with a current ED. RESULTS: Among the total sample, the prevalence of a current ED at baseline was 8.9% (men: 1/109, 0.9%; women: 17/94, 18.1%). The acceptance rate of referral to ED-specific treatment was 17%, whereas having a current ED at baseline was significantly associated with a higher probability of dropping out of the SC program at 4 weeks (OR = 21.8, 95%CI: 3.0-161.2, P = 0.003). DISCUSSION: Screening for EDs in outpatient SC seems worthwhile and easily implementable, but patients who are identified with a current ED might not be prone to accept referral to specific treatment and tend to drop out early. This study underlines the need to explore this topic in larger clinical samples. (c) 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:1018-1022). PMID- 27218669 TI - Immunomodulatory effects of natural polysaccharides assessed in human whole blood culture and THP-1 cells show greater sensitivity of whole blood culture. AB - Immunomodulatory drugs are available to maintain immune homeostasis but some have undesirable side effects. Six oligo- and poly-saccharides were assessed for their pro- and anti-inflammatory responses in two in vitro model systems, the monocytic THP-1 cell line and human whole blood cultures (HWBC). The compounds were first characterised for their molecular mass and physical properties. Following incubation with lipopolysaccharide (LPS) or the compounds, cytokine and chemokine secretion was assayed in both models and intracellular TNF-alpha was measured by flow cytometry in HWBC cell sub-populations. LPS, inulin, galacturonan, heteroglycan and fucoidan demonstrated pro-inflammatory properties and intracellular TNF-alpha expression was increased in the monocytes of HWBC. Mannan and xyloglucan did not elicit any significant responses. Inulin induced maximum cytokine secretion and heteroglycan induced maximum chemokine secretion in HWBC. This study emphasises the potential of inulin and heteroglycan as potential immunomodulatory therapeutics and that HWBC had a greater and more varied response in comparison to THP-1 cells. PMID- 27218670 TI - Molecular and Functional Characterization of Rare CACNA1C Variants in Sudden Unexplained Death in the Young. AB - INTRODUCTION: Perturbations in the CACNA1C-encoded L-type calcium channel alpha subunit have been linked recently to heritable arrhythmia syndromes, including Timothy syndrome, Brugada syndrome, early repolarization syndrome, and long QT syndrome. These heritable arrhythmia syndromes may serve as a pathogenic basis for autopsy-negative sudden unexplained death in the young (SUDY). However, the contribution of CACNA1C mutations to SUDY is unknown. OBJECTIVE: We set out to determine the spectrum, prevalence, and pathophysiology of rare CACNA1C variants in SUDY. METHODS: Mutational analysis of CACNA1C was conducted in 82 SUDY cases using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct sequencing. Identified variants were engineered using site-directed mutagenesis, and heterologously expressed in TSA-201 or HEK293 cells. RESULTS: Two SUDY cases (2.4%) harbored functional variants in CACNA1C. The E850del and N2091S variants involve highly conserved residues and localize to the II-III linker and C-terminus, respectively. Although observed in publically available exome databases, both variants confer abnormal CaV 1.2 electrophysiological characteristics. Examination of the electrophysiological properties revealed the E850del mutation in CACNA1C led to a 95% loss-of-function in ICa , and the N2091S variant led to a 105% gain-of-function in ICa. Additionally, N2091S led to minor kinetic alterations including a -3.4 mV shift in V1/2 of activation. CONCLUSION: This study provides molecular and functional evidence that rare CACNA1C genetic variants may contribute to the underlying pathogenic basis for some cases of SUDY in either a gain or loss-of-function mechanism. PMID- 27218671 TI - The Intersection of GERD, Aspiration, and Lung Transplantation. AB - Lung transplantation is a radical but life-saving treatment option for patients with end-stage lung diseases, such as idiopathic pulmonary fibrosis (IPF) and scleroderma. In light of the proposed association and controversy linking gastroesophageal reflux disease (GERD) to IPF and lung transplant outcome, the American Gastroenterological Association convened during the DDW in Washington in May 2015 a multidisciplinary group of experts in the field of GERD and lung transplantation to make considerations about the care of these patients based on available data and subsequent expert panel discussion at this symposium. The following topics were discussed: (1) pathophysiology of GERD-induced pulmonary symptoms, (2) GERD evaluation before and after lung transplantation, (3) outcome of lung transplantation for IPF and scleroderma, and (4) role of laparoscopic fundoplication before or after lung transplantation. PMID- 27218672 TI - Endovascular treatment of Budd-Chiari syndrome: Single center experience. AB - BACKGROUND AND AIM: Percutaneous radiologic interventions are increasingly being used in management of Budd-Chiari syndrome (BCS). Minimal invasive approach has resulted in excellent long-term outcomes. We evaluated the treatment efficacy and safety of radiological intervention in patients with BCS. METHODS: Between January 2008 and June 2014, 190 patients with BCS underwent endovascular procedures (hepatic vein, collateral vein or inferior vena cava [IVC] plasty with or without stenting, or transjugular intrahepatic portosystemic shunting [TIPSS]). Clinical features, biochemical profile, and stent patency were monitored pre-procedure and post-procedure, and for a median duration of 42 (12 88) months. RESULTS: Of 190 patients (mean [SD] age = 26.9 [11.5] years; 102 men), imaging revealed hepatic vein obstruction in 147 patients, IVC obstruction in 40 patients, and concomitant hepatic vein and IVC obstruction in three patients. At presentation, the radiological interventions included hepatic vein plasty/stenting in 38 patients, collateral vein stenting in three patients, IVC plasty/stenting in 40 patients, both IVC and hepatic vein stenting in three patients, and TIPSS in 106 patients. Response was seen in 153 patients (80.5%). Repeat interventions were required in 19 patients (10.0%). Complications were noted in nine patients (4.7%). CONCLUSION: Our study demonstrates that venous recanalization and TIPSS for BCS are safe and efficacious. PMID- 27218673 TI - Communicating Health at Work: Organizational Wellness Programs as Identity Bridges. AB - With the growth in workplace health promotion (WHP) initiatives, organizations are asking employees to enact their personal health identities at work. To understand this prominent yet poorly understood phenomenon, we surveyed 204 employees at a company with a WHP program and found that participation in the wellness program mediated personal health and organizational identities. Results fill a gap in communication literature by demonstrating the effect of individual identity enactment on organizational identification and contribute to recent research stressing the relationship between identity and health behaviors. In addition, findings illuminate the role of situated activity in identity negotiation, suggesting that certain activities in organizations, like wellness programs, serve as identity bridges between personal and work-related identity targets. PMID- 27218674 TI - In Vivo Pharmacokinetics/Pharmacodynamics of Cefquinome in an Experimental Mouse Model of Staphylococcus Aureus Mastitis following Intramammary Infusion. AB - Staphylococcus aureus remains the major cause of morbidity of bovine mastitis worldwide leading to massive economic losses. Cefquinome is a fourth generation cephalosporin, which preserves susceptibility and antibacterial activity against S. aureus. This work aims to study the pharmacokinetic (PK) and pharmacodynamic (PD) modeling following intramammary administration of cefquinome against S. aureus mastitis. The mouse model of S. aureus mastitis was developed for the PK/PD experiments. The plasma PK characteristics after intramammary injection of cefquinome at various single doses of 25, 50, 100, 200, 400 MUg per gland (both fourth pairs of glands: L4 and R4) were calculated using one-compartment and first-order absorption model. PD study was investigated based on twenty-one intermittent dosing regimens, of which total daily dose ranged from 25 to 4800 MUg per mouse and dosage intervals included 8, 12 or 24 h. The sigmoid Emax model of inhibitory effect was employed for PK/PD modeling. The results of PK/PD integration of cefquinome against S. aureus suggested that the percentage of duration that drug concentration exceeded the minimal inhibitory concentration (%T>MIC) and the ratio of area under time-concentration curve over MIC (AUC/MIC) are important indexes to evaluate the antibacterial activity. The PK/PD parameters of %T>MIC and AUC0-24/MIC were 35.98% and 137.43 h to obtain a 1.8 logCFU/gland reduction of bacterial colony counts in vivo, against S. aureus strains with cefquinome MIC of 0.5MUg/ml. PMID- 27218675 TI - Phosphine-Catalyzed [3 + 3]-Domino Cycloaddition of Ynones and Azomethine Imines To Construct Functionalized Hydropyridazine Derivatives. AB - The first phosphine-catalyzed [3 + 3]-domino annulation reaction of ynones and azomethine imines has been developed. With this simple and efficient method, the functionalized hydropyridazine derivatives were obtained in good to excellent yields with highly stereoselectivies. PMID- 27218677 TI - Collision-Induced Dissociation of Electrosprayed Protein Complexes: An All-Atom Molecular Dynamics Model with Mobile Protons. AB - Electrospray ionization mass spectrometry (ESI-MS) has become an indispensable technique for examining noncovalent protein complexes. Collision-induced dissociation (CID) of these multiply protonated gaseous ions usually culminates in ejection of a single subunit with a disproportionately large amount of charge. Experiments suggest that this process involves subunit unfolding prior to separation from the residual complex, as well as H(+) migration onto the unravelling chain. Molecular dynamics (MD) simulations are a promising avenue for gaining detailed insights into these CID events. Unfortunately, typical MD algorithms do not allow for mobile protons. Here we address this limitation by implementing a strategy that combines atomistic force fields (such as OPLS/AA and CHARMM36) with a proton hopping algorithm, focusing on the tetrameric complexes transthyretin and streptavidin. Protons are redistributed over all acidic and basic sites in 20 ps intervals, subject to an energy function that reflects electrostatic interactions and proton affinities. Our simulations predict that nativelike conformers at the onset of collisional heating contain multiple salt bridges. Collisional heating initially causes subtle structural changes that lead to a gradual decline of these zwitterionic patterns. Many of the MD runs show gradual unfolding of a single subunit in conjunction with H(+) migration, culminating in subunit separation from the complex. However, there are also instances where two or more chains start to unfold simultaneously, giving rise to charge competition. The scission point where the "winning" subunit separates from the complex can be attained for different degrees of unfolding, giving rise to product ions in various charge states. The simulated product ion distributions are in close agreement with experimental CID data. Proton enrichment in the departing subunit is driven by charge-charge repulsion, but the combination of salt bridge depletion, charge migration, and proton affinity causes surprising compensation effects among the various energy terms. It appears that this work provides the most detailed account to date of the mechanism whereby noncovalent protein complexes disassemble during CID. PMID- 27218676 TI - Randomised clinical trial: a phase 1, dose-ranging study of the anti-matrix metalloproteinase-9 monoclonal antibody GS-5745 versus placebo for ulcerative colitis. AB - BACKGROUND: Matrix metalloproteinase-9 is a proteolytic enzyme whose expression is increased in ulcerative colitis. AIM: To evaluate the safety and efficacy of GS-5745, a fully humanised anti-matrix metalloproteinase-9 monoclonal antibody, in moderately-to-severely active ulcerative colitis. METHODS: We randomised 74 patients with ulcerative colitis to treatment with single or multiple ascending intravenous or subcutaneous doses of GS-5745 or placebo. Multiple-dose cohorts received either IV infusions (0.3, 1.0, 2.5 or 5.0 mg/kg GS-5745 or placebo) every 2 weeks (three total IV infusions) or five weekly SC injections (150 mg GS 5745 or placebo). The primary outcomes were the safety, tolerability and pharmacokinetics of escalating single and multiple doses of GS-5745. Exploratory analyses in the multiple-dose cohorts included clinical response (>=3 points or 30% decrease from baseline in Mayo Clinic score and >=1 point decrease in the rectal bleeding subscore or a rectal bleeding subscore <=1) and clinical remission (a complete Mayo Clinic score <=2 with no subscore >1) at Day 36. Biological effects associated with a clinical response to GS-5745 were explored using histological and molecular approaches. RESULTS: Twenty-three of the 42 patients (55%) receiving multiple doses of GS-5745 had adverse events, compared with 5/8 patients (63%) receiving placebo. GS-5745 showed target-mediated drug disposition, approximately dose-proportional increases in maximum plasma concentration and more than dose-proportional increases in the area under the plasma drug concentration-time curve. Clinical response occurred in 18/42 patients (43%) receiving GS-5745 compared with 1/8 patients (13%) receiving placebo. Clinical remission occurred in 6/42 patients (14%) receiving GS-5745 and 0/8 (0%) receiving placebo. Patients with a clinical response to GS-5745 had reductions in matrix metalloproteinase-9 tissue levels (mean 48.9% decrease from baseline compared with a mean 18.5% increase in nonresponders, P = 0.008) significant improvements in histopathology scores (confirmed with three separate histological disease activity indices), as well as changes in colonic gene expression that were consistent with reduced inflammation. CONCLUSION: This phase 1 trial provides preliminary evidence for the safety and therapeutic potential of GS-5745 in the treatment of ulcerative colitis. PMID- 27218678 TI - Medication-assisted treatment for substance use disorders within a national community health center research network. AB - BACKGROUND: The Affordable Care Act increases access to treatment services for people who suffer from substance use disorders (SUDs), including alcohol use disorders (AUDs) and opioid use disorders (OUDs). This increased access to treatment has broad implications for delivering health services and creates a dramatic need for transformation in clinical care, service lines, and collaborative care models. Medication-assisted treatments (MAT) are effective for helping SUD patients reach better outcomes. This article uses electronic health record (EHR) data to examine the prevalence of EHR-documented SUDs, patient characteristics, and patterns of MAT prescribing and screening for patients within the Community Health Applied Research Network (CHARN), a national network of 17 community health centers that facilitates patient-centered outcomes research among underserved populations. METHODS: Hierarchical generalized linear models examined patient characteristics, SUD occurrence rates, MAT prescription, and human immunodeficiency virus (HIV) and hepatitis virus C screening for patients with AUDs or OUDs. Results: Among 572,582 CHARN adult patients, 16,947 (3.0%) had a documented AUD diagnosis and 6,080 (1.1%) an OUD diagnosis. Alcohol MAT prescriptions were documented for 547 AUD patients (3.2%) and opioid MAT for 1,764 OUD patients (29.0%). Among OUD patients, opioid MAT was significantly associated with HIV screening (odds ratio [OR] = 1.31, P < .001) in OUD patients, as was alcohol MAT among AUD patients (OR = 1.30, P = .013). CONCLUSIONS: These findings suggest that effective opioid and alcohol MAT may be substantially underprescribed among safety-net patients identified as having OUDs or AUDs. PMID- 27218679 TI - A Surface-Confined Proton-Driven DNA Pump Using a Dynamic 3D DNA Scaffold. AB - A proton-driven molecular pump is devised using a surface-confined dynamic 3D DNA scaffold. A dynamic DNA tetrahedral nanostructure is designed by incorporating a pH-sensitive i-motif sequence in one edge, which serves as the scaffold to ensure highly ordered orientation and spatial isolation of this nanomachine on the macroscopic gold surface. It is found that the switching ability of this dynamic tetrahedron is fully maintained on the surface. Importantly, this proton-driven nanomachine can reversibly pump water and ferricynide in response to pH variation in solution. PMID- 27218680 TI - Serum amyloid A1 levels and amyloid deposition following a high-fat diet challenge in transgenic mice overexpressing hepatic serum amyloid A1. AB - Serum amyloid A (SAA) is an acute-phase response protein in the liver, and SAA1 is the major precursor protein involved in amyloid A amyloidosis. This amyloidosis has been reported as a complication in chronic inflammatory conditions such as arthritis, lupus, and Crohn's disease. Obesity is also associated with chronic, low-grade inflammation and sustained, elevated levels of SAA1. However, the contribution of elevated circulating SAA1 to metabolic disturbances and their complications is unclear. Furthermore, in several recent studies of transgenic (TG) mice overexpressing SAA1 that were fed a high-fat diet (HFD) for a relatively short period, no relationship was found between SAA1 up regulation and metabolic disturbances. Therefore, we generated TG mice overexpressing SAA1 in the liver, challenged these mice with an HFD, and investigated the influence of elevated SAA1 levels. Sustained, elevated levels of SAA1 were correlated with metabolic parameters and local cytokine expression in the liver following 16 weeks on the HFD. Moreover, prolonged consumption (52 weeks) of the HFD was associated with impaired glucose tolerance and elevated SAA1 levels and resulted in systemic SAA1-derived amyloid deposition in the kidney, liver, and spleen of TG mice. Thus, we concluded that elevated SAA1 levels under long-term HFD exposure result in extensive SAA1-derived amyloid deposits, which may contribute to the complications associated with HFD-induced obesity and metabolic disorders. PMID- 27218682 TI - Clinical trials in transcatheter aortic valve replacement. AB - PURPOSE OF REVIEW: Clinical trials in transcatheter aortic valve replacement (TAVR) have been essential in establishing the effectiveness as well as the limitations of this exciting and disruptive technology. This review will focus on clinical trials related to TAVR that have been presented in the past year or are currently enrolling, as well as future trials that are in the planning stages. RECENT FINDINGS: The currently available devices have gone through iterations to improve safety and outcomes, including lower profiles to reduce bleeding complications as well as adding a sealing skirt or allowing for re-positioning in order to decrease para-valvular regurgitation and need for a permanent pacemaker. The intermediate-risk clinical trials will be finishing soon and will be followed by low-risk trials. Ancillary devices will likely continue to expand the access to this therapy. One of the main challenges moving forward will be the post-TAVR pharmacotherapy. SUMMARY: Recently, improvements in first-generation devices have led to improved outcomes. Current trials evaluating novel TAVR platforms and lower risk patients as well as ancillary devices will likely continue to expand the access to this therapy. PMID- 27218683 TI - IMPROVE-IT: what have we learned? AB - PURPOSE OF REVIEW: Recent studies and dyslipidemia treatment guidelines indicate that combination lipid-lowering therapy is frequently needed and its use has increased in recent years. Ezetimibe and simvastatin as a fixed dose is an efficacious treatment choice based on positive results of the recent IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT). In this review, we discuss recent controversies surrounding ezetimibe and provide clinical perspective on the results of the IMPROVE-IT study. RECENT FINDINGS: IMPROVE-IT is the first trial that demonstrates a significant clinical benefit of a nonstatin hypolipidemic agent (ezetimibe) used in combination with statin (simvastatin) therapy in patients who have experienced an acute coronary syndrome. For almost a decade, the use of ezetimibe was limited by a relative lack of definitive evidence. However, the most recent Plaque Regression With Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound study showed greater coronary plaque regression by statin/ezetimibe combination compared with statin monotherapy. The results of the IMPROVE-IT trial are fostering new debate about the value of adjunctive low density lipoprotein cholesterol lowering over and above a statin. SUMMARY: Ezetimibe/simvastatin combination, either as a single pill or as the combined use of the individual compounds, represents a well-tolerated and efficacious choice for dyslipidemia treatment in high-risk subjects, including patients with diabetes. Limited additional risk for adverse events compared with simvastatin monotherapy is observed, and an individualized, patient-centered approach to therapy is recommended. PMID- 27218681 TI - Developmentally Sensitive Interaction Effects of Genes and the Social Environment on Total and Subcortical Brain Volumes. AB - Smaller total brain and subcortical volumes have been linked to psychopathology including attention-deficit/hyperactivity disorder (ADHD). Identifying mechanisms underlying these alterations, therefore, is of great importance. We investigated the role of gene-environment interactions (GxE) in interindividual variability of total gray matter (GM), caudate, and putamen volumes. Brain volumes were derived from structural magnetic resonance imaging scans in participants with (N = 312) and without ADHD (N = 437) from N = 402 families (age M = 17.00, SD = 3.60). GxE effects between DAT1, 5-HTT, and DRD4 and social environments (maternal expressed warmth and criticism; positive and deviant peer affiliation) as well as the possible moderating effect of age were examined using linear mixed modeling. We also tested whether findings depended on ADHD severity. Deviant peer affiliation was associated with lower caudate volume. Participants with low deviant peer affiliations had larger total GM volumes with increasing age. Likewise, developmentally sensitive GxE effects were found on total GM and putamen volume. For total GM, differential age effects were found for DAT1 9-repeat and HTTLPR L/L genotypes, depending on the amount of positive peer affiliation. For putamen volume, DRD4 7-repeat carriers and DAT1 10/10 homozygotes showed opposite age relations depending on positive peer affiliation and maternal criticism, respectively. All results were independent of ADHD severity. The presence of differential age-dependent GxE effects might explain the diverse and sometimes opposing results of environmental and genetic effects on brain volumes observed so far. PMID- 27218684 TI - Mortality in isodicentric chromosome 15 syndrome: The role of SUDEP. AB - PURPOSE: To ascertain the cause of mortality and incidence of sudden unexpected death in epilepsy (SUDEP) in patients with supernumerary isodicentric chromosome 15 (idic15). METHODS: Cases were obtained from those reported to the Dup15q Alliance (www.dup15q.org) between April 2006 and June 2012; ~709 families were registered in their database. We performed a case-control study comparing reported SUDEP cases to living patients with epilepsy from the Dup15q Alliance registry who volunteered to be interviewed to examine clinical risk factors. KEY FINDINGS: There were nineteen deaths with idic15; 17 had epilepsy, and nine deaths were due to probable or definite SUDEP (4 females, median age of death was 13.5years, range: 3-26years). Possible SUDEP occurred in 2 others. The remainder died from status epilepticus (3), pneumonia (3), aspiration (1), and drowning (1). Nonambulatory status and lack of seizure control were more common among SUDEP cases than living dup15q patients. SIGNIFICANCE: Our findings suggest that SUDEP is a common cause of death among children and young adults with isodicentric chromosome 15q11.2q13 duplications and patients with the most severe neurologic dysfunction may be at highest risk. Further studies are needed to examine if this specific genetic defect plays a role in the mechanism of SUDEP in these patients. PMID- 27218685 TI - Association between maternal socioeconomic factors and nutritional outcomes in children under 5 years of age. AB - OBJECTIVE: To estimate the association between maternal socioeconomic factors and the occurrence of nutritional outcomes in children under five years of age in a representative sample of the Brazilian population. METHODS: This was a cross sectional study that evaluated data from the latest National Survey of Children and Women's Demographics and Health, carried out in Brazil in 2006-2007. Maternal employment and maternal level of schooling were the main exposures. The following nutritional outcomes in children were considered: height/age <-2 standard deviations (SD) for short stature and BMI/age >2SD for overweight. Generalized estimating equations (GEE) were utilized as the regression method. RESULTS: After adjustments, it was observed that children whose mothers had low level of schooling had a higher chance of having short stature (OR=3.97, 95% CI, 1.23 12.80) and children whose mothers worked outside the home were more likely to have excess weight (OR=1.57, 95% CI, 1.02-2.42). Maternal employment was not associated with short stature in children (OR=1.09, 95% CI, 0.67-1.77). CONCLUSION: Maternal level of schooling was associated with short stature in children and maternal employment with overweight, indicating the need to take into account the socioeconomic factors when proposing programs and strategies aimed at health and nutrition improvement of children, considering inter-sectoral interventions. PMID- 27218686 TI - The influence of sampled biomass on species-area relationships of grassland plants. PMID- 27218687 TI - Obstructive Sleep Apnea and Diabetic Nephropathy. AB - Obstructive sleep apnea (OSA), a condition with important implications for hypertension, diabetes, and cardiovascular disease, has been less researched for diabetes-associated microvascular disease. Such research is particularly important for developing countries (in particular, China and India), which are showing rapidly increasing prevalence of obesity, diabetes, and diabetic nephropathy (DN). In particular, independent association between OSA and DN needs more research inputs, keeping commonalty of risk factor profile for both diseases in mind. Finally, although weight loss remains the most effective strategy for OSA and also to some extent for DN, whether treatment with continuous positive airway pressure improves DN, similar to its positive effects on insulin resistance and glucose metabolism, remains to be established. PMID- 27218688 TI - In Vivo Bone-Targeting of Bis(phosphonate)-Conjugated Double Helical RNA Monitored by Positron Emission Tomography. AB - A bis(phosphonate) conjugate of 2'-O-methyl oligoribonucleotide (microRNA-21) was synthesized and used as a bone-targeting carrier in the systemic delivery of a (68)Ga-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)-chelated 2'-O-methyl oligoribonucleotide (anti-microRNA-21). The whole-body biodistribution of the double helical RNA was monitored by positron emission tomography (PET), which verified the expected bis(phosphonate)-induced bone accumulation in healthy rats. PMID- 27218689 TI - Synergistic Effects between Biogenic Ligands and a Reductant in Fe Acquisition from Calcareous Soil. AB - Organisms have developed different strategies to cope with environmental conditions of low Fe availability based on the exudation of reducing, ligating, and acidifying compounds. In the context of Fe acquisition from soil, the effects of these reactive compounds have generally been considered independent and additive. However, highly efficient Fe acquisition strategies may rely on synergistic effects between reactive exudates. In the present study, we demonstrate that synergistic effects between biogenic ligands and a reductant (ascorbate) can occur in Fe mobilization from soil. Synergistic Fe mobilization was found for all ligands examined (desferrioxamine B (DFOB), 2'-deoxymugineic acid (DMA), esculetin, and citrate). The size and duration of the synergistic effect on Fe mobilization varied with ligand: larger effects were observed for the sideorphores compared to esculetin and citrate. For DFOB, the synergistic effect lasted for the 168 h duration of the experiment; for DMA, an initial synergistic effect turned into an antagonistic effect after 4 h because of enhanced mobilization of competing metals; and for esculetin and citrate, the synergistic effect was temporary (less than 24 h). Our results demonstrate that synergistic effects greatly enhance the reactivity of mixtures of compounds known to be exuded in response to Fe limitation. These synergistic effects could be decisive for the survival of plants and microorganisms under conditions of low Fe availability. PMID- 27218690 TI - Retroreflective-type Janus microspheres as a novel contrast agent for enhanced optical coherence tomography. AB - Optical coherence tomography (OCT) is a well-developed technology that utilizes near-infrared light to reconstruct three-dimensional images of biological tissues with micrometer resolution. Improvements of the imaging contrast of the OCT technique are able to further widen its extensive biomedical applications. In this study, Janus microspheres were developed and used as a positive contrast agent for enhanced OCT imaging. Phantom and ex vivo liver tissue experiments as well as in vivo animal tests were conducted, which validated that Janus microspheres, as a novel type of OCT tracer, were very effective in improving the OCT imaging contrast. Working principle and SEM image of Janus microsphere (top). Enhanced OCT imaging (bottom) of Janus microspheres in zebrafish stomach (blue dash line) and sinusoids (green arrows) of nude liver. PMID- 27218692 TI - Inadvertent Reduction of Symphyseal Diastasis During Computed Tomography. AB - OBJECTIVE: To determine the quantifiable difference in pubic symphysis diastasis when comparing computed tomography (CT) and pelvic radiographs in individuals with anterior pelvic ring injuries. DESIGN: Retrospective chart and radiographic review. SETTING: Level 1 trauma center. PATIENTS/PARTICIPANTS: Between 2002 and 2013, all individuals requiring internal fixation of the anterior pelvic ring were reviewed. Of the 163 patients, 72 met the inclusion criteria. Patients with a symphysis dislocation were included if the pelvic radiograph and CT were performed without a pelvic binder, and imaging was adequate for required measurements. INTERVENTION: Symphyseal diastasis was measured on the initial pelvic radiograph, the CT scout, and axial views. MAIN OUTCOME MEASUREMENTS: Comparison of measured symphyseal diastasis on CT and pelvic radiographs. RESULTS: Seventy-two patients met the inclusion criteria. Ninety-seven percent (70/72) had a reduction of their symphysis diastasis in the CT with an average reduction of 6.6 mm (Range, -2.6 to 35.5 mm). The average diastasis on radiograph was 26.3 mm compared with 19.7 mm on CT scout (P < 0.001). Fourteen patients (19.2%) had a reduction from greater than 25 mm to less than 25 mm-a traditional cutoff for operative intervention. CONCLUSIONS: The anteroposterior pelvis radiograph remains an important part of the workup for trauma patients. Reliance on CT alone may underestimate the true degree of pelvic displacement. Failure to obtain pelvic radiographs in the acute setting limits the information in which the medical team can base both immediate and definitive decisions about pelvic ring injuries. LEVEL OF EVIDENCE: Diagnostic level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 27218691 TI - Self-Immolative Thiocarbamates Provide Access to Triggered H2S Donors and Analyte Replacement Fluorescent Probes. AB - Hydrogen sulfide (H2S) is an important biological signaling molecule, and chemical tools for H2S delivery and detection have emerged as important investigative methods. Key challenges in these fields include developing donors that are triggered to release H2S in response to stimuli and developing probes that do not irreversibly consume H2S. Here we report a new strategy for H2S donation based on self-immolation of benzyl thiocarbamates to release carbonyl sulfide, which is rapidly converted to H2S by carbonic anhydrase. We leverage this chemistry to develop easily modifiable donors that can be triggered to release H2S. We also demonstrate that this approach can be coupled with common H2S-sensing motifs to generate scaffolds which, upon reaction with H2S, generate a fluorescence response and also release caged H2S, thus addressing challenges of analyte homeostasis in reaction-based probes. PMID- 27218693 TI - Extraperiosteal Dual Plate Fixation of Acute Mid-Shaft Clavicle Fractures: A Technical Trick. AB - Historically, surgical treatment of acute mid-shaft clavicle fractures has excellent outcomes with low rates of nonunion. More complex fracture patterns with significant comminution may limit the fixation that can be obtained with a single plate. The authors describe the surgical technique and case series of patients treated with extraperiosteal dual plating for acute mid-shaft clavicle fractures. PMID- 27218694 TI - Variation in Treatment of Displaced Geriatric Acetabular Fractures Among 15 Level I Trauma Centers. AB - OBJECTIVES: To document the initial treatment of displaced acetabular fractures among older adults across multiple trauma centers and to investigate the factors that influence the decision to operate and the choice of operative procedure [open reduction internal fixation (ORIF) vs. total hip arthroplasty (THA)]. DESIGN: Retrospective observational study. SETTING: Fifteen US level-I trauma centers participating in the Major Extremity Trauma Research Consortium. PATIENTS/PARTICIPANTS: Overall, 269 patients aged 60 years or older admitted for the treatment of a displaced acetabular fracture. INTERVENTION: None. MAIN OUTCOME MEASUREMENTS: Treatment. RESULTS: Sixty percent of fractures (n = 162) were treated operatively. Younger age (<80 years), injury from high-energy mechanism, fractures with femoral head impaction, and fractures without hip congruency were significantly associated with receiving operative treatment (P < 0.05). Significant site variation in operative versus nonoperative treatment occurred even after accounting for these factors (P = 0.0044). Among operatively treated patients, 88% (n = 142) received ORIF and 12% (n = 20) received THA as the initial treatment. Women were more likely to be treated with initial THA compared with men; of the known risk factors for poor outcomes with ORIF (ie, dome or roof impaction, femoral head impaction, or posterior wall involvement), only dome impaction was significantly associated with receiving initial THA (P < 0.05). CONCLUSIONS: Currently, no treatment guidelines exist for acetabular fractures in older adults, which likely explains the significant site variation in operative versus nonoperative treatment. This study identifies patient and injury factors that drive treatment decisions, which will be important in planning and designing future trials needed to determine the best treatment for these fractures. PMID- 27218695 TI - Suprapatellar Intramedullary Nail Technique Lowers Rate of Malalignment of Distal Tibia Fractures. AB - OBJECTIVES: To report on the immediate postoperative alignment of distal tibia fractures (within 5 cm of the tibial plafond) treated with suprapatellar intramedullary nail (IMN) insertion compared with the infrapatellar technique. Primary outcomes include alignment on both the anteroposterior and lateral radiographic views. DESIGN: Retrospective cohort study. SETTING: Two urban level I trauma centers. PATIENTS: A total of 266 skeletally mature patients with a distal tibia fracture were treated with an IMN. One hundred thirty-two patients underwent this procedure through a suprapatellar technique. INTERVENTION: Intramedullary nail placement. MAIN OUTCOME MEASURES: Alignment. RESULTS: The 2 treatment groups were evenly matched with respect to age, gender, fracture grade, and the presence of open fracture. Within the suprapatellar group, the fibula was intact, fixed, and remained fractured in 6 (4.5%), 22 (16.7%), and 104 (78.8%) cases, respectively. The fibula was intact, repaired, and remained fractured in 9 (6.7%), 32 (23.9%), and 93 (69.4%) cases, respectively, in the infrapatellar group. There was no difference in the rate of fibular fixation between the groups (P = 0.2). Primary angular malalignment of >=5 degrees occurred in 35 (26.1%) patients with infrapatellar IMN insertion and in 5 (3.8%) patients who underwent suprapatellar IMN insertion (P < 0.0001). CONCLUSIONS: This is the largest patient series directly comparing the suprapatellar with infrapatellar IMN insertion technique in the treatment of distal tibia fractures. In the treatment of distal tibia fractures, suprapatellar IMN technique results in a significantly lower rate of malalignment compared with the infrapatellar IMN technique. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 27218696 TI - Clustering multivariate functional data with phase variation. AB - When functional data come as multiple curves per subject, characterizing the source of variations is not a trivial problem. The complexity of the problem goes deeper when there is phase variation in addition to amplitude variation. We consider clustering problem with multivariate functional data that have phase variations among the functional variables. We propose a conditional subject specific warping framework in order to extract relevant features for clustering. Using multivariate growth curves of various parts of the body as a motivating example, we demonstrate the effectiveness of the proposed approach. The found clusters have individuals who show different relative growth patterns among different parts of the body. PMID- 27218697 TI - Parvovirus B19 congenital infection. PMID- 27218698 TI - Differences in Behavioral Responding in Adult and Aged Rats Following Chronic Ethanol Exposure. AB - BACKGROUND: Research suggests symptoms of chronic alcoholism, and withdrawal may be more severe in elderly compared with younger adults. However, examination of the effects of long-term ethanol (EtOH) consumption and withdrawal is limited in aged rodents. We thus investigated EtOH withdrawal and potential deficits in cognitive and motor behavior in young adult and aged rats. We also examined the effects of acute allopregnanolone as a potential mechanism contributing to age related differences in EtOH's cognitive-impairing effects. METHODS: Male young adult (postnatal days 70 to 72) and aged (approximately 18 months) Sprague-Dawley rats were treated with liquid EtOH diet in a modified chronic intermittent EtOH (modified-CIE) paradigm. The severity of EtOH withdrawal was determined using a 4 item rating scale, and withdrawal-induced anxiety-like behavior was assessed in the elevated plus maze (EPM) and open field. After a 14-day EtOH-free period, spatial performance was assessed in the Morris water maze (MWM) during sober acquisition and in response to a subsequent EtOH and allopregnanolone challenge. RESULTS: Modified-CIE adults consumed more EtOH during treatment and exhibited robust EtOH withdrawal using a behavioral rating scale compared to aged rats. In the EPM, adult and aged modified-CIE groups spent increased time in the closed arms, while aged animals also made significantly more closed arm entries, fewer open arm entries, and spent less time in the open arms during withdrawal compared to controls. Modified-CIE decreased MWM performance of adult and aged rats, but did not result in motor impairments in either age group. Finally, acute allopregnanolone increased time to the MWM platform in adults but not aged animals. CONCLUSIONS: The elderly may be vulnerable to EtOH withdrawal as modified-CIE aged rats displayed anxiety-like behavior compared to controls during withdrawal despite achieving lower blood EtOH concentrations during treatment than younger adults. Our data also indicate that modified-CIE and EtOH withdrawal cause persistent cognitive impairments in both age groups. The results from this study provide further evidence indicating the elderly may be sensitive to the effects of alcohol. PMID- 27218699 TI - Community Structure of Tintinnid Ciliates of the Microzooplankton in the South West Pacific Ocean: Comparison of a High Primary Productivity with a Typical Oligotrophic Site. AB - Transient 'hot spots' of phytoplankton productivity occur in the generally oligotrophic Southern Pacific Ocean and we hypothesized that the population structure of tintinnid ciliates, planktonic grazers, would differ from that of a typical oligotrophic sites. Samples were collected over a 1-wk period at each of two sites between Fiji and Tahiti: one of elevated chlorophyll a concentrations and primary productivity with an abundance of N-fixing cyanobacteria Trichodesmium, and a distant oligotrophic site. Tintinnid abundance differed between the sites by a factor of 2. A single species (Favella sp.), absent from the oligotrophic site, highly dominated the 'hot spot' site. However, total species richness was identical (71 spp.) as well as short-term temporal variability (2-4 d). At both sites, species abundance distributions most closely fit a log-series or log-normal distribution and the abundance distributions of ecological types, forms of distinct lorica oral diameter, were the typical geometric. Morphological diversity was only slightly lower at the high productivity site. We found that communities of these plankton grazers in 'hot spots' of phytoplankton productivity in oligotrophic systems, although harboring different species, differ little from surrounding oligotrophic areas in community structure. PMID- 27218700 TI - Standardization and adult norms for the sequential subtracting tasks of serial 3's and 7's. AB - The Serial 3's and 7's subtraction tasks are traditionally used in mental status examinations. The usefulness of these tasks is based upon the assumption that they measure attention and mental concentration. However, there is no uniform method of administration, and there are no recognized norms for these subtraction tasks, which has led some in the field of psychiatry and neuropsychology to conclude that the tests are not useful. The purpose of this research had three goals: (a) to create a standardization of the administration, (b) to provide a structured and consistent framework for the data evaluation, and (c) to create adult norms as a frame of reference for interpretation. The study investigated normal control subjects (N = 204) and specific variables of interest included both efficiency and accuracy of performance. The results demonstrated that when used conjointly, Serial 3's and Serial 7's are an efficient and accurate measure of sequential subtracting, but even more importantly, the study revealed the hierarchical increase in cognitive demand when the performances between 3's and 7's were compared. With standardization and norms, serial subtraction becomes a more effective screening technique within the context of a mental status examination. Similarly, the conjoint administration of these tasks yields synergistic data that can be useful in determining deficits in the cognitive domains of attention and working memory. PMID- 27218701 TI - Administrative Challenges to the Integration of Oral Health With Primary Care: A SWOT Analysis of Health Care Executives at Federally Qualified Health Centers. AB - Inadequate access to preventive oral health services contributes to oral health disparities and is a major public health concern in the United States. Federally Qualified Health Centers play a critical role in improving access to care for populations affected by oral health disparities but face a number of administrative challenges associated with implementation of oral health integration models. We conducted a SWOT (strengths, weaknesses, opportunities, and threats) analysis with health care executives to identify strengths, weaknesses, opportunities, and threats of successful oral health integration in Federally Qualified Health Centers. Four themes were identified: (1) culture of health care organizations; (2) operations and administration; (3) finance; and (4) workforce. PMID- 27218702 TI - Shortened equilibration time can compromise clinical outcomes in human embryo vitrification. AB - Vitrification is an important way to cryopreserve human embryos and the recommended time of embryo exposure to the vitrification solution is 1 min. However, practically speaking, the duration of embryos exposure to equilibration solution can vary from 5 to 15 min. The purpose of this study was to investigate the effect of different equilibration times on the outcomes of frozen-thawed embryo transfer cycles. The data were collected from our medical records from January 2012 to June 2013 and a total of 517 cycles were included. These cycles were divided into four groups according to the equilibration time: (i) 5-6 min; (ii) 7-8 min; (iii) 9-10 min and (iv) 11-12 min. The results show that there were no differences in terms of survival rate and fully intact embryo rate among the four groups. However, lower clinical pregnancy, embryo implantation and live birth rates were observed in the 5-6 min exposure group (54.6%, 31.9% and 48.2%, respectively) compared with the three other groups. The corresponding rates in the 9-10 min group (73.5%, 47.6% and 64.7%) were the highest. This study indicated that different equilibration times influenced the clinical outcomes of human embryo vitrification and vitrification with shortened equilibration time compromised the clinical outcomes. Appropriate prolongation of the equilibrium time would probably improve the clinical outcomes. PMID- 27218703 TI - Common Dysregulated Genes in Endometriosis and Malignancies. AB - Several authors have investigated the malignant transformation of endometriosis, which supports the hypothesis of the pre-neoplastic state of endometriotic lesions, but there are few data about the pathways and molecular events related to this phenomenon. This review provides current data about deregulated genes that may function as key factors in the malignant transition of endometriotic lesions. In order to do so, we first searched for studies that have screened differential gene expression between endometriotic tissues and normal endometrial tissue of women without endometriosis, and found only two articles with 139 deregulated genes. Further, using the PubMed database, we crossed the symbol of each gene with the terms related to malignancies, such as cancer and tumor, and obtained 9,619 articles, among which 444 were studies about gene expression associated with specific types of tumor. This revealed that more than 68% of the analyzed genes are also deregulated in cancer. We have also found genes functioning as tumor suppressors and an oncogene. In this study, we present a list of 95 informative genes in order to understand the genetic components that may be responsible for endometriosis' malignant transformation. However, future studies should be conducted to confirm these findings. PMID- 27218704 TI - Effect of Phosphatidylcholine Unsaturation on the Lateral Segregation of Palmitoyl Ceramide and Palmitoyl Dihydroceramide in Bilayer Membranes. AB - To better understand the interactions of saturated ceramides with unsaturated glycerophospholipids in bilayer membranes, we measured how palmitoyl ceramide (PCer) and dihydroceramide (dihydro-PCer, lacking the trans 4 double bond of the sphingoid base of ceramide) can interact with phosphatidylcholines (PCs) with palmitic acid in the sn-1 position and increasingly unsaturated acyl chains in the sn-2 position. The PCs were 16:0/18:1 (POPC), 16:0/18:2 (PLPC), 16:0/20:4 (PAPC), and 16:0(22:6 (PDPC). We also included di-18:1-PC (DOPC) to compare it with POPC. Because the ceramides were expected to segregate laterally to an ordered ceramide-rich phase, we determined the formation of the ordered phase using lifetime analysis of trans-parinaric acid (tPA) fluorescence. The presence of ordered domains, as indicated by tPA lifetime analysis, was verified by an analysis of tPA anisotropy as a function of temperature. The interaction between PCer and POPC was clearly more favored than interactions with DOPC, as seen from a more thermostable gel phase in POPC than in DOPC at equal ceramide content. The concentration needed for PCer gel phase formation was also lower in POPC than in the DOPC bilayers, suggesting that POPC had better miscibility in the ordered phase. The increased unsaturation of the sn-2 acyl chains of the PCs had more clear effects of dihydro-PCer segregation than on PCer segregation, and the dihydro-PCer gel phase became more thermostable as the unsaturation in the PC increased. We conclude that the interactions between ceramides and PCs were complex and affected both by the trans 4 double bond of PCer by the palmitoyl acyl in the sn-1 position and by the overall degree of unsaturation of the sn-2 acyl chain of the PCs. PMID- 27218705 TI - Miniaturized Flow Stacked Immunoassay for Detecting Escherichia coli in a Single Step. AB - Commercially available systems that provide cost-effective, fast, simple, and portable solutions for health and environmental applications are few despite advancements in bioassays and biosensor research. We have developed a new system based on stacked membranes, each layer with a specific function. Samples were added onto the bottom-most layer, and as each layer becomes wet, the analyte pushes through to the next membrane layers. During migration, the analyte attaches with the corresponding antibody, itself conjugated with horseradish peroxidase (HRP) to produce a measurable signal. To prevent false positive results, blocking layer membranes are added to stop unbound antibodies from reaching the top membrane. Thus, only analyte/antibody-HRP complex will generate a signal. In order to prove this concept, Escherichia coli was used as the target analyte. After optimization, our immunoassay sensitivity was adjusted to 100 cells mL(-1). Different environmental water sources were also tested to demonstrate the sensitivity and specificity of our proposed stacked bioassay. Simplicity, low price, sensitivity, and modularity (capability to change to any target analyte) make this idea very promising for future commercialization. PMID- 27218706 TI - Complete clinical remission with tocilizumab in two infants with systemic juvenile idiopathic arthritis: a case series. PMID- 27218782 TI - Small GTPases. AB - Members of the protein superfamily of small guanosine triphosphatases, also known as small GTPases, small G-proteins, or the Ras superfamily, are involved in nearly every aspect of cell biology. Small GTPases are tightly regulated molecular switches that make binary on/off decisions through controlled loading of GTP (activation) and hydrolysis of GTP to GDP (inactivation). Small GTPases typically function as nodal points that integrate broad upstream regulatory inputs and disseminate broad effector outputs. The superfamily comprises five families that are conserved across eukaryotes: Ras, Rho, Rab, Arf, and Ran. Each family, besides Ran, has radiated functionally since our last common ancestor with fungi, and certain subfamilies persist throughout metazoa. The double genome duplication leading to vertebrates resulted in two to four genes for many subfamilies, plus some novel mammalian additions. Here we discuss general principles of small GTPase biology, survey the C. elegans complement of small GTPases and how they compare to their mammalian counterparts, and note atypical nematode members that do not fall into discrete subfamilies. We do not discuss the multitude of other proteins with catalytic guanosine triphosphatase domains that fall outside the small GTPase/Ras superfamily. PMID- 27218784 TI - Are Ocular and Ocular Adnexal Cancers Overdiagnosed? Historical Perspectives on Diagnosis. PMID- 27218707 TI - Why are rods more sensitive than cones? AB - One hundred and fifty years ago Max Schultze first proposed the duplex theory of vision, that vertebrate eyes have two types of photoreceptor cells with differing sensitivity: rods for dim light and cones for bright light and colour detection. We now know that this division is fundamental not only to the photoreceptors themselves but to the whole of retinal and visual processing. But why are rods more sensitive, and how did the duplex retina first evolve? Cells resembling cones are very old, first appearing among cnidarians; the emergence of rods was a key step in the evolution of the vertebrate eye. Many transduction proteins have different isoforms in rods and cones, and others are expressed at different levels. Moreover rods and cones have a different anatomy, with only rods containing membranous discs enclosed by the plasma membrane. These differences must be responsible for the difference in absolute sensitivity, but which are essential? Recent research particularly expressing cone proteins in rods or changing the level of expression seem to show that many of the molecular differences in the activation and decay of the response may have each made a small contribution as evolution proceeded stepwise with incremental increases in sensitivity. Rod outer-segment discs were not essential and developed after single-photon detection. These experiments collectively provide a new understanding of the two kinds of photoreceptors and help to explain how gene duplication and the formation of rod-specific proteins produced the duplex retina, which has remained remarkably constant in physiology from amphibians to man. PMID- 27218783 TI - A comprehensive investigation of sperm DNA damage and oxidative stress injury in infertile patients with subclinical, normozoospermic, and astheno/oligozoospermic clinical varicocoele. AB - One of the main pathogeneses of varicocoele and infertility is oxidative stress (OS), nevertheless, the oxidative damaged DNA in infertile patients with varicocoele remains poorly clarified. The objective of this study was to comprehensively investigate whether sperm DNA damage and OS injury were related with different issues of varicocoele. According to the varicocoele practice guidelines, surgical treatment was not indicated in the infertile patients with subclinical (SubVc, n = 15) and normozoospermic clinical varicocoele (NCVc, n = 22), the infertile astheno/oligozoospermic patients with clinical varicocoele (AOCVc, n = 51) would receive microsurgerical varicocoelectomy. Normozoospermic healthy donors with proven fertility (n = 25) were recruited as controls. Thiobarbituric acid and sperm chromatin structure assay (SCSA) methods were preformed to analyze seminal lipid peroxidation product malondialdehyde (MDA) and sperm DNA fragmentation index (DFI). We found that AOCVc and NCVc, except SubVc, could significantly elevate sperm DFI and seminal MDA levels. Varicocoelectomy could substantially improve semen parameters, and reduce sperm DFI and seminal MDA levels in the AOCVc patients. However, the non-operative NCVc patients would possibly suffer a severe deterioration of semen parameters accompanied by aberrantly higher levels of sperm DFI and seminal MDA, whereas no differences occurred in the non-operative SubVc patients. Sperm DFI level in the pregnant group was much lower compared to the non-pregnant group (AOCVc, p < 0.01; NCVc, p < 0.05) with the best cutoff value of 19.73%, while no differences in seminal MDA (p > 0.05) could be observed. Finally, a strong positive correlation was found between sperm DFI and seminal MDA (Rs = 0.504, p < 0.01), and they were also closely correlated with crucial semen parameters except normal morphology. Therefore, sperm DNA damage in clinical varicocoele, but not in SubVc, might be associated with the role of seminal reactive oxygen species (ROS) in mediating such damage. Varicocoelectomy could be beneficial for reducing OS injury and sperm DFI, and males with low sperm fragmented-DNA level had more opportunities to become pregnant. PMID- 27218785 TI - Assessing Prognosis in Uveal Melanoma. AB - BACKGROUND: Because uveal melanoma is the most common primary malignant intraocular tumor in adults and carries a significant risk of metastases, which are mostly unresponsive to available systemic therapy, researchers have been searching for prognostic indicators to identify patients at increased risk for developing such metastasis. METHODS: The purpose of this study is to describe recent advances in prognostic testing of patients with uveal melanoma and the impact of these advances on the management of uveal melanoma. The relevant, peerreviewed literature as extracted and then further reviewed for scientific content. RESULTS: Demographic characteristics, clinical, and histopathological features alone are inadequate for predicting metastatic risk in individual patients with uveal melanoma. Some research has shown that cytogenetic abnormalities and principally transcriptomic features of tumor cells can independently predict high risk for uveal melanoma metastatic spread. Gene expression profiling of uveal melanoma cells may be accurate and biologically informative for molecular prognostication. Methods for detecting chromosomal gains and losses have predictive value but require additional clinical and cytological information. The latest step in the evolution of molecular testing has been the discovery of major driver mutations for possible use in targeted therapy. CONCLUSIONS: Assay validation, quality control, and interpretation of results are essential for the reliability and reproducibility of these tests. Although these prognostic tests have improved the ability to identify patients at increased risk for developing metastasis, their use has not changed the management of uveal melanoma. However, genomic, analytical, and sequencing technologies will provide a critical step toward useful targeted therapies for patients with high-risk uveal melanoma. PMID- 27218786 TI - Therapeutic Options for Retinoblastoma. AB - BACKGROUND: Retinoblastoma is the most common primary intraocular malignancy in children. The management of retinoblastoma is complex and depends on several factors. METHODS: This review provides an update on current and emerging therapeutic options for retinoblastoma. The medical literature was searched for articles relevant to the management of retinoblastoma. The results of prospective and retrospective studies on chemotherapy and focal therapy for retinoblastoma are summarized. Animal models for novel therapeutic agents are also discussed. RESULTS: Treatment strategies for retinoblastoma involve intravenous chemoreduction, local administration routes of chemotherapy (eg, intra-arterial, intravitreal), focal therapy for tumor consolidation (eg, photocoagulation, thermotherapy, cryotherapy, plaque brachytherapy), external beam radiotherapy, and surgical enucleation. Emerging therapies include alternative chemotherapeutic agents, molecularly targeted therapies, and novel drug-delivery systems. CONCLUSION: In the past 10 years, the management strategy for retinoblastoma has significantly changed, shifting toward local chemotherapy and away from systemic chemotherapy. Innovations in the field of molecular biology and the development of targeted therapies have led to improvements in survival rates and ocular salvage for this disease. However, the need still exists to further assess the long-term effects of such directional changes in Therapy. PMID- 27218787 TI - Primary Vitreoretinal Lymphoma: Management of Isolated Ocular Disease. AB - BACKGROUND: The prognosis for patients with primary vitreoretinal is dismal. The close association of primary vitreoretinal lymphoma with primary central nervous system lymphoma is responsible for high rates of mortality. Traditional treatments consist of systemic chemotherapy and whole-brain radiotherapy. The optimal approach for the treatment of isolated primary vitreoretinal lymphoma is unclear. METHODS: A review of the relevant medical and scientific literature was performed, focusing on the clinical features of primary vitreoretinal lymphoma and the progress made in the management of isolated ocular disease. RESULTS: Ocular treatment options for primary vitreoretinal lymphoma have recently expanded with the addition of intravitreal chemotherapeutic agents and localized radiation. Based on several retrospective reports, a general shift has been made toward local therapy (eg, orbital radiotherapy, intravitreal chemotherapy) for ocular disease. No prospective, randomized clinical trials yet exist to guide therapy. CONCLUSIONS: Optimal treatment regimens for isolated primary vitreoretinal lymphoma continue to evolve. Further investigations into novel therapies and protocols are needed to decrease recurrence rates, reduce or prevent central nervous system involvement, and improve rates of overall survival. PMID- 27218788 TI - Management of Primary Acquired Melanosis, Nevus, and Conjunctival Melanoma. AB - BACKGROUND: The management of conjunctival melanoma is difficult because of the rarity of the disease, confusing terminology, high rates of local tumor recurrence, controversies regarding treatment, a poor evidence base, unreliable prognostication, and significant mortality rates. METHODS: The medical literature was reviewed, focusing on treatment and management options for conjunctival melanoma. Recent trends and developments were summarized with respect to terminology, local treatment, histology, genetic analysis, prognostication, and systemic treatment, highlighting the scope for research and possible improvements in patient care. RESULTS: Histopathological diagnostic terminology for primary acquired melanosis is being superseded by more explicit terminology, thus differentiating hypermelanosis from conjunctival melanocytic intraepithelial neoplasia. Topical chemotherapy and increased use of adjunctive radiotherapy have helped improve rates of local tumor control. Use of exenteration has become rare. Regional and systemic metastases are common in patients with nonbulbar conjunctival melanoma, although long-term survivors with metastases are growing in number. Prognostication is mainly based on tumor size and location, but histological and genetic data into multivariate analyses will soon be incorporated. The role of sentinel lymph-node biopsy continues to be controversial. Chemotherapy for metastatic disease is being superseded by targeted therapy based on genetic abnormalities such as BRAF mutations. CONCLUSIONS: The management of conjunctival melanoma requires expert care from an experienced, multidisciplinary team. The goal of therapy is to provide good local tumor control with minimal morbidity, high-quality pathology, and adequate psychological support. Maximizing patient enrollment in multicenter clinical trials is likely to strengthen evidence-based decision-making. PMID- 27218789 TI - Sebaceous Carcinoma of the Eyelid. AB - BACKGROUND: Periocular sebaceous carcinoma (PSC) is a rare but aggressive neoplasm that tends to clinically and histopathologically mimic other conditions. PSC can be challenging to diagnose using histomorphology alone given its overlap with 2 more common tumors that occur in this area (basal cell carcinoma [BCC] and squamous cell carcinoma [SCC]). Use of immunohistochemistry can help resolve this differential diagnosis. METHODS: A review of the literature was performed, focusing on the epidemiology, morphology, and immunohistochemical features of PSC. RESULTS: The most useful immunostains in the differential diagnosis of PSC are epithelial membrane antigen, Ber-Ep4, androgen receptor (AR), and adipophilin. To discern PSC from BCC, one should use EMA, Ber-Ep4, AR, and adipophilin, whereas discerning PSC from SCC can be achieved by evaluating AR and adipophilin. In addition, p53 and ERBB2 (formally known as HER2/neu) are other potentially useful immunohistochemical markers for the differential diagnosis of PSC. CONCLUSIONS: Use of new immunohistochemical techniques, as well as the elucidation of molecular alterations, such as the presence of ERBB2 amplification, will advance our understanding of PSC. PMID- 27218790 TI - Role of Vismodegib in the Management of Advanced Periocular Basal Cell Carcinoma. AB - BACKGROUND: Vismodegib is the first selective hedgehog pathway inhibitor approved to treat locally advanced and metastatic basal cell carcinoma (BCC). Limited information is available concerning its role in managing advanced BCC around the eye. METHODS: The medical literature was searched for cases of nonsyndromic periocular BCC treated with vismodegib. Clinical information was abstracted and analyzed. In addition, a review of the pharmacology of vismodegib, including general effectiveness and safety, was conducted. RESULTS: Thirty study patients with nonsyndromic periocular BCC treated with vismodegib were found in the literature. Vismodegib was used in 3 ways: medical therapy, adjuvant therapy prior to surgery or radiotherapy, and treatment of positive surgical margins. Complete regression was reported in 9 study patients (30%), with follow-up visits after therapy averaging fewer than 5 months. Four study participants developed squamous cell carcinoma while receiving treatment. CONCLUSIONS: Too few cases exist to draw any conclusions on the role that vismodegib might play in the management of periocular BCC. In addition, long-term follow-up data are not yet available. Although the objective response rate of advanced BCC is impressive in study patients receiving vismodegib, well-controlled clinical studies are needed to determine whether vismodegib has any impact on survival or quality of life. PMID- 27218791 TI - Extranodal Marginal Zone B-cell Lymphoma of the Ocular Adnexa. AB - BACKGROUND: Low-grade B-cell lymphomas located around the eye present unique challenges in diagnosis and treatment. Extranodal marginal zone B-cell lymphoma is the most common lymphoma of the ocular adnexa (conjunctiva, orbit, lacrimal gland, and eyelid). METHODS: A systematic search of the relevant literature was performed. Material pertinent to the diagnosis, prognosis, pathogenesis, and treatment of extranodal marginal zone B-cell lymphoma of the ocular adnexa was identified, reviewed, and analyzed, focusing on management strategies for primary localized disease. RESULTS: The primary cause of extranodal marginal zone B-cell lymphoma of the ocular adnexa remains elusive, although an infectious agent is suspected. Radiotherapy is the most common initial treatment for localized disease. Initial treatment with chemotherapy, immunotherapy, and antibiotics has shown promising results, but the number of series is limited and controlled trials do not exist. CONCLUSIONS: Although the long-term outcome of localized extranodal marginal zone B-cell lymphoma of the ocular adnexa is good, optimal treatment remains a goal. The variation in rates of local and systemic relapse among treated stage 1E tumors suggests that critical factors affecting outcomes are not fully understood. Radiotherapy is the standard of care; at this time, the evidence is insufficient to recommend chemotherapy, immunotherapy, or antibiotics for initial treatment of extranodal marginal zone B-cell lymphoma localized to the ocular adnexa. Well-controlled comparative studies are needed. PMID- 27218792 TI - Ophthalmic Complications Related to Chemotherapy in Medically Complex Patients. AB - BACKGROUND: Systemic cancer therapies cause a variety of ophthalmic complications. Mitigating harmful adverse events involves screening patients at risk for ocular injury and vision loss. METHODS: A review of the relevant literature on the ophthalmic complications of cancer therapy was used to formulate an approach to screening patients for serious complications presenting at a nonophthalmic specialty center. RESULTS: Rarely, ocular complications of cancer therapy can occur. Establishing a causal association for any given agent is complicated because many treatment-related adverse events result in symptoms and ocular findings indistinguishable from primary eye disorders. CONCLUSIONS: Recognizing potentially serious ocular complications of cancer therapy before they result in irreversible injury starts with taking a relevant clinical history and performing a basic eye examination, including assessments of visual acuity and fields. Given the wide range of treatment-related adverse events and the challenges of diagnosis, the screening process plays an important role in expediting referral to an ophthalmologic specialist. PMID- 27218793 TI - Disparities Report: Disparities Among Minority Women With Breast Cancer Living in Impoverished Areas of California. AB - BACKGROUND: Interaction effects of poverty and health care insurance coverage on overall survival rates of breast cancer among women of color and non-Hispanic white women were explored. METHODS: We analyzed California registry data for 2,024 women of color (black, Hispanic, Asian, Pacific Islander, American Indian, or other ethnicity) and 4,276 non-Hispanic white women (Anglo-European ancestries and no Hispanic-Latin ethnic backgrounds) diagnosed with breast cancer between the years 1996 and 2000 who were then followed until 2011. The 2000 US census categorized rates of neighborhood poverty. Health care insurance coverage was either private, Medicare, Medicaid, or none. Cox regression was used to model rates of survival. RESULTS: A 3-way interaction between ethnicity, health care insurance coverage, and poverty was observed. Women of color inadequately insured and living in poor or near-poor neighborhoods in California were the most disadvantaged. Women of color adequately insured and who lived in such neighborhoods in California were also disadvantaged. The incomes of such women of color were typically lower than the incomes of non-Hispanic white women. CONCLUSIONS: Women of color with or without insurance coverage are disadvantaged in poor and near-poor neighborhoods of California. Such women may be less able to bare the indirect, direct, or uncovered costs of health care for breast cancer treatment. PMID- 27218794 TI - Infectious Disease Report: Bordetella pertussis Infection in Patients With Cancer. AB - We illustrate 2 cases of pneumonia associated with Bordetella pertussis infection in 72-year-old and 61-year-old patients with cancer receiving myelosuppressive therapy after hematopoietic stem cell transplantation. Bacterial infections are a significant cause of morbidity and mortality in patients with cancer, and those receiving hematopoietic stem cell transplant, solid organ transplant, or myelosuppressive therapy are at increased risk. The infection was detected and the 2 patients had good outcomes following azithromycin treatment. Pertussis, also known as whooping cough, is a contagious respiratory illness that has become a public health challenge due to decreased immunity of the pertussis vaccine. Therefore, it is critical to recognize pertussis early in the course of the disease. PMID- 27218795 TI - Pharmacy Report: Megestrol Acetate-Induced Adrenal Insufficiency. AB - A man aged 65 years with metastatic renal cell carcinoma presented for evaluation after a recent fall. A thorough workup of the case was performed and secondary adrenal insufficiency induced by the administration of megestrol acetate was determined to be the cause. Adrenal insufficiency is a serious disorder that is a potential adverse event of megestrol acetate, a medication used to help patients with cancer cachexia increase their appetite and gain weight. This association is not well recognized in clinical practice, so this case highlights the importance of distinguishing possible endocrine complications induced by the long-term administration or sudden discontinuation of megestrol acetate. PMID- 27218797 TI - Second Annual Moffitt Anatomic Pathology Symposium. PMID- 27218796 TI - Pathology Report: Presacral Noncommunicating Enteric Duplication Cyst. AB - BACKGROUND: Gastrointestinal (GI) tract duplication cysts or enteric duplication cysts are rare congenital malformations sometimes found on the mesenteric aspect of segments of the alimentary tract. Enteric duplication cysts are lined by normal GI epithelium and may be classified as foregut, mid-gut, and hindgut cysts. Except in very rare cases of retroperitoneal enteric duplication cysts, these cysts communicate with the GI tract and share a common blood supply. Concurrent congenital malformations are not uncommon and malignant transformation within enteric duplication cysts has also been reported. METHODS: We describe a case of a noncommunicating enteric duplication cyst in a 52-year-old woman. RESULTS: The patient presented with a presacral cystic mass requiring frequent drainage procedures that was primarily believed to be of neural origin. Upon resection, the lesion contained heterotopic tissue, including ciliated bronchial epithelium, squamous and transitional epithelia, and pancreatic and gastric tissue. Focal, low-grade intestinal adenoma was present, but malignancy was not detected in this case. CONCLUSION: To our knowledge, this is the sixth reported case of a noncommunicating enteric duplication cyst in the English medical literature. PMID- 27218798 TI - Crystal structure of human dendritic cell inhibitory receptor C-type lectin domain reveals the binding mode with N-glycan. PMID- 27218799 TI - Anti-infective potential of Citrus bergamia Risso et Poiteau (bergamot) derivatives: a systematic review. AB - Infectious diseases remain among the leading causes of morbidity and mortality worldwide, mainly because of the increase of resistance to chemotherapeutic drugs. Nature is the major source of anti-infective drugs and could represent a font of medicines that may help overcome antibiotic resistance. Recently, the potential antimicrobial effect of certain plant extracts has attracted attention within the scientific community as alternatives to synthetic drugs. Here, we present a systematic review on the anti-infective properties of bergamot derivatives that highlight the activity of bergamot essential oil against bacteria, mycetes and larvae, as well as the anti-Helicobacter pylori effect of bergamot juice and the antimicrobial properties of extracts from bergamot peel. Findings presented herein could be used to develop novel and alternative preventive and therapeutic strategies aimed to overcome antibiotic resistance. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27218800 TI - Gunslinger Effect and Muller-Lyer Illusion: Examining Early Visual Information Processing for Late Limb-Target Control. AB - The multiple process model contends that there are two forms of online control for manual aiming: impulse regulation and limb-target control. This study examined the impact of visual information processing for limb-target control. We amalgamated the Gunslinger protocol (i.e., faster movements following a reaction to an external trigger compared with the spontaneous initiation of movement) and Muller-Lyer target configurations into the same aiming protocol. The results showed the Gunslinger effect was isolated at the early portions of the movement (peak acceleration and peak velocity). Reacted aims reached a longer displacement at peak deceleration, but no differences for movement termination. The target configurations manifested terminal biases consistent with the illusion. We suggest the visual information processing demands imposed by reacted aims can be adapted by integrating early feedforward information for limb-target control. PMID- 27218801 TI - Synthesis of Optically Active Polystyrene Catalyzed by Monophosphine Pd Complexes. AB - Cationic Pd(II) monophosphine complexes derived from alpha- and beta cyclodextrins (CDs) promote the homopolymerization of styrene under carbon monoxide pressure. Although reversible CO coordination takes place under catalytic conditions according to (13) C NMR studies with (13) C-enriched CO, both complexes catalyze the formation of CO-free styrene polymers. These macromolecules display optical activity as a result of the presence of stereoregular sequences within the overall atactic polymer. PMID- 27218802 TI - Correction: The Impact of Juvenile Coxsackievirus Infection on Cardiac Progenitor Cells and Postnatal Heart Development. AB - [This corrects the article DOI: 10.1371/journal.ppat.1004249.]. PMID- 27218804 TI - Clustering-Induced Attraction in Granular Mixtures of Rods and Spheres. AB - Depletion-induced aggregation of rods enhanced by clustering is observed to produce a novel model of attractive pairs of rods separated by a line of spheres in a quasi-2D, vertically-shaken, granular gas of rods and spheres. We show that the stability of these peculiar granular aggregates increases as a function of shaking intensity. Velocity distributions of spheres inside and outside of a pair of rods trapping a line of spheres show a clear suppression of the momentum acquired by the trapped spheres. The condensed phase formed between the rods is caused by a clustering instability of the trapped spheres, enhanced by a vertical guidance produced by the confining rods. The liberated area corresponding to direct excluded-volume pairs and indirect depletion-aggregated pairs is measured as a function of time. The stability of rod pairs mediated by spheres reveals an attraction comparable in strength to the one purely induced by depletion forces. PMID- 27218803 TI - Computational Framework for Prediction of Peptide Sequences That May Mediate Multiple Protein Interactions in Cancer-Associated Hub Proteins. AB - A considerable proportion of protein-protein interactions (PPIs) in the cell are estimated to be mediated by very short peptide segments that approximately conform to specific sequence patterns known as linear motifs (LMs), often present in the disordered regions in the eukaryotic proteins. These peptides have been found to interact with low affinity and are able bind to multiple interactors, thus playing an important role in the PPI networks involving date hubs. In this work, PPI data and de novo motif identification based method (MEME) were used to identify such peptides in three cancer-associated hub proteins-MYC, APC and MDM2. The peptides corresponding to the significant LMs identified for each hub protein were aligned, the overlapping regions across these peptides being termed as overlapping linear peptides (OLPs). These OLPs were thus predicted to be responsible for multiple PPIs of the corresponding hub proteins and a scoring system was developed to rank them. We predicted six OLPs in MYC and five OLPs in MDM2 that scored higher than OLP predictions from randomly generated protein sets. Two OLP sequences from the C-terminal of MYC were predicted to bind with FBXW7, component of an E3 ubiquitin-protein ligase complex involved in proteasomal degradation of MYC. Similarly, we identified peptides in the C terminal of MDM2 interacting with FKBP3, which has a specific role in auto ubiquitinylation of MDM2. The peptide sequences predicted in MYC and MDM2 look promising for designing orthosteric inhibitors against possible disease associated PPIs. Since these OLPs can interact with other proteins as well, these inhibitors should be specific to the targeted interactor to prevent undesired side-effects. This computational framework has been designed to predict and rank the peptide regions that may mediate multiple PPIs and can be applied to other disease-associated date hub proteins for prediction of novel therapeutic targets of small molecule PPI modulators. PMID- 27218805 TI - Initial Experience With the Pediatric Impella Device: A Feasibility Study in a Porcine Model. AB - OBJECTIVE: This study's objective was to evaluate insertion techniques and device fit of the pediatric version of the Impella ventricular assist device in swine which had similar sized carotids and left ventricles (LVs) as children weighing 10-20 kg. BACKGROUND: Options for minimally invasive circulatory support in children are limited. A modified device based on the current Impella 2.5 platform was created in an effort to provide minimally invasive circulatory support for children. METHODS: Animal studies (n = 10) were performed to determine technical feasibility of device implant via the right common carotid artery (RCCA) in swine with a carotid and LV size similar to children with a BSA < 1 m2 and weight 10-20 kg. The RCCA diameter was measured on pre-implant ultrasound and the LV length was measured at necropsy. The animals were supported for 4 hr and the device explanted. Blood samples and post-explant necropsy was performed to evaluate for device related complications. RESULTS: All animals underwent successful device insertion. Mean carotid artery diameter by ultrasound was 3.5 +/- 0.3 mm. There was no LV or aortic/mitral valve damage with a minimum LV length of 5.4 cm. CONCLUSIONS: Minimally invasive circulatory support is needed in small children. Limitations are primarily related to vessel and chamber size. The Impella Pediatric catheter was safely and successfully implanted in carotid arteries similar in size to children weighing 10-20 kg with minimal complications. (c) 2016 Wiley Periodicals, Inc. PMID- 27218806 TI - Advances in Organic Near-Infrared Materials and Emerging Applications. AB - Much progress has been made in the field of research on organic near-infrared materials for potential applications in photonics, communications, energy, and biophotonics. This account mainly describes our research work on organic near infrared materials; in particular, donor-acceptor small molecules, organometallics, and donor-acceptor polymers with the bandgaps less than 1.2 eV. The molecular designs, structure-property relationships, unique near-infrared absorption, emission and color/wavelength-changing properties, and some emerging applications are discussed. PMID- 27218807 TI - Integrated oxygen-doping and dye sensitization of graphitic carbon nitride for enhanced visible light photodegradation. AB - Graphitic carbon nitride (GCN) is a promising metal-free photocatalyst while suffering from low charge mobility induced inefficient photocatalysis. In this work, oxygen doping was employed to enhance the photodegradation of organic pollutants in water on graphitic carbon nitride (GCNO) under visible light. For further absorption extension, four organic dyes (Eosin-Y, Perylene, Nile-red and Coumarin) were adopted to dye-sensitize the GCNO photocatalyst. It was found that O-doping can promote dye sensitization, which was dependent on the type of dyes and influenced the photodegradation efficiencies of methylene blue (MB) and phenol. Nile-red sensitized GCNO presented the best activity in MB degradation under lambda>480nm irradiations while Eosin-Y showed the best sensitization performance for phenol degradation under lambda>420nm light source. However, dye sensitization was not effective for enhanced pollutant degradation on GCN without O-doping. UV-vis diffuse reflectance spectra (UV-vis DRS), photoluminescence (PL) spectra, and photocurrent analyses were applied to investigate the mechanism of carriers' transfer, which indicated that dye molecules could inject extra electrons into GCNO energy band and the energy dislocation could suppress electron/hole recombination, enhancing photocatalytic performances. PMID- 27218808 TI - gamma-Fe2O3 nanocrystals-anchored macro/meso-porous graphene as a highly efficient adsorbent toward removal of methylene blue. AB - An adsorbent, gamma-Fe2O3 nanocrystals-anchored macro/meso-porous graphene was synthesized by metal etching approach toward removal of methylene blue, exhibiting rapid adsorption rate, high adsorption capacity and good recyclability, thus holding a great promise for treatment of methylene blue in wastewater. PMID- 27218809 TI - Xanthelasma-Like Reaction to Filler Injection. AB - PURPOSE: The purpose of this study is to describe a new complication of a xanthelasma-like reaction which appeared after dermal filler injection in the lower eyelid region. METHODS: A retrospective case analysis was performed on 7 patients presenting with xanthelasma-like reaction after filler injection to the lower eyelids. RESULTS: Seven female subjects with no history of xanthelasma presented with xanthelasma-like reaction in the lower eyelids post filler injection. Fillers included hyaluronic acid (2 patients), synthetic calcium hydroxyapatite (4 patients), and polycaprolactone microspheres (one patient). Average time interval between filler injection and development of xanthelasma like reaction was 12 months (range: 6-18 months). Treatment included steroid injections, 5FU injections, ablative or fractionated CO2 laser, and direct excision. Pathology confirmed the lesion was a true xanthelasma in one patient. In treated patients, there was subtotal resolution after laser. Xanthelasma-like reaction resolved completely after direct excision. Three patients elected to have no treatment. CONCLUSIONS: Previously there has been one reported case of xanthelasma after filler injection. This case series is the largest to date. Furthermore, this series is notable because xanthelasma-like reactions appeared after injection with 3 different types of fillers. None of the patients had evidence of xanthelasma prefiller injection. The precise mechanism by which filler injection can lead to the formation of xanthelasma-like reaction is unclear. A possible mechanism may be related to binding of low-density lipoprotein and internalization by macrophages. Further investigation is required. Nevertheless, physicians performing filler injections should be aware of this new complication and treatment options. PMID- 27218810 TI - Orbitofacial Metastatic Basal Cell Carcinoma: Report of 10 Cases. AB - PURPOSE: To explore the clinical features, management, and prognosis of metastatic basal cell carcinoma originating in the orbitofacial region. METHODS: Ten cases of orbitofacial metastatic basal cell carcinoma were identified by searching databases at 2 institutions from 1995 to 2015. A retrospective chart review was performed. Main outcome measures included patient demographics, lesion size, location of metastases, histologic subtype, recurrence rate, time between primary tumor diagnosis and metastasis, perineural invasion, treatment modalities, and survival from time of metastasis. RESULTS: The median tumor size at largest dimension was 3.3 cm (range, 1.9-11.5 cm), and 6 of 10 patients had at least 1 local recurrence before metastasis (range, 0-2 recurrences). The most common sites of metastasis included the ipsilateral parotid gland (n = 6) and cervical lymph nodes (n = 5). Histologic subtypes included infiltrative (n = 5), basosquamous (n = 2), nodular (n = 1), and mixed (n = 1). The median time from primary tumor diagnosis to metastasis was 7.5 years (range, 0-13). The median survival time from diagnosis of metastasis to last documented encounter or death was 5.3 years (range, 7 months-22.8 years). Treatment regimens included surgical excision, radiotherapy, and hedgehog inhibitors. CONCLUSIONS: Based on our findings, the following features may be markers of high risk orbitofacial basal cell carcinoma: 1) increasing tumor size, 2) local recurrence of the primary tumor, 3) aggressive histologic subtype, and 4) perineural invasion. Screening should include close observation of the primary site and tissues in the distribution of regional lymphatics, particularly the parotid gland and cervical lymph nodes. PMID- 27218811 TI - Key Issues When Reconstructing Extensive Upper Eyelid Defects With Description of a Dynamic, Frontalis Turnover Flap. AB - Reconstruction of full thickness, total upper eyelid defects represents a significant challenge in terms of recreating an upper eyelid which has acceptable cosmesis and a degree of dynamic function. Options include bridging, eyelid sharing techniques (e.g., Cutler-Beard), or nonbridging techniques such as an anterior lamella-based flap combined with a posterior lamella free graft or a "sandwich flap." The success of these techniques depends on the size of the defect, postoperative cosmesis and whether or not the upper eyelid still has a degree of dynamic function to avoid ptosis and exposure keratopathy. The authors present an innervated frontalis turnover flap supporting anterior and posterior lamella grafts as a reconstructive solution for an extensive upper eyelid defect. This technique is cosmetically acceptable, preserves local tissues, and maintains a degree of dynamic function, which keeps the patient's eye comfortable and does not adversely affect visual acuity. PMID- 27218812 TI - Chocolate Cyst After an Orbital Floor Fracture Repair. PMID- 27218813 TI - Autogenous Fascia Lata Graft Fixation to Treat Exotropia Resulting From Iatrogenic Medial Rectus Transection. AB - PURPOSE: To describe autogenous fascia lata graft fixation as a novel method to treat exotropia related to medial rectus (MR) muscle injury following functional endoscopic sinus surgery. METHODS: Three consecutive patients with MR transection and exotropia after functional endoscopic sinus surgery were selected. Preoperative examination was performed; no MR function was noted for over 3 months after injury. CT and dynamic functional MRI were performed, where MR transection and medial wall breach were noted. An autogenous fascia lata graft was harvested and fixated from the remaining periosteum of the posterior-most extent of the medial orbital wall and attached to the globe at the MR insertion. In addition, an ipsilateral lateral rectus muscle recession was performed. RESULTS: Alignment of the eyes in primary gaze and downgaze was achieved and remained so at the 3-month postoperative examinations, with minimal head turn or prism correction (<5 prism diopters) necessary to control diplopia. Two patients required recession of the fascial graft for a minor overcorrection and have remained stable for over 6 months. CONCLUSIONS: Severe exotropia secondary to MR damage following functional endoscopic sinus surgery is a known complication historically difficult to treat. Traditional surgical methods, including vertical muscle transposition, commonly result in complete recurrence of exotropia and increase risk of anterior ocular ischemia. Unlike simple nonabsorbable suture fixation, fascial grafts are completely biointegratable, do not result in significant inflammation, and are unlikely to rupture. Fascia lata graft fixation of the MR to the posterior orbital medial wall is a new and successful method to eliminate exotropia after MR injury. PMID- 27218814 TI - Abnormal Pupil Finding After an Orbital Floor Fracture in a Child. AB - PURPOSE: Trauma to the pupillary fibers can occur during repair of orbital floor fracture resulting in a fixed and dilated pupil. The authors report, discuss, and propose an etiology of an abnormal pupil in a child with an orbital floor fracture before surgical repair. METHODS: A case report is described. RESULTS: Although the orbital fracture was repaired, anisocoria persisted 18 months after the initial trauma. CONCLUSIONS: Pupillary function must be assessed before surgical repair of an orbital floor fracture as damage of the pupillary fibers can occur secondary to the orbital floor fracture. PMID- 27218815 TI - Current irritability robustly related to current and prior anxiety in bipolar disorder. AB - BACKGROUND: Although current irritability and current/prior anxiety have been associated in unipolar depression, these relationships are less well understood in bipolar disorder (BD). We investigated relationships between current irritability and current/prior anxiety as well as other current emotions and BD illness characteristics. METHODS: Outpatients referred to the Stanford Bipolar Disorders Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation. Prevalence and clinical correlates of current irritability and current/prior anxiety and other illness characteristics were examined. RESULTS: Among 497 BD outpatients (239 Type I, 258 Type II; 58.1% female; mean +/- SD age 35.6 +/- 13.1 years), 301 (60.6%) had baseline current irritability. Patients with versus without current irritability had significantly higher rates of current anxiety (77.1% versus 42.9%, p < 0.0001) and history of anxiety disorder (73.1% versus 52.6%, p < 0.0001). Current irritability was more robustly related to current anxiety than to current anhedonia, sadness, or euphoria (all p < 0.001), and current irritability-current anxiety associations persisted across current predominant mood states. Current irritability was more robustly related to past anxiety than to all other assessed illness characteristics, including 1 degrees family history of mood disorder, history of alcohol/substance use disorder, bipolar subtype, and current syndromal/subsyndromal depression (all p < 0.05). LIMITATIONS: Limited generalizability beyond our predominately white, female, educated, insured American BD specialty clinic sample. CONCLUSIONS: In BD, current irritability was robustly related to current/prior anxiety. Further studies are warranted to assess longitudinal clinical implications of relationships between irritability and anxiety in BD. PMID- 27218816 TI - Insomnia brings soldiers into mental health treatment, predicts treatment engagement, and outperforms other suicide-related symptoms as a predictor of major depressive episodes. AB - Given the high rates of suicide among military personnel and the need to characterize suicide risk factors associated with mental health service use, this study aimed to identify suicide-relevant factors that predict: (1) treatment engagement and treatment adherence, and (2) suicide attempts, suicidal ideation, and major depressive episodes in a military sample. Army recruiters (N = 2596) completed a battery of self-report measures upon study enrollment. Eighteen months later, information regarding suicide attempts, suicidal ideation, major depressive episodes, and mental health visits were obtained from participants' military medical records. Suicide attempts and suicidal ideation were very rare in this sample; negative binomial regression analyses with robust estimation were used to assess correlates and predictors of mental health treatment visits and major depressive episodes. More severe insomnia and agitation were significantly associated with mental health visits at baseline and over the 18-month study period. In contrast, suicide-specific hopelessness was significantly associated with fewer mental health visits. Insomnia severity was the only significant predictor of major depressive episodes. Findings suggest that assessment of sleep problems might be useful in identifying at-risk military service members who may engage in mental health treatment. Additional research is warranted to examine the predictive validity of these suicide-related symptom measures in a more representative, higher suicide risk military sample. PMID- 27218817 TI - A study of genetic and environmental contributions to structural brain changes over time in twins concordant and discordant for bipolar disorder. AB - This is the first longitudinal twin study examining genetic and environmental contributions to the association between liability to bipolar disorder (BD) and changes over time in global brain volumes, and global and regional measures of cortical surface area, cortical thickness and cortical volume. A total of 50 twins from pairs discordant or concordant for BD (monozygotic: 8 discordant and 3 concordant pairs, and 1 patient and 3 co-twins from incomplete pairs; dizygotic: 6 discordant and 2 concordant pairs, and 1 patient and 7 co-twins from incomplete pairs) underwent magnetic resonance imaging twice. In addition, 57 twins from healthy twin pairs (15 monozygotic and 10 dizygotic pairs, and 4 monozygotic and 3 dizygotic subjects from incomplete pairs) were also scanned twice. Mean follow up duration for all twins was 7.5 years (standard deviation: 1.5 years). Data were analyzed using structural equation modeling software OpenMx. The liability to BD was not associated with global or regional structural brain changes over time. Although we observed a subtle increase in cerebral white matter in BD patients, this effect disappeared after correction for multiple comparisons. Heritability of brain changes over time was generally low to moderate. Structural brain changes appear to follow similar trajectories in BD patients and healthy controls. Existing brain abnormalities in BD do not appear to progressively change over time, but this requires additional confirmation. Further study with large cohorts is recommended to assess genetic and environmental influences on structural brain abnormalities in BD, while taking into account the influence of lithium on the brain. PMID- 27218818 TI - Patients' experiences of healthcare encounters in severe irritable bowel syndrome: an analysis based on narrative and feminist theory. AB - AIMS AND OBJECTIVES: This study aimed to explore patients' experiences of healthcare encounters in severe irritable bowel syndrome. BACKGROUND: Irritable bowel syndrome is a common functional disorder with symptoms such as abdominal pain and disturbed bowel habits, the cause of which is not completely known. Treatments options are limited, and healthcare encounters in irritable bowel syndrome have been described as unsatisfying and frustrating for both patients and professional healthcare providers. Furthermore, the influence of power on healthcare encounters has long been recognised, especially regarding the disadvantaged position of those suffering from functional illness which cannot be identified by commonly used tests or investigations. METHODS: We interviewed 10 patients during 2014, all attending an outpatient clinic and suffering from severe irritable bowel syndrome. Relying on narrative and feminist theory, we explored how they actively negotiate professional discourse communicated to them in the clinical encounter. RESULTS: The patients' experiences of healthcare encounters in irritable bowel syndrome were mostly described as negative, and often induced feelings of confusion and self-doubt. Positive encounters were described as being listened to, believed and taken seriously. Narrators found it especially problematic when healthcare professionals described irritable bowel syndrome as a minor disorder with primarily stress or psychological aetiology and put the responsibility for recovery onto the patient. Patients' actively negotiated such professional discourse by presenting a counternarrative describing their own suffering and strengths, experienced healthcare shortcomings and possible organic aetiology of irritable bowel syndrome. CONCLUSIONS: Patients suffering from severe irritable bowel syndrome described how they often felt a need to protect their positive identities in the face of trivialisation and disbelief by healthcare professionals. RELEVANCE TO CLINICAL PRACTICE: A deepened understanding of patients' experiences of healthcare encounters in irritable bowel syndrome could enable more helpful and supporting interventions by healthcare professionals. PMID- 27218819 TI - Straightforward and Controlled Shape Access to Efficient Macrocyclic Imidazolylboronium Anion Receptors. AB - A straightforward synthesis of air- and water-stable bis-cationic macrocyclic imidazolylboronium anion receptors is described herein. By taking advantage of the bulky and rigid 9-borabicyclo[3.3.1]-nonane (9-BBN) attaching point and a well-designed bis-imidazolylaryl, highly stable dimeric imidazolylboronium macrocycles were synthesized. Additionally, NMR spectroscopy ((1) H, DOSY, and HOESY), mass spectrometry (MS), and X-ray diffraction studies revealed that these macrocyclic scaffolds can bind several monoanions with high association constants in DMSO, and are particularly sensitive for the MS detection of anions (with concentrations in the nm range). This anion/receptor interaction involves eight C H binding sites, which include Csp2 -H and unusual Csp3 -H hydrogen-bonding donors. PMID- 27218820 TI - Indications for Three Independent Domestication Events for the Tea Plant (Camellia sinensis (L.) O. Kuntze) and New Insights into the Origin of Tea Germplasm in China and India Revealed by Nuclear Microsatellites. AB - BACKGROUND: Tea is the world's most popular non-alcoholic beverage. China and India are known to be the largest tea producing countries and recognized as the centers for the domestication of the tea plant (Camellia sinensis (L.) O. Kuntze). However, molecular studies on the origin, domestication and relationships of the main teas, China type, Assam type and Cambod type are lacking. METHODOLOGY/PRINCIPAL FINDINGS: Twenty-three nuclear microsatellite markers were used to investigate the genetic diversity, relatedness, and domestication history of cultivated tea in both China and India. Based on a total of 392 samples, high levels of genetic diversity were observed for all tea types in both countries. The cultivars clustered into three distinct genetic groups (i.e. China tea, Chinese Assam tea and Indian Assam tea) based on STRUCTURE, PCoA and UPGMA analyses with significant pairwise genetic differentiation, corresponding well with their geographical distribution. A high proportion (30%) of the studied tea samples were shown to possess genetic admixtures of different tea types suggesting a hybrid origin for these samples, including the Cambod type. CONCLUSIONS: We demonstrate that Chinese Assam tea is a distinct genetic lineage from Indian Assam tea, and that China tea sampled from India was likely introduced from China directly. Our results further indicate that China type tea, Chinese Assam type tea and Indian Assam type tea are likely the result of three independent domestication events from three separate regions across China and India. Our findings have important implications for the conservation of genetic stocks, as well as future breeding programs. PMID- 27218822 TI - Highly Ordered TiO2 Microcones with High Rate Performance for Enhanced Lithium Ion Storage. AB - The perpendicularly oriented anatase TiO2 microcones for Li-ion battery application were synthesized via anodization of a Ti foil in aqueous HF + H3PO4 solution. The TiO2 microcones exhibited a high active surface area with a hollow core depending on applied voltage and reaction time, confirmed by SEM, XRD and TEM with EDS mapping. Li insertion/desertion into TiO2 microcones was evaluated for the first time in half-cell configuration in terms of various current density and long-term cyclability. The electrochemical experiments demonstrated that the as-prepared TiO2 microcones as anode material exhibited 3 times higher capacity as compared with TiO2 nanotubular structures, excellent rate performance (0.054 mAhcm(-2) even at 50 C) and reliable capacity retention during 500 cycles, which was attributed to facile diffusion of Li-ions induced in hollow anatase TiO2 microcones structure with multilayered nanofragment. PMID- 27218821 TI - Differential Expression of Extracellular Matrix and Adhesion Molecules in Fetal Origin Amniotic Epithelial Cells of Preeclamptic Pregnancy. AB - Preeclampsia is a common disease that can occur during human pregnancy and is a leading cause of both maternal and neonatal morbidity and mortality. Inadequate trophoblast invasion and deficient remodeling of uterine spiral arteries are associated with preeclampsia (PE). The development of this syndrome is thought to be related to multiple factors. Recently, we isolated patient-specific human amniotic epithelial cells (AECs) from the placentas of 3 women with normal pregnancy and 3 with preeclamptic pregnancy. Since the characteristics of human AECs in PE are different from those in normal pregnancy, we sought to confirm the genes differentially expressed between preeclamptic pregnancy and normal pregnancy. Therefore, we performed transcriptome analysis to investigate the candidate genes associated with the possible pathophysiology of preeclampsia. Pathway analysis was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) and Kyoto Encyclopedia of Genes and Genomes (KEGG) online resource. In this study, we selected a total of 12 pathways and focused on extracellular matrix-related and biological adhesion molecules. Using RT-PCR array and real-time PCR, we confirmed that COL16A1, ITGB2, and LAMA3 were significantly up-regulated, but ITGA1, ITGA3, ITGA6, MMP1, MMP3, MMP10 and MMP11 were significantly down-regulated in preeclamptic fetal origin cells. Taken together, we suggest that the genes and pathways identified here may be responsible for the occurrence and development of PE, and controlling their expression may play a role in communication with fetal-maternal placenta to keep normal pregnancy. PMID- 27218823 TI - Synthesis and characterization of metallo-supramolecular polymers. AB - The incorporation of metal centers into the backbone of polymers has led to the development of a broad range of organometallic and coordination compounds featuring properties that are relevant for potential applications in diverse areas of research, ranging from energy storage/conversion to bioactive or self healing materials. In this review, the basic concepts and synthetic strategies leading to these types of materials as well as the scope of available characterization techniques will be summarized and discussed. PMID- 27218824 TI - Correction: Why Are Some Population Interventions for Diet and Obesity More Equitable and Effective Than Others? The Role of Individual Agency. AB - [This corrects the article DOI: 10.1371/journal.pmed.1001990.]. PMID- 27218825 TI - Nucleoside analogs: ready to enter the era of precision medicine? AB - INTRODUCTION: The term 'precision medicine' has garnered significant attention in the oncological setting in relation to attempts to optimize anticancer treatment. Precision medicine is mostly associated with oral targeted therapies and biotherapies, however, to date classic cytotoxics still remain the backbone of most regimens for treating solid tumors or in hematology, both in children and in adults. Among the existing cytotoxic therapies, nucleosides are widely used for treating a variety of cancerous diseases, alone or as part of combination therapies. AREAS COVERED: Several markers at the tumor or the germinal levels have been identified as being associated with clinical outcome (e.g. CDA, DPD, EONFS1, hENT1, TYMS, MTHFR), however little effort has been made to implement bioguided therapy with nucleoside analogs. Still, growing clinical evidence has demonstrated how the efficacy-toxicity balance of these drugs could be improved by developing bioguided strategies at the bedside. This review covers the current knowledge regarding putative markers to be used with nucleoside analogs, what is known on their pharmacokinetic/pharmacodynamic relationships, and provides clues for implementing precision medicine with those old, yet pivotal drugs. EXPERT OPINION: Through a variety of strategies ranging from pharmacogenetics, tumor genomics and pharmacokinetically-driven adaptive dosing procedures, nucleoside analogs could enter the era of precision medicine in oncology. PMID- 27218826 TI - Copy number changes of clinically actionable genes in melanoma, non-small cell lung cancer and colorectal cancer-A survey across 822 routine diagnostic cases. AB - Targeted deep massive parallel sequencing has been implemented in routine molecular diagnostics for high-throughput genetic profiling of formalin-fixed paraffin-embedded (FFPE) cancer samples. This approach is widely used to interrogate simple somatic mutations but experience with the analysis of copy number variations (CNV) is limited. Here, we retrospectively analyzed CNV in 822 cancer cases (135 melanoma, 468 non-small cell lung cancers (NSCLC), 219 colorectal cancers (CRC)). We observed a decreasing frequency of CNV in clinically actionable genes from melanoma to NSCLC to CRC. The overall cohort displayed 168 (20%) amplifications in 17 druggable targets. The majority of BRAF mutant melanomas (54%) showed co-occurring CNV in other genes, mainly affecting CDKN2A. Subsets showed clustered deletions in ABL1, NOTCH1, RET or STK11, GNA11, and JAK3. Most NRAS mutant melanomas (49%) harbored CNVs in other genes with CDKN2A and FGFR3 being most frequently affected. Five BRAF/NRASwt tumors had co amplifications of KDR, KIT, PDGFRA and another six mutated KIT. Among all NSCLC, we identified 14 EGFRamp (with ten EGFRmut) and eight KRASamp (with seven KRASmut). KRASmut tumors displayed frequent amplifications of MYC (n = 10) and MDM2 (n = 5). Fifteen KRAS/EGFR/BRAFwt tumors had MET mutations/amplifications. In CRC, amplified IGF2 was most prevalent (n = 13) followed by MYC (n = 9). Two cases showed amplified KRAS wildtype alleles. Two of the KRASmut cases harbored amplifications of NRAS and three KRASwt cases amplification of EGFR. In conclusion, we demonstrate that our approach i) facilitates detection of CNV, ii) enables detection of known CNV patterns, and iii) uncovers new CNV of clinically actionable genes in FFPE tissue samples across cancers. (c) 2016 Wiley Periodicals, Inc. PMID- 27218827 TI - Synthesis of Ultrasmall Cu2 O Nanocubes and Octahedra with Tunable Sizes for Facet-Dependent Optical Property Examination. AB - Size-tunable small to ultrasmall Cu2 O nanocubes and octahedra are synthesized in aqueous solution without the introduction of any surfactant. These nanocrystals provide strong evidence of the existence of facet-dependent optical absorption properties of Cu2 O nanoparticles, showing nanocubes always have a more redshifted absorption band than that of octahedra having a similar volume by about 15 nm. PMID- 27218828 TI - Transport properties through graphene grain boundaries: strain effects versus lattice symmetry. AB - As most materials available at the macroscopic scale, graphene samples usually appear in a polycrystalline form and thus contain grain boundaries. In the present work, the effect of uniaxial strain on the electronic transport properties through graphene grain boundaries is investigated using atomistic simulations. A systematic picture of transport properties with respect to the strain and lattice symmetry of graphene domains on both sides of the boundary is provided. In particular, it is shown that strain engineering can be used to open a finite transport gap in all graphene systems where the two domains are arranged in different orientations. This gap value is found to depend on the strain magnitude, on the strain direction and on the lattice symmetry of graphene domains. By choosing appropriately the strain direction, a large transport gap of a few hundred meV can be achieved when applying a small strain of only a few percents. For a specific class of graphene grain boundary systems, strain engineering can also be used to reduce the scattering on defects and thus to significantly enhance the conductance. With a large strain-induced gap, these graphene heterostructures are proposed to be promising candidates for highly sensitive strain sensors, flexible electronic devices and p-n junctions with non linear I-V characteristics. PMID- 27218829 TI - Assessing Greater Sage-Grouse Selection of Brood-Rearing Habitat Using Remotely Sensed Imagery: Can Readily Available High-Resolution Imagery Be Used to Identify Brood-Rearing Habitat Across a Broad Landscape? AB - Greater sage-grouse populations have decreased steadily since European settlement in western North America. Reduced availability of brood-rearing habitat has been identified as a limiting factor for many populations. We used radio-telemetry to acquire locations of sage-grouse broods from 1998 to 2012 in Strawberry Valley, Utah. Using these locations and remotely-sensed NAIP (National Agricultural Imagery Program) imagery, we 1) determined which characteristics of brood-rearing habitat could be used in widely available, high resolution imagery 2) assessed the spatial extent at which sage-grouse selected brood-rearing habitat, and 3) created a predictive habitat model to identify areas of preferred brood-rearing habitat. We used AIC model selection to evaluate support for a list of variables derived from remotely-sensed imagery. We examined the relationship of these explanatory variables at three spatial extents (45, 200, and 795 meter radii). Our top model included 10 variables (percent shrub, percent grass, percent tree, percent paved road, percent riparian, meters of sage/tree edge, meters of riparian/tree edge, distance to tree, distance to transmission lines, and distance to permanent structures). Variables from each spatial extent were represented in our top model with the majority being associated with the larger (795 meter) spatial extent. When applied to our study area, our top model predicted 75% of naive brood locations suggesting reasonable success using this method and widely available NAIP imagery. We encourage application of our methodology to other sage-grouse populations and species of conservation concern. PMID- 27218830 TI - A Comparison of the Cheater Detection and the Unrelated Question Models: A Randomized Response Survey on Physical and Cognitive Doping in Recreational Triathletes. AB - PURPOSE: This study assessed the prevalence of physical and cognitive doping in recreational triathletes with two different randomized response models, that is, the Cheater Detection Model (CDM) and the Unrelated Question Model (UQM). Since both models have been employed in assessing doping, the major objective of this study was to investigate whether the estimates of these two models converge. MATERIAL AND METHODS: An anonymous questionnaire was distributed to 2,967 athletes at two triathlon events (Frankfurt and Wiesbaden, Germany). Doping behavior was assessed either with the CDM (Frankfurt sample, one Wiesbaden subsample) or the UQM (one Wiesbaden subsample). A generalized likelihood-ratio test was employed to check whether the prevalence estimates differed significantly between models. In addition, we compared the prevalence rates of the present survey with those of a previous study on a comparable sample. RESULTS: After exclusion of incomplete questionnaires and outliers, the data of 2,017 athletes entered the final data analysis. Twelve-month prevalence for physical doping ranged from 4% (Wiesbaden, CDM and UQM) to 12% (Frankfurt CDM), and for cognitive doping from 1% (Wiesbaden, CDM) to 9% (Frankfurt CDM). The generalized likelihood-ratio test indicated no differences in prevalence rates between the two methods. Furthermore, there were no significant differences in prevalences between the present (undertaken in 2014) and the previous survey (undertaken in 2011), although the estimates tended to be smaller in the present survey. DISCUSSION: The results suggest that the two models can provide converging prevalence estimates. The high rate of cheaters estimated by the CDM, however, suggests that the present results must be seen as a lower bound and that the true prevalence of doping might be considerably higher. PMID- 27218831 TI - Deficits in axon-associated proteins in prefrontal white matter in bipolar disorder but not schizophrenia. AB - OBJECTIVES: Brain imaging studies have implicated white matter dysfunction in the pathophysiology of both bipolar disorder (BD) and schizophrenia (SCZ). However, the contribution of axons to white matter pathology in these disorders is not yet understood. Maintenance of neuronal function is dependent on the active transport of biological material, including synaptic proteins, along the axon. In this study, the expression of six proteins associated with axonal transport of synaptic cargoes was quantified in postmortem samples of prefrontal white matter in subjects with BD, those with SCZ, and matched controls, as a measure of axonal dysfunction in these disorders. METHODS: Levels of the microtubule-associated proteins beta-tubulin and microtubule-associated protein 6 (MAP6), the motor and accessory proteins kinesin-1 and disrupted-in-schizophrenia 1 (DISC1), and the synaptic cargoes synaptotagmin and synaptosomal-associated protein-25 (SNAP-25) were quantified in white matter adjacent to the dorsolateral prefrontal cortex in subjects with BD (n = 34), subjects with SCZ (n = 35), and non-psychiatric controls (n = 35) using immunoblotting and an enzyme-linked immunosorbent assay (ELISA). RESULTS: Protein expression of beta-tubulin, kinesin-1, DISC1, synaptotagmin, and SNAP-25 was significantly lower in subjects with BD compared to controls. Levels of axon-associated proteins were also lower in subjects with SCZ, but failed to reach statistical significance. CONCLUSIONS: These data provide evidence for deficits in axon-associated proteins in prefrontal white matter in BD. Findings are suggestive of decreased axonal density or dysregulation of axonal function in this disorder. PMID- 27218832 TI - Bayesian analysis of censored response data in family-based genetic association studies. AB - Biomarkers are subject to censoring whenever some measurements are not quantifiable given a laboratory detection limit. Methods for handling censoring have received less attention in genetic epidemiology, and censored data are still often replaced with a fixed value. We compared different strategies for handling a left-censored continuous biomarker in a family-based study, where the biomarker is tested for association with a genetic variant, S, adjusting for a covariate, X. Allowing different correlations between X and S, we compared simple substitution of censored observations with the detection limit followed by a linear mixed effect model (LMM), Bayesian model with noninformative priors, Tobit model with robust standard errors, the multiple imputation (MI) with and without S in the imputation followed by a LMM. Our comparison was based on real and simulated data in which 20% and 40% censoring were artificially induced. The complete data were also analyzed with a LMM. In the MICROS study, the Bayesian model gave results closer to those obtained with the complete data. In the simulations, simple substitution was always the most biased method, the Tobit approach gave the least biased estimates at all censoring levels and correlation values, the Bayesian model and both MI approaches gave slightly biased estimates but smaller root mean square errors. On the basis of these results the Bayesian approach is highly recommended for candidate gene studies; however, the computationally simpler Tobit and the MI without S are both good options for genome-wide studies. PMID- 27218833 TI - The metaethics of nursing codes of ethics and conduct. AB - Nursing codes of ethics and conduct are features of professional practice across the world, and in the UK, the regulator has recently consulted on and published a new code. Initially part of a professionalising agenda, nursing codes have recently come to represent a managerialist and disciplinary agenda and nursing can no longer be regarded as a self-regulating profession. This paper argues that codes of ethics and codes of conduct are significantly different in form and function similar to the difference between ethics and law in everyday life. Some codes successfully integrate these two functions within the same document, while others, principally the UK Code, conflate them resulting in an ambiguous document unable to fulfil its functions effectively. The paper analyses the differences between ethical-codes and conduct-codes by discussing titles, authorship, level, scope for disagreement, consequences of transgression, language and finally and possibly most importantly agent-centeredness. It is argued that conduct-codes cannot require nurses to be compassionate because compassion involves an emotional response. The concept of kindness provides a plausible alternative for conduct-codes as it is possible to understand it solely in terms of acts. But if kindness is required in conduct-codes, investigation and possible censure follows from its absence. Using examples it is argued that there are at last five possible accounts of the absence of kindness. As well as being potentially problematic for disciplinary panels, difficulty in understanding the features of blameworthy absence of kindness may challenge UK nurses who, following a recently introduced revalidation procedure, are required to reflect on their practice in relation to The Code. It is concluded that closer attention to metaethical concerns by code writers will better support the functions of their issuing organisations. PMID- 27218834 TI - Recent advances in marine N-cycle studies using 15N labeling methods. AB - 15N enriched compounds such as ammonium and nitrate, as well as 15-15N2 gas are invaluable tools in marine N-cycle research. 15N stable isotope approaches allow researchers to delve into the often complex world of N-transformations and trace microbially mediated processes such as nitrification, denitrification, anammox and N-fixation. While 15N stable isotope approaches are well established, experimental approaches which take advantage of them are constantly evolving. Here we summarize recent advances in methodology, including in the direct application of 15N stable isotopes themselves, improved experimental design and the use of 15N stable isotopes in single cell studies. Furthermore, we discuss how these advances have led to new insights into marine N-cycling, particularly in the fields of nitrification and N-fixation. PMID- 27218835 TI - The Glasgow Coma Scale and evidence-informed practice: a critical review of where we are and where we need to be. AB - AIMS AND OBJECTIVES: This paper aims to critically consider the evidence since the Glasgow Coma Scale was first launched, reflecting on how that evidence has shaped practice. It illustrates the lack of clarity and consensus about the use of the tool in practice and draws upon existing evidence to determine the route to clarity for an evidence-informed approach to practice. BACKGROUND: The Glasgow Coma Scale has permeated and influenced practice for over 40 years, being well established worldwide as the key tool for assessing level of consciousness. During this time, the tool has been scrutinised, evaluated, challenged and re launched in a plethora of publications. This has led to an insight into the challenges, and to some extent the opportunities, in using the Glasgow Coma Scale in practice but has also resulted in a lack of clarity. DESIGN: This is a discursive paper that invites readers to explore and arrive at a more comprehensive understanding of the Glasgow Coma Scale in practice and is based on searches of Scopus, Web of Knowledge, PubMed, Science Direct and CINAHL databases. RESULTS: While the Glasgow Coma Scale has been rivalled by other tools in an attempt to improve upon it, a shift in practice to those tools has not occurred. The tool has withstood the test of time in this respect, indicating the need for further research into its use and a clear education strategy to standardise implementation in practice. CONCLUSION: Further exploration is needed into the application of painful stimuli in using the Glasgow Coma Scale to assess level of consciousness. In addition, a robust educational strategy is necessary to maximise consistency in its use in practice. RELEVANCE TO CLINICAL PRACTICE: The evidence illustrates inconsistency and confusion in the use of the Glasgow Coma Scale in practice; this has the potential to compromise care and clarity around the issues is therefore necessary. PMID- 27218837 TI - New Xist-Interacting Proteins in X-Chromosome Inactivation. PMID- 27218836 TI - Online Health Communities and Chronic Disease Self-Management. AB - This research uses content analysis (N = 1,960) to examine the computer-mediated communication within online health communities for evidence of chronic disease self-management behaviors, including the perceived benefits and perceived barriers to participating in such behaviors. Online health communities act as informal self-management programs led by peers with the same chronic disease through the exchange of health information. Online health communities provide opportunities for health behavior change messages to educate and persuade regarding chronic disease self-management behaviors. PMID- 27218838 TI - period-Regulated Feeding Behavior and TOR Signaling Modulate Survival of Infection. PMID- 27218839 TI - Magic and cognitive neuroscience. AB - In recent years, neuroscientists have shown an increasing interest in magic. One reason for this is the parallels that can be drawn between concepts that have long been discussed in magic theory, particularly misdirection, and those that are routinely studied in cognitive neuroscience, such as attention and, as argued in this essay, different forms of memory. A second and perhaps more attractive justification for this growing interest is that magic tricks offer novel experimental approaches to cognitive neuroscience. In fact, magicians continuously demonstrate in very engaging ways one of the most basic principles of brain function - how the brain constructs a subjective reality using assumptions based on relatively little and ambiguous information. PMID- 27218840 TI - Shelterin. AB - Schmutz and de Lange discuss the shelterin complex, which binds to mammalian telomeres and allows for the natural ends of chromosomes to be distinguished from sites of DNA damage. PMID- 27218841 TI - Molecular clocks. AB - In the 1960s, several groups of scientists, including Emile Zuckerkandl and Linus Pauling, had noted that proteins experience amino acid replacements at a surprisingly consistent rate across very different species. This presumed single, uniform rate of genetic evolution was subsequently described using the term 'molecular clock'. Biologists quickly realised that such a universal pacemaker could be used as a yardstick for measuring the timescale of evolutionary divergences: estimating the rate of amino acid exchanges per unit of time and applying it to protein differences across a range of organisms would allow deduction of the divergence times of their respective lineages (Figure 1). PMID- 27218842 TI - Tending a dying adult in a wild multi-level primate society. AB - Responses of nonhuman species to dying and dead conspecifics range from hard wired, fixed-action patterns - as in social insects - to varied, flexible behaviors with cognitive and emotional correlates - as in some larger-brained mammals [1,2]. Comparative thanatology addresses issues that include empathy, compassion, and conceptual understanding of death across species [1-3]. Several aspects of how great apes react to illness, injury and death of others recall human behavior in comparable situations [1-5]. However, the extent to which more distantly related primates share these responses is largely unknown. Here, we describe behaviors shown toward a dying adult female in wild Sichuan snub-nosed monkeys (Rhinopithecus roxellana) [6] and argue that empathy and compassion surrounding death extend beyond humans and their closest evolutionary relatives. PMID- 27218843 TI - Best practice for minimising unmanned aerial vehicle disturbance to wildlife in biological field research. AB - The use of unmanned aerial vehicles (UAVs), colloquially referred to as 'drones', for biological field research is increasing [1-3]. Small, civilian UAVs are providing a viable, economical tool for ecology researchers and environmental managers. UAVs are particularly useful for wildlife observation and monitoring as they can produce systematic data of high spatial and temporal resolution [4]. However, this new technology could also have undesirable and unforeseen impacts on wildlife, the risks of which we currently have little understanding [5-7]. There is a need for a code of best practice in the use of UAVs to mitigate or alleviate these risks, which we begin to develop here. PMID- 27218844 TI - Global proliferation of cephalopods. AB - Human activities have substantially changed the world's oceans in recent decades, altering marine food webs, habitats and biogeochemical processes [1]. Cephalopods (squid, cuttlefish and octopuses) have a unique set of biological traits, including rapid growth, short lifespans and strong life-history plasticity, allowing them to adapt quickly to changing environmental conditions [2-4]. There has been growing speculation that cephalopod populations are proliferating in response to a changing environment, a perception fuelled by increasing trends in cephalopod fisheries catch [4,5]. To investigate long-term trends in cephalopod abundance, we assembled global time-series of cephalopod catch rates (catch per unit of fishing or sampling effort). We show that cephalopod populations have increased over the last six decades, a result that was remarkably consistent across a highly diverse set of cephalopod taxa. Positive trends were also evident for both fisheries-dependent and fisheries-independent time-series, suggesting that trends are not solely due to factors associated with developing fisheries. Our results suggest that large-scale, directional processes, common to a range of coastal and oceanic environments, are responsible. This study presents the first evidence that cephalopod populations have increased globally, indicating that these ecologically and commercially important invertebrates may have benefited from a changing ocean environment. PMID- 27218845 TI - Hygrosensation: Feeling Wet and Cold. AB - Identification of ionotropic receptors required for hygrosensation in Drosophila supports the notion that hygrosensory neurons across insects share common morphological and anatomical features. This further advances the field by uncovering central circuits that respond to both humidity and temperature. PMID- 27218846 TI - Mitochondrial Evolution: Going, Going, Gone. AB - Monocercomonoides is the first example of a eukaryote lacking even the most reduced form of a mitochondrion-related organelle. This has important implications for cellular processes and our understanding of reductive mitochondrial evolution across the eukaryotic tree of life. PMID- 27218847 TI - Imitation: Not in Our Genes. AB - A powerful longitudinal study has failed to find any evidence that newborn babies can imitate facial gestures, hand movements or vocalisations. After 40 years of uncertainty, these findings indicate that humans learn to imitate; this capacity is not inborn. PMID- 27218848 TI - Evolution: How Some Birds Survived When All Other Dinosaurs Died. AB - The end-Cretaceous mass extinction wiped out the dinosaurs, including many birds. But some bird lineages survived. May seed-eating have been the key? PMID- 27218849 TI - Plant Organ Growth: Stopping Under Stress. AB - Plant organs reproducibly reach a set size and shape, and a key question is what prevents overgrowth. A new study uses imaging and computer modelling of the Arabidopsis sepal to show that mechanics determines growth arrest and thus final organ shape. PMID- 27218850 TI - Quantity Cognition: Numbers, Numerosity, Zero and Mathematics. AB - Physical quantities differ from abstract numbers and mathematics, but recent results are revealing the neural representation of both: a new study demonstrates how an absence of quantity is transformed into a representation of zero as a number. PMID- 27218851 TI - Vocal Development: How Marmoset Infants Express Their Feelings. AB - A new study shows that vocal sequences produced by newborn marmoset monkeys are driven by slow fluctuations in physiological state; the results shed light on the evolution of vocal communication between newborns and parents. PMID- 27218852 TI - Animal Evolution: Are Phyla Real? AB - A recent study compares developmental gene expression among very distantly related animal species and interprets the results as providing biological justification for phyla. Several problems in the design and interpretation of the study call this conclusion into question. PMID- 27218853 TI - Evolution: Endogenous Viruses Provide Shortcuts in Antiviral Immunity. AB - Endogenous viruses are occasionally co-opted by their hosts to combat other viruses. The discovery of the widespread recruitment of endogenous viruses as regulatory elements for immune genes points to a systematic evolutionary process in their co-option for host immunity. PMID- 27218854 TI - Host-Symbiont Interactions: Male-Killers Exposed. AB - Male-killing is one strategy used by maternally transmitted bacterial symbionts to boost transmission and spread in populations. In Drosophila melanogaster, Spiroplasma target males by hijacking an essential, male-limited epigenetic process. A new study reveals clues to the mode of killing. PMID- 27218855 TI - The Circadian Clock and Human Health. AB - Epidemiological studies provided the first evidence suggesting a connection between the circadian clock and human health. Mutant mice convincingly demonstrate the principle that dysregulation of the circadian system leads to a multitude of pathologies. Chrono-medicine is one of the most important upcoming themes in the field of circadian biology. Although treatments counteracting circadian dysregulation are already being applied (e.g., prescribing strong and regular zeitgebers), we need to comprehend entrainment throughout the body's entire circadian network before understanding the mechanisms that tie circadian dysregulation to pathology. Here, we attempt to provide a systematic approach to understanding the connection between the circadian clock and health. This taxonomy of (mis)alignments on one hand exposes how little we know about entrainment within any organism and which 'eigen-zeitgeber' signals are used for entrainment by the different cells and tissues. On the other hand, it provides focus for experimental approaches and tools that will logically map out how circadian systems contribute to disease as well as how we can treat and prevent them. PMID- 27218856 TI - Understanding the Formation of Salt-Inclusion Phases: An Enhanced Flux Growth Method for the Targeted Synthesis of Salt-Inclusion Cesium Halide Uranyl Silicates. AB - Salt-inclusion compounds (SICs) are known for their structural diversity and their potential applications, including luminescence and radioactive waste storage forms. Currently, the majority of salt-inclusion phases are grown serendipitously and the targeted growth of SICs has met with only moderate success. We report an enhanced flux growth method for the targeted growth of SICs. Specifically, the use of (1) metal halide reagents and (2) reactions with small surface area to volume ratios are found to favor the growth of salt inclusion compounds over pure oxides and thus enable a more targeted synthetic route for their preparation. The Cs-X-U-Si-O (X = F, Cl) pentanary phase space is used as a model system to demonstrate the generality of this enhanced flux method approach. Single crystals of four new salt-inclusion uranyl silicates, [Cs3F][(UO2)(Si4O10)], [Cs2Cs5F][(UO2)2(Si6O17)], [Cs9Cs6Cl][(UO2)7(Si6O17)2(Si4O12)], and [Cs2Cs5F][(UO2)3(Si2O7)2], were grown using this enhanced flux growth method. A detailed discussion of the factors that favor salt-inclusion phases during synthesis and why specifically uranyl silicates make excellent frameworks for salt-inclusion phases is given. PMID- 27218857 TI - Question order bias in retrospective evaluations of item and associative recognition. AB - Previous research has demonstrated a retrospective memory bias in metacognitive judgments regarding performance on general knowledge questions: Test-takers rate their own performance more optimistically when tests begin with easy questions than when tests begin with hard questions. An anchoring heuristic has been proposed to explain this finding, in which experience with the early questions constrains global performance evaluations of the test. In the current study we report on two experiments using tasks of item recognition and associative recognition to investigate the generality of question order bias. As predicted by an anchoring explanation, participants' estimates of performance were higher for item recognition tests beginning with easy items. However, the effect was reversed in the associative recognition task: Participants' estimates of performance were higher for tests beginning with hard items. Specific recollections, if present, may have a greater impact on test performance perception than more general global impressions. PMID- 27218858 TI - Educational differences in likelihood of attributing breast symptoms to cancer: a vignette-based study. AB - BACKGROUND: Stage at diagnosis of breast cancer varies by socio-economic status (SES), with lower SES associated with poorer survival. We investigated associations between SES (indexed by education), and the likelihood of attributing breast symptoms to breast cancer. METHOD: We conducted an online survey with 961 women (47-92 years) with variable educational levels. Two vignettes depicted familiar and unfamiliar breast changes (axillary lump and nipple rash). Without making breast cancer explicit, women were asked 'What do you think this [.....] could be?' After the attribution question, women were asked to indicate their level of agreement with a cancer avoidance statement ('I would not want to know if I have breast cancer'). RESULTS: Women were more likely to mention cancer as a possible cause of an axillary lump (64%) compared with nipple rash (30%). In multivariable analysis, low and mid education were independently associated with being less likely to attribute a nipple rash to cancer (OR 0.51, 0.36-0.73 and OR 0.55, 0.40-0.77, respectively). For axillary lump, low education was associated with lower likelihood of mentioning cancer as a possible cause (OR 0.58, 0.41-0.83). Although cancer avoidance was also associated with lower education, the association between education and lower likelihood of making a cancer attribution was independent. CONCLUSION: Lower education was associated with lower likelihood of making cancer attributions for both symptoms, also after adjustment for cancer avoidance. Lower likelihood of considering cancer may delay symptomatic presentation and contribute to educational differences in stage at diagnosis. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27218859 TI - Determination of 7alpha-OH cholesterol by LC-MS/MS: Application in assessing the activity of CYP7A1 in cholestatic minipigs. AB - An LC-MS/MS method was developed and validated to determine 7alpha-OH cholesterol in liver microsome. This method was convenient and fast with high specificity and sensitivity. Briefly, a gradient elution was performed on a Synergi polar-C18 column (50*4.6mm i.d., 3MUm). The mobile phase (consisting of 0.1% HCOOH solution and acetonitrile) eluted in gradient at a flow rate of 1ml/min. MS detection was operated on APCI (+) mode; the MRM transitions for 7alpha-OH cholesterol and D7 cholesterol (I.S.) were 385.1>=159.1 and 376.4>=266.3, respectively. The linear response range of 7alpha-OH cholesterol was covered from 1.563 to 100.0ng/ml. All of the validation items meet the requirement of FDA guidance for bioanalytical method validation. This method was applied to enzymatic studies for determination of cholesterol 7alpha-hydroxylation activity catalyzed by CYP7A1 in the cholestatic minipigs liver microsomes. PMID- 27218861 TI - Importance of Esophageal Manometry and pH Monitoring in the Evaluation of Patients with Refractory Gastroesophageal Reflux Disease: A Multicenter Study. AB - BACKGROUND: Patients who have heartburn are treated with acid-reducing medications on the assumption that gastroesophageal reflux disease (GERD) is causing the symptom. In the absence of a response to therapy, patients are often assumed to have refractory GERD, and they are referred for laparoscopic antireflux surgery (LARS), often without further diagnostic evaluation. HYPOTHESIS: We hypothesized that (1) in some patients with refractory GERD, the heartburn is not secondary to reflux, but rather to stasis and fermentation of food in the presence of achalasia and (2) esophageal manometry and pH monitoring are essential to establish proper diagnosis. PATIENTS AND METHODS: Five hundred twenty-four patients, whose final diagnosis was achalasia, were referred to two quaternary care centers. Symptomatic evaluation, barium swallow, endoscopy, manometry, and pH monitoring were performed in all patients. RESULTS: One hundred fifty-two patients (29%) had been treated with acid-reducing medications for an average of 29.3 months, and were referred for LARS because of lack of response to medical therapy. One patient had already been treated with a Nissen fundoplication. All patients were diagnosed with achalasia and underwent Heller myotomy and partial fundoplication. CONCLUSIONS: The results of this study showed that (1) one-third of achalasia patients complained of heartburn and (2) patients with heartburn not responding to medical treatment must be carefully evaluated before referral to surgery. These data confirm the importance of esophageal manometry and pH monitoring in any patient considered for LARS. PMID- 27218860 TI - 5,10b-Ethanophenanthridine amaryllidaceae alkaloids inspire the discovery of novel bicyclic ring systems with activity against drug resistant cancer cells. AB - Plants of the Amaryllidaceae family produce a large variety of alkaloids and non basic secondary metabolites, many of which are investigated for their promising anticancer activities. Of these, crinine-type alkaloids based on the 5,10b ethanophenanthridine ring system were recently shown to be effective at inhibiting proliferation of cancer cells resistant to various pro-apoptotic stimuli and representing tumors with dismal prognoses refractory to current chemotherapy, such as glioma, melanoma, non-small-cell lung, esophageal, head and neck cancers, among others. Using this discovery as a starting point and taking advantage of a concise biomimetic route to the crinine skeleton, a collection of crinine analogues were synthetically prepared and evaluated against cancer cells. The compounds exhibited single-digit micromolar activities and retained this activity in a variety of drug-resistant cancer cell cultures. This investigation resulted in the discovery of new bicyclic ring systems with significant potential in the development of effective clinical cancer drugs capable of overcoming cancer chemotherapy resistance. PMID- 27218862 TI - ExActa: blood pressure. PMID- 27218863 TI - gamma-Aminobutyric acid addition alleviates ammonium toxicity by limiting ammonium accumulation in rice (Oryza sativa) seedlings. AB - Excessive use of nitrogen (N) fertilizer has increased ammonium (NH4+ ) accumulation in many paddy soils to levels that reduce rice vegetative biomass and yield. Based on studies of NH4+ toxicity in rice (Oryza sativa, Nanjing 44) seedlings cultured in agar medium, we found that NH4+ concentrations above 0.75 mM inhibited the growth of rice and caused NH4+ accumulation in both shoots and roots. Use of excessive NH4+ also induced rhizosphere acidification and inhibited the absorption of K, Ca, Mg, Fe and Zn in rice seedlings. Under excessive NH4+ conditions, exogenous gamma-aminobutyric acid (GABA) treatment limited NH4+ accumulation in rice seedlings, reduced NH4+ toxicity symptoms and promoted plant growth. GABA addition also reduced rhizosphere acidification and alleviated the inhibition of Ca, Mg, Fe and Zn absorption caused by excessive NH4+ . Furthermore, we found that the activity of glutamine synthetase/NADH-glutamate synthase (GS; EC 6.3.1.2/NADH-GOGAT; EC1.4.1.14) in root increased gradually as the NH4+ concentration increased. However, when the concentration of NH4+ is more than 3 mM, GABA treatment inhibited NH4+ -induced increases in GS/NADH-GOGAT activity. The inhibition of ammonium assimilation may restore the elongation of seminal rice roots repressed by high NH4+ . These results suggest that mitigation of ammonium accumulation and assimilation is essential for GABA-dependent alleviation of ammonium toxicity in rice seedlings. PMID- 27218864 TI - Electron-Driven Metal Oxide Effusion and Graphene Gasification at Room Temperature. AB - Metal oxide nanoparticles decorating graphene have attracted abundant interest in the scientific community owing to their significant application in various areas such as batteries, gas sensors, and photocatalysis. In addition, metal and metal oxide nanoparticles are of great interest for the etching of graphene, for example, to form nanoribbons, through gasification reactions. Hence it is important to have a good understanding of how nanoparticles interact with graphene. In this work we examine, in situ, the behavior of CuO and ZnO nanoparticles on graphene at room temperature while irradiated by electrons in a transmission electron microscope. ZnO is shown to etch graphene through gasification. In the gasification reaction C from graphene is released as CO or CO2. We show that the reaction can occur at room temperature. Moreover, CuO and ZnO particles trapped within a graphene fold are shown to effuse out of a fold through small ruptures. The mass transport in the effusion process between the CuO and ZnO particles is fundamentally different. Mass transport for CuO occurs in an amorphous phase, while for ZnO mass transport occurs through the short lived gliding of vacancies and dislocations. The work highlights the potential and wealth of electron beam driven chemical reactions of nanomaterials, even at room temperature. PMID- 27218865 TI - Weight misperception among young adults with overweight/obesity associated with disordered eating behaviors. AB - OBJECTIVE: The purpose of this study was to examine the cross-sectional association between weight misperception among young adults with overweight/obesity and disordered eating behaviors. METHOD: In a subsample of young adults with overweight or obesity participating in Wave III (2001-2002) of The National Longitudinal Study of Adolescent to Adult Health (n = 5,184), we examined the cross-sectional association between weight under-perception (i.e., perceiving oneself to be at a healthy body weight or underweight) and disordered eating (fasting/meal skipping for weight control, purging/pills for weight control, overeating/loss of control eating, and use of performance-enhancing products/substances). RESULTS: About 20% of young adult females under-perceived their weight compared to 48% of males. Individuals who misperceived their weight as healthy were significantly less likely to report fasting/meal skipping (Females: OR: 0.25, 95% CI: 0.14-0.43; Males: OR: 0.31, 95% CI: 0.20-0.48) and vomiting or taking diet pills/laxatives/diuretics (Females: OR: 0.10, 95% CI: 0.04-0.25; Males: OR: 0.10, 95% CI: 0.04-0.25) for weight control. Among females, those who misperceived their weight status as healthy were also less likely to report overeating or loss of control eating (OR: 0.41, 95% CI: 0.24-0.71). Greater use of performance-enhancing products/substances was seen among males who under-perceived their weight as healthy (OR: 2.06, 95% CI: 1.57-2.72) and among both females (OR: 2.29, 95% CI: 1.40-20.0) and males (OR: 2.27, 95% CI: 1.13 4.55) who perceived themselves to be underweight. DISCUSSION: Weight under perception among young adults with overweight/obesity may convey some benefit related to disordered eating behaviors, but could be a risk factor for the use of performance-enhancing products/substances. (c) 2016 Wiley Periodicals, Inc. (Int J Eat Disord ; 49:937-946). PMID- 27218866 TI - The treatment of CML at an environment with limited resources. AB - OBJECTIVES: This article reviews clinical experiences in the treatment of chronic myeloid leukemia (CML) in an environment of limited resources. METHODS: We reviewed recent publications on Pub med and abstracts from mayor congresses relevant to the disease. RESULTS: CML is a hematological neoplasm observed more frequently in adults, regardless of their socioeconomic status. Until recently, available treatments improved patients' quality of life but did not modify survival. It was not until interferon appeared that patients received a drug that reduced and even eliminated Philadelphia chromosome-positive (Ph+) cells. DISCUSSION: With the start of the new millennium, the International Randomized Study of Interferon-alpha plus cytarabine versus STI571 (IRIS) trial demonstrated a dramatic improvement in survival by comparing imatinib versus interferon alpha plus cytarabine. The Food and Drug Administration (FDA) approved imatinib as first-line treatment for newly diagnosed CML in 2001 due to its outstanding effectiveness. Years later, three second-generation (dasatinib, nilotinib, bosutinib) and one third-generation (ponatinib) tyrosine-kinase inhibitors (TKIs) were developed and approved. These highly effective treatment options, however, are not affordable for many low-income patients. Additionally, the use of drugs that effectively treat but do not cure the disease has resulted in an important economic impact for patients and health care systems worldwide, especially those in developing countries. Imatinib is the least expensive and a very effective TKI in many low-income countries. Early allogeneic stem cell transplantation must be considered in the management of selected patients before CML transformation. PMID- 27218867 TI - Central nervous system involvement in breast cancer patients: Is the therapeutic landscape changing too slowly? AB - Central nervous system (CNS) involvement from breast cancer (BC) has been historically considered a relatively rare event. However, the development of new therapeutic strategies with a better control of extra-cranial disease and a longer overall survival (OS) has determined an increased incidence of brain metastases. Patients with HER2-positive or triple negative BC have higher occurrence of CNS involvement than patients with luminal-like disease. Moreover, after development of brain metastases, the prognosis is highly influenced by biological subtype. In patients with multiple brain metastases who experience important neurological symptoms, palliative treatment, with or without whole brain radiation therapy (WBRT), needs to be considered the first step of a multidisciplinary therapeutic approach. Patients with a good performance status and 1-3 brain lesions should be considered for radical surgery; patients technically inoperable with 4-5 metastases smaller than 3cm may undergo stereotactic radiosurgery. The role of systemic therapy in the management of patients with brain metastases is controversial. Preliminary data suggest that systemic therapy after WBRT may improve survival in BC patients with brain lesions. In patients with HER2-positive disease, several retrospective or post hoc analyses showed a longer brain progression-free survival with trastuzumab in combination with or followed by other anti-HER2 drugs (such as pertuzumab, lapatinib, and T-DM1). Until now, no new strategies or drugs are available for triple-negative and luminal-like BC. PMID- 27218868 TI - Efficacy of mirtazapine for the treatment of fibromyalgia without concomitant depression: a randomized, double-blind, placebo-controlled phase IIa study in Japan. AB - To evaluate the efficacy and safety of mirtazapine in Japanese patients with fibromyalgia (FM), a parallel-group, randomized, double-blind, placebo-controlled phase IIa study was conducted at 57 sites between November 2012 and February 2014. Patients aged 20 to 64 years who met the American College of Rheumatology 1990 diagnostic FM criteria and had stably high pain scores during a placebo run in period were randomly assigned (1:1) by a computer-generated allocation sequence (block size 4) to receive mirtazapine orally (15 mg/d for 1 week and then 30 mg/d) or matching placebo for 12 weeks. The primary endpoint was change in mean numerical rating scale (NRS) pain score from baseline to endpoint (week 12 or early discontinuation). Of the 430 patients randomized (n = 215 each group), 422 (n = 211 each group) were analyzed for the primary endpoint. At the study endpoint, mirtazapine caused a significantly greater reduction in the mean NRS pain score compared with placebo (difference, 0.44; 95% confidence interval, 0.72 to -0.17; P = 0.0018). The reduction by mirtazapine remained significantly greater compared with placebo from week 6 onward. More patients treated with mirtazapine had their NRS pain score reduced by >=30% from baseline (45.5% vs 30.8%). Mirtazapine also improved pain-related quality of life assessed by the Japanese version of the Fibromyalgia Impact Questionnaire and the Short-Form 36 Questionnaire. Adverse events were more common with mirtazapine than placebo (68.8% vs 56.7%), including somnolence (32.1% vs 7.4%), weight gain (17.7% vs 0.9%), and increased appetite (11.6% vs 3.3%). In conclusion, mirtazapine was an effective and safe treatment for Japanese patients with FM. PMID- 27218870 TI - Insular balance of glutamatergic and GABAergic signaling modulates pain processing. AB - Neuroimaging studies of patients with chronic pain have shown that neurotransmitter abnormalities, including increases in glutamate and decreases in GABA, could be responsible for the cortical hyperactivity and hyperalgesia/allodynia observed in some pain conditions. These finding are particularly evident in the insula, a brain region known to play a role in both the sensory-discriminative and the affective-motivational aspects of pain processing. However, clinical studies are not entirely able to determine the directionality of these findings, nor whether they are causal or epiphenomenon. Thus, a set of animal studies was performed to determine whether alterations in glutamate and GABA are the result of injury, the cause of augmented pain processing, or both. Compared with controls, the excitatory neurotransmitters glutamate and aspartate are significantly higher in the rat insula after chronic constriction injury of the sciatic nerve (CCI). The CCI also produced significant increases in allodynia (mechanical and cold), thermal hyperalgesia, and nociceptive aversiveness. Unilateral microinjection of ionotropic glutamate receptor antagonists restored these nociceptive behaviors to preinjury values. Increasing endogenous levels of GABA or enhancing signaling at inhibitory glycinergic receptors had similar effects as the glutamate receptor antagonists. In naive rats, increasing endogenous levels of glutamate, decreasing endogenous levels of GABA, or blocking strychnine-sensitive glycine receptors in the insula significantly increased thermal hyperalgesia and mechanical allodynia. These data support the hypothesis that an altered balance of excitatory and inhibitory neurotransmitters in brain regions such as the insula occurs in chronic pain states and leads to augmented central pain processing and increased pain sensitivity. PMID- 27218869 TI - Group II mGluRs suppress hyperexcitability in mouse and human nociceptors. AB - We introduce a strategy for preclinical research wherein promising targets for analgesia are tested in rodent and subsequently validated in human sensory neurons. We evaluate group II metabotropic glutamate receptors, the activation of which is efficacious in rodent models of pain. Immunohistochemical analysis showed positive immunoreactivity for mGlu2 in rodent dorsal root ganglia (DRG), peripheral fibers in skin, and central labeling in the spinal dorsal horn. We also found mGlu2-positive immunoreactivity in human neonatal and adult DRG. RNA seq analysis of mouse and human DRG revealed a comparative expression profile between species for group II mGluRs and for opioid receptors. In rodent sensory neurons under basal conditions, activation of group II mGluRs with a selective group II agonist produced no changes to membrane excitability. However, membrane hyperexcitability in sensory neurons exposed to the inflammatory mediator prostaglandin E2 (PGE2) was prevented by (2R,4R)-4-aminopyrrolidine-2,4 dicarboxylate (APDC). In human sensory neurons from donors without a history of chronic pain, we show that PGE2 produced hyperexcitability that was similarly blocked by group II mGluR activation. These results reveal a mechanism for peripheral analgesia likely shared by mice and humans and demonstrate a translational research strategy to improve preclinical validation of novel analgesics using cultured human sensory neurons. PMID- 27218871 TI - Lactate administration increases mRNA expression of PGC-1alpha and UCP3 in mouse skeletal muscle. AB - To examine the potential role of lactate as a signalling molecule in skeletal muscle, we performed global gene expression analysis of the mouse gastrocnemius muscle, 3 h after lactate administration using the Affymetrix GeneChip system (Affymetrix, Santa Clara, Calif., USA). Among the top 15 genes with the largest fold change, increased expression of Ppargc1a, Pdk4, and Ucp3 was confirmed using real-time quantitative polymerase chain reaction. Our findings suggest that lactate serves as a signal for upregulating genes related to mitochondrial function. PMID- 27218872 TI - Arterial blood pressure in anesthetized neonates and infants: a retrospective analysis of 1091 cases. AB - BACKGROUND: Hypotension during general anesthesia in neonates and infants is considered to contribute to poor neurological outcome. AIM: The aim of this retrospective analysis was to determine the incidence of hypotension after induction of anesthesia and sustained hypotension (>10 min) during the anesthesia, and to determine factors contributing to the development of (sustained) hypotension. METHOD: We performed a retrospective analysis of 1091 electronic anesthesia records from children <1 year. Patients were stratified for age (group 1: <1 month, group 2: 1-3 months, group 3: 4-6 months, group 4: >6 months). Hypotension was defined as a mean arterial pressure (MAP) <35 mmHg in patients <=6 months and <43 mmHg in patients >6 months. RESULTS: The incidence of hypotension after induction was highest in group 1 (25.5%) [P = 0.009 vs group 2 (13.3%), P < 0.0001 vs groups 3 (3.4%) and 4 (1.0%)], in group 2, it was higher than in groups 3 and 4 (P < 0.0001), and in group 3, it was higher than in group 4 (P = 0.033). The incidence of sustained hypotension was highest in group 1 (43.6%) (P < 0.0001 vs groups 2-4), followed by group 2 (15.7%) [P < 0.0001 vs group 3 (3.4%) and P = 0.006 vs group 4 (8.8%)] and group 4 (P = 0.004 vs group 3). Hypotension after induction occurred more often in emergency procedures than in elective procedures in groups 1 (P = 0.002), 2 (P = 0.029), and 3 (P = 0.037). CONCLUSION: Hypotension, both postinduction and sustained during surgery, is a common phenomenon in anesthetized children under 1 year, peaking in neonates. Generally accepted lower limits of MAP in anesthetized infants urgently need to be defined, enabling us to develop anesthesia strategies avoiding cerebral hypoperfusion. PMID- 27218873 TI - Development and application of cognitive-pragmatic language ability assessment protocol for traumatic brain injury. AB - The study aim was to introduce a newly-developed multifaceted cognitive-pragmatic language assessment protocol. This study was also designed to assess the reliability and validity of the assessment protocol in the discrimination between mild traumatic brain injury (mTBI) and normal control. Individuals in this study were 25 to 64 years old. Ten mTBIs and twenty-two control group were recruited for the preliminary study. Their mean ages were 45.20 and 41.23, respectively. For the main study, we recruited 39 mTBIs and 100 healthy individuals whose mean ages were 44.67 and 40.84, respectively. The newly-developed protocol was completed through a systematic review based on an item analysis. We administered the CAPTBI based on nine domains, 22 subcategories, and 57 items. All nine domains of the CAPTBI were found to be significant variables by which mTBI individuals can be distinguished from normal individuals (p < .001). We also presented the cut-off points by education level to maximize the validity of differentiating the two groups. This study is the first attempt to evaluate mTBI by means of the cognitive-linguistic protocol with multiple domains. The CAPTBI is an appropriate tool for differentiating the cognitive-pragmatic language abilities between mTBI and control group. PMID- 27218874 TI - Beer Drinking Associates with Lower Burden of Amyloid Beta Aggregation in the Brain: Helsinki Sudden Death Series. AB - BACKGROUND: Controversy surrounds the effect of alcohol consumption on the development of dementia and cognitive impairment. We investigated the association between consumption of different alcoholic beverages and beta-amyloid (Abeta) aggregation in the brain, 1 of the neuropathological lesions of Alzheimer's disease. METHODS: In total, 125 males of the Helsinki Sudden Death autopsy Series were included with an age range at death 35 to 70 years. The consumption of alcohol, Abeta aggregation in the brain, and Apolipoprotein E (APOE) genotype were assessed. Relatives answered a questionnaire to gather alcohol consumption history, and Abeta was visualized by implementing immunohistochemical staining of brain sections. Abeta immunoreactivity (IR) was assessed in a dichotomized (yes/no) fashion and as a stained area fraction (%). APOE genotype was assessed in DNA extracted from paraffin-embedded cardiac muscle samples. RESULTS: Increased age (p = 0.001; odds ratio [OR] = 1.09, confidence interval [CI] = 1.04 to 1.15) was associated with higher prevalence of Abeta-IR. Beer drinking decreased (p = 0.024; OR = 0.35, CI = 0.14 to 0.87) the prevalence of Abeta-IR and was associated with a significantly lower extent of Abeta-IR (p = 0.022). The amount of alcohol consumed was not linked with Abeta aggregation and neither was spirit nor wine consumption. CONCLUSIONS: Beer consumption may protect against Abeta aggregation in brain. Further studies are necessary to fully understand the effects of alcohol on Abeta pathology seen in brain tissue. PMID- 27218875 TI - The association between serum uric acid and 1-year mortality in patients with ST segment elevation myocardial infarction and chronic kidney disease: contrast induced acute kidney injury and bleeding complications should be adjusted. PMID- 27218876 TI - How Does Nucleophilic Aromatic Substitution Really Proceed in Nitroarenes? Computational Prediction and Experimental Verification. AB - The aim of this paper is to present a correct and complete mechanistic picture of nucleophilic substitution in nitroarenes based on the results obtained by theoretical calculations and experimental observations coming from numerous publications, reviews, and monographs. This work gives the theoretical background to the very well documented experimentally yet still ignored observations that the addition of nucleophiles to halo nitroarenes resulting in the formation of sigma(H) adducts, which under proper reaction conditions can be transformed into the product of the SNArH reaction, is faster than the competing process of addition to the carbon atom bearing a nucleofugal group (usually a halogen atom) resulting in the "classic" SNAr reaction. Only when the sigma(H) adduct cannot be transformed into the SNArH reaction product, SNAr reaction is observed. PMID- 27218878 TI - Homology and isomorphism: Bourdieu in conversation with New Institutionalism. AB - Bourdieusian Field Theory (BFT) provided decisive inspiration for the early conceptual formulation of New Institutionalism (NI). This paper attempts to reinvigorate the stalled intellectual dialogue between NI and BFT by comparing NI's concept of isomorphism with BFT's notion of homology. I argue that Bourdieu's understanding of domination-oriented social action, transposable habitus, and a non-linear causality, embodied in his neglected concept of homology, provides an alternative theorization of field-level convergence to New Institutionalism's central idea of institutional isomorphism. To showcase how BFT can be useful for organizational research, I postulate a habitus-informed and field-conditioned theory of transference to enrich NI's spin-off thesis of 'diffusion'. I propose that while NI can benefit from BFT's potential of bringing social structure back into organizational research, BFT can enrich its social analysis by borrowing from NI's elaboration of the symbolic system of organizations. PMID- 27218879 TI - Use of platelet transfusions prior to lumbar punctures or epidural anaesthesia for the prevention of complications in people with thrombocytopenia. AB - BACKGROUND: People with a low platelet count (thrombocytopenia) often require lumbar punctures or an epidural anaesthetic. Lumbar punctures can be diagnostic (haematological malignancies, epidural haematoma, meningitis) or therapeutic (spinal anaesthetic, administration of chemotherapy). Epidural catheters are placed for administration of epidural anaesthetic. Current practice in many countries is to correct thrombocytopenia with platelet transfusions prior to lumbar punctures and epidural anaesthesia, in order to mitigate the risk of serious procedure-related bleeding. However, the platelet count threshold recommended prior to these procedures varies significantly from country to country. This indicates significant uncertainty among clinicians of the correct management of these patients. The risk of bleeding appears to be low but if bleeding occurs it can be very serious (spinal haematoma). Therefore, people may be exposed to the risks of a platelet transfusion without any obvious clinical benefit. OBJECTIVES: To assess the effects of different platelet transfusion thresholds prior to a lumbar puncture or epidural anaesthesia in people with thrombocytopenia (low platelet count). SEARCH METHODS: We searched for randomised controlled trials (RCTs) in CENTRAL (The Cochrane Library 2016, Issue 3), MEDLINE (from 1946), EMBASE (from 1974), the Transfusion Evidence Library (from 1950) and ongoing trial databases to 3 March 2016. SELECTION CRITERIA: We included RCTs involving transfusions of platelet concentrates, prepared either from individual units of whole blood or by apheresis, and given to prevent bleeding in people of any age with thrombocytopenia requiring insertion of a lumbar puncture needle or epidural catheter. We only included RCTs published in English. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We identified no completed or ongoing RCTs in English. We did not exclude any completed or ongoing RCTs because they were published in another language. AUTHORS' CONCLUSIONS: There is no evidence from RCTs to determine what is the correct platelet transfusion threshold prior to insertion of a lumbar puncture needle or epidural catheter. There are no ongoing registered RCTs assessing the effects of different platelet transfusion thresholds prior to the insertion of a lumbar puncture or epidural anaesthesia in people with thrombocytopenia. Any future RCT would need to be very large to detect a difference in the risk of bleeding. We would need to design a study with at least 47,030 participants to be able to detect an increase in the number of people who had major procedure-related bleeding from 1 in 1000 to 2 in 1000. PMID- 27218880 TI - Nonspecific Binding Domains in Lipid Membranes Induced by Phospholipase A2. AB - Phospholipase A2 (PLA2) is a peripheral membrane protein that can hydrolyze phospholipids to produce lysolipids and fatty acids. It has been found to play crucial roles in various cellular processes and is thought as a potential candidate for triggering drug release from liposomes for medical treatment. Here, we directly observed that PLA2 hydrolysis reaction can induce the formation of PLA2-binding domains at lipid bilayer interface and found that the formation was significantly influenced by the fluidity of the lipid bilayer. We prepared supported lipid bilayers (SLBs) with various molar ratios of 1,2-dipalmitoyl-sn glycero-3-phosphocholine (DPPC) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) to adjust the reactivity and fluidity of the lipid bilayers. A significant amount of the PLA2-induced domains was observed in mixtures of DPPC and DOPC (1,2 dioleoyl-sn-glycero-3-phosphocholine) but not in either pure DPPC or pure DOPC bilayer, which might be the reason that previous studies rarely observed these domains in lipid bilayer systems. The fluorescently labeled PLA2 experiment showed that newly formed domains acted as binding templates for PLA2. The AFM result showed that the induced domain has stepwise plateau structure, suggesting that PLA2 hydrolysis products may align as bilayers and accumulate layer by layer on the support, and the hydrophobic acyl chains at the side of the layer structure may be exposed to the outside aqueous environment. The introduced hydrophobic region could have hydrophobic interactions with proteins and therefore can attract the binding of not only PLA2 but also other types of proteins such as proteoglycans and streptavidin. The results suggest that the formation of PLA2-induced domains may convert part of a zwitterionic nonsticky lipid membrane to a site where biomolecules can nonspecifically bind. PMID- 27218881 TI - Mesoscale Modeling Reveals Hierarchical Looping of Chromatin Fibers Near Gene Regulatory Elements. AB - While it is well-recognized that chromatin loops play an important role in gene regulation, structural details regarding higher order chromatin loops are only emerging. Here we present a systematic study of restrained chromatin loops ranging from 25 to 427 nucleosomes (fibers of 5-80 Kb DNA in length), mimicking gene elements studied by 3C contact data. We find that hierarchical looping represents a stable configuration that can effectively bring distant regions of the GATA-4 gene together, satisfying connections reported by 3C experiments. Additionally, we find that restrained chromatin fibers larger than 100 nucleosomes (~20Kb) form closed plectonemes, whereas fibers shorter than 100 nucleosomes form simple hairpin loops. By studying the dependence of loop structures on internal parameters, we show that loop features are sensitive to linker histone concentration, loop length, divalent ions, and DNA linker length. Specifically, increasing loop length, linker histone concentration, and divalent ion concentration are associated with increased persistence length (or decreased bending), while varying DNA linker length in a manner similar to experimentally observed "nucleosome free regions" (found near transcription start sites) disrupts intertwining and leads to loop opening and increased persistence length in linker histone depleted (-LH) fibers. Chromatin fiber structure sensitivity to these parameters, all of which vary throughout the cell cycle, tissue type, and species, suggests that caution is warranted when using uniform polymer models to fit chromatin conformation capture genome-wide data. Furthermore, the folding geometry we observe near the transcription initiation site of the GATA-4 gene suggests that hierarchical looping provides a structural mechanism for gene inhibition, and offers tunable parameters for design of gene regulation elements. PMID- 27218882 TI - Routine ultrasonography surveillance of native kidneys for renal cell carcinoma in kidney transplant candidates. AB - Renal cell carcinoma (RCC) has a high incidence in the kidney transplant population and annual surveillance detects these tumors early in their natural history. Minimal guidelines exist regarding RCC surveillance in ESRD patients awaiting transplant. A retrospective review of our kidney transplant database examined the outcomes of annual ultrasonographic surveillance during initial kidney transplant evaluation and upon annual reassessment. Of 2642 patients listed for transplant, 145 patients were found to have masses during initial kidney transplant evaluation or annual imaging consistent with new complex cystic disease or RCC. A total of 71 patients had RCC identified, with 52 found on initial kidney transplant evaluation and 19 identified on annual surveillance. Male gender and African-American race were independently associated with RCC (P<.05). RCC was detected a median of 2.0 years after listing (two annual ultrasonography studies). Patients with complex cysts were more likely to undergo transplantation (48.7%) compared to patients with RCC (21.1%; P<.001). There was no significant difference in survival between RCC patients and those found to have complex cystic disease, suggesting incidental RCC can be diagnosed early in the natural history and at a curable stage through implementation of a biennial surveillance program. PMID- 27218883 TI - The Semaphorin 4D-RhoA-Akt Signal Cascade Regulates Enamel Matrix Secretion in Coordination With Cell Polarization During Ameloblast Differentiation. AB - During tooth development, oral epithelial cells differentiate into ameloblasts in order to form the most mineralized tissue in the vertebrate body: enamel. During this process, ameloblasts directionally secrete enamel matrix proteins and morphologically change from low columnar cells to polarized tall columnar cells, both of which are essential for the proper formation of enamel. In this study, we elucidated the molecular mechanism that integrates ameloblast function and morphology. Immunohistochemistry revealed that the restricted expression of semaphorin 4D (Sema4D) and RhoA activation status are closely associated with ameloblast differentiation in mouse incisors. In addition, in vitro gain-of function and loss-of-function experiments demonstrated that Sema4D acts upstream of RhoA to regulate cell polarity and amelogenin expression via the Plexin B1/Leukemia-associated RhoGEF (LARG) complex during ameloblast differentiation. Experiments in transgenic mice demonstrated that expression of a dominant negative form of RhoA in dental epithelium hindered ameloblast differentiation and subsequent enamel formation, as well as perturbing the establishment of polarized cell morphology and vectorial amelogenin expression. Finally, we showed that spatially restricted Akt mediates between Sema4D-RhoA signaling and these downstream cellular events. Collectively, our results reveal a novel signaling network, the Sema4D-RhoA-Akt signal cascade, that coordinates cellular function and morphology and highlights the importance of specific spatiotemporally restricted components of a signaling pathway in the regulation of ameloblast differentiation. (c) 2016 American Society for Bone and Mineral Research. PMID- 27218884 TI - Single-Electron Transmetalation: Protecting-Group-Independent Synthesis of Secondary Benzylic Alcohol Derivatives via Photoredox/Nickel Dual Catalysis. AB - Protecting-group-independent cross-coupling of alpha-alkoxyalkyl- and alpha acyloxyalkyltrifluoroborates with aryl and heteroaryl bromides is achieved through application of photoredox/nickel dual catalysis. Reactions occur under exceptionally mild conditions, with outstanding functional group compatibility and excellent observed tolerance of heteroarenes. This method offers expedient access to protected secondary benzylic alcohol motifs bearing benzyl, pivaloyl, and N,N-diisopropylcarbamoyl protecting groups. PMID- 27218885 TI - Full-Polarization 3D Metasurface Cloak with Preserved Amplitude and Phase. AB - A full-polarization arbitrary-shaped 3D metasurface cloak with preserved amplitude and phase in microwave frequencies is experimentally demonstrated. By taking the unique feature of metasurfaces, it is shown that the cloak can completely restore the polarization, amplitude, and phase of light for full polarization as if light was incident on a flat mirror. PMID- 27218887 TI - Enhancing the Applicability of Satellite Remote Sensing for PM2.5 Estimation Using MODIS Deep Blue AOD and Land Use Regression in California, United States. AB - We estimated daily ground-level PM2.5 concentrations combining Collection 6 deep blue (DB) Moderate Resolution Imaging Spectroradiometer (MODIS) aerosol optical depth (AOD) data (10 km resolution) with land use regression in California, United States, for the period 2006-2012. The Collection 6 DB method for AOD provided more reliable data retrievals over California's bright surface areas than previous data sets. Our DB AOD and PM2.5 data suggested that the PM2.5 predictability could be enhanced by temporally varying PM2.5 and AOD relations at least at a seasonal scale. In this study, we used a mixed effects model that allowed daily variations in DB AOD-PM2.5 relations. Because DB AOD might less effectively represent local source emissions compared to regional ones, we added geographic information system (GIS) predictors into the mixed effects model to further explain PM2.5 concentrations influenced by local sources. A cross validation (CV) mixed effects model revealed reasonably high predictive power for PM2.5 concentrations with R(2) = 0.66. The relations between DB AOD and PM2.5 considerably varied by day, and seasonally varying effects of GIS predictors on PM2.5 suggest season-specific source emissions and atmospheric conditions. This study indicates that DB AOD in combination with land use regression can be particularly useful to generate spatially resolved PM2.5 estimates. This may reduce exposure errors for health effect studies in California. We expect that more detailed PM2.5 concentration patterns can help air quality management plan to meet air quality standards more effectively. PMID- 27218888 TI - Fluorescent Carbon Quantum Dots Incorporated into Dye-Sensitized TiO2 Photoanodes with Dual Contributions. AB - Fluorescent carbon quantum dots (CQDs) were prepared through bottom-up synthesis, which possess excitation wavelength-dependent photoluminescence properties upon excitation by near visible light. For the first time, CQDs were incorporated into N719-sensitized TiO2 photoelectrodes as the electron-transport medium, presenting dual contributions to the photo-to-electrical energy conversion: 1) spectral response compensation for the dye-sensitized TiO2 film at around 400 nm was successfully observed in the incident photon-to-current conversion measurements; and 2) intensity modulated photocurrent/photovoltage spectroscopy showed that the electron transport time, charge collection efficiency, and electron diffusion length in the TiO2 electrode were all improved after CQDs incorporation. An example of using the CQDs- containing photoanode in a solar cell device resulted in enhancements of 32 % and 21 % for the short-circuit current density and photo to-electrical conversion efficiency, respectively. PMID- 27218889 TI - Barriers to Leisure-Time Physical Activities in Individuals with Spinal Cord Injury. AB - This study investigated the personal, environmental, and activity barriers to leisure-time physical activities (LTPAs) among individuals with spinal cord injury (SCI). A survey instrument was administered to 85 participants with SCI. Personal barriers to LTPAs included issues involving motivation, pain, scheduling, and financial resources. Environmental barriers marked the issues regarding availability and accessibility to specialized programs, activities, and professional services. Activity barriers included limitations in equipment, training, and personal skills required by the selected activities. Significant negative correlations were found between these barriers and the levels of physical activity and satisfaction with physical activity. While working with clients with SCI, occupational therapists should identify those LTPA barriers and possible solutions in order to establish individualized action plans for enhancing participation in LTPAs. PMID- 27218890 TI - An agricultural survey for more than 9,500 African households. AB - Surveys for more than 9,500 households were conducted in the growing seasons 2002/2003 or 2003/2004 in eleven African countries: Burkina Faso, Cameroon, Ghana, Niger and Senegal in western Africa; Egypt in northern Africa; Ethiopia and Kenya in eastern Africa; South Africa, Zambia and Zimbabwe in southern Africa. Households were chosen randomly in districts that are representative for key agro-climatic zones and farming systems. The data set specifies farming systems characteristics that can help inform about the importance of each system for a country's agricultural production and its ability to cope with short- and long-term climate changes or extreme weather events. Further it informs about the location of smallholders and vulnerable systems and permits benchmarking agricultural systems characteristics. PMID- 27218886 TI - Personalized in vitro cancer models to predict therapeutic response: Challenges and a framework for improvement. AB - Personalized cancer therapy focuses on characterizing the relevant phenotypes of the patient, as well as the patient's tumor, to predict the most effective cancer therapy. Historically, these methods have not proven predictive in regards to predicting therapeutic response. Emerging culture platforms are designed to better recapitulate the in vivo environment, thus, there is renewed interest in integrating patient samples into in vitro cancer models to assess therapeutic response. Successful examples of translating in vitro response to clinical relevance are limited due to issues with patient sample acquisition, variability and culture. We will review traditional and emerging in vitro models for personalized medicine, focusing on the technologies, microenvironmental components, and readouts utilized. We will then offer our perspective on how to apply a framework derived from toxicology and ecology towards designing improved personalized in vitro models of cancer. The framework serves as a tool for identifying optimal readouts and culture conditions, thus maximizing the information gained from each patient sample. PMID- 27218891 TI - Perception of hearing impairment and the willingness to use hearing aids in an elderly population in southern Taiwan: A community-based study. AB - OBJECTIVES: To estimate the prevalence and severity of hearing impairment (HI), the self-perception of HI, and the willingness to use a hearing aid (HA) in the elderly population in southern Taiwan. DESIGN: This community-based study was performed in a metropolitan hospital. A questionnaire about the perception of HI and the willingness to use a HA was used. The severity of HI in speech-frequency pure-tone average (PTA) was evaluated. The associations between sex, age, severity of HI, self-perception of HI, and the willingness to use a HA were analysed. STUDY SAMPLE: A total of 599 volunteers were recruited from the health management center; 324 (54.1%) males and 275 (45.9%) females, who were 65 years of age or older. RESULTS: The prevalence of HI >25 dBHL in the elderly was 78%. The predicted levels for elderly persons to perceive HI and hearing difficulties were 34.38 dBHL and 54.38 dBHL, respectively. Males and younger participants were more willing to use HA. The primary reasons for refusing HA use were discomfort (25.1%) and a self-perception that the HA was unnecessary (19.7%). CONCLUSIONS: The prevalence of HI was high among the elderly population in southern Taiwan. Age and sex were the determinants of HA use. PMID- 27218892 TI - The dependence of Hyalomma aegyptium on its tortoise host Testudo graeca in Algeria. AB - Hyalomma aegyptium (Linnaeus, 1758) (Ixodida: Ixodidae) has recently been confirmed as a carrier of numerous pathogenic, including zoonotic, agents. Four environmentally distinct regions of Algeria, located between the humid coastal zone and the arid Saharan Atlas range, were selected in order to compare differences in tick abundance among localities, and the correlations between tick abundance and host population characteristics and other environmental conditions. Sampling was carried out during May and early June in 2010-2012. A total of 1832 H. aegyptium were removed from 201 tortoises. Adult ticks accounted for 52% of the collection. In the pre-adult stages, larvae were dominant. Data on prevalence, intensity (mean +/- standard deviation, range) and abundance of tick infestation were calculated for each locality. Locally, prevalences reached 100%. The sex ratio was biased in favour of males (4.2). Intensities of infestation differed significantly among the localities studied for all developmental stages of the tick. The intensity of infestation by adult ticks was positively correlated to the size of the tortoise and with tortoise population density in the habitat. However, findings for immature tick stages were independent of both variables. No significant correlations between infestation intensities and the climatic parameters tested were found. Immature ticks were observed to prefer the front parts of their tortoise hosts, whereas the majority of adults were attached to the rear parts. PMID- 27218894 TI - Chiroplasmonic Assemblies of Gold Nanoparticles for Ultrasensitive Detection of 8 Hydroxy-2'-deoxyguanosine in Human Serum Sample. AB - Gold nanoparticles (AuNPs) have been extensively explored to be used in analytical methods such as electrochemical, colorimetric methods, and so on. However, only a few methods have been reported by using chirality of AuNPs although their chiral assembly has been studied extensively and circular dichroism (CD) spectroscopy is also a simple and sensitive analytical method. In this paper, sensitive CD spectroscopy method has been explored for detection of 8 hydroxy-2'-deoxyguanosine (8-OHdG), a well-known biomarker for oxidative DNA damage, based on DNA-induced chiroplasmonic assemblies of AuNPs. First, 8-OHdG aptamer hybridized with its complementary sequence that modified with AuNPs based on precision matched bases. DNA-modified AuNPs were assembled into AuNPs dimers by 8-OHdG aptamer, which displayed strong chiroptical activity. Subsequently, in the presence of 8-OHdG, the high specific recognition and affinity constants of aptamer and 8-OHdG destroyed the hybrid of aptamer and its complementary sequence; as a result, AuNPs dimers were destroyed and showed low CD signal. The CD intensity was in log-linear correlation with the concentration of 8-OHdG ranging from 0.05 to 2 nM, with a correlation coefficient of 0.9951 and a detection limit of 33 pM (S/N = 3). The method has been successfully applied in a complex matrix such as human serum samples. The recoveries were from 92.5% to 107% and the relative standard derivations were in the range of 4.89% ~ 7.27%, indicating that the method had good accuracy and high precision. Therefore, these results indicated that the proposed CD method was simple and reliable, which held great potential for clinical examinations. PMID- 27218893 TI - Adsorption and desorption of arsenate on sandy sediments from contaminated and uncontaminated saturated zones: Kinetic and equilibrium modeling. AB - Application of empirical models to adsorption of contaminants on natural heterogeneous sorbents is often challenging due to the uncertainty associated with fitting experimental data and determining adjustable parameters. Sediment samples from contaminated and uncontaminated portions of a study site in Maine, USA were collected and investigated for adsorption of arsenate [As(V)]. Two kinetic models were used to describe the results of single solute batch adsorption experiments. Piecewise linear regression of data linearized to fit pseudo-first order kinetic model resulted in two distinct rates and a cutoff time point of 14-19 h delineating the biphasic behavior of solute adsorption. During the initial rapid adsorption stage, an average of 60-80% of the total adsorption took place. Pseudo-second order kinetic models provided the best fit to the experimental data (R(2) > 0.99) and were capable of describing the adsorption over the entire range of experiments. Both Langmuir and Freundlich isotherms provided reasonable fits to the adsorption data at equilibrium. Langmuir-derived maximum adsorption capacity (St) of the studied sediments ranged between 29 and 97 mg/kg increasing from contaminated to uncontaminated sites. Solid phase As content of the sediments ranged from 3.8 to 10 mg/kg and the As/Fe ratios were highest in the amorphous phase. High-pH desorption experiments resulted in a greater percentage of solid phase As released into solution from experimentally loaded sediments than from the unaltered samples suggesting that As(V) adsorption takes place on different reversible and irreversible surface sites. PMID- 27218895 TI - Expression of tumor suppressor genes related to the cell cycle in endometrial cancer patients. AB - PURPOSE: Endometrial cancer is the most common gynecological malignancy in developed countries. The role of tumor suppressor genes (TSG) in endometrioid endometrial adenocarcinoma (EEC) has an important impact on patient survival prognosis. Thus, it is important to identify TSG transcripts that differentiate endometrial adenocarcinoma into various pathomorphological grades. The aim of this study was to analyze the expression profile of tumor suppressor genes related to the cell cycle in patients with endometrial adenocarcinoma across histological differentiation and to identify transcripts which differentiate endometrium into various pathomorphological grades. MATERIAL AND METHODS: Gene expression analysis was completed for 19 endometrial endometrioid adenocarcinomas and 5 normal specimens (obtained from women with diagnosed uterine fibroids, benign ovarian tumors and a prolapsed uterus with histopathologically confirmed endometrium in the proliferative phase) using Affymetrix HG-U133A oligonucleotide microarrays. The statistical analysis was performed using the GeneSpring13.0 software and PANTHER classification system. RESULTS: Significant changes in gene expression were observed across histological differentiation. The WT-1, CYR 61, TSPYL5 genes were statistically and biologically significant in all cancer grades, and were considered to be primary for the G1 grade in endometrial cancer. The G2 cancer specific genes were BCL2L2 and HNRNPA0, whereas in G3 there was only BAK. CONCLUSION: In conclusion, the WT-1, CYR61 and TSPYL5 gene expressions are potentially correlated with patient survival in all endometrial cancer grades. The TSGs identified are considered to be important in EEC pathogenesis and further research is needed to confirm this. PMID- 27218897 TI - Interprofessional Education and Collaborative Practice-If Not Now, When? PMID- 27218896 TI - Error signals driving locomotor adaptation: cutaneous feedback from the foot is used to adapt movement during perturbed walking. AB - KEY POINTS: Sensory input from peripheral receptors are important for the regulation of walking patterns. Cutaneous input mediates muscle responses to deal with immediate external perturbations. In this study we focused on the role of cutaneous feedback in locomotor adaptation that takes place over minutes of training. We show that interfering with cutaneous feedback reduced adaptation to ankle perturbations during walking. These results help us understand the neural mechanisms underlying walking adaptation, and have clinical implications for treating walking impairments after neurological injuries. ABSTRACT: Locomotor patterns must be adapted to external forces encountered during daily activities. The contribution of different sensory inputs to detecting perturbations and adapting movements during walking is unclear. In the present study, we examined the role of cutaneous feedback in adapting walking patterns to force perturbations. Forces were applied to the ankle joint during the early swing phase using an electrohydraulic ankle-foot orthosis. Repetitive 80 Hz electrical stimulation was applied to disrupt cutaneous feedback from the superficial peroneal nerve (foot dorsum) and medial plantar nerve (foot sole) during walking (Choi et al. 2013). Sensory tests were performed to measure the cutaneous touch threshold and perceptual threshold of force perturbations. Ankle movement were measured when the subjects walked on the treadmill over three periods: baseline (1 min), adaptation (1 min) and post-adaptation (3 min). Subjects (n = 10) showed increased touch thresholds measured with Von Frey monofilaments and increased force perception thresholds with stimulation. Stimulation reduced the magnitude of walking adaptation to force perturbation. In addition, we compared the effects of interrupting cutaneous feedback using anaesthesia (n = 5) instead of repetitive nerve stimulation. Foot anaesthesia reduced ankle adaptation to external force perturbations during walking. The results of the present study suggest that cutaneous input plays a role in force perception, and may contribute to the 'error' signal involved in driving walking adaptation when there is a mismatch between expected and actual force. PMID- 27218898 TI - Responding to the Call for Improving Resident Wellness. PMID- 27218899 TI - Responding to the Call for Improving Resident Wellness. PMID- 27218900 TI - In Reply to Chaukos et al and to Tabatabai. PMID- 27218901 TI - Taking Mastery Learning One Step Further. PMID- 27218902 TI - In Reply to Petersen. PMID- 27218903 TI - Improving Mastery Learning With Comparative Effectiveness. PMID- 27218904 TI - In Reply to Udani et al. PMID- 27218905 TI - The Value of the Primary Care Residency Expansion Program Should Have Been Obvious by Now. PMID- 27218906 TI - The Dangers of Labeling. PMID- 27218907 TI - Artists' Statement: ADLs-Activities of "Disabled" Living. PMID- 27218908 TI - Beggar Seated on a Bank. PMID- 27218909 TI - Commentary on Beggar Seated on a Bank. PMID- 27219002 TI - Correction: Targeted Isolation of Antibodies Directed against Major Sites of SIV Env Vulnerability. AB - [This corrects the article DOI: 10.1371/journal.ppat.1005537.]. PMID- 27219004 TI - Active coping of prenatally stressed rats in the forced swimming test: involvement of the Nurr1 gene. AB - Depending on genetic predisposition, prenatal stress may result in vulnerability or resilience to develop psychiatric disorders in adulthood. Nurr1 is an immediate early gene, important in the brain for the stress response. We tested the hypothesis that prenatal stress and the decrease of hippocampal Nurr1 alter offspring behavioral responses in the forced swimming test (FST). Pregnant Wistar rats were exposed to restraint stress (45 min, thrice daily) from gestation day 14. Prenatally stressed (PS) and non-prenatally stressed (NPS) male offspring were treated bilaterally with a Nurr1 antisense oligodeoxynucleotide (ODN; or control) into the hippocampus at 97 d of age. After 1 h, the rats were exposed to the FST (acute stressor) to analyze their behavioral responses. Thirty minutes after the FST, we analyzed the gene expression of Nurr1, Bdnf and Nr3c1 (genes for Nurr1, brain-derived neurotrophic factor (BDNF) and glucocorticoid receptor (GR), respectively) in the hippocampus, prefrontal cortex (PFC) and hypothalamus. Results showed that the decrease of hippocampal Nurr1 after the antisense ODN in adult NPS rats induces immobility (indicating depressive-like behavior). The PS adult rats, including the group with decreased hippocampal Nurr1, presented low immobility in the FST. This low immobility was concordant with maintenance of Nurr1 and Bdnf expression levels in the three analyzed brain regions; Nr3c1 gene expression was also maintained in the PFC and hypothalamus. These findings suggest that Nurr1 and associated genes could participate in the brain modifications induced by prenatal stress, allowing active coping (resilience) with acute stress in adulthood. PMID- 27219003 TI - Clinical and Molecular Epidemiology of Multidrug-Resistant P. aeruginosa Carrying aac(6')-Ib-cr, qnrS1 and blaSPM Genes in Brazil. AB - We described a comprehensive analysis of the molecular epidemiology of multidrug resistant (MDR) P. aeruginosa. Molecular analysis included typing by Pulsed Field Gel Electrophoresis, identification of genes of interest through PCR-based assays and sequencing of target genes. Case-control study was conducted to better understand the prognostic of patients and the impact of inappropriate therapy in patients with bacteremia, as well as the risk factors of MDR infections. We observed a high rate of MDR isolates (40.7%), and 51.0% of them was independently associated with inappropriate antibiotic therapy. Bacteremia was detected in 66.9% of patients, and prolonged hospital stay was expressive in those resistant to fluoroquinolone. Plasmid-mediated quinolone resistance genes (PMQR), qnrS1 and aac(6')Ib-cr, were detected in two different nosocomial isolates (5.3%), and the aac(6')-Ib7 variant was detected at a high frequency (87.5%) in those negative to PMQR. The presence of mutations in gyrA and parC genes was observed in 100% and 85% of selected isolates, respectively. Isolates harboring PMQR genes or mutations in gyrA and parC were not closely related, except in those containing SPM (Sao Paulo metallo-beta-lactamase) clone. In addition, there is no study published in Brazil to date reporting the presence of Pseudomonas aeruginosa isolates harboring both qnrS1 and aac(6')Ib-cr genes, with alarming frequency of patients with inappropriate therapy. PMID- 27219005 TI - HIV Incidence and Predictors of Incident HIV among Men Who Have Sex with Men Attending a Sexual Health Clinic in Melbourne, Australia. AB - INTRODUCTION: The aim of this study was to determine the risk factors for HIV infection and the incidence in men who have sex with men (MSM). It is important to identify subgroups of MSM in which preventive interventions such as pre exposure prophylaxis (PrEP) offered at the time of their last negative test would be considered cost-effective. METHODS: We conducted a retrospective cohort study of MSM attending Melbourne Sexual Health Centre (MSHC) during 2007-2013 with at least two HIV tests within 12 months of each other. Demographic characteristics, sexual and other behaviours, and bacterial sexually transmitted infection (STI) diagnoses were extracted from the date of the last negative HIV test. HIV incidence rate (IR) per 100 person-years for each risk factor was calculated. RESULTS: Of the 13907 MSM who attended MSHC, 5256 MSM had at least two HIV tests and were eligible, contributing 6391 person-years follow-up. 81 new HIV diagnoses were identified within 12 months of an HIV negative test with an incidence of 1.3 (95% CI: 1.0-1.6) per 100 person-years. Significant associations with subsequent HIV infection were: rectal gonorrhea (HIV IR: 3.4 95% CI: 2.1-5.2), rectal chlamydia (HIV IR: 2.6 95% CI: 1.7-3.7), inconsistent condom use (HIV IR: 2.1 95% CI: 1.6-2.7), use of post-exposure prophylaxis (HIV IR: 2.3 95% CI: 1.7-3.1), and injecting drug use (HIV IR: 8.5 95% CI: 3.4-17.5). CONCLUSION: The incidence of HIV was above 2.0% in subgroups of MSM with specific characteristics at the last HIV negative test. PrEP is considered cost effective at this incidence and could potentially be used along with other preventive interventions for these individuals in more than half of the population. PMID- 27219006 TI - The Effect of Monaural Auditory Stimulus on Hand Selection When Reaching. AB - This study investigated the effect of monaural auditory stimulus on hand selection when reaching. Healthy right-handed participants were asked to reach to a visual target and were free to use either the right or left hand. A visual target appeared at one of 11 positions in the visual field between -25 and 25 degrees of the horizontal visual angle. An auditory stimulus was given either in the left or right ear 100 ms after the presentation of the visual target, or no auditory stimulus was given. An auditory stimulus in the right ear increased right hand selection, and that in the left ear slightly increased left hand selection when reaching to a target around the midline of the visual field. The horizontal visual angle, where the probabilities of right hand selection and left hand selection were equal when reaching, shifted leftward when an auditory stimulus was given in the right ear, but the angle did not shift in either direction when an auditory stimulus was given in the left ear. The right-ear dominant auditory stimulus effect on hand selection indicates hemispheric asymmetry of cortical activity for hand selection. PMID- 27219007 TI - CTCF and CohesinSA-1 Mark Active Promoters and Boundaries of Repressive Chromatin Domains in Primary Human Erythroid Cells. AB - BACKGROUND: CTCF and cohesinSA-1 are regulatory proteins involved in a number of critical cellular processes including transcription, maintenance of chromatin domain architecture, and insulator function. To assess changes in the CTCF and cohesinSA-1 interactomes during erythropoiesis, chromatin immunoprecipitation coupled with high throughput sequencing and mRNA transcriptome analyses via RNA seq were performed in primary human hematopoietic stem and progenitor cells (HSPC) and primary human erythroid cells from single donors. RESULTS: Sites of CTCF and cohesinSA-1 co-occupancy were enriched in gene promoters in HSPC and erythroid cells compared to single CTCF or cohesin sites. Cell type-specific CTCF sites in erythroid cells were linked to highly expressed genes, with the opposite pattern observed in HSPCs. Chromatin domains were identified by ChIP-seq with antibodies against trimethylated lysine 27 histone H3, a modification associated with repressive chromatin. Repressive chromatin domains increased in both number and size during hematopoiesis, with many more repressive domains in erythroid cells than HSPCs. CTCF and cohesinSA-1 marked the boundaries of these repressive chromatin domains in a cell-type specific manner. CONCLUSION: These genome wide data, changes in sites of protein occupancy, chromatin architecture, and related gene expression, support the hypothesis that CTCF and cohesinSA-1 have multiple roles in the regulation of gene expression during erythropoiesis including transcriptional regulation at gene promoters and maintenance of chromatin architecture. These data from primary human erythroid cells provide a resource for studies of normal and perturbed erythropoiesis. PMID- 27219008 TI - Pauci- and Multibacillary Leprosy: Two Distinct, Genetically Neglected Diseases. AB - After sustained exposure to Mycobacterium leprae, only a subset of exposed individuals develops clinical leprosy. Moreover, leprosy patients show a wide spectrum of clinical manifestations that extend from the paucibacillary (PB) to the multibacillary (MB) form of the disease. This "polarization" of leprosy has long been a major focus of investigation for immunologists because of the different immune response in these two forms. But while leprosy per se has been shown to be under tight human genetic control, few epidemiological or genetic studies have focused on leprosy subtypes. Using PubMed, we collected available data in English on the epidemiology of leprosy polarization and the possible role of human genetics in its pathophysiology until September 2015. At the genetic level, we assembled a list of 28 genes from the literature that are associated with leprosy subtypes or implicated in the polarization process. Our bibliographical search revealed that improved study designs are needed to identify genes associated with leprosy polarization. Future investigations should not be restricted to a subanalysis of leprosy per se studies but should instead contrast MB to PB individuals. We show the latter approach to be the most powerful design for the identification of genetic polarization determinants. Finally, we bring to light the important resource represented by the nine-banded armadillo model, a unique animal model for leprosy. PMID- 27219010 TI - Chiral Catalyst Design: Cyclopentadiene-Based Bronsted Acids. AB - The combination of -I and -M effects and the aromaticity of the conjugate base renders the chiral pentacarboxy-substituted cyclopentadienes (PCCPs) acidic. Their convenient synthesis together with substrates derived from the chiral pool and their performance in the tested reactions renders them prodigious candidates to become a new and highly competitive class of chiral Bronsted acid catalysts. PMID- 27219009 TI - Pigment Epithelium-Derived Factor Mediates Autophagy and Apoptosis in Myocardial Hypoxia/Reoxygenation Injury. AB - Pigment epithelium-derived factor (PEDF) is a multifunctional protein that exhibits anti-angiogenic, antitumor, anti-inflammatory, antioxidative, anti atherogenic, and cardioprotective properties. While it was recently shown that PEDF expression is inhibited under low oxygen conditions, the functional role of PEDF in response to hypoxia/reoxygenation (H/R) remains unclear. The goal of this study was to therefore investigate the influence of PEDF on myocardial H/R injury. For these analyses, PEDF-specific small interfering RNA-expressing and PEDF-expressing lentivirus (PEDF-LV) vectors were utilized to knockdown or stably overexpress PEDF, respectively, within human cardiomyocytes (HCM) in vitro. We noted that reactive oxygen species (ROS) play important roles in the induction of cell death pathways, including apoptosis and autophagy in ischemic hearts. Our findings demonstrate that overexpression of PEDF resulted in a significant reduction in ROS production and attenuation of mitochondrial membrane potential depletion under H/R conditions. Furthermore, PEDF inhibited the activation of a two-step apoptotic pathway in which caspase-dependent (caspase-9 and caspase-3) and caspase-independent (apoptosis inducing factor and endonuclease G), which in turn cleaves several crucial substrates including the DNA repair enzyme poly (ADP ribose) polymerase. Meanwhile, overexpression of PEDF also promoted autophagy, a process that is typically activated in response to H/R. Therefore, these findings suggest that PEDF plays a critical role in preventing H/R injury by modulating anti-oxidant and anti-apoptotic factors and promoting autophagy. PMID- 27219011 TI - Mangiferin: A xanthonoid with multipotent anti-inflammatory potential. AB - Over the last era, small molecules sourced from different plants have gained attention for their varied and long-term medicinal benefits. Their advantageous therapeutic effects in diverse pathological complications lead researchers to give an ever-increasing emphasis on them and discover their novel therapeutic potentials. Among these, the heat stable, xanthonoid group of organic molecules has gained special importance with distinctive regards to the bioactive molecule mangiferin due to its solubility in water. Mangiferin, a yellow polyphenol having C-glycosyl xanthone structure, is widely present in different edible sources like mango, and possesses numerous biological activities. Extensive research with this molecule shows its antioxidant, anti-inflammatory, antidiabetic, anticancer, antimicrobial, analgesic, and immunomodulatory properties. Thus, it provides protection against a wide range of physiological disorders. The C-glucosyl linkage and polyhydroxy groups in mangiferin's structure contribute essentially to its free radical-scavenging activity. Moreover, its ability in regulating various transcription factors like NF-kappaB, Nrf-2, etc. and modulating the expression of different proinflammatory signaling intermediates like tumor necrosis factor-alpha, COX-2, etc. contribute to its anti-inflammatory, anticancer, and antidiabetic potentials. In this comprehensive article, information has been provided about the sources, chemical structure, metabolism, and different biological activities of mangiferin with special emphasis on the underlying cellular signal transduction pathways. Insights into an in-depth assessment of mangiferin's anti-inflammatory therapeutic potential have also been discussed in detail. On an overall perspective, this review aims to stage mangiferin's diversified therapeutic applications and its emerging possibility as a promising drug in future based on its anti-inflammatory property. (c) 2016 BioFactors, 42(5):459-474, 2016. PMID- 27219012 TI - Ani9, A Novel Potent Small-Molecule ANO1 Inhibitor with Negligible Effect on ANO2. AB - Anoctamin1 (ANO1)/transmembrane protein 16A (TMEM16A), a calcium-activated chloride channel (CaCC), is involved in many physiological functions such as fluid secretion, smooth muscle contraction, nociception and cancer progression. To date, only a few ANO1 inhibitors have been described, and these have low potency and selectivity for ANO1. Here, we performed a high-throughput screening to identify highly potent and selective small molecule inhibitors of ANO1. Three novel ANO1 inhibitors were discovered from screening of 54,400 synthetic small molecules, and they were found to fully block ANO1 channel activity with an IC50 < 3 MUM. Electrophysiological analysis revealed that the most potent inhibitor, 2 (4-chloro-2-methylphenoxy)-N-[(2-methoxyphenyl)methylideneamino]-acetamide (Ani9), completely inhibited ANO1 chloride current with submicromolar potency. Notably, unlike previous small-molecule ANO1 inhibitors identified to date, Ani9 displayed high selectivity for ANO1 as compared to ANO2, which shares a high amino acid homology to ANO1. In addition, Ani9 did not affect the intracellular calcium signaling and CFTR chloride channel activity. Our results suggest that Ani9 may be a useful pharmacological tool for studying ANO1 and a potential development candidate for drug therapy of cancer, hypertension, pain, diarrhea and asthma. PMID- 27219013 TI - A comparative reference study for the validation of HLA-matching algorithms in the search for allogeneic hematopoietic stem cell donors and cord blood units. AB - The accuracy of human leukocyte antigen (HLA)-matching algorithms is a prerequisite for the correct and efficient identification of optimal unrelated donors for patients requiring hematopoietic stem cell transplantation. The goal of this World Marrow Donor Association study was to validate established matching algorithms from different international donor registries by challenging them with simulated input data and subsequently comparing the output. This experiment addressed three specific aspects of HLA matching using different data sets for tasks of increasing complexity. The first two tasks targeted the traditional matching approach identifying discrepancies between patient and donor HLA genotypes by counting antigen and allele differences. Contemporary matching procedures predicting the probability for HLA identity using haplotype frequencies were addressed by the third task. In each task, the identified disparities between the results of the participating computer programs were analyzed, classified and quantified. This study led to a deep understanding of the algorithms participating and finally produced virtually identical results. The unresolved discrepancies total to less than 1%, 4% and 2% for the three tasks and are mostly because of individual decisions in the design of the programs. Based on these findings, reference results for the three input data sets were compiled that can be used to validate future matching algorithms and thus improve the quality of the global donor search process. PMID- 27219014 TI - Thermal preference predicts animal personality in Nile tilapia Oreochromis niloticus. AB - Environmental temperature gradients provide habitat structure in which fish orientate and individual thermal choice may reflect an essential integrated response to the environment. The use of subtle thermal gradients likely impacts upon specific physiological and behavioural processes reflected as a suite of traits described by animal personality. In this study, we examine the relationship between thermal choice, animal personality and the impact of infection upon this interaction. We predicted that thermal choice in Nile tilapia Oreochromis niloticus reflects distinct personality traits and that under a challenge individuals exhibit differential thermal distribution. Nile tilapia were screened following two different protocols: 1) a suite of individual behavioural tests to screen for personality and 2) thermal choice in a custom built tank with a thermal gradient (TCH tank) ranging from 21 to 33 degrees C. A first set of fish were screened for behaviour and then thermal preference, and a second set were tested in the opposite fashion: thermal then behaviour. The final thermal distribution of the fish after 48 h was assessed reflecting final thermal preferendum. Additionally, fish were then challenged using a bacterial Streptococcus iniae model infection to assess the behavioural fever response of proactive and reactive fish. Results showed that individuals with preference for higher temperatures were also classified as proactive with behavioural tests and reactive contemporaries chose significantly lower water temperatures. All groups exhibited behavioural fever recovering personality-specific thermal preferences after 5 days. Our results show that thermal preference can be used as a proxy to assess personality traits in Nile tilapia and it is a central factor to understand the adaptive meaning of animal personality within a population. Importantly, response to infection by expressing behavioural fever overrides personality-related thermal choice. PMID- 27219015 TI - Autophagy Induced by Intracellular Infection of Propionibacterium acnes. AB - BACKGROUND: Sarcoidosis is caused by Th1-type immune responses to unknown agents, and is linked to the infectious agent Propionibacterium acnes. Many strains of P. acnes isolated from sarcoid lesions cause intracellular infection and autophagy may contribute to the pathogenesis of sarcoidosis. We examined whether P. acnes induces autophagy. METHODS: Three cell lines from macrophages (Raw264.7), mesenchymal cells (MEF), and epithelial cells (HeLa) were infected by viable or heat-killed P. acnes (clinical isolate from sarcoid lymph node) at a multiplicity of infection (MOI) of 100 or 1000 for 1 h. Extracellular bacteria were killed by washing and culturing infected cells with antibiotics. Samples were examined by colony assay, electron-microscopy, and fluorescence-microscopy with anti-LC3 and anti-LAMP1 antibodies. Autophagy-deficient (Atg5-/-) MEF cells were also used. RESULTS: Small and large (>=5 MUm in diameter) LC3-positive vacuoles containing few or many P. acnes cells (LC3-positive P. acnes) were frequently found in the three cell lines when infected by viable P. acnes at MOI 1000. LC3-positive large vacuoles were mostly LAMP1-positive. A few small LC3-positive/LAMP1-negative vacuoles were consistently observed in some infected cells for 24 h postinfection. The number of LC3-positive P. acnes was decreased at MOI 100 and completely abolished when heat-killed P. acnes was used. LC3-positive P. acnes was not found in autophagy-deficient Atg5-/- cells where the rate of infection was 25.3 and 17.6 times greater than that in wild-type Atg5+/+ cells at 48 h postinfection at MOI 100 and 1000, respectively. Electron-microscopic examination revealed bacterial cells surrounded mostly by a single-membrane including the large vacuoles and sometimes a double or multi-layered membrane, with occasional undigested bacterial cells in ruptured late endosomes or in the cytoplasm. CONCLUSION: Autophagy was induced by intracellular P. acnes infection and contributed to intracellular bacterial killing as an additional host defense mechanism to endocytosis or phagocytosis. PMID- 27219016 TI - Childhood leukaemia and distance from power lines in California: a population based case-control study. AB - BACKGROUND: Studies have reported an increased risk of childhood leukaemia associated with living near high-voltage electric power transmission lines that extend to distances at which magnetic fields from lines are negligible. We conducted a large records-based case-control study of childhood leukaemia risk in the population living near power lines in California. METHODS: The study included 5788 childhood leukaemia and 3308 central nervous system (CNS) cancer cases (for comparison) born in and diagnosed in California (1986-2008), and matched to population-based controls by age and sex. We geocoded birth address and estimated the distance from residence to transmission lines using geographic information systems, aerial imagery, and, for some residences, site visits. RESULTS: For leukaemia, there was a slight excess of cases within 50 m of a transmission line over 200 kV (odds ratio 1.4, 95% confidence interval 0.7-2.7). There was no evidence of increased risk for distances beyond 50 m, for lower-voltage lines, or for CNS cancers. CONCLUSIONS: Our findings did not clearly support an increased childhood leukaemia risk associated with close proximity (<50 m) to higher voltage lines, but could be consistent with a small increased risk. Reports of increased risk for distances beyond 50 m were not replicated. PMID- 27219017 TI - Are there biological differences between screen-detected and interval colorectal cancers in the English Bowel Cancer Screening Programme? AB - BACKGROUND: We measured biomarkers of tumour growth and vascularity in interval and screen-detected colorectal cancers (CRCs) in the English Bowel Cancer Screening Programme in order to determine whether rapid tumour growth might contribute to interval CRC (a CRC diagnosed between a negative guaiac stool test and the next scheduled screening episode). METHODS: Formalin-fixed, paraffin embedded sections from 71 CRCs (screen-detected 43, interval 28) underwent immunohistochemistry for CD31 and Ki-67, in order to measure the microvessel density (MVD) and proliferation index (PI), respectively, as well as microsatellite instability (MSI) testing. RESULTS: Interval CRCs were larger (P=0.02) and were more likely to exhibit venous invasion (P=0.005) than screen detected tumours. There was no significant difference in MVD or PI between interval and screen-detected CRCs. More interval CRCs displayed MSI-high (14%) compared with screen-detected tumours (5%). A significantly (P=0.005) higher proportion (51%) of screen-detected CRC resection specimens contained at least one polyp compared with interval CRC (18%) resections. CONCLUSIONS: We found no evidence of biological differences between interval and screen-detected CRCs, consistent with the low sensitivity of guaiac stool testing as the main driver of interval CRC. The contribution of synchronous adenomas to occult blood loss for screening requires further investigation. PMID- 27219018 TI - Hallmarks of cancer stem cell metabolism. AB - Cancer cells adapt cellular metabolism to cope with their high proliferation rate. Instead of primarily using oxidative phosphorylation (OXPHOS), cancer cells use less efficient glycolysis for the production of ATP and building blocks (Warburg effect). However, tumours are not uniform, but rather functionally heterogeneous and harbour a subset of cancer cells with stemness features. Such cancer cells have the ability to repopulate the entire tumour and thus have been termed cancer stem cells (CSCs) or tumour-initiating cells (TICs). As opposed to differentiated bulk tumour cells relying on glycolysis, CSCs show a distinct metabolic phenotype that, depending on the cancer type, can be highly glycolytic or OXPHOS dependent. In either case, mitochondrial function is critical and takes centre stage in CSC functionality. Remaining controversies in this young and emerging research field may be related to CSC isolation techniques and/or the use of less suitable model systems. Still, the apparent dependence of CSCs on mitochondrial function, regardless of their primary metabolic phenotype, represents a previously unrecognised Achilles heel amendable for therapeutic intervention. Elimination of highly chemoresistant CSCs as the root of many cancers via inhibition of mitochondrial function bears the potential to prevent relapse from disease and thus improve patients' long-term outcome. PMID- 27219020 TI - Associations of antibiotic use with risk of primary liver cancer in the Clinical Practice Research Datalink. AB - BACKGROUND: Use of antibiotics could alter human microbiota composition and decrease bacterial diversity. Such microbial dysbiosis may have implications in hepatocarcinogenesis; however, the association between antibiotic use and liver cancer risk has been minimally examined in humans. METHODS: We performed a nested case-control study (1195 primary liver cancer cases and 4640 matched controls) within the United Kingdom's Clinical Practice Research Datalink. Antibiotic use was obtained from prescription records. Multivariable-adjusted odds ratio (OR) and 95% confidence interval (CI) were estimated using conditional logistic regression. RESULTS: Ever-use of prescription antibiotics was associated with a slightly increased risk of liver cancer, compared to non-use (OR=1.22, 95% CI=1.03-1.45). However, there was no clear dose-response relationship by the number of prescriptions or cumulative dose of antibiotic use, suggesting a non causal association. CONCLUSIONS: Our results do not support a role of antibiotic use in liver cancer development. PMID- 27219019 TI - Mutational analysis of anal cancers demonstrates frequent PIK3CA mutations associated with poor outcome after salvage abdominoperineal resection. AB - BACKGROUND: A better understanding of the molecular profile of anal squamous cell carcinomas (ASCCs) is necessary to consider new therapeutic approaches, and the identification of prognostic and predictive factors for response to treatment. METHODS: We retrospectively analysed tumours from ASCC patients for mutational analysis of KRAS, NRAS, HRAS, BRAF, PIK3CA, MET, TP53 and FBXW7 genes by HRM and Sanger sequencing analysis. RESULTS: Specimens from 148 patients were analysed: 96 treatment-naive tumours and 52 recurrences after initial radiotherapy (RT) or chemoradiotherapy (CRT). Mutations of KRAS, PIK3CA, FBXW7 and TP53 genes were present in 3 (2.0%), 30 (20.3%), 9 (6.1%) and 7 tumours (4.7%), respectively. The distribution of the mutations was similar between treatment-naive tumours and recurrences, except for TP53 mutations being more frequent in recurrences (P=0.0005). In patients treated with abdominoperineal resection (APR) after relapse (n=38, median follow-up of 18.2 years), overall survival (OS) was significantly correlated with HPV16 status (P=0.048), gender (P=0.045) and PIK3CA mutation (P=0.037). The PIK3CA status retained its prognostic significance in Cox multivariate regression analysis (P=0.025). CONCLUSIONS: Our study identified PIK3CA mutation as an independent prognostic factor in patients who underwent APR for ASCC recurrence, suggesting a potential benefit from adjuvant treatment and the evaluation of targeted therapies with PI3K/Akt/mTor inhibitors in PIK3CA mutated patients. PMID- 27219021 TI - Distinct Roles for APPL1 and APPL2 in Regulating Toll-like Receptor 4 Signaling in Macrophages. AB - Macrophages are activated by contact with pathogens to mount innate immune defenses against infection. Toll-like receptor 4 (TLR4) at the macrophage surface recognizes and binds bacterial lipopolysaccharide (LPS), setting off signaling and transcriptional events that lead to the secretion of pro- and anti inflammatory cytokines; these in turn control inflammatory and antimicrobial responses. Although the complex regulatory pathways downstream of TLR4 have been extensively studied, further molecules critical for modulating the resulting cytokine outputs remain to be characterized. Here we establish potential roles for APPL1 and 2 signaling adaptors as regulators of LPS/TLR4-induced signaling, transcription, and cytokine secretion. APPL1 and 2 are differentially localized to distinct signaling-competent membrane domains on the surface and in endocytic compartments of LPS-activated macrophages. By depleting cells of each adaptor respectively we show separate and opposing functions for APPL1 and 2 in Akt and MAPK signaling. Specifically, APPL2 has a dominant role in nuclear translocation of NF-KB p65 and it serves to constrain the secretion of pro- and anti inflammatory cytokines. The APPLs, and in particular APPL2, are thus revealed as adaptors with important capacity to modulate inflammatory responses mounted by LPS/TLR4 during infection. PMID- 27219022 TI - Exciton formation in monolayer transition metal dichalcogenides. AB - Two-dimensional transition metal dichalcogenides provide a unique platform to study excitons in confined structures. Recently, several important aspects of excitons in these materials have been investigated in detail. However, the formation process of excitons from free carriers has yet to be understood. Here we report time-resolved measurements on the exciton formation process in monolayer samples of MoS2, MoSe2, WS2, and WSe2. The free electron-hole pairs, injected by an ultrashort laser pulse, immediately induce a transient absorption signal of a probe pulse tuned to the exciton resonance. The signal quickly drops by about a factor of two within 1 ps and is followed by a slower decay process. In contrast, when excitons are resonantly injected, the fast decay component is absent. Based both on its excitation excess energy and intensity dependence, this fast decay process is attributed to the formation of excitons from the electron hole pairs. This interpretation is also consistent with a model that shows how free electron-hole pairs can be about twice more effective than excitons in altering the exciton absorption strength. From our measurements and analysis of our results, we determined that the exciton formation times in these monolayers to be shorter than 1 ps. PMID- 27219023 TI - Global transcriptomic profiling in barramundi (Lates calcarifer) from rivers impacted by differing agricultural land uses. AB - Most catchments discharging into the Great Barrier Reef lagoon have elevated loads of suspended sediment, nutrients, and pesticides, including photosystem II inhibiting herbicides, associated with upstream agricultural land use. To investigate potential impacts of declining water quality on fish physiology, RNA sequencing (RNASeq) was used to characterize and compare the hepatic transcriptomes of barramundi (Lates calcarifer) captured from 2 of these tropical river catchments in Queensland, Australia. The Daintree and Tully Rivers differ in upstream land uses, as well as sediment, nutrient, and pesticide loads, with the area of agricultural land use and contaminant loads lower in the Daintree. In fish collected from the Tully River, transcripts involved in fatty acid metabolism, amino acid metabolism, and citrate cycling were also more abundant, suggesting elevated circulating cortisol concentrations, whereas transcripts involved in immune responses were less abundant. Fish from the Tully also had an increased abundance of transcripts associated with xenobiotic metabolism. Previous laboratory-based studies observed similar patterns in fish and amphibians exposed to the agricultural herbicide atrazine. If these transcriptomic patterns are manifested at the whole organism level, the differences in water quality between the 2 rivers may alter fish growth and fitness. Environ Toxicol Chem 2017;36:103-112. (c) 2016 SETAC. PMID- 27219024 TI - Cytogenetic and molecular profile of endometrial stromal sarcoma. AB - Recent cytogenetic and molecular investigations have improved our understanding of endometrial stromal tumors, including sarcomas (ESS), and helped redefine their classification into more pathogenetically meaningful categories. Because much more can be gained through such studies, we add information on another 22 ESS examined by karyotyping, PCR analysis, expression array analysis, and transcriptome sequencing. In spite of the known preference for certain pathogenetic pathways, we found considerable genetic heterogeneity in high-grade (HG) as well as in low-grade (LG) ESS. Not all HG tumors showed a YWHAE-NUTM chimeric transcript and as many as six LGESS showed no hitherto known ESS-related fusions. Among the transcripts identified by transcriptome sequencing and verified by Sanger sequencing, new variants of ZC3H7-BCOR and its reciprocal BCOR ZC3H7 were identified as was involvement of the CREBBP and MLLT4 genes (both well known leukemia-related genes) in two new fusions. FISH analysis identified a known EPC1-PHF1 fusion which led to the identification of a new variant at the molecular level. The fact that around 70 genes were found differentially expressed, by microarray analysis, when comparing LGESS showing ESS-related fusions with LGESS without such transcripts, underscores the biochemical importance of the observed genetic heterogeneity and hints that new subgroups/entities in LGESS still remain undiscovered. (c) 2016 The Authors. Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc. PMID- 27219025 TI - Negative Treatment by Family as a Predictor of Depressive Symptoms, Life Satisfaction, Suicidality, and Tobacco/Alcohol Use in Vietnamese Sexual Minority Women. AB - PURPOSE: Research linking family rejection and health outcomes in sexual minority people is mostly limited to North America. We assessed the associations between negative treatment by family members and depressive symptoms, life satisfaction, suicidality, and tobacco/alcohol use in sexual minority women (SMW) in Viet Nam. METHODS: Data were from an anonymous internet survey (n = 1936). Latent class analysis characterized patterns of negative treatment by family members experienced by respondents. Latent class with distal outcome modeling was used to regress depressive symptoms, life satisfaction, suicidality, and tobacco/alcohol use on family treatment class, controlling for predictors of family treatment and for two other types of sexual prejudice. RESULTS: Five latent family treatment classes were extracted, including four negative classes representing varying patterns of negative family treatment. Overall, more than one negative class predicted lower life satisfaction, more depressive symptoms, and higher odds of attempted suicide (relative to the non-negative class), supporting the minority stress hypothesis that negative family treatment is predictive of poorer outcomes. Only the most negative class had elevated alcohol use. The association between family treatment and smoking status was not statistically significant. The most negative class, unexpectedly, did not have the highest odds of having attempted suicide, raising a question about survivor bias. CONCLUSION: This population requires public health attention, with emphasis placed on interventions targeting the family to promote acceptance and to prevent negative treatment, and interventions supporting those SMW who encounter the worst types of negative family treatment. PMID- 27219026 TI - Interfacial Octahedral Rotation Mismatch Control of the Symmetry and Properties of SrRuO3. AB - Epitaxial strain can be used to tune the properties of complex oxides with perovskite structure. Beyond just lattice mismatch, the use of octahedral rotation mismatch at heterointerfaces could also provide an effective route to manipulate material properties. Here, we examine the evolution of the structural motif (i.e., lattice parameters, symmetry, and octahedral rotations) of SrRuO3 films grown on substrates engineered to have the same lattice parameters, but different octahedral rotations. SrRuO3 films grown on SrTiO3 (001) (no octahedral rotations) and GdScO3-buffered SrTiO3 (001) (with octahedral rotations) substrates are found to exhibit monoclinic and tetragonal symmetry, respectively. Electrical transport and magnetic measurements reveal that the tetragonal films exhibit higher resistivity, lower magnetic Curie temperatures, and more isotropic magnetism as compared to those with monoclinic structure. Synchrotron-based quantification of the octahedral rotation network reveals that the tilting pattern in both film variants is the same (albeit with slightly different magnitudes of in-plane rotation angles). The abnormal rotation pattern observed in tetragonal SrRuO3 indicates a possible decoupling between the internal octahedral rotation and lattice symmetry, which could provide new opportunities to engineer thin-film structure and properties. PMID- 27219027 TI - Syphilis screening in pregnancy in the United Kingdom, 2010-2011: a national surveillance study. AB - OBJECTIVE: To evaluate the national antenatal syphilis screening programme and provide evidence for improving screening and management strategies. DESIGN: National population-based surveillance. SETTING: United Kingdom (UK). POPULATION: All pregnant women screening positive for syphilis, 2010-2011. METHODS: Demographic, laboratory and treatment details for each pregnancy were collected from UK antenatal units (~210), along with follow-up information on all infants born to women requiring syphilis treatment in pregnancy. MAIN OUTCOME MEASURES: Proportion of women with newly or previously diagnosed syphilis among those with positive screening tests in pregnancy; proportion requiring treatment. RESULTS: Overall, 77% (1425/1840) of reported pregnancies were confirmed syphilis screen positive. Of these, 71% (1010/1425) were in women with previously diagnosed syphilis (155 requiring treatment), 26% (374/1425) with newly diagnosed syphilis (all requiring treatment) and 3% (41/1425) required treatment but the reason for treatment was unclear. Thus 40% (570/1425) required treatment overall; of these, 96% (516/537) were treated (missing data: 33/570), although for 18% (83/456), this was not until the third trimester (missing data: 60/537). Follow up of infants born to treated women was poor, with at least a third not followed. Six infants were diagnosed with congenital syphilis; two mothers were untreated, three had delayed treatment and one had incomplete treatment (first trimester). CONCLUSION: Over 2 years, among pregnant women with confirmed positive syphilis screening results in the UK, a quarter had newly diagnosed infections and 40% required treatment. Despite high uptake of treatment, antenatal syphilis management could be improved by earlier detection, earlier treatment, and stronger links between healthcare teams. TWEETABLE ABSTRACT: 25% of pregnant women screening positive for syphilis in the UK were newly diagnosed and 40% needed treatment. PMID- 27219028 TI - The Association of Prenatal Exposure to Perfluorinated Chemicals with Glucocorticoid and Androgenic Hormones in Cord Blood Samples: The Hokkaido Study. AB - BACKGROUND: Perfluorinated chemicals (PFCs) disrupt cholesterol homeostasis. All steroid hormones are derived from cholesterol, and steroid hormones such as glucocorticoids and androgenic hormones mediate several vital physiologic functions. However, the in utero effects of PFCs exposure on the homeostasis of these steroid hormones are not well understood in humans. OBJECTIVES: We examined the relationship between prenatal exposure to perfluorooctane sulfonate (PFOS)/perfluorooctanoate (PFOA) and cord blood levels of glucocorticoid and androgenic hormones. METHODS: We conducted a hospital-based birth cohort study between July 2002 and October 2005 in Sapporo, Japan (n = 514). In total, 185 mother-infant pairs were included in the present study. Prenatal PFOS and PFOA levels in maternal serum samples were measured using liquid chromatography-tandem mass spectrometry (LC-MS-MS). Cord blood levels of glucocorticoid (cortisol and cortisone) and androgenic hormones [dehydroepiandrosterone (DHEA) and androstenedione] were also measured in the same way. RESULTS: We found a dose response relationship of prenatal PFOS, but not PFOA, exposure with glucocorticoid levels after adjusting for potential confounders. Cortisol and cortisone concentrations were -23.98-ng/mL (95% CI: -0.47.12, -11.99; p for trend = 0.006) and -63.21-ng/mL (95% CI: -132.56, -26.72; p for trend < 0.001) lower, respectively, in infants with prenatal PFOS exposure in the fourth quartile compared with those in the first quartile. The highest quartile of prenatal PFOS exposure was positively associated with a 1.33-ng/mL higher DHEA level compared with the lowest quartile (95% CI: 0.17, 1.82; p for trend = 0.017), whereas PFOA showed a negative association with DHEA levels (quartile 4 vs. quartile 1: -1.23 ng/mL, 95% CI: -1.72, -0.25; p for trend = 0.004). We observed no significant association between PFCs and androstenedione levels. CONCLUSIONS: Our results indicate that prenatal exposure to PFCs is significantly associated with glucocorticoid and DHEA levels in cord blood. Citation: Goudarzi H, Araki A, Itoh S, Sasaki S, Miyashita C, Mitsui T, Nakazawa H, Nonomura K, Kishi R. 2017. The association of prenatal exposure to perfluorinated chemicals with glucocorticoid and androgenic hormones in cord blood samples: the Hokkaido Study. Environ Health Perspect 125:111-118; http://dx.doi.org/10.1289/EHP142. PMID- 27219040 TI - Mechanisms and causes of hypomagnesemia. AB - PURPOSE OF REVIEW: Identification of the mechanisms of magnesium absorption and reabsorption has markedly enhanced our understanding of the causes of hypomagnesemia. RECENT FINDINGS: New gastrointestinal and renal causes of hypomagnesemia have been recently documented. SUMMARY: The recognition of new mechanisms and causes of magnesium absorption and reabsorption should enhance the ability to monitor patients at risk for hypomagnesemia and improve our ability to mitigate the serious symptoms associated with this disorder. PMID- 27219041 TI - Nicotinamide and phosphate homeostasis in chronic kidney disease. AB - PURPOSE OF REVIEW: Higher serum phosphate concentration is a central driver of the chronic kidney disease (CKD) mineral bone disorder (MBD). Although phosphate binders are commonly used to lower phosphate, they are minimally effective in CKD. Nicotinamide (vitamin B3) decreases intestinal phosphate transport in animals. Its efficacy and safety in CKD is uncertain. RECENT FINDINGS: We review data differentiating nicotinamide from nicotinic acid (niacin) and compare the metabolism and side-effect profile of each. Several recent studies have tested the safety and efficacy of nicotinamide in patients with CKD and the general population. Available data on efficacy and safety, gaps in knowledge, and ongoing studies to address them are described. SUMMARY: Nicotinamide is a novel potential tool to treat hyperphosphatemia in patients with CKD, but additional data on safety and efficacy are required before widespread clinical use. PMID- 27219042 TI - Skeletal manifestations of renal disease in childhood. AB - PURPOSE OF REVIEW: This review summarizes recent findings on musculoskeletal health in three chronic renal conditions of childhood: chronic kidney disease stages 2-5D, nephrotic syndrome, and urolithiasis. Findings with important clinical implications warranting further investigation are highlighted. RECENT FINDINGS: Recent cohort studies have demonstrated a high burden of fracture and progressive deficits of cortical bone in children with chronic kidney disease. Lower cortical density is associated with incident fracture and may be an important therapeutic target. Parathyroid hormone and calcium are independent correlates of cortical density, and modifiable factors for fracture include parathyroid hormone and phosphate binder use. Children with nephrotic syndrome, even with normal renal function, have evidence of abnormal bone metabolism and structure, and vitamin D deficiency may be an important modifiable risk factor in this population. Urolithiasis has been associated with reduced bone mineral density and is increasingly common in children and adolescents. Population-based data found a significantly increased risk of fracture in adolescent males and young women. SUMMARY: Recent findings substantiate concern regarding the particular vulnerability of the growing skeleton to chronic renal disease. Studies are needed to determine how to optimize assessment and management of bone health in children with these conditions, particularly in terms of calcium and vitamin D requirements, with the goal of improving childhood bone accrual for lifelong fracture prevention. PMID- 27219045 TI - Paper-disc method: An efficient assay for evaluating metal toxicity to soil algae. AB - The probabilistic ecological risk assessment using terrestrial toxicity data has been mainly based on microfauna or mesofauna. Soil algae, which are food source for microfauna and mesofauna, may be alternatively used for assessing soil toxicity. However, there are no internationally recommended guidelines for soil algal bioassays, and the collection of algae from the test soils has some limitations. In this study, we suggested the paper-disc method as an easy-to-use alternative. This method has been widely used for testing the antibacterial toxicity of various chemicals in agar media by measuring the diameter of the inhibition zone around the disc. We adapted the paper-disc method for screening the toxicity of copper (Cu) and nickel (Ni) to the soil alga Chlorococcum infusionum using various evaluation endpoints, such as growth zone, chlorophyll fluorescence, and photosynthetic activity. Chlorophyll fluorescence and photosynthetic activity decreased with the increasing concentrations of Cu(+2) or Ni(+2) contaminated soils. Algal growth zone was analyzed visually and showed similar results to those of chlorophyll fluorescence. The direct ethanol extraction method and indirect culture medium extraction method were similarly effective; however, the former was easier to perform, while the latter might facilitate the analysis of additional endpoints in future studies. Overall, the results suggested that the paper-disc method was not only a user-friendly assay for screening soil toxicity, but also effective due to its association with indirect soil quality indicators. PMID- 27219043 TI - The role of fibroblast growth factor 23 and Klotho in uremic cardiomyopathy. AB - PURPOSE OF REVIEW: In chronic kidney disease (CKD), multiple factors contribute to the development of cardiac hypertrophy by directly targeting the heart or indirectly by inducing systemic changes such as hypertension, anemia, and inflammation. Furthermore, disturbances in phosphate metabolism have been identified as nonclassical risk factors for cardiovascular mortality in these patients. With declining kidney function, the physiologic regulators of phosphate homeostasis undergo changes in their activity as well as their circulating levels, thus potentially contributing to cardiac hypertrophy once they are out of balance. Recently, two of these phosphate regulators, fibroblast growth factor 23 (FGF23) and Klotho, have been shown to affect cardiac remodeling, thereby unveiling a novel pathomechanism of cardiac hypertrophy in CKD. Here we discuss the potential direct versus indirect effects of FGF23 and the soluble form of Klotho on the heart, and their crosstalk in the regulation of cardiac hypertrophy. RECENT FINDINGS: In models of CKD, FGF23 can directly target cardiac myocytes via FGF receptor 4 and induce cardiac hypertrophy in a blood pressure independent manner. Soluble Klotho may directly target the heart via an unknown receptor thereby protecting the myocardium from pathologic stress stimuli that are associated with CKD, such as uremic toxins or FGF23. SUMMARY: Elevated serum levels of FGF23 and reduced serum levels of soluble Klotho contribute to uremic cardiomyopathy in a synergistic manner. PMID- 27219046 TI - Probabilistic ecological risk assessment of effluent toxicity of a wastewater reclamation plant based on process modeling. AB - The growing use of reclaimed wastewater for environmental purposes such as stream flow augmentation requires comprehensive ecological risk assessment and management. This study applied a system analysis approach, regarding a wastewater reclamation plant (WRP) and its recipient water body as a whole system, and assessed the ecological risk of the recipient water body caused by the WRP effluent. Instead of specific contaminants, two toxicity indicators, i.e. genotoxicity and estrogenicity, were selected to directly measure the biological effects of all bio-available contaminants in the reclaimed wastewater, as well as characterize the ecological risk of the recipient water. A series of physically based models were developed to simulate the toxicity indicators in a WRP through a typical reclamation process, including ultrafiltration, ozonation, and chlorination. After being validated against the field monitoring data from a full scale WRP in Beijing, the models were applied to simulate the probability distribution of effluent toxicity of the WRP through Latin Hypercube Sampling to account for the variability of influent toxicity and operation conditions. The simulated effluent toxicity was then used to derive the predicted environmental concentration (PEC) in the recipient stream, considering the variations of the toxicity and flow of the upstream inflow as well. The ratio of the PEC of each toxicity indicator to its corresponding predicted no-effect concentration was finally used for the probabilistic ecological risk assessment. Regional sensitivity analysis was also performed with the developed models to identify the critical control variables and strategies for ecological risk management. PMID- 27219044 TI - Multiple faces of fibroblast growth factor-23. AB - PURPOSE OF REVIEW: This review examines the role of fibroblast growth factor-23 (FGF-23) in mineral metabolism, innate immunity and adverse cardiovascular outcomes. RECENT FINDINGS: FGF-23, produced by osteocytes in bone, activates FGFR/alpha-Klotho (alpha-Kl) complexes in the kidney. The resulting bone-kidney axis coordinates renal phosphate reabsorption with bone mineralization, and creates a counter-regulatory feedback loop to prevent vitamin D toxicity. FGF-23 acts to counter-regulate the effects of vitamin D on innate immunity and cardiovascular responses. FGF-23 is ectopically expressed along with alpha-Kl in activated macrophages, creating a proinflammatory paracrine signaling pathway that counters the antiinflammatory actions of vitamin D. FGF-23 also inhibits angiotensin-converting enzyme 2 expression and increases sodium reabsorption in the kidney, leading to hypertension and left ventricular hypertrophy. Finally, FGF-23 is purported to cause adverse cardiac and impair neutrophil responses through activation of FGFRs in the absence of alpha-Kl. Although secreted forms of alpha-Kl have FGF-23 independent effects, the possibility of alpha-Kl independent effects of FGF-23 is controversial and requires additional experimental validation. SUMMARY: FGF-23 participates in a bone-kidney axis regulating mineral homeostasis, proinflammatory paracrine macrophage signaling pathways, and in a bone-cardio-renal axis regulating hemodynamics that counteract the effects of vitamin D. PMID- 27219047 TI - Detection of protozoa in water samples by formalin/ether concentration method. AB - Methods to detect protozoa in water samples are expensive and laborious. We evaluated the formalin/ether concentration method to detect Giardia sp., Cryptosporidium sp. and Toxoplasma in water. In order to test the properties of the method, we spiked water samples with different amounts of each protozoa (0, 10 and 50 cysts or oocysts) in a volume of 10 L of water. Immunofluorescence assay was used for detection of Giardia and Cryptosporidium. Toxoplasma oocysts were identified by morphology. The mean percent of recovery in 10 repetitions of the entire method, in 10 samples spiked with ten parasites and read by three different observers, were for Cryptosporidium 71.3 +/- 12, for Giardia 63 +/- 10 and for Toxoplasma 91.6 +/- 9 and the relative standard deviation of the method was of 17.5, 17.2 and 9.8, respectively. Intraobserver variation as measured by intraclass correlation coefficient, was fair for Toxoplasma, moderate for Cryptosporidium and almost perfect for Giardia. The method was then applied in 77 samples of raw and drinkable water in three different plant of water treatment. Cryptosporidium was found in 28 of 77 samples (36%) and Giardia in 31 of 77 samples (40%). Theses results identified significant differences in treatment process to reduce the presence of Giardia and Cryptosporidium. In conclusion, the formalin ether method to concentrate protozoa in water is a new alternative for low resources countries, where is urgently need to monitor and follow the presence of theses protozoa in drinkable water. PMID- 27219048 TI - Environmental factors shaping cultured free-living amoebae and their associated bacterial community within drinking water network. AB - Free-living amoebae (FLA) constitute an important part of eukaryotic populations colonising drinking water networks. However, little is known about the factors influencing their ecology in such environments. Because of their status as reservoir of potentially pathogenic bacteria, understanding environmental factors impacting FLA populations and their associated bacterial community is crucial. Through sampling of a large drinking water network, the diversity of cultivable FLA and their bacterial community were investigated by an amplicon sequencing approach, and their correlation with physicochemical parameters was studied. While FLA ubiquitously colonised the water network all year long, significant changes in population composition were observed. These changes were partially explained by several environmental parameters, namely water origin, temperature, pH and chlorine concentration. The characterisation of FLA associated bacterial community reflected a diverse but rather stable consortium composed of nearly 1400 OTUs. The definition of a core community highlighted the predominance of only few genera, majorly dominated by Pseudomonas and Stenotrophomonas. Co occurrence analysis also showed significant patterns of FLA-bacteria association, and allowed uncovering potentially new FLA - bacteria interactions. From our knowledge, this study is the first that combines a large sampling scheme with high-throughput identification of FLA together with associated bacteria, along with their influencing environmental parameters. Our results demonstrate the importance of physicochemical parameters in the ecology of FLA and their bacterial community in water networks. PMID- 27219049 TI - Synthesis of magnetically separable Bi2O4/Fe3O4 hybrid nanocomposites with enhanced photocatalytic removal of ibuprofen under visible light irradiation. AB - Ibuprofen (IBU) is one of the representative persistent organic pollutants (POPs) which can cause severe adverse effects in humans and wildlife. Therefore, effectively removing IBU from water is a worldwide necessity. In this study, a novel superparamagnetic Bi2O4/Fe3O4 nanocomposite was successfully prepared by an in-situ growth method and utilized for photocatalytic removal of IBU. The structural characterization of the Bi2O4/Fe3O4 nanocomposite indicates that the monodisperse Fe3O4 nanoparticles of diameter 10 nm are highly assembled on the Bi2O4 nanorods of diameter 120 nm. Under visible light irradiation, using an optimum molar ratio of Bi2O4/Fe3O4 (1:2.5) resulted in a complete photocatalytic degradation of IBU within 2 h, which is a 1.7 times higher efficiency than pure Bi2O4, and a complete mineralization of IBU with a prolonged irradiation time of 4 h. In addition, the potential practicality of Bi2O4/Fe3O4 (1:2.5) was also demonstrated by the efficient photocatalytic degradation of IBU in actual drinking water. The photocatalytic mechanisms of Bi2O4/Fe3O4 (1:2.5) were revealed, indicating that the enhanced photocatalytic performance was mainly attributed to the accelerated separation of electron-hole pairs after surface modification of Fe3O4, and that the photogenerated h(+) was the primary reactive species for the photocatalytic removal of IBU. Furthermore, the Bi2O4/Fe3O4 (1:2.5) can be magnetically recycled and shows good reusability without significant loss of photocatalytic activity or structural change even after reuse over five cycles, showing a promising application for the photocatalytic degradation of POPs from water. PMID- 27219050 TI - Correction: Presequence-Independent Mitochondrial Import of DNA Ligase Facilitates Establishment of Cell Lines with Reduced mtDNA Copy Number. AB - [This corrects the article DOI: 10.1371/journal.pone.0152705.]. PMID- 27219051 TI - The use of stent retrievers in acute ischemic stroke. AB - INTRODUCTION: Acute ischemic stroke (AIS) is one of the leading causes of mortality and adult disability worldwide. For two decades, the preferred approach for AIS was intravenous recombinant tissue plasminogen activator (IV tPA). However, IV tPA cannot be given to many AIS patients who do not meet strict criteria for its use. IV tPA has also had lesser benefit in patients with large clot burden in the context of large vessel occlusion (LVO). AREAS COVERED: Endovascular stroke therapy had been an 'unproven' therapy despite numerous trials of intra-arterial pharmacologic thrombolysis and mechanical thrombectomy. With the advent of stent-retriever devices, there has been a paradigm shift in the utilization of endovascular therapies for AIS. Our review discusses cerebrovascular hemodynamics, the basis of the recanalization models in AIS, aspects of intravenous thrombolysis, prior generations of endovascular therapy, and the recent successful AIS stent retriever trials. Expert commentary: Recently 'stent-retrievers', a new generation of mechanical thrombectomy devices, were shown to be associated with improved functional outcomes in AIS secondary to proximal intracranial anterior circulation LVO. Stent retrievers are a major advance in AIS care and will have significant impact on the evolution of stroke systems of care. PMID- 27219052 TI - Global Carrier Rates of Rare Inherited Disorders Using Population Exome Sequences. AB - Exome sequencing has revealed the causative mutations behind numerous rare, inherited disorders, but it is challenging to find reliable epidemiological values for rare disorders. Here, I provide a genetic epidemiology method to identify the causative mutations behind rare, inherited disorders using two population exome sequences (1000 Genomes and NHLBI). I created global maps of carrier rate distribution for 18 recessive disorders in 16 diverse ethnic populations. Out of a total of 161 mutations associated with 18 recessive disorders, I detected 24 mutations in either or both exome studies. The genetic mapping revealed strong international spatial heterogeneities in the carrier patterns of the inherited disorders. I next validated this methodology by statistically evaluating the carrier rate of one well-understood disorder, sickle cell anemia (SCA). The population exome-based epidemiology of SCA [African (allele frequency (AF) = 0.0454, N = 2447), Asian (AF = 0, N = 286), European (AF = 0.000214, N = 4677), and Hispanic (AF = 0.0111, N = 362)] was not significantly different from that obtained from a clinical prevalence survey. A pair-wise proportion test revealed no significant differences between the two exome projects in terms of AF (46/48 cases; P > 0.05). I conclude that population exome based carrier rates can form the foundation for a prospectively maintained database of use to clinical geneticists. Similar modeling methods can be applied to many inherited disorders. PMID- 27219053 TI - The Reaumuria trigyna leucoanthocyanidin dioxygenase (RtLDOX) gene complements anthocyanidin synthesis and increases the salt tolerance potential of a transgenic Arabidopsis LDOX mutant. AB - Reaumuria trigyna is a typical, native desert halophyte that grows under extreme conditions in Inner Mongolia. In a previous transcriptomic profiling analysis, flavonoid pathway-related genes in R. trigyna showed significant differences in transcript abundance under salt stress. Leucoanthocyanidin dioxygenase (LDOX, EC 1.14.11.19) is one of three dioxygenases in the flavonoid pathway that catalyzes the formation of anthocyanidins from leucoanthocyanidins. In this study, we cloned the full-length cDNA of R. trigyna LDOX (RtLDOX), and found RtLDOX recombinant protein was able to replace flavanone-3-hydroxylase (F3H, EC 1.14.11.9), another dioxygenase in the flavonoid pathway, to convert naringenin to dihydrokaempferol in vitro. R. trigyna LDOX can complement the Arabidopsis LDOX mutant transparent testa11 (tt11-11), which has reduced proanthocyanin (PA) and anthocyanin levels in seeds, to accumulate these two compounds. Thus, RtLDOX acts as a multifunctional dioxygenase to effect the synthesis of PA and anthocyanins and can perform F3H dioxygenase activities in the flavonoid biosynthesis pathway. The RtLDOX promoter harbored many cis-acting elements that might be recognized and bound by transcription factors related to stress response. RtLDOX expression was strongly increased under salt stress, and RtLDOX transgenic Arabidopsis mutant under NaCl stress accumulated the content of flavonoids leading to an increased antioxidant activities and plant biomass. These results suggest that RtLDOX as a multifunctional dioxygenase in flavonoid biosynthesis involves in enhancing plant response to NaCl stress. PMID- 27219055 TI - Autophagy Determines the Path on the TRAIL to Death. AB - Macroautophagy facilitates degradation of cellular constituents and can positively or negatively affect cell death depending on the context. In this issue of Developmental Cell, Goodall and colleagues (2016) add to this complexity by showing that autophagy regulators can determine not only cell viability, but also the mechanism by which cells die. PMID- 27219056 TI - The Secret of Centriole Length: Keep a LID on It. AB - An outstanding challenge in biology is to elucidate the mechanisms that establish and limit organelle structure and size. In this issue of Developmental Cell, Sharma et al. (2016) report how a conserved centriole protein dynamically caps centriole microtubule plus ends to limit the organelle's length. PMID- 27219054 TI - The Burden of Cryptosporidium Diarrheal Disease among Children < 24 Months of Age in Moderate/High Mortality Regions of Sub-Saharan Africa and South Asia, Utilizing Data from the Global Enteric Multicenter Study (GEMS). AB - BACKGROUND: The importance of Cryptosporidium as a pediatric enteropathogen in developing countries is recognized. METHODS: Data from the Global Enteric Multicenter Study (GEMS), a 3-year, 7-site, case-control study of moderate-to severe diarrhea (MSD) and GEMS-1A (1-year study of MSD and less-severe diarrhea [LSD]) were analyzed. Stools from 12,110 MSD and 3,174 LSD cases among children aged <60 months and from 21,527 randomly-selected controls matched by age, sex and community were immunoassay-tested for Cryptosporidium. Species of a subset of Cryptosporidium-positive specimens were identified by PCR; GP60 sequencing identified anthroponotic C. parvum. Combined annual Cryptosporidium-attributable diarrhea incidences among children aged <24 months for African and Asian GEMS sites were extrapolated to sub-Saharan Africa and South Asian regions to estimate region-wide MSD and LSD burdens. Attributable and excess mortality due to Cryptosporidium diarrhea were estimated. FINDINGS: Cryptosporidium was significantly associated with MSD and LSD below age 24 months. Among Cryptosporidium-positive MSD cases, C. hominis was detected in 77.8% (95% CI, 73.0%-81.9%) and C. parvum in 9.9% (95% CI, 7.1%-13.6%); 92% of C. parvum tested were anthroponotic genotypes. Annual Cryptosporidium-attributable MSD incidence was 3.48 (95% CI, 2.27-4.67) and 3.18 (95% CI, 1.85-4.52) per 100 child-years in African and Asian infants, respectively, and 1.41 (95% CI, 0.73-2.08) and 1.36 (95% CI, 0.66-2.05) per 100 child-years in toddlers. Corresponding Cryptosporidium-attributable LSD incidences per 100 child-years were 2.52 (95% CI, 0.33-5.01) and 4.88 (95% CI, 0.82-8.92) in infants and 4.04 (95% CI, 0.56 7.51) and 4.71 (95% CI, 0.24-9.18) in toddlers. We estimate 2.9 and 4.7 million Cryptosporidium-attributable cases annually in children aged <24 months in the sub-Saharan Africa and India/Pakistan/Bangladesh/Nepal/Afghanistan regions, respectively, and ~202,000 Cryptosporidium-attributable deaths (regions combined). ~59,000 excess deaths occurred among Cryptosporidium-attributable diarrhea cases over expected if cases had been Cryptosporidium-negative. CONCLUSIONS: The enormous African/Asian Cryptosporidium disease burden warrants investments to develop vaccines, diagnostics and therapies. PMID- 27219057 TI - Linking Separase to Microtubule Dynamics. AB - The Arabidopsis separase homolog, AtESP, associates with microtubules and affects cell polarity but does not bind microtubules directly. In this issue of Developmental Cell, Moschou et al. (2016) show that AtESP teams up with the CENP E kinesin Kin7 to promote microtubule stabilization, an activity independent of separase proteolytic activity. PMID- 27219058 TI - Accessories to Limb Regeneration. AB - In a recent issue of Nature, Nacu et al. (2016) identified FGF and HH ligands as interacting molecular influences that are necessary and sufficient to induce the formation of supernumerary limbs from blastemal tissue in axolotl salamanders. PMID- 27219059 TI - Fanconi Anemia Genes, of Menders and Sweepers. AB - Reporting recently in Cell, Sumpter et al. (2016) provide evidence that Fanconi anemia (FA) pathway genes, which are mutated in the homonymous disease and are tumor suppressors known as damaged nuclear DNA "menders," also act as intracellular sweepers in selective virophagy and mitophagy. PMID- 27219060 TI - Extracellular Vesicles: Satellites of Information Transfer in Cancer and Stem Cell Biology. AB - The generation and shedding of extracellular vesicles (EVs), including exosomes and microvesicles (MVs), by cells has emerged as a form of intercellular communication with important roles in several physiological processes and diseases such as cancer. These membrane-enclosed packets can transfer specific proteins, RNA transcripts, microRNAs, and even DNA to target cells, thereby altering their function. Despite the exponential growth of the EV field, a great deal remains unclear about the mechanisms that regulate exosome and MV biogenesis, as well as about how to isolate different classes of EVs and how to best take advantage of them for clinical applications. PMID- 27219061 TI - Kinesin 1 Drives Autolysosome Tubulation. AB - Autophagic lysosome reformation (ALR) plays an important role in maintaining lysosome homeostasis. During ALR, lysosomes are reformed by recycling lysosomal components from autolysosomes. The most noticeable step of ALR is autolysosome tubulation, but it is currently unknown how the process is regulated. Here, using an approach combining in vivo studies and in vitro reconstitution, we found that the kinesin motor protein KIF5B is required for autolysosome tubulation and that KIF5B drives autolysosome tubulation by pulling on the autolysosomal membrane. Furthermore, we show that KIF5B directly interacts with PtdIns(4,5)P2. Kinesin motors are recruited and clustered on autolysosomes via interaction with PtdIns(4,5)P2 in a clathrin-dependent manner. Finally, we demonstrate that clathrin promotes formation of PtdIns(4,5)P2-enriched microdomains, which are required for clustering of KIF5B. Our study reveals a mechanism by which autolysosome tubulation was generated. PMID- 27219062 TI - The Autophagy Machinery Controls Cell Death Switching between Apoptosis and Necroptosis. AB - Although autophagy controls cell death and survival, underlying mechanisms are poorly understood, and it is unknown whether autophagy affects only whether or not cells die or also controls other aspects of programmed cell death. MAP3K7 is a tumor suppressor gene associated with poor disease-free survival in prostate cancer. Here, we report that Map3k7 deletion in mouse prostate cells sensitizes to cell death by TRAIL (TNF-related apoptosis-inducing ligand). Surprisingly, this death occurs primarily through necroptosis, not apoptosis, due to assembly of the necrosome in association with the autophagy machinery, mediated by p62/SQSTM1 recruitment of RIPK1. The mechanism of cell death switches to apoptosis if p62-dependent recruitment of the necrosome to the autophagy machinery is blocked. These data show that the autophagy machinery can control the mechanism of programmed cell death by serving as a scaffold rather than by degrading cargo. PMID- 27219063 TI - Separase Promotes Microtubule Polymerization by Activating CENP-E-Related Kinesin Kin7. AB - Microtubules play an essential role in breaking cellular symmetry. We have previously shown that separase associates with microtubules and regulates microtubule-dependent establishment of cell polarity in Arabidopsis. However, separase lacks microtubule-binding activity, raising questions about mechanisms underlying this phenomenon. Here we report that the N-terminal non-catalytic domain of separase binds to the C-terminal tail domain of three homologs of the centromeric protein CENP-E Kinesin 7 (Kin7). Conformational changes of Kin7 induced upon binding to separase facilitate recruitment of Kin7/separase complex (KISC) onto microtubules. KISC operates independently of proteolytic activity of separase in promoting microtubule rescue and pauses, as well as in suppressing catastrophes. Genetic complementation experiments in conditional separase mutant rsw4 background demonstrate the importance of KISC for the establishment of cell polarity and for plant development. Our study establishes a mechanism governing microtubule dynamics via the separase-dependent activation of CENP-E-related kinesins. PMID- 27219064 TI - Centriolar CPAP/SAS-4 Imparts Slow Processive Microtubule Growth. AB - Centrioles are fundamental and evolutionarily conserved microtubule-based organelles whose assembly is characterized by microtubule growth rates that are orders of magnitude slower than those of cytoplasmic microtubules. Several centriolar proteins can interact with tubulin or microtubules, but how they ensure the exceptionally slow growth of centriolar microtubules has remained mysterious. Here, we bring together crystallographic, biophysical, and reconstitution assays to demonstrate that the human centriolar protein CPAP (SAS 4 in worms and flies) binds and "caps" microtubule plus ends by associating with a site of beta-tubulin engaged in longitudinal tubulin-tubulin interactions. Strikingly, we uncover that CPAP activity dampens microtubule growth and stabilizes microtubules by inhibiting catastrophes and promoting rescues. We further establish that the capping function of CPAP is important to limit growth of centriolar microtubules in cells. Our results suggest that CPAP acts as a molecular lid that ensures slow assembly of centriolar microtubules and, thereby, contributes to organelle length control. PMID- 27219065 TI - The Centrosome Undergoes Plk1-Independent Interphase Maturation during Inflammation and Mediates Cytokine Release. AB - Cytokine production is a necessary event in the immune response during inflammation and is associated with mortality during sepsis, autoimmune disorders, cancer, and diabetes. Stress-activated MAP kinase signaling cascades that mediate cytokine synthesis are well established. However, the downstream fate of cytokines before they are secreted remains elusive. We report that pro inflammatory stimuli lead to recruitment of pericentriolar material, specifically pericentrin and gamma-tubulin, to the centrosome. This is accompanied by enhanced microtubule nucleation and enrichment of the recycling endosome component FIP3, all of which are hallmarks of centrosome maturation during mitosis. Intriguingly, centrosome maturation occurs during interphase in an MLK-dependent manner, independent of the classic mitotic kinase, Plk1. Centrosome disruption by chemical prevention of centriole assembly or genetic ablation of pericentrin attenuated interleukin-6, interleukin-10, and MCP1 secretion, suggesting that the centrosome is critical for cytokine production. Our results reveal a function of the centrosome in innate immunity. PMID- 27219066 TI - Retrogradation of Maize Starch after High Hydrostatic Pressure Gelation: Effect of Amylose Content and Depressurization Rate. AB - High hydrostatic pressure (HHP) has been employed to gelatinize or physically modify starch dispersions. In this study, waxy maize starch, normal maize starch, and two high amylose content starch were processed by a HHP of the order of 600 MPa, at 25 degrees C for 15min. The effect of HHP processing on the crystallization of maize starches with various amylose content during storage at 4 degrees C was investigated. Crystallization kinetics of HHP treated starch gels were investigated using rheology and FTIR. The effect of crystallization on the mechanical properties of starch gel network were evaluated in terms of dynamic complex modulus (G*). The crystallization induced increase of short-range helices structures were investigated using FTIR. The pressure releasing rate does not affect the starch retrogradation behaviour. The rate and extent of retrogradation depends on the amylose content of amylose starch. The least retrogradation was observed in HHP treated waxy maize starch. The rate of retrogradation is higher for HHP treated high amylose maize starch than that of normal maize starch. A linear relationship between the extent of retrogradation (phase distribution) measured by FTIR and G* is proposed. PMID- 27219067 TI - A New Approach for On-Demand Generation of Various Oxygen Tensions for In Vitro Hypoxia Models. AB - The development of in vitro disease models closely mimicking the functions of human disease has captured increasing attention in recent years. Oxygen tensions and gradients play essential roles in modulating biological systems in both physiologic and pathologic events. Thus, controlling oxygen tension is critical for mimicking physiologically relevant in vivo environments for cell, tissue and organ research. We present a new approach for on-demand generation of various oxygen tensions for in vitro hypoxia models. Proof-of-concept prototypes have been developed for conventional cell culture microplate by immobilizing a novel oxygen-consuming biomaterial on the 3D-printed insert. For the first time, rapid (~3.8 minutes to reach 0.5% O2 from 20.9% O2) and precisely controlled oxygen tensions/gradients (2.68 mmHg per 50 MUm distance) were generated by exposing the biocompatible biomaterial to the different depth of cell culture media. In addition, changing the position of 3D-printed inserts with immobilized biomaterials relative to the cultured cells resulted in controllable and rapid changes in oxygen tensions (<130 seconds). Compared to the current technologies, our approach allows enhanced spatiotemporal resolution and accuracy of the oxygen tensions. Additionally, it does not interfere with the testing environment while maintaining ease of use. The elegance of oxygen tension manipulation introduced by our new approach will drastically improve control and lower the technological barrier of entry for hypoxia studies. Since the biomaterials can be immobilized in any devices, including microfluidic devices and 3D-printed tissues or organs, it will serve as the basis for a new generation of experimental models previously impossible or very difficult to implement. PMID- 27219068 TI - Personalised treatment for cognitive dysfunction in individuals with schizophrenia spectrum disorders. AB - Cognitive deficits are a well-recognised issue for individuals diagnosed with schizophrenia spectrum disorders. Despite positive group findings for the use of cognitive remediation (CR) interventions, there are substantial individual differences in response to treatment. In addition, the aggregate CR literature reports low moderate effect sizes for cognitive and functional outcomes. Based on personalised medicine theory, this paper uses extant CR literature to examine the individual characteristics determined to predict treatment response. These characteristics, which fall into the broad categories of cognitive, psychological, and biological can be used as tailoring variables to personalise CR to an individual's unique profile. Personalisation through the use of these tailoring variables has the potential to improve the delivery of CR to maximise treatment outcomes. PMID- 27219069 TI - Multifaceted Studies of the DNA Interactions and In Vitro Cytotoxicity of Anticancer Polyaromatic Platinum(II) Complexes. AB - This study reports a detailed biophysical analysis of the DNA binding and cytotoxicity of six platinum complexes (PCs). They are of the type [Pt(PL )(SS dach)]Cl2 , where PL is a polyaromatic ligand and SS-dach is 1S,2S diaminocyclohexane. The DNA binding of these complexes was investigated using six techniques including ultraviolet and fluorescence spectroscopy, linear dichroism, synchrotron radiation circular dichroism, isothermal titration calorimetry and mass spectrometry. This portfolio of techniques has not been extensively used to study the interactions of such complexes previously; each assay provided unique insight. The in vitro cytotoxicity of these compounds was studied in ten cell lines and compared to the effects of their R,R enantiomers; activity was very high in Du145 and SJ-G2 cells, with some submicromolar IC50 values. In terms of both DNA affinity and cytotoxicity, complexes of 5,6-dimethyl-1,10-phenanthroline and 2,2'-bipyridine exhibited the greatest and least activity, respectively, suggesting that there is some correlation between DNA binding and cytotoxicity. PMID- 27219070 TI - Are there gender differences in locus of control specific to alcohol dependence? AB - AIMS AND OBJECTIVES: To investigate gender differences in locus of control in an alcohol-dependent population. BACKGROUND: Locus of control helps to explain behaviour in terms of internal (the individual is responsible) or external (outside forces, such as significant other people or chance, are responsible) elements. Past research on gender differences in locus of control in relation to alcohol dependence has shown mixed results. There is a need then to examine gender and locus of control in relation to alcohol dependence to ascertain the veracity of any locus of control differences as a function of gender. DESIGN AND METHODS: The Multidimensional Health Locus of Control form-C was administered to clients from alcohol dependence treatment centres in the West of Scotland. Independent t-tests were carried out to assess gender differences in alcohol dependence severity and internal/external aspects of locus of control. RESULTS: One hundred and eighty-eight (53% females) participants were recruited from a variety of alcohol dependence treatment centres. The majority of participants (72%) came from Alcoholics Anonymous groups. Women revealed a greater internal locus of control compared with men. Women also had a greater 'significant others' locus of control score than men. Men were more reliant on 'chance' and 'doctors' than women. All these trends were not, however, statistically significant. CONCLUSIONS: Gender differences in relation to locus of control and alcohol dependence from past studies are ambiguous. This study also found no clear statistically significant differences in locus of control orientation as a function of gender. RELEVANCE TO CLINICAL PRACTICE: This article helps nurses to contextualise health behaviours as a result of internal or external forces. It also helps nursing staff to better understand alcohol dependence treatment in relation to self-efficacy and control. Moreover, it highlights an important concept in health education theory. PMID- 27219071 TI - High-Performance Upconversion Nanoprobes for Multimodal MR Imaging of Acute Ischemic Stroke. AB - Multimodal magnetic resonance (MR) imaging, including MR angiography (MRA) and MR perfusion (MRP), plays a critical role in the diagnosis and surveillance of acute ischemic stroke. However, these techniques are hindered by the low T1 relaxivity, short circulation time, and high leakage rate from vessels of clinical Magnevist. To address these problems, nontoxic polyethylene glycol (PEG)ylated upconversion nanoprobes (PEG-UCNPs) are synthesized and first adopted for excellent MRA and MRP imaging, featuring high diagnostic sensitivity toward acute ischemic stroke in high-resolution imaging. The investigations show that the agent possesses superior advantages over clinical Magnevist, such as much higher relaxivity, longer circulation time, and lower leakage rate, which guarantee much better imaging efficiency. Remarkably, an extremely small dosage (5 mg Gd kg(-1) ) of PEG-UCNPs provides high-resolution MRA imaging with the vascular system delineated much clearer than the Magnevist with clinical dosage as high as 108 mg Gd kg(-1) . On the other hand, the long circulation time of PEG-UCNPs enables the surveillance of the progression of ischemic stroke using MRA or MRP. Once translated, these PEG-UCNPs are expected to be a promising candidate for substituting the clinical Magnevist in MRA and MRP, which will significantly lengthen the imaging time window and improve the overall diagnostic efficiency. PMID- 27219072 TI - Association between smoking, glycaemia, blood lipoproteins and risk of oral leukoplakia. AB - BACKGROUND: Among potentially malignant disorders, oral leukoplakia is the most common in clinical practice. The aim of this study was to assess risk factors associated with oral leukoplakia. METHODS: This retrospective study included 142 patients diagnosed with oral leukoplakia according to World Health Organization clinical and histopathological criteria and a control group of healthy subjects matched for age and gender. Sociodemographic data were registered for each patient: age, gender, smoking and alcohol consumption. Leukoplakia characteristics were also registered: size, position, clinical form, and presence or absence of dysplasia; all cases of leukoplakia were classified systematically according to clinicopathological stage. Blood lipid component levels of total cholesterol, high-density lipoproteins, low-density lipoproteins and triglycerides were compared between groups. RESULTS: Smoking had a significant effect on the risk of leukoplakia (P = 0.01, odds ratio (OR) = 8.33). High glucose levels also increased the probability of leukoplakia (P = 0.03, OR = 6.35), as did low-density lipoproteins (P = 0.049, OR = 5.65). The risk of dysplasia increased among patients presenting the non-homogeneous form of leukoplakia (P = 0.039, OR = 9.06) and among smokers (P = 0.044, OR = 28.33). CONCLUSIONS: Smoking, increased glucose and low-density lipoproteins in the blood are associated with a risk of oral leukoplakia. PMID- 27219073 TI - Intentional Rounding: a staff-led quality improvement intervention in the prevention of patient falls. AB - AIMS AND OBJECTIVES: This study designed and evaluated the use of a specific implementation strategy to deliver a nursing staff-led Intentional Rounding intervention to reduce inpatient falls. BACKGROUND: Patient falls are a common cause of harm during hospital treatment. Intentional Rounding has been proposed as a potential strategy for prevention, but has not received much objective evaluation. Previous work has suggested that logical interventions to improve patient care require an integrated implementation strategy, using teamwork training and systems improvement training, to instigate positive change and improvement. METHODS: Customised Intentional Rounding was implemented and evaluated as part of a staff-led quality improvement intervention to reduce falls on a neuroscience ward. Intentional Rounding was instigated using a prespecified implementation strategy, which comprised of: (1) engagement and communication activities, (2) teamwork and systems improvement training, (3) support and coaching and (4) iterative Plan-Do-Check-Act cycles. Process (compliance with hourly visiting to patients by staff) and outcome (incidence of falls) measures were recorded pre- and postintervention. Falls measured on the active ward were compared with incidence of falls in 50 wards across the rest of the same Trust. RESULTS: There was a 50% reduction in patient falls on the active ward vs. a minimal increase across the rest of the Trust (3.48%). Customised Intentional Rounding, designed by staff specifically for the context, appeared to be effective in reducing patient falls. CONCLUSIONS: Improvement programmes based on integrating teamwork training and staff-led systems redesign, together with a preplanned implementation strategy, can deliver effective change and improvement. RELEVANCE TO CLINICAL PRACTICE: This study demonstrates, through the implementation of a specific strategy, an effective improvement intervention to reduce patient falls. It provides insight into the effective design and practical implementation of integrated improvement programmes to reduce risk to patients at the frontline. PMID- 27219074 TI - A new approach to the determination of the synthetic or natural origin of red pigments through spectroscopic analysis. AB - This work suggests a way of differentiation between the natural or synthetic origin of inorganic materials that were historically used in the Cultural Heritage field. An exhaustive review of different reported procedures of synthesis of pigments was conducted, as well as a review of the accompanying minerals in case of natural pigments. The natural or synthetic origin of the pigments studied in this work was performed through the characterization of the accompanying minerals, in the case of the natural pigments, or the trace elements that are present as part of synthesis by-products or washing/purifying reagents and/or reactants that have only been partly removed in the final steps of these processes. This work characterized red pigments due to their wide variety, complexity and possibility of use in different mixtures. The following pigments were studied: cinnabar-vermilion, red lead and iron pigments. Also mixtures of these pigments between them and with red lake were also studied. Natural cinnabar was accompanied by silicon oxide (opal, chalcedony or quartz), calcite, clay minerals and, sometimes, pyrite. K together with S indicated a synthetic pigment (vermilion) obtained through the wet method. Nevertheless, K has not been found in layers containing only vermilion in our samples. The presence of Sn in some cases indicated vermilion that came from the dry process. K from the synthesis always appeared in the red lead pigment. The red natural ochre was confirmed by presence of clay minerals and iron. It should be said that Ca and S, and sometimes Al and K, were usually found in Mars red pigment. The presence of Al and Ca allowed the identification of carmine lake. PMID- 27219075 TI - Thiazine dyes: Evaluation of monomeric and aggregate forms. AB - The aggregation phenomenon of Azure B, monobrominated Azure B, Thionine and Methylene Blue was studied by UV-Visible spectrophotometry in different media as a function of dye concentration and temperature variations. The tests carried out in organic solvents allowed the identification of monomeric species of these compounds, which have not been reported in literature and have been wrongly assigned for years. The results obtained in water allowed demonstrating that different kinds of aggregates are present in this medium. In addition, the aggregation tendency of these dyes in organic solvent and aqueous media was established. Several parameters such as lipophilicity, effect of bulky substituents and interactions with media were considered to interpret the aggregation behavior of thiazine dyes. PMID- 27219077 TI - Organic Nitrate Contribution to New Particle Formation and Growth in Secondary Organic Aerosols from alpha-Pinene Ozonolysis. AB - The chemical kinetics of organic nitrate production during new particle formation and growth of secondary organic aerosols (SOA) were investigated using the short lived radioactive tracer (13)N in flow-reactor studies of alpha-pinene oxidation with ozone. Direct and quantitative measurements of the nitrogen content indicate that organic nitrates accounted for ~40% of SOA mass during initial particle formation, decreasing to ~15% upon particle growth to the accumulation-mode size range (>100 nm). Experiments with OH scavengers and kinetic model results suggest that organic peroxy radicals formed by alpha-pinene reacting with secondary OH from ozonolysis are key intermediates in the organic nitrate formation process. The direct reaction of alpha-pinene with NO3 was found to be less important for particle-phase organic nitrate formation. The nitrogen content of SOA particles decreased slightly upon increase of relative humidity up to 80%. The experiments show a tight correlation between organic nitrate content and SOA particle-number concentrations, implying that the condensing organic nitrates are among the extremely low volatility organic compounds (ELVOC) that may play an important role in the nucleation and growth of atmospheric nanoparticles. PMID- 27219076 TI - Isolation of Stenotrophomonas maltophilia in asymptomatic lung transplant recipients: effects of treatment on eradication and outcome. AB - In this retrospective, single-center data analysis, we audited our clinical practice to treat Stenotrophomonas maltophilia in asymptomatic lung transplant recipients (LTRs). Eighteen LTRs with confirmed isolation of S. maltophilia were identified. Twelve of these LTRs have been treated with antibiotics, while 6 were managed without treatment. Treatment was based on antibiograms (trimethoprim/sulfamethoxazole [TMP/SMX] (8/12), levofloxacin (1/12), or both (3/12). Clearance (12/12 vs 6/6), eradication (10/12 vs 3/6, P=.27), and freedom from S. maltophilia recurrence (83%+/-11% vs 40%+/-22% after one year, log-rank P=.09) were not found to differ significantly between treated and untreated patients. None of the patient groups showed significant changes in lung function or biochemical variables. Creatinine levels at the end of the study period were found to be higher in treated patients compared to the untreated group (P=.049). De novo acquired TMP/SMX resistance in S. maltophilia strains was not observed. These results indicate no evidence that antibiotic treatment for S. maltophilia in asymptomatic LTRs alters lung function or the clinical outcome. PMID- 27219078 TI - Carbene-Catalyzed Dynamic Kinetic Resolution of Carboxylic Esters. AB - Carbene-catalyzed reaction of carboxylic esters has the potential to offer effective synthetic solutions that cannot be readily achieved by using the more conventional aldehyde-type substrates. Here we report the first carbene-catalyzed dynamic kinetic resolution of alpha,alpha-disubstituted carboxylic esters with up to 99:1 er and 99% yield. The present study clearly illustrates the unique power of carbene-catalyzed reactions of readily available and easy to handle carboxylic esters. PMID- 27219079 TI - [In Process Citation]. AB - Obsessive-compulsive disorder (OCD), characterized by repetitive intrusive thoughts and ritualized behaviors, is a highly debilitating disorder with an estimated lifetime prevalence of about 2 %. Approximately 10 % of these patients have severe symptoms despite having received all available treatments, thus considered treatment refractory. Deep brain stimulation (DBS), a reversible, safe and adaptive method widely used for movement disorders, enables specific targeting of deep brain structures of relevance in OCD. About 60% of the patients with treatment refractory OCD show ameliorated symptoms and improved quality of life with DBS. Taking ethical aspects into consideration DBS is a viable option for patients with treatment refractory OCD though further studies are needed to fully understand and individualize this treatment. PMID- 27219080 TI - [In Process Citation]. AB - A 19-year old female was admitted with intractable nausea, vomiting and intermittent abdominal pain. The medical history of the patient contained nine previous, similar admissions and extensive investigations within several medical specialties at several hospitals in the vicinity of Copenhagen, as well as abroad during the patient's holidays. All of the investigations were without findings that could explain the recurring condition. The patient reported chronic morning sickness, exacerbating with vomiting and abdominal pain every month since the age of 13. Especially during these exacerbations, the patient took frequent hot baths for symptom relief. Cannabinoid hyperemesis syndrome (CHS) was suspected and the patient admitted having used cannabis daily for the past seven years. She received parenteral rehydration and counseling regarding cannabis cessation. Two months after discharge the patient was no longer using cannabis and was symptom free. This case report intends to raise clinicians' awareness of CHS in Sweden, a country where 55 000 of the inhabitants aged 16 years and older report having used cannabis during the past 30 day period. PMID- 27219081 TI - [In Process Citation]. AB - The global burden of mosquito-borne diseases has seen major changes during the last few decades. Viruses like dengue, chikungunya and zika have spread rapidly all around the world. Modern transportation has facilitated the spread of vectors and pathogens to new geographical areas, sometimes resulting in large epidemics in nonimmune populations. Malaria is still an enormous burden to healthcare systems in Sub-Saharan Africa, but significant progress has been made in the global control and elimination of the disease. Climatic, ecological, demographic, social and political changes may affect the complex transmission networks, and there has been much discussion about the possible epidemiological outcomes of such changes. The present article reviews literature on possible reasons behind the shifts in the disease burden, highlighting the complexity of the problem and the need for further research on, improved surveillance of, and public education on mosquitoes and the pathogens they carry, in order to prevent and effectively treat mosquito-borne infections. PMID- 27219083 TI - [In Process Citation]. PMID- 27219082 TI - [In Process Citation]. AB - The international trend "value-based care" (VbC) started with a book by Porter and Olmsted Teisberg in 2006 followed by Porter's 7-point proposal for value based reform of health care in 2009. VbC may have relevance for delimited, procedure-related health problems with a foreseeable course of development. Most health problems in health care, however, do not involve such delimited problems. VbC is probably not suited as a steering model for chronic health conditions or for multiple health problems. VbC is being rapidly introduced to steer health care without scientific evidence. PMID- 27219084 TI - [In Process Citation]. PMID- 27219085 TI - [In Process Citation]. PMID- 27219086 TI - [In Process Citation]. PMID- 27219087 TI - [In Process Citation]. PMID- 27219088 TI - [In Process Citation]. PMID- 27219089 TI - [In Process Citation]. PMID- 27219090 TI - [In Process Citation]. PMID- 27219091 TI - Venlafaxine-Associated Euprolactinemic Galactorrhea and Hypersexuality: A Case Report and Review of the Literature. PMID- 27219092 TI - Statistics Commentary Series: Commentary #15-Reliability. PMID- 27219094 TI - Effect of sleep disorders on threatened premature delivery. AB - AIM: The present observational study aimed to clarify the effects of sleep disorders on threatened premature delivery, especially preterm uterine contraction. METHODS: The participants included 122 healthy singleton pregnant women. The Pittsburgh sleep quality index was used to evaluate the quality of sleep during the previous month at the initial examination and at 16, 24, and 32 weeks of gestation; scores >5 indicate poor sleep. Threatened premature delivery was defined as preterm uterine contraction >6 times/h and requiring tocolytic therapy before 37 weeks of gestation. We analyzed the relationship between poor sleep and threatened premature delivery. RESULTS: Poor sleep affected 27% (n=33) at the initial examination, 34% (n=41) at 16 weeks, 37% (n=45) at 24 weeks, and 41% (n=50) at 32 weeks of gestation. There were 23 patients (19%) with threatened premature delivery. Poor sleep affected 35% and 25% of patients with threatened and non-threatened premature delivery at the initial examination, respectively, 52% and 29% at 16 weeks, 48% and 34% at 24 weeks, and 43% and 40% at 32 weeks of gestation. CONCLUSIONS: Sleep disorders at 16 weeks of gestation were the most significantly associated with threatened premature delivery. PMID- 27219093 TI - Effectiveness of Risperidone Augmentation in Obsessive-Compulsive Disorder: Experience From a Specialty Clinic in India. AB - Risperidone is the most widely used augmenting agent in the treatment of obsessive-compulsive disorder (OCD). However, a recent controlled study found risperidone to be no different from placebo, raising doubts about its effectiveness. In this context, we sought to examine the real-world effectiveness of risperidone from the large database of an OCD clinic in India. A total of 1314 consecutive patients who registered at the OCD clinic between 2004 and 2014 were evaluated with structured interviews and scales. Patients with OCD initiated on risperidone augmentation without concurrent cognitive behavior therapy and who were on stable and adequate doses of serotonin reuptake inhibitors for at least 12 preceding weeks were included for analysis. The primary outcome measure was all-cause discontinuation. Logistic regression was performed to identify the factors predicting improvement with risperidone augmentation. A total of 92 patients were eligible for analysis. Risperidone continued to be used in 23 patients (25%) at the time of last follow-up, and the remaining discontinued either because of ineffectiveness or intolerability. The fall in the Yale-Brown Obsessive-Compulsive Scale scores was significantly greater in patients who continued to take risperidone when compared with those who did not (41.6% vs 3.7%, t = 6.95, P < 0.001). A total of 22 patients (24%) were noted to have at least a 25% reduction on the Yale-Brown Obsessive-Compulsive Scale scores. On regression analysis, no predictors of improvement with risperidone augmentation could be identified. The study demonstrated, in a real-world setting, that risperidone may be a useful augmenting agent in a proportion of patients with partial/poor response to serotonin reuptake inhibitors. PMID- 27219095 TI - Clinical utility of transcutaneous bilirubinometer (TcB) in very low birth weight (VLBW) infants. AB - OBJECTIVE: This is a comprehensive study designed to evaluate the clinical usefulness of transcutaneous bilirubinometry (TcB) in very low birth weight (VLBW) newborns of African American (AA) descent. METHODS: TcB was conducted at the anterior superior iliac spine (ASIS), temporal region and sternum within 2 h of total serum bilirubin (TSB) measurements in newborns born at <=32 weeks' gestation prospectively. Average (AVG) TcB levels were also calculated. The relationships between TSB and TcB levels were analyzed using non-parametric Spearman bivariate correlations, a Bland-Altman plot procedure and a decision tree (DT) analysis. RESULTS: One hundred newborns and 555 TSB data points were available. Eighty-nine percent of the newborns were AA. A significant correlation (P<0.0001) was observed between TSB and TcB values obtained at the ASIS (r=0.73), sternum (0.73), temporal region (0.61) and AVG (0.77). The Bland-Altman plot revealed a good agreement between AVG TcB values and TSB values. A DT analysis indicated that AVG TcB was also found to be the most significant predictor of TSB values in both the no phototherapy (PT) and biliblanket subgroups. CONCLUSION: TcB can be used reliably in VLBW AA newborns in the absence of overhead PT. The use of TcB in monitoring jaundice in VLBW newborns would help decrease the number of blood draws and cost of care. PMID- 27219096 TI - Outcome of monochorionic-biamniotic twins conceived by assisted reproduction: a population-based study. AB - : Objecive: To evaluate the perinatal outcome of monochorionic-diamniotic twins conceived by assisted reproduction technology (ART). METHODS: We compared data from a national population-based perinatal registry on perinatal outcomes of monochorionic-diamniotic twins conceived by ART with their dichorionic counterparts and with spontaneous monochorionic-diamniotic twins. We compared maternal characteristics, pregnancy complications and perinatal outcomes. RESULTS: Monochorionic-diamniotic twin pregnancies (n=45) comprised 5.5% of all ART twins, and 9.3% of all monochorionic twins in this dataset. ART does not appear to increase the already high risk of monochorionicity compared to spontaneous conception, with the latter having an increased incidence for birth weight <1500 g [odds ratio (OD) 2.6, 95% confidence interval (CI) 1.2-5.4]. CONCLUSION: Our results disagree with hospital-based data and suggest that monochorionic-diamniotic twins following ART are not at increased risk of adverse perinatal outcomes compared to spontaneous monochorionic-diamniotic twins as well as to dichorionc twins conceived by ART. PMID- 27219098 TI - Multi-fetal pregnancy reduction (MFPR) to twins or singleton - medical justification and ethical slippery slope. AB - Multi-fetal pregnancy reduction (MFPR) is an ethically acceptable procedure aimed to increase survival and well-being of the remaining fetuses from high-order multiple gestations. In most cases we offer the procedure to triplets or quadruplets and opt to preserve twins; lately, the option to maintain a single fetus was suggested. We examined the outcomes of 140 pregnancies that underwent MFPR in our center and were followed to delivery - 105 were reduced to twins and 35 to singletons. The rate of procedure-related pregnancy loss was identical (2.9%). Leaving only one fetus was associated with a higher gestational age at delivery (35.4+/-2.4 weeks vs. 37.7+/-2.1 weeks, P<0.0001), with heavier neonates (2222 g vs. 3017 g, P<0.0001) and with a reduction in the cesarean section (CS) rate (76% in twins vs. 51.4% in singletons, P=0.02). Six pregnancies reduced to twins (5.8%) ended before 32 weeks as compared to one pregnancy reduced to a singleton. We conclude that reduction of triplets to singletons is medically and ethically acceptable, after thorough counseling of patients. However, considering the pregnancy loss risk of MFPR and the relatively good outcome of twin gestations, reduction of twins to singletons is ethically acceptable only in extraordinary maternal or fetal conditions. PMID- 27219097 TI - Evaluating fetal head dimension changes during labor using open magnetic resonance imaging. AB - AIM: Fetal skull molding is important for the adaptation of the head to the birth canal during vaginal delivery. Importantly, the fetal head must rotate around the maternal symphysis pubis. The goals of this analysis were to observe a human birth in real-time using an open magnetic resonance imaging (MRI) scanner and describe the fetal head configuration during expulsion. METHODS: Real-time cinematic MRI series (TSE single-shot sequence, TR 1600 ms, TE 150 ms) were acquired from the midsagittal plane of the maternal pelvis during the active second stage of labor at 37 weeks of gestation. Frame-by-frame analyses were performed to measure the frontooccipital diameter (FOD) and distance from the vertex to the base of the fetal skull. RESULTS: During vaginal delivery in an occiput anterior position, the initial FOD was 10.3 cm. When expulsion began, the fetal skull was deformed and elongated, with the FOD increasing to 10.8 cm and 11.2 cm at crowning. In contrast, the distance from the vertex to the base of the skull was reduced from 6.4 cm to 5.6 cm at expulsion. CONCLUSIONS: Fetal head molding is the change in the fetal head due to the forces of labor. The biomechanics of this process are poorly understood. Our visualization of the normal mechanism of late second-stage labor shows that MRI technology can for the first time help define the changes in the diameters of the fetal head during active labor. PMID- 27219099 TI - Effect of Alcohol on Encoding and Consolidation of Memory for Alcohol-Related Images. AB - BACKGROUND: Drug and alcohol abusers develop strong memories for drug-related stimuli. Preclinical studies suggest that such memories are a result of drug actions on reward pathways, which facilitate learning about drug-related stimuli. However, few controlled studies have investigated how drugs affect memory for drug-related stimuli in humans. METHODS: The current study examined the direct effect of alcohol on memory for images of alcohol-related or neutral beverages. Participants received alcohol (0.8 g/kg) either before viewing visual images (encoding condition; n = 20) or immediately after viewing them (consolidation condition; n = 20). A third group received placebo both before and after viewing the images (control condition; n = 19). Memory retrieval was tested exactly 48 hours later, in a drug-free state. RESULTS: Alcohol impaired memory in the encoding condition and enhanced memory in the consolidation condition, but these effects did not differ for alcohol-related and neutral beverage stimuli. However, in the encoding condition, participants who experienced greater alcohol-induced stimulation exhibited better memory for alcohol-related, but not neutral beverage stimuli. CONCLUSIONS: These findings suggest that individual differences in sensitivity to the positive, rewarding effects of alcohol are associated with greater propensity to remember alcohol-related stimuli encountered while intoxicated. As such, stimulant responders may form stronger memory associations with alcohol-related stimuli, which might then influence their drinking behavior. PMID- 27219100 TI - Simultaneous determination of ginsenoside Rg1 , Re and notoginsenoside R1 in human plasma by LC-MS/MS and its application in a pharmacokinetic study in Chinese volunteers. AB - A rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed and validated for simultaneous quantification of ginsenosides Rg1 , Re and notoginsenoside R1 in human plasma. Chromatography was performed on Capcell Pak C18 MG II column using a binary gradient using mobile phase A (5 mm ammonium formate solution) and B (methanol, containing 5 mm ammonium formate) at a flow rate of 0.3 mL/min. The entire chromatographic run time was 3.2 min. Quantification was achieved using multiple reaction monitoring in positive mode using API 3000. This method was validated in terms of specificity, linearity, precision, accuracy, matrix effect and stability. The calibration curves were linear in the concentration range of 0.020-5.00 ng/mL for ginsenosides Rg1 , Re and notoginsenoside R1 . The lower limit of quantification (LLOQ) of this method was 0.020 ng/mL. The intra-run and inter-run precision values were within 12.31% for ginsenoside Rg1 , 14.13% for ginsenoside Re and 11.46% for notoginsenoside R1 at their LLOQ levels. The samples were stable under all tested conditions. This method was successfully applied to study the pharmacokinetics of ginsenoside Rg1 and notoginsenoside R1 in 24 healthy volunteers following oral administration of 200 mg Sanqi Tongshu Enteric-Pellets Capsule. PMID- 27219101 TI - Socially Important Faces Are Processed Preferentially to Other Familiar and Unfamiliar Faces in a Priming Task across a Range of Viewpoints. AB - Using a priming paradigm, we investigate whether socially important faces are processed preferentially compared to other familiar and unfamiliar faces, and whether any such effects are affected by changes in viewpoint. Participants were primed with frontal images of personally familiar, famous or unfamiliar faces, and responded to target images of congruent or incongruent identity, presented in frontal, three quarter or profile views. We report that participants responded significantly faster to socially important faces (a friend's face) compared to other highly familiar (famous) faces or unfamiliar faces. Crucially, responses to famous and unfamiliar faces did not differ. This suggests that, when presented in the context of a socially important stimulus, socially unimportant familiar faces (famous faces) are treated in a similar manner to unfamiliar faces. This effect was not tied to viewpoint, and priming did not affect socially important face processing differently to other faces. PMID- 27219102 TI - Preliminary Report of Clinical Outcomes After Single Crossover Bioresorbable Scaffold Implantation Without Routine Side Branch Strut Dilation. AB - OBJECTIVES: The objective of this study was to investigate clinical outcomes following single crossover bioresorbable scaffold (BRS) implantation without routine side branch (SB) strut dilation. BACKGROUND: It is unknown whether SB strut dilation is routinely required after single crossover BRS implantation if there is no compromise of the jailed SB. METHODS: Among 187 bifurcation lesions treated with Absorb BRS, 115 lesions (101 patients) were treated with single crossover BRS implantation. Strut dilation toward SB was considered only when SB was compromised (SB TIMI flow < 3 or SB ostium > 75%) after main branch (MB) BRS implantation. Clinical outcomes including cardiac death, follow-up myocardial infarction (MI), target lesion revascularization (TLR), target vessel revascularization (TVR), and definite scaffold thrombosis (ST) were investigated. RESULTS: The majority of target lesions were in the left anterior descending artery (73.0%) and the rate of true bifurcation lesions was 42.6%. SB strut dilation was performed in only 20% of lesions (n = 23), and intravascular imaging was used in most cases (90.4%). The rates of TLR per lesion at 1-year was 3.1% in MB, and 0% in SB. In all patients, the cumulative rate of cardiac death was 1.1% at 1-year, follow-up MI 2.2%, TVR 3.5%, and definite ST 1.0%. CONCLUSION: Clinical outcomes were acceptable in bifurcation lesions treated with single crossover BRS implantation without routine SB strut dilation. (c) 2016 Wiley Periodicals, Inc. PMID- 27219103 TI - Pyrene-fused Acenes and Azaacenes: Synthesis and Applications. AB - In this account, the synthesis and applications of pyrene-fused acenes, as well as pyrene-fused azaacenes, have been carefully reviewed. Moreover, the synthetic methods involving two key synthons (different lengths of dienes and ynes) have been included. Furthermore, the "clean reaction" strategy has been introduced for the preparation of pyrene-fused acenes with a single terminal-pyrene unit from tetracene to octacene, as well as for the synthesis of pyrene-fused octatwistacenes and nonatwistacenes with double terminal-pyrene units. Similarly, the synthons and the synthetic methods for pyrene-fused azaacenes have also been summarized. The applications of pyrene-fused acenes and pyrene-fused azaacenes have been included. PMID- 27219104 TI - A commentary on Roggli's "The So-Called Short-Fiber Controversy". AB - Dr. Victor Roggli republished a "literature review and critical analysis" of the toxicity of short fiber asbestos. His paper was originally prepared and presented at a conference of asbestos defense lawyers. His review omitted published papers that indicate that short fiber asbestos is a carcinogen. We critically review his paper. PMID- 27219105 TI - Association between Exposure to Benzodiazepines and Related Drugs and Survivorship of Total Hip Replacement in Arthritis: A Population-Based Cohort Study of 246,940 Patients. AB - BACKGROUND: Total hip replacement (THR) is successful in treating hip arthritis. Prosthetic survivorship may depend on the medications taken by the patient; particularly, the role of benzodiazepines and related drugs (Z-drugs) with THR revision has been poorly investigated. Our objective was to compare THR short term survivorship according to level of exposure to benzodiazepine and Z-drugs. DESIGN, SETTING AND PARTICIPANTS: All French patients aged 40 years or older, having undergone primary THR from January 1, 2009, through December 31, 2012, for arthritis according to French national health insurance databases were included in the cohort. Outcome of interest was THR revision, including any surgical procedure in which the implant or any component was changed or removed. Follow-up started the day the primary THR was performed. Observations were right-censored on December 31, 2014, if neither revision nor death had yet occurred. Exposure of interest was the cumulative defined daily doses per day (cDDD/day) of benzodiazepines and Z-drugs dispensed within 6 months before or after inclusion. We defined four exposure groups; cDDD/d = 0: unexposed; <0.08: low exposure;] 0.08-0.38]: medium exposure; >0.38: high exposure. THR survivorship was assessed according to level of exposure to benzodiazepines and Z-drugs in univariate and multivariate Cox models adjusted for patient, THR and implanting center characteristics. RESULTS: The study cohort comprised 246,940 individuals: mean age at baseline, 69.9 years; women, 57.9%; unexposed: 51.7%; low exposure: 16.7%; medium exposure: 15.9%; and high exposure: 15.7%. During the median 45-month follow-up, 9043 individuals underwent prosthetic revision. Adjusted hazard ratios in low, medium and high exposed groups were 1.18 (95%CI, 1.12-1.26; P<0.001), 1.32 (95%CI, 1.24-1.40; P<0.001) and 1.37 (95%CI, 1.29-1.45; P<0.001), respectively, compared to unexposed. CONCLUSION AND RELEVANCE: Exposure to benzodiazepines and Z-drugs is associated with an increased risk of THR revision, with a dose-response relationship. Cautious prescribing might be needed as well as careful history examination and assessment of risk for patients with a hip prosthesis. PMID- 27219106 TI - Risk Belief and Attitude Formation From Translated Scientific Messages About PFOA, an Environmental Risk Associated With Breast Cancer. AB - Evidence regarding possible environmental causes of breast cancer is advancing. Often, however, the public is not informed about these advances in a manner that is easily understandable. This research translates findings from biologists into messages at two literacy levels about perfluorooctanoic acid (PFOA), a possible environmental contributor to breast cancer. The Heuristic Systematic Model (HSM) was used to investigate how ability, motivation, and systematic and heuristic processing lead to risk beliefs and, ultimately, to negative attitudes for individuals receiving translated scientific messages about PFOA. Participants (N = 1,389) came from the Dr. Susan Love Research Foundation's Army of Women. Findings indicated that ability, in the form of translated messages, predicted systematic processing, operationalized as knowledge gain, which was negatively associated with formation of risk beliefs that led to negative attitudes toward PFOA. Heuristic processing cues, operationalized as perceived message quality and source credibility, were positively associated with risk beliefs, which predicted negative attitudes about PFOA. Overall, more knowledge and lower literacy messages led to lower perceived risk, while greater involvement and ratings of heuristic cues led to greater risk perceptions. This is an example of a research, translation, and dissemination team effort in which biologists created knowledge, communication scholars translated and tested messages, and advocates were participants and those who disseminated messages. PMID- 27219107 TI - Emergence of a New Population of Rathayibacter toxicus: An Ecologically Complex, Geographically Isolated Bacterium. AB - Rathayibacter toxicus is a gram-positive bacterium that infects the floral parts of several Poaceae species in Australia. Bacterial ooze is often produced on the surface of infected plants and bacterial galls are produced in place of seed. R. toxicus is a regulated plant pathogen in the U.S. yet reliable detection and diagnostic tools are lacking. To better understand this geographically-isolated plant pathogen, genetic variation as a function of geographic location, host species, and date of isolation was determined for isolates collected over a forty year period. Discriminant analyses of recently collected and archived isolates using Multi-Locus Sequence Typing (MLST) and Inter-Simple Sequence Repeats (ISSR) identified three populations of R. toxicus; RT-I and RT-II from South Australia and RT-III from Western Australia. Population RT-I, detected in 2013 and 2014 from the Yorke Peninsula in South Australia, is a newly emerged population of R. toxicus not previously reported. Commonly used housekeeping genes failed to discriminate among the R. toxicus isolates. However, strategically selected and genome-dispersed MLST genes representing an array of cellular functions from chromosome replication, antibiotic resistance and biosynthetic pathways to bacterial acquired immunity were discriminative. Genetic variation among isolates within the RT-I population was less than the within-population variation for the previously reported RT-II and RT-III populations. The lower relative genetic variation within the RT-I population and its absence from sampling over the past 40 years suggest its recent emergence. RT-I was the dominant population on the Yorke Peninsula during the 2013-2014 sampling period perhaps indicating a competitive advantage over the previously detected RT-II population. The potential for introduction of this bacterial plant pathogen into new geographic areas provide a rationale for understanding the ecological and evolutionary trajectories of R. toxicus. PMID- 27219109 TI - Watching Kinetic Studies as Chemical Maps Using Open-Source Software. AB - A nonproprietary software package, "PyMca", primarily developed for X-ray fluorescence analysis offers an easy-to-use interface for calculating maps, by integrating intensity (of X-ray fluorescence, as well as any spectral data) over Regions Of Interest (ROI), by performing per pixel operations or by applying multivariate analysis. Here we show that, while initially developed to analyze hyperspectral two-dimensional (spatial) maps, this tool can be beneficial as well to anyone interested in measuring spectral variations over one or two dimensions, these dimensions being time, temperature, and so on. Different possibilities offered by the software (preprocessing, simultaneous analysis of replicas, of different conditions, ROI calculation, multivariate analysis, determination of reaction rate constant and of Arrhenius plot) are illustrated with two examples. The first example is the Fourier transform infrared spectroscopy (FTIR) follow-up of the saponification of oil by lead compounds. The disappearance of reagent (oil) and formation of products (lead carboxylates and glycerol) can be easily followed and quantified. The second example is a combined extended X-ray absorption fine structure (EXAFS), diffuse reflectance infrared Fourier transform spectroscopy (DRIFT), and mass spectroscopy (MS) analysis of RhAl2O3 catalyst under NO reduction by CO in the presence of O2. It is possible to appreciate, in a single shot, Rh particles' structure and surface changes and gas release and adsorption in the reaction conditions. PMID- 27219108 TI - Second-opinion interpretations of neuroimaging studies by oncologic neuroradiologists can help reduce errors in cancer care. AB - BACKGROUND: The purpose of this study was to investigate the utility and clinical impact of second-opinion interpretations of outside neuroimaging studies by oncologic neuroradiologists at a National Cancer Institute-designated cancer center. METHODS: We performed a retrospective analysis of initial outside and second-opinion radiology reports from 300 computed tomography and magnetic resonance imaging studies and identified cases with discrepancies between the two reports. An adult neuro-oncologist, pediatric neuro-oncologist, and head and neck surgeon reviewed each pair of discrepant reports based on their area of expertise, patient age, and the type of study performed. The clinicians were blinded to the origin of each report and recorded whether the differences in the reports would have led to a change in patient management and/or disease staging. Histopathologic analysis, clinical assessment, and/or minimum 3-month imaging follow-up served as the reference standards to establish which of the 2 reports was correct. RESULTS: Among the 283 cases that met our study criteria, there were 55 neuroimaging studies with disagreements (19%) between the initial outside report and second-opinion interpretation. Patient management and/or disease stage would have been altered in 42 of 283 cases (15%) based on report differences as determined by the 2 neuro-oncologists and the surgeon participating in the study. Sufficient follow-up was available in 35 of 42 cases (83%). The second-opinion interpretation was correct 100% of the time (35/35). CONCLUSION: Second-opinion interpretations of neuroimaging studies by subspecialized oncologic neuroradiologists provide added value by reducing error and optimizing the care of cancer patients. Cancer 2016. (c) 2016 American Cancer Society. Cancer 2016;122:2708-2714. (c) 2016 American Cancer Society. PMID- 27219110 TI - Influence of the Oil Phase and Topical Formulation on the Wound Healing Ability of a Birch Bark Dry Extract. AB - Triterpenes from the outer bark of birch are known for various pharmacological effects including enhanced wound healing (WH). A birch bark dry extract (TE) obtained by accelerated solvent extraction showed the ability to form oleogels when it is suspended in oils. Consistency of the oleogels and the dissolved amount of triterpenes varies largely with the used oil. Here we wanted to know to what extent different oils and formulations (oleogel versus o/w emulsion) influence WH. Looking at the plain oils, medium-chain triglycerides (MCT) enhanced WH (ca. 1.4-fold), while e.g. castor oil (ca.0.3-fold) or light liquid paraffin (LLP; ca. 0.5-fold) significantly decreased WH. Concerning the respective oleogels, TE-MCT showed no improvement although the solubility of the TE was high. In contrast, the oleogel of sunflower oil which alone showed a slight tendency to impair WH, enhanced WH significantly (ca. 1.6-fold). These results can be explained by release experiments where the release rate of betulin, the main component of TE, from MCT oleogels was significantly lower than from sunflower oil oleogels. LLP impaired WH as plain oil and even though it released betulin comparable to sunflower oil it still results in an overall negative effect of the oleogel on WH. As a further formulation option also surfactant free o/w emulsions were prepared using MCT, sunflower oil and LLP as a nonpolar oil phase. Depending on the preparation method (suspension or oleogel method) the distribution of the TE varied markedly and affected also release kinetics. However, the released betulin was clearly below the values measured with the respective oleogels. Consequently, none of the emulsions showed a significantly positive effect on WH. In conclusion, our data show that the oil used as a vehicle influences wound healing not only by affecting the release of the extract, but also by having its own vehicle effect on wound healing. This is also of importance for other applications where drugs have to be applied in non polar vehicles because these solvents likely influence the outcome of the experiment substantially. PMID- 27219112 TI - Correlating skeletal and dental developmental stages using radiographic parameters. AB - The demand for age estimation of living and deceased children considerably increased in the last years. It was mainly justified by the growing globalization trend and the enlarged amount of violent crimes involving young victims. The present research aims to correlate skeletal and dental developmental stages using radiographic parameters. Lateral cephalometric (n = 576) and panoramic (n = 576) radiographs taken in the same moment were used to asses skeletal and dental development according to the methods of Hassel and Farman (1995) and Bacetti et al. (2002), and Demirjian et al. (1973), respectively. Likelihood-ratio test was used to verify the positive prediction in correlations between developmental stages. Spearman's correlation coefficient was calculated between skeletal and dental developmental stages, as well between estimated and chronological ages. Higher prediction in correlation for the skeletal starting stage (stage 1) with stage E in mandibular canines, and with stage D in mandibular premolars and second molars was detected. Higher staging correlations were observed considering the mandibular left second premolar (0.652, p < 0.001 for the technique of Bacetti et al.; and 0.646, p < 0.001 for the technique of Hassel and Farman). Despite the correlations between skeletal and dental developmental stages, the results must be carefully interpreted once it reached moderate values (<0.652). Further researches must test different classifications of skeletal and dental development, in order to verify the possibility of replacing one technique for another with stronger correlation. PMID- 27219111 TI - Persistent Organic Pollutants and the Association with Maternal and Infant Thyroid Homeostasis: A Multipollutant Assessment. AB - BACKGROUND: Disruption of thyroid homeostasis has been indicated in human studies targeting effects of persistent organic pollutants (POPs). Influence on the maternal thyroid system by POPs is of special interest during pregnancy because such effects could impair infant thyroid homeostasis. OBJECTIVES: We investigated the association between POPs and thyroid-stimulating hormone (TSH) and thyroid hormones (THs) in mother and child pairs from the Northern Norway Mother-and Child Contaminant Cohort Study (MISA). METHODS: Nineteen POPs and 10 thyroid parameters were analyzed in serum from 391 pregnant women in their second trimester. In addition, TSH concentrations in heel-prick samples from the infants were analyzed by the Norwegian Newborn Screening program. Association studies with a multipollutant approach were performed using multivariate analyses; partial least squares (PLS) regression, hierarchical clustering, and principal component analysis (PCA). RESULTS: Several POPs were significantly associated with TSH and THs: a) PFOS was positively associated with TSH; b) PCBs, HCB, and nonachlors were inversely associated with T3, T4, and FT4; and, c) PFDA and PFUnDA were inversely associated with T3 and FT3. After mutual adjustments for the other contaminants, only PFDA and PFUnDA remained significantly associated with T3 and FT3, respectively. Infants born to mothers within the highest TSH quartile had 10% higher mean concentrations of TSH compared with children born to mothers in the lowest TSH quartile. CONCLUSION: The present results suggest that background exposures to POPs can alter maternal thyroid homeostasis. This research contributes to the understanding of multipollutant exposures using multivariate statistical approaches and highlights the complexity of investigating environmental concentrations and mixtures in regard to maternal and infant thyroid function. Citation: Berg V, Nost TH, Pettersen RD, Hansen S, Veyhe AS, Jorde R, Odland JO, Sandanger TM. 2017. Persistent organic pollutants and the association with maternal and infant thyroid homeostasis: a multipollutant assessment. Environ Health Perspect 125:127-133; http://dx.doi.org/10.1289/EHP152. PMID- 27219113 TI - Retrospective analysis of 319 hanging and strangulation cases between 2001 and 2014 in Shanghai. AB - In this study, we retrospectively analyzed 141 cases of hanging and 178 cases of ligature strangulation recorded in the Shanghai Municipal Public Security Bureau between January 2001 and December 2014 to explore the characteristics of hanging and ligature strangulation and to supply a scientific reference for forensic pathology. Several significant differences between hanging and ligature strangulation were found. Hanging cases were mostly suicide, with some accidental cases. Strangulation cases were mostly homicide, with a few cases of suicide or sexual asphyxia. Male hanging was more common than female hanging, with a ratio of 5:2. However, there were more female than male strangulation cases, with a ratio of 13:5. The ligature marks in hanging cases were almost all of a "U" type and above the hyoid bone. The ligature marks in strangulation cases were almost always a closed circle, but the position varied. The most common vital reactions were subcutaneous hemorrhage, exfoliation and blister, which are strong evidence of antemortem injury. Hemorrhagic spots were found on the temporalis, scalp, chest and back in strangulation cases, but were rare in hanging cases. Hemorrhagic manifestations were most common in the sternocleidomastoid muscle in hanging cases, and in the sternohyoid and sternothyroid muscles in strangulation cases. Fractures occurred in only ~17% of victims. There are notable differences between hanging and ligature strangulation, which can help distinguish between these causes of death. These characteristics should be considered in forensic practice. PMID- 27219114 TI - Ultrafast Response p-Si/n-ZnO Heterojunction Ultraviolet Detector Based on Pyro Phototronic Effect. AB - A light-self-induced pyro-phototronic effect in wurtzite ZnO nanowires is proposed as an effective approach to achieve ultrafast response ultraviolet sensing in p-Si/n-ZnO heterostructures. The relatively long response/recovery time of zinc-oxide-based ultraviolet sensors in air/vacuum has long been an obstacle to developing such detectors for practical applications. The response/recovery time and photoresponsivity are greatly improved by the pyro phototronic effect. PMID- 27219115 TI - Effect of Acupuncture on Reducing Duration of Postoperative Ileus After Gastrectomy in Patients with Gastric Cancer: A Pilot Study Using Sitz Marker. AB - OBJECTIVES: Postoperative ileus (POI) is a common problem after abdominal surgery. Acupuncture is being accepted as an option for reducing POI and managing various functional gastrointestinal disorders. Therefore, this pilot study was conducted to evaluate the effect of acupuncture on reducing duration of POI and other surgical outcomes in patients who underwent gastric surgery. DESIGN: A prospective, randomized, controlled pilot study was conducted on patients who underwent gastric cancer surgery from January 2013 to December 2013. Ten patients were randomly assigned into the acupuncture (A) or nonacupuncture (NA) groups at a 1:1 ratio. INTERVENTIONS: The acupuncture treatment was performed by Korean traditional medicine doctors (KMDs). The style of acupuncture was Korean. In the A group, acupuncture treatment was given once daily for 5 consecutive days starting on postoperative day 1. Each patient received acupuncture at 16 acupoints based on expert consensus provided by qualified and experienced KMDs. No acupuncture treatment was performed in the NA group. OUTCOME MEASURES: The primary outcome measure was the number of remnant Sitz markers in the small intestine on abdominal radiography. Secondary outcome measures were time to first flatus, start of sips water, start of soft diet, hospital stay, and laboratory findings. RESULTS: The A group had significantly fewer remnant Sitz markers in the small intestine on postoperative days 3 and 5 compared with those in the NA group (p = 0.025 and 0.005). A significant difference was observed in the numbers of remnant Sitz marker in the small intestine with respect to time difference by group (p = 0.019). The A group showed relatively better surgical outcomes, but without statistical significance. CONCLUSIONS: Although further studies are warranted, acupuncture may reduce duration of POI after gastric surgery and could be a potential factor in enhanced recovery after surgery protocols. PMID- 27219116 TI - Climate Change and Maize Yield in Iowa. AB - Climate is changing across the world, including the major maize-growing state of Iowa in the USA. To maintain crop yields, farmers will need a suite of adaptation strategies, and choice of strategy will depend on how the local to regional climate is expected to change. Here we predict how maize yield might change through the 21st century as compared with late 20th century yields across Iowa, USA, a region representing ideal climate and soils for maize production that contributes substantially to the global maize economy. To account for climate model uncertainty, we drive a dynamic ecosystem model with output from six climate models and two future climate forcing scenarios. Despite a wide range in the predicted amount of warming and change to summer precipitation, all simulations predict a decrease in maize yields from late 20th century to middle and late 21st century ranging from 15% to 50%. Linear regression of all models predicts a 6% state-averaged yield decrease for every 1 degrees C increase in warm season average air temperature. When the influence of moisture stress on crop growth is removed from the model, yield decreases either remain the same or are reduced, depending on predicted changes in warm season precipitation. Our results suggest that even if maize were to receive all the water it needed, under the strongest climate forcing scenario yields will decline by 10-20% by the end of the 21st century. PMID- 27219117 TI - Large-Area Deposition of MoS2 by Pulsed Laser Deposition with In Situ Thickness Control. AB - A scalable and catalyst-free method to deposit stoichiometric molybdenum disulfide (MoS2) films over large areas is reported, with the maximum area limited by the size of the substrate holder. The method allows deposition of MoS2 layers on a wide range of substrates without any additional surface preparation, including single-crystal (sapphire and quartz), polycrystalline (HfO2), and amorphous (SiO2) substrates. The films are deposited using carefully designed MoS2 targets fabricated with excess sulfur and variable MoS2 and sulfur particle size. Uniform and layered MoS2 films as thin as two monolayers, with an electrical resistivity of 1.54 * 10(4) Omega cm(-1), were achieved. The MoS2 stoichiometry was confirmed by high-resolution Rutherford backscattering spectrometry. With the method reported here, in situ graded MoS2 films ranging from ~1 to 10 monolayers can be deposited. PMID- 27219118 TI - The STBUR questionnaire for identifying children at risk for sleep-disordered breathing and postoperative opioid-related adverse events. AB - BACKGROUND: Children with symptoms of sleep-disordered breathing (SDB) appear to be at risk for perioperative respiratory events (PRAE). Furthermore, these children may be more sensitive to the respiratory-depressant effects of opioids compared with children without SDB. AIMS: The aim of this prospective observational study was to confirm that otherwise healthy children with symptoms of SDB are at greater risk for PRAE compared with children with no symptoms and to determine if these children are also at increased risk for postoperative opioid-related adverse events (ORAE). METHODS: Six hundred and seventy-eight parents of children scheduled for surgery completed the Snoring, Trouble Breathing, and Un-Refreshed (STBUR) questionnaire preoperatively. Data regarding the incidence of PRAE were collected prospectively. Postoperative pulse oximetry desaturation alarm events were downloaded from the institutional secondary alarm notification system. RESULTS: Children with symptoms of SDB per STBUR (>=3 symptoms) had a two-fold increased likelihood of PRAE compared with children without SDB (52.8% vs 27.9% respectively, LR(+) = 2.00, 95% CI = 1.60-2.49, P = 0.0001). A subset analysis of children undergoing airway procedures requiring hospital admittance (n = 179) showed that those with SDB were given the same postoperative opioid doses as children without SDB. However, children with SDB symptoms generated a greater number of postoperative oxygen desaturation alarms (14.14 +/- 29.3 vs 7.12 +/- 13.2, mean difference = 7.02, 95% CI = 0.39-13.64, P = 0.038) and more frequently required escalation of care (15.3% vs 7.1%, LR(+) = 1.67, 95% CI = 1.22-2.16, P = 0.001) compared with children with no SDB symptoms. CONCLUSIONS: Children presenting for surgery with SDB symptoms are at increased risk for PRAE. Children undergoing airway-related procedures also appear to be at increased risk for ORAE. Furthermore, regardless of the preoperative assessment of risk using the STBUR questionnaire, children received the same doses of opioids postoperatively. Given the increased incidence of postoperative oxygen desaturations among children with SDB symptoms, it would seem prudent to consider titration of opioid doses according to identified risk. PMID- 27219119 TI - Translation, Validation, and Adaptation of the Time Use Diary from English into the Malay Language for Use in Malaysia. AB - Valid translations of time use scales are needed by occupational therapists for use in different cross-cultural contexts to gather relevant data to inform practice and research. The purpose of this study was to describe the process of translating, adapting, and validating the Time Use Diary from its current English language edition into a Malay language version. Five steps of the cross-cultural adaptation process were completed: (i) translation from English into the Malay language by a qualified translator, (ii) synthesis of the translated Malay version, (iii) backtranslation from Malay to English by three bilingual speakers, (iv) expert committee review and discussion, and (v) pilot testing of the Malay language version with two participant groups. The translated version was found to be a reliable and valid tool identifying changes and potential challenges in the time use of older adults. This provides Malaysian occupational therapists with a useful tool for gathering time use data in practice settings and for research purposes. PMID- 27219120 TI - Identification of autoimmune polyendocrine syndrome type 1 in patients with isolated hypoparathyroidism. AB - OBJECTIVE: The prevalence of autoimmune polyendocrine syndrome type 1 (APS1) among isolated hypoparathyroidism (HP) or primary adrenal insufficiency (PAI) is not well established. We studied the frequency of APS1 in patients with HP or PAI by measuring interferon-alpha (IFN-alpha) antibody levels, a highly sensitive and specific marker for APS1. DESIGN, PATIENTS AND MEASUREMENTS: In a single-centre cross-sectional study, 37 Indian patients with isolated HP and 40 patients with PAI were tested for IFN-alpha antibody using an indirect ELISA. In patients with elevated IFN-alpha antibody, the autoimmune regulator (AIRE) gene was bidirectionally sequenced. RESULTS: Three (8.1%) patients with isolated HP had elevated IFN-alpha antibody levels (range: 367-17382 units; positive titre >56 units). Homozygous or compound heterozygous AIRE mutations were detected in all three patients, including a novel mutation (p.T68P). All three APS1 patients had atypical features. The first patient, diagnosed at 7 years of age, died suddenly 5 months later. The second patient had late-onset HP (at the age of 34 years) and a solitary episode of transient mucocutaneous candidiasis 5 years later. The final patient developed HP at the age of 14 years and premature ovarian insufficiency 14 years later. Interleukin-22 antibodies, as well as most other organ-specific antibodies, were absent in the 3 APS1 patients. All patients with PAI were negative for IFN-alpha antibody. CONCLUSION: Eight percentage of patients with isolated HP had elevated IFN-alpha antibody levels and AIRE mutation-positive APS1. All APS1 patients had atypical clinical features. Testing for IFN-alpha antibody should be considered in patients with idiopathic HP. PMID- 27219121 TI - Immunohistochemical Analysis of Scarring Trachoma Indicates Infiltration by Natural Killer and Undefined CD45 Negative Cells. AB - INTRODUCTION: The phenotype and function of immune cells infiltrating the conjunctiva in scarring trachoma have yet to be fully characterized. We assessed tissue morphology and immunophenotype of cellular infiltrates found in trachomatous scarring compared to control participants. METHODOLOGY: Clinical assessments and conjunctival biopsy samples were obtained from 34 individuals with trachomatous scarring undergoing trichiasis surgery and 33 control subjects undergoing cataract or retinal detachment surgery. Biopsy samples were fixed in buffered formalin and embedded in paraffin wax. Hematoxylin and eosin (H&E) staining was performed for assessment of the inflammatory cell infiltrate. Immunohistochemical staining of single markers on individual sections was performed to identify cells expressing CD3 (T-cells), CD4 (helper T-cells), CD8 (suppressor/cytotoxic T-cells and Natural Killer, NK, cells), NCR1 (NK cells), CD20 (B-cells), CD45 (nucleated hematopoietic cells), CD56 (NK and T-cells), CD68 (macrophages/monocytes) and CD83 (mature dendritic cells). The degree of scarring was assessed histologically using cross-polarized light to visualize collagen fibres. PRINCIPLE FINDINGS: Scarring, regardless of clinical inflammation, was associated with increased inflammatory cell infiltrates on H&E and CD45 staining. Scarring was also associated with increased CD8+ and CD56+ cells, but not CD3+ cells, suggestive of a NK cell infiltrate. This was supported by the presence of NCR1+ cells. There was some increase in CD20+ cells, but no evidence for increased CD4+, CD68+ or CD83+ cells. Numerous CD45 negative cells were also seen in the population of infiltrating inflammatory cells in scarred conjunctiva. Disorganization of the normal collagen architecture was strongly associated with clinical scarring. CONCLUSIONS/SIGNIFICANCE: These data point to the infiltration of immune cells with a phenotype suggestive of NK cells in conjunctival trachomatous scarring. A large proportion of CD45 negative inflammatory cells were also present. Future work should seek to understand the stimuli leading to the recruitment of these cells and their role in progressive scarring. PMID- 27219122 TI - Small Molecule DFPM Derivative-Activated Plant Resistance Protein Signaling in Roots Is Unaffected by EDS1 Subcellular Targeting Signal and Chemical Genetic Isolation of victr R-Protein Mutants. AB - The small molecule DFPM ([5-(3,4-dichlorophenyl)furan-2-yl]-piperidine-1 ylmethanethione) was recently shown to trigger signal transduction via early effector-triggered immunity signaling genes including EDS1 and PAD4 in Arabidopsis thaliana accession Col-0. Chemical genetic analyses of A. thaliana natural variants identified the plant Resistance protein-like Toll/Interleukin1 Receptor (TIR)-Nucleotide Binding (NB)-Leucine-Rich Repeat (LRR) protein VICTR as required for DFPM-mediated root growth arrest. Here a chemical genetic screen for mutants which disrupt DFPM-mediated root growth arrest in the Col-0 accession identified new mutant alleles of the TIR-NB-LRR gene VICTR. One allele, victr-6, carries a Gly216-to-Asp mutation in the Walker A domain supporting an important function of the VICTR nucleotide binding domain in DFPM responses consistent with VICTR acting as a canonical Resistance protein. The essential nucleo-cytoplasmic regulator of TIR-NB-LRR-mediated effector-triggered immunity, EDS1, was reported to have both nuclear and cytoplasmic actions in pathogen resistance. DFPM was used to investigate the requirements for subcellular EDS1 localization in DFPM mediated root growth arrest. EDS1-YFP fusions engineered to localize mainly in the cytoplasm or the nucleus by tagging with a nuclear export signal (NES) or a nuclear localization signal (NLS), respectively, were tested. We found that wild type EDS1-YFP and both the NES and NLS-tagged EDS1 variants were induced by DFPM treatments and fully complemented eds1 mutant plants in root responses to DFPM, suggesting that enrichment of EDS1 in either compartment could confer DFPM mediated root growth arrest. We further found that a light and O2-dependent modification of DFPM is necessary to mediate DFPM signaling in roots. Chemical analyses including Liquid Chromatography-Mass Spectrometry and High-Resolution Atmospheric Pressure Chemical Ionization Mass Spectrometry identified a DFPM modification product that is likely responsible for bioactivity mediating root growth arrest. We propose a chemical structure of this product and a possible reaction mechanism for DFPM modification. PMID- 27219123 TI - Cytokine Profile in Gout: Inflammation Driven by IL-6 and IL-18? AB - INTRODUCTION: Gout is considered to be an autoinflammatory disease and the presence of monosodium urate (MSU) crystals stimulates activation of NPRL3 inflammasome and subsequently caspase-1, generating production of active IL-1beta and IL-18. However, the association between serum cytokines levels and clinical manifestations of the disease is not yet well understood. We evaluated the serum profile of proinflammatory cytokines (IL-1beta, IL-6, IL-8, IL-17A, IL-18, IL-22, and IL-23) and described their relationship with clinical and laboratory data. METHODOLOGY: Thirty-nine male patients with gout (GG) were assessed for clinical and laboratory variables and cytokine levels were measured by ELISA. For the purposes of comparison, 34 males with no previous history of arthritis were also included in the study (CG). RESULTS: Seventeen participants (43%) exhibited active arthritis on evaluation. Levels of IL-18 were significantly higher in patients in relation to the CG (p = 0.0013). No statistically significant differences were found between the GG and CG for the other measured cytokines. There was a moderate correlation between IL-18 and ESR (R = 0.43, p = 0.0073), CRP (R = 0.47, p = 0.0025), and serum levels of IL-6 (R = 0.36, p = 0.023). An association was observed between serum levels of IL-6 and the presence of tophi (p = 0.005) and deformities (p = 0.0008), as well as a correlation between this cytokine and ESR (R = 0.41, p = 0.011) and CRP (R = 0.48, p = 0.02). CONCLUSIONS: IL-18 is associated with inflammatory activity in gout, as well as with IL-6 levels, while IL-6 is associated with clinical and laboratory activity, the presence of tophi and articular deformities, and may be a prognostic marker of this pathology. PMID- 27219124 TI - Effect of intravenous vitamin C on postoperative pain in uvulopalatopharyngoplasty with tonsillectomy. AB - BACKGROUND: Postoperative pain is a common problem in hospitals. Adults undergoing uvulopalatopharyngoplasty (UPPP) with tonsillectomy experience an unacceptable level of intense postoperative pain, especially during the first 24 h after surgery. This study investigated the analgesic effects of vitamin C in patients undergoing UPPP and tonsillectomy. METHOD: This study was done on forty patients that were evaluated in a randomised double-blinded clinical trial. Patients included in the study were within the age range of 25-50 years with BMI<35, physical status I,II according to the American Society of Anesthesia (ASA) and who underwent uvulopalatopharyngoplasty and tonsillectomy. Patients with epilepsy, BMI>35, any neuropsychiatric disorders, a history of chronic pain, liver and/or renal disease, drug allergy, and drug abuse were excluded from the study. All patients underwent the same method of anaesthesia and surgical procedure. During the first 30 min after the beginning of the surgery, group C (vitamin C) received infusion of 3 g vitamin C in 500 mL of Ringer and group P received 6 mL normal saline in 500 mL of Ringer. Measurements of systolic blood pressure, diastolic blood pressure, mean arterial blood pressure and heart rate were recorded before and during anaesthesia and at intervals of 0,15,30 and 60 min after extubation. Pain severity was recorded according to VAS score at intervals of 0 (recovery room), 6, 12 and 24 h after the procedure, request for analgesic drugs (iv paracetamol or pethedine) according to total number of times of analgesic request and time of the first dose of analgesic use and dose of pethidine were also recorded by questionnaire. RESULTS: There was a significant difference in evaluations for mean pain severity between the two groups at recovery room, 6, 12 and 24 h after surgery (P-value = 0.001). There was a significant difference in mean times that patient requested an analgesic, time of first dose of analgesic and pethidine dose between the two groups (P-value< 0.05). There was no significant differences in measurements of systolic blood pressure, diastolic blood pressure, mean arterial blood pressure and heart rate in different times between the two groups (P-value> 0.05). Blood loss was similar in the two groups (P-value> 0.05). CONCLUSION: According to this study, administration of vitamin C 3 g IV intraoperative reduced postoperative pain without increased side-effects in patients undergoing UPPP and tonsillectomy. PMID- 27219126 TI - Model for the effects of invalid styles of response. AB - Over the last 20-25 years, considerable research has been devoted to the development of the science involved with detecting invalid symptom presentations and performances in psychological and neuropsychological examinations. Early work on these concepts drove the construction and validation of several measures of symptom and performance validity leading to the eventual utilization of these measures to establish base rates across various populations. More recent works have sought to demonstrate correlations between select domains and researchers have further labored to investigate the real world costs of invalid response styles. In this article, a hierarchical model is developed to explain and classify the manifestations and consequences of invalid responding. The primary goals of this work are (a) to outline a model characterizing the pervasive implications of select styles of invalid responding and (b) to provide a heuristic for the development of research on secondary and tertiary consequences of such response styles across health care evaluations. PMID- 27219125 TI - Resistance training-induced changes in integrated myofibrillar protein synthesis are related to hypertrophy only after attenuation of muscle damage. AB - KEY POINTS: Skeletal muscle hypertrophy is one of the main outcomes from resistance training (RT), but how it is modulated throughout training is still unknown. We show that changes in myofibrillar protein synthesis (MyoPS) after an initial resistance exercise (RE) bout in the first week of RT (T1) were greater than those seen post-RE at the third (T2) and tenth week (T3) of RT, with values being similar at T2 and T3. Muscle damage (Z-band streaming) was the highest during post-RE recovery at T1, lower at T2 and minimal at T3. When muscle damage was the highest, so was the integrated MyoPS (at T1), but neither were related to hypertrophy; however, integrated MyoPS at T2 and T3 were correlated with hypertrophy. We conclude that muscle hypertrophy is the result of accumulated intermittent increases in MyoPS mainly after a progressive attenuation of muscle damage. ABSTRACT: Skeletal muscle hypertrophy is one of the main outcomes of resistance training (RT), but how hypertrophy is modulated and the mechanisms regulating it are still unknown. To investigate how muscle hypertrophy is modulated through RT, we measured day-to-day integrated myofibrillar protein synthesis (MyoPS) using deuterium oxide and assessed muscle damage at the beginning (T1), at 3 weeks (T2) and at 10 weeks of RT (T3). Ten young men (27 (1) years, mean (SEM)) had muscle biopsies (vastus lateralis) taken to measure integrated MyoPS and muscle damage (Z-band streaming and indirect parameters) before, and 24 h and 48 h post resistance exercise (post-RE) at T1, T2 and T3. Fibre cross-sectional area (fCSA) was evaluated using biopsies at T1, T2 and T3. Increases in fCSA were observed only at T3 (P = 0.017). Changes in MyoPS post-RE at T1, T2 and T3 were greater at T1 (P < 0.03) than at T2 and T3 (similar values between T2 and T3). Muscle damage was the highest during post-RE recovery at T1, attenuated at T2 and further attenuated at T3. The change in MyoPS post-RE at both T2 and T3, but not at T1, was strongly correlated (r ~ 0.9, P < 0.04) with muscle hypertrophy. Initial MyoPS response post-RE in an RT programme is not directed to support muscle hypertrophy, coinciding with the greatest muscle damage. However, integrated MyoPS is quickly 'refined' by 3 weeks of RT, and is related to muscle hypertrophy. We conclude that muscle hypertrophy is the result of accumulated intermittent changes in MyoPS post-RE in RT, which coincides with progressive attenuation of muscle damage. PMID- 27219128 TI - Contrasting Effects of a Rigid Core and an Alkyl Chain in nCB on the Phase Behavior of Lipid Bilayers. AB - Molecules incorporated into biomembranes often bear both a core and an alkyl chain in a single molecule (e.g., sterols). To clarify the effects of these two parts of a molecule, the phase behavior of a 1,2-dipalmitoyl-sn-glycero-3 phosphocholine (DPPC) bilayer containing 4-n-alkyl-4'-cyanobiphenyl (nCB) (n = 0 8) was investigated. The trends of the main transition temperature (Tm) with respect to n and of the pretransition temperature (Tp) with respect to nCB content changed at n = 3. It was therefore suggested that the two parts of the molecule had opposing effects on the phase behavior of DPPC bilayers. The core appears to perturb molecular ordering in the gel phase and lowers Tm (like cholesterol), while alkyl chains appear to order the lipids in the gel phase and raise Tm (like n-alkanes). In addition, Tm exhibits the so-called odd-even effect based on the alkyl chain length of the minor component, nCB. Depending on the value of n, the variation in Tp was dependent on the additive content, although the pretransition was rarely observed at high contents. PMID- 27219127 TI - MIMIC-III, a freely accessible critical care database. AB - MIMIC-III ('Medical Information Mart for Intensive Care') is a large, single center database comprising information relating to patients admitted to critical care units at a large tertiary care hospital. Data includes vital signs, medications, laboratory measurements, observations and notes charted by care providers, fluid balance, procedure codes, diagnostic codes, imaging reports, hospital length of stay, survival data, and more. The database supports applications including academic and industrial research, quality improvement initiatives, and higher education coursework. PMID- 27219129 TI - Elucidation of the Conversion Reaction of CoMnFeO4 Nanoparticles in Lithium Ion Battery Anode via Operando Studies. AB - Conversion reactions deliver much higher capacities than intercalation/deintercalation reactions of commercial Li ion batteries. However, the complex reaction pathways of conversion reactions occurring during Li uptake and release are not entirely understood, especially the irreversible capacity loss of Mn(III)-containing oxidic spinels. Here, we report for the first time on the electrochemical Li uptake and release of Co(II)Mn(III)Fe(III)O4 spinel nanoparticles and the conversion reaction mechanisms elucidated by combined operando X-ray diffraction, operando and ex-situ X-ray absorption spectroscopy, transmission electron microscopy, (7)Li NMR, and molecular dynamics simulation. The combination of these techniques enabled uncovering the pronounced electronic changes and structural alterations on different length scales in a unique way. The spinel nanoparticles undergo a successive phase transition into a mixed monoxide caused by a movement of the reduced cations from tetrahedral to octahedral positions. While the redox reactions Fe(3+) <-> Fe(0) and Co(2+) <-> Co(0) occur for many charge/discharge cycles, metallic Mn nanoparticles formed during the first discharge can only be oxidized to Mn(2+) during charge. This finding explains the partial capacity loss reported for Mn(III)-based spinels. Furthermore, the results of the investigations evidence that the reaction mechanisms on the nanoscale are very different from pathways of microcrystalline materials. PMID- 27219130 TI - Interferon-induced sterile alpha motif and histidine/aspartic acid domain containing protein 1 expression in astrocytes and microglia is mediated by microRNA-181a. AB - OBJECTIVE: Sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1), a newly discovered HIV-1 host restriction factor, has been found to be induced by interferons and to be regulated by microRNA-181a (miR 181a). However, the mechanism of interferons-induced SAMHD1 expression is unclear. DESIGN: We hypothesized that interferons induce SAMHD1 expression through Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathways, which is mediated by miR-181a. METHODS: We examined the effect of IFN-alpha and IFN-gamma on SAMHD1 mRNA and protein expression, as well as the levels of phosphorylated SAMHD1 and miR-181a in astrocytes and microglia. To determine whether interferons-induced SAMHD1 expression was mediated by miR 181a, we overexpressed or inhibited miR-181a in these cells and exposed them to interferons. We also detected the effect of SAMHD1 and miR-181a on HIV-1 infection in astrocytes and microglia. RESULTS: Both IFN-alpha and IFN-gamma increased SAMHD1 mRNA and protein expression, and reduced miR-181a levels, particularly in microglia. Phosphorylated SAMHD1was not induced by interferons. Overexpression of miR-181a counteracted induction of SAMHD1 expression by interferons, and inhibition of miR-181a mimicked interferons treatment. Inhibition of JAK-STAT signaling pathways resulted in increased miR-181a levels and decreased SAMHD1 mRNA expression. Knock-down of SAMHD1 or overexpression of miR-181a enhanced HIV-1 infection, whereas inhibition of miR-181a reduced HIV-1 infection. However, inhibition of HIV-1 infection induced by IFN-alpha was not significantly affected by miR-181a and SAMHD1. CONCLUSION: MiR-181a is an important mediator for interferons-induced SAMHD1 expression in astrocytes and microglia, but not for inhibition of HIV-1 infection induced by IFN-alpha. PMID- 27219131 TI - Risks and benefits HIV preexposure prophylaxis with tenofovir/emtricitabine in an older male with comorbidities. AB - Renal toxicity in a 73-year-old male, using tenofovir/emtricitabine as preexposure prophylaxis, is described. Reduced renal reserve, a higher exposure to comedications and comorbidities can present a challenge when assessing the risks and benefits of tenofovir-based preexposure prophylaxis in the ageing population. PMID- 27219132 TI - Toward evidence-based medical statistics: a Bayesian analysis of double-blind placebo-controlled antidepressant trials in the treatment of anxiety disorders. AB - The Food and Drug Administration (FDA) uses a p < 0.05 null-hypothesis significance testing framework to evaluate "substantial evidence" for drug efficacy. This framework only allows dichotomous conclusions and does not quantify the strength of evidence supporting efficacy. The efficacy of FDA approved antidepressants for the treatment of anxiety disorders was re-evaluated in a Bayesian framework that quantifies the strength of the evidence. Data from 58 double-blind placebo-controlled trials were retrieved from the FDA for the second-generation antidepressants for the treatment of anxiety disorders. Bayes factors (BFs) were calculated for all treatment arms compared to placebo and were compared with the corresponding p-values and the FDA conclusion categories. BFs ranged from 0.07 to 131,400, indicating a range of no support of evidence to strong evidence for the efficacy. Results also indicate a varying strength of evidence between the trials with p < 0.05. In sum, there were large differences in BFs across trials. Among trials providing "substantial evidence" according to the FDA, only 27 out of 59 dose groups obtained strong support for efficacy according to the typically used cutoff of BF >= 20. The Bayesian framework can provide valuable information on the strength of the evidence for drug efficacy. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27219201 TI - Placenta previa and long-term morbidity of the term offspring. AB - OBJECTIVE: The long-term impact of placenta previa on term infants is unknown. We aimed to investigate whether abnormal placentation increases the risk for long term morbidity of the term offspring. STUDY DESIGN: A population-based cohort study compared the incidence of long-term hospitalizations up to the age of 18 due to cardiovascular, endocrine, neurological, hematological, respiratory and urinary morbidity of children born at term in pregnancies diagnosed with placenta previa and those without. Deliveries occurred between the years 1991-2013 in a tertiary medical center. Multiple pregnancies, and fetal congenital malformations were excluded. Kaplan-Meier survival curves were used to compare cumulative morbidity incidence over time. A multivariable generalized estimating equation (GEE) logistic regression model analysis was used to control for confounders and for maternal clusters. RESULTS: During the study period 233,123 term deliveries met the inclusion criteria; 0.2% (n=502) of the children were born to mothers with placenta previa. During the follow-up period, children born to mothers with placenta previa did not have an increased risk for long-term cardiovascular, endocrine, hematological, neurological, respiratory, and urinary morbidity. CONCLUSION: Term offsprings of mothers diagnosed with placenta previa do not appear to be at an increased risk for long-term morbidity up to the age of 18. PMID- 27219202 TI - Positive predictive value of endometrial polyps in Pipelle aspiration sampling: a histopathological study of 195 cases. AB - OBJECTIVE: To estimate the positive predictive value of Pipelle endometrial sampling in detecting the presence of an underlying endometrial polyp. The secondary objective is to examine the histologic features that can predict the presence of endometrial polyps. STUDY DESIGN: This is a retrospective case review study. 195 women who had undergone diagnostic hysteroscopy and/or polypectomy were identified in a University teaching hospital. All patients had a prior polyp diagnosis in the Pipelle endometrial sample. The histology of these samples were compared and analyzed with subsequent DH findings and final hysteroscopic biopsies. Slides were reviewed by 2 gynaecological pathologists. RESULTS: 162 women were premenopausal (mean age 46.1, SD=4.6) and 33 were postmenopausal (mean age 57.2, SD=8.1). The commonest indication for a Pipelle endometrial sampling was abnormal uterine bleeding. Presence of polyp was confirmed by DH in 56.3% (111/195) cases. Of these, 81.1% (90/111) were confirmed histologically. The positive predictive value of detection of polyps in Pipelle endometrial samples for premenopausal and postmenopausal women was 53.7% and 72.7%, respectively (p=.05). The most reliable histologic features that can predict the presence of an underlying polyp was fibrous stroma (p=.01) and focal glandular clustering (p=.03). The prevalence of endometrial hyperplasia and carcinoma in women who was confirmed to have polyp was 11.7% (13/111). CONCLUSION: The positive predictive value of Pipelle endometrial samples in detecting endometrial polyps was 56.3%. It was higher in the postmenopausal women (72.7%) compared to premenopausal women (53.7%). The prevalence of endometrial hyperplasia and carcinoma in women who was confirmed to have polyp was consistent with the rate reported in the literature. Using ultrasonography as an adjunct maybe helpful in diagnosing endometrial polyps. PMID- 27219203 TI - Multimodal and non-linear optical microscopy applications in reproductive biology. AB - A plethora of optical techniques is currently available to obtain non destructive, contactless, real time information with subcellular spatial resolution to observe cell processes. Each technique has its own unique features for imaging and for obtaining certain biological information. However none of the available techniques can be of universal use. For a comprehensive investigation of biological specimens and events, one needs to use a combination of bioimaging methods, often at the same time. Some modern confocal/multiphoton microscopes provide simultaneous fluorescence, fluorescence lifetime imaging, and four dimensional imaging. Some of them can also easily be adapted for harmonic generation imaging, and to permit cell manipulation technique. In this work we present a multimodal optical workstation that extends a commercially available confocal microscope to include nonlinear/multiphoton microscopy and optical manipulation/stimulation tools. The nonlinear microscopy capabilities were added to the commercial confocal microscope by exploiting all the flexibility offered by the manufacturer. The various capabilities of this workstation as applied directly to reproductive biology are discussed. Microsc. Res. Tech. 79:567-582, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27219204 TI - Measuring conflict management, emotional self-efficacy, and problem solving confidence in an evaluation of outdoor programs for inner-city youth in Baltimore, Maryland. AB - Substantial evidence supports the value of outdoor education programs for promoting healthy adolescent development, yet measurement of program outcomes often lacks rigor. Accurately assessing the impacts of programs that seek to promote positive youth development is critical for determining whether youth are benefitting as intended, identifying best practices and areas for improvement, and informing decisions about which programs to invest in. We generated brief, customized instruments for measuring three outcomes among youth participants in Baltimore City Outward Bound programs: conflict management, emotional self efficacy, and problem solving confidence. Measures were validated through exploratory and confirmatory factor analyses of pilot-testing data from two groups of program participants. We describe our process of identifying outcomes for measurement, developing and adapting measurement instruments, and validating these instruments. The finalized measures support evaluations of outdoor education programs serving urban adolescent youth. Such evaluations enhance accountability by determining if youth are benefiting from programs as intended, and strengthen the case for investment in programs with demonstrated success. PMID- 27219205 TI - Titania Composites with 2 D Transition Metal Carbides as Photocatalysts for Hydrogen Production under Visible-Light Irradiation. AB - MXenes, a family of two-dimensional transition-metal carbides, were successfully demonstrated as co-catalysts with rutile TiO2 for visible-light-induced solar hydrogen production from water splitting. The physicochemical properties of Ti3 C2 Tx MXene coupled with TiO2 were investigated by a variety of characterization techniques. The effect of the Ti3 C2 Tx loading on the photocatalytic performance of the TiO2 /Ti3 C2 Tx composites was elucidated. With an optimized Ti3 C2 Tx content of 5 wt %, the TiO2 /Ti3 C2 Tx composite shows a 400 % enhancement in the photocatalytic hydrogen evolution reaction compared with that of pure rutile TiO2 . We also expanded our exploration to other MXenes (Nb2 CTx and Ti2 CTx ) as co catalysts coupled with TiO2 , and these materials also exhibited enhanced hydrogen production. These results manifest the generality of MXenes as effective co-catalysts for solar hydrogen production. PMID- 27219206 TI - Speech-language Pathology in Acute Pediatric Chemical or Button Battery Ingestion Injury. AB - OBJECTIVES: Dysphagia is a common consequence of pediatric ingestion injury, yet there is a lack of data relating to recommencement of oral (per os; PO) intake or use of feeding therapy. We describe patterns of early PO intake, and referral to speech-language pathology (SLP) for feeding therapy, during the acute admission of a pediatric cohort postchemical or button battery ingestion injury. METHODS: Retrospective chart review of pediatric ingestion injuries admitted to a quaternary hospital from 2008 to 2013. Clinical parameters, PO intake progression, and nature of referrals for feeding therapy during the acute admission were examined. RESULTS: Fifty-one children (26 boys; mean age: 31.5, range 4-170 months) were identified (75% with grade II or III mucosal injuries), of whom 31 (60%) had impaired PO intake. Of these, 5 recommenced premorbid PO intake during admission. At discharge, 16 remained on modified PO intake, and 10 remained nil PO. Eight (26%) were referred to SLP for feeding therapy during acute admission, or within 4 months of discharge. Feeding therapy-referred children were more likely to have pediatric intensive care admission (PICU) (100% vs 26%), and longer hospital admission (36.1 vs 9.3 days for those not referred). CONCLUSIONS: More than half of the cohort had impaired PO intake, and one-third were nil PO at time of discharge. Referrals for feeding therapy were limited. Our findings may provide some guidance for clinicians, patients, and their families regarding possible PO intake recovery patterns, as well as provide background for evaluating the potential for feeding therapy and SLP involvement within this population. PMID- 27219218 TI - Accelerating the pace of discovery in orthopaedic research: A vision toward team science. AB - The landscape of basic science in the United States and around the world is changing, and the field of orthopaedic research is positioned to lead by embracing a culture of collaborative, team science that reflects our field's interdisciplinary nature. In this article we hope to address some of the cultural challenges and programmatic barriers that impede a team science approach in the US and suggest opportunities for change. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1673-1679, 2016. PMID- 27219219 TI - Correction: Electrochemical metallization switching with a platinum group metal in different oxides. AB - Correction for 'Electrochemical metallization switching with a platinum group metal in different oxides' by Zhongrui Wang, et al., Nanoscale, 2016, DOI: 10.1039/c6nr01085g. PMID- 27219221 TI - The potential role of mangiferin in cancer treatment through its immunomodulatory, anti-angiogenic, apoptopic, and gene regulatory effects. AB - Mangiferin (1,3,6,7-tetrahydroxyxanthone-C2-beta-D-glucoside) is a natural bioactive xanthonoid that can be found in many plant species, among which the mango tree (Mangifera indica L), a plant widely used in the traditional medicinal, is one of its primary sources. The use of mangiferin for cancer treatment has attracted the attention of research groups around the World. Single administration of mangiferin or in combination with known anticancer chemicals has shown the potential benefits of this molecule in lung, brain, breast, cervix, and prostate cancers, and leukemia. Mangiferin mechanisms of action against cancer cells through in vitro, ex vivo, or in vivo models are discussed besides its antioxidant and anti-inflammatory properties. Nevertheless, pharmaceutical development and, therefore, clinical trials on cancer targets are still lacking. (c) 2016 BioFactors, 42(5):475-491, 2016. PMID- 27219222 TI - Discussion: Bacterial Biofilm Infection Detected in Breast Implant-Associated Anaplastic Large-Cell Lymphoma. PMID- 27219220 TI - Harnessing the Versatility of Bacterial Collagen to Improve the Chondrogenic Potential of Porous Collagen Scaffolds. AB - Collagen I foams are used in the clinic as scaffolds to promote articular cartilage repair as they provide a bioactive environment for cells with chondrogenic potential. However, collagen I as a base material does not allow for precise control over bioactivity. Alternatively, recombinant bacterial collagens can be used as "blank slate" collagen molecules to offer a versatile platform for incorporation of selected bioactive sequences and fabrication into 3D scaffolds. Here, we show the potential of Streptococcal collagen-like 2 (Scl2) protein foams modified with peptides designed to specifically and noncovalently bind hyaluronic acid and chondroitin sulfate to improve chondrogenesis of human mesenchymal stem cells (hMSCs) compared to collagen I foams. Specific compositions of functionalized Scl2 foams lead to improved chondrogenesis compared to both nonfunctionalized Scl2 and collagen I foams, as indicated by gene expression, extracellular matrix accumulation, and compression moduli. hMSCs cultured in functionalized Scl2 foams exhibit decreased collagens I and X gene and protein expression, suggesting an advantage over collagen I foams in promoting a chondrocytic phenotype. These highly modular foams can be further modified to improve specific aspects chondrogenesis. As such, these scaffolds also have the potential to be tailored for other regenerative medicine applications. PMID- 27219223 TI - Breast Cancer-Related Lymphedema: Quality of Life after Lymph Node Transfer. AB - BACKGROUND: Breast cancer-related lymphedema affects multiple aspects of patients' daily lives. The main aim of this study was to assess the impact of vascularized lymph node transfer on the quality of life in patients with lymphedema. METHODS: Between 2007 and 2012, 25 female patients with breast cancer related lymphedema underwent vascularized lymph node transfer. In 22 cases, the patients underwent a simultaneous deep inferior epigastric artery perforator flap breast reconstruction based on the superficial circumflex iliac artery. The influence on quality of life was evaluated using the Upper Limb Lymphedema-27 questionnaire, which includes physical, psychological, and social dimensions. The authors also investigated risk factors for lymphedema, such as body mass index, smoking, age, and time between start of lymphedema and vascularized lymph node transfer, and their impact on quality of life. RESULTS: Twenty-one patients (84 percent) had an improvement of quality of life after vascularized lymph node transfer. The mean physical, psychological, and social scores were significantly improved postoperatively (p < 0.001). Risk factors for the development of lymphedema did not influence quality of life among patients with breast cancer related lymphedema. Skin infections disappeared in 50 percent of the cases. Eleven patients (44 percent) discontinued compression therapy at a mean postoperative time interval of 29 months (range, 8 to 64 months). In the other patients (56 percent), the average frequency of compression therapy decreased from three sessions to one session per week. CONCLUSION: Vascularized lymph node transfer significantly improves quality of life among patients with breast cancer related lymphedema. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27219224 TI - Breast Reconstruction with SIEA Flaps: A Single-Institution Experience with 145 Free Flaps. AB - BACKGROUND: Refinements in microsurgical breast reconstruction have refined superficial inferior epigastric artery (SIEA) and superficial circumflex iliac artery (SCIA) flaps, yet technical difficulties and varied success rates limit widespread acceptance. The authors present the outcomes of their experience with 145 consecutive SIEA/SCIA flaps and suggest technical tips to improve success with this important flap. METHODS: An institutional review board-approved retrospective chart review of all SIEA/SCIA free flaps performed by the senior authors between January 1, 2006, and February 6, 2014, was conducted. Data on patient demographics, flap characteristics, and complications were collected. RESULTS: There were 145 flaps performed in 119 patients. Arterial donor and recipient mismatch occurred in 55 instances (38 percent). In these cases, 48 arteries (87 percent) were spatulated and seven (13 percent) were back-cut to improve size concordance. Nine flaps required operative return for flap viability concerns. Five were arterial, three were venous, and one flap had concomitant arterial and venous thrombosis. Total flap loss rate attributable to thrombotic events was 4.8 percent. No flaps with arterial thrombosis on reoperation were salvageable. Furthermore, 80 percent had arterial revisions at initial operation. No patients had an abdominal bulge or hernia, and the fat necrosis rate was 10.3 percent. CONCLUSIONS: SIEA/SCIA breast reconstruction can be reliably performed; however, flaps exhibiting postoperative arterial thrombosis with revision at initial surgery are unlikely salvageable on reoperation. Spatulation did not correlate with an increased thrombosis rate; in fact, the authors advocate for donor artery manipulation to manage size mismatch. CLINCAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27219225 TI - Revisions in Implant-Based Breast Reconstruction: How Does Direct-to-Implant Measure Up? AB - BACKGROUND: Immediate direct-to-implant breast reconstruction is increasingly performed for breast cancer treatment or prevention. The advantage over traditional tissue expander/implant reconstruction includes the potential for fewer surgical procedures. METHODS: Retrospective, single-institution, three surgeon review identified patients undergoing implant-based reconstruction from 2006 to 2011. RESULTS: Six hundred eighty-two reconstructions were performed in 432 women with an average follow-up of 5 years. Four hundred sixty-five were direct-to-implant reconstructions with acellular dermal matrix while 217 were tissue expander/implant reconstructions without acellular dermal matrix. The overall revision rate in direct-to-implant reconstruction was 20.9 percent. There was no difference in total revision rates between direct-to-implant and tissue expander reconstruction (20.9 percent versus 20.3 percent; p = 0.861). Subgroup analysis showed no difference in revision for malposition (3.4 percent versus 5.5 percent; p = 0.200), size change (6.7 percent versus 5.5 percent; p = 0.569), fat grafting (8.6 percent versus 9.7 percent; p = 0.647), or capsular contracture (4.5 percent versus 3.2 percent; p = 0.429). Multivariable logistic regression analysis showed complications were associated with higher rates of revision for malposition or size in both groups (OR, 2.8; 95 percent CI, 1.56 to 5.13; p = 0.001). Smoking, preoperative irradiation, skin necrosis, and one surgeon were associated with higher rates of fat grafting, whereas increasing body mass index was associated with lower rates. Postoperative radiotherapy and hematoma were predictive of revision for capsular contracture. CONCLUSIONS: The 5-year revision rate in this series of direct-to-implant reconstruction was approximately 21 percent and similar to the revision rate in tissue expander/implant reconstruction. Surgical complications, radiotherapy, and the surgeon influenced the rate of revision similarly in both groups. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 27219226 TI - Skin-Reduction Breast Reconstructions with Prepectoral Implant. AB - Skin-reduction mastectomy with prepectoral implant reconstruction is a novel technique for immediate breast reconstruction, with subcutaneous implant placement in patients eligible for skin-reducing mastectomy. Implants were placed above the pectoralis muscles in a compound pocket made by a dermal flap and acellular dermal matrix. The procedure was performed on 33 breasts in 27 selected patients. In three cases, there was skin ischemia; in one case, it healed spontaneously; and in two patients, a surgical necrosectomy and primary closure were needed. No implant loss occurred. This new technique proved to be a useful alternative, with good cosmetic results, in selected patients requiring mastectomy. These preliminary results need to be confirmed by long-term and comparative studies. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27219227 TI - Discussion: A Comparison of the Full and Short-Scar Face-Lift Incision Techniques in Multiple Sets of Identical Twins. PMID- 27219228 TI - A Comparison of the Effectiveness of Triamcinolone and Radiation Therapy for Ear Keloids after Surgical Excision: A Systematic Review and Meta-Analysis. AB - BACKGROUND: The ear is a common site for keloid formation, usually after trauma or ear piercing. This study is a meta-analysis to identify effective treatments for ear keloids after surgical excision. METHODS: A systematic literature review and meta-analysis were performed using core databases. Postoperative adjuvant treatment modalities for ear keloids and recurrence rates were extracted and analyzed. Fixed and random effect models were applied. RESULTS: Twenty-five studies published before August of 2015 were identified. The recurrence rate after surgical excision of an ear keloid in the triamcinolone group was estimated as 15.4 percent (95 percent CI, 9.4 to 24.1 percent; p < 0.001). The recurrence rate in the radiation therapy group was estimated as 14.0 percent (95 percent CI, 9.6 to 19.9 percent; p < 0.001). CONCLUSION: Although a large-scale, randomized study is required for confirmation, both triamcinolone and radiation therapy provided outstanding treatment for ear keloids after surgical excision without a significant difference between the two treatments. PMID- 27219229 TI - Design for Natural Breast Augmentation: The ICE Principle. AB - BACKGROUND: The authors' published studies have helped define breast beauty in outlining key parameters that contribute to breast attractiveness. The "ICE" principle puts design into practice. It is a simplified formula for inframammary fold incision planning as part of the process for determining implant selection and placement to reproduce the 45:55 ratio previously described as fundamental to natural breast appearance. The formula is as follows: implant dimensions (I) - capacity of the breast (C) = excess tissue required (E). The aim of this study was to test the accuracy of the ICE principle for producing consistent natural beautiful results in breast augmentation. METHODS: A prospective analysis of 50 consecutive women undergoing primary breast augmentation by means of an inframammary fold incision with anatomical or round implants was performed. The ICE principle was applied to all cases to determine implant selection, placement, and incision position. Changes in parameters between preoperative and postoperative digital clinical photographs were analyzed. RESULTS: The mean upper pole-to-lower pole ratio changed from 52:48 preoperatively to 45:55 postoperatively (p < 0.0001). Mean nipple angulation was also statistically significantly elevated from 11 degrees to 19 degrees skyward (p <= 0.0005). Accuracy of incision placement in the fold was 99.7 percent on the right and 99.6 percent on the left, with a standard error of only 0.2 percent. There was a reduction in variability for all key parameters. CONCLUSION: The authors have shown using the simple ICE principle for surgical planning in breast augmentation that attractive natural breasts may be achieved consistently and with precision. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27219230 TI - Redefining the Ideal Buttocks: A Population Analysis. AB - BACKGROUND: The buttocks are a key element of female beauty, with aesthetic gluteoplasty becoming one of the fastest growing plastic surgery procedures. However, there remains no clear standard for the ideal buttocks. The authors performed a population analysis of the characteristics of the ideal buttocks to guide surgical planning. METHODS: Images of buttocks were digitally altered to create buttocks of varying proportions on posterior and lateral views. Waist-to hip ratios and varying vertical proportions were studied. Data were stratified and analyzed according to age range, gender, ethnicity, and nationality of the respondents. RESULTS: A total of 1146 responses were collected. Of 989 respondents who submitted their gluteal preferences, 482 respondents (48.7 percent) were women and 507 (51.3 percent) were men. Overall, the most attractive buttocks waist-to-hip ratio is 0.65 from the posterior view (44.2 percent of respondents). The next most attractive ratio was 0.60 (25 percent of respondents). Positioning of the lateral prominence at the inferior gluteal fold was rated by 26.3 percent of respondents as the most attractive. From the lateral view, the most attractive buttocks have a waist-to-hip ratio of 0.70 (29.8 percent of respondents), with the most prominent portion positioned at the midpoint of the buttocks (45.1 percent of respondents), which is a 50:50 vertical ratio. There were no significant differences in preferences between respondent ages, genders, or ethnicities. CONCLUSIONS: New ideal waist-to-hip ratios of 0.6 and 0.65 update the previous standards and indicate a more dramatic and "curvier" new ideal, signaling an important preference paradigm shift. The information derived from this study has the potential to guide gluteoplasty practices and techniques. PMID- 27219231 TI - Concomitant Liposuction Reduces Complications of Vertical Medial Thigh Lift in Massive Weight Loss Patients. AB - BACKGROUND: Medial thigh lift procedures in the massive weight loss population have been associated with significant complication rates. Liposuction-assisted medial thighplasty has recently been introduced as a technical advancement to improve outcomes. To date, no study is available directly comparing the traditional approach and this new technique. Here, the authors evaluate outcomes and complications of both techniques in a retrospective cohort study. METHODS: Outcomes of 59 patients undergoing vertical medial thighplasty at the authors' institution between 2008 and 2014 were assessed retrospectively. Evaluated parameters include age, sex, body mass indices, method of weight loss, comorbidities, and complications (e.g., seroma, infection, wound dehiscence, hematoma, and surgical revision). Appropriate statistical analysis was performed. RESULTS: There were 29 patients in the excision-only group and 30 patients in the liposuction-assisted group (all women; average age, 41.5 years). The overall complication rate was significantly reduced in the liposuction-assisted group (13 percent versus 59 percent; p < 0.001). The incidence of individual complications such as seroma formation (zero patients versus 10 patients; p < 0.001) and wound infection (one patient versus eight patients; p = 0.01) was significantly less in the liposuction-assisted group. In addition, we observed a significantly shorter hospital stay (6.0 days versus 7.8 days), reduced number of follow-up visits (2.0 versus 4.4), and reduced time to drain removal (1.8 days versus 4.1 days; p < 0.001) in the liposuction-assisted group. CONCLUSIONS: Liposuction-assisted medial thighplasty led to a significant reduction of complications and faster recovery in the massive weight loss patient population. As a consequence, the excision-only vertical thigh lift has been completely abandoned in the authors' clinical practice. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 27219232 TI - Facial Feminization: Systematic Review of the Literature. AB - BACKGROUND: Facial feminization surgery encompasses a broad range of craniomaxillofacial surgical procedures designed to change masculine facial features into feminine features. The surgical principles of facial feminization surgery can be applied to male-to-female transsexuals and anyone desiring feminization of the face. Although the prevalence of these procedures is difficult to quantify, because of the rising prevalence of transgenderism (approximately one in 14,000 men) along with improved insurance coverage for gender-confirming surgery, surgeons versed in techniques, outcomes, and challenges of facial feminization surgery are needed. This review is designed to critically appraise the current facial feminization surgery literature. METHODS: A comprehensive literature search of the Medline, PubMed, and EMBASE databases was conducted for studies published through October of 2014 with multiple search terms related to facial feminization. Data on techniques, outcomes, complications, and patient satisfaction were collected. RESULTS: Fifteen articles were selected and reviewed from the 24 identified, all of which were either retrospective or case series/reports. Articles covered a variety of facial feminization procedures. A total of 1121 patients underwent facial feminization surgery, with seven complications reported, although many articles did not explicitly comment on complications. Satisfaction was high, although most studies did not use validated or quantified approaches to address satisfaction. CONCLUSIONS: Facial feminization surgery appears to be safe and satisfactory for patients. Further studies are required to better compare different techniques to more robustly establish best practices. Prospective studies and patient-reported outcomes are needed to establish quality-of-life outcomes for patients. However, based on these studies, it appears that facial feminization surgery is highly efficacious and beneficial to patients. PMID- 27219233 TI - Discussion: Growth Hormone Therapy Accelerates Axonal Regeneration, Promotes Motor Reinnervation, and Reduces Muscle Atrophy following Peripheral Nerve Injury. PMID- 27219234 TI - The Effects of Mucoperichondrial Flap Elevation on Septal L-Strut Cartilage: A Biomechanical and Histologic Analysis in a Rabbit Model. AB - BACKGROUND: The harvesting of septal cartilage following mucoperichondrial flap elevation has almost become a standard step in rhinoplasty. However, the strength of the remaining septum has not yet been evaluated. In the current experimental study of a rabbit rhinoplasty model, the remaining septum following a graft harvest was analyzed both biomechanically and pathologically. METHODS: Forty New Zealand rabbits were classified into four equal groups. Group 1 consisted of the animals in which unilateral elevation of the mucoperichondrial flaps was undertaken before the graft harvest, group 2 consisted of the animals in which bilateral elevation was undertaken, group 3 included the animals where the septum was exposed and left untouched after a bilateral mucosal flap elevation, and group 4 was designated as the control group. Specimens were analyzed under light microscopy for multiple parameters. Biomechanical analyses were performed with a universal testing device at the Department of Engineering, Biomechanical Laboratories, Istanbul Technical University. RESULTS: Biomechanical analysis in terms of maximum tension revealed significant results among the groups (p = 0.008). Although insignificant results were observed overall using a pathologic analysis, the amount of chondrocytes was lower in group 2 than in group 1 (p = 0.099). The amounts of matrix collagen (p = 0.184) and fibrosis were (p = 0.749) higher in group 2 than in group 1. CONCLUSIONS: From these data, the authors conclude that mucoperichondrium integrity plays a crucial role in the biomechanical strength of the septum. More sophisticated studies with further pathologic analysis are required to determine the exact mechanism of strength loss observed with mucoperichondrial flap elevation. PMID- 27219235 TI - Percutaneous Aponeurotomy and Lipofilling (PALF) versus Limited Fasciectomy in Patients with Primary Dupuytren's Contracture: A Prospective, Randomized, Controlled Trial. AB - BACKGROUND: As an alternative to needle aponeurotomy release and limited fasciectomy treatment of Dupuytren's contracture, the authors introduced an extensive percutaneous aponeurotomy and lipofilling (PALF) procedure. In their previous study, the authors reported that contractures significantly improved and most patients returned to normal use of the hand within 2 to 4 weeks. To establish the safety and efficacy of PALF, the authors compared it to the standard limited fasciectomy in a single-blind, multicenter, prospective, randomized, controlled trial. METHODS: Patients with a primary Dupuytren's contracture were assigned randomly to the limited fasciectomy group or the PALF group. Patients were measured at baseline and at 2 weeks, 3 weeks, 6 months, and 1 year postoperatively. Primary outcome of the trial was contracture correction and convalescence time. Groups were compared using a mixed models approach. RESULTS: Eighty patients were randomized to PALF or limited fasciectomy. In both groups, almost full metacarpophalangeal joint contracture correction was obtained, whereas for the proximal interphalangeal joint, some residual contracture remained. Patients in the PALF group returned significantly earlier to their normal daily activity. At 1 year after surgery, no significant differences in recurrence rate or hand function were present. However, limited fasciectomy seems to have a higher incidence of permanent complications. CONCLUSIONS: PALF demonstrates a significantly shorter convalescence, similar operative contracture correction, lower incidence of long-term complications, and no significant difference regarding 1-year postoperative results compared with limited fasciectomy. It is therefore a valuable, minimally invasive alternative to limited fasciectomy in the treatment of Dupuytren's disease. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 27219236 TI - Discussion: Which Factors Are Associated with Open Reduction of Adult Mandibular Condylar Injuries? PMID- 27219237 TI - Modified Furlow Palatoplasty Using Small Double-Opposing Z-Plasty: Surgical Technique and Outcome. AB - BACKGROUND: A smaller Z-plasty is applied in a modified Furlow palatoplasty. The purpose of this study was to assess its surgical and functional outcome. METHODS: The surgical technique included mucoperiosteal flap elevation in the hard palate, complete pedicle dissection and release, double-opposing Z-plasty using 5-mm limbs and muscle dissection in the soft palate, and the buccal fat pad covering lateral relaxing wounds. A retrospective chart review was conducted for 231 consecutive nonsyndromic patients undergoing modified palatoplasty from May of 2007 to December of 2014. The demographic, postoperative, and follow-up data were collected. Statistical analyses were performed. RESULTS: Average age at palatoplasty was 8.3 months. The overall oronasal fistula rate was 0.4 percent; oronasal fistula occurred in only one case with bilateral cleft. Other complications included postoperative bleeding in two cases (0.8 percent), postoperative airway obstruction in one case (0.4 percent), obstructive sleep apnea in one case (0.4 percent), stitch abscess in one case (0.4 percent), and distal uvula dehiscence in two cases (0.8 percent). One hundred twenty-seven patients had full speech evaluation, and seven (5.5 percent) were diagnosed with velopharyngeal insufficiency requiring surgical correction. CONCLUSION: This modified palatoplasty using a small double-opposing Z-plasty provided adequate cleft palate closure, with a low fistula rate and satisfactory speech outcome. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27219238 TI - Surgical Management of Polyostotic Craniofacial Fibrous Dysplasia: Long-Term Outcomes and Predictors for Postoperative Regrowth. AB - BACKGROUND: The mainstay of treatment for craniofacial fibrous dysplasia is surgical; however, optimal indications and techniques are poorly understood, particularly in polyostotic disease and McCune-Albright syndrome. This study investigated surgical indications and risk factors for recurrence in a large cohort. METHODS: One hundred thirty-three craniofacial fibrous dysplasia subjects in a natural history study were evaluated. Radiographic studies, operative reports, and clinical records were reviewed. RESULTS: Thirty-six subjects underwent 103 craniofacial procedures (mean, 2.8 operations per subject), with 13.5 +/- 10.5-year follow-up (range, 0 to 39 years). The most common indication was craniofacial deformity (n = 61 operations), including 36 initial operations (59 percent) and 26 reoperations (41 percent). Mean time to reoperation was 3.4 +/- 3.2 years (range, 0.3 to 13.3 years). Regrowth occurred after 42 operations (68 percent), and was more frequent after operations in subjects with McCune Albright syndrome growth hormone excess [22 of 25 operations (88 percent)] than without growth hormone excess [15 of 36 operations (58 percent); p = 0.02]. Of 11 subjects with growth hormone excess, nine (82 percent) were undiagnosed at the time of their initial operation. Regrowth was more frequent after debulking procedures [31 of 38 (82 percent)] than after more aggressive reconstructions [nine of 20 (45 percent); p = 0.007]. Eleven subjects underwent treatment for aneurysmal bone cysts, with recurrence in one subject. Eleven subjects underwent biopsies and none had complications or regrowth. CONCLUSIONS: Craniofacial fibrous dysplasia regrowth and reoperation are common, particularly after debulking procedures. Outcomes are favorable for aneurysmal bone cysts and biopsies. McCune-Albright syndrome growth hormone excess is a risk factor for regrowth, and may be underdiagnosed in surgical patients. Surgeons should be aware of appropriate screening for endocrinopathies in fibrous dysplasia. These findings highlight the importance of a multidisciplinary approach to craniofacial fibrous dysplasia, and individualized care with long-term follow-up. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27219239 TI - The Face Transplantation Update: 2016. AB - BACKGROUND: Ten years after the first face transplantation, the available data in peer-reviewed literature, various media outlets, and recent specialty meetings and courses are conflicting and inconsistently reported. The purpose of this study was to consolidate the available data by means of multiple sources to reflect an accurate and current state of facial vascularized composite allotransplantation as of December of 2015. METHODS: Using applied search terms pertaining to face transplantation, a systematic PubMed search, Google search, and review of Plastic Surgery Education Network News Connection e-mailed newsletters were performed, and data presented at three meetings (i.e., the most recent American Society of Reconstructive Transplantation biennial meeting, the American Society of Reconstructive Microsurgery annual meeting, and the biennial AO North America State of the Art: Face Reconstruction and Transplantation course) were consolidated to capture the most contemporary and accurate data in face transplantation. RESULTS: A total of 37 face transplants have been performed (20 partial and 17 full face) from 2005 to December of 2015. A discrepancy between actual transplantations performed and peer-reviewed reports exists at multiple time points, with a propensity for underreporting. Ten cases were described through media outlets but were not reported by the surgical teams in peer-reviewed literature. Two clinical cases were not described in peer-reviewed literature or media. There have been a total of five deaths, and posttransplant malignancy and revision surgery have been underreported. CONCLUSIONS: This serves as the most contemporary and all-inclusive face transplantation review. There is a critical need for timely reporting and outcome transparency in the reconstructive transplant community. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 27219240 TI - Simultaneous Scalp, Skull, Kidney, and Pancreas Transplant from a Single Donor. AB - BACKGROUND: Vascularized composite allotransplantation is an emerging field, but the complications of lifelong immunosuppression limit indications. Vascularized composite allotransplantation in solid organ recipients represents a unique opportunity because immunosuppression has already been accepted. This report of a simultaneous scalp, skull, kidney, and pancreas transplant represents both the first skull-scalp transplant and combination of a vascularized composite allotransplantation with double organ transplantation. METHODS: A previous recipient of a kidney-pancreas transplant presented with osteoradionecrosis of the calvaria and a large area of unstable scalp following successful, curative treatment of a scalp tumor. His kidney and pancreas functions were also critically poor. A multidisciplinary, multi-institutional plan was developed to perform a simultaneous scalp, skull, and repeated kidney and pancreas transplantation, all from a single donor. RESULTS: Eighteen months after the patient was listed with the United Network for Organ Sharing, a donor was identified and the multiorgan vascularized composite allotransplantation was performed. Twenty physicians and 15 hours were required to perform donor and recipient procedures. The patient recovered well and was discharged on postoperative day 15. He has had one episode of scalp rejection confirmed by biopsy and treated successfully. His creatinine value is currently 0.8 mg/dl, from 5.0 mg/dl, and his blood glucose levels are normal without supplemental insulin. Aesthetic outcome is very satisfactory. The patient is now 1 year post transplantation and doing well. CONCLUSIONS: Vascularized composite allotransplantation in solid organ recipients is an expansion of current indications to already immunosuppressed patients. Rejection of the vascularized composite allotransplant without solid organ rejection can occur and is treatable. Methodical planning, an interdisciplinary approach, and careful management of all organs are critical to success. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 27219241 TI - Application of Computed Tomography Angiography Mapping and Located Template for Accurate Location of Perforator in Head and Neck Reconstruction with Anterolateral Thigh Perforator Flap. AB - BACKGROUND: The authors introduce a new method of preoperative computed tomography angiography mapping and virtual and printed located template for accurate location of perforators in the anterolateral thigh perforator flap for head and neck reconstruction. METHODS: Between April and December of 2014, a cohort study was performed with 29 patients who underwent head and neck reconstruction with anterolateral thigh perforator flaps. Computed tomography angiography images were processed for maximum intensity projection and volume rendering to obtain and evaluate the perforator information. The virtual and printed templates with grid were used to transfer the perforator information for intraoperative guidance during flap harvest. The preoperative angiography results were compared with the high-frequency color Doppler results and with the intraoperative real-time findings to evaluate the accuracy of computed tomography angiography mapping. RESULTS: The source vessel, origin, location, direction, number, and caliber of the perforators were determined by preoperative computed tomography angiography mapping. All of the perforator data were accurately mapped on a virtual template and printed on the located template to guide flap harvest. The flap was actually used and survived successfully in 20 patients. The results for perforators identified by mapping were more accurate than those for perforators identified by Doppler. There was no significant difference between the preoperative computed tomography angiography results and the intraoperative findings (p > 0.05). CONCLUSIONS: The role of preoperative computed tomography angiography mapping in guiding anterolateral thigh perforator flap harvest and reducing the unpredictable risk of surgery is acceptable. Located virtual and printed template with grid can transform preoperative computed tomography angiography information to the intraoperative setting accurately and easily. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, II. PMID- 27219242 TI - Management of the Salivary Glands and Facial Nerve in Face Transplantation. AB - BACKGROUND: Since the first face transplant in 2005, 35 cases have been performed worldwide with acceptable graft survival and satisfactory return of function and appearance. With increasing experience, it is emerging that the salivary glands can contribute to the challenges encountered in the perioperative period. METHODS: A comprehensive review of the literature regarding management of the salivary glands and facial nerve in facial transplantation was performed. Data gathered included inclusion or exclusion of submandibular and parotid glands in the recipient and allograft, extent of mucosal inclusion in the allograft, salivary complications and treatment, level and method of facial nerve repair, and motor nerve outcomes. RESULTS: Information on salivary gland management was available for 25 cases. Undesirable salivary events were documented in 12 cases (48 percent). The source of complications was the parotid in five cases (42 percent), a combination of the parotid and submandibular glands in three cases (25 percent), and minor salivary glands in four cases (33 percent). Postoperative botulinum toxin injections resolved salivary collections in four cases. Facial nerve continuity was restored at the level of the trunk/primary divisions (66 percent) or the terminal branches (34 percent), with inclusion of the whole parotid dictating a trunk repair and exclusion of the parotid dictating a terminal branch repair. CONCLUSIONS: The salivary glands warrant increased attention in surgical planning and postoperative care. Exclusion of the salivary glands from the facial allograft with repair of the terminal branches of the facial nerve appears to be preferable. Botulinum toxin should be considered for prophylaxis and treatment of salivary collections. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 27219243 TI - Discussion: Management of the Salivary Glands and Facial Nerve in Face Transplantation. PMID- 27219244 TI - Discussion: Evolving Concepts of Keystone Perforator Island Flaps (KPIF): Principles of Perforator Anatomy, Design Modifications, and Extended Clinical Applications. PMID- 27219245 TI - Unnecessary Emergency Transfers for Evaluation by a Plastic Surgeon: A Burden to Patients and the Health Care System. AB - BACKGROUND: Plastic surgeons are frequently consulted for hand and facial injuries, and patients are often transferred to trauma centers for evaluation of these problems. The authors sought to identify the frequency and impact of "unnecessary" transfers for emergency evaluation by a plastic surgeon at a Level I trauma center. METHODS: The authors reviewed more than 32,000 consecutive emergency department encounters at their institution between April of 2009 and April of 2013 and found 1181 patients transferred for evaluation by plastic surgery. Using a retrospective chart review, necessity of transfer was determined based on the intervention performed at the authors' institution and the availability of resources at the transferring site. RESULTS: Of all the patients referred for "emergency" evaluation, 860 (74.1 percent) were unnecessary. Transfers for hand-related issues were more likely to be coded as unnecessary compared with referrals for facial trauma and infection (76 percent versus 66 percent; p < 0.001). The average time from referral to discharge from the emergency department was 412 minutes. The expense for these unnecessary transfers exceeded $4.6 million. CONCLUSIONS: This is the first intervention-based study evaluating the impact of unnecessary transfer for evaluation of hand and facial emergencies. Using a framework based on objective outcomes, the authors found that fewer than one-third of patients required emergent transfer for evaluation by a plastic surgeon, and almost half did not receive an intervention following transfer. Based on patient time and financial expenses for these unnecessary evaluations, improvements could be made in both quality and cost of care by limiting inappropriate emergency department referrals. PMID- 27219246 TI - Medical Student Mentorship in Plastic Surgery: The Mentee's Perspective. AB - BACKGROUND: Mentorship is a universal concept that has a significant impact on nearly every surgical career. Although frequently editorialized, true data investigating the value of mentorship are lacking in the plastic surgery literature. This study evaluates mentorship in plastic surgery from the medical student perspective. METHODS: An electronic survey was sent to recently matched postgraduate year-1 integrated track residents in 2014, with a response rate of 76 percent. RESULTS: Seventy-seven percent of students reported a mentoring relationship. Details of the mentoring relationship were defined. Over 80 percent of students reported a mentor's influence in their decision to pursue plastic surgery, and nearly 40 percent of students expressed interest in practicing the same subspecialty as their mentor. Benefits of the relationship were also described. Mentees value guidance around career preparation and advice and prioritized "a genuine interest in their career and personal development" above all other mentor qualities (p <= 1.6 * 10). Mentees prefer frequent, one-on-one interactions over less frequent interaction or group activities. Students did not prefer "assigned" relationships (91 percent), but did prefer "facilitated exposure." Major barriers to mentorship included mentor time constraints and lack of exposure to plastic surgery. Indeed, significant differences in the presence of a mentoring relationship correlated with involvement of the plastic surgery department in the medical school curriculum. CONCLUSIONS: This study defines successes and highlights areas for improvement of mentorship of plastic surgery medical students. Successful mentorship may contribute to the future of plastic surgery, and a commitment toward this endeavor is needed at the local, departmental, and national leadership levels. PMID- 27219247 TI - Discussion: Low Levels of Evidence on the Plastic Surgery In-Service Training Exam. PMID- 27219248 TI - Discussion: Analysis of References on the Plastic Surgery In-Service Training Exam. PMID- 27219249 TI - Underpromise. PMID- 27219253 TI - The Effect of Norepinephrine and Dopamine on Radial Forearm Flap Partial Tissue Oxygen Pressure and Microdialysate Metabolite Measurements: A Randomized Controlled Trial. AB - BACKGROUND: Patients undergoing ablative and reconstructive head and neck surgery with a microvascular flap have multiple factors that potentially decrease postoperative mean arterial pressure, which may endanger flap survival. The safety of vasopressor use has long been a topic of discussion. The authors analyzed the effect of vasopressors on microvascular flap perfusion after head and neck cancer reconstruction. METHODS: A total of 27 patients were enrolled in a randomized, controlled, clinical trial. A microvascular radial forearm flap was used for reconstruction. Patients were allocated into one of three groups: dopamine, norepinephrine, and control. The intervention groups received the vasoactive drug, aiming to maintain the mean arterial pressure between 80 and 90 mmHg. Normovolemia was maintained according to central venous pressure. Flap perfusion was monitored with continuous tissue partial pressure of oxygen and microdialysate metabolite (lactate-to-pyruvate ratio) measurements. RESULTS: No adverse effects were observed, and postoperative recovery was free of complications in all groups. Neither the lactate-to-pyruvate ratio nor continuous tissue partial pressure of oxygen values differed significantly between groups during the first 24 hours of the vasoactive drug infusion period or during the 72 hour follow-up. CONCLUSIONS: Norepinephrine and dopamine are safe and effective vasopressors for use during the postoperative period following head and neck cancer surgery with microvascular reconstruction. Dopamine should be used with caution, however, because of the risk of side effects. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 27219252 TI - Malignant Pyoderma Associated with Granulomatosis with Polyangiitis (Wegener Granulomatosis) as a Unique Indication for Facial Vascularized Composite Allotransplantation: Part I. AB - BACKGROUND: Granulomatosis with polyangiitis (Wegener granulomatosis) is a rare disease that commonly starts in the craniofacial region and can lead to considerable facial disfigurement. Granulomas and vasculitis, however, can involve many other tissues (especially pulmonary and renal). Dermatologic and subcutaneous components can lead to malignant pyoderma. METHODS: The authors describe a unique pathologic condition, where significant Le Fort type trauma was associated with subsequent development of granulomatosis with polyangiitis and malignant pyoderma. Successive operations to excise necrotic tissue and reconstruct the defects were followed by worsening inflammation and tissue erosions. Trauma and surgery in proximity to the eye and sinuses masked the initial clinical presentation and led to delay in diagnosis and disease progression. The resultant facial disfigurement and tissue loss were substantial. RESULTS: Despite multiple confounding factors, accurate diagnosis was eventually established. This was based on persistence of sinus inflammations in the absence of infective agents, proven sterility of lung lesions, and antineutrophil cytoplasmic antibody positivity with proteinase 3 specificity. Skin lesion biopsy specimens were identified as pyoderma gangrenosum and later as malignant pyoderma. Institution of immunosuppressive therapy allowed successful control of the disease and wound healing. The resulting craniofacial destruction, however, necessitated facial vascularized composite allotransplantation. CONCLUSION: Recognition of this rare pathologic association is essential, to prevent delays in diagnosis and treatment that can lead to major craniofacial tissue loss. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 27219254 TI - Anatomy of the Vascularized Lateral Femoral Condyle Flap. AB - BACKGROUND: The perforators of the free lateral femoral condyle flap have yet to be adequately described in humans. Therefore, the authors investigated the perforator vessels of the lateral femoral condyle flap in an anatomical study and discussed potential clinical applications with a particular interest in its indication with vascularized bone and/or iliotibial band for tendon repair surgery. METHODS: The authors dissected thighs of 28 cadavers to evaluate the anatomical properties of perforator vessels that branch from the superior lateral genicular artery and supply bone, cartilage, subcutaneous tissue, and the iliotibial band of the lateral femoral condyle. RESULTS: In each dissected thigh, the superior lateral genicular artery was present and the average pedicle length was 38 +/- 10 mm. The average diameter of the superior lateral genicular artery, proximal to its distribution into the deep articular and superficial patellar branches, was 2 +/- 0.5 mm. A communication between deep articular and superficial patellar branches was seen in 96 percent of the dissected thighs. In 24 cases (86 percent), the authors were able to show the iliotibial band perforating vessel and harvest a free lateral femoral condyle flap as an osteochondral fasciocutaneous bone flap with vascularized tendon. CONCLUSIONS: Altogether, the authors' results indicate that the blood supply of the lateral femoral condyle flap is consistent and the lateral femoral condyle flap could serve as a free composite flap for complex indications in hand or limb reconstructive surgery. Clinical studies to compare the lateral femoral condyle to other well-established microsurgical free flaps are warranted. PMID- 27219255 TI - Principles and Planning in Nasal and Facial Reconstruction: Making a Normal Face. AB - LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Understand the rationale and value of principles of facial reconstruction in the complex patient. 2. Understand the importance of diagnosis and planning. 3. Appreciate the value of surgical staging. 4. Modify tissues to the requirements of the defect. 5. Know how to treat ischemic cover and lining complications. 6. Learn methods of late revision. SUMMARY: It is easy to be overwhelmed by a complex defect. What to do? How? When? In what order? Success is determined by careful planning, guided by principles. The aesthetic and anatomical deficiencies must be identified. Then, what is absent, both visually and anatomically, and what is missing must be determined. What are the priorities? What is the best timing for each stage? What are the available options and what will be the likely result? Should I choose another option? How can the surgeon maintain vascularity, transfer tissue, and improve tissue quality and contour? What are potential backup salvage maneuvers? Sound surgical principles based on the contributions of Gillies and Millard provide strategic instructions that help the surgeon "make sense" of a complex problem. They provide coordinated rules that clarify the diagnosis, planning, timing, and stages of repair. These should be combined with a regional unit approach to facial repair that provides tactical rules to establish the skin quality, border outline, and three-dimensional shape of the normal face. PMID- 27219256 TI - Face-Lift Satisfaction Using the FACE-Q. PMID- 27219257 TI - Reply: Face-Lift Satisfaction Using the FACE-Q. PMID- 27219258 TI - Clinical Significance of Internal Mammary Lymph Node Biopsy during Microsurgical Breast Reconstruction: Review of 264 Cases. AB - BACKGROUND: Despite the knowledge of alternate lymphatic draining patterns of the breast, routine evaluation of the internal mammary lymph node basin is still not considered standard of care. The advent of microsurgical breast reconstruction using the internal mammary vessels as recipients, however, has allowed sampling of internal mammary lymph nodes with technical ease, thus revisiting their role in breast cancer management. In the present study, the authors reviewed their experience with this practice. METHODS: A retrospective analysis of patients who underwent internal mammary lymph node biopsy at the time of autologous breast reconstruction using the internal mammary vessels between 2004 and 2012 was performed. Parameters of interest included patient age, timing of reconstruction (immediate versus delayed), disease stage, and pathologic findings of internal mammary lymph nodes. RESULTS: A total of 264 autologous breast reconstructions using the internal mammary vessels were performed in 204 patients with a median age of 44.5 years. The majority of reconstructions were immediate [n = 211 (79.9 percent)]. Seventy-two percent of patients had either stage I [72 patients (35.3 percent)] or stage II disease [75 patients (36.8 percent)]. Six patients were found to have internal mammary lymph node metastasis. Stage migration and alteration in adjuvant therapy occurred in all patients. CONCLUSION: Internal mammary lymph node sampling at the time of autologous breast reconstruction using the internal mammary system should become routine practice, as the morbidity associated with internal mammary lymph node harvest is low and the impact in cases of nodal involvement is quite substantial. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27219259 TI - Coagulation Changes following Combined Ablative and Reconstructive Breast Surgery. AB - BACKGROUND: This study assessed hemostatic function in cancer patients at high risk for venous thromboembolism. METHODS: Thirty-eight female patients (age, 53 +/- 9 years) undergoing immediate postmastectomy reconstruction were prospectively studied with informed consent. Blood was sampled preoperatively, on postoperative day 1, and at 1 week follow-up. Rotational thromboelastography clotting time, alpha-angle (clot kinetics), clot formation time, and maximum clot firmness were studied with three different activating agents: intrinsically activated test using ellagic acid, extrinsically activated test with tissue factor, and fibrin-based extrinsically activated test with tissue factor and the platelet inhibitor cytochalasin D. Thromboprophylaxis was unfractionated heparin plus sequential compression devices if not contraindicated. Hypercoagulability was defined by one or more parameters outside the reference range. RESULTS: Preoperatively, 29 percent of patients were hypercoagulable, increasing to 67 percent by week 1 (p = 0.017). Clotting time, clot formation time, and alpha angle remained relatively constant over time, but maximum clot formation increased in intrinsically activated test using ellagic acid, extrinsically activated test with tissue factor, and fibrin-based extrinsically activated test with tissue factor and the platelet inhibitor cytochalasin D (all p < 0.05). Body mass index was 28 +/- 5 kg/m, 23 percent received preoperative chemotherapy, and 15 percent had a history of tobacco use, but there was no association between these risk factors and hypercoagulability. CONCLUSIONS: Despite perioperative thromboprophylaxis, two-thirds of patients undergoing combined tumor resection and reconstructive surgery for breast cancer were hypercoagulable 1 week after surgery. Hypercoagulability was associated with increased clot strength mediated by changes in platelet and fibrin function. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27219260 TI - Implant-Based Breast Reconstruction Using a Polyester Mesh (Surgimesh-PET): A Retrospective Single-Center Study. AB - BACKGROUND: Although the introduction of acellular dermal matrices is considered one of the most important advancements in alloplastic breast reconstruction, costs and local policy limit their use in Italy. The purpose of this study was to assess short-term outcomes following Surgimesh-PET-based breast reconstruction. METHODS: A single-center, retrospective, case-control study was performed from January 1, 2012, to December 31, 2013, by enrolling 206 breast reconstructions performed in 196 patients after oncologic (n = 200) or prophylactic (n = 6) mastectomy. Group A included 63 patients who underwent 70 immediate Surgimesh-PET assisted breast reconstructions, and group B included 133 patients who underwent 136 standard breast reconstructions. RESULTS: No significant differences between groups occurred for early postoperative complications (p = 0.610), major complications that required surgical revision (p = 0.887), volume (p = 0.498) or width of the prosthesis (p = 0.201), skin-sparing mastectomy (p = 0.315), or axillary surgery (p = 0.265). Multivariate logistic regression showed that prior radiotherapy was the only significant variable for early postoperative complications in both whole series (p = 0.011) and group B (p = 0.046), whereas body mass index greater than 25 was an independent predictor in group A (p = 0.041). Prior radiotherapy was the only variable that reached statistical significance in the multivariate model for major complications in the whole series (p = 0.005). CONCLUSIONS: Short-term outcomes of Surgimesh-PET-based alloplastic breast reconstruction are promising. Further studies are needed to evaluate the long-term results of this surgical approach. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 27219262 TI - Discussion: Dynamics of the Subdomal Graft. PMID- 27219261 TI - Dynamics of the Subdomal Graft. AB - BACKGROUND: The authors examined the dynamics of the subdomal graft and its frequency of use in primary and secondary rhinoplasty in detail. METHODS: One hundred consecutive primary and 100 consecutive secondary rhinoplasty patients with at least 1 year of follow-up were reviewed retrospectively. The nose sheet containing a detailed intraoperative recording of all rhinoplasty maneuvers was reviewed to analyze the frequency of subdomal graft use. Intraoperative observations of the effects of the subdomal graft on the nasal tip and the surrounding structures were recorded. Data were tabulated in an Excel file and analyzed. RESULTS: The subdomal graft was used in 77 percent of 100 primary rhinoplasty patients and 31 percent of 100 secondary rhinoplasty patients. After placement of the subdomal graft, the intraoperative changes included (1) improved dome symmetry in all three dimensions, (2) precise control of interdomal distance, (3) lateral and cephalic rotation of the lateral crura of the lower lateral cartilages, (4) widening of the nostrils secondary to lateral rotation of the lower lateral cartilages, (5) external valve function improvement, (6) prevention of lateral crura concavity by preventing overtightening of the transdomal suture, and (7) prevention of excessive narrowing of the domal arch. CONCLUSIONS: The subdomal graft improves domal symmetry, precisely controls the interdomal distance, reorients the domes/lateral crura, widens the nostrils, prevents excessive narrowing of the medial genu angle, and prevents lateral crura concavity from transdomal sutures. The graft should be strongly considered in primary and secondary rhinoplasty patients with (1) pinched tip deformity, (2) excessive narrowing of the interdomal distance, (3) asymmetric domes, (4) caudally positioned lower lateral cartilages, and (5) narrow nostrils with external valve dysfunction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27219263 TI - Digital Imaging in Secondary Rhinoplasty. AB - BACKGROUND: Rhinoplasty remains one of the most commonly performed operations in plastic surgery. Little is known regarding the use of imaging in secondary rhinoplasty. Secondary rhinoplasty is a far more complex operation than primary rhinoplasty. The objective of this study was to assess the role of software imaging in patients undergoing secondary rhinoplasty. METHODS: A retrospective review was performed to identify patients undergoing secondary rhinoplasty performed by the senior author (R.J.R.) from January of 2000 to August of 2013. Forty consecutive patients met inclusion criteria. The degree of improvement was graded in comparison with both the preoperative photographs and software imaging using a graded scale. RESULTS: A total of 40 patients met inclusion criteria. There were 35 women (87.5 percent) and five men (12.5 percent). The nasal dorsum was found to have an average rating of 2.36 between the two observers, the midvault had an average rating of 2.65, the nasal tip had an average rating of 2.27, the nasal alae had an average rating of 2.63, and the nasal base had an average score of 2.99 CONCLUSIONS:: Based on the results of this study, the authors have determined that preoperative digital imaging can provide a reasonable expectation for patients undergoing secondary rhinoplasty. However, digital imaging must be used with caution, as secondary rhinoplasty patients have heightened expectations and unknown anatomy from their previous operation. The nasal tip and dorsum are especially difficult to adequately predict, and this should be discussed with the patient before surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27219264 TI - Prospective Analysis of Primary Breast Augmentation on Body Image Using the BREAST-Q: Results from a Nationwide Study. AB - BACKGROUND: The Breast Implant Follow-up Study is a large, ongoing observational study of women who received Natrelle round silicone-filled or saline-filled breast implants. This analysis describes patient-reported outcomes in the cohort who underwent breast augmentation. METHODS: Subjects prospectively completed two validated scales of the BREAST-Q (satisfaction with breasts and psychosocial well being) preoperatively and at 1 and 4 years postoperatively. Effect size and z tests were used to compare differences between preoperative versus postoperative scores; multivariate mixed models were used to compare differences in scores between silicone-filled and saline-filled implants. RESULTS: Of 17,899 subjects completing the BREAST-Q preoperatively, 14,514 (81.1 percent) completed the postoperative questionnaire (12,726 received silicone-filled implants and 1788 received saline-filled implants). Overall, satisfaction with breasts and psychosocial well-being increased significantly at postoperative year 1 (p < 0.0001 for both), and the improvement was sustained at year 4 (p < 0.0001 for both). Large effect sizes were observed for satisfaction with breasts (2.0 at year 1; 1.8 at year 4) and psychosocial well-being (1.2 at year 1; 1.0 at year 4). In the multivariate model, silicone-filled implants were associated with significantly greater improvement compared with saline-filled implants for satisfaction with breasts and psychosocial well-being at year 1 (p < 0.0001 for both) and year 4 (p < 0.0001 and p < 0.0019, respectively). CONCLUSIONS: Breast implants are effective in improving women's quality of life. The authors found significant and sustained improvements in satisfaction and psychosocial well being in women undergoing breast augmentation with Natrelle silicone-filled or saline-filled implants. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27219265 TI - Global Aesthetics Consensus: Avoidance and Management of Complications from Hyaluronic Acid Fillers-Evidence- and Opinion-Based Review and Consensus Recommendations. AB - BACKGROUND: Although the safety profile of hyaluronic acid fillers is favorable, adverse reactions can occur. Clinicians and patients can benefit from ongoing guidance on adverse reactions to hyaluronic acid fillers and their management. METHODS: A multinational, multidisciplinary group of experts in cosmetic medicine convened the Global Aesthetics Consensus Group to review the properties and clinical uses of Hylacross and Vycross hyaluronic acid products and develop updated consensus recommendations for early and late complications associated with hyaluronic acid fillers. RESULTS: The consensus panel provided specific recommendations focusing on early and late complications of hyaluronic acid fillers and their management. The impact of patient-, product-, and technique related factors on such reactions was described. Most of these were noted to be mild and transient. Serious adverse events are rare. Early adverse reactions to hyaluronic acid fillers include vascular infarction and compromise; inflammatory reactions; injection-related events; and inappropriate placement of filler material. Among late reactions are nodules, granulomas, and skin discoloration. Most adverse events can be avoided with proper planning and technique. Detailed understanding of facial anatomy, proper patient and product selection, and appropriate technique can further reduce the risks. Should adverse reactions occur, the clinician must be prepared and have tools available for effective treatment. CONCLUSIONS: Adverse reactions with hyaluronic acid fillers are uncommon. Clinicians should take steps to further reduce the risk and be prepared to treat any complications that arise. PMID- 27219266 TI - Early versus Delayed Excision and Grafting of Full-Thickness Burns in a Porcine Model: A Randomized Study. AB - BACKGROUND: The standard of care for full-thickness burns is tangential excision followed by skin autografting; however, the timing of excision and grafting is subject to debate. The authors compared early (2 days) versus delayed (14 days) excision and grafting in a porcine full-thickness burn model. METHODS: Full thickness burns (n = 12) were created on the backs of two anesthetized pigs and assigned randomly to no excision, tangential excision followed by skin autografting 2 days after injury, or tangential excision followed by skin autografting 14 days after injury. Digital images and full-thickness biopsy specimens were taken at 16, 21, 28, and 42 days after injury to determine percentage reepithelialization and scar depth. RESULTS: At day 16, all burns that were excised early were completely reepithelialized, whereas only eight of 11 nonexcised burns (72.7 percent) were reepithelialized (p = 0.02). By day 21, all burns were completely reepithelialized. Scar thickness was greatest at 42 days in nonexcised burns (7.5 +/- 2.1 mm); scars were thinner after early excision than after late excision (2.2 +/- 1.8 mm versus 4.0 +/- 1.1 mm; p < 0.001, analysis of variance). Wounds treated with early or late tangential excision followed by skin autografting were flat and minimally contracted, whereas all nonexcised burns were red, contracted, and slightly raised. Scar contraction at 28 and 42 days was greatest in nonexcised control wounds compared with early and late excised wounds. CONCLUSIONS: Both early and late excision followed by autografting reduce scarring in a full-thickness porcine burn model. However, early excision (2 days after injury) reduces scar thickness to a greater extent than later (after 14 days) excision. PMID- 27219267 TI - Medicare Spending and Evidence-Based Approach in Surgical Treatment of Thumb Carpometacarpal Joint Arthritis: 2001 to 2010. AB - BACKGROUND: Despite equivalent outcomes among surgical treatments of thumb carpometacarpal arthritis, little is known about the variation in spending. Because of its complexities, the authors hypothesized that trapeziectomy with ligament reconstruction and tendon interposition incurs the greatest cost to Medicare compared with other surgical procedures. METHODS: Using a random 5 percent sample of Medicare beneficiaries diagnosed with thumb carpometacarpal joint arthritis, the authors examined total and out-of-pocket spending for 3530 patients who underwent a surgical treatment between 2001 and 2010. The authors used generalized linear regression models, controlling for patient characteristics and place of surgery, to examine variations in spending. RESULTS: Eighty-nine percent of patients who underwent surgery received trapeziectomy with ligament reconstruction and tendon interposition, with total and out-of-pocket spending of $2576 (95 percent CI, $2333 to $2843; p < 0.001) and $436 (95 percent CI, $429 to $531; p < 0.001), respectively. Simple complete trapeziectomy was the least expensive procedure, performed in 5 percent of patients, with total and out of-pocket spending of $1268 (95 percent CI, $1089 to $1476; p < 0.001) and $236 (95 percent CI, $180 to $258; p < 0.001), respectively. Because of increasingly higher facility costs, performing the same procedure in a hospital outpatient setting compared with an ambulatory center would increase Medicare spending by more than two-fold (p < 0.001). CONCLUSIONS: With a consistent rise in health care spending, adherence to an evidence-based approach in medicine is more important than ever. Most surgeons continue to perform trapeziectomy with ligament reconstruction and tendon interposition, the most expensive surgical option. Medicare could potentially save $7.4 million annually if simple complete trapeziectomy was the procedure of choice. PMID- 27219268 TI - Not All Clefts Are Created Equal: Patterns of Hospital-Based Care Use among Children with Cleft Lip and Palate within 4 Years of Initial Surgery. AB - BACKGROUND: This study compares hospital-based care and associated charges among children with cleft lip, cleft palate, or both, and identifies subgroups generating the greatest cumulative hospital charges. METHODS: The authors conducted a retrospective cohort study of cleft lip, cleft palate, or cleft lip and palate who underwent initial surgery from 2006 to 2008 in four U.S. states. Primary outcome was hospital-based care-emergency, outpatient, inpatient-within 4 years of surgery. Regression models compared outcomes and classification tree analysis identified patients at risk for being in the highest quartile of cumulative hospital charges. RESULTS: The authors identified 4571 children with cleft lip (18.2 percent), cleft palate (39.2 percent), or cleft lip and palate (42.6 percent). Medical comorbidity was frequent across all groups, with feeding difficulty (cleft lip, 2.4 percent; cleft palate, 13.4 percent; cleft lip and palate, 6.0 percent; p < 0.001) and developmental delay (cleft lip, 1.8 percent; cleft palate, 9.4 percent; cleft lip and palate, 3.6 percent; p < 0.001) being most common. Within 30 days of surgery, those with cleft palate were most likely to return to the hospital (p < 0.001). Hospital-based care per 100 children within 4 years was lowest among the cleft lip group, yet comparable among those with cleft palate and cleft lip and palate (p < 0.001). Cumulative 4-year charges, however, were highest among the cleft palate cohort (cleft lip, $56,966; cleft palate, $106,090; cleft lip and palate, $91,263; p < 0.001). Comorbidity, diagnosis (cleft lip versus cleft palate with or without cleft lip), and age at initial surgery were the most important factors associated with the highest quartile of cumulative hospital charges. CONCLUSIONS: Cleft lip and palate children experience a high rate of hospital-based care early in life, with degree of medical comorbidity being a significant burden. Understanding this relationship and associated needs may help deliver more efficient, patient centered care. PMID- 27219269 TI - Prenatal Features Predictive of Robin Sequence Identified by Fetal Magnetic Resonance Imaging. AB - BACKGROUND: Prenatal magnetic resonance imaging is increasingly used to detect congenital anomalies. The purpose of this study was to determine whether prenatal magnetic resonance imaging accurately characterizes features predictive of postnatal Robin sequence so that possible airway compromise and feeding difficulty at birth can be anticipated. METHODS: The authors retrospectively identified pregnant women who underwent fetal magnetic resonance imaging between 2002 and 2014 and were found to be carrying a fetus with micrognathia. Micrognathia was subjectively categorized as minor, moderate, or severe. Pregnancy outcome was determined as follows: intrauterine fetal demise, elective termination, early neonatal death, or viable infant. Postnatal findings of micrognathia, Robin sequence, and associated anomalies were compared to prenatal findings. RESULTS: Micrognathia was identified in 123 fetuses. Fifty-two pregnancies (42.3 percent) produced a viable infant. The remainder resulted in termination in the fetal period or death shortly after birth resulting from unrelated causes. For infants who lived, prenatal micrognathia was categorized as minor (55.1 percent), moderate (30.6 percent), or severe (14.3 percent). Forty two percent of neonates with minor prenatal micrognathia had postnatal micrognathia; however, only 11.1 percent had Robin sequence. All neonates with moderate fetal micrognathia had postnatal micrognathia, and the majority had Robin sequence (86.7 percent). All newborns with severe micrognathia had Robin sequence and all prenatally diagnosed with glossoptosis had Robin sequence. CONCLUSIONS: Prenatal findings of moderate or severe micrognathia or glossoptosis are predictive of postnatal Robin sequence, thus expediting appropriate perinatal management of airway and feeding problems. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, IV. PMID- 27219270 TI - Professor Wilfried H.O. Ernst (1937-2016). PMID- 27219271 TI - Tigecycline Susceptibility and Molecular Resistance Mechanisms Among Clinical Klebsiella pneumoniae Strains Isolated During Non-Tigecycline Treatment. AB - Tigecycline is one of the few therapeutic options that are available for treating serious clinical infections. However, tigecycline nonsusceptible Enterobacteriaceae has emerged recently in China. In this study, a total of 28 clinical Klebsiella pneumoniae isolates that were not previously exposed to tigecycline were collected and confirmed for tigecycline minimum inhibitory concentrations (MICs) using standard broth microdilution tests. To elucidate the mechanisms underlying molecular resistance to tigecycline, the expression levels of efflux pumps AcrAB and OqxAB and their regulators RamA, MarA, RarA, and SoxS were determined by quantitative polymerase chain reaction. The expression levels of the genes acrB, ramA, marA, and soxS were statistically different in different MIC groups (p < 0.05). Sequence analysis of the acrR and ramR genes revealed several nonsynonymous mutations in the nine resistance isolates. The values of MIC in these isolated strains with ramR mutations were significantly higher than those without ramR mutation (p = 0.029). Moreover, mutations in the ramR gene led to the overexpression of RamA. These results indicated that the mutation of the ramR gene through the upregulated expression of RamA contributed to tigecycline resistance and that several of the newly identified types of mutations in ramR and acrR were not previously reported in K. pneumoniae clinical isolates. PMID- 27219272 TI - Early lymphocyte recovery predicts superior outcomes after unmanipulated haploidentical blood and marrow transplant for acute myeloid leukemia. AB - We investigated whether early lymphocyte recovery, after unmanipulated haploidentical blood and marrow transplant (HBMT), affected clinical outcomes in 134 patients with acute myeloid leukemia (AML). Lymphocyte recovery was based on the absolute lymphocyte count on day 30 (ALC-30). Patients with high ALC-30 (>=294 cells/MUL) had higher overall survival (OS) (77.6% vs 59.7%, P=.020) and higher leukemia-free survival (LFS) (74.6% vs 53.7%, P=.016) than those with low ALC-30 values. Multivariate analysis demonstrated that a high ALC-30 was associated with improved overall survival (HR: 0.443, 95% CI: 0.233-0.841; P=.013) and LFS (HR: 0.499, 95% CI: 0.275-0.906; P=.022). Our results suggest that the ALC-30 can predict a superior outcome after unmanipulated HBMT. PMID- 27219273 TI - Update on orbital lymphatic malformations. AB - PURPOSE OF REVIEW: The purpose of this article is to review the recent published literature in 2015 on lymphatic malformation and provide updated information on the disease. Specifically, this article will describe recent advances in identifying and managing lymphatic malformations. RECENT FINDINGS: All articles discussed in this article emphasize the difficulty in treating lymphatic malformations. Most patients have long complicated histories with multiple recurrences. Studies are trying to identify which lesions will be successful treated by certain therapeutic modality. Treatment includes nonsurgical and surgical therapies. SUMMARY: Lymphatic malformations are difficult lesions to treat because they do not respect tissue planes. The use of sclerosing agents shows great promise for treating macrocysts. More knowledge is needed in the development of the disease process. Hopefully, antilymphangiogenic agent can provide targeted treatment. PMID- 27219274 TI - Clinicians' Views of Hepatitis C Virus Treatment Candidacy With Direct-Acting Antiviral Regimens for People Who Inject Drugs. AB - BACKGROUND: Direct-acting antivirals (DAAs) are curative in most persons with chronic hepatitis C virus (HCV) infection. However, high cost and concerns about adherence and reinfection may present continued barriers to treatment, particularly for people who inject drugs (PWID). OBJECTIVE: To understand changes in assessments of treatment candidacy, given advances in treatment. METHODS: Clinicians attending the Liver Meeting(r) in 2014 who reported prescribing HCV treatment in the past three years were invited to complete a survey regarding HCV treatment decisions. Participants assessed their likelihood to treat HCV in PWID in association with time of abstinence from injection drug use and what impacts their decision to provide treatment using interferon and DAAs. RESULTS: 108 clinicians completed the survey; 10% were willing to treat an active PWID (last injection within 30 days) using interferon-containing regimens, and 15% with all oral regimens. For each increasing time interval of injection abstinence, there was an increase in the odds of a clinician reporting willingness to treat with DAAs (Odds Ratio (OR) 2.57, 95% CI 2.18, 3.03) and with interferon-based treatment (OR 2.22 (95% CI 1.90, 2.61), Reinfection and medication cost were cited as most important concerns when determining candidacy. CONCLUSIONS: A cure is now the norm in HCV treatment, and there is an increasing need to address the barriers to treating PWID, the population with the highest burden of infection. Understanding treatment candidacy assessments is essential to improving uptake. This study provides insight into how clinicians view treatment candidacy in this era of DAAs and can help identify supportive treatment environments and concurrent programs. PMID- 27219275 TI - Corticosteroids Are Essential for Maintaining Cardiovascular Function in Male Mice. AB - Activation of the hypothalamic-pituitary-adrenal axis results in the release of hormones from the adrenal glands, including glucocorticoids and mineralocorticoids. The physiological association between corticosteroids and cardiac disease is becoming increasingly recognized; however, the mechanisms underlying this association are not well understood. To determine the biological effects of corticosteroids on the heart, we investigated the impact of adrenalectomy in C57BL/6 male mice. Animals were adrenalectomized (ADX) at 1 month of age and maintained for 3-6 months after surgery to evaluate the effects of long-term adrenalectomy on cardiac function. Morphological evaluation suggested that ADX mice showed significantly enlarged hearts compared with age matched intact controls. These changes in morphology correlated with deficits in left ventricular (LV) function and electrocardiogram (ECG) abnormalities in ADX mice. Correlating with these functional defects, gene expression analysis of ADX hearts revealed aberrant expression of a large cohort of genes associated with cardiac hypertrophy and arrhythmia. Combined corticosterone and aldosterone replacement treatment prevented the emergence of cardiac abnormalities in ADX mice, whereas corticosterone replacement prevented the effects of adrenalectomy on LV function but did not block the emergence of ECG alterations. Aldosterone replacement did not preserve the LV function but prevented ECG abnormalities. Together, the data indicate that adrenal glucocorticoids and mineralocorticoids either directly or indirectly have selective effects in the heart and their signaling pathways are essential in maintaining normal cardiac function. PMID- 27219276 TI - Glucocorticoid-Induced Attenuation of the Inflammatory Response in Zebrafish. AB - Glucocorticoids are steroid hormones that are secreted upon stress. Their effects are mediated by the glucocorticoid receptor, which acts as a transcription factor. Because the antiinflammatory activity of glucocorticoids has been well established, they are widely used clinically to treat many inflammatory and immune-related diseases. However, the exact specificity, mechanisms, and level of regulation of different inflammatory pathways have not been fully elucidated. In the present study, a tail fin amputation assay was used in 3-day-old zebrafish larvae to study the immunomodulatory effects of the synthetic glucocorticoid beclomethasone. First, a transcriptome analysis was performed, which showed that upon amputation mainly immune-related genes are regulated. This regulation was inhibited by beclomethasone for 86% of regulated genes. For two immune-related genes, tlr4bb and alox5ap, the amputation-induced increase was not attenuated by beclomethasone. Alox5ap is involved in eicosanoid biosynthesis, but the increase in leukotriene B4 concentration upon amputation was abolished, and lipoxin A4 levels were unaffected by beclomethasone. Furthermore, we studied the migration of neutrophils and macrophages toward the wound site. Our results show that amputation induced migration of both types of leukocytes and that this migration was dependent on de novo protein synthesis. Beclomethasone treatment attenuated the migratory behavior of neutrophils in a glucocorticoid receptor-dependent manner but left the migration of macrophages unaffected. In conclusion, beclomethasone has a dramatic inhibitory effect on the amputation-induced proinflammatory gene regulation, and this is reflected in an inhibition of the neutrophil migration but not the migration of macrophages, which are likely to be involved in inflammation resolution. PMID- 27219277 TI - A Mixture Reflecting Polybrominated Diphenyl Ether (PBDE) Profiles Detected in Human Follicular Fluid Significantly Affects Steroidogenesis and Induces Oxidative Stress in a Female Human Granulosa Cell Line. AB - Brominated flame retardants are incorporated into consumer products to prevent flame propagation. These compounds leach into the domestic environment, resulting in chronic exposure. Pregnancy failure is associated with high levels of polybrominated diphenyl ethers (PBDEs), a major class of brominated flame retardants, in human follicular fluid, raising serious questions regarding their impact on female fertility. Our goal was to elucidate the effects of a mixture of PBDEs, similar to the profile found in human follicular fluid, on an immortalized human granulosa cell line, the KGN cell line. We showed that cell viability was altered and oxidative stress was induced as reflected by increased reactive oxygen species formation at 100 MUM of the PBDE mixture. Transcriptomic analysis revealed that PBDE treatments of 1, 5, and 20 MUM altered the expression of several genes involved in the reactive oxygen species signaling pathway. Significant dose-dependent reductions in progesterone and estradiol levels in the culture medium were measured after PBDE treatment; in parallel, the expression of genes involved in estradiol metabolism, namely CYP1A1, was up-regulated by 5 and 20 MUM of the PBDE mixture. Treatment with 20 MUM PBDE also increased the expression and secretion of the proinflammatory factor, IL-6, into the KGN cell culture medium. Our results demonstrate that PBDEs can alter human granulosa cell functions by inducing oxidative stress and disrupting steroidogenesis. These results indicate that PBDEs may be detrimental to ovarian functions and thus may adversely affect female reproductive health after chronic exposure. PMID- 27219278 TI - Emerging Physicochemical Phenomena along with New Opportunities at the Biomolecular-Nanoparticle Interface. AB - Efforts to create new nanoparticle-biomolecule hybrids for diverse applications including biosensing, theranostics, drug delivery, and even biocomputation continue to grow at an unprecedented rate. As the composite designs become more sophisticated, new and unanticipated physicochemical phenomena are emerging at the nanomaterial-biological interface. These phenomena arise from two interrelated factors, namely, the novel architecture of nanoparticle bioconjugates and the unique physicochemical properties of their interfacial environment. Here we examine how the augmented functionality imparted by such hybrid structures, including accessing concentric energy transfer, enhanced enzymatic activity, and sensitivity to electric fields, is leading to new applications. We discuss some lesser-understood phenomena that arise at the nanoparticle interface, such as the complex and confounding issue of protein corona formation, along with their unexpected benefits. Overall, understanding these complex phenomena will improve the design of composite materials while uncovering new opportunities for their application. PMID- 27219279 TI - Is physical exercise a multiple sclerosis disease modifying treatment? AB - INTRODUCTION: There is consensus that exercise represents a behavioral approach for the restoration of function and management of symptoms among persons with multiple sclerosis (MS). The current paper provides a review on the topic of exercise and physical activity as MS-disease modifying treatments. AREAS COVERED: Firstly, metrics for evaluating disease modification and progression in MS are described. Secondly, evidence for exercise as a MS-disease modifying therapy based on individual studies, literature reviews, and meta-analyses is summarized. Finally, the paper focuses on major limitations of the existing body of research. Expert commentary: Exercise and physical activity have been associated with reduced relapse rate, mobility disability and its progression, and lesion volume, and improved neuroperformance, particularly walking outcomes. This evidence provides a positive, yet preliminary, picture for exercise having possible effects on markers of disease modification and progression in MS. PMID- 27219281 TI - The Role of Triplet Exciton Diffusion in Light-Upconverting Polymer Glasses. AB - Light upconversion (UC) via triplet-triplet annihilation (TTA) by using noncoherent photoexcitation at subsolar irradiance power densities is extremely attractive, particularly for enhanced solar energy harvesting. Unfortunately, practical TTA-UC application is hampered by low UC efficiency of upconverting polymer glasses, which is commonly attributed to poor exciton diffusion of the triplet excitons across emitter molecules. The present study addresses this issue by systematically evaluating triplet exciton diffusion coefficients and diffusion lengths (LD) in a UC model system based on platinum-octaethylporphyrin-sensitized poly(methyl methacrylate)/diphenylanthracene (emitter) films as a function of emitter concentration (15-40 wt %). For this evaluation time-resolved photoluminescence bulk-quenching technique followed by Stern-Volmer-type quenching analysis of experimental data was employed. The key finding is that although increasing emitter concentration in the disordered PMMA/DPA/PtOEP films improves triplet exciton diffusion, and thus LD, this does not result in enhanced UC quantum yield. Conversely, improved LD accompanied by the accelerated decay of UC intensity on millisecond time scale degrades TTA-UC performance at high emitter loadings (>25 wt %) and suggests that diffusion-enhanced nonradiative decay of triplet excitons is the major limiting factor. PMID- 27219280 TI - Different pathways explain alcohol-related problems in female and male college students. AB - OBJECTIVES: Comprehensive models elucidating the intricate associations of depressive symptoms, coping motives, alcohol use, alcohol-related problems (ARPs), and gender among young adults have been scarcely examined. This study investigated relationships among these variables and the effect of gender on these pathways. METHODS: College students (N = 163; 49.7% female) completed self report measures on alcohol consumption, depressive symptoms, coping motives, and ARPs. RESULTS: Structural equation modeling showed that the association between depressive symptoms and ARPs was mediated by coping motives in both females and males. However, frequency of heavy alcohol use mediated the association between depressive symptoms and ARPs in females but not in males. CONCLUSIONS: Different models explain the association between depressive symptoms and ARPs in male and female college students. Prevention programs aimed at reducing ARPs should focus on increasing alcohol screening among students with depressive symptoms, teaching coping skills, and emphasizing moderation in alcohol consumption. PMID- 27219282 TI - Incorporation of Porphyrin to pi-Conjugated Backbone for Polymer-Dot-Sensitized Photodynamic Therapy. AB - The photosensitizers used in photodynamic therapy are mainly based on porphyrin derivatives. However, clinical applications encounter several limitations regarding photosensitizers such as their low absorption coefficients, poor water solubility, and leaching from delivery carriers. Here, we describe covalent incorporation of porphyrin in conjugated polymer backbone for development of efficient polymer-dot photosensitizer. Spectroscopic characterizations revealed that the light-harvesting polymer dominantly transfer the excitation energy to the porphyrin unit, yielding efficient singlet oxygen generation for photodynamic therapy. The polymer dots (Pdots) also possess excellent stability that overcomes the photosensitizer leaching problem as encountered in other nanoparticle carriers. In vitro cytotoxicity and photodynamic efficacy of the Pdots were evaluated in MCF-7 cells by in vitro assay, indicating that the Pdots can efficiently damage cancer cells. In vivo photodynamic therapy by using the Pdots was further investigated with xenograft tumors in Balb/c nude mice, which show that the tumors were significantly inhibited or eradicated in certain cases. The high-yield singlet oxygen generation and excellent stability of porphyrin incorporated Pdots are promising for photodynamic treatment of malignant tumors. PMID- 27219283 TI - Phosphine toxicity: a story of disrupted mitochondrial metabolism. AB - Rodenticides and pesticides pose a significant threat not only to the environment but also directly to humans by way of accidental and/or intentional exposure. Metal phosphides, such as aluminum, magnesium, and zinc phosphides, have gained popularity owing to ease of manufacture and application. These agents and their hydrolysis by-product phosphine gas (PH3 ) are more than adequate for eliminating pests, primarily in the grain storage industry. In addition to the potential for accidental exposures in the manufacture and use of these agents, intentional exposures must also be considered. As examples, ingestion of metal phosphides is a well-known suicide route, especially in Asia; and intentional release of PH3 in a populated area cannot be discounted. Metal phosphides cause a wide array of effects that include cellular poisoning, oxidative stress, cholinesterase inhibition, circulatory failure, cardiotoxicity, gastrointestinal and pulmonary toxicity, hepatic damage, neurological toxicity, electrolyte imbalance, and overall metabolic disturbances. Mortality rates often exceed 70%. There are no specific antidotes against metal phosphide poisoning. Current therapeutic intervention is limited to supportive care. The development of beneficial medical countermeasures will rely on investigative mechanistic toxicology; the ultimate goal will be to identify specific treatments and therapeutic windows for intervention. PMID- 27219284 TI - Imaging and identification of brown adipose tissue on CT scan. AB - Two types of adipose tissue (AT) have been described in the field of physiology: white (W) and brown (B) AT. Although WAT is well identified on human imaging, BAT imaging aspect remains to be further explored. The aim of this study was to investigate imaging aspect of BAT and its identification on CT (computed tomography) with iodine-based contrast media injection. We retrospectively reviewed 464 positron emission tomography (PET)/CT, performed during 21 months on adults younger than 37 years. In 39 cases only, the PET revealed the presence of activated BAT. ROI was placed on both white and brown adipose tissue simultaneously on both PET and CT. Several patients' characteristics (blood sugar level, gender, age, body mass index) as well as BAT and WAT parameters were assessed. Mean CT densities for WAT and BAT were -99.5 HU versus -32.6, mean SUV were 1.38 versus 13.2 and SUVmax were 1.79 versus 16.57, respectively. We found a statistically significant inverse relation between BMI and BAT density. BAT has a higher density than WAT. In this manner, BAT can be misinterpreted as an infiltration of adipose tissue in neoplasic and inflammatory context. Contrast enhanced CT scan allows visualization and identification of BAT. PMID- 27219285 TI - A Methodology for Robust Comparative Life Cycle Assessments Incorporating Uncertainty. AB - We propose a methodology for conducting robust comparative life cycle assessments (LCA) by leveraging uncertainty. The method evaluates a broad range of the possible scenario space in a probabilistic fashion while simultaneously considering uncertainty in input data. The method is intended to ascertain which scenarios have a definitive environmentally preferable choice among the alternatives being compared and the significance of the differences given uncertainty in the parameters, which parameters have the most influence on this difference, and how we can identify the resolvable scenarios (where one alternative in the comparison has a clearly lower environmental impact). This is accomplished via an aggregated probabilistic scenario-aware analysis, followed by an assessment of which scenarios have resolvable alternatives. Decision-tree partitioning algorithms are used to isolate meaningful scenario groups. In instances where the alternatives cannot be resolved for scenarios of interest, influential parameters are identified using sensitivity analysis. If those parameters can be refined, the process can be iterated using the refined parameters. We also present definitions of uncertainty quantities that have not been applied in the field of LCA and approaches for characterizing uncertainty in those quantities. We then demonstrate the methodology through a case study of pavements. PMID- 27219286 TI - Identification and assessment of intimate partner violence in nurse home visitation. AB - AIMS AND OBJECTIVES: To develop strategies for the identification and assessment of intimate partner violence in a nurse home visitation programme. BACKGROUND: Nurse home visitation programmes have been identified as an intervention for preventing child abuse and neglect. Recently, there is an increased focus on the role these programmes have in addressing intimate partner violence. Given the unique context of the home environment, strategies for assessments are required that maintain the therapeutic alliance and minimise client attrition. DESIGN: A qualitative case study. METHODS: A total of four Nurse-Family Partnership agencies were engaged in this study. Purposeful samples of nurses (n = 32), pregnant or parenting mothers who had self-disclosed experiences of abuse (n = 26) and supervisors (n = 5) participated in this study. A total of 10 focus groups were completed with nurses: 42 interviews with clients and 10 interviews with supervisors. The principles of conventional content analysis guided data analysis. Data were categorised using the practice-problem-needs analysis model for integrating qualitative findings in the development of nursing interventions. RESULTS: Multiple opportunities to ask about intimate partner violence are valued. The use of structured screening tools at enrolment does not promote disclosure or in-depth exploration of women's experiences of abuse. Women are more likely to discuss experiences of violence when nurses initiate nonstructured discussions focused on parenting, safety or healthy relationships. Nurses require knowledge and skills to initiate indicator-based assessments when exposure to abuse is suspected as well as strategies for responding to client-initiated disclosures. CONCLUSION: A tailored approach to intimate partner violence assessment in home visiting is required. RELEVANCE TO CLINICAL PRACTICE: Multiple opportunities for exploring women's experiences of violence are required. A clinical pathway outlining a three-pronged approach to identification and assessment was developed. PMID- 27219287 TI - Countering immunotoxin immunogenicity. PMID- 27219288 TI - Comment on 'New-onset type 2 diabetes, elevated HbA1c, anti-diabetic medications, and risk of pancreatic cancer'. PMID- 27219290 TI - Investigation of fragrance stability used in the formulation of cosmetic and hygienic products using headspace solid-phase microextraction by nanostructured materials followed by gas chromatography with mass spectrometry. AB - A new composite coating of polypyrrole and sodium lauryl ether sulfate was electrochemically prepared on a stainless-steel wire using cyclic voltammetry. The application and performance of the fiber was evaluated for the headspace solid-phase microextraction of a fragrance in aqueous bleach samples followed by gas chromatography combined with mass spectrometry to assess the fragrance stability in this kind of household cleaning product. To obtain a stable and efficient composite coating, parameters related to the coating process such as scan rate and numbers of cycles were optimized using a central composite design. In addition, the effects of various parameters on the extraction efficiency of the headspace solid-phase microextraction process such as extraction temperature and time, ionic strength, sample volume, and stirring rate were investigated by experimental design methods using Plackett-Burman and Doehlert designs. The optimum values of 53 degrees C and 28 min for sample temperature and time, respectively, were found through response surface methodology. Results show that the combination of polypyrrole and sodium lauryl ether sulfate in a composite form presents desirable opportunities to produce new materials to study fragrance stability by headspace solid-phase microextraction. PMID- 27219289 TI - Reply to 'Comment on 'New-onset type 2 diabetes, elevated HbA1c, anti-diabetic medications, and risk of pancreatic cancer''. PMID- 27219291 TI - 4-MCHM sorption to and desorption from granular activated carbon and raw coal. AB - 4-Methylcyclohexanemethanol (4-MCHM) is a saturated higher alicyclic primary alcohol that is used in the froth flotation process for cleaning coal. In early 2014, a large spill of crude chemical (containing primarily 4-MCHM) to the Elk River near Charleston, WV contaminated the local water supply. Carbon filters at the affected water treatment facility quickly became saturated, and the contaminated water was distributed to nearby homes and businesses. Sorption of 4 MCHM to granular activated carbon (GAC) was studied in the laboratory using head space (HS) analysis via gas chromatography with a flame ionization detector (GC FID). Sorption to raw coal was also investigated, since this material may be of interest as a sorbent in the case of an on-site spill. As expected, sorption to both materials increased with decreased particle size and with increased exposure time; although exposure time proved to be much more important in the case of GAC than for coal. Under similar conditions, GAC sorbed more 4-MCHM than raw coal (e.g., 84.9 vs. 63.1 mg/g, respectively, for 20 * 30 mesh particles exposed to 860 mg/L 4-MCHM solution for 24 h). Desorption from both materials was additionally evaluated. Interestingly, desorption of 4-MCHM on a mass per mass basis was also higher for GAC than for raw coal. Overall, results indicated that GAC readily sorbs 4-MCHM but can also readily release a portion of the chemical, whereas coal sorbs somewhat less 4-MCHM but holds it tightly. PMID- 27219292 TI - Microcystin-LR induced developmental toxicity and apoptosis in zebrafish (Danio rerio) larvae by activation of ER stress response. AB - Recent studies have demonstrated that cyanobacteria-derived Microcystin-LR (MC LR) can cause developmental toxicity and trigger apoptosis in zebrafish (Danio rerio) larvae, but the underlying mechanisms remain largely unknown. In this study, we tested the hypothesis that the mechanism by which MC-LR induces developmental toxicity is through activation of endoplasmic reticulum (ER) stress. MC-LR (4.0 MUM) exposure through submersion caused serious developmental toxicity, such as malformation, growth delay and decreased heart rates in zebrafish larvae, which could be inhibited by ER stress blocker, tauroursodeoxycholic acid (TUDCA, 20 MUM). Meanwhile, acridine orange (AO) staining showed TUDCA could rescue cell apoptosis in heart area in zebrafish larvae resulted by MC-LR exposure. Real-time polymerase chain reaction (real-time PCR) analysis demonstrated that MC-LR induced activation of ER stress which consequently triggered apoptosis in zebrafish larvae. Protein expression examined by western blot indicated that MC-LR could activate MAPK8/Bcl-2/Bax pathway and caspase-dependent apoptotic pathway in zebrafish larva and the effects were mitigated by inhibition of ER stress. Taken together, the results observed in this study suggested that ER stress plays a critical role in developmental toxicity and apoptosis in zebrafish embryos exposed to MC-LR. PMID- 27219293 TI - Bioaccumulation of HCHs and DDTs in organs of Pacific salmon (genus Oncorhynchus) from the Sea of Okhotsk and the Bering Sea. AB - Concentrations of isomers of hexachlorocyclohexane (alpha-, beta-, gamma-HCH) and dichlorodiphenyltrichloroethane (DDT) and its metabolites (dichlorodiphenyldichloroethane (DDD) and dichlorodiphenyldichloroethylene (DDE) were assessed in organs of the pink (Oncorhynchus gorbuscha), chum (Oncorhynchus keta), chinook (Oncorhynchus tshawytscha), and sockeye salmon (Oncorhynchus nerka), caught near the Kuril Islands (the northern-western part of the Pacific Ocean), in the Sea of Okhotsk and the Bering Sea. Pesticides have been found to accumulate in fish organs in the following: muscles < liver < eggs < male gonads. The highest concentrations in muscles and liver have been recorded from sockeye. Of the DDT group, only DDE has been detected. The average concentration of HCHs + DDE in the muscles of pink, chum, chinook, and sockeye was 141, 125, 1241, 1641 ng/g lipids, respectively; and in the liver, 279, 183, 1305, 3805 ng/g lipids, respectively. The total concentration of HCHs isomers was higher than that of DDE. Average HCHs + DDE concentration in organs of salmon from study area is lower than that in salmon from Pacific coast of North America. PMID- 27219294 TI - Study on the influential factors of Cd(2+) on the earthworm Eisenia fetida in oxidative stress based on factor analysis approach. AB - When earthworms are exposed to pollutants, their antioxidant system will have responses immediately. Consequently earthworms are widely used to monitor various pollutants as a sensitive bio-indicator. However, there are a large number of indices associated with the oxidative stress response. Finding out the key monitoring indices in the stress process becomes a practical demand of the pollution monitoring and warning process. Factor analysis approach is a statistical method that uses a few factors to replace many original factors. This paper is aimed at analyzing and sorting factors related to Cd(2+) on the earthworm Eisenia fetida in oxidative stress. We studied two groups, the short term test and the long-term test. The former test lasted for ten days, removing an earthworm every day for analysis; The latter test lasted for 30 days, taking out an earthworm every ten days. The Cd(2+) concentration was set at 0, 50, 100, 125, 250 and 500 mg kg(-1), post-clitellum segments of earthworms were chosen to determine SOD, POD, GPX, GST, CAT, VE, MDA and AChE. The results showed that in the short-term group, the main bioindicator associated with oxidative stress reaction was CAT at the exposure time of 1-3 days, at 4-5 days MDA, 6-7 days POD, and GST and GPX at 8th day, CAT at 9-10 days. While with the long-term test, the main bioindicator associated with oxidative stress reaction was GPX. PMID- 27219295 TI - Differences between first and fourth year medical students' interest in pursuing careers in academic medicine. AB - OBJECTIVE: The purpose of this pilot study was to assess the differences in the attitudes of first and fourth-year medical students regarding careers in academics. We also sought to identify any factors associated with an increased interest in academic medicine. METHODS: A cross-sectional study was conducted during October 2013 at the University of Louisville. All first and fourth year medical students were invited to complete an online survey utilizing a survey instrument developed through literature review. Demographic data and information about background experiences were collected in addition to participants' perceptions regarding careers in academia using a 5-point Likert scale. Participants were also queried about their current interest in a career in academics and the likelihood they would pursue academic medicine. RESULTS: Of the 330 potential participants, 140 (42.4%) agreed to participate. Overall, fourth years reported a higher likelihood of pursuing an academic career than first years. Research experience, publications, distinction track interest or involvement, and belief that a career in academics would reduce salary potential were positively correlated with reported likelihood of pursuing academic medicine. CONCLUSIONS: Findings from this pilot study demonstrate differences in interest in academic medicine between junior and senior medical students. Additionally, several factors were associated with a high likelihood of self reported interest in academic. Based on these findings, efforts to increase medical students' interest in academic medicine careers could be supported by providing more research and teaching opportunities or distinction track options as a structured part of the medical school curriculum. PMID- 27219297 TI - [Expert Opinion Cases - What documentation is necessary from a legal perspective?]. AB - Doctors are obliged by professional code and civil law (630 f German Civil Code [BGB] S) to document their medical activities in relation to patients. The documentation serves as proof of executed measures and thus for backing up medical/therapeutic issues. Documentation shall be made immediately after or during the treatment and if the original content remains recognizable, can be supplemented/modified. The patient record may be kept in paper form or in electronic form. Medical records are to be stored at least for 10 years. Some special laws (eg. laws governing X rays, Transfusion Act) require that documents be stored for longer periods. Documentation errors are - unlike patient information errors/medical malpractice - no basis for damages claims by the patient, but may result in medical malpractice process with the burden of proof in favor of the patient (S 630 h BGB). The patient has, in principle, the right to inspect the medical documents relating to him. PMID- 27219298 TI - A Catalyst-Enabled Diastereodivergent Aza-Diels-Alder Reaction: Complementarity of N-Heterocyclic Carbenes and Chiral Amines. AB - Highly efficient and diastereodivergent aza-Diels-Alder reactions have been developed to access either diastereomeric series of benzofuran-fused delta lactams and dihydropyridines in nearly perfect stereoselectivity (d.r. >20:1, >99 % ee for all examples). The complementarity of N-heterocyclic carbene and chiral amine as the catalyst was demonstrated for the first time, together with an excellent level of catalytic efficiency (1 mol % loading). PMID- 27219296 TI - Respirable indium exposures, plasma indium, and respiratory health among indium tin oxide (ITO) workers. AB - BACKGROUND: Workers manufacturing indium-tin oxide (ITO) are at risk of elevated indium concentration in blood and indium lung disease, but relationships between respirable indium exposures and biomarkers of exposure and disease are unknown. METHODS: For 87 (93%) current ITO workers, we determined correlations between respirable and plasma indium and evaluated associations between exposures and health outcomes. RESULTS: Current respirable indium exposure ranged from 0.4 to 108 MUg/m(3) and cumulative respirable indium exposure from 0.4 to 923 MUg yr/m(3) . Plasma indium better correlated with cumulative (rs = 0.77) than current exposure (rs = 0.54) overall and with tenure >=1.9 years. Higher cumulative respirable indium exposures were associated with more dyspnea, lower spirometric parameters, and higher serum biomarkers of lung disease (KL-6 and SP D), with significant effects starting at 22 MUg-yr/m(3) , reached by 46% of participants. CONCLUSIONS: Plasma indium concentration reflected cumulative respirable indium exposure, which was associated with clinical, functional, and serum biomarkers of lung disease. Am. J. Ind. Med. 59:522-531, 2016. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. PMID- 27219299 TI - Radical Cation and Neutral Radical of Aza-thia[7]helicene with SOMO-HOMO Energy Level Inversion. PMID- 27219300 TI - Quality of life and its influence on clinical competence among nurses: a self reported study. AB - AIM AND OBJECTIVE: This study aimed to investigate the quality of life and its influence on self-reported clinical competence among nurses. BACKGROUND: Over the years, various studies have focused on the competence of nurses in clinical settings, indicating the paramount importance placed on ensuring superior levels of competence among nurses. The nature of the work in this profession is both stressful and challenging, which can pose a threat to the nurses and may impact their quality of life. Low quality of life may affect the quality of services that nurses are duty bound to provide to their patients. METHODS: A convenience sample of 163 staff nurses was surveyed in this descriptive, cross-sectional study using the RAND 36-Item Health Survey 1.0, and the Nurse Competence Scale, with which to gather the data. Multivariate multiple regression and stepwise multiple linear regression analyses were conducted to examine the relationships among variables. RESULTS: A majority of the respondents were married, females, holding a bachelor's degree and with >=7 years of clinical experience. The respondents reported the highest mean score for quality of life in the 'role limitation due to emotional problems' dimension, whereas 'vitality' dimension received the lowest. A very good competence in all the categories measured for clinical competence was also reported. 'Managing situation' received the highest score among the dimensions of clinical competence, whereas 'ensuring quality' received the lowest. Number of years of clinical experience, educational level, marital status, 'role limitation due to emotional problems', 'emotional well being', 'social functioning' and 'physical functioning' were identified as key factors that were likely to influence clinical competence. CONCLUSIONS: Improved quality of life may possibly affect the level of competence of staff nurses. RELEVANCE TO CLINICAL PRACTICE: Ensuring good quality of life among nurses is underscored. Efforts to enhance quality of life of nurses should be initiated to ensure high quality of care. Resultant findings should be taken into account by nurse managers when planning programmes and activities for improvement of competence among nurses. PMID- 27219301 TI - Flexibility for Dance; Lessons for Occupational Rheumatology. PMID- 27219302 TI - Joint Hypermobility and Joint Range of Motion in Young Dancers. AB - BACKGROUND: Joint range of motion (ROM) refers to the extent of movement of the joint, recorded using standard goniometers. Joint hypermobility (JHM) is a condition in which most of the synovial joints move beyond the "normal" limits. Joint hypermobility is recognized as a feature of heritable disorders of the connective tissue and can be identified mostly by the Beighton scale. Data on the possible relationship between JHM and joint ROM are lacking in the literature. The main objective of the present study was to evaluate the relationship between JHM and joint ROM in the different lower-extremity joints in young dancers. METHODS: Joint hypermobility and ROM were assessed among 240 female dancers, aged 8 to 16 years, and 226 nondancers of similar age. RESULTS: The prevalence of JHM is significantly higher among dancers compared with the control subjects (P < 0.001). Joints' ROM is higher among dancers with JHM compared with dancers without JHM (P < 0.05). This phenomenon, however, is age dependent; as in young dancers (aged 8-10 years), this pertains only to the ankle dorsiflexion ROM. In adolescent dancers (aged 11-13 years), this relationship has been observed in most joints: ankle/foot en pointe, ankle dorsiflexion, hip external rotation, hip abduction, and hip extension. In mature dancers (aged 14-16 years), dancers with JHM had greater ROM in ankle/foot en pointe, hip abduction, and knee flexion (P < 0.05). CONCLUSIONS: (1) Joint ROM and JHM are associated one with the other; (2) the relationship between joint ROM and JHM is age dependent; and (3) JHM is common among young nonprofessional dancers compared with control subjects. The main clinical implications of the current study are to try and reduce the risk of injuries among JHM dancers by developing proprioceptive trainings to improve the correct alignment of the hyperextended joints, to increase their muscle strength for better stabilization of the hypermobile joints, and to provide them additional balancing and stabilizing exercises for their supporting muscles. PMID- 27219303 TI - Does a Simplified 6-Joint Ultrasound Index Correlate Well Enough With the 28 Joint Disease Activity Score to Be Used in Clinical Practice? AB - OBJECTIVE: Ultrasound (US) has become an important tool in the management of rheumatoid arthritis (RA) but it is time consuming in clinical practice. We compared 3 US indices (with different numbers of joints) with disease activity measured by the 28-Joint Disease Activity Score (DAS28) in order to find the most parsimonious index still useful in clinical practice. METHODS: Sixty consecutive RA patients were included. The DAS28 score was calculated by the attending rheumatologist, and later in the day, they underwent US examination by another rheumatologist trained in US (bilateral gray-scale and power Doppler examination of the wrist and metacarpophalangeal and proximal interphalangeal joints). Three different US indices were constructed: index A (22 joints), index B (10 joints), and index C (6 joints). RESULTS: All 3 US indices were significantly higher in patients with active disease versus inactive disease (P < 0.05 for all 3). Ultrasound index C showed the best correlation with DAS28 (rho = 0.5020, P < 0.0001) and a very good discriminative value for moderate to high disease activity (DAS28 >3.2) and for absence of remission (DAS28 >2.6) (areas under receiver operating characteristic curve = 0.75 and 0.80, respectively). A cutoff value of 3 in US index C showed sensitivity of 88.89% and specificity of 66.67% for absence of remission. Correlation between the 3 US indices was excellent. CONCLUSIONS: A US index of 6 joints (both wrists and second and third metacarpophalangeal joints bilaterally) correlated well with disease activity measured by DAS28 and may be used to evaluate RA patients in daily practice. PMID- 27219304 TI - Predictors of Dissection in Aortic Aneurysms From Giant Cell Arteritis. AB - BACKGROUND: Factors associated with dissection from inflammatory aortic aneurysms may be different from those in the general population. OBJECTIVE: The aim of this study was to evaluate the risk factors for aortic dissection/rupture in patients with giant cell arteritis (GCA) and aortic aneurysms. METHODS: A population-based incident cohort of patients with a diagnosis of GCA from 1950 to 2004 was used. All patients with aortic aneurysms diagnosed 1 year prior to GCA diagnosis or any time thereafter were included. Cox proportional hazard models were used to evaluate risk factors for aortic dissection/rupture. RESULTS: The study included 33 patients (91% women) with GCA and aortic aneurysms. Mean age at diagnosis of aortic aneurysm was 83.6 years. There were 27 thoracic aneurysms and 19 abdominal aneurysms. Eight patients developed aortic dissection/rupture (both thoracic and abdominal aorta in 5 cases, thoracic aorta only in 2 cases, and isolated abdominal aorta in 1 case).Older age (hazard ratio [HR], 0.27 per 10 years; 95% confidence interval [CI], 0.09-0.86) and later calendar year at diagnosis of aortic aneurysm (HR, 0.29 per 10 years; 95% CI, 0.13-0.69) were associated with decreased risk of dissection/rupture. Size of the thoracic aneurysm (HR, 1.17; 95% CI, 0.69-1.99) was not associated with dissection/rupture. Histopathology showed active aortitis in 4 of 7 patients with aortic dissection/rupture compared with 0 of 7 patients with aortic aneurysm without dissection/rupture. CONCLUSIONS: Aneurysm size was not a predictor of aortic dissection/rupture in this cohort of patients with GCA. The higher frequency of active aortitis in patients with dissection suggests that active inflammation may play a role. PMID- 27219305 TI - Rheumatic Diseases in Chihuahua, Mexico: A COPCORD Survey. AB - BACKGROUND: Rheumatic diseases (RDs) represent a global problem for health care systems and patients. Community Oriented Program for Control of Rheumatic Diseases (COPCORD) is a low-cost screening tool for detecting musculoskeletal (MSK) pain and RDs. OBJECTIVE: The aim of this study was to examine the pattern of MSK pain and RDs in clinic population in Chihuahua City, Mexico. METHODS: A cross-sectional study was conducted in 7 primary health clinics using the COPCORD methodology in subjects older than 18 years. People with MSK pain not induced by trauma (positive cases) were evaluated by primary care physicians and rheumatologists. RESULTS: The study included 1006 individuals with a mean age of 46.0 (SD, 15.8) years; 751 (74.7%) were women. Musculoskeletal pain in the previous 7 days was reported by 571 individuals (56.75%; 95% confidence interval [CI], 53.8%-60.1%), and 356 cases (35.4%; 95% CI, 32.5%-38.4%) were COPCORD positive. The mean pain intensity in visual analog scale was 6.62 (SD, 2.4). The most common painful joint was the knee (54.7%; 95% CI, 51.1%-59.0%). Two hundred eighty subjects with MSK pain (49.0%) previously sought medical attention, and 375 (65.7%) were under treatment. Functional impairment was reported by 69.8% of the COPCORD-positive subjects. The prevalence of RDs was 21.4% (95% CI, 18.9% 23.8%). The most prevalent disease was osteoarthritis (10.3%; 95% CI, 8.6% 12.4%), followed by regional pain syndromes (5.5%; 95% CI, 4.1%-7.0%), rheumatoid arthritis (1.4%; 95% CI, 0.8%-2.2%), and mechanical low-back pain (1.4%; 95% CI, 0.7%-2.2%). CONCLUSIONS: Musculoskeletal pain is an important problem that affects our community. The data provided in this study will be presented to the local authorities to help in the development of prevention strategies. PMID- 27219306 TI - Takayasu Arteritis in Major Rheumatology Centers in Malaysia. AB - OBJECTIVE: There is paucity of data for Takayasu arteritis (TAK) among South Asians. We aimed to evaluate the clinical features, angiographic findings, as well as treatment and outcome of TAK among Malaysian multiethnic groups. METHODS: This is a retrospective review of 40 patients with TAK seen in major rheumatology centres in Malaysia between April 2006 and September 2013. RESULTS: Majority were female patients (92.5%), with a female-to-male ratio of 12:1. Median duration of disease from diagnosis was 66 months (interquartile range, 33-177 months). Fifteen (37.5%) were Malays, 9 (22.5%) each were Indians and indigenous from East Malaysia and 7 (17.5%) were Chinese. Indian and indigenous from East Malaysia were overrepresented in this disease. The mean (SD) age of symptom onset and diagnosis were 25.5 (8.1) and 27.4 (8.4), respectively. The 3 most common clinical presentations at diagnosis were diminished or absent pulse, which occurred in 80% of the patients, followed by blood pressure discrepancy (60%) and arterial bruit (52.5%). There was no difference in clinical presentation among ethnic groups. The subclavian artery was the commonest vessel involved (72.5%), followed by the carotid artery (65%) and renal artery (47.5%). Eight patients had coronary artery involvement, and 2 patients had pulmonary artery involvement. Type I arterial involvement was the commonest (80.0%), followed by type IV (35%), present in isolation or mixed type. Glucocorticoid was the main medical treatment (90.0%). Nineteen patients (47.5%) underwent revascularization procedures. Five patients died during the follow-up period. CONCLUSIONS: The Malaysian TAK cohort had similarities with and differences from other published TAK cohort. A nationwide TAK registry is needed to determine the prevalence of the disease among different ethnic groups. PMID- 27219307 TI - Overview of Auditing for the Busy Rheumatologist. AB - Medical audits have become commonplace in the United States. A variety of companies service government and private payers to document accuracy of medical services provided as reflected in the medical record. When audited, the physician may not understand the nature of the inquiry, jurisdictions, methods, or purpose. This article gives practicing rheumatologists a reference to learn the types of audits and suggests responses that should minimize the impact of the audit to the practice. PMID- 27219308 TI - Queen Alexandra's Knee. AB - In 1867, Alexandra, the 22-year-old Princess of Wales, late in her third pregnancy, had sudden onset of a febrile illness. There was a brief period of migratory arthritis, followed by persistent, severe inflammation in 1 knee. A diagnosis of rheumatic fever was made by her physicians, but the course of her illness differed greatly from the expected one. In this report reviewing her disorder, the suggestion is made that she more likely had gonococcal arthritis and that the infection was transmitted to her by her husband, the future King Edward VII, then known as "The Playboy Prince." PMID- 27219309 TI - Chikungunya Virus Disease: An Emerging Challenge for the Rheumatologist. AB - Chikungunya is caused by an alphavirus that is transmitted to humans via the Aedes species mosquito. Chikungunya is endemic to tropical Africa and South and Southeast Asia, but over the past decade, the geographic distribution of the virus has been expanding rapidly. The disease is characterized by fever and severe polyarthritis, and although symptoms typically resolve within 7 to 10 days, some patients experience persistent arthritis and arthralgias for months to years.In December 2013, the first local transmission of chikungunya virus in the Americas was identified in the Caribbean Island of Saint Martin. Since then, the number of afflicted individuals has spread throughout the Caribbean and Central America, as well as into South America. The United States reported 2788 chikungunya virus disease cases among travelers returning from affected areas in 2014. In addition, 11 locally acquired cases were reported in Florida. Further spread and establishment of the disease in the Americas are likely considering the high levels of viremia in infected individuals, widespread distribution of effective vectors, lack of immunity among people living in the Americas, and the popularity of international travel.Considering the prominent rheumatic manifestations of chikungunya, rheumatologists are likely to encounter patients with the disease in their practice. We recommend that rheumatologists consider chikungunya in their differential diagnosis when evaluating patients presenting with fever and joint pain following travel to a chikungunya endemic area. Early diagnosis would ensure timely management and reduction of polypharmacy and its associated complications. In this article, we briefly describe the epidemiology of chikungunya, the clinical features, laboratory testing, prevention, and treatment of disease. PMID- 27219311 TI - Large Nasopalatine Fistula in a Cocaine User. PMID- 27219310 TI - Hepatic and Mesenteric Vasculitis as Presenting Manifestation of Mixed Cryoglobulinemia Related to Chronic Hepatitis C Virus Infection in a Female Patient. AB - Approximately 80% of patients with hepatitis C virus infection develop chronic liver disease as cirrhosis, and 40% develop autoimmune complications as mixed cryoglobulinemia (MC). Gastrointestinal involvement in MC is rare, and even more so is hepatic involvement. We report a case of an 87-year-old woman with a 10 year history of blood transfusion-acquired hepatitis C virus infection, without treatment. She consulted the emergency department for diffuse abdominal pain, associated with vomiting. After 2 weeks of hospitalization in the intensive care unit, a diagnosis of MC was made; cirrhosis and secondary mesenteric and hepatic vasculitis were confirmed by a diagnostic laparoscopy. Unfortunately the condition of the patient worsened with sepsis and resulted in death in the fourth week from admission. This case highlights the importance of having in mind gastrointestinal tract vasculitis as a medical cause of abdominal pain in patients with chronic hepatitis C virus infection and using data laboratory tests, images, and histopathologic studies to aid with the diagnosis. PMID- 27219312 TI - Tuberculous Sacroiliitis. PMID- 27219313 TI - Striatal Hand Deformity in Parkinson Disease. PMID- 27219314 TI - Nailfold Capillary Patterns in a Patient With Multicentric Reticulohistiocytosis and Raynaud Phenomenon. PMID- 27219315 TI - Fingering Puzzle. PMID- 27219316 TI - Recurrent Kawasaki Disease: Mind the Age, But It Does Not Matter. PMID- 27219318 TI - Vitamin D Status and Quality of Life in Systemic Sclerosis Patients. PMID- 27219317 TI - Granulomatosis With Polyangiitis Presenting as Acute Compartment Syndrome. PMID- 27219319 TI - Effect of an Educational Intervention for Surgeons on Osteoporosis Management at 2-Year Follow-up in Patients With Fragility Fracture. PMID- 27219320 TI - Brain Abscesses Due to Listeria monocytogenes After Rituximab Therapy. PMID- 27219322 TI - Statistical Thermodynamic Model for Surface Tension of Aqueous Organic Acids with Consideration of Partial Dissociation. AB - With statistical mechanics, an isotherm-based surface tension model for single solute aqueous solutions was derived previously (Wexler et al. J. Phys. Chem. Lett. 2013) for the entire concentration range, from infinite dilution to pure liquid solute, as a function of solute activity. In recent work (Boyer et al. J. Phys. Chem. Lett. 2015), empirical model parameters were reduced through physicochemical interpretations of both electrolyte and organic solutes, enabling surface tension predictions for systems where there is little or no data. The prior binary model is extended in the current work for the first time to treat multicomponent systems to predict surface tensions of partially dissociating organic acids (acetic, butyric, citric, formic, glutaric, maleic, malic, malonic, oxalic, propionic, and succinic acids). These organic acids are especially applicable to the study of atmospheric aqueous aerosols, due to their abundance in the atmosphere. In the model developed here, surface tension depends explicitly on activities of both the neutral organic and deprotonated components of the acid. The relative concentrations of the nondissociated and dissociated mole fractions are found using known dissociation constants. Model parameters strongly depend on molecular size, number of functional groups, O:C ratio, and number of carbons. For all organic acids in this study, fully predictive modeling of surface tensions is demonstrated. PMID- 27219323 TI - Carotid stenting versus endarterectomy for the treatment of carotid artery stenosis: Contemporary results from a large single center study. AB - OBJECTIVE: To compare the complication rates associated with carotid endarterectomy (CEA) versus carotid artery stenting (CAS). BACKGROUND: Carotid stenosis is a well-known cause of stroke and increased mortality. The safety of carotid revascularization may be related to symptom status, medical comorbidities, use of embolic protection devices, as well as operator experience and these factors may vary across patient populations within a single operating center. METHODS: We retrospectively analyzed patients with carotid artery stenosis admitted to our hospital for carotid revascularization between January 1, 2007 and December 1, 2013. The primary end point was a composite endpoint of periprocedural death, stroke, and myocardial infarction (MI). RESULTS: Of the 718 patients admitted for carotid revascularization 525 (73.1%) underwent CEA and 193 (26.9%) underwent CAS. Both groups demonstrated similar rates of the composite endpoint, MI, and death; the stenting group demonstrated a higher rate of stroke (4.2% vs. 1.3%; P = 0.020). Adjusting for baseline medical comorbidities and symptom status mitigated this difference (P = 0.091 and 0.113, respectively). When stratified by department performing CAS, there was a significant difference in the occurrence of stroke (P = 0.033), which likewise disappeared in the multivariate regression analysis. CONCLUSION: The risk of the composite endpoint did not differ significantly between those undergoing CAS versus CEA. The stenting group demonstrated a higher rate of periprocedural stroke, which was also apparent when patients were stratified by stenting department. These differences were likely driven by variation in baseline medical comorbidities and symptom status. (c) 2016 Wiley Periodicals, Inc. PMID- 27219321 TI - Meta-Analysis Reveals Significant Association of the 3'-UTR VNTR in SLC6A3 with Alcohol Dependence. AB - BACKGROUND: Although many studies have analyzed the association of 3' untranslated region variable-number tandem repeat (VNTR) polymorphism in SLC6A3 with alcohol dependence (AD), the results remain controversial. This study aimed to determine whether this variant indeed has any genetic effect on AD by integrating 17 reported studies with 5,929 participants included. METHODS: The A9 dominant genetic model that considers A9-repeat and non-A9 repeat as 2 genotypes and compared their frequencies in alcoholics with that in controls was adopted. Considering the potential influence of ethnicity, differences in diagnostic criteria of AD, and alcoholic subgroups, stratified meta-analyses were conducted. There existed no evidence for the presence of heterogeneity among the studied samples, indicating the results under the fixed-effects model are acceptable. RESULTS: We found a significant association of VNTR A9 genotypes with AD in all ethnic populations (pooled odds ratio [OR] 1.12; 95% confidence interval [CI] 1.00, 1.25; p = 0.045) and the Caucasian population (pooled OR 1.15; 95% CI 1.01, 1.31; p = 0.036). We also found VNTR A9 genotypes to be significantly associated with alcoholism as defined by the DSM-IV criteria (pooled OR 1.18; 95% CI 1.03, 1.36; p = 0.02). Further, we found a significant association between VNTR A9 genotypes and alcoholism associated with alcohol withdrawal seizure or delirium tremens (pooled OR 1.55; 95% CI 1.24, 1.92; p = 1.0 * 10(-4) ). In all these meta analyses, no evidence of publication bias was detected. CONCLUSIONS: We concluded that the VNTR polymorphism has an important role in the etiology of AD, and individuals with at least 1 A9 allele are more likely to be dependent on alcohol than persons carrying the non-A9 allele. PMID- 27219324 TI - Recent Progress on Nazarov Cyclizations: The Use of Iron Salts as Catalysts in Ionic Liquid Solvent Systems. AB - Nazarov cyclization is an important and versatile method for the synthesis of five-membered carbocycles, and extensive studies have been conducted to optimize the reaction. Among recent studies, several trends are recognized. One is the combination of different reactions with Nazarov cyclization in a one-pot reaction system which enables the preparation of unique cyclization products. The second is the use of a transition-metal catalyst, though Lewis or Bronsted acids have generally been used for the reaction. The third is the realization of the asymmetric Nazarov cyclization. The fourth is the base-catalyzed Nazarov cyclization. Furthermore, several useful protocols for realizing Nazarov cyclization have also been developed. The recent progress on Nazarov cyclizations is summarized in Section 2. Section 3 is our chronicle in this field. We focused on the use of iron as the catalyst in Nazarov cyclizations and ionic liquids as solvents: Nazarov cyclization of thiophene derivatives using FeCl3 as the catalyst was accomplished and we succeeded in demonstrating the first example of an iron-catalyzed asymmetric Nazarov reaction. We next established Nazarov cyclization of pyrrole or indole derivatives using Fe(ClO4 )3 .Al2 O3 as the catalyst with high trans selectivities in excellent yields. Since the cyclized product was reacted with a vinyl ketone in the presence of the same iron salt, the system allowed realization of the sequential type of Nazarov/Michael reaction of pyrrole derivatives. Furthermore, we demonstrated the recyclable use of the iron catalyst and obtained the desired Nazarov/Michael reaction products in good yields for five repetitions of the reactions without any addition of the catalyst using an ionic liquid, [bmim][NTf2 ], as the solvent. We expect that the iron catalyzed Nazarov cyclization, in particular, in an ionic liquid solvent might become a useful method to synthesize functional molecules that include cycloalkene moieties. PMID- 27219325 TI - Correction: Impact on Patients' Treatment Outcomes of XpertMTB/RIF Implementation for the Diagnosis of Tuberculosis: Follow-Up of a Stepped-Wedge Randomized Clinical Trial. AB - [This corrects the article DOI: 10.1371/journal.pone.0123252.]. PMID- 27219326 TI - Lead poisoning due to Ayurvedic medicine: how about the risk? PMID- 27219327 TI - Intermediate-Range Migration Furnishes a Narrow Margin of Efficiency in the Two Strategy Competition. AB - It is well-known that the effects of spatial selection on the two-strategy competition can be quantified by the structural coefficient sigma under weak selection. We here calculate the accurate value of sigma in group-structured populations of any finite size. In previous similar models, the large population size has been explicitly required for obtaining sigma, and here we analyze quantitatively how large the population should be. Unlike previous models which have only involved the influences of the longest and the shortest migration rang on sigma, we consider all migration ranges together. The new phenomena are that an intermediate range maximizes sigma for medium migration probabilities which are of the tiny minority and the maximum value is slightly larger than those for other ranges. Furthermore, we find the ways that migration or mutation changes sigma can vary significantly through determining analytically how the high frequency steady states (distributions of either strategy over all groups) impact the expression of sigma obtained before. Our findings can be directly used to resolve the dilemma of cooperation and provide a more intuitive understanding of spatial selection. PMID- 27219328 TI - Palmitoylethanolamide Modulates Inflammation-Associated Vascular Endothelial Growth Factor (VEGF) Signaling via the Akt/mTOR Pathway in a Selective Peroxisome Proliferator-Activated Receptor Alpha (PPAR-alpha)-Dependent Manner. AB - BACKGROUND AND AIM: Angiogenesis is emerging as a pivotal process in chronic inflammatory pathologies, promoting immune infiltration and prompting carcinogenesis. Ulcerative Colitis (UC) and Crohn's Disease (CD) represent paradigmatic examples of intestinal chronic inflammatory conditions in which the process of neovascularization correlates with the severity and progression of the diseases. Molecules able to target the angiogenesis have thus the potential to synergistically affect the disease course. Beyond its anti-inflammatory effect, palmitoylethanolamide (PEA) is able to reduce angiogenesis in several chronic inflammatory conditions, but no data about its anti-angiogenic activity in colitis have been produced, yet. METHODS: The effects of PEA on inflammation associated angiogenesis in mice with dextran sulphate sodium (DSS)-induced colitis and in patients with UC were assessed. The release of Vascular Endothelial Growth Factor (VEGF), the hemoglobin tissue content, the expression of CD31 and of phosphatidylinositol 3-kinase/Akt/mammalian-target-of-rapamycin (mTOR) signaling axis were all evaluated in the presence of different concentrations of PEA and concomitant administration of PPAR-alpha and -gamma antagonists. RESULTS: Our results demonstrated that PEA, in a selective peroxisome proliferator activated receptor (PPAR)-alpha dependent mechanism, inhibits colitis-associated angiogenesis, decreasing VEGF release and new vessels formation. Furthermore, we demonstrated that the mTOR/Akt axis regulates, at least partly, the angiogenic process in IBD and that PEA directly affects this pathway. CONCLUSIONS: Our results suggest that PEA may improve inflammation driven angiogenesis in colonic mucosa, thus reducing the mucosal damage and potentially affecting disease progression and the shift towards the carcinogenesis. PMID- 27219329 TI - Can Native T1 Mapping Differentiate between Healthy and Diffuse Diseased Myocardium in Clinical Routine Cardiac MR Imaging? AB - OBJECTIVES: T1 mapping allows quantitative myocardial assessment, but its value in clinical routine remains unclear. We investigated, whether the average native myocardial T1 value can be used as a diagnostic classifier between healthy and diffuse diseased myocardium. METHODS: Native T1 mapping was performed in 54 persons with healthy hearts and in 150 patients with diffuse myocardial pathologies (coronary artery disease (CAD): n = 76, acute myocarditis: n = 19, convalescent myocarditis: n = 26, hypertrophic cardiomyopathy (HCM): n = 12, dilated cardiomyopathy (DCM): n = 17) at 1.5 Tesla in a mid-ventricular short axis slice using a modified Look-Locker inversion recovery (MOLLI) sequence. The average native myocardial T1 value was measured using dedicated software for each patient. The mean as well as the range of the observed average T1 values were calculated for each group, and compared using t-test. The ability of T1 mapping to differentiate between healthy and diffuse diseased myocardium was assessed using receiver operating characteristic analysis (ROC). RESULTS: The mean T1 value of the group "healthy hearts" (955+/-34ms) differed significantly from that of the groups DCM (992+/-37ms, p<0.001), HCM (980+/-44ms, p = 0.035), and acute myocarditis (974+/-36ms, p = 0.044). No significant difference was observed between the groups "healthy hearts" and CAD (951+/-37ms, p = 0.453) or convalescent myocarditis (965+/-40ms, p = 0.240). The average native T1 value varied considerably within all groups (range: healthy hearts, 838-1018ms; DCM, 882-1034ms; HCM, 897-1043ms; acute myocarditis, 925-1025ms; CAD, 867-1082ms; convalescent myocarditis, 890-1071ms) and overlapped broadly between all groups. ROC analysis showed, that the average native T1 value does not allow for differentiating between healthy and diffuse diseased myocardium, except for the subgroup of DCM. CONCLUSIONS: The average native T1 value in cardiac MR imaging does not allow differentiating between healthy and diffusely diseased myocardium in individual cases. PMID- 27219330 TI - Psychometric Examination, Adaptation, and Evaluation of the Hebrew Translation of the MMPI-2-RF VRIN-r and TRIN-r Validity Scales. AB - In this study we examined the utility of the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF; Ben-Porath & Tellegen, 2008/2011; Tellegen & Ben-Porath, 2008/2011) Variable Response Inconsistency-Revised (VRIN r) and True Response Inconsistency-Revised (TRIN-r) scales, including alternative versions of the scales, in the Hebrew translation of the test. First, we examined the applicability of the U.S. VRIN-r and TRIN-r scales in an Israeli Hebrew speaking mixed clinical sample, and replaced original item pairs that did not meet the development criteria with substitution item pairs that did. Then, using the Israeli normative sample and a pure clinical sample, we compared the psychometric functioning of the adapted Hebrew-language VRIN-r and TRIN-r scales with that of the original versions of these scales under various conditions of simulated non-content-based (random and fixed) responding. Overall, results showed that the adapted versions of the scales did not improve on the original ones. We therefore recommend using the U.S. VRIN-r and TRIN-r versions, which could also facilitate cross-cultural comparisons. PMID- 27219331 TI - A Systematic Comparison of Linear Regression-Based Statistical Methods to Assess Exposome-Health Associations. AB - BACKGROUND: The exposome constitutes a promising framework to improve understanding of the effects of environmental exposures on health by explicitly considering multiple testing and avoiding selective reporting. However, exposome studies are challenged by the simultaneous consideration of many correlated exposures. OBJECTIVES: We compared the performances of linear regression-based statistical methods in assessing exposome-health associations. METHODS: In a simulation study, we generated 237 exposure covariates with a realistic correlation structure and with a health outcome linearly related to 0 to 25 of these covariates. Statistical methods were compared primarily in terms of false discovery proportion (FDP) and sensitivity. RESULTS: On average over all simulation settings, the elastic net and sparse partial least-squares regression showed a sensitivity of 76% and an FDP of 44%; Graphical Unit Evolutionary Stochastic Search (GUESS) and the deletion/substitution/addition (DSA) algorithm revealed a sensitivity of 81% and an FDP of 34%. The environment-wide association study (EWAS) underperformed these methods in terms of FDP (average FDP, 86%) despite a higher sensitivity. Performances decreased considerably when assuming an exposome exposure matrix with high levels of correlation between covariates. CONCLUSIONS: Correlation between exposures is a challenge for exposome research, and the statistical methods investigated in this study were limited in their ability to efficiently differentiate true predictors from correlated covariates in a realistic exposome context. Although GUESS and DSA provided a marginally better balance between sensitivity and FDP, they did not outperform the other multivariate methods across all scenarios and properties examined, and computational complexity and flexibility should also be considered when choosing between these methods. Citation: Agier L, Portengen L, Chadeau-Hyam M, Basagana X, Giorgis-Allemand L, Siroux V, Robinson O, Vlaanderen J, Gonzalez JR, Nieuwenhuijsen MJ, Vineis P, Vrijheid M, Slama R, Vermeulen R. 2016. A systematic comparison of linear regression-based statistical methods to assess exposome health associations. Environ Health Perspect 124:1848-1856; http://dx.doi.org/10.1289/EHP172. PMID- 27219332 TI - Flexible and Transparent Surface-Enhanced Raman Scattering (SERS)-Active Metafilm for Visualizing Trace Molecules via Raman Spectral Mapping. AB - Raman spectral mapping is a powerful tool for directly visualizing the composition, structure, and distribution of molecules on any surface of interest. However, one major limitation of Raman mapping is its overlong imaging time caused by the intrinsic weak Raman signal. Here, we developed a fast Raman imaging approach based on a flexible and transparent surface-enhanced Raman scattering (SERS)-active metafilm. This particular SERS substrate can be conformably attached to a sample surface to enhance the Raman signal of analytes and the good optical transparency allow excitation and collection of signal from the backside of the substrate. Therefore, by simply attaching it to the surface of interest, a fast Raman imaging can be realized. We noticed that the imaging speed can be increased by several orders of magnitude, compared to a conventional Raman mapping approach. Importantly, the proposed approach required little or no sample preparation and exhibited good generalizability that can be performed perfectly on different surfaces. It is believed that the proposed methodology will provide new trends for chemical imaging using Raman microscopy. PMID- 27219333 TI - Alphavirus Restriction by IFITM Proteins. AB - Interferon inducible transmembrane proteins (IFITMs) are broad-spectrum antiviral factors. In cell culture the entry of many enveloped viruses, including orthomyxo , flavi-, and filoviruses, is inhibited by IFITMs, though the mechanism(s) involved remain unclear and may vary between viruses. We demonstrate that Sindbis and Semliki Forest virus (SFV), which both use endocytosis and acid-induced membrane fusion in early endosomes to infect cells, are restricted by the early endosomal IFITM3. The late endosomal IFITM2 is less restrictive and the plasma membrane IFITM1 does not inhibit normal infection by either virus. IFITM3 inhibits release of the SFV capsid into the cytosol, without inhibiting binding, internalization, trafficking to endosomes or low pH-induced conformational changes in the envelope glycoprotein. Infection by SFV fusion at the cell surface was inhibited by IFITM1, but was equally inhibited by IFITM3. Furthermore, an IFITM3 mutant (Y20A) that is localized to the plasma membrane inhibited infection by cell surface fusion more potently than IFITM1. Together, these results indicate that IFITMs, in particular IFITM3, can restrict alphavirus infection by inhibiting viral fusion with cellular membranes. That IFITM3 can restrict SFV infection by fusion at the cell surface equivalently to IFITM1 suggests that IFITM3 has greater antiviral potency against SFV. PMID- 27219335 TI - Correction: Validation of qPCR Methods for the Detection of Mycobacterium in New World Animal Reservoirs. AB - [This corrects the article DOI: 10.1371/journal.pntd.0004198.]. PMID- 27219334 TI - Cytokine and Chemokine Expression in Kidneys during Chronic Leptospirosis in Reservoir and Susceptible Animal Models. AB - Leptospirosis is caused by pathogenic spirochetes of the genus Leptospira. Humans can be infected after exposure to contaminated urine of reservoir animals, usually rodents, regarded as typical asymptomatic carriers of leptospires. In contrast, accidental hosts may present an acute form of leptospirosis with a range of clinical symptoms including the development of Acute Kidney Injury (AKI). Chronic Kidney Disease (CKD) is considered as a possible AKI-residual sequela but little is known about the renal pathophysiology consequent to leptospirosis infection. Herein, we studied the renal morphological alterations in relation with the regulation of inflammatory cytokines and chemokines, comparing two experimental models of chronic leptospirosis, the golden Syrian hamster that survived the infection, becoming carrier of virulent leptospires, and the OF1 mouse, a usual reservoir of the bacteria. Animals were monitored until 28 days after injection with a virulent L. borgpetersenii serogroup Ballum to assess chronic infection. Hamsters developed morphological alterations in the kidneys with tubulointerstitial nephritis and fibrosis. Grading of lesions revealed higher scores in hamsters compared to the slight alterations observed in the mouse kidneys, irrespective of the bacterial load. Interestingly, pro fibrotic TGF-beta was downregulated in mouse kidneys. Moreover, cytokines IL 1beta and IL-10, and chemokines MIP-1alpha/CCL3 and IP-10/CXCL-10 were significantly upregulated in hamster kidneys compared to mice. These results suggest a possible maintenance of inflammatory processes in the hamster kidneys with the infiltration of inflammatory cells in response to bacterial carriage, resulting in alterations of renal tissues. In contrast, lower expression levels in mouse kidneys indicated a better regulation of the inflammatory response and possible resolution processes likely related to resistance mechanisms. PMID- 27219336 TI - Parental preparedness for late effects and long-term quality of life in survivors of childhood cancer. AB - BACKGROUND: Parents of children with cancer desire information regarding the late effects of treatment. In the current study, the authors assessed parents' preparedness for late effects at least 5 years after their child's diagnosis. METHODS: A cross-sectional survey was conducted of all eligible parents of children with cancer between April 2004 and September 2005 at Dana-Farber/Boston Children's Cancer and Blood Disorders Center within 1 year of diagnosis, and a follow-up questionnaire was administered at least 5 years later. RESULTS: Approximately 66% of parents of children who were still living, and who were able to be contacted, completed the follow-up questionnaire (91 of 138 parents). Approximately 77% of respondents (70 of 91 respondents) were parents of disease free survivors and 23% (21 of 91 respondents) were parents of children with recurrent disease. The majority of parents believed they were well prepared for their child's oncology treatment (87%), but fewer felt prepared for future limitations experienced by their children (70%; P = .003 using the McNemar test) or for life after cancer (62%; P<.001). On bivariable analysis among parents of disease-free survivors, parents were more likely to believe themselves to be prepared for future limitations when they also reported that communication with the oncologist helped to address worries regarding the future (odds ratio, 4.50; P = .01). At the time of diagnosis, both parents and physicians underestimated a child's risk of future limitations; 45% of parents and 39% of clinicians predicted future limitations in physical abilities, intelligence, or quality of life, but at the time of the follow-up questionnaire >5 years later, 72% of children experienced limitations in at least 1 domain. CONCLUSIONS: Parents believe themselves to be less prepared for survivorship than for treatment. High quality communication may help parents to feel more prepared for life after cancer therapy. Cancer 2016;122:2587-94. (c) 2016 American Cancer Society. PMID- 27219337 TI - Down-Regulation of AKT Signalling by Ursolic Acid Induces Intrinsic Apoptosis and Sensitization to Doxorubicin in Soft Tissue Sarcoma. AB - Several important biological activities have been attributed to the pentacyclic triterpene ursolic acid (UA), being its antitumoral effect extensively studied in human adenocarcinomas. In this work, we focused on the efficacy and molecular mechanisms involved in the antitumoral effects of UA, as single agent or combined with doxorubicin (DXR), in human soft tissue sarcoma cells. UA (5-50 MUM) strongly inhibited (up to 80%) the viability of STS cells at 24 h and its proliferation in soft agar, with higher concentrations increasing apoptotic death up to 30%. UA treatment (6-9 h) strongly blocked the survival AKT/GSK3beta/beta catenin signalling pathway, which led to a concomitant reduction of the anti apoptotic proteins c-Myc and p21, altogether resulting in the activation of intrinsic apoptosis. Interestingly, UA at low concentrations (10-15 MUM) enhanced the antitumoral effects of DXR by up to 2-fold, while in parallel inhibiting DXR induced AKT activation and p21 expression, two proteins implicated in antitumoral drug resistance and cell survival. In conclusion, UA is able to induce intrinsic apoptosis in human STS cells and also to sensitize these cells to DXR by blocking the AKT signalling pathway. Therefore, UA may have beneficial effects, if used as nutraceutical adjuvant during standard chemotherapy treatment of STS. PMID- 27219338 TI - Antigenic characterization of influenza viruses produced using synthetic DNA and novel backbones. AB - The global system for manufacturing seasonal influenza vaccines has been developed to respond to the natural evolution of influenza viruses, but the problem of antigenic mismatch continues to be a challenge in certain years. In some years, mismatches arise naturally due to the antigenic drift of circulating viruses after vaccine strain selection has already been made. In other years, antigenic differences between the vaccine virus and circulating viruses are introduced as part of the current system, which relies on the use of egg-adapted isolates as a starting material for candidate vaccine viruses (CVVs). Improving the current process for making vaccine viruses can provide great value. We have previously established a synthetic approach for rapidly generating influenza viruses in a vaccine-approved Madin Darby canine kidney (MDCK) cell line using novel, high-growth backbones that increase virus rescue efficiency and antigen yield. This technology also has the potential to produce viruses that maintain antigenic similarity to the intended reference viruses, depending on the hemagglutinin (HA) and neuraminidase (NA) sequences used for gene synthesis. To demonstrate this utility, we generated a panel of synthetic viruses using HA and NA sequences from recent isolates and showed by hemagglutination inhibition (HI) tests that all synthetic viruses were antigenically-like their conventional egg- or cell-propagated reference strains and there was no impact of the novel backbones on antigenicity. This synthetic approach can be used for the efficient production of CVVs that may be more representative of circulating viruses and may be used for both egg- and cell-based vaccine manufacturing platforms. When combined with mammalian cell culture technology for antigen production, synthetic viruses generated using HA and NA sequences from a non-egg-adapted prototype can help to reduce the potential impact of antigenic differences between vaccine virus and circulating viruses on vaccine effectiveness. PMID- 27219339 TI - Humoral, T-cell and B-cell immune responses to seasonal influenza vaccine in solid organ transplant recipients receiving anti-T cell therapies. AB - BACKGROUND: We analyzed the impact of the anti-T-cell agents basiliximab and antithymocyte globulins (ATG) on antibody and cell-mediated immune responses after influenza vaccination in solid-organ transplant recipients. METHODS: 71 kidney and heart transplant recipients (basiliximab [n=43] and ATG [n=28]) received the trivalent influenza vaccine. Antibody responses were measured at baseline and 6 weeks post-vaccination by hemagglutination inhibition assay; T cell responses were measured by IFN-gamma ELISpot assays and intracellular cytokine staining (ICS); and influenza-specific memory B-cell (MBC) responses were evaluated using ELISpot. RESULTS: Median time of vaccination from transplantation was 29 months (IQR 8-73). Post-vaccination seroconversion rates were 26.8% for H1N1, 34.1% for H3N2 and 4.9% for influenza B in the basiliximab group and 35.7% for H1N1, 42.9% for H3N2 and 14.3% for influenza B in the ATG group (p=0.44, p=0.61, and p=0.21, respectively). The number of influenza specific IFN-gamma-producing cells increased significantly after vaccination (from 35 to 67.5 SFC/10(6) PBMC, p=0.0007), but no differences between treatment groups were observed (p=0.88). Median number of IgG-MBC did not increase after vaccination (H1N1, p=0.94; H3N2 p=0.34; B, p=0.79), irrespective of the type of anti-T-cell therapy. CONCLUSIONS: After influenza vaccination, a significant increase in antibody and T-cell immune responses but not in MBC responses was observed in transplant recipients. Immune responses were not significantly different between groups that received basiliximab or ATG. PMID- 27219340 TI - A national examination of pharmacy-based immunization statutes and their association with influenza vaccinations and preventive health. AB - BACKGROUND: A series of state-level statute changes have allowed pharmacists to provide influenza vaccinations in community pharmacies. The study aim was to estimate the effects of pharmacy-based immunization statutes changes on per capita influenza vaccine prescriptions, adult vaccination rates, and the utilization of other preventive health services. METHODS: A quasi-experimental study that compares vaccination outcomes over time before and after states allowed pharmacy-based immunization. Measures of per capita pharmacy prescriptions for influenza vaccines in each state came from a proprietary pharmacy prescription database. Data on adult vaccination rates and preventive health utilization were studied using multiple waves of the Behavioral Risk Factor Surveillance System (BRFSS). The primary outcomes were changes in per capita influenza vaccine pharmacy prescriptions, adult vaccination rates, and preventive health interventions following changes. RESULTS: Between 2007 and 2013, the number of influenza vaccinations dispensed in community pharmacies increased from 3.2 to 20.9 million. After one year, adopting pharmacist immunization statutes increased per capita influenza vaccine prescriptions by an absolute difference (AD) of 2.6% (95% CI: 1.1-4.2). Adopting statutes did not lead to a significant absolute increase in adult vaccination rates (AD 0.9%, 95% CI: -0.3, 2.2). There also was no observed difference in adult vaccination rates among adults at high-risk of influenza complications (AD 0.8%, 95% CI: -0.2, 1.8) or among standard demographic subgroups. There also was no observed difference in the receipt of preventive health services, including routine physician office visits (AD -1.9%, 95% CI: -4.9, 1.1). CONCLUSIONS: Pharmacists are providing millions of influenza vaccines as a consequence of immunization statutes, but we do not observe significant differences in adult influenza vaccination rates. The main gains from pharmacy-based immunization may be in providing a more convenient way to obtain an important health service. PMID- 27219341 TI - The impact of implementing a demand forecasting system into a low-income country's supply chain. AB - OBJECTIVE: To evaluate the potential impact and value of applications (e.g. adjusting ordering levels, storage capacity, transportation capacity, distribution frequency) of data from demand forecasting systems implemented in a lower-income country's vaccine supply chain with different levels of population change to urban areas. MATERIALS AND METHODS: Using our software, HERMES, we generated a detailed discrete event simulation model of Niger's entire vaccine supply chain, including every refrigerator, freezer, transport, personnel, vaccine, cost, and location. We represented the introduction of a demand forecasting system to adjust vaccine ordering that could be implemented with increasing delivery frequencies and/or additions of cold chain equipment (storage and/or transportation) across the supply chain during varying degrees of population movement. RESULTS: Implementing demand forecasting system with increased storage and transport frequency increased the number of successfully administered vaccine doses and lowered the logistics cost per dose up to 34%. Implementing demand forecasting system without storage/transport increases actually decreased vaccine availability in certain circumstances. DISCUSSION: The potential maximum gains of a demand forecasting system may only be realized if the system is implemented to both augment the supply chain cold storage and transportation. Implementation may have some impact but, in certain circumstances, may hurt delivery. Therefore, implementation of demand forecasting systems with additional storage and transport may be the better approach. Significant decreases in the logistics cost per dose with more administered vaccines support investment in these forecasting systems. CONCLUSION: Demand forecasting systems have the potential to greatly improve vaccine demand fulfilment, and decrease logistics cost/dose when implemented with storage and transportation increases. Simulation modeling can demonstrate the potential health and economic benefits of supply chain improvements. PMID- 27219342 TI - Interaction and behaviour imaging: a novel method to measure mother-infant interaction using video 3D reconstruction. AB - Studying early interaction is essential for understanding development and psychopathology. Automatic computational methods offer the possibility to analyse social signals and behaviours of several partners simultaneously and dynamically. Here, 20 dyads of mothers and their 13-36-month-old infants were videotaped during mother-infant interaction including 10 extremely high-risk and 10 low-risk dyads using two-dimensional (2D) and three-dimensional (3D) sensors. From 2D+3D data and 3D space reconstruction, we extracted individual parameters (quantity of movement and motion activity ratio for each partner) and dyadic parameters related to the dynamics of partners heads distance (contribution to heads distance), to the focus of mutual engagement (percentage of time spent face to face or oriented to the task) and to the dynamics of motion activity (synchrony ratio, overlap ratio, pause ratio). Features are compared with blind global rating of the interaction using the coding interactive behavior (CIB). We found that individual and dyadic parameters of 2D+3D motion features perfectly correlates with rated CIB maternal and dyadic composite scores. Support Vector Machine classification using all 2D-3D motion features classified 100% of the dyads in their group meaning that motion behaviours are sufficient to distinguish high-risk from low-risk dyads. The proposed method may present a promising, low cost methodology that can uniquely use artificial technology to detect meaningful features of human interactions and may have several implications for studying dyadic behaviours in psychiatry. Combining both global rating scales and computerized methods may enable a continuum of time scale from a summary of entire interactions to second-by-second dynamics. PMID- 27219343 TI - Transcriptome analysis of cortical tissue reveals shared sets of downregulated genes in autism and schizophrenia. AB - Autism (AUT), schizophrenia (SCZ) and bipolar disorder (BPD) are three highly heritable neuropsychiatric conditions. Clinical similarities and genetic overlap between the three disorders have been reported; however, the causes and the downstream effects of this overlap remain elusive. By analyzing transcriptomic RNA-sequencing data generated from post-mortem cortical brain tissues from AUT, SCZ, BPD and control subjects, we have begun to characterize the extent of gene expression overlap between these disorders. We report that the AUT and SCZ transcriptomes are significantly correlated (P<0.001), whereas the other two cross-disorder comparisons (AUT-BPD and SCZ-BPD) are not. Among AUT and SCZ, we find that the genes differentially expressed across disorders are involved in neurotransmission and synapse regulation. Despite the lack of global transcriptomic overlap across all three disorders, we highlight two genes, IQSEC3 and COPS7A, which are significantly downregulated compared with controls across all three disorders, suggesting either shared etiology or compensatory changes across these neuropsychiatric conditions. Finally, we tested for enrichment of genes differentially expressed across disorders in genetic association signals in AUT, SCZ or BPD, reporting lack of signal in any of the previously published genome-wide association study (GWAS). Together, these studies highlight the importance of examining gene expression from the primary tissue involved in neuropsychiatric conditions-the cortical brain. We identify a shared role for altered neurotransmission and synapse regulation in AUT and SCZ, in addition to two genes that may more generally contribute to neurodevelopmental and neuropsychiatric conditions. PMID- 27219344 TI - Developmental suppression of schizophrenia-associated miR-137 alters sensorimotor function in zebrafish. AB - The neurodevelopmentally regulated microRNA miR-137 was strongly implicated as risk locus for schizophrenia in the most recent genome wide association study coordinated by the Psychiatric Genome Consortium (PGC). This molecule is highly conserved in vertebrates enabling the investigation of its function in the developing zebrafish. We utilized this model system to achieve overexpression and suppression of miR-137, both transiently and stably through transgenesis. While miR-137 overexpression was not associated with an observable specific phenotype, downregulation by antisense morpholino and/or transgenic expression of miR-sponge RNA induced significant impairment of both embryonic and larval touch-sensitivity without compromising overall anatomical development. We observed miR-137 expression and activity in sensory neurons including Rohon-Beard neurons and dorsal root ganglia, two neuronal cell types that confer touch-sensitivity in normal zebrafish, suggesting a role of these cell types in the observed phenotype. The lack of obvious anatomical or histological pathology in these cells, however, suggested that subtle axonal network defects or a change in synaptic function and neural connectivity might be responsible for the behavioral phenotype rather than a change in the cellular morphology or neuroanatomy. PMID- 27219345 TI - Aberrant emotion networks in early major depressive disorder patients: an eigenvector centrality mapping study. AB - Major depressive disorder (MDD) is a serious mental disorder that negatively affects the quality of life of many individuals, and is a heavy economic burden to society. In recent years it was thought that depression is a 'disconnection syndrome'. Disorganized brain activity and un-modulated emotion responses were considered the key neuropathologies underlying depression. In the present study, we investigated the alteration of whole brain network connectivity in 28 first episode, drug-naive patients, using resting-state functional magnetic resonance imaging and a new analytical method called voxel-based eigenvector centrality mapping. We found that compared with normal controls, MDD patients had lower functional connectivity in the bilateral middle frontal gyrus, insula, hippocampus, amygdala and cerebellum, and higher functional connectivity in the medial prefrontal cortex. The functional connectivity strength at the right hippocampus (r=-0.413, P=0.032) and the right insula (r=-0.372, P=0.041) negatively correlated with the severity of the disease. We further examined coordination among these regions, and found that frontal-subcortical connection was reduced and insula-medial prefrontal cortex (mPFC) connection was increased. These results are consistent with previous hypotheses on the neural mechanism of MDD, and provide further evidence that emotion networks are already interrupted in early stages of depression. PMID- 27219348 TI - Lack of Association between MYO9B Gene Polymorphisms and Susceptibility to Coeliac Disease in Caucasians: Evidence from a Meta-Analysis. AB - OBJECTIVE: Coeliac disease (CD) is a complex disorder influenced by environmental and genetic factors. Recently, a number of studies reported MYO9B gene is associated with CD, but the results are controversial. The aim of this study is to clarify this dispute by means of a meta-analysis. METHODS: The databases of PubMed, Web of Science, and Embase updated to August 2015 were retrieved. Crude odds ratio (OR) and corresponding 95% confidence interval (95%CI) as effect size were calculated by fixed or random effect model according to the heterogeneity. RESULTS: A total of 8 studies including 2272 cases and 5419 controls were enrolled in this meta-analysis. There was no significant association both in allele and genotype comparisons between the MYO9B (rs2305764, rs2305767, rs1457092) polymorphism and CD in Caucasian populations. No publication bias was detected in this meta-analysis. CONCLUSIONS: This meta-analysis indicates that MYO9B gene polymorphisms might be not associated with CD susceptibility in Caucasians. Further studies are still needed for definitive conclusions. PMID- 27219349 TI - Chemical Dealloying Derived 3D Porous Current Collector for Li Metal Anodes. AB - A 3D porous Cu current collector is fabricated through chemical dealloying from a commerial Cu-Zn alloy tape. The interlinked porous framework naturally integrated can accommodate Li deposition, suppressing dendrite growth and alleviating the huge volume change during cycling. The Li metal anode combined with such a porous Cu collector demonstrates excellent performance and commerial potentials in Li based secondary batteries. PMID- 27219346 TI - Genome-wide gene-based analysis suggests an association between Neuroligin 1 (NLGN1) and post-traumatic stress disorder. AB - Post-traumatic stress disorder (PTSD) develops in only some people following trauma exposure, but the mechanisms differentially explaining risk versus resilience remain largely unknown. PTSD is heritable but candidate gene studies and genome-wide association studies (GWAS) have identified only a modest number of genes that reliably contribute to PTSD. New gene-based methods may help identify additional genes that increase risk for PTSD development or severity. We applied gene-based testing to GWAS data from the Grady Trauma Project (GTP), a primarily African American cohort, and identified two genes (NLGN1 and ZNRD1-AS1) that associate with PTSD after multiple test correction. Although the top SNP from NLGN1 did not replicate, we observed gene-based replication of NLGN1 with PTSD in the Drakenstein Child Health Study (DCHS) cohort from Cape Town. NLGN1 has previously been associated with autism, and it encodes neuroligin 1, a protein involved in synaptogenesis, learning, and memory. Within the GTP dataset, a single nucleotide polymorphism (SNP), rs6779753, underlying the gene-based association, associated with the intermediate phenotypes of higher startle response and greater functional magnetic resonance imaging activation of the amygdala, orbitofrontal cortex, right thalamus and right fusiform gyrus in response to fearful faces. These findings support a contribution of the NLGN1 gene pathway to the neurobiological underpinnings of PTSD. PMID- 27219350 TI - Proton Reduction Using a Hydrogenase-Modified Nanoporous Black Silicon Photoelectrode. AB - Metalloenzymes featuring earth-abundant metal-based cores exhibit rates for catalytic processes such as hydrogen evolution comparable to those of noble metals. Realizing these superb catalytic properties in artificial systems is challenging owing to the difficulty of effectively interfacing metalloenzymes with an electrode surface in a manner that supports efficient charge-transfer. Here, we demonstrate that a nanoporous "black" silicon (b-Si) photocathode provides a unique interface for binding an adsorbed [FeFe]-hydrogenase enzyme ([FeFe]-H2ase). The resulting [FeFe]-H2ase/b-Si photoelectrode displays a 280 mV more positive onset potential for hydrogen generation than bare b-Si without hydrogenase, similar to that observed for a b-Si/Pt photoelectrode at the same light intensity. Additionally, we show that this H2ase/b-Si electrode exhibits a turnover frequency of >=1300 s(-1) and a turnover number above 10(7) and sustains current densities of at least 1 mA/cm(2) based on the actual surface area of the electrode (not the smaller projected geometric area), orders of magnitude greater than that observed for previous enzyme-catalyzed electrodes. While the long-term stability of hydrogenase on the b-Si surface remains too low for practical applications, this work extends the proof-of-concept that biologically derived metalloenzymes can be interfaced with inorganic substrates to support technologically relevant current densities. PMID- 27219351 TI - Effects of heavy metals and chelants on phytoremediation capacity and on rhizobacterial communities of maize. AB - Heavy metals (HMs) are one of the major ecological problem related to human activities. Phytoremediation is a promising "green technology" for soil and water reclamation, and it can be improved by means of the use of chelants. In the past particular attention was paid on the effects of HMs and/or chelants on plant health, but much less on their effects on rhizosphere communities. To shed light on the interaction among plant-HM-chelant-rhizobacterial community a pot experiment was set up. Maize plants were grown on uncontaminated, multi-metal (copper and zinc) contaminated and chelants artificially amended soils. A high concentration of HMs was detected in the different maize organs; chelants improved the accumulation capacity of the maize plants. The rhizosphere bacterial community isolated from control plants showed the largest biodiversity in terms of bacterial genera. However, the addition of HMs reduced the number of taxa to three: Bacillus, Lysinibacillus and Pseudomonas. The effects of HM treatment were counteracted by the addition of chelants in terms of the genetic biodiversity. Furthermore, several bacterial strains particularly resistant to HMs and chelants were isolated and selected. Our study suggests that the combined use of resistant bacteria and chelants could improve the phytoremediation capacity of maize. PMID- 27219352 TI - Morphology Change of C60 Islands on Organic Crystals Observed by Atomic Force Microscopy. AB - Organic-organic heterojunctions are nowadays highly regarded materials for light emitting diodes, field-effect transistors, and photovoltaic cells with the prospect of designing low-cost, flexible, and efficient electronic devices.1-3 However, the key parameter of optimized heterojunctions relies on the choice of the molecular compounds as well as on the morphology of the organic-organic interface,4 which thus requires fundamental studies. In this work, we investigated the deposition of C60 molecules at room temperature on an organic layer compound, the salt bis(benzylammonium)bis(oxalato)cupurate(II), by means of noncontact atomic force microscopy. Three-dimensional molecular islands of C60 having either triangular or hexagonal shapes are formed on the substrate following a "Volmer-Weber" type of growth. We demonstrate the dynamical reshaping of those C60 nanostructures under the local action of the AFM tip at room temperature. The dissipated energy is about 75 meV and can be interpreted as the activation energy required for this migration process. PMID- 27219353 TI - Acquired Localized (Monodactylous) Longitudinal Pachyonychia and Onychocytic Carcinoma In Situ (2 Cases): Part II. AB - The authors have recently proposed to use the name pachyonychia as an umbrella term that includes 2 distinctly different entities in the form of congenital pachyonychia and acquired longitudinal pachyonychia. Congenital pachyonychia is defined by a diffuse hyperkeratosis of the nail bed. Acquired longitudinal pachyonychia correspond to the true definition of pachyonychia, that is, a thickened nail plate without subungual keratosis. Acquired (monodactylous) pachyonychia can be diffuse typifying onychomatricoma or localized as a longitudinal band with three etiological possibilities: onychomatricoma, onychocytic matricoma, and onychocytic carcinoma. On histopathological examination, onychomatricoma is a fibroepithelial tumor; conversely, onychocytic matricoma and carcinoma are purely epithelial tumors. The purpose of this study was to present the clinical, pathological, and immunohistochemical profiles of 2 cases of in situ onychocytic carcinoma, to discuss the role of high-risk human papillomavirus in the pathogenesis of this tumor, and to confirm the interest value of nail clipping microscopy in the surgical planning of the acquired (monodactylous) pachyonychia band pattern. Two men were referred for a longitudinal thickening of the lateral part of the nail plate of their fingers. The bands were yellowish with a faint to dominant black coloration. Nail clippings were obtained before excision in one case; the nail plate was thickened with minute holes in a honeycomb pattern. Nail biopsy specimens revealed an onychocytic carcinoma with epithelial projections inducing active production of the nail plate and multiple minute cavitations into the thick nail plate. Hair related keratins were expressed in all specimens. One tumor expressed p16 in a diffuse pattern, whereas the other showed an unspecific faint patchy staining. p53 was negative. A clinical finding of longitudinal pachyonychia, which by nail clipping microscopy contains small cavities in a honeycomb-like pattern, should be considered an alert to the possibility of a malignant lesions. PMID- 27219347 TI - Alterations in leukocyte transcriptional control pathway activity associated with major depressive disorder and antidepressant treatment. AB - Major depressive disorder (MDD) is associated with a significantly elevated risk of developing serious medical illnesses such as cardiovascular disease, immune impairments, infection, dementia and premature death. Previous work has demonstrated immune dysregulation in subjects with MDD. Using genome-wide transcriptional profiling and promoter-based bioinformatic strategies, we assessed leukocyte transcription factor (TF) activity in leukocytes from 20 unmedicated MDD subjects versus 20 age-, sex- and ethnicity-matched healthy controls, before initiation of antidepressant therapy, and in 17 of the MDD subjects after 8 weeks of sertraline treatment. In leukocytes from unmedicated MDD subjects, bioinformatic analysis of transcription control pathway activity indicated an increased transcriptional activity of cAMP response element binding/activating TF (CREB/ATF) and increased activity of TFs associated with cellular responses to oxidative stress (nuclear factor erythroid-derived 2-like 2, NFE2l2 or NRF2). Eight weeks of antidepressant therapy was associated with significant reductions in Hamilton Depression Rating Scale scores and reduced activity of NRF2, but not in CREB/ATF activity. Several other transcriptional regulation pathways, including the glucocorticoid receptor (GR), nuclear factor kappa-B cells (NF-kappaB), early growth response proteins 1-4 (EGR1-4) and interferon-responsive TFs, showed either no significant differences as a function of disease or treatment, or activities that were opposite to those previously hypothesized to be involved in the etiology of MDD or effective treatment. Our results suggest that CREB/ATF and NRF2 signaling may contribute to MDD by activating immune cell transcriptome dynamics that ultimately influence central nervous system (CNS) motivational and affective processes via circulating mediators. PMID- 27219354 TI - Chinese Medicine in Australia. AB - OBJECTIVES: Chinese medicine is a complex domain of theoretical and practical approaches that is being increasingly put under the research spotlight. The "Chinese Medicine in Australia" research project attempted to capture the clinical features of practitioners of Chinese medicine. PARTICIPANTS AND INTERVENTIONS: The project involved a national survey of Chinese medicine professional association members and registered practitioners in the state of Victoria, Australia (n = 655; response rate, 42%-55%) completed in 2012-2013. DESIGN: The content and face validated survey was developed using new and previous workforce survey questions. RESULTS: This paper reports on the workforce and practice characteristics of the survey respondents. Chinese medicine practitioners are highly educated, come from diverse backgrounds, and have chosen to practice predominantly in sole or multipractitioner private practice settings. An interest in the philosophy of Chinese medicine and previous experiences contributed to practitioners' decisions to study and practice Chinese medicine. Incorporating a variety of techniques, practitioners describe themselves as practicing predominantly Chinese acupuncture and herbal medicine. CONCLUSIONS: The results from this survey contribute to the understanding of the nature and description of Chinese medicine practice in Australia. PMID- 27219355 TI - Correction: Methylation Markers for the Identification of Body Fluids and Tissues from Forensic Trace Evidence. AB - [This corrects the article DOI: 10.1371/journal.pone.0147973.]. PMID- 27219356 TI - Tailored nurse navigation for women treated for breast cancer: Design and rationale for a pilot randomized controlled trial. PMID- 27219453 TI - Complement MASP-1 enhances adhesion between endothelial cells and neutrophils by up-regulating E-selectin expression. AB - The complement system and neutrophil granulocytes are indispensable in the immune response against extracellular pathogens such as bacteria and fungi. Endothelial cells also participate in antimicrobial immunity largely by regulating the homing of leukocytes through their cytokine production and their pattern of cell surface adhesion molecules. We have previously shown that mannan-binding lectin associated serine protease-1 (MASP-1), a complement lectin pathway enzyme, is able to activate endothelial cells by cleaving protease activated receptors, which leads to cytokine production and enables neutrophil chemotaxis. Therefore, we aimed to investigate how recombinant MASP-1 (rMASP-1) can modify the pattern of P-selectin, E-selectin, ICAM-1, ICAM-2, and VCAM-1 adhesion molecules in human umbilical vein endothelial cells (HUVEC), and whether these changes can enhance the adherence between endothelial cells and neutrophil granulocyte model cells (differentiated PLB-985). We found that HUVECs activated by rMASP-1 decreased the expression of ICAM-2 and increased that of E-selectin, whereas ICAM-1, VCAM-1 and P-selectin expression remained unchanged. Furthermore, these changes resulted in increased adherence between differentiated PLB-985 cells and endothelial cells. Our finding suggests that complement MASP-1 can increase adhesion between neutrophils and endothelial cells in a direct fashion. This is in agreement with our previous finding that MASP-1 increases the production of pro-inflammatory cytokines (such as IL-6 and IL-8) and chemotaxis, and may thereby boost neutrophil functions. This newly described cooperation between complement lectin pathway and neutrophils via endothelial cells may be an effective tool to enhance the antimicrobial immune response. PMID- 27219454 TI - The Value of Continuity between Primary Care and Surgical Care in Colon Cancer. AB - BACKGROUND: Improving continuity between primary care and cancer care is critical for improving cancer outcomes and curbing cancer costs. A dimension of continuity, we investigated how regularly patients receive their primary care and surgical care for colon cancer from the same hospital and whether this affects mortality and costs. METHODS: Using Surveillance, Epidemiology, and End Results Program Registry (SEER)-Medicare data, we performed a retrospective cohort study of stage I-III colon cancer patients diagnosed between 2000 and 2009. There were 23,305 stage I-III colon cancer patients who received primary care in the year prior to diagnosis and underwent operative care for colon cancer. Patients were assigned to the hospital where they had their surgery and to their primary care provider's main hospital, and then classified according to whether these two hospitals were same or different. Outcomes examined were hazards for all-cause mortality, subhazard for colon cancer specific mortality, and generalized linear estimate for costs at 12 months, from propensity score matched models. RESULTS: Fifty-two percent of stage I-III colon patients received primary care and surgical care from the same hospital. Primary care and surgical care from the same hospital was not associated with reduced all-cause or colon cancer specific mortality, but was associated with lower inpatient, outpatient, and total costs of care. Total cost difference was $8,836 (95% CI $2,746-$14,577), a 20% reduction in total median cost of care at 12 months. CONCLUSIONS: Receiving primary care and surgical care at the same hospital, compared to different hospitals, was associated with lower costs but still similar survival among stage I-III colon cancer patients. Nonetheless, health care policy which encourages further integration between primary care and cancer care in order to improve outcomes and decrease costs will need to address the significant proportion of patients receiving health care across more than one hospital. PMID- 27219455 TI - Comparison of severe acute respiratory illness (sari) and clinical pneumonia case definitions for the detection of influenza virus infections among hospitalized patients, western Kenya, 2009-2013. AB - Although the severe acute respiratory illness (SARI) case definition is increasingly used for inpatient influenza surveillance, pneumonia is a more familiar term to clinicians and policymakers. We evaluated WHO case definitions for severe acute respiratory illness (SARI) and pneumonia (Integrated Management of Childhood Illnesses (IMCI) for children aged <5 years and Integrated Management of Adolescent and Adult Illnesses (IMAI) for patients aged >=13 years) for detecting laboratory-confirmed influenza among hospitalized ARI patients. Sensitivities were 84% for SARI and 69% for IMCI pneumonia in children aged <5 years and 60% for SARI and 57% for IMAI pneumonia in patients aged >=13 years. Clinical pneumonia case definitions may be a useful complement to SARI for inpatient influenza surveillance. PMID- 27219457 TI - A New Method of Using Polyethylene Glycol (PEG) Precipitation of Macroprolactin to Detect Genuine Hyperprolactinemia. AB - BACKGROUND: The most commonly used method of polyethylene glycol (PEG) precipitation for macroprolactinemia (MP) screening has some significant drawbacks. The aim of this study was to establish a new method using PEG for precipitation of macroprolactin (macroPRL) to detect genuine hyperprolactinemia (genuine HP). METHODS: The optimal PEG concentration for precipitation and the effect of PEG on the precipitation of PRL were analyzed to establish and optimize our PEG precipitation method. The PRL recovery rate and genuine HP detection rate were compared between our method and MP screening method. RESULTS: About 25% PEG6000 was determined to be the optimal PEG concentration for precipitation. Along with an increase in protein concentration in the PRL calibration solution, the PRL recovery rate after precipitation decreased gradually. The PRL recovery rate increased when the precipitation was carried out with diluted PRL calibration solution; the recovery rate reached greater than 90% after a 5-fold dilution of the calibration solution. The genuine HP detection rate and PRL recovery rate using our diluted serum PEG precipitation method were significantly higher than those obtained with the MP screening method. Our method successfully detected 31 cases of genuine HP, which was significantly higher than the detection rate obtained using the MP screening method (25 cases; P < 0.001). CONCLUSION: Precipitation using 5-fold diluted serum with 25% PEG6000 can effectively reduce the macroPRL concentration, increasing the PRL recovery rate and detection rate of genuine HP after precipitation, which is an effective and convenient method for the detection of genuine HP. PMID- 27219456 TI - Prenatal Air Pollution Exposures, DNA Methyl Transferase Genotypes, and Associations with Newborn LINE1 and Alu Methylation and Childhood Blood Pressure and Carotid Intima-Media Thickness in the Children's Health Study. AB - BACKGROUND: Although exposure to ambient air pollutants increases cardiovascular disease risk in adults little is known about the effects of prenatal exposure. Genetic variation and epigenetic alterations are two mechanisms that may influence the effects of early-life exposures on cardiovascular phenotypes. OBJECTIVES: We investigated whether genetic and epigenetic variation modify associations between prenatal air pollution on markers of cardiovascular risk in childhood. METHODS: We used linear regression analysis to investigate the associations between prenatal pollutants (PM2.5, PM10, NO2, O3), long interspersed nuclear elements (LINE1) and AluYb8 DNA methylation levels measured in newborn blood spot tests, and carotid intima-media thickness (CIMT) and blood pressure (BP) in 459 participants as part of the Children's Health Study. Interaction terms were also included to test for effect modification of these associations by genetic variation in methylation reprogramming genes. RESULTS: Prenatal exposure to NO2 in the third trimester of pregnancy was associated with higher systolic BP in 11-year-old children. Prenatal exposure to multiple air pollutants in the first trimester was associated with lower DNA methylation in LINE1, whereas later exposure to O3 was associated with higher LINE1 methylation levels in newborn blood spots. The magnitude of associations with prenatal air pollution varied according to genotype for 11 SNPs within DNA methyltransferase 1 (DNMT1), DNA methyltransferase 3 Beta (DNMT3B), Tet methylcytosine dioxygenase 2 (TET2), and Thymine DNA glycosylase (TDG) genes. Although first-trimester O3 exposure was not associated with CIMT and systolic BP overall, associations within strata of DNMT1 or DNMT3B were observed, and the magnitude and the direction of these associations depended on DNMT1 genotypes. CONCLUSIONS: Genetic and epigenetic variation in DNA methylation reprogramming genes and in LINE1 retrotransposons may play important roles in downstream cardiovascular consequences of prenatal air pollution exposure. Citation: Breton CV, Yao J, Millstein J, Gao L, Siegmund KD, Mack W, Whitfield-Maxwell L, Lurmann F, Hodis H, Avol E, Gilliland FD. 2016. Prenatal air pollution exposures, DNA methyl transferase genotypes, and associations with newborn LINE1 and Alu methylation and childhood blood pressure and carotid intima-media thickness in the Children's Health Study. Environ Health Perspect 124:1905-1912; http://dx.doi.org/10.1289/EHP181. PMID- 27219458 TI - Changing Epidemiology of Common Cancers in Southern Iran, 2007-2010: A Cross Sectional Study. AB - We have evaluated the ever changing epidemiology of cancers in Fars province, Iran since the re-establishment of Fars cancer registry. Based on the collected data from all related sources in Fars province from 2007-2010 we calculated the cancer age-standardized rates per 100,000 person-years (ASRs). The results are presented as incidence rates of cases by site according to the International Classification of Diseases for Oncology (ICD-O), sex, age, crude rate, and ASRs. In women the total ASR was 41.70 per 100,000 from 1985-1989 which had increased to 55.50 and 95.46 during 1998-2002 and 2007-2010. The incidence of breast cancer in women during 2007-2010 was about two and four times higher than 1998-2002 and 1985-1989. The incidence of colorectal cancer in women during 2007-2010 was about three and five times higher than 1998-2002 and 1985-1989. In men the total ASR was 62.9 per 100,000 in 1985-1989 that increased to 64.50 and 101.48 during 1998 2002 and 2007-2010. Although stomach cancer was the most common cancer among men during 1985-1989 and 1998-2002, but in recent study bladder cancer was the most common cancer among men in Fars province. The incidence of colorectal cancer in men during 2007-2010 was about three times higher than 1998-2002 and 1985-1989. This study shows growing incidence of cancer in southern Iran. The colorectal cancer in both genders had increased and its pattern is similar to western countries. In men, bladder and prostate cancers had a growing rate and the incidences of these cancers in the present study were greater than stomach cancer. PMID- 27219459 TI - Changes in the rotational axes of the tibiofemoral joint caused by resection of the anterior cruciate ligament. AB - Kinematic alignment is a method of aligning implants in total knee arthroplasty (TKA) that strives to restore the native flexion-extension (F-E) and longitudinal rotation (LR) axes of the tibiofemoral joint. The anterior cruciate ligament (ACL) is typically resected at the time of TKA, which might change the position, and orientation of these axes from that of the native knee. Our objective was to determine whether resecting the ACL causes changes in the F-E and LR axes. A custom designed and validated instrumented spatial linkage (ISL) measured the F-E and LR axes in nine cadaveric knees before and after ACL resection. Changes in these axes were computed for knee flexion from 0 degrees to 120 degrees . For the F-E axis, the two statistically significant yet relatively small changes were internal rotation of 0.5 degrees (p = 0.02) and posterior translation of 0.3 mm (p = 0.04). For the LR axis, the statistically significant and relatively large change was medial translation of 2.1 mm (p = 0.01). Changes to the LR axis in both medial-lateral position and varus-valgus orientation varied widely; 77% of a population of knees would have a medial-lateral position change greater than 1 mm, and 53% of a population of knees would have a varus-valgus orientation change greater than 1 degrees . Knowledge of changes of the F-E and LR axes caused by resecting the ACL provides an important baseline for determining the changes in these axes caused by kinematic alignment and mechanical alignment of bi-cruciate retaining, posterior cruciate retaining, and posterior cruciate substituting implants. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:886-893, 2017. PMID- 27219460 TI - Identifying Lesbian, Gay, Bisexual, and Transgender Search Terminology: A Systematic Review of Health Systematic Reviews. AB - Research on the health of lesbian, gay, bisexual, and transgender (LGBT) populations can provide important information to address existing health inequalities. Finding existing research in LGBT health can prove challenging due to the plethora of terminology used. We sought to describe existing search strategies and to identify more comprehensive LGBT search terminology. We iteratively created a search string to identify systematic reviews and meta analyses about LGBT health and implemented it in Embase, PubMed/MEDLINE, and PsycINFO databases on May 28-29, 2015. We hand-searched the journal LGBT Health. Inclusion criteria were: systematic reviews and meta-analyses that addressed LGBT health, used systematic searching, and used independent coders for inclusion. The published search terminology in each record and search strings provided by authors on request were cross-referenced with our original search to identify additional terminology. Our search process identified 19 systematic reviews meeting inclusion criteria. The number of search terms used to identify LGBT related records ranged from 1 to 31. From the included studies, we identified 46 new search terms related to LGBT health. We removed five search terms as inappropriate and added five search terms used in the field. The resulting search string included 82 terms. There is room to improve the quality of searching and reporting in LGBT health systematic reviews. Future work should attempt to enhance the positive predictive value of LGBT health searches. Our findings can assist LGBT health reviewers in capturing the diversity of LGBT terminology when searching. PMID- 27219462 TI - Location and release time identification of pollution point source in river networks based on the Backward Probability Method. AB - The pollution of rivers due to accidental spills is a major threat to environment and human health. To protect river systems from accidental spills, it is essential to introduce a reliable tool for identification process. Backward Probability Method (BPM) is one of the most recommended tools that is able to introduce information related to the prior location and the release time of the pollution. This method was originally developed and employed in groundwater pollution source identification problems. One of the objectives of this study is to apply this method in identifying the pollution source location and release time in surface waters, mainly in rivers. To accomplish this task, a numerical model is developed based on the adjoint analysis. Then the developed model is verified using analytical solution and some real data. The second objective of this study is to extend the method to pollution source identification in river networks. In this regard, a hypothetical test case is considered. In the later simulations, all of the suspected points are identified, using only one backward simulation. The results demonstrated that all suspected points, determined by the BPM could be a possible pollution source. The proposed approach is accurate and computationally efficient and does not need any simplification in river geometry and flow. Due to this simplicity, it is highly recommended for practical purposes. PMID- 27219463 TI - Complex Thermodynamic Behavior of Single-Stranded Nucleic Acid Adsorption to Graphene Surfaces. AB - In just over a decade since its discovery, research on graphene has exploded due to a number of potential applications in electronics, materials, and medicine. In its water-soluble form of graphene oxide, the material has shown promise as a biosensor due to its preferential absorption of single-stranded polynucleotides and fluorescence quenching properties. The rational design of these biosensors, however, requires an improved understanding of the binding thermodynamics and ultimately a predictive model of sequence-specific binding. Toward these goals, here we directly measured the binding of nucleosides and oligonucleotides to graphene oxide nanoparticles using isothermal titration calorimetry and used the results to develop molecular models of graphene-nucleic acid interactions. We found individual nucleosides binding KD values lie in the submillimolar range with binding order of rG < rA < rC < dT < rU, while 5mer and 15mer oligonucleotides had markedly higher binding affinities in the range of micromolar and submicromolar KD values, respectively. The molecular models developed here are calibrated to quantitatively reproduce the above-mentioned experimental results. For oligonucleotides, our model predicts complex binding features such as double-stacked bases and a decrease in the fraction of graphene stacked bases with increasing oligonucleotide length until plateauing beyond ~10 15 nucleotides. These experimental and computational results set the platform for informed design of graphene-based biosensors, further increasing their potential and application. PMID- 27219461 TI - Lymphatic pumping: mechanics, mechanisms and malfunction. AB - A combination of extrinsic (passive) and intrinsic (active) forces move lymph against a hydrostatic pressure gradient in most regions of the body. The effectiveness of the lymph pump system impacts not only interstitial fluid balance but other aspects of overall homeostasis. This review focuses on the mechanisms that regulate the intrinsic, active contractions of collecting lymphatic vessels in relation to their ability to actively transport lymph. Lymph propulsion requires not only robust contractions of lymphatic muscle cells, but contraction waves that are synchronized over the length of a lymphangion as well as properly functioning intraluminal valves. Normal lymphatic pump function is determined by the intrinsic properties of lymphatic muscle and the regulation of pumping by lymphatic preload, afterload, spontaneous contraction rate, contractility and neural influences. Lymphatic contractile dysfunction, barrier dysfunction and valve defects are common themes among pathologies that directly involve the lymphatic system, such as inherited and acquired forms of lymphoedema, and pathologies that indirectly involve the lymphatic system, such as inflammation, obesity and metabolic syndrome, and inflammatory bowel disease. PMID- 27219465 TI - Oral contraceptives versus physical exercise on cardiovascular and metabolic risk factors in women with polycystic ovary syndrome: a randomized controlled trial. AB - BACKGROUND: Although oral contraceptives (OCs) are one the most widespread therapy in young polycystic ovary syndrome (PCOS) women and physical exercise represents a crucial first step in the treatment of overweight and obese PCOS, no studies were performed to compare the effects on cardiovascular risk (CVR) of OCs and physical exercise in PCOS. OBJECTIVE: To compare the effects of OCs administration and physical exercise on the CVR, clinical, hormonal and metabolic parameters in PCOS women. METHODS: One hundred and fifty PCOS women were enrolled and were randomized to OCs (3 mg drospirenone plus 30 MUg ethinyloestradiol), structured exercise training programme (SETP) or polyvitamin tablets. The intervention phase study was of 6 months. Primary outcome was intima-media thickness (IMT) and flow-mediated dilation (FMD). Secondary outcomes were clinical, hormonal and metabolic changes. RESULTS: A significant reduction of IMT and a significant increase of FMD were observed in the SETP group after treatment. Compared to baseline, in the SETP group, a significant improvement in anthropometric measures, insulin sensitivity indexes, lipid profile, cardiopulmonary function, inflammatory markers and frequency of menses was observed. Oral contraceptives use was associated with a significant decrease of hyperandrogenism and a significant improvement of frequency of menses. Further, OCs use had a neutral effect on CVR risk factors. CONCLUSION: OCs effectively treat hyperandrogenism and menstrual disturbances, while SETP is more effective in improving cardiometabolic profile and cardiopulmonary function in PCOS. PMID- 27219464 TI - A practical guide to the oral microbiome and its relation to health and disease. AB - The oral microbiome is incredibly complex with the average adult harboring about 50-100 billion bacteria in the oral cavity, which represent about 200 predominant bacterial species. Collectively, there are approximately 700 predominant taxa of which less than one-third still have not yet been grown in vitro. Compared to other body sites, the oral microbiome is unique and readily accessible. There is extensive literature available describing the oral microbiome and discussing the roles that bacteria may play in oral health and disease. However, the purpose of this review is not to rehash these detailed studies but rather to educate the reader with understanding the essence of the oral microbiome, namely that there are abundant bacteria in numbers and types, that there are molecular methods to rapidly determine bacterial associations, that there is site specificity for colonization of the host, that there are specific associations with oral health and disease, that oral bacteria may serve as biomarkers for non-oral diseases, and that oral microbial profiles may have potential use to assess disease risk. PMID- 27219466 TI - How Does National Scientific Funding Support Emerging Interdisciplinary Research: A Comparison Study of Big Data Research in the US and China. AB - How do funding agencies ramp-up their capabilities to support research in a rapidly emerging area? This paper addresses this question through a comparison of research proposals awarded by the US National Science Foundation (NSF) and the National Natural Science Foundation of China (NSFC) in the field of Big Data. Big data is characterized by its size and difficulties in capturing, curating, managing and processing it in reasonable periods of time. Although Big Data has its legacy in longstanding information technology research, the field grew very rapidly over a short period. We find that the extent of interdisciplinarity is a key aspect in how these funding agencies address the rise of Big Data. Our results show that both agencies have been able to marshal funding to support Big Data research in multiple areas, but the NSF relies to a greater extent on multi program funding from different fields. We discuss how these interdisciplinary approaches reflect the research hot-spots and innovation pathways in these two countries. PMID- 27219468 TI - An asymmetric approach to bicyclo[2.2.1]heptane-1-carboxylates via a formal [4 + 2] cycloaddition reaction enabled by organocatalysis. AB - An organocatalytic formal [4 + 2] cycloaddition reaction has been realized that permits rapid access to a wide range of bicyclo[2.2.1]heptane-1-carboxylates in a highly enantioselective manner from simple starting materials under mild and operationally simple conditions. PMID- 27219467 TI - Antibody and Cytokine Responses of Koalas (Phascolarctos cinereus) Vaccinated with Recombinant Chlamydial Major Outer Membrane Protein (MOMP) with Two Different Adjuvants. AB - Developing a vaccine against Chlamydia is key to combating widespread mortalities and morbidities associated with this infection in koalas (Phascolarctos cinereus). In previous studies, we have shown that two or three doses of a Recombinant Major Outer Membrane Protein (rMOMP) antigen-based vaccine, combined with immune stimulating complex (ISC) adjuvant, results in strong cellular and humoral immune responses in koalas. We have also separately evaluated a single dose vaccine, utilising a tri-adjuvant formula that comprises polyphosphazine based poly I: C and host defense peptides, with the same antigen. This formulation also produced strong cellular and humoral immune responses in captive koalas. In this current study, we directly compared the host immune responses of two sub-groups of wild Chlamydia negative koalas in one population vaccinated with the rMOMP protein antigen and adjuvanted with either the ISC or tri-adjuvant formula. Overall, both adjuvants produced strong Chlamydia-specific cellular (IFN gamma and IL-17A) responses in circulating PBMCs as well as MOMP-specific and functional, in vitro neutralising antibodies. While the immune responses were similar, there were adjuvant-specific immune differences between the two adjuvants, particularly in relation to the specificity of the MOMP epitope antibody responses. PMID- 27219469 TI - Noninvasive Follicular Variant of Papillary Thyroid Carcinoma and the Afirma Gene Expression Classifier. AB - BACKGROUND: It is now recognized that noninvasive follicular variant of papillary thyroid carcinoma (NFVPTC) is a distinct subset of FVPTC with an exceedingly indolent clinical course. The Afirma gene-expression classifier (GEC) helps guide clinicians in the management of thyroid nodules with indeterminate fine-needle aspiration (FNA) results. Thyroid surgery is recommended for nodules with a suspicious Afirma result, whereas observation is deemed reasonable for most nodules with a benign result. The aim of this study was to confirm that the Afirma test detects NFVPTCs and to determine how many carcinomas detected by the Afirma GEC represent NFVPTCs. METHODS: From a database of 249 FNAs sent for Afirma testing between January 2012 and October 2014, a search was conducted for cases with a preceding FNA diagnosis of atypia/follicular lesion of undetermined significance (AUS/FLUS) or suspicious for a follicular neoplasm (SFN), a suspicious Afirma result, and a corresponding resection specimen reviewed at Brigham and Women's Hospital. The diagnoses of the prior FNAs and subsequent resection specimens were recorded. Slides for all resection specimens with a diagnosis of FVPTC were reviewed to identify NFVPTCs. RESULTS: Sixty-three cases met the inclusion criteria. The preceding FNA diagnosis was AUS/FLUS in 34 (54%) cases and SFN in 29 (46%) cases. The surgical resection specimen demonstrated 16 (25%) FVPTCs, five (8%) follicular thyroid carcinomas, one (2%) classical type PTC, and 41 (65%) benign tumors/nodules. Of the 16 FVPTCs, 14 (88%) were NFVPTCs. Thus, NFVPTCs accounted for 64% of the carcinomas in the cohort. CONCLUSION: These results indicate that the Afirma GEC detects NFVPTCs and that many of the carcinomas detected by Afirma are NFVPTCs. While all care should be individualized and include clinical and sonographic assessment, these results suggest lobectomy as opposed to total thyroidectomy should be considered for nodules with a preceding AUS/FLUS or SFN on cytology and a suspicious Afirma result. PMID- 27219470 TI - Inhibition in the Human Auditory Cortex. AB - Despite their indispensable roles in sensory processing, little is known about inhibitory interneurons in humans. Inhibitory postsynaptic potentials cannot be recorded non-invasively, at least in a pure form, in humans. We herein sought to clarify whether prepulse inhibition (PPI) in the auditory cortex reflected inhibition via interneurons using magnetoencephalography. An abrupt increase in sound pressure by 10 dB in a continuous sound was used to evoke the test response, and PPI was observed by inserting a weak (5 dB increase for 1 ms) prepulse. The time course of the inhibition evaluated by prepulses presented at 10-800 ms before the test stimulus showed at least two temporally distinct inhibitions peaking at approximately 20-60 and 600 ms that presumably reflected IPSPs by fast spiking, parvalbumin-positive cells and somatostatin-positive, Martinotti cells, respectively. In another experiment, we confirmed that the degree of the inhibition depended on the strength of the prepulse, but not on the amplitude of the prepulse-evoked cortical response, indicating that the prepulse evoked excitatory response and prepulse-evoked inhibition reflected activation in two different pathways. Although many diseases such as schizophrenia may involve deficits in the inhibitory system, we do not have appropriate methods to evaluate them; therefore, the easy and non-invasive method described herein may be clinically useful. PMID- 27219472 TI - Predictive value of E/A and E/E' Doppler indexes for cardiac events in heart transplant recipients. AB - BACKGROUND: Doppler-derived indexes associated with high left ventricular filling pressures are risk factors for cardiac events in various populations. The aim of this study was to evaluate the predictive value of two of these Doppler indexes during the long-term follow-up of heart transplantation. METHODS AND RESULTS: In this cohort study, we measured E/A ratio combining early filling velocity (E) with late filling velocity (A) and E/E' ratio combining E wave with relaxation velocity on tissue doppler (E') in 122 transplant heart recipients, 6.9+/-5.9 years after transplantation. The patients were followed for 97+/-32 months after Doppler measurements. We found an E/A>2 in 68 patients and an E/E'>15 in 23 patients. Forty patients had a cardiac event (cardiac death, retransplantation, acute coronary events, hospitalization for heart failure, treated acute rejection episodes, and coronary revascularization procedures) during the follow-up. In multivariate analysis, E/A and E/E' were significantly associated with cardiac events (hazard ratio 2.2, 95% CI: 1.1-4.4; P=.02 and hazard ratio 2.3, 95% CI: 1.1-4.8; P=.02, respectively). E/E', E/A, and significant coronary stenoses were the strongest predictors of cardiac events. CONCLUSIONS: E/A and E/E' Doppler indexes may be used to predict cardiac events during the long-term follow-up of heart transplant recipients. PMID- 27219471 TI - Value of percent change in tumoral volume measured at T2 -weighted and diffusion weighted MRI to identify responders after neoadjuvant chemoradiation therapy in patients with locally advanced rectal carcinoma. AB - PURPOSE: To evaluate the percent change in tumoral volume measured at T2 weighted magnetic resonance imaging (T2 WMRI) and diffusion-weighted (DWI) as a method to identify responders after chemo- and radiation therapy (CRT) in patients with locally advanced rectal carcinoma. MATERIALS AND METHODS: Forty five consecutive patients (mean age +/- SD: 72 years +/- 9.7; male/female = 24/21) with locally advanced rectal carcinoma underwent CRT followed by surgery. Each patient underwent T2 WMRI and DWI at 1.5T before and 6 weeks after the completion of CRT. The percent change in tumoral volume before and 6 weeks after CRT was compared in patients classified as responders and nonresponders according to rectal cancer regression grade. RESULTS: Twenty-five patients were classified as responders with either partial (n = 20) or complete response (n = 5), while 20 patients were classified as nonresponders due to stable disease (n = 18) or disease progression (n = 2). Responders vs. nonresponders differed in the percent change of tumoral volume at T2 WMRI (-67% +/- 26% vs. -29% +/- 26%; P < 0.05) and DWI images (-72% +/- 24% vs. -33% +/- 28%; P < 0.05) with a cutoff <= -70% for T2 WMRI (sensitivity = 69%, 95% confidence interval [CI]: 48-85%; specificity = 100%, 95% CI 81-100%) and <=66% for DWI (sensitivity = 73%, 95% CI: 52-88%; specificity = 100%, 95% CI 81-100%). CONCLUSION: The percent change in tumoral volume at T2 WMRI and DWI images can differentiate responders from nonresponders in patients with locally advanced rectal carcinoma after neoadjuvant CRT. J. Magn. Reson. Imaging 2016;44:1415-1424. PMID- 27219473 TI - Perception of High Alcohol Use of Peers Is Associated With High Personal Alcohol Use in First-Year University Students in Three Central and Eastern European Countries. AB - OBJECTIVES: The objectives of this study were to assess discrepancies between estimated peer and personal drinking behavior and to determine associations between perceptions of peer and personal drinking behavior among university students from Hungary (HU), Lithuania (LT), and the Slovak Republic (SK). METHODS: 2,554 freshman university students completed an online questionnaire on the frequency of their personal alcohol use, the number of heavy drinking occasions and on their perception concerning the corresponding drinking behavior of a typical student. Associations between perceived peer and personal use were analyzed by means of logistic regression, adjusting for sex. RESULTS: The majority of students across all countries thought their peers drink more frequently and are more often involved in heavy drinking occasions than themselves. Students who perceived the frequency of peer alcohol use to be higher were more likely to drink alcohol twice a week or more often (SR: OR = 3.81, 95% CI = 2.51-5.79; LT: OR = 3.16, 95% CI = 2.11-4.75; HU: OR = 2.10, 95% CI = 1.53 2.87) compared with students who drink alcohol monthly or less. Those who perceived the number of peer heavy drinking occasions as high were more likely to report heavy drinking weekly or more often (SR: OR = 3.16, 95% CI = 1.92-5.20; LT:OR = 3.56, 95% CI = 2.14-5.94; HU:OR = 1.41, 95% CI = 0.79-2.51) compared with students who report heavy drinking less than monthly. CONCLUSIONS/IMPORTANCE: University students perceived peer alcohol use to be higher than their personal use. Given the association between perceptions and personal alcohol use, future research should investigate if targeting perceptions in the surveyed countries may have an impact on alcohol use. PMID- 27219474 TI - Distinct changes of myocyte autophagy during myocardial hypertrophy and heart failure: association with oxidative stress. AB - NEW FINDINGS: What is the central question of this study? We investigated the changes of myocyte autophagy during the stages of myocardial hypertrophy and failure and the relationship between autophagy and oxidative stress. What is the main findings and its importance? Myocyte autophagy is reduced during myocardial hypertrophy and increased during heart failure. Reduced autophagy is correlated with myocyte hypertrophy, and increased autophagy is correlated with myocyte apoptosis. The distinct alterations are associated with oxidative stress. Hydrogen peroxide causes distinct, concentration-dependent changes in autophagy in cultured cardiomyocytes. Oxidative stress may mediate the distinct alterations of myocyte autophagy during cardiac hypertrophy and failure. Myocyte autophagy occurs at basal levels in the heart in normal conditions and increases in heart failure. However, the changes of myocyte autophagy during the stages of myocardial hypertrophy and failure are not fully understood. Little is known about the relationship among myocyte autophagy, hypertrophy, apoptosis and oxidative stress. In the present study, we first examined the changes of myocyte autophagy in mice with chronic pressure overload and the relationships between myocyte autophagy and hypertrophy, apoptosis and oxidative stress. Second, we determined the direct role of hydrogen peroxide on autophagy in cultured cardiomyocytes. Eight-week-old male C57BL/6J mice underwent transverse aortic constriction (TAC) or sham operation. In TAC mice, left ventricular wall thickness was increased at 1 week and increased further at 9 weeks. Left ventricular end-diastolic dimension showed no change at 1 week, but increased at 9 weeks in association with systolic dysfunction. Myocyte autophagy was decreased at 1 week after TAC, and the decrease was correlated with increased myocyte size. Myocyte autophagy was increased at 9 weeks after TAC, and the increase was correlated with increased myocyte apoptosis. The alterations in autophagy after TAC were associated with myocardial oxidative stress. Hydrogen peroxide caused distinct, concentration-dependent changes in autophagy in cultured cardiomyocytes. In conclusion, myocyte autophagy was decreased during myocardial hypertrophy and increased during heart failure. The distinct changes were associated with myocyte hypertrophy, apoptosis and oxidative stress. These findings suggest that oxidative stress may mediate the distinct alterations of myocyte autophagy during myocardial hypertrophy and heart failure. PMID- 27219475 TI - Reciprocal white matter alterations due to 16p11.2 chromosomal deletions versus duplications. AB - Copy number variants at the 16p11.2 chromosomal locus are associated with several neuropsychiatric disorders, including autism, schizophrenia, bipolar disorder, attention-deficit hyperactivity disorder, and speech and language disorders. A gene dosage dependence has been suggested, with 16p11.2 deletion carriers demonstrating higher body mass index and head circumference, and 16p11.2 duplication carriers demonstrating lower body mass index and head circumference. Here, we use diffusion tensor imaging to elucidate this reciprocal relationship in white matter organization, showing widespread increases of fractional anisotropy throughout the supratentorial white matter in pediatric deletion carriers and, in contrast, extensive decreases of white matter fractional anisotropy in pediatric and adult duplication carriers. We find associations of these white matter alterations with cognitive and behavioral impairments. We further demonstrate the value of imaging metrics for characterizing the copy number variant phenotype by employing linear discriminant analysis to predict the gene dosage status of the study subjects. These results show an effect of 16p11.2 gene dosage on white matter microstructure, and further suggest that opposite changes in diffusion tensor imaging metrics can lead to similar cognitive and behavioral deficits. Given the large effect sizes found in this study, our results support the view that specific genetic variations are more strongly associated with specific brain alterations than are shared neuropsychiatric diagnoses. Hum Brain Mapp 37:2833-2848, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27219476 TI - Hierarchically-Porous Carbon Derived from a Large-Scale Iron-based Organometallic Complex for Versatile Energy Storage. AB - Inspired by the preparation of the hierarchically-porous carbon (HPC) derived from metal organic frameworks (MOFs) for energy storage, in this work, a simple iron-based metal- organic complex (MOC), which was simpler and cheaper compared with the MOF, was selected to achieve versatile energy storage. The intertwined 1 D nanospindles and enriched-oxygen doping of the HPC was obtained after one-step carbonization of the MOC. When employed in lithium-ion batteries, the HPC exhibited reversible capacity of 778 mA h g(-1) after 60 cycles at 50 mA g(-1) . Moreover, the HPC maintained a capacity of 188 mA h g(-1) after 400 cycles at 100 mA g(-1) as the anode material in a sodium-ion battery. In addition, the HPC served as the cathode matrix for evaluation of a lithium-sulfur battery. The general preparation process of the HPC is commercial, which is responsible for the large-scale production for its practical application. PMID- 27219482 TI - The safety and efficacy of Onivyde (irinotecan liposome injection) for the treatment of metastatic pancreatic cancer following gemcitabine-based therapy. AB - INTRODUCTION: Patients with advanced and metastatic pancreatic cancer refractory to gemcitabine based therapy have a dismal prognosis and limited therapeutic options. Recently, the FDA approved nanoliposomal irinotecan combined with fluorouracil/folinic acid for such patients based upon results of the NAPOLI-1 study which showed this regimen compared to fluorouracil/folinic acid significantly prolonged progression free survival (3.1 vs. 1.5 months) and overall survival (6.2 vs. 4.1 months). AREAS COVERED: The pharmacokinetic and pharmacogenetic characteristics of this novel formulation of irinotecan, its safety profile, and use in a clinical context for patients with pancreatic cancer are reviewed. Expert commentary: Nanoliposomal irinotecan, in combination with 5 FU/folinic acid, represents an important step forward in improving second line treatment options in patients with progression of metastatic pancreatic cancer. Furthermore, the novel drug formulation offers pharmacokinetic advantages which serve as a basis for further clinical testing in a various pancreatic cancer settings and other malignancies. PMID- 27219477 TI - Structure, Regulation, and Inhibition of the Quorum-Sensing Signal Integrator LuxO. AB - In a process called quorum sensing, bacteria communicate with chemical signal molecules called autoinducers to control collective behaviors. In pathogenic vibrios, including Vibrio cholerae, the accumulation of autoinducers triggers repression of genes responsible for virulence factor production and biofilm formation. The vibrio autoinducer molecules bind to transmembrane receptors of the two-component histidine sensor kinase family. Autoinducer binding inactivates the receptors' kinase activities, leading to dephosphorylation and inhibition of the downstream response regulator LuxO. Here, we report the X-ray structure of LuxO in its unphosphorylated, autoinhibited state. Our structure reveals that LuxO, a bacterial enhancer-binding protein of the AAA+ ATPase superfamily, is inhibited by an unprecedented mechanism in which a linker that connects the catalytic and regulatory receiver domains occupies the ATPase active site. The conformational change that accompanies receiver domain phosphorylation likely disrupts this interaction, providing a mechanistic rationale for LuxO activation. We also determined the crystal structure of the LuxO catalytic domain bound to a broad-spectrum inhibitor. The inhibitor binds in the ATPase active site and recapitulates elements of the natural regulatory mechanism. Remarkably, a single inhibitor molecule may be capable of inhibiting an entire LuxO oligomer. PMID- 27219483 TI - Three-Dimensional Porous Sponges from Collagen Biowastes. AB - Three-dimensional, functional, and porous scaffolds can find applications in a variety of fields. Here we report the synthesis of hierarchical and interconnected porous sponges using a simple freeze-drying technique, employing collagen extracted from animal skin wastes and superparamagnetic iron oxide nanoparticles. The ultralightweight, high-surface-area sponges exhibit excellent mechanical stability and enhanced absorption of organic contaminants such as oils and dye molecules. Additionally, these biocomposite sponges display significant cellular biocompatibility, which opens new prospects in biomedical uses. The approach highlights innovative ways of transforming biowastes into advanced hybrid materials using simple and scalable synthesis techniques. PMID- 27219484 TI - Can short-billed nectar thieving sunbirds replace long-billed sunbird pollinators in transformed landscapes? AB - Pollinator specialisation through exploitation barriers (such as long floral tubes) does not necessarily mean a lack of pollination when the favoured pollinator is rare or absent. Theory predicts that suboptimal visitors will contribute to plant reproduction in the absence of the most effective pollinator. Here I address these questions with Chasmanthe floribunda a long-tubed plant species in the Cape Floristic Region, which is reliant on one species of pollinator, the long-billed Malachite Sunbird. In contrast to short-billed sunbirds, the Malachite Sunbird occurs in lower abundance or is absent in transformed landscapes. Short-billed sunbirds rob and thieve nectar from long tubed flowers, but their potential contribution towards pollination is unknown. Experiments assessing seed set after single flower visits were performed to determine whether thieving short-billed sunbirds can act as substitute pollinators. To determine whether short-billed sunbirds reduce pollen limitation in transformed areas, pollen supplementation was done by hand and compared to natural fruit set. Short billed sunbirds are unable to act as substitute pollinators, and seed set is significantly lower in the flowers that they visited, compared to flowers visited by long-billed sunbirds. This is substantiated on a landscape scale, where fruit production in Chasmanthe floribunda could artificially be increased by 35% in transformed landscapes, but not so in natural areas. These findings have important consequences for the management and conservation of long-tubed bird-pollinated plant species that exist in recently transformed landscapes. The potential vulnerability of specialised plant species in transformed landscapes is highlighted. PMID- 27219485 TI - Spiral artery remodeling and maternal cardiovascular risk: the spiral artery remodeling (SPAR) study. AB - BACKGROUND: Women with a history of placental bed disorders, including preeclampsia and intrauterine growth restriction have an increased long-term risk of cardiovascular disease (CVD). Further, similarities exist between atherosclerosis and abnormalities observed in placental bed spiral arteries in pregnancies affected by preeclampsia and intrauterine growth restriction, such as acute atherosis and defective remodeling. This suggests a common pathophysiological pathway underlying both disorders. OBJECTIVES: The aim of this study was to investigate vascular and inflammatory lesions in the placental bed of women with preeclampsia and normal pregnancy using a systematic approach to characterize lesions of the placental bed, and relate spiral artery pathology to postpartum CVD risk assessment. METHODS: Placental bed punch biopsies were performed following caesarean section and systematically studied to assess vascular pathology, arterial remodeling, and the presence of CD3, CD56, and CD68 cells. In addition, levels of modifiable CVD risk factors were assessed immediately postpartum. RESULTS: We found fewer spiral arteries with complete remodeling in women with preeclampsia than in the control group (21 vs. 68%; P = 0.008). Further, women with preeclampsia showed less presence of CD3 cells in both the decidua and the myometrium. Preliminary findings of CVD risk factor assessment postpartum suggest a correlation between acute atherosis and higher triglyceride and low-density lipoprotein cholesterol levels. CONCLUSION: Systematic study of vascular pathology in uterine spiral artery biopsy samples in relation to CVD risk factors provides valuable insight into the link between cardiovascular health and placental bed disorders. PMID- 27219487 TI - Heart rate dependent and independent effects of beta-blockers on central hemodynamic parameters: a propensity score analysis. AB - OBJECTIVES: Central hemodynamic parameters are better predictors of the cardiovascular burden than peripheral blood pressure (BP). Beta-blockers are known to reduce central BP to a lesser extent than peripheral BP, a hypothesized mechanistic consequence of heart rate (HR) reduction. METHODS: The association between beta-blocker use, HR and central hemodynamics indices was studied in treated hypertensive participants of the CARTaGENE study using propensity score analyses and multivariate linear regressions. RESULTS: Of the 20 004 participants, 2575 were treated hypertensive patients with valid pulse wave analysis. Using propensity score analyses, beta-blocker users (n = 605) were matched to nonusers having similar clinical characteristics with (Model 1) and without (Model 2) adjustment for HR. This resulted in 457 and 510 pairs with adequate balance, except for a HR difference in Model 2 (62.5 +/- 10.5 vs. 70.4 +/- 11.5 bpm, p < 0.001). In Model 1, the central pulse pressure (PP) was 46.5 +/ 12.9 mmHg with beta-blocker compared with 45.4 +/- 11.0 mmHg without (p = 0.045). PP amplification, augmentation index and augmented pressure were also less favorable with the use of beta-blocker. The HR difference in Model 2 further increased the difference in central PP observed with beta-blocker to 46.5 +/- 13.0 vs. 43.3 +/- 11.3 without (p < 0.001). These findings were similar when atenolol, metoprolol and bisoprolol were assessed separately using multivariate linear regression models. CONCLUSION: This study shows that the unfavorable central hemodynamic profile of beta-blocker has both HR-dependent and HR independent components that are similar for all frequently used beta1-selective beta-blocker. PMID- 27219486 TI - Transfer function-derived central pressure and cardiovascular disease events: the Framingham Heart Study. AB - BACKGROUND: Relations between central pulse pressure (PP) or pressure amplification and major cardiovascular disease (CVD) events are controversial. Estimates of central aortic pressure derived using radial artery tonometry and a generalized transfer function may better predict CVD risk beyond the predictive value of brachial SBP. METHODS: Augmentation index, central SBP, central PP, and central-to-peripheral PP amplification were evaluated using radial artery tonometry and a generalized transfer function as implemented in the SphygmoCor device (AtCor Medical, Itasca, Illinois, USA). We used proportional hazards models to examine relations between central hemodynamics and first-onset major CVD events in 2183 participants (mean age 62 years, 58% women) in the Framingham Heart Study. RESULTS: During median follow-up of 7.8 (limits 0.2-8.9) years, 149 participants (6.8%) had an incident event. Augmentation index (P = 0.6), central aortic systolic pressure (P = 0.20), central aortic PP (P = 0.24), and PP amplification (P = 0.15) were not related to CVD events in multivariable models that adjusted for age, sex, brachial cuff systolic pressure, use of antihypertensive therapy, total and high-density lipoprotein cholesterol concentrations, smoking, and presence of diabetes. In a model that included standard risk factors, model fit was improved (P = 0.03) when brachial systolic pressure was added after central, whereas model fit was not improved (P = 0.30) when central systolic pressure was added after brachial. CONCLUSION: After considering standard risk factors, including brachial cuff SBP, augmentation index, central PP and PP amplification derived using radial artery tonometry, and a generalized transfer function were not predictive of CVD risk. PMID- 27219488 TI - Hypertensive patients with left ventricular hypertrophy have global left atrial dysfunction and impaired atrio-ventricular coupling. AB - OBJECTIVE: The aim of this study was to comprehensively investigate left atrial (LA) reservoir, conduit, and booster pump functions, as well as their predictors in patients with primary systemic arterial hypertension (HTN) and left ventricular (LV) hypertrophy. METHODS: Thirty patients with HTN and LV hypertrophy, but no history of atrial arrhythmia or heart failure, were compared with 29 normotensive controls. Speckle-tracking echocardiography of the LA wall was used to measure systolic and diastolic strains and strain rates. Early diastolic velocity of transmitral flow/early diastolic mitral annular motion velocity (E/E')/peak systolic LA strain (S-LAs) was used as an index of LA stiffness. RESULTS: HTN patients had higher LV mass index, impaired LV diastolic function, and higher LA volume index than controls. LA reservoir, conduit, and booster pump functions were significantly lower and LA stiffness was greater. Multiple regression analysis indicated that increased LV mass and LV filling pressures as well as reduced LV strain or E' were predictors for reduced atrial function. CONCLUSION: HTN patients showed a significant impairment of the three components of LA function. These changes were correlated with LV hypertrophy and dysfunction, and presumably related to LA fibrotic changes, underlining the importance of LA-LV coupling. The prognostic value of these new speckle-tracking echocardiography-based LA strain indices needs to be evaluated by future studies. PMID- 27219489 TI - Determination of pesticides in sugarcane juice employing microextraction by packed sorbent followed by gas chromatography and mass spectrometry. AB - This paper describes the development of a method for the determination of six pesticides (tebuthiuron, carbofuran, atrazine, metribuzine, ametryn, and bifenthrin) in sugarcane juice using microextraction by packed sorbent as the extraction technique. The extraction steps were optimized by factorial design, being the variables pH, ionic strength, desorption solvent and solvent volume optimized for comparisons among sorbent materials. Among the evaluated materials C18-Chromabond((r)) showed better extraction efficiency. A factorial design 2(3) with central point was used for the extraction cycles optimization. Draw/eject and washes cycles showed significant improvements in the extraction efficiency when the number of cycles increased. The method was validated and showed a limit of quantification in the range of 2.0-10.0 MUg.L(-1) . The calibration curves were constructed by weighting models that reduced the sum of absolute residues values and improved determination coefficient. The matrix factor and extraction efficiency were 97.3-77.3% and 27.1-64.8%, respectively. The accuracy was 71.7 106.9%; precision evaluated as the coefficient of variance obtained in intra and inter day analysis was 4.5-15.9%. The method was applied to the determination of pesticide residues in four sugarcane juice samples commercially available in markets from different cities from Sao Paulo state, Brazil. PMID- 27219490 TI - Reprogramming of the Epigenome by MLL1 Links Early-Life Environmental Exposures to Prostate Cancer Risk. AB - Tissue and organ development is a time of exquisite sensitivity to environmental exposures, which can reprogram developing tissues to increase susceptibility to adult diseases, including cancer. In the developing prostate, even brief exposure to endocrine-disrupting chemicals (EDCs) can increase risk for developing cancer in adulthood, with disruption of the epigenome thought to play a key role in this developmental reprogramming. We find that EDC-induced nongenomic phosphoinositide 3-kinase; (PI3K) signaling engages the histone methyltransferase mixed-lineage leukemia 1 (MLL1), responsible for the histone H3 lysine 4 trimethylation (H3K4me3) active epigenetic mark, to increase cleavage and formation of active MLL1 dimers. In the developing prostate, EDC-induced MLL1 activation increased H3K4me3 at genes associated with prostate cancer, with increased H3K4me3 and elevated basal and hormone-induced expression of reprogrammed genes persisting into adulthood. These data identify a mechanism for MLL1 activation that is vulnerable to disruption by environmental exposures, and link MLL1 activation by EDCs to developmental reprogramming of genes involved in prostate cancer. PMID- 27219492 TI - Differential Associations of Specific Selective Serotonin Reuptake Inhibitors With Resting-State Heart Rate and Heart Rate Variability: Implications for Health and Well-Being. AB - OBJECTIVE: Debate has focused on the effects of the selective serotonin reuptake inhibitor (SSRI) antidepressants on heart rate (HR) and HR variability (HRV), both of which are predictors of adverse cardiovascular events. Here, we examine the associations between specific SSRI antidepressants and resting state HR (and HRV) after accounting for a host of potential confounding factors using propensity score techniques. METHODS: Participants included 10,466 not taking antidepressants, 46 participants taking escitalopram, 86 taking citalopram, 66 taking fluoxetine, 103 taking paroxetine, and 139 taking sertraline. HR and HRV (root mean square of successive squared differences, high frequency) were extracted from 10-minute resting-state ECGs. Analyses including propensity score weighting and matching were conducted using R-statistics to control for potentially confounding variables. RESULTS: Major findings indicated that users of all SSRI medications-except fluoxetine-displayed lower HRV relative to nonusers. Users of paroxetine also displayed significantly lower HRV relative to users of citalopram (Cohen's d = 0.42), fluoxetine (Cohen's d = 0.54), and sertraline (Cohen's d = 0.35), but not escitalopram. Although associations were also observed for HR, these were less robust than those for HRV. CONCLUSIONS: Although paroxetine is associated with decreases in HRV relative to nonusers, as well as users of other SSRI medications, fluoxetine was the only medication not to display significant alterations in HR or HRV. These conclusions are limited by the cross-sectional design and nonrandomized nature of medication prescriptions. Findings highlight the importance of focusing on specific medications, rather than more heterogeneous groupings according to antidepressant action, and may have implications for health and well-being for the longer term. PMID- 27219491 TI - Cholinergic interneurons in the Q140 knockin mouse model of Huntington's disease: Reductions in dendritic branching and thalamostriatal input. AB - We have previously found that thalamostriatal axodendritic terminals are reduced as early as 1 month of age in heterozygous Q140 HD mice (Deng et al. [] Neurobiol Dis 60:89-107). Because cholinergic interneurons are a major target of thalamic axodendritic terminals, we examined the VGLUT2-immunolabeled thalamic input to striatal cholinergic interneurons in heterozygous Q140 males at 1 and 4 months of age, using choline acetyltransferase (ChAT) immunolabeling to identify cholinergic interneurons. Although blinded neuron counts showed that ChAT+ perikarya were in normal abundance in Q140 mice, size measurements indicated that they were significantly smaller. Sholl analysis further revealed the dendrites of Q140 ChAT+ interneurons were significantly fewer and shorter. Consistent with the light microscopic data, ultrastructural analysis showed that the number of ChAT+ dendritic profiles per unit area of striatum was significantly decreased in Q140 striata, as was the abundance of VGLUT2+ axodendritic terminals making synaptic contact with ChAT+ dendrites per unit area of striatum. The density of thalamic terminals along individual cholinergic dendrites was, however, largely unaltered, indicating that the reduction in the areal striatal density of axodendritic thalamic terminals on cholinergic neurons was due to their dendritic territory loss. These results show that the abundance of thalamic input to individual striatal cholinergic interneurons is reduced early in the life span of Q140 mice, raising the possibility that this may occur in human HD as well. Because cholinergic interneurons differentially affect striatal direct vs. indirect pathway spiny projection neurons, their reduced thalamic excitatory drive may contribute to early abnormalities in movement in HD. J. Comp. Neurol. 524:3518 3529, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27219493 TI - Huntington Disease: A Disease of DNA Methylation or DNA Breaks? AB - This commentary highlights the article by Mollica et al that describes an interesting model for the clinical evolution of Huntington disease. PMID- 27219496 TI - AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY COMPREHENSIVE CLINICAL PRACTICE GUIDELINES FOR MEDICAL CARE OF PATIENTS WITH OBESITY. AB - OBJECTIVE: Development of these guidelines is mandated by the American Association of Clinical Endocrinologists (AACE) Board of Directors and the American College of Endocrinology (ACE) Board of Trustees and adheres to published AACE protocols for the standardized production of clinical practice guidelines (CPGs). METHODS: Recommendations are based on diligent review of clinical evidence with transparent incorporation of subjective factors. RESULTS: There are 9 broad clinical questions with 123 recommendation numbers that include 160 specific statements (85 [53.1%] strong [Grade A]; 48 [30.0%] intermediate [Grade B], and 11 [6.9%] weak [Grade C], with 16 [10.0%] based on expert opinion [Grade D]) that build a comprehensive medical care plan for obesity. There were 133 (83.1%) statements based on strong (best evidence level [BEL] 1 = 79 [49.4%]) or intermediate (BEL 2 = 54 [33.7%]) levels of scientific substantiation. There were 34 (23.6%) evidence-based recommendation grades (Grades A-C = 144) that were adjusted based on subjective factors. Among the 1,790 reference citations used in this CPG, 524 (29.3%) were based on strong (evidence level [EL] 1), 605 (33.8%) were based on intermediate (EL 2), and 308 (17.2%) were based on weak (EL 3) scientific studies, with 353 (19.7%) based on reviews and opinions (EL 4). CONCLUSION: The final recommendations recognize that obesity is a complex, adiposity-based chronic disease, where management targets both weight-related complications and adiposity to improve overall health and quality of life. The detailed evidence-based recommendations allow for nuanced clinical decision making that addresses real-world medical care of patients with obesity, including screening, diagnosis, evaluation, selection of therapy, treatment goals, and individualization of care. The goal is to facilitate high-quality care of patients with obesity and provide a rational, scientific approach to management that optimizes health outcomes and safety. ABBREVIATIONS: A1C = hemoglobin A1c AACE = American Association of Clinical Endocrinologists ACE = American College of Endocrinology ACSM = American College of Sports Medicine ADA = American Diabetes Association ADAPT = Arthritis, Diet, and Activity Promotion Trial ADHD = attention-deficit hyperactivity disorder AHA = American Heart Association AHEAD = Action for Health in Diabetes AHI = apnea-hypopnea index ALT = alanine aminotransferase AMA = American Medical Association ARB = angiotensin receptor blocker ART = assisted reproductive technology AUC = area under the curve BDI = Beck Depression Inventory BED = binge eating disorder BEL = best evidence level BLOOM = Behavioral Modification and Lorcaserin for Overweight and Obesity Management BLOSSOM = Behavioral Modification and Lorcaserin Second Study for Obesity Management BMI = body mass index BP = blood pressure C-SSRS = Columbia Suicidality Severity Rating Scale CAD = coronary artery disease CARDIA = Coronary Artery Risk Development in Young Adults CBT = cognitive behavioral therapy CCO = Consensus Conference on Obesity CHF = congestive heart failure CHO = carbohydrate CI = confidence interval COR-I = Contrave Obesity Research I CPG = clinical practice guideline CV = cardiovascular CVD = cardiovascular disease DASH = Dietary Approaches to Stop Hypertension DBP = diastolic blood pressure DEXA = dual-energy X-ray absorptiometry DPP = Diabetes Prevention Program DSE = diabetes support and education EL = evidence level ED = erectile dysfunction ER = extended release EWL = excess weight loss FDA = Food and Drug Administration FDG = 18F fluorodeoxyglucose GABA = gamma-aminobutyric acid GERD = gastroesophageal reflux disease GI = gastrointestinal GLP-1 = glucagon-like peptide 1 HADS = Hospital Anxiety and Depression Scale HDL-c = high-density lipoprotein cholesterol HR = hazard ratio HTN = hypertension HUNT = Nord-Trondelag Health Study ICSI = intracytoplasmic sperm injection IFG = impaired fasting glucose IGT = impaired glucose tolerance ILI = intensive lifestyle intervention IVF = in vitro fertilization LAGB = laparoscopic adjustable gastric banding LDL-c = low-density lipoprotein cholesterol LES = lower esophageal sphincter LSG = laparoscopic sleeve gastrectomy LV = left ventricle LVH = left ventricular hypertrophy LVBG = laparoscopic vertical banded gastroplasty MACE = major adverse cardiovascular events MAOI = monoamine oxidase inhibitor MI = myocardial infarction MNRCT = meta analysis of non-randomized prospective or case-controlled trials MRI = magnetic resonance imaging MUFA = monounsaturated fatty acid NAFLD = nonalcoholic fatty liver disease NASH = nonalcoholic steatohepatitis NES = night eating syndrome NHANES = National Health and Nutrition Examination Surveys NHLBI = National Heart, Lung, and Blood Institute NHS = Nurses' Health Study NICE = National Institute for Health and Care Excellence OA = osteoarthritis OGTT = oral glucose tolerance test OR = odds ratio OSA = obstructive sleep apnea PHQ-9 = Patient Health Questionnaire PCOS = polycystic ovary syndrome PCP = primary care physician POMC = pro-opiomelanocortin POWER = Practice-Based Opportunities for Weight Reduction PPI = proton pump inhibitor PRIDE = Program to Reduce Incontinence by Diet and Exercise PSA = prostate specific antigen QOL = quality of life RA = receptor agonist RCT = randomized controlled trial ROC = receiver operator characteristic RR = relative risk RYGB = Roux-en-Y gastric bypass SAD = sagittal abdominal diameter SBP = systolic blood pressure SCOUT = Sibutramine Cardiovascular Outcome Trial SG = sleeve gastrectomy SHBG = sex hormonebinding globulin SIEDY = Structured Interview on Erectile Dysfunction SNRI = serotonin norepinephrine reuptake inhibitors SOS = Swedish Obese Subjects SS = surveillance study SSRI = selective serotonin reuptake inhibitors STORM = Sibutramine Trial on Obesity Reduction and Maintenance TCA = tricyclic antidepressant TONE = Trial of Nonpharmacologic Intervention in the Elderly TOS = The Obesity Society T2DM = type 2 diabetes mellitus UKPDS = United Kingdom Prospective Diabetes Study U.S = United States VAT = visceral adipose tissue VLDL = very low-density lipoprotein WC = waist circumference WHO = World Health Organization WHR = waist-hip ratio WHtR = waist-to-height ratio WMD = weighted mean difference WOMAC = Western Ontario and McMaster Universities osteoarthritis index XENDOS = XEnical in the Prevention of Diabetes in Obese Subjects. PMID- 27219495 TI - Primer ID ultra-deep sequencing reveals dynamics of drug resistance-associated variants in breakthrough hepatitis C viruses: relevance to treatment outcome and resistance screening. AB - BACKGROUND: Use of direct-acting antiviral drugs (DAAs) that target HCV may be hampered by the rapid selection of viral strains that harbour drug resistance associated variants (RAVs). These RAVs are often associated with a fitness cost and tend to occur on low-frequency strains within treatment-naive subjects. To address the clinical relevance of low frequency RAVs in the setting of DAAs, this study utilized a Primer ID ultra-deep sequencing approach to mitigate PCR errors and bias to accurately quantify viral sequences in subjects that failed DAA treatment. METHODS: Subjects were enrolled in the follow-up study P05063, and had previous treatment with boceprevir and all had detectable RAVs at virological failure (VF) based on Sanger-based population sequencing. Twelve subjects had three time points available: baseline, VF and follow-up (median 830.5 days). Viral RNA was amplified using unique primer identifiers (Primer IDs) and sequenced using 454 ultra-deep sequencing. RESULTS: The sequencing strategy used in this study improved the detection of clinically relevant low frequency strains bearing RAVs compared to population sequencing and showed that these strains can persist for up to 2 years post-treatment failure. Strains carrying multiple RAVs were common in breakthrough viruses. Putative compensatory mutations were identified. CONCLUSIONS: The Primer ID ultra-deep sequencing approach identifies RAVs that can reduce drug sensitivity at levels below the detection threshold for population sequencing. The approach also removes PCR errors and biases, suggesting this sequencing strategy should become the standard approach by which to perform temporal quasispecies studies and resistance screening. ClinicalTrials.gov NCT00689390. PMID- 27219497 TI - Utilizing Participatory Mapping and GIS to Examine the Activity Spaces of Homeless Youth. AB - Although previous studies have informed our understanding of certain aspects of youth homelessness, few studies have critically examined the spatial and social environments utilized by youth as they navigate life on the streets. This study employed participatory mapping and Geographic Information Systems (GIS) to examine the activity spaces of homeless youth as they relate to sense of community and psychological well-being. Participants were 28 youth experiencing homelessness in Portland, Oregon, USA. Results suggest that youth engage most frequently in service-related activities, and their activity participation is significantly associated with sense of community and psychological well-being. The utility of innovative participatory methods for better understanding the diverse experiences of homeless youth is discussed alongside examination of their practical implications. PMID- 27219498 TI - Alcohol Intervention for Adolescents with Fetal Alcohol Spectrum Disorders: Project Step Up, a Treatment Development Study. AB - BACKGROUND: Project Step Up proposed to reduce alcohol consumption and alcohol related negative outcomes in adolescents with fetal alcohol spectrum disorders (FASD). METHODS: The 54 participants (30 females, 24 males) were assigned to either Project Step Up Intervention (SUI) or Control conditions and were assessed prior to intervention, immediately following intervention, and at 3-month follow up. Adolescents in the SUI condition participated in a 6-week, 60-minute group intervention that provided alcohol education and promoted adaptive responses to alcohol-related social pressures. Caregivers attended concurrent but separate sessions on the effects of prenatal alcohol exposure on the brain and how to handle parenting challenges associated with alcohol use in teens with FASD. RESULTS: Thirty-three percent (n = 18) of adolescents were classified as light/moderate drinkers, and 67% (n = 36) were abstinent/infrequent drinkers based on their lifetime drinking histories. Results revealed a significant decrease in self-reported alcohol risk and in alcohol-related negative behaviors (Cohen's d = 1.08 and 0.99) in light/moderate drinkers in the SUI compared to the Control group. These results were partially sustained at 3-month follow-up. Furthermore, adolescents in the abstinent/infrequent group exhibited no increase in alcohol-related outcomes suggesting that the group intervention used in this study was not iatrogenic. CONCLUSIONS: The success of this treatment development study provides preliminary support for effective treatment of adolescents with FASD to prevent or reduce alcohol use and its negative consequences in this high risk population. PMID- 27219499 TI - Extending Stannyl Anion Chemistry to the Actinides: Synthesis and Characterization of a Uranium-Tin Bond. AB - We have synthesized a rare example of a uranium(IV) stannyl (kappa(4) N(CH2CH2NSi((i)Pr)3)3U(SnMe3), 1) via transmetalation with LiSnMe3. This complex has been characterized crystallographically and shown to have a U-Sn bond length of 3.3130(3) A, substantially longer than the only other crystallographically observed U-Sn bond (3.166 A). Computational studies suggest that the U-Sn bond in 1 is highly polarized, with significant charge transfer to the stannylate ligand. We briefly discuss plausible mechanistic scenarios for the formation of 1, which may be relevant to other transmetalation processes involving heavy main group atoms. Furthermore, we demonstrate the reducing ability of [SnMe3](-) in the absence of strongly donating ligands on U(IV). PMID- 27219500 TI - Cage-to-Cage Cascade Transformations. AB - A series of Pd2 L4 -type binuclear self-assembled coordination cages (1-4), where L stands for a nonchelating bidentate ligand, were prepared. The strategies adopted for the synthesis of the cages were: combination of Pd(II) with 1) a selected ligand or 2) subcomponents of the ligand. Highly efficient cage-to-cage transformation reactions are demonstrated by suitable covalent modification (from 1 to 2 or 3 or 4) or ligand-exchange reactions (from 1 to 2 or 3 or 4; from 2 to 3 or 4). Thus, new cascade transformations (from 1 to 2 to 3; from 1 to 2 to 4) are achieved beautifully. PMID- 27219501 TI - The correlation between quality of life and social support in female nurses. AB - AIMS AND OBJECTIVES: To investigate the relationship between quality of life and social support in female nurses. BACKGROUND: Nurses play an important role in providing care and managing patients' health in hospitals. However, limited studies have shown an association between quality of life and social support in female nurses in China. DESIGN: Questionnaire survey. METHODS: To investigate 320 full-time female nurses in different departments at four comprehensive hospitals in Harbin with a cross-sectional correlational design using questionnaires. A demographic data questionnaire, menopause-specific quality of life questionnaire and social support scale were used. RESULTS: The scores on the physical (36.93 +/ 17.65) and psychological (17.57 +/- 9.45) subscales were higher than those of the vasomotor (4.88 +/- 3.48) and sexual (4.53 +/- 3.23) subscales of quality of life. The average score of objective support (25.12 +/- 4.32) was higher than those of subjective support (9.80 +/- 3.04) and utilisation of social support (7.80 +/- 1.97). A significant association between quality of life and social support was found (p < 0.01). CONCLUSIONS: Social support influenced quality of life. Social support as a buffer for pressure can influence individual stress perception, help individuals cope with pressure and reduce the negative impact of stress on mental and physical health, thus improving different aspects of health. RELEVANCE TO CLINICAL PRACTICE: Enhancing social support in an active environment would allow female nurses to enjoy a better quality of life in their clinical practice. PMID- 27219502 TI - Land use effects on pesticides in sediments of prairie pothole wetlands in North and South Dakota. AB - Prairie potholes are the dominant wetland type in the intensively cultivated northern Great Plains of North America, and thus have the potential to receive pesticide runoff and drift. We examined the presence of pesticides in sediments of 151 wetlands split among the three dominant land use types, Conservation Reserve Program (CRP), cropland, and native prairie, in North and South Dakota in 2011. Herbicides (glyphosate and atrazine) and fungicides were detected regularly, with no insecticide detections. Glyphosate was the most detected pesticide, occurring in 61% of all wetlands, with atrazine in only 8% of wetlands. Pyraclostrobin was one of five fungicides detected, but the only one of significance, being detected in 31% of wetlands. Glyphosate was the only pesticide that differed by land use, with concentrations in cropland over four times that in either native prairie or CRP, which were equal in concentration and frequency of detection. Despite examining several landscape variables, such as wetland proximity to specific crop types, watershed size, and others, land use was the best variable explaining pesticide concentrations in potholes. CRP ameliorated glyphosate in wetlands at concentrations comparable to native prairie and thereby provides another ecosystem service from this expansive program. PMID- 27219503 TI - Effects of Bt-transgenic rice cultivation on planktonic communities in paddy fields and adjacent ditches. AB - The non-target effects of transgenic plants are issues of concern; however, their impacts in cultivated agricultural fields and adjacent natural aquatic ecosystems are poorly understood. We conducted field experiments during two growing seasons to determine the effects of cultivating Bacillus thuringiensis (Bt)-transgenic rice on the phytoplankton and zooplankton communities in a paddy field and an adjacent ditch. Bt toxin was detected in soil but not in water. Water quality was not significantly different between non-Bt and Bt rice fields, but varied among up-, mid- and downstream locations in the ditch. Cultivation of Bt-transgenic rice had no effects on zooplankton communities. Phytoplankton abundance and biodiversity were not significantly different between transgenic and non transgenic rice fields in 2013; however, phytoplankton were more abundant in the transgenic rice field than in the non-transgenic rice field in 2014. Water quality and rice type explained 65.9% and 12.8% of this difference in 2014, respectively. Phytoplankton and zooplankton were more abundant in mid- and downstream, than upstream, locations in the ditch, an effect that we attribute to water quality differences. Thus, the release of Bt toxins into field water during the cultivation of transgenic crops had no direct negative effects on plankton community composition, but indirect effects that alter environmental conditions should be taken into account during the processes of management planning and policymaking. PMID- 27219504 TI - Emission factors of air pollutants from CNG-gasoline bi-fuel vehicles: Part II. CO, HC and NOx. AB - The estimation of emission factors (EFs) is the basis of accurate emission inventory. However, the EFs of air pollutants for motor vehicles vary under different operating conditions, which will cause uncertainty in developing emission inventory. Natural gas (NG), considered as a "cleaner" fuel than gasoline, is increasingly being used to reduce combustion emissions. However, information is scarce about how much emission reduction can be achieved by motor vehicles burning NG (NGVs) under real road driving conditions, which is necessary for evaluating the environmental benefits for NGVs. Here, online, in situ measurements of the emissions from nine bi-fuel vehicles were conducted under different operating conditions on the real road. A comparative study was performed for the EFs of black carbon (BC), carbon monoxide (CO), hydrocarbons (HCs) and nitrogen oxides (NOx) for each operating condition when the vehicles using gasoline and compressed NG (CNG) as fuel. BC EFs were reported in part I. The part II in this paper series reports the influence of operating conditions and fuel types on the EFs of CO, HC and NOx. Fuel-based EFs of CO showed good correlations with speed when burning CNG and gasoline. The correlation between fuel-based HC EFs and speed was relatively weak whether burning CNG or gasoline. The fuel-based NOx EFs moderately correlated with speed when burning CNG, but weakly correlated with gasoline. As for HC, the mileage-based EFs of gasoline vehicles are 2.39-12.59 times higher than those of CNG vehicles. The mileage based NOx EFs of CNG vehicles are slightly higher than those of gasoline vehicles. These results would facilitate a detailed analysis of the environmental benefits for replacing gasoline with CNG in light duty vehicles. PMID- 27219505 TI - Heterogeneous road networks have no apparent effect on the genetic structure of small mammal populations. AB - Roads are widely recognized to represent a barrier to individual movements and, conversely, verges can act as potential corridors for the dispersal of many small mammals. Both barrier and corridor effects should generate a clear spatial pattern in genetic structure. Nevertheless, the effect of roads on the genetic structure of small mammal populations still remains unclear. In this study, we examine the barrier effect that different road types (4-lane highway, 2-lane roads and single-lane unpaved roads) may have on the population genetic structure of three species differing in relevant life history traits: southern water vole Arvicola sapidus, the Mediterranean pine vole Microtus duodecimcostatus and the Algerian mouse Mus spretus. We also examine the corridor effect of highway verges on the Mediterranean pine vole and the Algerian mouse. We analysed the population structure through pairwise estimates of FST among subpopulations bisected by roads, identified genetic clusters through Bayesian assignment approaches, and used simple and partial Mantel tests to evaluate the relative barrier or corridor effect of roads. No strong evidences were found for an effect of roads on population structure of these three species. The barrier effect of roads seems to be site-specific and no corridor effect of verges was found for the pine vole and Algerian mouse populations. The lack of consistent results among species and for each road type lead us to believe that the ability of individual dispersers to use those crossing structures or the habitat quality in the highway verges may have a relatively higher influence on gene flow among populations than the presence of crossing structures per se. Further research should include microhabitat analysis and the estimates of species abundance to understand the mechanisms that underlie the genetic structure observed at some sites. PMID- 27219506 TI - Clinically defined non-specific symptoms in the vicinity of mobile phone base stations: A retrospective before-after study. AB - The number of mobile phone base station(s) (MPBS) has been increasing to meet the rapid technological changes and growing needs for mobile communication. The primary objective of the present study was to test possible changes in prevalence and number of NSS in relation to MPBS exposure before and after increase of installed MPBS antennas. A retrospective cohort study was conducted, comparing two time periods with high contrast in terms of number of installed MPBS. Symptom data were based on electronic health records from 1069 adult participants, registered in 9 general practices in different regions in the Netherlands. All participants were living within 500m from the nearest bases station. Among them, 55 participants reported to be sensitive to MPBS at T1. A propagation model combined with a questionnaire was used to assess indoor exposure to RF-EMF from MPBS at T1. Estimation of exposure at T0 was based on number of antennas at T0 relative to T1. At T1, there was a >30% increase in the total number of MPBS antennas. A higher prevalence for most NSS was observed in the MPBS-sensitive group at T1 compared to baseline. Exposure estimates were not associated with GP registered NSS in the total sample. Some significant interactions were observed between MPBS-sensitivity and exposure estimates on risk of symptoms. Using clinically defined outcomes and a time difference of >6years it was demonstrated that RF-EMF exposure to MPBS was not associated with the development of NSS. Nonetheless, there was some indication for a higher risk of NSS for the MPBS sensitive group, mainly in relation to exposure to UMTS, but this should be interpreted with caution. Results have to be verified by future longitudinal studies with a particular focus on potentially susceptible population subgroups of large sample size and integrated exposure assessment. PMID- 27219507 TI - Sampling Error: Impact on the Quantitative Analysis of Nanoparticle-Based Surface Enhanced Raman Scattering Immunoassays. AB - This paper examines the impact of the sampling error caused by the small size of the focused laser spot when using surface-enhanced Raman scattering (SERS) as a quantitative readout tool to analyze a sandwich immunoassay. The assay consists of a thin-film gold substrate that is modified with a layer of capture monoclonal antibodies (mAbs) and extrinsic Raman labels (ERLs) that consist of gold nanoparticle cores (60 nm diameter) coated with a monolayer of a Raman reporter molecule and a layer of human IgG mAbs to tag the captured antigen. The contribution of sampling error to the measurement is delineated first by constructing and analyzing an antigenic random accumulation model; this is followed by an experimental study of the analysis of an assay substrate using two different laser spot sizes. Both sets of findings indicate that the analysis with a small laser spot can lead to a sampling error (i.e., undersampling) much like that found when the size of a measured soil sample fails to accurately match that of a larger, more representative sample. That is, the smaller the laser spot size, the larger probable deviation in the accuracy of the measurement and the greater the imprecision of the measurement. Possible implications of these results with respect to the general application of SERS for quantitative measurements are also briefly discussed. PMID- 27219508 TI - Increased expression of brother of the regulator of imprinted sites in peripheral blood neutrophils is associated with both benign and malignant breast lesions. AB - BACKGROUND: BORIS, a paralog of the multifunctional CCCTC-binding factor (CTCF) gene is restricted to testis and normally not present in females. It is aberrantly activated in various human cancers including cancer breast. Using immunohistochemistry, western blot and/or RT-PCR, significantly higher levels of BORIS expression were reported in the neutrophils of cancer breast patients. We hypothesized that Flow Cytometry might be a better technique for objective quantitative evaluation of BORIS in neutrophils and we wanted to investigate if BORIS would discriminate between benign and malignant breast lesions. METHODS: The study included 85 females; 52 breast cancer, 13 benign breast lesions and 20 age-matched healthy controls. BORIS expression in the neutrophils was detected by Flow Cytometry. RESULTS: High level of BORIS was detected in all malignant (64.4 +/- 16.6%) and benign cases (67 +/- 12.3), mean florescent intensity ratio (MFIR) of 7.2 +/- 4.1 and 7 +/- 3.5, median 5.8 and 6.6%; and staining index (SI) 8.3 +/ 3.9 and 8.2 +/- 3.4, median 7.6 and 7.9 respectively vs.13.4 +/- 11.5% MFI 1.8 +/- 0.7, median1.6 and SI 2.6 +/- 0.69, median 2.5 for the control. BORIS level was comparable in the malignant and benign group (P = 0.934) and significantly higher than control (P = 0.0001). There was no correlation between neutrophil BORIS expression and ER/PR status, HER-2/neu expression or tumor stage or size. CONCLUSIONS: Increased BORIS expression in peripheral blood neutrophils is associated with both benign and malignant breast lesions; apparently, increased proliferation of breast tissue is the determining factor. This excludes BORIS as a tumor marker but it does not jeopardize its value as a potential therapeutic target. (c) 2016 International Clinical Cytometry Society. PMID- 27219509 TI - Functionalized Biopolymer Particles Enhance Performance of a Tissue-Protective Peptide under Proteolytic and Thermal Stress. AB - Cutaneous burns are often exacerbated by poor perfusion and subsequent necrosis of the microvasculature surrounding the primary injury. Preservation of these vessels can reduce necrotic tissue expansion and increase success rates of skin graft procedures. Recent work has identified a peptide derived from erythropoietin, ARA290, with the ability to mediate tissue protection in a variety of cell types. Here we demonstrate the advantages of fusing ARA290 to an elastin-like polypeptide (ELP) to salvage microvascular endothelial cells in harsh proteolytic conditions following thermal shock. These fusion proteins were expressed recombinantly in bacterial hosts and rapidly purified by inverse transition cycling. They were shown to spontaneously aggregate into particles at subphysiological temperatures. The bifunctional submicron particles were resistant to digestion in enzymes upregulated after burn injury. Furthermore, the data strongly suggest these ARA290-functionalized particles were superior to treatment with the peptide alone in preventing microvascular cell death in these conditions. The results bring to light an efficient and cost-effective strategy for the delivery therapeutic peptides to proteolytically active wound sites. PMID- 27219510 TI - Correction: Relative Importance and Additive Effects of Maternal and Infant Risk Factors on Childhood Asthma. AB - [This corrects the article DOI: 10.1371/journal.pone.0151705.]. PMID- 27219511 TI - Vegetable dietary fibres made with minimal processing improve health-related faecal parameters in a valid rat model. AB - Dietary fibre-induced faecal bulking and hydration are important contributors to large bowel function and health, and are affected by the dietary fibre structure. To determine faecal bulk-related parameters for vegetable dietary fibres with retained structure, cold water fragmentation of vegetables was used to make minimally processed vegetable fibres (MPVF) from swede, broccoli and asparagus. A valid adult rat model was used to subject the fibres to processes of hind gut fermentation and faecal accumulation similar to those in humans. All the MPVFs had high faecal bulking indexes (FBIs, mean +/- sem: wheat bran (reference), 100 +/- 6.0; asparagus 168 +/- 5.7; swede 135 +/- 6.1; broccoli 135 +/- 5.9; broccoli rind 205 +/- 10.4), and caused large increases in the theoretical colonic water load at 10 g per 100 g diet (increase over baseline (%): wheat bran, 137 +/- 8.3; asparagus, 236 +/- 25, swede 193 +/- 8.8; broccoli 228 +/- 12; broccoli rind 223 +/- 8.5). Faecal bulking by MPVFs was much greater than by fermentable extracted polysaccharides such as pectin and raftilose, or by commercial fibres made from highly processed cell walls. The results show natural, non-degraded vegetable fibres with retained botanical structure have beneficial effects not provided by structure-less fermentable dietary fibres. Dietary fibre-deficient diets supplemented with prebiotics cannot, therefore, adequately substitute for varied diets containing adequate vegetables, fruits and wholegrain cereals in which fermentation is associated with enough retained structure to conserve physicochemical properties of benefit to colonic function. PMID- 27219512 TI - Endoscopic ultrasound-guided pancreatic duct drainage: technical approaches to a challenging procedure. PMID- 27219513 TI - Suicide mortality among firefighters: Results from a large, urban fire department. AB - BACKGROUND: Research regarding suicide mortality among firefighters within the U.S. has been sparse and has yielded inconsistent findings. This study aimed to: (i) describe suicide rates within a large, urban fire department; and (ii) compare firefighter suicide rates with demographically adjusted general population suicide rates. METHODS: Rosters were obtained from the Philadelphia Fire Department (PFD) for all members employed by or separated from the department between 1993 and 2014 (N = 4,395). Vital statistics for each member were obtained from the CDC's National Death Index. RESULTS: Overall, 272 deaths were recorded; 11 (4.0%) were certified as suicides. The overall suicide rate among firefighter affiliates of the PFD between 1993 and 2014 was 11.61 per 100,000 person-years. CONCLUSIONS: The suicide rate among firefighters appears comparable to, and perhaps lower than, demographically adjusted general population estimates. Infrastructure to triangulate and monitor suicide rates from multiple departments, both career and volunteer, is needed to derive a more representative and informative estimate of firefighter suicide rates. Am. J. Ind. Med. 59:942-947, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27219514 TI - Evaluation of the in vitro efficacy of hemodialysis, hemoperfusion, and the combined approach on the removal of metaldehyde from canine plasma. AB - OBJECTIVE: To evaluate the effect of hemodialysis, hemoperfusion, and a combined approach on the removal of metaldehyde from canine plasma. DESIGN: In vitro study. SETTING: University veterinary teaching hospital laboratory. ANIMALS: None. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Metaldehyde-fortified canine plasma was prepared. Hemodialysis (HD), charcoal hemoperfusion (HP), and in-series hemodialysis and charcoal hemoperfusion (HD/HP) were applied in triplicate to eliminate metaldehyde from plasma. Plasma samples were obtained before starting the procedure and subsequently after every processed total plasma volume until plasma had been processed 10 times. Plasma metaldehyde concentration was quantitatively assayed by gas chromatography-mass spectrometry. Statistical analysis was performed using one-way ANOVA, repeated measures ANOVA, and Bonferroni post hoc test, and by calculating the coefficient of variation from duplicate measurements, binomial distribution, and by Bland-Altman analysis. Statistically significant reduction in metaldehyde concentration was reached by all 3 techniques. Reduction of metaldehyde concentration of more than 95% was achieved after processing the plasma volume 4 times applying HD, 8 times applying HP, and 2 times applying HD/HP. Efficacy in reduction of metaldehyde concentration differed significantly between the 3 procedures (P < 0.001). In series hemodialysis and charcoal hemoperfusion was more effective in metaldehyde removal than HD (P = 0.003) and HP (P < 0.001), and HD was more effective than HP (P = 0.002). CONCLUSIONS: Metaldehyde was effectively removed by all applied extracorporeal blood purification techniques in vitro. However, the combination of both techniques was more effective than HD or HP alone. Further clinical studies are warranted to confirm therapeutic benefits in patients. PMID- 27219515 TI - A New Transferrin Receptor Aptamer Inhibits New World Hemorrhagic Fever Mammarenavirus Entry. AB - Pathogenic New World hemorrhagic fever mammarenaviruses (NWM) utilize Glycoprotein 1 (GP1) to target the apical domain of the human transferrin receptor (hTfR) for facilitating cell entry. However, the conservation between their GP1s is low. Considering this and the slow evolutionary progression of mammals compared to viruses, therapeutic targeting of hTfR provides an attractive avenue for cross-strain inhibition and diminishing the likelihood of escape mutants. Aptamers present unique advantages for the development of inhibitors to vial entry, including ease of synthesis, lack of immunogenicity, and potentially cold-chain breaking solutions to diseases endemic to South America. Here, recognizing that in vivo competition with the natural ligand, transferrin (Tf), likely drove the evolution of GP1 to recognize the apical domain, we performed competitive in vitro selections against hTfR-expressing cells with supplemented Tf. The resultant minimized aptamer, Waz, binds the apical domain of the receptor and inhibits infection of human cells by recombinant NWM in culture (EC50 ~400 nmol/l). Aptamer multimerization further enhanced inhibition >10-fold (EC50 ~30 nmol/l). Together, our results highlight the ability to use a competitor to bias the outcome of a selection and demonstrate how avidity effects can be leveraged to enhance both aptamer binding and the potency of viral inhibition. PMID- 27219516 TI - Workplace spirituality in health care: an integrated review of the literature. AB - AIM: The aim is to describe workplace spirituality as a concept and phenomenon in health care and to explore the points of view from which it has been studied in nursing. BACKGROUND: Personnel in nursing are ageing and recruitment is challenging; workplace spirituality might benefit both employees and organisations. Workplace spirituality has three levels - individual, group and organisational - and presents different components at each level. EVALUATION: An integrated literature search identified 632 studies; after screening for relevance and quality, we identified eight peer-reviewed articles. The data were analysed with qualitative content analysis. KEY ISSUES: Workplace spirituality in nursing is mostly defined and researched from the individual viewpoint. The definition includes dimensions of inner life, meaningful work, interconnectedness, transcendence and alignment between values. CONCLUSION: A sense of community and meaningful work are the most important dimensions of workplace spirituality in health care. Group and organisational levels of workplace spirituality are the most important and still the least studied. Research is concentrated in Canada and Asia; more research in Europe is needed. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse managers can enhance workplace spirituality by contributing to organisational culture and emphasising teamwork. This requires more education and training in workplace spirituality. PMID- 27219517 TI - Midkine Increases Diagnostic Yield in AFP Negative and NASH-Related Hepatocellular Carcinoma. AB - Robust biomarkers for population-level hepatocellular carcinoma (HCC) surveillance are lacking. We compared serum midkine (MDK), dickkopf-1 (DKK1), osteopontin (OPN) and AFP for HCC diagnosis in 86 HCC patients matched to 86 cirrhotics, 86 with chronic liver disease (CLD) and 86 healthy controls (HC). Based on the performance of each biomarker, we assessed a separate longitudinal cohort of 28 HCC patients, at and before cancer diagnosis. Serum levels of MDK and OPN were higher in HCC patients compared to cirrhosis, CLD and HC groups. DKK1 was not different between cases and controls. More than half of HCC patients had normal AFP. In this AFP-negative HCC cohort, 59.18% (n = 29/49) had elevated MDK, applying the optimal cut-off of 0.44 ng/ml. Using AFP >= 20 IU/ml or MDK >= 0.44 ng/ml, a significantly greater number (76.7%; n = 66/86) of HCC cases were detected. The area under the receiver operating curve for MDK was superior to AFP and OPN in NASH-HCC diagnosis. In the longitudinal cohort, MDK was elevated in 15/28 (54%) of HCC patients at diagnosis, of whom 67% had elevated MDK 6 months prior. CONCLUSION: AFP and MDK have a complementary role in HCC detection. MDK increases the diagnostic yield in AFP-negative HCC and has greater diagnostic performance than AFP, OPN and DKK-1 in the diagnosis of NASH-HCC. Additionally, MDK has a promising role in the pre-clinical diagnosis of HCC. PMID- 27219518 TI - Differentially Isotope-Labeled Nucleosomes To Study Asymmetric Histone Modification Crosstalk by Time-Resolved NMR Spectroscopy. AB - Post-translational modifications (PTMs) of histones regulate chromatin structure and function. Because nucleosomes contain two copies each of the four core histones, the establishment of different PTMs on individual "sister" histones in the same nucleosomal context, that is, asymmetric histone PTMs, are difficult to analyze. Here, we generated differentially isotope-labeled nucleosomes to study asymmetric histone modification crosstalk by time-resolved NMR spectroscopy. Specifically, we present mechanistic insights into nucleosomal histone H3 modification reactions in cis and in trans, that is, within individual H3 copies or between them. We validated our approach by using the H3S10phK14ac crosstalk mechanism, which is mediated by the Gcn5 acetyltransferase. Moreover, phosphorylation assays on methylated substrates showed that, under certain conditions, Haspin kinase is able to produce nucleosomes decorated asymmetrically with two distinct types of PTMs. PMID- 27219519 TI - Constituents of Cypriol Oil (Cyperus scariosus R.Br.): N-Containing Molecules and Key Aroma Components. AB - Cypriol oil, the essential oil from Cyperus scariosus R.Br., has been investigated to reveal minor nitrogen-containing molecules and minor components responsible for the odor. A total of 21 nitrogenous components are reported, of which epi-guaipyridine (32 mg/kg), guaia-9,11-dienpyridine (9 mg/kg), and cananodine (10 mg/kg) were the most abundant. A new ketone, cyperen-8-one, with a significant woody, ambery odor could also be isolated and identified along with a novel lactone, cyperolactone, and an alcohol. Rotundone was found to have the highest odor-activity value of the measured compounds and, together with the other ketones, contributes to the woody-amber character of cypriol oil. PMID- 27219521 TI - Detection of Cancer-Specific Proteases Using Magnetic Relaxation of Peptide Conjugated Nanoparticles in Biological Environment. AB - Protease expression is closely linked to malignant phenotypes of different solid tumors; as such, their detection is promising for diagnosis and treatment of cancers, Alzheimer's, and vascular diseases. Here, we describe a new method for detecting proteases by sensitively monitoring the magnetic relaxation of monodisperse iron oxide nanoparticles (IONPs) using magnetic particle spectrometer (MPS). In this assay, tailored peptides functioning as activatable nanosensors link magnetic nanoparticles and possess selective sites that are recognizeable and cleaveable by specific proteases. When these linker peptides, labeled with biotin at N- and C-terminals, are added to the neutravidin functionalized IONPs, nanoparticles aggregate, resulting in well-defined changes in the MPS signal. However, as designed, in the presence of proteases these peptides are cleaved at predetermined sites, redispersing IONPs, and returning the MPS signal(s) close to its preaggregation state. These changes observed in all aspects of the MPS signal (peak intensity, its position as a function of field amplitude, and full width at half-maximum-when combined, these three also eliminate false positives), help to detect specific proteases, relying only on the magnetic relaxation characteristics of the functionalized nanoparticles. We demonstrate the general utility of this assay by detecting one each from the two general classes of proteases: trypsin (digestive serine protease, involved in various cancers, promoting proliferation, invasion, and metastasis) and matrix metalloproteinase (MMP-2, observed through metastasis and tumor angiogenesis). This MPS based protease-assay is rapid, reproducible, and highly sensitive and can form the basis of a feasible, high-throughput method for detection of various other proteases. PMID- 27219520 TI - The effect of two different renal denervation strategies on blood pressure in resistant hypertension: Comparison of full-length versus proximal renal artery ablation. AB - BACKGROUND: Renal denervation (RDN) is used to manage blood pressure (BP) in patients with resistant hypertension (rHT), but effectiveness is still a concern, and key arterial portion for successful RDN is not clear. OBJECTIVE: The aim of this study was to investigate the efficacy and safety of proximal versus full length renal artery ablation in patients with resistant hypertension (rHT). METHODS: Forty-seven patients with rHT were randomly assigned to receive full length ablation (n = 23) or proximal ablation (n = 24) of the renal arteries. All lesions were treated with radiofrequency energy via a saline-irrigated catheter. Office BP was measured during 12 months of follow-up and ambulatory BP at baseline and 6 months (n = 15 in each group). RESULTS: Compared with full-length ablation, proximal ablation reduced the number of ablation points in both the right (6.1 +/- 0.7 vs. 3.3 +/- 0.6, P < 0.001) and the left renal arteries (6.2 +/- 0.7 vs. 3.3 +/- 0.8, P < 0.001), with significantly shorter RF delivery time (P < 0.001), but higher RF power (P = 0.011). Baseline office BPs was 179.4 +/- 13.7/102.8 +/- 9.4 mm Hg in the full-length group and 181.9 +/- 12.8/103.5 +/- 8.9 mm Hg in the proximal group (P > 0.5). Similar office BPs was reduced by 39.4 +/- 11.5/-20.9 +/- 7.1 mm Hg at 6 months and -38.2 +/- 10.3/-21.5 +/- 5.8 mm Hg at 12 months in the full-length group (P < 0.001), -42.0 +/- 11.6/-21.4 +/- 7.9 mm Hg at 6 months and -40.9 +/- 10.3/-22.1 +/- 5.6 mm Hg at 12 months in the proximal group (P < 0.001), and progressive BP reductions were observed over the 6 months (P < 0.001) in both groups. The drop in ambulatory 24-hr SBP and DBP were significantly less than the drop in office BP (P < 0.001). No renovascular or other adverse complications were observed. CONCLUSIONS: The results indicate that proximal RDN has a similar efficacy and safety profile compared with full length RDN, and propose the proximal artery as the key portion for RDN. (c) 2016 Wiley Periodicals, Inc. PMID- 27219523 TI - Corrigendum. PMID- 27219524 TI - Efficient White-Light Generation from Ionically Self-Assembled Triply-Fluorescent Organic Nanoparticles. AB - Low cost, simple, and environmentally friendly strategies for white-light generation which do not require rare-earth phosphors or other toxic or elementally scare species remain an essentially unmet challenge. Progress in the area of all-organic approaches is highly sought, single molecular systems remaining a particular challenge. Taking inspiration from the designer nature of ionic-liquid chemistry, we now introduce a new strategy toward white-light emission based on the facile generation of nanoparticles comprising three different fluorophores assembled in a well-defined stoichiometry purely through electrostatic interactions. The building blocks consist of the fluorophores aminopyrene, fluorescein, and rhodamine 6G which represent blue, green, and red emitting species, respectively. Spherical nanoparticles 16(+/-5) nm in size were prepared which display bright white-light emission with high fluorescence quantum efficiency (26 %) and color coordinate at (0.29, 0.38) which lie in close proximity to pure white light (0.33, 0.33). It is noteworthy that this same fluorophore mixture in free solution yields only blue emission. Density functional theory calculations reveal H-bond and ground-state proton transfer mediated absolute non-parallel orientation of the constituent units which result in frustrated energy transfer, giving rise to emission from the individual centers and concomitant white-light emission. PMID- 27219525 TI - Entropy-Driven Conformational Control of alpha,omega-Difunctional Bidentate Dithiol Azo-Based Adsorbates Enables the Fabrication of Thermally Stable Surface Grafted Polymer Films. AB - Thermally stable radical initiator monolayers were prepared from uniquely designed alpha,omega-difunctional adsorbates with bidentate headgroups for the growth of nanoscale polymer films on metal surfaces. The length of the spacer separating the bidentate headgroups was varied to afford 4,4'-(diazene-1,2 diyl)bis(N-(16-(3,5-bis(mercaptomethyl)phenoxy)hexadecyl)-4-cyanopentanamide) (B16), 4,4'-(diazene-1,2-diyl)bis(N-(16-(3,5-bis(mercapto-methyl)phenoxy)decyl)-4 cyanopentanamide) (B10), and 4,4'-(diazene-1,2-diyl)bis(N-(4-(3,5 bis(mercaptomethyl)phenoxy)butyl)-4-cyanopentanamide) (B4). The structural features of the self-assembled monolayers (SAMs) derived from B16, B10, and B4 were characterized by X-ray photoelectron spectroscopy (XPS), ellipsometry, and polarization modulation infrared reflection-absorption spectroscopy (PM-IRRAS) and compared to those derived from an analogous alpha,omega-difunctional adsorbate with monodentate headgroups, 4,4'-(diazene-1,2-diyl)bis(4-cyano-N-(16 mercaptohexadecyl)pentanamide (M). These studies demonstrate that the conformation (i.e., hairpin vs standing up) of the bidentate initiator adsorbates on gold surfaces was easily controlled by adjusting the concentration of the adsorbates in solution. The results of solution-phase thermal desorption tests revealed that the radical initiator monolayers generated from B16, B10, and B4 exhibit an enhanced thermal stability when compared to those generated from M. Furthermore, a study of the growth of polymer films was performed to evaluate the utility of these new bidentate adsorbate SAMs as film-development platforms for new functional materials and devices. Specifically, surface-grafted polystyrene films were successfully generated from SAMs derived from B16. In contrast, attempts to grow polystyrene films from SAMs derived from M under a variety of analogous conditions were unsuccessful. PMID- 27219522 TI - PMH 9907: Long-term outcomes of a randomized phase 3 study of short-term bicalutamide hormone therapy and dose-escalated external-beam radiation therapy for localized prostate cancer. AB - BACKGROUND: The role of hormone therapy (HT) with dose-escalated external-beam radiotherapy (DE-EBRT) in the treatment of intermediate-risk prostate cancer (IRPC) remains controversial. The authors report the long-term outcome of a phase 3 study of DE-EBRT with or without HT for patients with localized prostate cancer (LPC). METHODS: From 1999 to 2006, 252 of an intended 338 patients with LPC were randomized to receive DE-EBRT with or without 5 months of neoadjuvant and concurrent bicalutamide 150 mg once daily. The study was closed early because of contemporary concerns surrounding bicalutamide. The primary outcome was biochemical failure (BF) incidence, and the secondary endpoints were overall survival (OS), local control (LC), and quality of life. The BF and OS rates were estimated using the cumulative incidence function and Kaplan-Meier methods and were compared using the Gray test and the log-rank test. RESULTS: Eleven patients were excluded from analysis. Characteristics were well balanced in each treatment arm. Ninety-five percent of patients had IRPC. The prescribed dose increased from 75.6 grays (Gy) in 42 fractions to 78 Gy in 39 fractions over the period. At a median follow-up of 9.1 years, 98 BFs occurred, with no significant effect of HT versus no HT on the BF rate (40% vs 47%; P = .32), the OS rate (82% vs 86%; P = .37), the LC rate (52% vs 48 %; P = .32) or quality of life, in the patients who completed the questionnaires. Dose escalation to 75.6 Gy versus >75.6 Gy reduced the BF rate by 26% (P = .004). CONCLUSIONS: For patients who predominantly have IRPC, the addition of HT to DE-EBRT did not significantly affect BF, OS, or LC. Bicalutamide appeared to be well tolerated. The conclusions from the study are limited by incomplete recruitment. Cancer 2016;122:2595-603. (c) 2016 American Cancer Society. PMID- 27219526 TI - The validation of the Italian Edinburgh Cognitive and Behavioural ALS Screen (ECAS). AB - This study presents the Italian validation of the recently developed Edinburgh Cognitive and Behavioural ALS Screen (ECAS), a short screen for cognitive/behavioural alterations in patients with amyotrophic lateral sclerosis (ALS). We evaluated the psychometric properties of the ECAS Italian version in terms of reliability and convergent validity for both cognitive and behavioural features. Furthermore, we investigated the relationship with affective and clinical variables, in addition to ECAS usability and patients' insight into cognitive/behaviour changes. Finally, correlations between genetic and cognitive/behavioural data were analysed. We recruited 107 patients with ALS. Normative data were collected on 248 healthy subjects. Participants were administered the ECAS and two standard cognitive screening tools (FAB, MoCA), two psychological questionnaires (BDI, STAI/Y) and an ad hoc usability questionnaire. The FBI was also carried out with caregivers. Results showed that the ECAS Italian version discriminated well between patients and controls. The most prevalent deficit occurred in executive functions and fluency. Correlations were observed between the ECAS and standard cognitive screening tools and between the ECAS carer interview and the FBI, supporting its full convergent validity. In conclusion, the ECAS Italian version provides clinicians with a rapid, feasible and sensitive tool, useful to identify different profiles of cognitive behavioural impairment in ALS. PMID- 27219527 TI - Trillin Reduces Liver Chronic Inflammation and Fibrosis in Carbon Tetrachloride (CCl4) Induced Liver Injury in Mice. AB - Trillin is an active ingredient isolated from Dioscorea nipponica Makino. This study investigated the anti-inflammatory and anti-fibrosis effects of trillin on CCl4-induced hepatotoxicity in C57BL/6 mice. Chronic inflammation and fibrosis were induced by intraperitoneal administration of CCl4 0.5 MUL/g of body weight twice a week for 6 weeks. Trillin (50 mg/kg, 100 mg/kg) was administered by gavage for 12 days before finishing the CCl4 induction. Aspartate amino transferase (AST) and glutamic-pyruvic transaminase (ALT) in serum were determined by AST and ALT kits. Superoxidase dismutase (SOD) activity and malondialdehyde (MDA) levels in serum were assayed by SOD and MDA kits. Meanwhile, the levels of inflammatory mediators including tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1beta (IL-1beta) in serum were detected by enzyme-linked immunosorbent assay (ELISA) method. Pathological changes were observed by hematoxylin-eosin (HE) staining. The proteins of the NF-kappaB pathway and the TGF-beta/Smad pathway were measured by western blot. The trillin-treated group exhibited reduced AST, ALT, MDA, IL-6, TNF-alpha, and IL-1beta, and increased SOD. Histological analyses of the trillin treated group exhibited reduced inflammatory process and prevented liver fibrosis. Western blot analyses of the trillin-treated group showed reduced NF kappaB pathway and TGF-beta/Smad pathway. SIGNIFICANCE: Based on the results of the present study, trillin can be used as a potential anti-inflammatory drug for chronic hepatic inflammation. PMID- 27219528 TI - WITHDRAWN: Preoperative statin therapy for patients undergoing cardiac surgery. PMID- 27219529 TI - Effect of calculation method on kidney dosimetry in 177Lu-octreotate treatment. AB - BACKGROUND: 177Lu-octreotate is an effective treatment modality for patients with metastatic neuroendocrine tumors. The kidney is a critical dose-limiting organ in that modality. We investigated the absorbed doses in the kidney and compared whole kidney volume (WKV) and small (4 cm3) volume of the kidney (SV) methods. We also evaluated a new calculation method that was based on two single photon emission computed tomography/computed tomography (SPECT/CT) scans. METHODS: Absorbed radiation doses in the kidneys were calculated for 24 patients with neuroendocrine tumors. All patients received four cycles of 177Lu-octreotate given at eight-week intervals with a mean activity of 7.1 GBq (range 3.28-8.79 GBq). Absorbed doses and half-lives were calculated by the WKV and SV methods. Dosimetry was determined for the cortex and medulla in the first treatment cycle. RESULTS: The mean absorbed radiation dose was 0.44 +/- 0.15 Gy/GBq for the WKV method and, 0.74 +/- 0.28 Gy/GBq for the SV method. Three patients had a 20% increase of the absorbed dose over the four treatment cycles for the WKV method compared to eight patients for the SV method. The mean absorbed dose in the medulla was 0.62 +/- 0.27 Gy/GBq, whereas the mean absorbed dose in the cortex was 0.41 +/- 0.22 Gy/GBq. Both regions had similar half-lives. Patients who received lower activities for medical reasons still had similar absorbed doses to kidneys compared to those who received the full activities. Our study indicates that absorbed doses can be calculated reliably using two SPECT/CT scans, at 24 and 168 hours after each treatment. CONCLUSIONS: Absorbed doses in the kidneys from systemic radionuclide therapy that are measured by the WKV method and SV method cannot be directly compared. There were regional differences within kidneys for the uptake of 177Lu-octreotate. Two SPECT/CTs are sufficient for kidney dosimetry based on our new calculation method. PMID- 27219530 TI - Calculations of the Energetics of Oxidation of Aqueous Nucleosides and the Effects of Prototropic Equilibria. AB - Recently the calculated standard reduction potentials of the radical-cations of N methyl substituted DNA bases have been reported that agree fairly well with the experimental results. However, there are issues reflecting the fact that the experimental results usually relate to the couple E(o)(Nuc(*),H(+)/NucH(+)), whereas the calculated results are for the E(o)(Nuc(*+)/Nuc) couple. To calculate the midpoint reduction potential at pH 7 (Em7), it is important to have accurate acid dissociation constants (pKs) for both ground-state bases and their radicals, and the effects of uncertainty in some of these values (e.g., that of the adenosine radical) must be considered. Calculations of the pKs of the radicals of the nucleic acid bases (as nucleosides) have been performed to explore the effects the various pKs have on calculating the values of Em7 and to see what improvements can be made with the accuracy of the calculations. PMID- 27219531 TI - Therapeutic alliance mediates the association between personality and treatment outcome in patients with major depressive disorder. AB - BACKGROUND: Patient personality traits have been shown to influence treatment outcome in those with major depressive disorder (MDD). The trait agreeableness, which reflects an interpersonal orientation, may affect treatment outcome via its role in the formation of therapeutic alliance. No published studies have tested this hypothesis in patients with MDD. METHOD: Participants were 209 outpatients with MDD who were treated in a randomized control trial. Mediation analyses were conducted to examine the role of therapeutic alliance in the association between pretreatment personality and the reduction of depression symptom severity during treatment. Separate models were estimated for patient- versus therapist-rated therapeutic alliance. RESULTS: We found a significant indirect effect of agreeableness on the reduction of depression severity via patient-rated therapeutic alliance. Results were replicated across two well-validated measures of depression symptom severity. Results also partially supported indirect effects for extraversion and openness. Therapist ratings of alliance did not mediate the association between personality and treatment outcomes. LIMITATIONS: Patients were recruited as part of a randomized control trial, which may limit the generalizability of results to practice-based clinical settings. Due to constraints on statistical power, intervention-specific mediation results were not examined. CONCLUSIONS: These results highlight the importance of personality and the role it plays in treatment process as well as outcome. PMID- 27219532 TI - The cross-race effect in face recognition memory by bicultural individuals. AB - Social-cognitive models of the cross-race effect (CRE) generally specify that cross-race faces are automatically categorized as an out-group, and that different encoding processes are then applied to same-race and cross-race faces, resulting in better recognition memory for same-race faces. We examined whether cultural priming moderates the cognitive categorization of cross-race faces. In Experiment 1, monoracial Latino-Americans, considered to have a bicultural self, were primed to focus on either a Latino or American cultural self and then viewed Latino and White faces. Latino-Americans primed as Latino exhibited higher recognition accuracy (A') for Latino than White faces; those primed as American exhibited higher recognition accuracy for White than Latino faces. In Experiment 2, as predicted, prime condition did not moderate the CRE in European-Americans. These results suggest that for monoracial biculturals, priming either of their cultural identities influences the encoding processes applied to same- and cross race faces, thereby moderating the CRE. PMID- 27219533 TI - An empirical test of the decision to lie component of the Activation-Decision Construction-Action Theory (ADCAT). AB - Meta-analyses reveal that behavioral differences between liars and truth tellers are small. To facilitate lie detection, researchers are currently developing interviewing approaches to increase these differences. Some of these approaches assume that lying is cognitively more difficult than truth telling; however, they are not based on specific cognitive theories of lie production, which are rare. Here we examined one existing theory, Walczyk et al.'s (2014) Activation-Decision Construction-Action Theory (ADCAT). We tested the Decision component. According to ADCAT, people decide whether to lie or tell the truth as if they were using a specific mathematical formula to calculate the motivation to lie from (a) the probability of a number of outcomes derived from lying vs. telling the truth, and (b) the costs/benefits associated with each outcome. In this study, participants read several hypothetical scenarios and indicated whether they would lie or tell the truth in each scenario (Questionnaire 1). Next, they answered several questions about the consequences of lying vs. telling the truth in each scenario, and rated the probability and valence of each consequence (Questionnaire 2). Significant associations were found between the participants' dichotomous decision to lie/tell the truth in Questionnaire 1 and their motivation to lie scores calculated from the Questionnaire 2 data. However, interestingly, whereas the expected consequences of truth telling were associated with the decision to lie vs. tell the truth, the expected consequences of lying were not. Suggestions are made to refine ADCAT, which can be a useful theoretical framework to guide deception research. PMID- 27219534 TI - The microglial ATP-gated ion channel P2X7 as a CNS drug target. AB - Based on promising preclinical evidence, microglial P2X7 has increasingly being recognized as a target for therapeutic intervention in neurological and psychiatric diseases. However, despite this knowledge no P2X7-related drug has yet entered clinical trials with respect to CNS diseases. We here discuss the current literature on P2X7 being a drug target and identify unsolved issues and still open questions that have hampered the development of P2X7 dependent therapeutic approaches for CNS diseases. It is concluded here that the lack of brain penetrating P2X7 antagonists is a major obstacle in the field and that central P2X7 is a yet untested clinical drug target. In the CNS, microglial P2X7 activation causes neuroinflammation, which in turn plays a role in various CNS disorders. This has resulted in a surge of brain penetrant P2X7 antagonists. P2X7 is a viable, clinically untested CNS drug target. GLIA 2016;64:1772-1787. PMID- 27219536 TI - Partial Brain Tissue Oxygen Levels Predict Arrhythmia and Prognosis in Patients With Brain Injury. AB - The objective of this study was to examine the clinical determinants of incidence and prognosis of arrhythmias in the setting of acute brain injury. Acute brain injury is known to cause electrocardiographic abnormalities and cardiac arrhythmias. The relation between partial brain tissue oxygen (PBTO) and intracranial pressure (ICP) with arrhythmia incidence and prognosis remains unknown. Consecutive patients with acute brain injury and intracranial bleed admitted to the neurosurgical intensive care unit were enrolled in the study. Baseline characteristics [demographics, medical history, etiology of brain injury, Glasgow Coma Scale (GCS) score, blood pressure, and respiratory rate] were documented. Patient's telemetry recordings were reviewed for daily mean heart rates and arrhythmias. If arrhythmia was noted, PBTO levels at the beginning of arrhythmia, ICP, brain tissue temperature, and outcomes were recorded. A total of 106 subjects (53% men, age 39 +/- 18 years, 65 traumatic and 41 nontraumatic brain injuries) were studied. Overall, 62% of subjects developed a total of 241 arrhythmia episodes. Ventricular arrhythmias were associated with significantly higher daily mean heart rates, low PBTO levels, and low GCS scores, whereas atrial arrhythmias were associated with lower daily mean heart rates, normal PBTO levels, and higher GCS and ICP. Three or more episodes of arrhythmia predicted worse outcomes, including mortality (P = 0.001). In patients with acute brain injury, poor PBTO levels are associated with higher incidence of ventricular tachyarrhythmias. In contrast, atrial tachyarrhythmias occur in patients with normal PBTO levels and higher ICP. Incidence of ventricular arrhythmia in those with poor PBTO is associated with increased mortality. PMID- 27219535 TI - Particulate Air Pollution and Fasting Blood Glucose in Nondiabetic Individuals: Associations and Epigenetic Mediation in the Normative Aging Study, 2000-2011. AB - BACKGROUND: Among nondiabetic individuals, higher fasting blood glucose (FBG) independently predicts diabetes risk, cardiovascular disease, and dementia. Ambient PM2.5 (particulate matter with aerodynamic diameter <= 2.5 MUm) is an emerging determinant of glucose dysregulation. PM2.5 effects and mechanisms are understudied among nondiabetic individuals. OBJECTIVES: Our goals were to investigate whether PM2.5 is associated with an increase in FBG and to explore potential mediating roles of epigenetic gene regulation. METHODS: In 551 nondiabetic participants in the Normative Aging Study, we measured FBG, and DNA methylation of four inflammatory genes (IFN-gamma, IL-6, ICAM-1, and TLR-2), up to four times between 2000 and 2011 (median = 2). We estimated short- and medium term (1-, 7-, and 28-day preceding each clinical visit) ambient PM2.5 at each participant's address using a validated hybrid land-use regression satellite based model. We fitted covariate-adjusted regression models accounting for repeated measures. RESULTS: Mean FBG was 99.8 mg/dL (SD = 10.7), 18% of the participants had impaired fasting glucose (IFG; i.e., 100-125 mg/dL FBG) at first visit. Interquartile increases in 1-, 7-, and 28-day PM2.5 were associated with 0.57 mg/dL (95% CI: 0.02, 1.11, p = 0.04), 1.02 mg/dL (95% CI: 0.41, 1.63, p = 0.001), and 0.89 mg/dL (95% CI: 0.32, 1.47, p = 0.003) higher FBG, respectively. The same PM2.5 metrics were associated with 13% (95% CI: -3%, 33%, p = 0.12), 27% (95% CI: 6%, 52%, p = 0.01) and 32% (95% CI: 10%, 58%, p = 0.003) higher odds of IFG, respectively. PM2.5 was negatively correlated with ICAM-1 methylation (p = 0.01), but not with other genes. Mediation analysis estimated that ICAM-1 methylation mediated 9% of the association of 28-day PM2.5 with FBG. CONCLUSIONS: Among nondiabetics, short- and medium-term PM2.5 were associated with higher FBG. Mediation analysis indicated that part of this association was mediated by ICAM-1 promoter methylation. Citation: Peng C, Bind MA, Colicino E, Kloog I, Byun HM, Cantone L, Trevisi L, Zhong J, Brennan K, Dereix AE, Vokonas PS, Coull BA, Schwartz JD, Baccarelli AA. 2016. Particulate air pollution and fasting blood glucose in nondiabetic individuals: associations and epigenetic mediation in the Normative Aging Study, 2000-2011. Environ Health Perspect 124:1715-1721; http://dx.doi.org/10.1289/EHP183. PMID- 27219537 TI - Effectiveness of neuroendoscopic ventricular irrigation for ventriculitis. AB - OBJECTIVES: Ventriculitis is an uncommon condition with a poor prognosis, especially when complicated by brain abscess. We compared the therapeutic efficacy of neuroendoscopic ventricular irrigation with those of conventional treatments such as ventricular drainage and continuous irrigation via a ventricular drain. PATIENTS AND METHODS: We retrospectively analyzed 14 consecutive patients treated for ventriculitis at our institution between 2001 and 2015. Included were the six patients treated with neuroendoscopic (NE) irrigation (NE group), which we adopted in 2011, and the eight patients treated before 2011 with conventional treatments (non-NE group). We compared mortality, modified Rankin Scale (mRS) score 6 months postoperatively, and duration of ventricular/spinal drainage-catheter placement between groups. RESULTS: Mean age at onset was 49.3 years (range, 32-68 years) in the NE group and 50.3 years (range, 8-78 years) in the non-NE group. At 6-month follow-up, good clinical outcome (mRS<=3) was observed in 66.7% of the NE group, whereas it was observed in 25.0% of the non-NE group. There were three deaths (37.5%) in the non-NE group but none in the NE group. Duration of drainage-catheter placement was significantly shorter in the NE group than in the non-NE group (19.8days vs. 70.9days, p<0.001). Among patients in the NE group, only those who underwent irrigation on the day of diagnosis maintained a low mRS score. CONCLUSION: Neuroendoscopic ventricular irrigation was safe and effective in the treatment of ventriculitis. Immediate intervention after diagnosis may lead to an improved prognosis. PMID- 27219538 TI - Mechanical Unfolding of an Autotransporter Passenger Protein Reveals the Secretion Starting Point and Processive Transport Intermediates. AB - The backbone of secreted autotransporter passenger proteins generally attains a stable beta-helical structure. The secretion of passengers across the outer membrane was proposed to be driven by sequential folding of this structure at the cell surface. This mechanism would require a relatively stable intermediate as starting point. Here, we investigated the mechanics of secreted truncated versions of the autotransporter hemoglobin protease (Hbp) of Escherichia coli using atomic force microscopy. The data obtained reveal a beta-helical structure at the C terminus that is very stable. In addition, several other distinct metastable intermediates are found which are connected during unfolding by multiroute pathways. Computational analysis indicates that these intermediates correlate to the beta-helical rungs in the Hbp structure which are clamped by stacked aromatic residues. Our results suggest a secretion mechanism that is initiated by a stable C-terminal structure and driven forward by several folding intermediates that build up the beta-helical backbone. PMID- 27219539 TI - Adaptive Neuro-Fuzzy Determination of the Effect of Experimental Parameters on Vehicle Agent Speed Relative to Vehicle Intruder. AB - Intelligent Transportation Systems rely on understanding, predicting and affecting the interactions between vehicles. The goal of this paper is to choose a small subset from the larger set so that the resulting regression model is simple, yet have good predictive ability for Vehicle agent speed relative to Vehicle intruder. The method of ANFIS (adaptive neuro fuzzy inference system) was applied to the data resulting from these measurements. The ANFIS process for variable selection was implemented in order to detect the predominant variables affecting the prediction of agent speed relative to intruder. This process includes several ways to discover a subset of the total set of recorded parameters, showing good predictive capability. The ANFIS network was used to perform a variable search. Then, it was used to determine how 9 parameters (Intruder Front sensors active (boolean), Intruder Rear sensors active (boolean), Agent Front sensors active (boolean), Agent Rear sensors active (boolean), RSSI signal intensity/strength (integer), Elapsed time (in seconds), Distance between Agent and Intruder (m), Angle of Agent relative to Intruder (angle between vehicles degrees ), Altitude difference between Agent and Intruder (m)) influence prediction of agent speed relative to intruder. The results indicated that distance between Vehicle agent and Vehicle intruder (m) and angle of Vehicle agent relative to Vehicle Intruder (angle between vehicles degrees ) is the most influential parameters to Vehicle agent speed relative to Vehicle intruder. PMID- 27219540 TI - Pre-Natal Exposure to Mouse Parvovirus at Day 5 and 12 Gestation Does Not Induce Immune Tolerance. AB - Parvoviruses have a predilection for rapidly dividing cells such as occurs during embryonic development. Potentially, in utero exposure could lead to immune tolerance in progeny mice. To determine if MPV infection in utero results in immune tolerance, pregnant mice were inoculated by oral gavage with 50 ID50 MPV1e or sham inoculated with phosphate buffered saline at day 5 and 12 gestation. Offspring were fostered to MPV-negative recipient dams prior to development of a milk spot. After confirming the offspring were seronegative for MPV by serology and not shedding by fecal PCR, they were challenged with 50 ID50 MPV1e by oral gavage at weaning or sham inoculated. At 4 weeks post inoculation, all weanlings exposed in utero developed antibodies to MPV, and MPV was detected by fecal PCR. Similarly, all weanlings from sham-inoculated dams challenged with MPV developed antibodies and MPV was detected by fecal PCR. None of the sham inoculated weanling mice from MPV infected dams or sham infected dams developed antibodies to MPV nor was MPV detected by fecal PCR. These results demonstrate that in utero exposure to MPV1e via oral gavage was insufficient to induce immune tolerance and provides greater confidence that rederivation techniques may successfully eliminate colonies of MPV. Furthermore, our findings do not provide evidence that MPV tolerance may contribute to hidden infections in mouse colonies. PMID- 27219615 TI - Parametric analysis of glenoid implant design and fixation type. AB - Common post-operative problems in shoulder arthroplasty such as glenoid loosening and joint instability may be reduced by improvements in glenoid design, shape, material choice, and fixation method. A framework for parametric analysis of different implant fixation configurations was developed in order to efficiently sift through potential glenoid component designs. We investigated the influence of design factors such as fixation type, component thickness, and peg position, number, diameter, and length in a multi-factorial design investigation. The proposed method allowed for simultaneous comparison of the mechanical performance of 344 different parametric variations of 10 different reference geometries with either large central fixation features or small peripheral pegs, undergoing four different worst-case scenario loading conditions, and averaging 64.7 s per model. The impact of design parameters were assessed for different factors responsible for post-operative problems in shoulder arthroplasty, such as bone volume preservation, stresses in the implant, central displacement or fixation stability, and the worst performing geometries all relied on conventional central fixation. Of the remaining geometries, four peripheral fixation configurations produced von Mises stresses comfortably below the material's yield strength. We show that the developed method allows for simple, direct, rapid, and repeatable comparison of different design features, material choices, or fixation methods by analyzing how they influence the bone-implant mechanical environment. The proposed method can provide valuable insight in implant design optimization by screening through multiple potential design modifications at an early design evaluation stage and highlighting the best performing combinations according to the failure mechanism to mitigate. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:775-784, 2017. PMID- 27219616 TI - Targeting the sympatho-adrenergic link in chronic rheumatic mitral regurgitation: assessing the role of oral beta-blockers. AB - INTRODUCTION: Chronic mitral regurgitation (MR) is characterized by adverse ventricular remodeling and progressive LV dysfunction leading to heart failure (HF). Beta-blockers (BB) improve LV remodeling and prognosis in patients with HF. As chronic severe MR results in neuroendocrine activation similar to HF, it is likely that BB may also exert favorable effects in these patients. No study has assessed the role of oral BB therapy in chronic rheumatic MR. AIMS: A total of 100 patients of chronic rheumatic MR (mean age 30+/-13.48 years, NYHA 2.2+/-0.5) were randomized to BB (Metoprolol, 37+/-13.5 mg, n=48) vs no BB (n=52) in addition to standard therapy. RESULTS: Baseline BNP and echocardiographic parameters were comparable in the two groups. At 3 months, BB therapy resulted in significantly lower NYHA class (1.97 vs 2.35), BNP (141 vs 207 pg/mL), LV end systolic (35.89 vs 51.30) and LV end-diastolic volumes (101 vs 128 mL/m(2) ), LV end-systolic stress (81.1 vs 93.3 dyn/cm(2) ), LV mass (122 vs 154 gm/m(2) ), and LV work (737.02 vs 952.82 mm Hg L/min, all P significant). Therapy with BB resulted in a -15.6%, -10.4%,-12.1%, and -7.3% reduction in LV end-systolic and end-diastolic dimensions and LVESVi and LVEDVi, respectively. Following BB therapy, BNP levels, end-systolic stress, indexed LV mass, and LV work also reduced significantly by 27.3%, 15.6%, 8.7%, and 28%, respectively. The control group had no significant change. The MR grade reduced from severe to moderate in 11% of those on BB (controls: no change). At 6 months, the BB group had further improvement in all echocardiographic parameters ranging from +9.1 to -18.2%. CONCLUSION: In this first study of BB in rheumatic MR, targeting the sympatho adrenergic axis exerted favorable effects on NYHA class, LV volumes, LV end systolic stress, and LV work. Further studies are required to elucidate the role of BB in rheumatic MR. PMID- 27219617 TI - Access to Specialized Care Through Telemedicine in Limited-Resource Country: Initial 1,065 Teleconsultations in Albania. AB - OBJECTIVE: To analyze the initial experience of the nationwide clinical telemedicine program of Albania, as a model of implementation of telemedicine using "Initiate-Build-Operate-Transfer" strategy. METHODS: This was a retrospective study of prospectively collected data from teleconsultations in Albania between January 1, 2014 and August 26, 2015, delivered synchronously, asynchronously, or a combination of both methods. Patient's demographics, mode of consultation, clinical specialty, hospitals providing referral and consultation, time from initial call to completion of consultation, and patient disposition following teleconsultation were analyzed. Challenges of the newly created program have been identified and analyzed as well. RESULTS: There were 1,065 teleconsultations performed altogether during the study period. Ninety-one patients with autism managed via telemedicine were not included in this analysis and will be reported separately. Of 974 teleconsults, the majority were for radiology, neurotrauma, and stroke (55%, 16%, and 10% respectively). Asynchronous technology accounted for nearly two-thirds of all teleconsultations (63.7%), followed by combined (24.3%), and then synchronous (12.0%). Of 974 cases, only 20.0% of patients in 2014 and 22.72% of patients in 2015 were transferred to a tertiary hospital. A majority (98.5%) of all teleconsultations were conducted within the country itself. CONCLUSIONS: The Integrated Telemedicine and e-Health program of Albania has become a useful tool to improve access to high-quality healthcare, particularly in high demanding specialty disciplines. A number of challenges were identified and these should serve as lessons for other countries in their quest to establish nationwide telemedicine programs. PMID- 27219618 TI - The New 3D Printed Left Atrial Appendage Closure with a Novel Holdfast Device: A Pre-Clinical Feasibility Animal Study. AB - INTRODUCTION: Many patients undergoing cardiac surgery have risk factors for both atrial fibrillation (AF) and stroke. The left atrial appendage (LAA) is the primary site for thrombi formation. The most severe complication of emboli derived from LAA is stroke, which is associated with a 12-month mortality rate of 38% and a 12-month recurrence rate of 17%. The most common form of treatment for atrial fibrillation and stroke prevention is the pharmacological therapy with anticoagulants. Nonetheless this form of therapy is associated with high risk of major bleeding. Therefore LAA occlusion devices should be tested for their ability to reduce future cerebral ischemic events in patients with high-risk of haemorrhage. AIM: The aim of this study was to evaluate the safety and feasibility of a novel left atrial appendage exclusion device with a minimally invasive introducer in a swine model. MATERIALS AND METHODS: A completely novel LAA device, which is composed of two tubes connected together using a specially created bail, was designed using finite element modelling (FEM) to obtain an optimal support force of 36 N at the closure line. The monolithic form of the occluder was obtained by using additive manufacturing of granular PA2200 powder with the technology of selective laser sintering (SLS). Fifteen swine were included in the feasibility tests, with 10 animals undergoing fourteen days of follow-up and 5 animals undergoing long-term observation of 3 months. For one animal, the follow-up was further prolonged to 6 months. The device was placed via minithoracotomy. After the observation period, all of the animals were euthanized, and their hearts were tested for LAA closure and local inflammatory and tissue response. RESULTS: After the defined observation period, all fifteen hearts were explanted. In all cases the full closure of the LAA was achieved. The macroscopic and microscopic evaluation of the explanted hearts showed that all devices were securely integrated in the surrounding tissues. No pericarditis or macroscopic signs of inflammation at the site of the device were found. All pigs were in good condition with normal weight gain and no other clinical symptoms. CONCLUSION: This novel 3D printed left atrial appendage closure technique with a novel holdfast device was proven to be safe and feasible in all pigs. A benign healing process without inflammation and damage to the surrounding structures or evidence of new thrombi formation was observed. Moreover, the uncomplicated survival and full LAA exclusion in all animals demonstrate the efficacy of this novel and relatively cheap device. Further clinical evaluation and implementation studies should be performed to introduce this new technology into clinical practice. PMID- 27219619 TI - Lysosomal Acid Lipase Activity Is Reduced Both in Cryptogenic Cirrhosis and in Cirrhosis of Known Etiology. AB - CONCLUSION: Liver cirrhosis is characterized by a severe acquired reduction of LAL-activity, the precise causes and consequences of which need to be further addressed. DBS-determined lysosomal enzyme activities seem to be affected by white blood cell and platelet counts, and the specificity of these tests can be reduced when applied to determined populations, such as cirrhotics. PMID- 27219620 TI - Time course of EPSCs in ON-type starburst amacrine cells is independent of dendritic location. AB - KEY POINTS: Direction selectivity has been widely studied as an example of a complex neural computation. Directional GABA release from starburst amacrine cells (SBACs) is critical for generating directional signals in direction selective ganglion cells. The mechanisms producing the directional release remain unclear. For SBACs, ordered distribution of sustained and transient bipolar cell inputs along the dendrites is proposed to generate directional GABA release. This study tests whether this hypothesis applies to ON-type SBACs. EPSCs activated at proximal and distal dendritic locations have the same time course. Therefore, the ordered arrangement of inputs from bipolar cells with different kinetic properties cannot be responsible for generating directional GABA release from ON type SBACs. ABSTRACT: Direction selectivity in the retina relies critically on directionally asymmetric GABA release from the dendritic tips of starburst amacrine cells (SBACs). GABA release from each radially directed dendrite is larger for motion outward from the soma toward the dendritic tips than for motion inwards toward the soma. The biophysical mechanisms generating these directional signals remain controversial. A model based on electron-microscopic reconstructions of the mouse retina proposed that an ordered arrangement of kinetically distinct bipolar cell inputs to ON- and OFF-type SBACs could produce directional GABA release. We tested this prediction by measuring the time course of EPSCs in ON-type SBACs in the mouse retina, activated by proximal and distal light stimulation. Contrary to the prediction, the kinetics of the excitatory inputs were independent of dendritic location. Computer simulations based on 3D reconstructions of SBAC dendrites demonstrated that the response kinetics of distal inputs were not significantly altered by dendritic filtering. These direct physiological measurements, do not support the hypothesis that directional signals in SBACs arise from the ordered arrangement of kinetically distinct bipolar cell inputs. PMID- 27219621 TI - Comparison of Cardiac and Non-Cardiac Biomarkers for Risk Stratification in Elderly Patients with Non-Massive Pulmonary Embolism. AB - Biomarkers unrelated to myocardial necrosis, such as cystatin C, copeptin, and mid-regional pro-adrenomedullin (MR-proADM), showed promise for cardiovascular risk prediction. Knowing whether they are comparable to cardiac biomarkers such as high-sensitive cardiac-troponin T (hs-cTnT) or N-terminal pro-Brain natriuretic peptide (NT-proBNP) in elderly patients with acute non-massive pulmonary embolism (NMPE) remains elusive. This study aims at comparing the prognostic accuracy of cardiac and non-cardiac biomarkers in patients with NMPE aged >=65 years over time. In the context of the SWITCO65+ cohort, we evaluated 227 elderly patients with an available blood sample taken within one day from diagnosis. The primary study endpoint was defined as PE-related mortality and the secondary endpoint as PE-related complications. The biomarkers' predictive ability at 1, 3, 12 and 24 months was determined using C-statistics and Cox regression. For both study endpoints, C-statistics (95% confidence interval) were stable over time for all biomarkers, with the highest value for hs-cTnT, ranging between 0.84 (0.68-1.00) and 0.80 (0.70-0.90) for the primary endpoint, and between 0.74 (0.63-0.86) and 0.65 (0.57-0.73) for the secondary endpoint. For both study endpoints, cardiac biomarkers were found to be independently associated with risk, NT-proBNP displaying a negative predictive value of 100%. Among non-cardiac biomarkers, only copeptin and MR-proADM were independent predictors of PE-related mortality but they were not independent predictors of PE related complications, and displayed lower negative predictive values. In elderly NMPE patients, cardiac biomarkers appear to be valuable prognostic to identify very low-risk individuals. TRIAL REGISTRATION: ClinicalTrials.gov NCT00973596. PMID- 27219622 TI - Salivary and Serum Antibody Response Against Neisseria meningitidis After Vaccination With Conjugate Polysaccharide Vaccines in Ethiopian Volunteers. AB - Meningococcal conjugate vaccines induce serum antibodies crucial for protection against invasive disease. Salivary antibodies are believed to be important for hindering meningococcal acquisition and/or clearance of established carriage. In this study, we measured salivary IgA and IgG antibodies induced by vaccination with a monovalent serogroup A conjugate vaccine or a tetravalent A, C, W and Y conjugate vaccine, in comparison with antibody levels in serum. Saliva and serum samples from Ethiopian volunteers (1-29 years) collected before and eight times on a weekly basis after receiving the serogroup A conjugate vaccine, the tetravalent serogroup A, C, W and Y conjugate vaccine, or no vaccine (control group), were analysed using a multiplex microsphere immunoassay for antibody detection. Serogroup-specific IgG antibody levels in saliva increased significantly after vaccination with both vaccines. The monovalent serogroup A vaccine also induced an increase in salivary IgA antibodies. A strong correlation between serogroup-specific IgG antibodies in saliva and serum, and a somewhat lower correlation for IgA, was observed for all serogroups. There was also a strong correlation between specific secretory IgA and IgA antibodies in saliva for all serogroups. Meningococcal conjugate vaccines are able to elicit salivary antibodies against serogroup A, C, W and Y correlating with antibody levels in serum. The strong correlation between saliva and serum antibody levels indicates that saliva may be used as a surrogate of systemic antibody responses. PMID- 27219624 TI - Cumulative and booster effects of tdcs sessions on drug cravings, lapse, and cognitive impairment in methamphetamine use disorder: A case study report. AB - BACKGROUND AND OBJECTIVES: Transcranial Direct Current Stimulation (tDCS) is a non-invasive brain stimulation method, which shows promising therapeutic effects in controlling drug cravings. METHODS: In this study, we present cumulative and booster effects of tDCS sessions on methamphetamine cravings, lapse, and cognitive impairment in a methamphetamine dependent subject. RESULTS: Our study shows cumulative effects of continuous anodal tDCS sessions on right dorsolateral prefrontal cortex (DLPFC) could reduce drug cravings and their consequences. DISCUSSION AND CONCLUSIONS: Moreover, booster tDCS treatments might be helpful in controlling psychological stress and drug cravings. (Am J Addict 2016;25:264 266). PMID- 27219625 TI - Rapid and efficient analysis of gene function using CRISPR-Cas9 in Xenopus tropicalis founders. AB - Recent advances in genome editing using programmable nucleases, such as zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas system, have facilitated reverse genetics in Xenopus tropicalis. To establish a practical workflow for analyzing genes of interest using CRISPR-Cas9, we examined various experimental procedures and conditions. We first compared the efficiency of gene disruption between Cas9 protein and mRNA injection by analyzing genotype and phenotype frequency, and toxicity. Injection of X. tropicalis embryos with Cas9 mRNA resulted in high gene-disrupting efficiency comparable with that produced by Cas9 protein injection. To exactly evaluate the somatic mutation rates of on-target sites, amplicon sequencing and restriction fragment length polymorphism analysis using a restriction enzyme or recombinant Cas9 were performed. Mutation rates of two target genes (slc45a2 and ltk) required for pigmentation were estimated to be over 90% by both methods in animals exhibiting severe phenotypes, suggesting that targeted somatic mutations were biallelically introduced in almost all somatic cells of founder animals. Using a heteroduplex mobility assay, we also showed that off-target mutations were induced at a low rate. Based on our results, we propose a CRISPR-Cas9-mediated gene disruption workflow for a rapid and efficient analysis of gene function using X. tropicalis founders. PMID- 27219626 TI - Why We Study Disparities: The Human Stories Behind the Data. PMID- 27219623 TI - High-Resolution Mapping of Crossover and Non-crossover Recombination Events by Whole-Genome Re-sequencing of an Avian Pedigree. AB - Recombination is an engine of genetic diversity and therefore constitutes a key process in evolutionary biology and genetics. While the outcome of crossover recombination can readily be detected as shuffled alleles by following the inheritance of markers in pedigreed families, the more precise location of both crossover and non-crossover recombination events has been difficult to pinpoint. As a consequence, we lack a detailed portrait of the recombination landscape for most organisms and knowledge on how this landscape impacts on sequence evolution at a local scale. To localize recombination events with high resolution in an avian system, we performed whole-genome re-sequencing at high coverage of a complete three-generation collared flycatcher pedigree. We identified 325 crossovers at a median resolution of 1.4 kb, with 86% of the events localized to <10 kb intervals. Observed crossover rates were in excellent agreement with data from linkage mapping, were 52% higher in male (3.56 cM/Mb) than in female meiosis (2.28 cM/Mb), and increased towards chromosome ends in male but not female meiosis. Crossover events were non-randomly distributed in the genome with several distinct hot-spots and a concentration to genic regions, with the highest density in promoters and CpG islands. We further identified 267 non-crossovers, whose location was significantly associated with crossover locations. We detected a significant transmission bias (0.18) in favour of 'strong' (G, C) over 'weak' (A, T) alleles at non-crossover events, providing direct evidence for the process of GC-biased gene conversion in an avian system. The approach taken in this study should be applicable to any species and would thereby help to provide a more comprehensive portray of the recombination landscape across organism groups. PMID- 27219627 TI - A National Report of Nursing Home Information Technology Adoption and Quality Measures. PMID- 27219629 TI - Training improves the oxidative phenotype of muscle during the transition from cardiac hypertrophy to heart failure without altering MyoD and myogenin. AB - NEW FINDINGS: What is the central question of this study? We investigated the effects of physical training on phenotypic (fibre-type content) and myogenic features (MyoD and myogenin expression) in skeletal muscle during the transition from cardiac hypertrophy to heart failure. What is the main finding and its importance? We provide new insight into skeletal muscle adaptations by showing that physical training increases the type I fibre content during the transition from cardiac hypertrophy to heart failure, without altering MyoD and myogenin expression. These results have important clinical implications for patients with heart failure, because this population has reduced muscle oxidative capacity. The purpose of this study was to investigate the effects of physical training (PT) on phenotypic features (fibre-type content) and myogenic regulatory factors (MyoD and myogenin) in rat skeletal muscle during the transition from cardiac hypertrophy to heart failure. We used the model of ascending aortic stenosis (AS) to induce heart failure in male Wistar rats. Sham-operated animals were used as age-matched controls. At 18 weeks after surgery, rats with ventricular dysfunction were randomized into the following four groups: sham-operated, untrained (Sham-U; n = 8); sham-operated, trained (Sham-T; n = 6); aortic stenosis, untrained (AS-U; n = 6); and aortic stenosis, trained (AS-T; n = 8). The AS-T and Sham-T groups were submitted to a 10 week aerobic PT programme, while the AS-U and Sham-U groups remained untrained for the same period of time. After the PT programme, the animals were killed and the soleus muscles collected for phenotypic and molecular analyses. Physical training promoted type IIa-to-I fibre conversion in the trained groups (Sham-T and AS-T) compared with the untrained groups (Sham-U and AS-U). No significant (P > 0.05) differences were found in type I or IIa fibre content in the AS-U group compared with the Sham-U group. Additionally, there were no significant (P > 0.05) differences in the myogenic regulatory factors MyoD and myogenin (gene and protein) expression between the groups. Therefore, our results indicate that PT may be a suitable strategy to improve the oxidative phenotype in skeletal muscle during the transition from cardiac hypertrophy to heart failure, without altering MyoD and myogenin. PMID- 27219630 TI - The safety and efficacy of cobimetinib for the treatment of BRAF V600E or V600K melanoma. AB - INTRODUCTION: In the recent years, melanoma patients' outcome and survival improved, mainly because of systemic treatment improvement with targeted therapy and checkpoint blockade. Targeted therapy with BRAF and MEK inhibitors was approved to treat patients with unresectable or metastatic melanoma, harboring BRAF V600 mutations. This paper addresses the safety and efficacy of cobimetinib, when used in combination with vemurafenib, in the previous mentioned setting. AREAS COVERED: This article presents an overview on the rationale for clinical development of cobimetinib, as well as the mechanism of action, the efficacy and safety, and the most important trials that led to the approval of the combination therapy with vemurafenib. We searched the PubMed for published papers related to safety and efficacy of cobimetinib, and resistance mechanisms to BRAF inhibition. The abstract databases of the American Society of Clinical Oncology and European Society for Medical Oncology were also searched for updates on the mentioned clinical trials. Expert commentary: Patients treated with targeted therapy experience a rapid tumor response. However, virtually all patients will develop resistance to treatment. Therapeutic combinations to overcome resistance mechanisms are currently addressed. In the future, targeted therapy strategy will include three or more drugs, probably from different therapeutic classes. PMID- 27219631 TI - In vivo and in vitro effects of curcumin on head and neck carcinoma: a systematic review. AB - BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) contributes globally to a great number of deaths and morbidity, in spite of new therapeutic strategies. There is a great need of new drugs that are significantly effective and less deleterious to the patients' general health. In this sense, phytotherapy is a tendency, with results pointing to its use as a chemo-preventive and adjuvant therapy. Therefore, the objective of this systematic review was to investigate the effects of curcumin on proliferation and survival of HNSCC. MATERIALS AND METHODS: The search was conducted on six databases: Cochrane, LILACS, EMBASE, MEDLINE, PubMed, and Web of Science. In vitro and in vivo studies that evaluated the effects of curcumin on cell viability, tumor growth, cell cycle and/or cell death pattern in HNSCC cell lines or animal models were selected. RESULTS: Of the 525 initially gathered studies, 30 met the inclusion criteria. These studies demonstrated that curcumin induces cytotoxicity, apoptosis (via intrinsic pathway), and cell cycle arrest in G2 /M phase in HSNCC cell lines. It also reduces tumor measurements in animal models. These events were mostly studied through MTT assay, flow cytometry, and cell cycle- and apoptosis-related proteins expression. CONCLUSION: This systematic review demonstrated that curcumin is effective on HNSCC cell proliferation and survival, reinforcing the currently available evidence that curcumin could be an adjuvant drug in HNSCC treatment. PMID- 27219632 TI - Informing the Design and Evaluation of Superuser Care Management Initiatives: Accounting for Regression-to-the-Mean. AB - BACKGROUND: Health care spending is concentrated among a small number of high cost patients, and the popularity of initiatives to improve care and reduce cost among such "superusers" (SUs) is growing. However, SU costs decline naturally over time, even without intervention, a statistical phenomenon known as regression-to-the-mean (RTM). OBJECTIVES: We assess the magnitude of RTM in hospital costs for cohorts of hospital SUs identified on the basis of high inpatient (IP) or emergency department (ED) utilization. We further examine how cost and RTM are associated with patient characteristics including behavioral health (BH) problems, multiple chronic conditions, and indicators of vulnerability. STUDY DESIGN: Using longitudinally linked all-payer hospital billing data, we selected patient cohorts with >=2 IP stays (IP SUs) or >=6 ED visits (ED SUs) during a 6-month baseline period, and additional subgroups defined by combinations of IP and ED superuse. POPULATION STUDIED: A total of 289,060 NJ hospital IP and treat-and-release ED patients over 2009-2011. RESULTS: Hospital costs among IP and ED SUs declined 70% and 38%, respectively, over 8 quarters following the baseline period. The decrease occurs more quickly for IP SUs compared with ED SUs. Presence of BH problems was positively associated with costs among patients overall, but the relationship varied by SU cohort. CONCLUSIONS: Understanding patterns of RTM among SU populations is important for designing intervention strategies, as there is greater potential for savings among patients with more persistent costs (less RTM). Further, as many SU initiatives lack resources for rigorous evaluation, quantifying the extent of RTM is vital for interpreting program outcomes. PMID- 27219633 TI - The Impact of Integrated Case Management on Health Services Use and Spending Among Nonelderly Adult Medicaid Enrollees. AB - BACKGROUND: Medicaid plans, whose patients often have complex medical, social, and behavioral needs, seek tools to effectively manage enrollees and improve access to quality care while containing costs. OBJECTIVES: The aim of this study is to examine the effects of an integrated case management (ICM) program operated by a Medicaid managed care plan on health service use and spending for nonelderly, nonpregnant adults. RESEARCH DESIGN: We estimate the relationship between intensity of ICM program involvement and changes in utilization and spending for patients who participated in ICM. We examine whether effects differ between high-risk and lower-risk individuals and between the early and late stages of the program, given that the latter relied on more targeted and patient centered approaches. Specifically, we estimate linear regressions modeling changes in utilization and spending outcomes as a function of number of program contacts, conditional on number of days over which contacts occurred, as well as individual-level covariates and case manager fixed effects. RESULTS: In the late ICM program period, we observe significant decreases in outpatient utilization associated with program involvement intensity among high-risk ICM participants. We also observe decreases in spending associated with program involvement intensity among the lower-risk group in the late period, although there is no significant impact on spending among high-risk enrollees. CONCLUSIONS: ICM can be a successful strategy for impacting health services use and spending. Our findings suggest that careful program targeting, well-structured client engagement, and direct one-on-one contact are vitally important for achieving program objectives. PMID- 27219634 TI - Impact of Adherence to Quality Measures for Localized Prostate Cancer on Patient reported Health-related Quality of Life Outcomes, Patient Satisfaction, and Treatment-related Complications. AB - BACKGROUND AND OBJECTIVE: Quality measures used in pay-for-performance systems are intended to address specific quality goals, such as safety, efficiency, effectiveness, timeliness, equity, and patient-centeredness. Given the small number of narrowly focused measures in prostate cancer care, we sought to determine whether adherence to any of the available payer-driven quality measures influences patient-centered outcomes, including health-related quality of life (HRQOL), patient satisfaction, and treatment-related complications. METHODS: The Comparative Effectiveness Analysis of Surgery and Radiation study is a population based, prospective cohort study that enrolled 3708 men with clinically localized prostate cancer during 2011 and 2012, of whom 2601 completed the 1-year survey and underwent complete chart abstraction. Compliance with 6 quality indicators endorsed by national consortia was assessed. Multivariable regression was used to determine the relationship between indicator compliance and Expanded Prostate Cancer Index Composite (EPIC-26) instrument summary scores, satisfaction scale scores (service satisfaction scale for cancer care), and treatment-related complications. RESULTS: Overall rates of compliance with these quality measures ranged between 64% and 88%. Three of the 6 measures were weakly associated with 1 year sexual function and bowel function scores (beta=-4.6, 1.69, and 2.93, respectively; P<=0.05), whereas the remaining measures had no significant relationship with patient-reported HRQOL outcomes. Satisfaction scores and treatment-related complications were not associated with quality measure compliance. CONCLUSIONS: Compliance with available nationally endorsed quality indicators, which were designed to incentivize effective and efficient care, was not associated with clinically important changes in patient-centered outcomes (HRQOL, satisfaction, or complications) within 1-year. PMID- 27219635 TI - Characteristics and Service Use of Medicare Beneficiaries Using Federally Qualified Health Centers. AB - BACKGROUND: Federally Qualified Health Centers (FQHCs) provide primary care for millions of Americans, but little is known about Medicare beneficiaries who use FQHCs. OBJECTIVE: To compare patient characteristics and health care service use among Medicare beneficiaries stratified by FQHC use. RESEARCH DESIGN: Cross sectional analysis of 2011 Medicare fee-for-service beneficiaries aged 65 years and older. SUBJECTS: Subjects included beneficiaries with at least 1 evaluation and management (E&M) visit in 2011, categorized as FQHC users (>=1 E&M visit to FQHCs) or nonusers living in the same primary care service areas as FQHC users. Users were subclassified as predominant if the majority of their E&M visits were to FQHCs. MEASURES: Demographic characteristics, physician visits, and inpatient care use. RESULTS: Most FQHC users (56.6%) were predominant users. Predominant and nonpredominant users, compared with nonusers, markedly differed by prevalence of multiple chronic conditions (18.2%, 31.7% vs. 22.7%) and annual mortality (2.8%, 3.8% vs. 4.0%; all P<0.05). In adjusted analyses (reference: nonusers), predominant users had fewer physician visits (RR=0.81; 95% CI, 0.81-0.81) and fewer hospitalizations (RR=0.84; 95% CI, 0.84-0.85), whereas nonpredominant users had higher use of both types of service (RR=1.18, 95% CI, 1.18-1.18; RR=1.09, 95% CI, 1.08-1.10, respectively). CONCLUSIONS: Even controlling for primary care delivery markets, nonpredominant FQHC users had a higher burden of chronic illness and service use than predominant FQHC users. It will be important to monitor Medicare beneficiaries using FQHCs to understand whether primary care only payment incentives for FQHCs could induce fragmented care. PMID- 27219636 TI - Social Determinants of Health, Cost-related Nonadherence, and Cost-reducing Behaviors Among Adults With Diabetes: Findings From the National Health Interview Survey. AB - BACKGROUND: Cost-related nonadherence (CRN) is prevalent among individuals with diabetes and can have significant negative health consequences. We examined health-related and non-health-related pressures and the use of cost-reducing strategies among the US adult population with and without diabetes that may impact CRN. METHODS: Data from the 2013 wave of National Health Interview Survey (n=34,557) were used to identify the independent impact of perceived financial stress, financial insecurity with health care, food insecurity, and cost-reducing strategies on CRN. RESULTS: Overall, 11% (n=4158) of adults reported diabetes; 14% with diabetes reported CRN, compared with 7% without diabetes. Greater perceived financial stress [prevalence ratio (PR)=1.07; 95% confidence interval (CI), 1.05-1.09], financial insecurity with health care (PR=1.6; 95% CI, 1.5 1.67), and food insecurity (PR=1.30; 95% CI, 1.2-1.4) were all associated with a greater likelihood of CRN. Asking the doctor for a lower cost medication was associated with a lower likelihood of CRN (PR=0.2; 95% CI, 0.2-0.3), and 27% with CRN reported this. Other cost-reducing behavioral strategies (using alternative therapies, buying prescriptions overseas) were associated with a greater likelihood of CRN. CONCLUSIONS: Half of the adults with diabetes perceived financial stress, and one fifth reported financial insecurity with health care and food insecurity. Talking to a health care provider about low-cost options may be protective against CRN in some situations. Improving screening and communication to identify CRN and increase transparency of low-cost options patients are pursuing may help safeguard from the health consequences of cutting back on treatment. PMID- 27219637 TI - Marginal Hospital Cost of Surgery-related Hospital-acquired Pressure Ulcers. AB - BACKGROUND: Patients who develop hospital-acquired pressure ulcers (HAPUs) are more likely to die, have longer hospital stays, and are at greater risk of infections. Patients undergoing surgery are prone to developing pressure ulcers (PUs). OBJECTIVE: To estimate the hospital marginal cost of a HAPU for adults patients who were hospitalized for major surgeries, adjusted for patient characteristics, comorbidities, procedures, and hospital characteristics. RESEARCH DESIGN AND SUBJECTS: Data are from the Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases and the Medicare Patient Safety Monitoring System for 2011 and 2012. PU information was obtained using retrospective structured record review from trained MPMS data abstractors. Costs are derived using HCUP hospital-specific cost-to-charge ratios. Marginal cost estimates were made using Extended Estimating Equations. We estimated the marginal cost at the 25th, 50th, and 75th percentiles of the cost distribution using Simultaneous Quantile Regression. RESULTS: We find that 3.5% of major surgical patients developed HAPUs and that the HAPUs added ~$8200 to the cost of a surgical stay after adjusting for comorbidities, patient characteristics, procedures, and hospital characteristics. This is an ~44% addition to the cost of a major surgical stay but less than half of the unadjusted cost difference. In addition, we find that for high-cost stays (75th percentile) HAPUs added ~$12,100, whereas for low-cost stays (25th percentile) HAPUs added ~$3900. CONCLUSIONS: This paper suggests that HAPUs add ~44% to the cost of major surgical hospital stays, but the amount varies depending on the total cost of the visit. PMID- 27219639 TI - Patient-centered Medical Home, Make Room for Your New Neighbor: The Person centered Wellness HomeTM. PMID- 27219638 TI - Dental Care in an Equal Access System Valuing Equity: Are There Racial Disparities? AB - BACKGROUND: Racial disparities in dental care have previously been shown in the Veterans Health Administration (VA)-a controlled access setting valuing equitable, high-quality care. OBJECTIVES: The aim of this study is to examine current disparities in dental care by focusing on the receipt of root canal therapy (RCT) versus tooth extraction. RESEARCH DESIGN: This is a retrospective analysis of data contained in the VA's electronic health records. We performed logistic regressions on the independent measures along with a facility-specific random effect, using dependent binary variables that distinguished RCT from tooth extraction procedures. SUBJECTS: VA outpatients who had at least 1 tooth extraction or RCT visit in the VA in fiscal year 2011. MEASURES: A dependent binary measure of tooth extraction or RCT. Other measures are medical record data on medical comorbidities, dental morbidity, prior dental utilization, and demographic characteristics. RESULTS: The overall rate of preferred tooth preserving RCT was 18.1% during the study period. Black and Asian patients were most dissimilar with respect to dental morbidity, medical and psychological disorders, and black patients had the least amount of eligibility for comprehensive dental care. After adjustment for known confounding factors of RCT, black patients had the lowest RCT rates, whereas Asians had the highest. CONCLUSIONS: Current quality improvement efforts and a value to improve the equity of care are not sufficient to address racial/ethnic disparities in VA dental care; rather more targeted efforts will be needed to achieve equity for all. PMID- 27219640 TI - Stability and Nonlinear Optical Response of Alkalides that Contain a Completely Encapsulated Superalkali Cluster. AB - Guided by density functional theory (DFT) computations, a new series of superalkali-based alkalides, namely FLi2 (+) (aza222)K(-) , OLi3 (+) (aza222)K(-) , NLi4 (+) (aza222)K(-) , and Li3 (+) (aza222)K(-) were designed with various superalkali clusters embedded into an aza222 cage-complexant. These species possess diverse isomeric structures in which the encapsulated superalkalis preserve their identities and behave as alkali metal atoms. The results show that these novel alkalides possess larger complexation energies and enhanced hyperpolarizabilities (beta0 ) compared with alkali-metal-based and previous superalkali-based clusters. Especially, a prominent structural dependence of beta0 is observed for these studied compounds. Hence, the geometric factors that affect the nonlinear optical (NLO) response of such alkalides is elucidated in detail in this work. This study not only provides novel candidates for alkalides, it also offers an effective way to enhance the NLO response and stability of alkalides. PMID- 27219641 TI - Fast regioselective sulfonylation of pyridine/quinoline N-oxides induced by iodine. AB - Fast sulfonylation of pyridine/quinoline N-oxides induced by iodine is demonstrated herein. The regioselective protocol occurs under metal-free conditions in a short reaction time (10 min), exhibiting high efficiency (up to 92% yield) and good compatibility (up to 33 examples). A gram-scale reaction was conducted with only a slight loss of production. PMID- 27219642 TI - Novice nurse practitioner workforce transition and turnover intention in primary care. AB - PURPOSE: Little is known about the workforce transition and turnover intention of novice nurse practitioners (NPs) in primary care (PC). This research aimed to describe the individual characteristics, role acquisition and job satisfaction of novice NPs, and identify factors associated with their successful transition and turnover intention in the first year of PC practice. DATA SOURCES: A descriptive, cross-sectional study was conducted via online survey administered to a national sample of 177 NPs who graduated from an accredited NP program and were practicing in a PC setting for 3-12 months. CONCLUSIONS: This study demonstrated that greater professional autonomy in the workplace is a critical factor in turnover intention in novice NPs in the PC setting. IMPLICATIONS FOR PRACTICE: Further research is needed regarding the novice NP workforce transition to provide adequate professional autonomy and support during this critical period. PMID- 27219643 TI - Changes in Drug Use Among Belgian Higher Education Students: A Comparison Between 2005, 2009, and 2013. AB - BACKGROUND: Most drug users initiate illicit drug use during adolescence and young adulthood. Although in the general population a trend towards a decrease in drug use can be seen, patterns of drug use among students are unclear. OBJECTIVES: The objective of the study was to look at drug use patterns among students in higher education in Belgium. METHODS: A survey study in Antwerp (Belgium) was conducted on three occasions (2005, 2009, and 2013) at several institutes for higher education. Students (total sample size 24,478; 29,210, and 31,950, respectively) were asked if they had used legal or illicit drugs in the past year. To compare whether drug use differed between the separate years, chi(2)-tests were performed on past-year drug use for all three time points. If significant, chi(2)-tests between pairs were performed. Gender and age differences were also analyzed. RESULTS: The use of nondistilled alcohol, spirits, and cannabis decreased during this period but no change in student's use patterns was seen for beer, wine, sedative hypnotics, stimulating medication, XTC, cocaine, or amphetamines. Tobacco use decreased initially, but increased in 2013. More men indicated having used drugs in the past year than women. Only for cannabis did more younger students indicate having used in the past year. CONCLUSIONS/IMPORTANCE: The data from this study could provide valuable insights for academic and governmental bodies and health care professionals into the use of drugs by higher education students since this subgroup shows specific use patterns. PMID- 27219644 TI - Protective Effect of Cod (Gadus macrocephalus) Skin Collagen Peptides on Acetic Acid-Induced Gastric Ulcer in Rats. AB - This research was performed to explore the protective effect of cod skin collagen peptides (CCP) on gastric ulcer induced by acetic acid. The CCP were fractionated into low molecular CCP (LMCCP, Mw < 3 kDa) and high molecular CCP (HMCCP, Mw > 3 kDa). In HMCCP and LMCCP, glycine of accounted for about one-third of the total amino acids without cysteine and tryptophan, and hydrophobic amino acids accounted for about 50%. After 21 d CCP treatment (60 or 300 mg/kg, p.o./daily), the healing effects on acetic acid-induced gastric ulcers were evaluated by macroscopic measure, microscopic measure, and immune histochemistry. Moreover, the expression levels of the growth factors, such as vascular endothelial growth factor, epidermal growth factor, transforming growth factor beta1 (TGFbeta1), and the heat shock protein 70 (HSP70) was detected. The results showed that both LMCCP and HMCCP could significantly decrease the ulcer areas and promote the healing of the lesions. They also could improve the levels of hexosamine, glutathione, superoxide dismutase, and glutathione peroxidase, and reduce the content of malondialdehyde and inducible nitric oxide synthase. In addition, the expression level of TGFbeta1 gene and HSP70 mRNA was significantly improved by the treatment. It suggested that CCP could be able to improve symptoms of gastric ulcer and probably be used in the treatment of gastric ulcer. PMID- 27219645 TI - Additive manufactured polymeric 3D scaffolds with tailored surface topography influence mesenchymal stromal cells activity. AB - Additive manufactured three-dimensional (3D) scaffolds with tailored surface topography constitute a clear advantage in tissue regeneration strategies to steer cell behavior. 3D fibrous scaffolds of poly(ethylene oxide terephthalate)/poly(butylene terephthalate) block copolymer presenting different fiber surface features were successfully fabricated by additive manufacturing combined with wet-spinning, in a single step, without any post-processing. The optimization of the processing parameters, mainly driven by different solvent/non solvent combinations, led to four distinct scaffold types, with average surface roughness values ranging from 0.071 +/- 0.012 MUm to 1.950 +/- 0.553 MUm, average pore sizes in the x- and y-axis between 351.1 +/- 33.6 MUm and 396.1 +/- 32.3 MUm, in the z-axis between 36.5 +/- 5.3 MUm and 70.7 +/- 8.8 MUm, average fiber diameters between 69.4 +/- 6.1 MUm and 99.0 +/- 9.4 MUm, and porosity values ranging from 60.2 +/- 0.8% to 71.7 +/- 2.6%. Human mesenchymal stromal cells (hMSCs) cultured on these scaffolds adhered, proliferated, and produced endogenous extracellular matrix. The effect of surface roughness and topography on hMSCs differentiation was more evident for cells seeded at lower density, where the percentage of cells in direct contact with the surface was higher compared to more densely seeded scaffolds. Under osteogenic conditions, lower surface roughness values (0.227 +/- 0.035 MUm) had a synergistic effect on hMSCs behavior, while chondrogenesis was favored on rougher surfaces (1.950 +/- 0.553 MUm). PMID- 27219646 TI - Unraveling the Conformational Landscape of Ligand Binding to Glucose/Galactose Binding Protein by Paramagnetic NMR and MD Simulations. AB - Protein dynamics related to function can nowadays be structurally well characterized (i.e., instances obtained by high resolution structures), but they are still ill-defined energetically, and the energy landscapes are only accessible computationally. This is the case for glucose-galactose binding protein (GGBP), where the crystal structures of the apo and holo states provide structural information for the domain rearrangement upon ligand binding, while the time scale and the energetic determinants for such concerted dynamics have been so far elusive. Here, we use GGBP as a paradigm to define a functional conformational landscape, both structurally and energetically, by using an innovative combination of paramagnetic NMR experiments and MD simulations. Anisotropic NMR parameters induced by self-alignment of paramagnetic metal ions was used to characterize the ensemble of conformations adopted by the protein in solution while the rate of interconversion between conformations was elucidated by long molecular dynamics simulation on two states of GGBP, the closed-liganded (holo_cl) and open-unloaded (apo_op) states. Our results demonstrate that, in its apo state, the protein coexists between open-like (68%) and closed-like (32%) conformations, with an exchange rate around 25 ns. Despite such conformational heterogeneity, the presence of the ligand is the ultimate driving force to unbalance the equilibrium toward the holo_cl form, in a mechanism largely governed by a conformational selection mechanism. PMID- 27219661 TI - Correction: Early Treatment Critical: Bexarotene Reduces Amyloid-Beta Burden In Silico. AB - [This corrects the article DOI: 10.1371/journal.pone.0153150.]. PMID- 27219660 TI - A surface-based technique for mapping homotopic interhemispheric connectivity: Development, characterization, and clinical application. AB - The functional organization of the human brain consists of a high degree of connectivity between interhemispheric homologous regions. The degree of homotopic organization is known to vary across the cortex and homotopic connectivity is high in regions that share cross-hemisphere structural connections or are activated by common input streams (e.g., the visual system). Damage to one or both regions, as well as damage to the connections between homotopic regions, could disrupt this functional organization. Here were introduce and test a computationally efficient technique, surface-based homotopic interhermispheric connectivity (sHIC), that leverages surface-based registration and processing techniques in an attempt to improve the spatial specificity and accuracy of cortical interhemispheric connectivity estimated with resting state functional connectivity. This technique is shown to be reliable both within and across subjects. sHIC is also characterized in a dataset of nearly 1000 subjects. We confirm previous results showing increased interhemispheric connectivity in primary sensory regions, and reveal a novel rostro-caudal functionally defined network level pattern of sHIC across the brain. In addition, we demonstrate a structural-functional relationship between sHIC and atrophy of the corpus callosum in multiple sclerosis (r = 0.2979, p = 0.0461). sHIC presents as a sensitive and reliable measure of cortical homotopy that may prove useful as a biomarker in neurologic disease. Hum Brain Mapp 37:2849-2868, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27219662 TI - Modeling and Simulations in Photoelectrochemical Water Oxidation: From Single Level to Multiscale Modeling. AB - This review summarizes recent developments, challenges, and strategies in the field of modeling and simulations of photoelectrochemical (PEC) water oxidation. We focus on water splitting by metal-oxide semiconductors and discuss topics such as theoretical calculations of light absorption, band gap/band edge, charge transport, and electrochemical reactions at the electrode-electrolyte interface. In particular, we review the mechanisms of the oxygen evolution reaction, strategies to lower overpotential, and computational methods applied to PEC systems with particular focus on multiscale modeling. The current challenges in modeling PEC interfaces and their processes are summarized. At the end, we propose a new multiscale modeling approach to simulate the PEC interface under conditions most similar to those of experiments. This approach will contribute to identifying the limitations at PEC interfaces. Its generic nature allows its application to a number of electrochemical systems. PMID- 27219663 TI - Sensitivity of mass spectrometry analysis depends on the shape of the filtration unit used for filter aided sample preparation (FASP). AB - Efficient protein solubilization using detergents is required for in-depth proteome analysis, but successful LC-MS/MS analysis greatly depends on proper detergents removal. A commonly used sample processing method is the filter-aided sample preparation (FASP), which allows protein digestion and detergent removal on the same filtration device. Many optimizations of the FASP protocol have been published, but there is no information on the influence of the filtration unit typology on the detergents removal. The aim of this study was to compare the performance of conic and flat bottom filtration units in terms of number of proteins identified by LC-MS/MS. We have analyzed 1, 10 and 100 MUg of total cell lysate prepared using lysis buffer with different SDS concentrations. We compared the FASP protocol using conic and flat bottom filtration units to ethanol precipitation method. Subsequently, we applied our most performant protocol to single murine pancreatic islet, and identified up to 2463 protein using FASP versus 1169 proteins using ethanol precipitation. We conclude that FASP performance depends strongly on the filter shape: flat bottom devices are better suited for low-protein samples, as they allow better SDS removal leading to the identification of greater number of proteins. PMID- 27219665 TI - Covalently Bound Clusters of Alpha-Substituted PDI-Rival Electron Acceptors to Fullerene for Organic Solar Cells. AB - A cluster type of electron acceptor, TPB, bearing four alpha-perylenediimides (PDIs), was developed, in which the four PDIs form a cross-like molecular conformation while still partially conjugated with the BDT-Th core. The blend TPB:PTB7-Th films show favorable morphology and efficient charge dissociation. The inverted solar cells exhibited the highest PCE of 8.47% with the extraordinarily high Jsc values (>18 mA/cm(2)), comparable with those of the corresponding PC71BM/PTB7-Th-based solar cells. PMID- 27219664 TI - Proteomic analysis of skeletal deformity in diploid and triploid rainbow trout (Oncorhynchus mykiss) larvae. AB - A proteomic screening approach was employed to achieve a better understanding of the changes that occur in protein expression patterns associated with skeletal deformities in both diploid and triploid rainbow trout larvae. Triploidy was induced through the application of heat shock of 28 degrees C for 10min to eggs 10-min post fertilization in an aquarium equipped with a heater. Percentage of skeletal deformity in heat-shocked larvae (2.88+/-0.30, mean+/-S.E.) was significantly (P<0.05) greater than that of the diploids (0.55+/-0.24). At five days after hatching, proteins of normal and deformed specimens of deyolked larvae were subjected to proteomic analysis using two-dimensional electrophoresis and mass spectrometry. Among the identified protein spots from diploids, creatine kinase was found to be increased in larvae with skeletal deformities, while apolipoprotein A-I-2, apolipoprotein A-II and calmodulin were found to be decreased in deformed fish. Among the five protein spots that were identified in heat-shocked fish, apolipoprotein A-I-2, apolipoprotein A-II, parvalbumin, myosin light chain 1-1 and nucleoside diphosphate kinase were found to be decreased in deformed larvae. The identification of nine protein spots showing altered expression in deformed fish allows us to reach a preliminary view of the molecular mechanisms that are involved in the development of skeletal malformations in diploid and triploid fish. PMID- 27219666 TI - Paraquat use among farmers in Korea after the ban. AB - The purpose of this study was to examine the proportion of paraquat use among farmers and to describe their epidemiologic characteristics after the paraquat ban in 2012. We interviewed 249 farmers in Korea in 2014. Approximately 20% of the farmers reported using paraquat in 2014. Farmers with longer farming experience, longer pesticide application years, and upland farming reported an increased risk of paraquat use although the trend was not statistically significant. The majority of the farmers used preexisting paraquat (85.7%), but some farmers purchased it illegally (14.3%). Farmers who used paraquat perceived paraquat as a dangerous chemical; however, they disagreed with the necessity of the paraquat ban. PMID- 27219667 TI - SPECTRAL DOMAIN-OPTICAL COHERENCE TOMOGRAPHY IMAGE CONTRAST AND BACKGROUND COLOR SETTINGS INFLUENCE IDENTIFICATION OF RETINAL STRUCTURES. AB - PURPOSE: To evaluate image contrast and color setting on assessment of retinal structures and morphology in spectral-domain optical coherence tomography. METHODS: Two hundred and forty-eight Spectralis spectral-domain optical coherence tomography B-scans of 62 patients were analyzed by 4 readers. B-scans were extracted in 4 settings: W + N = white background with black image at normal contrast 9; W + H = white background with black image at maximum contrast 16; B + N = black background with white image at normal contrast 12; B + H = black background with white image at maximum contrast 16. Readers analyzed the images to identify morphologic features. Interreader correlation was calculated. Differences between Fleiss-kappa correlation coefficients were examined using bootstrap method. Any setting with significantly higher correlation coefficient was deemed superior for evaluating specific features. RESULTS: Correlation coefficients differed among settings. No single setting was superior for all respective spectral-domain optical coherence tomography parameters (P = 0.3773). Some variables showed no differences among settings. Hard exudates and subretinal fluid were best seen with B + H (kappa = 0.46, P = 0.0237 and kappa = 0.78, P = 0.002). Microaneurysms were best seen with W + N (kappa = 0.56, P = 0.025). Vitreomacular interface, enhanced transmission signal, and epiretinal membrane were best identified using all color/contrast settings together (kappa = 0.44, P = 0.042, kappa = 0.57, P = 0.01, and kappa = 0.62, P <= 0.0001). CONCLUSION: Contrast and background affect the evaluation of retinal structures on spectral domain optical coherence tomography images. No single setting was superior for all features, though certain changes were best seen with specific settings. PMID- 27219669 TI - Gas-Phase Synthesis of 1-Silacyclopenta-2,4-diene. AB - Silole (1-silacyclopenta-2,4-diene) was synthesized for the first time by the bimolecular reaction of the simplest silicon-bearing radical, silylidyne (SiH), with 1,3-butadiene (C4 H6 ) in the gas phase under single-collision conditions. The absence of consecutive collisions of the primary reaction product prevents successive reactions of the silole by Diels-Alder dimerization, thus enabling the clean gas-phase synthesis of this hitherto elusive cyclic species from acyclic precursors in a single-collision event. Our method opens up a versatile and unconventional path to access a previously rather obscure class of organosilicon molecules (substituted siloles), which have been difficult to access through classical synthetic methods. PMID- 27219670 TI - Sonographic appearance of a cesarean scar pregnancy with placenta percreta invading the bladder in the first trimester and management with fertility preservation. AB - A 36-year-old, gravida 8, para 6, woman with six prior cesarean sections presented at 6 weeks with a cesarean scar pregnancy. Medical management was performed initially; however, subsequent three-dimensional sonographic examinations revealed trophoblastic invasion into the bladder. This led to robotic-assisted partial cystectomy, fulguration of invaded pregnancy, and repair of the uterine defect. (c) 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:163 167, 2017. PMID- 27219671 TI - Using Link Disconnection Entropy Disorder to Detect Fast Moving Nodes in MANETs. AB - Mobile ad-hoc networks (MANETs) are dynamic by nature; this dynamism comes from node mobility, traffic congestion, and other transmission conditions. Metrics to evaluate the effects of those conditions shine a light on node's behavior in an ad-hoc network, helping to identify the node or nodes with better conditions of connection. In this paper, we propose a relative index to evaluate a single node reliability, based on the link disconnection entropy disorder using neighboring nodes as reference. Link disconnection entropy disorder is best used to identify fast moving nodes or nodes with unstable communications, this without the need of specialized sensors such as GPS. Several scenarios were studied to verify the index, measuring the effects of Speed and traffic density on the link disconnection entropy disorder. Packet delivery ratio is associated to the metric detecting a strong relationship, enabling the use of the link disconnection entropy disorder to evaluate the stability of a node to communicate with other nodes. To expand the utilization of the link entropy disorder, we identified nodes with higher speeds in network simulations just by using the link entropy disorder. PMID- 27219672 TI - PKCalpha-GSK3beta-NF-kappaB signaling pathway and the possible involvement of TRIM21 in TRAIL-induced apoptosis. AB - Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a highly promising therapeutic agent for cancer treatment, owing to its ability to selectively target tumor cells for cell death while having little effect on most normal cells. However, recent research has found that many cancers, including non small cell lung cancer (NSCLC), display resistance to TRAIL. Therefore, it is important to elucidate the molecular mechanisms governing the resistance of tumor cells to TRAIL treatment. In this study, we show that GSK3beta antagonized TRAIL induced apoptosis in H1299 NSCLC cells, and determined that the PKCalpha isozyme is an upstream regulator of GSK3beta that phosphorylates and inactivates GSK3beta, thereby sensitizing cancer cells to TRAIL-induced apoptosis. Furthermore, we demonstrated that the anti-apoptotic effect of GSK3beta is mediated by the NF-kappaB pathway, whereas the tripartite motif 21 (TRIM21) was able to inhibit the activation of NF-kappaB by GSK3beta, and leads to the promotion of cell apoptosis. Taken together, our study further delineated the underpinning mechanism of resistance to TRAIL-induced apoptosis in H1299 cells, and provided new clues for sensitizing NSCLC cells to TRAIL therapy. PMID- 27219674 TI - Ureaplasma parvum as a possible enhancer agent of HPV-induced cervical intraepithelial neoplasia: Preliminary results. PMID- 27219673 TI - Intimate partner violence and pregnancy intentions: a qualitative study. AB - AIM AND OBJECTIVE: In this qualitative study, we explored women's pregnancy intentions and experiences of intimate partner violence before, during and after pregnancy. BACKGROUND: Unintended pregnancies in the context of intimate partner violence can have serious health, social and economic consequences for women and their children. DESIGN: Feminist and phenomenological philosophies underpinned the study to gain a richer understanding of women's experiences. METHODS: Eleven women who had been pregnant in the previous two years were recruited from community-based women's refuges in one region of the UK. Of the 11 women, eight had unplanned pregnancies, two reported being coerced into early motherhood, and only one woman had purposively planned her pregnancy. Multiple in-depth interviews focused on participants' accounts of living with intimate partner violence. Experiential data analysis was used to identify, analyse and highlight themes. RESULTS: Three major themes were identified: men's control of contraception, partner's indiscriminate response to the pregnancy and women's mixed feelings about the pregnancy. Participants reported limited influence over their sexual relationship and birth control. Feelings of vulnerability about themselves and fear for their unborn babies' safety were intensified by their partners' continued violence during pregnancy. CONCLUSION: Women experiencing intimate partner violence were more likely to have an unintended pregnancy. This could be attributed to male dominance and fear, which impacts on a woman's ability to manage her birth control options. The women's initial excitement about their pregnancy diminished in the face of uncertainty and ongoing violence within their relationship. RELEVANCE TO CLINICAL PRACTICE: Women experiencing violence lack choice in relation to birth control options leading to unintended pregnancies. Interpreting the findings from the victim-perpetrator interactive spin theory of intimate partner violence provides a possible framework for midwives and nurses to better understand and respond to women's experiences of violence during pregnancy. PMID- 27219675 TI - Heteronuclear Ir(III)-Ln(III) Luminescent Complexes: Small-Molecule Probes for Dual Modal Imaging and Oxygen Sensing. AB - Luminescent, mixed metal d-f complexes have the potential to be used for dual (magnetic resonance imaging (MRI) and luminescence) in vivo imaging. Here, we present dinuclear and trinuclear d-f complexes, comprising a rigid framework linking a luminescent Ir center to one (Ir.Ln) or two (Ir.Ln2) lanthanide metal centers (where Ln = Eu(III) and Gd(III), respectively). A range of physical, spectroscopic, and imaging-based properties including relaxivity arising from the Gd(III) units and the occurrence of Ir(III) -> Eu(III) photoinduced energy transfer are presented. The rigidity imposed by the ligand facilitates high relaxivities for the Gd(III) complexes, while the luminescence from the Ir(III) and Eu(III) centers provide luminescence imaging capabilities. Dinuclear (Ir.Ln) complexes performed best in cellular studies, exhibiting good solubility in aqueous solutions, low toxicity after 4 and 18 h, respectively, and punctate lysosomal staining. We also demonstrate the first example of oxygen sensing in fixed cells using the dyad Ir.Gd, via two-photon phosphorescence lifetime imaging (PLIM). PMID- 27219678 TI - Reliability of a decision-tree model in predicting occupational lead poisoning in a group of highly exposed workers. AB - OBJECTIVE: This study aimed to provide the toxicological profile of some lead exposed workers and obtain a predictive model for lead poisoning. METHODS: Data regarding external and absorbed exposure were collected from 585 subjects employed in ten metallurgical production departments. Airborne lead concentration, blood lead level (BLL), cumulative blood lead index (CBLI), urine delta-aminolevulinic acid (DALA), age, workplace/section, exposure period, and whether reported lead poisoning as occupational disease were examined using ANOVA, and, post-ANOVA, Pearson correlation matrix, PCA (principal component analysis), decision-tree modeling, and logistic modeling. RESULTS: BLL was less sensitive than CBLI in predicting poisoning. Decision-tree modeling highlighted the importance of CBLI >=1,041 ug.years/dl and air lead concentration >=0.3 mg/m(3) in the occurrence of occupational poisoning. Age >=48 years and DALA >=19.3 mg/L were also factors. CONCLUSIONS: Workers were at risk of poisoning as a result of their long term unacceptable exposure. Decision-tree modeling is potentially useful for risk management. Am. J. Ind. Med. 59:575-582, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27219676 TI - Structure-Based Design of Tetrahydroisoquinoline-7-carboxamides as Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors. AB - The structure-based design of 1, 2, 3, 4-tetrahydroisoquinoline derivatives as selective DDR1 inhibitors is reported. One of the representative compounds, 6j, binds to DDR1 with a Kd value of 4.7 nM and suppresses its kinase activity with an IC50 value of 9.4 nM, but it is significantly less potent for a panel of 400 nonmutated kinases. 6j also demonstrated reasonable pharmacokinetic properties and a promising oral therapeutic effect in a bleomycin-induced mouse pulmonary fibrosis model. PMID- 27219679 TI - Comparison of two fabricated aptasensors based on modified carbon paste/oleic acid and magnetic bar carbon paste/Fe3O4@oleic acid nanoparticle electrodes for tetracycline detection. AB - In this research, we have improved two aptasensors based on a modified carbon paste electrode (CPE) with oleic acid (OA), and a magnetic bar carbon paste electrode (MBCPE) with Fe3O4 magnetic nanoparticles and oleic acid (OA). After the immobilization process of anti-TET at the electrode surfaces, the aptasensors were named CPE/OA/anti-TET and MBCPE/Fe3O4NPs/OA/anti-TET respectively. In this paper, the detection of tetracycline is compared using CPE/OA/anti-TET and MBCPE/Fe3O4NPs/OA/anti-TET aptasensors. These modified electrodes were characterized by infrared spectroscopy (IR), scanning electron microscopy (SEM), electrochemical impedance spectroscopy (EIS), UV-vis spectroscopy, and voltammetric methods. The linear range and the detection limit for TET with the CPE/OA/anti-TET aptasensor were found to be 1.0*10(-12)-1.0*10(-7)M and 3.0*10( 13)M respectively by EIS method. The linear range and the detection limit for TET with the CPE/OA/anti-TET aptasensor were found to be 1.0*10(-10)-1.0*10(-7)M with a limit of detection of 2.9*10(-11)M using differential pulse voltammetry (DPV) technique. The MBCPE/Fe3O4NPs/OA/anti-TET aptasensor was used for determination of TET, and a liner range of 1.0*10(-14)-1.0*10(-6)M with a detection limit of 3.8*10(-15)M was obtained by EIS method. Also, the linear range and detection limit of 1.0*10(-12)-1.0*10(-6)M and 3.1*10(-13)M respectively, were obtained for MBCPE/Fe3O4NPs/OA/anti-TET aptasensor using DPV. The proposed aptasensors were applied for determination of tetracycline in some real samples such as drug, milk, honey and blood serum samples. PMID- 27219680 TI - Host responses to a strontium releasing high boron glass using a rabbit bilateral femoral defect model. AB - Borate glasses have shown promising potential as bioactive materials. With recent research demonstrating that glass properties may be modulated by appropriate compositional design. This may provide for indication specific material characteristics and controlled release of therapeutic inorganic ions (i.e., strontium); controlling such release is critical in order to harness the therapeutic potential. Within this sub-chronic pilot study, a rabbit long-bone model was utilized to explore the safety and efficacy of a high borate glass (LB102: 70B2 O3 -20SrO-6Na2 O-4La2 O3 ) particulate (90 - 710 MUm) for bone regeneration. Six bilateral full-thickness defects (O = 3.5 mm; L = 8 mm) were created in three white New Zealand rabbits. Longitudinal non-decalcified sections of each defect site were produced and stained with Goldner's Trichrome. Histopathological examination revealed that LB102 demonstrated osteoconductive and osseointegrative properties with greater new bone being formed within and surrounding LB102 particles, when compared to the sham control. The inflammatory cell infiltration was observed to be slightly higher in the control when compared to LB102 defect sites, while no significant difference in fibrosis and neovascularization was determined, indicating that healing was occurring in a normal fashion. These data further suggest the possible utility of high borate glasses with appropriate compositional design for medical applications, such as bone augmentation. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1818-1827, 2017. PMID- 27219681 TI - Tailoring Supramolecular Peptide-Poly(ethylene glycol) Hydrogels by Coiled Coil Self-Assembly and Self-Sorting. AB - Physical hydrogels are extensively used in a wide range of biomedical applications. However, different applications require hydrogels with different mechanical and structural properties. Tailoring these properties demands exquisite control over the supramolecular interactions involved. Here we show that it is possible to control the mechanical properties of hydrogels using de novo designed coiled coil peptides with different affinities for dimerization. Four different nonorthogonal peptides, designed to fold into four different coiled coil heterodimers with dissociation constants spanning from MUM to pM, were conjugated to star-shaped 4-arm poly(ethylene glycol) (PEG). The different PEG-coiled coil conjugates self-assemble as a result of peptide heterodimerization. Different combinations of PEG-peptide conjugates assemble into PEG-peptide networks and hydrogels with distinctly different thermal stabilities, supramolecular, and rheological properties, reflecting the peptide dimer affinities. We also demonstrate that it is possible to rationally modulate the self-assembly process by means of thermodynamic self-sorting by sequential additions of nonpegylated peptides. The specific interactions involved in peptide dimerization thus provides means for programmable and reversible self-assembly of hydrogels with precise control over rheological properties, which can significantly facilitate optimization of their overall performance and adaption to different processing requirements and applications. PMID- 27219682 TI - Non-polyphenolic compounds of a specific kind of dried grape (Maviz) inhibit memory impairments induced by beta-amyloid peptide. AB - OBJECTIVES: Although grape has been recently the topic of many investigations, Maviz (a kind of dried one) has remained neglected. The aim of this study was to assess anti-Alzheimer activity of Maviz. METHODS: To reach this goal, total phenolic content (TPC) of ethanolic (Eth) and aqueous (Aq) extracts were determined and radical scavenging activity was assayed by 2,2-diphenyl-1 picrylhydrazyl. Chemical compositions of each extract were also determined via GC Mass. Behavioral changes were studied via passive avoidance and Morris water maze in Abeta-induced model of Alzheimer's disease. Catalase (CAT) and superoxide dismutase (SOD) determination were also done on rats' hippocampus. RESULTS: The results showed that seed Eth extract has a high level of TPC and radical scavenging activity. However, this extract had surprisingly no effect on memory and CAT and SOD activities. In contrast, fruit Aq and Eth extracts (containing furfurals as major compounds) inhibited memory impairment (P < 0.001) and elevated brain levels of CAT and SOD(P < 0.05). CONCLUSION: It seems that Maviz non-phenolic compounds-most probably 5-hydroxymethylfurfural and other similar derivatives-are responsible for these actions. PMID- 27219683 TI - A 2-year Retrospective Clinical study of Enamic Crowns Performed in a Private Practice Setting. AB - OBJECTIVES: To evaluate the clinical performance and survival of Enamic crowns placed in a prosthodontic dental practice. METHODS: Thirty-five patients and 45 crowns were included in the study. At 1-year recall appointments, the restorations were examined for survival. At the 2-year recall appointment, all restorations were clinically evaluated by an independent evaluator for CDA clinical criteria. Kaplan-Meier method and a log-rank test were used to compare the survival of the restorations placed with resin and resin-modified glass ionomer (RMGI) cements. RESULTS: Out of the 45 crowns that were followed, 2 were lost to follow-up by 1 year and 7 were lost to follow-up by 2 years. Severe complications were observed in 2 teeth by the 2-year follow-up and were recorded as failures due to recurrent decay, and an internal crack in the abutment tooth. There was no difference between the survival probability for crowns cemented with resin cement (96.8%) and with RMGI cements (92.9%) (p = 0.42), however, 1 out of the 14 crowns cemented with RMGI cement debonded. The crowns were evaluated according the CDA criteria with over 90% alfa scores for all categories aside from surface texture (86% alfa). CONCLUSION: The estimated 2-year survival of Enamic crowns is >90%. CLINICAL SIGNIFICANCE: Based on the preliminary 2-year results achieved in a clinical practice, Enamic is a suitable material for full coverage single-unit crowns. Further studies are necessary to evaluate the long term success. (J Esthet Restor Dent 28:231-237, 2016). PMID- 27219684 TI - Cationic polymers for DNA origami coating - examining their binding efficiency and tuning the enzymatic reaction rates. AB - DNA origamis are fully tailored, programmable, biocompatible and readily functionalizable nanostructures that provide an excellent foundation for the development of sophisticated drug-delivery systems. However, the DNA origami objects suffer from certain drawbacks such as low cell-transfection rates and low stability. A great deal of studies on polymer-based transfection agents, mainly focusing on polyplex formation and toxicity, exists. In this study, the electrostatic binding between a brick-like DNA origami and cationic block copolymers was explored. The effect of the polymer structure on the binding was investigated and the toxicity of the polymer-origami complexes evaluated. The study shows that all of the analyzed polymers had a suitable binding efficiency irrespective of the block structure. It was also observed that the toxicity of polymer-origami complexes was insignificant at the biologically relevant concentration levels. Besides brick-like DNA origamis, tubular origami carriers equipped with enzymes were also coated with the polymers. By adjusting the amount of cationic polymers that cover the DNA structures, we showed that it is possible to control the enzyme kinetics of the complexes. This work gives a starting point for further development of biocompatible and effective polycation-based block copolymers that can be used in coating different DNA origami nanostructures for various bioapplications. PMID- 27219685 TI - Efficient Trapping of 1,2-Cyclohexadienes with 1,3-Dipoles. AB - 1,2-Cyclohexadienes are transient intermediates that undergo rapid dimerization and intermolecular trapping with activated olefins and heteroatomic nucleophiles. Fluoride-mediated desilylative elimination of readily accessible 6 silylcyclohexene-1-triflates allows the mild, chemoselective, and functional group tolerant generation of cyclic allene intermediates, which undergo efficient trapping reactions with stable 1,3-dipoles. The reactions proceed with high levels of both regio- and diastereoselectivity. The reaction of cyclic allenes with azides is accompanied by the facile loss of dinitrogen, resulting in the formation of tetrahydroindoles or polycylic aziridines depending on the azide employed. PMID- 27219686 TI - Diabetes and Cancer: a Review of Current Knowledge. AB - Diabetes mellitus (DM), one of the most common life-threatening illnesses worldwide, is a group of metabolic diseases, characterized by sustained hyperglycemia. The global prevalence of diabetes mellitus among adults reached 387 millions in 2014 and is still rising. It is suggested there is a strong association between diabetes mellitus (especially type 2 diabetes mellitus) and carcinogenesis. The possible biological links between diabetes mellitus and cancer comprise hyperinsulinemia, hyperglycemia and fat-induced chronic inflammation. Although, the strongest association refers to pancreas and liver, there are many other organs involved in carcinogenesis in diabetic patients including breast, endometrium, bladder and kidney.Recent studies suggest that there is also association between cancer incidence and anti-diabetic medications. It was observed that some medications decrease the risk of carcinogenesis and some increase that risk. The majority of studies concern metformin, a drug of choice in type 2 diabetes mellitus, and its anti-neoplastic and tumor-suppressing activity. The positive effect of metformin was found in numerous researches investigating breast, pancreas, liver, colon, ovaries and prostate tumors.Because a variety of studies have suggested that diabetes mellitus and cancer are frequently coexisting diseases, recently published studies try to explain the influence of diabetes mellitus and anti-diabetic medications on carcinogenesis in different organs.We present the review of the latest studies investigating the association between both diabetes mellitus and anti-diabetic medications and cancer incidence and prognosis.Particularly we highlight the problem of concomitant head and neck cancers in diabetics, rarely analysed and often omitted in studies. PMID- 27219687 TI - Evaluation of Electrophysiological Effects of Melatonin and Alpha Lipoic Acid in Rats with Streptozotocine Induced Diabetic Neuropathy. AB - INTRODUCTION: Neuropathy is a common complication of diabetes mellitus and is closely related to quality of life. There are many studies in which biological ingredients, such as alpha lipoic acid (ALA), that may inhibit or reduce the generation of diabetic neuropathy were investigated. Another biological agent that may reduce the generation of diabetic neuropathy is melatonin and there are a few studies that investigate the effects of melatonin on diabetic neuropathy. In this study we aimed to examine the effect of melatonin on experimentally induced diabetic neuropathy by comparing it with both ALA and control groups. METHODS: We included 24 male Wistar rats. Tibial motor nerve conduction and cortical tibial nerve somatosensory evoked potentials (SEP) studies were performed before and after diabetes mellitus (DM) for all rats. Rats were divided into 3 (ALA, melatonin and control) groups. After 2 weeks of treatment period, tibial motor nerve conduction and cortical tibial SEP studies were repeated. RESULTS: Our data showed that ALA significantly increased nerve conduction velocity and amplitude in rats with diabetic neuropathy (p=0,001; p=0,002). Also, melatonin significantly increased nerve conduction velocity and amplitude in rats with diabetic neuropathy (p=0.002; p=0.002). There was no significant difference between the electrophysiological effects of ALA and melatonin. Besides, neither ALA nor melatonin did significantly affect P1 and N1 latency values on cortical tibial nerve SEP studies. CONCLUSION: Our study is the study in which both tibial nerve conduction and cortical tibial SEP studies were performed to compare effects of ALA and melatonin on experimental diabetic neuropathy. Lack of significant difference on cortical tibial SEP study would be attributed to the involvement of other central nervous system pathways which do not include ALA or melatonin in the pathogenesis. RESULTS of ALA group are important by means of giving objective evidences for results of biochemical studies about the role of ALA in the pathogenesis of diabetic neuropathy. However, there is not enough information about the effect of melatonin in the pathogenesis of diabetic neuropathy. Consequently, results of our study may anticipate further biochemical and clinic studies which investigate the about the role of melatonin in diabetic neuropathy. PMID- 27219688 TI - Diabetes-Related Burden and Distress is Low in People with Diabetes at Outpatient Tertiary Care Level. AB - OBJECTIVE: The importance of diabetes-related distress (DRD) for the treatment of diabetes is emphasized in national and international guidelines recommending routinely screening for psychosocial problems. To detect DRD, the PAID (Problem Area In Diabetes) questionnaire provides a valid and reliable instrument. RESEARCH DESIGN AND METHODS: 783 patients with diabetes mellitus type 1 (DM1, n=191, age 54.5 y, diabetes duration 22.5 y, HbA1c 7.2% (55 mmol/mol)) and type 2 (DM2, n=592, age 66.6 y, diabetes duration 15.6 y, HbA1c 7.0% (60.1 mmol/mol)) were interviewed with the PAID and WHO-5 questionnaire in a University outpatient department for endocrinology and metabolic diseases in 2012. A PAID score>=40 (range 0-100) was considered as high DRD. RESULTS: The mean PAID score was 17.1+/ 15.1 in all participants. Only 8.9% of all responders showed high DRD (score>=40). The PAID score neither differed in people with DM1 and DM2, nor between participants with DM2 with or without insulin therapy. Females achieved significantly higher scores than men (19.0+/-16.6 vs. 15.6+/-13.7, p=0.003). A strong negative correlation existed between the PAID score and the WHO-5 Well being Index (r=- 0.482, p<0.001). A 10 points higher WHO-5 Well-being Index was associated with 15.9 points lower PAID score in people with DM1 (p<0.001), and 9.2 points lower PAID score in DM2 (p<0.001), respectively. One percent higher HbA1c was associated with an increase of diabetes-related distress by 2.5 points in people with DM1 and by 2.0 points in people with DM2. CONCLUSIONS: Less than 10% of our outpatients with diabetes showed high diabetes-related distress. PMID- 27219689 TI - Association of K121Q Polymorphism in Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 with Clinical Characteristics of Metabolic Syndrom. AB - PURPOSE: This study aimed to investigate the relationships between K121Q polymorphism of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) and clinical characteristics of metabolic syndrome (MS) in northern Han Chinese. MATERIALS AND METHODS: A total of 209 MS patients and 248 healthy controls of Han ethnic group in northern China were enrolled in this study. Various clinical parameters of these participants were firstly collected and compared, including age, sex, body mass index (BMI), waist circumference (WC), systolic and diastolic blood pressures (SBP/DBP), fasting plasma glucose (FPG), fasting insulin (FINS), homeostasis model assessment of insulin resistance index (HOMA-IR), total cholesterol (TC), triglycerides (TG), high-density and low-density lipoprotein cholesterol (LDL-C/HDL-C). Then K121Q polymorphism of ENPP1 was determined by PCR and restriction enzyme digestion, and its relations with related clinical parameters were finally analyzed. RESULTS: When compared with healthy controls, the age, BMI, WC, SBP, DBP, FPG, FINS, HOMA-IR, TC, TG and LDL-C were all significantly increased in MS patients (P<0.001). The allele frequencies of K and Q alleles in ENPP1 were 90.19% and 9.81% in MS patients, and 91.73% and 8.27% in healthy controls, respectively. Besides, only BMI and WC were significantly increased in MS patients carrying Q alleles (P<0.001), while no significant relations were found between K121Q polymorphism and other clinical parameters in either MS patients or healthy controls. CONCLUSION: The K121Q polymorphism of ENPP1 showed no direct correlation with MS, although it showed some correlation with BMI and WC in MS patients. PMID- 27219690 TI - Coordinating chemists for global development. PMID- 27219691 TI - Challenges and opportunities for chemistry in Africa. PMID- 27219692 TI - A lab in Argentina. PMID- 27219693 TI - Two-dimensional materials: Polyphony in B flat. PMID- 27219694 TI - Surface spectroscopy: Between a rock and a soft place. PMID- 27219695 TI - Membraneless organelles: Phasing in and out. PMID- 27219696 TI - Counting on natural products for drug design. AB - Natural products and their molecular frameworks have a long tradition as valuable starting points for medicinal chemistry and drug discovery. Recently, there has been a revitalization of interest in the inclusion of these chemotypes in compound collections for screening and achieving selective target modulation. Here we discuss natural-product-inspired drug discovery with a focus on recent advances in the design of synthetically tractable small molecules that mimic nature's chemistry. We highlight the potential of innovative computational tools in processing structurally complex natural products to predict their macromolecular targets and attempt to forecast the role that natural-product derived fragments and fragment-like natural products will play in next-generation drug discovery. PMID- 27219698 TI - Detecting the oxyl radical of photocatalytic water oxidation at an n SrTiO3/aqueous interface through its subsurface vibration. AB - Although the water oxidation cycle involves the critical step of O-O bond formation, the transition metal oxide radical thought to be the catalytic intermediate for this step has eluded direct observation. The radical represents the transformation of charge into a nascent catalytic intermediate, which lacks a newly formed bond and is therefore inherently difficult to detect. Here, using theoretical calculations and ultrafast in situ infrared spectroscopy of photocatalysis at an n-SrTiO3/aqueous interface, we reveal a subsurface vibration of the oxygen directly below, and uniquely generated by, the oxyl radical (Ti O(*)). Intriguingly, this interfacial Ti-O stretch vibration, once decoupled from the lattice, couples to reactant dynamics (water librations). These experiments demonstrate subsurface vibrations and their coupling to solvent and electron dynamics to detect nascent catalytic intermediates at the solid-liquid interface at the molecular level. One can envision using the subsurface vibrations and their coupling across the interface to track and control catalysis dynamically. PMID- 27219697 TI - An autonomous molecular assembler for programmable chemical synthesis. AB - Molecular machines that assemble polymers in a programmed sequence are fundamental to life. They are also an achievable goal of nanotechnology. Here, we report synthetic molecular machinery made from DNA that controls and records the formation of covalent bonds. We show that an autonomous cascade of DNA hybridization reactions can create oligomers, from building blocks linked by olefin or peptide bonds, with a sequence defined by a reconfigurable molecular program. The system can also be programmed to achieve combinatorial assembly. The sequence of assembly reactions and thus the structure of each oligomer synthesized is recorded in a DNA molecule, which enables this information to be recovered by PCR amplification followed by DNA sequencing. PMID- 27219699 TI - Evolution of thermophilic DNA polymerases for the recognition and amplification of C2'-modified DNA. AB - The PCR amplification of oligonucleotides enables the evolution of sequences called aptamers that bind specific targets with antibody-like affinity. However, in many applications the use of these aptamers is limited by nuclease-mediated degradation. In contrast, oligonucleotides that are modified at their sugar C2' positions with methoxy or fluorine substituents are stable to nucleases, but they cannot be synthesized by natural polymerases. Here we report the development of a polymerase-evolution system and its use to evolve thermostable polymerases that efficiently interconvert C2'-OMe-modified oligonucleotides and their DNA counterparts via 'transcription' and 'reverse transcription' or, more importantly, that PCR-amplify partially C2'-OMe- or C2'-F-modified oligonucleotides. A mechanistic analysis demonstrates that the ability to amplify the modified oligonucleotides evolved by optimizing interdomain interactions that stabilize the catalytically competent closed conformation of the polymerase. The evolved polymerases should find practical applications and the developed evolution system should be a powerful tool for tailoring polymerases to have other types of novel function. PMID- 27219700 TI - Experimental realization of two-dimensional boron sheets. AB - A variety of two-dimensional materials have been reported in recent years, yet single-element systems such as graphene and black phosphorus have remained rare. Boron analogues have been predicted, as boron atoms possess a short covalent radius and the flexibility to adopt sp(2) hybridization, features that favour the formation of two-dimensional allotropes, and one example of such a borophene material has been reported recently. Here, we present a parallel experimental work showing that two-dimensional boron sheets can be grown epitaxially on a Ag(111) substrate. Two types of boron sheet, a beta12 sheet and a chi3 sheet, both exhibiting a triangular lattice but with different arrangements of periodic holes, are observed by scanning tunnelling microscopy. Density functional theory simulations agree well with experiments, and indicate that both sheets are planar without obvious vertical undulations. The boron sheets are quite inert to oxidization and interact only weakly with their substrate. We envisage that such boron sheets may find applications in electronic devices in the future. PMID- 27219701 TI - Membraneless organelles can melt nucleic acid duplexes and act as biomolecular filters. AB - Membraneless organelles are cellular compartments made from drops of liquid protein inside a cell. These compartments assemble via the phase separation of disordered regions of proteins in response to changes in the cellular environment and the cell cycle. Here we demonstrate that the solvent environment within the interior of these cellular bodies behaves more like an organic solvent than like water. One of the most-stable biological structures known, the DNA double helix, can be melted once inside the liquid droplet, and simultaneously structures formed from regulatory single-stranded nucleic acids are stabilized. Moreover, proteins are shown to have a wide range of absorption or exclusion from these bodies, and can act as importers for otherwise-excluded nucleic acids, which suggests the existence of a protein-mediated trafficking system. A common strategy in organic chemistry is to utilize different solvents to influence the behaviour of molecules and reactions. These results reveal that cells have also evolved this capability by exploiting the interiors of membraneless organelles. PMID- 27219702 TI - A supramolecular ruthenium macrocycle with high catalytic activity for water oxidation that mechanistically mimics photosystem II. AB - Mimicking the ingenuity of nature and exploiting the billions of years over which natural selection has developed numerous effective biochemical conversions is one of the most successful strategies in a chemist's toolbox. However, an inability to replicate the elegance and efficiency of the oxygen-evolving complex of photosystem II (OEC-PSII) in its oxidation of water into O2 is a significant bottleneck in the development of a closed-loop sustainable energy cycle. Here, we present an artificial metallosupramolecular macrocycle that gathers three Ru(bda) centres (bda = 2,2'-bipyridine-6,6'-dicarboxylic acid) that catalyses water oxidation. The macrocyclic architecture accelerates the rate of water oxidation via a water nucleophilic attack mechanism, similar to the mechanism exhibited by OEC-PSII, and reaches remarkable catalytic turnover frequencies >100 s(-1). Photo driven water oxidation yields outstanding activity, even in the nM concentration regime, with a turnover number of >1,255 and turnover frequency of >13.1 s(-1). PMID- 27219703 TI - Controlling activity and selectivity using water in the Au-catalysed preferential oxidation of CO in H2. AB - Industrial hydrogen production through methane steam reforming exceeds 50 million tons annually and accounts for 2-5% of global energy consumption. The hydrogen product, even after processing by the water-gas shift, still typically contains ~1% CO, which must be removed for many applications. Methanation (CO + 3H2 -> CH4 + H2O) is an effective solution to this problem, but consumes 5-15% of the generated hydrogen. The preferential oxidation (PROX) of CO with O2 in hydrogen represents a more-efficient solution. Supported gold nanoparticles, with their high CO-oxidation activity and notoriously low hydrogenation activity, have long been examined as PROX catalysts, but have shown disappointingly low activity and selectivity. Here we show that, under the proper conditions, a commercial Au/Al2O3 catalyst can remove CO to below 10 ppm and still maintain an O2-to-CO2 selectivity of 80-90%. The key to maximizing the catalyst activity and selectivity is to carefully control the feed-flow rate and maintain one to two monolayers of water (a key CO-oxidation co-catalyst) on the catalyst surface. PMID- 27219704 TI - Sequence-defined bioactive macrocycles via an acid-catalysed cascade reaction. AB - Synthetic macrocycles derived from sequence-defined oligomers are a unique structural class whose ring size, sequence and structure can be tuned via precise organization of the primary sequence. Similar to peptides and other peptidomimetics, these well-defined synthetic macromolecules become pharmacologically relevant when bioactive side chains are incorporated into their primary sequence. In this article, we report the synthesis of oligothioetheramide (oligoTEA) macrocycles via a one-pot acid-catalysed cascade reaction. The versatility of the cyclization chemistry and modularity of the assembly process was demonstrated via the synthesis of >20 diverse oligoTEA macrocycles. Structural characterization via NMR spectroscopy revealed the presence of conformational isomers, which enabled the determination of local chain dynamics within the macromolecular structure. Finally, we demonstrate the biological activity of oligoTEA macrocycles designed to mimic facially amphiphilic antimicrobial peptides. The preliminary results indicate that macrocyclic oligoTEAs with just two-to-three cationic charge centres can elicit potent antibacterial activity against Gram-positive and Gram-negative bacteria. PMID- 27219706 TI - Tuning the driving force for exciton dissociation in single-walled carbon nanotube heterojunctions. AB - Understanding the kinetics and energetics of interfacial electron transfer in molecular systems is crucial for the development of a broad array of technologies, including photovoltaics, solar fuel systems and energy storage. The Marcus formulation for electron transfer relates the thermodynamic driving force and reorganization energy for charge transfer between a given donor/acceptor pair to the kinetics and yield of electron transfer. Here we investigated the influence of the thermodynamic driving force for photoinduced electron transfer (PET) between single-walled carbon nanotubes (SWCNTs) and fullerene derivatives by employing time-resolved microwave conductivity as a sensitive probe of interfacial exciton dissociation. For the first time, we observed the Marcus inverted region (in which driving force exceeds reorganization energy) and quantified the reorganization energy for PET for a model SWCNT/acceptor system. The small reorganization energies (about 130 meV, most of which probably arises from the fullerene acceptors) are beneficial in minimizing energy loss in photoconversion schemes. PMID- 27219705 TI - Covalent functionalization and passivation of exfoliated black phosphorus via aryl diazonium chemistry. AB - Functionalization of atomically thin nanomaterials enables the tailoring of their chemical, optical and electronic properties. Exfoliated black phosphorus (BP)-a layered two-dimensional semiconductor-exhibits favourable charge-carrier mobility, tunable bandgap and highly anisotropic properties, but it is chemically reactive and degrades rapidly in ambient conditions. Here we show that covalent aryl diazonium functionalization suppresses the chemical degradation of exfoliated BP even after three weeks of ambient exposure. This chemical modification scheme spontaneously forms phosphorus-carbon bonds, has a reaction rate sensitive to the aryl diazonium substituent and alters the electronic properties of exfoliated BP, ultimately yielding a strong, tunable p-type doping that simultaneously improves the field-effect transistor mobility and on/off current ratio. This chemical functionalization pathway controllably modifies the properties of exfoliated BP, and thus improves its prospects for nanoelectronic applications. PMID- 27219707 TI - Parameterization of phosphine ligands reveals mechanistic pathways and predicts reaction outcomes. AB - The mechanistic foundation behind the identity of a phosphine ligand that best promotes a desired reaction outcome is often non-intuitive, and thus has been addressed in numerous experimental and theoretical studies. In this work, multivariate correlations of reaction outcomes using 38 different phosphine ligands were combined with classic potentiometric analyses to study a Suzuki reaction, for which the site selectivity of oxidative addition is highly dependent on the nature of the phosphine. These studies shed light on the generality of hypotheses regarding the structural influence of different classes of phosphine ligands on the reaction mechanism(s), and deliver a methodology that should prove useful in future studies of phosphine ligands. PMID- 27219708 TI - A highly stretchable autonomous self-healing elastomer. AB - It is a challenge to synthesize materials that possess the properties of biological muscles-strong, elastic and capable of self-healing. Herein we report a network of poly(dimethylsiloxane) polymer chains crosslinked by coordination complexes that combines high stretchability, high dielectric strength, autonomous self-healing and mechanical actuation. The healing process can take place at a temperature as low as -20 degrees C and is not significantly affected by surface ageing and moisture. The crosslinking complexes used consist of 2,6 pyridinedicarboxamide ligands that coordinate to Fe(III) centres through three different interactions: a strong pyridyl-iron one, and two weaker carboxamido iron ones through both the nitrogen and oxygen atoms of the carboxamide groups. As a result, the iron-ligand bonds can readily break and re-form while the iron centres still remain attached to the ligands through the stronger interaction with the pyridyl ring, which enables reversible unfolding and refolding of the chains. We hypothesize that this behaviour supports the high stretchability and self-healing capability of the material. PMID- 27219710 TI - Probing bohrium. PMID- 27219709 TI - Fast response dry-type artificial molecular muscles with [c2]daisy chains. AB - Hierarchically organized myosin and actin filaments found in biological systems exhibit contraction and expansion behaviours that produce work and force by consuming chemical energy. Inspired by these naturally occurring examples, we have developed photoresponsive wet- and dry-type molecular actuators built from rotaxane-based compounds known as [c2]daisy chains (specifically, [c2]AzoCD2 hydrogel and [c2]AzoCD2 xerogel). These actuators were prepared via polycondensation between four-armed poly(ethylene glycol) and a [c2]daisy chain based on alpha-cyclodextrin as the host component and azobenzene as a photoresponsive guest component. The light-induced actuation arises from the sliding motion of the [c2]daisy chain unit. Ultraviolet irradiation caused the gels to bend towards the light source. The response of the [c2]AzoCD2 xerogel, even under dry conditions, is very fast (7 degrees every second), which is 10,800 times faster than the [c2]AzoCD2 hydrogel (7 degrees every 3 h). In addition, the [c2]AzoCD2 xerogel was used as a crane arm to lift an object using ultraviolet irradiation to produce mechanical work. PMID- 27219711 TI - Does the antibiotic amoxicillin affect haemocyte parameters in non-target aquatic invertebrates? The clam Ruditapes philippinarum and the mussel Mytilus galloprovincialis as model organisms. AB - Amoxicillin (AMX) is one of the most widely used antibiotics worldwide, and its levels in aquatic ecosystems are expected to be detectable. At present, information concerning the toxic effects of AMX on non-target aquatic organisms, such as bivalves, is scarce. Consequently, in this study, we investigated for the first time the effects of AMX on the haemocyte parameters of two bivalve species, the clam Ruditapes philippinarum and the mussel Mytilus galloprovincialis, which share the same habitat in the Lagoon of Venice, in order to compare the relative sensitivity of the two species. The bivalves were exposed to 100, 200 and 400 MUg AMX/L for 1, 3 and 7 days, and the effects on the total haemocyte count (THC), the diameter and volume of the haemocytes, haemocyte proliferation, lactate dehydrogenase (LDH) activity in cell-free haemolymph, the haemolymph pH, and the formation of micronuclei were evaluated. The actual concentrations of AMX in the seawater samples from the experimental tanks were also measured. Overall, the obtained results demonstrated that AMX affected slightly the haemocyte parameters of bivalves. In addition, no clear differences in terms of sensitivity to AMX exposure were recorded between the two bivalve species. PMID- 27219712 TI - Attachment relationships of preschool-aged children of mothers with HIV and HIV related psychosis. AB - Children from mothers with HIV-related psychosis are frequently raised in challenging contexts, yet the extent to which these children grow up in insecure or disordered attachment relationships is unknown. Using the Strange Situation Procedure the distribution of attachment relationships of children from mothers with HIV and psychosis (n = 45) was compared with children from mothers with HIV without psychosis (n = 41). No significant differences in the distributions were found between the two groups and attachment was not associated with specific psychotic symptomatology. Security of attachment was associated with more people providing the mother with emotional support, but only in the psychosis group. Disordered attachment (24%) was more often found in the total sample than in studies with other normal and high risk populations. Recommendations were made for future research about factors facilitating resilience in the children and on interventions increasing emotional support for affected mothers. PMID- 27219713 TI - Amidines for Versatile Cobalt(III)-Catalyzed Synthesis of Isoquinolines through C H Functionalization with Diazo Compounds. AB - A cobalt(III)-catalyzed C-H/N-H bond functionalization for the synthesis of 1 aminoisoquinolines from aryl amidines and diazo compounds has been developed. The reaction proceeds under mild reaction conditions, obviates the need for oxidants, produces only N2 and H2O as the byproducts, and features a broad substrate scope. PMID- 27219714 TI - Preprocedural fractional flow reserve and microvascular resistance predict increased hyperaemic coronary flow after elective percutaneous coronary intervention. AB - BACKGROUND: Epicardial focal coronary artery stenosis, diffuse coronary disease, and microvascular resistance (MR) may limit coronary flow. The purpose of percutaneous coronary intervention (PCI) is to increase coronary flow by targeting epicardial lesions. After PCI, MR might change and affect coronary flow. We investigated whether PCI influences MR using the index of microcirculatory resistance (IMR) and if pre-PCI fractional flow reserve (FFR) or MR predicts the post-PCI change in hyperaemic coronary flow. METHODS AND RESULTS: This prospective study included 245 vessels from 229 patients with stable angina pectoris undergoing elective PCI. FFR and IMR were measured before and after PCI. Post-PCI increase in hyperaemic coronary flow was assessed using the change in thermodilution-derived transit time (pre-PCI Tmn - post-PCI Tmn ). IMR significantly decreased after PCI (median 1.9; interquartile range, -4.9 to 10.1) and was significantly associated with pre-PCI IMR (r = 0.70, P < 0.001). Increased coronary flow was significantly correlated with pre-PCI IMR (r = 0.62, P < 0.001) and pre-PCI FFR (r = 0.51, P < 0.001). In multivariate analysis, factors significantly associated with decreased post-PCI IMR were pre-PCI IMR (odds ratio [OR], 1.13; 95% confidence interval [CI], 1.08-1.19; P < 0.001) and angiographic reference diameter (OR, 2.44; 95% CI; 1.09-5.48; P = 0.03). Factors significantly associated with increased coronary flow post-PCI were pre-PCI IMR (OR, 1.15; 95% CI, 1.08-1.23; P < 0.001) and pre-PCI FFR (OR, <0.001; 95% CI, 0.000-0.003; P < 0.001). CONCLUSION: PCI affected MR. Pre-PCI FFR and MR were independent predictors of post-PCI changes in hyperaemic coronary flow. (c) 2016 Wiley Periodicals, Inc. PMID- 27219716 TI - Self-Assembled Fibers Containing Stable Organic Radical Moieties: Alignment and Magnetic Properties in Liquid Crystals. AB - Macroscopically oriented stable organic radicals have been obtained by using a liquid-crystalline (LC) gel composed of an l-isoleucine-based low molecular weight gelator containing a 2,2,6,6-tetramethylpiperidine 1-oxyl moiety. The LC gel has allowed magnetic measurements of the oriented organic radical. The gelator has formed fibrous aggregates in liquid crystals via intermolecular hydrogen bonds. The fibrous aggregates of the radical gelator are formed and oriented on cooling by applying a magnetic field to the mixture of liquid crystals and the gelator. Superconducting quantum interference device (SQUID) measurements have revealed that both oriented and nonoriented fibrous aggregates exhibited antiferromagnetic interactions, in which super-exchange interaction constant J is estimated as -0.89 cm(-1) . PMID- 27219715 TI - Predicting advanced neoplasia at colonoscopy in a diverse population with the National Cancer Institute colorectal cancer risk-assessment tool. AB - BACKGROUND: Tailoring screening to colorectal cancer (CRC) risk could improve screening effectiveness. Most CRCs arise from advanced neoplasia (AN) that dwells for years. To date, no available colorectal neoplasia risk score has been validated externally in a diverse population. The authors explored whether the National Cancer Institute (NCI) CRC risk-assessment tool, which was developed to predict future CRC risk, could predict current AN prevalence in a diverse population, thereby allowing its use in risk stratification for screening. METHODS: This was a prospective examination of the relation between predicted 10 year CRC risk and the prevalence of AN, defined as advanced or multiple (>=3 adenomatous, >=5 serrated) adenomatous or sessile serrated polyps, in individuals undergoing screening colonoscopy. RESULTS: Among 509 screenees (50% women; median age, 58 years; 61% white, 5% black, 10% Hispanic, and 24% Asian), 58 (11%) had AN. The prevalence of AN increased progressively from 6% in the lowest risk-score quintile to 17% in the highest risk-score quintile (P = .002). Risk-score distributions in individuals with versus without AN differed significantly (median, 1.38 [0.90-1.87] vs 1.02 [0.62-1.57], respectively; P = .003), with substantial overlap. The discriminatory accuracy of the tool was modest, with areas under the curve of 0.61 (95% confidence interval [CI], 0.54-0.69) overall, 0.59 (95% CI, 0.49-0.70) for women, and 0.63 (95% CI, 0.53-0.73) for men. The results did not change substantively when the analysis was restricted to adenomatous lesions or to screening procedures without any additional incidental indication. CONCLUSIONS: The NCI CRC risk-assessment tool displays modest discriminatory accuracy in predicting AN at screening colonoscopy in a diverse population. This tool may aid shared decision-making in clinical practice. Cancer 2016. (c) 2016 American Cancer Society. Cancer 2016;122:2663-2670. (c) 2016 American Cancer Society. PMID- 27219717 TI - Site-Directed Conjugation of Antibodies to Apoferritin Nanocarrier for Targeted Drug Delivery to Prostate Cancer Cells. AB - Herein, we describe a novel approach for targeting of ubiquitous protein apoferritin (APO)-encapsulating doxorubicin (DOX) to prostate cancer using antibodies against prostate-specific membrane antigen (PSMA). The conjugation of anti-PSMA antibodies and APO was carried out using HWRGWVC heptapeptide, providing their site-directed orientation. The prostate-cancer-targeted and nontargeted nanocarriers were tested using LNCaP and HUVEC cell lines. A total of 90% of LNCaP cells died after treatment with DOX (0.25 MUM) or DOX in nontargeted and prostate-cancer-targeted APO, proving that the encapsulated DOX toxicity for LNCaP cells remained the same. Free DOX showed higher toxicity for nonmalignant cells, whereas the toxicity was lower after treatment with the same dosage of APO encapsulated DOX (APODOX) and even more in prostate-cancer-targeted APODOX. Hemolytic assay revealed exceptional hemocompatibility of the entire nanocarrier. The APO encapsulation mechanism ensures applicability using a wide variety of chemotherapeutic drugs, and the presented surface modification enables targeting to various tumors. PMID- 27219719 TI - Utilising Medicare annual wellness visits to implement interprofessional education in the primary care setting. AB - Interprofessional education (IPE) is an important component of healthcare professional curriculum in order to optimally prepare students for their roles as part of the healthcare team. Integrating IPE activities into direct patient care in the primary care clinic setting can help improve perceptions and student understanding of other healthcare professionals' responsibilities in this ever evolving practice setting. This report describes the implementation of an interprofessional clinic including a variety of healthcare professionals and students in the context of the Medicare Annual Wellness Visits (AWV). Design of the clinic and general roles of the professionals in optimising preventive care are described. Student perceptions of IPE and their knowledge of other healthcare professionals were also surveyed. Student knowledge of other professionals mildly improved. Student perception of actual cooperation and interprofessional interaction statistically improved, while perception of interprofessional learning slightly worsened. Utilising Medicare AWVs can be a way for various professionals to improve IPE in the primary care setting. PMID- 27219718 TI - The effect of angiotensin-converting enzyme polymorphism on hemodynamic response to endotracheal intubation in hypertensive patients. AB - Endotracheal intubation elicits a hemodynamic response associated with increased heart rate and blood pressure that is influenced by the angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) genetic polymorphism which may be of importance also for the pressure response to anesthesia. A total of 337 patients underwent abdominal surgery in general anesthesia and 16% were D/D-homozygotes, 45% were I/D heterozygotes and 39% of the patients were I/I homozygotes. Before surgery most patients were in treatment for arterial hypertension. Systolic and diastolic pressure, heart rate and concentrations of catecholamines in blood were determined before and after induction of anesthesia and for up to 10 minutes following endotracheal intubation. Anesthesia decreased blood pressure and for patients presenting ID and DD, blood pressure and heart rate reached similar levels but compared to II-homozygotes, D-carriers demonstrated significantly higher levels for systolic pressure and heart rate before and after intubation (p < 0.05). The blood levels of catercholamines were similar in the three genotype groups. The incidence of ECG-determined myocardial ischemia was higher in D allele carriers compared to I-allele homozygotes (DD 22%, ID 25% vs. II 5%). In response to anesthesia and intubation and independent of sympathetic nervous activity, D-allele carriers for ACE polymorphism increased blood pressure response and higher risk for development of cardiovascular complications compared to patients homozygous for the I-allele. PMID- 27219720 TI - Influence of FDG-PET on primary nodal target volume definition for head and neck carcinomas. AB - BACKGROUND: The role of 2-[18F]-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in routine diagnostic staging remains controversial. In case of discordance between FDG-PET and CT, a compromise has to be made between the risk of false positive FDG-PET and the risk of delaying appropriate salvage intervention. Second, with intensity modulated radiation therapy (IMRT), smaller radiation fields allow tissue sparing, but could also lead to more marginal failures. METHODS: We retrospectively studied 283 patients with head and neck carcinoma scheduled for radiotherapy between 2002 and 2010. We analyzed the influence of FDG-PET/CT versus CT alone on defining nodal target volume definition and evaluated its long-term clinical results. Second, the location of nodal recurrences was related to the radiation regional dose distribution. RESULTS: In 92 patients, CT and FDG-PET, performed in mold, showed discordant results. In 33%, nodal staging was altered by FDG-PET. In 24%, FDG-PET also led to an alteration in nodal treatment, including a nodal upstage of 18% and downstage of 6%. In eight of these 92 patients, a regional recurrence occurred. Only two patients had a recurrence in the discordant node on FDG-PET and CT and both received a boost (high dose radiation). CONCLUSION: These results support the complementary value of FDG-PET/CT compared to CT alone in defining nodal target volume definition for radiotherapy of head and neck cancer. PMID- 27219721 TI - Midterm Results After Coated and Uncoated TKA: A Randomized Controlled Study. AB - Patients undergoing total knee arthroplasty (TKA) who have hypersensitivity to metals usually receive hypoallergenic TKA implants. Coating of a standard implant is a common solution. Although in vitro tests have demonstrated reduction in polyethylene wear for these coatings, it is unknown whether these costly implants have a clinical benefit for patients. One hundred twenty patients undergoing TKA were randomly assigned to receive a novel 7-layer-coating implant or a standard TKA implant. One revision occurred in the standard group, resulting in a calculated 5-year survival of 100% in the coated group and 98.1% in the standard group. The Oxford Knee Score improved substantially in both groups from a mean of 21.6 points preoperatively in the coated group and 21.9 points in the standard group to 39.2 points and 39.2 points, respectively. The current authors observed no adverse effects with the new coating during midterm follow-up. However, longer follow-up time is needed to evaluate possible advantages of this coating. [Orthopedics. 2016; 39(3):S13-S17.]. PMID- 27219722 TI - How Much Improvement in Patient Activity Can Be Expected After TKA? AB - Most patients expect an improvement of physical activity after total knee arthroplasty (TKA). The aim of this study was to evaluate improvement in physical activity after TKA. An accelerometer was used to measure activity in 221 patients before and 1 year after TKA. The measurements included the total number of steps and time spent lying, sitting/standing, or walking. Threshold for achievement of health-enhancing physical activity (HEPA) guidelines and step-defined lifestyle were applied to the data. Measured steps per day improved from 5371 to 6587. Only 50 patients (22.6%) met the HEPA guidelines, whereas 31% achieved an active lifestyle. Improvement in daily step number was influenced by age (P<.001), body mass index (P<.001) and preoperative activity (P<.001). After TKA, patients improved in physical activity and one-third achieved an active lifestyle. Patient specific characteristics and preoperative levels of physical activity had a relevant influence on activity after TKA. [Orthopedics. 2016; 39(3):S18-S23.]. PMID- 27219723 TI - Influence of Surface Coating on Metal Ion Release: Evaluation in Patients With Metal Allergy. AB - Nickel, chromium, and cobalt in stainless steel and Cobalt-chrome-molybdenum (CoCrMo) alloys may induce allergy. The objectives of this study were to evaluate surface coating regarding ion release, patch test reactivity, and arthroplasty performance. Materials and methods included patch test in 31 patients with metal allergy and 30 patients with no allergy to stainless steel and CoCrMo disks that are uncoated or coated by titanium nitride/zirconium nitride (TiN/ZrN). Assessment include atomic absorption spectrometry of released nickel, cobalt, and chromium from the disks after exposure to distilled water, artificial sweat and culture medium. Results showed that both coatings reduced the nickel and chromium release from stainless steel and CoCrMo disks and mostly the cobalt release from the disks (maximally 11.755 ug/cm(2)/5 d to 1.624 by Ti-N and to 0.442 by ZrN). Six of the 31 patients with metal allergy reacted to uncoated disks, but none reacted to the coated disks. The current authors report on exemplary patients with metal allergy who had symptom relief by revision with surface-coated arthroplasty. The authors concluded that the surface coating may prevent cutaneous and peri-implant allergic reactions. [Orthopedics. 2016; 39(3):S24 S30.]. PMID- 27219724 TI - Retrospective 5-Year Analysis of Revision Rate and Functional Outcome of TKA With and Without Patella Implant. AB - The aim of this study was to compare a patient cohort after total knee arthroplasty (TKA) in terms of the revision rate and the functional outcome, with and without patella resurfacing. Sixty-six patients (71 TKAs) were implanted with the mobile-bearing knee prosthesis system e.motion UC (Aesculap AG, Tuttlingen, Germany). These patients were divided into 2 groups, 1 of which received primary patella resurfacing (PPR; 51 TKAs) and 1 of which did not (non-PPR; 20 TKAs), with an average follow-up of 65.6 months (+/-6.9). The cohort was recorded consecutively. The evaluation was performed using the Knee Society Score and selected questions relating to the Knee Injury and Osteoarthritis Outcome Score, as well as with radiographs. Results showed that PPR was no better than non-PPR in terms of functional outcome. Two knees (10%) were revised in the non-PPR group, and 1 knee (1.96%) in the PPR group (not significant). In this cohort, 100% of implants, including the 5 TKAs of patients who did not attend the follow up examination, had neither explanted nor loosened at the time of follow-up examination. The authors concluded that the revision rate for PPR is slightly lower, and this avoids the need for secondary patella resurfacing. The risk for complications is low, and the functional outcome is comparable. [Orthopedics. 2016; 39(3):S31-S35.]. PMID- 27219725 TI - TKA for Posttraumatic Osteoarthritis Is More Complex and Needs More Surgical Resources. AB - The purpose of this study was to evaluate the surgical effort of total knee arthroplasty (TKA) for posttraumatic osteoarthritis (PTOA) compared with primary osteoarthritis (OA). A total of 1841 TKAs were analyzed, including 170 patients with PTOA, that resulted from soft tissue trauma in 83 patients and fractures in 87 patients. Results showed that patients were significantly younger at the time of surgery in the posttraumatic group (62 vs 71 years; P<.001). Furthermore, fracture was associated with 3.7 years earlier need of TKA compared with soft tissue trauma. Operation time was significantly longer for both of the posttraumatic groups compared with OA (P<.001). Patients undergoing TKA after knee injuries are younger and surgical treatment is more challenging compared with TKA for OA. Extended operation time and implant systems with higher constraint and modular options are required. [Orthopedics. 2016; 39(3):S36-S40.]. PMID- 27219726 TI - Tibiofemoral Rotation During Sit-to-Stand Activity After TKA. AB - The objective of this study was to describe how tibiofemoral internal/external rotation varies in patients after total knee arthroplasty (TKA) when compared with control participants during a sit-to-stand (STS) maneuver. Motion analysis was used to measure internal/external knee rotation during STS in the control and TKA groups. Fourteen participants were included in the study. Six patients with 7 TKA knees (6 posterior stabilized and 1 cruciate-retaining TKA) were compared with 8 control participants with 8 knees from the current authors' laboratory database. Participants performed 3 STS maneuvers, and the average internal/external rotation of the femur with respect to the tibia was compared. All control participants and 2 TKA participants had internal rotation of the femur with respect to the tibia, whereas 4 TKA participants had external rotation, and 1 had no rotation during STS. Further investigation into the surgical and patient- and implant-related factors that affect this resulting reverse kinematic profile seems to be warranted. [Orthopedics. 2016; 39(3):S41 S44.]. PMID- 27219728 TI - Current Aspects in Total Knee Arthroplasty. PMID- 27219727 TI - Total Knee Post-Cam Design Variations and Their Effects on Kinematics and Wear Patterns. AB - Post-cam designs for posterior-stabilized total knee arthroplasy (TKA) implants have evolved over the last 2 decades. These designs have evolved from symmetric post and cam to asymmetric designs that include anterior post interactions to affect a kinematic change in full extension. All design changes have consequences on the resulting femorotibial contact kinematics and, depending on the amount of constraint built into the design, these changes may have significant consequences on the wear patterns on the tibial polyethylene insert. The current authors review the kinematic effects of symmetric and asymmetric cam designs and use a retrieval database of TKA implants obtained at the time of necropsy to show how different design variables may affect polyethylene wear patterns after 10 or more years of implantation or from modeled wear in simulators. More modern designs seem to have moved the post posteriorly and sloped the anterior aspect to avoid impingement of the anterior post in terminal flexion on the inferior aspect of the patella button. [Orthopedics. 2016; 39(3):S45-S49.]. PMID- 27219729 TI - Effect of Rotational Component Alignment on Clinical Outcome 5 to 7 Years After TKA With the Columbus Knee System. AB - The aim of the study was to examine the effects of rotational component alignment on outcome after total knee arthroplasty (TKA) with a minimum follow-up of 5 years. For this study, 96 patients were available for follow-up at a mean of 5.7 years after TKA. Computed tomography scans were available in 55 patients. Outcome (Oxford Knee Score [KSS], Knee Injury and Osteoarthritis Outcome Score [KOOS], 36 item Short Form Health Survey) was correlated with postoperative femoral and tibial component malrotation or femorotibial rotational alignment mismatch. Results showed that femoral or tibial component malrotation or femorotibial mismatch were present in 15.5%, 38.2%, and 29.1% of patients, respectively. Although femoral componoent malrotation was associated with significantly poorer, KSS and KOOS scores, outcome was comparable for patients with or without tibial component malrotation or femorotibial mismatch. In conclusion, both internal and external rotational femoral malalignment exceeding 3 degrees is associated with significantly poorer subjective and objective outcome 5 to 7 years after TKA. Tibial component malrotation and femorotibial mismatch were more common, but did not significantly compromise outcome. [Orthopedics. 2016; 39(3):S50-S55.]. PMID- 27219730 TI - Postoperative Radiographic Assessment of the Vega Posterior-Stabilized TKA. AB - Different biomechanical designs are incorporated into various total knee arthroplasty (TKA) implants. The posterior-stabilized prosthesis design utilizes a polyethylene post and femoral cam in place of the posterior cruciate ligament. This produces a more stable component interface, increased range of motion, and potentially a less technical procedure. This study aimed to assess the short-term (>2 year) outcomes associated with the Vega System posterior-stabilized knee prosthesis (Aesculap Implant Systems, Center Valley, Pennsylvania) based on postoperative radiographs using the Knee Society Roentgenographic Evaluation and Scoring System (KSRESS). Thirty-seven TKA patients who had received the Vega posterior-stabilized knee prosthesis and had postoperative radiographs at each follow-up for a minimum of 2 years were enrolled, retrospectively. Two independent observers evaluated the radiographs using KSRESS. Descriptive statistics were used to analyze the data. The average age and body mass index of patients enrolled was 67 years (range, 51-89 years) and 38.5 kg/m(2) (range, 21.2 54 kg/m(2)), respectively. Patients had radiographic follow-up for an average of 36 months (range, 24-58 months). Comparison between first and last available postoperative radiographs revealed a stable femoral and tibial interface with no significant change in prosthesis alignment over the follow-up period. Assessment of the short-term survivorship of the Vega posterior-stabilized prosthesis using KSRESS revealed no significant change in alignment after 2 years of follow-up; however, mid- to long-term studies assessing this junction are needed. A future prospective study using KSRESS in combination with clinical follow-up is recommended to allow comparison of the Vega posterior-stabilized to other prostheses. [Orthopedics. 2016; 39(3):S56-S60.]. PMID- 27219731 TI - Do Well-Balanced Primary TKA Patients Achieve Better Outcomes Within the First Year After Surgery? AB - Some surgically modifiable factors are related to soft tissue balance. With computer-assisted surgery, it is possible to access these variables quantitatively. The aim of this analysis was to study the influence of gap balance on clinical outcomes within the first year after computer-navigated total knee arthroplasty (TKA). Based on navigation data, 3 independent variables reflecting gap balance were used to split the patients in 2 groups. The Knee Society Scores (Function [KSS-F] and Knee [KSS-K]) and the maximal knee flexion (MKF) measured preoperatively and at 3, 6 and 12 months were compared using analyses of variance (2*4 design) for repeated measures. Higher flexion-extension gap equality led to statistically higher KSS-F and KSS-K scores at 1 year (P=.02). Higher medial-lateral flexion gap equality led to superior mean MKF at all measurement points; however the differences were statistically only significant at 3 months (P=.01). The coefficients of variation of the variables used to select the patients were overall very low. With computer-assisted navigation, it is possible to access quantitatively the size of the medial and lateral flexion and extension gaps. Higher flexion-extension gap equality values led to statistically significant better KSS-F and KSS-K scores at 1 year. Higher medial-lateral flexion gap equality values led to better MKF values; however the differences were only statistically significant at 3 months. [Orthopedics. 2016; 39(3):S6-S12.]. PMID- 27219732 TI - Economics of All-Polyethylene Versus Metal-Backed Tibial Prosthesis Designs. AB - With the large number of total knee arthroplasties being performed and expectations that these numbers will be on the rise over the coming decades, efforts to provide cost-efficient care are of greater interest. The preferred design of knee arthroplasty implants has changed over time, with the original all polyethylene tibial (APT) design being replaced by metal-backed tibial (MBT) components, as well as more recent considerations of newer APT designs. Modern APT components have been shown to have similar or superior outcomes than MBT components. Despite their limitations, APT components can be used to reduce the economic burden to the provider, medical institution, and health care system as a whole. There is a paucity of evidence-based literature directly comparing the cost associated with APT and MBT components. The purpose of this report is to review the literature to assess the available data regarding direct and indirect costs of both designs so that orthopedic surgeons can account for economic differences in everyday practice. [Orthopedics. 2016; 39(3):S61-S66.]. PMID- 27219733 TI - Assessing Tibial Tray Rotation in TKA: A Cadaveric Study. AB - Tibial anatomical landmarks for transverse plane rotation of the tibial tray have not been validated. The current authors propose aligning the tibial tray with both the anterior tibial center point of rotation (ATCPR) and the femoral trochlear groove (FTG) to establish the ideal tibial tray rotation in total knee arthroplasty (TKA). When the tibial tray centerline was aligned with ATCPR and FTG lines, the mean range of motion (ROM) was 144.3 degrees (preoperatively 145 degrees ) and tibial rotation range was 22.8 mm (preoperatively, 24.9 mm). When the tibial component was rotated 5 mm medially to the ATCPR, the knee ROM decreased in flexion with patellar subluxation, while it decreased in extension when rotated 5 mm laterally. This method identifies the ideal tibial tray rotation in TKA, at which maximal range of tibial rotation and knee ROM are achieved without obvious overriding of components. [Orthopedics, 2016; 39(3):S67 S71.]. PMID- 27219734 TI - 10-Year Survival of Navigated Versus Conventional TKAs: A Retrospective Study. AB - The computer-assisted navigation of total knee arthroplasty (TKA) offers a radiologically demonstrated higher precision of implantation than conventional implantation in relation to the axis alignment. The impact on long-term clinical outcomes is currently unknown. In 1999, 217 consecutive TKAs were performed in a total of 213 patients (113 navigated and 104 conventional). After 10 years, it was possible to follow up on 94 patients with 96 TKAs, of which 46 were conventional and 50 were navigated. The radiographs were evaluated using the Knee Society protocol. In addition to the Hospital for Special Surgery Score and Knee Society Score, the current authors also used the patient-focused 36-item Short Form Health Survery. After 10 years, 8 TKAs were revised because of aseptic loosening, 7 in the conventional group and 1 in navigated group. This equates to an 87% survival rate for conventional and 98% for navigated implantation. This difference was statistically significant (P<.05). After conclusion of the follow up, 17% of the conventional and 9.8% of the navigated TKAs were found to have undergone aseptic loosening. All of the TKAs subject to aseptic loosening presented a mechanical femorotibial angle outside the optimal zone of +/-3 degrees around neutral axis. The study indicates a clinically significant advantage of the navigation technique compared with the conventional procedure. [Orthopedics. 2016; 39(3):S72-S76.]. PMID- 27219735 TI - Navigated TKA After Osteotomy Versus Primary Navigated TKA: A Matched-Pair Analysis. AB - This article presents clinical and radiological outcome analysis of navigated total knee arthroplasty (TKA) following osteotomy compared with primary navigated TKA implantation. The study group (29 legs) received navigated TKA (Columbus with deep-dish, cruciate-retaining inlay, Aesculap AG, Tuttlingen, Germany) following distal femoral (6 legs) or high tibial (23 legs) osteotomy, and the control group (29 legs) received a primary navigated TKA. All patients were examined clinically and radiologically in a retrospective matched-pair analysis. Both groups showed comparable clinical scores (Oxford Knee Score, Tegner and Lysholm scores, and Knee Society Score). Radiological evaluations offered no relevant differences. The study group showed a significant mediolateral ligamentous instability (3 legs <=5 degrees , 1 leg 6 degrees -9 degrees , 25 legs >=10 degrees mediolateral deviation) compared with the control group (14 legs <=5 degrees , 9 legs 6 degrees -9 degrees , 6 legs >10 degrees ; P<.001). Significantly higher mediolateral ligamentous instability was seen in otherwise comparable clinical and radiological results in patients with navigated TKA implantation following osteotomy, compared with primary TKA. [Orthopedics; 2016. 39(3):S77-S82.]. PMID- 27219736 TI - A Comparative Study Between Patient-Specific Instrumentation and Conventional Technique in TKA. AB - Patient-specific instrumentation (PSI) was developed to improve the accuracy of component positioning through custom cutting blocks constructed based on preoperative 3-dimensional imaging in total knee arthroplasty (TKA). The purpose of this study was to compare the clinical and radiological outcomes between the patients who underwent PSI-assisted TKA or conventional TKA. Sixty-four patients (64 knees) underwent TKA by a single surgeon: 32 patients (32 knees) underwent TKA with PSI, 32 patients (32 knees) underwent TKA with conventional instrumentation. The mean age of the patients was 67.6 years, and the mean follow up duration is 26.2 months. Patients were evaluated preoperatively and after surgery. The current authors evaluated clinical outcomes including knee range of motion, Hospital for Special Survey scale, Western Ontario and McMaster University Osteoarthritis Index, and Knee Society pain and function scores. The current authors also compared radiological outcomes including mechanical axis and coronal and sagittal alignment. The current authors found no significant differences in any clinical outcomes between the PSI-assisted TKA group and the conventional TKA group. In terms of radiological outcomes, the PSI-assisted TKA group had fewer alignment outliers. The current authors found that PSI-assisted TKA restores limb alignment better than conventional TKA, but PSI does not confer a substantial advantage in early functional outcomes after TKA. Further follow-up is needed to ascertain the long-term impact of these findings. [Orthopedics. 2016; 39(3):S83-S87.]. PMID- 27219737 TI - Long term end-stage renal disease and death following acute renal replacement therapy in the ICU. AB - INTRODUCTION: In ICU the need for acute renal replacement therapy (RRT) associates with high mortality and risk of end-stage renal disease (ESRD), but there are limited long-term data. We investigated these outcomes and their risk factors. METHODS: Retrospective analysis of all adult patients admitted to a general, university hospital ICU 2005-2012, excluding chronic dialysis patients. ESRD was defined as need of RRT > 90 days or kidney transplant. RESULTS: Of 5766 patients included, 1004 (16%) received acute RRT; their 30-day mortality was 42% vs. 16% for those not requiring acute RRT (adjusted hazard ratio (HR) 1.13 (0.96 1.32)). The 90-day mortality was 55% for patients receiving acute RRT vs. 22% for those who did not (adjusted HR 1.32 (1.15-1.51)) and 1-year mortality was 63% vs. 30%, respectively, (adjusted HR 1.31 (1.16-1.48)). The 7-year risk of ESRD for ICU patients surviving 90 days was 10% for patients who received acute RRT vs. 0.5% among those who did not (adjusted HR 5.9 (2.9-12.4)). Independent risk factors for ESRD included pre-existing kidney disease, pre-existing peripheral vascular disease and use of acute RRT in ICU. CONCLUSIONS: The need of acute RRT was associated with markedly increased long term risk of death and ESRD; in contrast its use was not associated with 30-day mortality. In addition to acute RRT, decreased kidney function and peripheral vascular disease before ICU admission were risk factors for ESRD. It seems warranted offering medical follow up to patients after acute RRT in ICU. PMID- 27219738 TI - Task difficulty and inertial properties of hand-held tools: An assessment of their concurrent effects on precision aiming. AB - Aiming hand-held tools at targets in space entails adjustments in the dynamical organization of aiming patterns according to the required precision. We asked whether and how these adjustments are modified by the tool's mass distribution. Twelve participants performed reciprocal aiming movements with a 50-cm long wooden probe. Kinematic patterns of probe movements were used as a window into the behavioral dynamic underlying performance of a reciprocal aiming task. We crossed three levels of task difficulty (IDs 2.8, 4.5 and 6.1) with two types of probe varying in their mass distribution (proximal vs distal loading). Movement duration was affected by task difficulty and probe loading (shorter for larger targets and proximal probe loading). Progressive deviations from a sinusoidal movement pattern were observed as task difficulty increased. Such deviations were more pronounced with proximal probe loading. Results point to a higher degree of non-linearity in aiming dynamics when the probe was loaded proximally, which might reflect employment of additional perceptual-motor processes to control the position of its less stable tip at the vicinity of the targets. More generally, the effects of probe loading on aiming pattern and dynamics suggest that perceptual-motor processes responding to task level constraints are sensitive to, and not independent from, biomechanical, end-effector constraints. PMID- 27219739 TI - Training compliance control yields improved drawing in 5-11year old children with motor difficulties. AB - There are a large number of children with motor difficulties including those that have difficulty producing movements qualitatively well enough to improve in perceptuo-motor learning without intervention. We have developed a training method that supports active movement generation to allow improvement in a 3D tracing task requiring good compliance control. Previously, we tested a limited age range of children and found that training improved performance on the 3D tracing task and that the training transferred to a 2D drawing test. In the present study, school children (5-11years old) with motor difficulties were trained in the 3D tracing task and transfer to a 2D drawing task was tested. We used a cross-over design where half of the children received training on the 3D tracing task during the first training period and the other half of the children received training during the second training period. Given previous results, we predicted that younger children would initially show reduced performance relative to the older children, and that performance at all ages would improve with training. We also predicted that training would transfer to the 2D drawing task. However, the pre-training performance of both younger and older children was equally poor. Nevertheless, post-training performance on the 3D task was dramatically improved for both age groups and the training transferred to the 2D drawing task. Overall, this work contributes to a growing body of literature that demonstrates relatively preserved motor learning in children with motor difficulties and further demonstrates the importance of games in therapeutic interventions. PMID- 27219740 TI - Effect of melphalan 140 mg/m(2) vs 200 mg/m(2) on toxicities and outcomes in multiple myeloma patients undergoing single autologous stem cell transplantation a single center experience. AB - Although melphalan at a dose of 140 mg/m(2) (MEL140) is an acceptable conditioning regimen for autologous stem cell transplantation (ASCT) in multiple myeloma (MM) patients, very few studies compared it to the most commonly used dose of 200 mg/m(2) (MEL200). A retrospective review of records of MM patients (2001-2010) identified 33 patients who received MEL140 and 96 patients who received MEL200. As expected, significantly higher percentage of patients in the MEL140 arm were >65 years or had cardiac ejection fraction <50%, had Karnofsky score <80, or had creatinine >2 at the time of ASCT (P<=.01). There were no significant differences in incidence of treatment related mortality and morbidity. At a median follow-up of 74 months from ASCT, there were no significant differences in relapse free survival (RFS) and overall survival (OS) between the two groups. Similar proportion had myeloma status improve to >=VGPR at 3 months post-ASCT. Usage of post-ASCT maintenance was similar. In multivariate cox proportional hazards model, only disease status of >=VGPR at the time of ASCT significantly improved RFS (P=.024), but not OS (P=.104). In conclusion, MM patients who received MEL140 had similar long-term outcomes to MEL200 patients despite their older age and co-morbidities. PMID- 27219741 TI - Echocardiographic Features that May Predict Acute Left Ventricular Failure after Mitral Valve Replacement in Patients with Severe Mitral Stenosis. PMID- 27219742 TI - Rocket Science at the Nanoscale. AB - Autonomous propulsion at the nanoscale represents one of the most challenging and demanding goals in nanotechnology. Over the past decade, numerous important advances in nanotechnology and material science have contributed to the creation of powerful self-propelled micro/nanomotors. In particular, micro- and nanoscale rockets (MNRs) offer impressive capabilities, including remarkable speeds, large cargo-towing forces, precise motion controls, and dynamic self-assembly, which have paved the way for designing multifunctional and intelligent nanoscale machines. These multipurpose nanoscale shuttles can propel and function in complex real-life media, actively transporting and releasing therapeutic payloads and remediation agents for diverse biomedical and environmental applications. This review discusses the challenges of designing efficient MNRs and presents an overview of their propulsion behavior, fabrication methods, potential rocket fuels, navigation strategies, practical applications, and the future prospects of rocket science and technology at the nanoscale. PMID- 27219743 TI - Early Exposure to Traffic-Related Air Pollution, Respiratory Symptoms at 4 Years of Age, and Potential Effect Modification by Parental Allergy, Stressful Family Events, and Sex: A Prospective Follow-up Study of the PARIS Birth Cohort. AB - BACKGROUND: The relation between traffic-related air pollution (TRAP) exposure and the incidence of asthma/allergy in preschool children has been widely studied, but results remain heterogeneous, possibly due to differences in methodology and susceptibility to TRAP. OBJECTIVES: We aimed to study the relation of early TRAP exposure with the development of respiratory/allergic symptoms and asthma during preschool years, and to investigate parental allergy, "stressful" family events, and sex as possible effect modifiers. METHODS: We examined data of 2,015 children from the PARIS birth cohort followed up with repeated questionnaires completed by parents until age 4 years. TRAP exposure in each child's first year of life was estimated by nitrogen oxides (NOx) air dispersion modeling, taking into account both home and day care locations. Association between TRAP exposure and patterns of wheezing, dry night cough, and rhinitis symptoms was studied using multinomial logistic regression models adjusted for potential confounders. Effect modification by parental history of allergy, stressful family events, and sex was investigated. RESULTS: An interquartile range (26 MUg/m3) increase in NOx levels was associated with an increased odds ratio (OR) of persistent wheezing at 4 years (adjusted OR = 1.27; 95% confidence interval: 1.09, 1.47). TRAP exposure was positively associated with persistent wheeze, dry cough, and rhinitis symptoms among children with a parental allergy, those experiencing stressful family events, and boys, but not in children whose parents did not have allergies or experience stressful events, or in girls (all interaction p-values < 0.2). CONCLUSIONS: This study supports the hypothesis that not all preschool children are equal regarding TRAP health effects. Parental history of allergy, stressful family events, and male sex may increase their susceptibility to adverse respiratory effects of early TRAP exposure. PMID- 27219817 TI - Consequences of Expiratory Flow Limitation at Rest in Subjects with Cystic Fibrosis. AB - RATIONALE: Expiratory flow limitation at resting tidal volume (EFLTV) presents a severe mechanical constraint in chronic lung diseases and has not yet been studied longitudinally in cystic fibrosis. OBJECTIVES: To study the effect of EFLTV as it emerged from simple spirometry on lung function and clinical status in cystic fibrosis. METHODS: Best year spirometry that included tidal flow/volume curves and the related clinical data were retrospectively collected over 12 +/- 3.0 yr/person from 108 subjects with cystic fibrosis. The year in which forced expiratory flow, midexpiratory phase (FEF25-75%, L/s) was equal to tidal peak expiratory flow (L/s) was defined as EFLTV-onset year. MEASUREMENTS AND MAIN RESULTS: EFLTV occurred in 55 (51%) subjects, at age 23 +/- 6 years. At EFLTV onset, tidal peak expiratory flow and FEF25-75% values were 1.44 +/- 0.23 L/s and FEV1 was 62 +/- 10% predicted. Within the following 2 years, FEV1 dropped to 48 +/- 11% predicted, and 35 (63%) of the subjects reported shortness of breath at rest. Hospital days increased from 5.3 +/- 24.6 to 24.12 +/- 9.0 d/yr (P = 0.0001). Of the 55 subjects, 29 (53%) received transplant or died, with survival time being 6.9 +/- 3.9 years. CONCLUSIONS: EFLTV onset may be an important pathophysiological event that could influence the natural history of lung function decline in subjects with cystic fibrosis. This may lead to a significant deterioration in lung function in the following 2 years alongside an increase in the number of hospitalization days. The monitoring of FEV1 alone does not offer as good a threshold signal, because values are only moderately reduced. Therefore, identifying EFLTV appearance is potentially a signal for therapeutic intervention. Further studies are warranted to confirm our findings. PMID- 27219818 TI - The Predictors study: Development and baseline characteristics of the Predictors 3 cohort. AB - INTRODUCTION: The Predictors study was designed to predict the length of time to major disease outcomes in Alzheimer's disease (AD) patients. Here, we describe the development of a new, Predictors 3, cohort. METHODS: Patients with prevalent or incident AD and individuals at-risk for developing AD were selected from the North Manhattan community and followed annually with instruments comparable to those used in the original two Predictors cohorts. RESULTS: The original Predictors cohorts were clinic based and racially/ethnically homogenous (94% white, 6% black; 3% Hispanic). In contrast, the 274 elders in this cohort are community-based and ethnically diverse (39% white, 40% black, 21% other; 78% Hispanic). Confirming previous observations, psychotic features were associated with poorer function and mental status and extrapyramidal signs with poorer function. DISCUSSION: This new cohort will allow us to test observations made in our original clinic-based cohorts in patients that may be more representative of the general community. PMID- 27219820 TI - This is what I need a clinical feedback system to do for me: A qualitative inquiry into therapists' and patients' perspectives. AB - : Routine outcome monitoring and clinical feedback systems (ROM/CFSs) are promising methods of providing naturalistic research data and enhancing mental health care. However, implementation in routine care is challenging, and we need more knowledge about clinicians' and patients' needs from such systems. OBJECTIVE: We aimed to study perspectives of clinicians and patients to explore how ROM/CFS can be helpful and acceptable to them. METHOD: We interviewed 55 participants in focus groups and individual interviews and analyzed the data through rigorous team-based qualitative analyses. RESULTS: We report 3 overarching domains: (a) Shared needs, (b) Specific patient needs, and (c) Specific therapist needs. Shared needs, in which perspectives of different stakeholders converge, was the dominant domain in the material. Under each domain, we report 3 specific themes: (a1) Degree of trust in therapy, (a2) Allowing for openness, (a3) Monitoring joint objectives; (b1) Life functioning, (b2) Canary in the coal mine, (b3) Holistic report; and (c1) Emotional presence and style, (c2) Monitoring risk and symptoms, and (c3) Agency and ownership of process. CONCLUSIONS: In what should increase our confidence toward core aspects of ROM, we suggest that an integration of relational feedback concepts and stringent clinical dimension tracking into the ROM/CFS can be beneficial. PMID- 27219819 TI - Impact of Autologous Mesenchymal Stem Cell Infusion on Neuromyelitis Optica Spectrum Disorder: A Pilot, 2-Year Observational Study. AB - AIMS: We evaluate safety and efficacy of autologous bone marrow-derived mesenchymal stem cells (MSCs) as a potential treatment for neuromyelitis optica spectrum disorder (NMOSD). METHODS: Fifteen patients with NMOSD were recruited. All patients received a single intravenous infusion of 1.0 * 10(8) autologous MSC within 3-4 generations derived from bone marrow. The primary endpoints of the study were efficacy as reflected by reduction in annualized relapse rates (ARRs) and inflammatory lesions observed by MRI. RESULTS: At 12 months after MSC infusion, the mean ARR was reduced (1.1 vs. 0.3, P = 0.002), and the T2 or gadolinium-enhancing T1 lesions decreased in the optic nerve and spinal cord. Disability in these patients was reduced (EDSS, 4.3 vs. 4.9, P = 0.021; visual acuity, 0.4 vs. 0.5, P = 0.007). The patients had an increase in retinal nerve fiber layer thickness, optic nerve diameters and upper cervical cord area. We did not identify any serious MSC-related adverse events. At 24 months of MSC infusion, of 15 patients, 13 patients (87%) remained relapse-free, the mean ARR decreased to 0.1; the disability of 6 patients (40%) was improved, and the mean EDSS decreased to 4.0. CONCLUSIONS: This pilot trial demonstrates that MSC infusion is safe, reduces the relapse frequency, and mitigates neurological disability with neural structures in the optic nerve and spinal cord recover in patients with NMOSD. The beneficial effect of MSC infusion on NMOSD was maintained, at least to some degree, throughout a 2-year observational period. PMID- 27219821 TI - Thinned stone fruits are a source of polyphenols and antioxidant compounds. AB - BACKGROUND: Thinned fruits are agricultural by-products that contain large quantities of interesting compounds due to their early maturity stage. In this work, the phenolic profile and the antioxidant activity of six thinned stone fruits (apricot, cherry, flat peach, peach, plum and nectarine) have been investigated, focussing on proanthocyanidins. RESULTS: Thinned nectarine had the highest content of total phenols [67.43 mg gallic acid equivalents (GAE) g-1 dry weight (DW)] and total flavonoids (56.97 mg CE g-1 DW) as well as the highest antioxidant activity measured by DPPH scavenging (133.30 mg [Trolox equivalents (TE) g-1 DW] and FRAP assay (30.42 mg TE g-1 DW). Proanthocyanidins were very abundant in these by-products, and the main phenolic group quantified in cherry (10.54 mg g-1 DW), flat peach (33.47 mg g-1 DW) and nectarine (59.89 mg g-1 DW), while hydroxycinnamic acids predominate in apricot, peach and plum (6.67, 22.04 and 23.75 mg g-1 DW, respectively). The low, mean degree of polymerisation of proanthocyanidins suggests that their bioavailability could be very high. CONCLUSIONS: This study shows that thinned stone fruit extracts might be used as antioxidants in foods or as a source of compounds with health-related benefits that can be used in the pharmaceutical, cosmetic and food industries. (c) 2016 Society of Chemical Industry. PMID- 27219822 TI - K27M mutation in H3F3A in ganglioglioma grade I with spontaneous malignant transformation extends the histopathological spectrum of the histone H3 oncogenic pathway. PMID- 27219823 TI - Incorporation of poison center services in a state-wide overdose education and naloxone distribution program. AB - BACKGROUND: To help curb the opioid overdose epidemic, many states are implementing overdose education and naloxone distribution (OEND) programs. Few evaluations of these programs exist. Maryland's OEND program incorporated the services of the poison center. It asked bystanders to call the poison center within 2 hours of administration of naloxone. Bystanders included law enforcement (LE). OBJECTIVE: Description of the initial experience with this unique OEND program component. METHODS: Retrospective case series of all cases of bystander administered naloxone reported to the Maryland Poison Center over 16 months. Cases were followed to final outcome, for example, hospital discharge or death. Indications for naloxone included suspected opioid exposure and unresponsiveness, respiratory depression, or cyanosis. Naloxone response was defined as person's ability to breathe, talk, or walk within minutes of administration. RESULTS: Seventy-eight cases of bystander-administered naloxone were reported. Positive response to naloxone was observed in 75.6% of overall cases. Response rates were 86.1% and 70.9% for suspected exposures to heroin and prescription opioids, respectively. Two individuals failed to respond to naloxone and died. DISCUSSION: Naloxone response rates were higher and admission to the intensive care unit rates were lower in heroin overdoses than prescription opioid overdoses. CONCLUSIONS: This retrospective case series of 78 cases of bystander-administered naloxone reports a 75.6% overall rate of reversal. SCIENTIFIC SIGNIFICANCE: The findings of this study may be more generalizable. Incorporation of poison center services facilitated the capture of more timely data not usually available to OEND programs. (Am J Addict 2016;25:301-306). PMID- 27219824 TI - Correction: The Chromatin Remodelling Enzymes SNF2H and SNF2L Position Nucleosomes adjacent to CTCF and Other Transcription Factors. AB - [This corrects the article DOI: 10.1371/journal.pgen.1005940.]. PMID- 27219825 TI - Effects of home-based exercise and branched-chain amino acid supplementation on aerobic capacity and glycemic control in patients with cirrhosis. AB - AIM: The aim of the current study is to examine whether home-based step exercise at anaerobic threshold (AT) and branched-chain amino acid (BCAA) supplementation improve aerobic capacity, ectopic fat in liver and muscle, and glycemic control in patients with liver cirrhosis. METHODS: Six female patients with compensated liver cirrhosis received oral BCAA and were instructed to undertake bench step exercises at an intensity that corresponded to AT, with a goal of performing 140 min of exercise per week at home for 12 months. Fat deposition in liver (liver to spleen ratio) and intramuscular adipose tissue content were assessed at baseline and after 6 and 12 months by computed tomography. Glycemic control indices (homeostasis model assessment of insulin resistance, hemoglobin A1c [HbA1c ], glycated albumin [GA] and chronic liver disease [CLD]-HbA1c [average of HbA1c and GA/3]) were also measured. RESULTS: Twelve months of moderate training significantly increased AT, which is an index of aerobic capacity, but no changes were observed in body weight, liver to spleen ratio, or intramuscular adipose tissue content. Glycated albumin significantly decreased (P < 0.05) and there tended to be a similar decrease in CLD-HbA1c (P < 0.1) after the exercise. The baseline serum triglyceride level correlated with changes in GA (P < 0.01) and CLD-HbA1c (P < 0.1). CONCLUSION: The current results suggest that the combination of home-based step exercise at AT and BCAA supplementation enhances aerobic capacity and potentially improves glycemic control in patients with cirrhosis without changes in body weight. The baseline serum serum triglyceride may partially explain the degree of improvement in glycemic control with exercise and BCAA intervention. PMID- 27219826 TI - Antibiotic prescribing for acute bronchitis. AB - INTRODUCTION: Acute bronchitis is a self-limiting infectious disease characterized by acute cough with or without sputum but without signs of pneumonia. About 90% of cases are caused by viruses. AREAS COVERED: Antibiotics for acute bronchitis have been associated with an approximately half-day reduction in duration of cough. However, at follow-up there are no significant differences in overall clinical improvement inpatients treated with antibiotics compared with those receiving placebo. Despite this, antibiotics are administered to approximately two thirds of these patients. This review discusses the reason for this antibiotic overprescription. Other therapies targeted to control symptoms have also demonstrated a marginal or no effect. Expert commentary: Clinicians should be aware of the marginal effectiveness of antibiotic therapy. Some strategies like the use of rapid tests, delayed prescribing of antibiotics and the use of leaflets for patients have been associated with a reduction of their unnecessary utilization. PMID- 27219827 TI - Do Patient-Centered Medical Home Access and Care Coordination Measures Reflect the Contribution of All Team Members? A Systematic Review. AB - Patient-Centered Medical Home (PCMH) evaluations have primarily focused on primary care providers and not on the primary care team. This systematic literature review examined the extent to which access and care coordination measures in PCMH reflect the involvement of associate care providers (ACPs), which include registered and licensed practical nurses, nursing and medical assistants, clerks, pharmacists, social workers, and dietitians. Among 42 studies, few measures specified ACP roles or linked ACP care to outcomes. Increasing attention on team-based care emphasizes a vital need to reframe measures within a team context. PMID- 27219828 TI - Parents' Perspectives on "Keeping Their Children Safe" in the Hospital. AB - This study explored parents' perspectives regarding their involvement in safety for their hospitalized children. We employed qualitative description and semistructured interviews of parents of children in an urban tertiary hospital ward. Content analysis revealed 4 parent themes: risks to child safety and comfort, hospital role as a protector, participation in safety varies by individual and organizational factors, and balancing safety with "speaking up" interpersonal risks. We suggest key concepts to incorporate into staff education and family engagement/safety programs to develop effective partnerships between clinicians and parents. PMID- 27219829 TI - Off-premise alcohol purchasing in Australia: Variations by age group, income level and annual amount purchased. AB - INTRODUCTION AND AIMS: To delineate what type and how much alcohol is purchased from different types of off-licence premises and how this varies across demographic sub-groups, as a basis for public debate and decisions on pricing and planning policies to reduce alcohol-related harm in Australia. DESIGN AND METHODS: The data on alcohol purchasing from off-licence premises are taken from the Australian Alcohol Consumption and Purchasing survey-a nationally representative landline and mobile telephone survey in 2013 on the experiences with alcohol consumption and purchasing of 2020 Australians aged 16+. The present analysis uses data from 1730 respondents who purchased alcohol from off-licence premises in the previous 6 months. RESULTS: The majority (54%) of alcohol purchased from off-licence premises was sold from liquor barns (large warehouse style alcohol stores), with bottle shops (31%) the second most common outlet. Cask wine was the cheapest alcohol available at off-licence premises in Australia. Respondents in higher alcohol purchasing quintiles and with those with lower income purchased a higher percentage of cheaper alcohol in their total volume of purchasing than lower purchasing quintiles and those with middle and higher income, and younger respondents purchased more expensive alcohol than older age groups. DISCUSSION AND CONCLUSIONS: A minimum unit price or increasing alcohol taxes may effectively reduce alcohol purchasing for lower income heavy alcohol purchasers and older age groups from off-licence premise sources, and may be less effective on younger age groups. [Jiang H, Callinan S, Livingston M, Room R. Off-premise alcohol purchasing in Australia: Variations by age group, income level and annual amount purchased. Drug Alcohol Rev 2017;36:210-219]. PMID- 27219830 TI - Airborne particle emission of a commercial 3D printer: the effect of filament material and printing temperature. AB - The knowledge of exposure to the airborne particle emitted from three-dimensional (3D) printing activities is becoming a crucial issue due to the relevant spreading of such devices in recent years. To this end, a low-cost desktop 3D printer based on fused deposition modeling (FDM) principle was used. Particle number, alveolar-deposited surface area, and mass concentrations were measured continuously during printing processes to evaluate particle emission rates (ERs) and factors. Particle number distribution measurements were also performed to characterize the size of the emitted particles. Ten different materials and different extrusion temperatures were considered in the survey. Results showed that all the investigated materials emit particles in the ultrafine range (with a mode in the 10-30-nm range), whereas no emission of super-micron particles was detected for all the materials under investigation. The emission was affected strongly by the extrusion temperature. In fact, the ERs increase as the extrusion temperature increases. Emission rates up to 1*1012 particles min-1 were calculated. Such high ERs were estimated to cause large alveolar surface area dose in workers when 3D activities run. In fact, a 40-min-long 3D printing was found to cause doses up to 200 mm2 . PMID- 27219831 TI - Focal depth measurements of the vaginal wall: a new method to noninvasively quantify vaginal wall thickness in the diagnosis and treatment of vaginal atrophy. AB - OBJECTIVE: The aim of the study was to evaluate if vaginal focal depth measurement could be a noninvasive method to quantify vaginal wall thickness. METHODS: Postmenopausal women undergoing topical estrogen therapy because of vaginal atrophy (VA) were recruited. VA was diagnosed based on the presence of symptoms and vaginal pH at least 5.5. The control group consisted of women above 40 years without VA. Focal depth measurements were performed before and after treatment using the Cytocam-Incident Dark Field device assessing the distance between the subepithelial microcirculation and the epithelial surface. Measurements were performed before and after treatment in the intervention group and at two different time points in the control group. Vaginal pH was measured. Symptoms were evaluated using the most bothersome symptom approach. RESULTS: Eight women with VA and nine controls were included. Pretreatment median focal depth was not significantly different between both groups. Pretreatment focal depth more than doubled after a median of 7 weeks of topical estrogen treatment (80 MUm [interquartile range 80-120 MUm] vs 220 MUm [148-248 MUm], P = 0.02), whereas the measurements in the control group did not change. Pretreatment vaginal pH differed between both groups (5.5 vs 5.1, respectively, P < 0.01). Vaginal pH did not change after treatment. CONCLUSIONS: Using in vivo microscopy we introduced a new noninvasive measure of vaginal wall thickness. A significant increase in vaginal focal depth was observed in participants with VA treated with topical estrogens. This innovative measurement of vaginal wall thickness could become the preferred objective measure to evaluate treatment effect. Moreover, it has great potential for other applications in the field of urogynecology. PMID- 27219832 TI - The relationship between phytoestrogens and speed of processing. AB - OBJECTIVE: This study examined the cross-sectional association between phytoestrogens and speed of processing. We hypothesized that higher levels of phytoestrogens would be related to better cognitive performance among older women. METHODS: Participants were from the National Health and Nutrition Examination Survey and consisted of 200 older women (M = 74.4 y). Stepwise regressions examined indicators of speed of processing, measured by the Digit Symbol Substitution Test. Isoflavones, lignans, and individual phytoestrogens were added to the regression after including covariates of age, education, race, smoking, and creatinine. Isoflavones were further broken into quartiles among the sample to further evaluate the nature of the curvilinear association. RESULTS: Results showed a relationship between cognition and lignans, explaining 3.8% of the variance after including the covariates, indicating fewer lignans were associated with better speed of processing (P < 0.001). A significant curvilinear relationship with isoflavones explained 1.3% additional variance (P < 0.001). The moderate-high, low-moderate, and the lowest quartile of isoflavones were associated with better cognition, whereas the highest amount was associated with worse speed of processing. Among the individual phytoestrogens, only enterodiol accounted for 4.4% additional variance after taking into account covariates and indicated a negative association with cognition (P = 0.03). CONCLUSIONS: Results suggest that moderate levels of isoflavones, but not lignans, may be associated with better speed of processing. Caution must remain for high isoflavone amounts due to the negative association with cognition. Given the results, phytoestrogens have the potential to be an intervention target for older females' cognition. To become a viable intervention, further research is needed. PMID- 27219833 TI - Relationship between sociodemographic, reproductive, and lifestyle factors and the severity of menopausal symptoms among Egyptian women in Alexandria. AB - OBJECTIVE: During menopause, women often experience some symptoms which may affect their daily activities. Information about menopausal experiences among different racial and ethnic groups is important for healthcare personnel to provide appropriate and specific interventions. The aim of the present study was thus to determine the frequency and determinants of severity of menopausal symptoms among Egyptian women using the Menopause Rating Scale as a screening tool for identification of menopausal symptoms. METHODS: A total of 540 women (aged 40-65 y) were recruited in this cross-sectional study. Demographic information was collected, and the Menopause Rating Scale questionnaire was administered. RESULTS: Most frequently reported symptoms were joint and muscular discomfort (501, 92.8%) followed by urogenital symptoms (460, 85.2%). A significant association was found between the number of menopausal symptoms and working status of participants (r = 0.504, P = 0.005), number of children (r = 0.474, P = 0.042), and body mass index (r = 0.544, P = 0.006). Women who reported urogenital symptoms and self-perceived general health as poor were more frequently referred to a gynecologist for moderate-to-severe menopausal symptoms. CONCLUSIONS: Participant-related information such as working status, which was shown to increase the frequency of psychological symptoms in our ethnic group, should be noted by the physician, and a suitable approach should be adopted to achieve better therapy outcomes. Counseling about the importance of maintaining an ideal body weight and exercise should be emphasized to reduce menopausal symptoms. Appropriate advice and support in improving the overall state of the postmenopausal women is essential. PMID- 27219834 TI - Hot flashes: emerging cardiovascular risk factors in recent and late postmenopause and their association with higher blood pressure. AB - OBJECTIVE: The aim of the study was to compare the endothelial function of symptomatic (self-reported hot flashes >3 on a scale of 0-10) versus asymptomatic (<=3) women in different postmenopause stages, and to examine if the association between hot flashes and endothelial function was independent of classical cardiovascular risk factors observed during the analysis. METHODS: Noninvasive venous occlusion plethysmography within two groups: recent (recent postmenopause [RPM], <10 y, n = 63) and late (late postmenopause [LPM], >=10 y, n = 67) postmenopause. RESULTS: Symptomatic women showed lower forearm blood flow and lower percentage increment of it during the reactive hyperemia response; higher systolic (P < 0.0001 in RPM and P = 0.0008 in LPM) and diastolic (P = 0.0005 in RPM and P = 0.0219 in LPM) blood pressure; highest score for perimenopausal hot flashes (P = 0.0007 in RPM and P < 0.0001 in LPM), longer duration of prior oral contraceptive use (P = 0.009 in RPM and P = 0.0253 in LPM), and higher current sleep disorders (P < 0.0001 in RPM and P = 0.0281 in LPM) compared with asymptomatic ones. In the LPM group, symptomatic women also had higher prevalence of previous hypertension diagnosis (P = 0.0092). During multivariate analysis, blood flow during the reactive hyperemia response was associated with hot flashes after adjusting for age, body mass index, and systolic blood pressure (odds ratio 0.55 [0.36-0.84] in RPM and odds ratio 0.7 [0.5-0.97] in LPM). CONCLUSIONS: In both phases, recent and late post menopause, hot flashes were associated with endothelial dysfunction and higher systolic and diastolic blood pressure, but the relationship between hot flashes and endothelial dysfunction was independent of blood pressure. PMID- 27219835 TI - Pelvic floor muscles training to reduce symptoms and signs of vulvovaginal atrophy: a case study. AB - OBJECTIVE: Vulvovaginal atrophy (VVA), caused by decreased levels of estrogen, is a common problem in aging women. Main symptoms of VVA are vaginal dryness and dyspareunia. First-line treatment consists of the application of local estrogen therapy (ET) or vaginal moisturizer. In some cases however, symptoms and signs persist despite those interventions. This case study describes a 77-year-old woman with severe VVA symptoms despite use of local ET and the addition of pelvic floor muscle (PFM) training to her treatment. METHODS: A patient with stress urinary incontinence and VVA was referred to a randomized clinical trial on PFM training. On pretreatment evaluation while on local ET, she showed VVA symptoms on the ICIQ Vaginal Symptoms questionnaire and the ICIQ-Female Sexual Matters associated with lower urinary tract Symptoms questionnaire, and also showed VVA signs during the physical and dynamometric evaluation of the PFM. She was treated with a 12-week PFM training program. RESULTS: The patient reported a reduction in vaginal dryness and dyspareunia symptoms, as well as a better quality of sexual life after 12 weeks of PFM training. On posttreatment physical evaluation, the PFMs' tone and elasticity were improved, although some other VVA signs remained unchanged. CONCLUSIONS: Pelvic floor muscle training may improve some VVA symptoms and signs in women taking local ET. Further study is needed to investigate and confirm the present case findings and to explore mechanisms of action of this intervention for VVA. PMID- 27219837 TI - Menopausal symptoms in Bangladeshi women in midlife. PMID- 27219836 TI - A cross-cultural comparison of climacteric symptoms, self-esteem, and perceived social support between Mosuo women and Han Chinese women. AB - OBJECTIVE: This cross-cultural study aimed to compare climacteric symptoms, self esteem, and perceived social support between Mosuo and Han Chinese women, and to explore the interaction between culture and climacteric symptoms. Mosuo is a Chinese minority group with a matriarchal structure, and Han Chinese is the majority ethnic group in China with a patriarchal structure. METHODS: Through convenience sampling, 54 Mosuo women and 52 Han Chinese women between 40 and 60 years of age completed the sociodemographic questionnaire, the Menopause Rating Scale, the Self-Esteem Scale, and the Perceived Social Support Scale. RESULTS: Compared with Han Chinese women, Mosuo women scored lower on the psychological (P < 0.001) and the somato-vegetative (P = 0.047) subscales of the Menopause Rating Scale, but higher on the Self-Esteem Scale (P = 0.006) and the "support from family" subscale of the Perceived Social Support Scale (P = 0.004). Multiple linear regressions indicated that minority ethnicity (beta = 0.207, P = 0.016) was one of the predictive variables of psychological symptoms severity. Referring to the severity of all symptoms, predictive variables were: perceived support from family (beta = -0.210, P = 0.017); self-esteem (beta = 0.320, P < 0.001); previous history of premenstrual syndrome (beta = 0.293, P < 0.001); number of family members (beta = -0.229, P = 0.003); and family income (beta = -0.173, P = 0.028). CONCLUSIONS: Differences in climacteric symptoms were found between two groups. Cultural variables such as familial structure, women's self-esteem, and perceived social support were correlated with symptomatology. PMID- 27219838 TI - Strategies to reduce the use of seclusion with tangata whai i te ora (Maori mental health service users). AB - Maori, the indigenous people of New Zealand, have the highest crude population based rate of seclusion events reported internationally (McLeod et al. ). This qualitative study explored Maori clinical, cultural and consumer perspectives on potential strategies and initiatives considered likely to facilitate prevention of, and reduction in, the use of seclusion, with tangata whai i te ora (Maori mental health service users) in mental health inpatient services. A hui (gathering) over 2 days was held with 16 Maori participants with high levels of clinical, cultural and consumer expertise. The gathering was taped and the tapes transcribed. A thematic analysis of the hui data generated three key categories: Te Ao Maori (access to a Maori worldview); Te Ao Hurihuri (transforming practice); and Rangatiratanga (leadership, power, and control). The findings of this study align with the "six core strategies" for best practice to reduce the use of seclusion (Huckshorn ). A comprehensive approach to the reduction of the use of seclusion with tangata whai i te ora is required, which is clearly based on a Maori model of care and a vision for transformation of practice in mental health inpatient services, which involves Maori leadership. PMID- 27219839 TI - Child Problems as a Moderator of Relations Between Maternal Impulsivity and Family Environment in a High-Risk Sample. AB - OBJECTIVE: Previous studies have suggested that maternal characteristics are related to family environment; however, the relation between maternal impulsivity, in particular, and family environment is not well understood. As such, we examined direct relations between maternal impulsivity and family environment, as well as whether the relation between maternal impulsivity and family environment was moderated by child problems for sons and daughters. We hypothesized that child problems would moderate the association between maternal impulsivity and family environment. We also explored whether these associations differ for boys and girls. METHOD: Data from the initial visit of a longitudinal study was used for the current study. Participants included 297 youth (137 boys; 160 girls) of 10 to 12 years of age (M = 10.99, SD = .84) and their mothers. The majority of the sample had a family history of substance use disorder (n = 236). RESULTS: Hierarchical linear regressions showed that for sons there was a significant interaction between maternal impulsivity and child problems on family environment. Maternal impulsivity was positively related to family environment problems among sons with few emotional and behavioral problems, but there was no significant correlation among sons with high problem levels. Among daughters, there was no significant interaction between maternal impulsivity and child emotional and behavioral problems on family environment. CONCLUSIONS: The results suggest that the association between maternal impulsivity and family environment may depend on problem level and child gender. Thus, addressing maternal impulsivity in therapy may benefit some families. PMID- 27219840 TI - Ethyl Acetate Extract of Origanum vulgare L. ssp. hirtum Prevents Streptozotocin Induced Diabetes in C57BL/6 Mice. AB - Type 1 diabetes (T1D) is an autoimmune disease that develops as a consequence of pancreatic beta-cell death induced by proinflammatory mediators. Because Origanum vulgare L. ssp. hirtum (Greek oregano) contains antiinflammatory molecules, we hypothesized that it might be beneficial for the treatment of T1D. An ethyl acetate extract of oregano (EAO) was prepared from the leaves by a polar extraction method. Phytochemical composition was determined by liquid chromatography-UV diode array coupled to ion-trap mass spectrometry with electrospray ionization interface (LC/DAD/ESI-MS(n) ). In vitro immunomodulatory effect of EAO was estimated by measuring proliferation (MTT) or cytokine secretion (ELISA) from immune cells. Diabetes was induced by multiple low doses of streptozotocin (MLDS) in male C57BL/6 mice and EAO was administered intraperitoneally for 10 d. Determination of cellular composition (flow cytometry) and cytokine production (ELISA) was performed on 12th d after diabetes induction. EAO suppressed the function of both macrophages and lymphocytes in vitro. In vivo, EAO treatment significantly preserved pancreatic islets and reduced diabetes incidence in MLDS-challenged mice. Besides down-modulatory effect on macrophages, EAO reduced the number of total CD4(+) and activated CD4(+) CD25(+) T cells. Furthermore, EAO affected the number of T helper 1 (Th1) and T helper 17 (Th17) cells through downregulation of their key transcription factors T-bet and RORgammaT. Because EAO treatment protects mice from development of hyperglycemia by reducing proinflammatory macrophage/Th1/Th17 response, this plant extract could represent a basis for future diabetes therapy. PMID- 27219841 TI - Use of p16 FISH for differential diagnosis of mesothelioma in smear preparations. AB - Because most of malignant pleural mesothelioma (MPM) patients first present with pleural effusion, detection of mesothelioma cells on effusion smears is critical for early diagnosis. Recently, accumulating evidence indicating that the cytological diagnosis of MPM supported by ancillary techniques is as reliable as that based on histopathology has led to new guidelines for the cytopathologic diagnosis of MPM. Based on the guidelines, a combination of cytomorphological criteria and verification by ancillary techniques is required for the cytologic diagnosis of MPM. Detection of p16 homozygous deletion by fluorescence in situ hybridization (FISH) is the most reliable ancillary technique for differentiating MPM from reactive mesothelial cells (RMC) because of its relatively high sensitivity and extremely high specificity. We showed that the p16 deletion status of MPM cells in pleural effusions reflected that of the underlying invasive MPM tissues, indicating the usefulness of p16 FISH in effusion smear cytology for MPM diagnosis. Thus, for differentiating MPM from RMC, we propose to perform p16 FISH as often as possible. A positive p16 homozygous deletion supports the diagnosis of MPM. However, a negative result does not rule out the possibility of MPM. In such cases, a morphological assessment is critical. Therefore, we analyzed the morphological characteristics of p16 deletion-positive mesothelioma cells using a combination of virtual microscopy and p16 FISH, and identified three morphological characteristics useful for the differentiation, including cell-in-cell engulfment with or without hump formation, multinucleate cells, and larger berry-like cell aggregates. Diagn. Cytopathol. 2016;44:774-780. (c) 2016 Wiley Periodicals, Inc. PMID- 27219842 TI - Interlimb Coordination during Tied-Belt and Transverse Split-Belt Locomotion before and after an Incomplete Spinal Cord Injury. AB - Coordination between the arms/forelimbs and legs/hindlimbs is often impaired in humans and quadrupedal mammals after incomplete spinal cord injury. In quadrupeds, the forelimbs often take more steps than the hindlimbs, producing a two-to-one forelimb-hindlimb (2-1 FL-HL) coordination. In locomotor performance scales, this is generally considered a loss of FL-HL coordination. Here, FL-HL coordination was quantified before and 8 weeks after a lateral spinal hemisection at the sixth thoracic segment in six adult cats. Cats were tested during tied belt locomotion (equal front and rear speeds) and transverse split-belt locomotion with the forelimbs or hindlimbs stepping faster. The results show that consistent phasing between forelimb and hindlimb movements was maintained after hemisection, even with the appearance of 2-1 FL-HL coordination, indicating that new stable forms of coordination emerge. Moreover, transverse split-belt locomotion potently modulated interlimb coordination and was capable of restoring a one-to-one FL-HL coordination with a faster treadmill speed for the hindlimbs. In conclusion, the results suggest that neural communication persists after an incomplete spinal cord injury, despite an unequal number of steps between the forelimbs and hindlimbs, and that interlimb coordination can be modulated by having the forelimbs or hindlimbs move at a faster frequency. We propose that locomotor recovery scales incorporate more sensitive methods to quantify FL-HL coordination, to better reflect residual functional capacity and possible cervicolumbar neural communication. Lastly, devising training protocols that make use of the bidirectional influences of the cervical and lumbar locomotor pattern generators could strengthen interlimb coordination and promote locomotor recovery. PMID- 27219843 TI - Simulating infinite vortex lattices in superfluids. AB - We present an efficient framework to numerically treat infinite periodic vortex lattices in rotating superfluids described by the Gross-Pitaevskii theory. The commonly used split-step Fourier (SSF) spectral methods are inapplicable to such systems as the standard Fourier transform does not respect the boundary conditions mandated by the magnetic translation group. We present a generalisation of the SSF method which incorporates the correct boundary conditions by employing the so-called magnetic Fourier transform. We test the method and show that it reduces to known results in the lowest-Landau-level regime. While we focus on rotating scalar superfluids for simplicity, the framework can be naturally extended to treat multicomponent systems and systems under more general 'synthetic' gauge fields. PMID- 27219844 TI - Protein-Protein Interaction Inhibition (2P2I)-Oriented Chemical Library Accelerates Hit Discovery. AB - Protein-protein interactions (PPIs) represent an enormous source of opportunity for therapeutic intervention. We and others have recently pinpointed key rules that will help in identifying the next generation of innovative drugs to tackle this challenging class of targets within the next decade. We used these rules to design an oriented chemical library corresponding to a set of diverse "PPI-like" modulators with cores identified as privileged structures in therapeutics. In this work, we purchased the resulting 1664 structurally diverse compounds and evaluated them on a series of representative protein-protein interfaces with distinct "druggability" potential using homogeneous time-resolved fluorescence (HTRF) technology. For certain PPI classes, analysis of the hit rates revealed up to 100 enrichment factors compared with nonoriented chemical libraries. This observation correlates with the predicted "druggability" of the targets. A specific focus on selectivity profiles, the three-dimensional (3D) molecular modes of action resolved by X-ray crystallography, and the biological activities of identified hits targeting the well-defined "druggable" bromodomains of the bromo and extraterminal (BET) family are presented as a proof-of-concept. Overall, our present study illustrates the potency of machine learning-based oriented chemical libraries to accelerate the identification of hits targeting PPIs. A generalization of this method to a larger set of compounds will accelerate the discovery of original and potent probes for this challenging class of targets. PMID- 27219851 TI - Design and characterization of microcapsules-integrated collagen matrixes as multifunctional three-dimensional scaffolds for soft tissue engineering. AB - Three-dimensional (3D) porous scaffolds based on collagen are promising candidates for soft tissue engineering applications. The addition of stimuli responsive carriers (nano- and microparticles) in the current approaches to tissue reconstruction and repair brings about novel challenges in the design and conception of carrier-integrated polymer scaffolds. In this study, a facile method was developed to functionalize 3D collagen porous scaffolds with biodegradable multilayer microcapsules. The effects of the capsule charge as well as the influence of the functionalization methods on the binding efficiency to the scaffolds were studied. It was found that the binding of cationic microcapsules was higher than that of anionic ones, and application of vacuum during scaffolds functionalization significantly hindered the attachment of the microcapsules to the collagen matrix. The physical properties of microcapsules integrated scaffolds were compared to pristine scaffolds. The modified scaffolds showed swelling ratios, weight losses and mechanical properties similar to those of unmodified scaffolds. Finally, in vitro diffusional tests proved that the collagen scaffolds could stably retain the microcapsules over long incubation time in Tris-HCl buffer at 37 degrees C without undergoing morphological changes, thus confirming their suitability for tissue engineering applications. The obtained results indicate that by tuning the charge of the microcapsules and by varying the fabrication conditions, collagen scaffolds patterned with high or low number of microcapsules can be obtained, and that the microcapsules-integrated scaffolds fully retain their original physical properties. PMID- 27219850 TI - White matter deficits mediate effects of prenatal alcohol exposure on cognitive development in childhood. AB - Fetal alcohol spectrum disorders comprise the spectrum of cognitive, behavioral, and neurological impairments caused by prenatal alcohol exposure (PAE). Diffusion tensor imaging (DTI) was performed on 54 children (age 10.1 +/- 1.0 years) from the Cape Town Longitudinal Cohort, for whom detailed drinking histories obtained during pregnancy are available: 26 with full fetal alcohol syndrome (FAS) or partial FAS (PFAS), 15 nonsyndromal heavily exposed (HE), and 13 controls. Using voxelwise analyses, children with FAS/PFAS showed significantly lower fractional anisotropy (FA) in four white matter (WM) regions and higher mean diffusivity (MD) in seven; three regions of FA and MD differences (left inferior longitudinal fasciculus (ILF), splenium, and isthmus) overlapped, and the fourth FA cluster was located in the same WM bundle (right ILF) as an MD cluster. HE children showed lower FA and higher MD in a subset of these regions. Significant correlations were observed between three continuous alcohol measures and DTI values at cluster peaks, indicating that WM damage in several regions is dose dependent. Lower FA in the regions of interest was attributable primarily to increased radial diffusivity rather than decreased axonal diffusivity, suggesting poorer axon packing density and/or myelination. Multiple regression models indicated that this cortical WM impairment partially mediated adverse effects of PAE on information processing speed and eyeblink conditioning. Hum Brain Mapp 37:2943-2958, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27219852 TI - Olefin Epoxidation in Aqueous Phase Using Ionic-Liquid Catalysts. AB - Hydrophobic imidazolium-based ionic liquids (IL) act as catalysts for the epoxidation of unfunctionalized olefins in water using hydrogen peroxide as oxidant. Although the catalysts are insoluble in both the substrate and in water, surprisingly, they are very well soluble in aqueous H2 O2 solution, owing to perrhenate-H2 O2 interactions. Even more remarkably, the presence of the catalyst also boosts the solubility of substrate in water. This effect is crucially dependent on the cation design. Hence, the imidazolium perrhenates enable both the transfer of hydrophobic substrate into the aqueous phase, and serve as actual catalysts, which is unprecedented. At the end of the reaction and in absence of H2 O2 the IL catalyst forms a third phase next to the lipophilic product and water and can easily be recycled. PMID- 27219853 TI - Selective Catalytic Hydrogenations of Nitriles, Ketones, and Aldehydes by Well Defined Manganese Pincer Complexes. AB - Hydrogenations constitute fundamental processes in organic chemistry and allow for atom-efficient and clean functional group transformations. In fact, the selective reduction of nitriles, ketones, and aldehydes with molecular hydrogen permits access to a green synthesis of valuable amines and alcohols. Despite more than a century of developments in homogeneous and heterogeneous catalysis, efforts toward the creation of new useful and broadly applicable catalyst systems are ongoing. Recently, Earth-abundant metals have attracted significant interest in this area. In the present study, we describe for the first time specific molecular-defined manganese complexes that allow for the hydrogenation of various polar functional groups. Under optimal conditions, we achieve good functional group tolerance, and industrially important substrates, e.g., for the flavor and fragrance industry, are selectively reduced. PMID- 27219854 TI - Assessment of airborne bacteria in selected occupational environments in Quezon City, Philippines. AB - Exposure to bioaerosols has been associated with health deterioration among workers in several occupational environments. This highlights the need to study the microbiological quality of air of workplaces as no such study has been conducted yet in the Philippines. To detect and characterize the culturable mesophilic airborne bacteria in selected occupational environments we used passive sedimentation technique. It was observed that the number of colony forming units was highest in junk shop, followed by the light railway transit station and last the office. By contrast, the bacterial composition was similar in all sites: Gram-positive cocci > Gram-positive bacilli > Gram-negative bacteria. Staphylococcus aureus and Bacillus spp. were also detected in all sites. These findings suggest that the presence of airborne bacteria may be a potential health hazard in urban occupational environments in the Philippines. PMID- 27219855 TI - Assessment of SRM, MRM(3) , and DIA for the targeted analysis of phosphorylation dynamics in non-small cell lung cancer. AB - Hypothesis-driven MS-based targeted proteomics has gained great popularity in a relatively short timespan. Next to the widely established selected reaction monitoring (SRM) workflow, data-independent acquisition (DIA), also referred to as sequential window acquisition of all theoretical spectra (SWATH) was introduced as a high-throughput targeted proteomics method. DIA facilitates increased proteome coverage, however, does not yet reach the sensitivity obtained with SRM. Therefore, a well-informed method selection is crucial for designing a successful targeted proteomics experiment. This is especially the case when targeting less conventional peptides such as those that contain PTMs, as these peptides do not always adhere to the optimal fragmentation considerations for targeted assays. Here, we provide insight into the performance of DIA, SRM, and MRM cubed (MRM(3) ) in the analysis of phosphorylation dynamics throughout the phosphoinositide 3-kinase mechanistic target of rapamycin (PI3K-mTOR) and mitogen activated protein kinase (MAPK) signaling network. We observe indeed that DIA is less sensitive when compared to SRM, however demonstrates increased flexibility, by postanalysis selection of alternative phosphopeptide precursors. Additionally, we demonstrate the added benefit of MRM(3) , allowing the quantification of two poorly accessible phosphosites. In total, targeted proteomics enabled the quantification of 42 PI3K-mTOR and MAPK phosphosites, gaining a so far unachieved in-depth view mTOR signaling events linked to tyrosine kinase inhibitor resistance in non-small cell lung cancer. PMID- 27219856 TI - Rhodium-Catalyzed Geminal Oxyfluorination and Oxytrifluoro-Methylation of Diazocarbonyl Compounds. AB - A new reaction for the rhodium-catalyzed geminal-difunctionalization-based fluorination is presented. The substrates are aromatic and aliphatic diazocarbonyl compounds. As the fluorine source a stable and easily accessible benziodoxole reagent was used. A variety of alcohol, phenol, and carboxylic acid reagents were employed to introduce the second functionality. The reaction was extended to trifluoromethylation using a benziodoxolon reagent. The fluorination and trifluoromethylation reactions probably proceed by a rhodium-containing onium ylide type intermediate, which is trapped by either the F or CF3 electrophiles. PMID- 27219857 TI - Myofibrillogenesis Regulator 1 Rescues Renal Ischemia/Reperfusion Injury by Recruitment of PI3K-Dependent P-AKT to Mitochondria. AB - To investigate whether myofibrillogenesis regulator 1 (MR-1) attenuates renal ischemia/reperfusion (I/R) injury via inhibiting phosphorylated Akt (p-Akt) mitochondrial translocation-mediated opening of the mitochondrial permeability transition pore (mPTP), we injected adenovirus containing MR-1 gene or its siRNAs to the left kidney subcapsular areas of Sprague-Dawley rats, which subsequently underwent experimental renal I/R injury. Renal functions and the severity of the tubular injury were evaluated by the serum creatinine and blood urea nitrogen levels and the pathological scores. We also examined the mitochondrial morphology and functions. Total/p-Akt were assessed by western blot using the mitochondrial and the cytosolic fractions of cortex of renal tissue, respectively. We found that mitochondrial and cytosolic MR-1 levels and mitochondrial p-Akt decreased, and cytosolic p-Akt increased after reperfusion. Subcapsular injection of adenovirus led to higher MR-1 expression in the mitochondria/cytosol, inhibited mPTP opening, and alleviated renal I/R injury; adenovirus injection also upregulated mitochondrial total and p-Akt levels more prominently compared with the normal saline (NS) group. Subcapsular injection of MR-1 siRNAs significantly lowered MR-1 expression and induced renal injury, with increased mPTP opening and mitochondrial damage, similar to I/R injury. MR-1 interacted with Akt in renal cortex homogenate. Wortmannin, a phosphatidylinositol 3 kinase (PI3K) inhibitor, abolished both mitochondrial p-Akt recruitment and the protective effect of MR-1 overexpression on I/R injury. To conclude, MR-1 protects kidney against I/R injury through inhibiting mPTP opening and maintaining mitochondrial integrity, through the recruitment of PI3K-dependent p-Akt to the mitochondria. MR-1 could be a new therapeutic strategy for renal I/R injury. PMID- 27219858 TI - Mesenteric Lymph Duct Ligation Alleviating Lung Injury in Heatstroke. AB - To explore the roles of mesenteric lymph on lung injury in heatstroke (HS), HS rat model was prepared in a prewarmed incubator. Vascular endothelium injury biomarkers (circulating endothelial cell [CEC] as well as von Willebrand factor [vWF] and thrombomodulin [TM]), proinflammatory factors (tumor necrosis factor alpha [TNF-alpha], interleukin-1beta [IL-1beta], IL-6, and high mobility group box 1), and coagulant markers (activated partial thromboplastin time, prothrombin time, D-Dimer, and platelet count) were tested in HS and HS with mesenteric lymph duct ligation (LDL) rats. In addition, lung histopathology; arterial blood gas; Evans Blue dye (EBD) and protein lung permeability; intralung inflammatory parameters including bronchoalveolar lavage fluid (BALF) TNF-alpha, IL-1beta, and IL-6 levels; myeloperoxidase (MPO) activity; and vWF immune staining were analyzed. LDL prolonged HS onset time but not HS survival time. LDL significantly attenuated endothelial cell injury for decreased CEC counts as well as plasma vWF and TM concentrations; downregulated systemic inflammation for decreased plasma TNF-alpha, IL-1beta, IL-6, and high mobility group box 1 levels; and ameliorated coagulant disorders for decreased activated partial thromboplastin time, prothrombin time, and D-Dimer levels as well as increased platelet counts. LDL also significantly reduced acute lung pathological injury; improved lung function indexes including arterial blood PaO2, pH, PaCO2, and lactic acid; decreased BALF TNF-alpha, IL-1beta, and IL-6 levels and lung MPO activity; improved EBD and protein lung permeability; and inhibited lung vascular endothelium vWF expression. However, all of these parameters were not recovered to the normal states. In summary, LDL developed protection roles systemically and alleviated lung injury in HS rats which indicated that modulating mesenteric lymph flow may have some potential benefits in HS. PMID- 27219859 TI - Therapeutic Administration of a Monoclonal Anti-Il-1beta Antibody Protects Against Experimental Melioidosis. AB - BACKGROUND: Melioidosis, caused by the gram-negative bacterium Burkholderia pseudomallei, is a common cause of community-acquired sepsis in Southeast Asia and Northern Australia. The NLRP3 inflammasome and its downstream product interleukin-1 beta (IL-1beta) have been proposed to play crucial roles in melioidosis. In this study, we characterized the role of IL-1beta more closely and we assessed its therapeutic potential. METHODS: mRNA expression of inflammasome components was determined in isolated leukocytes of 32 healthy controls and 34 patients with sepsis caused by B pseudomallei.Wild-type (WT), NLRP3-deficient (Nlrp3), and Asc mice were infected with B pseudomallei. In additional experiments, infected WT mice were treated with an anti-IL-1beta antibody. After 24, 48, and 72 hours (h) mice were sacrificed and organs were harvested. Furthermore, survival studies were performed. RESULTS: Patients with melioidosis exhibited lower mRNA levels of caspase-1, NLRP3, and ASC. Bacterial dissemination and organ damage were increased in B pseudomallei-infected Nlrp3 and Asc mice, together with a reduced pulmonary cell influx. Anti-IL-1beta treatment of B pseudomallei challenged mice resulted in strongly reduced bacterial counts, organ damage, and pulmonary granulocyte influx together with reduced mortality. Postponement of anti-IL-1beta treatment for 24 h postinfection still protected mice during melioidosis. CONCLUSION: Expression of caspase-1, NLRP3, and ASC is altered in melioidosis patients. In mice, both NLRP3 and ASC contribute to the host defense against melioidosis. Anti-IL-1beta treatment protects mice against B pseudomallei infection and might be a novel treatment strategy in melioidosis. PMID- 27219860 TI - Chelation-Induced Polymer Structural Hierarchy/Complexity in Water. AB - Understanding nanoscale structural hierarchy/complexity of hydrophilic flexible polymers is imperative because it can be viewed as an analogue to protein-alike superstructures. However, current understanding is still in infancy. Herein the first demonstration of nanoscale structural hierarchy/complexity via copper chelation-induced self-assembly (CCISA) is presented. Hierarchically-ordered colloidal networks and disks can be achieved by deliberate control of spacer length and solution pH. Dynamic light scattering, transmission electron microscopy, and atomic force microscopy demonstrate that CCISA underwent supramolecular-to-supracolloidal stepwise-growth mechanism, and underline amazing prospects to the hierarchically-ordered superstructures of hydrophilic flexible polymers in water. PMID- 27219861 TI - What Does Anonymization Mean? DataSHIELD and the Need for Consensus on Anonymization Terminology. AB - Anonymization is a recognized process by which identifiers can be removed from identifiable data to protect an individual's confidentiality and is used as a standard practice when sharing data in biomedical research. However, a plethora of terms, such as coding, pseudonymization, unlinked, and deidentified, have been and continue to be used, leading to confusion and uncertainty. This article shows that this is a historic problem and argues that such continuing uncertainty regarding the levels of protection given to data risks damaging initiatives designed to assist researchers conducting cross-national studies and sharing data internationally. DataSHIELD and the creation of a legal template are used as examples of initiatives that rely on anonymization, but where the inconsistency in terminology could hinder progress. More broadly, this article argues that there is a real possibility that there could be possible damage to the public's trust in research and the institutions that carry it out by relying on vague notions of the anonymization process. Research participants whose lack of clear understanding of the research process is compensated for by trusting those carrying out the research may have that trust damaged if the level of protection given to their data does not match their expectations. One step toward ensuring understanding between parties would be consistent use of clearly defined terminology used internationally, so that all those involved are clear on the level of identifiability of any particular set of data and, therefore, how that data can be accessed and shared. PMID- 27219862 TI - Postoperative intermediate care unit and life-threatening complications: How much and how are they linked? PMID- 27219863 TI - Effectiveness of an adolescent healthcare training programme for enhancing paediatric nurses' competencies. AB - AIMS AND OBJECTIVES: To evaluate the effects of an educational intervention programme on improving paediatric nurses' competencies in performing adolescent healthcare practice in central China. BACKGROUND: The WHO Adolescent Health Framework was integrated into this training programme to examine the effects of educational interventions on the competencies of paediatric nurses in promoting adolescent healthcare. This study is one of the first in central China to evaluate paediatric nurses' competencies in promoting adolescent health. DESIGN: The study used a mixed-method design with a quasi-experimental approach and focus group interviews. METHODS: The study was conducted with 57 paediatric nurses from 28 institutes and hospitals in central China in 2010 to evaluate their competencies in adolescent health and development, specifically with regard to conducting needs assessments, planning effective interventions and evaluating outcome measures. The paediatric nurses received training and were assessed by individual and group work during the structured three-week programme. Data were collected before and after the training programme as pre- and post-tests. The researchers gathered information about their experiences by conducting focus group interviews. RESULTS: The paediatric nurses demonstrated significant improvements in their adolescent healthcare practice after attending the three week structured training programme. The post-test scores had significant effects on the dimensions of the adolescent healthcare practice competency checklist. The qualitative data also showed positive and encouraging experiences and feedback from the paediatric nurses in this study. CONCLUSION: The findings suggest that an educational intervention can change knowledge, attitudes and practice among paediatric nurses in adolescent healthcare. All the paediatric nurses in this study demonstrated increased competencies in carrying out adolescent healthcare practice after participating in the three-week intensive intervention programme. RELEVANCE TO CLINICAL PRACTICE: This study showed that paediatric nurses have an important role in promoting and coordinating adolescent healthcare practice in primary healthcare practice. PMID- 27219864 TI - Transient midventricular ballooning syndrome with thrombus post pericardiocentesis in a patient with malignant breast cancer. AB - One day after pericardiocentesis for pericardial effusion in a patient with malignant breast cancer, the clinical and echocardiographic examination for recurrent dyspnea suggested stress cardiomyopathy with mid left ventricular ballooning and thrombus rather than pericardial decompression syndrome. Physicians should therefore pay attention to the possibility of ventricular dysfunction with thrombus post pericardiocentesis and to differences between stress cardiomyopathy and pericardial decompression syndrome. (c) 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:53-57, 2017. PMID- 27219865 TI - High prevalence of diffuse large B-cell lymphoma in occult hepatitis B virus infected patients in the Tohoku district in Eastern Japan. AB - Occult hepatitis B virus (HBV) infection is a clinical challenge, but its relationship to clinicopathologic features and the risk of progression to malignant lymphoma (ML) are poorly defined. We estimated the prevalence of HBV infection of 1,358 patients with newly diagnosed ML. HBV infection was more prevalent in ML than in control patients. The occult HBV infection group had a higher median onset age, no liver or spleen involvement, and higher prevalence of diffuse large B-cell lymphoma than the other groups, indicating that occult HBV infection is a distinct clinicopathologic entity. J. Med. Virol. 88:2206-2210, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27219866 TI - Bottlebrush Polymer Synthesis by Ring-Opening Metathesis Polymerization: The Significance of the Anchor Group. AB - Control over bottlebrush polymer synthesis by ring-opening metathesis polymerization (ROMP) of macromonomers (MMs) is highly dependent on the competition between the kinetics of the polymerization and the lifetime of the catalyst. We evaluated the effect of anchor group chemistry-the configuration of atoms linking the polymer to a polymerizable norbornene-on the kinetics of ROMP of polystyrene and poly(lactic acid) MMs initiated by (H2IMes)(pyr)2(Cl)2Ru?CHPh (Grubbs third generation catalyst). We observed a variance in the rate of propagation of >4-fold between similar MMs with different anchor groups. This phenomenon was conserved across all MMs tested, regardless of solvent, molecular weight (MW), or repeat unit identity. The observed >4-fold difference in propagation rate had a dramatic effect on the maximum obtainable backbone degree of polymerization, with slower propagating MMs reducing the maximum bottlebrush MW by an order of magnitude (from ~10(6) to ~10(5) Da). A chelation mechanism was initially proposed to explain the observed anchor group effect, but experimental and computational studies indicated that the rate differences likely resulted from a combination of varying steric demands and electronic structure among the different anchor groups. The addition of trifluoroacetic acid to the ROMP reaction substantially increased the propagation rate for all anchor groups tested, likely due to scavenging of the pyridine ligands. Based on these data, rational selection of the anchor group is critical to achieve high MM conversion and to prepare pure, high MW bottlebrush polymers by ROMP grafting-through. PMID- 27219867 TI - Diving into the Water: Inducible Binding Conformations for BRD4, TAF1(2), BRD9, and CECR2 Bromodomains. AB - The biological role played by non-BET bromodomains remains poorly understood, and it is therefore imperative to identify potent and highly selective inhibitors to effectively explore the biology of individual bromodomain proteins. A ligand efficient nonselective bromodomain inhibitor was identified from a 6-methyl pyrrolopyridone fragment. Small hydrophobic substituents replacing the N-methyl group were designed directing toward the conserved bromodomain water pocket, and two distinct binding conformations were then observed. The substituents either directly displaced and rearranged the conserved solvent network, as in BRD4(1) and TAF1(2), or induced a narrow hydrophobic channel adjacent to the lipophilic shelf, as in BRD9 and CECR2. The preference of distinct substituents for individual bromodomains provided selectivity handles useful for future lead optimization efforts for selective BRD9, CECR2, and TAF1(2) inhibitors. PMID- 27219870 TI - Horizontal transfer of mitochondria between mammalian cells: beyond co-culture approaches. AB - Current dogma holds that genes are the property of individual mammalian cells and partition between daughter cells during cell division. However, and rather unexpectedly, recent research has demonstrated horizontal cell-to-cell transfer of mitochondria and mitochondrial DNA in several mammalian cell culture systems. Furthermore, unequivocal evidence that mitochondrial DNA transfer occurs in vivo has now been published. While these studies show horizontal transfer of mitochondrial DNA in pathological settings, it is also possible that intercellular mitochondrial transfer is a fundamental physiological process with a role in development and tissue homeostasis. PMID- 27219869 TI - Synergism between sinusoidal-50 Hz magnetic field and formaldehyde in triggering carcinogenic effects in male Sprague-Dawley rats. AB - BACKGROUND: Experimental rodent bioassays performed up to now have failed to provide conclusive confirmation of the carcinogenicity of extremely low frequency magnetic fields (ELFMF). OBJECTIVES: To evaluate the potential synergistic carcinogenic effects of concurrent exposure to ELFMF and formaldehyde in four groups of male and female Sprague-Dawley rats. METHODS: One group was exposed from prenatal life until natural death to S-50 Hz MF and to formaldehyde in drinking water from 6 weeks of age for 104 weeks, two groups were treated only with formaldehyde or only with MF and one group served as untreated control. RESULTS: Compared to untreated controls, exposure to MF and formaldehyde causes in males a statistically significant increased incidence of malignant tumors (P <= 0.01), thyroid C-cell carcinomas (P <= 0.01), and hemolymphoreticular neoplasias (P <= 0.05). No statistically significant differences were observed among female groups. CONCLUSIONS: Life-span exposure to MF and formaldehyde induces statistically significant carcinogenic effects in male rats. Am. J. Ind. Med. 59:509-521, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27219871 TI - Mitochondria and mtDNA integrity in stem cell function and differentiation. AB - Stem cells require tight control of energy metabolism to maintain homeostasis. They possess few immature mitochondria, repress mitochondrial respiration and instead use glycolysis to produce energy, yet mitochondrial defects can lead to severe stem cell dysfunction. Recent studies have shown that mitochondrial mass, function and integrity are tightly controlled in stem cells and the integrity of the mitochondrial genome is equally important to nuclear genome integrity for proper stem cell homeostasis. Mitochondria are now considered central in regulating stem cell function and governing cellular fate choices. This review will summarize recent advances highlighting the importance of mitochondrial integrity in stem cells. PMID- 27219872 TI - The accelerating effect of chitosan-silica hybrid dressing materials on the early phase of wound healing. AB - Commercialized dressing materials with or without silver have played a passive role in early-phase wound healing, protecting the skin defects from infections, absorbing exudate, and preventing dehydration. Chitosan (CTS)-based sponges have been developed in pure or hybrid forms for accelerating wound healing, but their wound-healing capabilities have not been extensively compared with widely used commercial dressing materials, providing limited information in a practical aspect. In this study, we have developed CTS-silica (CTS-Si) hybrid sponges with water absorption, flexibility, and mechanical behavior similar to those of CTS sponges. In vitro and in vivo tests were performed to compare the CTS-Si sponges with three commercial dressing materials [gauze, polyurethane (PU), and silver containing hydrofiber (HF-Ag)] in addition to CTS sponges. Both in vitro and in vivo tests showed that CTS-Si sponges promoted fibroblast proliferation, leading to accelerated collagen synthesis, whereas the CTS sponges did not exhibit significant differences in fibroblast proliferation and collagen synthesis from gauze, PU, and HF-Ag sponges. In case of CTS-Si, the inflammatory cells were actively recruited to the wound by the influence of the released silicon ions from CTS-Si sponges, which, in return, led to an enhanced secretion of growth factors, particularly TGF-beta during the early stage. The higher level of TGF beta likely improved the proliferation of fibroblasts, and as a result, collagen synthesis by fibroblasts became remarkably productive, thereby increasing collagen density at the wound site. Therefore, the CTS-Si hybrid sponges have considerable potential as a wound-dressing material for accelerating wound healing. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1828-1839, 2017. PMID- 27219873 TI - Dual behavior of N-acetylcysteine during ethanol-induced oxidative stress in embryonic chick brains. AB - OBJECTIVES: Ethanol (EtOH) causes oxidative stress in embryos. Because N acetylcysteine (NAC) failures and successes in ameliorating EtOH-induced oxidative stress have been reported, the objective was to determine if exogenous NAC ameliorated EtOH-induced oxidative stress within embryonic chick brains. METHODS: Control eggs were injected with approximately 25 ul of water on day 0, 1, and 2 of development (E0-2). Experimental eggs were injected with dosages of either 3.0 mmol EtOH/kg egg; 747 umol NAC/kg egg; 3.0 mmol EtOH and 747 umol NAC/kg egg; 1000 umol NAC/kg egg; or 3.0 mmol EtOH and 1000 umol NAC/kg during the first 3 days of development (E0-2). At 11 days of development (E11; late embryogenesis), brains were harvested and subsequently assayed for oxidative stress markers including the loss of long-chain membrane polyunsaturated fatty acids (PUFAs); the accumulation of lipid hydroperoxides (LPO); decreased glutathione (GSH) and glutathione/glutathione disulfide (GSSG) levels; and decreased glutathione peroxidase (GPx) activities. RESULTS: EtOH (3 mmol/kg egg), medium NAC (747 umol/kg egg), and EtOH and medium NAC promoted oxidative stress. These treatments caused decreased brain membrane long-chain PUFAs; increased LPO levels; decreased GSH levels and GSH/GSSG levels; and decreased Se-dependent GPx activities. High NAC dosages (1000 umol/kg egg) attenuated EtOH-induced oxidative stress within EtOH and high NAC-treated chick brains. DISCUSSION: Exogenous EtOH and/or medium NAC propagated oxidative stress. Meanwhile, high NAC ameliorated EtOH-induced oxidative stress. PMID- 27219874 TI - Outcome of paravalvular leak repair after transcatheter aortic valve replacement with a balloon-expandable prosthesis. AB - BACKGROUND: Significant paravalvular leak (PVL) occurs in up to 13% of patients after transcatheter aortic valve replacement (TAVR) with a balloon-expandable bioprosthesis. Transcatheter PVL repair has emerged as a less invasive alternative for this problem. OBJECTIVES: The aim of this study was to evaluate the safety, feasibility, and clinical outcomes of transcatheter PVL repair after TAVR with balloon-expandable valve. METHODS: We retrospectively identified 15 patients who underwent 16 PVL repair procedures after the TAVR at our center. Procedural characteristics, results, and clinical outcomes were analyzed. The association of PVL repairs with subsequent hospitalizations and mortality was assessed and compared to 57 patients who did not undergo repair for at least moderate PVL after TAVR. RESULTS: The PVL repair was successful in 13 (87%) patients, without significant procedure or device related complications. In patients with successful PVL repair, there was an improvement in symptom status, subsequent hospitalizations, and B-type natriuretic peptide levels. There was 1 (out of 13, 8%) death in the group of patients who successfully underwent PVL repair whereas 24 (out of 57, 42%) patients died during follow up in the group that did not undergo repair of their PVL. Similarly, there was significant reduction in the subsequent heart failure related hospitalization after the PVL repair, compared with the patients who did not undergo PVL repair (P = 0.03). CONCLUSION: Transcatheter repair of PVL after TAVR can be safely and effectively accomplished in carefully selected patients, and may lead to reduction in hospitalizations, improvement in symptoms, and long-term survival. (c) 2016 Wiley Periodicals, Inc. PMID- 27219875 TI - Development of (99m)Tc-Labeled Pyridyl Benzofuran Derivatives To Detect Pancreatic Amylin in Islet Amyloid Model Mice. AB - While islet amyloid deposition comprising amylin is one of pathological hallmarks of type 2 diabetes mellitus (T2DM), no useful amylin-imaging probe has been reported. In this study, we evaluated two (99m)Tc-labeled pyridyl benzofuran derivatives as novel amylin-imaging probes using the newly established islet amyloid model mouse. Binding experiments in vitro demonstrated that [(99m)Tc]1 displayed a higher affinity for amylin aggregates than [(99m)Tc]2. Autoradiographic studies using human pancreas sections with T2DM revealed that [(99m)Tc]1 clearly labeled islet amyloid in T2DM pancreatic sections, while [(99m)Tc]2 did not. Although the initial uptake of [(99m)Tc]1 by the normal mouse pancreas was low (0.74%ID/g at 2 min post-injection), [(99m)Tc]1 showed higher retention in the model mouse pancreas than that of the normal mouse, and exhibited strong binding to amylin aggregates in the living pancreas of the model mice. These results suggest that [(99m)Tc]1 is a potential imaging probe targeting islet amyloids in the T2DM pancreas. PMID- 27219876 TI - Harnessing C-H Activation of Benzhydroxamates as a Macrocyclization Strategy: Synthesis of Structurally Diverse Macrocyclic Isoquinolones. AB - Macrocycles are arising considerable interest in medicinal chemistry. With the goal of harnessing C-H activation reactions for the development of efficient macrocyclization processes, the ruthenium(II)-catalyzed cyclization of O-methyl benzhydroxamates possessing an omega-acetylenic chain was investigated to access new structurally diverse macrocyclic isoquinolones. A slow addition of the substrate and the presence of Cu(OAc)2 ?H2 O as an additive were crucial for the success of the macrocyclization that features an excellent functional-group compatibility, as illustrated by the successful synthesis of a library of 21 macrocyclic isoquinolones of different ring sizes and substitution patterns. These results contribute to significantly highlight the synthetic interest of C-H activation-mediated processes for the synthesis of new macrocyles incorporating heterocyclic scaffolds of potential interest in medicinal chemistry. PMID- 27219877 TI - Women Transmits Type 2 Diabetes Mellitus (T2DM) More Than Men: Evidences from Parental Inheritance of T2DM Among Bahrainis. AB - INTRODUCTION: Heritability in type 2 diabetes mellitus (T2DM) is observed but not well understood. METHODS: In this study, family history and clinical/biochemical data from 789 Bahrainis (418 T2DM, 371 controls) was analyzed. Fasting blood glucose (FBG) and HbA1c were measured and angiotensin-converting enzyme (ACE) and methylene tetrahydrofolate reductase (MTHFR) polymorphisms (SNPs) were analyzed. RESULTS: Patients compared to controls have higher proportions of diabetic mothers (50.2% vs. 32.7%, p=0.005), fathers (35.2% vs. 12.1%, p<0.001) and siblings (56% vs. 15.3%, p<0.001). The proportions of diabetic mothers was higher than the proportions of diabetic fathers among the patients (50.2% vs. 35.2%, p<0.001) and the controls (32.7% vs. 12.1%, p<0.001). Patients born to diabetic mothers compared to the other patients were smaller in age at the time of enrollment in this study (p=0.005), and at onset of T2DM (p<0.001), and also had higher FBG (p=0.033). Interestingly, the prevalence of T1DM was highest amongst the siblings of the controls compared to patients (p=0.04). Finally, the heterozygote I/D genotype of the ACE gene was over expressed in patients born to diabetic mothers when compared to patients born to diabetic fathers, p=0.007. CONCLUSIONS: there was strong clustering of T2DM in families, with significant dominant maternal role in transmission of T2DM and associated severity markers. Patients (T2DM) born to diabetic mothers were genetically and phenotypically different from the other patients. PMID- 27219878 TI - Long-Term Supplementation of Microencapsulated ursodeoxycholic Acid Prevents Hypertension in a Mouse Model of Insulin Resistance. AB - Hypertension is a significant comorbidity associated with insulin resistance and type-2 diabetes. Limited evidence show that ursodeoxycholic acid (UDCA) has some anti-hypertensive effects. However, the potential effect of UDCA on hypertension induced by type-2 diabetic insulin resistance has not been reported. In C57Bl6 wild-type mice, insulin resistance was induced by the chronic ingestion of diet enriched in fat and fructose (HFF). HFF mice were randomized to treatment with UDCA or candersartan incorporated into the diet to achieve an ingested dose of approximately 70 mg/kg/day of UDCA or 3 mg/kg/day respectively. Systolic and diastolic blood pressure were measured with tail-cuff method. At 4 weeks of dietary treatment systolic and diastolic blood pressure were comparable in HFF and low-fat (LF) control mice. Co-administration of candesartan at 4 weeks significantly decreased systolic and diastolic blood pressure, UDCA showed no anti-hypertensive effect at 4 weeks. At 24 weeks of dietary intervention, HFF fed mice had substantially elevated systolic blood pressure compared to LF controls. The provision of UDCA substantially attenuated the dietary HFF induced increase in systolic blood pressure concomitant with significantly lower plasma angiotensin II. The anti-hypertensive effect of UDCA in HFF mice was comparable to candesartan. The data suggests that long term supplementation of UDCA effectively lowers hypertension in a dietary induced model of type-2 diabetic insulin resistance. PMID- 27219879 TI - Are Obese Individuals with no Feature of Metabolic Syndrome but Increased Waist Circumference Really Healthy? A Cross Sectional Study. AB - AIM: Patients displaying the metabolically healthy but obese phenotype have an intermediate cardiometabolic prognosis compared to normal weight healthy and metabolically unhealthy obese subjects. We aimed to evaluate the proportion of patients with a definite metabolically healthy obese phenotype and better characterize them. METHODS: Definite metabolically healthy obese phenotype was defined as having none of the International Diabetes Federation metabolic syndrome criteria, excluding waist circumference. We recruited 1 159 obese patients (body mass index 38.4+/-6.3 kg/m(2)) including 943 women, without known diabetes. Patients were characterized for cardiometabolic disorders. RESULTS: As the 202 (17.4%) metabolically healthy obese individuals were younger and had lower body mass indexes than the 957 metabolically unhealthy obese patients, they were matched for gender, age and body mass index with 404 metabolically unhealthy obese patients. In addition to the features of metabolic syndrome, when compared to unhealthy subjects, definite metabolically healthy obese patients were less frequently found with either homeostasis model assessment of insulin resistance index>3 (23.6 vs. 38.9%, p<0.001), or abnormal oral glucose tolerance test (13.9 vs. 33.9%, p<0.001), or HbA1c value>=5.7% (43.9 vs. 54.2%, p<0.05) or pulse pressure>=60 mmHg (11.7 vs. 64.9%, p<0.001). However, there were no significant differences in the prevalence of microalbuminuria (11.1 vs. 12.3%), cardiac autonomic dysfunction (45.5 vs. 35.3%) and fatty liver index >= 60 (5.6 vs. 10.2%). CONCLUSION: Our data do not support the characterization of metabolically healthy obesity, even definite, as really healthy, as many patients with this phenotype have abnormal cardiovascular markers and glucose or liver abnormalities. HbA1c measurement seems to be more sensitive than OGTT to detect dysglycemia in this population. PMID- 27219880 TI - Macrophage Infiltration into Subcutaneous Adipose Tissue is Associated with Local Levels of 11BHSD1. AB - The present study aimed to evaluate the infiltration of macrophages in form of crown-line structures (CLS) in subcutaneous adipose tissue (SAT) of obese individuals, and to investigate the effect of these on both metabolic parameters and adipose tissue 11-beta-hydroxysteroid dehydrogenase type 1 (11BHSD1) enzyme levels. A total of 53 obese (10 men, 43 woman) enrolled in the study. Body mass index (BMI), waist circumference (WC), hip circumfrence, and systolic (SBP) and diastolic blood pressures (DBP) of all subjects were recorded. Insulin resistance was determined using the homeostasis model assessment (HOMA). The concentration of SAT, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, 11BHSD1 were performed by enzyme-linked immunosorbent assay (ELISA) method. The infiltration of macrophages in form of CLS in adipose tissue were determined using cell specific stains against CD68. There was no significant difference between the CLS+group and the CLS- group in terms of age, gender, BMI, WC, waist-to-hip circumference ratio (WHR), SBP and DBP levels. Fasting plasma glucose (FPG), HOMA IR, insulin and SAT TNF-alpha levels were higher in the CLS+group compared to the CLS- group. FPG and SAT TNF-alpha levels were significantly higher in participants with high CLS density compared to participants with low density CLS. SAT 11BHSD1 levels was significant higher in the CLS+group compare to the CLS- group and in the high CLS density group compared to the low density group. In conclusion, the infiltration of macrophages in the form of CLS in SAT is associated with increased 11BHSD1 levels. It may be an important mechanism in the development of metabolic disorders. PMID- 27219881 TI - Osteoporosis Management in a Real Clinical Setting: Heterogeneity in Intervention Approach and Discrepancy in Treatment Rates when Compared with the NOGG and NOF Guidelines. AB - Objective: The National Osteoporosis Guideline Group (NOGG) proposes intervention thresholds that vary by age. Instead, the National Osteoporosis Foundation (NOF) proposes a fixed threshold for decision. The aim of the present study was to compare the actual therapeutic decisions taken in a routine clinical practice setting with those recommended by the NOF and NOGG guidelines. Material and methods: A cross-sectional study was conducted in individuals referred to a densitometric unit who were not receiving antiresorptive therapy. The absolute risk of major and hip fracture was calculated using the British formula provided by the FRAX(r) tool. NOGG and NOF guidelines' therapeutic intervention thresholds were used. Agreement was calculated using Cohen's kappa. Results: A total of 640 individuals were included, of which 95% were women, with a median age of 59.4 (IQR=14) years. 31.7% of subjects who were analyzed received treatment for osteoporosis. The type of treatment that was mainly prescribed (71.9%) consisted of bisphosphonates. When applying the NOGG criteria, treatment was recommended in 22.7% of cases; this percentage increased to 42.2% with the NOF guidelines. According to both guidelines, 20.4% of patients would not have received treatment. The concordance, expressed as the kappa index, was low; 0.25 (CI 95% 0.17-0.34) and 0.49 (CI 95% 0.42-0.55), with the NOGG and NOF, respectively. Conclusions: Important heterogeneity exists in the treatment of osteoporosis in real practice. The choice of guideline has a major impact on the proportion and selection of individuals recommended for treatment and, subsequently, on treatment-related expenditures. PMID- 27219882 TI - Clinical and Pathological Characteristics of Hypertensive and Normotensive Adrenal Pheochromocytomas. AB - INTRODUCTION: Pheochromocytoma/Paraganglioma (PPGL) present with an extremely variable clinical picture which ranges from dramatic, to mild, to silent, depending on tumor attitude to release catecholamines. Hypertension is the hallmark of these tumors but is not always present. Distinct differences of clinical manifestations exist in hypertensive pheochromocytomas (HPs) and normotensive pheochromocytomas (NPs), however the comparative analysis is lacking. METHODS: The objective was to assess the clinical symptoms, hemodynamics, metabolism, radiological and histological features of patients with HPs and NPs. This study included 104 pheochromocytoma patients who were categorized into HPs (n=69) and NPs (n=35) groups. All clinical records were reviewed. Tumor samples were examined to determine the Adrenal Gland Scale Score and were available for measurement of gene transcriptions. Biochemical examinations of 95 subjects with primary hypertension (PH) were recorded for comparative study. RESULTS: Patients with NPs showed lower proportion of clinical triad, inapparent metabolic disorders and lower urinary catecholamine levels than HPs, but higher than PH. Tumor weight positively correlated with 24 h urinary norepinephrine level in patients with HPs (P=0.028), and tumor diameter negatively correlated with phenylethanolamine-N-methyltransferase (PNMT) immunohistochemistry (P=0.011) in NPs but not in HPs. The Adrenal Gland Scale Score of NPs group was similar to that of HPs group. The positive percentage of epinephrine type (E-type) of catecholamine in HPs group was higher than that in the NPs. The transcript gene levels of PNMT, secretogranin II (SGII) and neuropeptide Y (NPY) from tissue samples were significantly lower in NPs than in HPs (PPNMT=0.038, PSGII=0.040, PNPY=0.032), while vesicular monoamine transporter 1 (VMAT1) had no difference between HPs and NPs (PVMAT1=0.053). CONCLUSION: HPs and NPs have distinct differences in clinical, biochemical and pathological phenotypes, which are closely related with productions involved in tumor occurrence and development. PMID- 27219883 TI - Monocyte and Basophil Counts as Predictors of Neutrophil Count Recovery in Patients with Thiamazole-Induced Agranulocytosis. AB - Purpose: Thiamazole (MMI) is frequently used for the treatment of Graves' disease, but it occasionally induces agranulocytosis at the beginning of the treatment. To date, the predictive factors of recovery from MMI-induced agranulocytosis remain unclear. The primary aim of this study was to evaluate the predictive factor of the recovery time from MMI-induced agranulocytosis. Method: This was a retrospective cohort study performed in a university hospital and a thyroid hospital. We included 27 Japanese patients with Graves' disease with MMI induced agranulocytosis diagnosed during follow-up. All patients were administrated recombinant human granulocyte colony-stimulating factor daily until they had a neutrophil count>1 000/MUL, which was defined as recovery. The predictive factors associated with recovery time were estimated using multivariable regression analysis. Results: At the onset of agranulocytosis, the median administration period of MMI was 33 days, the average white blood cell count was 1 896/MUL, and the median neutrophil count was 22/MUL. The median recovery time was 4 days. Stepwise multivariate regression analysis identified the monocyte and basophil counts to be significant predictors of MMI-induced agranulocytosis. Conclusion: Patients with agranulocytosis and decreased monocyte and basophil counts at onset may recover late and require careful treatment. PMID- 27219884 TI - Clinical Evaluation of Human Umbilical Cord Mesenchymal Stem Cell Transplantation After Angioplasty for Diabetic Foot. AB - Aims: The multilineage differentiation potential of human umbilical cord mesenchymal stem cells (HUCMSCs) holds therapeutic promise for non-healing ulcers and tissue regeneration. The present study evaluated the effects of HUCMSC transplantation after angioplasty for treatment of diabetic foot. Methods: Included in the study were 53 patients (72 limbs) with severe symptoms of Fontaine II-IV diabetic foot accompanied by varying degrees of lower extremity arterial disease. The patients were randomly apportioned to a control group (25 patients; 38 limbs) or an experimental group (28 patients; 34 limbs). Patients of both groups received interventional treatment with angioplasty; those in the experimental group also received HUCMSCs by endovascular infusion and injection around the foot ulcer. Results: Within the 3-month follow-up, relative to patients in the control group, those in the experimental group experienced significantly greater and more stable improvements in skin temperature, ankle brachial pressure index, transcutaneous oxygen tension, and claudication distance. Notably, 3 months after treatment a significant increase in neovessels, accompanied by complete or gradual ulcer healing, was shown in the experimental group. In addition, no serious complications or adverse reactions were associated with the treatment. Conclusion: Therefore, our results indicate that HUCMSC transplantation after angioplasty is a safe and effective clinical therapy for severe diabetic foot. PMID- 27219885 TI - HbA1c and Age in Non-Diabetic Subjects: An Ignored Association? AB - Objective: Target HbA1c values given in the most National Therapeutic Guidelines for patients with diabetes and cut-off HbA1c values for diabetes diagnosis are usually not taking the age of the respective patients into account; despite the fact that an increase in HbA1c in subjects without diabetes with age is known for some time. In order to further quantify the association between age and HbA1c in non-diabetic subjects an analysis of one German register was performed. Methods: In this cross-sectional study we analyzed data from 7 699 visits of 2 921 patients without diabetes (age 46.6 y [range 18-93 y]; 69.1% women; BMI 27.6+/ 6.4 kg/m2) who had at least one HbA1c and blood glucose measurement. Data were drawn from an electronic patient record system (EMILTM) in which data were collected between 01/1992 and 01/2014. The patients were divided in 6 age groups (< 30 years [n=1 057];>30-40 years [n=1 160];>40-50 years [n=1 693];>50-60 years [n=1 523];>60-70 years [n=1 310];>70 years [n=956]) and the HbA1c values of these groups were compared. Patients with: gestational diabetes, use of systemic glucocorticoids, malignant neoplasm, age<18 y at time of first visit and IGT were excluded. HbA1c measurements were DCCT adjusted. Results: Patients with age>70 years have a 0.47% [5.14 mmol/mol] higher HbA1c compared to those<30 years. The mean HbA1c of the age groups was:<30 4.98% [30.96 mmol/mol],>30-40 5.07% [31.99 mmol/mol],>40-50 5.17% [33.10 mmol/mol],>50-60 5.33% [34.79 mmol/mol],>60-70 5.42% [35.79 mmol/mol] and>70 years 5.45% [36.10 mmol/mol]. In a multiple linear model the regression coefficient for each year of age increase was beta=0.0074 (p<0.001); thus age results in an increase of 0.074% in HbA1c per decade. Conclusion: HbA1c increases significantly with ageing in people without diabetes. The use of different cut-off values for every age range for diagnosis of diabetes should be discussed. PMID- 27219886 TI - A Randomized Controlled Clinical Trial Investigating the Effect of Synbiotic Administration on Markers of Insulin Metabolism and Lipid Profiles in Overweight Type 2 Diabetic Patients with Coronary Heart Disease. AB - Objective: The current study was performed to evaluate the effects of synbiotic administration on metabolic profiles in overweight diabetic patients with coronary heart disease (CHD). Methods: This randomized, double-blind, placebo controlled trial was done among 60 diabetic patients with CHD. Participants were randomly divided into 2 groups: group A (n=30) received synbiotic supplements containing 3 probiotic bacteria spices Lactobacillus acidophilus 2*109, Lactobacillus casei 2*109, Bifidobacterium bifidum 2*109 CFU/g plus 800 mg inulin and group B (n=30) received placebo for 12 weeks. Fasting blood samples were taken at baseline and after 12-week intervention to determine metabolic profiles. Results: After 12 weeks of intervention, patients who consumed synbiotic capsule had significantly decreased fasting plasma glucose (- 19.6+/-74.6 vs.+19.2+/-66.9 mg/dL, P=0.03), serum insulin concentrations (- 0.7+/-5.1 vs.+3.3+/-6.3 uIU/mL, P=0.01), the homeostasis model of assessment-estimated b cell function (- 3.4+/ 19.5 vs.+11.5+/-21.0, P=0.006) and increased the quantitative insulin sensitivity check index (+ 0.002+/-0.01 vs.-0.01+/-0.02, P=0.03) compared with the placebo. In addition, changes in HLDL-cholesterol levels (+ 1.8+/-5.7 vs.-2.2+/-6.0 mg/dL, P=0.01) in supplemented patients were significantly different from those of patients in the placebo group. Conclusion: Synbiotic supplementation for 12 weeks among diabetic patients with CHD had beneficial effects on markers of insulin metabolism and HDL-cholesterol levels. PMID- 27219887 TI - Cumulative Risk of Metabolic Syndrome Correlated with the Coexistence of ( 1306C/T) and Altered Circulating MMP2 level. AB - BACKGROUND: Interindividual genetic variations and environmental factors both play pivotal roles in the pathogenesis of metabolic syndrome (MetS). The rationale of this study conducted was to analyze the association of Matrix Metalloproteinase (MMP) gene variants, MMP-1 (-1607 1G/2G) and MMP-2 (-1306 C/T) with susceptibility to MetS and its effect on serum MMP level. METHODS: Study involved 370 subjects with 1:1 distribution of cases and controls. Patients were recruited according to modified NCEP-ATP III criteria for MetS. Clinical, biochemical analysis, PCR-RFLP and ELISA methods were employed for genotyping and estimation of serum MMP level. RESULTS: Significantly (p<0.001) higher Serum MMP 2 (39.13+/-19.96 ng/ml) was detected in cases as compared to controls. The MMP-2 (-1306 C/T) was significantly associated with the risk of MetS. The variant genotype TT was significantly associated with increased risk of MetS. (p=0.032; OR=2.31; 95%CI=1.07-4.97). No significant association of MMP-1(-1607 1G/2G) was found with risk of MetS. CONCLUSION: Our study concluded that presence of MMP-2 ( 1306 C/T) might be associated the risk of MetS. Serum MMP2 level was significantly higher in patients and correlated with clinical parameters of MetS. Clinical implication of the work may help to identify the individuals with high risk of MetS and further complications. PMID- 27219888 TI - Positive Correlation between Serum Osteocalcin and Testosterone in Male Hyperthyroidism Patients with High Bone Turnover. AB - PURPOSE: Animal studies suggested that there is an independent bone-osteocalcin gonadal axis, except of the hypothalamic-pituitary-gonadal axis. Based on this hypothesis, the higher osteocalcin during the high bone turnover should be followed by higher testosterone formation. Yet such clinical evidence is limited. The patients with uncontrolled hyperthyroidism are proper model with high bone turnover. If this hypothesis is true, there should be high testosterone level in patients with uncontrolled hyperthyroidism. Therefore, Graves' disease patients were recruited to study the correlation between osteocalcin and testosterone. MATERIALS AND METHODS: 50 male hyperthyroidism patients with Graves' disease and 50 health persons matched by age and gender were enrolled in our cross-section study. Serum markers for thyroid hormone, sex hormone and bone metabolic markers including free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and osteocalcin (OC), C-terminal telopeptide fragments of type I collagen (CTX) were examined. The demographic parameters such as duration of disease were also collected. All data was analyzed by SPSS 20.0. RESULTS: High testosterone and osteocalcin level was observed in the hyperthyroidism patients (T 36.35+/-10.72 nmol/l and OC 46.79+/-26.83 ng/ml). In simple Pearson correlation, testosterone was positively associated with OC (r=0.486, P<0.001), and this positive relation still existed after adjusted for age, BMI, smoking, drinking, duration of disease, FT3, FT4, LH, FSH, CTX in multi-linear regression analysis (See Model 1-4). CONCLUSION: In male hyperthyroidism patients, osteocalcin was positively correlated with serum testosterone, which indirectly supports the hypothesis that serum osteocalcin participates in the regulation of sex hormone. PMID- 27219889 TI - Recent Developments in Primary Aldosteronism. AB - Primary aldosteronism (PA) is the most frequent endocrine cause of secondary arterial hypertension. Sporadic forms of PA caused mainly by an aldosterone producing adenoma (APA) or idiopathic adrenal hyperplasia (IAH) predominate; in contrast, familial forms (familial hyperaldosteronism types I, II and III) affect only a minor proportion of PA patients. Patient based registries and biobanks, international networks and next generation sequencing technologies have emerged over recent years. Somatic hot-spot mutations in the potassium channel GIRK4 (encoded by KCNJ5), in ATPases and a L-type voltage-gated calcium-channel correlate with the autonomous aldosterone production in approximately half of all APAs. The recently discovered form FH III is caused by different germline KCNJ5 mutations with variable clinical presentations and severity. Autoantibodies to the angiotensin II Type 1 receptor have been identified in patients with PA and possibly play a pathophysiological role in the development of PA. Adrenal vein sampling (AVS) represents the gold standard in differentiating unilateral and bilateral forms of PA. Recent consensus papers have tried to implement current guidelines in order to standardise the technique of AVS. New techniques like segmental AVS might allow a finer mapping of the aldosterone production within the adrenal gland. The measurement of the steroids 18-hydroxycortisol and 18 oxocortisol by liquid chromatography tandem mass spectrometry has been shown to be useful to distinguish between unilateral and bilateral forms of PA. PMID- 27219890 TI - Dicarbonyl Stress Mimics Diabetic Neurovascular Damage in the Retina. AB - The net effect of euglycemic treatment is grossly overestimated in diabetes mellitus and retinopathy, similar to what is observed in diabetic individuals, is found in the absence of chronic hyperglycemia. Explanations of this clinical paradox include the excess generation of reactive intermediates of metabolism. Excess formation or impaired detoxification of reactive intermediates can also result in multiple posttranslational modifications with a wide range of cellular dysfunctions. The multicellular neurovascular unit represents the response element of the retina which is crucial for the development of diabetic retinopathy. Current evidence suggests that increased reactive intermediates in the retina induce (micro-)glial activation, neurodegeneration and vasoregression similar to alterations found in the diabetic retina. Reactive metabolites can be lowered by metabolic signal blockade, by an activation of detoxification pathways and by quenching. The translation of these novel findings into treatment of patients with complications is important to reduce individual suffering and financial burden for societies.Quick Summary:Increased levels of reactive intermediates, independent of blood glucose levels, are linked to damage of the neurovascular unit of the diabetic retina. PMID- 27219891 TI - Disputes in the Treatment of Diabetic Nephropathy: The Dual Blockade of Renin Angiotensin System. AB - The prevention and the treatment with drugs interacting with the renin angiotensin system (RAAS) are one of the greatest successes of the pharmacological research in the last years. Many trials demonstrated the efficacy of ARBs and ACEi in preventing or reducing the progression of albuminuria, the loss of kidney function and the mortality in diabetic population.The rationale for applying a dual RAAS blockade is based on data showing that ACEi mono-therapy produces an incomplete RAAS blockade with angiotensin I and renin accumulation and the subsequent angiotensin II 'escape' production by non-ACE pathways. The use of ARBs and ACEi in combination could lead to a stronger RAAS block and consequently to a more effective nephroprotection. Years ago, some studies performed in small groups of patients with diabetic nephropathy confirmed the effectiveness of this pharmacological approach.In contrast recent important trials, like ONTARGET, ALTITUDE and VA NEPHRON-D failed to demonstrate the effectiveness of this therapeutic strategy, suggesting that probably not all the diabetic patients with nephropathy should be considered equal as regard the response to this therapy. These 3 long-term studies showed that the dual blockade of RAAS may bring cardiovascular and renal adverse events, even in presence of a reduction of albuminuria. Dual blockade of RAAS is not currently feasible in patients with diabetic nephropathy, but we consider that the effort to try to apply a complete RAAS blockade should be pursued and that probably through an accurate selection of patients in the future we could reconsider this kind of therapy. PMID- 27219892 TI - Renal Artery Stenosis - are there Patients who Benefit from Intervention? AB - Atherosclerotic renal artery stenosis (ARAS) is one of the most relevant long term complications of atherosclerotic disease. It is associated both with hypertension and increased renal and cardiovascular risk and overall mortality. Diagnostic modalities include non-invasive duplex ultrasound, dynamic magnetic resonance angiography (MRA) and computer tomography angiography (CTA) and are confirmed by using invasive renal angiography. Percutaneous revascularization of renal artery stenosis has been studied in various clinical trials. With regard to hypertension, several case series could show a clinical response to revascularization. However, the majority of randomized clinical trials could not confirm the correlation between intervention and the improvement of hypertension, kidney function, cardiovascular events, and mortality. Based on this predication the crucial tool in the treatment of ARAS is an optimal medical therapy, including statins, antihypertensive agents and platelet inhibition. Today the core point is to select subgroups and appropriate indications for better outcomes and avoiding unnecessary procedures very carefully. Therefore in patients with typical manifestations of ARAS including resistant or malignant hypertension, progressive decline of renal function, flash pulmonary edema or angina, renal artery intervention remains a sensible therapeutic option - after hemodynamic testing prior to revascularization. In the future further trials targeting patients who fulfill rational selection criteria need to be undertaken to confirm the efficacy of revascularization. PMID- 27219894 TI - The importance of being a regulatory T cell in pregnancy. AB - Natural Foxp3(+) regulatory T cells (nTregs) defined by expression of the Foxp3 marker generated in the thymus against self autoantigens prevent systemic autoimmune and inflammatory disease. A second population of Tregs induced by exogenous antigens in the periphery (iTregs) are currently thought to play a key role in preventing infertility, recurrent pregnancy loss (occult and clinically evident), pre-eclampsia, fetal growth restriction, and premature birth in outbred matings where the father is histoincompatible with the mother. Curiously, when iTregs are ablated in mice, fertility is usually not impaired and resorption rates in matings with allogeneic males can range from 0% to 100% in individual females. Analysis of possible explanations suggest iTregs prevent abortions by countering effects of environmental stressors. Depletion of iTregs at mid pregnancy in mice only causes abortions in an artificial transgenic model. Effects of iTreg depletion on pre-eclampsia, fetal growth restriction, and premature birth remain to be tested. Tregs induced during pregnancy may also affect the health of offspring in post natal life as well as the health of the mother. PMID- 27219893 TI - Acoustic variation during passage reading for speakers with dysarthria and healthy controls. AB - PURPOSE: Acoustic variation in a passage read by speakers with dysarthria and healthy speakers was examined. METHOD: 15 speakers with Multiple Sclerosis (MS), 12 speakers with Parkinson's disease (PD), and 14 healthy speakers were studied. Acoustic variables included measures of global speech timing (e.g., articulation rate, pause characteristics), vocal intensity (e.g., mean sound pressure level and intensity modulation), and segmental articulation (i.e., utterance-level second formant interquartile range (F2 IQR)). Acoustic measures were obtained from three segments operationally defined to represent the beginning, middle, and end of a reading passage. Two speaking conditions associated with common treatment techniques for dysarthria were included for comparison to a habitual speaking condition. These conditions included a slower-than-habitual rate (Slow) and greater-than-habitual intensity (Loud). RESULTS: There was some degree of acoustic variation across the three operationally-defined segments of the reading passage. The Slow, Loud and Habitual conditions yielded comparable characteristics of variation. Patterns of acoustic variation across the three passage segments also were largely similar across speaker groups. CONCLUSIONS: Within-task acoustic variation during passage reading should be considered when making decisions regarding speech sampling in clinical practice and research. The contributions of speech disorder severity and linguistic variables to within-task acoustic change warrant further investigation. LEARNING OUTCOMES: Readers will be able to (1) discuss the motivation for studying and understanding within-task variation in contextual speech, (2) describe patterns of acoustic variation for speakers with dysarthria and healthy speakers during passage reading, (3) discuss the relationship between non-habitual speaking conditions and within-task variation, (4) understand the need to consider within-speaker, within-task variation in speech sampling. PMID- 27219895 TI - From informed consent to dissemination: Using participatory visual methods with young people with long-term conditions at different stages of research. AB - Research with young people suffering from a long-term illness has more recently incorporated the use of visual methods to foster engagement of research participants from a wide age range, capture the longitudinal and complex factors involved in young people's experiences of care, and allow young people to express their views in multiple ways. Despite its contributions, these methods are not always easy to implement and there is a possibility that they might not generate the results or engagement initially anticipated by researchers. We hope to expand on the emerging discussion on the use of participatory visual methods by presenting the practical issues we have faced while using this methodology during different stages of research: informed assent/consent, data collection, and the dissemination of findings. We propose a combination of techniques to make sure that the research design is flexible enough to allow research participants to shape the research process according to their needs and interests. PMID- 27219897 TI - Regarding realities: Using photo-based projective techniques to elicit normative and alternative discourses on gender, relationships, and sexuality in Mozambique. AB - This paper argues for the methodological merit of photo-based projective techniques (PT) in formative HIV communication research. We used this technique in Mozambique to study multiple sexual partnerships (MSPs) and the roles of social and gender norms in promoting or discouraging these behaviours. Facilitators used ambiguous photographs and vignettes to ease adult men and women into discussions of sexual risk behaviour and HIV transmission. Visuals upheld a third-person perspective in discussions, enabling participants to safely project their worldviews onto the photographed characters, and indirectly share their attitudes, normative environments, personal and peer experiences, perceived risks and benefits, and theories about motivations for extramarital sex. Visually grounded storylines contained rich detail about the circumstances and interpersonal conversations that contextualise MSP behaviour and norms. The research yielded findings about conflicting social practices of public encouragement and private disapproval. Despite concerns around the verifiability of PTs, the repetition and convergence in the elicited conversations - and confirmation through subsequent campaign design and evaluation - suggest these techniques can reliably elicit information for formative public health and communication research on psychosocial and normative factors. PMID- 27219896 TI - 'People like me don't make things like that': Participatory video as a method for reducing leprosy-related stigma. AB - The Stigma Assessment and Reduction of Impact project aims to assess the effectiveness of stigma-reduction interventions in the field of leprosy. Participatory video seemed to be a promising approach to reducing stigma among stigmatized individuals (in this study the video makers) and the stigmatisers (video audience). This study focuses on the video makers and seeks to assess the impact on them of making a participatory video and to increase understanding of how to deal with foreseeable difficulties. Participants were selected on the basis of criteria and in collaboration with the community health centre. This study draws on six qualitative methods including interviews with the video makers and participant observation. Triangulation was used to increase the validity of the findings. Two videos were produced. The impact on participants ranged from having a good time to a greater sense of togetherness, increased self-esteem, individual agency and willingness to take action in the community. Concealment of leprosy is a persistent challenge, and physical limitations and group dynamics are also areas that require attention. Provided these three areas are properly taken into account, participatory video has the potential to address stigma at least at three levels - intrapersonal, interpersonal and community - and possibly more. PMID- 27219898 TI - Inhibitory Effects of Metabolites of 5-Demethylnobiletin on Human Nonsmall Cell Lung Cancer Cells. AB - 5-Demethylnobiletin is a unique flavonoid found in citrus fruits with potential chemopreventive effects against human cancers. We previously identified three metabolites of 5DN, namely 5,4'-didemethylnobiletin (M1), 5,3',4'- tridemethylnobiletin (M2), and 5,3'-didemethylnobiletin (M3) in mice fed 5DN. Herein, we investigated the inhibitory effects of these three metabolites on NSCLC cells. Our results demonstrated that M1, M2, and especially M3 showed stronger inhibition on the growth and colony formation of H460 and H1299 cells compared to 5DN. Three metabolites significantly inhibited the tumorsphere formation of A549 cells. Flow cytometry analysis showed that all metabolites induced cell cycle arrest and cellular apoptosis, and these effects were also stronger than that of 5DN. The inhibitory effects of these metabolites were associated with their ability to modulate the key signaling proteins related to cell proliferation and apoptosis. Overall, our results provided a basis for utilizing 5DN and its metabolites for chemoprevention of lung cancer. PMID- 27219899 TI - Exposure to Community Violence and the Trajectory of Internalizing and Externalizing Symptoms in a Sample of Low-Income Urban Youth. AB - This study examined trajectories of psychopathology in a sample of low-income urban youth and tested exposure to community violence as a predictor of these trajectories. Self-report and parent-report survey measures of psychological problems and exposure to community violence were collected annually over 3 years from a sample of 364 fifth- to ninth-grade low-income urban youth (64% female; 95% youth of color). Linear growth models showed that youth experienced declines in both internalizing and externalizing symptoms across adolescence. Exposure to community violence was more strongly associated with externalizing symptoms than with internalizing symptoms but predicted declines in both types of symptoms. Results also indicated that youth reported more internalizing and externalizing symptoms than their parents reported for them. Exposure to community violence may explain unique trajectories of mental health problems among low-income urban youth. In addition, youth efforts to adopt a tough facade in the face of community violence could lead to higher rates of externalizing problems relative to internalizing problems, whereas desensitization processes may better explain reductions in both types of symptoms over time. Finally, youth report may be more valid than parent report in the context of urban poverty. PMID- 27219900 TI - Metal-Free Mediated Meerwein-Type Reaction: A Radical Cascade Arylation/Aryl Migration/Desulfonylation of Conjugated Alkenes. AB - A metal-free cascade arylation/aryl migration/desulfonylation of N-phenyl-N (phenylsulfonyl)methacrylamide is described. The in situ generated diazonium salts from anilines and t-BuONO are used as aryl precursors. This process provides an efficient strategy for the synthesis of alpha-all-carbon quaternary stereocenters amides. A radical mechanism was proposed for this transformation. PMID- 27219901 TI - Invasive angiography and revascularization in patients with stable angina following prior coronary artery bypass grafting: Results from the East Denmark heart registry. AB - BACKGROUND: There are limited data to guide the optimum approach to patients presenting with angina after coronary artery bypass grafting (CABG). Although often referred for invasive angiography, the effectiveness of this is unknown; angina may also result from diffuse distal or micro-vascular coronary disease and it is not known how often targets for intervention are identified. METHODS: Retrospective review of 50,460 patients undergoing angiography in East Denmark between January 2010 and December 2014. Clinical and procedural data were prospectively stored in a regional electronic database. Follow-up data were available for all patients, by means of records linked to each Danish social security number. RESULTS: In patients with prior CABG and stable angina (n = 2,309), diagnostic angiography led to revascularization in 574 (24.9%) cases. Chronic kidney disease (HR 1.93 [1.08-3.44], P = 0.027), significant angina (HR 1.49 [1.18-1.88], P = 0.006 for angina class >= II, and HR 2.04 [1.61-2.58], P < 0.001 for angina class >= III) and a positive pre-procedural stress test (HR 2.56 [1.42-4.60], P < 0.001) were independent predictors of revascularization. Stress testing was, however, used less frequently than in patients without prior CABG (17.2% vs. 24.2%, P < 0.001). The positive predictive values for subsequent revascularization were 47.8%, 51.4%, and 66.9% for exercise ECG, stress echocardiography, and myocardial perfusion scintigraphy (MPS), respectively. CONCLUSIONS: Invasive angiography leads to revascularization in a quarter of patients with angina and prior CABG; the threshold for referral may be too low. Non-invasive stress testing predicts the need for revascularization but appears underused and MPS, in particular, may better identify patients likely to require revascularization. (c) 2016 Wiley Periodicals, Inc. PMID- 27219903 TI - Enhanced Catalytic Activity in Liquid-Exfoliated FeOCl Nanosheets as a Fenton Like Catalyst. AB - A facile liquid-phase exfoliation method to prepare few-layer FeOCl nanosheets in acetonitrile by ultrasonication is reported. The detailed exfoliation mechanism and generated products were investigated by combining first-principle calculations and experimental approaches. The similar cleavage energies of FeOCl (340 mJ m(-2) ) and graphite (320 mJ m(-2) ) confirm the experimental exfoliation feasibility. As a Fenton reagent, FeOCl nanosheets showed outstanding properties in the catalytic degradation of phenol in water at room temperature, under neutral pH conditions, and with sunlight irradiation. Apart from the increased surface area of the nanosheets, the surface state change of the nanosheets also plays a key role in improving the catalytic performance. The changes of charge density, density of states (DOS), and valence state of Fe atoms in the exfoliated FeOCl nanosheets versus plates illustrated that surface atomistic relationships made the few-layer nanosheets higher activity, indicating the exfoliation process of the FeOCl nanosheets also brought about surface state changes. PMID- 27219902 TI - An observational study to examine changes in metabolic syndrome components in patients with breast cancer receiving neoadjuvant or adjuvant chemotherapy. AB - BACKGROUND: The authors sought to determine the effect of chemotherapy on the development of metabolic syndrome (MetS) in premenopausal and postmenopausal women undergoing (neo)adjuvant therapy for early-stage breast cancer. METHODS: A total of 86 women with early-stage (AJCC stage I-III) breast cancer who were free from clinically diagnosed MetS (defined as 3 of 5 components of MetS) were prospectively tested for the presence of the 5 components of MetS within 1 week before initiating and after completing (neo)adjuvant chemotherapy. The 5 components of MetS measured were waist circumference; blood pressure; and fasting levels of blood glucose, triglycerides, and high-density lipoprotein cholesterol. Anthropometrics (body weight, percentage body fat, fat mass), lipid profile (total cholesterol, low-density lipoprotein cholesterol), glucose metabolism (insulin, homeostatic model assessment of insulin resistance, glycated hemoglobin), and inflammation (C-reactive protein) also were examined before initiating and after completing treatment. RESULTS: The current study included 46 premenopausal and 40 postmenopausal women. All individual MetS components and the overall MetS score were found to be statistically significantly increased (P<.01) after chemotherapy. Body weight, percentage body fat, fat mass, lipids, glucose metabolism, and inflammation also were found to be statistically significantly increased (P<.01). CONCLUSIONS: A 12-week to 18-week course of chemotherapy appears to statistically significantly increase MetS and related anthropometrics, biomarkers of glucose metabolism, and inflammation in patients with early-stage breast cancer with no preexisting MetS. Lifestyle interventions such as diet and exercise may be preventive approaches for use during chemotherapy to reduce the onset of MetS in patients with breast cancer. Cancer 2016. (c) 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. Cancer 2016;122:2646-2653. (c) 2016 American Cancer Society. PMID- 27219904 TI - When security and medicine missions conflict: confidentiality in prison settings. AB - Purpose - It is a simple fact that prisons cannot exist - practically, legally, ethically or morally - without the support of physicians and other health professionals. Access to adequate healthcare is one of the fundamental measures of the legitimacy of a jail or prison. At the same time, there is a fundamental tension in the missions of the prison and doctor. The primary mission of the prison is security and often punishment. Reform and rehabilitation have intermittently been stated goals of prisons in the last century, but in practice those humane goals have rarely governed prison administrative culture. The primary mission of the physician is to promote the health and welfare of his or her patient. The paper aims to discuss these issues. Design/methodology/approach At times, what is required to serve the patient's best interest is at odds with the interests of security. Much of the work of the prison physician does not conflict with the operation of security. Indeed, much of the work of the prison physician is allowed to proceed without much interference from the security regime. But given the fundamental discord in the legitimate missions of security vs medicine, conflict between the doctor and the warden is inevitable. Findings - In this paper, the authors consider the example of patient confidentiality to illustrate this conflict, using case examples inspired by real cases from the experience of the authors. Originality/value - The authors provide an ethical and practical framework for health professionals to employ when confronting these inevitable conflicts in correctional settings. PMID- 27219905 TI - Trials and tribulations of conducting bio-behavioral surveys in prisons: implementation science and lessons from Ukraine. AB - Purpose - Ukraine is home to Europe's worst HIV epidemic, overwhelmingly fueled by people who inject drugs who face harsh prison sentences. In Ukraine, HIV and other infectious diseases are concentrated in prisons, yet the magnitude of this problem had not been quantified. The purpose of this paper is to evaluate the systematic health survey of prisoners in the former Soviet Union (FSU). Design/methodology/approach - Qualitative interviews were carried out with research and prison administrative staff to assess the barriers and facilitators to conducting a bio-behavioral survey in Ukrainian prisons. Findings - Crucial barriers at the institutional, staff, and participant level require addressing by: first, ensuring Prison Department involvement at every stage; second, tackling pre-conceived attitudes about drug addiction and treatment among staff; and third, guaranteeing confidentiality for participants. Originality/value - The burden of many diseases is higher than expected and much higher than in the community. Notwithstanding the challenges, scientifically rigorous bio-behavioral surveys are attainable in criminal justice systems in the FSU with collaboration and careful consideration of this specific context. PMID- 27219906 TI - Blood-borne viral co-infections among human immunodeficiency virus-infected inmates. AB - Purpose - The purpose of this paper is to evaluate the prevalence of HBV and/or HCV co-infection among HIV-infected inmates entering the correctional facility. Design/methodology/approach - Prospective collection of data of HIV-infected inmates entered the institution over a ten-year period. Findings - During study period 365 consecutive different inmates were evaluated. HCV co-infection was observed in more than 80 per cent of the tested HIV-infected inmates, past HBV infection in 71.6 per cent and active HBV co-infection was detected in 7.1 per cent; triple coinfection (HIV, HCV and HBs-Ag positivity) was present in 6 per cent of the total. Originality/value - This study confirms high prevalence of co infections among HIV-infected inmates. Testing for HBV and HCV in all HIV infected inmates at entry in any correctional system is recommended to identify those in need of specific care and/or preventing interventions. PMID- 27219907 TI - Hepatitis A immunity and region-of-origin in a Swiss prison. AB - Purpose - The environmental and demographic characteristics of closed institutions, particularly prisons, precipitate morbidity during hepatitis A virus (HAV) outbreaks. Given the high prevalence of chronic liver disease and other risk factors in the prison setting, the purpose of this paper is to examine HAV-immunity and its associated factors in this population. Design/methodology/approach - The cross-sectional study was conducted in 2009: a serology screening for HAV IgG was carried out among 116 inmates in Switzerland's largest pre-trial prison. Other participant characteristics were collected through a structured face-to-face questionnaire with a physician. Findings - In terms of significant demographics, Africa (53.5 percent) and the Balkans/Eastern Europe (36.2 percent) were the main regions of origin; a minority of inmates were from Western Europe (6.9 percent), Latin America (2.6 percent) or Asia (0.9 percent). The authors identified hepatitis A antibody-negative serology (lack of immunity) in five out of 116 prisoners (4.3 percent, 95 percent CI 1.4-9.7). Among participants of European origin alone, five out of 50 inmates were hepatitis A antibody-negative (10 percent, 95 percent CI 3.3-21.8), whereas the 66 inmates from other all continents were hepatitis A antibody-positive (immune) (p=0.026). Originality/value - In this prison population composed of mostly African migrants, hepatitis A immunity was high. This reaffirms that region of origin is highly associated with childhood immunity against HAV. HAV vaccination should take into account a patient's area of origin and his/her risk factors for systemic complications, if ever infected. This targeted strategy would offer herd immunity, and seek out the most vulnerable individuals who are potentially at risk of new exposure in this precarious setting. PMID- 27219908 TI - Varicella zoster virus transmission in youth during incarceration. AB - Purpose - Facility-based Varicella zoster virus (VZV) transmission is reported in a Canadian youth offender correctional centre (YOCC). Transmission occurred from an immunocompetent youth offender (YO) with localized Herpes zoster to another immunocompetent single dose vaccinated YO, resulting in Varicella zoster (VZ) breakthrough disease. The purpose of this paper is to identify infection prevention and control (IPAC) measures utilized in this setting. Design/methodology/approach - A retrospective chart and immunization record review was conducted for two VZV cases and 27 exposed YO contacts in order to obtain demographic, clinical and immunization data. Descriptive data analysis was performed. Findings - All VZV cases and exposed contacts were male with an average age of 14.2 and 15.6 years for cases and contacts, respectively. Both cases shared the same living unit in the YOCC. There were 28 identified YO contacts, of whom 70 percent were single dose vaccinated with univalent vaccine, followed by 22 percent with a previous history of Varicella disease. All cases and contacts were born in Canada. No foreign-born populations were involved with this event. Infection control measures included additional precaution management, enhanced surveillance and environmental cleaning. As such, no hospitalizations or post-exposure immunizations were required. Originality/value - This report highlights the role that VZ breakthrough disease could play in fueling an outbreak in a high-risk environment without rapid recognition and implementation of preventative measures. It also underscores the importance of IPAC presence and public health immunization programs within correctional centers to avoid infectious disease threats. PMID- 27219909 TI - Deterioration and the long term prisoner: a descriptive analysis of Myra Hindley. AB - Purpose - The purpose of this paper is to explore supposed inevitable personal decline for long-term prisoners, particularly those serving a sentence of life without parole. Design/methodology/approach - Using the prison records of a life without parole sentenced prisoner. Findings - Findings suggest that prisoner deterioration is not inevitable in a whole life prison sentence. Research limitations/implications - Findings are based on one account, of a female prisoner. Practical implications - Distinct services and support are required for those with a natural life prison sentence. Originality/value - To date, there is limited research of prisoners serving life without parole, particularly the mental health implications of denying a prisoner future parole. PMID- 27219910 TI - Nicotinic acid treatment for Paralepistopsis acromelalga intoxication: assessment using magnetic resonance imaging. AB - CONTEXT: Paralepistopsis acromelalga, formerly known as Clitocybe acromelalga, is a rare poisonous mushroom. The mycotoxins in this mushroom cause symptoms resembling those of erythromelalgia; however, its pathogenesis remains unclear. In this report, a patient who received nicotinic acid treatment for P. acromelalga poisoning and radiological evaluation for erythromelalgia has been presented. Case detail: A 59-year-old woman was hospitalized for redness, swelling, and burning pain in her extremities that rendered difficulty in walking, and a diagnosis of P. acromelalga poisoning was made by detailed interview and mushroom identification. She was treated with intravenous nicotinic acid for 17 days followed by oral nicotinic acid amide for 2 months. She exhibited rapid symptomatic improvement and walked independently after 11 days of initial treatment. Initial MRI of her feet revealed toe-dominated subcutaneous thickening. After nicotinic acid treatment, those radiological findings improved dramatically. DISCUSSION: The subcutaneous thickening evident on MRI indicated P. acromelalga poisoning-induced erythromelalgia involved subcutaneous inflammatory edema. The typical duration of edema without treatment is more than a month. The improvement on MRI after nicotinic acid treatment indicated that the adequate vasodilation induced by nicotinic acid contributed to resolution of the symptoms. Nicotinic acid was associated with the improvement of the edematous changes caused by the P. acromelalga intoxication. PMID- 27219911 TI - Magnesium Fluoride Electron-Selective Contacts for Crystalline Silicon Solar Cells. AB - In this study, we present a novel application of thin magnesium fluoride films to form electron-selective contacts to n-type crystalline silicon (c-Si). This allows the demonstration of a 20.1%-efficient c-Si solar cell. The electron selective contact is composed of deposited layers of amorphous silicon (~6.5 nm), magnesium fluoride (~1 nm), and aluminum (~300 nm). X-ray photoelectron spectroscopy reveals a work function of 3.5 eV at the MgF2/Al interface, significantly lower than that of aluminum itself (~4.2 eV), enabling an Ohmic contact between the aluminum electrode and n-type c-Si. The optimized contact structure exhibits a contact resistivity of ~76 mOmega.cm(2), sufficiently low for a full-area contact to solar cells, together with a very low contact recombination current density of ~10 fA/cm(2). We demonstrate that electrodes functionalized with thin magnesium fluoride films significantly improve the performance of silicon solar cells. The novel contacts can potentially be implemented also in organic optoelectronic devices, including photovoltaics, thin film transistors, or light emitting diodes. PMID- 27219912 TI - Clinical characteristics and dose-volume histogram parameters associated with the development of pleural effusions in non-small cell lung cancer patients treated with chemoradiation therapy. AB - BACKGROUND: To investigate descriptive characteristics and dose metric (DM) parameters associated with development of pleural effusions (PlEf) in non-small cell lung cancer (NSCLC) treated with definitive chemoradiation therapy (CRT). MATERIALS AND METHODS: We retrospectively assessed treatment records and follow up imaging of 66 NSCLC patients to identify PlEf formation after CRT. PlEf association between mean heart dose (MHD), mean lung dose (MLD), heart V5-V60 (HV), and lung V5-V60 (LV) were evaluated using Cox Proportional Hazard Models. RESULTS: A total of 52% (34 of 66 patients) of our population developed PlEf and the actuarial rates at 6 months, 12 months, and 18 months were 7%, 30%, and 42%, respectively. Median time to diagnosis was five months (range 0.06-27 months). The majority of PlEfs were grade one (67%) and developed at a median of four (0.06-13) months, followed by grade two (15%) at a median 11 (5-12) months, and grade three (18%) at a median of 11 (3-27) months. On multivariate analysis, increasing HV5-HV50, LV5-LV50, MHD, and MLD were associated with greater risk of PlEf. Higher grade PlEf was also associated with higher doses of radiation to the heart, while lung DM parameters were not significantly associated with higher PlEf grades. At five-months post-CRT, MHD of 25 Gy was associated with a 100% chance of grade one PlEf, an 82% risk of grade two PlEf, and a 19% risk of grade three PlEf. CONCLUSIONS: Post-CRT PlEf is common in NSCLC with the majority being grade one. Increasing heart and lung irradiation was associated with increased risk of PlEf. Increasing heart irradiation also correlated with development of increasing grades of PlEf. The impact of potential cardiopulmonary toxicity and resultant PlEfs after CRT requires additional study. PMID- 27219914 TI - Abstracts of the Heart Failure 2016 Conference, Florence, Italy, 21-24 May 2016. PMID- 27219913 TI - Anxiety in Multiple Sclerosis: psychometric properties of the State-Trait Anxiety Inventory. AB - OBJECTIVE: The aims of the present study were to examine psychometric properties of the Spielberger State-Trait Anxiety Inventory (STAI-Y-1 and STAI-Y-2, respectively) in a Multiple Sclerosis (MS) population and to identify a cut-off score to detect those MS patients with high level of state and/or trait anxiety who could be more vulnerable to development of depression and/or cognitive defects. MATERIAL AND METHODS: The STAI-Y-1 and STAI-Y-2 was completed by a group of patients (n = 175) affected by MS and a group of healthy subjects (n = 150) matched for age, educational level, and gender. In MS patients internal consistency, divergent and discriminant validities were evaluated. Construct validity was examined by exploratory factor analysis for each scale. RESULTS: There was no missing data, no floor or ceiling effects for both scales. The two scales showed high internal consistency, good divergent, and Known-groups validities. To identify high levels of state and trait anxiety in a patient with MS, we proposed three gender specific screening cut-off values (1, 1.5, 2 SD) for the STAI-Y-1 and the STAI-Y-2. CONCLUSIONS: The findings showed that the STAI-Y-1 and the STAI-Y-2 are a valid tool for clinical use in MS patients and can be useful to measure the severity of anxiety and to identify those patients with high anxiety to introduce them in specific non-pharmacological intervention. PMID- 27220007 TI - Interaction of light quality and fertility on biomass, shoot pigmentation and xanthophyll cycle flux in Chinese kale. AB - BACKGROUND: Nutritionally important carotenoids in 21-day-old brassica microgreens increase following short and long-term exposure to narrow-band wavelengths from light-emitting diodes (LED). The present study aimed to measure the impact of: (1) fluorescent/incandescent light and different percentages of blue/red LED light and (2) different levels of nutrient fertility on biomass and pigment concentrations in 30-day-old 'Green Lance' Chinese kale (Brassica oleracea var. alboglabra). Kale plants were exposed to four light treatments and two fertility levels and were harvested 30 days after seeding and analyzed for nutritionally important shoot pigments. RESULTS: Kale under the fluorescent/incandescent light treatment had a significantly higher shoot fresh and dry mass. The shoot tissue concentrations of most pigment were significantly higher under blue/red LED light treatments. The higher fertility level resulted in higher concentrations for most pigments. Interestingly, the pool of xanthophyll cycle pigments and de-epoxidized xanthophylls was higher under all LED treatments. CONCLUSION: The results obtained in the present study support previous data demonstrating the stimulation of nutritionally important shoot tissue pigment concentrations following exposure to sole source blue/red LEDs compared to traditional lighting. Xanthophyll cycle flux was impacted by LEDs and this may support the role of zeaxanthin in blue light perception in leafy specialty crops. (c) 2016 Society of Chemical Industry. PMID- 27220009 TI - Correction: Deep Evolutionary Comparison of Gene Expression Identifies Parallel Recruitment of Trans-Factors in Two Independent Origins of C4 Photosynthesis. AB - [This corrects the article DOI: 10.1371/journal.pgen.1004365.]. PMID- 27220010 TI - Does parental monitoring and disapproval explain variations in alcohol use among adolescents from different countries of birth? AB - INTRODUCTION AND AIMS: This study investigated the extent to which parental monitoring and parental disapproval of alcohol use account for the association between country of birth and adolescent alcohol use. DESIGN AND METHODS: The sample consisted of 10 273 adolescents from grades 7 (Mean age = 12.5 years), 9 (14.5 years) and 11 (16.4 years) in Victoria, Australia. Participants completed a questionnaire during class time. Mediation analyses were performed to examine the extent to which parental monitoring and parental disapproval of alcohol use accounted for variations in past 30 day alcohol use between Australian-born and immigrant adolescents. RESULTS: Alcohol use in the past 30 days ranged from 8.0% to 44.4% for participants from different countries/regions of birth. Those born in Asia (odds ratio 0.20-0.51, P < 0.05) and Africa (odds ratio 0.45, P < 0.01) were much less likely to have consumed alcohol compared to those born in Australia. Adolescents from these two regions (except for Western Asia) reported higher levels of parental monitoring and parental disapproval of alcohol use (P < 0.05). Higher levels of parental monitoring and parental disapproval of alcohol use partially mediated the association between birth place and alcohol use (P < 0.05). DISCUSSION AND CONCLUSIONS: There were large variations in alcohol use between Australian-born and immigrant adolescents from different countries/regions. Adolescents from Asia or Africa were much less likely to consume alcohol, and this protective effect was partially accounted for by parental monitoring and disapproval of alcohol use.[Chan GCK, Kelly AB, Connor JP, Hall WD, Young RM, Williams JW. Does parental monitoring and disapproval explain variations in alcohol use among adolescents from different countries of birth? Drug Alcohol Rev 2016;35:741-749]. PMID- 27220011 TI - Non-aflatoxigenic Aspergillus flavus as potential biocontrol agents to reduce aflatoxin contamination in peanuts harvested in Northern Argentina. AB - Biological control is one of the most promising strategies for preventing aflatoxin contamination in peanuts at field stage. A population of 46 native Aspergillus flavus nonaflatoxin producers were analysed based on phenotypic, physiological and genetic characteristics. Thirty-three isolates were characterized as L strain morphotype, 3 isolates as S strain morphotype, and 10 isolates did not produce sclerotia. Only 11 of 46 non-aflatoxigenic isolates did not produce cyclopiazonic acid. The vegetative compatibility group (VCG) diversity index for the population was 0.37. For field trials we selected the non aflatoxigenic A. flavus AR27, AR100G and AFCHG2 strains. The efficacy of single and mixed inocula as potential biocontrol agents in Northern Argentina was evaluated through a 2-year study (2014-2015). During the 2014 peanut growing season, most of the treatments reduced the incidence of aflatoxigenic strains in both soil and peanut kernel samples, and no aflatoxin was detected in kernels. During the 2015 growing season, there was a reduction of aflatoxigenic strains in kernel samples from the plots treated with the potential biocontrol agents. Reductions of aflatoxin contamination between 78.36% and 89.55% were observed in treated plots in comparison with the un-inoculated control plots. This study provides the first data on aflatoxin biocontrol based on competitive exclusion in the peanut growing region of Northern Argentina, and proposes bioproducts with potential use as biocontrol agents. PMID- 27220012 TI - High prevalence of extended-spectrum and plasmidic AmpC beta-lactamase-producing Escherichia coli from poultry in Tunisia. AB - This study was conducted to detect extended spectrum beta-lactamases (ESBLs) and plasmidic AmpC beta-lactamase (pAmpC-BL)-producing Escherichia coli isolates in industrial poultry samples were collected from healthy chickens of the three farms. Samples were inoculated onto desoxycholate-lactose-agar plates supplemented with cefotaxime (2mg/L). E. coli was identified by biochemical and molecular methods and antibiotic susceptibility testing by the disk diffusion method. Genes encoding ESBLs and pAmpC-BL were detected by PCR and sequencing. Phylogenetic groups were determined by triplex PCR. The molecular typing of strains was done by pulsed field gel electrophoresis (PFGE) and Multilocus Sequence Typing (MLST) in those isolates showing different PFGE patterns. Cefotaxime-resistant E. coli isolates were recovered in 48 of 137 fecal samples (35%), and one isolate/sample was further studied. The following beta-lactamase genes were detected: blaCTX-M-1 (29 isolates, isolated in all three farms), blaCTX-M-15 (5 isolates, confined in farm II), blaCTX-M-14 and blaCMY-2 (one isolate and 13 isolates, respectively, in farm III). The 48 cefotaxime-resistant isolates were distributed into phylogroups: B1 (n=21), A (n=15) and D (n=12). PFGE analysis revealed 19 unrelated patterns: 15 different profiles among ESBL positive strains and 4 among the CMY-2-positive isolates. The following sequence types-associated phylogroups were detected: a) CTX-M-1-positive strains: lineages ST542-B1, ST212-B1, ST58-B1, ST155-B1 and ST349-D; b) CTX-M-15-positive strain: lineage ST405-D; c) CTX-M-14-positive strain: lineage ST1056-B1; d) CMY-2 positive strains: lineages ST117-D, ST2197-A, and ST155-B1. Healthy chickens constitute an important reservoir of ESBL- and pAmpC-BL-producing E. coli isolates that potentially could be transmitted to humans via the food chain or by direct contact. PMID- 27220013 TI - Pharmacokinetics of prolonged-release tacrolimus and implications for use in solid organ transplant recipients. AB - Prolonged-release tacrolimus was developed as a once-daily formulation with ethylcellulose as the excipient, resulting in slower release and reduction in peak concentration (Cmax ) for a given dose compared with immediate-release tacrolimus, which is administered twice daily. This manuscript reviews pharmacokinetic information on prolonged-release tacrolimus in healthy subjects, in transplant recipients converted from immediate-release tacrolimus, and in de novo kidney and liver transplant recipients. As with the immediate-release formulation, prolonged-release tacrolimus shows a strong correlation between trough concentration (Cmin ) and area under the 24-hour time-concentration curve (AUC24 ), indicating that trough whole blood concentrations provide an accurate measure of drug exposure. We present the pharmacokinetic similarities and differences between the two formulations, so that prescribing physicians will have a better understanding of therapeutic drug monitoring in patients receiving prolonged-release tacrolimus. PMID- 27220014 TI - Biomimetic fiber mesh scaffolds based on gelatin and hydroxyapatite nano-rods: Designing intrinsic skills to attain bone reparation abilities. AB - Intrinsic material skills have a deep effect on the mechanical and biological performance of bone substitutes, as well as on its associated biodegradation properties. In this work we have manipulated the preparation of collagenous derived fiber mesh frameworks to display a specific composition, morphology, open macroporosity, surface roughness and permeability characteristics. Next, the effect of the induced physicochemical attributes on the scaffold's mechanical behavior, bone bonding potential and biodegradability were evaluated. It was found that the scaffold microstructure, their inherent surface roughness, and the compression strength of the gelatin scaffolds can be modulated by the effect of the cross-linking agent and, essentially, by mimicking the nano-scale size of hydroxyapatite in natural bone. A clear effect of bioactive hydroxyapatite nano rods on the scaffolds skills can be appreciated and it is greater than the effect of the cross-linking agent, offering a huge perspective for the upcoming progress of bone implant technology. PMID- 27220015 TI - Rapid Quantification of Trimethylamine. AB - Sensitive detection of trimethylamine both in aqueous and gaseous phases has been accomplished using an inexpensive colorimetric sensor array. Distinctive color change patterns provide facile discrimination over a wide range of concentrations for trimethylamine with >99% accuracy of classification. Calculated limits of detection are well below the diagnostically significant concentration for trimethylaminuria (fish malodor syndrome). The sensor array shows good reversibility after multiple uses and is able to cleanly discriminate trimethylamine from similar amine odorants. Portable sensing of trimethylamine vapors at ppb concentrations is described using a cell phone camera or a hand held optoelectronic nose. Application of the sensor array in detecting mouth and skin odor as a potential tool for portable diagnosis of trimethylaminuria is also illustrated. PMID- 27220016 TI - Adipose Stromal Vascular Fraction Isolation: A Head-to-Head Comparison of 4 Cell Separation Systems #2. AB - INTRODUCTION: With stromal vascular fraction (SVF) cell and adipose-derived stem cell-based technologies translating into the clinical setting, numerous isolation systems have been developed for the point of care isolation of SVF cells from adipose tissue. A relative lack of performance data on these systems can make objective assessment difficult for prospective clinicians. This study compared the performance of 4 SVF cell isolation systems. METHODS: Four isolation systems were compared: the MultiStation by PNC International, the LipoKit by MediKhan, the GID SVF-2 platform by GID Europe Ltd, and the StemSource 900/MB system by Cytori Therapeutics, Inc. Identical lipoaspirate samples for 5 separate donors were used. Stromal vascular fraction output was compared in terms of nucleated cell yield, viability, residual collagenase activity, sterility of the output, colony-forming unit-fibroblast frequency, frequency of CD31-/CD34+/CD45- cells, and operating statistics. RESULTS: Mean process time ranged from 65.4 to 120.8 minutes. Mean nucleated cell yield per milliliter of tissue processed ranged from 1.01 * 10 cells/mL to 6.24 * 10 cells/mL. Mean cellular viability ranged from 50.3% to 84.02%. Residual collagenase activity was negligible across all systems. Observed colony-forming unit-fibroblast frequency ranged from 0.495% to 1.704%. No significant difference was observed in frequency of CD31-/CD34+/CD45- cells. Results of the anaerobic/aerobic cultures were mixed. CONCLUSIONS: There was considerable variability between the outputs of each system. The system used by a clinician should be tailored to the individual needs of the practice. There is a range of cost options available. This study may help clinicians make more educated decisions when choosing an isolation system to meet their clinical needs. PMID- 27220017 TI - Mycobacterium abscessus Infection After Facial Injection With Autologous Fat: A Case Report. AB - We report a case of Mycobacterium abscessus infection in a 29-year-old woman after facial injection with autologous fat. Nineteen months previously, she received a facial surgery of autologous fat injection with the fat harvested from her inner thigh. On examination, she had multiple painful and fluctuant abscesses associated with local pyrexia in her bilateral temporal and lower orbital regions. A B ultrasound revealed multiple fat liquefaction in her bilateral temporal and lower orbital regions. The acid-fast bacilli culture and polymerase chain reaction sequencing confirmed M. abscessus infection. She was treated with moxifloxacin, clarithromycin, and ethambutol for 12 months, and finally the symptoms subsided. To avoid infection after fat graft, aseptic technique as well as standard operation of the fat harvest and process should be strictly enforced. In cases of persistent infection, or invalid cases treated with conventional antibiotic therapy, nontuberculous mycobacteria should be suspected, and a polymerase chain reaction sequencing as well as a drug sensitivity test should be carried out. PMID- 27220018 TI - Propeller Flaps With Reduced Rotational Angles: Clinical Experience on 40 Consecutive Reconstructions Performed at Different Anatomical Sites. AB - BACKGROUND: Despite of the widespread use of 180-degree propeller flaps in the field of soft tissue reconstruction, less information are available in the current literature to standardize the use of propeller flaps with reduced degrees of rotation.The authors report their experience with propeller flaps with reduced rotational angles reviewing clinical applications and outcomes of the technique in a series of 40 consecutive reconstructions. PATIENTS AND METHODS: Forty elective defects of various etiologies located in different regions of the body (head and neck, trunk, buttocks and perineum, extremities) were reconstructed with less than 180 degrees rotated propeller flaps. The technique was applied to patients presenting with a strong audible perforator detected in close proximity to the wound and the defect located in a position adjacent to the axis of the chosen perforasome. RESULTS: Defect size ranged from 2 * 2 to 15 * 9 cm. Flap dimensions ranged from 5 * 2 to 21 * 10 cm. The flaps were based on 1 (34) or 2 (6) perforators and were mobilized with an angle of rotation of 45, 90, and 135 degrees in 7, 24, and 9 patients, respectively. Mean operative time was 105 minutes. All flaps survived postoperatively. In only 4 cases (10%) partial flap necrosis was registered. All flaps achieved adequate and durable reconstruction with excellent contour, with a follow-up ranging between 6 months and 2 years. CONCLUSIONS: Propeller flaps with reduced rotational angles represent a safe and versatile option to reconstruct soft tissues defects at different anatomical sites. PMID- 27220019 TI - The Impact of Financial Conflicts of Interest in Plastic Surgery: Are They All Created Equal? AB - BACKGROUND: Recently, several studies have demonstrated that articles that disclose conflicts of interests (COI) are associated with publication of positive results. The purpose of this study was to learn more about the different types of COI as they relate to the general topic of COI in plastic surgery. Specifically, we aimed to examine whether different types of COI are more likely than others to be associated with the presentation of positive findings. METHODS: We reviewed all original articles in Annals of Plastic Surgery, Journal of Plastic, Reconstructive, and Aesthetic Surgery, and Plastic & Reconstructive Surgery from January 1, 2012, to December 31, 2013. All scientific articles were analyzed, and several article characteristics were extracted. Disclosed COI were categorized into the following categories: consultant/employee, royalties/stock options, and research support. The findings reported in each article abstract were blindly graded as reporting a positive, negative, neutral, or not applicable result. A multivariable analysis was performed to determine whether an association existed between certain types of COI and publication of positive conclusions. RESULTS: A total of 3124 articles were identified of which 1185 fulfilled the inclusion criteria. Financial COI were reported in 153 studies (12.9%). The most common type of COI was "research support" (7.3%), whereas the least common was "royalties/stock options" (1.2%). Rates of different types of COI varied significantly by plastic surgery subspecialty field (P < 0.001). In the multivariable analysis, authors who disclosed COI related to research support, consultant/employee, and royalties/stock options were 1.31, 6.62, and 8.72 times more likely, respectively, to publish positive findings when compared with authors that disclosed no COI after correcting for potential confounding factors. However, consultancy/employee status was the only COI category statistically associated with publication of positive results (P < 0.001). CONCLUSIONS: Self reported COI are uncommon in plastic surgery research. Our results provide evidence that certain types of financial COI are more likely than others to be associated with the presentation of positive findings. This analysis suggests that certain investigators may be more biased, consciously or unconsciously, by the type of financial benefit offered by industry. PMID- 27220020 TI - Re: Effectiveness of a Novel Augmented Reality-Based Navigation System in Treatment of Orbital Hypertelorism. PMID- 27220022 TI - Soft Tissue Adjuncts in Revisionary Aesthetic Breast Surgery. AB - Reconstructive breast surgery is challenging and continually evolving. In the past decade, numerous soft tissue adjuncts, such as acellular dermal matrices (ADMs), have revolutionized breast reconstruction serving as a tool to improve results and minimize the need for revision. The use of ADMs has been widely discussed in primary and secondary breast reconstruction after mastectomy. They have been shown to be an effective and safe option to correct complications; however, there is a relative paucity of literature on their use in revisional surgery after aesthetic breast procedures. The authors queried PubMed for existing literature regarding the use of ADMs in secondary breast surgery. Five case series from an initial search of 278 articles met the inclusion criteria. An overall infection rate of 2% and a complication rate of implant malposition was 0.8% with the use of ADMs. Although the literature is sparse regarding their use in this setting, early reports indicate that they are both safe and efficacious with a reasonable rate of complications. PMID- 27220023 TI - Salvage of Ear Framework Exposure in Total Auricular Reconstruction. AB - BACKGROUND: One of the most common complications of total auricular reconstruction is delayed wound healing, which results in skin necrosis and exposure of the ear framework. Various options exist for salvage of the exposed ear framework. METHODS: From January 2009 to May 2014, 149 patients underwent total auricular reconstruction using an autogenous cartilage framework or porous polyethylene framework (Medpor; Stryker, USA). An autogenous cartilage framework was used in 48 patients, and a Medpor framework was used in 101 cases. Three cases of framework exposure (3/48, 6.3%) were observed among the patients treated with an autogenous cartilage framework. In contrast, framework exposure took place in 11 patients who were treated with a Medpor framework (11/101, 10.9%). Depending on the method of total ear reconstruction and the location of exposure, the authors used local skin flaps, temporoparietal fascia flaps, deep temporal fascia (DTF) flaps, or mastoid fascia (MF) flaps with skin grafting. RESULTS: Among the 11 patients who experienced framework exposure after being treated with a Medpor framework, a DTF flap with skin grafting was used in 6 patients and an MF flap with skin grafting in 6 patients; 1 patient was treated with both a DTF flap and an MF flap. All 3 cases of cartilage framework exposure were salvaged using a temporoparietal fascia flap with skin grafting, and a local skin flap was used in 1 case. In all 3 cases, the exposed framework was completely covered with the flap, and the reconstructed ears showed well-defined convolutions. CONCLUSIONS: Salvage of framework exposure remains a challenging issue in total auricular reconstruction. However, appropriate wound management using various flaps allows the reconstructed ear to be safely preserved. PMID- 27220024 TI - Pulp Rotation Flap for Lateral Oblique Fingertip Defects. AB - BACKGROUND: Fingertip amputations are among the most common injuries seen in the hand. According to the geometry of the amputation, it may be classified as transverse or oblique (dorsal, volar, or lateral type). Although numerous repair techniques have been described in the literature, there are few alternatives suitable for lateral oblique type fingertip amputations. METHODS: Between 2012 and 2016, we operated on 16 patients with simple rotation flap from the remaining part of the pulpa in a rotation and advancement manner for the reconstruction of lateral oblique type fingertip amputations. RESULTS: All but two of the flaps healed completely with full flap survival. Superficial distal flap necrosis was observed in two patients. They healed by secondary intention. No obvious hooked nail occurred in patients. Cold intolerance was observed in one patient; joint stiffness or hypersensitivity was not observed in any of the patients. Stiffness of the proximal interphalangeal joint did not occur. Two point discrimination test results were found to be normal. CONCLUSION: This technique is simple, rapid, and free from relatively major complications. This flap allows for anatomical reconstruction of the fingertip by using a similar tissue in cases of lateral oblique fingertip amputations, where only a few flap options can be successful. PMID- 27220025 TI - Editorial Comment to Effectiveness and safety of silodosin in the treatment of lower urinary tract symptoms in patients with benign prostatic hyperplasia: A European phase IV clinical study (SiRE study). PMID- 27220027 TI - Mesenchymal stem cell therapy to promote limb transplant functional recovery. AB - BACKGROUND: Limb transplantation is a viable option for reconstruction after traumatic limb loss; however, functional recovery can be suboptimal. The aim of this study was to determine whether mesenchymal stem cell (MSC) administration can improve limb transplant functional recovery. METHODS: Orthotopic syngeneic hindlimb transplants were performed in Lewis rats, followed by topical and intravenous injections of syngeneic MSCs (5 * 106 ) or vehicle. Transplanted limb sensory and motor functions were tested by cutaneous pain reaction and walking track analysis, respectively. RESULTS: MSCs expanded ex vivo were CD29+ , CD31- , CD34- , CD44+ , CD45low , CD90+ , MHC Class-I+ , Class-II- , and pluripotent. Greater than 90% of limb transplants survived. At 4 weeks post-transplantation, the mean sensory nerve (tibial, peroneal, or sural) function in MSC (n = 9) and vehicle (n = 9) groups was <0.3 on a scale of Grades 0-3 (0 = No function; 3 = Normal). By 8 weeks, the sensory scores for tibial, peroneal, and sural nerves were 2.2 +/- 0.7, 1.2 +/- 0.5, and 1.7 +/- 0.9 in the vehicle, and 2.6 +/- 0.4, 1.0 +/- 0.9, and 1.7 +/- 0.9 in the MSC group, respectively (n = 9/group). At 4, 8, 16, and 24 weeks, the overall sensory function was higher in MSC group (>=7/group). Sciatic Function Index (SFI), a measure of motor function, could not be calculated because of poor foot prints; therefore, a novel grading system was developed. Bone fusion/vascularization as determined by X-ray films/laser Doppler (>=2 week post-transplantation) were normal (n = 3/group). Gastrocnemius muscle was atrophied (P < 0.05), and flexion contractures were evident by 24 weeks. CONCLUSIONS: Bone marrow-derived MSC therapy appears to improve sensory function recovery in a rat limb transplant model. Published 2016. This article is a U.S. Government work and is in the public domain in the USA Microsurgery 37:222-234, 2017. PMID- 27220026 TI - Adverse Environmental Exposures During Gestation and Childhood: Predictors of Adolescent Drinking. AB - Adverse conditions, including exposures to drugs and other environmental influences during early development, may affect behaviors later in life. This study examined the role of environmental influences from the gestation and childhood on adolescent drinking behavior. 917 mother/offspring dyads were followed prospectively from pregnancy to a 16-year follow-up assessment. Interim assessments occurred at delivery, 6, 10, and 14 years. Prenatal exposures to alcohol, tobacco, and marijuana were measured during gestation. Data were collected at each phase on childhood environment, including parenting practices, quality of the home environment, maternal depression and hostility, and lifetime exposure to child maltreatment and community violence. Alcohol outcomes were offspring age of drinking initiation and level of drinking at age 16 years. Cox Proportional Hazards ratios were used to model offspring age of drinking initiation. Logistic regression analyses were used to evaluate significant predictors of drinking level. Childhood environment, including less parental strictness, greater exposure to violence and childhood maltreatment, significantly predicted earlier age of alcohol initiation. Level of drinking among the adolescent offspring was significantly predicted by prenatal exposure to alcohol, less parental strictness, and exposures to maltreatment and violence during childhood. Whites and offspring with older mothers were more likely to initiate alcohol use early and drink at higher levels. Early and heavier alcohol use was associated with early exposures to adversity such as prenatal alcohol exposure, and child exposures to maltreatment and violence. These results highlight the importance of environmental adversity and less effective parenting practices on the development of adolescent drinking behavior. PMID- 27220028 TI - Role of heart rate in the relation between regional body fat and subendocardial viability ratio in women. AB - Subendocardial viability ratio (SEVR) is a measure of left ventricular function, specifically; it is an index of myocardial perfusion relative to left ventricular workload. Women have lower SEVR than men, partly due to a faster resting heart rate that reduces diastolic time (i.e., time for myocardial perfusion). It is unclear if body fat relates to SEVR, thus the purpose of this study was to examine the relation between body fat and SEVR in women. Twenty-eight middle-aged (31-45 years) and 31 older (60-80 years) women were examined. Radial artery applanation tonometry was used to calculate SEVR from a synthesized central aortic pressure wave. Dual-energy X-ray absorptiometry was used to assess body composition including fat in the trunk, legs, android and gynoid regions. Body fat was not related (P>.05) with SEVR in older women. In middle-aged women, all measures of regional fat were correlated with heart rate (range, r=.49-.59, P<=.01) and SEVR (range, r=.43-.53, P<=.01). Android-to-gynoid ratio was identified as the strongest predictor (r(2) =-.26, P<.01) of SEVR among measures of regional fat. Middle-aged women with lower android-to-gynoid fat ratio had higher SEVR (1.96+/-0.33 vs 1.66+/-0.20, P=.009) than women with higher fat ratio, even after adjusting for age, height, daily physical activity, and aortic mean pressure (P=.02). Adjusting for heart rate or diastolic time abolished the difference in SEVR between groups (1.80+/-0.09 vs 1.82+/-0.09, P=.56). These results suggest that middle-aged women with a greater distribution of fat in the abdomen have poorer left ventricular function that is dependent on the negative influence of heart rate on diastolic time. PMID- 27220029 TI - College Students' Health Information Activities on Facebook: Investigating the Impacts of Health Topic Sensitivity, Information Sources, and Demographics. AB - College students tend to lack access to health information. Because social networking sites (SNSs) are popularly adopted by college students, SNSs are considered to be good media channels for college students to obtain health related information. This study examines the factors that influence college students' health information-seeking and -sharing activities on Facebook. An online survey was distributed to college students between the ages of 18 and 29 to determine intentions pertaining to health information activities according to the factors identified for the study. The factors included both contextual factors (such as health topic sensitivity and health information sources) as well as user factors (such as demographics). Our findings showed that college students are willing to read and post health-related information on Facebook when the health topic is not sensitive. In addition, there are clear differences in preferences between professional sources and personal sources as health information sources. It was found that most user factors, except gender, have no influence on health information activities. The impacts of SNS contexts, awareness of information sources, types of interlocutors, and privacy concerns are further discussed. PMID- 27220030 TI - Language Barriers and Immigrant Health. AB - We study the impact of language deficiency on the health status of childhood migrants to Australia. Our identification strategy relies on a quasi-experiment comparing immigrants arriving at different ages and from different linguistic origins. In the presence of considerable non-classical measurement error in self reported language proficiency, our results provide lower and upper bounds for a strong negative effect of English deficiency on health of between one half and a full standard deviation in the health score. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27220034 TI - Discrepancy Between Standing Posture and Sagittal Balance During Walking in Adult Spinal Deformity Patients. AB - STUDY DESIGN: Retrospective case series. OBJECTIVE: The present study aimed to determine the characteristics of patients with adult spinal deformity (ASD) with a discrepancy between standing and walking postures. SUMMARY OF BACKGROUND DATA: Standing radiographic parameters are typically used to evaluate patients with ASD. Patients with ASD with relatively good sagittal alignment on standing radiography have, however, been reported to walk with a forward trunk tilt. METHODS: Patients with ASD (n = 93; 13 men, 80 women; mean age, 65.0 yr) who underwent corrective surgery and preoperative gait analysis at our hospital between 2011 and 2013 were included. Spine radiographs and gait analysis data were acquired preoperatively. Standing-trunk tilt angle (STA) on lateral standing x-ray, gait-trunk tilt angle (GTA) from lateral gait images, and radiographic parameters of the spine and pelvis (lumbar lordosis [LL], pelvic tilt, and sagittal vertical axis) were measured. We calculated the increasing trunk tilt angle (ITA), by subtracting the STA from the GTA, for use as an index of discrepancy between standing posture and sagittal balance during walking. We examined the relation between radiographic parameters and ITA. RESULTS: The mean preoperative STA and GTA were 3.5 degrees and 11.1 degrees , respectively. The mean preoperative ITA, which represents the degree of discrepancy between standing posture and sagittal balance during walking, was 7.6 degrees . The mean preoperative sagittal vertical axis, LL, pelvic incidence (PI), pelvic tilt, and PI minus LL were 102.6 mm, 20.3 degrees , 52.9 degrees , 32.1 degrees , and 32.6 degrees , respectively. The PI minus LL mismatch was positively correlated with the ITA (R = 0.237, P = 0.023). In particular, patients with ASD with a PI minus LL mismatch of more than 40 degrees had a significantly greater ITA. CONCLUSION: Gait analysis revealed that a preoperative standing-walking discrepancy is associated with severe PI - LL mismatch. LEVEL OF EVIDENCE: 4. PMID- 27220036 TI - The Promise of Pre-Exposure Prophylaxis for Black Men Who Have Sex with Men: An Ecological Approach to Attitudes, Beliefs, and Barriers. AB - Research has demonstrated the clinical effectiveness of pre-exposure prophylaxis (PrEP) for HIV prevention, but little is known about how factors at the individual-, interpersonal-, community-, and structural levels impact PrEP use for black men who have sex with men (BMSM). We advance existing work by examining how all levels of the ecological framework must be addressed for PrEP to be successfully implemented as an effective HIV prevention approach. We interviewed 31 BMSM three times each and 17 community stakeholders once each; interviews were taped, transcribed, and analyzed using the constant comparative method. Factors that influence how BMSM experienced PrEP emerged across all levels of the ecological framework: At the individual level, respondents were wary of giving medication to healthy people and of the potential side-effects. At the interpersonal level, BMSM believed that PrEP use would discourage condom use and that PrEP should only be one option for HIV prevention, not the main option. At the community level, men described not trusting the pharmaceutical industry and described PrEP as an option for others, not for themselves. At the structural level, BMSM talked about HIV and sexuality-related stigmas and how they must overcome those before PrEP engagement. BMSM are a key population in the US National HIV/AIDS Strategy, yet few individuals believe that PrEP would be personally helpful. Our research indicates the urgent need to raise awareness and address structural stigma and policies that could be substantial barriers to the scale-up and implementation of PrEP-related services. PMID- 27220037 TI - LppM impact on the colonization of macrophages by Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis produces several bacterial effectors impacting the colonization of phagocytes. Here, we report that the putative lipoprotein LppM hinders phagocytosis by macrophages in a toll-like receptor 2-dependent manner. Moreover, recombinant LppM is able to functionally complement the phenotype of the mutant, when exogenously added during macrophage infection. LppM is also implicated in the phagosomal maturation, as a lppM deletion mutant is more easily addressed towards the acidified compartments of the macrophage than its isogenic parental strain. In addition, this mutant was affected in its ability to induce the secretion of pro-inflammatory chemokines, interferon-gamma-inducible protein 10, monocyte chemoattractant protein-1 and macrophage inflammatory protein 1alpha. Thus, our results describe a new mycobacterial protein involved in the early trafficking of the tubercle bacillus and its manipulation of the host immune response. PMID- 27220038 TI - Myosin-10 independently influences mitotic spindle structure and mitotic progression. AB - The iconic bipolar structure of the mitotic spindle is of extreme importance to proper spindle function. At best, spindle abnormalities result in a delayed mitosis, while worse outcomes include cell death or disease. Recent work has uncovered an important role for the actin-based motor protein myosin-10 in the regulation of spindle structure and function. Here we examine the contribution of the myosin tail homology 4 (MyTH4) domain of the myosin-10 tail to the protein's spindle functions. The MyTH4 domain is known to mediate binding to microtubules and we verify the suspicion that this domain contributes to myosin-10's close association with the spindle. More surprisingly, our data demonstrate that some but not all of myosin-10's spindle functions require microtubule binding. In particular, myosin-10's contribution to spindle pole integrity requires microtubule binding, whereas its contribution to normal mitotic progression does not. This is demonstrated by the observation that dominant negative expression of the wild-type MyTH4 domain produces multipolar spindles and an increased mitotic index, whereas overexpression of a version of the MyTH4 domain harboring point mutations that abrogate microtubule binding results in only the mitotic index phenotype. Our data suggest that myosin-10 helps to control the metaphase to anaphase transition in cells independent of microtubule binding. (c) 2016 Wiley Periodicals, Inc. PMID- 27220039 TI - The Intrinsic Fragility of DNA (Nobel Lecture). AB - Our cells contain common molecules, such as water or oxygen, that can damage DNA. In his studies Tomas Lindahl has shown how specific repair enzymes remove and replace damaged parts of DNA in a process of vital importance. PMID- 27220040 TI - Vaginal fine-needle aspiration: A useful alternative to biopsy. AB - BACKGROUND: Vaginal fine-needle aspiration (FNA) is infrequently performed to assess palpable lesions. We perform the first multi-institutional study to evaluate this procedure. METHODS: We retrospectively reviewed vaginal FNAs performed at two institutions for the past 27 years. Clinical, cytological and histological data were reviewed and tabulated. RESULTS: We identified 43 specimens from 39 patients (mean age 56 years, range 18-86 years). Twenty four patients (62%) had prior malignancies from the following sites: gynecologic tract (22), bladder (1), and breast (1). Twenty four specimens were malignant, 18 were benign (including eight cases from patients with prior malignancy) and one was unsatisfactory. Of 28 FNA specimens from patients with a malignant history, 18 (64%) were positive for malignancy. The most common malignancies were metastatic ovarian carcinoma (50%), squamous cell carcinoma (25%), and uterine cancer (17%). Mean time to metastasis/recurrence was 16 months and was longest in patients with ovarian metastasis (26 months) compared to other malignancies (P = 0.002). The most common benign diagnoses were cysts (33%) and inflammation (22%). In 27 cases with histological correlation, there were 20 true positives, six true negatives and one false negative (sensitivity =95%, specificity =100%). Seven patients had a recent Pap test with two true positives, two true negatives, and three false negatives (sensitivity = 40%, specificity = 100%). CONCLUSION: Vaginal FNA is usually performed to rule out a secondary malignancy, often of ovarian origin. Vaginal metastases from extra-gynecologic sites are rare. FNA is both highly sensitive and specific and may be a safe and effective alternative to biopsy. Diagn. Cytopathol. 2016;44:665-669. (c) 2016 Wiley Periodicals, Inc. PMID- 27220041 TI - In vivo correlates of thermoregulatory defense in humans: Temporal course of sub cortical and cortical responses assessed with fMRI. AB - Extensive studies in rodents have established the role of neural pathways that are activated during thermoregulation. However, few studies have been conducted in humans to assess the complex, hierarchically organized thermoregulatory network in the CNS that maintains thermal homeostasis, especially as it pertains to cold exposure. To study the human thermoregulatory network during whole body cold exposure, we have used functional MRI to characterize changes in the BOLD signal within the constituents of the thermoregulatory network in 20 young adult controls during non-noxious cooling and rewarming of the skin by a water-perfused body suit. Our results indicate significant decreases of BOLD signal during innocuous whole body cooling stimuli in the midbrain, the right anterior insula, the right anterior cingulate, and the right inferior parietal lobe. Whereas brain activation in these areas decreased during cold exposure, brain activation increased significantly in the bilateral orbitofrontal cortex during this period. The BOLD signal time series derived from significant activation sites in the orbitofrontal cortex showed opposed phase to those observed in the other brain regions, suggesting complementary processing mechanisms during mild hypothermia. The significance of our findings lies in the recognition that whole body cooling evokes a response in a hierarchically organized thermoregulatory network that distinguishes between cold and warm stimuli. This network seems to generate a highly resolved interoceptive representation of the body's condition that provides input to the orbitofrontal cortex, where higher-order integration takes place and invests internal states with emotional significance that motivate behavior. Hum Brain Mapp 37:3188-3202, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27220052 TI - Modified Dietary Fiber from Cassava Pulp and Assessment of Mercury Bioaccessibility and Intestinal Uptake Using an In Vitro Digestion/Caco-2 Model System. AB - The ability of modified dietary fiber (MDF) generated from cassava pulp to modulate the bioaccessibility and intestinal absorption of heavy metals may be helpful to mitigate health risk associated with select foods including select fish high in methyl mercury. Using a coupled in vitro digestion/Caco-2 human intestinal cell model, the reduction of fish mercury bioaccessibility and intestinal uptake by MDF was investiaged. MDF was prepared from cassava pulp, a byproduct of tapioca production. The highest yield (79.68%) of MDF was obtained by enzymatic digestion with 0.1% alpha-amylase (w/v), 0.1% amyloglucosidase (v/v) and 1% neutrase (v/v). MDF and fish tissue were subjected to in vitro digestion and results suggest that MDF may reduce mercury bioaccessibility from fish to 34% to 85% compared to control in a dose-dependent manner. Additionally, accumulation of mercury from digesta containing fish and MDF was only modestly impacted by the presence of MDF. In conclusion, MDF prepared from cassava pulp may be useful as an ingredient to reduce mercury bioavailability from food such as fish specifically by inhibiting mercury transfer to the bioaccessibile fraction during digestion. PMID- 27220053 TI - KIBRA promotes prostate cancer cell proliferation and motility. AB - KIBRA is a regulator of the Hippo-yes-associated protein (YAP) pathway, which plays a critical role in tumorigenesis. In the present study, we show that KIBRA is a positive regulator in prostate cancer cell proliferation and motility. We found that KIBRA is transcriptionally upregulated in androgen-insensitive LNCaPC4 2 and LNCaP-C81 cells compared to parental androgen-sensitive LNCaP cells. Ectopic expression of KIBRA enhances cell proliferation, migration and invasion in both immortalized and cancerous prostate epithelial cells. Accordingly, knockdown of KIBRA reduces migration, invasion and anchorage-independent growth in LNCaP-C4-2/C81 cells. Moreover, KIBRA expression is induced by androgen signaling and KIBRA is partially required for androgen receptor signaling activation in prostate cancer cells. In line with these findings, we further show that KIBRA is overexpressed in human prostate tumors. Our studies uncover unexpected results and identify KIBRA as a tumor promoter in prostate cancer. PMID- 27220055 TI - The Development of Multidimensional Analysis Tools for Asymmetric Catalysis and Beyond. AB - In most modern organic chemistry reports, including many of ours, reaction optimization schemes are typically presented to showcase how reaction conditions have been tailored to augment the reaction's yield and selectivity. In asymmetric catalysis, this often involves evaluation of catalyst, solvent, reagent, and, sometimes, substrate features. Such an article will then detail the process's scope, which mainly focuses on its successes and briefly outlines the "limitations". These limitations or poorer-performing substrates are occasionally the result of obvious, significant changes to structure (e.g., a Lewis basic group binds to a catalyst), but frequently, a satisfying explanation for inferior performance is not clear. This is one of several reasons such results are not often reported. These apparent outliers are also commonplace in the evaluation of catalyst structure, although most of this information is placed in the Supporting Information. These practices are unfortunate because results that appear at first glance to be peculiar or poor are considerably more interesting than ones that follow obvious or intuitive trends. In other words, all of the data from an optimization campaign contain relevant information about the reaction under study, and the "outliers" may be the most revealing. Realizing the power of outliers as an entry point to entirely new reaction development is not unusual. Nevertheless, the concept that no data should be wasted when considering the underlying phenomena controlling the observations of a given reaction is at the heart of the strategy we describe in this Account. The idea that one can concurrently optimize a reaction to expose the structural features that control its outcomes would represent a transformative addition to the arsenal of catalyst development and, ultimately, de novo design. Herein we outline the development of a recently initiated program in our lab that unites optimization with mechanistic interrogation by correlating reaction outputs (e.g., electrochemical potential or enantio-, site, or chemoselectivity) with structural descriptors of the molecules involved. The ever-evolving inspiration for this program is rooted in outliers of classical linear free energy relationships. These outliers encouraged us to ask questions about the parameters themselves, suggest potential interactions at the source of the observed effects, and, of particular applicability, identify more sophisticated physical organic descriptors. Throughout this program, we have integrated techniques from disparate fields, including synthetic methodology development, mechanistic investigations, statistics, computational chemistry, and data science. The implementation of many of these strategies is described, and the resulting tools are illustrated in a wide range of case studies, which include data sets with simultaneous and multifaceted changes to the reagent, substrate, and catalyst structures. This tactic constitutes a modern approach to physical organic chemistry wherein no data are wasted and mechanistic hypotheses regarding sophisticated processes can be developed and probed. PMID- 27220056 TI - Factors associated with self-care agency in patients after percutaneous coronary intervention. AB - AIMS AND OBJECTIVES: The aim of this study is to assess the factors associated with self-care agency in postpercutaneous coronary intervention patients. BACKGROUND: Patients after percutaneous coronary intervention need to perform self-care to reduce the side effects and increase the quality of life. Self-care agency is considered to be an important factor in guaranteeing self-care actions. DESIGN: In this descriptive study a total number of 300 postpercutaneous coronary intervention patients participated. Data were collected from the four hospitals affiliated with Shahid Beheshti University of Medical Sciences in Iran between February-May 2015. METHODS: The data were gathered using demographic and basic conditioning factors questionnaire and appraisal of self-care agency scale. Data analysis was performed by anova and t-test. RESULTS: The mean age of the participants was 62.10 +/- (8.14), which included 52.7% men and 47.3% women. Most patients (72%) had good level of self-care agency. Self-care agency had higher level in married and higher income patients. CONCLUSION: Self-care agency is influenced by economic and marital situation. RELEVANCE TO CLINICAL PRACTICE: Identifying factors associated with self-care agency can help healthcare professionals to consider these factors in self-care planning. PMID- 27220057 TI - Feasibility study of a peer-facilitated low intensity cognitive-behavioral intervention for mild to moderate depression and anxiety in older adults. AB - OBJECTIVES: The majority of older adults experiencing depression and/or anxiety do not receive adequate treatment due to limited access to evidence-based practices. Low intensity cognitive-behavioral intervention has been established as an evidence-based practice with the potential to increase the reach to older adults. The purpose of the current study is to evaluate the feasibility, acceptability, and potential efficacy of a low intensity, peer-supported, cognitive-behavioral intervention for mild to moderate depression and/or anxiety delivered by a local intergovernmental agency serving older adults. METHOD: Sixty two older adults (81% female) between 55 and 96 years of age were randomly assigned to either a peer-facilitated cognitive-behavioral bibliotherapy condition (n = 31) or a wait-list control condition (n = 31). RESULTS: The 10 week feasibility trial data indicated that (1) a majority of the participants were highly engaged in the intervention with an average number of 7.3 peer sessions attended and 2.1 workbooks completed, (2) the participants were quite satisfied with the peer mentoring sessions and moderately satisfied with the workbooks, and (3) there were clinically meaningful reductions in depressive symptoms for those assigned to the treatment condition compared to those that were wait-listed (d = .43), though the effect was non-significant (p = .099) due to the small sample size. The evidence for the impact on reducing anxiety symptoms was more equivocal with a non-significant, small effect size favoring the treatment condition. CONCLUSION: The pilot study provided preliminary evidence for the feasibility, acceptability, and potential efficacy of the peer facilitated low intensity cognitive-behavioral therapy intervention approach. PMID- 27220058 TI - Carryover: More than just a major hangover for the clinical laboratory. PMID- 27220059 TI - Prognostic value of gamma-glutamyl transferase in patients with diabetes mellitus and coronary artery disease. AB - OBJECTIVES: The aim of the study was to investigate the association between gamma glutamyl transferase (GGT) activity and mortality in patients with diabetes mellitus and coronary artery disease (CAD). DESIGN AND METHODS: The study included 1448 patients with diabetes and angiography-proven CAD who underwent percutaneous coronary intervention (PCI). Baseline GGT measurements were available in all patients. The primary outcome was 3-year mortality. RESULTS: Patients were divided into 3 groups: a group consisting of patients with a GGT activity in the 1st tertile (GGT<=29.4U/L; n=487), a group consisting of patients with a GGT activity in the 2nd tertile (GGT>29.4-52.5U/L; n=479) and a group consisting of patients with GGT in the 3rd tertile (GGT>52.5U/L; n=482). Overall, there were 179 deaths: 46 (11.9%), 49 (12.1%) and 84 deaths (21.4%) among patients of the 1st, 2nd and 3rd GGT tertiles, respectively (adjusted hazard ratio [HR]=1.25, 95% confidence interval [CI] 1.05-1.49, P=0.011). Cardiac death occurred in 101 patients: 22 (5.8%), 30 (7.2%) and 49 deaths (12.9%) among patients of the 1st, 2nd and 3rd GGT tertiles, respectively (adjusted HR=1.23 [0.96-1.58], P=0.104, with risk estimates calculated per standard deviation increase in the logarithmic scale of GGT). GGT improved the risk prediction of models of all-cause (P=0.020) but not cardiac (P=0.135) mortality (P values show the difference in C-statistics between the models without and with GGT). CONCLUSION: In patients with diabetes and CAD treated with PCI, elevated GGT was independently associated with the risk of 3-year all-cause mortality. PMID- 27220060 TI - Analytical evaluation of a real-time PCR-based DNA demethylation assay to assess the frequency of naturally occurring regulatory T cells in peripheral blood. AB - OBJECTIVES: Regulatory T cells (Tregs) which may indicate operational tolerance provide a promising biomarker for individualization of immunosuppression. Naturally thymus-derived Tregs (nTregs) represent the major suppressive phenotype and can be identified by their demethylation status in the Tregs Specific Demethylated Region (TSDR) of the Forkhead-Box-P3 (FOXP3) gene using quantitative PCR (qPCR). DESIGN AND METHODS: The analytical performance of a TSDR demethylation qPCR assay was assessed in whole blood of healthy individuals (HI) and kidney transplant recipients (KTR). The assay was compared to conventional flow cytometry and the agreement of results between two laboratories using a comparable qPCR protocol was assessed. In addition, the effect of gender, age, and medications was investigated. RESULTS: Within and between series imprecision was <20% (n=6). Whole blood samples are suitable for analysis within 3days when stored at room temperature; both whole blood and DNA samples - within 12months when frozen at -80 degrees C. A significant correlation between the qPCR results and flow cytometry was lacking both with samples from HI and KTR. qPCR results between laboratories showed a bias of 76% but correlated well (r=0.645; p=0.0002, n=29). nTregs determined by qPCR were significantly (p<0.05) higher in HI (0.73%+/-0.23%, n=60) than in KTR (0.45%+/-0.21%, n=60) and in female HI (1.0%+/ 0.27%, n=30) than in male HI (0.45%+/-0.23%, n=27). No effect of drugs or age was observed. CONCLUSIONS: The qPCR assay for nTregs provides reproducible results and is of sufficient quality for working with patient samples although inter laboratory differences can be encountered due to a lack of method standardization. It was confirmed that gender-specific reference ranges are required. PMID- 27220061 TI - Spontaneous trait inference and spontaneous trait transference are both unaffected by prior evaluations of informants. AB - This article reports results from a study in which participants encountered either (a) previously known informants who were positive (e.g. Abraham Lincoln), neutral (e.g., Jay Leno), or negative (e.g., Adolf Hitler), or (b) previously unknown informants. The informants ostensibly described either a trait implicative positive behavior, a trait-implicative negative behavior, or a neutral behavior. These descriptions were framed as either the behavior of the informant or the behavior of another person. Results yielded evidence of informant-trait linkages for both self-informants and for informants who described another person. These effects were not moderated by informant type, behavior valence, or the congruency or incongruency between the prior knowledge of the informant and the behavior valence. Results are discussed in terms of theories of Spontaneous Trait Inference and Spontaneous Trait Transference. PMID- 27220062 TI - Oligometastases in AJCC stage IVc nasopharyngeal carcinoma: A subset with better overall survival. AB - BACKGROUND: The purpose of this study was to analyze the patterns of metastasis and therapeutic approaches in American Joint Committee on Cancer (AJCC) stage IVc nasopharyngeal carcinoma (NPC). METHODS: A retrospective analysis of 263 patients with stage IVc NPC revealed the incidence of bone, liver, and lung metastases was 67.7%, 32.3%, and 16.0%, respectively. All patients received chemotherapy; 160 patients received radiotherapy (RT) to the primary tumor. RESULTS: The factors associated with poor overall survival (OS) were Karnofsky Performance Scale (KPS) <=70, liver metastasis, multiple-organ metastasis, >=6 lesions, no RT to the primary tumor, and <4 chemotherapy cycles. Two subgroups of M1 disease were divided into: M1a (oligometastases) = single-organ metastases or 1 to 5 lesions; and M1b = multiple-organ metastases or >=6 lesions. The 5-year OS rates for M1a and M1b were 38.7% versus 7.0%, respectively. CONCLUSION: Patients with oligometastases have significantly better OS than patients with widespread metastases. Long-term disease-free survival can be achieved in selected patients with oligometastases after systemic chemotherapy and definitive RT. (c) 2016 Wiley Periodicals, Inc. Head Neck 38:1152-1157, 2016. PMID- 27220064 TI - The chorionic bump: Etiologic insights from two pathologic pregnancies. AB - The clinical significance and etiology of the chorionic bump remain unclear. We describe two pregnancies characterized by chorionic bumps, which subsequently were diagnosed with a complete mole and trisomy 18, respectively. We hypothesize that placental pathology, including edema and hydropic villi, may contribute to or cause the sonographic finding of some chorionic bumps. An association between chorionic bumps and aneuploidy awaits future study. (c) 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:452-454, 2016. PMID- 27220065 TI - Leoligin, the Major Lignan from Edelweiss (Leontopodium nivale subsp. alpinum), Promotes Cholesterol Efflux from THP-1 Macrophages. AB - Leoligin is a natural lignan found in Edelweiss (Leontopodium nivale ssp. alpinum). The aim of this study was to examine its influence on cholesterol efflux and to address the underlying mechanism of action. Leoligin increases apo A1- as well as 1% human plasma-mediated cholesterol efflux in THP-1 macrophages without affecting cell viability as determined by resazurin conversion. Western blot analysis revealed that the protein levels of the cholesterol efflux transporters ABCA1 and ABCG1 were upregulated, whereas the SR-B1 protein level remained unchanged upon treatment with leoligin (10 MUM, 24 h). Quantitative reverse transcription PCR further uncovered that leoligin also increased ABCA1 and ABCG1 mRNA levels without affecting the half-life of the two mRNAs in the presence of actinomycin D, a transcription inhibitor. Proteome analysis revealed the modulation of protein expression fingerprint in the presence of leoligin. Taken together, these results suggest that leoligin induces cholesterol efflux in THP-1-derived macrophages by upregulating ABCA1 and ABCG1 expression. This novel activity suggests leoligin as a promising candidate for further studies addressing a possible preventive or therapeutic application in the context of atherosclerosis. PMID- 27220066 TI - Cognitive flexibility deficits in a mouse model for the absence of full-length dystrophin. AB - Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disorder, caused by mutations in the DMD gene and the resulting lack of dystrophin. The DMD gene has seven promoters, giving rise to multiple full-length and shorter isoforms. Besides the expression of dystrophin in muscles, the majority of dystrophin isoforms is expressed in brain and dystrophinopathy can lead to cognitive deficits, including intellectual impairments and deficits in executive function. In contrast to the muscle pathology, the impact of the lack of dystrophin on the brain is not very well studied. Here, we study the behavioral consequences of a lack of full-length dystrophin isoforms in mdx mice, particularly with regard to domains of executive functions and anxiety. We observed a deficit in cognitive flexibility in mdx mice in the absence of motor dysfunction or general learning impairments using two independent behavioral tests. In addition, increased anxiety was observed, but its expression depended on the context. Overall, these results suggest that the absence of full-length dystrophin in mice has specific behavioral effects that compare well to deficits observed in DMD patients. PMID- 27220067 TI - Effect of nitrogen regime on microalgal lipid production during mixotrophic growth with glycerol. AB - Mixotrophic growth of microalgae to boost lipid production is currently under active investigation. Such a process could be of practical importance if a cheap source of organic carbon, such as waste glycerol from biodiesel production, could be used. Several previous studies have already demonstrated that this carbon source can be used by different indigenous strains of microalgae. In this study it is shown that different nitrogen limitation strategies can be applied to further increase lipid production during growth with glycerol. In one strategy, cultures were grown in nitrogen replete medium and then resuspended in nitrogen free medium. In a second strategy, cultures were grown with different initial concentrations of nitrate. Lipid production by the two microalgal strains used, Chlorella sorokiniana (PCH02) and Chlorella vulgaris (PCH05), was shown to be boosted by strategies of nitrogen limitation, but they responded differently to how nitrogen limitation was imposed. PMID- 27220068 TI - Accurate diagnosis of latent tuberculosis in children, people who are immunocompromised or at risk from immunosuppression and recent arrivals from countries with a high incidence of tuberculosis: systematic review and economic evaluation. AB - BACKGROUND: Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB) [(Zopf 1883) Lehmann and Neumann 1896], is a major cause of morbidity and mortality. Nearly one-third of the world's population is infected with MTB; TB has an annual incidence of 9 million new cases and each year causes 2 million deaths worldwide. OBJECTIVES: To investigate the clinical effectiveness and cost-effectiveness of screening tests [interferon-gamma release assays (IGRAs) and tuberculin skin tests (TSTs)] in latent tuberculosis infection (LTBI) diagnosis to support National Institute for Health and Care Excellence (NICE) guideline development for three population groups: children, immunocompromised people and those who have recently arrived in the UK from high-incidence countries. All of these groups are at higher risk of progression from LTBI to active TB. DATA SOURCES: Electronic databases including MEDLINE, EMBASE, The Cochrane Library and Current Controlled Trials were searched from December 2009 up to December 2014. REVIEW METHODS: English-language studies evaluating the comparative effectiveness of commercially available tests used for identifying LTBI in children, immunocompromised people and recent arrivals to the UK were eligible. Interventions were IGRAs [QuantiFERON((r))-TB Gold (QFT-G), QuantiFERON((r))-TB Gold-In-Tube (QFT-GIT) (Cellestis/Qiagen, Carnegie, VA, Australia) and T-SPOT.TB (Oxford Immunotec, Abingdon, UK)]. The comparator was TST 5 mm or 10 mm alone or with an IGRA. Two independent reviewers screened all identified records and undertook a quality assessment and data synthesis. A de novo model, structured in two stages, was developed to compare the cost-effectiveness of diagnostic strategies. RESULTS: In total, 6687 records were screened, of which 53 unique studies were included (a further 37 studies were identified from a previous NICE guideline). The majority of the included studies compared the strength of association for the QFT-GIT/G IGRA with the TST (5 mm or 10 mm) in relation to the incidence of active TB or previous TB exposure. Ten studies reported evidence on decision-analytic models to determine the cost-effectiveness of IGRAs compared with the TST for LTBI diagnosis. In children, TST (>= 5 mm) negative followed by QFT-GIT was the most cost-effective strategy, with an incremental cost effectiveness ratio (ICER) of L18,900 per quality-adjusted life-year (QALY) gained. In immunocompromised people, QFT-GIT negative followed by the TST (>= 5 mm) was the most cost-effective strategy, with an ICER of approximately L18,700 per QALY gained. In those recently arrived from high TB incidence countries, the TST (>= 5 mm) alone was less costly and more effective than TST (>= 5 mm) positive followed by QFT-GIT or T-SPOT.TB or QFT-GIT alone. LIMITATIONS: The limitations and scarcity of the evidence, variation in the exposure-based definitions of LTBI and heterogeneity in IGRA performance relative to TST limit the applicability of the review findings. CONCLUSIONS: Given the current evidence, TST (>= 5 mm) negative followed by QFT-GIT for children, QFT-GIT negative followed by TST (>= 5 mm) for the immunocompromised population and TST (>= 5 mm) for recent arrivals were the most cost-effective strategies for diagnosing LTBI that progresses to active TB. These results should be interpreted with caution given the limitations identified. The evidence available is limited and more high-quality research in this area is needed including studies on the inconsistent performance of tests in high-compared with low-incidence TB settings; the prospective assessment of progression to active TB for those at high risk; the relative benefits of two-compared with one-step testing with different tests; and improved classification of people at high and low risk for LTBI. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014009033. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 27220069 TI - Isolation, Structure Elucidation, Biosynthesis, and Synthesis of Antalid, a Secondary Metabolite from Polyangium species. AB - The isolation, structure elucidation, and synthesis of antalid (1), a novel secondary metabolite from Polyangium sp., is described herein. The structure elucidation of 1 was performed with the aid of mass spectrometry, high field NMR experiments, and crystal structure analysis. The absolute configuration of antalid was confirmed through the Mosher ester method and ultimately by total synthesis. In addition, the biosynthetic origin of this hybrid PKS-NRPS natural product was unraveled by the in silico analysis of its biosynthetic gene cluster. PMID- 27220070 TI - Ecological and Pharmacological Activities of Antarctic Marine Natural Products. AB - Antarctic benthic communities are regulated by abundant interactions of different types among organisms, such as predation, competition, etc. Predators are usually sea stars, with omnivorous habits, as well as other invertebrates. Against this strong predation pressure, many organisms have developed all sorts of defensive strategies, including chemical defenses. Natural products are thus quite common in Antarctic organisms with an important ecological and pharmacological potential. In this paper, the chemical defenses of the Antarctic organisms studied during the ECOQUIM and ACTIQUIM projects, as well as their pharmacological potential, are reviewed. For the ecological defenses, predation against the sea star Odontaster validus is analyzed and evaluated along depth gradients as well as considering the lifestyle of the organisms. For the pharmacological activity, the anticancer, anti-inflammatory, and antibacterial activities tested are evaluated here. Very often, only crude extracts or fractions have been tested so far, and therefore, the natural products responsible for such activities remain yet to be identified. Even if the sampling efforts are not uniform along depth, most ecologically active organisms are found between 200 and 500 m depth. Also, from the samples studied, about four times more sessile organisms possess chemical defenses against the sea star than the vagile ones; these represent 50 % of sessile organisms and 35 % of the vagile ones, out of the total tested, being active. Pharmacological activity has not been tested uniformly in all groups, but the results show that relevant activity is found in different phyla, especially in Porifera, Cnidaria, Bryozoa, and Tunicata, but also in others. No relationship between depth and pharmacological activity can be established with the samples tested so far. More studies are needed in order to better understand the ecological relationships among Antarctic invertebrates mediated by natural products and to fully explore their pharmacological potential. PMID- 27220071 TI - Phytochemical Analysis and Antioxidant Potential of the Phytonutrient-Rich Decoction of Cichorium spinosum and C. intybus. AB - The Cretan diet, as the basis of the Mediterranean diet, has provided traditional remedies for the general well being of people through the long-established consumption of cooked wild greens and vegetables. The intake of the water decoctions of Cichorium spinosum and Cichorium intybus in the context of the daily dietary regime in Greece has been long associated with "liver detoxifying" properties. In the current study, we performed an in-depth investigation of the water decoctions traditionally prepared from C. spinosum and C. intybus through qualitative UHPLC-HRMS profiling and direct quantification of cichoric and caftaric acid as major antioxidant components of the decoction. In addition, we developed a one-step countercurrent chromatography method for the isolation of the two phenolic acids, along with a sulfoconjugate sesquiterpene lactone present only in the Cretan C. spinosum. All water decoctions were found not to be cytotoxic in human fibroblasts, whereas they all significantly reduced the intracellular reactive oxygen species, which is consistent with the major presence of strong antioxidant compounds such as cichoric acid. This work demonstrates that the intake of these decoctions in doses suggested by Greek traditional use is comparable to the ingestion of a phytomedical preparation of antioxidants. These results contribute to our current knowledge on the beneficial health effect of the Cretan diet. PMID- 27220072 TI - Evaluation of Antiparasitc Activity of Mentha crispa Essential Oil, Its Major Constituent Rotundifolone and Analogues against Trypanosoma brucei. AB - Considering the pressing need for new drugs to treat sleeping sickness and Nagana disease, Mentha crispa essential oil, its principal constituent rotundifolone, and four related p-menthane-type monoterpenes (two stereoisomers of limonene epoxide, perillyl alcohol, and perillyl aldehyde) were investigated for their activity against bloodstream forms of Trypanosoma brucei. The general cytotoxicity of the compounds was determined with human myeloid HL-60 cells. The effect of the M. crispa essential oil and the monoterpenes on the growth of parasite and human cells was evaluated in cell cultures with the resazurin viability assay. Of all of the compounds tested, M. crispa essential oil, rotundifolone, and perillyl aldehyde showed the highest trypanocidal activities with 50 % growth inhibition (GI50) and minimum inhibitory concentration values of 0.3 ug/mL and 1 ug/mL, respectively. In contrast, HL-60 cells were considerably less sensitive to the compounds with minimum inhibitory concentration values of 100 ug/mL and GI50 values ranging between 3.4 to 13.8 ug/mL. As a consequence of this, GI50 and minimum inhibitory concentration ratios of cytotoxic to trypanocidal activity (selectivity index) of these three compounds were promising with values of 11-45 and 100, respectively. These results indicate that the p menthane-type monoterpenes rotundifolone and perillyl aldehyde are interesting lead candidates for further rational antitrypanosomal drug development. PMID- 27220073 TI - Therapeutic Potential of Hydroxypropyl-beta-Cyclodextrin-Based Extract of Medicago sativa in the Treatment of Mucopolysaccharidoses. AB - Mucopolysaccharidoses are inherited metabolic disorders resulting in the dysfunction of enzymes involved in the degradation of glycosaminoglycans, leading to severe clinical symptoms and a significantly shortened life span of patients. Flavonoids are recognized as glycosaminoglycan metabolism modulators, able to correct glycosaminoglycan cell storage. Therefore, the aim of this work was the development of an efficient and eco-friendly extraction process of phytochemicals from Medicago sativa by simultaneous use of ultrasound extraction and hydroxypropyl-beta-cyclodextrin complexation, and investigation of the potential of such an extract as a glycosaminoglycan metabolism modulator. The Box-Behnken design and response surface methodology were used in order to optimize the extraction process, considering hydroxypropyl-beta-cyclodextrin concentration, ultrasonic power, and extraction time as the key parameters. The dependent variables included total phenolicand total flavonoid content, DPPH radical scavenging activity, and Fe2+ chelating activity, due to the importance of oxidative stress in the pathology of mucopolysaccharidoses. The developed technology using hydroxypropyl-beta-cyclodextrin led to more selective flavonoid extraction from M. sativa than obtained either by the use of water or ethanol. The lyophilization of extracts resulted in products with high radical scavenging activity, suitable for further use. The application of 20 mM hydroxypropyl-beta cyclodextrin solution, 432 W ultrasonic power, and an extraction time of 45 min resulted in an extract with both the highest total flavonoid content and the lowest radical scavenging activity IC50. This extract reduced the levels of glycosaminoglycans in skin fibroblasts of mucopolysaccharidose III patient in a dose-dependent manner. At concentrations of 3 and 6 ug/mL, the observed levels of glycosaminoglycans were reduced by 41.2 and 51.1 %, respectively, clearly demonstrating the validity of the selected approach. PMID- 27220074 TI - Diarylheptanoids from Alnus viridis ssp. viridis and Alnus glutinosa: Modulation of Quorum Sensing Activity in Pseudomonas aeruginosa. AB - Diarylheptanoids from the barks of Alnus viridis ssp. viridis (green alder) and Alnus glutinosa (black alder) were explored for anti-quorum sensing activity. Chemicals with anti-quorum sensing activity have recently been examined for antimicrobial applications. The anti-quorum sensing activity of the selected diarylheptanoids was determined using two biosensors, namely Pseudomonas aeruginosa PAO1 and Chromobacterium violaceum CV026. Although all of the investigated compounds negatively influenced the motility of P. aeruginosa PAO1, four were able to inhibit biofilm formation of this human opportunistic pathogen for 40-70 %. Three of the diarylheptanoids (3, 4, and 5) negatively influenced the biosynthesis of pyocyanin, which is under the control of quorum sensing. Platyphyllenone (7) and hirsutenone (5) were able to inhibit the biosynthesis of violacein in C. violaceum CV026, with 5 being able to inhibit the synthesis of both biopigments. Only one of the tested diarylheptanoids (1) was shown to significantly decrease the production of acyl homoserine lactones (AHL) in P. aeruginosa PAO1, more specifically, production of the long chain N-(3 oxododecanoyl)-l-HSL. On the other side, four diarylheptanoids (2-5) significantly reduced the synthesis of 2-alkyl-4-quinolones, part of the P. aeruginosa quinolone-mediated signaling system. To properly assess therapeutic potential of these compounds, their in vitro antiproliferative effect on normal human lung fibroblasts was determined, with doses affecting cell proliferation between 10 and 100 ug/mL. This study confirms that the barks of green and black alders are rich source of phytochemicals with a wide range of biological activities that could further be exploited as natural agents against bacterial contaminations and infections. PMID- 27220075 TI - The Protective Potential of Phyllanthus niruri and Corilagin on Gastric Lesions Induced in Rodents by Different Harmful Agents. AB - The gastroprotective effect of the methanol extract of Phyllantus niruri and its main constituent, corilagin, were studied in vivo. The extract (50, 125, or 250 mg/kg, p. o.) inhibited ethanol-induced lesions in rats by 43 % (p < 0.001), 69 % (p < 0.001), and 99 % (p < 0.001), respectively. It also inhibited the formation of indomethacin-induced gastric ulcers in rats by 80 % (p < 0.01), 89 % (p < 0.01), and 97 % (p < 0.01). A decrease in lipid hydroperoxide levels (p < 0.01) and in myeloperoxidase activity (p < 0.05) evidenced a reduction of oxidative damage and neutrophil infiltration in gastric tissues from ulcerated mice using ethanol/HCl. Potent in vitro free radical scavenger activity (IC50 = 0.07) using the DPPH assay was observed. In contrast, the extract (250 mg/kg, i. d.) did not show antisecretory activity in pylorus-ligated rats, and also failed to inhibit the H+,K+-ATPase activity in vitro. However, in pylorus-ligated rats, the extract (50, 125, and 250 mg/kg, i. d.) increased adhered mucus content by 22 % (p < 0.05), 28 % (p < 0.01), and 38 % (p < 0.01), respectively. The involvement of prostaglandins, nonprotein endogenous sulfhydryl compounds, alpha2-receptors, and endogenous nitric oxide in the gastroprotection elicited by the extract was also evaluated. Finally, corilagin reduced the lesion area of ethanol-induced gastric ulcers in mice by 88 % (30 mg/kg, p. o.; p < 0.001). Based on these results, it has been concluded that P. niruri methanol extract possesses gastroprotective activity by different and complementary pathways, which together promote an improvement in gastric cytoprotection. The presence of corilagin may partially explain the effectiveness of the extract against gastric damage. PMID- 27220076 TI - Cytotoxic Steroidal Glycosides from the Whole Plant of Calamus acanthophyllus. AB - A new steroidal glycoside, callaphylloside (1), together with seven known glycosides (2-8), was isolated from the whole plant of Calamus acanthophyllus. The structure of the new compound was elucidated by spectral data analyses and chemical transformations. Compounds 5 and 8 exhibited strong cytotoxic activity against four cancer cell lines (0.7 <= IC50 <= 3.4 uM). Evaluation of the structure-activity relationship among steroidal glycosides revealed that the structure of spirostanol with an alpha-L-rhamnopyranosyl linked to C-2 of the inner glucopyranosyl residue both play a critical role in the effects of these compounds on the cancer cell lines. PMID- 27220077 TI - Characterization of the XIAP-Inhibiting Proanthocyanidin Fraction of the Aerial Parts of Ephedra sinica. AB - The X-linked inhibitor of apoptosis protein is a cellular protein that inhibits the activity of mammalian caspases and promotes resistance to apoptosis. The ethanol extract of the aerial parts of Ephedra sinica has been identified to possess inhibitory activity of the X-linked inhibitor of apoptosis protein by an in vitro fluorescence polarization assay using the BIR3 domain of the X-linked inhibitor of apoptosis protein. Bioactivity-guided fractionation identified proanthocyanidin-enriched fractions as the active principles. The most active fraction showed an IC50 value of 27.3 ug/mL (CI95: 25.9-28.9 ug/mL) corresponding to 9.6 uM (CI95: 9.1-10.1 uM) calculated by the use of the determined average molecular weight of 2853.5. Samples were analyzed by a thiolytic degradation/HPLC MS assay, UHPLC-HRMS, and 1D NMR.The thiolytic degradation/HPLC-MS assay revealed a mean degree of polymerization of 9.5 +/- 0.2 units (calculated average MW 2853.5) for the active fraction and 11.4 +/- 0.6 units (calculated average MW 3437.0) for the most related inactive fraction. Chemical characterization identified (epi)gallocatechin (76.6 +/- 1.0 % active; 80.7 +/- 2.7 % inactive sample) and (epi)catechin units as building blocks. Interestingly, the investigated proanthocyanidins turned out to be a complex mixture of double linked A-type (binding 2-O-7", 4-6") and single linked B-type units.This study identified oligomeric proanthocyanidins as active principles of E. sinica in vitro by a fluorescence polarization assay and via protein fragment complementation analysis. PMID- 27220078 TI - Enhancing Topical Delivery of Resveratrol through a Nanosizing Approach. AB - Resveratrol is a naturally occurring polyphenol with strong antioxidant and free radical scavenging properties, recently proposed as a therapeutic agent for skin diseases. In this study, we investigated the possibility of improving the dermal bioavailability of the poorly water-soluble drug resveratrol by nanocrystal technology. To this purpose, nanosuspensions were prepared by the wet media milling technique, using Poloxamer 188 or Tween 80 as stabilizers, and characterized by means of both solid state and morphological and dimensional studies. All analytical data demonstrated that neither a modification of the drug crystalline pattern nor the isomerization of the trans double bond were observed after the wet media milling particle size reduction process, which produced rounded and smooth nanocrystals with a mean diameter ranging between 0.2-0.3 um. Resveratrol skin delivery from nanosuspension formulations was evaluated by the pig ear skin model via tape stripping. Results of the experiments showed that after application of nanosuspension formulations, higher amounts of resveratrol could penetrate the skin at deeper levels compared to drug coarse suspensions. The antioxidant activity of resveratrol in nanocrystals was assessed by the DPPH assay, which demonstrated that the size reduction process as well as the formulation compositions did not modify the drug antioxidant activity. PMID- 27220079 TI - Chemical Constituents from Campylotropis hirtella. AB - A phytochemical investigation on the roots of Campylotropis hirtella afforded nine new isoflavones (3-9, 12, 15), two new isoflavans (10 and 11), one new coumestan (1), and three new prenylated benzoic acid derivatives (2, 13, 14), together with twenty-four known compounds. Their structures were established by spectroscopic analysis and circular dichroism data. The isolated compounds were also evaluated for their antibacterial activities against Enterococcus faecalis, Salmonella gallinarum, Streptococcus suis, Streptococcus agalactiae, Aeromonas hydrophila, Pseudomonas aeruginosa, Bacillus subtilis, Riemerella anatipestifer, and Vibrio alginolyticus. PMID- 27220080 TI - Cytochromes P450 Inhibitory Excipient-Based Self-Microemulsions for the Improved Bioavailability of Protopanaxatriol and Protopanaxadiol: Preparation and Evaluation. AB - Protopanaxatriol and protopanaxadiol exhibit limited oral bioavailability due to the poor solubility and intestinal cytochromes P450-mediated metabolism. This study set out to develop a novel cytochromes P450 inhibitory excipient(s)-based self-microemulsion to encapsulate protopanaxatriol and protopanaxadiol so as to enhance the in vivo bioavailability by inhibiting intestinal metabolism. After screening the inhibitory effect of pharmaceutical excipients on the cytochromes P450-mediated metabolism, two self-microemulsions, SME-1 and SME-2, with similar physicochemical properties were prepared by using either active inhibitory excipients or corresponding inactive excipients. The results showed that no significant difference existed in the profiles of in vitro release, cellular uptake, and permeability in Caco-2 cells, and in vivo lymphatic transport between self-microemulsion-1 and self-microemulsion-2. The in vivo pharmacokinetic experiments indicated that self-microemulsion-1 conferred to significantly higher absolute bioavailability of protopanaxatriol (19.55 %) and protopanaxadiol (100.07 %) than those of the free drug (2.21 % and 23.70 %, respectively) or of self-microemulsion-2 (4.95 % and 45.35 %, respectively). The present work demonstrated that the presence of cytochromes P450 inhibitory excipients in self microemulsion-1 tended to inhibit intestinal cytochromes P450-mediated metabolism and subsequently improved the oral bioavailability of protopanaxatriol and protopanaxadiol. PMID- 27220081 TI - Bryophyllum pinnatum and Related Species Used in Anthroposophic Medicine: Constituents, Pharmacological Activities, and Clinical Efficacy. AB - Bryophyllum pinnatum (syn. Kalanchoe pinnata) is a succulent perennial plant native to Madagascar that was introduced in anthroposophic medicine in the early 20th century. In recent years, we conducted a large collaborative project to provide reliable data on the chemical composition, pharmacological properties, and clinical efficacy of Bryophyllum. Here, we comprehensively review the phytochemistry, as well as the pharmacological and clinical data. As to the pharmacology, special emphasis is given to properties related to the use in anthroposophic medicine as a treatment for "hyperactivity diseases", such as preterm labor, restlessness, and sleep disorders. Studies suggesting that B. pinnatum may become a new treatment option for overactive bladder syndrome are also reviewed. Tolerability is addressed, and toxicological data are discussed in conjunction with the presence of potentially toxic bufadienolides in Bryophyllum species. The few data available on two related species with medicinal uses, Bryophyllum daigremontianum and Bryophyllum delagoense, have also been included. Taken together, current data support the use of B. pinnatum for the mentioned indications, but further studies are needed to fully understand the modes of action, and to identify the pharmacologically active constituents. PMID- 27220082 TI - Review - Lichen-Associated Bacteria as a Hot Spot of Chemodiversity: Focus on Uncialamycin, a Promising Compound for Future Medicinal Applications. AB - This review presents the state of knowledge on the medicinal potential of bacteria associated with lichens. In fact, besides the classical symbiotic partners (photobiont and mycobiont) forming the lichen thallus, associated bacteria have been recently described as a third partner. Various studies demonstrated the diversity of these communities with a predominance of Alphaproteobacteria. Bacterial groups more relevant for secondary metabolite synthesis have also been revealed. This article summarizes studies reporting the abilities of these communities to produce metabolites with relevant bioactivities. The biotechnological interest of these bacteria for drug discovery is highlighted regarding the production of compounds with therapeutic potential. Special focus is given to the synthesis of the most promising compound, uncialamycin, a potent enediyne isolated from a Streptomyces sp. associated with Cladonia uncialis. PMID- 27220083 TI - Secondary Metabolites from the Marine Algal-Derived Endophytic Fungi: Chemical Diversity and Biological Activity. AB - Marine algal-derived endophytic fungi have attracted considerable attention in the most recent two decades due to their prolific production of structurally diverse secondary metabolites with various biological activities. This review summarizes a total of 182 natural products isolated from marine algal-derived endophytic fungi in the past two decades. The emphasis is on the unique chemical diversity of these metabolic products, together with relevant biological activities. PMID- 27220084 TI - A fluorometric assay platform for caffeic acid detection based on the G quadruplex/hemin DNAzyme. AB - In this paper, a fluorometric assay platform for fluorescence detection of caffeic acid was designed based on the peroxidase-mimicking activities of G quadruplex/hemin DNAzyme. Under the catalysis of the formed G-quadruplex/hemin complex, H2O2 could be decomposed into hydroxyl radicals with strong oxidation properties. Then caffeic acid would be oxidized by the released hydroxyl radicals, resulting in the product caffeic acid-quinone. Normally, caffeic acid has no influence on the fluorescence of graphene quantum dots. But when mixed with the G-quadruplex/hemin complex and H2O2, the fluorescence of graphene quantum dots was obviously quenched by the oxidized caffeic acid. Under the optimized experimental conditions, the quenched fluorescence intensity was linearly correlated with the concentration of caffeic acid, ranging from 2 MUM to 350 MUM with a detection limit of 200 nM. The proposed method was applied to the determination of caffeic acid in human serum samples with satisfactory results. PMID- 27220085 TI - A One-Pot Synthesis of N-Aryl-2-Oxazolidinones and Cyclic Urethanes by the Lewis Base Catalyzed Fixation of Carbon Dioxide into Anilines and Bromoalkanes. AB - The multicomponent assembly of pharmaceutically relevant N-aryl-oxazolidinones through the direct insertion of carbon dioxide into readily available anilines and dibromoalkanes is described. The addition of catalytic amounts of an organosuperbase such as Barton's base enables this transformation to proceed with high yields and exquisite substrate functional-group tolerance under ambient CO2 pressure and mild temperature. This report also provides the first proof-of principle for the single-operation synthesis of elusive seven-membered ring cyclic urethanes. PMID- 27220086 TI - Physical activity profiles and selected muscular fitness variables in English schoolchildren: A north-south divide? AB - The aim of the study was to compare and contrast habitual physical activity (PA) profiles and muscular fitness in schoolchildren from northern and southern regions of England. Data were collected from two secondary schools in the north east (NE) of England. The study procedures followed methods employed by the East of England Healthy Hearts Study in 10-16-year-old boys and girls based in the south east (SE) region of England and data were compared. Habitual physical activity (PAQ-A), vertical jump test, and hand-grip (HG) strength were assessed. We converted raw scores from all assessments to age- and sex-normalised z-scores. We recruited 597 children (58% boys) in the NE and compared findings to 597 age- and sex-matched boys and girls from the SE. Boys in the SE had significantly stronger HG scores, jumped higher, were more powerful (mean peak power: 2131 W vs. 1782 W; P < 0.0001), and reported being more physically active (mean PAQ-A: 2.9 vs. 2.5; P < 0.0001) than their male counterparts in the NE. In girls, the opposite trend was evident. Girls from the NE of England had a higher HG score, jumped higher, and were more powerful (mean peak power: 2114 W vs. 1839 W; P < .0001) than their peers from the SE. Regional variations in the habitual PA profiles and muscular fitness of schoolchildren from the SE and NE of England do exist. The systematic surveillance of children's PA and fitness profiles throughout England would help identify regional inequalities on a larger scale. PMID- 27220087 TI - Inflammatory bowel disease: exploring gut pathophysiology for novel therapeutic targets. AB - Ulcerative colitis and Crohn's disease are the 2 major phenotypes of inflammatory bowel disease (IBD), which are influenced by a complex interplay of immunological and genetic elements, though the precise etiology still remains unknown. With IBD developing into a globally prevailing disease, there is a need to explore new targets and a thorough understanding of the pathophysiological differences between the healthy and diseased gut could unearth new therapeutic opportunities. In this review, we provide an overview of the major aspects of IBD pathogenesis and thereafter present a comprehensive analysis of the gut pathophysiology leading to a discussion on some of the most promising targets and biologic therapies currently being explored. These include various gut proteins (CXCL-10, GATA-3, NKG2D, CD98, microRNAs), immune cells recruited to the gut (mast cells, eosinophils, toll-like receptors 2, 4), dysregulated proinflammatory cytokines (interleukin-6, -13, -18, -21), and commensal microbiota (probiotics and fecal microbiota transplantation). We also evaluate some of the emerging nonconventional therapies being explored in IBD treatment focusing on the latest developments in stem cell research, oral targeting of the gut-associated lymphoid tissue, novel anti-inflammatory signaling pathway targeting, adenosine deaminase inhibition, and the beneficial effects of antioxidant and nutraceutical therapies. In addition, we highlight the growth of biologics and their targets in IBD by providing information on the preclinical and clinical development of over 60 biopharmaceuticals representing the state of the art in ulcerative colitis and Crohn's disease drug development. PMID- 27220088 TI - Bleeding complications of triple antithrombotic therapy after percutaneous coronary interventions. AB - BACKGROUND: 5% of patients undergoing coronary stenting have an indication for anticoagulation. The aim of our study was to determine the bleeding rates and complications in patients on triple oral antithrombotic therapy (TOAT) after coronary stenting. METHODS: We studied patients who underwent coronary stenting in our institution between 2003-2013 and were started on TOAT. Bleeding was the primary outcome. RESULTS: Totally, 999 patients were treated with TOAT with a median follow up of 127 days. All patients were treated with warfarin as an anticoagulant. 267 patients (26.7%) developed a total of 331 bleeding events. 100 patients had bleeding during the first 30 days of therapy. Major bleeding, minor bleeding, bleeding requiring medical attention, and minimal bleeding developed in 2.9%, 3.3%, 17.2%, and 3.3% of the patients respectively as their most significant bleeding event. Patients with anticoagulation initiated at time of stenting had a significantly higher bleeding rate compared to those already on chronic anticoagulation [adjusted HR (95% CI): 1.37 (1.03-1.79), P = 0.03]. The bleeding likelihood was significantly higher for patients with drug-eluted stents (DES) compared to bare-metal stents (BMS) [adjusted OR (95% CI): 1.52 (1.14 - 2.04), P < 0.05]. Patients with atrial fibrillation had an increased rate of bleeding after 6 month of initiation of TOAT with significantly worse outcomes. CONCLUSIONS: TOAT after coronary stenting is associated with high bleeding rates. Patients with AF had worse outcomes. Patients with newly initiated anticoagulation at time of stenting bleed significantly more than people already on chronic anticoagulation prior to stenting. (c) 2016 Wiley Periodicals, Inc. PMID- 27220089 TI - The impact velocity and bone fracture pattern: Forensic perspective. AB - Studies on bone-energy interaction are meager and revealed only a general correlation between the fracture pattern and the mechanism of the insult. This study has two objectives, to establish a usable fracture analysis method and to reveal the association between the energy of the force and the fracture pattern. Dynatup Model POE 2000 (Instron Co.) low energy pendulum impact machine was utilized to apply impact loading on fresh pig femoral bones (n=30). The bone clamp shaft was adjusted to position the bone for three-point bending with additional bone compression. Three different velocities of the forced applied were carried out. On average, the number, length and the curviness of the fracture lines created under moderate and high-energy impact is significantly higher compared to a low-energy impact. Most fractures lines were located on the impacted aspect in bones subjected to moderate- and high-velocity impact. Four oblique-radial fracture lines running from the point of impact creating a double butterfly pattern were found in bones subjected to moderate and high-velocity impact. Only "false" wedge-shaped (butterfly) fragments were found in the current study. Our results suggest an association between fracture pattern and the velocity of the impact. PMID- 27220090 TI - Performance of vegetated swales for improving road runoff quality in a moderate traffic urban area. AB - In recent years, due to their economic and ecological advantages, green infrastructures for stormwater management have been widely implemented. The present study focused on vegetated swales and compared two vegetated covers, grassed or planted with macrophytes in order to evaluate their performance in terms of water quality improvement. These swales collected runoff of a moderately busy road (<2500vehday(-1)) in a commercial area. Twelve storm events were analyzed over a two year period with measurement of total suspended solids (TSS), chemical oxygen demand (COD), biochemical oxygen demand (BOD), total hydrocarbons (THC), total phosphorous (TP), total Kjeldahl nitrogen (TKN), trace elements and 16 polycyclic aromatic hydrocarbons (PAHs). The grass cover led to poor results due to lower retention of soil particles on which trace elements and PAHs are bounded. The swales planted with macrophytes, with a deeper root system more capable of retaining soil particles, led to reductions of concentrations from 17 to 45% for trace elements such as lead, zinc and copper and 30% for the 16 PAHs in infiltrated waters. In addition, the macrophyte cover showed lower variability of pollutant concentrations in infiltrated waters compared to incoming waters. This buffering capacity is interesting to mitigate the impact of moderate peak pollution on surface water or ground water quality. PMID- 27220091 TI - Estimation of health and economic costs of air pollution over the Pearl River Delta region in China. AB - The Pearl River Delta region (PRD) is the economic growth engine of China and also one of the most urbanized regions in the world. As a two-sided sword, rapid economic development causes air pollution and poses adverse health effects to the citizens in this area. This work estimated the negative health effects in the PRD caused by the four major ambient pollutants (SO2, NO2, O3 and PM10) from 2010 to 2013 by using a log linear exposure-response function and the WRF-CMAQ modeling system. Economic loss due to mortality and morbidity was evaluated by the value of statistical life (VSL) and cost of illness (COI) methods. The results show that the overall possible short-term all-cause mortality due to NO2, O3 and PM10 reached the highest in 2013 with the values being 13,217-22,800. The highest total economic loss, which ranged from 14,768 to 25,305million USD, occurred in 2013 and was equivalent to 1.4%-2.3% of the local gross domestic product. The monthly profile of cases of negative health effects varied by city and the types of ambient pollutants. The ratio of mortality attributed to air pollutants to total population was higher in urban areas than in rural areas. People living in the countryside should consider the possible adverse health effects of urban areas before they plan a move to the city. The results show that the health burden caused by the ambient pollutants over this region is serious and suggest that tighter control policies should be implemented in the future to reduce the level of air pollution. PMID- 27220092 TI - Toxicological studies for adults and children of insecticide residues with common mode of action (MoA) in pome, stone, berries and other small fruit. AB - The presence of pesticide residues in fruit is a serious health concern. This paper for the first time demonstrated the Hazard Index (HI) method to carry out acute, chronic and cumulative health risk assessment to the 14 groups of insecticides for three subpopulations. The challenge of this study was to present results from a long period of research (years 2005-2014) with toxicological aspects, especially in multiresidue samples. Near 1000 fresh pome, stone, berries and small fruit were prepared by two accredited MSPD and QuEChERS methods followed by liquid and gas chromatography analyses with various systems of detection ECD/NPD/MS/MS. Twenty percent of the fruit samples contained 16 insecticide residues in the range of 0.01-0.81mg/kg and 3% over MRL. The class of pesticide with the highest contribution to the ADI was found to be OPPs: dimethoate and diazinon for adults 48% and 66% of the ADI whereas for infants 144% and 294% of the ADI. The highest contributions of the cHQ to common MoA pesticides were AChE inhibitors: 135% for adults and 528% for infants, sodium channel modulators 4.9% and 20%, nicotic acetylocholine receptor <2.9% and <10.6% for adults and infants, respectively. The fruit with the highest contribution to the ADI were found to be apples (316%, 58%), cherries (96%, 37%) and pears (129%, 33%) for infants and adults. The study findings indicated that dietary exposures to insecticide residues in fruit would be unlikely to pose unacceptable health risks for the infants, toddlers and adults. PMID- 27220093 TI - Personality traits and environmental choices: On the search for understanding. AB - In this paper we hypothesize that individuals will choose among alternative courses of action for power generation from wind farms according to their personality profiles. Through a factor analysis we found that certain characteristics of personality do indeed have an effect on environmental choice. The study involves an extensive survey based on the Big Five Traits model to find a pattern of choice that will help to better understand environmental decisions and be useful for policy makers to identify target groups and preview reactions to different courses of action. The research is potentially useful for the better preparation and design of publicity material, awareness raising campaigns and information provision for complex or unpopular policies affecting the environment or in environmental education in general. This research is especially interested in shedding some light on how personality is involved in the processes of environmental decision making, despite the limitations of the present study. PMID- 27220094 TI - Solar and atmospheric forcing on mountain lakes. AB - We investigated the influence of long-term external forcing on aquatic communities in Alpine lakes. Fossil microcrustacean (Cladocera) and macrobenthos (Chironomidae) community variability in four Austrian high-altitude lakes, determined as ultra-sensitive to climate change, were compared against records of air temperature, North Atlantic Oscillation (NAO) and solar forcing over the past ~400years. Summer temperature variability affected both aquatic invertebrate groups in all study sites. The influence of NAO and solar forcing on aquatic invertebrates was also significant in the lakes except in the less transparent lake known to have remained uniformly cold during the past centuries due to summertime snowmelt input. The results suggest that external forcing plays an important role in these pristine ecosystems through their impacts on limnology of the lakes. Not only does the air temperature variability influence the communities but also larger-scale external factors related to atmospheric circulation patterns and solar activity cause long-term changes in high-altitude aquatic ecosystems, through their connections to hydroclimatic conditions and light environment. These findings are important in the assessment of climate change impacts on aquatic ecosystems and in greater understanding of the consequences of external forcing on lake ontogeny. PMID- 27220095 TI - Continuous measurement of soil carbon efflux with Forced Diffusion (FD) chambers in a tundra ecosystem of Alaska. AB - Soil is a significant source of CO2 emission to the atmosphere, and this process is accelerating at high latitudes due to rapidly changing climates. To investigate the sensitivity of soil CO2 emissions to high temporal frequency variations in climate, we performed continuous monitoring of soil CO2 efflux using Forced Diffusion (FD) chambers at half-hour intervals, across three representative Alaskan soil cover types with underlying permafrost. These sites were established during the growing season of 2015, on the Seward Peninsula of western Alaska. Our chamber system is conceptually similar to a dynamic chamber, though FD is more durable and water-resistant and consumes less power, lending itself to remote deployments. We first conducted methodological tests, testing different frequencies of measurement, and did not observe a significant difference between collecting data at 30-min and 10-min measurement intervals (averaged half-hourly) (p<0.001). Temperature and thaw depth, meanwhile, are important parameters in influencing soil carbon emission. At the study sites, we observed cumulative soil CO2 emissions of 62.0, 126.3, and 133.5gCm(-2) for the growing period, in sphagnum, lichen, and tussock, respectively, corresponding to 83.8, 63.7, and 79.6% of annual carbon emissions. Growing season soil carbon emissions extrapolated over the region equated to 0.17+/-0.06 MgC over the measurement period. This was 47% higher than previous estimates from coarse resolution manual chamber sampling, presumably because it better captured high efflux events. This finding demonstrates how differences in measurement method and frequency can impact interpretations of seasonal and annual soil carbon budgets. We conclude that annual CO2 efflux-measurements using FD chamber networks would be an effective means for quantifying growing and non-growing season soil carbon budgets, with optimal pairing with time-lapse imagery for tracking local and regional changes in environment and climate in a warming Arctic. PMID- 27220096 TI - The erosion of the beaches on the coast of Alicante: Study of the mechanisms of weathering by accelerated laboratory tests. AB - One of the main problems that coasts around the world present, is the regression and erosion of beaches. However, the factors involved in these processes are unclear. In this study, the influence of sediment erosion on beach regression has been analysed. In order to do that, a three-step investigation has been carried out. Firstly, coastline variations of four Spanish beaches have been analysed. Secondly, a study on sediment position along the beach profile has been developed. Finally, the process that beach sediments undergo along the surf zone when they are hit by the incident waves has been simulated by an accelerated particle weathering test. Samples of sand and shells were subjected to this accelerated particle weathering test. Results were supplemented with those from carbonate content test, XRD, SEM and granulometric analysis. Results shows a cross-shore classification of sediments along the beach profile in which finer particles move beyond offshore limit. Besides, it was observed that sediment erosion process is divided into three sages: i) particles wear due to crashes ii) dissolution of the carbonate fraction, and iii) breakage and separation of mineral and carbonate parts of particles. All these processes lead to a reduction of particle size. The mechanism responsible of beach erosion would consist of multiples and continuous particle location exchanges along the beach profile as a consequence of grain-size decrease due to erosion. PMID- 27220097 TI - Shifting paradigms in coastal restoration: Six decades' lessons from China. AB - With accelerating degradation of coastal environment worldwide, restoration has been elevated as a global strategy to enhance the functioning and social services of coastal ecosystems. While many developing countries suffer from intense coastal degradation, current understanding of the science and practice of their coastal restorations is extremely limited. Based on analysis of >1000 restoration projects, we provide the first synthesis of China's coastal restorations. We show that China's coastal restoration has recently entered a rapidly developing stage, with an increasing number of restoration projects carried out in multiple types of coastal ecosystems. While long-term, national-level restorations enforced by the government appear promising for some coastal ecosystems, especially mangroves, restorations of many other coastal ecosystems, such as salt marshes, seagrasses and coral reefs, have been much less implemented, likely due to under appreciation of their ecosystem services values. Furthermore, the planning, techniques, research/assessment, and participation models underlying current restorations remain largely inadequate for restoration to effectively halt rapid coastal degradation. To promote success, we propose a framework where paradigms in current restorations from planning to implementation and assessment are transformed in multiple ways. Our study has broad implications for coastal environmental management policies and practices, and should inform sustainable development of coupled human-ocean systems in many countries. PMID- 27220098 TI - Plant diversity moderates drought stress in grasslands: Implications from a large real-world study on (13)C natural abundances. AB - Land-use change and intensification play a key role in the current biodiversity crisis. The resulting species loss can have severe effects on ecosystem functions and services, thereby increasing ecosystem vulnerability to climate change. We explored whether land-use intensification (i.e. fertilization intensity), plant diversity and other potentially confounding environmental factors may be significantly related to water use (i.e. drought stress) of grassland plants. Drought stress was assessed using delta(13)C abundances in aboveground plant biomass of 150 grassland plots across a gradient of land-use intensity. Under water shortage, plants are forced to increasingly take up the heavier (13)C due to closing stomata leading to an enrichment of (13)C in biomass. Plants were sampled at the community level and for single species, which belong to three different functional groups (one grass, one herb, two legumes). Results show that plant diversity was significantly related to the delta(13)C signal in community, grass and legume biomass indicating that drought stress was lower under higher diversity, although this relation was not significant for the herb species under study. Fertilization, in turn, mostly increased drought stress as indicated by more positive delta(13)C values. This effect was mostly indirect by decreasing plant diversity. In line with these results, we found similar patterns in the delta(13)C signal of the organic matter in the topsoil, indicating a long history of these processes. Our study provided strong indication for a positive biodiversity-ecosystem functioning relationship with reduced drought stress at higher plant diversity. However, it also underlined a negative reinforcing situation: as land-use intensification decreases plant diversity in grasslands, this might subsequently increases drought sensitivity. Vice-versa, enhancing plant diversity in species-poor agricultural grasslands may moderate negative effects of future climate change. PMID- 27220099 TI - The role of mangrove revegetation as a means of restoring macrofaunal communities along degraded coasts. AB - As coastal habitats face unprecedented pressure globally, there is a need to better understand how revegetation can fortify or restore biodiversity. We examined the early-stage outcomes of mangrove revegetation efforts for benthic invertebrate communities within degraded mangrove habitats in south eastern Brazil. We followed changes in macrofaunal abundance and species richness within small-scale Avicennia schaueriana revegetation plots over a 12month period. The assemblages of revegetation plots (RP) became progressively more diverse when compared to structural (SC) and blank controls (BC). The trajectory of change also differed with RP communities demonstrating convergence with those of remnant mangrove forest. After 12months, RP had greater abundances of crustaceans (41%) and polychaetes (13%) as well as higher but variable numbers of gastropods and bivalves than both SC and BC. A spatial examination of revegetation outcomes showed that success may vary across sheltered vs. exposed coastal microhabitats. Indeed, subsequent analysis using generalised linear mixed models pointed to a stronger influence of tidal height, than many of the commonly attributed sedimentary variables such as grain-size and organic matter content as determinants of community structure. Given the encouraging results of this study, we advocate an intensification of revegetation initiatives to augment natural recovery, increase benthic biodiversity and restore ecosystems services to degraded coasts. PMID- 27220100 TI - Identification of chemical compositions and sources of atmospheric aerosols in Xi'an, inland China during two types of haze events. AB - High time resolution (1h) of TSP filter samples was collected in Xi'an in inland China from December 5 to 13, 2012, during which a 9-day long of haze episode occurred. The hazy days were classified as two types, i.e., Light-haze period with moderate degradation in visibility (5-10km) and relatively dry conditions (RH: 53+/-19%) and Severe-haze period with a daily visibility less than 5km and humid conditions (RH: 73+/-14%). TSP in the two periods (415+/-205 and 530+/ 180MUgm(-3) in Light-haze and Severe-haze periods, respectively) was comparable, but crustal Fe and Ca elements presented higher concentrations and strong correlation (R(2)=0.72) with TSP in Light-haze period. SO4(2-), NO3(-) and NH4(+) in Light-haze period were 16+/-5.9, 12+/-6.7 and 4.1+/-2.8MUgm(-3), respectively, and increased dramatically to 51+/-15, 44+/-9.7 and 23+/-5.6MUgm(-3) in Severe haze period. Contributions of Fe and Ca to TSP decreased from 9.2% in Light-haze period to 5.3% in Severe-haze period, but those of SO4(2-), NO3(-) and NH4(+) increased from 3.8%, 2.9% and 1.0% in Light-haze period to 9.6%, 8.3% and 4.4% in Severe-haze period, respectively. These results suggest that dust-derived particles were more significant in Light-haze period while secondary aerosols were more important in Severe-haze period. Hopanes (33+/-24 and 38+/-29ngm(-3) in Light-haze and Severe-haze periods, respectively) during the two types of haze periods are comparable, indicating that differences in contribution of primary organic aerosols from fossil fuel combustions to TSP were insignificant. In contrast, the ratio of secondary organic aerosols (e.g., o-phthalic acid) to EC was much higher in Severe-haze period (5.8+/-2.7ngMUg(-1)) than in Light-haze period (3.4+/-2.1ngMUg(-1)), probably indicating that the humid conditions in Severe-haze period are favorable for secondary organic aerosol formation. PMID- 27220101 TI - Trace elements and Pb isotopes in soils and sediments impacted by uranium mining. AB - The purpose of this study is to evaluate the contamination in As, Ba, Co, Cu, Mn, Ni, Sr, V, Zn and REE, in a high uranium activity (up to 21,000Bq?kg(-1)) area, downstream of a former uranium mine. Different geochemical proxies like enrichment factor and fractions from a sequential extraction procedure are used to evaluate the level of contamination, the mobility and the availability of the potential contaminants. Pb isotope ratios are determined in the total samples and in the sequential leachates to identify the sources of the contaminants and to determine the mobility of radiogenic Pb in the context of uranium mining. In spite of the large uranium contamination measured in the soils and the sediments (EF?40), trace element contamination is low to moderate (2 0.8 for the early study years), was not directly related to resource availability or previous-year breeding success. Local recruitment decreased rapidly at a threshold population size, however, when other satellite colonies became established at Dofiana. Our study suggests that even when recruitment at an early age and high productivity are observed, immigration can still play a pivotal role in promoting the fast growth of new populations at the edge of a species range, at least until density-dependent effects arise. This process can be so fast that within a few years a new population can itself become a source population, further driving range expansion of the species. PMID- 27220221 TI - Leave before it's too late: anthropogenic and environmental triggers of autumn migration in a hunted ungulate population. AB - Autumn has to a large extent been neglected in the climate effect literature, yet autumn events, e.g., plant senescence and animal migration, affect fitness of animals differently than spring events. Understanding how variables including plant phenology influence timing of autumn migrations is important to gain a comprehensive understanding of the full annual cycle of migratory species. Here we use 13 yr of data from 60 male and 168 female red deer (Cervus elaphus) to identify triggers of autumn migration. We relate the timing of autumn migration to environmental variables like snow fall, temperature, and plant phenology (NDVI), and to onset of hunting, sex, and migration distance. Severe weather has been suggested as the main trigger of autumn migration, but we found that the majority of the individuals had left the summer range well before snow fall (80.3%) and frost (70.5%), and also before the peak deterioration in forage quality (71.9%). Declining temperatures were associated with a higher daily migration potential. Onset of hunting showed the largest effect on migration potential, with a marked increase during the first days of hunting. Individuals still present in the summer range when snow fall, frost, or peak forage deterioration occurred showed a significantly higher migration potential around these events. Males were less responsive to environmental cues, suggesting rutting activity, starting earlier in males, initiate movement prior to such conditions. Also, individuals with longer migration distances had a higher migration potential late in the season than individuals with shorter migration distances. Our study shows that factors beyond weather and plant phenology, such as onset of hunting, may be important triggers of autumn migration. Severe weather and forage deterioration were important triggers for the individuals experiencing this, which suggests a hierarchical response to environmental cues. The trade-off between staying longer in the summer range and increased energy expenditures if surprised by severe weather is asymmetric, and leaving well in advance can be seen as a risk-averse tactic. PMID- 27220222 TI - A meta-analysis of zooplankton functional traits influencing ecosystem function. AB - The use of functional traits to characterize community composition has been proposed as a more effective way to link community structure to ecosystem functioning. Organismal morphology, body stoichiometry, and physiology can be readily linked to large-scale ecosystem processes through functional traits that inform on interspecific and species-environment interactions; yet such effect traits are still poorly included in trait-based approaches. Given their key trophic position in aquatic ecosystems, individual zooplankton affect energy fluxes and elemental processing. We compiled a large database of zooplankton traits contributing to carbon, nitrogen, and phosphorus cycling and examined the effect of classification and habitat (marine vs. freshwater) on trait relationships. Respiration and nutrient excretion rates followed mass-dependent scaling in both habitats, with exponents ranging from 0.70 to 0.90. Our analyses revealed surprising differences in allometry and respiration between habitats, with freshwater species having lower length-specific mass and three times higher mass-specific respiration rates. These differences in traits point to implications for ecological strategies as well as overall carbon storage and fluxes based on habitat type. Our synthesis quantifies multiple trait relationships and links organisms to ecosystem processes they influence, enabling a more complete integration of aquatic community ecology and biogeochemistry through the promising use of effect traits. PMID- 27220223 TI - Ocular surface reconstruction in limbal stem cell deficiency. AB - The purpose of our review was to familiarize the readers with the new concepts in ocular surface diseases and reconstruction. Limbal stem cell deficiency is characterized by the progressive invasion of conjunctival epithelial cells onto the cornea, superficial vascularisation, destruction of the corneal basement membrane, and chronic inflammatory cell infiltration. Depending on the severity of the disease and the time passed from the primary injury amniotic membrane transplantation, keratolimbal allograft and autograft are the available treatments hoping that, in the nearest future, stem cell transplantation and tissue engineering will become the usual therapeutic choices. PMID- 27220224 TI - Smile--the next generation of laser vision correction. AB - Our paper is an introduction in this new generation of Laser vision correction, called SMILE. It also reveals our experience in the past year, since we started to perform this new procedure in our patients. Small Incision Lenticule Extraction technique is the 3rd generation of Laser vision correction that completely redefines refractive surgery. Being performed entirely with femtosecond laser, SMILE is tissue preserving and very gentle for the eye. In 2011, it was launched internationally. We have started with SMILE in October 2014. Since then, we have performed more than 200 procedures, with the range of corrected diopters between -2 and -10 and astigmatism between -2 and -5. In the near future, hyperopic diopters will be corrected with SMILE. PMID- 27220225 TI - Wet age related macular degeneration management and follow-up. AB - Age-related macular degeneration (AMD) is referred to as the leading cause of irreversible visual loss in developed countries, with a profound effect on the quality of life. The neovascular form of AMD is characterized by the formation of subretinal choroidal neovascularization, leading to sudden and severe visual loss. Research has identified the vascular endothelial growth factor (VEGF) as an important pathophysiological component in neovascular AMD and its intraocular inhibition as one of the most efficient therapies in medicine. The introduction of anti-VEGF as a standard treatment in wet AMD has led to a great improvement in the prognosis of patients, allowing recovery and maintenance of visual function in the vast majority of cases. However, the therapeutic benefit is accompanied by a difficulty in maintaining the treatment schedule due to the increase in the amount of patients, stress of monthly assessments, as well as the associated economic burden. Therefore, treatment strategies have evolved from fixed monthly dosing, to individualized regimens, aiming for comparable results, with fewer injections. One such protocol is called "pro re nata", or "treat and observe". Patients are given a loading dose of 3 monthly injections, followed by an as needed decision to treat, based on the worsening of visual acuity, clinical evidence of the disease activity on fundoscopy, or OCT evidence of retinal thickening in the presence of intra or subretinal fluid. A different regimen is called "treat and extend", in which the interval between injections is gradually increased, once the disease stabilization is achieved. This paper aims to review the currently available anti-VEGF agents--bevacizumab, ranibizumab, aflibercept, and the aforementioned treatment strategies. PMID- 27220226 TI - Starflo glaucoma implant: early experience in Hungary. AB - AIM: To present the early experience with the implantation technique, safety and efficiency of STARflo device for open angle glaucoma (OAG). METHODS: referring intra- and postoperative clinical experience with a series of seven cases in three glaucoma centers in Hungary. RESULTS: No intraoperative complications were observed. Postoperative inflammatory signs disappeared rapidly. The mean IOP reduction was from 27.6 +/- 5.0 mmHg to 18.9 +/- 3.4 mmHg (32% reduction/ patient) at six months postoperatively. CONCLUSION: STARflo implant was safe and (except for one case with neovascular glaucoma) effective in our cases. The learning curve for experienced anterior segment surgeons was short. PMID- 27220227 TI - Refractive results with the use of AT.Lisa intraocular lens (2008-2015). AB - The purpose of the study was to evaluate the refractive results on a large cohort of patients who were implanted spherical or toric multifocal IOL's for cataract surgery or for refractive purpose. Preoperative refractive investigations included auto refractometer topography, pentacam, contact and noncontact biometry and many non-refractive investigations. The target in multifocal IOL usage was emmetropia and it was achieved in most cases. Ametropia occurrence involved correction in different ways. PMID- 27220228 TI - Evaluation of peripheral binocular visual field in patients with glaucoma: a pilot study. AB - OBJECTIVE: The objective of this study was to evaluate the peripheral binocular visual field (PBVF) in patients with glaucoma using the threshold strategy of Humphrey Field Analyzer. METHODS: We conducted a case-control pilot study in which we enrolled 59 patients with glaucoma and 20 controls. All participants were evaluated using a custom PBVF test and central 24 degrees monocular visual field tests for each eye using the threshold strategy. The central binocular visual field (CBVF) was predicted from the monocular tests using the most sensitive point at each field location. The glaucoma patients were grouped according to Hodapp classification and age. The PBVF was compared to controls and the relationship between the PBVF and CBVF was tested. RESULTS: The areas of frame-induced artefacts were determined (over 50 degrees in each temporal field, 24 degrees superiorly and 45 degrees inferiorly) and excluded from interpretation. The patients presented a statistically significant generalized decrease of the peripheral retinal sensitivity compared to controls for Hodapp initial stage--groups aged 50-59 (t = 11.93 > 2.06; p < 0.05) and 60-69 (t = 7.55 > 2.06; p < 0.05). For the initial Hodapp stage there was no significant relationship between PBVF and CBVF (r = 0.39). For the moderate and advanced Hodapp stages, the interpretation of data was done separately for each patient. CONCLUSIONS: This pilot study suggests that glaucoma patients present a decrease of PBVF compared to controls and CBVF cannot predict the PBVF in glaucoma. PMID- 27220229 TI - Collagen crosslinking in the management of microbial keratitis. AB - OBJECTIVE: The evaluation of the efficiency of corneal cross linking in the management of corneal ulcers. METHOD: A prospective study that included 10 patients, 10 eyes, with chronic corneal ulcer, bacterial and/ or fungal. The patients were divided into two groups. Group A included 5 patients with unperforated corneal ulcer and group B included 5 patients with perforated corneal ulcer. These patients were treated with general and local antibiotic and antifungal drugs, but the response was poor after two weeks. The crosslinking procedure was performed and the local treatment was continued for two weeks. An additional partial or total conjunctival coverage was done on group B. Patients were evaluated after 3 days, one week, two weeks, one month, 3 months, 6 months and one year after the procedure. Slit lamp and tomographic aspects of the cornea were assessed as well as the visual acuity. RESULTS: All ten patients experienced a decrease in pain from the first postoperative day. The ulcer healed by more than 50% in the first week in 3 patients from group A and closed completely after one month for 4 patients in group A, respectively 4 patients in group B. Hypopyon did not reappear after the crosslinking procedure in group A. However, it did persist in one patient from group B. Postoperative results were the same at 3, 6 and 12 months after the procedure. An opacification of the lens was observed in 3 patients after crosslinking. There were not any intra operative and postoperative complications. CONCLUSION: Corneal crosslinking is efficient in the management of patients with chronic corneal ulcer. PMID- 27220230 TI - Vitrectomy surgery of diabetic retinopathy complications. AB - Abstract PURPOSE: To assess the anatomical and functional results after vitreoretinal surgery, in a large number of patients with complications due to diabetic retinopathy. Also, to compare the 23G vs. the 20G surgical procedures in these cases, regarding efficacy, facility, safety, and postoperative recovery. METHODS: Interventional, retrospective, comparative study of cases operated for different complications of diabetic retinopathy between January 2000 and December 2014. All cases were operated under a local anesthesia by the same surgeon, by using standard 20G Vitrectomy (between January 2000 and October 2011) and ambulatory 23G vitrectomy (since November 2011). Cases had a complete ophthalmic evaluation and were followed-up for at least 12 months. RESULTS: 1.267 eyes of 1.129 patients were operated between January 2000 and December 2014. 23G vitrectomy was performed in 578 eyes. The mean age in the study group was of 57.49 +/- 14.17 years (ranging from 16 to 78 years old), with a male/female ratio of 0.916. The surgery indications were represented by media opacities (609 cases 48.06%), vitreoretinal tractions and detachments (583 cases - 46.01%), persistent macular edema (38 cases - 3%) and persistent neovascularization with rubeosis (37 cases - 2.93%). A final anatomical success was obtained in 1174 cases (92.65%). Preoperative best corrected visual acuity (BCVA) (less or equal to counting fingers in 936 eyes - 73.87%), improved postoperatively in 923 eyes (72.84%), stabilized in 201 eyes (15.86%), and decreased in 143 eyes (11.28%). At a final examination, 932 eyes (73.55%) had a BCVA equal or better to 0.1. Cases operated with the 23G vitrectomy had a shorter surgery and a quicker postoperative recovery. Overall, simpler cases like vitreous hemorrhage and epimacular membranes had a better anatomical and functional result as compared to long standing or macular involvement detachments. The main intra and postoperative complications, lower with the 23G vitrectomy, were represented by iatrogenic retinal breaks, recurrent hemorrhages, redetachment, and neovascular glaucoma. CONCLUSIONS: These results confirmed the efficacy and safety of vitreoretinal surgery in improving most complications of diabetic retinopathy on a large series. With modern, less invasive techniques, the chance of a better surgery and also a quicker patient recovery increased significantly. PMID- 27220232 TI - Acanthamoeba keratitis challenges a case report. AB - Acanthamoeba keratitis is a rare, chronic, mainly contact lens-related infection caused by a free-living amoeba found ubiquitously in water and soil. A case of a 9-year-old child, who presented to our clinic with painful, red left eye, associated with photophobia, and decreased visual acuity, wais reported. The clinical examination revealed a discoid opacity inferiorly bounded by a dense, gray infiltrate. The progressive nature of the corneal infiltrate, the epithelial defect, and the lack of response to treatment was highly suggestive for Acanthamoeba keratitis. The distinctiveness of this case was the presence of Acanthamoeba keratitis in a child without a history of trauma or contact lens usage, the lack of an appropriate diagnosis and management of this vision threatening infection. PMID- 27220231 TI - Secondary congenital aphakia. AB - Abstract PURPOSE: We present the clinical, paraclinical and therapeutic features in a patient with secondary congenital aphakia. METHODS: A 2-year-old patient, diagnosed with congenital rubella syndrome including sensorineural deafness, congenital heart disease, intellectual disability, microcephaly, microphthalmia, and congenital cataract, presented to our clinic for the surgical treatment of cataract. RESULTS: During the surgery, the absence of the lens' cortex was observed, hence, the final diagnose was of secondary congenital aphakia. Surgery was then continued with a posterior capsulorhexis and an anterior vitrectomy, deciding to postpone the implantation of the posterior chamber intraocular lens. PMID- 27220233 TI - Clinical particularities in an atypical case of retinitis pigmentosa. AB - We present a case of Retinitis Pigmentosa with atypical aspect of fundus (Punctata Albescens), associated with Cystoid Macular Oedema and Optic Disc Drusen. PMID- 27220234 TI - Unilateral pigmentary retinopathy--a review of literature and case presentation. AB - OBJECTIVES: To report a rare case of unilateral pigmentary retinopathy and describe the clinical and visual field characteristics of this particular case. METHODS: We present the case of a 30-year-old male patient with a gradual loss of the visual field on his left eye (LE) for the past 10 years, with further gradual painless loss of his central visual field in the last year, and no similar symptoms in his right eye. His past medical and ocular history were unremarkable. No family history of acquired or inherited diseases was determined. RESULTS: Based on the history, clinical findings, and visual field examination, the diagnosis of unilateral pigmentary retinopathy was established. Visual acuity and visual field in the left eye (LE) were severely affected, while in the right eye (RE), they were completely normal. CONCLUSIONS: In this case, distinct features of pigmentary retinopathy were observed only in one eye, with the fellow eye being unaffected. The diagnosis requires a long follow-up period, visual field and electrophysiological testing to rule out a delayed onset of a bilateral form of pigmentary retinopathy. PMID- 27220235 TI - [BEHAVIORAL AND FUNCTIONAL VESTIBULAR DISTURBANCES AFTER SPACE FLIGHT. 2. FISHES, AMPHIBIANS AND BIRDS]. AB - The review contains data on functional shifts in fishes, amphibians and birds caused by changes in the otolith system operation after stay under weightlessness conditions. These data are of theoretical and practical significance and are important to resolve some fundamental problems of vestibulogy. The analysis of the results of space experiments has shown that weightlessness conditions do not exert a substantial impact on formation and functional state of the otolith system in embryonic fishes, amphibians and birds developed during space flight. Weightlessness conditions do pot inhibit embryonic development of lower vertebrates but even have rather beneficial effect on it. This is consistent with conclusions concerning development of mammalian fetuses. The experimental results show that weightlessness can cause similar functional and behavioral vestibular shifts both in lower vertebrates and in mammals. For example, immediately after an orbital flight the vestibuloocular reflex in fish larvae and tadpoles (without lordosis) was stronger than in control individuals. A similar shift of the otolith reflex was observed in the majority of cosmonauts after short-term orbital flights. Immediately after landing adult terrestrial vertebrates, as well as human beings, exhibit lower activity levels, worse equilibrium and coordination of movements. Another interesting finding observed after landing of the cosmic apparatus was an unusual looping character of tadpole swimming. It is supposed that the unusual motor activity of animals as well as appearance of illusions in cosmonauts and astronauts after switching from 1 to 0 g have the same nature and are related to the change in character of otolith organs stimulation. Considering this similarity of vestibular reactions, using animals seems rather perspective. Besides it allows applying in experiments various invasive techniques. PMID- 27220236 TI - [THE EFFECT OF HORMONAL STIMULATION OF STERLET (ACIPENSER RUTHENUS L.) ON STEROID LEVELS IN TISSUE INCUBATES]. AB - Sex steroids and corticol levels in Leibovitz's L-15 media samples after incubation of intact female and male sterlet (Acipenser rhutenus L.) tissue fragments and those if fishes treated with a superactive analogue of mammalian luteinising hormone-releasing hormone (LH-RH-A) were compared. 17,20beta,21 trihydroxy-4-pregnen-3-one (20betaS) levels were significantly higher in the media samples after incubation of ovarian follicles taken from females 5 h after treatment with LH-RH-A in comparison with 20betaS levels in intact female samples. 20betaS levels also increased after 1 MUM progesterone (P4) adding to the media before incubation of ovarian follicles. Cortisol and testosterone levels in the media samples demonstrated the same tendency. Significant elevation of cortisol levels was observed in the blood serum samples of females 5 h after LH-RH-A treatment. The androgens (testosterone and 11-ketotestosterone) levels after incubation of testicular and liver fragments were high in the media samples in males who had high serum levels of these androgens before hormonal stimulation. Sex steroids and cortisol production was stimulated by P4 adding to the media before incubation of gonad fragments. 20betaS media levels increased after P4 adding before incubation of liver fragments. PMID- 27220238 TI - [SPECTRAL AND ACID-BASE PROPERTIES OF HEMOLYMPH PLASMA AND ITS FRACTIONS FROM GASTROPOD PULMONATE MOLLUSC ACHATINA FULICA]. AB - The set of normal biochemical indicators of the hemolymph plasma of gastropod pulmonate mollusc Achatinafulica is described. Comparative analysis of the whole plasma and its subfractions enriched and depleted of oxygen-carrying protein hemocyanin was performed by spectrophotometry and spectrofluorimetry methods. Individual features of the absorption spectra were analyzed using fourth derivatives. The optimum method for estimating protein concentration was chosen. To characterize acid-base properties of plasma hemolymph and its sub-fractions we calculated buffer capacity, equivalence points and pK values of dominant buffer groups. It is shown that the major role in maintaining the buffer capacity of hemolymph belongs to the bicarbonate system. These results are compared with data for Helix pomatia available in literature. In the future the indicators studied in this work will be used to develop ecotoxicological criteria for the environmental assessment. PMID- 27220237 TI - [MOLECULAR EVOLUTION OF ION CHANNELS: AMINO ACID SEQUENCES AND 3D STRUCTURES]. AB - An integral part of modern evolutionary biology is comparative analysis of structure and function of macromolecules such as proteins. The first and critical step to understand evolution of homologous proteins is their amino acid sequence alignment. However, standard algorithms fop not provide unambiguous sequence alignments for proteins of poor homology. More reliable results can be obtained by comparing experimental 3D structures obtained at atomic resolution, for instance, with the aid of X-ray structural analysis. If such structures are lacking, homology modeling is used, which may take into account indirect experimental data on functional roles of individual amino-acid residues. An important problem is that the sequence alignment, which reflects genetic modifications, does not necessarily correspond to the functional homology. The latter depends on three-dimensional structures which are critical for natural selection. Since alignment techniques relying only on the analysis of primary structures carry no information on the functional properties of proteins, including 3D structures into consideration is very important. Here we consider several examples involving ion channels and demonstrate that alignment of their three-dimensional structures can significantly improve sequence alignments obtained by traditional methods. PMID- 27220239 TI - [TRANSFORMATION OF INDIVIDUAL CONTRACTILE RESPONSES DURING TETANUS IN FAST AND SLOW RAT SKELETAL MUSCLES]. AB - The last contractile responses (LCRN), where N is the number of individual contractile responses within tetanus, were separated from the integral tetanic responses of fast, m. Extensor digitorum longus (m. EDL), and slow, m. Soleus, rat muscles using a computer-graphic technique. The average amplitude of LCR5 in m. Soleus at a 20 Hz stimulation rate decreased to 64 +/- 9 % re the amplitude of a single contraction. As N was increasing, a restoration of LCRN was observed with their subsequent rise to values almost twofold exceeding the initial single contractile responses of that muscle (up to 211 +/- 10 % for LCR50). Simultaneously, against the background of rise of individual contractile responses of these muscles, a considerable shortening of their half-life time (to ~ 50%) and formation of a stationary plateau within LCRN were observed. In m. EDL at a 50 Hz stimulation rate only single-phase rise of LCRN was observed (up to 165 +/- 18% for LCR50) without change of their half-life time and plateau formation. After the end of tetanic responses in muscles of both types a prolonged (up to 30 s) "hyper-relaxation effect was shown to develop manifested as a decrease of muscle tension with its subsequent restoration to the initial values. Possible mechanisms of these effects are discussed. It is supposed that transformation of individual contractile responses in skeletal muscles may be executed at the expense of specialized microdomains in muscle fibers regulating accumulation and extrusion levels of Ca2+ ions during tetanic activity. The possible involvement of an additional, Ca(2+)-induced Ca2+ release (CICR), in the basic, depolarization-induced Ca2+ release (DICR), is analyzed. PMID- 27220240 TI - [ACTIVITY OF HYPOTHALAMIC-PITUITARY-ADRENAL AXIS OF PRENATALLY STRESSED MALE RATS IN EXPERIMENTAL MODEL OF DEPRESSION]. AB - The hypothalamic-pituitary-adrenal (HPA) axis activity changes were examined in the adult, prenatally stressed male rats in the experimental depression model- the paradigm of "learned helplessness". It was shown that in males descending from intact mothers a depressive-like state was accompanied by an increase in HPA activity. The expression of corticotrophin-releasing hormone (CRH) in the hypothalamic paraventricular nucleus (PVN) increases, coupled with a rise in plasma levels of ACTH and corticosterone as well as in adrenal weight. At the same time in males born from mothers stressed during the last week of pregnancy we observed a decrease in activity of both the central (hypothalamus) and the peripheral (adrenal cortex) parts of regulation of this hormonal axis similar to that revealed for these animals in our previous study in "stress-restress" paradigm. It is concluded that prenatal stress modifies the sensitivity of animals to the inescapable intense stress impact, which manifests itself in a specific pattern of the HPA axis activity after stress load. PMID- 27220241 TI - [PHARMACOLOGICAL CORRECTION OF APOPTOSIS LEVEL OF CORTICAL NEURONS IN AGED HER2/NEU TRANSGENIC MICE]. AB - Neurodegenerative changes and neuronal death are the basis for development of the nervous system aging. We investigated the mechanism of apoptosis of the sensorimotor cortex neurons of transgenic mice HER2/neu during aging, changes in the cortex function and the participation of exogenous neurometabolites (cytoflavin, piracetam) in regulation of neuronal death and locomotor and psycho emotional status of mice. The level of apoptosis and expression of apoptosis markers (TUNEL, immunohistochemistry, Western blotting) in HER2/neu transgenic mice as compared to wild type mice (FBV line) were determined. In aging FBV mice the basal activity was shown to decrease and anxiety to increase correlating with the high level of neuronal apoptosis. We identified behavioral characteristics of transgenic HER2/neu mice and found that their low basal activity does not change with aging. Previously we have shown that in this strain of mice the apoptosis level is low, without any age-related changes, due to the suppression, first of all, of the p53-dependent pathway by HER2 (tyrosine kinase receptor) overexpression. Cytoflavin and piracetam were revealed to possess a marked neuroprotective effect, preserving and restoring functions of the nervous system (improving locomotion and psychological status) in both strains of mice. The effect of neurometabolites studied on neuronal apoptosis is ambiguous. In case of its low level it is a moderate stumulation of apoptosis via the external p53 dependent pathways with activation of caspase-3 in transgenic HER2/neu mice with high carcinogenesis level that can possibly prevent tumor development. On the contrary, in old wild-type animals we observed a significant decrease of age dependent apoptosis level (by stimulating expression of the anti-apoptotic protein Mcl-1), which prevents neurodegeneration. PMID- 27220242 TI - [EXPRESSION OF SEROTONIN TRANSPORTER IN THE DORSAL RAPHE NUCLEUS DURING THE EARLY POSTNATAL PERIOD IN NORMAL STATE AND UNDER PRENATAL DEFICIENCY OF THE SEROTONERGIC SYSTEM IN RATS]. AB - The expression of the serotonin transport membrane protein (5-NTT) in the dorsal raphe nucleus (DNR) was investigated in laboratory Wistar rats during the early postnatal period. The results of the immunocytochemical study using primary antibodies--anti-Serotonin transporter antibody (AbCam, UK)--showed that during the first 3 postnatal weeks the intensity of 5-NTT expression in DNR of control animals changes. At the earliest postnatal times the main part of subnuclear neurons (dorsal, ventral and lateral ones) of the dorsal raphe nucleus (DNR-d, DNR-v, DNR-lat) was shown to intensely express 5-NTT. Sites of 5-NTT localization are found on the membrane surface of neuron bodies and processes in neuropile. The reduction in the number of neurons expressing 5-NTT and of its binding sites was observed on P10. At this time a redistribution of 5-NTT localization sites occurs: they are very few on neuron bodies and dendrites but are located rather densely on the plasma membrane of axons. The number of neurons expressing 5-NTT gradually increases with age and in neuropile the density of 5-NTT localization sites rises. It is shown that during the prenatal development the reduction of serotonin level in all parts of the DNR leads to a reduction in both the number of neurons expressing 5-NTT and sites of its localization in the early postnatal period, this trend continuing with age. PMID- 27220243 TI - [ROLE OF THE INDUCIBLE Hsp70 PROTEIN IN MODULATION OF NEURODEGENERATIVE PATHOLOGY OF NIGROSTRIATAL SYSTEM TYPICAL FOR THE PARKINSON'S DISEASE]. PMID- 27220244 TI - [PHYSIOLOGICAL REGENERATION MECHANISM IN SKIN AND INTESTINAL EPITHELIA OF SACCOGLOSSUS MERESCHKOWSKII (ENTEROPNEUSTA, HEMICHORDATA)]. PMID- 27220245 TI - [SLOW-WAVE SLEEP AND MOLECULAR CHAPERONES]. AB - From ancient times the mankind has been interested in a topical issue: why is it necessary to spend about one-third of human life for sleep? This review considers the main data on the key function of slow-wave sleep (SWS) and the molecular mechanisms of its regulation; the basic conclusions are presented below as a summary and hypotheses. 1. SWS has an energy-conserving function developed simultaneously with the evolution of tachimetabolism and endothermy/homoiothermy. 2. The most significant reduction of energy demands in the brain occurs during the deep SWS (characterized by increased EEG-delta power), thus creating the optimal conditions for enhancing anabolic processes and realizing the key biological function of sleep--the increase in protein synthesis rate in the brain. 3. The conditions of the paradoxical sleep (PS) as an 'archeowakefulness' state, containing the elements of endogenous stress, seem to be acceptable for expression of chaperones required for repairing misfolded proteins newly synthesized during the deep SWS. 4. The close integration of two molecular systems, HSP70 and HSP40, contained in the sleep 'center' in the preoptic area of the hypothalamus, and their compensatory interrelations contribute significantly to the maintenance of sleep homeostasis and to implementation of its functions under non-stress conditions and during long-term deficiency of chaperones in the brain that is intrinsic for aging and various neuropathologies. 5. Occurring daily throughout the lifetime cyclical changes of the protein synthesis rate (during the deep SWS) and the expression of HSP70 chaperonez (during wakefulness and, possibly, during PS) are crucial for functions of homeothermic organisms, including recuperation of the nervous system's structure and functions. PMID- 27220246 TI - [EFFECTS OF DIFFERENT CLASSES OF PLANT HORMONES ON MAMMALIAN CELLS]. AB - Plant hormones are signal molecules of different chemical structure, secreted by plant cells and acting at low concentrations as regulators of plant growth and differentiation. Certain plant hormones are similar to animal hormones or can be produced by animal cells. A number of studies show that the effect of biologically active components of plant origin including plant/phytohormones is much wider than was previously thought, but so far there are no objective criteria for assessing the influence of phytohormones on the physiological state of animal cells. Presented in the survey data show that plant hormones, which have different effects on plant growth and development (jasmonic, abscisic and gibberellic acids), are not neutral to the cells of animal origin, and animal cells response to them may be either positive or negative. PMID- 27220247 TI - [ULTRASTRUCTURAL CHANGES OF THE STEM CELLS IN THE CYCLE MONOLAYER--SPHERES- MONOLAYER]. AB - Sphere formation can be used to prepare stem cells (SCs) prior to transplantation. Here SCs isolated from human subepicardial adipose tissue were analyzed at different stages of the monolayer-spheres-monolayer cycle by transmission electron microscopy. The results obtained with both adherent-induced and hanging-drop induced spheres were similar. At first 2-3 passages (stage 1), isolated SCs displayed embryonal cell-like ultrastructure. With increasing passage times (stage 2), SCs became bigger and more electron-dark with a multilobed nucleus, well-developed rough endoplasmic reticulum (RER), prominent Golgi apparatus and numerous vacuoles. After 2 h from the initiation of the formation of spheres (stage 3), SCs gathered into clusters and formed desmosome like intercellular contacts. Their nucleus possessed a large loose fibrillo granular nucleoli, the cytoplasm was densely packed with disintegrated cisternae of RER, Golgi apparatus was not detected. After 24 h from the initiation of spheres (stage 4), SCs in well-formed spheres exhibited large dense nucleoli and poorly developed Golgi apparatus and RER. One day after sphere dissociating (stage 5), SCs were embryonal cell-like and morphologically similar to the cells of the first stage except for the presence of a large nucleolus and numerous Golgi complexes. After 48 h from sphere dissociating (stage 6), SCs became electron-dark and resembled the SCs of the second stage by the presence of irregularly shaped nuclei and the cetoplasm filled with RER. We interpreted the results as senescence of the SCs with the number of passages after isolation from tissue and a day after dissociation of the spheres and as rejuvenation of the SCs just after sphere dissociation. Further research is needed to reveal the genetic, biochemical and physiological parameters of the SCs on established morphologically distinct stages in order to provide higher-quality cellular material for disease cell therapy. PMID- 27220248 TI - [PHENOTYPE OF PERIPHERAL BLOOD NEUTROPHILS IN THE INITIAL STAGE OF ENDOMETRIAL CANCER]. AB - We have examined peripheral blood neutrophils from 123 patients with primary endometrial cancer at stage Ia. Receptor system and the ability of neutrophils to form extracellular traps were assessed by fluorescence microscopy, the spontaneous production of cytokines IL-2, IFN-gamma, g-CSF, matrix metalloproteinases-1,9,13 by the method of enzyme-linked immunosorbent assay, phagocytic activity, myeloperoxidase activity, the level of cationic proteis activity in NBT-test were evaluated by cytochemical methods, activity of neutrophils in the spontaneous NBT-test was used to evaluate the oxygen-dependent bactericidal action of neutrophils. The topology and the rigidity of the membrane of neutrophils were assessed by scanning probe microscopy. We have shown that the increase in the relative number of neutrophils lead to a change in their receptor system, aerobic and anaerobic cytotoxicity and ability to phagocytosis are enchanced while reducing NET-activity. We have observed a change in the secretory activity of neutrophils, which is characterized by increased level of MMP-1, possibly initiated by enhanced production of reactive oxygen species, by a reduction in the IL-2 level (inductor of cytotoxic activity) and a sharp increase in the level of the G-CSF. Architectonics of neutrophils in the case of endonetrial cancer at stage Ia is characterized by changing the shape and loss of grit. The rigidity of the cell membrane decreased. Changes in the morphology of neutrophils on the background of the continuing hyperactivity suggests that a state of balance between the immune system and the tumor is already in stage Ia endometrial cancer. PMID- 27220249 TI - [AGGREGATION OF METABOLICALLY DEPLETED HUMAN ERYTHROCYTES]. AB - An aggregation of erythrocytes in autologous plasma after blood storage for 14 days at 4 degrees C was studied using photometry and light microscopy. The decrease of ATP content, the formation of echinocytes and spheroechinocytes, the decrease of rouleaux form of erythrocyte aggregation were observed during the storage. On the other hand the aggregates of echinocytes were formed in the stored blood. The addition of plasma from the fresh blood didn't restore the normal discocytic shape and aggregation of erythrocytes in the stored blood. The possible mechanisms of erythrocytes and echinocytes aggregation are discussed. PMID- 27220250 TI - [MORPHOLOGY OF NCTC CELLS ONE DAY AFTER RESEEDING]. AB - Development of regenerative medicine based on the use of stem cells is substantially dependent on the prediction of the changes that the cells undergo after culturing them in vitro. Therefore, the accumulation of knowledge in the field, which can be denoted as biology of cells in culture, is of special importance. Features of functioning cells in vitro is better to study in the permanent cells lines as their morphological and functional characteristics in numerous passages can be regarded as the result of adaptation of cells to grow outside the body. The aim of the present study was to test whether there is a relationship between the density of the cell culture prior to the formation of a monolayer of cells and morphometric parameters of the cells. The NCTC fibroblast like cells (clone 929 were examined one day after reseeding. By this time, the culture density was such that there was virtually no direct contact between the cells. The cell area, spreading and polarization coefficients were used to characterize the cells. It has been shown that, in the same culture flask, the cells in the areas with a higher density of cells are smaller than in areas of lower density. At the same time, polarization of cells increases by increasing the cell density. Such cell reaction may be the result of the remote transfer of information between the cells. Analysis of the data obtained allows us to assume that the change in shape of the cells is related to early steps of monolayer formation. PMID- 27220251 TI - [INFLUENCE OF TITANIUM COATING ON THE BIOCOMPATIBILITY OF POLYPROPYLENE IMPLANTS]. AB - Comparative analysis of the proliferative activity of inflammatory cells and distribution of collagen types I and III was carried out around the net materials of polypropylene and titanium coating polypropylene using im- munohistochemical method and polarization microscopy. Experimental modeling of implanted mesh material were made in the soft tissues of the lumbar region of rats. On the 7th postoperative day, quantitative analysis of proliferating cells delected using antibodies to the Ki-67 protein showed, a significant decrease (p < 0.001) in the number of proliferating cells around the network elements of the polypropylene (29.1 +/- 5.7 %), when com- pared to similar figures of infiltrates in titanium coating polypropylene (33.6 +/- 3.1 %). Similar patterns were found on the 30th day of the experiment--15.9 +/- 4.3 and 26.9 +/- 3.6%--respectively (p < 0.001). Different types of collagen fibers in the granulomas around various types of implanted mesh material were detected on sections stained with Sirius red at polarizing light. On the 7th day after surgery, the ratio of collagen fibers ty- pe I and III in granulomas around the mesh material made of polypropylene was 1.085 +/- 0.022 and this rati around materials of titanium coated polypropylene was higher--1.107 +/- 0.013 (p = 0.017). On the 30th posto- perative day in the interface area ratio I/III collagen significantly increased and amounted to 1.174 +/- 0.036 and 1.246 +/- 0.102, respectively (p = 0.045). Assessing the impact of the use of titanium as a coating on the po- lypropylene, it can be argued that it promotes the formation of collagen I type and a more mature connective tis- sue around the mesh of the implants. PMID- 27220252 TI - [THE EFFECT OF ACID RAIN ON ULTRASTRUCTURE AND FUNCTIONAL PARAMETERS OF PHOTOSYNTHETIC APPARATUS OF PEA LEAVES]. AB - The effects of simulated acid rain (SAR) on the ultrastructure and functional parameters of the photosynthetic apparatus were studied using 14-day-old pea leaves as test system. Pea plants were sprayed with an aqueous solution containing NaNO3(0.2 mM) and Na2SO4(0.2 mM) (pH 5.6, a control variant), or with the same solution, which was acidified to pH 2.5 (acid variant). Functional characteristics were determined by chlorophyll fluorescence analysis. Acid rain application caused reduction in the efficiency of the photosynthetic electron transport by 25%, which was accompanied by an increase by 85% in the quantum yield of thermal dissipation of excess light quanta. Ultrastructural changes in chloroplast were registered by transmission electron microscopy (TEM) after two days of the SAR-treatment of pea leaves. In this case, the changes in the structure of grana, heterogeneity of thylakoids packaging in granum, namely, the increase of intra-thylakoid gaps and thickness of granal thylakoids compared to the control were found. The migration of protein complexes in thylakoid membranes of chloroplasts isolated from leaves treated with SAR was suppressed. It was shown also that carbonic anhydrase activity was inhibited in chloroplast preparations isolated from SAR-treated pea leaves. We proposed a hypothesis on the possible inactivation of thylakoid carbonic anhydrase under SAR and its involvement in the inhibition of photochemical activity of chloroplasts. The data obtained allows to suggest that acid rains negatively affect the photosynthetic apparatus disrupting the membrane system of chloroplast. PMID- 27220253 TI - [FUNCTIONAL DIFFERENTIATION IN BRYOZOAN COLONY: A PROTEOMIC ANALYSIS]. AB - Bryozoans are typical modular organisms. They consist of repetitive structural units, the zooids. Bryozoan colonies grow by zooidal budding, with the distribution pattern of the budding loci underlying the diversity of colony forms. Budding is usually restricted to the zooids at the periphery of the colony, which form a "growing edge" or local terminal growth zones. Non-budding parts of the colony can be functionally subdivided, too. In many species colonies consists of regular, often repetitive zones of feeding and non-feeding modules, associated with a periodical degeneration and regeneration of the polypide, retractile tentacle crown with a gut and the accompanying musculature. So, there is functional differentiation in bryozoan colonies but its mechanisms are unknown. Presumably, budding and/or polypide recycling in different colony parts are induced or inhibited by certain determinants of functional specialization. An effective tool of their identification is the comparison of proteomes of functionally different zones. Here we report the results of proteomic analysis of three bryozoan species from the White Sea, which have a different colony form: Flustrellidra hispida, Terminoflustra membranaceotruncata and Securiflustra securifrons. Using differential two-dimensional electrophoresis (2D-DIGE), we compared proteomes of the growing edge and the zones consisting of feeding and non-feeding zooids in these species. We estimated the overall proteome variability, revealed proteins whose relative abundance gradually changed along the proximal-distal colony axis and suggested that they might be involved in the functional differentiation of the colony. PMID- 27220255 TI - Immobilization of Anions on Polymer Matrices for Gel Electrolytes with High Conductivity and Stability in Lithium Ion Batteries. AB - This study reports on a high ionic-conductivity gel polymer electrolyte (GPE), which is supported by a TiO2 nanoparticle-decorated polymer framework comprising poly(acrylonitrile-co-vinyl acetate) blended with poly(methyl methacrylate), i.e. , PAVM: TiO2. High conductivity GPE-PAVM: TiO2 is achieved by causing the PAVM:TiO2 polymer framework to swell in 1 M LiPF6 in carbonate solvent. Raman analysis results demonstrate that the poly(acrylonitrile) (PAN) segments and TiO2 nanoparticles strongly adsorb PF6(-) anions, thereby generating 3D percolative space-charge pathways surrounding the polymer framework for Li(+)-ion transport. The ionic conductivity of GPE-PAVM: TiO2 is nearly 1 order of magnitude higher than that of commercial separator-supported liquid electrolyte (SLE). GPE-PAVM: TiO2 has a high Li(+) transference number (0.7), indicating that most of the PF6( ) anions are stationary, which suppresses PF6(-) decomposition and substantially enlarges the voltage that can be applied to GPE-PAVM: TiO2 (to 6.5 V vs Li/Li(+)). Immobilization of PF6(-) anions also leads to the formation of stable solid-electrolyte interface (SEI) layers in a full-cell graphite|electrolyte|LiFePO4 battery, which exhibits low SEI and overall resistances. The graphite|electrolyte|LiFePO4 battery delivers high capacity of 84 mAh g(-1) even at 20 C and presents 90% and 71% capacity retention after 100 and 1000 charge-discharge cycles, respectively. This study demonstrates a GPE architecture comprising 3D space charge pathways for Li(+) ions and suppresses anion decomposition to improve the stability and lifespan of the resulting LIBs. PMID- 27220254 TI - First finding of Trypanosoma cruzi II in vampire bats from a district free of domestic vector-borne transmission in Northeastern Argentina. AB - Establishing the putative links between sylvatic and domestic transmission cycles of Trypanosoma cruzi, the etiological agent of Chagas disease, is of public health relevance. We conducted three surveys to assess T. cruzi infection in wild mammals from a rural and a preserved area in Misiones Province, Northeastern Argentina, which had recently been declared free of vector- and blood-borne transmission of human T. cruzi infection. A total of 200 wild mammals were examined by xenodiagnosis (XD) and/or polymerase chain reaction (PCR) amplification of the hyper-variable region of kinetoplast DNA minicircles of T. cruzi (kDNA-PCR). The overall prevalence of T. cruzi infection was 8%. Nine (16%) of 57 Didelphis albiventris opossums and two (7%) of 29 Desmodus rotundus vampire bats were positive by both XD and kDNA-PCR. Additionally, one D. rotundus positive for T. cruzi by kDNA-PCR tested positive by satellite-DNA-PCR (SAT-DNA PCR). The T. cruzi-infected bats were captured indoors and in the yard of a vacant dwelling. All D. albiventris were infected with TcI and both XD-positive D. rotundus by TcII. Fifty-five opossum cubs within the marsupium were negative by XD. The mean infectiousness to the vector was 62% in D. albiventris and 50% in D. rotundus. Mice experimentally infected with a parasite isolate from a vampire bat displayed lesions typically caused by T. cruzi. Our study documents the presence of the genotype TcII in a sylvatic host for the first time in Argentina, and the occurrence of two transmission cycles of T. cruzi in a district free of domestic vector-borne transmission. PMID- 27220257 TI - [Advanced practice in nursing and new organisational healthcare models]. PMID- 27220256 TI - A novel redox-active metalloporphyrin reduces reactive oxygen species and inflammatory markers but does not improve marginal mass engraftment in a murine donation after circulatory death islet transplantation model. AB - Islet transplantation is a highly effective treatment for stabilizing glycemic control for select patients with type-1 diabetes. Despite improvements to clinical transplantation, single-donor transplant success has been hard to achieve routinely, necessitating increasing demands on viable organ availability. Donation after circulatory death (DCD) may be an alternative option to increase organ availability however, these organs tend to be more compromised. The use of metalloporphyrin anti-inflammatory and antioxidant (MnP) compounds previously demonstrated improved in vivo islet function in preclinical islet transplantation. However, the administration of MnP (BMX-001) in a DCD islet isolation and transplantation model has yet to be established. In this study, murine donors were subjected to a 15-min warm ischemic (WI) period prior to isolation and culture with or without MnP. Subsequent to one-hour culture, islets were assessed for in vitro viability and in vivo function. A 15-minute WI period significantly reduced islet yield, regardless of MnP-treatment relative to yields from standard isolation. MnP-treated islets did not improve islet viability compared to DCD islets alone. MnP-treatment did significantly reduce the presence of extracellular reactive oxygen species (ROS) (p < 0 .05). Marginal, syngeneic islets (200 islets) transplanted under the renal capsule exhibited similar in vivo outcomes regardless of WI or MnP-treatment. DCD islet grafts harvested 7 d post-transplant exhibited sustained TNF-alpha and IL-10, while MnP-treated islet bearing grafts demonstrated reduced IL-10 levels. Taken together, 15-minute WI in murine islet isolation significantly impairs islet yield. DCD islets do indeed demonstrate in vivo function, though MnP therapy was unable to improve viability and engraftment outcomes. PMID- 27220258 TI - [Re-analysis from a correlational approach of dimension impairment-of-functioning of Integrated Fatigue Assessment Scale]. PMID- 27220259 TI - Floating bioplato for purification of waste quarry waters from mineral nitrogen compounds in the Arctic. AB - A bioplato was organized at Kirovogorskiy pond-settling of OLKON Company (the city of Olenegorsk, in Murmansk region) to reduce the content of nitrogen mineral compounds in water which come into the pond with the quarry waters after blasting operations using nitrogen compounds. The assortment of aboriginal plants was selected, a method of fixing and growing them on the water surface was developed, and observations of their vegetation were carried out. The dynamics of nitrogen compounds was determined in the laboratory and with full-scale tests. The coverage area pond by plants for the effective reduction of mineral nitrogen compounds was calculated. The use of floating bioplato helped to reduce content of ammonium and nitrite to maximum permissible levels or even lower in pond water. Also there was a tendency towards reduction of nitrate concentrations in water. The developmental technology can be used in any climatic zone with a specific assortment of plants-ameliorants. PMID- 27220260 TI - Development of Strabismus in Children Initially Diagnosed with Pseudostrabismus. AB - PURPOSE: To evaluate the incidence of strabismus in children initially diagnosed with pseudostrabismus and to identify risk factors for the development of strabismus. METHODS: The medical records of patients who were diagnosed with pseudostrabismus at initial examinations in outpatient clinic were reviewed retrospectively. Follow-up examinations were made at the strabismus department. Age at first examination, gender, family and developmental history, ophthalmic and orthoptic findings including orbit, and eyelid pathologies were investigated. RESULTS: Sixty-five patients with the diagnosis of pseudostrabismus were identified; 2 patients (3.1%) had pseudoexotropia, and 63 patients (96.9%) had pseudoesotropia. The mean age at the initial exam was 29.26+/-26.68 months (range; 4-120 months). Epicanthal skin folds (n=35), flat broad nasal bridge (n=17), blepharophimosis syndrome (n=1), hypertelorism (n=1), telecanthus (n=1), and multiple pathologies (n=10) were the reasons for pseudostrabismus. Six patients (9.2%) had clinically significant hypermetropia. Anisometropia and amblyopia were detected in 1 (1.5%) and 3 patients (4.6%), respectively, at the initial examination. The mean follow-up period was 25.2+/-23.28 months (range; 1 154 months). During the follow-up period, true strabismus was detected in 8 cases (12%); of these, 5 cases had non-refractive esotropia, 2 cases had refractive accommodative esotropia, and 1 case had exotropia. Binocular single vision was not developed following amblyopia therapy and refractive correction in esotropic cases. Binocular single vision and best corrected visual acuity were statistically significant risk factors for the development of strabismus (P=0.001). CONCLUSION: The pseudostrabismic children with subnormal binocular single vision or low visual acuity require follow-up for the risk of development of true strabismus. PMID- 27220261 TI - Synthesis of (Z)-alpha-Trifluoromethyl Alkenyl Triflate: A Scaffold for Diverse Trifluoromethylated Species. AB - An efficient method for the synthesis of (Z)-selective alpha-trifluoromethyl alkenyl triflates is described. As an important fluorinated building block, it is utilized successfully for the synthesis of various trifluoromethyl derivatives such as diarylethylenes, enynes, alkynes, and benzofurans. PMID- 27220264 TI - Employment Status as an Indicator of Recovery and Function One Year after Hematopoietic Stem Cell Transplantation. AB - Employment after hematopoietic stem cell transplantation (HSCT) is an indicator of post-transplantation recovery and function, with economic and social implications. As survival rates for HSCT continue to improve, greater emphasis can be placed on factors affecting the quality of post-transplantation survival, including the ability to resume employment. A sample of recipients of autologous or allogeneic HSCT was accrued (n = 1000) to complete a longitudinal lifestyle survey before transplantation and at 1 year after transplantation. The present study examines associations between employment and patient characteristics, disease variables, illness status, and quality of life among 1-year survivors (n = 702). Participants had a mean age of 55 years (range, 18 to 78) and were predominately male (59.7%), married/partnered (77.1%), and non-Hispanic Caucasian (89.5%); most (79.4%) had received autologous transplantation. Of the 690 participants reporting some form of employment before illness diagnosis, 62.4% had returned to work by 1 year after HSCT. Full-time employment at 1 year after HSCT was significantly associated with remission of illness, improved illness, fewer post-transplantation hospitalizations, less fatigue and pain, higher quality of life, and higher rating of perceived health. Those unemployed because of their health reported the highest rates of fatigue and pain and lowest quality of life, and they were most likely to report poor perceived health. These findings highlight work reintegration as an important outcome and marker of survivors' overall adjustment after transplantation. Identifying factors affecting post-transplantation employment offers opportunities for behavioral interventions to target modifiable risk factors to optimize post-transplantation survivorship, inclusive of increased rates of return to work and decreased rates of associated disability. PMID- 27220262 TI - Donor KIR B Genotype Improves Progression-Free Survival of Non-Hodgkin Lymphoma Patients Receiving Unrelated Donor Transplantation. AB - Donor killer immunoglobulin-like receptor (KIR) genotypes are associated with relapse protection and survival after allotransplantation for acute myelogenous leukemia. We examined the possibility of a similar effect in a cohort of 614 non Hodgkin lymphoma (NHL) patients receiving unrelated donor (URD) T cell-replete marrow or peripheral blood grafts. Sixty-four percent (n = 396) of donor recipient pairs were 10/10 allele HLA matched and 26% were 9/10 allele matched. Seventy percent of donors had KIR B/x genotype; the others had KIR A/A genotype. NHL patients receiving 10/10 HLA-matched URD grafts with KIR B/x donors experienced significantly lower relapse at 5 years (26%; 95% confidence interval [CI], 21% to 32% versus 37%; 95% CI, 27% to 46%; P = .05) compared with KIR A/A donors, resulting in improved 5-year progression-free survival (PFS) (35%; 95% CI, 26% to 44% versus 22%; 95% CI, 11% to 35%; P = .007). In multivariate analysis, use of KIR B/x donors was associated with significantly reduced relapse risk (relative risk [RR], .63, P = .02) and improved PFS (RR, .71, P = .008). The relapse protection afforded by KIR B/x donors was not observed in HLA-mismatched transplantations and was not specific to any particular KIR-B gene. Selecting 10/10 HLA-matched and KIR B/x donors should benefit patients with NHL receiving URD allogeneic transplantation. PMID- 27220263 TI - Mogamulizumab Treatment Prior to Allogeneic Hematopoietic Stem Cell Transplantation Induces Severe Acute Graft-versus-Host Disease. AB - Mogamulizumab (MOG), a humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, has recently played an important role in the treatment of adult T cell leukemia/lymphoma (ATLL). Because CCR4 is expressed on normal regulatory T cells as well as on ATLL cells, MOG may accelerate graft-versus-host disease (GVHD) by eradicating regulatory T cells in patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there is limited information about its safety and efficacy in patients treated with MOG before allo-HSCT. In the present study, 25 patients with ATLL were treated with MOG before allo-HSCT, after which 18 patients (72%) achieved remission. The overall survival and progression-free survival at 1 year post-transplantation were 20.2% (95% CI, 6.0% to 40.3%) and 15.0% (95% CI, 4.3% to 32.0%), respectively. The cumulative incidence of acute GVHD was 64.0% (95% CI, 40.7% to 80.1%) for grade II-IV and 34.7% (95% CI, 15.8% to 54.4%) for grade III-IV. The cumulative incidence of transplantation-related mortality (TRM) was 49.0% (95% CI, 27.0% to 67.8%). Six of 7 patients with acute GVHD grade III-IV died from GVHD, which was the leading cause of death. In particular, a shorter interval from the last administration of MOG to allo-HSCT was associated with more severe GVHD. MOG use before allo-HSCT may decrease the ATLL burden; however, it is associated with an increase in TRM due to severe GVHD. Because MOG is a potent anti-ATLL agent, new treatment protocols should be developed to integrate MOG at suitable doses and timing of administration to minimize unwanted GVHD development. PMID- 27220265 TI - Changing Trends of Unrelated Umbilical Cord Blood Transplantation for Hematologic Diseases in Patients Older than Fifty Years: A Eurocord-Center for International Blood and Marrow Transplant Research Survey. PMID- 27220266 TI - Oxytocin is involved in the proconvulsant effects of Sildenafil: Possible role of CREB. AB - Sildenafil is a phosphodiesterase type 5 inhibitor mainly used for male erectile dysfunction. One of rare yet serious adverse effects of Sildenafil is its potential to decrease seizure threshold. Ample evidence suggests that Sildenafil exerts central effects through induction of Oxytocin (OT) secretion and CREB phosphorylation. The aim of the present study is to evaluate potential roles of OT and CREB in the proconvulsant effects of Sildenafil. The Pentylenetetrazole induced seizure was used as a standard convulsion model in this study. OT release and pCREB expression were evaluated in the hippocampus of mice using ELISA and western blot assays, respectively. Our results showed that Sildenafil at the dose of 10mgkg(-1) or higher, significantly decreased seizure threshold. Pretreatment with a non-effective dose of OT, potentiated while OT receptor antagonist, Atosiban, reversed fully the proconvulsant effects of Sildenafil (5mgkg(-1)). At biochemical inspection, Sildenafil markedly increased CREB which was attenuated by coadministration of Atosiban. The present study shows for the first time that OT release and the subsequent CREB phosphorylation are involved in the proconvulsant effects of acute Sildenafil treatment in an experimental model of seizure. PMID- 27220267 TI - Gestational dexamethasone alters fetal neuroendocrine axis. AB - This study tested whether the maternal transport of dexamethasone (DEXA) may affect the development of the neuroendocrine system. DEXA (0.2mg/kg b.w., subcutaneous injection) was administered to pregnant rats from gestation day (GD) 1-20. In the DEXA-treated group, a decrease in maternal serum thyroxine (T4), triiodothyronine (T3), and increase in thyrotropin (TSH) levels (hypothyroid status) were observed at GDs 15 & 20 with respect to control group. The reverse pattern (hyperthyroid status) was observed in their fetuses at embryonic days (EDs) 15 & 20. Although the maternal body weight was diminished, the weight of the thyroid gland was increased at studied GDs as compared to the control group. The fetal growth retardation, hyperleptinemia, hyperinsulinism, and cytokines distortions (transforming growth factor-beta; TGF-beta, tumor necrosis factor alpha; TNF-alpha, and interferon-gamma; IFN-gamma) were noticed at examined EDs if compared to the control group. Alternatively, the maternofetal thyroid dysfunctions due to the maternal DEXA administration attenuated the levels of fetal cerebral norepinephrine (NE) and epinephrine (E), and elevated the levels of dopamine (DA) and 5-hydroxytryptamine (5-HT) at considered days. These alterations were age-dependent and might damage the nerve transmission. Finally, maternal DEXA might act as neuroendocrine disruptor causing dyshormonogenesis and fetal cerebral dysfunction. PMID- 27220269 TI - Letter to the Editor. PMID- 27220268 TI - Suppression of Bim by microRNA-19a may protect cardiomyocytes against hypoxia induced cell death via autophagy activation. AB - Microvascular obstruction (MO), one of unfavorable complications of percutaneous coronary intervention (PCI), is responsible for the lost benefit of reperfusion therapy. Determination of microRNA-19a, a member of the miR-17-92 cluster, using quantitative real-time polymerase chain reaction (PCR) revealed notably down regulated microRNA-19a, in myocardium with MO. Nonetheless, the role of miR-19a in MO and the underlying mechanism remains to be elucidated. To this end, an in vitro microembolization model in cardiomyocytes was used. Our data revealed that hypoxic exposure prompted cardiomyocyte apoptosis in a time-dependent manner accompanied by reduced miR-19a. miR-19a overexpression clearly ameliorated hypoxia-induced cell death (necrosis and apoptosis), at least in part, through switching on autophagy. Further dual-luciferase reporter assay and immunoblotting studies demonstrated that miR-19a-induced cytoprotection might be achieved in part through modulation of the specific target Bcl-2 interacting mediator of cell death, Bim, an apoptotic activator. Bim sufficiently interfered with miR-19a induced LC3 conversion and increased cardiomyocyte apoptosis under hypoxia. Moreover, cardiomyocytes pretreated with 3-methyladenine conferred resistance to the cytoprotective effect of miR-19a and displayed notably increased TUNEL staining and caspase-3 activity. In conclusion, miR-19a protected cardiomyocytes against hypoxia-induced lethality at least in part via Bim suppression and subsequently autophagy activation. PMID- 27220270 TI - HPTLC-aptastaining - Innovative protein detection system for high-performance thin-layer chromatography. AB - Protein analysis using high-performance thin-layer chromatography (HPTLC) is not commonly used but can complement traditional electrophoretic and mass spectrometric approaches in a unique way. Due to various detection protocols and possibilities for hyphenation, HPTLC protein analysis is a promising alternative for e.g., investigating posttranslational modifications. This study exemplarily focused on the investigation of lysozyme, an enzyme which is occurring in eggs and technologically added to foods and beverages such as wine. The detection of lysozyme is mandatory, as it might trigger allergenic reactions in sensitive individuals. To underline the advantages of HPTLC in protein analysis, the development of innovative, highly specific staining protocols leads to improved sensitivity for protein detection on HPTLC plates in comparison to universal protein derivatization reagents. This study aimed at developing a detection methodology for HPTLC separated proteins using aptamers. Due to their affinity and specificity towards a wide range of targets, an aptamer based staining procedure on HPTLC (HPTLC-aptastaining) will enable manifold analytical possibilities. Besides the proof of its applicability for the very first time, (i) aptamer-based staining of proteins is applicable on different stationary phase materials and (ii) furthermore, it can be used as an approach for a semi quantitative estimation of protein concentrations. PMID- 27220271 TI - An immunoinhibition approach to overcome the impact of pre-existing antibodies on cut point establishment for immunogenicity assessment of moxetumomab pasudotox. AB - Immunogenicity can impact PK, PD, efficacy and safety of biopharmaceuticals, and is often evaluated as a secondary objective in clinical studies. Methods to detect anti-drug antibodies (ADA) and neutralizing ADA (NAb) are semi quantitative and utilize cut points to determine positive or negative samples. Assay cut points are established by the statistical analysis of treatment-naive subject specimens that are assumed ADA and NAb-negative. Pre-existing antibodies to various biopharmaceuticals have been observed in treatment-naive subjects and may artificially elevate the cut point, resulting in compromised assay sensitivities, inaccuracy in immunogenicity reporting and ultimately misleading assessment of the impact of immunogenicity on clinical outcomes. Although several approaches such as removal of pre-existing antibody samples or increasing the sample dilution could be used for cut point establishment to mitigate impact of pre-existing antibodies, they each have limitations, especially when a high prevalence of pre-existing antibodies is observed. Here we describe an innovative approach used to establish cut points for ADA and NAb assays of moxetumomab pasudotox (moxetumomab), a recombinant anti-CD22 immunotoxin, to which a high prevalence of pre-existing antibodies was observed. In order to overcome the challenges associated with this high prevalence and prevent establishment of an artificially elevated cut point, we developed an immunoinhibition approach that allowed generation of pseudo ADA and NAb-negative populations for cut point determination. Immunoinhibition was performed by adding excess moxetumomab (for ADA) or a non-CD22 binding PE38-containing immunotoxin, CAT-5001 (for NAb), to treatment-naive samples prior to evaluating samples for cut point establishment. This approach successfully eliminated pre-existing antibody activity in treatment naive samples, enabling establishment of more accurate ADA and NAb assay cut points. A comparative analysis of the clinical immunogenicity results using cut points derived with immunoinhibition and without immunoinhibition (conventional method) demonstrated that the immunoinhibition approach markedly improved detection sensitivity and accuracy of immunogenicity characterization in patient samples. This innovative approach provides an alternative, practical solution for immunogenicity assay cut point establishment when biopharmaceuticals have a high prevalence of pre-existing antibodies. PMID- 27220276 TI - Effectiveness of a Web-Based Screening and Fully Automated Brief Motivational Intervention for Adolescent Substance Use: A Randomized Controlled Trial. AB - BACKGROUND: Mid-to-late adolescence is a critical period for initiation of alcohol and drug problems, which can be reduced by targeted brief motivational interventions. Web-based brief interventions have advantages in terms of acceptability and accessibility and have shown significant reductions of substance use among college students. However, the evidence is sparse among adolescents with at-risk use of alcohol and other drugs. OBJECTIVE: This study evaluated the effectiveness of a targeted and fully automated Web-based brief motivational intervention with no face-to-face components on substance use among adolescents screened for at-risk substance use in four European countries. METHODS: In an open-access, purely Web-based randomized controlled trial, a convenience sample of adolescents aged 16-18 years from Sweden, Germany, Belgium, and the Czech Republic was recruited using online and offline methods and screened online for at-risk substance use using the CRAFFT (Car, Relax, Alone, Forget, Friends, Trouble) screening instrument. Participants were randomized to a single session brief motivational intervention group or an assessment-only control group but not blinded. Primary outcome was differences in past month drinking measured by a self-reported AUDIT-C-based index score for drinking frequency, quantity, and frequency of binge drinking with measures collected online at baseline and after 3 months. Secondary outcomes were the AUDIT-C-based separate drinking indicators, illegal drug use, and polydrug use. All outcome analyses were conducted with and without Expectation Maximization (EM) imputation of missing follow-up data. RESULTS: In total, 2673 adolescents were screened and 1449 (54.2%) participants were randomized to the intervention or control group. After 3 months, 211 adolescents (14.5%) provided follow-up data. Compared to the control group, results from linear mixed models revealed significant reductions in self-reported past-month drinking in favor of the intervention group in both the non-imputed (P=.010) and the EM-imputed sample (P=.022). Secondary analyses revealed a significant effect on drinking frequency (P=.037) and frequency of binge drinking (P=.044) in the non-imputation-based analyses and drinking quantity (P=.021) when missing data were imputed. Analyses for illegal drug use and polydrug use revealed no significant differences between the study groups (Ps>.05). CONCLUSIONS: Although the study is limited by a large drop-out, significant between-group effects for alcohol use indicate that targeted brief motivational intervention in a fully automated Web-based format can be effective to reduce drinking and lessen existing substance use service barriers for at-risk drinking European adolescents. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Registry: ISRCTN95538913; http://www.isrctn.com/ISRCTN95538913 (Archived by WebCite at http://www.webcitation.org/6XkuUEwBx). PMID- 27220277 TI - TLR signals posttranscriptionally regulate the cytokine trafficking mediator sortilin. AB - Regulating the transcription, translation and secretion of cytokines is crucial for controlling the appropriate balance of inflammation. Here we report that the sorting receptor sortilin plays a key role in cytokine production. We observed interactions of sortilin with multiple cytokines including IFN-alpha, and sortilin depletion in plasmacytoid dendritic cells (pDCs) led to a reduction of IFN-alpha secretion, suggesting a pivotal role of sortilin in the exocytic trafficking of IFN-alpha in pDCs. Moreover, sortilin mRNA was degraded posttranscriptionally upon stimulation with various TLR ligands. Poly-rC-binding protein 1 (PCBP1) recognized the C-rich element (CRE) in the 3' UTR of sortilin mRNA, and depletion of PCBP1 enhanced the degradation of sortilin transcripts, suggesting that PCBP1 can act as a trans-acting factor to stabilize sortilin transcripts. The nucleotide-binding ability of PCBP1 was impaired by zinc ions and alterations of intracellular zinc affect sortilin expression. PCBP1 may therefore control the stability of sortilin transcripts by sensing intracellular zinc levels. Collectively, our findings provide insights into the posttranslational regulation of cytokine production through the posttranscriptional control of sortilin expression by TLR signals. PMID- 27220279 TI - Unified reaction pathways for the prebiotic formation of RNA and DNA nucleobases. AB - The reaction pathways for the prebiotic formation of nucleobases are complex and lead to the formation of a mixture of products. In the past 50 years, there has been a concerted effort for identifying a unified mechanism for the abiotic origin of the biomolecules but with little success. In the present theoretical study, we identified two prominent precursors for the building up of RNA and DNA nucleobases under prebiotic conditions: (a) 1,2-diaminomaleonitrile (DAMN), which is a tetramer of hydrogen cyanide (HCN), and (b) formamide, a hydrolysis product of HCN; it is important to emphasize that HCN is the source of both precursors. We find that free radical pathways are potentially appropriate to account for the origin of nucleobases from HCN. The current study unites the formamide pathways with the DAMN pathways. The mechanisms for the formation of the RNA and DNA nucleobases (uracil, adenine, purine, cytosine) were studied by quantum chemical computations using density functional theory at the B3LYP/6-311G(d,p) level. All the routes involved proceed with relatively low energy barriers (within the error margin of DFT methods). We showed that the radical mechanisms for the formation of nucleobases could be unified through common precursors. The results demonstrated that 4-aminoimidazole-5-carbonitrile (AICN), which is a known precursor for nucleobases, is a product of DAMN. The overall mechanisms are internally consistent with the abiotic formation of the nucleobases, namely (a) under a meteoritic impact scenario on the early Earth's surface that generated high internal energy, and/or (b) in the (gas phase) interstellar regions without the presence of catalysts. PMID- 27220278 TI - Risk allelic load in Th2 and Th3 cytokines genes as biomarker of susceptibility to HPV-16 positive cervical cancer: a case control study. AB - BACKGROUND: Alterations in the host cellular immune response allow persistent infections with High-Risk Human Papillomavirus (HR-HPV) and development of premalignant cervical lesions and cervical cancer (CC). Variations of immunosuppressive cytokine levels in cervix are associated with the natural history of CC. To assess the potential role of genetic host immunity and cytokines serum levels in the risk of developing CC, we conducted a case-control study paired by age. METHODS: Peripheral blood samples from patients with CC (n = 200) and hospital controls (n = 200), were used to evaluate nine biallelic SNPs of six cytokine genes of the adaptive immune system by allelic discrimination and cytokines serum levels by ELISA. RESULTS: After analyzing the SNP association by multivariate logistic regression adjusted by age, CC history and smoking history, three Th2 cytokines (IL-4, IL-6 and IL-10) and one Th3 (TGFB1) cytokine were significantly associated with CC. Individuals with at least one copy of the following risk alleles: T of SNP (-590C > T IL-4), C of SNP (-573G > C IL-6), A of SNP (-592C > A IL-10), T of SNP (-819C > T IL-10) and T of SNP (-509C > T TGFB1), had an adjusted odds ratio (OR) of 2.08 (95 % CI 1.475-2.934, p = 0.0001), an OR of 1.70 (95 % CI 1.208-2.404, p = 0.002), an OR of 1.87 (95 % CI 1.332-2.630, p = 0.0001), an OR of 1.67 (95 % CI 1.192-2.353, p = 0.003) and an OR of 1.91 (95 % CI 1.354-2.701, p = 0.0001), respectively, for CC. The burden of carrying two or more of these risk alleles was found to have an additive effect on the risk of CC (p trend = 0.0001). Finally, the serum levels of Th2 and Th3 cytokines were higher in CC cases than the controls; whereas IFNG levels, a Th1 cytokine, were higher in controls than CC cases. CONCLUSION: The significant associations of five SNPs with CC indicate that these polymorphisms are potential candidates for predicting the risk of development of CC, representing a risk allelic load for CC and can be used as a biomarker of susceptibility to this disease. PMID- 27220280 TI - Micromonospora sediminis sp. nov., isolated from mangrove sediment. AB - The novel actinomycete, strain CH3-3T, was isolated from mangrove sediment collected from Chonburi Province, Thailand. On the basis of its spore morphology and chemotaxonomic characteristics, the strain belonged to the genus Micromonospora. It contained meso-diaminopimelic acid, glucose, mannose, xylose, ribose and rhamnose in the whole-cell hydrolysate, MK-10(H4), MK-10(H6) and MK 10(H8) as major menaquinones, and iso-C15 : 0, iso-C16 : 0 and iso-C17 : 0 as major cellular fatty acids. blast analysis of 16S rRNA gene sequences revealed that the strain showed highest similarity with Micromonospora palomenae NEAU-CX1T (98.97 %) and Micromonospora coxensis 2-30-b(28)T (98.97 %). Based on phylogenetic tree analysis of the 16S rRNA gene sequence, the strain formed a cluster with M. palomenae NEAU-CX1T, Micromonospora halophytica DSM 43171T, M. coxensis 2-30-b(28)T and Micromonospora purpureochromogenes DSM 43821T. On the basis of phenotypic differences and DNA-DNA relatedness evidence, strain CH3-3T could be clearly distinguished from the closely related species of the genus Micromonospora and represents a novel species of the genus Micromonospora for which the name Micromonospora sediminis sp. nov. is proposed. The type strain is CH3-3T (=JCM 18523T=PCU 350T=TISTR 2396T). PMID- 27220281 TI - Idiopathic Premature Ventricular Contraction Conducting over a Ventricle Myocardial Extension from the Pulmonary Artery. AB - Ventricle myocardial extensions (VMEs) from the right ventricular outflow tract to the pulmonary artery (PA) serve as arrhythmogenic foci for idiopathic ventricular arrhythmias (VAs). Although an autopsy study revealed the heterogeneity of the VME, only the electrocardiographic features of PA-VAs arising from septal VMEs have been discussed. Here, we describe a case of idiopathic PA-VAs conducting over a VME accompanied by unique ventricle activation patterns, which contributed to the appearance of an S wave in the inferior limb leads despite an arrythmogenic focus in the outflow tract. PMID- 27220282 TI - Molecular analysis of dolphin morbillivirus: A new sensitive detection method based on nested RT-PCR. AB - Cetacean Morbillivirus (CeMV) has been identified as the most pathogenic virus for cetaceans. Over the past three decades, this RNA virus has caused several outbreaks of lethal disease in odontocetes and mysticetes worldwide. Isolation and identification of CeMV RNA is very challenging in whales because of the poor preservation status frequently shown by tissues from stranded animals. Nested reverse transcription polymerase chain reaction (nested RT-PCR) is used instead of conventional RT-PCR when it is necessary to increase the sensitivity and the specificity of the reaction. This study describes a new nested RT-PCR technique useful to amplify small amounts of the cDNA copy of Cetacean morbillivirus (CeMV) when it is present in scant quantity in whales' biological specimens. This technique was used to analyze different tissues (lung, brain, spleen and other lymphoid tissues) from one under human care seal and seven cetaceans stranded along the Italian coastline between October 2011 and September 2015. A well characterized, 200 base pair (bp) fragment of the dolphin Morbillivirus (DMV) haemagglutinin (H) gene, obtained by nested RT-PCR, was sequenced and used to confirm DMV positivity in all the eight marine mammals under study. In conclusion, this nested RT-PCR protocol can represent a sensitive detection method to identify CeMV-positive, poorly preserved tissue samples. Furthermore, this is also a rather inexpensive molecular technique, relatively easy to apply. PMID- 27220283 TI - Synaptotagmin-like protein 2 gene promotes the metastatic potential in ovarian cancer. AB - Ovarian cancer (OC) metastasis has unique biological behavior and most commonly occurs via the transcoelomic route. Previously, we established a mouse xenograft model of human ovarian carcinoma and analyzed alterations in gene expression during metastasis. Among the genes that were differentially expressed more than 2 fold in the xenografts compared with the SK-OV-3 cells, we selected synaptotagmin like protein 2 (SYTL2) and investigated the mechanisms regulating its expression and its gene function in OC. The mRNA expression of SYTL2 was significantly upregulated and the methylation of specific CpG sites within the SYTL2 promoter was decreased in the metastatic implants from the ovarian carcinoma xenografts compared to wild-type SK-OV-3 cells. Treatment with the demethylating agent 5-aza 2'-deoxycytidine and/or the histone deacetylase inhibitor Trichostatin A induced upregulation of SYTL2 in SK-OV-3 cells, implying that a DNA methylation-dependent epigenetic mechanism is involved in the regulation of SYTL2 expression. We also found that overexpression of SYTL2 promoted metastatic potential, including increased migration and invasiveness in the ovarian carcinoma cells. Furthermore, we utilized publicly available gene expression data to confirm the correlation between SYTL2 expression and poor prognosis in serous-type OC patients. Our findings provide novel evidence for the direct association of SYTL2 with the metastatic potential of ovarian carcinoma cells and its influence on metastatic recurrence of OC. PMID- 27220284 TI - Clinicopathological features of colloid adenocarcinoma of the lung: A report of six cases. AB - OBJECTIVES: Colloid adenocarcinoma of the lung (CA) is a rare neoplasm that is associated with abundant mucin, which destroys alveoli. We evaluated the clinicopathological features of CA. METHODS: A total of 4,648 patients underwent surgical resection of primary lung cancer at our institution from 2002 to 2014. We analyzed the clinicopathological features of CA in six (0.13%) of these patients. RESULTS: All patients were asymptomatic. The median age was 60.5 years. The median tumor size was 2.4 cm. All tumors appeared as solitary solid nodules on computed tomography (CT). Four of the six showed intense (18) F fluorodeoxyglucose positron emission tomography ((18) F-FDG-PET) accumulation, and the remaining two showed weak (18) F-FDG accumulation. All patients underwent lobectomy with systematic lymph node dissection. Histologically, CAs presented with various degrees of a non-mucinous component in addition to abundant mucin. Only one patient with pN2 had recurrence. CONCLUSIONS: On CT, CA appears a solitary solid nodule. Further, FDG-PET findings present various (18) F-FDG accumulations. Lobectomy with systematic lymph node dissection is an appropriate procedure in view of lymph node metastasis. Since the definitive diagnosis of CA of the lung is difficult, further immunohistochemical and genetic analyses are needed. J. Surg. Oncol. 2016;114:211-215. (c) 2016 Wiley Periodicals, Inc. PMID- 27220285 TI - The Richness Available Within Medication Management. AB - PROBLEM: An 18-year-old male patient comes in for an initial evaluation of his anxiety. His anxiety is not in remission on his current medication, and he is experiencing tics when his anxiety escalates. METHODS: Time and patience are used to complete a comprehensive evaluation of the patient by interviewing him, gathering collateral information from a family member, utilizing a screening tool, reviewing past history and treatment regimens, and conceptualizing the patient. FINDINGS: A thorough interview and assessment reveals a rich history of possible antecedents to the anxiety of the patient. CONCLUSION: In order to make a thorough biopsychosocial assessment, the practitioner needs to approach the patient with a genuine interest. By utilizing time and patience, the practitioner has a greater opportunity to gather pertinent information for comprehensive recommendations. Underlying issues contributing to the patient's anxiety may be alleviated through nonpharmacologic management in addition to medication. PMID- 27220287 TI - Composition and aggregation of extracellular polymeric substances (EPS) in hyperhaline and municipal wastewater treatment plants. AB - As important constituents of activated sludge flocs, extracellular polymeric substances (EPS) play significant roles in pollutants adsorption, the formation and maintenance of microbial aggregates, and the protection of microbes from external environmental stresses. In this work, EPS in activated sludge from a municipal wastewater treatment plant (M-WWTP) with anaerobic/anoxic/oxic (A(2)/O) process and a hyperhaline wastewater treatment plant (H-WWTP) with anaerobic/oxic (A/O) process were extracted by ultrasound method. The proteins and polysaccharides contents in EPS were determined by using a modified Lowry method and anthrone colorimetry respectively to analyze the detail differences in two types of WWTPs. Fourier transform-infrared spectroscopy and three-dimensional excitation-emission matrix fluorescence spectroscopy demonstrated proteins and polysaccharides were the dominant components of the two types of EPS, and the aromatic protein-like substances accounted for a larger proportion in EPS proteins. The results of the aggregation test indicated that EPS were good for the sludge aggregation, and the EPS in oxic sludge were more beneficial to sludge aggregation than that in anoxic sludge. Anoxic sludge EPS in H-WWTP showed a negligible effect on sludge aggregation. Comparative study on EPS of different tanks in the M-WWTP and H-WWTP was valuable for understanding the characteristics of EPS isolated from two typical wastewater treatment processes. PMID- 27220288 TI - [Attaching importance to standardization of diagnosis and treatment in otitis media]. PMID- 27220289 TI - [Experts consensus on diagnosis and treatment of laryngopharyngeal reflux disease (2015)]. PMID- 27220286 TI - Remodeling of lipid bodies by docosahexaenoic acid in activated microglial cells. AB - BACKGROUND: Organelle remodeling processes are evolutionarily conserved and involved in cell functions during development, aging, and cell death. Some endogenous and exogenous molecules can modulate these processes. Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid, has mainly been considered as a modulator of plasma membrane fluidity in brain development and aging, while DHA's role in organelle remodeling in specific neural cell types at the ultrastructural level remains largely unexplored. DHA is notably incorporated into dynamic organelles named lipid bodies (LBs). We hypothesized that DHA could attenuate the inflammatory response in lipopolysaccharide (LPS)-activated microglia by remodeling LBs and altering their functional interplay with mitochondria and other associated organelles. RESULTS: We used electron microscopy to analyze at high spatial resolution organelle changes in N9 microglial cells exposed to the proinflammogen LPS, with or without DHA supplementation. Our results revealed that DHA reverses several effects of LPS in organelles. In particular, a large number of very small and grouped LBs was exclusively found in microglial cells exposed to DHA. In contrast, LBs in LPS stimulated cells in the absence of DHA were sparse and large. LBs formed in the presence of DHA were generally electron-dense, suggesting DHA incorporation into these organelles. The accumulation of LBs in microglial cells from mouse and human was confirmed in situ. In addition, DHA induced numerous contacts between LBs and mitochondria and reversed the frequent disruption of mitochondrial integrity observed upon LPS stimulation. Dilation of the endoplasmic reticulum lumen was also infrequent following DHA treatment, suggesting that DHA reduces oxidative stress and protein misfolding. Lipidomic analysis in N9 microglial cells treated with DHA revealed an increase in phosphatidylserine, indicating the role of this phospholipid in normalization and maintenance of physiological membrane functions. This finding was supported by a marked reduction of microglial filopodia and endosome number and significant reduction of LPS-induced phagocytosis. CONCLUSIONS: DHA attenuates the inflammatory response in LPS stimulated microglial cells by remodeling LBs and altering their interplay with mitochondria and other associated organelles. Our findings point towards a mechanism by which omega-3 DHA participates in organelle reorganization and contributes to the maintenance of neural cell homeostasis. PMID- 27220290 TI - [Explanation of the experts consensus on diagnosis and treatment of laryngopharyngeal reflux disease (2015)]. PMID- 27220291 TI - [Analyses of the factors relevant to revision tympanomastoid surgery]. AB - OBJECTIVE: To analyze factors relevant to revisional tympanomastoid surgery for chronic otitis media(COM). METHODS: The clinical data of 159 patients (159 ears), who exhibited either wet ear or relapsed after the initial operation, and were subjected to revisional tympanomastoid surgery, were retrospectively analyzed in this study. Of those 159 consecutive patients, 85 were males and 74 were females, aged 11-64 years, with a median age of 36 years old. The situations in terms of intra-operative findings, surgical procedures, change dressing post-operation, dry ear time, and the improvement of aural ability during the second operation, were recorded and analyzed. RESULTS: The second surgery found that, of those 159 patients underwent the re-operation, 67 presented with cholesteatoma and 92 had no cholesteatoma. In addition, the inadequate skeletonization and insufficient opening for mastoid cavity accounted for 70.4% (112/159) of all previous operations, the external auditory canal stenosis for 98.7% (157/159), the high facial ridge leading to insufficient drainage for 61.0% (97/159), the lesion in tympanic ostium of Eustachian tube for 34.6% (55/159), the insufficient drainage due to inappropriate post-operating dressing for 5.0% (8/159), the postauricular incision for 30.8% (49/159), and the endaural incision for 69.2% (110/159). As for the re-operation of the canal wall down mastoidectomy, tympanoplasty plus plastic repairing of cavity of concha were performed in 94 cases, the modified Bondy plus plastic repairing of cavity of concha in four cases, the radical mastoidectomy plus plastic repairing of cavity of concha in 59 cases, and the simple cleaning for mastoid cavity in two cases. Since one to two weeks after the revisional operations, the post-operating dressing was performed with aid of microscopy once a week on average. The average dry ear time ranged from 2 to 6 weeks (median=3 weeks). During a period of 6-93 months for the follow-up, all patients presented with dry ears. The epithelialization of the operating cavity was well and the tympanic membranes were integrity. Neither granulation tissue nor cholesteatoma was found to reoccur. Both pure tone hearing thresholds and air bone gap decreased in 87 cases after the revisional operation, with statistically significant different in comparison to those two parameters before the operation (P<0.05). CONCLUSION: The primary causes responsible for the wet ear or reoccurrent cholesteatoma after tympanomastoid surgery may be related to the improper operation procedures and selection of incision, the non-standard operation, inexhaustive removal of pathological tissues, as well as the irregular postoperation change dressing, and other factors. PMID- 27220292 TI - [Analyses of the operative efficacy of 102 cases of acquired middle ear cholesteatoma]. AB - OBJECTIVE: To investigate the efficacy of operations of acquired middle ear cholesteatoma. METHODS: Retrospectively analyzed clinical data of 102 patients whom received tympanoplasty with CWU or CWD with mastoid obliteration in our hospital between January 2014 and December 2014. Patients were divided into different groups according to types of the cholesteatoma as well as the different surgical procedures. Patients were followed up for 12-24 months, the pre and post operative PTA was performed and evaluated. The post-operative hearing was assessed in terms of average ABG. RESULTS: The average dry ear time was (5.4+/ 1.7)weeks. The dry ear time of patients of attic cholesteatoma was shorter than those of tensa cholesteatoma[(4.9+/-1.7)weeks vs(6.1+/-1.5)weeks, t=-3.52, P=0.001]; the dry ear time of patients underwent CWU was shorter than those underwent CWD with mastoid obliteration[(2.3+/-0.5)weeks vs(5.8+/-1.4)weeks, t= 8.43, P=0.000]. Mean pre and post-operative air bone gaps in 93 ears underwent ossiculoplasty were (34.2+/-11.8)dB and (19.0+/-5.5)dB respectively and these differences were statistically significant. Both the pre and post-operative air bone gaps of ears of attic cholesteatoma were smaller than those ears of tensa cholesteatoma(P<0.05). In the patients who underwent ossiculoplasty with CWD with mastoid obliteration, the post-operative air bone gaps of attic cholesteatoma were smaller than those of tensa cholesteatoma(P<0.05). Both the pre and post operative air bone gaps of ears underwent CWU were smaller than those underwent CWD with mastoid obliteration(P<0.05). The post-operative air bone gaps of ears underwent PORP with CWD with mastoid obliteration were smaller than those underwent TORP with CWD with mastoid obliteration(P<0.05). CONCLUSIONS: Both the hearing loss and the outcome of tensa cholesteatoma are worser than attic cholesteatoma. The outcome of PORP is better than TORP. The patients who will accept CWU should be selected more carefully and be followed up regularly. PMID- 27220293 TI - [Analyses of chronic otitis media with intact tympanic membrane concurrent with intracranial complication]. AB - OBJECTIVE: To investigate the clinical and imaging characteristics of chronic otitis media with intact tympanic membrane. METHOD: Ten patients were retrospective studied in the department of otorhinolaryngology of Guangdong general hospital from December 2006 to January 2015. The clinical characteristics of their manifestations, audiology and imaging examinations were analyzed. RESULTS: All the cases could be divided into two groups: the intracranial complication group who was primarily diagnosed as intracranial complications, and the hearing loss group who primarily complained of hearing loss. Five cases belonged to the first group, which include 1 cerebellar abscess, 3 meningitis and 1 meningoencephalitis, 2 of them were profound hearing loss, 2 were mixed hearing loss, and 1 was normal hearing. The other 5 cases belonged to the hearing loss group, 3 were mixed deafness, 2 were conductive deafness. All the case showed positive high-resolution computed tomography (HRCT) features. In the first group, four cases showed the soft tissue shadow in tympanic antrum/superior tympanic pouch and 1 case showed a wide damage of skull base, in addition to intracranial complications. In the second group, five cases showed soft tissue imaging in tympanic antrum/superior tympanic pouch. Pathology showed that 2 cases were cholesterol granuloma(one was in the first group and the other was in the second group), 4 were intracranial inflammatory(the first group) and 4 were cholesteatoma(the seond group). CONCLUSIONS: In chronic otitis media with intact tympanic membrane, intracranial complications may be the primarily diagnosis, which should be paid much attention by multidisciplinary team. HRCT and audiology were valuable for early diagnosis. PMID- 27220294 TI - [Analyses of the clinical characteristics of unilateral conductive hearing loss with intact tympanic membrane]. AB - OBJECTIVE: To analyze the clinical characteristics of unilateral conductive hearing loss with intact tympanic membrane, and summarize the key diagnostic points, differential diagnosis and observe the effects of surgical treatment. METHODS: We reviewed data from 82 patients with unilateral conductive hearing loss with intact tympanic membranes who accepted the exploratory tympanotomy from April 2011 to September 2013. There were 41 males and 41 females, aged from 7 to 66( averaged 26.5+/-13.7)years, with a history of one month to 50 years. The history, clinical symptoms, audiological evaluation, high resolution temporal bone CT, the results of surgical exploration and hearing reconstruction were analyzed. RESULTS: The exploratory tympanotomy revealed 43 cases of congenital middle ear malformations (52.4%), 22 cases of otosclerosis (26.8%), eight cases of congenital cholesteatoma (9.8%), six cases of trauma induced conductive hearing loss (7.3%), three cases of congenital ossicular malformations with congenital cholesteatoma (3.7%). Progressive hearing loss was common in patients with otosclerosis and congenital cholesteatoma, and patients with congenital middle ear malformations described their hearing loss since childhood. High resolution temporal bone CT of congenital middle ear malformation, trauma induced conductive hearing loss, congenital cholesteatoma diagnosis rate was 40.0%, 50.0%, and 83.3% respectively. The preoperative air-conductive threshold of patients with absence of the oval window were increased to (66.9+/-1.1)dBHL, the preoperative bone-conductive threshold achieved (28.3+/-10.4)dBHL at 2 000 Hz. While patients with stapes fixation and that with ossicular chain discontinuity were (27.2+/-9.7)dBHL and (17.8+/-8.8)dBHL(P=0.000)respectively. Through the tympanic exploration with endaural incision under the microscope, different hearing reconstruction were applied according to different lesions. After the operation, the hearing level of 52 patients with return visit were improved, the mean air-conductive threshold were decreased from (60.0+/-11.4)dBHL to (32.2+/ 12.1)dBHL(P=0.000); and the mean ABG were decreased from (43.2+/-12.0)dB to (16.3+/-9.4)dB(P=0.000). CONCLUSIONS: Congenital middle ear malformations, otosclerosis, congenital cholesteatoma are the most common causes in unilateral conductive hearing loss with an intact tympanic membrane. The diagnosis rate can be improved by analyzing the clinical features. Through exploratory tympanotomy and hearing reconstruction, we can clarify the diagnosis and achieve a satisfying hearing recover. PMID- 27220295 TI - [The application of subjective visual gravity in assessment of vestibular compensation: a pilot study]. AB - OBJECTIVE: To discuss the characteristics of subjective visual gravity (subjective visual vertical/horizontal, SVV/SVH) and assess its clinical application for peripheral unilateral vestibular compensation. METHODS: 69 cases of acute peripheral unilateral vestibular dysfunction patients (case group) accepted SVV/SVH, spontaneous nystagmus (SN), caloric test (CT) and other vestibular function tests. 49 healthy people (control group) accepted SVV/SVH only. SVV/SVH, SN and unilateral weakness (UW) were selected as for the observation indicators. The correlations between SVV/SVH, SN, UW and courses were investigated respectively, as well as the characteristic of SVV/SVH, SN in period of vestibular compensation. RESULTS: Among case group SVV, SVH positive in 42 patients(60.9%) and 44 patients(63.8%), the absolute values of the skew angle were in the range between 2.1 degrees -20.0 degrees , 2.1 degrees -22.2 degrees . Skew angles of SVV/SVH in control were in the range between -1.5 degrees -2.0 degrees and -2.0 degrees -1.6 degrees , and had no statistical significance with case group(t=5.336 and 5.864, P<0.05). SN-positive 28 cases (40.6%), the range of intensities at 2.4 degrees -17.1 degrees ; UW-positive 50 cases (72.5%). In case group, positive correlation between SVV and SVH(r=0.948, P=0.00), negatively correlated between SVV/SVH and SN respectively(r values were -0.720, -0.733, P values were 0.00), no correlation between the skew angle of SVV/SVH, strength of SN and UW value(r values were 0.191, 0.189, and 0.179, P>0.05), there was no correlation between the absolute value of SVV, SVH, SN, UW with the duration (rs values were -0.075, -0.065, -0.212, and 0.126, P>0.05). CONCLUSION: Subjective visual gravity can be used not only to assess the range of unilateral peripheral vestibular dysfunction, but also help assess the static compensatory of otolithic, guidance and assessment of vestibular rehabilitation. PMID- 27220296 TI - [Analysis of influencing factors on rehabilitation effects for 1 422 preschool deaf children following cochlear implantation]. AB - OBJECTIVE: To investigate the basic factors of the progress amplitude of hearing and speech rehabilitation effect of preschool deaf children with cochlear implants, and provide guidance for the improvement and optimization of rehabilitation strategies. METHOD: Using the standard hearing and language assessment tools, tracked and evaluated 1 422 CI preschool deaf children for a period of one year, and calculated the effect of hearing and speech rehabilitation, carried out the correlation analysis and variance analysis among different grouping variables. RESULT: (1) There was a negative correlation (P<0.01) between the rehabilitation effect and cochlear implantation age, existed the different degree of positive correlation (P<0.01) between the rehabilitation effect and parents cultural level, but no correlation between the rehabilitation effect and parents hearing status.(2) Father's education level, in comparison to mother's education level, had greater impact on the children rehabilitation effect.(3)There was positive correlation(r=0.689, P<0.01) between the progress amplitude of hearing and speech rehabilitation effect. (4) The progress amplitude of auditory and language rehabilitation effect of 2-3 years old group was the highest value(the progress amplitude of hearing and speech recognition rate reached 77.5%, the progress amplitude of language age progress rate reached 2.02 years old), and there were significant differences (P<0.05) between over 3 years old groups. CONCLUSIONS: (1) To expect the better progress amplitude of rehabilitation effect, cochlear implant age should not be more than 3 years old. (2) Father's effect in the process of rehabilitation is more helpful for deaf children's learning enthusiasms. PMID- 27220297 TI - [The clinical experience of transnasal endoscopic approach for skull base osteoradionecrosis after radiotherapy for nasopharyngeal carcinoma]. AB - OBJECTIVE: To investigate the method of surgical treatment via trans-nasal endoscopic approach in osteoradionecrosis of skull base after radiotherapy for nasopharyngeal carcinoma. METHODS: Fifteen patients with osteoradionecrosis of skull base after radiotherapy for nasopharyngeal carcinoma who underwent operation via trans-nasal endoscopic approach from 2008 to 2013 were retrospectively reviewed. The typical clinical manifestations included headache (NRS 6-9: 11 cases), foul odor (10 cases), epistaxis (4 cases), hearing loss (5 cases, 7 ears), tinnitus (4 cases, 5 ears). All patients underwent operation via trans-nasal endoscopic approach. During the operation, the diseased region was fully exposed, the necrotic tissue was resected, the necrotic bone was removed by high-speed electric drill, and the drainage was made unobstructed. The perioperative treatment and follow-up were carried out. RESULTS: After operation, all patients were diagnosed pathologically as osteoradionecrosis and mucosal chroinic inflammation, 1 case combined with fungal sphenoid sinusitis. Headache (9 cases) and foul odor (9 cases) resolved after operation. The follow-up was lasted 18-82 months, 13 cases were survival, 1 case lost to follow-up, 1 case died of cerebral hemorrhage. CONCLUSION: Surgical treatment via trans-nasal endoscopic approach is safe and effective in osteoradionecrosis of skull base after radiotherapy for nasopharyngeal carcinoma, and is helping to improve the survival rate and survival quality. PMID- 27220298 TI - [Effective analysis of non-surgical combined treatments for laryngeal organ preservation in locally advanced laryngeal carcinoma]. AB - OBJECTIVE: To evaluate the therapeutic effects, larynx preservation and adverse events of non-surgical combined treatments for laryngeal organ preservation in locally advanced laryngeal squamous cell carcinomas(SCCs). METHODS: Forty-six patients with locally advanced laryngeal carcinoma (T2-4, N0-N3) were treated individually with non-surgical combined treatments for larynx preservation (LP). These treatments included concurrent chemoradiotherapy (CCRT)(+/-epidermal growth factor receptor (EGFR) inhibitor), induction chemotherapy (ICT) followed by CCRT(+/- EGFR inhibitor), or concurrent radiotherapy and EGFR inhibitor. Radiation therapy was given to a total dose of 60-70 Gy. The Kaplan-Meier method was used to determine the overall survival. Side-effects were evaluated with the established Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 criteria. RESULTS: The average follow-up time was 31.8 months (range 6-95 months). All patients completed the planned radiotherapy without treatment breaks, and 45(97.8%) of 46 patients completed the planned chemotherapy.The 3 year and 5-year overall survival rates were 87.3%and 67.2%, respectively.The 5 year larynx preservation rate was 100.0%. The 3-year and 5-year progression free survival rates were 95.1% and 87.7%, respectively. The most common acute side effect in grade 3 was oropharyngeal mucositis. After treatment, tracheotomy was still required in 2 patients with glottis cancer for laryngeal edema or stenosis. No patient depended on a percutaneous gastrostomy and experienced speech impairment. CONCLUSION: Patients with locally advanced laryngeal cancer can be offered non-surgical combined treatments for laryngeal preservation and the high quality of life, showing a higher laryngeal preservation survival rate with minimal toxicities. PMID- 27220300 TI - [Two cases of congenital middle ear cholesteatoma with secretory otitis media as the main manifestation in children]. PMID- 27220301 TI - [Application of hair transplantation for vibrissae reconstruction: a case report]. PMID- 27220299 TI - [The value of thyroglobulin measurement in fine-needle aspiration for diagnosis of suspicious lymph nodes in patients with thyroid carcinoma after thyroidectomy]. AB - OBJECTIVE: To investigate the value of thyroglobulin measurement in ultrasound guided fine-needle aspiration(FNA-Tg)for detecting neck node metastasis in patients with papillary thyroid carcinoma(PTC)after thyroidectomy. METHODS: A total of 128 suspicious metastatic lymph nodes in 112 patients were retrospectively analyzed. Postoperative pathologic results were taken as the gold standard. The values of FNA and FNA-Tg combined FNA in the diagnosis of metastatic lymph nodes were compared with different ultrasonic features. RESULTS: The sensitivity, specificity and accuracy of single FNA for the diagnosis of neck node metastasis were 67.5%, 98.0% and 79.7% respectively, and those of FNA-Tg combined FNA were 87.0%, 100.0% and 92.2% respectively. Compared with single FNA, the sensitivity and accuracy of FNA-Tg combined FNA were increased significantly(chi(2)=8.319, P=0.004; chi(2)=8.275, P=0.004). When the ultrasonographic characteristics met any one of five indicators for neck node metastasis, the sensitivity, specificity and accuracy of single FNA for the diagnosis of neck node metastasis were 38.1%, 95.7% and 68.2% respectively, and those of FNA-Tg combined FNA were 71.0%, 100.0% and 86.4% respectively. Compared with single FNA, the sensitivity and accuracy of FNA-Tg combined FNA were increased significantly(chi(2)=4.709, P=0.030; chi(2)=4.141, P=0.042). When the ultrasonographic characteristics met any two of five indicators for neck node metastasis, the sensitivity, specificity and accuracy of single FNA for the diagnosis of neck node metastasis were 55.0%, 100.0% and 73.5% respectively, and those of FNA-Tg combined FNA were 90.0%, 100.0% and 94.1% respectively. Compared with single FNA, the sensitivity and accuracy of FNA-Tg combined FNA were increased significantly(chi(2)=6.140, P=0.013; chi(2)=5.314, P=0.021). The ultrasonographic characteristics met any three, four or five of five indicators or did not meet any of the indicators, there was no significant difference in the value of the diagnosis of metastatic lymph nodes between single FNA and FNA-Tg combined FNA(P>0.05). CONCLUSIONS: The combination of FNA with FNA-Tg could be helpful in diagnosis of lymph node metastasis. When the suspicious lymph nodes had one or two ultrasound characteristics for neck node metastasis, FNA-Tg could raise the sensitivity and accuracy of FNA, and FNA-Tg could not significantly improve in the diagnosis of FNA when presenting with no or with more than 2 ultrasonographic features. PMID- 27220302 TI - [Verrucous carcinoma in the left lateral skull base: a case report]. PMID- 27220303 TI - [Spontaneous expulsion of an unusual bronchial foreign body from digestive tract: a case report]. PMID- 27220304 TI - [Congenital absence of the left submandibular gland: a case report]. PMID- 27220305 TI - [Research progress of thyroid imaging reporting and data system (TIRADS)]. AB - The prevalence of thyroid nodules in population is increasing around the world.To categorize thyroid nodules and stratify their malignant risk, thyroid imaging reporting and data system(TIRADS)was developed 6 years ago based on US , which is similar to breast imaging reporting and data system (BI-RADS). This paper aims at summarizing the particular content of kinds of TIRADS proposed by different researcher, clinic value of the application of TIRADS, the research status of TIRADS application, as well as the prospect of TIRADS based on CT and MRI. PMID- 27220306 TI - [Staged tympanoplasty]. PMID- 27220307 TI - [Role of narrow-band imaging endoscopy in the laryngology surgery of CO2 laser]. PMID- 27220308 TI - Hybrid sterility and evolution in Hawaiian Drosophila: differential gene and allele-specific expression analysis of backcross males. AB - The Hawaiian Drosophila are an iconic example of sequential colonization, adaptive radiation and speciation on islands. Genetic and phenotypic analysis of closely related species pairs that exhibit incomplete reproductive isolation can provide insights into the mechanisms of speciation. Drosophila silvestris from Hawai'i Island and Drosophila planitibia from Maui are two closely related allopatric Hawaiian picture-winged Drosophila that produce sterile F1 males but fertile F1 females, a pattern consistent with Haldane's rule. Backcrossing F1 hybrid females between these two species to parental species gives rise to recombinant males with three distinct sperm phenotypes despite a similar genomic background: motile sperm, no sperm (sterile), and immotile sperm. We found that these three reproductive morphologies of backcross hybrid males produce divergent gene expression profiles in testes, as measured with RNA sequencing. There were a total of 71 genes significantly differentially expressed between backcross males with no sperm compared with those backcross males with motile sperm and immotile sperm, but no significant differential gene expression between backcross males with motile sperm and backcross males with immotile sperm. All of these genes were underexpressed in males with no sperm, including a number of genes with previously known activities in adult testis. An allele-specific expression analysis showed overwhelmingly more cis-divergent than trans-divergent genes, with no significant difference in the ratio of cis- and trans-divergent genes among the sperm phenotypes. Overall, the results indicate that the regulation of gene expression involved in sperm production likely diverged relatively rapidly between these two closely related species. PMID- 27220309 TI - Fast-Track, One-Step E. coli Detection: A Miniaturized Hydrogel Array Permits Specific Direct PCR and DNA Hybridization while Amplification. AB - A timesaving and convenient method for bacterial detection based on one-step, one tube deoxyribonucleic acid (DNA) hybridization on hydrogel array while target gene amplification is described. The hydrogel array is generated by a fast one pot synthesis, where N,N'-dimethylacrylamide/polyethyleneglycol(PEG1900 ) bisacrylamide mixture polymerizes via radical photoinitiation by visible light within 20 min concomitant with in situ capture probe immobilization. These DNA functionalized hydrogel droplets arrayed on a planar glass surface are placed in the polymerase chain reaction (PCR) mixture during the thermal amplification cycles. The bacterial cells can be implemented in a direct PCR reaction, omitting the need for prior template DNA extraction. The resulting fluorescence signal is immediately detectable after the end of the PCR (1 h) following one short washing step by microscopy. Therefore a valid signal can be reached within 1.5 h including 10 min for pipetting and placement of the tubes and chips. The performance of this novel hydrogel DNA array was successfully proven with varying cell numbers down to a limit of 10(1) Escherichia coli cells. PMID- 27220310 TI - Two-year results from a randomized clinical trial of revascularization in patients with intermittent claudication. AB - BACKGROUND: Intermittent claudication is associated with significant impairment of health-related quality of life. The use of revascularization techniques to improve health-related quality of life remains controversial. METHODS: Patients with intermittent claudication due to iliac or femoropopliteal peripheral artery disease were enrolled in the IRONIC trial. They were randomized to either best medical therapy (BMT), including a structured, non-supervised exercise programme, or revascularization with either endovascular or open techniques in addition to BMT. The primary outcome was health-related quality of life at 2 years assessed using the Short Form 36 (SF-36((r)) ) questionnaire. Secondary outcomes included VascuQoL questionnaire results, treadmill walking distances and achievement of patient-specified treatment goals. RESULTS: Both randomized groups had improved health-related quality of life and treadmill walking distance at 2-year follow up. Overall SF-36((r)) physical component summary score, three SF-36((r)) physical domain scores, overall VascuQoL score, and three of five VascuQoL domain scores showed significantly greater improvement in the group that also received invasive treatment. Intermittent claudication distance on a graded treadmill improved more in the revascularization + BMT group (117 versus 55 m; P = 0.003) whereas maximum walking distance and 6-min walk test distance were similar. Some 44 per cent of patients in the revascularization + BMT group reported they had fully achieved their treatment goal versus 10 per cent in the BMT group. CONCLUSION: A revascularization strategy with unsupervised exercise improved health-related quality of life and intermittent claudication distance more than standard BMT and an unsupervised exercise programme in patients with lifestyle limiting claudication. REGISTRATION NUMBER: NCT01219842 (http://www.clinicaltrials.gov). PMID- 27220312 TI - Living in Sin? How Gay Catholics Manage Their Conflicting Sexual and Religious Identities. AB - Religious principles and values provide meaning and affect personal identity. They may also conflict with intimate needs and desires. This article examines how gay Catholics manage conflicting areas between their sexual and religious selves. Eight Polish gays with a Catholic background, who identified themselves as strong believers, shared their experiences during semi-structured interviews that were subjected to interpretative phenomenological analysis. Results showed that internalization of the principles taught by the Roman Catholic Church triggered a conflict when participants became aware of their homosexuality. They used a number of strategies to reconcile conflicting identities, including limiting their religious involvement, questioning interpretation of the doctrine, undermining priests' authority, trying to reject homosexual attraction, putting trust in God's plan, using professional help, and seeking acceptance from clergy. This study alerts mental health professionals to specific risk factors associated with experiencing a religious conflict, and offers guidelines for counseling and further research. PMID- 27220313 TI - Lung Ultrasound as a Predictor of Mechanical Ventilation in Neonates Older than 32 Weeks. AB - BACKGROUND: The prognosis of neonatal respiratory distress may be difficult to estimate at admission. Lung ultrasound is a useful diagnostic tool that is quick, requires little training, and is radiation free. OBJECTIVE: This study aims to analyze whether early lung ultrasound can predict respiratory failure. METHODS: From January to December 2014, lung ultrasound was performed on neonates admitted with breathing difficulties if they were older than 32 weeks and not intubated. A neonatologist, not aware of the patient's clinical condition, analyzed the stored ultrasound images. The findings were classified into the following 2 groups according to the potential risk of a bad respiratory outcome: low risk (normal or transient tachypnea of the newborn) or high risk (respiratory distress syndrome, meconium aspiration syndrome, pneumothorax, or pneumonia). A second investigator made the same classification after reading the chest X-rays. Respiratory failure was defined as a need for mechanical ventilation during the first day of life. RESULTS: In total, 105 neonates were recruited (64.8% in the low-risk sonography group and 35.2% in the high-risk sonography group). Of those, 20% needed intubation, and this was more frequent in the high-risk group (relative risk = 17.5; 95% CI 4.3-70.9, p < 0.01). As predictors of respiratory failure, lung ultrasound and chest X-ray showed a high index of agreement (kappa coefficient = 0.91; 95% CI 0.83-1, p < 0.01) and good accuracy (ultrasound: 95% sensitivity, 82.5% specificity, and a negative predictive value of 98.5%). CONCLUSIONS: Early lung ultrasound is a useful tool to determine which neonates admitted with respiratory distress will require mechanical ventilation. It may help the clinician to carrying out appropriate transfers. PMID- 27220311 TI - "The Pleasure Is Better as I've Gotten Older": Sexual Health, Sexuality, and Sexual Risk Behaviors Among Older Women Living With HIV. AB - There is limited research examining the sexual health and well-being of older women living with HIV (OWLH). Most studies focus on sexual dysfunction, leaving aside the richer context of sexuality and sexual health, including the effect of age-related psychosocial and interpersonal changes on sexual health behaviors. Guided by the integrative biopsychosocial model and the sexual health model, this study explored the importance of sex and sexuality among OWLH to identify their sexual health and HIV prevention needs for program planning. A purposive sample (n = 50) of OWLH was selected from a parent study (n = 2052). We conducted 8 focus groups and 41 in-depth interviews with 50 African American and Latina OWLH aged 50-69 years old in three U.S. cities. The triangulation approach was used to synthesize the data. Six salient themes emerged: sexual pleasure changes due to age, sexual freedom as women age, the role of relationships in sexual pleasure, changes in sexual ability and sexual health needs, sexual risk behaviors, and ageist assumptions about older women's sexuality. We found that sexual pleasure and the need for intimacy continue to be important for OWLH, but that changing sexual abilities and sexual health needs, such as the reduction of sexual desire, as well as increased painful intercourse due to menopause-associated vaginal drying, were persistent barriers to sexual fulfillment and satisfaction. Particular interpersonal dynamics, including low perceptions of the risk of HIV transmission as related to gender, viral suppression, and habitual condomless sex with long-term partners without HIV transmission have resulted in abandoning safer sex practices with serodiscordant partners. These findings suggest that HIV prevention for OWLH should focus on how sexual function and satisfaction intersect with sexual risk. HIV prevention for OWLH should promote ways to maintain satisfying and safe sex lives among aging women. PMID- 27220314 TI - Polish nurses' perceived barriers in using evidence-based practice in pain management. AB - AIM: The aim of this work was to present current practices, perceived barriers and perceived facilitators of Polish nurses in using EBP in the assessment and management of acute pain during the postoperative period in elderly patients. BACKGROUND: Advances in the study of pain and the methods for its relief since the late 1980s have led to a rise in the role of the nurse in pain management and monitoring. INTRODUCTION: The application of evidence-based practice associated with acute pain is on the increase in the world at large. METHODS: Eleven hospitals participated in this study. The project involved 1300 nurses working on surgical hospital wards. In this study, case study research and qualitative content analysis were used. The study was conducted using a dedicated questionnaire. RESULTS: Access to journals on evidence-based practice on the assessment and management of pain in elderly patients was assessed as less important by the respondents. Knowledge drawn from the media, scientific and medical journals was assessed by the respondents as unsatisfactory. The greatest barrier to nurses was the fact that scientific articles were published in English. CONCLUSION: Nurses' awareness of evidence-based practice increases with their education. Among the key problems are the lack of available professional publications in Polish literature, ignorance of English, shortage of time and lack of support from chief physicians of the ward. IMPLICATIONS FOR NURSING AND HEALTH POLICY: There is a need for the introduction of innovative strategies of teaching and approaches to the problem of evidence-based practice in approach to pain management in elder people among the Polish nurses. It is necessary to promote these issues in Polish scientific literature. PMID- 27220315 TI - Exogenous H2O2 induces growth inhibition and cell death of human pulmonary artery smooth muscle cells via glutathione depletion. AB - Reactive oxygen species (ROS) are associated with various pathophysiological processes of vascular smooth muscle cells (VSMCs). Pyrogallol (PG) induces the superoxide anion (O2*-)-mediated cell death of numerous cell types. The present study aimed to investigate the effects of exogenous hydrogen peroxide (H2O2) and PG treatment on the cell growth and death of human pulmonary artery smooth muscle cells (HPASMCs), with regards to intracellular ROS and glutathione (GSH) levels, as determined by MTT and cell number assays. H2O2 led to reduced growth of HPASMCs, with a half maximal inhibitory concentration of 250-500 uM at 24 h, and induced apoptosis, as determined by Annexin V-staining and benzyloxycarbonyl-Val Ala-Asp-fluoromethylketone treatment. However, PG did not strongly induce growth inhibition and death of HPASMCs. In addition, H2O2 led to increased ROS levels, including mitochondrial O2*-, and induced GSH depletion in HPASMCs. Treatment with N-acetyl cysteine (NAC) attenuated apoptotic cell death and ROS levels in H2O2-treated HPASMCs, and also prevented GSH depletion. Notably, PG treatment did not increase ROS levels, including mitochondrial O2*-. Furthermore, NAC induced a significant increase in mitochondrial O2*- levels in PG-treated HPASMCs, and cell death and GSH depletion were significantly increased. L-buthionine sulfoximine intensified cell death and GSH depletion in PG-treated HPASMCs. In conclusion, exogenous H2O2 induced growth inhibition and cell death of HPASMCs via GSH depletion. PMID- 27220316 TI - A Founder Effect of c.257 + 2T > C Mutation in NCF2 Gene Underlies Severe Chronic Granulomatous Disease in Eleven Patients. AB - Chronic granulomatous disease (CGD) is the prototypic functional neutrophil disorder caused by genetic defects in one of the five genes encoding the superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase subunits of phagocytes. Mutations causing the most prevalent form of CGD in western populations are located in the X-linked-CYBB gene. The four remaining autosomal recessive (AR) forms collectively account for one-third of CGD cases. We investigated the clinical and molecular features of eleven patients with CGD from 6 consanguineous families, originating from contiguous regions in the west of Tunisia. The patients' clinical phenotype is characterized by a high incidence of mycobacterial infections. Five out of the eleven patients died despite treatment arguing in favor of a severe clinical form of CGD. These findings correlated with the absence of functional p67phox protein as well as the absence of residual reactive oxygen intermediates (ROI) production. Genetic analysis showed the presence, in all patients, of a unique mutation (c.257 + 2T > C) in NCF2 gene predicted to affect RNA splicing. Segregating analysis using nine polymorphic markers overlapping the NCF2 gene revealed a common haplotype spanning 4.1 Mb. The founder event responsible for this mutation was estimated to have arisen approximately 175 years ago. These findings will facilitate the implementation of preventive approaches through genetic counseling in affected consanguineous families. PMID- 27220317 TI - Long-Term Tolerability, Safety, and Efficacy of Recombinant Human Hyaluronidase Facilitated Subcutaneous Infusion of Human Immunoglobulin for Primary Immunodeficiency. AB - PURPOSE: Treatment of primary immunodeficiency diseases (PIDD) with subcutaneous (SC) infusions of IgG preceded by injection of recombinant human hyaluronidase (rHuPH20) (IGHy) to increase SC tissue permeability was evaluated in two consecutive, prospective, non-controlled, multi-center studies. METHODS: Subjects >4 years of age received SC IgG replacement at a weekly dose equivalent of 108 % of their previous intravenous (IV) dose, facilitated by prior injection of 75 U/g IgG of rHuPH20. Starting with weekly SC infusions, the interval was increased (ramped-up) to a 3- or 4-week schedule. RESULTS: Eighty-three subjects (24 < 18 years; 59 >= 18 years) received 2729 infusions (excluding ramp-up) at a mean dose of 0.155 g/kg/week in the pivotal and 0.156 g/kg/week in the extension study. IGHy exposure exceeded 30 months in 48 subjects. During 187.7 subject-years of IGHy exposure, 2005 adverse events (AEs) (10.68 per subject-year) occurred. The rate of related systemic AEs during consecutive 1-year periods remained low; the rate of related local AEs decreased from 3.68/subject-year in months 1-12 to approximately 1.50/subject-year after 30 months of treatment. Fifteen subjects transiently developed anti-rHuPH20 binding antibody. There was no difference in AE rates in these subjects before and after the first titer increase to >=1:160. The rate of infections during IGHy exposure was 2.99 per subject-year and did not increase during the studies. Annual infection rates were 3.02 in subjects <18 years and 2.98 in subjects >=18 years. CONCLUSIONS: Long-term replacement therapy with IGHy was safe and effective in 83 pediatric and adult subjects with PIDD. PMID- 27220318 TI - Evaluation of 68Ga-labeled iNGR peptide with tumor-penetrating motif for microPET imaging of CD13-positive tumor xenografts. AB - The aim of the study is to evaluate the efficacy of 68Ga-labeled iNGR, containing Asn-Gly-Arg (NGR) homing sequence and CendR (R/KXXR/K) penetrating motif, as a new molecular probe for microPET imaging of CD13-positive xenografts. The synthesized iNGR and NGR peptides were conjugated with DOTA and then labeled with 68Ga. 68Ga-iNGR and 68Ga-NGR were compared in the performance of the in vitro stability, partition coefficient, binding affinity, cell uptake analysis, in vivo microPET imaging, and biodistribution studies in CD13-positive HT-1080 and CD13 negative HT-29 cell lines. The in vitro results revealed that both probes exhibited high radiochemical purity and stability, and no significant difference between two probes was observed in terms of the binding affinity to CD13. In vivo microPET/CT imaging showed that the uptake of 68Ga-iNGR in HT-1080 tumor was significantly higher than that of 68Ga-NGR. Moreover, tumor 68Ga-iNGR uptake could be completely blocked by cold NGR and partially blocked by neutralizing NRP 1 antibody. We concluded that 68Ga-iNGR has a higher tumor uptake and better tumor retention than 68Ga-NGR through NRP-1, indicating that CendR motif modification is a promising method for improving NGR peptide performance. PMID- 27220319 TI - Expression and clinical significance of Wee1 in colorectal cancer. AB - Wee1 is a nuclear kinase regulating cell cycle progression, and has emerged as a promising therapeutic target in cancer. Expression of Wee1 has been associated with poor outcome in certain tumor types, but the prognostic impact and clinical significance in colorectal cancer is unknown. The expression of Wee1 was examined by immunohistochemistry in primary colorectal carcinomas from a prospectively collected patient cohort, and associations with clinicopathological parameters and outcome were investigated. Cell culture experiments were performed using the cell lines RKO and SW620, and the relationship with the metastasis-promoting protein S100A4 was investigated. Nuclear expression was detected in 229 of the 258 tumors analyzed (89 %). Wee1 staining was associated with low pT stage, but no other significant associations with demographic or histopathological variables were found. Moderate Wee1 staining intensity was a predictor of favorable metastasis-free and overall survival compared to strong intensity and no or weak staining. The fraction of positive cells was not a prognostic factor in the present cohort. Inhibition of Wee1 expression using siRNA or treatment with the Wee1 inhibitor MK-1775 reduced expression of the metastasis-promoting protein S100A4, but no relationship between Wee1 and S100A4 was found in the patient samples. In conclusion, Wee1 is highly expressed in primary colorectal carcinomas, but few relevant associations with clinicopathological parameters or outcome were found. The lack of clinical significance of Wee1 expression could indicate that other tumor types might be better suited for further development of Wee1 inhibitors. PMID- 27220320 TI - MicroRNA-125b promotes invasion and metastasis of gastric cancer by targeting STARD13 and NEU1. AB - MicroRNAs have been documented playing key roles in cancer development and progression. Here, we investigate the role of miR-125b in gastric cancer metastasis. We found that the expression of miR-125b was up-regulated in gastric cancer tissue specimens compared with their corresponding nontumorous tissues, and the up-regulated miR-125b level was significantly associated with TNM stage and lymph node-metastasis. Overexpression of miR-125b promoted gastric cancer cell migration and invasion in vitro and metastasis in vivo. STARD13 and NEU1 were identified as direct target genes of miR-125b by luciferase assays, and they were involved in the cell migration and invasion regulated by miR-125b in gastric cancer. Taken together, miR-125b functions as an oncogene in gastric cancer and represents a new potential therapeutic target for gastric cancer. PMID- 27220322 TI - Characterization of Integrons and qnr Genes in Proteeae from a Teaching Hospital in China. AB - BACKGROUND: Proteeae isolates displaying multidrug-resistance (MDR) are the second most common causes of hospital-associated infections. The aim of this study was to screen class 1-3 integrons and plasmid-mediated quinolone resistance (PMQR) genes in Proteeae isolates from the First Affiliated Hospital of the Wenzhou Medical University. MATERIALS AND METHODS: 176 Proteeae isolates were collected from clinical specimens of inpatients between January 2011 and December 2013. Susceptibility testing was determined by the agar dilution method. Class 1 3 integrons and PMQR genes were amplified by polymerase chain reaction, and the variable regions of integrons were determined by restriction fragment length polymorphisms. RESULTS: 68.2% Proteeae isolates exhibited MDR phenotypes: 46.6 and 10.8% Proteeae isolates were positive for intI1 and intI2, respectively. The resistance rate of integron-positive isolates to aminoglycosides, fluoroquinolones, and trimethoprim/sulfamethoxazole was significantly higher than integron-negative isolates. Sequence analysis revealed that dfrA1-sat2-aadA1, dfrA1-catB2-sat2-aadA1, and sat2-aadA1 were first detected in Morganella morganii strains isolated from China. PMQR was determined by qnrD in 40 strains (22.7%). CONCLUSION: Our results indicate that class 1 and 2 integrons are common among Proteeae isolates. Meanwhile, qnrD are highly prevalent in Proteeae isolated from our hospital. PMID- 27220321 TI - SH3GL1 inhibition reverses multidrug resistance in colorectal cancer cells by downregulation of MDR1/P-glycoprotein via EGFR/ERK/AP-1 pathway. AB - Multidrug resistance is one of the major reasons colorectal cancer (CRC) chemotherapy-based treatments fail, and novel biologically based therapies are urgently needed. Src homology 3 (SH3)-domain GRB2-like protein 1 (SH3GL1) is a membrane-bound protein which was found to be involved in tumor formation, progression, and metastasis. In this study, immunohistochemistry staining, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot analysis revealed a high expression of SH3GL1 in human CRC tumor specimens and several CRC cells resistant to chemotherapeutics. Cell Counting Kit-8 (CCK-8) assay showed that transfection of pCDNA3.1(+)-SH3GL1 increased while transfection of SH3GL1 siRNA decreased cell viability in response to 5-fluorouracil (5-FU) treatment (P < 0.05). Further studies indicated that transfection of SH3GL1 siRNA significantly downregulated multidrug resistance protein 1 (MDR1)/P-glycoprotein expression (P < 0.05), decreased MDR1 promoter activity and activator protein-1 (AP-1) binding activity (P < 0.05), and inhibited the activation of epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinases 1/2 (ERK1/2) signaling (P < 0.05) in CRC cells resistant to chemotherapeutics. Transfection of pCDNA3.1(+)-SH3GL1 caused the opposite effect. Additionally, pre treatment with either EGFR kinase inhibitor PD153035 or ERK1/2 kinase inhibitor PD98059 in HCT116/5-FU cells partly inhibits P-glycoprotein expression and AP-1 binding activity (P < 0.05). In conclusion, we confirmed that inhibition of SH3GL1 reverses multidrug resistance through declining P-glycoprotein expression via the EGFR/ERK/AP-1 pathway. PMID- 27220323 TI - Serum magnesium and risk of new onset heart failure in men: the Kuopio Ischemic Heart Disease Study. AB - Serum magnesium is an essential intracellular cation involved in processes that regulate cardiovascular function and has been linked to the risk of several cardiovascular disease outcomes. We aimed to investigate the association of serum magnesium concentrations with risk of incident heart failure (HF). We studied 2181 middle-aged men without prevalent HF (aged 42-61 years) enrolled in the finnish Kuopio Ischemic Heart Disease prospective cohort study with serum magnesium measurements made at baseline. Hazard ratios (95 % confidence intervals [CI]) for HF were assessed. During a median follow-up of 24.8 years, 278 HF events occurred. Baseline serum magnesium was weakly and inversely associated with several clinical markers and was continuously associated with risk of HF. The age-adjusted HR (95 % CIs) for HF per 1 standard deviation (SD) higher serum magnesium levels was 0.86 (0.76-0.97). The HR (95 % CIs) was 0.87 (0.76-0.98) after controlling for measures of adiposity, socio-economic variables, medical history, blood pressure, renal function, alcohol consumption, and lipids. These findings remained consistent in analyses accounting for incident coronary heart disease. The results were comparable across several clinically relevant subgroups and analyses with atrial fibrillation as a competing risk yielded similar results. Serum magnesium was continuously, inversely and independently associated with future risk of HF. Further research is needed to assess any potential relevance of serum magnesium in HF prevention. PMID- 27220324 TI - Atypical speech and language development: a consensus study on clinical signs in the Netherlands. AB - BACKGROUND: Atypical speech and language development is one of the most common developmental difficulties in young children. However, which clinical signs characterize atypical speech-language development at what age is not clear. AIM: To achieve a national and valid consensus on clinical signs and red flags (i.e. most urgent clinical signs) for atypical speech-language development in children from 1 to 6 years of age. METHODS & PROCEDURES: A two-round Delphi study in the Netherlands with a national expert panel (n = 24) of speech and language therapists was conducted. The panel members responded to web-based questionnaires addressing clinical signs. Consensus was defined as >= 70% of the experts agreeing on an issue. OUTCOMES & RESULTS: The first round resulted in a list of 161 characteristics of atypical speech and language development. The second round led to agreement on 124 clinical signs and 34 red flags. CONCLUSIONS & IMPLICATIONS: Dutch national consensus concerns 17-23 clinical signs per age year for the description of an atypical speech-language development in young children and three to 10 characteristics per age year being red flags for atypical speech language development. This consensus contributes to early identification and diagnosis of children with atypical speech-language development, awareness and research. PMID- 27220327 TI - Highly efficient synthesis of functionalized alpha-oxyketones via Weinreb amides homologation with alpha-oxygenated organolithiums. AB - An efficient, chemoselective homologation of Weinreb amides to the corresponding variously substituted alpha-oxyketones has been developed via the addition of lithiated alpha-oxygenated species. This one-step, experimentally easy, high yielding protocol is amenable not only for accessing simple alpha-oxyketones but also for more complex substituted ones ranging from primary and secondary alkyl type to aromatic ones. Full delivery of the stereochemical information contained in the starting materials is observed through both the employment of enantioenriched Weinreb amides and optically active organolithium species. PMID- 27220325 TI - Isoeugenol is a selective potentiator of camptothecin cytotoxicity in vertebrate cells lacking TDP1. AB - Camptothecin (CPT), a topoisomerase I (TOP1) inhibitor, exhibits anti-tumor activity against a wide range of tumors. Redundancy of TOP1-mediated repair mechanisms is a major challenge facing the efficiency of TOP1-targetting therapies. This study aims to uncover new TOP1 targeting approaches utilising a selection of natural compounds in the presence or absence of tyrosyl DNA phosphodiesterase I (TDP1); a key TOP1-mediated protein-linked DNA break (PDB) repair enzyme. We identify, isoeugenol, a phenolic ether found in plant essential oils, as a potentiator of CPT cytotoxicity in Tdp1 deficient but not proficient cells. Consistent with our cellular data, isoeugenol did not inhibit Tdp1 enzymatic activity in vitro nor it sensitized cells to the PARP1 inhibitor olaparib. However, biochemical analyses suggest that isoeugenol inhibits TDP2 catalytic activity; a pathway that can compensate for the absence of TDP1. Consistent with this, isoeugenol exacerbated etoposide-induced cytotoxicity, which generates TOP2-mediated PDBs for which TDP2 is required for processing. Together, these findings identify isoeugenol as a potential lead compound for developing TDP2 inhibitors and encourage structure-activity relationship studies to shed more light on its utility in drug discovery programs. PMID- 27220328 TI - Application of the WHOQOL-HIV-BREF Questionnaire in HIV-Infected Thai Patients: Reliability and Validity of the Instrument. AB - Given the prolonged survival of HIV-infected individuals as a result of widespread availability of treatment, health-related quality of life (HRQOL) becomes a relevant endpoint for assessing the impacts of HIV interventions. We examined the reliability and validity of the World Health Organization Quality of Life in HIV-infected Persons instrument (WHOQOL-HIV-BREF) using data from 329 HIV infected Thai patients who received outpatient care at seven public hospitals. Our findings revealed acceptable reliability, construct validity, and convergent validity of the WHOQOL-HIV-BREF. No significant difference in HRQOL was found between groups with different CD4+ T cell counts. Conversely, the subgroup with a history of opportunistic infection appeared to have a higher HRQOL compared to those in the latency stage. Challenges to the interpretation of the questions related to culture are discussed. In conclusion, the WHOQOL-HIV-BREF can be added to the limited list of instruments for comprehensive outcome evaluation of HIV interventions in Thailand. PMID- 27220329 TI - Abrp, a new gene, confers reduced susceptibility to tetracycline, glycylcine, chloramphenicol and fosfomycin classes in Acinetobacter baumannii. AB - Acinetobacter baumannii, a non-fermenting gram-negative coccobacillus, is a major pathogen responsible for a variety of healthcare-associated infections, including pneumonia, urinary tract and bloodstream infections. Moreover, A. baumannii is associated with alarming increases in drug resistance rates to almost all available antibiotics leaving limited treatment options. Here, we characterize the biological functions of a novel gene, abrp, which encodes a peptidase C13 family. We demonstrate that the abrp is associated with decreased susceptibility to tetracycline, minocycline, doxycycline, tigecycline, chloramphenicol and fosfomycin. Deletion of abrp was able to increase cell membrane permeability and display slower cell growth rate. Results from the present study show that abrp plays an important role in conferring reduced susceptibility to different classes of antibiotics and cell growth in A. baumannii. The change of antibiotic sensitivities may result from modifications to the cell membrane permeability of A. baumannii. PMID- 27220331 TI - Experimental and clinical nephroprotection by the xanthine oxidase inhibitor febuxostat. PMID- 27220330 TI - Prevalence, resistance patterns, and characterization of integrons of Shigella flexneri isolated from Jiangsu Province in China, 2001-2011. AB - OBJECTIVE: To provide the epidemiology, resistance pattern, and characterization of integrons in Shigella flexneri isolated between 2001 and 2011 in Jiangsu Province. METHOD: A total of 624 strains of S. flexneri were collected from both outpatients and inpatients in hospitals in Jiangsu Province from January 2001 to December 2011. The Kirby-Bauer disk diffusion method was used to perform the antimicrobial susceptibility test. Polymerase chain reaction (PCR) was used in the detection of integrons. Pulsed-field gel electrophoresis (PFGE) was applied in the homology studies. RESULT: Serotype 2a accounted for the largest proportion in S. flexneri, namely 26.4 %. Notably, an increasing trend was detected in the resistance to common antimicrobial agents during the period 2001-2011. In recent years, more than 80.0 % isolates of S. flexneri have proved to be resistant to ampicillin, nalidixic acid, and tetracycline. The positive rates of class 1, class 2, and the atypical class 1 integrons in S. flexneri are 69.3 %, 87.8 %, and 89.2 % respectively. Most integrons detected in our research carry genes encoding resistance to trimethoprim and streptomycin. CONCLUSION: Antimicrobial resistance in S. flexneri has demonstrated a continuous rising trend in Jiangsu Province. A high prevalence of integrons and gene cassettes play an important role in the transmission of drug resistance in S. flexneri. Effective measures are urgently needed to control the spread of multi-drug-resistant S. flexneri, and more continuing active surveillance of antimicrobial resistance should be established worldwide, especially in developing countries. PMID- 27220332 TI - Robotic-Assisted Transanal Repair of a Rectovaginal Fistula. AB - BACKGROUND: Various methods exist for the treatment of rectovaginal fistulas, with the choice of repair largely dependent on the fistula location. Options include local repair with mucosal advancement flaps, the use of agents like fibrin glue, and an abdominal approach with resection and colo-anal reconstruction. Traditionally, local repair with mucosal advancement flaps is reserved for simple, low rectovaginal fistulas, while high rectal fistulas require a transabdominal approach.1,2 METHODS: Here, we demonstrate an innovative approach for the treatment of a complex, high rectovaginal fistula in a patient with a hostile pelvis via a transanal approach with robotic assistance. The video demonstrates the basic steps of a repair of a rectovaginal fistula: debridement of the fistula tract, mobilization of the mucosal advancement flap, primary closure of the fistula tract, suturing of the mucosal advancement flap, and flexible sigmoidoscopy to confirm lumen patency and visualization of the closure. RESULTS: By utilizing robotic assistance, we were provided with improved dexterity, precision, and scalability to accomplish the complex task of dissection, suturing, and knot tying in the confines of the rectum. CONCLUSIONS: We suggest that this approach can be used on selected patients with high rectovaginal fistula or other rectal pathology who are otherwise not candidates for a transanal approach. PMID- 27220333 TI - Mild Hyperbaric Oxygen Improves Decreased Oxidative Capacity of Spinal Motoneurons Innervating the Soleus Muscle of Rats with Type 2 Diabetes. AB - Rats with type 2 diabetes exhibit decreased oxidative capacity, such as reduced oxidative enzyme activity, low-intensity staining for oxidative enzymes in fibers, and no high-oxidative type IIA fibers, in the skeletal muscle, especially in the soleus muscle. In contrast, there are no data available concerning the oxidative capacity of spinal motoneurons innervating skeletal muscle of rats with type 2 diabetes. This study examined the oxidative capacity of motoneurons innervating the soleus muscle of non-obese rats with type 2 diabetes. In addition, this study examined the effects of mild hyperbaric oxygen at 1.25 atmospheres absolute with 36 % oxygen for 10 weeks on the oxidative capacity of motoneurons innervating the soleus muscle because mild hyperbaric oxygen improves the decreased oxidative capacity of the soleus muscle in non-obese rats with type 2 diabetes. Spinal motoneurons innervating the soleus muscle were identified using nuclear yellow, a retrograde fluorescent neuronal tracer. Thereafter, the cell body sizes and succinate dehydrogenase activity of identified motoneurons were analyzed. Decreased succinate dehydrogenase activity of small-sized alpha motoneurons innervating the soleus muscle was observed in rats with type 2 diabetes. The decreased succinate dehydrogenase activity of these motoneurons was improved by mild hyperbaric oxygen. Therefore, we concluded that rats with type 2 diabetes have decreased oxidative capacity in motoneurons innervating the soleus muscle and this decreased oxidative capacity is improved by mild hyperbaric oxygen. PMID- 27220334 TI - Caspase-3-Dependent Proteolytic Cleavage of Tau Causes Neurofibrillary Tangles and Results in Cognitive Impairment During Normal Aging. AB - Mouse models of neurodegenerative diseases such as Alzheimer's disease (AD) are important for understanding how pathological signaling cascades change neural circuitry and with time interrupt cognitive function. Here, we introduce a non genetic preclinical model for aging and show that it exhibits cleaved tau protein, active caspases and neurofibrillary tangles, hallmarks of AD, causing behavioral deficits measuring cognitive impairment. To our knowledge this is the first report of a non-transgenic, non-interventional mouse model displaying structural, functional and molecular aging deficits associated with AD and other tauopathies in humans with potentially high impact on both new basic research into pathogenic mechanisms and new translational research efforts. Tau aggregation is a hallmark of tauopathies, including AD. Recent studies have indicated that cleavage of tau plays an important role in both tau aggregation and disease. In this study we use wild type mice as a model for normal aging and resulting age-related cognitive impairment. We provide evidence that aged mice have increased levels of activated caspases, which significantly correlates with increased levels of truncated tau and formation of neurofibrillary tangles. In addition, cognitive decline was significantly correlated with increased levels of caspase activity and tau truncated by caspase-3. Experimentally induced inhibition of caspases prevented this proteolytic cleavage of tau and the associated formation of neurofibrillary tangles. Our study shows the strength of using a non-transgenic model to study structure, function and molecular mechanisms in aging and age related diseases of the brain. PMID- 27220335 TI - 3,4-Dihydroxyphenylethanol (Hydroxytyrosol) Mitigates the Increase in Spontaneous Oxidation of Dopamine During Monoamine Oxidase Inhibition in PC12 Cells. AB - The catecholaldehyde hypothesis predicts that monoamine oxidase (MAO) inhibition should slow the progression of Parkinson's disease, by decreasing production of the autotoxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL). Inhibiting MAO, however, diverts the fate of cytoplasmic dopamine toward potentially harmful spontaneous oxidation products, indicated by increased 5-S cysteinyl-dopamine (Cys-DA) levels. 3,4-Dihydroxyphenylethanol (hydroxytyrosol) is an abundant anti-oxidant phenol in constituents of the Mediterranean diet. Whether hydroxytyrosol alters enzymatic or spontaneous oxidation of dopamine has been unknown. Rat pheochromocytoma PC12 cells were incubated with hydroxytyrosol (10 uM, 180 min) alone or with the MAO-A inhibitor clorgyline (1 nM) or the MAO-B inhibitors rasagiline or selegiline (0.5 uM). Hydroxytyrosol decreased levels of DOPAL by 30 % and Cys-DA by 49 % (p < 0.0001 each). Co-incubation with hydroxytyrosol prevented the increases in Cys-DA seen with all 3 MAO inhibitors. Hydroxytyrosol therefore inhibits both enzymatic and spontaneous oxidation of endogenous dopamine and mitigates the increase in spontaneous oxidation during MAO inhibition. PMID- 27220337 TI - A Collaborative Approach for Scoping Ecosystem Services with Stakeholders: The Case of Arrabida Natural Park. AB - This paper presents an innovative approach for conducting collaborative scoping processes aiming to elicit multiple values of ecosystem services. The proposed methodology rests on three steps combining different participatory tools that promote a comprehensive examination of the perceptions hold by relevant stakeholder groups. The first step consists of an institutional and stakeholder analysis developed in the study area. The second includes a participatory workshop, where a sequence of scoping exercises is conducted with the active collaboration of the invited stakeholders. The final step aims to validate scoping results and develop dependency networks between organizations and the identified ecosystem services. The approach was tested in the Arrabida Natural Park, a marine and coastal protected area in Portugal. Invited participants were able to identify an extensive list of ecosystem services in the natural area, establish linkages between those services and human wellbeing, identify drivers of change and perform a preliminary screening of the associated ecological, social, and economic values. The case study evaluation provided positive feedback on the usefulness of the approach, which advances the existing set of methods for participatory identification of ecosystem services and sets the scene for involvement of stakeholder groups in assessment and management processes. PMID- 27220336 TI - Epigenetic Suppression of GADs Expression is Involved in Temporal Lobe Epilepsy and Pilocarpine-Induced Mice Epilepsy. AB - Recent studies have shown that histone acetylation is involved with the regulation of enzyme glutamate decarboxylases (GADs), including GAD67 and GAD65. Here, we investigated the histone acetylation modifications of GADs in the pathogenesis of epilepsy and explored the therapeutic effect of a novel second generation histone deacetylase inhibitor (HDACi) JNJ-26481585 in epilepsy animals. We revealed the suppression of GADs protein and mRNA level, and histone hypoacetylation in patients with temporal lobe epilepsy and pilocarpine-induced epilepsy mice model. Double-immunofluorescence also indicated that the hypoacetyl H3 was located in hippocampal GAD67/GAD65 positive neurons in epilepsy mice. JNJ 26481585 significantly reversed the decrease of the GAD67/GAD65 both protein and mRNA levels, and the histone hypoacetylation of GABAergic neurons in epilepsy mice. Meanwhile, single-cell real-time PCR performed in GFP-GAD67/GAD65 transgenic mice demonstrated that JNJ-26481585 induced increase of GAD67/GAD65 mRNA level in GABAergic neurons. Furthermore, JNJ-26481585 significantly alleviated the epileptic seizures in mice model. Together, our findings demonstrate inhibition of GADs gene via histone acetylation plays an important role in the pathgenesis of epilepsy, and suggest JNJ-26481585 as a promising therapeutic strategy for epilepsy. PMID- 27220338 TI - Tracheostomy is associated with decreased hospital mortality after moderate or severe isolated traumatic brain injury. AB - BACKGROUND: Data regarding the impact and timing of tracheostomy in patients with isolated traumatic brain injury (TBI) are ambiguous. Our goal was to evaluate the impact of tracheostomy on hospital mortality in patients with moderate or severe isolated TBI. MATERIALS AND METHODS: We performed a retrospective cohort analysis of data prospectively collected at 87 Austrian intensive care units (ICUs). All patients continuously admitted between 1998 and 2010 were evaluated for the study. In total, 4,735 patients were admitted to ICUs with isolated TBI. Of these patients, 2,156 had a moderate or severe TBI (1,603 patients were endotracheally intubated only, 553 patients underwent tracheostomy). Epidemiological data (trauma severity, treatment, and outcome) of the two groups were compared. RESULTS: Patients with moderate or severe isolated TBI undergoing tracheostomy had a similar Glasgow Coma Scale score, median (interquartile range): 6 (3-8) vs 6 (3-8); p = 0.90, and Simplified Acute Physiology Score II, 45 (37-54) vs 45 (35 56); p = 0.86, compared with intubated patients not undergoing tracheostomy. Furthermore, patients undergoing tracheostomy exhibited higher Abbreviated Injury Scale Head scores and had a longer ICU stay for survivors, 30 (22-42) vs 9 (3-17) days; p < 0.0001). In contrast, risk-adjusted mortality was lower in patients undergoing tracheostomy compared with patients who remained intubated, observed to-expected mortality ratio (95 % confidence interval): 0.62 (0.53-0.72) vs 1.00 (0.95-1.05) respectively. CONCLUSIONS: Despite the greater severity of head injury, patients with isolated TBI who underwent tracheostomy had a lower risk adjusted mortality than patients who remained intubated. Reasons for this difference in outcome may be multifactorial and require further investigation. PMID- 27220339 TI - Emergence of multidrug-resistant Proteus mirabilis in a long-term care facility in Croatia. AB - BACKGROUND: An increased frequency of Proteus mirabilis isolates resistant to expanded-spectrum cephalosporins was observed recently in a long-term care facility in Zagreb (Godan). The aim of this study was the molecular characterization of resistance mechanisms to new cephalosporins in P. mirabilis isolates from this nursing home. METHODS: Thirty-eight isolates collected from 2013-2015 showing reduced susceptibility to ceftazidime were investigated. Antibiotic susceptibilities were determined by broth microdilution method. Inhibitor-based tests were performed to detect extended-spectrum (ESBLs) and AmpC beta-lactamases. AmpC beta-lactamases were characterized by polymerase chain reaction (PCR) followed by sequencing of bla ampC genes. Quinolone resistance determinants (qnr genes) were characterized by PCR. Genotyping of the isolates was performed by repetitive element sequence (rep)-PCR and pulsed-field gel electrophoresis (PFGE). RESULTS: Presence of an AmpC beta-lactamase was confirmed in all isolates by combined-disk test with phenylboronic acid. All isolates were resistant to amoxicillin alone and combined with clavulanate, cefotaxime, ceftriaxone, cefoxitin, and ciprofloxacin; but susceptible to cefepime, imipenem, and meropenem. PCR followed by sequencing using primers targeting bla ampc genes revealed CMY-16 beta-lactamase in all but one strain. Bla cmy-16 was carried by a non-conjugative plasmid which did not belong to any known plasmid-based replicon typing (PBRT) group. Rep-PCR identified one large clone consisting of 15 isolates, three pairs or related isolates, one triplet, and four singletons. PFGE confirmed the clonality of the isolates. CONCLUSIONS: This is the first report of multidrug resistant P. mirabilis in a nursing home in Croatia. Cephalosporin resistance was due to plasmid-mediated AmpC beta-lactamase CMY-16. PMID- 27220340 TI - Determination of process-related impurities in N-acetylglucosamine prepared by chemical and enzymatic methods: structural elucidation and quantification. AB - beta-N-acetylglucosamine (beta-AG) is a monosaccharide distributed widely in living organisms with various pivotal roles. The presence of particulates and impurities can affect the safety and efficacy of a product for its intended duration of use. Thus, the current study was carried out to identify and quantify the potentially-harmful process related impurities; namely alpha-N,6 diacetylglucosamine (alpha-DAG) and alpha-N-acetylglucosamine (alpha-AG), derived from the chemical and enzymatic synthesis of beta-AG. The impurities were characterized using a high resolution mass spectrometry, a nuclear magnetic resonance spectroscopy, and liquid chromatography-tandem mass spectrometry (LC/MS/MS). The developed method showed a good linearity (R (2) >= 0.998), satisfactory precision (<=6.1 % relative standard deviation), intra- and inter day accuracy (88.20-97.50 %), extraction recovery (89.30-110.50 %), matrix effect (89.70-105.20 %), and stability (92.70-101.60 %). The method was successfully applied to determine the level of alpha-DAG that was 3.04 and 0.07 % of the total beta-AG, following chemical and enzymatic methods, respectively. It can be concluded that the enzymatic rather than the chemical method is more efficient for the synthesis of beta-AG. Characterization of impurities heeds the signal for acquiring and evaluating data that establishes biological safety. PMID- 27220341 TI - Receptor FGFRL1 does not promote cell proliferation but induces cell adhesion. AB - Fibroblast growth factor receptor (FGFR)-like protein 1 (FGFRL1) is the most recently discovered member of the FGFR family. Owing to the fact that it interacts with FGF ligands, but lacks the intracellular tyrosine kinase domain, several researchers have speculated that it may function as a decoy receptor and exert a negative effect on cell proliferation. In this study, we performed overexpression experiments with TetOn-inducible cell clones and downregulation experiments with siRNA oligonucleotides, and found that FGFRL1 had absolutely no effect on cell growth and proliferation. Likewise, we did not observe any influence of FGFRL1 on ERK1/2 activation and on the phosphorylation of 250 other signaling proteins analyzed by the Kinexus antibody microarray. On the other hand, with bacterial petri dishes, we observed a clear effect of FGFRL1 on cell adhesion during the initial hours after cell seeding. Our results suggest that FGFRL1 is a cell adhesion protein similar to the nectins rather than a signaling receptor similar to FGFR1-FGFR4. PMID- 27220342 TI - Zidovudine, abacavir and lamivudine increase the radiosensitivity of human esophageal squamous cancer cell lines. AB - Telomerase is a type of reverse transcriptase that is overexpressed in almost all human tumor cells, but not in normal tissues, which provides an opportunity for radiosensitization targeting telomerase. Zidovudine, abacavir and lamivudine are reverse transcriptase inhibitors that have been applied in clinical practice for several years. We sought to explore the radiosensitization effect of these three drugs on human esophageal cancer cell lines. Eca109 and Eca9706 cells were treated with zidovudine, abacavir and lamivudine for 48 h before irradiation was administered. Samples were collected 1 h after irradiation. Clonal efficiency assay was used to evaluate the effect of the combination of these drugs with radiation doses of 2, 4, 6 and 8 Gy. DNA damage was measured by comet assay. Telomerase activity (TA) and relative telomere length (TL) were detected and evaluated by real-time PCR. Apoptosis rates were assessed by flow cytometric analysis. The results showed that all the drugs tested sensitized the esophageal squamous cell carcinoma (ESCC) cell lines to radiation through an increase in radiation-induced DNA damage and cell apoptosis, deregulation of TA and decreasing the shortened TL caused by radiation. Each of the drugs investigated (zidovudine, abacavir and lamivudine) could be used for sensitizing human esophageal cancer cell lines to radiation. Consequently, the present study supports the potential of these three drugs as therapeutic agents for the radiosensitization of esophageal squamous cell cancer. PMID- 27220343 TI - Message from the Editor-in-Chief. PMID- 27220344 TI - Sea cucumber peptides exert anti-inflammatory activity through suppressing NF kappaB and MAPK and inducing HO-1 in RAW264.7 macrophages. AB - The anti-inflammatory effect of sea cucumber peptides (SCP) in lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophages was tested. SCP significantly reduced LPS-induced nitric oxide release by inhibiting the inducible nitric oxide synthase mRNA expression without affecting the cell viability. The mRNA expression of LPS-induced inflammatory cytokines including tumour necrosis factor alpha, interleukin (IL)-1beta and IL-6 was suppressed. SCP inhibited LPS-induced degradation of the inhibitor of kappaBalpha (IkappaBalpha) and nuclear transposition of NF-kappaB p65, resulting in decreased NF-kappaB transactivation. Moreover, SCP suppressed the LPS-induced phosphorylation of JNK, ERK and p38. In addition, the expression of heme oxygenase (HO)-1 in macrophages was up-regulated by SCP in a dose-dependent manner. The inhibition effect of SCP on the mRNA expression of LPS-induced inflammatory cytokines was partially reversed by co treatment with a HO-1 inhibitor. The SCP with anti-inflammatory activity was made up of low-molecular-weight peptides rich in glycine, glutamic acid and aspartic acid. Collectively, these results demonstrate that SCP exerts anti-inflammatory function through inhibiting NF-kappaB and MAPK activation and inducing HO-1 expression in macrophages. PMID- 27220345 TI - Genomic and phenotypic differentiation of Arabidopsis thaliana along altitudinal gradients in the North Italian Alps. AB - Altitudinal gradients in mountain regions are short-range clines of different environmental parameters such as temperature or radiation. We investigated genomic and phenotypic signatures of adaptation to such gradients in five Arabidopsis thaliana populations from the North Italian Alps that originated from 580 to 2350 m altitude by resequencing pools of 19-29 individuals from each population. The sample includes two pairs of low- and high-altitude populations from two different valleys. High-altitude populations showed a lower nucleotide diversity and negative Tajima's D values and were more closely related to each other than to low-altitude populations from the same valley. Despite their close geographic proximity, demographic analysis revealed that low- and high-altitude populations split between 260 000 and 15 000 years before present. Single nucleotide polymorphisms whose allele frequencies were highly differentiated between low- and high-altitude populations identified genomic regions of up to 50 kb length where patterns of genetic diversity are consistent with signatures of local selective sweeps. These regions harbour multiple genes involved in stress response. Variation among populations in two putative adaptive phenotypic traits, frost tolerance and response to light/UV stress was not correlated with altitude. Taken together, the spatial distribution of genetic diversity reflects a potentially adaptive differentiation between low- and high-altitude populations, whereas the phenotypic differentiation in the two traits investigated does not. It may resemble an interaction between adaptation to the local microhabitat and demographic history influenced by historical glaciation cycles, recent seed dispersal and genetic drift in local populations. PMID- 27220346 TI - Prescribing sodium oxybate for narcolepsy: end the postcode lottery and apply some common sense. PMID- 27220347 TI - Erythropoietin production by PDGFR-beta(+) cells. AB - PDGFR-beta-expressing cells of the kidneys are considered as a relevant site of erythropoietin (EPO) production. The origin of these cells, their contribution to renal EPO production, and if PDGFR-beta-positive cells in other organs are also capable to express EPO are less clear. We addressed these questions in mice, in which hypoxia-inducible transcription factors were stabilized in PDGFR-beta(+) cells by inducible deletion of the von Hippel-Lindau (Vhl) protein. Vhl deletion led to a 600-fold increase of plasma EPO concentration, 170-fold increase of renal EPO messenger RNA (mRNA) levels, and an increase of hematocrit values up to 70 %. Intrarenal localization of EPO-expressing cells coincided with the zonal heterogeneity and distribution of cells expressing PDGFR-beta. Amongst a variety of extrarenal organs only adrenal glands showed significant EPO mRNA expression after Vhl deletion in PDGFR-beta(+) cells. EPO mRNA, plasma EPO, and hematocrit fell to subnormal values if HIF-2alpha, but not HIF-1alpha, was deleted either alone or in combination with Vhl in PDGFR-beta(+) cells. Treatment of mice with a prolyl-hydroxylase inhibitor caused an increase of EPO mRNA abundance and plasma EPO concentrations in wild-type mice and in mice lacking HIF-1alpha in PDGFR beta(+) cells but exerted no effect in mice lacking HIF-2alpha in PDGFR-beta(+) cells. These findings suggest that PDGFR-beta(+) cells are the only relevant site of EPO expression in the kidney and that HIF-2 is the essential transcription factor triggering EPO expression therein. Moreover, our findings suggest that PDGFR-beta(+) cells elaborating EPO might arise from the metanephric mesenchyme, rather than from the neural crest. PMID- 27220348 TI - The impact of tabalumab on the kidney in systemic lupus erythematosus: results from two phase 3 randomized, clinical trials. AB - INTRODUCTION: Tabalumab is a monoclonal antibody that neutralizes membrane and soluble B-cell activating factor. Two 52-week, randomized, double-blind, placebo controlled phase 3 trials evaluated the safety and efficacy of tabalumab in systemic lupus erythematosus. METHODS: Patients with moderate to severe active systemic lupus erythematosus (without severe active lupus nephritis) were randomly assigned 1:1:1 to receive tabalumab (120 mg subcutaneously every 2 or 4 weeks) or placebo for 52 weeks. Serum creatinine concentration, estimated glomerular filtration rate, urine protein/creatinine ratio, renal flares and renal adverse events were determined monthly. Data were analyzed for the intent to-treat population and for intent-to-treat patients with baseline urine protein/creatinine ratio >20 mg/mmol (intent-to-treat plus urine protein/creatinine ratio). RESULTS: The trials enrolled 2262 patients. At baseline, demographics, systemic lupus erythematosus disease activity, serum creatinine concentration, estimated glomerular filtration rate and urine protein/creatinine ratio were similar among the treatment arms (with the exception of disease duration). In the intent-to-treat and intent-to-treat plus urine protein/creatinine ratio populations, there were no differences between the arms in the baseline-to-endpoint change in serum creatinine concentration, glomerular filtration rate, urine protein/creatinine ratio, or renal flare rates. Tabalumab resulted in a significant B-cell reduction and decreased immunoglobulin G levels at both doses. CONCLUSIONS: Compared to placebo, tabalumab did not significantly affect the serum creatinine concentration, glomerular filtration rate, urine protein/creatinine ratio, or renal flare rates over 1 year in intent to-treat or intent-to-treat plus urine protein/creatinine ratio patients. There were no significant renal safety signals.ClinicalTrials.gov identifiers: NCT01205438 and NCT01196091 Lupus (2016) 25, 1597-1601. PMID- 27220349 TI - Teen pregnancies fall to record low in England. PMID- 27220351 TI - Treatment of acromegaly increases BMD but reduces trabecular bone score: a longitudinal study. AB - CONTEXT: Bone turnover is increased in acromegaly. Despite normalization of bone turnover after treatment, the risk for vertebral fractures remains increased. Gonadal status, but not BMD, is correlated with vertebral fractures. Trabecular bone score (TBS) is related to bone microarchitecture. OBJECTIVE: The aim of this study is to assess the longitudinal change in TBS and BMD following treatment for acromegaly. DESIGN, SETTING, PATIENTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: This longitudinal study included 48 patients with acromegaly between 2005 and 2015. BMD, TBS, and markers for bone turnover (P1NP and CTX-1) were measured at baseline and following treatment. RESULTS: Following treatment, the mean TBS decreased by 3.0 (+/-7.0) %, whereas the BMD at the lumbar spine (LS) increased by 3.2 (+/-4.9) % (both P<0.01). The changes in BMD LS and TBS were not correlated (P=0.87). The TBS change was found to be -4.5 % (+/-6.7; P=0.003) in men and -0.3 % (+/-6.8; P=0.85) in women (P=0.063 for interaction men vs women). The mean BMD LS increased in men +4.2 g/cm(2) (+/-4.3; P<0.001), but not in women +1.5 g/cm(2) (+/-5.6; P=0.36); (P=0.073 for interaction). BMD increased in the ultradistal radius and total body (both P<0.01). The increase in BMD LS was associated with a decrease in P1NP and CTX-1 (P<0.001) and with lower P1NP and CTX-1 at the follow-up (P<0.02). CONCLUSION: Treatment of acromegaly affects TBS and BMD at LS in different manners. The reduction of bone turnover markers predicts the increase in BMD but not the decrease in TBS. The DXA changes were more pronounced in men. Alterations in trabecular bone architecture may explain the persistent fracture risk despite the increase in BMD after disease control. PMID- 27220350 TI - Effect of Heated Humidification on CPAP Therapy Adherence in Subjects With Obstructive Sleep Apnea With Nasopharyngeal Symptoms. AB - BACKGROUND: The addition of heated humidification to CPAP has been shown to improve nasal adverse effects in subjects with obstructive sleep apnea (OSA). However, current data regarding improvement in CPAP adherence is conflicting. Furthermore, there are no data from a tropical climate area with a high humidity level. METHODS: In this prospective randomized crossover study conducted in Thailand, subjects with moderate to severe OSA with nasopharyngeal symptoms post split-night study were enrolled in the study. Subjects were randomly assigned to receive CPAP with or without heated humidification for 4 weeks and then crossed over. Information on CPAP adherence, quality of life assessed by the Functional Outcomes of Sleep Questionnaire, nasopharyngeal symptoms assessed by a modified XERO questionnaire, and bedroom ambient humidity and temperature data were obtained. RESULTS: Data were collected on 20 subjects with OSA during the period of January to December 2014. Although the addition of heated humidification appeared to improve average hours of use for all days when compared with conventional CPAP, the difference was not statistically significant (CPAP with heated humidification = 4.6 +/- 1.7 h/night; conventional CPAP = 4.0 +/- 1.7 h/night, P = .1). However, the addition of heated humidification improved CPAP adherence on the days of use (5.5 +/- 1.5 h/night) compared with conventional CPAP (5.2 +/- 1.4 h/night), P = .033. Quality of life was also improved according to the Functional Outcomes of Sleep Questionnaire score (median 17.6 [interquartile range 3.5]) in the heated humidification group compared with conventional CPAP group (median 17.6 [interquartile range 4.5]), P = .046. Significant reduction in the dry throat/sore throat symptom was noted only when CPAP with heated humidification was used. CONCLUSIONS: Even in a tropical climate area, CPAP adherence and quality of life appeared to improve when heated humidification was employed in subjects with moderate to severe OSA with nasopharyngeal symptoms post-split-night polysomnography. The improvement may be related to a reduction in the dry throat/sore throat symptom. PMID- 27220352 TI - Curcumin inhibits lipolysis via suppression of ER stress in adipose tissue and prevents hepatic insulin resistance. AB - Curcumin is natural polyphenol with beneficial effects on lipid and glucose metabolism and this study aimed to investigate the effects of curcumin on lipolysis and hepatic insulin resistance. Endoplasmic reticulum (ER) stress and lipolysis signaling in adipose and FFA influx, lipid deposits, and glucose production in liver were examined. Palmitate challenge and high-fat diet feeding evoked ER stress-associated lipolysis with cAMP accumulation in adipose tissue. Curcumin treatment inhibited adipose tissue ER stress by dephosphorylation of inositol-requiring enzyme 1alpha and eukaryotic initiation factor 2alpha and reduced cAMP accumulation by preserving phosphodiesterase 3B induction. Knockdown of mitogen-activated protein kinase alpha1/2alpha with siRNAs diminished such effects of curcumin. As a result from downregulation of cAMP, curcumin blocked protein kinase (PK)A/hormone-sensitive lipase lipolysis signaling, and thereby reduced glycerol and FFA release from adipose tissue. Curcumin reduced FFA influx into the liver by blocking FFA trafficking, and then prevented diacylglycerol deposits and PKCepsilon translocation in the liver, resultantly improving insulin action in the suppression of hepatic gluconeogenesis. Curcumin decreased adipose lipolysis by attenuating ER stress through the cAMP/PKA pathway, reduced FFA influx into the liver by blocking FFA trafficking, and thereby improved insulin sensitivity to inhibit hepatic glucose production. These findings suggested a novel pathway of curcumin to prevent lipid deposits and insulin resistance in liver by beneficial regulation of adipose function. PMID- 27220354 TI - Exploring the drivers of health and healthcare access in Zambian prisons: a health systems approach. AB - BACKGROUND: Prison populations in sub-Saharan Africa (SSA) experience a high burden of disease and poor access to health care. Although it is generally understood that environmental conditions are dire and contribute to disease spread, evidence of how environmental conditions interact with facility-level social and institutional factors is lacking. This study aimed to unpack the nature of interactions and their influence on health and healthcare access in the Zambian prison setting. METHODS: We conducted in-depth interviews of a clustered random sample of 79 male prisoners across four prisons, as well as 32 prison officers, policy makers and health care workers. Largely inductive thematic analysis was guided by the concepts of dynamic interaction and emergent behaviour, drawn from the theory of complex adaptive systems. RESULTS: A majority of inmates, as well as facility-based officers reported anxiety linked to overcrowding, sanitation, infectious disease transmission, nutrition and coercion. Due in part to differential wealth of inmates and their support networks on entering prison, and in part to the accumulation of authority and material wealth within prison, we found enormous inequity in the standard of living among prisoners at each site. In the context of such inequities, failure of the Zambian prison system to provide basic necessities (including adequate and appropriate forms of nutrition, or access to quality health care) contributed to high rates of inmate-led and officer-led coercion with direct implications for health and access to healthcare. CONCLUSIONS: This systems-oriented analysis provides a more comprehensive picture of the way resource shortages and human interactions within Zambian prisons interact and affect inmate and officer health. While not a panacea, our findings highlight some strategic entry-points for important upstream and downstream reforms including urgent improvement in the availability of human resources for health; strengthening of facility-based health services systems and more comprehensive pre-service health education for prison officers. PMID- 27220355 TI - 1,25(OH)2D3 inhibits high glucose-induced apoptosis and ROS production in human peritoneal mesothelial cells via the MAPK/P38 pathway. AB - The regulation of cell proliferation, differentiation and immunomodulation are affected by 1,25(OH)2D3. However, its function during apoptosis and oxidative stress in human peritoneal mesothelial cells (HPMCs) remains unknown. The aim of the present study was to investigate whether the regulation of apoptosis and oxidative stress have therapeutic relevance in peritoneal dialysis (PD) therapy. The present study investigated the effects of 1,25(OH)2D3 on high glucose (HG) induced apoptosis and reactive oxygen species (ROS) production in HPMCs, and examined the underlying molecular mechanisms. Flow cytometry and western blotting were performed to detect cell apoptosis, 2,7-dichlorofluorescein diacetate was used to measure reactive oxygen species production and 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide was used to measure cell viability. The results of the present study demonstrated that exposure to HG increased apoptosis and ROS production in HPMCs, whereas pretreatment with 1,25(OH)2D3 significantly inhibited HG-induced apoptosis and ROS production. Further analysis revealed that 1,25(OH)2D3 facilitated cell survival via the MAPK/P38 pathway. The results of the present study indicate that 1,25(OH)2D3 inhibits apoptosis and ROS production in HG-induced HPMCs via inhibition of the MAPK/P38 pathway. PMID- 27220353 TI - Exercise-like effects by Estrogen-related receptor-gamma in muscle do not prevent insulin resistance in db/db mice. AB - Dissecting exercise-mimicking pathways that can replicate the benefits of exercise in obesity and diabetes may lead to promising treatments for metabolic disorders. Muscle estrogen-related receptor gamma (ERRgamma) is induced by exercise, and when over-expressed in the skeletal muscle mimics exercise by stimulating glycolytic-to-oxidative myofiber switch, mitochondrial biogenesis and angiogenesis in lean mice. The objective of this study was to test whether muscle ERRgamma in obese mice mitigates weight gain and insulin resistance. To do so, ERRgamma was selectively over-expressed in the skeletal muscle of obese and diabetic db/db mice. Muscle ERRgamma over-expression successfully triggered glycolytic-to-oxidative myofiber switch, increased functional mitochondrial content and boosted vascular supply in the db/db mice. Despite aerobic remodeling, ERRgamma surprisingly failed to improve whole-body energy expenditure, block muscle accumulation of triglycerides, toxic diacylglycerols (DAG) and ceramides or suppress muscle PKCepsilon sarcolemmal translocation in db/db mice. Consequently, muscle ERRgamma did not mitigate impaired muscle insulin signaling or insulin resistance in these mice. In conclusion, obesity and diabetes in db/db mice are not amenable to selective ERRgamma-directed programming of classic exercise-like effects in the skeletal muscle. Other biochemical pathways or integrated whole-body effects of exercise may be critical for resisting diabetes and obesity. PMID- 27220356 TI - Histopathologic features of multiple cutaneous squamous cell carcinomas of the lower extremity. AB - Recent studies suggest cutaneous squamous cell carcinomas (SCCs) of the leg, particularly those occurring multiply in sun exposed skin of nonimmunosuppressed women, are a distinct clinical subtype. There are few reports of the histopathologic features of this subtype. A retrospective chart review of 4 patients with multiple SCCs on the leg was performed and a total of 35 biopsies from the legs examined. Histopathologically, the tumors lacked adjacent actinic keratosis (AK) and often had adjacent basaloid retiform proliferations. Most lesions (all but one) were well differentiated and about 40% could be classified histopathologically as keratoacanthoma. Perineural invasion was absent in all but one case. Using the American Joint Committee on Cancer (AJCC) staging criteria for SCC, 21 tumors were Stage I, and 9 Stage II. During 7-10 years of follow-up, no recurrence or metastasis occurred. Patients with multiple SCCs on the lower extremities can have a range of histopathologic features, from keratoacanthoma like to well-differentiated SCC. PMID- 27220357 TI - Physical rehabilitation interventions for adult patients during critical illness: an overview of systematic reviews. AB - BACKGROUND: Physical rehabilitation interventions aim to ameliorate the effects of critical illness-associated muscle dysfunction in survivors. We conducted an overview of systematic reviews (SR) evaluating the effect of these interventions across the continuum of recovery. METHODS: Six electronic databases (Cochrane Library, CENTRAL, DARE, Medline, Embase, and Cinahl) were searched. Two review authors independently screened articles for eligibility and conducted data extraction and quality appraisal. Reporting quality was assessed and the Grading of Recommendations Assessment, Development and Evaluation approach applied to summarise overall quality of evidence. RESULTS: Five eligible SR were included in this overview, of which three included meta-analyses. Reporting quality of the reviews was judged as medium to high. Two reviews reported moderate-to-high quality evidence of the beneficial effects of physical therapy commencing during intensive care unit (ICU) admission in improving critical illness polyneuropathy/myopathy, quality of life, mortality and healthcare utilisation. These interventions included early mobilisation, cycle ergometry and electrical muscle stimulation. Two reviews reported very low to low quality evidence of the beneficial effects of electrical muscle stimulation delivered in the ICU for improving muscle strength, muscle structure and critical illness polyneuropathy/myopathy. One review reported that due to a lack of good quality randomised controlled trials and inconsistency in measuring outcomes, there was insufficient evidence to support beneficial effects from physical rehabilitation delivered post-ICU discharge. CONCLUSIONS: Patients derive short-term benefits from physical rehabilitation delivered during ICU admission. Further robust trials of electrical muscle stimulation in the ICU and rehabilitation delivered following ICU discharge are needed to determine the long-term impact on patient care. This overview provides recommendations for design of future interventional trials and SR. TRIAL REGISTRATION NUMBER: CRD42015001068. PMID- 27220358 TI - Co-delivery and controlled release of stromal cell-derived factor-1alpha chemically conjugated on collagen scaffolds enhances bone morphogenetic protein-2 driven osteogenesis in rats. AB - There has been considerable focus in investigations on the delivery systems and clinical applications of bone morphogenetic protein-2 (BMP-2) for novel bone formation. However, current delivery systems require high levels of BMP-2 to exert a biological function. There are several concerns in using of high levels of BMP-2, including safety and the high cost of treatment. Therefore, the development of strategies to decrease the levels of BMP-2 required in these delivery systems is required. In our previous studies, a controlled-release system was developed, which used Traut's reagent and the cross-linker, 4-(N maleimi-domethyl) cyclohexane-1-carboxylic acid 3-sulfo-N-hydroxysuccinimide ester sodium salt (Sulfo-SMCC), to chemically conjugate BMP-2 directly on collagen discs. In the current study, retention efficiency and release kinetics of stromal cell-derived factor-1alpha (SDF-1alpha) cross-linked on collagen scaffolds were detected. In addition, the osteogenic activity of SDF-1alpha and suboptimal doses of BMP-2 cross-linked on collagen discs following subcutaneous implantation in rats were evaluated. Independent two-tailed t-tests and one-way analysis of variance were used for analysis. In the present study, the controlled release of SDF-1alpha chemically conjugated on collagen scaffolds was demonstrated. By optimizing the concentrations of Traut's reagent and the Sulfo SMCC cross-linker, a significantly higher level of SDF-1alpha was covalently retained on the collagen scaffold, compared with that retained using a physical adsorption method. Mesenchymal stem cell homing indicated that the biological function of the SDF-1alpha cross-linked on the collagen scaffolds remained intact. In rats, co-treatment with SDF-1alpha and a suboptimal dose of BMP-2 cross-linked on collagen scaffolds using this chemically conjugated method induced higher levels of ectopic bone formation, compared with the physical adsorption method. No ectopic bone formation was observed following treatment with a suboptimal dose of BMP-2 alone. Therefore, the co-delivery of SDF-1alpha and a suboptimal dose of BMP-2 chemically conjugated on collagen scaffolds for the treatment of bone injuries reduced the level of BMP-2 required, reducing the risks of side effects. PMID- 27220359 TI - Effects of platelet-derived growth factor on chondrocyte proliferation, migration and apoptosis via regulation of GIT1 expression. AB - The formation of fibrocartilage, cartilaginous and bony calluses is vital for bone healing following a fracture. Fibroblasts, chondrocytes and osteoblasts are critical functional cells that are involved in these three processes, respectively. Platelet-derived growth factor (PDGF), a growth factor that is released from platelet particles and appears during the early stages at the site of fractures, is essential in bone healing via regulation of cell proliferation and differentiation. However, the effects of PDGF on the chondrocytes remain unclear. In the present study, PDGF promoted phosphorylation of Src and upregulated the expression level of G-protein-coupled receptor kinase interacting protein-1 (GIT1) according to the results of the cell culture of chondrocytes in vitro and western blotting. However, the effect of PDGF on the upregulation of GIT1 expression was mostly inhibited by the Src inhibitor, PP2. After knocking down GIT1 expression using siRNA, the phosphorylation of Src continued to be induced by PDGF, although the expression of GIT1 was inhibited. Furthermore, the results indicated that PDGF promoted chondrocyte proliferation and migration, however, the effect on cell apoptosis induction was suppressed after adding the Src inhibitor, PP2. Additionally, when knocking down GIT1 using siRNA, the expression level of GIT1 decreased, which is similar to the effect of the Src inhibitor, PP2. The current study demonstrates that PDGF may initially activate the phosphorylation of Src, and subsequently induce GIT1 expression to promote chondrocyte proliferation and migration, but suppress cell apoptosis. PMID- 27220360 TI - Circulating aberrant plasma cells allows risk stratification of patients with myeloma. PMID- 27220361 TI - Probation Staff Attitudes Toward Substance Abuse Treatment and Evidence-Based Practices. AB - Given the substantial need for and relatively low access to effective substance use disorder treatment for people on probation, it is critical to understand organizational and staff attitudes that may hinder or facilitate treatment linkage and willingness to adopt evidence-based practices. This study used survey data from a large county probation department to assess staff members' attitudes and perceptions regarding their organization's climate for innovation, role of substance use disorder treatment, support for evidence-based treatment, and organizational barriers to change. Probation staff were open to incorporating treatment into probation supervision, expressed support for rehabilitation models, and agreed that they would adopt innovations if required or they found them to be appealing. However, they expressed some concerns about the level of agency support for innovation and collaboration. Attitudes and perceptions varied by staff characteristics. Implications for expanding organizational change and adoption of evidence-based treatment practices in probation are discussed. PMID- 27220362 TI - Female Offenders, HIV Peer Programs, and Attachment: The Importance of Prison Based Civilian Staff in Creating Opportunities to Cultivate Prosocial Behaviors. AB - As women commit to a conventional lifestyle, the bond of attachment becomes a fundamental component in sustaining the desistance process. If weak attachments in the community cannot be replaced or enhanced with the cultivation of strong conventional attachments while incarcerated, female offenders will leave prison without a supportive network. Strong social networks and a high level of social capital are essential for female offenders to reintegrate successfully; if social bonds are constructed before release, there is a greater chance of maintaining a crime-free lifestyle. One way to cultivate strong bonds of attachment during incarceration is through prison-based programming. This qualitative study, based on the narratives of 49 female offenders, examines the potential for inmates to form prosocial attachments with staff in two HIV prison-based peer programs in New York State. Strong attachments were formed between the inmates and civilian staff during incarceration, maintained upon release, and served to reinforce the establishment of bourgeoning conventional identities. The dedication and commitment of the civilian staff, and the support they provided to the inmates, was essential to achieving both rehabilitative and reintegrative goals. PMID- 27220363 TI - Autism-relevant behaviors are minimally impacted by conditional deletion of Pten in oxytocinergic neurons. AB - Germline heterozygous mutations in Pten (phosphatase and tensin homolog) are associated with macrocephaly and autism spectrum disorders (ASD). Pten germline heterozygous (Pten+/- ) mice approximate these mutations, and both sexes show widespread brain overgrowth and impaired social behavior. Strikingly similar behavior phenotypes have been reported in oxytocin (Oxt) and/or oxytocin receptor (OxtR) knockout mice. Thus, we hypothesized that the behavioral phenotypes of germline Pten+/- mice may be caused by reduced Pten function in Oxt-expressing cells. To investigate this, we tested mice in which Pten was conditionally deleted using oxytocin-Cre (Oxt-Cre+ ; PtenloxP/+ , Oxt-Cre+ ; PtenloxP/loxP ) on a battery including assays of social, repetitive, depression-like, and anxiety like behaviors. Minimal behavioral abnormalities were found; decreased anxiety like behavior in the open field test in Oxt-Cre+ ; PtenloxP/loxP males was the only result that phenocopied germline Pten+/- mice. However, Oxt cell size was dramatically increased in Oxt-Cre+ ; PtenloxP/loxP mice in adulthood. Thus, conditional deletion of Pten using Oxt-Cre has a profound effect on Oxt cell structure, but not on ASD-relevant behavior. We interpret these results as inconsistent with our starting hypothesis that reduced Pten function in Oxt expressing cells causes the behavioral deficits observed in germline Pten+/- mice. Autism Res 2016, 9: 1248-1262. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 27220364 TI - Atomic force microscopy-guided fractionation reveals the influence of cranberry phytochemicals on adhesion of Escherichia coli. AB - Cranberry juice has been long used to prevent infections because of its effect on the adhesion of the bacteria to the host surface. Proanthocyanidins (PACs) comprise of one of the major classes of phytochemicals found in cranberry, which have been extensively studied and found effective in combating adhesion of pathogenic bacteria. The role of other cranberry constituents in impacting bacterial adhesion haven't been studied very well. In this study, cranberry juice fractions were prepared, characterized and tested for their effect on the surface adhesion of the pathogenic clinical bacterial strain E. coli B78 and non pathogenic control E. coli HB101. The preparations tested included crude cranberry juice extract (CCE); three fractions containing flavonoid classes including proanthocyanidins, anthocyanins and flavonols; selected sub-fractions, and commercially available flavonol glycoside, quercetin-3-O-galactoside. Atomic force microscopy (AFM) was used to quantify the adhesion forces between the bacterial surface and the AFM probe after the treatment with the cranberry fractions. Adhesion forces of the non-pathogenic, non fimbriated lab strain HB101 are small (average force 0.19 nN) and do not change with cranberry treatments, whereas the adhesion forces of the pathogenic, Dr adhesion E. coli strain B78 (average force of 0.42 nN) show a significant decrease when treated with cranberry juice extract or fractions (average force of 0.31 nN, 0.37 nN and 0.39 nN with CCE, Fraction 7 and Fraction 4 respectively). In particular, the fractions that contained flavonols in addition to PACs were more efficient at lowering the force of adhesion (average force of 0.31 nN-0.18 nN between different sub-fractions containing flavonols and PACs). The sub-fractions containing flavonol glycosides (from juice, fruit and commercial quercetin) all resulted in reduced adhesion of the pathogenic bacteria to the model probe. This strongly suggests the anti adhesive role of other classes of cranberry compounds in conjunction with already known PACs and may have implications for development of alternative anti bacterial treatments. PMID- 27220365 TI - The effect of soluble E-selectin on tumor progression and metastasis. AB - BACKGROUND: Distant metastasis resulting from vascular dissemination of cancer cells is the primary cause of mortality from breast cancer. We have previously reported that E-selectin expression on the endothelial cell surface mediates shear-resistant adhesion and migration of circulating cancer cells via interaction with CD44. As a result of shedding, soluble E-selectin (sE-selectin) from the activated endothelium is present in the serum. In this study, we aimed to understand the role of sE-selectin in tumor progression and metastasis. METHODS: We investigated the effect of sE-selectin on shear-resistant adhesion and migration of metastatic breast cancer cells and leukocytes in vitro and in vivo. RESULTS: We found that sE-selectin promoted migration and shear-resistant adhesion of CD44(+) (/high) breast cancer cell lines (MDA-MB-231 and MDA-MB-468) to non-activated human microvessel endothelial cells (ES-HMVECs), but not of CD44(-/low) breast cancer cell lines (MCF-7 and T-47D). This endothelial E selectin independent, sE-selectin-mediated shear-resistant adhesion was also observed in a leukocyte cell line (HL-60) as well as human peripheral blood mononuclear cells (PBMCs). Additionally, the incubation of MDA-MB-231 cells with sE-selectin triggered FAK phosphorylation and shear-resistant adhesion of sE selectin-treated cells resulted in increased endothelial permeabilization. However, CD44 knockdown in MDA-MB-231 and HL-60 cells resulted in a significant reduction of sE-selectin-mediated shear-resistant adhesion to non-activated HMVECs, suggesting the involvement of CD44/FAK. Moreover, functional blockade of ICAM-1 in non-activated HMVECs resulted in a marked reduction of sE-selectin mediated shear-resistant adhesion. Finally, the pre-incubation of CD44(+) 4 T1 murine breast cancer cells with sE-selectin augmented infiltration into the lung in E-selectin K/O mice and infusion of human PBMCs pre-incubated with sE-selectin stimulated MDA-MB-231 xenografted breast tumor growth in NSG mice. CONCLUSIONS: Our data suggest that circulating sE-selectin stimulates a broad range of circulating cells via CD44 and mediates pleiotropic effects that promote migration and shear-resistant adhesion in an endothelial E-selectin independent fashion, in turn accelerating tissue infiltration of leukocytes and cancer cells. PMID- 27220366 TI - Discriminative gene co-expression network analysis uncovers novel modules involved in the formation of phosphate deficiency-induced root hairs in Arabidopsis. AB - Cell fate and differentiation in the Arabidopsis root epidermis are genetically defined but remain plastic to environmental signals such as limited availability of inorganic phosphate (Pi). Root hairs of Pi-deficient plants are more frequent and longer than those of plants grown under Pi-replete conditions. To dissect genes involved in Pi deficiency-induced root hair morphogenesis, we constructed a co-expression network of Pi-responsive genes against a customized database that was assembled from experiments in which differentially expressed genes that encode proteins with validated functions in root hair development were over represented. To further filter out less relevant genes, we combined this procedure with a search for common cis-regulatory elements in the promoters of the selected genes. In addition to well-described players and processes such as auxin signalling and modifications of primary cell walls, we discovered several novel aspects in the biology of root hairs induced by Pi deficiency, including cell cycle control, putative plastid-to-nucleus signalling, pathogen defence, reprogramming of cell wall-related carbohydrate metabolism, and chromatin remodelling. This approach allows the discovery of novel of aspects of a biological process from transcriptional profiles with high sensitivity and accuracy. PMID- 27220367 TI - Brain trauma elicits non-canonical macrophage activation states. AB - BACKGROUND: Macrophage polarization programs, commonly referred to as "classical" and "alternative" activation, are widely considered as distinct states that are exclusive of one another and are associated with different functions such as inflammation and wound healing, respectively. In a number of disease contexts, such as traumatic brain injury (TBI), macrophage polarization influences the extent of pathogenesis, and efforts are underway to eliminate pathogenic subsets. However, previous studies have not distinguished whether the simultaneous presence of both classical and alternative activation signatures represents the admixture of differentially polarized macrophages or if they have adopted a unique state characterized by components of both classical and alternative activation. METHODS: We analyzed the gene expression profiles of individual monocyte-derived brain macrophages responding to TBI using single-cell RNA sequencing. RNA flow cytometry was used as another single-cell analysis technique to validate the single-cell RNA sequencing results. RESULTS: The analysis of signature polarization genes by single-cell RNA sequencing revealed the presence of diverse activation states, including M(IL4), M(IL10), and M(LPS, IFNgamma). However, the expression of a given polarization marker was no more likely than at random to predict simultaneous expression or repression of markers of another polarization program within the same cell, suggesting a lack of exclusivity in macrophage polarization states in vivo in TBI. Also unexpectedly, individual TBI macrophages simultaneously expressed high levels of signature polarization genes across two or three different polarization states and in several distinct and seemingly incompatible combinations. CONCLUSIONS: Single-cell gene expression profiling demonstrated that monocytic macrophages in TBI are not comprised of distinctly polarized subsets but are uniquely and broadly activated. TBI macrophage activation in vivo is deeply complex, with individual cells concurrently adopting both inflammatory and reparative features with a lack of exclusivity. These data provide physiologically relevant evidence that the early macrophage response to TBI is comprised of novel activation states that are discordant with the current paradigm of macrophage polarization-a key consideration for therapeutic modulation. PMID- 27220368 TI - Impact of Hospitalization for Acute Myocardial Infarction on Adherence to Statins Among Older Adults. AB - BACKGROUND: Little is known about the impact of hospitalization for an acute myocardial infarction (AMI) on subsequent adherence to statins. METHODS AND RESULTS: Using administrative claims from a 5% random sample of Medicare beneficiaries, we identified a cohort of Medicare patients aged >=65 years, hospitalized from 2007 to 2011, taking statins in the year before AMI hospitalization (n=6618). We then determined the proportion of patients nonadherent to statins (proportion of days covered <80%) in the year before AMI hospitalization who became statin adherent (proportion of days covered >=80%) in the year after AMI hospitalization. The proportion of statin-adherent patients who became nonadherent was also studied. These proportions were compared with patients hospitalized for pneumonia (n=11 471) and patients not hospitalized (n=158 099) in 2010 and 2011. Among patients nonadherent to statins before AMI hospitalization, 37.7% became adherent after discharge. Patients hospitalized for AMI were more likely to become adherent than patients hospitalized for pneumonia (adjusted relative risk: 1.70; 95% confidence interval, 1.57-1.84) or patients not hospitalized (adjusted relative risk: 1.79; 95% confidence interval, 1.68 1.90). Among patients adherent to statins before AMI hospitalization, 32.6% became nonadherent after discharge. Those hospitalized for AMI were less likely to become nonadherent than those hospitalized for pneumonia (adjusted relative risk: 0.93; 95% confidence interval 0.88-0.98) but more likely to become nonadherent than patients without hospitalizations (adjusted relative risk: 1.41; 95% confidence interval, 1.35-1.48). CONCLUSIONS: Among nonadherent patients, hospitalization for AMI was associated with increased likelihood of becoming adherent to statins compared with hospitalization for pneumonia or no hospitalizations. Among adherent patients, hospitalization for AMI was associated with increased likelihood of becoming nonadherent to statins compared with no hospitalizations. PMID- 27220369 TI - Predicting Adverse Outcomes After Myocardial Infarction Among Patients With Diabetes Mellitus. AB - BACKGROUND: Although patients with diabetes mellitus experience high rates of adverse events after acute myocardial infarction (AMI), including death and recurrent ischemia, some diabetic patients are likely at low risk, whereas others are at high risk. We sought to develop prediction models to stratify risk after AMI in patients with diabetes mellitus. METHODS AND RESULTS: We developed prediction models for long-term mortality and angina among 1613 patients with diabetes mellitus discharged alive after AMI from 24 US hospitals and then validated the models in a separate, multicenter registry of 786 patients with diabetes mellitus. Event rates in the derivation cohort were 27% for 5-year mortality and 27% for 1-year angina. Parsimonious prediction models demonstrated good discrimination (c-indices=0.78 and 0.69, respectively) and excellent calibration. Within the context of the predictors we estimated, the strongest predictors for mortality were higher creatinine, not working at the time of the AMI, older age, lower hemoglobin, left ventricular dysfunction, and chronic heart failure. The strongest predictors for angina were angina burden in the 4 weeks before the AMI, younger age, history of prior coronary bypass graft surgery, and non-white race. The lowest and highest deciles of predicted risk ranged from 4% to 80% for mortality and 12% to 59% for angina. The models also performed well in external validation (c-indices=0.78 and 0.73, respectively). CONCLUSIONS: We found a wide range of risk for adverse outcomes after AMI in diabetic patients. Predictive models can identify patients with diabetes mellitus for whom closer follow-up and aggressive secondary prevention strategies should be considered. PMID- 27220370 TI - Feasibility of a Team Approach to Complex Congenital Heart Defect Neurodevelopmental Follow-Up: Early Experience of a Combined Cardiology/Neonatal Intensive Care Unit Follow-Up Program. AB - Infants with complex congenital heart disease are at high risk for poor neurodevelopmental outcomes. However, implementation of dedicated congenital heart disease follow-up programs presents important infrastructure, personnel, and resource challenges. We present the development, implementation, and retrospective review of 1- and 2-year outcomes of a Complex Congenital Heart Defect Neurodevelopmental Follow-Up program. This program was a synergistic approach between the Pediatric Cardiology, Cardiothoracic Surgery, Pediatric Intensive Care, and Neonatal Intensive Care Unit Follow-Up teams to provide a feasible and responsible utilization of existing infrastructure and personnel, to develop and implement a program dedicated to children with congenital heart disease. Trained developmental testers administered the Ages and Stages Questionnaire-3 over the phone to the parents of all referred children at least once between 6 and 12 months' corrected age. At 18 months' corrected age, all children were scheduled in the Neonatal Intensive-Care Unit Follow-Up Clinic for a visit with standardized neurological exams, Bayley III, multidisciplinary therapy evaluations and continued follow-up. Of the 132 patients identified in the Cardiothoracic Surgery database and at discharge from the hospital, a total number of 106 infants were reviewed. A genetic syndrome was identified in 23.4% of the population. Neuroimaging abnormalities were identified in 21.7% of the cohort with 12.8% having visibly severe insults. As a result, 23 (26.7%) received first-time referrals for early intervention services, 16 (13.8%) received referrals for new services in addition to their existing ones. We concluded that utilization of existing resources in collaboration with established programs can ensure targeted neurodevelopmental follow-up for all children with complex congenital heart disease. PMID- 27220371 TI - User Preferences for Content, Features, and Style for an App to Reduce Harmful Drinking in Young Adults: Analysis of User Feedback in App Stores and Focus Group Interviews. AB - BACKGROUND: Electronic screening and brief intervention (eSBI) is effective in reducing weekly alcohol consumption when delivered by a computer. Mobile phone apps demonstrate promise in delivering eSBI; however, few have been designed with an evidence-based and user-informed approach. OBJECTIVE: This study aims to explore from a user perspective, preferences for content, appearance, and operational features to inform the design of a mobile phone app for reducing quantity and frequency of drinking in young adults engaged in harmful drinking (18-30 year olds). METHODS: Phase 1 included a review of user reviews of available mobile phone apps that support a reduction in alcohol consumption. Apps were identified on iTunes and Google Play and were categorized into alcohol reduction support, entertainment, blood alcohol content measurement (BAC), or other. eSBI apps with >=18 user reviews were subject to a content analysis, which coded praise, criticism, and recommendations for app content, functionality, and esthetics. Phase 2 included four focus groups with young adults drinking at harmful levels and residing in South London to explore their views on existing eSBI apps and preferences for future content, functionality, and appearance. Detailed thematic analysis of the data was undertaken. RESULTS: In Phase 1, of the 1584 apps extracted, 201 were categorized as alcohol reduction, 154 as BAC calculators, 509 as entertainment, and 720 as other. We classified 32 apps as eSBI apps. Four apps had >=18 user reviews: Change for Life Drinks Tracker, Drinksmeter, Drinkaware, and Alcohol Units Calculator. The highest proportion of content praises were for information and feedback provided in the apps (12/27, 44%), followed by praise for the monitoring features (5/27, 19%). Many (8/12, 67%) criticisms were for the drinking diary; all of these were related to difficulty entering drinks. Over half (18/32, 56%) of functionality criticisms were descriptions of software bugs, and over half of those (10/18, 56%) were for app crashing or freezing. Drinksmeter and Alcohol Units Calculator were the most highly praised apps overall (23/57 and 22/57; 39% of praise overall). In Phase 2, two main themes were identified. The meaningfulness theme reflected how young adults thought apps needed to be tailored to the interests and values of their age group, particularly emphasizing content and feedback around broader health and well-being factors such as exercise, diet, and image. The community theme suggested that young adults want to be able to engage with other app users, both in groups of friends and with online users for motivation and support. CONCLUSIONS: Targeted and relevant information and feedback, in addition to easy to-use monitoring tools, were found to be important features of a mobile phone app to support a reduction in drinking. Future app development should consider tailoring all app aspects to the needs of young adults, considering broader well being monitoring tools and online community functions. PMID- 27220372 TI - Periostin expression induced by oxidative stress contributes to myocardial fibrosis in a rat model of high salt-induced hypertension. AB - Periostin is an extracellular matrix protein involved in fibrosis. The present study investigated the importance of periostin in hypertension-induced myocardial fibrosis. Rats were randomly divided into either the normal group (0.4% NaCl diet; n=8) or hypertension group (8% NaCl diet; n=8). For 36 weeks, the blood pressure and heart rate of the rats were monitored. At week 36, the hearts were extracted for further analysis. Masson's staining and western blotting were performed to determine the levels of periostin protein expression, oxidative stress and fibrosis. In addition, fibroblasts were isolated from adult rats and cultured in vitro, and following treatment with angiotensin II (Ang II) and N acetyl-L-cysteine (NAC), western blotting, immunofluorescence and 2',7' dichlorodihydrofluorescin staining were performed to examine reactive oxygen species production, and periostin and alpha-smooth muscle actin (alpha-SMA) expression levels. The results demonstrated that periostin expression and oxidative stress were increased in hypertensive hearts compared with normal hearts. The in vitro experiments demonstrated that Ang II upregulated the expression levels of periostin and alpha-SMA compared with the control, whereas, pretreatment with NAC inhibited oxidative stress, periostin and alpha-SMA expression in fibroblasts. In conclusion, the results of the current study suggested that oxidative stress-induced periostin is involved in myocardial fibrosis and hypertension. The present study demonstrated that periostin inhibition may be a promising approach for the inhibition of hypertension-induced cardiac remodeling. PMID- 27220373 TI - Treatment of aging oily wastewater by demulsification/flocculation. AB - The aging oily wastewater (AOW) from Tarim oilfield in China was treated by demulsification/flocculation. A novel sewage treatment agent (YL-7) was developed using a cationic surfactant (LY) and flocculants (polydimethyl diallyl ammonium chloride (PDMDAAC)/polyaluminum chloride (PAC)). At an YL-7 dosage of 320 mg L( 1) at 323 K for 90 min, the oil content of AOW was reduced from 728.8 mg L(-1) to 23.7 mg L(-1), and oil removal efficiency reached 96.7%. Microorganism flocs (extracted from AOW) with high negative zeta potential enhanced the stability of oil/water emulsion. LY and PDMDAAC neutralized the negative charge on the oil droplet surface. PDMDAAC and PAC mainly bridged and swept flocs during the flocculation process. YL-7 was found to be a suitable sewage treatment agent in removing oil from AOW. PMID- 27220375 TI - Competition between Displacement and Dissociation of a Strong Acid Compared to a Weak Acid Adsorbed on Silica Particle Surfaces: The Role of Adsorbed Water. AB - The adsorption of nitric (HNO3) and formic (HCOOH) acids on silica particle surfaces and the effect of adsorbed water have been investigated at 296 K using transmission FTIR spectroscopy. Under dry conditions, both nitric and formic acids adsorb reversibly on silica. Additionally, the FTIR spectra show that both of these molecules remain in the protonated form. At elevated relative humidities (RH), adsorbed water competes both for surface adsorption sites with these acids as well as promotes their dissociation to hydronium ions and the corresponding anions. Compared to HNO3, the extent of dissociation is much smaller for HCOOH, very likely because it is a weaker acid. This study provides valuable insights into the interaction of HNO3 and HCOOH with silica surface on the molecular level and further reveals the complex roles of surface-adsorbed water in atmospheric heterogeneous chemistry of mineral dust particles-many of these containing silica. PMID- 27220374 TI - Development of a novel microbubble-liposome complex conjugated with peptide ligands targeting IL4R on brain tumor cells. AB - Gas (SF6)-filled microbubbles (MBs) were prepared by emulsion and solvent evaporation method. The prepared MBs were further conjugated with doxorubicin (Dox)-loaded nano-sized liposome and peptide ligands to interleukin-4 receptor (IL4R) for targeting brain tumor cells. The final MB-liposome (Dox)-IL4R targeting peptide ligand [MB-Lipo (Dox)-IL4RTP] had a spherical structure with the mean size of 1,500 nm. The MB-Lipo (Dox)-IL4RTP exhibited cellular uptake in U87MG brain tumor cells (a brain tumor cell line expressing strongly IL4R) with frequency ultrasound energy suggesting that MB-Lipo (Dox)-IL4RTP provided effective targeting ability for brain tumor cells. In addition, WST-1 assay results showed that MB-Lipo (Dox)-IL4RTP inhibited the proliferation of U87MG cells IL4R-dependently. This was confirmed by western blotting of gammaH2AX, phospho (Ser15)-p53, p53 and p21 which are signal transduction proteins involved in DNA damage response and cell cycle arrest. Taken together, these results indicate that MB-Lipo (Dox)-IL4RTP represents a promising ultrasonic contrast agent for tumor-targeting ultrasonic imaging. PMID- 27220376 TI - SEI Formation and Interfacial Stability of a Si Electrode in a LiTDI-Salt Based Electrolyte with FEC and VC Additives for Li-Ion Batteries. AB - An electrolyte based on the new salt, lithium 4,5-dicyano-2 (trifluoromethyl)imidazolide (LiTDI), is evaluated in combination with nano-Si composite electrodes for potential use in Li-ion batteries. The additives fluoroethylene carbonate (FEC) and vinylene carbonate (VC) are also added to the electrolyte to enable an efficient SEI formation. By employing hard X-ray photoelectron spectroscopy (HAXPES), the SEI formation and the development of the active material is probed during the first 100 cycles. With this electrolyte formulation, the Si electrode can cycle at 1200 mAh g(-1) for more than 100 cycles at a coulombic efficiency of 99%. With extended cycling, a decrease in Si particle size is observed as well as an increase in silicon oxide amount. As opposed to LiPF6 based electrolytes, this electrolyte or its decomposition products has no side reactions with the active Si material. The present results further acknowledge the positive effects of SEI forming additives. It is suggested that polycarbonates and a high LiF content are favorable components in the SEI over other kinds of carbonates formed by ethylene carbonate (EC) and dimethyl carbonate (DMC) decomposition. This work thus confirms that LiTDI in combination with the investigated additives is a promising salt for Si electrodes in future Li-ion batteries. PMID- 27220381 TI - Regional disparities in botulinum toxin A (BoNT-A) therapy for spasticity in Sweden: budgetary consequences of closing the estimated treatment gap. AB - OBJECTIVES: As no national treatment guidelines for spasticity have been issued in Sweden, different regional treatment practices may potentially occur. This study examines botulinum toxin A (BoNT-A) treatment for spasticity on a regional level in Sweden and presents budgetary consequences of closing the estimated treatment gap. MATERIALS AND METHODS: Prevalence of spasticity in Sweden was estimated from published data. Regional sales data for BoNT-A were acquired from IMS Health. A set proportion of hospital BoNT-A use was assumed to represent treatment of spasticity. Total intervention cost of BoNT-A treatment was gathered from healthcare regional tariffs, while costs associated with spasticity were derived from publications on multiple sclerosis and stroke. RESULTS: Results show that the regional variation in treatment of spasticity with BoNT-A is large, with approximately every fourth patient being treated in Southern healthcare region compared to every tenth in the Stockholm-Gotland or Western healthcare regions. The incremental cost of filling the reported treatment gap was also assessed and was estimated at around 9.4 million EUR. However, for the incremental cost to be offset by savings in spasticity-related costs, only a small proportion of treatment responders (defined as patients transitioning to a lower severity grade of spasticity) was required (12%). CONCLUSIONS: The study revealed apparent regional disparities of BoNT-A treatment for spasticity in Sweden. The results further suggest that the incremental cost of eliminating the treatment gap has a high probability of being offset by savings in direct costs, even at a low proportion of the patients reaching clinical improvement. PMID- 27220382 TI - [Skeletal Class III patients treated with Frankel function regulator type III in the early and late mixed dentition]. AB - OBJECTIVE: To investigate the outcome of skeletal Class III patients treated with Frankel function regulator type III (FR III)in the early mixed and late mixed dentition. METHODS: The samples consisted of 45 mild and moderate skeletal Class III patients(26 males, 19 females; meanage, [7.9+/-1.3] years) treated with FR III. According to Hellman's dental developmental stages, these samples were divided into early-treated group(n=24) and late-treated group(n=21). Lateral cephalograms were taken at the beginning and the end of treatment. Twenty-one measurements on hard and soft tissue were included. RESULTS: After treatment, SNA, ANB, NA-Apo, Wits, U1-SN, U1-NA, Overjet, UL-EP were significantly increased (1.0+/-1.9) degrees , (1.2+/-1.6) degrees , (2.6+/-4.2) degrees , (1.8+/-2.7) mm, (4.2+/-7.6) degrees , (2.6+/-7.5) degrees , (3.6+/-2.3) mm and (0.8+/-2.2) mm(P<0.05). OP-SN and IMPA were significantly decreased (1.5+/-3.7) degrees and (1.4+/-4.2) degrees (P<0.05). There were significant differences in SNA, ANB, UL EP, IMPA, L1-NB between early-treated group and late-treated group(P<0.05). CONCLUSIONS: FR III was suitable for the treatment of mild and moderate skeletal Class III patients. The result was better in the early-treated patients than in late-treated ones. PMID- 27220384 TI - [The prevalence of Candida albicans and its relationship with early childhood caries among children of Uygur and Han nationalities in Kashi city]. AB - OBJECTIVE: To explore the relationship between the prevalence of Candida albicans and early childhood caries(ECC) among 3-5 years old children of Uygur and Han nationalities in Kashi city, Xinjiang province. METHODS: Totally 397 generally healthy children(Uyghurs 256, Hans141) aged 3-5 years were recruited randomly in Kashi city using the stratified cluster random method. Dental plaque samples were collected from carious tooth tissues of children with ECC and from supragingival tooth sites of caries free(CF) children, respectively. Plaque samples were cultured and Candida albicans were isolated selectively by using CHROM agar candida medium. The isolates were further identified using methods of germ tubes test, Gram stain and PCR molecular biology. The data were analyzed using Pearson chi(2) test and Spearman analysis. RESULTS: The prevalenses of Candida albicans were 44.5% (114/256) in Han children and 31.2%(44/141) in Urgur children, respectively(P=0.009). Candida albicans could be isolated from 48.8% (124/254) of ECC children, while 23.8% (34/143) of CF ones(P=0.000). The frequencies of Candida albicans acquisition of boys and girls of Uygur children were 51.2%(66/129) and 37.8%(48/127), respectively (P=0.031). The frequencies of Candida albicans acquisition increased with the decayed missing filled tooth (dmft) scores. For both Uygur and Hanchildren, the detection rates of Candida albicans were correlated with dmft scores(Uygur r=0.350, P=0.001; Han r=0.276, P=0.000). CONCLUSIONS: The oral Candida albicans distributions were different in Uygur and Han ethnic groups. There were significant correlations between the presence of Candida albicans and ECC severityas well as score of dmft. There was a difference of the Candida albicans distributions between boys and girls among Uygur children. Candida albicans might be one of the important cariogenic microorganisms in ECC. PMID- 27220383 TI - [Evaluation of the orthodontic treatment outcome in patients with impacted maxillary central incisor in the mixed dentition]. AB - OBJECTIVE: To evaluate the orthodontic treatment outcome in patients with impacted maxillary central incisor in the mixed dentition. METHODS: Nine patients, aged 8 to 11 years, with impacted maxillary central incisor were treated orthodontically. The cone-beam CT(CBCT) was taken before treatment, after treatment and one year out of retention to evaluate the root length, root canal wall thickness, width of the apical foramen, and degree of root bending, alveolar bone height and thickness. The crown-to-root ratio was calculated. The periodontal and endodontic conditions were evaluated. The parameters of the treated incisors and contralateral ones served as controls were compared. RESULTS: Nine impacted teeth were treated successfully. Throughout the treatment, the root of impacted central incisor continued to develop and the alveolar bones also continued to develop and remodel. The condition of the alveolar bone of vertically impacted teeth was better than that of horizontally impacted ones. No periodontal pocket or pulp necrosis was found after treatment. Seven patients were examined one year after treatment. No significant difference was found in root length, palatal alveolar bone level and palatal alveolar bone thickness. The control group root length was (13.07+/-2.15) mm, the treatment group root length was (12.06+/-2.00) mm. No further alveolar bone loss, gingival recession and pulp necrosis were found. The control group labial and palatal alveolar bone levels were (0.90+/-0.62), (0.45+/-0.52) mm, labial and palatal alveolar bone thickness were (0.85+/-0.14), (1.21+/-0.41) mm. The treatment group labial and palatal alveolar bone levels were (2.18+/-1.59) mm, (0.57+/-0.71) mm, labial and palatal alveolar bone thickness were (0.48+/-0.29), (1.43+/-0.31) mm. CONCLUSIONS: Orthodontic therapy for impacted maxillary central incisor in the mixed dentition could promote root development and alveolar bone remodeling. Good periodontal and endodontic conditions were achieved. PMID- 27220385 TI - [Comprehensive oral treatment of an incontinentia pigmenti patient with congenital hypodontia]. PMID- 27220386 TI - [A Summary of the 8th National Conference of Pediatric Dentistry]. PMID- 27220387 TI - [Digital modeling for the individual mandibular 3D mesh scaffold based on 3D printing technology]. AB - OBJECTIVE: To investigate an ideal modeling method of designing 3D mesh scaffold substitutes based on tissue engineering to restore mandibular bone defects. By analyzing the theoretical model from titanium scaffolds fabricated by 3D printing, the feasibility and effectiveness of the proposed methodology were verified. METHODS: Based on the CT scanned data of a subject, the Mimics 15.0 and Geomagic studio 12.0 reverse engineering software were adopted to generate surface model of mandibular bone and the defect area was separated from the 3D model of bone. Then prosthesis was designed via mirror algorithm, in which outer shape was used as the external shape of scaffold. Unigraphics software NX 8.5 was applied on Boolean calculation of subtraction between prosthesis and regular microstructure structure and ANSYS 14.0 software was used to design the inner construction of 3D mesh scaffolds. The topological structure and the geometrical parameters of 3D mesh titanium scaffolds were adjusted according to the aim of optimized structure and maximal strength with minimal weight. The 3D mesh scaffolds solid model through two kinds of computer-aided methods was input into 3D printing equipment to fabricate titanium scaffolds. RESULTS: Individual scaffolds were designed successfully by two modeling methods. The finite element optimization made 10% decrease of the stress peak and volume decrease of 43%, and the porosity increased to 76.32%. This modeling method was validated by 3D printing titanium scaffold to be feasible and effective. CONCLUSIONS: 3D printing technology combined with finite element topology optimization to obtain the ideal mandibular 3D mesh scaffold is feasible and effective. PMID- 27220388 TI - [Expression of long non-coding RNA colon cancer associated transcript 2 and its clinicopathologic significance in oral squamous cell carcinoma]. AB - OBJECTIVE: To investigate the expression of long non-coding RNA(lncRNA) colon cancer associated transcript 2(CCAT2) and its association with clinicopathologic features in oral squamous cell carcinoma(OSCC). METHODS: The expression of lncRNA was detected with microarray assay in three samples of OSCC tumor and matched adjacent tissues. The profiles of lncRNAs in OSCC tissues were identified. The CCAT2 expression was evaluated by real-time quantitative PCR(RT-qPCR) in 86 OSCC tumor samples and matched adjacent tissues. The relationship between the expression of CCAT2 and its clinicopathologic features of OSCC was analyzed. Tumor cell proliferation was assessed following siRNA knockdown of CCAT2 by using the CCK-8 kits. RESULTS: A total of 1 685 lncRNA expressed in OSCC tumor samples and matched adjacent tissues were identified using microarray assay(P<0.05). RT qPCR showed that the expression of CCAT2 was significantly higher in OSCC than that in adjacent tissues(P< 0.01). High CCAT2 expression was associated with cell differentiation and pathological stage of OSCC. CCAT2 expression in low differentiated OSCC was significantly higher than that in high-differentiated cancer (P=0.015). In addition, CCAT2 level in stage III/IV OSCC was significantly higher than that in stage I/II cancer (P=0.022). Furthermore, inhibition of CCAT2 expression suppressed the proliferation of human tongue carcinoma Tca8113 cells. CONCLUSIONS: Abnormal expression of lncRNA may be involved in the development of OSCC. Up-regulation of CCAT2 expression in tumor tissue might act as an oncogene and promote the development of OSCC. PMID- 27220389 TI - [The influence of the different polishing methods on the marginal sealing property of the computer aided design and computer aided manufacture zirconium dioxide full crown]. AB - OBJECTIVE: To evaluate the influence of different polishing methods on marginal microleakage of zirconium dioxide full crown. METHODS: Thirty extracted premolars were selected and randomly divided into three groups, A, B and C, with 10 in each group. Group A was prepared with MANI TF-13 bur completely without the treatment of shoulder. The shoulder of group B was polished with MANI TR13-EF bur after the preparation using MANI TF-13. The shoulder of group C was polished with the dental pneumatic ultrasonic hand-piece of KaVo SONICflex after the preparation using MANI TF-13 bur. Five specimens after preparation were selected in each group. Fifteen CAD/CAM zirconium dioxide full crowns have been made. The crowns were bonded using PULPDENT resin cement, and the root canals were sealed using nail polish, and apical foramen were closed using flow resin. The test-pieces have been immersed in a 3% solution of methylene blue for 24 h. The condition of shoulder marginal microleakage was observed using light stereomicroscopy and evaluated in classification index. The remaining specimens in each group were used for roughness test and scanning electron microscope(SEM) experiment. The marginal microleakage situations of specimens in three groups was analyzed by SPSS 17.0. The enamel surface of different polishing methods was observed using SEM. RESULTS: The specimens in group C demonstrated the least marginal microleakage, and those in group B showed an intermediate level of marginal microleakage, and those in group A characterized the most serious marginal microleakage (total, chi2=44.610, P<0.01; among the different groups, P<0.05). The roughness experiment showed that specimens in group C achieve the smoothest results ([0.27+/-0.03] MUm). Preparation shoulder polished using the dental pneumatic ultrasonic hand-piece demonstrated the best result under the SEM among the three groups. CONCLUSIONS: The anti-microleakage effectiveness of dental pneumatic ultrasonic hand-piece in shoulder refinement is better than ordinary shoulder treatment. PMID- 27220390 TI - [Comparison of adaptation of crowns of different lithium disilicate glass ceramic]. AB - OBJECTIVE: To evaluate the adaptation of different lithium disilicate glass ceramic crown and whether different fabrication processes affect the adaptation of crowns. METHODS: Thirty epoxy dies crowns were divided into 3 groups. They were cemented to domestic lithium disilicate glass-ceramic crowns in Group A, to IPS e.max CAD crowns in Group B and to IPS e.max Press crowns in Group C respectively. All crowns were cut by cutting machine. A confocal laser scanning microscope was used to measure the gap between crown tissue surface and die. RESULTS: There were significant differences in the three groups of measurement points(P<0.05). Within the groups, specimens in group A showed in the lowest marginal fit([46.8+/-9.1] MUm). Those in group B showed the lowest shoulder suitability([59.3+/-7.9] MUm), axial plane([50.5+/-3.6] MUm) and occlusal surface([87.6+/-11.6 MUm]. Those in group C demonstrated the lowest axial plane angle[(84.4+/-10.1) MUm]. In addition to the axial plane angle, the CAD/CAM system exhibited good accuracy of fit. CONCLUSIONS: The three groups of lithium disilicate glass-ceramic crowns appeared to have clinically acceptable fit. PMID- 27220391 TI - [Influence of polishing and glazing on the wear of zirconia and enamel]. AB - OBJECTIVE: To investigate the effect of different surface treatment of zirconia and to find the best way to reduce the wear of its antagonist. METHODS: Twenty five plates(5 mm*10 mm*15 mm) made of zirconia were divided into five equal groups. Group A was only ground, group B was ground and polished, group C was ground and polished then polished by prophylaxis paste, group D was ground and glazed, group E was ground, polishsed, and then reglazed. Five central incisors were embedded in autopolymerizing acrylic resin with a size of 5 mm*10 mm*15 mm as the control group F. Thirty upper premolars buccal cusps were prepared as the antagonist. Cusps were embedded in autopolymerizing acrylic resin with a shape of circular column whose diameter were 3.1 mm. The wear test was performed in the universal micro-tribotester in artificial saliva. The roughness of each group was measured with rough meter before the wear test. The volume loss of the antagonist was measured using a 3D scanner. The wear surface was observed with scanning electron microscopy to determine the wear characteristics. Data were analyzed using one-way analysis of variance. RESULTS: Each group of surface roughness and mass loss of antagonist showed significant statistical difference (P<0.05). Antagonist of group D showed the maximum volume loss([0.905+/-0.018] mm3). Antagonist of control group showed the least volume loss([0.235+/-0.017] mm3). Antagonist of group C showed less volume loss than antagonist of control group did([0.413+/-0.017] mm3). Wear type of enamel of control group and the antagonist of the groups in which the samples were polished with prophylaxis paste was fatigue wear, and the other groups showed abrasive and adhesive wear. CONCLUSIONS: In the surface treatment methods of zirconia, polishing is better than glazing. Ground and polishing and then polishing with prophylaxis paste can decrease the wear of the antagonist. PMID- 27220392 TI - [Measurement of the metabolites in the cortical masticatory area of patients with sleep bruxism: a magnetic resonance spectroscopy study]. AB - OBJECTIVE: To determine whether there are in vivo differences of metabolites levels in bilateral cortical masticatory area(CMA) of patients with sleep bruxism, compared with healthy controls using proton magnetic resonance spectroscopy(1H-MRS). Accordingly to explore if cortical control of the central jaw motor system is abnormal in sleep bruxism patients. METHODS: Fifteen sleep bruxism patients and fifteen age- and gender-matched healthy controls underwent 1H-MRS of bilateral CMA using J-difference edited point-resolved spectroscopy sequence(MEGA-PRESS) technique. Levels of metabolites were quantified from the ratio of the metabolite integral to the unsuppressed water signal. Differences of levels of gamma-aminobutyric acid(GABA), glutmate(Glu) and N-acetyl aspartate(NAA) in bilateral CMA between sleep bruxism patients and healthy controls were tested using two-way ANOVA. RESULTS: Edited spectra were successfully obtained from the bilateral CMA in all of the participants. Levels of GABA+, glutmate and NAA in right and left CMA in sleep bruxism patients were (2.45+/-0.48)*10(-3), (2.35+/-0.62)*10(-3), (10.65+/-1.84)*10(-3), (10.49+/ 2.37)*10(-3), (10.70+/-3.61)*10(-3), and (11.26+/-4.01)*10(-3) respectively. In contrast, levels of GABA+, glutmate and NAA in right and left CMA in healthy controls were (2.63+/-0.68)*10(-3), (2.65+/-0.97)*10(-3), (11.19+/- 1.34)*10(-3), (10.58+/-3.14)*10(-3), (11.82+/-1.80)*10(-3), and (11.95+/-3.23)*10(-3). There were no differences in levels of GABA+(P=0.196), Glu(P=0.590), and NAA(P=0.292) between sleep bruxism patients and healthy controls, nor in inbilateral CMA(GABA+: P=0.837; Glu: P=0.510; NAA: P=0.628). CONCLUSIONS: The results indicate the absence of any alteration of the cortical control of the central jaw motor system in the levels of GABA, Glu and NAA in patients with sleep bruxism. PMID- 27220393 TI - [Research progress in peri-implant soft tissue engineering augmentation method]. AB - The sufficiency of hard and soft tissue at the implant site is the guarantee of long-term function, health and the appearance of implant denture. Problem of soft tissue recession at the implant site has always been bothering dentists. Traditional methods for augmentation of soft tissue such as gingival transplantation have disadvantages of instability of the increased soft-tissue and more trauma. Lately the methods that base on tissue engineering to increase the soft tissue of peri-implant sites have drawn great attention. This review focuses on the current methods of peri-implant restoration through tissue engineering, seed cells, biological scaffolds and cytokines. PMID- 27220394 TI - [The influence of orthodontic treatment on dental pulp and periapical tissues]. AB - The pathogenesis of pulpal and periapical diseases is related with not only bacterial infection but also physicochemical irritations such as trauma and thermal changes. During orthodontic therapy, the application of orthodontic forces on teeth may produce a series of changes in periodontal ligament, alveolar bone and pulpo-dentinal complex. This article reviewed the influences of orthodontic therapy on dental pulp and periapical tissues. PMID- 27220395 TI - Effectiveness of an aquatic exercise program and low-level laser therapy on articular cartilage in an experimental model of osteoarthritis in rats. AB - OBJECTIVE: The aim of this study was to evaluate the effects of an aquatic exercise program and low-level laser therapy (LLLT) (associated or not) on degenerative modifications and inflammatory mediators on the articular cartilage using an experimental model of knee OA. METHOD: Forty male Wistar rats were divided into 4 groups: knee OA - without treatment (OA); OA plus exercise program group (OAE); OA plus LLLT (OAL); OA plus exercise program associated with LLLT (OAEL). Trained rats performed a water-jumping program carrying a load equivalent to 50-80 % of their body mass strapped to their chest. The laser irradiation was used either as the only method or after the exercise training had been performed, at 2 points contact mode (medial and lateral side of the left joint). The treatments started 4 weeks after the surgery, 3 days/week for 8 weeks. RESULTS: The results revealed that all treated groups (irradiated or not) exhibited a better pattern of tissue organization, with less fibrillation and irregularities along the articular surface and improved chondrocytes organization. Also, a lower cellular density and structural damage (OARSI score) and higher thickness values were observed in all treated groups. Additionally, OAE and OAEL showed a reduced expression in IL-1beta and caspase-3 as compared with OA. Furthermore, a statistically lower MMP-13 expression was only observed in OAEL as compared with OA. CONCLUSION: These results suggest that aquatic exercise program and LLLT were effective in preventing cartilage degeneration. Also, physical exercise program presented anti-inflammatory effects in the knees in OA rats. PMID- 27220396 TI - Construction and functional analysis of an anti-human cervical carcinoma/anti human CD3 single-chain bispecific antibody. AB - The aim of the present study was to construct a single-chain bispecific antibody (scBsAb) against cervical carcinoma and to investigate its biological activities. The scBsAb was constructed using a genetic cloning technique and antigen binding activities were detected by ELISA. The iodogen method was used to analyze the pharmacokinetics. The Rosette formation test was used to detect the binding ability between peripheral blood lymphocytes (PBLs) and Cs1213 cervical cancer cells. In addition, the MTT method was performed to detect the killing effect of PBLs. The molecular weight of the scBsAb was ~60 kDa. The antigen binding activities of scBsAbs were compared with the anti-human cervical carcinoma antibody single-chain Fv fragment (CSAs-1 scFv) and anti-cluster of differentiation (CD)3 scFv (P>0.05). In addition, a pharmacokinetics assay demonstrated that compared with the two corresponding scFvs, scBsAbs exhibited a significantly prolonged retention time in the body (P<0.01). In addition, the number of rosettes formed by PBLs and Cs1213 cells in the scBsAb group was markedly greater than that in the scFv groups or the RPMI-1640 group (P<0.05 and P<0.01, respectively). The killing activity of PBLs against scBsAb-mediated Cs1213 cells was significantly greater than that mediated by the other antibodies (P<0.05). When the concentration of scBsAb was 40 ug/ml, the killing rate was 64.5%. Thus, anti-human cervical carcinoma/anti-CD3 scBsAbs may possess two types of antigen binding activity, prolong the duration in vivo and improve the killing activity of PBLs against cancer cells. PMID- 27220397 TI - The Location of the Pivot Point of the Eye. Part I. PMID- 27220398 TI - Identification of novel potent human testis-specific and bromodomain-containing protein (BRDT) inhibitors using crystal structure-based virtual screening. AB - Human testis-specific and bromodomain-containing protein (hBRDT) is essential for chromatin remodeling during spermatogenesis and is therefore an attractive target for the discovery of male contraceptive drugs. In this study, pharmacophore modeling was carried out based on the crystal structure of hBRDT in complex with the inhibitor, JQ1. The established pharmacophore model was used as a 3D search query to identify potent hBRDT inhibitors from an in-house chemical database. A molecular docking analysis was carried out to filter the obtained hit compounds. A total of 125 compounds was finally selected based on the ranking order and visual examination. These compounds were further evaluated by a protein-based in vitro assay. Four compounds with new chemical scaffolds were identified to be hBRDT inhibitors. The most active of these compounds, T480, had a half maximal inhibitory concentration (IC50) of 9.02 uM. The detailed analysis of the binding mode of compound T480 provides important information for the further development of novel BRDT inhibitors. PMID- 27220399 TI - HMGB1 knockdown effectively inhibits the progression of rectal cancer by suppressing HMGB1 expression and promoting apoptosis of rectal cancer cells. AB - Rectal cancer is a malignant gastrointestinal tumor, which is associated with high morbidity and mortality. High-mobility group protein 1 (HMGB1) is widely present in the nucleus of eukaryotic cells, and is highly conserved between humans and rodents. Recently, HMGB1 has been reported to be involved in the progression and metastasis of human cancer; however, its role in the development and metastasis of human rectal cancer remains unclear. The present study detected the expression levels of HMGB1 in pathological specimens from patients with clinically identified rectal cancer using immunohistochemistry and western blotting. The results demonstrated that HMGB1 was highly expressed in samples from patients with rectal cancer. The positive rate of HMGB1 in rectal cancer tissues was 96.08% (49/51), which was significantly higher compared with 3.92% (2/51) in normal tissues. In addition, western blotting indicated that HMGB1 was distributed and located not only in the nucleus, but also in the cytoplasm of colorectal cancer cells. HMGB1-specific short hairpin (sh)RNA was used to silence the endogenous expression of HMGB1 in colorectal cancer cells. A functional assay demonstrated that knockdown of endogenous HMGB1 expression significantly inhibited the proliferation of SW620 and Colo320 cells. Furthermore, western blotting revealed that knockdown of endogenous HMGB1 expression contributed to activation of caspase-3 and the substrate poly (ADP-ribose) polymerase. The expression levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) were also detected by western blotting. As expected, decreased levels of Bcl-2 and increased levels of Bax were detected in the HMGB1 shRNA-transfected colorectal cancer cells, and the Bax/Bcl-2 ratio was increased in HMGB1 shRNA transfected cells. These data indicated that HMGB1 may act as an oncogene in rectal cancer, and knockdown of endogenous HMGB1 expression may significantly inhibit the proliferation of colorectal cancer cells and promote apoptosis of tumor cells. Further research regarding the mechanisms underlying the effects of HMGB1 on the progression of rectal cancer may provide novel targets for the treatment of rectal cancer, and provide a theoretical reference for clinical treatment. PMID- 27220400 TI - Inhibition of gold nanoparticles (AuNPs) on pathogenic biofilm formation and invasion to host cells. AB - Owing to the growing infectious diseases caused by eukaryotic and prokaryotic pathogens, it is urgent to develop novel antimicrobial agents against clinical pathogenic infections. Biofilm formation and invasion into the host cells are vital processes during pathogenic colonization and infection. In this study, we tested the inhibitory effect of Au nanoparticles (AuNPs) on pathogenic growth, biofilm formation and invasion. Interestingly, although the synthesized AuNPs had no significant toxicity to the tested pathogens, Candida albicans and Pseudomonas aeruginosa, the nanoparticles strongly inhibited pathogenic biofilm formation and invasion to dental pulp stem cells (DPSCs). Further investigations revealed that AuNPs abundantly bound to the pathogen cells, which likely contributed to their inhibitory effect on biofilm formation and invasion. Moreover, treatment of AuNPs led to activation of immune response-related genes in DPSCs, which may enhance the activity of host immune system against the pathogens. Zeta potential analysis and polyethylene glycol (PEG)/polyethyleneimine (PEI) coating tests further showed that the interaction between pathogen cells and AuNPs is associated with electrostatic attractions. Our findings shed novel light on the application of nanomaterials in fighting against clinical pathogens, and imply that the traditional growth inhibition test is not the only way to evaluate the drug effect during the screening of antimicrobial agents. PMID- 27220403 TI - A multicaloric material as a link between electrocaloric and magnetocaloric refrigeration. AB - The existence and feasibility of the multicaloric, polycrystalline material 0.8Pb(Fe1/2Nb1/2)O3-0.2Pb(Mg1/2W1/2)O3, exhibiting magnetocaloric and electrocaloric properties, are demonstrated. Both the electrocaloric and magnetocaloric effects are observed over a broad temperature range below room temperature. The maximum magnetocaloric temperature change of ~0.26 K is obtained with a magnetic-field amplitude of 70 kOe at a temperature of 5 K, while the maximum electrocaloric temperature change of ~0.25 K is obtained with an electric field amplitude of 60 kV/cm at a temperature of 180 K. The material allows a multicaloric cooling mode or a separate caloric-modes operation depending on the origin of the external field and the temperature at which the field is applied. PMID- 27220401 TI - Regulation of cell apoptosis and proliferation in pancreatic cancer through PI3K/Akt pathway via Polo-like kinase 1. AB - Pancreatic cancer has a poor prognosis. It is reported that the PI3K/Akt pathway is activated in many cancers, and inhibition of the PI3K/Akt pathway can induce cell apoptosis in most cancers. Polo-like kinase 1 (Plk1) is also overexpressed in most malignancies, and it controls multiple aspects of mitosis and apoptosis. Previous studies identified that PI3K/Akt-dependent phosphorylation of Plk1-Ser99 is required for metaphase-anaphase transition. In this study, we aimed to investigate the molecular mechanism of PI3K/Akt pathway regulating cell proliferation and apoptosis in pancreatic cancer cell lines (AsPC-1, BxPC-3, PANC 1). Immunohistochemistry (IHC) was used to assess Akt levels in human pancreatic tissues and pancreatic cancer tissues. MTT assay was used to detect cell proliferation. The mRNA was quantified by quantitative reverse transcription-PCR. Western blot analysis was used to detect the protein levels of p-Akt, Akt, Plk1, BAX, Bcl-2, XIAP, cleaved caspase-3 and caspase-3. Recombinant adenovirus vector containing Plk1-shRNA was constructed to inhibit Plk1 expression. Cell apoptosis was detected by flow cytometry and the apoptosis of tumor xenograft was assessed by TUNEL assay. The study showed that inhibition of PI3K/Akt pathway can induce cell apoptosis and reduce cell proliferation by downregulating Plk1 in vitro and in vivo. Additionally, Plk1 inhibition can lead to cancer cell apoptosis through inactivating XIAP, activating caspase-3, upregulating BAX and downregulating Bcl 2. Therefore, this study provided the molecular mechanism of PI3K/Akt pathway and Plk1 in the pancreatic cancer cell proliferation and apoptosis, which may benefit for the therapy of pancreatic cancer. PMID- 27220404 TI - Leishmania mexicana: promastigotes and amastigotes secrete protein phosphatases and this correlates with the production of inflammatory cytokines in macrophages. AB - Phosphatase activity of Leishmania spp. has been shown to deregulate the signalling pathways of the host cell. We here show that Leishmania mexicana promastigotes and amastigotes secrete proteins with phosphatase activity to the culture medium, which was higher in the Promastigote Secretion Medium (PSM) as compared with the Amastigote Secretion Medium (ASM) and was not due to cell lysis, since parasite viability was not affected by the secretion process. The biochemical characterization showed that the phosphatase activity present in PSM was higher in dephosphorylating the peptide END (pY) INASL as compared with the peptide RRA (pT)VA. In contrast, the phosphatase activity in ASM showed little dephosphorylating capacity for both peptides. Inhibition assays demonstrated that the phosphatase activity of both PSM and ASM was sensible only to protein tyrosine phosphatases inhibitors. An antibody against a protein phosphatase 2C (PP2C) of Leishmania major cross-reacted with a 44.9 kDa molecule in different cellular fractions of L. mexicana promastigotes and amastigotes, however, in PSM and ASM, the antibody recognized a protein about 70 kDa. By electron microscopy, the PP2C was localized in the flagellar pocket of amastigotes. PSM and ASM induced the production of tumor necrosis factor alpha, IL-1beta, IL-12p70 and IL 10 in human macrophages. PMID- 27220405 TI - Terminator Operon Reporter: combining a transcription termination switch with reporter technology for improved gene synthesis and synthetic biology applications. AB - Synthetic biology is characterized by the development of novel and powerful DNA fabrication methods and by the application of engineering principles to biology. The current study describes Terminator Operon Reporter (TOR), a new gene assembly technology based on the conditional activation of a reporter gene in response to sequence errors occurring at the assembly stage of the synthetic element. These errors are monitored by a transcription terminator that is placed between the synthetic gene and reporter gene. Switching of this terminator between active and inactive states dictates the transcription status of the downstream reporter gene to provide a rapid and facile readout of the accuracy of synthetic assembly. Designed specifically and uniquely for the synthesis of protein coding genes in bacteria, TOR allows the rapid and cost-effective fabrication of synthetic constructs by employing oligonucleotides at the most basic purification level (desalted) and without the need for costly and time-consuming post-synthesis correction methods. Thus, TOR streamlines gene assembly approaches, which are central to the future development of synthetic biology. PMID- 27220406 TI - Notch signaling represses hypoxia-inducible factor-1alpha-induced activation of Wnt/beta-catenin signaling in osteoblasts under cobalt-mimicked hypoxia. AB - The modification of Wnt and Notch signaling pathways by hypoxia, and its association with osteoblast proliferation and apoptosis remain to be fully elucidated. To investigate Wnt-Notch crosstalk, and its role in hypoxia-induced osteoblast proliferation and apoptosis regulation, the present study investigated the effects of cobalt-mimicked hypoxia on the mouse pre-osteoblast-like cell line, MC3T3-E1, when the Notch signals were repressed using a gamma-secretase inhibitor DAPT. The data showed that the cobalt-mimicked hypoxia suppressed cell proliferation under normal conditions, but increased cell proliferation under conditions of Notch repression, in a concentration-dependent manner. The results of western blot and reverse transcription-quantitative polymerase chain reaction analyses showed that the cobalt treatment increased the levels of activated beta catenin protein and the expression levels of the target genes, axis inhibition protein 2 and myelocytomatosis oncogene, under DAPT-induced Notch repression. However, no significant changes were found in the expression levels of the Notch intracellular domain protein or the Notch target gene, hes1. In a beta-catenin gene-knockdown experiment, the proliferation of the MC3T3-E1 cells under hypoxia were decreased by DAPT treatment, and knockdown of the expression of hypoxia inducible factor-1alpha (HIF-1alpha) suppressed the cobalt-induced increase in Wnt target gene levels. No significant difference in cell proliferation rate was found following DAPT treatment when the expression of HIF-1alpha was knocked down. The results of the present study showed the opposing effects of Wnt and Notch signaling under cobalt-mimicked hypoxia, which were partially regulated by HIF-1alpha, The results also showed that osteoblast proliferation was dependent on Wnt-Notch signal crosstalk. PMID- 27220408 TI - Actinoquinolines A and B, anti-inflammatory quinoline alkaloids from a marine derived Streptomyces sp., strain CNP975. AB - Actinomycete bacteria of the common genus Streptomyces can be routinely isolated from shallow and deep ocean sediments. Although commonly considered a terrestrial genus, and most abundantly found in soil, Streptomyces strains are found that have distinct requirements for seawater and routinely do not show significant similarity, with terrestrial strains by 16S ribosomal DNA phylogenetic sequence comparisons. Our examination of the culture broth of a Streptomyces sp., strain CNP975, isolated from a local La Jolla, California sediment sample, resulted in the isolation of actinoquinolines A and B (1, 2), which show significant inhibition of the arachidonic acid pathway enzymes cyclooxygenases-1 and -2. The new compounds contain the 3-hydroxyquinaldic acid (3HQA) motif found in numerous peptide antibiotics. In the actinoquinolines, 3HQA forms an amide linkage with a linear six-carbon fragment, formally a 2, 6-diamino-1, 5-dihydroxyhexane unit, a component of likely amino acid reductive off-loading origin. Actinoquinoline A illustrated amide rotational isomerism leading to complex NMR spectral data. Actinoquinoline B was assigned as the C-13 aldehyde analog isolated as an intramolecular hemiacetal. Reduction of 2 with NaBH4 yielded actinoquinoline A thus confirming the relative configurations of all centers in the actinoquinolines. PMID- 27220407 TI - RNAi down-regulation of cinnamate-4-hydroxylase increases artemisinin biosynthesis in Artemisia annua. AB - Cinnamate-4-hydroxylase (C4H) converts trans-cinnamic acid (CA) to p-coumaric acid (COA) in the phenylpropanoid/lignin biosynthesis pathway. Earlier we reported increased expression of AaCYP71AV1 (an important gene of artemisinin biosynthesis pathway) caused by CA treatment in Artemisia annua. Hence, AaC4H gene was identified, cloned, characterized and silenced in A. annua with the assumption that the elevated internal CA due to knock down may increase the artemisinin yield. Accumulation of trans-cinnamic acid in the plant due to AaC4H knockdown was accompanied with the reduction of p-coumaric acid, total phenolics, anthocyanin, cinnamate-4-hydroxylase (C4H) and phenylalanine ammonia lyase (PAL) activities but increase in salicylic acid (SA) and artemisinin. Interestingly, feeding trans-cinnamic acid to the RNAi line increased the level of artemisinin along with benzoic (BA) and SA with no effect on the downstream metabolites p coumaric acid, coniferylaldehyde and sinapaldehyde, whereas p-coumaric acid feeding increased the content of downstream coniferylaldehyde and sinapaldehyde with no effect on BA, SA, trans-cinnamic acid or artemisinin. SA is reported earlier to be inducing the artemisinin yield. This report demonstrates the link between the phenylpropanoid/lignin pathway with artemisinin pathway through SA, triggered by accumulation of trans-cinnamic acid because of the blockage at C4H. PMID- 27220409 TI - Allocyclinones, hyperchlorinated angucyclinones from Actinoallomurus. AB - A screening program on a limited number of strains belonging to the Actinoallomurus genus yielded a series of new angucyclinones. NMR and MS analyses established that these compounds are characterized by an unusual lactone ring and present up to four halogens per molecule, with one congener representing the first natural product containing a trichloromethyl substitution on an aromatic system. Remarkably, this family of metabolites seems to be produced by phylogenetically distinct Actinoallomurus isolates. Because of the unique structural features and wide distribution among Actinoallomurus, we have designated these angucyclinones as allocyclinones. Allocyclinones possess interesting activity against different Gram-positive bacteria, including antibiotic-resistant strains, with antibacterial potency increasing with the number of chlorine substituents. The tetrachlorinated compound is the most abundant congener in the allocyclinone complex. PMID- 27220410 TI - Isolation and structural determination of a new antibacterial compound demethyl-L 681,217 from Streptomyces cattleya. PMID- 27220411 TI - Local atomic arrangements and lattice distortions in layered Ge-Sb-Te crystal structures. AB - Insights into the local atomic arrangements of layered Ge-Sb-Te compounds are of particular importance from a fundamental point of view and for data storage applications. In this view, a detailed knowledge of the atomic structure in such alloys is central to understanding the functional properties both in the more commonly utilized amorphous-crystalline transition and in recently proposed interfacial phase change memory based on the transition between two crystalline structures. Aberration-corrected scanning transmission electron microscopy allows direct imaging of local arrangement in the crystalline lattice with atomic resolution. However, due to the non-trivial influence of thermal diffuse scattering on the high-angle scattering signal, a detailed examination of the image contrast requires comparison with theoretical image simulations. This work reveals the local atomic structure of trigonal Ge-Sb-Te thin films by using a combination of direct imaging of the atomic columns and theoretical image simulation approaches. The results show that the thin films are prone to the formation of stacking disorder with individual building blocks of the Ge2Sb2Te5, Ge1Sb2Te4 and Ge3Sb2Te6 crystal structures intercalated within randomly oriented grains. The comparison with image simulations based on various theoretical models reveals intermixed cation layers with pronounced local lattice distortions, exceeding those reported in literature. PMID- 27220412 TI - Emergence of diversity and stereochemical outcomes in the biosynthetic pathways of cyclobutane-centered marine alkaloid dimers. AB - Covering: up to 2016Dictazoles and sceptrins are singular metabolites of marine origin. The present dichotomic case study provides a comprehensive perspective on these cyclobutane-centered alkaloids and their respective families. Indeed, their upstream and downstream chemistry are both treated herein. Relevant isolation reports and bio-inspired total syntheses are used to decipher the currently admitted biosynthetic hypotheses as well as the emergence of diversity in the two series. This review proposes a transversal vision of the topic, where most aspects of natural product chemistry have a critical importance. PMID- 27220413 TI - In-plane interfacing effects of two-dimensional transition-metal dichalcogenide heterostructures. AB - In-plane heterostructures of two-dimensional transition-metal dichalcogenides (TMDs) demonstrate the formation of one-dimensional interfaces (or interlines), leading to new exciting properties and device functionalities. In this work, the interfacing effects have been studied in MoS2/WS2 quantum-well and superlattice in-plane heterostructures on the basis of first-principles electronic calculations. In light of the orbital-projected band structures, MoS2/WS2 in plane heterostructures illustrate type-II band alignments with rather a small band offset for the valence band maximum and a relatively large band offset for the conduction band minimum. Upon increasing the width of TMD constituents, the band gap varies within a small range. In MoS2 and WS2, the surline energy and work function of zigzag edges with S-terminations are obviously higher than those of metal-terminations, and charge transfer from MoS2 to WS2 could be addressed due to the difference in the Fermi level. In-gap levels induced by S vacancies in MoS2/WS2 in-plane heterostructures are discrete and, interestingly, change to consecutive bands due to the built-in electric field. PMID- 27220414 TI - The role of starch and saliva in tribology studies and the sensory perception of protein-added yogurts. AB - Increasing the protein content of yogurts would be a good strategy for enhancing their satiating ability. However, the addition of protein can affect product palatability, contributing astringency or an inhomogeneous texture. Increasingly, studies mimicking oral tribology and oral lubrication have been attracting interest among food researchers because of their link with oral texture sensations. In the present study, four double-protein stirred yogurts were prepared by adding extra skimmed milk powder (MP) or whey protein concentrate (WPC) and by adding a physically modified starch to each (samples MPS and WPCS, respectively) to increase the consistency of the yogurts. The lubricating properties of the four yogurts were examined by tribological methods with the aim of relating these properties to the sensory perception described by flash profiling. Samples were also analysed after mixing with saliva. The tribology results clearly showed that addition of starch reduced the friction coefficient values regardless of the type of protein. Saliva addition produced a further decrease in the friction coefficient values in all the samples. Consequently, adding saliva is recommended when performing tribology measurements of foods in order to give a more realistic picture. The sensory results confirmed that the addition of starch reduced the astringent sensation, especially in sample WPC, while the MP and MPS samples were creamier and smoother. On the other hand, the astringency of sample WPC was not explained by the tribology results. Since this sample was described as "grainy", "gritty", "rough", "acid" and "sour", further studies are necessary to investigate the role of the number, size, shape and distribution of particles in yogurt samples, their role in astringency perception and their interaction with the perception of the tastes mentioned. Oral tribology has shown itself to be an in vitro technique that may aid a better understanding of the dynamics of in-mouth lubrication and the physical mechanisms underlying texture and mouthfeel perception. PMID- 27220415 TI - Thermal conductivity of polymer composites with the geometrical characteristics of graphene nanoplatelets. AB - One of the most important physical factors related to the thermal conductivity of composites filled with graphene nanoplatelets (GNPs) is the dimensions of the GNPs, that is, their lateral size and thickness. In this study, we reveal the relationship between the thermal conductivity of polymer composites and the realistic size of GNP fillers within the polymer composites (measured using three dimensional (3D) non-destructive micro X-ray CT analysis) while minimizing the effects of the physical parameters other than size. A larger lateral size and thickness of the GNPs increased the likelihood of the matrix-bonded interface being reduced, resulting in an effective improvement in the thermal conductivity and in the heat dissipation ability of the composites. The thermal conductivity was improved by up to 121% according to the filler size; the highest bulk and in plane thermal conductivity values of the composites filled with 20 wt% GNPs were 1.8 and 7.3 W/m.K, respectively. The bulk and in-plane thermal conductivity values increased by 650 and 2,942%, respectively, when compared to the thermal conductivity values of the polymer matrix employed (0.24 W/m.K). PMID- 27220416 TI - Access to mass media messages, and use of family planning in Nigeria: a spatio demographic analysis from the 2013 DHS. AB - BACKGROUND: Nigeria has the highest population in sub-Saharan Africa with high birth and growth rates. There is therefore need for family planning to regulate and stabilize this population. This study examined the relationship between access to mass media messages on family planning and use of family planning in Nigeria. It also investigated the impacts of spatio-demographic variables on the relationship between access to mass media messages and use of family planning. METHODS: Data from the 2013 demographic and health survey of Nigeria which was conducted in all the 36 states of Nigeria, and Abuja were used for the study. The sample was weighted to ensure representativeness. Univariate, bivariate and binary logistic regressions were conducted. The relationship between each of the access to mass media messages, and the family planning variables were determined with Pearson correlation analysis. RESULTS: The correlation results showed significant but weak direct relationships between the access to mass media messages and use of family planning at p < 0.0001 with access to television messages (r = 0.239) being associated with highest use of family planning. Some of the results of the adjusted regression analysis showed that access to television messages (OR = 1.2.225; p < 0.0001), and radio messages (OR = 1.945; p < 0.0001) increase the likelihood of the use of family planning. The adjusted regression model also indicated increased likelihood in the use of family planning by respondents with secondary education (OR = 2.709; p < 0.0001), the married (OR = 1.274; p < 0.001), and respondents within the highest wealth quintiles (OR = 3.442; p < 0.0001). CONCLUSIONS: There exist significant variations within spatio-demographic groups with regards to having access to mass media messages on family planning, and on the use of family planning. The results showed that access to mass media messages increases the likelihood of the use of family planning. Also people with higher socioeconomic status and those from the Southern part of the country make more use of family planning. There is need to improve the socioeconomic status of the populations. Also, the quality and regularity of mass media messages should be improved, while other communication avenues such as traditional institutions, blogs, and seminars for youths should be used to make family planning messages more acceptable. PMID- 27220417 TI - The Use of Mobile Phone and Medical Apps among General Practitioners in Hangzhou City, Eastern China. AB - BACKGROUND: Mobile phones and mobile phone apps have expanded new forms of health professionals' work. There are many studies on the use of mobile phone apps for different specialists. However, there are no studies on the current use of mobile phone apps among general practitioners (GPs). OBJECTIVE: The objective of the study was to investigate the extent to which GPs own smartphones with apps and use them to aid their clinical activities. METHODS: A questionnaire survey of GPs was undertaken in Hangzhou, Eastern China. Data probing GPs' current use of medical apps in their clinical activities and factors influencing app use were collected and analyzed RESULTS: 125 GPs participated in the survey. 90.4% of GPs owned a mobile phone, with 48.7% owning an iPhone and 47.8% owning an Android phone. Most mobile phone owners had 1-3 medical-related apps, with very few owning more than 4. There was no difference in number of apps between iPhone and Android owners (chi(2)=1.388, P=0.846). 36% of GPs reported using medical-related apps on a daily basis. The majority of doctors reported using apps to aid clinical activities less than 30 minutes per day. CONCLUSIONS: A high level of mobile phone ownership and usage among GPs was found in this study, but few people chose medical-related apps to support their clinical practice. PMID- 27220418 TI - miR-153 regulates apoptosis and autophagy of cardiomyocytes by targeting Mcl-1. AB - MicroRNAs (miRs) are a class of important regulators, which are involved in the regulation of apoptosis. Oxidative stress-induced apoptosis is the predominant factor accounting for cardiac ischemia-reperfusion injury. miR-153 has been previously shown to have an antitumor effect in cancer. However, whether miR-153 is involved in oxidative stress-induced apoptosis in the heart remains to be elucidated. To this end, the present study used reverse transcription quantitative polymerase chain reaction to detect miR-153 levels upon oxidative stress, and evaluated apoptosis, autophagy and expression of critical genes by western blotting. A luciferase assay was also used to confirm the potential target gene. In the present study, it was found that the expression of miR-153 was significantly increased upon H2O2 stimulation, and the inhibition of endogenous miR-153 decreased apoptosis. To further identify the mechanism underlying the pro-apoptotic effect of miR-153, the present study analyzed the 3'untranslated region of myeloid cell leukemia-1 (Mcl-1), and found that Mcl-1 was potentially targeted by miR-153. The forced expression of miR-153 inhibited the expression of Mcl-1 and luciferase activity, which was reversed by its antisense inhibitor. Furthermore, it was shown that the inhibition of miR-153 induced autophagy during oxidative stress, and that its effects of autophagy induction and apoptosis inhibition were efficiently abrogated by Mcl-1 small interfering RNA. In conclusion, the results of the present study elucidated a novel mechanism by which miR-153 regulates the survival of cardimyocytes during oxidative stress through the modulation of apoptosis and autophagy. These effects may be mediated directly by targeting Mcl-1. These finding revealed the potential clinical value of miR-153 in the treatment of cardiovascular disease. PMID- 27220419 TI - Arsenic and lead contamination in soil and in feathers of three resident passerine species in a semi-arid mining region of the Mexican plateau. AB - The current study aimed at quantifying arsenic and lead in feathers from three passerine species that are residents from areas exposed to mining activities (Toxostoma curvirostre, Campylorhynchus brunneicapillus, and Melozone fusca). Lead and As contents in bird feathers and in superficial soil samples were measured with AAS. Levels of these metals were compared between sites exposed and unexposed to mining. Possible correlations of As and Pb between superficial soil and bird feathers were also investigated. Soil metal concentrations were significantly higher near mining sites, and metal concentrations in bird feathers showed a behavior similar to those recorded for soil samples. Individual birds from polluted sites had higher mean feather metal concentrations in comparison with non-polluted sites; no differences in metal concentrations were recorded among bird species. This work constitutes a basis for monitoring contaminants, and for future toxicological studies attempting to understand the impact that some mining activities may have on bird populations. PMID- 27220420 TI - Inhibition of myeloperoxidase oxidant production by N-acetyl lysyltyrosylcysteine amide reduces brain damage in a murine model of stroke. AB - BACKGROUND: Oxidative stress plays an important and causal role in the mechanisms by which ischemia/reperfusion (I/R) injury increases brain damage after stroke. Accordingly, reducing oxidative stress has been proposed as a therapeutic strategy for limiting damage in the brain after stroke. Myeloperoxidase (MPO) is a highly potent oxidative enzyme that is capable of inducing both oxidative and nitrosative stress in vivo. METHODS: To determine if and the extent to which MPO generated oxidants contribute to brain I/R injury, we treated mice subjected to middle cerebral artery occlusion (MCAO) with N-acetyl lysyltyrosylcysteine amide (KYC), a novel, specific and non-toxic inhibitor of MPO. Behavioral testing, ischemic damage, blood-brain-barrier disruption, apoptosis, neutrophils infiltration, microglia/macrophage activation, and MPO oxidation were analyzed within a 7-day period after MCAO. RESULTS: Our studies show that KYC treatment significantly reduces neurological severity scores, infarct size, IgG extravasation, neutrophil infiltration, loss of neurons, apoptosis, and microglia/macrophage activation in the brains of MCAO mice. Immunofluorescence studies show that KYC treatment reduces the formation of chlorotyrosine (ClTyr), a fingerprint biomarker of MPO oxidation, nitrotyrosine (NO2Tyr), and 4 hydroxynonenal (4HNE) in MCAO mice. All oxidative products colocalized with MPO in the infarcted brains, suggesting that MPO-generated oxidants are involved in forming the oxidative products. CONCLUSIONS: MPO-generated oxidants play detrimental roles in causing brain damage after stroke which is effectively reduced by KYC. PMID- 27220422 TI - Biobased Nano Porous Active Carbon Fibers for High-Performance Supercapacitors. AB - Activated carbon fibers (ACFs) with different pore structure have been prepared from wood sawdust using the KOH activation method. A study was conducted to examine the influence of the activation parameters (temperature, alkali/carbon ratio, and time) on the morphology and structure of the as-prepared ACFs developed in the process of pore generation and evolution. Activation temperature was very essential for the formation of utramicropores (<0.6 nm), which greatly contributed to the electric double layer capacitance. The significance of metallic potassium vapor evolved when the temperature was above 800 degrees C, since the generation of 0.8- and 1.1 nm micropores cannot be ignored. When the the KOH/fiber ratio was increased and the activation time was prolonged, to some extent, the micropores were enlarged to small mesopores within 2-5 nm. The sample with the optimal condition exhibited the highest specific capacitance (225 F g( 1) at a current density of 0.5 A g(-1)). Its ability to retain capacitance corresponding to 10 A g(-1) and 6 M KOH was 85.3%, demonstrating a good rate capability. With 10 000 charge-discharge cycles at 3 A g(-1), the supercapacitor kept 94.2% capacity, showing outstanding electrochemical performance as promising electrode material. PMID- 27220421 TI - Cancer stem cell metabolism. AB - Cancer is now viewed as a stem cell disease. There is still no consensus on the metabolic characteristics of cancer stem cells, with several studies indicating that they are mainly glycolytic and others pointing instead to mitochondrial metabolism as their principal source of energy. Cancer stem cells also seem to adapt their metabolism to microenvironmental changes by conveniently shifting energy production from one pathway to another, or by acquiring intermediate metabolic phenotypes. Determining the role of cancer stem cell metabolism in carcinogenesis has become a major focus in cancer research, and substantial efforts are conducted towards discovering clinical targets. PMID- 27220431 TI - Two Novel Heparin-binding Vascular Endothelial Growth Factor Splices, L-VEGF144 and L-VEGF138, are Expressed in Human Glioblastoma Cells. AB - The expression levels of different vascular endothelial growth factor A (VEGF) isoforms are associated with the angiogenesis and the patient's prognoses in human cancers. Ribosomes specifically scan from 5' to 3' CUG initiation codon in the long 5'-untranslated region (5'-UTR) of the VEGF mRNA, resulting in the generation of high mol wt VEGF isoform [call large VEGF (L-VEGF)]. Alternative splicing of VEGF mRNA transcripts results in several isoforms with distinct properties that are dependent up their exon compositions. In this study, we observed two novel kinds of splicing VEGF isoforms that transcripted at the first upstream CUG codon, and which we have named large-VEGF144 (LVEGF144), and large VEGF138 (L-VEGF138). The expression levels of messenger RNA for the different VEGF splice forms were analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR). After DNA sequencing, the genetic structure of L-VEGF144 involved not only a partial exon 1, exon 6a, and exons 7-8, but also an unique 108- nucleotides insertion of VEGF intron 5 interposed between exon 1 and exon 6. At the same time, L-VEGF144 lacked most of the Nterminal fragments (exons 1-5). We further found that a specific detection model could easily and rapidly confirm the presence of L-VEGF144 mRNA fragments in the biopsies or cell lines via RT-PCR assay. In addition, we used visible fluorescent fusion proteins to prove that both L-VEGF144 and L-VEGF138 have nuclear localization ability. Taken together, the findings of this study indicate that, unlike previously identified isoforms, these novel VEGF isoforms are likely to suggest a further level of complexity in the angiogenic process. PMID- 27220432 TI - [Effect of SET deficiency on the trichloroethylene-induced alteration of cell proliferation and cell apoptosis and DNA methylation in human hepatic L-02 cells]. AB - OBJECTIVE: To compare the trichloroethylene (TCE) -induced alteration in cell proliferation, cell apoptosis, histone deacetylase activity and expression levels in human hepatic L-02 cells (L-02 cells) and SET deficient cells, and reveal the TCE-induced effect in histone modification and the role of SET on epigenetic pathway. METHODS: The L-02 cells and preestablished SET deficient cells were treated with different TCE concentrations. For the changes of cell proliferation level and apoptosis rate, The L-02 cells and SET deficiency cells without TCE treatment were served as the control group, the TCE treatment was in the concentration of 2.0 and 8.0 mmol/L for 24 h. For histone deacetylase activity and expression levels, the TCE treatment was in the concentration of 0.25, 0.50, 1.0, 2.0, 4.0, and 8.0 mmol/L for 24 h. RESULTS: After treatment with TCE for 24 h, the cell proliferation level was significantly decreased and the apoptotic rate was significantly increased in both cell lines. When concentration of TCE were reached to 8.0 mmol/L, the difference of cell proliferation level and apoptotic rate between two groups was statistically significant (t=-4.362 for proliferation level and t=23.950 for apoptotic rate, both P<0.05). After treatment with TCE for 24 h in various concentration (0, 0.25, 0.50, 1.00, 2.00, 4.00 and 8.00 mmol/L) , the activity of histone deacetylases was significantly increased in both cell lines. When the TCE concentration were high than 0.50 mmol/L, compared with control group of L-02 cells, the enzymes activity were significantly increased (F=403.26, P<0.001). When TCE concentration was reached 1.00 mmol/L, the enzyme activity is highest. Compared with control group of SET deficiency cells, the enzyme activity was significantly increased when TCE concentration was reached 1.00 mmol/L (F=44.01, P<0.001). When concentration of TCE reached 0.50 mmol/L, the difference of enzyme activity between two groups was statistically significant. For the protein expression, compared with control group of L-02 cells, TCE exposure can induced a significant increased expression level of HDAC2 in TCE-treated L-02 cells (F values were 79.99, P<0.001). But the alteration in SET deficiency cells was not significant. CONCLUSION: TCE exposure can induce a significant alteration on cell proliferation, apoptotic rate and, the activity and expression on histone deacetylases. SET deficiency can attenuate the TCE-induced alteration in histone modification in L-02 cells. Our results indicated that SET is involved in the mechanism of TCE-induced cytotoxicity and epigenetic regulation in L-02 cells. PMID- 27220430 TI - Vitamin D interferes with glucocorticoid responsiveness in human peripheral blood mononuclear target cells. AB - Glucocorticoids (GCs) are widely used in the treatment of inflammatory and autoimmune diseases; however, patients are often resistant to GC effects. Current studies indicate that vitamin D reduces the risk or modifies the course of autoimmune diseases posing vitamin D supplementation as a prevention or therapeutic option. Herein, we investigated whether vitamin D can modify the response to GCs at the molecular level. To this end, peripheral blood mononuclear cells (PBMCs) were isolated from healthy vitamin D-deficient women and incubated with either the active metabolite 1,25(OH)2D3 (VitD) for 11 days or dexamethasone (Dex) for the last 2 days in the presence or absence of VitD. Ex vivo GC sensitivity was assessed by the expression of the glucocorticoid receptor (GR) responsive gene GILZ with RT-PCR. Long-term incubation of PBMCs with VitD significantly decreased the Dex-induced augmentation of GILZ expression. Since the intracellular concentration of GR and the GR nuclear translocation are critical determinants of GC sensitivity, we next evaluated the effect of VitD on these factors. RT-PCR and western-blot analysis revealed that VitD reduced the expression of GR. This effect was abolished by the HDAC-specific inhibitor trichostatin A, implying that HDAC was implicated in this effect. Moreover, NCoR1 mRNA was significantly decreased upon treatment with VitD either alone or as pre treatment to Dex, suggesting that a possible increase in expression of this co repressor was not involved. In addition, immunofluorescence analysis showed that VitD hindered the Dex-induced GRalpha nuclear translocation, an effect verified by subcellular fractionation and western-blot experiments. To further explore the underpinning mechanism, we examined the potential of VitD to: (1) strengthen the FK506-binding protein 5 (FKBP5) negative feedback loop and (2) modify the phosphorylation status of GR. Remarkably, VitD decreased FKBP5 expression and decreased phosphorylation at Ser211, while enhancing phosphorylation of GR at Ser203. Overall, VitD decreases the ex vivo GC sensitivity and this effect is, at least in part, attributed both to decrease of GR expression owing to a mechanism that engages HDAC and inhibition of GR translocation to nucleus via differential modulation of the phosphorylation state of GR. Our study provides, for the first time, evidence that long-term action of VitD induces GC resistance in PBMCs from healthy volunteers and offers a possible mechanistic basis for VitD-triggered attenuation of GC effects. PMID- 27220433 TI - [Mechanism research and effect of ulinastatin in the brain tissue injury of acute hydrogen sulfide intoxicated rats]. AB - OBJECTIVE: To observe the effect of Ulinastatin (UTI) in the dynamic changes of aquaporin 4 (AQP4) and cyclooxygenase-2 (COX-2) in the brain tissue injury of acute hydrogen sulfide (H2S) intoxicated, to explore the Mechanism of brain tissue injury of acute H2S-intoxicated and the protection effect of UTI. METHODS: A total of 96 SD rats of clean grade were divided randomly into four groups: normal control group (NS group, n=8) , UTI control group (UTI group, n=8) , H2S intoxicated model group (H2S group, n=40) , UTI treatment group (H2S+UTI group, n=40). The H2S group and H2S+UTI group were exposed to H2S (284 mg/m(3)) by inhalation for 1 h, then H2S+UTI group was intraperitoneally exposed to UTI at the dose of 10(5) U/kg for 2 h, H2S group and H2S+UTI group were sacrificed at 2, 6, 12, 24 and 48 h after exposure, respectively. Remove the brain tissue, observe the rats behavioral changes at each time points. The mRNA expression of AQP4,COX 2 and NSE in the brain tissue were measured by RT-PCR method, and the protein expression of AQP4,COX-2 and NSE in the brain tissue were detected by immunohistochemical Streptavidin-perosidase method. Pathological changes of brain tissue were observed by lightmicroscope. RESULTS: 1,Nerve cells in the H2S group rats had edema, degeneration, focal inflammatory cell infiltrate, capillary hyperplasia, expansion. Compared with NS group, the cerebral NSE mRNA and protein expression at each time point in H2S group after exposure were significantly increased (P<0.01). 2,Compared with NS group, the cerebral AQP4 and COX-2 mRNA and protein expression at each time point in H2S group after exposure were significantly increased (P<0.01). 3,The degree of brain damage was significantly decreased in H2S+UTI group than that in H2S group. Compared with H2S group, the cerebral NSE mRNA and protein expression at 6, 12, 24 and 48 h in H2S+UTI group after exposure were significantly decreased (P<0.01) , no significantly difference at 2h (P>0.05). 4,Compared with the H2S group, the cerebral AQP4 and COX-2 mRNA and protein expression at 6, 12, 24 and 48 h in H2S+UTI group after exposure were significantly decreased (P<0.01) , slightly decreased at 2 h. CONCLUSION: The mechanism of brain injury of acute hydrogen sulfide intoxicated associated with abnormal expression of the cerebral AQP4, COX-2 levels. Intervention of UTI can reduce the cerebral AQP4 and COX-2 levels after hydrogen sulfide intoxicated, reduce the degree of brain injury. PMID- 27220434 TI - [Nickel smelting dust exposures to NIH/3T3 cellular mitochondrial damage and L ascorbic acid interference effect]. AB - OBJECTIVE: To study the protection of L-ascorbic acid on mouse embryonic fibroblasts (NIH/3T3) from carcinogenic effects caused by nickel smelting smoke subjects. METHODS: The NIH/3T3 cells were divided into experimental and L ascorbic acid in the intervention group. Plus exposure group concentration of nickel refining dusts were formulate 0.00, 25.00, 50.00, 100.00 MUg/ml suspension, the intervention group on the basis of the added exposure group containing L-ascorbic acid (100 mmol/L) , contacted. Then, the cell viability was detected by MTT assay, we used Calcein-AM fluorescence probe to detect cell mitochondrial permeability transition pore (MPTP) changes, JC-1 staining to observe and detect the cell mitochondrial membrane potential (MMP) change, colorimetric quantitative to study the activity of mitochondrial respiratory chain complex I,II,III,IV. RESULTS: Upon 24 h incubation, both cell relative inhibition rate, openness of MPTP were increasing enhanced by different concentrations, on the other hand, MMP and the activity of mitochondrial respiratory chain complexI, II, IV were obviously decreased, the differences were statistically significant (P<0.05) .After L-ascorbic acid intervention treatment, the results of the intervention group were lower than that of the exposure group, and the difference was statistically significant (P<0.05) , indicating the protection of L-ascorbic acid on cell mitochondrial from the nickel exposure damage. CONCLUSION: The damage effects of nickel on NIH/3T3 cell mitochondrial was significantly enhanced with the increasing concentration, and L-ascorbic acid has certain protection on cellular mitochondrial. PMID- 27220435 TI - [Observed levels of C-reactionprotein of pneumoconiosis after rehabilitation treatment]. PMID- 27220436 TI - [The effect of paraquat on autophagy in human embryonic neural progenitor cells]. AB - OBJECTIVE: To explore the effect of paraquat (PQ) on autophagy in human embryonic neural progenitor cells. METHODS: Using ReNcell CX cell model. After treatment with various concentration (0.00, 1.00, 10.00 and 100.00 MUmol/L) of PQ, CCK8 assay was used to detect the cell viability, the transmission electron microscope was used to observe the the cell ultrastructure, the real-time polymerase chain reaction (RT-PCR) was adopted to detect mRNA expression of autophagy related genes which including LC3, Atg12, Atg5, beclin1, Atg7 and mTOR and apoptosis related genes Bax and Bcl-2. RESULTS: The cell viability was significantly inhibited after administered with 100.00 MUmol/L of PQ (P<0.01). The mRNA expression of Beclin1 was significantly up-regulated and the emergency of autophagosome were observed at the concentration of 1.00 MUmol/L group, while mild cell apoptosis, significantly up-regulated Atg5, Atg8, Atg7 and Atg12 mRNA expression as well as down-regulated expression of mTOR and Bax were detected at the 10.00 MUmol/L of PQ group, howere, the obvious apoptosis and the up-regulated mRNA expression of mTOR and Bax were observed at the 100.00 MUmol/L of PQ group, the mRNA expression of Bcl-2 were all down-regulated after administered with 1.00, 10.00 and 100.00 MUmol/L of PQ and reached the lowest level at the concentration of 10.00 MUmol/L. CONCLUSION: PQ can induced autophagy at the low concentration in ReNcell CX cell and autophagy might serve as a protective mechanism to ameliorate PQ-induced cytotoxic effects but apoptosis will be induced at the 100 MUmol/L concentration. PMID- 27220437 TI - [Role of kallikrein kinin system activation in kidney injury induced by trichloroethylene sensitized mice]. AB - OBJECTIVE: Through testing the expression of complement C3 fragment C3b and iC3b, C5b-9 as well as indexes of KKS before and after using kallikrein-kinin system inhibitor PKSI-527, observing the relevant between KKS and complement system, we preliminary study on the mechanism how KKS works on the renal injury of sensitized mice model induced by trichloroethylene. METHODS: Female BALB/c mice (6~8 weeks) were randomly divided into blank control group (5), TCE treated group (15), PKSI-527+TCE treated group (15). Mice were sensitized with TCE in the 1,3,7,10 days, the first and the last challenge were on day 17 and 19. 24h before every challenge, mice in PKSI-527+TCE group were treated with intraperitoneal injection of KKS inhibitor PKSI-527 inhibitor (50mg/kg). Mice were killed 72h after the last challenge. The function of kidney in mice were detected and kidney B1R, B2R expression were detected using real-time quantitative PCR, mice kidney complement C3 fragments C3b, iC3b and C5b-9 deposition were also detected by chemoimmunology. RESULTS: Compared with blank control group, all indexes expressions in the solvent control group have no significant change. Compared with the solvent control group, BUN,Cr level and B1R,B2R level have an significant increase (P< 0.05) in TCE sensitized group and PKSI-527+TCE sensitized group; There is a sharp decrease in PKSI-527+TCE sensitized group compared to TCE sensitized group(P< 0.05). CONCLUSION: The renal damage in the TCE sensitization mouse model may aggravated by upregulate complement system followed by the activation of kallikrein-kinin system. PMID- 27220438 TI - [Effect of hydroquinone on the histone deacetylase in human bone marrow mononuclear cells]. AB - OBJECTIVE: To observe the activity of histone deacetylase and the mRNA expression level of HDAC1 and HDAC2 in human bone marrow mononuclear cells, which induced by hydroquinone and exposed to hydroquinone plus Trichostatin as a histone deacetylase inhibitor for 10 hours respectively. METHODS: Collect the bone marrow mononuclear cells suspension,divided into control group,HQ group (3 h, 6 h, 12 h, 24 h) , HQ+TSA 10 h group and HQ 10 h group. Extract the nuclear proteins and RNA, test the activity of histone deacetylase with the colorimetric HDAC assay kit and detect the mRNA expression level of HDAC1 and HDAC2 by real-time Polymerase Chain Reaction (PCR). RESULTS: The HDAC activity of HQ3 h group, HQ6 h group and HQ12 h group were 1.31 times, 1.53 times and 1.148 times than that of control group respectively. And the difference was statistically significant (P<0.05). Except the HQ24 h group (P>0.05) , the HDAC1 mRNA expression of HQ3 h group, HQ6 h group and HQ12 h group were 1.173 times, 1.901 times and 2.348 times than that of control group respectively. And the difference was statistically significant (P<0.05). The HDAC2 mRNA expression of HQ6 h group and HQ12 h group were 1.426 times and 1.766 times than that of the control group respectively. And the difference was statistically significant (P<0.05). No significant difference was observed between HQ3 h group, HQ24 h group and control group (P>0.05). The cells were treated by hydroquinone plus TSA for 10 hours. The HDAC activity of HQ+TSA 10h group was reduced by 25.6% than that of HQ 10 h group (P<0.05) and rised 13.0% compared to the control group (P<0.05). And the difference was statistically significant between groups (P<0.05) .The cells were treated by hydroquinone plus TSA for 10 hours. The HDAC1 mRNA expression of the HQ+TSA 10h group is reduced by 26.9% than that of HQ10h group. The HDAC2 mRNA expression is reduced by 19.3% compared to the HQ 10h group.And the difference was statistically significant between groups (P<0.05). The HDAC1 and HDAC2 mRNA expression is obviously higher than the control group, the difference was statistically significant (P<0.05). CONCLUSION: Treatment of hydroquinone, the histone deacetylase activity and the mRNA expression of HDAC1 and HDAC2 were increased in a certain time range. The histone deacetylase inhibitor (TSA) can reduce the histone deacetylase activity and the mRNA expression level of HDAC1 and HDAC2 in the bone marrow mononuclear cell induce by hydroquinone.It can be confirmed that hematopoietic damage induced by the benzene metabolites is related to the histone acetylation modification level. PMID- 27220439 TI - [The expressions of intercellular adhesion molecule-1 in renal tissue of rats with paraquat poisoning and the effect of melatonin]. AB - OBJECTIVE: To study the mechanism of paraquat (PQ) -induced renal injury in rats, the expression changes of ICAM-1 to assess the protective effect of Melatonin in PQ poisoning. METHODS: Ninety adult healthy Sprague-Dawley (SD) rats were divided into three groups at random. CONTROL GROUP: 30 rats; Poisoned group: 30 rats; Melatonin group: 30 rats. Control group and Poisoned group were treated intragastrically with 1 ml of PQ (50 mg/kg) diluted with normal saline. Control groupwere treated with the same dose of normal saline as Poisoned group and Melatonin group. Melatonin group were given 1 ml of Melatonin at a dose of 10 mg/kg diluted with normal saline (once daily, intraperitoneally) Control and Poisoned group were treated with the same dose of normal saline (once daily, intraperitoneally) as Melatonin group. Pathology of renal tissue were oberserved by HE staining, and electron microscope. The histopathological changes and the expression of ICAM-1 were observed with mmunohistochemistry (IHC). RESULTS: (1) There were no obvious pathological changes in Control group. Poisoned group Renal glomerulus had hyperemia and distension.Renal tubule epith elial cell had edema and vacuolar degeneration and renal tubule lumina was narrowing on day 1, There were serious edema exudation and necrosis on day 5,which gradually lessened furthermore; Compared with Poisoned group, the aforementioned pathological lesion was more palliative in Melatonin group. (2) No obvious abnomal changes in ultrastructure of renal tissues in Control group. There were swelling of mitochondrion and rupture of renal tubule epithelial cell and endoplasmic reticulum had extension, lysosome was mult and had much phagocytosis in Poisoned group. (3) There was a very weak expression of ICAM-1 in Control group. while in Poisoned group, there was already a significant higher expression of ICAM-1 of renal tubule on day 1 after PQ poisoning, Immunohistochemistry score (IHS) of Poisoned group on day 1, 3, 5, 7, 14 were (0.1561+/-0.0295,0.2572+/ 0.0259,0.3028+/-0.0153,0.2083+/-0.0227,0.9309+/-0.0059) , compared with Control group (P<0.01) ; Melatonin group were (0.1259+/-0.0061,0.2109+/-0.0280,0.2679+/ 0.0233,0.1771+/-0.0186,0.0791+/-0.0135) , compared with Control group (P<0.01) , compared with Poisoned group (P<0.05) ; CONCLUSION: ICAM-1 was involved in the procedures of renal injury; MT surely had a protective effect, which might be mediated by ICAM-1 in the paraquat-induced renal injury, but its regulation path still need a further exploration. PMID- 27220440 TI - [The role of smoking and metabolic enzyme polymorphisms in the organic solvent induced chronic encephalopathy]. AB - OBJECTIVE: The organic solvents and other exogenous compounds of metabolic enzymes genetic variation may affect the risk of the toxic effect of organic solvents exposure. Therefore, this research we observed the glutathione transferase M1 and T1 (GSTM1, GSTT1) deletion mutation genotype, two kinds of microsomal epoxide hydrolase (mEPHX) genetic polymorphism, organic solvents exposure and smoking effection in chronic cases of toxic encephalopathy (CTE) correlation. METHODS: The object was 115 patients who had a long history of organic solvents exposure, were divieded into two groups: CTE (n=83) , no CET (n=32) according to clinical diagnosis. DNA was isolated from patients in white blood cells through the multiple-polymerase chain reaction to determine the loss of GSTM1 and GSTT1 genotype. two kinds of mEPHX polymorphism were analysised through the PCR-RFLP (restriction fragment length polymorphism). RESULTS: The relative risk has obviously improved when lack of GSTM1 genotypes to CTE (RR=2.35, 95% CI 2.35 0.96). in according to the patient's Smoking condition and classify genotype, patients lack of GSTM1 genotypes had a significantly higher risk CTE than GSTM1+genotype patients (RR=3.13, 95% CI 3.13 1.2) , both mEPHX polymorphisms had nothing to do with an increased risk of CTE. CONCLUSION: The GSTM1 genotypes played an important role in the organic solvent induced the CTE of susceptibility.it was Influenced by the interaction between smoking at the same time. PMID- 27220441 TI - [The incidence of asbestos-related diseases about on asbestos enterprises in Qingdao from 1988 to 2014]. AB - OBJECTIVE: It can provide statistics reference for the prevention and treatment by analysising the status and characteristics related to the asbestos disease of an asbestos products enterprises from 1988 to 2014. METHODS: We have collected the data concerning the case of asbestos-related disease between 1988 and 2014, then the data were arranged, collecteted and analyzed using statistical method. RESULTS: The total of patients is 625 (male: 225, female: 400). Diagnosis of asbestosis is 617 cases, Accordingly, stage Iis 500, stage IIis 112 and stage III is 5. Average age of morbidity is 64.84+/-9.87 and working age is 24.45+/-7.40 years; The patients of lung cancer caused by asbestos are 12 people, and average age of morbidity is 66.25+/-11.20 years, and the working age is 29.18+/ 7.77years; The patients of mesothelioma are 4 people, average age of morbidity is 49-78 (M=60) and working age is 27years. Asbestosis patients with complications of pleural plaque is 37.44%, complications of pulmonary tuberculosis is 5.19%., and there are 239 patients lose their lives, motality is 38.74%. CONCLUSION: There is a high incidence of a disease about asbestos related disease in the asbestos products factory, it has close relationship with asbestos exposure time, the dust concentration of workplace and type of work et al. Asbestos related diseases are still the main problem in Qingdao. PMID- 27220443 TI - [Analysis on pathogenetic characteristics of newfound pneumoconiosis in Jinan, 2006 to 2014]. PMID- 27220444 TI - [The analysis of the silicosis misdiagnosis in the silica bricks industry]. PMID- 27220442 TI - [The relationship of vitamin D receptor gene and blood lead: a meta-analysis]. AB - OBJECTIVE: The correlation of vitamin D receptor (VDR) gene polymorphism and blood lead level had been in doult, which allowed us to write this article. METHODS: Relevant studies about the blood lead and VDR B/b gene polymorphism which published from 1979-2015, were searched in multiple bibliographic databases, such as: CNKI, Wanfang Database, PUBMED. Of the ten references selceted, three were divided into two groups which were classified as different researches, so there were thirteen studies in the meta-analysis. According to the level of blood lead, the studies were analyzed by three groups: normal group, low dose grou and high dose group. The analysis was performed by stata 12.0 software. RESULTS: The blood lead level of VDR B/b genotype was significantly difference in all the three groups (P<0.05) , but there were apparent heterogeneity between normal group and low dose group (P<0.05, I(2)=84.2%; P<0.05, I(2)=88.9%) , except the high dose group (P>0.05, I(2)=12.7%) ; after adjusted, all showed no heterogeneity, and the results were still the same. CONCLUSION: The genotype of VDR may be correlated with blood lead, and the levels of blood lead varied with different genetypes. PMID- 27220445 TI - [Occupational cancer diagnosis analysis in Jiangsu from 2006 to 2014]. PMID- 27220446 TI - [Image features and clinical significance of pneumoconiosis with large shadow]. AB - OBJECTIVE: To investigate the image features, categories, and clinical significances of Pneumoconiosis SH with large shadow. METHODS: The research is based on the analysis of image features of 168 pneumoconiosis SH patients who are directly diagnosed by qualified medical professionals in our institution. These image features are large shadows bigger than 2 cm*1 cm which can be observed by high kilovolt chest radiographs, DR chest radiography and chest CT scan. RESULTS: Large shadows bigger than 2*1 cm show noticeable imaging characteristics, like distribution of superior and middle lung regions (95.2%) , irregular shapes (97.6%) , splayed or sausage like changes on both sides perpendicular with ribs (89.2%) , small shadows of pneumoconiosis (98.8%) , and convergence of large shadow to hilum or mediastinal (53.6%). CT scan is significantly better than DR radiography on detection rate of focal emphysema, focal cavities and swollen lymph node of mediastinal. CONCLUSION: Combining the image features of high kilovolt chest radiographs, DR chest radiographs and CT scan are the main methods to identify the shadows, and thus direct diagnose pneumoconiosis SH; CT scan plays an important role in differential diagnosis. PMID- 27220447 TI - [The clinical observation of 62 cases with third-phase pneumoconiosis and suspected pulmonary tuberculosis]. PMID- 27220448 TI - [The investigation and analysis of an acute poisoning accident cased by solvent pollution]. PMID- 27220449 TI - [Study on diagnostic standard of occupational hard metal lung disease]. PMID- 27220450 TI - [Introduction and enlightment of Japanese pneumoconiosis diagnosis and health management]. PMID- 27220451 TI - [Research progress of hard metal lung disease]. PMID- 27220452 TI - [Research progress on bromoform toxicology]. PMID- 27220453 TI - [Recent advance in the pathogenesis of pulmonary fibrosis induced by paraquat poisoning]. PMID- 27220454 TI - [Recent advance in the pathogenesis of pulmonary fibrosis induced by paraquat poisoning]. PMID- 27220455 TI - Challenges in vaccine therapy in hematological malignancies and strategies to overcome them. AB - INTRODUCTION: Hematological malignancies (HM) are a promising platform for immunotherapy when considering the marked durable remissions historically achieved through allogeneic stem cell transplantation in select patients. Both non-cell and cell-based vaccine models have been utilized to elicit T cell tumor specific eradication of malignant cells with resultant striking immunologic effects, but only modest clinical outcomes. In the last decade, the field of oncology has garnered greater insight into the complex mechanisms underpinning immune dysregulation in HM. AREAS COVERED: This review addresses the development of vaccine strategies for HM examining the challenges of effectively inducing tumor-specific immunity and overcoming the barriers created by the tumor microenvironment. EXPERT OPINION: Through a better understanding of the tumor immunosuppressive milieu and immunobiology of HM, rational immunotherapeutic combination therapies can be designed incorporating the potency of vaccine therapy to stimulate native immune responses. In current practice, the use of combinatorial immunotherapies in the treatment of HM is becoming more recognized. This strategy, with vaccines as the backbone, will likely lead to paradigm changing therapeutic regimens in the decades to come, affording HM patients with durable remissions and improved quality of life. PMID- 27220457 TI - Zeranol stimulates proliferation and aromatase activation in human breast preadipocytes. AB - Aromatase is a crucial enzyme for the biosynthesis of estrogens and is involved in the process of breast carcinogenesis. Concerns have been raised regarding the effects of environmental estrogens as potential regulators of aromatase expression in human breast cells. Zeranol is a non-steroidal agent with potent estrogenic activity, which is widely used as a growth promoter for cattle in certain countries. The present study hypothesized that aromatase expression and activity may be elevated by low dose zeranol exposure, providing a source of estrogens that may stimulate cell proliferation. In the present study, primary cultured human breast preadipocytes were used as an in vitro model. The effects of zeranol on cell proliferation were measured using the MTS assay, aromatase expression levels were determined by immunocytochemical staining and reverse transcription-polymerase chain reaction, and aromatase enzyme activity and estrogen production were analyzed using corresponding assay kits. The results demonstrated that low dose zeranol (2-50 nM) was able to significantly promote cell proliferation, aromatase mRNA expression, aromatase activity and estrogen production in primary cultured human breast preadipocytes, thus suggesting that zeranol may act as an aromatase activator. The findings of the present study suggest that zeranol promotes breast cancer cell growth by stimulating aromatase activation and increasing estrogen biosynthesis in adipose tissue. PMID- 27220458 TI - Dynamics of Interocular Suppression in Amblyopic Children during Electronically Monitored Occlusion Therapy: First Insight. AB - PURPOSE: Interocular suppression is assumed to be the mechanism leading to impaired visual acuity, especially in strabismic amblyopia. Little is known about the dynamics of suppression during treatment. The aim of our study was to assess the development of the depth of suppression and its relation to changes in visual acuity during electronically monitored occlusion treatment. METHODS: In a prospective pilot study, 15 amblyopes (8 with and 7 without strabismus) aged 5 to 16 years (mean 10.24 years) were examined before initiation of patching and then every 3 to 6 weeks for 4 months. To quantify suppression, a red filter ladder (Sbisa bar) was used, attenuating the image of the dominant eye until the patients reported a binocular perception (diplopia, rivalry, color mixture) or a change in eye dominance. Acuity was assessed with crowded Landolt rings. Daily occlusion was recorded using occlusion dose monitors. RESULTS: The depth of interocular suppression showed a biphasic change: it increased significantly during the first month (P=0.02), while visual acuity improved (mean 0.14 log units +/-0.13; P<0.01). During the following 3 months, median suppression decreased back to the initial values. This reduction in suppression was more pronounced in anisometropic patients without strabismus than in amblyopes with strabismus. The average visual acuity steadily improved (P<0.01) during the 4 months of treatment. Mean recorded patching dose rate was 3.91 h/d. The correlation between mean daily occlusion and suppression changes was not statistically significant. CONCLUSIONS: This first insight into the functional changes during electronically monitored patching suggests a complex relationship between visual acuity and interocular suppression that seems to be influenced by the presence of strabismus. Knowledge of the dynamics of interocular suppression is crucial for enhancing the outcome of occlusion treatment and also for the evaluation of its future role compared to emerging dichoptic treatments. PMID- 27220459 TI - Reliability of Functional Connectivity of Electroencephalography Applying Microstate-Segmented Versus Classical Calculation of Phase Lag Index. AB - Connectivity analysis characterizes normal and altered brain function, for example, using the phase lag index (PLI), which is based on phase relations. However, reliability of PLI over time is limited, especially for single- or regional-link analysis. One possible cause is repeated changes of network configuration during registration. These network changes may be associated with changes of the surface potential fields, which can be characterized by microstate analysis. Microstate analysis describes repeating periods of quasistable surface potential fields lasting in the subsecond time range. This study aims to describe a novel combination of PLI with microstate analysis (microstate-segmented PLI = msPLI) and to determine its impact on the reliability of single links, regional links, and derived graph measures. msPLI was calculated in a cohort of 34 healthy controls three times over 2 years. A fully automated processing of electroencephalography was used. Resulting connectomes were compared using Pearson correlation, and test-retest reliability (TRT reliability) was assessed using the intraclass correlation coefficient. msPLI resulted in higher TRT reliability than classical PLI analysis for single or regional links, average clustering coefficient, average shortest path length, and degree diversity. Combination of microstates and phase-derived connectivity measures such as PLI improves reliability of single-link, regional-link, and graph analysis. PMID- 27220460 TI - Protective role of magnesium isoglycyrrhizinate in non-alcoholic fatty liver disease and the associated molecular mechanisms. AB - Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide and there is an urgent need to identify effective pharmacological strategies to treat NAFLD. For this purpose, in the present study, we examined the the possible molecular mechanisms responsible for the effects of MgIG and the protective effects of MgIG in a model of NAFLD. The human hepatic L02 cell line and oleic acid were employed to establish an in vitro model of NAFLD. The CCK-8 assay, Hoechst 33258 staining and Annexin V-PI staining were performed in order to evaluate cell viability and apoptosis. Oil red O staining was used to detect lipid accumulation within the L02 cells. We found that MgIG significantly inhibited lipid accumulation and protected the L02 cells against lipid accumulation-induced apoptosis. Key molecules involved in unfolded protein response (UPR) signaling were upregulated in lipid-overloaded hepatic cells whereas MgIG suppressed the activation of the UPR. Furthermore, MgIG significantly inhibited the expression of the downstream inflammatory cytokines which had been induced by lipid accumulation. Taken together, these findings suggest that the activation of UPR signaling induces the expression of inflammatory cytokines through the activation of nuclear factor-kappaB (NF kappaB) in lipid-overloaded hepatic cells. In addition, MgIG may suppress the activation of UPR signaling thereby protecting hepatic cells from NAFLD-induced injury. PMID- 27220461 TI - Distinct doping dependence of critical temperature and critical current density in Ba1-xKxFe2As2 superconductor. AB - Since the high transition temperature (High-Tc) superconductivity was discovered in the series of materials containing iron (Fe), their potential for the applications has been extensively scrutinized. In particular, a lot of effort has been made in achieving the high current-carrying ability by revealing the vortex pinning behavior. Here, we report on the critical current density (Jc) for the pristine Ba1-xKxFe2As2 single crystals with various K concentrations (0.25 <= x <= 0.52) determined by the magnetization hysteresis loop measurements. The x dependence of Jc is characterized by a spike-like peak at x ~ 0.30, which corresponds to the under-doped region. This behavior is distinct from a moderate Tc dome with a broad maximum spanning from x ~ 0.3 to 0.5. For the under-doped samples, with increasing magnetic field (H), a second magnetization peak in Jc is observed, whereas for the optimally- and over-doped samples, Jc monotonically decreases with H. This result emphasizes that fine tuning of doping composition is important to obtain strong flux pinning. The origin of the characteristic doping dependence of Jc is discussed in connection with the orthorhombic phase domain boundary, as well as the chemical inhomogeneity introduced by the dopant substitutions. PMID- 27220462 TI - Effects of TMEM9 gene on cell progression in hepatocellular carcinoma by RNA interference. AB - Hepatocellular carcinoma (HCC) is a malignant tumor that has become a global health issue. The aim of the present study was to examine the role of transmembrane protein 9 (TMEM9) in cell progression, such as cell growth, cell cycle, cell metastasis of hepatoma cells, and to discuss the TMEM9 gene-encoding protein as a potential therapy target of hepatoma. RT-qPCR was performed to examine TMEM9 expression in tumor tissues and adjacent tissues of patients with liver cancer. siRNAs were used to interfere TMEM9 in HepG2 and 7721 cells. A CCK 8 assay was performed to evaluate cell growth at 24, 48 and 72 h. Cell cycle and apoptosis were analyzed using flow cytometry. Transwell assays were used to determine cell invasion, migration and adhesion. The results showed that TMEM9 was expressed abnormally in liver cancers. TMEM9 expression increased significantly in the 34 examined patients. TMEM9 knockdown inhibited proliferation in the HepG2 and 7721 cells. The flow cytometric analysis revealed that TMEM9 knockdown by RNA interference resulted in G1 arrest and induced apoptosis. Cell invasion, migration and adhesion ability were also decreased. Western blotting indicated that expression of the cell cycle-related proteins CDK1, EIF3H, RPL10L, S100A10, CCNB1 and CCNB2 was significantly decreased. In conclusion, TMEM9 plays an important role in the cell growth of hepatoma cells. PMID- 27220463 TI - Telomeric repeat silencing in germ cells is essential for early development in Drosophila. PMID- 27220464 TI - The RNA-binding protein TTP is a global post-transcriptional regulator of feedback control in inflammation. AB - RNA-binding proteins (RBPs) facilitate post-transcriptional control of eukaryotic gene expression at multiple levels. The RBP tristetraprolin (TTP/Zfp36) is a signal-induced phosphorylated anti-inflammatory protein guiding unstable mRNAs of pro-inflammatory proteins for degradation and preventing translation. Using iCLIP, we have identified numerous mRNA targets bound by wild-type TTP and by a non-MK2-phosphorylatable TTP mutant (TTP-AA) in 1 h LPS-stimulated macrophages and correlated their interaction with TTP to changes at the level of mRNA abundance and translation in a transcriptome-wide manner. The close similarity of the transcriptomes of TTP-deficient and TTP-expressing macrophages upon short LPS stimulation suggested an effective inactivation of TTP by MK2, whereas retained RNA-binding capacity of TTP-AA to 3'UTRs caused profound changes in the transcriptome and translatome, altered NF-kappaB-activation and induced cell death. Increased TTP binding to the 3'UTR of feedback inhibitor mRNAs, such as Ier3, Dusp1 or Tnfaip3, in the absence of MK2-dependent TTP neutralization resulted in a strong reduction of their protein synthesis contributing to the deregulation of the NF-kappaB-signaling pathway. Taken together, our study uncovers a role of TTP as a suppressor of feedback inhibitors of inflammation and highlights the importance of fine-tuned TTP activity-regulation by MK2 in order to control the pro-inflammatory response. PMID- 27220465 TI - Sequence-dependent nanometer-scale conformational dynamics of individual RecBCD DNA complexes. AB - RecBCD is a multifunctional enzyme that possesses both helicase and nuclease activities. To gain insight into the mechanism of its helicase function, RecBCD unwinding at low adenosine triphosphate (ATP) (2-4 MUM) was measured using an optical-trapping assay featuring 1 base-pair (bp) precision. Instead of uniformly sized steps, we observed forward motion convolved with rapid, large-scale (~4 bp) variations in DNA length. We interpret this motion as conformational dynamics of the RecBCD-DNA complex in an unwinding-competent state, arising, in part, by an enzyme-induced, back-and-forth motion relative to the dsDNA that opens and closes the duplex. Five observations support this interpretation. First, these dynamics were present in the absence of ATP. Second, the onset of the dynamics was coupled to RecBCD entering into an unwinding-competent state that required a sufficiently long 5' strand to engage the RecD helicase. Third, the dynamics were modulated by the GC-content of the dsDNA. Fourth, the dynamics were suppressed by an engineered interstrand cross-link in the dsDNA that prevented unwinding. Finally, these dynamics were suppressed by binding of a specific non-hydrolyzable ATP analog. Collectively, these observations show that during unwinding, RecBCD binds to DNA in a dynamic mode that is modulated by the nucleotide state of the ATP binding pocket. PMID- 27220466 TI - Engineering and characterization of fluorogenic glycine riboswitches. AB - A set of 12 fluorogenic glycine riboswitches with different thermodynamic and kinetic response properties was engineered. For the design of functional riboswitches, a three-part RNA approach was applied based on the idea of linking a RNA sensor, transmitter and actuator part together. For the RNA sensor and actuator part, we used the tandem glycine aptamer structure from Bacillus subtillis, and fluorogenic aptamer Spinach, respectively. To achieve optimal signal transduction from the sensor to the actuator, a riboswitch library with variable transmitter was screened with a microfluidic large-scale integration chip. This allowed us to establish the complete thermodynamic binding profiles of the riboswitch library. Glycine dissociation constants of the 12 strong fluorescence response riboswitches varied between 99.7 and 570 MUM. Furthermore, the kinetic glycine binding (k(on)), and dissociation (k(off)) rates, and corresponding energy barriers of the 10 strongest fluorescence response riboswitches were determined with the same chip platform. k(on) and k(off) were in the order of 10(-3)s(-1) and 10(-2)s(-1), respectively. Conclusively, we demonstrate that systematic screening of synthetic and natural linked RNA parts with microfluidic chip technology is an effective approach to rapidly generate fluorogenic metabolite riboswitches with a broad range of biophysical response properties. PMID- 27220467 TI - Preferential extension of short telomeres induced by low extracellular pH. AB - The majority of tumor cells overcome proliferative limit by expressing telomerase. Whether or not telomerase preferentially extends the shortest telomeres is still under debate. When human cancer cells are cultured at neutral pH, telomerase extends telomeres in telomere length-independent manner. However, the microenvironment of tumor is slightly acidic, and it is not yet known how this influences telomerase action. Here, we examine telomere length homeostasis in tumor cells cultured at pHe 6.8. The results indicate that telomerase preferentially extends short telomeres, such that telomere length distribution narrows and telomeres become nearly uniform in size. After growth at pHe 6.8, the expression of telomerase, TRF1, TRF2 and TIN2 decreases, and the abundance of Cajal bodies decreases. Therefore, telomerase are insufficient for extending every telomere and shorter telomeres bearing less shelterin proteins are more accessible for telomerase recruitment. The findings support the 'protein-counting mechanism' in which extended and unextended state of telomere is determined by the number of associated shelterin proteins and the abundance of telomerase. Decreased expression of telomerase and preferential extension of short telomeres have important implications for tumor cell viability, and generate a strong rationale for research on telomerase-targeted anti-cancer therapeutics. PMID- 27220468 TI - MGME1 processes flaps into ligatable nicks in concert with DNA polymerase gamma during mtDNA replication. AB - Recently, MGME1 was identified as a mitochondrial DNA nuclease with preference for single-stranded DNA (ssDNA) substrates. Loss-of-function mutations in patients lead to mitochondrial disease with DNA depletion, deletions, duplications and rearrangements. Here, we assess the biochemical role of MGME1 in the processing of flap intermediates during mitochondrial DNA replication using reconstituted systems. We show that MGME1 can cleave flaps to enable efficient ligation of newly replicated DNA strands in combination with POLgamma. MGME1 generates a pool of imprecisely cut products (short flaps, nicks and gaps) that are converted to ligatable nicks by POLgamma through extension or excision of the 3'-end strand. This is dependent on the 3'-5' exonuclease activity of POLgamma which limits strand displacement activity and enables POLgamma to back up to the nick by 3'-5' degradation. We also demonstrate that POLgamma-driven strand displacement is sufficient to generate DNA- but not RNA-flap substrates suitable for MGME1 cleavage and ligation during replication. Our findings have implications for RNA primer removal models, the 5'-end processing of nascent DNA at OriH, and DNA repair. PMID- 27220470 TI - CasHRA (Cas9-facilitated Homologous Recombination Assembly) method of constructing megabase-sized DNA. AB - Current DNA assembly methods for preparing highly purified linear subassemblies require complex and time-consuming in vitro manipulations that hinder their ability to construct megabase-sized DNAs (e.g. synthetic genomes). We have developed a new method designated 'CasHRA (Cas9-facilitated Homologous Recombination Assembly)' that directly uses large circular DNAs in a one-step in vivo assembly process. The large circular DNAs are co-introduced into Saccharomyces cerevisiae by protoplast fusion, and they are cleaved by RNA-guided Cas9 nuclease to release the linear DNA segments for subsequent assembly by the endogenous homologous recombination system. The CasHRA method allows efficient assembly of multiple large DNA segments in vivo; thus, this approach should be useful in the last stage of genome construction. As a proof of concept, we combined CasHRA with an upstream assembly method (Gibson procedure of genome assembly) and successfully constructed a 1.03 Mb MGE-syn1.0 (Minimal Genome of Escherichia coli) that contained 449 essential genes and 267 important growth genes. We expect that CasHRA will be widely used in megabase-sized genome constructions. PMID- 27220469 TI - Widespread transcriptional gene inactivation initiated by a repair intermediate of 8-oxoguanine. AB - DNA damage can significantly modulate expression of the affected genes either by direct structural interference with transcription components or as a collateral outcome of cellular repair attempts. Thus, DNA glycosylases of the base excision repair (BER) pathway have been implicated in negative transcriptional response to several spontaneously generated DNA base modifications, including a common oxidative DNA base modification 8-oxoguanine (8-oxoG). Here, we report that single 8-oxoG situated in the non-transcribed DNA strand of a reporter gene has a pronounced negative effect on transcription, driven by promoters of various strength and with different structural properties, including viral, human, and artificial promoters. We further show that the magnitude of the negative effect on the gene expression correlates with excision of the modified base by OGG1 in all promoter constructs tested. Moreover, by using expression vectors with nuclease resistant backbone modifications, we demonstrate that OGG1 does not catalyse DNA strand cleavage in vivo. Rather, cleavage of the phosphate bond 5' to 8-oxodG (catalysed by APE1) is essential and universally required for the onset of transcriptional silencing, regardless of the promoter structure. Hence, induction of transcriptional silencing emerges as a ubiquitous mode of biological response to 8-oxoG in DNA. PMID- 27220471 TI - Evaluation of Microemulsion and Lamellar Liquid Crystalline Systems for Transdermal Zidovudine Delivery. AB - This study proposed to investigate and to compare colloidal carrier systems containing Zidovudine (3'-azido-3'-deoxythymidine) (AZT) for transdermal administration and optimization of antiretroviral therapy. Microemulsion (ME) and lamellar phase (LP) liquid crystal were obtained and selected from pseudoternary diagrams previously developed. Small-angle X-ray scattering and rheology analysis confirmed the presence of typical ME and liquid crystalline structures with lamellar arrangement, respectively. Both colloidal carrier systems, ME, and LP remained stable, homogeneous, and isotropic after AZT addition. In vitro permeation study (using pig ear skin) showed that the amount of permeated drug was higher for ME compared to the control and LP, obtaining a permeation enhancing effect on the order of approximately 2-fold (p < 0.05). Microscopic examination after in vivo skin irritation studies using mice suggested few histological changes in the skin of animals treated with the ME compared to the control group (hydrogel). Thus, ME proved to be adequate and have promising effects, being able to promote the drug permeation without causing apparent skin irritation. On the order hand, LP functioned as a drug reservoir reducing AZT partitioning into the skin. PMID- 27220472 TI - VUR timing on VCUG as a predictive factor of VUR resolution after endoscopic therapy. AB - BACKGROUND: The timing of reflux onset on VCUG (VUR timing) has been considered a predictive factor of spontaneous resolution in VUR children. While the voiding reflux is associated with a greater rate of spontaneous resolution, the filling reflux is more likely to require surgical intervention. However, the VUR timing in children with primary VUR has not been evaluated with regard to the prognostic value of endoscopic therapy. The aim of this study was to evaluate the effect of VUR timing on the surgical outcome after endoscopic therapy for primary VUR. METHOD: We retrospectively reviewed the medical records of 94 primary VUR patients who underwent endoscopic injection for their initial surgical management. Radiologic success was defined as grade I or less on VCUG at 3-6 months following endoscopic therapy. We allocated patients to a filling reflux group or a voiding reflux group on the basis of their most recent preoperative VCUG. We evaluated the patients' demographics and outcomes after endoscopic therapy according to VUR timing. Predictive factors for radiologic success were analyzed using a multivariate logistic regression model. RESULTS: Of the 94 children (136 ureters), 68 (101 ureters) were classified as the filling reflux group and 26 (35 ureters) were placed in the voiding reflux group. The preoperative VUR grade in the filling reflux group was significantly higher than that in the voiding reflux group (p = 0.001). Radiologic success was observed in 56.44% (57/101 ureters) in the filling reflux group and in 88.57% (31/35 ureters) in the voiding reflux group (p = 0.001). Multivariate analysis showed that VUR grade and VUR timing on VCUG were predictive factors of radiologic success after endoscopic therapy (p = 0.001 and p = 0.005). CONCLUSIONS: Despite the clinical importance of VUR timing, no studies have investigated the prognostic value of VUR timing for endoscopic therapy in primary VUR children. In this study, multivariate analysis revealed that the VUR grade and VUR timing on preoperative VCUG were significant predictors of success after endoscopic injection. Although the VUR grade is the most well-known factor that can affect the success of the procedure, VUR timing was a newly identified predictive factor. While patients with a filling reflux have lower success rates, patients with a voiding reflux were observed to show higher resolution rates after endoscopic injection. VUR timing on preoperative VCUG was found to be an independent predictive factor of VUR resolution after endoscopic therapy. PMID- 27220473 TI - Adherence to Monitoring Tests in Patients With Chronic Myeloid Leukemia in Lebanon. AB - The present study was performed to determine whether the adherence to regular follow-up assessments using standardized real-time quantitative polymerase chain reaction (qPCR) and/or cytogenetic tests in Lebanese patients with chronic myeloid leukemia (CML) meet the European LeukemiaNet recommendations. The present study was a retrospective analysis of 34 patients diagnosed with chronic phase CML who had been treated with tyrosine kinase inhibitors and monitored with regular cytogenetic tests and/or measurement of the BCR-ABL transcript level at 3, 6, and 12 months from 2006 until 2015 in 3 university hospitals in Lebanon. All patients were included and monitored in an adherence program (SAWA program). The male/female ratio was 3:1. The median age was 50 years, and the mean age was 50 years. As frontline treatment, 29 patients started imatinib and 5 patients received second-generation tyrosine kinase inhibitors. We defined compliance to the monitoring tests as regulary realizing the qPCR at 3, 6, and 12 months. Of the 36 patients, 15 underwent the recommended tests at 3, 6, and 12 months, representing a compliance rate of 41.6%; 28 of the 34 patients underwent the recommended tests only twice in the first follow-up year. Only 14 patients underwent qPCR at 3 months. We believe that despite the inclusion of our patients in an adherence program, the compliance rate is still low. We also believe that greater effort is required to improve the adherence to regular follow-up examinations. PMID- 27220474 TI - SDF-1/CXCR4 axis induces apoptosis of human degenerative nucleus pulposus cells via the NF-kappaB pathway. AB - Intervertebral disc degeneration (IVDD) is a major cause of lower back pain, and increased cell apoptosis is a key characteristic of IVDD. The present study aimed to investigate the effects and mechanism of the stromal cell-derived factor-1 (SDF-1)/C-X-C motif chemokine receptor 4 (CXCR4) axis on apoptosis in human degenerative nucleus pulposus cells (NPCs). The expression levels of SDF-1 and CXCR4 in human intervertebral discs (IVD) were determined using immunohistochemistry and western blot analysis. Apoptosis of primary cultured NPCs was quantified by Annexin V/propidium iodide staining following stimulation with SDF-1 and knockdown of CXCR4 using small interfering RNA (siRNA). The association with the nuclear factor-kappaB (NF-kappaB) signaling pathway was investigated using CXCR4-siRNA and NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC), treatment. The results demonstrated that SDF-1 and its receptor, CXCR4, were upregulated in degenerative IVD samples compared with normal samples. Stimulation with SDF-1 increased the level of apoptosis in cultured NPCs, and conversely, the apoptosis level was suppressed post transfection with CXCR4 siRNA compared with SDF-1 stimulation alone. Furthermore, SDF-1 treatment increased the level of phosphorylated NF-kappaB subunit P65, which was downregulated following CXCR4 siRNA and PDTC treatment. In addition, CXCR4 siRNA and PDTC inhibited the nuclear translocation of P65, which was induced by SDF-1. Taken together, SDF-1-mediated apoptosis was suppressed by NF kappaB inhibition using PDTC. In conclusion, the SDF-1/CXCR4 axis promoted cell apoptosis in human degenerative NPCs via the NF-kappaB pathway, thus suggesting that SDF-1/CXCR signaling may be a therapeutic target for the treatment of degenerative IVD diseases. PMID- 27220475 TI - IL36RN Mutations Affect Protein Expression and Function: A Basis for Genotype Phenotype Correlation in Pustular Diseases. AB - Homozygous or compound heterozygous IL36RN gene mutations underlie the pathogenesis of psoriasis-related pustular eruptions including generalized pustular psoriasis, palmoplantar pustular psoriasis, acrodermatitis continua of Hallopeau, and acute generalized exanthematous pustular eruption. We identified two unreported IL36RN homozygous mutations (c.41C>A/p.Ser14X and c.420_426del/p.Gly141MetfsX29) in patients with familial generalized pustular psoriasis. We analyzed the impact of a spectrum of IL36RN mutations on IL-36 receptor antagonist protein by using site-directed mutagenesis and expression in HEK293T cells. This enabled us to differentiate null mutations with complete absence of IL-36 receptor antagonist (the two previously unreported mutations, c.80T>C/p.Leu27Pro, c.28C>T/p.Arg10X, c.280G>T/p.Glu94X, c.368C>G/p.Thr123Arg, c.368C>T/p.Thr123Met, and c.227C>T/p.Pro76Leu) from mutations with decreased (c.95A>G/p.His32Arg, c.142C>T/p.Arg48Trp, and c.308C>T/p.Ser113Leu) or unchanged (c.304C>T/p.Arg102Trp and c.104A>G/p.Lys35Arg) protein expression. Functional assays measuring the impact of mutations on the capacity to repress IL-36 dependent activation of the NF-kappaB pathway showed complete functional impairment for null mutations, whereas partial or no impairment was observed for other mutations considered as hypomorphic. Finally, null mutations were associated with severe clinical phenotypes (generalized pustular psoriasis, acute generalized exanthematous pustular eruption), whereas hypomorphic mutations were identified in both localized (palmoplantar pustular psoriasis, acrodermatitis continua of Hallopeau) and generalized variants. These results provide a preliminary basis for genotype-phenotype correlation in patients with deficiency of the IL-36Ra (DITRA), and suggest the involvement of other factors in the modulation of clinical expression. PMID- 27220478 TI - Tumour microenvironment: Genotype puts tension on a tumour. PMID- 27220477 TI - Micromonospora luteifusca sp. nov. isolated from cultivated Pisum sativum. AB - Three novel actinobacterial strains, GUI2(T), GUI42 and CR21 isolated from nodular tissues and the rhizosphere of a sweet pea plant collected in Canizal, Spain were identified according to their 16S rRNA gene sequences as new members of the genus Micromonospora. The closest phylogenetic members were found to be Micromonospora saelicesensis (99.2%) "Micromonospora zeae" (99.1%), "Micromonospora jinlongensis" (99%), Micromonospora lupini (98.9%) and Micromonospora zamorensis (98.8%). To resolve their full taxonomic position, four additional genes (atpD, gyrB, recA, rpoB) were partially sequenced and compared to available Micromonospora type strain sequences. DNA-DNA hybridization, BOX-PCR and ARDRA profiles confirmed that these strains represent a novel genomic species. All strains contained meso-diaminopimelic and hydroxy-diaminopimelic acids in their cell wall. Their fatty acid profiles comprised iso-C15:0, iso C16:0 and anteiso-C15:0 as major components. The polar lipids diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylinositol were found in the type strain GUI2(T) which also contained MK-10(H4) as the major menaquinone. Physiological and biochemical characteristics also differentiated the new isolates. Based on the integration of the above studies, strains GUI2(T), GUI42 and CR21 represent a novel Micromonospora species and we propose the name Micromonospora luteifusca sp. nov. The type strain is GUI2(T) (=CECT 8846(T); =DSM 100204(T)). PMID- 27220476 TI - Nonoverlapping Clinical and Mutational Patterns in Melanomas from the Female Genital Tract and Atypical Genital Nevi. AB - Genital melanomas (GM) are the second most common cancer of the female external genitalia and may be confused with atypical genital nevi (AGN), which exhibit atypical histological features but have benign behavior. In this study, we compared the clinical, histological, and molecular features of 19 GM and 25 AGN. We described chromosomal copy number aberrations and the mutational status of 50 oncogenes and tumor suppressor genes in both groups. Our study showed that a pigmented lesion occurring in mucosal tissue, particularly in postmenopausal women, was more likely to be a melanoma than a nevus. GM had high levels of chromosomal instability, with many copy number aberrations. Furthermore, we found a completely nonoverlapping pattern of oncogenic mutations when comparing GM and AGN. In GM, we report somatic mutations in KIT and TP53. Conversely, AGN had frequent BRAF V600E mutations, which were not seen in any of the GM. Our results show that GM and AGN have distinct clinical and molecular changes and that GM have a different mutational pattern compared with AGN. PMID- 27220479 TI - Targeted therapy: RAS mimetic revealed. PMID- 27220480 TI - Beyond transcription factors: how oncogenic signalling reshapes the epigenetic landscape. AB - Cancer, once thought to be caused largely by genetic alterations, is now considered to be a mixed genetic and epigenetic disease. The epigenetic landscape, which is dictated by covalent DNA and histone modifications, is profoundly altered in transformed cells. These abnormalities may arise from mutations in, or altered expression of, chromatin modifiers. Recent reports on the interplay between cellular signalling pathways and chromatin modifications add another layer of complexity to the already complex regulation of the epigenome. In this Review, we discuss these new studies and how the insights they provide can contribute to a better understanding of the molecular pathogenesis of neoplasia. PMID- 27220483 TI - Sound coding in the auditory nerve of gerbils. AB - Gerbils possess a very specialized cochlea in which the low-frequency inner hair cells (IHCs) are contacted by auditory nerve fibers (ANFs) having a high spontaneous rate (SR), whereas high frequency IHCs are innervated by ANFs with a greater SR-based diversity. This specificity makes this animal a unique model to investigate, in the same cochlea, the functional role of different pools of ANFs. The distribution of the characteristic frequencies of fibers shows a clear bimodal shape (with a first mode around 1.5 kHz and a second around 12 kHz) and a notch in the histogram near 3.5 kHz. Whereas the mean thresholds did not significantly differ in the two frequency regions, the shape of the rate intensity functions does vary significantly with the fiber characteristic frequency. Above 3.5 kHz, the sound-driven rate is greater and the slope of the rate-intensity function is steeper. Interestingly, high-SR fibers show a very good synchronized onset response in quiet (small first-spike latency jitter) but a weak response under noisy conditions. The low-SR fibers exhibit the opposite behavior, with poor onset synchronization in quiet but a robust response in noise. Finally, the greater vulnerability of low-SR fibers to various injuries including noise- and age-related hearing loss is discussed with regard to patients with poor speech intelligibility in noisy environments. Together, these results emphasize the need to perform relevant clinical tests to probe the distribution of ANFs in humans, and develop appropriate techniques of rehabilitation. This article is part of a Special Issue entitled . PMID- 27220482 TI - Mechanisms of human lymphoid chromosomal translocations. AB - Analysis of chromosomal translocation sequence locations in human lymphomas has provided valuable clues about the mechanism of the translocations and when they occur. Biochemical analyses on the mechanisms of DNA breakage and rejoining permit formulation of detailed models of the human chromosomal translocation process in lymphoid neoplasms. Most human lymphomas are derived from B cells in which a DNA break at an oncogene is initiated by activation-induced deaminase (AID). The partner locus in many cases is located at one of the antigen receptor loci, and this break is generated by the recombination activating gene (RAG) complex or by AID. After breakage, the joining process typically occurs by non homologous DNA end-joining (NHEJ). Some of the insights into this mechanism also apply to translocations that occur in non-lymphoid neoplasms. PMID- 27220481 TI - Bone metastasis: the importance of the neighbourhood. AB - During the past decade preclinical studies have defined many of the mechanisms used by tumours to hijack the skeleton and promote bone metastasis. This has led to the development and widespread clinical use of bone-targeted drugs to prevent skeletal-related events. This understanding has also identified a critical dependency between colonizing tumour cells and the cells of bone. This is particularly important when tumour cells first arrive in bone, adapt to their new microenvironment and enter a long-lived dormant state. In this Review, we discuss the role of different bone cell types in supporting disseminated tumour cell dormancy and reactivation, and highlight the new opportunities this provides for targeting the bone microenvironment to control dormancy and bone metastasis. PMID- 27220485 TI - Reagents for diverse iodosilane-mediated transformations. AB - It was observed that a PhSiH2I-mediated protocol using PhSiH3 and cat. I2 caused the deiodination of 2-(iodomethyl)-2-phenyltetrahydrofuran. Stemming from the investigation of the mechanism, we found that the PhSiH3-I2 system selectively promotes diverse cascade transformations from cyclic ethers to acyclic alkyl iodides, and the PhSiH3-N-iodosuccinimide (NIS) system also promotes cascade transformations from cyclic ethers to acyclic alcohols. PMID- 27220484 TI - Cochlear perfusion with a viscous fluid. AB - The flow of viscous fluid in the cochlea induces shear forces, which could provide benefit in clinical practice, for example to guide cochlear implant insertion or produce static pressure to the cochlear partition or wall. From a research standpoint, studying the effects of a viscous fluid in the cochlea provides data for better understanding cochlear fluid mechanics. However, cochlear perfusion with a viscous fluid may damage the cochlea. In this work we studied the physiological and anatomical effects of perfusing the cochlea with a viscous fluid. Gerbil cochleae were perfused at a rate of 2.4 MUL/min with artificial perilymph (AP) and sodium hyaluronate (Healon, HA) in four different concentrations (0.0625%, 0.125%, 0.25%, 0.5%). The different HA concentrations were applied either sequentially in the same cochlea or individually in different cochleae. The perfusion fluid entered from the round window and was withdrawn from basal scala vestibuli, in order to perfuse the entire perilymphatic space. Compound action potentials (CAP) were measured after each perfusion. After perfusion with increasing concentrations of HA in the order of increasing viscosity, the CAP thresholds generally increased. The threshold elevation after AP and 0.0625% HA perfusion was small or almost zero, and the 0.125% HA was a borderline case, while the higher concentrations significantly elevated CAP thresholds. Histology of the cochleae perfused with the 0.0625% HA showed an intact Reissner's membrane (RM), while in cochleae perfused with 0.125% and 0.25% HA RM was torn. Thus, the CAP threshold elevation was likely due to the broken RM, likely caused by the shear stress produced by the flow of the viscous fluid. Our results and analysis indicate that the cochlea can sustain, without a significant CAP threshold shift, up to a 1.5 Pa shear stress. Beside these finding, in the 0.125% and 0.25% HA perfusion cases, a temporary CAP threshold shift was observed, perhaps due to the presence and then clearance of viscous fluid within the cochlea, or to a temporary position shift of the Organ of Corti. After 0.5% HA perfusion, a short latency positive peak (P0) appeared in the CAP waveform. This P0 might be due to a change in the cochlea's traveling-wave pattern, or distortion in the cochlear microphonic. PMID- 27220486 TI - Re-irradiation using proton beam therapy combined with weekly intra-arterial chemotherapy for recurrent oral cancer. AB - AIM: The purpose of this study was to clarify the efficacy and toxicities of re irradiation using proton beam therapy combined with weekly intra-arterial chemotherapy for recurrent oral cancer. METHODS: Between October 2009 and July 2014, 34 patients who had recurrent oral cancer were treated by proton beam therapy combined with intra-arterial infusion chemotherapy at the Southern Tohoku Proton Therapy Center, Japan. RESULTS: For all patients, the median follow-up was 25 months (range, 3-77 months). After treatment, 22 patients (65%) achieved a complete response, and 12 patients (35%) achieved a partial response at the primary tumor site. One-year and 2-year overall survival (OS) rates were 62% and 42%, respectively. One-year and 2-year LC rates were 77% and 60%, respectively. No treatment-related deaths were observed during the treatment and follow-up periods. CONCLUSION: Re-irradiation using proton beam therapy combined with weekly intra-arterial chemotherapy improved OS and local control rates compared with other treatment modalities and could become a new treatment modality for patients with recurrent oral cancer. PMID- 27220487 TI - Reasons for unplanned pediatric readmissions at a referral eye center in the Middle East. AB - Unplanned hospital readmissions are of major interest for health care quality control across all medical subspecialties; however, published data for pediatric ophthalmology are lacking. We reviewed the most common reasons for unplanned pediatric readmissions within 30 days of discharge at a referral eye center in the Middle East. Of the top 5 reasons, 3 were related to problems following corneal suturing, often in the context of penetrating keratoplasty, highlighting that children for whom this is done require particular care and follow-up. PMID- 27220488 TI - Accuracy of heritability estimations in presence of hidden population stratification. AB - The heritability of a trait is the proportion of its variance explained by genetic factors; it has historically been estimated using familial data. However, new methods have appeared for estimating heritabilities using genomewide data from unrelated individuals. A drawback of this strategy is that population stratification can bias the estimates. Indeed, an environmental factor associated with the phenotype may differ among population subgroups. This factor being associated both with the phenotype and the genetic variation in the population would be a confounder. A common solution consists in adjusting on the first Principal Components (PCs) of the genomic data. We study this procedure on simulated data and on 6000 individuals from the Three-City Study. We analyse the geographical coordinates of the birth cities, which are not genetically determined, but the heritability of which should be overestimated due to population stratification. We also analyse various anthropometric traits. The procedure fails to correct the bias in geographical coordinates heritability estimates. The heritability estimates of the anthropometric traits are affected by the inclusion of the first PC, but not by the following PCs, contrarily to geographical coordinates. We recommend to be cautious with heritability estimates obtained from a large population. PMID- 27220489 TI - Nocturnal hemoglobin desaturation is associated with reticulocytosis in adults with sickle cell disease and is independent of obstructive sleep apnea. PMID- 27220491 TI - Fluorescence enhancement through the formation of a single-layer two-dimensional supramolecular organic framework and its application in highly selective recognition of picric acid. AB - A two-dimensional (2D) supramolecular organic framework (SOF) has been constructed through the co-assembly of a triphenylamine-based building block and cucurbit[8]uril (CB[8]). Fluorescence turn-on of the non-emissive building block was observed upon the formation of the 2D SOF, which displayed highly selective and sensitive recognition of picric acid over a variety of nitroaromatics. PMID- 27220492 TI - Risk factors for requiring cholecystectomy for gallstone disease in a prospective population-based cohort study. AB - BACKGROUND: The relationship between different lifestyle factors and the risk of needing cholecystectomy for gallstone disease is not clear. This study aimed to assess the association between anthropometric, lifestyle and sociodemographic risk factors and the subsequent risk of requiring cholecystectomy for gallstone disease during long-term follow-up in a defined population cohort. METHODS: Data from a large population-based cohort study performed from 1995 to 1997 were used (the second Norwegian Nord-Trondelag health study, HUNT2). Following HUNT2, from 1998 to 2011, all patients operated on for gallstone disease with cholecystectomy at the two hospitals in the county, Levanger Hospital and Namsos Hospital, were identified. A Cox proportional hazards model was used for multivariable risk analysis. RESULTS: The HUNT2 cohort included 65 237 individuals (69.5 per cent response rate), aged 20-99 years. During a median follow-up of 15.3 (range 0.6 16.4) years, 1162 cholecystectomies were performed. In multivariable analysis, overweight individuals (body mass index (BMI) 25.0-29.9 kg/m(2) ) had a 58 per cent increased risk of cholecystectomy compared with individuals with normal weight (BMI less than 25.0 kg/m(2) ). Obese individuals (BMI 30 kg/m(2) or above) had a twofold increased risk. Increasing waist circumference independently increased the risk of cholecystectomy. In women, current hormone replacement therapy (HRT) increased the risk, whereas hard physical activity and higher educational level were associated with reduced risk of cholecystectomy. CONCLUSION: High BMI and waist circumference increased the risk of having cholecystectomy for both sexes. In women, the risk was increased by HRT, and decreased by hard physical activity and higher educational level. PMID- 27220493 TI - Effect of timing of cannulation on outcome for pediatric extracorporeal life support. AB - PURPOSE: Literature reports worse outcomes for operations performed during off hours. As this has not been studied in pediatric extracorporeal life support (ECLS), we compared complications based on the timing of cannulation.. METHODS: This is a retrospective review of 176 pediatric ECLS patients between 2004 and 2015. Patients cannulated during daytime hours (7:00 A.M. to 7:00 P.M., M-F) were compared to off-hours (nighttime or weekend) using t-test and Chi-square. RESULTS: The most common indications for ECLS were congenital diaphragmatic hernia (33 %) and persistent pulmonary hypertension (23 %). When comparing regular hours (40 %) to off-hours cannulation (60 %), there were no significant differences in central nervous system complications, hemorrhage (extra-cranial), cannula repositioning, conversion from venovenous to venoarterial, mortality on ECLS, or survival-to-discharge. The overall complication rate was slightly lower in the off-hours group (45.7 % versus 61.9 %, P = 0.034). CONCLUSION: Outcomes were not significantly worse for patients undergoing ELCS cannulation during off hours compared to normal weekday working hours. PMID- 27220494 TI - MiR-21 modulates radiosensitivity of cervical cancer through inhibiting autophagy via the PTEN/Akt/HIF-1alpha feedback loop and the Akt-mTOR signaling pathway. AB - MiR-21 is an important microRNA (miRNA) modulating radiosensitivity of cervical cancer cells. However, the underlying mechanism of miR-21 upregulation in radioresistant cervical cancer has not been fully understood. In addition, autophagy may either promote or alleviate radioresistance, depending on the types of cancer and tumor microenvironment. How autophagy affects radiosensitivity in cervical cancer and how miR-21 is involved in this process has not been reported. This study showed that miR-21 upregulation in radioresistant cervical cancer is related to HIF-1alpha overexpression. MiR-21 overexpression decreases PTEN, increases p-Akt, and subsequently increases HIF-1alpha expression, while miR-21 inhibition results in increased PTEN, decreased p-Akt, and then decreased HIF 1alpha. Therefore, we inferred that there is a HIF-1alpha-miR-21 positive feedback loop through the PTEN/Akt/HIF-1alpha pathway in cervical cancer cells. In addition, we also demonstrated that miR-21 confers decreased autophagy in cervical cancer cells after IR via the Akt-mTOR signaling pathway. Decreased autophagy is one of the potential mechanisms of increased radioresistance in cervical cancer cells. These findings expand our understanding of radioresistance development in cervical cancer. PMID- 27220495 TI - Exosomes derived from gastric cancer cells activate NF-kappaB pathway in macrophages to promote cancer progression. AB - Exosomes are nano-sized membrane vesicles secreted by both normal and cancer cells. Emerging evidence indicates that cancer cells derived exosomes contribute to cancer progression through the modulation of tumor microenvironment. However, the effects of exosomes derived from gastric cancer cells on macrophages are not well understood. In this study, we investigated the biological role of gastric cancer cells derived exosomes in the activation of macrophages. We demonstrated that gastric cancer cells derived exosomes activated macrophages to express increased levels of proinflammatory factors, which in turn promoted tumor cell proliferation and migration. In addition, gastric cancer cells derived exosomes remarkably upregulated the phosphorylation of NF-kappaB in macrophages. Inhibiting the activation of NF-kappaB reversed the upregulation of proinflammatory factors in macrophages and blocked their promoting effects on gastric cancer cells. Moreover, we found that gastric cancer cells derived exosomes could also activate macrophages from human peripheral blood monocytes through the activation of NF-kappaB. In conclusion, our results suggest that gastric cancer cells derived exosomes stimulate the activation of NF-kappaB pathway in macrophages to promote cancer progression, which provides a potential therapeutic approach for gastric cancer by interfering with the interaction between exosomes and macrophages in tumor microenvironment. PMID- 27220496 TI - A Pragmatic Bayesian Perspective on Correlation Analysis : The exoplanetary gravity - stellar activity case. AB - We apply the Bayesian framework to assess the presence of a correlation between two quantities. To do so, we estimate the probability distribution of the parameter of interest, rho, characterizing the strength of the correlation. We provide an implementation of these ideas and concepts using python programming language and the pyMC module in a very short (~ 130 lines of code, heavily commented) and user-friendly program. We used this tool to assess the presence and properties of the correlation between planetary surface gravity and stellar activity level as measured by the log([Formula: see text]) indicator. The results of the Bayesian analysis are qualitatively similar to those obtained via p-value analysis, and support the presence of a correlation in the data. The results are more robust in their derivation and more informative, revealing interesting features such as asymmetric posterior distributions or markedly different credible intervals, and allowing for a deeper exploration. We encourage the reader interested in this kind of problem to apply our code to his/her own scientific problems. The full understanding of what the Bayesian framework is can only be gained through the insight that comes by handling priors, assessing the convergence of Monte Carlo runs, and a multitude of other practical problems. We hope to contribute so that Bayesian analysis becomes a tool in the toolkit of researchers, and they understand by experience its advantages and limitations. PMID- 27220497 TI - Selective Phosphonylation of 5'-Adenosine Monophosphate (5'-AMP) via Pyrophosphite [PPi(III)]. AB - We describe here experiments which demonstrate the selective phospho-transfer from a plausibly prebiotic condensed phosphorus (P) salt, pyrophosphite [H2P2O52 ; PPi(III)], to the phosphate group of 5'-adenosine mono phosphate (5'-AMP). We show further that this P-transfer process is accelerated both by divalent metal ions (M2+) and by organic co-factors such as acetate (AcO-). In this specific case of P-transfer from PPi(III) to 5'-AMP, we show a synergistic enhancement of transfer in the combined presence of M2+ & AcO-. Isotopic labelling studies demonstrate that hydrolysis of the phosphonylated 5'-AMP, [P(III)P(V)-5'-AMP], proceeds via nuceophilic attack of water at the Pi(III) terminus. PMID- 27220498 TI - Chronic Myeloid Leukemia in the Era of Tyrosine Kinase Inhibitors: An Evolving Paradigm of Molecularly Targeted Therapy. AB - Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, characterized by the unrestrained expansion of pluripotent hematopoietic stem cells. CML was the first malignancy in which a unique chromosomal abnormality was identified and a pathophysiologic association was suggested. The hallmark of CML is a reciprocal chromosomal translocation between the long arms of chromosomes 9 and 22, t(9; 22)(q34; q11), creating a derivative 9q+ and a shortened 22q-. The latter, known as the Philadelphia (Ph) chromosome, harbors the breakpoint cluster region abelson (BCR-ABL) fusion gene, encoding the constitutively active BCR-ABL tyrosine kinase that is necessary and sufficient for initiating CML. The successful implementation of tyrosine kinase inhibitors (TKIs) for the treatment of CML remains a flagship for molecularly targeted therapy in cancer. TKIs have changed the clinical course of CML; however, some patients nonetheless demonstrate primary or secondary resistance to such therapy and require an alternative therapeutic strategy. Therefore, the assessment of early response to treatment with TKIs has become an important tool in the clinical monitoring of CML patients. Although mutations in the BCR-ABL have proven to be the most prominent mechanism of resistance to TKIs, other mechanisms-either rendering the leukemic cells still dependent on BCR-ABL activity or supporting oncogenic properties of the leukemic cells independent of BCR-ABL signaling-have been identified. This article provides an overview of the current understanding of CML pathogenesis; recommendations for diagnostic tools, treatment strategies, and management guidelines; and highlights the BCR-ABL-dependent and -independent mechanisms that contribute to the development of resistance to TKIs. PMID- 27220500 TI - Spatial decorrelation stretch of annual (2003-2014) Daymet precipitation summaries on a 1-km grid for California, Nevada, Arizona, and Utah. AB - A method is presented for elevation (H) and spatial position (X, Y) decorrelation stretch of annual precipitation summaries on a 1-km grid for SW USA for the period 2003 to 2014. Multiple linear regression analysis of the first and second principal component (PC) quantifies the variance in the multi-temporal precipitation imagery that is explained by X, Y, and elevation (h). The multi temporal dataset is reconstructed from the PC1 and PC2 residual images and the later PCs by taking into account the variance that is not related to X, Y, and h. Clustering of the reconstructed precipitation dataset allowed the definition of positive (for example, in Sierra Nevada, Salt Lake City) and negative (for example, in San Joaquin Valley, Nevada, Colorado Plateau) precipitation anomalies. The temporal and spatial patterns defined from the spatially standardized multi-temporal precipitation imagery provide a tool of comparison for regions in different geographic environments according to the deviation from the precipitation amount that they are expected to receive as function of X, Y, and h. Such a standardization allows the definition of less or more sensitive to climatic change regions and gives an insight in the spatial impact of atmospheric circulation that causes the annual precipitation. PMID- 27220499 TI - Primary Care Physicians' Perspectives of Their Role in Cancer Care: A Systematic Review. AB - BACKGROUND: As survival rates improve, cancer is increasingly considered a chronic illness associated with significant long-term burden and sequelae, both physical and psychological. Various models of cancer care, including primary care physician (PCP)-led and shared-care, have been proposed, though a systematic review of PCPs' perspectives of their role and challenges in providing cancer care remains lacking. This systematic review summarises available literature on PCPs' perspectives of their role in cancer care. METHODS: Five databases (MEDLINE, MEDLINE In-Process, EMBASE, PsycINFO and CINAHL) were systematically searched using keywords and MeSH headings for articles from 1993-2015 exploring PCPs' views of their role in the care of patients/survivors of both child and adult cancers. Two independent reviewers screened abstracts for full-text review, abstracted data and performed a quality assessment. RESULTS: Thirty-five articles representing the perspectives of 10,941 PCPs were captured. PCPs' confidence to provide care varied according to cancer phase (e.g. treatment versus survivorship), care domain (e.g. acute medical care versus psychological late effects), and disease prevalence (e.g. breast malignancies versus childhood cancers), with preferences for shared- versus independent-care models varying accordingly. Barriers included a lack of timely and specific information/communication from oncologists and limited knowledge/lack of guidelines, as well as lack of time, remuneration and patient trust. LIMITATIONS: The data was limited by a lack of consideration of the preferences of patients and oncologists, leading to uncertainty about the acceptability and feasibility of suggested changes to cancer care. DISCUSSION: PCPs appear willing to provide cancer care for patients/survivors; however, they report barriers and unmet needs related to providing such care. Future research/interventions should take into account the preferences and needs of PCPs. PMID- 27220501 TI - Transient variation of aerosol size distribution in an underground subway station. AB - As the number of people using rapid transit systems (subways) continues to rise in major cities worldwide, increasing attention has been given to the indoor air quality of underground stations. This study intended to observe the change of PM distribution by size in an underground station with PSDs installed located near the main road in downtown Seoul, as well as to examine causes for the changes. The results indicate that the PM suspended in the tunnel flowed into the platform area even in a subway station where the effect of train-induced wind is blocked by installed PSDs, as this flow occurred when the PSDs were opened. The results also indicate that coarse mode particles generated by mechanical friction in the tunnel, such as that between wheels and rail, also flowed into the platform area. The PM either settled or was re-suspended according to size and whether the ventilation in the platform area was in operation or if the platform floor had been washed. The ventilation system was more effective in removing PM of smaller sizes (fine particles) while the wash-out performed after train operations had stopped reduced the suspension of coarse mode particles the next morning. Despite installation of the completely sealed PSDs, inflow of coarse mode particles from the tunnel seems unavoidable, indicating the need for measures to decrease the PM generated there to lower subway user exposure since those particles cannot be reduced by mechanical ventilation alone. This research implicate that coarse PM containing heavy metals (generated from tunnel side) proliferated especially during rush hours, during which it is very important to control those PM in order to reduce subway user exposure to this hazardous PM. PMID- 27220502 TI - Desorption and mobilization of three strobilurin fungicides in three types of soil. AB - Phenamacril (JS399-19 with independent intellectual property developed by China), azoxystrobin, and kresoxim-methyl are strobilurin fungicide. Due to their broad spectrum and good control of most of known fungi, strobilurin fungicide has been widely used in agriculture management. Thus, it is important to evaluate their environmental behaviors particularly in soils and underground water. In this study, the sorption/desorption and mobility of strobilurin fungicides in three Chinese soils (Jiangxi red soil, Taihu paddy soil, and Northeast China black soil) were conducted using comprehensively analytic approaches including batch experiment and soil thin-layer chromatography. The strobilurin fungicides were hard to be adsorbed in Jiangxi red soil but had medium adsorption capability in Tanhu paddy soil and Northeast China black soil, while the desorption of three strobilurin fungicides ranked in the order of Jiangxi red soil > Taihu paddy soil > Northeast China black soil. Soil properties including soil organic matter (SOM), pH, and cationic exchange capacity (CEC) affected the adsorption/desorption of the fungicides. Azoxystrobin and kresoxim-methyl had weak mobility in the soils. JS399-19 was moderately mobile in Jiangxi red soil but was not easily moved in Taihu paddy soil and Northeast China black soil. Due to their weak mobility in soils, these strobilurin fungicides tended to remain in the soil phase but not to shift downward to underground water. As azoxystrobin and JS399-19 had a long retention period in soil, there may become persistent residues in the soil environment. PMID- 27220503 TI - Characterization of fish assemblages and population structure of freshwater fish in two Tunisian reservoirs: implications for fishery management. AB - To monitor and assess the state of Tunisian freshwater fisheries, two surveys were undertaken at Ghezala and Lahjar reservoirs. Samples were taken in April and May 2013, a period when the fish catchability is high. The selected reservoirs have different surface areas and bathymetries. Using multi-mesh gill nets (EN 14575 amended) designed for sampling fish in lakes, standard fishing methods were applied to estimate species composition, abundance, biomass, and size distribution. Four species were caught in the two reservoirs: barbel, mullet, pike-perch, and roach. Fish abundance showed significant change according to sampling sites, depth strata, and the different mesh sizes used. From the reservoir to the tributary, it was concluded that fish biomass distribution was governed by depth and was most abundant in the upper water layers. Species size distribution differed significantly between the two reservoirs, exceeding the length at first maturity. Species composition and abundance were greater in Lahjar reservoir than in Ghezala. Both reservoirs require support actions to improve fish productivity. PMID- 27220504 TI - Assessment of uncertainty in constructed wetland treatment performance and load estimation methods. AB - Constructed wetlands (CWs) are commonly established to reduce pollution load from different sources. In environmental permits, the load remaining after CW purification is typically estimated through concentration and flow measurements. This load monitoring is often carried out using long water quality sampling intervals, which causes uncertainty in load estimation. In this study, a large suspended solids (SSs) and dissolved organic carbon (DOC) dataset was used to quantify the uncertainty in load estimation at the inlet and outlet of a CW with different sampling frequencies (sampling every 1, 2, 3 or 4 weeks). A method to reduce the uncertainty by dividing the CW flow duration curve (FDC) into four equal categories and assigning mean/median concentration for each category according to the measured concentrations was also tested. The results showed that estimated SS load was associated with considerable uncertainty and that this uncertainty increased with lower sampling frequency. The FDC method was able to decrease the uncertainty, but much still remained, especially when concentrations of the measured variable showed great variation. In such cases, sensor technology might be a feasible option for further reducing the uncertainty. PMID- 27220505 TI - Phosphorous fractionation in mangrove sediments of Kerala, south west coast of India: the relative importance of inorganic and organic phosphorous fractions. AB - The study of phosphorous dynamics in mangrove ecosystems of the northern Kerala coast aims to delineate its relationships with other biogeochemical parameters. Our intension is to check the validity of the hypothesis that these mangrove ecosystems act as an efficient trap of organic phosphorous by acting as P sink. The dissolved inorganic phosphate displayed higher concentration in monsoon that could be correlated with higher P leaching from mangrove litter as well as terrigenous input during wet season. Fe(OOH)~P was much higher in monsoon (235.23 to 557.70 MUg g(-1)) and lower in pre-monsoon (36.50 to 154.97 MUg g(-1)), and displayed significant contribution towards the inorganic sedimentary P fractions. In monsoon, adsorption of P on iron hydroxides is enhanced by fresh water conditions, but pre-monsoon is characterised by the reductive dissolution of iron oxy hydroxides and the subsequent efflux of P to water column. CaCO3~Pinorg may be present as an inert fraction in the sediment matrix, and did not display any interrelationship with other geochemical parameters. The abundant total organic P (25 to 73 %) fractions, largely derived from P bound with humic/fulvic acid, played a major role in immobilising P and regulating its dynamics in the nearby estuarine and coastal environment. PMID- 27220506 TI - Emission inventory estimation of an intercity bus terminal. AB - Intercity bus terminals are hotspots of air pollution due to concentrated activities of diesel buses. In order to evaluate the bus terminals' impact on air quality, it is necessary to estimate the associated mobile emission inventories. Since the vehicles' operating condition at the bus terminal varies significantly, conventional calculation of the emissions based on average emission factors suffers the loss of accuracy. In this study, we examined a typical intercity bus terminal-the Southern City Bus Station of Xi'an, China-using a multi-scale emission model-(US EPA's MOVES model)-to quantity the vehicle emission inventory. A representative operating cycle for buses within the station is constructed. The emission inventory was then estimated using detailed inputs including vehicle ages, operating speeds, operating schedules, and operating mode distribution, as well as meteorological data (temperature and humidity). Five functional areas (bus yard, platforms, disembarking area, bus travel routes within the station, and bus entrance/exit routes) at the terminal were identified, and the bus operation cycle was established using the micro-trip cycle construction method. Results of our case study showed that switching to compressed natural gas (CNG) from diesel fuel could reduce PM2.5 and CO emissions by 85.64 and 6.21 %, respectively, in the microenvironment of the bus terminal. When CNG is used, tail pipe exhaust PM2.5 emission is significantly reduced, even less than brake wear PM2.5. The estimated bus operating cycles can also offer researchers and policy makers important information for emission evaluation in the planning and design of any typical intercity bus terminals of a similar scale. PMID- 27220507 TI - Preoperative Nutritional Assessment by Controlling Nutritional Status (CONUT) is Useful to estimate Postoperative Morbidity After Esophagectomy for Esophageal Cancer. AB - BACKGROUND: A nutritional indicator suitable for predicting complications after esophagectomy has not been confirmed. The nutritional screening tool CONUT is a potential candidate. METHODS: We retrospectively analyzed 352 patients who underwent elective esophagectomy with lymphadenectomy for esophageal cancer between April 2005 and December 2014. Patients were divided into three groups according to the malnutrition degree in controlling nutritional status (CONUT): normal, light malnutrition, moderate or severe malnutrition. RESULTS: The numbers of patients assigned to the normal, light malnutrition, and moderate or severe malnutrition groups were 205, 126, and 21, respectively. One hundred forty-seven (41.8 %) patients were considered malnourished. Patients with moderate or severe malnutrition had a significantly high incidence of any morbidity, severe morbidities, and surgical site infection. Hospital stay in patients with moderate or severe malnutrition was significantly longer. Logistic regression analysis suggested that moderate or severe malnutrition was an independent risk factor for any morbidity [hazard ratio (HR) 2.75, 95 % confidence interval (CI) 1.081-7.020; p = 0.034] and severe morbidities (HR 3.07, 95 % CI 1.002-9.432; p = 0.049). CONCLUSIONS: CONUT was a convenient and useful tool to assess nutritional status before esophagectomy. Patients with moderate or severe malnutrition according to CONUT are at high risk for postoperative complications. PMID- 27220508 TI - Staging PET-CT Scanning Provides Superior Detection of Lymph Nodes and Distant Metastases than Traditional Imaging in Locally Advanced Breast Cancer. AB - BACKGROUND: This study was designed to evaluate the role of a single 18-FDG positron emission tomography and computed tomography (PET-CT) scan in comparison to multiple organ-directed conventional investigations (CI) as a staging tool in locally advanced breast cancer (LABC) to detect regional and distant metastasis. METHODS: All eligible patients were subjected to CI (chest X-ray, abdominal sonography, and bone scintigraphy) followed by a single 18-FDG PET-CT scan. Standard imaging criteria were used for diagnosis of metastasis. Histopathological confirmation was undertaken for suspicious lesions. An exploratory analysis was done to assess the impact of PET-CT on the staging of LABC and how it resulted in a change in management. RESULT: The study included 79 patients of LABC. PET-CT detected distant metastasis in 36 (45.5 %) patients while CI could identify distant metastasis in 20 (25.3 %) patients. Two of the 36 patients in whom PET-CT detected distant metastasis were false positive. Overall PET-CT upstaged the disease in 38 (48.1 %) patients as compared to CI: stage III to stage IV migration in 14 (17.7 %) patients due to identification of additional sites of distant metastasis, and within stage III upstaging in 24 (30.3 %) patients due to identification of additional regional lymphadenopathy. PET-CT led to a change in management plan in 14 (17.7 %) patients. CONCLUSION: PET-CT has a role in identifying additional sites of regional lymphadenopathy and distant metastasis to upstage the disease in a significant number of LABC patients in comparison to CI; this would help in accurate staging, selecting optimal treatment, and better prognostication of disease. PMID- 27220509 TI - Radiofrequency Ablation to Improve Survival After Conversion Chemotherapy for Colorectal Liver Metastases. AB - INTRODUCTION: Systemic chemotherapy is able to convert colorectal liver metastases (CRLM) that are initially unsuitable for local treatment into locally treatable disease. Surgical resection further improves survival in these patients. Our aim was to evaluate disease-free survival (DFS), overall survival, and morbidity for patients with CRLM treated with RFA following effective downstaging by chemotherapy, and to identify factors associated with recurrence and survival. MATERIALS AND METHODS: Included patients had liver-dominant CRLM initially unsuitable for local treatment but eligible for RFA or RFA with resection after downstaging by systemic chemotherapy. Chemotherapeutic regimens consisted predominantly of CapOx, with or without bevacizumab. Follow-up was conducted with PET-CT or thoraco-pelvic CT. RESULTS: Fifty-one patients had a total of 325 CRLM (median = 7). Following chemotherapy, 183 lesions were still visible on CT (median = 3). Twenty-six patients were treated with RFA combined with resection. During surgery, 309 CRLM were retrieved on intraoperative ultrasound (median = 5). Median survival was 49 months and was associated with extrahepatic disease at time of presentation and recurrences after treatment. Estimated cumulative survival at 1, 3 and 4 years was 90, 63 and 45 %, respectively. Median DFS was 6 months. Twelve patients remained free of recurrence after a mean follow-up of 32.6 months. CONCLUSION: RFA of CRLM after conversion chemotherapy provides potential local control and a good overall survival. To prevent undertreatment, the involvement of a multidisciplinary team in follow-up imaging and assessment of local treatment possibilities after palliative chemotherapy for liver-dominant CRLM should always be considered. PMID- 27220510 TI - Intraoperative Near-infrared Imaging for Parathyroid Gland Identification by Auto fluorescence: A Feasibility Study. AB - BACKGROUND: Parathyroid glands (PGs) can be particularly hard to distinguish from surrounding tissue and thus can be damaged or removed during thyroidectomy. Postoperative hypoparathyroidism is the most common complication after thyroidectomy. Very recently, it has been found that the parathyroid tissue shows near-infrared (NIR) auto-fluorescence which could be used for intraoperative detection, without any use of contrast agents. The work described here presents a histological validation ex vivo of the NIR imaging procedure and evaluates intraoperative PG detection by NIR auto-fluorescence using for the first time to our knowledge a commercially available clinical NIR imaging device. METHODS: Ex vivo study on resected operative specimens combined with a prospective in vivo study of consecutive patients who underwent total or partial thyroid, or parathyroid surgery at a comprehensive cancer center. During surgery, any tissue suspected to be a potential PG by the surgeon was imaged with the Fluobeam 800 ((r)) system. NIR imaging was compared to conventional histology (ex vivo) and/or visual identification by the surgeon (in vivo). RESULTS: We have validated NIR auto-fluorescence with an ex vivo study including 28 specimens. Sensitivity and specificity were 94.1 and 80 %, respectively. Intraoperative NIR imaging was performed in 35 patients and 81 parathyroids were identified. In 80/81 cases, the fluorescence signal was subjectively obvious on real-time visualization. We determined that PG fluorescence is 2.93 +/- 1.59 times greater than thyroid fluorescence in vivo. CONCLUSIONS: Real-time NIR imaging based on parathyroid auto-fluorescence is fast, safe, and non-invasive and shows very encouraging results, for intraoperative parathyroid identification. PMID- 27220511 TI - Synthesis and Characterization of Ln(III) Complexes and its Luminescence Properties. AB - Hexadentate ligand L and its Ln(3+) complexes EuLCl3 (1), TbLCl3 (2), SmLCl3 (3) are synthesised. All these complexes are well characterized for their photophysical properties such as luminescence lifetime decay(tau) and overall quantum yield(Phi). These complexes being water soluble, depicts their intense metal centred luminescence. Effect of pH on these complexes suggest that their emission intensities are stable in the pH range 4-9 and show their compatibility to function in the physiological pH. Graphical Abstract Normalized emisson spectra of complex 1, 2 and 3 (1x10(-5)M) in HEPES Buffer at pH 7.4 (lambdaexc=276nm). PMID- 27220512 TI - Synthesis, Spectral Characterization and Fluorescent Assessment of 1,3,5-Triaryl 2-pyrazoline Derivatives: Experimental and Theoretical Studies. AB - Two new pyrazoline derivatives, namely 5-(4-bromophenyl)-3-(5-chlorothiophen-2 yl)-1-phenyl-4,5-dihydro-1H-pyrazole (3) and 5-(4-bromophenyl)-3-(2,5 dichlorothiophen-3-yl)-1-phenyl-4,5-dihydro-1H-pyrazole (4) have been synthesized and characterized based on their spectral (IR, (1)H and (13)C NMR and MS) data and microanalysis. The fluorescence properties of 3 and 4 were studied by UV-Vis and emission spectroscopy. For compound 3, a fluorescence emission was observed in the blue region of the visible spectrum. The effect of different solvents on fluorescence was also investigated. Density Functional Theory calculations have also been performed to gain insight into geometric, electronic and spectroscopic properties of the pyrazoline derivatives. Both structures are analysed and compared in order to rationalize the different behaviour in 3 and 4. PMID- 27220513 TI - Corrigendum: 3D printed cellular solid outperforms traditional stochastic foam in long-term mechanical response. PMID- 27220514 TI - Parental smoking and cessation during pregnancy and the risk of childhood asthma. AB - BACKGROUND: To evaluate the association between maternal and paternal smoking during pregnancy, and asthma among offspring. METHODS: We conducted a hospital based birth retrospective observational birth cohort study in a University-based Obstetrics and Gynecology Department, Kuopio University Hospital, Finland. 39 306 women, delivering between 1989 and 2006, were linked to the national register for asthma reimbursement for their offspring (2641 asthmatics). Pregnancy factors were recorded during pregnancy. RESULTS: The risk of asthma was significantly elevated if both parents smoked (aOR 3.7; 95 % Cl 3.2-4.4) and it remained high in only paternal smoking families (aOR 2.9; 95 % Cl 2.5-3.3) as well as only maternal smoking families (aOR 1.7; 95 % Cl 1.2-2.2). Paternal cessation of smoking during pregnancy seemed to reduce the risk of asthma regardless of maternal smoking (aOR 0.3-0.4). CONCLUSIONS: Parental smoking, and especially paternal smoking, was significantly associated with the risk of asthma in offspring and paternal cessation of smoking during pregnancy was associated with a decreased risk of childhood asthma regardless of maternal smoking. The results indicate that both parents should be encouraged to quit smoking during pregnancy, since it is a relatively easy and cheap way to reduce the risk of asthma in offspring. TRIAL REGISTRATION: The study is registered in Kuopio University Hospital register (TUTKI): ID5302448. PMID- 27220515 TI - Enzymatic Pretreatment Coupled with the Addition of p-Hydroxyanisole Increased Levulinic Acid Production from Steam-Exploded Rice Straw Short Fiber. AB - Levulinic acid production, directly from lignocellulosic biomass, resulted in low yields due to the poor substrate accessibility and occurrence of side reactions. The effects of reaction conditions, enzymatic pretreatment, and inhibitor addition on the conversion of steam-exploded rice straw (SERS) short fiber to levulinic acid catalyzed by solid superacid were investigated systematically. The results indicated that the optimal reaction conditions were temperature, time, and solid superacid concentration combinations of 200 degrees C, 15 min, and 7.5 %. Enzymatic pretreatment improved the substrate accessibility to solid superacid catalyst, and p-hydroxyanisole inhibitor reduced the side reactions during reaction processes, which helped to increase levulinic acid yield. The levulinic acid yield reached 25.2 % under the optimal conditions, which was 61.5 % higher than that without enzymatic pretreatment and inhibitor addition. Therefore, enzymatic pretreatment coupled with the addition of p-hydroxyanisole increased levulinic acid production effectively, which contributed to the value-added utilization of lignocellulosic biomass. PMID- 27220517 TI - Impact of public reporting on the quality of hospital care in Germany: A controlled before-after analysis based on secondary data. AB - BACKGROUND: Since 2005 all German hospitals are obliged to publish structured quality reports (QR). International studies suggest that mandatory reporting motivates hospitals to improve the quality of care. We examine whether such an effect can be demonstrated for hospitals in Germany and whether differences exist between for-profit and non-profit hospitals. METHOD: The study was designed as a controlled pre-post intervention study, whereby the intervention consisted in the first notification of the obligation to publish values for clinical quality indicators (QI). The data basis consisted of those QI reported in identical manner from 2006 to 2012 and multivariable statistical analyses were performed. QI from the same clinical area but without reporting obligation in 2006, served as control group. RESULTS: Six QI were included in the intervention group and demonstrated significant quality improvement. The major part of improvements occurred immediately after the intervention. 31 QI were included in the control group, with about 60% showing improvement trends. In comparison, the biggest proportional improvements were registered for publicly reported QI. No significant differences in relation to profit orientation were found. CONCLUSION: Results indicate a positive effect of public reporting on hospital care, independent of a hospital's profit orientation. Improvements in the quality of care were registered for all observed QI over time, but public reporting stimulated an accelerated QI improvement. PMID- 27220518 TI - Evidence is missing to diagnose a public health tragedy. PMID- 27220516 TI - Chemical activation of a food deprivation signal extends lifespan. AB - Model organisms subject to dietary restriction (DR) generally live longer. Accompanying this lifespan extension are improvements in overall health, based on multiple metrics. This indicates that pharmacological treatments that mimic the effects of DR could improve health in humans. To find new chemical structures that extend lifespan, we screened 30 000 synthetic, diverse drug-like chemicals in Caenorhabditis elegans and identified several structurally related compounds that acted through DR mechanisms. The most potent of these NP1 impinges upon a food perception pathway by promoting glutamate signaling in the pharynx. This results in the overriding of a GPCR pathway involved in the perception of food and which normally acts to decrease glutamate signals. Our results describe the activation of a dietary restriction response through the pharmacological masking of a novel sensory pathway that signals the presence of food. This suggests that primary sensory pathways may represent novel targets for human pharmacology. PMID- 27220519 TI - Difficulties encountered by hospitalized Syrian refugees and their expectations from nurses. AB - BACKGROUND: Treating patients with care and respecting their cultural values are key factors necessary to enhance the quality of nursing care. AIM: The objective of this study was to explore and describe the difficulties experienced by hospitalized Syrian refugees and their expectations from nurses and hospital administration. METHODS: We used a descriptive qualitative research approach to engage 30 Syrian refugees undergoing treatment in internal medicine who met the study criteria. Data were collected using a descriptive questionnaire and a semi structured interview with open-ended interview questions. Interview transcripts were analysed using an inductive coding approach. Descriptive questions were analysed and presented via number and percentage. Other data were assessed using content analysis methods. RESULTS: Three major themes were developed following the analysis of the interviews. We determined that the refugees who participated in the study experienced difficulties in communicating, meeting their personal needs and correctly following treatment instructions. They also had certain expectations from the hospital administration and nurses, and they felt gratitude for both nurses and the nation of Turkey. CONCLUSIONS: The results of this study, shared with the executive administration of the hospital, may result in new policies which will help new Syrian refugee patients and patients with similar needs to have better experience related to patient care, communications and meeting personal needs. IMPLICATION FOR NURSING AND HEALTH POLICY: It is important that nurses and other healthcare provider consider the difficulties and expectations of refugees regarding healthcare services and include same in the development of provider training programmes. Development of public health welfare and employment law and policies help to lay the groundwork for successful integration of refugees in new cultures and countries. PMID- 27220520 TI - [The biomechanics of hyperextension injuries of the subaxial cervical spine]. AB - Hyperextension injuries of the subaxial cervical spine are potentially hazardous due to relevant destabilization. Depending on the clinical condition, neurologic or vascular damage may occur. Therefore an exact knowledge of the factors leading to destabilization is essential. In a biomechanical investigation, 10 fresh human cadaver cervical spine specimens were tested in a spine simulator. The tested segments were C4 to 7. In the first step, physiologic motion was investigated. Afterwards, the three steps of injury were dissection of the anterior longitudinal ligament, removal of the intervertebral disc/posterior longitudinal ligament, and dissection of the interspinous ligaments/ligamentum flavum. After each step, the mobility was determined. Regarding flexion and extension, an increase in motion of 8.36 % after the first step, 90.45 % after the second step, and 121.67 % after the last step was observed. Testing of lateral bending showed an increase of mobility of 7.88 %/27.48 %/33.23 %; axial rotation increased by 2.87 %/31.16 %/45.80 %. Isolated dissection of the anterior longitudinal ligament led to minor destabilization, whereas the intervertebral disc has to be seen as a major stabilizer of the cervical spine. Few finite-element studies showed comparable results. If a transfer to clinical use is undertaken, an isolated rupture of the anterior longitudinal ligament can be treated without surgical stabilization. PMID- 27220522 TI - The palatability of oral nutritional supplements: before, during, and after chemotherapy. AB - PURPOSE: Oral nutritional supplements (ONS) are commonly prescribed to malnourished patients to improve their nutritional status. Taste and smell changes in patients with cancer can affect the palatability of ONS. The present study investigated: (1) the palatability of six ONS in testicular cancer patients before, during the first two cycles, and after chemotherapy; (2) the relation between the palatability and taste and smell function; (3) the metallic taste of these ONS. METHODS: Twenty-one testicular cancer patients undergoing first-line cisplatin-based chemotherapy participated. Two milk-based (vanilla; strawberry), two juice-based (apple; orange), and two yoghurt-based (vanilla-lemon; peach orange) ONS were tested. A questionnaire was used to assess the palatability of ONS and to which extent the attribute 'metallic' was applicable. Taste and smell function were measured using taste strips and 'Sniffin' Sticks', respectively. RESULTS: The palatability of ONS was highly variable among patients. The milk based strawberry ONS was preferred most before, during, and after chemotherapy. The liking of the milk-based vanilla ONS tended to decrease over time (p = 0.053), whereas the liking of the other ONS remained stable. A higher smell threshold and a lower sour taste threshold were correlated to a decreased liking of the milk-based vanilla ONS. The two juice-based ONS tended to taste more metallic during than before chemotherapy. CONCLUSION: Health care professionals and patients should be aware that the palatability of ONS can change over time. Regular structured contact between health care professionals and patients regarding the choice of ONS seems warranted. PMID- 27220521 TI - Processing and transcriptome expansion at the mRNA 3' end in health and disease: finding the right end. AB - The human transcriptome is highly dynamic, with each cell type, tissue, and organ system expressing an ensemble of transcript isoforms that give rise to considerable diversity. Apart from alternative splicing affecting the "body" of the transcripts, extensive transcriptome diversification occurs at the 3' end. Transcripts differing at the 3' end can have profound physiological effects by encoding proteins with distinct functions or regulatory properties or by affecting the mRNA fate via the inclusion or exclusion of regulatory elements (such as miRNA or protein binding sites). Importantly, the dynamic regulation at the 3' end is associated with various (patho)physiological processes, including the immune regulation but also tumorigenesis. Here, we recapitulate the mechanisms of constitutive mRNA 3' end processing and review the current understanding of the dynamically regulated diversity at the transcriptome 3' end. We illustrate the medical importance by presenting examples that are associated with perturbations of this process and indicate resulting implications for molecular diagnostics as well as potentially arising novel therapeutic strategies. PMID- 27220524 TI - Site-directed introduction of disulfide groups on antibodies for highly sensitive immunosensors. AB - The interface between the sample and the transducer surface is critical to the performance of a biosensor. In this work, we compared different strategies for covalent self-assembly of antibodies onto bare gold substrates by introducing disulfide groups into the immunoglobulin structure, which acted as anchor molecules able to chemisorb spontaneously onto clean gold surfaces. The disulfide moieties were chemically introduced to the antibody via the primary amines, carboxylic acids, and carbohydrates present in its structure. The site-directed modification via the carbohydrate chains exhibited the best performance in terms of analyte response using a model system for the detection of the stroke marker neuron-specific enolase. SPR measurements clearly showed the potential for creating biologically active densely packed self-assembled monolayers (SAMs) in a one-step protocol compared to both mixed SAMs of alkanethiol compounds and commercial immobilization layers. The ability of the carbohydrate strategy to construct an electrochemical immunosensor was investigated using electrochemical impedance spectroscopy (EIS) and differential pulse voltammetry (DPV) transduction. Graphical Abstract Left: Functionalization strategies of bare gold substrates via direct bio-SAM using disulfide-containing antibody chemically modified via their primary amines (A), carbohydrates (B) and carboxylic acids (C). Right: Dependence of the peak height with NSE concentration at NSE21-CHO modified electrochemical immunosensor. Inset: Logarithmic calibration plot. PMID- 27220523 TI - Evaluation of quality of life using a tablet PC-based survey in cancer patients treated with radiotherapy: a multi-institutional prospective randomized crossover comparison of paper and tablet PC-based questionnaires (KROG 12-01). AB - PURPOSE: This study compared a tablet PC questionnaire with a paper method for reliability and patient preferences in the acquisition of patient-reported outcomes (PROs) for patients treated with radiotherapy. By comparing the two modes of PRO administration, we aimed to evaluate the adequacy of using tablet PC questionnaires in future clinical use. METHODS: Patients were randomized in a crossover study design using two different methods for PRO entry. A group of 89 patients answered a paper questionnaire followed by the tablet PC version, whereas 89 patients in another group completed the tablet PC questionnaire followed by the paper version. Surveys were performed four times per patient throughout the course of the radiotherapy. The Korean versions of the M.D. Anderson Symptom Inventory (MDASI-K) and the Brief Fatigue Inventory (BFI-K) were used. The primary endpoint of our current study was an assessment of patient preference for the survey method. The proportions of patients preferring each mode of questionnaire were evaluated. RESULTS: The proportion of patients who preferred the tablet PC version, paper form, or who had no preference was 52.2, 22.1, and 25.7 %, respectively. More than half of the patients preferred the tablet PC to the paper version in all four surveys. Age, gender, educational status, prior experience of using a tablet PC, and the order of paper to tablet PC administration did not impact patient preferences. Inter-class correlation coefficients (ICCs) between the modes were 0.92 for MDASI-K and 0.94 for BFI-K and ranged from 0.91 to 0.96 on both instruments during the four surveys. CONCLUSIONS: A tablet PC-based PRO is an acceptable and reliable method compared with paper-based data collection for Korean patients receiving radiotherapy. PMID- 27220526 TI - Certified reference materials for testing of the presence/absence of Staphylococcus aureus enterotoxin A (SEA) in cheese. AB - Staphylococcal enterotoxins (SEs) account for a substantial number of food poisoning outbreaks. European legislation (Commission Regulation 1441/2007) stipulates the reference procedure for SE analysis in milk and dairy products, which is based on extraction, dialysis concentration and immunochemical detection using one of two approved assays (VIDAS((r)) SET2, Ridascreen((r)) SET Total). However, certified reference materials (CRMs) are lacking to support laboratories in performing reliable detection of Staphylococcus aureus enterotoxin A (SEA) in relevant matrices at sub-nanogram per gram levels. The certification of a set of three reference materials (blank and two SEA-containing materials) for testing of the presence/absence of SEA in cheese is described. The reference procedure was applied in an intercomparison with 15 laboratories, and results were reported in a qualitative manner (presence or absence of SEA in the sample). No false negative or false-positive results were obtained. The certified values were stated as diagnostic specificity (blank material) or diagnostic sensitivity (SEA containing materials) and were 100 % in all cases. Stability studies demonstrated suitable material stability when stored cooled or frozen. An in-house study on the recovery of SEA in the cheese materials using a double-sandwich enzyme-linked immunosorbent assay (ELISA) revealed comparable recovery values of around 45 % at the two spiking levels and in both the SEA-containing CRMs as well as blank CRM freshly spiked prior to analysis. The values were also comparable over time and among different analysts. The materials provide valuable support to laboratories for method validation and method performance verification and will increase the reliability of measuring SEA in cheese. PMID- 27220527 TI - Short-term effects of high-intensity laser therapy, manual therapy, and Kinesio taping in patients with subacromial impingement syndrome. AB - Subacromial impingement syndrome (SAIS) is a major contributing factor of shoulder pain; and treatment approaches (Kinesio(r) taping [KT], Exercise [EX], manual therapy [MT], and high-intensity laser therapy [HILT]) have been developed to treat the pain. The key objective of this study was to compare the effects of KT, MT, and HILT on the pain, the range of motion (ROM), and the functioning in patients with SAIS. Seventy patients with SAIS were randomly divided into four groups based on the treatment(s) each group received [EX (n = 15), KT + EX (n = 20), MT + KT + EX (n = 16), and MT + KT + HILT + EX (n = 19)]. All the patients were assessed before and at the end of the treatment (15th day). The main outcome assessments included the evaluation of severity of pain by visual analogue scale (VAS) and shoulder flexion, abduction, and external rotation ROM measurements by a universal goniometry. Shoulder pain and disability index (SPADI) was used to measure pain and disability associated with shoulder pathology. Statistically significant differences were found in the treatment results of all parameters in MT + KT + EX and HILT + MT + KT + EX groups (p < 0.05). When the means of ROM and SPADI results of three groups were compared, statistically significant differences were found between all the groups (p < 0.05). These differences were significant especially between the groups MT + KT + EX and KT + EX (p < 0.05) and HILT + MT + KT + EX and KT + EX (p < 0.05). HILT and MT were found to be more effective in minimizing pain and disability and increasing ROM in patients with SAIS. Further studies with follow-up periods are required to determine the advantages of these treatments conclusively. PMID- 27220528 TI - Towards the intra-operative use of Raman spectroscopy in breast cancer-overcoming the effects of theatre lighting. AB - The ability to use Raman spectroscopy to assess tissue in the operative theatre setting could be advantageous for both patients and clinicians. In this study, a method of overcoming the deleterious effects of theatre lighting on the Raman spectra is demonstrated. The effectiveness of this technique is highlighted both within the theatre setting and using human lymph node tissue. The portable MiniRam II Raman spectroscopy device that incorporated a 785-nm laser was used in all experiments. This is an important step towards the use of Raman spectroscopy as a means of analysing sentinel lymph nodes in patients who have been newly diagnosed with breast cancer. PMID- 27220529 TI - Cognitive enhancement by transcranial laser stimulation and acute aerobic exercise. AB - This is the first randomized, controlled study comparing the cognitive effects of transcranial laser stimulation and acute aerobic exercise on the same cognitive tasks. We examined whether transcranial infrared laser stimulation of the prefrontal cortex, acute high-intensity aerobic exercise, or the combination may enhance performance in sustained attention and working memory tasks. Sixty healthy young adults were randomly assigned to one of the following four treatments: (1) low-level laser therapy (LLLT) with infrared laser to two forehead sites while seated (total 8 min, 1064 nm continuous wave, 250 mW/cm(2), 60 J/cm(2) per site of 13.6 cm(2)); (2) acute exercise (EX) of high-intensity (total 20 min, with 10-min treadmill running at 85-90 % VO2max); (3) combined treatment (LLLT + EX); or (4) sham control (CON). Participants were tested for prefrontal measures of sustained attention with the psychomotor vigilance task (PVT) and working memory with the delayed match-to-sample task (DMS) before and after the treatments. As compared to CON, both LLLT and EX reduced reaction time in the PVT [F(1.56) = 4.134, p = 0.01, eta (2) = 0.181] and increased the number of correct responses in the DMS [F(1.56) = 4.690, p = 0.005, eta (2) = 0.201], demonstrating a significant enhancing effect of LLLT and EX on cognitive performance. LLLT + EX effects were similar but showed no significantly greater improvement on PVT and DMS than LLLT or EX alone. The transcranial infrared laser stimulation and acute aerobic exercise treatments were similarly effective for cognitive enhancement, suggesting that they augment prefrontal cognitive functions similarly. PMID- 27220530 TI - Low-level infrared laser modulates muscle repair and chromosome stabilization genes in myoblasts. AB - Infrared laser therapy is used for skeletal muscle repair based on its biostimulative effect on satellite cells. However, shortening of telomere length limits regenerative potential in satellite cells, which occurs after each cell division cycle. Also, laser therapy could be more effective on non-physiologic tissues. This study evaluated low-level infrared laser exposure effects on mRNA expression from muscle injury repair and telomere stabilization genes in myoblasts in normal and stressful conditions. Laser fluences were those used in clinical protocols. C2C12 myoblast cultures were exposed to low-level infrared laser (10, 35, and 70 J/cm(2)) in standard or normal (10 %) and reduced (2 %) fetal bovine serum concentrations; total RNA was extracted for mRNA expression evaluation from muscle injury repair (MyoD and Pax7) and chromosome stabilization (TRF1 and TRF2) genes by real time quantitative polymerization chain reaction. Data show that low-level infrared laser increases the expression of MyoD and Pax7 in 10 J/cm(2) fluence, TRF1 expression in all fluences, and TRF2 expression in 70 J/cm(2) fluence in both 10 and 2 % fetal bovine serum. Low-level infrared laser increases mRNA expression from genes related to muscle repair and telomere stabilization in myoblasts in standard or normal and stressful conditions. PMID- 27220531 TI - Vessel wall perforation mechanism of the excimer laser-assisted non-occlusive anastomosis technique. AB - The excimer laser assisted non-occlusive anastomosis (ELANA) technique is used to make anastomoses on intracerebral arteries. This end-to-side anastomosis is created without temporary occlusion of the recipient artery using a 308-nm excimer laser with a ring-shaped multi-fiber catheter to punch an opening in the arterial wall. Over 500 patients have received an ELANA bypass. However, the vessel wall perforation mechanism of the laser catheter is not known exactly and not 100 % successful. In this study, we aimed to understand the mechanism of ELANA vessel perforation using specialized imaging techniques to ultimately improve its effectiveness. High-speed imaging, high-contrast imaging, and high sensitivity thermal imaging were used to study the laser wall perforation mechanism and reveal the mechanical and thermal effects involved. In vitro, rabbit arteries were exposed with the special designed laser catheter in a setup representative for the clinical setting, in which blood was replaced with a transparent UV absorbing liquid for visualization. We observed that laser vessel wall perforation was caused by explosive vapor bubbles tearing through the vessel wall, mostly within the first 20 of the total 200 pulses. Thermal effects were minimal. Unsymmetrical tension in the vessel wall inducing migration of the flap during laser exposure was observed in case of unsuccessful wall perforations. The laser wall perforation mechanism in the ELANA technique is primarily mechanical. Symmetric tension in the recipient vessel wall is essential and should be trained by neurosurgeons. PMID- 27220532 TI - Hierarchical self-assembly of di-, tri- and tetraphenylalanine peptides capped with two fluorenyl functionalities: from polymorphs to dendrites. AB - Homopeptides with 2, 3 and 4 phenylalanine (Phe) residues and capped with fluorenylmethoxycarbonyl and fluorenylmethyl esters at the N-terminus and C terminus, respectively, have been synthesized to examine their self-assembly capabilities. Depending on the conditions, the di- and triphenylalanine derivatives self-organize into a wide variety of stable polymorphic structures, which have been characterized: stacked braids, doughnut-like shapes, bundled arrays of nanotubes, corkscrew-like shapes and spherulitic microstructures. These highly aromatic Phe-based peptides also form incipient branched dendritic microstructures, even though they are highly unstable, making their manipulation very difficult. Conversely, the tetraphenylalanine derivative spontaneously self assembles into stable dendritic microarchitectures made of branches growing from nucleated primary frameworks. The fractal dimension of these microstructures is ~1.70, which provides evidence for self-similarity and two-dimensional diffusion controlled growth. DFT calculations at the M06L/6-31G(d) level have been carried out on model beta-sheets since this is the most elementary building block of Phe based peptide polymorphs. The results indicate that the antiparallel beta-sheet is more stable than the parallel one, with the difference between them growing with the number of Phe residues. Thus, the cooperative effects associated with the antiparallel disposition become more favorable when the number of Phe residues increases from 2 to 4, while those of the parallel disposition remained practically constant. PMID- 27220533 TI - Effect of Cardiac-Cycle-Synchronized Selective Vagal Stimulation on Heart Rate and Blood Pressure in Rats. AB - INTRODUCTION: Activation of the baroreflex system through the selective vagal nerve stimulation (sVNS) may become a treatment option for therapy-resistant hypertension, which is a frequently observed problem in the antihypertensive therapy. In previous studies, we used continuous sVNS to lower blood pressure (BP) without major side effects in a rat model. As continuous stimulation is energy consuming and sVNS could be implemented in an antihypertensive stimulator, it was the aim of this study to investigate the efficacy of pulsatile, cardiac cycle-synchronized sVNS (cssVNS) on the reduction of BP. METHODS: A multichannel cuff electrode was wrapped around the left vagal nerve in six male Wistar rats under Isoflurane anesthesia. BP was recorded in the left carotid artery. An electrocardiogram (ECG) was obtained via subcutaneous needle electrodes. The aortic depressor nerve fibers in the vagal nerve bundle were selectively stimulated with 18 parameter settings within a window of 15-30 ms after the R peak in the ECG. The stimulation paradigm included every heartbeat, every second heart beat, and every third heart beat. BP and heart rate were initially recorded over 10 min. RESULTS: Using cssVNS, BP could be significantly reduced over 30 min and maintained at this level. While the highest BP reduction was seen during cssVNS at every heartbeat with minimal bradycardia, less-yet significant-BP reduction was seen during cssVNS at every second or third heartbeat without causing detectable bradycardia. CONCLUSION: cssVNS can chronically reduce BP in rats avoiding measurable bradycardic side effects. This energy-efficient technique might allow the implementation of sVNS using an implantable device to permanently lower BP in patients. FUNDING: The study was funded by Bundesministerium fur Bildung und Forschung/German Federal Ministry of Education and Research among the call "Individualisierte Medizintechnik" under the grant number FKZ 13GW0120B. PMID- 27220534 TI - Negative pressure induces p120-catenin-dependent adherens junction disassembly in keratinocytes during wound healing. AB - A negative-pressure of 125mmHg (NP) has been widely used to treat chronic wounds in modern medicine. Keratinocytes under NP treatment have shown accelerated cell movement and decreased E-cadherin expression. However, the molecular mechanism of E-cadherin regulation under NP remains incompletely understood. Therefore, we investigated the E-cadherin regulation in keratinocytes (HaCaT cells) under NP. HaCaT cells were treated at ambient pressure (AP) and NP for 12h. Cell movement was measured by traditional and electric wound healing assays at the 2 different pressures. Mutants with overexpression of p120-catenin (p120(ctn)) were used to observe the effect of NP on p120(ctn) and E-cadherin expression during wound healing. Cell fractionation and immunoblotting data showed that NP increased Y228 phosphorylated p120(ctn) level and resulted in the translocation of p120(ctn) from the plasma membrane to cytoplasm. Immunofluorescence images revealed that NP decreased the co-localization of p120(ctn) and E-cadherin on the plasma membrane. Knockdown of p120(ctn) reduced E-cadherin expression and accelerated cell movement under AP. Overexpression of the Y228-phosphorylation-mimic p120(ctn) decreased E-cadherin membrane expression under both AP and NP. Phosphorylation deficient mutants conferred restored adherens junctions (AJs) under NP. The Src inhibitor blocked the phosphorylation of p120(ctn) and impeded cell migration under NP. In conclusion, Src-dependent phosphorylation of p120(ctn) can respond rapidly to NP and contribute to E-cadherin downregulation. The NP-induced disassembly of the AJ further accelerates wound healing. PMID- 27220535 TI - Transcatheter Leadless Cardiac Pacing in Renal Failure with Limited Venous Access. AB - Entirely leadless cardiac pacemakers that are delivered transvenously required the use of large-diameter delivery sheath and femoral venous approach. The complexity of external femoral and iliac venous anatomy may limit their implantation. We describe a hemodialysis patient without subclavian venous access and a conventional pacemaker with a failed right ventricular lead, who had difficult iliac venous anatomy that was also compressed by an external endovascular abdominal aortic stent. Successful leadless pacing using a MicraTM (Medtronic Inc., Minneapolis, MN, USA) was accomplished with a strong support wire, hydrophilic delivery sheath, and guided by venography. PMID- 27220537 TI - Heated Humidified High-Flow Nasal Cannula for Weaning from Continuous Positive Airway Pressure in Preterm Infants: A Randomized Controlled Trial. AB - BACKGROUND: Heated humidified high-flow nasal cannula (HHHFNC) therapy has been widely used in preterm infants. However, evidence to support its use as a continuous positive airway pressure (CPAP) weaning method is still controversial. OBJECTIVES: We aimed to compare time to wean directly off CPAP vs. weaning by using HHHFNC. METHODS: Infants with a gestational age (GA) of <32 weeks who met the predefined criteria for weaning off CPAP, i.e. with a CPAP of <=6 cm H2O and a fraction of inspired oxygen (FiO2) of <=0.3 for at least 24 h, were randomly assigned to wean by using HHHFNC or wean directly from CPAP. In the HHHFNC group, flow rate was reduced by 1 liter/min every 24 h to 2-3 liters/min depending on body weight (i.e. < or >=1,000 g), and then HHHFNC was discontinued. In the CPAP group, pressure was reduced by 1 cm H2O every 24 h until stable on CPAP 4 cm H2O and then discontinued. The primary outcome was the time it took to wean off the use of the CPAP or HHHFNC devices. RESULTS: One-hundred and one infants were enrolled, 51 in the HHHFNC and 50 in the CPAP group. Both groups had similar demographics and respiratory conditions before enrollment. There was no difference in time to successfully wean between the 2 groups [median (IQR): 11 (4 21) days in the HHHFNC group vs. 11 (4-29) days in the CPAP group; p = 0.12]. There were no differences in morbidities or related complications. Infants in the HHHFNC group had significantly less nasal trauma (20 vs. 42%; p = 0.01). CONCLUSIONS: In our study, the time to wean off CPAP using HHHFNC was not different from when weaning directly from CPAP. PMID- 27220536 TI - Neuroprotective effects of the immunomodulatory drug FK506 in a model of HIV1 gp120 neurotoxicity. AB - BACKGROUND: HIV-associated neurocognitive disorders (HAND) continue to be a common morbidity associated with chronic HIV infection. It has been shown that HIV proteins (e.g., gp120) released from infected microglial/macrophage cells can cause neuronal damage by triggering inflammation and oxidative stress, activating aberrant kinase pathways, and by disrupting mitochondrial function and biogenesis. Previous studies have shown that FK506, an immunophilin ligand that modulates inflammation and mitochondrial function and inhibits calcineurin, is capable of rescuing the neurodegenerative pathology in models of Parkinson's disease, Alzheimer's disease, and Huntington's disease. In this context, the main objective of this study was to evaluate if FK506 could rescue the neuronal degeneration and mitochondrial alterations in a transgenic (tg) animal model of HIV1-gp120 neurotoxicity. METHODS: GFAP-gp120 tg mice were treated with FK506 and analyzed for neuropathology, behavior, mitochondrial markers, and calcium flux by two-photon microscopy. RESULTS: We found that FK506 reduced the neuronal cell loss and neuro-inflammation in the gp120 tg mice. Moreover, while vehicle-treated gp120 tg mice displayed damaged mitochondria and increased neuro-inflammatory markers, FK506 rescued the morphological mitochondrial alterations and neuro inflammation while increasing levels of optic atrophy 1 and mitofusin 1. By two photon microscopy, calcium levels were not affected in the gp120 tg mice and no effects of FK506 were detected. However, at a functional level, FK506 ameliorated the gp120 tg mice hyperactivity in the open field. CONCLUSIONS: Together, these results suggest that FK506 might be potentially neuroprotective in patients with HAND by mitigating inflammation and mitochondrial alterations. PMID- 27220538 TI - Prognosis of T1 synovial sarcoma depends upon surgery by oncologic surgeons. AB - BACKGROUND: The prognosis of early stage synovial sarcomas is not well-defined since long-term follow-up is lacking in most studies. The optimal use of surgery, radiation, and chemotherapy needs to be clarified for this group. METHODS: From 1994 to 2012, 63 patients were treated for localized synovial sarcoma with T1 (<5 cm) tumors. There were 27 males and 36 females. Mean follow-up was 85 months (range 13-210). RESULTS: At 10 years, local recurrence-free survival was 82% (95% confidence interval [CI] 67-97%), and distant recurrence-free survival was 95% (95%CI 89-100%). Two patients developed metastases after 10 years. Local recurrence was associated with lack of re-excision and treatment by non-oncologic surgeons. Microscopic residual tumor was found in 43% of re-excised specimens. Metastasis was associated with local recurrence, tumor size >=3 cm, and treatment by non-oncologic surgeons. Radiation and chemotherapy treatment did not have a significant effect in this patient cohort. CONCLUSIONS: Early stage synovial sarcomas with T1 tumors have a relatively favorable prognosis but the potential for late relapse, and long-term follow-up beyond 10 years is recommended. Re excision of the tumor bed and definitive treatment by trained oncologic surgeons may decrease the risk of local recurrence and metastasis. J. Surg. Oncol. 2016;114:490-494. (c) 2016 Wiley Periodicals, Inc. PMID- 27220539 TI - Corrigendum: Identification of two novel Chlorotoxin derivatives CA4 and CTX-23 with chemotherapeutic and anti-angiogenic potential. PMID- 27220540 TI - Urine proteome analysis in heart failure with reduced ejection fraction complicated by chronic kidney disease: feasibility, and clinical and pathogenetic correlates. AB - AIMS: Urine proteome analysis (UPA) has already provided accurate discriminatory patterns of urinary peptides for renal disease, coronary artery disease, and asymptomatic LV diastolic dysfunction. UPA has now been used to characterize a discriminatory peptide biomarker pattern and establish a diagnostic classifier for heart failure patients with reduced ejection fraction (HFrEF) in the presence of chronic kidney disease (CKD). METHODS AND RESULTS: We analysed the urine proteome profiles obtained by capillary electrophoresis online coupled to micro TOF (time of flight) mass spectrometry of 126 individuals, 59 HFrEF patients and 67 controls matched for age, sex, and renal function. In total, 107 significant discriminatory peptides were identified and used to establish a support vector machine-based classifier that was successfully applied to a test set of 25 HFrEF patients and 33 controls, achieving 84% sensitivity and 91% specificity. The majority of sequenced peptides were fragments of collagen type I and III. CONCLUSION: UPA was able to identify a set of HFrEF-specific urinary peptide biomarkers on a background of CKD that were successfully utilized to establish a syndrome's classifier. PMID- 27220541 TI - Cutaneous angiosarcoma mimicking xanthoma: a challenging histopathologic diagnosis with important consequences. AB - Cutaneous angiosarcoma may show protean histopathologic features. Rare or uncommon variants include epithelioid, clear cell, granular cell, verrucous, pseudolymphomatous and signet-ring cell types. Perhaps the rarest type consists of cutaneous angiosarcoma with xanthomization of neoplastic cells. We report an extraordinary case with almost all neoplastic cells exhibiting a xanthomatous appearance that was studied both histopathologically and immunohistochemically. We discuss the histopathologic differential diagnosis of foamy cell angiosarcoma with other neoplasms that may show similar histopathology. PMID- 27220542 TI - Raising the Level of Nursing Involvement in the National Precision Medicine Initiative: An Example. AB - PURPOSE: The Precision Medicine Initiative (PMI) goal of ushering in a new and more effective era of health care that benefits all Americans requires two critical and interdependent components: a cohort assembly of 1 million or more Americans who reflect the diversity of the United States of America and an interdisciplinary workforce that includes nursing. The purpose of this article is to provide an example of nursing involvement in PM, specifically as related to gathering biospecimens (saliva) from vulnerable, understudied adolescents with disruptive behavior disorders and their family members. SOURCE(S): First, we provide a brief description of important concepts related to PM as well as current roles of nurses in PM. Then, we share lessons learned from our feasibility study aimed at increasing the diversity of our statewide cohort assembly that has provided biospecimens for the Indiana Biobank. CONCLUSION: Nurses can definitely contribute to biobanks in support of the PMI. This article is a call to action for nurses to take their rightful place in PM. PMID- 27220543 TI - Islet cell-associated autoantibodies in Ethiopians with diabetes mellitus. AB - BACKGROUND & AIMS: Our understanding of the role of autoimmunity in the pathogenesis of diabetes in African populations is limited. This study aims to evaluate the prevalence of 4 different islet cell-associated antibodies in Ethiopian patients with diabetes and non-diabetic controls. METHODS: A total of 187 subjects from a diabetic clinic at an Ethiopian hospital were evaluated in a cross-sectional study. Fifty-five patients had type 1 diabetes mellitus (T1DM), 86 had type 2 diabetes mellitus (T2DM) and 46 were non-diabetic controls. Islet cell-associated antibodies were measured using 4 different assays for antibodies against islet cells (ICA), glutamic acid decarboxylase (GADA), insulin (IAA) and the protein tyrosine phosphatase-like IA-2 (IA-2A). RESULTS: Comparing the antibody positivity in subjects with T1DM versus T2DM, the results were as follows: 29% versus 3.5% for GADA; 21% versus 2.7% for ICA; 27% versus 16% for IAA. In the control group, the only positive result was for IAA at 2%. IA-2A was absent in all groups. The combi-assay for GADA and IA-2A detected all GADA positive subjects. T2DM patients who were GADA positive had lower BMI, lower C peptide levels and all of them were on insulin therapy. CONCLUSIONS: Compared to Caucasians, Ethiopians with T1DM have less prevalence of islet cell-associated antibodies, but the rates are higher than in T2DM. GADA is present in Ethiopians, whereas IA-2A seems to be absent. GADA positivity in T2DM correlates with clinical features of T1DM, indicating the existence in Ethiopia of the subgroup, latent autoimmune diabetes in adults. PMID- 27220544 TI - Clinical effects of liraglutide are possibly influenced by hypertriglyceridemia and remaining pancreatic beta-cell function in subjects with type 2 diabetes mellitus. AB - We searched for factors influencing the clinical effects of GLP-1 analogue liraglutide in subjects with type 2 diabetes. Multivariate analyses showed that hypertriglyceridemia and baseline HbA1c levels were independent predictors for the efficacy of liraglutide and that CPR index was an independent predictor for the durability of liraglutide. PMID- 27220545 TI - See what we say: using concept mapping to visualize Latino immigrant's strategies for health interventions. AB - OBJECTIVES: Researchers need specific tools to engage community members in health intervention development to ensure that efforts are contextually appropriate for immigrant populations. The purpose of the study was to generate and prioritize strategies to address obesity, stress and coping, and healthcare navigation that are contextually appropriate and applicable to the Latino immigrant community in Cincinnati, Ohio, and then use the results to develop specific interventions to improve Latino health in our area. METHODS: A community-academic research team used concept mapping methodology with over 200 Latino immigrants and Latino serving providers. A community intervention planning session was held to share the final concept maps and vote on strategies. RESULTS: The concept maps and results from the intervention planning session emphasized a community lay health worker model to connect the Latino immigrant community with resources to address obesity, stress and coping, and healthcare navigation. CONCLUSIONS: Concept maps allowed for the visualization of health intervention strategies prioritized by the larger Latino immigrant community. Concept maps revealed the appropriate content for health interventions as well as the process community members preferred for intervention delivery. PMID- 27220546 TI - Stunting and weight statuses of adolescents differ between public and private schools in urban Gambia. AB - OBJECTIVES: This study assessed the disparity in nutritional status of adolescents between public and private schools in urban Gambia. METHODS: This is a school-based cross-sectional study in six private and six public upper basic schools in urban Gambia. This study recruited 491 students from public and 469 students from private schools (13-15 years of age). RESULTS: The prevalence of stunting (WHO height-for-age Z < -2SD) was 13.4 % for public school students and 4.5 % for private schools. After adjustment for children's sex, age, and family socioeconomic status, the differences in prevalence of stunting and underweight were significant between public and private schools. Private school students are more likely to be overweight/obese (WHO BMI-for-age Z > +1SD) (OR = 2.85, 95 % CI 1.55-5.22), but less likely to be thin (BMI-for-age Z < -2SD) (OR = 0.61 [0.39 0.96]), compared to public school students. Children from lower income families had lower odds for overweight/obese than normal weight, compared to those from higher income families (OR = 0.34 [0.15-0.76]). CONCLUSIONS: Public and private schools in urban regions of the Gambia may face different nutritional challenges due to differences in school environment and resources. PMID- 27220547 TI - Absolute and relative educational inequalities in depression in Europe. AB - OBJECTIVES: To investigate (1) the size of absolute and relative educational inequalities in depression, (2) their variation between European countries, and (3) their relationship with underlying prevalence rates. METHODS: Analyses are based on the European Social Survey, rounds three and six (N = 57,419). Depression is measured using the shortened Centre of Epidemiologic Studies Depression Scale. Education is coded by use of the International Standard Classification of Education. Country-specific logistic regressions are applied. RESULTS: Results point to an elevated risk of depressive symptoms among the lower educated. The cross-national patterns differ between absolute and relative measurements. For men, large relative inequalities are found for countries including Denmark and Sweden, but are accompanied by small absolute inequalities. For women, large relative and absolute inequalities are found in Belgium, Bulgaria, and Hungary. Results point to an empirical association between inequalities and the underlying prevalence rates. However, the strength of the association is only moderate. DISCUSSIONS: This research stresses the importance of including both measurements for comparative research and suggests the inclusion of the level of population health in research into inequalities in health. PMID- 27220548 TI - Vestibulo-ocular reflex function in children with high-functioning autism spectrum disorders. AB - Sensorimotor processing alterations are a growing focus in the assessment and treatment of Autism Spectrum Disorders (ASD). The rotational vestibulo-ocular reflex (rVOR), which functions to maintain stable vision during head movements, is a sensorimotor system that may be useful in understanding such alterations and their underlying neurobiology. In this study, we assessed post-rotary nystagmus elicited by continuous whole body rotation among children with high-functioning ASD and typically developing children. Children with ASD exhibited increased rVOR gain, the ratio of eye velocity to head velocity, indicating a possible lack of cerebellar inhibitory input to brainstem vestibular nuclei in this population. The ASD group also showed less regular or periodic horizontal eye movements as indexed by greater variance accounted for by multiple higher frequency bandwidths as well as greater entropy scores compared to typically developing children. The decreased regularity or dysrhythmia in the temporal structure of nystagmus beats in children with ASD may be due to alterations in cerebellum and brainstem circuitry. These findings could potentially serve as a model to better understand the functional effects of differences in these brain structures in ASD. Autism Res 2017, 10: 251-266. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 27220551 TI - Progressive reduction of circulating B lymphocytes in patients with X-linked lymphoproliferative disease (XLP). PMID- 27220550 TI - Tm7sf2 may participate in the healing of burn wounds. AB - The transmembrane 7 superfamily member 2 (Tm7sf2) gene been reported to be involved in the reduced cholesterol levels of patients with large burn areas. To investigate the importance of Tm7sf2 in the burn wound healing process, a total of 10 Sprague-Dawley rats underwent electrical burns. Blood serum was collected for the culture of HaCaT human keratinocyte cells. Tm7sf2 small interfering RNAs (siRNAs) were prepared and transfected into the normal- and burn serum-cultured HaCaT cells. Monocyte-endothelial cellular adhesion ability and cell proliferation, as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay, and the levels of autophagy proteins Beclin1 and LC3-II, which were detected by western blot assay and real time-quantitative polymerase chain reaction, and it was identified that Tm7sf2 siRNAs were successfully transfected. Cell proliferation was reduced and monocyte-endothelial cell adhesion increased in the burn serum group compared with the normal serum group (P<0.05). Additionally, the expression levels of Beclin1 and LC3-II were increased, and the addition of siTm7sf2 had a similar effect as the burn serum. Thus, Tm7sf2 may take part in the burn wound healing process by interacting with LC3-II and Beclin1, and targeting Tm7sf2 may have therapeutic benefits. PMID- 27220549 TI - Differential changes in Neuregulin-1 signaling in major brain regions in a lipopolysaccharide-induced neuroinflammation mouse model. AB - Neuregulin 1 (Nrg1) is involved in multiple biological processes in the nervous system. The present study investigated changes in Nrg1 signaling in the major brain regions of mice subjected to lipopolysaccharide (LPS)-induced neuroinflammation. At 24 h post-intraperitoneal injection of LPS, mouse brain tissues, including tissues from the cortex, striatum, hippocampus and hypothalamus, were collected. Reverse transcription-polymerase chain reaction was used to determine the expression of Nrg1 and its receptors, Neu and ErbB4, at the mRNA level. Western blotting was performed to determine the levels of these proteins and the protein levels of phosphorylated extracellular signal-regulated kinases (Erk)1/2 and Akt1. Immunohistochemical staining was utilized to detect the levels of pNeu and pErbB4 in these regions. LPS successfully induced sites of neuroinflammation in these regions, in which changes in Nrg1, Neu and ErbB4 at the mRNA and protein levels were identified compared with controls. LPS induced a reduction in pNeu and pErbB4 in the striatum and hypothalamus, although marginally increased pErbB4 levels were found in the hippocampus. LPS increased the overall phosphorylation of Src but this effect was reduced in the hypothalamus. Moreover, increased phosphorylation of Akt1 was found in the striatum and hippocampus. These data suggest diverse roles for Nrg1 signaling in these regions during the process of neuroinflammation. PMID- 27220552 TI - Absence of haemoparasite infection in the fossorial amphisbaenian Trogonophis wiegmanni. AB - Blood parasites such as haemogregarines and haemosporidians have been identified in almost all groups of vertebrates. However, very little is known about biodiversity of these parasites and their effects on some major groups of reptiles such as amphisbaenians, a distinctive group with many morphological and ecological adaptations to fossorial life. Conditions of the fossorial environment might also affect host-parasite relationships. We investigated the presence and the potential prevalence of three genera of haemoparasitic aplicomplexan blood parasites (Hepatozoon, Plasmodium and Haemoproteus) in the amphisbaenian Trogonophis wiegmanni, a fossorial worm lizard species from North West Africa. Blood parasite infection was not detected in T. wiegmanni, both in visual surveys of blood smears and using molecular methods to detect DNA of such parasites in the blood of the potential amphisbaenian hosts. We discuss how conditions of the fossorial environment might affect blood parasitaemias in amphisbaenians as well as in other fossorial reptiles. PMID- 27220553 TI - Doped penta-graphene and hydrogenation of its related structures: a structural and electronic DFT-D study. AB - The structure of penta-graphene (penta-C), an irregular pentagonal two dimensional (2D) structure, has been predicted recently. In this communication we carried out a dispersion-corrected density functional theory (DFT-D) study of the penta-C doped with Si, Ge and Sn atoms and its related hydrogenated penta-C structures (H-penta-C-X). We predict various new structures as thermally stable based on Born-Oppenheimer molecular dynamics (BOMD) calculations. Moreover, their dynamical stability is attested by phonon dispersions spectra. In general, we found that the bandgap value of doped structures reduces, while H-penta-C-X show large bandgap values. This feature can be exploited for potential uses of hydrogenated doped-penta-C structures as dielectric layers in electronic devices. PMID- 27220554 TI - Multicolour Multilevel STED nanoscopy of Actin/Spectrin Organization at Synapses. AB - Superresolution fluorescence microscopy of multiple fluorophores still requires development. Here we present simultaneous three-colour stimulated emission depletion (STED) nanoscopy relying on a single STED beam at 620 nm. Toggling the STED beam between two or more power levels ("multilevelSTED") optimizes resolution and contrast in all colour channels, which are intrinsically co aligned and well separated. Three-colour recording is demonstrated by imaging the nanoscale cytoskeletal organization in cultured hippocampal neurons. The down to ~35 nm resolution identified periodic actin/betaII spectrin lattices along dendrites and spines; however, at presynaptic and postsynaptic sites, these patterns were found to be absent. Both our multicolour scheme and the 620 nm STED line should be attractive for routine STED microscopy applications. PMID- 27220555 TI - Evolutionary melting pots: a biodiversity hotspot shaped by ring diversifications around the Black Sea in the Eastern tree frog (Hyla orientalis). AB - Hotspots of intraspecific genetic diversity, which are of primary importance for the conservation of species, have been associated with glacial refugia, that is areas where species survived the Quaternary climatic oscillations. However, the proximate mechanisms generating these hotspots remain an open issue. Hotspots may reflect the long-term persistence of large refugial populations; alternatively, they may result from allopatric differentiation between small and isolated populations, that later admixed. Here, we test these two scenarios in a widely distributed species of tree frog, Hyla orientalis, which inhabits Asia Minor and southeastern Europe. We apply a fine-scale phylogeographic survey, combining fast evolving mitochondrial and nuclear markers, with a dense sampling throughout the range, as well as ecological niche modelling, to understand what shaped the genetic variation of this species. We documented an important diversity centre around the Black Sea, composed of multiple allopatric and/or parapatric diversifications, likely driven by a combination of Pleistocene climatic fluctuations and complex regional topography. Remarkably, this diversification forms a ring around the Black Sea, from the Caucasus through Anatolia and eastern Europe, with terminal forms coming into contact and partially admixing in Crimea. Our results support the view that glacial refugia generate rather than host genetic diversity and can also function as evolutionary melting pots of biodiversity. Moreover, we report a new case of ring diversification, triggered by a large, yet cohesive dispersal barrier, a very rare situation in nature. Finally, we emphasize the Black Sea region as an important centre of intraspecific diversity in the Palearctic with implications for conservation. PMID- 27220556 TI - Prevalence, Motivations, and Social, Mental Health and Health Consequences of Cyberbullying Among School-Aged Children and Youth: Protocol of a Longitudinal and Multi-Perspective Mixed Method Study. AB - BACKGROUND: While the online environment may promote important developmental and social benefits, it also enables the serious and rapidly growing issue of cyberbullying. Cyberbullying constitutes an increasing public health problem - victimized children and youth experience a range of health and mental health concerns, including emotional and psychosomatic problems, maladaptive behaviors, and increased suicidality. Perpetrators demonstrate a lack of empathy, and may also struggle with health and mental health issues. OBJECTIVE: This paper describes the protocols applied in a longitudinal and multi-perspective mixed methods study with five objectives: (1) to explore children/youth's experiences, and children/youth's, parents', and teachers' conceptions, definitions, and understanding of cyberbullying; (2) to explore how children/youth view the underlying motivations for cyberbullying; (3) to document the shifting prevalence rates of cyberbullying victimization, witnessing, and perpetration; (4) to identify risk and protective factors for cyberbullying involvement; and (5) to explore social, mental health, and health consequences of cyberbullying. METHODS: Quantitative survey data were collected over three years (2012-2014) from a stratified random baseline sample of fourth (n=160), seventh (n=243), and tenth (n=267) grade children/youth, their parents (n=246), and their teachers (n=103). Quantitative data were collected from students and teachers during in-person school visits, and from parents via mail-in surveys. Student, parent, and teacher surveys included questions regarding: student experiences with bullying/cyberbullying; student health, mental health, and social and behavioral issues; socio-demographics; and information and communication technology use. In depth semi-structured qualitative interviews were conducted twice with a sub sample of students (n=57), purposively selected based on socio-demographics and cyberbullying experience, twice with their parents (n=50), and once with their teachers (n=30). RESULTS: Data collection for this study is complete. Planned analyses include transition probabilities and repeated measures analyses to determine involvement in cyberbullying. Repeated measures analyses, including between-subject factors (eg, socio-demographics), will be utilized to determine factors that protect or increase risk of involvement in cyberbullying. Qualitative analysis utilizing grounded theory is planned, to permit rich understanding of participant experiences and perspectives. Results will be reported in 2016 and 2017. CONCLUSIONS: This study will offer insight into the contemporary phenomenon of cyberbullying while also informing interventions to curb cyberbullying and address its pervasive social, mental health, and health consequences. Knowledge mobilization strategies and implications for research and practice are discussed. PMID- 27220557 TI - Dietary alpha-linolenic acid-rich flaxseed oil prevents against alcoholic hepatic steatosis via ameliorating lipid homeostasis at adipose tissue-liver axis in mice. AB - Low levels of n-3 polyunsaturated fatty acids (PUFAs) in serum and liver tissue biopsies are the common characteristics in patients with alcoholic liver disease. The alpha-linolenic acid (ALA) is a plant-derived n-3 PUFA and is rich in flaxseed oil. However, the impact of ALA on alcoholic fatty liver is largely unknown. In this study, we assessed the potential protective effects of ALA-rich flaxseed oil (FO) on ethanol-induced hepatic steatosis and observed that dietary FO supplementation effectively attenuated the ethanol-induced hepatic lipid accumulation in mice. Ethanol exposure stimulated adipose lipolysis but reduced fatty acid/lipid uptake, which were normalized by FO. Our investigations into the corresponding mechanisms demonstrated that the ameliorating effect of FO might be associated with the lower endoplasmic reticulum stress and normalized lipid metabolism in adipose tissue. In the liver, alcohol exposure stimulated hepatic fatty acid uptake and triglyceride synthesis, which were attenuated by FO. Additionally, dietary FO upregulated plasma adiponectin concentration, hepatic adiponectin receptor 2 expression, and the activation of hepatic adenosine monophosphate-activated protein kinase. Collectively, dietary FO protects against alcoholic hepatic steatosis by improving lipid homeostasis at the adipose tissue liver axis, suggesting that dietary ALA-rich flaxseed oil might be a promising approach for prevention of alcoholic fatty liver. PMID- 27220558 TI - Synthesis and performance evaluation of Al/Fe oxide coated diatomaceous earth in groundwater defluoridation: Towards fluorosis mitigation. AB - The quest to reduce fluoride in groundwater to WHO acceptable limit of 1.5 mg/L to prevent diseases such as teeth mottling and skeletal fluorosis was the motivation for this study. Al/Fe oxide-modified diatomaceous earth was prepared and its defluoridation potential evaluated by batch method. The sorbent with pHpzc 6.0 +/- 0.2 is very reactive. The maximum 82.3% fluoride removal attained in 50 min using a dosage of 0.3 g/100 mL in 10 mg/L fluoride was almost attained within 5 min contact time; 81.3% being the percent fluoride removal at 5 min contact time. The sorbent has a usage advantage of not requiring solution pH adjustment before it can exhibit its fluoride removal potential. A substantial amount of fluoride (93.1%) was removed from solution when a sorbent dosage of 0.6 g/100 mL was contacted with 10 mg/L fluoride solution for 50 min at a mixing rate of 200 rpm. The optimum adsorption capacity of the adsorbent was 7.633 mg/g using a solution containing initially 100 mg/L fluoride. The equilibrium pH of the suspensions ranged between 6.77 and 8.26 for 10 and 100 mg/L fluoride solutions respectively. Contacting the sorbent at a dosage of 0.6 g/100 mL with field water containing 5.53 mg/L at 200 rpm for 50 min reduced the fluoride content to 0.928 mg/L-a value below the upper limit of WHO guideline of 1.5 mg/L fluoride in drinking water. The sorption data fitted to both Langmuir and Freundlich isotherms but better with the former. The sorption data obeyed only the pseudo second-order kinetic, which implies that fluoride was chemisorbed. PMID- 27220559 TI - Oculocardiac Reflex during Strabismus Surgery: Experience from a Tertiary Hospital. AB - PURPOSE: To evaluate the incidence of the oculocardiac reflex (OCR) and its associated risk factors during strabismus surgery at a tertiary referral center. METHODS: Over a 2-year period, all strabismus surgery candidates were enrolled in the study. OCR was defined as heart rate reduction >=15% after traction on extraocular muscle(s). The rate of OCR was determined and possible associations were explored. Variables included age, gender, type of strabismus, nature of surgery (weakening versus strengthening), specified extraocular muscle, times of surgery, and the sequence of operated muscles (eg, first, second, or third operated muscle). We avoided the use of atropine pre- and postoperatively. RESULTS: Seventy-six patients with mean age of 15+/-12 years were enrolled; 51.3% of subjects were male. OCR occurred in 65 out of 76 (85.5%) patients and with 84 out of 173 (48.6%) operated muscles. OCR was more common in subjects less than 20 years of age; however, it showed a decreasing trend afterwards. OCR was more frequent during operation on cyclovertical muscles than horizontal recti (P=0.02). Moreover, during procedures on horizontal rectus muscles, OCR was more common if baseline heart rate was more than 61 (P=0.008). OCR was not correlated with gender, type of strabismus, nature of surgery, times of the surgery, or the sequence of operated extraocular muscles. CONCLUSIONS: The great majority of patients undergoing strabismus surgery, especially younger subjects, those undergoing operation on cyclovertical muscles, and subjects with higher baseline heart rate, experience OCR during strabismus surgery. During surgery on cyclovertical muscles, the amount of pull is usually more due to more difficult exposure. PMID- 27220560 TI - Non-Imidazole Histamine H3 Ligands. Part VI. Synthesis and Preliminary Pharmacological Investigation of Thiazole-Type Histamine H3-Receptor Antagonists with Lacking a Nitrogen Nucleus in the Side Chain. AB - BACKGROUND: Antagonists to the H3 receptor are considered to be potential drugs for the treatment of Alzheimer's disease, attention deficit-hyperactive disorder, memory and learning deficits, and epilepsy. The initial development of potent H3 receptor antagonists focused on extensive modification of the natural ligand histamine. However, it has appeared that imidazole-containing ligands are associated with inhibition of cytochrome P450 enzymes, caused by imidazole nitrogen complexation to heme iron in the active site of the enzyme. For these reasons, the development of potent non-imidazole H3receptor antagonists was eagerly awaited. OBJECTIVE: Previously, we reported the synthesis and pharmacological in vitro characterization of series of potent histamine H3receptor non-imidazole antagonists belonging to the class of substituted 2 thiazol-4-n-propylpiperazines. A lead compound 1 of this family was a derivative carrying the ethylaminomethylpropyl chain. METHODS: With the aim of increasing lipophilicity, that will help the ligands to cross the blood-brain barrier, we synthesized a series of new 2-thiazol-4-n-propylpiperazines where the ethylaminomethylpropyl moiety was replaced by a p-substituted-, an unsubstituted benzene ring, and omega-phenylalkyl substituent at positions 4 and 5 of thiazole ring, respectively. All compounds were tested for H3 antagonistic effects in vitro using the electrically contracting guinea pig jejunum. RESULTS: The most active compounds of presented series 3d, 3e, and 3j showed lower affinity than the lead compound 1 and additionally, derivatives 3d and 3j possessed weak, competitive H1 antagonistic activity. This is in contrast to the lead compound 1 that has no affinity at H1 receptor. CONCLUSION: We can conclude that a side chain in the 2-thiazol-4-n-propylpiperazine scaffold should contain a basic center and should be present at a favorable position 5 of thiazole ring. PMID- 27220561 TI - Benzoflavonoids Structure Hinders Human Colon Cancer Clonogenicity. AB - BACKGROUND: Since flavonoids fused by benzene have been known for their potent chemopreventive effects, in this study, we examined the relationship between the structures and activities of benzoflavones, benzoflavanones, benzochalcones, and benzochalcone derivatives bearing the pyrazole moiety against human colon cancer cells. METHODS: We investigated the effect of 34 benzoflavonoids on the inhibition of colon cancer cells based on the clonogenicity. The biological activity values used for the quantitative structure-activity relationship (QSAR) calculations were obtained from the cell growth inhibition on the basis of clonogenicity. 3D-QSAR calculations were performed using comparative molecular field analyses (CoMFA) and comparative molecular similarity index analyses (CoMSIA). RESULTS: Of several CoMFA and CoMSIA models, the best models showing the highest cross validated correlation coefficient were selected and validated. The cell growth inhibition values were calculated using the above models. The structural conditions to show good cell growth inhibitory effects on human colon cancer cells were analyzed by CoMFA and CoMSIA contour maps. The contribution of steric fields remarkably decreased without any change in the contribution of the electrostatic field, which means that electrostatic contribution is more crucial than the steric contribution in the modification of benzoflavonoids. Furthermore, the increase in the hydrogen bond donor contribution was approximately proportional to the decrease in steric field contribution. CONCLUSION: This study demonstrated that benzoflavonoids structure hinders colon cancer clonogenicity. Most of the benzoflavonoids structures comprised a C-3 linkage between the naphthalene and phenyl moieties, which contained diverse functional moieties such as oxygen-fused rings, double bonds, pyrazole rings, and sulfur constituents, and were able to exhibit great potential in diverse anticancer effects. Also, the positions of the hydroxyl group close to the naphthalene and phenyl rings were crucial for activity against colon cancer. The structural conditions obtained here may help us design potent benzoflavonoids against colon cancer cells and predict their activities. PMID- 27220562 TI - Structural characterization and immunomodulatory activity of Grifola frondosa polysaccharide via toll-like receptor 4-mitogen-activated protein kinases-nuclear factor kappaB pathways. AB - We isolated a neutral polysaccharide from the fruiting body of a mushroom Grifola frondosa (GFP-A). The aim of this study was to characterize a neutral alpha-d polysaccharide derived from G. frondosa and evaluate its immunomodulatory effect on toll-like receptor 4, mitogen-activated protein kinases and nuclear factor kappaB pathways of protein expression in macrophages. The structural features of GFP-A were characterized by physicochemical and instrumental analyses. Its molecular weight was found to be 8.48 * 10(2) kDa. The main chain of GFP-A consisted of (1 -> 4)-linked and (1 -> 6)-linked alpha-d-glucopyranosyl, and (1 > 3,6)-linked alpha-d-mannopyranosyl residues, which branched at C-3. The branches consisted of (1 -> 6)-linked alpha-d-galactopyranosyl and t-l rhamnopyranosyl residues. An in vitro immunomodulatory assay for pro-inflammatory cytokines (interleukin-1beta, interleukin-2, tumor necrosis factor alpha, etc.) using the macrophage cell line, RAW 264.7, revealed that GFP-A exhibited significant immunomodulatory activity by stimulating the toll-like receptor 4, mitogen-activated protein kinases to nuclear factor kappaB/pathway. PMID- 27220563 TI - Surfactant-assisted Nanocasting Route for Synthesis of Highly Ordered Mesoporous Graphitic Carbon and Its Application in CO2 Adsorption. AB - Highly ordered mesoporous graphitic carbon was synthesized from a simple surfactant-assisted nanocasting route, in which ordered mesoporous silica SBA-15 maintaining its triblock copolymer surfactant was used as a hard template and natural soybean oil (SBO) as a carbon precursor. The hydrophobic domain of the surfactant assisted SBO in infiltration into the template's mesoporous channels. After the silica template was carbonized and removed, a higher yield of highly ordered graphitic mesoporous carbon with rod-like morphology was obtained. Because of the improved structural ordering, the mesoporous carbon after amine modification could adsorb more CO2 compared with the amine-functionalized carbon prepared without the assistance of surfactant. PMID- 27220565 TI - Reaction Coordinate-Free Approach to Recovering Kinetics from Potential-Scaled Simulations: Application of Kramers' Rate Theory. AB - Enhanced sampling techniques are used to increase the frequency of "rare events" during computer simulations of complex molecules. Although methods exist that allow accurate thermodynamics to be recovered from enhanced simulations, recovering kinetics proves to be more challenging. Here we present an extrapolation approach that allows reliable kinetics to be recovered from potential-scaled MD simulations. The approach, based on Kramers' rate theory, is simple and computationally efficient, and allows kinetics to be recovered without defining reaction coordinates. To test our approach, we use it to determine the kinetics of barrier crossing between two metastable states on the 2D-Muller potential and the C7eq to alphaR transition in alanine dipeptide. The mean first passage time estimates obtained are in excellent agreement with reference values obtained from direct simulations on the unscaled potentials performed over times that are orders of magnitude longer. PMID- 27220564 TI - Streptomyces chitinivorans sp. nov., a chitinolytic strain isolated from estuarine lake sediment. AB - A novel actinobacterial strain RC1832T was isolated from the sediment of a fish dumping yard at Balugaon near Chilika Lake. The strain is halotolerant (15 % NaCl, w/v), alkali-tolerant (pH 7-10) and hydrolyzes chitin, starch, gelatin, cellulose, carboxymethyl cellulose, Tween 80, tributyrin, lecithin and casein. Apart from showing typical genus-specific morphological and chemotaxonomic features, the comparision and analysis of the near complete 16S rRNA gene sequence clearly revealed that the strain RC1832T represented a member of the genus Streptomyces. It exhibited the highest sequence similarities with the strains Streptomyces fenghuangensis GIMN4.003T (99.78 %), Streptomyces nanhaiensis DSM 41926T (99.07 %), Streptomyces radiopugnans R97T(98.71 %), Streptomyces atacamensis DSM 42065T (98.65 %) and Streptomyces barkulensis DSM 42082T (98.25 %). The DNA-DNA relatedness of strain RC 1832T with the closest phylogenetic neighbours S. fenghuangensis GIMN4.003T and S. nanhaiensis DSM 41926T were 20+/-2 % and 21+/-2 %, respectively. Thus, based on a range of phenotypic and genotypic properties, strain RC1832T was suggested to represent a novel species of the genus Streptomyces for which the name Streptomyces chitinivorans sp. nov. is proposed. The type strain is RC1832T (=JCM 30611=KCTC 29696). PMID- 27220569 TI - [Follow the evidences to further optimize coronary intervention]. PMID- 27220566 TI - Analgesic opioid use in a health-insured epilepsy population during 2012: Response to Derakhshan. PMID- 27220570 TI - [Deepening the idea of systems biology and promoting the development of pan vascular medical science]. PMID- 27220572 TI - [Complications related to transvenous percutaneous left atrial appendage occlusion and prevention methods]. PMID- 27220571 TI - [Ablation of atrial fibrillation in patients with heart failure]. PMID- 27220573 TI - [Chinese guideline for percutaneous coronary intervention(2016)]. PMID- 27220574 TI - [A multicenter prospective controlled study of catheter ablation for patients with persistent atrial fibrillation using domestic 3D cardiac electrophysiological mapping system]. AB - OBJECTIVE: To verify the safety and efficacy of the domestic 3D cardiac electrophysiological mapping system for catheter ablation of persistent atrial fibrillation (AF). METHODS: From December 2011 to April 2014, 255 patients (184 male) with persistent AF in 13 centers were enrolled in this multicenter prospective controlled study.The patients were allocated to catheter ablation group (experiment group) and antiarrhythmics drugs cardioversion group (control group) with the ratio 2?1 according to the patients' intention. Left atria were constructed with 3D cardiac electrophysiology mapping system, magnetic sensored saline irrigated radiofrequency ablation catheter (FireMagicTM Cool 3D) and surface reference (ColumbusTM). Pulmonary vein isolation and left atrial roof line, mitral annulus isthmus line, three tricuspid annulus isthmus line, superior vena cava, the coronary sinus and complex atrial fragmented potentials were targeted if necessary under the guidance of the 3D mapping system. Antiarrhythmics drugs (except amiodarone) were applied to patients for 2 to 3 months after ablation. The patients were followed up for 9 months after 3 months blanking period. The patients in the control group underwent cardioversion with amiodarone and electrical cardioversion if needed. Patients in the control group were also followed up for 9 months. RESULTS: Of the 255 patients, 167 cases were in the experiment group and 88 cases were in the control group. In per protocol set (PPS), 155 cases were in the experiment group, 79 cases in the control group. Catheter ablation was successful for all patients in the experiment group under the guidance of the 3D cardiac electrophysiological mapping system. Pumononary veins isolation was achieved in all patients. After 9 months follow-up beyond blanking period, in full analysis set, the success rate was 66.5% (111/167) in the experiment group, which was significantly higher than that in the control group (21.6% (19/88), P<0.001). In PPS, the success rate was also significantly higher in the experiment group than in the control group (67.1% (104/155) vs. 22.8%(18/79), P<0.001). The incidence of adverse events was 19.8% in the experiment group and 13.6% in the control group(P=0.223). The adverse events associated with catheter ablation included 1 case of left subclavian hematoma, 1 case of left subclavian bleeding and 1 case of pericardial effusion, which was alleviated by pericardiocentesis. No pulmonary vein stenosis occurred. CONCLUSION: Domestic 3D cardiac electrophysiological mapping system can safely and effectively guide catheter ablation of persistent AF. PMID- 27220575 TI - [Ideal current of injury and R-wave sensingvalues for identifying optimized placement of right ventricular active-fixation pacing leads]. AB - OBJECTIVE: To define the ideal COI and R-wave sensing values for optimized placement of right ventricular active-fixation pacing leads. METHODS: Three hundred and six patients underwent right ventricular active-fixation lead implantation in our department from January 2013 to December 2014 were enrolled in this prospective pilot cohort study. According to the times needed for successful implantation, patients were divided into group SP (success poisoning after single procedure, n=229) and group MP (success poisoning after multiple procedures, n=77). Current of injury (COI) was characterized as the magnitude of ST-segment elevation. Pacing parameters were measured up to 10 minutes after lead fixation. RESULTS: (1) COI at 1 minute (COI1, (9.34+/-2.44)mV vs. (3.19+/ 1.36)mV, P<0.001) and 10 minutes (COI10, (4.99+/-2.04)mV vs. (1.91+/-0.62)mV, P<0.001) after lead fixation was significantly higher in SP group compared to MP group. R-wave sensing measured at 10 minutes after lead fixation (R10 min) was also significantly higher in SP group than in MP group ((14.2+/-4.5)mV vs. (5.4+/ 0.7)mV, P<0.001). Pacing threshold measured at 10 minutes after lead fixation was significantly lower ((0.65+/-0.18)V vs. (1.90+/-0.40)V, P<0.001) in SP group than in MP group. (2) The optimized placement of pacing lead was related with COI1(OR=0.247, 95%CI 0.098-0.623, P=0.003) and R10 min(OR=0.081, 95%CI 0.015 0.428, P=0.003). (3) The cut-off value of COI1 was 4.77 mV(sensibility 0.97, specificity 0.95), the cut-off value of R10 min was 7.25 mV (sensibility 0.96, specificity 1.00) for optimized lead fixation. After 3 months follow up, pacing threshold was (0.68+/-0.19)V, R-wave sensing was (12.1+/-3.6)mV, and pacing impedance was (543+/-107)Omega for right ventricular active-fixation pacing leads. CONCLUSIONS: COI1>4.77 mV and R10 min>7.25 mV are the ideal parameters for identifying optimized placement of right ventricular active-fixation pacing leads. PMID- 27220576 TI - [Mutation screening for the causative gene in a four-generation Chinese pedigree with progressive cardiac conduction defect]. AB - OBJECTIVE: To define the potential causative gene mutation in a Chinese pedigree with progressive cardiac conduction defect (PCCD). METHODS: Sanger sequencing was performed to define potential causative gene mutation in a four-generation family with 68 members including seven PCCD patients (5 male) from 2010 to 2015.No causative gene was detected by screening known candidate genes related to PCCD including SCN5A, NKX2.5 and LMNA.High-throughput sequencing technology on exon enriched DNA was then used to search the causative genes in 2 patients and one normal family member. RESULTS: Eight new non-synonymous single nucleotide variants including AQP7 gene (exon5: c.T343C: p.Y115H), CACNA1B gene (NM_001243812: exon19: c.A2986G: p.T996A), CATSPERB gene (exon27: c.C3254G: p.P1085R), CLCA2 gene (exon11: c.G1725T: p.W575C), CLCA3P gene (ncRNA_intronic), MYLK-AS1 gene (ncRNA_intronic), TTN gene (ncRNA_UTR3), LMNA gene (LMNA: NM_170708: exon5: c.C922T: p.Q308X) were identified by comparing and filtering the results with known public databases.Then, more detailed biological analysis on these 8 genes was conducted.Traditional Sanger sequencing validated the exome sequencing results, and found that the mutation c. 1725G>T in gene CLCA2 segregated with the phenotype of this PCCD pedigree.The mutation c. 1725G>T in gene CLCA2 was thus be considered as the causative PCCD gene in this pedigree from the perspective of genetics and genomics. CONCLUSION: The heterozygote mutation c. 1725G>T in gene CLCA2 might be causative gene in this PCCD pedigree.This finding adds new gene mutation variant responsible for PCCD. PMID- 27220577 TI - [The pathogenic gene screening in a cardiomyopathy pedigree of Yunnan province]. AB - OBJECTIVE: In this study, the sreening of candidate pathogenic gene is done among family members of an dilated cardiomyopathy(DCM)and hypertrophic cardiomyopathy (HCM) coexistence, and find the relationship between the genotype and the phenotype. METHODS: The inheritance atlas was drawn, analysis of genetic characteristics and clinical phenotype.Peripheral venous blood samples of proband and family members were candidated gene exon high-throughput sequencing sub target capture, make the result compares with related database, ultimately screening the target area of the exon and mutations of candidate genes and then using bidirectional sequencing of Sanger to sequence other family members and the health group which were matching with gender and age to testify whether there is the above mutations. RESULTS: In this family, the proband and his father carry three missense mutations, about TTNc.604 A>G(p.Lys202Glu),TAZ c. 580A>G(p.Ile194Val)and MYH7c.730 T>C(p.Phe244Leu). The heart function of proband was failure, and accompanied malignant arrhythmia.But his father has no obvious clinical symptoms.In this family, the same genetic mutation of disease causing gene lead to different clinical phenotype, but different genetic mutation of disease causing gene lead to the same clinical phenotype.None of the mutations found in this family was found in the health group. CONCLUSION: The patient of this family carries the genetic mutation of MYH7, TTN and TAZ.The patient of this family carries the composite mutation of MYH7(+) /TTN(+) heterozygous missense mutation and TAZ(+) /TTN(+) heterozygous missense mutation may be show the performance of the genetic characteristics of early onset, severe phenotype. PMID- 27220578 TI - [Impact of blood pressure control on coronary flow reserve in hypertensive patients]. AB - OBJECTIVE: To investigate the impacts of blood pressure control on coronary flow reserve (CFR) in hypertensive patients. METHODS: A total of 236 patients without significant coronary stenosis (defined as <50% luminal narrowing which was confirmed by coronary angiography or coronary artery CT scan) between January 2011 to July 2015 were retrospectively enrolled in this study. CFR was measured in the left anterior descending coronary artery (LAD) during adenosine triphosphate-induced hyperemia by transthoracic Doppler echocardiography. Patients were divided into hypertension group (n=173) and non-hypertension group (n=63). The hypertension patients were further divided into ideally controlled (n=31, defined as SBP <120 mmHg (1 mmHg=0.133 kPa) and DBP <80 mmHg), controlled (n=82, defined as SBP 120 to 139 mmHg and DBP <90 mmHg) and uncontrolled groups (n=60, defined as SBP>=140 mmHg and/or diastolic DBP>=90 mmHg) based on their blood pressure after systematic antihypertensive therapy and CFR values were compared among the 4 groups. Multivariate regression analyses were performed to identify the independent determinants of CFR in patients with hypertension. RESULTS: Compared with non-hypertension group, the CFR was significantly lower in controlled (3.27+/-0.71 vs. 2.87+/-0.56, P<0.001) and uncontrolled groups (3.27+/ 0.71 vs. 2.61+/-0.71, P<0.001), but was similar in ideally controlled group (3.27+/-0.71 vs. 3.21+/-0.85, P=0.68). Furthermore, the CFR was significantly lower in uncontrolled group than that of the other two hypertension groups and was significantly lower in controlled group than that of ideally controlled group. Higher blood pressure (beta=-0.17, P=0.03) and age(beta=-0.02, P=0.03) were independent predictors of lower CFR in patients with hypertension. CONCLUSIONS: Higher blood pressure is an independent predictor of decreased CFR in patients with hypertension. Hypertensive patients with ideally controlled blood pressure have similar CFR level as patients without hypertension. PMID- 27220579 TI - [Comparative study on the coronary artery anomalies between the Han and Tibetan nationalities living in middle and high altitude]. AB - OBJECTIVE: To analyze the differences of coronary artery anomalies between Han and Tibetan nationality living in middle and high altitude. METHODS: A total of 7 028 adults living in the Qinghai Plateau(1 800-7 720 m altitude), who underwent coronary CT angiography in Qinghai Cardio-cerebro-vascular Disease Special Hospital between 2010 to 2015, were included in this study.There were 6 391 cases of the Han nationality and 637 cases of the Tibetan nationality. The differences of coronary artery anomalies between Han and Tibetan nationality were analyzed retrospectively. RESULTS: (1) Incidence of coronary artery anomalies was lower in Han nationality than in the Tibetan nationality (1.596%(102/6 391)vs. 4.239%(27/637), P<0.001). (2) There was 64.7%(66/102) male residents with coronary artery anomalies in Han nationality, and 74.1% (20/27) male residents with coronary artery anomalies in Tibetan nationality(P=0.359). (3) Left side coronary artery anomalies in Han nationality was similar as in Tibetan nationality (64.4%(67/104) vs. 55.6%(15/27), P=0.396). (4) Incidence of benign coronary artery anomalies was significantly lower in Han nationality than in Tibetan nationality (0.720%(46/6 391) vs. 2.200%(14/637), P<0.001). Incidence of potentially dangerous coronary artery anomalies was also significantly lower in Han nationality than in Tibetan nationality (0.876%(56/6 391) vs. 2.041%(13/637), P=0.004). (5)Ten kinds of coronary artery anomalies were found in this study. There were significant differences between Han and Tibetan nationality in left coronary artery originated from right coronary sinus(0.046%(3/6 391) vs. 0.471%(3/637), P=0.012), in left circumflex branch originated from right coronary sinus(0.046%(3/6 391)vs. 0.471%(3/637), P=0.012), and opening of right coronary artery in left coronary sinus or left anterior descending(0.704%(45/6 391)vs. 1.570%(10/637), P=0.018). CONCLUSION: The incidences of coronary artery anomalies and benign coronary artery anomalies were significantly lower in Han nationality residents than that of the in Tibetan nationality residents living in middle and high altitude. PMID- 27220580 TI - [Role and related mechanism of S1P/S1P1 signal pathway during post conditioning of hypertrophic cardiomyocytes]. AB - OBJECTIVE: To study the role and mechanism of sphingosine-1-phosphate (S1P)/ sphingosine-1-phosphate receptor 1(S1P1) signal pathway during post conditioning of hypertrophic cardiomyocytes. METHODS: Neonatal rat cardiomyocytes were isolated and cultured, then stimulated by norepinephrine (NE) to induce cardiomyocytes hypertrophy. Using tri-gas incubator to create hypoxia and reoxygenation enviroment to mimic ischemia-reperfusion and postconditioning. Hypertrophic cardiomyoctyes were divided into five groups according to the presence or absence of various drugs and postconditiong and relevant signal pathways changes were detected: (1) IPost group (hypoxia+ postconditioning); (2) IPost+ S1P group (cells were pretreated with S1P (1 MUmol/L) for 2 h before IPost); (3) IPost+ W-146+ S1P group (cells in IPost+ W-146+ S1P group were pretreated with S1P1 inhibitor W-146 (0.4 MUmol/L) for 20 min); (4) IPost+ PD98059+ S1P group (cells in IPost+ S1P group were pretreated with MAPK antagonist PD98059 (125 MUmol/L) for 20 min); (5) IPost+ LY-294002+ S1P group (cells in IPost+ S1P group were pretreated with PI3K antagonist LY294002 (0.1 MUmol/L) for 20 min). Apoptosis was detected by flow cytometry and protein expression of relevant signal pathways were detected by Western blot. RESULTS: (1)Apoptosis rate was significantly increased in hypoxia/reoxygenation (27.90+/ 4.49)% group compared with normal control group (7.97+/-2.18)%, which could be significantly reduced in IPost group (15.90+/-1.77)% (all P<0.05). (2)Apoptosis rate and caspase-3 expression were both significantly lower in IPost+ S1P and IPost+ S1P+ LY-294002 groups than in IPost and IPost+ S1P+ W-146 and IPost+ S1P+ PD98059 group (all P<0.05). (3)p-ERK1/2 expression was significantly higher in IPost+ S1P and IPost+ S1P+ LY-294002 group than in IPost and IPost+ S1P+ W-146 group and IPost+ S1P+ PD98059 group (all P<0.05) while p-Akt expression was similar among IPost, IPost+ S1P+ W-146 and IPost+ S1P+ PD98059 groups. p-ERK1/2 and p-Akt levels in IPost+ S1P+ W-146 group and IPost+ S1P+ PD98059 were similar as in IPost group. CONCLUSIONS: S1P can play protective role on NE induced cardiomyocytes hypertrophy during post conditioning through downregulating caspase-3 expression and reducing apoptosis rate via targeting S1P1 and activating ERK1/2 signal pathway. PMID- 27220581 TI - [Co-overexpression of human tissue kallikrein 1 and human metalloproteinase 1 tissue inhibitor inhibits neointima formation in the rat artery after balloon angioplasty]. AB - OBJECTIVE: To investigate the effects of adenovirus-mediated human tissue kallikrein 1(hTK-1) and/or human tissue metalloproteinase inhibitor 1 (hTIMP-1) gene delivery on the neointima formation in balloon-injured rat carotids and related mechanism. METHODS: Forty-six male Sprague-Dawley rats were randomly assigned into 6 groups with the random number table: (1) sham-operated group(n=6), (2) angioplasty group (n=8), (3) vector virus group (n=8), (4) hTK-1 group (n=8), (5) hTIMP-1 group (n=8), (6) hTK-1-hTIMP-1 group (n=8). Except sham rats, all rats underwent carotid artery balloon injury and local delivery of saline or different recombined adenoviruses respectively. Rats were sacrificed 14 days later. Intima/media area ratio was assessed on hematoxylin-eosin stained tissue section. Immunofluorescence images stained for hTK-1, hTIMP-1 were obtained and analyzed by the confocal microscope for co-localization examination of hTK-1 and hTIMP-1. The protein expression levels of hTK-1, hTIMP-1, matrix metalloproteinases(MMP)-2 and MMP-9 were determined by Western blot. Immune histochemical staining for PCNA was also performed. RESULTS: (1)Intima area, intima/media area ratio, PCNA, MMP-2 and MMP-9 levels were all significantly increased in rats underwent angioplasty (did or did not receive vector virus) compared with sham-operated rats (all P<0.01) while above parameters were similar between rats underwent angioplasty or vector virus delivery (all P>0.05). (2) The intima area of rats received vector virus, hTK-1, hTIMP-1 or dual gene transfer were (0.160+/-0.010), (0.110+/-0.015), (0.121+/-0.016) or (0.081+/-0.008) mm(2) respectively, intima area was similar between rats received hTK-1 or hTIMP-1 (P>0.05), differences were found between other groups (all P<0.01). The intima/media area ratio of rats received vector virus, hTK-1, hTIMP-1 or dual gene transfer were 2.035+/-0.117, 1.443+/-0.097, 1.522+/-0.078 or 0.972+/-0.072 respectively, no difference was found between rats received hTK-1 or hTIMP-1 in intima/media area ratio (all P>0.05), differences were found between other groups (all P<0.01). The MMP-2 and MMP-9 expression of rats received vector virus, hTK 1, hTIMP-1 or dual gene transfer were 0.817+/-0.036, 0.606+/-0.044, 0.571+/-0.061 or 0.455+/-0.030 and 0.745+/-0.057, 0.613+/-0.038, 0.582+/-0.050 or 0.473+/-0.038 respectively, no difference was found between rats received hTK-1 or hTIMP-1 in MMP-2 or MMP-9 expression (all P>0.05), differences were found between other groups (all P<0.01). The PCNA expression of rats received vector virus, hTK-1, hTIMP-1 or dual gene transfer were 0.065+/-0.007, 0.052+/-0.004, 0.055+/-0.007 or 0.031+/-0.004 respectively, no difference was found between rats received hTK-1or hTIMP-1 in PCNA expression (all P>0.05), differences were found between other groups (all P<0.01). CONCLUSION: hTK-1 and hTIMP-1 co-overexpression may synergistically inhibit neointimal hyperplasia, attenuate vascular remodeling and reduce restenosis possibly via down regulating the expressions of PCNA, MMP-2 and MMP-9 in balloon-injured rat carotids. PMID- 27220583 TI - [Clinical characteristics of a male patient with apical ballooning syndrome]. PMID- 27220582 TI - [Relationship between myocardial microRNA-30a expression and myocardial fibrosis in rats post myocardial infarction]. AB - OBJECTIVE: To explore the potential role and mechanism of microRNA(miR)-30a in myocardial fibrosis after myocardial infarction (MI). METHODS: Rats were randomly divided into 1 week MI group (n=11), 2 weeks MI group (n=13) and 4 weeks MI group (n=15) by applying random number table after left anterior descending coronary artery ligation. Rats in Sham group were examined at respective time points (n=16). Heart function was monitored by echocardiography. Myocardial collagen volume fraction (CVF) was determined on Masson stained sections. Myocardial expression of collagen I and III was determined by immunohistochemistry. The myocardial mRNA level of miR-30a, TGF-beta1 and CTGF were detected by real time quantitative PCR analysis. The myocardial protein levels of TGF-beta1 and CTGF were measured by Western blot analysis. RESULTS: The LVEDD ((8.37+/-0.58) mm) and LVESD ((6.12+/-0.82) mm) in 4 weeks MI group were significantly higher than those in Sham group ((6.08+/-0.57) mm, (4.17+/-0.60) mm), all P<0.01. The FS ((27.0+/ 3.9) %) and LVEF ((51.0+/-6.3) %) in 4 weeks MI group were significantly lower than those in Sham group ((47.0+/-2.1) %, (82.0+/-2.3)%), all P<0.01. The level of myocardial CVF in 1 week MI group, 2 weeks MI group and 4 weeks MI group were significantly higher than in Sham group (all P<0.01) in a time-dependent manner. The level of myocardial collagen I and III was increased gradually from 1 week to 4 weeks post MI compared with Sham group (all P<0.01). The collagen I/III ratio was similar between 1 week MI group and Sham group (P=0.58), however, which was significantly higher in 2 weeks MI group and 4 weeks MI group compared with Sham group (all P<0.01), and the ratio was significantly higher in 4 weeks MI group than 2 weeks MI group (P<0.01). The level of miR-30a was significantly and gradually reduced in all MI groups compared with Sham group (all P<0.01). The mRNA and protein levels of TGF-beta1 and CTGF were significantly and gradually increased after MI compared with Sham group (all P<0.001). CONCLUSIONS: Our results indicate that overexpression of miR-30a after MI might be a potential strategy for suppressing myocardial fibrosis by modulating the mRNA and protein levels of TGF-beta1 and CTGF. PMID- 27220584 TI - [A case of Takayasu arteritis with acute myocardial infarction as the initial presentation]. PMID- 27220586 TI - [Pericardial tamponade resulting from a fishbone punctured into the left ventricle: case report]. PMID- 27220585 TI - [Interventional therapy of ventricular septal defect in a patient with mirror image dextrocardia]. PMID- 27220587 TI - [Research progress on statins use and the risk of new onset diabetes]. PMID- 27220588 TI - [Research update on the anti-senescence effects of statins and related mechanisms]. PMID- 27220589 TI - [Effects of large conductance calcium activated K(+) channels on ischemia reperfusion injury and related mechanisms]. PMID- 27220590 TI - Care Quality Commission does not take into account what really matters to patients. PMID- 27220591 TI - Linking Spending and Quality Indicators to Measure Value and Efficiency in Health Care. AB - Policy makers and stakeholders have reached a consensus that both quality and spending or resource use indicators should be jointly measured and prioritized to meet the objectives of our health system. However, the relative merits of alternative approaches that combine quality and spending indicators are not well understood. We conducted a literature review to identify different approaches that combine indicators of quality and spending measures to profile provider efficiency in the context of specific applications in health care. Our investigation identified seven alternative models that are either in use or have been proposed to evaluate provider efficiency. We then used publicly available data to profile hospitals using these approaches. Profiles of hospital efficiency using alternative models yielded wide variation in performance, underscoring the importance of model selection. By identifying the current efficiency models and evaluating their trade-offs within specific programmatic contexts, our analysis informs stakeholder and policy maker decisions about how to link quality and spending indicators when measuring efficiency in health care. PMID- 27220592 TI - Do dressings prevent infection of closed primary wounds after surgery? PMID- 27220593 TI - Pulmonary Artery Pressure-Guided Heart Failure Management Reduces 30-Day Readmissions. AB - BACKGROUND: This study examines the impact of pulmonary artery pressure-guided heart failure (HF) care on 30-day readmissions in Medicare-eligible patients. METHODS AND RESULTS: The CardioMicroelectromechanical system (CardioMEMS) Heart Sensor Allows Monitoring of Pressures to Improve Outcomes in New York Heart Association Class III Heart Failure Patients (CHAMPION) Trial included 550 patients implanted with a permanent MEMS-based pressure sensor in the pulmonary artery. Subjects were randomized to a treatment group (uploaded pressures were made available to investigators) or a control group (uploaded pressures were not made available to investigators). This analysis focuses on the 245 Medicare eligible subjects for whom compliance with daily transmissions was 93% compared with 88% for the overall population. Medications were changed more often in the treatment group using pressure information compared with the control group using symptoms and daily weights alone. During the 515 days follow-up after implant, the overall rate of HF hospitalizations was 49% lower in the treatment group (60 HF hospitalizations, 0.34 events/patient-year) compared with control (117 HF hospitalizations, 0.67 events/patient-year; hazard ratio 0.51, 95% confidence interval 0.37-0.70; P<0.0001). Of the 177 HF hospitalizations, 155 qualified as an index HF hospitalization. All-cause 30-day readmissions were 58% lower in the treatment group (0.07 events/patient-year) compared with 0.18 events/patient-year in the control group (hazard ratio 0.42, 95% confidence interval 0.22-0.80; P=0.0080). CONCLUSIONS: Pulmonary artery pressure-guided HF management in Medicare-eligible patients led to a 49% reduction in total HF hospitalizations and a 58% reduction in all-cause 30-day readmissions. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00531661. PMID- 27220594 TI - Predictors and outcomes of sustained, intermittent or never achieving remission in patients with recent onset inflammatory polyarthritis: results from the Norfolk Arthritis Register. AB - OBJECTIVES: Early remission is the current treatment strategy for patients with inflammatory polyarthritis (IP) and RA. Our objective was to identify baseline factors associated with achieving remission: sustained (SR), intermittent (IR) or never (NR) over a 5-year period in patients with early IP. METHODS: Clinical and demographic data of patients with IP recruited to the Norfolk Arthritis Register (NOAR) were obtained at baseline and years 1, 2, 3 and 5. Remission was defined as no tender or swollen joints (out of 51). Patients were classified as NR or PR, respectively, if they were in remission at: no assessment or ?3 consecutive assessments after baseline, and IR otherwise. Ordinal regression and a random effects model, respectively, were used to examine the association between baseline factors, remission group and HAQ scores over time. RESULTS: A total of 868 patients (66% female) were included. Of these, 54%, 34% and 12% achieved NR, IR and SR, respectively. In multivariate analysis, female sex (odds ratio, OR 0.47, 95% CI: 0.35, 0.63), higher tender joint count (OR = 0.94, 95% CI: 0.93, 0.96), higher HAQ (OR = 0.59, 95% CI: 0.48, 0.74), being obese (OR = 0.70, 95% CI: 0.50, 0.99), hypertensive (OR = 0.67, 95% CI: 0.50, 0.90) or depressed (OR = 0.74, 95% CI: 0.55, 1.00) at baseline were independent predictors of being in a lower remission group. IR and SR were associated with lower HAQ scores over time and lower DAS28 at year 5. CONCLUSION: Women with higher tender joint count and disability at baseline, depression, obesity and hypertension were less likely to achieve remission. This information could help when stratifying patients for more aggressive therapy. PMID- 27220600 TI - Effects of the eukaryotic initiation factor 6 gene on expression levels of inflammatory mediators in M2 macrophages during scar repair. AB - The aim of the present study was to evaluate the effects of the eukaryotic initiation factor 6 (eIF6) gene on the secretion of M2 macrophage fibrosis associated factors and the expression levels of key proteases during scar repair. Male eIF6 wild-type (eIF6+/+) and knockout (eIF6+/-) C57BL/6 mice were intraperitoneally lavaged to obtain macrophages, which were induced to the M2 type using interleukin-4. Differences between the gene expression profiles of these macrophages were compared with gene microarrays, and the results were validated using reverse transcription-quantitative polymerase chain reaction analysis and ELISA. Compared with the eIF6+/- mice, the mRNA and protein expression levels of vascular endothelial growth factor (VEGF) and tissue inhibitor of metalloproteinase-2 (TIMP-2) in the M2 macrophages of the eIF6+/+ mice were significantly downregulated (P<0.05), whereas the mRNA and protein expression levels of matrix metalloproteinase-2 (MMP-2) were significantly upregulated (P<0.05). Therefore, the results indicated that eIF6 alleviated cicatrization, possibly by inhibiting the generation of VEGF, in order to prevent overgrowth of blood vessels and granulation tissues, and to regulate the MMP 2/TIMP-2 ratio to balance the degradation and deposition of the extracellular matrix. PMID- 27220595 TI - STAT3 regulates hypoxia-induced epithelial mesenchymal transition in oesophageal squamous cell cancer. AB - Hypoxia plays a key role in tumour initiation and metastasis; one of the mechanisms is to induce epithelial-mesenchymal transition (EMT). Signal transducer and activator of transcription 3 (STAT3) is involved in EMT by regulating the transcriptional regulators of E-cadherin, the biomarker of EMT. Until now, however, few studies have focused on the effects of STAT3 in hypoxia induced EMT in tumour cells. The goal of this study was to investigate the roles of STAT3 in hypoxia-induced EMT in oesophageal squamous cell carcinoma (ESCC). The ESCC cells, TE-1 and EC-1, were incubated in normoxia, or in CoCl2, which was used to mimic hypoxia. With CoCl2, the ESCC cells showed increased migration and invasion abilities, accompanied with upregulation of HIF-1alpha, STAT3, and vimentin, and downregulation of E-cadherin. Knockdown of STAT3 inhibited EMT of ESCC cells and downregulated HIF-1alpha in vitro and in vivo. In ChIP assays, STAT3 bound to the promoter of HIF-1alpha, suggesting that STAT3 regulates transcription of HIF-1alpha. In conclusion, hypoxia induces EMT of ESCC, and STAT3 regulates this process by promoting HIF-1alpha expression. PMID- 27220601 TI - Biological effects of rutin on skin aging. AB - Rutin, a quercetin glycoside is a member of the bioflavonoid family which is known to possess antioxidant properties. In the present study, we aimed to confirm the anti-aging effects of rutin on human dermal fibroblasts (HDFs) and human skin. We examined the effects of rutin using a cell viability assay, senescence-associated-beta-galactosidase assay, reverse transcription quantitative polymerase chain reaction, and by measuring reactive oxygen species (ROS) scavenging activity in vitro. To examine the effects of rutin in vivo, rutin-containing cream was applied to human skin. A double-blind clinical study was conducted in 40 subjects aged between 30-50 years and divided into control and experimental groups. The test material was applied for 4 weeks. After 2 and 4 weeks, dermal density, skin elasticity, the length and area of crow's feet, and number of under-eye wrinkles following the application of either the control or the rutin-containing cream were analyzed. Rutin increased the mRNA expression of collagen, type I, alpha 1 (COL1A1) and decreased the mRNA expression of matrix metallopeptidase 1 (MMP1) in HDFs. We verified that ROS scavenging activity was stimulated by rutin in a dose-dependent manner and we identified that rutin exerted protective effects under conditions of oxidative stress. Furthermore, rutin increased skin elasticity and decreased the length, area and number of wrinkles. The consequences of human aging are primarily visible on the skin, such as increased wrinkling, sagging and decreased elasticity. Overall, this study demonstrated the biological effects of rutin on ROS-induced skin aging. PMID- 27220602 TI - Single-cell analysis reveals new subset markers of murine peritoneal macrophages and highlights macrophage dynamics upon Staphylococcus aureus peritonitis. AB - Resident macrophages play a central role in maintaining tissue homeostasis and immune surveillance. Here, we used single cell-based qPCR coupled with flow cytometry analysis to further define the phenotypes of large and small resident peritoneal macrophages (LPMs and SPMs, respectively) in mice. We demonstrated that the expression of Cxcl13, IfngR1, Fizz-1 and Mrc-1 clearly distinguished between LPMs and SPMs subsets. Using these markers, the dynamics of peritoneal macrophages in a Staphylococcus aureus-induced peritonitis model were analyzed. We found that S. aureus infection triggers a massive macrophage disappearance reaction in both subsets. Thereafter, inflammatory monocytes rapidly infiltrated the cavity and differentiated to replenish the SPMs. Although phenotypically indistinguishable from resident SPMs by flow cytometry, newly recruited SPMs had a different pattern of gene expression dominated by M2 markers combined with M1 associated features (inos expression). Interestingly, S. aureus elicited SPMs showed a robust expression of Cxcl13, suggesting that these cells may endorse the role of depleted LPMs and contribute to restoring peritoneal homeostasis. These data provide information on both resident and recruited macrophages dynamics upon S. aureus infection and demonstrate that single-cell phenotyping is a promising and highly valuable approach to unraveling macrophage diversity and plasticity. PMID- 27220603 TI - Are condylar morphologic changes associated with temporomandibular disorders in patients with orthognathia? AB - OBJECTIVE: To determine the association between morphologic condylar changes and temporomandibular disorders (TMDs) in patients with orthognathia. STUDY DESIGN: Data from 89 patients were analyzed. TMDs were classified according to the Research Diagnostic Criteria for TMDs. TMD severity was scored according to the Helkimo indices. Calculation of the condylar area, perimeter, and height was performed by using a specific computational method including panoramic radiography. RESULTS: Sixty-five (73%) patients presented with morphologic condylar changes. Decreases in condylar perimeter and area were found to be predictors of postoperative TMDs (P = .009; odds ratio [OR] = 3.66) and disk displacement (P = .008; OR = 4.43), respectively. Condylar area and height decreases were associated with worsening of TMDs (P = .03 and 0.04). CONCLUSIONS: This study demonstrated that in orthognathic patients, postoperative condylar changes are associated with postoperative TMDs as well as with the degree of TMD severity and that preoperative TMDs are associated with such condylar changes. PMID- 27220604 TI - AAOM Clinical Practice Statement: Subject: Oral Cancer Examination and Screening. PMID- 27220605 TI - Implementation of Salmonella serotype determination using pulsed-field gel electrophoresis in a state public health laboratory. AB - We examined the use of pulsed-field gel electrophoresis (PFGE) to predict serotype for Salmonella isolates. Between 2012 and 2014 we assessed 4481 isolates, resulting in >90% assigned serotypes. PFGE is efficient for determining serotype in the majority of cases and results in expedited serotype determination, as well as cost savings. PMID- 27220606 TI - Lactational mastitis caused by Streptococcus lactarius. AB - Human infections caused by Streptococcus lactarius have not been previously reported. In the present report, we describe a lactational mastitis caused by this organism. The infection occurred in a 28-year-old breast-feeding female, with a 10-days history of moderate pain on the right breast. The patient was cured after antibiotic treatment with levofloxacin for 21 days. Our case shows that S. lactarius should be considered as a cause of lactational mastitis. The introduction of molecular microbiology techniques can be extremely useful for knowing the implication of streptococci in lactational mastitis. PMID- 27220607 TI - Evaluation of urine pneumococcal antigen test performance among adults in Western Kenya. AB - When used in an area of rural western Kenya, the BinaxNOW(r) urine antigen test had a sensitivity of 67% (95% Confidence Interval [CI]: 43-85%) among 21 adults >=15 years old with acute respiratory illnesses and pneumococcal bacteremia and a specificity of 98% (95% CI: 96-99%) among 660 adults >=15 years old without fever or cough. The specificity of the test was not significantly affected by pneumococcal colonization, regardless of patients' HIV status, age, or sex. Use of the pneumococcal urine antigen test in clinical assessments of adults in Africa with acute respiratory illness is a viable option regardless of whether a patient is colonized by pneumococci, even among HIV-infected adults, although the moderate sensitivity of the urine antigen test indicates that the test is probably best used clinically as part of a panel with other tests that can detect pneumococci. PMID- 27220608 TI - Multiplex PCR assay underreports true bloodstream infections with coagulase negative staphylococci in hematological patients with febrile neutropenia. AB - SeptiFast multiplex PCR assay was evaluated for detecting true bloodstream infections (BSIs) with coagulase-negative staphylococci (CoNS) in neutropenic hematological patients. Sensitivity for samples representing true CoNS-BSIs was 23.3% with an integrated cutoff and increased to 83.3% if the cutoff was neglected. Hence, the cutoff may prohibit timely targeted antimicrobial therapy. PMID- 27220609 TI - Characterization of urban waste management practices in developing Asian countries: A new analytical framework based on waste characteristics and urban dimension. AB - This paper characterizes municipal solid waste (MSW) management practices in developing Asia, with a focus on low and middle-income countries. The analysis that is conducted supports a proposed framework that maps out the trends observed in the region in relation to two parameters, waste compositions and urban dimension, which was prepared based on a set of national and urban case studies. The management of MSW in developing Asian countries is driven, first and foremost, by a public health imperative: the collection and disposal of waste in order to avoid the spread of disease vectors from uncollected waste. This comes, however, at a high cost, with local government authorities in these countries spending up to 50% of their budgets in the provision of these services. Little or no value is derived from waste, which is typically seen as a liability and not as a resource that can be harnessed. On the other hand, in many cities in developing Asia there is an informal sector that ekes out a living from the recovery of recyclable materials found in waste. Members of this "informal waste sector" are especially active in areas that are not served by formal waste collection systems, such as slums or squatter areas. A distinctive element shared among many cities in developing Asian countries concerns the composition of the municipal solid waste. MSW in those countries tends to be richer in biodegradable organic matter, which usually accounts for more than 50% of the total waste composition, suggesting that biological methods are more appropriate for treating this organic fraction. Conversely, thermal combustion technologies, which are extensively applied in high-income countries, are technically and economically challenging to deploy in light of the lower calorific value of waste streams which are rich in organics and moisture. Specific approaches and methods are therefore required for designing adequate waste management systems in developing Asian countries. In addition, despite some common characteristics shared among cities in developing Asia, their specific circumstances can significantly vary, even within the same country, calling for the need for context-specific waste management approaches. Set against this background, this paper proposes a guiding framework in the form of a matrix that maps out approaches observed in the management of municipal solid waste in cities of developing Asian countries as a function of the city dimension, share of organics on waste streams, and wealth generated by the city. The cities of Surabaya (Indonesia), Bangalore (India), Quy Nhon (Viet Nam), and Matale (Sri Lanka) are showcased as good practices in the region in the management of solid waste, with their experiences used to illustrate the framework laid out in the matrix. PMID- 27220610 TI - A high lymph node yield in colon cancer is associated with age, tumour stage, tumour sub-site and priority of surgery. Results from a prospective national cohort study. AB - AIM: To determine the relation between patient-related and histopathological factors, as well as the influence of national programs for diagnosing and treatment of colon cancer and a lymph node yield (LNY) >= 12. METHOD: An analysis was carried out of the LNY in a nationwide Danish cohort treated by curative resection of stage I-III colon cancer in the period 2003-2011. The association between a LNY >= 12 and age, sex, body mass index, open vs. laparoscopic surgery, acute vs. elective surgery, pT stage, tumour sub-site and year of diagnosis was analysed. RESULTS: A total of 13,766 patients were eligible for the analysis. In total, 71.4 % of the patients had a LNY >= 12. In multivariate analysis, age, pT stage, tumour sub-site and priority of surgery were independently associated with the probability of a LNY >= 12. Odds ratios (ORs) were as follows: age <65 1, 65 75 0.685 (confidence interval (CI) 0.586-0.800), >75 0.517 (CI 0.439-0.609); T1 1, T2 2.750 (CI 2.168-3.487), T3 6.016 (CI 4.879-7.418), T4 6.317 (CI 4.950 8.063); right colon 1, left colon 0.568 (0.511-0.633); elective surgery 1, acute surgery 0.748 (CI 0.625-0.894). Moreover, year of diagnosis was associated with the probability of a LNY >= 12: OR 1.480 (CI 1.445-1.516) for each increasing year in the study period. CONCLUSION: A LNY >= 12 is significantly associated with age, pT stage, tumour sub-site and priority of surgery. A significant increase in the LNY over the period of the study was observed, probably reflecting the effect of national programmes initiated by the Danish Colorectal Cancer Group. PMID- 27220611 TI - Colic PEComa: one disease, two outcomes. PMID- 27220612 TI - FTY720 enhances osteogenic differentiation of bone marrow mesenchymal stem cells in ovariectomized rats. AB - Sphingosine-1-phosphate and its structural analog FTY720 (fingolimod) are important in the inhibition of osteoclast differentiation and bone resorption, however, it remains unknown whether they enhance osteogenic differentiation of the bone marrow mesenchymal stem cells (BM-MSCs). The present study investigated the effect of FTY720 on the osteogenic differentiation of BM-MSCs from the femurs of the ovariectomized (OVX) rats. Three different concentrations (1, 10 and 100 nM) of FTY720 were demonstrated to markedly upregulate mRNA expression levels of Runt-related transcription factor 2 (Runx2) and Sp7 transcription factor (Sp7) at 2 weeks, and alkaline phosphatase (ALP) at 3 weeks. The osteocalcin (OCN) expression was similar at weeks 2 and 3. The protein expression levels of Runx2, Sp7, OCN and ALP induced by three different concentrations of FTY720 were higher than those in the control groups at 3 weeks in the OVX and sham groups. The findings of the current study suggested a beneficial effect of FTY720 on bone formation in OVX rats, and provided a potential therapeutic method of FTY720 to prevent alveolar bone resorption in patients with post-menopausal osteoporosis. PMID- 27220613 TI - QM/MM study of l-lactate oxidation by flavocytochrome b2. AB - In this work, we have performed molecular dynamics simulations using a hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) scheme to study the mechanism of l lactate oxidation by flavocytochrome b2 (Fcb2). Our results obtained at the QM(AM1)/MM level have been improved by single-point corrections using density functional theory (DFT) methods. Free energy surfaces have been calculated in the framework of the hydride transfer hypothesis. This mechanism involves the transfer of the lactate hydroxyl proton to H373 while the substrate alphaH atom is transferred as a hydride to the flavin mononucleotide (FMN) prosthetic group anchored in the active site. Four different systems have been modeled: wild-type enzyme considering R289 in a distal or a proximal conformation observed in crystal structures and the D282N and Y254L variants (with R289 in a distal position). Simulation results highlight the influence of the environment on the catalytic mechanism by describing a step-wise process in the WT enzyme with R289 in a distal position and a concerted mechanism for the other systems. In the step wise mechanism, the hydride transfer to flavin can occur only after a proton transfer from substrate to H373. Modifications of the electrostatic field around l-lactate or H373 disfavor the highly charged complex resulting from this proton transfer. Simulations of the Y254L variant also reveal some effect of steric changes. PMID- 27220614 TI - A novel mechanistic interpretation of instantaneous temperature responses of leaf net photosynthesis. AB - Steady-state rates of leaf CO2 assimilation (A) in response to incubation temperature (T) are often symmetrical around an optimum temperature. A/T curves of C3 plants can thus be fitted to a modified Arrhenius equation, where the activation energy of A close to a low reference temperature is strongly correlated with the dynamic change of activation energy to increasing incubation temperature. We tested how [CO2] < current atmospheric levels and saturating light, or [CO2] at 800 umol mol(-1) and variable light affect parameters that describe A/T curves, and how these parameters are related to known properties of temperature-dependent thylakoid electron transport. Variation of light intensity and substomatal [CO2] had no influence on the symmetry of A/T curves, but significantly affected their breadth. Thermodynamic and kinetic (physiological) factors responsible for (i) the curvature in Arrhenius plots and (ii) the correlation between parameters of a modified Arrhenius equation are discussed. We argue that the shape of A/T curves cannot satisfactorily be explained via classical concepts assuming temperature-dependent shifts between rate-limiting processes. Instead the present results indicate that any given A/T curve appears to reflect a distinct flux mode, set by the balance between linear and cyclic electron transport, and emerging from the anabolic demand for ATP relative to that for NADPH. PMID- 27220615 TI - The Built Environment and Child Health: An Overview of Current Evidence. AB - Urbanization and the shaping of the built environment have provided a number of socioeconomic benefits, but they have also brought unwanted side effects on health. We aimed to review the current epidemiological evidence of the associations between the built environment, closely related exposures, and child health. We focused on growth and obesity, neuropsychological development, and respiratory and immune health. We used existing review articles and supplemented these with relevant work published and not included in existing reviews. The present review shows that there is good evidence for an association between air pollution and fetal growth restriction and respiratory health, whereas for other exposure and outcome combinations, further evidence is needed. Future studies should make efforts to integrate the different built environment features and to include the evaluation of environments other than home, as well as accessibility, qualitative and perception assessment of the built environment, and, if possible, with improved and standardized tools to facilitate comparability between studies. Efforts are also needed to conduct longitudinal and intervention studies and to understand potential mechanisms behind the associations observed. Finally, studies in low- and middle-income countries are needed. PMID- 27220618 TI - Corticotropin-releasing hormone family evolution: five ancestral genes remain in some lineages. AB - The evolution of the peptide family consisting of corticotropin-releasing hormone (CRH) and the three urocortins (UCN1-3) has been puzzling due to uneven evolutionary rates. Distinct gene duplication scenarios have been proposed in relation to the two basal rounds of vertebrate genome doubling (2R) and the teleost fish-specific genome doubling (3R). By analyses of sequences and chromosomal regions, including many neighboring gene families, we show here that the vertebrate progenitor had two peptide genes that served as the founders of separate subfamilies. Then, 2R resulted in a total of five members: one subfamily consists of CRH1, CRH2, and UCN1. The other subfamily contains UCN2 and UCN3. All five peptide genes are present in the slowly evolving genomes of the coelacanth Latimeria chalumnae (a lobe-finned fish), the spotted gar Lepisosteus oculatus (a basal ray-finned fish), and the elephant shark Callorhinchus milii (a cartilaginous fish). The CRH2 gene has been lost independently in placental mammals and in teleost fish, but is present in birds (except chicken), anole lizard, and the nonplacental mammals platypus and opossum. Teleost 3R resulted in an additional surviving duplicate only for crh1 in some teleosts including zebrafish (crh1a and crh1b). We have previously reported that the two vertebrate CRH/UCN receptors arose in 2R and that CRHR1 was duplicated in 3R. Thus, we can now conclude that this peptide-receptor system was quite complex in the ancestor of the jawed vertebrates with five CRH/UCN peptides and two receptors, and that crh and crhr1 were duplicated in the teleost fish tetraploidization. PMID- 27220617 TI - Low-Affinity Neurotrophin Receptor p75 Promotes the Transduction of Targeted Lentiviral Vectors to Cholinergic Neurons of Rat Basal Forebrain. AB - Basal forebrain cholinergic neurons (BFCNs) are one of the most affected neuronal types in Alzheimer's disease (AD), with their extensive loss documented at late stages of the pathology. While discriminatory provision of neuroprotective agents and trophic factors to these cells is thought to be of substantial therapeutic potential, the intricate topography and structure of the forebrain cholinergic system imposes a major challenge. To overcome this, we took advantage of the physiological enrichment of BFCNs with a low-affinity p75 neurotrophin receptor (p75NTR) for their targeting by lentiviral vectors within the intact brain of adult rat. Herein, a method is described that affords selective and effective transduction of BFCNs with a green fluorescence protein (GFP) reporter, which combines streptavidin-biotin technology with anti-p75NTR antibody-coated lentiviral vectors. Specific GFP expression in cholinergic neurons was attained in the medial septum and nuclei of the diagonal band Broca after a single intraventricular administration of such targeted vectors. Bioelectrical activity of GFP-labeled neurons was proven to be unchanged. Thus, proof of principle is obtained for the utility of the low-affinity p75NTR for targeted transduction of vectors to BFCNs in vivo. PMID- 27220619 TI - Transcriptome landmarks of the functional maturity of rat beta-cells, from lactation to adulthood. AB - Research on the postnatal development of pancreatic beta-cells has become an important subject in recent years. Understanding the mechanisms that govern beta cell postnatal maturation could bring new opportunities to therapeutic approaches for diabetes. The weaning period consists of a critical postnatal window for structural and physiologic maturation of rat beta-cells. To investigate transcriptome changes involved in the maturation of beta-cells neighboring this period, we performed microarray analysis in fluorescence-activated cell-sorted (FACS) beta-cell-enriched populations. Our results showed a variety of gene sets including those involved in the integration of metabolism, modulation of electrical activity, and regulation of the cell cycle that play important roles in the maturation process. These observations were validated using reverse hemolytic plaque assay, electrophysiological recordings, and flow cytometry analysis. Moreover, we suggest some unexplored pathways such as sphingolipid metabolism, insulin-vesicle trafficking, regulation of transcription/transduction by miRNA-30, trafficking proteins, and cell cycle proteins that could play important roles in the process mentioned above for further investigation. PMID- 27220620 TI - MECHANISMS IN ENDOCRINOLOGY: Brown adipose tissue in humans: regulation and metabolic significance. AB - The recent discovery that functional brown adipose tissue (BAT) persists in adult humans has enkindled a renaissance in metabolic research, with a view of harnessing its thermogenic capacity to combat obesity. This review focuses on the advances in the regulation and the metabolic significance of BAT in humans. BAT activity in humans is stimulated by cold exposure and by several factors such as diet and metabolic hormones. BAT function is regulated at two levels: an acute process involving the stimulation of the intrinsic thermogenic activity of brown adipocytes and a chronic process of growth involving the proliferation of pre existing brown adipocytes or differentiation to brown adipocytes of adipocytes from specific white adipose tissue depots. BAT activity is reduced in the obese, and its stimulation by cold exposure increases insulin sensitivity and reduces body fat. These observations provide strong evidence that BAT plays a significant role in energy balance in humans and has the potential to be harnessed as a therapeutic target for the management of obesity. PMID- 27220621 TI - Two-year trends and predictors of e-cigarette use in 27 European Union member states. AB - OBJECTIVE: This study assessed changes in levels of ever use, perceptions of harm from e-cigarettes and sociodemographic correlates of use among European Union (EU) adults during 2012-2014, as well as determinants of current use in 2014. METHODS: We analysed data from the 2012 (n=26 751) and 2014 (n=26 792) waves of the adult Special Eurobarometer for Tobacco survey. Point prevalence of current and ever use was calculated and logistic regression assessed correlates of current use and changes in ever use, and perception of harm. Correlates examined included age, gender, tobacco smoking, education, area of residence, difficulties in paying bills and reasons for trying an e-cigarette. RESULTS: The prevalence of ever use of e-cigarettes increased from 7.2% in 2012 to 11.6% in 2014 (adjusted OR (aOR)=1.91). EU-wide coefficient of variation in ever e-cigarette use was 42.1% in 2012 and 33.4% in 2014. The perception that e-cigarettes are harmful increased from 27.1% in 2012 to 51.6% in 2014 (aOR=2.99), but there were major differences in prevalence and trends between member states. Among those who reported that they had ever tried an e-cigarette in the 2014 survey, 15.3% defined themselves as current users. Those who tried an e-cigarette to quit smoking were more likely to be current users (aOR=2.82). CONCLUSIONS: Ever use of e-cigarettes increased during 2012-2014. People who started using e-cigarettes to quit smoking tobacco were more likely to be current users, but the trends vary by country. These findings underscore the need for more research into factors influencing e-cigarette use and its potential benefits and harms. PMID- 27220616 TI - Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis. AB - Arboviruses are arthropod-borne viruses that exhibit worldwide distribution, contributing to systemic and neurologic infections in a variety of geographical locations. Arboviruses are transmitted to vertebral hosts during blood feedings by mosquitoes, ticks, biting flies, mites, and nits. While the majority of arboviral infections do not lead to neuroinvasive forms of disease, they are among the most severe infectious risks to the health of the human central nervous system. The neurologic diseases caused by arboviruses include meningitis, encephalitis, myelitis, encephalomyelitis, neuritis, and myositis in which virus- and immune-mediated injury may lead to severe, persisting neurologic deficits or death. Here we will review the major families of emerging arboviruses that cause neurologic infections, their neuropathogenesis and host neuroimmunologic responses, and current strategies for treatment and prevention of neurologic infections they cause. PMID- 27220622 TI - Close, but no cigar: certain cigars are pseudo-cigarettes designed to evade regulation. AB - An abundance of evidence suggests that the tobacco industry's response to increased regulation imposed on cigarettes has been the development of little cigars and filtered cigars which are tobacco products that are merely cigarettes in disguise. Emphasising these products' physical attributes, the tobacco industry has offered cigar products to its consumers as pseudo-cigarettes. For decades, tobacco manufacturers' response to increased cigarette regulation and taxation has been to exploit policy loopholes by offering these little cigars and filtered cigars pseudo-cigarettes that are exempted from this regulatory oversight. As a result, in spite of increased regulations and taxes on cigarettes, smokers can purchase cigars that are almost physically indistinguishable from their cigarettes at a lower cost. This commentary describes the recent evolution of the cigar market in response to federal regulation, and highlights historical cigar industry attempts to evade taxation, capitalise on product features that are off-limits to cigarettes, and capture the shrinking market of cigarette smokers. We present the case that little cigars and filtered cigars, differing very little physically from cigarettes, are products deserving the same regulatory scrutiny. PMID- 27220623 TI - Solvent Effects on the Electronic Absorption and Fluorescence Spectra of HNP: Estimation of Ground and Excited State Dipole Moments. AB - We report the effect of solvents on absorption and fluorescence spectra of biologically active 3(2H)-pyridazinone namely 5-(2-hydroxy-naphthalen-1-yl)-2 phenyl-2H-pyridazin-3-one (HNP) in different solvents at room temperature. The ground and the excited state dipole moments of HNP molecule was estimated from Lippert's, Bakshiev's and Kawski-Chamma-Viallet's equations using the solvatochromic shift method. The ground state dipole moment (MU g ) was also estimated by Guggenheim and Higasi method using the dielectric constant and refractive index of solute at different concentrations, the MU g value obtained from these two methods are comparable to the MU g value obtained by the solvatochromic shift method. The excited state dipole moment (MU e ) is greater than the ground state dipole moment (MU g ), which indicates that the excited state is more polar than the ground state. Further, we have evaluated the change in dipole moment (DeltaMU) from the solvatochromic shift method and on the basis of molecular-microscopic solvent polarity parameter[Formula: see text], later on the values were compared. PMID- 27220624 TI - Optical Sensing Properties of Pyrene-Schiff Bases toward Different Acids. AB - A set of (4-substituted-phenyl)-pyren-1-ylmethylene-amine (PMA) was prepared by the reaction of pyrene-1-carboxaldehyde and the corresponding 4-substituted aniline. The structure of the PMA compounds were confirmed by spectroscopic data (IR, (1)HNMR, (13)CNMR, ISI-MS and elemental analysis. The structure of (4-bromo phenyl)-pyren-1-ylmethylene-amine (BrPMA) was further confirmed by the single X ray crystallography. The absorption and emission spectroscopic behaviors were investigated in variant acids. The compounds showed dramatic spectroscopic changes upon acidifying with strong acids and negligible effects when weak acids are used in the acidifications. Hence, the PMA compounds can be used as sensors to distinguish between weak and strong acids. PMID- 27220625 TI - Gender and duration of disease differentiate responses to rituximab-dexamethasone therapy in adults with immune thrombocytopenia. AB - Adults often develop chronic immune thrombocytopenia (ITP) for which treatment order is uncertain. Rituximab and three cycles of dexamethasone (4R + 3Dex) improve treatment responses and short-term disease control but long-term outcome is not known. In adults with ITP treated with 4R + 3D, we sought long-term outcome and associated prognostic variables. Forty-nine adults treated at Weill Cornell received 4R + 3Dex. Their clinical characteristics were reviewed. Duration was median time to treatment failure; Kaplan-Meier estimates were developed. Vbeta Tcell receptor (VBTCR) repertoire was obtained after treatment in 36 patients. Patients were adults with ITP 18-64 years old, median age 37. The 27 females were twice as likely to have an ongoing response to 4R + 3Dex (44.1%) as males (19.6%; P = 0.009). For ITP duration <12 months, 52.7% of patients had continuing responses to 4R + 3Dex compared to 15.3% of patients with diagnosis >12 months (P = 0.02). Females with ITP duration of <12 months had continuing responses in 78.6%, compared to males with <12 months duration of ITP (21.2%). For patients with disease duration <12 months, 67% of females had continuing responses, compared to 31% of males (P = 0.004). Post-treatment polyclonal VBTCR was seen in 9/10 continuing responders (six female, three male) but only 13/26 relapsers/nonresponders (P = 0.068). Durable remissions after treatment with 4R + 3Dex were more frequent in female patients with <12 months of ITP duration and those with polyclonal VBTCR after treatment, emphasizing the roles of duration of disease, gender and T cells in chronic ITP. Differences in pathophysiology of ITP by gender and by duration of ITP require further study. Am. J. Hematol. 91:907 911, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27220626 TI - Multispectral fluorescence imaging of human ovarian and fallopian tube tissue for early-stage cancer detection. AB - With early detection, 5-year survival rates for ovarian cancer exceed 90%, yet no effective early screening method exists. Emerging consensus suggests over 50% of the most lethal form of the disease originates in the fallopian tube. Twenty eight women undergoing oophorectomy or debulking surgery provided informed consent for the use of surgical discard tissue samples for multispectral fluorescence imaging. Using multiple ultraviolet and visible excitation wavelengths and emissions bands, 12 fluorescence and 6 reflectance images of 47 ovarian and 31 fallopian tube tissue samples were recorded. After imaging, each sample was fixed, sectioned, and stained for pathological evaluation. Univariate logistic regression showed cancerous tissue samples had significantly lower intensity than noncancerous tissue for 17 image types. The predictive power of multiple image types was evaluated using multivariate logistic regression (MLR) and quadratic discriminant analysis (QDA). Two MLR models each using two image types had receiver operating characteristic curves with area under the curve exceeding 0.9. QDA determined 56 image type combinations with perfect resubstituting using as few as five image types. Adaption of the system for future in vivo fallopian tube and ovary endoscopic imaging is possible, which may enable sensitive detection of ovarian cancer with no exogenous contrast agents. PMID- 27220627 TI - Antioxidant and Hepatoprotective Efficiency of Selenium Nanoparticles Against Acetaminophen-Induced Hepatic Damage. AB - Overdoses of acetaminophen (APAP), a famous and widely used drug, may have hepatotoxic effects. Nanoscience is a novel scientific discipline that provides specific tools for medical science problems including using nano trace elements in hepatic diseases. Our study aimed to assess the hepatoprotective role of selenium nanoparticles (Nano-Se) against APAP-induced hepatic injury. Twenty-four male rats were classified into three equal groups: a control group that received 0.9 % NaCl, an APAP-treated group (oral administration), and a group treated with Nano-Se (10-20 nm, intraperitoneal (i.p.) injection) and APAP (oral administration). APAP overdose induced significant elevations in liver function biomarkers, hepatic lipid peroxidation, hepatic catalase, and superoxide dismutase (SOD), decreased the reduced glutathione (GSH) content and glutathione reductase (GR) activity, and stimulated significant DNA damage in hepatocytes, compared to control rats. Nano-Se administration improved the hepatic antioxidant protection mechanism and decreased cellular sensitivity to DNA fragmentation. Nano-Se exhibits a protective effect against APAP-induced hepatotoxicity through improved liver function and oxidative stress mediated by catalase, SOD, and GSH and decreases hepatic DNA fragmentation, a hepatic biomarker of cell death. Nano Se could be a novel hepatoprotective strategy to inhibit oxidative stress. PMID- 27220628 TI - Chromium Accumulation in Medicinal Plants Growing Naturally on Tannery Contaminated and Non-contaminated Soils. AB - Herbal preparations used to treat human ailments globally can be contaminated with various heavy metals (HMs) originating from the raw materials or from the manufacturing processes. Therefore, we assessed 22 medicinal plants growing naturally on tannery pollutant contaminated (Site-C) and non-contaminated (Site NC) sites for their ability to accumulate chromium (Cr). The Cr contents in soil and various plant parts were estimated using an atomic absorption spectrophotometer. Translocation and bioconcentration factors were calculated. The soil at Site-C had 27-fold higher concentration of total Cr than at Site-NC. Chromium accumulation is reported for the first time in 50 % of the medicinal plants examined and varied significantly among the sites. Shoots of Ricinus communis and Amaranthus viridis had maximum concentrations of Cr at Site-C, whereas in Site-NC, none of the plants had Cr accumulation >30 ppm. Ricinus communis, Amaranthus viridis, and Amaranthus spinosus had translocation factor (TF) greater than the one in the Site-C and Lantana camara had TF >1 in Site-NC. The bioconcentration factor (BCF) was >1 only for Ricinus communis at both the sites. The majority of the medicinal plants at Site-NC had Cr content exceeding the permissible limit of 2 ppm suggested for herbal raw material. The results of the study clearly emphasize the need for screening plants of therapeutic value for the presence of HMs even when collected from non-contaminated soils. Moreover, proportional allocation of Cr in different plant parts provided an insight on the safety of these parts when specifically used in herbal preparations. PMID- 27220629 TI - Impact of the 2012 extreme drought conditions on private well owners in the United States, a qualitative analysis. AB - BACKGROUND: Extreme hot and dry weather during summer 2012 resulted in some of the most devastating drought conditions in the last half-century in the United States (U.S.). While public drinking water systems have contingency plans and access to alternative resources to maintain supply for their customers during drought, little is known about the impacts of drought on private well owners, who are responsible for maintaining their own water supply. The purpose of this investigation was to explore the public health impacts of the 2012 drought on private well owners' water quality and quantity, identify their needs for planning and preparing for drought, and to explore their knowledge, attitudes, and well maintenance behaviors during drought. METHODS: In the spring of 2013, we conducted six focus group discussions with private well owners in Arkansas, Indiana, and Oklahoma. RESULTS: There were a total of 41 participants, two-thirds of whom were men aged 55 years or older. While participants agreed that 2012 was the worst drought in memory, few experienced direct impacts on their water quantity or quality. However, all groups had heard of areas or individuals whose wells had run dry. Participants conserved water by reducing their indoor and outdoor consumption, but they had few suggestions on additional ways to conserve, and they raised concerns about limiting water use too much. Participants wanted information on how to test their well and any water quality issues in their area. CONCLUSIONS: This investigation identified information needs regarding drought preparedness and well management for well owners. PMID- 27220630 TI - A novel glutathione-S transferase immunosensor based on horseradish peroxidase and double-layer gold nanoparticles. AB - GSTs, a biotransformation enzyme group, can perform metabolism, drug transfer and detoxification functions. Rapid detection of the GSTs with more sensitive approaches is of great importance. In the current study, a novel double-layer gold nanoparticles-electrochemical immunosensor electrode (DGN-EIE) immobilized with Glutathione S-Transferase (GST) antibody derived from Balb/c mice was developed. To increase the fixed quantity of antibodies and electrochemical signal, an electrochemical biosensing signal amplification system was utilized with gold nanoparticles-thionine-chitosan absorbing horseradish peroxidase (HRP). In addition, transmission electron microscope (TEM) was used to characterize the nanogold solution. To evaluate the quality of DGN-EIE, the amperometric I-t curve method was applied to determine the GST in PBS. The results showed that the response current had a good linear correlation with the GST concentration ranged from 0.1-10(4) pg/mL. The lowest detection limit was found at 0.03 pg/mL(S/N = 3). The linear equation was deduced as ?I/% = 7.386lgC + 22.36 (R(2) = 0.998). Moreover, it was validated with high sensitivity and reproducibility. Apparently, DGN-EIE may be a very useful tool for monitoring the GST. PMID- 27220631 TI - Structure of Human GIVD Cytosolic Phospholipase A2 Reveals Insights into Substrate Recognition. AB - Cytosolic phospholipases A2 (cPLA2s) consist of a family of calcium-sensitive enzymes that function to generate lipid second messengers through hydrolysis of membrane-associated glycerophospholipids. The GIVD cPLA2 (cPLA2delta) is a potential drug target for developing a selective therapeutic agent for the treatment of psoriasis. Here, we present two X-ray structures of human cPLA2delta, capturing an apo state, and in complex with a substrate-like inhibitor. Comparison of the apo and inhibitor-bound structures reveals conformational changes in a flexible cap that allows the substrate to access the relatively buried active site, providing new insight into the mechanism for substrate recognition. The cPLA2delta structure reveals an unexpected second C2 domain that was previously unrecognized from sequence alignments, placing cPLA2delta into the class of membrane-associated proteins that contain a tandem pair of C2 domains. Furthermore, our structures elucidate novel inter-domain interactions and define three potential calcium-binding sites that are likely important for regulation and activation of enzymatic activity. These findings provide novel insights into the molecular mechanisms governing cPLA2's function in signal transduction. PMID- 27220632 TI - Structural characterization and anti-inflammatory activity of two novel polysaccharides from the sea squirt, Ascidiella aspersa. AB - It is now recognized that certain polysaccharides can exhibit anti-inflammatory activity, including the glycosaminoglycan (GAG) heparin that is widely used as an anti-coagulant drug. However, it would be desirable to identify molecules that retain the anti-inflammatory actions of heparin, but that are devoid of significant anti-coagulant activity. In the present study we have identified a number of novel GAG and GAG-like polysaccharides (VRP327) from marine organisms, most of which were resistant to digestion by heparinase II and chondroitinase ABC. Fourier transform infra-red spectrum (FTIR) revealed species with variable degrees of sulphation and monosaccharide analysis revealed a range of sugar compounds, which in some cases included sugars not present in mammalian GAGs. (1)H NMR spectra of these species are consistent with the structures of complex polysaccharides. From an initial screening cascade to remove compounds having significant anti-coagulant activity and no overt cytotoxicity, we identified a high molecular weight oversulphated dermatan sulphate (VRP327) isolated from the tunicate Ascidiella aspersa which was fully characterised by NMR spectroscopy. This material was depolymerised to produce well characterized low molecular weight fractions which were demonstrated to be non-toxic, with low levels of anti coagulant activity, and to have demonstrable anti-inflammatory activity assessed in several in vitro and in vivo models. The identification of low molecular weight polysaccharides having significant anti-inflammatory activity without significant anti-coagulant activity may provide novel templates for the development of a novel class of anti-inflammatory drugs. PMID- 27220633 TI - ALTE and smoking exposure: which role of detoxification genes polymorphisms? PMID- 27220634 TI - Salinity stress response in estuarine fishes from the Murray Estuary and Coorong, South Australia. AB - Estuaries are unstable ecosystems and can be changed by the environmental and anthropogenic impact. The Murray Estuary and Coorong were degraded by drought and low freshwater input in the last decade and therefore transformed into the largest hyper-saline lagoon in Australia. This study evaluates the physiological stress of two estuarine fish species (small-mouthed hardyhead Atherinosoma microstoma and Tamar goby Afurcagobius tamarensis) to the induced salinity change in captivity. The test fishes were collected from the Coorong and transported to the laboratory in the water from the Coorong. Each fish species was exposed to different levels of salinity, and a number of enzymes were assessed to measure the stress response of fish to salinity change. The activity of reactive oxygen species was significantly increased with the salinity change in both fish species compared with the fish in the control. Significant salinity effect on superoxide dismutase activity was observed on Tamar goby but not on small-mouthed hardyhead. Conversely, the impact of salinity on catalase activity was detected on small mouthed hardyhead but not on Tamar goby. The study reveals that the induction of physical stress by salinity changes occurred in both Tamar goby and small-mouthed hardyhead despite the varying response of antioxidant enzymes between fish species. The study provides an insight into the understanding of physiological adaptation in estuarine fish to salinity change. The results could improve our knowledge on stress response and resilience of estuarine fish to hypo- and hyper salinity stress. PMID- 27220635 TI - Which factors are associated with extremely short-term survival after surgery in patients with esophageal squamous cell carcinoma? AB - AIMS: Esophageal squamous cell carcinoma (ESCC) is associated with a short median survival and low cure rates. The postoperative survival time of some patients with ESCC is extremely short. It is important to understand risk factors in subsets of patients associated with extremely short-term survival. The standard factors such as T and N stage, which are predictive of actuarial survival, become less important as patients live for <=1 year. However, the prevalence of these factors in these patient populations has not been well documented. We evaluated factors predictive of <=1 year survival in this research. METHODS: We analyzed 1596 patients underwent esophagectomy for ESCC retrospectively. The demographic and clinicopathologic characteristics were compared between patients who died within 1 year of esophagectomy and patients who survived more than 1 year after esophagectomy. RESULTS: Univariate analysis showed significant differences between the two groups regarding gender, weight loss, comorbidity, neoadjuvant treatment, completeness of resection, pathological T stage, pathological N stage, histologic grade, the number of metastatic lymph nodes, postoperative complications, postoperative pulmonary infection and postoperative hospital stay. Based on logistic regression analysis, significant factors associated with extremely short-term survival were male gender, incomplete tumor resection, higher pathological T stage, higher pathological N stage and postoperative pulmonary infection. CONCLUSION: The independent positive predictors for extremely short-term survival are male gender, incomplete tumor resection and postoperative pulmonary infection besides higher pathological T stage and higher pathological N stage. PMID- 27220636 TI - Fiber-Type Random Laser Based on a Cylindrical Waveguide with a Disordered Cladding Layer. AB - This letter reports a fiber-type random laser (RL) which is made from a capillary coated with a disordered layer at its internal surface and filled with a gain (laser dye) solution in the core region. This fiber-type optical structure, with the disordered layer providing randomly scattered light into the gain region and the cylindrical waveguide providing confinement of light, assists the formation of random lasing modes and enables a flexible and efficient way of making random lasers. We found that the RL is sensitive to laser dye concentration in the core region and there exists a fine exponential relationship between the lasing intensity and particle concentration in the gain solution. The proposed structure could be a fine platform of realizing random lasing and random lasing based sensing. PMID- 27220637 TI - SIRT1 is downregulated during peripheral blood stem cell mobilization in healthy donors by granulocyte-colony stimulating factor. PMID- 27220638 TI - Evolution of chronic myelomonocytic leukemia to myeloproliferative neoplasm. PMID- 27220639 TI - Prediction of high risk for death in patients with follicular lymphoma receiving rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in first-line chemotherapy. AB - Risk stratification of patients with relapsed and refractory follicular lymphoma (FL) remains challenging. Recently, much attention has been paid to the impact of early progression of disease within 2 years of diagnosis (early POD) on subsequent survival. The aim of this study was to clarify the clinical features and prognostic factors of patients with FL who experienced early POD. Data were available for 94 patients diagnosed with FL (clinical stage II-IV) who had received immunochemotherapy. Early POD was seen in 20 % of these patients. The Cox proportional hazards model showed worse overall survival (OS) in the patients with early POD compared with those without early POD (5-year OS rates 48 % vs. 96 %, P < 0.0001). In multivariate analysis, early POD (P = 0.003) and poor performance status (P = 0.006) remained a significant factor for subsequent OS. In Follicular Lymphoma International Prognostic Index (FLIPI)- and Follicular Lymphoma International Prognostic Index-2 (FLIPI2)-adjusted Cox regression analysis, early POD was associated with markedly reduced OS with a hazard ratio of 11.2 [95 % confidence interval (CI) 3.13-40.3, P < 0.001] and 13.5 (95 % CI 3.22-56.3, P < 0.003), respectively. Among patients who had early POD, high levels of serum lactate dehydrogenase (LDH) both at the time of initial diagnosis and first progression could be associated with worse survival (2-year OS rates 33 vs. 92 %, P < 0.0001). Evaluation of LDH levels at the time of initial diagnosis and first progression may be important to define patients who were associated with worse prognosis. Risk stratification of patients with early POD could lead to improved clinical outcomes for FL patients. Further research is needed to investigate its value for decision making. PMID- 27220641 TI - Chromatin: BRD4 kicks out nucleosomes with its HAT. PMID- 27220642 TI - A four-lane highway to cancer. PMID- 27220640 TI - Introducing STRaNDs: shuttling transcriptional regulators that are non-DNA binding. AB - Many proteins originally identified as cytoplasmic - including many associated with the cytoskeleton or cell junctions - are increasingly being found in the nucleus, where they have specific functions. Here, we focus on proteins that translocate from the cytoplasm to the nucleus in response to external signals and regulate transcription without binding to DNA directly (for example, through interaction with transcription factors). We propose that proteins with such characteristics are classified as a distinct group of extracellular signalling effectors, and we suggest the term STRaND (shuttling transcriptional regulators and non-DNA binding) to refer to this group. Crucial roles of STRaNDs include linking cell morphology and adhesion with changes in transcriptional programmes in response to signals such as mechanical stresses. PMID- 27220643 TI - [Guideline-adherent psychiatric psychotherapeutic treatment of bipolar disorders : Which resources are needed?] AB - In this article the guideline-adherent psychiatric psychotherapeutic treatment of patients with bipolar disorders is outlined and the required resources are estimated. Based on the core recommendations of the S3 guidelines for diagnostics and treatment of bipolar disorders published in 2012, inpatient treatment needs in hours per week and per patient are determined for both manic and bipolar depressive episodes. The resulting staffing requirements are estimated on this basis. In summary, for guideline-adherent inpatient psychiatric psychotherapeutic treatment the additional needs regarding the physician/psychotherapeutic domain add up to 44 min per patient and week during a manic episode and 88 min for patients with bipolar depression when compared to current psychiatry staffing regulations. PMID- 27220644 TI - [Not Available]. PMID- 27220645 TI - [An unacceptable study]. PMID- 27220646 TI - Fishing for Function in the Human Gene Pool. AB - Identification and characterization of causal non-coding variants in human genomes is challenging and requires substantial experimental resources. A new study by Tehranchi et al. describes a cost-effective approach for accurate mapping of molecular quantitative trait loci (QTLs) from pooled samples, a powerful way to link disease-associated changes to molecular functions. PMID- 27220647 TI - Supportive care services in hemato-oncology centers: a national survey. AB - BACKGROUND: In the field of hemato-oncology, there is paucity of data assessing models of integration between hemato-oncology and other partner specialties. The aim of this national survey was to gather information about the status of the integration of this kind of activity in hemato-oncologic units existing in Italy. METHODS: A national telephone survey was conducted to gather information about the status of the integration of hemato-oncologic and supportive care/anesthesiological services. From the national registry of hemato-oncology units, 149 centers were contacted by phone and a dedicated doctor was identified to gather information about the center through a telephone interview. RESULTS: Eighty-one centers (54.3 %) agreed to participate. A mean of 206 (SD 132) painful procedures/year/center were performed. No significant differences among regions and centers were found (P = 0.680). Of the centers, 41.9 % usually asked for anesthesiological consultation to perform painful procedures. No differences were found between the regions (P = 0.137). A mean of 1.8 (SD 1.2) days elapsed from the request to the procedure performance (P = 0.271). No differences among the regions were found (P = 0.350). A mean of 220 (SD 89) central venous vascular accesses/year/center were performed. No differences among regions were found (P = 0.170). No differences among the centers were found (P = 0.691). A mean of 1.8 (SD 1.2) days elapsed from the request to the performance of procedure. Of the centers, 64.2 % had a palliative care team. No differences among regions were found (P = 0.331). A mean of 31.5 (SD 12.2) consultations/year/center for pain control were required. No differences among the regions were found (P = 0.556). Of the centers, 30.8 % had some beds for palliative care. No differences among the regions were found (P = 0.641). Of the centers, 32 % had a hospice was available. No differences among regions were found (P = 0.298). CONCLUSION: Integration between hemato-oncology and other professionals is unlikely to be optimal in Italy. Such integration is complex and needs great efforts to solve several organizational problems. PMID- 27220648 TI - Importance of sexuality in colorectal cancer: predictors, changes, and response to an intimacy enhancement intervention. AB - PURPOSE: The primary objectives were (1) to examine the importance of sexuality within the self-view and cross-sectional correlates for 120 colorectal cancer patients and (2) to determine whether the importance of sexuality changed for 46 colorectal cancer patients and partners participating in an intimacy enhancement intervention. METHODS: Two newly developed items assessed importance of sexuality within the self-view (1) currently and (2) before cancer; a calculated change score assessed perceived change. In the cross-sectional sample, associations between importance of sexuality and demographic and medical factors and sexual function status were examined. Intervention participants' importance ratings before and after participation were used to calculate effect sizes. RESULTS: For patients, importance of sexuality before cancer was greater (M = 65.7) than current importance (M = 56.8, p = .001). Greater current importance of sexuality was associated with partnered status, non-metastatic disease, and not being in treatment. Scoring in the sexually functional range was associated with greater current importance of sexuality for men and a smaller perceived change in importance for both men and women (p values <.05). Sexual function status also significantly predicted current importance independent of covariates. Small to medium effect sizes for intervention patients (.37) and partners (.60) were found for increases in importance of sexuality. Items showed evidence of test-retest reliability and construct validity. CONCLUSIONS: Coping with sexual concerns is important to those affected by colorectal cancer. Findings suggest that the importance of sexuality can decrease through colorectal cancer and associated sexual problems and can increase through participating in an intimacy-focused intervention. PMID- 27220649 TI - Electrochemical detection of Piscirickettsia salmonis genomic DNA from salmon samples using solid-phase recombinase polymerase amplification. AB - Electrochemical detection of solid-phase isothermal recombinase polymerase amplification (RPA) of Piscirickettsia salmonis in salmon genomic DNA is reported. The electrochemical biosensor was constructed by surface functionalization of gold electrodes with a thiolated forward primer specific to the genomic region of interest. Solid-phase RPA and primer elongation were achieved in the presence of the specific target sequence and biotinylated reverse primers. The formation of the subsequent surface-tethered duplex amplicons was electrochemically monitored via addition of streptavidin-linked HRP upon completion of solid-phase RPA. Successful quantitative amplification and detection were achieved in less than 1 h at 37 degrees C, calibrating with PCR amplified genomic DNA standards and achieving a limit of detection of 5 . 10-8 MUg ml-1 (3 . 103 copies in 10 MUl). The presented system was applied to the analysis of eight real salmon samples, and the method was also compared to qPCR analysis, observing an excellent degree of correlation. Graphical abstract Schematic of use of electrochemical RPA for detection of Psiricketessia salmonis in salmon liver. PMID- 27220650 TI - Optimized Spiral Metal-Gallium-Nitride Nanowire Cavity for Ultra-High Circular Dichroism Ultraviolet Lasing at Room Temperature. AB - Circularly polarized laser sources with small footprints and high efficiencies can possess advanced functionalities in optical communication and biophotonic integrated systems. However, the conventional lasers with additional circular polarization converters are bulky and hardly compatible with nanophotonic circuits, and most active chiral plasmonic nanostructures nowadays exhibit broadband emission and low circular dichroism. In this work, with spirals of gallium nitride (GaN) nanowires (NWRs) covered by a metal layer, we demonstrated an ultrasmall semiconductor laser capable of emitting circularly-polarized photons. The left- and right-hand spiral metal nanowire cavities with varied periods were designed at ultraviolet wavelengths to achieve the high quality factor circular dichroism metastructures. The dissymmetry factors characterizing the degrees of circular polarizations of the left- and right-hand chiral lasers were 1.4 and -1.6 (+/-2 if perfectly circular polarized), respectively. The results show that the chiral cavities with only 5 spiral periods can achieve lasing signals with the high degrees of circular polarizations. PMID- 27220651 TI - Streamlining emergent hand and wrist radiography with a modified four-view protocol. AB - This study aims to determine whether a modified four-view hand and wrist study performs comparably to the traditional seven views in the evaluation of acute hand and wrist fractures. This retrospective study was approved by the institutional review board with waiver of informed consent. Two hundred forty patients (50 % male; ages 18-92 years) with unilateral three-view hand (posteroanterior, oblique, and lateral) and four-view wrist (posteroanterior, oblique, lateral, and ulnar deviation) radiographs obtained concurrently following trauma were included in this study. Four emergency radiologists interpreted the original seven images, with two radiologists independently evaluating each study. The patients' radiographs were then recombined into four view series using the three hand images and the ulnar deviated wrist image. These were interpreted by the same radiologists following an 8-week delay. Kappa statistics were generated to measure inter-observer and inter-method agreement. Generalized linear mixed model analysis was performed between the seven- and four view methods. Of the 480 reports generated in each of the seven- and four-view image sets, 142 (29.6 %) of the seven-view and 126 (26.2 %) of the four-view reports conveyed certain or suspected acute osseous findings. Average inter observer kappa coefficients were 0.7845 and 0.8261 for the seven- and four-view protocols, respectively. The average inter-method kappa was 0.823. The odds ratio of diagnosing injury using the four-view compared to the seven-view algorithm was 0.69 (CI 0.45-1.06, P = 0.0873). The modified four-view hand and wrist radiographic series produces diagnostic results comparable to the traditional seven views for acute fracture evaluation. PMID- 27220652 TI - What is the diagnostic value of head MRI after negative head CT in ED patients presenting with symptoms atypical of stroke? AB - The diagnostic value of head magnetic resonance imaging after negative head computed tomography for emergency department patients with vague neurologic symptoms, such as dizziness and altered mental status, remains an ongoing discussion. The objective of this study is to detect the subgroup of patients with such presentations having minor strokes whom may benefit from primary and secondary stroke prevention. We conducted a retrospective analysis and stratified patient risk factors associated with positive findings on subsequent head MRI ordered by the emergency department physician following a normal head CT. Two hundred fifty-two patients presenting with atypical stroke symptoms to the emergency department had a negative head CT followed by head MRI within 24 h ordered by emergency department clinician (123 males and 129 females; mean age of 59.4). Twenty nine of the 252 patients (11.5 %) had findings of acute to subacute infarct on the subsequent MRI. Positive MRI findings were statistically correlated with the following variables: age (p < 0.001), history of hyperlipidemia (p = 0.019), hypertension (p < 0.001), diabetes (p = 0.004), anticoagulation use (p = 0.029), and prior transient ischemic attack or stroke (p < 0.001). The mean age of the MRI-positive group was 74.1 years, with a mean difference of 16.7 +/- 2.4 years more than the MRI-negative group (95 % CI, 11.8 21.5 years) (t = 6.8, p < 0.001). Emergency physicians caring for patients with vague neurologic complaints should maintain a lower threshold for ordering a head MRI despite a negative head CT for elderly patients with a history of prior stroke or transient ischemic attack to exclude a CT occult or minor ischemic stroke. PMID- 27220653 TI - Efficiency and safety of coronary CT angiography compared to standard care in the evaluation of patients with acute chest pain: a Canadian study. AB - The optimal assessment of patients with chest pain and possible acute coronary syndrome (ACS) remains a diagnostic dilemma for emergency physicians. Cardiac computed tomographic angiography (CCTA) may identify patients who can be safely discharged home from the emergency department (ED). The objective of the study was to compare the efficiency and safety of CCTA to standard care in patients presenting to the ED with low- to intermediate-risk chest pain. This was a single center before-after study enrolling ED patients with chest pain and low to intermediate risk of ACS, before and after implementing a cardiac CT-based management protocol. The primary outcome was efficiency (time to diagnosis). Secondary outcomes included safety (30-day incidence of major adverse cardiovascular events (MACE)) and length of stay in the ED. We enrolled 258 patients: 130 in the standard care group and 128 in the cardiac CT-based management group. The cardiac CT group had a shorter time to diagnosis of 7.1 h (IQR 5.8-14.0) compared to 532.9 h (IQR 312.8-960.5) for the standard care group (p < 0.0001) but had a longer length of stay in the ED of 7.9 h (IQR 6.5-10.8) versus 5.5 h (IQR 3.9-7.7) (p < 0.0001). The MACE rate was 1.6 % in the standard care group and 0 % in the cardiac CT group. In conclusion, a cardiac CT-based management strategy to rule out ACS in ED patients with low- to intermediate-risk chest pain was safe and led to a shorter time to diagnosis but increased length of stay in the ED. PMID- 27220654 TI - Acute aortic syndrome-pitfalls on gated and non-gated CT scan. AB - Acute aortic syndrome (AAS) is a life-threatening condition which includes aortic dissection (AD), penetrating aortic ulcer (PAU) and intramural hematoma (IMH). Multi-detector computed tomography (MDCT) plays a crucial role in the diagnosis of this condition and for further clinical follow-up. It is important for radiologists to be aware of common pitfalls in cardiac-gated and non-gated CT in diagnosing AAS. They should also be wary of common mimics of AAS which may make a significant difference towards management of these patients. In this review, we present from our practice some of the common pitfalls and mimics of AAS on MDCT. PMID- 27220655 TI - Kigelia africana (Lam.) Benth. (Sausage tree): Phytochemistry and pharmacological review of a quintessential African traditional medicinal plant. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Kigelia africana is a quintessential African herbal medicinal plant with a pan-African distribution and immense indigenous medicinal and non-medicinal applications. The plant is use traditionally as a remedy for numerous disease such as use wounds healing, rheumatism, psoriasis, diarrhea and stomach ailments. It is also use as an aphrodisiac and for skin care. AIM OF THE REVIEW: The present review aims to compile an up-to-date review of the progress made in the continuous pharmacological and phytochemistry investigation of K. africana and the corresponding commercial and pharmaceutical application of these findings with the ultimate objective of providing a guide for future research on this plant. METHOD: The scholarly information needed for this paper were predominantly sourced from the electronic search engines such as Google, Google scholar; publishing sites such as Elsevier, scienceDirect, BMC, PubMed; other scientific database sites for chemicals such as ChemSpider, PubChem, and also from online books. RESULTS: Pharmacological investigations conducted confirm the anti-inflammatory, analgesic, antioxidant and anticancer activity of the extract of different parts of the plant. Bioactive constituents are found to be present in all parts of the plant. So far, approximately 150 compounds have been characterized from different part of the plant. Iridoids, naphthoquinones, flavonoids, terpenes and phenylethanoglycosides are the major class of compounds isolated. Novel compounds with potent antioxidant, antimicrobial and anticancer effect such as verbascoside, verminoside and pinnatal among others, have been identified. Commercial trade of K. africana has boosted in the las few decades. Its effect in the maintenance of skin has been recognized resulting in a handful of skin formulations in the market. CONCLUSIONS: The pharmaceutical potentials of K. africana has been recognized and have witness a surge in research interest. However, till date, many of its traditional medicinal uses has not been investigated scientifically. Further probing of the existential researches on its pharmacological activity is recommended with the end-goal of unravelling the pharmacodynamics, pharmacokinetics, clinical relevance and possible toxicity and side effects of both the extract and the active ingredients isolated. PMID- 27220656 TI - Effects of riparian forest removal on the trophic dynamics of a Neotropical stream fish assemblage. AB - The effects of riparian forest removal on a neotropical stream fish assemblage were assessed in the Mata Atlantica. Fish assemblage structure and fish feeding patterns were quantified at three sites along a pristine-to-deforested gradient in a Serra do Mar stream: (1) a pristine site fully covered by canopy with no light penetration and transparent waters, (2) an intermediate site with partially removed forest and (3) a fully removed forest site with no canopy and full light penetration where siltation and turbid waters predominate. Fish assemblage structure, fish densities and their feeding patterns differed widely among sites. Whilst the same five fish species occurred at the three sites, forest removal favoured the occurrence of sediment-tolerant iliophagous benthic species at the deforested site. At the pristine site, invertebrate prey predominated in water column fish diet and feeding overlap among species was low. Severe shifts in the feeding patterns were noticed in both deforested sites. Invertebrates were replaced by detritus, organic matter and algae at both sites and feeding overlap increased markedly. The overwhelming feeding adaptability of these neotropical fishes appeared capable of buffering the deleterious effects of forest removal on stream quality in terms of increased light penetration, siltation and water turbidity. Forest cutting in this Mata Atlantica stream clearly caused strong functional changes associated with forest clearance through important modifications in the assemblage organization and trophic patterns of the main species, but did not eliminate species. PMID- 27220657 TI - A case of simultaneous esophageal squamous cell carcinoma and Barrett's adenocarcinoma. AB - A 77-year-old male with a long history of alcohol consumption and smoking was admitted for hoarseness and dysphagia. Computed tomography revealed thickening of the middle intrathoracic esophageal wall and multiple mediastinal lymph node swellings. Esophagogastroduodenoscopic examination disclosed an advanced-stage squamous cell carcinoma lesion in the middle intrathoracic esophagus with synchronous early stage Barrett's adenocarcinoma. The patient underwent endoscopic submucosal dissection for the adenocarcinoma followed by chemoradiation therapy for the squamous cell carcinoma. In spite of their common risk factors, the simultaneous manifestation of esophageal squamous cell carcinoma and Barrett's adenocarcinoma is extremely rare and requires further study. PMID- 27220658 TI - Circulating serum irisin levels in obesity and type 2 diabetes mellitus. AB - Irisin is an exercise-regulated myokine inducing browning of white adipose tissue and has gained interest as a potential new strategy to combat obesity and its associated disorders, such as type 2 diabetes mellitus (T2DM). The aim of this study is to evaluate the circulating serum irisin levels in obesity and T2DM and also to elucidate possible relationships between serum irisin levels with anthropometric and metabolic parameters of obesity and T2DM. One hundred fifty newly diagnosed T2DM patients as well as 150 nondiabetic control subjects were enrolled in this study. Nondiabetic controls were then stratified according to their body mass index (BMI) into three subgroups; lean, overweight, and obese. Serum irisin levels were evaluated by enzyme-linked immunosorbent assay. Serum irisin levels were significantly decreased in T2DM patients compared with nondiabetic controls. Obese nondiabetic controls had significantly higher serum irisin levels compared with lean nondiabetic controls. In both nondiabetic controls and T2DM patients, serum irisin was significantly positively correlated with BMI (r = 0.985, P < 0.001 and r = 0.218, P = 0.007, respectively), fat mass (r = 0.959, P < 0.001 and r = 0.202, P = 0.013, respectively), fat-free mass (r = 0.606, P < 0.001 and r = 0.194, P = 0.017, respectively), fat-free mass index (r = 0.820, P < 0.001 and r = 0.179, P = 0.028, respectively), waist-to-hip ratio (r = 0.880, P < 0.001 and r = 0.194, P = 0.017, respectively), fasting insulin (r = 0.989, P < 0.001 and r = 0.207, P = 0.011, respectively), and HOMA-IR (r = 0.989, P < 0.001 and r = 0.185, P = 0.023, respectively), whereas; significantly negatively correlated with insulin sensitivity (r = -0.992, P < 0.001 and r = 0.187, P = 0.022, respectively). In this study, we demonstrated that circulating serum irisin levels were increased in obese nondiabetic subjects, while decreased in T2DM patients. Moreover, serum irisin levels were correlated with anthropometric and metabolic markers of obesity and T2DM. (c) 2016 IUBMB Life, 68(7):544-556, 2016. PMID- 27220659 TI - International clinimetric evaluation of the MG-QOL15, resulting in slight revision and subsequent validation of the MG-QOL15r. AB - INTRODUCTION: The MG-QOL15 is a validated, health-related quality of life (HRQOL) measure for myasthenia gravis (MG). Widespread use of the scale gave us the opportunity to further analyze its clinimetric properties. METHODS: We first performed Rasch analysis on >1,300 15-item Myasthenia Gravis Quality of Life scale (MG-QOL15) completed surveys. Results were discussed during a conference call with specialists and biostatisticians. We decided to revise 3 items and prospectively evaluate the revised scale (MG-QOL15r) using either 3, 4, or 5 responses. Rasch analysis was then performed on >1,300 MG-QOL15r scales. RESULTS: The MGQOL15r performed slightly better than the MG-QOL15. The 3-response option MG-QOL15r demonstrated better clinimetric properties than the 4- or 5-option scales. Relative distributions of item and person location estimates showed good coverage of disease severity. CONCLUSIONS: The MG-QOL15r is now the preferred HRQOL instrument for MG because of improved clinimetrics and ease of use. This revision does not negate previous studies or interpretations of results using the MG-QOL15. Muscle Nerve 54: 1015-1022, 2016. PMID- 27220660 TI - A DNA Hypermethylation Profile Independently Predicts Biochemical Recurrence Following Radical Prostatectomy. AB - PURPOSE: Detection of DNA hypermethylation is emerging as a novel molecular biomarker for different malignancies. We intend to define whether a hypermethylation profile of patients with prostate cancer (PCa) predicts biochemical recurrence (BCR) after radical prostatectomy (RP). MATERIAL AND METHODS: Genome-wide methylation analysis was performed using the GoldenGate Methylation Cancer Panel-I (Illumina, Inc.) on 10 normal prostate tissues and 58 tumor samples from patients treated by RP followed for prostate-specific antigen (PSA) failure (>0.4 ng/ml) and disease progression. Patients were classified on the basis of D'Amico criteria according to clinical staging, PSA at diagnosis and Gleason score after pathologist review. Hypermethylation status of 1505 CpGs present in the promoter region of 807 genes was studied. Hierarchical clustering analysis was performed and relationships with outcome were investigated using log rank analysis and Cox regression model. RESULTS: We found 28 genes significantly hypermethylated in >20% of the tumors analyzed. Four clusters of patients were characterized by their DNA methylation profile, one at higher risk to develop BCR (p = 0.005). Multivariate analysis revealed patients in this cluster (HR 2.56), and high-risk patients (HR 4.34) according to D'Amico classification were independent predictors of BCR after prostatectomy. From the selected genes MT1A, ALOX12, GSTM2, APC, MYCL2 and RARB hypermethylation predicted BCR and GSTM2 (HR 3.78) and MYCL2 hypermethylation (HR 2.71) did so independently. CONCLUSION: Epigenetic silencing of GSTM2 and MYCL2 comprise novel molecular markers to predict BCR after surgery for medium- and high-risk localized PCa undergoing surgical treatment and hypermethylation of these genes could be incorporated to the clinical and pathological factors defining the patient at higher risk of PSA failure after prostatectomy. The limitation of the study is that no independent validation cohort is analysed. PMID- 27220661 TI - Development of three specific PCR-based tools to determine quantity, cellulolytic transcriptional activity and phylogeny of anaerobic fungi. AB - Anaerobic fungi (AF) decompose plant material with their rhizoid and multiple cellulolytic enzymes. They disintegrate the complex structure of lignocellulosic substrates, making them more accessible and suitable for further microbial degradation. There is also much interest in their use as biocatalysts for biotechnological applications. Here, three novel polymerase chain reaction (PCR) based methods for detecting AF and their transcriptional activity in in vitro cultures and environmental samples were developed. Two real-time quantitative PCR (qPCR)-based methods targeting AF were developed: AF-SSU, was designed to quantify the 18S rRNA genes of AF. AF-Endo, measuring transcripts of an endoglucanase gene from the glycoside hydrolase family 5 (GH5), was developed to quantify their transcriptional cellulolytic activity. The third PCR based approach was designed for phylogenetical analysis. It targets the 28S rRNA gene (LSU) of AF revealing their phylogenetic affiliation. The in silico-designed primer/probe combinations were successfully tested for the specific amplification of AF from animal and biogas plant derived samples. In combination, these three methods represent useful tools for the analysis of AF transcriptional cellulolytic activity, their abundance and their phylogenetic placement. PMID- 27220662 TI - Effect of edible coatings with essential oils on the quality of red raspberries over shelf-life. AB - BACKGROUND: The objective of the present work was to develop strategies for increasing the shelf-life of red raspberries (Rubus idaeus L.), by preventing microorganism growth. RESULTS: Fruits coated with alginate plus lemon essential oil (0.2%) or orange essential oil (0.1%) after 15 days of storage had less red skin than the remaining samples. The less red color verified in these samples was also coincident with the lower concentration of anthocyanins at the end of the experiment as well as the lower capacity for scavenging ABTS free radicals or quenching singlet oxygen. Cyanidin and pelargonidin glucosides were found in raspberries fruits. The edible coatings supplemented with the essential oil of orange either at 0.1% or 0.2% were very efficient for controlling yeast and mold growth after 15 days of storage. To control the development of aerobic mesophilic bacteria the use of essential oil of lemon 0.2% and essential oil of orange 0.1% were the most efficient. CONCLUSION: The application of the film improved post harvest quality of raspberry, since the addition of essential oils of citrus films promoted to the inhibitory effect of fungi and bacteria growth after 15 days of storage, without changing quality parameters. (c) 2016 Society of Chemical Industry. PMID- 27220663 TI - Effect of tyrosine kinase inhibitors on stemness in normal and chronic myeloid leukemia cells. AB - Although tyrosine kinase inhibitors (TKIs) efficiently cure chronic myeloid leukemia (CML), they can fail to eradicate CML stem cells (CML-SCs). The mechanisms responsible for CML-SC survival need to be understood for designing therapies. Several previous studies suggest that TKIs could modulate CML-SC quiescence. Unfortunately, CML-SCs are insufficiently available. Induced pluripotent stem cells (iPSCs) offer a promising alternative. In this work, we used iPSCs derived from CML patients (Ph+). Ph+ iPSC clones expressed lower levels of stemness markers than normal iPSCs. BCR-ABL1 was found to be involved in stemness regulation and ERK1/2 to have a key role in the signaling pathway. TKIs unexpectedly promoted stemness marker expression in Ph+ iPSC clones. Imatinib also retained quiescence and induced stemness gene expression in CML SCs. Our results suggest that TKIs might have a role in residual disease and confirm the need for a targeted therapy different from TKIs that could overcome the stemness-promoting effect caused by TKIs. Interestingly, a similar pro stemness effect was observed in normal iPSCs and hematopoietic SCs. These findings could help to explain CML resistance mechanisms and the teratogenic side effects of TKIs in embryonic cells. PMID- 27220664 TI - Inhibition of precursor B-cell malignancy progression by toll-like receptor ligand-induced immune responses. PMID- 27220665 TI - Clinical response to ibrutinib is accompanied by normalization of the T-cell environment in CLL-related autoimmune cytopenia. PMID- 27220666 TI - The JAK inhibitor ruxolitinib impairs dendritic cell migration via off-target inhibition of ROCK. PMID- 27220667 TI - Discovery of a highly potent FLT3 kinase inhibitor for FLT3-ITD-positive AML. PMID- 27220668 TI - Aberrations identified by genomic arrays in normal karyotype CMML can be detected in 40% of patients, but do not add prognostic information to molecular mutations. PMID- 27220669 TI - Robustness of comprehensive DNA- and RNA-based assays at diagnosis of acute myeloid leukemia using blood and bone marrow stored on filter cards. PMID- 27220670 TI - Increased sensitivity of BRCA defective triple negative breast tumors to plumbagin through induction of DNA Double Strand Breaks (DSB). AB - We have earlier shown that Plumbagin (PB) can induce selective cytotoxicity to BRCA1 defective ovarian cancer cells; however, the effect of this molecule in BRCA1 mutated breast cancers has not been analyzed yet. Here, we report that reactive oxygen species (ROS) induced by PB resulted in DNA DSB and activates downstream signaling by ATR/ATM kinases and subsequent apoptosis. PB reduces DNA- dependent protein kinase (DNA-PK) expression and inhibits NHEJ (Non Homologous End Joining) activity in BRCA1 defective breast cancer cells. Also, PB induces apoptosis in two different BRCA1 conditional knock out murine models: MMTV-Cre; BRCA1(Co/Co) and WAP-Cre; BRCA1(Co/Co), at 2 mg/kg body weight, but 32 mg/kg of carboplatin (CN) was needed to induce apoptosis in them. This is the first study where two different tissue specific promoter driven transgenic mice models with BRCA1 exon 11 deletions are used for preclinical drug testing. The apoptosis induced by PB in HR (Homologous Recombination) defective triple negative BRCA1 mutant cell lines and in mouse models occur by inducing ROS mediated DNA DSB. The toxicity profile as compared with CN in transgenic mice provides evidence for PB's safer disposition as a therapeutic lead in breast cancer drug development. PMID- 27220671 TI - Clinical Significance of ST Elevation in Lead aVR in Acute Pulmonary Embolism. AB - BACKGROUND: Prognostic stratification of patients with acute pulmonary embolism (PTE) is crucial in identifying patients who would benefit from more aggressive treatment. We aimed to examine the value of ST elevation in lead aVR (STEaVR ) in predicting hospital mortality following PTE. MATERIALS: Two hundred patients with a diagnosis of PTE were allocated into two groups based on the presence or absence of STEaVR . Multivariate logistic regression analysis was used to investigate the role of "STEaVR " in relation to the other risk factors in predicting prognosis of PTE. RESULTS: Out of 200 patients, 24 (12.0%) had STEaVR . Patients with STEaVR were more likely to present with hypotension and tachycardia than those who did not have this electrocardiographic finding. A total of 33.3% of patients with STEaVR and 13.1% of those without STEaVR died during hospitalization. STEaVR had a low sensitivity of 25.8% but a high specificity of 90.5% for predicting hospital mortality. Odds ratio for hospital mortality was 3.32 for STEaVR with 95% confidence interval of 1.28-8.64 (P = 0.017) in univariate analysis. In multivariate analysis shock was the strongest predictor of hospital mortality. CONCLUSION: The presence of STEaVR is indicative of hemodynamic instability, thereby having the ability to predict poor outcome. However, its impact on hospital mortality disappears when the presence of shock on admission is factored in the prediction model. PMID- 27220672 TI - Heart Failure Association of the European Society of Cardiology heart failure nurse curriculum. AB - Recent advances in care and management of heart failure have improved outcome, largely as a result of the developing evidence basis for medications, implantable devices and the organization of heart failure follow-up. Such developments have also increased the complexity of delivering and coordinating care. This has led to a change to the way in which heart failure services are organized and to the traditional role of the heart failure nurse. Nurses in many countries now provide a range of services that include providing care for patients with acute and with chronic heart failure, working in and across different sectors of care (inpatient, outpatient, community care, the home and remotely), organising care services around the face-to-face and the remote collection of patient data, and liaising with a wide variety of health-care providers and professionals. To support such advances the nurse requires a skill set that goes beyond that of their initial education and training. The range of nurses' roles across Europe is varied. So too is the nature of their educational preparation. This heart failure nurse curriculum aims to provide a framework for use in countries of the European Society of Cardiology. Its modular approach enables the key knowledge, skills, and behaviours for the nurse working in different care settings to be outlined and so facilitate nursing staff to play a fuller role within the heart failure team. PMID- 27220673 TI - Fecal Human Neutrophil Peptide Levels Correlate with Intestinal Inflammation in Ulcerative Colitis. AB - BACKGROUND/AIM: Fecal markers have recently been found to provide convenient and noninvasive assessment of intestinal inflammation in inflammatory bowel disease (IBD). In this study, we examined the clinical significance of fecal human neutrophil peptides (F-HNP) in the evaluation of IBD disease activity. METHODS: This study enrolled 70 patients with IBD, consisting of 45 patients with ulcerative colitis (UC), 25 patients with Crohn's disease (CD), and 11 non-IBD controls. Stools samples were evaluated for the association between F-HNP concentration and disease and endoscopic activity in each group and the correlation between F-HNP and fecal calprotectin (F-CP) concentrations. RESULTS: Median F-HNP levels were as follows: UC: 25.6 ng/ml; CD: 20.1 ng/ml; and non-IBD controls: 4.9 ng/ml. F-HNP levels were significantly higher in each IBD group, especially in the UC group, than in the control group. In the UC group, both F HNP and F-CP levels were significantly higher during active disease compared to the remission phase. Both markers were significantly correlated with the Mayo endoscopic score, although the correlation was stronger for F-HNP than for F-CP (r = 0.66 vs. r = 0.54). CONCLUSION: F-HNP is a noninvasive marker that is useful for evaluating UC endoscopic activity. PMID- 27220674 TI - Intraperitoneally administered IgG from patients with amyotrophic lateral sclerosis or from an immune-mediated goat model increase the levels of TNF-alpha, IL-6, and IL-10 in the spinal cord and serum of mice. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that involves the selective loss of the upper and lower motor neurons (MNs). Neuroinflammation has been implicated in the pathogenesis of the sporadic form of the disease. We earlier developed immune-mediated animal models of ALS and demonstrated humoral and cellular immune reactions in the nervous system and in the sera of patients and animals. The accumulation of immunoglobulin G (IgG), an elevated intracellular level of calcium, ultrastructural alterations in the MNs, and activation of the microglia were noted in the spinal cord of ALS patients. Similar alterations developed in mice inoculated intraperitoneally with IgG from ALS patients or from an immune-mediated goat model. METHODS: We have now examined whether the intraperitoneal injection of mice with IgG from sporadic ALS patients or from immunized goats with the homogenate of the anterior horn of the bovine spinal cord is associated with changes in the pro-inflammatory (TNF-alpha and IL 6) and anti-inflammatory (IL-10) cytokines in the spinal cord and serum of the mice. The levels of cytokines were measured by ELISA. RESULTS: Intraperitoneally administered IgG from the ALS patients induced subclinical signs of MN disease, while the injection of IgG from immunized goats resulted in a severe respiratory dysfunction and limb paralysis 24 h after the injections. Significantly increased levels of TNF-alpha and IL-10 were detected in the spinal cord of the mice injected with the human ALS IgG. The level of IL-6 increased primarily in the serum. The IgG from the immunized goats induced highly significant increases in the levels of all three cytokines in the serum and the spinal cord of mice. CONCLUSIONS: Our earlier experiments had proved that when ALS IgG or IgG from immune-mediated animal models was inoculated into mice, it was taken up in the MNs and had the ability to initiate damage in them. The pathological process was paralleled by microglia recruitment and activation in the spinal cord. The present experiment revealed that these forms of IgG cause significant increases in certain cytokine levels locally in the spinal cord and in the serum of the inoculated mice. These results suggest that IgG directed to the MNs may be an initial element in the damage to the MNs both in human ALS and in its immune mediated animal models. PMID- 27220676 TI - Withaferin A inhibits inflammatory responses induced by Fusobacterium nucleatum and Aggregatibacter actinomycetemcomitans in macrophages. AB - Periodontitis is a progressive chronic inflammatory disease and a major cause of tooth loss in humans. As a withanolides, withaferin A (WA) is known to exhibit strong anti-inflammatory activity. The present study examined whether WA inhibited inflammatory responses in macrophages in response to two representative periodontal pathogens, Fusobacterium nucleatum and Aggregatibacter actinomycetemcomitans. Murine bone marrow-derived macrophages (BMDMs) were used in this study and cytokine production in culture supernatants was measured by enzyme-linked immunosorbent assays. Western blot analysis was performed to determine the activation of nuclear factor-kappaB and mitogen-activated protein kinases (MAPKs) and the expression of inducible nitric oxide synthase (iNOS), toll-like receptor (TLR) 2 and TLR4. The production of nitric oxide (NO) was determined by the Griess reaction. WA treatment was shown to decrease interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha production in BMDMs in response to F. nucleatum and A. actinomycetemcomitans in a dose-dependent manner. The phosphorylation of IkappaB-alpha and MAPKs (p38, extracellular signal-regulated kinases and c-Jun N-terminal kinases) induced by F. nucleatum and A. actinomycetemcomitans was also inhibited by WA. F. nucleatum and A. actinomycetemcomitans induced iNOS expression and NO production in BMDMs, which was inhibited by WA in a dose-dependent manner. WA also reduced endogenous and induced expression of TLR2 and TLR4 in these cells. These results suggest that WA may be a potential therapeutic agent or preventive additive for periodontitis control. PMID- 27220675 TI - Magnesium nebulization utilization in management of pediatric asthma (MagNUM PA) trial: study protocol for a randomized controlled trial. AB - BACKGROUND: Up to 30 % of children with acute asthma are refractory to initial therapy, and 84 % of this subpopulation needs hospitalization. Finding safe, noninvasive, and effective strategies to treat this high-risk group would substantially decrease hospitalizations, healthcare costs, and the psycho-social burden of the disease. Whereas intravenous magnesium (Mg) is effective in severe refractory asthma, its use is sporadic due to safety concerns, with the main treatment goal being to prevent intensive care unit admission. In contrast, nebulized Mg is noninvasive, allows higher pulmonary drug concentrations, and has a much higher safety potential due to the lower rate of systemic delivery. Previous studies of inhaled Mg show disparate results due to the use of unknown/inefficient delivery methods and other methodological flaws. METHODS/DESIGN: The study is a randomized double-blind controlled trial in seven Canadian pediatric Emergency Departments (two-center pilot 2011 to 2014, Canada wide November 2014 to December 2017). The trial will include 816 otherwise healthy children who are 2 to 17 years old, having had at least one previous wheezing episode, have received systemic corticosteroids, and have a Pediatric Respiratory Assessment Measure (PRAM) >= 5 points after three salbutamol and ipratropium treatments for a current acute asthma exacerbation. Eligible consenting children will receive three experimental treatments of nebulized salbutamol with either 600 mg of Mg sulfate or placebo 20 min apart, using an Aeroneb Go nebulizer, which has been shown to maximize pulmonary delivery while maintaining safety. The primary outcome is hospitalization within 24 h of the start of the experimental therapy for persistent respiratory distress or supplemental oxygen. Secondary outcomes include all-cause hospitalization within 24 h, PRAM, vital signs, number of bronchodilator treatments by 240 min, and the association between the difference in the primary outcome between the groups, age, gender, baseline PRAM, atopy, and "viral induced wheeze" phenotype (Fig. 1). DISCUSSION: If effective, inhaled Mg may represent an effective strategy to minimize morbidity in pediatric refractory acute asthma. Unlike previous works, this trial targets nonresponders to optimized initial therapy who are the most likely to benefit from inhaled Mg. Future dissemination of results will include knowledge translation, incorporation into a Cochrane Review, presentation at scientific meetings, and a peer-reviewed publication. TRIAL REGISTRATION: NCTO1429415 , registered 2 September 2011. PMID- 27220677 TI - Prevalence and associated features of autism spectrum disorder in extremely low gestational age newborns at age 10 years. AB - We sought to estimate the prevalence of autism spectrum disorder (ASD) in children born extremely preterm relative to the U.S. population risk of 1.5% [CDC, 2014] using the best-available diagnostic procedures and minimizing confounding with other neurodevelopmental impairments. Eight hundred and eighty nine of 966 (92%) 10-year-old children from the Extremely Low Gestational Age Newborn birth cohort, delivered at 23-27 weeks gestation in 2002-2004, participated. Children meeting ASD screening criteria on the Social Communication Questionnaire were evaluated with the Autism Diagnostic Interview-Revised (ADI R). Those meeting ADI-R criteria were assessed with the Autism Diagnostic Observation Schedule-2 (ADOS-2). A positive ADOS-2 score was the criterion for ASD. Twenty-six participants were not assessed for ASD because of severe sensory or motor impairment. In the remaining sample, 61 children met criteria for ASD, resulting in a prevalence of 7.1% (95% CI = 5.5-9.0). ASD risk decreased with increasing gestational age, from 15.0% (95% CI = 10.0-21.2) for 23-24 weeks, 6.5% (95% CI = 4.2-9.4) for 25-26 weeks, to 3.4% (95% CI = 1.6-6.1) for 27 weeks gestational age, and this association was independent of IQ. Among children with ASD, 40% had intellectual disability. The male-to-female ratio of children with ASD was 2.1:1 (95% CI = 1.2:1-3.5:1), lower than in the general population (4:1). ASD prevalence in the ELGAN cohort was four times higher than in the general population, and was strongly associated with gestational age, underscoring the need for enhanced ASD screening of children born preterm, and suggesting that some risk factors associated with preterm birth may also play a role in the etiology of autism. Autism Res 2017, 10: 224-232. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 27220678 TI - Receptor-interacting protein kinase 3-mediated programmed cell necrosis in rats subjected to focal cerebral ischemia-reperfusion injury. AB - In the current study, the activation of tumor necrosis factor-alpha receptor 1 (TNFR1) and receptor-interacting protein kinase 3 (RIP3) were investigated following cerebral ischemia-reperfusion injury (CIRI). Healthy SD rats were randomly divided into 3 groups: Sham operation group, model group and inhibitor group. The model group and inhibitor group were further divided into 4 subgroups of 6, 12, 24 and 72 h following CIRI. Using right middle cerebral artery embolization, the CIRI model was generated. To confirm that the CIRI model was established, neurological scores, TTC staining and brain water content measurements were conducted. Immunohistochemistry and western blotting were conducted to investigate the expression of TNFR1 and RIP3 in the cerebral cortex. It was observed that nerve cell necrosis occurred following 6 h of CIRI. The appearance of necrotic cells was gradually increased with increasing CIRI duration. TNFR1 and RIP3 were positively expressed following 6 h of CIRI. With increasing durations of CIRI, the protein expression levels of TNFR1 and RIP3 were significantly increased. Pre-administration with Z-VAD-FMK (zVAD) significantly increased the protein level of RIP3, however, had no effect on the levels of TNFR1, and was accompanied by a reduction in necrosis. In conclusion, RIP3-mediated cell necrosis was enhanced by caspase blockade zVAD and the function of zVAD was independent of TNFR1 signaling following IR. PMID- 27220679 TI - SphK1 inhibitor potentiates the anti-cancer effect of EGCG on leukaemia cells. PMID- 27220680 TI - Functional characterization of X-prolyl aminopeptidase from Toxoplasma gondii. AB - In the present study, a recombinant aminopeptidase P (rTgAPP) from Toxoplasma gondii was expressed in Escherichia coli to evaluate its enzyme parameters. The rTgAPP showed strong activity against a synthetic substrate for aminopeptidase P at pH 8.0 with a K m value of 0.255 u m and a k cat value of 35.6 s-1. The overall catalytic efficiency (k cat/K m) of the rTgAPP was 139.6 * 105 M-1 s-1. The activity of rTgAPP was enhanced by the addition of divalent cations and inhibited by bestatin. Deletion of TgAPP gene in the parasite through a CRISPR/Cas9 system resulted in inhibition of growth indicating the importance of TgAPP. Thus our findings reveal that TgAPP is an active enzyme in T. gondii and provide an insight into the function of TgAPP. PMID- 27220681 TI - pi-Conjugated phospholes and their incorporation into devices: components with a great deal of potential. AB - This review serves as a brief introduction to phospholes and discusses their unique favorable properties for application in organic electronic materials. Over the past several years, pi-conjugated phospholes have been slowly making their way into devices. We report here the mode of synthesis of these pi-conjugated phospholes as well as discuss the performances of the devices. PMID- 27220682 TI - The minimal amount of starting DNA for Agilent's hybrid capture-based targeted massively parallel sequencing. AB - Targeted capture massively parallel sequencing is increasingly being used in clinical settings, and as costs continue to decline, use of this technology may become routine in health care. However, a limited amount of tissue has often been a challenge in meeting quality requirements. To offer a practical guideline for the minimum amount of input DNA for targeted sequencing, we optimized and evaluated the performance of targeted sequencing depending on the input DNA amount. First, using various amounts of input DNA, we compared commercially available library construction kits and selected Agilent's SureSelect-XT and KAPA Biosystems' Hyper Prep kits as the kits most compatible with targeted deep sequencing using Agilent's SureSelect custom capture. Then, we optimized the adapter ligation conditions of the Hyper Prep kit to improve library construction efficiency and adapted multiplexed hybrid selection to reduce the cost of sequencing. In this study, we systematically evaluated the performance of the optimized protocol depending on the amount of input DNA, ranging from 6.25 to 200 ng, suggesting the minimal input DNA amounts based on coverage depths required for specific applications. PMID- 27220683 TI - Assessment of the Density of Suppression to Identify Risk of Intractable Diplopia in the United Kingdom. AB - BACKGROUND/AIMS: Occlusion used to treat amblyopia towards the end of the developmental component of the critical period gives a risk of inducing intractable diplopia. In the United Kingdom, the density of suppression is assessed via the Sbisa/Bagolini filter bar, but there is very little research evidence to guide clinical practice or interpretation of the tests used. The aims of this study were to determine current practice and estimate the incidence of intractable diplopia following amblyopia treatment. METHODS: Current practice and incidence of intractable diplopia following amblyopia were determined via a questionnaire distributed to head orthoptists in every eye department in the United Kingdom. The questionnaire explored testing and test conditions, interpretation of the test results, and cases of intractable diplopia over the last 5 years. RESULTS: There was considerable variation in clinical practice of the measurement of the density of suppression and interpretation of the results to guide the treatment of amblyopia. The minimum age of patients taking the test ranged from 2 to 8 years and the minimum filter considered still safe to continue treatment ranged from 4 to 17. It is estimated there were 24 cases of intractable diplopia over the last 5 years. CONCLUSION: The issue of intractable diplopia and amblyopia treatment is likely to become increasingly important as there appears to be greater plasticity and scope to treat amblyopia in teenagers and adults than was previously thought. Lack of knowledge of how to evaluate the risk may lead to more cases of intractable diplopia or alternatively treatment being withheld unnecessarily. PMID- 27220685 TI - Can new psychoactive substances be regulated effectively? An assessment of the British Psychoactive Substances Bill. AB - The regulation of new psychoactive substances (NPS) has confounded governments throughout the western world. In 2014 the UK government convened an NPS Review Expert Panel to consider a range of approaches. Ultimately the Panel recommended that the government ban all new psychoactive drugs and allow only psychoactive substances specifically exempted, such as alcohol, tobacco and those allowed as medicines. The government introduced the Psychoactive Substances Bill (PSB) in response to that recommendation. Passed in 2016, the Bill has attracted a torrent of criticism from scientists and experts. The Bill could be improved with revision, but the problems of the total ban, as envisioned by the PSB, with respect to the NPS, may be inherent: (1) defining psychoactivity is conceptually fraught, with great consequence for the scope of the prohibition; (2) operationalizing psychoactivity as a usable concept for legal control purposes is extremely difficult, perhaps impossible; and (3) the detachment of penalties for violating a total ban from establishing the harmfulness of a substance is normatively troubling. Given the uncertainties about the effects of a total ban, it is appropriate at this time for other governments to assess more fully the nature of the NPS problem, and the potential control approaches. PMID- 27220684 TI - Open and closed evolutionary paths for drastic morphological changes, involving serial gene duplication, sub-functionalization, and selection. AB - Twin-tail goldfish strains are examples of drastic morphological alterations that emerged through domestication. Although this mutation is known to be caused by deficiency of one of two duplicated chordin genes, it is unknown why equivalent mutations have not been observed in other domesticated fish species. Here, we compared the chordin gene morphant phenotypes of single-tail goldfish and common carp (close relatives, both of which underwent chordin gene duplication and domestication). Morpholino-induced knockdown depleted chordin gene expression in both species; however, while knockdown reproduced twin-tail morphology in single tail goldfish, it had no effect on common carp morphology. This difference can be explained by the observation that expression patterns of the duplicated chordin genes overlap completely in common carp, but are sub-functionalized in goldfish. Our finding implies that goldfish drastic morphological changes might be enhanced by the subsequent occurrence of three different types of evolutionary event (duplication, sub-functionalization, and selection) in a certain order. PMID- 27220686 TI - State-space models' dirty little secrets: even simple linear Gaussian models can have estimation problems. AB - State-space models (SSMs) are increasingly used in ecology to model time-series such as animal movement paths and population dynamics. This type of hierarchical model is often structured to account for two levels of variability: biological stochasticity and measurement error. SSMs are flexible. They can model linear and nonlinear processes using a variety of statistical distributions. Recent ecological SSMs are often complex, with a large number of parameters to estimate. Through a simulation study, we show that even simple linear Gaussian SSMs can suffer from parameter- and state-estimation problems. We demonstrate that these problems occur primarily when measurement error is larger than biological stochasticity, the condition that often drives ecologists to use SSMs. Using an animal movement example, we show how these estimation problems can affect ecological inference. Biased parameter estimates of a SSM describing the movement of polar bears (Ursus maritimus) result in overestimating their energy expenditure. We suggest potential solutions, but show that it often remains difficult to estimate parameters. While SSMs are powerful tools, they can give misleading results and we urge ecologists to assess whether the parameters can be estimated accurately before drawing ecological conclusions from their results. PMID- 27220687 TI - Efficient chemoenzymatic synthesis of uridine 5'-diphosphate N-acetylglucosamine and uridine 5'-diphosphate N-trifluoacetyl glucosamine with three recombinant enzymes. AB - Uridine 5'-diphosphate N-acetylglucosamine (UDP-GlcNAc) is a natural UDP monosaccharide donor for bacterial glycosyltransferases, while uridine 5' diphosphate N-trifluoacetyl glucosamine (UDP-GlcNTFA) is its synthetic mimic. The chemoenzymatic synthesis of UDP-GlcNAc and UDP-GlcNTFA was attempted by three recombinant enzymes. Recombinant N-acetylhexosamine 1-kinase was used to produce GlcNAc/GlcNTFA-1-phosphate from GlcNAc/GlcNTFA. N-acetylglucosamine-1-phosphate uridyltransferase from Escherichia coli K12 MG1655 was used to produce UDP GlcNAc/GlcNTFA from GlcNAc/GlcNTFA-1-phosphate. Inorganic pyrophosphatase from E. coli K12 MG1655 was used to hydrolyze pyrophosphate to accelerate the reaction. The above enzymes were expressed in E. coli BL21 (DE3) and purified, respectively, and finally mixed in one-pot bioreactor. The effects of reaction conditions on the production of UDP-GlcNAc and UDP-GlcNTFA were characterized. To avoid the substrate inhibition effect on the production of UDP-GlcNAc and UDP GlcNTFA, the reaction was performed with fed batch of substrate. Under the optimized conditions, high production of UDP-GlcNAc (59.51 g/L) and UDP-GlcNTFA (46.54 g/L) were achieved in this three-enzyme one-pot system. The present work is promising to develop an efficient scalable process for the supply of UDP monosaccharide donors for oligosaccharide synthesis. PMID- 27220688 TI - The effect of the olive fruit fly (Bactrocera oleae) on quality parameters, and antioxidant and antibacterial activities of olive oil. AB - The present study was performed on olives from two Algerian cultivars (Limli and Rougette de Metidja) with different rates of attack by the Bactrocera oleae fly (0%, not attacked; 100%, all attacked; and real attacked %) and the corresponding olive oils. The aim was to verify the attack effect on quality parameters (free fatty acid, peroxide value, K232 and K270, oxidation stability), bioactive compounds (fatty acids and tocopherols, and total phenols and flavonoids), and on the antioxidant (reducing power, FRAP, beta-carotene bleaching inhibition, ABTS and DPPH) and antibacterial (against 8 referenced human enteropathogenic bacteria by the agar disc diffusion method) capacities. Oils from infested olives were downgraded to the virgin olive oil category. Rougette de Metidja, the cultivar with a higher drupe size, was more attacked than Limli. The B. oleae attack causes an important decrease in the total phenolic contents (>30%) but to a lesser degree in the case of tocopherols. Among them, alpha-tocopherol is the most affected. The antioxidant and antibacterial activities were highly correlated with phenolic levels. The results of this study show the importance of controlling the fly attack because it causes a decrease in the beneficial health effects of olive oils. PMID- 27220690 TI - Wild type huntingtin toxicity in yeast: Implications for the role of amyloid cross-seeding in polyQ diseases. AB - Proteins with expanded polyglutamine (polyQ) regions are prone to form amyloids, which can cause diseases in humans and toxicity in yeast. Recently, we showed that in yeast non-toxic amyloids of Q-rich proteins can induce aggregation and toxicity of wild type huntingtin (Htt) with a short non-pathogenic polyglutamine tract. Similarly to mutant Htt with an elongated N-terminal polyQ sequence, toxicity of its wild type counterpart was mediated by induced aggregation of the essential Sup35 protein, which contains a Q-rich region. Notably, polymerization of Sup35 was not caused by the initial benign amyloids and, therefore, aggregates of wild type Htt acted as intermediaries in seeding Sup35 polymerization. This exemplifies a protein polymerization cascade which can generate a network of interdependent polymers. Here we discuss cross-seeded protein polymerization as a possible mechanism underlying known interrelations between different polyQ diseases. We hypothesize that similar mechanisms may enable proteins, which possess expanded Q-rich tracts but are not associated with diseases, to promote the development of polyQ diseases. PMID- 27220691 TI - The Fontan circulation after 45 years: update in physiology. AB - The Fontan operation was first performed in 1968. Since then, this operation has been performed on thousands of patients worldwide. Results vary from very good for many decades to very bad with a pleiad of complications and early death. A good understanding of the physiology is necessary to further improve results. The Fontan connection creates a critical bottleneck with obligatory upstream congestion and downstream decreased flow; these two features are the basic cause of the majority of the physiologic impairments of this circulation. The ventricle, while still the engine of the circuit, cannot compensate for the major flow restriction of the Fontan bottleneck: the suction required to compensate for the barrier effect cannot be generated, specifically not in a deprived heart. Except for some extreme situations, the heart therefore no longer controls cardiac output nor can it significantly alter the degree of systemic venous congestion. Adequate growth and development of the pulmonary arteries is extremely important as pulmonary vascular impedance will become the major determinant of Fontan outcome. Key features of the Fontan ventricle are early volume overload and overgrowth, but currently chronic preload deprivation with increasing filling pressures. A functional decline of the Fontan circuit is expected and observed as pulmonary vascular resistance and ventricular filling pressure increase with time. Treatment strategies will only be successful if they open up or bypass the critical bottleneck or act on immediate surroundings (impedance of the Fontan neoportal system, fenestration, enhanced ventricular suction). PMID- 27220689 TI - A robust (re-)annotation approach to generate unbiased mapping references for RNA seq-based analyses of differential expression across closely related species. AB - BACKGROUND: RNA-seq based on short reads generated by next generation sequencing technologies has become the main approach to study differential gene expression. Until now, the main applications of this technique have been to study the variation of gene expression in a whole organism, tissue or cell type under different conditions or at different developmental stages. However, RNA-seq also has a great potential to be used in evolutionary studies to investigate gene expression divergence in closely related species. RESULTS: We show that the published genomes and annotations of the three closely related Drosophila species D. melanogaster, D. simulans and D. mauritiana have limitations for inter specific gene expression studies. This is due to missing gene models in at least one of the genome annotations, unclear orthology assignments and significant gene length differences in the different species. A comprehensive evaluation of four statistical frameworks (DESeq2, DESeq2 with length correction, RPKM-limma and RPKM-voom-limma) shows that none of these methods sufficiently accounts for inter specific gene length differences, which inevitably results in false positive candidate genes. We propose that published reference genomes should be re annotated before using them as references for RNA-seq experiments to include as many genes as possible and to account for a potential length bias. We present a straight-forward reciprocal re-annotation pipeline that allows to reliably compare the expression for nearly all genes annotated in D. melanogaster. CONCLUSIONS: We conclude that our reciprocal re-annotation of previously published genomes facilitates the analysis of significantly more genes in an inter-specific differential gene expression study. We propose that the established pipeline can easily be applied to re-annotate other genomes of closely related animals and plants to improve comparative expression analyses. PMID- 27220692 TI - Diagnostic performance and reference values of novel biomarkers of paediatric heart failure. AB - OBJECTIVE: Biomarkers play a pivotal role in heart failure (HF) management. Reference values and insights from studies in adults cannot be extrapolated to the paediatric population due to important differences in pathophysiology and compensatory reserve. We assessed the diagnostic utility of four novel biomarkers in paediatric HF. METHODS: Midregional (MR) pro-atrial natriuretic peptide (proANP), soluble ST2 (sST2), growth differentiation factor-15 (GDF-15), MR-pro adrenomedullin (proADM) and N-terminal pro-B natriuretic peptide (NT-proBNP) were measured in 114 patients and 89 controls. HF was defined as the presence of HF symptoms and/or abnormal systolic ventricular function. Receiver-operating characteristics were plotted, and the area under the curve (AUC) was measured. This was repeated for subgroups with cardiomyopathy and congenital heart disease (CHD). Ventricular systolic function was measured by magnetic resonance or echocardiography. Reference values were calculated according to the current guidelines. RESULTS: The AUC for diagnosing HF was 0.76 for MR-proANP (CI 0.70 to 0.84) and 0.82 for NT-proBNP (CI 0.75 to 0.88). These parameters performed similarly in the subgroups with CHD and cardiomyopathy. By contrast, MR-proADM, GDF-15 and sST2 performed poorly. When used in conjunction with NT-proBNP, no parameter added significantly to its diagnostic accuracy. NT-proBNP, MR-proANP, GDF-15 and sST2 could accurately discriminate between patients with preserved and patients with poor functional status. In a subset of patients with dilated cardiomyopathy, NT-proBNP, MR-proANP, MR-proADM and GDF-15 were associated with poor LV function. CONCLUSIONS: MR-proANP could accurately detect HF in children and adolescents. Its diagnostic performance was comparable with that of NT proBNP, regardless of the underlying condition. Reference values are presented. PMID- 27220693 TI - Progression of aortic regurgitation after subpulmonic infundibular ventricular septal defect repair. AB - OBJECTIVE: In patients with subpulmonic infundibular ventricular septal defect (VSD), postoperative progression of aortic regurgitation (AR) sometimes occurs despite early operation before the development of AR. The present study was aimed to identify the occurrence rate and predictors of late AR progression after VSD repair alone. METHODS: We retrospectively investigated 91 consecutive patients who underwent subpulmonic infundibular VSD repair alone and were followed up with echocardiography for >3 years postoperatively. The clinical backgrounds and chronological changes in postoperative AR were evaluated. RESULTS: The median follow-up period after VSD repair was 13.4 years. Among 91 patients, 7 patients showed postoperative AR progression (AR progression group) and 84 patients did not (No AR progression group). No patient in AR progression group revealed more than moderate AR preoperatively. The incidence of postoperative VSD leakage was significantly higher in AR progression group than No AR progression group (43.0% vs 2.4%, respectively; p<0.01). No significant differences were present in sex, age, preoperative AR severity, VSD diameter or rate of cusp herniation. All patients in AR progression group showed deformity of the right coronary cusp or leaflet, resulting in AR progression. CONCLUSIONS: Among patients with subpulmonic infundibular VSD, the incidence of late AR progression after VSD repair alone was unexpectedly high (7.7%). Postoperative VSD leakage may be a significant risk factor for late AR progression. Long-term follow-up of postoperative AR is needed even for patients who undergo VSD repair alone. PMID- 27220694 TI - Efficacy of cardiac rehabilitation after balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension. AB - OBJECTIVE: To determine safety and efficacy of cardiac rehabilitation (CR) initiated immediately following balloon pulmonary angioplasty (BPA) in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) who presented with continuing exercise intolerance and symptoms on effort even after a course of BPA; 2-8 sessions/patient. METHODS: Forty-one consecutive patients with inoperable CTEPH who underwent their final BPA with improved resting mean pulmonary arterial pressure of 24.7+/-5.5 mm Hg and who suffered remaining exercise intolerance were prospectively studied. Participants were divided into two groups just after the final BPA (6.8+/-2.3 days): patients with (CR group, n=17) or without (non-CR group, n=24) participation in a 12-week CR of 1-week inhospital training followed by an 11-week outpatient programme. Cardiopulmonary exercise testing, haemodynamics, and quality of life (QOL) were assessed before and after CR. RESULTS: No significant between-group differences were found for any baseline characteristics. At week 12, peak oxygen uptake (VO2), per cent predicted peak VO2 (70.7+/-9.4% to 78.2+/-12.8%, p<0.01), peak workload, and oxygen pulse significantly improved in the CR group compared with the non-CR group, with a tendency towards improvement in mental health-related QOL. Quadriceps strength and heart failure (HF) symptoms (WHO functional class, 2.2 1.8, p=0.01) significantly improved within the CR group. During the CR, no patient experienced adverse events or deterioration of right-sided HF or haemodynamics as confirmed via catheterisation. CONCLUSIONS: The combination of BPA and subsequent CR is a new treatment strategy for inoperable CTEPH to improve exercise capacity to near-normal levels and HF symptoms, with a good safety profile. PMID- 27220695 TI - Histology of debris captured by a cerebral protection system during transcatheter valve-in-valve implantation. AB - OBJECTIVE: Histological analyses of debris captured by a cerebral protection system (CPS) during transcatheter valve-in-valve (VIV) procedures have not been reported. METHODS: Fifteen consecutive patients with stenotic aortic (n=13) or mitral (n=2) surgical or transcatheter bioprostheses were treated with implantation of a transcatheter heart valve (THV) in the presence of a dual filter CPS. Mean patient age was 75 years; mean logistic EuroSCORE was 31%. Filters were collected and histological assessment of debris was performed. Patients were followed clinically until discharge. RESULTS: Debris captured by either or both filters was detected in all patients. Acute thrombus was the most common type of debris, found in all patients, followed in frequency by arterial wall tissue (n=12 patients (80%)), calcification (n=11 (73%)) and valve tissue (n=9 (60%)). Less frequently found were organised thrombus (n=5 (30%)), foreign material (n=4 (27%)) and myocardium (n=2 (13%)). A median of 123 debris particles per patient was detected, with a trend towards a greater median number of particles collected in proximal filters (78 vs 39, p=0.065). The average maximum particle diameter was 88 (range 56-175) um, with a median of 20 particles >=150 um. No stroke or transient ischaemic attack (TIA) had occurred by the time of discharge (mean 8 days). CONCLUSIONS: Transcatheter VIV procedures were associated with the release of particulate debris into the cerebral circulation in all patients. The type of debris suggests that debris originates predominantly from arterial and valvular passage of the THV. PMID- 27220696 TI - Effect of Stearylguanidinium-Modified POPC Vesicles on the Melting Behavior of tRNA Molecules. AB - Lipid membranes interact with biomolecules via noncovalent bonding interactions, wherein the physicochemical membrane properties are key factors in the recognition and rearrangement of biomolecule conformation. In this study, vesicles were prepared using 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and stearylguanidinium (SG) to improve the affinity between the membrane and tRNA. Membrane fluidity decreased and dehydration of the membrane surface increased with increasing SG levels, suggesting that SG molecules could make the membrane rigid and induce a liquid-ordered (lo)-like phase. The binding constant (Ka) between nucleotide and lipid was evaluated by turbidity analysis; the Ka value for POPC/SG = (86/14) was 2.9 * 10(4) M(-1) but was slightly decreased by vesicles in the lo-like phase. CD spectra of tRNA by the presence of POPC/SG vesicles showed C-G selective base cleavage in tRNA during heat denaturation. POPC/SG = (61/39) and POPC/SG = (40/60) effectively led to C-G base pair cleavage at the melting temperature of tRNA. PMID- 27220697 TI - Effect on quality of life of switching to combined oral contraception based on natural estrogen: an observational, multicentre, prospective phase IV study (ZOCAL Study). AB - OBJECTIVES: This observational, multicentre, prospective phase IV study examined change in health-related quality of life (QOL) from baseline to 6 months in women initiating combined oral contraception (COC) based on natural estrogen. METHODS: Eligible women attending a baseline and 6-month gynaecology appointment belonged to one of three groups: group 1 used barrier contraception (condoms) and elected to continue this method; group 2 used condoms and elected to switch to COC based on natural estrogen; group 3 used COC based on ethinylestradiol and elected to switch to COC based on natural estrogen. The Spanish Society of Contraception (SEC)-QOL scale assessed health-related QOL. Secondary outcomes included symptoms of premenstrual syndrome, intermenstrual bleeding, duration and intensity of menstrual bleeding, contraception continuation rate, and tolerability. RESULTS: A total of 857 women were enrolled and 785 completed the study. Group 2 (n = 224 completed) had significantly lower SEC-QOL global and dimension scores at baseline and significantly greater increases in SEC-QOL from baseline to 6 months compared with groups 1 (n = 72) and 3 (n = 489). Group 3 reported a similar SEC QOL score to that of group 1 at baseline but showed significantly greater improvement in SEC-QOL global and psychological scores from baseline to 6 months. Among women receiving COC based on natural estrogen, the contraception continuation rate was 713/780 (91.4%); treatment-related adverse events were reported by 13/780 (1.7%). CONCLUSIONS: Improved SEC-QOL after 6 months was found in women who were dissatisfied with their current contraception at baseline and chose to switch to COC based on natural estrogen. PMID- 27220698 TI - Perspectives on Anti-Glycan Antibodies Gleaned from Development of a Community Resource Database. AB - Antibodies are used extensively for a wide range of basic research and clinical applications. While an abundant and diverse collection of antibodies to protein antigens have been developed, good monoclonal antibodies to carbohydrates are much less common. Moreover, it can be difficult to determine if a particular antibody has the appropriate specificity, which antibody is best suited for a given application, and where to obtain that antibody. Herein, we provide an overview of the current state of the field, discuss challenges for selecting and using antiglycan antibodies, and summarize deficiencies in the existing repertoire of antiglycan antibodies. This perspective was enabled by collecting information from publications, databases, and commercial entities and assembling it into a single database, referred to as the Database of Anti-Glycan Reagents (DAGR). DAGR is a publicly available, comprehensive resource for anticarbohydrate antibodies, their applications, availability, and quality. PMID- 27220699 TI - Learning curve of MRI-based planning for high-dose-rate brachytherapy for prostate cancer. AB - PURPOSE: To evaluate introduction of MRI-based high-dose-rate brachytherapy (HDRBT), including procedure times, dose-volume parameters, and perioperative morbidity. METHODS AND MATERIALS: Study included 42 high-risk prostate cancer patients enrolled in a clinical protocol, offering external beam radiotherapy + two HDRBT 8.5 Gy boosts. Time was recorded for initiation of anesthesia (A), fixation of needle implant (B), end of MR imaging (C), plan approval (D), and end of HDRBT delivery (E). We defined time A-E as total procedure time, A-B as operating room time, B-C as MRI procedure time, C-D as treatment planning time, and D to E as treatment delivery time. Dose-volume parameters were retrieved from the dose planning system. Results from the first 21 patients were compared with the last 21 patients. RESULTS: Total procedure time, operating room time, MRI procedure time, and treatment planning time decreased significantly from average 7.6 to 5.3 hours (p < 0.01), 3.6 to 2.4 hours (p < 0.01), 1.6 to 0.8 hours (p < 0.01), and 2.0 to 1.3 hours (p < 0.01), respectively. HDRBT delivery time remained unchanged at 0.5 hours. Clinical target volume prostate+3mmD90 fulfilled planning aim in 92% of procedures and increased significantly from average 8.3 to 9.0 Gy (p < 0.01). Urethral D0.1 cm(3) and rectal D2 cm(3) fulfilled planning aim in 78% and 95% of procedures, respectively, and did not change significantly. Hematuria occurred in (95%), hematoma (80%), moderate to strong pain (35%), and urinary retention (5%) of procedures. CONCLUSIONS: After introduction of MRI based HDRBT, procedure times were significantly reduced. D90 Clinical target volumeprostate+3mm fulfilled constraints in most patients and improved over time, but not at expense of an increased urethral or rectal dose. PMID- 27220700 TI - Rubrivirga profundi sp. nov., isolated from deep-sea water, and emended description of the genus Rubrivirga. AB - A Gram-staining-negative, rod-shaped, facultatively anaerobic, non-motile and pale-red-pigmented bacterium, designated SAORIC-476T, was isolated from deep-sea water from the Pacific Ocean. 16S rRNA gene sequence analyses showed that strain SAORIC-476T was most closely related to Rubrivirga marinaSAORIC-28T (96.8 % similarity) and formed a robust phylogenetic clade with Rubrivirga marinaof the family Rhodothermaceae. Optimal growth of strain SAORIC-476T was observed at 25 degrees C, pH 7.5 and in the presence of 3.0 % (w/v) NaCl. The DNA G+C content of strain SAORIC-476T was 66.2 mol%, and the sole isoprenoid quinone was MK-7. The predominant cellular fatty acids were summed feature 9 (iso-C17 : 1omega9c and/or 10-methyl C16 : 0), iso-C17 : 0, C17 : 1omega8c and iso-C15 : 0. The major polar lipids constituted phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, three unknown phospholipids and four unknown polar lipids. On the basis of taxonomic data obtained in this study, it was concluded that strain SAORIC-476T represents a novel species of the genus Rubrivirga, for which the name Rubrivirga profundi sp. nov. is proposed. The type strain of Rubrivirga profundi is SAORIC-476T (=NBRC 110607T=KACC 18401T). PMID- 27220701 TI - How older persons explain why they became victims of abuse. AB - BACKGROUND: elder abuse greatly impacts the quality of life of older individuals. Prevalence rates range from 3 to 30% depending on the definition used. Only about a dozen studies have explored how older victims themselves experience and explain abuse. It is essential that healthcare professionals understand the perceptions of older victims as they are among the most important groups to handle and report abuse. DESIGN: a qualitative study on the perceptions and experiences of victims of elder abuse was conducted using in-depth semi-structured interviews. SETTING: abused individuals living independently, in residential care facilities and nursing homes. SUBJECTS: six males and 11 females aged 63-90 years. RESULTS: the main causes of abuse identified by older victims themselves were mutual dependency between victim and perpetrator, power and control imbalances, loneliness and a marginalised social position of older persons. Effects of abuse included negative feelings, physical and psychological distress, a change of personal norms and values, changed perspectives on money and low self-efficacy. These differential effects depended upon the types of abuse experienced and the relationship with the perpetrator. Coping strategies mentioned by victims were seeking informal or professional help and using self-help strategies. CONCLUSION: older victims perceive abuse differently depending on the expected acceptability of the type(s) of abuse experienced and the anticipated stigma associated with the perpetrator involved. The effects and chosen coping strategies are influenced by these considerations and therewith also influence their help-seeking behaviour. Healthcare professionals are encouraged to use these findings in practice to prevent, detect and intervene in elder abuse. PMID- 27220702 TI - Ciprofloxacin-associated bilateral iliopsoas tendon rupture: a case report. AB - Fluoroquinolone use is associated with the development of tendinopathy, most commonly affecting the Achilles tendon. Here we present the first reported case of bilateral iliopsoas tendon rupture associated with prolonged ciprofloxacin use. This older woman presented with non-traumatic, sudden onset hip pain which was diagnosed as a right iliopsoas rupture on MRI. Despite stopping ciprofloxacin, she went on to develop rupture of the contralateral iliopsoas tendon. This case highlights the time lag between fluoroquinolone use and susceptibility to this rare but important complication. PMID- 27220703 TI - [Progression and challenge of anti-vascular endothelial growth factor therapy in retinal neovascular disease]. AB - Anti-vascular endothelial growth factor (VEGF) therapy as an effective therapeutic method has been a standard treatment strategy in retinal neovascular disease, contributing to restore vision and reduce the prevalence of blindness. With the research on the pathogenesis of retinal neovascular disease and implementation of clinical trials, anti-VEGF therapy is continuously optimized. Meanwhile, the complications after the use of anti-angiogenetic drugs are exposed. The present article summarizes the update and challenge of anti-VEGF therapy in retinal neovascular disease. PMID- 27220704 TI - [Observation on long-term efficacy of half-dose photodynamic therapy with chronic central serous chorioretinopathy using optical coherence tomography]. AB - OBJECTIVE: To evaluate long-term efficacy of half-dose photodynamic therapy on chronic central serous chorioretinopathy using optical coherence tomography. METHODS: A retrospective, interventional case series. Thirty-five eyes of 32 patients (35 eyes) with chronic central serous chorioretinopathy were included, with CSC durations from 6 to 60 months. Patients treated with half-dose verteporfin (3 mg/m(2)) PDT were followed up for 24 months. Best-corrected visual acuity (BCVA), fluorescein angiography (FA), indocyanine green angiography (ICGA) and optical coherence tomography (OCT) pre and post-treatment were all examined to observe the anatomic and functional changes. OCT findings highlighted the alterations of the ellipsoid zone (EZ), the interdigitation zone (IZ) and the central neural retina thickness (CNT) from 3 month to 24 month post-treatment. Regression analysis was applied to determine the correlation between the visual function (BCVA) and structure status (EZ, IZ, CNT). RESULTS: Thirty-five eyes of 32 patients with chronic CSC were treated with half-dose PDT. The logMAR BCVA was 0.53+/-0.36 at baseline, 0.49+/-0.39 at 3 months and 0.15+/-0.38 at 24 months post-PDT. There was no statistical significance between baseline and 3 month BCVA (t=1.952, P>0.05). There existed statistical significance between baseline and 24 month BCVA(t=10.761, P<0.01) as well as 3month and 24 month BCVA(t=8.930, P<0.01). OCT demonstrated the recovery of EZ and IZ. Statistical differences of EZ and IZ integrity degree were found between the 3 month and 24 month (Z=-3.419, -4.082, P<0.01). The mean CNT was (126.8+/-34.9) MUm at baseline. And it kept constant at 3 month [(125.6+/-34.3)MUm] and the 24 month visit [(124.8+/ 35.1)MUm]. No statistical significance was found between any two values (t= 1.830, -1.569, 0.793, P>0.05). At baseline, 3 month and 24 month, there was negative correlation between logMAR BCVA and CNT (beta=-0.604, -0.634, -0.685, P<0.01) . At 3 month and 24 month, negative correlation between logMAR BCVA and EZ as well as logMAR BCVA and IZ were also found(beta=-0.376, -0.394, -0.628, 0.496, P<0.05). A complete resolution of subretinal fluid was noted in 94.3% eyes at 3 month, further increased to 100% eyes at 24 month. The mean session of PDT was 1.03+/-0.17. CONCLUSIONS: Half-dose PDT was safe and effective for chronic CSC both functionally and morphologically in the long term. Visual benefits may not appear in a short run, yet became remarkable in a long run. Visual benefits might be attributed to recovery of EZ and IZ. PMID- 27220705 TI - [The clinical features and value of macular ganglion cell complex thickness patterns in patients with optic chiasma lesion]. AB - OBJECTIVE: To evaluate patterns of macular retinal ganglion cell complex thickness (mRGCCT) in patients with two types of neurologic lesions in optic chiasm region. METHODS: Retrospective case review study. Visual field test was conducted with automated perimetry (HAAG-STREIT OCTOPUS101 V6.07g Seven-in-One and 2010(HFA II750-40220-5.1.1/5.1.1) Carl Zeiss Meditec), and visual field in the central 30 degree region was measured. Three types of thickness mapping including macular retinal thickness (MRT), macular ganglion cell complex thickness (mGCCT) and peripapillary retinal nerve fiber layer (pRNFL) were recorded with TOPCON 3D-OCT 2000 spectral domain OCT. The results of OCT were compared with visual field. RESULTS: Sixteen cases were included in this study, male 10 cases, female 6 cases. Age 5 to 77 years (average 48.2). Neurologic lesions including pituitary tumor (9 cases), craniopharyngioma (3 cases), optic canal dysplasia in optic chiasm region (1 case), meningioma (1 case), hemangioma (1 case) and aneurysm (1 case). 14 cases have chronic, progressive, long course of disease, OCT showed characteristic perpendicular bisector delimitation, bilateral nasal mGCCT atrophy and corresponding temporal hemianopsia. 2 cases (both were pituitary tumor ) have a chronic, short duration, accelerated attack, visual acuity and visual field rapidly declined, mGCCT is swelling or approach high limit of normal range. In pRNFL thickness map, atrophy of mRNFL in temporal peripapillary and nasal macular region could be observed. CONCLUSIONS: Chronic, progressive, long course of disease, combined with characteristic perpendicular bisector delimitation, bilateral nasal mGCCT atrophy and corresponding temporal hemianopsia is helpful to predict lesion of disease. mGCCT map is of equal importance with visual field test for diagnosis of lesion within optic chiasm. In cases with a chronic, short disease course, and accelerated attack, mGCCT could be swelling, but pRNFL could be thinner in temporal peripapillary and nasal macular region of single or both eyes, and visual field test is thus necessary in these cases. PMID- 27220706 TI - [Clinical study of vitrectomy with epiretinal membrane peeling for idiopathic macular epiretinal membrane]. AB - OBJECTIVE: To investigate the result of vitrectomy with epiretinal membrane (ERM) peeling for idiopathic macular epiretinal membrane (IMEM). METHODS: Clinical data of 51 patients (51 eyes) of IMEM who underwent vitrectomy with ERM peeling were retrospectively investigated. All the patients were examined by visual acuity, slit lamp, fundus under mydriasis, optical coherence tomography (OCT) before and after the surgery. The 3-18 months follow-up were included, mean (5.8+/-3.2) months. All the macular ERM were removed successfully. Paired-sample t test was used to study the visual acuity and macular foveal thickness before and after surgery. The Pearson correlation analysis was used to study the correlation between visual acuity and macular foveal thickness. RESULTS: In the 51 patients, the best visual acuity improved from 4.25+/-0.34 to 4.65+/-0.23 postoperatively. The difference was statistically significant (t=-9.012, P=0.000), and the mean foveomacular thickness decreased from (432.7 +/- 91.7) to (333.3 +/- 66.1)MUm postoperatively, the difference was statistically significant (t=10.565, P=0.000). There was negative correlation between visual acuity and mean foveomacular thickness (r=- 0.452, P=0.001), and it was obvious postoperatively (r=-0.602, P=0.000). The increase of visual acuity was strongly correlated with the decline of mean foveomacular thickness (r=0.382, P=0.006). Twelve eyes have developed cataract in 3 to 6 months after vitrectomy which affect the visual acuity. All of them went phacoemulsification and intraocular lenses(IOL) implantation and visual acuity after surgery had an obviously improvement. CONCLUSIONS: Vitrectomy with ERM peeling can improve visual acuity and ease macular edema. And it is a safe and effective therapy to treat patients of IMEM. PMID- 27220707 TI - [Comparative analysis of the characteristics of bilateral rhegmatogenous retinal detachment]. AB - OBJECTIVE: To investigate the characteristics of bilateral rhegmatogenous retinal detachment (RRD) in a hospital-based population. METHODS: Six hundred and three patients diagnosed with bilateral RRD in the Beijing Tongren Hospital between January 2000 and January 2014 were identified and included into the study. The clinical features including the age when retinal detachment occurrence, time interval between the occurrence of the bilateral RRDs, predisposing characteristics such as myopia, trauma, et al. were recorded by a chart review. RESULTS: Out of 8 283 patients treated for primary RRD in the study period, (7.30+/-2.45)%(603 patients) developed a RRD in the contralateral eye, with a mean age of (30.76 +/- 15.31)years (range: 2-68) when the first RRD occurred. 4.8% of the patients primarily presented with a simultaneous bilateral RRD. Most RRD occurred firstly in the left eye (52.90%). Compared with the follow eye, the first RRD occurred with more macula detachment (P=0.03, OR: 1.59, 95%CI: 1.04 2.45) and retinal proliferation (P=0.04, OR: 1.57, 95% CI: 1.02-2.42), the visual outcome was more worse. Mean interval between the bilateral RRDs was (3.73+/ 7.05) years (mean+/-standard deviation, range: 0-56 years) The younger, more severe symptoms of the firstly occurred RRD, the shorter interval between the bilateral RRD. Time interval between the bilateral RRD was shorter in those RRD firstly occurred with macula detachment, giant tears, horse-shoe tear, located in the temporal superior region, or with retinal degeneration. Compared with highly myopic eyes, the interval between the bilateral RRD were shorter in moderately myopic eyes. CONCLUSIONS: For patients newly diagnosed with RRD, regardless of age, are required to a lifelong follow-up for the contralateral eye, especially within one year. Patients who were young, with heavier symptoms, low to moderate myopia or present with retinal degeneration, should be closely followed up in a short time after the first RRD occurred. PMID- 27220708 TI - [Clinical effects of gas tamponade followed by scleral cryotherapy on rhegmatogenous retinal detachment]. AB - OBJECTIVE: To evaluate the effects of intravitreal injection of sterile air followed by scleral cryotherapy on simple rhegmatogenous retinal detachment (RRD). METHODS: Retrospective study. Thirty-five cases (thirty-five eyes) with RRD were collected from Oct 2013 to Mar 2014. Among them, macular detachment was observed in 31cases, all accompanied with obvious synchesis. All retinal breaks were horseshoe shaped and holes located above 9 o'clock to 3 o'clock position, with size ranged from 0.5 to 1.5 PD. Subretinal fluid was drained by scleral puncture, after that 0.5-2.0 ml sterile air was injected into the vitreous cavity. Cryotherapy was done under binocular indirect ophthalmoscope followed by scleral buckling. RESULTS: Retina reattachment was seen in 32 cases at the first day after operation. A small amount of subretinal fluid was found in 2 cases, which absorbed completely in one week after the surgery. Vitrectomy was done in 1 case because of aggravation of vitreous opacity and failure of retinal reattachment. The success rate of single operation and final operation was 97.1% and 100.0%, respectively. Visual improvement was observed in 33 cases. Ocular hypertension was seen in 6 cases and was controlled by topical antiglaucomatous eyedrops. No recurrence of RRD was found in all cases during the 5-10 months follow-up visit. CONCLUSION: Gas tamponade followed by scleral cryotherapy can improve the success rate of operation for simple rhegmatogenous retinal detachment with obvious synchesis and retinal holes located at the upper quadrant. PMID- 27220709 TI - [Retinal vessel diameter variation analysis in diabetic patients]. AB - OBJECTIVE: To explore the influence factors of retinal vascular changes in diabetes patients. METHODS: Case control study. One hundred and fifty-five type 2 diabetes patients were divided into NDR group (n=80) and DR group (n=70) according to the presence of diabetic retinopathy. Fundus photographs were taken after pupil dilated, the diameter of retinal arterioles and venules were measured between 1.0 PD and 1.5 PD. To analyze the relationship between retinal artery diameter, vein diameter and hypertension, diabetes duration, and DR stage. With retinal artery and vein diameter as the dependent variable, DR stage, hypertension, diabetes duration, insulin using time and age as independent variables, using step method, multiple linear regression was undergoing. RESULTS: The diameter of retinal vein in DR group and NDR group were (90.37+7.95) and (83.45+/-7.80) MUm, the difference was statistically significant (t=5.446, P=0.000). Retinal vein diameter was positively correlated with DR stage and diabetes duration (r=0.377, 0.250; P=0.000, 0.002). DR stage (b=2.382, P=0.000) had a linear relationship with retinal vein diameter (R(2)=0.142, F=25.285). The regression equation was: retinal vein diameter =84.269+ 2.382 . DR stage. Retinal artery diameter was negatively correlated with DR stage, diabetes duration, and hypertension duration (r=-0.453, -0.343, -0.199. P=0.000, 0.000, 0.013). DR stage (b=-2.091, P=0.000) and age (b=-0.182, P=0.000) has a linear relationship with retinal artery diameter (R(2)=0.290, F=31.088). The regression equation was: retinal artery diameter =64.011-2.091.DR stage -0.182.age. CONCLUSIONS: With DR developed, retinal vein diameter increases, retinal artery diameter decreases in diabetic patients. The duration of diabetes mellitus and hypertension were not related to the diameter of retinal artery and vein. PMID- 27220710 TI - [Apply of RetCam II and color Doppler imaging in persistent hyperplastic primary vitreous]. AB - OBJECTIVE: To observe the manifestations of RetCam II and color Doppler imaging (CDI) in a retrospective case series of persistent hyperplastic primary vitreous (PHPV). METHODS: Retrospective study. The medical records of 9 eyes/9 patients with PHPV went through RetCamII and CDI from 2009 to 2014. RESULTS: There were 6 young boys and 3 young girl in this study, age from 2 months to 5 years. All the patients were born at full term. 9 eyes had complication (cataract). The manifestations of RetCam II: There were pale in optic disc. There were white fibre rod connected with optic disc, then prolonged to vitreous cavity, connected with posterior lens capsule. CDI showed arterial blood stream signal in band shaped echogenic structure within vitreous cavity, prolonged to lens from the optic disc, or showed funnel-shaped echogenic mass at the posterior surface of lens and anterior of vitreous body, adhered to ciliary body, lens and the optic disc. CONCLUSIONS: PHPV is congenital ocular anomalies because of a failure of primary vitreous and the hyaloids vascular system to regress. It manifests as unilateral and boys. We diagnosis PHPV by RetCamII and CDI. PMID- 27220711 TI - [To investigate the safety and efficacy of indocyanine green-assisted vitrectomy combined with internal limiting membrane peeling for treatment of idiopathic macular epiretinal membranes]. AB - OBJECTIVE: To observe the efficacy of indocyanine green-assisted vitrectomy combined with internal limiting membrane peeling for treatment of idiopathic macular epiretinal membranes(IMEM). METHODS: Retrospectively studied 60 patients with IMEM who all underwent the surgery of vitrectomy combined with internal limiting membrane peeling from 2011 to 2013. Best corrected visual acuity (BCVA), intraocular pressure(NCT), slit-lamp examination, fundus photography, optical coherence tomography (OCT) were committed. Patients were followed for 6 months. They were divided into two groups according to whether indocyanine green(ICG) was used or not with 32 members in ICG group and 28 members in none ICG group. They were divided into two groups according to the intergrity or disruption of the ellipsoid zone (EZ band) with 26 members in EZ band intergrity group and 34 members in EZ band disruption group. RESULTS: Age ranged from 28 to 79 years and the average age was 60.3 +/- 10.9. Twenty-five males and 35 females were included. Twenty-five left eyes and 35 right eyes were incorporate. Among the 60 patients, 38 cases (63.33%) underwent visual acuity improvement after operation(BCVA improved at least 2 rows) and 21 (35%)patients' vision remained the same(BCVA changes less than 2 rows), while only one patient(1.67%) experienced decreased visual acuity(BCVA decline at least 2 rows). Average best corrected visual acuity (BCVA) (LogMar)and central retina thickness(CRT) (MUm)of all patients preoperationwere 0.85 +/- 0.44 and 578.45+/-144.61 respectively, which were 0.57+/-0.40 , 466.31+/-87.80 for one month and 0.54+/-0.42, 442.33+/- 98.92 three and six months postoperation(P<0.05). Compared to group of disruption EZ band, the BCVA of group of integral EZ band was better(P<0.05). 15 of 26 members in group of integral EZ band came up with EZ band cells loss in one month after operation and recovered by three or six months later. There was no statistical significance in BCVA and CRT between ICG group and none ICG group(P<0.05). CONCLUSIONS: Indocyanine green-assisted vitrectomy combined with internal limiting membrane peeling in the treatment of IMEM is safe and effective. The symptoms of decreased vision, metamorphopsia were greatly ameliorated. Besides, retinal organization structures showed a certain extent of improvement. The transient occurrence of EZ band disruption postoperation could recovery 3 to 6 months later. And internal limiting membrane peeling assisted with ICG is a promising approach to the accomplishment of surgery without obvious toxicity. (Chin J Ophthalmol, 2016, 52:366-372). PMID- 27220712 TI - [Influence of tert-butylhydroquinone on the islets function and expression of HO 1 and VEGF in retina of type 2 diabetic rats]. AB - OBJECTIVE: To observe the effect of tert-butylhydroquinone (tBHQ) on the islets function and expression of HO-1 and VEGF in retina of type 2 diabetic rats. METHODS: Experimental study. Forty healthy male Sprague-Dawley rats with 6 weeks old were given high-fat and high-sugar diet for 4 weeks and then intraperitoneal injection with streptozotocin(STZ) 30mg/kg to induce diabetic model. Model group were further randomly divided into normal group and model group. Ten age matched health rats were chosen as control group. 4 and 12 weeks later, weight of rats , fasting blood glucose (FBG), fasting serum insulin (FINS), the levels of serum liqids were measured. The HO-1 and vascular endothelial growth factor (VEGF) expression in retina were determined by immunohistochmistry and quantitative real time PCR. The differences of the mean values among the three groups were analyzed by one-factor analysis of variance. The multiple comparisons of the mean values among the three groups were analyzed by LSD-t analysis. RESULTS: Type 2 diabetic model was successfully established in 32 rats, the success rate was 80.0%. Compared with normal gourp, plasma triglyceride (TG), plasma total cholesterol (TC) and plasma low density lipoprotein (LDL-C) of diabetic rats increased dramatically, and plasma high density lipoprotein (HDL-C) decreased. FBG was significant different between all groups(chi(2)4w=10.631, P4W=0.005; chi(2)12w=15.053, P12w=0.001), and was significantly increased in tBHQ intervention group than that in diabetic group at the end of 12 week. The levels of FINS and homeostasis model assessment for insulin resistance (HOMA-IR) were significantly higher , and insulin sensitivity index (ISI) was significantly lower in diabetic and tBHQ intervention group compared with normal group(P<0.05), but there is no significantly difference between diabetic and tBHQ intervention group(P>0.05). The immunohistochemistry staining results showed the protein leveI of retinal HO-1 (F4w=689.535, P4w=0.000; F12w=287.988, P12w=0.000)and VEGF(F4w=1084.956, P4w=0.000; F12w= 1107.553, P12w=0.000) was significant different beteween all groups. The expression of HO-1 mRNA increased significantly in diabetic group(t4w=10.21, t12w=9.95)and tBHQ intervention group(t4w=14.01, t12w= 25.64)than that in normal group(P<0.05). The expression of HO-1 mRNA increased significantly in tBHQ intervention group(t4w=6.04, t12w=19.00)than that in diabetic group(P<0.05). The expression of VEGF mRNA increased significantly in diabetic group(t4w=11.92, t12w=29.27)and tBHQ intervention group(t4w=12.50, t12w= 11.24)than that in normal group(P<0.05). The expression of VEGF mRNA increased significantly in tBHQ intervention group(t4w= 6.36, t12w=-20.22)than that in diabetic group(P<0.05). CONCLUSION: tBHQ can promote the secretion of insulin in diabetic rats, lowered glucose levels, also induce the expression of HO-1 and suppress the expression of VEGF in retina to confer protection to islets function and retina of type 2 diabtic rats. PMID- 27220713 TI - [The immunomodulatory role of retinal microglial cells in age-related macular degeneration]. AB - Age-related macular degeneration (AMD) is one of the major causes of visual impairment in the elder population. Recent studies have revealed that retinal microgliacytes may play an important role in the pathogenesis of AMD, and the activation of retinal microglia could regulate the progress of AMD. The immunomodulatory role of retinal microglial cells is reviewed in this article, so as to investigate the mechanism and provide new insight for prevention and treatment of AMD. PMID- 27220714 TI - [The relationship between autophagy and ocular diseases]. AB - Autophagy is an intracellular degradative process used by eukaryotes that delivers cellular constituents to lysosomal degradation, such as damaged, degenerated or long-lived proteins, and excessive or defective organelles. Dysfunction of autophagy is involved in many human diseases, such as cancers, ageing, infectious and neurodegenerative diseases. A number of studies have shown that autophagy-related proteins are constitutively expressed in the eye, and abnormal autophagy is an important pathological feature of some ocular diseases. This article reviews recent advances in understanding the role of autophagy in the pathogenesis of ocular diseases, including cataract. PMID- 27220715 TI - [Research advances of retinal nerve fiber layer thickness and its association with myopia]. AB - Recently, the distribution characteristics of retinal nerve fiber layer thickness in myopic population have raised scholars' attention. The retinal nerve fiber layer thickness is varied with different refractive statuses, and is correlated to many factors like age, eye elongation, and fundus changes. Further exploration of the relationship between myopia and retinal structure and function will promote our understanding and knowledge of the pathogenesis of myopia. The article reviews the structure characteristics of the retinal nerve fiber layer, its associations with demographic characteristics, its characteristics in myopia, and the structural-functional relationship. PMID- 27220716 TI - Pooled patient level data are better suited than study level data to investigate the link between dipeptidyl peptidase-4 inhibitors and the risk of heart failure in type 2 diabetes. PMID- 27220717 TI - Nurses' narratives of moral identity: Making a difference and reciprocal holding. AB - BACKGROUND: Explicating nurses' moral identities is important given the powerful influence moral identity has on the capacity to exercise moral agency. RESEARCH OBJECTIVES: The purpose of this study was to explore how nurses narrate their moral identity through their understanding of their work. An additional purpose was to understand how these moral identities are held in the social space that nurses occupy. RESEARCH DESIGN: The Registered Nurse Journal, a bimonthly publication of the Registered Nurses' Association of Ontario, Canada, features a regular column entitled, 'In the End ... What Nursing Means to Me ...' These short narratives generally include a story of an important moment in the careers of the authors that defined their identities as nurses. All 29 narratives published before June 2015 were analysed using a critical narrative approach, informed by the work of Margaret Urban Walker and Hilde Lindemann, to identify a typology of moral identity. Ethical considerations: Ethics approval was not required because the narratives are publicly available. FINDINGS: Two narrative types were identified that represent the moral identities of nurses as expressed through their work: (1) making a difference in the lives of individuals and communities and (2) holding the identities of vulnerable individuals. DISCUSSION: Nurses' moral identities became evident when they could see improvement in the health of patients or communities or when they could maintain the identity of their patients despite the disruptive forces of illness and hospitalization. In reciprocal fashion, the responses of their patients, including expressions of gratitude, served to hold the moral identities of these nurses. CONCLUSION: Ultimately, the sustainability of nurses' moral identities may be dependent on the recognition of their own needs for professional satisfaction and care in ways that go beyond the kind of acknowledgement that patients can offer. PMID- 27220718 TI - EU exit would have a detrimental effect on the NHS, academics warn. PMID- 27220722 TI - Childhood emotional support and borderline personality features in a sample of Canadian psychiatric outpatients. AB - BACKGROUND: Despite links between early relational experiences and psychopathology, data regarding childhood emotional neglect among Canadian mental health services users are scarce. AIMS: To explore the absence of emotional support experiences reported by Canadian psychiatric outpatients, and to examine the relationship between childhood emotional support and borderline personality disorder (BPD) features. METHODS: A survey regarding childhood emotional support was completed by consecutively admitted adult outpatients, along with self-report assessments of symptom distress and BPD features. RESULTS: A substantial proportion of outpatients reported absent emotional support experiences. After controlling for the effects of age and symptom distress, childhood emotional support was found to be significantly negatively associated with BPD features. CONCLUSION: The findings add further support to the need for clinical attention to the early relational experiences of mental health service users. PMID- 27220723 TI - Design, synthesis and inhibitory activity against human dihydroorotate dehydrogenase (hDHODH) of 1,3-benzoazole derivatives bearing amide units. AB - A series of 1,3-benzoazole derivatives possessing amide moieties were designed, synthesized and evaluated as inhibitors against human dihydroorotate dehydrogenase (hDHODH). Compounds A11, A14 and A26 exhibited good to excellent activities against hDHODH at the concentration of 10MUM. In particular, compound A14 displayed an IC50 value of 0.178MUM with 2-fold preference over A771726. The result implied that a proper degree of steric size and electron density of the C 6 amide moiety was necessary to retain the inhibitory activity of the synthesized compounds. PMID- 27220724 TI - Photoactivatable protein labeling by singlet oxygen mediated reactions. AB - Protein-protein interactions regulate many biological processes. Identification of interacting proteins is thus an important step toward molecular understanding of cell signaling. The aim of this study was to investigate the use of photo generated singlet oxygen and a small molecule for proximity labeling of interacting proteins in cellular environment. The protein of interest (POI) was fused with a small singlet oxygen photosensitizer (miniSOG), which generates singlet oxygen ((1)O2) upon irradiation. The locally generated singlet oxygen then activated a biotin-conjugated thiol molecule to form a covalent bond with the proteins nearby. The labeled proteins can then be separated and subsequently identified by mass spectrometry. To demonstrate the applicability of this labeling technology, we fused the miniSOG to Skp2, an F-box protein of the SCF ubiquitin ligase, and expressed the fusion protein in mammalian cells and identified that the surface cysteine of its interacting partner Skp1 was labeled by the biotin-thiol molecule. This photoactivatable protein labeling method may find important applications including identification of weak and transient protein-protein interactions in the native cellular context, as well as spatial and temporal control of protein labeling. PMID- 27220725 TI - Cloning and functional analysis of human acyl coenzyme A: Cholesterol acyltransferase1 gene P1 promoter. AB - Acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1) catalyzes the conversion of free cholesterol (FC) to cholesterol ester. The human ACAT1 gene P1 promoter has been cloned. However, the activity and specificity of the ACAT1 gene P1 promoter in diverse cell types remains unclear. The P1 promoter fragment was digested with KpnI/XhoI from a P1 promoter cloning vector, and was subcloned into the multiple cloning site of the Firefly luciferase vector pGL3-Enhancer to obtain the construct P1E-1. According to the analysis of biological information, the P1E-1 plasmid was used to generate deletions of the ACAT1 gene P1 promoter with varying 5' ends and an identical 3' end at +65 by polymerase chain reaction (PCR). All the 5'-deletion constructs of the P1 promoter were identified by PCR, restriction enzyme digestion mapping and DNA sequencing. The transcriptional activity of each construct was detected after transient transfection into THP-1, HepG2, HEK293 and Hela cells using DEAE-dextran and Lipofectamine 2000 liposome transfection reagent. Results showed that the transcriptional activity of the ACAT1 gene P1 promoter and deletions of P1 promoter in THP-1 and HepG2 cells was higher than that in HEK293 and HeLa cells. Moreover, the transcriptional activity of P1E-9 was higher compared with those of other deletions in THP-1, HepG2, HEK293 and HeLa cells. These findings indicate that the transcriptional activity of the P1 promoter and the effects of deletions vary with different cell lines. Thus, the P1 promoter may drive ACAT1 gene expression with cell-type specificity. In addition, the core sequence of ACAT1 gene P1 promoter was suggested to be between -125 and +65 bp. PMID- 27220726 TI - Tert-butylhydroquinone attenuates the ethanol-induced apoptosis of and activates the Nrf2 antioxidant defense pathway in H9c2 cardiomyocytes. AB - Tert-butylhydroquinone (tBHQ), an inducer of nuclear factor erythroid 2-related factor 2 (Nrf2), has been demonstrated to attenuate oxidative stress-induced injury and the apoptosis of human neural stem cells and other cell types. However, whether tBHQ is able to exert a protective effect against oxidative stress and the apoptosis of cardiomyocytes has not yet been determined. Thus, the objective of the present study was to determine whether tBHQ protects H9c2 cardiomyocytes against ethanol-induced apoptosis. For this purpose, four sets of experiments were performed under standard culture conditions as follows: i) untreated control cells; ii) cell treatment with 200 mM ethanol; iii) cell treatment with 5 uM tBHQ; and iv) cell pre-treatment with 5 uM tBHQ for 24 h, followed by medium change and co-culture with 200 mM ethanol containing 5 uM tBHQ for a further 24 h. The viability of the cardiomyocytes was evaluated by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The levels of intracellular reactive oxygen species (ROS) and apoptosis were assessed by flow cytometry. Protein expression was measured by western blot analysis, and Nrf2 nuclear localization was observed by immunofluorescence. Exposure to ethanol led to a decrease in the protein expression of Nrf2 and its downstream antioxidant enzymes, accompanied by an increase in ROS generation and in the apoptosis of H9c2 cells. Pre-treatment with tBHQ significantly prevented the H9c2 cells from undergoing ethanol-induced apoptosis. tBHQ also increased the expression of B cell lymphoma-2 (Bcl-2), whereas Bcl-2-associated X protein (Bax) expression was decreased. tBHQ promoted Nrf2 nuclear localization and increased the expression of Nrf2, superoxide dismutase (SOD), catalase (CAT) and heme oxygenase-1 (HO-1), and simultaneously inhibited the ethanol-induced overproduction of intracellular ROS. Therefore, tBHQ confers protection against the ethanol-induced apoptosis of and activates the Nrf2 antioxidant pathway in H9c2 cardiomyocytes. PMID- 27220727 TI - Dehydroepiandrosterone inhibits cell proliferation and improves viability by regulating S phase and mitochondrial permeability in primary rat Leydig cells. AB - Dehydroepiandrosterone (DHEA) is widely used as a nutritional supplement and exhibits putative anti-aging properties. However, the molecular basis of the actions of DHEA, particularly on the biological characteristics of target cells, remain unclear. The aim of the current study was to investigate the effects of DHEA on cell viability, cell proliferation, cell cycle and mitochondrial function in primary rat Leydig cells. Adult Leydig cells were purified by Percoll gradient centrifugation, and cell proliferation was detected using a Click-iT(r) EdU Assay kit and cell cycle assessment performed using flow cytometry. Mitochondrial membrane potential was detected using JC-1 staining assay. The results of the current study demonstrate that DHEA decreased cell proliferation in a dose dependent manner, whereas it improved cell viability in a time-dependent and dose dependent manner. Flow cytometry analysis demonstrated that DHEA treatment increased the S phase cell population and decreased the G2/M cell population. Cyclin A and CDK2 mRNA levels were decreased in primary rat Leydig cells following DHEA treatment. DHEA treatment decreased the transmembrane electrical gradient in primary Leydig cells, whereas treatment significantly increased succinate dehydrogenase activity. These results indicated that DHEA inhibits primary rat Leydig cell proliferation by decreasing cyclin mRNA level, whereas it improves cells viability by modulating the permeability of the mitochondrial membrane and succinate dehydrogenase activity. These findings may demonstrate an important molecular mechanism by which DHEA activity is mediated. PMID- 27220728 TI - Downregulation of miR-34a contributes to the proliferation and migration of laryngeal carcinoma cells by targeting cyclin D1. AB - Laryngeal carcinoma is one of the most common head and neck cancers. MicroRNAs are a class of small non-coding RNAs 18-25 nucleotides in length that post transcriptionally regulate gene expression and have a pivotal role in many biological processes including cancer development. In this study, we investigated the role of miR-34a in laryngeal carcinoma and confirmed the regulation of cyclin D1 (CCND1) by miR-34a. We examined miR-34a expression levels in 71 laryngeal carcinoma patient specimens by quantitative reverse transcription-PCR, and analyzed the clinicopathological significance of the obtained data. Then, functional assays were performed to investigate the potential effects of miR-34a on cancer cell proliferation and migration. In addition, western blotting, luciferase reporter assay and several algorithms were conducted to confirm that CCND1 is directly regulated by miR-34a. We demonstrated that the miR-34a expression level was significantly downregulated in laryngeal carcinoma clinical specimens compared with that observed in their paired adjacent normal tissues. Additionally, miR-34a expression was also inversely correlated with lymph node metastasis and clinical stage. Functional assays showed that ectopic expression of miR-34a inhibited cell proliferation and migration in laryngeal carcinoma cells. Bioinformatic analysis identified CCND1 as a potential target of miR-34a. Moreover, we confirmed that miR-34a inhibited the expression of CCND1 by directly binding to its 3'-untranslated region. Silencing of CCND1 induced effects similar to those of miR-34a ectopic expression, and in laryngeal carcinoma tissues, miR 34a and CCND1 were inversely correlated. Our data suggest that tumor suppressor miR-34a could serve as a new potential diagnostic marker and that ectopic expression of miR-34a may be used as a therapeutic target for laryngeal carcinoma. PMID- 27220729 TI - Photosynthesis in developing leaf of juveniles and adults of three Mediterranean species with different growth forms. AB - Leaf development is influenced by almost all the prevailing environmental conditions as well as from the conditions at the time of bud formation. Furthermore, the growth form of a plant determines the leaf longevity and subsequently the investment in biomass and the internal structure of the mesophyll. Therefore, photosynthetic traits of a growing leaf, though, partly predetermined, should also acclimate to temporal changes during developmental period. In addition, the age of the plant can affect photosynthesis of the growing leaf, yet, in the majority of studies, the age is associated to the size of the plant. To test if the reproductive status of the plant affects the time kinetics of the photosynthetic capacity of a growing leaf and the relative contribution of the plants' growth form to the whole procedure, field measurements were conducted in juveniles (prereproductive individuals) and adults (fully reproductive individuals) of an evergreen sclerophyllous shrub (Nerium oleander), a semi-deciduous dimorphic shrub (Phlomis fruticosa), and a winter deciduous tree with pre-leafing flowering (Cercis siliquastrum). PSII structural and functional integrity was progressively developed in all species, but already completed, only some days after leaf expansion in P. fruticosa. Developing leaf as well as fully developed leaf in adults of C. siliquastrum showed enhanced relative size of the pool of final PSI electron acceptors. Photosynthetic traits between juveniles and adults of P. fruticosa were similar, though the matured leaf of adults exhibited lower transpiration rates and improved water-use efficiency than that of juveniles. Adults of the evergreen shrub attained higher CO2 assimilation rate than juveniles in matured leaf which can be attributed to higher electron flow devoted to carboxylation, and lower photorespiration rate. The reproductive phase of the plant seemed to be involved in modifications of the PSII and PSI functions of the deciduous tree, in carboxylation and photorespiration traits of the evergreen shrub, and in water conductance efficiency of the semi-deciduous shrub. However, it is interesting, that regardless of the growth form of the plant and the prospective leaf longevity of the developing leaf, adults need to support flowering outmatch juveniles, in terms of photosynthesis. PMID- 27220730 TI - Alcohol use among recent immigrant Latino/a youth: acculturation, gender, and the Theory of Reasoned Action. AB - OBJECTIVE: Latino/a youth are at risk for alcohol use. This risk seems to rise with increasing US cultural orientation and decreasing Latino cultural orientation, especially among girls. To ascertain how acculturation may influence Latino/a youth alcohol use, we integrated an expanded multi-domain model of acculturation with the Theory of Reasoned Action. DESIGN: Participants were 302 recent Latino/a immigrant youth (141 girls, 160 boys; 152 from Miami, 150 from Los Angeles) who completed surveys at 4 time points. Youth completed measures of acculturation, attitudes toward drinking, perceived subjective norms regarding alcohol use, intention to drink, and alcohol use. RESULTS: Structural equation modeling indicated that collectivistic values predicted more perceived disapproval of drinking, which negatively predicted intention to drink. Intention to drink predicted elevated alcohol use. CONCLUSION: Although the association between collectivistic values and social disapproval of drinking was relatively small (beta = .19, p < .05), findings suggest that collectivistic values may help protect Latino/a immigrant youth from alcohol use by influencing their perceived social disapproval of drinking, leading to lower intention to drink. Educational preventive interventions aimed at reducing or preventing alcohol use in recent Latino/a immigrant youth could promote collectivistic values and disseminate messages about the negative consequences of drinking. PMID- 27220731 TI - Teaching Medical Students and Residents about Homelessness: Complex, Evidence Based, and Imperative. PMID- 27220732 TI - Designing a social and assistive robot for seniors. AB - BACKGROUND: The development of social assistive robots is an approach with the intention of preventing and detecting falls among seniors. There is a need for a relatively low-cost mobile robot with an arm and a gripper which is small enough to navigate through private homes. MATERIAL AND METHODS: User requirements of a social assistive robot were collected using workshops, a questionnaire and interviews. Two prototype versions of a robot were designed, developed and tested by senior citizens (n = 49) in laboratory trials for 2 h each and in the private homes of elderly persons (n = 18) for 3 weeks each. RESULTS: The user requirement analysis resulted in a specification of tasks the robot should be able to do to prevent and detect falls. It was a challenge but possible to design and develop a robot where both the senior and the robot arm could reach the necessary interaction points of the robot. The seniors experienced the robot as happy and friendly. They wanted the robot to be narrower so it could pass through narrow passages in the home and they also wanted it to be able to pass over thresholds without using ramps and to drive over carpets. CONCLUSION: User trials in seniors' homes are very important to acquire relevant knowledge for developing robots that can handle real life situations in the domestic environment. Very high reliability of a robot is needed to get feedback about how seniors experience the overall behavior of the robot and to find out if the robot could reduce falls and improve the feeling of security for seniors living alone. PMID- 27220733 TI - Social service robots to support independent living : Experiences from a field trial. AB - BACKGROUND: Assistive robots could be a future means to support independent living for seniors. OBJECTIVE: This article provides insights into the latest developments in social service robots (SSR) based on the recently finished HOBBIT project. The idea of the HOBBIT project was to develop a low-cost SSR which is able to reduce the risk of falling, to detect falls and handle emergencies in private homes. The main objective of the project was to raise the technology to a level that allows the robot to be fully autonomously deployed in the private homes of older users and to evaluate technology market readiness, utility, usability and affordability under real-world conditions. METHOD: During the initial phase of the project, a first prototype (PT1) was developed. The results of laboratory tests with PT1 were used for the development of a second prototype (PT2), which was finally tested in seven households of senior adults (mean age 79 years) for 3 weeks each, i.e. in total more than 5 months. RESULTS: The results showed that PT2 is intuitive to handle and that the functions offered meet the needs of older users; however, the robot was considered more as a toy than a supportive device for independent living. Furthermore, despite an emergency function of the robot, perceived security did not increase. CONCLUSION: Reasons for this might be a lack of technological robustness and slow performance of the prototype and also the good health conditions of the users; however, users believed that a market-ready version of the robot would be vital for supporting people who are more fragile and more socially isolated. Thus, SSRs have the potential to support independent living of older people although the technology has to be considerably improved to reach market readiness. PMID- 27220734 TI - Ethical challenges in the use of social service robots for elderly people. AB - Socially assistive robots are increasingly discussed as solutions in care and domestic use for the support of senior adults; however, this raises ethical questions which hitherto have not been considered or were not predictable. The most important questions are those of privacy and data protection, safety and responsibility as well as involvement of vulnerable persons and deception. Consequently, the ethical principles of nonmaleficence, beneficence, autonomy and fairness should be transposed to robotics. Clear answers and solutions are not yet available for every ethical challenge in robotics; however, the development of ethical guidelines for deployment of robots and research in the field of social service robots (SSR) are essential steps in order to embed ethics into dealing with socially assistive robots. This article provides some practical suggestions on this issue from a robotics project. PMID- 27220735 TI - [Low back pain during pregnancy]. AB - OBJECTIVE: Low back pain is a common complaint among pregnant women. It is estimated that about 50% of pregnant women complain of some form of back pain at some point in pregnancy or during the postpartum period. The aim of this study was to evaluate the frequency of low back pain during pregnancy and its characteristics. METHODS: Cross-sectional study with low-risk pregnant women. After approval by the Human Research Ethics Committee and receiving written informed consent, we included pregnant women over 18 years of age and excluded those with psychiatric disorders, previous lumbar pathologies, and receiving treatment for low back pain. RESULTS: We interviewed 97 pregnant women. The frequency of low back pain was 68%. The mean age was 26.2 years and the median gestational age was 30 weeks. Fifty-eight pregnant women declared themselves as brown (58%). Most (88.6%) were married or living in common-law marriage, fifty six (57.7%) worked outside the home, and 71 (73.2%) had completed high school. Low back pain was more frequent during the second trimester of pregnancy (43.9%), referred to as a "burning" sensation in 37.8% of patients, with intermittent frequency in 96.9% of the women. The symptoms got worse at night (71.2%). Resting reduced low back pain in 43.9% of pregnant women, while the standing position for a long time worsened it in 27.2% of patients. CONCLUSION: Low back pain is common in pregnant women, has specific characteristics, and is more frequent in the second trimester of pregnancy. This indicates the need for prevention strategies that enable better quality of life for pregnant women. PMID- 27220736 TI - Mechanism of baicalin compatibility in chinese medicine formula Banxia Xiexin Decoction () by pharmacokinetics and indirect competitive enzyme-linked immunosorbent assays in mice. AB - OBJECTIVE: To determine the effects of different formulations of Banxia Xiexin Decoction ( , BXD) on the pharmacokinetics of baicalin (BAL) in mice. METHODS: Pungent, bitter, and sweet components of BXD (totaling 7 Chinese herbs) were formulated into the following groups: K (bitter herbs), XK (pungent and bitter herbs), KG (bitter and sweet herbs), and BXD (all 7 herbs) groups. These different formulations were administered intragastrically in mice, and blood was collected via the tail vein for continuous monitoring. BAL, which is a main active constituent in Scutellaria baicalensis Georgi., was detected in this study. Indirect competitive enzyme-linked immunosorbent assays (icELISAs) based on anti-BAL-monoclonal antibodies were employed to determine BAL concentrations in each group. RESULTS: The concentrations of BAL in blood samples from mice in the K and XK groups were lower than those in other groups. In all groups, BAL concentrations peaked at around 1-1.5 h and again at 5-7 h. There were no significant differences in the timing of peak BAL concentrations between groups. However, the peak concentrations and area under curve (AUC)0-36 h in the KG and BXD groups were almost 3 times of those in the K and XK groups. CONCLUSIONS: Differing compatibilities of BXD caused dissimilar pharmacokinetics of BAL. Moreover, we demonstrated a method for the continuous detection of blood concentrations of Chinese medicines in mice, and icELISA may be a feasible technique for the study of pharmcokinetic mechanisms of Chinese medicine. PMID- 27220738 TI - Hypoglycemic potential of herbal product dolabi compared with pioglitazone in streptozotocin-induced diabetic rats. AB - OBJECTIVES: To investigate and compare the hypoglycemic potential of commonly used polyherbal formulation dolabi with pioglitazone in streptozotocin-induced diabetic rats. METHODS: A total of 24 adult male Wistar rats were randomized into diabetic control group, diabetic group receiving dolabi (17.6 mg kg-1 day-1), diabetic group receiving dolabi (35.2 mg kg-1 day-1) and diabetic group receiving pioglitazone (2.7 mg kg-1 day-1), with 6 rats in each group. The study was conducted for 4 weeks. Blood samples were collected for fructosamine estimation, fasting plasma glucose (FPG) and oral glucose tolerance test (OGTT) were measured at different time points. RESULTS: Compared with baseline, the groups receiving dolabi (35.2 mg kg-1 day-1) and pioglitazone showed signififi cant reductions (P<0.05) in fructosamine levels at the end point and same was the case for FPG and OGTT with pioglitazone showing greater hypoglycemic potential. However, the group receiving dolabi (17.6 mg kg-1 day-1) showed significant reduction (P<0.05) only in FPG level and failed to achieve significant changes either in fructosamine level or OGTT. Moreover, signififi cant differences (P<0.05) in FPG and fructosamine levels were observed between groups receiving dolabi (17.6 mg kg 1 day-1) and pioglitazone at the end point. CONCLUSIONS: These results showed sluggish hypoglycemic effects of dolabi at manufacturer's recommended doses. At a higher dose however, good glycemic control was achieved with dolabi and the results were comparable to pioglitazone. The shorter duration of study (4 weeks) might be the reason of poor glycemic control associated with dolabi at a normal dose. PMID- 27220737 TI - Short-term efficacy of treating hepatitis B virus-related acute-on-chronic liver failure based on cold pattern differentiation with hot herbs: A randomized controlled trial. AB - OBJECTIVE: To evaluate the clinical efficacy and safety of Yinchen Zhufu Decoction (, YCZFD) in the treatment of acute-on-chronic liver failure caused by hepatitis B virus (HBV-ACLF) with cold pattern in Chinese medicine (CM). METHODS: This is a multi-center randomized controlled trial of integrative treatment of CM and Western medicine (WM) for the management of HBV-ACLF patients. A total of 200 HBV-ACLF patients with cold pattern were equally randomly assigned to receive YCZFD and WM (integrative treatment) or WM conventional therapy alone respectively for 4 weeks. The primary end point was the mortality for HBV-ACLF patients. Secondary outcome measures included Model for End-Stage Liver disease (MELD) score, liver biochemical function, coagulation function and complications. Adverse events during treatment were reported. RESULTS: The mortality was decreased 14.28% in the integrative treatment group compared with WM group (chi(2) =6.156, P=0.013). The integrative treatment was found to signifificantly improve the MELD score (t=2.353, P=0.020). There were statistically signifificant differences in aspartate transaminase, total bilirubin, indirect bilirubin, direct bilirubin and prothrombin time between the two groups (P<0.05 or P<0.01). The complications of ascites (chi(2)=9.033, P=0.003) and spontaneous bacteria peritonitis (chi(2)=4.194, P=0.041) were improved signifificantly in the integrative treatment group. No serious adverse event was reported. CONCLUSIONS: The integrative treatment of CM and WM was effective and safe for HBV-ACLF patients with cold pattern in CM. The Chinese therapeutic principle "treating cold pattern with hot herbs" remains valuable to the clinical therapy. (Trial registration No. ChiCTR-TRC-10000766). PMID- 27220739 TI - Gene regulation in the immediate-early response process. AB - Immediate-early genes (IEGs) can be activated and transcribed within minutes after stimulation, without the need for de novo protein synthesis, and they are stimulated in response to both cell-extrinsic and cell-intrinsic signals. Extracellular signals are transduced from the cell surface, through receptors activating a chain of proteins in the cell, in particular extracellular-signal regulated kinases (ERKs), mitogen-activated protein kinases (MAPKs) and members of the RhoA-actin pathway. These communicate through a signaling cascade by adding phosphate groups to neighboring proteins, and this will eventually activate and translocate TFs to the nucleus and thereby induce gene expression. The gene activation also involves proximal and distal enhancers that interact with promoters to simulate gene expression. The immediate-early genes have essential biological roles, in particular in stress response, like the immune system, and in differentiation. Therefore they also have important roles in various diseases, including cancer development. In this paper we summarize some recent advances on key aspects of the activation and regulation of immediate early genes. PMID- 27220740 TI - Investigation of trimethylacetic acid adsorption on stoichiometric and oxygen deficient CeO2(111) surfaces. AB - We studied the interactions between the carboxylate anchoring group from trimethylacetic acid (TMAA) and CeO2(111) surfaces as a function of oxygen stoichiometry using in situ X-ray photoelectron spectroscopy (XPS). The stoichiometric CeO2(111) surface was obtained by annealing the thin film under 2.0 * 10(-5) Torr of oxygen at ~550 degrees C for 30 min. In order to reduce the CeO2(111) surface, the thin film was annealed under ~5.0 * 10(-10) Torr vacuum conditions at 550 degrees C, 650 degrees C, 750 degrees C and 850 degrees C for 30 min to progressively increase the oxygen defect concentration on the surface. The saturated TMAA coverage on the CeO2(111) surface determined from XPS elemental composition is found to increase with increasing oxygen defect concentration. This is attributed to the increase of under-coordinated cerium sites on the surface with the increase in the oxygen defect concentrations. XPS results were in agreement with periodic density functional theory (DFT) calculations and indicate a stronger binding between the carboxylate group from TMAA and the oxygen deficient CeO2-delta(111) surface through dissociative adsorption. PMID- 27220741 TI - The Psychological Impact of Prenatal Diagnosis and Disclosure of Susceptibility Loci: First Impressions of Parents' Experiences. AB - Genomic microarray may detect susceptibility loci (SL) for neurodevelopmental disorders such as autism and epilepsy, with a yet unquantifiable risk for the fetus. The prenatal disclosure of susceptibility loci is a topic of much debate. Many health care professionals fear that reporting susceptibility loci may put a psychological burden on pregnant couples. It is our policy to disclose prenatal susceptibility loci as we recognize them as actionable for prospective parents. The aim of this report was to evaluate the psychological impact of disclosing a prenatal diagnosis of susceptibility loci. The psychological impact of disclosing susceptibility loci was evaluated in the first patients who received such results. Eight out of 15 women who had a susceptibility locus disclosed and four of their partners consented to share their experiences through a telephonic evaluation (n = 12). Follow-up time ranged from 3 to 15 months after their prenatal test result. The reporting of susceptibility loci was initially 'shocking' for five parents while the other seven felt 'worried'. Ten out of 12 participants indicated they would like to be informed about the susceptibility locus again, two were unsure. Most had no enduring worries. Participants unanimously indicated that pregnant couples should have an individualized pre test choice about susceptibility loci (non)disclosure. We observed no negative psychological impact with the prenatal diagnosis and disclosure of SL on participants. A key factor in mitigating parental anxiety with SL disclosure appears to be post-test genetic counseling. Our report confirms that pregnant women and their partners prefer an individualized choice regarding the scope of prenatal testing. PMID- 27220742 TI - The Greatest Priority for Genetic Counseling: Effectively Meeting Our Clients' Needs 2014 NSGC Natalie Weissberger Paul National Achievement Award. AB - Receipt of the 2014 Natalie Weissberger Paul (NWP) National Achievement Award was a highlight of my career. Thank you to all who nominated me for this prestigious NSGC recognition. I am humbled to join past NWP award winners many of whom are admired mentors, treasured colleagues and friends. I would like to express what a privilege it is to honor Natalie Weissberger Paul for whom this award is named. Twenty-nine years ago I co-edited a volume of the Birth Defects Original Article Series with Natalie summarizing a conference co-funded by the March of Dimes and NSGC (Biesecker et al., 1987). Natalie demonstrated her devotion to children with special needs through her work at the March of Dimes. As such I believe she would concur with the focus of my remarks on the partners in our work: our clients. PMID- 27220744 TI - Diversity of Quill Mites of the Family Syringophilidae (Acari: Prostigmata) Parasitizing Owls (Aves: Strigiformes) With Remarks on the Host-Parasite Relationships. AB - The quill mite fauna of the family Syringophilidae (Acari: Prostigmata: Cheyletoidea) associated with owls (Aves: Strigiformes) is reviewed. A new genus is proposed, Neobubophilus Skoracki & Unsoeld gen. nov. It differs from closely related Bubophilus (Bubophilus Philips and Norton, 1978) by the absence of leg setae vsII in the both sexes. In addition, four new species are described: (1) Neobubophilus cunicularius Skoracki & Unsoeld sp. nov. from Athene cunicularia (Molina, 1782) (Strigidae) from Paraguay; (2) Neobubophilus atheneus Skoracki & Unsoeld sp. nov. from Athene noctua (Scopoli, 1769) and Athene brama (Temminck, 1821) (Strigidae), both from India; (3) Bubophilus tytonus Skoracki & Unsoeld sp. nov. from Tyto alba affinis (Blyth, 1862) (Tytonidae) from Cameroon, and (4) Megasyringophilus dalmas Skoracki & Unsoeld sp. nov. from Megascops choliba (Vieillot, 1817) (Strigidae) from Venezuela. The following new host species are given: Bubo bubo (Linnaeus, 1758) (Strigidae) from Nepal for Bubophilus ascalaphus (Philips and Norton 1978) and Strix woodfordii (Smith, 1834) (Strigidae) from Tanzania for Bubophilus aluconis (aluconis Nattress and Skoracki 2009). A key for syringophilid genera and species associated with owls is constructed. The host-parasite relationships of syringophilid mites and owls are discussed. PMID- 27220743 TI - Methylphenidate for Treating ADHD: A Naturalistic Clinical Study of Methylphenidate Blood Concentrations in Children and Adults With Optimized Dosage. AB - BACKGROUND: Methylphenidate (MPH), along with behavioral and psychosocial interventions, is the first-line medication to treat attention-deficit hyperactivity disorder (ADHD) in Sweden. The dose of MPH for good symptom control differs between patients. However, studies of MPH concentration measurement in ADHD treatment are limited. OBJECTIVE: To describe blood and oral fluid (OF) concentrations of MPH after administration of medication in patients with well adjusted MPH treatment for ADHD, and to identify the most suitable matrix for accurate MPH concentration during treatment. METHODS: Patients were recruited from Child and Adolescent Psychiatry (CAP), General Psychiatry (GP), and the Department of Dependency (DD). Blood and OF samples were collected in the morning before MPH administration as well as 1 and 6 h after administration of the prescribed morning dose of MPH. RESULTS: Fifty-nine patients aged between 9 and 69 years, 76 % males. The daily dose of MPH varied from 18 to 180 mg, but the median daily dose per body weight was similar, approximately 1.0 mg/kg body weight. The median MPH concentration in blood 1 and 6 h after the morning dose was 5.4 and 9.3 ng/mL, respectively. Highly variable OF-to-blood ratios for MPH were found at all time points for all three groups. CONCLUSIONS: Weight is a reliable clinical parameter for optimal dose titration. Otherwise, MPH blood concentration might be used for individual dose optimization and for monitoring of the prescribed dose. Relying only on the outcome in OF cannot be recommended for evaluation of accurate MPH concentrations for treatment monitoring. PMID- 27220745 TI - Caterpillar mimicry by plant galls as a visual defense against herbivores. AB - Plant galls, induced by arthropods and various other organisms have an intimate relationship with host plants, and gall-inducers have limited mobility. In addition to their own photosynthesis, galls are resource sinks rich with nutrients, with neighboring plant organs commonly serving as external photosynthate sources. Galls, if not well defended, may therefore be attractive food sources for herbivores. Galls produced by some aphids, jumping plant lice, thrips, and gall midges in Japan, Palearctic region and in the Middle East visually resemble lepidopteran caterpillars. I propose that such visual resemblance may reduce herbivory of galls and surrounding plant tissues, resulting in an increase in galler survival due to reduced gall damage and in enhanced galler growth due to improved nutrient inflow to the galls, when herbivores avoid colonizing or consuming plant parts that look as if they have been occupied by other herbivores. Potential predators and parasitoids of caterpillars may be attracted to the caterpillar-like galls and then attack real caterpillars and other invertebrate herbivores, which would also be beneficial for both gallers and their hosts. PMID- 27220746 TI - The liquorice root derivative glycyrrhetinic acid can ameliorate ionoregulatory disturbance in rainbow trout (Oncorhynchus mykiss) abruptly exposed to ion-poor water. AB - To consider the idea that a dietary botanical supplement could act as an adaptogen in a teleost fish, the effect of a liquorice root derivative (18beta glycyrrhetinic acid, 18betaGA) on rainbow trout following an acute ionoregulatory stressor was examined. Freshwater (FW) trout were fed a control or 18betaGA supplemented diet (0, 5, or 50MUg 18betaGA/g diet) for 2weeks, then abruptly exposed to ion-poor water (IPW) for 24h. Following IPW exposure, muscle moisture content and serum cortisol levels elevated and serum [Na(+)] and/or [Cl(-)] reduced in control and 50MUg/g 18betaGA-fed fish. However, these endpoints were unaltered in 5MUg/g 18betaGA-fed fish. Gill tissue was investigated for potential mechanisms of 18betaGA action by examining mRNA abundance of genes encoding corticosteroid receptors (CRs), 11beta-hydroxysteroid dehydrogenase 2 (11beta hsd2), and tight junction (TJ) proteins, as well as Na(+)-K(+)-ATPase and H(+) ATPase activity, and mitochondrion-rich cell (MRC) morphometrics. Following IPW exposure, CR and 11beta-hsd2 mRNA, MRC fractional surface, Na(+)-K(+)-ATPase and H(+)-ATPase activity were unaltered or decreased in 50MUg 18betaGA fish, as was mRNA encoding select TJ proteins. In contrast, 5MUg 18betaGA-fed fish exhibited elevated 11beta-hsd2 and CR mRNA abundance versus 50MUg 18betaGA-fed, and reduced MRC apical area as well as some differences in TJ protein mRNA abundance versus control fish. Data suggest that 18betaGA, at low levels, may be adaptogenic in trout and might help to ameliorate ionoregulatory perturbation following IPW exposure. This seems to occur, in part, through 18betaGA-induced alterations in the biochemistry and physiology of the gill. PMID- 27220747 TI - Genetic, epidemiologic and clinicopathologic studies of Japanese Asian patients with Birt-Hogg-Dube syndrome. AB - Birt-Hogg-Dube syndrome (BHD) is a rare genetic disorder characterized by fibrofolliculomas, pulmonary cysts and renal cell carcinomas (RCCs). The affected individuals inherit germline mutations in the folliculin gene (FLCN). We investigated the mutation spectrum and clinicopathologic findings of 312 patients from 120 different families (119 Japanese and 1 Taiwanese). A total of 31 different FLCN sequence variants were identified. The majority were c.1285dupC (n = 34), c.1533_1536delGATG (n = 25), and c.1347_1353dupCCACCCT (n = 19). Almost all patients presented with pulmonary cysts. The incidence of RCCs in FLCN mutation carriers over the age of 40 was 34.8% (40/115). Fifty-five RCC lesions were surgically resected; most were either chromophobe RCC (n = 24; 43.6%) or hybrid oncocytic/chromophobe tumors (19; 34.5%). Seventy-six of 156 FLCN mutation carriers (120 probands and 36 sibs, 48.7%) had skin papules; however, cutaneous manifestations were so subtle that only one patient voluntarily consulted dermatologists. Japanese Asian BHD families have three FLCN mutational hotspots. Recurrent episodes of pneumothoraces are the major symptoms suggestive of a BHD diagnosis in our cohort. Characteristic features of lung and kidney lesions may be more informative than fibrofolliculomas as diagnostic criteria for BHD in the Japanese Asian population. PMID- 27220748 TI - "There's a housing crisis going on in Sydney for Aboriginal people": focus group accounts of housing and perceived associations with health. AB - BACKGROUND: Poor housing is widely cited as an important determinant of the poor health status of Aboriginal Australians, as for indigenous peoples in other wealthy nations with histories of colonisation such as Canada, the United States of America and New Zealand. While the majority of Aboriginal Australians live in urban areas, most research into housing and its relationship with health has been conducted with those living in remote communities. This study explores the views of Aboriginal people living in Western Sydney about their housing circumstances and what relationships, if any, they perceive between housing and health. METHODS: Four focus groups were conducted with clients and staff of an Aboriginal community-controlled health service in Western Sydney (n = 38). Inductive, thematic analysis was conducted using framework data management methods in NVivo10. RESULTS: Five high-level themes were derived: the battle to access housing; secondary homelessness; overcrowding; poor dwelling conditions; and housing as a key determinant of health. Participants associated their challenging housing experiences with poor physical health and poor social and emotional wellbeing. Housing issues were said to affect people differently across the life course; participants expressed particular concern that poor housing was harming the health and developmental trajectories of many urban Aboriginal children. CONCLUSIONS: Housing was perceived as a pivotal determinant of health and wellbeing that either facilitates or hinders prospects for full and healthy lives. Many of the specific health concerns participants attributed to poor housing echo existing epidemiological research findings. These findings suggest that housing may be a key intervention point for improving the health of urban Aboriginal Australians. PMID- 27220749 TI - Body mass index and risk of luminal, HER2-overexpressing, and triple negative breast cancer. AB - Triple negative (TN, tumors that do not express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2)) and HER2-overexpressing (H2E, ER-/HER2+) tumors are two particularly aggressive subtypes of breast cancer. There is a lack of knowledge regarding the etiologies of these cancers and in particular how anthropometric factors are related to risk. We conducted a population-based case-case study consisting of 2659 women aged 20-69 years diagnosed with invasive breast cancer from 2004 to 2012. Four case groups defined based on joint ER/PR/HER2 status were included: TN, H2E, luminal A (ER+/HER2-), and luminal B (ER+/HER2+). Polytomous logistic regression was used to estimate odds ratios (ORs) and associated 95 % confidence intervals (CIs) where luminal A patients served as the reference group. Obese premenopausal women [body mass index (BMI) >=30 kg/m(2)] had an 82 % (95 % CI 1.32-2.51) increased risk of TN breast cancer compared to women whose BMI <25 kg/m(2), and those in the highest weight quartile (quartiles were categorized based on the distribution among luminal A patients) had a 79 % (95 % CI 1.23-2.64) increased risk of TN disease compared to those in the lowest quartile. Among postmenopausal women obesity was associated with reduced risks of both TN (OR = 0.74, 95 % CI 0.54-1.00) and H2E (OR = 0.47, 95 % CI 0.32-0.69) cancers. Our results suggest obesity has divergent impacts on risk of aggressive subtypes of breast cancer in premenopausal versus postmenopausal women, which may contribute to the higher incidence rates of TN cancers observed among younger African American and Hispanic women. PMID- 27220750 TI - Biological subtyping of early breast cancer: a study comparing RT-qPCR with immunohistochemistry. AB - The biological subtype of breast cancer influences the selection of systemic therapy. Distinction between luminal A and B cancers depends on consistent assessment of Ki-67, but substantial intra-observer and inter-observer variability exists when immunohistochemistry (IHC) is used. We compared RT-qPCR with IHC in the assessment of Ki-67 and other standard factors used in breast cancer subtyping. RNA was extracted from archival breast tumour tissue of 769 women randomly assigned to the FinHer trial. Cancer ESR1, PGR, ERBB2 and MKI67 mRNA content was quantitated with an RT-qPCR assay. Local pathologists assessed ER, PgR and Ki-67 expression using IHC. HER2 amplification was identified with chromogenic in situ hybridization (CISH) centrally. The results were correlated with distant disease-free survival (DDFS) and overall survival (OS). qPCR-based and IHC-based assessments of ER and PgR showed good concordance. Both low tumour MKI67 mRNA (RT-qPCR) and Ki-67 protein (IHC) levels were prognostic for favourable DDFS [hazard ratio (HR) 0.42, 95 % CI 0.25-0.71, P = 0.001; and HR 0.56, 0.37-0.84, P = 0.005, respectively] and OS. In multivariable analyses, cancer MKI67 mRNA content had independent influence on DDFS (adjusted HR 0.51, 95 % CI 0.29-0.89, P = 0.019) while Ki-67 protein expression had not any influence (P = 0.266) whereas both assessments influenced independently OS. Luminal B patients treated with docetaxel-FEC had more favourable DDFS and OS than those treated with vinorelbine-FEC when the subtype was defined by RT-qPCR (for DDFS, HR 0.52, 95 % CI 0.29-0.94, P = 0.031), but not when defined using IHC. Breast cancer subtypes approximated with RT-qPCR and IHC show good concordance, but cancer MKI67 mRNA content correlated slightly better with DDFS than Ki-67 expression. The findings based on MKI67 mRNA content suggest that patients with luminal B cancer benefit more from docetaxel-FEC than from vinorelbine-FEC. PMID- 27220751 TI - Synthesis and Characterization of an Alumina Forming Nanolaminated Boride: MoAlB. AB - The 'MAlB' phases are nanolaminated, ternary transition metal borides that consist of a transition metal boride sublattice interleaved by monolayers or bilayers of pure aluminum. However, their synthesis and properties remain largely unexplored. Herein, we synthesized dense, predominantly single-phase samples of one such compound, MoAlB, using a reactive hot pressing method. High-resolution scanning transmission electron microscopy confirmed the presence of two Al layers in between a Mo-B sublattice. Unique among the transition metal borides, MoAlB forms a dense, mostly amorphous, alumina scale when heated in air. Like other alumina formers, the oxidation kinetics follow a cubic time-dependence. At room temperature, its resistivity is low (0.36-0.49 MUOmegam) and - like a metal - drops linearly with decreasing temperatures. It is also a good thermal conductor (35 Wm(-1)K(-1) at 26 degrees C). In the 25-1300 degrees C temperature range, its thermal expansion coefficient is 9.5 * 10(-6 )K(-1). Preliminary results suggest the compound is stable to at least 1400 degrees C in inert atmospheres. Moderately low Vickers hardness values of 10.6 +/- 0.3 GPa, compared to other transition metal borides, and ultimate compressive strengths up to 1940 +/- 103 MPa were measured at room temperature. These results are encouraging and warrant further study of this compound for potential use at high temperatures. PMID- 27220752 TI - The role of tryptophan degradation in the association between inflammatory markers and depressive symptoms in chronic dialysis patients. AB - Background: Among chronic dialysis patients, associations have been found between inflammatory markers and depressive symptoms. In this population, no studies have examined the mechanism linking the association between inflammatory markers and depressive symptoms. We examined whether the association between inflammatory markers and depressive symptoms is mediated by tryptophan (TRP) degradation along the kynurenine (KYN) pathway. Methods: The data are part of an observational, prospective cohort study in five urban dialysis centres in The Netherlands. Depressive symptoms were determined with the Beck Depression Inventory. Peripheral blood was collected before dialysis to measure inflammatory markers [high sensitivity C-reactive protein (HsCRP), interleukin (IL)-1beta, IL-6, IL-10 and tumour necrosis factor-alpha (TNF-alpha)], TRP, KYN and 3-hydroxykynurenine. The KYN/TRP ratio was used as a measure of TRP degradation. The association between inflammatory markers and depressive symptoms was determined using linear regression analysis and adjusted for the KYN/TRP ratio. Results: In total, 490 chronic dialysis patients were included. HsCRP [ beta = 3.8; confidence interval (CI): 1.0-6.6], IL-6 ( beta = 9.1; CI: 4.0-14.1) and TNF-alpha ( beta = 1.3; CI: 0.9-1.7) were associated with the KYN/TRP ratio. We found significant associations between HsCRP ( beta = 0.8; CI: 0.3-1.3) and IL-6 ( beta = 1.2; CI: 0.3-2.2) levels and depressive symptoms. However, this association was not attenuated after adjustment for the KYN/TRP ratio. Also, no significant associations were found between the KYN/TRP ratio and depressive symptoms. Conclusion: The association between inflammatory markers and depressive symptoms in chronic dialysis patients was not mediated by TRP degradation along the KYN pathway. PMID- 27220753 TI - Dialysis modality and nutritional status are associated with variability of inflammatory markers. AB - BACKGROUND: Inflammation is a common feature in dialysis patients and is associated with cardiovascular complications and poor outcome. Measuring the variability of inflammatory markers may help in understanding underlying factors triggering inflammation. Whether the inflammatory pattern in hemodialysis (HD) and peritoneal dialysis (PD) patients differs has scarcely been studied. Here we explored factors associated with the magnitude and variability of inflammation markers in HD and PD patients. METHODS: In two 3-month, prospective cohort studies comprising 228 prevalent HD and 80 prevalent PD patients, interleukin-6 (IL-6) and high-sensitivity C-reactive protein (CRP) were measured in blood samples drawn each month and every week, respectively. Information on comorbidity, protein-energy wasting (PEW) and medications was gathered at baseline, and information on symptoms potentially related to inflammation was gathered weekly. A mixed-effect model was used for multivariate analysis of factors linked to CRP and IL-6 variation. RESULTS: IL-6 and CRP levels were higher and showed higher variability in HD versus PD patients [median IL-6 8.3 (interquartile range, IQR, 5.3-14.5) versus 6.7 (IQR 4.2-10.0) pg/mL, P < 0.001 and median CRP 6.1 (IQR 2.5-14.0) versus 5.4 (IQR 1.6-9.0) mg/L, P < 0.001). PEW predicted increased inflammation variability after correcting for age, sex, dialysis vintage, modality and comorbidity. Increased comorbidity predicted IL-6, but not CRP, variability. CONCLUSIONS: Circulating concentrations as well as variability of IL-6 and CRP levels were higher in HD as compared with PD patients. In HD and PD patients, short-term variability of IL-6 and CRP levels associated strongly with PEW, while comorbidity was related to IL-6 but not to CRP variability. PMID- 27220755 TI - Fibroblast growth factor 23 modifies the pharmacological effects of angiotensin receptor blockade in experimental renal fibrosis. AB - Background: Blockade of the renin-angiotensin-aldosterone system (RAAS) retards progression of chronic kidney disease. Yet, in many patients, the renoprotective effect is incomplete. A high circulating level of the phosphaturic hormone fibroblast growth factor 23 is associated with an impaired response to RAAS blockade-based therapy in clinical studies. Therefore, we addressed whether administration of recombinant fibroblast growth factor 23 (FGF23) interferes with the efficacy of angiotensin receptor blocker (ARB) treatment in a mouse model of renal fibrosis [unilateral ureteral obstruction (UUO)]. Methods: UUO mice were treated with losartan (100 mg/L in drinking water), recombinant FGF23 (160 ng/kg i.p. twice daily), their combination or vehicle ( n = 10 per group). Seven days after the UUO procedure, kidney tissue was analyzed for markers of RAAS activity, inflammation and fibrosis using real-time PCR and immunohistochemistry. Results: In the contralateral (non-affected) kidneys of ARB-treated UUO mice, administration of FGF23 reversed the induction of renin, ACE, ACE2 and AT1 receptor mRNA expression, suggesting interference with the physiological response to RAAS blockade by FGF23. Furthermore, recombinant FGF23 infusion prevented ARB induced klotho upregulation in contralateral kidneys. In the UUO kidneys, klotho was majorly reduced in all groups. Pro-inflammatory gene expression (MCP-1, TNF alpha) induced in UUO kidneys was reduced by ARB treatment; this anti inflammatory effect was reversed by FGF23. In contrast, ARB-induced reduction of (pre-)fibrotic gene expression was not reversed by FGF23. Conclusions: Our findings show pharmacological interaction between exogenous FGF23 and losartan, thus serving as a proof of principle for crosstalk between the FGF23-klotho axis and RAAS. PMID- 27220754 TI - Associations of dysnatremias with mortality in chronic kidney disease. AB - Background: Hyponatremia and hypernatremia are associated with death in the general population and those with chronic kidney disease (CKD). We studied the associations between dysnatremias, all-cause mortality and causes of death in a large cohort of Stage 3 and 4 CKD patients. Methods: We included 45 333 patients with Stage 3 and 4 CKDs followed in a large healthcare system. Associations between hyponatremia (<136 mmol/L) and hypernatremia (>145), and all-cause mortality and causes of death (cardiovascular, malignancy related and non cardiovascular/non-malignancy related) were studied using Cox proportional hazards and competing risk models. Results: Dysnatremias were found in 9.2% of the study population. In separate multivariable Cox proportional hazards models using baseline serum sodium levels and time-dependent repeated measures, both hyponatremia and hypernatremia were associated with all-cause mortality. In the competing risk analyses, hyponatremia was significantly associated with increased risk for various cause-specific mortality categories [cardiovascular (hazard ratio, HR 1.16, 95% confidence interval, CI: 1.04, 1.30), malignancy related (HR 1.48, 95% CI: 1.33, 1.65) and non-cardiovascular/non-malignancy deaths (HR 1.25, 95% CI: 1.13, 1.39)], while hypernatremia was significantly associated with higher non-cardiovascular/non-malignancy mortality only (HR 1.36, 95% CI: 1.08, 1.72). Conclusions: In those with CKD, hyponatremia was associated with all-cause mortality, cardiovascular, malignancy and non-cardiovascular/non-malignancy related deaths. Hypernatremia was associated with all-cause and non cardiovascular/non-malignancy-related deaths. Further studies are needed to elucidate the mechanisms of differences in cause-specific death among CKD patients with hyponatremia and hypernatremia. PMID- 27220757 TI - Pretransplant angiotensin II type 1-receptor antibodies are a risk factor for earlier detection of de novo HLA donor-specific antibodies. AB - BACKGROUND: Angiotensin II type 1 receptor antibodies (AT1Rabs) have been associated with significantly reduced graft survival. Earlier graft loss has been observed in patients who had pretransplant AT1Rabs and posttransplant donor specific antibodies (DSA). METHODS: The main goal of this retrospective cohort study was to examine the association between AT1Rabs and the time period to detection of de novo human leukocyte antigen (HLA-DSA) posttransplantation in living donor kidney transplant recipients (KTR). The analysis included 141 KTRs. Pretransplant frozen serum samples were tested for AT1Rabs by ELISA and HLA-DSA by SAB (Luminex) at both the pre- and post-KT time points. RESULTS: The median AT1Rab level was 9.13 U (interquartile range 5.22-14.33). After a mean follow-up period of 3.55 years, 48 patients were found to harbour de novo HLA-DSAs. The presence of AT1Rabs [hazard ratio (HR) 1.009, 95% confidence interval (CI) 1.002 1.01, P = 0.010], male-to-male transplantation (HR 2.57, 95% CI 1.42-4.67, P = 0.002) and antecedent borderline changes or acute cellular rejection (ACR) (HR 2.47, 95% CI 1.29-4.75, P = 0.006) were significantly associated with de novo DSA detection. A dose-dependent association between AT1Rab levels (<10 U, 10.1-16.9 U, 17-29.9 U and >30 U) and de novo DSA detection was observed (log-rank P = 0.0031). After multivariate analysis of AT1Rab levels (continuous variable), AT1Rabs >30 U, male-to-male transplantation, donor age, higher class I percentage of Panel Reactive Antibody and antecedent borderline changes or ACR remained as independent significant risk factors for the detection of de novo DSAs. CONCLUSIONS: The findings suggest that higher levels of pretransplant circulating antibodies against AT1R (>30 U) in kidney graft recipients constitute an independent risk factor for earlier de novo HLA-DSA detection during the posttransplant period. PMID- 27220758 TI - A regenerable potassium and phosphate sorbent system to enhance dialysis efficacy and device portability: a study in awake goats. AB - Background: Patients on standard intermittent haemodialysis suffer from strong fluctuations in plasma potassium and phosphate. Prolonged dialysis with a wearable device, based on continuous regeneration of a small volume of dialysate using ion exchangers, could moderate these fluctuations and offer increased clearance of these electrolytes. We report in vivo results on the efficacy of potassium and phosphate adsorption from a wearable dialysis device. We explore whether equilibration of ion exchangers at physiological Ca 2+ , Mg 2+ and hypotonic NaCl can prevent calcium/magnesium adsorption and net sodium release, respectively. Effects on pH and HCO3- were studied. Methods: Healthy goats were instrumented with a central venous catheter and dialysed. Potassium and phosphate were infused to achieve plasma concentrations commonly observed in dialysis patients. An adsorption cartridge containing 80 g sodium poly(styrene divinylbenzene) sulphonate and 40 g iron oxide hydroxide beads for potassium and phosphate removal, respectively, was incorporated in a dialysate circuit. Sorbents were equilibrated and regenerated with a solution containing NaCl, CaCl 2 and MgCl 2 . Blood was pumped over a dialyser and dialysate was recirculated over the adsorption cartridge in a countercurrent direction. Results: Potassium and phosphate adsorption was 7.7 +/- 2.7 and 4.9 +/- 1.3 mmol in 3 h, respectively. Adsorption capacity remained constant during consecutive dialysis sessions and increased with increasing K + and PO43-. Equilibration at physiological Ca 2+ and Mg 2+ prevented net adsorption, eliminating the need for post-cartridge calcium and magnesium infusion. Equilibration at hypotonic NaCl prevented net sodium release Fe 2+ and arterial pH did not change. Bicarbonate was adsorbed, which could be prevented by equilibrating at HCO3- 15 mM. Conclusion: We demonstrate clinically relevant, concentration-dependent, pH neutral potassium and phosphate removal in vivo with small volumes of regenerable ion exchangers in our prototype wearable dialysis device. Application of the selected ion exchangers for potassium and phosphate removal in a wearable dialysis device appears to be effective with a low-risk profile. PMID- 27220759 TI - The role of body image and self-perception in anorexia nervosa: the neuroimaging perspective. AB - Anorexia nervosa is a severe psychiatric illness characterized by intense fear of gaining weight, relentless pursuit of thinness, deep concerns about food and a pervasive disturbance of body image. Functional magnetic resonance imaging tries to shed light on the neurobiological underpinnings of anorexia nervosa. This review aims to evaluate the empirical neuroimaging literature about self perception in anorexia nervosa. This narrative review summarizes a number of task based and resting-state functional magnetic resonance imaging studies in anorexia nervosa about body image and self-perception. The articles listed in references were searched using electronic databases (PubMed and Google Scholar) from 1990 to February 2016 using specific key words. All studies were reviewed with regard to their quality and eligibility for the review. Differences in brain activity were observed using body image perception and body size estimation tasks showing significant modifications in activity of specific brain areas (extrastriate body area, fusiform body area, inferior parietal lobule). Recent studies highlighted the role of emotions and self-perception in anorexia nervosa and their neural substrate involving resting-state networks and particularly frontal and posterior midline cortical structures within default mode network and insula. These findings open new horizons to understand the neural substrate of anorexia nervosa. PMID- 27220760 TI - In Vivo Visualization of Stromal Macrophages via label-free FLIM-based metabolite imaging. AB - Macrophage infiltration and recruitment in breast tumors has been correlated with poor prognosis in breast cancer patients and has been linked to tumor cell dissemination. Much of our understanding comes from animal models in which macrophages are labeled by expression of an extrinsic fluorophore. However, conventional extrinsic fluorescence labeling approaches are not readily applied to human tissue and clinical use. We report a novel strategy that exploits endogenous fluorescence from the metabolic co-factors NADH and FAD with quantitation from Fluorescence Lifetime Imaging Microscopy (FLIM) as a means to non-invasively identify tumor-associated macrophages in the intact mammary tumor microenvironment. Macrophages were FAD(HI) and demonstrated a glycolytic-like NADH-FLIM signature that was readily separated from the intrinsic fluorescence signature of tumor cells. This non-invasive quantitative technique provides a unique ability to discern specific cell types based upon their metabolic signatures without the use of exogenous fluorescent labels. Not only does this provide high resolution temporal and spatial views of macrophages in live animal breast cancer models, this approach can be extended to other animal disease models where macrophages are implicated and has potential for clinical applications. PMID- 27220761 TI - UGT1A1 gene polymorphism is associated with toxicity and clinical efficacy of irinotecan-based chemotherapy in patients with advanced colorectal cancer. AB - OBJECTIVES: To investigate the relationship between uridine diphosphate glucoronosyltransferase 1A1 (UGT1A1)*28/*6 and toxicity and clinical efficacy of irinotecan-based chemotherapy in patients with advanced colorectal cancer (CRC) in Xinjiang Uygur and Han population. METHODS: A total of 183 patients (Uygur, 114; Han, 69) with advanced CRC who received the irinotecan-based chemotherapy were enrolled in this retrospective analysis. Polymerase chain reaction amplification and direct sequencing method were used for UGT1A1*28 and UGT1A1*6 polymorphism detection. The patients were followed up to analyze the relationship between different genotypes with adverse reactions and the clinical outcome of irinotecan-based chemotherapy. RESULTS: Significant differences were found in genotype frequencies of UGT1A1*28 and UGT1A1*28/*6 between Uygur and Han (P = 0.02 and P = 0.002). Uygur and Han patients carrying wild UGT1A1*28 and *6 genotypes appeared to have significantly lower diarrhea incidence (I/II and III/IV) than those carrying mutant genotypes (all P < 0.05). In Uygur patients, UGT1A1*28 genotypes were related with objective response rate and disease control rate (P < 0.05). Compared with *1 allele *1/*1, *1 allele *1/*28*1/*28 mutant of UGT1A1*28 was associated with shorter OS in both Uygur and Han ethnicities (all P < 0.05). Compared with double allele variants (DW), single allele variants (SV), and double allele variants (DV) of UGT1A1*28/*6 were associated with shorter overall survival (OS) in Uygur and Han (all P < 0.05). Cox regression analysis revealed factors significantly influencing OS, including UGT1A1*28, UGT1A1*6, combined genotypes and chemotherapy line in Ugyur, and only combined genotypes in Han (all P < 0.05). CONCLUSION: UGT1A1 gene polymorphism predicts irinotecan related adverse reactions in advanced CRC patients of Xinjiang Uygur and Han nationality; UGT1A1 gene polymorphism is correlated with efficacy and prognosis in Uygur nationality, but only related to prognosis in Han nationality in irinotecan-based chemotherapy. PMID- 27220762 TI - Peritoneal dissemination in early gastric cancer: importance of the lymphatic route. AB - The current paradigm concerning the mechanism of peritoneal dissemination of gastric cancer is that it occurs through an invasive process in which cancer cells directly penetrate the gastric wall and exfoliate into the peritoneal cavity. However, some experimental studies suggest the lymphatic route as an alternative. We present five early gastric cancer cases, which support this alternative pathway of peritoneal dissemination without direct invasion in the serosa. We investigated all patients with early gastric cancer who underwent curative gastrectomy between September 2002 and February 2015 at the Shizuoka Cancer Center, Japan. We examined them by intraoperative peritoneal lavage cytology and frozen section diagnosis of peritoneal nodules during laparotomy. Peritoneal dissemination was defined as peritoneal metastasis by positive cytology or histological diagnosis. Among 1509 early gastric cancers, five cases (0.3 %, 95 % CI 0.1-0.8 %) presented peritoneal dissemination detected by lavage cytology and frozen section diagnosis of peritoneal nodules. Histological examination revealed that the primary tumors invaded the submucosal layer using the lymphatic route, through which they metastasized to regional lymph nodes. Our data indicate that gastric cancer may give rise to peritoneal dissemination even at an early stage, probably through the lymphatic route without direct invasion into the serosa. PMID- 27220763 TI - Prognostic factors in the myoepithelial-like spindle cell type of metaplastic breast cancer. AB - Metaplastic breast carcinoma (MBC) comprises a heterogeneous group of tumors with difficult to predict biological behavior. A subset of MBC, characterized by spindle-shaped tumor cells with a myoepithelial-like immunophenotype, was entered into a retrospective study (n = 42, median follow-up time 43 months). Molecular parameters (DNA sequences of mutation hot spots in AKT1, ALK, APC, BRAF, CDH1, CTNNB1, EGFR, ERBB2, FBXW7, FGFR2, FOXL2, GNAQ, GNAS, KIT, KRAS, MAP2K1, MET, MSH6, NRAS, PDGFRA, PIK3CA, PTEN, SF3B1, SMAD4, SRC, SRSF2, STK11, TP53, and U2AF1; copy numbers for EGFR, c-myc, FGFR, PLAG, c-met) were assessed. None of the patients had axillary lymph node involvement. In 13 cases, local recurrence developed after surgery (30.9 %). Distant metastasis occurred in seven patients (17 %; four after local recurrence). The most frequent genetic alteration was PIK3CA mutation (50 % of cases). None of the pathological parameters (size, grade, stage, Ki-67 labeling index) was significantly associated with disease free survival (DFS) or overall survival (OS). PIK3CA mutation, especially the H1047R type, tended to adversely affect OS. Type of resection (mastectomy vs. breast-conserving therapy, width of margins) or adjuvant radiotherapy had no influence on DFS or OS, whereas in the group treated with radio-/chemotherapy, no local recurrence or metastasis and no death occurred. We conclude that the spindle cell type of MBC with myoepithelial features exhibits a higher frequency of PIK3CA mutation than other types of metaplastic or basal-like breast cancer and may benefit from combined radio-/chemotherapy. Classical pathological parameters are not helpful in identifying the high-risk tumors among this subgroup of MBC. PMID- 27220764 TI - Immunohistochemical staining for p16 and BRAFV600E is useful to distinguish between sporadic and hereditary (Lynch syndrome-related) microsatellite instable colorectal carcinomas. AB - DNA mismatch repair (MMR) protein analysis by immunohistochemistry (IHC) can identify colorectal cancer (CRC) with microsatellite instability (MSI). As MLH1 deficient CRC can be hereditary or sporadic, markers to distinguish between them are needed. MLH1 promoter methylation assay is the reference method; however, sometimes, it is challenging on formalin-fixed paraffin-embedded tissue samples. We assessed by IHC the expression of BRAFV600E, p16, MGMT, and CDX2 in 55 MLH1 deficient MSI CRC samples (of which 8 had a germline MLH1 mutation) to determine whether this panel differentiates between sporadic and hereditary CRCs. We also analyzed MLH1 promoter methylation by methylation-specific PCR and pyrosequencing and BRAF status by genotyping. None of the hereditary CRCs showed MLH1 methylation, BRAF mutation, BRAFV600E-positive immunostaining, or loss of p16 expression. We detected MLH1 promoter methylation in 67 % and a BRAF mutation in 42 % of CRC, all showing MLH1 promoter methylation. BRAFV600E IHC and BRAF genotyping gave concordant results in all but two samples. Loss of expression of p16 was found in 30 % of CRC with methylation of the MLH1 promoter, but its expression was retained in all non-methylated and part of MLH1-methylated tumors (100 % specificity, 30 % sensitivity). CDX2 and MGMT expression was not associated with MLH1 status. Thus, BRAFV600E and p16 IHC may help in differentiating sporadic from hereditary MLH1-deficient CRC with MSI. Specifically, p16 IHC might be used as a surrogate marker for MLH1 promoter methylation, because all p16-negative CRCs displayed MLH1 methylation, whereas hereditary CRCs were all p16-positive. PMID- 27220765 TI - Impact of the 2013 ASCO/CAP HER2 revised guidelines on HER2 results in breast core biopsies with invasive breast carcinoma: a retrospective study. PMID- 27220766 TI - Endoplasmic reticulum stress, unfolded protein response and development of colon adenocarcinoma. AB - When misfolded proteins accumulate in the endoplasmic reticulum (ER), the cell is said to experience ER stress. This triggers an unfolded protein response (UPR) to restore the balance between misfolded proteins and ER chaperones such as BiP. UPR signalling is required for the growth of many solid cancers. In chronic ER stress, factors including CHOP have been shown to mediate cell death. Colorectal adenocarcinoma arises due to progressive changes within pre-malignant lesions. Our aim was to test the hypothesis that the expression of BiP and CHOP correlates with the progression of those pre-malignant lesions.Eighty-one patients with colon neoplasms treated at Rouen University Hospital between January 1, 2003 and January 1, 2013 were randomly selected. The expression of BiP and CHOP was estimated by immunohistochemical staining of a tissue microarray generated from colon cores: normal tissue, low-grade and high-grade adenoma, invasive colon adenocarcinoma and lymph node metastasis of colon adenocarcinoma. In parallel, nine cases comprising areas from normal epithelium to dyplasia to invasive carcinoma and included in the TMA were analysed on whole sections.As colon epithelium shows increasing evidence of pre-malignant and then malignant changes, BiP expression significantly increases (p for trend < 0.001), whereas CHOP expression is attenuated (p for trend < 0.001).We identified a positive relationship between BiP expression and colon carcinogenesis, and a negative correlation for CHOP expression. These findings are consistent with a model in which ER stress accompanies oncogenesis and in which loss of proteins that mediate the toxicity of ER stress, such as CHOP, may facilitate tumorigenesis. This raises the exciting possibility that restoration of the negative feedback loop of UPR, if achievable, might antagonise the malignant process. PMID- 27220767 TI - Are simultaneous postural adjustments (SPA) programmed as a function of pointing velocity? AB - This paper deals with the influence of velocity on the postural adjustments that occur during the course of a voluntary movement, that is to say, simultaneous postural adjustments (SPA). To this aim, a pointing task performed at different velocities (V) was considered. Upper limb kinematics and body kinetics were recorded. Using a 2-DOF model, the body was divided into two parts: the right upper limb (termed the "focal" chain) and the rest of the body (termed the "postural" chain). This model allowed us to calculate the kinetics of both subsystems (-F x and [Formula: see text]), with one corresponding to the resultant action on the shoulder (AoSh: -F x) and the other to the resultant reaction of the shoulder (RoSh: [Formula: see text]). The influence of pointing velocity on peak amplitudes and durations was evaluated, as was their instantaneous relationship ("Lissajous ellipse"). The results showed that RoSh and AoSh display similar diphasic profiles, whose amplitude and duration vary with movement velocity. In addition, RoSh is in phase advance of AoSh, the advance being all the shorter as the focal movement velocity becomes faster. Finally, SPA appears to play a dual role, which includes a propulsive action during upper limb acceleration and body stabilization during deceleration. These new findings strengthen the hypothesis that the postural chain is programmed according to task velocity in the same way as the focal chain and that both are coping in order to make the task more efficient. PMID- 27220768 TI - Body-scaled perception is subjected to adaptation when repetitively judging opportunities for grasping. AB - Experimental evidence is given that the perceptual system adapts to repetitive task execution in a perceptual two-choice judgment task. Participants were tested with respect to their perception of opportunities for plank grasping. Participants had to report whether planks were perceived as objects being graspable with either one hand or two hands. When the plank size was gradually increased and subsequently decreased, transitions from one hand judgments to two hands judgments and vice versa were observed. Analysis of the transition scores revealed that the perceptual judgments were body-scaled, as it is known in the literature. However, judgments were also found to be context dependent. Judgment transition scores were affected in a systematic way by the kind of and the number of previously made judgments. The latter quantitative impact was observed in three related experiments and suggests that perceptual judgments about opportunities for action adapt to task repetition. Overall, the experimental findings are consistent with the predictions of a dynamical systems model, which assumes that perceptual judgments are emergent properties of a self-organizing process that involves inhibitory top-down feedback. PMID- 27220770 TI - [Avoiding pitfalls in the diagnostics of bone neoplasms from pathologists point of view : Importance of reference pathology]. AB - Bone tumors account for only approximately 1 % of the total number of malignant tumors in humans so that they are only rarely diagnosed and appropriate experience is difficult to acquire. Although the number of entities is limited there exist very different clinical and radiological images depending on the manifestation in the different regions of the skeleton. Bone tumors are also histologically structured very differently even within a particular entity. Prior to the histopathological diagnosis the location of the lesion within the entire skeleton and in relation to the tumor-bearing bone must be clarified based on imaging findings, i.e. which bone is affected, which portion of the bone is affected and is the tumor centrally located in the marrow cavity, in the area of the corticalis or on the outside? It is known that bone tumors show diagnostically relevant preferential locations in both the total skeleton as well as within the affected bone depending on the entity and that the age of onset also varies. In this article the most common reasons for errors in assessment are discussed. In most cases it is possible for reference pathology to still correctly classify specific cases by a consistent consideration of diagnostic radiology in combination with morphology. Although diagnostic progress for specific entities of bone tumors has been achieved using molecular methods, the established principle of interdisciplinary cooperation is the prerequisite for the correct diagnosis of these tumors. The therapeutic consequences for patients can be substantial and result in life-long functional limitations depending on the diagnosis (e.g. joint resection for osteosarcoma in childhood and adolescence). A correct diagnosis is therefore of great importance for far reaching therapeutic decision-making. PMID- 27220769 TI - Two Ears Are Not Always Better than One: Mandatory Vowel Fusion Across Spectrally Mismatched Ears in Hearing-Impaired Listeners. AB - Hearing loss and auditory prostheses can alter auditory processing by inducing large pitch mismatches and broad pitch fusion between the two ears. Similar to integration of incongruent inputs in other sensory modalities, the mismatched, fused pitches are often averaged across ears for simple stimuli. Here, we measured parallel effects on complex stimulus integration using a new technique based on vowel classification in five bilateral hearing aid users and eight bimodal cochlear implant users. Continua between five pairs of synthetic vowels were created by varying the first formant spectral peak while keeping the second formant constant. Comparison of binaural and monaural vowel classification functions for each vowel pair continuum enabled visualization of the following frequency-dependent integration trends: (1) similar monaural and binaural functions, (2) ear dominance, (3) binaural averaging, and (4) binaural interference. Hearing aid users showed all trends, while bimodal cochlear implant users showed mostly ear dominance or interference. Interaural pitch mismatches, frequency ranges of binaural pitch fusion, and the relative weightings of pitch averaging across ears were also measured using tone and/or electrode stimulation. The presence of both large interaural pitch mismatches and broad pitch fusion was not sufficient to predict vowel integration trends such as binaural averaging or interference. The way that pitch averaging was weighted between ears also appears to be important for determining binaural vowel integration trends. Abnormally broad spectral fusion and the associated phoneme fusion across mismatched ears may underlie binaural speech perception interference observed in hearing aid and cochlear implant users. PMID- 27220771 TI - Bilateral sequential Propionibacterium acnes exogenous endophthalmitis. AB - A 68-year-old man underwent uncomplicated sequential cataract extractions performed more than a year apart. He presented 6 months after the second surgery with persistent intraocular inflammation in both eyes. Cultures from both eyes grew Propionibacterium acnes and he responded well to treatment. Suspicion for delayed-onset post-operative endophthalmitis must remain high in uveitis cases that fail to resolve with anti-inflammatory treatments. The authors believe this is the first reported case of bilateral sequential P. acnes exogenous endophthalmitis. PMID- 27220772 TI - Involvement of herbal medicine as a cause of mesenteric phlebosclerosis: results from a large-scale nationwide survey. AB - BACKGROUND: Mesenteric phlebosclerosis (MP) is a rare disease characterized by venous calcification extending from the colonic wall to the mesentery, with chronic ischemic changes from venous return impairment in the intestine. It is an idiopathic disease, but increasing attention has been paid to the potential involvement of herbal medicine, or Kampo, in its etiology. Until now, there were scattered case reports, but no large-scale studies have been conducted to unravel the clinical characteristics and etiology of the disease. METHODS: A nationwide survey was conducted using questionnaires to assess possible etiology (particularly the involvement of herbal medicine), clinical manifestations, disease course, and treatment of MP. RESULTS: Data from 222 patients were collected. Among the 169 patients (76.1 %), whose history of herbal medicine was obtained, 147 (87.0 %) used herbal medicines. The use of herbal medicines containing sanshishi (gardenia fruit, Gardenia jasminoides Ellis) was reported in 119 out of 147 patients (81.0 %). Therefore, the use of herbal medicine containing sanshishi was confirmed in 70.4 % of 169 patients whose history of herbal medicine was obtained. The duration of sanshishi use ranged from 3 to 51 years (mean 13.6 years). Patients who discontinued sanshishi showed a better outcome compared with those who continued it. CONCLUSIONS: The use of herbal medicine containing sanshishi is associated with the etiology of MP. Although it may not be the causative factor, it is necessary for gastroenterologists to be aware of the potential risk of herbal medicine containing sanshishi for the development of MP. PMID- 27220773 TI - How Much Do We Know about Maintaining Treatment Response after Successful Acne Therapy? Systematic Review on the Efficacy and Safety of Acne Maintenance Therapy. AB - After cessation of successful initial acne therapy, patients often experience flares. Consecutive maintenance treatment after successful induction therapy is promoted by guidelines; however, little is known about the efficacy/safety of different maintenance regimens. A systematic review on acne maintenance treatments was conducted. We identified 5 randomized controlled trials [RCTs; adapalene vs. vehicle or vs. no treatment (3 RCTs), adapalene/benzoyl peroxide (BPO) vs. vehicle, combination/monotherapy of minocycline (systemic)/tazarotene/placebo] and 3 non-RCTs on systemic isotretinoin, adapalene/BPO and azelaic acid. The results of adapalene versus vehicle/no treatment varied depending on the reported outcome. The 'number of patients maintaining at least 50% improvement' counting inflammatory lesions/non inflammatory lesions with adapalene was superior to vehicle (risk ratio, RR 1.24, 95% confidence interval, CI 1.08-1.43/RR 1.34, 95% CI 1.18-1.59). However, no significant differences were found in 2 of 3 RCTs for maintaining 'clear/almost clear' or 'mild acne' or on the global grading score. For the combination regimens of minocycline/tazarotene/placebo, no significant differences were found. Adapalene/BPO was superior to vehicle counting inflammatory lesions/non inflammatory lesions (RR 1.61, 95% CI 1.31-1.99; RR 1.80, 95% CI 1.44-2.26). Due to the scarcity of studies, few conclusions can be drawn. More homogeneous outcome measures and specific maintenance study designs may lead to more robust findings. PMID- 27220775 TI - Seasonal migration of the starry smooth-hound shark Mustelus asterias as revealed from tag-recapture data of an angler-led tagging programme. AB - The primary aim of this long-term angler-led tagging programme was to gain information about seasonal changes in distribution of the starry smooth-hound shark Mustelus asterias, along the Dutch coast for management and conservation purposes. Between 2011 and 2014, M. asterias comprised 92.6% (n = 2418) of the total elasmobranch catch (n = 2612) by the licenced group of taggers within the Dutch Delta of which 2244 M. asterias were fin-tagged with plastic rototags. Sex and total length (LT ) composition inside the eastern tidal basin (Oosterschelde) were significantly different, i.e. more females and larger individuals, than outside indicating a pupping ground, which was confirmed by the capture of 30 newborn pups (<=32 cm). The distribution pattern of reported recaptured M. asterias (return-rate 3.6%, n = 80) showed a circannual migration between summering in the southern North Sea and wintering in the English Channel and the Bay of Biscay, and suggests that M. asterias is philopatric. The Dutch angling season for M. asterias runs from approximately mid-May to mid-October when the water temperature is above 13 degrees C. Recaptures of eight mature females, but no males in the Bay of Biscay, indicate partial spatial segregation by sex, where mature females migrate over larger distances than immature females and males. These observations, with the absence of recaptures in other known summering areas (i.e. the Irish Sea and Bristol Channel), suggest that the southern North Sea is used by a separate population. Implications for management and recommendations to improve and expand the study approach are discussed. PMID- 27220774 TI - Fungal endophytes of Catharanthus roseus enhance vindoline content by modulating structural and regulatory genes related to terpenoid indole alkaloid biosynthesis. AB - Not much is known about the mechanism of endophyte-mediated induction of secondary metabolite production in Catharanthus roseus. In the present study two fungal endophytes, Curvularia sp. CATDLF5 and Choanephora infundibulifera CATDLF6 were isolated from the leaves of the plant that were found to enhance vindoline content by 229-403%. The isolated endophytes did not affect the primary metabolism of the plant as the maximum quantum efficiency of PSII, net CO2 assimilation, plant biomass and starch content of endophyte-inoculated plants was similar to endophyte-free control plants. Expression of terpenoid indole alkaloid (TIA) pathway genes, geraniol 10-hydroxylase (G10H), tryptophan decarboxylase (TDC), strictosidine synthase (STR), 16-hydoxytabersonine-O-methyltransferase (16OMT), desacetoxyvindoline-4-hydroxylase (D4H), deacetylvindoline-4-O acetyltransferase (DAT) were upregulated in endophyte-inoculated plants. Endophyte inoculation upregulated the expression of the gene for transcriptional activator octadecanoid-responsive Catharanthus AP2-domain protein (ORCA3) and downregulated the expression of Cys2/His2-type zinc finger protein family transcriptional repressors (ZCTs). The gene for the vacuolar class III peroxidase (PRX1), responsible for coupling vindoline and catharanthine, was upregulated in endophyte-inoculated plants. These endophytes may enhance vindoline production by modulating the expression of key structural and regulatory genes of vindoline biosynthesis without affecting the primary metabolism of the host plant. PMID- 27220777 TI - Hsa-miR-495 acts as a tumor suppressor gene in glioma via the negative regulation of MYB. AB - MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at the post-transcriptional level. Previous studies have reported that there are causative links between the abnormal regulation of miRNAs and cancer development. Hsa-miR-495 has previously been demonstrated to be downregulated, and to function as a tumor suppressor, in numerous types of human cancer. However, the function and molecular mechanism of hsa-miR-495 in glioma remains unclear. In the current study, the expression and effects of hsa-miR-495 on glioma were evaluated. It was identified that the expression levels of hsa-miR 495 were downregulated in glioma tissues and cell lines. Furthermore, restoration of hsa-miR-495 inhibited glioma cell proliferation and invasion in vitro. Notably, a luciferase reporter assay revealed that hsa-miR-495 was able to directly target v-myb avian myeloblastosis viral oncogene homolog (MYB) in glioma cells. In addition, an RNA interference assay indicated that MYB knockdown inhibited glioma cell proliferation and invasion in vitro. In conclusion, the results of the present study suggested that hsa-miR-495 may act as a tumor suppressor gene in glioma by directly inhibiting MYB expression, which may provide a novel therapeutic strategy for the treatment of glioma. PMID- 27220778 TI - High glucose-induced fibronectin upregulation in cultured mesangial cells involves caveolin-1-dependent RhoA-GTP activation via Src kinase. AB - Increasing evidence indicates that diabetes-mediated renal interstitial fibrosis through extracellular matrix (ECM) protein accumulation is an important event in the development of diabetic kidney disease (DKD), however, the underlying mechanism remains unclear. In the current study, it was observed that high levels of glucose (HG) time- and dose-dependently increased the production of the ECM protein, fibronectin (FN), in primary rat mesangial cells. Inhibition of the Rho pathway blocked HG-induced FN upregulation. HG-induced RhoA activation was prevented by inhibiting caveolae with filipin III or caveolin-1 siRNA and rescued by exogenous caveolin-1. HG also increased caveolin-1/Src association and activated Src kinase, whereas the inhibition of Src blocked RhoA activation and FN upregulation. Src-mediated phosphorylation of caveolin-1 on Y14 has also been implicated in signaling responses. Overexpression of the nonphosphorylatable caveolin-1 Y14A mutant prevented the HG-induced RhoA activation and FN upregulation. In conclusion, HG-induced FN upregulation requires caveolae and caveolin-1 to interact with RhoA and Src kinases. Interference with Src/caveolin 1/RhoA signaling may provide novel mechanistic targets for the treatment of DKD. PMID- 27220776 TI - Inflammatory profile in LRRK2-associated prodromal and clinical PD. AB - BACKGROUND: There is evidence for a relevant role of inflammation in the pathogenesis of Parkinson's disease (PD). Mutations in the LRRK2 gene represent the most frequent genetic cause for autosomal dominant PD. LRRK2 is highly expressed in macrophages and microglia suggesting an involvement in inflammatory pathways. The objectives are to test (1) whether idiopathic PD and LRRK2 associated PD share common inflammatory pathways or present distinct profiles and (2) whether non-manifesting LRRK2 mutation carriers present with similar aspects of inflammatory profiles as seen in PD-affected patients. METHODS: We assessed serum profiles of 23 immune-associated markers and the brain-derived neurotrophic factor in 534 individuals from the MJFF LRRK2 consortium. RESULTS: A large proportion of inflammatory markers were gender-dependent. Both PD-affected cohorts showed increased levels of the pro-inflammatory marker fatty-acid-binding protein. Additionally, idiopathic PD but not LRRK2-associated PD patients showed increased levels of the pro-inflammatory marker interleukin-12-p40 as well as the anti-inflammatory species interleukin-10, brain-derived neurotrophic factor, and stem cell factor. Non-manifesting LRRK2 mutation carriers including those with prodromal characteristics of PD presented with control-like inflammatory profiles. CONCLUSIONS: Concomitant inflammation seems to be associated with idiopathic and LRRK2-associated PD. Identifying PD patients in whom inflammatory processes play a major role in their pathophysiology might offer a new therapeutic window at least for a subgroup of patients. Since non-manifesting LRRK2 mutation carriers with symptoms of the prodromal phase of PD did not show inflammatory profiles, activation of the immune system seems not an early event in the disease cascade. PMID- 27220779 TI - Ecce Homo: Science and Society Need Anthropological Collections. AB - Scientific collections are crucial to understanding the biological and cultural diversity of the Earth. Anthropological collections document the human experience and the interactions between people, ecosystems, and organisms. Unfortunately, anthropological collections are often poorly known by the public and face a variety of threats to their permanent care and conservation. PMID- 27220780 TI - Predictive Value of Exercise Stress Test-Induced ST-Segment Changes in Leads V1 and avR in Determining Angiographic Coronary Involvement. AB - BACKGROUND: The significance of electrocardiographic changes during exercise tolerance testing for distinguishing occluded artery is not well known. We tried to determine the role of ST elevation in leads aVR and V1 during exercise in detecting stenosis of left main coronary artery and proximal left anterior descending artery. METHODS: ST segment changes during exercise in 230 patients, who underwent diagnostic angiography, were documented. The association of ST elevation in lead aVR, V1 , leads aVR + V1 , and STE in leads aVR + V1 with ST depression in other leads with pattern of coronary stenosis were investigated. RESULTS: Left main and proximal left anterior artery stenosis were more common in patients with ST elevation in lead aVR (P < 0.001 for both). Similar association was found in the presence of ST elevation in lead V1 . The presence of ST elevation >=1 mm in lead aVR had a sensitivity of 100% and 94.3% for detecting left main and left anterior descending artery stenosis, respectively. The specificity was 33.5% and 26.6%, respectively. ST elevation in leads aVR + V1 had a sensitivity of 74.4% and 65.9% and a specificity of 68.5% and 64.4% for detecting left main and left anterior descending arteries stenosis, respectively. CONCLUSION: ST elevation in lead aVR is highly sensitive for left main and proximal left anterior descending artery lesions. Using ST elevation in lead V1 in addition to lead aVR as a positive finding increases the specificity with a further decrease in sensitivity. PMID- 27220781 TI - What does EEG tell us about arithmetic strategies? A review. AB - Arithmetic strategies refer to the set of procedures used to solve arithmetic problems. Previous studies revealed that participants can solve arithmetic problems by using several arithmetic strategies. In this review, we discuss the added value of using electroencephalography (EEG) to investigate such strategies. Indeed, this technique enables to delineate different aspects of information processing, and can further our understanding of arithmetic strategies. The investigation of processes involved within arithmetic strategies with event related potentials (ERPs) and frequency analyses allows to discover how participants solve different types of problems by enabling to distinguish arithmetic strategies on the bases of their electrophysiological signatures. Moreover, this technique is fruitful to investigate the time course of arithmetic strategy selection and execution. EEG can also help to investigate the role of general cognitive processes during execution of arithmetic strategies. Finally, EEG is also a powerful tool to specify how strategy use differs between groups of different skills or ages. Overall, by addressing these ends, EEG further our understanding of variations in participants' arithmetic performance as a function of different characteristics, such as participants' (e.g., age, skills), problems' (e.g., problem or split size, rule violation), or situations' (e.g., strategy execution on previous problems, correctness of proposed answers) characteristics. PMID- 27220782 TI - Multinucleated giant cells in Langerhans cell histiocytosis. PMID- 27220783 TI - [Bioinformatics in Cancer Clinical Sequencing -- An Emerging Field of Cancer Personalized Medicine]. AB - Thus far, bioinformatics has mostly been applied in basic science research. It was initially used to analyze protein sequences in unicellular organisms, aiding discoveries in basic biology. Following the completion of human genome sequencing, it has also facilitated numerous discoveries in basic medicine. Recently, several clinical applications of bioinformatics have been reported. Most relevantly, bioinformatics has been applied to clinical sequencing - an emerging field of personalized medicine, or precision medicine. In this review, I will introduce basic techniques of bioinformatics used in clinical sequencing, avoiding excessive technical details. I will also discuss future directions for data analysis using bioinformatics in the field of personalized medicine. PMID- 27220784 TI - [Combination Therapy of Molecular-Targeted Drugs for Breast Cancer -- Their Potential in the Future]. AB - In breast cancer treatment, molecular-targeted drugs such as trastuzumab and lapatinib have been used for many y ears, and the benefits have been seen in many patients. The molecular-targeted drugs have mainly been used in combination with cytotoxic agents; however, combination therapies with 2 molecular-targeted drugs are currently being investigated. The combination therapy of 2 HER2 receptor antibodies, pertuzumab and trastuzumab, has tremendous benefit for HER2 positive metastatic breast cancer patients. However, the combination of trastuzumab with tyrosine-kinase inhibitor lapatinib showed small benefits and its usage is limited. The combination of T-DM1 plus pertuzumab was not anymore effective than T-DM1 alone. The potentials of combined hormone therapies have been examined for ages. The combination of fulvestrant and aromatase inhibitor(AI)was shown to be beneficial in one phase III study; however, a conflicting result was reported by another large trial. To overcome hormone therapy resistance, the combinations of hormone therapy drugs with mTOR inhibitors(everolimus), pan-PI3K inhibitor(buparlisib), and CDK4/6 inhibitors(palbociclib, ribociclib, abemaciclib)are being investigated in various settings. PMID- 27220785 TI - [Melanoma]. AB - Since 2011, several effective drugs for patients with metastatic melanoma, including BRAF inhibitors, MEK inhibitors, and immune checkpoint inhibitors, have been approved. The combination of BRAF and MEK inhibitors achieve response rates of 70% and a median progression-free survival of >11 months in patients. The combination of ipilimumab and nivolumab has shown response rates of up to 60-70% and a median progression-free survival of 11-14 months, despite increased toxicities. Moreover, many clinical trials for new combination therapies are still ongoing. PMID- 27220786 TI - [Current Progress and Feasibility of Using Molecular-Targeted Agent Combinations for Metastatic Colorectal Cancer]. AB - The efficacy of molecular-targeted agent combinations for the treatment of metastatic colorectal cancer has become increasingly evident over recent years, although none of these combinations have been recognized yet as a standard therapy. The intention here is to provide a synopsis of current progress in this developing area by reviewing existing publications and ongoing clinical trials. While bevacizumab plus anti-EGFR agents exhibit detrimental effects in first-line setting , a combination of bevacizumab with erlotinib has been suggested as an effective maintenance therapy. Dabrafenib plus panitumumab in combination with trametinib and encorafenib plus cetuximab in combination with alpelisib, are very promising combination treatments and are currently being developed in clinical trials for patients with BRAF mutant-type tumors. An earlier nonclinical trial suggested that a combination of panitumumab plus trametinib was effective in patients who were resistant to anti- EGFR agents but developing KRAS- or NRAS mutated tumors. The HERACLES trial further indicated that a combination of trastuzumab and lapatinib showed promising antitumor effects in patients with emerging HER2 amplification. Other reports suggest that irinotecan and cetuximab in combination with tivantinib were more effective than a combination of irinotecan and cetuximab alone for patients with MET amplification, although further research is needed for this application, as results were based upon the analysis of subgroups. It is clear that data arising from both primary research and clinical trials support the combined use of molecular-targeted drugs in the treatment of metastatic colorectal cancer. As clinical trials progress, it is likely that such treatment combinations will become recognized as standard therapies. PMID- 27220787 TI - [Combined Therapy with Targeted Drugs in Lung Cancer]. AB - As targeted therapies for lung cancer, EGFR tyrosine kinase inhibitors(EGFR TKIs)and ALK-TKIs have been approved for EGFR mutation-positive advanced non small cell lung cancer(NSCLC)and ALK-fusion gene-positive advanced NSCLC, respectively. Very recently, an anti-immune checkpoint antibody was approved for advanced or recurrent NSCLC. In this article, the current status of combined therapy is reviewed with a focus on EGFR-TKIs, which are the most frequently used targeted therapies in clinical practice for lung cancer. To increase the efficacy of EGFR-TKIs in EGFR-mutant NSCLC, a large number of clinical trials using EGFR TKIs and other agents, such as cytotoxic chemotherapy, angiogenesis inhibitors, or antiimmune checkpoint antibodies, are being conducted. On the other hand, several trials have also been conducted to examine the efficacy of EGFR-TKIs in adjuvant settings for earlier staged EGFR-mutant NSCLC. Based on the results of these trials, a paradigm shift concerning treatment with targeted therapy for EGFR-mutant NSCLC is possible in the future. PMID- 27220788 TI - [Safety and Tolerance of Dose-Dense Epirubicin and Cyclophosphamide (EC) with Pegfilgrastim for Japanese Patients with Early Breast Cancer]. AB - With the approval of pegfilgrastim, the use of dose-dense epirubicin and cyclophosphamide (EC) for breast cancer has become acceptable in Japan. Thus, we aimed to evaluate its safety and tolerability in Japanese patients. Nine breast cancer patients with a high risk of preoperative or postoperative recurrence received EC therapy(epirubicin 90 mg/m(2) and cyclo- phosphamide 600 mg/m(2))for 4 cycles every 2 weeks in combination with a subcutaneous injection of pegfilgrastim (3.6 mg) on day 2 of each cycle. Treatment was discontinued in 1 and extended in 1 of the 9 patients, and the mean relative dose intensity(RDI)was good at 0.93. No serious adverse events were observed, indicating good tolerability. The regimen has potential for use in cases in which the treatment dose needs to be increased. grade 4 neutropenia was observed in all the 9 patients on day 8, with 6 patients developing febrile neutropenia. In Japan, data on changes in neutrophil count associated with pegfilgrastim administration under anthracycline-based chemotherapy are currently insufficient, and further study is required. PMID- 27220789 TI - [Clinicopathological Outcome of Perforated Colorectal Cancer]. AB - We investigated the clinicopathological findings of 90 patients with colorectal perforation who underwent emergency surgery between January 2008 and July 2015.T he patients were divided into 2 groups, namely those with perforation due to colorectal cancer(colorectal cancer group, n=20)and those with perforation due to benign colorectal disease(non-colorectal cancer group, n=70).We investigated the clinicopathological findings of the 2 groups.The SOFA score was significantly lower in the colorectal cancer group than in the non-colorectal cancer group.Of the 20 cases of primary cancer, 11 were located in the sigmoid colon; 5, in the rectum; 2, in the transverse colon; 1, in the ascending colon; and 1, in the cecum.The perforation occurred at the tumor site in 8 patients and at the oral site of cancer in 12.Eleven patients had stage II cancer, 1 had stage IIIa, and 8 had stage IV.Ten patients underwent curability A resection; 1, curability B resection; and 8, curability C resection.Recurrence was observed in 6 of the 10 patients who had undergone curability A resection and in 1 patient who had undergone curability B resection.The initial recurrence site was the liver in 3 cases, the peritoneum in 2 cases, and a local site in 2 cases.Even if the patents underwent curative operation, the recurrence rate was high.Therefore, we conclude that adjuvant chemotherapy is required along with careful follow-up. PMID- 27220790 TI - [Local Control of Advanced Breast Cancer with Mohs Paste and Systemic Therapy]. AB - Unresectable locally advanced breast cancer results in a decline in patient quality of life because of the presence of bleeding, exudates, and strong odor. The clinical application of supportive care using Mohs paste for improving quality of life has become widespread. We report 2 cases of locally advanced breast cancer treated with systemic therapy and chemosurgery. Case 1 was a Japanese woman in her fifties who had a locally advanced left breast cancer. She had continuous bleeding and exudates, and received Mohs chemosurgery and endocrine therapy. One month later, the surface healed and dried up. The bleeding, exudates, and strong odor disappeared almost completely. Case 2 was a Japanese woman in her forties who had a locally advanced left breast cancer with massive exudates and oozing blood. She underwent Mohs chemosurgery 20 times, but the exudates and bleeding were not controlled. According to pathological findings, we confirmed her breast cancer to be of the triple negative subtype. After 2 courses of therapy with 5-fluorouracil, epirubicin, and cyclophosphamide, the tumor immediately decreased in diameter by 65%. The bleeding, exudates, and strong odor disappeared. Although Mohs chemosurgery is useful for local control of locally advanced breast cancer, this alone is insufficient to treat the disease. Early introduction of systemic therapy is considered essential in breast cancer treatment. PMID- 27220791 TI - [A Case of Squamous Cell Carcinoma of the Esophagus with Achalasia -- Conversion from Chemoradiotherapy to Surgery]. AB - The patient was a 67-year-old woman with achalasia and squamous cell carcinoma(SCC)of the esophagus. She presented with a difficulty in swallowing. The cancer was on the surface of the esophagus. The patient initially received systemic chemotherapy with 5-FU and cisplatin, and radiation therapy. The difficulty in swallowing persisted due to insufficiency of radiation treatment caused by achalasia. Therefore, we shifted the treatment plan from chemoradiotherapy to surgery. Endoscopic examination performed before surgery showed that there was no obvious cancer in the esophagus. We resected the esophagus routinely. On the specimen, no cancer cells were detected upon macroscopic and microscopic examinations; metastasis was not detected in the lymph node. Achalasia is a recognized risk factor for esophageal SCC. In the treatment of superficial SCC, no difference of therapeutic effect was observed between surgery and chemoradiation. However, for the treatment of certain cases of SCC with achalasia, including the treatment of achalasia itself, surgery can be the preferred option of treatment. PMID- 27220792 TI - [A Case of Recurred Gastric Cancer of the Anastomosis Completely Responding to Docetaxel, Cisplatin, and S-1 Triplet Therapy]. AB - A 51-year-old man who had undergone distal gastrectomy for gastric cancer was admitted in Kagoshima University Hospital under the diagnosis of anastomotic recurrence of gastric cancer. From abdominal CT results, the recurred tumor was suspected to invade into the pancreas with regional node metastases. Because of the intense radicality of surgical intervention, we planned 3 courses of docetaxel, cisplatin, and S-1 triplet therapy(DCS therapy). After the chemotherapy, the recurred tumor and lymph node metastases shrunk drastically. Segmental gastrectomy with lymph node dissection was performed with curative intent. Final pathology revealed complete regression of both the recurred tumor and lymph node metastases. The patient's postoperative course was uneventful without tumor relapse. DCS therapy seems to be suitable to obtain drastic tumor regression before surgical intervention as a neoadjuvant chemotherapy for locally advanced gastric cancer. PMID- 27220793 TI - [A Case of Virchow's Lymph Node Recurrence of Gastric Cancer Who Had Underwent Gastrectomy, and Treated with S-1 Monotherapy Leading to Complete Response (CR)]. AB - We report the case of a 67-year-old male with Virchow's lymph node recurrence of gastric cancer, who underwent distal gastrectomy for type 2 forecourt part of pylorus gastric cancer, showing complete response(CR)in response to S-1 monotherapy. The tumor was pathologically diagnosed as Stage IIIb(well to poorly differentiated adenocarcinoma, T3[SE], N2 [20/51], M0). Virchow's lymph node metastasis was confirmed 2 months after surgery. One week after S-1 administration, a reduction in lymph node size was observed. After 5 courses of S 1 monotherapy, he achieved CR. The patient maintained CR for 2 years, before we switched to uracil and tegafur(UFT)monotherapy. The patient maintained CR for 2 years, after which UFT was discontinued. No relapse was observed 22 months after discontinuation. PMID- 27220794 TI - [A Case of Locally Advanced Pancreatic Cancer Showing R0 Resection after Resection of the Portal Vein Following Preoperative Chemoradiotherapy]. AB - We report a case of pancreatic cancer showing R0 resection after resection of the portal vein(PV)following preoperative chemoradiotherapy. A 71-year-old woman was admitted to our hospital with back pain. We diagnosed the patient with pancreatic cancer using computed tomography scan and fine-needle aspiration biopsy. Because the tumor directly invaded the PV, we diagnosed it as a borderline resectable locally advanced pancreatic cancer. Radiation therapy(40 Gy/20 Fr)was administered with S-1 monotherapy(120 mg/body/day on days 1-5 and days 8-12). After the treatment, the main tumor was stable without distant metastasis. Therefore, we performed pancreaticoduodenectomy with resection of the PV. Pathological examination confirmed negative margin status. The patient was healthy and showed no sign of recurrence eight months after surgery. PMID- 27220795 TI - [Effective Prevention of Hand-Foot Syndrome by the Consumption of Dried Bonito Broth]. AB - To examine whether the consumption of dried bonito both is effective for the prevention of hand-foot syndrome(HFS), concentrated bonito broth was administered to 10 patients with HCC who were treated with sorafenib. Among the 10 patients, seven showed an increase in peripheral blood flow, as observed on Doppler ultrasonography. Only one patient showed Grade 1 HFS on day 14 after the initiation of sorafenib (10%); this incidence rate of HFS was significantly lower than that obtained in our previous studies and reported data. These results suggest that consumption of dried bonito broth contributes to the prevention of HFS by maintaining peripheral blood flow. PMID- 27220796 TI - [Activity and Future Perspective of Local Independent Clinical Trial Group (OGSG)]. AB - Osaka Gastrointestinal Cancer Chemotherapy Study Group (OGSG) was established in 2000 and has been conducting investigator initiated multi-institutional collaboration trials regarding the treatment of gastrointestinal cancer, especially using chemotherapeutic agents. Although organization of OGSG has been renovated to perform post-marketing clinical trials with high quality, OGSG is now facing severe financial crisis because of shortage of donation from pharmaceutical companies. Here, present problems and future perspectives are discussed. PMID- 27220797 TI - [Standard Cancer Therapy Are Established by the Investigator-Initiated Post Marketing Clinical Trials, Not by the Indication-Directed Clinical Trials]. AB - The financial supports for investigator-initiated post-marketing clinical trial in clinical oncology are reduced after scandals related to the other fields of clinical trials in Japan. These clinical trials are the essential final steps of clinical development in newer cancer therapy, which should be conducted in the investigator-initiated clinical trial groups with well-organized infrastructure and continuous financial supports. The present problems are discussed and summarized. Future perspectives with the national viewpoints needed to be included the idea of "health technology assessment". PMID- 27220798 TI - [A Critical Condition of Clinical Studies in Japan -- A Battle of Clinical Study Groups]. AB - The post-marketing clinical study groups have been losing their activity due to stop of financial support. As the result, clinical study groups cannot achieve any EBM for treatment guidelines. Financial supports should be restarted immediately not to extinguish the post-marketing clinical studies and study groups. PMID- 27220799 TI - [Importance of Post-Marketing Studies in Gathering of Clinical Evidences for Proper Usage of Anti-Cancer Drugs, and the StudyRequirements for Their Credibility]. AB - Pharmaceutical companies recognize the importance of post-marketing studies because they are crucial in the generation of clinical evidences for the usage of new medicines. To generate clinical evidences, quality of post-marketing studies should be well controlled from view point of "ethical conduction" and "reliability of results". In addition, control of conflict of interest (COI) between researchers and industries is also indispensable and is requested for the transparency of the studies. Japan Pharmaceutical Manufacturers Association(JPMA)stresses its commitment to the progressof transparency in post marketing studies. PMID- 27220800 TI - [National Strategic Promotion for Large-Scale Clinical Cancer Research]. AB - The number of clinical research by clinical cancer study groups has been decreasing this year in Japan. They say the reason is the abolition of donations to the groups from the pharmaceutical companies after the Diovan scandal. But I suppose fundamental problem is that government-supported large-scale clinical cancer study system for evidence based medicine (EBM) has not been fully established. An urgent establishment of the system based on the national strategy is needed for the cancer patients and the public health promotion. PMID- 27220801 TI - [Response of Pharmaceutical Companies to the Crisis of Post-Marketing Clinical Trials of Anti-Cancer Agents -- Results of Questionnaires to Pharmaceutical Companies]. AB - Investigator-oriented post-marketing clinical trials of anti-cancer agents are faced to financial crisis due to drastic decrease in research-funds from pharmaceutical companies caused by a scandal in 2013. In order to assess the balance of research funds between 2012 and 2014, we made queries to 26 companies manufacturing anti-cancer agents, and only 10 of 26 responded to our queries. Decrease in the fund was observed in 5 of 10, no change in 1, increase in 3 and no answer in 1. Companies showed passive attitude to carry out doctor-oriented clinical trials of off-patent drugs or unapproved drugs according to advanced medical care B program, though some companies answered to proceed approved routines of these drugs if clinical trials showed good results. Most companies declined to make comments on the activity of Japan Agency for Medical Research and Development (AMED), but some insisted to produce good corroboration between AMED and pharmaceutical companies in order to improve the quality of trials. Further corroboration must be necessary for this purpose among researchers, governmental administrative organs, pharmaceutical companies, patients' groups, and mass-media. PMID- 27220802 TI - [Let Us to Know the Post-Marketing Clinical Studies and Critical Situation of Study Groups -- Now We Should Talk about How to Achieve the Safe and Most Effective Treatment for Cancer Patients]. AB - Not to leave something to be regretted in the life of patients and their family, it is important to find the best way during and after treatment for cancer. We, cancer survivors association, propose a corporated actions among patients, administration, medical stuffs, and enterprises to solve the problems of clinical studies. And we express our opinion on the present problems and to do for patients and citizens. PMID- 27220804 TI - Mechanoluminescence of SrAl2 O4 :Eu,Dy nanophosphors induced by low impact velocity. AB - The present paper reports the impulsive excitation of mechanoluminescence (ML) in Sr0.97 Al2 O4 :Eu0.01 ,Dy0.02 nanophosphors prepared using a combustion technique. The phosphors are characterized using X-ray powder diffraction (XRD), high-resolution transmission electron microscopy (HRTEM) and photoluminescence (PL). The XRD results show that the samples exhibit a monoclinic alpha-phase in the crystal structure. The space group of SrAl2 O4 :Eu,Dy nanophosphors is monoclinic P21 . The PL and ML spectra of SrAl2 O4 :Eu,Dy nanophosphors are excited using light with a wavelength of 365 nm and emission is found at 516 nm. The prepared nanophosphors exhibits an intense ML that can be seen in daylight with the naked eye. When a sample powder is deformed impulsively by the impact of a moving piston, the ML intensity initially increases linearly with time, attains a peak value, Im , at time tm , and then decreases with time. The peak ML intensity, Im , and total ML intensity, IT , increase linearly with applied pressure and impact velocity. The ML intensity decreases with successive impacts of load onto the phosphors, and the diminished ML intensity can be approximately recovered by UV irradiation. The activation energy using thermoluminescence is found to be 0.57 eV for SrAl2 O4 :Eu,Dy nanophosphors. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27220803 TI - Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy. AB - Palmitoylethanolamide (PEA) has been suggested to have useful analgesic properties and to be devoid of unwanted effects. Here, we have examined critically this contention, and discussed available data concerning the pharmacokinetics of PEA and its formulation. Sixteen clinical trials, six case reports/pilot studies and a meta-analysis of PEA as an analgesic have been published in the literature. For treatment times up to 49 days, the current clinical data argue against serious adverse drug reactions (ADRs) at an incidence of 1/200 or greater. For treatment lasting more than 60 days, the number of patients is insufficient to rule out a frequency of ADRs of less than 1/100. The six published randomized clinical trials are of variable quality. Presentation of data without information on data spread and nonreporting of data at times other than the final measurement were among issues that were identified. Further, there are no head-to-head clinical comparisons of unmicronized vs. micronized formulations of PEA, and so evidence for superiority of one formulation over the other is currently lacking. Nevertheless, the available clinical data support the contention that PEA has analgesic actions and motivate further study of this compound, particularly with respect to head-to-head comparisons of unmicronized vs. micronized formulations of PEA and comparisons with currently recommended treatments. PMID- 27220806 TI - A sexually dichotomous, autistic-like phenotype is induced by Group B Streptococcus maternofetal immune activation. AB - Group B Streptococcus (GBS) is a commensal bacterium present in the lower genital tract of 15-30% of healthy pregnant women. GBS is the leading cause of chorioamnionitis and cerebral injuries in newborns, occurring most often in the absence of maternofetal pathogen translocation. Despite GBS being the most frequent bacterium colonizing pregnant women, no preclinical studies have investigated the impact of end-gestational maternal GBS exposure on the offspring's brain development and its behavioral correlates. Our hypothesis is that GBS-induced gestational infection/inflammation has a deleterious neurodevelopmental impact on uninfected offspring. Our goal was to study the impact of maternal GBS infection on the placental and neurodevelopmental features in the offspring using a new preclinical rat model. GBS-exposed placentas exhibited chorioamnionitis characterized by the presence of Gram-positive cocci and polymorphonuclear cells, with the latter being significantly more prominent in the labyrinth of male offspring. GBS-exposed male offspring had reduced thickness of periventricular white matter. In addition, they exhibited autistic like behaviors, such as abnormal social interaction and communication, impaired processing of sensory information and hyperactivity. Overall, these data show for the first time that gestational exposure to GBS plays an important role in the generation of neurodevelopmental abnormalities reminiscent of human autism spectrum disorders (ASD). These results provide new evidence in favor of the role of a common and modifiable infectious/inflammatory environmental factor in human ASD pathophysiology. Autism Res 2017, 10: 233-245. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 27220807 TI - Molybdenum diselenide/reduced graphene oxide based hybrid nanosheets for supercapacitor applications. AB - In the present study, molybdenum diselenide/reduced graphene oxide (MoSe2/rGO) nanosheets were synthesized via a facile hydrothermal process and the electrochemical performance of the nanosheets was evaluated for supercapacitor applications. The MoSe2 nanosheets were uniformly distributed on the surface of the rGO matrix. The MoSe2/rGO nanosheet electrode exhibited an enhanced specific capacitance (211 F g(-1)) with excellent cycling stability, compared with pristine MoSe2. The enhanced electrochemical performance of the MoSe2/rGO nanosheet electrode is mainly attributed to the improved electron and ion transfer mechanism involving the synergistic effects of pseudocapacitance (from the MoSe2 nanosheets) and the electric double layer charge (EDLC, from the rGO nanosheets) storage behavior. These results demonstrate that the enhanced electrochemical performance of MoSe2/rGO nanosheets could be obtained via a facile and scalable approach. PMID- 27220808 TI - P2Y2 purinergic receptors are highly expressed in cardiac and diaphragm muscles of mdx mice, and their expression is decreased by suramin. AB - INTRODUCTION: In Duchenne muscular dystrophy (DMD) and in the mdx mouse model of DMD, the lack of dystrophin leads to increased calcium influx and muscle necrosis. Patients suffer progressive muscle loss, and cardiomyopathy is an important determinant of morbidity. P2 purinergic receptors participate in the increased calcium levels in dystrophic skeletal muscles. METHODS: In this study, we evaluated whether P2 receptors are involved in cardiomyopathy in mdx mice at later stages of the disease. RESULTS: Western blotting revealed that P2Y2 receptor levels were upregulated (54%) in dystrophic heart compared with a normal heart. Suramin reduced the levels of P2Y2 to almost normal values. Suramin also decreased heart necrosis (reduced CK-MB) and the expression of the stretch activated calcium channel TRPC1. CONCLUSIONS: This study suggests that P2Y2 may participate in cardiomyopathy in mdx mice. P2-selective drugs with specific actions in the dystrophic heart may ameliorate cardiomyopathy in dystrophinopathies. Muscle Nerve 55: 116-121, 2017. PMID- 27220809 TI - Effect of Valeriana fauriei extract on the offspring of adult rats exposed to prenatal stress. AB - Exposing a pregnant female to stress is a risk factor for the development of psychiatric disorders in the offspring. In the present study, we examined the effects of an extract of Valeriana fauriei (VF) root (100 mg/kg/day, administered on postnatal days 35-56) on behavioral patterns as well as protein expression in the prefrontal cortex of the offspring of prenatally-stressed rats. Modified behavioral tests, including the forced swim test, the open field test, a social interaction test and the prepulse inhibition test were performed and many of the parameters were found to decrease in the offspring of the rats exposed to PNS compared with the offspring of the non-stressed rats. Western blot and immunohistochemical analyses of the prefrontal cortex revealed that the downregulation of several neurodevelopmental proteins in the offspring of rats dams exposed to PNS was reversed after treatment with VF extract. These findings demonstrate that the downregulation of several proteins in the prefrontal cortex of the offspring of prenatally-stressed rats may be associated with subsequent behavioral changes, and that these phenomena recovered following VF treatment. Our results suggest that VF decreases the incidence of prenatal stress related psychiatric disorders, such as depression and schizophrenia. PMID- 27220810 TI - Application of a stir bar sorptive extraction method for the determination of volatile compounds in different grape varieties. AB - BACKGROUND: Stir bar sorptive extraction (SBSE) has been employed for the analysis of aroma compounds directly from Spanish and Italian grape extracts. The extraction conditions have been optimized using a statistical approach, obtaining results that improve the current state of the art. RESULTS: The proposed analytical conditions were: sample volume 40 mL, extraction time 80 min, 25% (w/v) NaCl and stirring speed 750 rpm using 20 mm * 0.5 mm stir bars. Performance characteristics of the SBSE procedure were further studied and showed correlation coefficients, detection and quantification limits, linear ranges, recoveries and precision values adequate for analysing these compounds in grapes. Twenty-four grape varieties (aromatic and non-aromatic) were analysed. Statistically significant differences (P < 0.05) according to geographical origin were found, being derived mainly from the terpenoid content. By principal component analysis it was possible to note that the terpenoids were more effective in the separation of the non-aromatic samples, showing negative and positive scores for Italian and Spanish grapes, respectively. CONCLUSION: For non-aromatic grape varieties, the factor 'geographic location' was the most significant, thus corroborating the high influence of this parameter on the volatile composition of grapes and therefore on the genuineness of wines. (c) 2016 Society of Chemical Industry. PMID- 27220811 TI - EGb761 improves cognitive function and regulates inflammatory responses in the APP/PS1 mouse. AB - There is accumulating evidence that the Ginkgo biloba extract EGb761 may help to prevent Alzheimer's disease (AD). However, the underlying mechanism of its action remains to be elaborated. In this study, we examined the effects of EGb761 using the APP/PS1 transgenic mouse model of AD. Two-month-old APP/PS1 mice were supplemented with EGb761 daily for 6months. We found that this chronic treatment with EGb761 improved the cognitive function of these mice and also significantly alleviated amyloid plaque deposition. Although the level of insoluble amyloid beta (Abeta) was decreased, the soluble content of Abeta was not changed after administration of EGb761. We then determined the changes in central inflammation and observed that the activated microglia around amyloid plaque was increased in these treated mice. We also found that chronic EGb761 treatment downregulated pro inflammatory cytokines and inducible nitric oxide synthase (iNOS), and upregulated anti-inflammatory cytokines and Arginase-1 (Arg-1), suggesting that EGb761 regulated the phenotype of activated microglia in the APP/PS1 mouse brain. In support of this, pretreatment of the BV2 microglial cell line with EGb761 inhibited the inflammatory reaction to Abeta. Furthermore, the addition of conditioned media derived from BV2 cells that were co-treated with Abeta and EGb761, protected neurons against treatment of Abeta and inhibited apoptotic damage. Taken together, our results demonstrated that EGb761 provided a protective effect in APP/PS1 mouse. This protection was correlated with an inhibition of the pro-inflammatory effects of microglia and an induction of anti inflammatory effects. These results strongly suggest that EGb761 provides a protective effect in APP/PS1 mouse via regulation of inflammation in the brain. PMID- 27220812 TI - Synthesis of Reduced Graphene Oxide-Modified LiMn0.75Fe0.25PO4 Microspheres by Salt-Assisted Spray Drying for High-Performance Lithium-Ion Batteries. AB - Microsized, spherical, three-dimensional (3D) graphene-based composites as electrode materials exhibit improved tap density and electrochemical properties. In this study, we report 3D LiMn0.75Fe0.25PO4/reduced graphene oxide microspheres synthesized by one-step salt-assisted spray drying using a mixed solution containing a precursor salt and graphene oxide and a subsequent heat treatment. During this process, it was found that the type of metal salt used has significant effects on the morphology, phase purity, and electrochemical properties of the synthesized samples. Furthermore, the amount of the chelating agent used also affects the phase purity and electrochemical properties of the samples. The composite exhibited a high tap density (1.1 g cm(-3)) as well as a gravimetric capacity of 161 mA h g(-1) and volumetric capacity of 281 mA h cm(-3) at 0.05 C-rate. It also exhibited excellent rate capability, delivering a discharge capacity of 90 mA h g(-1) at 60 C-rate. Furthermore, the microspheres exhibited high energy efficiency and good cyclability, showing a capacity retention rate of 93% after 1000 cycles at 10 C-rate. PMID- 27220813 TI - Influenza A virus-induced release of interleukin-10 inhibits the anti-microbial activities of invariant natural killer T cells during invasive pneumococcal superinfection. AB - During influenza A virus (IAV) infection, changes in the lung's physical and immunological defenses predispose the host to bacterial superinfections. Invariant natural killer T (iNKT) cells are innate-like T lymphocytes that have beneficial or harmful functions during infection. We investigated the iNKT cells' role in a model of invasive pneumococcal superinfection. The use of Jalpha18-/- mice indicated that iNKT cells limited susceptibility to influenza-pneumococcal infection and reduced the lethal synergism. This role did not depend on immune based anti-bacterial mechanisms. At the time of bacterial exposure, iNKT cells from IAV-experienced mice failed to produce antipneumococcal interferon-gamma and adoptive transfer of fresh iNKT cells before Streptococcus pneumoniae challenge did not restore anti-bacterial host defenses. Impaired iNKT cell activation in superinfected animals was related to the IAV-induced immunosuppressive cytokine interleukin-10 (IL-10), rather than to an intrinsic functional defect. IL-10 dampened the activation of iNKT cells in response to pneumococci by inhibiting the production of IL-12 by pulmonary monocyte-derived dendritic cells. Neutralization of IL-10 restored iNKT cell activation and tends to increase resistance to secondary bacterial infection. Overall, iNKT cells have a beneficial role (upstream of bacterial colonization) in controlling influenza pneumococcal superinfection, although they represent novel targets of immunosuppression at the time of bacterial challenge. PMID- 27220814 TI - Regulation of human intestinal T-cell responses by type 1 interferon-STAT1 signaling is disrupted in inflammatory bowel disease. AB - Type 1 interferon (IFN-1) promotes regulatory T-cell function to suppress inflammation in the mouse intestine, but little is known about IFN-1 in the human gut. We therefore assessed the influence of IFN-1 on CD4+ T-cells isolated from human colon tissue obtained from healthy controls or patients with inflammatory bowel disease (IBD). Immunofluorescent imaging revealed constitutive expression of IFNbeta in human intestinal tissue, and colonic T-cells were responsive to exogenous IFN-1 as assessed by phosphorylation of signal transduction and activator of transcription 1 (pSTAT1) and induction of interferon stimulated genes (ISGs). Unlike their blood counterparts, intestinal T-cells from non inflamed regions of IBD colon displayed enhanced responsiveness to IFN-1, increased frequency of pSTAT1+ cells, and greater induction of ISGs upon IFN-1 exposure in vitro. In healthy tissue, antibody neutralization of IFNbeta selectively reduced T-cell production of the pro-regulatory cytokine interleukin 10 (IL-10) and increased IFNgamma synthesis. In contrast, neutralization of IFNbeta in IBD tissue cultures increased the frequency of T-cells producing inflammatory cytokines but did not alter IL-10 expression. These data support a role for endogenous IFN-1 as a context-dependent modulator of T-cell function that promotes regulatory activity in healthy human intestine, but indicate that the IFN-1/STAT1 pathway is dysregulated in inflammatory bowel disease. PMID- 27220816 TI - Trends in heart failure: going in the right direction? PMID- 27220815 TI - Intranasal administration of RSV antigen-expressing MCMV elicits robust tissue resident effector and effector memory CD8+ T cells in the lung. AB - Cytomegalovirus vectors are promising delivery vehicles for vaccine strategies that aim to elicit effector CD8+ T cells. To determine how the route of immunization affects CD8+ T-cell responses in the lungs of mice vaccinated with a murine cytomegalovirus vector expressing the respiratory syncytial virus matrix (M) protein, we infected CB6F1 mice via the intranasal or intraperitoneal route and evaluated the M-specific CD8+ T-cell response at early and late time points. We found that intranasal vaccination generated robust and durable tissue-resident effector and effector memory CD8+ T-cell populations that were undetectable after intraperitoneal vaccination. The generation of these antigen-experienced cells by intranasal vaccination resulted in earlier T-cell responses, interferon gamma secretion, and viral clearance after respiratory syncytial virus challenge. Collectively, these findings validate a novel approach to vaccination that emphasizes the route of delivery as a key determinant of immune priming at the site of vulnerability. PMID- 27220817 TI - Self-assembly of PEGylated tetra-phenylalanine derivatives: structural insights from solution and solid state studies. AB - Water soluble fibers of PEGylated tetra-phenylalanine (F4), chemically modified at the N-terminus with the DOTA chelating agent, have been proposed as innovative contrast agent (CA) in Magnetic Resonance Imaging (MRI) upon complexation of the gadolinium ion. An in-depth structural characterization of PEGylated F4-fibers, in presence (DOTA-L6-F4) and in absence of DOTA (L6-F4), is reported in solution and at the solid state, by a multiplicity of techniques including CD, FTIR, NMR, DLS, WAXS and SAXS. This study aims to better understand how the aggregation process influences the performance of nanostructures as MRI CAs. Critical aggregation concentrations for L6-F4 (43 MUM) and DOTA-L6-F4 (75 MUM) indicate that self-aggregation process occurs in the same concentration range, independently of the presence of the CA. The driving force for the aggregation is the pi-stacking between the side chains of the aromatic framework. CD, FTIR and WAXS measurements indicate an antiparallel beta-sheet organization of the monomers in the resulting fibers. Moreover, WAXS and FTIR experiments point out that in solution the nanomaterials retain the same morphology and monomer organizations of the solid state, although the addition of the DOTA chelating agent affects the size and the degree of order of the fibers. PMID- 27220818 TI - Metacognition and proofreading: the roles of aging, motivation, and interest. AB - The current study examined younger and older adults' error detection accuracy, prediction calibration, and postdiction calibration on a proofreading task, to determine if age-related differences would be present in this type of common error detection task. Participants were given text passages, and were first asked to predict the percentage of errors they would detect in the passage. They then read the passage and circled errors (which varied in complexity and locality), and made postdictions regarding their performance, before repeating this with another passage and answering a comprehension test of both passages. There were no age-related differences in error detection accuracy, text comprehension, or metacognitive calibration, though participants in both age groups were overconfident overall in their metacognitive judgments. Both groups gave similar ratings of motivation to complete the task. The older adults rated the passages as more interesting than younger adults did, although this level of interest did not appear to influence error-detection performance. The age equivalence in both proofreading ability and calibration suggests that the ability to proofread text passages and the associated metacognitive monitoring used in judging one's own performance are maintained in aging. These age-related similarities persisted when younger adults completed the proofreading tasks on a computer screen, rather than with paper and pencil. The findings provide novel insights regarding the influence that cognitive aging may have on metacognitive accuracy and text processing in an everyday task. PMID- 27220819 TI - Morphology of gametes, post-fertilization events and the effect of temperature on the embryonic development of Astyanax altiparanae (Teleostei, Characidae). AB - The aim of this study was to describe the morphology of gametes, post fertilization events and subsequent temperature effects on the early developmental stages of the neotropical species Astyanax altiparanae. The sperm of this species presents a typical morphology of teleost sperm with a spherical head (diameter = 1.88 um), midpiece (diameter = 0.75 um) and a single flagellum (length = 18.67 um). The extrusion of the second polar body and fusion of male and female pronucleus were reported for the first time in this species. Additionally, we observed the formation of the fertilization cone, which prevents polyspermic fertilization. Developmental stages at 22 degrees C, 26 degrees C and 30 degrees C gave rise to fertilization rates at 91.12, 91.42 and 93.04% respectively. Hatching occurred at 25 hpf at 22 degrees C, 16 hpf at 26 degrees C and 11 hpf at 30 degrees C and the hatching rates were 61.78%, 62.90% and 59.45%, respectively. At 22 degrees C, the second polar body was extruded at ~6 mpf and the male and female pronucleus fused at ~10 mpf. This fundamental information is important for the field and opens up new possibilities in fish biotechnology, including micromanipulation and chromosome-set manipulation. PMID- 27220821 TI - Towards monitoring dysplastic progression in the oral cavity using a hybrid fiber bundle imaging and spectroscopy probe. AB - Intraepithelial dysplasia of the oral mucosa typically originates in the proliferative cell layer at the basement membrane and extends to the upper epithelial layers as the disease progresses. Detection of malignancies typically occurs upon visual inspection by non-specialists at a late-stage. In this manuscript, we validate a quantitative hybrid imaging and spectroscopy microendoscope to monitor dysplastic progression within the oral cavity microenvironment in a phantom and pre-clinical study. We use an empirical model to quantify optical properties and sampling depth from sub-diffuse reflectance spectra (450-750 nm) at two source-detector separations (374 and 730 MUm). Average errors in recovering reduced scattering (5-26 cm(-1)) and absorption coefficients (0-10 cm(-1)) in hemoglobin-based phantoms were approximately 2% and 6%, respectively. Next, a 300 MUm-thick phantom tumor model was used to validate the probe's ability to monitor progression of a proliferating optical heterogeneity. Finally, the technique was demonstrated on 13 healthy volunteers and volume-averaged optical coefficients, scattering exponent, hemoglobin concentration, oxygen saturation, and sampling depth are presented alongside a high-resolution microendoscopy image of oral mucosa from one volunteer. This multimodal microendoscopy approach encompasses both structural and spectroscopic reporters of perfusion within the tissue microenvironment and can potentially be used to monitor tumor response to therapy. PMID- 27220820 TI - The Priority position paper: Protecting Europe's food chain from prions. AB - Bovine spongiform encephalopathy (BSE) created a global European crisis in the 1980s and 90s, with very serious health and economic implications. Classical BSE now appears to be under control, to a great extent as a result of a global research effort that identified the sources of prions in meat and bone meal (MBM) and developed new animal-testing tools that guided policy. Priority ( www.prionpriority.eu ) was a European Union (EU) Framework Program 7 (FP7)-funded project through which 21 European research institutions and small and medium enterprises (SMEs) joined efforts between 2009 and 2014, to conduct coordinated basic and applied research on prions and prion diseases. At the end of the project, the Priority consortium drafted a position paper ( www.prionpriority.eu/Priority position paper) with its main conclusions. In the present opinion paper, we summarize these conclusions. With respect to the issue of re-introducing ruminant protein into the feed-chain, our opinion is that sustaining an absolute ban on feeding ruminant protein to ruminants is essential. In particular, the spread and impact of non-classical forms of scrapie and BSE in ruminants is not fully understood and the risks cannot be estimated. Atypical prion agents will probably continue to represent the dominant form of prion diseases in the near future in Europe. Atypical L-type BSE has clear zoonotic potential, as demonstrated in experimental models. Similarly, there are now data indicating that the atypical scrapie agent can cross various species barriers. More epidemiological data from large cohorts are necessary to reach any conclusion on the impact of its transmissibility on public health. Re-evaluations of safety precautions may become necessary depending on the outcome of these studies. Intensified searching for molecular determinants of the species barrier is recommended, since this barrier is key for important policy areas and risk assessment. Understanding the structural basis for strains and the basis for adaptation of a strain to a new host will require continued fundamental research, also needed to understand mechanisms of prion transmission, replication and how they cause nervous system dysfunction and death. Early detection of prion infection, ideally at a preclinical stage, also remains crucial for development of effective treatment strategies. PMID- 27220822 TI - Age-related changes in gut microbiota composition from newborn to centenarian: a cross-sectional study. AB - BACKGROUND: It has been reported that the composition of human gut microbiota changes with age; however, few studies have used molecular techniques to investigate the long-term, sequential changes in gut microbiota composition. In this study, we investigated the sequential changes in gut microbiota composition in newborn to centenarian Japanese subjects. RESULTS: Fecal samples from 367 healthy Japanese subjects between the ages of 0 and 104 years were analyzed by high-throughput sequencing of amplicons derived from the V3-V4 region of the 16S rRNA gene. Analysis based on bacterial co-abundance groups (CAGs) defined by Kendall correlations between genera revealed that certain transition types of microbiota were enriched in infants, adults, elderly individuals and both infant and elderly subjects. More positive correlations between the relative abundances of genera were observed in the elderly-associated CAGs compared with the infant- and adult-associated CAGs. Hierarchical Ward's linkage clustering based on the abundance of genera indicated five clusters, with median (interquartile range) ages of 3 (0-35), 33 (24-45), 42 (32-62), 77 (36-84) and 94 (86-98) years. Subjects were predominantly clustered with their matched age; however, some of them fell into mismatched age clusters. Furthermore, clustering based on the proportion of transporters predicted by phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) showed that subjects were divided into two age-related groups, the adult-enriched and infant/elderly enriched clusters. Notably, all the drug transporters based on Kyoto Encyclopedia of Genes and Genomes (KEGG) Orthology groups were found in the infant/elderly enriched cluster. CONCLUSION: Our results indicate some patterns and transition points in the compositional changes in gut microbiota with age. In addition, the transporter property prediction results suggest that nutrients in the gut might play an important role in changing the gut microbiota composition with age. PMID- 27220824 TI - Experience of a specialist emergency bariatric surgical service. AB - BACKGROUND: Bariatric surgery is associated with late and procedure-specific acute surgical complications. There is very little evidence available regarding the volume, nature, and outcomes of acute surgical admissions directly stemming from bariatric surgery. Centralization of bariatric elective services in the United Kingdom may have an adverse impact on the ability of local services to manage such unpredictable complications. To address this potential problem, we set up a comprehensive and specialist emergency bariatric service. OBJECTIVES: The aim of this study was to quantify and characterize the workload of a specialist emergency surgical bariatric service. SETTING: University National Health Service hospital. METHODS: Over 2 years, we prospectively collected data on demographic characteristics, management, and outcomes of all acute surgical admissions related directly to previous bariatric surgery. RESULTS: Between December 2011 and November 2013, 69 patients had 71 emergency admissions due to a surgical emergency directly related to previous bariatric surgery. Thirty-seven (54%) had undergone primary bariatric surgery at our institution, 13 (19%) at a different National Health Service hospital, 16 (23%) at private U.K. hospitals, and 3 (4%) at private overseas hospitals. Forty-four endoscopic or surgical interventions were required, of which 17 (39%) were performed on nights or weekends and within 12 hours of admission. Of 27 operations, 25 (93%) were completed laparoscopically. Median length of stay was 2 days, there were no mortalities, and there was 1 readmission within 30 days. CONCLUSIONS: There is a significant volume of late bariatric surgical emergencies, many requiring urgent intervention. These may be effectively managed by a specialist bariatric service. PMID- 27220823 TI - Comparative effectiveness of 3 bariatric surgery procedures: Roux-en-Y gastric bypass, laparoscopic adjustable gastric band, and sleeve gastrectomy. AB - BACKGROUND: Bariatric surgery is associated with improved co-morbidities, quality of life, and survival in severely obese patients. Common bariatric surgery procedures include Roux-en-Y gastric bypass (RYGB), laparoscopic adjustable gastric band (LAGB), and sleeve gastrectomy (SG). Currently, literature studying comparative effectiveness on different bariatric surgery procedures in veterans is limited. OBJECTIVES: To compare effectiveness of 3 bariatric surgery procedures performed in veterans. SETTING: Veterans Affairs Loma Linda Healthcare Systems (VALLHS), Loma Linda, California, United States. METHODS: This study was a single-institution, retrospective cohort study. Primary outcome was weight reduction, expressed as kilograms lost, body mass index (BMI) reduction, percentage weight loss (%WL), and percentage excess weight loss (%EWL) after 12 months of bariatric surgery. Secondary outcomes were reduction in number of medications and laboratory markers for obesity-related chronic conditions. Inverse-probability weighting propensity score method was used to balance baseline characteristics among the procedures. RESULTS: A total of 162 patients were included in the study. At 12 months, the kilograms lost, BMI reduction, %WL, and %EWL were 40.7+/-14.5 kg, 13.4+/-4.1 kg/m(2), 31.5+/-8.5%, and 41.4+/-11.6% for RYGB; 24.4+/-22.1 kg, 7.9+/-7.3 kg/m(2), 20.2+/-21.5%, and 26.7+/-27.6% for SG; and 15.3+/-15.7 kg, 5.0+/-5.0 kg/m(2), 12.0+/-11.7%, and 16.1+/-15.9% for LAGB, respectively (RYGB versus SG, RYGB versus LAGB, and SG versus LAGB, all P<.01). The reduction in number of medications, total cholesterol, and low density lipoprotein (LDL) also showed significant improvement with RYGB. CONCLUSION: For the short term, RYGB appears to achieve better weight reduction and management of obesity-associated co-morbid conditions compared with the SG and LAGB procedures in veteran patients. SG could be the next alternative over LAGB for the bariatric surgery procedure in patients who are not candidates for RYGB. PMID- 27220825 TI - A postoperative nutritional consult improves bariatric surgery outcomes. AB - BACKGROUND: Bariatric surgery is the most effective treatment for obesity. Guidelines for optimizing postoperative care are emerging, and roles of the surgeon and registered dietician (RD) have opportunities for coordination. OBJECTIVES: The study objective was to better define the appropriate guidelines for postoperative care by investigating whether a combined surgeon and RD follow up for the initial postoperative visit within 2 to 6 weeks after surgery improves patient outcomes. SETTING: The setting was an accredited bariatric hospital in an academic setting. METHODS: A retrospective analysis of a prospective database was performed on patients who underwent bariatric surgery and were followed up by either a surgeon alone or by a surgeon and RD for initial postoperative visit. RESULTS: There were 302 patients in the surgeon follow-up group and 268 in the RD follow-up. Patients in the RD follow-up group had significantly fewer readmissions due to dietary-related problems (9 versus 0; P = .004), more favorable 3-month change in serum thiamine (-30.5 versus-4.04; P = .002), high density lipoprotein (-3.42 versus-1.67; P = .053), and triglycerides (-17.5 versus-31.5; P = .03), and trended lower number of minor complications (16 versus 6; P = .08). No significant differences in percent excess weight loss were observed at all time points after surgery. Multivariate logistic models controlling for demographic features found that RD follow-up predicted 3-month increase in thiamine (odds ratio = 2.49; P<.000) and high-density lipoprotein cholesterol (OR = 1.73; P = .01), and decrease in total cholesterol (OR = 1.58; P = .03) and triglycerides (OR = 1.55; P = .03). CONCLUSIONS: Follow-up with a surgeon and RD for the initial postoperative visit may help improve patient outcomes. PMID- 27220826 TI - Tipping point: factors influencing a patient's decision to proceed with bariatric surgery. AB - BACKGROUND: Despite the fact that bariatric surgery is the most effective intervention for morbid obesity, only a fraction of obese patients, even after undergoing evaluation for surgery, decide to undergo the surgery. Opting out by patients is fairly common yet little is known about factors that lead a patient to decide to undergo surgery. OBJECTIVE: The purpose of this qualitative study was to identify factors that "tipped the scales" in the patient's experience leading to a decision to move ahead with surgery. SETTING: The study was carried out in the bariatric surgical clinic of a southeastern regional medical center. METHODS: This qualitative descriptive study utilized semistructured interviews with patients (n = 24) at the time of their "decision visit" to determine the factors related to their positive decision to move forward. A modification of Colaizzi's procedural steps of analysis was used to extract, organize, and analyze data for central themes. RESULTS: Two main factors leading participants to decide to move ahead with bariatric surgery were their own worsening health issues and low energy levels that limited their activities. Participants also noted additional factors that impacted their "tipping point" such as financial considerations and family influences. CONCLUSIONS: The decision to move ahead with bariatric surgery is influenced by many factors to which this research provides additional insight. Further research is warranted to fully understand this phenomenon and develop appropriate outreach and educational approaches. PMID- 27220827 TI - High-throughput and Cost-effective Chicken Genotyping Using Next-Generation Sequencing. AB - Chicken genotyping is becoming common practice in conventional animal breeding improvement. Despite the power of high-throughput methods for genotyping, their high cost limits large scale use in animal breeding and selection. In the present paper we optimized the CornellGBS, an efficient and cost-effective genotyping by sequence approach developed in plants, for its application in chickens. Here we describe the successful genotyping of a large number of chickens (462) using CornellGBS approach. Genomic DNA was cleaved with the PstI enzyme, ligated to adapters with barcodes identifying individual animals, and then sequenced on Illumina platform. After filtering parameters were applied, 134,528 SNPs were identified in our experimental population of chickens. Of these SNPs, 67,096 had a minimum taxon call rate of 90% and were considered 'unique tags'. Interestingly, 20.7% of these unique tags have not been previously reported in the dbSNP. Moreover, 92.6% of these SNPs were concordant with a previous Whole Chicken-genome re-sequencing dataset used for validation purposes. The application of CornellGBS in chickens showed high performance to infer SNPs, particularly in exonic regions and microchromosomes. This approach represents a cost-effective (~US$50/sample) and powerful alternative to current genotyping methods, which has the potential to improve whole-genome selection (WGS), and genome-wide association studies (GWAS) in chicken production. PMID- 27220828 TI - The impact of extensive loss of telecommunications on general practice: A case study in rural Victoria. AB - OBJECTIVE: To describe the impact of major loss of telecommunications on general practice in a rural region of Australia. DESIGN: A multi-stage qualitative study. Purposively selected participants were invited to contribute to initial data collection using an online survey, followed by interviews with selected participants. Thematic analysis of the data was performed by both research team members. SETTING: South-western Victoria, Australia. PARTICIPANTS: Individuals from organisations involved in Telstra recovery efforts, disaster management, health care and general practice staff. MAIN OUTCOME MEASURES: The survey collected freeform responses from participants. Semi-structured interviews further explored a variety of experiences from purposively selected participants. RESULTS: Organisations and practices in the region were prepared for major disasters, but not for the unusual and 'limited' disaster of losing telecommunications, including lack of Internet access and loss of telephone services. Although alternative measures were found for telecommunications, there was still a significant impact on many health-care-related activities and general practice functionality during the outage period. In particular, there was an increase in duties for administrative staff to compensate for loss of telecommunications. Patient traffic for many services decreased due to uncertainty about availability and continuation of business. CONCLUSIONS: The Warrnambool outage could be used as a case study illustrating the dramatic impact of communication loss. Major impacts include changes in patient traffic, increased administrative duties and slowing of patient care. When developing or assessing disaster management plans, general practices should consider the impact of telecommunication loss on functionality and prepare appropriate alternative, accessible and reliable measures. PMID- 27220829 TI - Infliximab, adalimumab and golimumab for treating moderately to severely active ulcerative colitis after the failure of conventional therapy (including a review of TA140 and TA262): clinical effectiveness systematic review and economic model. AB - BACKGROUND: Ulcerative colitis (UC) is the most common form of inflammatory bowel disease in the UK. UC can have a considerable impact on patients' quality of life. The burden for the NHS is substantial. OBJECTIVES: To evaluate the clinical effectiveness and safety of interventions, to evaluate the incremental cost effectiveness of all interventions and comparators (including medical and surgical options), to estimate the expected net budget impact of each intervention, and to identify key research priorities. DATA SOURCES: Peer reviewed publications, European Public Assessment Reports and manufacturers' submissions. The following databases were searched from inception to December 2013 for clinical effectiveness searches and from inception to January 2014 for cost-effectiveness searches for published and unpublished research evidence: MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, The Cochrane Library including the Cochrane Systematic Reviews Database, Cochrane Controlled Trials Register, Database of Abstracts of Reviews of Effects, the Health Technology Assessment database and NHS Economic Evaluation Database; ISI Web of Science, including Science Citation Index, and the Conference Proceedings Citation Index-Science and Bioscience Information Service Previews. The US Food and Drug Administration website and the European Medicines Agency website were also searched, as were research registers, conference proceedings and key journals. REVIEW METHODS: A systematic review [including network meta-analysis (NMA)] was conducted to evaluate the clinical effectiveness and safety of named interventions. The health economic analysis included a review of published economic evaluations and the development of a de novo model. RESULTS: Ten randomised controlled trials were included in the systematic review. The trials suggest that adult patients receiving infliximab (IFX) [Remicade((r)), Merck Sharp & Dohme Ltd (MSD)], adalimumab (ADA) (Humira((r)), AbbVie) or golimumab (GOL) (Simponi((r)), MSD) were more likely to achieve clinical response and remission than those receiving placebo (PBO). Hospitalisation data were limited, but suggested more favourable outcomes for ADA- and IFX-treated patients. Data on the use of surgical intervention were sparse, with a potential benefit for intervention-treated patients. Data were available from one trial to support the use of IFX in paediatric patients. Safety issues identified included serious infections, malignancies and administration site reactions. Based on the NMA, in the induction phase, all biological treatments were associated with statistically significant beneficial effects relative to PBO, with the greatest effect associated with IFX. For patients in response following induction, all treatments except ADA and GOL 100 mg at 32-52 weeks were associated with beneficial effects when compared with PBO, although these were not significant. The greatest effects at 8-32 and 32-52 weeks were associated with 100 mg of GOL and 5 mg/kg of IFX, respectively. For patients in remission following induction, all treatments except ADA at 8-32 weeks and GOL 50 mg at 32-52 weeks were associated with beneficial effects when compared with PBO, although only the effect of ADA at 32 52 weeks was significant. The greatest effects were associated with GOL (at 8-32 weeks) and ADA (at 32-52 weeks). The economic analysis suggests that colectomy is expected to dominate drug therapies, but for some patients, colectomy may not be considered acceptable. In circumstances in which only drug options are considered, IFX and GOL are expected to be ruled out because of dominance, while the incremental cost-effectiveness ratio for ADA versus conventional treatment is approximately L50,300 per QALY gained. LIMITATIONS: The health economic model is subject to several limitations: uncertainty associated with extrapolating trial data over a lifetime horizon, the model does not consider explicit sequential pathways of non-biological treatments, and evidence relating to complications of colectomy was identified through consideration of approaches used within previous models rather than a full systematic review. CONCLUSIONS: Adult patients receiving IFX, ADA or GOL were more likely to achieve clinical response and remission than those receiving PBO. Further data are required to conclusively demonstrate the effect of interventions on hospitalisation and surgical outcomes. The economic analysis indicates that colectomy is expected to dominate medical treatments for moderate to severe UC. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013006883. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 27220830 TI - Colwellia sediminilitoris sp. nov., isolated from a tidal flat. AB - A Gram-stain-negative, aerobic, motile and rod-shaped or ovoid bacterial strain, designated YSM-23T, was isolated from a tidal flat on the South Sea in South Korea, and subjected to a polyphasic taxonomic study. Strain YSM-23T grew optimally at 30 degrees C, at pH 7.0-8.0 and in the presence of 1.0-2.0 % (w/v) NaCl. The phylogenetic trees based on 16S rRNA gene sequences showed that strain YSM-23T represented a member of the genus Colwellia. Strain YSM-23T exhibited 16S rRNA gene sequence similarity values of 98.0, 97.4 and 97.3 % to the type strains of Colwellia aestuarii, Colwellia polaris and Colwellia chukchiensis, respectively, and of 94.5-96.8 % to the type strains of the other species of the genus Colwellia. Strain YSM-23T contained Q-8 as the predominant ubiquinone and summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) as the major fatty acid. The major polar lipids detected in strain YSM-23T were phosphatidylglycerol and phosphatidylethanolamine. The DNA G+C content of strain YSM-23T was 43.8+/-0.08 mol% and its DNA-DNA relatedness values with the type strain of C. aestuarii, C. polaris and C. chukchiensis were 10+/-3.5-22+/-4.9 %. Differential phenotypic properties, together with its phylogenetic and genetic distinctiveness, revealed that strain YSM-23T is separated from species of the genus Colwelliawith validly published names. On the basis of the data presented, strain YSM-23T is considered to represent a novel species of the genus Colwellia, for which the name Colwellia sediminilitoris sp. nov. is proposed. The type strain is YSM-23T (=KCTC 52213T=NBRC 111994T). PMID- 27220831 TI - Enzymatic synthesis, structural characterization and antioxidant capacity assessment of a new lipophilic malvidin-3-glucoside-oleic acid conjugate. AB - The chemical modification of anthocyanins (water-soluble pigments) into more lipophilic compounds is very important to expand their application in the food, medical and cosmetic industries. In this work, the synthesis of a pure malvidin-3 glucoside-oleic acid ester derivative was achieved by enzymatic catalysis. This approach allowed us to synthesize a novel compound, malvidin-3-O-(6'' oleoyl)glucoside (Mv3glc-OA), which was structurally characterized by mass spectrometry and for the first time by NMR spectroscopy. The enzymatic reaction revealed to be regioselective giving only one ester product. Antioxidant features of the malvidin-3-glucoside lipophilic derivative by means of DPPH, FRAP and lipid peroxidation assays were assessed, which confirmed that the structural modification of the genuine malvidin-3-glucoside into a more lipophilic compound did not compromise its antioxidant potential and protected more effectively a lipidic substrate from oxidation, which is an important insight for future technological applications. PMID- 27220832 TI - MicroRNA-423-5p mediates H2O2-induced apoptosis in cardiomyocytes through O GlcNAc transferase. AB - Reactive oxygen species (ROS) have been clinically shown to be relevant in the progression of various apoptosis-associated heart diseases. Our previous study demonstrated that microRNA (miR)-423-5p is involved in congestive heart failure (CHF) through the direct targeting of O-GlcNAc transferase and the induction of apoptosis in cardiomyocytes. However, the role of miR-423-5p during ROS-induced apoptosis remains to be elucidated. In the present study, the expression of miR 423-5p in cardiomyocytes following exposure to H2O2 was determined using reverse transcription-quantitative polymerase chain reaction analysis. In addition, the effects of silencing of miR-423-5p, by using an miR-423-5p-mimic during H2O2 treatment, on cardiomyocyte apoptosis were detected using a terminal deoxynucleotidyl transferase-deoxyuridine triphosphate nick-end labeling assay. The expression levels of the direct target of miR-423-5p and associated downstream targets were also examined. The results demonstrated that H2O2 significantly induced the expression of miR-423-5p in cardiomyocytes, in a time- and concentration-dependent manner. The silencing of miR-423-5p by transfection with the miR-423-5p-mimic eliminated the H2O2-induced cardiomyocyte apoptosis and decrease in viability. The expression levels of the downstream targets of miR423 5p were also increased by H2O2, and were decreased following the silencing of miR 423-5p. Collectively, the results of the present study demonstrated that miR-423 5p mediated H2O2-induced apoptosis in the cardiomyocytes. Silencing of miR-423-5p significantly protected the cardiomyocytes from H2O2-induced apoptosis, and this may provide a novel therapeutic target for apoptosis-associated heart diseases. PMID- 27220833 TI - An elderly-onset limb girdle muscular dystrophy type 1B (LGMD1B) with pseudo hypertrophy of paraspinal muscles. AB - Mutations in LMNA, encoding A-type lamins, lead to diverse disorders, collectively called "laminopathies," which affect the striated muscle, cardiac muscle, adipose tissue, skin, peripheral nerve, and premature aging. We describe a patient with limb-girdle muscular dystrophy type 1B (LGMD1B) carrying a heterozygous p.Arg377His mutation in LMNA, in whom skeletal muscle symptom onset was at the age of 65 years. Her weakness started at the erector spinae muscles, which showed marked pseudo-hypertrophy even at the age of 72 years. Her first episode of syncope was at 44 years; however, aberrant cardiac conduction was not revealed until 60 years. The p.Arg377His mutation has been previously reported in several familial LMNA-associated myopathies, most of which showed muscle weakness before the 6th decade. This is the first report of pseudo-hypertrophy of paravertebral muscles in LMNA-associated myopathies. The pseudo-hypertrophy of paravertebral muscles and the elderly-onset of muscle weakness make this case unique and reportable. PMID- 27220835 TI - Adverse Events in Pediatric Patients Receiving Long-term Oral and Intravenous Antibiotics. AB - BACKGROUND AND OBJECTIVE: Children receiving long-term antibiotic therapy (LTAT) at Children's Hospital Colorado (CHCO) are treated with both oral and intravenous (i.v.) agents and often experience complications not comprehensively described by the literature. We sought to describe adverse drug events (ADEs) and venous access complications (VACs) in pediatric patients managed with oral and i.v. antibiotics so as to inform clinical decision-making, drug monitoring, and patient counseling at CHCO. METHODS: We conducted a retrospective review of children receiving LTAT through the CHCO infectious disease service from 2006 to 2012. Demographic, microbiologic, diagnostic data, ADEs, and VACs were recorded for each patient. RESULTS: From 2006 to 2012, 521 patients received 1876 courses, accounting for 71,306 days of antimicrobial therapy. A total of 219 patients (42%) developed an ADE with discontinuation of the offending agent in 65% of courses associated with an ADE. The most common ADEs were neutropenia, rash, and diarrhea. Central lines were placed in 376 patients with 106 (28%) experiencing >=1 VACs. I.v. agents were associated with a fourfold increase in the rate of ADEs compared with oral agents, and a fivefold increase when VACs were included. CONCLUSIONS: Practitioners may make more informed decisions and risk assessments by using descriptive ADE information for specific agents and mode of drug delivery to mitigate risk, thereby improving the quality of care. Patients should be counseled regarding risks of LTAT, including increased risk with i.v. therapy, and actively monitored for side effects. PMID- 27220836 TI - Femoral and sciatic nerve block for knee arthroscopy in a patient with acute intermittent porphyria. AB - Acute intermittent porphyria is an autosomal dominant disorder that results from a partial deficiency of porphobilinogen deaminase and that causes very severe symptoms. Attacks may be triggered by a series of drugs and by other factors that the anesthesiologist should be aware of in order to reduce morbidity and mortality. Our objective is to review anesthetic considerations in acute intermittent porphyria. We present the case of a patient diagnosed with acute intermittent porphyria who was scheduled for knee arthroscopy. The anesthetic technique used was a femoral and sciatic nerve block under sedation with an infusion of remifentanil. The surgery proceeded without incident and the patient was discharged home after 24h. We consider the use of a peripheral plexus block of the lower limb to have been the safest anesthetic technique for this patient. PMID- 27220837 TI - MicroRNA-18b inhibits the growth of malignant melanoma via inhibition of HIF 1alpha-mediated glycolysis. AB - MicroRNAs (miRs) have been demonstrated to play critical roles in the development and progression of malignant melanoma (MM). However, the exact role and underlying mechanism of miR-18b in MM growth remains unclear. In the present study, real-time PCR data indicated that miR-18b was significantly downregulated in MM tissues compared to their matched adjacent non-tumor tissues. Low miR-18b expression was significantly associated with the tumor thickness and stage, although no significant association was observed between the miR-18b expression and the age, gender, or lymph node metastasis. Besides, miR-18b was also significantly downregulated in MM B16 and A375 cells compared to normal skin HACAT cells. Ectopic expression of miR-18b decreased the proliferation of A375 and B16 cells, while induced a remarkable cell cycle arrest at G1 stage. Besides, miR-18b overexpression also inhibited the glycolysis in A375 and B16 cells. HIF 1alpha, a key regulator in glycolysis, was then identified as a target gene of miR-18b, and its expression was negatively mediated by miR-18b in A375 and B16 cells. Overexpression of HIF-1alpha rescued the suppressive effect of miR-18b on MM cell proliferation and glycolysis. In vivo study further showed that overexpression of miR-18b inhibited the MM growth as well as the tumor-related death, accompanied with HIF-1alpha downregulation. Taken together, the present study suggests that miR-18b inhibits the growth of MM cells in vitro and in vivo through directly targeting HIF-1alpha. PMID- 27220838 TI - Human Subjects Protection and Technology in Prevention Science: Selected Opportunities and Challenges. AB - Internet-connected devices are changing the way people live, work, and relate to one another. For prevention scientists, technological advances create opportunities to promote the welfare of human subjects and society. The challenge is to obtain the benefits while minimizing risks. In this article, we use the guiding principles for ethical human subjects research and proposed changes to the Common Rule regulations, as a basis for discussing selected opportunities and challenges that new technologies present for prevention science. The benefits of conducting research with new populations, and at new levels of integration into participants' daily lives, are presented along with five challenges along with technological and other solutions to strengthen the protections that we provide: (1) achieving adequate informed consent with procedures that are acceptable to participants in a digital age; (2) balancing opportunities for rapid development and broad reach, with gaining adequate understanding of population needs; (3) integrating data collection and intervention into participants' lives while minimizing intrusiveness and fatigue; (4) setting appropriate expectations for responding to safety and suicide concerns; and (5) safeguarding newly available streams of sensitive data. Our goal is to promote collaboration between prevention scientists, institutional review boards, and community members to safely and ethically harness advancing technologies to strengthen impact of prevention science. PMID- 27220839 TI - IL-1alpha induces apoptosis and inhibits the osteoblast differentiation of MC3T3 E1 cells through the JNK and p38 MAPK pathways. AB - Interleukin (IL)-1 is a proinflammatory cytokine that plays important roles in inflammation and host responses to infection. The present study aimed to evaluate the effects of IL-1alpha on the apoptosis and differentiation of osteoblasts, and to elucidate the mechanism responsible for these effects in the osteoblast-like cell line MC3T3-E1. The MC3T3-E1 cells were non-treated or treated with IL 1alpha. Following treatment, cell viability, alkaline phosphatase (ALP) activity and caspase-3 activity were evaluated. The expression of osteoblast-specific genes as well as Bax, Bcl-2 and caspase-3 were determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The protein levels of Bax, Bcl-2, caspase-3 and the phosphorylation of mitogen-activated protein kinases (MAPKs, also known as MAP kinases) were evaluated using western blot analysis. The MAPK signaling pathway was blocked by pre-treatment with MAPK inhibitors SB203580, PD98059 and SP600125. IL-1alpha treatment induced a significant decrease in cell viability and ALP activity in the MC3T3-E1 cells. IL 1alpha also significantly decreased the mRNA expression and protein levels of osteoblast-related genes in the MC3T3-E1 cells. On the other hand, IL-1alpha significantly upregulated the mRNA expression and protein levels of Bax and caspase-3 as well as caspase-3 activity, whereas Bcl-2 expression was decreased in the MC3T3-E1 cells. Furthermore, IL-1alpha activated the apoptotic signaling pathway by increasing the phosphorylation of c-Jun N-terminal kinase (JNK) and p38-MAPK, whereas it inhibited the phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2). Moreover, pre-treatment with MAPK inhibitors attenuated the phosphorylation of JNK, p38 and Bax expression enhanced by IL 1alpha. However, MAPK inhibitors markedly increased the protein expression of osteoblast-related genes and Bcl-xL in the MC3T3-E1 cells downregulated by IL 1alpha. Taken together, these findings suggest that IL-1alpha induces the apoptosis of osteoblasts and inhibits osteoblast differentiation by activating the JNK and the p38 MAPK pathways. PMID- 27220840 TI - Comparative Study of the Efficacy of Olmesartan/Amlodipine vs. Perindopril/Amlodipine in Peripheral and Central Blood Pressure Parameters After Missed Dose in Type 2 Diabetes. AB - BACKGROUND: Central aortic blood pressure (CBP) and CBP-derived parameters are independent predictors of cardiovascular risk. Angiotensin II receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors plus calcium channel blockers are the recommended first-line treatments in hypertensive diabetic patients; however, the effect in reducing CBP when a dose is skipped has not been established yet. The aim was to determine whether the fixed-dose combination of olmesartan/amlodipine (OLM/AML) provides equal efficacy and safety as the perindopril/AML (PER/AML) combination in reducing CBP, augmentation index (AIx), and pulse wave velocity (PWV) when a drug dose is missed. METHODS: In this noninferiority, randomized, double-blind, double-dummy parallel group, controlled design trial, 88 patients received either OLM 20-40mg/AML 5-10mg (41 patients) or PER 4-8mg/AML 5-10mg (47 patients) for 24 weeks. The main endpoint was the aortic systolic BP (SBP) after 24 weeks of treatment at 48 hours from the last administration. RESULTS: The OLM/AML combination reached the noninferiority criteria in reducing central systolic BP after 24 weeks of treatment and after the missed dose, compared to the PER/AML combination (-17 and -8mm Hg, respectively). Peripheral BP, AIx, and PWV were significantly lower in both groups after 24 weeks of treatment and 48 hours after the missed dose, observing a trend to a greater reduction in CBP-derived parameters in the OLM/AML group. CONCLUSIONS: The OLM/AML combination is safe, well tolerated, and not inferior to the combination of PER/AML in lowering CBP and CBP-derived parameters in diabetic patients. OLM/AML provides longer-lasting efficacy in terms of CBP reduction compared to PER/AML. PMID- 27220841 TI - Authors' reply to Thilagnathan. PMID- 27220842 TI - David Oliver: Delirium matters. PMID- 27220843 TI - Relation between therapy options for Graves' disease and the course of Graves' ophthalmopathy: a systematic review and meta-analysis. AB - BACKGROUND: The relation between therapy options for Graves' disease (GD) and the course of Graves' ophthalmopathy (GO) are still controversial. Our aim was to compare the occurrence of development or worsening of GO in patients who were treated with antithyroid drugs (ATDs) or radioactive iodine (RAI) or thyroidectomy (TX). METHODS: We conducted a comprehensive search of the Embase and PubMed database. Odds ratio (OR) was used as a measure of the effect of therapy options for GD on the risk of development or worsening of GO. The analysis was further stratified by factors that could affect the treatment effects. RESULTS: Nine trials involving 1773 patients were included. RAI therapy showed a significant effect on the risk of development or worsening GO compared with ATD (OR 2.25; 95 % CI 1.61-3.14; P < 0.00001). Glucocorticoid prophylaxis was effective in preventing GO development or worsening (0.40; 0.23-0.68; P = 0.002); especially for patients with preexisting GO (0.41; 0.23-0.73; P = 0.002). At 3 months, showed GO to be improved in 17 TX and 21 total thyroid ablation (TTA) patients, with no significant difference between the two groups; between 6 and 12 months, TTA did show significant beneficial effect on the improvement of GO (6.02; 2.80-12.96; P < 0.00001); GO was found to be inactive in a significantly higher percentage of patients in the TTA (2.17; 1.04-4.52; P = 0.04). CONCLUSION: Radioiodine therapy is a significant risk factor for development or worsening of GO in GD. But GO progression can be prevented by prophylactic glucocorticoids in patients with preexisting GO. Compared with TX alone, TTA induces an earlier and steadier GO improvement in patients with mild to moderate-severe and active GO. Whether this is sufficient to offer TTA to patients needs further investigation. PMID- 27220844 TI - Collision Cross Sections for 20 Protonated Amino Acids: Fourier Transform Ion Cyclotron Resonance and Ion Mobility Results. AB - We report relative dephasing cross sections for the 20 biogenic protonated amino acids measured using the cross sectional areas by Fourier transform ion cyclotron resonance (CRAFTI) technique at 1.9 keV in the laboratory reference frame, as well as momentum transfer cross sections for the same ions computed from Boltzmann-weighted structures determined using molecular mechanics. Cross sections generally increase with increasing molecular weight. Cross sections for aliphatic and aromatic protonated amino acids are larger than the average trend, suggesting these side chains do not fold efficiently. Sulfur-containing protonated amino acids have smaller than average cross sections, reflecting the mass of the S atom. Protonated amino acids that can internally hydrogen-bond have smaller than average cross sections, reflecting more extensive folding. The CRAFTI measurements correlate well with results from drift ion mobility (IMS) and traveling wave ion mobility (TWIMS) spectrometric measurements; CRAFTI results correlate with IMS values approximately as well as IMS and TWIMS values from independent measurements correlate with each other. Both CRAFTI and IMS results correlate well with the computed momentum transfer cross sections, suggesting both techniques provide accurate molecular structural information. Absolute values obtained using the various methods differ significantly; in the case of CRAFTI, this may be due to errors in measurements of collision gas pressure, measurement of excitation voltage, and/or dependence of cross sections on kinetic energy. Graphical Abstract ?. PMID- 27220845 TI - Sphenoidal pneumosinus dilatans due to anterior skull base meningiomas - CT and MRI aspects: Report of two new cases and literature review. AB - We report on two patients disclosing a pneumosinus dilatans (PSD) and an anterior skull base meningioma. Our findings, together with those from the pertinent literature, support the thought that this infrequent anomaly of paranasal sinuses is a useful clue to suspect a concomitant meningioma. Moreover, hypotheses concerning the pathophysiology of PSD are discussed. PMID- 27220846 TI - Phosphorylation-dependent Akt-Inversin interaction at the basal body of primary cilia. AB - A primary cilium is a microtubule-based sensory organelle that plays an important role in human development and disease. However, regulation of Akt in cilia and its role in ciliary development has not been demonstrated. Using yeast two-hybrid screening, we demonstrate that Inversin (INVS) interacts with Akt. Mutation in the INVS gene causes nephronophthisis type II (NPHP2), an autosomal recessive chronic tubulointerstitial nephropathy. Co-immunoprecipitation assays show that Akt interacts with INVS via the C-terminus. In vitro kinase assays demonstrate that Akt phosphorylates INVS at amino acids 864-866 that are required not only for Akt interaction, but also for INVS dimerization. Co-localization of INVS and phosphorylated form of Akt at the basal body is augmented by PDGF-AA Akt-null MEF cells as well as siRNA-mediated inhibition of Akt attenuated ciliary growth, which was reversed by Akt reintroduction. Mutant phosphodead- or NPHP2-related truncated INVS, which lack Akt phosphorylation sites, suppress cell growth and exhibit distorted lumen formation and misalignment of spindle axis during cell division. Further studies will be required for elucidating functional interactions of Akt-INVS at the primary cilia for identifying the molecular mechanisms underlying NPHP2. PMID- 27220847 TI - Substrate recruitment of gamma-secretase and mechanism of clinical presenilin mutations revealed by photoaffinity mapping. AB - Intramembrane proteases execute fundamental biological processes ranging from crucial signaling events to general membrane proteostasis. Despite the availability of structural information on these proteases, it remains unclear how these enzymes bind and recruit substrates, particularly for the Alzheimer's disease-associated gamma-secretase. Systematically scanning amyloid precursor protein substrates containing a genetically inserted photocrosslinkable amino acid for binding to gamma-secretase allowed us to identify residues contacting the protease. These were primarily found in the transmembrane cleavage domain of the substrate and were also present in the extramembranous domains. The N terminal fragment of the catalytic subunit presenilin was determined as principal substrate-binding site. Clinical presenilin mutations altered substrate binding in the active site region, implying a pathogenic mechanism for familial Alzheimer's disease. Remarkably, PEN-2 was identified besides nicastrin as additional substrate-binding subunit. Probing proteolysis of crosslinked substrates revealed a mechanistic model of how these subunits interact to mediate a stepwise transfer of bound substrate to the catalytic site. We propose that sequential binding steps might be common for intramembrane proteases to sample and select cognate substrates for catalysis. PMID- 27220848 TI - Histone H3.3 promotes IgV gene diversification by enhancing formation of AID accessible single-stranded DNA. AB - Immunoglobulin diversification is driven by activation-induced deaminase (AID), which converts cytidine to uracil within the Ig variable (IgV) regions. Central to the recruitment of AID to the IgV genes are factors that regulate the generation of single-stranded DNA (ssDNA), the enzymatic substrate of AID Here, we report that chicken DT40 cells lacking variant histone H3.3 exhibit reduced IgV sequence diversification. We show that this results from impairment of the ability of AID to access the IgV genes due to reduced formation of ssDNA during IgV transcription. Loss of H3.3 also diminishes IgV R-loop formation. However, reducing IgV R-loops by RNase HI overexpression in wild-type cells does not affect IgV diversification, showing that these structures are not necessary intermediates for AID access. Importantly, the reduction in the formation of AID accessible ssDNA in cells lacking H3.3 is independent of any effect on the level of transcription or the kinetics of RNAPII elongation, suggesting the presence of H3.3 in the nucleosomes of the IgV genes increases the chances of the IgV DNA becoming single-stranded, thereby creating an effective AID substrate. PMID- 27220849 TI - Higher-order oligomerization promotes localization of SPOP to liquid nuclear speckles. AB - Membrane-less organelles in cells are large, dynamic protein/protein or protein/RNA assemblies that have been reported in some cases to have liquid droplet properties. However, the molecular interactions underlying the recruitment of components are not well understood. Herein, we study how the ability to form higher-order assemblies influences the recruitment of the speckle type POZ protein (SPOP) to nuclear speckles. SPOP, a cullin-3-RING ubiquitin ligase (CRL3) substrate adaptor, self-associates into higher-order oligomers; that is, the number of monomers in an oligomer is broadly distributed and can be large. While wild-type SPOP localizes to liquid nuclear speckles, self association-deficient SPOP mutants have a diffuse distribution in the nucleus. SPOP oligomerizes through its BTB and BACK domains. We show that BTB-mediated SPOP dimers form linear oligomers via BACK domain dimerization, and we determine the concentration-dependent populations of the resulting oligomeric species. Higher-order oligomerization of SPOP stimulates CRL3(SPOP) ubiquitination efficiency for its physiological substrate Gli3, suggesting that nuclear speckles are hotspots of ubiquitination. Dynamic, higher-order protein self-association may be a general mechanism to concentrate functional components in membrane-less cellular bodies. PMID- 27220850 TI - Revisional Surgery Following Laparoscopic Gastric Plication. AB - BACKGROUND: The laparoscopic gastric plication (LGP) is a relative new bariatric procedure that has gained popularity over the last few years, but no real consensus exists and the evidence is unclear, especially in its real efficacy, safety, and durability. METHODS: Retrospective study analyzing the records patients submitted to LGP between 2009 and 2010. The primary objective was to describe the characteristics and outcomes of patients submitted to revisional surgery. Baseline data and evolution were obtained and analyzed. Surgical analysis included revision cause, perioperative outcome, type of surgery, complications, and weight loss after 18 months. A comparison between gastric bypass and sleeve gastrectomy was performed. RESULTS: One hundred LGP were performed. After a mean time of 13.5 months, 42 patients presented an overall excess weight loss (EWL) <50 % and 38 had severe symptoms. Thirty patients accepted revisional surgery with BMI before conversion of 38.6 +/- 4.2 kg/m2. There were 17 laparoscopic sleeve gastrectomy (LSG) and 13 laparoscopic gastric bypass (LGBP) with comparable preoperative characteristics. The LSG group had lower pneumoperitoneum time and less hospital stay. At 18 months, the LGBP group had lower BMI (24.1 +/- 1.1 vs. 25.8 +/- 1.3 kg/m2 for the LSG; p = 0.006) and higher %EWL (75.7 +/- 16.1 vs. 61.4 +/- 14.5 % for the LSG; p = 0.008). CONCLUSION: In our series, LGP presented a high failure rate and an increased number of symptomatic patients. Revisional surgery proved to be safe and effective. Revision to LSG was faster and had less hospital stay. Revision to LGBP showed better %EWL at 18 months. PMID- 27220851 TI - Do Changes in Perioperative and Postoperative Treatment Protocol Influence the Frequency of Pulmonary Complications? A Retrospective Analysis of Four Different Bariatric Groups. AB - : The current understanding of prophylaxis of pulmonary complications in bariatric surgery is weak. PURPOSE: The aim of this study was to observe how changes in perioperative and postoperative treatments affect the incidence of pulmonary complications in bariatric patients. MATERIALS: This is a retrospective clinical study of 400 consecutive bariatric patients. The patients, who either underwent a sleeve gastrectomy or a Roux-en-Y gastric bypass, were divided consecutively into four subgroups with different approaches to perioperative treatment. METHODS: The first group (patients 0-100) was recovered in the intensive care unit with minimal mobilization (ICU). They had a urinary catheter and a drain. The second group (patients 101-200) was similar to the first group, but the patients used a continuous positive airway pressure (CPAP) device intermittently (ICU-CPAP). The third group (patients 201-300) was recovered on a normal ward without a urinary catheter or a drain and used a CPAP device (ward slow). The fourth group (patients 301-400) walked to the operating theater and was mobilized in the recovery room during the first 2 h after the operation (ward fast). CPAP was also used. Primary endpoints were pulmonary complications, pneumonia, and infection, non-ultra descriptus (NUD). RESULTS: The number of pulmonary complications among the groups was significantly different. A long operation time increased the risk for infection (p < 0.001 95 % CI from 2.02 to 6.59 %). CONCLUSIONS: Operation time increases the risk for pulmonary complications. Changes in perioperative care toward the ERAS protocol may have a positive effect on the number of pulmonary complications. PMID- 27220853 TI - Public Health Concerns Associated with the New York City Blackout of 1977. AB - The 1977 New York City blackout began at 9:36 p.m. on 13 July and lasted some 25 h until 10:39 p.m. on 14 July. The New York City Department of Health rapidly set up a Blackout Contingency Plan, established priorities, and mobilized its staff to address remedial interventions. Top priorities included water supplies, sewage disposal, perishable food supplies, hospital and emergency room services, solid waste disposal, beach contamination with untreated sewage , and assisting those on electrically powered home life support systems. The 1977 blackout occurred during an extended heat wave. An analysis of total deaths and deaths due to pulmonary and cardiovascular/renal diseases by day correlated with temperatures. However, there was no direct correlation with the blackout itself, in part perhaps because of the confounding influence of high temperatures. The increase of deaths on very hot days outside of the blackout period lends strong support to the relationship between increased deaths and high ambient temperatures. The 1977 New York City blackout was distinguished from those of 1965 and 2003 by violence, arson, and looting that occurred in several areas. These acts resulted in 204 civilian injuries, 436 police injuries, 80 firefighter injuries, and 1037 fires. The violence, arson, and looting caused extensive long-term physical and functional damage to certain areas of two boroughs of the city, Brooklyn and the Bronx. Although the New York City Department of Health had not previously established a disaster preparedness plan, its professionals quickly rose to the occasion because they were able to draw upon vast public health practice experience and ingenuity. PMID- 27220852 TI - Modified thresholds for fibrosis risk scores in nonalcoholic fatty liver disease are necessary in the obese. AB - BACKGROUND: Obesity and its related comorbidities are significant risk factors for nonalcoholic fatty liver disease (NAFLD). Liver fibrosis is the major determinant of long-term outcomes in NAFLD. A non-invasive tool that accurately identifies obese patients at elevated risk of liver fibrosis would be of significant value. Fibrosis risk scores in patients with NAFLD have been proposed but have not been validated in obese populations. We aimed to validate established simple fibrosis scores in bariatric surgical patients. METHODS: We conducted a prospective study of 107 consecutive high-risk obese patients undergoing primary bariatric surgery. Proposed fibrosis scores (NAFLD fibrosis score; body mass index (BMI), aspartate aminotransferase (AST)/alanine aminotransferase ratio (ALT), and diabetes (BARD); Fibrosis-4 (FIB-4); Forn; and AST to platelet ratio index) were calculated and compared hepatic fibrosis determined by histology of intraoperative liver biopsies. Accuracy was determined, and fibrosis score thresholds were optimized. These modified thresholds were then validated in an independent bariatric surgical population. RESULTS: Liver biopsies were available in 101 patients. Sixty-eight patients had some degree of fibrosis, with 23 patients (23 %) having significant fibrosis (F2 4). The Forn score best predicted significant fibrosis (area under the receiver operator characteristic curve (AUROC) 0.724, p = 0.001). With standard thresholds, the sensitivity for the Forn score for identification of significant fibrosis (F2-4) was 0 %. Using modified thresholds of 3.5, the sensitivity and negative predictive value increased to 85.7 and 94.7 %. This threshold was applied to an independent validation cohort with good accuracy. CONCLUSIONS: Fibrosis risk scores using simple markers have moderate success at delineating obese patients with significant NAFLD-related fibrosis. Thresholds, however, need to be lowered to maximize diagnostic accuracy in this cohort. PMID- 27220855 TI - A comparison of wearable fitness devices. AB - BACKGROUND: Wearable trackers can help motivate you during workouts and provide information about your daily routine or fitness in combination with your smartphone without requiring potentially disruptive manual calculations or records. This paper summarizes and compares wearable fitness devices, also called "fitness trackers" or "activity trackers." These devices are becoming increasingly popular in personal healthcare, motivating people to exercise more throughout the day without the need for lifestyle changes. The various choices in the market for wearable devices are also increasing, with customers searching for products that best suit their personal needs. Further, using a wearable device or fitness tracker can help people reach a fitness goal or finish line. Generally, companies display advertising for these kinds of products and depict them as beneficial, user friendly, and accurate. However, there are no objective research results to prove the veracity of their words. This research features subjective and objective experimental results, which reveal that some devices perform better than others. METHODS: The four most popular wristband style wearable devices currently on the market (Withings Pulse, Misfit Shine, Jawbone Up24, and Fitbit Flex) are selected and compared. The accuracy of fitness tracking is one of the key components for fitness tracking, and some devices perform better than others. This research shows subjective and objective experimental results that are used to compare the accuracy of four wearable devices in conjunction with user friendliness and satisfaction of 7 real users. In addition, this research matches the opinions between reviewers on an Internet site and those of subjects when using the device. RESULTS: Withings Pulse is the most friendly and satisfactory from the users' viewpoint. It is the most accurate and repeatable for step and distance tracking, which is the most important measurement of fitness tracking, followed by Fitbit Flex, Jawbone Up24, and Misfit Shine. In contrast, Misfit Shine has the highest score for design and hardware, which is also appreciated by users. CONCLUSIONS: From the results of experiments on four wearable devices, it is determined that the most acceptable in terms of price and satisfaction levels is the Withings Pulse, followed by the Fitbit Flex, Jawbone Up24, and Misfit Shine. PMID- 27220854 TI - Heart failure and the holidays. AB - INTRODUCTION: Studies suggest increased cardiac morbidity and heart failure exacerbations during winter months with a peak around the holiday season. Major sporting events and intense encounters in sports have been shown to affect cardiovascular outcomes amongst its fans. METHODS: All patients admitted to Einstein Medical Center between January 1, 2003 and December 31, 2013 with a diagnosis of congestive heart failure were included in the study. They were included on the basis of the presence of an ICD-9CM code representing congestive heart failure as the primary diagnosis. Comparisons were made between the rates of heart failure admissions on the holiday, 4 days following the holiday and the rest of the month for 5 specific days: Christmas day, New Year's day, Independence day, Thanksgiving day and Super Bowl Sunday. RESULTS: Our study included 22,727 heart failure admissions at an average of 5.65 admissions per day. The mean patient age was 68 +/- 15 years. There was a significant increase in daily heart failure admissions following Independence day (5.65 vs. 5; p = 0.027) and Christmas day (6.5 vs. 5.5; p = 0.046) when compared to the rest of the month. A history of alcohol abuse or dependence did not correlate with the reported+ rise in heart failure admissions immediately following the holidays. The mean number of daily admissions on the holidays were significantly lower for all holidays compared to the following 4 days. All holidays apart from Super Bowl Sunday demonstrated lower admission rates on the holiday compared to the rest of the month. CONCLUSION: Christmas and Independence day were associated with increased heart failure admissions immediately following the holidays. The holidays themselves saw lower admission rates. Overeating on holidays, associated emotional stressors, lesser exercise and postponing medical around holidays may be among the factors responsible for the findings. PMID- 27220856 TI - Proopiomelanocortin, glucocorticoid, and CRH receptor expression in human ACTH secreting pituitary adenomas. AB - ACTH-secreting pituitary tumors are by definition partially autonomous, i.e., secrete ACTH independent of physiological control. However, only few, small-sized studies on proopiomelanocortin (POMC) and its regulation by corticotropin releasing hormone (CRH) or glucocorticoids are available. Objective of the present study was to report on constitutive and CRH- and dexamethasone-regulated POMC, CRH (CRH-R1), and glucocorticoid receptor (NR3C1) gene expression in a large series of human corticotrope adenomas. Fifty-three ACTH-secreting adenomas were incubated with 10 nM CRH or 10 nM dexamethasone for 24 h. POMC, CRH-R1, NR3C1, and its alpha and beta isoforms were quantified and medium ACTH measured. Constitutive POMC expression proved extremely variable, with macroadenomas exhibiting higher levels than microadenomas. POMC increased during CRH in most specimens; conversely, changes induced by dexamethasone were varied, ranging from decrease to paradoxical increase. No correlation between POMC and ACTH was detected in any experimental condition. CRH-R1 expression was not linked to the response to CRH while NR3C1 was expressed at greater levels in specimens who failed to inhibit during dexamethasone; glucocorticoid receptor alpha was the more abundant isoform and subject to down-regulation by dexamethasone. Our results demonstrate a considerable variability in POMC expression among tumors and no correlation between POMC and ACTH, suggesting that POMC peptide processing/transport plays a major role in modulating ACTH secretion. Further, CRH-R1 and NR3C1 expression were not linked to the expected ligand-induced outcome, indicating that receptor signaling rather than abundance determines corticotrope responses. Our findings pave the way to new avenues of research into Cushing's disease pathophysiology. PMID- 27220857 TI - Stay, stray or something in-between? A comment on Wlodarski et al. PMID- 27220858 TI - Predicting biotic interactions and their variability in a changing environment. AB - Global environmental change is altering the patterns of biodiversity worldwide. Observation and theory suggest that species' distributions and abundances depend on a suite of processes, notably abiotic filtering and biotic interactions, both of which are constrained by species' phylogenetic history. Models predicting species distribution have historically mostly considered abiotic filtering and are only starting to integrate biotic interaction. However, using information on present interactions to forecast the future of biodiversity supposes that biotic interactions will not change when species are confronted with new environments. Using bacterial microcosms, we illustrate how biotic interactions can vary along an environmental gradient and how this variability can depend on the phylogenetic distance between interacting species. PMID- 27220859 TI - Reply to Falcon. PMID- 27220860 TI - Exceptional body sizes but typical trophic structure in a Pleistocene food web. AB - In this study, we focused on the exceptionally large mammals inhabiting the Americas during the Quaternary period and the paramount role of body size in species ecology. We evaluated two main features of Pleistocene food webs: the relationship between body size and (i) trophic position and (ii) vulnerability to predation. Despite the large range of species sizes, we found a hump-shaped relationship between trophic position and body size. We also found a negative trend in species vulnerability similar to that observed in modern faunas. The largest species lived near the boundary of energetic constraints, such that any shift in resource availability could drive these species to extinction. Our results reinforce several features of megafauna ecology: (i) the negative relationship between trophic position and body size implies that large-sized species were particularly vulnerable to changes in energetic support; (ii) living close to energetic imbalance could favour the incorporation of additional energy sources, for example, a transition from a herbivorous to a scavenging diet in the largest species (e.g. Megatherium) and (iii) the interactions and structure of Quaternary megafauna communities were shaped by similar forces to those shaping modern fauna communities. PMID- 27220861 TI - Correction to: Rewriting the history of an extinction-was a population of Steller's sea cows (Hydrodamalis gigas) at St Lawrence Island also driven to extinction? PMID- 27220862 TI - Obituary: Paul Joyce (1958-2016). PMID- 27220863 TI - "Cytochrome c oxidase I DNA sequence of Camponotus ants with different nesting strategies is a tool for distinguishing between morphologically similar species". AB - The great diversity of Camponotus, high levels of geographic, intraspecific and morphological variation common to most species of this genus make the determination of the interspecific limits of Camponotus a complex task. The Cytochrome c oxidase 1 (COI) gene was sequenced in this study to serve as an auxiliary tool in the identification of two taxa of Camponotus thought to be morphologically similar. Additionally, characteristics related to nesting were described. Five to fifteen workers from twenty-one colonies were analyzed, collected from twigs scattered in the leaf litter and from trees located in different regions of Brazil. Phylogenetic reconstructions, haplotype network, and nesting strategies confirmed the existence of two species and that they correspond to Camponotus senex and Camponotus textor. Our results emphasize that the COI can be used as an additional tool for the identification of morphologically similar Camponotus species. PMID- 27220864 TI - Are the current guideline recommendations for neonatal cardiopulmonary resuscitation safe and effective? AB - A recently published review of approaches to optimize chest compressions in the resuscitation of asphyxiated newborns discussed the current recommendations and explored potential determinants of effective neonatal cardiopulmonary resuscitation (CPR). However, not all potential determinants of effective neonatal CPR were explored. Chest compression shallower than the current guideline recommendation of approximately 33% of the anterior-posterior (AP) chest diameter may be safer and more effective. From a physiological standpoint, high-velocity brief duration shallower compression may be more effective than current recommendations. The application of a 1- or 2-finger method of high impulse CPR, which would depend on the size of the subject, may be more effective than using a 2-thumb (TT) encircling hands method of CPR. Adrenaline should not be used in the treatment of asphyxiated neonates and when necessary titrated vasopressin should be used. PMID- 27220865 TI - The association between prehospital transportation and clinical outcomes in patients with non-STEMI. PMID- 27220866 TI - Spinocerebellar ataxia: relationship between phenotype and genotype - a review. AB - Spinocerebellar ataxia (SCA) comprises a large group of heterogeneous neurodegenerative disorders inherited in an autosomal dominant fashion. It is characterized by progressive cerebellar ataxia with oculomotor dysfunction, dysarthria, pyramidal signs, extrapyramidal signs, pigmentary retinopathy, peripheral neuropathy, cognitive impairment and other symptoms. It is classified according to the clinical manifestations or genetic nosology. To date, 40 SCAs have been characterized, and include SCA1-40. The pathogenic genes of 28 SCAs were identified. In recent years, with the widespread clinical use of next generation sequencing, the genes underlying SCAs, and the mutants as well as the affected phenotypes were identified. These advances elucidated the phenotype genotype relationship in SCAs. We reviewed the recent clinical advances, genetic features and phenotype-genotype correlations involving each SCA and its differentiation. The heterogeneity of the disease and the genetic diagnosis might be attributed to the regional distribution and clinical characteristics. Therefore, recognition of the phenotype-genotype relationship facilitates genetic testing, prognosis and monitoring of symptoms. PMID- 27220868 TI - Correlates of Worry About Health Care Costs Among Older Adults. AB - Although older adults in the United States incur more health care expenses than younger adults, little research has been done on their worry about health care costs. Using data from the 2013 National Health Interview Survey ( n = 7,253 for those 65+ years), we examined factors associated with older adults' health care cost worries, defined as at least a moderate level of worry, about ability to pay for normal health care and/or for health care due to a serious illness or accident. Bivariate analyses were used to compare worriers and nonworriers. Binary logistic regression analysis was used to examine the association of income, health status, health care service use, and insurance type with worry status. Older age and having Medicaid and Veterans Affairs (VA)/military health benefits were associated with lower odds of worry, while low income, chronic pain, functional limitations, psychological distress, and emergency department visits were associated with higher odds. Practice and policy implications for the findings are discussed. PMID- 27220867 TI - Accounting for dropout in xenografted tumour efficacy studies: integrated endpoint analysis, reduced bias and better use of animals. AB - PURPOSE: Xenograft studies are commonly used to assess the efficacy of new compounds and characterise their dose-response relationship. Analysis often involves comparing the final tumour sizes across dose groups. This can cause bias, as often in xenograft studies a tumour burden limit (TBL) is imposed for ethical reasons, leading to the animals with the largest tumours being excluded from the final analysis. This means the average tumour size, particularly in the control group, is underestimated, leading to an underestimate of the treatment effect. METHODS: Four methods to account for dropout due to the TBL are proposed, which use all the available data instead of only final observations: modelling, pattern mixture models, treating dropouts as censored using the M3 method and joint modelling of tumour growth and dropout. The methods were applied to both a simulated data set and a real example. RESULTS: All four proposed methods led to an improvement in the estimate of treatment effect in the simulated data. The joint modelling method performed most strongly, with the censoring method also providing a good estimate of the treatment effect, but with higher uncertainty. In the real data example, the dose-response estimated using the censoring and joint modelling methods was higher than the very flat curve estimated from average final measurements. CONCLUSIONS: Accounting for dropout using the proposed censoring or joint modelling methods allows the treatment effect to be recovered in studies where it may have been obscured due to dropout caused by the TBL. PMID- 27220869 TI - Preparations for Old Age and Well-Being in Later Life in Thailand: Gender Matters? AB - Data from the 2011 Survey of Older Persons in Thailand examines the association between preparations for old age (financial, health, caregiving, living arrangements, and spiritual) and three measures of well-being: financial satisfaction, life satisfaction, and physical health. The study further explores the role of social stratification and the gendered nature of these relationships. The sample ( N = 10,235) is restricted to adults 60 years and above, who are retired and answered the survey independently. Multivariate logistic regression analyses indicate that different forms of preparation are positively associated with post-retirement well-being for men and women but socioeconomic resources are positively associated with all three well-being outcomes. Furthermore, for women, there are significant negative interaction effects of income and financial preparation on life satisfaction, as well as negative interaction effects of disability and caregiver preparation on self-rated health. Implications for long term care, socioeconomic inequality, and gender inequality in paid labor are discussed. PMID- 27220870 TI - Endovascular treatment for ruptured and unruptured vertebral artery dissecting aneurysms: a meta-analysis. AB - BACKGROUND: Different endovascular modalities have been applied to the treatment of vertebral artery dissecting aneurysms, the most commonly used being internal trapping and stent-assisted coiling, although the ideal treatment remains controversial. OBJECTIVE: To perform a meta-analysis to study clinical outcomes of patients with vertebral artery dissecting aneurysms who were treated with internal trapping or stent-assisted coiling. MATERIALS AND METHODS: We conducted a meta-analysis of eight retrospective studies that compared internal trapping with stent-assisted coiling for the treatment of vertebral artery dissecting aneurysms. The primary outcomes of this study were immediate occlusion, long-term occlusion, good outcome ratio, perioperative mortality, and angiographic recurrence. Subgroup analyses were conducted of patients with ruptured versus unruptured vertebral artery dissecting aneurysms. RESULTS: Eight studies comprising a total of 188 patients were included in the analysis. For ruptured cases, in comparison with stent-assisted coiling groups, the patients treated with trapping techniques had a higher rate of immediate postoperative occlusion (OR=0.165; 95% CI 0.067 to 0.405; p<0.01), although there was no significant difference in long-term occlusion (OR=1.059; 95% CI 0.033 to 34.121; p=0.974), good clinical outcome rates, recurrence rates, and perioperative mortality. For unruptured cases, patients in the trapping groups also had higher immediate occlusion rates than those who underwent stent-assisted coiling (OR=0.175; 95% CI 0.043 to 0.709; p=0.015), while rates of both recurrence and good clinical outcome were similar between the two groups. CONCLUSIONS: Both internal trapping and stent-assisted coiling are technically feasible for ruptured vertebral artery dissecting aneurysms, with high rates of good long-term neurologic outcomes and low recurrence and mortality rates. For unruptured aneurysms, conservative treatment is recommended. When a posterior inferior cerebellar artery (PICA) origin is involved, bypass surgery or vertebral artery-to-PICA stent placement plus coil embolization should be considered. PMID- 27220871 TI - Auditory neuropathy spectrum disorder (ANSD) in referrals from neonatal hearing screening at a well-baby clinic. AB - Auditory neuropathy spectrum disorder (ANSD) is a particular kind of hearing disorder characterised by normal outer hair cell function and abnormal or absent auditory brain stem responses. Little data are available regarding the prevalence of this condition in healthy newborns. We performed a retrospective medical records review of 791 referrals from universal neonatal hearing screening (UNHS) at a well-baby clinic to investigate the prevalence of ANSD. Hearing screening was performed by automated auditory brain stem response (ABR) testing. A diagnosis of ANSD was established when ABR tracings were absent in the presence of otoacoustic emissions and/or a cochlear microphonic. Amongst 201 infants with confirmed congenital hearing loss, 13 infants were diagnosed with ANSD. The condition was unilateral in six and bilateral in seven infants. A risk factor for hearing loss could be identified in three infants. Abnormalities on magnetic resonance imaging were found in six infants; five of them had cochlear nerve deficiency. CONCLUSION: The prevalence of ANSD was 6.5 % amongst well babies with confirmed congenital hearing loss identified through UNHS. The estimated incidence of ANSD in our population of newborns at the well-baby clinic was 0.09/1000 live births. Magnetic resonance revealed an underlying anatomical abnormality in about half of the patients. WHAT IS KNOWN: * Auditory neuropathy dyssynchrony spectrum disorder (ANSD) is a particular form of hearing loss, mostly encountered in neonatal intensive care unit (NICU) graduates. * Little data are available on the prevalence and risk factors for ANSD in healthy newborns. What is new: * The estimated prevalence of ANSD in healthy newborns is 0.09/1000 live births. * In about half of the healthy newborns with ANSD, a structural abnormality was detected on magnetic resonance imaging of the posterior fossa/brain. PMID- 27220872 TI - Astragalus polysaccharide protects human cardiac microvascular endothelial cells from hypoxia/reoxygenation injury: The role of PI3K/AKT, Bax/Bcl-2 and caspase-3. AB - In the present study, the mechanisms associated with the Astragalus polysaccharide (APS)-mediated protection of human cardiac microvascular endothelial cells (HCMEC) against hypoxia/reoxygenation (HR) injury were investigated. Pretreatment of HCMECs with APS at various concentrations was performed prior to Na2S2O4-induced HR injury. Subsequently, cell viability and apoptosis were measured by MTT and Hoechst assays, respectively. The viability of HCMECs was reduced by Na2S2O4 and apoptosis was enhanced; however, cell viability was observed to be increased by APS via inhibition of apoptosis. Additionally, intracellular reactive oxygen species (ROS), Ca2+, nitric oxide (NO), malondialdehyde (MDA), superoxide dismutase (SOD), phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT), B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein (Bax) and caspase-3 were measured using detection kits or western blot analysis. In HCMECs with HR injury, the levels of ROS and Ca2+, MDA and Bax expression levels, and the activity of caspase-3 were elevated. By contrast, the level of NO, the protein expression levels of SOD, Bcl-2 and PI3K, and the phosphorylation of AKT were decreased. However, compared with the HR group, the effects of HR injury were significantly reduced by APS, with APS providing a protective effect on HCMECs, particularly at higher doses. The current study concluded that APS protects HCMECs from Na2S2O4-induced HR injury by reducing the levels of ROS, Ca2+, MDA and Bax, inhibiting the activity of caspase-3, and enhancing the levels of NO, SOD, Bcl-2, PI3K and phosphorylated AKT. These results may provide an insight into the clinical application of APS and novel therapeutic strategies for HR injury. PMID- 27220873 TI - Is adherence to diet, physical activity, and body weight cancer prevention recommendations associated with colorectal cancer incidence in African American women? AB - PURPOSE: The purpose of this study was to evaluate whether adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations was associated with colorectal cancer incidence in the Black Women's Health Study (BWHS). METHODS: In this ongoing prospective cohort of African American women (analytic cohort n = 49,103), 354 incident colorectal cancers were diagnosed between baseline (1995) and 2011. Adherence scores for seven WCRF/AICR recommendations (adherent = 1 point, non-adherent level 1 = 0.5 points, non-adherent level 2 = 0 points) were created using questionnaire data and summed to an overall adherence score (maximum = 7). Recommendation adherence and colorectal cancer incidence were evaluated using baseline and time-varying data in Cox regression models. RESULTS: At baseline, 8.5 % of women adhered >4 recommendations. In time-varying analyses, the HR was 0.98 (95 % CI 0.84-1.15) per 0.5 point higher score and 0.51 (95 % CI 0.23-1.10) for adherence to >4 compared to <3 recommendations. Adherence to individual recommendations was not associated with colorectal cancer risk. Results were similar in models that considered baseline exposures only. CONCLUSIONS: Adherence to cancer prevention recommendations was low and not associated with colorectal cancer risk among women in the BWHS. Research in diverse populations is essential to evaluate the validity of existing recommendations, and assess whether there are alternative recommendations that are more beneficial for cancer prevention in specific populations. PMID- 27220874 TI - Do Intron and Coding Sequences of Some Human-Mouse Orthologs Evolve as a Single Unit? AB - It has been previously suggested that both the coding and the associated non coding sequences of some human-mouse orthologs could evolve as a single unit. This letter deals with the observation that between mouse and humans some orthologs change significantly their compositional features as an indication that the molecular evolution is a local process. Moreover, the data shown indicate that the coding and the intron sequences of these orthologs do not evolve independently but instead both undergo a concerted evolution, evolving as a single unit, from a compositional cluster in mouse to a different compositional cluster in human. PMID- 27220875 TI - The PsbY protein of Arabidopsis Photosystem II is important for the redox control of cytochrome b559. AB - Photosystem II is a protein complex embedded in the thylakoid membrane of photosynthetic organisms and performs the light driven water oxidation into electrons and molecular oxygen that initiate the photosynthetic process. This important complex is composed of more than two dozen of intrinsic and peripheral subunits, of those half are low molecular mass proteins. PsbY is one of those low molecular mass proteins; this 4.7-4.9kDa intrinsic protein seems not to bind any cofactors. Based on structural data from cyanobacterial and red algal Photosystem II PsbY is located closely or in direct contact with cytochrome b559. Cytb559 consists of two protein subunits (PsbE and PsbF) ligating a heme-group in-between them. While the exact function of this component in Photosystem II has not yet been clarified, a crucial role for assembly and photo-protection in prokaryotic complexes has been suggested. One unique feature of Cytb559 is its redox heterogeneity, forming high, medium and low potential, however, neither origin nor mechanism are known. To reveal the function of PsbY within Photosystem II of Arabidopsis we have analysed PsbY knock-out plants and compared them to wild type and to complemented mutant lines. We show that in the absence of PsbY protein Cytb559 is only present in its oxidized, low potential form and plants depleted of PsbY were found to be more susceptible to photoinhibition. PMID- 27220876 TI - Computational simulation of bone fracture healing under inverse dynamisation. AB - Adaptive finite element models have allowed researchers to test hypothetical relationships between the local mechanical environment and the healing of bone fractures. However, their predictive power has not yet been demonstrated by testing hypotheses ahead of experimental testing. In this study, an established mechano-biological scheme was used in an iterative finite element simulation of sheep tibial osteotomy healing under a hypothetical fixation regime, "inverse dynamisation". Tissue distributions, interfragmentary movement and stiffness across the fracture site were compared between stiff and flexible fixation conditions and scenarios in which fixation stiffness was increased at a discrete time-point. The modelling work was conducted blind to the experimental study to be published subsequently. The simulations predicted the fastest and most direct healing under constant stiff fixation, and the slowest healing under flexible fixation. Although low fixation stiffness promoted more callus formation prior to bridging, this conferred little additional stiffness to the fracture in the first 5 weeks. Thus, while switching to stiffer fixation facilitated rapid subsequent bridging of the fracture, no advantage of inverse dynamisation could be demonstrated. In vivo data remains necessary to conclusively test this treatment protocol and this will, in turn, provide an evaluation of the model's performance. The publication of both hypotheses and their computational simulation, prior to experimental testing, offers an appealing means to test the predictive power of mechano-biological models. PMID- 27220877 TI - Resolution recovery and noise regularization in nuclear cardiology. PMID- 27220878 TI - Successful innovation: A time for change? AB - Innovation plays an important role in the advancement of nuclear cardiology, meeting the need for reduced exposure to radiation, and maintaining and improving image quality. As we innovate, it is important to understand the impact of these improvements on the clinical and research knowledge base that has made nuclear cardiology such a powerful clinical tool. The need for comparative studies insuring stability in the clinical applicability of our current guidelines and use of the prognostic power of radionuclide myocardial perfusion imaging in clinical practice is essential for new and innovative techniques. The existing data demonstrating the significant differences that can occur with the innovative techniques is explored. The need for tools to insure comparable data is available as we begin to utilize registries to inform our clinical practice and research will be an important part of the future of nuclear cardiology. PMID- 27220879 TI - Advances in image reconstruction software in nuclear cardiology: Is all that glitters gold? AB - The cornerstone results of nuclear cardiology in the last 25 years were obtained with the Filtered Back Projection as the preferred reconstruction method for tomographic studies. Recently, evolution of the OSEM iterative reconstruction algorithms was implemented by different vendors. The value and limitations of the new methods are briefly addressed. PMID- 27220880 TI - Molecular diagnostic toolkit for Rhizophagus irregularis isolate DAOM-197198 using quantitative PCR assay targeting the mitochondrial genome. AB - Rhizophagus irregularis (previously named Glomus irregulare) is one of the most widespread and common arbuscular mycorrhizal fungal (AMF) species. It has been recovered worldwide in agricultural and natural soils, and the isolate DAOM 197198 has been utilized as a commercial inoculant for two decades. Despite the ecological and economical importance of this taxon, specific markers for quantification of propagules by quantitative real-time PCR (qPCR) are extremely limited and none have been rigorously validated for quality control of manufactured products such as biofertilizers. From the sequencing of 14 complete AMF mitochondrial (mt) genomes, a qPCR assay using a hydrolysis probe designed in the single copy cox3-rnl intergenic region was tested and validated to specifically and accurately quantify the spores of R. irregularis isolate DAOM 197198. Specificity tests were performed using standard PCR and qPCR, and results clearly showed that the primers specifically amplified the isolate DAOM-197198, yielding a PCR product of 106 bp. According to the qPCR analyses on spores produced in vitro, the average copy number of mt genomes per spore was 3172 +/- 304 SE (n = 6). Quantification assays were successfully undertaken on known and unknown samples in liquid suspensions and commercial dry formulations to show the accuracy, precision, robustness, and reproducibility of the qPCR assay. This study provides a powerful molecular toolkit specifically designed to quantify spores of the model AMF isolate DAOM-197198. The approach of molecular toolkit used in our study could be applied to other AMF taxa and will be useful to research institutions and governmental and industrial laboratories running routine quality control of AMF-based products. PMID- 27220882 TI - Improving resolution in quantum subnanometre-gap tip-enhanced Raman nanoimaging. AB - Two-dimensional (2D) materials beyond graphene such as transition metal dichalcogenides (TMDs) have unique mechanical, optical and electronic properties with promising applications in flexible devices, catalysis and sensing. Optical imaging of TMDs using photoluminescence and Raman spectroscopy can reveal the effects of structure, strain, doping, edge states, and surface functionalization from materials to bioscience. However, Raman signals are inherently weak and so far have been limited in spatial resolution in TMDs to a few hundred nanometres which is much larger than the intrinsic scale of these effects. Here we overcome the diffraction limit by using resonant tip-enhanced Raman scattering (TERS) of few-layer MoS2, and obtain nanoscale optical images with ~20 nm spatial resolution. This becomes possible due to electric field enhancement in an optimized subnanometre-gap resonant tip-substrate configuration. We investigate the limits of signal enhancement by varying the tip-sample gap with sub-Angstrom precision and observe a quantum quenching behavior, as well as a Schottky-Ohmic transition, for subnanometre gaps, which enable surface mapping based on this new contrast mechanism. This quantum regime of plasmonic gap-mode enhancement with a few nanometre thick MoS2 junction may be used for designing new quantum optoelectronic devices and sensors with a wide range of applications. PMID- 27220881 TI - Simultaneous multislice magnetic resonance fingerprinting (SMS-MRF) with direct spiral slice-GRAPPA (ds-SG) reconstruction. AB - PURPOSE: To develop a reconstruction method to improve SMS-MRF, in which slice acceleration is used in conjunction with highly undersampled in-plane acceleration to speed up MRF acquisition. METHODS: In this work two methods are employed to efficiently perform the simultaneous multislice magnetic resonance fingerprinting (SMS-MRF) data acquisition and the direct-spiral slice-GRAPPA (ds SG) reconstruction. First, the lengthy training data acquisition is shortened by employing the through-time/through-k-space approach, in which similar k-space locations within and across spiral interleaves are grouped and are associated with a single set of kernel. Second, inversion recovery preparation (IR prepped), variable flip angle (FA), and repetition time (TR) are used for the acquisition of the training data, to increase signal variation and to improve the conditioning of the kernel fitting. RESULTS: The grouping of k-space locations enables a large reduction in the number of kernels required, and the IR-prepped training data with variable FA and TR provide improved ds-SG kernels and reconstruction performance. With direct-spiral slice-GRAPPA, tissue parameter maps comparable to that of conventional MRF were obtained at multiband (MB) = 3 acceleration using t-blipped SMS-MRF acquisition with 32-channel head coil at 3 Tesla (T). CONCLUSIONS: The proposed reconstruction scheme allows MB = 3 accelerated SMS-MRF imaging with high-quality T1 , T2 , and off-resonance maps, and can be used to significantly shorten MRF acquisition and aid in its adoption in neuro-scientific and clinical settings. Magn Reson Med 77:1966-1974, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27220883 TI - Fibrin Glue Spray as a Simple and Promising Method to Prevent Bleeding after Gastric Endoscopic Submucosal Dissection. AB - AIM: This study was conducted to evaluate the effectiveness of fibrin glue (FG) in preventing delayed bleeding after gastric endoscopic submucosal dissection (ESD). METHODS: From 2011 to 2014, 423 patients undergoing gastric ESDs were studied retrospectively. After excluding 26 patients, 397 were enrolled. The post ESD wounds were treated with only coagrasper/clips before April 2013. After that, additional FG spray was utilized for wound closure. The post-ESD bleeding rates were compared between the FG group (patients with postoperative use of FG) and the non-FG group (patients without the use of FG). RESULTS: A total of 397 lesions were successfully resected from 397 patients. The FG group significantly had more risk factors predisposing to delayed bleeding, such as advanced age, larger specimen size, more cancerous lesions and longer operation time. There was no significant difference in gender, comorbidity, lesion locations, numbers of coagrasper and hemoclips used between the 2 groups. The total rate of delayed bleeding was 4.53% (18/397). There were 18 cases of delayed bleeding (5.98%) in the non-FG group and none in the FG group (p = 0.03). Univariate analysis showed that FG reduced the risk of delayed bleeding significantly (p = 0.03). CONCLUSION: FG was simple and effective in preventing delayed bleeding after gastric ESDs. PMID- 27220884 TI - The influence of dopant concentration on temperature dependent emission spectra in LiLa1-x-yEuxTbyP4O12 nanocrystals: toward rational design of highly-sensitive luminescent nanothermometers. AB - Luminescence nanothermometry is gaining great interest, and different excitation and readout schemes have been sought to improve temperature sensitivity and sensing range, or to simplify the readout. Although many up-conversion based nanothermometers have been studied, Tb(3+) and Eu(3+) doped systems have not been widely considered, so far. Herein, we report the synthesis of new LiLa1-x yEuxTbyP4O12 nanocrystals for luminescent thermal sensing; their spectroscopic properties have been investigated in a wide range of compositions and temperatures. In particular, the impact of dopant concentration on energy transfer processes (such as energy transfer, back energy transfer, energy diffusion and cross relaxation) is presented in a quantitative manner, both experimentally and theoretically, which enables the intentional optimization of the composition to find the finest balance between temperature sensitive excitation and depletion phenomena, and thus, enhance the luminescent thermometry properties. The studied thermometers can be applied in as wide a temperature range as 77-600 K, where they demonstrate sensitivity up to 1% K(-1), which is the highest among the Tb(3+) and Eu(3+) doped inorganic phosphor based materials, to date. PMID- 27220885 TI - Polycystic ovary syndrome (PCOS) and the risk of coronary heart disease (CHD): a meta-analysis. AB - Some studies reported a significant association between polycystic ovary syndrome (PCOS) and risk of cardiovascular disease (CVD). However, the results are controversial. A systematic search was conducted in the PubMed, Science Direct, EMBASE, and Cochrane Library databases. Five case-control studies and 5 cohort studies were selected, involving a total of 104392 subjects in this meta analysis. PCOS was significantly associated with the increased risk of CVD (OR = 1.30; 95% CI 1.09 - 1.56; P = 0.004). In the subgroup analysis of study design, both case-control studies and prospective cohort studies showed significant results (OR = 1.79; 95% CI 1.16 - 2.77; P = 0.009; OR = 1.20; 95% CI 1.06 - 1.37; P = 0.005), while retrospective cohort studies did not show positive result (OR = 0.91; 95% CI 0.60 - 1.40; P = 0.68). In a further stratified analysis by type of CVD, a significant association was found between PCOS and coronary heart disease (CHD) (OR = 1.44; 95% CI 1.13 - 1.84; P = 0.004). However, no significant association was observed between PCOS and myocardial infarction (MI) (OR = 1.01; 95% CI 0.68 - 1.51; P = 0.95). In conclusion, this meta-analysis suggested that PCOS is significantly associated with increased CHD risk. PMID- 27220886 TI - Expression of the receptor for hyaluronic acid mediated motility (RHAMM) is associated with poor prognosis and metastasis in non-small cell lung carcinoma. AB - The receptor for hyaluronic acid-mediated motility (RHAMM) is upregulated in various cancers, but its role in primary and metastatic non-small cell lung carcinoma (NSCLC) remains to be determined. Here, we investigate the clinical relevance of RHAMM expression in NSCLC. RHAMM protein expression correlates with histological differentiation stages and extent of the primary tumor (T stages) in 156 patients with primary NSCLC. Importantly, while focal RHAMM staining pattern is present in 57% of primary NSCLC, intense RHAMM protein expression is present in 96% of metastatic NSCLC cases. In a publicly available database, The Cancer Genome Atlas (TCGA), RHAMM mRNA expression is 12- and 10-fold higher in lung adenocarcinoma and squamous lung carcinoma than in matched normal lung tissues, respectively. RHAMM mRNA expression correlates with stages of differentiation and inferior survival in more than 400 cases of lung adenocarcinoma in the Director's Challenge cohort. Of 4 RHAMM splice variants, RHAMMv3 (also known as RHAMMB) is the dominant variant in NSCLC. Moreover, shRNA-mediated knockdown of RHAMM reduced the migratory ability of two lung adenocarcinoma cell lines, H1975 and H3255. Taken together, RHAMM, most likely RHAMMv3 (RHAMMB), can serve as a prognostic factor for lung adenocarcinomas and a potential therapeutic target in NSCLC to inhibit tumor migration. PMID- 27220887 TI - Transcriptome sequencing identified hub genes for hepatocellular carcinoma by weighted-gene co-expression analysis. AB - Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and it remains a challenge to understand the genetic mechanisms underlying hepatocarcinogenesis. A global gene network of differential expression profiles in HCC has yet to be fully characterized. In the present study, we performed transcriptome sequencing (mRNA and lncRNA) in liver cancer and cirrhotic tissues of nine HCC patients. We identified differentially expressed genes (DEGs) and constructed a weighted gene co-expression network for the DEGs. In total, 755 DEGs (747 mRNA and eight lncRNA) were identified, and several co-expression modules were significantly associated with HCC clinical traits, including tumor location, tumor grade, and the alpha-fetoprotein (AFP) level. Of note, we identified 15 hub genes in the module associated with AFP level, and three (SPX, AFP and ADGRE1) of four hub genes were validated in an independent HCC cohort (n=78). Identification of hub genes for HCC clinical traits has implications for further understanding of the molecular genetic basis of HCC. PMID- 27220888 TI - Suppression of progranulin expression inhibits bladder cancer growth and sensitizes cancer cells to cisplatin. AB - We have recently demonstrated a critical role for progranulin in bladder cancer. Progranulin contributes, as an autocrine growth factor, to the transformed phenotype by modulating Akt-and MAPK-driven motility, invasion and anchorage independent growth. Progranulin also induces F-actin remodeling by interacting with the F-actin binding protein drebrin. In addition, progranulin is overexpressed in invasive bladder cancer compared to normal tissue controls, suggesting that progranulin might play a key role in driving the transition to the invasive phenotype of urothelial cancer. However, it is not established whether targeting progranulin could have therapeutic effects on bladder cancer. In this study, we stably depleted urothelial cancer cells of endogenous progranulin by shRNA approaches and determined that progranulin depletion severely inhibited the ability of tumorigenic urothelial cancer cells to migrate, invade and grow in anchorage-independency. We further demonstrate that progranulin expression is critical for tumor growth in vivo, in both xenograft and orthotopic tumor models. Notably, progranulin levels correlated with response to cisplatin treatment and were upregulated in bladder tumors. Our data indicate that progranulin may constitute a novel target for therapeutic intervention in bladder tumors. In addition, progranulin may serve as a novel biomarker for bladder cancer. PMID- 27220889 TI - Identification of FRA-1 as a novel player in pancreatic cancer in cooperation with a MUC1: ERK signaling axis. AB - The MUC1 glycoprotein is overexpressed and aberrantly glycosylated in >90% of pancreatic ductal adenocarcinoma cases and impacts tumor progression by initiating downstream signaling through phosphorylation of its cytoplasmic tail. Previous studies have demonstrated that MUC1 alters expression of known targets of activator protein 1 (AP-1); however, no studies have evaluated the precise impact of MUC1 signaling on the activity and formation of AP-1. Given the known role of these proteins in modulating migration, invasion, and tumor progression, we explored the effects of MUC1 on AP-1 dimer formation and function. We determined that MUC1 increased the protein levels of c-Jun, the major component of AP-1, and promoted dimerization of c-Jun with the Fos-protein FRA-1. We demonstrate that FRA-1 acts as a potent mediator of migration and invasion in a manner that is modulated by signals through MUC1, which acts as a dominant regulator of specific AP-1 and FRA-1 target genes. Our results provide the first in vivo evidence of a FRA-1 mediated expression profile that impacts pancreatic tumor growth properties. In summary, we show that MUC1 enhancement of ERK activation influences FRA-1 activity to modulate tumor migration, invasion and metastasis in a subset of pancreatic cancer cases. PMID- 27220890 TI - Effect of CYP1A1 gene polymorphism and psychological distress on seminal analysis parameters. AB - BACKGROUND: Psychological factor alters fertility hormones and contributes to male infertility. Anxiety and depression are common manifestations of psychological distress. Cytochrome P-4501A1 (CYP1A1) metabolizes xenobiotics and fertility hormones that influence male fertility. The effect of CYP1A1 polymorphism on male fertility has remained controversial. The present study was designed to assess the effect of psychological distress and CYP1A1 polymorphisms and their interactions on parameters of seminal analysis. METHODS: Eighty male partners of infertile couples were evaluated for level of distress using Hospital anxiety and depression score (HADS) questionnaire. As per WHO guidelines (2010), sperm count, motility and morphology were assessed and subjects were classified as (a) subjects having normal sperm characteristics and (b) subjects having abnormal sperm characteristics. CYP1A1 polymorphisms were detected by ASO-PCR. RESULTS: The significant odd's ratio indicates that psychological distress (OR:10.54; CI:3.72-29.84; P < 0.001), CYP1A1*4(OR:10.31; CI:3.01-35.24; P < 0.001) and CYP1A1*2C (OR:7.01; CI:1.78-27.56; P = 0.002) polymorphisms are risk factors for the development of abnormal sperm characteristics in male subjects. Data analysis with two way ANOVA shows that psychological distress, CYP1A1*4 and CYP1A1*2C polymorphisms significantly affect but do not interact among them to influence sperm parameters. CONCLUSIONS: It is concluded that CYP1A1 gene polymorphisms and psychological distress act independently but do not interact with each other in pathogenesis of male infertility. PMID- 27220891 TI - [More than just "stones" : On the history of urology in Regensburg]. AB - In recent years the regional aspects of medical history in the field of urology have been more intensively studied. There is already an interesting study on the history of urology in Rhineland. This article examines the checkered medical history aspects concerning urology in provincial areas of Germany, exemplified by the Bavarian town of Regensburg. The article combines the history of the over 1800-year-old town of Regensburg, one of the oldest German communities, with selected aspects of medical history and follows the route of "stones" from antiquity to the present day. The article explains what Regensburg, Galen of Pergamon and his professional colleagues from antiquity have in common, why monastery medicine was so successful here, how syphilis patients were treated in imperial cities (Reichsstadte), why one of the greatest "stone cutters" of the era met with an accident in the perpetual Reichstag town of Regensburg and how a main department of urology was finally founded after a delay but ultimately with tempo, which in 2003 led to the establishment of the most recent chair for urology in Germany. PMID- 27220892 TI - [Retroperitoneal tumors]. AB - BACKGROUND: Retroperitoneal tumors are rare malignancies. The retroperitoneum can host a wide spectrum of pathologies including primary or metastatic lesions. OBJECTIVE: Treatment of retroperitoneal tumors is often associated with several challenges because of their relative late presentation and anatomic location. MATERIALS AND METHODS: Because of various pathologies, a detailed case history, laboratory investigation and ultrasound should be performed. Radiologic examinations remain a major component in the diagnosis. In addition to computed tomography, magnetic resonance imaging and positron emission tomography are used. Although radiologic findings are often unspecific, there are often typical findings such as dissemination, margins, vascularization and tumor texture which contribute to the differential diagnosis even before making a definitive diagnosis. Due to the complexity of primary retroperitoneal tumors, which require different treatments depending on the final diagnosis, the treatment approach should be determined in a multidisciplinary tumor conference prior to histological confirmation and initiation of treatment. CONCLUSION: To ensure the best potential curative treatment modality for retroperitoneal tumors, treatment is best performed in high-volume centers by a multidisciplinary team. PMID- 27220893 TI - [Diagnosis and treatment of retroperitoneal abscesses]. AB - BACKGROUND: Retroperitoneal abscesses are rare but life threatening. Renal, perinephritic, and paranephritic abscesses are distinguished depending on their location and extent. They are mainly caused by ascending urologic infections of gram-negative bacteria. SYMPTOMATOLOGY: The variable symptomatology often leads to delayed diagnosis resulting in high morbidity and mortality. Typical symptoms are flank or abdominal pain, decreased appetite, weight loss, malaise, fever, and chills. Laboratory values show increased leukocytes and C-reactive protein. Creatinine levels may also be increased. CONCLUSION: If there is clinical evidence for a retroperitoneal abscess, sonography generally leads to further diagnostic via computed tomography. Small abscesses may be treated by antibiotics alone. Abscesses larger than 3 cm and those not responding to medical treatment should be percutaneously or surgically drained. PMID- 27220894 TI - Serum Level of Trefoil Factor 2 can Predict the Extent of Gastric Spasmolytic Polypeptide-Expressing Metaplasia in the H. pylori-Infected Gastric Cancer Relatives. AB - BACKGROUND & AIMS: Gastric cancer has familial clustering in incidence, and the familial relatives of gastric cancer sufferers are prone to have spasmolytic polypeptide-expressing metaplasia (SPEM), and intestinal metaplasia (IM) after H. pylori infection. This study tested whether serum pepsinogen I/II and trefoil factor family (TFF) proteins can predict SPEM or IM in the H. pylori-infected relatives of patients with gastric cancer. METHODS: We prospectively enrolled 119 H. pylori-infected relatives of gastric cancer patients of noncardiac gastric cancer patients, who then received panendoscopy to obtain gastric biopsy to define the presence of corpus gastritis index (CGI), SPEM, and IM. The advanced SPEM in histology was defined by TFF2 immunohistochemistry. Each patient also had checkups of serum TFF2, TFF3, and pepsinogen I/II by enzyme-linked immunosorbent assay (ELISA). RESULTS: The 119 H. pylori-infected relatives included 61 with SPEM, and 34 with IM. The presence of either IM or SPEM was not related to the serum TFF2, TFF3, and pepsinogen I/II levels (p > .05). Serum TFF2 levels were higher in relatives with CGI who also had advanced SPEM (p = .032). For relatives without CGI, the elevated serum TFF2 levels correlated with higher H. pylori density and more severe gastritis in antrum (p = .001). CONCLUSION: The serum TFF2 level cannot predict SPEM or IM in H. pylori-infected relatives of patients with gastric cancer. For H. pylori-infected relatives with CGI, serum TFF2 levels may predict the advanced severity of SPEM. Elevated serum TFF2 levels may indicate severe H. pylori-related inflammation, at risk of development or progression of SPEM in relatives without CGI. PMID- 27220895 TI - Phylogenomic approaches to determine the zoonotic potential of Shiga toxin producing Escherichia coli (STEC) isolated from Zambian dairy cattle. AB - This study assessed the prevalence and zoonotic potential of Shiga toxin producing Escherichia coli (STEC) sampled from 104 dairy units in the central region of Zambia and compared these with isolates from patients presenting with diarrhoea in the same region. A subset of 297 E. coli strains were sequenced allowing in silico analyses of phylo- and sero-groups. The majority of the bovine strains clustered in the B1 'commensal' phylogroup (67%) and included a diverse array of serogroups. 11% (41/371) of the isolates from Zambian dairy cattle contained Shiga toxin genes (stx) while none (0/73) of the human isolates were positive. While the toxicity of a subset of these isolates was demonstrated, none of the randomly selected STEC belonged to key serogroups associated with human disease and none encoded a type 3 secretion system synonymous with typical enterohaemorrhagic strains. Positive selection for E. coli O157:H7 across the farms identified only one positive isolate again indicating this serotype is rare in these animals. In summary, while Stx-encoding E. coli strains are common in this dairy population, the majority of these strains are unlikely to cause disease in humans. However, the threat remains of the emergence of strains virulent to humans from this reservoir. PMID- 27220896 TI - Exploratory behaviour and novel predator recognition: behavioural correlations across contexts. AB - It was hypothesized that the exploratory behaviour of an individual measured in a novel environment could predict its behaviour in response to a novel predator. This study examined novel predator recognition in the western mosquitofish Gambusia affinis, a species with individual differences in risk-taking, activity and exploration in novel environments. Prey responded with characteristic shoaling and avoidance in response to native predators, but did not show characteristic antipredator behaviour towards novel predators. Furthermore, G. affinis exhibited individual-level behavioural correlations across contexts but only when prey were tested with native predators. This could be the result of native predatory selection on behavioural correlations in the prey species. PMID- 27220897 TI - Prostate Specific Membrane Antigen Positron Emission Tomography May Improve the Diagnostic Accuracy of Multiparametric Magnetic Resonance Imaging in Localized Prostate Cancer. AB - PURPOSE: Positron emission tomography using ligands targeting prostate specific membrane antigen has recently been introduced. Positron emission tomography imaging with (68)Ga-PSMA-HBED-CC has been shown to detect metastatic prostate cancer lesions at a high rate. In this study we compare multiparametric magnetic resonance imaging and prostate specific membrane antigen positron emission tomography of the prostate with whole mount ex vivo prostate histopathology to determine the true sensitivity and specificity of these imaging modalities for detecting and locating tumor foci within the prostate. MATERIALS AND METHODS: In a prospective clinical trial setting 20 patients with localized prostate cancer and a planned radical prostatectomy were recruited. All patients underwent multiparametric magnetic resonance imaging and positron emission tomography before surgery, and whole mount histopathology slides were directly compared to the images. European Society of Urogenital Radiology guidelines for reporting magnetic resonance imaging were used as a template for regional units of analysis. The uropathologist and radiologists were blinded to individual components of the study, and the final correlation was performed by visual and deformable registration analysis. RESULTS: A total of 50 clinically significant lesions were identified from the whole mount histopathological analysis. Based on regional analysis the sensitivity, specificity, positive predictive value and negative predictive value for multiparametric magnetic resonance imaging were 44%, 94%, 81% and 76%, respectively. With prostate specific membrane antigen positron emission tomography the sensitivity, specificity, positive predictive value and negative predictive value were 49%, 95%, 85% and 88%, respectively. Prostate specific membrane antigen positron emission tomography yielded a higher specificity and positive predictive value. CONCLUSIONS: A significant proportion of cancers are potentially missed and underestimated by both imaging modalities. Prostate specific membrane antigen positron emission tomography may be used in addition to multiparametric magnetic resonance imaging to help improve local staging in those patients undergoing retropubic radical prostatectomy. PMID- 27220899 TI - Estrogen Receptors and Chronic Venous Disease. AB - OBJECTIVE/BACKGROUND: Chronic venous disease (CVD) is a common and relevant problem affecting Western people. The role of estrogens and their receptors in the venous wall seems to support the major prevalence of CVD in women. The effects of the estrogens are mediated by three estrogen receptors (ERs): ERalpha, ERbeta, and G protein-coupled ER (GPER). The expression of ERs in the vessel walls of varicose veins is evaluated. METHODS: In this prospective study, patients of both sexes, with CVD and varicose veins undergoing open venous surgery procedures, were enrolled in order to obtain vein samples. To obtain control samples of healthy veins, patients of both sexes without CVD undergoing coronary artery bypass grafting with autologous saphenous vein were recruited (control group). Samples were processed in order to evaluate gene expression. RESULTS: Forty patients with CVD (10 men [25%], 30 women [75%], mean age 54.3 years [median 52 years, range 33-74 years]) were enrolled. Five patients without CVD (three men, two women [aged 61-73 years]) were enrolled as the control group. A significant increase of tissue expression of ERalpha, ERbeta and GPER in patients with CVD was recorded (p < .01), which was also related to the severity of venous disease. CONCLUSION: ERs seem to play a role in CVD; in this study, the expression of ERs correlated with the severity of the disease, and their expression was correlated with the clinical stage. PMID- 27220898 TI - HIV-dependent depletion of influenza-specific memory B cells impacts B cell responsiveness to seasonal influenza immunisation. AB - Infection with HIV drives significant alterations in B cell phenotype and function that can markedly influence antibody responses to immunisation. Anti retroviral therapy (ART) can partially reverse many aspects of B cell dysregulation, however complete normalisation of vaccine responsiveness is not always observed. Here we examine the effects of underlying HIV infection upon humoral immunity to seasonal influenza vaccines. Serological and memory B cell responses were assessed in 26 HIV+ subjects receiving ART and 30 healthy controls immunised with the 2015 Southern Hemisphere trivalent inactivated influenza vaccine (IIV3). Frequencies and phenotypes of influenza hemagglutinin (HA) specific B cells were assessed by flow cytometry using recombinant HA probes. Serum antibody was measured using hemagglutination inhibition assays. Serological responses to IIV3 were comparable between HIV+ and HIV- subjects. Likewise, the activation and expansion of memory B cell populations specific for vaccine component influenza strains was observed in both cohorts, however peak frequencies were diminished in HIV+ subjects compared to uninfected controls. Lower circulating frequencies of memory B cells recognising vaccine-component and historical influenza strains were observed in HIV+ subjects at baseline, that were generally restored to levels comparable with HIV- controls post-vaccination. HIV infection is therefore associated with depletion of selected HA-specific memory B cell pools. PMID- 27220900 TI - Efficacy of the GemOx-R regimen leads to the identification of Oxaliplatin as a highly effective drug against Mantle Cell Lymphoma. AB - Mantle Cell Lymphoma (MCL) is an aggressive lymphoma subtype that accounts for 6 8% of non-Hodgkin lymphomas. The disease is mostly incurable and characterized by a continuous pattern of relapse. Major changes have recently been implemented in the management of MCL, but continuous relapses still mark this disease as a challenge for clinicians. We previously reported the efficacy of GemOx-R (Gemcitabine, Oxaliplatin and Rituximab) in patients with refractory and relapsing MCL. We present results for a larger series with longer follow-up and including high-risk frontline patients, showing an overall response rate of 83%. The efficacy of each component of GemOx-R was evaluated in a panel of MCL cell lines. Also, patient-derived primary cells were used in ex vivo experiments. The results show that oxaliplatin has a profound effect on cellular viability and is the most effective drug within this regimen. We further present synergistic efficacy of oxaliplatin combined with cytarabine in MCL cells. Interestingly, this synergistic effect was not seen when cisplatin and cytarabine were combined, indicating that among the platinum-derived agents oxaliplatin may be the preferred approach. Taken together our findings suggest that oxaliplatin alone or combined with cytarabine could constitute an alternative backbone for MCL regimens. PMID- 27220901 TI - Adiponectin ameliorates the apoptotic effects of paraquat on alveolar type II cells via improvements in mitochondrial function. AB - Previous studies have demonstrated that excessive reactive oxygen/nitrogen species (ROS/RNS)-induced apoptosis is an important feature of the injury to the lung epithelium in paraquat (PQ) poisoning. However the precise mechanisms of PQ induced dysfunction of the mitochondria, where ROS/RNS are predominantly produced, remain to be fully elucidated. Whether globular adiponectin (gAd), a potent molecule protective to mitochondria, regulates the mitochondrial function of alveolar type II cells to reduce PQ-induced ROS/RNS production remains to be investigated. The current study aimed to investigate the precise mechanisms of PQ poisoning in the mitochondria of alveolar type II cells, and to elucidate the role of gAd in protecting against PQ-induced lung epithelium injury. Therefore, lung epithelial injury was induced by PQ co-culture of alveolar type II A549 cells for 24 h. gAd was administrated to and removed from the injured cells in after 24 h. PQ was observed to reduce cell viability and increase apoptosis by ~1.5 fold in A549 cells. The oxidative/nitrative stress, resulting from ROS/RNS and disordered mitochondrial function were evidenced by increased O2-., NO production and reduced mitochondrial membrane potential (DeltaPsi), adenosine 5' triphosphate (ATP) content in PQ-poisoned A549 cells. gAd treatment significantly reversed the PQ-induced cell injury and mitochondrial dysfunction in A549 cells. The protective effects of gAd were partly abrogated by an adenosine 5' monophosphate-activated protein kinase (AMPK) inhibitor, compound C. The results suggest that reduced DeltaPsi and ATP content may result in PQ-induced mitochondrial dysfunction of the lung epithelium, which constitutes a novel mechanism for gAd exerting pulmonary protection against PQ poisoning via AMPK activation. PMID- 27220902 TI - Friction behavior of self-ligating and conventional brackets with different ligature systems. AB - OBJECTIVES: Self-ligating brackets are widely believed to offer better clinical efficiency and, in particular, less friction. Thus, the goal of this in vitro investigation was to assess the friction behavior of different bracket/archwire/ligature combinations during simulated canine retraction. An important aspect of this work was to determine whether conventional bracket systems behave differently in passive or active self-ligating brackets used with a SlideTM ligature, an elastic ligature, or a steel ligature. METHODS: Three conventional (Contour, Class One; Discovery((r)), Dentaurum; Mystique MB, GAC) and six self-ligating (Carriere SL, Class One; ClarityTM SL, 3M Unitek; Damon3, Ormco; In-Ovation((r)) C, GAC; Speed Appliance, Speed SystemTM; QuicKlear((r)), Forestadent((r))) bracket systems were analyzed. All brackets featured a 0.022" slot (0.56 mm). Each conventional system was tested with a steel ligature (0.25 mm; Remanium((r)), Dentaurum), an elastic ligature (1.3 mm in diameter; Dentalastics, Dentaurum), and a modified elastic ligature (SlideTM; Leone((r))). Each combination was used with four archwires, including rectangular stainless steel (0.46 * 0.64 mm, 0.018 * 0.025", Dentaurum), rectangular nickel-titanium with Teflon coating (0.46 * 0.64 mm, 0.018 * 0.025", Forestadent((r))), round coaxial nickel-titanium (0.46 mm, 0.018", Speed), and half-round/half-square (D profile) stainless steel (0.46 mm, 0.018", Speed). In the orthodontic measurement and simulation system (OMSS), retraction of a canine was simulated on a Frasaco model replicated in resin. Based on the force systems, the respective friction values were determined. For each combination of materials, five brackets of the same type were tested and five single measurements performed. RESULTS: Friction values were found to vary distinctly with the different combinations, modifiers being the ligature systems and the archwire types. Any significant friction differences between the steel-ligated, SlideTM-ligated, and self-ligated brackets were sporadic. All three systems were associated with average friction values of 40 %. Active self-ligating brackets and elastic-ligated conventional brackets, by contrast, generally differed significantly from the three above-mentioned bracket systems and showed distinctly higher friction values averaging 59 and 67 %, respectively. CONCLUSIONS: While passive self-ligating bracket systems have frequently been touted as advantageous in the literature, they should not be regarded as the only favorable system. Steel-ligated and SlideTM-ligated conventional bracket systems are capable of offering similar friction performance. PMID- 27220904 TI - The effect of different beverages on the color and translucency of flowable composites. AB - This study examined the changes in color and translucency of flowable composites after immersion in different beverages. Thirty composite samples were prepared from four flowable composites (G-aenial Universal Flo, Filtek Ultimate, Esthelite Flow Quick, and Clearfil Majesty ES Flow) and a microhybrid composite (Filtek Z 250) and stored in distilled water at 37 degrees C for 24 h. The samples were randomly divided into seven groups and then immersed in different beverages (Red Bull, coffee, black tea, Pepsi Cola, orange juice, and distilled water) for 7 days. The CIE L*a*b* values of each sample were measured against white and black backgrounds using a spectrophotometer before and after immersion. Data were analyzed using two-way analysis of variance and Tukey's post-hoc test (p < 0.05). The color changes were significantly different among the composite materials after immersion in beverages (p < 0.05). Filtek Ultimate and Esthelite Flow Quick exhibited less discoloration than did G-aenial Universal Flo and Clearfil Majesty ES Flow. No significant difference was found between Filtek Z-250 and either Filtek Ultimate or Esthelite Flow Quick (p > 0.05). Among the beverages, black tea and coffee caused the highest discoloration of all the materials. Immersion in coffee and black tea resulted in the highest negative changes in the translucency of the materials. The degree of discoloration for the composite resins depended on the material used and drinking beverage. SCANNING 38:701-709, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27220903 TI - Melatonin protects podocytes from angiotensin II-induced injury in an in vitro diabetic nephropathy model. AB - Diabetic nephropathy (DN) is a severe renal disorder characterized by podocyte damage and accumulation of extracellular matrix leading to further glomerulosclerosis, possibly via the activation of inflammatory signaling and the generation of oxidative stress. Melatonin has been considered a robust anti oxidant, and is able to attenuate DN in several animal models. In the present study, cell viability was examined by CCK-8 assay. Cell apoptosis, intracellular reactive oxygen species and mitochondrial membrane potential (MMP) levels were measured by flow cytometry. Western blot analysis was performed to detect the expression of Nephrin, B cell lymphoma-2 (Bcl-2)-associated X protein (Bax), Bcl 2, Caspase-3, Janus kinase (JAK)2 and Signal transducer and activator of transcription (STAT)3 in podocytes. Based on an in vitro podocyte injury model, the present study found that the application of melatonin significantly reduced AngII-induced apoptosis and increased the proliferative rate of cells, as evidenced by decreased expression levels of apoptotic proteins, including Caspase 3 and Bax, and a change in the ratio of Bax/Bcl-2. Further investigation demonstrated that a reduction in oxidative stress and the recovery of mitochondrial function were involved in this protective effect. In addition, the Jak/STAT signaling pathway was inhibited, indicating that cytokine-mediated inflammation was also targeted by melatonin. The present study demonstrated for the first time, to the best our knowledge, that melatonin exerted an anti apoptotic effect in AngII-mediated podocyte injury, and indicates a possible mechanism to explain the protective effect of melatonin in DN. PMID- 27220905 TI - Catalytic asymmetric [3 + 3] annulation of cyclopropanes with mercaptoacetaldehyde. AB - A highly diastereo- and enantioselective [3 + 3] annulation of donor-acceptor cyclopropanes with mercaptoacetaldehyde has been developed. In the presence of a N,N'-dioxide-Sc(iii) complex as the catalyst, a number of aromatic substituted cyclopropyl ketones reacted with mercaptoacetaldehyde smoothly, providing the corresponding chiral tetrahydrothiopyranols in moderate yields with excellent ee (up to 99% ee) and dr values (up to >19 : 1). PMID- 27220907 TI - A high affinity phage-displayed peptide as a recognition probe for the detection of Salmonella Typhimurium. AB - Salmonellosis is one of the most common and widely distributed foodborne diseases. A sensitive and robust detection method of Salmonella Typhimurium (S. Typhimurium) in food can critically prevent a disease outbreak. In this work, the use of phage displayed peptides was explored for the detection of S. Typhimurium. A phage-displayed random dodecapeptide library was subjected to biopanning against lipopolysaccharide (LPS) of S. Typhimurium. The peptide NFMESLPRLGMH (pep49) derived from biopanning displayed a high affinity (25.8nM) for the LPS of S. Typhimurium and low cross-reactivity with other strains of Salmonella and related Gram-negative bacteria. Molecular insights into the interaction of pep49 with the LPS of S. Typhimurium was gleaned using atomistic molecular dynamics simulations and docking. It was deduced that the specificity of pep49 with S. Typhimurium LPS originated from the interactions of pep49 with abequose that is found only in the O-antigen of S. Typhimurium. Further, pep49 was able to detect S. Typhimurium at a LOD of 10(3) CFU/mL using ELISA, and may be a potential cost efficient alternative to antibodies. PMID- 27220906 TI - LINX(r), a novel treatment for patients with refractory asthma complicated by gastroesophageal reflux disease: a case report. AB - BACKGROUND: Gastroesophageal reflux disease is one of the most common comorbidities in patients with asthma. Gastroesophageal reflux disease can be linked to difficult-to-control asthma. Current management includes gastric acid suppression therapy and surgical antireflux procedures. The LINX(r) procedure is a novel surgical treatment for patients with gastroesophageal reflux disease refractory to medical therapy. To the best of our knowledge, we report the first case of successful treatment of refractory asthma secondary to gastroesophageal reflux disease using the LINX(r) procedure. CASE PRESENTATION: Our patient was a 22-year-old white woman who met the American Thoracic Society criteria for refractory asthma that had remained poorly controlled for 5 years despite progressive escalation to step 6 treatment as recommended by National Institutes of Health-National Asthma Education and Prevention Program guidelines, including high-dose oral corticosteroids, high-dose inhaled corticosteroid plus long-acting beta2-agonist, leukotriene receptor antagonist, and monthly omalizumab. Separate trials with azithromycin therapy and roflumilast did not improve her asthma control, nor did bronchial thermoplasty help. Additional consultations with two other university health systems left the patient with few treatment options for asthma, which included cyclophosphamide. Instead, the patient underwent a LINX(r) procedure after failure of maximal medical therapy for gastroesophageal reflux disease with the additional aim of improving asthma control. After she underwent LINX(r) treatment, her asthma improved dramatically and was no longer refractory. She had normal exhaled nitric oxide levels and loss of peripheral eosinophilia after LINX(r) treatment. Prednisone was discontinued without loss of asthma control. The only immediate adverse effects due to the LINX(r) procedure were bloating, nausea, and vomiting. CONCLUSIONS: LINX(r) is a viable alternative to the Nissen fundoplication procedure for the treatment of patients with gastroesophageal reflux disease and poorly controlled concomitant refractory asthma. PMID- 27220908 TI - EXPLORING DEPRESSION AMONGST KIDNEY TRANSPLANT RECIPIENTS: A LITERATURE REVIEW. AB - BACKGROUND: Despite the benefits of receiving a donor kidney, there is evidence of persistent depression amongst the transplant population. Healthcare professionals should endeavour to put in place strategies for the prevention, identification and management of depression. OBJECTIVES: To critically examine recent research concerning the prevalence, detection and impact of depression amongst kidney transplant recipients, leading to recommendations for practice improvement. DESIGN: The 'matrix method' was used to identify and review relevant literature. An online search was performed using three electronic databases: Cumulative Index to Nursing and Allied Health Literature (CINAHL), MEDLINE(r) and Web of Science. The search limits were that the papers reported the findings of primary research studies, published in English in a peer-reviewed journal; involved adult participants and were published between 2000 and 2015. Following critical appraisal of the included studies, a review matrix was produced that identified four emerging themes. RESULTS: The review confirmed that kidney transplant recipients experience less depression than those who receive other renal replacement therapies. However, depressive illness is still more common amongst kidney transplant recipients than the general population. There are many risk factors for depression and there is evidence of an association between depression and mortality in the transplant population. Routine screening for depression is highly recommended yet rarely seen in practice. CONCLUSION: Increasing awareness and educating healthcare professionals about depression amongst kidney transplant recipients is essential to allow for earlier identification and treatment. Screening could provide earlier detection of depression and allow for higher social and psychological support for these patients. Further intervention studies and longitudinal assessments would enhance the understanding of the development and effective management of depressive symptoms. PMID- 27220909 TI - A novel de novo mutation in LAMB3 causes localized hypoplastic enamel in the molar region. AB - Amelogenesis imperfecta (AI) is a collection of diseases characterized by hereditary enamel defects and is heterogeneous in genetic etiology and clinical phenotype. In this study, we recruited a nuclear AI family with a proband having unique irregular hypoplastic pits and grooves in all surfaces of the deciduous molar teeth but not in the deciduous anterior teeth. Based on the candidate gene approach, we screened the laminin subunit beta 3 (LAMB3) gene and identified a novel de novo mutation in the proband. The mutation was a frameshift mutation caused by a heterozygous 7-bp deletion in the last exon (c.3452_3458delAGAAGCG, p.Glu1151Valfs*57). This study not only expands the mutational spectrum of the LAMB3 gene causing isolated AI but also broadens the understanding of genotype phenotype correlations. PMID- 27220910 TI - Erratum to: Gene expression profiling of the venom gland from the Venezuelan mapanare (Bothrops colombiensis) using expressed sequence tags (ESTs). PMID- 27220911 TI - Abundance and Temperature Dependency of Protein-Protein Interaction Revealed by Interface Structure Analysis and Stability Evolution. AB - Protein complexes are major forms of protein-protein interactions and implement essential biological functions. The subunit interface in a protein complex is related to its thermostability. Though the roles of interface properties in thermal adaptation have been investigated for protein complexes, the relationship between the interface size and the expression level of the subunits remains unknown. In the present work, we studied this relationship and found a positive correlation in thermophiles rather than mesophiles. Moreover, we found that the protein interaction strength in complexes is not only temperature-dependent but also abundance-dependent. The underlying mechanism for the observed correlation was explored by simulating the evolution of protein interface stability, which highlights the avoidance of misinteraction. Our findings make more complete the picture of the mechanisms for protein complex thermal adaptation and provide new insights into the principles of protein-protein interactions. PMID- 27220912 TI - Wenyingzhuangia fucanilytica sp. nov., a sulfated fucan utilizing bacterium isolated from shallow coastal seawater. AB - A Gram-staining-negative, rod-shaped, strictly aerobic, non-flagellated, non gliding and yellow-pigmented bacterial strain, designated as strain CZ1127T, capable of utilizing sulfated fucan, was isolated from shallow coastal seawater of Jiaozhou Bay, Qingdao, PR China. Its taxonomic position was investigated by a polyphasic approach. CZ1127T grew at 15-37 degrees C (optimum, 25 degrees C), pH 5.5-9.0 (optimum, pH 6.5-7.5) and in the presence of 0-4 % (w/v) NaCl [optimum, 0-3 % (w/v)]. CZ1127T contained MK-6 as the sole menaquinone, and iso C15 : 0, iso-C17 : 0 3-OH, C16 : 1omega7c/C16 : 1omega6c and iso-C15 : 0 3-OH as its major fatty acids. The DNA G+C content of strain CZ1127T was 32.2 mol%. Phylogenetic analysis based on the 16S rRNA gene indicated that strain CZ1127T clustered with members of the genus Wenyingzhuangia and was closely related to Wenyingzhuangia marina CGMCC 1.12162T (97.4 % 16S rRNA gene sequence similarity) and Wenyingzhuangia gracilariae KCTC 42246T (96.1 %). The DNA-DNA relatedness between strain CZ1127T and W. marina CGMCC 1.12162T was 41.9+/-1.5 %. On the basis of the phenotypic, chemotaxonomic and phylogenetic data, CZ1127T represents a novel species of the genus Wenyingzhuangia, for which the name Wenyingzhuangia fucanilytica sp. nov. is proposed. The type strain is CZ1127T (=CCTCC AB 2015089T=KCTC 42864T). PMID- 27220913 TI - Sublethal dose of phoxim and Bombyx mori nucleopolyhedrovirus interact to elevate silkworm mortality. AB - BACKGROUND: Silkworm (Bombyx mori) is an economically important insect. It is relatively less resistant to certain chemicals and environment exposures such as pesticides and pathogens. After pesticide exposures, the silkworms are more susceptible to microbial infections. The mechanism underlying the susceptibility might be related to immune response and oxidative stress. RESULTS: A sublethal dose of phoxim combined with Bombyx mori nucleopolyhedrovirus (BmNPV) elevated the silkworm mortality at 96 h. We found a higher content of H2 O2 and increased levels of genes related to oxidative stress and immune response after treatment with a sublethal dose of phoxim for 24 h or 48 h. However, such response decreased with longer pesticide treatment. Mortality increased by 44% when B. mori was exposed to combined treatment with BmNPV and phoxim rather than BmNPV alone. The level of examined immune-related and oxidative-stress-related genes significantly decreased in the combined treatment group compared with the BmNPV group. Our results indicated that, with long-term exposure to pesticides such as OPs, even at sublethal dose, the oxidative stress response and immune responses in silkworm were inhibited, which may lead to further immune impairment and accumulation of oxidative stress, resulting in susceptibility to the virus and harm to the silkworm. CONCLUSION: Our study provided insights for understanding the susceptibility to pathogen after pesticide exposures, which may promote the development of better pesticide controls to avoid significant economic losses. (c) 2016 Society of Chemical Industry. PMID- 27220914 TI - Patients' assessment of quality of care in public tertiary hospitals with and without accreditation: comparative cross-sectional study. AB - AIM: To compare patients' assessment of quality of care provided by public tertiary hospitals grouped according to accreditation status. BACKGROUND: Healthcare institutions worldwide are increasingly adopting accreditation as continuing initiative aimed at improving structures, processes and outcomes associated with quality of care. Patients being recipients of health care need to participate in assessing the quality of care they experienced while confined for therapeutic management. DESIGN: Comparative, cross-sectional. METHOD: Data were collected from patients confined in public tertiary hospitals (n = 517 in four with accreditation and n = 542 in four without accreditation) in Riyadh, Saudi Arabia between February 2011-June 2011. Patients rated key performance indicators grouped under the dimensions of structure, process and outcome. Mann-Whitney U test, Spearman Correlation Coefficient and coefficient of determination were used in analysing data. RESULTS: Patients in accredited public tertiary hospitals perceived structure, outcome and overall quality of care statistically higher than patients in non-accredited hospitals. No statistical differences were found in process (access and communication) indicators. Accreditation status is marginally associated with structure; outcome; and overall quality of care. The proportion of variance in the ranks of accreditation status explained the proportion of variance in the ranks of structure; outcome; and overall quality of care. CONCLUSION: The results apparently showed better structure, outcome and overall quality of care in accredited hospitals. Accreditation's association in the overall quality of care apparently remained unclear. Further studies are needed to appreciate the contribution of accreditation. PMID- 27220915 TI - Magnetically induced electrostimulation of human osteoblasts results in enhanced cell viability and osteogenic differentiation. AB - The application of electromagnetic fields to support the bone-healing processes is a therapeutic approach for patients with musculoskeletal disorders. The ASNIS III s-series screw is a bone stimulation system providing electromagnetic stimulation; however, its influence on human osteoblasts (hOBs) has not been extensively investigated. Therefore, in the present study, the impact of this system on the viability and differentiation of hOBs was examined. We used the ASNIS-III s screw system in terms of a specific experimental test set-up. The ASNIS-III s screw system was used for the application of electromagnetic fields (EMF, 3 mT, 20 Hz) and electromagnetic fields combined with an additional alternating electric field (EMF + EF) (3 mT, 20 Hz, 700 mV). The stimulation of primary hOBs was conducted 3 times per day for 45 min over a period of 72 h. Unstimulated cells served as the controls. Subsequently, the viability, the gene expression of differentiation markers and pro-collagen type 1 synthesis of the stimulated osteoblasts and corresponding controls were investigated. The application of both EMF and EMF + EF using the ASNIS-III s screw system revealed a positive influence on bone cell viability and moderately increased the synthesis of pro-collagen type 1 compared to the unstimulated controls. Stimulation with EMF resulted in a slightly enhanced gene expression of type 1 collagen and osteocalcin; however, stimulation with EMF + EF resulted in a significant increase in alkaline phosphatase (1.4-fold) and osteocalcin (1.6 fold) levels, and a notable increase in the levels of runt-related transcription factor 2 (RUNX-2; 1.54-fold). Our findings demonstrate that stimulation with electromagnetic fields and an additional alternating electric field has a positive influence on hOBs as regards cell viability and the expression of osteoblastic differentiation markers. PMID- 27220916 TI - Integrating cell biology, image analysis, and computational mechanical modeling to analyze the contributions of cellulose and xyloglucan to stomatal function. AB - Cell walls are likely to be essential determinants of the amazing strength and flexibility of the guard cells that surround each stomatal pore in plants, but surprisingly little is known about cell wall composition, organization, and dynamics in guard cells. Recent analyses of cell wall organization and stomatal function in the guard cells of Arabidopsis thaliana mutants with defects in cellulose and xyloglucan have allowed for the development of new hypotheses about the relative contributions of these components to guard cell function. Advanced image analysis methods can allow for the automated detection of key structures, such as microtubules (MTs) and Cellulose Synthesis Complexes (CSCs), in guard cells, to help determine their contributions to stomatal function. A major challenge in the mechanical modeling of dynamic biological structures, such as guard cell walls, is to connect nanoscale features (e.g., wall polymers and their molecular interactions) with cell-scale mechanics; this challenge can be addressed by applying multiscale computational modeling that spans multiple spatial scales and physical attributes for cell walls. PMID- 27220917 TI - Major Depression in Long-Term Oxygen Therapy Dependent Chronic Obstructive Pulmonary Disease. AB - PURPOSE: We aimed to investigate the frequency of major depression (MD) in long term oxygen therapy (LTOT) dependent chronic obstructive pulmonary disease (COPD) patients and the effect of depression on patients' compliance with the treatment. DESIGN AND METHODS: Fifty-four consecutive patients were enrolled in the study and diagnosed as stage 4 COPD according to Global Initiative for Chronic Obstructive Lung Disease guideline. MD was diagnosed with the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition/Clinical Version. FINDINGS: Thirty-four (63.0%) patients had MD. MD frequency was significantly higher in patients who were noncompliant with LTOT compared with compliant patients. PRACTICE IMPLICATIONS: MD is a common psychiatric disorder in COPD patients receiving LTOT. PMID- 27220920 TI - [Drainage for Subcutaneous Emphysema after Pulmonary Resection]. AB - Severe subcutaneous emphysema sometimes develops after pulmonary resection. We report our management of ten patients who were treated with subcutaneous Penrose drainage. Water seal test at chest closure showed no air leakage in 5, and a small amount in 5. Chest X-ray at the progression of massive subcutaneous emphysema showed no obvious pneumothorax in 2, and slight apical pneumothorax in 8. Subcutaneous emphysema developed after removal of chest tubes in 6, and before removal in 4. Subcutaneous drains were inserted at the midclavicular line or the side chest in 8, and both in 2. Subcutaneous emphysema improved immediately after subcutaneous Penrose drainage with active compressive massage. Subcutaneous penrose drainage is easy and useful for relieving massive subcutaneous emphysema. PMID- 27220919 TI - [Issues in Coronary Artery Bypass Grafting for Kawasaki Disease]. AB - Progressive narrowing at the entrance and exit of coronary artery aneurysm can develop at late phase of Kawasaki disease (KD). Evaluation and prediction of progressive coronary lesions remain a challenge in the treatment of post-KD coronary artery disease. We aimed to elucidate long-standing issues imposed on the patients who underwent coronary artry bypass grafting (CABG) for coronary artery lesions associated with KD. Between January, 2000 and December, 2013, CABG for coronary artery lesions associated with KD were performed in 6 patients (male/female: 5/1, mean age 14.5+/-10.0). There was no operative mortality. Follow-up for the 6 patients has been performed with the average period of 5 years (1~9 years). Cardiac events occurred in 2 patients during follow-up. In 1 patient, left internal thoracic artery (LITA) occluded due to flow competition between the native artery and LITA graft after LITA to LAD bypass grafting. The other patient required a re-do CABG using the free right internal thoracic artery to the circumflex branch because of occlusion at the coronary artery aneurysms after 4 years postoperatively. Meticulous preoperative diagnostic evaluations of coronary artery aneurysm may further improve the long-term outcome after surgical intervention for coronary lesions in conjunction with an aneurysm. PMID- 27220918 TI - Bio-inspired Hybrid Carbon Nanotube Muscles. AB - There has been continuous progress in the development for biomedical engineering systems of hybrid muscle generated by combining skeletal muscle and artificial structure. The main factor affecting the actuation performance of hybrid muscle relies on the compatibility between living cells and their muscle scaffolds during cell culture. Here, we developed a hybrid muscle powered by C2C12 skeletal muscle cells based on the functionalized multi-walled carbon nanotubes (MWCNT) sheets coated with poly(3,4-ethylenedioxythiophene) (PEDOT) to achieve biomimetic actuation. This hydrophilic hybrid muscle is physically durable in solution and responds to electric field stimulation with flexible movement. Furthermore, the biomimetic actuation when controlled by electric field stimulation results in movement similar to that of the hornworm by patterned cell culture method. The contraction and relaxation behavior of the PEDOT/MWCNT-based hybrid muscle is similar to that of the single myotube movement, but has faster relaxation kinetics because of the shape-maintenance properties of the freestanding PEDOT/MWCNT sheets in solution. Our development provides the potential possibility for substantial innovation in the next generation of cell-based biohybrid microsystems. PMID- 27220922 TI - [Vacuum-assisted Closure Therapy for Residual Space after Open Window Thoracotomy for Pleural Empyema due to Bronchopleural Fistula]. AB - A 73-year-old man underwent right middle-lower bilobectomy for lung adenocarcinoma. He suffered from pneumonia followed by empyema due to bronchopleural fistula. On day 19 after the operation, an open window thoracostomy was created. Then the pleural space was treated conservatively with saline irrigation and petrolatum gauze packing. Progressive formation of healthy granulation tissue was observed around the bronchopleural fistula and the adjacent pulmonary artery, resulting in a complete closure of the bronchopleural fistula. And then we applied vacuum-assisted closure (VAC) therapy to the residual pleural cavity. At 4 weeks after the initiation of VAC therapy, the pleural cavity was completely filled with granulation tissue and re-expanded residual lung. In conclusion, VAC therapy is a safe and effective treatment for residual space after open window thoracostomy for empyema due to bronchopleural fistula, if it is applied after closure of bronchopleural fistula and adequate granulation tissue formation on the great vessels. PMID- 27220921 TI - [Evaluation of Portable Coagulation Analyzer in Comparison with Conventional Hospital Laboratory Instrument with Stratification of International Normalized Ratios by Therapeutic Upper Limit]. AB - Point of care devices have been widely applied to outpatients receiving anticoagulation therapy with warfarin for monitoring prothrombin time international normalized ratio (PT-INR) regularly. However, accuracy in measurement with the device remains undetermined when PT-INR exceeds therapeutic range. We evaluated the performance of a portable CoaguChek XS coagulation analyzer in comparison with a conventional laboratory method according to therapeutic and supra-therapeutic PT-INR values in cardiac outpatients on oral vitamin K antagonists. All participants were classified into 2 groups on the basis of PT-INR 3.0 by the laboratory method; therapeutic group less than or equal to 3.0 (n=48) and supra-therapeutic group above 3.0 (n=8). The correlation coefficients in therapeutic and in supra-therapeutic groups were r=0.82 and r=0.78, respectively (p<0.05). The difference in PT-INR between the laboratory method and the CoaguChek XS was significantly larger in supra-therapeutic group than therapeutic group (1.03+/-0.73 versus 0.34+/-0.26, p=0.042). Our study indicates that CoaguChek XS can be useful handheld coagulation analyzer to determine PT-INR rapidly; however, the device may underestimate PT-INR in supra therapeutic range. PMID- 27220923 TI - [Long Term Placement of Endobronchial Watanabe Spigot for Empyema with Bronchopleural Fistula]. AB - A 63-years old man referred to our hospital complaining of fever and dyspnea. He had severe diabetes. Chest computed tomography revealed left empyema with bronchopleural fistula and right pneumonia. Chest drainage was performed, but his general condition was too bad to perform surgical treatment. We performed bronchial embolization with Endobronchial Watanabe Spigot (EWS) which successfully closed the bronchopleural fistula resulting in the cure of pneumonia. Even at 1 year after treatment, good condition is being kept under the placement of EWS. PMID- 27220924 TI - [Leaflet Augmentation with an Autologous Pericardial Patch for Severe Functional Tricuspid Regurgitation]. AB - An 85-year-old man, who had developed right-sided heart failure associated with isolated severe tricuspid regurgitation (TR), was referred to our institution to undergo cardiac surgery. Preoperative echocardiography revealed tricuspid annular dilatation and leaflet tethering, resulting in severe TR. The anterior leaflet was detached from the annulus with 1.5 mm margin for suture incorporation, and an autologous pericardial patch was sutured with 3 5-0 running interlocked sutures to augment the leaflet. Annuloplasty was then performed with an undersized ring. Postoperative echocardiography showed trivial TR with good coaptation of the tricuspid leaflets. This technique may be a therapeutic option for the surgical treatment of severe functional TR due to lack of leaflet coaptation. PMID- 27220925 TI - [Mobilization of the Liver for Farther Incision of the Diaphragm in Transdiaphragmatic Re-do Coronary Artery Bypass Grafting]. AB - Re-do coronary artery bypass grafting to the right coronary artery via the diaphragm is useful, especially when re-sternotomy may injure a patent internal thoracic artery graft under the sternum. When the target vessel is located on the posterior wall of the heart, however, anastomosis becomes difficult. In our case, we mobilized the liver from the diaphragm and divided the diaphragm more posteriorly. The gastroepiploic artery was successfully anastomosed to the target vessel. PMID- 27220926 TI - [Serial Pathological Changes Between Pre- and Post-pulmonary Artery Banding in a 21-trisomy Patient with Ventricular Septal Defect]. AB - Although many patients with a ventricular septa defect undergo primary intra cardiac repair surgery, some patients require 2-stage repair with pulmonary artery banding. Patients with 21-trisomy, who exhibit fragility of the pulmonary vasculature and respiratory systems, may be candidates for this approach. Herein, we report the case of a 21-trisomy patient with ventricular septal defect associated with pulmonary hypertension. She underwent pulmonary artery banding at 4 months of age, and a subsequent radical operation at 27 months. Serial pathological findings between pre- and post-pulmonary artery banding revealed that changes of pulmonary vasculature and respiratory systems were reversible. Her Heath-Edwards grade changed from 0 from II and index of pulmonary vasculature disease changed from 1.1 to 1.0. In conclusion, pulmonary artery banding in a case with pulmonary hypertension prevented the lung from becoming irreversible pathological changes. PMID- 27220927 TI - [Primary Cardiac Angiosarcoma with Superior Vena Cava Syndrome]. AB - Primary cardiac angiosarcoma is rare and its prognosis very poor. A 34-year-old woman complained of facial edema and dyspnea. Echocardiography, chest computed tomography scan and chest magnetic resonance imaging showed a huge tumor arising in the right atrium. Surgical excision of the tumor was performed for the purpose of relieving superior vena cava syndrome and making diagnosis of the tumor. The right atrial wall, including the tumor, was resected and reconstructed with Gore Tex patch under cardiopulmonary bypass. The tumor was diagnosed as angiosarcoma. Doxorubicin hydrochloride/ifosfamide were used to treat postoperative cardiac recurrence and lung metastasis. These drugs were effective to a certain degree, but she died of brain metastasis of the tumor in the 14th postoperative month. PMID- 27220929 TI - [Open Drainage for Mediastinitis after Endobronchial Ultrasonography-guided Transbronchial Needle Aspiration]. AB - A 61-year-old man had been diagnosed as lung cancer (cT4N2M0, stage IIIB) and radiochemotherapy was performed. After the treatment, endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) was done to identify the histrogical type and to detect the oncogenic driver mutation. After EBUS-TBNA, he developed a high grade fever and the findings of the chest computed tomography (CT) suggested the infection of puncture site in mediastinum. Symptoms disappeared once by oral and intravenous antibiotics, but the infection recurred again. Chest CT revealed an abscess cavity with possible communication to the airway. Open drainage and debridment were performed and the anticancer chemotherapy could be continued. PMID- 27220928 TI - [Suggesting the Significance of Pericardial Fat Pad in Bronchial Stump Fistula]. AB - Bronchial stump fistula is a post-operative complication with poor outcome after pulmonary lobectomy. In order to prevent this complication, the bronchial stump is covered with pericardial fat tissue in our hospital. The case was 58 year old male who received adjuvant chemotherapy after sigmoidectomy for sigmoid colon cancer. As he developed multiple pulmonary metastases, 48 courses of chemotherapy were performed. The lesions had been localized at the right lower lobe, and neither increase in the size of these lesions nor development of other lesions were observed. Hence, an operation was performed. After right lower lobectomy, the bronchial stump was covered with the pericardial fat tissue. Three months after the operation, he developed pneumothorax, and bubbles were detected inside the fat. The pneumothorax was cured conservatively, and the bubbles disappeared spontaneously after 10 months. It is rare that the patient with bubbles in the covering tissue observed for a long time is cured conservatively, suggesting the significance of the stump pad. PMID- 27220930 TI - [Intercostal Lung Hernia after Video-assisted Thoracoscopic Lobectomy]. AB - A 52-year-old woman had undergone video-assisted thoracoscopic right upper lobectomy for primary lung cancer. Although her postoperative course was uneventful progressive subcutaneous emphysema of the thorax and neck was developed 6 weeks after the lobectomy. Her chest computed tomography revealed intercostal lung herniation and subcutaneous emphysema. Surgical repair was performed via thoracoscopic assistance. The damaged portion of the lung was resected and the ribs were fixed using a wire for sternal suturing. PMID- 27220931 TI - [Severe Perioperative Coronary Artery Spasm in Thoracic Aortic Surgery; Report of Two Cases]. AB - We report 2 cases of severe perioperative coronary artery spasm in thoracic aortic surgery. Case 1 was a 72-year-old male with a distal arch aneurysm of 74 mm while case 2 was a 74-year-old male with acute type A aortic dissection. We performed thoracic aortic repair (total arch replacement and ascending aorta replacement) under moderately hypothermic circulatory arrest (25 degrees C) and selective cerebral perfusion in both cases. ST elevation, abnormal left ventricular wall motion, and hypotension were noted intraoperatively. Because we were not able to wean the patients from the cardiopulmonary bypass, intraaortic balloon pump was initiated in case 1 and a coronary artery bypass graft was added in case 2. In addition to using vasodilators such as diltiazem, case 1 recovered without further intervention, but case 2 developed cardiopulmonary arrest and needed resuscitation on postoperative day 5 because of recurrence of coronary spasm. Perioperative coronary artery spasm is rare especially in aortic surgery, and may become lethal. Early recognition and special hemodynamic support is required. PMID- 27220932 TI - [Ascending-to-abdominal Aorta Bypass under Percutaneous Cardiopulmonary Support for Lower Body Organ Malperfusion Secondary to Acute Type B Aortic Dissection; Report of a Case]. AB - A 66-year-old man was admitted to our hospital because of uncomplicated Stanford B acute aortic dissection. Antihypertensive therapy was initially started; however, he suddenly experienced vomiting, diarrhea, anuria, and paraparesis on the fourteenth hospital day. Contrast-enhanced computed tomography (CECT) revealed expansion of the false lumen and severe stenosis of the true lumen at the distal aortic arch, which caused malperfusion syndrome of the lower body. Percutaneous cardiopulmonary support (PCPS) was immediately initiated to restore lower body organ perfusion, and an extra-anatomic ascending-to-abdominal aorta bypass was performed with a 16-mm Dacron graft. Postoperative CECT revealed expansion and good patency of both of the true lumen and the bypass graft. His symptoms improved except for the paraparesis; he was eventually able to ambulate using a crutch after postoperative rehabilitation. PMID- 27220933 TI - [Native Valve Endocarditis due to Corynebacterium Striatum; Report of a Case]. AB - We recently encountered a case of native valve endocarditis caused by Corynebacterium striatum (C. striatum) in the absence of immunosuppression and a prosthetic valve. A 49-year-old woman was urgently admitted for disturbance of consciousness and nosebleeds. Careful clinical examination revealed infective endocarditis caused by C. striatum, for which replacement of aortic and mitral valves was performed. The postoperative course was favorable, and we were able to save the patient with no postoperative complications. Detection of C. striatum may be recognized as contamination because this organism is a rare pathogen. However, elderly patients and patients with immunosuppression are rapidly increasing, and it is important to keep C. striatum in mind when Gram-positive bacilli are detected in the clinical examination. PMID- 27220934 TI - [Double Chambered Right Ventricle with Annuloaortic Ectasia; Report of a Case]. AB - A 61-year-old man presented with lower leg edema, left-sided parasternal systolic heart murmur, and electrocardiographic abnormalities. Transthoracic echocardiography revealed myocardial hypertrophy and severe obstruction of the outflow tract of the right ventricle (RV) with a gradient of 134 mmHg. Cardiac catheterization confirmed the presence of double chambered right ventricle, with a pressure gradient of 84 mmHg between RV inlet and outlet. Chest computed tomography showed his aortic root enlarged to 55 mm. Holter electrocardiogram revealed nonsustained ventricular tachycardia originated from RV outlet. He underwent resection of the muscular band via right ventriculotomy, aortic valve sparing reimplantation using a straight graft in 28 mm diameter, and cryoablation of RV outflow tract under cardiopulmonary bypass. His postoperative course was uneventful. Postoperative examination showed removal of the obstruction of RV outflow tract. PMID- 27220935 TI - Nesting in perception of affordances for stepping and leaping. AB - Perception of affordances for a given behavior typically reflects the task specific action capabilities of the perceiver. However, many experiments have shown a discrepancy between the perceptual and behavioral boundaries for a given behavior. One possibility for such a discrepancy is that the context of many experimental tasks transformed what is typically a dynamic perception-action task into an analytical or reflective judgment. We investigated this hypothesis with respect to perception of maximum stepping and leaping distance. For both behaviors, perception of these affordances more closely reflected action capabilities when the perceptual task was nested within a superordinate task than when it was not (regardless of whether the behavior itself was performed). Additionally, verbal reports of perception of maximum leaping distance more closely reflected action capabilities when there was an explicit time limit on such reports. The results are discussed in the context of the ecological principle of nesting and in attentional focus during motor control tasks. PMID- 27220936 TI - Action-specific judgment, not perception: Fitts' law performance is related to estimates of target width only when participants are given a performance score. AB - Proponents of the action-specific account of perception and action posit that participants perceive their environment relative to their capabilities. For example, softball players who batted well judge the ball as being larger compared to players who did not hit as well. In the present study, we examined this issue in the context of a well-known speed-accuracy movement task that can be examined in the laboratory, repetitive Fitts aiming. In the Fitts task, a performer moved as quickly and as accurately as possible between two targets, D units of distance apart (between 2.5 and 20.0 cm) and of W width (1.0 cm or less). In the Fitts task, we posited that individuals do not have access to performance quality. Thus, we asked whether individual differences in Fitts task performance was related to perception of target width. If Fitts task performance is related to perception of target width, then the action-specific effect on perception does not require explicit knowledge of performance and, furthermore, these effects reside during on-line visual control of the task. We show that only when subjects were provided with a performance score was there a relation between Fitts task performance and target width judgment error. We interpret this result to mean that action-specific effects do not occur during perceptual processing of the task, but action-specific effects are the result of postperformance evaluation processes. PMID- 27220937 TI - Zika Virus: Two or Three Lineages? AB - Zika virus (ZIKV) infection has become an emerging concern of global public health. Several recent studies provide new insights into the evolution and diversity of ZIKV, with important implications for ongoing surveillance and control measures. PMID- 27220938 TI - The role of human parvovirus B19 and hepatitis C virus in the development of thyroid disorders. AB - The presence of viruses in the thyroid has been shown, but whether they are implicated in thyroid diseases or are only spectators is under investigation. The most important candidate viruses for autoimmune thyroid disorders (AITD) are hepatitis C virus (HCV) and human parvovirus B19 (or Erythrovirus B19 or EVB19). Retrospective and prospective case-control studies conducted on pathology slides showed (by PCR, in situ hybridization or immunohistochemistry) EVB19 was present in thyroid tissues of patients with autoimmune thyroiditis (AT), Graves' disease and thyroid cancer. Though AITD can be associated with acute EVB19 infection, it is not clear whether EVB19 could have a pathogenetic role in autoimmune thyroid diseases pathophysiology. Many studies have shown that frequently, patients with HCV chronic infection (CHC) show elevated serum anti-thyroperoxidase (TPOAb) and/or anti-thyroglobulin autoantibodies levels, ultrasonographic signs of chronic AT, and subclinical hypothyroidism. In patients with HCV-associated mixed cryoglobulinemia (MC + HCV), AITD were more prevalent with respect to controls, and also vs HCV patients without cryoglobulinemia. Papillary thyroid cancer was more prevalent in MC + HCV or CHC patients than in controls, especially in patients with AT. Recently it has been shown an elevated incidence of new cases of AT and thyroid dysfunction in MC patients. These results suggest an attentive monitoring of thyroid function and nodules in HCV patients with risk factors (female gender, a borderline high initial thyrotropin, TPOAb positivity, a hypoechoic and small thyroid) for the development of thyroid disorders. PMID- 27220939 TI - Advances in stem cell therapy for cardiovascular disease (Review). AB - Cardiovascular disease constitutes the primary cause of mortality and morbidity worldwide, and represents a group of disorders associated with the loss of cardiac function. Despite considerable advances in the understanding of the pathologic mechanisms of the disease, the majority of the currently available therapies remain at best palliative, since the problem of cardiac tissue loss has not yet been addressed. Indeed, few therapeutic approaches offer direct tissue repair and regeneration, whereas the majority of treatment options aim to limit scar formation and adverse remodeling, while improving myocardial function. Of all the existing therapeutic approaches, the problem of cardiac tissue loss is addressed uniquely by heart transplantation. Nevertheless, alternative options, particularly stem cell therapy, has emerged as a novel and promising approach. This approach involves the transplantation of healthy and functional cells to promote the renewal of damaged cells and repair injured tissue. Bone marrow precursor cells were the first cell type used in clinical studies, and subsequently, preclinical and clinical investigations have been extended to the use of various populations of stem cells. This review addresses the present state of research as regards stem cell therapy for cardiovascular disease. PMID- 27220940 TI - Glucose, cholesterol, and blood pressure: is lower always better for type 2 diabetes? AB - Diabetes mellitus is a major risk factor for cardiovascular disease. However, the excess risk of death may vary substantially in subgroups of patients with type 2 diabetes, being highest in those younger than 55 years of age. A HbA1c value of 7.0 % or less is recommended for most patients with type 2 diabetes to reduce the incidence of microvascular disease, although individualized approaches that balance the benefits of glycemic control against the harms of hypoglycemia are encouraged. The selection of antidiabetic medications is of paramount importance, as the drug should not aggravate, and ideally even improve cardiovascular risk factors, with the hope to reduce cardiovascular morbidity and mortality. Patients with diabetes mellitus between 40 and 75 years of age with LDL-C between 70 and 189 mg/dL should be treated with a moderate-intensity statin. Implicit in this recommendation is the aim to reduce further LDL-C level in diabetes, in order to improve the cardiovascular outlook. The new PCSK9 inhibitors (evolocumab and arilocumab) are very promising, but, at present, their cost-effectiveness ratios exceed commonly accepted thresholds. For many people with diabetes mellitus and hypertension blood pressure should be <140/90 mmHg, although lower systolic targets (e.g., <130 mmHg) may be appropriate for certain individuals. With the likely exception of LDL-C, it is difficult to define a universal HbA1c and blood pressure target for all patients with type 2 diabetes mellitus. Ultimately, in the face of uncertainty in medicine, the final decision regarding a specific patient is best left to the clinician. PMID- 27220942 TI - Sleep Disturbance and Emotional Distress in Patients With Advanced Cancer. PMID- 27220941 TI - The role of core-needle biopsy in the diagnosis of thyroid malignancy in 4580 patients with 4746 thyroid nodules: a systematic review and meta-analysis. AB - To evaluate the effectiveness and complications of core-needle biopsy (CNB) compared to fine-needle aspiration (FNA) for diagnosing thyroid malignancy. The Ovid-MEDLINE and EMBASE databases were searched for studies using CNB for diagnosing thyroid malignancy. A meta-analysis was performed to evaluate the diagnostic accuracy, the incidence of non-diagnostic, inconclusive results, and the complications of CNB and FNA. To overcome the heterogeneity, additional analyses based on three, homogeneous inclusion criteria were performed and subgroup analyses were performed. Twenty eligible studies of 4580 patients (4746 nodules) were included. Both CNB and FNA demonstrated a high sensitivity (91 %, 74 %, respectively; p = .053) and specificity (99 %, 100 %, respectively; p = .914). The area under the curve was larger in CNB (0.99) than in FNA (0.94). CNB demonstrated a significantly lower pooled proportion of non-diagnostic (5.5 %; p < .001) and inconclusive results (8.0 %; p < .001) than FNA (22.6 %, 40.2 %, respectively). The complications rate of FNA (0.0 %) was lower than that of CNB (0.01 %), although not significantly (p = .948). This meta-analysis showed variable heterogeneities, i.e., no heterogeneity to considerable heterogeneity. Additional meta-analyses based on three, homogeneous inclusion criteria demonstrated that heterogeneities were reduced, and the results are in agreement with those of all of the included studies. Subgroup analyses have explained the cause of heterogeneity across studies. Both CNB and FNA may be acceptable diagnostic tools for diagnosing thyroid malignancy. CNB may be a complementary diagnostic tool in nodules with initially non-diagnostic and indeterminate results on previous FNA. PMID- 27220944 TI - Understanding Treatment Effect Terminology in Pain and Symptom Management Research. AB - Within health services and medical research, there is a wide variety of terminology related to treatment effects. Understanding differences in types of treatment effects is especially important in pain and symptom management research where nonexperimental and quasiexperimental observational data analysis is common. We use the example of a palliative care consultation team leader considering implementation of a medication reconciliation program and a care coordination intervention reported in the literature to illustrate population level and conditional treatment effects and to highlight the sensitivity of values of treatment effects to sample selection and treatment assignment. Our goal is to facilitate appropriate reporting and interpretation of study results and to help investigators understand what information a decision maker needs when deciding whether to implement a treatment. Greater awareness of the reasons why treatment effects may differ across studies of the same patients in the same treatment settings can help policy makers and clinicians understand to whom a study's results may be generalized. PMID- 27220943 TI - Bispectral Index Monitoring in Terminally Ill Patients: A Validation Study. AB - CONTEXT: If regular therapies cannot relieve symptoms sufficiently in the last days of life, continuous palliative sedation may serve to reduce consciousness. Sedation level can be measured with EEG monitoring with the bispectral index (BIS) monitor. OBJECTIVES: To determine the feasibility and validity of BIS monitoring in terminally ill patients. METHODS: In this prospective study, BIS registrations were performed in unconscious end-of-life patients admitted to a palliative care center. Validated scores were used to measure level of sedation (Ramsay score), pain (Numeric Rating Scale or Rotterdam Elderly Pain Observations Scale), delirium (Delirium Observation Screening score), and overall comfort (Numeric Rating Scale). Validity and sensitivity to change of BIS values were considered, and the effects of medication and the time till death on BIS values were evaluated in a linear mixed model analysis. RESULTS: Fifty-eight patients were included for analysis. BIS monitoring was acceptable to patients, relatives, and medical staff. BIS values were moderately correlated with Ramsay scores (0.46) but were highly variable for deeply sedated patients. BIS values changed significantly before and after a midazolam dose (P < 0.001). Midazolam treatment resulted on average in a statistically significant reduction of the BIS values ( 4.5, 95% CI -7.0 to -2.0), whereas morphine and haloperidol did not. CONCLUSION: This is one of the first validation studies in which BIS monitoring in end-of life patients is described. BIS monitoring is feasible in unconscious terminally ill patients. However, based on our results, the wide range of BIS values in deeply sedated and comfortable patients seems to hamper its use in daily clinical practice. PMID- 27220945 TI - Characteristics of Patients in a Home-Based Palliative Medicine Consultation Service. PMID- 27220946 TI - Differences in Terminal Hospitalization Care Between U.S. Men and Women. AB - CONTEXT: In many settings, men and women receive different care. OBJECTIVES: We sought to determine whether men and women receive different care during terminal hospitalizations. METHODS: We analyzed data of 98,314 adult patients who died while hospitalized in 458 acute care hospitals in the U.S. during 2011. We examined sex-based differences in lengths of stay (LOS), resuscitation status, and intensive interventions and processes of care, adjusting for patient- and hospital-level characteristics. RESULTS: Women represented half of the sample (48,509; 49.34%), were older than men (73.8 vs. 70.6 years, P < 0.0001), and less likely to be married (27.7% vs. 48.3%, P < 0.001). Among all patients, median LOS was four days (interquartile range 2-10); 19.1% of subjects received cardiopulmonary resuscitation; 37.6% had a do-not-resuscitate order during the admission; and 51.6% received mechanical ventilation. Compared with men, women had slightly shorter hospitalizations (adjusted LOS: -0.16 days; 95% CI -0.19, 0.12) and were more likely to have a do-not-resuscitate order (odds ratio [OR] 1.08; 95% CI 1.05, 1.11). Women remained less likely to receive care in an intensive care unit (OR 0.95; 95% CI 0.93, 0.98), cardiopulmonary resuscitation (OR 0.83; 95% CI 0.80, 0.86), mechanical ventilation (OR 0.94; 95% CI 0.91, 0.97), hemodialysis (adjusted OR 0.81; 95% CI 0.78, 0.86), or surgical procedures (OR 0.88; 95% CI 0.84, 0.93). CONCLUSION: Men who die in hospitals receive more aggressive care than women. Further research should examine potential causes of this overall pattern. PMID- 27220947 TI - Author's Reply to Kawada. PMID- 27220949 TI - "I Can Breathe Again!" Patients' Self-Management Strategies for Episodic Breathlessness in Advanced Disease, Derived From Qualitative Interviews. AB - CONTEXT: Episodic breathlessness causes additional distress to breathless patients with advanced disease, but management is still insufficient and there is a lack of knowledge on effective coping strategies. OBJECTIVES: The aim was to explore patients' self-management strategies for episodic breathlessness. METHODS: In-depth interviews with patients suffering from episodic breathlessness as a result of chronic heart failure, chronic obstructive pulmonary disease, lung cancer, or motor neuron disease were conducted. Interviews were transcribed verbatim and analyzed guided by the analytic hierarchy of Framework analysis. RESULTS: A total of 51 participants were interviewed (15 chronic heart failure, 14 chronic obstructive pulmonary disease, 13 lung cancer, and nine motor neuron disease; age, mean [SD], 68 [12], 41% women, median Karnofsky index 60%). They described six main strategies for coping with episodes of breathlessness: reduction of physical exertion, cognitive and psychological strategies, breathing techniques and positions, air and oxygen, drugs and medical devices, and environmental and other strategies. Some strategies were used in an opposing way, e.g., concentrating on the breathing vs. distraction from any thoughts of breathlessness or laying down flat vs. standing up and raising hands. CONCLUSION: Patients used a number of different strategies to cope with episodic breathlessness, adding more detailed understanding of existing strategies for breathlessness. The findings, therefore, may provide a valuable aid for health care providers, affected patients, and their relatives. PMID- 27220948 TI - Quality of Life in Children With Advanced Cancer: A Report From the PediQUEST Study. AB - CONTEXT: Modifiable factors of health-related quality of life (HRQOL) are poorly described among children with advanced cancer. Symptom distress may be an important factor for intervention. OBJECTIVES: We aimed to describe patient reported HRQOL and its relationship to symptom distress. METHODS: Prospective, longitudinal data from the multicenter Pediatric Quality of Life and Symptoms Technology study included primarily patient-reported symptom distress and HRQOL, measured at most weekly with the Memorial Symptoms Assessment Scale and Pediatric Quality of Life inventory, respectively. Associations were evaluated using linear mixed-effects models adjusting for sex, age, cancer type, intervention arm, treatment intensity, and time since disease progression. RESULTS: Of 104 enrolled patients, 49% were female, 89% were white, and median age was 12.6 years. Nine hundred and twenty surveys were completed over nine months of follow-up (84% by patients). The median total Pediatric Quality of Life score was 74 (interquartile range 63-87) and was "poor/fair" (e.g., <70) 38% of the time. "Poor/fair" categories were highest in physical (53%) and school (48%) compared to emotional (24%) and social (16%) subscores. Thirteen of 24 symptoms were independently associated with reductions in overall or domain-specific HRQOL. Patients commonly reported distress from two or more symptoms, corresponding to larger HRQOL score reductions. Neither cancer type, time since progression, treatment intensity, sex, nor age was associated with HRQOL scores in multivariable models. Among 25 children completing surveys during the last 12 weeks of life, 11 distressing symptoms were associated with reductions in HRQOL. CONCLUSION: Symptom distress is strongly associated with HRQOL. Future research should determine whether alleviating distressing symptoms improves HRQOL in children with advanced cancer. PMID- 27220950 TI - Prevalence of Sudden Death in Palliative Care: Data From the Australian Palliative Care Outcomes Collaboration. AB - CONTEXT: Advanced, life-limiting illnesses are likely to have a predictable functional decline through a terminal phase to death, but some patients may also die suddenly. To date, empirical evidence characterizing "sudden death" in hospice/palliative care is lacking. OBJECTIVES: The aim of this study was to determine prevalence and clinicodemographic predictors of sudden death in hospice/palliative care. METHODS: This is a longitudinal consecutive cohort study of prospectively collected national data in 104 specialist palliative care services from the Australian Palliative Care Outcomes Collaboration. Patients who died between July 1, 2013, and June 30, 2014, with one or more measurement of Australian-modified Karnofsky Performance Status (AKPS) in the last 30 days of life were included. "Sudden death" was defined as a lowest AKPS score of 50 or more in the last seven days of life and excluded anyone with "terminal phase" as their last phase before death. Predictors were defined using logistic regression. RESULTS: In total, 13,966 patients were included, mean age 73.6 (SD 13.6) years, 46% women, and 77% had cancer. During the seven days before death, there were 20,992 AKPS measurements; median 1 (interquartile range 1-2) per patient. Four percent of deaths (one of 25) were sudden, predicted independently by having lung cancer (odds ratio [OR] 2.64), cardiovascular disease (OR 1.94), other cancers (OR 1.63), being male (OR 1.23), younger, worse fatigue, and worse breathlessness. Sudden death was associated with higher rates of death at home (OR 3.2; 95% CI 2.9 to 3.6). CONCLUSION: This study quantifies rates of sudden death in hospice/palliative care and has implications for conversations about prognosis between clinicians, patients, and their families. PMID- 27220951 TI - Characterization of the Ionic Profile of the Extracellular Space of the Injured and Ischemic Brain: A Microdialysis Study. AB - Traumatic brain injury (TBI) and ischemic stroke cause a variable disruption of ionic homeostasis and massive ionic fluxes with subsequent osmotic water movement across the cells that causes edema, brain swelling, and deformation of the damaged tissue. Although cerebral microdialysis (CMD) has been used to study the brain neurochemistry, the ionic profiles of brain interstitial space fluid have rarely been reported in humans. We studied the ionic profile in injured areas of the brain by using CMD. As a control group, we included seven patients who had undergone surgical treatment of posterior fossa lesions, without abnormalities in the supratentorial compartment. Inductively coupled plasma mass spectrometry (ICP MS) was used for ion determination. No significant differences were found in the [Na+]o, [K+]o, and [Cl-]o between normal injured brains and controls. The ionic profile of the ischemic core was characterized by very high [K+]o and an increase in [Na+]o, whereas [Cl-]o was linearly related to [Na+]o. In the traumatic core (TC), significantly higher levels of [Na+]o, [Cl-]o, and [K+]o were found. The main finding in the penumbra was a completely normal ionic profile for [Na+]o and [K+]o in 60% of the samples. ICP-MS coupled to ionic assays creates a powerful tool for a better understanding of the complex ionic disturbances that occur after severe TBI and ischemic stroke. PMID- 27220952 TI - Molecular evidence of functional progesterone withdrawal in human myometrium. AB - Progesterone suppresses uterine contractility acting through its receptors (PRA/B). The mechanism by which human labour is initiated in the presence of elevated circulating progesterone has remained an enigma since Csapo first theorized of a functional withdrawal of progesterone in 1965. Here we report that in vitro progesterone-liganded nuclear PRB forms a complex including JUN/JUN homodimers and P54(nrb)/Sin3A/HDAC to repress transcription of the key labour gene, Cx43. In contrast, unliganded PRA paradoxically activates Cx43 transcription by interacting with FRA2/JUND heterodimers. Furthermore, we find that while nuclear progesterone receptor (PR) is liganded during human pregnancy, it becomes unliganded during both term and preterm labour as a result of increased expression of the progesterone-metabolizing enzyme 20alpha HSD and reduced nuclear progesterone levels. Our data provide a mechanism by which human labour can occur in the presence of elevated circulating progesterone and suggests non-metabolizable progestogen might represent an alternative new therapeutic approach to preterm birth prevention. PMID- 27220953 TI - Talking with patients about sex: results of an interprofessional simulation-based training for clinicians. AB - Sexuality is often a neglected topic in healthcare consultations. Several factors have been identified by clinicians as barriers to communication around sexuality, including lack of time, inadequate training, and personal discomfort. Within the Program to Enhance Relational and Communication Skills (PERCS), we developed a half-day interdisciplinary workshop that focuses on communication skills around sexuality and management of sexual problems with patients (PERCS-sexuality). This study reports on the efficacy of six PERCS-sexuality workshops enrolling 84 clinicians. Through a pre-post-questionnaire, participants rated their preparation, confidence, anxiety, communication and relational skills in talking with patients about sexual issues. Qualitative questions were also asked on their learning experience. The workshop increased participants' preparation (p = 0.000), confidence (p = 0.000), communication (p = 0.000), and relational skills (p = 0.000). Anxiety did not decrease. Qualitative comments focused on: Acquisition of communication and relational skills, Importance of patient's sexuality, Appreciation of group dynamics, and Personal insights. The findings suggest that PERCS-sexuality is a useful training experience to improve clinicians' attitudes and skills in addressing sexuality with patients. PMID- 27220954 TI - Presence of portal vein thrombosis in liver cirrhosis is strongly associated with low levels of ADAMTS-13: a pilot study. AB - Portal vein thrombosis (PVT) dramatically changes the prognosis of cirrhotic patients, especially those waiting for liver transplantation. However, the possible contribution to PVT of von Willebrand factor (VWF) and ADAMTS-13 is poorly documented. The aim of our study was to assess the presence of alterations of VWF and ADAMTS-13 serum levels in cirrhotic patients with PVT. Twenty-four patients with PVT (group PVT) and 60 without PVT (group without PVT) were enrolled. A comprehensive analysis of biochemical and hemostatic parameters was performed. ADAMTS-13 activity was significantly lower in group A (median 16.8 vs. 69.1 %, p = 0.0047). Group PVT, compared to group without PVT, showed a significantly higher VWF:act, (median 308.4 vs 203.3 %, p = 0.032), whereas no difference was observed for VWF:Ag, FVIII level and the presence of risk factors for venous thromboembolism. No correlation was found between the Child-Pugh score and ADAMTS-13 activity. In multivariable logistic regression analysis performed on data concerning both group PVT and without PVT, only the ADAMTS-13 activity (p = 0.007) was independently and inversely associated with PVT. In conclusion, ADAMTS-13 activity is independently associated with PVT in cirrhotic patients. PMID- 27220956 TI - Authors' reply to Patel and colleagues. PMID- 27220957 TI - Clinical risk factors for pre-eclampsia early pregnancy: problems with systematic review. PMID- 27220955 TI - Metabolism of L-arabinose in plants. AB - L-Arabinose (L-Ara) is a plant-specific sugar accounting for 5-10 % of cell wall saccharides in Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa). L-Ara occurs in pectic arabinan, rhamnogalacturonan II, arabinoxylan, arabinogalactan protein (AGP), and extensin in the cell walls, as well as in glycosylated signaling peptides like CLAVATA3 and small glycoconjugates such as quercetin 3-O arabinoside. This review focuses on recent advances towards understanding the generation of L-Ara and the metabolism of L-Ara-containing molecules in plants. PMID- 27220958 TI - [Not Available]. PMID- 27220959 TI - Cancer Prevention and Interception: A New Era for Chemopreventive Approaches. AB - At several recent, internationally attended scientific meetings, including the American Association for Cancer Research (AACR)'s "Shaping the Future of Cancer Prevention: A Roadmap for Integrative Cancer Science and Public Health" summit in Leesburg (VA) and the AACR Annual Meeting in New Orleans, the focus on cancer prevention to reduce cancer-related deaths was extensively discussed with renewed attention and emphasis. Cancer prevention should be actively proposed even to healthy individuals, and not just to individuals with high cancer risk. We discuss evaluation of a high cancer risk versus the relatively low risk for side effects of chemopreventive agents. The concept of cancer interception, which is halting transformed cells from becoming malignant cancers, should be adopted for cancer prevention. Potential prevention/interception actions include adopting healthy life style and avoiding carcinogens, repressing inflammation and pathologic angiogenesis, controlling metabolism, correcting insulin resistance and other metabolic alterations. Current drugs with limited toxicity can be repurposed to reduce cancer incidence. Aspirin is now being recommended for the prevention of colorectal cancer and it prevents other neoplasms as well. Metformin and beta-blockers could be valuable for reducing pancreatic and breast cancer onset. On the basis of the evaluation of cancer risk, we here call for personalized approaches for cancer prevention and preventive interception and we envisage a list of measures and potential guidelines for preventive and interceptive strategies to reduce cancer burden. Investment into translational research to bring these approaches into public health policies and in the clinic is urgently needed. Clin Cancer Res; 22(17); 4322-7. (c)2016 AACR. PMID- 27220960 TI - Biomarker Analyses of Clinical Outcomes in Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib with or without Erlotinib in the SEARCH Trial. AB - PURPOSE: Sorafenib is the current standard therapy for advanced hepatocellular carcinoma, but validated biomarkers predicting clinical outcomes are lacking. This study aimed to identify biomarkers predicting prognosis and/or response to sorafenib, with or without erlotinib, in hepatocellular carcinoma patients from the phase III SEARCH trial. EXPERIMENTAL DESIGN: A total of 720 patients were randomized to receive oral sorafenib 400 mg twice daily plus erlotinib 150 mg once daily or placebo. Fifteen growth factors relevant to the treatment regimen and/or to hepatocellular carcinoma were measured in baseline plasma samples. RESULTS: Baseline plasma biomarkers were measured in 494 (69%) patients (sorafenib plus erlotinib, n = 243; sorafenib plus placebo, n = 251). Treatment arm-independent analyses showed that elevated hepatocyte growth factor [HGF; HR, 1.687 (high vs. low expression); endpoint multiplicity adjusted (e-adj) P = 0.0001] and elevated plasma VEGFA (HR, 1.386; e-adj P = 0.0377) were significantly associated with poor overall survival (OS) in multivariate analyses, and low plasma KIT [HR, 0.75 (high vs. low); P = 0.0233; e-adj P = 0.2793] tended to correlate with poorer OS. High plasma VEGFC independently correlated with longer TTP (HR, 0.633; e-adj P = 0.0010) and trended toward associating with improved disease control rate (univariate: OR, 2.047; P = 0.030; e-adj P = 0.420). In 67% of evaluable patients (339/494), a multimarker signature of HGF, VEGFA, KIT, EPGN, and VEGFC correlated with improved median OS in multivariate analysis (HR, 0.150; P < 0.00001). No biomarker predicted efficacy from erlotinib. CONCLUSIONS: Baseline plasma HGF, VEGFA, KIT, and VEGFC correlated with clinical outcomes in hepatocellular carcinoma patients treated with sorafenib with or without erlotinib. These biomarkers plus EPGN constituted a multimarker signature for improved OS. Clin Cancer Res; 22(19); 4870-9. (c)2016 AACR. PMID- 27220962 TI - Repurposing Sunitinib with Oncolytic Reovirus as a Novel Immunotherapeutic Strategy for Renal Cell Carcinoma. AB - PURPOSE: In addition to their direct cytopathic effects, oncolytic viruses are capable of priming antitumor immune responses. However, strategies to enhance the immunotherapeutic potential of these agents are lacking. Here, we investigated the ability of the multi-tyrosine kinase inhibitor and first-line metastatic renal cell carcinoma (RCC) agent, sunitinib, to augment the antitumor immune response generated by oncolytic reovirus. EXPERIMENTAL DESIGN: In vitro, oncolysis and chemokine production were assessed in a panel of human and murine RCC cell lines after exposure to reovirus, sunitinib, or their combination. In vivo, the RENCA syngeneic murine model of RCC was employed to determine therapeutic and tumor-specific immune responses after treatment with reovirus (intratumoral), sunitinib, or their combination. Parallel investigations employing the KLN205 syngeneic murine model of lung squamous cell carcinoma (NSCLC) were conducted for further validation. RESULTS: Reovirus-mediated oncolysis and chemokine production was observed following RCC infection. Reovirus monotherapy reduced tumor burden and was capable of generating a systemic adaptive antitumor immune response evidenced by increased numbers of tumor specific CD8+ IFNgamma-producing cells. Coadministration of sunitinib with reovirus further reduced tumor burden resulting in improved survival, decreased accumulation of immune suppressor cells, and the establishment of protective immunity upon tumor rechallenge. Similar results were observed for KLN205 tumor bearing mice, highlighting the potential broad applicability of this approach. CONCLUSIONS: The ability to repurpose sunitinib for augmentation of reovirus' immunotherapeutic efficacy positions this novel combination therapy as an attractive strategy ready for clinical testing against a range of histologies, including RCC and NSCLC. Clin Cancer Res; 22(23); 5839-50. (c)2016 AACR. PMID- 27220961 TI - Tyrosine Kinase Signaling in Clear Cell and Papillary Renal Cell Carcinoma Revealed by Mass Spectrometry-Based Phosphotyrosine Proteomics. AB - PURPOSE: Targeted therapies in renal cell carcinoma (RCC) are limited by acquired resistance. Novel therapeutic targets are needed to combat resistance and, ideally, target the unique biology of RCC subtypes. EXPERIMENTAL DESIGN: Tyrosine kinases provide critical oncogenic signaling and their inhibition has significantly impacted cancer care. To describe a landscape of tyrosine kinase activity in RCC that could inform novel therapeutic strategies, we performed a mass spectrometry-based system-wide survey of tyrosine phosphorylation in 10 RCC cell lines as well as 15 clear cell and 15 papillary RCC human tumors. To prioritize identified tyrosine kinases for further analysis, a 63 tyrosine kinase inhibitor (TKI) drug screen was performed. RESULTS: Among the cell lines, 28 unique tyrosine phosphosites were identified across 19 kinases and phosphatases including EGFR, MET, JAK2, and FAK in nearly all samples. Multiple FAK TKIs decreased cell viability by at least 50% and inhibited RCC cell line adhesion, invasion, and proliferation. Among the tumors, 49 unique tyrosine phosphosites were identified across 44 kinases and phosphatases. FAK pY576/7 was found in all tumors and many cell lines, whereas DDR1 pY792/6 was preferentially enriched in the papillary RCC tumors. Both tyrosine kinases are capable of transmitting signals from the extracellular matrix and emerged as novel RCC therapeutic targets. CONCLUSIONS: Tyrosine kinase profiling informs novel therapeutic strategies in RCC and highlights the unique biology among kidney cancer subtypes. Clin Cancer Res; 22(22); 5605-16. (c)2016 AACR. PMID- 27220964 TI - Ectoparasites of bats (Mammalia: Chiroptera) in Atlantic forest fragments in north-eastern Brazil. AB - In Brazil, most studies involving parasites of bats (bat flies) treat the mid west, south-east, and south of the country. This work aimed to characterize the ectoparasites community associated with bats in the Atlantic forest in the state of Sergipe, north-eastern Brazil. Sampling was conducted between January and June 2013 in the Serra de Itabaiana National Park (PNSI) and between November 2013 and June 2015 in the Wildlife Refuge Mata do Junco (RVSMJ). Parasitological indexes were determined, and the influence of host sex and the seasonality in prevalence rates and mean intensity for the most abundant parasites was evaluated. Some 129 parasites were collected in PNSI and 296 in RVSMJ, and 100 and 70.6 %, respectively, belong to the family Streblidae. The differences in parasitological rates in Sergipe in relation to other studies may be associated with the environmental characteristics and the composition of the host community. The influence of sex and the seasonal prevalence of Speiseria ambigua and Trichobius joblingi, associated with Carollia perspicillata, may be associated with a lower rate of female captures and low sampling in the dry season. This is a pioneer study in Sergipe that reveals the occurrence of 16 species of streblids and representatives of Acari and Basilia spp., highlighting the need for more studies to increase the wealth and understanding of host-parasite associations in the state. PMID- 27220966 TI - A Community Standard: Equivalency of Healthcare in Australian Immigration Detention. AB - The Australian government has long maintained that the standard of healthcare provided in its immigration detention centres is broadly comparable with health services available within the Australian community. Drawing on the literature from prison healthcare, this article examines (1) whether the principle of equivalency is being applied in Australian immigration detention and (2) whether this standard of care is achievable given Australia's current policies. This article argues that the principle of equivalency is not being applied and that this standard of health and healthcare will remain unachievable in Australian immigration detention without significant reform. Alternate approaches to addressing the well documented issues related to health and healthcare in Australian immigration detention are discussed. PMID- 27220967 TI - Spatial distribution of electrical reconnection after pulmonary vein isolation in patients with recurrent paroxysmal atrial fibrillation. AB - INTRODUCTION: Recurrence of atrial fibrillation after pulmonary vein isolation (PVI) occurs frequently and may be associated with electrical reconnection of the pulmonary veins (PV). We investigated spatial distribution of electrical reconnection during re-do procedures in patients with paroxysmal atrial fibrillation who had previous successful acute electrical PVI with either single irrigated tip, antral ablation (s-RF; n = 38) or multi-electrode, duty-cycled ablation (PVAC; n = 48). METHODS AND RESULTS: EP navigator, mapping and irrigated tip ablation catheters were used in all re-do procedures. Sites of reconnection were assessed in a 12-segment model. Baseline clinical and demographic characteristics were similar in both groups. The number of PVs reconnected per patient was similar in both groups (2.9 +/- 0.9 and 3.2 +/- 0.7 (p = 0.193), s-RF and PVAC, respectively), and each PV was equally affected. However, the inferior quadrant of the right lower PV was significantly more vulnerable to reconnection after previous PVAC ablation, whereas the superior quadrant of the right upper PV showed significantly more reconnection in the s-RF group. CONCLUSION: The overall number of PVs reconnected was equally high in both groups, and each PV was affected equally. However, there were significant differences in the spatial distribution of electrical reconnection. Better understanding of predilection sites for reconnection might help to improve the long-term success rate of PVI. PMID- 27220965 TI - The Psychosis Continuum: Testing a Bifactor Model of Psychosis in a General Population Sample. AB - Although the factor structure of psychosis continues to be debated by taxonomists, recent studies have supported a bifactor model consisting of a general psychosis factor and 5 uncorrelated symptom-specific factors. While this model has received support in clinical samples, it has not been tested at the general population level. Analysis was conducted on Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (N = 34 653). Twenty-two psychotic symptoms were used as observed indicators of psychosis. These items were chosen based on their conceptual similarity to the items used in a similar study based on clinical samples. Confirmatory factor analysis and confirmatory bifactor modeling were used to test a variety of competing models. The best fitting model consisted of a general psychosis factor that was uncorrelated with 5 specific factors: positive, negative, disorganization, mania, and depression. These findings suggest that the bifactor model can be extended to general population samples, supporting the continuity between clinical and subclinical psychotic experiences. Theoretical and practical implications are discussed. PMID- 27220963 TI - Focal Adhesion Kinase Regulates the DNA Damage Response and Its Inhibition Radiosensitizes Mutant KRAS Lung Cancer. AB - PURPOSE: Non-small cell lung cancer (NSCLC) is the leading cause of cancer related deaths worldwide due to the limited availability of effective therapeutic options. For instance, there are no effective strategies for NSCLCs that harbor mutant KRAS, the most commonly mutated oncogene in NSCLC. Thus, our purpose was to make progress toward the generation of a novel therapeutic strategy for NSCLC. EXPERIMENTAL DESIGN: We characterized the effects of suppressing focal adhesion kinase (FAK) by RNA interference (RNAi), CRISPR/CAS9 gene editing or pharmacologic approaches in NSCLC cells and in tumor xenografts. In addition, we tested the effects of suppressing FAK in association with ionizing radiation (IR), a standard-of-care treatment modality. RESULTS: FAK is a critical requirement of mutant KRAS NSCLC cells. With functional experiments, we also found that, in mutant KRAS NSCLC cells, FAK inhibition resulted in persistent DNA damage and susceptibility to exposure to IR. Accordingly, administration of IR to FAK-null tumor xenografts causes a profound antitumor effect in vivo CONCLUSIONS: FAK is a novel regulator of DNA damage repair in mutant KRAS NSCLC and its pharmacologic inhibition leads to radiosensitizing effects that could be beneficial in cancer therapy. Our results provide a framework for the rationale clinical testing of FAK inhibitors in NSCLC patients. Clin Cancer Res; 22(23); 5851-63. (c)2016 AACR. PMID- 27220968 TI - Minimally invasive posterior segmental instrumentation and fusion with an intraarticular facet joint device. PMID- 27220969 TI - The effects of intervertebral disc degeneration combined with osteoporosis on vascularization and microarchitecture of the endplate in rhesus monkeys. AB - PURPOSE: To evaluate the influence of osteoporosis on the microarchitecture and vascularization of the endplate in rhesus monkeys with or without intervertebral disc (IVD) degeneration using micro-computerized tomography (micro-CT), and to further analyze the correlation between osteoporosis and IVD degeneration. METHODS: Twelve rhesus monkeys were randomly divided into the ovariectomy (OVX, n = 6) and the sham group (n = 6). The subchondral bone adjacent to the lumbar IVDs (from L4/5 to L6/7) of each monkey was randomly injected with 4 ml pingyangmycin (PYM) solution (1.5 mg/ml, PYM), or 4 ml phosphate buffered saline (PBS) as vehicle treatment, or exteriorized but not injected anything as control (Cntrl). Degenerative and osteoporotic processes were evaluated at different time points. Micro-CT and histology were performed to analyze microarchitecture, calcification area and vascularization of the endplate. RESULTS: OVX resulted in significant decrease of bone mineral density (BMD). PYM injection induced progressively IVD degeneration, which was more progressive when combined with OVX. There was a negative correlation between BMD and Pfirrmann grade in the subgroups with PYM injection. The micro-CT analysis showed the combination of osteoporosis and IVD degeneration led to more calcification of endplate than any one thereof. The decrease of vascular volume percent in the endplate of the OVX-PYM subgroup was significantly greater than that in the Sham-PYM subgroup, both of which showed significant less vascularization compared to the other subgroups. CONCLUSION: In conclusion the osteoporosis could accumulate the calcification and decrease the vascularization in the endplates adjacent to the degenerated IVDs, which subsequently exacerbated degeneration of the degenerated IVDs. PMID- 27220971 TI - Lumbar plexus nervous distortion in XLIF(r) approach: an anatomic study. AB - PURPOSE: XLIF (r) is a widely used minimally invasive technique to treat different spine pathologies. The aim of this study was to quantify nerve distortion of lumbar plexus during XLIF (r) approach and to correlate it with morphometric data. METHODS: Nine fresh frozen cadaveric specimens were used. All specimens were subjected to the same dissection procedure cored on a left XLIF(r) approach at L2/L3 and L4/L5 levels. Distortion of cutaneous superficial nerves, femoral nerve (FN) at L4/L5 and genitofemoral nerve (GN) at L2/L3 and L4/L5 while opening the retractor were assessed and analyzed with respect to psoas muscle features. RESULTS: Superficial nerves were slightly displaced but never stretched. FN, as well as GN at L4/L5 level, could be displaced and stretched by the blades. Statistically significant correlation between FN distortion and the amount of psoas fibers interposed between the posterior blade of the retractor and the nerve itself (TCK) was found. GN distortion was found to be related to its clock position on an axial section of psoas muscle seen from cranially at L4/L5. CONCLUSION: FN was in close connection with the deep psoas muscle fibers and it is subjected to anterior translation that correlates with TCK. This mechanism may partly explain the rate of femoral nerve palsy that occurs despite neuromonitoring and safe entry zones respect. The GN location at L4/L5 should be considered not only for its projection in Zone I, but also for its clock position on the psoas muscle surface, since it affects its distortion. PMID- 27220970 TI - De novo degenerative lumbar scoliosis: a systematic review of prognostic factors for curve progression. AB - PURPOSE: To identify prognostic factors for curve progression in de novo degenerative lumbar scoliosis (DNDLS) by performing a systematic review of the literature. METHODS: Studies were selected for inclusion following a systematic search in the bibliographic databases PubMed and EMBASE prior to September 2015 and hand searches of the reference lists of retrieved articles. Two authors independently assessed methodological quality. Data were extracted and presented according to a best evidence synthesis. RESULTS: The literature search generated a total of 2696 references. After removing duplicates and articles that did not meet inclusion criteria, 12 studies were included. Due to the lack of statistical analyses, pooling of data was not possible. Strong evidence indicates that increasing intervertebral disk degeneration, lateral vertebral translation >=6 mm, and an intercrest line through L5 (rather than L4) are associated with DNDLS curve progression. Moderate evidence suggests that apical vertebral rotation Grade II or III is associated with curve progression. For the majority of other prognostic factors, we found limited, conflicting, or inconclusive evidence. Osteoporosis, a coronal Cobb angle <30 degrees , lumbar lordosis, lateral osteophytes difference of >=5 mm, and degenerative spondylolisthesis have not been shown to be risk factors. Clinical risk factors for progression were not identified. CONCLUSIONS: This review shows strong evidence that increased intervertebral disk degeneration, an intercrest line through L5, and apical lateral vertebral translation >=6 mm are associated with DNDLS curve progression. Moderate evidence was found for apical vertebral rotation (Grade II/III) as a risk factor for curve progression. These results, however, may not be directly applicable to the individual patient. PMID- 27220972 TI - Growth Behavior of E. coli, Enterococcus and Staphylococcus Species in the Presence and Absence of Sub-inhibitory Antibiotic Concentrations: Consequences for Interpretation of Culture-Based Data. AB - Culture-based approaches are used to monitor, e.g., drinking water or bathing water quality and to investigate species diversity and antibiotic resistance levels in environmental samples. For health risk assessment, it is important to know whether the growing cultures display the actual abundance of, e.g., clinically relevant antibiotic resistance phenotypes such as vancomycin-resistant Enterococcus faecium/Enterococcus faecalis (VRE) or methicillin-resistant Staphylococcus aureus. In addition, it is important to know whether sub inhibitory antibiotic concentrations, which are present in surface waters, favor the growth of antibiotic-resistant strains. Therefore, clinically relevant bacteria were isolated from different water sources and the growth behavior of 58 Escherichia coli, 71 Enterococcus, and 120 Staphylococcus isolates, belonging to different species and revealing different antibiotic resistance patterns, was studied with respect to "environmental" antibiotic concentrations. The finding that VRE could only be detected after specific enrichment can be explained by their slow growth compared to non-resistant strains. Interpreting their absence in standardized culture-based methods as nonexistent might be a fallacy. Sub inhibitory antibiotic concentrations that were detected in sewage and receiving river water did not specifically promote antibiotic-resistant strains. Generally, those antibiotics that influenced cell metabolism directly led to slightly reduced growth rates and less than maximal optical densities after 48 h of incubation. PMID- 27220973 TI - Bartonella, Rodents, Fleas and Ticks: a Molecular Field Study on Host-Vector Pathogen Associations in Saxony, Eastern Germany. AB - Bartonellae cause zoonotic diseases and are transmitted by arthropods. Rodents are reservoirs for most Bartonella spp. As the knowledge about Bartonella in rodents and their parasitizing ectoparasites is scarce in Germany, this study's objectives were to investigate Bartonella spp. in small mammals and in their ectoparasites. A total of 79 small mammals (seven species) were captured and their ectoparasites collected at seven sites around Leipzig, Saxony, Germany, in 2010 and 2011. Altogether, 79 spleen samples, 135 fleas (five species) and 365 ticks (three species) were investigated for Bartonella spp. by PCR targeting the ITS 16S-23S rRNA region. In total, 52 (65.8 %) small mammals, 73 (54.1 %) fleas and 51 (16.3 %) ticks were positive for Bartonella spp. Most small mammals were positive for uncultured Bartonella sp. (n = 29) followed by Bartonella grahamii (n = 12), Bartonella taylorii (n = 8) and Bartonella sp. N40 (n = 3). Likewise, most fleas were positive for uncultured Bartonella sp. (n = 45) followed by B. grahamii (n = 14), B. taylorii (n = 8), B. sp. N40 (n = 5) and Bartonella elizabethae (n = 2). Most ticks were positive for B. sp. (n = 19) followed by B. grahamii (n = 10), Bartonella chomelii (n = 3), B. taylorii (n = 2) and B. sp. N40 (n = 1). This study's results suggest that rodents and fleas may be reservoirs and vectors, respectively. Zoonotic B. grahamii and B. elizabethae were found in rodents and their fleas. Therefore, humans may contract Bartonella infection by contact to wild rodents. Ticks seem of minor importance in transmitting Bartonella spp. found in fleas and rodents. However, ticks might be vectors of B. chomelii. PMID- 27220974 TI - BMPOS: a Flexible and User-Friendly Tool Sets for Microbiome Studies. AB - Recent advances in science and technology are leading to a revision and re orientation of methodologies, addressing old and current issues under a new perspective. Advances in next generation sequencing (NGS) are allowing comparative analysis of the abundance and diversity of whole microbial communities, generating a large amount of data and findings at a systems level. The current limitation for biologists has been the increasing demand for computational power and training required for processing of NGS data. Here, we describe the deployment of the Brazilian Microbiome Project Operating System (BMPOS), a flexible and user-friendly Linux distribution dedicated to microbiome studies. The Brazilian Microbiome Project (BMP) has developed data analyses pipelines for metagenomic studies (phylogenetic marker genes), conducted using the two main high-throughput sequencing platforms (Ion Torrent and Illumina MiSeq). The BMPOS is freely available and possesses the entire requirement of bioinformatics packages and databases to perform all the pipelines suggested by the BMP team. The BMPOS may be used as a bootable live USB stick or installed in any computer with at least 1 GHz CPU and 512 MB RAM, independent of the operating system previously installed. The BMPOS has proved to be effective for sequences processing, sequences clustering, alignment, taxonomic annotation, statistical analysis, and plotting of metagenomic data. The BMPOS has been used during several metagenomic analyses courses, being valuable as a tool for training, and an excellent starting point to anyone interested in performing metagenomic studies. The BMPOS and its documentation are available at http://www.brmicrobiome.org . PMID- 27220975 TI - A gene encoding a polygalacturonase-inhibiting protein (PGIP) is a candidate gene for bruchid (Coleoptera: bruchidae) resistance in mungbean (Vigna radiata). AB - KEY MESSAGE: The Br locus confers bruchid resistance in mungbean; VrPGIP2 (encoding a polygalacturonase inhibitor) is a strong candidate gene for this resistance. The VrPGIP2 sequence differs between resistant and susceptible lines. Azuki bean weevil (Callosobruchus chinensis) and cowpea weevil (Callosobruchus maculatus) are serious insect pests of mungbean during storage. Bruchid resistance in mungbean is controlled by a single dominant locus, Br. Although the Br locus has been located on a genetic map, molecular basis and function of the gene remain unknown. In this study, high-resolution mapping using a BC11F2 population of 418 plants derived from a cross between 'Kamphaeng Saen 1' (KPS1; susceptible) and 'V2802' (resistant) using simple sequence repeat (SSR) markers delimited the Br locus to a genomic region of 38 Kb of chromosome 5 containing two annotated genes. EST-SSR marker DMB-SSR158 co-segregated perfectly with the Br locus. Bioinformatics analyses revealed that DMB-SSR158 corresponds to a gene encoding a polygalacturonase inhibitor (polygalacturonase-inhibiting protein PGIP) and was designated as VrPGIP2. Comparison of VrPGIP2 coding sequences between four bruchid-resistant (V2802, V1128, V2817 and TC1966) and four bruchid susceptible (KPS1, Sulu-1, CM and an unknown accession) mungbean lines revealed six single nucleotide polymorphisms (SNPs) between the resistant and susceptible groups. Three of the six SNPs resulted in amino acid changes; namely, alanine (A) to serine (S) at position 320, leucine (L) to proline (P) at position 332, and threonine (T) to P at position 335 of the VrPGIP2 sequence in resistant lines, compared with that in susceptible lines. The A to S change at position 320 may affect the interaction between PGIP and polygalacuronase. These results indicate that VrPGIP2 is very likely the gene at the Br locus responsible for bruchid resistance in mungbean. PMID- 27220976 TI - Tailored message interventions versus typical messages for increasing participation in colorectal cancer screening among a non-adherent population: A randomized controlled trial. AB - BACKGROUND: The purpose of this study was to examine the effectiveness and cost efficiency of a tailored message intervention compared with a non-tailored message intervention for increasing colorectal cancer (CRC) screening rates among a non-adherent population, in a community-based client reminder program. METHODS: After a baseline survey for psychological segmentation, 2140 eligible individuals were randomly assigned either to a group with a tailored matched-message condition (N = 356), a group with a non-tailored unmatched-message condition (N = 355), or to two control groups, one using a typical message with a professional design (N = 717) and one without a professional design (N = 712). The main outcome measure was attendance rates in a community-organized CRC screening program within five months of receiving a print reminder. RESULTS: There was a significant difference in fecal occult blood test (FOBT) attendance rates at follow-up assessments between the tailored matched-message condition (14.0 %) and the control (9.9 %; OR = 1.48, p = 0.026), while there was no significant difference between the unmatched-message condition (11.0 %) and the control (OR = 1.12, p = 0.558), and between the matched-message condition and the unmatched message condition (OR = 1.32, p = 0.219). The cost of a one-person increase in FOBT screening was 3,740 JPY for the tailored matched-message condition, while it was 2,747 JPY for the control. CONCLUSIONS: A tailored-message intervention for segmented individuals designed to increase CRC screening rates in a community based client reminder program was significantly effective compared to a usual reminder, but not more effective than an unmatched message in a randomized controlled trial, and was not sufficiently effective to highlight its value from a cost perspective. Therefore, the tailored intervention including target segmentation needs to be improved for future implementation in a CRC screening program for a non-adherent population. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000004384 . Date of Registration: March 2011. PMID- 27220979 TI - Primary Trauma Triage Performed by Bystanders: An Observation Study. AB - OBJECTIVE: The aim of this study was to evaluate whether bystanders with no training in triage can correctly prioritize three injured patients by using a triage instrument. METHOD: An observational study was conducted. Participants performed a primary triage on three paper-based patient cases and answered 11 questions during a public event in the center of Stockholm, Sweden. RESULTS: A total of 69 persons participated in the study. The success rate among all the participants for correct triage of the three patient cases was 52 percent. The female participants and younger participants (<55 years of age) performed correct triage to a greater extent. The over-triage was 12.5 percent and under-triage was 6.3 percent. CONCLUSION: Participants with no prior knowledge of triage instruments may be capable of triaging injured patients with the help of an easy triage instrument. The over- and under-triage percentages were low, and this may indicate that the developed triage instrument is relatively easy to use. It may also indicate that bystanders can identify a severely injured patient. Nordberg M , Castren M , Lindstrom V . Primary trauma triage performed by bystanders: an observation study. Prehosp Disaster Med. 2016;31(4):353-357. PMID- 27220977 TI - Heme oxygenase 1 induction protects myocardiac cells against hypoxia/reoxygenation-induced apoptosis : The role of JNK/c-Jun/Caspase-3 inhibition and Akt signaling enhancement. AB - BACKGROUND: Although recent studies have found that heme oxygenase (HO)-1 plays an important role in myocardiac cell survival, the precise mechanisms occurring during hypoxia/reoxygenation (H/R) injury remain unclear. Therefore, the aim of this study was to investigate the cytoprotective mechanisms of HO-1 against H/R induced myocardiac cell apoptosis and to explore whether the Akt signaling pathway contributed to the protection provided by HO-1. METHODS: Cobalt protoporphyrin (CoPP, a pharmacologic inducer of HO-1) was employed to induce the over-expression of HO-1 before H/R in H9c2 cells. Hoechst staining and flow cytometry were used to examine the extent of apoptosis. Furthermore, the effect of HO-1 on Akt, JNK, and the expression of apoptosis-related proteins (c-JUN and Caspase-3) was determined by Western blotting. RESULTS: The results showed that over-expressed HO-1 could significantly protect myocardiac cells against H/R induced apoptosis in H9c2 cells. Furthermore, the protein expression of p-Akt increased and of p-JNK decreased in the H/R injury H9c2 cells when treated with CoPP. The apoptosis-related proteins c-Jun and caspase-3 were both inhibited by over-expression of HO-1. At the same time, retreatment with zinc protoporphyrin (ZnPP, a specific inhibitor of HO-1 enzymatic activity) or LY294002 (an inhibitor of Akt1) reversed the HO-1-induced changes. CONCLUSION: In summary, our results suggest that HO-1 can decrease H/R-induced myocardiac cell apoptosis; the mechanism may be related to the activation of the Akt signaling pathway and, furthermore, to the inhibition of the JNK/c-Jun/caspase-3 signaling pathway. PMID- 27220978 TI - Aspiration thrombectomy and intracoronary tirofiban in ST-segment elevation myocardial infarction : Combination treatment for patients undergoing primary percutaneous coronary intervention. AB - AIM: Primary percutaneous coronary intervention is the most effective treatment for patients with ST-segment elevation myocardial infarction (STEMI). This study aimed to investigate whether the combination of aspiration thrombectomy with intracoronary tirofiban treatment can result in smaller infarcts and better patient prognosis compared with aspiration thrombectomy alone. PATIENTS AND METHODS: In all, 150 patients with STEMI underwent primary percutaneous coronary intervention. Group A received aspiration thrombectomy and group B received a combination treatment of aspiration thrombectomy with intracoronary tirofiban. The endpoint was major adverse cardiovascular events, including myocardial (re)infarction, cardiovascular death, and target vessel revascularization. RESULTS: The clinical characteristics of the groups were not significantly different (p > 0.05). The percentage of patients whose thrombolysis in myocardial infarction (TIMI) myocardial perfusion grades were less than 3 was significantly higher for group B than for group A (13.9 vs. 3.8 %, p = 0.029). The infarct size on cardiac magnetic resonance imaging was significantly different between groups (p = 0.036). At 6 months after the operation, the echocardiography results were better for patients in group B than for those in group A (p = 0.024 and p = 0.016, respectively). The frequency of bleeding complications and major adverse cardiac events of the groups were not significantly different (p > 0.05). CONCLUSION: Aspiration thrombectomy with intracoronary tirofiban in patients with STEMI is safe and effective. For cases with a large angiographic thrombus burden, tirofiban did not increase the rate of bleeding complications or major adverse cardiovascular events. PMID- 27220980 TI - Development and validation of the FertiMed questionnaire assessing patients' experiences with hormonal fertility medication. AB - STUDY QUESTION: Can a valid and reliable questionnaire be developed to assess patients' experiences with all of the characteristics of hormonal fertility medication valued by them? SUMMARY ANSWER: The FertiMed questionnaire is a valid and reliable tool that assesses patients' experiences with all medication characteristics valued by them and that can be used for all hormonal fertility medications, irrespective of their route of administration. WHAT IS KNOWN ALREADY: Hormonal fertility medications cause emotional strain and differ in their dosage regime and route of administration, although they often have comparable effectiveness. Medication experiences of former patients would be informative for medication choices. A recent literature review showed that there is no trustworthy tool to compare patients' experiences of medications with differing routes of administration, regarding all medication characteristics which patients value. STUDY DESIGN, SIZE, DURATION: The items of the new FertiMed questionnaire were generated by literature review and 23 patient interviews. In 2013, 411 IVF-patients were asked to retrospectively complete the FertiMed questionnaire to assess 1 out of the 8 different medications used for ovarian stimulation, induction of pituitary quiescence, ovulation triggering or luteal support. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 276 patients (on average 35 per medication) from 2 university fertility clinics (Belgium, the Netherlands) completed the FertiMed questionnaire (67% response rate). The FertiMed questionnaire questioned whether items were valued by patients and whether these items were experienced while using the assessed medication. Hence, the final outcome 'Experiences with Valued Aspects Scores' (EVAS) combined importance and experience ratings. The content and face validity, reliability, feasibility and discriminative potential of the FertiMed questionnaire were tested and changes were made accordingly. MAIN RESULTS AND THE ROLE OF CHANCE: Patient interviews defined 51 items relevant to seven medication characteristics previously proved to be important to patients. Item analysis deleted 10 items. The combined results from the reliability and content validity analysis identified 10 characteristics instead of 7. The final FertiMed questionnaire was valid (Adapted Goodness of Fit Index = 0.95) and all but one characteristic ('ease of use: disturbance') could be assessed reliably (Cronbach's alpha > 0.60). The EVAS per characteristic differed between the medications inducing pituitary quiescence (P = 0.001). LIMITATIONS, REASON FOR CAUTION: As all eight medications prescribed in the recruiting clinics were questioned, sample sizes per medication were rather small for presenting EVAS per medication and for testing the discriminative potential of the FertiMed questionnaire. WIDER IMPLICATION OF THE FINDINGS: The FertiMed questionnaire can be used for all hormonal fertility medications to assess in a valid and reliable way whether patients experience what they value regarding 10 medication characteristics (e.g. side effects and ease of use). Future randomized controlled trials (RCT) comparing medications could include the FertiMed questionnaire as a Patient Reported Experience Measure (PREM). Insights from these RCTs could be used to develop evidence-based decision aids aiming to facilitate shared physician patient medication choices. STUDY FUNDING/COMPETING INTERESTS: Funding was received from the University of Leuven and Amsterdam University Medical Centre. E.A.F.D. holds a postdoctoral fellowship of the Research Foundation of Flanders. T.D. was appointed Vice-President and Head Global Medical Affairs Fertility at Merck (Darmstadt, Germany) on 1 October 2015. The reported project was initiated and finished before this date. The other authors had no conflicts of interest to declare. PMID- 27220981 TI - Anti-Mullerian hormone in seminal plasma and serum: association with sperm count and sperm motility. AB - STUDY QUESTION: Is anti-Mullerian hormone (AMH) in seminal plasma and serum associated with sperm count and sperm motility? SUMMARY ANSWER: AMH in seminal plasma is positively associated with sperm concentration, total sperm count, and progressive sperm motility, while no association was found between serum AMH levels and semen characteristics. WHAT IS KNOWN ALREADY: AMH is secreted by the Sertoli cells and is detectable in both serum and seminal plasma in adult men. It has been suggested as a marker of spermatogenesis, however, its function in the adult male is largely unknown. STUDY DESIGN, SIZE, DURATION: Participants were recruited in between 2008 and 2013, from the general population (n = 94) and from couples with female factor infertility in a fertility clinic (n = 32). AMH data were available for 126 participants. PARTICIPANTS/MATERIALS, SETTING, METHODS: Mean age of the participants was 36 years, and BMI was between 19 and 39 kg/m(2). Semen quality was evaluated by semen analysis according to the World Health Organization, and AMH levels were measured in seminal plasma. Blood samples were analyzed for AMH, total testosterone, FSH, LH, and inhibin B. AMH analysis was performed using the improved Beckman Coulter method. MAIN RESULTS AND THE ROLE OF CHANCE: The central 95% intervals of AMH concentrations were 2-2812 pmol/l in seminal plasma and 15-134 pmol/l in serum. Total AMH (pmol/ejaculate) in seminal plasma was positively associated with sperm concentration (B = 0.177, P< 0.001) and total sperm count (B = 0.212, P< 0.001) when adjusted for age, BMI, time of abstinence, and positively associated with progressive sperm motility (B = 6.762, P = 0.001) when adjusted for age, BMI, time of abstinence, and site of sample collection. No association was found between serum AMH and semen characteristics. Serum levels of inhibin B were positively correlated with total AMH in seminal plasma (B = 18.52, P< 0.001) and concentration of AMH in serum (B = 0.507, P< 0.001). LIMITATIONS, REASONS FOR CAUTION: Participants were recruited both from the general population and from a fertility clinic. This may limit the applicability to men in the general population. WIDER IMPLICATIONS OF THE FINDINGS: The AMH levels found in this study show large inter-individual variation, especially in seminal plasma. AMH in seminal plasma may serve as a marker of sperm production, however, in the lower range the predictive value is low. STUDY FUNDING/COMPETING INTERESTS: All funding for this study was received from Oslo and Akershus University College of Applied Sciences. The authors have no conflicts of interest to declare. PMID- 27220982 TI - Zeaxanthinibacter aestuarii sp. nov., isolated from estuary sediment and emended description of the genus Zeaxanthinibacter Asker et al. 2007. AB - A Gram-staining-negative, strictly aerobic and yellow-pigmented bacterium, designated strain S2-22T, was isolated from estuary sediment in South Korea. Cells of strain S2-22T were oxidase- and catalase-positive rods without gliding motility. Growth was observed at 15-43 degrees C (optimum, 35-37 degrees C), at pH 5.5-9.0 (optimum, pH 6.5-7.5) and in the presence of 0.0-10.0 % (w/v) NaCl (optimum, 2.0 %). Phylogenetic analysis based on 16S rRNA gene sequences showed that strain S2-22T formed a tight phyletic lineage with Zeaxanthinibacter enoshimensis TD-ZE3T with a high bootstrap value and their 16S rRNA gene sequence similarity was 94.6 %. The respiratory quinone detected was menaquinone 6 (MK-6) only and iso-C15 : 0, iso-C17 : 0 3-OH, summed feature 3 (comprising C16 : 1omega7c/C16 : 1omega6c) and iso-C15 : 1G were the major fatty acids. Phosphatidylethanolamine was identified as the major polar lipid and five unidentified aminolipids, two unidentified phospholipids and three unidentified lipids were also detected as minor polar lipids. The G+C content of the genomic DNA was 45.5 mol%. Based on the phenotypic, chemotaxonomic and molecular features, strain S2-22T clearly represents a novel species of the genus Zeaxanthinibacter, for which the name Zeaxanthinibacter aestuarii sp. nov. is proposed. The type strain is S2-22T (=KACC 18503T=JCM 31155T). An emended description of the genus Zeaxanthinibacter is also proposed. PMID- 27220984 TI - A mechanism for solvent extraction of first row transition metals from chloride media with the ionic liquid tetraoctylammonium oleate. AB - Aqueous waste streams of the metallurgical industry often contain considerable concentrations of metal salts. Previous research showed that the metal chloride salts of zinc(ii), manganese(ii) and iron(iii) can be recovered by solvent extraction using a sustainable and renewable fatty acid based ionic liquid as the extractant. In this paper, the extraction mechanism of Zn(ii), Co(ii) and Ni(ii) from chloride media has been studied systematically. The metal extraction performances of the precursors, sodium oleate and tetraoctylammonium chloride, were compared to the extraction performance of the ionic liquid tetraoctylammonium oleate. Slope analysis experiments were performed to determine the number of ionic liquid molecules involved in the extraction. The experimental data showed that Co(ii) and Ni(ii) were extracted in the pH range from 6 to 8 by the formation of negatively charged metal carboxylate complexes with tetraalkylammonium counter ions. In contrast, Zn(ii) gets extracted as a mixed metal chloride carboxylate anionic complex with tetraalkylammonium counter ions. This extraction mechanism was supported by EXAFS measurements. PMID- 27220983 TI - A Thought Experiment in Wellness: Suppose the United States Matched Norway. PMID- 27220985 TI - Urine Ethyl Glucuronide Unraveling the Reality of Abstinence Monitoring in a Routine Outpatient Setting: A Cross-Sectional Comparison with Ethanol, Self Report and Clinical Judgment. AB - AIMS: To test the screening performance of urinary ethyl glucuronide (EtG) under routine clinical conditions in a sample of alcohol-dependent outpatients, comparing it against urinary ethanol, self reports and clinical judgment. METHODS: A cross-sectional study under routine conditions was conducted in February 2015, where 613 consecutive urinary samples, provided by 188 outpatients with alcohol use disorders, were analyzed for ethanol and EtG (cut-off level = 500 ng/ml). Clinical variables such as the presence of aversive medication, comorbidities and clinician judgment were also collected. The discrepancy between the number of alcohol and EtG positives was recorded. A logistic regression analysis including clinical variables was conducted to assess for predictors of EtG positivity. RESULTS: Urinary alcohol yielded 9 positives (1.5% of all urine samples) belonging to 8 patients. EtG yielded 136 positives (22% of all urine samples) belonging to 74 patients. Of these, 93.4% (127 of 136) were negative for alcohol. All urinary alcohol positives resulted in EtG positives. The clinician judged 48 samples from 26 patients as belonging to not abstinent patients and 550 samples from 178 patients as belonging to abstinent patients. She was unsure in 15 samples from 15 patients. When comparing it against EtG as the gold standard, the area under the curve was 0.592. Self reports were extremely unreliable in this study, with only 5 patients reporting drinking in a total of 6 urine samples. In the logistic regression model, only aversive medications (OR 2.1, 95% CI 1.3-3.3) and clinician judgment (OR 2, 95% CI 1.4-2.9) resulted in significant effects. CONCLUSIONS: EtG performed largely better than ethanol for urine screening in alcohol outpatients, detecting an extra 20.4% (125 out of 613) of positives. It means that for each alcohol-positive sample, there were 15 EtG positive samples. Although better than ethanol, clinician judgment was also not performed efficiently. If routinely implemented in the screening of alcohol outpatients, EtG might bring relevant changes that merit further research. PMID- 27220986 TI - Discovery of the New Plant Growth-Regulating Compound LYXLF2 Based on Manipulating the Halogenase in Amycolatopsis orientalis. AB - Analysis of the Amycolatopsis orientalis HCCB10007 genome revealed new gene clusters involved in natural product biosynthesis that were not associated with the production of known compounds. Halogenases are a type of tailoring enzymes that are usually found within these secondary gene clusters. In this study, we identified an indole-type halometabolite 6-chrolo-1H-indole-3-carboxamide, named LYXLF2, by whole genome mining and metabolic profiling of a flavin-dependent halogenase mutant. LYXLF2 is a new plant growth-regulating compound that promotes root elongation. The results of this study demonstrated that the special gene knock-out/comparative metabolic profiling approach provides a powerful tool for the discovery of novel natural products by genome mining. PMID- 27220988 TI - Membrane lipid profile of in vitro-produced embryos is affected by vitrification but not by long-term dietary supplementation of polyunsaturated fatty acids for oocyte donor beef heifers. AB - Dietary rumen-protected polyunsaturated fatty acids (PUFAs) rich in linoleic acid (LA) may affect embryo yield, and LA can modulate the molecular mechanisms of lipid uptake in bovine blastocysts produced in vitro. In embryos, membrane lipids, such as phosphatidylcholines (PCs) and sphingomyelins (SMs), affect cryopreservation success. The aim of the present study was to evaluate embryonic developmental rates after the IVF of oocytes retrieved from Nellore heifers fed for approximately 90 days with rumen-protected PUFAs rich in LA. In addition, we evaluated embryo cryotolerance and the membrane structure lipid composition using matrix-assisted laser desorption ionisation mass spectrometry of fresh and vitrified embryos. Embryo development to the blastocyst stage (mean 43.2%) and embryo survival after vitrification and warming (mean 79.3%) were unaffected by diet. The relative abundance of one lipid species (PC ether (PCe; 38:2, which means that this lipid has 38 carbon atoms and 2 double bonds in the fatty acyl residues) was increased after PUFAs supplementation. However, 10 ions were affected by cryopreservation; ions consistent with PC 32:0, PC 34:1, SM 24:1, PC 40:6 or PC 42:9, PC plasmalogen (PCp) 44:10 or PC 42:7, triacylglycerol (TAG) 54:9 and a not assigned ion (m/z 833.2) were lower in blastocysts that survived to the cryopreservation process compared with fresh blastocysts, whereas the abundance of the ions PC 36:3 or PC 34:0, PCe 38:2 or PC 36:6 and PC 36:5 or PCe 38:1 were increased after cryopreservation. Thus, the results demonstrate that the mass spectrometry profiles of PC, SM and TAG species differ significantly in bovine blastocysts upon cryopreservation. Because the lipid ion abundances of fresh and vitrified-warmed embryos were distinct, they can be used as potential markers of post-cryopreservation embryonic survival. PMID- 27220989 TI - Anticancer activity of 7,8-dihydroxyflavone in melanoma cells via downregulation of alpha-MSH/cAMP/MITF pathway. AB - Malignant melanoma is one of the most aggressive skin cancer and highly resistant to most conventional treatment. In the present study, we aimed to investigate the anticancer effects and mechanisms of action of 7,8-dihydroxyflavone (7,8-DHF), a monophenolic flavone, in melanoma cells. At concentrations not exhibiting cytotoxicity, 7,8-DHF potently inhibited growth and clonogenic survival of alpha melanocyte stimulating hormone (alpha-MSH)-stimulated B16F10 melanoma cells. Furthermore, it significantly blocked migration and invasion of the metastatic melanoma cells. We also observed that 7,8-DHF exhibits anti-melanogenic activity through inhibition of tyrosinase activity in alpha-MSH-stimulating condition. Notably, the suppressive activities of 7,8-DHF on melanoma progression were associated with the downregulation of microphthalmia-associated transcription factor (MITF) and its main downstream transcription targets, including hypoxia inducible factor 1alpha (HIF1alpha) and c-MET, by a decrease in cyclic adenosine monophosphate (cAMP) level. In addition, combination treatment with 7,8-DHF and resveratrol, a known therapeutic agent against melanoma, had greater anticancer activities and MITF inhibition than treatment with each single agent in alpha-MSH treated B16F10 cells. Collectively, these findings may contribute to the potential application of 7,8-DHF in the prevention and treatment of malignant melanoma. PMID- 27220990 TI - Erratum to: Effectiveness of a home-based cognitive behavioral program to manage concerns about falls in community-dwelling, frail older people: results of a randomized controlled trial. PMID- 27220987 TI - The Antenatal Corticosteroids Trial (ACT)'s explanations for neonatal mortality - a secondary analysis. AB - BACKGROUND: The Antenatal Corticosteroid Trial assessed the feasibility, effectiveness, and safety of a multifaceted intervention to increase the use of antenatal corticosteroids (ACS) in mothers at risk of preterm birth at all levels of care in low and middle-income countries. The intervention effectively increased the use of ACS but was associated with an overall increase in neonatal deaths. We aimed to explore plausible pathways through which this intervention increased neonatal mortality. METHODS: We conducted a series of secondary analyses to assess whether ACS or other components of the multifaceted intervention that might have affected the quality of care contributed to the increased mortality observed: 1) we compared the proportion of neonatal deaths receiving ACS between the intervention and control groups; 2) we compared the antenatal and delivery care process in all births between groups; 3) we compared the rates of possible severe bacterial infection between groups; and 4) we compared the frequency of factors related to ACS administration or maternal high risk conditions at administration between the babies who died and those who survived 28 days among all births in the intervention group identified as high risk for preterm birth and received ACS. RESULTS: The ACS exposure among the infants who died up to 28 days was 29 % in the intervention group compared to 6 % in controls. No substantial differences were observed in antenatal and delivery care process between groups. The risk of pSBI plus neonatal death was significantly increased in intervention clusters compared to controls (2.4 % vs. 2.0 %, adjusted RR 1.17, 95 % CI 1.04-1.30, p = 0.008], primarily for infants with birth weight at or above the 25(th) percentile. Regarding factors related to ACS administration, term infants who died were more likely to have mothers who received ACS within 7 days of delivery compared to those who survived 28 days (26.5 % vs 17.9 %, p = 0.014), and their mothers were more likely to have been identified as high risk for hypertension and less likely for signs of preterm labor. CONCLUSIONS: These results suggest that ACS more than other components of the intervention may have contributed to the overall increased neonatal mortality. ACS may have also been involved in the observed increased risk of neonatal infection and death. Further trials are urgently needed to clarify the effectiveness and safety of ACS on neonatal health in low resource settings. PMID- 27220991 TI - American College Students' Views of Depression and Utilization of On-Campus Counseling Services. AB - BACKGROUND: College students are becoming increasingly depressed; however, many do not attend university counseling to seek help. OBJECTIVES: What is the relationship between young adults' mental health literacy, perceived stigma of depression and treatment, knowledge of treatment benefits and risks, beliefs about alternative therapies, and influence of his or her social network with usage of university counseling? STUDY DESIGN: A survey was administered to N = 107 American undergraduate college students to ascertain the students' understanding of depression and their views of counseling services on campus. RESULTS: Both likelihood of using alternative therapies and perceived discrimination of social network accounted for 18% of the variance for likelihood of participants seeking campus counseling. CONCLUSIONS: When a young adult college student perceives stigma or discrimination of depression from family and friends, then they may be less likely to seek university counseling for depression as well as possible applications with alternative therapies as a favorable option. PMID- 27220992 TI - Optofluidic chlorophyll lasers. AB - Chlorophylls are essential for photosynthesis and also one of the most abundant pigments on earth. Using an optofluidic ring resonator of extremely high Q factors (>10(7)), we investigated the unique characteristics and underlying mechanism of chlorophyll lasers. Chlorophyll lasers with dual lasing bands at 680 nm and 730 nm were observed for the first time in isolated chlorophyll a (Chla). Particularly, a laser at the 730 nm band was realized in 0.1 mM Chla with a lasing threshold of only 8 MUJ mm(-2). Additionally, we observed lasing competition between the two lasing bands. The presence of laser emission at the 680 nm band can lead to quenching or significant reduction of laser emission at the 730 nm band, effectively increasing the lasing threshold for the 730 nm band. Further concentration-dependent studies, along with theoretical analysis, elucidated the mechanism that determines when and why the laser emission band appears at one of the two bands, or concomitantly at both bands. Finally, Chla was exploited as the donor in fluorescence resonance energy transfer to extend the laser emission to the near infrared regime with an unprecedented wavelength shift as large as 380 nm. Our work will open a door to the development of novel biocompatible and biodegradable chlorophyll-based lasers for various applications such as miniaturized tunable coherent light sources and in vitro/in vivo biosensing. It will also provide important insight into the chlorophyll fluorescence and photosynthesis processes inside plants. PMID- 27220993 TI - Lanthanide Coordination Polymer Nanoparticles as an Excellent Artificial Peroxidase for Hydrogen Peroxide Detection. AB - Lanthanide coordination polymer nanoparticles (Ln-CPNs) have been recently demonstrated as excellent platforms for biomolecule detection. In this work, we synthesized novel cerium coordination polymer nanoparticles ATP-Ce-Tris CPNs in a simple and quick way using ATP molecules as the biocompatible ligands to Ce(3+) ions in tris(hydroxymethyl)aminomethane hydrochloric (Tris-HCl) solution. In view of the excellent free radical scavenging property of cerium compounds, which is ascribed to the mixed valence state (Ce(3+), Ce(4+)) and the reversible switch from Ce(3+) to Ce(4+), the synthesized ATP-Ce-Tris CPNs was used as artificial peroxidase to selectively and sensitively detect H2O2. The sensing mechanism depends on the oxidation of the fluorescent ATP-Ce(III)-Tris CPNs to nonfluorescent ATP-Ce(IV)-Tris CPNs by H2O2. Compared with those inorganic cerium oxide sensors, this kind of fluoresence ATP-Ce-Tris CPNs sensor needs no additional organic redox dye, such as ABTS (2,20-azino-bis(3-ethylbenzthiazoline 6-sulfonic acid), TMB (3,3,5,5-tetramethylbenzidine), or fluorescein as signal molecules. Moreover, such ATP-Ce-Tris CPNs sensor exhibited a more sensitive response to H2O2 with a detection limit down to 0.6 nM, which is 2 orders of magnitude lower than those of cerium oxide sensors. This sensing platform was further extended to the detection of glucose in combination with the specific catalytic effect of glucose oxidase (GOx) for the oxidation of glucose and formation of H2O2. PMID- 27220994 TI - Metallic glassy Zr70Ni20Pd10 powders for improving the hydrogenation/dehydrogenation behavior of MgH2. AB - Because of its low density, storage of hydrogen in the gaseous and liquids states possess technical and economic challenges. One practical solution for utilizing hydrogen in vehicles with proton-exchange fuel cells membranes is storing hydrogen in metal hydrides. Magnesium hydride (MgH2) remains the best hydrogen storage material due to its high hydrogen capacity and low cost of production. Due to its high activation energy and poor hydrogen sorption/desorption kinetics at moderate temperatures, the pure form of MgH2 is usually mechanically treated by high-energy ball mills and catalyzed with different types of catalysts. These steps are necessary for destabilizing MgH2 to enhance its kinetics behaviors. In the present work, we used a small mole fractions (5 wt.%) of metallic glassy of Zr70Ni20Pd10 powders as a new enhancement agent to improve its hydrogenation/dehydrogenation behaviors of MgH2. This short-range ordered material led to lower the decomposition temperature of MgH2 and its activation energy by about 121 degrees C and 51 kJ/mol, respectively. Complete hydrogenation/dehydrogenation processes were successfully achieved to charge/discharge about 6 wt.%H2 at 100 degrees C/200 degrees C within 1.18 min/3.8 min, respectively. In addition, this new nanocomposite system shows high performance of achieving continuous 100 hydrogen charging/discharging cycles without degradation. PMID- 27220995 TI - Contextual cuing as a form of nonconscious learning: Theoretical and empirical analysis in large and very large samples. AB - Numerous studies have demonstrated that associative learning can affect visual cognition. In one such effect, search times for a target hidden among similar distractors are faster for repeated search configurations compared with novel configurations. This contextual cuing effect is particularly interesting, because researchers routinely have failed to find evidence of recognition of the repeated configurations, concluding that the effect is a form of nonconscious learning. Vadillo, Konstantinidis, and Shanks (2016) recently criticized this conclusion on a number of methodological and conceptual grounds that suggest the area suffers from a high probability of false-negative results on awareness tests and misinterpretation of weak or absent relationships between cuing and awareness measures. We developed further predictions from theoretical models assuming that single or independent memory sources drive learning and awareness and discuss how these predictions fare in three new contextual cuing experiments involving large (n > 60) and very large samples (n > 600). The data support the absence of a positive relationship between recognition and the cuing effect both at the participant and configuration level, the probability of which being a false negative is very low in a model assuming a single memory source drives learning and awareness. This was the case using both conventional and Bayesian analyses. The combination of this theoretical and empirical analysis suggests that contextual cuing is not dependent on cue recognition and provides evidence that it reflects a genuine form of nonconscious learning. PMID- 27220997 TI - Review of the genus Shirleyrhynchus Beveridge & Campbell, 1988 (Trypanorhyncha: Shirleyrhynchidae), with the resurrection of S. butlerae Beveridge & Campbell, 1988 and the description of S. panamensis n. sp. AB - A new species of trypanorhynch cestode is described from two species of stingrays, the Panamic stingray Urotrygon aspidura (Jordan & Gilbert) and the Pacific chupare Himantura pacifica (Beebe & Tee-Van) collected in the Golfo de Montijo in the Eastern Pacific Ocean off the coast of Panama. Shirleyrhynchus panamensis n. sp. represents an important addition to the family, which until now consisted of two monotypic genera. The new species is characterised by an elongate scolex with four, ovate bothria, presence of prebulbar organs, absence of gland cells within the muscular bulbs and an oncotaxy with a typical heteroacanthous, heteromorphous tentacular armature, a characteristic basal armature and the presence of a slight basal swelling. It is readily distinguished from its congeners by a smaller scolex and features of the oncotaxy, such as dissimilar hooks on opposing principle rows, a commencement of hook rows from the bothrial to the antibothrial surface and a much shorter basal armature. Although described only on the basis of immature worms lacking a strobila, the new species adds information on features of the oncotaxy within Shirleyrhynchus Beveridge & Campbell, 1988. Observation of the holotype of Shirleyrhynchus aetobatidis (Shipley & Hornell, 1906) revealed apparent differences from Australian specimens that have been described as Shirleyrhynchus butlerae Beveridge & Campbell, 1988 but which were later synonymised. Observations of type-specimens of S. butlerae also revealed differences from the original description and some morphological characteristics are amended. Shirleyrhynchus butlerae is herein resurrected and an amended generic diagnosis and a key to the identification of species are provided. The molecular voucher specimen of 'S. aetobatidis' utilised in previous molecular phylogenetic studies was re-observed which revealed a misidentification of the specimen with Parachristianella indonesiensis Palm, 2004. PMID- 27220996 TI - A unified account of categorical effects in phonetic perception. AB - Categorical effects are found across speech sound categories, with the degree of these effects ranging from extremely strong categorical perception in consonants to nearly continuous perception in vowels. We show that both strong and weak categorical effects can be captured by a unified model. We treat speech perception as a statistical inference problem, assuming that listeners use their knowledge of categories as well as the acoustics of the signal to infer the intended productions of the speaker. Simulations show that the model provides close fits to empirical data, unifying past findings of categorical effects in consonants and vowels and capturing differences in the degree of categorical effects through a single parameter. PMID- 27220999 TI - Revision of the genus Soricinia Spassky & Spasskaja, 1954 (Cestoda: Cyclophyllidea: Hymenolepididae) with redescriptions of three species, an amended generic diagnosis and an identification key to species. AB - Redescriptions of three species of Soricinia Spassky & Spasskaja, 1954 are provided. The type-species of the genus, Soricinia soricis (Baer, 1925), is redescribed on the basis of the holotype from the Alpine shrew Sorex alpinus Schinz collected in Saleve Mountain, France. Since the type-material of Soricinia infirma (Zarnowski, 1955) has apparently been lost, a neotype from the type-host Sorex araneus L. and from a region reasonably close to the type-locality (Poltavska Oblast' in the Ukraine), is designated. The type-material of Soricinia quarta (Karpenko, 1983) Karpenko, 1999 from Sorex isodon Turov in Khabarovsk Kray (Russia) is redescribed. A taxonomic revision and an overview of the geographical distribution of species of the genus Soricinia are presented. An amended generic diagnosis and a key to identification of Soricinia spp. are also presented. PMID- 27221000 TI - Broadening diversity in the Arostrilepis horrida complex: Arostrilepis kontrimavichusi n. sp. (Cyclophyllidea: Hymenolepididae) in the western red backed vole Myodes californicus (Merriam) (Cricetidae: Arvicolinae) from temperate latitudes of the Pacific Northwest, North America. AB - Specimens originally identified provisionally as Hymenolepis horrida (Linstow, 1901) [later Arostrilepis horrida (Linstow, 1901)] in Myodes californicus (Merriam) from near the Pacific coastal zone of southern Oregon are revised. Specimens in western red-backed voles represent an undescribed species of Arostrilepis Mas Coma & Tenora, 1997, contributing to recognition and resolution of a broadening complex encompassing cryptic diversity for these hymenolepidid tapeworms distributed across the Holarctic region. Consistent with recent studies defining diversity in the genus, the form, dimensions, and spination (pattern, shape and size) of the cirrus are diagnostic. Among 12 nominal congeners, specimens of A. kontrimavichusi n. sp. are further distinguished by the relative position and length of the cirrus-sac, arrangement of the testes and relative size of the external seminal vesicle and seminal receptacle. Specimens from Oregon voles represent the fifth endemic hymenolepidid in this genus from the Nearctic. Host range for the North American assemblage of species includes Cricetidae (Arvicolinae and Neotominae), Heteromyidae, Geomyidae, and rarely Sciuridae. PMID- 27220998 TI - Molecular characterisation of three avian haemoproteids (Haemosporida, Haemoproteidae), with the description of Haemoproteus (Parahaemoproteus) palloris n. sp. AB - DNA barcoding (molecular characterisation) is a useful tool for describing the taxonomy and systematics of organisms. Over 250 species of avian haemosporidian parasites have been described using morphological characters, yet molecular techniques based on polymerase chain reaction (PCR) suggest this diversity is underestimated. Moreover, molecular techniques are particularly useful for the detection of chronic infections and tissue stages of these parasites. Species delimitation is problematic among haemosporidians, and many questions about the mechanisms and patterns of speciation, host specificity and pathogenicity are still unresolved. Accumulation of additional genetic and morphological information is needed to approach these questions. Here, we combine microscopic examination with PCR-based methods to develop molecular characterisation of Haemoproteus (Parahaemoproteus) manwelli Bennett, 1978 and Haemoproteus (Parahaemoproteus) gavrilovi Valkiunas & Iezhova, 1990, both of which parasitise the bee-eater Merops apiaster L. We also describe a new species, Haemoproteus (Parahaemoproteus) palloris n. sp., from the blood of the willow warbler Phylloscopus trochilus (L.). We performed phylogenetic analyses with a set of mitochondrial cytochrome b (cyt b) gene lineages, which have been linked to parasite morphospecies and are available in the MalAvi database. Our findings show that morphological characters, which have been traditionally used in the description of haemosporidians, exhibit phylogenetic congruence. This study contributes to a better understanding of avian haemosporidian diversity and provides new molecular markers (cyt b and apicoplast gene sequences) for the diagnostics of inadequately investigated haemosporidian infections. PMID- 27221002 TI - Crocidurobia faini n. sp. (Acariformes: Myobiidae), a new mite species parasitising shrews of the genus Crocidura Wagler (Soricomorpha: Soricidae) in DR Congo. AB - A new species Crocidurobia faini n. sp. (Acariformes: Myobiidae) recorded on Crocidura denti Dollman (type-host) (Soricomorpha: Soricidae), Crocidura cf. niobe Thomas, Crocidura cf. littoralis Heller, and Crocidura sp. from DR Congo is described. This new species differs in both sexes from all other species of the subgenus Crocidurobia Jameson, 1970 by short setae c2, more than three times shorter than setae se. Females of the new species differ from those of the close species Crocidurobia toroensis Dusbabek, 1983 by setal bases e2 situated slightly anterior to the level of setal bases e1; males of the new species differ by the genital shield bearing five pairs of setae situated anterior to the level of setal bases d1. PMID- 27221001 TI - Two new species of Philometra Costa, 1845 (Nematoda: Philometridae) from Mycteroperca spp. (Serranidae) in the North-West Atlantic and northern Gulf of Mexico, USA. AB - Based on light and scanning electron microscopical studies, two new species of Philometra Costa, 1845 (Nematoda: Philometridae) are described from two species of Mycteroperca Gill (Serranidae), marine perciform fishes, in coastal waters off Florida, USA: Philometra deburonae n. sp. from the inner side of operculum of the yellowfin grouper Mycteroperca venenosa (L.) and P. incognita n. sp. from the ovary of the gag M. microlepis (Goode & Bean). Philometra deburonae n. sp. is mainly characterised by the body length of males (1.90-2.38 mm), the length of the spicules (78-84 um) and gubernaculum (54 um) and the presence of small outer cephalic papillae, a pair of fairly large caudal projections and the oesophageal gland extending anteriorly beyond the nerve-ring in subgravid females. Philometra incognita n. sp. is distinguished by the caudal mound consisting of two lateral reniform parts widely separated dorsally from each other, the absence of a pair of large papillae situated posteriorly to the cloaca, the shape and structure of the distal end of the gubernaculum plus the lengths of the spicules (117-141 um) and gubernaculum (60-81 um) in the male, the absence of caudal projections and the comparatively large larvae in the uterus (660-675 um long) of the gravid female, as well as, the body length of both males (2.45-3.11 mm) and gravid females (120-180 mm). The present descriptions of an additional two new philometrids increases the number of recorded nominal species of Philometra parasitising groupers (Serranidae) in the Gulf of Mexico to nine. PMID- 27221003 TI - A new species of Leposphilus Hesse, 1866 (Copepoda: Philichthyidae) parasitic in the interorbital canals of the whitemouth croaker Micropogonias furnieri (Desmarest) (Sciaenidae) off Brazil with an amended diagnosis of the genus. AB - A new species of the monotypic genus Leposphilus Hesse, 1866 (Cyclopoida: Philichthyidae), Leposphilus vogti n. sp., is described based on adult female and male specimens from the interorbital canals of Micropogonias furnieri (Desmarest) (Sciaenidae) in Sepetiba Bay, State of Rio de Janeiro, Brazil. The new species differs from its only congener, L. labrei Hesse, 1866, by the following combination of characters in the adult female: a globular cephalosome, a two segmented maxilla, and fourth abdominal somite fused to caudal ramus; and in the adult male: presence of maxilliped, leg 3 with five setae, and caudal rami tipped with six setae. In addition, an amendment of diagnosis of Leposphilus is provided based on the characters of the new species. Previous records of philichthyid copepods from actinopterygians in the Atlantic and Pacific Oceans off the American continent are also given. PMID- 27221004 TI - Morphological and molecular characterisation of Haemogregarina sp. (Apicomplexa: Adeleina: Haemogregarinidae) from the blood of the Caspian freshwater turtle Mauremys caspica (Gmelin) (Geoemydidae) in Iran. AB - To date, a number of species of Haemogregarina have been described from different turtle hosts, mainly based on the morphology of the developmental stages detected in the host erythrocytes. The diversity and overlapping morphological features in the old and recent descriptions has led to considerable complications in the taxonomy of Haemogregarina spp. In this study, different stages of maturity and developing gamonts of a putative new species of Haemogregarina were detected in erythrocytes of the Caspian turtle Mauremys caspica (Gmelin) (Geoemydidae) originating from a southern province in Iran. Although some of the morphological characteristics were consistent with Haemogregarina stepanowi Danilewsky, 1885, some new observations were made, particularly in the gamont stage. The phylogenetic analysis based on 18S rDNA sequences revealed that the present isolate appears as basal to a large clade of Haemogregarina spp. with sequences available in the GenBank database. In accordance with the phylogenetic results, the present Iranian isolate showed a higher degree of interspecific divergence (up to 3.3%) compared to the data for the taxa available in the GenBank database. Thus, molecular data indicate that this isolate may represent a new species. However, further genetic analyses are needed as a complementary tool to the morphological characterisation in order to elucidate the phylogenetic relationships of Haemogregarina spp. PMID- 27221005 TI - Oligoclonality and new agent evaluation in acute lymphoblastic leukaemia. AB - New agent development rests on the fundamental assumption that candidate agents or drug combinations that induce objective responses after relapse will prevent relapse, if applied prior to relapse. However, cumulative experience now includes at least 5 examples of interventions with post-relapse objective response rates greater than 50% that failed to improve outcomes when applied prior to relapse. Emerging insights into oligoclonality provide some explanation. In acute lymphoblastic leukaemia, the predominant clones at relapse differ from the predominant clones at presentation. Arguably, the more highly proliferative clones that predominate at relapse differ in drug sensitivity from the less proliferative clones that escape primary therapy. Interventions effective against the predominant clones at relapse may have no effect on the antecedent escapee clones. Response is not sufficient in new agent development. Duration of response has attracted less attention because of variability in post-remission therapy but some patient subsets have such a uniformly dismal outcome that details of post remission therapy may be irrelevant. Benchmarks are needed. Are recovering blasts members of the same clone or do they represent a new clone? When you eradicate the predominant clones you get a response. When you eradicate all clones, you get a cure. PMID- 27221006 TI - TNF-alpha enhances vascular cell adhesion molecule-1 expression in human bone marrow mesenchymal stem cells via the NF-kappaB, ERK and JNK signaling pathways. AB - The migration of circulating mesenchymal stem cells (MSCs) to injured tissue is an important step in tissue regeneration and requires adhesion to the microvascular endothelium. The current study investigated the underlying mechanism of MSC adhesion to endothelial cells during inflammation. In in vitro MSC culture, tumor necrosis factor-alpha (TNF-alpha) increased the level of vascular cell adhesion molecule-1 (VCAM-1) expression in a dose-dependent manner. The nuclear factor-kappaB (NF-kappaB), extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathway inhibitors, pyrrolidine dithiocarbamate (PDTC), U0126 and SP600125, respectively, suppressed VCAM-1 expression induced by TNF-alpha at the mRNA and protein levels (P<0.05). TNF alpha augmented the activation of NF-kappaB, ERK and JNK, and promoted MSC adhesion to human umbilical vein endothelial cells; however, the inhibitors of NF kappaB, ERK and JNK did not affect this process in these cells. The results of the current study indicate that adhesion of circulating MSCs to the endothelium is regulated by TNF-alpha-induced VCAM-1 expression, which is potentially mediated by the NF-kappaB, ERK and JNK signaling pathways. PMID- 27221007 TI - Quantitative systematic review of the effects of non-pharmacological interventions on reducing apathy in persons with dementia. AB - AIM: To review the quantitative evidence concerning the effects of non pharmacological interventions on reducing apathy in persons with dementia. BACKGROUND: Apathy, a prevalent behavioural symptom among persons with Alzheimer Disease, is defined as a disorder of motivation with deficits in behavioural, emotional and cognitive domains and is associated with serious social and physical obstacles. Non-pharmacological interventions show promise as symptom control modalities among persons with dementia. DESIGN: Quantitative systematic review. DATA SOURCES: CINAHL, PubMed, PSYCHinfo and Cochrane Trials databases were searched for published English language research inclusive through December 2014, with no early year limiters set. REVIEW METHODS: Comprehensive searches yielded 16 international randomized controlled trials or quasi-experimental studies based on inclusion criteria and a rigorous quality appraisal process. RESULTS: A narrative summary analysis revealed that non-pharmacological interventions for apathy varied substantially and lacked specificity, conceptual clarity and were methodologically heterogeneous. Select interventions demonstrated effectiveness, but lacked systematic long-term follow-up. Limitations include publication bias and lack of a meta-analytic approach due to the methodological heterogeneity of included studies. CONCLUSION: Study results demonstrate promise for the use of non-pharmacological interventions, particularly music-based interventions, in reducing apathy levels in individuals with dementia. Intervening to reduce apathy may have a positive clinical impact and healthcare providers should be encouraged to incorporate positive sources of interest and intellectual stimulation into care. However, future research is needed to examine the aetiologic mechanism and predictors of apathy, to improve evidence-based interventions and specificity and to optimize dosage and timing of non-pharmacological interventions across the disease trajectory. PMID- 27221009 TI - Tako-Tsubo syndrome: issue of incomplete recovery and recurrence. PMID- 27221008 TI - Effects of dexmedetomidine postconditioning on myocardial ischemia and the role of the PI3K/Akt-dependent signaling pathway in reperfusion injury. AB - The present study aimed to determine whether post-ischemic treatment with dexmedetomidine (DEX) protected the heart against acute myocardial ischemia/reperfusion (I/R)-induced injury in rats. The phosphatidylinositol-3 kinase/protein kinase B(PI3K/Akt)-dependent signaling pathway was also investigated. Male Sprague Dawley rats (n=64) were subjected to ligation of the left anterior descending artery (LAD), which produced ischemia for 25 min, followed by reperfusion. Following LAD ligation, rats were treated with DEX (5, 10 and 20 ug/kg) or underwent post-ischemic conditioning, which included three cycles of ischemic insult. In order to determine the role of the PI3K/Akt signaling pathway, wortmannin (Wort), a PI3K inhibitor, was used to treat a group of rats that had also been treated with DEX (20 ug/kg). Post-reperfusion, lactate dehydrogenase (LDH), cardiac troponin I (cTnI), creatine kinase isoenzymes (CK MB), superoxide dismutase (SOD) and malondialdehyde (MDA) serum levels were measured using an ultraviolet spectrophotometer. The protein expression levels of phosphorylated (p)-Akt, Ser9-p-glycogen synthase kinase-3beta (p-GSK-3beta) and cleaved caspase-3 were detected in heart tissue by western blotting. The mRNA expression levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) were detected using reverse transcription-polymerase chain reaction. At the end of the experiment, the hearts were removed and perfused in an isolated perfusion heart apparatus with Evans blue (1%) in order to determine the non ischemic areas. The risk and infarct areas of the heart were not dyed. As expected, I/R induced myocardial infarction, as determined by the increased serum levels of cTnI, CK-MB and MDA, and the decreased levels of SOD. Post-ischemic treatment with DEX increased the expression levels of p-Akt and p-GSK-3beta, whereas caspase-3 expression was reduced following DEX treatment compared with in the I/R group. Compared with the I/R group, the ratio of Bcl-2/Bax at the mRNA level was elevated in the DEX and ischemic post-conditioning groups, whereas the expression levels of Bax were decreased. Conversely, the effects of DEX were attenuated by Wort. These results indicated that, similar to post-ischemic conditioning, post-ischemic treatment with DEX protects the heart against I/R via the PI3K/Akt-dependent signaling pathway, possibly by activating GSK-3beta. PMID- 27221010 TI - Suppression of X-ray-induced dissociation of H2O molecules in dense ice under pressure. AB - We investigated molecular dissociation induced by 10-keV X-ray irradiation in dense ice at pressures up to 40 GPa at 300 K. The dissociation yield estimated from the oxygen K-edge X-ray Raman spectra, showed that the molecular dissociation was enhanced up to 14 GPa and gradually suppressed on further compression to 40 GPa. The molecular dissociation was detected for a rather narrow pressure span of 2-40 GPa by the X-ray spectroscopy. The pressure variation of the dissociation yield was similar to that observed in the electric conductivity of ice VII and likely interpreted in terms of proton mobility. PMID- 27221011 TI - Esophagus-Related Complications During Second-Generation Cryoballoon Ablation Insight from Simultaneous Esophageal Temperature Monitoring from 2 Esophageal Probes. AB - BACKGROUND: Monitoring luminal esophageal temperatures (LETs) helps predict esophageal thermal lesions (ETLs) after catheter ablation. This study aimed to evaluate esophagus-related complications after second-generation cryoballoon ablation under simultaneous LETs monitoring from 2 esophageal probes. METHODS: Forty consecutive paroxysmal atrial fibrillation patients undergoing second generation cryoballoon ablation under conscious sedation followed by esophagogastroscopy were prospectively included. Two temperature probes inserted bi-nasally (both non-deflectable in 13, non-deflectable and deflectable in 27 patients) were used for LET monitoring. Pulmonary vein isolation was performed with one 28-mm balloon using single 3-minute freeze techniques. RESULTS: The lowest LETs significantly correlated between different probes; however, deflectable probe showed significantly lower nadir LETs than non-deflectable probes (14.6 +/- 9.2 vs. 20.0 +/- 10.6 C, P<0.0001). Esophagogastroscopy post ablation demonstrated ETLs and gastroparesis in 8 (20%) and 7 (17.5%) patients (total 13 [32.5%]), respectively. The optimal cutoff for the lowest LET measured on any probe for predicting no ETLs was 12.8 C (sensitivity 78.1%, specificity 100%). When using deflectable and non-deflectable catheters, the optimal cutoff point for the lowest LET for predicting no ETLs was 11.4 C (sensitivity 70.0%, specificity 100%) and 19.4 C (sensitivity 63.6%, specificity 100%), respectively. No ETLs were detected in 12 (30%) patients with the esophagus located between the left atrium and spine. All esophagus-related complications were asymptomatic and had healed on repeat esophagogastroscopy by a mean of 53 +/- 25 days after the procedure. CONCLUSIONS: The lowest LET highly depended on the temperature probe location. However, if a different cutoff value was applied, LET monitoring, regardless of the probe type, and anatomical information might help predict ETLs during second-generation cryoballoon ablation. PMID- 27221012 TI - Becoming Geriatric. PMID- 27221013 TI - An Unusual Case of Tension Hydrothorax in a Pediatric Patient. PMID- 27221014 TI - Gallbladder Empyema. PMID- 27221015 TI - Rheolytic Thrombectomy of the Pulmonary Embolus in Impending Paradoxical Embolus. PMID- 27221017 TI - Regarding "Phenobarbital for Acute Alcohol Withdrawal: A Prospective Randomized Double-Blind Placebo-Controlled Study". PMID- 27221016 TI - Unsteady Gait and Dizziness. PMID- 27221018 TI - The Reply. PMID- 27221019 TI - Delayed Infant Subaponeurotic (Subgaleal) Fluid Collections: A Case Series of 11 Infants. AB - BACKGROUND: Although subgaleal hemorrhage can present very soon after delivery with catastrophic consequences, subaponeurotic or subgaleal fluid collections are rare and clinically distinct causes of infant scalp swelling that present weeks to months after birth. Their exact etiology remains uncertain; however, they are frequently associated with instrumental and traumatic delivery. AIM & METHODS: To characterize 11 subaponeurotic fluid collections that presented to the Temple Street Children's University Hospital Emergency Department (TSCUHED) from July 2013 to July 2015 by a retrospective chart review. CASE REPORT: Eleven infants were identified with delayed subaponeurotic fluid collections. Of note, all infants were either successful vacuum delivery or failed vacuum delivery with subsequent forceps delivery or emergency caesarean section. All infants were otherwise well at presentation, and resolution of the scalp swelling occurred within weeks to months. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This condition follows a benign course and conservative management is the treatment of choice. PMID- 27221020 TI - Acute Esophageal Necrosis Caused by Candidiasis in a Patient with Systemic Lupus Erythematosus. PMID- 27221022 TI - Non-targeted metabolomics by high resolution mass spectrometry in HPRT knockout mice. AB - AIMS: Lesch-Nyhan disease (LND) is characterized by hyperuricemia as well as neurological and neuropsychiatric symptoms including repetitive self-injurious behavior. Symptoms are caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) as a result of a mutation on the X chromosome. To elucidate the pathophysiology of LND, we performed a metabolite screening for brain and serum extracts from HPRT knockout mice as an animal model for LND. MAIN METHODS: Analyses were performed by high performance liquid chromatography (HPLC) coupled quadrupole time-of-flight mass spectrometry (QTOF-MS). KEY FINDINGS: In brain extracts, we found six metabolites with significantly different contents in wild-type and HPRT-deficient mice. Two compounds we could identify as 5 aminoimidazole-4-carboxamide ribotide (AICAR) and 1-methylimidazole-4-acetic acid (1-MI4AA). Whereas AICAR was accumulated in brains of HPRT knockout mice, 1-MI4AA was decreased in these mice. SIGNIFICANCE: Both metabolites play a role in histidine metabolism and, as a consequence, histamine metabolism. AICAR, in addition, is part of the purine metabolism. Our findings may help to better understand the mechanisms leading to the behavioral phenotype of LND. PMID- 27221021 TI - Low epinephrine levels and selective deficiency of beta2-adrenoceptor vasodilation at birth. AB - AIMS: Epinephrine is unique among biogenic catecholamines as a potent agonist of beta2-adrenoceptors. The beta2-adrenoceptor mediated effects during development might be linked to the increase of epinephrine synthesis. Our purpose was to characterize beta-adrenoceptor-mediated relaxation in the aorta of newborn and young rabbits (3 to 4months old), and to relate those responses with the epinephrine content of the adrenal gland. MAIN METHODS: The epinephrine levels and the tyrosine hydroxylase activity were determined in adrenal glands of newborn and young rabbits. Also, concentration-response curves to phenylephrine (selective alpha1-adrenoceptor agonist), dobutamine (selective beta1-adrenoceptor agonist), terbutaline (selective beta2-adrenoceptor agonist), and CL 316243 (selective beta3-adrenoceptor agonist) were determined in isolated aortic rings obtained from both groups. KEY FINDINGS: The adrenal gland content and the plasma concentrations of epinephrine were lower in newborn than in young rabbits. In contrast, the tyrosine hydroxylase activity was higher in newborn than in young rabbits. On the other hand, the maximal response to phenylephrine was lower in newborn than in young rabbits. Terbutaline at concentrations selective for beta2 adrenoceptors had no relaxing effects in neonates, in contrast to young rabbits. The potency and the maximal response of neither dobutamine nor CL 316243 were significantly different between the two groups. SIGNIFICANCE: In rabbits, as well as in humans, beta2-adrenoceptor-mediated responses and epinephrine synthesis are both immature at birth. On the other hand, the beta1 and beta3-adrenoceptor mediated responses are fully developed. We conclude that epinephrine may influence the development of the beta2-adrenoceptor-mediated responses at birth and the rabbit is an excellent model to study these issues. PMID- 27221025 TI - Potential pest transfer mediated by international ornamental plant trade. AB - In recent years, the keeping of ornamental freshwater animals and plants in garden ponds has been growing in popularity. Water hyacinth (Eichhornia crassipes) is one of the preferred macrophytes seasonally imported mainly from South-eastern Asia throughout the world. This constitutes a secondary introduction inasmuch as the species is native to South America. Although many assemblages of aquatic invertebrates have been described as associated with this plant in the wild, there has been no research focused on their potential introduction via the international plant trade. We examined 216 specimens of water hyacinths imported for ornamental purposes from Indonesia into the Czech Republic. Numerous meio- and macroinvertebrates belonging to at least 39 species were captured. On the total number of individuals, the highest prevalence was of Tubulinea and Rotifera. Most of these were still alive and vital, including a caterpillar of the Indo-Australian invasive moth Spodoptera litura. Water hyacinths are usually placed into outdoor ponds immediately after import, which facilitates the release of non-target alien species. The present paper aims to draw attention to "hitchhikers" associated with the ornamental trade. PMID- 27221023 TI - Andrographolide suppresses preadipocytes proliferation through glutathione antioxidant systems abrogation. AB - AIMS: Oxidative stress is considered to play a profound role in lipid storage and whole-body energy homeostasis. Inhibition of preadipocytes proliferation by natural products is one of the strategies to prevent obesity. Andrographolide, a small molecule, has been reported to possess versatile bioactivities. However, molecular mechanism underlying the potential effect of andrographolide on preadipocytes proliferation remains obscure. MAIN METHODS: In the present study, 3T3-L1 preadipocytes were employed to determine whether andrographolide could affect the proliferation of preadipocytes. KEY FINDINGS: Our results demonstrated andrographolide suppressed 3T3-L1 preadipocytes proliferation. The casual relationship analysis indicated that andrographolide (10 and 20MUg/ml) appeared to exert the proliferation inhibitory effect through suppression of glutathione peroxidase 1 (GPX1) activity and depleting GSH by promoting its efflux in 3T3-L1 preadipocytes, which subsequently resulted in 2.06-2.41 fold increase in ROS accumulation. Excessive ROS eruption could account for oxidative damage to mitochondrial membranes as well as ultimately inhibition of cell proliferation. SIGNIFICANCE: Taken together, our study reveals that suppression of GPX1 and GSH depletion by andrographolide seems to play a critical role in the inhibition of 3T3-L1 preadipocytes proliferation, which might have implication for obesity prevention and treatment. PMID- 27221024 TI - Characterization, expression analysis and localization pattern of toll-like receptor 1 (tlr1) and toll-like receptor 2 (tlr2) genes in grass carp Ctenopharyngodon idella. AB - In this study, the toll-like receptor 1 (tlr1) and toll-like receptor 2 (tlr2) genes of grass carp Ctenopharyngodon idella were cloned and characterized. tlr1 and tlr2 were found to be highly expressed in immune system organs such as spleen, middle kidney and heart kidney. The expression level of tlr1 and tlr2 was found to be up-regulated at the later stage of viral challenge process. Moreover, subcellular localization indicated that Tlr1 and Tlr2 shared similar localization pattern and both of them may locate in the plasma membrane of transfected cells. PMID- 27221026 TI - Effect of the combination of balloon Eustachian tuboplasty and tympanic paracentesis on intractable chronic otitis media with effusion. AB - OBJECTIVE: To evaluate the effect of the combination of balloon Eustachian tuboplasty (BET) and tympanic paracentesis (TP) on intractable chronic otitis media with effusion (COME). METHODS: Ninety patients with intractable COME were included and randomly assigned to three groups: BET only (30 patients), BET+paracentesis (30 patients), and paracentesis only (30 patients). Otic endoscopic findings and tympanograms were recorded before the surgery and at the month 1, month 3, and month 6 follow-up evaluations. RESULTS: Both the BET only and BET+paracentesis groups achieved better outcomes than the paracentesis group. The BET+paracentesis group exhibited better otic endoscopic scores than the BET only group (p<0.05) at 1month post-operation. However, no significant difference was found at month 3 or month 6 post-operation. No significant difference in the tympanograms was observed between these two groups at month 1, month 3, or month 6 post-operation. The otic endoscopic sign scores improved from month 1 to month 6 in the BET only group and from month 1 to month 3 in the BET+paracentesis group. The conversion of type B tympanograms improved from month 1 to month 6 in the BET and BET+paracentesis groups but not in the paracentesis only group. CONCLUSIONS: Our results suggested that the combination of BET and TP was effective for intractable COME and can help shorten the recovery period for middle ear effusion. PMID- 27221027 TI - How, when, and from whom neck dissection operative technique is learned: An international survey on neck dissection education among head and neck oncologic surgeons. AB - BACKGROUND: There is a paucity of evidence on how neck dissection (ND) technique is best learned. METHODS: Online survey of the American Head and Neck Society (AHNS). RESULTS: 283 of the 1010 (28%) AHNS surgeon members completed the survey. Most respondents had 3-4 mentors [n=157 (55.5%)] that they felt were most influential their ND technique. 134 (47.3% of surgeons who completed a fellowship) felt that fellowship training had the most impact on their ND technique. Most respondents ranked the most effective methods of learning ND operative technique in the following order: 1) physically performing the operation yourself (70.1%), 2) observing the attending perform maneuvers independent of verbal teaching (37.7%) and 3) verbal teaching by an attending in the operating room independent of actual maneuvers (36.3%). CONCLUSION: When learning an ND, the most benefit comes from empirical learning in the context a small group of surgeon mentors. PMID- 27221028 TI - The physiologic role of corticosteroids in Meniere's disease. AB - Multiple options exist to manage Meniere's disease (MD), ranging from dietary modifications to ablative surgery. Corticosteroids (CS) have long been used to manage MD, but their exact mechanism for disease alleviation is relatively uncertain. Glucocorticoid receptors have been shown to exist in the human inner ear and several studies propose they influence mechanisms of blood flow, fluid regulation, and ion regulation, with recent evidence describing the latter two. Corticosteroids have been shown to upregulate aquaporins and ion channels in the inner ear, and may have a positive effect on labyrinthine blood flow. Additionally, processes have been described in genomic and non-genomic manners. This text will review the literature on the actions of CS on the inner ear relevant to MD. PMID- 27221033 TI - Chemistry, Pharmacology and Health Benefits of Anthocyanins. AB - Anthocyanins are naturally occurring molecules belonging to the flavonoid class characterized by the presence of chromophores. Apart from their well-known antioxidant activity, they show a wide variety of health-promoting properties for human health, ranging from cytoprotective, antimicrobial and antitumour activities to neuroprotective, anti-obesity and lipidomic potential, properties for which anthocyanins have been prescribed as medicines in several countries for thousands of years. Despite this, these phytochemicals have received less attention than other flavonoids, and there is still a gap in the literature, particularly regarding pharmacological and toxicological aspects. Moreover, epidemiological evidence suggests a direct correlation between anthocyanin intake and a lower incidence of chronic and degenerative diseases. In light of this, the aim of this review is to cover the current literature on anthocyanins, their biological in vitro and in vivo effects and their potential therapeutic applications, as well as their bioavailability and pharmacokinetics, all of which are essential to gain a better understanding of their biological effectiveness and potential toxicity. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27221029 TI - On the mechanism of smell loss in patients with Type II congenital hyposmia. AB - BACKGROUND: Smell function has been initiated with theophylline treatment in 63% of patients with Type II congenital smell loss. Based upon a systematic evaluation of the protein components of nasal mucus we have demonstrated that interactions among four chemical moieties in nasal mucus may play significant roles in this initiation. Prior to treatment three of these moieties, cAMP, cGMP and sonic hedgehog (Shh), were significantly decreased in concentration whereas one of these moieties, TNFalpha, was increased in concentration. The mechanism(s) responsible for initiation of smell function in these patients, not immediately apparent, may depend upon understanding interactions among these moieties. METHODS: Measurements of cAMP, cGMP, Shh and TNFalpha in nasal mucus by specific spectrophotometric immunoassays before and after treatment with theophylline. RESULTS: Before theophylline treatment cAMP, cGMP and Shh in nasal mucus, which act as growth factors to support olfactory receptor function, were significantly decreased below normal levels whereas TNFalpha which acts as a "death factor" to inhibit olfactory receptor function was significantly increased above normal. After theophylline treatment cAMP, cGMP and Shh increased significantly whereas TNFalpha decreased significantly. CONCLUSIONS: These results indicate that there are specific biochemical changes associated with smell loss in patients with Type II congenital smell loss and that correction of these biochemical changes are associated with initiation of smell function in these patients. Understanding these relationships play an important role in understanding receptor action in smell function. PMID- 27221032 TI - Icariin alters the expression of glucocorticoid receptor, FKBP5 and SGK1 in rat brains following exposure to chronic mild stress. AB - Icariin, a flavonoid and a major constituent of Herba Epimedii, has been previously demonstrated to possess potential antidepressant-like effects. In the present study, we established a rat model of depression induced by unpredictable chronic mild stress (CMS) in order to examine the effects of icariin treatment. The rats were allocated into the control group or one of the treatment groups [exposure to CMS plus oral administration of saline, icariin (20 or 40 mg/kg) or fluoxetine (10mg/kg)]. We examined the therapeutic effects of icariin administration on depression-like behaviors (with a sucrose preference test), on the mRNA and protein expression of glucocorticoid receptor (GR), FK506 binding protein 5 (FKBP5) and serum- and glucocorticoid-inducible kinase 1 (SGK1), as well as on the distribution of GR (in the cytoplasm and nucleus) in both the hippocampus and the prefrontal cortex following exposure to CMS. Our results revealed that the oral administration of icariin (20 and 40 mg/kg) for 35 consecutive days attenuated the development of depression-like behaviors induced by exposure to CMS. The increased mRNA expression of GR and SGK1 in the prefrontal cortex was reversed by icariin treatment. Moreover, the CMS-induced increases in the levels of cytosolic GR and SGK1 were partially restored by icariin administration in both the hippocampus and the prefrontal cortex, particularly in the hippocampus. Icariin also partially reversed the upregulated epxression of nuclear GR in the prefrontal cortex and that of FKBP5 in the hippocampus. On the whole, our findings indicate that icariin may have therapeutic applications as a potential antidepressant with multiple targets in both the hippocampus and prefrontal cortex. It exerts antidepressant-like effects by restoring the negative feedback regulation of the hypothalamic-pituitary adrenal axis, which is at least partially attributed to normalization of the distribution of GR, and decreases in the expression levels of FKBP5 and SGK1. PMID- 27221036 TI - Superior mediastinal mature cystic teratoma with gastrointestinal adenocarcinoma transformation: Report of a case. AB - Presented herein is a case of mediastinal mature teratoma with adenocarcinomatous transformation predominantly composed of mucinous adenocarcinoma in a 25-year-old man. Disease progressed despite application of surgical removal, adjuvant radio- and chemotherapy. Further immunohistochemical stains indicated a gastrointestinal origin of the tumor. Consequently chemotherapy according to the FOLFIRI regimen was applied that resulted in good response. To our knowledge, this is the first report of a clinical remission from chemotherapy with the FOLFIRI regimen after comprehensive initial treatment with surgery, radio- and chemotherapy for a patient with teratoma with malignant transformation, highlighting the importance of choosing an appropriate chemotherapy regimen. PMID- 27221035 TI - A novel multi-target RNAi adenovirus inhibits hepatoma cell proliferation, migration, and induction of angiogenesis. AB - The pathogenesis of hepatocellular carcinoma (HCC) is a multi-step process involving many genes. Consequently, single gene targeting therapy has limited efficacy, making combination therapy targeting multiple genes a necessity. Based on our previous findings, we constructed a single vector mediating simultaneous expression of multiple short hairpin RNAs (shRNAs) against human vascular endothelial growth factor receptor 2 (VEGFR2), chemokine C-C motif receptor 1 (CCR1), and epithelial cell adhesion molecule (EpCAM), three genes closely related to HCC progression that act through separate pathways. The shRNA vector efficiently downregulated the mRNA and protein of all three molecules in Huh7 hepatoma cells. The vector also inhibited cell proliferation and migration and reduced angiogenesis. Furthermore, this shRNA vector can be recombined into adenovirus, a gene therapy vector, for better in vivo application. It thus offers a potentially effective future gene therapy approach to treating human liver cancer. PMID- 27221038 TI - Tumor-infiltrating immune cell subpopulations influence the oncologic outcome after intravesical Bacillus Calmette-Guerin therapy in bladder cancer. AB - Although Bacillus Calmette-Guerin (BCG) is the most successful immunotherapy for high-risk non-muscle-invasive bladder cancer, approximately 30% of patients are unresponsive to treatment. New biomarkers are important to identify patients who will benefit most from BCG during a worldwide BCG shortage. Local immune cell subsets were measured on formalin-fixed, paraffin-embedded tissue sections of bladder cancer by immunohistochemistry, using monoclonal antibodies to tumor associated macrophages (TAMs; CD68, CD163), B-lymphocytes (CD20) and T-lymphocyte subsets (CD3, CD4, CD8, GATA3, T-bet, FOXP3 and CD25). Cell densities in the lamina propria without invasion, at the invasive front if present, in the papillary tumor stroma, and in the neoplastic urothelium were calculated. Twenty nine (72.5%) of 40 patients were classified as BCG responders after a mean follow up of 35.3 months. A statistically significant association was observed for BCG failure with low density of CD4+ and GATA3+ T-cells, and increased expression of FOXP3+ and CD25+ regulatory T-cells (Tregs) as well as CD68+ and CD163+ TAMs. Survival analysis demonstrated prolonged recurrence-free survival (RFS) in patients with an increased count of CD4+ and GATA3+ T-cells. TAMs, Tregs and T bet+ T-cells were inversely correlated with RFS. Thus, the tumor microenvironment seems to influence the therapeutic response to BCG, permitting an individualized treatment. PMID- 27221034 TI - Laparoscopic repeat hepatectomy after right hepatopancreaticoduodenectomy. AB - Although laparoscopic hepatectomy is widely accepted for primary hepatectomy, the clinical value of laparoscopic hepatectomy for repeat hepatectomy is still challenging. We herein describe our experience with laparoscopic repeat hepatectomy after right hepatopancreaticoduodenectomy. A 72-year-old woman who had undergone right hepatopancreaticoduodenectomy for perihilar cholangiocarcinoma 31 months prior was diagnosed with liver metastasis in segment 3. We performed laparoscopic repeat hepatectomy. Because mild adhesions in the left side of the abdominal cavity were detected by laparoscopy, the planned procedure was accomplished. The operative time and intraoperative blood loss were 139 min and less than 1 mL, respectively. The patient was discharged at 6 days after surgery and was healthy with no evidence of recurrence at 21 months after laparoscopic repeat hepatectomy. Laparoscopic repeat hepatectomy is a suitable and safe procedure for minor hepatectomy, provided that careful technique is used after the working space is secured under pneumoperitoneum. PMID- 27221037 TI - Alterations of androgen receptor-regulated enhancer RNAs (eRNAs) contribute to enzalutamide resistance in castration-resistant prostate cancer. AB - Enzalutamide is a second-generation anti-androgen for treatment of castration resistant prostate cancer (CPRC). It prolongs survival of CRPC patients, but its overall survival benefit is relatively modest (4.8 months) and by 24 months most patients progress on enzalutamide. To date, however, the molecular mechanisms underlying enzalutamide resistance remain elusive. Herein, we report enzalutamide treatment-induced alterations of androgen receptor (AR)-regulated enhancer RNAs (AR-eRNAs) and their roles in enzalutamide-resistant growth and survival of CRPC cells. AR chromatin immunoprecipitation and high throughput sequencing (ChIP-seq) and RNA-seq analyses revealed that 188 and 227 AR-eRNAs were differentially expressed in enzalutamide-resistant LNCaP and C4-2 cells, respectively. The AR eRNAs upregulated in C4-2 cells and downregulated in LNCaP cells were selected through meta-analysis. Expression of AR-eRNAs and related mRNAs in the loci of FTO, LUZP2, MARC1 and NCAM2 were further verified by real-time RT-PCR. Silencing of LUZP2 inhibited, but silencing of MARC1 increased the growth of enzalutamide resistant C4-2 cells. Intriguingly, meta-analysis showed that expression of LUZP2 mRNA increased in primary tumors compared to normal prostate tissues, but decreased again in metastatic CRPC. Our findings suggest that eRNA alteration profiling is a viable new approach to identify functional gene loci that may not only contribute to enzalutamide-resistant growth of CRPC, but also serve as new targets for CRPC therapy. PMID- 27221041 TI - Constipation prophylaxis in children undergoing orthopedic surgery: A quasi experimental study. AB - PURPOSE: This study evaluated the effectiveness of constipation prophylaxis administered with the support of an advanced practice nurse. DESIGN: A quasi experimental study with a historical control group of 112 pediatric (age 1-18) orthopedic patients and an intervention group of 59 patients was conducted in a surgical ward in Switzerland. RESULTS: The implementation of a standardized constipation prophylaxis led to an absolute risk reduction (27%) of constipation. Fisher's exact test showed a significant difference in the prevalence of constipation in the two samples, p = .001. PRACTICE IMPLICATIONS: Constipation prophylaxis is a necessity in pediatric orthopedics. PMID- 27221040 TI - Next-generation sequencing of Chinese stage IV lung cancer patients reveals an association between EGFR mutation status and survival outcome. AB - Large-scale genomic characterization of non-small cell lung cancer (NSCLC) has revealed several putative oncogenic driver mutations that may constitute druggable therapeutic targets. However, there are little data to suggest that such gene alterations have clinical relevance. Over 12 consecutive months, tumor biopsy samples from 80 patients with stage IV NSCLC were analyzed for mutations in selected exons of 508 cancer-related genes using next-generation sequencing. From 85 specimens referred for genomic characterization, 80 (94%) specimens were successfully genotyped, and all had identifiable somatic alterations. Epidermal growth factor receptor (EGFR) and TP53 genes contained the highest frequency of observed mutations (65% and 40%, respectively) in the stage IV NSCLC cases. Notably, patients with EGFR mutations showed a significantly shorter survival time compared with patients expressing wild-type EGFR (p = 0.0053). Moreover, of the 32 patients harboring EGFR mutations, EGFR-L858R mutant patients showed a significantly shorter survival time compared with patients with other EGFR mutations (p = 0.036). In conclusion, tumors from stage IV NSCLC patients harbor characteristic gene alterations, of which EGFR L858R in particular appears to be a poor prognostic factor for overall survival. PMID- 27221042 TI - The Role of the Frontal Lobe in Complex Walking Among Patients With Parkinson's Disease and Healthy Older Adults: An fNIRS Study. AB - BACKGROUND: Gait is influenced by higher order cognitive and cortical control mechanisms. Functional near infrared spectroscopy (fNIRS) has been used to examine frontal activation during walking in healthy older adults, reporting increased oxygenated hemoglobin (HbO2) levels during dual task walking (DT), compared with usual walking. OBJECTIVE: To investigate the role of the frontal lobe during DT and obstacle negotiation, in healthy older adults and patients with Parkinson's disease (PD). METHODS: Thirty-eight healthy older adults (mean age 70.4 +/- 0.9 years) and 68 patients with PD (mean age 71.7 +/- 1.1 years,) performed 3 walking tasks: (a) usual walking, (b) DT walking, and (c) obstacles negotiation, with fNIRS and accelerometers. Linear-mix models were used to detect changes between groups and within tasks. RESULTS: Patients with PD had higher activation during usual walking (P < .030). During DT, HbO2 increased only in healthy older adults (P < .001). During obstacle negotiation, HbO2 increased in patients with PD (P = .001) and tended to increase in healthy older adults (P = .053). Higher DT and obstacle cost (P < .003) and worse cognitive performance were observed in patients with PD (P = .001). CONCLUSIONS: A different pattern of frontal activation during walking was observed between groups. The higher activation during usual walking in patients with PD suggests that the prefrontal cortex plays an important role already during simple walking. However, higher activation relative to baseline during obstacle negotiation and not during DT in the patients with PD demonstrates that prefrontal activation depends on the nature of the task. These findings may have important implications for rehabilitation of gait in patients with PD. PMID- 27221039 TI - FAM83 proteins: Fostering new interactions to drive oncogenic signaling and therapeutic resistance. AB - The FAM83 proteins were recently identified as novel transforming oncogenes that function as intermediaries in EGFR/RAS signaling. Using two distinct forward genetics screens, the Bissell and Jackson laboratories uncovered the importance of the FAM83 proteins in promoting resistance to EGFR tyrosine kinase inhibitors and therapies targeting downstream EGFR signaling effectors. The discovery of this novel oncogene family using distinct genetic screens provides compelling evidence that the FAM83 proteins are key oncogenic players in cancer-associated signaling when they are overexpressed or dysregulated. Consistent with a role in oncogenic transformation, the FAM83 genes are frequently overexpressed in diverse human cancer specimens. Importantly, ablation of numerous FAM83 members results in a marked suppression of cancer-associated signaling and loss of tumorigenic potential. Here, we review the current knowledge of the FAM83 proteins' involvement in cancer signaling and discuss the potential mechanisms by which they contribute to tumorigenesis. Both redundant activities shared by all 8 FAM83 members and non-redundant activities unique to each member are highlighted. We discuss the promise and challenges of the FAM83 proteins as novel points of attack for future cancer therapies. PMID- 27221043 TI - Circadian Melatonin Rhythm Following Traumatic Brain Injury. AB - BACKGROUND: Sleep-wake disturbances are highly prevalent following traumatic brain injury (TBI), impeding rehabilitaion and quality of life. However, the mechanisms underlying these sleep disturnbances are unclear, and efficacious treatments are lacking. To investigate possible mechanisms underlying sleep disturbance in TBI, we examined characteristics of the circadian rhythm of melatonin, a hormone involved in sleep-wake regulation. We compared TBI patients reporting sleep disturbance with age- and gender-matched healthy volunteers. METHODS: We conducted an overnight observational study with salivary melatonin samples collected hourly in 9 patients with severe TBI and 9 controls. Salivary dim light melatonin onset (DLMO) as well as melatonin synthesis onset (SynOn) and offset (SynOff) were used to determine circadian timing. Total overnight salivary melatonin production was calculated as the area under the curve from melatonin synthesis onset to offset. RESULTS: Compared with healthy individuals, TBI patients showed 42% less melatonin production overnight (d = 0.87; P = .034). The timing of DLMO was delayed by approximately 1.5 hours in patients with TBI compared with controls (d = 1.23; P = .003). CONCLUSIONS: In patients with TBI, melatonin production was attenuated overnight, and the timing of melatonin secretion was delayed. We suggest that disruption to the circadian regulation of melatonin synthesis is a feature of severe TBI, possibly contributing to the sleep difficulties that are commonly reported in this population. PMID- 27221045 TI - Inhibition of ceramide glucosylation sensitizes lung cancer cells to ABC294640, a first-in-class small molecule SphK2 inhibitor. AB - Sphingosine kinase 2 (SphK2) is proposed as a novel oncotarget for lung cancer. Here, we studied the anti-lung cancer cell activity by ABC294640, a first-in class SphK2 inhibitor. We showed that ABC294640 suppressed growth of primary and A549 human lung cancer cells, but sparing SphK2-low lung epithelial cells. Inhibition of SphK2 by ABC294640 increased ceramide accumulation, but decreased pro-survival sphingosine-1-phosphate (S1P) content, leading to lung cancer cell apoptosis activation. Significantly, we show that glucosylceramide synthase (GCS) might be a major resistance factor of ABC294640. The GCS inhibitor 1-phenyl-2 decanoylamino-3-morpholino-1-propanol (PDMP) or GCS shRNA/siRNA knockdown facilitated ABC294640-induced ceramide production and lung cancer cell apoptosis. Reversely, forced overexpression of GCS reduced ABC294640's sensitivity, resulting in decreased ceramide accumulation and apoptosis induction in A549 cells. These findings provide further evidences to support that targeting SphK2 by ABC294640 may be a rational treatment option for lung cancer. Ceramide glucosylation inhibition may further sensitize lung cancer cells to ABC294640. PMID- 27221044 TI - Novel 6-bp deletion in MEF2A linked to premature coronary artery disease in a large Chinese family. AB - The aim of the present study was to identify the genetic defect responsible for familial coronary artery disease/myocardial infarction (CAD/MI), which exhibited an autosomal dominant pattern of inheritance, in an extended Chinese Han pedigree containing 34 members. Using exome and Sanger sequencing, a novel 6-base pair (bp) 'CAGCCG' deletion in exon 11 of the myocyte enhancer factor 2A (MEF2A) gene was identified, which cosegregated with CAD/MI cases in this family. This 6-bp deletion was not detected in 311 sporadic cases of premature CAD/MI or in 323 unrelated healthy controls. Determination of a genetic risk profile has a key role in understanding the pathogenesis of CAD and MI. Among the reported risk conferring genes and their variants, mutations in MEF2A have been reported to segregate with CAD/MI in Caucasian families. Causative missense mutations have also been detected in sporadic CAD/MI cases. However, this suggested genetic linkage is controversial, since it could not be confirmed by ensuing studies. The discovery of a novel MEF2A mutation in a Chinese family with premature CAD/MI suggests that MEF2A may have a significant role in the pathogenesis of premature CAD/MI. To better understand this association, further in vitro and in vivo studies are required. PMID- 27221047 TI - Efficient biallelic mutation in porcine parthenotes using a CRISPR-Cas9 system. AB - The parthenotes represent ideal models mimicking the embryonic development and characterizing the function of maternal genomes as well as an alternative source of pluripotent cell lines. Besides, parthenogenetically activated (PA) embryos serve as a rapid assay system to maximize the efficiency of generating genetically modified pig CRISPR/Cas9 system, an efficient and multiplex gene editing tool, has been utilized to modify the genome of porcine parthenotes. However, lower biallelic mutation rate and high mosaicism frequency were observed. Here, we aimed to enhance the biallelic mutation rate with reduced mosaicism by optimization of the concentration and injection time of the Cas9/sgRNA mixture in porcine parthenotes. The results showed that the efficient biallelic mutation (93%) and low mosaicism (33%) could be achieved in porcine parthenotes by cytoplasmic injection of Cas9 mRNA/sgRNA (125/12.5 ng/MUl) after 8 h of parthenogenetical activation. Thus, our study provides an effective strategy for increasing the biallelic mutation rate and population homogeneity of genetically modified parthenotes, which will strengthen the role of parthenotes in uncovering early embryonic development and assessing the mutation efficiency due to the simplicity and adaptability of CRISPR/Cas9. PMID- 27221049 TI - The optical characterization of metal-mediated aggregation behaviour of amphiphilic Zn(ii) phthalocyanines. AB - Ag(+) mediated aggregation behaviour of two different amphiphilic zinc phthalocyanines (Zn-Pcs) (symmetric and asymmetric) has been investigated in solution, at the air-water interface and in Langmuir-Blodgett (LB) films transferred onto glass substrates. A 4 : 1 ([Ag(+)]/[Pc]) complexation was observed for both symmetric and asymmetric Zn-Pcs at high [Ag(+)] concentrations which led to the formation of H-aggregates in solution. At the air-water interface, both symmetric and asymmetric Zn-Pcs showed a tilted, edge-on orientation in columnar stacks. Addition of Ag(+) to the subphase enhanced the order in the monolayers. LB films on glass substrates showed a split Q-band indicating the presence of "herring-bone" type aggregation consisting of both H- and J-aggregates. For LB films deposited from a Ag(+) containing subphase, a shoulder appeared in the absorption spectra at longer wavelengths which indicates that the fraction of J-aggregates was enhanced by Ag(+) in LB films. The molecular orientation in LB films was investigated by polarized absorption spectroscopy and a tilt angle was calculated to be 49 degrees with the substrate normal for symmetric and 74.6 degrees for the asymmetric Zn-Pc. The presence of Ag(+) cations in the subphase decreased the tilt angles slightly by 4-5 degrees . These results indicate that Ag(+) induced the aggregation of Zn-Pcs and acted as a linker between Pc molecules in the ultrathin films of both symmetric and asymmetric Zn-Pcs. These results are important in inducing J-aggregates for the fabrication of molecular devices based on phthalocyanine thin films. PMID- 27221052 TI - Application of chromosomal microarray analysis in prenatal diagnosis of fetal growth restriction. AB - OBJECTIVE: To investigate the clinical value of chromosomal microarray analysis (CMA) in the prenatal diagnosis of chromosomal abnormalities in fetal growth restriction (FGR) cases. METHOD: The ultrasound findings of 107 FGR cases subjected to invasive prenatal diagnostic testing from March 2013 to October 2015 were retrospectively reviewed. Karyotyping was performed in all cases, and CMA was performed in 80 cases. RESULTS: In our study, karyotype analysis identified chromosomal aberrations in 9.3% (10/107) of the cases, while CMA detected abnormalities in 18.8% (15/80) of the cases. CMA achieved a 11.4% detection rate of chromosomal abnormalities among FGR cases with a normal karyotype. Among 53 FGR cases without malformations, CMA increased (9.4%; 95%CI, 1.6%-17.3%) the detection rate of chromosomal abnormalities. CMA identified more chromosomal abnormalities (50.0%; 95%CI, 19.0%-81.0%) than karyotyping (30.0%; 95%CI, 7.0% 65.0%) among the cases diagnosed during the second trimester. Further, the detection rate in cases with asymmetric FGR was higher with CMA (33.3%; 95%CI, 10.0%-65.0%) than with karyotyping (16.7 %; 95%CI, 2.0%-48.0%). CONCLUSION: Our study highlights the added value of CMA compared with karyotyping in evaluation of asymmetric FGR cases diagnosed during the second trimester without sonographic anomalies. (c) 2016 John Wiley & Sons, Ltd. PMID- 27221046 TI - ADAM10 is essential for cranial neural crest-derived maxillofacial bone development. AB - Growth disorders of the craniofacial bones may lead to craniofacial deformities. The majority of maxillofacial bones are derived from cranial neural crest cells via intramembranous bone formation. Any interruption of the craniofacial skeleton development process might lead to craniofacial malformation. A disintegrin and metalloprotease (ADAM)10 plays an essential role in organ development and tissue integrity in different organs. However, little is known about its function in craniofacial bone formation. Therefore, we investigated the role of ADAM10 in the developing craniofacial skeleton, particularly during typical mandibular bone development. First, we showed that ADAM10 was expressed in a specific area of the craniofacial bone and that the expression pattern dynamically changed during normal mouse craniofacial development. Then, we crossed wnt1-cre transgenic mice with adam10-flox mice to generate ADAM10 conditional knockout mice. The stereomicroscopic, radiographic, and von Kossa staining results showed that conditional knockout of ADAM10 in cranial neural crest cells led to embryonic death, craniofacial dysmorphia and bone defects. Furthermore, we demonstrated that impaired mineralization could be triggered by decreased osteoblast differentiation, increased cell death. Overall, these findings show that ADAM10 plays an essential role in craniofacial bone development. PMID- 27221054 TI - Albumin-Folate Conjugates for Drug-targeting in Photodynamic Therapy. AB - Photodynamic therapy (PDT) is based on the cytotoxicity of photosensitizers in the presence of light. Increased selectivity and effectivity of the treatment is expected if a specific uptake of the photosensitizers into the target cells, often tumor cells, can be achieved. An attractive transporter for that purpose is the folic acid receptor alpha (FRalpha), which is overexpressed on the surface of many tumor cells and mediates an endocytotic uptake. Here, we describe the synthesis and photobiological characterization of polar beta-carboline derivatives as photosensitizers covalently linked to folate-tagged albumin as the carrier system. The particles were taken up by KB (human carcinoma) cells within <90 min and then co-localized with a lysosomal marker. FRalpha antibodies prevented the uptake and also the corresponding conjugate without folate was not taken up. Accordingly, a folate-albumin-beta-carbolinium conjugate proved to be phototoxic, while the corresponding albumin-beta-carbolinium conjugates without FA were nontoxic, both with and without irradiation. An excess of free folate as competitor for the FRalpha-mediated uptake completely inhibited the photocytotoxicity. Interestingly, the albumin conjugates are devoid of photodynamic activity under cell-free conditions, as shown for DNA as a target. Thus, phototoxicity requires cellular uptake and lysosomal degradation of the conjugates. In conclusion, albumin-folate conjugates appear to be promising vehicles for a tumor cell targeted PDT. PMID- 27221048 TI - Role of flotillins in the endocytosis of GPCR in salivary gland epithelial cells. AB - Endocytosis has numerous functions in cellular homeostasis. Defects in the endocytic pathway of receptors may lead to dysfunction of salivary gland secretion. Therefore, elucidating the complex mechanisms of endocytosis may facilitate solutions for disease treatment and prevention. The muscarinic type 3 receptor (M3R), a G-protein-coupled receptor (GPCR) located in the plasma membrane, is involved in numerous physiological activities such as smooth muscle contraction and saliva secretion. M3R enters cells through clathrin-mediated endocytosis (CME), while flotillins (flot-1 and -2), highly conserved proteins residing in lipid-raft microdomains, make use of clathrin-independent endocytosis (CIE) for their internalization. Since these two proteins use two discrete pathways for endocytic entry, the association of flotillins with CME is poorly understood. We examined whether flotillins play a role in CME of M3R using immunoblotting, immunocytochemistry, confocal immunofluorescence microscopy, co immunoprecipitation, and RNA interference techniques in secretory epithelial cells. Upon stimulation with a cholinergic agonist, M3R, flot-1, and flot-2 each internalized from the plasma membrane into intracellular sites. The addition of chlorpromazine and cytochalasin D, well-known inhibitors of CME, inhibited internalization of M3R via CME. Filipin III and methyl-beta-cyclodextrin (mbetaCD) acting as lipid raft inhibitors disrupted internalization of flot-1/2 via CIE. Interestingly, filipin III and mbetaCD slightly reduced expression level of M3R whereas chlorpromazine and cytochalasin D did not affect internalization of the flotillin isoforms. M3R and flot-1/2 colocalized and interacted with each other as they entered the cytosol during limited periods of incubation. Moreover, knockdown of flot-1 or -2 by flotillin-specific siRNA prevented internalization and reduced the endocytic efficiency of M3R. Our results suggest that flot-1 and 2 are partially involved in CME of M3R by facilitating its internalization. PMID- 27221055 TI - Layered Double Hydroxide Nanotransporter for Molecule Delivery to Intact Plant Cells. AB - Here we report a powerful method that facilitates the transport of biologically active materials across the cell wall barrier in plant cells. Positively charged delaminated layered double hydroxide lactate nanosheets (LDH-lactate-NS) with a 0.5-2 nm thickness and 30-60 nm diameter exhibit a high adsorptive capacity for negatively charged biomolecules, including fluorescent dyes such as tetramethyl rhodamine isothiocyanate (TRITC), fluorescein isothiocyanate isomer I(FITC) and DNA molecules, forming neutral LDH-nanosheet conjugates. These neutral conjugates can shuttle the bound fluorescent dye into the cytosol of intact plant cell very efficiently. Furthermore, typical inhibitors of endocytosis and low temperature incubation did not prevent LDH-lactate-NS internalization, suggesting that LDH lactate-NS penetrated the plasma membrane via non-endocytic pathways, which will widen the applicability to a variety of plant cells. Moreover, the absence of unwanted side effects in our cytological studies, and the nuclear localization of ssDNA-FITC suggest that nano-LDHs have potential application as a novel gene carrier to plants. PMID- 27221053 TI - GABA A receptor pi subunit promotes apoptosis of HTR-8/SVneo trophoblastic cells: Implications in preeclampsia. AB - Gamma-aminobutyric acid (GABA) functions primarily as an inhibitory neurotransmitter through its receptors in the mature central nervous system. The GABA type A receptor pi subunit (GABRP) has been identified in the tissues of the reproductive system, particularly in the uterus. In addition, we have previously detected GABRP expression in both human and mouse placentas. To examine the role of GABRP in trophoblastic cell invasion, we constructed a pIRES2-GABRP-EGFP plasmid which was used for the transfection of a human placental cell line derived from first trimester extravillous trophoblasts (HTR-8/SVneo). The number of invaded cells was decreased by GABRP overexpression. Notably, the decrease in the invasive cell number may be due to the increased apoptosis of the HTR-8/SVneo cells following GABRP transfection, which was further confirmed by flow cytometry, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. Based on the increased apoptosis of trophoblastic cells in pregnancies complicated by preeclampsia (PE) and the fact that GABRP promotes the apoptosis of trophoblastic cells, we hypothesized that GABRP expression is increased in the placental tissues from patients with PE compared with that in the normal groups and this hypothesis was confirmed by RT-qPCR and immunohistochemical analysis. Taken together, these findings imply that GABRP plays an important role in placentation and this pathway may be a promising molecular target for the development of novel therapeutic strategies for PE. PMID- 27221057 TI - Beneficial effects of legumes on parameters of the metabolic syndrome: a systematic review of trials in animal models. AB - Legume consumption plays a pivotal role in the prevention and treatment of the metabolic syndrome (MetS). This systematic review aimed to highlight the beneficial effects of legume interventions for the prevention and/or improvement of parameters related to the MetS and the implicated metabolic pathways so far reported. The methodology involved a search in four electronic databases (Medline, Web of Science, Scopus, Cochrane Library) from January 2007 to December 2014, considering as descriptors 'Metabolic Syndrome' and 'Fabaceae' and adequately adjusting the equation in each one of them. In total, forty-one studies were finally included. The majority of the studies described a regulating effect on glucose and lipid metabolism due to legume administration, whereas effects on blood pressure and renal parameters are not fully described. Regarding the metabolic pathways involved, they include the up-regulation of genes related to beta-oxidation and acetyl-CoA degradation and the down-regulation of glycolytic and lipogenesis genes, as well as those associated with the acetyl-CoA synthesis. The ameliorating effects of legume consumption on the alterations associated with the MetS are clearly reported and coincide with changes in the expression of protein and genes involved in lipid and glucose metabolism. More research needs to be conducted including more legume species that are highly consumed as part of a healthy dietary pattern. PMID- 27221056 TI - Scaling and universality in glass transition. AB - Kinetic facilitated models and the Mode Coupling Theory (MCT) model B are within those systems known to exhibit a discontinuous dynamical transition with a two step relaxation. We consider a general scaling approach, within mean field theory, for such systems by considering the behavior of the density correlator and the dynamical susceptibility - (2). Focusing on the Fredrickson and Andersen (FA) facilitated spin model on the Bethe lattice, we extend a cluster approach that was previously developed for continuous glass transitions by Arenzon et al. (Phys. Rev. E 90, 020301(R) (2014)) to describe the decay to the plateau, and consider a damage spreading mechanism to describe the departure from the plateau. We predict scaling laws, which relate dynamical exponents to the static exponents of mean field bootstrap percolation. The dynamical behavior and the scaling laws for both density correlator and dynamical susceptibility coincide with those predicted by MCT. These results explain the origin of scaling laws and the universal behavior associated with the glass transition in mean field, which is characterized by the divergence of the static length of the bootstrap percolation model with an upper critical dimension dc = 8. PMID- 27221058 TI - Epithelial-mesenchymal transition and FOXA genes during tobacco smoke carcinogen induced transformation of human bronchial epithelial cells. AB - Lung cancer is largely an environmentally caused disease with poor prognosis. An in vitro transformation model of human bronchial epithelial cells (HBEC) was used to study long-term effects of tobacco smoke carcinogens on epithelial-mesenchymal transition (EMT) and the forkhead box transcription factors FOXA1 and FOXA2. CDK4 and hTERT immortalized HBEC2 and HBEC12 cell lines were exposed weekly to either cigarette smoke condensate (CSC), benzo[a]pyrene, or methylnitrosourea. Transformed cell lines were established from soft-agar colonies after 12weeks of exposure. HBEC12 was transformed by all exposures while HBEC2 was only transformed by CSC. Untransformed HBEC2 showed little invasive capacity, whereas transformed cell lines completely closed the gap in a matrigel scratch wound assay. CDH1 was down-regulated in all of the transformed cell lines. In contrast, CDH2 was up-regulated in both HBEC2 and one of the HBEC12 transformed cell lines. Furthermore, transformed cells showed activation of EMT markers including SNAI1, ZEB1, VIM, and MMP2. All transformed cell lines had significant down-regulation of FOXA1 and FOXA2, indicating a possible role in cell transformation and EMT. ChIP analysis showed increased binding of Histone-H3 and macroH2A in FOXA1 and FOXA2 in the transformed HBEC2 cell lines, indicating a compact chromatin. In conclusion, long-term carcinogen exposure lead to down-regulation of FOXA1 and FOXA2 concomitantly with the occurrence of EMT and in vitro transformation in HBEC cells. PMID- 27221060 TI - Microscopic origins of the terahertz carrier relaxation and cooling dynamics in graphene. AB - The ultrafast dynamics of hot carriers in graphene are key to both understanding of fundamental carrier-carrier interactions and carrier-phonon relaxation processes in two-dimensional materials, and understanding of the physics underlying novel high-speed electronic and optoelectronic devices. Many recent experiments on hot carriers using terahertz spectroscopy and related techniques have interpreted the variety of observed signals within phenomenological frameworks, and sometimes invoke extrinsic effects such as disorder. Here, we present an integrated experimental and theoretical programme, using ultrafast time-resolved terahertz spectroscopy combined with microscopic modelling, to systematically investigate the hot-carrier dynamics in a wide array of graphene samples having varying amounts of disorder and with either high or low doping levels. The theory reproduces the observed dynamics quantitatively without the need to invoke any fitting parameters, phenomenological models or extrinsic effects such as disorder. We demonstrate that the dynamics are dominated by the combined effect of efficient carrier-carrier scattering, which maintains a thermalized carrier distribution, and carrier-optical-phonon scattering, which removes energy from the carrier liquid. PMID- 27221050 TI - Inducing mitophagy in diabetic platelets protects against severe oxidative stress. AB - Diabetes mellitus (DM) is a growing international concern. Considerable mortality and morbidity associated with diabetes mellitus arise predominantly from thrombotic cardiovascular events. Oxidative stress-mediated mitochondrial damage contributes significantly to enhanced thrombosis in DM A basal autophagy process has recently been described as playing an important role in normal platelet activation. We now report a substantial mitophagy induction (above basal autophagy levels) in diabetic platelets, suggesting alternative roles for autophagy in platelet pathology. Using a combination of molecular, biochemical, and imaging studies on human DM platelets, we report that platelet mitophagy induction serves as a platelet protective mechanism that responds to oxidative stress through JNK activation. By removing damaged mitochondria (mitophagy), phosphorylated p53 is reduced, preventing progression to apoptosis, and preserving platelet function. The absence of mitophagy in DM platelets results in failure to protect against oxidative stress, leading to increased thrombosis. Surprisingly, this removal of damaged mitochondria does not require contributions from transcription, as platelets lack a nucleus. The considerable energy and resources expended in "prepackaging" the complex mitophagy machinery in a short lived normal platelet support a critical role, in anticipation of exposure to oxidative stress. PMID- 27221059 TI - Drug-induced phospholipidosis caused by combinations of common drugs in vitro. AB - Drug-induced phospholipidosis (DIPLD), characterized by the accumulation of phospholipids within lysosomes, is suspected to impair lysosomal function and considered an adverse side effect of the administered medication. The increasing use of polypharmacy and the resultant elevated risks of adverse drug reactions raise the need to explore the effects of drug combinations with respect to their influence on side effects, such as DIPLD. In this study, we utilized an in vitro assay to investigate DIPLD that was caused by 24 commonly used drugs applied alone and in binary combinations with each other. Moreover, we attempted to predict the extent of DIPLD resulting from the combinations using a simple additive approach based on the increase in phospholipid levels caused by the single drugs. The results suggest that DIPLD, which was caused by combinations of drugs, occurs in an additive manner, depending on total drug concentration. Furthermore, we show that the extent of DIPLD can be predicted from the DIPLD caused by the single drugs. Thus, the simultaneous use of multiple drugs with PLD inducing properties increases the event risk, as well as the severity of drug induced phospholipidosis. The findings underline the importance of considering the DIPLD-inducing properties of drugs, especially in the context of polypharmacy. PMID- 27221051 TI - TGFbeta signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype. AB - The heterogeneous nature of colorectal cancer (CRC) complicates prognosis and is suggested to be a determining factor in the efficacy of adjuvant therapy for individual patients. Based on gene expression profiling, CRC is currently classified into four consensus molecular subtypes (CMSs), characterized by specific biological programs, thus suggesting the existence of unifying developmental drivers for each CMS Using human organoid cultures, we investigated the role of such developmental drivers at the premalignant stage of distinct CRC subtypes and found that TGFbeta plays an important role in the development of the mesenchymal CMS4, which is of special interest due to its association with dismal prognosis. We show that in tubular adenomas (TAs), which progress to classical CRCs, the dominating response to TGFbeta is death by apoptosis. By contrast, induction of a mesenchymal phenotype upon TGFbeta treatment prevails in a genetically engineered organoid culture carrying a BRAF(V) (600E) mutation, constituting a model system for sessile serrated adenomas (SSAs). Our data indicate that TGFbeta signaling is already active in SSA precursor lesions and that TGFbeta is a critical cue for directing SSAs to the mesenchymal, poor prognosis CMS4 of CRC. PMID- 27221061 TI - A new functional role uncovered for RASGRF2 in control of nuclear migration in cone photoreceptors during postnatal retinal development. AB - Despite their homologous structure and central nervous system(CNS) expression patterns, the GRF1 and GRF2 guanine nucleotide exchange factors(GEF) appear to play distinct, non-overlapping functions in cellular excitability, synaptic plasticity or neuromodulation. We recently uncovered a new functional role of GRF2 controlling nuclear migration in cone photoreceptors during postnatal neuroepithelial differentiation of the mouse retina. Analyzing GRF2-KO mice, we detected the specific accumulation of abnormally located, "ectopic" cone photoreceptor nuclei in the photoreceptor segment(PS) layer of their retinas. This alteration was accompanied by defective electroretinograms(ERG) indicative of impaired cone-mediated visual function, and accumulation around the "ectopic" nuclei of signaling molecules known to be functionally relevant for intracellular organelle migration, cytoskeletal reorganization or cell polarity establishment including PAR3, PAR6, and the phosphorylated proteins pPAK, pMLC2 and pVASP. We propose a mechanism whereby the absence of a productive functional interaction between GRF2 and its downstream target CDC42 leads to altered formation/structure of PAR-containing, polarity-related macromolecular complexes and abnormal activation of downstream signaling mediated by activated, phosphorylated forms of PAK, VASP and MLC2. As cone photoreceptors are responsible for color vision and visual acuity, these observations are potentially relevant for degenerative diseases of the human retina, harboring almost double number of cones than mice. PMID- 27221062 TI - In vitro rapid diagnostic tests for severe drug hypersensitivity reactions in children. AB - BACKGROUND: Previous reports have demonstrated the utility of T-cell proliferation and cytokine release assays as in vitro diagnostic tests for drug causation in drug hypersensitivity reactions (DHR). However, data from pediatric populations are scarce compared with data in adults. OBJECTIVE: To compare the lymphocyte proliferation assay (LPA) with combination cytokine assays in the pediatric population and to identify its potential use in the acute and postrecovery phases. METHODS: A total of 18 in vitro tests were undertaken ex vivo to compare drug-specific proliferation and cytokine release (interferon gamma [IFN-gamma] and interleukin-4 [IL-4]). The study included 16 patients with DHR: 7 children tested in the acute phase, 7 tested after recovery, and 2 tested during both the acute and postrecovery phases. RESULTS: The sensitivity of the LPA was better during the acute stage of DHR in children. Cytokine assays revealed a higher frequency of positive drug-specific responses compared with LPA in both the acute (LPA, 77.8%; IFN-gamma, 88.9%; IL-4, 100%) and postrecovery phases (LPA, 33.3%; IFN-gamma, 66.7%; IL-4, 66.7%). Combination cytokine assays (IFN-gamma and IL-4) produced higher positive drug-specific responses in identifying culprit drugs compared with LPA in both the acute and postrecovery phases. CONCLUSION: In vitro drug-induced T-cell proliferation and cytokine release assays are useful for identification of the causative drug in children with DHR. Cytokine assays (IFN-gamma and IL-4) were better than LPA, but when combined, they offer even greater utility in the diagnosis of acute and postrecovery DHR. Cytokine detection is rapid and does not involve radioactivity. These novel in vitro assays may offer a significant advancement in our future management of DHR in children. PMID- 27221063 TI - Association of obesity and severity of acute asthma exacerbations in Filipino children. AB - BACKGROUND: Increased body mass index (BMI) may be a risk factor for the development and severity of asthma. However, the effect of obesity on asthma exacerbations is unclear. OBJECTIVE: To examine the association of obesity and the severity of acute asthma exacerbations. METHODS: A retrospective cohort of children aged 5 to 18 years who were seen in the emergency department and admitted for acute asthma exacerbation from 2009 to 2011 was reviewed. Weight and height data to compute the BMI were taken from the medical record review. The Centers for Disease Control and Prevention BMI-for-age growth charts for boys and girls aged 2 to 20 years were used to classify underweight, normal, overweight, and obese. Severity of asthma exacerbations into mild, moderate, or severe was determined using criteria by the Global Initiative for Asthma 2010. The chi(2) test of association or the Fisher exact probability test for small samples was used to determine the association between nutritional status and severity of asthma exacerbations. RESULTS: Of the 303 cases reviewed, most were boys with a mean (SD) age of 10 (3.8) years. The prevalence of overweight and obese children admitted for acute asthma exacerbation was 21% and 28%, respectively. No significant difference was found in the severity of asthma exacerbations, with 82.9% of the nonobese group and 86.8% of the overweight-obese group having moderate-to-severe exacerbation (likelihood ratio, 0.879; 95% CI, 0.42-0.41; P = .88). CONCLUSION: Our findings suggest that the severity of acute asthma exacerbations was not affected by increased BMI. PMID- 27221064 TI - Metered-dose inhaler technique per the Global Initiative for Asthma and Expert Panel Report 3: Why do pharmaceutical companies have one critical difference? PMID- 27221066 TI - Ultrasound-Guided Percutaneous Management of Splenic Ectopic Pregnancy. AB - Splenic ectopic pregnancies are a rare cause of abdominal pain in reproductive age women. A 21-year-old woman with worsening abdominal pain and a positive pregnancy test presented with hemoperitoneum and no intrauterine pregnancy on transvaginal ultrasound. After 2 nondiagnostic laparoscopies, a splenic pregnancy was diagnosed by computed tomography scan and abdominal ultrasound. Currently, diagnosis and treatment of splenic pregnancies involve exploratory surgery and splenectomy. We report the successful treatment of this splenic ectopic pregnancy with combined intramuscular plus ultrasound-guided percutaneous methotrexate injection, with preservation of the patient's spleen. Abdominal implantation must be considered in patients with pregnancy of unknown location, and in carefully selected patients splenic ectopic pregnancy can be successfully managed by minimally invasive methods. PMID- 27221065 TI - A systematic review of epinephrine degradation with exposure to excessive heat or cold. AB - BACKGROUND: Epinephrine is a lifesaving drug in the treatment of anaphylaxis and cardiac resuscitation. Current US storage recommendations are for controlled room temperature (20 degrees C-25 degrees C), with excursions permitted from 15 degrees C to 30 degrees C. Maintaining epinephrine within this required range is challenging, particularly for patients carrying autoinjectors and during storage in emergency vehicles. OBJECTIVE: To study epinephrine degradation with extreme temperature exposure for epinephrine concentrations used in anaphylaxis and cardiac resuscitation. METHODS: We searched the literature for all studies of epinephrine in sealed syringes, vials, or ampules in concentrations between 1:1,000 and 1:10,000, that measured epinephrine in samples exposed to temperatures above and/or below the recommended storage temperature compared with control samples. RESULTS: Nine studies were included. Heat exposure resulted in epinephrine degradation but only with prolonged exposure. Constant heat resulted in more degradation. None of the studies that evaluated epinephrine exposure to extreme cold found significant degradation. None of the studies evaluating the effects of real-world temperature fluctuations detected significant degradation. Only 2 small studies (1 evaluating heat and 1 freezing) involved autoinjectors, and all 40 devices tested fired correctly. CONCLUSION: Temperature excursions in real-world conditions may be less detrimental than previously suggested. Freezing and limited heat excursions did not result in epinephrine degradation. Refrigeration of epinephrine appears to reduce degradation. However, the effect of extreme temperatures, particularly freezing, on autoinjectors is not sufficiently well established. More research in needed at clinically relevant high temperatures, with limited exposure to heat, and involving autoinjector devices. PMID- 27221068 TI - Deciphering the function of non-coding RNAs in prostate cancer. AB - The advent of next-generation sequencing methods is fuelling the discovery of multiple non-coding RNA transcripts with direct implication in cell biology and homeostasis. This new layer of biological regulation seems to be of particular importance in human pathogenesis, including cancer. The aberrant expression of ncRNAs is a feature of prostate cancer, as they promote tumor-suppressive or oncogenic activities, controlling multicellular events leading to carcinogenesis and tumor progression. From the small RNAs involved in the RNAi pathway to the long non-coding RNAs controlling chromatin remodeling, alternative splicing, and DNA repair, the non-coding transcriptome represents the significant majority of transcriptional output. As such, ncRNAs appear as exciting new diagnostic, prognostic, and therapeutic tools. However, additional work is required to characterize the RNA species, their functions, and their applicability to clinical practice in oncology. In this review, we summarize the most important features of ncRNA biology, emphasizing its relevance in prostate carcinogenesis and its potential for clinical applications. PMID- 27221067 TI - TMPyP4 promotes cancer cell migration at low doses, but induces cell death at high doses. AB - TMPyP4 is widely considered as a potential photosensitizer in photodynamic therapy and a G-quadruplex stabilizer for telomerase-based cancer therapeutics. However, its biological effects including a possible adverse-effect are poorly understood. In this study, whole genome RNA-seq analysis was used to explore the alteration in gene expression induced by TMPyP4. Unexpectedly, we find that 27.67% of changed genes were functionally related to cell adhesion. Experimental evidences from cell adhesion assay, scratch-wound and transwell assay indicate that TMPyP4 at conventional doses (<=0.5 MUM) increases cell-matrix adhesion and promotes the migration of tumor cells. In contrast, a high dose of TMPyP4 (>=2 MUM) inhibits cell proliferation and induces cell death. The unintended "side effect" of TMPyP4 on promoting cell migration suggests that a relative high dose of TMPyP4 is preferred for therapeutic purpose. These findings contribute to better understanding of biological effects induced by TMPyP4 and provide a new insight into the complexity and implication for TMPyP4 based cancer therapy. PMID- 27221070 TI - Orchestrating immune responses: How size, shape and rigidity affect the immunogenicity of particulate vaccines. AB - Particulate carrier systems are promising drug delivery vehicles for subunit vaccination as they can enhance and direct the type of T cell response. In order to develop vaccines with optimal immunogenicity, a thorough understanding of parameters that could affect the strength and quality of immune responses is required. Pathogens have different dimensions and stimulate the immune system in a specific way. It is therefore not surprising that physicochemical characteristics of particulate vaccines, such as particle size, shape, and rigidity, affect multiple processes that impact their immunogenicity. Among these processes are the uptake of the particles from the site of administration, passage through lymphoid tissue and the uptake, antigen processing and activation of antigen-presenting cells. Herein, we systematically review the role of the size, shape and rigidity of particulate vaccines in enhancing and skewing T cell response and attempted to provide a "roadmap" for rational vaccine design. PMID- 27221069 TI - Time-programmed DCA and oxaliplatin release by multilayered nanofiber mats in prevention of local cancer recurrence following surgery. AB - Local recurrence following surgery in cancer treatment remains a major clinical challenge. To increase antitumor activity but maintain toxicity in an acceptable level in prevention of local cancer recurrence, we demonstrated a dual drug loaded multilayered fiber mats strategy, in which DCA and oxaliplatin were co electrospun into the distinct layer of resultant fabrics and the oxaliplatin loaded fibers layer was sealed between the basement film layer and other two fibers layers. The dual drug-loaded multilayered fiber mats exhibit time programmed dual release behavior and synergistic effect upon cancer cells. Nontoxic DCA selectively promotes apoptosis of cancer cells through modulating cellular metabolism, and oxaliplatin subsequently kills the remained cancer cells in a low concentration. After implantation on the resection margin of cervical carcinoma on a murine model, the dual drug-loaded multilayered fiber mats displayed enhanced anti-recurrence efficacy and decreased side toxic effects over 30days compared with drug-loaded monolayered fiber mats. The time-programmed combination of DCA and oxaliplatin within multilayered nanofiber mats appears to be a promising strategy for local cancer treatment following resection. PMID- 27221071 TI - Synthesis and evaluation of duocarmycin SA analogs incorporating the methyl 1,2,8,8a-tetrahydrocyclopropa[c]imidazolo[4,5-e]indol-4-one-6-carboxylate (CImI) alkylation subunit. AB - The design, synthesis, and evaluation of methyl 1,2,8,8a tetrahydrocyclopropa[c]imidazolo[4,5-e]indol-4-one-6-carboxylate (CImI) derivatives are detailed representing analogs of duocarmycin SA and yatakemycin containing an imidazole replacement for the fused pyrrole found in the DNA alkylation subunit. PMID- 27221072 TI - Systemic and organ involvement in monogenic autoinflammatory disorders: a global review filtered through internists' lens. AB - Monogenic autoinflammatory disorders (AIDs) are rare diseases driven by cytokine mediated extraordinary sterile inflammation that results from the activation of innate immune pathways. The clinical hallmark of these diseases is the recurrence of stereotyped episodes of systemic- and organ-specific inflammation; the most common systems involved being the skin, musculoskeletal system, gastrointestinal tract, and central nervous system. The autoinflammatory disorders may have a profound impact on the quality of life of the affected patients, and a delayed diagnosis may lead to severe complications, the most dreadful of which is AA Amyloidosis. This review gives an overview on the four main AIDs, namely familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, cryopyrinopathies, and mevalonate kinase deficiency, focusing on their clinical phenotype in adults and differential diagnosis, suggesting a diagnostic algorithm, and reviewing the available treatments. PMID- 27221073 TI - Highly efficient nonrigid motion-corrected 3D whole-heart coronary vessel wall imaging. AB - PURPOSE: To develop a respiratory motion correction framework to accelerate free breathing three-dimensional (3D) whole-heart coronary lumen and coronary vessel wall MRI. METHODS: We developed a 3D flow-independent approach for vessel wall imaging based on the subtraction of data with and without T2-preparation prepulses acquired interleaved with image navigators. The proposed method corrects both datasets to the same respiratory position using beat-to-beat translation and bin-to-bin nonrigid corrections, producing coregistered, motion corrected coronary lumen and coronary vessel wall images. The proposed method was studied in 10 healthy subjects and was compared with beat-to-beat translational correction (TC) and no motion correction for the left and right coronary arteries. Additionally, the coronary lumen images were compared with a 6-mm diaphragmatic navigator gated and tracked scan. RESULTS: No significant differences (P > 0.01) were found between the proposed method and the gated and tracked scan for coronary lumen, despite an average improvement in scan efficiency to 96% from 59%. Significant differences (P < 0.01) were found in right coronary artery vessel wall thickness, right coronary artery vessel wall sharpness, and vessel wall visual score between the proposed method and TC. CONCLUSION: The feasibility of a highly efficient motion correction framework for simultaneous whole-heart coronary lumen and vessel wall has been demonstrated. Magn Reson Med 77:1894-1908, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27221075 TI - Could allergen-specific immunotherapy benefit from the use of nanocarriers? PMID- 27221076 TI - Functional recruitment for drug delivery through protein-based nanotechnologies. PMID- 27221074 TI - Stem cells and diabetic cardiomyopathy: from pathology to therapy. AB - The worldwide increase trend in the prevalence of diabetes has highlighted the need for increased research efforts into treatment options for both the disease itself and its associated complications. Diabetes has been widely recognized as a major risk factor for cardiovascular diseases, such as coronary heart disease and hypertension. Diabetic cardiomyopathy (DCM) is a main complication of diabetes, contributing to specific forms of heart failure independent from ischemia or hypertension. Without considerably effective approaches, a dire need exists to further explore the mechanisms and potential therapeutic strategies to prevent or reverse the progression of DCM. In the past decades, stem cell-based therapies have held promises to various diseases including DCM. The aim of the present review was to summarize the current literature with regard to the pathological changes of diabetic cardiomyopathy, endogenous stem cells in diabetes, and the exogenous stem cells transplantation for DCM. If the best use is made of the advantages of stem cells and their mechanism of action is explicitly explored, stem cell-based therapies could served as an important tool for the prevention and treatment of DCM patients. PMID- 27221078 TI - Enhancement of immunogenic response and protection in model rats by CSTM nanoparticles anticaries DNA vaccine. AB - AIM: To construct anticaries DNA vaccine and evaluate its ability to elicit mucosal and systemic immune responses in rats. MATERIALS & METHODS: wapA fragment was cloned into pVAX1 plasmid to generate pVAX1-wapA. The pVAX1-wapA/trimethyl chitosan nanoparticles were prepared by complex coacervation method. RESULTS: Significantly higher specific IgG antibody titers were observed in rats immunized with nanoparticles compared with rats immunized with naked pVAX1-wapA. Anti-WapA IgA and IgG antibody levels after intranasal immunization were significantly higher than those following intramuscular delivery of nanoparticles or naked pVAX1-wapA. Furthermore, fewer enamel, slight dentin and dentin moderate lesions were observed in rats immunized with nanoparticles. CONCLUSION: The results implicate WapA as an excellent candidate for anticaries vaccine development and nanoparticles as an effective delivery system. PMID- 27221079 TI - Elastomeric Cellular Structure Enhanced by Compressible Liquid Filler. AB - Elastomeric cellular structures provide a promising solution for energy absorption. Their flexible and resilient nature is particularly relevant to protection of human bodies. Herein we develop an elastomeric cellular structure filled with nanoporous material functionalized (NMF) liquid. Due to the nanoscale infiltration in NMF liquid and its interaction with cell walls, the cellular structure has a much enhanced mechanical performance, in terms of loading capacity and energy absorption density. Moreover, it is validated that the structure is highly compressible and self-restoring. Its hyper-viscoelastic characteristics are elucidated. PMID- 27221077 TI - Inflammatory monocyte/macrophage modulation by liposome-entrapped spironolactone ameliorates acute lung injury in mice. AB - AIM: To examine the therapeutic/preventive potential of liposome-encapsulated spironolactone (SP; Lipo-SP) for acute lung injury (ALI) and fibrosis. MATERIALS & METHODS: Lipo-SP was prepared by the film-ultrasonic method, and physicochemical and pharmacokinetic characterized for oral administration (10 and 20 mg/kg for SP-loaded liposome; 20 mg/kg for free SP) in a mouse model bleomycin induced ALI. RESULTS: Lipo-SP enhanced bioavailability of SP with significant amelioration in lung pathology. Mechanistically, SP-mediated mineralocorticoid receptor antagonism contributes to inflammatory monocyte/macrophage modulation via an inhibitory effect on Ly6C(hi) monocytosis-directed M2 polarization of alveolar macrophages. Moreover, Lipo-SP at lower dose (10 mg/kg) exhibited more improvement in body weight gain. CONCLUSION: Our data highlight Lipo-SP as a promising approach with therapeutic/preventive potential for ALI and fibrosis. PMID- 27221080 TI - Reductions in tonic GABAergic current in substantia gelatinosa neurons and GABAA receptor delta subunit expression after chronic constriction injury of the sciatic nerve in mice. AB - BACKGROUND: Decreased Gamma-aminobutyric acid (GABA)-ergic phasic inhibitory transmission in the spinal cord is thought to be responsible for the development of neuropathic pain. However, the role of GABAergic tonic current in substantia gelatinosa (SG) neurons in neuropathic pain remains to be fully elucidated. In this study, we assessed GABAergic tonic currents of SG neurons in a sciatic nerve chronic constriction injury (CCI) mouse. METHOD: Whole-cell patch clamp recordings form lumbar spinal cord slices was performed to evaluate GABAergic currents. We also investigated the expression changes of GABAA receptor subunits which are considered to mediate tonic currents. RESULTS: The percentage of SG neurons receiving GABAergic tonic currents decreased in CCI mice compared with Naive mice. No significant change was observed in the mean amplitude of GABAergic tonic currents. RT-PCR and Western blot revealed that the expression of GABAA receptor delta subunits decreased following CCI. CONCLUSION: A reduction in the expression the delta subunit of the GABAA receptor and diminished GABAergic tonic current in SG neurons were observed after CCI in mice. GABAergic tonic current plays a key role in neuropathic pain. The GABAA receptor delta subunit may be a therapeutic target in neuropathic pain. WHAT DOES THIS STUDY ADD?: In spinal SG neurons, GABAergic inhibitory transmission operates through both phasic and tonic currents, but physiological role is largely unknown. In this study, we report dysregulation of GABAA receptor delta subunit-mediated tonic current in SG neurons may result in spinal disinhibition resulting in neuropathic pain in CCI mice. PMID- 27221081 TI - Analysis of the complementarity determining regions beta-chain genomic rearrangement using high-throughput sequencing in periphery cytotoxic T lymphocytes of patients with chronic hepatitis B. AB - Cytotoxic T lymphocytes (CTLs) are important for the recognition of the hepatitis B virus (HBV), mediating immunoprotective mechanisms and determining the clinical outcome following HBV infection. CTLs recognize the invading virus via the T cell receptor (TCR). The aim of the current study was to investigate the variability of TCR in lymphocytes from patients with chronic hepatitis B and whether TCR genomic recombination is regulated by the current treatment strategies. Peripheral blood mononuclear cells (PBMCs) were isolated from patients with chronic hepatitis B and high-throughput sequencing was performed to analyze the gene expression diversity of beta chain complementarity determining region. High throughput sequencing produced ~380,000 reads. The sequences of V and J family mRNAs of the beta chain V area were analyzed and databases were created for all 30 V family and J family genes. Using the Basic Local Alignment Search Tool, 15 genes were identified to be upregulated in the samples following treatment. Among them, the expression of T cell receptor beta variable 28 (TRBV28)_T cell receptor beta joining 1-5 (TRBJ1.5) and TRBV6_TRBJ2.10 were significantly different in the treated samples compared with samples taken prior to treatment. Genomic recombination patterns of TRBV and TRBJ of the beta chain V area were observed to be different in the samples following treatment. The data of the current study demonstrated that the genomic rearrangement of the V and J segments of TCR beta chain V area may be associated with the chronic progression of HBV and impact on treatment efficacy. PMID- 27221082 TI - Expression of cysteinyl leukotriene receptor 1 and 2 (CysLTR1 and CysLTR2) in the lymphocytes of hyperplastic tonsils: comparison between allergic and nonallergic snoring children. AB - BACKGROUND: Cysteinyl leukotriene receptor 1 and 2 (CysLTR1 and CysLTR2) are involved in allergic processes and play a role in adenotonsillar hyperplasia (AH). Clinically, only CysLTR1 may be blocked by montelukast. Our objective was to compare the expression of CysLTR1 and CysLTR2 in the B and T cells of hyperplasic tonsils of sensitized (SE) and control (NS) snoring children. METHODS: Sixty children, 5 to 10 years of age, referred for adenotonsillectomy, were divided into SE and NS groups, according to their responses to the skin prick test. Cells from the removed tissues were stained for CysLTR1, CysLTR2, CD19, and CD3 and counted via flow cytometry. messenger RNA (mRNA) expression of the CysLTRs genes was measured real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). RESULTS: The SE group showed reduced expression of the small CD3+/CysLTR1+ lymphocytes (4.6 +/- 2.2 vs 6.5 +/- 5.0; p = 0.04). Regarding the large lymphocytes, the SE group showed lower expression of CD3+/CysLTR1+ (40.9 +/- 14.5 vs 47.6 +/- 11.7; p = 0.05), CD19+/CysLTR1+ (44.6 +/ 16.9 vs 54.1 +/- 12.4; p = 0.01), and CD19+/CysLTR2+ (55.3 +/- 11.3 vs 61.5 +/- 12.6; p = 0.05) lymphocytes. Considering the total number of lymphocytes, the SE group had fewer CD3+/CysLTR1+ lymphocytes (11.1 +/- 5.5 vs 13.7 +/- 6.2; p = 0.04). All other cell populations exhibited reduced expression in the SE group without statistical significance. The expression of CysLTR2 was significantly higher (p < 0.05) than CysLTR1 in most studied cell populations. The mRNA expression did not show significant differences between the groups. CONCLUSION: The expression of CysLTR is higher in the lymphocytes of the NS children, and CysLTR2 shows greater expression than CysLTR1 Respiratory allergies do not appear to be a stimulus for AH occurrence. Newer drugs capable of blocking both CysLTRs warrant further study. PMID- 27221083 TI - [Arrhythmia in adults with congenital heart disease : Acute and long-term management]. AB - During the last few decades, the management of cardiac arrhythmias in adult patients with congenital heart disease (CHD) has undergone a significant change from a conservative, mainly pharmacological approach, to interventional techniques such as catheter ablation or device implantation (pacemakers, implantable cardioverter defibrillators [ICD]). The long-term efficacy of these strategies is as dependent on the hemodynamic status of the patient and the type of arrhythmia as it is on the underlying heart defect and any preceding surgery. Pharmacological agents and electrical cardioversion are at the forefront of treatment for tachyarrhythmias. Individualized thromboprophylaxis plays an important role in acute and in long-term management. Catheter ablation seems to show a more favorable outcome compared with a pharmacological approach in the long-term management of supraventricular tachyarrhythmias. Surgical procedures, including arrhythmia surgery (such as the Fontan conversion operation), may improve the arrhythmia. In symptomatic patients with bradyarrhythmias, such as sinus node dysfunction, pacemaker implantation is usually indicated. In the management of ventricular arrhythmias catheter ablation is also increasingly used. This is dominated by the individual risk stratification for the prevention of sudden cardiac death (SCD). However, the ICD is still the therapeutic cornerstone in most cases. The management of cardiac arrhythmias in adult CHD patients should be performed at specialized centers where all aspects of diagnosis and treatment are covered. PMID- 27221084 TI - [Antibradycardia therapy : Indication and implementation]. AB - Pacemaker therapy (PMT) in grown-up congenital heart disease (GUCH) must meet the demands of a young, dynamic and heterogeneous group of patients. The duration of the therapy has to be planned for several decades and should be accompanied by an invasive procedure at the very least. Most of the patients enter adulthood with their pacemaker (PM) already implanted; for others the indications can be derived from the published guidelines for GUCH and PMT, but need to be adjusted to the individual situation of the patient. Depending on the underlying heart disease the decision on the use of either an epimyocardial or a transvenous PM system has to be made. Both electrodes and PM should correspond to the latest technical developments to optimally adapt to the patients' multiple requirements. In the case of PM system revisions abandoned leads should be removed and vascular stenosis or occlusions cleared to be prepared for later revisions. During any cardiac surgery epimyocardial PM systems should be checked against the patient's needs and expanded or revised accordingly. Epimyocardial resynchronization systems in particular offer more opportunities for compensating for cardiac dysfunction with greater reliability using a second ventricular lead. The PMT is an essential part of the medical treatment for many patients with GUCH and contributes significantly to the well-being and quality of life. Against this background, a competent and consequent follow-up regime requires experienced physicians. An integrated telemetric monitoring system for the PM has proven valuable and supports the early recognition of cardiac arrhythmia. PMID- 27221087 TI - Use mefloquine for UK troops only as "last resort," MPs tell Ministry of Defence. PMID- 27221086 TI - Disparities in Prenatal Care Utilization Among U.S. Versus Foreign-Born Women with Chronic Conditions. AB - We examined disparities in prenatal care utilization (PNCU) among U.S. and foreign-born women with chronic conditions. We performed a cross-sectional analyses using data from 2011 to 2012 National Center for Health Statistics Natality Files (n = 6,644,577) to examine the association between maternal nativity (U.S. vs. foreign-born), presence of a chronic condition (diabetes or hypertensive disorder) and PNCU. After adjustment for selected maternal characteristics, overall and among those with chronic conditions, foreign-born women reported significantly lower odds of intensive and adequate PNCU and higher odds of intermediate and inadequate PNCU than U.S.-born women. Few differences in report of no care were found by maternal nativity. These findings suggest that foreign-born women may be receiving some form of prenatal care, but adequacy of care is likely to be lower compared to U.S.-born counterparts, even among those with chronic conditions. PMID- 27221085 TI - Discovery of rare variants for complex phenotypes. AB - With the rise of sequencing technologies, it is now feasible to assess the role rare variants play in the genetic contribution to complex trait variation. While some of the earlier targeted sequencing studies successfully identified rare variants of large effect, unbiased gene discovery using exome sequencing has experienced limited success for complex traits. Nevertheless, rare variant association studies have demonstrated that rare variants do contribute to phenotypic variability, but sample sizes will likely have to be even larger than those of common variant association studies to be powered for the detection of genes and loci. Large-scale sequencing efforts of tens of thousands of individuals, such as the UK10K Project and aggregation efforts such as the Exome Aggregation Consortium, have made great strides in advancing our knowledge of the landscape of rare variation, but there remain many considerations when studying rare variation in the context of complex traits. We discuss these considerations in this review, presenting a broad range of topics at a high level as an introduction to rare variant analysis in complex traits including the issues of power, study design, sample ascertainment, de novo variation, and statistical testing approaches. Ultimately, as sequencing costs continue to decline, larger sequencing studies will yield clearer insights into the biological consequence of rare mutations and may reveal which genes play a role in the etiology of complex traits. PMID- 27221088 TI - Identification of Enteric Viruses in Foods from Mexico City. AB - Foodborne viruses are a common and, probably, the most under-recognized cause of outbreaks of gastroenteritis. Among the main foods involved in the transmission of human enteric viruses are mollusks, and fruits and vegetables irrigated with wastewater and/or washed with non-potable water or contaminated by contact with surfaces or hands of the infected personnel during its preparation. In this study, 134 food samples were analyzed for the detection of Norovirus, Rotavirus, and Hepatitis A virus (HAV) by amplification of conserved regions of these viruses. From the 134 analyzed samples, 14 were positive for HAV, 6 for Norovirus, and 11 for Rotavirus. This is the first report in Mexico where emphasis is given to the presence of HAV and Norovirus on perishable foods and food from fisheries, as well as Rotavirus on frozen vegetables, confirming the role of vegetables and bivalve mollusks as transmitting vehicles of enteric viruses. PMID- 27221089 TI - Surgical management of thoracic idiopathic spinal cord herniation. Technical case report and review. AB - Idiopathic spinal cord herniation (ISCH) is a rare spinal disease, in which chronic cerebrospinal fluid pulsations push the arachnoid and adjacent thoracic spinal cord region through an antero-lateral dural defect of congenital, post traumatic, or inflammatory/erosive origin. Symptomatic patients commonly present around the 5th decade of life with slowly progressive myelopathy. Diagnosis relies on high-resolution magnetic resonance imaging. Stable mild cases may be observed, whereas in progressive symptomatic situations, surgical spinal cord reposition and dural defect repair with a dural patch is the preferred treatment. We present a case of ISCH at T5/6 and a review the literature. PMID- 27221091 TI - Retraction Note to: Archaeal amoA Genes Outnumber Bacterial amoA Genes in Municipal Wastewater Treatment Plants in Bangkok. PMID- 27221090 TI - Rainforest Conversion to Rubber Plantation May Not Result in Lower Soil Diversity of Bacteria, Fungi, and Nematodes. AB - Large areas of rainforest in Asia have been converted to plantations, with uncertain effects on soil biodiversity. Using standard metagenetic methods, we compared the soil biota of bacteria, fungi, and nematodes at three rainforest sites in Malaysia with two rubber plantation sites with similar soils and geology. We predicted the following: (1) that the rubber sites would have a lower alpha- and beta-diversity than the rainforest sites, due to the monospecific canopy cover and intensive management with herbicides, pesticides, and fertilizers, and (2) that due to differences in the physical and biotic environment associated with cultivation, there would be distinct communities of bacteria, fungi, and nematodes. However, regarding (1), the results showed no consistent difference in alpha- and beta-diversity of bacteria, fungi, or nematodes between rainforest and rubber plantation sites. It appears that conversion of rainforest to rubber plantations does not necessarily result in a decrease in diversity of soil biota. It may be that heterogeneity associated with the cultivation regimen compensates for loss of biotically imposed heterogeneity of the original rainforest. Regarding (2), as predicted there were statistically significant differences in community composition between rainforest and rubber plantation for bacteria, fungi, and nematodes. These differences could be related to a range of factors including light level, litter fall composition, pH, C and N, selecting a distinct set of soil taxa, and it is possible that this in itself would affect long-term soil function. PMID- 27221092 TI - Tetraspanin 7 autoantibodies in type 1 diabetes. AB - AIMS/HYPOTHESIS: Autoantibodies to pancreatic beta cell proteins are markers of asymptomatic type 1 diabetes. The aim was to determine whether autoantibodies to the beta cell protein tetraspanin 7 would improve the ability to identify autoimmunity against pancreatic beta cells. METHODS: Full length and external domain fragments of tetraspanin 7 were expressed as luciferase-tagged fusion proteins and used in immunoprecipitation assays to measure autoantibodies in samples from 363 patients with type 1 diabetes at onset of disease, 503 beta cell autoantibody negative first-degree relatives of patients, and 212 relatives with autoantibodies to insulin, glutamic acid decarboxylase, insulinoma antigen 2 or zinc transporter 8. RESULTS: Antibody binding was observed against the full length and external domains of tetraspanin 7, and was strongest against the full length protein. Autoantibodies that could be inhibited by untagged tetraspanin 7 were detected in 5 (1%) of 503 autoantibody negative relatives, 3 (3.2%) of 94 autoantibody negative patients, 95 (35.3%) of 269 autoantibody positive patients, 1 (1%) of 98 single autoantibody positive relatives and 25 (21.9%) of 114 multiple autoantibody positive relatives. Progression to diabetes did not differ between multiple autoantibody positive relatives with and without tetraspanin 7 autoantibodies. CONCLUSIONS/INTERPRETATION: Tetraspanin 7 is an autoantigen in type 1 diabetes. Tetraspanin 7 autoantibodies are a marker of type 1 diabetes, but provide minor additional value to existing autoantibodies in identifying beta cell autoimmunity. PMID- 27221094 TI - [Acidosis without marked hyperglycemia : Euglycemic diabetic ketoacidosis associated with SGLT2-Inhibitors]. AB - Sodium-glucose cotransporter 2 (SGLT2) inhibitors are new antidiabetic drugs that regulate blood glucose levels by increasing urinary glucose excretion. In May 2015, the U.S. Food and Drug Administration (FDA) issued a warning that SGLT2 inhibitors may lead to ketoacidosis. In this report, we describe a case of life threatening euglycemic ketoacidosis associated with SGLT2 inhibition and evaluate possible mechanisms and triggers. PMID- 27221093 TI - A novel hepatokine, HFREP1, plays a crucial role in the development of insulin resistance and type 2 diabetes. AB - AIMS/HYPOTHESIS: Type 2 diabetes is highly correlated with nonalcoholic fatty liver disease (NAFLD). Hepatocyte-derived fibrinogen-related protein 1 (HFREP1) is a hepatokine that mediates NAFLD development; however, the role of HFREP1 in the development of insulin resistance and diabetes remains obscure. METHODS: A total of 193 age- and sex-matched participants with normal glucose tolerance, impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and newly diagnosed diabetes (NDD) were recruited for a cross-sectional study. Plasma HFREP1 levels were measured and multivariate linear regression analysis was used to evaluate the relationship between HFREP1, IFG, IGT and NDD. The causal relationship between HFREP1 and insulin resistance was then investigated in animal and cell models. Glucose and insulin tolerance tests, and euglycaemic hyperinsulinaemic clamp, were used to evaluate insulin sensitivity in animals with Hfrep1 overexpression or knockdown in liver by lentiviral vectors. HepG2 cells were used to clarify the possible mechanism of HFREP1-induced insulin resistance. RESULTS: Plasma HFREP1 concentrations were significantly increased in participants with IFG, IGT and NDD. HFREP1 concentrations were independently associated with fasting plasma glucose levels, insulin resistance, IFG, IGT and NDD. Injection of recombinant HFREP1 or Hfrep1 overexpression induced insulin resistance in mice, and HFREP1 disrupted insulin signalling to induce insulin resistance through an extracellular signal-regulated kinase (ERK)1/2-dependent pathway. Moreover, hepatic knockdown of HFREP1 improved insulin resistance in both mice fed a high-fat diet and ob/ob mice. CONCLUSIONS/INTERPRETATION: These findings highlight the crucial role of HFREP1 in insulin resistance and diabetes, and provide a potential strategy and biomarker for developing therapeutic approaches to combat these diseases. PMID- 27221095 TI - [Critical care management of intracerebral hemorrhage]. AB - BACKGROUND: Intracerebral hemorrhage accounts for up to 20 % percent of all ischemic strokes. In addition to a higher mortality, they are often associated with severe neurological impairment for those affected. OBJECTIVES: Review of the current literature and guidelines addressing the critical care management of spontaneous intracerebral hemorrhage, including treatments to reduce primary and secondary neurological damage. RESULTS: Acute blood pressure lowering to less than 140 mmHg should be aspired immediately after intensive care admission. During the following days blood pressure variability should be minimized. Preexisting oral anticoagulation should be immediately reversed, while hemostatic therapy not associated with reversal of antithrombotic therapy should not be applied. Surgery for patients with impaired consciousness should be discussed. Use of pneumatic compression in immobile patients is recommended. Developing intracranial hypertension should be treated with combined physical and pharmacological measures in a stepwise approach. Administration of glucocorticoids is currently not recommended. CONCLUSIONS: Critical care management of spontaneous hemorrhage demands a multimodal, graded approach for reduction of both primary and secondary neurological damage. PMID- 27221097 TI - Kocuria pelophila sp. nov., an actinobacterium isolated from the rhizosphere of a mangrove. AB - A novel spherical actinobacterium, designated RS-2-3T, was isolated from the rhizosphere of a mangrove growing on Rambut Island, Indonesia, and its taxonomic position was investigated using a polyphasic approach. Phylogenetic analysis based on 16S rRNA gene sequence comparison revealed that strain RS-2-3T was related to the members of the genus Kocuria. The highest 16S rRNA gene sequence similarity value was observed with Kocuria marina KMM 3905T (97.0 %). The peptidoglycan type of strain RS-2-3T was found to be A3alpha with an interpeptide bridge comprising l-Ala4-5. The predominant menaquinone was MK-7(H2) and the major fatty acids were anteiso-C15 : 0 and iso-C15 : 0. The DNA G+C content was 71.8 mol%. These characteristics were consistent with those of members of the genus Kocuria. Meanwhile, physiological and biochemical characteristics revealed that strain RS-2-3T differed from the species of the genus Kocuria with validly published names. Therefore, strain RS-2-3T represents a novel species of the genus Kocuria, for which the name Kocuria pelophila sp. nov. is proposed. The type strain is RS-2-3T (=NBRC 110990T=InaCC A704T). PMID- 27221096 TI - Obsolete tobacco control themes can be hazardous to public health: the need for updating views on absolute product risks and harm reduction. AB - BACKGROUND: Leading themes have guided tobacco control efforts, and these themes have changed over the decades. When questions arose about health risks of tobacco, they focused on two key themes: 1) how bad is the problem (i.e., absolute risk) and 2) what can be done to reduce the risk without cessation (i.e., prospects for harm reduction). Using the United States since 1964 as an example, we outline the leading themes that have arisen in response to these two questions. Initially, there was the recognition that "cigarettes are hazardous to health" and an acceptance of safer alternative tobacco products (cigars, pipes, light/lower-tar cigarettes). In the 1980s there was the creation of the seminal theme that "Cigarettes are lethal when used as intended and kill more people than heroin, cocaine, alcohol, AIDS, fires, homicide, suicide, and automobile crashes combined." By around 2000, support for a less-dangerous light/lower tar cigarette was gone, and harm reduction claims were avoided for products like cigars and even for smokeless tobacco which were summarized as "unsafe" or "not a safe alternative to cigarettes." DISCUSSION: The Surgeon General in 2014 concluded that by far the greatest danger to public health was from cigarettes and other combusted products. At the same time the evidence base for smokeless tobacco and alternative nicotine delivery systems (ANDS) had grown. Product innovation and tobacco/nicotine bio-behavioral, epidemiological and public health sciences demonstrate that low nitrosamine smokeless tobacco (e.g., Swedish snus), and ANDS have substantially lower harms than cigarettes. Going forward, it is important to sharpen themes and key messages of tobacco control, while continuing to emphasize the extreme lethality of the inhaled smoke from cigarettes or from use of any combusting tobacco product. Implications of updating the leading themes for regulation, policymaking and advocacy in tobacco control are proposed as an important next step. A new reframing can align action plans to more powerfully and rapidly achieve population-level benefit and minimize harm to eliminate in our lifetime the use of the most deadly combustible tobacco products and thus prevent the premature deaths of 1 billion people projected to occur worldwide by 2100. PMID- 27221098 TI - A Rare Reason of Hyperinsulinism: Munchausen Syndrome by Proxy. AB - Hyperinsulinism, one of the most important causes of hypoglycaemia, can be congenital or acquired. Rarely, drug toxicity can be a reason for hyperinsulinism. In the context of Munchausen syndrome by proxy (MSP), toxicity usually occurs in children due to drug administration by a parent or caregiver. A 7-year-old girl was referred to our department due to a hyperglycaemic period and hypoglycaemic episodes. On admission, gliclazide was initiated due to her hyperglycaemia, which we attributed to maturity onset diabetes of the young. However, during follow-up, hypoglycaemic levels were detected. Despite cessation of gliclazide, hypoglycaemic seizures occurred. Even with the medications administered, hypoglycaemia could not be prevented. During follow-up, the mother's affect, characterized by anxiety and interest in her daughter's medical care, appeared discordant with the situation. Due to our suspicion of MSP, we discovered toxic levels of gliclazide in the blood and urine samples which had been sent to the toxicology laboratory to search for hypoglycaemic agents. The patient was isolated, and all medications were stopped. After isolation, her hypoglycaemia disappeared, and she became hyperglycaemic (250 mg/dl). Physicians should consider the possibility of MSP in hyperinsulinaemic patients with discordant laboratory results and clinical symptoms, even if the child's parents display great concern. PMID- 27221099 TI - Trends in the incidence of possible severe bacterial infection and case fatality rates in rural communities in Sub-Saharan Africa, South Asia and Latin America, 2010-2013: a multicenter prospective cohort study. AB - BACKGROUND: Possible severe bacterial infections (pSBI) continue to be a leading cause of global neonatal mortality annually. With the recent publications of simplified antibiotic regimens for treatment of pSBI where referral is not possible, it is important to know how and where to target these regimens, but data on the incidence and outcomes of pSBI are limited. METHODS: We used data prospectively collected at 7 rural community-based sites in 6 low and middle income countries participating in the NICHD Global Network's Maternal and Newborn Health Registry, between January 1, 2010 and December 31, 2013. Participants included pregnant women and their live born neonates followed for 6 weeks after delivery and assessed for maternal and infant outcomes. RESULTS: In a cohort of 248,539 infants born alive between 2010 and 2013, 32,088 (13 %) neonates met symptomatic criteria for pSBI. The incidence of pSBI during the first 6 weeks of life varied 10 fold from 3 % (Zambia) to 36 % (Pakistan), and overall case fatality rates varied 8 fold from 5 % (Kenya) to 42 % (Zambia). Significant variations in incidence of pSBI during the study period, with proportions decreasing in 3 sites (Argentina, Kenya and Nagpur, India), remaining stable in 3 sites (Zambia, Guatemala, Belgaum, India) and increasing in 1 site (Pakistan), cannot be explained solely by changing rates of facility deliveries. Case fatality rates did not vary over time. CONCLUSIONS: In a prospective population based registry with trained data collectors, there were wide variations in the incidence and case fatality of pSBI in rural communities and in trends over time. Regardless of these variations, the burden of pSBI is still high and strategies to implement timely diagnosis and treatment are still urgently needed to reduce neonatal mortality. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov ( NCT01073475 ). PMID- 27221101 TI - Graphical reduction of reaction networks by linear elimination of species. AB - The quasi-steady state approximation and time-scale separation are commonly applied methods to simplify models of biochemical reaction networks based on ordinary differential equations (ODEs). The concentrations of the "fast" species are assumed effectively to be at steady state with respect to the "slow" species. Under this assumption the steady state equations can be used to eliminate the "fast" variables and a new ODE system with only the slow species can be obtained. We interpret a reduced system obtained by time-scale separation as the ODE system arising from a unique reaction network, by identification of a set of reactions and the corresponding rate functions. The procedure is graphically based and can easily be worked out by hand for small networks. For larger networks, we provide a pseudo-algorithm. We study properties of the reduced network, its kinetics and conservation laws, and show that the kinetics of the reduced network fulfil realistic assumptions, provided the original network does. We illustrate our results using biological examples such as substrate mechanisms, post translational modification systems and networks with intermediates (transient) steps. PMID- 27221100 TI - Readmission and mortality one year after acute hospitalization in older patients with explained and unexplained anemia - a prospective observational cohort study. AB - BACKGROUND: Few studies have examined whether specific subtypes of anemia in older persons are more related to adverse outcomes such as hospital readmissions and death after acute hospitalization and post-acute care. METHODS: An observational prospective cohort study was conducted between 2011 and 2014. A total of 884 community-dwelling patients, >=70 years of age were transferred from acute medical and orthopaedic hospital departments to a skilled nursing home where they were examined by comprehensive geriatric assessment and had laboratory tests taken for the investigation of anemia. They were divided into three major groups and compared; 1) no anemia (reference group), 2) explained anemia (renal insufficiency, iron deficiency, vitaminB12/folate deficiency or multifactorial anemia) and 3) unexplained anemia. The groups were compared, and association of anemia with hospital readmission and death was estimated by logistic regression analyses. RESULTS: Compared to the patients with unexplained anemia (n=135), patients with explained anemia (n=275) had more often died (22 % vs. 14 %, p=0.05) and had more frequenlty been readmitted to hospital (39 % vs. 27 %, p=0.03). Compared to the patients without anemia (n=474), the patients with explained anemia had increased odds of hospital readmissions (OR = 1.54 (95 % CI: 1.05-2.25), p=0.03), while patients with unexplained anemia, (n=135), had neither increased odds of hospital readmissions, (OR=0.83, 95 % CI: 0.51-1.34, p=0.44) nor death (OR = 0.74, 95 % CI: 0.41-1.31, p=0.30), in adjusted regression analysis. CONCLUSION: Since no increased risk of hospital readmissions or death was seen in older patients with unexplained anemia in the first year after acute hospitalization, no further invasive investigations might be necessary to investigate the cause of anemia in these patients. A close clinical follow up might be the best way to care for older patients with a mild and unexplained anemia. PMID- 27221102 TI - How Has Elderly Migration Changed in the Twenty-First Century? What the Data Can and Cannot-Tell Us. AB - Interstate elderly migration has strong implications for state tax policies and health care systems, yet little is known about how it has changed in the twenty first century. Its relative rarity requires a large data set with which to construct reliable measures, and the replacement of the U.S. Census long form (CLF) with the American Community Survey (ACS) has made such updates difficult. Two commonly used alternative migration data sources-the Current Population Survey (CPS) and the Statistics of Income (SOI) program of the Internal Revenue Service (IRS)-suffer serious limitations in studying the migration of any subpopulation, including the elderly. Our study informs migration research in the post-2000 era by identifying methodological differences between data sources and devising strategies for reconciling the CLF and ACS. Our investigation focusing on the elderly suggests that the ACS can generate comparable migration data that reveal a continuation of previously identified geographic patterns as well as changes unique to the 2000s. However, its changed definition of residence and survey timing leaves us unable to construct a comparable national migration rate, suggesting that one must use national trends in the smaller CPS to investigate whether elderly migration has increased or decreased in the twenty-first century. PMID- 27221103 TI - Functional Contributions of Strong and Weak Cellular Oscillators to Synchrony and Light-shifted Phase Dynamics. AB - Light is the primary signal that calibrates circadian neural circuits and thus coordinates daily physiological and behavioral rhythms with solar entrainment cues. Drosophila and mammalian circadian circuits consist of diverse populations of cellular oscillators that exhibit a wide range of dynamic light responses, periods, phases, and degrees of synchrony. How heterogeneous circadian circuits can generate robust physiological rhythms while remaining flexible enough to respond to synchronizing stimuli has long remained enigmatic. Cryptochrome is a short-wavelength photoreceptor that is endogenously expressed in approximately half of Drosophila circadian neurons. In a previous study, physiological light response was measured using real-time bioluminescence recordings in Drosophila whole-brain explants, which remain intrinsically light-sensitive. Here we apply analysis of real-time bioluminescence experimental data to show detailed dynamic ensemble representations of whole circadian circuit light entrainment at single neuron resolution. Organotypic whole-brain explants were either maintained in constant darkness (DD) for 6 days or exposed to a phase-advancing light pulse on the second day. We find that stronger circadian oscillators support robust overall circuit rhythmicity in DD, whereas weaker oscillators can be pushed toward transient desynchrony and damped amplitude to facilitate a new state of phase-shifted network synchrony. Additionally, we use mathematical modeling to examine how a network composed of distinct oscillator types can give rise to complex dynamic signatures in DD conditions and in response to simulated light pulses. Simulations suggest that complementary coupling mechanisms and a combination of strong and weak oscillators may enable a robust yet flexible circadian network that promotes both synchrony and entrainment. A more complete understanding of how the properties of oscillators and their signaling mechanisms facilitate their distinct roles in light entrainment may allow us to direct and augment the circadian system to speed recovery from jet lag, shift work, and seasonal affective disorder. PMID- 27221104 TI - Prenatal ambient air pollution exposure and the risk of stillbirth: systematic review and meta-analysis of the empirical evidence. AB - BACKGROUND: Individual studies on the relations between ambient air pollution and the risk of stillbirth have provided contradictory results. We conducted a systematic review and meta-analysis to summarise the existing evidence. METHODS: We conducted a systematic search of three databases: PubMed, Scopus and Web of Science, from their time of inception to mid-April, 2015. Original studies of any epidemiological design were included. Data from eligible studies were extracted by two investigators. To calculate the summary effect estimates (EE), the random effects model was used with their corresponding 95% CI. RESULTS: 13 studies met the inclusion criteria. Although not reaching statistical significance, all the summary effect estimates for the risk of stillbirth were systematically elevated in relation to mean prenatal exposure to NO2 per 10 ppb (EE=1.066, 95% CI 0.965 to 1.178, n=3), CO per 0.4 ppm (EE=1.025, 95% CI 0.985 to 1.066, n=3), SO2 per 3 ppb (EE=1.022, 95% CI 0.984 to 1.062, n=3,), PM2.5 per 4 MUg/m(3) (EE=1.021, 95% CI 0.996 to 1.046, n=2) and PM10 per 10 MUg/m(3) (EE=1.014, 95% CI 0.948 to 1.085, n=2). The effect estimates for SO2, CO, PM10 and O3 were highest for the third trimester exposure. Two time series studies used a lag term of not more than 6 days preceding stillbirth, and both found increased effect estimates for some pollutants. CONCLUSIONS: The body of evidence suggests that exposure to ambient air pollution increases the risk of stillbirth. Further studies are needed to strengthen the evidence. PMID- 27221105 TI - Is it still important to study if ambient air pollution triggers stillbirth? PMID- 27221106 TI - Age-dependency of prescribing patterns of oral anticoagulant drugs in Austria during 2011-2014. AB - Direct oral anticoagulants (DOACs) have been introduced within the last years as alternative to vitamin K antagonists (VKAs) as oral anticoagulant drugs (OAC). The mean/median age of the patients included in DOAC-investigating trials was 70 72 years. The age-pattern of patients to whom DOAC are prescribed in clinical settings is largely unknown. Thus, aim of the study was to assess the age-pattern of patients who received OAC in the years 2011-2014 in Austria. The data analysis refers to the accounting data of the 13 major health insurance funds, covering >97 % of the Austrian population. The number of patients who received OAC in 2011 2014 increased by 43 % (182,464-261,347). Patients who received DOACs increased nearly fivefold (20,927-96,247), whereas patients who received VKAs increased by only 2 % (161,537-165,100). In 2011, the age of patients receiving VKAs was higher than DOACs (72 vs. 68 years), whereas in 2014, the age of the patients receiving VKAs was lower than DOACs (73 vs. 74 years). The proportion of patients >=80 years receiving VKAs declined from 26 to 21 % of all OAC, receiving DOACs increased from 1 to 12 %. Among nonagenarians, the proportion of patients receiving VKAs remained 2 % (3316-5858), whereas the proportion of patients receiving DOACs increased 40-fold (91-4296). DOACs are prescribed to patients >=80 years, although there are is a lack of data about efficacy and safety. There is an urgent need for data about this patient group. Since a randomized trial is rather unlikely in this specific age group we suggest subgroup analyses about octo-and nonagenarians, in case they have been included in previously completed or still ongoing trials or registries for OAC. PMID- 27221108 TI - Erratum: A specific mutation in TBL1XR1 causes Pierpont syndrome. PMID- 27221107 TI - PreSurgMapp: a MATLAB Toolbox for Presurgical Mapping of Eloquent Functional Areas Based on Task-Related and Resting-State Functional MRI. AB - The main goal of brain tumor surgery is to maximize tumor resection while minimizing the risk of irreversible postoperative functional sequelae. Eloquent functional areas should be delineated preoperatively, particularly for patients with tumors near eloquent areas. Functional magnetic resonance imaging (fMRI) is a noninvasive technique that demonstrates great promise for presurgical planning. However, specialized data processing toolkits for presurgical planning remain lacking. Based on several functions in open-source software such as Statistical Parametric Mapping (SPM), Resting-State fMRI Data Analysis Toolkit (REST), Data Processing Assistant for Resting-State fMRI (DPARSF) and Multiple Independent Component Analysis (MICA), here, we introduce an open-source MATLAB toolbox named PreSurgMapp. This toolbox can reveal eloquent areas using comprehensive methods and various complementary fMRI modalities. For example, PreSurgMapp supports both model-based (general linear model, GLM, and seed correlation) and data-driven (independent component analysis, ICA) methods and processes both task-based and resting-state fMRI data. PreSurgMapp is designed for highly automatic and individualized functional mapping with a user-friendly graphical user interface (GUI) for time-saving pipeline processing. For example, sensorimotor and language related components can be automatically identified without human input interference using an effective, accurate component identification algorithm using discriminability index. All the results generated can be further evaluated and compared by neuro-radiologists or neurosurgeons. This software has substantial value for clinical neuro-radiology and neuro-oncology, including application to patients with low- and high-grade brain tumors and those with epilepsy foci in the dominant language hemisphere who are planning to undergo a temporal lobectomy. PMID- 27221109 TI - Differential Cytokine Regulatory Effect of Three Lactobacillus Strains Isolated from Fermented Foods. AB - Lactic acid bacteria (LAB) isolated from fermented foods have potential as a treatment for immune-related disorders and the use of LAB has been increasing worldwide. In this study, the differential cytokine regulatory effect was examined with three isolates of lactobacilli strains; namely, Lactobacillus plantarum K55-5 isolated from dairy product, and L. sakei K101 and L. plantarum K8 previously isolated from kimchi (a Korean traditional fermented vegetable). Production of cytokines such as IL-10, IL-12, IFN-gamma, and TNF-alpha was significantly increased in L. sakei K101- and L. plantarum K55-5-treated splenocytes as compared with controls. The oral administration of L. sakei K101 and L. plantarum K55-5 increased cytokine production in the immunosuppressed mouse splenocytes and blood. NK cell cytotoxic activity was also increased in L. sakei K101- and L. plantarum K55-5-fed mice. On the other hand, L. plantarum K8 did not affect cytokine induction in all the experiments performed in this study. The cytokine-inducing effect of L. plantarum K55-5 was significantly increased by lysates of heat-killed bacteria as compared with live, heat-killed, or supernatant of cell lysates. TNF-alpha production by lipoteichoic acids (LTAs) isolated from the three isolates of lactobacilli was compared, and it was found that K55-5 LTA had a highest cytokine-inducing ability, which was mediated by TLR2-mediated NF-kappaB and ERK activation. Taken together, our study suggests that L. plantarum K55-5 and L. sakei K101 can be used for the treatment of immunosuppressed disorders. PMID- 27221110 TI - Bacterial Outer Membrane Vesicles as a Delivery System for Virulence Regulation. AB - Outer membrane vesicles (OMVs) are spherical nanostructures that are ubiquitously shed from gram-negative bacteria both in vitro and in vivo. Recent findings revealed that OMVs, which contain diverse components derived from the parent bacterium, play an important role in communication with neighboring bacteria and the environment. Furthermore, nanoscale proteoliposomes decorated with pathogen associated molecules attract considerable attention as a non-replicative carrier for vaccines and drug materials. This review introduces recent advances in OMV biogenesis and discusses the roles of OMVs in the context of bacterial communication and virulence regulation. It also describes the remarkable accomplishments in OMV engineering for diverse therapeutic applications. PMID- 27221111 TI - Combination Therapy of Lactobacillus plantarum Supernatant and 5-Fluouracil Increases Chemosensitivity in Colorectal Cancer Cells. AB - Colorectal cancer (CRC) is the third most common cancer in the world. Although 5 fluorouracil (5-FU) is the representative chemotherapy drug for colorectal cancer, it has therapeutic limits due to its chemoresistant characteristics. Colorectal cancer cells can develop into cancer stem cells (CSCs) with self renewal potential, thereby causing malignant tumors. The human gastrointestinal tract contains a complex gut microbiota that is essential for the host's homeostasis. Recently, many studies have reported correlations between gut flora and the onset, progression, and treatment of CRC. The present study confirms that the most representative symbiotic bacteria in humans, Lactobacillus plantarum (LP) supernatant (SN), selectively inhibit the characteristics of 5-FU-resistant colorectal cancer cells (HT-29 and HCT- 116). LP SN inhibited the expression of the specific markers CD44, 133, 166, and ALDH1 of CSCs. The combination therapy of LP SN and 5-FU inhibited the survival of CRCs and led to cell death by inducing caspase-3 activity. The combination therapy of LP SN and 5-FU induced an anticancer mechanism by inactivating the Wnt/beta-catenin signaling of chemoresistant CRC cells, and reducing the formation and size of colonospheres. In conclusion, our results show that LP SN can enhance the therapeutic effect of 5-FU for colon cancer, and reduce colorectal cancer stem-like cells by reversing the development of resistance to anticancer drugs. This implies that probiotic substances may be useful therapeutic alternatives as biotherapeutics for chemoresistant CRC. PMID- 27221112 TI - Persistence of Multidrug-Resistant Acinetobacter baumannii Isolates Harboring blaOXA-23 and bap for 5 Years. AB - The emergence and dissemination of carbapenemase-producing Acinetobacter baumannii isolates have been reported worldwide, and A. baumannii isolates harboring blaOXA-23 are often resistant to various antimicrobial agents. Antimicrobial resistance can be particularly strong for biofilm-forming A. baumannii isolates. We investigated the genetic basis for carbapenem resistance and biofilm-forming ability of multidrug-resistant (MDR) clinical isolates. Ninety-two MDR A. baumannii isolates were collected from one university hospital located in the Chungcheong area of Korea over a 5-year period. Multiplex PCR and DNA sequencing were performed to characterize carbapenemase and bap genes. Clonal characteristics were analyzed using REP-PCR. In addition, imaging and quantification of biofilms were performed using a crystal violet assay. All 92 MDR A. baumannii isolates involved in our study contained the blaOXA-23 and bap genes. The average absorbance of biomass in Bap-producing strains was much greater than that in non-Bap-producing strains. In our study, only three REP-PCR types were found, and the isolates showing type A or type B were found more than 60 times among unique patients during the 5 years of surveillance. These results suggest that the isolates have persisted and colonized for 5 years, and biofilm formation ability has been responsible for their persistence and colonization. PMID- 27221113 TI - Effect of Polylysine on Scrapie Prion Protein Propagation in Spleen during Asymptomatic Stage of Experimental Prion Disease in Mice. AB - Prion diseases are incurable neurodegenerative disorders. Our previous study demonstrated that polylysine was effective in prolonging the incubation period in a rodent model and in alleviating the scrapie prion protein (PrP(Sc)) burden in the brain at the terminal stage of the disease. Here, we report that intraperitoneal administration of polylysine suppresses the accumulation of prions in the spleen during the early stages of the disease. This study supports the congruence of PrP(Sc) inhibition by polylysine in both the spleen and brain. PMID- 27221114 TI - What Kinds of Skills Are Necessary for Physicians Involved in International Disaster Response? AB - Introduction Physicians are key disaster responders in foreign medical teams (FMTs) that provide medical relief to affected people. However, few studies have examined the skills required for physicians in real, international, disaster response situations. Problem The objectives of this study were to survey the primary skills required for physicians from a Japanese FMT and to examine whether there were differences in the frequencies of performed skills according to demographic characteristics, previous experience, and dispatch situations to guide future training and certification programs. METHODS: This cross-sectional survey used a self-administered questionnaire given to 64 physicians with international disaster-response site experience. The questionnaire assessed demographic characteristics (sex, age, years of experience as a physician, affiliation, and specialty), previous experience (domestic disaster-relief experience, international disaster-relief experience, or disaster medicine training experience), and dispatch situation (length of dispatch, post-disaster phase, disaster type, and place of dispatch). In addition, the frequencies of 42 performed skills were assessed via a five-point Likert scale. Descriptive statistics were used to assess the participants' characteristics and total scores as the frequencies of performed skills. Mean scores for surgical skills, health care-related skills, public health skills, and management and coordination skills were compared according to the demographic characteristics, previous experience, and dispatch situations. RESULTS: Fifty-two valid questionnaires (81.3% response rate) were collected. There was a trend toward higher skill scores among those who had more previous international disaster-relief experience (P=.03). The more disaster medicine training experience the participants had, the higher their skill score was (P<.001). Physicians reported involvement in 23 disaster-relief response skills, nine of which were performed frequently. There was a trend toward higher scores for surgical skills, health care-related skills, and management and coordination skills related to more disaster medicine training experience. CONCLUSION: This study's findings can be used as evidence to boost the frequency of physicians' performed skills by promoting previous experience with international disaster relief and disaster medicine training. Additionally, these results may contribute to enhancing the quality of medical practice in the international disaster relief and disaster training curricula. Noguchi N , Inoue S , Shimanoe C , Shibayama K , Matsunaga H , Tanaka S , Ishibashi A , Shinchi K . What kinds of skills are necessary for physicians involved in international disaster response? Prehosp Disaster Med. 2016;31(4):397-406. PMID- 27221117 TI - Liver-derived IGF-I regulates cortical bone mass but is dispensable for the osteogenic response to mechanical loading in female mice. AB - Low circulating IGF-I is associated with increased fracture risk. Conditional depletion of IGF-I produced in osteoblasts or osteocytes inhibits the bone anabolic effect of mechanical loading. Here, we determined the role of endocrine IGF-I for the osteogenic response to mechanical loading in young adult and old female mice with adult, liver-specific IGF-I inactivation (LI-IGF-I(-/-) mice, serum IGF-I reduced by ~70%) and control mice. The right tibia was subjected to short periods of axial cyclic compressive loading three times/wk for 2 wk, and measurements were performed using microcomputed tomography and mechanical testing by three-point bending. In the nonloaded left tibia, the LI-IGF-I(-/-) mice had lower cortical bone area and increased cortical porosity, resulting in reduced bone mechanical strength compared with the controls. Mechanical loading induced a similar response in LI-IGF-I(-/-) and control mice in terms of cortical bone area and trabecular bone volume fraction. In fact, mechanical loading produced a more marked increase in cortical bone mechanical strength, which was associated with a less marked increase in cortical porosity, in the LI-IGF-I(-/-) mice compared with the control mice. In conclusion, liver-derived IGF-I regulates cortical bone mass, cortical porosity, and mechanical strength under normal (nonloaded) conditions. However, despite an ~70% reduction in circulating IGF-I, the osteogenic response to mechanical loading was not attenuated in the LI-IGF-I(-/-) mice. PMID- 27221115 TI - Mathematical modeling of the circadian dynamics of the neuroendocrine-immune network in experimentally induced arthritis. AB - The circadian dynamics of important neuroendocrine-immune mediators have been implicated in progression of rheumatoid arthritis pathophysiology, both clinically as well as in animal models. We present a mathematical model that describes the circadian interactions between mediators of the hypothalamic pituitary-adrenal (HPA) axis and the proinflammatory cytokines. Model predictions demonstrate that chronically elevated cytokine expression results in the development of adrenal insufficiency and circadian variability in paw edema. Notably, our model also predicts that an increase in mean secretion of corticosterone (CST) after the induction of the disease is accompanied by a decrease in the amplitude of the CST oscillation. Furthermore, alterations in the phase of circadian oscillation of both cytokines and HPA axis mediators are observed. Therefore, by incorporating the circadian interactions between the neuroendocrine-immune mediators, our model is able to simulate important features of rheumatoid arthritis pathophysiology. PMID- 27221116 TI - beta-Cell deletion of Nr4a1 and Nr4a3 nuclear receptors impedes mitochondrial respiration and insulin secretion. AB - beta-Cell insulin secretion is dependent on proper mitochondrial function. Various studies have clearly shown that the Nr4a family of orphan nuclear receptors is essential for fuel utilization and mitochondrial function in liver, muscle, and adipose. Previously, we have demonstrated that overexpression of Nr4a1 or Nr4a3 is sufficient to induce proliferation of pancreatic beta-cells. In this study, we examined whether Nr4a expression impacts pancreatic beta-cell mitochondrial function. Here, we show that beta-cell mitochondrial respiration is dependent on the nuclear receptors Nr4a1 and Nr4a3. Mitochondrial respiration in permeabilized cells was significantly decreased in beta-cells lacking Nr4a1 or Nr4a3. Furthermore, respiration rates of intact cells deficient for Nr4a1 or Nr4a3 in the presence of 16 mM glucose resulted in decreased glucose mediated oxygen consumption. Consistent with this reduction in respiration, a significant decrease in glucose-stimulated insulin secretion rates is observed with deletion of Nr4a1 or Nr4a3. Interestingly, the changes in respiration and insulin secretion occur without a reduction in mitochondrial content, suggesting decreased mitochondrial function. We establish that knockdown of Nr4a1 and Nr4a3 results in decreased expression of the mitochondrial dehydrogenase subunits Idh3g and Sdhb. We demonstrate that loss of Nr4a1 and Nr4a3 impedes production of ATP and ultimately inhibits glucose-stimulated insulin secretion. These data demonstrate for the first time that the orphan nuclear receptors Nr4a1 and Nr4a3 are critical for beta-cell mitochondrial function and insulin secretion. PMID- 27221118 TI - Sodium nitrate co-ingestion with protein does not augment postprandial muscle protein synthesis rates in older, type 2 diabetes patients. AB - The age-related anabolic resistance to protein ingestion is suggested to be associated with impairments in insulin-mediated capillary recruitment and postprandial muscle tissue perfusion. The present study investigated whether dietary nitrate co-ingestion with protein improves muscle protein synthesis in older, type 2 diabetes patients. Twenty-four men with type 2 diabetes (72 +/- 1 yr, 26.7 +/- 1.4 m/kg(2) body mass index, 7.3 +/- 0.4% HbA1C) received a primed continuous infusion of l-[ring-(2)H5]phenylalanine and l-[1-(13)C]leucine and ingested 20 g of intrinsically l-[1-(13)C]phenylalanine- and l-[1-(13)C]leucine labeled protein with (PRONO3) or without (PRO) sodium nitrate (0.15 mmol/kg). Blood and muscle samples were collected to assess protein digestion and absorption kinetics and postprandial muscle protein synthesis rates. Upon protein ingestion, exogenous phenylalanine appearance rates increased in both groups (P < 0.001), resulting in 55 +/- 2% and 53 +/- 2% of dietary protein-derived amino acids becoming available in the circulation over the 5h postprandial period in the PRO and PRONO3 groups, respectively. Postprandial myofibrillar protein synthesis rates based on l-[ring-(2)H5]phenylalanine did not differ between groups (0.025 +/- 0.004 and 0.021 +/- 0.007%/h over 0-2 h and 0.032 +/- 0.004 and 0.030 +/- 0.003%/h over 2-5 h in PRO and PRONO3, respectively, P = 0.7). No differences in incorporation of dietary protein-derived l-[1-(13)C]phenylalanine into de novo myofibrillar protein were observed at 5 h (0.016 +/- 0.002 and 0.014 +/- 0.002 mole percent excess in PRO and PRONO3, respectively, P = 0.8). Dietary nitrate co-ingestion with protein does not modulate protein digestion and absorption kinetics, nor does it further increase postprandial muscle protein synthesis rates or the incorporation of dietary protein-derived amino acids into de novo myofibrillar protein in older, type 2 diabetes patients. PMID- 27221119 TI - Insulin decreases atherosclerotic plaque burden and increases plaque stability via nitric oxide synthase in apolipoprotein E-null mice. AB - It has been argued whether insulin accelerates or prevents atherosclerosis. Although results from in vitro studies have been conflicting, recent in vivo mice studies demonstrated antiatherogenic effects of insulin. Insulin is a known activator of endothelial nitric oxide synthase (NOS), leading to increased production of NO, which has potent antiatherogenic effects. We aimed to examine the role of NOS in the protective effects of insulin against atherosclerosis. Male apolipoprotein E-null mice (8 wk old) fed a high-cholesterol diet (1.25% cholesterol) were assigned to the following 12-wk treatments: control, insulin (0.05 U/day via subcutaneous pellet), N(omega)-nitro-l-arginine methyl ester hydrochloride (l-NAME, via drinking water at 100 mg/l), and insulin plus l-NAME. Insulin reduced atherosclerotic plaque burden in the descending aorta by 42% compared with control (plaque area/aorta lumen area: control, 16.5 +/- 1.9%; insulin, 9.6 +/- 1.3%, P < 0.05). Although insulin did not decrease plaque burden in the aortic sinus, macrophage accumulation in the plaque was decreased by insulin. Furthermore, insulin increased smooth muscle actin and collagen content and decreased plaque necrosis, consistent with increased plaque stability. In addition, insulin treatment increased plasma NO levels, decreased inducible NOS staining, and tended to increase phosphorylated vasodilator-stimulated phosphoprotein staining in the plaques of the aortic sinus. All these effects of insulin were abolished by coadministration of l-NAME, whereas l-NAME alone showed no effect. Insulin also tended to increase phosphorylated endothelial NOS and total neuronal NOS staining, effects not modified by l-NAME. In conclusion, we demonstrate that insulin treatment decreases atherosclerotic plaque burden and increases plaque stability through NOS-dependent mechanisms. PMID- 27221121 TI - MiR-206 is expressed in pancreatic islets and regulates glucokinase activity. AB - Glucose homeostasis is a complex indispensable process, and its dysregulation causes hyperglycemia and type 2 diabetes mellitus. Glucokinase (GK) takes a central role in these pathways and is thus rate limiting for glucose-stimulated insulin secretion (GSIS) from pancreatic islets. Several reports have described the transcriptional regulation of Gck mRNA, whereas its posttranscriptional mechanisms of regulation, especially those involving microRNAs (miR), are poorly understood. In this study, we investigated the role of miR-206 as a posttranscriptional regulator of Gck In addition, we examined the effects of miR 206 on glucose tolerance, GSIS, and gene expression in control and germ line miR 206 knockout (KO) mice fed either with chow or high-fat diet (HFD). MiR-206 was found in Gck-expressing tissues and was differentially altered in response to HFD feeding. Pancreatic islets showed the most profound induction in the expression of miR-206 in response to HFD. Chow- and HFD-fed miR-206KO mice have improved glucose tolerance and GSIS but unaltered insulin sensitivity. In silico analysis of Gck mRNA revealed a conserved 8-mer miR-206 binding site. Hence, the predicted regulation of Gck by miR-206 was confirmed in reporter and GK activity assays. Concomitant with increased GK activity, miR-206KO mice had elevated liver glycogen content and plasma lactate concentrations. Our findings revealed a novel mechanism of posttranscriptional regulation of Gck by miR-206 and underline the crucial role of pancreatic islet miR-206 in the regulation of whole body glucose homeostasis in a murine model that mimics the metabolic syndrome. PMID- 27221120 TI - Age-related impairments in skeletal muscle PDH phosphorylation and plasma lactate are indicative of metabolic inflexibility and the effects of exercise training. AB - The purpose of this study was to determine whether plasma lactate and skeletal muscle glucose regulatory pathways, specifically PDH dephosphorylation, are impaired during hyperinsulinemic conditions in middle- to older-aged individuals and determine whether exercise training could improve key variables responsible for skeletal muscle PDH regulation. Eighteen young (19-29 yr; n = 9 males and 9 females) and 20 middle- to older-aged (57-82 yr; n = 10 males and 10 females) individuals underwent a 2-h euglycemic hyperinsulinemic clamp. Plasma samples were obtained at baseline and at 30, 50, 90, and 120 min for analysis of lactate, and skeletal muscle biopsies were performed at 60 min for analysis of protein associated with glucose metabolism. In response to insulin, plasma lactate was elevated in aged individuals when normalized to insulin action. Insulin stimulated phosphorylation of skeletal muscle PDH on serine sites 232, 293, and 300 decreased in young individuals only. Changes in insulin-stimulated PDH phosphorylation were positively related to changes in plasma lactate. No age related differences were observed in skeletal muscle phosphorylation of LDH, GSK 3alpha, or GSK-3beta in response to insulin or PDP1, PDP2, PDK2, PDK4, or MPC1 total protein. Twelve weeks of endurance- or strength-oriented exercise training improved insulin-stimulated PDH dephosphorylation, which was related to a reduced lactate response. These findings suggest that impairments in insulin-induced PDH regulation in a sedentary aging population contribute to impaired glucose metabolism and that exercise training is an effective intervention for treating metabolic inflexibility. PMID- 27221122 TI - Aquaglyceroporins 3 and 7 in bull spermatozoa: identification, localisation and their relationship with sperm cryotolerance. AB - The present study aimed to determine the localisation of aquaglyceroporins 3 (AQP3) and 7 (AQP7) in bull spermatozoa and their relationship with the sperm cell's resilience to withstand cryopreservation (i.e. cryotolerance). A total of 18 bull ejaculates were cryopreserved and their sperm quality analysed before and after freeze-thawing. The presence and localisation of AQP3 and AQP7 was determined through immunoblotting and immunocytochemistry. AQP3 was found in the mid-piece and AQP7 in the mid-piece and post-acrosomal region of bull spermatozoa. Immunoblotting showed specific signal bands at 30 and 60kDa for AQP3 and at 25kDa for AQP7. Neither the relative abundance of AQP3 and AQP7 nor their localisation patterns was altered by cryopreservation but individual differences between bull ejaculates were found in immunoblots. In order to determine whether these individual differences were related to sperm cryotolerance, bull ejaculates were classified as having good (GFE) or poor freezability (PFE) on the basis of their sperm quality after thawing. While the relative abundance of AQP3 before cryopreservation did not differ between ejaculates with GFE and PFE, the abundance of AQP7 was higher in GFE than in PFE ejaculates. This finding was further confirmed through principal component and linear regression analyses. In conclusion, the relative abundance of AQP7 in fresh semen may be used as a marker to predict bull sperm cryotolerance. PMID- 27221124 TI - Correction. PMID- 27221123 TI - Lay Health Workers' Experience of Delivering a Problem Solving Therapy Intervention for Common Mental Disorders Among People Living with HIV: A Qualitative Study from Zimbabwe. AB - There is growing evidence supporting the use of lay health workers (LHWs) to address the treatment gap for common mental disorders (CMD) through task shifting. This study looks at the experience of LHWs delivering a problem solving therapy (PST) intervention for CMD for people living with HIV (PLWH) in a primary health care setting. Semi-structured interviews of LHWs (n = 7) and PLWH (10) who received PST were carried out using thematic content analysis. Over a 4 year period LHWs developed indigenous concepts of PST which were: Opening the mind (Kuvhura pfungwa), uplifting (kusimudzira), strengthening and strengthening further (kusimbisa and kusimbisisa) respectively. Using terms locally conceived through knowledge sharing amongst LHWs made it acceptable to deliver PST as part of their daily work. Indigenous terms conceived and developed by LWHs to describe components and processes of PST contribute to the therapy's acceptability and continued use in primary care facilities. PMID- 27221125 TI - Patterns and predictors of violence against children in Uganda: a latent class analysis. AB - OBJECTIVE: To explore patterns of physical, emotional and sexual violence against Ugandan children. DESIGN: Latent class and multinomial logistic regression analysis of cross-sectional data. SETTING: Luwero District, Uganda. PARTICIPANTS: In all, 3706 primary 5, 6 and 7 students attending 42 primary schools. MAIN OUTCOME AND MEASURE: To measure violence, we used the International Society for the Prevention of Child Abuse and Neglect Child Abuse Screening Tool-Child Institutional. We used the Strengths and Difficulties Questionnaire to assess mental health and administered reading, spelling and maths tests. RESULTS: We identified three violence classes. Class 1 (N=696 18.8%) was characterised by emotional and physical violence by parents and relatives, and sexual and emotional abuse by boyfriends, girlfriends and unrelated adults outside school. Class 2 (N=975 26.3%) was characterised by physical, emotional and sexual violence by peers (male and female students). Children in Classes 1 and 2 also had a high probability of exposure to emotional and physical violence by school staff. Class 3 (N=2035 54.9%) was characterised by physical violence by school staff and a lower probability of all other forms of violence compared to Classes 1 and 2. Children in Classes 1 and 2 were more likely to have worked for money (Class 1 Relative Risk Ratio 1.97, 95% CI 1.54 to 2.51; Class 2 1.55, 1.29 to 1.86), been absent from school in the previous week (Class 1 1.31, 1.02 to 1.67; Class 2 1.34, 1.10 to 1.63) and to have more mental health difficulties (Class 1 1.09, 1.07 to 1.11; Class 2 1.11, 1.09 to 1.13) compared to children in Class 3. Female sex (3.44, 2.48 to 4.78) and number of children sharing a sleeping area predicted being in Class 1. CONCLUSIONS: Childhood violence in Uganda forms distinct patterns, clustered by perpetrator and setting. Research is needed to understand experiences of victimised children, and to develop mental health interventions for those with severe violence exposures. TRIAL REGISTRATION NUMBER: NCT01678846; Results. PMID- 27221126 TI - Patient involvement in research priorities (PIRE): a study protocol. AB - INTRODUCTION: Patient involvement in healthcare has expanded from the clinical practice setting to include collaboration during the research process. There has been a growing international interest in patient and public involvement in setting research priorities to reduce the risk of discrepancy between what patients with cancer and their relatives experience as important unanswered questions and those which are actually researched. This study aims to challenge the conventional research process by inviting patients with life-threatening cancer (primary malignant brain tumours or acute leukaemia), relatives and patient organisations to join forces with clinical specialists and researchers to identify, discuss and prioritise supportive care and rehabilitation issues in future research. METHODS AND ANALYSIS: This is an exploratory qualitative study comprising two sets of three focus group interviews (FGIs): one set for primary malignant brain tumours and the other for acute leukaemia. Separate FGIs will be carried out with patients and relatives including representation from patient organisations and clinical specialists to identify important unanswered questions and research topics within each group. The FGIs will be video/audio recorded, transcribed and thematically analysed. This study will contribute to a patient centred research agenda that captures issues that patients, their relatives, clinical specialists and researchers consider important. ETHICS AND DISSEMINATION: The study is registered at the Danish Data Protection Agency (number: 2012-58-0004) and the Scientific Ethics Review Committee of the Capital Region of Denmark (number: H-15001485). Papers will be published describing the methods applied and the supportive care and rehabilitation issues that are identified as important for future research. TRIAL REGISTRATION NUMBER: ISRCTN57131943; Pre-results. PMID- 27221127 TI - Built Environment and Active Transport to School (BEATS) Study: protocol for a cross-sectional study. AB - INTRODUCTION: Active transport to school (ATS) is a convenient way to increase physical activity and undertake an environmentally sustainable travel practice. The Built Environment and Active Transport to School (BEATS) Study examines ATS in adolescents in Dunedin, New Zealand, using ecological models for active transport that account for individual, social, environmental and policy factors. The study objectives are to: (1) understand the reasons behind adolescents and their parents' choice of transport mode to school; (2) examine the interaction between the transport choices, built environment, physical activity and weight status in adolescents; and (3) identify policies that promote or hinder ATS in adolescents. METHODS AND ANALYSIS: The study will use a mixed-method approach incorporating both quantitative (surveys, anthropometry, accelerometers, Geographic Information System (GIS) analysis, mapping) and qualitative methods (focus groups, interviews) to gather data from students, parents, teachers and school principals. The core data will include accelerometer-measured physical activity, anthropometry, GIS measures of the built environment and the use of maps indicating route to school (students)/work (parents) and perceived safe/unsafe areas along the route. To provide comprehensive data for understanding how to change the infrastructure to support ATS, the study will also examine complementary variables such as individual, family and social factors, including student and parental perceptions of walking and cycling to school, parental perceptions of different modes of transport to school, perceptions of the neighbourhood environment, route to school (students)/work (parents), perceptions of driving, use of information communication technology, reasons for choosing a particular school and student and parental physical activity habits, screen time and weight status. The study has achieved a 100% school recruitment rate (12 secondary schools). ETHICS AND DISSEMINATION: The study has been approved by the University of Otago Ethics Committee. The results will be actively disseminated through reports and presentations to stakeholders, symposiums and scientific publications. PMID- 27221128 TI - Ultrasound assessment for grading structural tendon changes in supraspinatus tendinopathy: an inter-rater reliability study. AB - AIM: To evaluate the inter-rater reliability of measuring structural changes in the tendon of patients, clinically diagnosed with supraspinatus tendinopathy (cases) and healthy participants (controls), on ultrasound (US) images captured by standardised procedures. METHODS: A total of 40 participants (24 patients) were included for assessing inter-rater reliability of measurements of fibrillar disruption, neovascularity, as well as the number and total length of calcifications and tendon thickness. Linear weighted kappa, intraclass correlation (ICC), SEM, limits of agreement (LOA) and minimal detectable change (MDC) were used to evaluate reliability. RESULTS: 'Moderate-almost perfect' kappa was found for grading fibrillar disruption, neovascularity and number of calcifications (k 0.60-0.96). For total length of calcifications and tendon thickness, ICC was 'excellent' (0.85-0.90), with SEM(Agreement) ranging from 0.63 to 2.94 mm and MDC(group) ranging from 0.28 to 1.29 mm. In general, SEM, LOA and MDC showed larger variation for calcifications than for tendon thickness. CONCLUSIONS: Inter-rater reliability was moderate to almost perfect when a standardised procedure was applied for measuring structural changes on captured US images and movie sequences of relevance for patients with supraspinatus tendinopathy. Future studies should test intra-rater and inter-rater reliability of the method in vivo for use in clinical practice, in addition to validation against a gold standard, such as MRI. TRIAL REGISTRATION NUMBER: NCT01984203; Pre results. PMID- 27221129 TI - Moving forward through consensus: protocol for a modified Delphi approach to determine the top research priorities in the field of orthopaedic oncology. AB - INTRODUCTION: Orthopaedic oncology researchers face several obstacles in the design and execution of randomised controlled trials, including finite fiscal resources to support the rising costs of clinical research and insufficient patient volume at individual sites. As a result, high-quality research to guide clinical practice has lagged behind other surgical subspecialties. A focused approach is imperative to design a research programme that is economical, streamlined and addresses clinically relevant endpoints. The primary objective of this study will be to use a consensus-based approach to identify research priorities for international clinical trials in orthopaedic oncology. METHODS AND ANALYSIS: We will conduct a 3-phase modified Delphi method consisting of 2 sequential rounds of anonymous web-based questionnaires (phases I and II), and an in-person consensus meeting (phase III). Participants will suggest research questions that they believe are of particular importance to the field (phase I), and individually rate each proposed question on 5 criteria (phase II). Research questions that meet predetermined consensus thresholds will be brought forward to the consensus meeting (phase III) for discussion by an expert panel. Following these discussions, the expert panel will be asked to assign scores for each research question, and research questions meeting predetermined criteria will be brought forward for final ranking. The expert panel will then be asked to rank the top 3 research questions, and these 3 research questions will be distributed to the initial group of participants for validation. ETHICS AND DISSEMINATION: An ethics application is currently under review with the Hamilton Integrated Research Ethics Board in Hamilton, Ontario, Canada. The results of this initiative will be disseminated through peer-reviewed publications and conference presentations. PMID- 27221130 TI - Acute gastric volvulus associated with wandering spleen in an adult treated laparoscopically after endoscopic reduction: a case report. AB - A 43-year-old female was referred to our hospital for sudden onset of abdominal pain, fullness, and vomiting. Physical examination revealed abdominal distension with mild epigastric tenderness. Abdominal radiography showed massive gastric distension and plain computed tomography (CT) a markedly enlarged stomach filled with gas and fluid. A large volume of gastric contents was suctioned out via a nasogastric (NG) tube. Contrast-enhanced CT showed a grossly distended stomach with displacement of the antrum above the gastroesophageal junction, and the spleen was dislocated inferiorly. Upper gastrointestinal (GI) series showed the greater curvature to be elevated and the gastric fundus to be lower than normal. Acute mesenteroaxial gastric volvulus was diagnosed. GI endoscopy showed a distortion of the gastric anatomy with difficulty intubating the pylorus. Various endoscopic maneuvers were required to reposition the stomach, and the symptoms showed immediate and complete solution. GI fluoroscopy was performed 3 days later. Initially, most of the contrast medium accumulated in the fundus, which was drawn prominently downward, and then began flowing into the duodenum with anteflexion. Elective laparoscopic surgery was performed 1 month later. The stomach was in its normal position, but the fundus was folded posteroinferiorly. The spleen attached to the fundus was normal in size but extremely mobile. We diagnosed a wandering spleen based on the operative findings. Gastropexy was performed for the treatment of gastric volvulus and wandering spleen. The patient remained asymptomatic, and there was no evidence of recurrence during a follow-up period of 24 months. This report describes a rare adult case of acute gastric volvulus associated with wandering spleen. Because delay in treatment can result in lethal complications, it is critical to provide a prompt and correct diagnosis and surgical intervention. We advocate laparoscopic surgery after endoscopic reduction because it is a safe and effective procedure with lower invasiveness. PMID- 27221131 TI - A case report of bacteremia manifesting as an overwhelming postsplenectomy infection due to Streptococcus pneumoniae post vaccination. AB - A 62-year-old woman was admitted for acute epigastralgia and high-grade fever of over 39 degrees C. The patient had undergone splenectomy for idiopathic portal hypertension 1 year ago and vaccination against Streptococcus pneumoniae immediately post operation. She developed localized peritoneal irritation and abdominal distension. Her serum creatinine had increased to 1.5 mg/dL and procalcitonin was 12.5 ng/ml. Computed tomography of the abdomen revealed edematous large intestine and increased ascites. From these results, the patient was considered to have spontaneous bacterial peritonitis (SBP). Vancomycin (VCM) and doripenem (DRPM) were administered to control the infection. Unexpectedly, S. pneumoniae was detected in the blood culture. Hence, ampicillin/sulbactam was administered after discontinuing VCM. The patient recovered without any life threatening complications and was discharged after 10 days. In conclusion, overwhelming postsplenectomy infection (OPSI) due to S. pneumoniae could develop in patient with splenectomy even after vaccination. Although the bacteremia probably due to SBP and acute renal dysfunction was accompanied by OPSI, our patient recovered rapidly. PMID- 27221132 TI - Changes in Retinal N-Acylethanolamines and their Oxylipin Derivatives During the Development of Visual Impairment in a Mouse Model for Glaucoma. AB - Neurons are especially susceptible to oxidative damage, which is increasingly implicated in neurodegenerative disease. Certain N-acylethanolamines (NAEs) have been shown to protect neurons from oxidative stress. Since glaucoma may be considered a neurodegenerative disorder and the survival of retinal neurons could also be influenced by N-acylethanolamines, our goal was to quantify changes in certain N-acylethanolamine species and their oxylipin derivatives in the retina of a mouse model for glaucoma. We also sought to identify relationships between these and parameters of glaucoma disease development, specifically intraocular pressure, visual acuity, and contrast sensitivity. Five N-acylethanolamine species and three NAE oxylipin derivatives were quantified in retina from young and aged DBA/2Crl mice. N-Acylethanolamines and NAE-oxylipins in retinal extracts were quantified against deuterated standards by isotope dilution gas chromatography-mass spectrometry. Levels (nmol/g dry weight) of N arachidonoylethanolamine (anandamide; NAE 20:4) were significantly (p = 0.008) decreased in aged (2.875 +/- 0.6702) compared to young animals (5.175 +/- 0.971). Conversely, the anandamide oxylipin, 15(S)-HETE ethanolamide (15(S)-HETE EA), was significantly (p = 0.042) increased in aged (0.063 +/- 0.009) compared to young animals (0.039 +/- 0.011). Enzymatic depletion of the anandamide pool by 15 lipoxygenase and consequent accumulation of 15(S)-HETE ethanolamine may contribute to decreased visual function in glaucomatous mice. Since N acylethanolamines effectively attenuate glaucoma pathogenesis and associated visual impairment, our data provides additional rationale and novel targets for glaucoma therapies. PMID- 27221133 TI - Optimizing production and evaluating biosynthesis in situ of a herbicidal compound, mevalocidin, from Coniolariella sp. AB - Mevalocidin is a fungal secondary metabolite produced by Coniolariella sp. It is a unique phytotoxin that demonstrates broad spectrum post-emergent herbicidal properties. With limited options for weed control, the commercialization of a natural product pesticide would be beneficial to organic farming. In this study, two mevalocidin-producing fungal strains, coded MSX56446 and MSX92917, were explored under a variety of growth conditions, including time, temperature, and media. The concentration of mevalocidin was quantitatively measured via LC-MS to determine the optimal setting for each condition. Maximum production was achieved for each condition at 20 days, at 30 degrees C, with YESD + agar, and with a media containing 2.5 % dextrose. Furthermore, an advanced surface sampling technique was incorporated to gain a better understanding of the fungal culture's natural ability to biosynthesize and distribute this herbicide into its environment. It was shown that both fungi actively exude mevalocidin into their environment via liquid droplet formations known as guttates. PMID- 27221134 TI - Clinical and immunologic phenotype associated with activated phosphoinositide 3 kinase delta syndrome 2: A cohort study. AB - BACKGROUND: Activated phosphoinositide 3-kinase delta syndrome (APDS) 2 (p110delta-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency [PASLI]-R1), a recently described primary immunodeficiency, results from autosomal dominant mutations in PIK3R1, the gene encoding the regulatory subunit (p85alpha, p55alpha, and p50alpha) of class IA phosphoinositide 3-kinases. OBJECTIVES: We sought to review the clinical, immunologic, and histopathologic phenotypes of APDS2 in a genetically defined international patient cohort. METHODS: The medical and biological records of 36 patients with genetically diagnosed APDS2 were collected and reviewed. RESULTS: Mutations within splice acceptor and donor sites of exon 11 of the PIK3R1 gene lead to APDS2. Recurrent upper respiratory tract infections (100%), pneumonitis (71%), and chronic lymphoproliferation (89%, including adenopathy [75%], splenomegaly [43%], and upper respiratory tract lymphoid hyperplasia [48%]) were the most common features. Growth retardation was frequently noticed (45%). Other complications were mild neurodevelopmental delay (31%); malignant diseases (28%), most of them being B-cell lymphomas; autoimmunity (17%); bronchiectasis (18%); and chronic diarrhea (24%). Decreased serum IgA and IgG levels (87%), increased IgM levels (58%), B-cell lymphopenia (88%) associated with an increased frequency of transitional B cells (93%), and decreased numbers of naive CD4 and naive CD8 cells but increased numbers of CD8 effector/memory T cells were predominant immunologic features. The majority of patients (89%) received immunoglobulin replacement; 3 patients were treated with rituximab, and 6 were treated with rapamycin initiated after diagnosis of APDS2. Five patients died from APDS2 related complications. CONCLUSION: APDS2 is a combined immunodeficiency with a variable clinical phenotype. Complications are frequent, such as severe bacterial and viral infections, lymphoproliferation, and lymphoma similar to APDS1/PASLI CD. Immunoglobulin replacement therapy, rapamycin, and, likely in the near future, selective phosphoinositide 3-kinase delta inhibitors are possible treatment options. PMID- 27221135 TI - beta-Glucan exacerbates allergic asthma independent of fungal sensitization and promotes steroid-resistant TH2/TH17 responses. AB - BACKGROUND: Allergic sensitization to fungi has been associated with asthma severity. As a result, it has been largely assumed that the contribution of fungi to allergic disease is mediated through their potent antigenicity. OBJECTIVE: We sought to determine the mechanism by which fungi affect asthma development and severity. METHODS: We integrated epidemiologic and experimental asthma models to explore the effect of fungal exposure on asthma development and severity. RESULTS: We report that fungal exposure enhances allergen-driven TH2 responses, promoting severe allergic asthma. This effect is independent of fungal sensitization and can be reconstituted with beta-glucan and abrogated by neutralization of IL-17A. Furthermore, this severe asthma is resistant to steroids and characterized by mixed TH2 and TH17 responses, including IL-13+IL 17+CD4+ double-producing effector T cells. Steroid resistance is dependent on fungus-induced TH17 responses because steroid sensitivity was restored in IL-17rc /- mice. Similarly, in children with asthma, fungal exposure was associated with increased serum IL-17A levels and asthma severity. CONCLUSION: Our data demonstrate that fungi are potent immunomodulators and have powerful effects on asthma independent of their potential to act as antigens. Furthermore, our results provide a strong rationale for combination treatment strategies targeting IL-17A for this subgroup of fungus-exposed patients with difficult-to-treat asthma. PMID- 27221137 TI - Prostaglandin E2 and lipoxin A4 in PBMCs are associated with immune tolerance during venom immunotherapy. PMID- 27221136 TI - Maternal plasma total neopterin and kynurenine/tryptophan levels during pregnancy in relation to asthma development in the offspring. AB - BACKGROUND: Neopterin levels and kynurenine/tryptophan ratios (KTRs) increase with IFN-gamma stimulation, indicating TH1 immunity, and thus might be inversely associated with asthma. OBJECTIVE: We sought to examine the association of maternal neopterin levels and KTRs during pregnancy with asthma in the offspring. METHODS: We analyzed the associations of maternal plasma total neopterin levels and KTRs in midpregnancy with asthma at age 7 years among 2883 children in the Norwegian Mother and Child Cohort Study. Asthma was classified either based on registered dispensed asthma medications in the Norwegian Prescription Database or maternal report. We calculated adjusted relative risks using log-binomial regression. RESULTS: The median gestational week of blood sampling was 18 weeks (interquartile range, 17-19 weeks). The risk of dispensed asthma medications at age 7 years was highest among children of mothers in the highest quartile of neopterin levels, whereas the risk was similar in the 3 lowest quartiles. The adjusted relative risk of dispensed asthma medications was 1.66 (95% CI, 1.16 2.38) when comparing children of mothers in the highest quartile with those in the 3 lowest quartiles. A similar association was observed for maternal report of asthma at age 7 years. When we evaluated allergic versus nonallergic asthma, neopterin levels tended to be associated with nonallergic asthma. Maternal KTR was not associated with asthma development. CONCLUSIONS: Our findings indicate that high maternal levels of neopterin, a marker of cellular immune activation, during pregnancy were positively associated with asthma in offspring. Experimental studies would be needed to further elucidate underlying mechanisms. PMID- 27221138 TI - Synergistic Effects of Electroacupuncture and Mesenchymal Stem Cells on Intestinal Ischemia/Reperfusion Injury in Rats. AB - Electroacupuncture (EA) and transplantation of bone marrow mesenchymal stem cells (MSCs) are both promising therapeutic applications for intestinal disorders. The current study examined their combined effect on rat intestinal ischemia/reperfusion (I/R) injury and the possible mechanism. Five groups were performed: con group (shame operation),I/R group (model group), MSC group (I/R + MSC), EA group (I/R + EA), and combined group (I/R + MSC + EA). Intestinal histological damage, crypt cell proliferation degree, mucosal cytokines expression, and levels of inflammation factors were studied for each group. Compared with the I/R group, crypt cell proliferation index and mucosal mRNA concentration of SDF-1, CXCR4, EGF, EGFR in MSC group and EA group were significantly increased, with mucosal NF-kBp65 and serum inflammation factor (TNF alpha, IL-6) levels significantly decreased. Above all of these indicators except NF-kBp65 were improved more notably in combined group than the other two treatment groups. Chiu's score was only ameliorated remarkably in the combined group. The combined treatment of MSC transplantion and electroacupuncture could protect intestinal mucosal barrier from I/R injury. PMID- 27221139 TI - The Role of the T lymphocytes and Remodeling in Asthma. AB - In allergic asthma (AA), inflammatory changes in the airway epithelium may contribute to the characteristic pathophysiology and symptoms. The presence of T lymphocytes, eosinophils, mast cells and macrophages, the presence of cytokines, and also structural changes in the airway mucous membrane are characteristic for asthma. Bronchial biopsy specimens were obtained from 33 AA, 25 nonallergic asthma (NAA), and 20 healthy controls (HC). This study used immunohistochemical techniques for identified monoclonal antibodies (CD3, CD4, CD8, CD25, ECP, MBP, tenascin, and laminin) in the bronchi. The highest number of eosinophils and T lymphocyte cells in bronchial biopsies was found in AA, and NAA. The number of T lymphocytes in AA was significantly higher than in NAA and HC. The degree of epithelial damage was higher in the AA group compared to the other groups. The tenascin- and laminin-positive layers in AA were thicker than other groups. In AA, a significant negative correlation was found between epithelial integrity and the count for eosinophils or T lymphocytes. T lymphocytes and eosinophils in AA were found in the area of epithelial and lamina propria damage. This article suggests that T lymphocytes may not only contribute to the chronic airway inflammatory response, airway remodeling, and symptomatology but may also have a central role at the initiation of the allergic immune response. Th-targeted therapy would be of considerable interest in controlling AA. Having more knowledge on the roles of T lymphocytes in the pathogenesis of allergic inflammation highlights the contributions of these cells in regulating and may lead to a new therapeutic target-AA. PMID- 27221140 TI - The Effect of Pressure-Controlled Ventilation and Volume-Controlled Ventilation in Prone Position on Pulmonary Mechanics and Inflammatory Markers. AB - The aim of this present study is to compare the effect of pressure-controlled ventilation and volume-controlled ventilation on pulmonary mechanics and inflammatory markers in prone position. The study included 41 patients undergoing to vertebrae surgery. The patients were randomized into two groups: Group 1 received volume-controlled ventilation, while group 2 received pressure controlled ventilation. The demographic data, pulmonary mechanics, the inflammatory marker levels just after the induction of anesthetics, at the 6th and 12th hours, and gas analysis from arterial blood samples taken at the beginning and the 30th minute were recorded. The inflammatory marker levels increased in both groups, without any significant difference among groups. Peak inspiratory pressure level was higher in the volume-controlled ventilation group. This study revealed that there is no difference regarding inflammatory marker levels between volume- and pressure-controlled ventilation. PMID- 27221141 TI - Prescribing Preferences in the First-Line Treatment for Patients With Metastatic Renal Cell Carcinoma in the United States. AB - BACKGROUND: Despite existing guidelines for first-line treatment of metastatic renal cell carcinoma (mRCC), prescribing preferences in the United States have not been fully examined. The objectives of this study were to characterize US physicians' preferences and factors influencing first-line mRCC treatment. MATERIALS AND METHODS: A Web-based study presented physicians with hypothetical mRCC patient cases and recorded initial therapy preference and rationale. Descriptive statistics were used to characterize preferred treatment; logistic regression was used to determine patient characteristics associated with therapy changes. Analyses were conducted on pooled responses across cases. Model results were summarized using odds ratios (ORs), 95% confidence intervals, and P values for the covariates. RESULTS: One hundred nine physicians participated in the study; 96 (88.1%) chose a tyrosine kinase inhibitor as their preferred first-line mRCC treatment (62 [56.9%], sunitinib; 31 [28.4%], pazopanib). Perceived superior overall survival and progression-free survival were top reasons physicians chose sunitinib; enhanced tolerability and efficacy similar to sunitinib were top reasons physicians chose pazopanib. Initial sunitinib prescribers were more likely to change therapy in the presence of comorbid conditions (OR, 2.915; P = .0068), poor Eastern Cooperative Oncology Group performance status (OR, 2.368; P = .0106), or poor prognostic risk (OR, 3.884; P = .0224). This was not seen for initial pazopanib prescribers. CONCLUSION: Sunitinib and pazopanib were the most preferred agents for first-line mRCC treatment. Sunitinib preference was driven by perceptions of efficacy, and pazopanib was preferred for its perceived tolerability and efficacy similar to sunitinib. With varying clinical scenarios, initial pazopanib prescribers were more likely to maintain pazopanib and alter dosing; sunitinib prescribers were more likely to switch therapy. PMID- 27221142 TI - Assembly of alpha-Glucan by GlgE and GlgB in Mycobacteria and Streptomycetes. AB - Actinomycetes, such as mycobacteria and streptomycetes, synthesize alpha-glucan with alpha-1,4 linkages and alpha-1,6 branching to help evade immune responses and to store carbon. alpha-Glucan is thought to resemble glycogen except for having shorter constituent linear chains. However, the fine structure of alpha glucan and how it can be defined by the maltosyl transferase GlgE and branching enzyme GlgB were not known. Using a combination of enzymolysis and mass spectrometry, we compared the properties of alpha-glucan isolated from actinomycetes with polymer synthesized in vitro by GlgE and GlgB. We now propose the following assembly mechanism. Polymer synthesis starts with GlgE and its donor substrate, alpha-maltose 1-phosphate, yielding a linear oligomer with a degree of polymerization (~16) sufficient for GlgB to introduce a branch. Branching involves strictly intrachain transfer to generate a C chain (the only constituent chain to retain its reducing end), which now bears an A chain (a nonreducing end terminal branch that does not itself bear a branch). GlgE preferentially extends A chains allowing GlgB to act iteratively to generate new A chains emanating from B chains (nonterminal branches that themselves bear a branch). Although extension and branching occur primarily with A chains, the other chain types are sometimes extended and branched such that some B chains (and possibly C chains) bear more than one branch. This occurs less frequently in alpha-glucans than in classical glycogens. The very similar properties of cytosolic and capsular alpha-glucans from Mycobacterium tuberculosis imply GlgE and GlgB are sufficient to synthesize them both. PMID- 27221143 TI - Clinical genomics: from a truly personal genome viewpoint. AB - The path to Clinical Genomics is punctuated by our understanding of what types of DNA structural and sequence variation contribute to disease, the many technical challenges to detect such variation genome-wide, and the initial struggles to interpret personal genome variation in the context of disease. This review describes one perspective of the development of clinical genomics; whereas the experimental challenges, and hurdles to overcoming them, might be deemed readily apparent, the non-technical issues for clinical implementation may be less obvious. Some of these latter challenges, including: (1) informed consent, (2) privacy, (3) what constitutes potentially pathogenic variation contributing to disease, (4) disease penetrance in populations, and (5) the genetic architecture of disease, and the struggles sometimes faced for solutions, are highlighted using illustrative examples. PMID- 27221145 TI - Clinicopathological implications of vascular endothelial growth factor 165b expression in oral squamous cell carcinoma stroma. AB - Vascular endothelial growth factor (VEGF) is one of the most important angiogenic factors. VEGF165b was recently isolated as the anti-angiogenic VEGF splice variant. In the present study, we examined the association between VEGF165b expression and clinicopathological characteristics in order to determine how VEGF165b produced from oral squamous cell carcinoma (OSCC) affects the stromal cell biological activity. We examined the relationships between the expressions of both VEGF isoforms in normal human dermal fibroblasts (NHDFs) and OSCC cell lines (HSC2, 3, 4 and SAS). Our analyses indicated that both the mRNA and protein expression levels of VEGF165b in the HSC2 and SAS cells were higher than those in the NHDFs. VEGF165b did not promote cell growth or invasive capabilities, but it induced the cell adhesive capabilities to ECM. Although strong expression of the VEGF165 isoforms in tumor cells of OSCC tissues was observed, there was no significant difference in the VEGF165b expression level among the various degrees of malignancy. OSCC cells secrete VEGF165b into the stroma, and this factor may contribute to the process of anti-angiogenesis by inhibiting gelatinase expressing cells and activating cell adhesive capabilities to ECM, such as that of fibroblasts surrounding tumor cells. PMID- 27221144 TI - Engineering the Campylobacter jejuni N-glycan to create an effective chicken vaccine. AB - Campylobacter jejuni is a predominant cause of human gastroenteritis worldwide. Source-attribution studies indicate that chickens are the main reservoir for infection, thus elimination of C. jejuni from poultry would significantly reduce the burden of human disease. We constructed glycoconjugate vaccines combining the conserved C. jejuni N-glycan with a protein carrier, GlycoTag, or fused to the Escherichia coli lipopolysaccharide-core. Vaccination of chickens with the protein-based or E. coli-displayed glycoconjugate showed up to 10-log reduction in C. jejuni colonization and induced N-glycan-specific IgY responses. Moreover, the live E. coli vaccine was cleared prior to C. jejuni challenge and no selection for resistant campylobacter variants was observed. Analyses of the chicken gut communities revealed that the live vaccine did not alter the composition or complexity of the microbiome, thus representing an effective and low-cost strategy to reduce C. jejuni in chickens and its subsequent entry into the food chain. PMID- 27221147 TI - Brugada Syndrome Diagnosed from the ECG Leads in the High Intercostal Spaces: Searching for Answers from a Higher Source? PMID- 27221148 TI - Selective formation of silver(i) bis-phospholane macrocycles and further evidence that gold(i) is smaller than silver(i). AB - A new synthetic approach to highly flexible bis-phospholanes from 1 benzylphospholane (1) as starting material is described. Silver(i) macrocycles containing 16 ([Ag2(MU-3a)2](BF4)2, 4), 20 ([Ag2(MU-3b)2](BF4)2, 5), 24 ([Ag2(MU 3c)2](BF4)2, 6), and 28 ([Ag2(MU-3d)2](BF4)2, 7) atoms in the ring were obtained in one step from AgBF4 and the respective bis-phospholane (C4H8P)(CH2)n(PC4H8) (n = 5, 7, 9, 11; 3a-d) in excellent yields. Comparison of 6 with the previously reported isomorphous complex [Au2(MU-3c)2](BF4)2 gave further evidence that gold(i) is significantly smaller than silver(i). All complexes were fully characterized by NMR and IR spectroscopy, mass spectrometry, and X-ray diffraction. PMID- 27221146 TI - Human-to-mouse prion-like propagation of mutant huntingtin protein. AB - Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder of the central nervous system (CNS) that is defined by a CAG expansion in exon 1 of the huntingtin gene leading to the production of mutant huntingtin (mHtt). To date, the disease pathophysiology has been thought to be primarily driven by cell autonomous mechanisms, but, here, we demonstrate that fibroblasts derived from HD patients carrying either 72, 143 and 180 CAG repeats as well as induced pluripotent stem cells (iPSCs) also characterized by 143 CAG repeats can transmit protein aggregates to genetically unrelated and healthy host tissue following implantation into the cerebral ventricles of neonatal mice in a non-cell autonomous fashion. Transmitted mHtt aggregates gave rise to both motor and cognitive impairments, loss of striatal medium spiny neurons, increased inflammation and gliosis in associated brain regions, thereby recapitulating the behavioural and pathological phenotypes which characterizes HD. In addition, both in vitro work using co-cultures of mouse neural stem cells with 143 CAG fibroblasts and the SH-SY5Y human neuroblastoma cell line as well as in vivo experiments conducted in newborn wild-type mice suggest that exosomes can cargo mHtt between cells triggering the manifestation of HD-related behaviour and pathology. This is the first evidence of human-to-mouse prion-like propagation of mHtt in the mammalian brain; a finding which will help unravel the molecular bases of HD pathology as well as to lead to the development of a whole new range of therapies for neurodegenerative diseases of the CNS. PMID- 27221149 TI - The left hemisphere learns what is right: Hemispatial reward learning depends on reinforcement learning processes in the contralateral hemisphere. AB - Orienting biases refer to consistent, trait-like direction of attention or locomotion toward one side of space. Recent studies suggest that such hemispatial biases may determine how well people memorize information presented in the left or right hemifield. Moreover, lesion studies indicate that learning rewarded stimuli in one hemispace depends on the integrity of the contralateral striatum. However, the exact neural and computational mechanisms underlying the influence of individual orienting biases on reward learning remain unclear. Because reward based behavioural adaptation depends on the dopaminergic system and prediction error (PE) encoding in the ventral striatum, we hypothesized that hemispheric asymmetries in dopamine (DA) function may determine individual spatial biases in reward learning. To test this prediction, we acquired fMRI in 33 healthy human participants while they performed a lateralized reward task. Learning differences between hemispaces were assessed by presenting stimuli, assigned to different reward probabilities, to the left or right of central fixation, i.e. presented in the left or right visual hemifield. Hemispheric differences in DA function were estimated through differential fMRI responses to positive vs. negative feedback in the left vs. right ventral striatum, and a computational approach was used to identify the neural correlates of PEs. Our results show that spatial biases favoring reward learning in the right (vs. left) hemifield were associated with increased reward responses in the left hemisphere and relatively better neural encoding of PEs for stimuli presented in the right (vs. left) hemifield. These findings demonstrate that trait-like spatial biases implicate hemisphere-specific learning mechanisms, with individual differences between hemispheres contributing to reinforcing spatial biases. PMID- 27221150 TI - Regulation of Mucin 1 and multidrug resistance protein 1 by honokiol enhances the efficacy of doxorubicin-mediated growth suppression in mammary carcinoma cells. AB - Understanding the link between chemoresistance and cancer progression may identify future targeted therapy for breast cancer. One of the mechanisms by which chemoresistance is attained in cancer cells is mediated through the expression of multidrug resistance proteins (MRPs). Acquiring drug resistance has been correlated to the emergence of metastasis, accounting for the progression of the disease. One of the diagnostic markers of metastatic progression is the overexpression of a transmembrane protein called Mucin 1 (MUC1) which has been implicated in reduced survival rate. The objective of this study was to understand the relationship between MUC1 and MRP1 using natural phenolic compound isolated from Magnolia grandiflora, honokiol, in mammary carcinoma cells. We provide evidence that honokiol suppresses the expression level of MUC1 and MRP1 in mammary carcinoma cells. In a time-dependent manner, honokiol-mediated reduction of MUC1 is followed by a reduction of MRP1 expression in the breast cancer cells. Additionally, silencing MUC1 suppresses the expression level of MRP1 and enhances the efficacy of doxorubicin, an MRP1 substrate. Taken together, these findings suggest MUC1 regulates the expression of MRP1 and provides a direct link between cancer progression and chemoresistance in mammary carcinoma cells. PMID- 27221151 TI - Does consumption of an aqueous extract of Hibscus sabdariffa affect renal function in subjects with mild to moderate hypertension? AB - Hibiscus sabdariffa (HS) has been traditionally used as a herbal medicine in Nigeria mainly because of its antihypertensive action. In view of the recent increase in the prevalence of renal failure, we have investigated the effect of HS consumption on renal function in Nigerians with mild to moderate hypertension. A total of 78 newly diagnosed but untreated subjects with mild to moderate hypertension attending the medical outpatients unit of Enugu State University Teaching Hospital (Enugu, Nigeria) were recruited for the study. These subjects were randomly divided into three equally sized groups that received HS or lisinopril (treatment groups) or placebo (control group), once daily for 4 weeks. Indices of renal function (urine volume and creatinine clearance) were measured at baseline and weekly throughout the study period. HS and lisinopril significantly increased (P < 0.001) urine volume compared to placebo, and HS significantly (P < 0.001) increased urine volume more than lisinopril. HS significantly increased (P < 0.001) creatinine clearance compared to placebo whereas lisinopril did not. These results indicate that HS consumption improved indices of renal function in our study population of Nigerians with mild to moderate hypertension. PMID- 27221152 TI - An assessment of juvenile Atlantic cod Gadus morhua distribution and growth using diver operated stereo-video surveys. AB - Stereo-video scuba transects were conducted during daylight hours from June to September 2013 within a proposed marine protected area (MPA) in the Firth of Clyde, west of Scotland. More juvenile Atlantic cod Gadus morhua of fork length (LF ) range 6-11 cm were observed in substrata containing mixed gravel, including maerl, than in boulder-cobble substrata with high algal cover, or sand with low density seagrass. Community composition was significantly different between substratum types. A decrease in G. morhua abundance was observed over the period of data collection. Over time, mean and variance in G. morhua LF increased, indicating multiple recruitment events. Protecting mixed gravel substrata could be a beneficial management measure to support the survival and recruitment of juvenile G. morhua; other substrata might be important at night given their diel migratory behaviour. Stereo-video cameras provide a useful non-destructive fisheries-independent method to monitor species abundance and length measurements. PMID- 27221154 TI - Aptamer-aptamer linkage based aptasensor for highly enhanced detection of small molecules. AB - The multi-target colorimetric aptasensors can be easily fabricated by using two different aptamer sequences. However, there have been no research reports about improvement or enhancing of colorimetric signals based on the aggregation properties of AuNPs. Herein, we report a simple and efficient method to control and enhance the function of the multi-target aptasensor using an aptamer-aptamer linkage method. The aptasensor was developed for highly sensitive multiple-target detection of small molecules. The extension of aptamer DNA sequences using this method resulted in the enhanced analytical sensitivity of this aptasensor in sensing applications for two small molecule targets. Furthermore, the mechanism of the interaction between DNA aptamer and AuNPs was studied by measuring the zeta potential to explain the enhancement of the sensitivity of this multi-target aptasensor. The limit of detection of this multi-target aptasensor was found to be 1 nM and 37 nM for kanamycin (KAN) and chlortetracycline (CHLOR), respectively. It is 25-fold lower than in the previous report using an AuNP-based sensor for defining the limit of detection (LOD) of KAN and five times lower than the LOD for CHLOR. This aptasensor has great potential in the simultaneous detection of a wide range of KAN and CHLOR concentrations. PMID- 27221153 TI - FABP4-mediated homocysteine-induced cholesterol accumulation in THP-1 monocyte derived macrophages and the potential epigenetic mechanism. AB - Hyperhomocysteinemia (HHcy) is an independent risk factor for the development of atherosclerosis (AS), according to overwhelming number of clinical and epidemiological studies. However, the underlying pathogenic molecular mechanisms by which HHcy promotes AS remain to be fully elucidated. Fatty acid binding protein 4 (FABP4) has been shown to be important in macrophage cholesterol trafficking. The objective of the present study was to determine whether homocysteine (Hcy) accelerates AS through regulating FABP4, and then mediates cholesterol accumulation in macrophages. Hcy concentrations of 0, 50, 100, 200 and 500 uM, and 100 uM Hcy+30 uM vitamin B12 (VB12)+30 uM folic acid (FA) were respectively added to cultured THP-1 monocyte-derived macrophages for 24 h. The levels of FABP4, which acts as a key factor connecting cellular lipid accumulation to inflammation, were determined using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analyses in the macrophages. The present study used a nested touchdown methylation-specific PCR assay to detect the DNA methylation status of the FABP4 promoter region. In addition, the FABP4 gene fragment was inserted into the cloning vector, pcDNA3.1 EGFP, to construct the recombinant plasmid, pcDNA3.1-EGFP/FABP4, which was identified using restriction endonuclease digestion analysis and DNA sequencing. The pcDNA3.1-EGFP/FABP4 expression plasmid was transfected into THP-1 monocyte derived macrophages, mediated by liposome reagent, following which the expression levels of FABP4 were detected using RT-qPCR and western blot analyses. The present study also determined the intracellular accumulation of total cholesterol in the macrophages. The results indicated that Hcy decreased the levels of FABP4 promoter methylation, but increased the mRNA and protein expression levels of FABP4 in the macrophages, compared with the control group (0 uM Hcy). However, no dose-dependent changes were observed with increasing concentrations of Hcy. The recombinant fluorescent eukaryotic expression vector, pcDNA3.1-EGFP/FABP4, was successfully constructed and effectively expressed in the THP-1 macrophages. The results also showed that FABP4 accelerated the accumulation of cholesterol in the macrophages. Taken together, the results of the present study suggested that FABP4 DNA hypomethylation induced by Hcy may be involved in the overexpression of FABP4, thereby inducing cholesterol accumulation in macrophages. PMID- 27221155 TI - A novel method of real-time reverse-transcription loop-mediated isothermal amplification developed for rapid and quantitative detection of a new genotype (YHV-8) of yellow head virus. AB - A new genotype of yellow head virus (YHV), designated as YHV-8, was found in farmed shrimp Fenneropenaeus chinensis suffering suspectedly from EMS/AHPNS (early mortality disease/acute hepatopancreatic necrosis disease) in China in 2012. In this study, a one-step, real-time reverse-transcription loop-mediated isothermal amplification (rRT-LAMP) assay was developed for better detection of both genotypes of YHV-1 and YHV-8. A set of six specific primers was successfully designed targeting a conserved region of the YHV genome. The LAMP reaction was optimized to contain 8 mmol l(-1) Mg(2+) and 1.4 mmol l(-1) dNTPs, and to be performed at 58 degrees C for 60 min. The detection sensitivity of the rRT-LAMP method was as low as 7 * 10(0) copies per reaction. The specificity of the method was validated by the absence of any cross-reaction with the RNA samples extracted from other shrimp viruses (Taura syndrome virus, white spot syndrome virus, infectious hypodermal and haematopoietic necrosis virus, hepatopancreatic parvovirus) and specific pathogen-free (SPF) shrimp. The resulting standard curves showed high correlation coefficient values. Furthermore, the test of farm samples showed that YHV was detected in three of 111 Litopenaeus vannamei, six of eight Fenneropenaeus chinensis, five of 19 Macrobrachium rosenbergii and none of the nine Marsupenaeus japonicus. These results suggest that this assay is applicable widely as a new rapid and sensitive detection method in the research of YHV. SIGNIFICANCE AND IMPACT OF THE STUDY: In this study, we designate a new genotype of yellow head virus (YHV) as YHV genotype 8 (YHV-8) which was detected in diseased shrimp in China. A rapid, sensitive and specific rRT-LAMP detecting method for both YHV-8 and YHV-1 has been established. It is anticipated that this novel assay will be instrumental for diagnosis and surveillance of the virulent genotypes of YHV. PMID- 27221156 TI - Deciphering the genetic and modular connections between coronary heart disease, idiopathic pulmonary arterial hypertension and pulmonary heart disease. AB - Coronary heart disease (CHD), idiopathic pulmonary arterial hypertension (IPAH) and pulmonary heart disease (PHD) are circulatory system diseases that may simultaneously emerge in a patient and they are often treated together in clinical practice. However, the molecular mechanisms connecting these three diseases remain unclear. In order to determine the multidimensional characteristic correlations between these three diseases based on genomic networks to aid in medical decision-making, genes from the Online Mendelian Inheritance in Man database were obtained, and applied network construction and modularized analysis were conducted. Functional enrichment analysis was conducted to explore the associations between overlapping genes, modules and pathways. A total of 29 overlapping genes and 3 common modules were identifed for the 3 diseases. Glycosphingolipid biosynthesis and the arachidonic acid metabolism are common pathways, and the biosynthetic process is suggested to be the major function involved in the three diseases. The current study reported, to the best of our knowledge for the first time, the role of glycosphingolipid biosynthesis in IPAH and PHD. The present study provided an improved understanding of the pathological mechanisms underlying CHD, IPAH and PHD. The overlapping genes, modules and pathways suggest novel areas for further research, and drug targets. The observations of the current study additionally suggest that drug indications can be broadened because of the presence of common targets. PMID- 27221158 TI - What comes after standardised packaging for tobacco? PMID- 27221159 TI - A novel species of torque teno mini virus (TTMV) in gingival tissue from chronic periodontitis patients. AB - A new species of torque teno mini virus, named TTMV-222, was detected in gingival tissue from periodontitis patients using a viral metagenomics method. The 2803 nucleotide genome of TTMV-222 is closely related to TTMV1-CBD279, with 62.6% overall nucleotide similarity. Genetic analyses of the new virus genome revealed a classic genomic organization but a weak identity with known sequences. The prevalence of TTMV-222 in the periodontitis group (n = 150) was significantly higher than that in the healthy group (n = 150) (p = 0.032), suggesting that the new virus may be associated with inflammation in chronic periodontitis patients. However, this finding requires further investigation. PMID- 27221157 TI - Nutrition and the circadian system. AB - The human circadian system anticipates and adapts to daily environmental changes to optimise behaviour according to time of day and temporally partitions incompatible physiological processes. At the helm of this system is a master clock in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. The SCN are primarily synchronised to the 24-h day by the light/dark cycle; however, feeding/fasting cycles are the primary time cues for clocks in peripheral tissues. Aligning feeding/fasting cycles with clock-regulated metabolic changes optimises metabolism, and studies of other animals suggest that feeding at inappropriate times disrupts circadian system organisation, and thereby contributes to adverse metabolic consequences and chronic disease development. 'High-fat diets' (HFD) produce particularly deleterious effects on circadian system organisation in rodents by blunting feeding/fasting cycles. Time-of-day restricted feeding, where food availability is restricted to a period of several hours, offsets many adverse consequences of HFD in these animals; however, further evidence is required to assess whether the same is true in humans. Several nutritional compounds have robust effects on the circadian system. Caffeine, for example, can speed synchronisation to new time zones after jetlag. An appreciation of the circadian system has many implications for nutritional science and may ultimately help reduce the burden of chronic diseases. PMID- 27221161 TI - Assessment of anaerobic blood cultures in pediatric oncology patients. AB - INTRODUCTION: The routine use of a single aerobic bottle for blood culture in pediatric patients has become commonplace, as anaerobic bacteria are not frequently involved in clinically significant infections. The aim of this study was to assess the usefulness of routinely performing anaerobic blood cultures in pediatric oncology patients. METHODS: Prospective study was conducted on pediatric (<18 years) patients affected with febrile syndrome after receiving chemotherapy for hematological or solid malignancies. Samples were inoculated into pediatric aerobic and standard anaerobic bottles (BacT/Alert automatic system). Strains were considered clinically significant, or deemed as contaminants, depending on isolation circumstances and clinical criteria. RESULTS: A total of 876 blood cultures from 228 patients were processed during the 21-month study period (January 2014 to September 2015). Baseline diagnosis included 143 solid tumors and 67/18 cases of leukemia/lymphoma. Bacterial growth was detected in 90 (10.2%) blood cultures for 95 different isolates, of which 62 (7.1%)/63 isolates were considered clinically significant. Among the latter, 38 (60.3%) microorganisms grew in both aerobic and anaerobic bottles, 18 (28.6%) only in aerobic bottles, and 7 (11.1%) only in anaerobic bottles. Gram-negative bacilli (33; 52.4%), mainly from the Enterobacteriaceae family, were the most frequently isolated microorganisms. Overall, only 3 out of 90 isolates (3.3%) were strict anaerobes (Propionibacterium acnes), and all of them were deemed contaminants. CONCLUSION: Strict anaerobes did not cause significant infections in febrile pediatric oncology patients, and anaerobic blood culture bottles offered no additional advantages over aerobic media. Our results suggest that routine blood cultures should be solely processed in aerobic media in this group of patients. PMID- 27221160 TI - A large Rab GTPase family in a small GTPase world. AB - More than 60 Rab GTPases exist in the human genome to regulate vesicle trafficking between organelles. Rab GTPases are members of the Ras GTPase superfamily that broadly control budding, uncoating, motility and fusion of vesicles in most cell types. Rab proteins interconvert between active, GTP-bound form and inactive, GDP-bound form. In their active conformation, they interact with various effector molecules to carry out diverse functions. Rab GTPases are usually small containing only a GTPase domain with a C-terminal prenylation site for membrane anchoring. Recently, we identified a large G protein, CRACR2A (CRAC channel regulator 2A), which uncovers novel functions of Rab GTPases. First, CRACR2A encodes a large Rab GTPase containing multiple functional domains contrary to small Rab GTPases. Second, CRACR2A plays an unexpected role in regulating intracellular signaling pathways important for T cell activation, unlike the canonical role of small Rab GTPases. Vesicles containing CRACR2A bud out from the proximal Golgi area and translocate into the immunological synapse to activate these signaling pathways. Third, instead of recycling, CRACR2A is consumed by a unidirectional pathway. These events are sequentially regulated by prenylation, GTP binding, protein interaction with a signaling adaptor Vav1, and degradation. Together, our findings reveal a novel function of a large Rab GTPase in intracellular signaling pathways, which may be shared by other large Rab GTPases, Rab44 and Rab45. PMID- 27221165 TI - Fluticasone furoate and vilanterol trifenatate combination therapy for the treatment of asthma. AB - INTRODUCTION: Combination inhaled corticosteroids (ICS) and long acting beta2 adrenergic agonists (LABA) are used in a stepwise fashion for patients whose asthma is not controlled by low dose ICS alone. Adherence is one of the main issues facing clinicians in the control of asthma symptoms with currently available combination inhalers requiring twice-daily (BD) inhalation. Fluticasone furoate (FF) and vilanterol trifenatate (VI) both have prolonged retention in the lung with effects on lung function over 24-hours and as such the combination has been proposed for once-daily (OD) dosing. AREAS COVERED: The stepwise pharmacologic approach to asthma management is addressed, followed by a detailed assessment of the literature pertaining to the efficacy, tolerability and safety of FF/VI combination therapy for the treatment of asthma. Expert commentary: Doses of 100/25ug and 200/25ug inhaled OD, have similar improvements in lung function, asthma control as well as rates of side effects to one of the currently available BD ICS/LABA combinations, fluticasone propionate and salmeterol (FP/SAL) but have not been compared with other commonly used combinations. It is hoped that OD dosage of FF/VI can improve adherence and hence asthma control in these patients, however evidence to support this has yet to become available. PMID- 27221166 TI - Zika - more than just bad luck. PMID- 27221167 TI - Unrest in England. PMID- 27221168 TI - [In Process Citation]. PMID- 27221169 TI - [In Process Citation]. PMID- 27221170 TI - [In Process Citation]. PMID- 27221171 TI - [In Process Citation]. PMID- 27221172 TI - [In Process Citation]. PMID- 27221173 TI - [In Process Citation]. PMID- 27221175 TI - [In Process Citation]. PMID- 27221174 TI - [In Process Citation]. PMID- 27221176 TI - [Better reception of the acutely ill patient]. PMID- 27221177 TI - One Norwegian national tool for estimating date of delivery and fetal age. PMID- 27221178 TI - [Vaginal progesterone treatment in pregnancy does not prevent premature birth]. PMID- 27221179 TI - [In Process Citation]. PMID- 27221180 TI - Resection for oesophageal cancer - complications and survival. AB - BACKGROUND Surgery is considered necessary to achieve a cure for oesophageal cancer. Minimally invasive oesophageal resection is increasingly performed with the aim of reducing the number of complications compared with open surgery. The purpose of this study was to investigate postoperative complications, mortality and long-term survival following hybrid oesophageal resection by laparoscopy and thoracotomy.MATERIAL AND METHOD Patients with oesophageal cancer who underwent hybrid resection with curative intent at Oslo University Hospital Ulleval from 1 November 2007 to 1 June 2013 were included (n = 109). Complications were graded according to the Clavien-Dindo classification and survival figures were recorded.RESULTS Median age was 65 years, 79 % were men. Altogether 118 complications were recorded in 70 patients (64.2 %). Distribution of complications was 1.8 % for stage I, 29.4 % for stage II, 22.1 % for stage III and 11.0 % for stage IV. Anastomotic leakage occurred in 4.6 %. There was no postoperative mortality. The proportion of R0 resections with microscopic radicality was 91 % (n = 100). For the entire patient population, the estimated 5 year survival rate was 48 % (95 % CI 36 - 60 %), for R0 resection 51 % (38 - 63 %) and for R1-2 resection 0 %. Estimated median survival with R0-2, R0 and R1-2 resection was 55, 55 and 10 months (0 - 28 months), respectively. R status and stage had a significant bearing on survival.INTERPRETATION There was a low percentage of serious complications, no mortality and few anastomotic leakages after hybrid resection for oesophageal cancer. The 5-year survival rate was good. PMID- 27221181 TI - [How frequently is the WHO Surgical Safety Checklist used?]. AB - BACKGROUND Through its patient safety programme "In safe hands," the Norwegian Directorate of Health's objective is to ensure that the WHO Surgical Safety Checklist is used for all relevant surgical procedures. The purpose of this study was to investigate the recorded use of the WHO Surgical Safety Checklist, as well as to illuminate the factors that covary with its use, in order to be able to identify improvement measures.MATERIAL AND METHOD All surgical operations were reviewed at five surgical units at St Olavs Hospital Health Trust in three two week periods in 2013. Recorded use of the checklist at each unit was compared to time of surgery, day surgery, acute or elective surgery and operating theatre time before, during and after surgery.RESULTS A total of 2297 operations were included. In 47 % of the operations, use of the entire checklist was recorded, in 31 % use of only parts was recorded and in 22 % no parts of it were recorded as having been used. The unit to which the patient belonged had the most bearing on the extent to which the checklists were used. A short time spent in the operating theatre, as well as operations that were classified in advance as acute, were associated with less recorded use.INTERPRETATION St. Olavs Hospital Health Trust has not achieved the objective of full implementation of the WHO checklist. There is considerable variation in recorded use at the units studied, and less recorded use of the checklist in the case of short and acute operations. PMID- 27221182 TI - [Gastroparesis - causes, diagnosis and treatment]. AB - BACKGROUND Gastroparesis is a motility disorder of the stomach. The symptoms are non-specific: nausea and vomiting are most common. Stomach pains, early satiety, postprandial fullness and bloating are also frequent symptoms. Current diagnostic criteria require delayed gastric emptying in the absence of any detectable mechanical obstruction. In this review article we elucidate the causes, assessment and treatment options.MATERIAL AND METHOD Structured article search in Embase and PubMed.RESULTS A number of conditions can lead to gastroparesis. The most frequent somatic cause is diabetes mellitus. Gastroparesis may also be iatrogenically inflicted by means of surgery or drugs. It may be difficult to discriminate between functional dyspepsia and idiopathic gastroparesis. Examination is based on patient history, gastroscopy and measurement of the rate of gastric emptying. Biochemical tests are also relevant for differential diagnosis. The treatment is primarily symptomatic, and consists of dietary measures, fluid therapy, drugs, gastric electrical stimulation, or endoscopic or surgical intervention in the form of insertion of a feeding tube for nutrition and abdominal relief, pyloroplasty or gastrectomy.INTERPRETATION Gastroparesis is a serious motility disorder. The condition may have significant consequences for patients, entailing reduced quality of life, reduced workforce participation and a considerable need for health assistance. PMID- 27221183 TI - [Endoscopic surgery]. AB - Endoscopic surgery of the stomach/gastrointestinal tract was developed in the 1990s in Japan as a minimally invasive method of removing early-stage tumours, using a gastro-/coloscope instead of open or laparoscopic surgery. Its advantages are obvious, in that the patient is spared more major surgery, the hospital saves on resources as well as admission to a ward, and society is spared the costs of days of sickness absence. Endoscopic submucosal dissection is considered the most difficult technique, but it allows for the accurate dissection of large tumours. In 1999, Japanese surgeon Takuji Gotoda and his team were the first to perform these types of dissections of early cancers in the rectum using a diathermic needle and a flexible scope. PMID- 27221184 TI - [Gray substance gone astray]. PMID- 27221185 TI - [Myocardial infarction now and then - a 50-year perspective]. PMID- 27221186 TI - Cancer, epidemiology and nuclear accidents. PMID- 27221187 TI - [NSAID - when the most important thing was not to be cortisone]. PMID- 27221188 TI - [In Process Citation]. PMID- 27221189 TI - [In Process Citation]. PMID- 27221191 TI - Doctors' health and satisfaction - why should anyone care? PMID- 27221190 TI - [In Process Citation]. PMID- 27221192 TI - [In Process Citation]. PMID- 27221193 TI - [In Process Citation]. PMID- 27221194 TI - [In Process Citation]. PMID- 27221196 TI - [In Process Citation]. PMID- 27221195 TI - Award-winning medical researchers. PMID- 27221197 TI - MicroRNAs: New regulators of IL-22. AB - Interleukin-22 (IL-22) is a cytokine that belongs to the IL-10 family of interleukins. It can be produced by T helper 22 (Th22) cells, T helper 1 (Th1) cells, T helper 17 (Th17) cells, natural killer 22 (NK22) cells, natural killer T (NKT) cells, innate lymphoid cells (ILCs), and gammadelta T cells. IL-22 acts via binding to a heterodimeric transmembrane receptor complex that consists of IL 22R1 and IL-10R2 and mainly contributes to the tissue repair and host defense. Transcription factors such as retinoid orphan receptor gammat (RORgammat) and signal transducer and activator of transcription 3 (STAT3), have been reported to play important roles in regulation of IL-22 expression. Recently, it has been demonstrated in several studies that microRNAs (miRNAs) potently regulate expression of interleukins, including production of IL-22. Here, we review current knowledge about regulators of IL-22 expression with a particular emphasis on the role of miRNAs. PMID- 27221198 TI - Evolution of electronic states in n-type copper oxide superconductor via electric double layer gating. AB - The occurrence of electrons and holes in n-type copper oxides has been achieved by chemical doping, pressure, and/or deoxygenation. However, the observed electronic properties are blurred by the concomitant effects such as change of lattice structure, disorder, etc. Here, we report on successful tuning the electronic band structure of n-type Pr2-xCexCuO4 (x = 0.15) ultrathin films, via the electric double layer transistor technique. Abnormal transport properties, such as multiple sign reversals of Hall resistivity in normal and mixed states, have been revealed within an electrostatic field in range of -2 V to + 2 V, as well as varying the temperature and magnetic field. In the mixed state, the intrinsic anomalous Hall conductivity invokes the contribution of both electron and hole-bands as well as the energy dependent density of states near the Fermi level. The two-band model can also describe the normal state transport properties well, whereas the carrier concentrations of electrons and holes are always enhanced or depressed simultaneously in electric fields. This is in contrast to the scenario of Fermi surface reconstruction by antiferromagnetism, where an anti correlation is commonly expected. PMID- 27221199 TI - Mechanically Tunable Slippery Behavior on Soft Poly(dimethylsiloxane)-Based Anisotropic Wrinkles Infused with Lubricating Fluid. AB - We demonstrate a novel technique to fabricate mechanically tunable slippery surfaces using one-dimensional (anisotropic) elastic wrinkles. Such wrinkles show tunable topography (amplitude) on the application of mechanical strain. Following Nepenthes pitcher plants, lubricating fluid infused solid surfaces show excellent slippery behavior for test liquid drops. Therefore, combining the above two, that is, infusing suitable lubricating fluid on elastic wrinkles, would enable us to fabricate mechanically tunable slippery surfaces. Completely stretched (flat) wrinkles have uniform coating of lubricating fluid, whereas completely relaxed (full amplitude) wrinkles have most of the lubricating oil in the wrinkle grooves. Therefore, water drops on completely stretched surface show excellent slippery behavior, whereas on completely relaxed surface they show reduced slippery behavior. Therefore, continuous variation of wrinkle stretching provides reversibly tunable slippery behavior on such a system. Because the wrinkles are one-dimensional, they show anisotropic tunability of slippery behavior depending upon whether test liquid drops slip parallel or perpendicular to the wrinkles. PMID- 27221201 TI - Changes in serum metabolites with the stage of chronic kidney disease: Comparison of diabetes and non-diabetes. AB - BACKGROUND: The renal dysfunction of chronic kidney disease (CKD) alters serum metabolite levels, but it is not clear how diabetes mellitus (DM) affects the metabolic changes in CKD. METHODS: Serum metabolites from pre-dialysis CKD patients (n=291) with or without DM and from healthy controls (n=56) was measured using nuclear magnetic resonance. RESULTS: Initial principal components analysis and partial least squares-discriminant analysis score plots segregated the CKD patients according to CKD stage and separated DM from non-DM patients. In the CKD patients, associations were seen with clinical characteristics, hyperglycemia, altered amino acid metabolism, accumulated uremic toxins, and dyslipidemia. Of interest, diabetes more strongly affected the metabolic signature during early stage CKD. Furthermore, serum metabolite profiles were successfully applied to the PLS regression model to predict the estimated glomerular filtration rate. The R(2) values from the PLS models for CKD patients with DM were higher than those for CKD without DM. CONCLUSIONS: Metabolomics is useful clinically for providing a metabolic signature that is associated with the CKD phenotype and diabetes more seriously affects patients with early stage CKD compared to those with advanced CKD. PMID- 27221200 TI - Reduced SOD2 expression is associated with mortality of hepatocellular carcinoma patients in a mutant p53-dependent manner. AB - The development and progression of hepatocellular carcinoma (HCC) is accompanied with persistent oxidative stress, but the molecular basis is not well defined. Superoxide dismutase 2 (SOD2) is an important mitochondrial antioxidant and a key aging factor. Here we investigated the expression and clinical significance of SOD2 in a large cohort of HBV-positive HCC tumors. Both SOD2 mRNA and protein are reduced in human primary HCCs compared with matching liver tissues. Consistently, the SOD2 DNA copy numbers are decreased in HCCs, providing a genetic basis for the decrease in SOD2 mRNA expression. Reduced SOD2 expression in HCCs is correlated with older age, larger tumor size, multiple tumor nodules and tumor emboli, and cancer recurrence. Moreover, low SOD2 expression is strongly associated with poor overall survival (OS) and recurrence-free survival (RFS). Univariate and multivariate Cox regression analyses indicates that SOD2 is an independent prognostic predictor for OS and RFS. Intriguingly, reduced SOD2 mRNA is strongly associated with poor survival in a separate cohort of HCC patients carrying mutant p53. Altogether, our results provide clinical evidence for the importance of SOD2 in tumor progression and mortality, and the close relationship of SOD2 and p53 in HCC. PMID- 27221202 TI - Accurate quantification of sphingosine-1-phosphate in normal and Fabry disease plasma, cells and tissues by LC-MS/MS with (13)C-encoded natural S1P as internal standard. AB - We developed a mass spectrometric procedure to quantify sphingosine-1-phosphate (S1P) in biological materials. The use of newly synthesized (13)C5 C18-S1P and commercial C17-S1P as internal standards rendered very similar results with respect to linearity, limit of detection and limit of quantitation. Caution is warranted with determination of plasma S1P levels. Earlier it was reported that S1P is elevated in plasma of Fabry disease patients. We investigated this with the improved quantification. No clear conclusion could be drawn for patient plasma samples given the lack of uniformity of blood collection and plasma preparation. To still obtain insight, plasma and tissues were identically collected from alpha-galactosidase A deficient Fabry mice and matched control animals. No significant difference was observed in plasma S1P levels. A significant 2.3 fold increase was observed in kidney of Fabry mice, but not in liver and heart. Comparative analysis of S1P in cultured fibroblasts from normal subjects and classically affected Fabry disease males revealed no significant difference. In conclusion, accurate quantification of S1P in biological materials is feasible by mass spectrometry using the internal standards (13)C5 C18-S1P or C17-S1P. Significant local increases of S1P in the kidney might occur in Fabry disease as suggested by the mouse model. PMID- 27221203 TI - VOC breath biomarkers in lung cancer. AB - This review provides an overview of volatile organic compounds (VOCs) which are considered lung cancer biomarkers for diagnostic breath analysis. It includes results of scientific publications from 1985 to 2015. The identified VOCs are listed and ranked according to their occurrence of nomination. The applied detection and sampling methods are specified but not evaluated. Possible reasons for the different results of the studies are stated. Among the most frequently emerging biomarkers are 2-butanone and 1-propanol as well as isoprene, ethylbenzene, styrene and hexanal. The outcome of this review may be helpful for the development of a lung cancer screening device. PMID- 27221204 TI - Statin treatment is associated with a negative correlation between NT-proBNP and insulin resistance in patients without history of heart failure. AB - BACKGROUND: We investigated the effect of statin treatment on the relationship between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and insulin resistance in patients without history of heart failure. METHODS: Patients without history of heart failure and diabetes were recruited to undergo an oral glucose tolerance test. Blood samples were collected for measurements of NT proBNP, glucose, and insulin. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR). Linear mixed model analysis was used to examine the correlation between NT-proBNP and HOMA-IR. RESULTS: A total of 219 patients (mean age 61.1+/-11.8y, median NT-proBNP 64.3 [32.1-154.5] pg/ml) were analyzed. Overall, NT-proBNP was negatively correlated with HOMA-IR after an adjustment for confounders (beta coefficient -0.335, 95% CI [-0.516, -0.153], p=0.001). This correlation was significant in patients on statin treatment (n=91, beta coefficient -0.558, 95% CI [-0.802, -0.312], p<0.001), but was insignificant in patients not on statin treatment (n=128, beta coefficient -0.147, 95% CI [-0.412, 0.118], p=0.274, p for interaction=0.040). CONCLUSIONS: Statin treatment is associated with a negative correlation between NT-proBNP and insulin resistance in patients without history of heart failure. Our findings suggest that NT-proBNP may be related to insulin resistance associated with statin treatment. PMID- 27221205 TI - Standardisation and use of the alcohol biomarker carbohydrate-deficient transferrin (CDT). AB - Carbohydrate-deficient transferrin (CDT) is a glycoform profile of serum transferrin that increases in response to sustained high alcohol intake and over the last decades has become an important alcohol biomarker with clinical and forensic applications. However, the wide range of CDT measurement procedures has resulted in lack of uniform results and reference limits, and hampered comparison of results. In 2005, the IFCC therefore founded a special working group (WG) aiming for standardisation of CDT measurement. This review summarises the history of CDT and the actions taken by the WG-CDT. Initial steps included the definition of the measurand (serum disialotransferrin to total transferrin fraction expressed in %), and the determination of a well-defined anion-exchange HPLC procedure as the candidate reference measurement procedure (cRMP). Subsequent achievements were the establishment of a network of reference laboratories to perform the cRMP, setting a reference interval, and development of a reference material based on human serum for which the laboratory network assign values. Using a set of reference materials for calibration allowed for achieving equivalence of results of all present CDT measurement procedures. The final steps of the WG-CDT have been a full validation of the cRMP to make it an IFCC approved RMP, and providing guidance for international standardisation of all CDT measurement procedures. PMID- 27221206 TI - Effects of vitamin D and calcium supplementation on side effects profile in patients of breast cancer treated with letrozole. AB - BACKGROUND: Vitamin D deficiency (<10ng/mL) and insufficiency (10-30ng/mL) may contribute to musculoskeletal symptoms observed in patients taking letrozole. This study was undertaken to assess the vitamin D status in breast cancer patients who received letrozole for >2months and to see the effects of vitamin D3 and calcium supplementation on them. METHODS: Eighty-two breast cancer patients were included. Baseline serum 25-hydroxy vitamin D concentrations were assayed and standard questionnaire was completed. They were given vitamin D3 and calcium supplementation (2000IU/1000 mg and 4000IU/1000mg) based on their baseline serum 25-hydroxy vitamin D concentration for 12weeks. RESULTS: Baseline serum 25 hydroxy vitamin D concentrations showed that 13.4% of patients were deficient and 73.2% of patients were insufficient in 25-hydroxy vitamin D. There was an increase in the concentrations of calcium, phosphorus and decrease in the concentrations of parathyroid hormone, alkaline phosphatase as the concentration of serum 25-hydroxy vitamin D increases. Patients who received letrozole for a longer duration had a low concentration of serum 25 (OH) vitamin D. Vitamin D3 and calcium supplementation increased the concentrations of calcium, phosphorous and decreased the concentrations of parathyroid hormone and alkaline phosphatase. Patients who had low serum 25-hydroxy vitamin D concentrations had more musculoskeletal symptoms which was improved following supplementation (9.14 vs 8.10 p=0.000). CONCLUSION: Vitamin D3 supplementation significantly improved serum 25-hydroxy vitamin D concentrations and decreased letrozole-induced arthralgia. PMID- 27221207 TI - Safe sleep for pediatric inpatients. AB - PURPOSE: To improve sleep environment safety for inpatient infants. DESIGN AND METHODS: This quality improvement project involved assessment of sleep environment safety for inpatient infants before and after a bundled intervention of staff education and introduction of swaddle sacks and bedside storage bins. RESULTS: The proportion of infant cribs without loose objects in them increased (32-72%, p = .025), and safe sleep positioning remained stable (82% vs. 95%, p = .183). PRACTICE IMPLICATIONS: Staff education, swaddle sleep sacks, and bedside storage containers were associated with improved sleep safety among pediatric inpatients at our institution and may help at other institutions. PMID- 27221208 TI - Safety and tolerability of adjunctive brivaracetam as intravenous infusion or bolus in patients with epilepsy. AB - OBJECTIVES: An intravenous (IV) formulation of brivaracetam (BRV), a selective, high-affinity ligand for synaptic vesicle protein 2A, has been developed. We investigated the safety, tolerability, and pharmacokinetics of adjunctive IV BRV administered as a bolus or infusion to adults with epilepsy. METHODS: A phase III, multicenter, randomized, four-arm, parallel-group study (NCT01405508) of patients aged 16-70 years with focal or generalized epilepsy uncontrolled by 1-2 antiepileptic drugs was undertaken. The study comprised a 7-day baseline period, a 7-day double-blind run-in period (oral BRV 200 mg/day or placebo [PBO] twice daily [BID]), and 4.5-day open-label evaluation period (IV BRV 200 mg/day BID; 2 min bolus or 15-min infusion, total nine doses). Patients were randomized 1:1:1:1 PBO/BRV bolus; PBO/BRV infusion; BRV/BRV bolus; BRV/BRV infusion. Safety and tolerability were assessed using adverse events, electrocardiography, vital signs, and laboratory assessments. BRV plasma concentrations were measured before and 15 min after the first and last IV doses. RESULTS: Of the 105 patients randomized (53.3% women; 77.1% white; mean [standard deviation; SD] age 41.6 [12.2] years), 103 (98.1%) completed the study. Treatment-emergent adverse event (TEAE) incidence during IV BRV was similar whether IV BRV was initiated first (70.6%) or followed oral BRV (66.0%), and whether it was administered as a bolus (71.2%) or infusion (65.4%). Injection-related TEAEs were reported by 9.6% of patients following bolus and 11.5% following infusion. No serious TEAEs were reported. IV BRV plasma concentrations were higher after the first dose in the conversion groups than initiation groups, and slightly higher in the bolus arm than the infusion arm; concentrations were similar in all patients after the last IV dose. SIGNIFICANCE: IV BRV was generally well tolerated, with similar tolerability as a bolus or infusion and independent of de novo administration or as conversion from oral BRV tablets. IV BRV may be an option for patients who are unable to receive oral BRV. PMID- 27221209 TI - MicroRNA-874 inhibits growth, induces apoptosis and reverses chemoresistance in colorectal cancer by targeting X-linked inhibitor of apoptosis protein. AB - MicroRNA-874 (miR-874) is downregulated and acts as a tumor suppressor in several types of cancers, whereas the biological function of miR-874 in colorectal cancer (CRC) remains unclear. The aims of the present study were to investigate the clinical significance, biological effects, and the underlying mechanisms of miR 874 in CRC. Reverse transcription-quantitative PCR (RT-qPCR) was used to detect miR-874 expression in CRC cell lines and tissue samples. MTT and colony formation assays and flow cytometry were performed to analyze the effects of miR-874 expression on growth, apoptosis and the chemoresistance of CRC cells. Regulation of putative miR-874 targets was determined by dual-luciferase reporter assays. RT qPCR and western blot assays were performed to detected the levels of X-linked inhibitor of apoptosis protein (XIAP) mRNA and protein expression. It was found that expression of miR-874 was downregulated in CRC tissues and cell lines, and its expression was significantly negatively correlated with TNM stage and lymph node metastasis of the CRC patients. Functional assays revealed that restoration of miR-874 inhibited proliferation, reduced colony formation, enhanced apoptosis, as well as decreased the 5-fluorouracil (5-FU) resistance of the CRC cells. Through luciferase activity assay, RT-qPCR and western blot analysis, XIAP was shown to be a direct target of miR-874. In addition, XIAP expression was significantly increased in the CRC tissues and cell lines, and was inversely correlated with miR-874 expression. Importantly, downregulation of XIAP in CRC cells had an effect similar to that of miR-874 overexpression. Taken together, these data showed that miR-874 inhibits growth, increases apoptosis and enhances chemosensitivity in CRC cells by targeting XIAP, suggesting that miR-874 may be a potential molecular target for the treatment of human CRC. PMID- 27221210 TI - Are Mussels Always the Best Bioindicators? Comparative Study on Biochemical Responses of Three Marine Invertebrate Species to Chronic Port Pollution. AB - Bivalves have traditionally been considered good bioindicators due to their sensitivity to pollution, among other features. This characteristic is shared by several other non-bivalve species as well, though studies in this respect remain scarce. This work aims to compare biomarker sensitivity to chronic port pollution among three intertidal invertebrate species with good bioindicator characteristics. Mussels' immunological (phenoloxidase and peroxidases) and biotransformation (glutathione-S-transferase) responses were contrasted against those of limpets and barnacles. The three species under study evidenced activity of all the enzymes measured, although with differences. Barnacle Balanus glandula was the most sensitive species showing pollution modulation of the three enzymes, which suggests that mussels would not always be the best bioindicator species among marine invertebrates depending on the responses that are assessed. PMID- 27221211 TI - Interfacial electrofluidics in confined systems. AB - Electrofluidics is a versatile principle that can be used for high speed actuation of liquid interfaces. In most of the applications, the fundamental mechanism of electro-capillary instability plays a crucial role, yet it's potential richness in confined fluidic layers has not been well addressed. Electrofluidic displays which are comprised of thin pixelated colored films in a range of architectures are excellent systems for studying such phenomena. In this study we show theoretically and experimentally that confinement leads to the generation of a cascade of voltage dependent modes as a result of the electro capillary instability. In the course of reconciling theory with our experimental data we have observed a number of previously unreported phenomena such as a significant induction time (several milliseconds) prior to film rupture as well as a rupture location not corresponding to the minimum electric field strength in the case of the standard convex water/oil interface used in working devices. These findings are broadly applicable to a wide range of switchable electrofluidic applications and devices having confined liquid films. PMID- 27221213 TI - Polymorphisms of BDNF and CACNA1C are not associated with cognitive functioning in bipolar disorder or healthy controls. AB - INTRODUCTION: The cause of cognitive dysfunction in bipolar disorder (BD) is not well understood. BDNF and CACNA1C are two susceptibility genes for the disorder that have also been reported to be associated with cognitive deficits in the disorder, but the studies have been small and with conflicting results. We therefore attempted to replicate an association between cognitive dysfunction with the most commonly studied single nucleotide polymorphisms rs6265 and rs1006737. METHODS: Regression models with five aggregated cognitive domains derived from a comprehensive test battery and IQ score were run using directly genotyped risk variants of SNPs rs6265 and rs1006737 as predictors with covariates as appropriate. Models were performed in a clinical sample of Swedish patients with BD (N = 114) and sex- and age-matched population controls (N = 104). RESULTS: No significant associations (regardless of correction for multiple testing) between the BDNF and CACNA1C risk variants and cognitive functioning were found in either patients or controls. CONCLUSIONS: Our results do not support that the common genetic risk variants in rs6265 and rs1006737 are associated with cognitive dysfunction. PMID- 27221212 TI - CD5-mediated inhibition of TCR signaling proceeds normally in the absence of SHP 1. AB - The CD5 transmembrane glycoprotein functions as a co-receptor in the signaling pathway linking T-cell antigen receptor (TCR) engagement to activation and differentiation. Although CD5 effects on TCR signaling have been shown to be primarily inhibitory, the underlying mechanisms remain unclear. In view of recent data revealing the ability of CD5 to associate with the SHP-1 tyrosine phosphatase, a protein that also downregulates TCR signaling, we examined the role of SHP-1 in modulating CD5 function using thymocytes from SHP-1-deficient viable motheaten (mev) mice. The results revealed the association of SHP-1 with CD5 to be markedly increased following TCR stimulation and indicated that this interaction was enhanced by and was dependent on CD5 tyrosine phosphorylation. However, there was no difference of the tyrosine phosphorylation status of CD5 between resting and TCR-stimulated cells in SHP-1-deficient compared to wild-type thymocytes. Lack of SHP-1 activity did not affect the levels of CD5 surface expression, CD5 co-immunoprecipitable tyrosine phosphatase activity and intracellular calcium increase following co-crosslinking of the TCR and CD5. Similarly, an analysis of T-cell thymocyte populations in mev mice expressing an H-Y transgene as well as a construct mediating T-cell restricted CD5 overexpression, revealed that the reduction in the positive selection conferred by CD5 overexpression was unaffected by SHP-1 deficiency. CD5 is not a SHP-1 substrate and SHP-1 is not required for and possibly not involved in the CD5 mediated modulation of TCR signaling. PMID- 27221215 TI - 2'-O-Methyl- and 2'-O-propargyl-5-methylisocytidine: synthesis, properties and impact on the isoCd-dG and the isoCd-isoGd base pairing in nucleic acids with parallel and antiparallel strand orientation. AB - Oligonucleotides containing 2'-O-methylated 5-methylisocytidine (3) and 2'-O propargyl-5-methylisocytidine (4) as well as the non-functionalized 5-methyl-2' deoxyisocytidine (1b) were synthesized. MALDI-TOF mass spectra of oligonucleotides containing 1b are susceptible to a stepwise depyrimidination. In contrast, oligonucleotides incorporating 2'-O-alkylated nucleosides 3 and 4 are stable. This is supported by acid catalyzed hydrolysis experiments performed on nucleosides in solution. 2'-O-Alkylated nucleoside 3 was synthesized from 2'-O-5 dimethyluridine via tosylation, anhydro nucleoside formation and ring opening. The corresponding 4 was obtained by direct regioselective alkylation of 5 methylisocytidine (1d) with propargyl bromide under phase-transfer conditions. Both compounds were converted to phosphoramidites and employed in solid-phase oligonucleotide synthesis. Hybridization experiments resulted in duplexes with antiparallel or parallel chains. In parallel duplexes, methylation or propargylation of the 2'-hydroxyl group of isocytidine leads to destabilization while in antiparallel DNA this effect is less pronounced. 2'-O-Propargylated 4 was used to cross-link nucleosides and oligonucleotides to homodimers by a stepwise click ligation with a bifunctional azide. PMID- 27221214 TI - Capture of dengue viruses using antibody-integrated graphite-encapsulated magnetic beads produced using gas plasma technology. AB - Despite significant advances in medicine, global health is threatened by emerging infectious diseases caused by a number of viruses. Dengue virus (DENV) is a mosquito-borne virus, which can be transmitted to humans via mosquito vectors. Previously, the Ministry of Health, Labour and Welfare in Japan reported the country's first domestically acquired case of dengue fever for almost 70 years. To address this issue, it is important to develop novel technologies for the sensitive detection of DENV. The present study reported on the development of plasma-functionalized, graphite-encapsulated magnetic nanoparticles (GrMNPs) conjugated with anti-DENV antibody for DENV capture. Radiofrequency wave-excited inductively-coupled Ar and ammonia gas plasmas were used to introduce amino groups onto the surface of the GrMNPs. The GrMNPs were then conjugated with an antibody against DENV, and the antibody-integrated magnetic beads were assessed for their ability to capture DENV. Beads incubated in a cell culture medium of DENV-infected mosquito cells were separated from the supernatant by applying a magnetic field and were then washed. The adsorption of DENV serotypes 1-4 onto the beads was confirmed using reverse transcription-polymerase chain reaction, which detected the presence of DENV genomic RNA on the GrMNPs. The methodology described in the present study, which employed the plasma-functionalization of GrMNPs to enable antibody-integration, represents a significant improvement in the detection of DENV. PMID- 27221216 TI - Location, location, location: Variation in sensitivity to pain across the body. AB - BACKGROUND: There is evidence that sensitivity to noxious stimuli differs between the sexes and across the body, but few studies have investigated differences in the perception and experience of acute pain stimuli across the body in healthy individuals. METHODS: We recruited 52 healthy participants, aged 18-36 (50% men) and administered 39, 42 and 45 degrees C stimuli at four body sites bilaterally to examine differences in the experience of pain intensity and unpleasantness between body sites via an 11-point numerical rating scale. RESULTS: Noxious and innocuous thermal heat stimuli were perceived as significantly more intense when delivered to the wrist (M = 3.98, SD = 1.93) and back (M = 4.07, SD = 1.98) compared to the shoulder (M = 3.45, SD = 1.91) and leg (M = 3.46, SD = 1.87). Pain unpleasantness ratings yielded similar findings; stimuli were perceived as more unpleasant when administered to the wrist (M = 2.83, SD = 1.93) and lower back (M = 3.04, SD = 2.11) compared to the shoulder (M = 2.63, SD = 1.85) and leg (M = 2.26, SD = 1.82). CONCLUSIONS: These findings suggest that painful thermal stimuli delivered to the wrist and back are perceived as more intense and unpleasant compared with other body sites in healthy persons. These differences may be due to variations in receptor density, or the relative importance of these sites for daily living and survival. SIGNIFICANCE: Moreover, these insights are helpful for the design of studies investigating pain experience in healthy persons in experimental or clinical settings. WHAT DOES THIS STUDY ADD?: We tested sensitivity to acute suprathreshold thermal stimulations across a range of body sites to investigate for potential variability. We found significant differences in the perceived intensity and unpleasantness of noxious and innocuous thermal stimuli at the wrist and lower back, compared with the shoulder and leg. These results suggest that pain experience is driven by receptor density or the relative functional importance of these sites. PMID- 27221217 TI - Forced air warming to maintain normoTHERMIa during SEDation in the cardiac catheterization laboratory: protocol for the THERMISED pilot randomized controlled trial. AB - AIM: To determine whether applying forced air warming attenuates the impact of sedation-induced impairment of thermoregulation on body temperature of patients who are sedated during interventional procedures in the cardiac catheterization laboratory. BACKGROUND: A moderate proportion of sedated patients who undergo procedures in the cardiac catheterization laboratory with only passive warming become hypothermic. Hypothermia in the surgical population is associated with increased risk of adverse cardiac events, infections, thrombotic and haemorrhagic complications and prolonged hospital stay. For this reason, investigation of the clinical benefits of preventing hypothermia in sedated patients using active warming is required. DESIGN: Randomized controlled trial. METHODS: A total of 140 participants undergoing elective interventional procedures with sedation in a cardiac catheterization laboratory will be recruited from two hospitals in Australia. Participants will be randomized to receive forced air warming (active warming) or usual care (passive warming with heated cotton blankets) throughout procedures. The primary outcome is hypothermia (defined as temperature less than 36 degrees C) at the conclusion of the procedure. Secondary outcomes are postprocedure temperature, postprocedural shivering, thermal discomfort, major complications, disability-free survival to 30 days postprocedure, cost effectiveness and feasibility of conducting a larger clinical trial. DISCUSSION: The results from this study will provide high-level evidence for practice in an area where there is currently no guidance. Findings will be easily translatable into clinical practice because most hospitals already have forced air warming equipment available for use during general anaesthesia. REGISTRATION NUMBER: ACTRN12616000013460. PMID- 27221219 TI - Development of a Novel Covalent Folate-Albumin-Photosensitizer Conjugate. AB - There is considerable interest in the development of novel and more efficient delivery systems for improving the efficacy of photodynamic therapy (PDT). The authors in this highlighted issue describe the synthesis and the photobiological characterizations of two photosensitizer (PS) conjugates based on beta-carboline derivatives covalently conjugated to folic acid (FA) coupled to bovine serum albumin (BSA) as a carrier system specifically targeting cancer cells overexpressing FA receptor alpha (FRalpha). Accordingly, only the FA-BSA-beta carboline conjugates are internalized specifically in FRalpha-positive cells and are proved to be phototoxic. On the other hand, albumin-beta-carboline conjugates without FA or beta-carboline derivatives alone are not internalized and nontoxic. This conjugate is among the first to produce a conjugate composed of a PS and FA molecules that are directly conjugated to BSA. In addition, the in vitro studies are the first evidence that directly conjugated FA-BSA can be used as carriers to selectively enhance cytotoxicity by PDT relative to unmodified PS or nontargeted BSA-PS. This strategy is a positive step forward for the covalent design and construction of a photodynamic nanomedicine for FR-positive tumors. PMID- 27221218 TI - Phylogeographic analysis of hemorrhagic fever with renal syndrome patients using multiplex PCR-based next generation sequencing. AB - Emerging and re-emerging infectious diseases caused by RNA viruses pose a critical public health threat. Next generation sequencing (NGS) is a powerful technology to define genomic sequences of the viruses. Of particular interest is the use of whole genome sequencing (WGS) to perform phylogeographic analysis, that allows the detection and tracking of the emergence of viral infections. Hantaviruses, Bunyaviridae, cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) in humans. We propose to use WGS for the phylogeographic analysis of human hantavirus infections. A novel multiplex PCR based NGS was developed to gather whole genome sequences of Hantaan virus (HTNV) from HFRS patients and rodent hosts in endemic areas. The obtained genomes were described for the spatial and temporal links between cases and their sources. Phylogenetic analyses demonstrated geographic clustering of HTNV strains from clinical specimens with the HTNV strains circulating in rodents, suggesting the most likely site and time of infection. Recombination analysis demonstrated a genome organization compatible with recombination of the HTNV S segment. The multiplex PCR-based NGS is useful and robust to acquire viral genomic sequences and may provide important ways to define the phylogeographical association and molecular evolution of hantaviruses. PMID- 27221220 TI - Antenatal Saireito (TJ-114) Can Improve Pulmonary Hypoplasia and Pulmonary Vascular Remodeling in Nitrofen-Induced Congenital Diaphragmatic Hernia. AB - Congenital diaphragmatic hernia (CDH) can induce lung hypoplasia and pulmonary hypertension and is associated with high mortality. The purpose of this study is to examine the efficacy and safety of antenatal Saireito (TJ-114), a traditional Japanese herbal medicine, in a rat CDH model. Sprague-Dawley rats were exposed to an herbicide (nitrofen, 100 mg) on embryonic day 9 (E9) to induce CDH, and antenatal Saireito (2000 mg/kg/day) was orally administered from E10 to E20. On E21, fetuses were delivered. Antenatal Saireito significantly decreased the incidence of CDH (p < 0.01), increased lung volume (p < 0.01), improved alveolarization and pulmonary artery remodeling using histological analysis, and improved respiratory function using gasometric analysis (pH; p < 0.05, and PCO2 ; p < 0.01). In addition, antenatal Saireito significantly decreased endothelin-1 and endothelin receptor A expression in the pulmonary arteries. Taken together, our results demonstrated that antenatal Saireito can improve fetal pulmonary hypoplasia and pulmonary vascular remodeling and, as a result, can improve respiratory function in a rat CDH model. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27221221 TI - Liver is liver and blood is blood, and finally the twain have met. PMID- 27221223 TI - Distinct mucosal immunopathologic profiles in atopic and nonatopic chronic rhinosinusitis without nasal polyps in Central China. AB - BACKGROUND: The role of atopy to aeroallergens in chronic rhinosinusitis without nasal polyps (CRSsNP) remains unclear. This study aimed to investigate the mucosal immunopathologic characteristics of CRSsNP with and without atopy to inhalant allergens. METHODS: Thirteen nonatopic CRSsNP patients, 9 atopic CRSsNP patients, and 11 nonatopic control subjects were enrolled in this study. The expression of type 1, 2, and 17 cytokines, growth factors, and chemokines for T cell subsets and granulocytes in sinonasal mucosa was detected using Bio-Plex suspension chip technology or enzyme-linked immunosorbent assay (ELISA). Subjective symptoms were scored on a visual analogue scale (VAS), while disease severity on computed tomography (CT) was graded by the Lund-Mackay CT scoring system. RESULTS: There was no significant difference in VAS and CT scores between atopic and nonatopic CRSsNP. Compared with control, both atopic and nonatopic CRSsNP demonstrated increased interferon gamma (IFN-gamma) levels in sinonasal mucosa. In contrast, although no difference in interleukin 5 (IL-5), IL-13 and eotaxin-1 expression, or mucosal eosinophil infiltration, was found between the control and whole CRSsNP group, atopic CRSsNP manifested an increased expression of IL-5, IL-13 and eotaxin-1, as well as an enhanced infiltration of mucosal eosinophils in comparison with control and nonatopic CRSsNP. Mucosal eosinophil infiltration correlated with IL-5 and eotaxin-1 expression. No difference in IL 12, IL-4, IL-6, IL-17A, IL-8, myeloperoxidase, "regulated upon activation normal T cell expressed and presumably secreted" (RANTES), or chemokine (C-X-C motif) ligand 10 (CXCL10) protein expression was found among control, atopic CRSsNP, and nonatopic CRSsNP. CONCLUSION: Atopic and nonatopic CRSsNP have distinct mucosal immunopathologic profiles. CRSsNP is a heterogeneous disorder consisting of multiple groups of biological subtypes, or "endotypes," which may argue for different therapeutic strategies. PMID- 27221222 TI - klf2a couples mechanotransduction and zebrafish valve morphogenesis through fibronectin synthesis. AB - The heartbeat and blood flow signal to endocardial cell progenitors through mechanosensitive proteins that modulate the genetic program controlling heart valve morphogenesis. To date, the mechanism by which mechanical forces coordinate tissue morphogenesis is poorly understood. Here we use high-resolution imaging to uncover the coordinated cell behaviours leading to heart valve formation. We find that heart valves originate from progenitors located in the ventricle and atrium that generate the valve leaflets through a coordinated set of endocardial tissue movements. Gene profiling analyses and live imaging reveal that this reorganization is dependent on extracellular matrix proteins, in particular on the expression of fibronectin1b. We show that blood flow and klf2a, a major endocardial flow-responsive gene, control these cell behaviours and fibronectin1b synthesis. Our results uncover a unique multicellular layering process leading to leaflet formation and demonstrate that endocardial mechanotransduction and valve morphogenesis are coupled via cellular rearrangements mediated by fibronectin synthesis. PMID- 27221224 TI - Acquiring an H in MDS. PMID- 27221225 TI - Objective estimation of patient age through a new composite scale for facial aging assessment: The face - Objective assessment scale. AB - Most patients requesting aesthetic rejuvenation treatment expect to look healthier and younger. Some scales for ageing assessment have been proposed, but none is focused on patient age prediction. The aim of this study was to develop and validate a new facial rating scale assessing facial ageing sign severity. One thousand Caucasian patients were included and assessed. The Rasch model was used as part of the validation process. A score was attributed to each patient, based on the scales we developed. The correlation between the real age and scores obtained, the inter-rater reliability and test-retest reliability were analysed. The objective was to develop a tool enabling the assigning of a patient to a specific age range based on the calculated score. All scales exceeded criteria for acceptability, reliability and validity. The real age strongly correlated with the total facial score in both sex groups. The test-retest reliability confirmed this strong correlation. We developed a facial ageing scale which could be a useful tool to assess patients before and after rejuvenation treatment and an important new metrics to be used in facial rejuvenation and regenerative clinical research. PMID- 27221226 TI - Cross-generational THC exposure alters the developmental sensitivity of ventral and dorsal striatal gene expression in male and female offspring. AB - Cannabis (Cannabis sativa, Cannabis indica) is the illicit drug most frequently abused by young men and women. The growing use of the drug has raised attention not only on the impact of direct exposure on the developing brain and behavior later in life, but also on potential cross-generational consequences. Our previous work demonstrated that adolescent exposure to Delta9 tetrahydrocannabinol (THC), the main psychoactive component of cannabis, affects reward-related behavior and striatal gene expression in male offspring that were unexposed to the drug during their own lifespan. The significant sex differences documented for most addiction and psychiatric disorders suggest that understanding the perturbation of the brain in the two sexes due to cannabis could provide insights about neuronal systems underpinning vulnerability to psychiatric illnesses. In the current study, we expanded our previous observations in males by analyzing the female brain for specific aberrations associated with cross-generational THC exposure. Based on the impact of adolescent development on subsequent adult behavioral pathology, we examined molecular patterns during both adolescence and adulthood. The results revealed a switch from the ventral striatum during adolescence to the dorsal striatum in adulthood in alterations of gene expression related to synaptic plasticity in both sexes. Females, however, exhibited stronger correlation patterns between genes and also showed locomotor disturbances not evident in males. Overall, the findings demonstrate cross-generational consequences of parental THC exposure in both male and female offspring. PMID- 27221228 TI - Functionalized calcium silicate nanofibers with hierarchical structure derived from oyster shells and their application in heavy metal ions removal. AB - Inorganic hierarchical nanostructures have remarkable potential applications in environmental metal remediation; however, their applications usually suffer from low capacity, high cost, and difficulties in the recycling of adsorbents. We previously reported a facile strategy to synthesize acid-insoluble calcium silicate hydrates (CSH) from oyster shells, a representative kind of biowaste. However, little is known of the structure, size, and morphology of the as prepared CSH, which hampers the improvement of their adsorption capacities. In this work, systematic investigation of the structures of as-generated CSH demonstrate that they have a hierarchically porous structure composed of thin nano-sheets, where each nano-sheet is assembled by nano-fibers with width of around ten nanometers. The hierarchical nanostructures with pore size of ~12 nm provide a significant amount of active sites to graft polyethyleneimine (PEI), which enables the efficient extraction of both Cu(ii) cations and Cr(vi) anions from the aqueous solution. Batch experiments further indicate that the PEI modified PCSH exhibit a maximum adsorption capacity of 203 and 256 mg g(-1) for Cu(ii) and Cr(vi), respectively, much higher than that of CSH, OS and many other adsorbents in literature. The adsorption of Cu(ii) and Cr(vi) proved to be spontaneous and exothermic. Combining the pH-dependent experiments with X-ray photoelectron spectroscopy analysis, the underlying mechanism is discussed. PCSH derived from OS biowaste maintains an efficient extraction ability toward Cu(ii) and Cr(vi) after five adsorption-desorption cycles. It is also applicable for treating various kinds of heavy metal ions and organic pollutants, showing potentially wide applications in water treatment. PMID- 27221227 TI - TBBPA chronic exposure produces sex-specific neurobehavioral and social interaction changes in adult zebrafish. AB - The toxicity of tetrabromobisphenol A (TBBPA) has been extensively studied because of its high production volume. TBBPA is toxic to aquatic fish based on acute high concentration exposure tests, and few studies have assessed the behavioral effects of low concentration chronic TBBPA exposures in aquatic organisms. The present study defined the developmental and neurobehavioral effects associated with exposure of zebrafish to 0, 5 and 50nM TBBPA during 1 120days post-fertilization (dpf) following by detoxification for four months before the behaviors assessment. These low concentration TBBPA exposures were not associated with malformations and did not alter sex ratio, but resulted in reduced zebrafish body weight and length. Adult behavioral assays indicated that TBBPA exposed males had significantly higher average swim speeds and spent significantly more time in high speed darting mode and less time in medium cruising mode compared to control males. In an adult photomotor response assay, TBBPA exposure was associated with hyperactivity in male fish. Female zebrafish responses in these assays followed a similar trend, but the magnitude of TBBPA effects was generally smaller than in males. Social interaction evaluated using a mirror attack test showed that 50nM TBBPA exposed males had heightened aggression. Females exposed to 50nM TBBPA spent more time in the vicinity of the mirror, but did not show increased aggression toward the mirror compared to unexposed control fish. Overall, the hyperactivity and social behavior deficits ascribed here to chronic TBBPA exposure was most profound in males. Our findings indicate that TBBPA can cause developmental and neurobehavioral deficits, and may pose significant health risk to humans. PMID- 27221229 TI - Minimal number of runs and the sequential scheme for local discrimination between special unitary operations. AB - It has been shown that any two different multipartite unitary operations are perfectly distinguishable by local operations and classical communication with a finite number of runs. Meanwhile, two open questions were left. One is how to determine the minimal number of runs needed for the local discrimination, and the other is whether a perfect local discrimination can be achieved by merely a sequential scheme. In this paper, we answer the two questions for some unitary operations U1 and U2 with locally unitary equivalent to a diagonal unitary matrix in a product basis. Specifically, we give the minimal number of runs needed for the local discrimination, which is the same with that needed for the global discrimination. In this sense, the local operation works the same with the global one. Moreover, when adding the local property to U1 or U2, we present that the perfect local discrimination can be also realized by merely a sequential scheme with the minimal number of runs. Both results contribute to saving the resources used for the discrimination. PMID- 27221230 TI - [Arthroscopically assisted osteosynthesis of intraarticular distal radius fractures]. AB - OBJECTIVE: Anatomical reconstruction of the distal radius after intra-articular fractures with special consideration of the articular surface and treatment of concomitant ligament injuries. INDICATIONS: Intra-articular distal radius fractures in adults under 65 years of age. CONTRAINDICATIONS: Osteoporotic deterioration of metaphyseal bone, radiocarpal fracture dislocation and open fractures. SURGICAL TECHNIQUE: Conventional palmar approach for plate fixation of the fracture with a fixed angle locking plate. Arthroscopy of the wrist is performed for reduction of the articular fracture component using the standard 3 4 and 6R portals. Following temporary Kirschner (K) wire fixation of the fracture, angle stable locking screws are inserted into the most distal portion of the plate. Finally, the intercarpal ligaments and the triangular fibrocartilage complex (TFCC) are checked for concomitant lesions and if necessary subsequent treatment within the same operation. POSTOPERATIVE MANAGEMENT: Plaster cast fixation for 4 weeks followed by a physiotherapy program. RESULTS: After arthroscopically assisted reduction of an intra-articular distal radius fracture, 17 out of the 23 patients were available for follow-up examination an average of 31 months after the procedure. The mean disabilities of the arm, shoulder and hand (DASH) score was 4.9 and the mean patient-rated wrist evaluation (PRWE) score was 6.0 at final follow-up. Except for wrist flexion, an active range of motion at the wrist as well as forearm rotation of more than 90 % was achieved compared with the uninjured contralateral side. Grip strength averaged 96 % compared with the contralateral side and pain levels under stress varied between 1 and 3 on a visual analog scale (range 0-10). PMID- 27221231 TI - Allograft augmentation in proximal humerus fractures. AB - OBJECTIVE: Achieve stable fixation to initially start full range of motion (ROM) and to prevent secondary displacement in unstable fracture patterns and/or weak and osteoporotic bone. INDICATIONS: (Secondarily) displaced proximal humerus fractures (PHF) with an unstable medial hinge and substantial bony deficiency, weak/osteoporotic bone, pre-existing psychiatric illnesses or patient incompliance to obey instructions. CONTRAINDICATIONS: Open/contaminated fractures, systemic immunodeficiency, prior graft-versus-host reaction. SURGICAL TECHNIQUE: Deltopectoral approach. Identification of the rotator cuff. Disimpaction and reduction of the fracture, preparation of the situs. Graft preparation. Allografting. Fracture closure. Plate attachment. Definitive plate fixation. Radiological documentation. Postoperative shoulder fixation (sling). POSTOPERATIVE MANAGEMENT: Cryotherapy, anti-inflammatory medication on demand. Shoulder sling for comfort. Full active physical therapy as tolerated without pain. Postoperative radiographs (anteroposterior, outlet, and axial [as tolerated] views) and clinical follow-up after 6 weeks and 3, 6, and 12 months. RESULTS: Bony union and allograft incorporation in 9 of 10 noncompliant, high risk patients (median age 63 years) after a mean follow-up of 28.5 months. The median Constant-Murley Score was 72.0 (range 45-86). Compared to the uninjured contralateral side, flexion was impaired by 13 %, abduction by 14 %, and external rotation by 15 %. Mean correction of the initial varus displacement was 38 degrees (51 degrees preoperatively to 13 degrees postoperatively). PMID- 27221232 TI - First trimester trophoblasts forming endothelial-like tubes in vitro emulate a 'blood vessel development' gene expression profile. AB - Extravillous cytotrophoblasts isolated from first trimester placenta, and immortalised cell lines derived from them, have the intrinsic ability to form endothelial-like tubes when cultured on MatrigelTM extracellular matrix. This in vitro tube formation may model placental angiogenesis and/or endovascular differentiation by trophoblasts. To interpret the relevance of this phenomenon to placental development, we used a gene expression microarray approach to identify which genes and pathways are associated with the tube-forming phenotype of HTR8/SVneo first trimester trophoblasts (HTR8-M), compared with HTR8/SVneo not forming tubes on plastic culture surface (HTR8-P). Furthermore, we used weighted gene co-expression network analysis (WGCNA) of microarray data to identify modules of co-expressed genes underlying the biological processes. There were 481 genes differentially expressed between HTR8-M and HTR8-P and these were significantly enriched for blood vessel development and related gene ontologies. WGCNA clustered the genes into 9 co-expression modules. One module was significantly associated with HTR8-M (p = 1.15E-05) and contained genes involved in actin cytoskeleton organization, cell migration and blood vessel development, consistent with tube formation on Matrigel. Another module was significantly associated with HTR8-P (p = 1.94E-05) and was enriched for genes involved in mitosis, consistent with proliferation by cells on plastic which do not differentiate. Up-regulation of angiogenesis and vascular development pathways in endovascular trophoblasts in vivo could underpin spiral artery remodelling processes, which are defective in preeclamptic pregnancies. PMID- 27221234 TI - Selected benign cutaneous lesions that may simulate melanoma histologically. AB - As cutaneous melanomas manifest a wide spectrum of clinical and pathologic presentations, several other lesions enter into their differential diagnosis. This article considers those entities, including melanocytic hyperplasia, cellular nodules in congenital nevi, atypical lentiginous melanocytic proliferations, "special site" nevi, epithelioid histiocytoma, neurothekeoma, cellular schwannoma, and proliferating scars. PMID- 27221233 TI - Recent tissue engineering-based advances for effective rAAV-mediated gene transfer in the musculoskeletal system. AB - Musculoskeletal tissues are diverse and significantly different in their ability to repair upon injury. Current treatments often fail to reproduce the natural functions of the native tissue, leading to an imperfect healing. Gene therapy might improve the repair of tissues by providing a temporarily and spatially defined expression of the therapeutic gene(s) at the site of the injury. Several gene transfer vehicles have been developed to modify various human cells and tissues from musculoskeletal system among which the non-pathogenic, effective, and relatively safe recombinant adeno-associated viral (rAAV) vectors that have emerged as the preferred gene delivery system to treat human disorders. Adapting tissue engineering platforms to gene transfer approaches mediated by rAAV vectors is an attractive tool to circumvent both the limitations of the current therapeutic options to promote an effective healing of the tissue and the natural obstacles from these clinically adapted vectors to achieve an efficient and durable gene expression of the therapeutic sequences within the lesions. PMID- 27221235 TI - Floral traits influence pollen vectors' choices in higher elevation communities in the Himalaya-Hengduan Mountains. AB - BACKGROUND: How floral traits and community composition influence plant specialization is poorly understood and the existing evidence is restricted to regions where plant diversity is low. Here, we assessed whether plant specialization varied among four species-rich subalpine/alpine communities on the Yulong Mountain, SW China (elevation from 2725 to 3910 m). We analyzed two factors (floral traits and pollen vector community composition: richness and density) to determine the degree of plant specialization across 101 plant species in all four communities. Floral visitors were collected and pollen load analyses were conducted to identify and define pollen vectors. Plant specialization of each species was described by using both pollen vector diversity (Shannon's diversity index) and plant selectiveness (d' index), which reflected how selective a given species was relative to available pollen vectors. RESULTS: Pollen vector diversity tended to be higher in communities at lower elevations, while plant selectiveness was significantly lower in a community with the highest proportion of unspecialized flowers (open flowers and clusters of flowers in open inflorescences). In particular, we found that plant species with large and unspecialized flowers attracted a greater diversity of pollen vectors and showed higher selectiveness in their use of pollen vectors. Plant species with large floral displays and high flower abundance were more selective in their exploitation of pollen vectors. Moreover, there was a negative relationship between plant selectiveness and pollen vector density. CONCLUSIONS: These findings suggest that flower shape and flower size can increase pollen vector diversity but they also increased plant selectiveness. This indicated that those floral traits that were more attractive to insects increased the diversity of pollen vectors to plants while decreasing overlap among co-blooming plant species for the same pollen vectors. Furthermore, floral traits had a more important impact on the diversity of pollen vectors than the composition of anthophilous insect communities. Plant selectiveness of pollen vectors was strongly influenced by both floral traits and insect community composition. These findings provide a basis for a better understanding of how floral traits and community context shape interactions between flowers and their pollen vectors in species-rich communities. PMID- 27221236 TI - Separation of collagen-bound and porous bone-water longitudinal relaxation in mice using a segmented inversion recovery zero-echo-time sequence. AB - PURPOSE: Cortical bone mechanical properties are related to the collagen-bound water (CBW) and pore water (PW) components of cortical bone. The study evaluates the feasibility of zero-echo-time imaging in mice in vivo for longitudinal relaxation time (T1) measurements in cortical bone and separation of CBW and PW components. METHODS: Zero-echo-time data were acquired at 4.7 Tesla in six mice with 14 different inversion times (0-2,600 ms). Region-of-interest analysis was performed at level of femur diaphysis. The T1 of cortical bone and of CBW (T1cbw) and PW (T1pw) as well as the CBW fraction (cbwf) was computed using a mono exponential and a bi-exponential fitting approach, respectively. The sum of the squared residuals (Res) to the fit was provided for both approaches. RESULTS: For the mono-exponential model, mean T1 +/- standard deviation (SD) was 1,057 +/- 160 ms. The bi-exponential approach provided a reliable separation of two different bone-water components, with a mean T1cbw of 213 +/- 95 ms, T1pw of 2,152 +/- 894 ms, and cbwf of 7.4 +/- 2.7 %. Lower Res was obtained with bi-exponential approach (P < 0.001), and Res mean values +/- SD were 0.016 +/- 0.007 (bi exponential) and 0.033 +/- 0.016 (mono-exponential). CONCLUSION: Zero-echo-time imaging allows for longitudinal relaxation measurements of cortical bone in vivo in mice models, with a reliable separation of PW and CBW components using a bi exponential curve fitting approach. Magn Reson Med 77:1909-1915, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27221237 TI - A multi-faceted intervention including antenatal corticosteroids to reduce neonatal mortality associated with preterm birth: a case study from the Guatemalan Western Highlands. AB - BACKGROUND: The Global Network for Women's and Children's Health Research undertook a cluster-randomized trial to assess the impact of a multi-faceted intervention to identify women at high-risk of preterm birth at all levels of care, to administer corticosteroids to women and refer for facility delivery compared with standard care. Of the seven sites that participated in the ACT trial, only two sites had statistically significant reductions in the neonatal mortality among the target group of <5th percentile infants, and of the two, Guatemala's improvement in neonatal mortality was by far the largest. METHODS: We used data available from the ACT trial as well as pretrial data in an attempt to understand why neonatal mortality may have decreased in the intervention clusters in <5(th) percentile infants in Chimaltenango, Guatemala. The intervention and control clusters were compared in regards to ACS use, the various types of medical care, outcomes in facility and community births and among births in various birth weight categories. RESULTS: Neonatal mortality decreased to a greater extent in the intervention compared to the control clusters in the <5(th) percentile infants in Guatemala during the ACT Trial. ACS use for the <5(th) percentile infants in the intervention clusters was 49.1 % compared to 13.8 % in the control clusters. Many measures of the quality of obstetric and neonatal care improved to a greater extent in the intervention compared to the control clusters during the trial. Births in facilities and births weighing 1500 to 2500 g had the greatest reduction in neonatal mortality. CONCLUSIONS: The combination of improved care and greater ACS use may potentially account for the observed difference in neonatal mortality between the intervention and control clusters. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01084096 . PMID- 27221239 TI - On the fixed parameter tractability of agreement-based phylogenetic distances. AB - Three important and related measures for summarizing the dissimilarity in phylogenetic trees are the minimum number of hybridization events required to fit two phylogenetic trees onto a single phylogenetic network (the hybridization number), the (rooted) subtree prune and regraft distance (the rSPR distance) and the tree bisection and reconnection distance (the TBR distance) between two phylogenetic trees. The respective problems of computing these measures are known to be NP-hard, but also fixed-parameter tractable in their respective natural parameters. This means that, while they are hard to compute in general, for cases in which a parameter (here the hybridization number and rSPR/TBR distance, respectively) is small, the problem can be solved efficiently even for large input trees. Here, we present new analyses showing that the use of the "cluster reduction" rule-already defined for the hybridization number and the rSPR distance and introduced here for the TBR distance-can transform any [Formula: see text]-time algorithm for any of these problems into an [Formula: see text]-time one, where n is the number of leaves of the phylogenetic trees, p is the natural parameter and k is a much stronger (that is, smaller) parameter: the minimum level of a phylogenetic network displaying both trees. PMID- 27221238 TI - Human papillomavirus infection in Rwanda at the moment of implementation of a national HPV vaccination programme. AB - BACKGROUND: Cervical cancer is the most common female cancer in Rwanda that, in 2011, became the first African country to implement a national vaccination programme against human papillomavirus (HPV). METHODS: To provide a robust baseline for future evaluations of vaccine effectiveness, cervical cell specimens were obtained from 2508 women aged 18-69 years from the general population in Kigali, Rwanda, during 2013/14. 20 % of women were HIV-positive. Samples were used for liquid-based cytology and HPV testing (44 types) with GP5+/6+ PCR. RESULTS: HPV prevalence was 34 %, being highest (54 %) in women <=19 years and decreasing to 20 % at age >=50. Prevalence of high risk (HR) HPV and cytological abnormalities was 22 and 11 % respectively (including 2 % with high-grade squamous intraepithelial lesions, HSIL) decreasing with age. Age-standardised prevalence of HR HPV was 22 % (or 19 % among HIV-negative women), and HPV16 was the most common type. Prevalence of HPV and cytological abnormalities were significantly higher in HIV-positive than HIV-negative women, and the difference increased with age. Other significant risk factors for HPV positivity in multivariate analyses were high lifetime number of sexual partners, receiving cash for sex, and being a farmer. 40 % of women with HSIL were infected with HPV16/18 and there was no significant difference between HIV-positive and HIV negative women. CONCLUSIONS: This study confirms Rwanda to be a setting of high prevalence of HPV and cervical disease that is worsened by HIV. These data will serve as a robust baseline for future evaluations of HPV vaccine programme effectiveness. PMID- 27221240 TI - The Broselow and Handtevy Resuscitation Tapes: A Comparison of the Performance of Pediatric Weight Prediction. AB - OBJECTIVES: To assess the performance of two pediatric length-based tapes (Broselow and Handtevy) in predicting actual weights of US children. METHODS: In this descriptive study, weights and lengths of children (newborn through 13 years of age) were extracted from the 2009-2010 National Health and Nutrition Examination Survey (NHANES). Using the measured length ranges for each tape and the NHANES-extracted length data, every case from the study sample was coded into Broselow and Handtevy zones. Mean weights were calculated for each zone and compared to the predicted Broselow and Handtevy weights using measures of bias, precision, and accuracy. A sub-sample was examined that excluded cases with body mass index (BMI)>=95th percentile. Weights of children longer than each tape also were examined. RESULTS: A total of 3,018 cases from the NHANES database met criteria. Although both tapes underestimated children's weight, the Broselow tape outperformed the Handtevy tape across most length ranges in measures of bias, precision, and accuracy of predicted weights relative to actual weights. Accuracy was higher in the Broselow tape for shorter children and in the Handtevy tape for taller children. Among the sub-sample with cases of BMI>=95th percentile removed, performance of the Handtevy tape improved, yet the Broselow tape still performed better. When assessing the weights of children who were longer than either tape, the actual mean weights did not approximate adult weights; although, those exceeding the Handtevy tape were closer. CONCLUSIONS: For pediatric weight estimation, the Broselow tape performed better overall than the Handtevy tape and more closely approximated actual weight. Lowe CG , Campwala RT , Ziv N , Wang VJ . The Broselow and Handtevy resuscitation tapes: a comparison of the performance of pediatric weight prediction. Prehosp Disaster Med. 2016;31(4):364-375. PMID- 27221241 TI - Dealloying-based facile synthesis and highly catalytic properties of Au core/porous shell nanoparticles. AB - Porous nanostructures exhibit excellent catalytic properties due to high surface to-volume ratio, good surface reactivity and various structural features, but controlling the distribution, size, shape and density of pores and structural features of these particles is highly challenging. Herein, we report a tunable dealloying-based facile synthetic strategy to form highly porous Au core/porous shell nanoparticles (CPS NPs) in high yield by selectively dissolving Ag atoms from Au/Au-Ag core/alloy shell NPs. The CPS NPs exhibit a very short induction time, high conversion rate constant, low activation energy and high turnover frequency due to their catalytically active porous shells containing networked thin ligaments, surface defects, ultra-high porosity and photothermal properties. The CPS NPs are more catalytic Au NPs than other reported Au nanostructures, and the strategy and results open avenues in porous nanostructures and nanocatalysts. PMID- 27221242 TI - Effects of genotype and stocking density on broiler performance under three feeding regimes. AB - Ross 308 and Cobb Avian 48 broilers were used in a 49-day study. The effects of genotype, stocking density, and limited-time feeding on growth performance and carcass characteristics were investigated. Overall, Ross consumed more feed, gained more body weight, and was heavier at marketing age than Cobb. Ross also had a higher drumstick percentage, but the percentages of the other carcass parts were similar in the two genotypes. Birds reared at the stocking density of 30 kg BW/m(2) gained more body weight and were heavier at marketing than those raised at 40 kg BW/m(2), but both groups consumed similar quantities of feed and had similar carcass percentages. Neither genotype nor stocking density influenced feed conversion ratio and mortality rate, but genotype x stocking density interaction significantly affected feed consumption and mortality rate. The feed restricted birds consumed less feed, gained less weight, were lighter at market age, and had lower percentages of breast, neck, and heart than the full-fed birds. Feed restriction also significantly lowered mortality rate but had insignificant effects on feed conversion ratio and percentages of carcass, breast, back, drumstick, neck, wing, gizzard, heart, liver, and abdominal fat. For profitable poultry production in the tropics and subtropics, it is recommended that Ross 308 raised at the stocking density of 30 kg BW/m(2) and subjected to 10-h daily feed removal from 7 to 35 days of age in a 49-day production period be considered. PMID- 27221243 TI - Interleukin 27 is up-regulated in patients with active inflammatory bowel disease. AB - The aim of the study was to characterize and quantify tissue gene and protein expression of IL-27 in ulcerative colitis (UC) and Crohn's disease (CD) patients. This is an observational and cross-sectional study. Fifty-four patients with IBD were studied: 27 active UC, 12 inactive UC, 10 active CD, and 5 inactive CD. All patients belonged to the Inflammatory Bowel Disease Clinic at the Instituto Nacional de Ciencias Medicas y Nutricion. We found that IL-27 gene expression was significantly higher in active UC versus inactive UC group (P = 0.015). The IL-27 mRNA expression was increased in patients with active CD compared with inactive CD disease (P = 0.035). The percentage of IL-27 immunoreactive cells was higher in active UC versus active CD patients and non-inflamed tissue controls. The IL 27 was significantly elevated in active UC and CD patients, and it was associated with disease severity. PMID- 27221244 TI - Magnetic resonance advection imaging of cerebrovascular pulse dynamics. AB - We analyze the pulsatile signal component of dynamic echo planar imaging data from the brain by modeling the dependence between local temporal and spatial signal variability. The resulting magnetic resonance advection imaging maps depict the location of major arteries. Color direction maps allow for visualization of the direction of blood vessels. The potential significance of magnetic resonance advection imaging maps is demonstrated on a functional magnetic resonance imaging data set of 19 healthy subjects. A comparison with the here introduced pulse coherence maps, in which the echo planar imaging signal is correlated with a cardiac pulse signal, shows that the magnetic resonance advection imaging approach results in a better spatial definition without the need for a pulse reference. In addition, it is shown that magnetic resonance advection imaging velocities can be estimates of pulse wave velocities if certain requirements are met, which are specified. Although for this application magnetic resonance advection imaging velocities are not quantitative estimates of pulse wave velocities, they clearly depict local pulsatile dynamics. Magnetic resonance advection imaging can be applied to existing dynamic echo planar imaging data sets with sufficient spatiotemporal resolution. It is discussed whether magnetic resonance advection imaging might have the potential to evolve into a biomarker for the health of the cerebrovascular system. PMID- 27221245 TI - Effect of KiFAY on Performance, Insulin-like Growth Factor-1, and Thyroid Hormones in Broilers. AB - A comparative study was performed to investigate the efficacy of KiFAY as a feed additive on performance parameters, thyroid, and pancreatic hormone levels in broilers. Ninety birds (Vencobb 400) were randomly divided into three groups viz., Control (no DL-methionine supplementation), Treatment1 (containing added DL methionine) and Treatment 2 (containing KiFAY and without DL-methionine supplementation). The performance parameters (weekly body weight, body weight gain, feed intake, and feed consumption ratio) were recorded and calculated during the whole study of 4 weeks. Analyses of insulin and insulin-like growth factor (IGF 1), triiodothyronine (T3), thyroxine (T4) and thyroid stimulating hormone (TSH) were performed at the end of the study. The results show that birds on supplementation of KiFAY performed significantly (p<0.001) better than other treatments. The weekly body weight, body weight gain, feed in-take and feed consumption ratio improved in KiFAY treated birds. The study found an increase in insulin and IGF1 levels (p<0.001) in KiFAY compared with the other treatments. Serum T3, T4, and TSH levels in the Treatment 2 were higher than other treatments (p<0.001). The KiFAY supplementation was able to improve performance with associated responses at a hormonal level in broilers. PMID- 27221246 TI - A whole genome association study to detect additive and dominant single nucleotide polymorphisms for growth and carcass traits in Korean native cattle, Hanwoo. AB - OBJECTIVE: A whole genome association study was conducted to identify single nucleotide polymorphisms (SNPs) with additive and dominant effects for growth and carcass traits in Korean native cattle, Hanwoo. METHODS: The data set comprised 61 sires and their 486 Hanwoo steers that were born between spring of 2005 and fall of 2007. The steers were genotyped with the 35,968 SNPs that were embedded in the Illumina bovine SNP 50K beadchip and six growth and carcass quality traits were measured for the steers. A series of lack-of-fit tests between the models was applied to classify gene expression pattern as additive or dominant. RESULTS: A total of 18 (0), 15 (3), 12 (8), 15 (18), 11 (7), and 21 (1) SNPs were detected at the 5% chromosome (genome) - wise level for weaning weight (WWT), yearling weight (YWT), carcass weight (CWT), backfat thickness (BFT), longissimus dorsi muscle area (LMA) and marbling score, respectively. Among the significant 129 SNPs, 56 SNPs had additive effects, 20 SNPs dominance effects, and 53 SNPs both additive and dominance effects, suggesting that dominance inheritance mode be considered in genetic improvement for growth and carcass quality in Hanwoo. The significant SNPs were located at 33 quantitative trait locus (QTL) regions on 18 Bos Taurus chromosomes (i.e. BTA 3, 4, 5, 6, 7, 9, 11, 12, 13, 14, 16, 17, 18, 20, 23, 26, 28, and 29) were detected. There is strong evidence that BTA14 is the key chromosome affecting CWT. Also, BTA20 is the key chromosome for almost all traits measured (WWT, YWT, LMA). CONCLUSION: The application of various additive and dominance SNP models enabled better characterization of SNP inheritance mode for growth and carcass quality traits in Hanwoo, and many of the detected SNPs or QTL had dominance effects, suggesting that dominance be considered for the whole genome SNPs data and implementation of successive molecular breeding schemes in Hanwoo. PMID- 27221247 TI - Choline supplementation improves the lipid metabolism of intrauterine-growth restricted pigs. AB - OBJECTIVE: The objective of this study was to investigate the effects of dietary choline supplementation on hepatic lipid metabolism and gene expression in finishing pigs with intrauterine growth retardation (IUGR). METHODS: Using a 2*2 factorial design, eight normal birth weight (NBW) and eight IUGR weaned pigs were fed either a basal diet (NBW pigs fed a basal diet, NC; IUGR pigs fed a basal diet, IC) or a diet supplemented with two times more choline than the basal diet (NBW pigs fed a high-choline diet, NH; IUGR pigs fed a high-choline diet, IH) until 200 d of age. RESULTS: The results showed that the IUGR pigs had reduced body weight compared with the NBW pigs (p<0.05 from birth to d 120; p = 0.07 from d 120 to 200). Increased (p<0.05) free fatty acid (FFA) and triglyceride levels were observed in the IUGR pigs compared with the NBW pigs. Choline supplementation decreased (p<0.05) the levels of FFAs and triglycerides in the serum of the pigs. The activities of malate dehydrogenase and glucose 6-phosphate dehydrogenase were both increased (p<0.05) in the livers of the IUGR pigs. Choline supplementation decreased (p<0.05) malate dehydrogenase activity in the liver of the pigs. Gene expression of fatty acid synthase (FAS) was higher (p<0.05) in the IC group than in the other groups, and choline supplementation decreased (p<0.05) FAS and acetyl-CoA carboxylase alpha expression in the livers of the IUGR pigs. The expression of carnitine palmitoyl transferase 1A (CPT1A) was lower (p<0.05) in the IC group than in the other groups, and choline supplementation increased (p<0.05) the expression of CPT1A in the liver of the IUGR pigs and decreased (p<0.01) the expression of hormone-sensitive lipase in both types of pigs. The gene expression of phosphatidylethanolamine N methyltransferase (PEMT) was higher (p<0.05) in the IC group than in the other groups, and choline supplementation significantly reduced (p<0.05) PEMT expression in the liver of the IUGR pigs. CONCLUSION: In conclusion, the lipid metabolism was abnormal in IUGR pigs, but the IUGR pigs consuming twice the normal level of choline had improved circulating lipid parameters, which could be related to the decreased activity of nicotinamide adenine dinucleotide phosphate generating enzymes or the altered expressions of lipid metabolism-related genes. PMID- 27221248 TI - Effects of Combining Feed Grade Urea and a Slow-release Urea Product on Performance, Dietary Energetics and Carcass Characteristics of Feedlot Lambs Fed Finishing Diets with Different Starch to Acid Detergent Fiber Ratios. AB - Recent findings have shown that microbial nitrogen flow and digestible energy of diets are increased when urea is combined with a slow-release urea (SRU) in diets with a starch to acid detergent fibre ratio (S:F) 4:1. This affect is attributable to enhanced synchrony between ruminal N availability for microbial growth and carbohydrate degradation. To verify the magnitude of this effects on lamb performance, an experiment was conducted to evaluate the effects of combining urea and a SRU in diets containing S:F ratios of 3:1, 4:1, or 5:1 on performance, dietary energetics and carcass characteristics of finishing lambs. For that, 40 Pelibuey*Katahdin lambs (36.65+/-3 kg) were assigned to one of five weight groupings in 20 pens (5 repetition/treatments). The S:F ratio in the diet was manipulated by partially replacing the corn grain and dried distiller's grain with solubles by forage (wheat straw) and soybean meal to reach S:F ratios of 3:1, 4:1 or 5:1. An additional treatment of 4:1 S:F ratio with 0.8% urea as the sole source of non-protein nitrogen was used as a reference for comparing the effect of urea combination vs. conventional urea at the same S:F ratio. There were no treatment effects on dry matter intake (DMI). Compared the urea combination vs urea at the same S:F ratio, urea combination increased (p<0.01) average daily gain (ADG, 18.3%), gain for feed (G:F, 9.5%), and apparent energy retention per unit DMI (8.2%). Irrespective of the S:F ratio, the urea combination improved the observed-to-expected dietary ratio and apparent retention per unit DMI was maximal (quadratic effect, p<=0.03) at an S:F ratio of 4:1, while the conventional urea treatment did not modify the observed-to expected net energy ratio nor the apparent retention per unit DMI at 4:1 S:F ratio. Urea combination group tended (3.8%, p = 0.08) to have heavier carcasses with no effects on the rest of carcass characteristics. As S:F ratio increased, ADG, G:F, dietary net energy, carcass weight, dressing percentage and longissimus thoracis (LM) area increased linearly (p<=0.02). Combining urea and a slow release urea product results in positive effects on growth performance and dietary energetics, but the best responses are apparently observed when there is a certain proportion (S:F ratio = 4:1) of starch to acid detergent fibre in the diet. PMID- 27221249 TI - Effects of four dim vs high intensity red color light regimens on growth performance and welfare of broilers. AB - OBJECTIVE: Broilers show clear preference towards red color light (RL). However setting of an optimum light intensity is difficult since dim intensities that favor growth reduce welfare. This experiment was conducted to test the most effective RL intensity regimen (Dim [5 lux; DI] vs high [320 lux; HI]) in combination applied at different growth stages that favors for both performance and welfare. METHODS: Complete randomize design was adopted with 6 replicates. Treatments were; T1 = early DI (8-21 d)+latter HI (22-35 d); T2 = early DI (8-28 d)+latter HI (29-35 d), T3 = early HI (8-21 d)+latter DI (22-35 d), T4 = early HI (8-28 d)+latter DI (29-35 d) and T5 = control (white light; WT) (8-35 d) at medium intensity (20 lux). Body weight (BW), weight gain (WG), water/feed intake and ratio, feed conversion ratios (FCR) were assessed. Common behaviours (15) were recorded by scan sampling method. Lameness, foot pad dermatitis, breast blisters, hock burning damage were assessed as welfare parameters. Fear reactions were tested using Tonic Immobility Test. Ocular and carcass evaluations were done. Meat and tibiae were analyzed for fat and bone ash respectively. RESULTS: On 35 d, the highest BW (2,155.72+/-176 g), WG (1,967.78+/-174 g) were recorded by T2 compared to WT (BWWT = 1,878.22+/-155, WGWT = 1,691.83+/-160). But, application of RL, either DI, or HI during early/latter stage had no significant effect on FCR. Under HI, birds showed much higher active behaviours. DI encourages eating. Though LI changed from DI to HI, same trend could be seen even under HI. The highest leg strength (218.5+/-120 s) was recorded by T2. The lowest leg strength (64.58+/-33 s) and the highest ocular weight (2.48+/-1 g) were recorded by T1. Significantly (p<0.05) the highest skin weight (162.17+/-6 g) but the lowest fat% in meat (13.03%+/-5%) was recorded by T2. CONCLUSION: Early exposure to DI-RL up to 28 days followed by exposure to HI-RL is the most favorable lighting regimen for optimizing production, better welfare of broilers and improving health benefits of meat. PMID- 27221250 TI - Effect of feeding tamarind kernel powder extract residue on digestibility, nitrogen availability and ruminal fermentation in wethers. AB - OBJECTIVE: This study was to examine in vivo digestibility, nitrogen balance and ruminal fermentation of tamarind (Tamarind indica) kernel powder extract residue (TKPER) compared to soybean products and by-products in wethers. METHODS: Four wethers with initial body weight (BW) of 51.6+/-5.5 kg were assigned in a 4*4 Latin square design to investigate nutritional characteristics of TKPER, dry heat soybean (SB), dry soybean curd residue (SBCR) and soybean meal (SBM) feeding with ryegrass straw (R) at a ratio of 1:1 at 2% of BW in dry matter (DM) on a daily basis. RESULTS: The digestibility of DM, crude protein, and ether extract (EE) of TKPER-R diet were 57.0%, 87.0%, and 86.0%, respectively. Higher non-fiber carbohydrates digestibility was observed in TKPER-R diet (83.2%) than in SB-R diet (73.9%, p<0.05). Wethers fed the TKPER-R diet had lower retention of nitrogen (N) and ruminal ammonia nitrogen (NH3-N) contents at 4 h after feeding than those fed the SBM-R diet (p<0.05), which had values similar to the SB-R or SBCR-R diet. The TKPER feeding had higher propionate (C3) and lower butyrate content, as well as lower acetate to propionate ratio (C2:C3) in rumen fluid than SBM feeding at 4 h after feeding (p<0.05). CONCLUSION: TKPER did not bring any side effect to the wethers although it was lack of fiber, and could be used as a high protein and energy ingredient in concentrate with appropriate roughage to meet the fiber requirement for ruminants. PMID- 27221251 TI - Changes in expression of monocarboxylate transporters, heat shock proteins and meat quality of Large White Yorkshire and Ghungroo pigs during hot summer period. AB - OBJECTIVE: Present study explores the effect of hot summer period on the glycolytic rate of early post-mortem meat quality of Ghungroo and Large White Yorkshire (LWY) pig and comparative adaptability to high temperature between above breeds by shifting the expression of stress related genes like mono carboxylate transporters (MCTs) and heat shock proteins (HSPs). METHODS: Healthy pigs of two different breeds, viz., LYW and Ghungroo (20 from each) were maintained during hot summer period (May to June) with a mean temperature of about 38 degrees C. The pigs were slaughtered and meat samples from the longissimus dorsi (LD) muscles were analyzed for pH, glycogen and lactate content and mRNA expression. Following 24 h of chilling, LD muscle was also taken from the carcasses to evaluate protein solubility and different meat quality measurements. RESULTS: LWY exhibited significantly (p<0.01) higher plasma cortisol and lactate dehydrogenase concentration than Ghungroo indicating their higher sensitivity to high temperature. LD muscle from LWY pigs revealed lower initial and ultimate pH values and higher drip loss compared to Ghungroo, indicating a faster rate of pH fall. LD muscle of Ghungroo had significantly lower lactate content at 45 min postmortem indicating normal postmortem glycolysis and much slower glycolytic rate at early postmortem. LD muscle of LWY showed rapid postmortem glycolysis, higher drip loss and higher degrees of protein denaturation. Ghungroo exhibited slightly better water holding capacity, lower cooking loss and higher protein solubility. All HSPs (HSP27, HSP70, and HSP90) and MCTs (MCT1, MCT2, and MCT4) in the LD muscle of pigs inclined to increase more in Ghungroo than LWY when exposed to high temperature. CONCLUSION: Effect of high temperature on the variation of HSPs and MCTs may play a crucial role in thermal tolerance and adaptation to different climatic conditions, pH regulation, muscle acidification, drip loss, protein denaturation and also in postmortem meat quality development. PMID- 27221252 TI - Effects of 20-day litter weight on weaned piglets' fighting behavior after group mixing and on heart rate variability in an isolation test. AB - OBJECTIVE: The objective of this study was to investigate the effect of 20-day litter weight on behavior and heart rate variability (HRV) of piglets under stress. METHODS: Forty four original litters were categorized as high litter weight (HW) litters (n = 22) and low litter weight (LW) litters (n = 22) by 20 day litter weight. From each original HW litter, three males and three females were randomly selected after weaning and the 12 piglets from two original litters with similar age of days were regrouped into one new high litter weight (NHW) litter (11 NHW litters in total). The original LW litters were treated with a same program, so that there were 11 new low litter weight (NLW) litters as well. The latencies to first fighting, fighting frequencies and duration within three hours were recorded after regrouping and the lesions on body surface within 48 hours were scored. Besides, HR (heart rate, bpm, beats per minute) and activity count (ACT), time domain indexes and frequency domain indexes of the piglets were measured in an isolation trial to analyze the discrepancy in coping with stress between the original HW and LW litters. RESULTS: The results exhibited that piglets from the HW litters launched fighting sooner and got statistically higher skin lesion score than those from the LW litters (p = 0.03 and 0.02, respectively). Regarding the HRV detection, compared with the HW litters, the LW litters exhibited a lower mean HR (p<0.05). In the isolation test, a highly significant higher ACT value was observed between the HW litters, compared to the LW litters (p<0.01). Significant differences were observed in standard deviation of R-R intervals, standard deviation of all normal to normal intervals, and most frequency-domain indicators: very low-frequency, low-frequency, and high frequency between the HW and LW litters as well. The difference in LF:HF was not significant (p = 0.779). CONCLUSION: This study suggests that compared with litters of low 20-day litter weights, litters with higher 20-day litter weight take more positive strategies to cope with stress and have stronger HRV regulation capacity; HW litters demonstrate better anti-stress and adaptation capacity in the case of regrouping and isolation. PMID- 27221253 TI - Neural Activations of Guided Imagery and Music in Negative Emotional Processing: A Functional MRI Study. AB - BACKGROUND: The Bonny Method of Guided Imagery and Music uses music and imagery to access and explore personal emotions associated with episodic memories. Understanding the neural mechanism of guided imagery and music (GIM) as combined stimuli for emotional processing informs clinical application. OBJECTIVE: We performed functional magnetic resonance imaging (fMRI) to demonstrate neural mechanisms of GIM for negative emotional processing when personal episodic memory is recalled and re-experienced through GIM processes. METHODS: Twenty-four healthy volunteers participated in the study, which used classical music and verbal instruction stimuli to evoke negative emotions. To analyze the neural mechanism, activated regions associated with negative emotional and episodic memory processing were extracted by conducting volume analyses for the contrast between GIM and guided imagery (GI) or music (M). RESULTS: The GIM stimuli showed increased activation over the M-only stimuli in five neural regions associated with negative emotional and episodic memory processing, including the left amygdala, left anterior cingulate gyrus, left insula, bilateral culmen, and left angular gyrus (AG). Compared with GI alone, GIM showed increased activation in three regions associated with episodic memory processing in the emotional context, including the right posterior cingulate gyrus, bilateral parahippocampal gyrus, and AG. No neural regions related to negative emotional and episodic memory processing showed more activation for M and GI than for GIM. CONCLUSIONS: As a combined multimodal stimulus, GIM may increase neural activations related to negative emotions and episodic memory processing. Findings suggest a neural basis for GIM with personal episodic memories affecting cortical and subcortical structures and functions. PMID- 27221254 TI - Attitudes of Primary Care Health Workers Towards Mental Health Patients: A Cross Sectional Study in Osun State, Nigeria. AB - World Health Organization (WHO) recommends integration of mental health services into primary health services; however attitude of primary health care workers is one barrier to this. A cross sectional survey using the Community Attitudes towards Mental Illness (CAMI) was done. One hundred and twenty primary care workers were randomly selected from three local government areas. Descriptive and inferential statistics were used in analyses. The results showed that most primary health care workers hold a benevolent (mean = 2.47, SD = 0.52) attitude towards the mentally ill. Workers with 10 years or more experience tend to have less authoritarian (t = 3.19, p = 0.01) and less social restrictive (t = 3.90, p = 0.01) attitudes towards the mentally ill. There were no significant differences in attitude by gender, marital status, or designation of health care workers. The study showed that primary care workers have attitudes similar to that seen in the general population. PMID- 27221255 TI - Luteolysis in Bos indicus cows on Days 5 and 7 of estrous cycle with varying doses of PGF2alpha. AB - The aim of this study was to evaluate luteolysis using three doses of PGF2alpha on Day 5 or Day 7 of the estrous cycle in nonlactating Nellore (Bos indicus) cows. Cows (n = 323) were assigned within date of estrus (Day 0 of estrous cycle) to receive 12.5, 25.0, or 50.0 mg of PGF2alpha on either Day 5 or Day 7 of the estrous cycle in a 3 * 2 factorial arrangement. Blood samples for progesterone (P4) concentrations were collected at 0, 24, 48, and 72 hours after PGF2alpha to assess luteolysis (L). Luteolysis was defined on the basis of P4 concentrations at 72 hours using either less than 0.5 ng/mL (L0.5) or less than 1.0 ng/mL (L1.0) as the cut off. Luteolysis was considered "partial" when P4 concentration declined within 24 hours after PGF2alpha but failed to decline further or, in some cases, increased. Incidence of luteolysis was less (P < 0.01) on Day 5 than Day 7 of the estrous cycle (17.3 vs. 47.6% and 30.4 vs. 77.2%; for L0.5 and L1.0, respectively). Dose of PGF2alpha increased (P < 0.01) L1.0 (12.5 mg = 38.9%; 25.0 mg = 52.3%; and 50.0 mg = 70.4%). Incidence of partial luteolysis for cows on Day 5 (57.1%) was greater (P < 0.01) than that on Day 7 (19.1%) of the estrous cycle and was more prevalent (P < 0.01) with lower doses of PGF2alpha (12.5 mg = 49.1%; 25.0 mg = 37.4%; and 50.0 mg = 27.8%). In conclusion, both days of the estrous cycle and doses of PGF2alpha influenced the incidence of complete and partial luteolysis in Nellore cows and should be an important consideration when devising estrus synchronization programs in this species. PMID- 27221256 TI - Early embryo loss, morphology, and effect of previous immunization against androstenedione in the ewe. AB - In a naturally mated cycle, ova and viable embryo number as well as embryo size were assessed on Day 4, 10, 14, 18, and 30 of gestation in Romney ewes (n = 38-44 per gestational group). For Days 4-18 of gestation, embryos were recovered by flushing the reproductive tract after slaughtering of the ewe. Ovulation rate was determined by counting the number of corpora lutea present on both ovaries. For the Day 30 group, number of ovulations was measured by laparoscopic examination of the ovaries at Day 9-12 of the cycle, and number of embryos present was determined by ultrasound examination at approximately Day 30 of pregnancy. Most of embryo loss occurred before Day 14 of gestation with 6% loss before Day 4, and 12% loss between Day 4 and 14 of gestation. A similar proportion of viable embryos per number of ova ovulated were recovered on Day 14 and 18 (82%) and Day 30 (81%) of gestation. Fertilization failure was estimated at 1%. Conceptus and embryo size was most variable on Day 14, representing a period of rapid growth (conceptus length +/- standard deviation); Day 4 (169 +/- 8 MUm), Day 10 (379 +/- 93 MUm), Day 14 (23 +/- 32 mm), Day 18 (embryo length +/- standard deviation; 5.0 +/- 0.7 mm). Vaccination with commercially available fertility vaccines targeting androstenedione (Androvax and Ovastim) in previous seasons resulted in reduced conceptus size compared with controls. However, no difference in the proportion of viable embryos was observed between treatments, signifying maternal tolerance for considerable variation at this stage of development. Furthermore, the finding that most of loss occurs within the first 14 days of gestation highlights the importance of both oocyte quality and the uterine environment for the embryo to successfully overcome the challenges leading up to and including pregnancy recognition in the ewe. PMID- 27221258 TI - A novel intramedullary callus distraction system for the treatment of femoral bone defects. AB - An intramedullary device has some advantages over external fixation in callus distraction for bone defect reconstruction. There are difficulties controlling motorized intramedullary devices and monitoring the distraction rate which may lead to poor results. The aim of this study was to design a fully implantable and non-motorized simple distraction nail for the treatment of bone defects. The fully implantable device comprises a tube-in-tube system and a wire pulling mechanism for callus distraction. For the treatment of femoral bone defects, a traction wire, attached to the device at one end, is fixed to the tibial tubercle at its other end. Flexion of the knee joint over a predetermined angle generates a traction force on the wire triggering bone segment transport. This callus distraction system was implanted into the femur of four human cadavers (total 8 femora), and bone segment transport was conducted over 60-mm defects with radiographic monitoring. All bone segments were transported reliably to the docking site. From these preliminary results, we conclude that this callus distraction system offers an alternative to the current intramedullary systems for the treatment of bone defects. PMID- 27221259 TI - Strategies to improve first attempt success at intubation in critically ill patients. AB - Tracheal intubation in critically ill patients is a high-risk procedure. The risk of complications increases with repeated or prolonged attempts, making expedient first attempt success the goal for airway management in these patients. Patient related factors often make visualization of the airway and placement of the tracheal tube difficult. Physiologic derangements reduce the patient's tolerance for repeated or prolonged attempts at laryngoscopy and, as a result, hypoxaemia and haemodynamic deterioration are common complications. Operator-related factors such as experience, device selection, and pharmacologic choices affect the odds of a successful intubation on the first attempt. This review will discuss the 'difficult airway' in critically ill patients and highlight recent advances in airway management that have been shown to improve first attempt success and decrease adverse events associated with the intubation of critically ill patients. PMID- 27221260 TI - Diurnal and stress-reactive dehydroepiandrosterone levels and telomere length in youth. AB - The current investigation examined the association between the aging-related biomarkers dehydroepiandrosterone (DHEA) and telomere length (TL) in community recruited African-American youth. The examination of DHEA included stress reactive, basal and diurnal sampling, in order to elucidate the underlying physiological process that may overlap with TL. One hundred and two participants completed the Trier Social Stressor Test for children (TSST-C). TL was obtained from all youth from buccal swabs on the same day as the TSST-C. Saliva samples from 83 participants were obtained over the course of two additional days to measure waking and diurnal levels of DHEA. DHEA diurnal slope was a robust predictor of TL (B=0.516, P<0.05), while other DHEA values were not significantly associated with TL. This study is one of the first studies to examine basal, diurnal and reactivity measurements of DHEA in youth. Furthermore, this is the first study, to our knowledge, to demonstrate a positive association between DHEA, a putative anti-aging hormone, and TL, an indicator of cellular aging. PMID- 27221261 TI - [X-linked hypophosphatemic rickets due to mutations in PHEX: Clinical and evolutionary variability]. PMID- 27221262 TI - From ultrahigh to extreme field magnetic resonance: where physics, biology and medicine meet. PMID- 27221263 TI - Sustained-release dexamethasone intravitreal implant in juvenile idiopathic arthritis-related uveitis. AB - The purpose of this study is to review the results of treatment of juvenile idiopathic arthritis-related uveitis with the use of intravitreal dexamethasone implant. Sixteen eyes with Juvenile idiopathic arthritis (JIA)-associated uveitis received intravitreal dexamethasone implant to treat recalcitrant anterior segment inflammation (43.7 %), chronic macular edema (6.2 %), or a combination of both (50 %). One month after injection, mean visual acuity had improvement to 39.6 +/- 11 ETDRS letters (p < 0.001). Mean AC cells measure at 1 month was 0.79 and 0.75 at 3 months. One month after injection, there was a significant reduction of central retinal thickness (CRT) to 342.4 +/- 79.3 um (p < 0.01). One month after the second implant, 11 eyes (91.6 %) achieved improved activity of the anterior uveitis, and mean best-corrected visual acuity improved to 44.6 +/- 8.1 ETDRS letters (p < 0.01). At 1 month after the second injection, 4/5 eyes had resolution of macular edema with CRT of 250.4 +/- 13.7 um (p < 0.01). Of the 16 eyes, 12 eyes received a second injection at mean of 7.5 +/- 3.1 months after the first treatment, and 5 eyes received a third Ozurdex injection on average 7 +/- 4.6 months after the second injection. Of the 16 eyes, five eyes were pseudophakic prior to injection. Of the remaining 11 eyes, 8 (73 %) developed worsening posterior subcapsular cataract at a mean of 7.3 +/- 1.2 months after the first injection. After the first injection, only one eye required topical antiglaucoma therapy with maximum pressure of 25 mmHg. In patients with recalcitrant JIA-associated active uveitis, injection of sustained-release dexamethasone can achieve control of anterior inflammation and resolution of macular edema. PMID- 27221264 TI - Measurements of central corneal thickness and endothelial parameters with three different non-contact specular microscopy devices. AB - We aimed to compare the measurements of central corneal thickness (CCT) and endothelial parameters with three different non-contact specular microscopy (SM) devices. Fifteen eyes of 15 healthy individuals (6 males; 9 females) were enrolled in the study. Mean age was 37.93 +/- 15.13 years. Endothelial parameters and CCT were measured with Nidek CEM-530, Topcon SP-3000P, and Tomey EM-3000 SM devices by the same physician. Endothelial parameters included endothelial cell count (ECC), maximum, minimum, and average endothelial cell size. and hexagonality ratio. There were no statistically significant differences in ECC, CTT, and average endothelial size (AES) between the devices (p > 0.05). The measurement of maximum endothelial size (MES) was different between Nidek SM and Topcon SM devices (p = 0.001), but there was no difference in MES between Nidek SM and Tomey SM (p = 0.058), and between Topcon SM and Tomey SM (p = 0.081). There was no difference in minimum endothelial size (MinES) between Nidek SM and Topcon SM (p = 0.794); however, there was a significant difference in MinES between Tomey SM and Nidek SM (p < 0.001), and between Tomey SM and Topcon SM (p < 0.001). Comparison of hexagonality ratio showed statistically significant difference between the devices (p < 0.001). No significant differences in the measurements of ECC, CCT, and AES were detected between different SM devices, whereas a statistically significant difference in hexagonality ratio was detected between the devices. These devices should not be used alternatively in the endothelial morphology assessment in patient's follow-up. PMID- 27221265 TI - Ganciclovir ophthalmic gel treatment shortens the recovery time and prevents complications in the adenoviral eye infection. AB - The purpose of this study was to determine the effectiveness of ganciclovir ophthalmic gel (GOG) in the treatment of adenoviral eye infection (AEI) by looking at the effect of the drug on shortening recovery time, preventing transmission, reducing sequelae, and on complications such as corneal infiltrates and conjunctival pseudomembranes. 200 patients' examination records were evaluated retrospectively. Patients who were within the first 3 days of AEI were divided into two groups: Group 1 with 100 patients who used artificial tears as treatment, and Group 2 with 100 patients who used GOG plus artificial tears (GAT). All patients underwent an eye examination by the same ophthalmologist on the 1st, 5th, 10th, and 15th day after treatment. Using the examination records, variables were compared using SPSS 22.0. There was a statistically significant difference between Groups 1 and 2. Group 2 showed better and faster response to treatment. There was less transmission to the contralateral eye and environment, and less formation of corneal subepithelial infiltrate and conjunctival pseudomembrane in Group 2. Only three patients in Group 2 had corneal involvement. A comparison of each group pre-treatment and during treatment revealed improved signs and symptoms in Group 2 (p < 0.005). The study showed a trend toward more rapid improvement, less corneal and conjunctival involvement, and less transmission to the contralateral eye and environment in the GAT group. These results need to be confirmed by additional studies. PMID- 27221266 TI - Influence of surface light scattering in hydrophobic acrylic intraocular lenses on laser beam transmittance. AB - The aim of this study was to experimentally examine the changes in the transmittances of photocoagulation lasers when surface light scattering increases in AcrySof intraocular lenses (IOLs). SA60AT IOLs (Alcon) were acceleratingly aging for 0, 3, 5, and 10 years to simulate surface light scattering, and the surface light-scattering intensities of both IOL surfaces were measured using a Scheimpflug photographer. The powers of laser beams that passed from a laser photocoagulator through the aged IOLs were measured at 532, 577, and 647 nm. Changes in the laser power and transmittance with the years of aging and the intensities of surface light scattering were examined. Although the intensity of surface light scattering increased with the years of aging, the laser power did not change with the years of aging (P > 0.30, Kruskal-Wallis test). There were no significant changes in the laser transmittance with the years of aging or the laser wavelength (P > 0.30 and 0.57, respectively). The intensity of surface light scattering revealed no significant association with the laser transmittance at any wavelength (P > 0.37, liner regression). The increases in the surface light scattering of the AcrySof IOLs would not influence retinal photocoagulation treatments for up to 10 years after implantation. PMID- 27221267 TI - Predictors for treatment outcomes after corneal crosslinking for keratoconus: a validation study. AB - Previous research suggested that baseline corrected distance visual acuity (CDVA) and maximum keratometry (Kmax) are the predictors for effectiveness of corneal crosslinking (CXL) for keratoconus. The aim of this study was to validate the previously determined predictors in a new treatment cohort. A prospective cohort of 112 eyes in 90 consecutive patients was used to validate the results of 102 eyes in 79 patients from our previous prospective cohort. All patients were treated using epithelium-off corneal CXL in a tertiary hospital setting. Primary outcomes were changes in CDVA (LogMAR) and Kmax between baseline and 1-year post treatment. Predictive factors for both outcomes were determined using univariable and multivariable analyses. Lower pretreatment CDVA was found to be the sole independent factor predicting an improvement in CDVA 1 year after CXL (beta coefficient: -0.476, P < 0.01). Kmax flattening is more likely to take place in eyes with preoperative central cones (beta coefficient: 0.655, P < 0.01). These results are consistent with our initial research and indicate high reproducibility in the new cohort. The previously postulated prediction model for postoperative CDVA showed limited predictive value in the validation cohort (R 2 = 0.15). The clinical implication of these results is that patients with lower pretreatment visual acuity are more likely to benefit from CXL (with respect to visual acuity), and patients with more central cones will benefit more in terms of cone flattening. Furthermore, those results can be used to guide customization of the crosslinking treatment. PMID- 27221268 TI - Confocal microscopy evaluation of stromal fluorescence intensity after standard and accelerated iontophoresis-assisted corneal cross-linking. AB - The aim of this study is to determine modifications in stromal fluorescence intensity after different corneal cross-linking (CXL) procedures and to correlate stromal fluorescence to corneal biomechanical resistance. For confocal microscopy study, 15 human cadaver corneas were examined. Three served as control (group 1), three were just soaked with iontophoresis procedure (group 2), three were treated with standard epi-off technique (group 3), and six underwent iontophoresis imbibition. Three of later six were irradiated for 30 min with 3 mW/cm2 UVA (group 4) and three for 9 min at 10 mW/cm2 UVA (group 5). Confocal microscopy was performed to quantify the fluorescence intensity in the cornea at different stromal depths. For biomechanical study, 30 human cadaver corneas were randomly divided into five groups and treated as previously described. Static stress strain measurements of the corneas were performed. Iontophoresis imbibition followed by 10mW/cm2 irradiation proved to increase stromal fluorescence into the corneal stroma and significant differences were revealed between group 3 and 5 both at 100 (p = 0.0171) and 250 um (p = 0.0024), respectively. Biomechanical analysis showed an improvement of corneal resistance in group 5. Iontophoresis imbibition followed by accelerated irradiation increased the stromal fluorescence and is related to an improvement of biomechanical resistance. This approach may represent a new strategy to achieve greater concentrations of riboflavin without removing corneal epithelium and improve clinical results while reducing the side effects of CXL. PMID- 27221270 TI - Trends in suicidal behaviour and use of mental health services in Canadian military and civilian populations. AB - BACKGROUND: In the context of the Canadian mission in Afghanistan, substantial media attention has been placed on mental health and lack of access to treatment among Canadian Forces personnel. We compared trends in the prevalence of suicidal behaviour and the use of mental health services between Canadian military personnel and the general population from 2002 to 2012/13. METHODS: We obtained data for respondents aged 18-60 years who participated in 4 nationally representative surveys by Statistics Canada designed to permit comparisons between populations and trends over time. Surveys of the general population were conducted in 2002 (n = 25 643) and 2012 (n = 15 981); those of military personnel were conducted in 2002 (n = 5153) and 2013 (n = 6700). We assessed the lifetime and past-year prevalence of suicidal ideation, plans and attempts, as well as use of mental health services. RESULTS: In 2012/13, but not in 2002, military personnel had significantly higher odds of both lifetime and past-year suicidal ideation than the civilian population (lifetime: adjusted odds ratio [OR] 1.32, 95% confidence interval [CI] 1.17-1.50; past year: adjusted OR 1.34, 95% CI 1.09 1.66). The same was true for suicidal plans (lifetime: adjusted OR 1.64, 95% CI 1.35-1.99; past year: adjusted OR 1.66, 95% CI 1.18-2.33). Among respondents who reported past-year suicidal ideation, those in the military had a significantly higher past-year utilization rate of mental health services than those in the civilian population in both 2002 (adjusted OR 2.02, 95% CI 1.31-3.13) and 2012/13 (adjusted OR 3.14, 95% CI 1.86-5.28). INTERPRETATION: Canadian Forces personnel had a higher prevalence of suicidal ideation and plans in 2012/13 and a higher use of mental health services in 2002 and 2012/13 than the civilian population. PMID- 27221271 TI - Privacy risks when using mobile devices in health care. PMID- 27221272 TI - New tool evaluates risk of patient aggression. PMID- 27221269 TI - An update on the diagnosis and treatment of Parkinson disease. PMID- 27221273 TI - Why Canada needs CMAJ. PMID- 27221274 TI - Single-tablet antiretroviral treatment (once daily). PMID- 27221275 TI - Emergency management of autonomic dysreflexia with neurologic complications. PMID- 27221276 TI - "You have come to the right place". PMID- 27221277 TI - How do I cope with pain? Let me count the ways: awareness of pain coping behaviors and relationships with depression and anxiety. AB - Patients with chronic pain are often undertreated with medications alone and need alternative ways of coping. Identifying pain coping skills patients use may be beneficial; however, no research has investigated whether patients are aware of their coping skills. The purpose of this study was to determine whether patients are aware of their pain coping skills, whether certain patient characteristics were related to using coping strategies, and whether coping strategies were related to psychiatric symptoms. Chart reviews were conducted on seventy-eight chronic pain patients who completed a semi-structured psychological interview. Patients endorsed using more coping strategies on the measure compared to the verbal self-report. Identifying with certain patient demographics was related to higher use of some coping strategies. Symptoms of anxiety and depression were also related to the use of some coping strategies. Anxiety was negatively related to ignoring the pain and using self-talk coping statements and positively related to catastrophizing. Depression was negatively related to the use of distraction, ignoring the pain, and using self-talk coping statements. Depression and pain severity were both positively related to catastrophizing and prayer. Results suggest that clinicians may need to help patients become aware of adaptive coping strategies they already use and that the use of certain coping strategies is related to lower levels of depression and anxiety. PMID- 27221278 TI - Connexin 50 modulates Sox2 expression in spinal-cord-derived ependymal stem/progenitor cells. AB - Ion channels included in the family of Connexins (Cx) have been reported to influence the secondary expansion of traumatic spinal cord injury (SCI) and neuropathic pain following SCI. However, Cxs also contribute to spinal cord neurogenesis during the remyelinating process and functional recovery after SCI. Certain Cxs have been recently related to the control of cell proliferation and the differentiation of neuronal progenitors. Adult spinal-cord-derived ependymal stem progenitor cells (epSPC) show high expression levels of Cx50 in non pathological conditions and lower expression when they actively proliferate after injury (epSPCi). We explore the role of Cx50 in the ependymal population in the modulation of Sox2, a crucial factor of neural progenitor self-renewal and a promising target for promoting neuronal-cell-fate induction for neuronal tissue repair. Short-interfering-RNA ablation or over-expression of Cx50 regulates the expression of Sox2 in both epSPC and epSPCi. Interestingly, Cx50 and Sox2 co localize at the nucleus indicating a potential role for this ion channel beyond cell-to-cell communication in the spinal cord. In vivo and in vitro experiments with Clotrimazole, a specific pharmacological modulator of Cx50, show the convergent higher expression of Cx50 and Sox2 in the isolated epSPC/epSPCi and in spinal cord tissue. Therefore, the pharmacological modulation of Cx50 might constitute an interesting mechanism for Sox2 induction to modulate the endogenous regenerative potential of neuronal tissue with a potential application in regenerative therapies. PMID- 27221280 TI - Unpacking a century-old mystery: Winter buds and the latitudinal gradient in leaf form. PMID- 27221279 TI - MicroRNA 17-92 cluster regulates proliferation and differentiation of bovine granulosa cells by targeting PTEN and BMPR2 genes. AB - Granulosa cell proliferation and differentiation are key developmental steps involved in the formation of the dominant follicle eligible for ovulation. This process is, in turn, regulated by spatiotemporally emerging molecular events. MicroRNAs (miRNAs) are one of the molecular signatures believed to regulate granulosa cell function by fine-tuning gene expression. Previously, we showed that the miR-17-92 cluster was differentially expressed in granulosa cells from subordinate and dominant follicles at day 19 of the estrous cycle. However, the role of this miRNA cluster in bovine follicular cell function is not known. Therefore, in the present study, we investigate the role of the miR-17-92 cluster in granulosa cell function by using an in vitro model. Target prediction and luciferase assay analysis revealed that the miR-17-92 cluster coordinately regulated the PTEN and BMPR2 genes. Overexpression of the miR-17-92 cluster by using a mimic promoted granulosa cell proliferation and reduced the proportion of differentiated cells. However, cluster inhibition resulted in decreased proliferation and increased differentiation in granulosa cells. This was further supported by expression analysis of marker genes of proliferation and differentiation. The role of the miR-17-92 cluster was cross-validated by selective knockdown of its target genes by the short interfering RNA technique. Suppression of the PTEN and BMPR2 genes revealed similar phenotypic and molecular alterations as observed when the granulosa cells were transfected with the miR-17 92 cluster mimic. Thus, the miR-17-92 cluster is involved in granulosa cell proliferation and differentiation by coordinately targeting the PTEN and BMPR2 genes. PMID- 27221281 TI - Strongly asymmetric hybridization barriers shape the origin of a new polyploid species and its hybrid ancestor. AB - PREMISE OF THE STUDY: Hybridization between diploids and tetraploids can lead to new allopolyploid species, often via a triploid intermediate. Viable triploids are often produced asymmetrically, with greater success observed for "maternal excess" crosses where the mother has a higher ploidy than the father. Here we investigated the evolutionary origins of Mimulus peregrinus, an allohexaploid recently derived from the triploid M. *robertsii, to determine whether reproductive asymmetry has shaped the formation of this new species. METHODS: We used reciprocal crosses between the diploid (M. guttatus) and tetraploid (M. luteus) progenitors to determine the viability of triploid M. *robertsii hybrids resulting from paternal- vs. maternal-excess crosses. To investigate whether experimental results predict patterns seen in the field, we performed parentage analyses comparing natural populations of M. peregrinus to its diploid, tetraploid, and triploid progenitors. Organellar sequences obtained from pre existing genomic data, supplemented with additional genotyping was used to establish the maternal ancestry of multiple M. peregrinus and M. *robertsii populations. KEY RESULTS: We found strong evidence for asymmetric origins of M. peregrinus, but opposite to the common pattern, with paternal-excess crosses significantly more successful than maternal-excess crosses. These results successfully predicted hybrid formation in nature: 111 of 114 M. *robertsii individuals, and 27 of 27 M. peregrinus, had an M. guttatus maternal haplotype. CONCLUSION: This study, which includes the first Mimulus chloroplast genome assembly, demonstrates the utility of parentage analysis through genome skimming. We highlight the benefits of complementing genomic analyses with experimental approaches to understand asymmetry in allopolyploid speciation. PMID- 27221282 TI - Immunohistochemical study of toll-like receptors 2, 4, and 9 expressions in pemphigus and bullous pemphigoid lesions. AB - Pemphigus and bullous pemphigoid (BP) are severe autoimmune skin diseases. Whether innate immunity could be a trigger or a part of the pathogeneses is unknown. Toll-like receptors (TLRs) are important components of the innate immune system, with no previous evaluation of TLRs in autoimmune bullous diseases. This work aims to investigate TLRs 2, 4, and 9 expressions in pemphigus and bullous pemphigoid. Thirty-six patients with pemphigus vulgaris (PV), pemphigus foliaceus (PF), bullous pemphigoid (BP), and six healthy controls were studied. Skin biopsies from the patients and the controls were examined immunohistochemically for TLR2, 4, and 9 expressions. The TLR4 expressed mainly at the basal layer of epidermis in controls, but in the cases with autoimmune bullous diseases, TLR4 staining located at basal layer and suprabasal layer, even superficial layer of epidermis. The immunostaining-intensity-distribution (IID) index of TLR4 in patients with PF (13.83, P = 0.001), PV (13.08, P = 0.003), and BP (11.42, P = 0.042) were significantly higher than that of the controls (6.17). TLR2 and TLR9 showed no significantly changes at epidermal expression (P > 0.05) compared with controls. There was no correlation found between the expressions of these TLRs. This work, thus, shows a re-localization of TLR4 expression sites with increased expression in pemphigus and bullous pemphigoid lesions. Targeting TLR4 signaling is expected to be a novel treatment strategy for autoimmune bullous diseases. PMID- 27221283 TI - A Provably Secure RFID Authentication Protocol Based on Elliptic Curve for Healthcare Environments. AB - To enhance the quality of healthcare in the management of chronic disease, telecare medical information systems have increasingly been used. Very recently, Zhang and Qi (J. Med. Syst. 38(5):47, 32), and Zhao (J. Med. Syst. 38(5):46, 33) separately proposed two authentication schemes for telecare medical information systems using radio frequency identification (RFID) technology. They claimed that their protocols achieve all security requirements including forward secrecy. However, this paper demonstrates that both Zhang and Qi's scheme, and Zhao's scheme could not provide forward secrecy. To augment the security, we propose an efficient RFID authentication scheme using elliptic curves for healthcare environments. The proposed RFID scheme is secure under common random oracle model. PMID- 27221284 TI - Downregulation of the spinal NMDA receptor NR2B subunit during electro acupuncture relief of chronic visceral hyperalgesia. AB - The involvement of spinal NR2B, a N-methyl-D-aspartate (NMDA) receptor subunit, in the therapeutic effect of electro-acupuncture (EA) on chronic visceral hyperalgesia was investigated. Chronic visceral hyperalgesia was induced using an irritable bowel syndrome (IBS) model in rats. Graded colorectal distention (CRD) stimuli at strengths of 20, 40, 60 and 80 mmHg were applied, and behavioral tests were performed to measure the abdominal withdrawal reflex (AWR) in response to the CRD stimuli and assess the severity of the visceral hyperalgesia. Rats were randomly divided into four groups: normal intact (control) group, IBS model (model) group, EA-treated IBS rats (EA) group and sham EA-treated IBS rats (sham EA) group. For the EA treatment, electric stimuli were applied through needles inserted into two acupoints [Zu-san-li (ST-36) and Shang-ju-xu (ST-37)] in both hind limbs, while the sham EA treatment consisted of only the insertion of needles into these same acupoints without an application of electric stimuli. Our results showed that AWR scores of the model group responding to CRD stimuli of 20, 40, 60 and 80 mmHg were significantly increased. These increased scores subsequently decreased following EA treatment (P < 0.05) compared with those for the other groups. The expression of NR2B in the superficial laminae (SDH, laminae I and II), nucleus proprius (NP, laminae III and IV), neck of the dorsal horn (NECK, laminae V and VI) and central canal region (lamina X) at thoracolumbar (T13-L2) and lumbosacral (L6-S2) segmental level significantly increased in the model group versus the control group (P < 0.05) and significantly decreased after EA treatment (P < 0.05). There were no significant changes in neither AWR scores nor expression of the NR2B subunit in these spinal regions after the sham EA treatment. These results confirm that EA can relieve chronic visceral hyperalgesia in IBS model rats and suggest that such an effect is possibly mediated through the downregulation of the NR2B subunits of NMDA at the spinal level. PMID- 27221285 TI - Relationship between clozapine dose, serum concentration, and clinical outcome in children and adolescents in clinical practice. AB - Information on dose- and concentration-related clinical effects of clozapine treatment in children and adolescents is scarce. This study aimed to examine the relationship between dose, serum concentration, and clinical outcome as well as the influencing factors thereof in paediatric patients treated with clozapine. Data from a routine Therapeutic Drug Monitoring (TDM) service between 2004 and 2014 were studied in 68 patients, aged 11-18 years. Severity of illness, therapeutic effectiveness and adverse drug reactions (ADRs) were assessed by standardized means. A relationship between the daily dose (mean 319 mg, 4.9 mg/kg) and serum concentration (mean 387 ng/ml) of clozapine was found with the variation in dose explaining 30 % of the variability in clozapine serum concentrations. Also gender contributed to the variability, however, no influence of age or concomitant medications was detected. Furthermore, a significant association was found between clozapine serum concentration and the occurrence of ADRs. Patients without ADRs had a lower mean serum concentration than those with mild (261.4 vs 407.3 ng/ml, P = 0.018) and moderate ADRs (261.4 vs 416.3 ng/ml, P = 0.028). As clozapine was estimated to be effective in lower blood concentrations, guidance on a possibly lower therapeutic range of clozapine serum levels in paediatric patients is provided. With ADRs increasing under higher concentrations, TDM is strongly recommended in paediatric clozapine therapy for individualized dosing. Dose adjustment in females also might be reasonable according to gender-related differences in serum concentrations. However, regarding the limitations of this study results should be validated in larger studies with more standardized designs. PMID- 27221286 TI - Performance of the Global Assessment of Pediatric Patient Safety (GAPPS) Tool. AB - BACKGROUND AND OBJECTIVE: Efforts to advance patient safety have been hampered by the lack of high quality measures of adverse events (AEs). This study's objective was to develop and test the Global Assessment of Pediatric Patient Safety (GAPPS) trigger tool, which measures hospital-wide rates of AEs and preventable AEs. METHODS: Through a literature review and expert panel process, we developed a draft trigger tool. Tool performance was tested in 16 academic and community hospitals across the United States. At each site, a primary reviewer (nurse) reviewed ~240 randomly selected medical records; 10% of records underwent an additional primary review. Suspected AEs were subsequently evaluated by 2 secondary reviewers (physicians). Ten percent of records were also reviewed by external expert reviewers. Each trigger's incidence and positivity rates were assessed to refine GAPPS. RESULTS: In total, 3814 medical records were reviewed. Primary reviewers agreed 92% of the time on presence or absence of a suspected AE (kappa = 0.69). Secondary reviewers verifying AE presence or absence agreed 92% of the time (kappa = 0.81). Using expert reviews as a standard for comparison, hospital-based primary reviewers had a sensitivity and specificity of 40% and 91%, respectively. As primary reviewers gained experience, their agreement with expert reviewers improved significantly. After removing low-yield triggers, 27 and 30 (of 54) triggers met inclusion criteria to form final manual and automated trigger lists, respectively. CONCLUSIONS: GAPPS reliably identifies AEs and can be used to guide and monitor quality improvement efforts. Ongoing refinement may facilitate future interhospital comparisons. PMID- 27221287 TI - Living-Donor Liver Transplantation From a Heterozygous Parent for Infantile Refsum Disease. AB - Infantile Refsum disease (IRD) is a rare autosomal recessive disorder of peroxisome biogenesis characterized by generalized peroxisomal metabolic dysfunction, including accumulation of very long-chain fatty acids (VLCFAs) and phytanic acid (PA), as well as decreased plasmalogen contents (PL). An effective therapy for this intractable disease has not been established, and only supportive management with docosahexaenoic acid supplementation and low PA diet has been reported so far. A boy of 3 years and 8 months presented with facial dysmorphism, transaminitis, and psychomotor retardation. Biochemical analysis showed elevated PA and VLCFAs, with reduced PL in the serum. Immunofluorescence study of fibroblasts from the patient indicated a mosaic pattern of catalase positive and -negative particles, and molecular analysis revealed compound heterozygous mutations of PEX6 The failure of medical management to prevent the progression of clinical symptoms and abnormal biochemistry prompted us to consider liver transplantation (LT). With the chances of receiving a deceased donor liver being poor, we performed a living-donor LT from the patient's heterozygous mother. At 6-month follow-up, the patient's serum PA levels had normalized. VLCFAs and PL levels had declined and increased, respectively. To the best of our knowledge, this is the second reported case in which IRD was treated by living-donor LT by using a heterozygous donor. Only long-term follow-up will reveal if there is any clinical improvement in the present case. With the liver being a major site for peroxisomal pathways, its replacement by LT may work as a form of partial enzyme therapy for patients with IRD. PMID- 27221288 TI - Behavioral Interventions for Infant Sleep Problems: A Randomized Controlled Trial. AB - OBJECTIVES: To evaluate the effects of behavioral interventions on the sleep/wakefulness of infants, parent and infant stress, and later child emotional/behavioral problems, and parent-child attachment. METHODS: A total of 43 infants (6-16 months, 63% girls) were randomized to receive either graduated extinction (n = 14), bedtime fading (n = 15), or sleep education control (n = 14). Sleep measures included parent-reported sleep diaries and infant actigraphy. Infant stress was measured via morning and afternoon salivary cortisol sampling, and mothers' self-reported mood and stress. Twelve months after intervention, mothers completed assessments of children's emotional and behavioral problems, and mother-child dyads underwent the strange situation procedure to evaluate parent-child attachment. RESULTS: Significant interactions were found for sleep latency (P < .05), number of awakenings (P < .0001), and wake after sleep onset (P = .01), with large decreases in sleep latency for graduated extinction and bedtime fading groups, and large decreases in number of awakenings and wake after sleep onset for the graduated extinction group. Salivary cortisol showed small-to moderate declines in graduated extinction and bedtime fading groups compared with controls. Mothers' stress showed small-to-moderate decreases for the graduated extinction and bedtime fading conditions over the first month, yet no differences in mood were detected. At the 12-month follow-up, no significant differences were found in emotional and behavioral problems, and no significant differences in secure-insecure attachment styles between groups. CONCLUSIONS: Both graduated extinction and bedtime fading provide significant sleep benefits above control, yet convey no adverse stress responses or long-term effects on parent-child attachment or child emotions and behavior. PMID- 27221289 TI - Important cellular targets for antimicrobial photodynamic therapy. AB - The persistent problem of antibiotic resistance has created a strong demand for new methods for therapy and disinfection. Photodynamic inactivation (PDI) of microbes has demonstrated promising results for eradication of antibiotic resistant strains. PDI is based on the use of a photosensitive compound (photosensitizer, PS), which upon illumination with visible light generates reactive species capable of damaging and killing microorganisms. Since photogenerated reactive species are short lived, damage is limited to close proximity of the PS. It is reasonable to expect that the larger the number of damaged targets is and the greater their variety is, the higher the efficiency of PDI is and the lower the chances for development of resistance are. Exact molecular mechanisms and specific targets whose damage is essential for microbial inactivation have not been unequivocally established. Two main cellular components, DNA and plasma membrane, are regarded as the most important PDI targets. Using Zn porphyrin-based PSs and Escherichia coli as a model Gram negative microorganism, we demonstrate that efficient photoinactivation of bacteria can be achieved without detectable DNA modification. Among the cellular components which are modified early during illumination and constitute key PDI targets are cytosolic enzymes, membrane-bound protein complexes, and the plasma membrane. As a result, membrane barrier function is lost, and energy and reducing equivalent production is disrupted, which in turn compromises cell defense mechanisms, thus augmenting the photoinduced oxidative injury. In conclusion, high PDI antimicrobial effectiveness does not necessarily require impairment of a specific critical cellular component and can be achieved by inducing damage to multiple cellular targets. PMID- 27221290 TI - Biosynthesis of pyruvic acid from glucose by Blastobotrys adeninivorans. AB - The ability of taxonomically different yeasts to synthesize pyruvic acid (PA) from glucose was studied. The study showed that many yeasts are able to produce PA from glucose under the condition of growth limitation by thiamine. This ability was found in the yeast Blastobotrys adeninivorans for the first time. The production (oversynthesis) of PA in this yeast can be explained by disturbance in the function of thiamine-dependent pyruvate dehydrogenase. Namely, the partial inhibition of this enzyme brings about the excretion of PA from the yeast cells. Due to incomplete inhibition of pyruvate dehydrogenase, the formation of acetyl CoA continues, although at a lower level, maintaining the synthesis of alpha ketoglutaric acid (KGA) in the tricarboxylic acid (TCA) cycle. KGA is no longer oxidized in the TCA cycle, because thiamine limitation inhibits alpha ketoglutarate dehydrogenase. As a result, KGA is excreted from the yeast cells as a byproduct of PA oversynthesis. Furthermore, the increased level of KGA in the yeast cells inhibits NAD-dependent isocitrate dehydrogenase in the TCA cycle and enhances the production and excretion of citric acid, another byproduct of PA oversynthesis. During cultivation in a fermentor, the strain Blastobotrys adeninivorans VKM Y-2677 produced 43.2 g l(-1) PA from glucose with a product yield (YPA) of 0.77 g PA/g glucose. The proportion of PA to byproducts was 18:1 for KGA and 8:1 for citric acid. PMID- 27221291 TI - Performance and microbial community composition in a long-term sequential anaerobic-aerobic bioreactor operation treating coking wastewater. AB - The combined anaerobic-aerobic biosystem is assumed to consume less energy for the treatment of high strength industrial wastewater. In this study, pollutant removal performance and microbial diversity were assessed in a long-term (over 300 days) bench-scale sequential anaerobic-aerobic bioreactor treating coking wastewater. Anaerobic treatment removed one third of the chemical oxygen demand (COD) and more than half of the phenols with hydraulic retention time (HRT) of 42 h, while the combined system with total HRT of 114 h removed 81.8, 85.6, 99.9, 98.2, and 85.4 % of COD, total organic carbon (TOC), total phenols, thiocyanate, and cyanide, respectively. Two-dimensional gas chromatography with time-of-flight mass spectrometry showed complete removal of phenol derivatives and nitrogenous heterocyclic compounds (NHCs) via the combined system, with the anaerobic process alone contributing 58.4 and 58.6 % removal on average, respectively. Microbial activity in the bioreactors was examined by 454 pyrosequencing of the bacterial, archaeal, and fungal communities. Proteobacteria (61.2-93.4 %), particularly Betaproteobacteria (34.4-70.1 %), was the dominant bacterial group. Ottowia (14.1 46.7 %), Soehngenia (3.0-8.2 %), and Corynebacterium (0.9-12.0 %), which are comprised of phenol-degrading and hydrolytic bacteria, were the most abundant genera in the anaerobic sludge, whereas Thiobacillus (6.6-43.6 %), Diaphorobacter (5.1-13.0 %), and Comamonas (0.2-11.1 %) were the major degraders of phenol, thiocyanate, and NHCs in the aerobic sludge. Despite the low density of fungi, phenol degrading oleaginous yeast Trichosporon was abundant in the aerobic sludge. This study demonstrated the feasibility and optimization of less energy intensive treatment and the potential association between abundant bacterial groups and biodegradation of key pollutants in coking wastewater. PMID- 27221293 TI - Muscle activity during endotracheal intubation using 4 laryngoscopes (Macintosh laryngoscope, Intubrite, TruView Evo2 and King Vision) - A comparative study. AB - BACKGROUND: Successful endotracheal intubation requires mental activity and no less important physical activity from the anesthesiologist, so ergonomics of used devices is important. The aim of our study has been to compare 4 laryngoscopes regarding an operator's activity of selected muscles of the upper limb, an operator's satisfaction with used devices and an operator's fatigue during intubation attempts. MATERIAL AND METHODS: The study included 13 anesthesiologists of similar seniority. To measure muscle activity MyoPlus 2 with 2-channel surface ElectroMyoGraphy (sEMG) test device was used. Participant's satisfaction with studied devices was evaluated using Visual Analog Scale. An operator's fatigue during intubation efforts was evaluated by means of the modified Borg's scale. RESULTS: The highest activity of all the studied muscles was observed for the Intubrite laryngoscope, followed by the Mackintosh, TruView Evo2 and the lowest one - for the King Vision video laryngoscope. A significant statistical difference was observed for the King Vision and the rest of laryngoscopes (p < 0.05). No significant statistical differences were observed between the Macintosh, TruView Evo2 and Intubrite laryngoscopes (p > 0.05). The shortest time of intubation was achieved using the standard Macintosh blade laryngoscope. The highest satisfaction was noted for the King Vision video laryngoscope, and the lowest for - the TruView Evo2. The Intubrite was the most demanding in terms of workload, in the opinion of the participants', and the least demanding was the King Vision video laryngoscope. CONCLUSIONS: Muscle activity, namely the force used for intubation, is the smallest when the King Vision video laryngoscope is used with the highest satisfaction and lowest workload, and the highest muscle activity was proven for the Intubrite laryngoscope with the highest workload. Med Pr 2016;67(2):155-162. PMID- 27221292 TI - Occupational exposure to fungi and particles in animal feed industry. AB - BACKGROUND: Very few studies regarding fungal and particulate matter (PM) exposure in feed industry have been reported, although such contaminants are likely to be a significant contributing factor to several symptoms reported among workers. The purpose of this study has been to characterize fungal and dust exposure in one Portuguese feed industry. MATERIAL AND METHODS: Air and surface samples were collected and subject to further macro- and microscopic observations. In addition we collected other air samples in order to perform real time quantitative polymerase chain reaction (PCR) amplification of genes from Aspergillus fumigatus and Aspergillus flavus complexes as well as Stachybotrys chartarum. Additionally, two exposure metrics were considered - particle mass concentration (PMC), measured in 5 different sizes (PM0.5, PM1, PM2.5, PM5, PM10), and particle number concentration (PNC) based on results given in 6 different sizes in terms of diameter (0.3 MUm, 0.5 MUm, 1 MUm, 2.5 MUm, 5 MUm and 10 MUm). RESULTS: Species from the Aspergillus fumigatus complex were the most abundant in air (46.6%) and in surfaces, Penicillium genus was the most frequently found (32%). The only DNA was detected from A. fumigatus complex. The most prevalent in dust samples were smaller particles which may reach deep into the respiratory system and trigger not only local effects but also the systemic ones. CONCLUSIONS: Future research work must be developed aiming at assessing the real health effects of these co-exposures. Med Pr 2016;67(2):143-154. PMID- 27221294 TI - Occupational diseases among farmers in Poland. AB - BACKGROUND: The study's objective is to present epidemiological situation concerning the incidence of occupational diseases among farmers in Poland. MATERIAL AND METHODS: All 3438 cases of occupational diseases diagnosed among farmers and obligatorily reported to the Central Register of Occupational Diseases (covering all the national territory and all the cases of occupational diseases diagnosed in Poland after 1970) over the years 2000-2014 were subjected to analysis. RESULTS: The annual incidence in the analyzed period ranged 5-14 per 100 000 farmers. The analysis showed that about 90% of pathologies were induced by the biological agents. Almost every third pathology due to biological agents had allergic origin. Infectious and parasitic diseases accounted for 62% of the cases. Among them the diseases carried by ticks (93%) - borreliosis (85.8%) and tick-borne encephalitis (7.2%) were the most frequent ones. The age of farmers, in the case of whom bronchial asthma and allergic rhinitis were diagnosed, was significantly higher than the age of remaining employees of the national economy, in which these occupational diseases were recognized. CONCLUSIONS: The study indicates the necessity to introduce periodic health examinations programs focusing on agricultural workers to monitor health and well-being and improve working conditions and the working environment. Med Pr 2016;67(2):163-171. PMID- 27221295 TI - Quantitative olfactory disorders and occupational exposure to phenolic resins. AB - BACKGROUND: To investigate whether exposure to phenolic resins (PR) is associated with quantitative olfactory disorders (QOD), a cross-sectional study of self reported olfactory impairment (SROI) was performed in occupationally exposed subjects. MATERIAL AND METHODS: Sixty-six workers (45 males, 21 females) at the age (mean +/- standard deviation) of 39.8+/-10.15 years old were divided into 3 exposure groups on the basis of biological exposure indices (BEI) for urinary phenols. It was asked whether the sense of smell has been normal or abnormal during the recent 2 months: the participants were eventually divided into self reported normosmic, hyposmic, hyperosmic groups. RESULTS: Prevalence of the SROI was 45.5%, with 21 (31.8%) workers complaining about the hyposmia, 12 (18.2%) - anosmia and 9 (13.6%) - hyperosmia. In univariate analyses, female sex was associated with the SROI and the hyperosmia. Highly exposed workers showed the SROI more frequently (odds ratio (OR) = 4.714; 95% confidence interval (CI): 1.077-20.626) than those not exposed (reference) or low exposed (OR = 1.333; 95% CI: 0.416-4.274). In multivariate analyses, female sex was the main risk factor for the SROI (adjusted odds ratio (ORa) = 5.622; 95% CI: 1.525-20.722) and the hyperosmia (ORa = 25.143; 95% CI: 2.379-265.7) but a high exposure to phenol (ORa = 11.133; 95% CI: 1.060-116.9) was the main risk factor for the anosmia. CONCLUSIONS: This study has found slight evidence among the cross-section of chemical industry workers that the exposure to phenol may be associated with the SROI. On the other hand, self-reporting of the QOD may be biased by personal factors and further research with objective measurement is therefore required. Med Pr 2016;67(2):173-186. PMID- 27221296 TI - [Outcomes evaluation of the school staff health promotion project]. AB - BACKGROUND: This article presents selected outcomes of a 3-year project "Health promotion of school staff in health-promoting schools," as well as the achievements and difficulties in its implementation. MATERIAL AND METHODS: The research was conducted on 644 teachers and 226 members of non-teaching staff in 21 schools. The method involved opinion poll and authored questionnaires. A 2 part model of outcome evaluation was developed. RESULTS: Most participants appreciated the changes that took place within the 3 years of the project implementation. These included the improved level of their knowledge about health, health-conducive behaviors (62-93%) and the physical and social environment of the school (50-92%). Changes were more frequently acknowledged by teachers. About 80% of the participants had a positive attitude to the project, but only 20% assessed their involvement as considerable. About 90% believed that health promotion activities should be continued. According to the project leaders, insufficient support and financial resources, and difficulties in motivating school employees, particularly the nonteaching staff, to undertake health-promotion activities were the major handicaps in the project implementation. CONCLUSIONS: The project outcomes can be assessed as satisfying. They revealed that it is posssible to initiate health promotion among school staff. This can be effective on condition that participants are motivated, actively engaged in the project and supported by the head teacher and the local community. Necessarily, school leaders should be prepared to promote health among adults and to gain support from school policy decision makers, school administration, trade unions and universities involved in teacher training. Med Pr 2016;67(2):187-200. PMID- 27221297 TI - [Ruminations as predictors of negative and positive effects of experienced traumatic events in medical rescue workers]. AB - BACKGROUND: Emergency service workers are exposed to experienced traumatic events related to the nature of their work. The study aimed at identifying the role of cognitive processes, namely different forms of ruminations, as predictors of consequences of experienced trauma. MATERIAL AND METHODS: The data on 120 medical rescuers (80 men, 40 women) who had experienced in their worksite at least 1 traumatic event in the last 5 years, were analyzed. The age of the participants ranged from 25 to 61 years (mean (M) = 38.07; standard deviation (SD) = 8.92). The following Polish versions of standardized tools were used: the Impact of Event Scale - Revised (IES-R), the Posttraumatic Growth Inventory (PTGI) and the Event Related Rumination Inventory (ERRI). RESULTS: The results of regression analyses indicated 2 significant predictors, intrusive rumination for posttraumatic stress disorder (PTSD) and deliberate rumination for posttraumatic growth (PTG). CONCLUSIONS: Ruminations play an essential role in the occurrence of negative and positive outcomes of experienced trauma. The associations between PTSD and PTG, with different forms of ruminations, may be used in therapy, treating the appearance of intrusive rumination as an opportunity to turn towards active engagement in deliberate rumination, that facilitates the occurrence of posttraumatic growth. Med Pr 2016;67(2):201-211. PMID- 27221298 TI - [The incidence of accidents at work among paramedics in the years 2001-2013 based on the register of one selected hospital]. AB - BACKGROUND: Paramedics are exposed to a number of factors that may have a direct or indirect impact on the risk of an accident at work. The aim of the study was to analyze the incidence of accidents at work among paramedics as well as to discuss risk factors and measures to prevent such cases. MATERIAL AND METHODS: The data on accidents at work were obtained from unpublished internal hospital documentation. The results were subjected to statistical analysis. RESULTS: In the years 2001-2013 there were 40 events, including 6 collective accidents, in which 41 paramedics of the emergency department were injured. On average, around 3 accidents involving paramedics occurred each year. The accidents happened most frequently in the evening and at night and in the winter months (statistically insignificant relationship). Incorrect behavior of the paramedics was the most common cause of an accident (75.6%) and musculoskeletal injuries (75%) most frequently of upper and lower limbs (55%) were the most common effects of an accident. In none of the cases safety regulations were breached by employees or employer. CONCLUSIONS: Accidents among paramedics can be prevented by changing the interior design of and the medical equipment installation in the rear cabin of the ambulance, conducting regular training to upgrade the skills of paramedics and enriching their knowledge about health and safety in their widest meaning. Med Pr 2016;67(2):213-221. PMID- 27221299 TI - [The helpers' stress: Effectiveness of a web-based intervention for professionals working with trauma survivors in reducing job burnout and improving work engagement]. AB - BACKGROUND: The study aimed at evaluating effectiveness of the web-based intervention, "The Helpers' Stress," in reducing job burnout and enhancing work engagement among professionals working with trauma survivors. MATERIAL AND METHODS: Participants were randomly allocated to 1 of the 3 intervention modules: 1 - the self-efficacy enhancement (N = 87), 2 - the social support enhancement (N = 85), or to 3 - the educational module (comparison group, N = 81). Participants completed the online questionnaires before the intervention (T1), immediately after (T2), and 4 weeks after the intervention (T3). RESULTS: Due to high drop out rate at T2 and T3 in social support enhancement module, we excluded from analysis participants assigned to this condition. Participants assigned to the self-efficacy enhancement module presented higher levels of self-efficacy (at T2 and T3), compared to those assigned to the educational module. Job burnout decreased significantly between T1 and T2, and between T2 and T3, and work engagement increased significantly between T1 and T2, and between T1 and T3, among participants assigned to both modules mentioned above. Self-efficacy (T2) mediated the relationship between the group assignment (educational module vs. self-efficacy enhancement module) and respectively job burnout (T3) or work engagement (T3). CONCLUSIONS: The results of our study highlight the role of self efficacy in reducing job burnout and increasing work engagement. Med Pr 2016;67(2):223-237. PMID- 27221300 TI - [Testing of the composition of e-cigarette liquids - Manufacturer-declared vs. true contents in a selected series of products]. AB - BACKGROUND: Electronic cigarettes are currently in common use. However, in Poland there is no specific legislation governing the sale of these products. At the same time, no information has been made public about the hazards e-cigarettes pose to the users and bystanders - passive smokers. The aim of the study was to determine the qualitative composition of the analyzed liquid, which is an essential element of regulating the distribution of such cigarettes. MATERIAL AND METHODS: Under this study the method for determining the composition of e cigarette liquids was developed. This method employs gas chromatography with mass spectrometry (GC-MS). Levels of nicotine and flavoring components were determined in 50 e-liquid samples. The results were compared with the information provided by the manufacturer on the packaging. RESULTS: The applied method of qualitative determination helped to identify the main ingredients, such as nicotine and propylene glycol (PG). Propylene glycol was found to be present in all liquids, because it was used as the solvent for nicotine and flavors. There was a good agreement between the declared and the determined content of nicotine in the analyzed samples. The agreement was considerably poorer for the remaining e liquid ingredients, mainly flavors. CONCLUSIONS: There was no agreement between the flavor substances specified by the manufacturer and aroma identified in the e cigarette liquid, which may pose a risk to users of e-cigarettes, particularly those susceptible to allergies. Several unsaturated aliphatic alcohols and aldehydes found to be present in the liquids, unstable at elevated temperatures, may be more harmful to the smoker than the original compounds. Therefore, it is essential to implement in Poland the legal provisions regarding e-cigarettes. Med Pr 2016;67(2):239-253. PMID- 27221301 TI - [The effect of solar ultraviolet radiation (UVR) on induction of skin cancers]. AB - Ultraviolet radiation is a physical mutagenic and cancerogenic factor. About 95% of ultraviolet A (UVA) (320-400 nm) and 5% of UVB (280-320 nm) reach the Earth's surface. Melanin is a natural skin protective factor against UV radiation. Skin cancers associated with long-term exposure to UV radiation are: basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and cutaneous malignant melanoma (CMM). The high risk of BCC development is related to acute and repeated exposure to UV causing sunburn. Molecular studies of BBC demonstrated disorders in sonic hedgehog (SHH) cell signaling regulation pathway, associated with the suppressor protein patched homolog 1 gene (PTCH1) mutations. The risk of the BCC development is related to the polymorphism of melanokortin-1 receptor gene (MC1R). Tumor P53 gene mutations observed in BCC cells has been classified as secondary genetic changes. In SCC cells UV-induced mutations were mostly related to P53 gene. Increased expression of cyclooxigenase- 2 gene (COX-2) plays a significant role in the development of SCC. Other pathogenetic factors include intensification of the synthesis of pro-inflammatory cytokines (tumor necrosis factor alpha (TNF alpha), interleukin-1 alpha (IL-1alpha), IL-1beta and IL-6). Currently, the role of UVB has been recognized in the pathogenesis of CMM. In CMM cells the following gene mutations were noted: cyclindependent kinase inhibitor 2A INK4A (p16INK4A), cyclin-dependent kinase 4 (CDK4), Ras, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and proto-oncogene B-Raf (BRAF). The BRAF gene mutations were observed in ~50% of CMM cases. Mutations of P53 gene are not characteristic of CMM cells. Med Pr 2016;67(2):255-266. PMID- 27221302 TI - [Proficiency testing schemes as a quality rating in industrial hygiene laboratories]. AB - This publication presents the principles of organization, implementation, assessment and exploitation of proficiency testing results in the work environmental laboratory based on basic requirements included in standard PN-EN ISO/IEC 17043 and ISO 13528. The basis for the proper functioning of the laboratory is to use and observe the basic requirements for the competence to carry out the tests and the guidelines on ensuring reliable and accurate results, specified e.g., according to the guidelines described in the standard PN-EN ISO/IEC 17043. The confirmation of the laboratory competence is the obtained accreditation. To obtain this certificate several conditions, including proficiency testing (PT) should be met. The main aspects of this paper is to show the role of proficiency testing in the process of assuring a properly functioning quality system in the laboratory. The accreditation requirements, the types of proficiency testing schemes, methods of statistical analysis and interpretation of results are also discussed by the authors. Med Pr 2016;67(2):267-283. PMID- 27221303 TI - New US food labels reflect modern serving sizes and added sugar. PMID- 27221304 TI - [Report on relevant and common types of therapy]. PMID- 27221305 TI - [Spinal disorders in childhood and adolescence]. PMID- 27221306 TI - [Chronic recurrent multifocal osteomyelitis of the spine : Children and adolescent]. AB - Chronic non-bacterial osteomyelitis (CNO) in childhood and adolescence is a non infectious autoinflammatory disease of the bone with partial involvement of adjacent joints and soft tissue. The etiology is unknown. The disease can occur singular or recurrent. Individual bones can be affected and multiple lesions can occur. Chronic recurrent multifocal osteomyelitis (CRMO) shows the whole picture of CNO. Accompanying but temporally independent of the bouts of osteomyelitis, some patients show manifestations in the skin, eyes, lungs and the gastrointestinal tract. The article gives an overview of the clinical manifestations, diagnostic procedures, and treatment options for CRMO involvement of the spine based on the current literature and our own cases. PMID- 27221307 TI - [Spondylodiscitis in children and adolescents]. AB - BACKGROUND: Spondylodiscitis in children is rare. The condition has an incidence of 2 to 4 % of all infectious skeletal diseases in children. AIM: Aim of the article is the presentation of epidemiology, the clinical signs, radiological findings as well the treatment options of non-specific and specific spondylodiscitis in children. METHODS: The available literature was reviewed. RESULTS: Non-specific spondylodiscitis in children is caused by haematogenous spread of pathogens. Staphylococcus aureus is the most frequently detected bacterium. The clinical signs are unspecific and an Magnetic Resonance Imaging of the spine is the standard radiological procedure to detect spondylodiscitis. In general, the treatment is conservative and includes an antibiotic therapy as well an immobilization of the spine. In endemic areas of the world, specific spondylodiscitis is more common and is caused by Mycobacterium tuberculosis or Brucellae. The treatment is also conservative. For all entities of spondylodiscitis in children, a surgical intervention is only necessary in the case of severe deformities due to the infection or in the case of neurological symptoms. CONCLUSION: Elevated infectious laboratory values and back pain or other unspecific symptoms can indicate spondylodiscitis in children. MRI of the spine is necessary to rule out spondylodiscitis. PMID- 27221308 TI - Personal music systems and hearing. AB - OBJECTIVES: To measure the output sound pressure levels of personal music systems and evaluate their effect on hearing. METHODS: Output sound pressure levels at preferred volume settings and listening environment were measured using a manikin. Effects of personal music system use on hearing were evaluated using pure tone audiometry (in conventional and extended high frequency ranges), transient evoked otoacoustic emissions, syllable identification in noise, intensity discrimination, frequency discrimination and temporal modulation transfer function. RESULTS: Results showed, alarmingly, that large proportions of young adults are using personal music systems at levels higher than the safety limits set by regulatory bodies. Individuals who listened to personal music systems at levels higher than 80 dB LAeq exhibited poorer extended high frequency thresholds, reduced transient evoked otoacoustic emission amplitudes, poorer frequency discrimination, reduced modulation detection thresholds at 32 Hz modulation frequency, and reduced syllable identification in noise at -5 dB signal-to-noise ratio. Listening levels were significantly correlated with extended high frequency thresholds and transient evoked otoacoustic emission amplitudes. CONCLUSION: These results suggest that listening to music through personal music systems at higher volume levels may be hazardous to hearing. PMID- 27221309 TI - Tuning the ferromagnetic phase in the CDW compound SmNiC2 via chemical alloying. AB - We report a study on tuning the charge density wave (CDW) ferromagnet SmNiC2 to a weakly coupled superconductor by substituting La for Sm. X-ray diffraction measurements show that the doped compounds obey Vegard's law, where La (Lu) alloying expands (shrinks) the lattice due to its larger (smaller) atomic size than Sm. In the series Sm1-xLaxNiC2, CDW transition (TCDW = 148 K) for SmNiC2 is gradually suppressed, while the ferromagnetic (FM) ordering temperature (TC) at 17 K slightly increases up to x = 0.3. For x > 0.3, TC starts to decrease and there is no signature that could be related with the CDW phase. Electrical resistivity, magnetic susceptibility and specific heat measurements point toward the possible presence of a FM quantum critical point (QCP) near x = 0.92, where the TC is extrapolated to zero temperature. Superconductivity in LaNiC2 (Tsc = 2.9 K) is completely suppressed with small amount of Sm inclusion near the proposed FM critical point, indicating a competition between the two ordered phases. The tunable lattice parameters via chemical substitution (La,Lu) and the ensuing change among the ordered phases of ferromagnetism, CDW and superconductivity underscores that SmNiC2 provides a rich avenue to study the rare example of a FM QCP, where the broken symmetries are intricately correlated. PMID- 27221310 TI - Upregulation of ABCG2 via the PI3K-Akt pathway contributes to acidic microenvironment-induced cisplatin resistance in A549 and LTEP-a-2 lung cancer cells. AB - Hypoxia always exists in the processes involved in the development of lung cancer and contributes to an acidic microenvironment. Despite that hypoxia in the tumor microenvironment is associated with the formation of chemotherapeutic resistance, the exact role of an acidic microenvironment in the development of hypoxia induced lung cancer multidrug resistance is still unknown. In the present study, we acidized the medium with 2-(N-morpholino)-ethanesulfonic acid (MES monohydrate) to mimic the acidic tumor microenvironment and observed the effects of acidification on lung cancer cell viability, the expression of ATP-binding cassette sub-family G member 2 (ABCG2) and myeloid cell leukemia-1 (Mcl-1), and activation of the PI3K-Akt pathway. Thereafter, we investigated the mechanisms involved in the acidification-induced expression of ABCG2 and Mcl-1, and the potential therapeutic strategy to overcome acidification-associated multidrug resistance formation. We demonstrated that acidification obviously increased the expression of ABCG2 and Mcl-1 via PI3K-Akt-mTOR-S6 pathway activation and contributed to multidrug resistance. Inhibition of PI3K-Akt activity efficiently abolished the effect of acidification on cell viability, indicating that the PI3K Akt pathway may include potential therapeutic target molecules in acidized microenvironment-associated lung cancer chemotherapeutic resistance. PMID- 27221312 TI - SHARP hypofractionated stereotactic radiotherapy is well tolerated in prostate cancer : Toxicity and quality of life assessment. AB - BACKGROUND: Quality of life (QoL) is one of the most significant issues in prostate cancer treatment decisions. This study aimed to investigate the toxicity of hypofractionated stereotactic radiotherapy (SBRT) and QoL after treatment in localized prostate cancer patients. MATERIALS AND METHODS: A prospective single center clinical study was performed in low- and intermediate-risk prostate cancer patients. Patients received 33.5 Gy in 5 fractions (SHARP regimen). Acute and late toxicity was assessed according to RTOG/EORTC score. Patients filled out EORTC QLQ-C30 and prostate cancer-specific QLQ-PR25 questionnaires. RESULTS: The analysis included 68 prostate cancer patients (55-83 years, median 73) with clinical stage T1c-T2cN0M0, median combined Gleason score of 6 (3-8), and median prostate-specific antigen (PSA) level of 10 ng/mL (4-20 ng/mL). Neoadjuvant androgen deprivation therapy was given to 52 patients (76.5 %), and stopped in 31 patients (45.5 %) after 6 months; in 21 patients (31 %) after 2-3 years. Average and median follow-up was 24 months (18-45). Median nadir PSA level was 0.03 ng/mL for all patients and 0.6 ng/mL for patients without hormone treatment. No patients had PSA failure. There were no acute grade IV toxicities. One patient (1.5 %) developed grade III and 24 patients (35.3 %) grade II acute bladder toxicity. No one developed grade III and 7 patients (10.3 %) grade II acute rectal toxicity. No grade III or IV late gastrointestinal or genitourinary toxicities were reported. Grade II late urinary symptoms were observed in 8 patients (11.8 %) and gastrointestinal symptoms in 3 patients (4.4 %). Global health status/QoL was good and improved during the observational period. CONCLUSION: SBRT for prostate cancer patients is a well-tolerated treatment in terms of toxicity and QoL, has no negative impact on functioning and everyday life, with the important benefit of a short treatment period. However, long-term follow-up data are needed. PMID- 27221311 TI - Fluorescent probes for nanoscopy: four categories and multiple possibilities. AB - Nanoscopy enables breaking down the light diffraction limit and reveals the nanostructures of objects being studied using light. In 2014, three scientists pioneered the development of nanoscopy and won the Nobel Prize in Chemistry. This recognized the achievement of the past twenty years in the field of nanoscopy. However, fluorescent probes used in the field of nanoscopy are still numbered. Here, we review the currently available four categories of probes and existing methods to improve the performance of probes. PMID- 27221313 TI - Inclined head position improves dose distribution during hippocampal-sparing whole brain radiotherapy using VMAT. AB - PURPOSE: Hippocampal-sparing whole brain radiotherapy (HS-WBRT) aims to preserve neurocognitive functions in patients undergoing brain radiotherapy (RT). Volumetric modulated arc therapy (VMAT) involves intensity-modulated RT using a coplanar arc. An inclined head position might improve dose distribution during HS WBRT using VMAT. MATERIALS AND METHODS: This study analyzed 8 patients receiving brain RT with inclined head positioning. A comparable set of CT images simulating a non-inclined head position was obtained by rotating the original CT set. HS WBRT plans of coplanar VMAT for each CT set were generated with a prescribed dose of 30 Gy in 10 fractions. Maximum dose to the hippocampi was limited to 16 Gy; to the optic nerve, optic chiasm, and eyeballs this was confined to less than 37.5 Gy; for the lenses to 8 Gy. Dosimetric parameters of the two different plans of 8 patients were compared with paired t-test. RESULTS: Mean inclined head angle was 11.09 +/- 0.73 degrees . The homogeneity (HI) and conformity (CI) indexes demonstrated improved results, with an average 8.4 +/- 10.0 % (p = 0.041) and 5.3 +/- 3.9 % (p = 0.005) reduction, respectively, in the inclined vs. non-inclined position. The inclined head position had lower hippocampi Dmin (10.45 +/- 0.36 Gy), Dmax (13.70 +/- 0.25 Gy), and Dmean (12.01 +/- 0.38 Gy) values vs. the non inclined head position (Dmin = 12.07 +/- 1.07 Gy; Dmax = 15.70 +/- 1.25 Gy; Dmean = 13.91 +/- 1.01 Gy), with 12.8 +/- 8.9 % (p = 0.007), 12.2 +/- 6.8 % (p = 0.003), and 13.2 +/- 7.2 % (p = 0.002) reductions, respectively. Mean Dmax for the lenses was 6.34 +/- 0.72 Gy and 7.60 +/- 0.46 Gy, respectively, with a 16.3 +/- 10.8 % reduction in the inclined position (p = 0.004). Dmax for the optic nerve and Dmean for the eyeballs also decreased by 7.0 +/- 5.9 % (p = 0.015) and 8.4 +/- 7.2 % (p = 0.015), respectively. CONCLUSION: Inclining the head position to approximately 11 degrees during HS-WBRT using VMAT improved dose distribution in the planning target volume and allowed lower doses to the hippocampi and optic apparatus. PMID- 27221314 TI - Influence of different types of contact hypersensitivity on imiquimod-induced psoriasis-like inflammation in mice. AB - It is currently believed that psoriasis and allergic contact dermatitis (ACD) are different diseases; however, they share clinical similarities. The involvement of T helper 17 (Th17) cells in these disorders provides a novel opportunity to investigate the relationship between them. The present study aimed to determine whether the same or overlapping inflammatory pathways are involved in the two diseases, and the influence of different types of ACD on psoriasis. Compound mouse models of Th1 or Th2-type contact hypersensitivity (CHS) combined with imiquimod (IMQ)-induced psoriasis-like inflammation were established, in order to mimic the characteristics of ACD and psoriasis. Histopathology, immunohistochemistry and cytokine detection in blood serum and tissues were used to compare the differences between the mice treated with IMQ alone or IMQ combined with Th1 and Th2-type CHS. As compared with the IMQ-treated mice or IMQ treated Th1-type CHS mice, the mice with Th2-type CHS treated with IMQ exhibited more serious psoriasis-like inflammation with increased epidermal thickness and infiltrating cells in the derma. High mRNA expression levels of interleukin (IL) 17, IL-22, IL-23, TNF-alpha and RORgammat were detected in back skin lesions. Additionally, high levels of IL-17 and IL-22 in blood serum were detected in IMQ treated mice combined with Th2-type CHS. The mice treated with IMQ alone, and IMQ treatment combined with Th1-type CHS had a comparable psoriasis-like inflammatory response in the back skin. In conclusion, these data demonstrate that Th2-type CHS exacerbated the IMQ-treated psoriatic inflammation of mice via the IL-23/IL 17 axis. Th17 cells and associated pathways may link ACD and psoriasis. Therefore, patients with psoriasis should avoid contact with specific sensitizers, such as fragrance and rubber products, which may induce Th2 polarization. PMID- 27221315 TI - Control of Stress-Induced ACTH Secretion by Vasopressin and CRH: Additional Evidence. AB - Vasopressin and CRH have complementary roles in the secretion of ACTH following different stress modalities. The concomitant use of V1b and CRF1 receptor antagonists completely inhibits ACTH secretion in response to different stress modalities. The combination of the CRF1 antagonist SSR125543 with the V1b antagonist SSR149415 effectively suppressed plasma ACTH 1.30 h after injection in rats stressed by ether vapor inhalation for 1 min, restraint stress for 1 h or forced swimming for 5 min. The duration of the effect was also studied. The CRF1 antagonist effectively suppressed ACTH secretion in restraint stress, while the V1b antagonist was effective against ether inhalation. Both antagonists were necessary to block the forced swimming stress response. SSR125543 induced a prolonged effect and can be used in a model of prolonged HPA axis blockade. PMID- 27221316 TI - Acute Autonomic Engagement Assessed by Heart Rate Dynamics During Vagus Nerve Stimulation in Patients With Heart Failure in the ANTHEM-HF Trial. AB - BACKGROUND: Chronic vagus nerve stimulation (VNS) applied to produce biomimetic levels of parasympathetic activation is feasible, well tolerated, safe, improves left ventricular ejection fraction, NYHA class, heart rate variability, and baroreflex function, and reduces T-wave alternans (TWA) in patients with chronic heart failure. However, the acute effects of VNS on beat-to-beat heart rate dynamics have not been systematically characterized in humans. METHODS AND RESULTS: We evaluated acute effects of VNS on R-R-interval dynamics during the VNS titration period in patients (n = 59) enrolled in ANTHEM-HF trial by quantifying effects during continuous cyclic VNS (14-seconds on-time, 66-seconds off-time) adjusted to the maximum tolerable dose without excessive (<4 bpm) bradycardia during the 10-week titration period. VNS elicited an immediate change in heart rate that was correlated to VNS current amplitude, pulse width, and frequency. Heart rate decreased more in the 28 patients with right-sided stimulation (-2.22 +/- 0.13 bpm) than in the 31 patients with left-sided stimulation (-0.60 +/- 0.08 bpm, P < 0.001). The linear correlation between stimulus intensity and lengthening of the R-R interval was stronger among the 28 patients with right-sided VNS implantation (r = 0.88, P < 0.0001) than among the 31 patients with left-sided VNS implantation (r = 0.49, P < 0.002). In all patients, the heart rate change elicited by VNS was significantly greater than the change during the same timing intervals in 10 randomly selected patients without stimulation (+0.08 +/- 0.06 bpm, P < 0.001). CONCLUSION: Instantaneous heart rate change during therapeutic levels of VNS in patients with heart failure indicates consistent modulation of the autonomic nervous system for both left- and right-sided stimulation. PMID- 27221318 TI - Calsyntenin-1 mediates hepatitis C virus replication. AB - The hepatitis C virus (HCV) RNA genome of 9.6 kb encodes only 10 proteins, and so is highly dependent on host hepatocyte factors to facilitate replication. We aimed to identify host factors involved in the egress of viral particles. By screening the supernatant of HCV-infected Huh7 cells using SILAC-based proteomics, we identified the transmembrane protein calsyntenin-1 as a factor specifically secreted by infected cells. Calsyntenin-1 has previously been shown to mediate transport of endosomes along microtubules in neurons, through interactions with kinesin light chain-1. Here we demonstrate for the first time, we believe, a similar role for calsyntenin-1 in Huh7 cells, mediating intracellular transport of endosomes. In HCV-infected cells we show that calsyntenin-1 contributes to the early stages of the viral replication cycle and the formation of the replication complex. Importantly, we demonstrate in our model that silencing calsyntenin-1 disrupts the viral replication cycle, confirming the reliance of HCV on this protein as a host factor. Characterizing the function of calsyntenin-1 will increase our understanding of the HCV replication cycle and pathogenesis, with potential application to other viruses sharing common pathways. PMID- 27221320 TI - The bio-gripper: a fluid-driven micro-manipulator of living tissue constructs for additive bio-manufacturing. AB - We previously developed the Bio-Pick, Place, and Perfuse (Bio-P3) instrument to fabricate large perfusable tissue constructs by stacking and aligning scaffold free living microtissues with integrated lumens. The Bio-P3 required an actuating mechanism to manipulate living microtissues of various sizes and shapes that are fragile, and must remain in an aqueous environment. The optical transparency of the Bio-P3 gripping device was essential to provide unobstructed visuals for accurate alignment of microtissues. We previously engineered a pilot fluid force driven bio-gripper that can pick-and-place microtissue in planar position without causing cellular damage by pulling culture medium through track-etched membrane integrated cell culture inserts. In this study, we invented a new flexible bio gripper design that maximized the bio-gripper utilities. We utilized experimental approaches, multivariate analyzes, and theoretical modeling to elucidate how membrane characteristics (pore size, pore density, membrane thickness, membrane area, and surface chemistry) altered bio-gripper robustness and the flow rate (Q(c)) required for successful gripping. We devised two standardized tests and synthetic parts that mimicked microtissues, to systematically quantify bio gripper performance. All thirteen syringe pump-driven bio-grippers except one successfully gripped and released synthetic parts with values of Q(c) that coincided with our mathematical simulation of the fluid mechanics of gripping. The bio-gripper could grip synthetic parts of various sizes, shapes and masses, demonstrating the robustness of the actuating mechanism. Multivariate analysis of experimental data indicated that both membrane porosity and thickness modulated Q(c), and in addition, revealed that membrane pore density determined membrane optical transparency. Fabricating large tissue constructs requires repeated stacking of microtissues. We showed that one bio-gripper could pick-and-place living microtissues thirty times with Q(c) corresponding to our simulation. Our bio-gripper was capable of stacking and aligning twenty microtissues. In summary, we successfully engineered a robust controllable fluid-driven bio-gripper to efficiently manipulate living microtissues and micro-objects in an aqueous environment. PMID- 27221319 TI - The Antenatal Corticosteroids Trial (ACT): a secondary analysis to explore site differences in a multi-country trial. AB - BACKGROUND: The Antenatal Corticosteroid Trial (ACT) assessed the feasibility, effectiveness, and safety of a multifaceted intervention to increase the use of antenatal corticosteroids (ACS) in mothers at risk of preterm birth at all levels of care in low and middle-income countries. The intervention effectively increased the use of ACS but had no overall impact on neonatal mortality in the targeted <5(th) percentile birth weight infants. Being in the intervention clusters was also associated with an overall increase in neonatal deaths. We sought to explore plausible pathways through which this intervention increased neonatal mortality. METHODS: We conducted secondary analyses to assess site differences in outcome and potential explanations for the differences in outcomes if found. By site, and in the intervention and control clusters, we evaluated characteristics of the mothers and care systems, the proportion of the <5(th) percentile infants and the overall population that received ACS, the rates of possible severe bacterial infection (pSBI), determined from clinical signs, and neonatal mortality rates. RESULTS: There were substantial differences between the sites in both participant and health system characteristics, with Guatemala and Argentina generally having the highest levels of care. In some sites there were substantial differences in the health system characteristics between the intervention and control clusters. The increase in ACS in the intervention clusters was similar among the sites. While overall, there was no difference in neonatal mortality among <5(th) percentile births between the intervention and control clusters, Guatemala and Pakistan both had significant reductions in neonatal mortality in the <5(th) percentile infants in the intervention clusters. The improvement in neonatal mortality in the Guatemalan site in the <5(th) percentile infants was associated with a higher level of care at the site and an improvement in care in the intervention clusters. There was a significant increase overall in neonatal mortality in the intervention clusters compared to the control. Across sites, this increase in neonatal mortality was statistically significant and most apparent in the African sites. This increase in neonatal mortality was accompanied by a significant increase in pSBI in the African sites. CONCLUSIONS: The improvement in neonatal mortality in the Guatemalan site in the <5(th) percentile infants was associated with a higher level of care and an improvement in care in the intervention clusters. The increase in neonatal mortality in the intervention clusters across all sites was largely driven by the poorer outcomes in the African sites, which also had an increase in pSBI in the intervention clusters. We emphasize that these results come from secondary analyses. Additional prospective studies are needed to assess the effectiveness and safety of ACS on neonatal health in low resource settings. TRIAL REGISTRATION: TRIAL REGISTRATION: clinicaltrials.gov (NCT01084096). PMID- 27221321 TI - Use of antimicrobial resistance information and prescribing guidance for management of urinary tract infections: survey of general practitioners in the West Midlands. AB - BACKGROUND: There is a marked variation in both antibiotic prescribing practice and urine sampling rates for diagnostic microbiology across general practices in England. To help understand factors driving this variation, we undertook a survey in 2012/13 to determine sampling protocols and antibiotic formularies used by general practitioners (GPs) for managing urinary tract infections (UTIs) in the West Midlands region of England. METHOD: Cross-sectional survey of all eligible general practices in the West Midlands region of England undertaken in November 2012. GPs were invited to complete an online survey questionnaire to gather information on policies used within the practice for urine sampling for microbiological examination, and the source of antibiotic formularies used to guide treatment of UTIs. The questionnaire also gathered information on how they would manage five hypothetical clinical scenarios encountered in the community. RESULTS: The response rate was 11.3 % (409/3635 GPs), equivalent to a practice response rate of 26 % (248/950). Only 50 % of GPs reported having a practice policy for urine sampling. Although there was good agreement from GPs regarding collecting specimens in scenarios symbolising treatment failure (98 %), UTI in an adult male (98 %) and asymptomatic UTI in pregnancy (97 %), there was variation in GPs requesting a specimen for the scenarios involving a suspected uncomplicated urinary tract infection (UTI) and an asymptomatic catheterised elderly patient; with 40 and 38 % respectively indicating they would collect a specimen for microbiological examination. CONCLUSION: Standardised evidence based clinical management policies and antibiotic formularies for GPs should be readily available. This will promote the rational use of diagnostic microbiology services, improve antimicrobial stewardship and aid the interpretation of ongoing antimicrobial resistance surveillance. PMID- 27221322 TI - Polyphosphate: popping up from oblivion. AB - Phosphate is one of the essential elements supporting life. Cells accumulate phosphate in the form of a molecule called polyphosphate (polyP), which carries many functions in the physiology of cells that have not been wholly elucidated. Polyphosphate is present in all the types of cells from bacteria to mammals. It consists of a linear polymer constructed with anywhere from a few to hundreds of inorganic phosphate (Pi) molecules linked by phosphoanhydride bonds. Although polyP was described many years ago, difficulties in the study of its roles, most likely due to the many processes polyP is involved in and incomplete information obtained from multiple models and organisms relegate polyP into oblivion. But now, several interesting pieces of evidence are resurrecting the polyP as a key molecule in processes, such as protein folding, carbon metabolism, cell cycle progression, dNTP synthesis, and genomic stability. In this contribution, in addition to briefly summarize the polyP history and roles, we discuss its involvement in supporting cell cycle progression and genomic stability as well as the implications for the truthful replication of genomes. PMID- 27221323 TI - Brodalumab for the Treatment of Psoriasis: A Review of Phase III Trials. AB - INTRODUCTION: Interleukin (IL)-17 inhibitors are the most recent class of monoclonal antibodies approved by the FDA for psoriasis treatment. Preclinical and phase II studies of brodalumab, a high-affinity IL-17 receptor monoclonal antibody, have been encouraging. METHODS: We conducted a literature search using the PubMed database in order to assess the efficacy and safety profile of brodalumab. The search included the following key words: "psoriasis" and "IL-17" or "brodalumab." We also reviewed citations within articles to identify relevant sources. RESULTS: At week 12, the proportion of patients attaining a 75% improvement from the baseline Psoriasis Area and Severity Index (PASI 75) was similar among the three phase III trials (AMAGINE-1, 83%; AMAGINE-2, 86%; AMAGINE 3, 85%). Brodalumab remained efficacious through 52 weeks of treatment. It maintained a satisfactory safety profile; the most frequently reported adverse events consisted of nasopharyngitis, headache, upper respiratory tract infection, and arthralgia. CONCLUSION: Use of brodalumab revealed prompt clinical improvement and a favorable short-term safety profile in phase III trials, although further extension studies are needed to assess long-term safety. Based on the results, brodalumab appears to be a potent therapeutic option for patients with moderate-to-severe plaque-type psoriasis. PMID- 27221324 TI - Nonsense-mediated mRNA decay factor Upf2 exists in both the nucleoplasm and the cytoplasm. AB - Upf2 protein predominantly localizes to the cytoplasmic fraction, and binds to the exon junction complex (EJC) on spliced mRNA. The present study aimed to determine the cellular site where the interaction between Upf2 and EJC occurs. First, the cell lysate was fractionated into the cytoplasm and nucleoplasm, and western blotting to detect levels of Upf2 protein was performed. Upf2 was clearly detected in the cytoplasm and in the nucleoplasm. Secondly, immunostaining was performed, and the majority of Upf2 was detected in the cytoplasmic perinuclear region; a small quantity of Upf2 was detected in the intranuclear region. RNase treatment of the cells reduced the Upf2 immunostained signal. The immunopurified fractions containing nuclear and cytoplasmic Upf2 also contained one of the EJC core factors, RBM8A. These results implied the existence of Upf2 in the nucleoplasm and the cytoplasm, and it appeared to be involved in the construction of the mRNA complex. In order to verify the construction of Upf2-binding EJC in the nucleoplasm, an in situ proximity ligation assay was performed with anti-Upf2 and anti-RBM8A antibodies. These results demonstrated that their interaction occurred not only in the cytoplasmic region, but also in the intranuclear region. Taken together, these results suggested that Upf2 combines with EJC in both the cytoplasmic and the intranuclear fractions, and that it is involved in mRNA metabolism in human cells. PMID- 27221325 TI - High-frequency brain networks undergo modular breakdown during epileptic seizures. AB - OBJECTIVE: Cortical high-frequency oscillations (HFOs; 100-500 Hz) play a critical role in the pathogenesis of epilepsy; however, whether they represent a true epileptogenic process remains largely unknown. HFOs have been recorded in the human cortex but their network dynamics during the transitional period from interictal to ictal phase remain largely unknown. We sought to determine the high frequency network dynamics of these oscillations in patients with epilepsy who were undergoing intracranial electroencephalographic recording for seizure localization. METHODS: We applied a graph theoretical analysis framework to high resolution intracranial electroencephalographic recordings of 24 interictal and 24 seizure periods to identify the spatiotemporal evolution of community structure of high-frequency cortical networks at rest and during multiple seizure episodes in patients with intractable epilepsy. RESULTS: Cortical networks at all examined frequencies showed temporally stable community architecture in all 24 interictal periods. During seizure periods, high-frequency networks showed a significant breakdown of their community structure, which was characterized by the emergence of numerous small nodal communities, not limited to seizure foci and encompassing the entire recorded network. Such network disorganization was observed on average 225 s before the electrographic seizure onset and extended on average 190 s after termination of the seizure. Gamma networks were characterized by stable community dynamics during resting and seizure periods. SIGNIFICANCE: Our findings suggest that the modular breakdown of high-frequency cortical networks represents a distinct functional pathology that underlies epileptogenesis and corresponds to a cortical state of highest propensity to generate seizures. PMID- 27221326 TI - Proceedings of the World Molecular Imaging Congress 2015, Honolulu, Hawaii, September 2-5, 2015: Late-Breaking Abstracts. PMID- 27221327 TI - Ineffective Health Management in People With Heart Failure: A Pilot Study. AB - OBJETIVO: Investigar a aplicabilidade clinica das definicos conceituais e operacionais das caracteristicas definidoras (CD) e fatores relacionados (FR) de Controle ineficaz da saude em pessoas com insuficiencia cardiaca. METHODS: Estudo piloto transversal. A presenca das CD e FRfoi investigada com base nas definicoses conceituais e operacionais. As frequenciasforam utilizadas para analise. RESULTADOS: Dos 33 participantes, 32 (97%) tinham Controle ineficaz da saude.A principal CD foi Escolhas na vida diaria ineficazes para atingir as meta de saude, e oprincipal FR foi Impotencia CONCLUSAO: As definicoes conceituais e operacionais foram aplicaveis a pratica clinica, com excecao de Beneficio percebido, Suscetibilidade percebida e Gravidade da condicao percebida, as quais devem ser modificadas. PMID- 27221329 TI - The postantibiotic effect and post-beta-lactamase-inhibitor effect of ceftazidime, ceftaroline and aztreonam in combination with avibactam against target Gram-negative bacteria. AB - The magnitudes of the postantibiotic effect (PAE) and post-beta-lactamase inhibitory effect (PLIE) of ceftazidime-avibactam, ceftaroline-avibactam, and aztreonam-avibactam were determined against isolates of Enterobacteriaceae and Pseudomonas aeruginosa that either harboured genes encoding serine and/or metallo beta-lactamases, or did not harbour bla genes. The bla genes included ones that encoded extended spectrum beta-lactamases, AmpC and KPC beta-lactamases, and one metallo-beta-lactamase, NDM-1. No substantial PAE was observed for any combination against any isolate. One substantial PLIE was found: a value of 1.9 h for ceftazidime-avibactam against Klebsiella pneumoniae (blaKPC-2 ). From comparison with results in the literature, we propose that the existence of a substantial PLIE depends on the bacterial isolate and on the specific beta lactamase inhibitor and beta-lactam combination. SIGNIFICANCE AND IMPACT OF THE STUDY: A wave of new beta-lactamase inhibitors is entering either therapeutic use or clinical trials. The present work characterizes the postantibiotic effect (PAE) and post-beta-lactamase-inhibitory effect (PLIE) of the clinically most advanced of these compounds, avibactam. We show that the existence of a measurable PLIE is strain- (and possibly compound-) dependent, and cannot be relied upon as a standard component of the primary pharmacology of a new beta lactamase inhibitor. This variability was not reported in earlier studies of clavulanic acid or sulbactam. PMID- 27221328 TI - [Submandibular gland resection for the management of sialorrhea in paediatric patients with cerebral palsy and unresponsive to type A botullinum toxin. Pilot study]. AB - BACKGROUND: Sialorrhoea has a prevalence of between 10% and 58% in patients with cerebral palsy. Amongst the invasive treatments, botulinum toxin-A injections in submandibular and parotid glands and various surgical techniques are worth mentioning. There are no studies in Mexico on the usefulness of surgery to manage sialorrhoea. OBJECTIVE: To evaluate the usefulness of submandibular gland resection in improving sialorrhoea in patients with cerebral palsy and with a poor response to botulinum toxin. MATERIAL AND METHODS: Experimental, clinical, self-controlled, prospective trial was conducted to evaluate the grade of sialorrhoea before surgery, and 8, 16 and 24 weeks after. Statistical analysis was performed using a non-parametric repetitive measure assessment, considering a p < 0.05 as significant. Complications and changes in salivary composition were evaluated. RESULTS: Surgery was performed on 3 patients with severe sialorrhoea, and 2 with profuse sialorrhoea, with mean age of 10.8 years. The frequency and severity of sialorrhoea improved in the 5 patients, with mean of 76.7 and 87.5% improvement, respectively. The best results were seen after 6 months of surgery, with a statistically significant difference between the preoperative stage and 6 months after the procedure (p = 0.0039, 95% CI). No significant differences were observed in complications, increase in periodontal disease or cavities, or salivary composition. CONCLUSIONS: Submandibular gland resection is an effective technique for sialorrhoea control in paediatric patients with cerebral palsy, with a reduction in salivary flow greater than 80%. It has a low chance of producing complications compared to other techniques. It led to an obvious decrease in sialorrhoea without the need to involve other salivary glands in the procedure. PMID- 27221330 TI - Correlation between County-Level Surgeon Density and Mortality from Colorectal Cancer. AB - PURPOSE: We aimed to explore the effect of county-level general surgeon (GS) and colorectal surgeon (CS) density on colorectal cancer (CRC) mortality and to identify additional county characteristics associated with outcomes. METHODS: Using data from the Area Resource File, US Census, and National Cancer Institute, we developed multivariate regression models to determine the effect of density of GS and CS on CRC death between 2005 and 2009 while controlling for CRC incidence, county demographics, and other socioeconomic factors. RESULTS: In total, we included 1767 counties: Mean CRC incidence and death rates were 64.9 and 19.9 %, respectively. In this cohort, 45 % were metropolitan areas. Mean GS and CS densities were 7.2 and 0.15 per 100,000 people, respectively. Counties with at least 1 GS had a statistically significant decrease in CRC-specific mortality (beta coefficient -0.18, p < 0.001). Increasing GS density beyond 8 per 100,000 people did not result in any further meaningful reductions in mortality. The presence of at least 1 CS at the county-level was not associated with differences in CRC mortality (beta coefficient -0.021, p = 0.37). Metropolitan counties and a larger percentage of individuals who were <65 years old were associated with decreased CRC mortality. Conversely, a higher proportion below the poverty line was correlated with a significant increase in CRC mortality. CONCLUSION: Unlike CS, the presence of GS at the county-level was associated with lower CRC mortality. However, increasing GS density beyond a certain point did not result in further meaningful reductions in mortality. A balanced strategy of distributing the surgical workforce across all counties can result in population based improvements in CRC outcomes. PMID- 27221331 TI - Habitat use by Centropomus undecimalis in a rocky area of estuarine beach in north-east Brazil. AB - The influence of habitat, diel period, tidal phase and moon phase on the spatial distribution of Centropomus undecimalis was investigated at the mouth of the Timbo estuary, north-east Brazil. Underwater visual censuses were conducted in three areas comprising a mix of mud, sand and beach rock substrata; with one of the areas having additional structural complexity in the form of unused wooden debris. The area with debris housed significantly higher densities of juvenile and adult C. undecimalis whereas sub-adults were more abundant in an area lacking the wooden debris. Juvenile abundance was greatest during the day, whereas sub adult and adults were more abundant at night. There were significant interactions between habitat, diel period, tidal phase and moon phase for all ages of C. undecimalis. These results emphasize the need to account for a range of environmental factors when planning for the conservation of estuarine and coastal habitats. PMID- 27221332 TI - In Vivo Effects of Mesenchymal Stromal Cells in Two Patients With Severe Acute Respiratory Distress Syndrome. PMID- 27221333 TI - Hb Savaria [alpha49(CE7)Ser->Arg; HBA2: c.150C > A]: A New Case and Complete Description. AB - Hb Savaria [alpha49(CE7)Ser->Arg; HBA2: c.150C > A] is a rare hemoglobin (Hb) variant, initially described in Eastern Europe but present worldwide. It belongs to that class of variants which can be confused with Hb S [beta6(A3)Glu->Val; HBB: c.20A > T] by automated protein analysis and thus needs special tests for proper identification. Because it could arise from different nucleotide substitutions and according to the rules of the Human Genome Variation Society (HGVS) nomenclature, three 'Hb Savaria' variants are possible. In the case reported here it resulted from the HBA2: c.148A > C change. PMID- 27221334 TI - The effect of self-monitoring on Wisconsin Card Sorting Test performance in euthymic patients with bipolar disorder: a pilot study. AB - OBJECTIVES: Euthymic patients with bipolar disorder (BD) show executive impairment. Assisting cognitive function with non-pharmacological strategies has not been widely explored in BD. In schizophrenia, concomitant verbalisation (self monitoring) during executive tests improved performance. The present pilot study assesses the effects of self-monitoring whilst completing the Wisconsin Card Sorting Test (WCST) in BD patients. METHODS: Thirty-six euthymic BD patients and 42 healthy controls participated. Twenty patients with BD and 20 controls received standard administration and 16 patients and 22 controls used self monitoring during the test. RESULTS: ANCOVA revealed a significant "group by administration" interaction. Patients who received the standard administration were significantly worse than healthy controls (trials administered: p = .012, eta p (2) = 0.17; trials to first category: p = .046, eta p (2) = 0.11; failure to maintain set: p = .003, eta p (2) = 0.23). BD patients who self-monitored performed significantly better than patients receiving the standard administration (trials to first category: p = .020, eta p (2) = 0.17) and showed no significant differences in performance compared to controls. CONCLUSION: Self monitoring deserves further investigation as a tool that may be helpful for patients with BD. Further exploration of the utility, generalisability, and stability of the effects of self-monitoring is needed. PMID- 27221335 TI - Regenerative effect of hOPG gene-modified autologous PDLs in combination with cell transplantation on periodontal defection in beagle dogs. AB - This study evaluated the ability of human osteoprotegerin gene-modified autologous periodontal ligament cells (PDLCs) in combination with cell transplantation to promote periodontal regeneration in beagle dogs. Adenovirus Ad5-hOPG-EGFP-transfected PDLCs and BME-10X collagen membranes were fabricated and used for periodontal repair. Buccal periodontal defects (mesiodistal width * depth: 5 * 5 mm) were created on the second, third, and fourth mandibular premolars in six normal beagle dogs, and the defects were histologically and histomorphometrically assessed for periodontal regeneration in the following four groups: (1) hOPG-PDLCs + BME-10X, (2) mock-PDLCs + BME-10X, (3) PDLCs + BME-10X, and (4) BME-10X. The radiographic and histological results suggested that hOPG PDLCs significantly promoted periodontal defect repair. This study demonstrates the potential of hOPG-modified PDLCs for periodontal tissue regeneration. PMID- 27221337 TI - Whole-genome DNA methylation and hydroxymethylation profiling for HBV-related hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a common solid tumor worldwide with a poor prognosis. Accumulating evidence has implicated important regulatory roles of epigenetic modifications in the occurrence and progression of HCC. In the present study, we analyzed 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) levels in the tumor tissues and paired adjacent peritumor tissues (APTs) from four individual HCC patients using a (hydroxy)methylated DNA immunoprecipitation approach combined with deep sequencing [(h)MeDIP-Seq]. Bioinformatics analysis revealed that the 5-mC levels in the promoter regions of 2796 genes and the 5-hmC levels in 507 genes differed significantly between HCC tissues and APTs. These differential genes were grouped into various clusters and pathways and found to be particularly enriched in the 'metabolic pathways' that include 'Glycolysis/gluconeogenesis', 'Oxidative phosphorylation' and 'Citrate cycle (TCA cycle)', implicating a potential role of metabolic alterations in HCC. Furthermore, 144 genes had both 5-mC and 5-hmC changes in HCC patients, and 10 of them (PCNA, MDM2, STAG1, E2F4, FGF4, FGF19, RHOBTB2, UBE2QL1, DCN and HSP90AA1) were enriched and interconnected in five pathways including the 'Cell cycle', 'Pathway in cancer', 'Ubiquitin mediated proteolysis', 'Melanoma' and 'Prostate cancer' pathways. The genome-wide mapping of 5-mC and 5-hmC in HCC tissues and APTs indicated that both 5-mC and 5-hmC epigenetic modifications play important roles in the regulation of HCC, and there may be some interconnections between them. Taken together, in the present study we conducted the first genome-wide mapping of DNA methylation combined with hydroxymethylation in HBV-related HCC and provided a series of potential novel epigenetic biomarkers for HCC. PMID- 27221336 TI - Luteolin alleviates methylglyoxal-induced cytotoxicity in osteoblastic MC3T3-E1 cells. AB - Methylglyoxal (MG), a reactive sugar-derived metabolite, exerts harmful effects by inducing oxidative stress, which aggravates a series of diabetic complications, including osteoporosis. The present study was performed to examine the effects of luteolin, a dietary polyphenolic flavonoid, on MG-induced cytotoxicity in MC3T3-E1 osteoblastic cells. Pretreatment of MC3T3-E1 osteoblastic cells with luteolin prevented MG-induced cell death and production of tumor necrosis factor-alpha, intracellular reactive oxygen species, mitochondrial superoxide, and cardiolipin peroxidation. In addition, luteolin increased the levels of glutathione and nuclear factor erythroid 2-related factor 2 (Nrf2) and decreased the inhibition of heme oxygenase-1 activity by MG. Pretreatment with luteolin prior to MG exposure reduced MG-induced mitochondrial dysfunction and increased the peroxisome proliferator-activated receptor gamma co activator 1alpha (PGC-1alpha) and nitric oxide levels, suggesting that luteolin may induce mitochondrial biogenesis. Taken together, these observations indicated that luteolin has potential as a preventive agent against the development of diabetic osteopathy related to MG-induced oxidative stress in diabetes. PMID- 27221338 TI - C-Reactive Protein Promotes Diabetic Kidney Disease in db/db Mice via the CD32b Smad3-mTOR signaling Pathway. AB - C-reactive protein (CRP) is associated with progressive diabetic nephropathy in patients with type-2 diabetes (T2DN). However, role of CRP in T2DN remains unclear. We report here that CRP is pathogenic in T2DN in db/db mice that express human CRP (CRPtg-db/db). Compared to the littermate db/db mice, CRPtg-db/db developed more severe T2DN, showing higher levels of fasting blood glucose and microalbuminuria and more progressive renal inflammation and fibrosis. Enhanced T2DN in CRPtg-db/db mice were associated with over-activation of CRP-CD32b, NF kappaB, TGF-beta/Smad3, and mTOR signaling. Further studies in vitro defined that CRP activated Smad3 directly at 15 mins via the CD32b- ERK/p38 MAP kinase crosstalk pathway and indirectly at 24 hours through a TGF-beta1-dependent mechanism. Importantly, CRP also activated mTOR signaling at 30 mins via a Smad3 dependent mechanism as Smad3 bound mTOR physically and CRP-induced mTOR signaling was abolished by a neutralizing CD32b antibody and a specific Smad3 inhibitor. Finally, we also found that CRP induced renal fibrosis through a CD32b-Smad3-mTOR pathway because blocking mTOR signaling with rapamycin inhibited CRP-induced CTGF and collagen I expression. Thus, CRP is pathogenic in T2DN. CRP may promote CD32b NF-kappaB signaling to mediate renal inflammation; whereas, CRP may enhance renal fibrosis in T2DN via CD32b-Smad3-mTOR signaling. PMID- 27221339 TI - Reporter Systems to Study Cancer Stem Cells. AB - Cancer stem cells have been identified in primary tumors, patient derived xenografts, and established cancer cell lines. The development of reporters has enabled investigators to rapidly enrich for these cells and more importantly track these cells in real time. Here we describe the current state of the reporter field and their use and limitations in multiple cancers. PMID- 27221340 TI - Pigment Production Analysis in Human Melanoma Cells. AB - The human epidermal melanocyte is a highly specialized pigmented cell that serves to protect the epidermis from ultraviolet (UV) damage through the production of melanin, or melanogenesis. Misregulation in melanogenesis leading to either hyper or hypo-pigmentation is found in human diseases such as malasma and vitiligo. Current therapies for these diseases are largely unsuccessful and the need for new therapies is necessary. In order to identify genes and or compounds that can alter melanogenesis, methods are required that can detect changes in pigment production as well as expression of key melanogenesis transcription factors and enzymes. Here we describe methods to detect changes in melanogenesis in a human melanoma cell line, MNT-1, by (1) analyzing pigment production by measuring the absorbance of melanin present by spectrophotometry, (2) analyzing transcript expression of potent regulators of melanogenesis by qunatitative reverse transcription (RT)PCR and (3) analyzing protein expression of potent regulators of melanogenesis by Western blot (WB). PMID- 27221342 TI - Synthesis of TiO2 /CNT Composites and its Photocatalytic Activity Toward Sudan (I) Degradation. AB - Semiconductor photocatalysis has the potential for achieving sustainable energy generation and degrading organic contaminants. In TiO2 , the addition of carbonaceous nanomaterials has attracted extensive attention as a means to increase its photocatalytic activity. In this study, composites of TiO2 and carbon nanotubes (CNT) in various proportions were synthesized by the hydrothermal method. The crystalline structures, morphologies, and light absorption properties of the TiO2 /CNT photocatalysts were characterized by PXRD, TEM and UV-Vis absorption spectra. The photocatalytic efficiency of the composites was evaluated by the degradation of Sudan (I) in UV-Vis light. Introducing 0.1-0.5 wt% CNT was shown to substantially improve the photoactivity of TiO2 . The composite with 0.3 wt% CNT showed the best catalytic activity, and its reaction activation energy was calculated as 39.57 kJ mol(-1) from experimental rates. The degradation products of Sudan (I) with different irradiation durations were characterized by Fourier transform infrared spectroscopy, and a degradation reaction process was proposed. PMID- 27221343 TI - The Developmental History of IgE and IgG4 Antibodies in Relation to Atopy, Eosinophilic Esophagitis, and the Modified TH2 Response. AB - A common reaction from anyone confronted with allergy is the question: what prevents universal allergy? We will discuss recent findings in the mouse system that have provided us with clues on why allergy is not more common. We will also address one crucial aspect of atopic allergy in humans, which is absent in most mouse model systems, an IgG/IgE ratio <10. We consider the typical mouse IgE response to be more closely related to the "modified TH2" response in humans. We will discuss the similarities and differences between the IgE and IgG4 response to allergens and an update on the IgG4 B cell, partly derived from studies on eosinophilic esophagitis and IgG4-related diseases. PMID- 27221345 TI - The immiscibility of InAlN ternary alloy. AB - We have used two models based on the valence force field and the regular solution model to study the immiscibility of InAlN ternary alloy, and have got the spinodal and binodal curves of InAlN. Analyzing the spinodal decomposition curves, we obtain the appropriate concentration region for the epitaxial growth of the InN-AlN pseudobinary alloy. At a temperature most common for the epitaxial growth of InAlN (1000 K), the solubility of InN is about 10%. Then we introduce the mismatch strain item into the Gibbs free energy, and the effect of different substrates is taken into consideration. Considering Si, Al2O3, InN, GaN, AlN as a substrate respectively, it is found that all the five systems are stabilized with the upper critical solution temperature largely reduced. Finally, InN and GaN are potential substrates for In-rich InAlN, while AlN and GaN substrates are recommended in the Al-rich region. Si and Al2O3 may be ideal substrates for thin InAlN film. PMID- 27221344 TI - A conserved leucine occupies the empty substrate site of LeuT in the Na(+)-free return state. AB - Bacterial members of the neurotransmitter:sodium symporter (NSS) family perform Na(+)-dependent amino-acid uptake and extrude H(+) in return. Previous NSS structures represent intermediates of Na(+)/substrate binding or intracellular release, but not the inward-to-outward return transition. Here we report crystal structures of Aquifex aeolicus LeuT in an outward-oriented, Na(+)- and substrate free state likely to be H(+)-occluded. We find a remarkable rotation of the conserved Leu25 into the empty substrate-binding pocket and rearrangements of the empty Na(+) sites. Mutational studies of the equivalent Leu99 in the human serotonin transporter show a critical role of this residue on the transport rate. Molecular dynamics simulations show that extracellular Na(+) is blocked unless Leu25 is rotated out of the substrate-binding pocket. We propose that Leu25 facilitates the inward-to-outward transition by compensating a Na(+)- and substrate-free state and acts as the gatekeeper for Na(+) binding that prevents leak in inward-outward return transitions. PMID- 27221346 TI - Origin and spread of HIV-1 in persons who inject drugs in Bulgaria. AB - Increased HIV transmission in persons who inject drugs (PWIDs) has led to subepidemics and outbreaks in several countries in Europe, including Bulgaria. In this study in Bulgaria, we investigate the origin and spatiotemporal evolutionary history of HIV-1 infections in PWIDs and the distribution of antiretroviral resistance mutations and hepatitis co-infections in these populations. We analyzed HIV-1 polymerase sequences available from 117 of 359 PWIDs diagnosed with HIV/AIDS from 1999 to 2011. Of these, 50 (42.7%) were classified as CRF02_AG, 41 (35.0%) CRF01_AE, 12 (10.3%) URFs, ten (8.5%) subtype B, two (1.7%) subtype F1 and two (1.7%) CRF14_BG. Most recent common ancestor dating suggests that CRF01_AE was likely first introduced from Southeast Asia into persons reporting heterosexual infection in Bulgaria in 1992 and spread subsequently to PWIDs in the capital city of Sofia around 2003. Conversely, CRF02_AG in Bulgaria was likely first introduced into PWID from Germany in 2000 and later entered heterosexual populations around 2009. The overall prevalence of resistance mutations was 6.8% (8/117), of which 5.1% (5/117) was observed in patients on antiretroviral therapy and 1.7% (2/117) was from transmitted drug resistance mutations in drug-naive individuals. 189/204 (92.6%) PWIDs were also co-infected with hepatitis C (HCV) and 31/183 (16.9%) were co-infected with hepatitis B (HBV). Our study provides valuable molecular epidemiological information on the introduction and distribution of the main HIV-1 subtypes, resistance mutations and hepatitis co-infections among PWIDs with HIV-1 in Bulgaria which can be used to target prevention efforts. PMID- 27221347 TI - Green Synthesis of High-Purity Mesoporous Gold Sponges Using Self-Assembly of Gold Nanoparticles Induced by Thiolated Poly(ethylene glycol). AB - A facile and green synthesis method for mesoporous gold sponges has been developed, which involves a simple mixing of a very small amount of thiolated poly(ethylene glycol) (SH-PEG) and citrate-covered gold nanoparticles (Au NPs) in aqueous solution at room temperature. While SH-PEG molecules have been widely used as biocompatible hydrophilic capping agents for Au NPs for stable dispersion in aqueous solution, here they are used as destabilizing agents. When SH-PEG molecules are mixed with citrate-covered Au NPs at the molar ratio ranging from 3 to 20 (SH-PEG/Au NP), mesoporous gold sponges with randomly interconnected 3D network structures are formed within 2 to 3 h. This is driven by the destabilization of negatively charged citrate molecules on Au NPs by a small number of SH-PEG molecules bonded on the particle surface, which results in the decrease in zeta potential and thus the assembly of Au NPs into porous sponges. The use of very low concentration of SH-PEG (ca. 20-200 nM) in aqueous solution at room temperature makes the method highly eco-friendly as well as results in high-purity as-synthesized gold sponges (98.7 wt %). The mesoporous gold sponges fabricated with the present method exhibit a high SERS activity, making them highly applicable for sensitive SERS detection of molecules. PMID- 27221349 TI - A concept analysis of undergraduate nursing students speaking up for patient safety in the patient care environment. AB - AIM: An analysis of the concept of nursing students speaking up for patient safety in the workplace. BACKGROUND: 'Speaking up' is assertive communication in clinical situations that requires action through questions or statements of opinion or information with appropriate persistence and is linked to patient safety. Previously, the concept of speaking up has focused on the registered or experienced practitioners, there is minimal discussion relating to student nurses. Analysis of the elements of students speaking up will identify the key elements that will give understanding to their position and experiences. DESIGN: A concept analysis. DATA: Literature included publications between 1970-2015 from, MEDLINE, CINHAL, PUBMED and SCOPUS. Search terms included patient safety AND speaking up; AND pre-registration/undergraduate nursing students, patient advocate, error reporting, organizational silence, whistleblowing and clinical placement/practicum. METHODS: The Walker and Avant concept analysis model was modified and used to examine the literature. RESULTS: Nursing students speaking up behaviour is influenced by individual and contextual factors that differ from those influencing more experienced colleagues. Motivators and barriers to voicing concerns include moral and ethical beliefs, willingness and confidence to speak up in the workplace. Students' subordinate and often vulnerable position creates additional tensions and challenges that impact their decisions and actions. CONCLUSION: This concept analysis provides a clear definition of 'speaking up' in relation to nursing students. The analysis will facilitate understanding and operationalization of the concept applied to learning and teaching, practice and research. PMID- 27221348 TI - In vitro differentiation of endometrial regenerative cells into smooth muscle cells: Alpha potential approach for the management of pelvic organ prolapse. AB - Pelvic organ prolapse (POP), is a common condition in parous women. Synthetic mesh was once considered to be the standard of care; however, the use of synthetic mesh is limited by severe complications, thus creating a need for novel approaches. The application of cell-based therapy with stem cells may be an ideal alternative, and specifically for vaginal prolapse. Abnormalities in vaginal smooth muscle (SM) play a role in the pathogenesis of POP, indicating that smooth muscle cells (SMCs) may be a potential therapeutic target. Endometrial regenerative cells (ERCs) are an easily accessible, readily available source of adult stem cells. In the present study, ERCs were obtained from human menstrual blood, and phase contrast microscopy and flow cytometry were performed to characterize the morphology and phenotype of the ERCs. SMC differentiation was induced by a transforming growth factor beta1-based medium, and the induction conditions were optimized. We defined the SMC characteristics of the induced cells with regard to morphology and marker expression using transmission electron microscopy, western blot analysis, immunocytofluorescence and RT-PCR. Examining the expression of the components of the Smad pathway and phosphorylated Smad2 and Smad3 by western blot analysis, RT-PCR and quantitative PCR demonstrated that the 'TGFBR2/ALK5/Smad2 and Smad3' pathway is involved, and both Smad2 and Smad3 participated in SMC differentiation. Taken together, these findings indicate that ERCs may be a promising cell source for cellular therapy aimed at modulating SM function in the vagina wall and pelvic floor in order to treat POP. PMID- 27221350 TI - On the abnormal "forced hydration" behavior of P(MEA-co-OEGA) aqueous solutions during phase transition from infrared spectroscopic insights. AB - Turbidity, DLS and FTIR measurements in combination with the perturbation correlation moving window (PCMW) technique and 2D correlation spectroscopy (2Dcos) analysis have been utilized to investigate the LCST-type transition of a oligo ethylene glycol acrylate-based copolymer (POEGA) in aqueous solutions in this work. As demonstrated in turbidity and DLS curves, the macroscopic phase separation was sharp and slightly concentration dependent. Moreover, individual chemical groups along polymer chains also display abrupt changes in temperature variable IR spectra. However, according to conventional IR analysis, the C-H groups present obvious dehydration, whereas C[double bond, length as m-dash]O and C-O-C groups exhibit anomalous "forced hydration" during the steep phase transition. From these analyses together with the PCMW and 2Dcos results, it has been confirmed that the hydrophobic interaction among polymer chains drove the chain collapse and dominated the phase transition. In addition, the unexpected enhanced hydration behavior of C[double bond, length as m-dash]O and C-O-C groups was induced by forced hydrogen bonding between polar groups along polymer chains and entrapped water molecules in the aggregates, which originated from the special chemical structure of POEGA. PMID- 27221353 TI - Relatively speaking. AB - Protein X is a signalling molecule that stimulates apoptosis. Treatment of cells with Protein X results in five times higher levels of cell death than those seen in untreated cells (wild type), as measured by Caspase-positive cells. Based on previous work, the authors identify Protein Y as the putative receptor for Protein X and here try to test whether this is indeed the case. They claim that in a geneY mutant, where no receptor is expressed, treatment with Protein X no longer results in increased cell death, supporting the hypothesis that Protein Y is the receptor for signalling molecule X. PMID- 27221352 TI - Prognostic relevance of the interaction between short-term, metronome-paced heart rate variability, and inflammation: results from the population-based CARLA cohort study. AB - AIMS: To determine the interaction between HRV and inflammation and their association with cardiovascular/all-cause mortality in the general population. METHODS AND RESULTS: Subjects of the CARLA study (n = 1671; 778 women, 893 men, 45-83 years of age) were observed for an average follow-up period of 8.8 years (226 deaths, 70 cardiovascular deaths). Heart rate variability parameters were calculated from 5-min segments of 20-min resting electrocardiograms. High sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and soluble tumour necrosis factor-alpha receptor type 1 (sTNF-R1) were measured as inflammation parameters. The HRV parameters determined included the standard deviation of normal-to-normal intervals (SDNN), the root-mean-square of successive normal interval differences (RMSSD), the low- and high-frequency (HF) power, the ratio of both, and non-linear parameters [Poincare plot (SD1, SD2, SD1/SD2), short-term detrended fluctuation analysis]. We estimated hazard ratios by using covariate adjusted Cox regression for cardiovascular and all-cause mortality incorporating an interaction term of HRV/inflammation parameters. Relative excess risk due to interactions (RERIs) were computed. We found an interaction effect of sTNF-R1 with SDNN (RERI: 0.5; 99% confidence interval (CI): 0.1-1.0), and a weaker effect with RMSSD (RERI: 0.4; 99% CI: 0.0-0.9) and HF (RERI: 0.4; 99% CI: 0.0-0.9) with respect to cardiovascular mortality on an additive scale after covariate adjustment. Neither IL-6 nor hsCRP showed a significant interaction with the HRV parameters. CONCLUSION: A change in TNF-alpha levels or the autonomic nervous system influences the mortality risk through both entities simultaneously. Thus, TNF-alpha and HRV need to be considered when predicating mortality. PMID- 27221351 TI - Quantitative PPARgamma expression affects the balance between tolerance and immunity. AB - PPARgamma modulates energy metabolism and inflammation. However, its specific functions in the balance of immunity in vivo have been explored incompletely. In this study, by the age of 14 mo, Pparg(C/-) mice with PPARgamma expression at 25% of the normal level exhibited high autoantibody levels and developed mesangial proliferative glomerulonephritis, which resembled systemic lupus erythematosus (SLE)-like autoimmune disease. These symptoms were preceded by splenomegaly at an early age, which was associated with increases in splenocyte accumulation and B cell activation but not with relocation of hematopoiesis to the spleen. The mechanism of splenic lymphocyte accumulation involved reduced sphingosine-1 phosphate receptor 1 (S1P1) expression and diminished migration toward S1P in the Pparg(C/-) splenocytes, which impeded lymphocyte egression. Mechanistically, increased Th17 polarization and IL-17 signaling in the Pparg(C/-) CD4(+) T cells contributed to B-cell hyperactivation in the spleen. Finally, the activation of the remaining PPARgamma in Pparg(C/-) mice by pioglitazone increased S1P1 levels, reduced the Th17 population in the spleen, and ameliorated splenomegaly. Taken together, our data demonstrated that reduction of Pparg expression in T-helper cells is critical for spontaneous SLE-like autoimmune disease development; we also revealed a novel function of PPARgamma in lymphocyte trafficking and cross talk between Th17 and B cells. PMID- 27221354 TI - Fabry in the older patient: Clinical consequences and possibilities for treatment. AB - Baseline demographic and phenotypic characteristics of patients aged >=50years in the Fabry Outcome Survey (Shire; data extracted June 2014) were compared with younger adults to investigate potential factors influencing treatment decisions in later life. Age groups were defined using age at treatment initiation or at FOS entry for untreated patients: 18-49 (n=1344; 49.5% male; 64.6% received agalsidase alfa enzyme replacement therapy [ERT]); 50-64 (n=537; 35.4% male; 74.3% treated); 65-74 (n=137; 32.1% male; 68.6% treated); and >=75years (n=26; 26.9% male; 50.0% treated). Successive age groups showed higher median age at first symptom and diagnosis. Median alpha-galactosidase A activity, measured as percentage activity of the midpoint of the normal range, was much greater in females than males of all groups except >=75years (33.4% in females; 27.8% in males). Patients aged >=75years showed greater values than patients aged 18 49years for median left ventricular mass indexed to height (62.7 vs 42.4g/m(2.7)), mean ventricular wall thickness (15.0 vs 10.0mm) and prevalence of hypertension (57.7% vs 21.8%), and lower median estimated glomerular filtration rate (Modification of Diet in Renal Disease: 65.6 vs 98.5mL/min/1.73m(2)). Larger proportions in the groups aged >=50 exhibited cardiac and/or cerebrovascular manifestations compared with patients aged 18-49years. The smaller proportion of patients receiving ERT aged >=75years compared with the younger groups might reflect relatively milder disease burden or physician/patient reluctance to initiate/continue ERT at this age. Further studies are needed to increase knowledge of Fabry disease and ERT in later life. PMID- 27221355 TI - [N,P]-pyrrole PdCl2 complexes catalyzed the formation of dibenzo-alpha-pyrone and lactam analogues. AB - We herein report the synthesis and catalytic application of a new family of [N,P] ligands based on the pyrrole ring with alpha-phosphine or phosphole units. Their palladium complexes (3a-d) were obtained in very good yields and their catalytic properties were evaluated in the direct intramolecular arylation to obtain both benzopyranones and phenanthridinones. The air stable complex 3a exhibited the best catalytic performance of this series of complexes, using 1 mol% of catalyst in combination with microwaves to promote this reaction. PMID- 27221356 TI - The Parent Mealtime Action Scale revised (PMAS-R): Psychometric characteristics and associations with variables of clinical interest. AB - The purpose of the present study was to provide a revised and more psychometrically-examined version of the Parent Mealtime Action Scale (PMAS-R), then to examine how well the PMAS-R subscales explained variance for four variables relevant in clinical settings. Study participants included 238 parents of children referred to a hospital-based feeding program (72.3% male children; mean age = 72.2 months; 80 with autism spectrum disorder, 77 with other special needs, 81 with no special needs). Parents completed questionnaires to report child demographics and diet habits. Parents also used a five-point rating instead of the original three-point rating to report their usage of the 31 PMAS feeding practices. Using five-point ratings, the nine subscales of the PMAS-R demonstrated improved internal reliability and test-retest reliability compared to those published for the original PMAS. ANCOVA indicated that special needs status was the child demographic variable most associated with PMAS-R feeding practices. Hierarchical multiple regression revealed that after controlling for child demographics, the nine PMAS-R subscales explained 26-49% of the variance for four variables of clinical interest (fruit and vegetable consumption, snack consumption, total food variety, and weight status). These variables of clinical interest were most often associated with "permissive" feeding practices including low Daily Fruit and Vegetable (FV) Availability, rarely using Insistence on Eating during meals, often using Many Food Choices, and often using Child Selected Meals. The present study provides a more psychometrically-sound measure of child feeding practices, documents the association between "permissive feeding" and variables of clinical interest, and identifies specific parent practices included in "permissive feeding". PMID- 27221357 TI - Understanding ligand effects in gold clusters using mass spectrometry. AB - This review summarizes recent research on the influence of phosphine ligands on the size, stability, and reactivity of gold clusters synthesized in solution. Sub nanometer clusters exhibit size- and composition-dependent properties that are unique from those of larger nanoparticles. The highly tunable properties of clusters and their high surface-to-volume ratio make them promising candidates for a variety of technological applications. However, because "each-atom-counts" toward defining cluster properties it is critically important to develop robust synthesis methods to efficiently prepare clusters of predetermined size. For decades phosphines have been known to direct the size-selected synthesis of gold clusters. Despite the preparation of numerous species it is still not understood how different functional groups at phosphine centers affect the size and properties of gold clusters. Using electrospray ionization mass spectrometry (ESI MS) it is possible to characterize the effect of ligand substitution on the distribution of clusters formed in solution at defined reaction conditions. In addition, ligand exchange reactions on preformed clusters may be monitored using ESI-MS. Collision induced dissociation (CID) may also be employed to obtain qualitative insight into the fragmentation of mixed ligand clusters and the relative binding energies of differently substituted phosphines. Quantitative ligand binding energies and cluster stability may be determined employing surface induced dissociation (SID) in a custom-built Fourier transform ion cyclotron resonance mass spectrometer (FT-ICR-MS). Rice-Ramsperger-Kassel-Marcus (RRKM) based modeling of the SID data allows dissociation energies and entropy values to be extracted. The charge reduction and reactivity of atomically precise gold clusters, including partially ligated species generated in the gas-phase by in source CID, on well-defined surfaces may be explored using ion soft landing (SL) in a custom-built instrument combined with in situ time of flight secondary ion mass spectrometry (TOF-SIMS). Jointly, this multipronged experimental approach allows characterization of the full spectrum of relevant phenomena including cluster synthesis, ligand exchange, thermochemistry, surface immobilization, and reactivity. The fundamental insights obtained from this work will facilitate the directed synthesis of gold clusters with predetermined size and properties for specific applications. PMID- 27221358 TI - LYMPHA Technique to Prevent Secondary Lower Limb Lymphedema. AB - BACKGROUND: Inguinofemoral lymphadenectomy carries a high risk of lower limb lymphedema. This report describes the feasibility of performing multiple lymphatic-venous anastomoses (MLVA) after inguinofemoral lymph node completion (LYMPHA technique) and the possible benefit of LYMPHA for preventing lymphedema. METHODS: Between February, 2011 and October, 2014, 11 patients with vulvar cancer and 16 patients with melanoma of the trunk requiring inguinofemoral lymphadenectomy underwent lymph node dissection and the LYMPHA technique. Blue dye was injected into the thigh 10 min before surgery. Lymphatics afferent to the blue nodes were used to perform MLVA using a collateral branch of the great saphenous vein. RESULTS: The mean age of patients in the vulvar cancer group was 52 years (range, 48-75 years). The melanoma group comprised seven men and nine women with a mean age of 41 years (range, 37-56 years). Of the 16 patients, 5 with vulvar cancer underwent bilateral inguinofemoral lymphadenectomy, whereas the remaining 6 patients with vulvar cancer and all 16 patients with melanoma of the trunk had unilateral node dissection. All the patients were treated by the LYMPHA technique. No lymphocele or infectious complications occurred. Transient lower-extremity edema occurred for one melanoma patient (6.25 %), which resolved after 2 months, and permanent lower-extremity edema occurred for one patient (9 %) with vulvar cancer. CONCLUSIONS: The LYMPHA technique appears to be feasible, safe, and effective for the prevention of lower limb lymphedema, thereby improving the patient's quality of life and decreasing health care costs. PMID- 27221359 TI - Lobectomy is a more Cost-Effective Option than Total Thyroidectomy for 1 to 4 cm Papillary Thyroid Carcinoma that do not Possess Clinically Recognizable High-Risk Features. AB - BACKGROUND: Although lobectomy is a viable alternative to total thyroidectomy (TT) in low-risk 1 to 4 cm papillary thyroid carcinoma (PTC), lobectomy is associated with higher locoregional recurrence risk and need for completion TT upon discovery of a previously unrecognized histologic high-risk feature (HRF). The present study evaluated long-term cost-effectiveness between lobectomy and TT. METHODS: Our base case was a hypothetical female cohort aged 40 years with a low-risk 2.5 cm PTC. A Markov decision tree model was constructed to compare cost effectiveness between lobectomy and TT after 25 years. Patients with an unrecognized HRF (including aggressive histology, microscopic extrathyroidal extension, lymphovascular invasion, positive resection margin, nodal metastasis >5 mm, and multifocality) underwent completion TT after lobectomy. Outcome probabilities, utilities, and costs were estimated from the literature. The threshold for cost-effectiveness was set at US$50,000/quality-adjusted life-year (QALY). Sensitivity and threshold analyses were used to examine model uncertainty. RESULTS: After 25 years, each patient who underwent lobectomy instead of TT cost an extra US$772.08 but gained an additional 0.300 QALY. The incremental cost-effectiveness ratio was US$2577.65/QALY. In the sensitivity analysis, the lobectomy arm began to become cost-effective only after 3 years. Despite varying the reported prevalence of clinically unrecognized HRFs, complication from surgical procedures, annualized recurrence rates, unit cost of surgical procedure or complication, and utility score, lobectomy remained more cost-effective than TT. CONCLUSIONS: Despite the higher locoregional recurrence risk and having almost half of the patients undergoing completion TT after lobectomy upon discovery of a previously unrecognized HRF, initial lobectomy was a more cost-effective long-term option than initial TT for 1 to 4 cm PTCs without clinically recognized HRFs. PMID- 27221360 TI - A Population-Based Analysis of Three Treatment Modalities for Malignant Obstruction of the Proximal Colon: Acute Resection Versus Stent or Stoma as a Bridge to Surgery. AB - BACKGROUND: Malignant obstruction of the proximal colon (MOPC) traditionally has been treated with acute resection. However, morbidity and mortality rates following these emergency surgeries are high. Initial bowel decompression by stent placement or stoma construction has been used for distal obstructions as an alternative approach. This study evaluated whether these alternative treatment strategies could be beneficial for patients with a MOPC as well. METHODS: All patients undergoing a colonic resection for a MOPC between January 2009 and December 2013 and who were registered in the Dutch Surgical Colorectal Audit were analyzed. RESULTS: From the 49,013 patients registered in the DSCA, 1860 (3.8 %) were selected for further analysis. Acute resection was performed in 1774 patients (95.4 %), 44 patients (2.4 %) were treated with initial decompression using stent placement and resection, and 42 patients (2.3 %) with stoma construction followed by resection. Thirty-day mortality was 8.8, 2.4, and 2.4 %, respectively. Mortality was significantly lower after a bridging strategy (stent or stoma) compared with acute resection (p = 0.04). Complications following the resection occurred in 39.6% in the acute resection group and in 27.3 and 31.7% in the stent and stoma group, respectively (p = 0.167). CONCLUSIONS: Acute resection was performed in the vast majority of patients with obstructive proximal colon cancer and resulted in a 40 % morbidity and 9 % mortality rate. A bridging strategy may be a valid alternative in some of these patients, because a significantly lower postoperative mortality rate was seen in a subgroup of patients initially treated with a stent or stoma. PMID- 27221361 TI - A Phase II Trial Exploring the Success of Cryoablation Therapy in the Treatment of Invasive Breast Carcinoma: Results from ACOSOG (Alliance) Z1072. AB - BACKGROUND: Cryoablation is a well-established technique to treat fibroadenomas. Pilot studies suggest this could be an effective non-surgical treatment for breast cancer. American College of Surgeons Oncology Group Z1072 is a phase II trial exploring the effectiveness of cryoablation in the treatment of breast cancers. METHODS: The primary endpoint of Z1072 was the rate of complete tumor ablation, defined as no remaining invasive breast cancer (IBC) or ductal carcinoma in situ (DCIS) on pathologic examination of the targeted lesion. A secondary objective was to evaluate the negative predictive value of magnetic resonance imaging (MRI) to determine residual IBC or DCIS. Eligible patients included those with unifocal invasive ductal breast cancer <=2 cm, with <25 % intraductal component and tumor enhancement on MRI. A total of 19 centers contributed 99 patients, of which 86 patients (87 breast cancers) were evaluable for data analysis. RESULTS: Final pathology results, regardless of whether residual IBC/DCIS was in the targeted ablation zone or elsewhere in the breast, showed successful ablation in 66/87 (75.9 %) cancers. The 90 % confidence interval for the estimate of successful cryoablation was 67.1-83.2, with the one sided lower-sided 90 % CI of 69.0. The negative predictive value of MRI was 81.2 % (90 % CI 71.4-88.8). When multifocal disease outside of the targeted cryoablation zone was not defined as an ablation failure, 80/87 (92 %) of the treated cancers had a successful cryoablation. CONCLUSION: Further studies with modifications on the Z1072 protocol could be considered to evaluate the role for cryoablation as a non-surgical treatment of early-stage breast cancer. PMID- 27221362 TI - The Incidence of Unexpected Uterine Malignancy in Women Undergoing Hysterectomy for a Benign Condition: A National Population-Based Study. AB - BACKGROUND: Potential risks associated with using a laparoscopic power morcellator have been reported in terms of the intraperitoneal seeding of benign and malignant diseases; therefore, knowing the precise incidence of unexpected uterine malignancy (UUM) would have clinically significant value. OBJECTIVE: The aim of this study was to investigate the incidence of UUM after a hysterectomy for benign conditions. METHODS: We analyzed the national inpatient sample data that were extracted by a stratified random sampling (sex and age) method from the Korean National Health Insurance Database between 1 January 2010 and 31 December 2012. RESULTS: Among 1,878,507 women treated during the study period, 12,850 women who underwent a hysterectomy for benign conditions were enrolled in this study. The mean age of these women was 47.22 +/- 7.07 years. A laparotomic or laparoscopic hysterectomy was performed in 6623 and 6227 women, respectively, and UUM after hysterectomy was diagnosed in 24 women. No significant difference in the incidence of UUM was noted between the laparotomic and laparoscopic cases [laparotomy, 15 (0.23 %); laparoscopy, 9 (0.14 %); p = 0.28]. The incidence of UUM after hysterectomy was 0.19 % [confidence interval (CI) 0.11-0.26 %]; the incidence of unsuspected endometrial cancer after hysterectomy was 0.12 % (CI 0.06-0.19 %); and the incidence of UUM other than endometrial cancer after hysterectomy was 0.06 % (CI 0.02-0.11 %). CONCLUSION: This study shows that the incidence of UUM diagnosed after a hysterectomy for benign conditions was low, but has clinical significance with regard to the potential dissemination of UUM. PMID- 27221363 TI - Biomarkers of EBV-positive Gastric Cancers: Loss of PTEN Expression is Associated with Poor Prognosis and Nodal Metastasis. AB - BACKGROUND: Epstein-Barr virus-positive gastric carcinoma (EBVGC) constitutes approximately 10 % of all gastric carcinoma cases. While distinct molecular features have been characterized previously, there have not been studies identifying their clinical utility. The purpose of this study was to investigate the immunohistochemistry (IHC) profile of EBVGC and to evaluate the potential clinicopathologic and prognostic significance of each marker. METHODS: Clinicopathologic characteristics of 234 patients (203 males and 31 females) who underwent curative gastrectomy for EBVGCs from 1998 to 2013 at Asan Medical Center, were reviewed, and IHC for ARID1A, PTEN, PD-L1, p53, p16(INK4a), MLH1, and MSH2 were performed on tissue microarrays. These markers along with several tumor characteristics, e.g., lymphovascular invasion and the extent of differentiation, were analyzed for significant associations as well as any prognostic significance by multivariate analysis. RESULTS: In multivariate analysis, PTEN loss was as an independent factor associated with poor prognosis (p = 0.011). Furthermore, PTEN loss was an independent risk factor for nodal metastasis (p = 0.038). No other biomarkers, ARID1A, PD-L1, p53, p16(INK4a), MLH1, or MSH2, demonstrated significant prognostic value. CONCLUSIONS: PTEN loss in EBVGC is a poor prognostic factor associated with mortality and nodal metastasis in EBVGCs. Evaluation of PTEN expression may be helpful to determine the most appropriate treatment strategy, especially for endoscopically resected EBVGCs. PMID- 27221364 TI - Autoimmune thrombotic thrombocytopenic purpura associated with HHV8-related Multicentric Castleman disease. PMID- 27221366 TI - Evaluation of choroidal thickness in psoriasis using optical coherence tomography. PMID- 27221365 TI - Evaluation of foveal photoreceptor layer in eyes with macular edema associated with branch retinal vein occlusion after ozurdex treatment. AB - The aim of this study was to evaluate the central retinal thickness (CRT), outer nuclear layer thickness (ONLT), photoreceptor layer thickness (PLT), photoreceptor layer integrity, and the correlation between visual acuity and PLT in eyes with branch retinal vein occlusion (BRVO) 2 months after treatment with intravitreal dexamethasone implant (Ozurdex; Allergan, Inc, Irvine, CA). In this prospective study, 32 eyes of 32 patients were enrolled. A single injection of Ozurdex was administered to all the patients. CRT, ONLT, and PLT were measured using spectral-domain optical coherence tomography before and 2 months after the injection. Best-corrected visual acuity (BCVA [logMAR]) and photoreceptor cell integrity were also evaluated. The average CRT, ONLT, PLT, and BCVA values for the sample group before the treatment were as follows: 707 +/- 261, 608 +/- 288, 70 +/- 25, and 0.96 +/- 0.22 um, respectively. The average CRT, ONLT, PLT, and BCVA values for the sample group 2 months after the Ozurdex injection were as follows: 299 +/- 149, 211 +/- 138, 77 +/- 20, and 0.63 +/- 0.30 um, respectively (p < 0.05). Two months after the Ozurdex injection, BCVA correlated with ONLT and PLT (r = 0.365, p = 0.048 and r = -0.488, p = 0.021, respectively), whereas BCVA was not correlated with CRT (r = 0.239, p = 0.189). Photoreceptor layer is associated with the visual function of eyes with macular edema secondary to BRVO. Also, ONLT seems to be more closely related to visual acuity improvement than CRT decrement. PMID- 27221367 TI - Thyroid function and neuropsychological status in older adults. AB - Overt thyroid dysfunction is recognized as a risk factor for neuropsychological deficits in aging populations, yet evidence for how changes in levels of circulatory thyroid hormones impact specific neuropsychological domains is limited. Here we report cross-sectional associations between serum thyroid hormone concentrations and several neuropsychological function domains among men and women aged 55-74years. We administered neuropsychological tests to assess memory, learning, executive function, measures of attention, visuospatial function, affective state, and motor function. Multivariable linear regression analyses were performed adjusting for age, sex, education, and cigarette smoking. Effects were reported as differences in test scores per one interquartile range (IQR) increase in hormone concentration. Higher total thyroxine (T4) and free thyroxine (fT4) were associated with improved visuospatial function, as measured by Block Design Subtest total scores; associated increments per IQR differences in T4 and fT4 were 15% and 19%, respectively (false discovery rate q-values <0.05). We also detected statistical interactions between age and fT4 for effects in tasks of memory and learning. Concurrent increases in age and fT4 were associated with deficits in memory and learning as measured by California Verbal Learning Test subtests (10% and 16% deficits in t-score and short delay free recall score, respectively). Our findings suggest that changes in thyroid hormones may have important implications for neuropsychological function in aging populations. Further large-scale studies with comprehensive thyroid function and neuropsychological outcome assessments are warranted to confirm these results. PMID- 27221368 TI - Non-image forming effects of illuminance level: Exploring parallel effects on physiological arousal and task performance. AB - This study investigated diurnal non-image forming (NIF) effects of illuminance level on physiological arousal in parallel to NIF effects on vigilance and working memory performance. We employed a counterbalanced within-subjects design in which thirty-nine participants (mean age=21.2; SD=2.1; 11 male) completed three 90-min sessions (165 vs. 600lx vs. 1700lx at eye level) either in the morning (N=18) or afternoon (N=21). During each session, participants completed four measurement blocks (incl. one baseline block) each consisting of a 10-min Psychomotor Vigilance Task (PVT) and a Backwards Digit-Span Task (BDST) including easy trials (4-6 digits) and difficult trials (7-8 digits). Heart rate (HR), skin conductance level (SCL) and systolic blood pressure (SBP) were measured continuously. The results revealed significant improvements in performance on the BDST difficult trials under 1700lx vs. 165lx (p=0.01), while illuminance level did not affect performance on the PVT and BDST easy trials. Illuminance level impacted HR and SCL, but not SBP. In the afternoon sessions, HR was significantly higher under 1700lx vs. 165lx during PVT performance (p=0.05), while during BDST performance, HR was only slightly higher under 600 vs. 165lx (p=0.06). SCL was significantly higher under 1700lx vs. 165lx during performance on BDST easy trials (p=0.02) and showed similar, but nonsignificant trends during the PVT and BDST difficult trials. Although both physiology and performance were affected by illuminance level, no consistent pattern emerged with respect to parallel changes in physiology and performance. Rather, physiology and performance seemed to be affected independently, via unique pathways. PMID- 27221369 TI - Effects of cooling rate in microscale and pilot scale freeze-drying - Variations in excipient polymorphs and protein secondary structure. AB - Microscale freeze-drying makes rapid process cycles possible for early-stage formulation development. To investigate the effects of equipment scale and cooling rate on the solid state properties and the protein's secondary structure of a sample, three binary formulations of catalase were prepared and freeze-dried with sucrose, mannitol, or (2-hydroxypropyl)-beta-cyclodextrin (HP-beta-CD). The protein's secondary structure was assessed using attenuated total reflection Fourier transform infrared spectroscopy (FTIR-ATR). The solid state properties were assessed using differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The results were interpreted with respect to the biological activity of catalase after its reconstitution. According to the results of both the protein secondary structure and the reconstituted biological activity, scale-up could be achieved with the sucrose-catalase formulation when it was prepared at a high cooling rate and with the mannitol-catalase formulation when prepared at a low cooling rate. However, differences in the polymorph composition of crystalline mannitol were noted. No cooling rate influence was found with the HP-beta-CD formulation. The results clearly indicate that the effects of the cooling rate should be closely examined during microscale formulation development and scale-up of the freeze-drying process. PMID- 27221370 TI - Cued Speech Transliteration: Effects of Speaking Rate and Lag Time on Production Accuracy. AB - Many deaf and hard-of-hearing children rely on interpreters to access classroom communication. Although the exact level of access provided by interpreters in these settings is unknown, it is likely to depend heavily on interpreter accuracy (portion of message correctly produced by the interpreter) and the factors that govern interpreter accuracy. In this study, the accuracy of 12 Cued Speech (CS) transliterators with varying degrees of experience was examined at three different speaking rates (slow, normal, fast). Accuracy was measured with a high resolution, objective metric in order to facilitate quantitative analyses of the effect of each factor on accuracy. Results showed that speaking rate had a large negative effect on accuracy, caused primarily by an increase in omitted cues, whereas the effect of lag time on accuracy, also negative, was quite small and explained just 3% of the variance. Increased experience level was generally associated with increased accuracy; however, high levels of experience did not guarantee high levels of accuracy. Finally, the overall accuracy of the 12 transliterators, 54% on average across all three factors, was low enough to raise serious concerns about the quality of CS transliteration services that (at least some) children receive in educational settings. PMID- 27221371 TI - SerpinE2 promotes multiple cell proliferation and drug resistance in osteosarcoma. AB - SerpinE2 is a member of the Serpins family, which could inhibit serine protease and promote tumor progression, particularly in tumor metastasis. However, at present, its role in the progression of osteosarcoma has not been determined. The present study analyzed the expression profiles of SerpinE2 in cancer tissues, including tissues from osteosarcoma of different stages. Higher expression of SerpinE2 was shown in osteosarcoma tissues, particularly in tissue from patients with metastasis and a tumor-node-metastasis stage II-III. Following chemotherapy, the SerpinE2 expression levels were shown to be higher than those at diagnosis. Cell proliferation and colony formation were increased after transfection with SerpinE2 over-expression vector. Additionally, drug resistance to bortezomib and doxorubicin treatment following SerpinE2 transfection was analyzed. MG-63 and SAOS-2 cells showed less sensitivity following transfection with SerpinE2. The cell cycle-related genes, cyclin-dependent kinase (CDK)4 and cyclin D1 were positively correlated with SerpinE2 expression in patient-derived tissue and in osteosarcoma cells. Finally, the high expression of SerpinE2 contributes to poor survival rates in patients with osteosarcoma. In conclusion, high expression of SerpinE2 in osteosarcoma stimulates cell proliferation, promotes drug-resistance, and results in poor survival by regulating CDK4 and cyclin D1. Thus, SerpinE2 could be a potential target for treatment of patients with osteosarcoma. PMID- 27221372 TI - Fracture in Duchenne Muscular Dystrophy: Natural History and Vitamin D Deficiency. AB - The present study examined the natural history of fracture and vitamin D levels in Duchenne muscular dystrophy patients, who are vulnerable to osteoporosis and fractures. Retrospective analysis of a cohort of 48 Duchenne muscular dystrophy patients revealed that 43% of patients experienced >=1 fracture. Fracture probabilities at ages 6, 9, 12, and 15 years were 4%, 9%, 31%, and 60% respectively, accelerating around the time of ambulation loss (mean age 11.8 +/- 2.7 years). Chronic corticosteroid therapy was utilized in 69% of patients and was associated with all vertebral fractures. A history of vitamin D deficiency occurred in 84%, and 35% were currently deficient. Despite chronic vitamin D supplementation, 38% remained deficient. These results demonstrate that osteoporosis and fracture remain major concerns in Duchenne muscular dystrophy. Bone health should be optimized well before loss of ambulation, however current levels of vitamin D supplementation may be inadequate given high levels of deficiency. PMID- 27221373 TI - Persistent Headache and Cephalic Allodynia Attributed to Head Trauma in Children and Adolescents. AB - The aim of the study was to investigate clinical features of headache associated with minor versus moderate to severe traumatic brain injury and of posttraumatic versus primary headache in children and adolescents. Study group included 74 patients after mild (n = 60) or moderate to severe (n = 14) traumatic brain injury identified by retrospective review of the computerized files of a tertiary pediatric headache clinic. Forty patients (54%) had migraine-like headache, 23 (31.1%) tension-like headache, and 11 (14.9%) nonspecified headache. Fourteen patients (53.8%) had allodynia. In comparison with 174 control patients, the study group had a significantly lower proportion of patients with migraine-like headache and a higher proportion of male patients and patients with allodynia. There was no statistically significant correlation of any of the clinical parameters with the type or severity of the posttraumatic headache or rate of allodynia. The high rate of allodynia in the study group may indicate a central sensitization in posttraumatic headache. PMID- 27221374 TI - Association between antinuclear antibody titers and connective tissue diseases in a Rheumatology Department. AB - OBJECTIVE: To determine the dilution titles at antinuclear antibodies (ANA) by indirect immunofluorescence observed in cell substrate HEp-2 and its association with the diagnosis of systemic connective tissue disease in ANA test requested by a Rheumatology Unit. METHOD: Samples of patients attended for the first time in the rheumatology unit, without prior ANA test, between January 2010 and December 2012 were selected. The dilution titers, immunofluorescence patterns and antigen specificity were recorded. In January 2015 the diagnosis of the patients were evaluated and classified in systemic disease connective tissue (systemic lupus erythematosus, Sjogren's syndrome, systemic sclerosis, undifferentiated connective, antiphospholipid syndrome, mixed connective tissue and inflammatory myophaty) or not systemic disease connective tissue. RESULT: A total of 1282 ANA tests requested by the Rheumatology Unit in subjects without previous study, 293 were positive, predominance of women (81.9%). Patients with systemic connective tissue disease were recorded 105, and 188 without systemic connective tissue disease. For 1/640 dilutions the positive predictive value in the connective was 73.3% compared to 26.6% of non-connective, and for values >=1/1,280 85% versus 15% respectively. When performing the multivariate analysis we observed a positive association between 1/320 dilution OR 3.069 (95% CI: 1.237-7.614; P=.016), 1/640 OR 12.570 (95% CI: 3.659-43.187; P=.000) and >=1/1,280 OR 42.136 (95% CI: 8.604-206.345; P=.000). CONCLUSION: These results show association titles dilution >=1/320 in ANA's first test requested by a Rheumatology Unit with patients with systemic connective tissue disease. The VPP in these patients was higher than previous studies requested by other medical specialties. This may indicate the importance of application of the test in a targeted way. PMID- 27221375 TI - The pharmacokinetics of dexmedetomidine during long-term infusion in critically ill pediatric patients. A Bayesian approach with informative priors. AB - The purpose of this study was to assess the pharmacokinetics of dexmedetomidine in the ICU settings during the prolonged infusion and to compare it with the existing literature data using the Bayesian population modeling with literature based informative priors. Thirty-eight patients were included in the analysis with concentration measurements obtained at two occasions: first from 0 to 24 h after infusion initiation and second from 0 to 8 h after infusion end. Data analysis was conducted using WinBUGS software. The prior information on dexmedetomidine pharmacokinetics was elicited from the literature study pooling results from a relatively large group of 95 children. A two compartment PK model, with allometrically scaled parameters, maturation of clearance and t-student residual distribution on a log-scale was used to describe the data. The incorporation of time-dependent (different between two occasions) PK parameters improved the model. It was observed that volume of distribution is 1.5-fold higher during the second occasion. There was also an evidence of increased (1.3 fold) clearance for the second occasion with posterior probability equal to 62 %. This work demonstrated the usefulness of Bayesian modeling with informative priors in analyzing pharmacokinetic data and comparing it with existing literature knowledge. PMID- 27221376 TI - Effect of sleeping position on arousals from sleep in preterm infants. AB - PURPOSE: To evaluate the frequency of preterm infant positions during sleep, and to investigate the association among positions, arousals, sleep patterns, and time of day. DESIGN AND METHODS: This observational study was conducted in a neonatal unit with 10 preterm infants. Polysomnographic and video recordings during 24 hr identified sleep positions, arousals, sleep patterns, and time of day. RESULTS: Preterm infants were placed most frequently in the supine position (58.4%), followed by right side (24.9%), left side (15.5%), and prone (1.2%). The longest amount of time spent sleeping, and the most frequent number of arousals, occurred in the supine position, followed by prone, left-side, and right-side positions. After controlling for length of time spent in each position, the number of arousals per hour was the greatest in the supine position (13.562 +/- 0.732) and least in the prone position (11.56 +/- 4.754; p < .001). There were no significant differences in arousals according to position and sleep pattern (indeterminate, quiet, active sleep) or position and time of day (morning, afternoon, twilight, night). PRACTICE IMPLICATIONS: Nurses should evaluate the frequency of preterm infant arousals in each position, and use more often those positions that lead to a lower frequency of arousals and better sleep quality. PMID- 27221377 TI - FFR and iFR guided percutaneous coronary intervention. AB - Fractional flow reserve (FFR) is an invasive physiologic index measured in the cardiac catheterization laboratory to assess the functional significance of a coronary stenosis. It is now accepted as the reference standard to indicate whether a stenosis is likely to be responsible for ischemia. It is generally accepted that a stenosis with an ischemic value of FFR is responsible for symptom and a worse outcome and should be revascularized, whereas lesions with a non ischemic FFR have a more favorable prognosis and can be treated medically. Furthermore, FFR-guided revascularization strategy has been definitely proven to be better than angiography-guided strategy in pivotal landmark studies such as DEFER, FAME, and FAME2. Instantaneous wave-free ratio (iFR) is another physiological index which can be obtained at rest without hyperemic stimulation. iFR is conceptually different from FFR, leading to lively scientific debate about this index. In this review article, the concept, clinical value of FFR and iFR for clinical practice are reviewed. PMID- 27221380 TI - [Current knowledge on physiotherapy for scoliosis]. PMID- 27221378 TI - Radiofrequency ablation alone or in combination with cementoplasty for local control and pain palliation of sacral metastases: preliminary results in 11 patients. AB - PURPOSE: To determine the safety and effectiveness of radiofrequency ablation (RFA) to treat sacral metastases for pain palliation and local tumor control (LTC). MATERIALS AND METHODS: An institutional tumor ablation registry was retrospectively reviewed for sacral RFA procedures performed between January 2012 and December 2015. Clinical history, pre-procedural imaging, and procedural details were reviewed to document indication for treatment, primary tumor histology, tumor volumes, presence of concurrent cementoplasty after RFA, and the occurrence of peri-procedural complications. Pain scores before and 4 weeks after the procedure were recorded. Post-procedure imaging was reviewed for imaging evidence of tumor progression. Long-term complications and duration of clinical follow-up were recorded. RESULTS: During the study period, 11 RFA procedures were performed to treat 16 sacral metastases. All procedures were for pain palliation. Four procedures (36 %; 4 out of 11) were also performed with the intention of achieving LTC in patients with oligometastatic disease. Concurrent cementoplasty was performed in 63 % of cases (7 out of 11). The median pain score decreased from 8 (interquartile range, 6-9.25) at baseline to 3 (interquartile range, 1.75 6.3) 1 month following RFA (P = 0.004). In the 4 patients with oligometastatic disease, LTC was achieved in 3 patients (75 %; 3 out of 4) after a median follow up of 7.6 months (range, 3.6-11.9 months). No acute or long-term complications were documented during the overall median clinical follow-up of 4.7 months (range, 0.9-28.7 months). CONCLUSIONS: Radiofrequency ablation maybe a safe and potentially effective treatment for patients with painful sacral metastases and can achieve LTC in selected patients. PMID- 27221381 TI - HDAC6 promotes cell proliferation and confers resistance to gefitinib in lung adenocarcinoma. AB - Histone deacetylases (HDACs) are promising targets for cancer therapy, and first generation HDAC inhibitors are currently in clinical trials for the treatment of cancer patients. HDAC6, which is a key regulator of many signaling pathways that are linked to cancer, has recently emerged as an attractive target for the treatment of cancer. In the present study, HDAC6 was found to be overexpressed in lung adenocarcinoma cell lines and was negatively correlated with the prognosis of patients with lung adenocarcinoma. Overexpression of HDAC6 promoted the proliferation of lung adenocarcinoma cells in a deacetylase activity-dependent manner. HDAC6 overexpression conferred resistance to gefitinib via the stabilization of epidermal growth factor receptor (EGFR). The inhibition of HDAC6 by CAY10603, a potent and selective inhibitor of HDAC6, inhibited the proliferation of lung adenocarcinoma cells and induced apoptosis. CAY10603 downregulated the levels of EGFR protein, which in turn inhibited activation of the EGFR signaling pathway. Moreover, CAY10603 synergized with gefitinib to induce apoptosis of the lung adenocarcinoma cell lines via the destabilization of EGFR. Taken together, our results suggest that the inhibition of HDAC6 may be a promising strategy for the treatment of lung adenocarcinoma. PMID- 27221382 TI - Evolution of lesion-specific management of blunt thoracic aortic injury. AB - Developments in diagnosis and treatment have transformed the management of blunt thoracic aortic injuries (BTAIs). For patients in stable condition, treatment practice has shifted from early open repair to nonoperative management for low grade lesions and routine delayed endovascular repair for more significant injuries. However, effective therapy depends on accurate staging of injury grade and stability to select patients for appropriate management. Recent developments in BTAI risk stratification enable lesion-specific management tailored to the patient and aortic lesion. This review summarizes advances in lesion assessment and treatment and proposes an integrated scheme for the modern management of BTAI. PMID- 27221384 TI - Perioperative management of living-donor liver transplantation for methylmalonic acidemia. AB - Methymalonic acidemia (MMA) is a hereditary metabolic disorder characterized by a defect of the methylmalonyl-CoA mutase that breaks down propionate. The efficacy of liver transplantation for MMA was recently reported. However, the anesthetic management of liver transplant for MMA is not clear. The aim of this article is to describe an anesthetic management algorithm of liver transplant for MMA by reviewing our cases of liver transplant for MMA. Fourteen patients received a liver transplant; three cases showed metabolic decompensation during the transplant and two of the patients died. In the two patients who expired, propofol was used for maintenance anesthesia and preoperative continuous hemodiafiltration was used to reduce plasma methylmalonic acid level in one case, and to control severe metabolic decompensation before transplant for the other case. Their renal function was also worse than others and they were already experiencing metabolic decompensation before induction of anesthesia. Based on our experience of these 14 cases, we have established an anesthetic algorithm for patients with MMA undergoing liver transplant or other procedures. There are three important points in our experience: propofol should be avoided, dextrose infusion therapy should be continued to prevent metabolic decompensation, and liver transplant or other procedures should be avoided during metabolic decompensation. PMID- 27221385 TI - What Brexit would mean for employment of doctors. PMID- 27221383 TI - Identification and Characterization of Maize salmon silks Genes Involved in Insecticidal Maysin Biosynthesis. AB - The century-old maize (Zea mays) salmon silks mutation has been linked to the absence of maysin. Maysin is a C-glycosyl flavone that, when present in silks, confers natural resistance to the maize earworm (Helicoverpa zea), which is one of the most damaging pests of maize in America. Previous genetic analyses predicted Pericarp Color1 (P1; R2R3-MYB transcription factor) to be epistatic to the sm mutation. Subsequent studies identified two loci as being capable of conferring salmon silks phenotypes, salmon silks1 (sm1) and sm2 Benefitting from available sm1 and sm2 mapping information and from knowledge of the genes regulated by P1, we describe here the molecular identification of the Sm1 and Sm2 gene products. Sm2 encodes a rhamnosyl transferase (UGT91L1) that uses isoorientin and UDP-rhamnose as substrates and converts them to rhamnosylisoorientin. Sm1 encodes a multidomain UDP-rhamnose synthase (RHS1) that converts UDP-glucose into UDP-l-rhamnose. Here, we demonstrate that RHS1 shows unexpected substrate plasticity in converting the glucose moiety in rhamnosylisoorientin to 4-keto-6-deoxy glucose, resulting in maysin. Both Sm1 and Sm2 are direct targets of P1, as demonstrated by chromatin immunoprecipitation experiments. The molecular characterization of Sm1 and Sm2 described here completes the maysin biosynthetic pathway, providing powerful tools for engineering tolerance to maize earworm in maize and other plants. PMID- 27221386 TI - Noninvasive detection of enzyme activity in tumor models of human ovarian cancer using catalyCEST MRI. AB - PURPOSE: We proposed to detect the in vivo enzyme activity of gamma-glutamyl transferase (GGT) within mouse models of human ovarian cancers using catalyCEST MRI with a diamagnetic CEST agent. METHODS: A CEST-FISP MRI protocol and a diamagnetic CEST agent were developed to detect GGT enzyme activity in biochemical solution. A quantitative Michaelis-Menten enzyme kinetics study was performed to confirm that catalyCEST MRI can measure enzyme activity. In vivo catalyCEST MRI studies generated pixel-wise activity maps of GGT activities. Ex vivo fluorescence imaging was performed for validation. RESULTS: CatalyCEST MRI selectively detected two CEST signals from a single CEST agent, whereby one CEST signal was responsive to GGT enzyme activity and the other CEST signal was an unresponsive control signal. The comparison of these CEST signals facilitated in vivo catalyCEST MRI studies that detected high GGT activity in OVCAR-8 tumors, low GGT activity in OVCAR-3 tumors, and low or no GGT activity in muscle tissues. CONCLUSION: CatalyCEST MRI with a diamagnetic CEST agent can detect the level of GGT enzyme activity within in vivo tumor models of human ovarian cancers. Magn Reson Med 77:2005-2014, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27221387 TI - Effects of ozone (O3) therapy on cisplatin-induced ototoxicity in rats. AB - The aim of this study is to investigate the effect of rectal ozone and intratympanic ozone therapy on cisplatin-induced ototoxicity in rats. Eighteen female Wistar albino rats were included in our study. External auditory canal and tympanic membrane examinations were normal in all rats. The rats were randomly divided into three groups. Initially, all the rats were tested with distortion product otoacoustic emissions (DPOAE), and emissions were measured normally. All rats were injected with 5-mg/kg/day cisplatin for 3 days intraperitoneally. Ototoxicy had developed in all rats, as confirmed with DPOAE after 1 week. Rectal and intratympanic ozone therapy group was Group 1. No treatment was administered for the rats in Group 2 as the control group. The rats in Group 3 were treated with rectal ozone. All the rats were tested with DPOAE under general anesthesia, and all were sacrificed for pathological examination 1 week after ozone administration. Their cochleas were removed. The outer hair cell damage and stria vascularis damage were examined. In the statistical analysis conducted, a statistically significant difference between Group 1 and Group 2 was observed in all frequencies according to the DPOAE test. In addition, between Group 2 and Group 3, a statistically significant difference was observed in the DPOAE test. However, a statistically significant difference was not observed between Group 1 and Group 3 according to the DPOAE test. According to histopathological scoring, the outer hair cell damage score was statistically significantly high in Group 2 compared with Group 1. In addition, the outer hair cell damage score was also statistically significantly high in Group 2 compared with Group 3. Outer hair cell damage scores were low in Group 1 and Group 3, but there was no statistically significant difference between these groups. There was no statistically significant difference between the groups in terms of stria vascularis damage score examinations. Systemic ozone gas therapy is effective in the treatment of cell damage in cisplatin-induced ototoxicity. The intratympanic administration of ozone gas does not have any additional advantage over the rectal administration. PMID- 27221388 TI - Tongue reduction for OSAHS: TORSs vs coblations, technologies vs techniques, apples vs oranges. AB - Coblation tongue surgery and Trans-oral robotic surgery (TORS) proved to be the most published therapeutical options for the treatment of patients affected by obstructive sleep apneas (OSAHS). A systematic review of the literature and an analysis of the data are presented. The mean rates of failure were 34.4 and 38.5 %, respectively in TORS and Coblation groups. Complications occurred in 21.3 % of the patients treated with TORS and in 8.4 % of the patients treated with Coblation surgery. TORS seems to give slightly better results, allowing a wider surgical view and a measurable, more consistent removal of lingual tissue. However, the higher rate of minor complication and the significant costs of TORS must also be considered. Moreover, both technologies may be applied to a wide range of surgical techniques, each of them with different effectiveness. PMID- 27221390 TI - [Identification and economic evaluation of anesthesiologic secondary diagnoses on the basis of intraoperative medication]. AB - BACKGROUND: Complications and comorbidities are encodable in the German diagnosis related groups (G-DRG) system and can improve revenues. In this study, secondary diagnoses were identified through drug administrations during anaesthesia and were economically evaluated by regrouping these cases. METHODS: All intraoperative drug administrations from 2008 were extracted from a database. After exclusion of synonyms and procedure-specific drug administrations, all remaining drugs were matched to explicit secondary diagnoses. All cases were regrouped with their newly defined secondary diagnoses by G-DRG grouper software, and changes in cost weight were evaluated. RESULTS: A total of 29 drugs could be assigned to 18 secondary diagnoses. From 22,440 anaesthesia the S 21 data record could be extracted in 1,929 cases and was regrouped with 2,976 secondary diagnoses, according to additional proceeds of 125,330.25 ? in 2008 and 103,542.35 ? in 2014. Intraoperative secondary diagnoses influence cost weight only in small parts. The average increase in revenue in this study could have been about 50 ? per case. From 2008 to 2014 secondary diagnoses were continuously devaluated, although some of them, e. g. afibrinogenemia, have were revaluated. DISCUSSION: Our retrospective method of making a diagnosis and assuming a correct indication of drug administration is inapplicable to daily routine. The anaesthesiologic documentation has to make drug administration and thereby the secondary diagnosis plausible. PMID- 27221391 TI - [Mitochondrial disorders require a comprehensive perioperative management]. PMID- 27221389 TI - Transoral robotic surgery for the management of obstructive sleep apnea: a systematic review and meta-analysis. AB - Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a serious social health problem with significant implications on quality of life. Surgery for OSAHS has been criticized due to a lack of evidence to support its efficacy as well as the heterogeneous reporting of published outcomes. Moreover, the transoral robotic surgery (TORS) in the management of OSAHS is still in a relative infancy. Nevertheless, a review and meta-analysis of the published articles may be helpful. Among 195 articles, eight studies were included in the analysis. The mean of enrolled patients was 102.5 +/- 107.9 (range 6-289) comprising a total of 820 cases. The mean age was 49 +/- 3.27 and 285 patients underwent a previous sleep apnea surgery. The uvulopalatopharyngoplasty (UPPP) was the most common palatal procedure. The mean rate of failure was 34.4 % (29.5-46.2 %). Complications occurred in 21.3 % of the patients included in the analysis, most of them were classified as minor. Transient dysphagia represented the most common complication (7.2 %) followed by bleeding (4.2 %). TORS for the treatment of OSAHS appears to be a promising and safe procedure for selected patients seeking an alternative to continuous positive airway pressure (CPAP), although further researches are urgently needed. PMID- 27221392 TI - A Geographic Simulation Model for the Treatment of Trauma Patients in Disasters. AB - BACKGROUND: Though the US civilian trauma care system plays a critical role in disaster response, there is currently no systems-based strategy that enables hospital emergency management and local and regional emergency planners to quantify, and potentially prepare for, surges in trauma care demand that accompany mass-casualty disasters. OBJECTIVE: A proof-of-concept model that estimates the geographic distributions of patients, trauma center resource usage, and mortality rates for varying disaster sizes, in and around the 25 largest US cities, is presented. The model was designed to be scalable, and its inputs can be modified depending on the planning assumptions of different locales and for different types of mass-casualty events. METHODS: To demonstrate the model's potential application to real-life planning scenarios, sample disaster responses for 25 major US cities were investigated using a hybrid of geographic information systems and dynamic simulation-optimization. In each city, a simulated, fast onset disaster epicenter, such as might occur with a bombing, was located randomly within one mile of its population center. Patients then were assigned and transported, in simulation, via the new model to Level 1, 2, and 3 trauma centers, in and around each city, over a 48-hour period for disaster scenario sizes of 100, 500, 5000, and 10,000 casualties. RESULTS: Across all 25 cities, total mean mortality rates ranged from 26.3% in the smallest disaster scenario to 41.9% in the largest. Out-of-hospital mortality rates increased (from 21.3% to 38.5%) while in-hospital mortality rates decreased (from 5.0% to 3.4%) as disaster scenario sizes increased. The mean number of trauma centers involved ranged from 3.0 in the smallest disaster scenario to 63.4 in the largest. Cities that were less geographically isolated with more concentrated trauma centers in their surrounding regions had lower total and out-of-hospital mortality rates. The nine US cities listed as being the most likely targets of terrorist attacks involved, on average, more trauma centers and had lower mortality rates compared with the remaining 16 cities. CONCLUSIONS: The disaster response simulation model discussed here may offer insights to emergency planners and health systems in more realistically planning for mass-casualty events. Longer wait and transport times needed to distribute high numbers of patients to distant trauma centers in fast-onset disasters may create predictable increases in mortality and trauma center resource consumption. The results of the modeled scenarios indicate the need for a systems-based approach to trauma care management during disasters, since the local trauma center network was often too small to provide adequate care for the projected patient surge. Simulation of out-of-hospital resources that might be called upon during disasters, as well as guidance in the appropriate execution of mutual aid agreements and prevention of over-response, could be of value to preparedness planners and emergency response leaders. Study assumptions and limitations are discussed. Carr BG , Walsh L , Williams JC , Pryor JP , Branas CC . A geographic simulation model for the treatment of trauma patients in disasters. Prehosp Disaster Med. 2016;31(4):413-421. PMID- 27221393 TI - Future treatment directions for HPV-associated head and neck cancer based on radiobiological rationale and current clinical evidence. AB - A relatively new entity of head and neck squamous cell carcinoma located in the oropharynx and associated to the human papillomavirus (HPV) is on the rise. This cancer represents a distinct entity from the non-HPV tumours, holds different biological characteristics and responds differently to treatment. An outcome analysis of locoregionally-advanced oropharyngeal versus non-oropharyngeal cancers treated with chemo-radiotherapy revealed a statistically significant improvement for oropharyngeal cancers, which are thought to be due to their HPV association. Consequently, more attention is paid to HPV-related head and neck cancers, given that HPV status serves as prognostic marker in oropharyngeal cancer patients. Yet, HPV positivity is a simplistic approach for risk stratification, thus more robust biomarkers are needed to fulfil this task. Despite differences in clinical response, HPV-related oral cancers undergo similar therapy to their non-HPV counterparts. This review discusses future treatment directions for HPV-related oropharyngeal cancers based on radiobiological rationale and current clinical evidence. PMID- 27221394 TI - Essential amino acids: master regulators of nutrition and environmental footprint? AB - The environmental footprint of animal food production is considered several-fold greater than that of crops cultivation. Therefore, the choice between animal and vegetarian diets may have a relevant environmental impact. In such comparisons however, an often neglected issue is the nutritional value of foods. Previous estimates of nutrients' environmental footprint had predominantly been based on either food raw weight or caloric content, not in respect to human requirements. Essential amino acids (EAAs) are key parameters in food quality assessment. We re evaluated here the environmental footprint (expressed both as land use for production and as Green House Gas Emission (GHGE), of some animal and vegetal foods, titrated to provide EAAs amounts in respect to human requirements. Production of high-quality animal proteins, in amounts sufficient to match the Recommended Daily Allowances of all the EAAs, would require a land use and a GHGE approximately equal, greater o smaller (by only +/-1-fold), than that necessary to produce vegetal proteins, except for soybeans, that exhibited the smallest footprint. This new analysis downsizes the common concept of a large advantage, in respect to environmental footprint, of crops vs. animal foods production, when human requirements of EAAs are used for reference. PMID- 27221395 TI - Comparison of E test and agar dilution for testing activity of ceftriaxone against Neisseria gonorrhoeae. PMID- 27221396 TI - Utilization and access to healthcare services among community-dwelling people living with spinal cord injury. AB - OBJECTIVE: Describe the utilization, accessibility, and satisfaction of primary and preventative health-care services of community-dwelling individuals with spinal cord injury (SCI). DESIGN: Cross sectional, in-person or telephonic survey, utilizing a convenience sample. SETTING: Community. PARTICIPANTS: Individuals with SCI greater than 12-months post injury. INTERVENTIONS: N/A. OUTCOME MEASURES: Demographic, injury related, and 34-item questionnaire of healthcare utilization, accessibility, and satisfaction with services. RESULTS: The final sample consisted of 142 participants (50 female, 92 male). Ninety-nine percent of respondents had a healthcare visit in the past 12-months with primary care physicians (79%), with SCI physiatrists (77%) and urologists (50%) being the most utilized. 43% of the sample reported an ER visit within the past 12-months, with 21% reporting multiple visits. People who visited the ER had completed significantly less secondary education (P = 0.0386) and had a lower estimate of socioeconomic status (P = 0.017). The majority of individuals (66%) were satisfied with their primary care physician and 100% were satisfied with their SCI physiatrist. Individuals who did not visit an SCI physiatrist were significantly more likely to live in a rural area (P = 0.0075), not have private insurance (P = 0.0001), and experience a greater decrease in income post injury (P = 0.010). CONCLUSION: The delivery of care for people with SCI with low socioeconomic status may be remodeled to include patient-centered medical homes where care is directed by an SCI physiatrist. Further increased telehealth efforts would allow for SCI physiatrists to monitor health conditions remotely and focus on preventative treatment. PMID- 27221397 TI - Reducing neonatal mortality associated with preterm birth: gaps in knowledge of the impact of antenatal corticosteroids on preterm birth outcomes in low-middle income countries. AB - The Global Network's Antenatal Corticosteroids Trial (ACT), was a multi-country, cluster-randomized trial to improve appropriate use of antenatal corticosteroids (ACS) in low-resource settings in low-middle income countries (LMIC). ACT substantially increased ACS use in the intervention clusters, but the intervention failed to show benefit in the targeted < 5th percentile birth weight infants and was associated with increased neonatal mortality and stillbirth in the overall population. In this issue are six papers which are secondary analyses related to ACT that explore potential reasons for the increase in adverse outcomes overall, as well as site differences in outcomes. The African sites appeared to have increased neonatal mortality in the intervention clusters while the Guatemalan site had a significant reduction in neonatal mortality, perhaps related to a combination of ACS and improving obstetric care in the intervention clusters. Maternal and neonatal infections were increased in the intervention clusters across all sites and increased infections are a possible partial explanation for the increase in neonatal mortality and stillbirth in the intervention clusters, especially in the African sites. The analyses presented here provide guidance for future ACS trials in LMIC. These include having accurate gestational age dating of study subjects and having care givers who can diagnose conditions leading to preterm birth and predict which women likely will deliver in the next 7 days. All study subjects should be followed through delivery and the neonatal period, regardless of when they deliver. Clearly defined measures of maternal and neonatal infection should be utilized. Trials in low income country facilities including clinics and those without newborn intensive care seem to be of the highest priority. PMID- 27221398 TI - Adjunctive perampanel in adolescents with inadequately controlled partial-onset seizures: A randomized study evaluating behavior, efficacy, and safety. AB - OBJECTIVE: The noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist perampanel was shown in phase III trials to be an effective and well-tolerated adjunctive treatment for partial-onset seizures. In adolescents, it is necessary to characterize cognitive, neuropsychological, and behavioral side effects of antiepileptic drugs (AEDs). The current analysis focuses on behavioral outcomes, efficacy, and safety of perampanel in adolescents. METHODS: Adolescents (12-17 years) on a stable regimen of 1-3 AEDs for partial-onset seizures were randomized (2:1 ratio) to receive up to 12 mg/day perampanel or placebo. Alongside efficacy, cognitive, and neuropsychological assessments, behavioral outcomes were measured with the Child Behavior Checklist (CBCL) before and after a 19-week titration and maintenance phase. RESULTS: Of the randomized patients, 85 received perampanel and 48 received placebo. Median reduction in seizure frequency from baseline was 58.0% for perampanel and 24.0% for placebo (p = 0.079). More patients had seizure frequency reduced by 50% after perampanel (n = 49 [59.0%]) than placebo (n = 17 [37.0%]; p = 0.0144). Changes in behavior were minimal, and there were no differences between groups on competency (p = 0.619) or problems (p = 0.174). A greater proportion of placebo patients were classified in the CBCL "clinical" range for competency at end of treatment, whereas the number in the perampanel group remained unchanged. The overall safety profile was similar to that reported previously for perampanel; most frequently reported adverse events (AEs) were dizziness (26 patients [30.6% vs. 14.6% placebo]), somnolence (13 patients [15.3% vs. 4.2%]), and headache (nine patients [10.6% vs. 14.6%]). Aggression was reported in seven patients receiving perampanel (8.2% vs. 2.1% placebo); two of these were serious AEs, with neither requiring treatment discontinuation. SIGNIFICANCE: Adjunctive perampanel is efficacious and well tolerated in adolescents with partial-onset seizures, and appears to have no clinically important impact on behavior measured using the CBCL. PMID- 27221399 TI - Long-chain amine-templated synthesis of gallium sulfide and gallium selenide nanotubes. AB - We describe the soft chemistry synthesis of amine-templated gallium chalcogenide nanotubes through the reaction of gallium(iii) acetylacetonate and the chalcogen (sulfur, selenium) using a mixture of long-chain amines (hexadecylamine and dodecylamine) as a solvent. Beyond their role as solvent, the amines also act as a template, directing the growth of discrete units with a one-dimensional multilayer tubular nanostructure. These new materials, which broaden the family of amine-stabilized gallium chalcogenides, can be tentatively classified as direct large band gap semiconductors. Their preliminary performance as active material for electrodes in lithium ion batteries has also been tested, demonstrating great potential in energy storage field even without optimization. PMID- 27221400 TI - [Records must be kept for 10 years]. PMID- 27221401 TI - [Treating and billing chronic wounds faster]. PMID- 27221402 TI - [Did he acquire theses callosities from the toilet?]. PMID- 27221403 TI - [During long operations disinfect hands frequently!]. PMID- 27221404 TI - [Checklist should prevent vaccination errors]. PMID- 27221405 TI - [Cardio-metabolic fitness in 10 minutes]. PMID- 27221406 TI - [Control of noncompliance with e-health]. PMID- 27221407 TI - [Stable angina pectoris: assessment]. PMID- 27221408 TI - [Why children injure themselves]. PMID- 27221409 TI - [Benefits and risks of telemedicine]. PMID- 27221410 TI - [Naturopathy procedures for ailing joints]. PMID- 27221411 TI - [The skin is a mirror of glucose metabolism]. PMID- 27221412 TI - [How autism can complicate diabetes management]. PMID- 27221413 TI - [Also applies to physicians: humor is when one laughs anyway]. PMID- 27221414 TI - [Needlessly tortured]. PMID- 27221415 TI - [How does one vaccinate women against rubella?]. PMID- 27221416 TI - [Prevention in GOA: potential in men]. PMID- 27221417 TI - [The patient wants his records - what now?]. PMID- 27221418 TI - [Is this mother worried or only calculating?]. PMID- 27221419 TI - [I am the ear in the night]. PMID- 27221420 TI - [Now the doctors themselves distribute the fee]. PMID- 27221421 TI - [Integrated care in Kinzigtal]. PMID- 27221422 TI - [KV needs no proof of mailing from the postoffice]. PMID- 27221423 TI - [Before retirement still quickly into the MVZ - that will not do!]. PMID- 27221424 TI - [Is there a liability limitation for MVZ partners?]. PMID- 27221425 TI - [Cannabis politics - but truthful]. PMID- 27221426 TI - [After a mini-stroke special care is a responsibility]. PMID- 27221427 TI - [Extreme gout can get out of hand]. PMID- 27221428 TI - [Are physicians treating dementia too often with antipsychotics?]. PMID- 27221429 TI - [In any case a stye it is not!]. PMID- 27221430 TI - [The thinker defecates better]. PMID- 27221431 TI - [Diabetes in the family makes sports more arduous]. PMID- 27221432 TI - [Scabies works its way through the skin]. PMID- 27221433 TI - [Pediatrics for the general practitioner]. PMID- 27221434 TI - [Basic diagnostics for pediatric outpatients with susceptibility to infections and immundysregulation]. PMID- 27221435 TI - [Vaccination]. PMID- 27221436 TI - [Acquired adult flat foot deformity: Current concepts in diagnostics and therapy]. PMID- 27221437 TI - [Fever in a 78-year-old patient]. PMID- 27221438 TI - [Primary wound treatment in general practice]. PMID- 27221439 TI - [Could it be a stroke?]. PMID- 27221440 TI - [Treatment of extensor tendon injuries of the hand and finger]. PMID- 27221441 TI - [How to differentiate between uncontrolled and severe asthma]. PMID- 27221442 TI - [Pain and sleep disturbances]. PMID- 27221443 TI - [Help for treatment resistant patients with pulmonary emphysema]. PMID- 27221444 TI - [Effective blood pressure control with a fixed combination]. PMID- 27221445 TI - [Insulin aspartate reduces cardiovascular events]. PMID- 27221446 TI - [Blood coagulation self management increases safety]. PMID- 27221447 TI - [Oral steroids downgraded, biologics upgraded]. PMID- 27221448 TI - [Facilitated patient management with low molecular weight heparin]. PMID- 27221449 TI - [Phytotherapy drug relieves complaints]. PMID- 27221450 TI - [No fear of pregnancy]. PMID- 27221451 TI - [Iron deficiency therapy: focus is on the patient]. PMID- 27221452 TI - [Attention to acceptance and adherence]. PMID- 27221453 TI - [Hexal expands its antiviral portfolio]. PMID- 27221454 TI - [First fixed combination becomes available]. PMID- 27221455 TI - miR-410-3p suppresses breast cancer progression by targeting Snail. AB - miR-410-3p acts as an oncogene or tumor-suppressor gene in various types of cancer. However, its role in breast cancer remains unknown. In the present study, expression of miR-410-3p in 30 breast cancer and paired adjacent normal tissues was detected by RT-qPCR. The expression of miR-410-3p was downregulated in 76.7% of the breast cancer samples. To further validate the expression of miR-410-3p in breast cancer, we analyzed miR-410-3p expression profiling data set from The Cancer Genome Atlas (TCGA) including 683 breast cancer and 87 normal breast tissues. We observed that the expression of miR-410-3p was downregulated in breast cancer tissues. Next, we investigated the influence of miR-410-3p on cell proliferation by transiently transfecting the miR-410-3p mimic or inhibitor, as well as their corresponding controls in the MDA-MB-231 and MCF7 cell lines. miR 410-3p overexpression reduced cell growth, colony formation and the number of EdU positive cells in the MDA-MB-231 cells. In contrast, inhibition of miR-410-3p in the MCF7 cells resulted in a higher proliferation rate as assessed by MTT assay, plate colony formation and EdU assays. Furthermore, miR-410-3p inhibited epithelial-mesenchymal transition. In addition, Snail was found to be a direct target of miR-410-3p based on a luciferase assay. Overexpression of Snail was able to rescue the effect of miR-410-3p in breast cancer cells. Moreover, miR-410 3p was inversely expressed with Snail in breast cancer samples. Our data provide new knowledge regarding the role of miR-410-3p in breast cancer progression. PMID- 27221456 TI - A multicenter report of biologic agents for the treatment of secondary amyloidosis in Turkish rheumatoid arthritis and ankylosing spondylitis patients. AB - In this multicenter, retrospective study, we evaluated the efficacy and safety of biologic therapies, including anti-TNFs, in secondary (AA) amyloidosis patients with ankylosing spondylitis (AS) and rheumatoid arthritis (RA). In addition, the frequency of secondary amyloidosis in RA and AS patients in a single center was estimated. Fifty-one AS (39M, 12F, mean age: 46.7) and 30 RA patients (11M, 19F, mean age: 51.7) with AA amyloidosis from 16 different centers in Turkey were included. Clinical and demographical features of patients were obtained from medical charts. A composite response index (CRI) to biologic therapy-based on creatinine level, proteinuria and disease activity-was used to evaluate the efficacy of treatment. The mean annual incidence of AA amyloidosis in RA and AS patients was 0.23 and 0.42/1000 patients/year, respectively. The point prevalence in RA and AS groups was 4.59 and 7.58/1000, respectively. In RA group with AA amyloidosis, effective response was obtained in 52.2 % of patients according to CRI. RA patients with RF positivity and more initial disease activity tended to have higher response rates to therapy (p values, 0.069 and 0.056). After biologic therapy (median 17 months), two RA patients died and two developed tuberculosis. In AS group, 45.7 % of patients fulfilled the criteria of good response according to CRI. AS patients with higher CRP levels at the time of AA diagnosis and at the beginning of anti-TNF therapy had higher response rates (p values, 0.011 and 0.017). During follow-up after anti-TNF therapy (median 38 months), one patient died and tuberculosis developed in two patients. Biologic therapy seems to be effective in at least half of RA and AS patients with AA amyloidosis. Tuberculosis was the most important safety concern. PMID- 27221457 TI - Updates on cardiovascular comorbidities associated with psoriatic diseases: epidemiology and mechanisms. AB - Psoriasis and psoriatic arthritis are associated with a significantly increased risk of cardiovascular risk factors and major adverse cardiovascular events (MACE). Active research is ongoing to elucidate this relationship between psoriatic diseases and cardiovascular comorbidities, as well as their shared pathogenic mechanisms. This review focuses on (1) the epidemiologic association between psoriasis and cardiovascular risk factors, (2) the epidemiologic association between psoriasis and MACE, (3) the epidemiologic association between psoriatic arthritis, cardiovascular risk factors, and MACE, and (4) proposed mechanisms for the contribution of psoriatic diseases to cardiovascular diseases. The proposed mechanisms for shared pathogenesis between psoriatic diseases and cardiovascular diseases are inflammation, insulin resistance, dyslipidemia, angiogenesis, oxidative stress, and endothelial dysfunction. There is complex interplay and overlap among these mechanisms and their contributions to shared pathogenesis. Future translational research is necessary to elucidate the link between psoriatic diseases and cardiovascular diseases. Such findings may be applied clinically to improve the lives of psoriasis patients. PMID- 27221458 TI - Demographic, Medical, and Psychosocial Predictors of Pregnancy Anxiety. AB - BACKGROUND: Pregnancy anxiety is associated with risk of preterm birth and an array of other birth, infant, and childhood outcomes. However, previous research has not helped identify those pregnant women at greatest risk of experiencing this specific, contextually-based affective condition. METHODS: We examined associations between demographic, medical, and psychosocial factors and pregnancy anxiety at 24-26 weeks of gestation in a prospective, multicentre cohort study of 5271 pregnant women in Montreal, Canada. RESULTS: Multivariate analyses indicated that higher pregnancy anxiety was independently related to having an unintended pregnancy, first birth, higher medical risk, and higher perceived risk of complications. Among psychosocial variables, higher pregnancy anxiety was associated with lower perceived control of pregnancy, lower commitment to the pregnancy, more stressful life events, higher perceived stress, presence of job stress, lower self-esteem and more social support. Pregnancy anxiety was also higher in women who had experienced early income adversity and those who did not speak French as their primary language. Psychosocial variables explained a significant amount of the variance in pregnancy anxiety independently of demographic and medical variables. CONCLUSIONS: Women with pregnancy-related risk factors, stress of various kinds, and other psychosocial factors experienced higher pregnancy anxiety in this large Canadian sample. Some of the unique predictors of pregnancy anxiety match those of earlier US studies, while others point in new directions. Screening for high pregnancy anxiety may be warranted, particularly among women giving birth for the first time and those with high-risk pregnancies. PMID- 27221459 TI - Applications of isothermal titration calorimetry - the research and technical developments from 2011 to 2015. AB - Isothermal titration calorimetry is a widely used biophysical technique for studying the formation or dissociation of molecular complexes. Over the last 5 years, much work has been published on the interpretation of isothermal titration calorimetry (ITC) data for single binding and multiple binding sites. As over 80% of ITC papers are on macromolecules of biological origin, this interpretation is challenging. Some researchers have attempted to link the thermodynamics constants to events at the molecular level. This review highlights work carried out using binding sites characterized using x-ray crystallography techniques that allow speculation about individual bond formation and the displacement of individual water molecules during ligand binding and link these events to the thermodynamic constants for binding. The review also considers research conducted with synthetic binding partners where specific binding events like anion-pi and pi-pi interactions were studied. The revival of assays that enable both thermodynamic and kinetic information to be collected from ITC data is highlighted. Lastly, published criticism of ITC research from a physical chemistry perspective is appraised and practical advice provided for researchers unfamiliar with thermodynamics and its interpretation. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27221460 TI - Reply - Letter to the Editor - Malnutrition: The kiss of grim reaper. PMID- 27221461 TI - Bioengineering microbial communities: Their potential to help, hinder and disgust. AB - The bioengineering of individual microbial organisms or microbial communities has great potential in agriculture, bioremediation and industry. Understanding community level drivers can improve community level functions to enhance desired outcomes in complex environments, whereas individual microbes can be reduced to a programmable biological unit for specific output goals. While understanding the bioengineering potential of both approaches leads to a wide range of potential uses, public acceptance of such technology may be the greatest hindrance to its application. Public perceptions and expectations of "naturalness," as well as notions of disgust and dread, may delay the development of such technologies to their full benefit. We discuss these bioengineering approaches and draw on the psychological literature to suggest strategies that scientists can use to allay public concerns over the implementation of this technology. PMID- 27221462 TI - Multilayer perceptron neural network-based approach for modeling phycocyanin pigment concentrations: case study from lower Charles River buoy, USA. AB - This paper proposes multilayer perceptron neural network (MLPNN) to predict phycocyanin (PC) pigment using water quality variables as predictor. In the proposed model, four water quality variables that are water temperature, dissolved oxygen, pH, and specific conductance were selected as the inputs for the MLPNN model, and the PC as the output. To demonstrate the capability and the usefulness of the MLPNN model, a total of 15,849 data measured at 15-min (15 min) intervals of time are used for the development of the model. The data are collected at the lower Charles River buoy, and available from the US Environmental Protection Agency (USEPA). For comparison purposes, a multiple linear regression (MLR) model that was frequently used for predicting water quality variables in previous studies is also built. The performances of the models are evaluated using a set of widely used statistical indices. The performance of the MLPNN and MLR models is compared with the measured data. The obtained results show that (i) the all proposed MLPNN models are more accurate than the MLR models and (ii) the results obtained are very promising and encouraging for the development of phycocyanin-predictive models. PMID- 27221463 TI - Effects of benzo[a]pyrene as an environmental pollutant and two natural antioxidants on biomarkers of reproductive dysfunction in male rats. AB - Benzo[a]pyrene (B[a]P) is an environmental toxicant and endocrine disruptor. Therefore, the aim of the present study was to investigate the toxicity of B[a]P in testis of rats and also to study the role of silymarin and thymoquinone (TQ) as natural antioxidants in the alleviation of such toxicity. Data of the present study showed that levels of testosterone, estrogen and progesterone were significantly decreased after treatment of rats with B[a]P. In addition, B[a]P caused downregulation of the expressions of steroidogenic enzymes including CYP17A1 and CP19A1, and decreased the activity of 17-beta hydroxysteroid dehydrogenase (17beta-HSD). Moreover, B[a]P decreased the activities of antioxidant enzymes including catalase (CAT), glutathione peroxidase (GPX) and superoxide dismutase (SOD), and significantly increased free radicals levels in testis of male rats. However, pretreatment of rats with silymarin prior to administration of B[a]P was found to restore the level of free radicals, antioxidant status, and activities of steroidogenic enzymes to their normal levels in testicular tissues. Moreover, histopathological finding showed that silymarin recovered the abnormalities occurred in tubules caused by B[a] P in testis of rats. On the other hand, TQ showed pro-oxidant effects and did not ameliorate the toxic effects of B[a] P on the testicular tissue since it decreased antioxidant enzymes activities and inhibited the protein expression of CYP11A1 and CYP21A2 compared to control rats. Moreover, TQ decreased the levels of testosterone, estrogen, and progesterone either in the presence or absence of B[a]P. It is concluded that B[a]P decreased testosterone levels, inhibited antioxidant enzymes activities, caused downregulation of CYP isozymes involved in steroidogenesis, and increased free radical levels in testis. Moreover, silymarin was more effective than TQ in restoring organism health and alleviating the deleterious effects caused by B[a]P in the testis of rats. Due to its negative impact, it is highly recommended to limit the use of TQ as a dietary supplement since millions of people in the Middle East are using it to improve their health. PMID- 27221464 TI - Treatment and desalination of domestic wastewater for water reuse in a four chamber microbial desalination cell. AB - Microbial desalination cells (MDCs) have been studied for contaminant removal from wastewater and salinity reduction in saline water. However, in an MDC wastewater treatment and desalination occurs in different streams, and high salinity of the treated wastewater creates challenges for wastewater reuse. Herein, a single-stream MDC (SMDC) with four chambers was developed for simultaneous organic removal and desalination in the same synthetic wastewater. This SMDC could achieve a desalination rate of 12.2-31.5 mg L(-1) h(-1) and remove more than 90 % of the organics and 75 % of NH4 (+)-N; the pH imbalance between the anode and cathode chambers was also reduced. Several strategies such as controlling catholyte pH, increasing influent COD concentration, adopting the batch mode, applying external voltage, and increasing the alkalinity of wastewater were investigated for improving the SMDC performance. Under a condition of 0.4 V external voltage, anolyte pH adjustment, and a batch mode, the SMDC decreased the wastewater salinity from 1.45 to below 0.75 mS cm(-1), which met the salinity standard of wastewater for irrigation. Those results encourage further development of the SMDC technology for sustainable wastewater treatment and reuse. PMID- 27221465 TI - Beneficial role of ascorbic and folic acids antioxidants against thyroxin-induced testicular dysfunction in hyperthyroid rats. AB - Thyroid hormones play a fundamental role in the regulation of metabolism of almost all mammalian tissue including the reproductive system. Hyperthyroidism in early life may cause delayed sexual maturation, although physical development is normal and skeletal growth may be accelerated. Hyperthyroidism after puberty influences reproductive functions and increases testosterone level. The aim of this work is to study the effect of induced hyperthyroidism by L-thyroxine sodium administration on the testis of rats and to evaluate the ameliorating role of different antioxidants as ascorbic acid and folic acid on the hyperthyroid state via the assessment of different biochemical markers, histopathological and immunochemical sections. DNA analysis of the D1 deiodinase was performed to determine genetic mutation due to hyperthyroidism. The results showed partially disrupted in the measured biochemical parameters and spermatogenesis in hyperthyroid rats. Post-administration of both folic and ascorbic acids together in hyperthyroid rats showed the best ameliorating effects on the thyroid hormones, testosterone, testicular GGT and ALP, and all oxidative stress markers. There is no genetic mutations that occurred in D1 deiodinase due to hyperthyroidism. These findings were indicated by the proliferating cell nuclear antigen (PCNA) studies of testes. PMID- 27221466 TI - Spatial distribution of trace elements and ecotoxicity of bottom sediments in Rybnik reservoir, Silesian-Poland. AB - The aim of study was to integrate chemical analyses and toxicity bioassays in order to assess the environmental risk connected with the presence of trace elements in the sediments. This study examined the ecological significance of trace elements in bottom sediments by applying a set of complementary sediment quality assessment methods sediment quality guidelines (SQGs) (mean probable effect concentration quotient (PECQ)), potential ecological risk index (PERI), contamination degree (C d) and two bioassays: the bacterial luminescence inhibition test with Vibrio fischeri on sediment elutriates and the direct contact test with the ostracod crustacean Heterocypris incongruens. The samples were collected from 50 stations of Rybnik reservoir. The reservoir is a region with enormous concentration of industry, mainly hard coal mining, electric power industry, and transportation. Despite the high diversity in metal concentration in the sediments, the spatial distribution of trace elements in the sediments was very similar. Moreover, the strong positive correlations between individual pairs of trace elements indicate that they may derive from a similar source and move together. According to mean PECQs, 68 % of the samples were potentially non-toxic and 32 % of the samples were potentially toxic. PERI values suggested that 70 % of the sediment sampling sites exhibited low ecological risk from metal pollution while 24 % of the samples had severe and serious risk. Based on our combined evaluation, we believe that Cd and Cu in the sediment samples frequently caused adverse biological effects. Higher toxic responses were observed in the Microtox test than in the Ostracodtoxkit test. All the sediment samples were found toxic to V. fischeri, and 96 % of the samples had effect percentages >50 %. For H. incongruens, 12 % of the sediments were not toxic and 44 % had effect percentages >50 %. In order to perform a complex assessment of the environmental impact of metal pollution, both chemical and ecotoxicological analysis should be carried out. PMID- 27221468 TI - Hemispheric processing of memory is affected by sleep. AB - Sleep is known to affect learning and memory, but the extent to which it influences behavioural processing in the left and right hemispheres of the brain is as yet unknown. We tested two hypotheses about lateralised effects of sleep on recognition memory for words: whether sleep reactivated recent experiences of words promoting access to the long-term store in the left hemisphere (LH), and whether sleep enhanced spreading activation differentially in semantic networks in the hemispheres. In Experiment 1, participants viewed lists of semantically related words, then slept or stayed awake for 12h before being tested on seen, unseen but related, or unrelated words presented to the left or the right hemisphere. Sleep was found to promote word recognition in the LH, and to spread activation equally within semantic networks in both hemispheres. Experiment 2 ensured that the results were not due to time of day effects influencing cognitive performance. PMID- 27221469 TI - Biomimetic rehabilitation engineering: the importance of somatosensory feedback for brain-machine interfaces. AB - OBJECTIVE: Brain-machine interfaces (BMIs) re-establish communication channels between the nervous system and an external device. The use of BMI technology has generated significant developments in rehabilitative medicine, promising new ways to restore lost sensory-motor functions. However and despite high-caliber basic research, only a few prototypes have successfully left the laboratory and are currently home-deployed. APPROACH: The failure of this laboratory-to-user transfer likely relates to the absence of BMI solutions for providing naturalistic feedback about the consequences of the BMI's actions. To overcome this limitation, nowadays cutting-edge BMI advances are guided by the principle of biomimicry; i.e. the artificial reproduction of normal neural mechanisms. MAIN RESULTS: Here, we focus on the importance of somatosensory feedback in BMIs devoted to reproducing movements with the goal of serving as a reference framework for future research on innovative rehabilitation procedures. First, we address the correspondence between users' needs and BMI solutions. Then, we describe the main features of invasive and non-invasive BMIs, including their degree of biomimicry and respective advantages and drawbacks. Furthermore, we explore the prevalent approaches for providing quasi-natural sensory feedback in BMI settings. Finally, we cover special situations that can promote biomimicry and we present the future directions in basic research and clinical applications. SIGNIFICANCE: The continued incorporation of biomimetic features into the design of BMIs will surely serve to further ameliorate the realism of BMIs, as well as tremendously improve their actuation, acceptance, and use. PMID- 27221467 TI - MicroRNA-146a suppresses ROCK1 allowing hyperphosphorylation of tau in Alzheimer's disease. AB - MicroRNA-146a is upregulated in the brains of patients with Alzheimer's disease (AD). Here, we show that the rho-associated, coiled-coil containing protein kinase 1 (ROCK1) is a target of microRNA-146a in neural cells. Knockdown of ROCK1 mimicked the effects of microRNA-146a overexpression and induced abnormal tau phosphorylation, which was associated with inhibition of phosphorylation of the phosphatase and tensin homolog (PTEN). The ROCK1/PTEN pathway has been implicated in the neuronal hyperphosphorylation of tau that occurs in AD. To determine the function of ROCK1 in AD, brain tissue from 17 donors with low, intermediate or high probability of AD pathology were obtained and analyzed. Data showed that ROCK1 protein levels were reduced and ROCK1 colocalised with hyperphosphorylated tau in early neurofibrillary tangles. Intra-hippocampal delivery of a microRNA 146a specific inhibitor (antagomir) into 5xFAD mice showed enhanced hippocampal levels of ROCK1 protein and repressed tau hyperphosphorylation, partly restoring memory function in the 5xFAD mice. Our in vitro and in vivo results confirm that dysregulation of microRNA-146a biogenesis contributes to tau hyperphosphorylation and AD pathogenesis, and inhibition of this microRNA could be a viable novel in vivo therapy for AD. PMID- 27221470 TI - Changing Mechanical Strength in Cr(III)- Metallosupramolecular Polymers with Ligand Groups and Light Irradiation. AB - We have demonstrated the ability to control the mechanical properties of metallosupramolecular materials via choice of ligand binding group, as well as with external light irradiation. These photoresponsive Cr(III)-based materials were prepared from a series of modified hydrogenated poly(ethylene-co-butylene) polymers linked through metal-ligand interactions between a Cr(III) metal center and pyridyl ligand termini of the polymers. The introduction of these Cr(III) pyridine bonds gave rise to new mechanical and optical properties of the polymer materials. Depending on the type of pyridyl ligand, density functional theory calculations revealed changes in coordination to the Cr(III), which ultimately led to materials with significantly different mechanical properties. Electronic excitation of the Cr(III) materials with 450 and 655 nm CW lasers (800 mW/cm(2)) resulted in generation of excited state photophysical processes which led to temporary softening of the materials up to 143 kPa (41.5%) in storage modulus (G') magnitude. The initial mechanical strength of the materials was recovered when the light stimulus was removed, and no change in mechanical properties was observed with light irradiation where there was no absorbance by the Cr(III) moiety. These materials demonstrate that introduction of metal-ligand bonding interactions into polymers enables the design and synthesis of photoresponsive materials with tunable optical-mechanical properties not seen in traditional polymeric materials. PMID- 27221471 TI - Treatment of hypertensive patients with diabetes: beyond blood pressure control and focus on manidipine. AB - Renin-angiotensin system inhibitors should be considered as the first-line therapy in the treatment of patients with hypertension and diabetes. However, most of the diabetic subjects with hypertension require at least two drugs to achieve blood pressure targets. The ACCOMPLISH trial suggested that the best combination in the treatment of high-risk hypertensive patients should include a renin-angiotensin system inhibitor and a dihydropyridine. However, not all dihydropyridines block the same receptors. Those dihydropyridines that block T type calcium channel blockers may provide additional advantages. A number of studies suggest that compared with amlodipine, manidipine have the same antihypertensive efficacy, but with a lesser risk of ankle edema. In addition, manidipine, but not amlodipine, significantly reduces urinary albumin excretion rates. PMID- 27221472 TI - Improving Adherence to Post-Cervical Biopsy Sexual Abstinence in Kenyan Female Sex Workers. AB - PROBLEM: Cervical biopsies offer a unique opportunity for studying local immune response. To investigate hormonally induced immune fluctuations in cervical tissues of Kenyan female sex workers, we improved biopsy sampling protocol safety. Here, we report on steps taken to minimize exposure to HIV following two cervical biopsies. METHODS OF STUDY: Women were asked to abstain from vaginal intercourse to limit HIV exposure during wound healing with financial compensation. A comprehension tool for informed consent, on-site detection of prostate-specific antigens indicating unprotected intercourse within 48 hr, and bi-weekly text message reminders were implemented. RESULTS: The implemented methods improved compliance with post-procedure abstinence by two times (P = 0.013). Fourteen days following a cervical biopsy, no sign of genital inflammation or change in HIV T-cell target proportion were observed. CONCLUSIONS: This study provides new tools for limiting HIV exposure in studies requiring biopsy sampling among women at risk of acquiring HIV. PMID- 27221473 TI - Improving the provision of pregnancy care for Aboriginal and Torres Strait Islander women: a continuous quality improvement initiative. AB - BACKGROUND: Australian Aboriginal and Torres Strait Islander (Indigenous) women are at greater risk of adverse pregnancy outcomes than non-Indigenous women. Pregnancy care has a key role in identifying and addressing modifiable risk factors that contribute to adverse outcomes. We investigated whether participation in a continuous quality improvement (CQI) initiative was associated with increases in provision of recommended pregnancy care by primary health care centers (PHCs) in predominantly Indigenous communities, and whether provision of care was associated with organizational systems or characteristics. METHODS: Longitudinal analysis of 2220 pregnancy care records from 50 PHCs involved in up to four cycles of CQI in Australia between 2007 and 2012. Linear and logistic regression analyses investigated associations between documented provision of pregnancy care and each CQI cycle, and self-ratings of organizational systems. Main outcome measures included screening and counselling for lifestyle-related risk factors. RESULTS: Women attending PHCs after >=1 CQI cycles were more likely to receive each pregnancy care measure than women attending before PHCs had completed one cycle e.g. screening for cigarette use: baseline = 73 % (reference), cycle one = 90 % [odds ratio (OR):3.0, 95 % confidence interval (CI):2.2-4.1], two = 91 % (OR:5.1, 95 % CI:3.3-7.8), three = 93 % (OR:6.3, 95 % CI:3.1-13), four = 95 % (OR:11, 95 % CI:4.3-29). Greater self-ratings of overall organizational systems were significantly associated with greater screening for alcohol use (beta = 6.8, 95 % CI:0.25-13), nutrition counselling (beta = 8.3, 95 % CI:3.1-13), and folate prescription (beta = 7.9, 95 % CI:2.6-13). CONCLUSION: Participation in a CQI initiative by PHCs in Indigenous communities is associated with greater provision of pregnancy care regarding lifestyle-related risk factors. More broadly, these findings support incorporation of CQI activities addressing systems level issues into primary care settings to improve the quality of pregnancy care. PMID- 27221474 TI - Glycogen synthase kinase-3beta antagonizes ROS-induced hepatocellular carcinoma cell death through suppression of the apoptosis signal-regulating kinase 1. AB - Glycogen synthase kinase-3beta (GSK-3beta), a multifunctional kinase, is an important regulator of cancer cell survival. Apoptosis signal-regulating kinase 1 (ASK1) is also a key factor for controlling several cellular events including the cell cycle, senescence, and apoptosis, in response to reactive oxygen species (ROS). The role of GSK-3beta regulating the activity and protein level of ASK1 in the cancer cells remains largely unexplored. In this study, we showed that GSK 3beta inhibits ROS-induced hepatocellular carcinoma cell death by suppressing ASK1. We first found that ectopic expression of GSK-3beta suppressed hydrogen peroxide (H2O2)-induced cell death in HepG2 cells and knockdown of endogenous GSK 3beta expression exhibited opposite effects. Moreover, GSK-3beta expression clearly inhibited H2O2-induced phosphorylation of ASK1 in HepG2 cells, in association with a decrease in ASK1 protein level. Further exploration revealed that GSK-3beta induced ubiquitination and proteasome-dependent degradation of ASK1 via inhibition of ubiquitin-specific protease USP9X. Our results thus suggest that GSK-3beta is a key factor involved in ASK1 activation and ROS induced cell death. PMID- 27221475 TI - Identifying undiagnosed HIV in men who have sex with men (MSM) by offering HIV home sampling via online gay social media: a service evaluation. AB - BACKGROUND: An estimated one in eight men who have sex with men (MSM) in London lives with HIV, of which 16% are undiagnosed. It is a public health priority to minimise time spent undiagnosed and reduce morbidity, mortality and onward HIV transmission. 'Dean Street at Home' provided an online HIV risk self-assessment and postal home HIV sampling service aimed at hard-to-reach, high-risk MSM. OBJECTIVES: This 2-year service evaluation aims to determine the HIV risk behaviour of users, the uptake of offer of home sampling and the acceptability of the service. METHODS: Users were invited to assess their HIV risk anonymously through messages or promotional banners on several gay social networking websites. Regardless of risk, they were offered a free postal HIV oral fluid or blood self-sampling kit. Reactive results were confirmed in clinic. A user survey was sent to first year respondents. RESULTS: 17 361 respondents completed the risk self-assessment. Of these, half had an 'identifiable risk' for HIV and a third was previously untested. 5696 test kits were returned. 121 individuals had a reactive sample; 82 (1.4% of returned samples) confirmed as new HIV diagnoses linked to care; 14 (0.25%) already knew their diagnosis; and 14 (0.25%) were false reactives. The median age at diagnosis was 38; median CD4 505 cells/uL and 20% were recent infections. 61/82 (78%) were confirmed on treatment at the time of writing. The post-test email survey revealed a high service acceptability rate. CONCLUSIONS: The service was the first of its kind in the UK. This evaluation provides evidence to inform the potential roll-out of further online strategies to enhance community HIV testing. PMID- 27221476 TI - Ultrastructural and cytogenetic analyses of mature human oocyte dysmorphisms with respect to clinical outcomes. AB - PURPOSE: The study aimed to describe the ultrastructure of two human mature oocyte intracytoplasmic dysmorphisms, the bull-eye inclusion and the granular vacuole, with evaluation of clinical outcomes after intracytoplasmic sperm injection (ICSI) treatment. METHODS: We retrospectively evaluated 4099 consecutive ICSI cycles during the period 2003-2013. Three groups were compared: controls, those with a bulls-eye inclusion, and those with granular vacuoles. Oocyte dysmorphisms were evaluated by transmission electron microscopy and in situ fluorescence hybridization (FISH). Detailed data on demographic and stimulation characteristics, as well as on embryological, clinical, and newborn outcomes, are fully presented. RESULTS: The bull-eye inclusion is a prominent smooth round structure containing trapped vesicles, being surrounded by lipid droplets. The presence of this dysmorphism in the oocyte cohort had no clinical impact except when transferred embryos were exclusively derived from dysmorphism oocytes. The granular vacuole is delimited by a discontinuous double membrane and contains lipid droplets and vesicles. As FISH analysis revealed the presence of chromosomes, they probably represent pyknotic nuclei. The presence of this dysmorphism in the oocyte cohort had no clinical impact except when at least one transferred embryo was derived from dimorphic oocytes. CONCLUSIONS: Poor clinical outcomes were observed with transfer of embryos derived from dysmorphism oocytes, although without causing gestation or newborn problems. The bull-eye inclusion and granular vacuoles may thus be new prognostic factors for clinical outcomes. PMID- 27221478 TI - Associations of smoking with overall obesity, and central obesity: a cross sectional study from the Korea National Health and Nutrition Examination Survey (2010-2013). AB - OBJECTIVES: The association between smoking and obesity is a significant public health concern. Both are preventable risk factors of cardiovascular disease and a range of other conditions. However, despite numerous previous studies, no consensus has emerged regarding the effect of smoking on obesity. We therefore carried out a novel study evaluating the relationship between smoking and obesity. METHODS: A total of 5,254 subjects aged 19 years or older drawn from the 2010-2013 Korea National Health and Nutrition Examination Survey were included in this cross-sectional study. Smoking was examined both in terms of smoking status and the quantity of cigarettes smoked by current smokers. Multiple logistic regression analysis was used to assess the association between smoking and obesity. Overall obesity was defined as a body mass index (BMI) >=25 kg/m(2), and central obesity was defined as a waist circumference >=90 cm for males and >=85 cm for females. We adjusted for the possible confounding effects of age, sex, physical activity, alcohol consumption, and the presence of hypertension or diabetes. RESULTS: A statistically significant difference in central obesity according to smoking status was identified. Current smokers were more likely to be centrally obese than never-smokers (adjusted odds ratio,1.30; 95% confidence interval, 1.02 to 1.67). However, no significant association was found between smoking and obesity defined by BMI. Moreover, among current smokers, no statistically significant association was found between the daily amount of smoking and obesity or central obesity. CONCLUSIONS: Smoking was positively associated with central obesity. Current smokers should be acquainted that they may be more prone to central obesity. PMID- 27221477 TI - The endometrial preparation for frozen-thawed euploid blastocyst transfer: a prospective randomized trial comparing clinical results from natural modified cycle and exogenous hormone stimulation with GnRH agonist. AB - PURPOSE: The aim of the study was to evaluate two methods of endometrial preparation for frozen-thawed single euploid blastocyst transfer: modified natural and artificial cycle with GnRH-agonist pituitary suppression. METHODS: In this prospective, controlled randomized trial, a total of 236 patients undergoing infertility treatment were randomized in 1:1 ratio; 118 received a frozen-thawed single euploid blastocyst transfer in a modified natural cycle and 118 in an artificial cycle with GnRH-agonist pituitary suppression. In the artificial protocol, GnRH-agonist combined with estradiol valerate was administered. In the natural protocol, only final oocyte maturation was induced using human chorionic gonadotropin administration. The primary end-points were the clinical pregnancy and implantation rates; the secondary end-points were the cost-benefit in terms of drug cost and the number of visits and the woman psychological distress caused by the treatment. RESULTS: No significant differences were found in clinical pregnancy, implantation, and miscarriage rates between protocols. The number of clinical and ultrasound controls and the number of laboratory dosages and venous samplings were similar in both study groups. No significant differences were found between the groups in the anxiety and depression values before the start of treatment, on the days of progesterone administration, the blastocyst transfer, and pregnancy test. CONCLUSIONS: The findings of this study evidence that in case of frozen-thawed single euploid blastocyst transfer, both protocols are equally effective in terms of clinical outcomes, cost-benefit, and patient compliance. The choice of endometrial preparation protocol should be based on women menstrual and ovulatory characteristics or otherwise on patient need for cycle planning. TRIAL REGISTRATION: www.clinicaltrials.gov with number NCT02378584. PMID- 27221479 TI - Innate Immune Receptors. AB - For many years innate immunity was regarded as a relatively nonspecific set of mechanisms serving as a first line of defence to contain infections while the more refined adaptive immune response was developing. The discovery of pattern recognition receptors (PRRs) revolutionised the prevailing view of innate immunity, revealing its intimate connection with adaptive immunity and generation of effector and memory T- and B-cell responses. Among the PRRs, families of Toll like receptors (TLRs), C-type lectin receptors (CLR), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) and nucleotide-binding domain, leucine-rich repeat-containing protein receptors (NLRs), along with a number of cytosolic DNA sensors and the family of absent in melanoma (AIM)-like receptors (ALRs), have been characterised. NLR sensors have been a particular focus of attention, and some NLRs have emerged as key orchestrators of the inflammatory response through the formation of large multiprotein complexes termed inflammasomes. However, several other functions not related to inflammasomes have also been described for NLRs. This chapter introduces the different families of PRRs, their signalling pathways, cross-regulation and their roles in immunosurveillance. The structure and function of NLRs is also discussed with particular focus on the non inflammasome NLRs. PMID- 27221480 TI - Atypical Inflammasomes. AB - Pattern recognition receptors, including members of the NLR and PYHIN families, are essential for recognition of both pathogen- and host-derived danger signals. A number of molecules in these families are capable of forming multiprotein complexes termed inflammasomes that result in the activation of caspase-1. In addition to NLRP1, NLRP3, NLRC4, and AIM2, which form well-described inflammasome complexes, IFI16, NLRP6, NLRP7, NLRP12, and NLRC5 have also been proposed to form inflammasomes under specific conditions. The structure and function of these atypical inflammasomes will be highlighted here. PMID- 27221481 TI - Assessment of Inflammasome Activation by Cytokine and Danger Signal Detection. AB - The evaluation of the inflammasome activation usually addresses the presence of extracellular IL-1beta and IL-18 or the secretion of danger signal proteins such as HMGB-1 through their quantification using an enzyme-linked immunosorbent assay (ELISA). The ELISA is a routine laboratory technique that uses antibodies and colorimetric changes to identify a substance of interest. ELISA uses a solid phase enzyme immunoassay to detect the presence of a substance, usually an antigen, in a liquid or wet sample. Using 96 well plates, the ELISA technique enables to quantify the concentration of a single cytokine in multiple samples. However, a limitation of IL-1beta and IL-18 ELISA is the absence of discrimination between active and non-active form of the proteins, parameter critical, for example, to distinguish the biologically relevant IL-1beta from its poorly active form pro-IL-1beta. This issue can be solved using western blots or immunoblots (IB), a common analytical procedure to detect the presence of different proteins in biological samples. Using denaturating conditions, IB allows the visualization of different sizes of the proteins of choice and is a commonly used technique in the inflammasome field to evaluate, for instance, the maturation of pro-IL-1beta, pro-IL-18, and pro-caspase-1 into mature IL-1beta, mature IL-18, and mature caspase-1, respectively. Moreover inflammasome activation may lead to the release of inflammasome particles outside the cell through caspase-1- or caspase-11-dependent cell death mechanism termed pyroptosis. In this case, NLR, ASC, and caspase-1 components are detectable outside the cell using IB analysis. ELISA and IB can be performed on cell culture supernatant or cell extract and on ex vivo samples from organ homogenates or biological fluids such as serum and plasma or bronchoalveolar lavages. PMID- 27221483 TI - Measuring IL-1beta Processing by Bioluminescence Sensors I: Using a Bioluminescence Resonance Energy Transfer Biosensor. AB - IL-1beta processing is one of the hallmarks of inflammasome activation and drives the initiation of the inflammatory response. For decades, Western blot or ELISA have been extensively used to study this inflammatory event. Here, we describe the use of a bioluminescence resonance energy transfer (BRET) biosensor to monitor IL-1beta processing in real time and in living macrophages either using a plate reader or a microscope. PMID- 27221482 TI - Investigating IL-1beta Secretion Using Real-Time Single-Cell Imaging. AB - The pro-inflammatory cytokine interleukin (IL)-1beta is an important mediator of the inflammatory response. In order to perform its role in the inflammatory cascade, IL-1beta must be secreted from the cell, yet it lacks a signal peptide that is required for conventional secretion, and the exact mechanism of release remains undefined. Conventional biochemical methods have limited the investigation into the processes involved in IL-1beta secretion to population dynamics, yet heterogeneity between cells has been observed at a single-cell level. Here, greater sensitivity is achieved with the use of a newly developed vector that codes for a fluorescently labelled version of IL-1beta. Combining this with real-time single-cell confocal microscopy using the methods described here, we have developed an effective protocol for investigating the mechanisms of IL-1beta secretion and the testing of the hypothesis that IL-1beta secretion requires membrane permeabilisation. PMID- 27221484 TI - Measuring IL-1beta Processing by Bioluminescence Sensors II: The iGLuc System. AB - Inflammasomes are multimeric protein complexes that proteolytically activate caspase-1, which subsequently matures cytokines of the IL-1 family and initiates the induction of pyroptotic cell death. Although this process is central both to pathogen defense and sterile inflammatory processes, there is currently no standard readout available for inflammasome activation which would be suitable for high-throughput applications. We have recently developed a new method for measuring inflammasome activation via the use of a novel proteolytic reporter iGLuc, an IL-1beta Gaussia luciferase (iGLuc) fusion protein. Here, we provide detailed protocols for the use of iGLuc in transiently transfected or stably transduced cell lines. Using these protocols, IL-1beta maturation as the result of inflammasome activation or other processes can be indirectly measured via the gain of Gaussia luciferase activity of cleaved iGLuc, allowing for rapid inflammasome reconstitution assays and high-throughput screening of inflammasome activity. PMID- 27221485 TI - Assessing Extracellular ATP as Danger Signal In Vivo: The pmeLuc System. AB - Inflammation is the key pathophysiological response triggered by noxious agents in multicellular organisms. Central to inflammation is detection of exogenous or endogenous danger signals by immune cells. Extracellular ATP is a ubiquitous danger signal released during septic or sterile inflammation. The development of reliable techniques to measure extracellular ATP in vivo has become an urgent need in inflammation studies after the discovery that the most potent plasma membrane receptor responsible for NLRP3 inflammasome activation is an ATP activated receptor, P2RX7. Here we describe an easy bioluminescence technique for the measurement of extracellular ATP in vivo. PMID- 27221486 TI - Measuring NLR Oligomerization I: Size Exclusion Chromatography, Co immunoprecipitation, and Cross-Linking. AB - Oligomerization of nod-like receptors (NLRs) can be detected by several biochemical techniques dependent on the stringency of protein-protein interactions. Some of these biochemical methods can be combined with functional assays, such as caspase-1 activity assay. Size exclusion chromatography (SEC) allows separation of native protein lysates into different sized complexes by fast protein liquid chromatography (FPLC) for follow-up analysis. Using co immunoprecipitation (co-IP), combined with SEC or on its own, enables subsequent antibody-based purification of NLR complexes and associated proteins, which can then be analyzed by immunoblot and/or subjected to functional caspase-1 activity assay. Chemical cross-linking covalently joins two or more molecules, thus capturing the oligomeric state with high sensitivity and stability. Apoptosis associated speck-like protein containing a caspase activation domain (ASC) oligomerization has been successfully used as readout for NLR or AIM2-like receptor (ALR) inflammasome activation in response to various pathogen- or damage associated molecular patterns (PAMPs or DAMPs) in human and mouse macrophages and THP-1 cells. Here, we provide a detailed description of the methods used for NLRP7 oligomerization in response to infection with Staphylococcus aureus (S. aureus) in primary human macrophages, co-immunoprecipitation and immunoblot analysis of NLRP7 and NLRP3 inflammasome complexes, as well as caspase-1 activity assays. Also, ASC oligomerization is shown in response to dsDNA, LPS/ATP, and LPS/nigericin in mouse bone marrow-derived macrophages (BMDMs) and/or THP-1 cells or human primary macrophages. PMID- 27221487 TI - Measuring NLR Oligomerization II: Detection of ASC Speck Formation by Confocal Microscopy and Immunofluorescence. AB - Inflammasome assembly results in the formation of a large intracellular protein scaffold driven by the oligomerization of the adaptor protein apoptosis associated speck-like protein containing a CARD (ASC). Following inflammasome activation, ASC polymerizes to form a large singular structure termed the ASC "speck," which is crucial for recruitment of caspase-1 and its inflammatory activity. Hence, due to the considerably large size of these structures, ASC specks can be easily visualized by microscopy as a simple upstream readout for inflammasome activation. Here, we provide two detailed protocols for imaging ASC specks: by (1) live-cell imaging of monocyte/macrophage cell lines expressing a fluorescently tagged version of ASC and (2) immunofluorescence of endogenous ASC in cell lines and human immune cells. In addition, we outline a protocol for increasing the specificity of ASC antibodies for use in immunofluorescence. PMID- 27221488 TI - Measuring NLR Oligomerization III: Detection of NLRP3 Complex by Bioluminescence Resonance Energy Transfer. AB - Bioluminescent resonance energy transfer (BRET) is a natural phenomenon resulting from a non-radiative energy transfer between a bioluminescent donor (Renilla luciferase) and a fluorescent protein acceptor. BRET signal is dependent on the distance and the orientation between the donor and the acceptor and could be used to study protein-protein interactions and conformational changes within proteins in real time in living cells. This protocol describes the use of BRET technique to study NLRP3 oligomerization in living cells before and during NLRP3 inflammasome activation. PMID- 27221489 TI - Measuring NLR Oligomerization IV: Using Forster Resonance Energy Transfer (FRET) Fluorescence Lifetime Imaging Microscopy (FLIM) to Determine the Close Proximity of Inflammasome Components. AB - Intracellular signaling and cellular activation have been demonstrated to reside on multi-protein complexes rather than in isolated proteins. Consequently, techniques to resolve these complexes have gained much attention over the last few years. Forster Resonance Energy Transfer (FRET) coupled with Fluorescence Lifetime Imaging Microscopy (FLIM) is a powerful tool to discriminate direct interactions between two proteins within a multi-protein complex. Here, we present the use of FRET-FLIM as an experimental tool for the interpretation of the inflammasome composition. We also introduce some considerations required for the correct use of this technique and the control experiments that should be implemented. PMID- 27221490 TI - Measuring NLR Oligomerization V: In Situ Proximity Ligation Assay. AB - The NLRP3 inflammasome is assembled in macrophages and monocytes in response to inflammatory and danger stimuli. The atypical nature of the NLRP3 complex impedes detection of NLRP3 inflammasome formation by conventional biochemical and cell biology methods. In situ proximity ligation assay (PLA) provides an alternative method of detection, localization, and quantification of protein-protein interactions in tissue and cell samples. Two primary antibodies raised in different species detect the two proteins of interest. When the proteins are in close proximity, secondary antibodies conjugated with specific DNA probes hybridize with linking oligonucleotides to form a DNA bridge between the two proteins. Amplification of the DNA bridge then facilitates detection by microscopy using fluorescence probes. Here, we describe application of in situ PLA to detect NLRP3 inflammasome assembly in mouse bone marrow-derived macrophages and human monocyte cell line THP1. PMID- 27221491 TI - Assessing Caspase-1 Activation. AB - The caspase-1 enzymatic activity plays a major role in the innate immune response as it regulates the maturation of two major proinflammatory cytokines, the interleukin-1beta (IL-1beta) and IL-18. In this chapter, we describe the technique of Western blot to assess caspase-1 activation. This method provides multiple information within one experiment. It allows the detection of both unprocessed and processed caspase-1 and substrates. PMID- 27221492 TI - Cell-Free Assay for Inflammasome Activation. AB - Inflammasomes are multiprotein complexes, which assembly results in caspase-1 activation and subsequent IL-1beta and IL-18 activation and secretion. In a cell free system, based on cytosols of normally growing cells, the disruption of the cell membrane spontaneously activates the inflammasome. Studying the activation of the inflammasome in cytosolic extracts provides multiple advantages, as it is synchronized, rapid, strong, and mostly plasma membrane-free. This protocol covers the methods required to prepare cell lysates and study inflammasome activation using different read-outs. General considerations are provided that may help in the design of modified methods. This assay can be useful to study potential inflammasome interactors and the signaling pathways involved in its activation. PMID- 27221493 TI - Functional Reconstruction of NLRs in HEK293 Cells. AB - Inflammasomes are molecular complexes that initiate innate immune response. They are mainly expressed by immune cells; however, molecular manipulations in these cells remain very difficult. Here, we describe a simple protocol to overexpress and activate functional NRLP3 inflammasomes in HEK293 cells. PMID- 27221494 TI - Method to Measure Ubiquitination of NLRs. AB - Posttranslational modifications are crucial in determining the functions of proteins in the cell. Modification of the NLRP3 inflammasome by the ubiquitin system has recently emerged as a new level of regulation of the inflammasome complex. Here, we describe a method to detect polyubiquitination of NRLP3 using two different approaches: (1) detection with an ubiquin antibody or (2) using TUBE (Tandem Ubiquitin Binding entities). This approach can be used to detect ubiquitination of other NLR or other components of the inflammasome. PMID- 27221495 TI - Cytofluorometric Quantification of Cell Death Elicited by NLR Proteins. AB - Nucleotide-binding domain and leucine-rich repeat containing (NLR) proteins, also known as NOD-like receptors, are critical components of the molecular machinery that senses intracellular danger signals to initiate an innate immune response against invading pathogens or endogenous sources of hazard. The best characterized effect of NLR signaling is the secretion of various cytokines with immunostimulatory effects, including interleukin (IL)-1beta and IL-18. Moreover, at least under specific circumstances, NLRs can promote regulated variants of cell death. Here, we detail two protocols for the cytofluorometric quantification of cell death-associated parameters that can be conveniently employed to assess the lethal activity of specific NLRs or their ligands. PMID- 27221496 TI - NLR in Human Diseases: Role and Laboratory Findings. AB - Autoinflammatory diseases are a group of inherited and multifactorial disorders characterized by an overactivation of innate immune response. In most cases, the clinical manifestations are due to increased activity of the NLRP3 inflammasome resulting in increased IL-1beta secretion. Investigating inflammatory cells from subjects affected by autoinflammatory diseases presents a number of technical difficulties related to the rarity of the diseases, to the young age of most patients, and to the difficult modulation of gene expression in primary cells. However, since cell stress is involved in the pathophysiology of these diseases, the study of freshly drawn blood monocytes from patients affected by IL-1 mediated diseases strongly increases the chances that the observed phenomena is indeed pertinent to the pathogenesis of the disease and not influenced by the long-term cell culture conditions (e.g., the high O2 tension) or gene transfection in continuous cell lines that may lead to artifacts. PMID- 27221497 TI - Good Clinical Outcomes in Budd-Chiari Syndrome with Hepatic Vein Occlusion. AB - BACKGROUND: Budd-Chiari syndrome (BCS) with hepatic vein (HV) occlusion is manifested by severe liver damage in acute cases and esophageal variceal bleeding or refractory ascites in chronic cases, which is difficult to differentiate from cirrhotic portal hypertension. AIMS: To evaluate the clinical efficacy and safety of HV angioplasty and transjugular intrahepatic portosystemic shunt (TIPS) in the treatment of BCS with HV occlusion. METHODS: Between May 1995 and December 2014, 60 patients with HV occlusive BCS underwent HV angioplasty or TIPS. BCS was subacute or chronic in 55 patients and acute in 5 patients. HV angioplasty was performed in 18 patients with HV occlusion, combined HV and IVC angioplasty in 9 patients with HV and IVC occlusion, TIPS in 12 patients with HV occlusion, and modified TIPS in 21 patients with extensive HV occlusion. RESULTS: The interventional procedure was successfully performed in all 60 patients. The portal pressure decreased from 41.23 +/- 10.46 cmH2O preoperatively to 26.68 +/- 6.46 cmH2O postoperatively, while the portal flow velocity increased from 14.31 +/- 10.43 to 52.16 +/- 13.68 cm/s in patients undergoing TIPS or modified TIPS. During hospitalization, two patients died from hepatic failure, and acute shunt occlusion occurred in two other patients during subsequent treatment with repeated intervention. During 82.25 +/- 46.16 months of follow-up, three patients underwent re-intervention with a stenotic shunt, and other three with repeated dilation of the stenotic HV. CONCLUSION: HV angioplasty and TIPS yield excellent long-term outcomes in patients with HV occlusive BCS. PMID- 27221498 TI - Decreased Expression of EHD2 Promotes Tumor Metastasis and Indicates Poor Prognosis in Hepatocellular Carcinoma. AB - BACKGROUND: Metastasis remains the most common cause of lethal outcomes in hepatocellular carcinoma (HCC) after curative resection. Understanding molecular mechanisms that regulate metastasis process is crucial for improving treatment of hepatocellular carcinoma. AIMS: In this article, we examined whether Eps15 homology domain-containing 2 (EHD2) played a critical role in hepatocellular carcinoma metastasis and explored the possible mechanism. METHODS: EHD2 and E cadherin expression levels in hepatocellular carcinoma patients were examined using Western blotting and immunohistochemistry. The cell migration and invasion were evaluated by wound-healing assay and trans-well assay. Epithelial mesenchymal transition was analyzed by immunofluorescence, and the vital markers were detected by Western blotting. The correlation of EHD2 and E-cadherin was confirmed by co-immunoprecipitation. RESULTS: EHD2 expression, along with the epithelial marker E-cadherin, was markedly reduced in tumor tissues than in adjacent noncancerous tissues. Moreover, EHD2 was positively correlated with E cadherin, histological grade, tumor metastasis, and microvascular invasion. Kaplan-Meier survival analysis showed that hepatocellular carcinoma patients with decreased EHD2 expression had shorter overall survival times than those with higher EHD2 expression. Knockdown of EHD2 induced an increase in cell invasion and changes characteristic of epithelial-mesenchymal transition, while overexpression of EHD2 inhibited these processes. CONCLUSIONS: Molecular data indicated that EHD2 inhibited migration and invasion of hepatocellular carcinoma probably by interacting with E-cadherin and it might be an independent, significant risk factor for survival after curative resection. PMID- 27221499 TI - Treatment of Isolated Below the Knee Deep Vein Thrombosis. AB - The natural history of isolated distal deep-vein thrombosis (IDDVT) is still uncertain, as well as the real clinical risks associated with the disease and the need for its diagnosis and treatment. While more and more IDDVTs are diagnosed in everyday clinical practice, their appropriate therapeutic management is, unfortunately, far from straightforward, and different recommendations on how patients with diagnosed IDDVT should be treated are present between expert professionals and even among international guidelines. The present article aims at briefly reviewing the issue of IDDVT therapy in general, particularly focusing on the different approaches to the treatment of the disease that have been suggested by recent guidelines, those that are currently adopted in clinical practice, and necessary future directions. PMID- 27221500 TI - Role of cis-Monounsaturated Fatty Acids in the Prevention of Coronary Heart Disease. AB - The effects of cis-monounsaturated fatty acids (cis-MUFAs) on the risk of coronary heart disease (CHD) and on CHD mortality are not clear. Also, dietary recommendations for cis-MUFA as derived by various organizations are not in agreement. Earlier studies have mainly focused on the effects of cis-MUFA on serum lipids and lipoproteins. More recent studies, however, have also addressed effects of cis-MUFA on other non-traditional CHD risk markers such as vascular function markers, postprandial vascular function, and energy intake and metabolism. Although well-designed randomized controlled trials with CHD events as endpoints are missing, several large prospective cohort studies have recently been published on the relationship between cis-MUFA and CHD risk. The aim of this paper is to review these new studies that have been published in the last 3 years on the effects of cis-MUFA on cardiovascular risk markers and CHD. PMID- 27221501 TI - Monoclonal Antibodies for Lipid Management. AB - In recent years, biochemical and genetic studies have identified proprotein convertase subtilisin/kexin type 9 (PCSK9) as a major mediator of low-density lipoprotein cholesterol (LDL-c) levels and thereby a potential novel target for reducing risk of coronary heart disease (CHD). These observations led to the development of PCSK9 inhibitors, which lower LDL-c levels more than any other non invasive lipid-lowering therapy presently available. The PCSK9 inhibitors furthest along in clinical trials are subcutaneously injected monoclonal antibodies. These PCSK9 inhibitors have demonstrated LDL-c-lowering efficacy with acceptable safety in phase III clinical trials and may offer a useful therapy in addition to maximally tolerated HMG-CoA reductase inhibitors (statins) in certain patient groups. Longer-term data are required to ensure sustained efficacy and safety of this new class of medications. This review provides an overview of the biology, genetics, development, and clinical trials of monoclonal antibodies designed to inhibit PCSK9. PMID- 27221502 TI - Endovascular Interventions in Acute Ischemic Stroke: Recent Evidence, Current Challenges, and Future Prospects. AB - After many years of clinical research, endovascular thrombectomy has been conclusively proven to be an effective treatment in acute ischemic stroke. The evidence is compelling; however, it is generated in high volume stroke centers with stroke expertise. Challenges remain ahead on translating and implementing this evidence in routine clinical care across the world. The current evidence has opened up avenues for further research and innovation in this field. In this review, we will discuss the evolution of evidence on endovascular thrombectomy followed by a discussion of challenges and future prospects in this exciting field of stroke care. PMID- 27221503 TI - Discontinuation of Statins: What Are the Risks? AB - The key benefits of statin therapy have been well established in both primary and secondary prevention cardiovascular patients. Many studies have shown a significant statin discontinuation rate within the first year of initiation whether for primary or secondary prevention. National guidelines for the management of dyslipidemia highlight the lack of benefit seen with statin therapy in patients with chronic kidney disease receiving dialysis, heart failure with reduced ejection fraction, and patients greater than 75 years of age without atherosclerotic cardiovascular disease. Available data outside of these patient populations do not support discontinuation of statin therapy. Recent studies support an association with statin discontinuation and increased risk of myocardial infarction and cardiovascular death. Based on the available data, discontinuation of statin therapy should be carefully considered. PMID- 27221504 TI - Revisional Bariatric/Metabolic Surgery: What Dictates Its Indications? AB - Bariatric/metabolic surgery is currently the only effective long-term treatment for morbid obesity- and obesity-related diseases such as diabetes, heart disease, hypertension, obstructive sleep apnea, and dyslipidemia. In addition, bariatric/metabolic surgery has been shown to significantly reduce the incidence of diabetes and cancer and prolong life when compared to non-surgical therapies. However, as obesity is a chronic disease, recidivism of weight and comorbid conditions can occur. In addition, the surgical construct can lead to long-term consequences such as marginal ulceration, bowel obstruction, reflux, and nutritional deficiencies. Despite these drawbacks, prospective randomized controlled studies and long-term longitudinal population-based comparative studies greatly favor surgical intervention as opposed to traditional lifestyle, diet, and exercise programs. Revisional surgery can be quite complex and technically challenging and may offer the patient a wide variety of solutions for treatment of weight recidivism and complications after primary operations. Given the paucity of high quality published data, we have endeavored to provide indications for revisions after bariatric surgery. PMID- 27221505 TI - Reproductive biology of the stingrays, Myliobatis goodei and Myliobatis ridens (Chondrichthyes: Myliobatidae), in southern Brazil. AB - This study, carried out between spring 2012 and winter 2014, characterized the sexual development and reproductive cycle of Myliobatis goodei and Myliobatis ridens in the extreme south of Brazil to support future management and conservation plans. Ninety-five specimens of M. goodei (24 males and 71 females) and 175 M. ridens (24 males and 151 females) were sampled. Female M. goodei attained disc-width-at-50% maturity (WD50 ) at 683 mm. Uterine fecundity was four to five embryos. The largest male recorded, a mature individual, had a disc width of 650 mm. In M. ridens, WD50 was 662 mm. Uterine fecundity varied from one to eight embryos. The largest male on record was a maturing 590 mm WD individual. The hepato-somatic index was higher in autumn in females of M. goodei, and in the summer in M. ridens. The gonado-somatic index and the largest vitellogenic follicle diameter were higher in spring in both species. Pregnant females of both species were recorded during spring, although for M. ridens, these females also occurred in summer. Embryos had WD of 61-218 and 40-236 mm for M. goodei and M. ridens, respectively. The incidence of pregnant females in southern Brazil in spring-summer coincides with the small-scale beach artisanal fisheries season peak, when M. goodei and M. ridens suffer fishing mortality, while using the coastal shallow areas in the warmer periods (spring-summer) to give birth. PMID- 27221506 TI - Comparison of catalase immunoreactivity in the hippocampus between young, adult and aged mice and rats. AB - Catalase (CAT) is an important antioxidant enzyme and is crucial in modulating synaptic plasticity in the brain. In this study, CAT expression as well as neuronal distribution was compared in the hippocampus among young, adult and aged mice and rats. Male ICR mice and Sprague Dawley rats were used at postnatal month (PM) 1, PM 6 and PM 24 as the young, adult and aged groups, respectively (n=14/group). CAT expression was examined by immunohistochemistry and western blot analysis. In addition, neuronal distribution was examined by NeuN immunohistochemistry. In the present study, the mean number of NeuN immunoreactive neurons was marginally decreased in mouse and rat hippocampi during aging, although this change was not identified to be significantly different. However, CAT immunoreactivity was significantly increased in pyramidal and granule neurons in the adult mouse and rat hippocampi and was significantly decreased in the aged mouse and rat hippocampi compared with that in the young animals. CAT protein levels in the hippocampus were also lowest in the aged mouse and rat hippocampus. These results indicate that CAT expression is significantly decreased in the hippocampi of aged animals and decreased CAT expression may be closely associated with aging. PMID- 27221507 TI - Construction and Validation of Afterlife Belief Scale for Muslims. AB - The purpose of this study was to develop a scale in Urdu language for measuring different dimensions of afterlife belief. The scale was subjected to exploratory and confirmatory factor analysis on a sample of 504 individuals (235 men and 269 women) recruited from different cities in the Punjab, Pakistan. After exploratory and confirmatory factor analysis, 16 items were retained with three well-defined factor structures of afterlife belief: positive, negative, and extinction. The alpha coefficients of the subscales ranged from .65 to .78. Convergent and discriminant validity of the subscales of Afterlife Belief Scale was determined by finding its relationship with the Pleasant Afterlife Belief Scale, the Unpleasant Afterlife Belief Scale, the Anxiety Subscale of DASS, and the Belief in Equitable World Scale. The results support that the newly developed scale has promising validity. PMID- 27221508 TI - Actions of l-thyroxine and Nano-diamino-tetrac (Nanotetrac) on PD-L1 in cancer cells. AB - The PD-1 (programmed death-1)/PD-L1 (PD-ligand 1) checkpoint is a critical regulator of activated T cell-cancer cell interactions, defending tumor cells against immune destruction. Nano-diamino-tetrac (NDAT; Nanotetrac) is an anticancer/anti-angiogenic agent targeted to the thyroid hormone-tetrac receptor on the extracellular domain of integrin alphavbeta3. NDAT inhibits the cancer cell PI3-K and MAPK signal transduction pathways that are critical to PD-L1 gene expression. We examined actions in vitro of thyroid hormone (l-thyroxine, T4) and NDAT on PD-L1 mRNA abundance (qPCR) and PD-L1 protein content in human breast cancer (MDA-MB-231) cells and colon carcinoma (HCT116 and HT-29) cells. In MDA-MB 231 cells, a physiological concentration of T4 (10-7M total; 10-10M free hormone) stimulated PD-L1 gene expression by 38% and increased PD-L1 protein by 2.7-fold (p<0.05, all changes). NDAT (10-7M) reduced PD-L1 in T4-exposed cells by 21% (mRNA) and 39% (protein) (p<0.05, all changes). In HCT116 cells, T4 enhanced PD L1 gene expression by 17% and protein content by 24% (p<0.05). NDAT reduced basal PD-L1 mRNA by 35% and protein by 31% and in T4-treated cells lowered mRNA by 33% and protein by 66%. In HT-29 cells, T4 increased PD-L1 mRNA by 62% and protein by 27%. NDAT lowered basal and T4-stimulated responses in PD-L1 mRNA and protein by 35-40% (p<0.05). Activation of ERK1/2 was involved in T4-induced PD-L1 accumulation. We propose that, by a nongenomic mechanism, endogenous T4 may clinically support activity of the defensive PD-1/PD-L1 checkpoint in tumor cells. NDAT non-immunologically suppresses basal and T4-induced PD-L1 gene expression and protein accumulation in cancer cells. PMID- 27221509 TI - Electrocardiographic Spectral Features for Long-Term Outcome Prognosis of Atrial Fibrillation Catheter Ablation. AB - Atrial fibrillation (AF) is the most common arrhythmia in routine clinical practice. Despite many years of research, its mechanisms still are not well understood, thus reducing the effectiveness of AF treatments. Nowadays, pulmonary vein isolation by catheter ablation is the treatment of choice for AF resistant either to pharmacological or electrical cardioversion. However, given that long term recurrences are common, an appropriate patient selection before the procedure is of paramount relevance in the improvement of AF catheter ablation outcome. The present work studies how several spectral features of the atrial activity (AA) from a single lead of the surface electrocardiogram (ECG) can become potential pre-ablation predictors of long-term (>2 months) sinus rhythm maintenance. Among all the analyzed spectral features, results indicated that the most significant single predictor of paroxysmal AF ablation treatment outcome was related to the amplitude of the first harmonic of the dominant frequency, providing sensitivity (Se), specificity (Sp) and accuracy (Ac) values of 90%, 42.86 and 77.78%, respectively. On the other hand, the AA harmonic structure was the most significant single predictor for persistent AF, with Se, Sp and Ac values of 100%, 54.55 and 77.27%, respectively. A logistic regression analysis, mainly based on spectral amplitudes as well as on the harmonic structure of the AA, provided a higher predictive ability both for paroxysmal AF (Se = 100%, Sp = 57.14% and Ac = 88.89%) and persistent AF (Se = 90.91%, Sp = 72.73 and Ac = 81.82%). In conclusion, the study of key AA spectral features from the surface ECG can provide a significant preoperative prognosis of AF catheter ablation outcome at long-term follow-up. PMID- 27221510 TI - ADAM17-siRNA inhibits MCF-7 breast cancer through EGFR-PI3K-AKT activation. AB - A disintegrin and metalloproteinase-17 (ADAM17) can cut and release a wide variety of epidermal growth factor receptor (EGFR) ligands to promote survival, invasion and proliferation of cancer cell, and therefore, is considered to be a potential therapeutic target for cancer. The main goal of the present study was to observe the effects of ADAM17 small interfering RNA (ADAM17-siRNA) on human MCF-7 breast cancer and investigate its activation pathway. In vitro, MCF-7 cells were divided into ADAM17-siRNA groups, nonsense siRNA groups, AG1478 (selective EGFR blocker) groups, LY294002 [phosphatidylinositol 3-kinase (PI3K) phosphorylation inhibitor] groups, PD0325901 [mitogen extracellular kinase (MEK) inhibitor] groups and control groups. In vivo, MCF-7 cells were implanted subcutaneously into nude mice and then these mice were randomly divided into ADAM17-siRNA groups, vector groups and control groups. Our data showed that compared with the control groups, ADAM17-siRNA, AG1478 and LY294002 could inhibit the migration and proliferation of MCF-7 cells, but PD0325901 and nonsense siRNA did not show this effect. Except that specific ADAM17-siRNA could inhibit the expression of ADAM17 mRNA, others did not change it. Western blot analysis further confirmed that EGFR-PI3K-AKT signaling pathway is involved in ADAM17 siRNA inhibiting migration and proliferation of MCF-7 cells. Similarly to the former, the growth of MCF-7 breast cancer in nude mice was significantly inhibited by ADAM17-siRNA. Compared with the control group and the vector group, the tumor volume was smaller in the ADAM17-siRNA group, the tissues developed large areas of necrosis, immunohistochemistry showed low expressions of ADAM17 and Ki-67 and western blot analysis proved that the expression of ADAM17 protein in the tissue was also reduced. The present study suggests that ADAM17-siRNA inhibits MCF-7 breast cancer and is activated through the EGFR-PI3K-AKT signaling pathway. PMID- 27221512 TI - MicroRNA-27b reverses docetaxel resistance of non-small cell lung carcinoma cells via targeting epithelial growth factor receptor. AB - MicroRNA (miR)-27b has been reported to partici-pate in regulating the activity of non-small cell lung carcinoma (NSCLC) cells. Additionally, when downregulated in NSCLC it promotes resistance to docetaxel; however, the underlying molecular mechanism remains largely unknown. Using reverse transcription-quantitative polymerase chain reaction, the present study determined that the expression of miR-27b was significantly reduced in NSCLC cells that were resistant to docetaxel. In addition, epidermal growth factor receptor (EGFR) was identified as a possible target of miR-27b by searching the online miRNA database, TargetScan. A luciferase assay further validated EGFR as an effective target gene of miR-27b. In addition, it was determined that in tumor tissue samples resistant to docetaxel miR-27b was significantly downregulated, whilst EGFR was significantly upregulated. miR-27b negatively regulated the expression of EGFR. This was evident as the transfection of miR-27b mimics led to downregulation of the expression levels of EGFR, whilst miR-27b inhibitors upregulated the expression levels of EGFR. Furthermore, it was demonstrated that the transfection of miR-27b mimics significantly suppressed the apoptosis and promote the viability of A549 human lung carcinoma cells. In line with this, the introduction of miR-27b inhibitors significantly induced apoptosis and inhibited the proliferation of A549 cells. These results indicate that miR-27b may promote NSCLC cell viability and enhance resistance to docetaxel treatment through direct inhibition of EGFR expression. Additionally, miR-27b may become a promising molecular target for improving the effectiveness of chemotherapy with docetaxel. PMID- 27221513 TI - NMR detection in biofluid extracts at sub-MUM concentrations via para-H2 induced hyperpolarization. AB - NMR spectroscopy is one of the most powerful techniques to simultaneously obtain qualitative and quantitative information in chemical analysis. Despite its versatility, the applications of NMR in the study of biofluids are often limited by the insensitivity of the technique, further aggravated by the poor signal dispersion in the (1)H spectra. Recent advances in para-H2 induced hyperpolarization have proven to address both these limitations for specific classes of compounds. Herein, this approach is for the first time applied for quantitative determination in biofluid extracts. We demonstrate that a combination of solid phase extraction, para-hydrogen induced hyperpolarization and selective NMR detection quickly reveals a doping substance, nikethamide, at sub-MUM concentrations in urine. We suggest that this method can be further optimized for the detection of different analytes in various biofluids, anticipating a wider application of hyperpolarized NMR in metabolomics and pharmacokinetics studies in the near future. PMID- 27221511 TI - Improving Reperfusion Therapies in the Era of Mechanical Thrombectomy. AB - Recent positive clinical trials using mechanical thrombectomy proved that endovascular recanalization is an effective treatment for patients with acute stroke secondary to large vessel occlusions. The trials offer definite evidence that in acute ischemia recanalization is a powerful predictor of good outcome. However, even in the era of rapid and effective recanalization using endovascular approaches, the percentage of patients with good outcomes varies between 33 and 71 %. In addition, the number of patients who are eligible for endovascular thrombectomy is small and usually based on having salvageable tissue on imaging. There is therefore room for improvement to both enhance the effectiveness of current practice and expand treatment to a larger subset of stroke patients. In this review, we highlight some of the most promising approaches to improve endovascular therapy by combining with strategies to enhance collateral perfusion and vascular protection. PMID- 27221514 TI - Nurse practitioner screening for childhood adversity among adult primary care patients: A mixed-method study. AB - BACKGROUND AND PURPOSE: Researchers have demonstrated an association between experiencing childhood abuse and multiple chronic health conditions in adulthood, yet this evidence has not been routinely translated to practice. The purpose of this research study was to examine nurse practitioner (NP) practices, skills, attitudes, and perceived barriers associated with screening adult patients for childhood abuse to determine the extent to which evidence of the association between childhood abuse and negative health outcomes has been translated to NP practice. METHODS: A mixed-method approach with web-based questionnaires and online focus groups was used to examine NP screening for histories of childhood abuse. CONCLUSIONS: A total of 188 complete NP surveys were analyzed along with data from focus groups with 12 NPs. One third of the NPs regularly screened for childhood abuse and believed screening was their responsibility. Six barriers, including insufficient time and lack of confidence when inquiring about abuse, were significantly associated with NP screening practices. The focus group participants discussed how and when one should ask about childhood abuse, and the need for education about screening. IMPLICATIONS FOR PRACTICE: Time constraints and NPs' lack of confidence in their ability to screen for histories of childhood abuse must be addressed to encourage routine screening in primary care practice. PMID- 27221515 TI - Metabolomics as a tool in the identification of dietary biomarkers. AB - Current dietary assessment methods including FFQ, 24-h recalls and weighed food diaries are associated with many measurement errors. In an attempt to overcome some of these errors, dietary biomarkers have emerged as a complementary approach to these traditional methods. Metabolomics has developed as a key technology for the identification of new dietary biomarkers and to date, metabolomic-based approaches have led to the identification of a number of putative biomarkers. The three approaches generally employed when using metabolomics in dietary biomarker discovery are: (i) acute interventions where participants consume specific amounts of a test food, (ii) cohort studies where metabolic profiles are compared between consumers and non-consumers of a specific food and (iii) the analysis of dietary patterns and metabolic profiles to identify nutritypes and biomarkers. The present review critiques the current literature in terms of the approaches used for dietary biomarker discovery and gives a detailed overview of the currently proposed biomarkers, highlighting steps needed for their full validation. Furthermore, the present review also evaluates areas such as current databases and software tools, which are needed to advance the interpretation of results and therefore enhance the utility of dietary biomarkers in nutrition research. PMID- 27221516 TI - Symmetry of fMRI activation in the primary sensorimotor cortex during unilateral chewing. AB - OBJECTIVE: Functional magnetic resonance imaging (fMRI) is one of the most advanced techniques to analyze the cerebral effects on many behavior aspects of the oral system such as chewing and mastication. Studies on imaging of the cerebral representation of chewing demonstrated differential results with respect to cortical lateralization during unilateral chewing. The aim of our study is to clarify the effects of cerebral responses during unilateral chewing. MATERIAL AND METHODS: We used fMRI to compare brain activities during occlusal function in centric occlusion on natural teeth and chewing on a gum located on the right or the left teeth in 15 healthy subjects. Group data were performed by Talairach normalization and in addition by an assignment of activation maxima to individual anatomical landmarks in order to avoid possible loss of spatial preciseness of activation sites by normalization procedures. RESULTS: Evaluation of group data by Talairach normalization revealed representation sites for occlusal movements in bilateral primary (S1) and secondary (S2) somatosensory cortices, primary motor (M1) and premotor cortices, supplementary motor area (SMA) and medial cingulate gyrus, bilateral anterior cerebellar hemispheres and vermis, insula, orbitofrontal cortex, thalamus, and left pallidum. Right-sided chewing showed no differential activation to left-sided chewing, and both showed activation in areas also involved in bilateral occlusion. Both techniques, the one based on group normalization and the one based on an individual evaluation method, revealed remarkable low differences in activation maximum location in the primary motor, the primary and secondary somatosensory cortices, and the anterior cerebellar lobe. All chewing movements tested involved bilateral sensorimotor activation without a significant lateralization of activation intensities. CONCLUSION: Overall, a general lateralization of occlusion movements to the dominant side could not be verified in the present study. Chewing on the left or on the right side of teeth makes no difference for brain representation of chewing. CLINICAL RELEVANCE: The results describe the basic effects of what we can expect by evaluation of cerebral effects of chewing and mastication. Based on these results, clinical fMRI studies can be performed in different patient groups. PMID- 27221517 TI - Erratum to: Efficiency of powered systems for interproximal enamel reduction (IER) and enamel roughness before and after polishing-an in vitro study. PMID- 27221519 TI - Erratum to: Dual-phase amyloid PET: hitting two birds with one stone. PMID- 27221518 TI - Correlation between bond strength and nanomechanical properties of adhesive interface. AB - OBJECTIVES: The aims of this study were to evaluate the nanohardness and Young's modulus of the adhesive-dentin interface and to correlate them with the microtensile bond strength (MUTBS) after storage in water for 24 h and 6 months. METHODS: Eighty human third molar teeth were bonded to composite resin with the Adper Scotchbond Multipurpose (SBMP), Adper Single Bond 2 (SB2), Clearfil SE Bond (CSE) or Clearfil S3 Bond (CS3) adhesive systems and stored in water for 24 h and 6 months. Three bonded teeth were selected for each group for nanoindentation methodology to obtain the nanohardness and modulus values (n = 3), while seven bonded teeth each group were used for MUTBS (n = 7). Data were analyzed by two way ANOVA and Tukey's test (alpha = 0.05). Spearman correlation between nanohardness and modulus and MUTBS values was also calculated. RESULTS: Nanohardness and Young's modulus values for the dentin and hybrid layer were not significantly different regardless of the adhesive system or water storage periods (p > 0.05). Nanohardness and Young's modulus values for the adhesive layer were significantly higher for SB2 than for SBMP, CSE, and CS3 systems in both water storage periods. The MUTBS values for SBMP and CSE were significantly higher than for SB2 and CS3 in both storage periods. An inverse correlation between Young's modulus and MUTBS was observed for the adhesive layer. CONCLUSION: The water storage periods did not alter nanohardness, Young's modulus, and MUTBS of adhesives. The adhesive layer of SB2 showed the highest nanohardness and Young's modulus, but the highest dentin bond strength was obtained with SBMP and CSE. Thus, a lower Young's modulus yielded high bond strength. CLINICAL RELEVANCE: The inverse correlation between the Young's modulus of adhesive systems and dentin bond strength suggests adequate resistance of the adhesive to elastic deformation under stress, which are important properties to predict the success of the dental restoration. PMID- 27221520 TI - Cryoprotectant kinetic analysis of a human articular cartilage vitrification protocol. AB - We recently published a protocol to vitrify human articular cartilage and a method of cryoprotectant removal in preparation for transplantation. The current study's goal was to perform a cryoprotectant kinetic analysis and theoretically shorten the procedure used to vitrify human articular cartilage. First, the loading of the cryoprotectants was modeled using Fick's law of diffusion, and this information was used to predict the kinetics of cryoprotectant efflux after the cartilage sample had been warmed. We hypothesized that diffusion coefficients obtained from the permeation of individual cryoprotectants into porcine articular cartilage could be used to provide a reasonable prediction of the cryoprotectant loading and of the combined cryoprotectant efflux from vitrified human articular cartilage. We tested this hypothesis with experimental efflux measurements. Osteochondral dowels from three patients were vitrified, and after warming, the articular cartilage was immersed in 3 mL X-VIVO at 4 degrees C in two consecutive solutions, each for 24 h, with the solution osmolality recorded at various times. Measured equilibrium values agreed with theoretical values within a maximum of 15% for all three samples. The results showed that diffusion coefficients for individual cryoprotectants determined from experiments with 2-mm thick porcine cartilage can be used to approximate the rate of efflux of the combined cryoprotectants from vitrified human articular cartilage of similar thickness. Finally, Fick's law of diffusion was used in a computational optimization to shorten the protocol with the constraint of maintaining the theoretical minimum cryoprotectant concentration needed to achieve vitrification. The learning provided by this study will enable future improvements in tissue vitrification. PMID- 27221521 TI - Polyelectrolyte/surfactant films spread from neutral aggregates. AB - We describe a new methodology to prepare loaded polyelectrolyte/surfactant films at the air/water interface by exploiting Marangoni spreading resulting from the dynamic dissociation of hydrophobic neutral aggregates dispensed from an aqueous dispersion. The system studied is mixtures of poly(sodium styrene sulfonate) with dodecyl trimethylammonium bromide. Our approach results in the interfacial confinement of more than one third of the macromolecules in the system even though they are not even surface-active without the surfactant. The interfacial stoichiometry of the films was resolved during measurements of surface pressure isotherms in situ for the first time using a new implementation of neutron reflectometry. The interfacial coverage is determined by the minimum surface area reached when the films are compressed beyond a single complete surface layer. The films exhibit linear ripples on a length scale of hundreds of micrometers during the squeezing out of material, after which they behave as perfectly insoluble membranes with consistent stoichiometric charge binding. We discuss our findings in terms of scope for the preparation of loaded membranes for encapsulation applications and in deposition-based technologies. PMID- 27221525 TI - Commentary on Radiology imaging delays as independent predictors of length of hospital stay for emergency medical admissions. PMID- 27221522 TI - Current status of pediatric renal transplant pathology. AB - Histopathology is still an indispensable tool for the diagnosis of kidney transplant dysfunction in adult and pediatric patients. This review presents consolidated knowledge, recent developments and future prospects on the biopsy procedure, the diagnostic work-up, classification schemes, the histopathology of rejection, including antibody-mediated forms, ABO-incompatible transplants, protocol biopsies, recurrent and de novo disease, post-transplant lymphoproliferative disorder, infectious complications and drug-induced toxicity. It is acknowledged that frequently the correct diagnosis can only be reached in consensus with clinical, serological, immunogenetical, bacteriological and virological findings. This review shall enhance the understanding of the pediatric nephrologist for the thought processes of nephropathologists with the aim to facilitate teamwork between these specialist groups for the benefit of the patient. PMID- 27221523 TI - Minocycline Effects on IL-6 Concentration in Macrophage and Microglial Cells in a Rat Model of Neuropathic Pain. AB - BACKGROUND: Evidence indicates that neuropathic pain pathogenesis is not confined to changes in the activity of neuronal systems but involves interactions between neurons, inflammatory immune and immune-like glial cells. Substances released from immune cells during inflammation play an important role in development and maintenance of neuropathic pain. It has been found that minocycline suppresses the development of neuropathic pain. Here, we evaluated the analgesic effect of minocycline in a chronic constriction injury (CCI) model of neuropathic pain in rat and assessed IL-6 concentration from cultured macrophage and microglia cells. METHODS: Male Wistar rat (n=6, 150-200 g) were divided into three different groups: 1) CCI+vehicle, 2) sham+vehicle, and 3) CCI+drug. Minocycline (10, 20, and 40 mg/kg) was injected one hour before surgery and continued daily to day 14 post ligation. Von Frey filaments and acetone, as pain behavioral tests, were used for mechanical allodynia and cold allodynia, respectively. Experiments were performed on day 0 (before surgery) and days 1, 3, 5, 7, 10, and 14 post -injury. At day 14, rats were killed and monocyte-derived macrophage from right ventricle and microglia from lumbar part of the spinal cord were isolated and cultured in RPMI and Leibovitz's media, respectively. IL-6 concentration was evaluated in cell culture supernatant after 24 h. RESULTS: Minocycline (10, 20, and 40 mg/kg) attenuated pain behavior, and a decrease in IL-6 concentration was observed in immune cells compared to CCI vehicle-treated animals. CONCLUSION: Minocycline reduced pain behavior and decreased IL-6 concentration in macrophage and microglial cells. PMID- 27221526 TI - Cardiovascular MRI with ferumoxytol. AB - The practice of contrast-enhanced magnetic resonance angiography (CEMRA) has changed significantly in the span of a decade. Concerns regarding gadolinium (Gd) associated nephrogenic systemic fibrosis in those with severely impaired renal function spurred developments in low-dose CEMRA and non-contrast MRA as well as efforts to seek alternative MR contrast agents. Originally developed for MR imaging use, ferumoxytol (an ultra-small superparamagnetic iron oxide nanoparticle), is currently approved by the US Food and Drug Administration for the treatment of iron deficiency anaemia in adults with renal disease. Since its clinical availability in 2009, there has been rising interest in the scientific and clinical use of ferumoxytol as an MR contrast agent. The unique physicochemical and pharmacokinetic properties of ferumoxytol, including its long intravascular half-life and high r1 relaxivity, support a spectrum of MRI applications beyond the scope of Gd-based contrast agents. Moreover, whereas Gd is not found in biological systems, iron is essential for normal metabolism, and nutritional iron deficiency poses major public health challenges worldwide. Once the carbohydrate shell of ferumoxytol is degraded, the elemental iron at its core is incorporated into the reticuloendothelial system. These considerations position ferumoxytol as a potential game changer in the field of CEMRA and MRI. In this paper, we aim to summarise our experience with the cardiovascular applications of ferumoxytol and provide a brief synopsis of ongoing investigations on ferumoxytol-enhanced MR applications. PMID- 27221527 TI - Osteopontin affects macrophage polarization promoting endocytic but not inflammatory properties. AB - OBJECTIVE: Macrophages are the main drivers of obesity-induced adipose tissue (AT) inflammation that causes insulin resistance. Macrophages polarize toward different inflammatory (M1) or protective (M2) phenotypes. Osteopontin (OPN) is an inflammatory cytokine highly expressed in AT in obesity and known to be involved in chronic inflammatory processes. It was hypothesized that OPN polarizes macrophages into a proinflammatory phenotype. METHODS: AT macrophages (ATMs) of OPN-deficient (Spp1(-/-) ) and wild-type C57BL/6 (WT) mice with obesity and bone marrow-derived macrophages (BMDMs) of Spp1(-/-) and WT mice as well as human monocyte-derived macrophages (MDMs) polarized in the presence of OPN were investigated. RESULTS: While ATM infiltration was lower in Spp1(-/-) upon high fat diet, Spp1(-/-) ATMs expressed more M1 and less M2 markers but less tumor necrosis factor-alpha compared with WT. There was no effect of OPN deficiency on BMDM polarization. In human MDMs, the presence of OPN during polarization ambiguously altered M1/M2-related marker expression and diminished LPS-induced inflammatory cytokine production. Strikingly, phagocytic activity was elevated by the presence of OPN during polarization in both human MDMs and murine BMDMs. CONCLUSIONS: In contradiction to our hypothesis, data indicated that OPN does not induce inflammatory macrophages but was a signal to induce phagocytosis, which may be required due to increased adipocyte death in obesity. PMID- 27221528 TI - Unique spectral markers discern recurrent Glioblastoma cells from heterogeneous parent population. AB - An inability to discern resistant cells from bulk tumour cell population contributes to poor prognosis in Glioblastoma. Here, we compared parent and recurrent cells generated from patient derived primary cultures and cell lines to identify their unique molecular hallmarks. Although morphologically similar, parent and recurrent cells from different samples showed variable biological properties like proliferation and radiation resistance. However, total RNA sequencing revealed transcriptional landscape unique to parent and recurrent populations. These data suggest that global molecular differences but not individual biological phenotype could differentiate parent and recurrent cells. We demonstrate that Raman Spectroscopy a label-free, non-invasive technique, yields global information about biochemical milieu of recurrent and parent cells thus, classifying them into distinct clusters based on Principal-Component Analysis and Principal-Component-Linear-Discriminant-Analysis. Additionally, higher lipid related spectral peaks were observed in recurrent population. Importantly, Raman spectroscopic analysis could further classify an independent set of naive primary glioblastoma tumour tissues into non-responder and responder groups. Interestingly, spectral features from the non-responder patient samples show a considerable overlap with the in-vitro generated recurrent cells suggesting their similar biological behaviour. This feasibility study necessitates analysis of a larger cohort of naive primary glioblastoma samples to fully envisage clinical utility of Raman spectroscopy in predicting therapeutic response. PMID- 27221529 TI - Presentations of sickle cell disease patients to hospital in Ghana: key findings from a preliminary study at Volta Regional Hospital. PMID- 27221530 TI - Combinations of Oseltamivir and T-705 Extend the Treatment Window for Highly Pathogenic Influenza A(H5N1) Virus Infection in Mice. AB - Current anti-influenza therapy depends on administering drugs soon after infection, which is often impractical. We assessed whether combinations of oseltamivir (a neuraminidase inhibitor) and T-705 (a nonspecific inhibitor of viral polymerases) could extend the window for treating lethal infection with highly pathogenic A(H5N1) influenza virus in mice. Combination therapy protected 100% of mice, even when delayed until 96 h postinoculation. Compared to animals receiving monotherapy, mice receiving combination therapy had reduced viral loads and restricted viral spread in lung tissues, limited lung damage, and decreased inflammatory cytokine production. Next-generation sequencing showed that virus populations in T-705-treated mice had greater genetic variability, with more frequent transversion events, than did populations in control and oseltamivir treated mice, but no substitutions associated with resistance to oseltamivir or T 705 were detected. Thus, combination therapy extended the treatment window for A(H5N1) influenza infection in mice and should be considered for evaluation in a clinical setting. PMID- 27221531 TI - Urban and rural prevalence of diabetes and pre-diabetes and risk factors associated with diabetes in Tanzania and Uganda. AB - BACKGROUND: The increase in prevalence of diabetes and pre-diabetes in sub Saharan Africa underlines the importance of understanding its magnitude and causes in different population groups. We analyzed data from the Africa/Harvard Partnership for Cohort Research and Training (PaCT) studies to determine the prevalence of diabetes and pre-diabetes and risk factors associated with diabetes. METHODOLOGY: Participants were randomly selected from peri-urban (n=297) and rural (n=200) communities in Uganda, and teachers were recruited from schools (n=229) in urban Tanzania. We used a standardized questionnaire to collect socio-demographic and self-reported disease status including diabetes status. Blood glucose was also measured after participants fasted for 8 h. We used standard protocols for anthropometric and blood pressure measurement. RESULTS: The overall prevalence of diabetes was 10.1% and was highest in rural Ugandan residents (16.1%) compared to teachers in Tanzania (8.3%) and peri-urban Ugandan residents (7.6%). The prevalence of pre-diabetes was 13.8%. The prevalence of self-reported diabetes was low across all sites, where 68% of participants with diabetes were not captured by self-report. In multivariable logistic regression analysis, family history (OR 2.5, 95% CI: 1.1, 5.6) and hypertension (OR 2.3, 95% CI: 1.1, 5.2) were significantly associated with diabetes. CONCLUSIONS: The prevalence of diabetes and pre-diabetes in Uganda and Tanzania is high, differs markedly between population groups, and remains undiagnosed in an alarmingly high proportion of individuals. These findings highlight the need for large-scale, prospective studies to accurately quantify the burden and identify effective intervention and treatment strategies across diverse African populations. PMID- 27221532 TI - Population-based analysis of the frequency of HFE gene polymorphisms: Correlation with the susceptibility to develop hereditary hemochromatosis. AB - Hereditary hemochromatosis (HH) is an autosomal recessive genetic disease, characterized by increased dietary iron absorption. Due to the absence of an effective excretory mechanism, the excess iron in the body may accumulate resulting in toxic effects. The HFE gene also affects the activity of hepcidin, a hormone which acts as a negative regulator of iron metabolism. In this study, we performed a population-based analysis of the distribution of three hemochromatosis-related polymorphisms in the HFE gene (rs1800562, rs1799945 and rs1800730). DNA from 1,446 non-related individuals of Greek ethnicity was collected and analyzed, either from whole blood or buccal swabs. The frequency distribution of these HFE gene polymorphisms was then determined. The results revealed that in our Greek population cohort (gr) the frequencies of each polymorphism were as follows: rs1800562: GG (wild-type)=97.0%, GA=1.5%, AA=1.5%; rs1799945: CC (wild-type)=74.4%, CG=23.4%, GG=2.2%; rs1800730: AA (wild type)=98.1%, AT=1.5% and TT=0.4%. No association between the HFE polymorphisms rs1800562, rs1799945 and rs1800730 and gender could be established. As regards the rs1800562 polymorphism, the A allele (mutant) was ~1.8-fold more frequent in the European population (eur) than in the Greek population [(gr)=2,3%<(eur)=4%]. As for the rs1799945 polymorphism, the G allele (mutant) was 1.2-fold more frequent in the European population than in the Greek population [(gr)=13,9%<(eur)=17%]. As regards the rs1800730 polymorphism, the T allele (mutant) was ~1.7-fold more frequent in the European population than in the Greek population [(gr)=1.2%<(eur)=2%]. However, these pathogenic mutations were found more frequently in the Greek population compared to the global population (gl) [rs1800562: (gl)=1%<(gr)=2,3%; rs1799945: (gl)=7%<(gr)=13,9%; rs1800730: (gl)=<1%<(gr)=1.2%]. This suggests that the Greek population may differ genetically from the northern European population, due to influences from neighboring Asian and African populations. These findings also suggest that there is no gender-associated inheritance of these polymorphisms, and gender-specific symptoms appear as a result of independent biological processes. Thus, the early detection of the tendency towards iron accumulation may be achieved by the genotypic analysis of the polymorphisms that may contribute to the development of the hemochromatosis. PMID- 27221533 TI - Further evidence for population specific differences in the effect of DNA markers and gender on eye colour prediction in forensics. AB - The genetics of eye colour has been extensively studied over the past few years, and the identified polymorphisms have been applied with marked success in the field of Forensic DNA Phenotyping. A picture that arises from evaluation of the currently available eye colour prediction markers shows that only the analysis of HERC2-OCA2 complex has similar effectiveness in different populations, while the predictive potential of other loci may vary significantly. Moreover, the role of gender in the explanation of human eye colour variation should not be neglected in some populations. In the present study, we re-investigated the data for 1020 Polish individuals and using neural networks and logistic regression methods explored predictive capacity of IrisPlex SNPs and gender in this population sample. In general, neural networks provided higher prediction accuracy comparing to logistic regression (AUC increase by 0.02-0.06). Four out of six IrisPlex SNPs were associated with eye colour in the studied population. HERC2 rs12913832, OCA2 rs1800407 and SLC24A4 rs12896399 were found to be the most important eye colour predictors (p < 0.007) while the effect of rs16891982 in SLC45A2 was less significant. Gender was found to be significantly associated with eye colour with males having ~1.5 higher odds for blue eye colour comparing to females (p = 0.002) and was ranked as the third most important factor in blue/non-blue eye colour determination. However, the implementation of gender into the developed prediction models had marginal and ambiguous impact on the overall accuracy of prediction confirming that the effect of gender on eye colour in this population is small. Our study indicated the advantage of neural networks in prediction modeling in forensics and provided additional evidence for population specific differences in the predictive importance of the IrisPlex SNPs and gender. PMID- 27221534 TI - Age estimation based on pulp cavity/chamber volume of 13 types of tooth from cone beam computed tomography images. AB - AIM: The aims of this study are to identify which type of tooth has the strong relationship between age and pulp cavity/chamber volume among 13 types of tooth from the same dentition and to determine whether the inclusion of multiple types of tooth may improve the accuracy of age estimation. MATERIALS AND METHODS: Cone beam computed tomography (CBCT) images from 115 females and 125 males aged between 16 and 63 years were analyzed. The DICOM data of all the images were imported into ITK-SNAP 2.4 for the calculation of pulp cavity/chamber volumes. Logarithmic regression analysis and multiple linear regression analysis were applied to establish the relationship between age and pulp cavity/chamber volumes. RESULTS: Among the 13 types of tooth, maxillary second molars have the largest R (2) (0.491, 0.642, and 0.498) and the smallest SEE (8.119, 6.754, and 8.022) in male, female, and pooled gender samples, respectively. The multiple linear regression analysis for the combination of multi-types of tooth indicated that a larger R (2) (0.627, 0.701, and 0.631) and smaller SEE (7.100, 6.258, and 6.970) than the counterpart calculated from the logarithmic regression analysis of a single type of tooth in male, female, and pooled gender samples, respectively. CONCLUSION: The pulp chamber volume of the maxillary second molars has the largest correlation coefficient with age. Using multiple types of tooth may improve the accuracy of age estimation compared with only one type of tooth used. PMID- 27221535 TI - Performance of post-mortem CT compared to autopsy in children. AB - INTRODUCTION: Radiological techniques such as non-enhanced post-mortem computed tomography (PMCT) play an increasingly important role in death investigations, especially in cases of non-medicolegal context of death, where the consent of the next of kin is required to perform autopsy. Such consent is often difficult to obtain for deceased children, and radiological methods may be an acceptable alternative. The aim of our study was to evaluate the performance of PMCT explorations compared to medicolegal conventional autopsies in children and its potential usefulness in non-medicolegal situations. METHODS: We retrospectively reviewed a group of 26 children aged 0-12 years who died of different causes, which were investigated by both conventional autopsy and PMCT. We compared the findings extracted from radiological and autopsy reports. All findings were grouped according to their importance with respect to cause of death and to the anatomical structure they covered: organs, vascular system, soft tissue, and skeletal system. RESULTS: A significantly larger number of findings were detected by autopsy compared to PMCT. Autopsy proved to be superior to PMCT, notably at detecting organ, soft tissue, and vascular findings, while PMCT was superior at detecting bone findings. However, no statistically significant differences were found between the methods concerning the essential findings used to define the cause of death. CONCLUSIONS: In children, PMCT was less sensitive than conventional autopsy for detecting general findings. However, most essential findings were detected by both methods. PMCT was superior to autopsy for the detection of bone lesions in children. ADVANCES IN KNOWLEDGE: Up to today, very rare literature exists concerning PMCT in children, especially in a forensic setting. This article investigates the advantages and limitations of PMCT compared to autopsy in a unique study group and discusses possibilities for future developments. PMID- 27221537 TI - Asthma control and need for future asthma controller therapy among inner-city Hispanic asthmatic children engaged in a pediatric asthma disease management program (the Breathmobile program, Mobile Asthma Care for Kids Network). AB - OBJECTIVE: To determine whether significant numbers of asthmatic children with initially rated intermittent asthma later suffer poor asthma control and require the addition of controller medications. METHODS: Inner-city Hispanic children were followed prospectively in an asthma-specific disease management system (Breathmobile) for a period of 2 years. Clinical asthma symptoms, morbidity treatment, and demographic data were collected at each visit. Treatment was based upon National Heart, Lung, and Blood Institute (NHLBI) Expert Panel Report 3 asthma guidelines. Primary outcome was percentage of patients with intermittent asthma who had not well or poorly controlled asthma during subsequent visits and required controller agents. Secondary outcomes were factors associated with the maintenance of asthma control. RESULTS: About 30.9% of the patients with initial rating of intermittent asthma had not well controlled and poorly controlled asthma during subsequent visits and required the addition of controller agents. Factors associated with good asthma control were compliance, no previous emergency room visits and previous visit during spring season. CONCLUSION: Asthmatic children with intermittent asthma often lose asthma control and require controller therapy. This justifies asthma guideline recommendations to assess asthma control at follow-up visits and adjust therapy accordingly. PMID- 27221536 TI - Involvement of NADPH oxidases in alkali burn-induced corneal injury. AB - Chemical burns are a major cause of corneal injury. Oxidative stress, inflammatory responses and neovascularization after the chemical burn aggravate corneal damage, and lead to loss of vision. Although NADPH oxidases (Noxs) play a crucial role in the production of reactive oxygen species (ROS), the role of Noxs in chemical burn-induced corneal injury remains to be elucidated. In the present study, the transcription and expression of Noxs in corneas were examined by RT qPCR, western blot analysis and immunofluorescence staining. It was found that alkali burns markedly upregulated the transcription and expression of Nox2 and Nox4 in human or mouse corneas. The inhibition of Noxs by diphenyleneiodonium (DPI) or apocynin (Apo) effectively attenuated alkali burn-induced ROS production and decreased 3-nitrotyrosine (3-NT) protein levels in the corneas. In addition, Noxs/CD11b double-immunofluorescence staining indicated that Nox2 and Nox4 were partially co-localized with CD11b. DPI or Apo prevented the infiltration of CD11b positive inflammatory cells, and inhibited the transcription of inflammatory cytokines following alkali burn-induced corneal injury. In our mouse model of alkali burn-induced corneal injury, corneal neovascularization (CNV) occurred on day 3, and it affected 50% of the whole area of the cornea on day 7, and on day 14, CNV coverage of the cornea reached maximum levels. DPI or Apo effectively attenuated alkali burn-induced CNV and decreased the mRNA levels of angiogenic factors, including vascular endothelial growth factor (VEGF), VEGF receptors and matrix metalloproteinases (MMPs). Taken together, our data indicate that Noxs play a role in alkali burn-induced corneal injury by regulating oxidative stress, inflammatory responses and CNV, and we thus suggest that Noxs are a potential therapeutic target in the future treatment of chemical-induced corneal injury. PMID- 27221538 TI - Ralph Hoffman. PMID- 27221539 TI - Rationale for Developing a Specimen Bank to Study the Pathogenesis of High-Grade Serous Carcinoma: A Review of the Evidence. AB - Women with clinically detected high-grade serous carcinomas (HGSC) generally present with advanced-stage disease, which portends a poor prognosis, despite extensive surgery and intensive chemotherapy. Historically, HGSCs were presumed to arise from the ovarian surface epithelium (OSE), but the inability to identify early-stage HGSCs and their putative precursors in the ovary dimmed prospects for advancing our knowledge of the pathogenesis of these tumors and translating these findings into effective prevention strategies. Over the last decade, increased BRCA1/2 mutation testing coupled with performance of risk-reducing surgeries has enabled studies that have provided strong evidence that many, but probably not all, HGSCs among BRCA1/2 mutation carriers appear to arise from the fallopian tubes, rather than from the ovaries. This shift in our understanding of the pathogenesis of HGSCs provides an important opportunity to achieve practice changing advances; however, the scarcity of clinically annotated tissues containing early lesions, particularly among women at average risk, poses challenges to progress. Accordingly, we review studies that have kindled our evolving understanding of the pathogenesis of HGSC and present the rationale for developing an epidemiologically annotated national specimen resource to support this research. Cancer Prev Res; 9(9); 713-20. (c)2016 AACR. PMID- 27221541 TI - Genome sequence and characteristics of plasmid pWH12, a variant of the mcr-1 harbouring plasmid pHNSHP45, from the multi-drug resistant E. coli. PMID- 27221540 TI - Genomic Landscape of Colorectal Mucosa and Adenomas. AB - The molecular basis of the adenoma-to-carcinoma transition has been deduced using comparative analysis of genetic alterations observed through the sequential steps of intestinal carcinogenesis. However, comprehensive genomic analyses of adenomas and at-risk mucosa are still lacking. Therefore, our aim was to characterize the genomic landscape of colonic at-risk mucosa and adenomas. We analyzed the mutation profile and copy number changes of 25 adenomas and adjacent mucosa from 12 familial adenomatous polyposis patients using whole-exome sequencing and validated allelic imbalances (AI) in 37 adenomas using SNP arrays. We assessed for evidence of clonality and performed estimations on the proportions of driver and passenger mutations using a systems biology approach. Adenomas had lower mutational rates than did colorectal cancers and showed recurrent alterations in known cancer driver genes (APC, KRAS, FBXW7, TCF7L2) and AIs in chromosomes 5, 7, and 13. Moreover, 80% of adenomas had somatic alterations in WNT pathway genes. Adenomas displayed evidence of multiclonality similar to stage I carcinomas. Strong correlations between mutational rate and patient age were observed in at risk mucosa and adenomas. Our data indicate that at least 23% of somatic mutations are present in at-risk mucosa prior to adenoma initiation. The genomic profiles of at-risk mucosa and adenomas illustrate the evolution from normal tissue to carcinoma via greater resolution of molecular changes at the inflection point of premalignant lesions. Furthermore, substantial genomic variation exists in at-risk mucosa before adenoma formation, and deregulation of the WNT pathway is required to foster carcinogenesis. Cancer Prev Res; 9(6); 417-27. (c)2016 AACR. PMID- 27221543 TI - Zika virus infection: Control and prevention. PMID- 27221544 TI - Non-invasive brain stimulation of the aging brain: State of the art and future perspectives. AB - Favored by increased life expectancy and reduced birth rate, worldwide demography is rapidly shifting to older ages. The golden age of aging is not only an achievement but also a big challenge because of the load of the elderly on social and medical health care systems. Moreover, the impact of age-related decline of attention, memory, reasoning and executive functions on self-sufficiency emphasizes the need of interventions to maintain cognitive abilities at a useful degree in old age. Recently, neuroscientific research explored the chance to apply Non-Invasive Brain Stimulation (NiBS) techniques (as transcranial electrical and magnetic stimulation) to healthy aging population to preserve or enhance physiologically-declining cognitive functions. The present review will update and address the current state of the art on NiBS in healthy aging. Feasibility of NiBS techniques will be discussed in light of recent neuroimaging (either structural or functional) and neurophysiological models proposed to explain neural substrates of the physiologically aging brain. Further, the chance to design multidisciplinary interventions to maximize the efficacy of NiBS techniques will be introduced as a necessary future direction. PMID- 27221545 TI - Lessons from the fatal French study BIA-10-2474. PMID- 27221546 TI - Rapid detection of meticillin-resistant Staphylococcus aureus bacteraemia using combined three-hour short-incubation matrix-assisted laser desorption/ionization time-of-flight MS identification and Alere Culture Colony PBP2a detection test. AB - Meticillin-resistant Staphylococcus aureus (MRSA) bloodstream infection is responsible for significant morbidity, with mortality rates as high as 60 % if not treated appropriately. We describe a rapid method to detect MRSA in blood cultures using a combined three-hour short-incubation BRUKER matrix-assisted laser desorption/ionization time-of-flight MS BioTyper protocol and a qualitative immunochromatographic assay, the Alere Culture Colony Test PBP2a detection test. We compared this combined method with a molecular method detecting the nuc and mecA genes currently performed in our laboratory. One hundred and seventeen S. aureus blood cultures were tested of which 35 were MRSA and 82 were meticillin sensitive S. aureus (MSSA). The rapid combined test correctly identified 100 % (82/82) of the MSSA and 85.7 % (30/35) of the MRSA after 3 h. There were five false negative results where the isolates were correctly identified as S. aureus, but PBP2a was not detected by the Culture Colony Test. The combined method has a sensitivity of 87.5 %, specificity of 100 %, a positive predictive value of 100 % and a negative predictive value of 94.3 % with the prevalence of MRSA in our S. aureus blood cultures. The combined rapid method offers a significant benefit to early detection of MRSA in positive blood cultures. PMID- 27221547 TI - [In Process Citation]. PMID- 27221542 TI - Gametocyte carriage in uncomplicated Plasmodium falciparum malaria following treatment with artemisinin combination therapy: a systematic review and meta analysis of individual patient data. AB - BACKGROUND: Gametocytes are responsible for transmission of malaria from human to mosquito. Artemisinin combination therapy (ACT) reduces post-treatment gametocyte carriage, dependent upon host, parasite and pharmacodynamic factors. The gametocytocidal properties of antimalarial drugs are important for malaria elimination efforts. An individual patient clinical data meta-analysis was undertaken to identify the determinants of gametocyte carriage and the comparative effects of four ACTs: artemether-lumefantrine (AL), artesunate/amodiaquine (AS-AQ), artesunate/mefloquine (AS-MQ), and dihydroartemisinin-piperaquine (DP). METHODS: Factors associated with gametocytaemia prior to, and following, ACT treatment were identified in multivariable logistic or Cox regression analysis with random effects. All relevant studies were identified through a systematic review of PubMed. Risk of bias was evaluated based on study design, methodology, and missing data. RESULTS: The systematic review identified 169 published and 9 unpublished studies, 126 of which were shared with the WorldWide Antimalarial Resistance Network (WWARN) and 121 trials including 48,840 patients were included in the analysis. Prevalence of gametocytaemia by microscopy at enrolment was 12.1 % (5887/48,589), and increased with decreasing age, decreasing asexual parasite density and decreasing haemoglobin concentration, and was higher in patients without fever at presentation. After ACT treatment, gametocytaemia appeared in 1.9 % (95 % CI, 1.7 2.1) of patients. The appearance of gametocytaemia was lowest after AS-MQ and AL and significantly higher after DP (adjusted hazard ratio (AHR), 2.03; 95 % CI, 1.24-3.12; P = 0.005 compared to AL) and AS-AQ fixed dose combination (FDC) (AHR, 4.01; 95 % CI, 2.40-6.72; P < 0.001 compared to AL). Among individuals who had gametocytaemia before treatment, gametocytaemia clearance was significantly faster with AS-MQ (AHR, 1.26; 95 % CI, 1.00-1.60; P = 0.054) and slower with DP (AHR, 0.74; 95 % CI, 0.63-0.88; P = 0.001) compared to AL. Both recrudescent (adjusted odds ratio (AOR), 9.05; 95 % CI, 3.74-21.90; P < 0.001) and new (AOR, 3.03; 95 % CI, 1.66-5.54; P < 0.001) infections with asexual-stage parasites were strongly associated with development of gametocytaemia after day 7. CONCLUSIONS: AS-MQ and AL are more effective than DP and AS-AQ FDC in preventing gametocytaemia shortly after treatment, suggesting that the non-artemisinin partner drug or the timing of artemisinin dosing are important determinants of post-treatment gametocyte dynamics. PMID- 27221548 TI - [In Process Citation]. PMID- 27221549 TI - Comprehensive panel of cross-reacting monoclonal antibodies for analysis of different immune cells and their distribution in the common marmoset (Callithrix jacchus). AB - BACKGROUND: Common marmosets are extensively used in immunological and pharmacological research, and the usage of methods such as flow cytometry gain increasing importance. METHODS: Using multicolor flow cytometry cross-reactivity of monoclonal antibodies with cells of common marmosets was analyzed. Furthermore, frequencies of immune cells and immunological parameters were assessed in healthy common marmosets. RESULTS: A total of 97 clones of monoclonal antibodies raised against CD markers, chemokine receptors, and miscellaneous markers were tested. Additionally, baseline frequencies of different innate and adaptive immune cells as well as certain parameters, such as activation and memory T-cell and B-cell distribution, are provided. CONCLUSION: Our study gives an extended overview of cross-reactive antibodies for flow cytometric analysis of immune cells as well as baseline values for different immune parameters in healthy common marmosets. PMID- 27221550 TI - Non-disulfide-bridged peptides from Tityus serrulatus venom: Evidence for proline free ACE-inhibitors. AB - The present study purifies two T. serrulatus non-disulfide-bridged peptides (NDBPs), named venom peptides 7.2 (RLRSKG) and 8 (KIWRS) and details their synthesis and biological activity, comparing to the synthetic venom peptide 7.1 (RLRSKGKK), previously identified. The synthetic replicate peptides were subjected to a range of biological assays: hemolytic, antifungal, antiviral, electrophysiological, immunological and angiotensin-converting enzyme (ACE) inhibition activities. All venom peptides neither showed to be cytolytic nor demonstrated significant antifungal or antiviral activities. Interestingly, peptides were able to modulate macrophages' responses, increasing IL-6 production. The three venom peptides also demonstrated potential to inhibit ACE in the following order: 7.2>7.1>8. The ACE inhibition activity was unexpected, since peptides that display this function are usually proline-rich peptides. In attempt to understand the origin of such small peptides, we discovered that the isolated peptides 7.2 and 8 are fragments of the same molecule, named Pape peptide precursor. Furthermore, the study discusses that Pape fragments could be originated from a post-splitting mechanism resulting from metalloserrulases and other proteinases cleavage, which can be seen as a clever mechanism used by the scorpion to enlarge its repertoire of venom components. Scorpion venom remains as an interesting source of bioactive proteins and this study advances our knowledge about three NDBPs and their biological activities. PMID- 27221551 TI - [The adapting of a care plan after Kennedy terminal ulcer diagnosis]. AB - : A 69 year old man was admitted to the Intensive Care Unit (ICU) from the Emergency Department due to severe respiratory failure. Due to unsuccessful non invasive mechanical ventilation, endotracheal intubation was performed. A category I ulcer in coccyx was detected 48h after admission. Eight hours later, a double erythema (the second one darker than the first one) with displacement between 30-45 degrees over the bony prominence suggested there was a deep tissue injury. The lesion progressed rapidly during the next 24h. The shape and the rapid evolution of the injury lead us to diagnose a Kennedy terminal ulcer (KTU). At 72h after the admission, and once the causes of acute decompensation were ruled out, limitation of life-sustaining treatment was decided. An individualised plan of care was drawn up with the aim of identifying problems in a patient with KTU evolving from a critical to a terminal situation. Our overall objectives (NOC) were to adapt the care plan based on a realistic approach. Nursing interventions (NIC) included actions such as pain management, conservative treatment of the injury, agony care and support to help the family to make decisions. CONCLUSION: The diagnosis of KTU helped the health care team in the decision-making process when they considered limiting the life support, as well as in the adapting of the care plan to the actual situation. PMID- 27221552 TI - Hyperhomocysteinaemia in rats is associated with erectile dysfunction by impairing endothelial nitric oxide synthase activity. AB - To investigate the effect of hyperhomocysteinaemia (HHCy) on penile erectile function in a rat model, a methionine-rich diet was used in which erectile function, the reproductive system, and nitric oxide synthase were characterized. The intracavernous pressure, apomorphine experiments, measurement of oxidative stress, hematoxylin and eosin staining, immunohistochemistry analysis, reverse transcription-polymerase chain reactions and measurement of endothelial nitric oxide synthase activity were utilized. Our results showed that erections in the middle-dose, high-dose, and interference (INF) groups were significantly lower than the control (P < 0.05). INF group, being fed with vitamins B and folic acid, demonstrated markedly improved penile erections compared with the middle-dose group (P < 0.05). HHCy-induced eNOS and phospho-eNOS protein expression was reduced and the antioxidant effect was markedly impaired. The data of the present data provide evidence that HHCy is a vascular risk factor for erectile dysfunction by impairing cavernosa endothelial nitric oxide synthase activity. Intake of vitamins B can alleviate this abnormality. PMID- 27221553 TI - Hwang-Heuk-San induces apoptosis in HCT116 human colorectal cancer cells through the ROS-mediated activation of caspases and the inactivation of the PI3K/Akt signaling pathway. AB - Hwang-Heuk-San (HHS) is a polyherbal formulation that has been used in traditional Korean medicine for hundreds of years to treat gastrointestinal malignancy. However, to date, the mechanisms responsible for the anticancer effects remain unclear. In the present study, we investigated the anticancer effects of HHS using HCT116 human colorectal cancer (CRC) cells. Our results showed that HHS treatment significantly reduced cell survival and increased apoptotic cell death in a concentration-dependent manner. The treatment of HCT116 cells with HHS also significantly elevated the accumulation of reactive oxygen species (ROS), which was followed by the attenuation of the mitochondrial membrane potential through the upregulation of Bax and the downregulation of Bcl 2, which was accompanied by the release of cytochrome c to the cytosol. In addition, HHS treatment caused the truncation of Bid and activated the caspases (caspase-8, -9 and -3), which was associated with the induction of the Fas ligand, the death receptors (DRs), DR4 and DR5, downregulation of the inhibitors of protein expression in the apoptosis protein family, and the degradation of poly(ADP-ribose)-polymerase. However, a pan-caspase inhibitor reversed the HHS induced apoptosis and growth suppression, indicating that HHS induces apoptosis though a caspase-dependent intrinsic and extrinsic apoptotic pathway in HCT116 cells. Moreover, HHS treatment inhibited the activation of phosphatidylinositol-3 kinase (PI3K)/Akt signaling, and a pharmacological inhibitor of PI3K significantly potentiated the apoptotic effects of HHS when employed in combination in HCT116 cells. Furthermore, the blocking of ROS generation by antioxidant N-acetyl cysteine attenuated the HHS-induced release of cytochrome c, caspase activation and PI3K/Akt inactivation, thereby preventing HHS-induced apoptosis and reduction in cell viability. These findings suggest that HHS induced ROS generation is required for caspase-dependent apoptotic cell death involving inhibition of the PI3K/Akt signaling pathway in HCT116 cells. Overall, our findings suggest that HHS may be an effective treatment for CRC cancer, and further studies are required to identify the active compounds in HHS. PMID- 27221554 TI - [Anti-wrinkle creams with hyaluronic acid: how effective are they?]. AB - BACKGROUND: Anti-wrinkle creams containing hyaluronic-acid are often advertised as an efficacious option for the treatment of wrinkles and have even been presented as an option equal to some medical procedures in this regard. Evidence from conclusive and systematic research supporting those claims, however, is widely lacking. OBJECTIVES: During this trial we examined whether the daily use of anti-wrinkle creams containing hyaluronic-acid has an influence on the depth of wrinkles as well as skin tightness and elasticity. METHODS: We split up 20 patients into four groups, each of which were assigned an anti-wrinkle cream containing hyaluronic acid for daily use. Four different creams within different price ranges were chosen (Balea, Nivea, Lancome, Chanel). Before and after the 3 month trial, wrinkle depth was assessed using the PRIMOS(pico) (GFMesstechnik, Teltow, Germany) and skin-tightness and elasticity were evaluated using the Cutometer MP580 (Courage+Khazaka, Cologne, Germany). Additionally, after the trial, questionnaire data on patient satisfaction with their individual product was collected. RESULTS: The depth of perioral and orbital wrinkles decreased significantly in all groups, with depth reduction ranging between 10% and 20%. Skin-tightness increased significantly in all groups, rising by 13 to 30%. Minimal significant changes in skin-elasticity could only be shown in individual groups. CONCLUSIONS: The regular use of hyaluronic-acid containing anti-wrinkle creams for over 3 months showed clear and positive effects on wrinkle-depth and skin-tightness. Due to the design of the study, however, no clear indication on the efficacy of hyaluronic acid could be shown. PMID- 27221555 TI - [Insufficient symptom control under long-term treatment with PPI in GERD - fact or fiction?]. AB - BACKGROUND: Randomized controlled trials show that patients with gastroesophageal reflux disease (GERD) and treatment with proton pump inhibitors (PPI) in about 30% of the cases complain about persisting reflux symptoms (heartburn, regurgitation). The aim of the study was to evaluate the efficacy of PPI long term treatment in patients with GERD in the family doctor's office. METHOD: Patients with GERD and a PPI therapy of at least one year participated in a prospective, multicenter observational study. The patients obtained a questionnaire together with a further prescription of PPI. They were asked about the intensity and frequency of heartburn, regurgitation and sleep disorders due to reflux symptoms, satisfaction with PPI therapy, diagnostics performed up to now (endoscopy, pH monitoring, manometry) and surgical consultation. The questionnaire included a validated instrument for the diagnosis of GERD (GerdQ). Patients with the diagnosis "GERD " according to the questionnaire who were very dissatisfied with their current PPI therapy (score 1 or 2 on a 5-point Likert scale) were defined as "lost patients " (LOPA). RESULTS: 39% of the patients still suffered from heartburn at least two days a week, 30% of regurgitation. In 22% of the patients, reflux symptoms led to sleep disorder at least two days a week. 20% of the patients were very dissatisfied with the current PPI therapy. 70% of them (= 14% of the total patient population) were "lost patients " according to the definition. An endoscopy was performed in 86% of the patients and function diagnosis (pH monitoring +/- manometry) in 8%. A surgeon was consulted in 8% of the patients, a third of which had received function diagnosis before. CONCLUSIONS: A poor symptom control can often be found in GERD patients with PPI long-term therapy, but does not stand out in the daily routine. So diagnosis will not continue and treatment alternatives will not be searched for. In the future quality of treatment should be verified e. g. by questionnaires. PMID- 27221556 TI - [Gut microbiome and psyche: paradigm shift in the concept of brain-gut axis]. AB - BACKGROUND: The concept of the brain-gut axis describes the communication between the central and enteric nervous system. The exchange of information takes place in both directions. The great advances in molecular medicine in recent years led to the discovery of an enormous number of microorganisms in the intestine (gut microbiome), which greatly affect the function of the brain-gut axis. METHOD: Overview RESULTS AND CONCLUSIONS: Numerous studies indicate that the dysfunction of the brain-gut axis could lead to both inflammatory and functional diseases of the gastrointestinal tract. Moreover, it was shown that a faulty composition of the gut microbiota in childhood influences the maturation of the central nervous system and thus may favor the development of mental disorders such as autism, depression, or other. An exact causal relationship between psyche and microbiome must be clarified by further studies in order to find new therapeutic options. PMID- 27221557 TI - [Fecal microbiota transplantation in relapsing clostridium difficile colitis]. AB - BACKGROUND: Since the turn of the millennium there has been an alarming increase in the incidence and severity of clostridium difficile infections. Stopping medication with the triggering antibiotic and switching to a recommended antibiotic leads to healing up in 80%. However, patients who relapse have a 40% risk of an additional relapse and those with 2 or more episodes face a 60% risk. Fecal microbiota transplantation (FMT) is a new therapeutic option. Up to now there only exist two randomized studies (University of Amsterdam and the Massachusetts General Hospital in Boston). METHOD: Data from 16 patients with recurrent clostridium difficile infection who had undergone FMT at a local hospital in the city of Bremen, Germany, were reviewed and compared to the results of the 2 randomized studies. RESULTS: 11 out of 16 patients got cured after the first FMT (68.75%). The remaining 5 patients received a second FMT, with cure in 3 patients. The overall response rate was 14 from 16 patients (87.5%). CONCLUSIONS: In comparison to the response rates of the University of Amsterdam (81.3% after the first and 93.8% after the second FMT) and of the Massachusetts General Hospital in Boston (70% after the first and 90% after the second FMT) we received slightly worse results. But, treatment of notably older patients and intensive care patients in our group explain these findings well. Therefore, we advocate a wide use of FMT for the treatment of recurrent clostridium difficile colitis in non-university hospitals. PMID- 27221558 TI - A novel method to assess pial collateralization from stroke perfusion MRI: subdividing Tmax into anatomical compartments. AB - OBJECTIVES: To develop and validate a quantitative and observer-independent method to evaluate pial collateral circulation by DSC-perfusion MRI and test whether this novel method delivers diagnostic information which is redundant to or independent from conventional penumbra imaging by the mismatch approach. METHODS: We retrospectively identified 47 patients with M1 occlusion who underwent MR diffusion/perfusion imaging and mechanical thrombectomy at our facility. By automated registration and segmentation, Tmax delays were attributed specifically to the pial, cortical and parenchymal compartments. The resulting pial volumes at delay were defined as the pial Tmax map-assessed collateral score (TMACS) and correlated with gold standard digital subtraction angiography (DSA). Mismatch ratio was assessed by conventional penumbra defining MRI criteria. RESULTS: Strong correlation was found between TMACS and angiographically assessed collateral score (Pearson rho = -0.74, p < 0.001). In multiple logistic regression, both good collaterals according to TMACS [OR 4.3 (1.1-19, p = 0.04)] and mismatch ratio >= 3.5 [OR 12.3 (1.88-249, p = 0.03)] were independent predictors of favourable clinical outcome. CONCLUSIONS: Perfusion delay in the pial compartment, as evaluated by TMACS, closely reflects the extent of pial collaterals in gold-standard DSA. TMACS and mismatch ratio were found to be complementary predictors of a favourable clinical outcome, each adding independent predictive information. KEY POINTS: * MRI-DSC perfusion delay specific in the pial compartment reflects leptomeningeal collateralization. * A novel quantitative- and observer-independent marker of collateral status (TMACS) is introduced. * Quantification of collateral status leads to an independent predictor of neurological outcome. PMID- 27221559 TI - Use of computed tomography assessed kidney length to predict split renal GFR in living kidney donors. AB - OBJECTIVES: Screening of living kidney donors may require scintigraphy to split glomerular filtration rate (GFR). To determine the usefulness of computed tomography (CT) to split GFR, we compared scintigraphy-split GFR to CT-split GFR. We evaluated CT-split GFR as a screening test to detect scintigraphy-split GFR lower than 40 mL/min/1.73 m2/kidney. METHODS: This was a monocentric retrospective study on 346 potential living donors who had GFR measurement, renal scintigraphy, and CT. We predicted GFR for each kidney by splitting GFR using the following formula: Volume-split GFR for a given kidney = measured GFR*[volume of this kidney/(volume of this kidney + volume of the opposite kidney)]. The same formula was used for length-split GFR. We compared length- and volume-split GFR to scintigraphy-split GFR at donation and with a 4-year follow-up. RESULTS: A better correlation was observed between length-split GFR and scintigraphy-split GFR (r = 0.92) than between volume-split GFR and scintigraphy-split GFR (r = 0.89). A length-split GFR threshold of 45 mL/min/1.73 m2/kidney had a sensitivity of 100 % and a specificity of 75 % to detect scintigraphy-split GFR less than 40 mL/min/1.73 m2/kidney. Both techniques with their respective thresholds detected living donors with similar eGFR evolution during follow-up. CONCLUSION: Length split GFR can be used to detect patients requiring scintigraphy. KEY POINTS: * Excellent correlation between kidney length and scintigraphy predicted GFR * Kidney length screening detects all donors with GFR lower than 40 mL/min/1.73 m 2 * Kidney length screening can replace scintigraphy screening. PMID- 27221560 TI - Separation of type and grade in cervical tumours using non-mono-exponential models of diffusion-weighted MRI. AB - OBJECTIVES: Assessment of empirical diffusion-weighted MRI (DW-MRI) models in cervical tumours to investigate whether fitted parameters distinguish between types and grades of tumours. METHODS: Forty-two patients (24 squamous cell carcinomas, 14 well/moderately differentiated, 10 poorly differentiated; 15 adenocarcinomas, 13 well/moderately differentiated, two poorly differentiated; three rare types) were imaged at 3 T using nine b-values (0 to 800 s mm-2). Mono exponential, stretched exponential, kurtosis, statistical, and bi-exponential models were fitted. Model preference was assessed using Bayesian Information Criterion analysis. Differences in fitted parameters between tumour types/grades and correlation between fitted parameters were assessed using two-way analysis of variance and Pearson's linear correlation coefficient, respectively. RESULTS: Non mono-exponential models were preferred by 83 % of tumours with bi-exponential and stretched exponential models preferred by the largest numbers of tumours. Apparent diffusion coefficient (ADC) and diffusion coefficients from non-mono exponential models were significantly lower in poorly differentiated tumours than well/moderately differentiated tumours. alpha (stretched exponential), K (kurtosis), f and D* (bi-exponential) were significantly different between tumour types. Strong correlation was observed between ADC and diffusion coefficients from other models. CONCLUSIONS: Non-mono-exponential models were preferred to the mono-exponential model in DW-MRI data from cervical tumours. Parameters of non mono-exponential models showed significant differences between types and grades of tumours. KEY POINTS: * Non-mono-exponential DW-MRI models are preferred in the majority of cervical tumours. * Poorly differentiated cervical tumours exhibit lower diffusion coefficients than well/moderately differentiated tumours. * Non mono-exponential model parameters alpha, K, f, and D* differ between tumour types. * Micro-structural features are likely to affect parameters in non-mono exponential models differently. PMID- 27221561 TI - Intravenous injection of gadobutrol in an epidemiological study group did not lead to a difference in relative signal intensities of certain brain structures after 5 years. AB - PURPOSE: To investigate if application of macrocyclic gadolinium-based contrast agents in volunteers is associated with neuronal deposition detected by magnetic resonance imaging in a 5-year longitudinal survey. MATERIALS AND METHODS: Three hundred eighty-seven volunteers who participated in a population-based study were enrolled. Subjects underwent plain T1-weighted brain MRI at baseline and 5 years later with identical sequence parameters. At baseline, 271 participants additionally received intravenous injection of the macrocyclic contrast agent gadobutrol (0.15 mmol/kg). A control group including 116 subjects received no contrast agent. Relative signal intensities of thalamus, pallidum, pons and dentate nucleus were compared at baseline and follow-up. RESULTS: No difference in relative signal intensities was observed between contrast group (thalamus, p = 0.865; pallidum, p = 0.263; pons, p = 0.533; dentate nucleus, p = 0.396) and control group (thalamus, p = 0.683; pallidum; p = 0.970; pons, p = 0.773; dentate nucleus, p = 0.232) at both times. Comparison between both groups revealed no significant differences in relative signal intensities (thalamus, p = 0.413; pallidum, p = 0.653; pons, p = 0.460; dentate nucleus, p = 0.751). The study showed no significant change in globus pallidus-to-thalamus or dentate nucleus-to pons ratios. CONCLUSIONS: Five years after administration of a 1.5-fold dose gadobutrol to normal subjects, signal intensity of thalamus, pallidum, pons and dentate nucleus did not differ from participants who had not received gadobutrol. KEY POINTS: * Gadobutrol does not lead to neuronal signal alterations after 5 years. * Neuronal deposition of macrocyclic contrast agent could not be confirmed. * Macrocyclic contrast agents in a proven dosage are safe. PMID- 27221562 TI - C-arm flat-panel CT arthrography of the shoulder: Radiation dose considerations and preliminary data on diagnostic performance. AB - OBJECTIVES: To investigate radiation dose and diagnostic performance of C-arm flat-panel CT (FPCT) versus standard multi-detector CT (MDCT) shoulder arthrography using MRI-arthrography as reference standard. METHODS: Radiation dose of two different FPCT acquisitions (5 and 20 s) and standard MDCT of the shoulder were assessed using phantoms and thermoluminescence dosimetry. FPCT arthrographies were performed in 34 patients (mean age 44 +/- 15 years). Different joint structures were quantitatively and qualitatively assessed by two independent radiologists. Inter-reader agreement and diagnostic performance were calculated. RESULTS: Effective radiation dose was markedly lower in FPCT 5 s (0.6 mSv) compared to MDCT (1.7 mSv) and FPCT 20 s (3.4 mSv). Contrast-to-noise ratios (CNRs) were significantly (p < 0.05) higher in FPCT 20-s versus 5-s protocols. Inter-reader agreements of qualitative ratings ranged between k = 0.47-1.0. Sensitivities for cartilage and rotator cuff pathologies were low for FPCT 5-s (40 % and 20 %) and moderate for FPCT 20-s protocols (75 % and 73 %). FPCT showed high sensitivity (81-86 % and 89-99 %) for bone and acromioclavicular-joint pathologies. CONCLUSION: Using a 5-s protocol FPCT shoulder arthrography provides lower radiation dose compared to MDCT but poor sensitivity for cartilage and rotator cuff pathologies. FPCT 20-s protocol is moderately sensitive for cartilage and rotator cuff tendon pathology with markedly higher radiation dose compared to MDCT. KEY POINTS: * FPCT shoulder arthrography is feasible with fluoroscopy and CT in one workflow. * A 5-s FPCT protocol applies a lower radiation dose than MDCT. * A 20-s FPCT protocol is moderately sensitive for cartilage and tendon pathology. PMID- 27221564 TI - Reduced transforming growth factor beta1 (TGF-beta1) in the repair of airway epithelial cells of children with asthma. AB - BACKGROUND AND OBJECTIVE: Evidence into the role of TGF-beta1 in airway epithelial repair in asthma is still controversial. This study tested the hypothesis that the reduced TGF-beta1 levels previously observed in paediatric asthmatic airway epithelial cells directly contribute to the dysregulated repair seen in these cells. METHODS: Primary airway epithelial cells (pAEC) from children with asthma (n = 16) and non-asthmatic subjects (n = 20) were isolated, and subcultured for investigation of TGF-beta1 gene and protein via quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Expression of other associated genes such as integrins alphavbeta6, alphavbeta8 and MT1-MMP were also tested. Small interfering RNA (siRNA) was employed to assess the role of TGF-beta1 during wound repair. RESULTS: TGF-beta1 gene and protein expression were significantly downregulated in asthmatic pAEC over the course of repair, compared with cells from non-asthmatic children. Messenger RNA (mRNA) expression of TGF-beta1 was also directly implicated in non asthmatic and asthmatic pAEC proliferation over their quiescent counterparts. Small interfering RNA-mediated knockdown of TGF-beta1 compromised repair in non asthmatic pAEC and exacerbated the dysregulated repair seen in asthmatic pAEC. Expression of major TGF-beta1 activators of epithelial cells, integrin alphavbeta6 and alphavbeta8 was also measured and there was no difference in alphavbeta6 gene expression between the two cohorts. Although integrin alphavbeta8 gene expression was significantly higher in asthmatic pAEC, the expression of MT1-MMP (MMP14) which facilitates the alphavbeta8 mediated TGF beta1 activation was significantly downregulated. CONCLUSION: Our data has highlighted the importance of TGF-beta1 in pAEC wound repair in vitro. The significantly lower levels seen in asthmatic pAEC subsequently contributes to the dysregulated repair observed in these cells. PMID- 27221563 TI - Prediction of medial tibiofemoral compartment joint space loss progression using volumetric cartilage measurements: Data from the FNIH OA biomarkers consortium. AB - OBJECTIVES: Investigating the association between baseline cartilage volume measurements (and initial 24th month volume loss) with medial compartment Joint Space-Loss (JSL) progression (>0.7 mm) during 24-48th months of study. METHODS: Case and control cohorts (Biomarkers Consortium subset from the Osteoarthritis Initiative (OAI)) were defined as participants with (n=297) and without (n=303) medial JSL progression (during 24-48th months). Cartilage volume measurements (baseline and 24th month loss) were obtained at five knee plates (medial-tibial, lateral-tibial, medial-femoral, lateral-femoral and patellar), and standardized values were analysed. Multivariate logistic regression was used with adjustment for known confounders. Artificial-Neural-Network analysis was conducted by Multi Layer-Perceptrons (MLPs) including baseline determinants, and baseline (1) and interval changes (2) in cartilage volumes. RESULTS: Larger baseline lateral femoral cartilage volume was predictive of medial JSL (OR: 1.29 (1.01-1.64)). Greater initial 24th month lateral-femoral cartilage volume-loss (OR: 0.48 (0.27 0.84)) had protective effect on medial JSL during 24-48th months of study. Baseline and interval changes in lateral-femoral cartilage volume, were the most important estimators for medial JSL progression (importance values: 0.191(0.177 0.204), 0.218(0.207-0.228)) in the ANN analyses. CONCLUSIONS: Cartilage volumes (both at baseline and their change during the initial 24 months) in the lateral femoral plate were predictive of medial JSL progression. KEY POINTS: * Baseline lateral femoral cartilage volume is directly associated with medial JSL progression. * 24-month lateral femoral cartilage loss is inversely associated with medial JSL progression. * Lateral femoral cartilage volume is most important in association with medial JSL progression. PMID- 27221565 TI - [Positive and negative perceptions at work: Qualitative study with physicians in a teaching hospital]. AB - INTRODUCTION: Doctors see the suffering of patients and their families; their working conditions are often difficult. High prevalence of occupational diseases are shown in medical literature, especially burnout. Some risk factors are shown depending upon medical specialties and workplace, especially in hospital. The purpose of this article was to qualify these factors by qualitative research, according to hospital doctors' point of view. METHODS: It was a study with interviews. The analysis was done according to the Grounded Theory. RESULTS: Nine doctors were interviewed. They expressed difficulties and positive factors at work. Four major themes were demonstrated in selective coding: the organization of work, experienced as positive rather negative, teamwork, work at the hospital and academic work. The three last themes were both a source of well-being and ill being according to the situations specified in the results. CONCLUSION: The fact of working in a hospital is meaningful for physicians surveyed. But it could also be source of ill-being and anxiety. PMID- 27221566 TI - Ovarian Physiology and GWAS: Biobanks, Biology, and Beyond. AB - Ovarian function is central to female fertility, and several genome-wide association studies (GWAS) have been carried out to elucidate the genetic background of traits and disorders that reflect and affect ovarian physiology. While GWAS have been successful in reporting numerous genetic associations and highlighting involved pathways relevant to reproductive aging, for ovarian disorders, such as premature ovarian insufficiency and polycystic ovary syndrome, research has lagged behind due to insufficient study sample size. Novel approaches to study design and analysis methods that help to fit GWAS findings into biological context will improve our knowledge about genetics governing ovarian function in fertility and disease, and provide input for clinical tools and better patient management. PMID- 27221568 TI - Anterolateral Advancement Pharyngoplasty: A New Technique for Treatment of Obstructive Sleep Apnea. AB - OBJECTIVE: To investigate the efficacy of anterolateral advancement pharyngoplasty to enlarge pharyngeal airspace and to decrease palatal and lateral pharyngeal wall collapse in the treatment of obstructive sleep apnea (OSA). STUDY DESIGN: Prospective study. SETTING: University medical hospital. SUBJECTS AND METHOD: Forty-one patients underwent an anterolateral advancement pharyngoplasty procedure according to the following criteria: body mass index <30 kg/m(2), Friedman stage II or III, type I Fujita, nocturnal polysomnography diagnostic of OSA, retropalatal and lateral pharyngeal collapse, and diagnosis with flexible nasoendoscopy during a Muller's maneuver based on a 5-point scale. Patients with retroglossal airway collapse were excluded from the study. The principle of this technique is to advance and fix the palatopharyngeus muscle with the superior pharyngeus constrictor muscle without transecting any of their fascicules anterolateral to the pterygomandibular raphe and anterosuperior to the levator veli palatine muscle. RESULTS: Pre- and postoperative polysomnography findings (mean +/- SD) showed significant statistical differences: apnea hypopnea index (AHI) decreased from 42.1 +/- 16.34 to 16.3 +/- 10.3 (P <= .001); percentage of time with oxyhemoglobin saturation <90% decreased from 18.5% +/- 4.2% to 10.1% +/ 1.3% (P <= .001); and lowest oxygen saturation level increased from 79.9% +/- 14.8% to 89.3% +/- 11.1% (P <= .05). The mean time for patients to return to a normal diet was 12.2 days. There was no postoperative bleeding, velopharyngeal insufficiency, speech alternations, or taste loss. Based on a threshold of a 50% reduction in AHI and AHI <20, surgical success was 86.8%. CONCLUSION: Anterolateral advancement pharyngoplasty appears to be an effective technique with a high surgical success rate in the treatment of OSA patients with lateral pharyngeal wall collapse. PMID- 27221567 TI - Effects of urban fine particulate matter and ozone on HDL functionality. AB - BACKGROUND: Exposures to ambient particulate matter (PM) are associated with increased morbidity and mortality. PM2.5 (<2.5 MUm) and ozone exposures have been shown to associate with carotid intima media thickness in humans. Animal studies support a causal relationship between air pollution and atherosclerosis and identified adverse PM effects on HDL functionality. We aimed to determine whether brief exposures to PM2.5 and/or ozone could induce effects on HDL anti-oxidant and anti-inflammatory capacity in humans. METHODS: Subjects were exposed to fine concentrated ambient fine particles (CAP) with PM2.5 targeted at 150 MUg/m(3), ozone targeted at 240 MUg/m(3) (120 ppb), PM2.5 plus ozone targeted at similar concentrations, and filtered air (FA) for 2 h, on 4 different occasions, at least two weeks apart, in a randomized, crossover study. Blood was obtained before exposures (baseline), 1 h after and 20 h after exposures. Plasma HDL anti oxidant/anti-inflammatory capacity and paraoxonase activity were determined. HDL anti-oxidant/anti-inflammatory capacity was assessed by a cell-free fluorescent assay and expressed in units of a HDL oxidant index (HOI). Changes in HOI (DeltaHOI) were calculated as the difference in HOI from baseline to 1 h after or 20 h after exposures. RESULTS: There was a trend towards bigger DeltaHOI between PM2.5 and FA 1 h after exposures (p = 0.18) but not 20 h after. This trend became significant (p <0.05) when baseline HOI was lower (<1.5 or <2.0), indicating decreased HDL anti-oxidant/anti-inflammatory capacity shortly after the exposures. There were no significant effects of ozone alone or in combination with PM2.5 on the change in HOI at both time points. The change in HOI due to PM2.5 showed a positive trend with particle mass concentration (p = 0.078) and significantly associated with the slope of systolic blood pressure during exposures (p = 0.005). CONCLUSIONS: Brief exposures to concentrated PM2.5 elicited swift effects on HDL anti-oxidant/anti-inflammatory functionality, which could indicate a potential mechanism for how particulate air pollution induces harmful cardiovascular effects. PMID- 27221569 TI - Reflections: Volunteering at Home. AB - Many young people look forward to volunteering abroad and overlook the ample volunteer opportunities at home. There are several advantages to volunteering at home: you help people in your own community; you can make a long-term commitment; and you have continuity of care for your patients. There are >1200 free clinics in the United States whose main goal is to provide care to the indigent population. These free clinics are always looking for volunteers with specialized medical training. This article reviews the medically related and unrelated volunteer opportunities available in the United States. Volunteering at home is a worthwhile experience, and I encourage the otolaryngology community to explore these opportunities. PMID- 27221570 TI - MRI- and CT-Compatible Polymer Laryngoscope: A Step toward Image-Guided Transoral Surgery. PMID- 27221571 TI - Mobile Endoscopy vs Video Tower: A Prospective Comparison of Video Quality and Diagnostic Accuracy. AB - OBJECTIVE: To determine if any significant difference exists between endoscopic videos captured with a mobile adaptor and videos captured with a traditional tower. STUDY DESIGN: Prospective controlled blinded comparison of mobile endoscopic videos captured through 2 methods. METHODS: Thirty randomly selected patients underwent video endoscopy with both mobile and video tower recording methods. Sixty videos were edited into a series of 10-second clips. Thirteen otolaryngology staff and residents rated the video quality and provided a diagnosis for each video. RESULTS: We found no significant difference in the video quality ratings between mobile and tower videos (mean difference, -0.07; P < .37). Similarly, we found no significant difference in the observers' diagnostic accuracy (mean difference, 1.54%; P < .686). CONCLUSION: With adequate power, our study was unable to demonstrate a difference between mobile adapter videos and tower videos. Our findings suggest that mobile adapter videos may reasonably be used in lieu of tower videos in clinical practice. PMID- 27221572 TI - Retrosternal Goiter: 30-Day Morbidity and Mortality in the Transcervical and Transthoracic Approaches. AB - OBJECTIVE: Retrosternal goiters pose a significant challenge in determining the indications and appropriate approach for surgical removal while limiting postoperative morbidity and mortality. The objective of this study is to use the National Surgical Quality Improvement Program (NSQIP) database to compare outcomes of transcervical and transthoracic approaches for retrosternal goiter removal and to review the literature regarding the varying indications for the 2 surgical approaches. STUDY DESIGN: Administrative database analysis. SETTING: NSQIP database. SUBJECTS AND METHODS: The NSQIP database was queried for all cases of retrosternal thyroid: 2716 patients were included, which represents one of the largest data reviews of patients with retrosternal thyroid pathology who underwent surgery. Data were analyzed to examine morbidity and mortality of the cervical and transthoracic approaches. RESULTS: Patient demographics and preoperative comorbidities were similar between groups. Patients undergoing a transthoracic approach experienced increased rates of unplanned intubations and need for transfusion and length of stay postoperatively. CONCLUSIONS: A transthoracic approach is associated with increased rates of several critical postoperative morbidities, and the data indicate the potential of increased overall mortality. Given equivalent retrosternal extension, a transcervical approach should be attempted whenever anatomically possible, regardless of pathology. PMID- 27221573 TI - Lymph Node Density in Node-Positive Laryngeal Carcinoma: Analysis of Prognostic Value for Survival. AB - OBJECTIVE: We investigated the value of lymph node density (LND) as a predictor of survival in patients with laryngeal squamous cell carcinoma (SCC) and positive neck node (pN+) after laryngectomy. STUDY DESIGN: Case series with chart review. SETTING: Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey. SUBJECTS AND METHODS: We reviewed the records of 289 patients with newly diagnosed primary laryngeal carcinomas who underwent partial or total laryngectomy and combined neck dissection at a tertiary referral center between June 2006 and December 2014. Patients with pN+ laryngeal SCC (n = 101) were included in the study. Overall survival (OS) and disease-free survival (DFS) were used to evaluate the prognostic significance of LND. RESULTS: In 101 patients with pN+ laryngeal SCC, LND >=0.09 and number of metastatic lymph nodes >4 were significantly associated with OS and DFS but not the overall tumor, node, and metastasis stage. Forward stepwise Cox regression analysis revealed that LND >=0.09 was the only independent predictor of both DFS and OS. Furthermore, the odds ratio of LND >=0.09 was 10 times higher in patients with regional recurrence when compared patients without regional recurrence. CONCLUSIONS: LND was the only independent prognostic predictor of OS and DFS in patients with pN+ laryngeal SCC. Moreover, patients with LND >=0.09 were significantly associated with high risk of regional recurrence. Thus, patients with LND >=0.09 are at high risk of regional recurrence and death and may be considered for adjuvant chemoradiation. PMID- 27221574 TI - Incidence and Risk Factors for Prolonged Hospitalization and Readmission after Transsphenoidal Pituitary Surgery. AB - OBJECTIVE: To evaluate the incidence and factors associated with 30-day readmission and to analyze risk factors for prolonged hospital length of stay following transsphenoidal pituitary surgery. STUDY DESIGN: Retrospective longitudinal claims analysis. SETTING: American College of Surgeons National Surgical Quality Improvement Program. SUBJECTS AND METHODS: The database of the American College of Surgeons National Surgical Quality Improvement Program was queried for patients who underwent transsphenoidal pituitary surgery (Current Procedural Terminology code 61548 or 62165) between 2005 and 2014. Patient demographic information, indications for surgery, and incidence of hospital readmission and length of stay were reviewed. Risk factors for readmission and prolonged length of stay, defined as >75th percentile for the cohort, were identified through logistic regression modeling. RESULTS: A total of 1006 patients were included for analysis. Mean hospital length of stay after surgery was 4.1 +/- 0.2 days. Predictors of prolonged length of stay were operative time (P < .001, odds ratio [OR] = 1.7, 95% confidence interval [95% CI] = 1.5-2.0), bleeding disorder (P = .049, OR = 3.1, 95% CI = 1.0-9.5), insulin-dependent diabetes (P = .007, OR = 2.4, 95% CI = 1.3-4.4), and reoperation (P < .001, OR = 10.3, 95% CI = 4.7-23.9). In a subset analysis of 529 patients who had surgery between 2012 and 2014, 7.2% (n = 38) required hospital readmission. History of congestive heart failure (CHF) was a predictor of hospital readmission (P = 0.03, OR = 12.7, 95% CI = 1.1-144.0). CONCLUSION: This review of a large validated surgical database demonstrates that CHF is an independent predictor of hospital readmission after transsphenoidal surgery. Although CHF is a known risk factor for postoperative complications, it poses unique challenges to patients with potential postoperative pituitary dysfunction. PMID- 27221575 TI - Pathologic Findings of the Cochlea in Labyrinthitis Ossificans Associated with the Round Window Membrane. AB - OBJECTIVE: To quantitatively demonstrate and classify the histopathologic changes in the cochlea of the human temporal bones with labyrinthitis ossificans (LO). STUDY DESIGN: Comparative human temporal bone study. SETTING: Tertiary academic medical center. SUBJECTS AND METHODS: We compared 23 temporal bone specimens from 19 deceased donors with LO associated with the round window membrane (RWM) and 27 age-matched specimens from 20 deceased donors without any otologic diseases. We focused on the location of LO in the inner ear, the intensity of endolymphatic hydrops, the number of spiral ganglion cells and cochlear hair cells, and the areas of the stria vascularis and spiral ligament. In addition, we created a new pathologic grading system for temporal bone specimens from deceased donors with LO associated with the RWM. RESULTS: We most often observed LO in the scala tympani of the basal cochlear turn. In the LO group (as compared with the control group), the intensity of endolymphatic hydrops was significantly increased; the number of spiral ganglion cells was significantly decreased in all segments; the loss of outer and inner hair cells was significantly increased in all turns of the cochlea; the atrophy of the stria vascularis was significantly greater in all turns of the cochlea; and atrophy of the spiral ligament was significantly greater in the basal and middle cochlear turn. CONCLUSION: LO was associated with significant cochlear damage (to the spiral ganglion cells, cochlear hair cells, stria vascularis, and spiral ligament) and with increased intensity of endolymphatic hydrops. PMID- 27221576 TI - Sustained Inner Ear Steroid Delivery via Bioabsorbable Stent: A Tolerability and Feasibility Study on Guinea Pigs. AB - OBJECTIVE: To determine the feasibility and tolerability of a steroid-eluting middle ear device on an animal model. STUDY DESIGN: Prospective experimental. SETTING: Experimental animal study. SUBJECTS AND METHOD: Mometasone furoate (MF) eluting miniature sticks were implanted through a myringotomy incision into the middle ear of 10 guinea pigs. Two additional ears of 2 animals served as controls. Fourteen days after implantation, perilymphatic fluid was collected through an endaural cochleostomy. MF concentrations were measured with high performance liquid chromatography, and the middle ear mucosal inflammation was graded with hematoxylin and eosin colorations. RESULTS: Fourteen days after implantation, all tympanic membranes had fully healed. An average of 165 ng/mL of MF was detected in the perilymphatic fluid of the experimental ears, and none was measured in control ears. Microscopic residues of the ministicks were found in 90% of the samples, confirming the bioabsorbable properties of this device. Histologic analysis of the middle ear mucosa found similar inflammation profiles in both groups, thereby suggesting middle ear tolerability. CONCLUSION: MF-coated bioabsorbable miniature stick allows for prolonged delivery over 14 days without injuring the middle ear mucosa. Middle ear-sustained steroid delivery may prove to be beneficial in numerous neurotologic conditions. PMID- 27221577 TI - Systematic Review and Meta-analysis of Surgical Complications following Cochlear Implantation in Canal Wall Down Mastoid Cavities. AB - OBJECTIVE: We sought to assess the complication rates following cochlear implantation in canal wall down mastoid cavities in adults and children. DATA SOURCES: A systematic review of English articles from PubMed, Web of Science, EMBASE, and the Cochrane Library. Additional studies were identified by reviewing the reference lists of the originally identified studies. REVIEW METHODS: Studies were included that reported on surgical outcomes following cochlear implantation in canal wall down mastoid cavities. Two authors, using predefined data fields, independently reviewed all articles while tabulating study quality indicators. A meta-analysis of proportions was conducted on select cohorts to determine weighted complication rates. RESULTS: Forty-two articles were included that accounted for 424 patients and described surgical outcomes following cochlear implantation in canal wall down mastoid cavities. In a comparison of the postoperative complication rates, overclosing the external auditory meatus had significantly fewer global complications than did maintaining a canal wall down mastoid cavity (P = .027). In a comparison of the complication rates (1) between staging the cochlear implantation and performing external auditory meatus overclosure simultaneously with cochlear implantation and (2) between pediatric and adult cochlear implantation recipients with external auditory meatus overclosure, there were no significant differences (P = .085 and P = .92, respectively). CONCLUSION: Overclosing the external auditory meatus at the same time of cochlear implantation leads to significantly fewer complications when compared with maintaining a canal wall down mastoid cavity with soft tissue coverage of the electrode array. PMID- 27221578 TI - Lateral Skull Base Attenuation in Superior Semicircular Canal Dehiscence and Spontaneous Cerebrospinal Fluid Otorrhea. AB - OBJECTIVES: (1) To quantitatively assess the lateral skull base thickness in patients with superior semicircular canal dehiscense (SSCD) using a standardized and validated radiographic measure and to compare it with that of a population with spontaneous cerebrospinal fluid otorrhea (CSFO). (2) To analyze demographic and clinical factors associated with skull base thickness in the SSCD group. STUDY DESIGN: Case series with chart review. SETTING: Tertiary neurotologic referral center. SUBJECTS AND METHODS: Based on computed tomography imaging of the tegmen, mean skull base thickness was calculated for 16 patients with radiographic and clinical SSCD. Similar measures were performed in 4 comparison groups consisting of adults with spontaneous CSFO (n = 33), as well as 3 control groups recruited from our adult cochlear implant database: 30 obese controls (body mass index [BMI] >30 kg/m(2)), 11 overweight controls (BMI, 25-30 kg/m(2)), and 20 normal weight controls (BMI <25 kg/m(2)). RESULTS: The SSCD group had a significantly lower mean BMI (28.6 kg/m(2)) than the spontaneous CSFO group (37.7 kg/m(2); P = .0007). The mean skull base thickness of SSCD patients was 17% thinner than that of the CSFO group, 31% thinner vs obese controls, 49% thinner vs overweight controls, and 45% thinner vs normal weight controls. These differences were all statistically significant (P < .05). CONCLUSION: Patients with SSCD have a marked thinning of the lateral skull base, more so than patients with spontaneous CSF otorrhea and control groups with different BMIs. Skull base attenuation in SSCD patients did not correlate with BMI. PMID- 27221579 TI - Does the Press Ganey Survey Correlate to Online Health Grades for a Major Academic Otolaryngology Department? AB - OBJECTIVES: Analyze the correlation between online-based review websites and the Press Ganey Patient Satisfaction Survey (PGPSS) in an academic otolaryngology department. STUDY DESIGN: Retrospective cross sectional. SETTING: Tertiary academic institution. METHODS: All available data were collected for Vitals.com and Healthgrades.com, along with PGPSS data for 16 otolaryngology attending physicians from 2012 to 2014. A mean rating was calculated for each topic category for online websites and compared with 7 PGPSS content questions using zero-order correlations. A paired t test was used to analyze the difference between the PGPSS and online scores. RESULTS: There were no statistically significant correlations between time spent with the patient (r = 0.391, P = .208) and overall provider scores (r = 0.193, P = .508) when compared between Vitals.com and the PGPSS. The correlations were not statistically significant when Healthgrades.com was compared with the PGPSS in the items "probability of recommending the provider" (r = -0.122, P = .666) and "trust in provider" (r = 0.025, P = .929). The most important factors in a patient recommending the provider were as follows, per resource: time spent with the patient for Vitals.com (r = 0.685, P = .014), listening for Healthgrades.com (r = 0.981, P <= .001), and trust in the provider for the PGPSS (r = 0.971, P <= .001). CONCLUSION: This study suggests that online-based reviews do not have statistically significant correlations with the widely used PGPSS and may not be an accurate source of information for patients. Patients should have access to the most reliable and least biased surveys available to the public to allow for better-informed decisions regarding their health care. PMID- 27221580 TI - Coulomb drag in anisotropic systems: a theoretical study on a double-layer phosphorene. AB - We theoretically study the Coulomb drag resistivity in a double-layer electron system with highly anisotropic parabolic band structure using Boltzmann transport theory. As an example, we consider a double-layer phosphorene on which we apply our formalism. This approach, in principle, can be tuned for other double-layered systems with paraboloidal band structures. Our calculations show the rotation of one layer with respect to another layer can be considered a way of controlling the drag resistivity in such systems. As a result of rotation, the off-diagonal elements of the drag resistivity tensor have non-zero values at any temperature. In addition, we show that the anisotropic drag resistivity is very sensitive to the direction of momentum transfer between two layers due to highly anisotropic inter-layer electron-electron interaction and also the plasmon modes. In particular, the drag anisotropy ratio, [Formula: see text], can reach up to [Formula: see text]3 by changing the temperature. Furthermore, our calculations suggest that including the local field correction in the dielectric function changes the results significantly. Finally, We examine the dependence of drag resistivity and its anisotropy ratio on various parameters like inter-layer separation, electron density, short-range interaction and insulating substrate/spacer. PMID- 27221581 TI - Synthesis, crystal structure, and luminescence properties of a new europium silicate. AB - A new europium silicate, NaEuSi3O7(OH)2 (denoted as 1), was synthesized under high-temperature and high-pressure conditions, and structurally characterized by single-crystal and powder X-ray diffraction (XRD) analyses. The single-crystal XRD analysis of 1 revealed that its structure was based on SiO4 tetrahedron single chains, which were connected together by the EuO6 polyhedron via vertex oxygen atoms forming a three-dimensional framework of 1. It contained 4, 6-ring channels along the [010] direction, which were delimited by the SiO4 tetrahedron and EuO6 polyhedron. The Na(+) ions were located in the 6-ring channels along the [010] direction to achieve the charge balance. The luminescence properties of 1 were also investigated. PMID- 27221582 TI - MRI Patterns of Isolated Lesions in the Medulla Oblongata. AB - BACKGROUND AND PURPOSE: Isolated lesions of the medulla oblongata are difficult to diagnose due to their rarity and high biopsy risk. Several individual case reports have been published, but a systematic descriptive study is lacking. Our study has three objectives that 1) provide a differential diagnosis, 2) describe magnetic resonance imaging (MRI) findings, and 3) propose a stepwise MRI-based approach to the isolated lesions of the medulla oblongata in nonstroke patients. METHODS: We performed an institutional Review Board-approved retrospective analysis of 34 consecutive cases of isolated medullary lesions from nonstroke causes identified from our imaging database between January 2000 and May 2015. Eleven were excluded due to lack of pretreatment or follow-up MRI. MR studies were reviewed by two blinded neuroradiologists. The diagnosis, demographic data, and MR findings were reported using frequencies and proportions. An MRI-based diagnostic algorithm was proposed. RESULTS: Most lesions were neoplasms (47%), followed by vascular malformations (15%), demyelinating/inflammatory lesions (15%), others (12%), unknown (8%), and infection (3%). Five MRI patterns were identified: 1) cystic lesion, 2) exophytic noncystic lesion, 3) intrinsic lesion with T2 hypointensity, 4) enhancing intrinsic lesion, and 5) nonenhancing intrinsic lesion. All showing patterns 1 and 2 were neoplasms or cysts. All showing pattern 3 were vascular malformations. Patterns 4 and 5 comprised of multiple etiologies. CONCLUSIONS: Neoplasms are the most common cause of isolated medullary lesions in nonstroke patients. Other differential diagnoses include vascular malformations, demyelinating/inflammatory lesions, and infections. A stepwise MRI-based approach can help differentiate between various etiologies. PMID- 27221583 TI - Nanoscale Superconducting Honeycomb Charge Order in IrTe2. AB - Entanglement of charge orderings and other electronic orders such as superconductivity is in the core of challenging physics issues of complex materials including high temperature superconductivity. Here, we report on the observation of a unique nanometer scale honeycomb charge ordering of the cleaved IrTe2 surface, which hosts a superconducting state. IrTe2 was recently established to exhibit an intriguing cascade of stripe charge orders. The stripe phases coexist with a hexagonal phase, which is formed locally and falls into a superconducting state below 3 K. The atomic and electronic structures of the honeycomb and hexagon pattern of this phase are consistent with the charge order nature, but the superconductivity does not survive on neighboring stripe charge order domains. The present work provides an intriguing physics issue and a new direction of functionalization for two-dimensional materials. PMID- 27221584 TI - Effects of work-family-school role conflicts and role-related social support on burnout in Registered Nurses: a structural equation modelling approach. AB - AIM: To examine the effects of work-family-school role conflicts and role-related social support (RRSS) on burnout of nurses pursuing an advanced degree. DESIGN: A predictive correlational cross-sectional study design was used. BACKGROUND: Nurses were found to be a high-risk group for burnout, even more so among nurses pursuing an advanced degree. When nurses with a professional career marry and decide to become students, inter-role conflicts and burnout are possible outcomes of the resulting multiple roles. METHODS: Using convenience sampling, data were collected from October 2011-May 2012. A questionnaire about work-family-school role conflicts, RRSS, burnout and general information was completed by 286 nurses pursuing an advanced degree at 12 hospitals in Korea. Data were analysed using SPSS and structural equation modelling with the Analysis of Moment Structures program. RESULTS: The proposed model provided a good fit to the obtained data. Work-family-school role conflicts and social support exerted significant effects on burnout. Role-related social support was found to play a partial mediating role between work-family-school role conflicts and burnout. CONCLUSION: The findings of this study imply that RRSS significantly directly and indirectly influences burnout among the nurses pursuing an advanced degree. It is necessary for nursing managers to consider implementing family- and school-friendly policies (e.g. flexible work schedules) to help nurses to manage their multiple roles and thereby decrease their burnout rate. PMID- 27221585 TI - Preclinical Reproductive and Developmental Toxicity Profile of a Glycine Transporter Type 1 (Glyt1) Inhibitor. AB - Bitopertin is a glycine type 1 (GlyT1) inhibitor intended for the treatment of psychiatric disorders. The principle adverse effect in the regulatory reproductive toxicity studies was peri-natal pup death when rat dams were treated during parturition at a dose resulting in five-times the human therapeutic exposure (AUC). Cessation of dosing two days before parturition prevented the pup deaths. Investigatory experiments and pharmacokinetic modelling suggested that the neonatal mortality was related to transplacental passage of bitopertin leading to high systemic levels in the newborn pups. Brain levels of bitopertin in the rat fetus and neonate were two-fold higher than in the mother. As illustrated by knock-out mice models, GlyT1 function is essential for neonatal pup survival in rodents, but is not necessary for normal prenatal morphological development. The glycine transport systems are immature at birth in the rat, but are functionally well-developed in the human newborn. While the relevance to humans of the neonatal mortality seen in rats following late gestational exposure is unknown, bitopertin would not be recommended for use during late pregnancy unless the anticipated benefit for the mother outweighs the potential risk to the newborn. PMID- 27221586 TI - Sono assisted electrocoagulation process for the removal of pollutant from pulp and paper industry effluent. AB - In the present work, the efficiency of the sonication, electrocoagulation, and sono-electrocoagulation process for removal of pollutants from the industrial effluent of the pulp and paper industry was compared. The experimental results showed that the sono-electrocoagulation process yielded higher pollutant removal percentage compared to the sonication and electrocoagulation process alone. The effect of the operating parameters in the sono-electrocoagulation process such as electrolyte concentration (1-5 g/L), current density (1-5 A/dm2), effluent pH (3 11), COD concentration (1500-6000 mg/L), inter-electrode distance (1-3 cm), and electrode combination (Fe and Al) on the color removal, COD removal, and power consumption were studied. The maximum color and COD removal percentages of 100 and 95 %, respectively, were obtained at the current density of 4 A/dm2, electrolyte concentration of 4 g/L, effluent pH of 7, COD concentration of 3000 mg/L, electrode combination of Fe/Fe, inter-electrode distance of 1 cm, and reaction time of 4 h, respectively. The color and COD removal percentages were analyzed by using an UV/Vis spectrophotometer and closed reflux method. The results showed that the sono-electrocoagulation process could be used as an efficient and environmental friendly technique for complete pollutant removal. PMID- 27221587 TI - Pathogenicity of Aeromonas hydrophila isolated from the Malaysian Sea against coral (Turbinaria sp.) and sea bass (Lates calcarifer). AB - A study was carried out to determine the pathogenicity (hemolytic activity) on corals (Turbinaria sp.) and sea bass (Lates calcarifer) of Aeromonas hydrophila from water, sediment, and coral. Samples were collected from coastal water and coral reef areas. One hundred and sixty-two isolates were successfully isolated. Out of 162, 95 were from seawater, 49 from sediment, and 18 from coral. Sixteen isolates were picked and identified. Isolates were identified using a conventional biochemical test, the API 20NE kit, and 16S rRNA nucleotide sequences. Hemolytic activity was determined. Out of 16 isolates, 14 isolates were beta-hemolytic and two isolates were non-hemolytic. Corals infected with A. hydrophila suffered bleaching. Similar effect was observed for both hemolytic and non-hemolytic isolates. Intramuscular injection of A. hydrophila into sea bass resulted in muscular bleeding and death. Higher infection rates were obtained from hemolytic compared to non-hemolytic strains of A. hydrophila isolates. PMID- 27221588 TI - A triangular fuzzy TOPSIS-based approach for the application of water technologies in different emergency water supply scenarios. AB - Because of the increasing frequency and intensity of unexpected natural disasters, providing safe drinking water for the affected population following a disaster has become a global challenge of growing concern. An onsite water supply technology that is portable, mobile, or modular is a more suitable and sustainable solution for the victims than transporting bottled water. In recent years, various water techniques, such as membrane-assisted technologies, have been proposed and successfully implemented in many places. Given the diversity of techniques available, the current challenge is how to scientifically identify the optimum options for different disaster scenarios. Hence, a fuzzy triangular-based multi-criteria, group decision-making tool was developed in this research. The approach was then applied to the selection of the most appropriate water technologies corresponding to the different emergency water supply scenarios. The results show this tool capable of facilitating scientific analysis in the evaluation and selection of emergency water technologies for enduring security drinking water supply in disaster relief. PMID- 27221589 TI - Identification of Leishmania donovani Topoisomerase 1 inhibitors via intuitive scaffold hopping and bioisosteric modification of known Top 1 inhibitors. AB - A library of arylidenefuropyridinediones was discovered as potent inhibitors of Leishmania donovani Topoisomerase 1 (LdTop1) where the active molecules displayed considerable inhibition with single digit micromolar EC50 values. This molecular library was designed via intuitive scaffold hopping and bioisosteric modification of known topoisomerase 1 inhibitors such as camptothecin, edotecarin and etc. The design was rationalized by molecular docking analysis of the compound prototype with human topoisomerase 1 (HTop1) and Leishmania donovani topoisomerase 1(LdTop1). The most active compound 4 displayed no cytotoxicity against normal mammalian COS7 cell line (~100 fold less inhibition at the EC50). Similar to camptothecin, 4 interacted with free LdTop1 as observed in the preincubation DNA relaxation inhibition experiment. It also displayed anti-protozoal activity against Leishmania donovani promastigote. Crystal structure investigation of 4 and its molecular modelling with LdTop1 revealed putative binding sites in the enzyme that could be harnessed to generate molecules with better potency. PMID- 27221590 TI - Echo time-dependent quantitative susceptibility mapping contains information on tissue properties. AB - PURPOSE: Magnetic susceptibility is a physical property of matter that varies depending on chemical composition and abundance of different molecular species. Interest is growing in mapping of magnetic susceptibility in the human brain using magnetic resonance imaging techniques, but the influences affecting the mapped values are not fully understood. METHODS: We performed quantitative susceptibility mapping on 7 Tesla (T) multiple echo time gradient recalled echo data and evaluated the trend in 10 regions of the human brain. Temporal plots of susceptibility were performed in the caudate, pallidum, putamen, thalamus, insula, red nucleus, substantia nigra, internal capsule, corpus callosum, and fornix. We implemented an existing three compartment signal model and used optimization to fit the experimental result to assess the influences that could be responsible for our findings. RESULTS: The temporal trend in susceptibility is different for different brain regions, and subsegmentation of specific regions suggests that differences are likely to be attributable to variations in tissue structure and composition. Using a signal model, we verified that a nonlinear temporal behavior in experimentally computed susceptibility within imaging voxels may be the result of the heterogeneous composition of tissue properties. CONCLUSIONS: Decomposition of voxel constituents into meaningful parameters may lead to informative measures that reflect changes in tissue microstructure. Magn Reson Med 77:1946-1958, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27221591 TI - Recombinant expression of surfactant protein H (SFTA3) in Escherichia coli. AB - Surfactant proteins are broadly understood to be an important structural and functional part of the lung surfactant system. These proteins influence the intra alveolar surface tension and contribute to innate immunity of the lung. Beside the four already known surfactant proteins SP-A, SP-B, SP-C and SP-D, two novel SPs (SP-G/SFTA2 and SP-H/SFTA3) have recently been described. These show no sequential or structural similarity with the already known SPs. However, bioinformatic prediction tools suggest physicochemical properties, which have already been described for other surfactant proteins. Although it is known that SFTA2 and SFTA3 are expressed in different human tissues, their distinct functional properties remain unclear. Here, we describe the establishment of a stable expression system for recombinant SFTA3 protein synthesis in Escherichia coli. This gives rise to future experiments with the overall aim to further examine and characterize this novel protein in more detail. PMID- 27221592 TI - Stepwise phosphorylation of p65 promotes NF-kappaB activation and NK cell responses during target cell recognition. AB - NF-kappaB is a key transcription factor that dictates the outcome of diverse immune responses. How NF-kappaB is regulated by multiple activating receptors that are engaged during natural killer (NK)-target cell contact remains undefined. Here we show that sole engagement of NKG2D, 2B4 or DNAM-1 is insufficient for NF-kappaB activation. Rather, cooperation between these receptors is required at the level of Vav1 for synergistic NF-kappaB activation. Vav1-dependent synergistic signalling requires a separate PI3K-Akt signal, primarily mediated by NKG2D or DNAM-1, for optimal p65 phosphorylation and NF kappaB activation. Vav1 controls downstream p65 phosphorylation and NF-kappaB activation. Synergistic signalling is defective in X-linked lymphoproliferative disease (XLP1) NK cells entailing 2B4 dysfunction and required for p65 phosphorylation by PI3K-Akt signal, suggesting stepwise signalling checkpoint for NF-kappaB activation. Thus, our study provides a framework explaining how signals from different activating receptors are coordinated to determine specificity and magnitude of NF-kappaB activation and NK cell responses. PMID- 27221593 TI - Preservation of Archaeal Surface Layer Structure During Mineralization. AB - Proteinaceous surface layers (S-layers) are highly ordered, crystalline structures commonly found in prokaryotic cell envelopes that augment their structural stability and modify interactions with metals in the environment. While mineral formation associated with S-layers has previously been noted, the mechanisms were unconstrained. Using Sulfolobus acidocaldarius a hyperthermophilic archaeon native to metal-enriched environments and possessing a cell envelope composed only of a S-layer and a lipid cell membrane, we describe a passive process of iron phosphate nucleation and growth within the S-layer of cells and cell-free S-layer "ghosts" during incubation in a Fe-rich medium, independently of metabolic activity. This process followed five steps: (1) initial formation of mineral patches associated with S-layer; (2) patch expansion; (3) patch connection; (4) formation of a continuous mineral encrusted layer at the cell surface; (5) early stages of S-layer fossilization via growth of the extracellular mineralized layer and the mineralization of cytosolic face of the cell membrane. At more advanced stages of encrustation, encrusted outer membrane vesicles are formed, likely in an attempt to remove damaged S-layer proteins. The S-layer structure remains strikingly well preserved even upon the final step of encrustation, offering potential biosignatures to be looked for in the fossil record. PMID- 27221594 TI - Antimicrobial Susceptibility and Characterization of Virulence Genes of Enterococcus faecalis Isolates from Teeth with Failure of the Endodontic Treatment. AB - INTRODUCTION: The aim of this study was to investigate the prevalence of virulence factors and the antimicrobial resistance of Enterococcus faecalis isolates of teeth with failure of the endodontic treatment. METHODS: Twenty root canal samples were collected from teeth with apical periodontitis. E. faecalis was firstly identified based on phenotypic features and then by 16S ribosomal RNA gene sequencing. The antimicrobial susceptibility was determined by the minimum inhibitory concentration (MIC) of amoxicillin, amoxicillin + clavulanate, azithromycin, benzylpenicillin, ciprofloxacin, clindamycin, chloramphenicol, doxycycline, erythromycin, gentamicin, metronidazole, moxifloxacin, rifampicin, tetracycline, and vancomycin using the E test method. Virulence factors (ace, asa, asa373, cylA, efaA, esp, and gelE) were detected by polymerase chain reaction assay. RESULTS: Amoxicillin + clavulanate was effective against all strains. Intermediate and total resistance was found against the majority of the tested antimicrobials. The susceptibility of some microorganisms to some antimicrobial agents changed according to the evaluation time. MIC50 and MIC90 also varied according to the evaluation time. In relation to the virulence factors of the E faecalis isolates, ace was detected in 100% of the strains, asa (60%), asa373 (15%), efaA (95%), esp (70%), and gelE (75%), whereas cylA was not detected. CONCLUSIONS: It was concluded that E. faecalis isolates from persistent endodontic infections showed varied degrees of intermediate/total resistance to several antimicrobial agents, with amoxicillin + clavulanate being the most effective agent. Moreover, the strains showed different patterns for virulence gene detection. PMID- 27221595 TI - Prof. Gian Franco De Stefano (Turin, September 3rd 1939 - Rome, January 1st 2016). PMID- 27221596 TI - Nonseizure SUDEP: Sudden unexpected death in epilepsy without preceding epileptic seizures. AB - OBJECTIVE: To describe the phenomenology of monitored sudden unexpected death in epilepsy (SUDEP) occurring in the interictal period where death occurs without a seizure preceding it. METHODS: We report a case series of monitored definite and probable SUDEP where no electroclinical evidence of underlying seizures was found preceding death. RESULTS: Three patients (two definite and one probable) had SUDEP. They had a typical high SUDEP risk profile with longstanding intractable epilepsy and frequent generalized tonic-clonic seizures (GTCS). All patients had varying patterns of respiratory and bradyarrhythmic cardiac dysfunction with profound electroencephalography (EEG) suppression. In two patients, patterns of cardiorespiratory failure were similar to those seen in some patients in the Mortality in Epilepsy Monitoring Units Study (MORTEMUS). SIGNIFICANCE: SUDEP almost always occur postictally, after GTCS and less commonly after a partial seizure. Monitored SUDEP or near-SUDEP cases without a seizure have not yet been reported in literature. When nonmonitored SUDEP occurs in an ambulatory setting without an overt seizure, the absence of EEG information prevents the exclusion of a subtle seizure. These cases confirm the existence of nonseizure SUDEP; such deaths may not be prevented by seizure detection-based devices. SUDEP risk in patients with epilepsy may constitute a spectrum of susceptibility wherein some are relatively immune, death occurs in others with frequent GTCS with one episode of seizure ultimately proving fatal, while in others still, death may occur even in the absence of a seizure. We emphasize the heterogeneity of SUDEP phenomena. PMID- 27221598 TI - Contingency Learning Tracks With Stimulus-Response Proportion. AB - We investigate the processes involved in human contingency learning using the color-word contingency learning paradigm. In this task, participants respond to the print color of neutral words. Each word is frequently presented in one color. Results show that participants respond faster and more accurately to words presented in their expected color. In Experiment 1, we observed better performance for high- relative to medium-frequency word-color pairs, and for medium- relative to low-frequency pairs. Within the medium-frequency condition, it did not matter whether the word was predictive of a currently-unpresented color, or the color was predictive of a currently-unpresented word. We conclude that a given word facilitates each potential response proportional to how often they co-occurred. In contrast, there was no evidence for costs associated with violations of high-frequency expectancies. Experiment 2 further introduced a novel word baseline condition, which also provided no evidence for competition between retrieved responses. PMID- 27221597 TI - Visual Perceptual Organization Ability in Autopsy-Verified Dementia with Lewy Bodies and Alzheimer's Disease. AB - OBJECTIVES: Prominent impairment of visuospatial processing is a feature of dementia with Lewy bodies (DLB), and diagnosis of this impairment may help clinically distinguish DLB from Alzheimer's disease (AD). The current study compared autopsy-confirmed DLB and AD patients on the Hooper Visual Organization Test (VOT), a test that requires perceptual and mental reorganization of parts of an object into an identifiable whole. The VOT may be particularly sensitive to DLB since it involves integration of visual information processed in separate dorsal and ventral visual "streams". METHODS: Demographically similar DLB (n=28), AD (n=115), and normal control (NC; n=85) participants were compared on the VOT and additional neuropsychological tests. Patient groups did not differ in dementia severity at time of VOT testing. High and Low AD-Braak stage DLB subgroups were compared to examine the influence of concomitant AD pathology on VOT performance. RESULTS: Both patient groups were impaired compared to NC participants. VOT scores of DLB patients were significantly lower than those of AD patients. The diagnostic sensitivity and specificity of the VOT for patients versus controls was good, but marginal for DLB versus AD. High-Braak and low Braak DLB patients did not differ on the VOT, but High-Braak DLB performed worse than Low-Braak DLB on tests of episodic memory and language. CONCLUSIONS: Visual perceptual organization ability is more impaired in DLB than AD but not strongly diagnostic. The disproportionate severity of this visual perceptual deficit in DLB is not related to degree of concomitant AD pathology, which suggests that it might primarily reflect Lewy body pathology. (JINS, 2016, 22, 609-619). PMID- 27221599 TI - "This Isn't a Promise, It's a Threat". AB - Participants had their eye movements recorded as they read vignettes containing implied promises and threats. We observed a reading time penalty when participants read the word "threat" when it anaphorically referred to an implied promise. There was no such penalty when the word "promise" was used to refer to an implied threat. On a later measure of processing we again found a reading time penalty when the word "threat" was used to refer to a promise, but also when the word "promise" was used to refer to a threat. These results suggest that anaphoric processing of such expressions is driven initially by sensitivity to the semantic scope differences of "threats" versus "promises." A threat can be understood as a type of promise, but a promise cannot be understood as a type of threat. However, this effect was short lived; readers were ultimately sensitive to mismatched meaning, regardless of speech act performed. PMID- 27221600 TI - Spatial Estimation of Accelerated Stimuli Is Based on a Linear Extrapolation of First-Order Information. AB - We examined spatial estimation of accelerating objects (-8, -4, 0, +4, or +8 deg/s(2)) during occlusion (600, 1,000 ms) in a spatial prediction motion task. Multiple logistic regression indicated spatial estimation was influenced by these factors such that participants estimated objects with positive acceleration to reappear behind less often than those with negative acceleration, and particularly after the longer occlusion. Individual-participant logistic regressions indicated spatial estimation was better predicted by a first-order extrapolation of the occluded object motion based on pre-occlusion velocity rather than a second-order extrapolation that took account of object acceleration. We suggest a general principle of extrapolation is involved in prediction motion tasks whereby there is a contraction of the variable of interest (i.e., displacement in spatial prediction motion and time in temporal prediction motion). Such an approach to extrapolation could be advantageous as it would offer participants better opportunity to correct for an initial estimation error. PMID- 27221601 TI - The Simon Effect With Saccadic Eye Movements. AB - In the Simon effect performance is faster and more accurate when the task irrelevant spatial dimension of the stimulus corresponds to the location of the response, compared to when they do not correspond. In the prosaccade-antisaccade effect the latencies of saccades away from the stimulus location (i.e., antisaccades) are slower than the latencies of saccades toward the stimulus location (i.e., prosaccades). Because these two effects share a similar basis, the study of the Simon effect with saccadic eye movements needs to be decoupled from the prosaccade-antisaccade effect. A standard Simon task (Experiment 1) and a Simon task in which a distractor stimulus was also presented (Experiment 2) were implemented. In Experiment 1, results showed an effect likely attributable to the sum of the Simon effect and the prosaccade-antisaccade effect. In Experiment 2, in which the difference between the prosaccade and antisaccade was eliminated, only a Simon effect, cognitive in nature, manifested itself. PMID- 27221602 TI - Do Young Children Modulate Their Cognitive Control? AB - Dynamic, trial-by-trial modulations of inhibitory control are well documented in adults but rarely investigated in children. Here, we examined whether 5-to-7 year old children, an age range when inhibitory control is still partially immature, achieve such modulations. Fifty three children took flanker, Simon, and Stroop tasks. Above and beyond classic congruency effects, the present results showed two crucial findings. First, we found evidence for sequential modulations of congruency effects in these young children in the three conflict tasks. Second, our results showed both task specificities and task commonalities. These findings in young children have important implications as they suggest that, to be modulated, inhibitory control does not require full maturation and that the precise pattern of trial-by-trial modulations may depend on the nature of conflict. PMID- 27221603 TI - Moving Single Dots as Primes for Static Arrow Targets. AB - In response priming, responses are typically faster and more accurate if the prime calls for the same response as the target (i.e., compatible trials) than when primes and targets trigger different responses (i.e., incompatible trials). With moving rows-of-dots as primes for static arrow targets, participants instead responded faster to incompatible targets with longer SOAs (stimulus onset asynchrony, > 200 ms). Until now, it is unclear whether this effect is specific to the material. In the present research, a single moving dot was used as a prime. Further, we analyzed compatibility effects depending on reaction times (RTs). Positive compatibility effects in reaction times were found with an SOA of 147 ms and even with a relatively long SOA of 360 ms; for very long SOAs (800 1,200 ms), negative effects were found. We interpreted this as evidence that the specific type of motion is irrelevant for the occurrence of a negative compatibility effect. PMID- 27221604 TI - The Talbot Effect for two-dimensional massless Dirac fermions. AB - A monochromatic beam of wavelength lambda transmitted through a periodic one dimensional diffraction grating with lattice constant d will be spatially refocused at distances from the grating that are integer multiples of . This self refocusing phenomena, commonly referred to as the Talbot effect, has been experimentally demonstrated in a variety of systems ranging from optical to matter waves. Theoretical predictions suggest that the Talbot effect should exist in the case of relativistic Dirac fermions with nonzero mass. However, the Talbot effect for massless Dirac fermions (mDfs), such as those found in monolayer graphene or in topological insulator surfaces, has not been previously investigated. In this work, the theory of the Talbot effect for two-dimensional mDfs is presented. It is shown that the Talbot effect for mDfs exists and that the probability density of the transmitted mDfs waves through a periodic one dimensional array of localized scatterers is also refocused at integer multiples of zT. However, due to the spinor nature of the mDfs, there are additional phase shifts and amplitude modulations in the probability density that are most pronounced for waves at non-normal incidence to the scattering array. PMID- 27221605 TI - Economic downturns during the life-course and late-life health: an analysis of 11 European countries. AB - BACKGROUND: Research has shown that individual socio-economic circumstances throughout life affect health in older ages. However, little attention has been paid to the broad economic context affecting individual's life-chances. This paper examines whether economic downturns experienced during young and mid adulthood have long-run effects on physical health. METHODS: We exploit data on economic fluctuations in the period 1945-2010 in 11 European countries, linked to longitudinal data from three waves of the Survey of Health, Ageing and Retirement in Europe. We estimate a country fixed effect model assessing whether downturns experienced at 5-year intervals between ages 25 and 54 are associated with levels and onset of new limitations with Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) in older age (55-80). RESULTS: Experiencing an economic downturn at ages 45-59 is associated with increased risk of having at least one disability limitation in later-life (odds ratio [OR] for ADL = 1.66, 95% CI [Confidence Interval] 1.24, 2.22; OR for IADL = 1.46, 95% CI 1.10, 1.94). Economic downturns at ages 40-44 and 45-49 also increase the risk of a new functional limitation in later-life (OR for IADL ages 40-44 = 1.20, 95% CI 1.03, 1.40; OR for IADL ages 45-49 = 1.44, CI 1.10-1.88). Economic downturns experienced around these ages are also associated with significantly greater risks of smoking and excessive alcohol consumption as well as lower incomes in older age. CONCLUSIONS: Exposure to an economic downturn at ages 40-49 is associated with poorer health in older ages, possibly by increasing risk of unhealthy behaviours and low incomes persisting into older age. PMID- 27221606 TI - The impact of the housing crisis on self-reported health in Europe: multilevel longitudinal modelling of 27 EU countries. AB - BACKGROUND: Many EU nations experienced a significant housing crisis during the Great Recession of 2008-10. We evaluated the consequences of housing payment problems for people's self-reported overall health. METHODS: We used longitudinal data from the EU Statistics on Income and Living Conditions survey covering 27 countries from 2008 to 2010 to follow a baseline sample of persons who did not have housing debt and who were employed (45 457 persons, 136 371 person-years). Multivariate linear regression and multilevel models were used to evaluate the impact of transitions into housing arrears on self-reported health, correcting for the presence of chronic illness, health limitations, and other potential socio-demographic confounders. RESULTS: Persons who transitioned into housing arrears experienced a significant deterioration in self-reported overall health by - 0.03 U (95% CI - 0.01 to - 0.04), even after correcting for chronic illness, disposable income and employment status, and individual fixed effects. This association was independent and similar in magnitude to that for job loss (-0.02, 95% CI: -0.01 to - 0.04). We also found that the impact of housing arrears was significantly worse among renters, corresponding to a mean 0.11 unit additional drop in health as compared with owner-occupiers. These adverse associations were only evident in persons below the 75th percentile of disposable income. DISCUSSION: Our analysis demonstrates that persons who suffer housing arrears experience increased risk of worsening self-reported health, especially among those who rent. Future research is needed to understand the role of alternative housing support systems and available strategies for preventing the health consequences of housing insecurity. PMID- 27221607 TI - Socioeconomic inequalities in breast cancer incidence and mortality in Europe-a systematic review and meta-analysis. AB - BACKGROUND: Breast cancer is the leading cause of female cancer in Europe and is estimated to affect more than one in 10 women. Higher socioeconomic status has been linked to higher incidence but lower case fatality, while the impact on mortality is ambiguous. METHODS: We performed a systematic literature review and meta-analysis on studies on association between socioeconomic status and breast cancer outcomes in Europe, with a focus on effects of confounding factors. Summary relative risks (SRRs) were calculated. RESULTS: The systematic review included 25 articles of which 8 studied incidence, 10 case fatality and 8 mortality. The meta-analysis showed a significantly increased incidence (SRR 1.25, 1.17-1.32), a significantly decreased case fatality (SRR 0.72, 0.63-0.81) and a significantly increased mortality (SRR 1.16, 1.10-1.23) for women with higher socioeconomic status. The association for incidence became insignificant when reproductive factors were included. Case fatality remained significant after controlling for tumour characteristics, treatment factors, comorbidity and lifestyle factors. Mortality remained significant after controlling for reproductive factors. CONCLUSION: Women with higher socioeconomic status show significantly higher breast cancer incidence, which may be explained by reproductive factors, mammography screening, hormone replacement therapy and lifestyle factors. Lower case fatality for women with higher socioeconomic status may be partly explained by differences in tumour characteristics, treatment factors, comorbidity and lifestyle factors. Several factors linked to breast cancer risk and outcome, such as lower screening attendance for women with lower socioeconomic status, are suitable targets for policy intervention aimed at reducing socioeconomic-related inequalities in health outcomes. PMID- 27221608 TI - Geographic and socioeconomic differences in access to revascularization following acute myocardial infarction. AB - BACKGROUND: Geographic and socioeconomic barriers may hinder fair access to healthcare. This study assesses geographic and socioeconomic disparities in access to reperfusion procedures in acute myocardial infarction (AMI) patients residing in Piedmont (Italy). METHODS: Coronary Care Units (CCUs) were geocoded with a geographic information system (GIS) and the shortest drive time from CCUs to patients' residence was computed and categorized as 0 to <20, 20 to <40 and >=40 min. Using data on AMI emergency hospitalizations in 2004-2012, we employed a log-binomial regression model to evaluate the relation between drive time and use of Percutaneous Transluminal Coronary Angioplasty (PTCA) occurring within 2 days after a hospitalization for an episode of AMI, and whether this relation varied depending on the period of hospitalization. RESULTS: A total of 29% of all cases with a diagnosis of AMI (n = 66 097), were revascularized within 2 days from the index admission. The further AMI patients lived from CCUs, the less likely they were to receive revascularization: compared with distance <20 min, RRs were respectively 0.84 [95% CI 0.80-0.88] and 0.78 [95% CI 0.71-0.86]. Findings also showed that less educated people had a lower relative risk of being revascularized compared to more educated people (RR = 0.78; 95% CI = 0.74-0.82). Both inequalities have reduced in recent years. CONCLUSION: This study provides evidence of reduced geographical and socioeconomic differences in revascularization use over time. Geography and socioeconomic status should not determine the type of treatment received for life-threatening conditions such as AMI. PMID- 27221610 TI - Altered Expression of the Long Noncoding RNA NEAT1 in Huntington's Disease. AB - Huntington's disease (HD) is a devastating neurodegenerative disease caused by cytosine-adenine-guanine trinucleotide repeat expansion in the huntingtin gene. Growing evidence supports the regulatory functions of long noncoding RNAs (lncRNAs) in the disease process, but little is known about the association between lncRNAs and neuronal death in HD. Here, we evaluated the altered expression profiles of lncRNA in HD by using microarrays. Among dysregulated lncRNAs, we focused on the upregulation of nuclear paraspeckle assembly transcript 1 (NEAT1). Quantitative PCR analysis validated increased NEAT1 levels in the R6/2 mouse brain as well as the human HD postmortem brain. To determine the biological effects of NEAT1 on neuronal survival, neuro2A cells were transfected with the NEAT1 short isoform vector and were subjected to H2O2 induced injury. Subsequently, NEAT1-transfected cells showed increased viability under oxidative stress. Our observations support the notion that NEAT1 upregulation in HD contributes to the neuroprotective mechanism against neuronal injury rather than the pathological process underlying neurodegeneration in HD. PMID- 27221609 TI - Lamin A/C Is Required for ChAT-Dependent Neuroblastoma Differentiation. AB - The mouse neuroblastoma N18TG2 clone is unable to differentiate and is defective for the enzymes of the biosynthesis of neurotransmitters. The forced expression of choline acetyltransferase (ChAT) in these cells results in the synthesis and release of acetylcholine (Ach) and hence in the expression of neurospecific features and markers. To understand how the expression of ChAT triggered neuronal differentiation, we studied the differences in genome-wide transcription profiles between the N18TG2 parental cells and its ChAT-expressing 2/4 derived clone. The engagement of the 2/4 cells in the neuronal developmental program was confirmed by the increase of the expression level of several differentiation-related genes and by the reduction of the amount of transcripts of cell cycle genes. At the same time, we observed a massive reorganization of cytoskeletal proteins in terms of gene expression, with the accumulation of the nucleoskeletal lamina component Lamin A/C in differentiating cells. The increase of the Lmna transcripts induced by ChAT expression in 2/4 cells was mimicked treating the parental N18TG2 cells with the acetylcholine receptor agonist carbachol, thus demonstrating the direct role played by this receptor in neuron nuclei maturation. Conversely, a treatment of 2/4 cells with the muscarinic receptor antagonist atropine resulted in the reduction of the amount of Lmna RNA. Finally, the hypothesis that Lmna gene product might play a crucial role in the ChAT-dependent molecular differentiation cascade was strongly supported by Lmna knockdown in 2/4 cells leading to the downregulation of genes involved in differentiation and cytoskeleton formation and to the upregulation of genes known to regulate self-renewal and stemness. PMID- 27221611 TI - The Contributions of the Ribosome Biogenesis Protein Utp5/WDR43 to Craniofacial Development. AB - Fairly recently, it was recognized that human ribosomopathies-developmental defects caused by mutations in ribosome biogenesis proteins-can exhibit tissue specific defects rather than the expected global defects. This apparent anomaly that seemingly ubiquitously expressed and required ribosomal proteins can have distinct functions in cell and tissue differentiation-has spurred new areas of research focused on better understanding translational mechanisms, biogenesis, and function in diverse cell types. This renewed appreciation for, and need to better understand, roles for ribosomal proteins in human development and disease has identified surprising similarities and differences in a variety of human ribosomopathies. Here, we discuss ribosomal protein functions in health and disease, focusing on the ribosome biogenesis protein Utp5/WDR43. New and exciting research in this field is anticipated to provide insight into a variety of previously understudied craniofacial dysostoses and result in significantly improved knowledge and understanding of roles for translational machinery in human craniofacial development and disease. PMID- 27221612 TI - Letter to the Editor: Composites-The Best Choice for Load-Bearing Cavitated Lesions in Permanent Teeth? PMID- 27221613 TI - Response to Letter to the Editor: Composites-The Best Choice for Load-Bearing Cavitated Lesions in Permanent Teeth? PMID- 27221614 TI - A new non-muscle-invasive bladder tumor-homing peptide identified by phage display in vivo. AB - Bladder cancer is common and widespread, and its incidence is increasing. Many new diagnostic methods combined with state-of-the-art technology have been introduced in cystoscopy to collect real-time images of the bladder mucosa for diagnosis, but often miss inconspicuous early-stage tumors. Fluorophore-labeled peptides with high sensitivity and specificity for cancer would be a desirable tool for the detection and treatment of tiny or residual bladder tumors. Phage display and the human non-muscle-invasive bladder cancer cell line BIU-87 were used to identify a peptide. The isolated phage display peptide (CSSPIGRHC, named NYZL1) was tested in vitro for its binding specificity and affinity. Accumulation into xenograft tumors in a nude mouse model was analyzed with FITC-labeled NYZL1. NYZL1, with strong tumor-homing ability, was identified by in vivo phage library selection in the bladder cancer model. The NYZL1 phage and synthetic FITC-labeled NYZL1 peptides bound to tumor tissues and cells, but were hardly detected in normal control organs. Notably, accumulation of FITC-NYZL1 in bladder tumor cells was time-dependent. Biodistribution studies of xenografts of BIU-87 cells showed accumulation of injected FITC-NYZL1 in the tumors, and the bound peptide could not be removed by perfusion after 24 h. The mouse model of bladder tumor showed increased fluorescence intensity in the tumor-bearing bladder in comparison with normal bladder tissues after 4-6 h. In conclusion, NYZL1 may represent a lead peptide structure applicable in the development of optical molecular imaging. PMID- 27221616 TI - Calcium, Metaphors, and Zeitgeist in Plant Sciences. PMID- 27221615 TI - Impact of vitamin D deficiency on maternal and birth outcomes in the Saudi population: a cross-sectional study. AB - BACKGROUND: Low serum vitamin D [25(OH)D] has been associated with different health problems worldwide. However, its causal role in several diseases remains unclear. We aimed to correlate vitamin D status with maternal and neonatal outcomes in pregnant females. METHOD: One thousand pregnant women were recruited during early labour from the labour ward of King Khaled University Hospital, Riyadh, Saudi Arabia. Detailed medical data of all participants were collected from their records. Delivery events and birth outcomes were also documented. Serum 25(OH)D levels were measured using an enzyme-linked immunosorbent assay. A receiver operating characteristic (ROC) curve was constructed to evaluate the ability of vitamin D levels to predict complicated pregnancies. Regression analysis was used to test the correlation between serum 25(OH)D levels and different variables. RESULTS: Most of the participants were Saudis (89.9 %) and housewives (85.1 %) and 86.4 % of them had vitamin D deficiency (mean: 30.46 +/- 19.6 nmol/L). Gestational diabetes mellitus (GDM) was the commonest complication detected (11.1 %) while the history of miscarriage was elevated (24.5 %). There was no association between GDM and low 25(OH)D. Yet, there was a significant negative correlation between serum 25(OH)D levels and fasting blood glucose among females older than 35 years (r = -0.2, p = 0.03). Hypertensive disorders of pregnancy and pre-existing hypertension were less than 1.5 % of frequency. Nevertheless, they were only recorded in women with insufficient and deficient vitamin D. ROC curve revealed that 25(OH)D levels were not able to discriminate between normal and adverse pregnancy outcomes (AUROC curve: 0.51; 95 % confidence interval (CI): 0.44-0.58; p = 0.8). CONCLUSION: Hypovitaminosis D, a highly prevalent health problem among pregnant females in Riyadh, has no relation to adverse pregnancy outcomes except for a higher prevalence of miscarriage in women with low 25(OH)D. PMID- 27221617 TI - The Transcription Factor NIN-LIKE PROTEIN7 Controls Border-Like Cell Release. AB - The root cap covers the tip of the root and functions to protect the root from environmental stress. Cells in the last layer of the root cap are known as border cells, or border-like cells (BLCs) in Arabidopsis (Arabidopsis thaliana). These cells separate from the rest of the root cap and are released from its edge as a layer of living cells. BLC release is developmentally regulated, but the mechanism is largely unknown. Here, we show that the transcription factor NIN LIKE PROTEIN7 (NLP7) is required for the proper release of BLCs in Arabidopsis. Mutations in NLP7 lead to BLCs that are released as single cells instead of an entire layer. NLP7 is highly expressed in BLCs and is activated by exposure to low pH, a condition that causes BLCs to be released as single cells. Mutations in NLP7 lead to decreased levels of cellulose and pectin. Cell wall-loosening enzymes such as CELLULASE5 (CEL5) and a pectin lyase-like gene, as well as the root cap regulators SOMBRERO and BEARSKIN1/2, are activated in nlp7-1 seedlings. Double mutant analysis revealed that the nlp7-1 phenotype depends on the expression level of CEL5 Mutations in NLP7 lead to an increase in susceptibility to a root-infecting fungal pathogen. Together, these data suggest that NLP7 controls the release of BLCs by acting through the cell wall-loosening enzyme CEL5. PMID- 27221618 TI - Force measurements reveal how small binders perturb the dissociation mechanisms of DNA duplex sequences. AB - The force-driven separation of double-stranded DNA is crucial to the accomplishment of cellular processes like genome transactions. Ligands binding to short DNA sequences can have a local stabilizing or destabilizing effect and thus severely affect these processes. Although the design of ligands that bind to specific sequences is a field of intense research with promising biomedical applications, so far, their effect on the force-induced strand separation has remained elusive. Here, by means of AFM-based single molecule force spectroscopy, we show the co-existence of two different mechanisms for the separation of a short DNA duplex and demonstrate how they are perturbed by small binders. With the support of Molecular Dynamics simulations, we evidence that above a critical pulling rate one of the dissociation pathways becomes dominant, with a dramatic effect on the rupture forces. Around the critical threshold, we observe a drop of the most probable rupture forces for ligand-stabilized duplexes. Our results offer a deep understanding of how a stable DNA-ligand complex behaves under force driven strand separation. PMID- 27221619 TI - Bifurcation analysis of a two-compartment hippocampal pyramidal cell model. AB - The Pinsky-Rinzel model is a non-smooth 2-compartmental CA3 pyramidal cell model that has been used widely within the field of neuroscience. Here we propose a modified (smooth) system that captures the qualitative behaviour of the original model, while allowing the use of available, numerical continuation methods to perform full-system bifurcation and fast-slow analysis. We study the bifurcation structure of the full system as a function of the applied current and the maximal calcium conductance. We identify the bifurcations that shape the transitions between resting, bursting and spiking behaviours, and which lead to the disappearance of bursting when the calcium conductance is reduced. Insights gained from this analysis, are then used to firstly illustrate how the irregular spiking activity found between bursting and stable spiking states, can be influenced by phase differences in the calcium and dendritic voltage, which lead to corresponding changes in the calcium-sensitive potassium current. Furthermore, we use fast-slow analysis to investigate the mechanisms of bursting and show that bursting in the model is dependent on the intermediately slow variable, calcium, while the other slow variable, the activation gate of the afterhyperpolarisation current, does not contribute to setting the intraburst dynamics but participates in setting the interburst interval. Finally, we discuss how some of the described bifurcations affect spiking behaviour, during sharp-wave ripples, in a larger network of Pinsky-Rinzel cells. PMID- 27221620 TI - Effects of Composition and Mechanical Property of Injectable Collagen I/II Composite Hydrogels on Chondrocyte Behaviors. AB - Satisfactory repair of damaged articular cartilage is still a challenge, while tissue engineering provides a promising strategy. Collagen-based hydrogels have been widely applied in cartilage tissue engineering due to their biocompatibility. In this study, type I collagen and type II collagen were selected to prepare physically crosslinked composite hydrogels by self-assembly of collagen, and the effects of their physicochemical properties on chondrocyte phenotype maintenance and extracellular matrix (ECM) secretion were investigated. First, the microstructure of hydrogels was observed by a scanning electron microscope, and the compressive modulus was measured by a dynamic mechanical analyzer. Then, chondrocytes were encapsulated in hydrogels and detected by Live/Dead staining. The secretion of ECM was qualitatively estimated by histological staining and quantitatively analyzed by sulfated glycosaminoglycans and DNA content detection. Finally, cartilage-specific gene expression was analyzed by quantitative real-time polymerase chain reaction analysis. The results showed that the microstructure and mechanical property of hydrogels were relevant to the composition of composite hydrogels. The compressive modulus of hydrogels improved with the increase of type I collagen content in the hydrogels. Chondrocytes could maintain their round or oval morphology and secrete cartilage specific ECM in the four groups of hydrogels, but higher the compressive modulus of composite hydrogels, the more ECM secretion of chondrocytes. PMID- 27221621 TI - Kinectin-dependent ER transport supports the focal complex maturation required for chemotaxis in shallow gradients. AB - Chemotaxis in shallow gradients of chemoattractants is accomplished by preferential maintenance of protrusions oriented towards the chemoattractant; however, the mechanism of preferential maintenance is not known. Here, we test the hypothesis that kinectin-dependent endoplasmic reticulum (ER) transport supports focal complex maturation to preferentially maintain correctly oriented protrusions. We knocked down kinectin expression in MDA-MB-231 cells using small interfering RNA and observed that kinectin contributes to the directional bias, but not the speed, of cell migration. Kymograph analysis revealed that the extension of protrusions oriented towards the chemoattractant was not affected by kinectin knockdown, but that their maintenance was. Immunofluorescence staining and live-cell imaging demonstrated that kinectin transports ER preferentially to protrusions oriented towards the chemoattractant. ER then promotes the maturation of focal complexes into focal adhesions to maintain these protrusions for chemotaxis. Our results show that kinectin-dependent ER distribution can be localized by chemoattractants and provide a mechanism for biased protrusion choices during chemotaxis in shallow gradients of chemoattractants. PMID- 27221622 TI - Evidence for Inflammation-Associated Depression. AB - This chapter explores the evidence supporting inflammation-associated depression. Data to date suggest a bidirectional relationship between inflammation and depression wherein one process can drive the other. A wealth of animal and clinical studies have demonstrated an association between concentrations of pro inflammatory cytokines - specifically interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha - and depressive symptoms. There is also evidence that this pro-inflammatory state is accompanied by aberrant inflammation-related processes including platelet activation factor hyperactivity, oxidative and nitrosative stress, and damage to mitochondria. These complex and interrelated mechanisms can collectively contribute to negative neurobiological outcomes that may, in part, underlie the etiopathology of depression. Mounting evidence has shown a concomitant reduction in both depressive symptoms and pro-inflammatory cytokine concentrations following treatment with pharmacological anti-inflammatory interventions. Taken together, the reviewed preclinical and clinical findings may suggest the existence of a distinct inflammatory subtype of depression in which these patients exhibit unique biochemical and clinical features and may potentially experience improved clinical outcomes with inflammation-targeted pharmacotherapy. PMID- 27221623 TI - Suicidality and Activation of the Kynurenine Pathway of Tryptophan Metabolism. AB - A recent report by the World Health Organization declared suicide to be a major global problem. With more than 800,000 lives lost each year, suicide is calculated to be the 14th leading cause of death around the world. While the biological mechanisms causing suicidal ideation and behavior are not fully understood, increased levels of inflammation, arising from various sources, have been detected in the central nervous system and the peripheral blood of suicidal patients and suicide completers. Inflammation induces the kynurenine pathway of tryptophan metabolism, which generates a range of metabolites with potent effects on neurotransmitter systems as well as on inflammation. Recent evidence indicates that a dysregulation of the enzymes in the kynurenine pathway may be present in suicidal patients, with a resulting imbalance of metabolites that modulate glutamate neurotransmission and neuroinflammation. As the body of research in these areas grows, targeting the kynurenine pathway enzymes and metabolites may provide novel therapeutic opportunities for detection, treatment, and ultimately prevention of suicidal behavior. PMID- 27221624 TI - Conditioned Taste Avoidance Drug Discrimination Procedure: Assessments and Applications. AB - In the present chapter, we summarize much of the work on the taste avoidance drug discrimination procedure, presenting the logic for its initial introduction and the extension of the procedure in the investigation of the discriminative properties of various drugs. Results from these assessments parallel those from more traditional operant and maze designs in classifying and characterizing the discriminative properties of drug. At the same time, this design reveals a procedure that is sensitive in such assessments by indexing these stimulus properties more rapidly and at lower doses than in the more traditional procedures (in some cases for drugs heretofore resistant in their detection). Importantly, much remains to be learned about the taste avoidance procedure in that the nature of such learning remains unknown and the specific parameters under which it can be established and generalized and its neurochemical and neuroanatomical bases are largely unexplored. The application of drug discrimination learning to human drug abuse continues to be an important consideration for this specific design (as well as that of drug discrimination procedures in general), and recent parallels between drug use and food intake in terms of its regulation by interoceptive stimuli suggests a possible role of the loss of stimulus control in drug escalation and addiction (with possible therapeutic implications via the modulation of these interoceptive cues). PMID- 27221625 TI - Depression in Autoimmune Diseases. AB - Up to 50% of patients with autoimmune diseases show an impairment of health related quality of life and exhibit depression-like symptoms. The immune system not only leads to inflammation in affected organs, but also mediates behavior abnormalities including fatigue and depression-like symptoms. This review focuses on the different pathways involved in the communication of the immune system with the neuronal network and the body's timing system. The latter is built up by a hierarchically organized expression of clock genes. As discussed here, the activation of the immune system interferes with high amplitude expression of clock genes, an effect which may play a pivotal role in depression-like behavior in autoimmune diseases. PMID- 27221626 TI - Role of Inflammation in the Development of Neuropsychiatric Symptom Domains: Evidence and Mechanisms. AB - The finding that inflammatory markers are elevated in various neuropsychiatric disorders raises the need of identifying the precise research domain criteria driven by inflammation. Based on the model of inflammation-induced depression it has been possible to identify distinct pathophysiological pathways leading to alterations in neurotransmitter metabolism with specific relevance for the development of symptom constellations that are common to various neuropsychiatric and neurodegenerative conditions. Moreover, converging data indicate that these pathways interact with relevant vulnerability factors and modulatory systems to ultimately impact the presentation of inflammation-driven neuropsychiatric symptoms. Altogether, these findings make inflammation a key pivotal factor in psychopathology. Developing treatments that target inflammation and modulate the pathways and systems by which inflammatory processes selectively affect brain function will be of particular relevance for the treatment of specific neurobehavioral symptom domains. PMID- 27221627 TI - Role of Kynurenine Metabolism Pathway Activation in Major Depressive Disorders. AB - A proportion of depressed individuals show evidence of inflammation. Both animal, quasi-experimental, and longitudinal studies indicate that inflammatory processes may play a causal role in the developmental of depressive illness. While there may be multiple causal pathways through which inflammatory processes affect mood, activation of the kynurenine pathway is essential for the development of depression-like behavior in rodents. Studies of hepatitis C or cancer patients receiving treatment with inflammation-inducing medications show increased activation of the kynurenine pathway and decreased levels of tryptophan that correlate with inflammation-induced depression. Further, this treatment has been shown to lead to increased production of neurotoxic kynurenine pathway metabolites such as quinolinic acid (QA). Similarly, in non-medically ill patients with major depression, multiple studies have found activation of the kynurenine pathway and/or preferential activation of the neurotoxic (QA) pathway at the expense of the production of the NMDA antagonist, kynurenic acid. Initially, activation of the kynurenine pathway was believed to precipitate depressive symptoms by depleting brain serotonin, however, the weight of the evidence now suggests that an imbalance between neurotoxic and neuroprotective metabolites may be the principal driver of depression; conceivably via its effects on glutamatergic neurotransmission. PMID- 27221628 TI - Integrating Human Immunodeficiency Virus and Reproductive, Maternal and Child, and Tuberculosis Health Services Within National Health Systems. AB - Joint United Nations Programme on HIV/AIDS (UNAIDS) established 90-90-90 HIV treatment targets for 2020 including the following: 90 % of HIV-infected people know their HIV status, 90 % of HIV-infected people who know their status are on treatment, and 90 % of people on HIV treatment have a suppressed viral load. Integration of HIV and other programs into the national health system provides an important pathway to reach those targets. We examine the case for integrating HIV and other health services to ensure sustainability and improve health outcomes within national health systems. In this non-systematic review, we examined recent studies on integrating HIV, tuberculosis (TB), maternal-child health (MCH), and sexually transmitted infection (STI) programs. Existing evidence is limited about the effectiveness of integration of HIV and other services. Most studies found that service integration increased uptake of services, but evidence is mixed about the effect on health outcomes or quality of health services. More rigorous studies of different strategies to promote integration over a wider range of services and settings are needed. Research on how best to maximize benefits, including sustainability, of integrated services is necessary to help inform international and national policy. We recommend additional interventions to test how best to integrate HIV and MCH services, HIV and TB services, HIV testing and treatment, and STI testing and treatment. PMID- 27221629 TI - Lipopolysaccharide-induced podocyte injury is mediated by suppression of autophagy. AB - High-level autophagy has an important role in maintaining the stable state of podocytes. The present study explored the influence of lipopolysaccharide (LPS) on autophagic activity in podocytes and demonstrated its mechanistic involvement in LPS-induced injury. Conditionally immortalized podocytes were cultured in vitro and were treated with chloroquine (CQ), LPS, LPS+rapamycin or LPS+3 methyladenine (3-MA). The autophagic vesicles and endoplasmic reticulum were observed using transmission electron microscopy. The tandem mRFP-GFP-LC3 adenovirus was used to detect autophagosomes and autolysosomes. The expression levels of light chain 3-II (LC3 II), beclin-1, P62, CCAAT-enhancer-binding protein homologous protein (CHOP) and podocin were determined by western blot analysis. Autophagic vesicles were detected in podocytes under basic conditions. CQ was found to increase the protein levels of LC3 II in a time-dependent manner (2, 4 or 6 h), confirming the high activity of autophagy in podocytes. Compared with the control group, LPS induced the expansion of the endoplasmic reticulum and high expression levels of CHOP, while decreasing the protein expression of podocin. Notably, podocytes treated with LPS showed decreases in LC3 II and beclin-1 levels and autophagosome/autolysosome numbers, which was accompanied by high P62 levels. Furthermore, the autophagy enhancer rapamycin reversed the downregulation of LC3 II and podocin, and the upregulation of CHOP induced by LPS, while the autophagy inhibitor 3-MA aggravated the effects of LPS. In conclusion, the present study demonstrated that LPS inhibited podocyte autophagy, which contributed to LPS-induced injury of podocytes. PMID- 27221630 TI - Health effects following subacute exposure to geogenic dusts from arsenic-rich sediment at the Nellis Dunes Recreation Area, Las Vegas, NV. AB - Geogenic dust from arid environments is a possible inhalation hazard for humans, especially when using off-road vehicles that generate significant dust. This study focused on immunotoxicological and neurotoxicological effects following subacute exposure to geogenic dust generated from sediments in the Nellis Dunes Recreation Area near Las Vegas, Nevada that are particularly high in arsenic; the naturally-occurring arsenic concentrations in these surficial sediments ranged from 4.8 to 346MUg/g. Dust samples from sediments used in this study had a median diameter of 4.5MUm and also were a complex mixture of naturally-occurring metals, including aluminum, vanadium, chromium, manganese, iron, cobalt, copper, zinc, strontium, cesium, lead, uranium, and arsenic. Adult female B6C3F1 mice exposed via oropharyngeal aspiration to 0.01 to 100mg dust/kg body weight, four times, a week apart, for 28days, were evaluated 24h after the last exposure. Peripheral eosinophils were increased at all concentrations, serum creatinine was dose responsively increased beginning at 1.0mg/kg/day, and blood urea nitrogen was decreased at 10 and 100mg/kg/day. Antigen-specific IgM responses and natural killer cell activity were dose-responsively suppressed at 0.1mg/kg/day and above. Splenic CD4+CD25+ T cells were decreased at 0.01, 0.1, 10, and 100mg/kg/day. Antibodies against MBP, NF-68, and GFAP were selectively reduced. A no observed adverse effect level of 0.01mg/kg/day and a lowest observed adverse effect level of 0.1mg/kg/day were determined from IgM responses and natural killer cell activity, indicating that exposure to this dust, under conditions similar to our design, could affect these responses. PMID- 27221631 TI - TCDD modulation of gut microbiome correlated with liver and immune toxicity in streptozotocin (STZ)-induced hyperglycemic mice. AB - An increasing body of evidence has shown the important role of the gut microbiome in mediating toxicity following environmental contaminant exposure. The goal of this study was to determine if the adverse metabolic effects of chronic 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) exposure would be sufficient to exacerbate hyperglycemia, and to further determine if these outcomes were attributable to the gut microbiota alteration. Adult male CD-1 mice were exposed to TCDD (6MUg/kg body weight biweekly) by gavage and injected (i.p.) with STZ (4*50mg/kg body weight) to induced hyperglycemia. 16S rRNA sequencing was used to characterize the changes in the microbiome community composition. Glucose monitoring, flow cytometry, histopathology, and organ characterization were performed to determine the deleterious phenotypic changes of TCDD exposure. Chronic TCDD treatment did not appear to exacerbate STZ-induced hyperglycemia as blood glucose levels were slightly reduced in the TCDD treated mice; however, polydipsia and polyphagia were observed. Importantly, TCDD exposure caused a dramatic change in microbiota structure, as characterized at the phylum level by increasing Firmicutes and decreasing Bacteroidetes while at the family level most notably by increasing Lactobacillaceae and Desulfovibrionaceae, and decreasing Prevotellaceae and ACK M1. The changes in microbiota were further found to be broadly associated with phenotypic changes seen from chronic TCDD treatment. In particular, the phylum level Bacteroidetes to Firmicutes ratio negatively correlated with both liver weight and liver pathology, and positively associated with %CD3(+)NK(+) T cells, a key mediator of host-microbial interactions. Collectively, these findings suggest that the dysregulated gut microbiome may contribute to the deleterious effects (e.g., liver toxicity) seen with TCDD exposure. PMID- 27221632 TI - Gay-Straight Alliances are Associated with Lower Levels of School-Based Victimization of LGBTQ+ Youth: A Systematic Review and Meta-analysis. AB - Gay-straight alliances (GSAs) are school-based organizations for lesbian, gay, bisexual, transgender, and queer (LGBTQ+) youth and their allies that often attempt to improve school climate for sexual and gender minority youth. This meta analysis evaluates the association between school GSA presence and youth's self reports of school-based victimization by quantitatively synthesizing 15 primary studies with 62,923 participants. Findings indicate GSA presence is associated with significantly lower levels of youth's self-reports of homophobic victimization, fear for safety, and hearing homophobic remarks, and these results are robust, controlling for a variety of study-level factors. The findings of this meta-analysis provide evidence to support GSAs as a means of protecting LGTBQ+ youth from school-based victimization. PMID- 27221633 TI - Regulation of striatal astrocytic receptor for advanced glycation end-products variants in an early stage of experimental Parkinson's disease. AB - Convincing evidence indicates that advanced glycation end-products and danger associated protein S100B play a role in Parkinson's disease (PD). These agents operate through the receptor for advanced glycation end-products (RAGE), which displays distinct isoforms playing protective/deleterious effects. However, the nature of RAGE variants has been overlooked in PD studies. Hence, we attempted to characterize RAGE regulation in early stages of PD striatal pathology. A neurotoxin-based rodent model of PD was used in this study, through administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to C57BL/6 mice. Animals were killed 6 h post-MPTP to assess S100B/RAGE contents (RT-qPCR, ELISA) and RAGE isoform density (WB) and cellular distribution (immunohistochemistry). Dopaminergic and gliotic status were also mapped (HPLC ED, WB, immunohistochemistry). At this preliminary stage of MPTP-induced PD in mice, RAGE inhibitory isoforms were increased whereas full-length RAGE was not affected. This putative cytoprotective RAGE phenotype paired an inflammatory and pro-oxidant setting fueling DAergic denervation. Increased RAGE inhibitory variants occur in astrocytes showing higher S100B density but no overt signs of hypertrophy or NF-kappaB activation, a canonical effector of RAGE. These findings expand our understanding of the toxic effect of MPTP on striatum and offer first in vivo evidence of RAGE being a responder in early stages of astrogliosis dynamics, supporting a protective rather tissue-destructive phenotype of RAGE in the initial phase of PD degeneration. These data lay the groundwork for future studies on the relevance of astrocytic RAGE in DAergic neuroprotection strategies. We report increased antagonistic RAGE variants paralleling S100B up regulation in early stages of MPTP-induced astrogliosis dynamics . We propose that selective RAGE regulation reflects a self-protective mechanism to maintain low levels of RAGE ligands , preventing long-term inflammation and oxidative stress arising from sustained ligands/flRAGE activation . Understanding loss of RAGE protective response to stress may provide new therapeutic options to halt or slow down dopaminergic axonopathy and, ultimately, neuronal death . PMID- 27221634 TI - 4-Hydroxybutenolide impairs cell migration, and invasion of human oral cancer SCC 4 cells via the inhibition of NF-kappaB and MAPK signaling pathways. AB - 4-Hydroxybutenolide (K87), a synthetic compound from furfuryl alcohol via photooxidation, was used to investigate whether it can inhibit mobility, migration and invasion of SCC-4 human oral cancer cells in vitro. Cell viability was measured by flow cytometric assay, the enzymatic activities of MMP-2/9 were assayed by gelatin zymography analysis, the protein levels were assayed by western blotting, confocal laser microscopy and EMSA assay, and the gene expression of MMP-2/-7, FAK and ROCK1 mRNA were assayed by PCR. K87 decreased the percentage of viable cells in dose-dependent manner. K87 suppressed cell mobility, migration and invasion of SCC-4 cells dose-dependently. K87 inhibited the enzymatic activities of MMP-2/9 of SCC-4 cells. Western blot analysis revealed that K87 decreased the protein levels in NF-kappaBp65, COX-2, ROCK1 and Rho A, MMP-1, -2,- 7, -9, VEGF, GRB2, SOS1, PI3K, PKC, PERK, p-PERK, FAK, MEKK3, MKK7, ERK1/2, JNK1/2, p-p38, p38, p-c-Jun, AKT, TIMP2, but increased the protein levels of iNOS, Ras, IRE-1alpha, p-c-JNK, p-AKT(308), p-AKT(473) and TIMP1. Results from PCR indicated that K87 inhibited the gene expression of MMP-2/-7, FAK and ROCK1 mRNA. Furthermore, confocal laser microscopy was used to confirm that K87 inhibited the translocation of RHOA and ROCK1 in SCC-4 cells. EMSA assay also show that K87 suppressed the nuclear activation of NF-kappaB and these effects are time-dependent. Western blotting assay indicated that expression of NF-kappaBp105, NF-kappaBp50 and NF-kappaBp65 proteins were decreased and these effects are time-dependent. Based on these observations, we suggest that K87 may be used as a potential agent for anticancer metastasis of human oral cancer in the future. PMID- 27221636 TI - [Erratum to: Mimic activity of differentiated pain intensities. Correlation of characteristics of Facial Action Coding System and electromyography]. PMID- 27221635 TI - Cerebrospinal fluid lactate levels and brain [18F]FDG PET hypometabolism within the default mode network in Alzheimer's disease. AB - PURPOSE: It has been suggested that neuronal energy metabolism may be involved in Alzheimer's disease (AD). In this view, the finding of increased cerebrospinal fluid (CSF) lactate levels in AD patients has been considered the result of energetic metabolism dysfunction. Here, we investigated the relationship between neuronal energy metabolism, as measured via CSF lactate levels, and cerebral glucose metabolism, as stated at the 2-deoxy-2-(18F)fluoro-D-glucose positron emission tomography ([18F]FDG PET) in AD patients. METHODS: AD patients underwent lumbar puncture to measure CSF lactate levels and [18F]FDG PET to assess brain glucose metabolism. CSF and PET data were compared to controls. Since patients were studied at rest, we specifically investigated brain areas active in rest condition owing to the Default Mode Network (DMN). We correlated the CSF lactate concentrations with the [18F]FDG PET data in brain areas owing to the DMN, using sex, age, disease duration, Mini Mental State Examination, and CSF levels of tau proteins and beta-amyloid as covariates. RESULTS: AD patients (n = 32) showed a significant increase of CSF lactate levels compared to Control 1 group (n = 28). They also showed brain glucose hypometabolism in the DMN areas compared to Control 2 group (n = 30). Within the AD group we found the significant correlation between increased CSF lactate levels and glucose hypometabolism in Broadman areas (BA) owing to left medial prefrontal cortex (BA10, mPFC), left orbitofrontal cortex (BA11, OFC), and left parahippocampal gyrus (BA 35, PHG). CONCLUSION: We found high CSF levels of lactate and glucose hypometabolism within the DMN in AD patients. Moreover, we found a relationship linking the increased CSF lactate and the reduced glucose consumption in the left mPFC, OFC and PHG, owing to the anterior hub of DMN. These findings could suggest that neural glucose hypometabolism may affect the DMN efficiency in AD, also proposing the possible role of damaged brain energetic machine in impairing DMN. PMID- 27221638 TI - [Not Available]. PMID- 27221637 TI - [A uniform structure for provision of pain medicine in Germany]. PMID- 27221639 TI - Why didn't I know? Perspectives from adult children of elderly parents with dementia. AB - PURPOSE: Approximately 27 million adults are living with undiagnosed dementia worldwide. The purpose of this study was to learn about the experiences of adult children of elderly parents who were ultimately diagnosed with dementia. DATA SOURCES: A descriptive qualitative design was used for identifying if there were prodromal signs or symptoms that preceded the more commonly known warning signs of dementia. Twelve, 60-min interviews were conducted over the telephone. CONCLUSIONS: The overarching theme was: "Why didn't I know?" Subthemes were "We ignored it because we didn't want it to be," "We thought it was grief," and "They wouldn't diagnose dementia." Normal aging changes often mask the identification of mild cognitive impairment (MCI) and dementia. Healthcare providers should screen patients for dementia when cognitive concerns or changes become apparent. IMPLICATIONS FOR PRACTICE: The General Practitioner Assessment of Cognition and the Mini-Cog can be used for screening cognitive changes. Since depression may be misinterpreted as dementia, screening for depression should also be included if there is a potential for overlap. This is important in those patients who are experiencing grief, as many signs and symptoms of early grief are the same as early dementia. PMID- 27221640 TI - Residual increased valgus stress angulation and posterolateral rotatory translation after simple elbow dislocation. AB - PURPOSE: Purpose of this study was to evaluate increased valgus stress angulation and increased posterolateral rotatory translation after simple elbow dislocation and the associated clinical instability. METHODS: Ten patients [three women, seven men; mean age 38 +/- 11 years; mean follow-up 54 months (median 47 months; range 23-111 months)] with conservatively treated simple elbow dislocations were included into this study. The elbow function was graded by using the subjective elbow value (SEV), the Oxford Elbow Score (OES), the Mayo Elbow Performance Score (MEPS), as well as the DASH Score. Range of motion (ROM) and clinical signs of valgus and posterolateral rotatory instability (PLRI) were evaluated. Additionally, in all patients sonographic and fluoroscopic evaluation of valgus stress angulation and posterolateral rotatory translation was performed. RESULTS: Functional scores showed excellent to good results in all patients (SEV: 92 %; OES: mean 44 +/- 5 points; MES: mean 91 +/- 9 points; DASH Score: mean, 4 +/- 4 points). The ROM did not reveal any significant differences compared to the non affected side. Overall, three patients presented signs of clinical instability (valgus instability: n = 1; PLRI: n = 2). Sonographically, a slightly but not significantly increased valgus stress angulation in comparison with the non affected side was measured (n.s.). The posterolateral rotatory translation was significantly increased compared to the non-affected side (p < 0.05). In this context, sonographically, four of ten patients revealed a valgus stress angulation and seven of ten patients a posterolateral rotatory translation more than 50 % compared to the non-affected. In four patients an increased valgus stress angulation and in four patients an increased posterolateral rotatory translation could be seen fluoroscopically. CONCLUSION: Patients after conservatively treated simple elbow dislocations show good clinical and functional results. However, a sufficient anatomical ligamentary heeling does not exist. LEVEL OF EVIDENCE: IV. PMID- 27221641 TI - Long-term follow-up of isolated ACL tears treated without ligament reconstruction. AB - PURPOSE: The incidence of subsequent meniscal tears and arthritis among patients with isolated ACL tears treated without ligament reconstruction has not been clearly established. The purpose of this study was to (1) compare the risk of subsequent meniscal tears and osteoarthritis (OA) between patients with isolated ACL tears treated without ligament reconstruction and a matched cohort of individuals without ACL tears and (2) examine factors predictive of long-term sequelae after non-operative treatment of isolated ACL tears. METHODS: This study compared a population-based incidence cohort of 364 patients with new-onset, isolated ACL tears between 1990 and 2000, to an age and sex-matched cohort of 364 individuals without ACL tears. A chart review was performed to collect information related to the initial injury, treatment, and outcomes. Subjects were retrospectively followed for mean follow-up of 14.3 years (+/-7.4 years) to determine the development of subsequent meniscal injury, arthritis, or total knee arthroplasty (TKA). RESULTS: Patients treated without ligament reconstruction after ACL tears had a significantly higher risk of secondary meniscal tears (HR 18.0, 95 % CI 9.7, 33.3), arthritis (HR 14.2, 95 % CI 8.0, 25.2), and need of TKA (HR 5.0, 95 % CI 2.1, 12.2) than individuals without ACL tears. Lateral meniscal tear at diagnosis was associated with a higher risk of arthritis (HR 2.7, 95 % CI 1.4, 5.7) and TKA (HR 4.3, 95 % CI 1.3, 13.7). Treatment with meniscectomy was associated with an increased risk of additional meniscal tears (HR 51.5, 95 % CI 10.3, 936.8). CONCLUSIONS: Patients treated non-operatively after isolated ACL tears are at a significantly higher risk of secondary meniscal tears, arthritis, and TKA when compared to age and sex-matched subjects without ACL tears. Additionally, baseline lateral meniscal tears were significantly associated with an increased probability of developing arthritis and the need for TKA. This information may be helpful when counselling patients about the natural history of ACL tears treated without ligament reconstruction. LEVEL OF EVIDENCE: III. PMID- 27221642 TI - Iptakalim influences the proliferation and apoptosis of human pulmonary artery smooth muscle cells. AB - The aim of the present study was to determine the effect of an ATP-sensitive K+ (KATP) channel opener iptakalim (IPT) on the proliferation and apoptosis of human pulmonary artery smooth muscle cells (HPASMCs), and examine the potential value of IPT to hypoxic pulmonary hyper-tension (HPH) at a cellular level. HPASMCs were divided into the control, ET-1, ET-1+IPT and ET-1+IPT+glibenclamide (GLI) groups. GLI was administered 30 min prior to ET-1 and IPT. The 4 groups were incubated with corresponding reagents for 24 h. Cell viability was evaluated using a CCK-8 assay, cell proliferation by 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay, and cell apoptosis via the expression of apoptosis-related proteins, i.e., Bcl-2 associated X protein (Bax) and B-cell lymphoma 2 (Bcl-2) using western blotting. We incubated HPASMCs with varying concentrations of ET-1 for 24, 48 and 72 h, and found that cell survival rate was increased in a dose-dependent manner (P<0.05) rather than in a time-dependent manner (P>0.05). After co-incubation of HPASMCs with varying concentrations of IPT and ET-1 for 24 h, the cell survival rate was decreased in a dose-dependent manner. The cell survival rate in the IPT+ET-1 group was significantly lower than that in the ET-1 group (P<0.05). The cell viability (P<0.05) and proliferation (P<0.05) in the ET-1 group were higher than those in the control group, and the expression of Bax/Bcl-2 was lower than the control group (P<0.05). The cell viability (P<0.05) and proliferation (P<0.05) in the ET-1+IPT group were lower than those in the ET-1 group, and the expression of Bax/Bcl-2 was higher than that in the ET-1 group (P<0.05). The cell viability (P<0.05) and proliferation (P<0.05) in the ET-1+IPT+GLI group were higher than those in the ET-1+IPT group, and the expression of Bax/Bcl-2 was lower than that in the ET-1+IPT group (P<0.05). In conclusion, IPT inhibited ET-1-induced HPASMC proliferation and promoted cell apoptosis. Thus, it may play an important role in the treatment of HPH. PMID- 27221643 TI - Environmental parameters as risk factors for human and canine Leishmania infection in Thessaly, Central Greece. AB - Thessaly, Central Greece, is an endemic area for leishmaniasis with higher incidence rate during the last years. We herein investigated the geographical distribution of human leishmaniasis cases and Leishmania infected dogs in relation to environmental parameters to identify high-risk areas. All the human leishmaniasis cases (n = 82) reported to Hellenic Centre for Disease Control and Prevention from 2007 to 2014 and 85 Leishmania polymerase chain reaction positive dogs were included in this study. To analyse the data geographical information system (GIS) together with the Ecological Niche Model (ENM) were used. The most important findings of the study were: (i) Central plain of Thessaly together with the coast line and the western and eastern lowlands were identified as high-risk geographical areas. (ii) The highest percentage of the high-risk areas was found in low altitude (<200 m above sea level) and in irrigated and cultivated agricultural areas. (iii) A total of 20% of the human settlements was found in high-risk areas. (iv) The maximum temperature of the warmest month contributes the highest per cent to define both environmental niche profiles for humans and dogs. (v) The ENM could be a useful tool for the epidemiological study of leishmaniasis. Spatial analysis may allow the design of entomological studies and identify target population in order to implement preventive measures. PMID- 27221644 TI - A label-free fluorescent adenosine triphosphate biosensor via overhanging aptamer triggered enzyme protection and target recycling amplification. AB - Herein, a label-free fluorescent adenosine triphosphate (ATP) aptasensor is fabricated with a DNA hairpin and an overhanging aptamer. In the presence of ATP, the overhanging sequences of the aptamer may form preferred substrates of exo III, and thus trigger the enzyme-assisted amplification, which results in the release of G-rich sequences. Free G-rich sequences subsequently generate an enhanced flourescent signal by binding with thioflavin T. However, if ATP is absent, the overhanging sequence can induce steric hindrance and protect the DNA hairpin against the digestion of exo III, significantly reducing the noise of this biosensor. Accordingly, the signal-to-noise ratio of the sensing system is greatly improved, which ensures the desirable analytical performance of the proposed aptasensor both in pure samples and real samples. PMID- 27221646 TI - Repetition suppression - An integrative view. PMID- 27221645 TI - Geographic Accessibility of Pulmonologists for Adults With COPD: United States, 2013. AB - BACKGROUND: Geographic clusters in prevalence and hospitalizations for COPD have been identified at national, state, and county levels. The study objective is to identify county-level geographic accessibility to pulmonologists for adults with COPD. METHODS: Service locations of 12,392 practicing pulmonologists and 248,160 primary care physicians were identified from the 2013 National Provider Identifier Registry and weighted by census block-level populations within a series of circular distance buffer zones. Model-based county-level population counts of US adults >= 18 years of age with COPD were estimated from the 2013 Behavioral Risk Factor Surveillance System. The percentages of all estimated adults with potential access to at least one provider type and the county-level ratio of adults with COPD per pulmonologist were estimated for selected distances. RESULTS: Most US adults (100% in urbanized areas, 99.5% in urban clusters, and 91.7% in rural areas) had geographic access to a primary care physician within a 10-mile buffer distance; almost all (>= 99.9%) had access to a primary care physician within 50 miles. At least one pulmonologist within 10 miles was available for 97.5% of US adults living in urbanized areas, but only for 38.3% in urban clusters and 34.5% in rural areas. When distance increased to 50 miles, at least one pulmonologist was available for 100% in urbanized areas, 93.2% in urban clusters, and 95.2% in rural areas. County-level ratios of adults with COPD per pulmonologist varied greatly across the United States, with residents in many counties in the Midwest having no pulmonologist within 50 miles. CONCLUSIONS: County-level geographic variations in pulmonologist access for adults with COPD suggest that those adults with limited access will have to depend on care from primary care physicians. PMID- 27221647 TI - Excitation of vibrational soft modes in disordered systems using active oscillation. AB - We propose a new method to characterize the spatial distribution of particles' vibrations in solids with much lower computational costs compared to the usual normal mode analysis. We excite the specific vibrational mode in a two dimensional athermal jammed system by giving a small amplitude of active oscillation to each particle's size with an identical driving frequency. The response is then obtained as the real time displacements of the particles. We show remarkable correlations between the real time displacements and the eigen vectors obtained from conventional normal mode analysis. More importantly, from these real time displacements, we can measure the participation ratio and spatial polarization of particles' vibrations. From these measurements, we find three distinct frequency regimes which characterize the spatial distribution and correlation of particles' vibrations in jammed amorphous solids. Furthermore, we can possibly apply this method to a much larger system to examine the low frequency behaviour of amorphous solids with a much higher resolution of the frequency space. PMID- 27221649 TI - Endothelial function following glucose ingestion in adults with prediabetes: Role of exercise intensity. AB - OBJECTIVE: To determine whether high intensity exercise (HIE) would improve endothelial function more than an isocaloric bout of moderate intensity exercise (MIE) following glucose ingestion in adults with prediabetes. METHODS: Twelve subjects with prediabetes completed all three conditions: time-course matched control and isocaloric exercise (~200 kcal) at moderate (MIE; at lactate threshold) and high intensity (HIE; 75% of difference between lactate threshold and VO2 peak). Brachial artery flow-mediated dilation (FMD) was measured before exercise (baseline), within 30 min postexercise, and 1 and 2 hr following a 75 g oral glucose tolerance test (OGTT). Plasma F2-isoprostanes were also assessed during the protocol (i.e., baseline to 2 hr OGTT) as a biomarker of oxidative stress. RESULTS: MIE reduced postexercise F2-isoprostanesAUC compared with time course matched control and HIE. Although exercise had no statistical effect on FMD postexercise or during the OGTT, elevations in FMDAUC after MIE and HIE were associated with reduced postexercise F2-isoprostanesAUC . CONCLUSIONS: Exercise at either intensity had no effect on FMD immediately postexercise following glucose administration. However, individuals with reduced oxidative stress responses to exercise had greater exercise-induced improvement in FMD. Further work is required to identify the mechanism by which exercise alters oxidative stress to enhance endothelial function. PMID- 27221650 TI - Intersystem crossing-branched excited-state intramolecular proton transfer for o nitrophenol: An ab initio on-the-fly nonadiabatic molecular dynamic simulation. AB - The 6SA-CASSCF(10, 10)/6-31G (d, p) quantum chemistry method has been applied to perform on-the-fly trajectory surface hopping simulation with global switching algorithm and to explore excited-state intramolecular proton transfer reactions for the o-nitrophenol molecule within low-lying electronic singlet states (S0 and S1) and triplet states (T1 and T2). The decisive photoisomerization mechanisms of o-nitrophenol upon S1 excitation are found by three intersystem crossings and one conical intersection between two triplet states, in which T1 state plays an essential role. The present simulation shows branch ratios and timescales of three key processes via T1 state, non-hydrogen transfer with ratio 48% and timescale 300 fs, the tunneling hydrogen transfer with ratios 36% and timescale 10 ps, and the direct hydrogen transfer with ratios 13% and timescale 40 fs. The present simulated timescales might be close to low limit of the recent experiment results. PMID- 27221651 TI - Risk scores for predicting incidence of type 2 diabetes in the Chinese population: the Kailuan prospective study. AB - Few risk scores have been specifically developed to identify individuals at high risk of type 2 diabetes in China. In the present study, we aimed to develop such risk scores, based on simple clinical variables. We studied a population-based cohort of 73,987 adults, aged 18 years and over. After 5.35 +/- 1.59 years of follow-up, 4,726 participants (9.58%) in the exploration cohort developed type 2 diabetes and 2,327 participants (9.44%) in the validation cohort developed type 2 diabetes. Age, gender, body mass index, family history of diabetes, education, blood pressure, and resting heart rate were selected to form the concise score with an area under the receiver operating characteristic curve (AUC) of 0.67. The variables in the concise score combined with fasting plasma glucose (FPG), and triglyceride (TG) or use of lipid-lowering drugs constituted the accurate score with an AUC value of 0.77. The utility of the two scores was confirmed in the validation cohort with AUCs of 0.66 and 0.77, respectively. In summary, the concise score, based on non-laboratory variables, could be used to identify individuals at high risk of developing diabetes within Chinese population; the accurate score, which also uses FPG and TG data, is better at identifying such individuals. PMID- 27221652 TI - Loss of PUMA (BBC3) does not prevent thrombocytopenia caused by the loss of BCL XL (BCL2L1). AB - Apoptosis is required to maintain tissue homeostasis in multicellular organisms. Platelets, the anucleate cells that are essential for blood clotting, are a prime example. Their brief life span in the circulation is regulated by the intrinsic apoptosis pathway. Pro-survival BCL-XL (also termed BCL2L1) is essential for platelet viability. It functions to restrain the pro-apoptotic BCL-2 family members BAK (also termed BAK1) and BAX, the essential mediators of intrinsic apoptosis. Genetic deletion or pharmacological inhibition of BCL-XL results in thrombocytopenia. Conversely, deletion of BAK in platelets doubles their circulating life span. However, what triggers platelet apoptosis in vivo remains unclear. The pro-apoptotic BH3-only proteins are essential for initiating apoptosis in nucleated cells, and there is some evidence to suggest they also play a role in platelet biology. We investigated whether PUMA (also termed BBC3), a potent BH3-only protein that can inhibit all pro-survival BCL-2 family members as well as directly activate BAX, regulates the death of platelets. Surprisingly, loss of PUMA had no impact on the loss of platelets caused by loss of BCL-XL. It therefore remains to be established whether other BH3-only proteins play a critical role in induction of apoptosis in platelets or whether their death is controlled solely by the interactions between BCL-XL with BAK and BAX. PMID- 27221653 TI - Potential effect of smoking on semen quality through DNA damage and the downregulation of Chk1 in sperm. AB - Previous studies have found that smoking is associated with decreased male fertility via altering the quality of semen. However, the mechanism by which cigarette smoking affects semen quality remains to be fully elucidated. Heavy smoking-induced DNA damage has been reported to correlate with abnormal spermatozoa and male infertility. It has been reported that, in response to DNA damage, activation of the checkpoint kinase 1 (Chk1) facilitates S and G2 checkpoint arrest. The aim of the present study was to investigate the expression levels of Chk1 in sperm cells of smoking and non-smoking men, and to further examine the correlation between DNA fragmentation rates and the expression levels of Chk1 with smoking. The present study was performed on a cohort of 841 smoking men and 287 non-smoking men. In the investigation, sperm concentration, motility, viability, seminal plasma zinc concentration, acrosin activity and sperm DNA fragmentation were examined. The gene and protein expression levels of Chk1 were detected using reverse transcription-quantitative polymerase chain reaction and western blot analyses, respectively. It was observed that the progressive motility of the sperm was significantly decreased in the moderate and heavy smoking groups, whereas no significant changes were observed in the mild smoking group. The sperm in the medium-term smoking group had significantly decreased progressive motility, and the semen concentration, sperm count and progressive motility vitality were markedly decreased in the long-term smoking group. Compared with the non-smoking group, the abnormal head rates in the heavy smoking group and long-term smoking group were significantly increased. The sperm viability and seminal plasma zinc concentration were markedly increased in the smoking group. Increased DNA fragmentation rates were found in the smoking group. The expression of Chk1 was significantly decreased in the smoking group, compared with the non-smoking group. Progressive motility and sperm concentration showed a nonlinear association with the relative mRNA expression of Chk1. However, an inverse association was found between DNA fragmentation rates and the progressive motility and sperm concentration. These data suggested that the decrease of semen quality caused by cigarette smoking was not only correlated with sperm DNA fragmentation rates, but was also correlated with a decline in the expressive level of Chk1. The expression of Chk1 was associated with DNA damage and apoptosis, the reduction of which may lead to decreased sperm repair and increased sperm apoptosis, with a subsequent effect on semen quality. PMID- 27221654 TI - Interleukin-6 and rs1800796 locus single nucleotide polymorphisms in response to hypoxia/reoxygenation in hepatocytes. AB - Ischemia-reperfusion injury due to hypoxia/reoxygenation (H/R) is one of the main causes of liver damage during liver surgery. Donor interleukin-6 (IL-6) rs1800796 single nucleotide polymorphisms (SNPs) affect the metabolism of tacrolimus following liver transplantation-related hepatic H/R. This study investigated the response of IL-6 and its promoter polymorphisms to hepatic H/R in liver parenchymal cells. The association between IL-6 rs1800796 SNPs and IL-6 expression was measured in 84 disease-free liver tissues using tissue microarrays and immunohistochemistry. Subsequently, LO2G, LO2C and NC-LO2 cells were successfully constructed via stable lentivirus-mediated transfection. The effects of IL-6 and its SNPs on the biological function of LO2 cells were examined using a cell model of H/R. Our results revealed that IL-6 was mainly expressed in hepatocytes. The intermediate IL-6 expression rate in genotype CC carriers was higher than that in genotype CG/GG carriers (P=0.006), which was subsequently verified at the IL-6 mRNA level (P=0.002). The concentrations of alanine aminotransferase in the LO2G cells were significantly higher than those in the LO2C cells following H/R for 6 h and H/R for 24 h (P<0.05). The viability of the LO2C cells was higher than that of the LO2G cells (P<0.05). Furthermore, the expression of IL-6 and its downstream molecules was significantly increased in the LO2C cells compared with the LO2G cells (P<0.05). Therefore, the sequence variants of rs1800796 SNPs (G->C) exhibit an increased IL-6 transcription efficiency in liver parenchymal cells. In addition, the increased expression of IL-6 protects the hepatocytes following hepatic H/R injury. PMID- 27221655 TI - Childrens' left-turning preference is not modulated by magical ideation. AB - The literature on human turning preferences is inconsistent. While the few studies with children below 14 years of age uniformly describe an overall left turning (counterclockwise) tendency, a recent Internet study with more than 1500 adults found a right-sided (clockwise) bias. We set out to investigate spontaneous turning behaviour in children age 5-3 years and, based on neuropsychiatric work in adults, also explored a potential association with magical thinking. Findings indicated a clear left-turning preference, independent of a participant's sex and handedness. Whether a child responded a question about the existence of extrasensory communication in the affirmative or not was unrelated to direction and size of turning bias and lateral preference. Our results are consistent with a left-sided turning preference reported for children, but in opposition to the clockwise bias recently described in a large scale study with adults. Whether they point to a maturational gradient in the preferred direction of spontaneous whole-body rotation or rather to a lack of comparability between measures used in observational versus Internet-based studies remains to be further investigated. Regarding a purported association between body turns and magical thinking, our study is preliminary, as only one single question was used to probe the latter. PMID- 27221656 TI - Angiographic features and disease outcomes of symptomatic retinal arterial macroaneurysms. AB - PURPOSE: Symptomatic retinal arterial macroaneurysms (RAM) are primarily investigated by fundus fluorescein angiography after presenting with visual disturbance. The natural history includes spontaneous regression and occasionally occlusion of the arteriole distal to the aneurysm. RAM may be managed conservatively. Interventional treatment options include focal argon laser photocoagulation, Nd:YAG laser hyaloidotomy, and pars plana vitrectomy. The purpose of this study was to elicit the rates of distal vessel occlusion and aneurysm thrombosis in RAM at presentation, and their relevance to the treatment of RAM. Furthermore, visual outcomes were examined. METHODS: Retrospective review of cases of RAM presenting to a tertiary ophthalmology care centre was accomplished in a university teaching hospital. The angiographic features, treatment indications, and visual outcomes in patients with RAM were recorded. Angiographic features noted were distal vessel patency and aneurysm thrombosis at presentation. RESULTS: Ten patients with RAM were identified. Ninety percent had an angiographically patent distal arteriole, with 40 % showing spontaneous thrombosis of the aneurysm sac at presentation. Patients presenting with a spontaneously thrombosed RAM were managed conservatively, those with flow within the aneurysm wall were treated with focal laser, and those with subhyaloid haemorrhage underwent Nd:YAG laser hyaloidotomy. LogMAR visual acuity improved from 0.3 (+/-0) at presentation to 0.15 (+/-0.1) in the conservative group, and from 0.78 (+/-0.23) to 0.24 (+/-0.18) in those who underwent one intervention. One patient lost vision after multiple RAM. CONCLUSION: Thrombosis within the aneurysm wall is an important feature in deciding to treat RAM, and selective use of interventions improves vision in affected patients. PMID- 27221657 TI - The synthesis, regulation, and functions of sterols in Candida albicans: Well known but still lots to learn. AB - Sterols are the basal components of the membranes of the fungal pathogen Candida albicans, and these membranes determine the susceptibility of C. albicans cells to a variety of stresses, such as ionic, osmotic and oxidative pressures, and treatment with antifungal drugs. The common antifungal azoles in clinical use are targeted to the biosynthesis of ergosterol. In the past years, the synthesis, storage and metabolism of ergosterol in Saccharomyces cerevisiae has been characterized in some detail; however, these processes has not been as well investigated in the human opportunistic pathogen C. albicans. In this review, we summarize the genes involved in ergosterol synthesis and regulation in C. albicans. As well, genes in S. cerevisiae implicated in ergosterol storage and conversions with other lipids are noted, as these provide us clues and directions for the study of the homologous genes in C. albicans. In this report we have particularly focused on the essential roles of ergosterol in the dynamic process of cell biology and its fundamental status in the biological membrane system that includes lipid rafts, lipid droplets, vacuoles and mitochondria. We believe that a thorough understanding of this classic and essential pathway will give us new ideas about drug resistance and morphological switching in C. albicans. PMID- 27221658 TI - GqqA, a novel protein in Komagataeibacter europaeus involved in bacterial quorum quenching and cellulose formation. AB - BACKGROUND: We report on the functional screening and identification of an active quorum quenching (QQ) gene in the Komagataeibacter europaeus strain CECT 8546, which is a member of the acetic acid bacteria (AAB). RESULTS: Using a previously published screening protocol (Schipper et al., in Appl Environ Microbiol 75:224 233, 2009. doi: 10.1128/AEM.01389-08 ) for QQ genes, we identified a single gene, designated gqqA, that interfered strongly with bacterial quorum sensing (QS) in various reporter strains. It encodes for a 281-amino acid protein with a molecular mass of 30 kDa. Although the GqqA protein is similar to predicted prephenate dehydratases, it does not complement Escherichia coli mutants of the pheA gene, thus indicating a potentially different function. Recombinant GqqA protein attenuated QS-dependent pyocyanin production and swarming motility in the Pseudomonas aeruginosa strain PAO1. Moreover, GqqA quenched the QS response of the Agrobacterium tumefaciens NTL4 and the Chromobacterium violaceum CV026 reporter strains. Interestingly, the addition of recombinant GqqA protein to growing cultures of the Komagataeibacter europaeus strain CECT 8546 altered the cellulose production phenotype of CECT 8546 and other AAB strains. In the presence of GqqA protein, cells were planktonic, and no visible cellulose biofilms formed. The addition of low levels of N-acylhomoserine lactones maintained the biofilm formation phenotype. CONCLUSIONS: Our data provide evidence for an interconnection between QS and AAB cellulose biofilm formation as well as QQ activity of the GqqA protein. PMID- 27221659 TI - Lymph nodes from HIV-infected individuals harbor mature dendritic cells and increased numbers of PD-L1+ conventional dendritic cells. AB - The immune response induced by dendritic cells (DC) during the HIV infection has been of remarkable interest because of the therapeutic potential of DC for vaccine development. However, their beneficial or detrimental contribution in HIV infection remains unclear. The activation state of DC in lymph nodes (LN) is essential to induce T cell responses against HIV. In the present study, we characterized the immunophenotype and function of conventional (cDC) and plasmacytoid (pDC) dendritic cells from peripheral blood (PB) and LN of HIV(+) individuals. We observed that the frequency of PB pDC was decreased and exhibited an immature phenotype; whereas in the LN, activated pDC accumulated (CD40(+) and CD83(+)). In addition, the frequency of PB cDC from HIV(+) individuals was decreased and exhibited an immature phenotype, whereas LN harbored activated and mature cDC (CD40(+), CD83(+), CD80(+) and CD86(+)). However, an increased number of PD-L1(+) cDC was also observed in the LN. Moreover, pDC and cDC were able to produce inflammatory cytokines (IFN-alpha, TNF-alpha and IL-12) after TLR stimulation. These findings suggests that LN cDC expressing PD-L1 from HIV(+) individuals may negatively impact the generation of HIV-specific T cells and that DC might be contributing to tissue chronic immune activation. PMID- 27221661 TI - Revisit of fluoroquinolone and azithromycin susceptibility breakpoints for Salmonella enterica serovar Typhi. AB - In recent years, increase in occurrence of fluoroquinolone (FQ)-resistant S almonella Typhi isolates has caused considerable inconvenience in selecting appropriate antimicrobials for treatment of typhoid. The World Health Organization (WHO) recommends azithromycin for the empirical treatment option of uncomplicated typhoid. The CLSI updated the breakpoints of disc diffusion (DD) and MIC results of FQs and azithromycin for Salmonella Typhi in 2015, but DD breakpoints of ofloxacin and levofloxacin were not included. In this study, the inhibition zone diameters and MICs of nalidixic acid, ciprofloxacin, ofloxacin, levofloxacin and azithromycin were determined in Salmonella Typhi Kolkata isolates (n =146) over a 16-year period (1998 to 2013) and the data were compared with the available CLSI breakpoints. Very major error and major error (ME) of FQs were not observed in the study isolates, but the minor error of ciprofloxacin (15.8 %) and ME of azithromycin (3.5 %) exceeded the acceptable limit. A positive correlation between MICs of FQ and mutations in the quinolone-resistance determining region (QRDR) showed the reliability of MIC results to determine FQ susceptibility of Salmonella Typhi (n =74). Isolates showing decreased ciprofloxacin susceptibility (MIC 0.125-0.5 ug ml-1) were likely to have at least one mutation in the QRDR region. The results on DD breakpoints of ofloxacin (resistant, <=15 mm; intermediate, 16-24 mm, and susceptible, >=25 mm) and levofloxacin (resistant, <=18 mm; intermediate, 19-27 mm, and susceptible, >=28 mm) corroborated those of earlier studies. In view of the emerging FQ- and azithromycin-resistant Salmonella Typhi isolates, DD and MIC breakpoints of those antimicrobials should be revisited routinely. PMID- 27221662 TI - [Estimation of postoperative mortality after partial liver resection for perihilar cholangiocarcinoma]. PMID- 27221663 TI - Chronic Administration of Visfatin Ameliorated Diabetic Nephropathy in Type 2 Diabetic Mice. AB - BACKGROUND/AIMS: Visfatin is a known adipokine which may improve insulin resistance in obesity and have an anti-diabetic effect via the insulin receptor. We studied the effects of visfatin on diabetic nephropathy in type 2 diabetic mice. METHODS: Diabetic male db/db mice were treated with intraperitoneal injections of visfatin. Basal parameters were measured in all mice and glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed in diabetic mice. The histopathological and molecular changes were evaluated in diabetic nephropathy. RESULTS: Visfatin treatment had no effect on body weight, water and food intake, urinary volume, blood glucose, and HbA1c level. However, visfatin improved HOMA-IR, GTT, ITT and decreased plasma insulin and visfatin level, but not adiponectin level. Plasma cholesterol and triglyceride level were also improved by visfatin treatment. Significantly, visfatin decreased albuminuria in diabetic mice. Glomerulosclerotic change and mesangial expansion in the kidneys were significantly reduced. In addition, visfatin inhibited the expression of proinflammatory and profibrotic cytokines such as MCP-1, TGFbeta1, type IV collagen, and PAI-1. The enzymes related to lipid metabolism in the kidney, HMG CoAR was suppressed by visfatin treatment, whereas FXR and ABCA1 were significantly elevated by treatment. CONCLUSION: Visfatin might have a protective effect in diabetic nephropathy without the hypoglycemic effect. PMID- 27221660 TI - DNA Damage Response in Hematopoietic Stem Cell Ageing. AB - Maintenance of tissue-specific stem cells is vital for organ homeostasis and organismal longevity. Hematopoietic stem cells (HSCs) are the most primitive cell type in the hematopoietic system. They divide asymmetrically and give rise to daughter cells with HSC identity (self-renewal) and progenitor progenies (differentiation), which further proliferate and differentiate into full hematopoietic lineages. Mammalian ageing process is accompanied with abnormalities in the HSC self-renewal and differentiation. Transcriptional changes and epigenetic modulations have been implicated as the key regulators in HSC ageing process. The DNA damage response (DDR) in the cells involves an orchestrated signaling pathway, consisting of cell cycle regulation, cell death and senescence, transcriptional regulation, as well as chromatin remodeling. Recent studies employing DNA repair-deficient mouse models indicate that DDR could intrinsically and extrinsically regulate HSC maintenance and play important roles in tissue homeostasis of the hematopoietic system. In this review, we summarize the current understanding of how the DDR determines the HSC fates and finally contributes to organismal ageing. PMID- 27221664 TI - Prediction of rates of thromboembolic and major bleeding outcomes with dabigatran or warfarin among patients with atrial fibrillation: new initiator cohort study. AB - OBJECTIVES: To compare stratified event rates from randomized controlled trials with predicted event rates from models developed in observational data, and assess their ability to accurately capture observed rates of thromboembolism and major bleeding for patients treated with dabigatran or warfarin as part of routine care. DESIGN: New initiator cohort study. SETTING: Data from United Health (October 2009 to June 2013), a commercial healthcare claims database in the United States. PARTICIPANTS: 21 934 adults with atrial fibrillation initiating dabigatran (150 mg dose only) or warfarin treatment as part of routine care. MAIN OUTCOME MEASURES: Predicted annual rates of thromboembolism or major bleeding, based on estimates from randomized controlled trials, models developed in routine care patients, and baseline risk scores (CHADS2, CHA2DS2-VASc, and HAS BLED). Thromboembolism was a composite outcome, including primary inpatient diagnosis codes for ischemic or ill defined stroke, transient ischemic attack, pulmonary embolism, deep vein thrombosis, and systemic embolism. Major bleeding was a composite outcome including codes occurring in an inpatient setting for hemorrhagic stroke; major upper, lower, or unspecified gastrointestinal bleed; and major urogenital or other bleed. RESULTS: 6516 (30%) and 15 418 (70%) of patients initiated dabigatran and warfarin, respectively. Annual event rates per 100 patients were 1.7 for thromboembolism and 4.6 for major bleeding. For thromboembolism, calibration of estimates from randomized controlled trials was similar to calibration for model based predictions; however, trial estimates for major bleeding consistently underestimated the rate of bleeding among patients in routine care. Underestimation of bleeding rates was particularly pronounced in warfarin initiators with high HAS-BLED scores, where event rates were underestimated by up to 4.0 per 100 patient years. Harrell's c indices for discrimination for thromboembolism or major bleeding in dabigatran and warfarin initiators ranged between 0.59 and 0.66 for randomized controlled trial predictions, and between 0.52 and 0.70 for cross validated model based predictions. CONCLUSION: Estimated rates of thromboembolism under dabigatran or warfarin treatment in randomized controlled trials were close to observed rates in routine care patients. However, rates of major bleeding were underestimated. Models developed in routine care patients can provide accurate, tailored estimates of risk and benefit under alternative treatment to enhance patient centered care. PMID- 27221665 TI - Building for the future: essential infrastructure for rodent ageing studies. AB - When planning ageing research using rodent models, the logistics of supply, long term housing and infrastructure provision are important factors to take into consideration. These issues need to be prioritised to ensure they meet the requirements of experiments which potentially will not be completed for several years. Although these issues are not unique to this discipline, the longevity of experiments and indeed the animals, requires a high level of consistency and sustainability to be maintained throughout lengthy periods of time. Moreover, the need to access aged stock or material for more immediate experiments poses many issues for the completion of pilot studies and/or short term intervention studies on older models. In this article, we highlight the increasing demand for ageing research, the resources and infrastructure involved, and the need for large-scale collaborative programmes to advance studies in both a timely and a cost-effective way. PMID- 27221666 TI - Falling through the gaps: how should HIV programmes respond to families that persistently deny treatment to children? AB - INTRODUCTION: Children living with HIV rely on adult caregivers for access to HIV testing and care, including clinical monitoring and adherence to treatment. Yet, many caregivers confront barriers to ensuring children's care, including fear of disclosure of the child's or the parents' HIV status, competing family demands, fluctuating care arrangements and broader structural factors such as entrenched poverty or alternative beliefs about HIV's aetiology and treatment. Thus, many children are "falling through the gaps" because their access to testing and care is mediated by guardians who appear unable or unwilling to facilitate it. These children are likely to suffer treatment failure or death due to their caregivers' recalcitrance. DISCUSSION: This Commentary presents three cases from paediatric HIV services in Zimbabwe that highlight the complexities facing health care providers in providing HIV testing and care to children, and discusses the implications as a child's rights issue requiring both legal and programmatic responses. The cases provide examples of how disagreements between family members about appropriate care, conflicts between a child and caregiver and religious objections to medical treatment interrupt children's engagement with HIV services. In all three cases, no social or legal mechanisms were in place for health staff to intervene and prevent "loss to follow up." CONCLUSIONS: We suggest that conceptualizing this as a child's rights issue may be a useful way to raise the debate and move towards improved treatment access. Our cases reflect policy failure to facilitate access to children's HIV testing and treatment, and are likely to be similar across international settings. We propose sharing experiences and encouraging dialogue between health practitioners and global advocates for children's right to health to raise awareness that children are the bearers of rights even if they lack legal capacity, and that the failure of either the state or their caregiver to facilitate access to care is in fact a rights violation. PMID- 27221667 TI - Multikinase Inhibitor-Induced Hand-Foot Skin Reaction: A Review of Clinical Presentation, Pathogenesis, and Management. AB - Multikinase inhibitors (MKIs) are targeted cancer therapies designed to inhibit multiple tyrosine kinase pathways responsible for tumor proliferation, growth, and survival. These agents are more able to target cancer cells and possess better safety profiles than conventional chemotherapies. However, MKIs can produce significant cutaneous adverse events, hand-foot skin reaction (HFSR) being the most clinically significant. Although not life threatening, HFSR can lead to MKI dose modification, interruption, or termination, potentially limiting the anti-tumor effect. This article summarizes the current knowledge concerning the epidemiology, clinical presentation, pathogenesis, histopathology, prognostic implication, and current evidence-based prophylactic and reactive treatment options for MKI-induced HFSR. Its high incidence and significant impact on the quality of life emphasizes the great need to understand the pathogenesis and improve management of this condition. PMID- 27221668 TI - Networked Community Change: Understanding Community Systems Change through the Lens of Social Network Analysis. AB - Addressing complex problems in communities has become a key area of focus in recent years (Kania & Kramer, 2013, Stanford Social Innovation Review). Building on existing approaches to understanding and addressing problems, such as action research, several new approaches have emerged that shift the way communities solve problems (e.g., Burns, 2007, Systemic Action Research; Foth, 2006, Action Research, 4, 205; Kania & Kramer, 2011, Stanford Social Innovation Review, 1, 36). Seeking to bring clarity to the emerging literature on community change strategies, this article identifies the common features of the most widespread community change strategies and explores the conditions under which such strategies have the potential to be effective. We identify and describe five common features among the approaches to change. Then, using an agent-based model, we simulate network-building behavior among stakeholders participating in community change efforts using these approaches. We find that the emergent stakeholder networks are efficient when the processes are implemented under ideal conditions. PMID- 27221669 TI - Genomic features of uncultured methylotrophs in activated-sludge microbiomes grown under different enrichment procedures. AB - Methylotrophs are organisms that are able to grow on C1 compounds as carbon and energy sources. They play important roles in the global carbon cycle and contribute largely to industrial wastewater treatment. To identify and characterize methylotrophs that are involved in methanol degradation in wastewater-treatment plants, methanol-fed activated-sludge (MAS) microbiomes were subjected to phylogenetic and metagenomic analyses, and genomic features of dominant methylotrophs in MAS were compared with those preferentially grown in laboratory enrichment cultures (LECs). These analyses consistently indicate that Hyphomicrobium plays important roles in MAS, while Methylophilus occurred predominantly in LECs. Comparative analyses of bin genomes reconstructed for the Hyphomicrobium and Methylophilus methylotrophs suggest that they have different C1-assimilation pathways. In addition, function-module analyses suggest that their cell-surface structures are different. Comparison of the MAS bin genome with genomes of closely related Hyphomicrobium isolates suggests that genes unnecessary in MAS (for instance, genes for anaerobic respiration) have been lost from the genome of the dominant methylotroph. We suggest that genomic features and coded functions in the MAS bin genome provide us with insights into how this methylotroph adapts to activated-sludge ecosystems. PMID- 27221672 TI - Corrigendum to 'Visualizing viral protein structures in cells using genetic probes for correlated light and electron microscopy' [Methods 90 (2015) 39-48]. PMID- 27221671 TI - Single minimal incision fasciotomy for chronic exertional compartment syndrome of the lower leg. AB - BACKGROUND: Chronic exertional compartment syndrome (CECS) involves a painful increase in compartment pressure caused by exercise and relieved by rest, common in athletes. The most common site for CECS in the lower limbs is the anterior leg compartment. The aim of this study is to evaluate the outcomes of a single minimal incision fasciotomy in athletes and their capability to return to high level sport activity. METHODS: The study reports mid-term results in a series of 18 consecutive athletes with chronic exertional compartment syndrome of the leg who had undergone minimally invasive fasciotomy. Between 2000 and 2007, we prospectively enrolled 18 consecutive athletes (12 males and six females, median age 27 years) with unilateral or bilateral chronic exertional compartment syndrome undergoing unilateral or bilateral minimally invasive fasciotomy. Clinical outcomes were assessed with Short-Form Health Survey-36 (SF-36) and European Quality of Life-5 Dimension (EQ-5D) scale. The ability to participate in sport before and after surgery and the time to return to training (RTT) and to sport (RTS) were recorded. RESULTS: The median follow-up after surgery was 36 months. Both questionnaires showed a statistically significant improvement (P < 0.0001) after surgery. At the time of the latest follow-up, 17 of 18 patients (94 %) had returned to pre-injury or higher levels of sport. Only one patient (6 %) returned to sport at lower levels than those of pre-injury status. The median time to return to training and to return to sport was 8 and 13 weeks, respectively. No severe complications or recurrence of the symptoms were recorded. CONCLUSIONS: Minimally invasive fasciotomy is effective and safe for athletes suffering from unilateral or bilateral chronic exertional compartment syndrome of the anterior and lateral compartments of the leg with good results in the mid-term. PMID- 27221673 TI - Evaluation of Bioelectrical Impedance Analysis in Critically Ill Patients: Results of a Multicenter Prospective Study. AB - BACKGROUND: In critically ill patients, muscle loss is associated with adverse outcomes. Raw bioelectrical impedance analysis (BIA) parameters (eg, phase angle [PA] and impedance ratio [IR]) have received attention as potential markers of muscularity, nutrition status, and clinical outcomes. Our objective was to test whether PA and IR could be used to assess low muscularity and predict clinical outcomes. METHODS: Patients (>=18 years) having an abdominal computed tomography (CT) scan and admitted to intensive care underwent multifrequency BIA within 72 hours of scan. CT scans were landmarked at the third lumbar vertebra and analyzed for skeletal muscle cross-sectional area (CSA). CSA <=170 cm2 for males and <=110 cm2 for females defined low muscularity. The relationship between PA (and IR) and CT muscle CSA was evaluated using multivariate regression and included adjustments for age, sex, body mass index, Charlson Comorbidity Index, and admission type. PA and IR were also evaluated for predicting discharge status using dual-energy x-ray absorptiometry-derived cut-points for low fat-free mass index. RESULTS: Of 171 potentially eligible patients, 71 had BIA and CT scans within 72 hours. Area under the receiver operating characteristic (c-index) curve to predict CT-defined low muscularity was 0.67 ( P <= .05) for both PA and IR. With covariates added to logistic regression models, PA and IR c-indexes were 0.78 and 0.76 ( P < .05), respectively. Low PA and high IR predicted time to live ICU discharge. CONCLUSION: Our study highlights the potential utility of PA and IR as markers to identify patients with low muscularity who may benefit from early and rigorous intervention. PMID- 27221674 TI - Ursolic acid inhibits proliferation and reverses drug resistance of ovarian cancer stem cells by downregulating ABCG2 through suppressing the expression of hypoxia-inducible factor-1alpha in vitro. AB - Hypoxia in tumors is closely related to drug resistance. It has not been verified whether hypoxia-inducible factor-1alpha (HIF-1alpha) or ABCG2 is related to hypoxia-induced resistance. Ursolic acid (UA), when used in combination with cisplatin can significantly increase the sensitivity of ovarian cancer stem cells (CSCs) to cisplatin, but the exact mechanism is unknown. The cell growth inhibitory rate of cisplatin under different conditions was evaluated using Cell Counting Kit-8 (CCK-8) in adherence and sphere cells (SKOV3, A2780, and HEY). The expression of HIF-1alpha and ABCG2 was tested using quantitative PCR, western blotting, and immuno-fluorescence under different culture conditions and treated with UA. Knockdown of HIF-1alpha by shRNA and LY294002 was used to inhibit the activity of PI3K/Akt pathway. Ovarian CSCs express stemness-related genes and drug resistance significantly higher than normal adherent cells. Under hypoxic conditions, the ovarian CSCs grew faster and were more drug resistant than under normoxia. UA could inhibit proliferation and reverse the drug resistance of ovarian CSC by suppressing ABCG2 and HIF-1alpha under different culture conditions. HIF-1alpha inhibitor YC-1 combined with UA suppressed the stemness genes and ABCG2 under hypoxic condition. The PI3K/Akt signaling pathway activation plays an important functional role in UA-induced downregulation of HIF 1alpha and reduction of ABCG2. UA inhibits the proliferation and reversal of drug resistance in ovarian CSCs by suppressing the expression of downregulation of HIF 1alpha and ABCG2. PMID- 27221675 TI - Do not let sleeping dogmas lie! PMID- 27221676 TI - The cosmetic outcome of external dacryocystorhinostomy scar and factors affecting it. AB - PURPOSE: To study the cosmetic outcome of external dacryocystorhinostomy (Ex-DCR) and to detect the factors affecting it. PATIENTS AND METHODS: Prospective randomized interventional study included forty patients who were treated by 40 Ex DCRs. In twenty patients, medial canthal vertical incision was used and in the other twenty cases, subciliary incision was used. The skin was closed using vicryl 6-0 or prolene 6-0 interrupted sutures, and each one was randomly used in twenty patients (10 patients of each incision type). Cosmetic outcome was evaluated 6 months postoperative by the patients and by an oculoplastic surgeon on a four grades scale. Cosmetic results and its correlation to patients' age, sex, skin complexion, type of incision, and type of skin sutures were studied. RESULTS: The mean scar grading was 0.98 +/- 1.0 and 1.3 +/- 1.0 in patients' and examiner's assessment. About 27.5% described their scars as cosmetically significant. The cosmetic outcome was significantly affected by the type of incision with only 5% significant scars in subciliary incision group. Prolene 6-0 suture was associated with better cosmetic results with 15% significant scars. 50% of dark-skinned patients showed cosmetically significant scars. Although no correlation was found between patients' age and cosmetic outcome, pediatric patients showed higher tendency to scar visibility with mean scar grade 1.2 +/- 1.0 and 1.5 +/- 0.9 in patients' and examiner's assessment. CONCLUSION: Dark skinned and pediatric patients are more prone to visible Ex-DCR scar. The use of subciliary approach and prolene 6-0 skin sutures is associated with more favorable cosmetic outcome. PMID- 27221677 TI - Attack rate and household secondary attack rate of acute conjunctivitis during an outbreak in South India: A community-based survey. AB - INTRODUCTION: Knowledge on epidemiology of the disease in the contemporary world will help to develop appropriate strategies to curtail the transmission during an outbreak. This study was carried out during an outbreak of conjunctivitis in selected areas of Puducherry, South India, to assess the attack rate of conjunctivitis, identify factors associated with developing conjunctivitis and calculate household secondary attack rate (HSAR) of conjunctivitis and its correlates. METHODOLOGY: During December 2014, a community-based survey was conducted in a selected urban and rural area in Puducherry, South India. Simple random sampling was used to select primary sampling units and systematic sampling to select households. All individuals in the selected households were studied. A questionnaire was used to obtain data on sociodemographic characteristics, conjunctivitis during September-November, 2014, and number of household contacts who developed conjunctivitis within 7 days of index case. The attack rate and HSAR of conjunctivitis was expressed as percentage. Multivariate logistic regression was used to find factors independently associated with developing conjunctivitis and also 100% HSAR. RESULTS: Of 3193 study participants from 772 households, 509 (15.9%, 95% confidence interval 14.7-17.2%) had an attack of conjunctivitis during the reference period. Of the 772 households, 218 (28.2%) had at least one case of conjunctivitis. Of 218 households, 33 (15.1%) households had 100% HSAR. Lower age, not being unemployed, low socioeconomic status, and residing in rural area were independently associated with developing conjunctivitis. Index case being male and living in a household with >=5 members were independently associated with 100% HSAR. CONCLUSION: In the outbreak under study, more than one-fourth of households had at least one case of conjunctivitis and about one in every six individuals had an attack of conjunctivitis. PMID- 27221678 TI - Knowledge and awareness about diabetes mellitus and diabetic retinopathy in suburban population of a South Indian state and its practice among the patients with diabetes mellitus: A population-based study. AB - CONTEXT: Ocular complications due to diabetes mellitus (DM) were on the rise despite good literacy levels in South India. AIMS: To assess the knowledge and attitude toward DM and diabetic retinopathy of the general population in a suburban town of South India. SETTINGS AND DESIGN: Door-to-door population survey in suburban town of South India in May 2013. MATERIALS AND METHODS: A 30-point questionnaire was prepared and the data were collected and analyzed to determine statistically the knowledge, attitude, and practice (KAP) scores of the general and diabetic population and also to determine significant demographic associations. RESULTS: In this study, 6211 people (3528 [56.8%] women and 2683 [43.2%] men) with a mean age of 55.6 +/- 11.7 years (range 21-98 years) were included. Good knowledge and positive attitude were observed in 3457 (55.6%) and 3280 (52.8%) people. Among 1538 (25.4%) people known to have DM, only 619 (40.7%) had good knowledge, 828 (53.8%) had a positive attitude, and 886 (57.6%) had good practice patterns. Although half of them followed general diabetic care, only 9.6% had undergone screening for retinopathy. Literacy showed a significant association with good KAP (P < 0.001 each) in general population and those with DM. Overall, women had significantly better knowledge (P < 0.001). CONCLUSIONS: Better literacy, especially among women, is contributory to better public awareness; however, the trend for poor practice patterns needs to be radically changed with aggressive public motivation emphasizing on the necessity of retinopathy screening and periodic follow-ups. PMID- 27221679 TI - Optic nerve head parameters of high-definition optical coherence tomography and Heidelberg retina tomogram in perimetric and preperimetric glaucoma. AB - BACKGROUND: Heidelberg retina tomogram (HRT) and optical coherence tomography (OCT) are two widely used imaging modalities to evaluate the optic nerve head (ONH) in glaucoma. PURPOSE: To compare the ONH parameters of HRT3 and high definition OCT (HD-OCT) and evaluate their diagnostic abilities in perimetric and preperimetric glaucoma. DESIGN: Cross-sectional analysis. METHODS: 35 control eyes (24 subjects), 21 preperimetric glaucoma eyes (15 patients), and 64 perimetric glaucoma eyes (44 patients) from the Longitudinal Glaucoma Evaluation Study underwent HRT3 and HD-OCT examinations. STATISTICAL ANALYSIS: Agreement between the ONH parameters of HRT and HD-OCT were assessed using Bland-Altman plots. Diagnostic abilities of ONH parameters were evaluated using area under the receiver operating characteristic curves (AUCs), sensitivity at fixed specificity, and likelihood ratios (LR). RESULTS: Optic disc area, vertical cup to disc ratio, and cup volume with HD-OCT were larger than with HRT, while the rim area was smaller with HD-OCT (P < 0.001 for all comparisons). AUCs of all HD OCT ONH parameters (0.90-0.97 in perimetric and 0.62-0.71 in preperimetric glaucoma) were comparable (P > 0.10) to the corresponding HRT ONH parameters (0.81-0.95 in perimetric and 0.55-0.72 in preperimetric glaucoma). LRs associated with diagnostic categorization of ONH parameters of both HD-OCT and HRT were associated with larger effects on posttest probability of perimetric compared to preperimetric glaucoma. CONCLUSIONS: ONH measurements of HD-OCT and HRT3 cannot be used interchangeably. Though the diagnostic abilities of ONH parameters of HD OCT and HRT in glaucoma were comparable, the same were significantly lower in preperimetric compared to perimetric glaucoma. PMID- 27221681 TI - Clinical efficacy of oral and topical acyclovir in herpes simplex virus stromal necrotizing keratitis. AB - PURPOSE: To evaluate the efficacy of systemic and topical antiviral therapy in the treatment of active herpes simplex virus (HSV) necrotizing stromal keratitis (NSK). DESIGN: Prospective interventional case series. METHODOLOGY: Patients with a diagnosis of HSV NSK based on history and clinical findings were enrolled in the study. A standard protocol was used for microbiologic investigations. Ten weeks regime of systemic acyclovir and 2 weeks of topical acyclovir was given. Complete ophthalmic examination was performed at every visit. Outcome measures were a reduction in the area of infiltration and improvement in visual acuity. RESULTS: Fifteen patients were enrolled in the study. The mean age of presentation was 51.53 years. The duration of symptoms at presentation ranged from 2 to 8 weeks. HSV1 DNA polymerase chain reaction was positive in 70% cases of those tested. Area of infiltration at trial entry and at the end of 2 weeks of antiviral treatment reduced significantly (P = 0.007). All patients showed a complete resolution of keratitis at the end of study. CONCLUSION: Topical and systemic acyclovir for treatment of NSK facilitates healing of ulceration. Topical steroids after initial antiviral therapy are safe and decreases inflammation and improve visual recovery. Early initiation of therapy has better outcomes as compared to late presentations. PMID- 27221680 TI - Visual outcomes and optical quality after implantation of a diffractive multifocal toric intraocular lens. AB - BACKGROUND: This study evaluated the visual function after implantation of a multifocal toric intraocular lenses (IOLs). MATERIALS AND METHODS: This study involved 10 eyes from eight cataract patients with corneal astigmatism of 1.0 diopter (D) or higher who had received phacoemulsification with implantation of an AcrySof IQ ReSTOR Toric IOL. Six-month evaluations included visual acuity, spherical equivalent (SE), defocus curve, residual astigmatism, IOL rotation, contrast sensitivity (CS), wavefront aberrations, modulation transfer function (MTF), and patient satisfaction assessments. RESULTS: At 6 months postoperatively, uncorrected distance visual acuity (logarithm of the minimum angle of resolution) was 0.09 +/- 0.04, corrected distance visual acuity was 0.02 +/- 0.11, and uncorrected near visual acuity was 0.12 +/- 0.07. The mean SE was 0.095 +/- 0.394 D (+/-0.50 D in 90%). Refractive astigmatism at the 6-month follow-up visit was significantly reduced to 0.35 +/- 0.32 D from 1.50 +/- 0.41 D presurgery (P < 0.05). The mean IOL axis rotation was 3.20 +/- 1.55 degrees . Postoperative CS levels were high. Postoperative total order aberrations (TOAs), lower-order aberrations (LOAs), higher-order aberrations (HOAs), and spherical aberrations were decreased compared with preoperative values (P < 0.05). At 3 months postoperatively, TOAs, LOAs, and HOAs with a 3 mm pupil diameter as well as TOAs, LOAs, and astigmatism aberrations with a 5 mm pupil diameter were statistically lower than those at 1-month post surgery, but without subsequent significant changes (P > 0.05). There was an increase in MTF results between preoperative and postoperative evaluations at all spatial frequencies. CONCLUSIONS: The diffractive multifocal toric IOL is able to provide a predictable astigmatic correction with apparently outstanding levels of optical quality after implantation. PMID- 27221682 TI - Comparison of diagnostic capability of macular ganglion cell complex and retinal nerve fiber layer among primary open angle glaucoma, ocular hypertension, and normal population using Fourier-domain optical coherence tomography and determining their functional correlation in Indian population. AB - CONTEXT: Analysis of diagnostic ability of macular ganglionic cell complex and retinal nerve fiber layer (RNFL) in glaucoma. AIM: To correlate functional and structural parameters and comparing predictive value of each of the structural parameters using Fourier-domain (FD) optical coherence tomography (OCT) among primary open angle glaucoma (POAG) and ocular hypertension (OHT) versus normal population. SETTING AND DESIGN: Single centric, cross-sectional study done in 234 eyes. MATERIALS AND METHODS: Patients were enrolled in three groups: POAG, ocular hypertensive and normal (40 patients in each group). After comprehensive ophthalmological examination, patients underwent standard automated perimetry and FD-OCT scan in optic nerve head and ganglion cell mode. The relationship was assessed by correlating ganglion cell complex (GCC) parameters with mean deviation. Results were compared with RNFL parameters. STATISTICAL ANALYSIS: Data were analyzed with SPSS, analysis of variance, t-test, Pearson's coefficient, and receiver operating curve. RESULTS: All parameters showed strong correlation with visual field (P < 0.001). Inferior GCC had highest area under curve (AUC) for detecting glaucoma (0.827) in POAG from normal population. However, the difference was not statistically significant (P > 0.5) when compared with other parameters. None of the parameters showed significant diagnostic capability to detect OHT from normal population. In diagnosing early glaucoma from OHT and normal population, only inferior GCC had statistically significant AUC value (0.715). CONCLUSION: In this study, GCC and RNFL parameters showed equal predictive capability in perimetric versus normal group. In early stage, inferior GCC was the best parameter. In OHT population, single day cross-sectional imaging was not valuable. PMID- 27221683 TI - Prevalence and antibacterial resistance patterns of extended-spectrum beta lactamase producing Gram-negative bacteria isolated from ocular infections. AB - PURPOSE: Extended-spectrum beta-lactamases (ESBLs) mediated resistance is more prevalent worldwide, especially among Gram-negative bacterial isolates, conferring resistance to the expanded spectrum cephalosporins. As limited data were available on the prevalence of ESBLs in this area, the current study was undertaken to determine the prevalence, antibacterial resistance patterns, and molecular detection and characterization of ESBL encoding resistance genes among ocular Gram-negative bacterial isolates from ocular infections. MATERIALS AND METHODS: A prospective study was done on 252 ocular Gram-negative bacterial isolates recovered from ocular infections during a study period from February 2011 to January 2014. All isolates were subjected to detection of ESBLs by cephalosporin/clavulanate combination disc test and their antibacterial resistance pattern was studied. Molecular detection and characterization of ESBL encoding blaTEM -, blaSHV , blaOXA -, and blaCTX-M (phylogenetic groups 1, 2, 9, and 8/25) resistance genes by multiplex polymerase chain reaction and DNA sequence analysis. RESULTS: Of all Gram-negative bacteria, Pseudomonas aeruginosa (44%) was the most common strain, followed by Enterobacter agglomerans and Klebsiella pneumoniae each (10%). Among the 252, 42 (17%) were ESBL producers. The major source of ESBL producers were corneal scraping specimens, highest ESBL production was observed in P. aeruginosa 16 (38%) and Escherichia coli 7 (16.6%). Among ESBL-producing genes, the prevalence of blaTEM -gene was the highest (83%) followed by blaOXA -gene (35%), blaSHV -gene (18.5%), and blaCTX-M-1 -gene (18.5%) alone or together. CONCLUSION: The higher rate of prevalence of ESBLs encoding genes among ocular Gram-negative bacteria is of great concern, as it causes limitation to therapeutic options. This regional knowledge will help in guiding appropriate antibiotic use which is highly warranted. PMID- 27221684 TI - Nodular scleritis as a presenting feature of Takayasu's arteritis. PMID- 27221685 TI - Bilateral congenital infantile hemangioma of upper eyelids. PMID- 27221686 TI - Blepharoptosis and hypertrophic osteoarthropathy: A case report. AB - A 52-year-old male patient presented to our hospital with a history of secondary hypertrophic osteoarthropathy (HOA) associated with an abdominal neoplasia and blepharoptosis. He had finger clubbing, hyperhidrosis, and hypertrichosis. He also had a recent history of extensive abdominal surgery with a pathology report of myelolipoma. Routine blood work was unremarkable. Upper eyelid reconstruction with blepharoplasty, upper eyelid wedge resection, and brow suspension was performed to address his eyelid concerns. By this case report, we would like to attract notice that the eyelid involvement may be a part of HOA and to emphasize the importance of systemic and pathologic evaluation in failed blepharoptosis surgery. PMID- 27221687 TI - Scleral tunnel phacoemulsification: Approach for eyes with severe microcornea. AB - Cataract surgery in eyes with microcornea is associated with frequent complications such as corneal edema, posterior capsular rent, and risk of unplanned aphakia. We describe an improved surgical technique for the creation of surgical incisions during phacoemulsification in eyes with cataract associated with microcornea. A retrospective analysis of eight patients (8 eyes) operated at our center was undertaken. The mean age of the patients was 29.5 +/- 10.9 years. All eyes were operated using the scleral pocket incision for phacoemulsification. This scleral pocket incision was tangential to the limbus and created approximately 2.5 mm behind limbus through which phacoemulsification probe was inserted. Because of the posterior placement of incision, the anterior chamber crowding was minimized. There was no incidence of port-site peripheral corneal edema. Fifty percent eyes developed transient central corneal edema, the intraocular lens in bag was implanted in 5/8 eyes, and none developed Descemet's membrane detachment. Mean best-corrected visual acuity improved from 1.85 +/- 0.38 logarithm of minimum angle of resolution (LogMAR) to 1.26 +/- 0.70 LogMAR postoperatively (P = 0.01; paired t-test). Posterior incision placement during phacoemulsification in microcornea helps achieve favorable postoperative outcomes in contrast to outcomes using clear corneal approach described in literature. PMID- 27221688 TI - Direct, spontaneous carotid-cavernous fistula with a contracted kidney: A rare association. AB - We report a case of a 20-year-old female having systemic hypertension who presented with right-sided proptosis, chemosis, and diminished vision, preceded by an acute episode of unilateral throbbing headache. Imaging studies revealed a right-sided direct, spontaneous carotid-cavernous fistula (CCF), aneurysm of internal carotid artery, bleed in the parieto-frontal lobe, and swelling of extraocular muscles. Abdominal ultrasound revealed a small contracted right kidney measuring 64 mm * 27 mm. A direct spontaneous CCF can occur spontaneously following rupture of intracranial aneurysm without any history of trauma or connective tissue disorder. Prompt diagnosis of intravascular malformations at initial presentation can prevent neurological complications and vision loss. A team approach including emergency physicians, neurosurgeons, and ophthalmologists is needed for the proper management of such patients. PMID- 27221689 TI - A case of perforating injury of eyeball and traumatic cataract caused by acupuncture. AB - Perforating globe injury is the leading cause of monocular blindness and vision loss. A 58-year-old male was injured by acupuncture needle during acupuncture treatment for his cerebral infarction. To the best of our knowledge, this is the first case report of perforating injury of the eyeball and traumatic cataract caused by acupuncture. The patient was hospitalized due to diagnosis of perforating ocular injury, traumatic cataract, and corneal and iris perforating injury. Moreover, he had to accept treatments of phacoemulsification, anterior vitrectomy along with intraocular lens implantation in the sulcus to improve his visual acuity. As acupuncture therapy has been widely performed for various diseases and achieved highly approval, the aim of this report is to remind acupuncturists operating accurately to avoid unnecessary injury during the treatment process, or the cure can also become the weapon. PMID- 27221690 TI - Comparison of surgically induced astigmatism between horizontal and X-pattern sutures in the scleral tunnel incisions for manual small incision cataract surgery. PMID- 27221691 TI - Why methotrexate suboptimal dosing is a potential source of bias in biologic drugs clinical trials. PMID- 27221692 TI - Does the prevalence of radiographic hand osteoarthritis in patients with HIV-1 infection increase or not? PMID- 27221693 TI - Predicting improvement in diffuse scleroderma: lessons learnt. PMID- 27221695 TI - A DPA-based highly selective and sensitive fluorescent probe for mercuric ions and its imaging in living cells. AB - Based on the 2,2-dipicolylamine (DPA) receptor and naphthalimide fluorophore, three fluorescent probes, RDPA, MDPA and VDPA have been developed for the recognition of mercuric ions. Among them, VDPA, bearing a diglycol group in the imine chain, exhibits good water solubility, and high selectivity towards mercuric ions in PBS water solution. With DPA as the receptor, VDPA showed very high affinity and sensitivity towards Hg(2+), and the binding constant and detection limit were calculated to be 2.8 * 10(10) M(-1) and 5.49 nM, respectively. The MTT assay and living cell imaging experiments suggested that the probe VDPA has potential application for detecting Hg(2+) in living cells. PMID- 27221694 TI - Substance Use Screening, Brief Intervention, and Referral to Treatment Among Medicaid Patients in Wisconsin: Impacts on Healthcare Utilization and Costs. AB - Unhealthy substance use in the USA results in significant mortality and morbidity. This study measured the effectiveness of paraprofessional-administered substance use screening, brief intervention, and referral to treatment (SBIRT) services on subsequent healthcare utilization and costs. The pre-post with comparison group study design used a population-based sample of Medicaid patients 18-64 years receiving healthcare services from 33 clinics in Wisconsin. Substance use screens were completed by 7367 Medicaid beneficiaries, who were compared to 6751 randomly selected treatment-as-usual Medicaid patients. Compared to unscreened patients, those screened changed their utilization over the 24-month follow-up period by 0.143 outpatient days per member per month (PMPM) (p < 0.001), -0.036 inpatient days PMPM (p < 0.05), -0.001 inpatient admissions PMPM (non-significant), and -0.004 emergency department days PMPM (non-significant). The best estimate of net annual savings is $391 per Medicaid adult beneficiary (2014 dollars). SBIRT was associated with significantly greater outpatient visits and significant reductions in inpatient days among working-age Medicaid beneficiaries in Wisconsin. PMID- 27221696 TI - Inguinoscrotal Pathology on Computed Tomography: An Alternative Perspective. AB - Computed tomography (CT) is not the imaging technique of choice to assess inguinoscrotal pathology, as magnetic resonance or ultrasonography have superior soft tissue contrast resolution and do not involve gonadal exposure to ionizing radiation. However, testicular and inguinoscrotal pathology may be found both as an extension of intra-abdominal processes or incidentally on CT scans requested for other reasons. CT also plays a role in the evaluation of testicular injury when associated to pelvic trauma and in perineal infections with scrotal extension. A pictorial review of testicular and inguinoscrotal involvement in vascular, neoplastic, traumatic, infectious, or inflammatory diseases and in complications of abdominal surgeries is presented. Additionally, the CT appearance of several congenital anomalies and benign processes is depicted. PMID- 27221697 TI - Imaging of the Painful Hip Arthroplasty. AB - The incidence of complications following total hip arthroplasty is low, but due to the frequency of the procedure, they are quite commonly encountered and require appropriate investigation. Complications include aseptic loosening, infection, foreign body granulomatosis (osteolysis), adverse reactions to metal debris, periprosthetic fracture, heterotopic ossification, hardware failure, and a range of soft tissue complications, all of which may result in pain. Relevant imaging findings are illustrated and the role of various imaging modalities is reviewed. A suggested approach for the radiological investigation of each potential complication is outlined, based on our experience at a specialist referral unit. PMID- 27221698 TI - Normal Magnetic Resonance Imaging Anatomy of the Capsular Ligamentous Supporting Structures of the Knee. AB - Recognition of the normal magnetic resonance (MR) imaging appearances of the capsular ligaments of the knee is of great importance. These ligaments contribute to stability of the knee joint and are frequently injured. In this article, we describe the normal MR imaging anatomy of the capsular ligaments of the knee including the lateral and medial collateral ligamentous complexes, the extensor mechanism, and the supporting ligamentous structures of the proximal tibiofibular joint. Normal MR imaging findings and important anatomic variants of the neurovascular structures of the knee are also described. PMID- 27221699 TI - iNKT cells in chronic HBV: a balancing act. PMID- 27221700 TI - End-stage liver disease patients with MELD >40 have higher waitlist mortality compared to Status 1A patients. AB - BACKGROUND AND AIMS: Status 1A patients are prioritized over end-stage liver disease (ESLD) for liver transplantation (LT). ESLD patients with high MELD may have higher waitlist mortality than Status 1A patients, and may require LT more urgently. METHODS: Using United Network for Organ Sharing registry data, we retrospectively evaluated LT waitlist mortality and probability of LT between adults in the United States with Status 1A or ESLD with MELD >30 listed for LT from 2003-2013. Overall waitlist mortality and probability of LT were evaluated with Kaplan-Meier and multivariate logistic regression models. RESULTS: From 2003 2013, 15,049 ESLD patients with MELD >30 and 3049 Status 1A patients were listed for LT. While overall 14-day waitlist survival decreased with increasing MELD score among ESLD patients (54.0 % for MELD 31-35; 37.1 % for MELD 36-40; 27.5 % for MELD >40), overall survival at 14 days was significantly lower among Status 1A (14.4 %). Compared to Status 1A, ESLD patients with MELD >40 had significantly higher 14-day waitlist mortality (OR 1.92; 95 % CI 1.56-2.36; p < 0.001), whereas ESLD patients with MELD 36-40 had a non-significant trend towards higher waitlist mortality (OR 1.16; 95 % CI 0.93-1.45; p = 0.181). No difference in probability of LT within 14 days was observed between ESLD with MELD >40 and Status 1A (p = 0.89). ESLD patients with MELD >40 had higher post-LT survival compared to Status 1A on multivariate regression modeling (HR 0.80; 95 % CI 0.66-0.96; p < 0.02). CONCLUSION: Among adults in the United States awaiting LT, ESLD patients with MELD >40 have significantly higher waitlist mortality, but similar probability of receiving LT compared to Status 1A patients. PMID- 27221701 TI - Secondary traumatic stress in the emergency department. AB - AIM: To investigate the prevalence of secondary traumatic stress among Emergency nurses in the West of Scotland and explore their experiences of this. BACKGROUND: Unexpected death, trauma and violence are regular occurrences that contribute to the stressful environment nurses working in the Emergency department experience. A potential consequence of repeated exposure to such stressors can be referred to as secondary traumatic stress. DESIGN: Triangulation of methods of data collection, using two distinct phases: Phase 1 - quantitative Phase 2 - qualitative METHODS: Quantitative data were collated via postal questionnaire, from a convenience sample of Emergency nurses. Qualitative data were subsequently collated from a focus group constituting of a random sample of these Emergency nurses. Descriptive statistics were computed and thematic analysis conducted. All data were collated during February 2013. RESULTS/FINDINGS: 75% of the sampled Emergency nurses reported at least one secondary traumatic stress symptom in the last week. Participants said that acute occupational stressors such as resuscitation and death were the influencing factors towards this. Strategies such as formal debriefing and social support were cited as beneficial tools for the management of secondary traumatic stress; however, barriers such as time and experience were found to inhibit their common use. CONCLUSION: Secondary traumatic stress is a prevalent phenomenon among Emergency nurses in the West of Scotland and if not managed appropriately, could represent a significant barrier to the mental health of this group and their capacity to provide quality care. PMID- 27221702 TI - A Buffered Alcohol-Based Fixative for Histomorphologic and Molecular Applications. AB - Formalin-fixed paraffin-embedded (FFPE) tissue is the predominant preparation for diagnostic histopathological evaluation and increasingly the biospecimen on which molecular diagnostics are performed. However, formalin is carcinogenic and results in cross-linking of proteins and nicking and alterations of nucleic acids. Alternative fixatives, including 70% ethanol, improved biomolecular integrity; however, they have yet to replace neutral-buffered formalin (NBF). Herein, we describe the phosphate-buffered ethanol 70% (BE70) fixative. The histomorphology of BE70-fixed tissue is very similar to that of NBF; however, it is a non-cross-linking fixative and lacks the carcinogenic profile of formaldehyde-based fixatives. RNA isolated from tissue fixed in BE70 was of substantially higher quality and quantity than that was recovered from formalin fixed tissue. Furthermore, the BE70 fixative showed excellent RNA and DNA integrity compared with that of NBF fixative based on real-time polymerase chain reaction analysis results. Immunohistochemical staining was similar for the antigen tested. In conclusion, BE70 is a non-cross-linking fixative that is superior to NBF and 70% ethanol with reference to biomolecule recovery and quality from paraffin-embedded tissue. Additional studies to compare the histomorphologic and immunohistochemical performance and utility in a clinical setting are required. PMID- 27221703 TI - Tissue Factor Induced by Epithelial-Mesenchymal Transition Triggers a Procoagulant State That Drives Metastasis of Circulating Tumor Cells. AB - Epithelial-mesenchymal transition (EMT) is prominent in circulating tumor cells (CTC), but how it influences metastatic spread in this setting is obscure. Insofar as blood provides a specific microenvironment for tumor cells, we explored a potential link between EMT and coagulation that may provide EMT positive CTCs with enhanced colonizing properties. Here we report that EMT induces tissue factor (TF), a major cell-associated initiator of coagulation and related procoagulant properties in the blood. TF blockade by antibody or shRNA diminished the procoagulant activity of EMT-positive cells, confirming a functional role for TF in these processes. Silencing the EMT transcription factor ZEB1 inhibited both EMT-associated TF expression and coagulant activity, further strengthening the link between EMT and coagulation. Accordingly, EMT-positive cells exhibited a higher persistance/survival in the lungs of mice colonized after intravenous injection, a feature diminished by TF or ZEB1 silencing. In tumor cells with limited metastatic capability, enforcing expression of the EMT transcription factor Snail increased TF, coagulant properties, and early metastasis. Clinically, we identified a subpopulation of CTC expressing vimentin and TF in the blood of metastatic breast cancer patients consistent with our observations. Overall, our findings define a novel EMT-TF regulatory axis that triggers local activation of coagulation pathways to support metastatic colonization of EMT-positive CTCs. Cancer Res; 76(14); 4270-82. (c)2016 AACR. PMID- 27221704 TI - Adenosine 2B Receptor Expression on Cancer Cells Promotes Metastasis. AB - Adenosine plays an important role in inflammation and tumor development, progression, and responses to therapy. We show that an adenosine 2B receptor inhibitor (A2BRi) decreases both experimental and spontaneous metastasis and combines with chemotherapy or immune checkpoint inhibitors in mouse models of melanoma and triple-negative breast cancer (TNBC) metastasis. Decreased metastasis upon A2BR inhibition is independent of host A2BR and lymphocytes and myeloid cells. Knockdown of A2BR on mouse and human cancer cells reduces their metastasis in vivo and decreases their viability and colony-forming ability, while transiently delaying cell-cycle arrest in vitro The prometastatic activity of adenosine is partly tumor A2BR dependent and independent of host A2BR expression. In humans, TNBC cell lines express higher A2BR than luminal and Her2(+) breast cancer cell lines, and high expression of A2BR is associated with worse prognosis in TNBC. Collectively, high A2BR on mouse and human tumors promotes cancer metastasis and is an ideal candidate for therapeutic intervention. Cancer Res; 76(15); 4372-82. (c)2016 AACR. PMID- 27221705 TI - MicroRNA-211 Enhances the Oncogenicity of Carcinogen-Induced Oral Carcinoma by Repressing TCF12 and Increasing Antioxidant Activity. AB - miR-211 expression in human oral squamous cell carcinoma (OSCC) has been implicated in poor patient survival. To investigate the oncogenic roles of miR 211, we generated K14-EGFP-miR-211 transgenic mice tagged with GFP. Induction of oral carcinogenesis in transgenic mice using 4-nitroquinoline 1-oxide (4NQO) resulted in more extensive and severe tongue tumorigenesis compared with control animals. We found that 4NQO and arecoline upregulated miR-211 expression in OSCC cells. In silico and experimental evidence further revealed that miR-211 directly targeted transcription factor 12 (TCF12), which mediated suppressor activities in OSCC cells and was drastically downregulated in tumor tissues. We used GeneChip analysis and bioinformatic algorithms to identify transcriptional targets of TCF12 and confirmed through reporter and ChIP assays that family with sequence similarity 213, member A (FAM213A), a peroxiredoxin-like antioxidative protein, was repressed transcriptionally by TCF12. FAM213A silencing in OSCC cells diminished oncogenic activity, reduced the ALDH1-positive cell population, and increased reactive oxygen species. TCF12 and FAM213A expression was correlated inversely in head and neck carcinoma samples according to The Cancer Genome Atlas. OSCC patients bearing tumors with high FAM213A expression tended to have worse survival. Furthermore, 4NQO treatment downregulated TCF12 and upregulated FAM213A by modulating miR-211 both in vitro and in vivo Overall, our findings develop a mouse model that recapitulates the molecular and histopathologic alterations of human OSCC pathogenesis and highlight a new miRNA-mediated oncogenic mechanism. Cancer Res; 76(16); 4872-86. (c)2016 AACR. PMID- 27221706 TI - Tumor Cell Invasion Can Be Blocked by Modulators of Collagen Fibril Alignment That Control Assembly of the Extracellular Matrix. AB - Abnormal architectures of collagen fibers in the extracellular matrix (ECM) are hallmarks of many invasive diseases, including cancer. Targeting specific stages of collagen assembly in vivo presents a great challenge due to the involvement of various crosslinking enzymes in the multistep, hierarchical process of ECM build up. Using advanced microscopic tools, we monitored stages of fibrillary collagen assembly in a native fibroblast-derived 3D matrix system and identified anti lysyl oxidase-like 2 (LOXL2) antibodies that alter the natural alignment and width of endogenic fibrillary collagens without affecting ECM composition. The disrupted collagen morphologies interfered with the adhesion and invasion properties of human breast cancer cells. Treatment of mice bearing breast cancer xenografts with the inhibitory antibodies resulted in disruption of the tumorigenic collagen superstructure and in reduction of primary tumor growth. Our approach could serve as a general methodology to identify novel therapeutics targeting fibrillary protein organization to treat ECM-associated pathologies. Cancer Res; 76(14); 4249-58. (c)2016 AACR. PMID- 27221707 TI - Suppressing the killer instinct. AB - Natural killer (NK) cells are innate lymphoid cells that have adopted activating and inhibitory signaling mechanisms enabling them to be tolerant of normal cells but to distinguish and eliminate tumor cells and virus-infected cells. In this issue of Science Signaling, Matalon et al show how inhibitory receptors disrupt NK cell activation by stimulating dephosphorylation of the adaptor protein LAT (linker of activated T cells) and phospholipase C-gamma by the phosphatase SHP-1 [Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 1], as well as ubiquitylation of LAT by Cbl family E3 ubiquitin ligases. PMID- 27221708 TI - Forget about thrombosis: Platelets and Alzheimer's disease, yet another sticky situation. AB - In this issue of Science Signaling, Donner et al define a highly interesting role for platelets in mediating the pathogenesis of Alzheimer's disease via a mechanism linked to integrin alphaIIbbeta3 outside-in signaling and adenosine diphosphate release. These findings raise the intriguing prospect of harnessing antiplatelet drugs for disrupting the nexus between Abeta-induced activated platelets and Abeta fibril and aggregate formation. PMID- 27221709 TI - Science Signaling podcast for 24 May 2016: Designer estrogens. AB - This Podcast features an interview with Zeynep Madak-Erdogan, Benita Katzenellenbogen, and John Katzenellenbogen, authors of a Research Article that appears in the 24 May 2016 issue of Science Signaling, about designer estrogens that have the therapeutic benefits of natural estrogens, but less cancer risk. In addition to controlling female reproduction and secondary sex characteristics, estrogen is also an important regulator of metabolism, the vasculature, and bone. Estrogen production decreases as women enter menopause, leading to changes in metabolism, a reduced ability to repair blood vessels, and decreased bone density. Although hormone replacement therapy can alleviate these symptoms, it can also promote the growth of uterine and breast cancers. Madak-Erdogan et al engineered synthetic forms of estrogen that activate the cytosolic signaling pathways that are associated with the beneficial effects of this hormone without also activating the nuclear signaling events associated with cancer growth.Listen to Podcast. PMID- 27221710 TI - Platelets contribute to amyloid-beta aggregation in cerebral vessels through integrin alphaIIbbeta3-induced outside-in signaling and clusterin release. AB - Cerebral amyloid angiopathy (CAA) is a vascular dysfunction disorder characterized by deposits of amyloid-beta (Abeta) in the walls of cerebral vessels. CAA and Abeta deposition in the brain parenchyma contribute to dementia and Alzheimer's disease (AD). We investigated the contribution of platelets, which accumulate at vascular Abeta deposits, to CAA. We found that synthetic monomeric Abeta40 bound through its RHDS (Arg-His-Asp-Ser) sequence to integrin alphaIIbbeta3, which is the receptor for the extracellular matrix protein fibrinogen, and stimulated the secretion of adenosine diphosphate (ADP) and the chaperone protein clusterin from platelets. Clusterin promoted the formation of fibrillar Abeta aggregates, and ADP acted through its receptors P2Y1 and P2Y12 on platelets to enhance integrin alphaIIbbeta3 activation, further increasing the secretion of clusterin and Abeta40 binding to platelets. Platelets from patients with Glanzmann's thrombasthenia, a bleeding disorder in which platelets have little or dysfunctional alphaIIbbeta3, indicated that the abundance of this integrin dictated Abeta-induced clusterin release and platelet-induced Abeta aggregation. The antiplatelet agent clopidogrel, which irreversibly inhibits P2Y12, inhibited Abeta aggregation in platelet cultures; in transgenic AD model mice, this drug reduced the amount of clusterin in the circulation and the incidence of CAA. Our findings indicate that activated platelets directly contribute to CAA by promoting the formation of Abeta aggregates and that Abeta, in turn, activates platelets, creating a feed-forward loop. Thus, antiplatelet therapy may alleviate fibril formation in cerebral vessels of AD patients. PMID- 27221712 TI - Dephosphorylation of the adaptor LAT and phospholipase C-gamma by SHP-1 inhibits natural killer cell cytotoxicity. AB - Natural killer (NK) cells discriminate between healthy cells and virally infected or transformed self-cells by tuning activating and inhibitory signals received through cell surface receptors. Inhibitory receptors inhibit NK cell function by recruiting and activating the tyrosine phosphatase Src homology 2 (SH2) domain containing protein tyrosine phosphatase-1 (SHP-1) to the plasma membrane. However, to date, the guanine nucleotide exchange factor VAV1 is the only direct SHP-1 substrate identified in NK cells. We reveal that the adaptor protein linker for activation of T cells (LAT) as well as phospholipase C-gamma1 (PLC-gamma1) and PLC-gamma2 are SHP-1 substrates. Dephosphorylation of Tyr(132) in LAT by SHP 1 in NK cells abrogated the recruitment of PLC-gamma1 and PLC-gamma2 to the immunological synapse between the NK cell and a cancer cell target, which reduced NK cell degranulation and target cell killing. Furthermore, the ubiquitylation of LAT by the E3 ubiquitin ligases c-Cbl and Cbl-b, which was induced by LAT phosphorylation, led to the degradation of LAT in response to the engagement of inhibitory receptors on NK cells, which abrogated NK cell cytotoxicity. Knockdown of the Cbl proteins blocked LAT ubiquitylation, which promoted NK cell function. Expression of a ubiquitylation-resistant mutant LAT blocked inhibitory receptor signaling, enabling cells to become activated. Together, these data identify previously uncharacterized SHP-1 substrates and inhibitory mechanisms that determine the response of NK cells. PMID- 27221711 TI - Design of pathway preferential estrogens that provide beneficial metabolic and vascular effects without stimulating reproductive tissues. AB - There is great medical need for estrogens with favorable pharmacological profiles that support desirable activities for menopausal women, such as metabolic and vascular protection, but that lack stimulatory activities on the breast and uterus. We report the development of structurally novel estrogens that preferentially activate a subset of estrogen receptor (ER) signaling pathways and result in favorable target tissue-selective activity. Through a process of structural alteration of estrogenic ligands that was designed to preserve their essential chemical and physical features but greatly reduced their binding affinity for ERs, we obtained "pathway preferential estrogens" (PaPEs), which interacted with ERs to activate the extranuclear-initiated signaling pathway preferentially over the nuclear-initiated pathway. PaPEs elicited a pattern of gene regulation and cellular and biological processes that did not stimulate reproductive and mammary tissues or breast cancer cells. However, in ovariectomized mice, PaPEs triggered beneficial responses both in metabolic tissues (adipose tissue and liver) that reduced body weight gain and fat accumulation and in the vasculature that accelerated repair of endothelial damage. This process of designed ligand structure alteration represents a novel approach to develop ligands that shift the balance in ER-mediated extranuclear and nuclear pathways to obtain tissue-selective, non-nuclear PaPEs, which may be beneficial for postmenopausal hormone replacement. The approach may also have broad applicability for other members of the nuclear hormone receptor superfamily. PMID- 27221713 TI - Wall thickness of the pulmonary vein-left atrial junction rather than electrical information as the major determinant of dormant conduction after contact force guided pulmonary vein isolation. AB - PURPOSE: The usefulness of electrogram (EGM)-based information has been reported for assessing lesion transmurality during atrial fibrillation (AF) ablation, but the wall thickness of the pulmonary vein-left atrial (PV-LA) junction has not been considered. We conducted a study to evaluate the relation between PV-LA junction wall thickness and the presence of adenosine triphosphate (ATP)-provoked dormant PV conduction. METHODS: Eighteen AF patients underwent extensive encircling pulmonary vein isolation (EEPVI) with a target CF of >10 g. RF energy was delivered point-by-point at a power setting of 25-30 W for 30 s, and EGM based information (change in filtered unipolar EGM morphology and bipolar EGM amplitude), decrease in impedance, CF, and CT-based measurement of the PV-LA junction wall thickness were characterized at sites of ATP-provoked dormant conduction. RESULTS: After EEPVI, ATP-induced dormant conduction was observed at 12 of the 288 PV sites (8 segments per ipsilateral PVs * 2 * 18 patients). Of the 974 ablation points, 72 were located at dormant conduction sites and were strongly associated with thickened PV-LA junction walls (1.02+/- 0.23 vs. 0.86 +/ 0.26 mm, p < 0.0001) and decreased impedance (13.3 +/- 6.4 vs. 14.9 +/- 7.1 Omega, p = 0.0498) but not with EGM-based information or CF. Multivariate analysis identified the thickened PV-LA junction wall as the strongest predictor of dormant conduction. CONCLUSIONS: A thickened PV-LA junction wall is a robust predictor of ATP-provoked dormant conduction; EGM-based information appears to be insufficient for ensuring adequate lesions during CF-guided EEPVI. PMID- 27221714 TI - Time-limited cryomapping during tachycardia: improved long-term outcomes for cryoablation of AVNRT. AB - PURPOSE: Cryothermal ablation (CTA) for atrioventricular nodal reentrant tachycardia (AVNRT) is considered safer than radiofrequency ablation (RFA) since it eliminates the risk of inadvertent AV block. However, it has not been widely adopted due to high late recurrence rate (LRR). In an effort to improve LRR, we evaluated a new approach to cryothermal mapping (CTM): "time to tachycardia termination" (TTT). METHODS: This single-center study had 88 consecutive patients who underwent CTA using TTT for AVNRT. The CTA catheter was positioned in sinus rhythm at the posteroseptal tricuspid annulus, and then AVNRT was induced. The CTA target site was identified by prompt tachycardia termination in <=20 s during CTM. Procedural success was defined as no inducible AVNRT and <=1 single AV nodal echoes. RESULTS: Acute procedural success was achieved in 87 of 88 patients (98.9 %) and was similar to prior studies for both CTA and RFA. No permanent AV block was observed. LRR was 3.7 % at a mean follow-up of 19.7 months. LRR was equivalent to that commonly reported for RFA and improved when compared to conventional CTA. CONCLUSION: TTT for CTA of AVNRT provides enhanced safety and similar long-term efficacy when compared to RFA. Based upon this experience, TTT provides an enhancement to conventional CTA that appears to result in improved long-term outcomes. In light of these findings, it seems reasonable to undertake additional randomized trials to determine whether RFA or CTA using TTT is the optimal approach for the catheter ablation of AVNRT. PMID- 27221715 TI - CD49d shows superior performance characteristics for flow cytometric prognostic testing in chronic lymphocytic leukemia/small lymphocytic lymphoma. AB - BACKGROUND: CD49d is emerging as a powerful adverse prognostic marker in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). However, flow cytometric testing for CD49d has not yet been widely adopted in the United States, in part due to the lack of establishment of its performance characteristics in the clinical setting, especially in comparison with the more common CLL/SLL prognostic markers CD38 and ZAP-70. METHODS: CD49d expression levels in 124 CLL/SLL cases were assessed among peripheral blood (PB), bone marrow (BM), and lymph node (LN) specimens and correlated with available CD38 and ZAP-70 expression and cytogenetic findings. For 10 PB/BM specimens, the stability of CD49d, CD38, and ZAP-70 expression was assessed at <24 hours, 48 hours, 72 hours, and 96 hours. RESULTS: 39% (28 of 71) PB, 56% (18 of 32) BM, and 71% (15 of 21) LN involved by CLL/SLL were CD49d+, using a >=30% threshold. The mean for the CD49d+ cases was 2.8 standard deviations (SD) above the cutoff for positivity, compared with 1.7 SD for CD38 and 1.1 SD for ZAP-70. CD49d demonstrated the lowest mean SD (0.91) and coefficient of variation (CV) (8.0%) compared with CD38 (SD = 2.1, CV = 10.4%) and ZAP-70 (SD = 9.8, CV = 40.5%) in stability studies over a 96-hours time period. CD49d+ CLL/SLL correlated with trisomy 12 (P = 0.025) and lack of isolated deletion (13q) (P = 0.005). CD38+ CLL/SLL correlated with deletion (11q) (P = 0.025). ZAP-70 did not correlate with any underlying cytogenetic abnormality. CONCLUSIONS: CD49d is a robust adverse prognostic marker in CLL/SLL with superior performance characteristics. (c) 2016 International Clinical Cytometry Society. PMID- 27221716 TI - Upper airway microbial colonization in patients with neuromuscular disorders. AB - BACKGROUND AND OBJECTIVE: Inherited neuromuscular disorders (NMD) inevitably result in severe lung volume restriction and cough insufficiency associated with high morbidity and mortality. The aim of this retrospective study was to evaluate whether the airways of patients with NMD are colonized with potential pathogenic microorganisms that might contribute to the pulmonary morbidity in NMD. METHODS: In this cross-sectional study, cough swabs were obtained and cultured for microbiological analyses from 77 patients with NMD and different degrees of lung volume restriction and cough insufficiency. Upper airway microbial colonization was compared to lung function parameters and cough peak flow values. RESULTS: Upper airway microbial colonization with potential pathogenic pathogens was identified in 39/77 (51%) of the subjects. Upper airway microbial colonization was associated with lower forced vital capacity (% pred.) 26.6 +/- 19.7 versus 41.8 +/- 20.4, P < 0.001 and cough peak flow (l/min) 125 +/- 55 versus 207 +/- 100, P < 0.001. In the subgroup colonized with potential pathogenic Gram-negative bacteria or Staphylococcus aureus forced vital capacity and cough peak flow remained significantly lower compared with subjects without upper airway colonization (FVC (% pred.): 22.6 +/- 16.5 vs 37.9 +/- 21.5, P = 0.003; CPF (l/min): 123 +/- 60 vs 179 +/- 93, P = 0.013). CONCLUSION: Severe respiratory compromise in patients with NMD is associated with upper airway microbial airway colonization, which might contribute to respiratory morbidity/insufficiency. PMID- 27221717 TI - Timing of Hepatitis C Antiviral Therapy in Liver Transplant Recipients With Direct-acting Agents. AB - Chronic hepatitis C virus infection is a substantial health care burden worldwide and is the leading cause of liver transplant in adults. In patients with detectable hepatitis C virus RNA at the time of transplant, interferon-based therapies for hepatitis C virus were poorly tolerated with low virologic response rates. Although reinfection after transplant is inevitable, the recent advent of direct-acting antiviral agents has revolutionized treatment of hepatitis C virus in the pre- and posttransplant settings. These antiviral agents have been shown to have high-sustained virologic response rates, shorter courses of treatment, and decreased frequencies of adverse effects. Here, we review the current literature on the use of direct-acting agents for treatment of patients with hepatitis C virus before and after liver transplant. PMID- 27221718 TI - Predictability and Risk Factors for Development of New-Onset Type 2 Diabetes Mellitus After Transplant in the Saudi Population. AB - OBJECTIVES: The study objective was to investigate the predictability and risk factors for the development of new-onset type 2 diabetes mellitus after transplant in the Saudi population. MATERIALS AND METHODS: This was a retrospective observational cohort study in adult kidney transplant recipients who developed new-onset type 2 diabetes mellitus after transplant. Patients with and without new-onset type 2 diabetes mellitus after transplant were compared for demographic factors, blood glucose levels at 4-hour intervals for 24 hours after transplant, and serum creatinine levels at 6 and 12 months after transplant. RESULTS: Of 279 patients included in our study, 15.5% developed new-onset type 2 diabetes mellitus after a mean follow-up of 4.6 +/- 2.1 years after transplant. Patients with new-onset type 2 diabetes mellitus after transplant were significant older (P = .001), had a higher body mass index (P = .001), and had higher fasting blood glucose levels 24 hours after transplant (P = .03). No significant differences were observed regarding sex, transplant type, or serum creatinine levels at 6 and 12 months. Risk factors for new-onset type 2 diabetes mellitus after transplant are body mass index (P = .001; relative risk of 1.26), fasting blood glucose at 24 hours (P = .001; relative risk of 1.3), age (P = .001; relative risk of 1.44), and family history of diabetes mellitus (P = .001; relative risk of 31.3). CONCLUSIONS: Risk factors for developing new-onset type 2 diabetes mellitus were age, heavier weight, body mass index, family history of diabetes mellitus, and having higher fasting blood glucose levels 24 hours after transplant, with family history of diabetes mellitus being an especially very high significant risk factor. PMID- 27221719 TI - Comparative Outcomes of Hand-assisted Laparoscopic Donor Nephrectomy Using Midline Incision or Low Transverse Incision for Hand-assisted Port Placement. AB - OBJECTIVES: Hand-assisted laparoscopic donor nephrectomy is performed in many centers for donor nephrectomy. A midline incision for hand-assisted port placement is generally used but produces an unsightly scar. In this study, patients who had hand-assisted laparoscopic donor nephrectomy with low transverse incision were compared with those who received a midline incision. MATERIALS AND METHODS: Our study group included patients who received hand-assisted laparoscopic donor nephrectomy from February 2012 to December 2014 at Korea University Anam Hospital. We retrospectively compared outcomes of these patients based on midline incision (45 patients) versus low transverse incision (17 patients). Risk factors, including age, sex, body mass index, creatinine level, glomerular filtration rate of allograft, side of graft kidney, number of renal arteries, duration of surgical procedure, and warm ischemic time, were compared between the midline and low transverse incision groups. RESULTS: When we compared the midline versus low transverse incision groups, duration of surgical procedure (P = .043), postoperative day 3 glomerular filtration rate (P = .017), and postoperative day 3 pain score (P = .049) were significantly higher in the low transverse incision group versus the midline incision group. Postoperative day 3 results for duration of hospitalization (P = .030) and pain score (P = .021) were also significantly higher in the low transverse versus midline incision groups when we focused on patients with left nephrectomy. CONCLUSIONS: Hand-assisted laparoscopic donor nephrectomy with low transverse incision is more painful and necessitates a longer hospital stay and longer surgical procedure. Despite these disadvantages, hand-assisted laparoscopic donor nephrectomy with low transverse incision can offer a better cosmetic outcome with no definitive differences regarding renal function compared with a midline incision. Surgeons should consider these aspects when deciding on the best method for donor nephrectomy. PMID- 27221720 TI - Outcomes of Early Steroid Withdrawal in Recipients of Deceased-Donor Expanded Criteria Kidney Transplants in the Era of Induction Therapy. AB - OBJECTIVES: This study explored the safety of early steroid withdrawal in recipients of expanded criteria deceased-donor kidney transplants. MATERIALS AND METHODS: Using the Organ Procurement and Transplant Network-United Network of Organ Sharing database, we identified patients who underwent expanded criteria deceased-donor kidney transplant between January 2000 and December 2008 after receiving induction with rabbit-antithymocyte globulin (n = 3717), alemtuzumab (n = 763), or interleukin 2 blocking agent (n = 2600) followed by calcineurin inhibitor and mycophenolate mofetil-based maintenance with and without steroid therapy. RESULTS: Adjusted overall graft survival (hazard ratio 1.32; 95% confidence interval, 1.1-1.56; P = .002) and patient survival (hazard ratio 1.46, 95% confidence interval, 1.16-1.83, P = .001) were inferior, whereas death censored graft survival (hazard ratio 1.13; 95% confidence interval, 0.87-1.47; P = .35) was similar for chronic steroid maintenance versus early steroid withdrawal groups in rabbit-antithymocyte globulin-induced patients. Graft and patient outcomes were similar for chronic steroid maintenance versus early steroid withdrawal groups among alemtuzumab and interleukin 2 blocking agent induced patients. Among rabbit-antithymocyte globulin-induced patients, adjusted overall graft survival (hazard ratio 1.57; 95% confidence interval, 1.2-2.0; P < .001) and patient survival (hazard ratio 1.5; 95% CI, 1.15-2.1; P = .004) were inferior, whereas death-censored graft survival (hazard ratio 1.5; 95% confidence interval, 0.97-2.43; P = .07) trended inferior for chronic steroid maintenance versus early steroid withdrawal groups in recipients > 60 years old (n = 1729). CONCLUSIONS: Our study showed safety of early steroid withdrawal in recipients of expanded criteria deceased-donor kidney transplants who underwent perioperative induction followed by calcineurin inhibitor and mycophenolate mofetil maintenance. Among rabbit-antithymocyte globulin-induced patients, chronic steroid maintenance was associated with inferior graft and patient outcomes, an effect limited to older recipients. PMID- 27221721 TI - Donor Desmopressin Treatment Does Not Affect Transplant Outcome in the Fischer to Lewis Rat Renal Transplant Model. AB - OBJECTIVES: Retrospective studies suggest that donor desmopressin (DDAVP) treatment improves renal transplant outcome. The present study tests the hypothesis that desmopressin neutralizes the graft's endothelium from proinflammatory angiopoietin 2 containing Weibel-Palade bodies in the donor, resulting in reduced Weibel-Palade body release at the time of reperfusion in the recipient. MATERIALS AND METHODS: Using rat models, we examined the influence of desmopressin treatment on the expression of vasopressin 2 receptors and adhesion molecules in brain-dead donors, with renal function examined in allogeneic recipients. The influence of desmopressin on the expression of adhesion molecules also was tested in vitro. RESULTS: Vasopressin 2 receptors were restricted to collecting ducts and distal tubules and only scarcely found in the renal vasculature. Vasopressin 2 receptor expression was down-regulated in brain-dead rats by desmopressin. Renal expression of vascular cellular adhesion molecule 1 and intercellular adhesion molecule 1 were significantly reduced in these rats. In contrast, angiopoietin 2 did not influence the expression of adhesion molecules in in vitro cultured endothelial cells after tumor necrosis factor ? stimulation. Donor desmopressin treatment improved neither renal function nor histology in allogeneic renal transplant recipients. CONCLUSIONS: Our data do not support the hypothesis that the clinically observed salutary effect of desmopressin is mediated by depletion of Weibel-Palade bodies in renal allografts. PMID- 27221722 TI - Possible Association Between the Methylenetetrahydrofolate Reductase Gene C677T Polymorphism and Preexisting Portal Vein Thrombosis in Liver Transplant Recipients. AB - OBJECTIVES: Liver transplant in patients with preexisting portal vein thrombosis involves complicated surgical procedures and increased blood loss, indicating the need for further surgical innovations to overcome these difficulties. Patients who are at high risk of developing portal vein thrombosis may benefit from prophylactic anticoagulant therapy while on the transplant wait list. Homozygosity for C677T polymorphism in the methylenetetrahydrofolate reductase gene has been associated with a high plasma homocysteine concentration, which is a risk factor for venous thrombosis. This study investigated the association between C677T polymorphism in the methylenetetrahydrofolate reductase gene and preexisting portal vein thrombosis in patients with liver cirrhosis undergoing liver transplant. MATERIALS AND METHODS: C677T polymorphism in the methylenetetrahydrofolate reductase gene was investigated in 48 patients who underwent liver transplant at Nagoya University. RESULTS: Of 48 patients, 7 (14.6%) had preexisting portal vein thrombosis confirmed at transplant. The frequency of methylenetetrahydrofolate reductase gene C677T genotype in recipients was significantly associated with preexisting portal vein thrombosis (P = .009, with P <= .013 considered significant). Logistic regression analysis showed that the TT genotype of the methylenetetrahydrofolate reductase gene was significantly associated with a higher incidence of preexisting portal vein thrombosis compared with the CC and CT genotypes (odds ratio of 14.6, 95% confidence interval, 1.86-115.21; P = .011). CONCLUSIONS: The TT genotype of the methylenetetrahydrofolate reductase gene may be associated with a higher incidence of preexisting portal vein thrombosis, as confirmed at liver transplant. Identification of this genotype in patients with liver cirrhosis at the time of placement on a wait list for liver transplant may enable preventive therapy for portal vein thrombosis in these patients, reducing the complexity of surgical procedures. PMID- 27221723 TI - Use of Monitoring Gamma-Glutamyl Transpeptidase Levels After Liver Transplant: A Longitudinal Retrospective Analysis of a Single-Center's Experience. AB - OBJECTIVES: Recently, gamma-glutamyl transpeptidase has garnered increased attention as a diagnostic tool in the early identification of liver disease. However, its value in liver transplant is largely unknown, as the disease processes leading to abnormal gamma-glutamyl transpeptidase levels and the expected temporal trends in gamma-glutamyl transpeptidase levels during the period after liver transplant remain unclear. MATERIALS AND METHODS: Between January 2010 and August 2013, consecutive patients who underwent liver transplant at Vancouver General Hospital (Vancouver, Canada) were assessed longitudinally up to 1 year after liver transplant. A "gamma-glutamyl transpeptidase event" was defined as 2 abnormal gamma-glutamyl transpeptidase values (exceeding sex specific limits of normal, at 55 U/L for female and 80 U/L for male patients) >= 1 week apart. RESULTS: Our study included 147 liver transplant recipients. The median gamma-glutamyl transpeptidase level on day 1 after liver transplant was 73 U/L, which peaked to 435 U/L during the first month after liver transplant and returned to within normal parameters by 1 year. In total, there were 282 gamma glutamyl transpeptidase events, with biliary complications (22%), acute rejection (16%), and hepatitis C virus recurrence (10%) being the most common causes. In 39% of events, no cause was identified. When attempting to identify a disease associated event, if gamma-glutamyl transpeptidase was the initial liver biochemistry test to double in value, it had 42% sensitivity and 40% specificity. Comparatively, if gamma-glutamyl transpeptidase was the initial liver biochemistry test to become abnormal, it had 3% sensitivity and 93% specificity. CONCLUSIONS: Although gamma-glutamyl transpeptidase almost universally becomes abnormal after liver transplant, a specific pathologic cause was not commonly identified. Interpreting the characteristics of gamma-glutamyl transpeptidase elevation has limited use for identifying the underlying reason for its elevation. PMID- 27221725 TI - [Benefits of otoscopy in forensic autopsy practice: A prospective study]. AB - The otoscopy is an examination of the external auditory canal, the eardrum, and the middle ear with an instrument called an otoscope. It is a simple, inexpensive, and time-saving endoscopic method typically used by general practitioners and otorhinolaryngologists. Authors present a prospective study of otoscopic findings investigated consecutively at autopsy. Of the 250 examined persons, 50 positive findings were identified: 38 cases with petechial hemorrhages and 12 cases with tympanic membrane perforation or hemotympanon. Hemorrhages of the tympanic membrane detected through the otoscopy may serve as evidence of congestion within head and neck potentially associated with asphyxiation either in the death or in the living (similar to periorbital and conjuctival petechial hemorrhages). In our study, hemorrhages of the tympanic membrane were related to heart failure, hanging and asphyxiation. Perforated tympanic membrane and hemotympanum have been sporadically reported in victims of fatal lightning strike and rarely in strangulation. This findings were in our study associated with craniocerebral injuries: traffic accidents, falls from height and gunshot injuries. The otoscopy may help to reveal various traumatic and pathological changes within the outer and the middle ear, and, thus, provide important forensic evidence. The otoscopy is also highly recommended in the investigation of the sudden deaths in the young. PMID- 27221724 TI - Effects of Contrast-Enhanced Ultrasonography in Monitoring Hepatic Microcirculation After Rat Liver Ischemia-Reperfusion Injury. AB - OBJECTIVES: Our objective was to evaluate the effects of contrast-enhanced ultrasonography in monitoring microcirculation after rat liver ischemia reperfusion injury. MATERIALS AND METHODS: Male Wistar rats (n = 36) were divided into sham-operated and ischemia-reperfusion groups. Rats in the ischemia reperfusion groups underwent normothermic liver ischemia for 15 minutes followed by 1, 6, or 24 hours of reperfusion. At different time points, contrast-enhanced ultrasonography was performed to determine peak intensity in monitoring hepatic microcirculation. In addition, serum levels of alanine aminotransferase, aspartate aminotransferase, tumor necrosis factor alpha, and interleukin 1beta levels were measured. Histopathologic changes were also observed. RESULTS: One hour after reperfusion, peak intensity values decreased, and serum levels of alanine aminotransferase, tumor necrosis factor alpha, and interleukin 1beta increased significantly in the ischemia-reperfusion group compared with the sham operated group. Histology results showed mild injury. Six hours after reperfusion, peak intensity values decreased continuously, serum levels of alanine aminotransferase, tumor necrosis factor alpha, and interleukin 1beta decreased, and aspartate aminotransferase levels increased. Histology results showed severe injury compared with 1 hour after reperfusion. Twenty-four hours after reperfusion, peak intensity values increased, alanine aminotransferase and aspartate aminotransferase levels decreased, and histology results showed moderate injury compared with 6 hours after reperfusion. Peak intensity values were negatively correlated to alanine aminotransferase (P < .05; gamma = -0.38) and aspartate aminotransferase (P < .01; gamma = -0.78) levels. CONCLUSIONS: Microcirculation dysfunction after liver ischemia-reperfusion injury can be monitored by contrast-enhanced ultrasonography. The perfusion of contrast agents negatively correlates to the severity of injuries. PMID- 27221726 TI - Right haemothorax related to the rupture of abdominal aortic aneurysm. AB - Reported case was 63 years old forester died suddenly in the village. Autopsy examination revealed massive coagulated haemorrhage filling the right hemithorax, neither free fluid nor blood were observed in the abdominal cavity. Abdominal aortic aneurysm 20x15x15 cm in size was examined. We aimed to report the rare case of abdominal aortic aneurysm presented with transdiafragmatic rupture and bleeding in the right hemithorax. PMID- 27221727 TI - [Injury of upper cervical spine]. AB - Injuries of the upper cervical spine represent 1/3 of all cervical spine injuries and approximately 40 % result by the death. Every level of the cervical spine can be injured - fractures of condyles of the occipital bone (CO), atlantooccipital dislocation (AOD), fractures of the Atlas (C1), atlantoaxial dislocation (AAD) and fractures of the axis (C2). Most of cases in younger patients are caused by high-energy trauma, while by elderly people, because of the osteoporosis, is needed much less energy and even simple falls can cause the injury of the cervical spine. That's why the etiology of injuries can be different. In younger patients are caused mainly by car accidents, motorcycle and bicycle accidents and pedestrian crashes by car and in elderly populations are the main reason falls. The mechanism of the injury is axial force, hyperflexion, hyperextension, latero flexion, rotation and combination of all. The basic diagnostic examination is X ray in AP, lateral and transoral projection. But in the most of cases is CT examination necessary and in the suspicion of the ligamentous injury and neurological deterioration must be MRI examination added. Every injury of the upper cervical spine has its own classification. Clinical symptoms can vary from the neck pain, restricted range of motion, antalgic position of the head, injury of the cranial nerves and different neurologic symptoms from the irritation of nerves to quadriplegia. A large percentage of deaths is at the time of the injury. Therapy is divided to conservative treatment, which is indicated in bone injuries with minimal dislocation. In more severe cases, with the dislocation and ligamentous injury, when is high chance of the instability, is indicated the surgical treatment. We can use anterior or posterior approach, make the osteosynthesis, stabilisation and fusion of the spine. Complex fractures and combination of different types of injuries are often present in this part of the spine. Correct and early diagnosis with the best treatment option is necessary for successful result of the cervical spine injuries. PMID- 27221729 TI - Pharmacokinetics and excretion of (14)C-omacetaxine in patients with advanced solid tumors. AB - Background Omacetaxine mepesuccinate is indicated in adults with chronic myeloid leukemia resistant and/or intolerant to >= 2 tyrosine kinase inhibitor treatments. This phase I study assessed the disposition, elimination, and safety of (14)C-omacetaxine in patients with solid tumors. Methods The study comprised a 7-days pharmacokinetic assessment followed by a treatment period of <= six 28 days cycles. A single subcutaneous dose of 1.25 mg/m(2) (14)C-omacetaxine was administered to six patients. Blood, urine, and feces were collected through 168 h or until radioactivity excreted within 24 h was <1 % of the dose. Total radioactivity (TRA) was measured in all matrices and concentrations of omacetaxine, 4'-desmethylhomoharringtonine (4'-DMHHT), and cephalotaxine were measured in plasma and urine. For each treatment cycle, patients received 1.25 mg/m(2) omacetaxine twice daily for 7 days. Results Mean TRA recovered was approximately 81 % of the dose, with approximately half of the radioactivity recovered in feces and half in urine. Approximately 20 % of the dose was excreted unchanged in urine; cephalotaxine (0.4 % of dose) and 4' DMHHT (9 %) were also present. Plasma concentrations of TRA were higher than the sum of omacetaxine and known metabolites, suggesting the presence of other (14)C-omacetaxine-derived compounds. Fatigue and anemia were common, consistent with the known toxicity profile of omacetaxine. Conclusion Renal and hepatic processes contribute to the elimination of (14)C-omacetaxine-derived radioactivity in cancer patients. In addition to omacetaxine and its known metabolites, other (14)C-omacetaxine derived materials appear to be present in plasma and urine. Omacetaxine was adequately tolerated, with no new safety signals. PMID- 27221728 TI - Use of Biomarkers in the Evaluation and Treatment of Hypertensive Patients. AB - The current definition of hypertension is based on blood pressure values, and blood pressure also drives treatment decisions, is the most important treatment monitoring tool and helps estimating risk of hypertension-related organ damage. In an era of precision medicine, additional biomarkers are needed in the diagnosis and management of patients with hypertension. In this review, we outline the areas in which functional, imaging and circulating biomarkers could help in a more individualised definition of hypertension and associated risk. We will cover biomarkers for diagnosis; of pathophysiology and prediction of hypertension; response to treatment, organ damage; and to monitor treatment. A clear focus is on the vasculature, the heart and the kidneys, whereas we see a need to further develop biomarkers of cerebral function in order to diagnose cognition deficits and monitor changes in cognition in the future to support addressing the growing burden of hypertension-associated vascular dementia. PMID- 27221730 TI - The imidazoline compound RX871024 promotes insulinoma cell death independent of AMP-activated protein kinase inhibition. AB - We have previously shown that the insulinotropic imidazoline compound RX871024 induces death of insulinoma MIN6 cells, an effect involving stimulation of c-Jun N-terminal kinase (JNK) and caspase 3. It has also been reported that AMP activated protein kinase (AMPK) activates JNK and induces beta-cell death. Here we show that RX871024, but not another insulinotropic imidazoline compound (BL11282), suppressed AMPK activity in MIN6 cells. The inhibitory effect of RX871024 on AMPK was supported by the observation that the imidazoline induced lipid droplet formation in the cytoplasm of MIN6 cells. This reflects stimulation of anabolic pathways and inhibition of catabolic pathways in the cell that happen under conditions when AMPK is inhibited. Activation of AMPK by 5-aminoimidazole-4 carboxamide riboside (AICAR) elevated basal and cytokine-induced death in primary beta-cells and in insulinoma MIN6 cells. RX871024 aggravated AICAR-induced insulinoma MIN6 cell death regardless of the presence of pro-inflammatory cytokines. The specific cytotoxic effect of imidazoline compound RX871024 on insulinoma cell death but not primary beta-cell death is independent of its action on AMPK and may suggest the possibility of using this type of compound in the treatment of insulinomas. PMID- 27221731 TI - Primary tumor site is a useful predictor of cetuximab efficacy in the third-line or salvage treatment of KRAS wild-type (exon 2 non-mutant) metastatic colorectal cancer: a nationwide cohort study. AB - BACKGROUND: Previous studies have shown left-sided colorectal cancer (LCRC) and right-sided colorectal cancer (RCRC) exhibit different molecular and clinicopathological features. We explored the association between the primary tumor site and cetuximab efficacy in KRAS wild-type colorectal cancer (CRC). METHODS: This study enrolled a cohort of patients, who had received cetuximab treatment after two or more lines of chemotherapy for KRAS wild-type (exon 2 nonmutant) metastatic CRC, from the databases of Taiwan Cancer Registry (2004 2010) and National Health Insurance (2004-2011). Survival data were obtained from the National Death Registry. Time to treatment discontinuation (TTD) and overall survival (OS) after the start of cetuximab treatment were compared between patients with LCRC (splenic flexure to rectum) and RCRC (cecum to hepatic flexure). RESULTS: A total of 969 CRC patients were enrolled. Among them, 765 (78.9 %) and 136 (14.0 %) patients had LCRC and RCRC, respectively. Patients with LCRC, compared to patients with RCRC, had longer TTD (median, 4.59 vs. 2.75 months, P = .0005) and OS (median, 12.62 vs. 8.07 months, P < .0001) after the start of cetuximab treatment. Multivariate analysis revealed a right-sided primary tumor site was an independent predictor of shorter TTD (adjusted hazard ratio [HR] = 1.32, using the LCRC group as a reference, 95 % confidence interval: 1.08-1.61, P = .0072) and OS (adjusted HR = 1.45, 95 % CI: 1.18-1.78, P = .0003). CONCLUSION: Our findings demonstrate that a left-sided primary tumor site is a useful predictor of improved cetuximab efficacy in the third-line or salvage treatment of KRAS wild-type (exon 2 nonmutant) metastatic CRC. PMID- 27221732 TI - Poor congruence with guidelines in the use of antibiotics for acute bronchitis: a descriptive study based on electronic health records. AB - BACKGROUND: Although acute bronchitis is frequently viral in nature, antibiotics are usually inappropriately prescribed in Primary Care to treat this condition, with serious public health consequences. OBJECTIVE: To determine the prevalence and predictors of appropriate management of antibiotic use in acute bronchitis processes diagnosed in outpatients in the Spanish region of Aragon. METHODS: Four different electronic health databases provided demographic and clinical information pertaining to patients diagnosed with acute bronchitis in Primary Care in Aragon during 2011, as well as data for corresponding antibiotic prescriptions dispensed at pharmacies. We evaluated adherence to recommendations for antibiotic use in acute bronchitis episodes in adults collected in both international and national guidelines. Finally, regression analyses were used to identify factors associated with appropriate antibiotic management. RESULTS: A total of 54701 episodes of acute bronchitis were registered, 9.5% of which corresponded to patients with an underlying chronic respiratory disease. In adults, antibiotics were prescribed in 64.9% of episodes, 17.9% of which involved prescription of a first-choice agent. Overall, 48.5% of episodes were appropriately managed according to guidelines. The likelihood of appropriate treatment was higher for female patients, and lower for patients who were older, presented chronic co-morbidities or were using corticoids. CONCLUSIONS: We observed poor levels of adherence to recommendations for antibiotic prescribing in adults with acute bronchitis, in terms of both the decision to prescribe and the choice of antibiotic agent. Older acute bronchitis patients and those with co morbidities were at greater risk of being inappropriately treated. PMID- 27221733 TI - Do GPs want or need formal support following a patient suicide?: a mixed methods study. AB - BACKGROUND: Patient suicide can be a devastating event for some general practitioners (GPs). Few guidelines exist to aid or support GPs in the aftermath of patient suicide. AIM: To explore GPs views on how they are affected by a patient suicide and the formal support available to them following a patient suicide. DESIGN: Questionnaires and semi-structured interviews. SETTING: General practices in the northwest of England. METHODS: About 198 semi-structured interviews were conducted as part of a retrospective study. Interviews were transcribed verbatim and analysed using descriptive statistics and a framework thematic approach. RESULTS: GPs were aged between 31 and 67 years, 144 (73%) were male and the number of years in practice varied between 8 and 40 years (median = 24 years). GPs were based at 133 (67%) urban and 65 (33%) rural practices, 30 (15%) were single-handed GP practices and 168 (85%) practices had two or more GPs. About 131 (66%) GPs reported being affected by patient suicide through feelings of grief, guilt and self-scrutiny. A greater number of years in practice may have been protective against these effects. About 54 (27%) GPs reported having mostly 'informal' support from peers or colleagues and support was less available to younger and single handed GPs. CONCLUSIONS: Our findings suggest that the majority of GPs are affected by patient suicide and most seek informal support from their peers and colleagues. Although many indicated that informal support systems were adequate and provided a protective environment, procedures should be developed to ensure the availability of guidelines for those who may require formal support. PMID- 27221734 TI - Trends in Authorship of Articles in Major Ophthalmology Journals by Gender, 2002 2014. AB - PURPOSE: To evaluate trends in the prevalence of women authors in ophthalmology in recent years. DESIGN: Cohort study. PARTICIPANTS: Authors listed in publications of 6 leading ophthalmology journals between January 2002 and December 2014. METHODS: Using the PubMed search engine, we conducted an observational study of trends in gender distribution of all authors in 6 leading ophthalmology journals between January 2002 and December 2014. In multiauthored articles, the first listed author often is the lead investigator and the last author is the senior author. Therefore, the full names and positions (first, middle, or last) of all authors in every article were collected. A Google-based name identifier was used to assign the gender of authors. MAIN OUTCOME MEASURES: Proportion of women authors throughout the study period in all journals, general ophthalmology versus subspecialty journals, and basic science versus clinical research journals. Furthermore, we assessed the proportion of women in different authorship positions (first, middle, and last). RESULTS: A total of 102 254 authors from 23 026 published articles were analyzed. There was a significant rise over time in the percentage of women authors, with a steeper slope for first authors than for last authors (P<0.001), although in 2014, women authors were less than the 50% mark in all categories of authorship. The rise in the percentage of women authors was similar in basic and clinical research, but was steeper for first authorship than for last authorship (P<0.001). In all 3 authorship positions (first, middle, or last), women's contributions consistently were higher in basic research publications. The rise in the percentage of women authors was significantly steeper for general journals than for subspecialty journals (P<0.001). There was no significant rise for last authorship in subspecialty journals. In all 3 authorship positions, the proportion of women was consistently higher in general ophthalmology journals than for subspecialty journals. CONCLUSIONS: Despite an overall increase in the contribution of women to the field of ophthalmology, contributions to articles published in subspecialty ophthalmology journals and the proportion of women listed as last authors on overall articles published in ophthalmology journals are still low. PMID- 27221735 TI - Peripapillary Diffuse Chorioretinal Atrophy in Children as a Sign of Eventual Pathologic Myopia in Adults. AB - PURPOSE: To search for a morphologic biomarker to differentiate between pathologic myopia and simple childhood myopia. DESIGN: Retrospective case series. PARTICIPANTS: The study included children (age <=15 years) with high myopia (as defined by the Japanese Ministry of Health and Welfare) who attended the High Myopia Clinic between April 1982 and March 1994, had undergone fundus photography, and had a follow-up of 20 years or more. METHODS: Fundus photographs obtained in childhood and adulthood were examined for presence of pathologic myopia, defined by high myopia (myopic refractive error >8 diopters or axial length >=26.5 mm) and the presence of stage 2 or higher myopic maculopathy. MAIN OUTCOME MEASURES: Myopic maculopathy in childhood. RESULTS: The study included 56 eyes of 29 patients with a mean age of 10.2+/-3.6 years at the initial visit and an age of 36.0+/-7.6 years at the last visit. Mean axial length was 27.0+/-1.4 mm at baseline and 29.7+/-2.0 mm at the last visit. At the last visit, 19 eyes (34%) had tessellated fundus alone, 31 eyes (55%) had diffuse chorioretinal atrophy, 3 eyes (5%) showed patchy chorioretinal atrophy, and 1 eye (2%) had macular atrophy. Thus, 35 eyes (63%) had pathologic myopia in adulthood. Among the 35 eyes, 29 (83%) already had diffuse chorioretinal atrophy at the initial visit in childhood and the remaining 6 eyes (17%) showed tessellated fundus in childhood. The diffuse chorioretinal atrophy seen in childhood was restricted to the area temporal to the peripapillary region. CONCLUSIONS: The presence of peripapillary diffuse chorioretinal atrophy in children with high axial myopia may be an indicator for the eventual development of advanced myopic chorioretinal atrophy in later life. These features in children may be helpful for differentiating simple childhood myopia from eventual pathologic myopia. PMID- 27221736 TI - The Philadelphia Glaucoma Detection and Treatment Project: Detection Rates and Initial Management. AB - PURPOSE: To evaluate the detection rates of glaucoma-related diagnoses and the initial treatments received in the Philadelphia Glaucoma Detection and Treatment Project, a community-based initiative aimed at improving the detection, treatment, and follow-up care of individuals at risk for glaucoma. DESIGN: Retrospective analysis. PARTICIPANTS: A total of 1649 individuals at risk for glaucoma who were examined and treated in 43 community centers located in underserved communities of Philadelphia. METHODS: Individuals were enrolled if they were African American aged >=50 years, were any other adult aged >=60 years, or had a family history of glaucoma. After attending an informational glaucoma workshop, participants underwent a targeted glaucoma examination including an ocular, medical, and family history; visual acuity testing, intraocular pressure (IOP) measurement, and corneal pachymetry; slit-lamp and optic nerve examination; automated visual field testing; and fundus color photography. If indicated, treatments included selective laser trabeculoplasty (SLT), laser peripheral iridotomy (LPI), or IOP-lowering medications. Follow-up examinations were scheduled at the community sites after 4 to 6 weeks or 4 to 6 months, depending on the clinical scenario. MAIN OUTCOME MEASURES: Detection rates of glaucoma related diagnoses and types of treatments administered. RESULTS: Of the 1649 individuals enrolled, 645 (39.1%) received a glaucoma-related diagnosis; 20.0% (n = 330) were identified as open-angle glaucoma (OAG) suspects, 9.2% (n = 151) were identified as having narrow angles (or as a primary angle closure/suspect), and 10.0% (n = 164) were diagnosed with glaucoma, including 9.0% (n = 148) with OAG and 1.0% (n = 16) with angle-closure glaucoma. Overall, 39.0% (n = 64 of 164) of those diagnosed with glaucoma were unaware of their diagnosis. A total of 196 patients (11.9%) received glaucoma-related treatment, including 84 (5.1%) who underwent LPI, 13 (0.8%) who underwent SLT, and 103 (6.2%) who were prescribed IOP-lowering medication. CONCLUSIONS: Targeting individuals at risk for glaucoma in underserved communities in Philadelphia yielded a high detection rate (39.1%) of glaucoma-related diagnoses. Providing examinations and offering treatment, including first-line laser procedures, at community-based sites providing services to older adults are effective to improve access to eye care by underserved populations. PMID- 27221737 TI - Immediate Sequential Bilateral Pediatric Vitreoretinal Surgery: An International Multicenter Study. AB - PURPOSE: To determine the feasibility and safety of bilateral simultaneous vitreoretinal surgery in pediatric patients. DESIGN: International, multicenter, interventional, retrospective case series. PARTICIPANTS: Patients 17 years of age or younger from 24 centers worldwide who underwent immediate sequential bilateral vitreoretinal surgery (ISBVS)-defined as vitrectomy, scleral buckle, or lensectomy using the vitreous cutter-performed in both eyes sequentially during the same anesthesia session. METHODS: Clinical history, surgical details and indications, time under anesthesia, and intraoperative and postoperative ophthalmic and systemic adverse events were reviewed. MAIN OUTCOME MEASURES: Ocular and systemic adverse events. RESULTS: A total of 344 surgeries from 172 ISBVS procedures in 167 patients were included in the study. The mean age of the cohort was 1.3+/-2.6 years. Nonexclusive indications for ISBVS were rapidly progressive disease (74.6%), systemic morbidity placing the child at high anesthesia risk (76.0%), and residence remote from surgery location (30.2%). The most common diagnoses were retinopathy of prematurity (ROP; 72.7% [P < 0.01]; stage 3, 4.8%; stage 4A, 44.4%; stage 4B, 22.4%; stage 5, 26.4%), familial exudative vitreoretinopathy (7.0%), abusive head trauma (4.1%), persistent fetal vasculature (3.5%), congenital cataract (1.7%), posterior capsular opacification (1.7%), rhegmatogenous retinal detachment (1.7%), congenital X-linked retinoschisis (1.2%), Norrie disease (2.3%), and viral retinitis (1.2%). Mean surgical time was 143+/-59 minutes for both eyes. Higher ROP stage correlated with longer surgical time (P = 0.02). There were no reported intraoperative ocular complications. During the immediate postoperative period, 2 eyes from different patients demonstrated unilateral vitreous hemorrhage (0.6%). No cases of endophthalmitis, choroidal hemorrhage, or hypotony occurred. Mean total anesthesia time was 203+/-87 minutes. There were no cases of anesthesia-related death, malignant hyperthermia, anaphylaxis, or cardiac event. There was 1 case of reintubation (0.6%) and 1 case of prolonged oxygen desaturation (0.6%). Mean follow-up after surgery was 103 weeks, and anatomic success and globe salvage rates were 89.8% and 98.0%, respectively. CONCLUSIONS: This study found ISBVS to be a feasible and safe treatment paradigm for pediatric patients with bilateral vitreoretinal pathologic features when repeated general anesthesia is undesirable or impractical. PMID- 27221738 TI - miR-30c and miR-181a synergistically modulate p53-p21 pathway in diabetes induced cardiac hypertrophy. AB - p53-p21 pathway mediates cardiomyocyte hypertrophy and apoptosis and is upregulated in diabetic cardiomyopathy (DbCM). We investigated role of microRNAs in regulating p53-p21 pathway in high glucose (HG)-induced cardiomyocyte hypertrophy and apoptosis. miR-30c and miR-181a were identified to target p53. Cardiac expression of microRNAs was measured in diabetic patients, diabetic rats, and in HG-treated cardiomyocytes. Effect of microRNAs over-expression and inhibition on HG-induced cardiomyocyte hypertrophy and apoptosis was examined. Myocardial expression of p53 and p21 genes was increased and expression of miR 30c and miR-181a was significantly decreased in diabetic patients, DbCM rats, and in HG-treated cardiomyocytes. Luciferase assay confirmed p53 as target of miR-30c and miR-181a. Over-expression of miR-30c or miR-181a decreased expression of p53, p21, ANP, cardiomyocyte cell size, and apoptosis in HG-treated cardiomyocytes. Concurrent over-expression of these microRNAs resulted in greater decrease in cardiomyocyte hypertrophy and apoptosis, suggesting a synergistic effect of these microRNAs. Our results suggest that dysregulation of miR-30c and miR-181a may be involved in upregulation of p53-p21 pathway in DbCM. PMID- 27221741 TI - In situ tuning of gold nanorod plasmon through oxidative cyanide etching. AB - Single gold nanorods exhibit great opportunities for bio-sensing, enhanced spectroscopies and photothermal therapy. A key property of these particles is the surface plasmon resonance, that is strongly dependent on their shape. Methods for tuning this resonance after the synthesis of the particles are of great interest for many applications. In this work we show that, through very well known chemistry between gold atoms and cyanide ions, it is possible to tune the surface plasmon of single 25 * 50 nm rods by more than 100 nm towards longer wavelengths. This is achieved by slowly etching gold atoms from the surface of the particles, preserving their specific optical properties. PMID- 27221739 TI - Regulation of nucleolin expression by miR-194, miR-206, and HuR. AB - Nucleolin is a proliferation-associated protein that is overexpressed in multiple types of cancer. The mechanisms leading to overexpression of nucleolin in specific cancers are not fully understood. This study found that nucleolin is notably elevated in breast cancer cell lines MCF-7 and MDA-231 compared to nonmalignant breast epithelial MCF-10A cells. In silico analyses revealed the presence of putative binding sites for microRNAs miR-194 and miR-206 in the 3' untranslated region (3'-UTR) of Ncl mRNA. Transfection of the three cell lines with pre-miR-194 or pre-miR-206 specifically decreased the Ncl mRNA and protein expression. Treatments of the cells with antagomiR-194 or antagomiR-206 upregulated nucleolin expression ~2- to 3-fold. Co-transfection of cells with a reporter vector containing the Ncl 3'-UTR downstream from the Renilla luciferase gene and pre-miR-194 or pre-miR-206 led to a ~3-fold decrease in Renilla/firefly luciferase activity. Cytoplasmic levels of the RNA-binding protein HuR were higher in MCF-7 and MDA-231 cells than those in MCF-10A cells. RNA immunoprecipitation assays demonstrated that HuR binds to Ncl mRNA in all the three cell types. ShRNA-mediated knock-down of HuR induced a decrease in nucleolin expression, while exogenous expression of HuR led to upregulation of nucleolin expression. Analysis of the polysome-monosome distribution of Ncl mRNA in HuR knock-down cells demonstrated that HuR enhances the translation efficiency of Ncl mRNA. These findings demonstrate that nucleolin expression is down regulated by miR-194 and miR-206 and upregulated by HuR. PMID- 27221740 TI - Enhanced lysosomal activity by overexpressed aminopeptidase Y in Saccharomyces cerevisiae. AB - Saccharomyces cerevisiae contains vacuoles corresponding to lysosomes in higher eukaryotes. Lysosomes are dynamic (not silent) organelles in which enzymes can be easily integrated or released when exposed to stressful conditions. Changes in lysosomal enzymes have been observed due to oxidative stress, resulting in an increased function of lysosomes. The protein profiles from H2O2- and NH4Cl treated lysosomes showed different expression patterns, observed with two dimensional gel electrophoresis. The aminopeptidase Y protein (APE3) that conspicuously enhanced antimicrobial activity than other proteins was selected for further studies. The S. cerevisiae APE3 gene was isolated and inserted into pYES2.0 expression vector. The GFP gene was inserted downstream to the APE3 gene for confirmation of APE3 targeting to lysosomes, and S. cerevisiae was transformed to pYES2::APE3::GFP. The APE3 did not enter in lysosomes and formed an inclusion body at 30 degrees C, but it inserted to lysosomes as shown by the merger of GFP with lysosomes at 28 degrees C. Antimicrobial activity of the cloned S. cerevisiae increased about 5 to 10 % against eight strains, compared to normal cells, and galactose induction is increased more two folds than that of normal cells. Therefore, S. cerevisiae was transformed to pYES2::APE3::GFP, accumulating a large amount of APE3, resulting in increased lysosomal activity. Increase in endogenous levels of lysosomes and their activity following genetic modification can lead to its use in applications such as antimicrobial agents and apoptosis-inducing materials for cancer cells, and consequently, it may also be possible to use the organelles for improving in vitro functions. PMID- 27221742 TI - Serpin peptidase inhibitor (SERPINB5) haplotypes are associated with susceptibility to hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) represents the second leading cause of cancer related death worldwide. The serpin peptidase inhibitor SERPINB5 is a tumour suppressor gene that promotes the development of various cancers in humans. However, whether SERPINB5 gene variants play a role in HCC susceptibility remains unknown. In this study, we genotyped 6 SNPs of the SERPINB5 gene in an independent cohort from a replicate population comprising 302 cases and 590 controls. Additionally, patients who had at least one rs2289520 C allele in SERPINB5 tended to exhibit better liver function than patients with genotype GG (Child-Pugh grade A vs. B or C; P = 0.047). Next, haplotype blocks were reconstructed according to the linkage disequilibrium structure of the SERPINB5 gene. A haplotype "C-C-C" (rs17071138 + rs3744941 + rs8089204) in SERPINB5 correlated promoter showed a significant association with an increased HCC risk (AOR = 1.450; P = 0.031). Haplotypes "T-C-A" and "C-C-C" (rs2289519 + rs2289520 + rs1455555) located in the SERPINB5 coding region had a decreased (AOR = 0.744; P = 0.031) and increased (AOR = 1.981; P = 0.001) HCC risk, respectively. Finally, an additional integrated in silico analysis confirmed that these SNPs affected SERPINB5 expression and protein stability, which significantly correlated with tumour expression and subsequently with tumour development and aggressiveness. Taken together, our findings regarding these biomarkers provide a prediction model for risk assessment. PMID- 27221743 TI - A Qualitative Evaluation of the Acceptability of an Interactive Voice Response System to Enhance Adherence to Isoniazid Preventive Therapy Among People Living with HIV in Ethiopia. AB - Interactive voice response (IVR) is increasingly used to monitor and promote medication adherence. In 2014, we evaluated patient acceptability toward IVR as part of the ENRICH Study, aimed to enhance adherence to isoniazid preventive therapy for tuberculosis prevention among HIV-positive adults in Ethiopia. Qualitative interviews were completed with 30 participants exposed to 2867 IVR calls, of which 24 % were completely answered. Individualized IVR options, treatment education, and time and cost savings facilitated IVR utilization, whereas poor IVR instruction, network and power malfunctions, one-way communication with providers, and delayed clinic follow-up inhibited utilization. IVR acceptability was complicated by HIV confidentiality, mobile phone access and literacy, and patient-provider trust. Incomplete calls likely reminded patients to take medication but were less likely to capture adherence or side effect data. Simple, automated systems that deliver health messages and triage clinic visits appear to be acceptable in this resource-limited setting. PMID- 27221744 TI - A DFT study on the role of long range correlation interaction and solvent effects in homochiral and heterochiral cyclic trimerization of imidazole based heterocyclic amino acids. AB - Using B3LYP and B97D functionals of density functional theory (DFT), homochiral and heterochiral cyclic trimerization of imidazole based heterocyclic amino acids are studied in gas phase and solvent phase, i. e., Acetonitrile. Both the functionals show that formation of homochiral cyclic tripeptide is thermodynamically and kinetically favorable over its heterochiral counterpart in gas phase. The functional, B97D, decreases the height of reaction barriers significantly compared to those predicted by the functional B3LYP. The reaction pathways explored using PCM implicit solvent model show reduced kinetic favorability for formation of the homochiral cyclic tripeptide over its heterochiral counterpart. The results are substantiated by structural aspects. PMID- 27221747 TI - Developments in non-gynaecological cytology reporting terminologies. PMID- 27221745 TI - [Structure of pain management facilities in Germany : Classification of medical and psychological pain treatment services-Consensus of the Joint Commission of the Professional Societies and Organizations for Quality in Pain Medicine]. AB - On behalf of the Medical/Psychological Pain Associations, Pain Patients Alliance and the Professional Association of Pain Physicians and Psychologists, the Joint Commission of Professional Societies and Organizations for Quality in Pain Medicine, working in close collaboration with the respective presidents, has developed verifiable structural and process-related criteria for the classification of medical and psychological pain treatment facilities in Germany. Based on the established system of graded care in Germany and on existing qualifications, these criteria also argue for the introduction of a basic qualification in pain medicine. In addition to the first-ever comprehensive description of psychological pain facilities, the criteria presented can be used to classify five different levels of pain facilities, from basic pain management facilities, to specialized institutions, to the Centre for Interdisciplinary Pain Medicine. The recommendations offer binding and verifiable criteria for quality assurance in pain medicine and improved pain treatment. PMID- 27221748 TI - Arthur Ivens Spriggs, DM, FRCP, FRCPath b. 12th September 1919, d. 12th December 2015. PMID- 27221749 TI - The Papanicolaou Society of Cytopathology classification for pulmonary specimens: an overview. AB - The Papanicolaou Society of Cytopathology has formulated guidelines for respiratory cytology which include a classification scheme. The recommended classification scheme is based on the expertise of the committee members, extensive review of the literature and feedback from presentations at national and international meetings. Each category of the classification system is closely defined and link to a known risk for malignancy. The classification contains six categories designated as: 1) Non-diagnostic; 2) Negative for Malignancy; 3) Atypical; 4) Neoplastic (Benign and low grade cancer); 5) Suspicious for Malignancy; and 6) Malignant. PMID- 27221750 TI - A review of the Paris system for reporting urinary cytology. AB - After the 2013 International Congress of Cytology in Paris, consensus groups were formed to establish an international reporting system for urinary tract (UT) specimens. The recommended guidelines, known as The Paris System (TPS) for Reporting Urinary Cytology, focus on reducing the rate of unnecessary indeterminate diagnoses while maintaining the excellent performance UT cytology has for identifying high-grade urothelial carcinoma. This review highlights the major features of TPS. PMID- 27221751 TI - Pancreatic cytology: standardised terminology and nomenclature. AB - Pancreatic cytology can make a real difference to the management of patients. However it is a challenge in those cases where a definitive diagnosis of malignancy cannot be made with confidence. This creates the need for a unified terminology and nomenclature system that provides intra- and interdepartmental guidance for diagnosis. The Papanicolaou Society of Cytopathology (PSC) has published new guidelines for pancreaticobiliary cytology, addressing indications, techniques, terminology and nomenclature, ancillary studies, and postprocedure management. PMID- 27221752 TI - Thyroid cytology: a review of current international reporting systems and emerging developments. AB - Fine needle aspiration (FNA) is a widely available initial diagnostic tool for the investigation of thyroid nodules. The findings are paramount for appropriate patient management, which is best determined in the multidisciplinary setting. However, while international classification systems utilise similar criteria, there are areas, particularly in the management of the 'indeterminate' category, which require resolution. This review article compares the current classification systems used worldwide and explores how the developing fields of molecular/sequencing techniques, as well as the use of rapid on-site assessment, may improve our diagnostic certainty. PMID- 27221753 TI - Corrigendum. PMID- 27221754 TI - Flotillin-1 downregulates K(+) current by directly coupling with Kv2.1 subunit. PMID- 27221755 TI - The membrane tethered matrix metalloproteinase MT1-MMP at the forefront of melanoma cell invasion and metastasis. AB - The Extracellular Matrix (ECM) plays an important role in normal physiological development and functioning of cells, tissues and organs [1]. Under normal physiological conditions degradation of the ECM is a finely regulated process, and altered homeostasis of ECM degradation (excessive or insufficient) is associated with many diseases [2-5] such as cancer, fibrosis, arthritis, nephritis, encephalomyelitis and chronic ulcers. The remodeling of the ECM is carried out by a family of enzymes known as matrix metalloproteinases (MMP). MMPs constitute a large group of multidomain, zinc dependent endopeptidases capable of hydrolyzing all protein components of the ECM [6]. Additional functions of MMPs have also been identified. MMPs, and in particular MT1-MMP, the prototypic membrane-tethered matrix metalloproteinase, are no longer only ECM remodeling enzymes but rather regulators of several cellular functions including growth, migration, invasion and gene expression. Here we will focus on the role of the membrane bound MT1-MMP in melanoma growth, invasion and metastasis. MT1-MMP has in fact emerged as a multifaceted protease capable of influencing melanoma metastasis by canonical means, i.e. ECM degradation, but also via regulation of genes involved in several pro-tumorigenic functions including tumor cell growth and motility. PMID- 27221756 TI - l-Asparaginase as morpheein: A potential drug target. PMID- 27221757 TI - Differences in the efficacy of climate forcings explained by variations in atmospheric boundary layer depth. AB - The Earth has warmed in the last century and a large component of that warming has been attributed to increased anthropogenic greenhouse gases. There are also numerous processes that introduce strong, regionalized variations to the overall warming trend. However, the ability of a forcing to change the surface air temperature depends on its spatial and temporal distribution. Here we show that the efficacy of a forcing is determined by the effective heat capacity of the atmosphere, which in cold and dry climates is defined by the depth of the planetary boundary layer. This can vary by an order of magnitude on different temporal and spatial scales, and so we get a strongly amplified temperature response in shallow boundary layers. This must be accounted for to assess the efficacy of a climate forcing, and also implies that multiple climate forcings cannot be linearly combined to determine the temperature response. PMID- 27221758 TI - Ultra-high density optical data storage in common transparent plastics. AB - The ever-increasing demand for high data storage capacity has spurred research on development of innovative technologies and new storage materials. Conventional GByte optical discs (DVDs and Bluray) can be transformed into ultrahigh capacity storage media by encoding multi-level and multiplexed information within the three dimensional volume of a recording medium. However, in most cases the recording medium had to be photosensitive requiring doping with photochromic molecules or nanoparticles in a multilayer stack or in the bulk material. Here, we show high-density data storage in commonly available plastics without any special material preparation. A pulsed laser was used to record data in micron sized modified regions. Upon excitation by the read laser, each modified region emits fluorescence whose intensity represents 32 grey levels corresponding to 5 bits. We demonstrate up to 20 layers of embedded data. Adjusting the read laser power and detector sensitivity storage capacities up to 0.2 TBytes can be achieved in a standard 120 mm disc. PMID- 27221759 TI - Caffeine exposure alters adenosine system and neurochemical markers during retinal development. AB - Evidence points to beneficial properties of caffeine in the adult central nervous system, but teratogenic effects have also been reported. Caffeine exerts most of its effects by antagonizing adenosine receptors, especially A1 and A2A subtypes. In this study, we evaluated the role of caffeine on the expression of components of the adenosinergic system in the developing avian retina and the impact of caffeine exposure upon specific markers for classical neurotransmitter systems. Caffeine exposure (5-30 mg/kg by in ovo injection) to 14-day-old chick embryos increased the expression of A1 receptors and concomitantly decreased A2A adenosine receptors expression after 48 h. Accordingly, caffeine (30 mg/kg) increased [(3) H]-8-cyclopentyl-1,3-dipropylxanthine (A1 antagonist) binding and reduced [(3) H]-ZM241385 (A2A antagonist) binding. The caffeine time-response curve demonstrated a reduction in A1 receptors 6 h after injection, but an increase after 18 and 24 h. In contrast, caffeine exposure increased the expression of A2A receptors from 18 and 24 h. Kinetic assays of [(3) H]-S-(4 nitrobenzyl)-6-thioinosine binding to the equilibrative adenosine transporter ENT1 revealed an increase in Bmax with no changes in Kd , an effect accompanied by an increase in adenosine uptake. Immunohistochemical analysis showed a decrease in retinal content of tyrosine hydroxylase, calbindin and choline acetyltransferase, but not Brn3a, after 48 h of caffeine injection. Furthermore, retinas exposed to caffeine had increased levels of phosphorylated extracellular signal-regulated kinase and cAMP-response element binding protein. Overall, we show an in vivo regulation of the adenosine system, extracellular signal regulated kinase and cAMP-response element binding protein function and protein expression of specific neurotransmitter systems by caffeine in the developing retina. The beneficial or maleficent effects of caffeine have been demonstrated by the work of different studies. It is known that during animal development, caffeine can exert harmful effects, impairing the correct formation of CNS structures. In this study, we demonstrated cellular and tissue effects of caffeine's administration on developing chick embryo retinas. Those effects include modulation of adenosine receptors (A1 , A2 ) content, increasing in cAMP response element-binding protein (pCREB) and extracellular signal-regulated kinase phosphorylation (pERK), augment of adenosine equilibrative transporter content/activity, and a reduction of some specific cell subpopulations. ENT1, Equilibrative nucleoside transporter 1. PMID- 27221761 TI - Use of Polymerase Chain Reaction for Bivalve Pathogen Surveillance in the Yellow Clam Mesodesma mactroides. AB - The yellow clam Mesodesma mactroides is a valuable shellfish occurring from the southeastern coast of Brazil to the northern coast of Argentina. Populations of yellow clams are disappearing from their entire range, and the cause is still unknown. The objective of this paper was to search for World Organisation for Animal Health (OIE)-listed pathogens and their relatives in the genera Marteilia, Bonamia, and Perkinsus as well as Mikrocytos mackini and the virus OsHV-1 MU var the yellow clam population in southern Brazil using molecular techniques and classic histology protocols. A total of 180 clams were manually collected in the intertidal region at six sampling points covering the entire coast of Rio Grande do Sul State (length, 622 km) in 2013. Tissue samples were tested by OIE recommended single-step conventional polymerase chain reaction assays. The screening showed no evidence of the specific sequences of the protistan parasites and viral pathogens at any site within the six zones under study. We recommend continuous monitoring of the mollusks in the region. Received July 3, 2015; accepted February 3, 2016. PMID- 27221760 TI - Alterations in voltage-sensing of the mitochondrial permeability transition pore in ANT1-deficient cells. AB - The probability of mitochondrial permeability transition (mPT) pore opening is inversely related to the magnitude of the proton electrochemical gradient. The module conferring sensitivity of the pore to this gradient has not been identified. We investigated mPT's voltage-sensing properties elicited by calcimycin or H2O2 in human fibroblasts exhibiting partial or complete lack of ANT1 and in C2C12 myotubes with knocked-down ANT1 expression. mPT onset was assessed by measuring in situ mitochondrial volume using the 'thinness ratio' and the 'cobalt-calcein' technique. De-energization hastened calcimycin-induced swelling in control and partially-expressing ANT1 fibroblasts, but not in cells lacking ANT1, despite greater losses of mitochondrial membrane potential. Matrix Ca(2+) levels measured by X-rhod-1 or mitochondrially-targeted ratiometric biosensor 4mtD3cpv, or ADP-ATP exchange rates did not differ among cell types. ANT1-null fibroblasts were also resistant to H2O2-induced mitochondrial swelling. Permeabilized C2C12 myotubes with knocked-down ANT1 exhibited higher calcium uptake capacity and voltage-thresholds of mPT opening inferred from cytochrome c release, but intact cells showed no differences in calcimycin-induced onset of mPT, irrespective of energization and ANT1 expression, albeit the number of cells undergoing mPT increased less significantly upon chemically-induced hypoxia than control cells. We conclude that ANT1 confers sensitivity of the pore to the electrochemical gradient. PMID- 27221762 TI - Comparison between intraocular pressure spikes with water loading and postural change. AB - BACKGROUND: To compare the agreement between peak intraocular pressures measured through the water drinking test and the supine test, in patients with primary open angle glaucoma. DESIGN: Consecutive, prospective, blinded. PARTICIPANTS: Twenty-one patients from the Glaucoma Unit, Prince of Wales Hospital, Sydney, Australia. METHODS: For the supine test, intraocular pressure was recorded immediately after the patient had lain down and at 20 and 40 min. At the second evaluation, intraocular pressure was measured in each patient after drinking 10 mL/kg body weight of water for the water drinking test. Again, all patients had their intraocular pressure measured at 20 and 40 min (t = 20 and t = 40, respectively). Patients were excluded from the study if they had pre-existing cardiac, renal or pulmonary complications or had concurrent ocular disease or an anatomical abnormality (including angle recession, peripheral anterior synechiae and developmental anomalies of the angle) that may have influenced intraocular pressure. MAIN OUTCOME MEASURE: Bland-Altman analysis. RESULTS: Bland-Altman analysis indicated an overall excellent agreement in terms of mean difference between methods (1.0, -1.0 and -0.90 mmHg, at 0, 20 and 40 min, respectively). Further, with the exception of t = 40, all measured time points had 95% confidence intervals within 6.5 mmHg of their mean difference on the Bland-Altman plot. CONCLUSIONS: There was close agreement between the intraocular pressure values of the supine test and water drinking test. However, as the water drinking test may be uncomfortable and potentially hazardous, there is potential that the supine test may be a safer and more comfortable alternative. PMID- 27221763 TI - Highly sensitive detection of cancer-related genes based on complete fluorescence restoration of a molecular beacon with a functional overhang. AB - The accurate detection of cancer-related genes is of great significance for early diagnosis and targeted therapy of cancer. In this contribution, an automatically cycling operation of a functional overhang-containing molecular beacon (OMB) based sensing system was proposed to perform amplification detection of the p53 gene. Contrary to the common molecular beacon (MB), a target DNA is designated to hybridize with a label-free recognition probe (RP) with a hairpin structure rather than OMB. In the presence of a target DNA of interest, the locked primer in RP opens and triggers the subsequent amplification procedures. The newly developed OMB is not only capable of accomplishing cyclical nucleic acid strand displacement polymerization (CNDP) with the help of polymerase and nicking endonuclease, but is also cleaved by restriction endonucleases, removing the quencher away from the fluorophore. Thus, the target DNA at an extremely low concentration is expected to generate a considerable amount of double-stranded and cleaved OMBs, and the quenched fluorescence is completely restored, leading to a dramatic increase in fluorescence intensity. Utilizing this sensing platform, the target gene can be detected down to 8.2 pM in a homogeneous way, and a linear response range of 0.01 to 150 nM could be obtained. More strikingly, the mutant genes can be easily distinguished from the wild-type ones. The proof of-concept demonstrations reported herein are expected to promote the development of DNA biosensing systems, showing great potential in basic research and clinical diagnosis. PMID- 27221764 TI - A retrospective comparison of two vaginal mesh kits in the management of anterior and apical vaginal prolapse: long-term results for apical fixation and quality of life. AB - INTRODUCTION AND HYPOTHESIS: To compare apical correction in stage >=3 cystocele between two mesh kits. METHODS: This was a retrospective, nonrandomized study that compared two groups matched on anterior/apical POP-Q stage: 84 received Elevate AntTM single-incision mesh (Elevate Ant group) and 42 PerigeeTM transvaginal mesh (Perigee group). Follow-up at 1 and 2 years comprised objective (POP-Q) and subjective (PFDI-20, PFIQ-7, PISQ-12) assessments. The primary endpoint was objective success: 2-year apical POP-Q stage <=1. Secondary endpoints were anterior POP-Q stage, subjective results and complications. RESULTS: Groups were comparable in terms of age (66.6 and 64.7 years, respectively; p = 0.19), BMI (both 25.4 kg/m2; p = 0.93), and history of hysterectomy (7.2 % and 14.3 %; p = 0.21) or prolapse surgery (12 % and 14.3 %; p = 0.72). Operative time was shorter in the Elevate Ant group (54.1 vs. 62.5 min; p = 0.048), and the 2-year objective apical success rate was higher (92.9 % vs. 66.7 %; p < 0.0001), with better point C correction (-5 vs. -3.8; p = 0.006). Function improved in both groups, with significantly better PFIQ-7 (p = 0.03) and PFDI-20 (p = 0.02) scores in the Elevate Ant group at 2 years. Vaginal exposure was not seen in the Elevate Ant group but occurred in two patients in the Perigee group (p = 0.33). Factors associated with success were age >65 years (OR 7.16, 95 % CI 1.83 - 27.97) and treatment with Elevate Ant mesh (OR 10.16, 95 % CI 2.78 - 37.14). Postoperative stress urinary incontinence rate was greater with the Elevate Ant group (29.8 % and 16.7 %; p = 0.11). CONCLUSIONS: The use of the Elevate Ant mesh was associated with significantly better apical correction at 2 years. Function improved in both groups, but with a significantly better PFDI-20 score in the Elevate Ant group at 1 and 2 years. The postoperative stress urinary incontinence rate, however, tended to be greater in the Elevate Ant group. The results need confirming with longer follow-up of these cohorts and in randomized studies. PMID- 27221765 TI - Latcripin-13 domain induces apoptosis and cell cycle arrest at the G1 phase in human lung carcinoma A549 cells. AB - Latcripin-13 domain, isolated from the transcriptome of Lentinula edodes C91-3, contains a regulator of chromosome condensation (RCC1) domain/beta-lactamase inhibitor protein II (BLIP-II) and a plant homeodomain (PHD). Latcripin-13 domain has been shown to have antitumor effects. However, the underlying molecular pharmacology is largely unknown. We report here that Latcripin-13 domain induced cell cycle arrest in the G1 phase and caused the apoptosis of human lung carcinoma A549 cells via the GSK3beta-cyclin D1 and caspase-8/NF-kappaB signaling pathways. Western blot analysis showed that Latcripin-13 domain decreased cyclin D1 and cyclin-dependent kinase 4 (CDK4), while it increased the ratio of GSK3beta/phosphorylated GSK3beta. Importantly, Latcripin-13 domain induced nuclear fragmentation and chromatin condensation in the A549 cells. In addition, treatment of the A549 cells with Latcripin-13 domain resulted in the loss of mitochondrial membrane potential, accompanied by an increase in the Bax/Bcl-2 ratio and activation of caspase-3, -8, and -9. Intriguingly, western blot analysis revealed that NF-kappaB was significantly downregulated by Latcripin-13 domain. These results demonstrated that Latcripin-13 domain induced apoptosis and cell cycle arrest at G1 phase in the A549 cells, providing a mechanism for the antitumor effects of Latcripin-13 domain. PMID- 27221766 TI - Resolving phase ambiguity in dual-echo dixon imaging using a projected power method. AB - PURPOSE: To develop a fast and robust method to resolve phase ambiguity in dual echo Dixon imaging. METHODS: A major challenge in dual-echo Dixon imaging is to estimate the phase error resulting from field inhomogeneity. In this work, a binary quadratic optimization program was formulated to resolve the phase ambiguity. A projected power method was developed to efficiently solve the optimization problem. Both the 1-peak fat model and 6-peak fat model were applied to three-dimensional (3D) datasets. Additionally, the proposed method was extended to dynamic magnetic resonance imaging (MRI) applications using the 6 peak fat model. With institutional review board (IRB) approval and patient consent/assent, the proposed method was evaluated and compared with region growing on 29 consecutive 3D high-resolution patient datasets. RESULTS: Fast and robust water/fat separation was achieved by the proposed method in different representative 3D datasets and dynamic 3D datasets. Superior water/fat separation was achieved using the 6-peak fat model compared with the 1-peak fat model. Compared to region growing, the proposed method reduced water/fat swaps from 76 to 7% of the patient cohort. CONCLUSION: The proposed method can achieve fast and robust phase error estimation in dual-echo Dixon imaging. Magn Reson Med 77:2066 2076, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27221767 TI - Porous dimanganese trioxide microflowers derived from microcoordinations for flexible solid-state asymmetric supercapacitors. AB - Dimanganese trioxide microflowers are easily obtained from a Mn(ii) 8 hydroxyquinoline microcoordination after calcination in air. We also look into the possible formation mechanism of the flower-like morphology, and find that the reaction time affects the morphology of the coordination. Furthermore, the as prepared porous Mn2O3 microflowers are made of many nanoplates which form many nanogaps and nanochannels. Interestingly, the assembled electrode based on the as prepared porous Mn2O3 microflowers proves to be a high-performance electrode material for supercapacitors. The electrode shows a specific capacitance of 994 F g(-1), which can work well even after 4000 cycles at 0.75 A g(-1). More importantly, the porous Mn2O3 microflowers and activated carbons are assembled into a high-performance flexible solid-state asymmetric supercapacitor with a specific capacitance of 312.5 mF cm(-2). The cycle test shows that the device can offer 95.6% capacity of the initial capacitance at 2.0 mA cm(-2) after 5000 cycles with little decay. The maximum energy density of the device can achieve 6.56 mWh cm(-3) and the maximum power density can also achieve 283.5 mW cm(-3), which are among the best results for manganese based materials. PMID- 27221768 TI - Application of the Healthy Eating Index-2010 to the hunger relief system. AB - OBJECTIVE: To demonstrate the feasibility of applying the Healthy Eating Index 2010 (HEI-2010) to the hunger relief setting, specifically by assessing the nutritional quality of foods ordered by food shelves (front-line food provider) from food banks (warehouse of foods). DESIGN: This Healthy FOOD (Feedback On Ordering Decisions) observational study used electronic invoices detailing orders made by 269 food shelves in 2013 and analysed in 2015 from two large Minnesota, USA food banks to generate HEI-2010 scores. Initial development and processing procedures are described. RESULTS: The average total HEI-2010 score for the 269 food shelves was 62.7 out of 100 with a range from 28 to 82. Mean component scores for total protein foods, total vegetables, fatty acids, and seafood and plant proteins were the highest. Mean component score for whole grains was the lowest followed by dairy, total fruits, refined grains and sodium. Food shelves located in micropolitan areas and the largest food shelves had the highest HEI 2010 scores. Town/rural and smaller food shelves had the lowest scores. Monthly and seasonal differences in scores were detected. Limitations to this approach are identified. CONCLUSIONS: Calculating HEI-2010 for food shelves using electronic invoice data is novel and feasible, albeit with limitations. HEI-2010 scores for 2013 identify room for improvement in nearly all food shelves, especially the smallest agencies. The utility of providing HEI-2010 scores to decision makers in the hunger relief setting is an issue requiring urgent study. PMID- 27221770 TI - Solo Schistocephalus solidus tapeworms are nasty. AB - Trophically transmitted parasites must trade-off own growth on one hand and energy drain from the intermediate host on the other hand, since killing the host before transmission to the next host is a dead end for both parasites and hosts. This challenge becomes especially intriguing when multiple parasites find themselves within the same individual host. The tapeworm Schistocephalus solidus may gain more than 98% of its final body mass within few months infecting its three-spined stickleback (Gasterosteus aculeatus) intermediate host. During these months the tapeworms may achieve a mass even larger than its host. We studied virulence of single and multiple infections of S. solidus, by comparing body condition of wild stickleback hosts in two perennial stickleback populations located at high latitudes, and each population was studied in two different years. Our results demonstrated multiple compared with single infections to be a highly significant predictor of the condition of stickleback hosts, with multiple infected hosts having relatively higher body condition. However, this applied only after adjusting for parasite mass, which was another significant predictor for host condition. Thus, our results suggested that, at a given parasite mass, S. solidus was more harmful towards their host's body condition in single compared with multiple infections. PMID- 27221769 TI - Subcellular propagation of calcium waves in Muller glia does not require autocrine/paracrine purinergic signaling. AB - The polarized morphology of radial glia allows them to functionally interconnect different layers of CNS tissues including the retina, cerebellum, and cortex. A likely mechanism involves propagation of transcellular Ca2+ waves which were proposed to involve purinergic signaling. Because it is not known whether ATP release is required for astroglial Ca2+ wave propagation we investigated this in mouse Muller cells, radial astroglia-like retinal cells in which in which waves can be induced and supported by Orai/TRPC1 (transient receptor potential isoform 1) channels. We found that depletion of endoplasmic reticulum (ER) stores triggers regenerative propagation of transcellular Ca2+ waves that is independent of ATP release and activation of P2X and P2Y receptors. Both the amplitude and kinetics of transcellular, depletion-induced waves were resistant to non selective purinergic P2 antagonists such as pyridoxalphosphate-6-azophenyl-2',4' disulfonic acid (PPADS). Thus, store-operated calcium entry (SOCE) is itself sufficient for the initiation and subcellular propagation of calcium waves in radial glia. PMID- 27221771 TI - Efficacy of an orlistat-resveratrol combination for weight loss in subjects with obesity: A randomized controlled trial. AB - OBJECTIVE: To evaluate the efficacy of an orlistat-resveratrol (O-R) combination in subjects with obesity over a 6-month period. METHODS: This study was a double blind, parallel, randomized controlled clinical trial. Patients fulfilling the selection criteria (age from 20 to 60 years and body mass index (BMI) >=30 and <=39.9 kg/m(2) ) consumed an energy-reduced diet with 500 fewer calories than their usual diet for 2 weeks. Then the participants were randomly assigned to four groups, placebo, resveratrol, orlistat, or O-R, and they consumed the energy reduced diet for 6 months. The study consisted of seven visits. During each visit, a 24-h recall was performed, along with measurements of anthropometric and serum biochemical parameters. RESULTS: A total of 161 participants were selected. Of these, 84 participants completed the study. A significant weight loss of -6.82 kg (95% CI -8.37 to -5.26) was observed in the O-R group compared with -3.50 kg ( 5.05 to -1.95, P = 0.021) in the placebo group. In contrast, the -6.02 kg (-7.68 to -4.36) orlistat and -4.68 kg (-6.64 to -2.71) resveratrol monotherapy losses did not significantly differ from the placebo. Significant decreases in BMI, waist circumference, fat mass, triglycerides, leptin, and leptin/adiponectin ratio were observed with the O-R combination. CONCLUSIONS: The O-R combination was the most effective weight loss treatment. PMID- 27221772 TI - Epidermal NLRP10 contributes to contact hypersensitivity responses in mice. AB - The nucleotide binding and oligomerization domain-like receptor (NLR) protein NLRP10 is highly expressed in the epidermis and contributes to cell-autonomous responses against invasive bacteria. To investigate the role of NLRP10 in inflammatory responses of the skin we analyzed the effect of full-body and keratinocyte-specific depletion of NLRP10 in croton oil-induced irritant contact dermatitis (ICD) and 1-fluoro-2,4-dinitrobenzene (DNFB)-induced contact hypersensitivity (CHS) in mice. Nlrp10(-/-) mice were phenotypically normal and skin repair after wounding was not affected by lack of NLRP10. Similarly, we did not detect a contribution of NLRP10 to the ICD response induced by croton oil. In contrast, Nlrp10(-/-) mice showed significantly reduced inflammation in the DNFB induced CHS response as compared to control animals. Microscopic analysis revealed significantly reduced numbers of CD4(+) and CD8(+) T cells in the infiltrates of animals lacking NLRP10 expression after CHS challenge. Epidermis specific deletion of Nlrp10 by keratin-14 promotor driven Cre-recombinase was sufficient to account for this phenotype, although lymphocyte recruitment seemed to be unaltered in animals lacking NLRP10 expression in keratinocytes. Taken together, we provide evidence that NLRP10 contributes to T-cell-mediated inflammatory responses in the skin and highlight a physiological role of NLRP10 in epidermal keratinocytes. PMID- 27221773 TI - Apparent contact angle and contact angle hysteresis on liquid infused surfaces. AB - We theoretically investigate the apparent contact angle and contact angle hysteresis of a droplet placed on a liquid infused surface. We show that the apparent contact angle is not uniquely defined by material parameters, but also has a dependence on the relative size between the droplet and its surrounding wetting ridge formed by the infusing liquid. We derive a closed form expression for the contact angle in the limit of vanishing wetting ridge, and compute the correction for small but finite ridge, which corresponds to an effective line tension term. We also predict contact angle hysteresis on liquid infused surfaces generated by the pinning of the contact lines by the surface corrugations. Our analytical expressions for both the apparent contact angle and contact angle hysteresis can be interpreted as 'weighted sums' between the contact angles of the infusing liquid relative to the droplet and surrounding gas phases, where the weighting coefficients are given by ratios of the fluid surface tensions. PMID- 27221774 TI - Flavonoid myricetin inhibits TNF-alpha-stimulated production of inflammatory mediators by suppressing the Akt, mTOR and NF-kappaB pathways in human keratinocytes. AB - Flavonoid myricetin has been shown to exhibit anti-inflammatory and anti-oxidant effects. Nevertheless, the effect of myricetin on the TNF-alpha-stimulated production of inflammatory mediators in keratinocytes has not been studied. Using human keratinocytes, we examined the effect of myricetin on the TNF-alpha stimulated production of inflammatory mediators in relation to the Akt, mTOR and NF-kappaB pathways, which regulate the transcription genes involved in immune and inflammatory responses. TNF-alpha stimulated production of the inflammatory mediators and reactive oxygen species in keratinocytes, and activation of the Akt, mTOR and NF-kappaB pathways in HaCaT cells and primary keratinocytes. Myricetin, Akt inhibitor, Bay 11-7085 (an inhibitor of NF-kappaB activation), rapamycin (mTOR inhibitor) and N-acetylcysteine attenuated TNF-alpha-induced activation of Akt, mTOR and NF-kappaB. Myricetin and N-acetylcysteine attenuated the TNF-alpha-stimulated production of cytokines and chemokines, and production of reactive oxygen species in keratinocytes. The results show that myricetin may reduce TNF-alpha-stimulated inflammatory mediator production in keratinocytes by suppressing the activation of the Akt, mTOR and NF-kappaB pathways. The effect of myricetin appears to be associated with inhibition of the production of reactive oxygen species. Further, myricetin appears to attenuate the proinflammatory mediator-induced inflammatory skin diseases. PMID- 27221775 TI - Furosemide modifies heart hypertrophy and glycosaminoglycan myocardium content in a rat model of neurogenic hypertension. AB - Hypertension is a major risk factor for atherogenesis and heart hypertrophy, both of which are associated with specific morphological and functional changes of the myocardium. Glycosaminoglycans (GAGs) are complex molecules involved both in tissue morphology and function. In the present study, we investigated the effects of neurogenic hypertension and subsequent antihypertensive treatment with furosemide, on heart hypertrophy and the content of GAGs in the myocardium. Neurogenic hypertension was achieved in male Wistar rats by bilateral aortic denervation (bAD). At days 2, 7 and 15 after surgery, animals were sacrificed and the hearts were dissected away, weighted, and homogenized. Total GAGs were assessed by measuring the uronic acid content colorimetrically and individual GAGs were isolated and characterized by enzymatic treatment, with GAG-degrading enzymes, using electrophoresis on polyacrylamide gradient gels and cellulose acetate membranes. In bAD-animals blood pressure, blood pressure lability, heart rate and heart weight were significantly increased 15 days postoperatively. These effects were prevented by treatment with furosemide. Major GAGs identified in the heart were chondroitin sulphates, heparin (H), heparan sulphate (HS) and hyaluronic acid. The content of uronic and the relative content of H and HS in the heart in bAD animals significantly decreased from day 2 to day 15 postoperatively. Furosemide prevented the bAD induced decrease in GAG content. Considering that H and HS are potent inhibitors of cardiomyocyte hypertrophy, our results indicate that heart hypertrophy induced by neurogenic hypertension may be associated with decreases in the relative content of heparin and heparan sulphate in the heart. PMID- 27221776 TI - Increased regucalcin gene expression extends survival in breast cancer patients: Overexpression of regucalcin suppresses the proliferation and metastatic bone activity in MDA-MB-231 human breast cancer cells in vitro. AB - Human breast cancer is highly metastatic to bone and drives bone turnover. Breast cancer metastases cause osteolytic lesions and skeletal damage that leads to bone fractures. Regucalcin, which plays a pivotal role as an inhibitor of signal transduction and transcription activity, has been suggested to act as a suppressor of human cancer. In the present study, we compared the clinical outcome between 44 breast cancer patients with higher regucalcin expression and 43 patients with lower regucalcin expression. Prolonged relapse-free survival was identified in the patients with increased regucalcin gene expression. We further demonstrated that overexpression of full length, but not alternatively spliced variants of regucalcin, induces G1 and G2/M phase cell cycle arrest, suppressing the proliferation of MDA-MB-231 cells, a commonly used in vitro model of human breast cancer that metastasize to bone causing osteolytic lesions. Overexpression of regucalcin was found to suppress multiple signaling pathways including Akt, MAP kinase and SAPK/JNK, and NF-kappaB p65 and beta-catenin along with increased p53, a tumor suppressor, and decreased K-ras, c-fos and c-jun. Moreover, we found that co-culture of regucalcin-overexpressing MDA-MB-231 cells with mouse bone marrow cells prevented enhanced osteoclastogenesis and suppressed mineralization in mouse bone marrow cells in vitro. Taken together, the present study suggests that regucalcin may have important anticancer properties in human breast cancer patients. Mechanistically, these effects are likely mediated through suppression of multiple signaling pathways, upregulation of p53 and downregulation of oncogenes leading to anti-proliferative effects and reduced metastases to bone, a phenotype associated with poor clinical outcome. PMID- 27221777 TI - Enterotoxigenic Escherichia coli infection alters intestinal immunity in mice. AB - Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrhea in humans and piglets. However, research regarding alterations of intestinal immunity following ETEC infection remains limited and the results controversial. The present study investigated the effects of ETEC on the expression levels of pro inflammatory cytokines and innate immune regulators from plasma cells, goblet cells and Paneth cells, and the activation of toll-like receptor 4-nuclear factor (NF)-kappaB and mitogen-activated protein kinase (MAPK) pathways using reverse transcription-quantitative polymerase chain reaction and western blot analysis, in a mouse model infected with a porcine isolated ETEC strain. ETEC infection significantly reduced the expression of pro-inflammatory cytokines in the mouse jejunum (P<0.05). Additionally, ETEC infection significantly affected the expression of immune regulators of plasma cells, goblet cells and Paneth cells in the mouse intestine (P<0.05). ETEC influenced the intestinal immunity via the NF kappaB and MAPK signaling pathways. In conclusion, ETEC colonization affects intestinal immunity as observed in a mouse model. This study provides a greater understanding of the pathogenesis of ETEC infection in animals and humans. PMID- 27221779 TI - Transmural electrophysiological heterogeneity, the T-wave and ventricular arrhythmias. AB - Heterogeneous distribution of electrophysiological behavior across the heart is essential for normal cardiac function. If this heterogeneity becomes excessive it may contribute to arrhythmogenesis and sudden cardiac death. Controversy exists regarding the localization of activation and repolarization gradients in the diseased heart and how these heterogeneities contribute to arrhythmogenesis. In this review we focus on the genesis and existence of transmural heterogeneity in activation and repolarization. We will describe a possible embryonic origin of these heterogeneities and address the question how heterogeneities contribute to the genesis of the electrocardiogram and how they may cause reentrant arrhythmias. This review subsequently concentrates on several pathologies in which transmural heterogeneities are thought to play a role. PMID- 27221778 TI - miR-9 and miR-124 synergistically affect regulation of dendritic branching via the AKT/GSK3beta pathway by targeting Rap2a. AB - A single microRNA (miRNA) can regulate expression of multiple proteins, and expression of an individual protein may be controlled by numerous miRNAs. This regulatory pattern strongly suggests that synergistic effects of miRNAs play critical roles in regulating biological processes. miR-9 and miR-124, two of the most abundant miRNAs in the mammalian nervous system, have important functions in neuronal development. In this study, we identified the small GTP-binding protein Rap2a as a common target of both miR-9 and miR-124. miR-9 and miR-124 together, but neither miRNA alone, strongly suppressed Rap2a, thereby promoting neuronal differentiation of neural stem cells (NSCs) and dendritic branching of differentiated neurons. Rap2a also diminished the dendritic complexity of mature neurons by decreasing the levels of pAKT and pGSK3beta. Our results reveal a novel pathway in which miR-9 and miR-124 synergistically repress expression of Rap2a to sustain homeostatic dendritic complexity during neuronal development and maturation. PMID- 27221780 TI - Expression analysis of Shh signaling members in early stages of chick lung development. AB - Lung organogenesis is guided by epithelial-mesenchymal interactions that coordinate cellular events responsible for the formation of the respiratory system. Several signaling pathways have been implicated in this process; among them, sonic hedgehog (Shh) signaling has emerged as a crucial regulator of branching morphogenesis in the mammalian lung. Canonical Shh signaling requires the presence of patched (Ptch) and smoothened (Smo) transmembrane receptors in order to induce the activation of glioblastoma (Gli) zinc finger transcription factors that are the true effectors of the pathway. Signal transduction is finely regulated by Ptch1, Gli, and Hhip (hedgehog-interacting protein). The present work characterizes, for the first time, the expression pattern of shh, ptch1, smo, gli1, and hhip in early stages of the embryonic chick lung. In situ hybridization studies revealed that these genes are expressed in the same cellular compartments as their mammalian counterparts, although their proximo distal distribution is slightly changed. Moreover, the molecular interactions between fibroblast growth factor (FGF) and Shh signaling pathway were assessed, in vitro, by grafting beads soaked in SU5402 (an FGF receptor inhibitor). In the chick lung, Shh signaling seems to have some features that are species specific since shh is not a downstream target of FGF signaling. Nonetheless and despite the observed differences, these findings suggest a role for Shh signaling in the epithelial-mesenchymal interactions that control chick lung morphogenesis. PMID- 27221781 TI - Licochalcone A induces T24 bladder cancer cell apoptosis by increasing intracellular calcium levels. AB - Licochalcone A (LCA) has been reported to significantly inhibit cell proliferation, increase reactive oxygen species (ROS) levels, and induce apoptosis of T24 human bladder cancer cells via mitochondria and endoplasmic reticulum (ER) stress-triggered signaling pathways. Based on these findings, the present study aimed to investigate the mechanisms by which LCA induces apoptosis of T24 cells. Cultured T24 cells were treated with LCA, and cell viability was measured using the sulforhodamine B assay. Apoptosis was detected by flow cytometry with Annexin V/propidium iodide staining, and by fluorescent microscopy with Hoechst 33258 staining. The levels of intracellular free calcium ions were determined using Fluo-3 AM dye marker. Intracellular ROS levels were assessed using the 2',7'-dichlorodihydrofluorescein diacetate probe assay. The mitochondrial membrane potential was measured using 5,5',6,6'-tetrachloro 1,1',3,3'-tetraethyl benzimidazole carbocyanine iodide. Furthermore, the mRNA expression levels of B-cell lymphoma (Bcl)-extra large, Bcl-2-associated X protein, Bcl-2-interacting mediator of cell death, apoptotic protease activating factor-1 (Apaf-1), calpain 2, cysteinyl aspartate specific proteinase (caspase) 3, caspase-4 and caspase-9 were determined using reverse transcription semiquantitative and quantitative polymerase chain reaction analyses. Treatment with LCA inhibited proliferation and induced apoptosis of T24 cells, and increased intracellular Ca2+ levels and ROS production. Furthermore, LCA induced mitochondrial dysfunction, decreased mitochondrial membrane potential, and increased the mRNA expression levels of Apaf-1, caspase-9 and caspase-3. Exposure of T24 cells to LCA also triggered calpain 2 and caspase-4 activation, resulting in apoptosis. These findings indicated that LCA increased intracellular Ca2+ levels, which may be associated with mitochondrial dysfunction. In addition, the ER stress pathway may be considered an important mechanism by which LCA induces apoptosis of T24 bladder cancer cells. PMID- 27221782 TI - Atomic-level structural and chemical analysis of Cr-doped Bi2Se3 thin films. AB - We present a study of the structure and chemical composition of the Cr-doped 3D topological insulator Bi2Se3. Single-crystalline thin films were grown by molecular beam epitaxy on Al2O3 (0001), and their structural and chemical properties determined on an atomic level by aberration-corrected scanning transmission electron microscopy and electron energy loss spectroscopy. A regular quintuple layer stacking of the Bi2Se3 film is found, with the exception of the first several atomic layers in the initial growth. The spectroscopy data gives direct evidence that Cr is preferentially substituting for Bi in the Bi2Se3 host. We also show that Cr has a tendency to segregate at internal grain boundaries of the Bi2Se3 film. PMID- 27221783 TI - Extending the use of the gracilis muscle flap in perineal reconstruction surgery. AB - Reconstruction of the perineum is required following oncological resections. Plastic surgical techniques can be used to restore the aesthetics and function of the perineum. The gracilis myocutaneous flap provides a substantial skin paddle, with minimal donor site morbidity. The flap is pedicled on a perforator from the medial circumflex femoral artery, giving it limited reach across the perineum. Tunnelling the flap under the adductor longus muscle may free up more of the arterial pedicle, increasing its reach. On three female cadavers, bilateral gracilis flaps were raised in the standard surgical manner, giving six flaps in total. With the flaps pedicled across the perineum, the distance from the tip of each flap was measured to the anterior superior iliac spine (ASIS). The flaps were then tunnelled under the adductor longus muscle. The distances to the ASIS were measured again. The average pedicle length was greater than 7 cm. Tunnelling the flap under the adductor longus muscle increased the reach by more than 4 cm on average. Cadaveric dissection has shown that tunnelling of the flap in a novel way increase its reach across the perineum. This additional flexibility improves its use clinically and is of benefit to plastic surgeons operating in perineal reconstruction. PMID- 27221784 TI - Percutaneous needle fasciotomy for Dupuytren's: Further insights. PMID- 27221785 TI - Total Laparoscopic Treatment of an Adult Gastric Duplication Cyst with Intrapancreatic Extension. AB - BACKGROUND: Gastric duplication is a rare malformation mostly diagnosed during childhood. Symptoms in adults are atypical, rare, or may be completely absent. The diagnosis is suggested after a morphological and histological assessment. The treatment is a complete surgical resection. CASE REPORT: We report on a case of a 28-year-old woman referred to our unit for a surgical assessment of a gastric duplication of the antropyloric area associated with paraduodenal and pancreatic extensions, diagnosed by several image tools and histological confirmation. She had undergone a total laparoscopic resection of the duplication without violation of the gastric lumen or any other splanchnic injury. The postoperative course was uneventful and the patient was discharged on postoperative day seven without any complains. CONCLUSIONS: The present report illustrates that complete resection of a distal gastric duplication is feasible by a laparoscopic minimal invasive procedure and therefore is considered to be a safe therapeutic modality. Our case is the first distal gastric duplication cyst with pancreatic and paraduodenal extension reported in the literature completely resected by laparoscopic approach. PMID- 27221786 TI - Effects of repetition on age differences in associative recognition. AB - The study reported here examined the effect of repetition on age differences in associative recognition using a paradigm designed to encourage recollection at test. Young and older adults studied lists of unrelated word pairs presented one, two, four, or eight times. Test lists contained old (intact) pairs, pairs consisting of old words that had been studied with other partners (rearranged lures), and pairs consisting of two unstudied words (new lures). Participants gave old/new responses and then indicated whether their responses were based on details that they could recollect or on familiarity. Older adults exhibited an ironic effect of repetition-an increase in false alarms on rearranged lures with more study opportunities-whereas young adults did not. Older adults also claimed to recall details of the study episode for rearranged lures whose constituent words were presented more frequently, but this was not true for young adults. Although both young and older adults said that they based correct rejections of rearranged lures on memory for details of the study episode, this effect was stronger for young adults. The observed age differences are consistent with older adults having reduced use of recollection in associative recognition tasks. PMID- 27221787 TI - Activation of AMP-activated protein kinase reduces collagen production via p38 MAPK in cardiac fibroblasts induced by coxsackievirus B3. AB - Collagen deposition is the major cause of myocardial fibrosis, contributing to impaired cardiac contractile function in coxsackie virus B3 (CVB3)-infected hearts. Adenosine monophosphate-activated protein kinase (AMPK) has been considered as a cellular fuel gauge and super metabolic regulator, however, whether AMPK has an effect on collagen production in CVB3-infected heart remains to be elucidated. In the present study, the association between AMPK activation and CVB3-infected neonatal rat cardiac fibroblasts (NRCFs) was investigated. Collagen production was determined by the hydroxyproline content of the supernatant and by the expression of type I/IV collagen in the cell lysate. Rat hydroxyproline ELISA was used to detect hydroxyproline content in the supernatant. The expression of type I/IV collagen, and the phosphorylation of AMPKalpha-Thr172 and p38 in the cell lysate were evaluated using western blotting. As expected, it was found that the hydroxyproline content in the supernatant, and the production of collagen I/IV in the cell lysate were significantly promoted at 48 h post-CVB3-infection. However, this effect was inhibited in a dose-dependent manner when pretreated with 5-aminoimidazole-4 carboxamide-1-4-ribofuranoside (AICAR) for 2 h prior to CVB3-infection. However, if the cells were preincubated with compound C or SB203580 for 30 min prior the treatment with AICAR, the inhibitive effects of AICAR were reversed. The results of the western blotting indicated that the phosphorylation of AMPKalpha-Thr172 and p38 were significantly increased by AICAR in the NRCFs. However, only the phosphorylation of p38 mitogen-activated protein kinase (MAPK) was inhibited by SB203580. In conclusion, AMPK activation reduced collagen production via the p38 MAPK-dependent pathway in the cardiac fibroblasts induced by CVB3. The results of the present study may contribute to identifying an effective therapy for CVB3 induced myocarditis and CVB3-associated dilated cardiomyopathy. PMID- 27221788 TI - The effects of cytotoxic necrotizing factor 1 expression in the uptake of Escherichia coli K1 by macrophages and the onset of meningitis in newborn mice. AB - Macrophages are a permissive niche for E. coli K1 multiplication for which the interaction of the bacterial outer membrane protein A and its cognate receptor CD64 are critical. Using in vitro immunofluorescence and live microscopy with ex vivo macrophage cultures from RFP-Lifeact mice, we show that cytotoxic necrotizing factor 1 (CNF1) secreted by E. coli K1 sequesters cellular actin toward microspike formation, thereby limiting actin availability for OmpA mediated bacterial invasion. Surprisingly, the observed effects of CNF1 occur despite the absence of 67-kDa laminin receptor in macrophages. Concomitantly, the CNF1 deletion mutant of E. coli K1 (Deltacnf1) invades macrophages and the brains of newborn mice in greater numbers compared to wild-type. However, the Deltacnf1 strain induces less severe pathology in the brain. These results suggest a novel role for CNF1 in limiting E. coli K1 entry into macrophages while exacerbating disease severity in the brains of newborn mice. PMID- 27221789 TI - A harmonization effort for acceptable daily exposure derivation - Considerations for application of adjustment factors. AB - Acceptable daily exposures (ADEs) are established to determine the quantity of one drug substance that can contaminate another drug product without causing harm to the patient. An important part in setting an ADE for a drug substance, after identification of the unwanted critical effect(s) of the compound (see Bercu et al., 2016, this issue), is the determination of an appropriate overall margin of safety that is need to be maintained below the dose causing a certain critical effect (i.e., the point of departure or PoD). The overall margin of safety used to protect the general patient population from critical effects is derived as the product (i.e., composite adjustment factor) of various individual factors that account for variability and uncertainty in extrapolating from the PoD to an ADE. These factors address the considerations of interindividual variability, interspecies extrapolation, LOAEL-to-NOAEL extrapolation, exposure duration adjustment, effect severity, and database completeness. The factors are considered individually, but are not necessarily independent and their interdependence should be identified, with subsequent adjustment to the composite factor, as appropriate. It is important to identify all sources of variability and uncertainty pertinent to the derivation of the ADE and ensure each is considered in the assessment, at least by one of the adjustment factors. This manuscript highlights the basis for and selection of factors that address variability and uncertainty as used in the guidance documents on setting ADEs or other related health-based limits. PMID- 27221791 TI - The early days of PEG and PEGylation (1970s-1990s). AB - The idea to conjugate PEG [poly(ethylene glycol)] to a protein, i.e., to "PEGylate" a protein, was first proposed by Prof. Frank Davis (Rutgers Univ.) in the late 1960s. He wanted to make the new recombinant proteins less immunogenic in our bodies, and thereby enhance their circulation and activity lifetimes. He thought that if he could conjugate a hydrophilic polymer to the "new" protein, it might not be recognized by the immune system as a foreign molecule. This article is a contribution to the Zwitterionic Special Issue as a personal commentary tracing the story of PEGylation from its beginning with Dr. Davis through a current day post-script. STATEMENT OF SIGNIFICANCE: The author knows (or knew) personally most of the early workers in the fields of PEG, PEGylation and non fouling surfaces, and he has also been personally active in the field since its early days. PMID- 27221792 TI - Development of a new family of monolithic calcium (pyro)phosphate glasses by soft chemistry. AB - The development of bioactive phosphate-based glasses is essential in biomaterials science, and especially for bone substitution applications. In this context, the preparation of amorphous calcium-phosphorus hydroxide/oxide monoliths at low temperature is a key challenge for being able to develop novel hybrid materials for these applications. We herein report for the first time the synthesis and physical chemical characterisation of a novel family of pyrophosphate-based glasses (with the formula: {[(Ca(2+))1-x(H(+)/K(+))2x]2[(P2O7(4-))1-y(PO4(3 ))4y/3]} n(H2O)), which were prepared by soft chemistry using low temperatures (T<70 degrees C) and water as a solvent. The effect of the initial Ca/Pyrophosphate ratio on the structure and morphology of these pyrophosphate glasses was investigated in detail. Depending on this ratio, a glass (mixed calcium pyro- and orthophosphate) or a glass-ceramic (Ca10K4(P2O7)6.9H2O crystals embedded in the amorphous phase) was obtained. The proportion of the crystalline phase increased with an increase in the Ca/Pyrophosphate ratio in the batch solution. As expected for a glass, the formation of the glassy material was demonstrated not to be thermodynamically but rather kinetically driven, and the washing step was found to be crucial to prevent crystallisation. The stability of the amorphous phase was discussed considering the structural degrees of freedom of pyrophosphate entities, ionic strength of the initial solution and the inhibitory effect of orthophosphate ions. Overall, this new strategy of preparation of monolithic calcium-(pyro)phosphate based glasses using soft chemistry in water is highly promising in view of preparing new functional organic-inorganic hybrids for bone substitution applications. STATEMENT OF SIGNIFICANCE: Phosphate-based glasses have gradually emerged as a potential alternative to silicate bioactive glasses in order to induce different biological mechanisms of degradation. The synthesis of such monolithic glasses at low temperature is a key step to allow new inorganic glass compositions to be reached and hybrid materials to be prepared. Although sol-gel and coacervate methods (respectively orthophosphate and metaphosphate precursors) have already been described to prepare such glasses, the use of toxic solvents and/or the final temperature treatment associated to these processes could limit the use of these materials for biomedical applications and/or the further development of hybrids. It is shown here that pyrophosphate precursors are an alternative strategy to obtain monolithic calcium (pyro)phosphate glasses under soft conditions (water solvent, 70 degrees C). PMID- 27221790 TI - Tat-NOL3 protects against hippocampal neuronal cell death induced by oxidative stress through the regulation of apoptotic pathways. AB - Oxidative stress-induced apoptosis is associated with neuronal cell death and ischemia. The NOL3 [nucleolar protein 3 (apoptosis repressor with CARD domain)] protein protects against oxidative stress-induced cell death. However, the protective mechanism responsible for this effect as well as the effects of NOL3 against oxidative stress in ischemia remain unclear. Thus, we examined the protective effects of NOL3 protein on hydrogen peroxide (H2O2)-induced oxidative stress and the mechanism responsible for these effects in hippocampal neuronal HT22 cells and in an animal model of forebrain ischemia using Tat-fused NOL3 protein (Tat-NOL3). Purified Tat-NOL3 protein transduced into the H2O2-exposed HT22 cells and inhibited the production of reactive oxygen species (ROS), DNA fragmentation and reduced mitochondrial membrane potential (DeltaPsim). In addition, Tat-NOL3 prevented neuronal cell death through the regulation of apoptotic signaling pathways including Bax, Bcl-2, caspase-2, -3 and -8, PARP and p53. In addition, Tat-NOL3 protein transduced into the animal brains and significantly protected against neuronal cell death in the CA1 region of the hippocampus by regulating the activation of microglia and astrocytes. Taken together, these findings demonstrate that Tat-NOL3 protein protects against oxidative stress-induced neuronal cell death by regulating oxidative stress and by acting as an anti-apoptotic protein. Thus, we suggest that Tat-NOL3 represents a potential therapeutic agent for protection against ischemic brain injury. PMID- 27221793 TI - Pangolin armor: Overlapping, structure, and mechanical properties of the keratinous scales. AB - The pangolin has a flexible dermal armor consisting of overlapping keratinous scales. Although they show potential for bioinspired flexible armor, the design principles of pangolin armor are barely known. Here we report on the overlapping organization, hierarchical structure (from the nano to the mesolevel), and mechanical response of scales from ground (Chinese) and arboreal (African tree) pangolins. Both scales exhibit the same overlapping organization, with each scale at the center of neighboring scales arranged in a hexagonal pattern. The scales have a cuticle of several layers of loosely attached flattened keratinized cells, while the interior structure exhibits three regions distinguished by the geometry and orientations of the keratinized cells, which form densely packed lamellae; each one corresponds to one layer of cells. Unlike most other keratinous materials, the scales show a crossed-lamellar structure (~5MUm) and crossed fibers (~50MUm). A nano-scale suture structure, observed for the first time, outlines cell membranes and leads to an interlocking interface between lamellae, thus enhancing the bonding and shear resistance. The tensile response of the scales shows an elastic limit followed by a short plateau prior to failure, with Young's modulus ~1 GPa and tensile strength 60-100MPa. The mechanical response is transversely isotropic, a result of the cross lamellar structure. The strain rate sensitivity in the range of 10(-5)-10(-1)s(-1) region is found to be equal to 0.07-0.08, typical of other keratins and polymers. The mechanical response is highly dependent on the degree of hydration, a characteristic of keratins. STATEMENT OF SIGNIFICANCE: Although many fish and reptiles have protective scales and carapaces, mammals are characteristically fast and light. The pangolin is one of the few mammal possessing a flexible dermal armor for protection from predators, such as lions. Here we study the arrangement of the scales as well as their hierarchical structure from the nano to the mesolevel and correlate it to the mechanical properties. The study reveals a unique structure consisting of crossed lamellae and interlocking sutures that provide exceptional performance and in-plane isotropy. PMID- 27221794 TI - Biomimetic contact lenses eluting olopatadine for allergic conjunctivitis. AB - Combination of the ability of contact lenses (CLs) to act as a physical barrier against airborne antigen and to serve as a sustained depot of antihistaminic drugs may improve the efficiency of treatments of some ocular allergic diseases. The aim of this work was to develop CLs that exhibit affinity to olopatadine by mimicking the composition of the natural H1-receptor for which olopatadine behaves as a selective antagonist. Functional monomers that match the chemical groups of the receptor and application of the molecular imprinting technology led to hydrogels able to load high amounts of olopatadine and to sustain the release once in contact with lachrymal fluid. Optimized hydrogels prepared with acrylic acid, 2-acrylamido-2-methyl-1-propanesulfonic acid and benzylmethacrylate as functional monomers provided in few hours olopatadine concentrations similar to those of commercially available eye drops but the levels could be sustained for a whole day, demonstrating their efficacy. Olopatadine-loaded CLs successfully passed the HET-CAM test of ocular irritancy and showed good compatibility with mast cells. They were able to inhibit the release of histamine and TNF-alpha from sensitized mast cells, proving their potential application in preventing and treating allergic conjunctivitis. STATEMENT OF SIGNIFICANCE: Contact lenses (CLs) with affinity for antiallergic drugs may constitute an advantageous alternative to eye drops in management of ocular allergies for both contact lens wearers and patients who eventually use neutral CLs as therapeutic platforms. The present work represents a step forward in the state of the art of drug-CL combo products by (i) mimicking the composition of the human receptor of the drug, (ii) exploring combinations of functional monomers that include a monomer (2 acrylamido-2-methyl-1-propanesulfonic acid; AMPSA) with a strong acid group (pKa<4) able to enhance the interaction of the network with olopatadine in the saline environment of the lachrymal fluid, and (iii) analysing in detail the antihistamic effects provided by olopatadine released from the CLs on sensitized mast cells. PMID- 27221795 TI - Fatigue behaviors of HP-Mg, Mg-Ca and Mg-Zn-Ca biodegradable metals in air and simulated body fluid. AB - The dynamic loading in human body, along with the corrosive body fluid, presents a great challenge for the practical use of biodegradable magnesium implants. In this study, a high purity magnesium (99.99wt.%) and two typical promising biodegradable magnesium alloys (binary Mg-1Ca and ternary Mg-2Zn-0.2Ca) were chosen as the experimental materials. Their dynamic mechanical performances were comparatively evaluated by carrying out fatigue tests in air and in simulated body fluid (SBF). The fatigue strengths of HP-Mg, Mg-1Ca and Mg-2Zn-0.2Ca were all around 90MPa in air, however, they decreased to 52MPa, 70MPa and 68MPa in SBF at 4*10(6)cycles, respectively. The fatigue cracks initiated from the microstructural defects when tested in air, but nucleated from surface corrosion pits when tested in SBF. Cyclic loading significantly increased the corrosion rates of all the experimental materials compared to that in static SBF. Moreover, based on our findings, the fatigue failure processes and interactions between material, corrosion and cyclic loading were systematically discussed. STATEMENT OF SIGNIFICANCE: Fatigue strength and life are vital parameters to the design of metallic implant devices. For the corrosion fatigue of biomedical magnesium alloys, we reported the corrosion fatigue behavior of AZ91D and WE43 in SBF (Acta Biomaterialia, 6 (2010) 4605-4613), and till now there is no other reports to our knowledge. We spent 3years to finish the fatigue testing and get S-N curves for three more magnesium biomaterials, and our significant finding is that the fatigue strengths of HP-Mg, Mg-1Ca and Mg-2Zn-0.2Ca are all around 90MPa in air but 52MPa, 70MPa and 68MPa in SBF at 4*10(6)cycles, which will provide the first hand data for the future magnesium implants design. PMID- 27221796 TI - All Yersinia enterocolitica are pathogenic: virulence of phylogroup 1 Y. enterocolitica in a Galleria mellonella infection model. AB - Yersinia enterocolitica is a zoonotic pathogen and a common cause of gastroenteritis in humans. The species is composed of six diverse phylogroups, of which strains of phylogroup 1 are considered non-pathogenic to mammals due to the lack of the major virulence plasmid pYV, and their lack of virulence in a mouse infection model. In the present report we present data examining the pathogenicity of strains of Y. enterocolitica across all six phylogroups in a Galleria mellonellla model. We have demonstrated that in this model strains of phylogroup 1 exhibit severe pathogenesis with a lethal dose of as low as 10 c.f.u., that this virulence is an active process and that flagella play a major role in the virulence phenotype. We have also demonstrated that the complete lack of virulence in Galleria of the mammalian pathogenic phylogroups is not due to carriage of the pYV virulence plasmid. Our data suggest that all Y. enterocolitica can be pathogenic, which may be a reflection of the true natural habitat of the species, and that we may need to reconsider the eco-evo perspective of this important bacterial species. PMID- 27221797 TI - Tuberculous arthritis of the hip with Staphylococcus aureus superinfection. AB - Skeletal tuberculosis (TB) accounts for a small percentage of all cases of TB. It is often difficult to diagnose, especially in the hip joint. TB arthritis can be masked by superinfection with other pathogens, leading to a delay in diagnosis and treatment. Trauma or surgery is a reported risk factor of TB arthritis. In contrast, descriptions of TB arthritis after a closed bone fracture are rare. We herein report a case involving an 81-year-old woman with septic arthritis superinfected with methicillin-resistant Staphylococcus aureus (MRSA) and Mycobacterium tuberculosis. Three months before presentation, she sustained a bone fracture of the left femur and was treated conservatively without surgery. She developed a fever at another hospital and was transferred to our institution. Computed tomography revealed the presence of abnormal fluid around the left hip joint. MRSA was detected from the fluid and blood cultures. The patient was diagnosed with MRSA arthritis and treated with antibiotics and surgical drainage. However, her fever persisted, and the abscess further developed and enlarged around the left hip. It was punctured and cultured again. Three weeks later, Mycobacterium tuberculosis was identified from the abscess culture. The septic arthritis was confirmed to have been caused by MRSA and M. tuberculosis. After the initiation of antituberculosis therapy, her fever subsided and the treatment was continued. This case demonstrates that the diagnosis of TB arthritis can be hindered by the existence of other pathogens and that TB arthritis can occur at a closed fracture site in the hip joint. PMID- 27221798 TI - [Comorbidity in psoriasis]. AB - Psoriasis is a systemic chronic inflammatory disease associated with comorbidity. Many epidemiological studies have shown that psoriasis is associated with psoriatic arthritis as well as cardiovascular and metabolic diseases. Furthermore, obesity and psychological diseases such as depression and anxiety disorders are linked with psoriasis and play a central role in its management. The association of psoriasis and its comorbidity can be partly explained by genetic and pathophysiological mechanisms. Approximately 40 psoriasis susceptibility loci have been described with the majority linked to the innate and adaptive immune system. In some associated diseases, such as psoriatic arthritis, an overlap of their genetic susceptibility exists. Pathophysiologically the "psoriatic march" is a model that describes the development of metabolic and cardiovascular diseases due to the presence of underlying systemic inflammation. Dermatologists are the gatekeepers to treatment for patients with psoriasis. The early detection and the management of comorbidity is part of their responsibility. Concepts for the management of psoriasis and tools to screen for psoriatic comorbidity have been developed in order to support dermatologists in daily practice. PMID- 27221799 TI - Three Decades of Atherosclerotic Reno-vascular Disease Management - Changing Outcomes in an Observational Study. AB - BACKGROUND/AIMS: Optimized medical therapy has improved cardiovascular outcomes in the general population. To investigate whether changes in the management of atherosclerotic renovascular disease (ARVD) have had an impact on clinical outcomes. METHODS: Recruitment into this single-center prospective cohort study started in 1986. Data was analyzed retrospectively. Patients were divided into four groups based on relationship of diagnosis year to landmark randomized controlled trials (RCT); group 1 - pre-large RCT data (1986-2000); group 2 - post early RCT (2001-2004); group 3 - ASTRAL study recruitment era (2004-2009); group 4 - post-ASTRAL (2009-2014). RESULTS: In total, 872 patients were followed for a median 54.9 months (IQR 20.2-96.2). Over successive time-periods, there was an increase in baseline utilization of renin angiotensin blockade (RAB) (group 4: 69% vs. group 1: 31%, p<0.001), statins (74% vs 20%, p<0.001) and beta-blockers (43% vs 30%, p=0.024). Median time to death, end-stage kidney disease and cardiovascular events improved except in group 4, which displayed more baseline cardiovascular comorbidities. The number of investigative angiograms performed decreased from 139 per year between 2006 and 2008 to 74 per year in group 4. CONCLUSIONS: Although fewer patients are being investigated for ARVD in our center, these have more cardiovascular comorbidities. Nonetheless, optimized medical therapy may have contributed towards improved proteinuria, renal function and clinical outcomes in patients diagnosed with ARVD. PMID- 27221800 TI - The Impact of Youth Risk on Mentoring Relationship Quality: Do Mentor Characteristics Matter? AB - Although mentoring is a widely used intervention strategy, effect sizes for at risk youth remain modest. Research is therefore needed to maximize the impact of mentoring for at-risk youth who might struggle to benefit from mentoring relationships. This study tested the hypothesis that different types of youth risk would have a negative impact on mentoring relationship quality and duration and explored whether mentor characteristics exacerbated or mitigated these negative effects. Results showed that elevated environmental stress at a youth's home and/or school predicted shorter match duration, and elevated rates of youth behavioral problems, such as poor academic performance or misconduct, predicted greater youth dissatisfaction and less positive mentor perceptions of relationship quality. Mentors with greater self-efficacy and more previous involvement with youth in their communities were able to buffer the negative effects of environmental stress on match duration. Similarly, mentors' previous involvement with youth buffered the negative effects of youth behavioral problems on mentor perceptions of relationship quality. Findings have important implications for the matching of mentors and at-risk youth in a way that improves mentoring outcomes. PMID- 27221802 TI - Nanomaterials: Friend or foe to male fertility? PMID- 27221803 TI - Money back guarantees for non-reproducible results? PMID- 27221801 TI - Abnormal intrinsic dynamics of dendritic spines in a fragile X syndrome mouse model in vivo. AB - Dendritic spine generation and elimination play an important role in learning and memory, the dynamics of which have been examined within the neocortex in vivo. Spine turnover has also been detected in the absence of specific learning tasks, and is frequently exaggerated in animal models of autistic spectrum disorder (ASD). The present study aimed to examine whether the baseline rate of spine turnover was activity-dependent. This was achieved using a microfluidic brain interface and open-dura surgery, with the goal of abolishing neuronal Ca(2+) signaling in the visual cortex of wild-type mice and rodent models of fragile X syndrome (Fmr1 knockout [KO]). In wild-type and Fmr1 KO mice, the majority of baseline turnover was found to be activity-independent. Accordingly, the application of matrix metalloproteinase-9 inhibitors selectively restored the abnormal spine dynamics observed in Fmr1 KO mice, without affecting the intrinsic dynamics of spine turnover in wild-type mice. Such findings indicate that the baseline turnover of dendritic spines is mediated by activity-independent intrinsic dynamics. Furthermore, these results suggest that the targeting of abnormal intrinsic dynamics might pose a novel therapy for ASD. PMID- 27221805 TI - Effect of fragmented Lactobacillus amylovorus CP1563 on lipid metabolism in overweight and mildly obese individuals: a randomized controlled trial. AB - BACKGROUND: Previously, we showed that fragmented Lactobacillus amylovorus CP1563 (CP1563) functions as a dual agonist of peroxisome proliferator-activated receptor alpha and gamma in vitro and in vivo. OBJECTIVE: Here, we examined the safety and effect of CP1563 ingestion on body fat in obese class I participants in a double-blinded, placebo-controlled, randomized clinical trial (RCT). DESIGN: In the RCT, 200 participants with a body mass index (BMI) of 25-30 kg/m(2) consumed test beverages with or without 200 mg of CP1563 daily for 12 weeks. In total, 197 subjects completed the study without any adverse effects. RESULTS: Body fat percentage, whole body fat, and visceral fat were significantly decreased in the test group compared with the placebo group (p<0.001, p<0.001, and p<0.001, respectively). Triglycerides, total cholesterol, LDL-cholesterol, and diastolic blood pressure showed significant reductions in the test group compared with the placebo group (p<0.001, p<0.001, p<0.001, and p<0.001, respectively). Additionally, significant differences in the changes in blood glucose, insulin, homeostasis model assessment-insulin resistance (HOMA-IR), and uric acid were observed between the two groups (p<0.001, p=0.004, p<0.001, and p<0.001, respectively). Improvements in anthropometric measurements and markers were observed in obese class I subjects in the test group. CONCLUSIONS: Daily consumption of beverages containing fragmented CP1563 for 12 weeks by obese class I subjects improved anthropometric measurements and markers related to lipid and glucose metabolism without any adverse effects. These results suggest that the consumption of foods containing fragmented CP1563 reduces body fat and prevents metabolic syndrome. PMID- 27221804 TI - Immigrant status and cardiovascular risk over time: results from the Multi-Ethnic Study of Atherosclerosis. AB - PURPOSE: Despite cross-sectional evidence that foreign-born United States (US) residents often have better health than US-born residents of similar race and/or ethnicity, we know little about overall cardiovascular risk progression over time among immigrants as they age in the US. METHODS: Using longitudinal data from the Multiethnic Study of Atherosclerosis on 6446 adults aged 45-84 years at baseline, we examined how nativity and length of US residence related to change in cardiovascular health (CVH) and cardiovascular event incidence over 11-year follow-up. CVH was measured using the American Heart Association's CVH measure (range, 0-14; higher is better). RESULTS: Immigrants, particularly those with shorter US residence, had better baseline CVH and lower cardiovascular event incidence than the US born. Baseline CVH scores ranged from 8.67 (8.42-8.92) among immigrants living in the US less than 10 years to 7.86 (7.76-7.97) among the US born. However, recent immigrants experienced the largest CVH declines over time: 10-year declines ranged from -1.04 (-1.27 to -0.80) among immigrants living in the US less than 10 years at baseline to -0.47 (-0.52 to -0.42) among the US born. CONCLUSIONS: Public health prevention efforts targeting new immigrants may help slow the deterioration of CVH and reduce future cardiovascular risk. PMID- 27221806 TI - Cost-Effectiveness of Dapagliflozin as Add-On to Metformin for the Treatment of Type 2 Diabetes Mellitus in Greece. AB - BACKGROUND AND OBJECTIVE: Type 2 diabetes mellitus (T2DM) is a chronic progressive disease that has been spread worldwide over the past three decades and associated with increased morbidity and mortality resulting in considerable socioeconomic implications for national healthcare systems. Effective management of disease is highly needed ensuring patients receive the best possible care within the available budget. The objective of this study was to evaluate the long term cost-effectiveness of dapagliflozin, a sodium-glucose co-transporter-2 (SGLT 2) inhibitor, compared with a sulfonylurea (SU) or a dipeptidyl-peptidase-4 inhibitor (DPP-4i), when added to metformin, in T2DM patients inadequately controlled on metformin alone in Greece. METHODS: The published and validated Cardiff diabetes model, a lifetime micro-simulation model, was adapted to a Greek healthcare setting to determine the incidence of micro- and macro-vascular complications and diabetes-specific and all-cause mortality. Clinical, cost, and utility data were retrieved from literature and assigned to model parameters to calculate total quality-adjusted life-years (QALYs) and total costs as well as incremental cost-effectiveness ratios (ICERs). The analysis was conducted from the perspective of a third-party payer in Greece. Uncertainty surrounding important model parameters was explored with univariate and probabilistic sensitivity analyses (PSA). RESULTS: Over a patient's lifetime, dapagliflozin was associated with 0.48 and 0.04 incremental QALYs compared with SU and DPP-4i, respectively, at additional costs of ?5142 and ?756, respectively. The corresponding ICERs were ?10,623 and ?17,695 per QALY gained versus the treatment with SU and DPP-4i, respectively. Results were robust across various univariate and scenario analyses. At the defined willingness-to-pay threshold of ?34,000 per QALY gained, PSA estimated that treatment with dapagliflozin had a 100 % and 79.7 % probability of being cost-effective relative to the SU and DPP-4i treatments. CONCLUSIONS: Dapagliflozin in combination with metformin was shown to be a cost effective treatment alternative for patients with T2DM whose metformin regimen does not provide sufficient glycemic control in a Greek healthcare setting. PMID- 27221807 TI - An adaptive dose-finding method using a change-point model for molecularly targeted agents in phase I trials. AB - The paradigm of oncology drug development is expanding from developing cytotoxic agents to developing biological or molecularly targeted agents (MTAs). Although it is common for the efficacy and toxicity of cytotoxic agents to increase monotonically with dose escalation, the efficacy of some MTAs may exhibit non monotonic patterns in their dose-efficacy relationships. Many adaptive dose finding approaches in the available literature account for the non-monotonic dose efficacy behavior by including additional model parameters. In this study, we propose a novel adaptive dose-finding approach based on binary efficacy and toxicity outcomes in phase I trials for monotherapy using an MTA. We develop a dose-efficacy model, the parameters of which are allowed to change in the vicinity of the change point of the dose level, in order to consider the non monotonic pattern of the dose-efficacy relationship. The change point is obtained as the dose that maximizes the log-likelihood of the assumed dose-efficacy and dose-toxicity models. The dose-finding algorithm is based on the weighted Mahalanobis distance, calculated using the posterior probabilities of efficacy and toxicity outcomes. We compare the operating characteristics between the proposed and existing methods and examine the sensitivity of the proposed method by simulation studies under various scenarios. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27221808 TI - Comparative analysis of macrophage transcriptomes reveals a key mechanism of the immunomodulatory activity of Tricholoma matsutake polysaccharide. AB - In the present study, we performed a proliferation assay, phagocytosis assay and cell cycle analysis of macrophages and sequenced the transcriptomes of control group macrophages and TMP-A group macrophages using Illumina sequencing technology to identify differentially expressed genes (DEGs) and determine the molecular mechanisms associated with differences in the immunomodulatory activity of TMP-A in macrophages. The results showed that TMP-A exhibits strong proliferation activity and phagocytosis activity in RAW264.7 cells in vitro and could also promote the proliferation of macrophage cells by abolishing cell-cycle arrest in the G0/G1 phase and promoting the cell cycle in the G2/M phase, which may induce cell division. A total of 12,616,096 and 11,798,839 bp paired-end reads were obtained for the control group and TMP-A group, respectively, and they corresponded to a total size of 12.5 G bp and 11.7 G bp, respectively, after the low-quality reads and adapter sequences were removed. Approximately 79.8% of the total number of genes (10,191) were expressed (RPKM >=1), and more than 1,372 genes were highly expressed (RPKM >60) in the TMP-A group. A total of 1,043 unigenes were identified as DEGs, and approximately 486 genes were upregulated, whereas 557 genes were down-regulated, which might have contributed to the proliferation activity and phagocytosis activity of TMP-A in the RAW264.7 cells in vitro. A Gene Ontology (GO) enrichment analysis generated 13,042 assignments to cellular components, 13,094 assignments to biological processes, and 13,135 assignments to molecular functions. A KEGG pathway enrichment analysis showed that the MAPK and NF-kappaB signaling pathways are significantly enriched for DEGs between the two cell groups. Based on the experimental data, we believe that the significant antitumor activities of TMP-A in vivo involve the MAPK and NF kappaB signaling pathways because the two signaling pathways intersect. PMID- 27221809 TI - Veterinarians' role in clients' decision-making regarding seriously ill companion animal patients. AB - BACKGROUND: When companion animals become seriously ill clients may have doubts about treatment choices, if any, and turn to veterinarians for help. But how should veterinarians reply? Influence on clients' decision-making may or may not be acceptable-depending on one's attitude to principles such as 'paternalism', 'respect for autonomy' and 'shared decision-making'. This study takes as a starting point a situation where the animal is chronically ill, or aged, with potentially reduced animal welfare and client quality of life, and thus where clients need to consider treatment options or euthanasia. It is assumed throughout that both veterinarians and clients have the animals' best interest at heart. The purpose of the study was to explore the challenges these situations hold and to investigate how clients experience veterinary influence. A second aim was to reflect on the ethical implications of the role of veterinarians in these situations. Qualitative interviews were conducted with 12 dog owners considering treatment or euthanasia of their chronically ill or aged dogs. RESULTS: Challenges relating to the dog and to the client were identified. Some situations left the interviewees hesitant, e.g. if lacking a clear cut-off point, the dog appeared normal, the interviewee felt uncertain about treatments or animal welfare, or experienced conflicting concerns. Some interviewees found that veterinarians could influence their decisions. Such influence was received in different ways by the interviewees. Some interviewees wanted active involvement of the veterinarian in the decision-making process, and this may challenge a veterinarian's wish to respect client autonomy. CONCLUSIONS: Different preferences are likely to exist amongst both veterinarians and clients about veterinary involvement in clients' decision-making, and such preferences may vary according to the situation. It is suggested, that one way to handle this challenge is to include respect for client preference on veterinary involvement under a wider understanding of respect for autonomy, and to apply models of shared decision-making to veterinary practice. In any case there is a need to further explore the challenges these situations raise, and for the veterinary profession to engage in more formal and structured deliberation over the role of veterinarians in relation to clients' decision-making. PMID- 27221810 TI - A multi-centre randomised controlled trial comparing radiofrequency and mechanical occlusion chemically assisted ablation of varicose veins - Final results of the Venefit versus Clarivein for varicose veins trial. AB - Background Endovenous thermal ablation has revolutionised varicose vein treatment. New non-thermal techniques such as mechanical occlusion chemically assisted endovenous ablation (MOCA) allow treatment of entire trunks with single anaesthetic injections. Previous non-randomised work has shown reduced pain post operatively with MOCA. This study presents a multi-centre randomised controlled trial assessing the difference in pain during truncal ablation using MOCA and radiofrequency endovenous ablation (RFA) with six months' follow-up. Methods Patients undergoing local anaesthetic endovenous ablation for primary varicose veins were randomised to either MOCA or RFA. Pain scores using Visual Analogue Scale and number scale (0-10) during truncal ablation were recorded. Adjunctive procedures were completed subsequently. Pain after phlebectomy was not assessed. Patients were reviewed at one and six months with clinical scores, quality of life scores and duplex ultrasound assessment of the treated leg. Results A total of 170 patients were recruited over a 21-month period from 240 screened. Patients in the MOCA group experienced significantly less maximum pain during the procedure by Visual Analogue Scale (MOCA median 15 mm (interquartile range 7-36 mm) versus RFA 34 mm (interquartile range 16-53 mm), p = 0.003) and number scale (MOCA median 3 (interquartile range 1-5) versus RFA 4 mm (interquartile range 3 6.5), p = 0.002). ' Average' pain scores were also significantly less in the MOCA group; 74% underwent simultaneous phlebectomy. Occlusion rates, clinical severity scores, disease specific and generic quality of life scores were similar between groups at one and six months. There were two deep vein thromboses, one in each group. Conclusion Pain secondary to truncal ablation is less painful with MOCA than RFA with similar short-term technical, quality of life and safety outcomes. PMID- 27221811 TI - Denoising of HD-sEMG signals using canonical correlation analysis. AB - High-density surface electromyography (HD-sEMG) is a recent technique that overcomes the limitations of monopolar and bipolar sEMG recordings and enables the collection of physiological and topographical informations concerning muscle activation. However, HD-sEMG channels are usually contaminated by noise in an heterogeneous manner. The sources of noise are mainly power line interference (PLI), white Gaussian noise (WGN) and motion artifacts (MA). The spectral components of these disruptive signals overlap with the sEMG spectrum which makes classical filtering techniques non effective, especially during low contraction level recordings. In this study, we propose to denoise HD-sEMG recordings at 20 % of the maximum voluntary contraction by using a second-order blind source separation technique, named canonical component analysis (CCA). For this purpose, a specific and automatic canonical component selection, using noise ratio thresholding, and a channel selection procedure for the selective version (sCCA) are proposed. Results obtained from the application of the proposed methods (CCA and sCCA) on realistic simulated data demonstrated the ability of the proposed approach to retrieve the original HD-sEMG signals, by suppressing the PLI and WGN components, with high accuracy (for five different simulated noise dispersions using the same anatomy). Afterward, the proposed algorithms are employed to denoise experimental HD-sEMG signals from five healthy subjects during biceps brachii contractions following an isometric protocol. Obtained results showed that PLI and WGN components could be successfully removed, which enhances considerably the SNR of the channels with low SNR and thereby increases the mean SNR value among the grid. Moreover, the MA component is often isolated on specific estimated sources but requires additional signal processing for a total removal. In addition, comparative study with independent component analysis, CCA wavelet and CCA-empirical mode decomposition (EMD) proved a higher efficiency of the presented method over existing denoising techniques and demonstrated pointless a second filtering stage for denoising HD-sEMG recordings at this contraction level. PMID- 27221812 TI - Mapped Chebyshev pseudo-spectral method for simulating the shear wave propagation in the plane of symmetry of a transversely isotropic viscoelastic medium. AB - Shear wave elastography is a versatile technique that is being applied to many organs. However, in tissues that exhibit anisotropic material properties, special care must be taken to estimate shear wave propagation accurately and efficiently. A two-dimensional simulation method is implemented to simulate the shear wave propagation in the plane of symmetry in transversely isotropic viscoelastic media. The method uses a mapped Chebyshev pseudo-spectral method to calculate the spatial derivatives and an Adams-Bashforth-Moulton integrator with variable step sizes for time marching. The boundaries of the two-dimensional domain are surrounded by perfectly matched layers to approximate an infinite domain and minimize reflection errors. In an earlier work, we proposed a solution for estimating the apparent shear wave elasticity and viscosity of the spatial group velocity as a function of rotation angle through a low-frequency approximation by a Taylor expansion. With the solver implemented in MATLAB, the simulated results in this paper match well with the theory. Compared to the finite element method simulations we used before, the pseudo-spectral solver consumes less memory and is faster and achieves better accuracy. PMID- 27221813 TI - Biliary Brush Cytology Revisited. AB - PURPOSE: To evaluate the diagnostic yield of biliary brush cytology and the factors affecting positive results in patients with biliary strictures. PATIENTS AND METHODS: The medical records of all patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) with biliary brush cytology at our institution from November 2004 to December 2013 were reviewed in this retrospective study. The yield of positive brush cytology and the factors affecting positive yield, such as stricture location, age, gender and preprocedure CA 19.9 level were assessed. The final histopathology, diagnosis obtained by other methods, such as endoscopic ultrasound-guided fine-needle aspiration cytology, CT scan, Tru-Cut biopsy and/or clinical/radiological follow up were used to identify true- and false-positive/negative results. The brush cytology results were divided into 4 main categories: malignant, benign, atypical cells and inadequate. RESULTS: A total of 1,168 patients underwent ERCP during this 9-year period. Out of these, 142 patients had ERCP and biliary brushings for diagnosis. The mean age of the patients at presentation was 58.7 years (range 23 84 years; 64.8% males). The indication for referral was obstructive jaundice in all patients. Of the 142 patients, 77 (54.2%) had a distal common bile duct (CBD) stricture and 65 (45.8%) had a proximal /complex hilar stricture. The strictures were classified as proximal or distal, based on their relationship with the cystic duct; those below the cystic duct insertion were classified as distal and those above it were considered proximal. The diagnostic yield of brush cytology was 58.5%. The diagnostic yield was higher for proximal than for distal CBD strictures (67 vs. 50%; p = 0.047). It was also higher for females (58 vs. 57.6%; p = 0.94), patients >50 years (60 vs. 50%; p = 0.29) and those with a CA 19.9 level >300 IU/ml (59.4 vs. 55.5%; p = 0.65) but did not reach statistical significance for any of these parameters. Complete follow-up data were available for 96 patients and 46 patients were lost to follow-up. The sensitivity, specificity, positive predictive value and negative predictive value were 65.3, 100, 100 and 27%, respectively. When patients with atypia were included in the group with positive results, the diagnostic yield increased to 65.5% with a diagnostic sensitivity of 68.6%. There were 27 false-negative diagnoses, 10 patients were true-negative and no patients had a false-positive diagnosis. CONCLUSION: Biliary brush cytology is a safe and simple initial diagnostic procedure in patients with biliary strictures and can be performed at the time of therapeutic ERCP. If performed correctly and then interpreted by a dedicated cytopathologist, it has a good diagnostic yield and sensitivity. We feel that the low rates of success with this technique reported in some earlier studies have led to a feeling that this is not a particularly useful technique. We recommend that this topic should be revisited, and that the technique should be used more often. PMID- 27221814 TI - A gadolinium(iii) complex that shows room-temperature phosphorescence in the crystalline state. AB - This paper presents a gadolinium(iii) complex that shows blue phosphorescence in the crystalline state at room temperature under air atmosphere; color of the crystals can be changed to pale-green from blue by doping of 1-naphthol. PMID- 27221815 TI - Reply to 'PEM or MBI?'. PMID- 27221816 TI - Relationship of myocardial substrate characteristics as assessed by myocardial perfusion imaging and cardiac reverse remodeling levels after cardiac resynchronization therapy. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) can provide cardiac reverse remodeling (RR), which may include mechanical reverse remodeling (MRR) and/or electrical reverse remodeling (ERR). However, uncoupling of MRR and ERR is not uncommon, and the underlying mechanisms are not clear. This study aimed to evaluate the relationship of myocardial substrate characteristics as assessed by myocardial perfusion imaging (MPI) and cardiac RR post-CRT. MATERIALS AND METHODS: Forty-one patients (26 men, mean age 66 +/- 10 years) with heart failure received CRT for at least 12 months were assigned to three groups according to their levels of RR: I, MRR + ERR (ESV reduced >=15 % and intrinsic QRS duration reduced >=10 ms); II, MRR only (ESV reduced >=15 %); and III, non-responder (the others). All the patients also underwent MPI under transient CRT-off to evaluate the intrinsic myocardial substrates, including myocardial scar, LV volumes and function, systolic dyssynchrony, and activation sequences. In addition, ventricular tachycardia (VT) and ventricular fibrillation (VF) detected by the CRT devices during follow-up periods were also recorded. RESULTS: Quantitative analysis of MPI showed that there were significant differences for scar burden [15.9 +/- 9.5, 26.8 +/- 16.1, and 45.6 +/- 15.1 % for group I (n = 15), II (n = 16), and III (n = 10), respectively, p < 0.001], EDV (136.6 +/- 64.9, 221.6 +/- 123.9, and 351.8 +/- 216.3 ml, p = 0.002), ESV (82.6 +/- 59.8, 172.3 +/- 117.2, and 293.3 +/- 209.6 ml, p = 0.001), LVEF (44.9 +/- 15.0, 25.6 +/- 10.9, and 21.5 +/- 11.7 %, p < 0.001), systolic phase SD (23.4 degrees +/- 10.3 degrees , 36.0 degrees +/- 16.2 degrees , and 57.0 degrees +/- 22.2 degrees , p < 0.001), and bandwidth (72.5 degrees +/- 31.1 degrees , 113.4 degrees +/- 56.4 degrees , and 199.1 degrees +/- 90.1 degrees , p < 0.001). Myocardial scar interfered with the normal propagation of mechanical activation, resulting in heterogeneous activation sequences. Compared with group II (MRR only), group I (ERR + MRR) had significantly less initial activation segments (1.9 +/- 1.0 vs. 2.6 +/- 0.7, p < 0.05) and shorter maximal contraction delay (46.9 degrees +/- 12.9 degrees vs. 58.8 degrees +/- 18.5 degrees , p < 0.05). During the periods of follow-up, 21 patients developed VT/VF, including only 1 patient (1 VT) in group I (6.7 %), 8 patients (7 VT and 1 VF) in group II (50 %), and 9 patients (7 VT and 5 VF) in group III (90 %). CONCLUSION: The characteristics of myocardial substrates as assessed by MPI differed significantly between different levels of cardiac RR post-CRT. Myocardial scar played an important role in the development of ERR. Different cardiac RR levels contributed to different incidences of ventricular arrhythmia, and the combination of ERR and MRR provided highest anti-arrhythmic effects. PMID- 27221817 TI - FDG-PET characteristics of Hurthle cell and follicular adenomas. AB - OBJECTIVE: Follicular (FN) and Hurthle cell neoplasms (HCN) are considered indeterminate on thyroid fine needle aspiration cytology and are preoperative diagnostic challenges. The role of [(18)F]-2-fluoro-2-deoxy-D-glucose (FDG) in characterizing indeterminate thyroid nodules remains equivocal, because of the increased FDG uptake by some benign thyroid nodules. The objective of this study was to compare the FDG positron emission tomography/computerized tomography (PET/CT) characteristics of follicular (FA) and Hurthle cell adenomas (HCA). METHODS: Twenty-nine patients with 31 thyroid nodules underwent FDG-PET/CT scans of the neck and superior mediastinum for indeterminate FN/HCN, and were later found to have benign adenomas on final histopathology. All scans were reported by a single observer, who was blinded to the surgical and pathology findings. Receiver operating characteristic (ROC) curve analysis of maximum standardized uptake value (SUVmax) and the area under the curve (AUROC) were used to assess discrimination between FA and HCA. Youden index was used to identify the optimal cut-off SUVmax. Sensitivity, specificity, predictive values and overall accuracy were used as measures of performance. RESULTS: The mean age of our study cohort was 60.7 +/- 12.6 years and 77 % of the patients were females. Age of the patients (p = 0.48), their gender (p = 0.52), and the size of thyroid nodules (p = 0.79) were similar for FA and HCA. Increased focal FDG uptake was observed in 100 % of HCA and 52 % of FA (p = 0.02). SUVmax of HCA was significantly higher (p < 0.001) than that of FA. SUVmax of 5 was the best cut-off for discrimination between HCA and FA, with AUROC of 0.90 (95 % CI, 0.79-1.00; p = 0.001). With this cut-off, FDG-PET/CT had sensitivity of identifying HCA of 88 % (95 % CI 47-99 %), specificity of 87 % (95 % CI 65-97 %), positive predictive value of 70 % (95 % CI 35-92 %), and negative predictive value of 95 % (95 % CI 74-99 %). The overall accuracy was 87 %. CONCLUSIONS: HCA shows significantly higher focal FDG uptake as compared to FA and should always be considered in the differential diagnosis of FDG-PET positive thyroid nodules. PMID- 27221818 TI - Integrated care for childhood epilepsy: ongoing challenges and lessons for other long-term conditions. AB - Epilepsy care has been identified as a major global issue-and there are many recognised concerns in the UK for children and young people with the condition. A proposed new model could help to increase multisector integration, facilitate better outcomes and offer lessons for improving care of other long-term conditions. PMID- 27221819 TI - Cytotoxicity of modified glass ionomer cement on odontoblast cells. AB - Recently a modified glass ionomer cement (GIC) with enhanced bioactivity due to the incorporation of wollastonite or mineral trioxide aggregate (MTA) has been reported. The aim of this study was to evaluate the cytotoxic effect of the modified GIC on odontoblast-like cells. The cytotoxicity of a conventional GIC, wollastonite modified GIC (W-mGIC), MTA modified GIC (M-mGIC) and MTA cement has been evaluated using cement extracts, a culture media modified by the cement. Ion concentration and pH of each material in the culture media were measured and correlated to the results of the cytotoxicity study. Among the four groups, conventional GIC showed the most cytotoxicity effect, followed by W-mGIC and M mGIC. MTA showed the least toxic effect. GIC showed the lowest pH (6.36) while MTA showed the highest (8.62). In terms of ion concentration, MTA showed the largest Ca(2+) concentration (467.3 mg/L) while GIC showed the highest concentration of Si(4+) (19.9 mg/L), Al(3+) (7.2 mg/L) and Sr(2+) (100.3 mg/L). Concentration of F(-) was under the detection limit (0.02 mg/L) for all samples. However the concentrations of these ions are considered too low to be toxic. Our study showed that the cytotoxicity of conventional GIC can be moderated by incorporating calcium silicate based ceramics. The modified GIC might be promising as novel dental restorative cements. PMID- 27221820 TI - Preoperative Hip Injections Increase the Rate of Periprosthetic Infection After Total Hip Arthroplasty. AB - BACKGROUND: Intraarticular injections are both diagnostic and therapeutic for patients with osteoarthritis. A potential risk of periprosthetic joint infection (PJI) after total hip arthroplasty (THA) may occur from direct inoculation and/or immune suppression by corticosteroids. Large population-level databases were used to evaluate hip injection on the 1-year rate of PJI in patients undergoing primary THA. METHODS: State-level ambulatory surgery and inpatient databases for Florida and California (2005-2012) were used to identify primary THA patients with 1-year preoperative and postoperative windows to evaluate possible injections or PJI, respectively. Patients were grouped as no injection or as THA performed 6-12 months, 3-6 months, or 0-3 months after injection. Risk adjustment was performed with multivariable regression. RESULTS: A total of 173,958 patients were included; 5421 (3.1%) underwent THA after an injection: 1395 (1.1%) of patients after 6-12 months, 1863 patients after 3-6 months, and 2163 (1.2%) after 0-3 months. In the 0-3 month group, PJI was significantly increased at 3 months (1.58%, P = .015), 6 months (1.76%, P = .022), and 1 year (2.04%, P = .031) compared with the noninjection control group (1.04%, 1.21%, and 1.47%, respectively). There were no differences in the 3- to 6-month and 6- to 12-month injection groups. CONCLUSION: There is an increased risk of PJI when THA is performed within 3 months of hip injection. We recommend that patients and their surgeons consider delaying elective THA until 3 months after an injection to avoid this elevated risk of infection. PMID- 27221821 TI - Infectious Triggers of Chronic Lung Allograft Dysfunction. AB - Survival after lung transplantation is limited in large part due to the high incidence of chronic rejection, known as chronic lung allograft dysfunction (CLAD). Pulmonary infections are a frequent complication in lung transplant recipients, due both to immunosuppressive medications and constant exposure of the lung allograft to the external environment via the airways. Infection is a recognized risk factor for the development of CLAD, and both acute infection and chronic lung allograft colonization with microorganisms increase the risk for CLAD. Acute infection by community acquired respiratory viruses, and the bacteria Pseudomonas aeruginosa and Staphylococcus aureus are increasingly recognized as important risk factors for CLAD. Colonization by the fungus Aspergillus may also augment the risk of CLAD. Fostering this transition from healthy lung to CLAD in each of these infectious episodes is the persistence of an inflammatory lung allograft environment. PMID- 27221822 TI - Sensitivity of Ethiopian aquatic macroinvertebrates to the pesticides endosulfan and diazinon, compared to literature data. AB - The aims of the present study were to present a methodology for toxicity tests that can be used when analytical resources to verify the test concentrations are limited, and to evaluate whether the sensitivity of a limited number of Ethiopian species to pesticides differs from literature values for, mainly, temperate species. Acute toxicity tests were performed using three Ethiopian aquatic invertebrate species, one crustacean (Diaphanosoma brachyurum) and two insects (Anopheles pharoensis and Culex pipiens) and using the pesticides endosulfan and diazinon. All species-pesticide combinations were tested in duplicate to estimate the consistency, i.e. the intra-laboratory variation, in test results. Daphnia magna was tested as well to allow the test results to be compared directly with values from the literature. Results indicate that the differences between the EC50s obtained for D. magna in this study and those reported in the literature were less than a factor of 2. This indicates that the methodology used is able to provide credible toxicity values. The results of the duplicated tests showed intra-laboratory variation in EC50 values of up to a factor of 3, with one test showing a difference of a factor of 6 at 48 h. Comparison with available literature results for arthropod species using species sensitivity distributions indicated that the test results obtained in this study fit well in the log-normal distribution of the literature values. We conclude that the methodology of performing multiple tests to check for consistency of test results and performing tests with D. magna for comparison with literature values to check for accuracy is able to provide reliable effect threshold levels and that the tested Ethiopian species did not differ in sensitivity from the arthropod species reported on in the literature. PMID- 27221823 TI - Activated thrombin-activatable fibrinolysis inhibitor (TAFIa) attenuates breast cancer cell metastatic behaviors through inhibition of plasminogen activation and extracellular proteolysis. AB - BACKGROUND: Thrombin activatable fibrinolysis inhibitor (TAFI) is a plasma zymogen, which can be converted to activated TAFI (TAFIa) through proteolytic cleavage by thrombin, plasmin, and most effectively thrombin in complex with the endothelial cofactor thrombomodulin (TM). TAFIa is a carboxypeptidase that cleaves carboxyl terminal lysine and arginine residues from protein and peptide substrates, including plasminogen-binding sites on cell surface receptors. Carboxyl terminal lysine residues play a pivotal role in enhancing cell surface plasminogen activation to plasmin. Plasmin has many critical functions including cleaving components of the extracellular matrix (ECM), which enhances invasion and migration of cancer cells. We therefore hypothesized that TAFIa could act to attenuate metastasis. METHODS: To assess the role of TAFIa in breast cancer metastasis, in vitro migration and invasion assays, live cell proteolysis and cell proliferation using MDA-MB-231 and SUM149 cells were carried out in the presence of a TAFIa inhibitor, recombinant TAFI variants, or soluble TM. RESULTS: Inhibition of TAFIa with potato tuber carboxypeptidase inhibitor increased cell invasion, migration and proteolysis of both cell lines, whereas addition of TM resulted in a decrease in all these parameters. A stable variant of TAFIa, TAFIa CIIYQ, showed enhanced inhibitory effects on cell invasion, migration and proteolysis. Furthermore, pericellular plasminogen activation was significantly decreased on the surface of MDA-MB-231 and SUM149 cells following treatment with various concentrations of TAFIa. CONCLUSIONS: Taken together, these results indicate a vital role for TAFIa in regulating pericellular plasminogen activation and ultimately ECM proteolysis in the breast cancer microenvironment. Enhancement of TAFI activation in this microenvironment may be a therapeutic strategy to inhibit invasion and prevent metastasis of breast cancer cells. PMID- 27221824 TI - Systematic methodological review: developing a framework for a qualitative semi structured interview guide. AB - AIM: To produce a framework for the development of a qualitative semi-structured interview guide. BACKGROUND: Rigorous data collection procedures fundamentally influence the results of studies. The semi-structured interview is a common data collection method, but methodological research on the development of a semi structured interview guide is sparse. DESIGN: Systematic methodological review. DATA SOURCES: We searched PubMed, CINAHL, Scopus and Web of Science for methodological papers on semi-structured interview guides from October 2004 September 2014. Having examined 2,703 titles and abstracts and 21 full texts, we finally selected 10 papers. REVIEW METHODS: We analysed the data using the qualitative content analysis method. RESULTS: Our analysis resulted in new synthesized knowledge on the development of a semi-structured interview guide, including five phases: (1) identifying the prerequisites for using semi structured interviews; (2) retrieving and using previous knowledge; (3) formulating the preliminary semi-structured interview guide; (4) pilot testing the guide; and (5) presenting the complete semi-structured interview guide. CONCLUSION: Rigorous development of a qualitative semi-structured interview guide contributes to the objectivity and trustworthiness of studies and makes the results more plausible. Researchers should consider using this five-step process to develop a semi-structured interview guide and justify the decisions made during it. PMID- 27221826 TI - Survival in Head and Neck Cancers - Results of A Multi- Institution Study. AB - BACKGROUND: The prime output of Hospital Based Cancer Registries is stage and treatment based survival to evaluate patient care, but because of challenges of obtaining follow-up details a separate study on Patterns of Care and Survival for selected sites was initiated under the National Cancer Registry Programme of India. The results of stage and treatment based survival for head and neck cancers by individual organ sites are presented. MATERIALS AND METHODS: A standardized Patient Information Form recorded the details and entered on-line at www.hbccrindia.org to a central repository - National Centre for Disease Informatics and Research. Cases from 12 institutions diagnosed between 1 January 2006 and 31 December 2008 comprised the study subjects. The patterns of treatment were examined for 14053 and survival for 4773 patients from five institutions who reported at least 70% follow-up as of 31 December 2012. RESULTS: Surgical treatment with radiation for cancer tongue and mouth showed five year cumulative survival (FCS) of 67.5% and 60.4% respectively for locally advanced stage. Chemo radiation compared to radiation alone showed better survival benefit of around 15% in both oro and hypo-pharyngeal cancers and their FCS was 40.0%; Hazard Ratio (HR):1.5;CI=1.2-1.9) and 38.7%; (HR):1.7; CI=1.3-2.2). CONCLUSIONS: The awareness about the requirement of concurrent chemo-radiation in specifically cancers of the oro and hypopharynx has to be promoted in developing countries. The annual (2014) estimate number of new Head and Neck cancers with locally advanced disease in India is around 140,000 and 91,000 (65%) patients do not receive the benefit of optimal treatment with ensuing poorer survival. PMID- 27221827 TI - Recent Progress in Triple Negative Breast Cancer Research. AB - Triple-negative breast cancer (TNBC) is defined as a type of breast carcinoma that is negative for expression of oestrogene and progesterone hormone receptors (ER, PR) and HER2. This form of breast cancer is marked by its aggressiveness, low survival rate and lack of specific therapies. Recently, important molecular characteristics of TNBC have been highlighted and led to the identification of some biomarkers that could be used in diagnosis, as therapeutic targets or to assess the prognosis. In this review, we summarize recent progress in TNBC research focusing on the genetic and epigenetic alterations of TNBC and the potential use of these biomarkers in the targeted therapy for better management of TNBC. PMID- 27221825 TI - Impact of T cell activation, HIV replication and hepatitis C virus infection on neutrophil CD64 expression. AB - BACKGROUND: Overexpression of the Fc receptor CD64 on neutrophils is associated with innate immune response and bacterial infections. During HIV infection a large set of immune disorders including T-lymphocyte over-activation, microbial translocation, impairment of neutrophil functions, and immunodeficiency may interplay with neutrophil CD64 expression. METHODS: Associations of neutrophil CD64 expression with CD8+ T cell activation, CD4+ T cells number, HIV, and HCV replications were investigated in HIV infected patients using a standardized method. RESULTS: Higher neutrophil CD64 expression was observed in HIV infected subjects compared to healthy controls (0.91 vs. 0.75, P < 0.001). Among 115 HIV infected patients, nine (8.8%) had a CD64 expression over the clinical threshold as calculated against bead standard (i.e., 1.5). HIV viremic patients were more likely to have an index above 1.5 (OR: 6.68, P values: 0.01). A trend for correlation between CD64 expression and CD8 T cell activation was observed (P values: 0.08). Blood CD4+ T lymphocyte depletion and HCV replication did not affect neutrophil CD64 expression. CONCLUSIONS: HIV infection and HIV replication are associated with up-regulation of neutrophil CD64. CD64 overexpression above the clinical threshold was observed in a minor proportion of HIV infected individuals treated by antiretroviral therapy and may be a marker of neutrophil activation related to non-AIDS-linked comorbidities. (c) 2016 International Clinical Cytometry Society. PMID- 27221828 TI - HER-2 Positive Breast Cancer - a Mini-Review. AB - Breast cancer is one of among all cancers with increased incidence, high mortality rate, and high economic and social costs. The the most common type of cancer among females worldwide, breast cancer is actually the uncontrolled proliferation of cells which attain malignancy. Recently it has shown that breast cancer contributes 11% among all types of cancer diagnosed globally on an annual basis and it is one of the leading causes of death among women. The human epidermal growth factor receptor 2 (HER-2) is a receptor tyrosine-protein kinase erbB-2 normally involved in the proliferation and division of breast cells. In some abnormal cases the HER2 gene does not work correctly and makes too many copies of itself. HER2-positive (HER2+) breast cancers constitute an aggressive type of breast cancer and tend to grow faster and are more likely to spread. However, therapies that specifically target HER2, such as Herceptin(r) (traztuzumab), are very effective. HER2 targeted therapies, has significantly improved the therapeutic outcome for patients with HER2 positive breast cancer. PMID- 27221829 TI - Three Weekly Versus Weekly Cisplatin as Radiosensitizer in Head and Neck Cancer: a Decision Dilemma. AB - Cisplatin-based concurrent chemoradiation plays an undisputed key role as definitive treatment in unresectable patients with locally advanced squamous cell carcinoma head and neck or as an organ preservation strategy. Treatment with 100 mg/m2 3-weekly cisplatin is considered the standard of care but is often associated with several adverse events. The optimum drug schedule of administration remains to be defined and presently, there is insufficient data limiting conclusions about the relative tolerability of one regimen over the other. This review addresses regarding the optimal dose schedule of cisplatin focusing mainly on three-weekly and weekly dose of cisplatin based concurrent chemoradiotherapy in locally advanced head and neck cancer with an emphasis on mucositis, dermatitis, systemic toxicity, compliance, and treatment interruptions. To derive a definitive conclusion, large prospective randomized trials are needed directly comparing standard 3-weekly cisplatin (100 mg/m2) with weekly schedule (30 - 40 mg/m2) of concurrent cisplatin based chemoradiotherapy in locally advanced squamous cell carcinoma head and neck. PMID- 27221830 TI - Multimodality Treatment for Patients with Node-Positive Prostate Cancer: the Role of Radiation Therapy. AB - Prostate cancer is the secondary most frequently diagnosed cancer in the world. Although numerous prospective randomized trial have been conducted to guide the management of patients with localized or locally advanced prostate cancer, few clinical trials targeting node-positive prostate cancer have been reported. Therefore, there are still controversies in the optimal management of node positive prostate cancer. Recently, efficacy of multimodality treatment, including radiation therapy (RT), for such patients has been reported in several articles. The results indicate potential benefit of RT both in adjuvant therapy after prostatectomy and in definitive therapy for node-positive prostate cancer. The aim in this article was to summarize the current evidence for RT and evaluate the role in multimodality treatment for patients with node-positive prostate cancer. PMID- 27221831 TI - Diagnosis of Helicobacter pylori Infection. AB - Helicobacter pylori infection plays an important role in the pathogenesis of chronic gastritis, peptic ulcer disease and gastric malignancy. A diagnosis of infection is thus an important part of a treatment strategy of many gastrointestinal tract diseases. Many diagnostic tests are available but all have some limitations in different clinical situations and laboratory settings. A single gold standard cannot available, but be used for diagnosis of Helicobacter pylori infection in daily clinical practice in all areas, so several techniques have been developed to give reliable results, especially focusing on real time endoscopic features. The narrow band imaging system (NBI) and high resolution endoscopy are imaging techniques for enhanced visualization of infected mucosa and premalignant gastric lesions. The aim of this article is to review the current diagnostic options and possible future developments detection of Helicobacter pylori infection. PMID- 27221832 TI - Clinical Features of Oxaliplatin Induced Hypersensitivity Reactions and Therapeutic Approaches. AB - Oxaliplatin, a third generation novel platinum compound is the most effective first line chemotherapeutic agent for colorectal cancer (CRC) in combination with 5FU and leucovorin. It is indicated for pancreatic, gastric and testicular cancers combined with bevacuzimab, capecitabine, irinotecan and other cytotoxic agents. However, moderate to severe hypersensitivity reactions (HSR) during or after oxaliplatin infusion usually require cessation of chemotherapy or substitution of the key therapeutic drug which largely interferes with improved patient prognosis. This mini- review showcases recent and accepted opinions/approaches in oxaliplatin induced HSR management. Physicians and oncologists have varying attitudes regarding the decision to rechallenge the patient after an HSR experience, efficacy of desensitization protocols, effectiveness and selection of drugs for premedication and possibilities of cross sensitivity to other platinum agents (e.g. carboplatin). A brief insight into underlying molecular mechanisms and clinical manifestations of oxaliplatin induced HSR is offered. We have also discussed the management of oxaliplatin induced HSR and risk stratification for a successful and complete chemotherapeutic plan. PMID- 27221833 TI - Ganglioside as a Therapy Target in Various Types of Cancer. AB - Since their discovery in 1940, it has been well established that gangliosides are associated with a number of biological pathways and cellular processes such as growth, differentiation and toxin uptake. Gangliosides are glycosphingolipids containing neuraminic acid which are expressed on the plasma membrane of cells particularly in the nervous system. Heterogeneity and structural variation in the carbohydrate chains of gangliosides contributes to unique features of each of these molecules. Thirty five years ago it was discovered that aberrant glycosylation occurs in a variety of human cancers, including aberrant glycosylation of gangliosides. Ganglioside expression in terms of quality and quantity varies in different cancers and different roles may be played. Gangliosides, by affecting the immune system, including esxpression of cytokines and adhesion molecules, may inhibit anti-tumor mechanisms, as well as having direct impact on angiogenesis, cell movement and metastasis. It should be noted that different kinds of gangliosides do not all act by the same mechanisms. PMID- 27221834 TI - Anti-Cancer Effects of Green Tea by Either Anti- or Pro- Oxidative Mechanisms. AB - Tea derived from the leaves and buds of Camellia sinensis (Theaceae) is consumed worldwide. Green tea contains various components with specific health-promoting effects, and is believed to exert protective effects against diseases including cancer, diabetes and hepatitis, as well as obesity. Of the various tea components, the polyphenol catechins have been the subject of extensive investigation and among the catechins, (-)-epigallocatechin gallate has the strongest bioactivity in most cases. Our research group has postulated that hepatocyte nuclear factor-4alpha, sterol regulatory element-binding proteins, and tumor necrosis factor-alpha are targets of green tea constituents including (-) epigallocatechin gallate for their anti-diabetes, anti-obesity, and anti hepatitis effects, respectively. Published papers were reviewed to determine whether the observed changes in these factors can be correlated with anti-cancer effects of green tea. Two major action mechanisms of (-)-epigallocatechin gallate have been proposed; one associated with its anti-oxidative properties and the other with its pro-oxidative activity. When reactive oxygen species are assumed to be involved, our findings that (-)-epigallocatechin gallate down- regulated hepatocyte nuclear factor-4alpha, sterol regulatory element-binding proteins, and tumor necrosis factor-alpha may explain the anti-cancer effect of green tea as well. However, further studies are required to elucidate which determinant directs (-)-epigallocatechin gallate action as an anti-oxidant or a pro-oxidant for favorable activity. PMID- 27221835 TI - Celecoxib, a COX-2 Selective Inhibitor, Induces Cell Cycle Arrest at the G2/M Phase in HeLa Cervical Cancer Cells. AB - Celecoxib, a selective inhibitor of COX-2, showed cytotoxic effects in many cancer cell lines including cervical cancer cells. This study investigated the effect of celecoxib on cell cycle arrest in HeLa cervical cancer cells through p53 expression. In vitro anticancer activity was determined with the 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) method. A double staining method was applied to investigate the mechanism of cell death, cell cycling was analyzed by flow cytometryand immunocytochemistry was employed to stain p53 expression in cells. Celecoxib showed strong cytotoxic effects and induced apoptosis with an IC50 value of 40 MUM. It induced cell cycle arrest at G2/M phase by increasing level of p53 expression on HeLa cells. PMID- 27221836 TI - Efficacy and Safety of Neurokinin-1 Receptor Antagonists for Prevention of Chemotherapy-Induced Nausea and Vomiting: Systematic Review and Meta-analysis of Randomized Controlled Trials. AB - OBJECTIVES: Can addition of neurokinin-1 receptor antagonists (NK1-RAs) be considered as an ideal strategy for the prevention of chemotherapy-induced nausea and vomiting (CINV)? Researchers differ on this question. MATERIALS AND METHODS: Electronic databases were searched for randomized control trials (RCTs) that evaluated the effectiveness and safety of NK1-RAs in preventing CINV. The primary end point was complete response (CR) in the acute, delayed, and overall phases after chemotherapy. Subgroup analyses evaluated the types of NK1-RAs, routines of administration, types of malignancies, regimens used in combination with NK1-RAs, and age of patients included in the studies. The incidences of different types of adverse events were also extracted to estimate the safety of NK1-RAs. RESULTS: A total of 38 RCTs involving 13,923 patients were identified. The CR rate of patients receiving NK-RAs was significantly higher than patients in the control groups during overall phase (70.8% vs 56.0%, <0.001), acute phase (85.1% vs 79.6%, <0.001), and delayed phase (71.4% vs 58.2%, <0.001). There were three studies including patients of children or adolescents, the CR rate was also significantly higher in the treatment group (overall phase: OR=2.807, <0.001; acute phase: OR=2.863, P =0.012; delayed phase: OR=2.417, <0.001). For all the other outcomes, patients in the NK1-RAs groups showed improvements compared to the control groups (incidence of nausea: 45.2% vs 45.9%, <0.001; occurrence of vomiting: 22.6% vs 38.9%, <0.001; usage of rescue drugs: 23.5% vs 34.1%, <0.001). The pooled side effects from NK1-RAs did not significantly differ from previous reports and the toxicity rates in patients less than eighteen years old also did not diff between the two groups (P=0.497). However, we found that constipation and insomnia were more common in the patients of control groups, whereas diarrhea and hiccups were more frequently detected in patients receiving NK1-RAs. CONCLUSIONS: NK1-RAs improved the CR rate of CINV. They are effective for both adults and children. The use of NK1-RAs might be associated with the appearance of diarrhea and hiccups, while decreasing the possibility of constipation and insomnia. PMID- 27221837 TI - Quality of Life among Breast Cancer Patients In Malaysia. AB - BACKGROUND: Among the factors reported to determine the quality of life of breast cancer patients are socio- demographic background, clinical stage, type of treatment received, and the duration since diagnosis. OBJECTIVE: The objective of this study was to determine the quality of life (QOL) scores among breast cancer patients at a Malaysian public hospital. MATERIALS AND METHODS: This cross sectional study of breast cancer patients was conducted between March to June 2013. QOL scores were determined using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and its breast cancer supplementary measure (QLQ-BR23). Both the QLQ-C30 and QLQ-BR23 assess items from functional and symptom scales. The QLQ-C30 in addition also measures the Global Health Status (GHS). Systematic random sampling was used to recruit patients. RESULTS: 223 breast cancer patients were recruited with a response rate of 92.1%. The mean age of the patients was 52.4 years (95% CI = 51.0, 53.7, SD=10.3). Majority of respondents are Malays (60.5%), followed by Chinese (19.3%), Indians (18.4%), and others (1.8%). More than 50% of respondents are at stage III and stage IV of malignancy. The mean Global Health Status was 65.7 (SD = 21.4). From the QLQ-C30, the mean score in the functioning scale was highest for 'cognitive functioning' (84.1, SD=18.0), while the mean score in the symptom scale was highest for 'financial difficulties' (40.1, SD=31.6). From the QLQ BR23, the mean score for functioning scale was highest for 'body image' (80.0, SD=24.6) while the mean score in the symptom scale was highest for 'upset by hair loss' (36.2, SD=29.4). Two significant predictors for Global Health Status were age and employment. The predictors explained 10.6% of the variation of global health status (R2=0.106). CONCLUSIONS: Age and employment were found to be significant predictors for Global Health Status (GHS). The Quality of Life among breast cancer patients reflected by the GHS improves as age and employment increases. PMID- 27221838 TI - Dosimetric Characteristics of 6 MV Modified Beams by Physical Wedges of a Siemens Linear Accelerator. AB - Physical wedges still can be used as missing tissue compensators or filters to alter the shape of isodose curves in a target volume to reach an optimal radiotherapy plan without creating a hotspot. The aim of this study was to investigate the dosimetric properties of physical wedges filters such as off-axis photon fluence, photon spectrum, output factor and half value layer. The photon beam quality of a 6 MV Primus Siemens modified by 150 and 450 physical wedges was studied with BEAMnrc Monte Carlo (MC) code. The calculated present depth dose and dose profile curves for open and wedged photon beam were in good agreement with the measurements. Increase of wedge angle increased the beam hardening and this effect was more pronounced at the heal region. Using such an accurate MC model to determine of wedge factors and implementation of it as a calculation algorithm in the future treatment planning systems is recommended. PMID- 27221839 TI - Data Mining for Identification of Molecular Targets in Ovarian Cancer. AB - Ovarian cancer is possibly the sixth most common malignancy worldwide, in Mexico representing the fourth leading cause of gynecological cancer death more than 70% being diagnosed at an advanced stage and the survival being very poor. Ovarian tumors are classified according to histological characteristics, epithelial ovarian cancer as the most common (~80%). We here used high-density microarrays and a systems biology approach to identify tissue-associated deregulated genes. Non-malignant ovarian tumors showed a gene expression profile associated with immune mediated inflammatory responses (28 genes), whereas malignant tumors had a gene expression profile related to cell cycle regulation (1,329 genes) and ovarian cell lines to cell cycling and metabolism (1,664 genes). PMID- 27221840 TI - Global Incidence and Mortality Rates of Stomach Cancer and the Human Development Index: an Ecological Study. AB - BACKGROUND: Stomach cancer (SC) is the second leading cause of cancer death with the rate of 10.4% in the world. The correlation between the incidence and mortality rates of SC and human development index (HDI) has not been globally determined. Therefore, this study aimed to determine the association between the incidence and mortality rates of SC and HDI in various regions. MATERIALS AND METHODS: In this global ecological study, we used the data about the incidence and mortality rate of SC and HDI from the global cancer project and the United Nations Development Programme database, respectively. RESULTS: In 2012, SCs were estimated to have affected a total of 951,594 individuals (crude rate: 13.5 per 100,000 individuals) with a male/female ratio of 1.97, and caused 723,073 deaths worldwide (crude rate: 10.2 per 100,000 individuals). There was a positive correlation between the HDI and both incidence (r=0.28, <0.05) and mortality rates of SC (r=0.13, P = 0.1) in the world in 2012. CONCLUSIONS: The high incidence and mortality rates of SC in countries with high and very high HDI is remarkable which should be the top priority of interventions for global health policymakers. In addition, health programs should be provided to reduce the burden of this disease in the regions with high incidence and mortality rates of SC. PMID- 27221841 TI - Association of Viral Infections with Risk of Human Lymphomas, Egypt. AB - BACKGROUND: The aim of this study was to determine and evaluate the association of different viral infections, with hepatitis B and C viruses, Epstein-Barr virus, cytomegalovirus and human herpes virus-8 (HBV, HCV, EBV, CMV, HHV-8) with the risk of lymphomas (Hodgkin and non-Hodgkin) among Egyptian patients, and correlate with the histopathological staging and typing as well as the prevalence of combined infections. MATERIALS AND METHODS: A total of 100 newly diagnosed lymphoma patients with 100 healthy age and sex matched normal controls were assayed for viral infection using enzyme linked immunosorbant assay (ELISA) followed by real time polymerase chain reaction (RT-PCR). RESULTS: Our results showed a high statistical significant difference between cases and controls as regards clinical and laboratory findings (<0.001 and=0.003). A high statistical difference was seen for the association of most viruses and lymphoma cases (<0.001) except for positive HBs Ag, positive CMV IgG and HHV-8 (p=0.37, 0.70 and 1.0 respectively). No statistical significant difference was found between Hodgkin (HL) and non-Hodgkin (NHL) as regards viral prevalence except HCV antigen, 57.1% for HL and 26.5% for NHL (p = 0.03). Only, HBV DNA showed a high significant value among infiltrated bone marrow cases (p=0.003) and finally, a high significant association of 2 combined viral infections with infiltrated bone marrow lymphoma cases (p=0.04). CONCLUSIONS: Our results showed that infection with HBV, HCV, CMV and EBV were associated with increased risk of lymphoma among the Egyptian population. Detection of new associations between infectious agents and risk of cancer development will facilitate progress in elaboration of prophylactic measures, early diagnostic methods and, hopefully, novel therapy of malignant tumours. PMID- 27221843 TI - Parental Experiences with Chemotherapy-Induced Alopecia among Childhood Cancer Patients in Indonesia. AB - BACKGROUND: This study assessed parental experiences with chemotherapy-induced alopecia among children with cancer treated at an Indonesian academic hospital. MATERIALS AND METHODS: Fifty parents of childhood cancer patients were interviewed using semi-structured questionnaires. RESULTS: The moment that hair fell out was the moment that parents (84%) had to admit their child had cancer. Alopecia was a traumatizing painful experience (46%). Active strategies to hide alopecia, mainly hats, were used by 66% of children, while 34% never covered their bald head. If money had not been an issue, 40% would use another strategy. Alopecia made children limit outdoor daily activities (78%) and engagement with others (60%). Significantly more children from high-educated (95%) than low educated (60%) parents received sympathy from other people (P=0.012). Significantly more Christian (29%) than Muslim (0%) families confirmed that alopecia lowered the quality of life (P=0.046). Most parents (82%) had no prior plans about alopecia management, yet for significantly more girls (26%) than boys (0%) such plans existed (P=0.044). Parents received most information about alopecia from other parents (66%). Parents (92%) needed more alopecia education from doctors. Of all school-attending children, 53% were bullied and 47% did not want to attend school due to alopecia. Significantly more high-educated than low educated families received pity from teachers and pupils (94% vs. 0%, P=0.004), and acceptance by pupils (81% vs. 0%, P=0.021). CONCLUSIONS: Alopecia is a severe, far-stretching side-effect of chemotherapy with physical, psychological and social consequences for children and parents. Parents should be better informed about occurrence and impact of alopecia. Extra attention is required to facilitate children's return to school. Health- care providers should facilitate optimal supportive care through open dialogue and provision of educational materials for parents, children and their community. PMID- 27221842 TI - Implementation of Health Behavior Education Concerning Liver Flukes among Village Health Volunteers in an Epidemic Area of Thailand. AB - BACKGROUND: Liver fluke infection is associated with cholangiocarcinoma; the bile duct cancer found frequently in the northeast and north of Thailand. Prevention and control particularly requires health education and behavior change. OBJECTIVE: This study aimed to improve health behavior among village health volunteers (VHV) regarding liver fluke exposure in an epidemic area. MATERIALS AND METHODS: A quasi-experimental study was performed during July 2015 to January 2016 in Sang Kha district of Surin province, Thailand. A total of 67 VHVs underwent a health education program (HEP) and data were collected on knowledge, attitude, and practice (KAP) before and after participation for HEP 3 months with a pre-designed questionnaire. The Students paired T-test was used for comparisons of mean KAP levels before/after the intervention. RESULTS: The results revealed that knowledge (P-value=0.004), attitude (P-value=0.004), and practice level (P value=0.000) were significantly improved after participation in the HBP. Attitude was significantly associated with knowledge (r=0.266, <0.05), and practice (r=0.348, <0.01) . CONCLUSIONS: The implementation of health education among VHVs is feasible and increases their KAP. This improvement should have potential in liver fluke prevention and control in local communities in rural Thailand. PMID- 27221844 TI - Screening for Del 185 AG and 4627C>A BRCA1 Mutations in Breast Cancer Patients from Lahore, Pakistan. AB - Breast cancer contributes to approximately 23% of the cancer cases identified and 14% of cancer related deaths worldwide. Including a strong association between genetic and environmental factors, breast cancer is a complex and multi factorial disorder. Two high penetration breast cancer susceptibility genes (BRCA1 and BRCA2) have been identified, and germ line mutations in these are thought to account for between 5% and 10% of all breast cancer cases. The human BRCA1 gene, located on 17q, is involved in the regulation of cell proliferation by aiding in DNA repair, transcriptional responses to DNA damage and cell cycle check points. Mutations in this gene enhance cell proliferation and facilitate formation of tumors. Two mutations, the 185 deletion of AG and the 4627 substitution from C to A, are founder mutations in the BRCA1 gene for breast cancer in Asian populations. Allele specific PCR was performed to detect these selected mutations in 120 samples. No mutation of 4627 C to A was detected in the samples and only one of the patients had the 185 del AG mutation in the heterozygous condition. Our collected samples had lower consanguinity and family history indicating the greater involvement of environmental as compared to genetic factors. PMID- 27221845 TI - Correlation between RAS Test Results and Prognosis of Metastatic Colorectal Cancer Patients: a Report from Western Iran. AB - In the patients with metastatic colorectal cancer (mCRC), RAS testing is the first step to identify those that could benefit from anti-EGFR therapy. This study examined associations between KRAS mutations and clinicopathological and survival data in Iranian patients with mCRC. Between 2008 to2015 in a retrospective study, 83 cases of mCRC were referred to the Clinic of Medical Oncology. The mean follow-up was 45 months that there were 27 deaths. The 3 patients that did not complete follow-up were censored from the study. KRAS and NRAS were analyzed using allele-specific PCR primers and pyrosequencing in exons 2, 3 and 4. Multivariate survival analysis using Cox's regression model was used for affecting of variables on overall survival (OS). The mean age at diagnosis for patients was 57.7 (range, 18 to 80 years) and 61.4% were male. There was no significant different between prognostic factors and KRAS mutation with wild type. Also, There was no significant different between KRAS mutation and KRAS wild-type for survival, but there was a significant different between KRAS 12 and 13 mutations for survival (HR 0.13, 95% CI 0.03-0.66, P=0.01). In conclusion, the prevalence of KRAS mutations in CRC patients was below 50% but higher than in other studies in Iran. As in many studies, patients with KRAS 12 mutations had better OS thn those with KRAS 13 mutation. In addition to KRAS testing, other biomarkers are needed to determine the best treatment for patients with mCRC. PMID- 27221846 TI - Prevalence of Tobacco and Alcohol Consumption among Fishermen in Udupi Taluk' Karnataka, India: a Cross-Sectional Study. AB - BACKGROUND: Stress associated with fishing is known to trigger consumption of alcohol and tobacco among fishermen. This study aimed to assess the prevalence of tobacco and alcohol consumption among fishermen in Udupi Taluk in the state of Karnataka, India, and to study associations with health status and job stress. MATERIALS AND METHODS: The study was conducted among 825 fishermen in Udupi Taluk of Karnataka between January-June 2015, using a two stage cluster sampling procedure. Associations between variables of interest were assessed using multivariable analysis and logistic regression models. RESULTS: The prevalences of consumption of tobacco, alcohol and either of these substances were 64.2%, 45.6% and 86.9% respectively. There was a positive association between alcohol and any form of tobacco consumption with income but none with respondent's job stress and health status. CONCLUSIONS: Our study concluded that fishermen with poor health status are seen more among tobacco and alcohol users. PMID- 27221847 TI - Evaluation of Anticancer Activity of Curcumin Analogues Bearing a Heterocyclic Nucleus. AB - We report herein an in vitro anticancer evaluation of a series of seven curcumin analogues (3a-g). The National Cancer Institute (NCI US) Protocol was followed and all the compounds were evaluated for their anticancer activity on nine different panels (leukemia, non small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer) represented by 60 NCI human cancer cell lines. All the compounds showed significant anticancer activity in one dose assay (drug concentration 10 MUM) and hence were evaluated further in five dose assays (0.01, 0.1, 1, 10 and 100 MUM) and three dose related parameters GI50, TGI and LC50 were calculated for each (3a g) in micro molar drug concentrations (MUM). The compound 3d (NSC 757927) showed maximum mean percent growth inhibition (PGI) of 112.2%, while compound 3g (NSC 763374) showed less mean PGI of 40.1% in the one dose assay. The maximum anticancer activity was observed with the SR (leukemia) cell line with a GI50 of 0.03 MUM. The calculated average sensitivity of all cell lines of a particular subpanel toward the test agent showed that all the curcumin analogues showed maximum activity on leukemia cell lines with GI50 values between 0.23 and 2.67 MUM. PMID- 27221848 TI - Predictive Effect of Preoperative Anemia on Long-Term Survival Outcomes with Non Muscle Invasive Bladder Cancer. AB - BACKGROUND: Anemia is the most common hematologic abnormality in bladder cancer (BC) patients. We evaluated the impact of preoperative anemia on oncologic outcomes in BC undergoing transurethral resection of a bladder tumor (TURBT) for the first time diagnosis. MATERIALS AND METHODS: We retrospectively evaluated the data collected from 639 patients who underwent TURBT between January 2006 and September 2014 in our department. Of these patients, 320 qualified for inclusion in the study. The primary efficacy endpoint was the effect of preoperative anemia status on cancer-specific and overall survival. Independent t-test and chi-square analyses were performed to assess the effects of anemia on oncologic outcomes. Survival was estimated by using the Kaplan-Meier test. RESULTS: There were 118 (36.9%) and 202 (63.1%) patients in the anemia (Group-1) and non-anemia groups (Group-2), respectively. The median follow-up duration was 68 months. Anemia was associated with decreased overall survival (<0.001). Comparison between cancer specific survival of two groups did not show any statistically significant difference (p=0.17). CONCLUSIONS: Preoperative anemia status of BC patients according to World Health Organization classification is associated with decreased overall survival, but not with cancer-specific survival. We think that preoperative hemoglobin levels should be considered in patient counseling and decision-making for additional therapy. PMID- 27221849 TI - Uterine Sarcoma: Clinical Presentation, Treatment and Survival Outcomes in Thailand. AB - BACKGROUND: Uterine sarcoma is a group of rare gynecologic tumors with various natures, and different lines of treatment. Most have a poor treatment outcome. This study targeted clinical characteristics, treatment, overall survival (OS), progression-free survival (PFS), and prognostic factors in uterine sarcoma patients in one tertiary center for cancer care. MATERIALS AND METHODS: Uterine sarcoma patients who were treated at the Department of Obstetrics and Gynecology, Faculty of Medicine Vajira Hospital between January 1994 and December 2014 were identified. Clinico-pathological data were analyzed. Prognostic outcomes were examined by Kaplan-Meier curves and Cox regression analysis. RESULTS: We identified 46 uterine sarcoma patients: 25 carcinosarcoma (CS) (54.3%), 15 leiomyosarcoma (LMS) (32.6%), and 6 undifferentiated uterine sarcoma (UUS) (13.1%) cases. Mean age was 54.0+/-11.9 years (range 25-82 years). Abnormal uterine bleeding was the most common presenting symptom (63.0%). Among 33 patients (71.7%) who had pre-operative tissue collected, diagnosis of malignancy was correct in 29 (87.9%). All patients received primary surgery and retroperitoneal lymph nodes were resected in 34 (73.9%). After surgery, 5 (10.9%) had gross residual tumors. Stage I disease was most commonly found (56.5%). Adjuvant treatment was given to 27 (58.7%), most commonly chemotherapy. After a median follow-up of 16.0 months (range 0.8-187.4 months), recurrence was encountered in 22 patients (47.8%). Median time to recurrence was 5.8 months (range1.0-105.5 months). Distant metastasis was more common than local or loco- regional failure. The 2-year PFS was 45.2% (95% confidence interval [CI], 30.6% 59.7%) and the 2-year OS was 48.3% (95% CI, 33.3%-60.7%). Multivariable analyses found residual disease after surgery as a significant factor only for PFS. CONCLUSIONS: Uterine sarcoma is a rare tumor entity. Even with multimodalities of treatment, the prognosis is still poor. Successful cytoreductive surgery is a key factor for a good survival outcome. PMID- 27221850 TI - Immunohistochemical Differentiation between Urothelial Papillomas and Papillary Neoplasms of Low Malignant Potential of the Urinary Bladder. AB - BACKGROUND: Urothelial papilloma and non-invasive papillary carcinoma are common neoplasms of the urinary bladder. Distinguishing papillomas and papillary carcinomas, especially the low grade type, is often debatable on the basis of histological features alone. MATERIALS AND METHODS: We investigated immunohistochemical expression of cytokeratin 20 (CK20), p53, and Ki-67 in a group of 20 urothelial papilloma cases and 30 noninvasive papillary neoplasms of low malignant potential (PNLMP) of the urinary bladder. Whole tissue sections were examined. RESULTS: Among the 30 carcinoma cases, 12 (40%) showed strong reactivity for the whole panel, 16 (53%) reacted positively for two markers, and 2 (7%) reacted just to one of them. Ki-67 was considered positive in 27 cases (90%) and p53 in 24 (80%), CK20 showed positive reactivity in 21 cases (70%). Only small percentages of papillomas were positive, and then only weakly. CONCLUSIONS: We concluded that the intense positivity of suspicious cells for at least one of these markers would confirm the presence of malignant changes and favours the diagnosis of carcinoma. PMID- 27221851 TI - Peripheral Blood Lymphocytes as In Vitro Model to Evaluate Genomic Instability Caused by Low Dose Radiation. AB - Diagnostic and therapeutic radiation fields are planned so as to reduce side effects while maximising the dose to site but effects on healthy tissues are inevitable. Radiation causes strand breaks in DNA of exposed cells which can lead to chromosomal aberrations and cause malfunction and cell death. Several researchers have highlighted the damaging effects of high dose radiation but still there is a lacuna in identifying damage due to low dose radiation used for diagnostic purposes. Blood is an easy resource to study genotoxicity and to estimate the effects of radiation. The micronucleus assay and chromosomal aberration can indicate genetic damage and our present aim was to establish these with lymphocytes in an in vitro model to predict the immediate effects low dose radiation. Blood was collected from healthy individuals and divided into 6 groups with increasing radiation dose i.e., 0Gy, 0.10Gy, 0.25Gy, 0.50Gy, 1Gy and 2Gy. The samples were irradiated in duplicates using a LINAC in the radiation oncology department. Standard protocols were applied for chromosomal aberration and micronucleus assays. Metaphases were stained in Giemsa and 200 were scored per sample for the detection of dicentric or acentric forms. For micronuclei detection, 200 metaphases. Giemsa stained binucleate cells per sample were analysed for any abnormality. The micronuclei (MN) frequency was increased in cells exposed to the entire range of doses (0.1- 2Gy) delivered. Controls showed minimal MN formation (2.0%+/-0.05) with triple MN (5.6%+/-2.0) frequency at the lowest dose. MN formation increased exponentially with the radiation dose thereafter with a maximum at 2Gy. Significantly elevated numbers of dicentric chromosomes were also observed, even at doses of 0.1- 0.5Gy, compared to controls, and acentric chromosomes were apparent at 2Gy. In conclusion we can state that lymphocytes can be effectively used to study direct effect of low dose radiation. PMID- 27221852 TI - Breaking Bad News: Patient Preferences and the Role of Family Members when Delivering a Cancer Diagnosis. AB - BACKGROUND: Western physicians tend to favour complete disclosure of a cancer diagnosis to the patient, while non-Western physicians tend to limit disclosure and include families in the process; the latter approach is prevalent in clinical oncology practice in India. Few studies, however, have examined patient preferences with respect to disclosure or the role of family members in the process. MATERIALS AND METHODS: Structured interviews were conducted with patients (N=127) in the medical oncology clinic of a tertiary referral hospital in Bangalore, India. RESULTS: Patients ranged in age from 18-88 (M=52) and were mostly male (59%). Most patients (72%) wanted disclosure of the diagnosis cancer, a preference significantly associated with higher education and English proficiency. A majority wanted their families to be involved in the process. Patients who had wanted and not wanted disclosure differed with respect to their preferences regarding the particulars of disclosure (timing, approach, individuals involved, role of family members). Almost all patients wanted more information concerning their condition, about immediate medical issues such as treatments or side effects, rather than long-term or non-medical issues. CONCLUSIONS: While most cancer patients wanted disclosure of their disease, a smaller group wished that their cancer diagnosis had not been disclosed to them. Regardless of this difference in desire for disclosure, both groups sought similar specific information regarding their cancer and largely favoured involvement of close family in decision making. Additional studies evaluating the influence of factors such as disease stage or family relationships could help guide physicians when breaking bad news. PMID- 27221853 TI - Lack of Utility of Cytokeratins in Differentiating Pseudocarcinomatous Hyperplasia of Granular Cell Tumors from Oral Squamous Cell Carcinoma. AB - Granular cell tumor (GCT) of the oral cavity is a benign lesion. Half of oral GCTs demonstrate pseudocarcinomatous hyperplasia (PCH) of the mucosa which can mimic invasive islands of oral squamous cell carcinoma (SCC). Such similarity can be confusing when diagnosing or evaluating the two conditions, potentially leading to misdiagnosis or misclassification. Indeed, several misdiagnosed cases of oral GCT have been reported in the literature as OSCC or malignant oral GCT that resulted in unnecessary aggressive treatment for the affected patients. The aim of this study was to investigate if the cytokeratin pattern of the PCH can help in differentiating GCT from oral SCC. To distinguish between these two entities, we examined 12 patient specimens of oral GCT-PCH and oral SCC histologically and via immunohistochemistry (IHC) for CK13, CK17 and P75. The results suggest that the cytokeratin profile of PCH is similar to that of oral SCC. Therefore, consideration of IHC findings for epithelial markers alone may lead to erroneous diagnosis; thus, the presence of the granular tumor underneath the PCH and its immunopositivity for P75 or other neural definition markers can be essential to identify the underlying tumor and exclude oral SCC. Finally we recommend more studies on the molecular biology of PCH to understand how it can mimic oral SCC histologically without harboring its malignant phenotype clinically, which could have significant translational potential for understanding invasive oral SCC. PMID- 27221854 TI - Evaluation of KiSS1 as a Prognostic Biomarker in North Indian Breast Cancer Cases. AB - BACKGROUND: Breast cancer is the commonest female cancer worldwide and its propensity to metastasize negatively impacts on therapeutic outcome. Several clinicopathological parameters with prognostic/predictive significance have been associated with metastatic suppressor expression levels. The role of metastatic suppressor gene (MSG) KiSS1 in breast cancer remains unclear. Our goal was to investigate the possible clinical significance of KiSS1 breast cancer. MATERIALS AND METHODS: The study was conducted on 87 histologically proven cases of breast cancer and background normal tiisue. Quantitative reverse transcriptase polymerase chain reaction (qRT PCR) and immunohistochemistry (IHC) were used to investigate KiSS1 at gene and protein levels, respectively, for correlation with several patient characteristics including age, family history, hormonal receptor status, stage, tumor size, nodal involvement and metastatic manifestation and finally with median overall survival (OS). RESULTS: Our study revealed (i) KiSS1 levels were generally elevated in breast cancer vs normal tissue (< 0.05). (ii) however, a statistically significant lower expression of KiSS1 was observed in metastatic vs non metastatic cases (P = 0.04). (iii) KiSS1 levels strongly correlated with T,N,M category, histological grade and advanced stage (<0.001) but not other studied parameters. (iv) Lastly, a significant correlation between expression of KiSS1 and median OS was found (P = 0.04). CONCLUSIONS: Conclusively, less elevated KiSS1 expression is a negative prognostic factor for OS, advancing tumor stage, axillary lymph node status, metastatic propensity and advancing grade of the breast cancer patient. Patients with negative KiSS1 expression may require a more intensive therapeutic strategy. PMID- 27221855 TI - Informational Needs of Women with Breast Cancer Treated with Chemotherapy. AB - BACKGROUND: Research in the field of informational needs of breast cancer patients is scarce. In the few published articles, these needs were usually not satisfied. The main objective of this study was to evaluate satisfaction regarding informational needs in women with breast cancer. The long-term goal was to guide physician-patient communication to meet these needs. MATERIALS AND METHODS: A survey with 21 questions was completed by 84 female patients receiving chemotherapy in a one-day hospital in Beirut, Lebanon. All patients were aware of their disease and agreed to participate in the survey. RESULTS: The doctor was the major source of information for patients followed by media (radio and television). The level of knowledge of patients concerning their disease was proportional to the number of information sources. Women aged younger than 45 years, diagnosed during the last three months before the survey and certified from high school were less satisfied with information given by the oncologist. The missing information was in relation with the steps of the treatment after the chemotherapy regimen, the risk of a family member (sisters and daughters) of developing the disease and management of lymphedema. CONCLUSIONS: This study generated a scale for the degree of satisfaction of information received by women with breast cancer from their oncologist. The physician can use this scale to improve his or her skills of communication to patients and diminish their level of fear and anxiety. PMID- 27221856 TI - Circulating Cell-free miRNA Expression and its Association with Clinicopathologic Features in Inflammatory and Non- Inflammatory Breast Cancer. AB - Recent discovery showing the presence of microRNAs (miRNAs) in the circulation sparked interest in their use as potential biomarkers. Our previous studies showed the diagnostic potential of miR-451 as a serological marker for inflammatory breast cancer (IBC), miR-337- 5p and miR-30b for non-inflammatory breast cancer (non-IBC). The aim of this study is to investigate the prognostic values of circulating miRNAs by comparing the amounts of 12 circulating miRNAs in the serum of IBC and non-IBC from Tunisian breast cancer patients, and by determinating whether correlated pairs of miRNAs could provide useful information in the diagnosis of IBC and non-IBC patients. TaqMan qPCR was performed to detect circulating expression of miRNAs in serum of 20 IBC, 20 non-IBC and 20 healthy controls. Nonparametric rank Spearman rho correlation coefficient was used to examine the prognostic value of miRNAs and to assess the correlation profile between miRNAs expression. Further, a large number of miRNAs were highly correlated (rho>0.5) in both patients groups and controls. Also, the correlations profiles were different between IBC, non-IBC and healthy controls indicating important changes in molecular pathways in cancer cells. Our results showed that miR-335 was significantly overexpressed in premenopausal non-IBC patients; miR-24 was significantly overexpressed in non-IBC postmenopausal patients. Patients with previous parity had higher serum of miR-342-5p levels than those without. Furthermore, patients with HER2+ IBC present lower serum levels of miR-15a than patients with HER2- disease. Together, these results underline the potential of miRNAs to function as diagnostic and prognostic markers for IBC and non-IBC, with links to the menopausal state, Her2 status and parity. PMID- 27221857 TI - Evaluation of Cholangiocarcinoma Risk and its Related Factors in Wetland Geographical Communities of Ubon Ratchathani, Thailand. AB - Wetland geographical areas have a higher incidence of Opisthorchis viverrini associated cholangiocarcinoma (CCA), confirmed by data from geographic information systems, than other areas. Behavioral data also indicate that people in these areas traditionally eat uncooked freshwater fish dishes, a vehicle for O. viverrini infection. The best approach to reducing CCA incidence is decreasing risk factors together with behavior alteration. Evaluation of CCA risk and its related factors are first needed for planning the prevention and control programs in the future. We therefore aimed to evaluate the CCA risk and explore its related factors among people in wetland communities of Ubon Ratchathani, Thailand. A cross-sectional study was conducted between July and August 2014. In total 906 participants, with informed consent, completed questionnaires. Overall risk of CCA was determined by multiplying odds ratios (ORs) of the risk factors for CCA from literature reviews. A mean score of 5.95 was applied as the cut-off point. Assessment of factors related to overall risk of CCA was accomplished using conditional logistic regression. Of all participants, 60.15% had a high level of the overall risk of CCA. Factors related to the overall risk of CCA were gender (<0.001), marital status (<0.001), perceived susceptibility (p=0.043) and prevention behavior for CCA (<0.001). In conclusion, most participants in this community had a high level of overall risk of CCA. Therefore, integrated prevention and control programs continue to be urgently required. PMID- 27221858 TI - Ginsenoside-Rh2 Inhibits Proliferation and Induces Apoptosis of Human Gastric Cancer SGC-7901 Side Population Cells. AB - OBJECTIVES: To observed the effects of ginsenoside -Rh2 (GS-Rh2) on proliferation and apoptosis of side population (SP) human gastric cancer SGC-7901 cells. MATERIALS AND METHODS: SGC-7901 SP and Non-SP cells were sorted by flow cytometry and assessed using the cck-8 method. Expression of apoptosis-related proteins Bax and Bcl-2 of SP before and after the intervention was determined by Western blotting. RESULTS: It was found that the proliferation of SP was significantly faster than that of NSP (<0.05). In addition, GS-Rh2 inhibited proliferation of gastric cancer SP cells, induced cell cycle arrest and cell apoptosis, and changed the expression of BAX/Bcl-2 proteins in a time-dependent and concentration-dependent manner (<0.05). CONCLUSIONS: With increase of GS-Rh2 dose, GS-Rh2 gradually inhibit the proliferation of SGC-7901 SP cells, which have high proliferation rate, through G1/G0 phase arrest, followed by apoptosis which involves the up-regulation of Bax and the down-regulation of Bcl-2. PMID- 27221859 TI - Dryocrassin ABBA Induces Apoptosis in Human Hepatocellular Carcinoma HepG2 Cells Through a Caspase-Dependent Mitochondrial Pathway. AB - BACKGROUND: Biological and pharmacological activities of dryocrassin ABBA, a phloroglucinol derivative extracted from Dryopteris crassirhizoma, have attracted attention. In this study, the apoptotic effect of dryocrassin ABBA on human hepatocellular carcinoma HepG2 cells was investigated. MATERIALS AND METHODS: We tested the effects of dryocrassin ABBA on HepG2 in vitro by MTT, flow cytometry, real-time PCR, and Western blotting. KM male mice were used to detect the effect of dryocrassin ABBA on H22 cells in vivo. RESULTS: Dryocrassin ABBA inhibited the growth of HepG2 cells in a concentration-dependent manner. After treatment with 25, 50, and 75 MUg/mL dryocrassin ABBA, the cell viability was 68%, 60% and 49%, respectively. Dryocrassin ABBA was able to induce apoptosis, measured by propidium iodide (PI)/annexin V-FITC double staining. The results of real-time PCR and Western ting showed that dryocrassin ABBA up-regulated p53 and Bax expression and inhibited Bcl-2 expression which led to an activation of caspase-3 and caspase-7 in the cytosol, and then induction of cell apoptosis. In vivo experiments also showed that dryocrassin ABBA treatment significantly suppressed tumor growth, without major side effects. CONCLUSIONS: Overall, these findings provide evidence that dryocrassin ABBA may induce apoptosis in human hepatocellular carcinoma cells through a caspase-mediated mitochondrial pathway. PMID- 27221860 TI - A Pilot Study on Screening of BRCA1 Mutations (185delAG, 1294del40) in Nepalese Breast Cancer Patients. AB - BACKGROUND: Breast cancer is the second most common malignancy among Nepalese women, accounting for 60% of the total cancer cases in females. Women diagnosed with germline mutations in BRCA1 like 185delAG, 1294del40 develop breast and/or ovarian cancer with a lifelong likelihood of up to 85% whereas presence of a mutation increases the risk for mutations to occur in other genes. The major objective of this study was to find the prevalence of these mutations in Nepalese cancer patients. MATERIALS AND METHODS: This prospective study was carried out at two cancer hospitals in the Kathmandu valley over a period of 11 months. Irrespective of age group and stage of canceran appropriate amount of blood was withdrawn from 50 breast cancer patients and 20 controls. DNA was extracted manually and subjected to PCR using primers for 185delAG and 1294del40 mutations. PCR products were then digested with restriction enzyme (DdeII) followed by electrophoresis. RESULTS: Prevalence of 185delAG in reference breast cancer patients was found to be 4/50 (8%) but no 1294del40 was apparent. CONCLUSIONS: Several mutations occurring in different exons of BRCA1 as well as mutations in other genes like BRCA2, for example, should also be taken in account. PMID- 27221861 TI - Multiple Myeloma: a Retrospective Analysis of 61 Patients from a Tertiary Care Center. AB - BACKGROUND: Multiple myeloma (MM) is an acquired clonal B-cell malignancy which primarily affects elderly individuals with an annual incidence of approximately 1% of all malignancies. Our aim is to study demographic and clinicopathological features of adult Pakistani MM patients at presentation. MATERIALS AND METHODS: This single centre retrospective study extended from January 2010 to December 2014. Data were retrieved from the patients' maintained records on predetermined performa. RESULTS: Overall, 61 patients were diagnosed at our institution with MM during the study period. There were 43 males and 18 females. Age ranged between 34 and 81 years with a mean of 56.1+/-12.8 and a median of 57 years. The male to female ratio was ~2:1. Common presenting complaints included fatigue (81.9%), backache (80.3%) and bone pain (67.2%). Physical findings revealed pallor (44.2%) as a presenting clinical feature. The mean hemoglobin value was 8.9+/-1.7g/dl with a mean MCV of 85.3+/-11.0 fl. Severe anemia with hemoglobin <8.5 gm/dl was seen in 40.9%. The mean total leukocyte count was 8.9+/-8.2x109/l, the ANC was 5.0+/-3.1x109/l and the mean platelet count was 188.4+/-150.6x109/l. CONCLUSIONS: MM in Pakistani patients is seen in a relatively young population with male preponderance. The majority of patients present with symptomatic anemia and backache to seek medical attention. However, clinico-pathological features appear comparable to the published literature. PMID- 27221862 TI - Colon Cancer among Older Saudis: Awareness of Risk Factors and Early Signs, and Perceived Barriers to Screening. AB - BACKGROUND: Colon cancer screening (CRCS) uptake is markedly affected by public awareness of the disease. This study was conducted to assess levels of knowledge of CRC, to explore the pattern of CRCS uptake and identify possible barriers to screening among Saudis older than 50 years of age and primary care providers (PCPs) in Al Hassa region, Saudi Arabia. MATERIALS AND METHODS: This cross sectional study was conducted in randomly selected primary health care (PHC) centers, 884 Saudis and 39 PCPs being enrolled for data collection. Structured interviews were conducted to obtain information regarding socio-demographic characteristics, personal information relevant to CRC, awareness about early signs/symptoms and risk factors, and barriers to CRCS. Also, a self- administered data collection form was used to assess barriers to CRCS from the physicians' perspectives. RESULTS: More than 66% of participants were lacking knowledge about CRC. Participants with higher educational levels, having ever heard about CRC, and having relatives with CRC had a significantly higher awareness of the disease. The rate of reported CRCS was low (8.6%). After conducting a logistic regression analysis, it was observed that female gender (OR=0.28; 95% CI=0.14 0.57; P=0.001), being unmarried (OR=0.11; 95% CI=0.10-0.23; P=0.001), lower levels of education (OR=0.36; 95% CI=0.16-0.82; P=0.015), and having no relatives with CRC (OR=0.30; 95% CI=0.17-0.56; P=0.001) were significantly associated with a lower CRCS uptake. There was a significant difference between most of the perceived barriers to CRCS and gender. Exploratory factor analysis showed that personal fear (especially fear of the screening results and shyness) was the major factor that hindered CRCS with high loading Eigen value of 2.951, explaining 34.8% of the barriers of the included sample toward utilization of CRCS, followed by lack of awareness of both person and providers (high Eigen value of 2.132, and explaining 23.7% of the barriers). The most frequently cited barriers to CRCS from the physicians' perspectives were lack of public awareness, lack of symptoms and signs, and fear of painful procedures. CONCLUSIONS: Poor levels of knowledge about CRC were found among older Saudis attending PHC centers in Al Hassa, Saudi Arabia. It is crucial to implement an organized national screening program in Saudi Arabia to increase public awareness. PMID- 27221863 TI - Clinical Significance of Smudge Cells in Peripheral Blood Smears in Hematological Malignancies and Other Diseases. AB - BACKGROUND: It is reported that the percentage of smudge cells in the blood smear could be a prognostic indicator in chronic lymphocytic leukemia. However, the clinical significance of smudge cells in other hematological malignancies, solid tumors or non-malignant diseases is less clear. Hence, this study was conducted to survey the clinical significance of smudge cells in hematological cancers and other disorders. MATERIALS AND METHODS: From January to November, 2015, the clinical data of patients who received blood examination with differential counts for clinical purpose and were found to have smudge cells in the peripheral blood film in Far Eastern Memorial Hospital were selected. The percentage of smudge cells and patient outcomes were evaluated for further univariate and survival analyses. RESULTS: A total of 102 patients with smudge cells in their blood smears were included. Smudge cells were frequently presented in out-of-hospital cardiac arrest (OHCA; n=30), infections (n=23), hematological cancers (n=23) and solid cancers (n=10). There was no relationship between the percentage of smudge cells and the patient mortality in all diseases (OR: 1.08, 95% CI: 0.47-2.48, P=1.000) as well as the OHCA group (OR: 1.91, 95% CI: 0.38-9.60, P=0.694). It was observed that in patients with all cancers with the percentage of smudge cells less than 50% had a lower mortality rate in comparison with those who had the percentage of smudge cells of 50% or more (OR: 22.29, 95% CI: 2.38-208.80, <0.001). Additionally, it was seemingly that patients with smudge cells of 50% or more had a lower survival rate than those with smudge cells less than 50% in all cancers with follow-up at 2-month intervals, but without statistical significance (P=0.064). CONCLUSIONS: Our survey indicated that in all cancers, those who had higher percentage of smudge cells were prone to have poor outcomes when compared with the subjects with lower percentage of smudge cells. This finding was quite different from the results of previous studies in which the race-ethnicity of most study populations was non-Asian; hence, further investigations are required. Besides, there was no apparent association of the percentage of smudge cells with patient outcomes in all diseases, including OHCA. PMID- 27221864 TI - Effects of SULT1A1 Copy Number Variation on Estrogen Concentration and Tamoxifen Associated Adverse Drug Reactions in Premenopausal Thai Breast Cancer Patients: A Preliminary Study. AB - Tamoxifen is a pharmacological estrogen inhibitor that binds to the estrogen receptor (ER) in breast cells. However, it shows an estrogenic effect in other organs, which causes adverse drug reactions (ADRs). The sulfotransferase 1A1 (SULT1A1) enzyme encoded by the SULT1A1 gene is involved in estrogen metabolism. Previous research has suggested that the SULT1A1 copy number is linked with the plasma estradiol (E2) concentration. Here, a total of 34 premenopausal breast cancer patients, selected from the Thai Tamoxifen (TTAM) Project, were screened for their SULT1A1 copy number, plasma E2 concentration and ADRs. The mean age was 44.3+/-11.1 years, and they were subtyped as ER+/ progesterone receptor (PR) + (28 patients), ER+/ PR- (5 patients) and ER-/PR- (1 patient). Three patients reported ADRs, which were irregular menstruation (2 patients) and vaginal discharge (1 patient). Most (33) patients had two SULT1A1 copies, with one patient having three copies. The median plasma E2 concentration was 1,575.6 (IQR 865.4) pg/ml. Patients with ADRs had significantly higher plasma E2 concentrations than those patients without ADRs (p = 0.014). The plasma E2 concentration was numerically higher in the patient with three SULT1A1 copies, but this lacked statistical significance. PMID- 27221865 TI - Frequency and Pattern of Bone Marrow Infiltration in Classical Hodgkin's Lymphoma: Experience from Southern Pakistan. AB - BACKGROUND: Hodgkin's lymphoma (formerly, Hodgkins disease) is a potentially curable malignancy with distinctive biological behavior and specific clinical characteristics. Limited information is available from developing countries for patients with classical Hodgkin's lymphoma (cHL). Therefore we reviewed the demographical and clinico-hematological profiles along with bone marrow infiltration patterns in adult patients presenting at Liaquat National Hospital and Medical College. MATERIALS AND METHODS: In this cross sectional study, 62 adult (>=15 years) patients with cHL were enrolled from January 2010 to December 2014. RESULTS: The mean age was 29.7+/-13.8 years with a median of 30 years. The male to female ratio was 2:1. B symptoms were present in 72.5% of patients and lymph node enlargement in 85.4%. The frequency of bone marrow infiltration in our cHL patients was found to be 27.4%, the pattern being predominantly focal followed by diffuse. The mean hemoglobin was 9.4+/-1.9g/dl with a mean MCV of 78.1+/-7.9 fl, a mean total leukocyte count of 10.9+/-20.6x109/l and a mean platelet count of 241.6+/-150.1x109/l. CONCLUSIONS: Our analysis shows that clinico-pathological features of cHL in Pakistan are comparable to published data. Peripheral lymphodenopathy associated with B symptoms is the commonest presentation. Bone marrow involvement is more common in our setup as patients usually presented at an advanced stage of disease. PMID- 27221866 TI - Improving the Accuracy of Early Diagnosis of Thyroid Nodule Type Based on the SCAD Method. AB - Although early diagnosis of thyroid nodule type is very important, the diagnostic accuracy of standard tests is a challenging issue. We here aimed to find an optimal combination of factors to improve diagnostic accuracy for distinguishing malignant from benign thyroid nodules before surgery. In a prospective study from 2008 to 2012, 345 patients referred for thyroidectomy were enrolled. The sample size was split into a training set and testing set as a ratio of 7:3. The former was used for estimation and variable selection and obtaining a linear combination of factors. We utilized smoothly clipped absolute deviation (SCAD) logistic regression to achieve the sparse optimal combination of factors. To evaluate the performance of the estimated model in the testing set, a receiver operating characteristic (ROC) curve was utilized. The mean age of the examined patients (66 male and 279 female) was 40.9 +/- 13.4 years (range 15- 90 years). Some 54.8% of the patients (24.3% male and 75.7% female) had benign and 45.2% (14% male and 86% female) malignant thyroid nodules. In addition to maximum diameters of nodules and lobes, their volumes were considered as related factors for malignancy prediction (a total of 16 factors). However, the SCAD method estimated the coefficients of 8 factors to be zero and eliminated them from the model. Hence a sparse model which combined the effects of 8 factors to distinguish malignant from benign thyroid nodules was generated. An optimal cut off point of the ROC curve for our estimated model was obtained (p=0.44) and the area under the curve (AUC) was equal to 77% (95% CI: 68%-85%). Sensitivity, specificity, positive predictive value and negative predictive values for this model were 70%, 72%, 71% and 76%, respectively. An increase of 10 percent and a greater accuracy rate in early diagnosis of thyroid nodule type by statistical methods (SCAD and ANN methods) compared with the results of FNA testing revealed that the statistical modeling methods are helpful in disease diagnosis. In addition, the factor ranking offered by these methods is valuable in the clinical context. PMID- 27221867 TI - Adenosine Deaminase - a Novel Diagnostic and Prognostic Biomarker for Oral Squamous Cell Carcinoma. AB - BACKGROUND: The number of patients with oral cancer in India is increasing gradually (especially in younger people). Although the diagnostic modalities and therapeutic management of oral cancer are improving, the treatment outcome and prognosis of oral cancer remain poor. The absence of definite early warning symptoms for most head and neck cancers suggests that sensitive and specific biomarkers are likely to be important in screening for high-risk patients. AIMS: To analyze serum adenosine deaminase (ADA) levels in oral squamous cell carcinoma (OSCC) cases who reported to our institute. MATERIALS AND METHODS: A prospective study was performed on 100 histopathologically proven cases of OSCC (study group) and 100 normal healthy individuals (control group). Independent sample and one sample t-tests and one way ANOVA followed by Tuckey's POST HOC test were conducted for analysis. RESULTS: Statistically significant increase in serum ADA levels was observed in OSCC cases compared to the control group. Also serum ADA level increased significantly with the histopathological grade. CONCLUSIONS: Serum ADA levels in OSCC may be a useful diagnostic and prognostic biomarkers in clinical practice and our findings suggest that a large-scale study is warranted to confirm clinical utility as a prognostic and diagnostic biomarker. PMID- 27221868 TI - Errors in Surgical Pathology Reports: a Study from a Major Center in Pakistan. AB - BACKGROUND: Errors in surgical pathology diagnosis can have serious consequences for the patient. Since the final product of a surgical pathology lab is the report, errors can be picked by reviewing reports of cases. AIM: To determine the frequency and types of error in surgical pathology reports of cases signed out in 2014 in a laboratory in Karachi, Pakistan. MATERIALS AND METHODS: All surgical pathology reports in which changes were made in the original report after sign out and an amended report was issued were included. Errors included: (1) misinterpretations; (2) missing critical information; (3) erroneous critical information; (4) misidentification; and (5) typographic errors. RESULTS: Errors were identified in 210 cases (0.37%). These comprised 199 formalin fixed specimens and 11 frozen sections. The latter represented 3.8% of a total of 2,170 frozen sections. Of the 11 frozen section errors, 10 were misinterpretations. Of the 199 permanent specimens, 99 (49.7%) were misinterpretations, 65 (32.7%) belonged to missing critical information category, 8 (4%) belonged to erroneous critical information category, 8(4%) were misidentifications, 16(8%) were typographic errors while 3 cases (1.5%) were other errors. Most misinterpretations occurred in the gastro intestinal, liver and pancreato biliary tract (23.2%) and breast (13.1%). Another 87 cases were reviewed on the clinicians' request. However diagnosis after review remained the same as the original diagnosis. In 49 out of these (56.3%), additional workup was performed at the time of the review. CONCLUSIONS: Our findings were similar to other published studies. We need to develop documented procedures for timely review of cases to detect errors. PMID- 27221869 TI - Rural Women's Awareness about Breast Cancer in Southeastern Iran: a Cross Sectional Study. AB - BACKGROUND: Breast cancer is the most common cancer among women worldwide. A very important factor in the timely treatment and prevention of progression is high breast cancer awareness. Rural women are at risk of latte stage breast cancer due to poor education and lack of access to medical facilities. MATERIALS AND METHODS: This cross-sectional-descriptive study was conducted on 266 women (out of 300) aged over 18 in rural areas of Zabol, Southeastern Iran during July 2015 to October 2015. The data collection tool was a researcher-made questionnaire that measured participant knowledge of breast cancer in four aspects (general awareness, risk factors, mammography, and symptoms). SPSS 22 was used for statistical analysis. RESULTS: Out of 266 participants, age information was available for 261. The age range was between 19 and 62, with a mean of 27+/-2.1 years. Most participants (154, 57.9%) had an average overall awareness of breast cancer. In the general awareness dimension, most participants (130, 48.9%) had poor scores. Most (166, 62.4%) also had average awareness about risk factors and many (137, 51.5%) had good awareness about mammography. Most participants did not know that changes in breast shape (232, 88.2%), dimpling of breast skin (192, 72.3%) and nipple discharge (183, 69.6%) are the main symptoms of breast cancer. ANOVA statistical analysis showed a significant relationship between awareness level and participant education and occupation (<0.05). CONCLUSIONS: This study indicated average awareness of participants about breast cancer. Since rural women have lower levels of education, it is recommended that educational courses with contents about breast cancer, its risk factors, and symptoms be held for these women. PMID- 27221870 TI - Impact of Preoperative Serum Levels of CA 125 on Epithelial Ovarian Cancer Survival. AB - BACKGROUND: CA125 is very helpful in treatment monitoring and detection of epithelial ovarian cancer (EOC) recurrence. However there is controversy as to its accuracy and optimal usage. What is the impact of the CA125 levels before primary surgery treatment to the survival of patients? This study aimed to detect any association of preoperative serum levels with prognosis and survival in EOC patients. MATERIALS AND METHODS: Our cohort comprised EOC patients in Dr. Sardjito Hospital, Yogyakarta, Indonesia, who complied with follow up. To explore the effect of preoperative CA125 levels and other variables on survival Cox's regression models were applied. RESULTS: A total of 90 cases of EOC who had surgery were available for follow up. The level of CA125 poroved to be a prognostic factor for overall survival of EOC patients, with an adjusted HR of 4.10 (p = 0.03). Adjuvant chemotherapy was another prognostic factor, 1 - 2 cycles having an adjusted HR of 0.17 (p = 0.04) and 3 - 8 cycles HR 0.39 (p = 0.06). Other factors such as age of patients adjusted HR 1.54 (p = 0.32), moderate differentiation (adjusted HR 1.61, p = 0.51) poor differentiation (adjusted HR 3.41, p = 0.15), and stage of disease (adjusted HR 1.98, p = 0.27) were statistically not significant. However, this might have been because the power of the study was low. CONCLUSIONS: Preoperative level of CA125 is a prognostic factor for overall survival in EOC patients. The best cut-off for prognostic classification of CA125 serum level is 70 U/ml. PMID- 27221871 TI - Micro RNA 34a and Let-7a Expression in Human Breast Cancers is Associated with Apoptotic Expression Genes. AB - Breast cancer is the most common cause of cancer-related death among women in the whole world. MiR- 34a and let-7a are well known tumor suppressors that participate in the regulation of apoptosis, invasion and other cellular functions. In this study, expression of miR-34a, let-7a and apoptosis pathway genes such as Bcl-2, Caspase-3 and P53 were evaluated using quantitative real time PCR in 45 paired samples of normal margin and tumor tissue collected from breast cancer patient at advanced stage (3-4). MiR-34a, let-7a, caspase-3 and P53 expression are reduced and Bcl-2 expression is increased within tumoral tissues in comparison with normal margin tissues. P53 expression directly or indirectly was correlated with miR-34a, let-7a, Bcl-2 and caspase-3 expression. In This study we found that MiR-34a and let-7a expression are reduced in the tumoral tissues. Down- regulation of these two molecules correlated with expression of genes associated with apoptosis. These results suggest that due to the correlation of miR-34a and let-7a with apoptotic and anti-apoptotic pathways these molecules could participate as regulators in advanced clinical stages of breast cancer and should be considered as markers for diagnosis, prognostic assessment and targeted therapy. PMID- 27221872 TI - Anti-Cancer Effects of Imperata cylindrica Leaf Extract on Human Oral Squamous Carcinoma Cell Line SCC-9 in Vitro. AB - Imperata cylindrica, a tall tufted grass which has multiple pharmacological applications is one of the key ingredients in various traditional medicinal formula used in India. Previous reports have shown that I. cylindrica plant extract inhibited cell proliferation and induced apoptosis in various cancer cell lines. To our knowledge, no studies have been published on the effect of I. cylindrica leaf extract on human oral cancers. The present study was undertaken in order to evaluate the anticancer properties of the leaf extract of I. cylindrica using an oral squamous cell carcinoma cell line SCC-9 as an in vitro model system. A methanol extract from dried leaves of I. cylindrica (ICL) was prepared by standard procedures. Effects of the ICL extract on the morphology of SCC-9 cells was visualized by microscopy. Cytotoxicity was determined by MTT assay. Effects of the ICL extract on colony forming ability of SCC-9 cells was evaluated using clonogenic assay. Cell cycle analysis was performed by flow cytometry and induction of apoptosis was determined by DNA fragmentation assay. The ICL extract treatment caused cytotoxicity and induced cell death in vitro in SCC-9 cells in a dose-dependent manner. This treatment also significantly reduced the clonogenic potential and inhibited cell proliferation by arresting the cell cycle in the G2/M phase. Furthermore, DNA fragmentation assays showed that the observed cell death was caused by apoptosis. This is the first report showing the anticancer activity of the methanol extracts from the leaves of I. cylindrica in human oral cancer cell line. Our data indicates that ICL extract could be considered as one of the lead compounds for the formulation of anticancer therapeutic agents to treat/manage human oral cancers. The natural abundance of I. cylindrica and its wide geographic distribution could render it one of the primary resource materials for preparation of anticancer therapeutic agents. PMID- 27221873 TI - Characteristics of Incident Testicular Cancer in Lebanon - 1990-2015 Single Institutional Experience. AB - BACKGROUND: Despite the fact that testicular cancer is a major health issue with its increasing incidence, very few studies have described its characteristics in the Middle East, particularly in Lebanon. MATERIALS AND METHODS: We report in this paper a retrospective pilot study of the characteristics of testicular cancer in Lebanon. The demographic, epidemiologic and survival characteristics of 178 patients diagnosed between 1990 and 2015 at an oncology clinic affiliated to Hotel Dieu de France Hospital were analyzed. RESULTS: The mean age at diagnosis was 32 +/-10 years. The most prevalent testicular tumor was the germ cell type (GCT) (95.2%) of which non-seminomatous tumors (NST) were the commonest (64.7%). Most of our patients were diagnosed at an early stage. Lymph node spread affected most commonly the retroperitoneal region and distant visceral metastases occurred in 14.6%. All patients underwent orchiectomy with 67% receiving adjuvant treatment, mainly chemotherapy. After a median follow up of 2,248 days (75.9 months) 16 patients were reported dead. Two, five and ten-year overall survival rates were 96%, 94% and 89% respectively. The median overall survival rate was not reached. CONCLUSIONS: Despite being part of the developing world, demographic, epidemiologic and survival analyses of testicular cancer reported in our study are in line with those reported from developed countries and would allow us to extrapolate management plans from these populations. PMID- 27221874 TI - Effect of IL-1 Polymorphisms, CYP2C19 Genotype and Antibiotic Resistance on Helicobacter pylori Eradication Comparing Between 10-day Sequential Therapy and 14-day Standard Triple Therapy with Four-Times-Daily-Dosing of Amoxicillin in Thailand: a Prospective Randomized Study. AB - BACKGROUND: Studies of effects of IL-1 polymorphisms, CYP2C19 genotype together with antibiotic resistance for H. pylori eradication are rare worldwide. The present study was designed to evaluate efficacy of 10-day sequential therapy (SQT) and 14-day standard triple therapy (STT) with four- times-daily dosing of amoxicillin for H. pylori eradication related to these important host and bacterial factors in Thailand. MATERIALS AND METHODS: This prospective randomized study was performed during March 2015 to January 2016. H. pylori infected gastritis patients were randomized to receive 10-day sequential therapy and 14 day standard triple therapy. CYP2C19 genotyping, IL1 polymorphism (IL-1B and IL 1RN genotypes) and antibiotic susceptibility tests were performed in all patients. 13C-UBT was conducted to confirm H. pylori eradication at least 4 weeks after treatment. RESULTS: A total of 100 patients (33 males and 67 females, mean age=51.1 years) were enrolled. Eradication rate by PP analysis was 97.9% (47/48) with the 10-day SQT regimen and 87.8% (43/49) with 14-day STT regimen (97.9% vs 87.8%; p-value=0.053). Antibiotic susceptibility testing demonstrated 45% resistance to metronidazole, 14.8% to clarithromycin, and 24.1% to levofloxacin. CYP2C19 genotyping revealed 44.9% RM, 49% IM and 6.1% PM. IL-1B and IL-1RN genotypes were demonstrated as 21.4% for CC, 48.1% for TC, 36.8% for TT, 72.7% for 1/1, and 21.2% for 1/2 genotypes, respectively. The 10-day SQT regimen provided 100% eradication in patients with clarithromycin or dual clarithromycin and levofloxacin H. pylori resistant strains. Moreover, the 10-day SQT regimen resulted in a 100% eradication rate in all patients with CYP2C19 genotype RM and almost type of IL-1B (TC and TT) and IL1-RN genotypes ( 1/2 and other). CONCLUSIONS: Treatment with 10-day sequential therapy is highly effective for H. pylori eradication regardless of the effects of clarithromycin resistance, dual clarithromycin and levofloxacin resistance, CYP2C19 genotype, IL-1B and IL1-RN genetic polymorphisms and can be used as effective first line therapy in Thailand. PMID- 27221875 TI - Tertiary Cytoreduction for Recurrent Epithelial Ovarian Cancer: a Multicenter Study in Turkey. AB - BACKGROUND: The purpose of this study was to determine the benefit of tertiary cytoreductive surgery (TC) for secondary recurrent epithelial ovarian cancer (EOC), focusing on whether optimal cytoreduction has an impact on disease-free survival, and whether certain patient characteristics could identify ideal candidates for TC. MATERIALS AND METHODS: Retrospective analysis of secondary recurrent EOC patients undergoing TC at three Turkish tertiary institutions from May 1997 to July 2014 was performed. All patients had previously received primary cytoreduction followed by intravenous platinum-based chemotherapy and secondary cytoreduction for first recurrence. Clinical and pathological data were obtained from the patients' medical records. Survival analysis was caried out using the Kaplan Meier method. Actuarial curves were compared by the two tailed Logrank test with a statistical significance level of 0.05. RESULTS: Median age of the patients was 49.6 years (range, 30-67) and thirty-eight (72%) had stage III-IV disease at initial diagnosis. Twenty six (49%) had optimal and 27 (51%) suboptimal cytoreduction during tertiary debulking surgery . Optimal initial cytoreduction, time to first recurrence, optimal secondary cytoreduction, time interval between secondary cytoreduction and secondary recurrence, size of recurrence, disease status at last follow-up were found to be significant risk factors to predict optimal TC. Optimal cytoreduction in initial and tertiary surgery and serum CA-125 level prior to TC were independent prognostic factors on univariate analysis. CONCLUSIONS: Our results and a literature review clearly showed that maximal surgical effort should be made in TC, since patients undergoing optimal TC have a better survival. Thus, patients with secondary recurrent EOC in whom optimal cytoreduction can be achieved should be actively selected. PMID- 27221876 TI - Screening for Lynch Syndrome in Young Colorectal Cancer Patients from Saudi Arabia Using Microsatellite Instability as the Initial Test. AB - BACKGROUND: Lynch Syndrome (LS) is a familial cancer condition caused by germline mutations in DNA mismatch repair genes. Individuals with LS have a greatly increased risk of developing colorectal cancer (CRC) and it is therefore important to identify mutation carriers so they can undergo regular surveillance. Tumor DNA from LS patients characteristically shows microsatellite instability (MSI). Our aim here was to screen young CRC patients for MSI as a first step in the identification of unrecognized cases of LS in the Saudi population. MATERIALS AND METHODS: Archival tumor tissue was obtained from 284 CRC patients treated at 4 institutes in Dammam and Riyadh between 2006 and 2015 and aged less than 60 years at diagnosis. MSI screening was performed using the BAT-26 microsatellite marker and positive cases confirmed using the pentaplex MSI analysis system. Positive cases were screened for BRAF mutations to exclude sporadic CRC and were evaluated for loss of expression of 4 DNA mismatch repair proteins using immunohistochemistry. RESULTS: MSI was found in 33/284 (11.6%) cases, of which only one showed a BRAF mutation. Saudi MSI cases showed similar instability in the BAT-26 and BAT-25 markers to Australian MSI cases, but significantly lower frequencies of instability in 3 other microsatellite markers. CONCLUSIONS: MSI screening of young Saudi CRC patients reveals that approximately 1 in 9 are candidates for LS. Patients with MSI are strongly recommended to undergo genetic counselling and germline mutation testing for LS. Other affected family members can then be identified and offered regular surveillance for early detection of LS associated cancers. PMID- 27221877 TI - Variant Alleles in XRCC1 Arg194Trp and Arg399Gln Polymorphisms Increase Risk of Gastrointestinal Cancer in Sabah, North Borneo. AB - BACKGROUND: The XRCC1 protein facilitates various DNA repair pathways; single nucleotide polymorphisms (SNPs) in this gene are associated with a risk of gastrointestinal cancer (GIC) with inconsistent results, but no data have been previously reported for the Sabah, North Borneo, population. We accordingly investigated the XRCC1 Arg194Trp and Arg399Gln SNPs in terms of GIC risk in Sabah. MATERIALS AND METHODS: We performed genotyping for both SNPs for 250 GIC patients and 572 healthy volunteers using a polymerase chain reaction- restriction fragment length polymorphism approach. We validated heterozygosity and homozygosity for both SNPs using direct sequencing. RESULTS: The presence of a variant 194Trp allele in the Arg194Trp SNP was significantly associated with a higher risk of GIC, especially with gastric and colorectal cancers. We additionally found that the variant 399Gln allele in Arg399Gln SNP was associated with a greater risk of developing gastric cancer. Our combined analysis revealed that inheritance of variant alleles in both SNPs increased the GIC risk in Sabah population. Based on our etiological analysis, we found that subjects >=50 years and males who carrying the variant 194Trp allele, and Bajau subjects carrying the 399Gln allele had a significantly increased risk of GIC. CONCLUSIONS: Our findings suggest that inheritance of variant alleles in XRCC1 Arg194Trp and Arg399Gln SNPs may act as biomarkers for the early detection of GIC, especially for gastric and colorectal cancers in the Sabah population. PMID- 27221878 TI - High Cadmium Levels in Cured Meat Products Marketed in Nigeria - Implications for Public Health. AB - Heavy metals are known to disrupt important physiological processes in living cells, and have been responsible for various pathological conditions with possible contributions to cancer development. Food contamination have been identified as one of the ways humans are exposed to heavy metals. In developing countries like Nigeria, the regulatory framework for enforcing compliance with globally acceptable exposure to deleterious contaminants is poor. In the current study, thirteen samples of cured meat products of diverse origin marketed in South-west Nigeria were evaluated for lead, cadmium, chromium and nickel contents using the atomic absorption spectroscopy technique. All the samples analysed contained cadmium between 0.35 and 1.20 ppm, levels considered higher than acceptable limits in consumable products. Lead, chromium and nickel were not detected in any of the samples. As known cumulative poisons, there is the need for stringent regulatory control of these heavy metals in cured meat products imported into or produced indigenously in the country in order to minimize the risks to public health. PMID- 27221879 TI - Meat Consumption, Related Nutrients, Obesity and Risk of Prostate Cancer: a Case Control Study in Uruguay. AB - BACKGROUND: In order to determine the role of meat consumption and related nutrients in the etiology of prostate cancer we conducted a case-control study among Uruguayan men in the time period 1998-2007. RESULTS: The study included 464 cases and 472 controls, frequency matched for age and residence. Both series were drawn from the four major public hospitals in Montevideo. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95 % confidence intervals (95 % CI) of prostate cancer by quartiles of meat intake and related nutrients. The highest vs. the lowest quartile of intake of total meat (OR = 5.19, 95 % CI 3.46-7.81), red meat (OR = 4.64, 95 % CI 3.10-6.95), and processed meat (OR = 1.78, 95% CI 1.22-2.59) were associated with increased risk of prostate cancer. Meat nutrients were directly associated with the risk of prostate cancer (OR for cholesterol 5.61, 95 % CI 3.75-8.50). Moreover, both total meat and red meat displayed higher risks among obese patients. CONCLUSIONS: This study suggests that total and red meat and meat nutrients may play a role in the etiology of prostate cancer in Uruguay. PMID- 27221880 TI - Harmal Extract Induces Apoptosis of HCT116 Human Colon Cancer Cells, Mediated by Inhibition of Nuclear Factor-kappaB and Activator Protein-1 Signaling Pathways and Induction of Cytoprotective Genes. AB - BACKGROUND: Colorectal cancer (CRC) is a major cause of morbidity and mortality, being the second most common type of cancer worldwide in both men and women. It accounts yearly for approximately 9% of all new cases of cancers. Furthermore, the current chemotherapeutic regimens seem unsatisfactory, so that exploration of novel therapeutic modalities is needed. The present study was undertaken to investigate the inhibitory effects of a crude alkaloid extract (CAERS) of a medicinal herb, Rhazya stricta, on proliferation of CRC HCT116 cells and to elucidate mechanisms of action. To achieve these aims, we utilized MTT, comet, DNA laddering and gene reporter assays, along with Western blot and RT-PCR analyses. RESULTS: We found that CAERS inhibited cell proliferation and induced apoptotic cell death in HCT116 cells. Hallmarks of morphological and biochemical signs of apoptosis were clearly evident. CAERS down-regulated DNA-binding and transcriptional activities of NF-kappaB and AP-1 proteins, while up-regulating expression of the Nrf-2 protein. It also down-regulated expression levels of the ERK MAPK, Bcl-2, cyclin D1, CDK-4, survivin and VEGF and up-regulated levels of Bax, caspase-3/7 and -9, p53, p21, Nrf-2. Markedly, it promoted mRNA expression levels of cytoprotective genes including the hemeoxygenase-1, NAD(P)H quinine oxidoreductase 1 and UDP-glucuronyltransferase. CONCLUSIONS: These findings indicate that CAERS exerts antiproliferative action on CRC cells through induction of apoptotic mechanisms, and suggest CAERS could be a promising agent for studying and developing novel chemotherapeutic agents aimed at novel molecular targets for the treatment of CRC. PMID- 27221881 TI - Premature Ejaculation and Erectile Dysfunction in Iranian Prostate Cancer Patients. AB - BACKGROUND: To investigate the prevalence of premature ejaculation (PE) and erectile dysfunction (ED) in a sample of patients with prostate cancer and to determine the utility of the previously suggested cutoffs of the Premature Ejaculation Diagnostic Tool (PEDT) for the diagnosis of PE and that of International Index of Erectile Function (IIEF-5) for ED. MATERIALS AND METHODS: A total of 1,202 men with prostate cancer were invited from urology clinics at the universities of Iran, Tehran, Qazvin, Ahvaz, Guilan and Tabriz. Clinical characteristics were collected through medical records. PE and ED diagnoses were made by trained urologists. In addition to the clinical diagnoses, PE and ED were measured through self-report using the PEDT and the IIEF-5. Questionnaire cutoff scores were determined using receiver operating characteristic (ROC) curves and confirmed by predictive ability using logistic regression. RESULTS: The prevalence of PE was 63.7% and that of ED was 66.2%. Prevalences of PE decreased and that of ED increased with advanced TNM stages. According to ROC, the suggested cutoff for the PEDT to diagnose a PE was >= 11 (sensitivity=0.988, 1 specificity=0.084, and predictive ability=0.914) and <= 17 for the IIEF-5 (sensitivity=0.966, 1-specificity=0.031, and predictive ability=0.967). CONCLUSIONS: Prevalence of sexual problems was high in prostate cancer patients in Iran, therefore oncologists should take into account these potential problems when deciding on treatment modalities. PMID- 27221882 TI - Neural Transdifferentiation: MAPTau Gene Expression in Breast Cancer Cells. AB - BACKGROUND: In tumor cells, aberrant differentiation programs have been described. Several neuronal proteins have been found associated with morphological neuronal-glial changes in breast cancer (BCa). These neuronal proteins have been related to mechanisms that are involved in carcinogenesis; however, this regulation is not well understood. Microtubule-associated protein tau (MAP-Tau) has been describing in BCa but not its variants. This finding could partly explain the neuronal-glial morphology of BCa cells. Our aim was to determine mRNA expression of MAP-tau variants 2, 4 and 6 in breast cancer cell lines. MATERIALS AND METHODS: Cultured cell lines MCF-10A, MDA-MB-231, SKBR3 and T47D were observed under phase-contrast microscopy for neural morphology and analyzed for gene expression of MAP-Tau transcript variants 2, 4 and 6 by real time PCR. RESULTS: Regarding morphology like neural/glial cells, T47D line shown more cells with these features than MDA-MB-231 and SKBR. In another hand, we found much greater mRNA expression of MAP-Tau transcript variants 2, and to a lesser extent 4 and 6, in T47D cells than the other lines. In conclusion, regulation of MAP- Tau could bring about changes in cytoskeleton, cell morphology and motility; these findings cast further light on neuronal transdifferentiation in BCa. PMID- 27221883 TI - Breast Cancer Molecular Subtypes Defined by ER/PR and HER2 Status: Association with Clinicopathologic Parameters in Ivorian Patients. AB - BACKGROUND: Breast cancer is a heterogeneous disease that represents a major public health problem. The immunohistochemical determination of breast cancer subtypes with regard to estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2) status can contribute to improved selection of therapy and patientcare. The purpose of this study was to determine the prevalence of the molecular breast cancer subtypes and to assess their associations with classical clinicopathologic parameters for better therapeutic decisions in women with breast cancer in the Ivory Coast. MATERIALS AND METHODS: Formalin- fixed and paraffin-embedded blocks of patients diagnosed with primary breast carcinoma were subjected to immunohistochemical assay for the assessment of ER/RP and HER2 expression. The one-way analysis of variance evaluated the difference between breast cancer subtypes and mean age of patients. The Chi square Test was used to compare standard clinicopathologic prognostic parameters with tumor subtypes. RESULTS: Among 302 patients, 57% were premenopausal and 43% were postmenopausal. The invasive ductal carcinoma not otherwise specified (IDC NOS) (82.8%) was the most frequent histological type, and the tumor grade 2 (56%) was predominant followed by grade 3 (20.9%). The proportion of positivity of ER, PR, and HER2 was 56%, 49%, and 15.6%, respectively. Half of patients of this study (51.6%) had luminal A breast tumor type followed by TN (32.1%). Other subtypes were luminal B (10.1% ) and non-luminal HER2+ (6.3%). CONCLUSIONS: The findings of the present study are in line with the literature and should assist in management of breast cancer in our country. PMID- 27221884 TI - Synergistic Effects of Jerusalem Artichoke in Combination with Pegylated Interferon Alfa-2a and Ribavirin Against Hepatic Fibrosis in Rats. AB - BACKGROUND: Complementary and alternative medicine has been highly appreciated as a supportive regimen for classical treatment strategies. Here we offer a nutrition-based adjuvant therapy for liver fibrosis, a major risk factor for cirrhosis and hepatocellular carcinoma. AIM OF THE STUDY: To evaluate the possible hepatoprotective effects of Jerusalem artichoke tubers (JAT) in combination with interferon and ribavirin. MATERIALS AND METHODS: Twelve groups of rats were administered JAT, interferon and ribavirin either separately or in combination from day one of CCL4 administration until the end of the study. Animals were killed after 8 weeks of CCL4- induced hepatotoxicity. RESULTS: Hepatocytes from rats treated with triple combination of interferon, ribavirin, and JAT showed more less normal architecture compared to CCL4- treated rats. We also detected significantly higher hepatic protein expression levels of p53, BAX and transforming growth factor-beta (TGF-beta) in the CCl4- intoxicated group compared to normal controls, as evidenced by immunohistochemical staining and western blotting analyses. Addition of JAT as a supportive regimen improved response to ribavirin and interferon and effectively participated in retaining normal histopathological and biochemical criteria and significantly lowered protein expression of p53, BAX, and TGF-beta. CONCLUSIONS: We suggest that addition of JAT as a supportive regimen to interferon and ribavirin effectively potentiates their anti-fibrotic effects. PMID- 27221885 TI - Screening of BRCA1/2 Mutations Using Direct Sequencing in Indonesian Familial Breast Cancer Cases. AB - Breast cancer has emerged as the most prevalent cancer among women worldwide, including in Indonesia. The contribution of genes associated with high-risk breast-ovarian cancers, BRCA1 and BRCA2, in the Indonesian population is relatively unknown. We have characterized family history of patients with moderate- to high-risk of breast cancer predisposition in 26 unrelated cases from Indonesia for BRCA1/2 mutation analyses using direct sequencing. Known deleterious mutations were not found in either BRCA1 or BRCA2 genes. Seven variants in BRCA2 were documented in 10 of 26 patients (38%). All variants were categorized as unclassified (VUSs). Two synonymous variants, c.3623A>G and c.4035T>C, were found in 5 patients. One variant, c4600T>C, was found in a 38 year old woman with a family history of breast cancer. We have found 4 novel variants in BRCA2 gene including c.6718C>G, c.3281A>G, c.10176C>G, and c4490T>C in 4 unrelated patients, all of them having a positive family history of breast cancer. In accordance to other studies in Asian population, our study showed more frequent variants in BRCA2 compared to BRCA1. Further studies involving larger numbers of hereditary breast cancer patients are required to reveal contribution of BRCA1/2 mutations and/or other predisposing genes among familial breast cancer patients in Indonesia. PMID- 27221886 TI - Telomere-Mitochondrion Links Contribute to Induction of Senescence in MCF-7 Cells after Carbon-Ion Irradiation. AB - The effects of carbon-ion irradiation on cancer cell telomere function have not been comprehensively studied. In our previous report cancer cells with telomere dysfunction were more sensitive to carbon-ion irradiation, but the underlying mechanisms remained unclear. Here we found that telomerase activity was suppressed by carbon-ion irradiation via hTERT down-regulation. Inhibition of telomere activity by MST-312 further increased cancer cell radiosensitivity to carbon-ion radiation. hTERT suppression caused by either carbon-ion irradiation or MST-312 impaired mitochondrial function, as indicated by decreased membrane potential, mtDNA copy number, mitochondrial mass, total ATP levels and elevated reactive oxygen species (ROS). PGC-1alpha expression was repressed after carbion ion irradiation, and hTERT inhibition by MST-312 could further exacerbate this effect. Lowering the mitochondrial ROS level by MitoTEMPO could partially counteract the induction of cellular senescence induced by carbon-ion radiation and MST-312 incubation. Taken together, the current data suggest that telomere mitochondrion links play a role in the induction of senescence in MCF-7 cells after carbon-ion irradiation. PMID- 27221888 TI - Impact of Interactions Between Self-Reported Psychological Stress and Habitual Exercise on the Dietary Intake of Japanese Men and Women: a Large-Scale Cross Sectional Study. AB - BACKGROUND: Modifying lifestyle factors such as diet and exercise can reduce the risk of cancer. Psychological stress (PS) might be indirectly associated with cancer because it alters lifestyle factors. However, the relationship among these variables has not been fully investigated. Thus, we examined interactions between self-reported PS (SRPS) and habitual exercise on diet. MATERIALS AND METHODS: In all, 5,587 men and 2,718 women were divided into "exerciser" and "non-exerciser" groups, based on whether they exercised regularly, and classified into three SRPS levels: low, moderate and high. Diet was estimated using a validated food frequency questionnaire. Using a general linear model, food and nutrient consumption was estimated for each SRPS level in the 2 exercise groups, and the interactions between SRPS levels and exercise were calculated. RESULTS: In women, the intake of pork and beef, low fat milk and yogurt, natto (fermented soybean), carrots and squash, other root vegetables, mushrooms, seaweeds, and wine, along with the nutrients vegetable protein, soluble, insoluble and total dietary fiber, daidzein, genistein, carotene, retinol equivalents, vitamin B2, pantothenic acid, potassium, calcium, magnesium, phosphorus and iron demonstrated significant interaction with SRPS and habitual exercise (p for interaction <0.05). In men, raw and green leafy vegetables and fruit and vegetable juice significantly interacted with SRPS and habitual exercise (p for interaction <0.05). CONCLUSIONS: We suggest that certain foods and nutrients, which are thought to have a protective effect against cancer, interact with SRPS and habitual exercise, especially in women. This information is valuable for understanding and improving interventions for cancer prevention. PMID- 27221887 TI - PHA-Induced Peripheral Blood Cytogenetics and Molecular Analysis: a Valid Diagnostic and Follow-up Modality for Acute Promyelocytic Leukemia Patients Treated with ATRA and/or Arsenic Tri-oxide. AB - BACKGROUND: Acute promyelocytic leukemia (APML) is characterized by the reciprocal translocation t(15;17) (q22;q12) resulting in the PML-RARalpha fusion gene. A dual diagnostic and follow up approach was applied including cytogenetic demonstration of the t(15;17) translocation and detection of PML-RARalpha chimeric transcripts by molecular means. PURPOSE: Conventional cytogenetics involving bone marrow is beset with high probability of poor metaphase index and was substituted with phytohemagglutinin (PHA)-induced peripheral blood culture based cytogenetic analysis as a diagnostic and follow up modality in APML patients of Kashmir (North India). Both qualitative (RT-PCR) and quantitative (Q PCR) tests were simultaneously carried out to authenticate the modified cytogenetics. MATERIALS AND METHODS: Patient samples were subjected to the said techniques to establish their baseline as well as follow-up status. RESULTS: Initial cytogenetics revealed 30 patients (81%) positive for t(15;17) whereas 7 (19%) had either cryptic translocation or were negative for t(15;17). Two cases had chromosome 16q deletion and no hallmark translocation t(15;17). Q-PCR status for PML-RARalpha was found to be positive for all patients. All the APML patients were reassessed at the end of consolidation phase and during maintenance phase of chemotherapy where 6 patients had molecular relapse, wherein 4 also demonstrated cytogenetic relapse. CONCLUSIONS: It was found that PHA-induced peripheral blood cytogenetics along with molecular analysis could prove a reliable modality in the diagnosis and assessment of follow up response of APML patients. PMID- 27221889 TI - Association of PINX1 but not TEP1 Polymorphisms with Progression to Hepatocellular Carcinoma in Thai Patients with Chronic Hepatitis B Virus Infection. AB - Hepatocellular carcinoma (HCC) is major health problem with high mortality rates, especially in patients with hepatitis B virus (HBV) infection. Telomerase function is one of common mechanisms affecting genome stability and cancer development. Recent studies demonstrated that genetic polymorphisms of telomerase associated genes such as telomerase associated protein 1 (TEP1) rs1713449 and PIN2/TERF1-interacting telomerase inhibitor 1 (PINX1) rs1469557 may be associated with risk of HCC and other cancers. In this study, 325 patients with HCC and 539 non-HCC groups [193 healthy controls, 80 patients with HBV-related liver cirrhosis (LC) and 266 patients with HBV-related chronic hepatitis (CH)] were enrolled to explore genetic polymorphisms of both SNPs using the allelic discrimination method based on MGB probe TaqMan real time PCR. We demonstrated that all genotypes of both genes were in Hardy-Wienberg equilibrium (>0.05). Moreover, there was no significant association between rs1713449 genotypes and HCC risk, HCC progression and overall survival (>0.05). Interestingly, we observed positive association of rs1469557 with risk of HCC when compared with the LC group under dominant (CC versus CT+TT, OR=1.89, 95% CI= 1.06-3.40, P=0.031) and allelic (C versus T alleles, OR=1.75, 95% CI=1.04-2.94, P=0.033) models, respectively. Moreover, overall survival of HCC patients with CC genotype of rs1469557 was significantly higher than non-CC genotype (Log-rank P=0.015). These findings suggest that PINX1 rs1469557 but not TEP1 rs1469557 might play a role in HCC progression in Thai patients with LC and be used as the prognosis marker to predict overall survival in HCC patients. PMID- 27221890 TI - Effect of Peripheral Blood CD4 + CD25 + Regulatory T Cell on Postoperative Immunotherapy for Patients with Renal Carcinoma. AB - OBJECTIVE: To investigate the effect of peripheral blood CD4 + CD25 + regulatory T cell on postoperative immunotherapy in patients with renal carcinoma. METHODS: 38 patients with renal cell carcinoma were recruited, and 20 patients from the operation group purely underwent the radical nephrectomy therapy, 18 patients from the combined group successively underwent the radical nephrectomy therapy and IFN-alpha adjuvant immunotherapy. Additionally, 12 healthy subjects were recruited in the same period of time and regarded as the control group. Flow cytometry was used to detect CD4 +, CD8 +, CD4 + CD25+ T lymphocyte subset content and the ratio of all parts in the pre-operative period, in the first post operative week and in the third post-operative month, compare and analyze its variation trend. RESULTS: The CD4+CD25+ T lymphocyte subset content of individual renal carcinoma patients was significantly higher than that of the control group, also increases with the progression in the tumor stage (<0.05). The post operative CD4 + CD25+T lymphocytes of individual operation group and combined group patients showed different degrees of increment, but the increment of the combined group was significantly lower than that of the operation group (<0.05). For the combined group patients with less pre-operative CD4 + CD25+T lymphocytes, their levels would increase after the immunotherapy, while the pre-operative patients with more CD4 + CD25+ T lymphocytes were the opposite situation. CONCLUSION: The detection of peripheral blood CD4+CD25+ regulatory T lymphocyte subset can reflect the anti-tumor immune status of renal cell carcinoma patient body. It can contribute to predict the prognosis of immunotherapy and provide reference for the choice of renal carcinoma post-operative adjuvant immunotherapy. PMID- 27221891 TI - International Scoring System in Symptomatic Multiple Myeloma: Experience from a Tertiary Care Center. AB - BACKGROUND: Symptomatic multiple myeloma (MM) is an acquired B-cell malignant proliferation of anti- body secreting plasma cells, characterized by end organ damage due to monoclonal immunoglobulin secretion. The aim of this study wa to determine the stage stratification according to an international scoring system in adult Pakistani MM patients at presentation. MATERIALS AND METHODS: This single centre retrospective study extendedfrom January 2012 to December 2015. Data were retrieved from the departmental maintained records. RESULTS: A total of 39 patients were diagnosed at our center with MM during the period of the study, 25 males and 14 females. Age ranged between 36 and 81 with a mean of 54.5+/-14.8 and a median of 57 years. Common presenting complaints included fatigue (80.9%), backache (79.3%) and bone pain (66.2%). Overall, 9 patients were in ISS stage I (23%), 12 were in stage II (30.7%) and 18 were in stage III (46.1%). Out of the total, 29 (74.3%) had kappa immunoglobulin andthe remaining 10 (25.6%) had lambda type myelomas. IgG myeloma was commonest, seen in 26 (66.6%) followed by IgA in 11 (28.2%) with non secretory myeloma in one (2.5%) and light chain disease also in one patient (2.5%). CONCLUSIONS: MM in Pakistani patients is seen in a relatively young population with male predominance. Primarily patients are symptomatic and risk stratification revealed a predominance of advanced stage III disease in our setting. PMID- 27221892 TI - Dietary Patterns and Risk of Breast Cancer in Women in Guilan Province, Iran. AB - BACKGROUND: Several studies have pointed to roles of dietary and food groups in the pathogenesis of breast cancer, but information on dietary patterns among women with breast cancer and their healthy counterparts in Iran is limited. Therefore the present investigation was conducted in Guilan province in 2014 2015. MATERIALS AND METHODS: In a case-control study, 450 women with breast cancer and one of their relatives (third-rank) were investigated. At first the phone numbers of patients in Razi Hospital in radiotherapy and chemotherapy and oncology centers of Guilan were taken. Data were collected through telephone interviews by the researcher. The questionnaire had two parts comprising demographic clinical and food frequency data including a list of 40 food items. To analyze the variables, Chi-square test and univariate logistic regression models were used. RESULTS: In each group, 225 subjects were investigated. The majority of samples in both groups of experiment and control were consumed than two glasses of milk and dairy products per day. Regarding consumption of meat and its products, 56% of the cancer group had more than three servings per day while 26.7% of the control group had less than 2 servings per day. The majority of subjects had less than six servings of cereal per day. Some 54. 7 % of the cancer and 62.2 % of the control group consumed less than two servings of fruit per day. Consumption of vegetables in experimental and control groups were 52.9% and 76.9% respectively, more than five servings per day. There was a meaningful difference between two groups regarding the consumption of milk and dairy items (OR=0.6,95%CI= 0.4-0.9), meat and its products (OR=0.49,95%CI=0.3-0.7), bread and cereals (OR=0.4,95%CI=0.2-0.8), vegetables (OR=0.5,95%CI= 0.3-0.9). (P value<0.05). CONCLUSIONS: The results of this study emphasize the importance of informing women, particularly those at higher risk of breast cancer, in relation to dietary factors. PMID- 27221893 TI - Incidence and Mortality of Liver Cancer and Their Relationship with Development in Asia. AB - BACKGROUND: Liver cancer (LC) is the sixth world most common cancer and the second leading cause of cancer death. Due to the importance and necessity of awareness about the incidence and mortality of diseases to perform prevention programs, this study focused on data for LC and its relationship with the human development index (HDI) and its components in Asia in 2012. MATERIALS AND METHODS: This ecological study was based on GLOBOCAN data for Asian countries. We assessed correlations between standardized incidence rates (SIR) and standardized mortality rates (SMR) of LC with HDI and its components using of SPSS18. RESULTS: A total of 582,420 incident cases and 557,097 deaths were recorded in Asian countries in 2012. The five with the highest SIR were Mongolia, Lao PDR, Vietnam, Republic of Korea and Thailand and those with the highest SMR were Mongolia, Lao PDR, Vietnam, Cambodia and Thailand. A negative relation was observed between HDI and LC for SIR of 0.049 (P=0.748) and for SMR of 0.07 (P=0.645), with life expectancy at birth a positive relation for SIR of 0.061 (P=0.687) and a negative relation for SMR of 0.079 (P=0.603), with the average years of education a negative relation fo SIR of 0.476 (p=0.952) and for SMR of 0.032 (P=0.832), and with the country income level per person a negative relation for SMI of 0.11 (p=0.465) and for SMR of 0.113 (P=0.455). CONCLUSIONS: The incidence of LC is more in less developed and developing countries but statistically significant correlations were not found between standardized incidence and mortality rates of LC, and HDI and its dimensions. PMID- 27221894 TI - Comparison of Ligasure Versus Conventional Surgery for Curative Gastric Cancer Resection: a Meta-Analysis. AB - BACKGROUND: The LigaSure vessel sealing system has been proposed to save operation time and reduce intraoperative blood loss for various surgeries. However, its usage for gastric cancer is still controversial. The aim of the present meta-analysis was to compare the effectiveness of LigaSure with conventional surgery in gastrectomy. MATERIALS AND METHODS: Sources were retrieved from the Cochrane Library, MEDLINE, EMBASE, SCOPUS and Google Scholar until February, 2015. All randomized controlled trials comparing LigaSure with conventional surgery in curative gastric cancer resection were selected. After data extraction, statistics were performed by Review Manager 5.1 software. RESULTS: Three eligible randomized controlled trials were evaluated, with a total of 335 patients. The quality of the included trials was good, yet some methodological and clinical heterogeneity existed. There were no significant differences between the LigaSure and conventional groups in operative time (weighted mean difference [WMD], -22.95 minutes; 95% confidence interval [CI], [ 59.75, 13.85]; P = 0.22), blood loss (WMD, -45.8 ml; 95% CI, [-134.5, 42.90]; P = 0.31), nor the incidence of surgical complications (odds ratio, 1.18; 95% CI, [0.68, 2.05]; P = 0.54). But there was a longer duration of hospital stay in LigaSure group (WMD, 1.41 days; 95% CI, [0.14, 2.68]; P = 0.03). CONCLUSIONS: All available randomized evidence has been summarized. LigaSure does not confer significant advantage over conventional surgery for curative gastric cancer resection. The usefulness of the device may be limited in gastrectomy. But, more trials are needed for further assessment of the LigaSure system for gastric cancer. PMID- 27221895 TI - Lack of Association between an XRCC1 Gene Polymorphism and Colorectal Cancer Survival in Thailand. AB - BACKGROUND: Colorectal cancer (CRC) is one of the most common causes of death worldwide and in Thailand. The X-ray repair cross-complementary protein 1 (XRCC1) is required for efficient DNA repair. The effects of this gene on survival in colorectal cancer remain controversial and have not been reported in Thailand. The aim of this study was to investigate the association of the XRCC1 gene with survival of colorectal cancer patients in a Thai population. MATERIALS AND METHODS: Data and blood samples were collected from 255 newly diagnosed and pathologically confirmed CRC patients who were recruited during the period 2002 to 2006 and whose vital status was followed up until 31 October, 2014. Real-time PCR-HRM was used for genotype identification. The Kaplan-Meier method, the log rank test, and Cox proportional hazard regression were used to estimate cumulative survival curves and compare various survival distributions and adjusted hazard ratios. RESULTS: Most of the cases were males, and the median age was 55 years. The median survival time was 2.43 years. The cumulative 1-, 3-, 5-, 7-, and 10 year survival rates were 76.70%, 39.25%, 26.50%, 16.60% and 3.56%, respectively. After adjustment, female gender, ages 50-59 and >= 60 years, tumour stage III+IV, a signet-ring cell carcinoma, and poor differentiation had significant associations with increased risk of CRC death. While the XRCC1 Arg/Arg homozygote appeared to be a risk factor for CRC death, the association was not significant. CONCLUSIONS: The genetic variant in the XRCC1 may not be associated with the survival of CRC patients in Thailand. Further studies are needed to verify our findings. PMID- 27221896 TI - Role of P57KIP2 Immunohistochemical Expression in Histological Diagnosis of Hydatidiform Moles. AB - PURPOSE: To determine the significance of P57KIP2 immunohistochemistry expression in the histopathological diagnosis of hydatidiform mole. MATERIALS AND METHODS: Hydatidiform mole patients at King Chulalongkorn Memorial Hospital between January 1999 and December 2011 were recruited. Two gynecologic pathologists reviewed histopathologic slides to confirm diagnosis. Formalin-fixed, paraffin embedded tissue sections were stained using a bstandard immunostaining system with monoclonal antibodies against P57KIP2 protein. Correlations among pathological features, immunohistochemical expression and clinical data were analyzed. RESULTS: One hundred and twenty-seven hydatidiform mole patients were enrolled. After consensus review, 97 cases were diagnosed as complet (CHM) and 30 cases as partial (PHM). Discordance between the first and final H and E diagnoses was found in 19 cases (14.9%, k= 0.578). Significant pathological features to classify the type of hydatidiform mole are central cisterns, trophoblastic proliferation, trophoblastic atypia, two populations of villi, fetal vessels and scalloped borders. After performing immunohistochemistry for P57KIP2, 107 cases were P57KIP2 negative and 20 cases positive. Discordant diagnoses between final H and E diagnosis and P57KIP2 immunohistochemistry was identified in 12 cases (9.4%). Sensitivity of final H and E diagnosis for CHM was 89.7%; specificity was 95.0%. PHM sensitivity and specificity of final H and E diagnosis was 95.0% and 89.7%, respectively. CONCLUSIONS: Histopathological diagnosis alone has certain limitations in accurately defining types of hydatidiform mole; P57KIP2 immunohistochemistry is practical and can be a useful adjunct to histopathology to distinguish CHM from non-CHM. PMID- 27221897 TI - Risk Factors for Cervical Cancer and CIN3 in Jewish Women in Israel - Two Case Control Studies. AB - PURPOSE: The aim of the study was to identify risk and protective factors/markers for cervical cancer and cervical intraepithelial neoplasia 3 (CIN3) in Israeli Jewish women in order to settle the discrepancy of low incidence rate of cervical cancer and relatively high incidence rate of CIN3. MATERIALS AND METHODS: We conducted two case control studies, which examined the association between potential risk and protective factors/markers for cervical cancer or CIN3 using self administered detailed questionnaires. RESULTS: For studying cervical cancer, 40 cases and 40 matched controls were interviewed. In the univariable and multivariable analyses older age, depression or anxiety and ever smoking seemed to act as independent risk factors/markers, while older age at first intercourse was protective. For studying CIN3, 99 cases and 79 controls were interviewed. Multivariable analysis has demonstrated that being born in Israel, depression or anxiety and ever smoking were independent risk factors/markers for CIN3. CONCLUSIONS: The risk factors/markers studied, that were associated with cervical cancer or CIN3 among Jewish women in Israel, are similar to those reported in other parts of the world, and do not explain the observed discrepancy of high in situ cervical cancer rates and low invasive cervical cancer incidence in Israel. PMID- 27221898 TI - Knowledge about Risk Factors for Breast Cancer and Having a Close Relative with Cancer Affect the Frequency of Breast Self-Examination Performance. AB - BACKGROUND: Breast cancer incidence and mortality rates are increasing in North Eastern Brazil and the patients with the disease often presented at advanced stages. The present study was focused on identifying variables that affect women's frequency of breast self- examination (BSE) performance. MATERIALS AND METHODS: Data on BSE, socio-economic parameters and risk factors for breast cancer were obtained from 417 women from a community in North-Eastern Brazil by a self-informant method. To identify independent variables that affect frequency of BSE, nominal logistic regression analysis was performed. RESULTS: Of 417 women, 330 (79.3%) reported performing BSE. Compared to high-income women, BSE performance by low-income women every month was 7.69 (OD=0.130; CI 95%: 0.044- 0.0386; p=0.000) times lower. Women who did not live in a stable union performed BSE each month 2.73 (OD=0.366; CI 95%: 0.171-0.782; p=0.010) less often than those living in a stable union. BSE performance every month and every six months or every year by women with poor knowledge about risk factors for breast cancer was 3.195 (OD=0.313; CI 95%: 0.141- 0.695; p=0.004) times and 2.028 (OD=0.493; CI 95%: 0.248- 0.979; p=0.043) times lower, compared to women with good knowledge. Participants who had a close relative with cancer performed BSE every month and every six months or every year 2.132 (OD=0.469; CI 95%: 0.220-0.997; p=0.049) times and 2.337 (OD=0.428; CI 95%: 0.219-0.836; p=0.013) times less often, compared to those women without close relatives with cancer. CONCLUSIONS: The results of this study indicated that income, marital status, knowledge about risk factors and having a close relative with breast cancer, affect the frequency of BSE performance. Information about risk factors in public health campaigns could additionally strengthen avoidance behaviour and also motivate BSE performance. PMID- 27221899 TI - Isolation and Structure Elucidation, Molecular Docking Studies of Screlotiumol from Soil Borne Fungi Screlotium rolfsii and their Reversal of Multidrug Resistance in Mouse Lymphoma Cells. AB - A new compound namely (13-(3,3-dihydroxypropyl)-1,6-dihydroxy-3,4-dihydro-1H isochromen-8(5H)-one (1) was isolated from an ethyl acetate extract of the borne fungi Screlotium rolfsii. Its chemical structure was elucidated by spectroscopic analysis. Screlotiumol 1 were evaluated for their effects on the reversion of multidrug resistant (MDR) mediated by P-glycoprotein (P-gp) of the soil borne fungi. The multidrug resistant P-glycoprotein is a target for chemotherapeutic drugs in cancer cells. In the present study rhodamine-123 exclusion screening test on human mdr1 gene transfected mouse gene transfected L5178 and L5178Y mouse T-cell lymphoma which showed excellent MDR reversing effect in a dose dependent manner against mouse T-lymphoma cell line. Moreover, molecular docking studies of compound-1 also showed better results as compared with the standard. Therefore the preliminary results obtained from this study suggest that screlotiumol 1 could be used as a potential agent for the treatment of cancer. PMID- 27221900 TI - Mean Platelet Volume as an Independent Predictive Marker for Pathologic Complete Response after Neoadjuvant Chemotherapy in Patients with Locally Advanced Breast Cancer. AB - BACKGROUND: The impact of mean platelet volume (MPV) on prognosis, diagnosis and response to therapy in cancer patients has been widely investigated. In the present study, we evaluated whether MPV at diagnosis has predictive value for pathologic complete response (pCR) after neoadjuvant chemotherapy in patients with locally advanced breast cancer (LABC). MATERIALS AND METHODS: A total of 109 patients with LABC from Akdeniz University and Antalya Research and Training Hospital were evaluated retrospectively. RESULTS: ROC curve analysis suggested that the optimum MPV cut-off point for LABC patients with pCR (+) was 8.15 (AUC:0.378, 95%CI [0.256- 0.499], p=0.077). The patients with MPV <8.15 had higher pCR rates (29.2% vs. 13.1%, p=0.038). After binary logistic regression analysis, MPV and estrogen receptor absence were independent predictors for pCR. CONCLUSIONS: MPV has an independent predictive value for pCR after neoadjuvant chemotherapy in patients with LABC. PMID- 27221901 TI - Association of Interleukin-27 rs 153109 Single Nucleotide Polymorphism with Spontaneous Resolution of Hepatitis C Virus - Genotype 4a Infection in Egyptian Patients. AB - BACKGROUND: HCV is a major global health problem. IL-27 is a member of the IL 6/IL-12 cytokine family with a broad range of anti-inflammatory properties. Recent studies highlighted the effect of a SNP in the IL-27 promoter region on modulating the progression of infectious diseases and individual responses to therapy. AIM OF THE WORK: The present study investigated the potential role of ( 964 A/G) SNP in the promoter region of IL-27p28 gene (alleles rs153109) on the outcome of HCV infection among genotype 4a infected patients. MATERIALS AND METHODS: HCV genotyping confirmed that all of the HCV-infected patients had genotype 4a infection. Genomic DNA was extracted from 111 patients with chronic HCV infection, 42 spontaneous resolvers (SR) and 16 healthy controls. IL- 27p28.rs153109 genotyping was assessed using PCR-RFLP then confirmed by DNA sequencing. RESULTS: The frequency of IL-27-p28.rs153109AA, AG, and GG genotypes among chronically infected subjects were 74.8 %, 25.2%, and 0% while among the SR, they were 57.1%, 35.7%, and 7.14%, respectively. Our data show the unique presence of G/G genotype in the SR group (3 patients; 7.14%). Moreover, the "G" allele frequencies among chronic and resolved subjects were 12.6% and 25.0%, respectively (p=0.0136). Importantly, subjects with the GG genotype were more likely to clear their HCV infection than those with the AA genotype (p=0.0118). CONCLUSIONS: HCV genotype 4a subjects with the IL-27-p28.rs153109 A/G and G/G genotype were more likely to clear their HCV infection. Therefore, we propose IL- 27p28.rs153109SNPas a genetic biomarker for predicting HCV infection outcome. PMID- 27221902 TI - Improved Detection of Helicobacter pylori Infection and Premalignant Gastric Mucosa Using Conventional White Light Source Gastroscopy. AB - BACKGROUND: The gold standard diagnosis of H. pylori related gastritis is evidence of bacteria on histopathological examination of gastric mucosa. Our aim was to study the correlation between gastric mucosal morphology and histopathological severity of H. pylori related gastritis. MATERIALS AND METHODS: Division was made on morphological features into:Type 1, showing regular arrangement of red dots; Type 2, showing cleft-like appearance; Type 3, with a mosaic appearance; and Type 4, having a mosaic appearance with focal or diffuse hyperemia. RESULTS: Types 1 and 2 gastric mucosal morphologies were statistically significant in predicting an H. pylori negative status (137/145, <0.01), while Types 3 and 4 were significant a positive status (139/155, <0.01). The sensitivity, specificity, positive and negative predictive values of Type 3 and 4 morphologies for predicting H. pylori positive were 94.6%, 89.5%, 89.7% and 94.5%, respectively, with a good correlation with inflammation grading (<0.01). CONCLUSIONS: Our study suggests that gastric mucosal morphology can be reliably identified using conventional white light source gastroscopy with good correlation between findings and inflammation grading. PMID- 27221903 TI - Factors Delaying Presentation of Sudanese Breast Cancer Patients: an Analysis Using Andersen's Model. AB - PURPOSE: A multicenter, observational, cross-sectional study was conducted to assess factors delaying presentation of breast cancer cases. MATERIALS AND METHODS: Data were collected from a pair of highly specialized referral centers, both located in the center of the Sudanese capital, Khartoum. For a total of 153 eligible respondents, durations of delay, clinicodemographic factors and reasons of referral were collected from our respondents through self-administered questionnaires. Logistic regression analysis and ANOVA were used to test the relation between periods of delay and different factors. Odd ratios (OR's) and their correspondent Confidence intervals (95% CI's). Delay periods were studied with Andersen's model. RESULTS: The average duration of delay in our study was 11.9 (+/-11.2) months. Only a quarter of our patients presented early within the first 3 months after onset of their symptoms. About 47.7% arrived later during the course of the first year, while it took beyond that for the last 27% to come. A prior diagnosis of BC was the only predictor of early presentation (for 3-12 months OR=9.6 (<0.00), 95% CI 9.55-9.75; for >12 months OR=9.3 (<0.00), 95% CI 9.33-9.33). Out of the 12 different reasons for delay given by our respondents, none showed a significant difference between patients presenting early or late. Financial incapacity (17.5%), ignorance about BC (14.3), and misinterpreting symptoms (12.7%) were the top three whys of delay. CONCLUSIONS: Our findings support existence of a non-uniform pattern of delay among Sudanese BC patients. Changing currently adopted awareness elevating strategies into much more inclusive approaches is strongly recommended. PMID- 27221904 TI - Health Behavior Regarding Liver Flukes among Rural People in Nakhon Ratchasima, Thailand. AB - Opisthorchiasis is a health problem in Thailand particularly in northeast and north regions where have been reported the highest of cholangiocarcinoma. Active surveillance is required, therefore a cross-sectional surveyed was conducted in Nong Bunnak sub-district of Nakhon Ratchasima province, Thailand. A total of 367 participants were selected by multistage sampling from 5 villages located near natural water resources. Participants completed a predesigned questionnaire containing behavior questions regarding liver fluke disease, covering reliability and validity knowledge (Kuder-Richardon-20) = 0.80, attitude and practice (Cronbach's alpha coefficient) = 0.82 and 0.79, respectively. Descriptive statistics included frequencies, percentages, means, and standard deviations. The majority of the participants were female (58.3%), age group between 21-30 years old (42.5%), with primary school education (59.9%), occupation in agriculture (38.1%), and married (80.9%). They had past histories of raw fish consumption (88.3%), stool examination (1.4%), anti-parasite medication used (4.6%). Heads of villages, village health volunteers, television, and village newstations were the main sources for disease information. Participants had a moderate level of behavior regarding liver fluke disease. The mean scored of knowledge regarding liver fluke life cycle, transmission, severities, treatment, prevention and control was 10.9 (SD=0.5), most of them had a moderate level, 95.1%. The mean score for attitude regarding liver fluke prevention and control was 45.7 (SD=9.7), and for practice was 30.6 (SD=10.5). Participants had a moderate level of attitude and practice, 94.5% and 47.7, respectively. This study indicates that health education is required in this community including stool examination for liver fluke as further active surveillance screening. PMID- 27221905 TI - Predictors of Complementary and Alternative Medicine Use by Breast Cancer Patients in Bandung, Indonesia. AB - BACKGROUND: The study aimed to assess complementary and alternative medicine (CAM) use and their associated factors with breast cancer patients in Bandung, Indonesia. MATERIALS AND METHODS: In total, 330 breast cancer patients were administered questionnaires on their CAM use and CAM predictive factors including socio-demographic parameters, clinical data and quality of life, trust in physicians, trust in hospitals, satisfaction and informational needs. Data were analyzed using univariate analysis and multivariate log regreesion analysis. RESULTS: Overall 33.3% of patients reported use of CAM. Lower income, lower education, presence of metastasis, prolonged diagnosis, less trust in physician were found to be highly associated with CAM use. CONCLUSIONS: CAM use by breast cancer patients can be interpreted as an attempt to explore all possible options, an expression of an active coping style, or expression of unmet needs in the cancer care continuum. Physicians need to openly discuss the use of CAM with their patients and identify whether they have other unmet supportive needs. PMID- 27221906 TI - Survival of Stomach Cancer Cases in Khon Kaen, Thailand 2000-2012. AB - BACKGROUND: Stomach cancer is an aggressive malignancy that is difficult to detect at an early stage and therefore is characterized by poor survival rates. Over the last two decades, there has been no report of gastric cancer survival in Khon Kaen province, Thailand. The aim of this retrospective cohort study was to provide up-to-date information about the survival of gastric cancer patients in this province. MATERIALS AND METHODS: Data from Khon Kaen population-based cancer registry, Faculty of Medicine, Khon Kaen University were newly obtained on 650 patients who were diagnosed with stomach cancer during the period 1 January, 2000 to 31 December, 2012. These were then followed up until death or the end of the study (31 December 2014). We calculated the observed survival with the actuarial life table method, and relative survival, defined as the ratio of observed survival in the group of the stomach cancer patients to the expected survival in the entire Thai population from the estimated generation life tables for Thailand of five-year birth cohorts from 1900 - 2000. RESULTS: The 5 year observed and 5 year relative survival rates were 17.2 % (95% CI: 13.54-21.14) and 18.2 % (95% CI: 14.3-22.4), respectively. The highest 5 year relative survival rates were demonstrated among patients aged 45-65, with stage I or II lesions, with adenocarcinomas, with a body of stomach location, well differentiated and receiving surgery and/or chemotherapy. CONCLUSIONS: The observed and relative survival rates were close to each other. Our findings provide basic information beneficial to development of an effective treatment system and appropriately improved population-based cancer registration. PMID- 27221907 TI - Estimating the Economic Burden of Premature Mortality Caused by Cancer in Iran: 2006-2010. AB - BACKGROUND: Cancer is currently one of the main public health problems all over the world and its economic burden is substantial both for health systems and for society as a whole.To inform priorities for cancer control, we here estimated years of potential life lost (YPLL) and productivity losses due to cancer-related premature mortality in Iran from 2006 to 2010. MATERIALS AND METHODS: The number of cancer deaths by sex and age groups for top ten leading cancers in Iran were obtained from the Ministry of Health and Medical Education. To estimate theYPLL and the cost of productivity loss due to cancer-related premature mortality, the life expectancy method and the human capital approach were used, respectively. RESULTS: There were 138,228 cancer-related deaths in Iran (without Tehran province) of which 76 % (106,954) were attributable to the top 10 ranked cancers. Some 63 % of total cancer-related deaths were of males. The top 10 ranked cancers resulted in 106,766,942 YPLL in total, 64,171,529 (60 %) in males and 42,595,412 (40%) in females. The estimated YPPLL due to top 10 ranked cancers was 58,581,737 during the period studied of which 32,214,524 (54%) was accounted for in males.The total cost of lost productivity caused by premature deaths because of top 10 cancers was 1.68 billion dollars (US$) from 2006 to 2010, ranging from 251 million dollars in 2006 to 283 million dollars in 2010. CONCLUSIONS: This study showed that the economic burden of premature mortality attributable to cancer is significant for Iranian society. The findings provide useful information about the economic impact of cancer for health system policy/ decision makers and should facilitate planning of preventive intervention and effective resource allocation. PMID- 27221908 TI - Radiological Downstaging with Neoadjuvant Therapy in Unresectable Gall Bladder Cancer Cases. AB - BACKGROUND: Gall bladder cancer (GBC) usually presents as unresectable or metastatic disease. We conducted a feasibility study to evaluate the effect of neoadjuvant therapy (NAT) on radiologic downstaging and resectability in unresectable GBC cases. MATERIALS AND METHODS: Patients with locally advanced disease were treated with chemoradiotherapy [CTRT] ( external radiotherapy (45Gy) along with weekly concurrent cisplatin 35mg/ m2 and 5-FU 500 mg) and those with positive paraaortic nodes were treated with neoadjuvant chemotherapy [NACT (cisplatin 25mg/m2 and gemcitabine 1gm/m2 day 1 and 8, 3 weekly for 3 cycles). Radiological assessment was according to RECIST criteria by evaluating downstaging of liver involvement and lymphadenopathy into complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). RESULTS: A total of 40 patients were evaluated from January 2012 to December 2014 (CTRT=25, NACT=15). Pretreatment CT scans revealed involvement of hilum (19), liver infiltration (38), duodenum involvement (n=22), colon involvement (n=11), N1 involvement (n=11), N2 disease (n=8), paraaortic LN (n=15), and no lymphadenopathy (n=6). After neoadjuvant therapy, liver involvement showed CR in 11(30%), PR in 4 (10.5%), SD in 15 (39.4%) and lymph node involvement showed CR in 17 (50%), PR in 6 (17.6%), SD in 4 (11.7 %). Six patients (CTRT=2, NACT=4) with 66.6 % and 83% downstaging of liver and lymphnodes respectively underwent extended cholecystectomy. There was 16.6 % and 83.3% rates of histopathological CR of liver and lymph nodes. All resections were R0. CONCLUSIONS: Neoadjuvant therapy in unresectable gall bladder cancer results in a 15% resectability rate. This approach has a strong potential in achieving R0 and node negative disease. Radiologic downstaging (CR+PR) of liver involvement is 40.5% and lymphadenopathy is 67.5%. Nodal regression could serve as a predictor of response to neoadjuvant therapy. PMID- 27221909 TI - Nurse Attitude-Related Barriers to Effective Control of Cancer Pain among Iranian Nurses. AB - BACKGROUND: Many cancer patients still experience pain worldwide. There are many barriers for effective control of cancer pain and many of these are related to health care providers. There is a need for further investigation of these barriers. The aim of this study was to investigate nurse-related barriers to control of cancer pain among Iranian nurses. MATERIALS AND METHODS: In this descriptive study 49 nurses from two hospitals affiliated to Tabriz and Ardebil Universities of Medical Sciences participated using a census sampling method. A demographic and profession related checklist and Barriers Questionnaire II (BQ II) were used for data collection. RESULTS: The results showed negative attitudes of participants regarding control of cancer pain. Participants believed that cancer pain medications do not manage cancer pain at acceptable levels; patients may become addicted by using these drugs; cancer pain medications have many uncontrollable effects; and controlling cancer pain may distract the physicians from treating disease. CONCLUSIONS: Iranian nurses have negative attitudes toward pain control in cancer patients especially about effectiveness of pain medication and their side effects. Educational intervention to reduce these misconceptions is needed. PMID- 27221910 TI - Distribution of Glutathione S-Transferase Omega Gene Polymorphism with Different Stages of HBV Infection Including Hepatocellular Carcinoma in the Egyptian Population. AB - BACKGROUND: Infection with hepatitis B virus (HBV) is a major global public health problem, with a wide spectrum of clinical manifestations. Human cytosolic glutathione-S-transferases (GSTs) include several classes such as alpha (A), mu (M), pi (P), sigma (S), zeta (Z), omega (O) and theta (T). The present study aimed to investigate the role of GST omega genes (GSTO1 and GSTO2) in different groups of patients infected with HBV. MATERIALS AND METHODS: HBV groups were classified according to clinical history, serological tests and histological analysis into normal carriers (N), acute (A), chronic (CH), cirrhosis (CI) and hepatocellular carcinoma (HCC) cases. The study focused on determination of the genotypes of GST omega genes (GSTO1 and GSTO2) and GST activity and liver function tests. RESULTS: The results showed that GSTO1 (A/A) was decreased in N, A, CH, CI and HCC groups compared to the C-group, while, GSTO1 (C/A) and GSTO1(C/C) genotypes were increased significantly in N, A, CH, CI and HCC groups. GSTO2 (A/A) was decreased in all studied groups as compared to the C-group but GSTO2(A/G) and GSTO2(G/G) genotypes were increased significantly. In addition, GST activities, albumin and TP levels were decreased in all studied groups compared to the C-group, while the activities of transaminases were increased to differing degrees. CONCLUSIONS: The results indicate that GSTO genetic polymorphisms may be considered as biomarkers for determining and predicting the progression of HBV infection. PMID- 27221911 TI - Scabraside D Derived from Sea Cucumber Induces Apoptosis and Inhibits Metastasis via iNOS and STAT-3 Expression in Human Cholangiocarcinoma Xenografts. AB - Scabraside D, a sulfated triterpene glycoside, was extracted from the sea cucumber Holothuria scabra. It shows anti-proliferation in many of cancer cell lines, but the function and mechanisms of action of scabraside D in human cholangiocarcinoma (HuCCA) have not previously determined. In this study, we investigated the activity of scabraside D on HuCCA cell apoptosis, lymphangiogenesis and metastasis in a nude mouse model. Scabraside D induced signs of apoptosis, such as cell shrinkage, nuclear condensation, nuclear fragmentation and DNA fragmentation on TUNEL assays, while effectively decreasing expression of BCl-2 but increasing caspase-3 gene level expression. Immunohistochemistry revealed that scabraside D significantly reduced lymphatic vessel density (LVD). Moreover, scabraside D treatment significantly decreased VEGF-C, MMP-9 and uPA gene expression, which play important roles in the lymphangiogenesis and invasion of cancer cells in metastasis processes. Quantitative real-time PCR showed that scabraside D significantly decreased iNOS and STAT-3 gene expression. This study demonstrated that scabraside D plays a role in activation of HuCCA tumor apoptosis and inhibition of lymphangiogenesis, invasion and metastasis through decreasing BCl-2, MMP-9, uPA and VEGF-C and increasing caspase-3 expression by suppression of iNOS and STAT-3 expression. Therefore, scabraside D could be a promising candidate for cholangiocarcinoma treatment. PMID- 27221912 TI - Diagnosis and Monitoring of Chronic Myeloid Leukemia: Chiang Mai University Experience. AB - BACKGROUND: A diagnosis of chronic myeloid leukemia (CML) is made on discovery of the presence of a Philadelphia (Ph) chromosome. The success of the treatment of this form of leukemia with tyrosine kinase inhibitor (TKI) is monitored by reduction of the Ph chromosome. OBJECTIVE: To compare the role of conventional cytogenetic (CC) methods with a real time quantitative polymerase chain reaction (RQ-PCR) and fluorescence in situ hybridization (FISH) for diagnosis and treatment monitoring of CML patients. The secondary outcome was to analyze the treatment responses to TKI in CML patients. MATERIALS AND METHODS: This was a retrospective study of CML patients who attended the Hematology clinic at Chiang Mai University Hospital from 2005-2010. Medical records were reviewed for demographic data, risk score, treatment response and the results of CC methods, FISH and RQ-PCR. RESULTS: One hundred and twenty three cases were included in the study, 57.7% of whom were male with a mean age of 46.9 years. Most of the patients registered as intermediate to high risk on the Sokal score. At diagnosis, 121 patients were tested using the CC method and 118 (95.9%) were identified as positive. Five patients failed to be diagnosed by CC methods but were positive for BCR-ABL1 using the FISH method. Imatinib was the first-line treatment used in 120 patients (97.6%). In most patients (108 out of 122, 88.5%), a complete cytogenetic response (CCyR) was achieved after TKI therapy and in 86 patients (70.5%) CCyR was achieved long term by the CC method. Five out of the 35 analyzed patients in which CCyR was achieved by the CC method had a positive FISH result. Out of the 76 patients in which CCyR was achieved, RQ-PCR classified patients to only CCyR in 17 patients (22.4%) with a deeper major molecular response (MMR) in 4 patients (5.3%) and complete molecular response (CMR) in 55 patients (72.4%). In the case of initial therapy, CCyR was achieved in 95 patients (79.1%) who received imatinib and in both patients who received dasatinib (100%). For the second line treatment, nilotinib were used in 30 patients and in 19 of them (63.3%) CCyR was achieved. In half of the 6 patients (50%) who received dasatinib as second line or third line treatment CCyR was also achieved. CONCLUSIONS: CML patients had a good response to TKI treatment. FISH could be useful for diagnosis in cases where CC analysis failed to detect the Ph chromosome. RQ-PCR was helpful in detecting any residual disease and determining the depth of the treatment response at levels greater than the CC methods. PMID- 27221913 TI - Hepatocellular Carcinoma in a Tertiary Referral Hospital in Indonesia: Lack of Improvement of One-Year Survival Rates between 1998-1999 and 2013-2014. AB - BACKGROUND: The survival of hepatocellular carcinoma (HCC) patients is usually low due to late diagnosis. Cipto Mangunkusumo Hospital as the largest tertiary referral hospital in Indonesia, has recently improved its modalities for advanced HCC management, but there has not been any evaluation on any improvement in HCC patient survival. MATERIALS AND METHODS: A retrospective analysis on 114 HCC patients in 2013-2014 were conducted and compared with the database for 77 HCC patients in 1998-1999. Clinical characteristics and treatment received were recorded and the survival of both groups was analyzed using the Kaplan-Meier method and compared using the log-rank test. RESULTS: The percentage of HBV positive patients had increased after fifteen years from 32.5% to 67.5%. Only two patients (1.8%) in 2013-2014 were diagnosed with HCC during surveillance program. Proportions of Barcelona Clinic Liver Cancer A, B, C, and D in 2013-2014 were 1.8%, 42%, 28.1%, and 28.1%, respectively. There was an increase in the use of potentially curative treatment, such as surgical resection or combination of loco regional therapies. The one-year survival rate increased from 24.1% in 1998-1999 to 29.4% in 2013-2014, while the median survival decreased from 146 days to 138 days, but the difference was not statistically significant (p=0.913). CONCLUSIONS: There was no improvement in the median survival of HCC patients after fifteen years because most continued to present at late stages. There is an urgent need for a nationwide implementation of a hepatitis screening program and HCC surveillance education. PMID- 27221914 TI - Trend of Cancer Incidence in Nepal from 2003 to 2012. AB - Trends in cancer incidence is a key tool to identify the pattern of cancer of any country. This retrospective study was performed to present the trends of change in cancer incidence in Nepal.The total number of cancer cases in males was 26,064 while the total number of females cancer cases was 29,867 throughout the 10 years from 2003 to 2012. The cancer incidence per 100,000 in males was 12.8 in 2003 and 25.8 people in 2012. Similarly, in females, the crude incidence rate was 15.1 in 2003 and 26.7 per 100,000 in 2012. Cancer incidence was low at early age but it was increased with age in both sexes in Nepal. Lung cancer was the most common cancer in males throughout, while it was the third most common cancer in females. Cervix uteri was the most common site of cancer in females throughout the 10 years, with a clear trend for increase in breast cancer within this time. PMID- 27221915 TI - Predictive Value of Malignancy Risk Indices for Ovarian Masses in Premenopausal and Postmenopausal Women. AB - BACKGROUND: To evaluate the predictive role of a risk of malignancy index in discriminating between benign and malignant adnexal masses preoperatively. MATERIALS AND METHODS: A total of 408 patients with adnexal masses managed surgically between January 2010 and February 2014 were included. The risk of malignancy indices (RMI) 1, 2, 3 and 4 were calculated using findings for ultrasonography, menopausal status, and CA125 levels. Histopathologic results were the end point. ROC analysis was used for the sensitivity and the specificity of the models. RESULTS: Some 37.6 % of the cases were malignant in the postmenopausal group while 7.9 % were malignant in the premenopausal group. Pelvic pain was the most common complaint, and the majority of the cases were diagnosed at stage 3. The RMI 1, 2, 3 and 4 yielded percentage sensitivities of 76.1, 79.1, 76.1 and 76.1 and specificities of 91.5, 89.1, 90.6, 88.6, respectively. RMI 1 was the most reliable test in the general population according to AUC levels and Kappa statistics. From ROC analysis results of post/ premenopausal women, the RMI 1 (cut off: 200) yielded sensitivities of 84.0/60.9 and specificities of 87.7/92.5. With RMI 2 they were 88.6/60.9 and 80.0/91.0, with RMI 3 84.0/ 60.9 and 87.7/91.8, and with RMI 4 (cut off:400) 81.8/47.8 and 83.6 /44.0. Although test performance of RMI methods were good in a general population and postmenopausal women, the RMI inter-agreement validity was only moderate or fair in premenopausal women. CONCLUSIONS: Our study confirms the effectiveness of RMI algorithms in postmenopausal women. However, more sensitive tests are needed for premenopausal women. PMID- 27221916 TI - Sensitive and Noninvasive Detection of Aberrant SFRP2 and MGMT-B Methylation in Iranian Patients with Colon Polyps. AB - BACKGROUND: The pathogenesis of sporadic colorectal cancer (CRC) is influenced by the patient genetic background and environmental factors. Based on prior understanding, these are classified in two major pathways of genetic instability. Microsatellite instability (MSI) and CPG island methylator phenotype (CIMP) are categorized as features of the hypermethylated prototype, and chromosomal instability (CIN) is known to be indicative of the non-hypermethylated category. Secreted frizzled related protein 2 (SFRP2), APC1A in WNT signaling pathway and the DNA repair gene, O6-methylguanine-DNA methyltransferase (MGMT), are frequently hypermethylated in colorectal cancer. Detection of methylated DNA as a biomarker by easy and inexpensive methods might improve the quality of life of patients with CRC via early detection of cancer or a precancerous condition. AIM: To evaluate the rate of SFRP2 and MGMT hypermethylation in both polyp tissue and serum of patients in south Iran as compared with matched control normal population corresponding samples. MATERIALS AND METHODS: Methylation-specific PCR was used to detect hypermethylation in DNA extracted from 48 polypoid tissue samples and 25 healthy individuals. RESULTS: Of total polyp samples, 89.5% had at least one promoter gene hypermethylation. The most frequent methylated locus was SFRP2 followed by MGMT-B (81.2 and 66.6 percent respectively). Serologic detection of hypermethylation was 95% sensitive as compared with polyp tissue. No hypermethylation was detected in normal tissue and serum and its detection in patients with polyps, especially of serrated type, was specific. CONCLUSIONS: Serologic investigation for detection of MGMT-B, SFRP2 hypermethylation could facilitate prioritization of high risk patients for colonoscopic polyp detection and excision. PMID- 27221917 TI - Clinicopathological Profile of Breast Cancer Patients at a Tertiary Care Hospital in Marathwada Region of Westen India. AB - BACKGROUND: Breast cancer is the most prevalent malignancy among women with wide differences in clinical profile from region to region. The present study aimed to describe the profile of breast cancer patients attending a tertiary care hospital in Marathwada region of Western India. MATERIALS AND METHODS: In this descriptive retrospective study, we reviewed records of pathologically diagnosed patients of breast cancer managed at our center from years 2009 to 2015. Data with respect to demographic status, detailed past, medical, familial and personal history, findings of clinical examination and histological features were obtained. Patients were staged according to the Tumor Node Metastasis (TNM) system. RESULTS: Among 260 cases, mean age of presentation was 52.6, with average age of menarche of 11.3 and menopause of 52.6 years. The majority of patients were from urban regions and were postmenopausal (64.3%). Main clinical features presentation were breast lumps. Most patients were in stage II and had infiltrating duct carcinomas. CONCLUSIONS: Most common risk factors for breast cancer observed are increasing age, low parity and obesity. Breast cancer was more prevalent among postmenopausal women presenting in stage II with infiltating duct carcinoma in our region of India. PMID- 27221918 TI - Prediction and Analysis of Breast Cancer Related Deleterious Non-Synonymous Single Nucleotide Polymorphisms in the PTEN Gene. AB - One of the most common cancer types faced by the women around the world is breast cancer. Among the several low, moderate and high penetrance genes conferring susceptibility to breast cancer, PTEN is one which is known to be mutated in many tumor types. In this study, we predicted and analyzed the impact of three deleterious coding non-synonymous single nucleotide polymorphisms rs121909218 (G129E), rs121909229 (R130Q) and rs57374291 (D107N) in the PTEN gene on the phenotype of breast tumors using computational tools SIFT, Polyphen-2, PROVEAN, MUPro, POPMusic and the GETAREA server. PMID- 27221919 TI - Surveillance of Populations at Risk of Cholangiocarcinoma Development in Rural Communities of Thailand Using the Korat-CCA Verbal Screening Test. AB - Cholangiocarcinoma (CCA) is a serious problem in Thailand, particularly in the northeastern region. Active surveillance in rural communities with an appropriat low-cost screening tool is required to facilitate early detection. Therefore, this study aimed to investigate the population at risk of CCA in Bua Yai district, Nakhon Ratchasima province, Northeastern Thailand using the Korat-CCA verbal screening test (KCVST) during June to October 2015. Reliability of KCVST demonstrated a Cronbach alpha coefficient=0.75 Stepwise-multiple regression showed that alcohol consumption was important for CCA screened, followed by agriculture and pesticide use, under-cooked cyprinoid fish consumption, praziquantel use, naive northeastern people, opisthorchiasis, family relatives with CCA, and cholangitis or cholecystitis or gallstones, respectively. Population at risk for CCA was classified to low risk (63.4%), moderate risk (33.7%), and high risk (1.32%) for CCA. When CCA was screened using ultrasonography, 4 of 32 high risk participants had an abnormal biliary tract with dilated bile ducts. This study indicates that KCVST is a potential useful too which decrease the cost of large scale CCA screening. PMID- 27221920 TI - Post-Loop Electrosurgical Excision Procedure Complications in Srinagarind Hospital. AB - The purpose of this study was to evaluate the prevalence and predictors of post Loop Electrosurgical Excision Procedure (LEEP) complications in Srinagarind Hospital, Khon Kaen, Thailand. Retrospective chart review was performed for 200 patients undergoing LEEP during January 2012 to February 2013. Their mean age was 45 years-old. Fifty-three (26.5%) were menopausal. The three most common preceding abnormal cervical cytology were high-grade squamous intraepithelial lesion (HSIL; 50%), atypical squamous cell cannot exclude HSIL (ASC-H; 10.5%), and low-grade squamous intraepithelial lesion (LSIL; 10%). The overall complications prevalence rate was 16.5% (95%CI, 11.4-21.6). Complications included bleeding (11%; 95%CI, 6.66-15.3), offensive discharge (4%; 95%CI, 1.28 6.72), and pelvic inflammatory disease (1.5%; 95%CI, 0.18-3.18). Only mode of delivery was an independent predictor of post-LEEP complications. Women with previous caesarean sections carried an increased risk of complications by 3.9 times (95%CI, 1.21-12.56) compared with vaginal delivery. In conclusion, LEEP is generally safe with an acceptable complication rate. Previous caesarean section was the only independent predictor for post-LEEP complications. However, this predictor still needs prudent evaluation as no clear cause-effect relationship was identified. PMID- 27221921 TI - VEGFR2 Expression in Head and Neck Squamous Cell Carcinoma Cancer Cells Mediates Proliferation and Invasion. AB - Vascular endothelial growth factor 2 (VEGFR2) was initially identified as a receptor of VEGF on endothelial cells with a role in regulating angiogenesis during organism development and tumorigenesis. Previously, in cancer tissue, VEGFR2 has been reported to be expressed in endothelial cells. In our research, we found that VEGFR2 was expressed not only in endothelial cells but also cancer cells in head and neck squamous cell carcinomas (HNSCCs). Knockdown of VEGFR2 in Hep2 cells could arrest the cell cycle in G0/G1, leading to a decrease in proliferation. We also present evidence that MAPK/ERK signal pathways and expression of CDK1 downstream of VEGFR2 might regulate proliferation and cell cycle arrest. Furthermore, we discovered that down-regulate VEGRF2 in Hep2 cells could significantly affect the invasion ability. Taken together, our data suggest that VEGFR2 might regulate proliferation and invasion in HNSCC cancer cells in vivo. PMID- 27221922 TI - Survival Rates for Breast Cancer in Iranian Patients: a Meta- Analysis. AB - BACKGROUND: Breast cancer is the most common cancer among Iranian women. Since development of the disease in Iranian women occurs relatively early, the survival rate matters considerably. In different countries, survival of breast cancer patients varies considerably. Therefore, the one-year, three-year, five-year, and ten- year survival rates for breast cancer in Iran were assessed using a meta analysis. MATERIALS AND METHODS: This systematic review and meta-analysis was based on valid Iranian sources including SID, MAGIRAN and IRANMEDEX, along with reliable English databases, namely, PUBMED and SCOPUS. In domestic databases, a search was conducted based on key words of breast cancer and survival rate, and in international databases, with "breast cancer" and the equivalent of "neoplasm" of Mesh Word, "survival rate" and "Iran. " Then all reviewed papers and theses which met the inclusion criteria were selected for investigation. To conduct the analysis STATA 11.2 software and random-effects models were used. RESULTS: In 24 studies, 22,745 participants were included. The one-year, three-year, five-year and ten-year survival rates were 0.956, 0.808, 0.695 and 0.559, respectively. The minimum and maximum survival rates for 5-years were 0.48 and 0.87. The average age of the onset of the disease was 48.3. CONCLUSIONS: As in Iran, since the onset of the disease is at low age, in spite of the relatively high survival rate as compared to other cancers, prevention and screening programs at early age for early stage diagnosis seems necessary. PMID- 27221923 TI - Is Health Locus of Control a Modifying Factor in the Health Belief Model for Prediction of Breast Self-Examination? AB - BACKGROUND: Breast cancer is one of the most common cancers among women in the world. Early detection is necessary to improve outcomes and decrease related costs. The aim of this study was to assess the predictive power of health locus of control as a modifying factor in the Health Belief Model (HBM) for prediction of breast self-examination. MATERIALS AND METHODS: In this cross- sectional study, 400 women selected through the convenience sampling from health centers. Data were collected using part of the Champion's HBM scale (CHBMS), the Health Locus of Control Scale and a self administered questionnaire. For data analysis by SPSS the independent T test, Chi square test, logistic and linear regression modes were appliedl. RESULTS: The results showed that 10.9% of the participants reported performing BSE regularly. Health locus of control did not act as a predictor of BSE as a modifying factor. In this study, perceived self-efficacy was the strongest predictor of BSE performance (Exp (B) =1.863) with direct effect, while awareness had direct and indirect influence. CONCLUSIONS: For increasing BSE, improvement of self-efficacy especially in young women and increasing knowledge about cancer is necessary. PMID- 27221924 TI - Preventive Effects of Spirogyra neglecta and a Polysaccharide Extract against Dextran Sodium Sulfate Induced Colitis in Mice. AB - Ulcerative colitis (UC) results from colonic epithelial barrier defects and impaired mucosal immune responses. In this study, we aimed to investigate the modifying effects of a Spirogyra neglecta extract (SNE), a polysaccharide extract (PE) and a chloroform fraction (CF) on dextran sodium sulfate (DSS)-induced colitis in mice and to determine the mechanisms. To induce colitis, ICR mice received 3% DSS in their drinking water for 7 days. Seven days preceding the DSS treatment, oral administration of SNE, PE and CF at doses of 50, 25 and 0.25 mg/kg body weight (low dose), 200, 100 and 1 mg/kg body weight (high dose) and vehicle was started and continued for 14 days. Histologic findings showed that DSS-induced damage of colonic epithelial structure and inflammation was attenuated in mice pre-treated with SNE, PE and CF. Furthermore, SNE and PE significantly protected colonic epithelial cells from DSS-induced cell cycle arrest, while SNE, PE and CF significantly diminished apoptosis. Proteome analysis demonstrated that SNE and PE might ameliorate DSS-induced colitis by inducing antioxidant enzymes, restoring impaired mitochondria function, and regulating inflammatory cytokines, proliferation and apoptosis. These results suggest that SNE and PE could prevent DSS-induced colitis in ICR mice by protection against and/or aiding recovery from damage to the colonic epithelium, reducing ROS and maintaining normal mitochondrial function and apoptosis. PMID- 27221925 TI - I Do Not Even Say "It" - a Mixed Methods Study on Breast Cancer Awareness of Omani Women. AB - BACKGROUND: The incidence of breast cancer is rising in Oman, and the disease is diagnosed at late stages, when treatment success is limited. Omani women might benefit from better awareness, so that breast cancer can be detected early and treated. This study was conducted to assess Omani women's levels of breast cancer awareness and early detection practice, and explore factors which might influence these levels. MATERIALS AND METHODS: A mixed methods study was conducted in 2014, including a quantitative survey of 1,372 and a qualitative assessment of 19 Omani women, aged >=20 years from five Omani governorates using convenient sampling. Demographic information and scores for awareness levels were used in a multivariate regression model to investigate factors associated with awareness. Thematic analysis and interpretive description were used to analyse the qualitative data. RESULTS: The overall means for early detection and general awareness scores were 0.58 (SD 0.24) and 0.46 (SD 0.21), respectively. General awareness was significantly associated with age, education, income and familiarity with cancer patients (<0.05), while early detection was significantly associated with age, marital status and education. A majority of women (59.5%) agreed with a belief in 'evil eye' or envy as a risk factor for breast cancer. Women discussed various factors which may empower or inhibit awareness, including the cultural-religion-fatalistic system, personal-familial-environmental system, and healthcare-political-social system. CONCLUSIONS: The overall low scores for awareness and early detection, and the survey of local beliefs highlight a severe necessity for a contextually-tailored breast cancer awareness intervention programme in Oman. PMID- 27221926 TI - Incidentally Detected Adenocarcinoma Prostate in Transurethral Resection of Prostate Specimens: a Hospital Based Study from India. AB - BACKGROUND: Awareness about prostate cancer has increased in the community, and prostate cancer screening examinations, including prostate specific antigen (PSA) assays, are now widely available. Prior to the PSA era, up to 27% of prostate cancers were detected incidentally at the time of transurethral resection of prostate (TURP). After PSA testing became widely available, the incidence of incidentally detected carcinoma prostate in TURP specimens without prior diagnosis reduced to 5-13%. However, the incidence of incidentally detected carcinoma prostate has been reported to vary across the globe since various factors can influence the identification of this malignancy in TURP specimens. In this paper, we focus on rates of incidentally detected prostate cancer in TURP specimens in our hospital and correlate it with various parameters. MATERIALS AND METHODS: This retrospective study of histopathological findings of biopsy specimens was conducted for patients undergoing TURP during a period of 5 years from April 2010. The inclusion criteria were patients diagnosed with benign prostatic hyperplasia (BPH) (digital rectal examination (DRE) not showing any abnormally hard areas and normal age adjusted PSA values). Patients with elevated PSA, abnormal DRE, documented urinary tract infection and proved adenocarcinoma prostate (CaP) were excluded from the study. The total weight of prostatectomy specimen, occurrence of carcinoma prostate in the chips, percentage of total tissue resected showing malignancy and Gleason's scores were recorded. RESULTS: A total of 597 patients belonging to the inclusion criteria were studied. The incidence of occult CaP in the study group was 5.2 % (31/597). Out of these, 8 belonged to T1a and 23 belonged to T1b stages. The age group 70 - 79 years had the maximum incidence of occult CaP. It was observed that the clinical grading of prostate did not have a bearing on the incidence of occult CaP whereas the weight of resected specimen correlated with the incidence of CaP. The incidence of occult CaP was greater with low volume prostates (<20 g). (P=0.15). CONCLUSIONS: The rate of incidentally detected adenocarcinoma prostate in patients undergoing TURP for clinically diagnosed BPH was found to be only 5.2 % in our study which is low when compared with similar studies done elsewhere. The age of the patient and weight of the resected specimen correlated with incidence of occult prostate cancer. The clinical grading of prostate by DRE however, demonstrated no correlation. PMID- 27221927 TI - Relation between Mammographic Parenchymal Patterns and Breast Cancer Risk: Considering BMI, Compressed Breast Thickness and Age of Women in Tabriz, Iran. AB - BACKGROUND: Mammographic density determined according paranchymal patterns is a risk factor for breast cancer and its relationships with body and other breast characteristics of women is important. The purpose of the present study was to correlate breast parenchymal patterns and mammography abnormality findings with women's BMI, compressed breast thickness (CBT) and age in Tabriz city, Iran. MATERIALS AND METHODS: From 1,100 mammograms interpreted by radiologists, breast parenchymal was classified into four categories from Types 1 (mostly fatty) through 4 (mostly fibroglandular tissue). Age, BMI, and CBT were recorded and their relation with risk for the development of breast abnormalities in mammograms was analyzed. RESULTS: In women with a mean age of 45.8+/-8.63 years 17.7% were in the high density group (Type 3 and 4). A comparison of four types of breast paranchymal with BMI, CBT and age showed inverse relations to breast density. Abnormal mammographic findings were 25.8% of all reported mammograms with a circular mass (12.7%) as the most common abnormality. About 21% abnormal cases were in less than 40 years. Increasing of BMI had significant relation with breast abnormality but in CBT was not observed. CONCLUSIONS: Measurement of women's body characteristics is useful for assistance in mammography diagnosis as well as selection of imaging instrument by high sensitivity for following patient in future. The effects of age, CBT and BMI groups on the breast paranchymal were significant. PMID- 27221928 TI - The rs61764370 Functional Variant in the KRAS Oncogene is Associated with Chronic Myeloid Leukemia Risk in Women. AB - BACKGROUND: Chronic myeloid leukemia (CML) is one of the most frequent hematopoietic malignancies in the elderly population; however, knowledge is limited regarding the genetic factors associated with increased risk for CML. Polymorphisms affecting microRNA (miRNA) biogenesis or mRNA:miRNA interactions are important risk factors in the development of different types of cancer. Thus, we carried out a case-control study to test the association with CML susceptibility of gene variants located in the miRNA machinery genes AGO1 (rs636832) and GEMIN4 (rs2740348), as well as in the miRNA binding sites of the genes BRCA1 (rs799917) and KRAS (rs61764370). MATERIALS AND METHODS: We determined the genotype of 781 Mexican-Mestizo individuals (469 healthy subjects and 312 CML cases) for the four polymorphisms using TaqMan probes to test the association with CML susceptibility. RESULTS: We found a borderline association of the minor homozygote genotype of the KRAS_rs61764370 polymorphism with an increased risk for CML susceptibility (P = 0.06). After gender stratification, this association was significant only for women (odds ratio [OR] = 13.41, P = 0.04). The distribution of the allelic and genotypic frequencies of the four studied SNPs was neither associated with advanced phases of CML nor treatment response. CONCLUSIONS: To the best of our knowledge, this study is the first to show a significant association of the KRAS_rs61764370 SNP with CML. To further determine such an association of with CML susceptibility, our results must be replicated in different ethnic groups. PMID- 27221929 TI - 5-Aminolevulinic Acid Fluorescence in Detection of Peritoneal Metastases. AB - BACKGROUND: The value of 5-aminolevulinic acid (ALA) in fluorescence detection of peritoneal metastases and the underlying mechanisms were evaluated in patients with peritoneal surface malignancies. MATERIALS AND METHODS: Oral 5-ALA was administered at a concentration of 20 mg /kg body weight with 50 ml of water 2 hours prior to surgery (n=115). The diagnostic value of 5-ALA based fluorescence production was evaluated following white light inspection during prior to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Then, peptide transporter PEPT1 (ALA influx transporter) and ATP-binding cassette transporter ABCG2 (porphyrin efflux transporter) gene expression was determined with quantitative real time (qRT)-PCR and pathological diagnoses confirmed for all tissue samples. RESULTS: The 5-ALA based photodynamic detection rate was 17% for appendiceal mucinous neoplasms, 54% for colorectal cancers, 33% for gastric cancers, 67% for diffuse malign peritoneal mesotheliomas, and 89% for epithelial ovarian cancer of peritoneal metastases. 5-ALA was detected in all cases of peritoneal metastases originating from cholangiocarcinomas whereas it was not able to detect any in granulosa cell and gastrointestinal stromal tumor cases. Furthermore, PEPT1 was overexpressed whereas ABCG2 expression was downregulated in tumors detected with fluorescence. CONCLUSIONS: 5-ALA provided 100% specificity and high sensitivity to detect peritoneal metastases in subgroups of patients with peritoneal surface mailgnancies. ALA influx transporter PEPT1 and porphyrin efflux transporter ABCG2 genes are important in tumor specific 5-ALA induced fluorescence in vivo. Further studies should clarify diagnostic utility of 5-ALA in peritoneal surface malignancies. PMID- 27221930 TI - Formulation and Cytotoxicity of Ribosome-Inactivating Protein Mirabilis Jalapa L. Nanoparticles Using Alginate-Low Viscosity Chitosan Conjugated with Anti-Epcam Antibodies in the T47D Breast Cancer Cell Line. AB - Ribosome-inactivating protein (RIP) from Mirabilis jalapa L. leaves has cytotoxic effects on breast cancer cell lines but is less toxic towards normal cells. However, it can easily be degraded after administration so it needs to be formulated into nanoparticles to increase its resistance to enzymatic degradation. The objectives of this study were to develop a protein extract of M. jalapa L. leaves (RIP-MJ) incorporated into nanoparticles conjugated with Anti EpCAM antibodies, and to determine its cytotoxicity and selectivity in the T47D breast cancer cell line. RIP-MJ was extracted from red-flowered M. jalapa L. leaves. Nanoparticles were formulated based on polyelectrolyte complexation using low viscosity chitosan and alginate, then chemically conjugated with anti-EpCAM antibody using EDAC based on carbodiimide reaction. RIP-MJ nanoparticles were characterised for the particle size, polydispersity index, zeta potential, particle morphology, and entrapment efficiency. The cytotoxicity of RIP-MJ nanoparticles against T47D and Vero cells was then determined with MTT assay. The optimal formula of RIP-MJ nanoparticles was obtained at the concentration of RIP MJ, low viscosity chitosan and alginate respectively 0.05%, 1%, and 0.4% (m/v). RIP-MJ nanoparticles are hexagonal with high entrapment efficiency of 98.6%, average size of 130.7 nm, polydispersity index of 0.380 and zeta potential +26.33 mV. The IC50 values of both anti-EpCAM-conjugated and non-conjugated RIP-MJ nanoparticles for T47D cells (13.3 and 14.9 MUg/mL) were lower than for Vero cells (27.8 and 33.6 MUg/mL). The IC50 values of conjugated and non- conjugated RIP-MJ for both cells were much lower than IC50 values of non-formulated RIP-MJ (>500 MUg/mL). PMID- 27221931 TI - Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma: Is It Different between Over and Under 50 Years of Age? AB - BACKGROUND: Epstein-Barr virus (EBV) positive diffuse large B-cell lymphoma (DLBCL) of the elderly is an entity introduced in the latest WHO classification of lymphoid tumors and defined in patients older than 50 years without prior lymphoma or immunodeficiency. However, recently it has also been seen in patients under 50. There is thus debate as to whether these are separate entities. MATERIALS AND METHODS: In this retrospective study, we analyzed de novo DLBCL admitted to our institute over a period of two years. Clinical data included age, sex, nodal and extranodal presentation. The results of an immunohistochemistry (IHC) panel were also reviewed. IHC findings were mainly used to sub-classify DLBCL as germinal center vs. non germinal center types. IHC for identification of LMP-1 (latent membrane protein) and in situ hybridization for detection of EBV- encoded RNA (EBER) was performed. EBV prevalence, clinical data and IHC findings were compared between patients under and over 50 years of age. RESULTS: Out of 95 DLBCL, 11.6% were EBV positive (7.5% and 14.5% in the young and old groups). We did not find any significant differences in IHC subclasses and clinical data between EBV positive DLBCL (EBV+DLBCL) of young and old groups. CONCLUSIONS: EBV+DLBCL are not exclusive to patients older than 50 years. With regard to clinical data as well as IHC subclasses, no differences were evident between EBV+DLBCL of young and old groups. Our suggestion is to eliminate any cut off age for EBV+DLBCL. PMID- 27221932 TI - Virtual Screening Approaches in Identification of Bioactive Compounds Akin to Delphinidin as Potential HER2 Inhibitors for the Treatment of Breast Cancer. AB - Small molecule tyrosine kinase inhibitors targeting HER 2 receptors have emerged as an important therapeutic approach in inhibition of downstream proliferation and survival signals for the treatment of breast cancers. Recent drug discovery efforts have demonstrated that naturally occurring polyphenolic compounds like delphinidin have potential to inhibit proliferation and promote apoptosis of breast cancer cells by targeting HER2 receptors. While delphinidin may thus reduce tumour size, it is associated with serious side effects like dysphonia. Owing to the narrow therapeutic window of delphinidin, the present study aimed to identify high affinity compounds targeting HER2 with safer pharmacological profiles than delphinidin through virtual screening approaches. Delphinidin served as the query parent for identification of structurally similar compounds by Tanimoto-based similarity searching with a threshold of 95% against the PubChem database. The compounds retrieved were further subjected to Lipinski and Verber's filters to obtain drug like agents, then further filtered by diversity based screens with a cut off of 0.6. The compound with Pubchem ID: 91596862 was identified to have higher affinity than its parent. In addition it also proved to be non-toxic with a better ADMET profile and higher kinase activity. The compound identified in the study can be put to further in vitro drug testing to complement the present study. PMID- 27221933 TI - Interferon Induced Transmembrane Protein-1 Gene Expression as a Biomarker for Early Detection of Invasive Potential of Oral Squamous Cell Carcinomas. AB - BACKGROUND: Early detection of malignant transformation with expression biomarkers has significant potential to improve the survival rate of patients as such biomarkers enable prediction of progression and assess sensitivity to chemotherapy. The expression of interferon inducible transmembrane protein 1 (IFITM1) has been associated with early invasion events in several carcinomas, including head and neck cancers, and hence has been proposed as a novel candidate biomarker. As the incidence of oral squamous cell carcinoma (OSCC) is highest in the Indian population, we sought to investigate: 1) the expression pattern of IFITM1 in OSCC tissue samples obtained from Indian patients of Dravidian origin; and 2) the possibility of using IFITM1 expression as a potential biomarker. MATERIALS AND METHODS: Total RNA extracted from thirty eight OSCC biopsy samples was subjected to semi-quantitative RT-PCR with IFITM1 and GAPDH specific primers. RESULTS: Of the thirty eight OSCC samples that were analyzed, IFITM1 overexpression was identified in fifteen (39%). Seven expressed a low level, while the remainder expressed high level of IFITM1. CONCLUSIONS: The overexpression of IFITM1 in OSCC samples indicates that IFITM1 may be explored for the possibility of use as a high confidence diagnostic biomarker in oral cancers. To the best of our knowledge, this is the first time that IFITM1 overexpression is being reported in Indian OSCC samples. PMID- 27221934 TI - Are Biomarkers Predictive of Anthracycline-Induced Cardiac Dysfunction? AB - BACKGROUND: The early detection of anthracycline- induced cardiotoxicity is very important since it might be useful in prevention of cardiac decompensation. This study was designed with the intent of assessing the usefulness of cardiac troponin T (cTnT) and NT- Pro BNP estimation in early prediction of anthracycline induced cardiotoxicity. MATERIALS AND METHODS: In this prospective study histologically proven breast cancer patients who were scheduled to receive anthracycline containing combination chemotherapy as a part of multimodality treatment were enrolled. Baseline cardiac evaluation was performed by echocardiography (ECHO) and biomarkers like cardiac troponin T (cTnT) and N terminal- pro brain natriuretic peptide (NT- Pro BNP). All patients underwent cTnT and NT- Pro BNP estimation within 24 hours of each cycle of chemotherapy and were followed up after 6 months of initiation of chemotherapy. Any changes in follow up ECHO were compared to ECHO at baseline and cTnT and NT- Pro BNP levels after each cycle of anthracycline-based chemotherapy. RESULTS: Initial data were obtained for 33 patients. Mean change in left ventricular diastolic diameter (LVDD) within 6 months was 0.154+/- 0 .433 cms (p value=0.049). Seven out of 33 patients had an increase in biomarker cTnT levels (p value=0.5). A significant change in baseline and follow up LVDD was observed in patients with raised cTnT levels (p value=0.026) whereas no change was seen in ejection fraction (EF) and left atrial diameters (LAD) within 6 months of chemotherapy. NT- Pro BNP levels increased in significant number of patients (p value <=0.0001) but no statistically significant change was observed in the ECHO parameters within 6 months. CONCLUSIONS: Functional monitoring is a poorly effective method in early estimation of anthracycline induced cardiac dysfunction. Estimation of biomarkers after chemotherapy may allow stratification of patients in various risk groups, thereby opening window for interventional strategies in order to prevent permanent damage to the myocardium. PMID- 27221935 TI - Acute Lymphoblastic Leukemia in Adults - an Analysis of 51 Cases from a Tertiary Care Center in Pakistan. AB - BACKGROUND: Acute lymphoblastic leukemia (ALL) is a malignant disease in which early lymphoid precursors proliferate and replace the normal hematopoiesis. It has distinctive clinical and biological features. In respect to adult ALL, available data from Pakistan are limited. Therefore we reviewed the demographical and clinico- hematological profiles along with FAB stratification of adult patients with ALL presented at our hospital. MATERIALS AND METHODS: In this cross sectional study, 51 adults (>=15 years) patients with ALL were enrolled from January 2010 to December 2014. RESULTS: The mean age was 23.8+/-12.9 years with the median age of 18.0 years. The male to female ratio was 2:1. The major complaints were fever (60.7%), generalized weakness (47.0%), overt bleeding (19.6%) and weight loss (13.7%). Physical examination revealed lymphodenopathy as a predominant finding detected in 43.1% followed by splenomegaly and hepatomegaly in 23.5% and 21.5%, respectively. The mean hemoglobin level was 9.0+/-2.75g/dl with a mean MCV of 82.2+/-15.4 fl, a mean total leukocyte count of 31.1+/ 64.0x109/l, a mean ANC of 2.1+/-3.0 x109/l and a mean platelet count of 71.7+/ 85.7x109/l. According to FAB classification, 47.1% were L1 type, 45.1% L2 and 7.8% L3 variant. CONCLUSIONS: Clinico-pathological features appeared comparable to published data. Febrile illness associated with lymphodenopathy was the commonest presentation. FAB classification revealed a predominance of ALL-L1 variant in Pakistani adult patients with ALL. PMID- 27221936 TI - Reversal of Multidrug Resistance and Computational Studies of Pistagremic Acid Isolated from Pistacia integerrima. AB - Pistagremic acid (PA) is a bioactive triterpenoid isolated from various parts of Pistacia integerrima plants. The aim of this research was to investigate PA for reversion of multidrug resistant (MDR) mediated by P-glycoprotein using rhodamine 123 exclusion study on a multidrug resistant human ABCB1 (ATP-binding cassette, sub-family B, member 1) gene-transfected mouse T-lymphoma cell line in vitro. Results were similar to those with verapamil as a positive control. Docking studies of PA and standard Rhodamine123 were carried out against a P-gp crystal structure which showed satisfactory results. Actually, PA cannot bind exactly where co-crystallized ligand of P-gp is already present. However, the docking study predicted that if a compound gives a lesser score then it may have some potency. The docking scores of PA and Rhodamine were similar. Therefore, we can conclude that there are certain important chemical features of PA which are responsible for the inhibiting potency of P-gp. PMID- 27221937 TI - Influence of Religious Beliefs on the Health of Cancer Patients. AB - BACKGROUND: This study investigated the influence of religious beliefs on the health of cancer patients and identified the factors contributing to the influence. MATERIALS AND METHODS: A questionnaire survey was conducted using a convenient sampling method. A structured questionnaire was used to the samplings, and the data of 200 cancer patients were collected. RESULTS: The effects of religion on the health of cancer patients achieved an average score of 3.58. The top five effects are presented as follows: (a) Religion provides me with mental support and strength, (b) religion enables me to gain confidence in health recovery, (c) religion motivates me to cope with disease-related stress positively and optimistically, (d) religion helps me reduce anxiety, and (e) religion gives me courage to face uncertainties regarding disease progression. Moreover, among the demographic variables, gender, type of religion, and experience of religious miracles contributed to the significantly different effects of religion on patients. Specifically, the effect of religion on the health of patients who were female and Christian and had miracle experiences was significantly (< .01) higher than that on other patients. CONCLUSIONS: These results are helpful in understanding the influence of religious beliefs on the health of cancer patients and identified the factors contributing to the influence. The result can serve as a reference for nursing education and clinical nursing practice. PMID- 27221938 TI - Lack of Variation in Inflammatory Hematological Parameters between Benign Nodular Goiter and Papillary Thyroid Cancer. AB - BACKGROUND: Inflammatory hematological parameters like the neutrophil/lymphocyte (N/L) ratio have been investigated in many cancer types and significant relationships found with prognosis, for example. The aim of this present study was to investigate the impact of hematological parameters notably on N/L ratio and mean platelet volume (MPV) in papillary thyroid cancer cases. MATERIALS AND METHODS: A total of 79 patients who underwent a thyroidectomy operation in Findikli, Goiter Research and Treatment Center during 2011- 2015 period were enrolled in the study, 41 with papillary thyroid cancer and 38 with benign goiter confirmed by pathological examination. We collected clinical and laboratory data for the patients from hospital records retrospectively. Blood samples taken at admission were assessed for parameters compared between the groups. RESULTS: No significant differences between papillary thyroid cancer and benign goiter groups were apparent in terms of age, the N/L ratio, MPV, white blood cell count (WBC), red blood cell count (RBC), hemoglobin, hematocrit, platelet, neutrophil, lymphocyte, red blood cell distribution width (RDW) and platelet crit (PCT) levels (>0.05). Only the level of platelet distribution width (PDW) significantly differed, being lower in the papillary cancer group (<0.05). CONCLUSIONS: No significant relationship between papillary thyroid cancer and inflammatory hematological parameters including in particular the N/L ratio and MPV. The relevance of the PDW values remains unclear. PMID- 27221939 TI - Randomized-Control Screening Trials to Lower Gall Bladder Cancer Mortality in High Risk Populations. AB - Gall bladder cancer is generally fatal. The high morbidity and mortality due to gall bladder cancer exerts a significant impact on efforts towards cancer control in high risk populations of the World and a rationale program for control of gall bladder cancer mortality has remained as an unmet need in these populations. Currently there are no effective strategies for controlling gall bladder cancer mortality. This mini review is to highlight the need and feasibility for secondary prevention of gall bladder cancer by screening in high risk populations. A way forward is to assess the role of secondary prevention of gall bladder cancers by conducting randomized- controlled screening trials in high risk populations. PMID- 27221940 TI - Prescription Errors with Chemotherapy: Quality Improvement through Standardized Order Templates. AB - BACKGROUND: Despite the existence of established guidelines advocating the use and value of chemotherapy order templates, chemotherapy orders are still handwritten in many hospitals in Lebanon. This manuscript describes the implementation of standardized chemotherapy order templates (COT) in a Lebanese tertiary teaching hospital through multiple steps. INITIAL ASSESSMENT: An initial assessment was conducted through a retrospective appraisal of completeness of handwritten chemotherapy orders for 100 adult patients to serve as a baseline for the project and identify parameters that might afford improvement. CHOICE OF SOLUTION: Development of over 300 standardized pre-printed COTs based on the National Comprehensive Cancer Network templates and adapted to the practice culture and patient population. IMPLEMENTATION: The COTs were implemented, using Kotter's 8-step model for leading change, by engaging health care providers, and identifying and removing barriers. EVALUATION: Assessment of physicians' compliance with the new practice (122 orders assessed) was completed through two phases and allowed for the identification of areas of improvement. LESSONS LEARNED: Overall, COT implementation showed an average improvement in order completion from 49.5% (handwritten orders) to 77.6% (phase 1-COT) to 87.6% (phase 2-COT) reflecting an increase of 38.1% between baseline and phase 2 and demonstrating that chemotherapy orders completeness was improved by pre-printed COT. As many of the hospitals in Lebanon are moving towards standardized COTs and computerized physician order entry (CPOE) in the next few years, this study provides a prototype for the successful implementation of COT and demonstrates their role in promoting quality improvement of cancer care. PMID- 27221941 TI - Educational Utilization of Microsoft Powerpoint for Oral and Maxillofacial Cancer Presentations. AB - Electronic presentations have become useful tools for surgeons, other clinicians and patients, facilitating medical and legal support and scientific research. Microsoft(r) PowerPoint is by far and away the most commonly used computer-based presentation package. Setting up surgical clinical cases with PowerPoint makes it easy to register and follow patients for the purpose of discussion of treatment plan or scientific presentations. It facilitates communication between professionals, supervising clinical cases and teaching. It is often useful to create a template to standardize the presentation, offered by the software through the slide master. The purpose of this paper was to show a simple and practical method for creating a Microsoft(r) PowerPoint template for use in presentations concerning oral and maxillofacial cancer. PMID- 27221942 TI - Does Indian Myelodysplastic Syndrome Have a Biology Different from That in the West ? AB - abstract. PMID- 27221943 TI - Outcome of Inversion 16 in TKD Positive and Negative Acute Myeloid Leukemia Patients. AB - abstract. PMID- 27221944 TI - Tobacco Control in India - Just a Legislative Measure? AB - abstract. PMID- 27221945 TI - Sharon Whelan. AB - abstract. PMID- 27221946 TI - Alteration of Leptin and Adiponectin in Multistep Colorectal Tumorigenesis. AB - BACKGROUND: There is an established link between obesity related metabolic derangement and colorectal cancer development. Recently, we developed a metabolic colorectal cancer risk score. In this follow-up study, we studied its association with colorectal neoplasm by measuring two major metabolic syndrome biomarkers, leptin and adiponectin. OBJECTIVES: To evaluate the serum levels of leptin and adiponectin in patients with colorectal polyps and colorectal cancer and to determine any correlation with metabolic risk score. RESULTS: In total, 130 individuals were studied: 30 controls without colonic pathology, 18 with colonic adenoma (CAP), and 82 with colorectal adenocarcinoma (CRC, 17 cases of T1-2 and 65 cases of T3-4). The metabolic risk scores in CAP and T1-2 CRC were higher than those in the controls and T3-4 CRC cases. There were no statistically significant differences in leptin levels among CAPs, CRCs, and controls. Both leptin and adiponectin levels reflected differences in body mass index and metabolic risk scores. Cases in the CAP group and early T-stage CRC groups had lower adiponectin levels (14.03 and 13.01 mg/ml, respectively) than the no polyps group (19.5mg/ml, p = 0.03). The average serum adiponectin level in the invasive cancer group (18.5 ng/ml) was comparable with that of the control group. CONCLUSIONS: The level of serum adiponectin was positively correlated with the metabolic risk score. Decreased serum adiponectin was significantly associated with the development of colorectal adenoma and early stage colorectal carcinoma. PMID- 27221947 TI - Resolving metal-molecule interfaces at single-molecule junctions. AB - Electronic and structural detail at the electrode-molecule interface have a significant influence on charge transport across molecular junctions. Despite the decisive role of the metal-molecule interface, a complete electronic and structural characterization of the interface remains a challenge. This is in no small part due to current experimental limitations. Here, we present a comprehensive approach to obtain a detailed description of the metal-molecule interface in single-molecule junctions, based on current-voltage (I-V) measurements. Contrary to conventional conductance studies, this I-V approach provides a correlated statistical description of both, the degree of electronic coupling across the metal-molecule interface, and the energy alignment between the conduction orbital and the Fermi level of the electrode. This exhaustive statistical approach was employed to study single-molecule junctions of 1,4 benzenediamine (BDA), 1,4-butanediamine (C4DA), and 1,4-benzenedithiol (BDT). A single interfacial configuration was observed for both BDA and C4DA junctions, while three different interfacial arrangements were resolved for BDT. This multiplicity is due to different molecular adsorption sites on the Au surface namely on-top, hollow, and bridge. Furthermore, C4DA junctions present a fluctuating I-V curve arising from the greater conformational freedom of the saturated alkyl chain, in sharp contrast with the rigid aromatic backbone of both BDA and BDT. PMID- 27221948 TI - Electrochemical and photophysical behavior of 1-naphthol in benzyl-n hexadecyldimethylammonium 1,4-bis(2-ethylhexyl)sulfosuccinate large unilamellar vesicles. AB - In the present contribution, 1-naphthol is investigated in large unilamellar vesicles formed from a new catanionic surfactant, benzyl-n hexadecyldimethylammonium 1,4-bis(2-ethylhexyl)sulfosuccinate, by electrochemical and spectroscopic techniques. The electrochemical results show that 1-naphthol experiences a partition process between the water phase and the large unilamellar vesicle bilayer phase, which is corroborated by absorption spectroscopic studies at pH = 6.40 and pH = 10.75. Interestingly, studies of 1-naphthol emission in benzyl-n-hexadecyldimethylammonium 1,4-bis(2-ethylhexyl)sulfosuccinate large unilamellar vesicles at pH = 10.75 and in sodium 1,4-bis(2 ethylhexyl)sulfosuccinate water solution show that when the 1,4-bis(2 ethylhexyl)sulfosuccinate moiety is part of the bilayer, the 1,4-bis(2 ethylhexyl)sulfosuccinate polar head interacts strongly with 1-naphthol, by favoring emission from the excited neutral species resulting in the appearance of a new band close to lambda = 355 nm. It seems that the large unilamellar vesicle bilayer of the catanionic vesicle slows down the proton transfer process observed in water, where only emission from 1-naphtholate is detected. PMID- 27221949 TI - Metals content of Glossoscolex paulistus extracellular hemoglobin: Its peroxidase activity and the importance of these ions in the protein stability. AB - In this work we investigate the presence of divalent cations bound to the Glossoscolex paulistus (HbGp) hemoglobin and their effect over the protein stability and the peroxidase (POD) activity. Atomic absorption studies show that the HbGp iron content is consistent with the presence of 144 ions per protein. Moreover, using iron as a reference, the content of calcium was estimated as 30+/ 4 ions per protein, independently of the EDTA pre-treatment or not prior to the acidic treatment performed in the protein digestion. The zinc content was 14+/-2 ions in the absence of EDTA pre-treatment, and 3+/-1 ions per protein in the presence of EDTA pre-treatment, implying the presence of one zinc ion per protomer (1/12 of the whole molecule). Finally, the copper concentration is negligible. Different from the vertebrate hemoglobins, where the effectors are usually organic anions, the hexagonal bilayer hemoglobins have as effectors inorganic cations that increase the oxygen affinity and stabilize the structure. Previous studies have suggested that the presence of divalent cations, such as copper and zinc, is related to the different types of antioxidant enzymatic activities as the superoxide dismutase (SOD) activity shown by giant hemoglobin from Lumbricus terrestris (HbLt). Recently, studies on HbGp crystal structure have confirmed the presence of Zn(2+) and Ca(2+) binding sites. The Ca(2+) sites are similar as observed in the HbLt crystal structure. Otherwise, the Zn(2+) sites have no relation with those observed in Cu/Zn SODs. Our peroxidase assays with guaiacol confirm the POD activity and the effect of the zinc ions for HbGp. Our present results on HbGp metal content and their stability effects is the first step to understand the role of these cations in HbGp function in the future. PMID- 27221950 TI - Synthesis, characterization and antitumoral activity of new cobalt(II)complexes: Effect of the ligand isomerism on the biological activity of the complexes. AB - The synthesis, physico-chemical characterization and cytotoxicity against five human tumoral cell lines (THP-1, U937, Molt-4, Colo205 and H460) of three new cobalt(II) coordination compounds are reported (i.e. Co(HL1)Cl (1), Co(HL2)Cl (2) and [Co(HL3)Cl]0.0.5 (CH3)2CHOH (3)). H2L2 (2-{[[2-hydroxy-3-(1 naphthyloxy)propyl](pyridin-2-ylmethyl)amino]methyl}phenol) and H2L3 (2-{[[2 hydroxy-3-(2-naphthyloxy)propyl](pyridin-2-ylmethyl)amino]methyl}phenol) present alpha and beta-naphthyl groups respectively, which is absent in H2L1 (N-(2 hydroxybenzyl)-N-(2-pyridylmethyl)[(3-chloro)(2-hydroxy)]propylamine. These compounds were characterized by a range of physico-chemical methods. X-ray diffraction studies were performed for complex (3), indicating the formation of a mononuclear complex. Complexes (2) and (3), which contain alpha and beta-naphthyl groups respectively, have presented lower IC50 values than those exhibited by complex (1). Complex (3) presents IC50 values lower than cisplatin against Colo205 (90 and 196MUmolL(-1), respectively) and H460 (147 and 197MUmolL(-1), respectively). These human neoplastic cells under investigation were also more susceptible toward complex (3) than peripheral blood mononuclear cells. Transmission electron microscopy investigations are in agreement with the loss of mitochondrial membrane potential (DeltaPsim) observed by JC-1 mitochondrial potential sensor and indicate that the activity of complex (3) against leukemic cell line (U937) is mediated by an apoptotic mechanism associated with mitochondrial dysfunction (intrinsic pathway). PMID- 27221951 TI - Statins for the prevention and treatment of acute lung injury and acute respiratory distress syndrome: A systematic review and meta-analysis. AB - The purpose of this meta-analysis was to assess whether statins could reduce the morbidity of acute lung injury and acute respiratory distress syndrome (ALI/ARDS) in high-risk patients and improve the clinical outcomes of patients with ALI/ARDS. Studies were obtained from PubMed, Medline, Embase and Cochrane Central Register of Controlled Trials. Randomized controlled trials (RCTs) and cohort studies, which reported morbidity, mortality, ventilator-free days, length of stay in intensive care unit and hospital or oxygenation index, were included in our meta-analysis. Risk ratio (RR) and weighted mean difference (WMD) were calculated using fixed or random effect model. A total of 13 studies covering 12 145 patients were included. Both the only RCT (P = 0.10) and cohort studies (RR, 1.02; 95% CI, 0.67 to 1.55; P = 0.94) showed that statin therapy did not lower the morbidity of ALI/ARDS in high-risk patients. The mortality of ALI/ARDS patients was less likely to be improved by statins (RCT, RR, 1.00; 95% CI, 0.84 to 1.20; P = 0.97; cohort studies, RR, 1.04; 95% CI, 0.85 to 1.27; P = 0.72). Moreover, no significant difference was observed in ventilator-free days, length of stay in intensive care unit as well as hospital and oxygenation index. This meta-analysis suggests that statins neither provide benefit for lowering the morbidity of ALI/ARDS in high-risk patients nor improve the clinical outcomes of ALI/ARDS patients. Hence, it may not be appropriate to advocate statin use for the prevention and treatment of ALI/ARDS. PMID- 27221952 TI - Sleep-time ambulatory blood pressure as a prognostic marker of vascular and other risks and therapeutic target for prevention by hypertension chronotherapy: Rationale and design of the Hygia Project. AB - This article describes the rationale, objectives, design and conduct of the ambulatory blood pressure monitoring (ABPM)-based Hygia Project. Given the substantial evidence of the significantly better prognostic value of ABPM compared to clinic BP measurements, several international guidelines now propose ABPM as a requirement to confirm the office diagnosis of hypertension. Nonetheless, all previous ABPM outcome investigations, except the Monitorizacion Ambulatoria para Prediccion de Eventos Cardiovasculares study (MAPEC) study, relied upon only a single, low-reproducible 24 h ABPM assessment per participant done at study inclusion, thus precluding the opportunity to explore the potential reduction in cardiovascular disease (CVD) risk associated with modification of prognostic ABPM-derived parameters by hypertension therapy. The findings of the single-center MAPEC study, based upon periodic systematic 48 h ABPM evaluation of all participants during a median follow-up of 5.6 years, constitute the first proof-of-concept evidence that the progressive reduction of the asleep systolic blood pressure (SBP) mean and correction of the sleep-time relative SBP decline toward the normal dipper BP profile, most efficiently accomplished by a bedtime hypertension treatment strategy, best attenuates the risk of CVD, stroke and development of new-onset diabetes. The Hygia Project, primarily designed to extend the use of ABPM in primary care as a requirement for diagnosis of hypertension, evaluation of response to treatment and individualized assessment of CVD and other risks, is a research network presently composed of 40 clinical sites and 292 investigators. Its main objectives are to (i) investigate whether specific treatment-induced changes in ABPM-derived parameters reduce risk of CVD events, stroke, new-onset diabetes and/or development of chronic kidney disease (CKD); and (ii) test the hypothesis that bedtime chronotherapy entailing the entire daily dose of >=1 conventional hypertension medications exerts better ambulatory BP control and CVD, metabolic and renal risk reduction than all such medications ingested in the morning upon awakening. Between 2007 and 2015, investigators recruited 18 078 persons [9769 men/8309 women, 59.1 +/- 14.3 years of age (mean +/- SD)], including 15 764 with hypertension according to ABPM criteria as participants in the prospective randomized chronotherapy trial. The initial evaluation includes 48 h ABPM, detailed medical history and screening laboratory blood and urine tests. The same evaluation procedure is scheduled annually, or more frequently when treatment adjustment is required for proper ambulatory BP control, targeting a median follow-up of >5 years. The primary CVD outcome end point is the composite of CVD death, myocardial infarction, coronary revascularization, heart failure, ischemic stroke and hemorrhagic stroke. The independent Hygia Project Events Committee periodically evaluates blinded clinical reports to ascertain and certify every documented event. Beyond the potential findings resulting from testing the main hypotheses, the Hygia Project has already demonstrated, as proof of concept, that the routine diagnosis of hypertension and individualized assessment of CVD and other risks by ABPM, as currently recommended, is fully viable in the primary care setting, where most people with either hypertension, dyslipidemia, type 2 diabetes or CKD receive routine medical attention. PMID- 27221953 TI - Factors That Control the Reactivity of Cobalt(III)-Nitrosyl Complexes in Nitric Oxide Transfer and Dioxygenation Reactions: A Combined Experimental and Theoretical Investigation. AB - Metal-nitrosyl complexes are key intermediates involved in many biological and physiological processes of nitric oxide (NO) activation by metalloproteins. In this study, we report the reactivities of mononuclear cobalt(III)-nitrosyl complexes bearing N-tetramethylated cyclam (TMC) ligands, [(14 TMC)Co(III)(NO)](2+) and [(12-TMC)Co(III)(NO)](2+), in NO-transfer and dioxygenation reactions. The Co(III)-nitrosyl complex bearing 14-TMC ligand, [(14 TMC)Co(III)(NO)](2+), transfers the bound nitrosyl ligand to [(12-TMC)Co(II)](2+) via a dissociative pathway, {[(14-TMC)Co(III)(NO)](2+) -> {(14-TMC)Co...NO}(2+)}, thus affording [(12-TMC)Co(III)(NO)](2+) and [(14-TMC)Co(II)](2+) as products. The dissociation of NO from the [(14-TMC)Co(III)(NO)](2+) complex prior to NO transfer is supported experimentally and theoretically. In contrast, the reverse reaction, which is the NO-transfer from [(12-TMC)Co(III)(NO)](2+) to [(14 TMC)Co(II)](2+), does not occur. In addition to the NO-transfer reaction, dioxygenation of [(14-TMC)Co(III)(NO)](2+) by O2 produces [(14 TMC)Co(II)(NO3)](+), which possesses an O,O-chelated nitrato ligand and where, based on an experiment using (18)O-labeled O2, two of the three O-atoms in the [(14-TMC)Co(II)(NO3)](+) product derive from O2. The dioxygenation reaction is proposed to occur via a dissociative pathway, as proposed in the NO-transfer reaction, and via the formation of a Co(II)-peroxynitrite intermediate, based on the observation of phenol ring nitration. In contrast, [(12-TMC)Co(III)(NO)](2+) does not react with O2. Thus, the present results demonstrate unambiguously that the NO-transfer/dioxygenation reactivity of the cobalt(III)-nitrosyl complexes bearing TMC ligands is significantly influenced by the ring size of the TMC ligands and/or the spin state of the cobalt ion. PMID- 27221954 TI - Current topics in red cell biology: report on the Red Cell Special Interest Group meeting held at NHS Blood and Transplant Bristol on 30 October 2015. AB - The Red Cell Special Interest Group (SIG) meeting, hosted by the British Blood Transfusion Society, provides an annual forum for the presentation of UK- and European-based red cell research. The 2015 meeting was held on Friday 30 October at the National Health Service Blood & Transplant (NHSBT) facility in Filton, Bristol and provided an exciting and varied programme on the themes of erythropoiesis, malaria biology and pathophysiology and red cells properties in stress and disease. Ten speakers presented on these topics over the course of one day. The meeting was well attended by over 90 delegates. Posters were presented during the lunch break, and abstracts from the posters are published at the end of this issue. PMID- 27221955 TI - Novel ECHS1 mutation in an Emirati neonate with severe metabolic acidosis. AB - ECHS1 is a mitochondrial matrix enzyme that catalyzes an important step in the beta-oxidation spiral of fatty acid catabolism, and individuals with mutations in the ECHS1 gene suffer from an autosomal recessive condition typified by delayed psychomotor development, mitochondrial encephalopathy, hypotonia, and cardiomyopathy. Here we report the first Arab case of ECHS1 Deficiency. The patient was born to consanguineous parents with all growth parameters being low for gestational age, and was persistently desaturated. Cord blood gas and later blood analysis showed severe metabolic acidosis. Tandem MS revealed increased levels of valine, and Leucine/Isoleucine and decreased level of Glutamine. There was also a large patent ductus arteriosus with right to left shunt and a possible small muscular ventricular septal defect. Whole Exome Sequencing revealed a novel homozygous missense mutation in the ECHS1 gene; c.842 A > G (p.Glu281Gly). In silico analysis suggests that the residue affected by this mutation may be involved in an important functional or structural role. PMID- 27221956 TI - Allogeneic peripheral blood stem cell transplantation and accelerated atherosclerosis: An intriguing association needing targeted surveillance. Lessons from a rare case of acute anterior myocardial infarction. AB - We report the case of a 23-year-old man who developed an acute ST-elevation myocardial infarction secondary to acute thrombotic occlusion of the proximal left anterior descending coronary artery five years after undergoing chemotherapy, radiotherapy, haematopoietic stem cell transplantation for acute lymphoblastic leukaemia and bulky mediastinal mass involving the pleura and pericardium. His medical history also included Graft versus Host Disease developed 13 months after transplantation and acute myocarditis three months before the actual hospital admission. To the best of our knowledge, coronary artery disease as a complication of haematopoietic stem cell transplantation and low-dose mediastinal radiation therapy in young patients has been rarely reported in the medical literature. Clinicians should have a high degree of suspicion of coronary artery disease in patients treated with allogeneic haematopoietic stem cell transplantation, especially in patients previously treated with target mediastinal radiotherapy, as a group at risk of premature and significantly accelerated atherosclerosis, in order to make a timely and correct diagnosis. PMID- 27221958 TI - Plasma concentrations of tissue factor and its inhibitor in chronic thromboembolic pulmonary hypertension: a step closer to explanation of the disease aetiology? AB - BACKGROUND: The aetiology of chronic thromboembolic pulmonary hypertension (CTEPH) is not clearly understood. In some patients, the disease is preceded by acute pulmonary embolism (APE), and is characterised by intravascular thrombosis, vasoconstriction, inflammation and remodelling of pulmonary arteries. Ensuing pulmonary hypertension leads to potentially fatal chronic right ventricle failure. Both inborn and acquired risk factors were identified. Pathogenesis of haemostatic disorders is not completely explained, and extrinsic coagulation pathway disorders may play a role in CTEPH aetiology. AIM: To evaluate levels of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in CETPH, and to delineate their role in the disease pathogenesis. METHODS: Plasma concentrations of TF and TFPI were evaluated in 21 CTEPH patients, in 12 patients with pulmonary arterial hypertension (PAH), in 55 APE survivors without persistent pulmonary hypertension after at least 6 months from the acute episode, and in 53 healthy volunteers (control group C). Most patients were treated with vitamin K antagonists (VKA), and some with unfractionated or low molecular weight heparin. Exclusion criteria included malignancy, inflammation, and recent operation. RESULTS: Tissue factor concentration was lower in CTEPH and in post-APE patients, not stratified by anticoagulation modality, as compared to control group (p = 0.042; p = 0.011) and PAH group (p = 0.024, p = 0.014). Patients with CTEPH and post-APE on adequate VKA-anticoagulation had similar TF concentration to group C. TFPI concentration was similar in CETPH and post-APE patients irrespective of anticoagulation, and higher as compared to group C (respectively, p = 0.012; p = 0.024; p = 0.004). TFPI concentration was similar in patients with CETPH and in post-APE group, both on adequate VKA-anticoagulation when compared to group C. In the post-APE group, there was no significant difference in TFPI concentration between patients receiving adequate and subjects without anticoagulation. Group C was significantly (p = 0.000) younger than any other group, and showed correlation (r = 0.31) between age and TFPI concentration. CONCLUSIONS: In CTEPH there is a high consumption of TF, leading to reduction in plasma concentration of TF and increase in TFPI. Adequate VKA-anticoagulation normalises TF and TFPI plasma concentrations, as is the case of APE survivors. PMID- 27221957 TI - Editor's Choice-Biomarkers of acute cardiovascular and pulmonary diseases. AB - Acute cardiothoracic and respiratory diseases frequently remain a challenge to diagnose and differentiate in the emergency setting. The main diseases that manifest with chest pain include ischaemic heart disease, myocarditis, acute pericarditis, aortic dissection/rupture and pulmonary embolism (PE). Diseases that primarily present with dyspnoea include heart failure (HF), acute respiratory distress syndrome (ARDS), pneumonia, asthma exacerbations and chronic obstructive pulmonary disease. Pre-test probabilities of clinical findings play a vital part in diagnostic decisions, and the use of a Bayesian approach to these greatly improves the ability to stratify patients more accurately. However, blood tests (biomarkers) are increasingly used to assist in rapid decision-making in the emergency setting in combination with imaging methods such as chest radiograph, ultrasound and increasingly computed tomography, as well as physiological tests such as the electrocardiogram in addition to physical examination. Specific tests for ischaemic heart disease and myocarditis (cardiac troponins), HF (B-type natriuretic peptide (BNP) and N-terminal proBNP (NT proBNP)), aortic dissection (smooth muscle markers) and PE (D-dimer) have been developed. Surfactant protein-D and interleukin-8 have been developed for ARDS. Additionally, circulating microRNAs have emerged as promising biomarker candidates in cardiovascular disease. With this increasing array of biochemical markers to aid in the diagnosis of chest diseases presenting with chest pain and dyspnoea, we herein review the clinical usefulness of these markers, in particular in differentiating cardiac from pulmonary diseases. A symptom-oriented assessment as necessary for use in the critical setting is described in addition to discussion of individual biomarkers. PMID- 27221959 TI - Myocardial injury biomarkers after radiofrequency catheter and cryoballoon ablation for atrial fibrillation and their impact on recurrence. AB - BACKGROUND: Myocardial injury induced by catheter ablation (CA) for atrial fibrillation (AF) leads to elevated biomarker levels. AIM: This prospective study examined levels of myocardial injury biomarkers (creatinine kinase [CK], myocardial bound for CK [CK-MB], and troponin I [TnI]) and their impact on AF recurrence following two different ablation strategies, namely: cryoballoon ablation (CBA) and radiofrequency ablation (RFA). We also aimed to evaluate the relationship between AF recurrence after CA and other clinical, echocardiographic and procedural parameters. METHODS: We enrolled 98 patients with AF, 21% of whom had persistent AF and 79% had paroxysmal AF. 58% of patients underwent CBA, and 42% underwent RFA. CK, CK-MB, and TnI levels were measured before and 6 h after the procedure. Patients had follow-up visits three, six, and nine months after the index procedure. Biomarker levels were compared between the patients with and without AF recurrence. RESULTS: Post-ablation CK (postCK), post-ablation CK-MB (postCKMB), and post-ablation TnI (postTnI) levels were significantly high in the CBA and RFA groups (p < 0.001 for all). TnI elevation (DTnI) was correlated with age (p = 0.033) and median temperature reached during ablation (p < 0.005) in the CBA group, while it was correlated with application time in the RFA group (p < 0.001). Multivariate analysis in the CBA group revealed age and left atrium diameter as positive independent predictors (p = 0.029 and p = 0.046), and DTnI as a negative independent predictor for AF recurrence (p = 0.001). Elevated cardiac biomarkers were not associated with AF recurrence in the RFA group (p > 0.05). CONCLUSIONS: The levels of all cardiac biomarkers were elevated after CBA and RFA. Elevated TnI levels after CBA were independent negative predictors of AF recurrence. Measurement of TnI levels after CBA may be useful for the prediction of better clinical outcome. PMID- 27221960 TI - Veno-arterial extracorporeal membrane oxygenation for short-term mechanical circulation support in adults with cardiogenic shock: a single centre experience. AB - BACKGROUND: Patients suffering from cardiogenic shock, with no response to conventional therapy, may significantly improve when put on support devices such as extracorporeal membrane oxygenation (ECMO), which maintains systemic and pulmonary circulation, and decongests the heart. This publication presents authors' own experience in qualifying and treating patients with cardiogenic shock, with the use of veno-arterial (VA) ECMO modality. AIM: The main goal of the study was to analyse factors influencing outcome of VA ECMO therapy in patients with cardiogenic shock. Survival data were compared for patients surviving treatment (n = 12, 41%), and for patients who died while VA ECMO. METHODS: Retrospective study included all patients treated between February 2009, when ECMO was first used in the clinic, and March 2015. Of those, 29 patients were treated with VA ECMO for respiratory support. Mean patient age was 42 years; 19 (66%) patients were male, and 10 (34%) patients were female. RESULTS: Total in hospital mortality rate was 59% (17/29). No difference was observed as to patient age, sex, body height, mode of hospital admission, comorbidities or left ventricular ejection fraction at hospital admission, when comparing survivors and patients who died despite treatment. The following parameters were analysed: number of days on VA ECMO, troponin levels during first days from treatment onset, platelet transfusions, and duration of mechanical ventilation. No significant differences were observed between the groups. Surviving patients were significantly longer hospitalised (p = 0.016), including a longer stay in the intensive care unit (p = 0.03). CONCLUSIONS: VA ECMO is an acceptable therapy for patients in a severe state of cardiogenic shock. In-hospital mortality rate was 59%, and 41% patients (12 subjects) were successfully treated with VA ECMO in course of cardiogenic shock. PMID- 27221961 TI - Epidemiology of out-of-hospital cardiac arrest in the Bielsko-Biala district: a 12-month analysis. AB - BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is the sudden, unexpected loss of heart function, which occurs out of specialist healthcare facilities and inevitably leads to death if uninterrupted by effective cardiopulmonary resuscitation (CPR). AIM: To evaluate the circumstances and basic epidemiological indices of OHCA in the population of adult inhabitants of Bielsko-Biala district within 12 months. METHODS: On the basis of standard ambulance dispatch cards of the Emergency Medical Services (EMS) teams, a retrospective analysis was made of 272 OHCA cases covering the period from 01.01.2013 to 31.12.2013. We assessed the basic demographic data of the victims, circumstances of the occurrence of OHCA, information on the potential cause and mechanism of the OHCA, and data related to the actions undertaken by witnesses and EMS teams. RESULTS: The overall OHCA incidence was 170/100,000 (243/100,000 in men; 99/100,000 in women). It increased with subjects' age (p < 0.01). The most frequent place of OHCA was the victim's home (82%). OHCA occurred in the presence of witnesses in 60% of cases. CPR was undertaken by a witness in 56% cases. Median CPR duration undertaken by a witness was 10 (IQR 8-14) min. Median time from notification receipt by the EMS to the team arrival was 9 (7-11) min. On the scene, defibrillation rhythm was recognised in 39% of cases. Sixty-seven patients were declared deceased after the arrival of the EMS teams. In the remaining 205 cases, CPR was undertaken, which was ineffective for 141 persons. Median CPR duration undertaken by the EMS team was 30 (20-40) min. The overall prehospital case fatality ratio was 76.5% (75.3% for men; 79.3% for women). CONCLUSIONS: OHCA incidence in the Bielsko-Biala population in 2013 was high, increased with age, and was twice as high for men than women. OHCA occurred most often at home, in the presence of a witness; however, CPR was not always undertaken promptly at the scene. CPR was effective for approximately 30% of the victims. The prehospital mortality was high with no differences between genders. PMID- 27221962 TI - The relation of serum thiol levels and thiol/disulphide homeostasis with the severity of coronary artery disease. AB - BACKGROUND: The balance of oxidant and antioxidant status plays a key role in the coronary artery diseases (CAD). Thiol is one of the most important antioxidant barriers in humans, and thiol/disulphide homeostasis is a novel oxidative stress marker. AIM: We aimed to investigate the relation of serum thiol levels and thiol/disulphide homeostasis with the presence and severity of CAD. METHODS: A total of 161 patients who underwent coronary angiography owing to stable angina pectoris were consecutively enrolled. They were divided into three groups. Group I - 47 age- and gender-matched subjects with normal coronary angiography (control); group II - 71 newly diagnosed CAD patients with noncritical stenosis; and group III - 43 newly diagnosed CAD patients with critical stenosis. Serum native thiol, total thiol, and disulphide levels were measured, and disulphide/thiol ratios were calculated. Gensini scores were calculated in CAD patients. RESULTS: While the highest thiol levels were found in group I, the lowest one was observed in group III (p < 0.001). Total and native thiol levels were significantly lower in group II than in group I (p < 0.001 for each), but they increased considerably in group II compared with group III (p = 0.031 and p = 0.028, respectively). Disulphide levels decreased in group II and III compared with group I (p < 0.001 for each). No statistically significant changes were observed in disulphide/thiol ratios (p > 0.05). Gensini scores were negatively correlated with total and native thiols, and positively with age and dyslipidaemia. Stepwise linear regression analyses showed that native thiol was an independent predictor in the final model for Gensini score. Receiver operating characteristic curve analysis demonstrated that thiol values of 310.7 or below could predict CAD with 89% sensitivity and 85% specificity (AUC = 0.918; 95% CI 0.870-0.965). CONCLUSIONS: While the disulphide/thiol ratio did not change significantly, decreased native thiol levels were associated with the presence and severity of CAD. This result indicates that the reduction of thiols may be an important factor in the development of CAD. PMID- 27221963 TI - Differentiating physiology from pathology in elite athletes. Left ventricular hypertrophy versus hypertrophic cardiomyopathy. PMID- 27221964 TI - NF-kappaB deregulation in Hodgkin lymphoma. AB - Hodgkin and Reed/Sternberg (HRS) cells in classical Hodgkin lymphoma (HL) show constitutive activity of both the canonical and non-canonical NF-kappaB signaling pathways. The central pathogenetic role of this activity is indicated from studies with HL cell lines, which undergo apoptosis upon NF-kappaB inhibition. Multiple factors contribute to the strong NF-kappaB activity of HRS cells. This includes interaction with other cells in the lymphoma microenvironment through CD30, CD40, BCMA and other receptors, but also recurrent somatic genetic lesions in various factors of the NF-kappaB pathway, including destructive mutations in negative regulators of NF-kappaB signaling (e.g. TNFAIP3, NFKBIA), and copy number gains of genes encoding positive regulators (e.g. REL, MAP3K14). In Epstein-Barr virus-positive cases of classical HL, the virus-encoded latent membrane protein 1 causes NF-kappaB activation by mimicking an active CD40 receptor. NF-kappaB activity is also seen in the tumor cells of the rare nodular lymphocyte predominant form of HL, but the causes for this activity are largely unclear. PMID- 27221965 TI - Plastic anisotropy and dislocation trajectory in BCC metals. AB - Plasticity in body-centred cubic (BCC) metals at low temperatures is atypical, marked in particular by an anisotropic elastic limit in clear violation of the famous Schmid law applicable to most other metals. This effect is known to originate from the behaviour of the screw dislocations; however, the underlying physics has so far remained insufficiently understood to predict plastic anisotropy without adjustable parameters. Here we show that deviations from the Schmid law can be quantified from the deviations of the screw dislocation trajectory away from a straight path between equilibrium configurations, a consequence of the asymmetrical and metal-dependent potential energy landscape of the dislocation. We propose a modified parameter-free Schmid law, based on a projection of the applied stress on the curved trajectory, which compares well with experimental variations and first-principles calculations of the dislocation Peierls stress as a function of crystal orientation. PMID- 27221966 TI - Involvement of the P2X7-NLRP3 axis in leukemic cell proliferation and death. AB - Lymphocyte growth and differentiation are modulated by extracellular nucleotides and P2 receptors. We previously showed that the P2X7 receptor (P2X7R or P2RX7) is overexpressed in circulating lymphocytes from chronic lymphocytic leukemia (CLL) patients. In the present study we investigated the P2X7R/NLRP3 inflammasome axis in lymphocytes from a cohort of 23 CLL patients. P2X7R, ASC and NLRP3 were investigated by Western blot, PCR and transfection techniques. P2X7R was overexpressed and correlated with chromosome 12 trisomy in CLL patients. ASC mRNA and protein were also overexpressed. On the contrary, NLRP3 was dramatically down modulated in CLL lymphocytes relative to lymphocytes from healthy donors. To further investigate the correlation between P2X7R, NLRP3 and cell growth, NLRP3 was silenced in THP-1 cells, a leukemic cell line that natively expresses both NLRP3 and P2X7R. NLRP3 silencing enhanced P2X7R expression and promoted growth. On the contrary, NLRP3 overexpression caused accelerated apoptosis. The P2X7R was also up-modulated in hematopoietic cells from NLRP3-KO mice. In conclusion, we show that NLRP3 down-modulation stimulates P2X7R expression and promotes growth, while NLRP3 overexpression inhibits cell proliferation and stimulates apoptosis. These findings suggest that NLRP3 is a negative regulator of growth and point to a role of the P2X7R/NLRP3 axis in CLL. PMID- 27221967 TI - Risk factors for deaths during the 2009 heat wave in Adelaide, Australia: a matched case-control study. AB - The extreme heat wave in Australia in 2009 resulted in significantly increased number of daily deaths. The circumstances that lead to deaths during extreme heat have not been explored before in Australia. This study aims to identify the individual and community risk factors for deaths during this extreme heat wave in Adelaide. A matched case-control study was conducted. Cases were those who died in the Adelaide metropolitan area during the heat wave period. For each case, two community controls were randomly selected, matched by age and gender. Face-to face or telephone interviews were conducted to collect data of demographic information, living environment, social support, health status and behavioural changes during the heat wave. Descriptive analysis, as well as simple and multiple conditional logistic regressions were performed. In total, 82 deaths and 164 matched community controls were included in the analysis, with a median age of 77.5 (range 26.6-100.7). The multiple logistic regression model indicated that, compared with controls, the risk of death during the heat wave was significantly increased for people living alone (AOR = 42.31, 95 % CI 2.3, 792.8) or having existing chronic heart disease (AOR = 22.4, 95 % CI 1.7, 303.0). In addition, having air conditioning in bedrooms (AOR = 0.004, 95 % CI 0.00006, 0.28) and participating in social activities more than once a week (AOR = 0.011, 95 % CI 0.0004, 0.29) indicated significant protective effects. We have identified factors that could significantly impact on the likelihood of deaths during heat waves. Our findings could assist in the development of future intervention programs and policies to reduce mortality associated with a warmer climate. PMID- 27221968 TI - Variability of growing degree days in Poland in response to ongoing climate changes in Europe. AB - An observed increase in air temperature can lead to significant changes in the phenology of plants and, consequently, changes in agricultural production. The aim of the study was to evaluate the spatial differentiation of thermal resources in Poland and their variability during a period of changing thermal conditions in Europe. Since the variability of thermal conditions is of paramount importance for perennial crops, the study focused on apple, plum, and cherry orchard regions in Poland. The analysis was conducted for the period of 1951-2010 using air temperature daily data. Thermal resources have been defined using the growing degree days (GDD) index calculated independently for the whole year and during in frost-free season for three air temperature thresholds: 0, 5, and 10 degrees C, which determine the non-winter period, growing season, and the period of full plant growth, respectively. In addition, due to the high significance for perennials in particular, the incidence and intensity of frost during flowering were calculated. In this study, a detailed analysis of the spatial differentiation of thermal resources was first performed, followed by an evaluation of long-term variability and associated change patterns. The obtained results confirmed an increase in thermal resources in Poland as a consequence of the lengthening of the growing season. However, the frequency and intensity of spring frost, especially during flowering or even during ripening of plants, remain a threat to harvests in both the eastern and western parts of the country. PMID- 27221969 TI - Methodology to estimate variations in solar radiation reaching densely forested slopes in mountainous terrain. AB - Solar radiation reaching densely forested slopes is one of the main factors influencing the water balance between the atmosphere, tree stands and the soil. It also has a major impact on site productivity, spatial arrangement of vegetation structure as well as forest succession. This paper presents a methodology to estimate variations in solar radiation reaching tree stands in a small mountain valley. Measurements taken in three inter-forest meadows unambiguously showed the relationship between the amount of solar insolation and the shading effect caused mainly by the contour of surrounding tree stands. Therefore, appropriate knowledge of elevation, aspect and tilt angles of the analysed planes had to be taken into consideration during modelling. At critical times, especially in winter, the diffuse and reflected components of solar radiation only reached some of the sites studied as the beam component of solar radiation was totally blocked by the densely forested mountain slopes in the neighbourhood. The cross-section contours and elevation angles of all obstructions are estimated from a digital surface model including both digital elevation model and the height of tree stands. All the parameters in a simplified, empirical model of the solar insolation reaching a given horizontal surface within the research valley are dependent on the sky view factor (SVF). The presented simplified, empirical model and its parameterisation scheme should be easily adaptable to different complex terrains or mountain valleys characterised by diverse geometry or spatial orientation. The model was developed and validated (R 2 = 0.92 , sigma = 0.54) based on measurements taken at research sites located in the Silesian Beskid Mountain Range. A thorough understanding of the factors determining the amount of solar radiation reaching woodlands ought to considerably expand the knowledge of the water exchange balance within forest complexes as well as the estimation of site productivity. PMID- 27221970 TI - Species diversity of the genus Osmundea (Ceramiales, Rhodophyta) in the Macaronesian region. AB - Species diversity within the genus Osmundea in the Macaronesian region was explored by conducting a comprehensive sampling in the Azores, the Canary, and the Madeira archipelagos. Toward identification, all specimens were first observed alive to verify the absence of corps en cerise, a diagnostic character for the genus and morphometric data were measured (thallus length and width, first-order branches length and width, branchlets length and width, cortical cell length and width in surface view, cortical cell length and width in transverse section). Specimens were sequenced for COI-5P (39 specimens) and three species delimitation methods (Generalized Mixed Yule Coalescent, Automatic Barcode Gap Discovery method, and Poisson Tree Processes) were used to assess the threshold between infra- and interspecific relationships. Subsequently, one or several sequences of plastid-encoded large subunit of RuBisCO (21 specimens) per delimited species were generated to assess the phylogenetic relationships among Macaronesian Osmundea. Moreover, for each delineated species, vegetative and reproductive anatomy was thoroughly documented and, when possible, specimens were either assigned to existing taxa or described as novel species. This integrative approach has provided data for (i) the presence of O. oederi, O. pinnatifida, and O. truncata in Macaronesia; (ii) the proposal of two novel species, O. prudhommevanreinei sp. nov. and O. silvae sp. nov.; and (iii) evidence of an additional species referred as "Osmundea sp.1," which is a sister taxon of O. hybrida. PMID- 27221971 TI - Epidemiology of lactic acidosis in type 2 diabetes patients with metformin in Japan. AB - PURPOSE: To estimate the incidence of lactic acidosis (LA) and role of metformin in Japanese patients with type 2 diabetes mellitus (T2DM) treated with anti diabetes drugs. METHODS: This retrospective propensity score matched cohort study was conducted using the Japanese Medical Data Vision claims database. T2DM patients aged 18 or above who received diabetes drugs during January 2010 through August 2014 were identified. Cases of LA were identified based on reimbursement codes and confirmed by lactic acid test and subsequent treatment by hemodialysis or intravenous sodium bicarbonate. Poisson regression and Cox proportional hazard models were used to estimate the incidence and assess if metformin use was associated with increased risk of LA. RESULTS: Thirty cases of LA were identified among 283 491 treated T2DM patients with 504 169 patient-years of follow-up. Crude incidence of LA was 5.95 per 100 000 patient-years. T2DM patients with chronic kidney disease (CKD) were seven-fold more likely to develop LA than those without CKD (adjusted hazard ratio (aHR), 7.33, 95%CI, 3.17-16.96). Use of metformin was not associated with risk of LA in the study population (aHR, 0.92, 95%CI, 0.33-2.55), and in the propensity score matched cohort (aHR, 0.90, 95%CI, 0.26-3.11). Similar findings were observed among diabetes patients with chronic liver disease (CLD) and CKD. The age-sex adjusted incidence rates in metformin users and non-users were 5.80 and 5.78 per 100 000 person-years, respectively (Incidence rate ratio, 1.00, p = 0.99). CONCLUSIONS: This study found that use of metformin was not associated with increased risk of LA in diabetic patients including those with CKD or CLD. (c) 2016 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd. PMID- 27221972 TI - Discriminating renal nutcracker syndrome from asymptomatic nutcracker phenomenon using multidetector computed tomography. AB - PURPOSE: To retrospectively evaluate the ability of computed tomographic (CT) findings to discriminate nutcracker syndrome (NCS) from asymptomatic nutcracker phenomenon (NCP) and to investigate the diagnostic value of CT findings in diagnosis of NCS. METHODS: From January 2014 to April 2015, 216 patients who underwent initial urographic CT were included. Initially, 216 patients were categorized as "nutcracker" or "normal," based on the following CT criteria: (1) the presence of beak sign and (2) hilar-aortomesenteric left renal vein diameter ratio >4. Patients who satisfied both of these criteria were diagnosed with nutcracker. The nutcracker was then divided into "NCS" and "asymptomatic NCP" based on the presence of characteristic symptoms. CT findings in sagittal and axial scans of corticomedullary phase were evaluated. Multivariate analysis was used to identify significant factors among 30 NCS, 51 asymptomatic NCP, and 135 normal patients. Diagnostic performance and threshold using receiver operating characteristic (ROC) curve were calculated. RESULTS: A total of 131 males and 85 females, with mean age of 38.6 years (range 18-89 years), were included. Multivariate analysis demonstrated superior mesenteric artery (SMA)-aortic angle (p < 0.001) and visualization of a dilated collateral vein with reflux (p = 0.001) were independent factors for distinguishing NCS from asymptomatic NCP. The combination of SMA-aortic angle <25 degrees and visualization of a dilated collateral vein with reflux provided the greatest diagnostic accuracy (area under the ROC curve, 0.841). CONCLUSIONS: The combination of SMA-aortic angle and visualization of a dilated collateral vein with reflux in multidetector CT can be useful to differentiate NCS from asymptomatic NCP. PMID- 27221973 TI - Molecular Architecture of Yeast Chromatin Assembly Factor 1. AB - Chromatin Assembly Complex 1 (CAF-1) is a major histone chaperone involved in deposition of histone H3 and H4 into nucleosome. CAF-1 is composed of three subunits; p150, p60 and p48 for human and Cac1, Cac2 and Cac3 for yeast. Despite of its central role in chromatin formation, structural features of the full CAF-1 in complex with histones and other chaperones have not been well characterized. Here, we dissect molecular architecture of yeast CAF-1 (yCAF-1) by cross-linking mass spectrometry (XL-MS) and negative stain single-particle electron microscopy (EM). Our work revealed that Cac1, the largest subunit of yCAF-1, might serve as a major histone binding platform linking Cac2 and Cac3. In addition, EM analysis showed that yCAF-1 adopts a bilobal shape and Cac1 connecting Cac2 and Cac3 to generate a platform for binding histones. This study provides the first structural glimpse of the full CAF-1 complex and a structural framework to understand histone chaperoning processes. PMID- 27221974 TI - Idiopathic granulomatous mastitis: imaging update and review. AB - OBJECTIVES: The purpose of this study was to review the imaging features of idiopathic granulomatous mastitis (IGM) with clinical and pathology correlation. METHODS: With institutional review board (IRB) approval, a retrospective search of the surgical pathology database from January 2000 to July 2015 was performed. Clinical, imaging and histology findings were reviewed. Cases of granulomatous mastitis without a known source, diagnosed with percutaneous or surgical biopsy, were included in our analysis. RESULTS: Seventeen cases of IGM were identified with imaging available for review. The majority of patients presented with a palpable abnormality, whereas a minority were asymptomatic with an abnormal screening mammogram. At imaging, IGM most often demonstrated a focal asymmetry at mammography, a hypoechoic mass with irregular or angular margins at ultrasound, and robust enhancement with mixed progressive and plateau kinetics at magnetic resonance imaging (MRI). Axillary lymph nodes were reactive in appearance at ultrasound. Molecular breast imaging performed in one case showed mild focal asymmetric radiotracer uptake. CONCLUSION: IGM is a rapidly progressive rare inflammatory condition of the breast resulting in non-necrotizing granuloma formation. Imaging features mimic breast carcinoma and diagnosis can be difficult. Radiologists' awareness of this condition is essential to prevent delayed or unnecessary treatment. TEACHING POINTS: * Idiopathic granulomatous mastitis is rapidly progressive inflammatory condition. * Imaging features may mimic breast carcinoma or infection. * Ultrasound shows irregular hypoechoic masses with increased vascularity and sinus tracts. * MRI shows irregular, enhancing masses or non-mass enhancement with microabscesses. * MRI is useful for assessment of breast involvement and response to treatment. PMID- 27221975 TI - Incremental value of PET and MRI in the evaluation of cardiovascular abnormalities. AB - The cardiovascular system is affected by a wide range of pathological processes, including neoplastic, inflammatory, ischemic, and congenital aetiology. Magnetic resonance imaging (MRI) and positron emission tomography (PET) are state-of-the art imaging modalities used in the evaluation of these cardiovascular disorders. MRI has good spatial and temporal resolutions, tissue characterization and multi planar imaging/reconstruction capabilities, which makes it useful in the evaluation of cardiac morphology, ventricular and valvar function, disease characterization, and evaluation of myocardial viability. FDG-PET provides valuable information on the metabolic activity of the cardiovascular diseases, including ischemia, inflammation, and neoplasm. MRI and FDG-PET can provide complementary information on the evaluation of several cardiovascular disorders. For example, in cardiac masses, FDG-PET provides the metabolic information for indeterminate cardiac masses. MRI can be used for localizing and characterizing abnormal hypermetabolic foci identified incidentally on PET scan and also for local staging. A recent advance in imaging technology has been the development of integrated PET/MRI systems that utilize the advantages of PET and MRI in a single examination. The goal of this manuscript is to provide a comprehensive review on the incremental value of PET and MRI in the evaluation of cardiovascular diseases. MAIN MESSAGES: * MRI has good spatial and temporal resolutions, tissue characterization, and multi-planar reconstruction * FDG-PET provides valuable information on the metabolic activity of cardiovascular disorders * PET and MRI provide complementary information on the evaluation of cardiovascular disorders. PMID- 27221976 TI - Effects of exposure to oil spills on human health: Updated review. AB - Oil spills may involve health risks for people participating in the cleanup operations and coastal inhabitants, given the toxicological properties of the oil components. In spite of this, only after a few major oil spills (crude oil or fuel oil no. 6) have studies on effects of exposure to diverse aspects of human health been performed. Previously, Aguilera et al. (2010) examined all documents published to that date dealing with any type of human health outcome in populations exposed to oil spills. The aim of the present review was to compile all new information available and determine whether evidence reported supports the existence of an association between exposure and adverse human health risks. Studies were classified in three groups according to type of health outcome addressed: (i) effects on mental health, (ii) physical/physiological effects, and (iii) genotoxic, immunotoxic, and endocrine toxicity. New studies published on oil-spill-exposed populations-coastal residents in the vicinity of the spills or participants in cleanup operations-provide additional support to previous evidence on adverse health effects related to exposure regarding different parameters in all three categories considered. Some of the observed effects even indicated that several symptoms may persist for some years after exposure. Hence, (1) health protection in these individuals should be a matter of concern; and (2) health risk assessment needs to be carried out not only at the time of exposure but also for prolong periods following exposure, to enable early detection of any potential exposure-related harmful effects. PMID- 27221977 TI - Are the outcomes of circumferential trabeculotomy for adult open angle glaucoma comparable to those of trabeculectomy? PMID- 27221978 TI - Class II transactivator knockdown limits major histocompatibility complex II expression, diminishes immune rejection, and improves survival of allogeneic bone marrow stem cells in the infarcted heart. AB - This study was performed to investigate how to overcome immunorejection associated with allogeneic stem cell therapy in the infarcted heart. Allogeneic bone marrow mesenchymal stem cell (MSC) differentiation increases major histocompatibility complex II (MHC II) expression, inducing transition from immunoprivileged to immunogenic phenotype. MHC II expression is regulated by the class II transactivator (CIITA). We isolated and characterized mouse and human MSCs and knocked down CIITA expression. Wild-type (WT) or CIITA-knockout (CIITA( )) mouse MSCs were implanted into infarcted mouse myocardia, and recipient allo antibody formation, cell survival, and cardiac function were measured. WT mouse and human MSCs that were myogenically differentiated showed increased MHC II and CIITA expression. Differentiated CIITA(-) MSCs lacked MHC II induction and showed reduced cytotoxicity in allogeneic leukocyte coculture. Differentiation of human MSCs increased MHC II expression, which resulted in cytotoxicity in allogeneic leukocyte coculture and was prevented by CIITA small interfering RNA. In contrast to WT MSCs, CIITA(-) MSCs did not initiate recipient allo-antibody formation and instead survived in the injured myocardium and significantly improved ventricular function. Decreasing CIITA expression in allogeneic MSCs abolished MHC II induction during myogenic differentiation and prevented immunorejection of these cells from the infarcted myocardium, which enhanced beneficial functional effects of MSC implantation on myocardial repair.-Huang, X.-P., Ludke, A., Dhingra, S., Guo, J., Sun, Z., Zhang, L., Weisel, R. D., Li, R.-K. Class II transactivator knockdown limits major histocompatibility complex II expression, diminishes immune rejection, and improves survival of allogeneic bone marrow stem cells in the infarcted heart. PMID- 27221979 TI - Centrality of bone marrow in the severity of gadolinium-based contrast-induced systemic fibrosis. AB - Systemic fibrosis can be induced in humans with gadolinium-based contrast, and cumulative doses correlate with severity. Bone marrow-derived fibrocytes accumulate in the dermis. Whether target organs liberate chemokines to recruit these fibrocytes or whether fibrocytes are stimulated to home to the affected tissue is unknown. Transgenic (tagged) donor rats were treated with gadolinium based contrast. Bone marrow was obtained from diseased animals and age-matched controls. Rats with subtotal nephrectomies were lethally irradiated and underwent salvage transplantation with either the contrast-naive or contrast-exposed bone marrow. Groups were randomly assigned to control or contrast treatment. Contrast treatment led to dermal fibrosis, and this was exacerbated in recipients of contrast-exposed marrow. Fibronectin, C-C chemokine receptors (CCRs)2 and 7, and oxidative stress were all increased in skin from contrast-treated animals-all parameters more severe in recipients of contrast-treated animals. The respective ligands, monocyte chemoattractant protein and C-C motif ligand 19, were both elevated in skin from contrast-treated animals. Coadministration of gadolinium based contrast and a CCR2 inhibitor reduced the severity of skin disease as well as dermal cellularity. The functional role of chemokines in the effects of gadolinium-based contrast was further confirmed in in situ coculture studies using neutralizing CCR2 antibodies. These data implicate dermal liberation of specific chemokines in the recruitment of circulating bone marrow-derived cells. The disease is augmented by bone marrow exposure to contrast, which explains why multiple exposures correlate with severity.-Drel, V. R., Tan, C., Barnes, J. L., Gorin, Y., Lee, D.-Y., Wagner, B. Centrality of bone marrow in the severity of gadolinium-based contrast-induced systemic fibrosis. PMID- 27221980 TI - Powering up the molecular therapy of RNA interference by novel nanoparticles. AB - RNA interference technology has been widely applied in biomedical therapy in recent years. A type of small RNA molecule - siRNA could regulate the expression of disease related genes by breaking down the integrity of mRNA with high specificity. However, the low efficiency of siRNA delivery to its target seriously hampered the RNAi therapy. Compared with viral-based delivery systems, non-viral-based nanoparticles are more suitable for disease treatment due to reduced cellular toxicity, higher loading capacity, and better biocompatibility. This review article highlights several nanoparticle-based siRNA delivery systems, including liposomes, cationic solid lipid nanoparticles, reconstituted high density lipoprotein, polymeric nanoparticles, cationic cell penetrating peptides, and inorganic nanoparticles. The molecular mechanism of gene silencing, clinical examples, and the limitations of current technology related to nanomaterial sciences, are also discussed. PMID- 27221981 TI - Notch2 is a crucial regulator of self-renewal and tumorigenicity in human hepatocellular carcinoma cells. AB - The Notch pathway plays an important role in both stem cell biology and cancer. Notch2 was reported to be upregulated in human hepatocellular carcinoma (HCC) tissues. However, the biological function of Notch2 in human HCC cells has not yet been documented. The aim of this study was to investigate its possible function on the progression of human HCC cells. The expression of Notch2 was detected in four human HCC cell lines by western blotting. Next, Notch2 was knocked down by small interference RNA (siRNA) in human HCC cells. The role of Notch2 in human HCC cells was investigated by cell proliferation assay, colony formation assay, chemoresistance and xenograft formation assay. In the present study, western blotting revealed that the expression of Notch2 was upregulated in human HCC cell lines. Genetic depletion of Notch2 in HCC cells not only resulted in significantly inhibited proliferation, cell cycle progression and colony formation ability but also increased its sensitivity to 5-fluorouracil (5-FU) compared with controls. In addition, upregulation of Notch2 was discovered in CD90 positive HCC cells, CD90 is a marker of hepatic stem cells. Most importantly, knockdown of Notch2 in HCC cells impaired the tumor formation in vivo. Taken together, our findings indicate that Notch2 may confer stemness properties in HCC; downregulation of Notch2 inhibited the proliferation and tumor formation of HCC cells and increase their sensitivity to 5-FU, suggesting Notch2 as a potential therapeutic target for HCC. PMID- 27221982 TI - Nano- and micro-patterning biotemplated magnetic CoPt arrays. AB - Patterned thin-films of magnetic nanoparticles (MNPs) can be used to make: surfaces for manipulating and sorting cells, sensors, 2D spin-ices and high density data storage devices. Conventional manufacture of patterned magnetic thin films is not environmentally friendly because it uses high temperatures (hundreds of degrees Celsius) and high vacuum, which requires expensive specialised equipment. To tackle these issues, we have taken inspiration from nature to create environmentally friendly patterns of ferromagnetic CoPt using a biotemplating peptide under mild conditions and simple apparatus. Nano-patterning via interference lithography (IL) and micro-patterning using micro-contact printing (MUCP) were used to create a peptide resistant mask onto a gold surface under ambient conditions. We redesigned a biotemplating peptide (CGSGKTHEIHSPLLHK) to self-assemble onto gold surfaces, and mineralised the patterns with CoPt at 18 degrees C in water. Ferromagnetic CoPt is biotemplated by the immobilised peptides, and the patterned MNPs maintain stable magnetic domains. This bioinspired study offers an ecological route towards developing biotemplated magnetic thin-films for use in applications such as sensing, cell manipulation and data storage. PMID- 27221983 TI - A decision-tree model to detect post-calving diseases based on rumination, activity, milk yield, BW and voluntary visits to the milking robot. AB - Early detection of post-calving health problems is critical for dairy operations. Separating sick cows from the herd is important, especially in robotic-milking dairy farms, where searching for a sick cow can disturb the other cows' routine. The objectives of this study were to develop and apply a behaviour- and performance-based health-detection model to post-calving cows in a robotic milking dairy farm, with the aim of detecting sick cows based on available commercial sensors. The study was conducted in an Israeli robotic-milking dairy farm with 250 Israeli-Holstein cows. All cows were equipped with rumination- and neck-activity sensors. Milk yield, visits to the milking robot and BW were recorded in the milking robot. A decision-tree model was developed on a calibration data set (historical data of the 10 months before the study) and was validated on the new data set. The decision model generated a probability of being sick for each cow. The model was applied once a week just before the veterinarian performed the weekly routine post-calving health check. The veterinarian's diagnosis served as a binary reference for the model (healthy sick). The overall accuracy of the model was 78%, with a specificity of 87% and a sensitivity of 69%, suggesting its practical value. PMID- 27221984 TI - Life events and functional somatic symptoms: A population study in older adolescents. AB - The purpose of this study was to investigate the effect of negative life events on functional somatic symptoms (FSSs) in adolescents, based on data from 957 participants of the population cohort TRacking Adolescents' Individual Lives Survey. Life events experienced between age 16 and age 19 were assessed with the Kendler's Life Stress interview. FSSs at age 19 and age 16 were measured with the Youth and Adult Self-Report. The hypotheses were tested by the use of a latent change model. Life events predicted FSSs, even when adjusted for pre-event levels of FSSs, symptoms of anxiety and depression, and socio-economic status (B = 0.006, 95% CI [0.003, 0.008], beta = .32). Whereas illness-related life events did not predict FSSs independently (B = -0.003, 95% CI [-0.005, 0.09], beta = .05), non-illness-related life events did (B = 0.007, 95% CI [0.004, 0.010], beta = .31). A past-year diagnosis of anxiety and/or depression had a significant influence on the association between life events and FSSs (B = 0.37, 95% CI [0.30, 0.46], beta = .71), while female sex, exposure to childhood adversities, and family malfunctioning had not. In conclusion, our findings show that FSSs are associated with negative life events in older adolescents. We did not find evidence for stronger effects of illness-related events. PMID- 27221985 TI - Iron acquisition in Leishmania and its crucial role in infection. AB - Iron is an essential cofactor for many basic metabolic pathways in pathogenic microbes and their hosts. It is also dangerous as it can catalyse the production of reactive free radicals. This dual character makes the host can either limit iron availability to invading microbes or exploit iron to induce toxicity to pathogens. Successful pathogens, including Leishmania species, must possess mechanisms to circumvent host's iron limitation and iron-induced toxicity in order to survive. In this review, we discuss the regulation of iron metabolism in the setting of infection and delineate the iron acquisition strategies used by Leishmania parasites and their subversions to host iron metabolism to overcome host's iron-related defences. PMID- 27221986 TI - A social Bayesian brain: How social knowledge can shape visual perception. AB - A growing body of research suggests that social contextual factors such as desires and goals, affective states and stereotypes can shape early perceptual processes. We suggest that a generative Bayesian approach towards perception provides a powerful theoretical framework to accommodate how such high-level social factors can influence low-level perceptual processes in their earliest stages. We review experimental findings that show how social factors shape the perception and evaluation of people, behaviour, and socially relevant objects or information. Subsequently, we summarize the generative view of perception within the 'Bayesian brain', and show how such a framework can account for the pervasive effects of top-down social knowledge on social cognition. Finally, we sketch the theoretical and experimental implications of social predictive perception, indicating new directions for research on the effects and neurocognitive underpinnings of social cognition. PMID- 27221987 TI - Recurrence risk of idiopathic venous thromboembolism. AB - For patients with idiopathic venous thromboembolism (unprovoked), the risk of recurrence is high. Secondary prophylaxis with anticoagulant therapy reduces the thrombotic risk but at the expense of an increased risk of haemorrhage. A number of factors, such as the male sex and an increase in dimer-D concentrations after completing the anticoagulation therapy, are associated with an increased risk of recurrence. Other factors such as residual venous thrombosis have a more controversial and sometimes contradictory relationship. A number of models have been proposed for predicting thrombotic recurrence risk after anticoagulation therapy in unprovoked TVD. However, these models need external validation to determine their current usefulness in clinical practice. In this article, we analyse the risk factors for thrombotic recurrence and the existing prediction models. PMID- 27221988 TI - Mass carbon monoxide poisoning among television viewers of a football match. AB - BACKGROUND: The objective was to study a mass carbon monoxide (CO) poisoning and the characteristics of the asymptomatic cases. METHODS: On the 2nd of February, 2015, a group of more than 30 television viewers of a football match contacted the emergency department due to suspected CO poisoning from a butane stove. A visual inspection of the location of the exposure and a descriptive epidemiological study were conducted. Based on the type of variable, the presence of a statistical association was studied with Fisher's exact test or the Kruskal Wallis test. RESULTS: Thirty-four of the 39 individuals were affected (87.2%). The exposed individuals had a mean age of 43.8 years (SD, 22.1), and 28.2% (11/39) were women. The time of exposure was 52.4min (SD, 21.0), and the mean distance from the oven was 4.2m (SD, 2.5). The most common symptoms were headache (50%), nausea (20.6%), weakness (20.6%) and dizziness (14.7%). The carboxyhaemoglobin (COHb) levels were very high (13.8% +/-5.8%). Some 97.1% of the individuals required oxygen therapy, and 39.4% required hyperbaric chamber treatment. Some 29.5% of the cases had no symptoms but showed COHb levels similar to those that did have symptoms (13.6% vs. 15.3%, nonsignificant difference). The asymptomatic cases had a shorter exposure time (38.3min vs. 53.3min; P<.036). CONCLUSIONS: Almost a third of the exposed individuals were asymptomatic, even with COHb levels similar to those of the symptomatic patients, and the majority of these asymptomatic patients even required oxygen treatment in a hyperbaric chamber. PMID- 27221989 TI - Endothoracic goitre as an uncommon cause of superior vena cava syndrome. PMID- 27221990 TI - Cross-Sectional Data That Explore the Relationship Between Outpatients' Quality of Life and Preferences for Quality Improvement in Oncology Settings. AB - PURPOSE: This cross-sectional study assessed the association between oncology outpatients' quality improvement preferences and health-related quality of life (HRQoL). Implementation of specific initiatives preferred by patients with lower HRQoL may be a strategic approach to enhancing care for potentially vulnerable patients. METHODS: English-speaking adults were recruited from five outpatient chemotherapy clinics located in New South Wales, Australia. Using touch screen devices, participants selected up to 25 initiatives that would improve their experiences and completed the Functional Assessment of Cancer Therapy-General (FACT-G) survey. The logistic odds of selecting an initiative according to FACT-G scores were calculated to determine whether preferences were associated with HRQoL after controlling for potential confounders. RESULTS: Of the 411 eligible outpatients approached to participate, 263 (64%) completed surveys. Commonly selected initiatives were up-to-date information on treatment and condition progress (19.8%), access to or information on financial assistance (18.3%), and reduced clinic wait times (17.5%). For those with relatively lower FACT-G scores, the adjusted odds of selecting five initiatives illustrated an increasing trend: convenient appointment scheduling systems (+23% [P = .002]), reduced wait times (+15% [P = .01]), information on medical emergencies (+14% [P = .04]), access to or information on financial assistance (+15% [P = .009]), help to maintain daily living activities (+18% [P = .007]). CONCLUSION: Two areas of improvement were commonly selected: easily accessible health services and information and support for self-management. Although the results suggest an association between a few quality improvement preferences and HRQoL, a wider spectrum of patient characteristics must be considered when targeting quality improvement to patient subgroups. PMID- 27221991 TI - Lower Patient Ratings of Physician Communication Are Associated With Unmet Need for Symptom Management in Patients With Lung and Colorectal Cancer. AB - PURPOSE: Little is known about factors associated with unmet needs for symptom management in patients with cancer. METHODS: Patients with a new diagnosis of lung and colorectal cancer from the diverse nationally representative Cancer Care Outcomes Research and Surveillance cohort completed a survey approximately 5 months after diagnosis (N = 5,422). We estimated the prevalence of unmet need for symptom management, defined as patients who report that they wanted help for at least one common symptom (pain, fatigue, depression, nausea/vomiting, cough, dyspnea, diarrhea) during the 4 weeks before the survey but did not receive it. We identified patient factors associated with unmet need by using logistic regression with random effects to account for clustering within study sites. RESULTS: Overall, 15% (791 of 5,422) of patients had at least one unmet need for symptom management. Adjusting for sociodemographic and clinical factors, African American race, being uninsured or poor, having early-stage lung cancer, and the presence of moderate to severe symptoms were associated with unmet need (all P < .05). Furthermore, patients who rated their physician's communication score < 80 (on a 0 to 100 scale) had adjusted rates of an unmet need for symptom management that were more than twice as high as patients who rated their physicians with a perfect communication score (23.1% v 10.0%; P < .001). CONCLUSION: A significant minority of patients with newly diagnosed lung and colorectal cancer report unmet needs for symptom management. Interventions to improve symptom management should consider the importance of physician communication to the patient's experience of disease. PMID- 27221992 TI - Quality of Patient-Provider Communication Among Cancer Survivors: Findings From a Nationally Representative Sample. AB - PURPOSE: Although patient-provider communication is an essential component of health care delivery, little is known about the quality of these discussions among patients with cancer. METHODS: Data are from the 2011 Medical Expenditure Panel Survey Experiences with Cancer survey among 1,202 adult cancer survivors. We evaluated discussions with any provider after a cancer diagnosis about: (1) follow-up care; (2) late or long-term treatment effects; (3) lifestyle recommendations, such as diet, exercise, and quitting smoking; and (4) emotional or social needs. Using a response scale ranging from "did not discuss" to "discussed in detail," a summary score was constructed to define communication quality as high, medium, or low. Patient factors associated with the quality of provider discussions were examined using multivariable polytomous logistic regression analyses. RESULTS: At the time of the survey, approximately one half of the patients (46%) were either within 1 year (24.1%) or between 1 and 5 years (22.0%) of treatment. More than one third of cancer survivors reported that they did not receive detailed communication about follow-up care, and more than one half reported that they did not receive detailed communication regarding late or long-term effects, lifestyle recommendations, or emotional and social needs. Only 24% reported high-quality communication for all four elements, indicating that the vast majority experienced suboptimal communication. In multivariable analysis, survivors reporting a high communication quality with providers included those who were within 1 year of treatment, between the ages of 18 and 64 years, non-Hispanic black or other ethnicity, and married. CONCLUSION: Study findings demonstrate gaps in the communication quality experienced by cancer survivors in the United States and help identify survivors for targeted interventions. PMID- 27221994 TI - Effectiveness of a Survivorship Program: An Assessment of Patients With Breast Cancer in a Community Setting. AB - PURPOSE: This study assesses the effectiveness of a single institution's breast cancer survivorship program on patient perceptions, quality of life (QOL), and compliance with National Comprehensive Cancer Network (NCCN) guidelines for follow-up. METHODS: Sampled patients completed all their breast cancer treatment at a single tertiary center. Surveys designed to evaluate QOL were obtained, and retrospective medical record review was conducted to assess NCCN compliance. Survivorship clinic (SC) attendees and nonattendees were matched for age and disease stage for comparison of the outcomes (QOL, NCCN compliance, and overall effectiveness). RESULTS: SC patients (n = 63) tended to perceive their concerns in various categories to be addressed more adequately than did nonattendees (n = 54), with significant differences in the areas of practical concerns (P = .03) and late-term adverse effects (P = .03). There was a significant difference in compliance with three NCCN guidelines (history and physical every 3 to 6 months, annual mammography, and a pelvic examination if on tamoxifen) between survivorship attendees and nonattendees (P < .001, P = .02, and P < .001, respectively). Women who attended an SC used other survivorship support resources more often. CONCLUSION: Survivorship programs can be time and resource consuming, but our study is one of the first to show that a survivorship program effectively changes patient behavior in important ways. Patients who attended an SC were more likely to be compliant with NCCN-recommended follow-up and to use other survivorship resources and felt their concerns were better addressed. These measures can be used to help us improve our survivorship services and by other institutions to measure the quality and effectiveness of their programs. PMID- 27221993 TI - Use of Gene Expression Profiling and Chemotherapy in Early-Stage Breast Cancer: A Study of Linked Electronic Medical Records, Cancer Registry Data, and Genomic Data Across Two Health Care Systems. AB - PURPOSE: The 21-gene recurrence score (RS) identifies patients with breast cancer who derive little benefit from chemotherapy; it may reduce unwarranted variability in the use of chemotherapy. We tested whether the use of RS seems to guide chemotherapy receipt across different cancer care settings. METHODS: We developed a retrospective cohort of patients with breast cancer by using electronic medical record data from Stanford University (hereafter University) and Palo Alto Medical Foundation (hereafter Community) linked with demographic and staging data from the California Cancer Registry and RS results from the testing laboratory (Genomic Health Inc., Redwood City, CA). Multivariable analysis was performed to identify predictors of RS and chemotherapy use. RESULTS: In all, 10,125 patients with breast cancer were diagnosed in the University or Community systems from 2005 to 2011; 2,418 (23.9%) met RS guidelines criteria, of whom 15.6% received RS. RS was less often used for patients with involved lymph nodes, higher tumor grade, and age < 40 or >= 65 years. Among RS recipients, chemotherapy receipt was associated with a higher score (intermediate v low: odds ratio, 3.66; 95% CI, 1.94 to 6.91). A total of 293 patients (10.6%) received care in both health care systems (hereafter dual use); although receipt of RS was associated with dual use (v University: odds ratio, 1.73; 95% CI, 1.18 to 2.55), there was no difference in use of chemotherapy after RS by health care setting. CONCLUSION: Although there was greater use of RS for patients who sought care in more than one health care setting, use of chemotherapy followed RS guidance in University and Community health care systems. These results suggest that precision medicine may help optimize cancer treatment across health care settings. PMID- 27221995 TI - Pathways Clinical Decision Support for Appropriate Use of Key Biomarkers. AB - PURPOSE: Breast cancer diagnostics have the ability to predict disease recurrence and the benefit of chemotherapy. This study measures the use of a diagnostic assay, Oncotype DX, when embedded in a breast cancer decision support algorithm and, on the basis of the assay results, the use of chemotherapy in the adjuvant setting. METHODS: UPMC CancerCenter retrospectively reviewed patients with estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)Neu negative disease with zero to three positive nodes navigated in the Via Pathways decision support portal during a 12-month period. The breast algorithm prompted input of the assay recurrence score (RS) and then recommended hormonal therapy alone (HT) for low RS, or chemotherapy followed by HT for high RS. The patient's RS was correlated with the treatment decision. RESULTS: During this time period, 643 patients had ER-positive, HER2Neu-negative disease with zero to three positive nodes. Of those, 596 (92.7%) had diagnostic testing to determine chemotherapy plus HT versus HT alone, and 47 had chemotherapy followed by HT without an RS. For node-negative patients classified with low or high RS, pathway treatment adherence rates were 99.7% and 96.6%, respectively; node-positive patients had 95.7% and 87.5% adherence rates, respectively. CONCLUSION: This analysis demonstrates the use of a clinical pathway to measure the adoption of a diagnostic test, the Oncotype DX breast assay, and the use of the appropriate therapy on the basis of the RS. As more diagnostics are established to aid in the personalized treatment of diseases, pathways may be important in maintaining clinician awareness of the appropriate disease presentations where these tests should be used, measuring usage of these tests, and tracking the treatment decisions on the basis of test results. PMID- 27221998 TI - Utilization of the organ care system for bilateral lung transplantation: preliminary results of a comparative study. AB - OBJECTIVES: Lung transplantation (LTx) remains the gold standard for patients with end-stage lung disease. However, due to donor organ shortage and brain stem death-related lung injury, only a small proportion of lungs are used increasing the mortality rate on the waiting list. A portable normothermic continuous ex vivo perfusion using the organ care system (OCS) represents one of the tools to increase the pool of donor organs and to improve the function of marginal lungs. We sought to assess mid-term outcomes after LTx using OCS and to compare outcomes including overall survival and freedom from bronchiolitis obliterans syndrome (BOS) with those after conventional preservation. METHODS: Included were 322 consecutive LTx performed at Harefield Hospital between January 2007 and December 2014. Recipients were divided into two groups depending on the organ storage strategy: the majority of patients (n = 308) were transplanted using lungs after cold storage (cold storage group), whereas 14 organs were preserved using OCS (OCS group). The primary end-points were overall survival and freedom from BOS after LTx. The secondary end-points were perioperative clinical characteristics and adverse events. RESULTS: There were no statistically significant differences in terms of most baseline donor and recipient characteristics. The percentage of heavy smokers among donors [8 (2.9%) vs 6 (42.9%), P < 0.001] and the median number of pack-years smoked by donors [14 (7;24) vs 25 (24;30), P = 0.026] were statistically higher in the OCS group. Patients from the OCS group had significantly better postoperative FEV1 at 3 [69 (54;86) vs 93 (87;89), P < 0.001] and 6 [77 (60;90) vs 94 (84;100), P = 0.006] months. There were no statistically significant differences in terms of cumulative survival and freedom from BOS between the two groups. CONCLUSIONS: Results after LTx using OCS are acceptable with excellent survival, and superior early outcome in terms of postoperative lung function despite higher risk in the OCS group. Further larger prospective trials are warranted to confirm our preliminary results and to elaborate long-term outcomes. PMID- 27221999 TI - In patients with a tumour invading the phrenic nerve does prophylactic diaphragm plication improve postoperative lung function? AB - A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was 'In patients with tumours involving the phrenic nerve, does prophylactic diaphragm plication improve lung function following tumour resection?' Using the reported search, 258 papers were found of which 6 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 are tabulated. Three case reports and one case series represent 37 patients in the literature along with two relevant animal studies. Patients treated with prophylactic plication at the time of injury or sacrifice of the phrenic nerve had reduced radiological evidence of diaphragm paralysis, lower reported shortness of breath and reduced requirement for ventilatory support. In patients with prophylactic diaphragm plication and a concurrent pulmonary resection, the predicted postoperative lung function correlated closely with the postoperative measured FEV1, FVC and gas transfer. The postoperative measured FEV1 was reported as 86-98%, the FVC 82-89% and gas transfer 97% of the predicted values. Two animal models investigate the mechanics of respiration, spirometry and gas exchange following diaphragmatic plication. A randomized control study in four dogs measured a 50% reduction in tidal volume and respiratory rate, a 40% decrease in arterial PO2 and a 43% increase in arterial CO2 when the phrenic nerve was crushed in animals with a pneumonectomy but without prophylactic diaphragm plication. A further randomized control animal study with 28 dogs found that plicating the diaphragm after unilateral phrenic nerve transection resulted in a significant increase in tidal volume and lung compliance and a significant decrease in respiratory frequency and the work of breathing. Prophylactic diaphragm plication may preserve lung function, reduce the risk of ventilator dependence and improve the mechanics of breathing in patients with phrenic nerve transection. If transection of the phrenic nerve occurs, and it is recognized intraoperatively, prophylactic diaphragm plication should be considered. PMID- 27222000 TI - Fungal infections in children in the early postoperative period after cardiac surgery for congenital heart disease: a single-centre experience. AB - OBJECTIVES: Postoperative infections are still an important problem in cardiac surgery, especially in the paediatric population, and may influence the final outcome of congenital heart disease treatment. Postoperative infections with fungi are uncommon. The aetiology is poorly understood, and the proper diagnosis and treatment is unclear. In this single-centre study, the frequency of invasive fungal disease in children who underwent surgical management of congenital heart diseases was determined along with the risk factors for infection, treatment options and outcomes. METHODS: All consecutive paediatric patients (<18 years of age) who underwent cardiac surgery for congenital heart disease between September 2008 and December 2015 in a paediatric cardiac centre in Poland were identified. Those who developed invasive fungal disease in the early postoperative period (30 days) were identified. RESULTS: Of the 1540 cardiosurgical procedures for congenital heart disease, 6 were complicated by fungal infection (0.39%). One patient had a high probability of fungal infection, but the diagnosis was unproved. Nevertheless, the patient was successfully treated with antifungal treatment. Five had proven invasive fungal disease. Of these, 3 were diagnosed with candidaemia. All had undergone cardiopulmonary bypass. Of the remaining 2 patients, 1 was a preterm newborn with complete atrioventricular septal defect who developed rib fungal invasion. The remaining patient had pulmonary atresia with ventricular septal defect and developed Fournier's gangrene after surgery. None of the patients died due to infection in the early postoperative period. However, the child with rib fungal invasion died 39 days after surgery as a result of multiorgan failure. CONCLUSIONS: Fungal infections in paediatric patients after cardiac surgery may markedly influence morbidity and mortality. Fungal infection prophylaxis in this specific group of children may reduce morbidity, whereas early empirical treatment followed by a targeted approach may improve outcomes. The 'hit fast, hit hard' treatment strategy may be the best rescue option for children who develop invasive fungal disease after cardiac surgery. PMID- 27222001 TI - The importance of preoperative oxygen saturation as a predictor of pulmonary arterial hypertension after surgery of atrial septal defects. AB - OBJECTIVES: There is no concrete predictor of the change of pulmonary arterial pressure after surgical closure of an atrial septal defect (ASD) in patients with pulmonary arterial hypertension (PAH). The aim of this study was to investigate the role of preoperative room air arterial oxygen saturation (SaO2) (arterial blood gas data) as a predictor of postoperative PAH. METHODS: The medical records of 36 patients [>20 years, mean pulmonary arterial pressure (mPAP) >=25 mmHg] who underwent surgical closure of an ASD between March 2004 and January 2014 were retrospectively reviewed. RESULTS: The median age was 47 years (range, 24.6-65.9 years) and mPAP was 38 +/- 14 mmHg. The mean pulmonary vascular resistance (Rp) was 3.9 +/- 4.2 Wood units, and fenestration was performed in 12 (33%) patients. Only 1 patient received anti-PAH medication preoperatively. The median follow-up period was 4 years (range, 0-10 years). There were two hospital deaths, one of which was related to PAH. At the last follow-up, PAH (estimated tricuspid regurgitation velocity >3 m/s) existed in 7 patients (19%), and 10 patients (28%) were receiving anti-PAH medications (considered as clinical PAH). Univariate analysis for persistent clinical PAH revealed that mPAP, Qp/Qs, Rp, room air arterial oxygen saturation and postoperative functional class were significant risk factors. Only SaO2 remained a significant risk factor in multivariate analysis (P = 0.03). CONCLUSIONS: Preoperative room air SaO2 is a useful predictor of persistent PAH in adult patients undergoing surgical closure of an ASD. PMID- 27222002 TI - Impact of hospital volume on outcomes following treatment of thoracic aortic aneurysms and type-B dissections. AB - Previous research suggests an association between hospital volume and outcomes in high-risk surgical pathologies. The association between hospital volume and outcomes in patients with isolated descending thoracic aortic aneurysms (DTAAs) and type-B thoracic aortic dissections (TBADs) is conflicting. We aimed to investigate this in a literature review and meta-analysis. A systematic review of the literature was performed to identify studies reporting mortality and morbidity following repair (elective or emergency) of DTAA and/or TBAD using the Medline and Embase Databases (2000-2015). Hospital volume was assessed based on the number of patients treated per institution: low volume (1-5 cases per year), medium volume (6-10) and high volume (>10). The primary outcome of interest was all-cause mortality during inpatient stay and at 30 days. Eighty-four series of non-dissecting DTAA or TBAD were included in data synthesis (4219 patients; mean age: 62 years; males: 73.5%). For all patients (emergency and elective) undergoing DTAA repair, in-hospital mortality was 8% [95% confidence interval (CI): 6-8%]. Results were not superior in high-volume centres (8 vs 6 vs 11% for high-, medium- and low-volume, respectively). Sub-analyses for emergency and elective repairs showed no significant differences. For TBAD repairs, in the combined population (emergency and elective), results reached borderline significance (P = 0.0475), favouring high-volume centres (6 vs 11 vs 14%), but this association disappeared when emergency and elective repairs were analysed separately. Nine series reported outcomes at 1 year and 5 series followed DTAA and 18 TBAD treatment. No meaningful long-term comparisons were possible due to the lack of data. No significant associations were detected between hospital volume and subsequent mortality following DTAA or TBAD treatment. Data were heterogeneous and long-term results were scarcely reported. A well-designed longitudinal study of sufficient size is required to inform future strategies in this area. PMID- 27222004 TI - Corrigendum. AB - Kahn M, Ward WHJ, LaRue N, Kalnoky M, Pal S, and Domingo GJ (2015). Maintaining specimen integrity for G6PD screening by cytofluorometric assays. J Histochem Cytochem 63:454-458. (Original DOI: 10.1369/0022155415580594). PMID- 27222003 TI - Handcycling: training effects of a specific dose of upper body endurance training in females. AB - PURPOSE: This study aims to evaluate a handcycling training protocol based on ACSM guidelines in a well-controlled laboratory setting. Training responses of a specific dose of handcycling training were quantified in a homogeneous female subject population to obtain a more in depth understanding of physiological mechanisms underlying adaptations in upper body training. METHODS: 22 female able bodied participants were randomly divided in a training (T) and control group (C). T received 7-weeks of handcycling training, 3 * 30 min/week at 65 % heart rate reserve (HRR). An incremental handcycling test was used to determine local, exercise-specific adaptations. An incremental cycling test was performed to determine non-exercise-specific central/cardiovascular adaptations. Peak oxygen uptake (peakVO2), heart rate (peakHR) and power output (peakPO) were compared between T and C before and after training. RESULTS: T completed the training sessions at 65 +/- 3 % HRR, at increasing power output (59.4 +/- 8.2 to 69.5 +/- 8.9 W) over the training program. T improved on handcycling peakVO2 (+18.1 %), peakPO (+31.9 %), and peakHR (+4.0 %). No improvements were found in cycling parameters. CONCLUSION: Handcycling training led to local, exercise-specific improvements in upper body parameters. Results could provide input for the design of effective evidence-based training programs specifically aimed at upper body endurance exercise in females. PMID- 27222006 TI - Micellization of long-chain ionic liquids in deep eutectic solvents. AB - The aggregation behavior of the ionic liquid (IL) 1-alkyl-3-methylimidazolium chloride with different alkyl chain lengths in a deep eutectic solvent (DES, composed of choline chloride and glycerol in a 1 : 2 mole ratio) was studied for the first time. The critical micellar concentration, micellar size and intermolecular interactions in IL/DES solutions were investigated by different techniques including the fluorescence probe technique, small angle X-ray scattering and Fourier transform infrared spectroscopy. The solvophobic effect dominates the micellization of CnmimCl in DES and the intermolecular hydrogen bond interaction plays a positive role to promote micelle formation. The micellar solutions were utilized for the synthesis of the water-unstable metal-organic framework Cu3(BTC)2 (BTC = 1,3,5-benzenetricarboxylate) at room temperature. X Ray diffraction, scanning electron microscopy, transmission electron microscopy and nitrogen adsorption-desorption isotherms confirm the formation of crystalline Cu3(BTC)2 nanocrystals with mesoporous structures. The morphologies and porosity properties of Cu3(BTC)2 nanocrystals can be modulated by varying the concentration of CnmimCl. PMID- 27222005 TI - Understanding the dimorphic lifestyles of human gastric pathogen Helicobacter pylori using the SWATH-based proteomics approach. AB - Helicobacter pylori may reside in the human stomach as two morphological forms: the culturable spiral form and the viable but non-culturable (VBNC) coccoid form. This bacterium transforms from spiral to coccoid under in vitro suboptimal conditions. However, both spiral and coccoid have demonstrated its infectivity in laboratory animals, suggesting that coccoid may potentially be involved in the transmission of H. pylori. To determine the relevance of the coccoid form in viability and infectivity, we compared the protein profiles of H. pylori coccoids obtained from prolonged (3-month-old) culture with that of 3-day-old spirals of two H. pylori standard strains using SWATH (Sequential Window Acquisition of all Theoretical mass spectra)-based approach. The protein profiles reveal that the coccoids retained basal level of metabolic proteins and also high level of proteins that participate in DNA replication, cell division and biosynthesis demonstrating that coccoids are viable. Most interestingly, these data also indicate that the H. pylori coccoids possess higher level of proteins that are involved in virulence and carcinogenesis than their spiral counterparts. Taken together, these findings have important implications in the understanding on the pathogenesis of H. pylori-induced gastroduodenal diseases, as well as the probable transmission mode of this bacterium. PMID- 27222007 TI - Preparation and application of a novel monoclonal antibody specific for human B7 H3. AB - Human B7-H3 (CD276), as a new member of the B7 family has been demonstrated to mediate T cell proliferation and the production of interferon-gamma. Two isoforms of B7-H3 have been identified in humans, 2IgB7-H3 and 4IgB7-H3. Since the costimulatory functions of the two isoforms remains to be fully elucidated, there are disagreements regarding their expression patterns as well as the T cell responses. In the present study, a single mouse anti-human monoclonal antibody (mAb), specific for 2IgB7-H3 and 4IgB7-H3 was established, termed 11F4. Using this antibody, the expression of B7-H3 was observed extensively in tumor cell lines, with the exception of certain human hematopoietic cell lines. Subsequently, the fusion proteins of the two B7-H3 isoforms were produced to analyze the biological function of 4IgB7-H3 and 2IgB7-H3 using a Cell Counting Kit-8 assay, and the data revealed that the two isoforms exhibited a similar function in promoting T cell proliferation. In addition, the effect of B7-H3 on the T cells was inhibited by the 11F4 mAb. Overall, the novel antibody produced was observed to exhibit an inhibitory effect offering a useful tool in further investigations of the function of B7-H3 isoforms. PMID- 27222008 TI - The Impact of maternal obesity and race/ethnicity on perinatal outcomes: Independent and joint effects. AB - OBJECTIVE: Independent and joint impacts of maternal race/ethnicity and obesity on adverse birth outcomes, including pre-eclampsia, low birth weight, and macrosomia, were characterized. METHODS: Retrospective cohort study of all 2007 California births was conducted using vital records and claims data. Maternal race/ethnicity and maternal body mass index (BMI) were the key exposures; their independent and joint impact on outcomes using regression models was analyzed. RESULTS: Racial/ethnic minority women of normal weight generally had higher risk as compared with white women of normal weight (e.g., African-American women, pre eclampsia adjusted odds ratio [aOR] 1.60, 95% confidence interval [CI]: 1.48-1.74 vs. white women). However, elevated BMI did not usually confer additional risk (e.g., pre-eclampsia aOR comparing African-American women with excess weight with white women with excess weight, 1.17, 95% CI: 0.89-1.54). Obesity was a risk factor for low birth weight only among white women (excess weight aOR, 1.24, 95% CI: 1.04-1.49 vs. white women of normal weight) and not among racial/ethnic minority women (e.g., African-American women, 0.95, 95% CI: 0.83-1.08). CONCLUSIONS: These findings add nuance to our understanding of the interplay between maternal race/ethnicity, BMI, and perinatal outcomes. While the BMI/adverse outcome gradient appears weaker in racial/ethnic minority women, this reflects the overall risk increase in racial/ethnic minority women of all body sizes. PMID- 27222009 TI - MicroRNAs regulate signaling pathways in osteogenic differentiation of mesenchymal stem cells (Review). AB - Osteogenesis is a complex multi-step process involving the differentiation of mesenchymal stem cells (MSCs) into osteoblast progenitor cells, preosteoblasts, osteoblasts and osteocytes, and the crosstalk between multiple cell types for the formation and remodeling of bone. The signaling regulatory networks during osteogenesis include various components, including growth factors, transcription factors, micro (mi)RNAs and effectors, a number of which form feedback loops controlling the balance of osteogenic differentiation by positive or negative regulation. miRNAs have been found to be important regulators of osteogenic signaling pathways in multiple aspects and multiple signaling pathways. The present review focusses on the progress in elucidating the role of miRNA in the osteogenesis signaling networks of MSCs as a substitute for bone implantation the the field of bone tissue engineering. In particular, the review classifies which miRNAs promote or suppress the osteogenic process, and summarizes which signaling pathway these miRNAs are involved in. Improvements in knowledge of the characteristics of miRNAs in osteogenesis provide an important step for their application in translational investigations of bone tissue engineering and bone disease. PMID- 27222011 TI - Outpatient titration of carbidopa/levodopa enteral suspension (Duopa). AB - Carbidopa/levodopa enteral suspension (CLES; Duopa) is a suspension or gel formulation of carbidopa/levodopa that is approved by the USA Food and Drug Administration for the treatment of advanced Parkinson's disease patients with motor fluctuations. CLES is delivered at a constant rate continuously throughout the day into the jejunum through an infusion pump via a PEG-J tube implanted surgically. The efficacy of CLES was established in the USA based on a randomized, double-blind, double-dummy, active controlled, parallel group and 12 week study, in which mean daily OFF time was reduced by 4.0 h, compared to 1.9 h with oral immediate release carbidopa/levodopa. The CLES hardware consists of a cassette containing the drug, a pump to deliver the drug and tubing to connect the PEG-J to the pump. It is critical to understand the appropriate conversion of the carbidopa/levodopa daily dosages to the CLES dosage and how to program the pump and titrate CLES to achieve the most effective dose. We describe one methodology for patient selection, outpatient titration and pump programming. PMID- 27222010 TI - Sympathetic neural signaling via the beta2-adrenergic receptor suppresses T-cell receptor-mediated human and mouse CD8(+) T-cell effector function. AB - Postganglionic sympathetic neurons innervate secondary lymphoid organs and secrete norepinephrine (NE) as the primary neurotransmitter. NE binds and signals through five distinct members of the adrenergic receptor family. In this study, we show elevated expression of the beta2-adrenergic receptor (ADRB2) on primary human CD8(+) effector memory T cells. Treatment of both human and murine CD8(+) T cells with NE decreased IFN-gamma and TNF-alpha secretion and suppressed their cytolytic capacity in response to T-cell receptor (TCR) activation. The effects of NE were specifically reversed by beta2-specific antagonists. Adrb2(-/-) CD8(+) T cells were completely resistant to the effects of NE. Further, the ADRB2 specific pharmacological ligand, albuterol, significantly suppressed effector functions in both human and mouse CD8(+) T cells. While both TCR activation and stimulation with IL-12 + IL-18 were able to induce inflammatory cytokine secretion, NE failed to suppress IFN-gamma secretion in response to IL-12 + IL18. Finally, the long-acting ADRB2-specific agonist, salmeterol, markedly reduced the cytokine secretion capacity of CD8(+) T cells in response to infection with vesicular stomatitis virus. This study reveals a novel intrinsic role for ADRB2 signaling in CD8(+) T-cell function and underscores the novel role this pathway plays in adaptive T-cell responses to infection. PMID- 27222012 TI - Spontaneous, resolving S1Q3T3 in pulmonary embolism: A case report and literature review on prognostic value of electrocardiography score for pulmonary embolism. AB - BACKGROUND: Electrocardiography findings in patients with pulmonary embolism have been investigated since 1935. As medicine has evolved, more effective modalities have surpassed the electrocardiogram in diagnostic utility. Despite the advent of these other modalities, the diagnosis of pulmonary embolism remains elusive and the prognosis is variable amongst each clinical presentation of its pathology. CASE REPORT AND LITERATURE REVIEW: After presenting a case of a resolving S1Q3T3 in subsequent electrocardiogram findings of a patient with pulmonary embolism, this literature review will provide information on a 21-point electrocardiogram scoring system that helps the emergency physician stratify the risk of a patient with an acute presentation of pulmonary embolism. Why should emergency care staff be aware of this? Given the time-sensitive nature of diagnosis and appropriate treatment, Electrocardiogram continues to be a tool in the assessment of patients with a clinical suspicion of pulmonary embolism. Based on the information provided, 21-point electrocardiogram score has been shown to have strong usefulness in assessing prognosis of patients presenting with acute pulmonary embolism. PMID- 27222013 TI - Heat stress pretreatment decreases lipopolysaccharide-induced apoptosis via the p38 signaling pathway in human umbilical vein endothelial cells. AB - The present study aimed to investigate vascular endothelial apoptosis, and the regulatory molecules involved in the condition of heatstroke caused by direct hyperthermia due to high core temperature and gut-derived endotoxemia. Human umbilical vascular endothelial cells (HUVECs) were isolated and treated with heat stress (43C for 1 h), lipopolysaccharide (LPS; 1 ug/ml), or a combination of heat stress pretreatment followed by LPS. Caspase-3 activity, DNA fragmentation, and cell viability, determined using a 3-(4, 5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, were measured to examine cellular apoptosis. Changes in the expression levels of heat shock protein (HSP) 27, HSP90 and B-cell lymphoma 2 (Bcl-2), and the phosphorylation of p38 were detected using Western blot assays. The specific inhibitor of p38, SB203580, was also used. LPS induced endothelial apoptosis, as indicated by increased caspase-3 activity, a high level of DNA fragmentation and low cell viability. LPS also increased p38 phosphorylation and decreased the expression levels of HSP27, HSP90 and Bcl-2. Heat stress pretreatment inhibited LPS-induced cellular apoptosis, increased the phosphorylation of p38, and increased the expression levels of HSP27, HSP90 and Bcl-2. Pretreatment with SB203580 had effects similar to those of heat stress in the amelioration of LPS-induced effects. These findings demonstrated that heat stress pretreatment decreased LPS-induced Bcl-2-associated apoptosis in HUVECs by attenuating p38 activation, thereby increasing the expression levels of HSP27 and HSP90. PMID- 27222014 TI - Gln3 is a main regulator of nitrogen assimilation in Candida glabrata. AB - After Candida albicans, the yeast Candida glabrata ranks second as an aetiological agent of candidaemia and is the most frequently encountered non Candida albicans species in patients with invasive candidiasis. Transcriptome analysis in C. albicans, C. glabrata and Cryptoccocus neoformans has revealed that, when engulfed by macrophages, these yeasts upregulate genes involved in nutrient acquisition, including nitrogen transporters such as the general amino acid permease Gap1, the dicarboxylic amino acid permease Dip5, the basic amino acid permease Can1 and the ammonium permeases Mep1 and Mep2. Nitrogen assimilation has been well studied in model species of fungi, such as Aspergillus nidulans, Neurospora crassa and Saccharomyces cerevisiae. However, little is known about nitrogen assimilation in C. glabrata. In the present study, we report a major role for Gln3 in the assimilation of glutamine, ammonium and proline. Ure2 also has a role in nitrogen assimilation, but it is only observable in ammonium and glutamine. In addition, Gat1 has a minor role, which is only observable in the absence of Ure2 and Gln3. Gln3 is absolutely necessary for full ammonium uptake from media. We have also shown that MEP2 gene expression in C. glabrata is completely dependent on Gln3, whereas GAP1 regulation is mainly exerted by Gln3, with the exception of proline where Gat1 has a minor role. In addition, in C. glabrata Ure2 appears to be a negative regulator of these NCR sensitive genes, similarly to what has been described in S. cerevisiae. Our data place Gln3 as a key regulator of nitrogen assimilation. PMID- 27222015 TI - Clinical Characteristics of Overhydration in Patients with Idiopathic Edema. AB - BACKGROUND: Idiopathic edema (IE) is a common clinical syndrome. Designing treatment plans for IE is problematic because of the difficulty in assessing volume status. We aimed to evaluate volume status, measured by bioimpedance spectroscopy (BIS), and investigated clinical parameters associated with volume overload (VO) in patients with IE. METHODS: Patients with IE were defined as those with symptomatic edema and without abnormal renal function or any other apparent cause of edema. A total of 124 patients were included. Overhydration (OH) and extracellular water (ECW) were calculated using BIS. Relative hydration status (x0394;HS) was defined as OH/ECW. Patients were classified into 2 groups: overhydrated group (OG; x0394;HS >=7%) and non-OG (NOG; x0394;HS <7). Simple and multiple logistic regression analyses were used to assess the influence of several variables on the incidence of VO. RESULTS: Of 124 patients, 37 (29.8%) were in the OG. The proportion of men in the OG was higher than that in the NOG (p = 0.020). Patients in the OG showed more frequent pretibial pitting edema (PTPE, p < 0.001) and had lower hemoglobin (p = 0.008) and serum albumin levels (p < 0.001). The multivariate analysis showed that the presence of PTPE (OR 10.62, 95% CI 1.98-57.1), low serum albumin level (OR 0.01, 95% CI 0.00-0.25) and lower fat tissue index (OR 0.78, 95% CI 0.63-0.97) were independent risk factors for the presence of VO. CONCLUSIONS: BIS helps to identify volume status and body composition in patients with IE. PMID- 27222016 TI - [Efferent tear ducts in the focus of ophthalmic and otorhinolaryngologic surgeons]. PMID- 27222017 TI - [Tumors of the lacrimal drainage system]. AB - BACKGROUND: The prevalence of tumors affecting the lacrimal drainage system is low, thus generating a risk of late diagnosis and treatment in clinical routine. However, these tumors can be potentially life-threatening, which emphasizes the relevance of early diagnosis and treatment. OBJECTIVE: This review focuses on the symptoms, incidence, management, and prognosis of the different tumor entities affecting the lacrimal drainage system. METHODS: The study provides a PubMed based literature review and presents own clinical results. RESULTS: Alongside detailed medical history taking and comprehensive clinical examination, precise inspection during external dacryocystography is important for diagnosis of tumors affecting the lacrimal drainage system. There is a wide spectrum of tumor entities located in the lacrimal drainage system. The tumors are classified into three groups: primary epithelial, primary nonepithelial, and inflammatory lesions. The most common primary epithelial tumors include papilloma, squamous cell carcinoma, and transitional cell carcinoma. The most common nonepithelial tumors include fibrous histiocytoma, malignant lymphoma, and malignant melanoma; while the most common inflammatory lesions comprise sarcoidosis, Wegener granulomatosis, and pyogenic granuloma. Treatment depends on the entity and stage of the tumor. In the case of malignancy, a multimodal and interdisciplinary approach is usually indicated. CONCLUSION: Differential diagnostic signs in favor of a malignancy include a long medical history, predisposing conditions in the patient's history, a mass above the medial canthal ligament, teleangiectasis above the mass, and serosanguinous secretion. PMID- 27222018 TI - A Review of Treatment Options for Progressive Supranuclear Palsy. AB - Progressive supranuclear palsy (PSP) is an atypical parkinsonian condition characterized by a symmetric akinetic-rigid syndrome, early falls, supranuclear gaze palsy, and a frontotemporal behavioral syndrome. The typical phenotype is termed Richardson's syndrome, but numerous other phenotypes have been described. The pathophysiology of PSP is not fully understood, but dysfunction of the tau protein seems to play a central role. Despite exciting new knowledge on the pathophysiology of PSP, there is still no highly effective symptomatic or disease modifying treatment. We review the evidence on pharmacotherapy and experimental therapies in PSP and provide levels of recommendation for the off-label use of commonly used drugs in this disorder. PMID- 27222019 TI - Effects of IL-33/ST2 pathway in acute inflammation on tissue damage, antioxidative parameters, magnesium concentration and cytokines profile. AB - AIM: The aim of this study was to examine the role of IL-33/ST2 pathway in a pathogenesis of acute inflammation and its effects on tissue damage, antioxidative capacity, magnesium concentration and cytokine profile in acutely inflamed tissue. MATERIAL AND METHODS: Male mice were randomly divided in four groups: wild-type control group (WT-C), ST2 knockout control group (KO-C), wild type inflammatory group (WT-I), and ST2 knockout inflammatory group (KO-I). Acute inflammation was induced in WT-I and KO-I by intramuscular injection of turpentine oil, while mice in WT-C and KO-C were treated with saline. After 12h, animals were euthanized, and blood was collected for determination of creatine kinase (CK) and aspartate transaminase (AST) activity. The treated tissue was used for histopathological analysis, determination of volume density of inflammatory infiltrate (Vdii) and necrotic fiber (Vdnf), gene expression of interleukin (IL)-33, ST2, tumor necrosis factor alpha (TNF-alpha), IL-6, IL 12p35, and transforming growth factor beta (TGF-beta), concentration of magnesium (Mg), copper (Cu), selenium (Se), manganese (Mn) and reduced glutathione (GSH), and superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity. RESULTS: Presence of inflammatory infiltration and necrosis in the treated tissue was histopathologically confirmed in WT-I and KO-I. Vdii was significantly higher in WT-I when compared to KO-I, whereas Vdnf did not significantly differ between WT-I and KO-I. CK and AST significantly increased in both inflammatory groups when compared to corresponding control groups. However, the values of CK and AST were significantly higher in WT-I than in KO-I. Mg in the treated tissue was significantly lower in WT-I in comparison to WT-C and KO-I, while there was no significant difference between KO-C and KO-I. There was no significant difference in Cu, Se, and Mn in the treated tissue between WT-C, KO-C, WT-I and KO-I. Gene expression of IL-33 in the treated tissue increased in both inflammatory groups when compared to the corresponding control groups, but it was significantly higher in KO-I than in WT-I. Gene expression of ST2 in the treated tissue was significantly higher in WT-I than in WT-C. Gene expression of TNF-alpha, IL-6, and IL-12p35 in the treated tissue was significantly higher in WT-I and KO-I than in the corresponding control groups, and IL-6 was significantly higher in KO-C than in WT-C. TGF-beta gene expression in the treated tissue was significantly higher in KO-I when compared to WT-I, while there was no difference between WT-C and KO-C. SOD activity decreased at the site of acute inflammation in both inflammatory groups, while the GPx activity increased. GSH in the treated tissue was significantly higher in KO-I than in KO-C or WT-I. CONCLUSION: The results of our study have indicated, to our knowledge for the first time, that IL-33/ST2 pathway plays a role in enhancing inflammation and tissue damage at the site of acute inflammation by affecting the concentration of magnesium and GSH, important for antioxidative capacity, as well as gene expression of anti-inflammatory cytokine TGF-beta. PMID- 27222020 TI - Present and future roles of FDG-PET/CT imaging in the management of malignant pleural mesothelioma. AB - Positron emission tomography/computed tomography (PET/CT) integrated with 2 [(18)F]fluoro-2-deoxy-D-glucose ((18)F-FDG) has emerged as a powerful tool for combined metabolic and anatomic evaluations in clinical oncologic imaging. This review discusses the utility of (18)F-FDG PET/CT as a tool to manage patients with malignant pleural mesothelioma. We discuss different stages of patient management in malignant pleural mesothelioma, including diagnosis, initial staging, therapy planning, early treatment response assessment, re-staging, and prognosis. PMID- 27222022 TI - Health anxiety in children and parents. PMID- 27222023 TI - Living Kidney Donors Who Develop Kidney Failure: Excerpts of Their Thoughts. AB - BACKGROUND: Psychosocial data about living kidney donors have been collected for almost 5 decades now. To date, however, no study has provided any psychosocial follow-up of donors who developed a serious health problem such as end-stage renal disease (ESRD). METHODS: Donors who developed ESRD were invited to participate in a qualitative interview if they met one or both of the inclusion criteria: (1) developed ESRD within 10 years of donating and/or (2) lacked health insurance at the time of donation. We contacted 38 individuals who met these criteria, and 22 participated (58%). Two were subsequently excluded from analysis. RESULTS: Twenty qualitative interviews were analyzed. Five findings are described: (1) donors describe the decision-making process as spontaneous and fast; (2) donors describe lack of appreciation for the need for post-donation self-care; (3) donors do not regret donating despite the adverse outcome; (4) donors advise future donors to have in place emotional and physical support post donation; and (5) donors appreciate the opportunity to tell their story from being a living donor to living with ESRD, which virtually all perceive as 2 separate unrelated events. CONCLUSIONS: Most donors are positive about their donation decision and experience and would donate again, despite developing ESRD themselves. They propose some important changes to the decision-making and informed-consent processes. Our data are reassuring regarding lack of donor regret, but highlight the need for living donor transplant programs to ensure that living donors understand their long-term risks and receive appropriate life long follow-up care to minimize these risks. PMID- 27222021 TI - Update on advances in molecular PET in urological oncology. AB - Integrated positron emission tomography/computed tomography (PET/CT) with 2 [(18)F]fluoro-2-deoxy-D-glucose ((18)F-FDG) has emerged as a powerful tool for the combined metabolic and anatomic evaluation of many cancers. In urological oncology, however, the use of (18)F-FDG has been limited by a generally low tumor uptake, and physiological excretion of FDG through the urinary system. (18)F-FDG PET/CT is useful when applied to specific indications in selected patients with urological malignancy. New radiotracers and positron emission tomography/magnetic resonance imaging (PET/MRI) are expected to further improve the performance of PET in uro-oncology. PMID- 27222024 TI - Characteristics, treatment and outcomes of women with immature ovarian teratoma, 1998-2012. AB - OBJECTIVE: To explore the presentation, management and outcomes of adult women diagnosed with immature ovarian teratoma. METHODS: The National Cancer Database (NCDB) was used to identify women>=18years of age diagnosed with an immature teratoma from 1998 to 2012. We analyzed demographic, clinical and tumor characteristics, and treatment trends. Multivariable models were employed to examine predictors of adjuvant chemotherapy use and survival. RESULTS: We identified a total of 1045 adult women with immature teratoma. The median age of diagnosis was 27years and most were diagnosed between ages 18 and 39 (88.9%). The majority presented with early-stage (I/II) disease (76.0%), underwent unilateral salpingo-oophorectomy (52.5%) and received adjuvant chemotherapy (56.8%). The probability of receiving chemotherapy increased with stage, grade, and treatment at academic compared to community based centers (P<0.05.). Older age, advanced stage, and grade III histology were associated with worse survival (P<0.05). Five year survival rates were: 98.3% (95% CI 96.8-99.1), 93.2% (95% CI 82.8-97.4), 82.7% (95% CI 74.3-88.5), and 72.0% (95% CI 50.1-85.5) for stages I, II, III, and IV disease, respectively. CONCLUSIONS: The incidence of immature teratoma is highest in young adults aged 18 to 39. Most patients present with early-stage disease, are managed with fertility sparing surgery and chemotherapy and have an excellent prognosis. Later age at diagnosis, advanced stage, and high-grade histology confer a worse prognosis. PMID- 27222025 TI - Surface-Modified Liposomal Formulation of Amphotericin B: In vitro Evaluation of Potential Against Visceral Leishmaniasis. AB - Surface modification of liposomes with targeting ligands is known to improve the efficacy with reduced untoward effects in treating infective diseases like visceral leishmaniasis (VL). In the present study, modified ligand (ML), designed by modifying polysaccharide with a long chain lipid was incorporated in liposomes with the objective to target amphotericin B (Amp B) to reticuloendothelial system and macrophages. Conventional liposomes (CL) and surface modified liposomes (SML) were characterized for size, shape, and entrapment efficiency (E.E.). Amp B SML with 3% w/w of ML retained the vesicular nature with particle size of ~205 nm, E.E. of ~95% and good stability. SML showed increased cellular uptake in RAW 264.7 cells which could be attributed to receptor-mediated endocytosis. Compared to Amp B solution, Amp B liposomes exhibited tenfold increased safety in vitro in RAW 264.7 and J774A.1 cell lines. Pharmacokinetics and biodistribution studies revealed high t 1/2, area under the curve (AUC)0-24, reduced clearance and prolonged retention in liver and spleen with Amp B SML compared to other formulations. In promastigote and amastigote models, Amp B SML showed enhanced performance with low 50% inhibitory concentration (IC50) compared to Amp B solution and Amp B CL. Thus, due to the targeting ability of ML, SML has the potential to achieve enhanced efficacy in treating VL. PMID- 27222026 TI - Early Stage HIV Management and Reduction of Stavudine-Induced Hepatotoxicity in Rats by Experimentally Developed Biodegradable Nanoparticles. AB - The objectives of this research work were to develop optimized nanoparticulate formulations of poly (d,l-lactic-co-glycolic acid) (PLGA) (85:15) with an anti AIDS drug stavudine and to evaluate their in-vitro uptake by the macrophages and hepatotoxicity in-vivo. Nanoparticles were prepared by nanoprecipitation method based on a factorial design with varying parameters such as the amounts of polymer and stabilizer used. Physicochemical characterizations such as drug excipient interaction, surface morphology, particle size, and zeta potential measurements were carried out. The best formulation was selected and tagged with fluorescein isothiocyanate (FITC) for cellular uptake study of the formulation. In-vitro uptake of nanoparticles by macrophages was carried out. Formulation induced hepatotoxicity was assessed by analyzing some serum hepatotoxic parameters and hepatic histology following 10-day treatment in comparison with the free drug. Nanoparticles exhibited smooth surface with particle size 84-238 nm, high entrapment efficiency (approx 85%), and negative surface charge. Formulations showed a sustained drug release pattern over the study period. In vitro uptake study by macrophages exhibited a time-dependent profile. In-vivo studies on rats showed improvement in the serum parameters and maintenance of the integrity of the hepatic architecture indicating decreased hepatotoxicity with the formulations as compared to the free drug. The experimental results showed a positive outcome in the development of antiretroviral drug carrier exhibiting sustained drug release, macrophage-targeted delivery characteristics, and having reduced hepatoxicity. This could be beneficial for the management of early stage of HIV infection besides reducing the drug load for effective treatment, thereby offering an attractive option in AIDS therapy. PMID- 27222027 TI - Occurrence of mycotoxins in refrigerated pizza dough and risk assessment of exposure for the Spanish population. AB - Mycotoxins are toxic metabolites produced by filamentous fungi, as Aspergillus, Penicillium and Fusarium. The first objective of this research was to study the presence of mycotoxins in 60 samples of refrigerated pizza dough, by extraction with methanol and determination by liquid chromatography associated with tandem mass spectrometry (LC-MS/MS). Then, the estimated dietary intakes (EDIs) of these mycotoxins, among the Spanish population, was calculated and the health risk assessment was performed, comparing the EDIs data with the tolerable daily intake values (TDIs). The mycotoxins detected in the analyzed samples were aflatoxin B1 (AFB1), aflatoxin B2 (AFB2), aflatoxin G1 (AFG1), zearalenone (ZEA), enniatin A (ENA), enniatin A1 (ENA1), enniatin (ENB), enniatin B1 (ENB1) and BEA (beauvericin) with average concentration of the positive samples of 4.09 MUg/kg, 0.50 MUg/kg, 0.79 MUg/kg, 77.78 MUg/kg, 14.96 MUg/kg, 4.54 MUg/kg, 3.37 MUg/kg, 1.69 MUg/kg and 22.39 MUg/kg, respectively. The presence of ZEA, ENA1, ENB and ENB1 was detected in 100% of the samples, AFB2 in 32%, AFB1 in 23%, ENA in 8% and BEA in 3%. Twelve percent of the samples contaminated with AFB1 and 12% of the doughs contaminated with ZEA exceeded the EU legislated maximum limits. The dietary intakes were estimated considering three different age groups of population, and the EDIs calculated for the mycotoxins detected in the samples were all below the established TDI. PMID- 27222028 TI - Pathophysiological mechanisms of diarrhea caused by the Vibrio cholerae O1 El Tor variant: an in vivo study in mice. AB - Cholera is caused by infection with Vibrio cholerae. This study aimed to investigate the pathophysiology of diarrhea caused by the V. cholerae O1 El Tor variant (EL), a major epidemic strain causing severe diarrhea in several regions. In the ligated ileal loop model of EL-induced diarrhea in the ICR mice, a cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor and a calcium activated chloride channel (CaCC) inhibitor similarly inhibited intestinal fluid secretion. In addition, barrier disruption and NF-kappaB-mediated inflammatory responses, e.g., iNOS and COX-2 expression, were observed in the infected ileal loops. Interestingly, intestinal fluid secretion and barrier disruption were suppressed by NF-kappaB and COX-2 inhibitors, whereas an iNOS inhibitor suppressed barrier disruption without affecting fluid secretion. Furthermore, EP2 and EP4 PGE2 receptor antagonists ameliorated the fluid secretion in the infected ileal loops. The amount of cholera toxin (CT) produced in the ileal loops by the EL was ~2.4-fold of the classical biotype. The CT transcription inhibitor virstatin, a toll-like receptor-4 (TLR-4) antibody and a CT antibody suppressed the EL-induced intestinal fluid secretion, barrier disruption and COX-2 expression. The CT at levels detected during EL infection induced mild intestinal barrier disruption without inducing inflammatory responses in mouse intestine. Collectively, this study indicates that CT-induced intestinal barrier disruption and subsequent TLR-4-NF-kappaB-mediated COX-2 expression are involved in the pathogenesis of EL-induced diarrhea and represent promising novel therapeutic targets of cholera. PMID- 27222029 TI - The active transport of histidine and its role in ATP production in Trypanosoma cruzi. AB - Trypanosoma cruzi, the aetiological agent of Chagas's disease, metabolizes glucose, and after its exhaustion, degrades amino acids as energy source. Here, we investigate histidine uptake and its participation in energy metabolism. No putative genes for the histidine biosynthetic pathway have been identified in genome databases of T. cruzi, suggesting that its uptake from extracellular medium is a requirement for the viability of the parasite. From this assumption, we characterized the uptake of histidine in T. cruzi, showing that this amino acid is incorporated through a single and saturable active system. We also show that histidine can be completely oxidised to CO2. This finding, together with the fact that genes encoding the putative enzymes for the histidine - glutamate degradation pathway were annotated, led us to infer its participation in the energy metabolism of the parasite. Here, we show that His is capable of restoring cell viability after long-term starvation. We confirm that as an energy source, His provides electrons to the electron transport chain, maintaining mitochondrial inner membrane potential and O2 consumption in a very efficient manner. Additionally, ATP biosynthesis from oxidative phosphorylation was found when His was the only oxidisable metabolite present, showing that this amino acid is involved in bioenergetics and parasite persistence within its invertebrate host. PMID- 27222031 TI - A Short Review of the Generation of Molecular Descriptors and Their Applications in Quantitative Structure Property/Activity Relationships. AB - BACKGROUND: Synthesis of organic compounds with specific biological activity or physicochemical characteristics needs a thorough analysis of the enumerable data set obtained from literature. Quantitative structure property/activity relationships have made it simple by predicting the structure of the compound with any optimized activity. For that there is a paramount data set of molecular descriptors (MD). This review is a survey on the generation of the molecular descriptors and its probable applications in QSP/AR. METHODS: Literatures have been collected from a wide class of research journals, citable web reports, seminar proceedings and books. The MDs were classified according to their generation. The applications of the MDs on the QSP/AR have also been reported in this review. RESULTS: The MDs can be classified into experimental and theoretical types, having a sub classification of the later into structural and quantum chemical descriptors. The structural parameters are derived from molecular graphs or topology of the molecules. Even the pixel of the molecular image can be used as molecular descriptor. In QSPR studies the physicochemical properties include boiling point, heat capacity, density, refractive index, molar volume, surface tension, heat of formation, octanol-water partition coefficient, solubility, chromatographic retention indices etc. Among biological activities toxicity, antimalarial activity, sensory irritant, potencies of local anesthetic, tadpole narcosis, antifungal activity, enzyme inhibiting activity are some important parameters in the QSAR studies. CONCLUSION: The classification of the MDs is mostly generic in nature. The application of the MDs in QSP/AR also has a generic link. Experimental MDs are more suitable in correlation analysis than the theoretical ones but are more expensive for generation. In advent of sophisticated computational tools and experimental design proliferation of MDs is inevitable, but for a highly optimized MD, studies on generation of MD is an unending process. PMID- 27222030 TI - Platelet to lymphocyte ratio as an independent prognostic indicator for prostate cancer patients receiving androgen deprivation therapy. AB - BACKGROUND: Platelet to Lymphocyte ratio (PLR) is thought to be associated with a worse outcome in multiple types of cancer. However, the prognostic significance of PLR has not been investigated in the prostate cancer (PCa) patients receiving hormonal therapy. The objective of this study was to determine the prognostic value of PLR in PCa patients treated with androgen deprivation therapy (ADT). METHODS: Two-hundred-ninety prostate cancer patients who had undergone ADT as first-line therapy were retrospectively analyzed. The blood cell counts were performed at the time of diagnosis. PLR was calculated as the ratio of platelet count to lymphocyte count. Patients were categorized in two groups using a cut off point of 117.58 as calculated by the receiver-operating curve analysis. Correlations between PLR and clinical characteristics were analyzed. Meanwhile, univariate and multivariate cox regression analyses were performed to determine the associations of PLR with progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). Prognostic accuracy was evaluated with the Harrell concordance index. RESULTS: The differences of age, serum prostate specific antigen (PSA) level, Gleason score, risk stratification and incidence of metastasis between low PLR group (<117.58) and high PLR group (>=117.58) were not statistically significant (p > 0.05). Multivariate analyses identified PLR as an independent prognostic factor for PFS (hazard ratio (HR) = 1.581, p = 0.013), CSS (HR = 1.768, p = 0.037) and OS (HR = 1.650, p = 0.044). The addition of PLR to the final model improved predictive accuracy (c-index: 0.747, 0.801 and 0.768) for PFS, CSS and OS compared with the clinicopathological base model (c-index: 0.730, 0.778 and 0.746), which included Gleason score and incidence of metastasis. CONCLUSIONS: PLR might play a significant role in the prognosis of PCa patients treated with ADT. Thus, we recommend adding PLR to traditional prognostic model to improve the predictive accuracy. PMID- 27222032 TI - Intercorrelation of Major DNA/RNA Sequence Descriptors - A Preliminary Study. AB - : A large number of alignment-free techniques of graphical representation and numerical characterization (GRANCH) of bio-molecular sequences have been proposed in the recent past years, but the relative efficacy of these methods in determining the degree of similarities and dissimilarities of such sequences have not been ascertained. OBJECTIVE: Our objective is to make an assessment of the relative efficacy of these methods in determining the degree of similarities and dissimilarities of bio-molecular sequences. METHOD: We have chosen 7 published/communicated methods that represent various classes of GRANCH techniques and computed the descriptors that are expected to characterize similarities and dissimilarities in several sets of gene sequences. We critically appraise the different methods and determine which of these yield non-redundant structural information that could be used to compute different properties of the sequences, and which are correlated enough to one another so that using the simplest representative of the group would suffice. We also do a principal component analysis (PCA) to determine how the variances in the calculated sequence descriptors are explained by the computed principal components (PCs). RESULTS: We found that some of the descriptors are strongly correlated implying a commonality of structural information encoded by them while others are distinctly separate. The PCA results show that the first three PC's explain >97% of the variances. CONCLUSION: We found that some mathematical DNA descriptors calculated by a few of these techniques correlate strongly with one another implying a redundancy in the structural information quantified by those descriptors; others are not strongly correlated with one another suggesting that they encode non redundant sequence information. From this and our PCA results, our recommendation would be to use minimally correlated set of descriptors or orthogonal descriptors like PCs derived from the descriptor set for the characterization of nucleic acid structure and function. PMID- 27222033 TI - Oxygen isotope in archaeological bioapatites from India: Implications to climate change and decline of Bronze Age Harappan civilization. AB - The antiquity and decline of the Bronze Age Harappan civilization in the Indus Ghaggar-Hakra river valleys is an enigma in archaeology. Weakening of the monsoon after ~5 ka BP (and droughts throughout the Asia) is a strong contender for the Harappan collapse, although controversy exists about the synchroneity of climate change and collapse of civilization. One reason for this controversy is lack of a continuous record of cultural levels and palaeomonsoon change in close proximity. We report a high resolution oxygen isotope (delta(18)O) record of animal teeth bone phosphates from an archaeological trench itself at Bhirrana, NW India, preserving all cultural levels of this civilization. Bhirrana was part of a high concentration of settlements along the dried up mythical Vedic river valley 'Saraswati', an extension of Ghaggar river in the Thar desert. Isotope and archaeological data suggest that the pre-Harappans started inhabiting this area along the mighty Ghaggar-Hakra rivers fed by intensified monsoon from 9 to 7 ka BP. The monsoon monotonically declined after 7 ka yet the settlements continued to survive from early to mature Harappan time. Our study suggests that other cause like change in subsistence strategy by shifting crop patterns rather than climate change was responsible for Harappan collapse. PMID- 27222034 TI - MicroRNA-184 Modulates Doxorubicin Resistance in Osteosarcoma Cells by Targeting BCL2L1. AB - BACKGROUND Early metastasis of osteosarcoma (OS) is highly lethal and responds poorly to drug and radiation therapies. MicroRNAs (miRNAs) are a class of small noncoding RNAs that modulate gene expression at the post-transcriptional level. However, the detailed functions of specific miRNAs are not entirely understood. The aim of the present study was to investigate the role of miR-184 as a mediator of drug resistance in human osteosarcoma. MATERIAL AND METHODS qRT-PCR was used to analyze the expression level of miR-184 in OS cell line U-2 OS and MG-63 treated with doxorubicin. MiR-184 agomir or miR-184 antagomir was transferred into cells to regulated miR-184. The target of miR-184 was predicted by TargetScan and confirmed by luciferase reporter assay. Bcl-2-like protein 1 (BCL2L1) expression was detected by Western blot. Cell apoptosis was determined by Annexin V staining and analysis by flow cytometry. RESULTS Doxorubicin induced time-dependent expression of miR-184 in OS cell line U-2 OS and MG-63. Luciferase reporter assay identified BCL2L1 as the direct target gene of miR-184. Furthermore, doxorubicin reduced BCL2L1 expression, which was reversed by miR-184 overexpression and further decreased by miR-184 inhibition in OS cells. In addition, miR-184 agomir reduced doxorubicin-induced cell apoptosis, whereas miR 184 antagomir enhanced apoptosis in OS cells, suggesting that up-regulation of miR-184 contributes to chemoresistance of the OS cell line. CONCLUSIONS Our data show that miR-184 was up-regulated in OS patients treated with doxorubicin therapy and leads to poor response to drug therapy by targeting BCL2L1. PMID- 27222035 TI - Erratum to: Description of Endozoicomonas arenosclerae sp. nov. using a genomic taxonomy approach. PMID- 27222036 TI - Examining the Influence of Context and Professional Culture on Clinical Reasoning Through Rhetorical-Narrative Analysis. AB - According to the dual process model of reasoning, physicians make diagnostic decisions using two mental systems: System 1, which is rapid, unconscious, and intuitive, and System 2, which is slow, rational, and analytical. Currently, little is known about physicians' use of System 1 or intuitive reasoning in practice. In a qualitative study of clinical reasoning, physicians were asked to tell stories about times when they used intuitive reasoning while working up an acutely unwell patient, and we combine socio-narratology and rhetorical theory to analyze physicians' stories. Our analysis reveals that in describing their work, physicians draw on two competing narrative structures: one that is aligned with an evidence-based medicine approach valuing System 2 and one that is aligned with cooperative decision making involving others in the clinical environment valuing System 1. Our findings support an understanding of clinical reasoning as distributed, contextual, and influenced by professional culture. PMID- 27222037 TI - The Role of Self-Management Practices as Mechanisms for Re-Establishing Normality in Cancer Survivors. AB - This article explores the relationship between cancer survivors' use of self management practices and their search for normality. Using Frank's illness narratives and other theoretical literature on normality in chronic illness, it draws on findings from a qualitative study to explore different ways cancer survivors use self-management practices to re-establish normality in their lives post-cancer. The findings suggest that "normality" represents different things to cancer survivors. We suggest that normality in survivorship is not a static concept but is fluid, and at certain times, cancer survivors may display some or all of these different versions of normality. The findings show that self management practices can help cancer survivors experiment with different health and lifestyle processes to help support their "normal" daily lifestyle activities, quality of life, and well-being. PMID- 27222038 TI - The Clinical Efficacy of Autologous Platelet-Rich Plasma Combined with Ultra Pulsed Fractional CO2 Laser Therapy for Facial Rejuvenation. AB - Ultra-pulsed fractional CO2 laser is an efficient, precise, and safe therapeutic intervention for skin refreshing, although accompanied with prolonged edema and erythema. In recent years, autologous platelet-rich plasma (PRP) has been proven to promote wound and soft tissue healing and collagen regeneration. To investigate whether the combination of PRP and ultra-pulsed fractional CO2 laser had a synergistic effect on therapy for facial rejuvenation. Totally, 13 facial aging females were treated with ultra-pulsed fractional CO2 laser. One side of the face was randomly selected as experimental group and injected with PRP, the other side acted as the control group and was injected with physiological saline at the same dose. Comprehensive assessment of clinical efficacy was performed by satisfaction scores, dermatologists' double-blind evaluation and the VISIA skin analysis system. After treatment for 3 months, subjective scores of facial wrinkles, skin texture, and skin elasticity were higher than that in the control group. Similarly, improvement of skin wrinkles, texture, and tightness in the experimental group was better compared with the control group. Additionally, the total duration of erythema, edema, and crusting was decreased, in the experimental group compared with the control group. PRP combined with ultra pulsed fractional CO2 laser had a synergistic effect on facial rejuvenation, shortening duration of side effects, and promoting better therapeutic effect. PMID- 27222039 TI - The Relation of Exposure to Traumatic Events and Longitudinal Mental Health Outcomes for Children Enrolled in Systems of Care: Results from a National System of Care Evaluation. AB - This study examined the relation between children's history of exposure to potentially traumatic events (PTEs) and clinical and functional mental health trajectories over a 18-month period among a national sample of youth referred for services in children's behavioral health systems of care (SOCs). Using data from the national evaluation of the Comprehensive Community Mental Health Services program for communities funded from 1997 to 2000, the study sample included 9556 children and their families. Latent growth modeling was used to assess the effect of history of exposure to PTEs on trajectories in a number of behavioral health outcomes during the 3-year period following referral to services, controlling for child demographic characteristics (gender, race, and age). Results revealed that, on average, children in SOCs exhibited significant improvements over time on all four outcome measures. Children with a history of exposure to PTEs had higher rates of internalizing and externalizing problem behaviors and functional impairments and fewer behavioral and emotional strengths at baseline, but experienced improvements in these outcomes at the same rates as children without exposure to a traumatic event. Finally, child race, gender, and age also were associated with differences in behavioral health trajectories among service recipients. Implications for SOCs, including approaches to make them more trauma informed, are discussed. PMID- 27222040 TI - Unveiling alterative splice diversity from human oligodendrocyte proteome data. AB - : Oligodendrocytes produce and maintain the myelin sheath of axons in the central nervous system. Because misassembled myelin sheaths have been associated with brain disorders such as multiple sclerosis and schizophrenia, recent advances have been made towards the description of the oligodendrocyte proteome. The identification of splice variants represented in the proteome is as important as determining the level of oligodendrocyte-associated proteins. Here, we used an oligodendrocyte proteome dataset deposited in ProteomeXchange to search against a customized protein sequence file containing computationally predicted splice variants. Our approach resulted in the identification of 39 splice variants, including one variant from the GTPase KRAS gene and another from the human glutaminase gene family. We also detected the mRNA expression of five selected splice variants and demonstrated that a fraction of these have their canonical proteins participating in direct protein-protein interactions. In conclusion, we believe our findings contribute to the molecular characterization of oligodendrocytes and may encourage other research groups working with central nervous system disorders to investigate the biological significance of these splice variants. The splice variants identified in this study may encode proteins that could be targeted in novel treatment strategies and diagnostic methods. SIGNIFICANCE: Several disorders of the central nervous system (CNS) are associated with misassembled myelin sheaths, which are produced and maintained by oligodendrocytes (OL). Recently, the OL proteome has been explored to identify key proteins and molecular functions associated with CNS disorders. We developed an innovative approach to select, with a higher level of confidence, a relevant list of splice variants from a proteome dataset and detected the mRNA expression of five selected variants: EEF1D, KRAS, MFF, SDR39U1, and SUGT1. We also described splice variants extracted from OL proteome data. Among the splice variants identified, some are from genes previously linked to CNS and related disorders. Our findings may contribute to oligodendrocyte characterization and encourage other research groups to investigate the biological role of splice variants and to improve current treatments and diagnostic methods for CNS disorders. PMID- 27222041 TI - A proteomic signature of ovarian cancer tumor fluid identified by highthroughput and verified by targeted proteomics. AB - Tumor fluid samples have emerged as a rich source for the identification of ovarian cancer in the context of proteomics studies. To uncover differences among benign and malignant ovarian samples, we performed a quantitative proteomic study consisting of albumin immunodepletion, isotope labeling with acrylamide and in depth proteomic profiling by LC-MS/MS in a pool of 10 samples of each histological type. 1135 proteins were identified, corresponding to 505 gene products. 223 proteins presented associated quantification and the comparative analysis of histological types revealed 75 differentially abundant proteins. Based on this, we developed a panel for targeted proteomic analysis using the multiple reaction monitoring (MRM) method for validation of 51 proteins in individual samples of high-grade serous ovarian tumor fluids (malignant) and benign serous cystadenoma tumor fluids. This analysis showed concordant results in terms of average amounts of proteins, and APOE, SERPINF2, SERPING1, ADAM17, CD44 and OVGP1 were statistically significant between benign and malignant group. The results observed in the MRM for APOE were confirmed by western blotting, where APOE was more abundant in malignant samples. This molecular signature can contribute to improve tumor stratification and shall be investigated in combination with current biomarkers in larger cohorts to improve ovarian cancer diagnosis. BIOLOGICAL SIGNIFICANCE: Despite advances in cancer research, ovarian cancer has a high mortality and remains a major challenge due to a number of particularities of the disease, especially late diagnosis caused by vague clinical symptoms, the cellular and molecular heterogeneity of tumors, and the lack of effective treatment. Thus, efforts are directed to better understand this neoplasia, its origin, development and, particularly the identification and validation of biomarkers for early detection of the disease in asymptomatic stage. In the present work, we confirmed by MRM method in individual ovarian tumor fluid samples the regulation of 27 proteins out of 33 identified in a highthroughput study. We speculate that the presence and/or differential abundance observed in tumor fluid is a cooperation primarily of high rates of secretion of such tumor proteins to extra tumor environment that will at the end accumulate in plasma, and also the accumulation of acute-phase proteins throughout the entire body. On top of that, consideration of physiological influences in the interpretation of expression observed, including age, menopause status, route-of-elimination kinetics and metabolism of the tumor marker, coexisting disease, hormonal imbalances, life-style influences (smoking, alcoholism, obesity), among others, are mandatory to enable the selection of good protein tumor marker candidates for extensive validation. PMID- 27222042 TI - Proteomic characterization of Nalpha- and Nepsilon-acetylation in Acinetobacter baumannii. AB - : Nalpha- and Nepsilon-acetylation represent a pivotal post-translational modification used by both eukaryotes and prokaryotes to modulate diverse biological processes. Acinetobacter baumannii has been described as an important nosocomial pathogen for the past 30 years, frequently involved in ventilator associated pneumonia, bloodstream and urinary tract infections. Many aspects of the biology of A. baumannii remain elusive, in particular the extent and function of N-acetylation. We investigated here N-acetylation in A. baumannii strain ATCC 17978 by proteomic analysis, and we showed the usefulness of using different analytical approaches. Overall, we identified 525 N-acetylated proteins in which, 145 were Nalpha-acetylated and 411 were Nepsilon-acetylated. Among them, 41 proteins carried both types of N-acetylation. We found that N-acetylation may play a role in biofilm formation, bacterial virulence (e.g. in several iron acquisition pathways), as well as a number of phenotypes, such as, stress adaptation and drug resistance. BIOLOGICAL SIGNIFICANCE: This study is the first to perform the N-acetylome of A. baumannii using different analytical approaches. Each analytical tool permitted to characterize distinctive modified peptides. The combination of all these methods allowed us to identify 145 and 411 Nalpha- and Nepsilon-acetylated proteins. Besides the fact that acetylation was involved in central metabolism as previously described in other bacteria, some N-acetylated proteins showed interesting role in bacterial virulence (iron acquisition), biofilm formation, stress adaptation and drug resistance of A. baumannii. PMID- 27222043 TI - Understanding the body-mind in primary care. AB - Patients' experience of symptoms does not follow the body-mind divide that characterizes the classification of disease in the health care system. Therefore, understanding patients in their entirety rather than in parts demands a different theoretical approach. Attempts have been made to formulate such approaches but many of these, such as the biopsychosocial model, are still basically dualistic or methodologically reductionist. In primary care, patients often present with diffuse symptoms, making primary care the ideal environment for understanding patients' undifferentiated symptoms and disease patterns which could readily fit both bodily and mental categories. In this article we discuss theoretical models that have attempted to overcome this challenge: The psychosomatic approach could be called holistic in the sense of taking an anti-dualistic stance. Primary care theorists have formulated integrative views but these have not gained a foothold in primary care medicine. McWhinney introduced a new metaphor, 'the body-mind', and Rudebeck advocated cultivating 'bodily empathy'. These views have much in common with both phenomenological thinking and mentalization, a psychological concept for understanding others. In the process of understanding patients there is a need for the physician to enter an intersubjectivity that aims at understanding the patient's experiences and sensations without initially jumping to diagnostic conclusions or into a division into mental and physical phenomena. Mentalization theory could form the basis of an approach to a more comprehensive understanding of patients. The success of such an approach is, however, dependent upon structural and organizational conditions that do not counteract it. PMID- 27222044 TI - Comparison of statin eligibility according to the Adult Treatment Panel III, ACC/AHA blood cholesterol guideline, and presence of carotid plaque by ultrasound in Mexican mestizo patients with rheumatoid arthritis. AB - Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in rheumatoid arthritis (RA) patients. Guidelines of the American College of Cardiology and the American Heart Association (ACC/AHA) 2013 and the Adult Treatment Panel III (ATP-III) differ in their strategies to recommend initiation of statin therapy. The presence of carotid plaque (CP) by carotid ultrasound is an indication to begin statin therapy. We aimed to compare the recommendation to initiate statin therapy according to the ACC/AHA 2013 guidelines, ATP-III guidelines, and CP by carotid ultrasound. We then carried out an observational, cross-sectional study of 62 statin-naive Mexican mestizo RA patients, aged 40 to 75, who fulfilled the 1987 or 2010 ACR/European League Against Rheumatism (EULAR) classification criteria. CP was evaluated with B-mode ultrasound. Cohen's kappa (k) was used to assess agreement between ACC/AHA 2013 guidelines, ATP-III guidelines, and the presence of CP, considering a p < 0.05 as statistically significant. Agreement was classified as slight (0.01-0.20), fair (0.21-0.40), moderate (0.41-0.60), substantial (0.61-0.80), and an almost perfect agreement (0.81-1.00). Slight agreement (k = 0.096) was found when comparing statin recommendation between CP and ATP-III. Fair agreement (k = 0.242) was revealed between ACC/AHA 2013 and ATP-III. Comparison between ACC/AHA 2013 and CP showed moderate agreement (k = 0.438). ACC/AHA 2013 guidelines could be an adequate and cost-effective tool to evaluate the need of statin therapy in Mexican mestizo RA patients, with moderate agreement with the presence of CP by ultrasound. PMID- 27222045 TI - Proliferative effects of gamma-amino butyric acid on oral squamous cell carcinoma cells are associated with mitogen-activated protein kinase signaling pathways. AB - Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the adult mammalian central nervous system, has been reported to play an important physiological role in peripheral non-neuronal tissues, such as tumors. However, whether deregulated GABA is associated with oral squamous cell carcinoma (OSCC) is currently unknown. In this study, we investigated the effects of GABA on the proliferation of the OSCC cell line, Tca8113. Immunohistochemical analyses were performed to examine the expression of GABA A type receptor pi subunit (GABRP) in human OSCC tissues, and reverse transcription polymerase chain reaction, immunofluorescence staining and western blot analysis were performed to examine the expression of GABRP in Tca8113 cells. The proliferative effects of GABA on Tca8113 cells were analyzed by CCK-8 assay and flow cytometry. The activation status of mitogen-activated protein kinases (MAPKs) was examined by western blot analysis. GABRP expression was observed in the cytoplasm with a higher level in poorly differentiated OSCC tissues. The mRNA and protein expression levels of GABRP were detected in the Tca8113 cells. The addition of GABA and the GABA A type receptor agonist, Muscimol, promoted cell proliferation and inhibited cell apoptosis through the activation of the p38 MAPK and the inhibition of the JNK MAPK signaling pathways. These results imply a novel role of GABA in OSCC. PMID- 27222046 TI - Rottlerin induces cyclooxygenase-2 upregulation through an ATF4 and reactive oxygen species-independent pathway in HEI-OC1 cells. AB - Hearing loss can be caused by infection, inflammation, loud noise and ototoxic drugs. The induction of cyclooxygenase-2 (COX-2) expression is an important event during the cellular inflammatory response. The present study investigated the effect of rottlerin on CO-2 mRNA and protein expression in HEI-OC1 cells. Cell viability was determined using an MTT assay. Western blotting was used to examine the expression of COX-2, endoplasmic reticulum stress-associated transcription factors and activation of the MAPK pathway. ROS was measured using the fluorescent probe 2', 7'-dichlorodihydrofluorescein diacetate. Treatment with the natural protein kinase C delta inhibitor, rottlerin, was shown to increase COX-2 expression at the protein and mRNA levels in a dose-dependent manner. Rottlerin was shown to induce increased reactive oxygen species (ROS) generation, however, ROS were not critical for rottlerin-induced upregulation of COX-2 expression in HEI-OC1 cells. In addition, rottlerin was shown to increase the phosphorylation of p38 mitogen-activated protein kinase (MAPK). The pharmacological inhibition of p38MAPK and suppression of activating transcription factor 4 (an ER stress associated transcription factor) expression by small interfering RNA inhibited rottlerin-induced COX-2 upregulation. Furthermore, COX-2 expression levels were increased further when cells were treated with rottlerin and interleukin-1beta or protein kinase C activator, PMA. In conclusion, the results of the present study demonstrated that rottlerin is a novel inducer of COX-2 expression and identified the mechanisms involved in this process. Rottlerin may be considered a potential activator of repair and remodeling. PMID- 27222047 TI - Downregulation of miR-377 contributes to IRX3 deregulation in hepatocellular carcinoma. AB - Iroquois homeobox (IRX) gene family, which plays essential roles in embryonic development, has recently been reported to be involved in tumor progression. However, the association of IRX3, a member of the IRX family, with hepatocellular carcinoma (HCC) has not previously been studied. In the present study, we found that IRX3 was upregulated in HCC cell lines (HepG2 and SMMC7721). We investigated the regulatory mechanism of IRX3 in HCC cells. Western blot and luciferase reporter assays identified that IRX3 is a direct target of miR-377. In addition, miR-377 was downregulated in HepG2 and SMMC7721 cell lines, and overexpression of miR-377 inhibited HepG2 cell proliferation, migration and invasion. Moreover, miR 377 restoration significantly abrogated IRX3-induced proliferation, migration and invasion of SMMC7721 cells. These findings demonstrate the tumor-promoting potential of IRX3, and that downregulation of miR-377 may contribute to the upregulation of IRX3 in HCC. The present study provides insights into HCC progression and a novel potential therapeutic target of HCC treatment. PMID- 27222048 TI - Fluid Balance and Kidney Injury. PMID- 27222049 TI - Monitored Anesthesia Care Versus General Anesthesia: Experience With the Medtronic CoreValve. AB - OBJECTIVE: To compare monitored anesthesia care (MAC) and general anesthesia (GA) for transcatheter aortic valve implantation (TAVI). DESIGN: Retrospective, case control study. SETTING: A large university-affiliated hospital system. PARTICIPANTS: The study comprised patients who underwent TAVI with the Medtronic CoreValve (Medtronic, Minneapolis, MN) between 2011 and 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: MAC (n = 44) and GA (n = 21) were compared in 65 patients who underwent TAVI. Baseline characteristics/demographics, hospital stay, intraoperative conditions, and intensive care unit (ICU)/hospital stays were compared using the chi-square test, unpaired t-test, or binomial regression where appropriate. There were no significant differences between patient populations with regard to 30-day mortality, ICU/hospital stay, and complication rates. The GA group used more blood product. The rate of ICU readmission was greater in the GA group but did not reach statistical significance. CONCLUSIONS: GA provides no significant advantages over MAC during TAVI. PMID- 27222050 TI - Safety of Sugammadex for Neuromuscular Reversal in Cardiac Transplant Patients. PMID- 27222051 TI - Effect of Hydroxyethyl Starch on Outcomes in High-Risk Vascular Surgery Patients: A Retrospective Analysis. AB - OBJECTIVE: To assess the effect of using hydroxyethyl starch (HES) for intraoperative fluid therapy on outcomes in high-risk vascular surgery patients. DESIGN: Retrospective case series. SETTING: Single-center academic hospital. PARTICIPANTS: The study included 1,395 adult vascular surgery patients with peripheral vascular disease. INTERVENTIONS: Retrospective review of hospital databases. MEASUREMENTS AND MAIN RESULTS: Outcomes were compared between patients who were intraoperatively administered HES (Voluven [Fresenius Kabi, Bad Homburg, Germany] or Pentaspan [Bristol-Myers Squibb Canada, Montreal, Quebec, Canada]) versus patients who received only crystalloids during their procedure. Logistic regression was used to assess for association between these groups and mortality (in-hospital, 30-day), intensive care unit admission, hemodialysis requirement, vasopressor requirement, and ventilator requirement. Overall, 796 patients had complete fluid records and were included in the analysis. After adjustment for potential confounders, receiving an HES solution was associated with increased likelihood of 30-day mortality (odds ratio [OR] 2.11, 95% confidence interval [CI] 1.05-3.80), postoperative requirement for hemodialysis (OR 6.17, 95% CI 1.09 35.10), intensive care unit admission (OR 3.52, 95% CI 2.15-5.74), and mechanical ventilation (OR 3.16, 95% CI 1.84-5.41). CONCLUSIONS: Intraoperative administration of HES was associated with an increased likelihood of adverse outcomes compared with use of crystalloids alone. PMID- 27222052 TI - Pro- and anti-tumour effects of B cells and antibodies in cancer: a comparison of clinical studies and preclinical models. AB - The primary immune role of B cells is to produce antibodies, but they can also influence T cell function via antigen presentation and, in some contexts, immune regulation. Whether their roles in tumour immunity are similar to those in other chronic immune responses such as autoimmunity and chronic infection, where both pro- and anti-inflammatory roles have been described, remains controversial. Many studies have aimed to define the role of B cells in antitumor immune responses, but despite this considerable body of work, it is not yet possible to predict how they will affect immunity to any given tumour. In many human cancers, the presence of tumour-infiltrating B cells and tumour-reactive antibodies correlates with extended patient survival, and this clinical observation is supported by data from some animal models. On the other hand, T cell responses can be adversely affected by B cell production of immunoregulatory cytokines, a phenomenon that has been demonstrated in humans and in animal models. The isotype and concentration of tumour-reactive antibodies may also influence tumour progression. Recruitment of B cells into tumours may directly reflect the subtype and strength of the anti-tumour T cell response. As the response becomes chronic, B cells may attenuate T cell responses in an attempt to decrease host damage, similar to their described role in chronic infection and autoimmunity. Understanding how B cell responses in cancer are related to the effectiveness of the overall anti-tumour response is likely to aid in the development of new therapeutic interventions against cancer. PMID- 27222054 TI - ESGAR 2016 Book of Abstracts. PMID- 27222053 TI - Antennal transcriptome analysis of the Asian longhorned beetle Anoplophora glabripennis. AB - Olfactory proteins form the basis of insect olfactory recognition, which is crucial for host identification, mating, and oviposition. Using transcriptome analysis of Anoplophora glabripennis antenna, we identified 42 odorant-binding proteins (OBPs), 12 chemosensory proteins (CSPs), 14 pheromone-degrading enzymes (PDEs), 1 odorant-degrading enzymes (ODE), 37 odorant receptors (ORs), 11 gustatory receptors (GRs), 2 sensory neuron membrane proteins (SNMPs), and 4 ionotropic receptor (IR). All CSPs and PBPs were expressed in antennae, confirming the authenticity of the transcriptome data. CSP expression profiles showed that AglaCSP3, AglaCSP6, and AglaCSP12 were expressed preferentially in maxillary palps and AglaCSP7 and AglaCSP9 were strongly expressed in antennae. The vast majority of CSPs were highly expressed in multiple chemosensory tissues, suggesting their participation in olfactory recognition in almost all olfactory tissues. Intriguingly, the PBP AglaPBP2 was preferentially expressed in antenna, indicating that it is the main protein involved in efficient and sensitive pheromone recognition. Phylogenetic analysis of olfactory proteins indicated AglaGR1 may detect CO2. This study establishes a foundation for determining the chemoreception molecular mechanisms of A. glabripennis, which would provide a new perspective for controlling pest populations, especially those of borers. PMID- 27222056 TI - Topical Use of Mammalian Target of Rapamycin (mTOR) Inhibitors in Tuberous Sclerosis Complex-A Comprehensive Review of the Literature. AB - BACKGROUND: Tuberous sclerosis complex is a genetically determined multisystem disorder that may affect almost any human organ. The discovery of the mammalian target of rapamycin (mTOR) pathway and its involvement in tuberous sclerosis complex-related pathology has led to the introduction of mTOR inhibitors into clinical practice. Topical administration of mTOR inhibitors for skin lesions related to tuberous sclerosis complex may represent a reasonable alternative for more invasive procedures. A growing number of patients have been described exhibiting positive therapeutic effects from the topical administration of these agents. The aim of this review was to systematically analyze available literature on the use of topical mTOR inhibitors to treat dermatologic lesions related to tuberous sclerosis complex. RESULTS: A comprehensive review of PubMed, Medscape, and Cochrane databases between 1995 and 2015 was performed to identify available studies describing topical use of mTOR inhibitors in individuals with tuberous sclerosis complex. In most studies, topical mTOR inhibitor application proved to be effective in the treatment of skin lesions related to tuberous sclerosis complex. Facial angiofibromas were the target lesions in most instances. Few studies reported clinical improvement of hypomelanotic macules. These drugs directly address the molecular defect related to tuberous sclerosis complex manifestations. CONCLUSIONS: Currently available clinical data suggest that topical application of mTOR inhibitors may be effective in the treatment of facial angiofibromas associated with tuberous sclerosis complex. Ongoing randomized clinical trials of topical mTOR inhibitors for TSC-related cutaneous lesions should add clarity to the role of these agents. PMID- 27222055 TI - Clinical and radiological features of extra-pulmonary sarcoidosis: a pictorial essay. AB - The aim of this manuscript is to describe radiological findings of extra pulmonary sarcoidosis. Sarcoidosis is an immune-mediated systemic disease of unknown origin, characterized by non-caseating epitheliod granulomas. Ninety percent of patients show granulomas located in the lungs or in the related lymph nodes. However, lesions can affect any organ. Typical imaging features of liver and spleen sarcoidosis include visceromegaly, with multiple nodules hypodense on CT images and hypointense on T2-weighted MRI acquisitions. Main clinical and radiological manifestations of renal sarcoidosis are nephrolithiasis, nephrocalcinosis, and acute interstitial nephritis. Brain sarcoidosis shows multiple or solitary parenchymal nodules on MRI that enhance with a ring-like appearance after gadolinium. In spinal cord localization, MRI demonstrates enlargement and hyperintensity of spinal cord, with hypointense lesions on T2 weighted images. Skeletal involvement is mostly located in small bone, showing many lytic lesions; less frequently, bone lesions have a sclerotic appearance. Ocular involvement includes uveitis, conjunctivitis, optical nerve disease, chorioretinis. Erythema nodosum and lupus pernio represent the most common cutaneous manifestations encountered. Sarcoidosis in various organs can be very insidious for radiologists, showing different imaging features, often non specific. Awareness of these imaging features helps radiologists to obtain the correct diagnosis. TEACHING POINTS: * Systemic sarcoidosis can exhibit abdominal, neural, skeletal, ocular, and cutaneous manifestations. * T2 signal intensity of hepatosplenic nodules may reflect the disease activity. * Heerfordt's syndrome includes facial nerve palsy, fever, parotid swelling, and uveitis. * In the vertebrae, osteolytic and/or diffuse sclerotic lesions can be found. * Erythema nodosum and lupus pernio represent the most common cutaneous manifestations. PMID- 27222057 TI - Structures of potassium calix[4]arene crown ether inclusion complexes and application in polymerization of rac-lactide. AB - Reaction of 1,3-dipropoxy-p-tert-butyl-calix[4]arene (L(1)H2) with KN(SiMe3)2 afforded a one-dimensional (1D) chain complex [K2L(1)]n (1). Upon reaction with 1 equivalent 18-crown-6, complex 1 can convert to complex [K2(18-crown-6)L(1)] (2) which possesses a sandwich structure. Treatment of two calix[4]arene-crown ligands of 1,3-dihydroxy-p-tert-butyl-calix[4]arene-crown-5 (L(2)H2) and 1,2 dihydroxy-p-tert-butyl-calix[4]arene-crown-5 (L(3)H2) with KN(SiMe3)2 gave the dinuclear complex [K2L(2)] (3) and the mononuclear complex [K(THF)L(3)H] (4), respectively. Complexes 1-4 were all characterized by single-crystal X-ray diffraction techniques. The variable temperature (1)H NMR spectrum indicates there is a quick rotation equilibrium of the two phenoxy groups in complex 3. In addition, complexes 1-4 have been tested for the ring-opening polymerization (ROP) of rac-lactide and the results showed that complexes 2 and 3 are highly active for the ROP of rac-lactide. The obtained polymers displayed low dispersity values (D) and the molecular weights are close to the calculated ones. Furthermore, complexes 2 and 3 show moderate isoselectivities of Pm = 0.67 and Pm = 0.73, respectively. PMID- 27222058 TI - Correlated probit analysis of repeatedly measured ordinal and continuous outcomes with application to the Health and Retirement Study. AB - The Health and Retirement Study was designed to evaluate changes in health and labor force participation during and after the transition from working to retirement. Every 2 years, participants provided information about their self rated health (SRH), body mass index (BMI), smoking status, and other characteristics. Our goal was to assess the effects of smoking and gender on trajectories of change in BMI and SRH over time. Joint longitudinal analysis of outcome measures is preferable to separate analyses because it allows to account for the correlation between the measures, to test the effects of predictors while controlling type I error, and potentially to improve efficiency. However, because SRH is an ordinal measure while BMI is continuous, formulating a joint model and parameter estimation is challenging. A joint correlated probit model allowed us to seamlessly account for the correlations between the measures over time. Established estimating procedures for such models are based on quasi-likelihood or numerical approximations that may be biased or fail to converge. Therefore, we proposed a novel expectation-maximization algorithm for parameter estimation and a Monte Carlo bootstrap approach for standard errors approximation. Expectation maximization algorithms have been previously considered for combinations of binary and/or continuous repeated measures; however, modifications were needed to handle combinations of ordinal and continuous responses. A simulation study demonstrated that the algorithm converged and provided approximately unbiased estimates with sufficiently large sample sizes. In the Health and Retirement Study, male gender and smoking were independently associated with steeper deterioration in self-rated health and with lower average BMI. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27222059 TI - Symptom trajectory and symptom burden in older people with multimorbidity, secondary outcome from the RCT AGe-FIT study. AB - AIM: The aim of this study was to follow the symptom trajectory of community dwelling older people with multimorbidity and to explore the effect on symptom burden from an ambulatory geriatric care unit, based on comprehensive geriatric assessment. BACKGROUND: Older community-dwelling people with multimorbidity suffer from a high symptom burden with a wide range of co-occurring symptoms often resulting to decreased health-related quality of life. There is a need to move from a single-disease model and address the complexity of older people living with multimorbidity. DESIGN: Secondary outcome data from the randomized controlled Ambulatory Geriatric Assessment Frailty Intervention Trial (AGe-FIT). METHODS: Symptom trajectory of 31 symptoms was assessed with the Memorial Symptom Assessment Scale. Data from 247 participants were assessments at baseline, 12 and 24 months, 2011-2013. Participants in the intervention group received care from an ambulatory geriatric care unit based on comprehensive geriatric assessment in addition to usual care. RESULTS: Symptom prevalence and symptom burden were high and stayed high over time. Pain was the symptom with the highest prevalence and burden. Over the 2-year period 68-81% of the participants reported pain. Other highly prevalent and persistent symptoms were dry mouth, lack of energy and numbness/tingling in the hands/feet, affecting 38-59% of participants. No differences were found between the intervention and control group regarding prevalence, burden or trajectory of symptoms. CONCLUSIONS: Older community dwelling people with multimorbidity had a persistent high burden of symptoms. Receiving advanced interdisciplinary care at an ambulatory geriatric unit did not significantly reduce the prevalence or the burden of symptoms. PMID- 27222060 TI - Timosaponin B-II Ameliorates Palmitate-Induced Insulin Resistance and Inflammation via IRS-1/PI3K/Akt and IKK/NF-[Formula: see text]B Pathways. AB - This study aimed to investigate the effect of timosaponin B-II (TB-II) on palmitate (PA)-induced insulin resistance and inflammation in HepG2 cells, and probe the potential mechanisms. TB-II, a main ingredient of the traditional Chinese medicine Anemarrhena asphodeloides Bunge, notably ameliorated PA-induced insulin resistance and inflammation, and significantly improved cell viability, decreased PA-induced production of tumor necrosis factor-[Formula: see text] (TNF [Formula: see text]) and interleukin-6 (IL-6) levels. Further, TB-II treatment notably decreased malondialdehyde (MDA) and lactate dehydrogenase (LDH) levels, and improved superoxide dismutase (SOD) and nitric oxide (NO). TB-II also reduced HepG2 cells apoptosis. Insulin receptor substrate-1 (IRS1)/phosphatidylinositol 3 kinase (PI3K)/Akt and inhibitor of nuclear factor [Formula: see text]-B kinase (IKK)/NF-[Formula: see text]B pathways-related proteins, and IKK[Formula: see text], p65 phosphorylation, serine phosphorylation of insulin receptor substrate 1 (IRS-1) at S307, tyrosine phosphorylation of IRS-1, and Akt activation were determined by Western blot. Compared to model group, TB-II significantly downregulated the expression of p-NF-[Formula: see text]Bp65, p-IKK[Formula: see text], p-IRS-1, p-PI3K and p-Akt. TB-II is a promising potential agent for the management of palmitate-induced insulin resistance and inflammation, which might be via IR/IRS-1/PI3K/Akt and IKK/NF-[Formula: see text]B pathways. PMID- 27222061 TI - Tanshinone IIA Protects Against Folic Acid-Induced Acute Kidney Injury. AB - Tanshinone IIA is a diterpene extracted from Salvia miltiorrhiza, a popular and safe herb medicine that has been widely used in China and other Asian countries. Previous studies have demonstrated the pleiotropic effects of Tanshinone IIA on many disease treatments via its antitoxicity, anti-inflammation, anti-oxidative stress, as well as antifibrosis activities. However, its effect on acute kidney injury (AKI) has not been fully investigated. Here, we show for the first time that systemic administration of Tanshinone IIA can lead to improved kidney function in folic acid-induced kidney injury mice. In the acute phase of AKI, Tanshinone IIA attenuated renal tubular epithelial injury, as determined by histologic changes and the detection of Neutrophil gelatinase-associated lipocalin (NGAL) in the kidney and urine. Additionally, Tanshinone IIA treatment resulted in elevated proliferating cell nuclear antigen (PCNA) expression and decreased inflammatory cells infiltration as well as chemokine expression, suggesting that Tanshinone IIA promoted renal repair following AKI and inhibited local inflammatory response in the injured kidney. This led to decreased long term fibrosis in the injured kidney, characterized by less accumulation of fibronectin and collagen I in tubulointerstitium. Taken together, these results suggest that Tanshinone IIA may represent a potential approach for AKI treatment. PMID- 27222062 TI - Punicalagin Prevents Hypoxic Pulmonary Hypertension via Anti-Oxidant Effects in Rats. AB - Punicalagin (PG), a major bioactive ingredient in pomegranate juice, has been proven to have anti-oxidative stress properties and to exert protective effects on acute lung injuries induced by lipopolysaccharides. This study aimed to investigate the effects of PG treatment on hypoxic pulmonary hypertension (HPH) and the underlying mechanisms responsible for the effects. Rats were exposed to 10% oxygen for 2 wk (8 h/day) to induce the HPH model. PG (5, 15, 45[Formula: see text]mg/kg) was orally administered 10[Formula: see text]min before hypoxia each day. PG treatments at the doses of 15 and 45[Formula: see text]mg/kg/d decreased the mean pulmonary arterial pressure (mPAP) and alleviated right ventricular hypertrophy and vascular remodeling in HPH rats. Meanwhile, PG treatment attenuated the hypoxia-induced endothelial dysfunction of pulmonary artery rings. The beneficial effects of PG treatment were associated with improved nitric oxide (NO)-cGMP signaling and reduced oxidative stress, as evidenced by decreased superoxide generation, gp91[Formula: see text] expression and nitrotyrosine content in the pulmonary arteries. Furthermore, tempol's scavenging of oxidative stress also increased NO production and attenuated endothelial dysfunction and pulmonary hypertension in HPH rats. Combining tempol and PG did not exert additional beneficial effects compared to tempol alone. Our study indicated for the first time that PG treatment can protect against hypoxia-induced endothelial dysfunction and pulmonary hypertension in rats, which may be induced via its anti oxidant actions. PMID- 27222063 TI - Suppressive Effects of Pelargonidin on Endothelial Protein C Receptor Shedding via the Inhibition of TACE Activity and MAP Kinases. AB - Beyond its role in the activation of protein C, the endothelial cell protein C receptor (EPCR) plays an important role in the cytoprotective pathway. EPCR can be shed from the cell surface, which is mediated by tumor necrosis factor [Formula: see text] converting enzyme (TACE). Pelargonidin is a well-known red pigment found in plants, and has been reported to have important biological activities that are potentially beneficial to human health. However, little is known about the effects of pelargonidin on EPCR shedding. We investigated this issue by monitoring the effects of pelargonidin on phorbol-12-myristate 13 acetate (PMA)-, tumor necrosis factor (TNF)-[Formula: see text]-, interleukin (IL)-1beta-, and cecal ligation and puncture (CLP)-mediated EPCR shedding and by investigating the underlying mechanism of pelargonidin action. Data demonstrate that pelargonidin induced potent inhibition of PMA-, TNF-[Formula: see text]-, IL 1beta-, and CLP-induced EPCR shedding by inhibiting the phosphorylation of mitogen-activated protein kinases (MAPKs) such as p38, janus kinase (JNK), and extracellular signal-regulated kinase (ERK) 1/2. Pelargonidin also inhibited the expression and activity of PMA-induced TACE in endothelial cells. These results demonstrate the potential of pelargonidin as an anti-EPCR shedding reagent against PMA- and CLP-mediated EPCR shedding. PMID- 27222064 TI - Anti-Aging Effect of Siraitia grosuenorii by Enhancement of Hematopoietic Stem Cell Function. AB - Anti-aging has always been a popular topic, and there are many claims about the existence of factors that can slow, stop, or even reverse the aging process. Siraitia grosuenorii, a local fruit in china, has been used for the treatment of gastritis, sore throats, and whooping cough in traditional Chinese medicine. The individuals who took the juice of Siraitia grosuenorii regularly had increased longevity in the Guangxi Province, which is located in the Southern part of China. In this paper, we fed mice with Siraitia grosuenorii for 10 months to identify the role of Siraitia grosuenorii in anti-aging and to investigate its corresponding mechanism. The results showed that mice fed with Siraitia grosuenorii displayed a slower aging process. The extension of the aging process was due to the enhanced function of HSCs. FACS analysis showed that the number of LSKs, LT-HSCs, ST-HSCs and MPPs from Siraitia grosuenorii mice was decreased. In vitro, a clonigenic assay showed that LT-HSCs from Siraitia grosuenorii mice increased the ability of self-renewal. Moreover, Siraitia grosuenorii mice maintained the quiescence of LSKs, decreased the level of ROS and reduced the amount of senescence associated beta-gal positive cells. Furthermore, Siraitia grosuenorii mice decreased the expression of senescence-associated proteins. Siraitia grosuenorii maintained quiescence, decreased senescence and enhanced the function of HSCs, slowing the aging process of mice. PMID- 27222065 TI - Electroacupuncture Ameliorates Propofol-Induced Cognitive Impairment via an Opioid Receptor-Independent Mechanism. AB - While general anesthesia is known to induce cognitive deficits in elderly and pediatric patients, its influence on adults is less well-characterized. The present study was designed to evaluate the influence of propofol on the learning and memory of young adult rats, as well as the potential neuroprotective role of electroacupuncture (EA) in propofol-induced cognitive impairment. Intravenous anesthesia with propofol was administered to young adult male Sprague-Dawley (SD) rats for 6 h, and EA was administered three times before and after anesthesia. The Morris Water Maze (MWM) test was conducted to determine the rat's cognitive performance following the anesthesia treatment. Our results showed that propofol induced obvious cognitive impairment in young adult rats, which could be ameliorated by multiple EA treatments. Moreover, the decreased level of phosphorylated glycogen synthase kinase 3 beta (pGSK-3beta) in the CA1 region of the hippocampus accompanying the cognitive impairment was also reversed by EA treatment. Further experiments demonstrated that neither 2 nor 10 mg/kg (I.P.) naloxone blocked the effect of EA, indicating that the neuroprotective effect of EA on propofol-induced cognitive impairment was not mediated via the opioid receptors. The present study suggests that EA could ameliorate the cognitive impairment induced by prolonged anesthesia with propofol in young adult rats, which is likely associated with pGSK-3beta levels in the CA1 independently of opioid receptors. These findings imply that EA may be used as a potential neuroprotective therapy for post-operative cognitive dysfunction (POCD). PMID- 27222067 TI - Cytotoxicity of Salvia miltiorrhiza Against Multidrug-Resistant Cancer Cells. AB - Salvia miltiorrhiza Bunge (Lamiaceae) is a well-known Chinese herb that possesses numerous therapeutic activities, including anticancer effects. In this study, the cytotoxicity and the biological mechanisms of S. miltiorrhiza (SM) root extract on diverse resistant and sensitive cancer cell lines were investigated. CEM/ADR5000 cells were 1.68-fold resistant to CCRF-CEM cells, while HCT116 (p53[Formula: see text] and U87.MG[Formula: see text]EGFR cells were hypersensitive (collateral sensitive) compared to their parental cells. SM root extract stimulated ROS generation, cell cycle S phase arrest and apoptosis. The induction of the intrinsic apoptotic pathway was validated by increased cleavage of caspase 3, 7, 9 and poly ADP-ribose polymerase (PARP). MAP kinases including JNK, ERK1/2 and p38 were obviously phosphorylated and nuclear P65 was downregulated upon SM treatment. Transcriptome-wide COMPARE analysis revealed that the expression of encoding genes with diverse functions were associated with the cellular response to cryptotanshinone, one of the main constituents of SM root extract. In conclusion, SM root extract exerted profound cytotoxicity towards various sensitive and resistant cancer cells and induced the intrinsic apoptotic pathway. PMID- 27222066 TI - Traditional Chinese Medications for Knee Osteoarthritis Pain: A Meta-Analysis of Randomized Controlled Trials. AB - Traditional Chinese medication (TCM) has analgesic and anti-inflammatory effects in patients with knee osteoarthritis (OA). We conducted the first systematic review of the best quantitative and qualitative evidence currently available in order to evaluate the effectiveness of TCM in relieving pain in knee OA. A comprehensive literature search was conducted using three English and four Chinese biomedical databases from their inception through March 1, 2015. We included randomized controlled trials of TCM for knee OA with intervention durations of at least two weeks. The effects of TCM on pain and other clinical symptoms were measured with the visual analog scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). The total effectiveness rate, which was used to assess overall pain, physical performance and wellness, was also measured. Two researchers independently extracted data on study design, population characteristics, duration, intervention, outcomes, risk of bias, and primary results. We performed a random-effects meta-analysis when appropriate. We also explored factors that could explain the heterogeneity by conducting subgroup and meta-regression analyses. Twenty-three studies, totaling 2362 subjects, met the eligibility criteria. Treatments were formulated with an average of 8 Chinese herbs and were prescribed based on the traditional Chinese diagnostic method of syndrome differentiation. The mean treatment duration was seven weeks, with oral administration occurring one to three times a day. Compared with non-steroidal anti-inflammatory drugs and intra-articular hyaluronate injections, 18 of the studies showed significantly improved VAS pain scores (Mean Difference [MD] [Formula: see text] 0.56; 95% confidence interval [CI], 0.18 to 0.94; [Formula: see text]), six of the studies showed significantly improved WOMAC pain subscale scores (MD [Formula: see text] 2.23; 95% CI, 0.56 to 3.91; [Formula: see text]), and 16 of the trials showed significantly improved total effectiveness rates (risk ratio [Formula: see text] 1.12; 95% CI, 1.05 to 1.19; [Formula: see text] 0.0003). In addition, TCM showed a lower risk of adverse events than standard western treatments. This evidence suggests that TCM is safe and effective for improving pain, function, and wellness in treatments of knee OA. However, there is inherent clinical heterogeneity (diverse TCM formulations, controls, and treatment regimens) among the included trials. Despite these limitations, the potential analgesic effects of TCM warrant further methodologically rigorous research to determine the clinical implications of TCM on pain management in knee OA. PMID- 27222068 TI - Effects of Panax notoginseng on the Metastasis of Human Colorectal Cancer Cells. AB - The goal of this study was to investigate the effect of the Panax notoginseng ethanol extract (PNEE) on the regulation of human colorectal cancer (CRC) metastasis. The migratory, invasive, and adhesive abilities and the expression of metastasis-associated regulatory molecules in cultured human CRC cells (HCT-116) treated with the PNEE were analyzed in this study. The migratory and invasive abilities of HCT-116 cells were reduced after PNEE treatment. The incubation of HCT-116 cells with the PNEE for 24 h decreased MMP-9 expression and increased E cadherin expression compared with the control group. The adhesion reaction assay indicated that treatment with the PNEE led to significantly decreased HCT-116 adhesion to endothelial cells (EA.hy926 cells). The integrin-1 protein levels in HCT-116 cells were significantly decreased following treatment with the PNEE. Similarly, the protein levels of E-selectin and intercellular adhesion molecule-1 (ICAM-1) were significantly decreased by treatment of the EA.hy926 endothelial cells with PNEE. A scanning electron microscope (SEM) examination indicated that HCT-116 cells treated with LPS combined with the PNEE had a less flattened and retracted shape compared with LPS-treated cells, and this change in shape was found to be a phenomenon of extravasation invasion. The transepithelial electrical resistance (TEER) of the EA.hy926 endothelial cell monolayer increased after incubation with the PNEE for 24 h. A cell-cell permeability assay indicated that HCT-116 cells treated with the PNEE displayed significantly reduced levels of phosphorylated VE-cadherin (p-VE-cadherin). These results demonstrate the antimetastatic properties of the PNEE and show that the PNEE affects cells by inhibiting cell migration, invasion, and adhesion and regulating the expression of metastasis-associated signaling molecules. PMID- 27222069 TI - Modulation of the Tumor Metastatic Microenvironment and Multiple Signal Pathways by Prunella vulgaris in Human Hepatocellular Carcinoma. AB - Prunella vulgaris (PV) is a traditional Chinese medicine that has been used clinically for centuries in Asian countries to treat herpetic keratitis. In previous studies, PV was shown to suppress TPA-induced activation of MMP-9 and inhibit cell invasion and migration in hepatoma cell lines. However, the detailed molecular mechanism underlying these effects is still unclear. In this study, we investigated the mechanisms underlying PV-mediated inhibition of 12-O Tetradecanoylphorbol-13-acetate (TPA)-induced cell invasion and inhibition of secreted and cytosolic MMP-9 production in human hepatoma cells (Huh-7 and HA22T). PV suppressed VEGF and MMP-9 transcription by inhibiting activator protein (AP)-1 and nuclear factor-[Formula: see text]B (NF-[Formula: see text]B) activity. PV suppressed TPA-induced AP-1 activity by inhibiting phosphorylation of the extracellular signal-related kinase (ERK), downregulating p38 signaling pathways, and suppressing TPA-induced inhibition of NF-[Formula: see text]B nuclear translocation through I[Formula: see text]B. PV suppressed TPA-induced activation of ERK/phosphatidylinositol-3-kinase/Akt upstream of NF-[Formula: see text]B and AP-1. These data suggest that PV modifies the metastatic microenvironment of hepatocellular carcinoma (HCC) by inhibiting multiple signal transduction pathways. PV thus may have the therapeutic potential to inhibit the migration and invasion of HCC and act as potential agent for systemic therapies. PMID- 27222070 TI - Geniposide Inhibits Alpha-Naphthylisothiocyanate-Induced Intrahepatic Cholestasis: The Downregulation of STAT3 and NF[Formula: see text]B Signaling Plays an Important Role. AB - Traditional medicinal formulation of Yin-zhi-huang (YZH) is widely used in the clinic for the treatment of jaundice and chronic liver diseases in East Asian countries. However, the pharmacologically active components of YZH and the underlying mechanism are still unknown. Geniposide (GEN) was recently identified as one of the most abundant circulating components in YZH. In this study, we investigated the protective effect of GEN against liver injuries induced by alpha naphthylisothiocyanate (ANIT). 50[Formula: see text]mg/kg of GEN was administered to ICR mice once daily for 5 days, and challenge of ANIT 75[Formula: see text]mg/kg was performed on the 4th day. Blood and liver tissues were collected on day 6 and subjected to biochemical, histopathological and pathway analyses. The biochemical and pathological findings showed that GEN almost totally attenuated ANIT-induced cholestasis and liver injury compared with the vehicle/ANIT group. The altered gene transcription related to bile acid metabolism and transport was normalized by co-treatment with GEN. The expressions of tumor necrosis factor-[Formula: see text] and the suppressor of cytokine signaling 3 were significantly decreased in the GEN/ANIT group. Western blot revealed that GEN inhibited the activation and expression of STAT3 and NF[Formula: see text]B. These data suggest GEN inhibits ANIT-induced hepatotoxicity. The protective effect is associated with the downregulation of STAT3 and NF[Formula: see text]B signaling. PMID- 27222071 TI - Screening of Intestinal Bacterial Metabolites of Platycodin D Using Ultra Performance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry. AB - Platycodin D (PD), a bioactive triterpenoid saponin isolated from Platycodi Radix (PR), possesses a vast range of biological activities. Although the pharmacological activities and pharmacokinetics of PD have been well demonstrated, information regarding the intestinal metabolisms of PD is very limited. In this study, human and rat fecal microflora were prepared and anaerobically incubated with PD at 37[Formula: see text]C for 48[Formula: see text]h, respectively. A highly sensitive and specific ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was developed for the analysis of PD and related metabolites in the reaction samples. A Liquid-liquid extraction method was used for sample pretreatment and the chromatographic separation was performed on a 1.7 [Formula: see text]m particle size Syncronis C[Formula: see text] column using gradient elution system. Finally, a total of seven metabolites were detected and tentatively identified, such as the demethylation metabolite (M1), deoxidation metabolites (M3, M7) and hydrolysis at the C-28 oligosaccharide metabolites (M5, M6), which were first discovered in this experiment. The results indicate that hydrolysis, demethylation, dehydroxylation, and acetylation were the major metabolic pathways of PDin vitro. Additionally, four bacterial strains from human feces including Enterococcus sp.41, Bacillus sp.46, Escherichia sp.49 A and Escherichia sp.64 were detected and further identified with 16S rRNA gene sequencing due to their relatively strong metabolic capacity toward PD. The present study provides important information about the metabolism of PD, which will help elucidate the impact of intestinal bacteria on this active component. PMID- 27222073 TI - The MIHARI project: establishing a new framework for pharmacoepidemiological drug safety assessments by the Pharmaceuticals and Medical Devices Agency of Japan. PMID- 27222072 TI - Evaluation of serum nucleoside diphosphate kinase A for the detection of colorectal cancer. AB - We previously described the over-expression of nucleoside diphosphate kinase A (NDKA) in tumours and serum from colorectal cancer (CRC) patients, suggesting its use as biomarker. In this study we evaluated the diagnostic accuracy of serum NDKA to detect advanced neoplasia (CRC or advanced adenomas). Furthermore, the performance of NDKA was compared with the faecal immunochemical test (FIT). The study population included a case-control cohort and a screening cohort (511 asymptomatic first-degree relatives of CRC patients that underwent a colonoscopy and a FIT). Serum NDKA was elevated in CRC patients in the case-control cohort (p = 0.002). In the screening cohort, NDKA levels were higher for advanced adenomas (p = 0.010) and advanced neoplasia (p = 0.006) compared to no neoplasia. Moreover, elevated NDKA was associated with severe characteristics of adenomas (>=3 lesions, size >= 1 cm or villous component). Setting specificity to 85%, NDKA showed a sensitivity of 30.19% and 29.82% for advanced adenomas and advanced neoplasia, respectively. NDKA combined with FIT (100 ng/mL cut-off) detected advanced adenomas and advanced neoplasia with 45.28% and 49.12% sensitivity, with specificity close to 90%. The combination of serum NDKA and FIT can improve the detection of advanced neoplasia, mainly for lesions located on the proximal colon, in asymptomatic individuals with CRC family-risk. PMID- 27222074 TI - Interface Engineering for the Enhancement of Carrier Transport in Black Phosphorus Transistor with Ultra-Thin High-k Gate Dielectric. AB - Black phosphorus (BP) is the most stable allotrope of phosphorus which exhibits strong in-plane anisotropic charge transport. Discovering its interface properties between BP and high-k gate dielectric is fundamentally important for enhancing the carrier mobility and electrostatics control. Here, we investigate the impact of interface engineering on the transport properties of BP transistors with an ultra-thin hafnium-dioxide (HfO2) gate dielectric of ~3.4 nm. A high hole mobility of ~536 cm(2)V(-1)s(-1) coupled with a near ideal subthreshold swing (SS) of ~66 mV/dec were simultaneously achieved at room temperature by improving the BP/HfO2 interface quality through thermal treatment. This is attributed to the passivation of phosphorus dangling bonds by hafnium (Hf) adatoms which produces a more chemically stable interface, as evidenced by the significant reduction in interface states density. Additionally, we found that an excessively high thermal treatment temperature (beyond 200 degrees C) could detrimentally modify the BP crystal structure, which results in channel resistance and mobility degradation due to charge-impurities scattering and lattice displacement. This study contributes to an insight for the development of high performance BP-based transistors through interface engineering. PMID- 27222075 TI - Electric field effects on the electronic properties of the silicene-amine interface. AB - We performed first-principles studies of electric field (EF) effects on the electronic properties of silicene-amine (NH3 and NH2CH3) hetero-interface systems focusing on the electronic interactions at the interface. The band gaps of the systems increase with a positive applied EF but decrease with a negative EF; that is, the band gaps monotonically vary on changing the applied EF from negative to positive. The phenomenon of band gap variation with the sign of the applied EF is a characteristic feature of hetero-interface systems. We revealed the mechanism of the electronic structure change in silicene-amine due to an applied EF by visualizing the electron density change. It is shown that the electronic polarizations in both the Si-N chemical bond region and the silicene-layer region determine the characteristic band gap variation. Furthermore, the tunable energy range of the band gap of the silicene-amine is considerably higher than the range of a silicene monolayer; thus, the idea of controlling the band gaps of hetero interface systems in combination with application of an EF bias is suitable for designing various devices that are difficult to fabricate with homogeneous two dimensional materials such as silicene and graphene. PMID- 27222076 TI - Biological adaptability under seasonal variation of light/dark cycles. AB - 3A substantial amount of experimental models designed to understand rhythms entrainment and the effects of different regimens of light exposure on health have been proposed. However, many of them do not relate to what occurs in real life. Our objective was to evaluate the influence of "seasonal-like" variation in light/dark cycles on biological rhythms. Twenty adult male Wistar rats were assigned to three groups: control (CT), kept in 12:12 light/dark (LD) cycle; long photoperiod/short photoperiod (LP/SP), kept in 16.5:7.5 LD cycle for 18 days (phase A), then 17 days of gradual reductions in light time (phase B), then 18 days of shorter exposure (7.5:16.5 LD cycle, phase C); short photoperiod/long photoperiod (SP/LP) group, with same modifications as the LP/SP group, but in reverse order, starting phase A in 7.5:16.5 LD cycle. Activity and temperature were recorded constantly, and melatonin and cortisol concentrations were measured twice. Activity and temperature acrophases of all groups changed according to light. The correlation between activity and temperature was, overall, significantly lower for SP/LP group compared with LP/SP and CT groups. Regarding melatonin concentration, LP/SP group showed significant positive correlation between phase A and C (p = 0.018). Animals changed temperature and activity according to photoperiod and demonstrated better adaptability in transitioning from long to short photoperiod. Since this model imitates seasonal variation in light in a species that is largely used in behavioral experiments, it reveals promising methods to improve the reliability of experimental models and of further environmental health research. PMID- 27222077 TI - If they don't degrade can indwelling pleural catheters evolve? PMID- 27222078 TI - Transition from anatomy school to the operating theatre for strabismus surgeons. PMID- 27222079 TI - Patients with chronic kidney disease have abnormal upper gastro-intestinal tract digestive function: A study of uremic enteropathy. AB - BACKGROUND AND AIM: Chronic kidney disease (CKD) affects gastrointestinal (GI) function and results in numerous adaptive and maladaptive responses. Disruption of the colonic microbiome and its attendant consequences-the loss of gut barrier integrity and increased generation of uremic toxins-has become well-recognized. However, less attention has been paid to characterizing the mechanisms behind dysfunction of the upper GI tract, largely owing to the difficulty of studying small bowel function in vivo. This present study was designed to comprehensively describe upper GI function in those with advanced renal impairment. METHODS: Thirty-five non-diabetic subjects (12 CKD stage 4/5 patients, 23 healthy controls) underwent detailed GI magnetic resonance imaging (MRI) in both fasted and fed states. Upper GI function was assessed by quantification of gastric emptying and intra-luminal small bowel water. Characterization of hydration and cardiovascular status was performed at baseline. Gut barrier integrity was assessed using serum endotoxin level. RESULTS: Chronic kidney disease was associated with dysmotility (gastric half-emptying time 96 +/- 32 vs 74 +/- 27 min, P = 0.04) and reduced fasting and post-prandial small bowel water (36 +/- 22 mL vs 78 +/- 42 mL, P < 0.001), reflecting abnormal digestive secretion, and absorption. This was related to the degree of endotoxemia (r = -0.60, P = 0.04) and poorer symptom scores, but not to disease severity, arterial stiffness or hydration status. CONCLUSION: Chronic kidney disease adversely affects digestive function. Abnormalities in digestive secretion and absorption may potentially have a broad impact in the prevention and treatment of both CKD and its complications. Further study is required to assess the factors that contribute to this dysfunction in a wider CKD population. PMID- 27222080 TI - Painful losses. PMID- 27222081 TI - [Treatment adherence with levetiracetam: a non-interventionist retrospective observation-based study]. AB - INTRODUCTION: Treatment adherence is a factor that is affecting the effectiveness of antiepileptic drugs. Levetiracetam is a drug whose effectiveness and safety is well established and is available in different oral formulations (granulates in sachets, tablets, oral solution), but information on treatment adherence/compliance with these oral formulations is limited. AIM: To determine treatment adherence with levetiracetam formulations (granulates in sachets, tablets) in adult and elderly people. PATIENTS AND METHODS: Retrospective observational non-interventionist study. During the three months before the study patients should be treated with levetiracetam (granulates in sachets or tablets), either alone or in combination. Compliance tests (Green-Morisky modified test) as well as a satisfaction questionnaire investigator and patient/caregiver is assessed. Data were analyzed using SPSS v. 21.0 program. RESULTS: A total of 466 patients completed the study. The average age was 52.75 +/- 19.17 years old and the average over 65 years of 72.79 +/- 6.15. 55.4% were men. Compliance is related to the variable 'pharmaceutical formulation' and with age (p = 0.031). The risk of non-compliance was 86.4% higher among those taking tablets versus granulates in sachets of levetiracetam (odds ratio: 1.864). Likewise, the non compliance was greater among patients over 65 years. The non-compliance was related to attributing of memory failures. CONCLUSIONS: Patients older are more difficult to compliance. The granulates levetiracetam in sachets improves compliance. PMID- 27222082 TI - [A study of sexual function in migraine and cluster headache]. AB - INTRODUCTION: The sexual erectile dysfunction are common symptoms and many chronic diseases whose diagnosis will determine the therapeutic management of patients. AIM: To assess sexual function in men with migraine or cluster headache (CH) compared with a control group. SUBJECTS AND METHODS: Cross-sectional study of 34 patients with migraine, 31 patients with CH and 60 control subjects less than 46 years old. Erectile dysfunction was assessed using the International Index of Erectile Dysfunction (IIEF). Emotional state was evaluated using the Beck Depression Inventory. RESULTS: The average score on the IIEF was 68.41 +/- 10.09, 64.26 +/- 5.73 and 59.33 +/- 15.89 in the control group, migraine and CH respectively (p = 0.041) being the significant difference between controls and CH (p = 0.036). In the group of migraine patients, three patients had mild and one moderate erectile dysfunction. In the group of patients with CH, twelve scored in rank of mild erectile dysfunction, and two met the criteria for severe erectile dysfunction (p < 0.05). By analyzing differences in the different domains of IIEF, they were significant in the domain of overall satisfaction (p = 0.015) between the control group and patients with CH (p = 0.012). CONCLUSIONS: In our study we found a higher frequency of and involvement in sexual function in terms of overall satisfaction in patients with migraine and CH. We believe that the evaluation of sexual function in this type of headache should be integrated into our clinical practice. PMID- 27222083 TI - [Analysis of the nutritional status and body composition of persons with intellectual disability]. AB - INTRODUCTION: Intellectual disability refers to substantial limitations in intellectual functioning, affecting 0.7-1.5% of the population. People with intellectual disability have higher rates of obesity, since caloric values and nutritional status, are deficient. AIMS: To determine the nutritional habits, analyze the effectiveness of nutritional education and evaluate the possible effect of improvement introducing exercise and nutrition workshops, in a group of people with intellectual disability. PATIENTS AND METHODS: Clinical, nutritional and anthropometric (weight, height, body mass index, body fat, waist circumference) assessment was conducted in 47 patients. An ad hoc survey was designed in which exercise habits, medical and dietary history, record of 72 hours (including 2 weekdays and 1 weekend) and the adherence to Mediterranean diet data were collected. The workshops of exercise and nutrition counted with a structure of theoretical-practical explanation and games. RESULTS: 76.1% presented weight excess at baseline. After the intervention values of total body fat (-0.94 +/- 4.4%) and visceral fat (-0.86 +/- 2%), weight (-0.4 +/- 3.3 kg) and body mass index (-0.2 +/- 1.6 kg/m2) decreased, more in women than in men. 60.5% of subjects did not meet a high adherence to the Mediterranean diet. After nutritional intervention, a significant difference (p <= 0,001) was observed in the KidMed score. The workshop of physical activity had positive effects on the anthropometry of subjects. CONCLUSIONS: Both the intake and the prevalence of obesity in this group of people are inadequate. Nutritional education and physical exercise workshops are useful for working with this group, achieving significant changes to prevent obesity and improve their health. PMID- 27222084 TI - [Autosomal recessive GTPCH 1 deficiency: the importance of the analysis of neurotransmitters in cerebrospinal fluid]. AB - INTRODUCTION: A deficiency of the enzyme guanosine triphosphate cyclohydrolase I (GTPCH 1) causes a reduction in the synthesis of tetrahydrobiopterin (BH4), a cofactor that is essential in the synthesis of tyrosine, dopamine and serotonin. It is an infrequent disease that produces psychomotor delay or regression and movement disorders, although treatment can improve or even correct the clinical signs and symptoms. CASE REPORT: We report the case of a girl with autosomal recessive GTPCH deficiency, who was diagnosed at 14 months by means of an analysis of the cerebrospinal fluid with pterin, HVA and 5-HIAA deficiency, and positive phenylalanine overload test and genetic study. The clinical features began at the age of 5 months with intermittent upper limb and brain tremors, both at rest and intentional, that disappeared after a month. Psychomotor development was normal, mild axial hypotonia being found in the examination while the complementary tests that were performed were normal. The patient later presented psychomotor regression with loss of head control, diminished active movements, difficulty in bimanual manipulation, hypomimia and severe global hypotonia, which was the reason for the study of a progressive encephalopathy. Following the diagnosis of GTPCH deficiency, replacement therapy was established with levodopa/carbidopa, OH tryptophan and BH4, with excellent progress made in motor and cognitive functioning. Today, the patient is 5 years old, has an adequate psychomotor development for her age, is in the third year of preschool education and has caught up with the level of the rest of her classmates. CONCLUSION: In this case attention must be drawn to the extremely satisfactory motor and cognitive improvement of the patient after starting replacement therapy, as in many cases the cognitive level is usually affected on a permanent basis. PMID- 27222085 TI - [The essence of essential tremor: neurochemical bases]. AB - INTRODUCTION: Essential tremor is the most frequent movement disorder in adults. It has been considered a benign disease, but can result in significant physical and psychosocial disability. Pharmacological treatment is still not very satisfactory. Its causation, pathophysiology and anatomy remain only partially understood. AIMS: An understanding of its neurochemical basis is essential to be able to develop more efficient therapies. We review what is currently known in this field in order to motivate further research and ideas that allow an enhanced understanding of the disease and which foster the development of new pharmacological therapies. DEVELOPMENT: We review the studies conducted to date in humans and in animal models of neurotransmitters (gamma-aminobutyric acid, glutamate, noradrenalin, serotonin, adenosine), proteins and other neurochemical phenomena, such as T-type calcium channels, in essential tremor. CONCLUSIONS: Four neurochemical dysfunctions have been described that basically occur in the cerebellum and the inferior olivary nucleus: alteration of the GABAergic system, increased post-inhibitory rebound via T-type calcium currents, decreased neuronal inhibition mechanisms and an increase in excitatory neurotransmitter activity. These neurochemical dysfunctions would involve an increase in the activity of the deep neurons of the cerebellum with an oscillatory activity that would shift to the thalamic nucleus and the motor cortex, which in turn would lead to the appearance of tremor. Further research is needed to be able to confirm these hypotheses and to continue to advance towards achieving more efficient pharmacological treatments for patients with essential tremor. PMID- 27222086 TI - [The dementia of King Ferdinand VI and the year with no king]. AB - INTRODUCTION: Ferdinand VI was king of Spain from 1746 until 1759. His last year of reign is known as the year without a king. Over this year the king suffered a rapidly progressive deterioration of his mental health status. The clinical condition has been always attributed to a pure psychiatric disorder, generally a bipolar disorder. DEVELOPMENT: We review the sources of information in the Spanish archives and libraries, in order to find clinical information about the illness suffered by the king. We made a clinical evaluation and discussion about the disease of the king according to the information that has been obtained and the different diseases that could have caused the illness. CONCLUSIONS: Last year clinical deterioration of Ferdinand VI started with the death of his lovely wife. At first, the symptoms were similar to the symptoms of a mayor depressive disorder. Although the king had a rapidly progressive deterioration with severe changes in behavior and conduct, long stay in bed, loss of sphincters control and seizures. During the last months of his life, the king fell into a state of prostration with a marked cognitive impairment. Although it is possible that Ferdinand VI could have had a previous psychiatric disorder, there is enough information to think about a rapidly progressive dementia as the main cause of his clinical worsening and dead. PMID- 27222087 TI - [Benefits of the combination of mucuna, green tea and levodopa/benserazide in Parkinson's disease]. PMID- 27222088 TI - [Overlap syndrome between myasthenia gravis and idiopathic inflammatory myopathies]. PMID- 27222089 TI - [How we, as neurologists, write. Reply]. PMID- 27222090 TI - [How we, as neurologists, write]. PMID- 27222091 TI - CRISPR-dCas9 and sgRNA scaffolds enable dual-colour live imaging of satellite sequences and repeat-enriched individual loci. AB - Imaging systems that allow visualization of specific loci and nuclear structures are highly relevant for investigating how organizational changes within the nucleus play a role in regulating gene expression and other cellular processes. Here we present a live imaging system for targeted detection of genomic regions. Our approach involves generating chimaeric transcripts of viral RNAs (MS2 and PP7) and single-guide RNAs (sgRNAs), which when co-expressed with a cleavage deficient Cas9 can recruit fluorescently tagged viral RNA-binding proteins (MCP and PCP) to specific genomic sites. This allows for rapid, stable, low-background visualization of target loci. We demonstrate the efficiency and flexibility of our method by simultaneously labelling major and minor satellite regions as well as two individual loci on mouse chromosome 12. This system provides a tool for dual-colour labelling, which is important for tracking the dynamics of chromatin interactions and for validating epigenetic processes identified in fixed cells. PMID- 27222092 TI - Recognising early onset neonatal sepsis: an essential step in appropriate antimicrobial use. AB - Early diagnosis and timely treatment of early onset neonatal sepsis (EOS) are essential to prevent life threatening complications. Subtle, nonspecific clinical presentation and low predictive values of biomarkers complicate early diagnosis. This uncertainty commonly results in unnecessary and prolonged empiric antibiotic treatment. Annually, approximately 395,000 neonates (7.9% of live term births) are treated for suspected EOS in the European Union, while the incidence of proven EOS varies between 0.01 and 0.53 per 1000 live births. Adherence to guidelines for the management of suspicion of EOS is poor. Pragmatic approaches to minimise overtreatment in neonates with suspected EOS, using combined stratified risk algorithms, based on maternal and perinatal risk factors, clinical characteristics of the neonate and sequential biomarkers are promising. PMID- 27222093 TI - E74-like factor 3 and nuclear factor-kappaB regulate lipocalin-2 expression in chondrocytes. AB - KEY POINTS: E74-like factor 3 (ELF3) is a transcription factor regulated by inflammation in different physio-pathological situations. Lipocalin-2 (LCN2) emerged as a relevant adipokine involved in the regulation of inflammation. In this study we showed for the first time the involvement of ELF3 in the control of LCN2 expression and its cooperation with nuclear factor-kappaB (NFkappaB). Our results will help to better understand of the role of ELF3, NFkappaB and LCN2 in the pathophysiology of articular cartilage. ABSTRACT: E74-like factor 3 (ELF3) is a transcription factor induced by inflammatory cytokines in chondrocytes that increases gene expression of catabolic and inflammatory mediators. Lipocalin 2 (LCN2) is a novel adipokine that negatively impacts articular cartilage, triggering catabolic and inflammatory responses in chondrocytes. Here, we investigated the control of LCN2 gene expression by ELF3 in the context of interleukin 1 (IL-1)-driven inflammatory responses in chondrocytes. The interaction of ELF3 and nuclear factor-kappaB (NFkappaB) in modulating LCN2 levels was also explored. LCN2 mRNA and protein levels, as well those of several other ELF3 target genes, were determined by RT-qPCR and Western blotting. Human primary chondrocytes, primary chondrocytes from wild-type and Elf3 knockout mice, and immortalized human T/C-28a2 and murine ATDC5 cell lines were used in in vitro assays. The activities of various gene reporter constructs were evaluated by luciferase assays. Gene overexpression and knockdown were performed using specific expression vectors and siRNA technology, respectively. ELF3 overexpression transactivated the LCN2 promoter and increased the IL-1-induced mRNA and protein levels of LCN2, as well as the mRNA expression of other pro inflammatory mediators, in human and mouse chondrocytes. We also identified a collaborative loop between ELF3 and NFkappaB that amplifies the induction of LCN2. Our findings show a novel role for ELF3 and NFkappaB in the induction of the pro-inflammatory adipokine LCN2, providing additional evidence of the interaction between ELF3 and NFkappaB in modulating inflammatory responses, and a better understanding of the mechanisms of action of ELF3 in chondrocytes. PMID- 27222095 TI - Abstracts of the 103rd Annual Congress of the Swiss Society of Surgery, held in Lugano, Switzerland, 1-3 June 2016. PMID- 27222094 TI - Chemical reactions at the graphitic step-edge: changes in product distribution of catalytic reactions as a tool to explore the environment within carbon nanoreactors. AB - A series of explorative cross-coupling reactions have been developed to investigate the local nanoscale environment around catalytically active Pd(ii)complexes encapsulated within hollow graphitised nanofibers (GNF). Two new fullerene-containing and fullerene-free Pd(ii)Salen catalysts have been synthesised, and their activity and selectivity towards different substrates has been explored in nanoreactors. The catalysts not only show a significant increase in activity and stability upon heterogenisation at the graphitic step-edges inside the GNF channel, but also exhibit a change in selectivity affected by the confinement which alters the distribution of isomeric products of the reaction. Furthermore, the observed selectivity changes reveal unprecedented details regarding the location and orientation of the catalyst molecules inside the GNF nanoreactor, inaccessible by any spectroscopic or microscopic techniques, thus shedding light on the precise reaction environment inside the molecular catalyst GNF nanoreactor. PMID- 27222096 TI - Mammary transcriptome analysis of lactating dairy cows following administration of bovine growth hormone. AB - The galactopoietic effect of growth hormone (GH) in lactating ruminants is well established; however the mechanisms that mediate these effects are not well understood. The first objective of this study was to determine the effect of GH on the synthesis of the major casein and whey proteins. The second objective was to identify the genes and pathways that may be involved in mediating the effect of GH on milk synthesis. A single subcutaneous injection of a commercially available slow release formulation of GH (Lactatropin(r)), or physiological saline solution (control) was administered to non-pregnant dairy cows (n=4/group) in mid-late lactation. Milk samples were collected for composition analysis and mammary lobulo-alveolar tissue was collected postmortem 6 days post injection. Gene expression profiles were evaluated using either a 22 000 bovine complementary DNA microarray or quantitative PCR (qPCR), and microarrays were validated by qPCR. The yield of all the major casein and whey proteins was increased 32% to 41% in GH-treated cows, with the exception of alpha-lactalbumin yield which was elevated by 70% relative to controls. Treatment with GH treatment tended to increase the concentration of alpha-lactalbumin but had no effect on the concentration of any of the major milk proteins. Messenger RNA (mRNA) abundance of the major whey and casein genes, with the exception of alpha-s2 casein, was increased in response to GH compared with controls, which is consistent with the positive effect of GH on milk production. Treatment with GH treatment influenced the mRNA abundance of genes involved in cell growth and proliferation, transcriptional and translational regulation, actin cytoskeleton signalling, lipid metabolism and cell death. This study has provided new insights into the cell signalling that may be involved in mediating the effect of GH on milk production in the mammary gland of lactating dairy cows. PMID- 27222097 TI - Preterm delivery after fetoscopic laser surgery for twin-twin transfusion syndrome: etiology and risk factors. AB - OBJECTIVE: Preterm delivery after fetoscopic laser surgery (FLS) for twin-twin transfusion syndrome (TTTS) is a major complication. The causative factors leading to preterm delivery continue to be elusive and a better understanding of the risk factors could reduce complications. The objective of this study was to determine the etiology of preterm delivery after FLS for TTTS and its associated risk factors. METHODS: This was a secondary analysis of a prospective study of 203 patients with TTTS who underwent FLS at a single center between September 2011 and December 2014. Preoperative, operative, postoperative, delivery and neonatal data were reviewed. Preterm delivery was categorized according to etiology into three groups: spontaneous (SPT), indicated (IND) and elective (ELC). Comparisons between groups were performed by ANOVA. Kaplan-Meier survival analysis was performed to compare the procedure-to-delivery interval between groups. To identify risk factors for preterm delivery, logistic regression, with calculation of relative risks (RR), was performed, with P < 0.05 considered statistically significant. RESULTS: Mean gestational age at time of FLS was 20.6 +/- 2.4 weeks and mean gestational age at delivery was 30.9 +/- 4.7 weeks. Iatrogenic preterm prelabor rupture of membranes (iPPROM) occurred in 39% of cases. SPT preterm delivery occurred in 97 (48%) patients, IND preterm delivery in 65 (32%) and ELC preterm delivery in 41 (20%). In the IND group, 30 (46%) patients delivered for fetal indications, 31 (48%) for maternal indications and four (6%) for combined fetal and maternal indications. The overall chorioamnionitis rate was 6.4%; of these, nine (9%) were in the SPT group and four (6%) were in the IND group, with no case occurring in the ELC group. There was a significant difference in procedure-to-delivery interval between groups (P < 0.0001). Using variables from the ELC group as a baseline, significant risk factors for SPT preterm delivery were iPPROM (RR, 16.2 (95% CI, 4.5-57.7)), preoperative cervical length (RR, 0.96 (95% CI, 0.92-0.998)) and number of anastomoses (RR, 1.14 (95% CI, 1.02-1.27)). Significant risk factors for IND preterm delivery were iPPROM (RR, 9.6 (95% CI, 2.6-35.0)) and number of ablated anastomoses (RR, 1.13 (95% CI, 1.02-1.30)). CONCLUSION: iPPROM and an increased number of ablated placental anastomoses were associated independently with SPT and IND preterm deliveries. A shorter preoperative cervical length was associated with SPT preterm delivery. Strategies to prevent iPPROM and for management of cervical length shortening are needed urgently in these pregnancies. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 27222098 TI - All-Optical Implementation of the Ant Colony Optimization Algorithm. AB - We report all-optical implementation of the optimization algorithm for the famous "ant colony" problem. Ant colonies progressively optimize pathway to food discovered by one of the ants through identifying the discovered route with volatile chemicals (pheromones) secreted on the way back from the food deposit. Mathematically this is an important example of graph optimization problem with dynamically changing parameters. Using an optical network with nonlinear waveguides to represent the graph and a feedback loop, we experimentally show that photons traveling through the network behave like ants that dynamically modify the environment to find the shortest pathway to any chosen point in the graph. This proof-of-principle demonstration illustrates how transient nonlinearity in the optical system can be exploited to tackle complex optimization problems directly, on the hardware level, which may be used for self routing of optical signals in transparent communication networks and energy flow in photonic systems. PMID- 27222099 TI - High viscosity to highly dispersed PtPd bimetallic nanocrystals for enhanced catalytic activity and stability. AB - A facile high-viscosity-solvent method is presented to synthesize PtPd bimetallic nanocrystals highly dispersed in different mesostructures (2D and 3D structures), porosities (large and small pore sizes), and compositions (silica and carbon). Further, highly catalytic activity, stability and durability of the nanometals have been proven in different catalytic reactions. PMID- 27222100 TI - Increased expression and activity of p75NTR are crucial events in azacitidine induced cell death in prostate cancer. AB - The high affinity nerve growth factor (NGF) NGF receptor, p75NTR, is a member of the tumor necrosis factor (TNF) receptor superfamily that shares a conserved intracellular death domain capable of inducing apoptosis and suppressing growth in prostate epithelial cells. Expression of this receptor is lost as prostate cancer progresses and is minimal in established prostate cancer cell lines. We aimed to verify the role of p75NTR in the azacitidine-mediated antitumor effects on 22Rv1 and PC3 androgen-independent prostate cancer cells. In the present study, we reported that the antiproliferative and pro-apoptotic effects of 5 azacytidine (azacitidine) were more marked in the presence of physiological concentrations of NGF and were reduced when a blocking p75NTR antibody or the selective p75NTR inhibitor, Ro 08-2750, were used. Azacitidine increased the expression of p75NTR without interfering with the expression of the low affinity NGF receptor TrkA and induced caspase 9-dependent caspase 3 activity. Taken together, our results suggest that the NGF network could be a candidate for future pharmacological manipulation in aggressive prostate cancer. PMID- 27222101 TI - Imaging and force probing RNA by atomic force microscopy. AB - In the past 30years, the atomic force microscope (AFM) has become a true enabling platform in the life sciences opening entire novel avenues for structural and dynamic studies of biological systems. It enables visualization, probing and manipulation across the length scales, from single molecules to living cells in buffer solution under physiological conditions without the need for labeling or staining of the specimen. In particular, for structural studies of nucleic acids and assemblies thereof, the AFM has matured into a routinely used tool providing nanometer spatial resolution. This includes ssRNA, dsRNA and nucleoprotein complexes thereof, as well as RNA aggregates and 2D RNA assemblies. By AFM unique information can be obtained on RNA based assemblies which are becoming increasingly important as novel unique building blocks in the emerging field of RNA nanotechnology. In addition, the AFM is of fundamental relevance to study biological relevant RNA interactions and dynamics. In this short review first the basic functioning principles of commonly used AFM modes including AFM based force spectroscopy will be briefly described. Next a brief overview will be given on structural studies that have been done related to AFM topographic imaging of RNA, RNA assemblies and aggregates. Finally, an overview on AFM beyond imaging will be provided. This includes force spectroscopy of RNA under physiological conditions in aqueous buffer to probe RNA interaction with proteins and ligands as well as other AFM tip based RNA probing. The main intention of this short review to give the reader a flavor of what AFM contributes to RNA research and engineering. PMID- 27222102 TI - Current status of Plasmodium knowlesi vectors: a public health concern? AB - Plasmodium knowlesi a simian malaria parasite is currently affecting humans in Southeast Asia. Malaysia has reported the most number of cases and P. knowlesi is the predominant species occurring in humans. The vectors of P. knowlesi belong to the Leucosphyrus group of Anopheles mosquitoes. These are generally described as forest-dwelling mosquitoes. With deforestation and changes in land-use, some species have become predominant in farms and villages. However, knowledge on the distribution of these vectors in the country is sparse. From a public health point of view it is important to know the vectors, so that risk factors towards knowlesi malaria can be identified and control measures instituted where possible. Here, we review what is known about the knowlesi malaria vectors and ascertain the gaps in knowledge, so that future studies could concentrate on this paucity of data in-order to address this zoonotic problem. PMID- 27222103 TI - A clinical procedures curriculum for undergraduate medical students: the eight year history of a third-year immersive experience. AB - BACKGROUND: Procedural skills training is a critical component of medical education, but is often lacking in standard clinical curricula. We describe a unique immersive procedural skills curriculum for medical students, designed and taught primarily by emergency medicine faculty at The Ohio State University College of Medicine. OBJECTIVES: The primary educational objective of this program was to formally introduce medical students to clinical procedures thought to be important for success in residency. The immersion strategy (teaching numerous procedures over a 7-day period) was intended to complement the student's education on third-year core clinical clerkships. PROGRAM DESIGN: The course introduced 27 skills over 7 days. Teaching and learning methods included lecture, prereading, videos, task trainers, peer teaching, and procedures practice on cadavers. In year 4 of the program, a peer-team teaching model was adopted. We analyzed program evaluation data over time. IMPACT: Students valued the selection of procedures covered by the course and felt that it helped prepare them for residency (97%). The highest rated activities were the cadaver lab and the advanced cardiac life support (97 and 93% positive endorsement, respectively). Lectures were less well received (73% positive endorsement), but improved over time. The transition to peer-team teaching resulted in improved student ratings of course activities (p<0.001). CONCLUSION: A dedicated procedural skills curriculum successfully supplemented the training medical students received in the clinical setting. Students appreciated hands-on activities and practice. The peer-teaching model improved course evaluations by students, which implies that this was an effective teaching method for adult learners. This course was recently expanded and restructured to place the learning closer to the clinical settings in which skills are applied. PMID- 27222104 TI - Changing trends in the management of intertrochanteric hip fractures - A single centre experience. AB - With an annual incidence greater than 65,000 in the United Kingdom, hip fractures are a common but debilitating injury predominantly affecting those over 65. Treatment is based on the anatomical location of the fracture relative to the capsule of the hip joint - fractures occurring within it are treated by arthroplasty, while extracapsular fractures are an indication for fixation. Intertrochanteric fractures are further grouped as stable (AO/OTA 31A1/A2) or unstable (31A3) which in turn governs in the current UK guidelines whether this fixation is achieved with a dynamic hip screw or intramedullary device. Anecdotally, some units are tending towards intramedullary devices for 31A2 fractures as well, a practice which from the evidence does not appear to confer benefit and carries an excess cost. We reviewed our data submitted to the National Hip Fracture Database over the last five years and identified all intertrochanteric fractures, from which cohort we identified all patients with 31A2 fractures by review of radiographs. The cohort comprised 370 patients. We then recorded age, gender, ASA grade, abbreviated mental test score, residence from where admitted, length of stay, destination on discharge and whether any further operations were required. There was no significant difference in the demographics of the groups, year-on-year, except gender mix. There was a significant, twenty-fold rise in the use of intramedullary devices between 2011 and 2015. Length of stay, length of overall episode of care, revision rates, mortality and destination on discharge were unchanged. This use is not supported by NICE guidelines and this study offers no evidence to contradict this position. We advocate all centres examine their practice to avoid a costly intervention without clinical benefit. PMID- 27222105 TI - Combination of micellar casein with calcium and vitamins D2 and K2 improves bone status of ovariectomized mice. AB - Nutritional approaches may help to preserve bone quality. The purpose of our study was to demonstrate the efficiency of an innovative bone health product (BHP) including micellar casein rich in calcium, vitamin D2 and vitamin K2, to improve bone mineral density. INTRODUCTION: The aim of postmenopausal osteoporosis treatment is to decrease bone resorption and/or increase bone formation. Because of the slow bone turnover, osteoporosis prevention and therapies are long-lasting, implying great costs and poor compliance. Even if the effects of nutrition on bone are not as marked as that of pharmaceutical agents, it can be of great help. The purpose of our study was to demonstrate the efficiency of an innovative bone health product (BHP) containing micellar casein rich in calcium, vitamin D2 and vitamin K2, for the improvement of bone mineral density (BMD). METHODS: An ovariectomized mice model was used to study the effect of different concentrations of the ingredient on BMD and microarchitectural parameters. Blood concentrations of C-terminal telopeptide of type I collagen (CTX), N-terminal propeptide of type 1 procollagene (PINP), alkaline phosphatase (ALP), osteocalcin (OC) and RANKL were also measured to evaluate bone remodelling, To evaluate the efficiency of the product to modulate osteoblast and osteoclast growth and differentiation, primary murine bone cells were used. RESULTS: In vivo studies showed that BMD and microarchitectural parameters were dose-dependently improved after ingestion of the supplement for 3 months. We also report increased osteoblast activity as shown by increased OC activity and decreased osteoclastogenesis as shown by reduced CTX activity. In vitro studies support that BHPs stimulate osteoblast differentiation and mineralization and inhibit osteoclast resorption activity. CONCLUSION: Our results show that, when chronically ingested, BHPs improve BMD of ovariectomized mice. This work supports that providing an ingredient including micellar casein rich in calcium, vitamin D2 and vitamin K2 is more efficient than the control diet to maintain bone quality. PMID- 27222106 TI - Self-Report Scales to Measure Expectations and Appearance-Related Psychosocial Distress in Patients Seeking Cosmetic Treatments. AB - BACKGROUND: The use of screening scales in cosmetic practices may help to identify patients who require education to modify inappropriate expectations and/or psychological support. OBJECTIVES: To describe the development and validation of scales that measure expectations (about how one's appearance and quality of life might change with cosmetic treatments) and appearance-related psychosocial distress. METHODS: The scales were field-tested in patients 18 years and older seeking facial aesthetic or body contouring treatments. Recruitment took place in clinics in the United States, United Kingdom, and Canada between February 2010 and January 2015. Rasch Measurement Theory (RMT) analysis was used for psychometric evaluation. Scale scores range from 0 to 100; higher scores indicate more inappropriate expectations and higher psychosocial distress. RESULTS: Facial aesthetic (n = 279) and body contouring (n = 90) patients participated (97% response). In the RMT analysis, all items had ordered thresholds and acceptable item fit. Person Separation Index and Cronbach alpha values were 0.88 and 0.92 for the Expectation scale, and 0.81 and 0.89 for the Psychosocial Distress scale respectively. Higher expectation correlated with higher psychosocial distress (R = 0.40, P < .001). In the facial aesthetic group, lower scores on the FACE-Q Satisfaction with Appearance scale correlated with higher expectations (R = -0.27, P = .001) and psychosocial distress (R = -0.52, P < .001). In the body contouring group, lower scores on the BODY-Q Satisfaction with Body scale correlated with higher psychosocial distress (R = -0.31, P = .003). Type of treatment and marital status were associated with scale scores in multivariate models. CONCLUSIONS: Future research could examine convergent and predictive validity. As research data are accumulated, norms and interpretation guidelines will be established. LEVEL OF EVIDENCE: 2 Risk. PMID- 27222107 TI - Resident Cosmetic Clinic: Practice Patterns, Safety, and Outcomes at an Academic Plastic Surgery Institution. AB - BACKGROUND: Comprehensive aesthetic surgery education is an integral part of plastic surgery residency training. Recently, the ACGME increased minimum requirements for aesthetic procedures in residency. To expand aesthetic education and prepare residents for independent practice, our institution has supported a resident cosmetic clinic for over 25 years. OBJECTIVES: To evaluate the safety of procedures performed through a resident clinic by comparing outcomes to benchmarked national aesthetic surgery outcomes and to provide a model for resident clinics in academic plastic surgery institutions. METHODS: We identified a consecutive cohort of patients who underwent procedures through our resident cosmetic clinic between 2010 and 2015. Major complications, as defined by CosmetAssure database, were recorded and compared to published aesthetic surgery complication rates from the CosmetAssure database for outcomes benchmarking. Fisher's exact test was used to compare sample proportions. RESULTS: Two hundred and seventy-one new patients were evaluated and 112 patients (41.3%) booked surgery for 175 different aesthetic procedures. There were 55 breast, 19 head and neck, and 101 trunk or extremity aesthetic procedures performed. The median number of preoperative and postoperative visits was 2 and 4 respectively with a mean follow-up time of 35 weeks. There were 3 major complications (2 hematomas and 1 infection requiring IV antibiotics) with an overall complication rate of 1.7% compared to 2.0% for patients in the CosmetAssure database (P = .45). CONCLUSIONS: Surgical outcomes for procedures performed through a resident cosmetic clinic are comparable to national outcomes for aesthetic surgery procedures, suggesting this experience can enhance comprehensive aesthetic surgery education without compromising patient safety or quality of care. LEVEL OF EVIDENCE: 4 Risk. PMID- 27222108 TI - Commentary on: Decrease in Seroma Rate After Adopting Progressive Tension Sutures Without Drains: A Single Surgery Center Experience of 451 Abdominoplasties Over 7 Years. PMID- 27222110 TI - Hierarchical Bayesian models of cognitive development. AB - This article provides an introductory overview of the state of research on Hierarchical Bayesian Modeling in cognitive development. First, a brief historical summary and a definition of hierarchies in Bayesian modeling are given. Subsequently, some model structures are described based on four examples in the literature. These are models for the development of the shape bias, for learning ontological kinds and causal schemata as well as for the categorization of objects. The Bayesian modeling approach is then compared with the connectionist and nativist modeling paradigms and considered in view of Marr's (1982) three description levels of information-processing mechanisms. In this context, psychologically plausible algorithms and ideas of their neural implementation are presented. In addition to criticism and limitations of the approach, research needs are identified. PMID- 27222109 TI - Vitamin D expenditure is not altered in pregnancy and lactation despite changes in vitamin D metabolite concentrations. AB - Pregnancy and lactation are associated with changes in vitamin D and calcium metabolism but the impact of these changes on vitamin D expenditure is unknown. We measured plasma 25(OH)D3 half-life with a stable-isotope tracer and investigated relationships with vitamin D metabolites in pregnant, lactating and 'non-pregnant, non-lactating' (NPNL) women. Vitamin D metabolites, vitamin D binding protein (DBP), PTH and 25(OH)D3 half-life were measured in third trimester pregnant women (n22) and repeated during lactation 12 weeks post-partum (n14) and twice in NPNL women (n23 and n10, respectively) in rural Gambia where calcium intakes are low with little seasonality in UVB-exposure. 25(OH)D3 half life was not significantly different between groups (mean(SD): 20.6(6.8), 22.6(7.7), 18.0(4.7) and 17.7(9.5) days in pregnant, lactating and NPNL women, respectively). Plasma 25(OH)D3, 1,25(OH)2D, and DBP were higher in pregnancy, and calculated free-25(OH)D3 and PTH were lower (P < 0.05). In lactation, 25(OH)D3 and 24,25(OH)2D3 were lower compared to pregnant (P < 0.001, P = 0.02) and NPNL women (P = 0.04, P = 0.07). Significant associations were observed between half life and 25(OH)D3 (+ve) in pregnancy, and in all groups between 25(OH)D3 and free 25(OH)D3 (+ve) and PTH and 25(OH)D3 (-ve) (P < 0.0001). These data suggest that adaptive changes in pregnancy and lactation occur that prevent pronounced changes in vitamin D expenditure. PMID- 27222111 TI - Hydrogen sulfide exhibits cardioprotective effects by decreasing endoplasmic reticulum stress in a diabetic cardiomyopathy rat model. AB - Endoplasmic reticulum (ER) stress is critical in the occurrence and development of diabetic cardiomyopathy (DC). Hydrogen sulfide (H2S) has been found to be the third gaseous signaling molecule with anti-ER stress effects. Previous studies have shown that H2S acts as a potent inhibitor of fibrosis in the heart of diabetic rats. This study aimed to demonstrate whether H2S exhibits protective effects on the myocardium of streptozotocin (STZ)-induced diabetic rats by suppressing ER stress. In this study, diabetic models were established by intraperitoneal (i.p.) injection of 40 mg/kg STZ. The STZ-treated mice were divided into three groups, and subsequently treated with normal saline, 30 umol/kg or 100 umol/kg NaHS, i.p., respectively, for 8 weeks. The extent of myocyte hypertrophy was measured using hematoxylin and eosin-stained sections and collagen components were investigated using immunostaining. The expression of glucose-regulated protein (Grp78), C/EBP-homologous protein (CHOP) and caspase-12 in the heart tissue of each group was detected by western blot analysis. It was demonstrated that H2S could improve myocardial hypertrophy and myocardial collagen deposition in diabetic rats. In addition, it could reduce the expression of Grp78, caspase-12 and CHOP. In conclusion, these findings demonstrate that H2S suppresses STZ-induced ER stress in the hearts of rats, and it may serve as a novel cardioprotective agent for DC. PMID- 27222112 TI - Multislice computed tomography-guided surgical repair of acquired posterior left ventricular aneurysms: demonstration of mitral valve and left ventricular reverse remodelling. AB - OBJECTIVES: Involvement of the mitral valve (MV) apparatus represents a challenge in surgical ventricular repair (SVR) of posterior left ventricular (LV) aneurysms. This study sought to investigate whether multislice computed tomography (MSCT) assessment can be used to optimize the surgical procedure for posterior LV aneurysms. METHODS: Thirty patients (m : w = 24 : 6, age 38-78, median 66 years; mean New York Heart Association class 2.98) with posterior LV aneurysm were operated upon. MSCT was performed in 24 patients before and after surgery. End-diastolic and end-systolic volumes of LV and aneurysm were indexed to body surface area (LVEDVI/LVESVI, AEDVI/AESVI). The MV apparatus was characterized by coaptation distance (CD), tenting area (TA), MV closure angle (MVCA), MV annulus area (MVAA) and interpapillary muscle distance (IMD). RESULTS: Thirty-day mortality was 10% and 5-year survival rate was 83%. After surgery, LVEDVI decreased from 151.2 +/- 84.1 to 85.7 +/- 28.3 ml/m(2) (P = 0.001) and LVESVI from 110.6 +/- 88.8 to 50.2 +/- 22.9 ml/m(2) (P = 0.001). LV ejection fraction increased from 31.5 +/- 15.1 to 43.4 +/- 9.9% (P = 0.001). Preoperative MSCT showed significantly higher values of MVAA, CD and TA in patients who needed MV repair or replacement. Postoperative reduction of mitral regurgitation in patients without MV surgery corresponded with significant reduction in intercommissural diameter, anteroposterior diameter, MVAA, TA, CD, MVCA and IMD. CONCLUSIONS: MSCT represents an excellent diagnostic tool for the assessment of MV and LV geometry. MSCT-guided SVR of submitral LV aneurysms leads to excellent mid-term results. On the basis of the MSCT assessment, we propose an algorithm for surgical planning in posterior LV aneurysms. PMID- 27222113 TI - Chemerin activation in human obesity. AB - OBJECTIVE: Chemerin is an inflammatory adipokine, whose activity is regulated by successive proteolytic cleavages at its C-terminus. It is secreted as an inactive precursor (chem163S); cleavage at Lys158 converts it to chem158K with modest activity. Chem157S is the most potent form and chem155A is inactive. The aim of this study was to determine if chemerin was activated in samples from patients with obesity. METHODS: Using specific ELISAs for different chemerin forms and a pan-chemerin ELISA, chemerin forms in human obesity were characterized. RESULTS: Plasma chemerin from patients with obesity (BMI 44.3 +/- 1.3 kg/m(2) , n = 29) was significantly higher than in lean controls (BMI 20.9 +/- 0.7 kg/m(2) , n = 10) (160 +/- 11 vs. 76.2 +/- 5.5 ng/mL, respectively, P < 0.0001). This increase in chemerin was due to increased previously unattributed chemerin, with further C terminal truncation demonstrated by mass spectrometry, accounting for ~35% of total plasma chemerin. Chemerin forms in adipose tissue showed a different profile, with minimal chem163S and significant levels of chem157S. Chem155A was present in omental but not in subcutaneous adipose tissue. Unattributed chemerin forms were undetectable in adipose tissue. CONCLUSIONS: Chemerin is activated in adipose tissue of subjects with obesity, and further C-terminal processing occurs during the disposition of chemerin from adipose tissue, resulting in substantial levels of novel degraded forms in plasma that correlate with obesity. PMID- 27222114 TI - Subclinical concentrations of sevoflurane reduce oxidative stress but do not prevent hippocampal apoptosis. AB - Sevoflurane is generally considered a pro-apoptotic agent in the neonatal brain. However, recent studies have suggested that low levels of sevoflurane anesthesia may be neuroprotective and have a memory enhancing effect. The present study aimed to investigate whether sevoflurane exerts a neuroprotective effect at subclinical concentrations, with regard to oxidative state. In the current study, postnatal day 7 (P7) Sprague-Dawley rats were continuously exposed to 0.3, 1.3, or 2.3% sevoflurane for 6 h. ELISA was used to quantify the levels of superoxide dismutase, glutathione peroxidase (GSH-px) and malondialdehyde (MDA) in the plasma and the hippocampus. Terminal deoxynucleotidyl-transferase dUTP nick-end labeling staining was used to observe hippocampal neuronal apoptosis. Altered object exploration tests for recognition memory were employed to investigate long term behavioral effects at postnatal day 28. The results demonstrated that a single 6 h exposure to a subclinical concentration (1.3%) of sevoflurane at P7 reduces MDA and GPH-px production in rats. Sevoflurane induced hippocampal apoptosis in a dose-dependent manner and altered recognition memory testing indicated no differences among the groups. Although early exposure to a subclinical concentration of sevoflurane reduced oxidative stress, it did not prevent the process of sevoflurane-induced hippocampal apoptosis. These changes did not affect subsequent recognition memory in juvenile rats. PMID- 27222116 TI - Do Urology Male Patients Prefer Same-Gender Urologist? AB - There are several studies on patients' preference for same-gender physicians, especially female preference for same-gender gynecologists. Data regarding the preferences of urology patients, of whom the majority are males, are scarce. The objective of this study is to assess provider gender preference among urology patients. One hundred and nineteen consecutive men (mean age 57.6 years) who attended a urology clinic in one university-affiliated medical center were prospectively enrolled. A self-accomplished 26-item anonymous questionnaire was used to assess patients' preferences in selecting their urologist. Of the 119 patients, 51 (42.8%) preferred a male urologist. Patients exhibited more same gender preference for physical examination (38.3%), or urological surgery (35.3%), than for consultation (24.4%). Most patients (97%) preferred a same gender urologist because they felt less embarrassed. Four patient characteristics were identified to be significantly associated with preference for a male urologist: religious status, country of origin, marital status, and a prior management by a male urologist. Of these, religious status was the most predictive parameter for choosing a male urologist. The three most important factors that affected actual selection, however, were professional skills (84.6%), clinical experience (72.4%), and medical knowledge (61%), rather than physician gender per se. Many male patients express gender bias regarding their preference for urologist. However, professional skills of the clinician are considered to be more important factors when it comes to actually making a choice. PMID- 27222115 TI - Leptin directly promotes T-cell glycolytic metabolism to drive effector T-cell differentiation in a mouse model of autoimmunity. AB - Upon activation, T cells require energy for growth, proliferation, and function. Effector T (Teff) cells, such as Th1 and Th17 cells, utilize high levels of glycolytic metabolism to fuel proliferation and function. In contrast, Treg cells require oxidative metabolism to fuel suppressive function. It remains unknown how Teff/Treg-cell metabolism is altered when nutrients are limited and leptin levels are low. We therefore examined the role of malnutrition and associated hypoleptinemia on Teff versus Treg cells. We found that both malnutrition associated hypoleptinemia and T cell-specific leptin receptor knockout suppressed Teff-cell number, function, and glucose metabolism, but did not alter Treg-cell metabolism or suppressive function. Using the autoimmune mouse model EAE, we confirmed that fasting-induced hypoleptinemia altered Teff-cell, but not Treg cell, glucose metabolism, and function in vivo, leading to decreased disease severity. To explore potential mechanisms, we examined HIF-1alpha, a key regulator of Th17 differentiation and Teff-cell glucose metabolism, and found HIF 1alpha expression was decreased in T cell-specific leptin receptor knockout Th17 cells, and in Teff cells from fasted EAE mice, but was unchanged in Treg cells. Altogether, these data demonstrate a selective, cell-intrinsic requirement for leptin to upregulate glucose metabolism and maintain function in Teff, but not Treg cells. PMID- 27222117 TI - Outcome of different facial nerve reconstruction techniques. AB - INTRODUCTION: There is no technique of facial nerve reconstruction that guarantees facial function recovery up to grade III. OBJECTIVE: To evaluate the efficacy and safety of different facial nerve reconstruction techniques. METHODS: Facial nerve reconstruction was performed in 22 patients (facial nerve interpositional graft in 11 patients and hypoglossal-facial nerve transfer in another 11 patients). All patients had facial function House-Brackmann (HB) grade VI, either caused by trauma or after resection of a tumor. All patients were submitted to a primary nerve reconstruction except 7 patients, where late reconstruction was performed two weeks to four months after the initial surgery. The follow-up period was at least two years. RESULTS: For facial nerve interpositional graft technique, we achieved facial function HB grade III in eight patients and grade IV in three patients. Synkinesis was found in eight patients, and facial contracture with synkinesis was found in two patients. In regards to hypoglossal-facial nerve transfer using different modifications, we achieved facial function HB grade III in nine patients and grade IV in two patients. Facial contracture, synkinesis and tongue atrophy were found in three patients, and synkinesis was found in five patients. However, those who had primary direct facial-hypoglossal end-to-side anastomosis showed the best result without any neurological deficit. CONCLUSION: Among various reanimation techniques, when indicated, direct end-to-side facial-hypoglossal anastomosis through epineural suturing is the most effective technique with excellent outcomes for facial reanimation and preservation of tongue movement, particularly when performed as a primary technique. PMID- 27222118 TI - Gastric lap-band infection due to Mycobacterium abscessus presenting as new-onset ascites in a cirrhotic patient. AB - Nontuberculous mycobacteria are ubiquitous environmental organisms that are infrequently implicated as pathogens. Peritoneal infection with nontuberculous mycobacteria is rare and published reports are most commonly associated with peritoneal dialysis. This study describes a case of a 41-year-old woman with cirrhosis who had Mycobacterium abscessus peritonitis and an abdominal abscess resulting from infection of a remotely placed gastric band (Lap-Band; Apollo Endosurgery, Inc). PMID- 27222119 TI - Daidzein attenuates abdominal aortic aneurysm through NF-kappaB, p38MAPK and TGF beta1 pathways. AB - The current study focuses on the protection of daidzein on nerves, as daidzein was demonstrated to have a protective effect on neurons of the central nervous system in a glutamate excitotoxicity and oxygen/glucose deprivation model. However, the effect of daidzein on the abdominal aortic aneurysm (AAA) remains unclear. The angiotensin II-induced AAA mouse model was utilized in the present study to determine the effect of daidzein on AAA. The results demonstrated that daidzein significantly attenuated incidence of AAA, max aortic aneurysm and mortality in the angiotensin II-induced AAA mice. Daidzein had an anti inflammatory effect by inhibiting tumor necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta) and nuclear factor kappaB (NF-kappaB) protein expression. In addition, daidzein strongly suppressed the gene expression of cyclooxygenase (COX)-2, matrix metalloproteinase 2 (MMP-2), tissue inhibitor of metalloproteinase 1 (TIMP-1), transforming growth factor beta1 (TGF-beta1), and inhibited inducible nitric oxide synthase (iNOS) protein expression in angiotensin II-induced AAA mice. It also inhibited phosphorylation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway. These results demonstrate, to the best of our knowledge for the first time, that the anti inflammatory effects and inhibitory mechanism of daidzein attenuates AAA in angiotensin II-induced mice. Daidzein contains strong anti-inflammatory activity and affects various mechanism pathways including the NF-kappaB, p38MAPK and TGF beta1 pathway. PMID- 27222121 TI - Psychiatry and the 'Gay Holocaust' - the lessons of Jill Soloway's Transparent. AB - OBJECTIVE: We aim to consider issues relevant to psychiatry raised by the television series, Transparent. CONCLUSIONS: Psychiatry's disturbing history regarding the lesbian, gay, bisexual, transgender and intersex (LGBTI) community shares many aspects with the group's persecution by the National Socialist regime in Germany. The medicalised 'otherness' conferred on LGBTI patients, latent homophobia and transphobia, and lack of culturally sensitive clinical services for these people represent a major ethical challenge for modern Australasian psychiatry. PMID- 27222120 TI - Impairment of toll-like receptors 2 and 4 leads to compensatory mechanisms after sciatic nerve axotomy. AB - BACKGROUND: Peripheral nerve injury results in retrograde cell body-related changes in the spinal motoneurons that will contribute to the regenerative response of their axons. Successful functional recovery also depends on molecular events mediated by innate immune response during Wallerian degeneration in the nerve microenvironment. A previous study in our lab demonstrated that TLR 2 and 4 develop opposite effects on synaptic stability in the spinal cord after peripheral nerve injury. Therefore, we suggested that the better preservation of spinal cord microenvironment would positively influence distal axonal regrowth. In this context, the present work aimed to investigate the influence of TLR2 and TLR4 on regeneration and functional recovery after peripheral nerve injury. METHODS: Eighty-eight mice were anesthetized and subjected to unilateral sciatic nerve crush (C3H/HeJ, n = 22, C3H/HePas, n = 22; C57Bl6/J, n = 22 and TLR2(-/-), n = 22). After the appropriate survival times (3, 7, 14 days, and 5 weeks), all mice were killed and the sciatic nerves and tibialis cranialis muscles were processed for immunohistochemistry and transmission electron microscopy (TEM). Gait analysis, after sciatic nerve crushing, was performed in another set of mice (minimum of n = 8 per group), by using the walking track test (CatWalk system). RESULTS: TLR4 mutant mice presented greater functional recovery as well as an enhanced p75(NTR) and neurofilament protein expression as compared to the wild type strain. Moreover, the better functional recovery in mutant mice was correlated to a greater number of nerve terminal sprouts. Knockout mice for TLR2 exhibited 30 % greater number of degenerated axons in the distal stump of the sciatic nerve and a decreased p75(NTR) and neurofilament protein expression compared to the wild type. However, the absence of TLR2 receptor did not influence the overall functional recovery. End-point equivalent functional recovery in transgenic mice may be a result of enhanced axonal diameter found at 2 weeks after lesion. CONCLUSIONS: Altogether, the present results indicate that the lack of TLR2 or the absence of functional TLR4 does affect the nerve regeneration process; however, such changes are minimized through different compensatory mechanisms, resulting in similar motor function recovery, as compared to wild-type mice. These findings contribute to the concept that innate immune-related molecules influence peripheral nerve regeneration by concurrently participating in processes taking place both at the CNS and PNS. PMID- 27222122 TI - Seven steps towards a PhD in psychiatry. AB - OBJECTIVES: The present review aims to describe the main steps for completing a psychiatric PhD thesis with success. METHODS: A selective review of the literature and the author's experience as a psychiatrist completing a PhD. RESULTS: Deciding upon a topic, choosing a mentor, organising your time, persevering and remaining motivated are the key elements. CONCLUSIONS: Preparedness and diligence lead the way towards a PhD. This advice is also relevant for those undertaking research at any stage of their career. PMID- 27222123 TI - Presentations by ambulance under the NSW Mental Health Act to an emergency department with a 24-hour mental health team. AB - OBJECTIVE: The objective of this study was to examine the presentations of patients by ambulance, under Section 20 of the NSW Mental Health Act of 2007, to a hospital emergency department (ED) with a 24-hour Mental Health Team. METHODS: Patient records between December 2013 and December 2014 were audited and analysed in Excel. RESULTS: There were 47 such presentations: 51% required a mental health admission. Patients required management for up to six of the nine identified mental health and physical problems. As the number of clinical problems in these patients increased, the length of their stay and the likelihood of discharge to home increased. The need for psychiatric admission did not appear to prolong their length of stay, though chemical sedation did. The availability of an ED mental health team did assist in achieving a length of stay that was in keeping with Australian National Emergency Access Target guidelines. CONCLUSIONS: A 24 hour ED mental health team provided specialised assessment and management for patients, alongside the necessary emergency medical intervention. This team assisted in easing the increasing pressure on the ED and minimising the patients' length of stay. The team redirected patients requiring admission, facilitated timely discharge of others and revoked Section 20 when less restrictive care was appropriate. PMID- 27222124 TI - Identification of amino acids related to catalytic function of Sulfolobus solfataricus P1 carboxylesterase by site-directed mutagenesis and molecular modeling. AB - The archaeon Sulfolobus solfataricus P1 carboxylesterase is a thermostable enzyme with a molecular mass of 33.5 kDa belonging to the mammalian hormone-sensitive lipase (HSL) family. In our previous study, we purified the enzyme and suggested the expected amino acids related to its catalysis by chemical modification and a sequence homology search. For further validating these amino acids in this study, we modified them using site-directed mutagenesis and examined the activity of the mutant enzymes using spectrophotometric analysis and then estimated by homology modeling and fluorescence analysis. As a result, it was identified that Ser151, Asp244, and His274 consist of a catalytic triad, and Gly80, Gly81, and Ala152 compose an oxyanion hole of the enzyme. In addition, it was also determined that the cysteine residues are located near the active site or at the positions inducing any conformational changes of the enzyme by their replacement with serine residues. [BMB Reports 2016; 49(6): 349-354]. PMID- 27222125 TI - Tau mis-splicing in the pathogenesis of neurodegenerative disorders. AB - Tau proteins, which stabilize the structure and regulate the dynamics of microtubules, also play important roles in axonal transport and signal transduction. Tau proteins are missorted, aggregated, and found as tau inclusions under many pathological conditions associated with neurodegenerative disorders, which are collectively known as tauopathies. In the adult human brain, tau protein can be expressed in six isoforms due to alternative splicing. The aberrant splicing of tau pre-mRNA has been consistently identified in a variety of tauopathies but is not restricted to these types of disorders as it is also present in patients with non-tau proteinopathies and RNAopathies. Tau mis splicing results in isoform-specific impairments in normal physiological function and enhanced recruitment of excessive tau isoforms into the pathological process. A variety of factors are involved in the complex set of mechanisms underlying tau mis-splicing, but variation in the cis-element, methylation of the MAPT gene, genetic polymorphisms, the quantity and activity of spliceosomal proteins, and the patency of other RNA-binding proteins, are related to aberrant splicing. Currently, there is a lack of appropriate therapeutic strategies aimed at correcting the tau mis-splicing process in patients with neurodegenerative disorders. Thus, a more comprehensive understanding of the relationship between tau mis-splicing and neurodegenerative disorders will aid in the development of efficient therapeutic strategies for patients with a tauopathy or other, related neurodegenerative disorders. [BMB Reports 2016; 49(8): 405-413]. PMID- 27222126 TI - Loss of Chromosome 18 in Neuroendocrine Tumors of the Small Intestine: The Enigma Remains. AB - BACKGROUND/AIMS: Neuroendocrine tumors of the small intestine (SI-NETs) exhibit an increasing incidence and high mortality rate. Until now, no fundamental molecular event has been linked to the tumorigenesis and progression of these tumors. Only the loss of chromosome 18 (Chr18) has been shown in up to two thirds of SI-NETs, whereby the significance of this alteration is still not understood. We therefore performed the first comprehensive study to identify Chr18-related events at the genetic, epigenetic and gene/protein expression levels. METHODS: We did expression analysis of all seven putative Chr18-related tumor suppressors by quantitative real-time PCR (qRT-PCR), Western blot and immunohistochemistry. Next generation exome sequencing and SNP array analysis were performed with five SI NETs with (partial) loss of Chr18. Finally, we analyzed all microRNAs (miRNAs) located on Chr18 by qRT-PCR, comparing Chr18+/- and Chr18+/+ SI-NETs. RESULTS: Only DCC (deleted in colorectal cancer) revealed loss of/greatly reduced expression in 6/21 cases (29%). No relevant loss of SMAD2, SMAD4, elongin A3 and CABLES was detected. PMAIP1 and maspin were absent at the protein level. Next generation sequencing did not reveal relevant recurrent somatic mutations on Chr18 either in an exploratory cohort of five SI-NETs, or in a validation cohort (n = 30). SNP array analysis showed no additional losses. The quantitative analysis of all 27 Chr18-related miRNAs revealed no difference in expression between Chr18+/- and Chr18+/+ SI-NETs. CONCLUSION: DCC seems to be the only Chr18 related tumor suppressor affected by the monoallelic loss of Chr18 resulting in a loss of DCC protein expression in one third of SI-NETs. No additional genetic or epigenetic alterations were present on Chr18. PMID- 27222127 TI - [Smart eye data : Development of a foundation for medical research using Smart Data applications]. AB - BACKGROUND: Smart Data means intelligent data accumulation and the evaluation of large data sets. This is particularly important in ophthalmology as more and more data are being created. Increasing knowledge and personalized therapies are expected by combining clinical data from electronic health records (EHR) with measurement data. OBJECTIVE: In this study we investigated the possibilities to consolidate data from measurement devices and clinical data in a data warehouse (DW). MATERIAL AND METHODS: An EHR was adjusted to the needs of ophthalmology and the contents of referral letters were extracted. The data were imported into a DW overnight. Measuring devices were connected to the EHR by an HL7 standard interface and the use of a picture archiving and communications system (PACS). Data were exported from the review software using a self-developed software. For data analysis the software was modified to the specific requirements of ophthalmology. RESULTS: In the EHR 12 graphical user interfaces were created and the data from 32,234 referral letters were extracted. A total of 23 diagnostic devices could be linked to the PACS and 85,114 optical coherence tomography (OCT) scans, 19,098 measurements from IOLMaster as well as 5,425 pentacam examinations were imported into the DW including over 300,000 patients. Data discovery software was modified providing filtering methods. CONCLUSION: By building a DW a foundation for clinical and epidemiological studies could be implemented. In the future, decision support systems and strategies for personalized therapies can be based on such a database. PMID- 27222128 TI - Health and Economic Burden of Running-Related Injuries in Dutch Trailrunners: A Prospective Cohort Study. AB - BACKGROUND: Trailrunning is becoming very popular. However, the risk and burden of running-related injuries (RRI) in trailrunning is not well established. OBJECTIVE: To investigate the prevalence, injury rate, severity, nature, and economic burden of RRIs in Dutch trailrunners. METHODS: This prospective cohort study included 228 trailrunners aged 18 years or over (range 23-67), and was conducted between October 2013 and December 2014. After completing the baseline questionnaire, the Oslo Sports Trauma Research Center Questionnaire on Health Problems was administered every 2 weeks to collect data on RRIs. Participants who reported RRIs were asked about healthcare utilization (direct costs) and absenteeism from paid work (indirect costs). RRI was defined as disorders of the musculoskeletal system or concussions experienced or sustained during participation in running. RESULTS: The mean prevalence of RRIs measured over time was 22.4 % [95 % confidence interval (CI) 20.9-24.0], and the injury rate was 10.7 RRIs per 1000 h of running (95 % CI 9.4-12.1). The prevalence was higher for overuse (17.7 %; 95 % CI 15.9-19.5) than for acute (4.1 %; 95 % CI 3.3-5.0) RRIs. Also, the injury rate was higher for overuse (8.1; 95 % CI 6.9-9.3) than for acute (2.7; 95 % CI 2.0-3.4) RRIs. The median of the severity score was 35.0 [25 75 %, interquartile range (IQR) 22.0-55.7], and the median of the duration of RRIs was 2.0 weeks (IQR 2.0-6.0) during the study. The total economic burden of RRIs was estimated at ?172.22 (95 % CI 117.10-271.74) per RRI, and ?1849.49 (95 % CI 1180.62-3058.91) per 1000 h of running. An RRI was estimated to have a direct cost of ?60.92 (95 % CI 45.11-94.90) and an indirect cost of ?111.30 (95 % CI 61.02-192.75). CONCLUSIONS: The health and economic burden of RRIs presented in this study are significant for trailrunners and for society. Therefore, efforts should be made in order to prevent RRIs in trailrunners. PMID- 27222129 TI - Preparation and Adsorption Properties of Novel Porous Microspheres with Different Concentrations of Bilirubin. AB - BACKGROUND: Plasma perfusion was widely used to clear toxic substances of plasma. Particle size and uniformity of adsorbent microspheres also affect the absorption rate. METHODS: Conventional suspension polymerization was improved using a pre dispersion homogenizer to obtain novel adsorbent microspheres, named ERM-0100. Microsphere-related characteristics and attributes were analysed. RESULT: The ERM 0100 microspheres efficiently adsorbed different bilirubin concentrations, with a maximum rate of 59.72 +/- 1.08%. At high bilirubin concentrations, ERM-0100 exhibited similar adsorption rate with BRS350 and BS330 (p = 0.303, p = 1.000, relatively), and higher than HB-H-6 (p = 0.000). At different concentration, ERM 0100 showed good adsorption performance. The ERM-0100 had no significant adsorption for electrolyte; for TP and ALB, the loss rates of ERM-0100 were 15.65 +/- 0.36 and 23.23 +/- 1.11%, respectively. In addition, ERM-0100 showed good blood compatibility. CONCLUSION: The ERM-0100 is a potential biomedical material for plasma perfusion for good effect, less costs and more safety. The microspheres may be coated to reduce its protein adsorption. PMID- 27222130 TI - Noradrenergic dysregulation in the pathophysiology of PTSD. AB - A central role for noradrenergic dysregulation in the pathophysiology of post traumatic stress disorder (PTSD) is increasingly suggested by both clinical and basic neuroscience research. Here, we integrate recent findings from clinical and animal research with the earlier literature. We first review the evidence for net upregulation of the noradrenergic system and its responsivity to stress in individuals with PTSD. Next, we trace the evidence that the alpha1 noradrenergic receptor antagonist prazosin decreases many of the symptoms of PTSD from initial clinical observations, to case series, to randomized controlled trials. Finally, we review the basic science work that has begun to explain the mechanism for this efficacy, as well as to explore its possible limitations and areas for further advancement. We suggest a view of the noradrenergic system as a central, modifiable link in a network of interconnected stress-response systems, which also includes the amygdala and its modulation by medial prefrontal cortex. Particular attention is paid to the evidence for bidirectional signaling between noradrenaline and corticotropin-releasing factor (CRF) in coordinating these interconnected systems. The multiple different ways in which the sensitivity and reactivity of the noradrenergic system may be altered in PTSD are highlighted, as is the evidence for possible heterogeneity in the pathophysiology of PTSD between different individuals who appear clinically similar. We conclude by noting the importance moving forward of improved measures of noradrenergic functioning in clinical populations, which will allow better recognition of clinical heterogeneity and further assessment of the functional implications of different aspects of noradrenergic dysregulation. PMID- 27222133 TI - NHS regulator will do fewer inspections as budgets are cut. PMID- 27222131 TI - A ventral root avulsion injury model for neurogenic underactive bladder studies. AB - Detrusor underactivity (DU) is defined as a contraction of reduced strength and/or duration during bladder emptying and results in incomplete and prolonged bladder emptying. The clinical diagnosis of DU is challenging when present alone or in association with other bladder conditions such as detrusor overactivity, urinary retention, detrusor hyperactivity with impaired contractility, aging, and neurological injuries. Several etiologies may be responsible for DU or the development of an underactive bladder (UAB), but the pathobiology of DU or UAB is not well understood. Therefore, new clinically relevant and interpretable models for studies of UAB are much needed in order to make progress towards new treatments and preventative strategies. Here, we review a neuropathic cause of DU in the form of traumatic injuries to the cauda equina (CE) and conus medullaris (CM) portions of the spinal cord. Lumbosacral ventral root avulsion (VRA) injury models in rats mimic the clinical phenotype of CM/CE injuries. Bilateral VRA injuries result in bladder areflexia, whereas a unilateral lesion results in partial impairment of lower urinary tract and visceromotor reflexes. Surgical re implantation of avulsed ventral roots into the spinal cord and pharmacological strategies can augment micturition reflexes. The translational research need for the development of a large animal model for UAB studies is also presented, and early studies of lumbosacral VRA injuries in rhesus macaques are discussed. PMID- 27222132 TI - Glial response to 17beta-estradiol in neonatal rats with excitotoxic brain injury. AB - White-matter injury is the most common cause of the adverse neurodevelopmental outcomes observed in preterm infants. Only few options exist to prevent perinatal brain injury associated to preterm delivery. 17beta-estradiol (E2) is the predominant estrogen in circulation and has been shown to be neuroprotective in vitro and in vivo. However, while E2 has been found to modulate inflammation in adult models of brain damage, how estrogens influence glial cells response in the developing brain needs further investigations. Using a model of ibotenate-induced brain injury, we have refined the effects of E2 in the developing brain. E2 provides significant neuroprotection both in the cortical plate and the white matter in neonatal rats subjected to excitotoxic insult mimicking white matter and cortical damages frequently observed in very preterm infants. E2 promotes significant changes in microglial phenotypes balance in response to brain injury and the acceleration of oligodendrocyte maturation. Maturational effects of E2 on myelination process were observed both in vivo and in vitro. Altogether, these data demonstrate that response of glial cells to E2 could be responsible for its neuroprotective properties in neonatal excitotoxic brain injury. PMID- 27222134 TI - P21 and p27 Immunoexpression in Upper Urinary Tract Urothelial Carcinomas. AB - p21 and p27 are members of cyclin-dependent kinase family, which function as tumor suppressors and they are involved in development and progression of several malignancies. We investigated their expression in upper urinary tract urothelial carcinoma (UUTUC). Radical nephroureterectomy materials of 34 patients were assessed by immunohistochemistry to evaluate expression of p21 and p27 in UUTUC. Results were correlated with various clinicopathological variables as age, gender, tumor grade and stage, tumor architecture, multifocality, subsequent bladder carcinoma development and clinical outcome.p21 and p27 expression was observed in 52.9 % (n = 18) and 88.2 % (n = 30), respectively. A total of 21 tumors (61.7 %) showed either total loss of p21 expression (n = 16, 47 %) or lower expression (n = 5, 14.7 %). No correlation was found between p21 expression and clinicopathologic variables. Cases showing total loss or lower p27 expression (11.7 % and <25.6 %, respectively) (n = 19, 55.8 %) constituted 67.6 % (n = 23) of the cases totally. This loss or lower p27 expression correlated with a shorter overall survival in both univariate and multivariate analysis (p = 0.039 and p = 0.037, respectively). None of the noninvasive tumors (papillary and nodular tumors) showed loss of p27 (p = 0.016) while 33.3 % of invasive ones showed p27 loss. Noninvasive tumor architecture also correlated with subsequent bladder carcinoma development (p = 0.032) while invasive tumor architecture correlated with advanced stage (T3 and T4) (p = 0.003). p27 is widely expressed in UUTUC, while p21 expression is observed in half of the cases. Loss of p27 expression correlated with tumor architecture and overall survival in UUTUC. However, further research is needed to assess their role in UUTUC. PMID- 27222135 TI - Association of cardiac injury with iron-increased oxidative and nitrative modifications of the SERCA2a isoform of sarcoplasmic reticulum Ca(2+)-ATPase in diabetic rats. AB - The role of iron in the etiology of diabetes complications is not well established. Thus, this study was performed to test whether the iron-induced increase of oxidative/nitrative damage is involved in SERCA2a-related diabetic heart complication. Four randomly divided groups of rats were used: normal control group; iron overload group; diabetes group, and diabetic plus iron overload group. Iron supplementation stimulated cardiomyocyte hypertrophy and led to an increase in cardiac protein carbonyls, nitrotyrosine (3-NT) formation, and iNOS protein expression, thus resulting in abnormal myocardium calcium homeostasis of diabetic rats. The levels of SECA2a oxidation/nitration were significantly increased in the iron overload diabetic rats, along with a decrease in SECA2a expression and activity. In order to elucidate the possible role of iron in SERCA2a dysfunction, the effects of iron (Fe(3+) or hemin) on peroxynitrite (ONOO(-)) induced SERCA2a oxidation and nitration were further investigated in vitro. It was found that tyrosine nitration played more important role in SERCA2a inactivation than thiol oxidation. These results present a potential mechanism in which iron exacerbates the diabetes-induced oxidative/nitrative modification of SERCA2a, which may cause functional deficits in the myocyte associated with diabetic cardiac dysfunction. Our findings may help to further understand the role of iron in the pathogenesis of diabetic complications. PMID- 27222137 TI - Treatment Options for Individuals with PTSD and Concurrent TBI: A Literature Review and Case Presentation. AB - Posttraumatic stress disorder (PTSD) is a well-studied mental health condition with existing guidelines and algorithms for treatment of PTSD. Those guidelines, while acknowledging an increased complexity, fail to provide clear PTSD treatment guidelines when an individual has a concurrent traumatic brain injury (TBI) diagnosis. Therefore, a literature review along with an accompanying case presentation is presented to demonstrate the minimum necessary considerations for approaching treatment of this complex population. Treatment approaches must be lead by providers that have the expertise and training necessary to consider all facets of the patient and their potential options. The provider must consider the pathophysiology of PTSD and TBI and be capable of leading a team to identify the patient's source(s) of dysfunction, current cognitive abilities, and potential indications for psychotropic medications and/or other types of therapeutic intervention. PMID- 27222136 TI - Psychiatric and Medical Comorbidity in the Primary Care Geriatric Patient-An Update. AB - The mental health needs of older primary care patients are now widely recognized if not widely addressed. The range of behavioral health approaches including co locating psychiatrists and integrating mental health professionals as care managers into primary care sites is extensive and growing. Nonetheless the primary care provider remains the first line of defense against mental disorders, most commonly depression and anxiety that accompany and exacerbate common physical conditions. The excess, potentially avoidable disability that results from comorbidity makes it imperative that early recognition and evidence based intervention occur. Multi-morbidity and polypharmacy make intervention a challenge. Psychotherapy can help overcome comorbidity depression however the most accessible intervention would be an antidepressant FDA approved for both anxiety and depressive disorders. For all these reasons, a focus on physical conditions most commonly associated with mental disorders can foster early recognition before the older patient's care becomes overwhelmingly complicated. PMID- 27222138 TI - New Directions in Medication-Facilitated Behavioral Treatment for Substance Use Disorders. AB - A promising approach to addressing substance use disorders is to integrate pharmacotherapy with a behavioral treatment with which synergy is possible. In this review, we focus on recent research suggesting that this approach may be effective for cocaine and cannabis use disorders, both of which currently lack efficacious medications. We summarize potential targets of pharmacotherapy of particular relevance to combined medication-behavioral treatment and examine preliminary evidence of clinical efficacy. Common to these promising medications is a hypothesized mechanism of action predicated on reversing drug-related neural adaptations, such as high reactivity to stress or drug cues, that might undermine fruitful engagement with behavioral treatment. We also review emerging medications, such as certain glutamatergic and serotonergic agents, which may be feasibly integrated with existing treatments. We conclude with an outline of future directions for research. PMID- 27222139 TI - Hormonal Factors and Disturbances in Eating Disorders. AB - This review summarizes the current state of the literature regarding hormonal correlates of, and etiologic influences on, eating pathology. Several hormones (e.g., ghrelin, CCK, GLP-1, PYY, leptin, oxytocin, cortisol) are disrupted during the ill state of eating disorders and likely contribute to the maintenance of core symptoms (e.g., dietary restriction, binge eating) and/or co-occurring features (e.g., mood symptoms, attentional biases). Some of these hormones (e.g., ghrelin, cortisol) may also be related to eating pathology via links with psychological stress. Despite these effects, the role of hormonal factors in the etiology of eating disorders remains unknown. The strongest evidence for etiologic effects has emerged for ovarian hormones, as changes in ovarian hormones predict changes in phenotypic and genetic influences on disordered eating. Future studies would benefit from utilizing etiologically informative designs (e.g., high risk, behavioral genetic) and continuing to explore factors (e.g., psychological, neural responsivity) that may impact hormonal influences on eating pathology. PMID- 27222140 TI - Disturbed Sleep and Postpartum Depression. AB - The perinatal period introduces a myriad of changes. One important but often overlooked change is an increased reporting of sleep disturbance. Although casually regarded as a consequence of pregnancy or postpartum, there is emerging evidence implicating significant sleep disturbance, characterized by insomnia symptoms and/or poor sleep quality, with adverse outcomes, such as an increase in depressive symptomatology or the development postpartum depression (PPD). Significant consequences may arise as a result including issues with maternal infant bonding, effective care for the infant, and behavioral or emotional difficulties in the infant. This review discusses the relevant literature as to how disturbed sleep during pregnancy as well as in the postpartum may increase the risk for PPD. PMID- 27222141 TI - Juvenile Sex Offenders. AB - Sexual offending by juveniles accounts for a sizable percentage of sexual offenses, especially against young children. In this article, recent research on female juvenile sex offenders (JSOs), risk factors for offending in juveniles, treatment, and the ways in which these youth may differ from general delinquents will be reviewed. Most JSOs do not go on to develop paraphilic disorders or to commit sex offenses during adulthood, and as a group, they are more similar to nonsexual offending juvenile delinquents than to adult sex offenders. Recent research has elucidated some differences between youth who commit sex offenses and general delinquents in the areas of atypical sexual interests, the use of pornography, and early sexual victimization during childhood. PMID- 27222144 TI - Quantitative Structure-Cytotoxic Activity Relationship 1-(Benzoyloxy)urea and Its Derivative. AB - Drug development is originally carried out on a trial and error basis and it is cost-prohibitive. To minimize the trial and error risks, drug design is needed. One of the compound development processes to get a new drug is by designing a structure modification of the mother compound whose activities are recognized. A substitution of the mother compounds alters the physicochemical properties: lipophilic, electronic and steric properties. In Indonesia, one of medical treatments to cure cancer is through chemotherapy and hydroxyurea. Some derivatives, phenylthiourea, phenylurea, benzoylurea, thiourea and benzoylphenylurea, have been found to be anticancer drug candidates. To predict the activity of the drug compound before it is synthesized, the in-silico test is required. From the test, Rerank Score which is the energy of interaction between the receptor and the ligand molecule is then obtained. Hydroxyurea derivatives were synthesized by modifying Schotten-Baumann's method by the addition of benzoyl group and its homologs resulted in the increase of lipophilic, electronic and steric properties, and cytotoxic activity. Synthesized compounds were 1 (benzoyloxy)urea and its derivatives. Structure characterization was obtained by the spectrum of UV, IR, H NMR, C NMR and Mass Spectrometer. Anticancer activity was carried out using MTT method on HeLa cells. The Quantitative Structure Cytotoxic Activity Relationships of 1-(benzoyloxy)urea compound and its derivatives was calculated using SPSS. The chemical structure was described, namely: ClogP, pi, sigma, RS, CMR and Es; while, the cytotoxic activity was indicated by log (1 / IC50). The results show that the best equation of Quantitative Structure-Cytotoxic Activity Relationships (QSAR) of 1- (benzoyloxy)urea compound and its derivatives is Log 1/IC50 = - 0.205 (+ 0.068) sigma - 0.051 (+ 0.022) Es - 1.911 (+ 0.020). PMID- 27222143 TI - Treatment During Civil Commitment for Sexual Offending Behaviors. AB - The first sex offender civil commitment legislation passed in Washington State in 1990. Since that time, 21 additional jurisdictions in the USA have passed similar statutes. Although considered controversial by some, the statutes have withstood legal scrutiny at the state and federal levels. These statutes have been found constitutional in large part because they offer treatment to those individuals detained under them. In the 25 years since sex offender civil commitment became a reality, significant advances in sex offender assessment and treatment have shaped the landscape of the associated treatment programs. This article reviews current practice in programs that treat individuals detained under these laws and provides a framework in which these programs are delivered. PMID- 27222142 TI - Systematic Review of Clozapine Cardiotoxicity. AB - Clozapine is exceptionally effective in psychotic disorders and can reduce suicidal risk. Nevertheless, its use is limited due to potentially life threatening adverse effects, including myocarditis and cardiomyopathy. Given their clinical importance, we systematically reviewed research on adverse cardiac effects of clozapine, aiming to improve estimates of their incidence, summarize features supporting their diagnosis, and evaluate proposed monitoring procedures. Incidence of early (<=2 months) myocarditis ranges from <0.1 to 1.0 % and later (3-12 months) cardiomyopathy about 10 times less. Diagnosis rests on relatively nonspecific symptoms, ECG changes, elevated indices of myocardial damage, cardiac MRI findings, and importantly, echocardiographic evidence of developing ventricular failure. Treatment involves stopping clozapine and empirical applications of steroids, diuretics, beta-blockers, and antiangiotensin agents. Mortality averages approximately 25 %. Safety of clozapine reuse remains uncertain. Systematic studies are needed to improve knowledge of the epidemiology, avoidance, early identification, and treatment of these adverse effects, with effective and practicable monitoring protocols. PMID- 27222145 TI - Stability and fitness costs associated with etoxazole resistance in Tetranychus urticae (Acari: Tetranychidae). AB - The two-spotted spider mite, Tetranychus urticae Koch, is one of the most important pests on a wide range of crops worldwide. Studies on stability of resistance and possible fitness costs associated with etoxazole resistance were carried out in T. urticae to provide basic information necessary to define effective acaricide resistance management strategies for this pest. Selection for resistance to etoxazole was performed in a population of T. urticae collected from a commercial rose field, in Holambra County, in the State of Sao Paulo, Brazil. After five rounds of selection for resistance, the resistance ratio (R/S) at the LC50 reached 8739 fold value in comparison with a susceptible strain (Brazabrantes S Strain). The stability of etoxazole resistance was studied under laboratory conditions, using a population with initial frequency of 75 % of resistant mites. The frequencies of etoxazole resistance were evaluated monthly for a period of 13 months. The frequency of etoxazole resistance decreased from 75 to 37 % in this period. Comparison of biological traits between resistant and susceptible strains indicated the presence of fitness costs associated with etoxazole resistance. The resistant strain showed lower fecundity and a higher proportion of males in the population. The figures for net reproductive rate (R 0), intrinsic rate of natural increase (r m) and finite rate of increase (lambda) were higher in the susceptible strain. The instability of etoxazole resistance is a favorable aspect for the acaricide resistance management in the spider mite. PMID- 27222146 TI - RbAp48, a novel inhibitory factor that regulates the transcription of human immunodeficiency virus type 1. AB - Retinoblastoma binding protein 4 (RbAp48) is a histone chaperone which has been suggested to play a role in gene silencing. However, the role of RbAp48 in human immunodeficiency virus type 1 (HIV-1) infection and gene replication has not been determined to date, to the best of our knowledge. For this purpose, we demonstrated in the present study that RbAp48 expression was upregulated by HIV-1 infection, whereas the knockdown of RbAp48 promoted HIV infection and the production of virus particles. The ectopic expression of RbAp48 inhibited HIV-1 expression, and this inhibition correlated with a marked decrease in the expression of HIV-1 genomic RNA and various RNA transcripts. Further experiments to determine the mechanism responsible for the inhibitory effects of RbAp48 revealed that the ectopic expression of RbAp48 repressed HIV-1 long terminal repeat (LTR)-mediated basal transcription as well as TNF-alpha- and phorbol 12 myristate 13-acetate (PMA)-activated transcription. Furthermore, the results of the electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) analysis revealed that RbAp48 binds to the HIV-1 LTR in vitro. Taken together, these findings demonstrate that, as a transcriptional cofactor, RbAp48 is likely to act as a potent antiretroviral defense. PMID- 27222147 TI - Dexmedetomidine attenuates repeated propofol exposure-induced hippocampal apoptosis, PI3K/Akt/Gsk-3beta signaling disruption, and juvenile cognitive deficits in neonatal rats. AB - Propofol is one of the most widely used intravenous anesthetics. However, repeated exposure to propofol may cause neurodegeneration in the developing brain. Dexmedetomidine (Dex), an alpha2 adrenoceptor agonist, has been previously demonstrated to provide neuroprotection against neuroapoptosis and neurocognitive impairments induced by several anesthetics. Thus, the current study aimed to investigate the effect of Dex on neonatal propofol-induced neuroapoptosis and juvenile spatial learning/memory deficits. Propofol (30 mg/kg) was intraperiotoneally administered to 7-day-old Sprague Dawley rats (n=75) three times each day at 90 min intervals for seven consecutive days with or without Dex (75 ug/kg) treatment 20 min prior to propofol injection. Following repeated propofol exposure, reduced Akt and GSK-3beta phosphorylation, increased cleaved caspase-3 expression levels, an increased Bax/Bcl-2 ratio, and increased terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells in the CA1 hippocampal subregion were observed. Morris Water Maze testing at postnatal day 29 also demonstrated spatial learning and memory deficits following propofol treatment compared with the control group. Notably, these changes were significantly attenuated by Dex pretreatment. The results of the current study demonstrated that Dex ameliorates the neurocognitive impairment induced by repeated neonatal propofol challenge in rats, partially via its anti apoptotic action and normalization of the disruption to the PI3K/Akt/GSK-3beta signaling pathway. The present study provides preliminary evidence demonstrating the safety of propofol on the neonatal brain and the potential use of dexmedetomidine pretreatment in pediatric patients. PMID- 27222148 TI - Ethylene glycol promoted catalyst-free pseudo three-component green synthesis of bis(coumarin)s and bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s. AB - An ethylene glycol promoted catalyst-free practically efficient and sustainable approach has been developed for the synthesis of several benzylidene-bis-(4 hydroxycoumarin)s and 4,[Formula: see text]-(arylmethylene)-bis(3-methyl-1-phenyl 1H-pyrazol-5-ol)s by the pseudo three-component reaction of an aldehyde with 4 hydroxycoumarin and 3-methyl-1-phenylpyrazol-5-one, respectively. Inexpensive, non-toxic, and easily available ethylene glycol used as the reaction solvent and promoter renders an efficient protocol in terms of catalyst-free reaction conditions, short reaction time, high yield, practical utility, and green approach. PMID- 27222149 TI - Network Signatures of IgG Immune Repertoires in Hepatitis B Associated Chronic Infection and Vaccination Responses. AB - The repertoire of IgG antibody responses to infection and vaccination varies depending on the characteristics of the immunogen and the ability of the host to mount a protective immune response. Chronic hepatitis B virus (HBV) infections are marked by persistent infection and immune tolerance to vaccination. This disease offers a unique opportunity to discover key repertoire signatures during infection and in response to vaccination. Complementarity determining region 3 of an antibody heavy chain (CDR-H3) has a major impact on the antigenic specificity of an antibody. We used next-generation sequencing to characterize the CDR-H3 sequences in paired siblings of 4 families in which only one member of each pair had chronic HBV infection. Blood samples were obtained before and 2 weeks after HBV vaccination. The analysis revealed a huge network of sequence-related CDR-H3 clones found almost exclusively among carriers. In contrast, vaccination induced significant increases of CDR-H3 cluster diversities among siblings without hepatitis B. Several vaccination-associated clone clusters were identified. Similar findings of vaccination-associated clone networks were observed in healthy adults receiving HBV boosters. These strategies can be used to identify signatures of other infectious diseases and accelerate discoveries of antibody sequences with important biomedical implications. PMID- 27222150 TI - Sedentary antlion larvae (Neuroptera: Myrmeleontidae) use vibrational cues to modify their foraging strategies. AB - Learning abilities are exhibited by many animals, including insects. However, sedentary species are typically believed to have low capacities and requirements for learning. Despite this view, recent studies show that even such inconspicuous organisms as larval antlions, which employ an ambush predation strategy, are capable of learning, although their learning abilities are rather simple, i.e., limited to the association of vibrational cues with the arrival of prey. This study demonstrates, for the first time, that antlion larvae can use vibrational cues for complex modifications of their foraging strategies. Specifically, antlion larvae rapidly learn to differentiate between the vibrational cues associated with prey of different sizes, and they save resources by ignoring smaller prey in favour of larger, more energetically profitable prey. Moreover, antlion larvae can learn to associate vibrational cues with the loss of their prey, and they respond by burying their victims under the sand more often and more rapidly than do individuals with no opportunities to form such associations. These findings provide not only new insights into the cognitive abilities of animals but also support for the optimal foraging strategy concept, suggesting the importance of maximizing fitness output by balancing the costs and benefits of alternative foraging strategies. PMID- 27222151 TI - External validation of MSKCC postoperative hypocalcaemia nomogram in Turkish papillary thyroid cancer patients. PMID- 27222152 TI - Role of Flow Cytometry in the Diagnosis of Chronic Granulomatous Disease: the Egyptian Experience. AB - INTRODUCTION: Chronic granulomatous disease (CGD) is an inherited mutational defect in any of the NADPH oxidase complex, CYBB (gp91-phox), NCF1 (p47-phox), CYBA (p22-phox), NCF2 (p67-phox), or NCF4 (p40-phox) leading to inability of phagocytes to perform effective respiratory burst and thus diminished killing of bacteria and fungi. The identification of defective proteins aids in establishing a diagnosis prior to genetic analysis, which is rather labor-intensive, expensive, and time-consuming. AIM: The present study aims at assessing the NADPH proteins by performing the intracellular staining with specific monoclonal antibodies and their assessment on flow cytometry. The use of flow cytometry is less laborious and faster to perform than western blot. It also confirms the diagnosis of CGD and detects the affected components allowing proper management of patients. MATERIALS AND METHODS: Twenty-eight patients from 25 different kindred, clinically suspected as CGD were recruited in Egypt. Dihydrorhodamine test was performed to confirm the diagnosis of the patients. Intracellular staining of NADPH components using specific monoclonal antibodies was performed followed by flow cytometric analysis. RESULTS: The present study revealed that the most common defective protein in our cohort is p22-phox, found in 13 patients (46.4 % of cases) followed by p47-phox in 8 patients (28.6 %), gp91-phox in 5 patients (17.9 %), and finally p67-phox in 2 patients (7.1 %). CONCLUSION: In countries with limited resources and yet large number of CGD patients, the analysis of the defective proteins by flow cytometry is an optimum solution for confirming the diagnosis and is a step for targeted sequencing in families seeking prenatal diagnosis. PMID- 27222153 TI - Cognitive ability, social desirability, body mass index and socioeconomic status as correlates of fourth-grade children's dietary-reporting accuracy. AB - BACKGROUND/OBJECTIVES: To investigate the relationship of reporting accuracy in 24-h dietary recalls to child-respondent characteristics-cognitive ability, social desirability, body mass index (BMI) percentile and socioeconomic status (SES). SUBJECTS/METHODS: Fourth-grade children (mean age 10.1 years) were observed eating two school meals and interviewed about dietary intake for 24 h that included those meals. (Eight multiple-pass interview protocols operationalized the conditions of an experiment that crossed two retention intervals-short and long-with four prompts (ways of eliciting reports in the first pass)). Academic achievement-test scores indexed cognitive ability; social desirability was assessed by questionnaire; height and weight were measured to calculate BMI; nutrition-assistance program eligibility information was obtained to index SES. Reported intake was compared to observed intake to calculate measures of reporting accuracy for school meals at the food-item (omission rate; intrusion rate) and energy (correspondence rate; inflation ratio) levels. Complete data were available for 425 of 480 validation-study participants. RESULTS: Controlling for manipulated variables and other measured respondent characteristics, for one or more of the outcome variables, reporting accuracy increased with cognitive ability (omission rate, intrusion rate, correspondence rate, P<0.001), decreased with social desirability (correspondence rate, P<0.0004), decreased with BMI percentile (correspondence rate, P=0.001) and was better by higher- than by lower-SES children (intrusion rate, P=0.001). Some of these effects were moderated by interactions with retention interval and sex. CONCLUSIONS: Children's dietary-reporting accuracy is systematically related to such respondent characteristics as cognitive ability, social desirability, BMI percentile and SES. PMID- 27222154 TI - Decreased serum vitamin D levels in early spontaneous pregnancy loss. AB - BACKGROUND/OBJECTIVES: Effects of vitamin D deficiency in pregnancy have been associated with some adverse pregnancy outcomes. The objective of this study was to analyze the relationship between vitamin D deficiency in childbearing aged women and pregnancy loss (PL) in the first trimester. SUBJECTS/METHODS: This is a cross-sectional study. Plasma was collected from 60 nulliparous women with singleton at 7-9 weeks of gestation (30 with viable gestation and 30 with PL) and 60 non-gravid childbearing aged women (30 with a successful pregnancy history, and 30 with one or more spontaneous first-trimester PL history). Quantitation of serum 25-hydroxyvitamin D (25(OH)D) and 25-hydroxyvitamin D-1 alpha hydroxylase (CYP27B1) was assayed. RESULTS: By pregnancy/non-gravid, normal pregnant women had higher 25(OH)D (49.32 MUg/l) and CYP27B1 (82.00 pg/ml) than PL women (34.49 MUg/l and 37.87 pg/ml, both P<0.01); the non-gravid women with a successful pregnancy history also had higher 25(OH)D (39.56 MUg/l) and CYP27B1 (39.04 pg/ml) than women with PL history (12.30 MUg/l and 12.35 pg/ml, both P<0.01). The 96.7% of non-gravid women with PL history and 43.3% of PL women had serum 25(OH)D concentrations below 30 MUg/l. There was a strong association between low vitamin D levels and PL (odds ratio 1.71; 95% confidence interval: 1.2-2.4, P<0.001). The regression analyses showed that PL was significantly inversely correlated with 25(OH)D (P<0.01) and CYP27B1 levels (P<0.01). CONCLUSIONS: Vitamin D deficiency associated with PL in the first trimester of pregnancy. Decreased serum vitamin D levels among childbearing aged women with the failed clinical pregnancies history may predispose to increased risk for PL. PMID- 27222155 TI - Factors associated with patient recall of individualized dietary recommendations for kidney stone prevention. AB - BACKGROUND/OBJECTIVES: Dietary approaches to preventing the recurrence of idiopathic calcium-containing kidney stones are effective. However, a lifelong commitment to prevention is challenging for many patients. Multiple patient factors likely account for compliance and adherence with dietary recommendations. We examined patients' recall and compliance with dietary recommendations provided during clinical evaluation. SUBJECTS/METHODS: Of 275 patients who received dietary recommendations from a dietitian, 112 completed an investigator-designed survey querying their recollection of dietary recommendations. Patients' responses were compared with the recommendations actually provided as entered in patients' medical records. RESULTS: Patients (62% male, 56+/-13 years; 38% female, 52+/-14 years) were provided 3.4+/-1.1 recommendations (min-max, 1-6) and recalled 67% of recommendations. Highest recalls were for (i) lower meat/fish/poultry intake, (ii) higher fluid intake and (iii) lower sodium (?68% for all). Lowest recalls were for weight loss, using citrus juices and increasing fruits/vegetables (?61% for all). Forty-seven percent of patients given 1-3 recommendations recalled 100%, whereas only 23% of patients provided >3 recommendations did so (P=0.011). Even though 38% of patients reported some difficulty following dietary recommendations, nearly all (91%) said that they were willing to continue following them. CONCLUSIONS: Higher patient recall is associated with ?3 dietary recommendations. Patient recall of recommendations that were not actually provided ('false recall') may contribute to reduced recall and confusion about the most important dietary strategies to reduce their stone risk. Accordingly, providers should prioritize the most important dietary recommendations, reserving those less important for follow-up, and address any confusion patients have from information received prior to evaluation. PMID- 27222156 TI - Association between lutein intake and lutein concentrations in human milk samples from lactating mothers in South Korea. AB - This study was performed to investigate the association between maternal lutein intake and lutein concentrations in human milk among exclusive breast-feeding and mixed-feeding groups of lactating mothers in South Korea. From 99 women who were recruited from March to July 2015, dietary data and breast milk samples were obtained. The means of the daily lutein intakes and breast milk lutein concentrations in lactating mothers were 4.04 mg/day and 10.06 MUg/dl, respectively, and they did not differ according to the type of breast-feeding. Breast milk lutein concentrations were positively correlated with the dietary lutein intake of lactating mothers after adjustment for the infant's age and supplement use by the lactating women (r=0.3337, P=0.0008). These correlations appeared in both groups. Further research is needed to identify whether breast milk lutein levels influence infant health, especially eye health.European Journal of Clinical Nutrition advance online publication, 25 May 2016; doi:10.1038/ejcn.2016.84. PMID- 27222157 TI - Combined fluoroscopic and ultrasound guided cervical nerve root injections. AB - PURPOSE: To assess the technical feasibility, safety and initial clinical efficacy of a combined ultrasound and fluoroscopy imaging approach to cervical nerve root blocks. Fluoroscopic guided cervical transforaminal and selective nerve root injections are often used in the investigation or treatment of radicular symptoms, although rare but serious complications including death have been reported. We report a combined technique developed to increase safety of selective nerve root injections, including the safety and early efficacy of this novel technique in our initial patient cohort. METHODS: We retrospectively reviewed a consecutive cohort of injections performed in 149 patients by a single consultant radiologist between December 2010 and August 2012. For all patients the outcome was assessed both immediately following the procedure and at six weeks. Primary outcome was reduction in radicular symptom level. Duration of symptoms were also assessed and all complications were recorded. RESULTS: One hundred and forty nine patients underwent injection at either one or two cervical levels. No patients experienced any complications during the follow-up period, and 72 % had an initial positive response to the injection. Of these, 42 % were discharged to the care of their General Practitioner, 23 % went on to have surgery, 18 % were actively monitored in a specialist clinic, 10 % were referred to our pain management service and 4 % had the injection repeated after symptoms recurred. CONCLUSION: Using this combined image guided technique cervical nerve root blocks appear both safe and effective in the investigation and management of radicular symptoms from the cervical spine. PMID- 27222158 TI - Adsorbent comparisons for anesthetic gas capture in hospital air emissions. AB - For the development of emission control strategies, activated carbon, zeolite, molecular sieves, and a silica gel were tested for adsorption of the newer anesthetic gases isoflurane, sevoflurane, and desflurane from air. The activated carbon Norit GCA 48 was selected for the best performance, and adsorption isotherms at room temperature were developed for the three anesthetics. Equilibrium capacities for this carbon were in the range of 500 to 1,000 mg g(-1) for these anesthetics at partial pressures ranging from 5 to 45 Torr, with the most volatile compound (desflurane) showing the least favorable adsorption. Activated carbons are therefore suggested for use as effective adsorbents in emission control of these anesthetic gases from hospitals. PMID- 27222159 TI - Morphological and physiological changes exhibited by a Cd-resistant Dictyosphaerium chlorelloides strain and its cadmium removal capacity. AB - Changes induced on freshwater microalga Dictyosphaerium chlorelloides (Dc(wt)) acclimated in the laboratory until their survival in culture media enriched with cadmium 100 uM have been studied. Cadmium removal by living cells of this Cd resistant (Dc(CdR100)) strain was tested in cultures exposed to 100 uM Cd during 30 days. Cell dimensions were measured under light microscopy, and cell growth was studied. Photosynthetic yield (PhiPSII) was analyzed and the photosynthetic oxygen development and respiration response was obtained. Results show that Dc(CdR100) strain exhibited significant cell morphology changes in comparison to Dc(wt) cells, which affected both surface area and cell biovolume. Malthusian fitness analysis showed that Dc(CdR100) strain living in Cd-enriched culture had developed a lower capacity of nearly 50% growth, and its photosynthetic oxygen development and respiration response were significantly reduced in both light and dark photosynthetic phases. Dc(CdR100) strain showed a very high capacity to remove cadmium from the aquatic environment (over 90%), although most of the removed heavy metal (~70%) is adhered to the cell wall. These specific characteristics of Dc(CdR100) cells suggest the possibility of using this strain in conjunction with Dc(wt) strain as bioelements into a dual-head biosensor, and in bioremediation processes on freshwater polluted with Cd. PMID- 27222160 TI - Health risk assessment through consumption of vegetables rich in heavy metals: the case study of the surrounding villages from Panasqueira mine, Central Portugal. AB - Panasqueira mine is a tin-tungsten mineralization hosted by metasediments with quartz veins rich in ferberite. The mineralization also comprises wolframite, cassiterite, chalcopyrite, several sulfides, carbonates and silver sulfosalts. The mining and beneficiation processes produce arsenic-rich mine wastes laid up in huge tailings (Barroca Grande and Rio tailings). The contents of As, Cd, Cr, Cu, Pb and Zn were estimated in rhizosphere soils, irrigation waters, road dusts and in potatoes, cabbages, lettuces and beans, collected on local gardens of four neighborhood Panasqueira mine villages: S. Francisco de Assis (SFA) and Barroca suffering the influence of tailings; Unhais-o-Velho and Casegas considered as non polluted areas. The mean concentrations of metals in rhizosphere soils and vegetables exceed the reference guidelines values and seem to be linked to the sulfides. The rhizosphere ecological risks were ranked in the order of Cd > As > Cu > Pb > Zn > Cr and SFA > Barroca > Casegas > Unhais-o-Velho. Metal concentrations, in vegetables, were found in the order of lettuce > cabbage > potatoes and SFA > Barroca > Casegas > Unhais-o-Velho. For cabbages and lettuces, the tendency of contamination is roots > leaves and for potatoes is roots > leaves > tubers. The risk for residents, due to ingesting of metals/metalloid, by consuming vegetables grown around the sampling area, was calculated and the result indicates that the inhabitants of these villages are probably exposed to some potential health risks through the intake of heavy metals and metalloids via consuming their vegetables. PMID- 27222161 TI - Natural Mentoring Relationships and the Adjustment to College among Underrepresented Students. AB - This study investigated associations between natural mentoring relationships and academic performance via psychological distress among underrepresented college students attending an elite predominantly White institution (PWI). Specifically, this study explored whether the quantity of natural mentors possessed upon college entry, the retention of natural mentors across the first year of college, and overall changes in the number of natural mentors possessed during the first year of college predicted improvements in students' semester grade point averages (GPAs) via reductions in psychological distress. Participants in this study included 336 first-year undergraduate students attending a selective PWI. Students were eligible to participate in this study if they were first-generation college students, students from economically disadvantaged backgrounds, or students from underrepresented racial/ethnic minority groups. Results of this study indicated that a greater number of retained natural mentoring relationships across the first year of college were associated with improvements in students' GPAs via reductions in symptoms of depression from the Fall to Spring semester. The results of this study suggest that institutional efforts to support the maintenance of preexisting mentoring relationships may be an effective approach to promoting the academic success of underrepresented college students during the first year of college. PMID- 27222162 TI - CHILE: Outcomes of a group randomized controlled trial of an intervention to prevent obesity in preschool Hispanic and American Indian children. AB - OBJECTIVE: We examined the outcomes of the Child Health Initiative for Lifelong Eating and Exercise (CHILE) study, a group randomized controlled trial to design, implement, and test the efficacy of a trans-community intervention to prevent obesity in children enrolled in Head Start centers in rural American Indian and Hispanic communities in New Mexico. METHODS: CHILE was a 5-year evidence-based intervention that used a socioecological approach to improving dietary intake and increasing physical activity of 1898 children. The intervention included a classroom curriculum, teacher and food service training, family engagement, grocery store participation, and healthcare provider support. Height and weight measurements were obtained four times (fall of 2008, spring and fall of 2009, and spring of 2010), and body mass index (BMI) z-scores in the intervention and comparison groups were compared. RESULTS: At baseline, demographic characteristics in the comparison and intervention groups were similar, and 33% of all the children assessed were obese or overweight. At the end of the intervention, there was no significant difference between the two groups in BMI z scores. CONCLUSIONS: Obesity prevention research among Hispanic and AI preschool children in rural communities is challenging and complex. Although the CHILE intervention was implemented successfully, changes in overweight and obesity may take longer than 2years to achieve. PMID- 27222163 TI - Single Phase Dual-energy CT Angiography: One-stop-shop Tool for Evaluating Aneurysmal Subarachnoid Hemorrhage. AB - Aneurysmal subarachnoid hemorrhages have extremely high case fatality in clinic. Early and rapid identifications of ruptured intracranial aneurysms seem to be especially important. Here we evaluate clinical value of single phase contrast enhanced dual-energy CT angiograph (DE-CTA) as a one-stop-shop tool in detecting aneurysmal subarachnoid hemorrhage. One hundred and five patients who underwent true non-enhanced CT (TNCT), contrast-enhanced DE-CTA and digital subtraction angiography (DSA) were included. Image quality and detectability of intracranial hemorrhage were evaluated and compared between virtual non-enhanced CT (VNCT) images reconstructed from DE-CTA and TNCT. There was no statistical difference in image quality (P > 0.05) between VNCT and TNCT. The agreement of VNCT and TNCT in detecting intracranial hemorrhage reached 98.1% on a per-patient basis. With DSA as reference standard, sensitivity and specificity on a per-patient were 98.3% and 97.9% for DE-CTA in intracranial aneurysm detection. Effective dose of DE-CTA was reduced by 75.0% compared to conventional digital subtraction CTA. Thus, single phase contrast-enhanced DE-CTA is optimal reliable one-stop-shop tool for detecting intracranial hemorrhage with VNCT and intracranial aneurysms with DE CTA with substantial radiation dose reduction compared with conventional digital subtraction CTA. PMID- 27222164 TI - Identification of heterologous Torque Teno Viruses in humans and swine. AB - Torque Teno Viruses (TTVs) are ubiquitous viruses which are highly prevalent in several mammalian species. Human TTV's are epidemiologically associated with several human disease conditions such as respiratory illnesses, auto-immune disorders and hepatitis. Recently it was found that swine TTV's (TTSuVs) can act as primary pathogens. The common occurrence of TTVs as environmental contaminants and the increasing interest in the use of swine organs for xenotransplantation lend importance to the question of whether TTV's can cross-infect across species. In this study, we examined human and swine sera by swine or human TTV-specific PCRs, to determine whether swine TTVs (TTSuV) DNA can be detected in humans and vice versa. Surprisingly, both human and TTSuV DNA were present in a majority of the samples tested. Transfection of human PBMC's with TTSuV1 genomic DNA resulted in productive viral infection which was sustained for the three serial passages tested. Lymphoproliferative responses in infected human PBMCs were diminished when compared to the controls. Furthermore, mild to moderate antibody responses against the TTSuV1 ORF2 protein was detected in 16 of the 40 human sera by ELISA. Therefore, these study findings provide initial and fundamental evidence for possible cross-species transmission of TTVs. PMID- 27222165 TI - Impact of thrombolysis in acute ischaemic stroke without occlusion: an observational comparative study. AB - BACKGROUND AND PURPOSE: The impact of intravenous recombinant tissue plasminogen activator (IV-rtPA) in patients with acute ischaemic stroke (AIS) but no arterial occlusion is currently a matter of debate. This study aimed to assess functional outcome of such patients with respect to IV-rtPA use. METHODS: A retrospective case-control analysis was performed comparing the outcome of AIS patients without arterial occlusion with or without IV-rtPA use. Patients were selected from prospective consecutive observational registries of five European university hospitals. The primary study outcome was excellent outcome at 3 months after stroke, as defined by a modified Rankin Scale (mRS) 0-1. RESULTS: A total of 488 patients without arterial occlusion documented by angiography were included in the present study; 300 received IV-rtPA and 188 did not. No between-group difference was found for excellent outcome before and after adjustment for baseline characteristics (adjusted odds ratio for no IV-rtPA use 0.79, 95% confidence interval 0.51-1.24, P = 0.31). Similar results were found for favourable outcome (defined as a 90-day mRS of 0-2) whereas a higher rate of early neurological improvement was found in IV-rtPA-treated patients (adjusted odds ratio 1.99; 95% confidence interval 1.29-3.07, P = 0.002). Sensitivity analyses yielded similar results. CONCLUSIONS: Our study suggests that AIS patients without visible arterial occlusion treated with IV-rtPA may have no better outcome at 3 months than those untreated. However, only a randomized controlled trial would provide a definitive answer about the impact of rtPA in acute stroke patients without occlusion. Until then, these patients should be treated by rtPA as recommended. PMID- 27222166 TI - Epimedium Polysaccharide Alleviates Polyglutamine-Induced Neurotoxicity in Caenorhabditis elegans by Reducing Oxidative Stress. AB - Epimedium has been traditionally used to treat a variety of medical conditions, including neurological disorders. In this study, an acidic polysaccharide EbPS-A1 is isolated from Epimedium brevicornum and found to contain mainly galacturonic acid, galactose, and rhamnose but also arabinose and glucuronic acid. Using Caenorhabditis elegans models, we show that EbPS-A1 is capable of inhibiting behavioral dysfunction mediated by polyglutamine (polyQ), which is implicated in several neurodegenerative disorders such as Huntington's disease. Interestingly, EbPS-A1 does not inhibit polyQ aggregation or extend lifespan in the nematodes; it does, however, improve the survival under increased oxidative stress of both polyQ and wild-type nematodes intoxicated by paraquat. Further studies reveal that EbPS-A1 is capable of not only scavenging free radicals in vitro but also reducing reactive oxygen species levels, enhancing antioxidant enzyme activities, and decreasing lipid peroxidation product in C. elegans models. Together, these results suggest that the protective effect of Epimedium polysaccharide against polyQ-mediated neurotoxicity is likely due to its antioxidant function. PMID- 27222168 TI - Iridium- and rhodium-catalyzed C-H activation and formyl arylation of benzaldehydes under chelation-assistance. AB - Mild and efficient synthesis of benzophenones via Ir(iii)- and Rh(iii)-catalyzed, directing group-assisted formyl C-H arylation of benzaldehydes has been achieved using diaryliodonium salts, in which Rh(iii) and Ir(iii) catalysts exhibited a complementary substrate scope. PMID- 27222167 TI - Polyhydroxyalkanoate (PHA) Granules Have no Phospholipids. AB - Polyhydroxybutyrate (PHB) granules, also designated as carbonosomes, are supra molecular complexes in prokaryotes consisting of a PHB polymer core and a surface layer of structural and functional proteins. The presence of suspected phospholipids in the surface layer is based on in vitro data of isolated PHB granules and is often shown in cartoons of the PHB granule structure in reviews on PHB metabolism. However, the in vivo presence of a phospholipid layer has never been demonstrated. We addressed this topic by the expression of fusion proteins of DsRed2EC and other fluorescent proteins with the phospholipid-binding domain (LactC2) of lactadherin in three model organisms. The fusion proteins specifically localized at the cell membrane of Ralstonia eutropha but did not co localize with PHB granules. The same result was obtained for Pseudomonas putida, a species that accumulates another type of polyhydroxyalkanoate (PHA) granules related to PHB. Notably, DsRed2EC-LactC2 expressed in Magnetospirillum gryphiswaldense was detected at the position of membrane-enclosed magnetosome chains and at the cytoplasmic membrane but not at PHB granules. In conclusion, the carbonosomes of representatives of alpha-proteobacteria, beta-proteobacteria and gamma-proteobacteria have no phospholipids in vivo and we postulate that the PHB/PHA granule surface layers in natural producers generally are free of phospholipids and consist of proteins only. PMID- 27222170 TI - Proteomic analysis of retinal proteins in rabbits following intravitreal PBS injection: analysis with tandem mass tag labeling coupled with LC-MS/MS. AB - OBJECTIVE: Intravitreal (IVT) injection has become one of the most commonly performed ophthalmologic procedures. We investigated the changes in retinal function and proteomics in rabbits receiving IVT injection of PBS to evaluate the safety of IVT injection. METHODS: Twenty Chinchilla rabbits were subjected to IVT injection of 50 uL PBS in the right eyes. On days 0, 4, 7 and day 14, the retinas of the rabbits were isolated after routine ophthalmic and electroretinogram examinations. The protein expressions in the retinas were quantified using tandem mass tag (TMT)-labeling coupled with LC-MS/MS, and bioinformatic analysis of the differentially expressed proteins (DEPs) was performed based on KEGG database to identify significantly enriched pathways. Functional network of the significant DEPs was analyzed using STRING. RESULTS: No noticeable fundus or functional changes occurred in the rabbit eyes following IVT injection of PBS. A total of 6042 retinal proteins were identified in the retina following the injection, among which 49 proteins (0.81%) exhibited over 5.0-fold up-regulation or over 80% down- regulation relative to the control. Most of the distinctly up-regulated or down-regulated proteins were associated with the cytoskeleton. Significantly enriched pathways involved focal adhesion, tight junction, riboflavin metabolism, extracellular matrix-receptor interaction and regulation of actin cytoskeleton. Functional network analysis showed that ACTC1 and ISG15 played central roles in the protein interaction networks. CONCLUSION: IVT PBS injection in rabbits causes alterations in proteins associated with cell adhesion, morphology, migration, differentiation, signal transduction and riboflavin metabolism, but the alterations of the retinal proteins appear not sufficient to cause observable pathology of the retina. PMID- 27222171 TI - Tea polyphenols promote cardiac function and energy metabolism in ex vivo rat heart with ischemic/reperfusion injury and inhibit calcium inward current in cultured rat cardiac myocytes. AB - OBJECTIVE: To investigate the protective effects of tea polyphenols (TP) against myocardial ischemia/reperfusion (IR) injuries and explore the possible mechanisms. METHODS: Langendorff-perfused rat hearts were subjected to ischemia for 30 min followed by reperfusion for another 30 min. Myocardial function indices were measured by a left ventricular cannula via a pressure transducer connected to the polygraph in isolated Langendorff hearts and energy metabolism was measured using (31)P nuclear magnetic resonance (NMR) spectroscopy. Whole cell atch-clamp technique was used to record calcium inward current (I(Ca-L)) in cultured rat cardiac myocytes. RESULTS: Compared with the control hearts, the ex vivo rat hearts with 2.5 mg/L TP treatment showed significantly increased left ventricular developed pressure (LVDP), maximal rise rate of LVDP (+dp/d(tmax)), maximal fall rate of LVDP (-dp/dt(max)), and coronary flow (CF) (P<0.05). During both cardiac ischemia and reperfusion phase, ATP and PCr levels were elevated significantly in TP-treated hearts compared with those in the control hearts (P<0.05). In cultured rat cardiac myocytes, ICa-L was remarkably decreased by TP at the doses of 2.5 and 5.0 mg/L (P<0.01). CONCLUSION: Our results support a possible protective role of TP against myocardial IR injury by improving myocardial energy metabolism and inhibiting I(Ca-L) in the cardiac myocytes. PMID- 27222172 TI - [Correlation between resting heart rate and blood glucose level in elderly patients with coronary heart disease and diabetes mellitus]. AB - OBJECTIVE: To explore the correlation between resting heart rate (RHR) and blood glucose level in elderly patients with coronary heart disease (CHD) complicated by diabetes mellitus. METHODS: Between April and July, 2011, a total of 1336 outpatients over 60 years of age recruited from 165 hospitals were asked to complete a questionnaire and received blood glucose and RHR examination. According to baseline RHR, the patients were divided into 3 groups with HRH <70 min-1 (group I, 372 cases), between 70 and 79 min(-1) (group II, 533 cases), and >=80 min(-1) (group III, 431cases) for analysis of the relationships of RHR with blood glucose control rate. RESULTS: HbA1c levels in the total, male and female patients differed significantly among the 3 groups (F=15.436, 15.436, and 24.270, respectively, P<0.05), and increased in the order from group I to group III. Blood glucose control rate in the total, male and female patients also differed significantly among the 3 groups (chi(2)=13.471, 6.752, and 6.522, respectively, P<0.05), and was significantly lower in group III than in group I (P<0.05). RHR was found to positively correlate with FPG, 2 hPG and HbA1c by Pearson correlation analysis (r=0.058, 0.085, and 0.058, respectively; P<0.05) and multiple linear regression analysis (beta=0.075, 0.075, and 0.018, respectively; P<0.05). Multivariable logistic regression equation showed that compared with patients with RHR <70 min-1, the total, male and female patients with RHR >=80 min(-1) had OR values of blood glucose control failure of 1.99 (95% CI: 1.23 2.37, P<0.05), 1.81 (95% CI: 1.17-2.77, P<0.05), and 2.18 (95% CI: 1.12-3.74, P<0.05), respectively. CONCLUSION: RHR in elderly CHD patients with MD is positively correlated with their blood glucose level, and an increased RHR is associated with an increased risk of poor blood glucose control. Rigorous RHR control in such high-risk patients may prove beneficial for both blood glucose control and secondary prevention of CHD. PMID- 27222169 TI - Predictions penetrate perception: Converging insights from brain, behaviour and disorder. AB - It is argued that during ongoing visual perception, the brain is generating top down predictions to facilitate, guide and constrain the processing of incoming sensory input. Here we demonstrate that these predictions are drawn from a diverse range of cognitive processes, in order to generate the richest and most informative prediction signals. This is consistent with a central role for cognitive penetrability in visual perception. We review behavioural and mechanistic evidence that indicate a wide spectrum of domains-including object recognition, contextual associations, cognitive biases and affective state-that can directly influence visual perception. We combine these insights from the healthy brain with novel observations from neuropsychiatric disorders involving visual hallucinations, which highlight the consequences of imbalance between top down signals and incoming sensory information. Together, these lines of evidence converge to indicate that predictive penetration, be it cognitive, social or emotional, should be considered a fundamental framework that supports visual perception. PMID- 27222173 TI - [Expressions of short palate, lung and nasal epithelium clone 1 in different human tissues]. AB - OBJECTIVE: To examine the expression patterns of short palate, lung and nasal epithelium clone 1 (SPLUNC1) gene in human tissues. METHODS: In situ hybridization was used to detect the expression of SPLUNC1 gene in 37 different human tissues. RESULTS: We found that SPLUNC1 gene was not expressed in squamous epithelial cells of the palate, epidermis, esophagus, or the esophagus-cardia junction, metaplastic squamous cells in the nasopharynx, trachea, or uterus cervix, or tumor cells of esophageal squamous cell carcinoma or lung squamous cell carcinoma. SPLUNC1 gene was not expressed in the single layer columnar epithelia cells in the stomach, gallbladder, jejunum, colon, endometrium, or uterus cervix. SPLUNC1 expression was detected mainly in pseudostratified columnar epithelial cells in the nasopharynx, trachea and bronchi, and was gradually down-regulated from the upper to lower end of the respiratory tract, but was not detected in the lung tissues. SPLUNC1 expression was detected not only in the duct and serous gland cells in the parotid and submandibular glands, but also in cells of submucosal serous glands in the nasopharynx and lung, but not in the cells of the mucosal glands. The parietal cells of the gastric submucosa and epithelial cells of the lobula and ducts of the mammary glands expressed SPLUNC1. The adenocarcinoma cells in the lung, stomach, colon, mammary gland, uterus endometrium and cervix showed strong expressions of SPLUNC1 gene. CONCLUSION: SPLUNC1 expression is highly cell-specific in association with the cell functions. PMID- 27222174 TI - [Long-term effects of ultrasound-guided microwave ablation in the treatment of small renal cell carcinoma]. AB - OBJECTIVE: To evaluate the long-term efficacy of microwave ablation in the treatment of small renal cell carcinoma (RCC). METHODS: We retrospectively analyzed 140 cases of small cell renal carcinoma (151 lesions with a mean diameter of 2.8+/-0.8 cm) treated between April, 2006 and October, 2015 with ultrasound-guided microwave ablation with cooled-shaft needle antenna. One microwave ablation antenna was used for tumors less than 2 cm in diameter and 2 antennas were used for larger tumors. The patients received enhanced ultrasound and CT/MRI examinations at 1, 3, and 6 months after the operation and every 6 months thereafter. The overall survival, disease-free survival, and local tumor progression rate of the patients were evaluated. RESULTS: The response rate of treatment (complete ablation at one month on enhanced images) was 100% in these patients. The local tumor progression rates at 1, 3, and 5 years were 0.9%, 2.0%, and 7.1%, respectively, and the 1-, 3-, and 5-year distant metastasis rates were 1.6%, 2.5%, and 7.9%, respectively. The overall survival rates of the patients at 1, 3, and 5 years were 98.4%, 94.8%, 89.5%, respectively, with disease-free survival rates of 98.4%, 93.0%, and 83.1%, respectively. No major complications occurred in these cases, and multivariate analysis showed that the tumor number (P=0.015) and tumor growth patterns (P=0.049) were independent risk factors that adversely affected the long-term outcome after surgery. CONCLUSION: Our data show that microwave ablation is a safe and effective modality for treatment of renal cell carcinoma. PMID- 27222175 TI - [Effects of dexmedetomidine on microcirculatory perfusion in rabbits with renal ischemia/reperfusion injury: quantitative evaluation with contrast-enhanced ultrasound]. AB - OBJECTIVE: To investigate the effects of dexmedetomidine on renal microcirculatory perfusion in rabbits with renal ischemia/reperfusion (I/R) injury rabbit by quantitative analysis of contrast-enhanced ultrasound (CEUS). METHODS: Twenty- four New Zealand rabbits were randomly divided into 3 groups (8 in each), including a control group, renal I/R injury group and dexmedetomidine group. In the latter two groups, the right kidney of the rabbits was resected and I/R injury was induced in the left kidney. In dexmedetomidine group, the rabbits received an intraperitoneal dose of 10 ug/kg dexmedetomidine 30 min before renal ischemia, and 24 h after reperfusion, the renal size and renal artery resistance (RI) were measured, and renal cortex perfusion was observed by CEUS. The time-to peak intensity (TTP), peak signal intensity (PSI), gradient between start frame to peak frame (Grad) and area under the curve (AUC) were quantitatively analyzed using the time-intensity curves. Pathological changes of the kidney were also observed. RESULTS: Compared with the control group, the rabbits in I/R and dexmedetomidine groups showed distinct changes of the renal size with obvious renal pathologies. RI, PPT and AUC all increased, and PSI and Grad decreased significantly in I/R and dexmedetomidine groups (P<0.05). Compared with I/R group, obvious improvement of the renal size and renal pathologies were observed in dexmedetomidine group, which showed significantly decreased RI, PPT and AUC and increased PSI and Grad (P<0.05). CONCLUSION: CEUS combined with the time intensity curve parameters allows quantitative and dynamic analysis of the protective effects of dexmedetomidine on microcirculatory perfusion in rabbits with renal I/R injury. PMID- 27222176 TI - [Effect of 2,3-butanedione monoxime on calcium paradox-induced heart injury in rats]. AB - OBJECTIVE: To investigate the Effect of 2,3-butanedione monoxime (BDM) on calcium paradox-induced heart injury and its underlying mechanisms. METHODS: Thirty-two adult male SD rats were randomized into 4 groups, namely the control group, BDM treatment control group, calcium paradox group, and BDM treatment group. Isolated Sprague Dawley male rat hearts underwent Langendorff perfusion and the left ventricular pressure (LVP) and left ventricular end-diastolic pressure (LVEDP) were monitored. Left ventricular developed pressure (LVDP) was calculated to evaluate the myocardial performance. Lactate dehydrogenase (LDH) content in the coronary flow was determined. Triphenyltetrazolium chloride staining was used to measure the infarct size, and myocardial cell apoptosis was tested with TUNEL method. Western blotting was used to determine the expression of cleaved caspase 3 and cytochrome c. RESULTS: Compared with the control group, BDM at 20 mmol/L had no effect on cardiac performance, cell death, apoptotic index or the content of LDH, cleaved caspase-3 and cytochrome c at the end of perfusion under control conditions (P>0.05). Calcium paradox treatment significantly decreased the cardiac function and the level of LVDP and induced a larger infarct size (P<0.01), an increased myocardial apoptosis index (P<0.01), and up-regulated expressions of cleaved caspase-3 and cytochrome c (P<0.01). BDM (20 mmol/L) significantly attenuated these effects induced by calcium paradox, and markedly down-regulated the levels of LVEDP and LDH (P<0.01), lowered myocardial apoptosis index, decreased the content of cleaved caspase-3 and cytochrome c (P<0.01), increased LVDP, and reduced the infarct size (P<0.01). CONCLUSION: BDM suppresses cell apoptosis and contracture and improves heart function and cell survival in rat hearts exposed to calcium paradox, suggesting the value of BDM as an potential drug for myocardial ischemia reperfusion injur. PMID- 27222177 TI - [Nanog promotes the invasion of breast cancer cells by increasing PKCepsilon expression]. AB - OBJECTIVE: To study the relationship between Nanog-promoted metastasis of breast cancer and ezrin(T567) phosphorylation, and explore the possible mechanism by which Nanog regulates ezrin(T567) phosphorylation. METHODS: A siRNA construct targeting Nanog was transfected in breast cancer cells to knock down Nanog expression, and the changes in the cell invasion was detected using Transwell assay. The expression levels of Nanog and PKC and the phosphorylation level of ezrin(T567) were detected using Western blotting and immunofluorescent staining; the protein interaction between PKCepsilon and ezrin was assayed by co immunoprecipitation and Western blotting. RESULTS: Nanog knockdown significantly decreased the expression of PKCepsilon protein, phosphorylation level of ezrin(T567) and the invasion ability of breast cancer cells. PKCepsilon knockdown obviously decreased the phosphorylation level of ezrin(T567) in the cells, and PKCepsilon and ezrin were co-immunoprecipitated. CONCLUDIONS: Nanogcan can upregulate the expression of PKCepsilon to promote the phosphorylation of ezrin(T567), which can be a new mechanism by which Nanog promotes tumor metastasis. PMID- 27222178 TI - [Preparation of SUN5-specific polyclonal antibody for detection of SUN5 expression in human germ cells]. AB - OBJECTIVE: To prepare a specific polyclonal antibody against full-length SUN5 for detecting the expression of SUN5 in human germ cells. METHODS: Bioinformatic methods were used to compare the full-length SUN5 and its variant SUN5beta, and a short peptide was designed based on the differential region to prepare SUN5 antibody. The prepared antibody was used to detect the expression of SUN5 in Ntera-2 cells and in human germ cells by Western blotting and immunofluorescence assay. RESULTS: The short peptide was correctly synthesized and SUN5 antibody was obtained and purified. Western blotting showed that the prepared antibody was capable of recognizing full-length SUN5 in Ntera-2 cells, and SUN5 expression was localized on the nuclear membrane and in the cytoplasm as shown by immunofluorescence assay. Using this antibody, we detected SUN5 expression in the spermatocytes, round spermatids and sperms in human germ cells. CONCLUSION: We successfully prepared SUN5-specific antibody. SUN5 is expressed in the spermatocytes, round spermatids and sperms in human germ cells, suggesting its important role in spermatogenesis. PMID- 27222179 TI - [Expression of protein 4.1 family in melanoma cell lines and its effect on cell proliferation]. AB - OBJECTIVE: To detect the expression of protein 4.1 family members in mouse melanoma cell lines and evaluate their effect on cell proliferation. METHODS: PCR and Western blot were used to detected to the expression of protein 4.1 family members (4.1R, 4.1B, 4.1G, and 4.1N) at the mRNA and protein levels in B16 and B16-F10 cell lines. The expression plasmid vector pEGFP-N1-EPB41L3 carrying 4.1B gene sequence amplified from genomic RNA of mouse embryo fibroblasts was constructed and transiently transfected into mouse melanoma cells. The change in cell proliferation was assessed using MTT assay. RESULTS: The mRNA and protein expressions of all the protein 4.1 family members, with the exception of 4.1B, were detected in both B16 and B16-F10 cells. Transfection of cells with the eukaryotic expression vector pEGFP-N1-EPB41L3 markedly inhibited cell proliferation as compared with the non-transfected cells. CONCLUSION: The eukaryotic expression vector carrying EPB41L3 sequence is capable of inhibiting the proliferation of mouse melanoma B16 and B16-F10 cells. PMID- 27222180 TI - [Palmitic acid induces hepatocellular oxidative stress and activation of inflammasomes]. AB - OBJECTIVE: To evaluate the effect of palmitic acid (PA) on oxidative stress and activation of inflammasomes in hepatocytes. METHODS: To test the dose-dependent effect of PA on normal murine hepatocytes AML12, the cells were treated with 0, 0.15, 0.25 and 0.4 mmol/L of palmitic acid (PA). The cells were also divided into blank control group, 0.25 mmol/L PA group and 0.25 mmol/L PA+N-acetylcysteine (NAC) group to examine the effect of reactive oxygen species (ROS) on the activation of inflammasomes. After 24 h of treatment, lipid accumulation, total ROS, mitochondrial ROS, expression and localization of NOX4, and expressions of inflammasomes and IL-1beta were detected in the hepatocytes. RESULTS: Compared with the control cells, PA treatment of the cells significantly increased cytoplasmic lipid accumulation, concentrations of total ROS (12 463.09+/-2.72 vs 6691.23+/-2.45, P=0.00) and mitochondrial ROS (64.98+/-0.94 vs 45.04+/-0.92, P=0.00), and the expressions of NOX4, NLRP3, ASC, caspase-1, and IL-1beta (1603.52+/-1.32 vs 2629.33+/-2.57, P=0.00). The mitochondria and NOX4 were found to be co-localized in the cytoplasm. NAC obviously reduced cellular ROS level stimulated by PA (7782.15+/-2.87 vs 5445.6+/-1.17, P=0.00) and suppressed the expressions of NLRP3, ASC and caspase-1. CONCLUSION: PA treatment can stimulate lipid accumulation in hepatocytes and induce oxidative stress through NOX4 and mitochondria pathway to activate inflammasomes and stimulate the secretion of IL 1beta. PMID- 27222181 TI - [Rapid eye-movement sleep for five days deprivation causes delayed depressive like behavior in mice]. AB - OBJECTIVE: To observe the effect of rapid eye movement sleep deprivation (REMSD) for 5 days on depressive-like behavior and monoamine oxidase A (MAOA) expression in the amygdale of mice. METHODS: Adult male C57BL/6J mice were divided into blank control group, control group and REMSD group. REMSD models were established by a modified multiple small platform method. The mice were examined for locomotive activity in open field test (OFT) and for depressive-like behavior in forced swimming test (FST) and sucrose preference test (SPT) after treatment. After all the tests, the protein and mRNA expressions of MAOA in the amygdala were detected with Western blotting and real-time PCR, respectively. RESULTS: REMSD for 5 days significantly impaired the locomotive activity of the mice, which was obvious in 1 to 3 days after REMSD. The locomotive activity became normal on day 4 after the 5-day REMSD. The immobility time of the mice was lengthened in days 7 to 14 (P<0.01), and sucrose preference rate was reduced significantly in days 8 and 9 (P<0.01). The expression level of MAOA in the amygdala was increased significantly after the 5-day REMSD (P<0.01). CONCLUSION: REMSD for 5 days causes delayed depressive-like behavior in mice possible in relation with the increased expression of MAOA in the amygdale. PMID- 27222182 TI - [Solanine inhibits prostate cancer Du145 xenograft growth in nude mice by inducing cell cycle arrest in G1/S phase]. AB - OBJECTIVE: To investigate the effect of solanine on the growth of human prostate cancer cell xenograft in nude mice. METHODS: Human prostate cancer Du145 cells were injected into the subcutaneous layers on the back of nude mice. After a week, the mice bearing subcutaneous tumor graft were randomly divided into solanine treatment group and saline control group for treatment for 3 weeks. The tumor grafts were then harvested to evaluate the inhibition rate. The mRNA and protein expressions of cell cycle-related genes in the tumors were detected by qRT-PCR and Western blotting, respectively, and tumor cell apoptosis was detected using TUNEL method. RESULTS: The tumor growth rate in solanine-treated group was significantly slower than that in the control group (P<0.01). The mRNA and protein expressions of C-myc, cyclin D1, cyclin E1, CDK2, CDK4 and CDK6 were significantly inhibited by solanine. Solanine significantly up-regulated p21 mRNA and protein expression in the tumors and induced a higher apoptosis rate of the tumor cells than saline (P<0.01). CONCLUSION: The tumor-inhibition effect of solanine is probably mediated by regulating the expressions of genes related with G1/S cell cycle arrest and cell apoptosis. PMID- 27222183 TI - [A method for combining Fluoro-Jade B staining and immunofluorescent staining]. AB - OBJECTIVE: To explore a method for combining Fluoro-Jade B (FJB) staining with immunofluorescent staining in rats with focal cortical infarction. METHOD: Permanent distal middle cerebral artery occlusion (dMCAO) was induced in rats by electrocoagulation. The rat models were randomized into two groups, and frozen sections of the brain tissues from each group were stained with FJB followed by immunofluorescent staining or in the reverse order. RESULTS: FJB staining followed by immunofluorescence staining clearly visualized both FJB-positive and immunofluorescence-positive cells in the frozen sections, but the staining protocol in the reverse sequence failed to clearly show the immunofluorescence positive cells. CONCLUSION: FJB staining prior to immunofluorescence staining does not affect the staining effect of protein immunofluorescent staining and better visualizes the positive cells. PMID- 27222184 TI - [MiR-135b promotes proliferation of endometrial carcinoma cells by targeting FOXO1]. AB - OBJECTIVE: To explore the expression of miR-135b in endometrial carcinoma and the mechanism by which miR-135b promotes the proliferation of endometrial cancer cells. METHODS: The expressions of miR-135b and FOXO1 were using RT-PCR detected in 22 fresh endometrial cancer tissues and paired adjacent tissues and also in endometrial cancer cell lines JEC, Ishikawa, HEC-1-B, and RL-952. The RL-952 and Ishikawa cell lines were transfected with miR-135b mimics or inhibitors, and the changes in their proliferative activity were detected with MTT assay; the expressions of FOXO1 mRNA and protein were detected by RT-PCR and Western blotting, respectively. RESULTS: The expression of miRNA135b was significantly up regulated and FOXO1 expression was down-regulated in endometrial carcinoma tissues as compared with the adjacent tissues (P<0.05). The mRNA expression of miR-135b was negatively correlated with the expression of FOXO1 in endometrial carcinoma. In RL-952 and Ishikawa cell lines, transfection with miR-135b mimics obviously promoted the cell proliferation (P<0.05). Up-regulation of miR-135b significantly decreased the expressions of FOXO1 protein and mRNA (P<0.05), and down- regulation of miR-135b increased FOXO1 expressions (P<0.05). CONCLUSIONS: MiR-135b plays an important role in the occurrence and development of endometrial carcinoma partially by regulating its target gene FOXO1. PMID- 27222185 TI - [Surgical ventricular restoration versus isolated coronary artery bypass grafting for left ventricular aneurysm: comparison of mid- to long-term outcomes]. AB - OBJECTIVE: To compare the mid- to long-term outcomes of patients receiving isolated coronary artery bypass grafting (CABG) versus surgical ventricular restoration (SVR) plus CABG for left ventricular aneurysms. METHODS: The clinical data were retrospectively analyzed in 205 patients with left ventricular aneurysms admitted to our hospital between January, 1997 and December, 2012, including 115 patients receiving SVR plus CABG and 90 undergoing isolated CABG. By matching preoperative echocardiographic parameters including aneurysm size, left ventricular ejection fraction (LVEF), left ventricular end-systolic volume index (LVESVI) and EuroSCORE risk factors, 32 patients receiving SVR plus CABG and another 32 with isolated CABG were enrolled in this study. The patients were compared for survival rates, major adverse cardiac or cerebrovascular events (MACCEs), left ventricular geometry and function at 1, 3 and 5 years of follow up. RESULTS: Compared with the patients receiving isolated CABG, those receiving SVR and CABG showed greater improvements in echocardiographic parameters and NYHA functional class. The differences in the echocardiographic parameters between the two groups gradually reduced with time and became comparable at 5 years after the operation (P>0.05). No significant difference was found in the mid- to long-term survival or the incidence of MACCEs between the two groups (P>0.05). CONCLUSION: Compared with isolated CABG, SVR plus CABG does not reduce the incidence of MACCEs or improve the mid- to long-term survival rate of patients with left ventricular aneurysm with a LVESVI <60 mL/m(2). PMID- 27222186 TI - [Investigation of antimicrobial resistance of Klebsiella pneumoniae and Pseudomonas aeruginosa isolates from rat-like animals around a hospital in Guangzhou]. AB - OBJECTIVE: To investigate antimicrobial resistance of Klebsiella pneumoniae and Pseudomonas aeruginosa isolates in fecal samples from rat-like animals. METHODS: Rat-like animals were captured using cages around a hospital and the neighboring residential area between March and October, 2015. K. pneumoniae and P. aeruginosa were isolated from the fecal samples of the captured animals. Antimicrobial susceptibility test was performed according to the guidelines of Clinical and Laboratory Standards Institute (2014). RESULTS: A total of 329 rat-like animals were captured, including 205 Suncus murinus, 111 Rattus norvegicus, 5 Rattus flavipectus and 8 Mus musculus. The positivity rates of K. pneumoniae and P. aeruginosa were 78.4% and 34.7% in the fecal samples from the captured animals, respectively. K. pneumoniae isolates from Suncus murinus showed a high resistance to ampicillin, cephazolin, nitrofurantoin, piperacillin and cefotaxime (with resistance rates of 100%, 51.2%, 44.2%, 37.2%, and 23.3%, respectively), and K. pneumoniae isolates from Rattus spp. showed a similar drug-resistance profile. The prevalence rates of multidrug resistance and ESBLs were 40.9% and 10.7%, respectively. P. aeruginosa from both Suncus murinus and Rattus spp. exhibited the highest resistance rates to aztreonam (12.4% and 16.0%, respectively), followed by penicillins and fluoroquinolones. P. aeruginosa isolates were susceptible to cephems, aminoglycosides and carbapenems (with resistance rates below 5%). CONCLUSION: K. pneumoniae and P. aeruginosa isolated from rat-like animals showed drug-resistance profiles similar to those of the strains isolated from clinical patients, suggesting that the possible transmission of K. pneumoniae and P. aeruginosa between rat-like animals and human beings. PMID- 27222187 TI - [Efficacy and safety of long pulse 1064 nm Nd:YAG laser for treatment of onychomycosis of the toenails]. AB - OBJECTIVE: To evaluate the efficacy and safety of long pulse 1064 nm Nd:YAG laser therapy in the treatment of onychomycosis of the toenails. METHODS: A total of 104 patients with onychomycosis (461 toenails) were divided by age into >=60 years group and <60 years group, and each group was further divided into subgroups according to Scoring Clinical Index of Onychomycosis (SCIO) scoring and the location of the compromised toenails. All the toenails were treated with 10 to12 sessions of long pulse 1064 nm Nd:YAG laser therapy at the interval of 1 week. All the patients were followed up for 48 weeks after the initial treatment to assess the clinical efficacy and adverse reactions. RESULTS: The overall clinical response rate in these patients was 72.5% by the end of the 48-week follow-up. In patients aged <60 years, the clinical response rate and mycological cure rate were significantly higher than the rates in patients aged >=60 years (P<0.05). No significant differences were observed in the response rates between different SCIO subgroups (P>0.05); the 2nd to 4th toenails showed better outcomes after the therapy than the 1st and 5th toenails (P<0.05). No adverse reactions related with the therapy were recorded in these patients. CONCLUSION: Long pulse 1064 nm Nd:YAG laser is an effective and safe approach for treatment of onychomycosis of the toenails. PMID- 27222188 TI - [Prevalence of chronic kidney disease and its risk factors in subjects with different glucose metabolism status]. AB - OBJECTIVE: To investigate the prevalence of chronic kidney disease (CKD) in subjects with different glucose metabolism status. METHODS: Between January, 2015 and October, 2015, a total of 934 subjects without a previous diagnosis of diabetes visiting the Department of Endocrinology or Health Examination Center underwent oral glucose tolerance test (OGTT), which identified 266 subjects with normal glucose tolerance (NGT group), 243 pre-diabetic subjects, and 425 patients with diabetes mellitus group. The baseline characteristics and laboratory test data of the subjects were collected. The diagnosis of CKD was established for an eGFR <60 mL/min/1.73 m(2) or a ACR>=30 mg/g, and the prevalence of CKD were compared among the 3 groups. Logistic regression model was used to analyze the OR value of the risk factors of CKD. RESULTS: The prevalences of CKD in NGT, pre diabetic and diabetic groups were 10.2%, 26.3% and 32.5%, respectively. Pairwise comparisons showed that the prevalence of CKD was significantly higher in pre diabetic group (P<0.001, OR=3.17, 95% CI 1.94-5.17) and diabetic group (P<0.001, OR=4.27, 95% CI 2.72-6.65) than in NGT group, and was comparable between the pre diabetic and diabetic groups (P=0.115, OR=1.35, 95% CI 0.95-1.91). Logistic regression analysis, after adjustment for age, gender, blood pressure, hypertension, blood lipids and uric acid, showed that pre-diabetes (OR=2.03, P=0.044) and diabetes mellitus (OR=2.22, P=0.016) were independently associated with CKD. CONCLUSION: Glucose metabolism status has a significant independent impact on the incidence of CKD, suggesting the importance of early detection of pre-diabetes and timely interventions in pre-diabetic subjects in prevention CKD. PMID- 27222189 TI - [Efficacy of periprostatic nerve block anesthesia for pain control in transrectal ultrasound- guided systematic prostate biopsy]. AB - OBJECTIVE: To evaluate the efficacy of periprostatic nerve block anesthesia (PPNB) for pain relief in transrectal ultrasound-guided systematic prostate biopsy (PBx). METHODS: We reviewed the data of patients undergoing initial PBx at our center from November, 2013 to January, 2015. Only the patients with 12-core systemic PBx were included and 111 patients were eligible for this study, among whom 52 patients received PPNB and 59 did not. PPNB was achieved by an injection of 5 mL of 1% lidocaine at the angle between the seminal vesicle and base of the prostate on each side before biopsy. The DRE pain score, probe insert pain score, and biopsy pain score were assessed by visual analogue scale (VAS) immediately after the biopsy. The complications were recorded and evaluated immediately after and at 7 days after the biopsy. RESULTS: The mean age, prostate volume, total prostate specific antigen (tPSA), free PSA (fPSA), and abnormal DRE were comparable between the 2 groups (P>0.05). Immediately after the biopsy, no difference was found between the 2 groups in DRE pain score (1.40+/-0.98 vs 1.39+/-0.91, P=0.102) or probe insert pain score (2.07+/-0.96 vs 2.03+/-0.90, P=0.960), but the biopsy pain score was significantly lower in PPNB group than in no PPNB group (2.54+/-1.42 vs 3.07+/-1.43, P=0.033). The incidence of the procedure-related complications was similar between the 2 groups (P>0.05). CONCLUSION: PPNB can significantly lower the biopsy pain score in PBx without increasing the incidence of complications. PMID- 27222190 TI - [Pathological and magnetic resonance imaging findings in a neonatal Tibet minipig model of hypoxic-ischemic encephalopathy]. AB - OBJECTIVE: To establish a neonatal Tibet minipig model of hypoxic-ischemic encephalopathy and evaluate the magnetic resonance imaging (MRI) manifestations and pathological findings. METHODS: Six neonatal (1-3 days old) Tibet minipigs were randomized into model group (n=4) and control group (n=2). In model group, hypoxic-ischemic encephalopathy was induced by surgical ligation of the bilateral carotid artery followedimmediately by hypoxic exposure in a hypoxia chamber for 1 h. ESWAN was performed at 2 h, 24 h, 3 days and 5 days after induction of HIE or at 2 h after sham surgery in the control animals to evaluate the brain damage. Conventional MRI scans (T2FLAIR, T2WI, and DWI) were also performed at 24 h after the modeling. RESULTS: In the neostriatum, values of T(2)*-weighted MRI increased and reached the peak level at 3 days post-injury (P<0.05). Subcortical white matter T(2)* values reached the peak level at 24 h (P<0.05). Neostriatum R(2)* values were at the lowest level at 3 days (P<0.05). Magnitude values were significantly increased after the model establishment (P<0.05). DWI showed multiple mild focal high signals in the bifrontal subcortical white matter and bilateral neostriatum; T2FLAIR showed slightly increased signal; T2WI showed no obvious abnormalities. SWI showed dilated medulla veins adjacent to the bilateral lateral ventricles and basal ganglia. In the early stage of HIE, brain pathologies were characterized mainly by edema and venous congestion with occasional focal necrosis and hemosiderin deposition. CONCLUSION: ESWAN sequence is capable of detecting bleeding and brain edema, and T(2)*, R(2)*, and magnitude values can be used to estimate the changes of brain damage following HIE. PMID- 27222191 TI - [Risk factors and clinical characteristics of gastroesophageal reflux disease: analysis based on a prospective database of functional gastrointestinal disease]. AB - OBJECTIVE: To explore the risk factors and clinical characteristics of non erosive reflux disease (NERD) based on a prospective single disease database of functional gastrointestinal disease. METHODS: Using a customized case report form, we collected the personal and clinical data of all study participants in an online database for further analysis. High-resolution manometry and multichannel intraluminal impedance-pH monitoring were performed in some cases. RESULTS: A total of 504 NERD cases and 152 control cases were included in our database. The NERD patients consisted of 266 (52.8%) female patients and 238 (47.2%) male patients; 32.7% of the patients were from rural areas and 67.3% from urban areas; 23.1% of the patients worked in the line of business, 19.6% were civil servants, 19.2% were unemployed, and 17.1% were workers; the mean disease duration of the patients was 27.88?16.33 month. Our analysis showed that adverse events in life (P=0.045, OR=1.954), frequent drinking (P=0.040, OR=3.957), snoring (P=0.002, OR=2.334), late meals (P=0.002, OR=2.752), and anxiety or depression (P=0.003, OR=2.723) were all independent risk factors for NERD. Of these patients, 60.81% had varying degrees of ineffective contraction of the esophageal body. The total liquid reflux events differed significantly between NERD patients with hiatal hernia and those without (P<0.05). CONCLUSION: Unhealthy eating habits and lifestyle, history of adverse events, anxiety and depression, snoring, poor esophageal motor function and hiatal hernia are significant factors contributing to NERD, which is related with occupation and living areas and occurs most commonly at 30-50 years of age. PMID- 27222192 TI - [Expression of circadian gene NPAS2 in colorectal cancer and its prognostic significance]. AB - OBJECTIVE: To study the expression of NPAS2 in colorectal cancer (CRC) and analyze its relationship with the clinicopathological parameters and prognosis of the patients. METHODS: Real-time q-PCR was used to detect the expression of NPAS2 mRNA in 40 fresh CRC tissues and paired adjacent tissues; immunohistochemistry was used to detect the expression of NPAS2 protein in 120 paraffin-embedded tumor and adjacent tissues. The relationship between NPAS2 expression level and the 5 year survival rate of 78 CRC patients with follow-up data were analyzed with Kaplan-Meier survival analysis. RESULTS: Compared with the adjacent tissues, fresh CRC tissue expressed significantly lower NPAS2 mRNA levels (P<0.01). Among the paraffin-embedded CRC tissues, 19.2% were positive for NPAS2 expression, as compared to a much higher rate of 62.5% in the adjacent tissues (P<0.05). The expression of NPAS2 was correlated with the tumor size, lymph node metastasis and TNM stages (P<0.05) but not with the patients' gender, age, distant tumor metastasis, differentiation, or invasion. Patients with high NPAS2 expression levels had a significantly higher 5-year survival rate than those with low NPAS2 expressions (P=0.0001). CONCLUSION: NPAS2 is down-regulated in CRC and closely correlated with the malignant biological behavior of the tumor and 5-year survival of the patients, suggesting its value in predicting the prognosis of the CRC patients. PMID- 27222193 TI - [Analysis of risk factors of ventilator-associated pneumonia in an intensive care unit]. AB - OBJECTIVE: To explore the risk factors of ventilator-associated pneumonia (VAP) in patients admitted in an intensive care unit (ICU) for pulmonary tuberculosis (TB). METHODS: The clinical data of 143 patients admitted in the ICU at our center between January, 2014 and June, 2015 were reviewed. The patients with VAP and those without VAP were analyzed for risk factors of VAP in the setting of an ICU for pulmonary TB and compared for the duration of ventilation and hospital stay. RESULTS: The patients with pulmonary TB showed a significantly higher incidence of VAP in the ICU than those without TB. Univariate analysis suggested that the occurrence of VAP was significantly correlated with the duration of mechanical ventilation, invasive examination, pulmonary tuberculosis, lung structure changes, use of multiple antibiotics, diabetes, tracheal incision, indwelling gastric tube, APACHE II score, and coma (P<0.05). Multivariate logistic regression analysis showed that pulmonary TB, duration of mechanical ventilation, APACHE II score, invasive operation, and use of multiple antibiotics were independent risk factors for VAP (P<0.05). The patients who developed VAP had a prolonged duration of mechanical ventilation and ICU stay (P<0.05). CONCLUSION: Patients admitted in tuberculosis ICU are exposed to a high risk of VAP with a high mortality rate as the result of multiple interacting risk factors. Pulmonary TB, prolonged mechanical ventilation, an APACHE II score >15, invasive operation, and use of multiple antibiotics are all independent risk factors for VAP in tuberculosis ICU. PMID- 27222194 TI - [Impact of particle size and morphology on zinc cation adsorption by hydroxyapatite and dentifrice containing hydroxyapatite]. AB - OBJECTIVE: To study the influence of particle size and morphology on zinc cation adsorption by hydroxyapatite (HA) and dentifrice containing HA. METHODS: Four HAs with different particle sizes and morphologies, HA-containing dentifrice and blank dentifrice were prepared into suspensions of serial concentrations. Zinc ion solutions with an initial concentration of 10 mg/L was mixed with the suspensions and kept for 24 h for adsorption reaction. The zinc ion concentration in the supernatant was measured by inductively coupled plasma emission spectrometer and the sorption rate of zinc ion was calculated. RESULTS: HA and HA containing dentifrice with various particle sizes and morphologies were all capable of absorbing zinc ions from simulated waste water, and the adsorption rate of HA-containing dentifrice was 3%-10% higher than that of HA. HA with a particle size of 12 um and a spherical morphology showed the strongest adsorption ability, followed by short bar-shaped HA with a particle size of 30 um. Both Langmuir and Freundlich equation could simulate the sorption processes of HA dentifrice, while only Langmuir equation could simulate the sorption processes of HA. CONCLUSION: Incorporation of HA in dentifrice can enhance zinc ion adsorption capacity of the material. The particle size and morphology of HA both affect the adsorption of zinc ions, and 12-um HA particle with a spherical morphology has the best adsorption ability. PMID- 27222195 TI - [Effect of DAPK overexpression on biological behaviors and caspase-3 expression in HL-60 cells]. AB - OBJECTIVE: To explore the effect of DAPK overexpression on the biological behaviors and caspase-3 expression in HL-60 cells. METHODS: The expression of DAPK mRNA was detected by RT-PCR leukemia cell lines K562, Molt4, U937, and HL-60 cells. HL-60 cells were transfected by a eukaryotic expression vector pReceiver M29-DAPK via LipofectamineTM 2000, and the impact of DAPK overexpression on cell apoptosis, cell cycle, cell differentiation and caspase-3 expression were analyzed. RESULTS: DAPK mRNA expression was positive in K562, Molt4 and U937 cells but negative in HL-60 cells. Significantly increased cell apoptosis was observed in pReceiver-M29-DAPK-transfected HL-60 cells by flow cytometry and Hoechst33342 staining. The cell cycle distribution and differentiation showed no significant changes after the transfection. The expression of caspase-3 was significantly increased in the cells after transfection. CONCLUSION: DAPK gene overexpression promotes apoptosis of HL-60 cells without affecting the cell cycle and differentiation. Caspase-3 may be involved in the regulation of cell apoptosis. PMID- 27222196 TI - [Endometrial adenocarcinoma and clear cell carcinoma in a young woman with polycystic ovarian syndrome: a case report]. AB - A 26-year-old unmarried woman with irregular menstruation for 4 years was admitted for an intrauterine space-occupying mass. Pathological examination before surgery showed moderately to poorly differentiated endometrial adenocarcinoma. The patient underwent laparoscopically assisted epifascial panhysterectomy with bilateral salpingo-oophorectomy. Pathological examination of the surgical specimens reported moderately to poorly differentiated endometrial adenocarcinoma and stage II clear cell carcinoma. The patient then received chemotherapy and remained alive without evidence of recurrence. Young women with polycystic ovarian syndrome are at high risk of developing endometrial carcinoma, but concurrent clear cell carcinoma is rare. Careful evaluation before and after treatment are essential to improve the patients prognosis. PMID- 27222197 TI - The evolution of prescription drug monitoring programs. PMID- 27222198 TI - Benchmarking the performance of fixed-image receptor digital radiographic systems part 1: a novel method for image quality analysis. AB - This is the first part of a two-part study in benchmarking the performance of fixed digital radiographic general X-ray systems. This paper concentrates on reporting findings related to quantitative analysis techniques used to establish comparative image quality metrics. A systematic technical comparison of the evaluated systems is presented in part two of this study. A novel quantitative image quality analysis method is presented with technical considerations addressed for peer review. The novel method was applied to seven general radiographic systems with four different makes of radiographic image receptor (12 image receptors in total). For the System Modulation Transfer Function (sMTF), the use of grid was found to reduce veiling glare and decrease roll-off. The major contributor in sMTF degradation was found to be focal spot blurring. For the System Normalised Noise Power Spectrum (sNNPS), it was found that all systems examined had similar sNNPS responses. A mathematical model is presented to explain how the use of stationary grid may cause a difference between horizontal and vertical sNNPS responses. PMID- 27222199 TI - Benchmarking the performance of fixed-image receptor digital radiography systems. Part 2: system performance metric. AB - This is part two of a two-part study in benchmarking system performance of fixed digital radiographic systems. The study compares the system performance of seven fixed digital radiography systems based on quantitative metrics like modulation transfer function (sMTF), normalised noise power spectrum (sNNPS), detective quantum efficiency (sDQE) and entrance surface air kerma (ESAK). It was found that the most efficient image receptors (greatest sDQE) were not necessarily operating at the lowest ESAK. In part one of this study, sMTF is shown to depend on system configuration while sNNPS is shown to be relatively consistent across systems. Systems are ranked on their signal-to-noise ratio efficiency (sDQE) and their ESAK. Systems using the same equipment configuration do not necessarily have the same system performance. This implies radiographic practice at the site will have an impact on the overall system performance. In general, systems are more dose efficient at low dose settings. PMID- 27222200 TI - Estimating the cumulative mean function for history process with time-dependent covariates and censoring mechanism. AB - In this paper, an approach to estimating the cumulative mean function for history process with time dependent covariates and right censored time-to-event variable is developed using the combined technique of joint modeling and inverse probability weighting method. The consistency of proposed estimator is derived. Theoretical analysis and simulation studies indicate that the estimator given in this paper is quite recommendable to practical applications because of its simplicity and accuracy. A real data set from a multicenter automatic defibrillator implantation trial is used to illustrate the proposed methodology. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27222201 TI - Luminescence behaviour of Mn(4+) ions in seven coordination environments of K3ZrF7. AB - A single-phased Mn(4+) doped fluorozirconate red phosphor, K3ZrF7:Mn(4+), has been successfully synthesized. Its structure, morphology, composition and optical properties were investigated by X-ray diffraction, scanning electron microscopy, energy-dispersive X-ray spectroscopy, atomic absorption spectroscopy, diffuse reflectance spectroscopy, photoluminescence spectroscopy and by using luminescence decay curves. It was found that Mn(4+) ions only coordinating with seven F(-) anions in a K3ZrF7 crystal field can possess intense red emission under blue light illumination. Mixing the obtained K3ZrF7:Mn(4+) red phosphor with commercial Y3Al5O12:Ce(3+) and coating the mixture on a blue-GaN chip, obvious warm white light with a low correlated color temperature (2970 K) and a high color rendering index (Ra = 91.4 and R9 = 72) were achieved from white light emitting diode devices. PMID- 27222202 TI - Genome-wide analysis of the effect of esophageal squamous cell carcinoma on human umbilical vein endothelial cells. AB - A large volume of data indicates that controlling tumor-associated angiogenesis is a promising therapy against cancer. However, angiogenesis is a complex process, little is known about the differential gene expression in the process of normal endothelial cell differentiation toward tumor vascular endothelial cells induced by tumor microenvironment. The aim of this study is to investigate the effect of tumor microenvironment simulated by the supernatant of esophageal squamous cancer cells (KYSE70) on normal endothelial cells (HUVECs) at the whole genome level. The gene expression profile was studied through gene ontology and signal pathway analysis. Compared with the normal HUVECs, a total of 3769 differentially expressed genes in induced HUVECs were detected, including 1609 upregulated genes and 2160 downregulated genes. Moreover, the microarray data analysis showed that 11 significant biological processes and 10 significant signaling pathways changed most, which are associated with angiogenesis and cell differentiation. According to the different expression levels in the microarrays and their functions, four differentially expressed genes involved in tumor angiogenesis and cell differentiation (IL6, VEGFA, S1PR1, TYMP) were selected and analyzed by qRT-PCR. The qRT-PCR results were consistent with the microarray data. Furthermore, we simulated the tumor microenvironment by human esophageal carcinoma tissue homogenate to investigate its effect on HUVECs, the qRT-PCR results indicated that the above genes were highly expressed in HUVECs after induction by esophageal carcinoma tissue homogenate. In conclusion, tumor microenvironment impact on normal endothelial cells differentiated toward tumor vascular endothelial cells, and the selected genes, which are associated with tumor angiogenesis, would be anti-angiogenesis targets against esophageal carcinoma. PMID- 27222203 TI - Effects of ensembles on methane hydrate nucleation kinetics. AB - By performing molecular dynamics simulations to form a hydrate with a methane nano-bubble in liquid water at 250 K and 50 MPa, we report how different ensembles, such as the NPT, NVT, and NVE ensembles, affect the nucleation kinetics of the methane hydrate. The nucleation trajectories are monitored using the face-saturated incomplete cage analysis (FSICA) and the mutually coordinated guest (MCG) order parameter (OP). The nucleation rate and the critical nucleus are obtained using the mean first-passage time (MFPT) method based on the FS cages and the MCG-1 OPs, respectively. The fitting results of MFPT show that hydrate nucleation and growth are coupled together, consistent with the cage adsorption hypothesis which emphasizes that the cage adsorption of methane is a mechanism for both hydrate nucleation and growth. For the three different ensembles, the hydrate nucleation rate is quantitatively ordered as follows: NPT > NVT > NVE, while the sequence of hydrate crystallinity is exactly reversed. However, the largest size of the critical nucleus appears in the NVT ensemble, rather than in the NVE ensemble. These results are helpful for choosing a suitable ensemble when to study hydrate formation via computer simulations, and emphasize the importance of the order degree of the critical nucleus. PMID- 27222204 TI - Patient safety competencies in undergraduate nursing students: a rapid evidence assessment. AB - AIMS: To identify patient safety competencies, and determine the clinical learning environments that facilitate the development of patient safety competencies in nursing students. BACKGROUND: Patient safety in nursing education is of key importance for health professional environments, settings and care systems. To be effective, safe nursing practice requires a good integration between increasing knowledge and the different clinical practice settings. Nurse educators have the responsibility to develop effective learning processes and ensure patient safety. DESIGN: Rapid Evidence Assessment. DATA SOURCES: MEDLINE, CINAHL, SCOPUS and ERIC were searched, yielding 500 citations published between 1 January 2004-30 September 2014. REVIEW METHODS: Following the Rapid Evidence Assessment process, 17 studies were included in this review. Hawker's (2002) quality assessment tool was used to assess the quality of the selected studies. RESULTS: Undergraduate nursing students need to develop competencies to ensure patient safety. The quality of the pedagogical atmosphere in the clinical setting has an important impact on the students' overall level of competence. Active student engagement in clinical processes stimulates their critical reasoning, improves interpersonal communication and facilitates adequate supervision and feedback. CONCLUSION: Few studies describe the nursing students' patient safety competencies and exactly what they need to learn. In addition, studies describe only briefly which clinical learning environments facilitate the development of patient safety competencies in nursing students. Further research is needed to identify additional pedagogical strategies and the specific characteristics of the clinical learning environments that encourage the development of nursing students' patient safety competencies. PMID- 27222205 TI - Essential strategies to optimize asymmetric PCR conditions as a reliable method to generate large amount of ssDNA aptamers. AB - Asymmetric PCR, a simple method to generate single-stranded DNA (ssDNA) aptamers in systematic evaluation of ligand by exponential enrichments rounds, is coupled with limitations. We investigated the essential strategies for optimization of conditions to perform a high-quality asymmetric PCR. Final concentrations of primers and template, the number of PCR cycles, and annealing temperature were selected as optimizing variables. The qualities of visualized PCR products were analyzed by ImageJ software. The highest proportion of interested DNA than unwanted products was considered as optimum conditions. Results revealed that the best values for primers ratio, final template concentration, annealing temperature, and PCR cycles were, respectively, 30:1, 1 ng/MUL, 55 degrees C, and 20 cycles for the first and 50:1, 2 ng/MUL, 59 degrees C, and 20 cycles for other rounds. No significant difference was found between optimized asymmetric PCR results in the rounds of two to eight (P > 0.05). The ssDNA quality in round 10 was significantly better than other rounds (P < 0.05). Generally, the ssDNA product with less dimers, double-stranded DNA (dsDNA), and smear are preferable. The dsDNA contamination is the worst, because it can act as antidote and inhibits aptameric performance. Therefore, to choose the best conditions, the lower amount of dsDNA is more important than other unwanted products. PMID- 27222206 TI - Relationship between insurance and 30-day readmission rates in patients 65 years and older discharged from an acute care hospital with hospice services. AB - BACKGROUND: Patients who are dual eligible for both Medicare and Medicaid have previously been shown to have increased healthcare utilization and cost. However, this relationship has not been examined for patients at the end of life. Dual eligible patients enrolled in hospice may receive more comprehensive care in the community, reducing readmissions in the final weeks or months of life. OBJECTIVE: Determine whether patients who have dual coverage with Medicare and Medicaid and are discharged with referral to hospice services after palliative care consult during their hospitalization differ in their 30-day readmission rate compared with similar patients with other types of insurance. DESIGN: Retrospective cohort study. SETTING: Three acute care hospitals affiliated with Montefiore Medical Center in the Bronx, New York. PATIENTS: In total, 2755 inpatients who received palliative care consultation and were discharged with hospice services. PREDICTOR: Dual eligible for Medicare and Medicaid compared with other insurance status. MEASUREMENTS: Readmission to Montefiore Medical Center for any reason within 30 days of the index admission. RESULTS: Overall, 9.24% of patients with dual Medicare and Medicaid coverage were readmitted within 30 days compared with 13.12% of others (adjusted odds ratio: 0.77; 95% confidence interval: 0.59-0.98; P = 0.041). CONCLUSIONS: Dual eligibility for Medicare and Medicaid is associated with lower 30-day readmission rates in patients enrolled in a hospice program. Insurance coverage that increases access to custodial care (home attendant hours and residential care) may help decrease burdensome hospital readmissions near the end of life. Journal of Hospital Medicine 2016;11:688-693. (c) 2016 Society of Hospital Medicine. PMID- 27222210 TI - Modifiable denominators of evolving post-stroke-autoimmunity. PMID- 27222209 TI - Production of fatty acid-derived oleochemicals and biofuels by synthetic yeast cell factories. AB - Sustainable production of oleochemicals requires establishment of cell factory platform strains. The yeast Saccharomyces cerevisiae is an attractive cell factory as new strains can be rapidly implemented into existing infrastructures such as bioethanol production plants. Here we show high-level production of free fatty acids (FFAs) in a yeast cell factory, and the production of alkanes and fatty alcohols from its descendants. The engineered strain produces up to 10.4 g l(-1) of FFAs, which is the highest reported titre to date. Furthermore, through screening of specific pathway enzymes, endogenous alcohol dehydrogenases and aldehyde reductases, we reconstruct efficient pathways for conversion of fatty acids to alkanes (0.8 mg l(-1)) and fatty alcohols (1.5 g l(-1)), to our knowledge the highest titres reported in S. cerevisiae. This should facilitate the construction of yeast cell factories for production of fatty acids derived products and even aldehyde-derived chemicals of high value. PMID- 27222211 TI - Does self-efficacy mediate the effect of oral health literacy on self-rated oral health in an Indigenous population? AB - OBJECTIVES: Mediation analyses are critical to understanding why behavioral interventions work. Health literacy is a known mediator between socio-economic factors, health behavior and oral health outcomes in various populations, explaining gradients in oral health status and outcomes. We explore whether self efficacy (SE) mediates the association between oral health literacy (OHL) and self-rated oral health (SROH) in an Indigenous population. METHODS: Cross sectional data collected from 278 rural-dwelling Indigenous Australians evaluated OHL, SE, SROH, socio-demographic and behavioral characteristics. OHL was measured using a validated OHL scale (HeLD-14), SE was measured using a validated SE scale and SROH was measured using a global, one-item statement. Theoretically-driven multivariable models, adjusted for age, sex, income, education, and dental service use estimated the prevalence ratios (PR) and 95 percent confidence intervals for poor SROH. RESULTS: The overall prevalence of poor SROH was 78.8 percent. The prevalence of low OHL was 46.0 percent, while the prevalence of low SE was 56.8 percent. Analysis showed a significant main effect of SE (PR = 2.5, 95 percent CI 1.3-4.6). SE attenuated the effects of OHL on poor SROH (from PR = 2.4 to PR = 2.0), supporting its associated role in the Indigenous population under study. Sobel and bootstrap testing confirmed the significance of the mediating effect (z = 2.2, SE 0.30, P < 0.05) and 95 percent CI (0.11-0.07) (P < 0.05) respectively. CONCLUSIONS: Given that SE is a construct amenable to change, our results suggest that interventions that aim to improve SE may have positive impacts on SROH among this vulnerable population. PMID- 27222212 TI - In situ and operando atomic force microscopy of high-capacity nano-silicon based electrodes for lithium-ion batteries. AB - Silicon is a promising next-generation anode material for high-energy-density lithium-ion batteries. While the alloying of nano- and micron size silicon with lithium is relatively well understood, the knowledge of mechanical degradation and structural rearrangements in practical silicon-based electrodes during operation is limited. Here, we demonstrate, for the first time, in situ and operando atomic force microscopy (AFM) of nano-silicon anodes containing polymer binder and carbon black additive. With the help of this technique, the surface topography is analyzed while electrochemical reactions are occurring. In particular, changes in particle size as well as electrode structure and height are visualized with high resolution. Furthermore, the formation and evolution of the solid-electrolyte interphase (SEI) can be followed and its thickness determined by phase imaging and nano-indentation, respectively. Major changes occur in the first lithiation cycle at potentials below 0.6 V with respect to Li/Li(+) due to increased SEI formation - which is a dynamic process - and alloying reactions. Overall, these results provide insight into the function of silicon-based composite electrodes and further show that AFM is a powerful technique that can be applied to important battery materials, without restriction to thin film geometries. PMID- 27222213 TI - Preparation and Characterization of Mucoadhesive Buccal Nanoparticles Using Chitosan and Dextran Sulfate. AB - The aim of this study was to formulate buccal mucoadhesive nanoparticles (NPs) using the natural mucoadhesive polymers. The natural mucoadhesive polymers chitosan (CS) and dextran sulfate sodium salt (DS) were used to prepare mucoadhesive NPs using the ionic gelation method. As the molecular weight of DS decreased, the amount of mucin and the number of buccal cells adsorbed on DS increased. The CS/DS NPs ranged from 100 to 200 nm in diameter. The adhesive interactions of CS/DS NPs with mucin were not significantly different from those of CS/sodium triphosphate pentabasic (TPP) NPs; however, CS/DS NPs exhibited 5 times greater mucoadhesive activity to buccal cells compared to control CS/TPP NPs in ex vivo adhesion tests. These results indicate that the buccal mucoadhesive properties of NPs can be improved using natural mucoadhesive polymers. PMID- 27222214 TI - Nomogram to predict perioperative blood transfusion for hepatopancreaticobiliary and colorectal surgery. AB - BACKGROUND: Predictive tools assessing risk of transfusion have not been evaluated extensively among patients undergoing complex gastrointestinal surgery. In this study preoperative variables associated with blood transfusion were incorporated into a nomogram to predict transfusion following hepatopancreaticobiliary (HPB) or colorectal surgery. METHODS: A nomogram to predict receipt of perioperative transfusion was developed using a cohort of patients who underwent HPB or colorectal surgery between January 2009 and December 2014. The discriminatory ability of the nomogram was tested using the area under the receiver operating characteristic (ROC) curve and internal validation performed via bootstrap resampling. RESULTS: Among 4961 patients undergoing either a HPB (56.3 per cent) or colorectal (43.7 per cent) resection, a total of 1549 received at least 1 unit of packed red blood cells, giving a perioperative transfusion rate of 31.2 per cent. On multivariable analysis, age 65 years and over (odds ratio (OR) 1.52), race (versus white: black, OR 1.58; Asian, OR 1.86), preoperative haemoglobin 8.0 g/dl or less (versus over 12.0 g/dl: OR 26.79), preoperative international normalized ratio more than 1.2 (OR 2.44), Charlson co-morbidity index score over 3 (OR 1.86) and procedure type (versus colonic surgery: major hepatectomy, OR 1.71; other pancreatectomy, OR 2.12; rectal surgery, OR 1.39; duodenopancreatectomy, OR 2.65) were associated with a significantly higher risk of transfusion and were included in the nomogram. A nomogram was constructed to predict transfusion using these seven variables. Discrimination and calibration of the nomogram revealed good predictive abilities (area under ROC curve 0.756). CONCLUSION: The nomogram predicted blood transfusion in major HPB and colorectal surgery. PMID- 27222215 TI - Standardized ileal digestibility of amino acids in eight genotypes of barley fed to growing pigs. AB - To determine chemical composition, physical characteristics and standardized ileal digestibility (SID) of CP and amino acids (AA) in eight current hulled barley genotypes, an experiment with growing pigs has been conducted. These genotypes included Yool, Campanile, Lomerit, Travira, Anisette, Canberra, Metaxa and Fridericus. Growing barrows with an average initial BW of 30+/-2 kg were surgically fitted with simple T-cannulas at the distal ileum, and allotted to an 8*9 Youden square design with eight periods of 6 days each and nine pigs. Barley was the sole dietary source of CP and AA. On average, the eight genotypes contained on as-fed basis 10.7% CP, 15.2% total non-starch polysaccharides (NSP), 17.1% NDF and 4.1% beta-glucan, and had a mean test weight (TW) of 72.2 kg/hl. The SID of CP in the barley genotypes varied from 69% to 74%, and was greater (P<0.01) for genotypes Travira, Anisette and Metaxa compared to Yool and Campanile. Standardized ileal digestibility of Lys, Met and Trp (P<0.05) but not of Thr differed between genotypes. Moreover, barley genotypes differed in their standardized ileal digestible content (cSID) of CP and AA. Furthermore, SID and cSID of CP and most AA linearly decreased (P<0.05) with increasing NDF and total sugar content. Standardized ileal digestibility of CP and some AA and cSID of CP and most AA decreased linearly with increasing TW (P<0.05). Additionally, SID and cSID of CP and AA of most barley genotypes were lower when compared to tabulated values. In conclusion, a comprehensive database on chemical composition and SID of CP and AA in eight current barley genotypes has been made available. However, as present SID values are lower compared to feed tables, adjustments are required to minimize the risk of overestimating the actual protein value of barley for pigs. PMID- 27222217 TI - Acetylcholine modulates human working memory and subsequent familiarity based recognition via alpha oscillations. AB - Working memory (WM) can be defined as the ability to maintain and process physically absent information for a short period of time. This vital cognitive function has been related to cholinergic neuromodulation and, in independent work, to theta (4-8Hz) and alpha (9-14Hz) band oscillations. However, the relationship between both aspects remains unclear. To fill this apparent gap, we used electroencephalography (EEG) and a within-subject design in healthy humans who either received the acetylcholinesterase inhibitor galantamine (8mg) or a placebo before they performed a Sternberg WM paradigm. Here, sequences of sample images were memorized for a delay of 5s in three different load conditions (two, four or six items). On the next day, long-term memory (LTM) for the images was tested according to a remember/know paradigm. As a main finding, we can show that both theta and alpha oscillations scale during WM maintenance as a function of WM load; this resembles the typical performance decrease. Importantly, cholinergic stimulation via galantamine administration slowed down retrieval speed during WM and reduced associated alpha but not theta power, suggesting a functional relationship between alpha oscillations and WM performance. At LTM, this pattern was accompanied by impaired familiarity based recognition. These findings show that stimulating the healthy cholinergic system impairs WM and subsequent recognition, which is in line with the notion of a quadratic relationship between acetylcholine levels and cognitive functions. Moreover, our data provide empirical evidence for a specific role of alpha oscillations in acetylcholine dependent WM and associated LTM formation. PMID- 27222218 TI - Column-like Ca(2+) clusters in the mouse neonatal neocortex revealed by three dimensional two-photon Ca(2+) imaging in vivo. AB - Neuronal network activity in the developing brain is generated in a discontinuous manner. In the visual cortex during the period of physiological blindness of immaturity, this activity mainly comprises retinally triggered spindle bursts or Ca(2+) clusters thought to contribute to the activity-dependent construction of cortical circuits. In spite of potentially important developmental functions, the spatial structure of these activity patterns remains largely unclear. In order to address this issue, we here used three-dimensional two-photon Ca(2+) imaging in the visual cortex of neonatal mice at postnatal days (P) 3-4 in vivo. Large-scale voxel imaging covering a cortical depth of 200MUm revealed that Ca(2+) clusters, identified as spindle bursts in simultaneous extracellular recordings, recruit cortical glutamatergic neurons of the upper cortical plate (CP) in a column-like manner. Specifically, the majority of Ca(2+) clusters exhibit prominent horizontal confinement and high intra-cluster density of activation involving the entire depth of the upper CP. Moreover, using simultaneous Ca(2+) imaging from hundreds of neurons at single-cellular resolution, we demonstrate that the degree of neuronal co-activation within Ca(2+) clusters displays substantial heterogeneity. We further provide evidence that co-activated cells within Ca(2+) clusters are spatially distributed in a non-stochastic manner. In summary, our data support the conclusion that dense coding in the form of column-like Ca(2+) clusters is a characteristic property of network activity in the developing visual neocortex. Such knowledge is expected to be relevant for a refined understanding of how specific spatiotemporal characteristics of early network activity instruct the development of cortical circuits. PMID- 27222219 TI - Genomic insights into a new acidophilic, copper-resistant Desulfosporosinus isolate from the oxidized tailings area of an abandoned gold mine. AB - Microbial sulfate reduction in acid mine drainage is still considered to be confined to anoxic conditions, although several reports have shown that sulfate reducing bacteria occur under microaerophilic or aerobic conditions. We have measured sulfate reduction rates of up to 60 nmol S cm(-3) day(-1) in oxidized layers of gold mine tailings in Kuzbass (SW Siberia). A novel, acidophilic, copper-tolerant Desulfosporosinus sp. I2 was isolated from the same sample and its genome was sequenced. The genomic analysis and physiological data indicate the involvement of transporters and additional mechanisms to tolerate metals, such as sequestration by polyphosphates. Desulfosporinus sp. I2 encodes systems for a metabolically versatile life style. The genome possessed a complete Embden Meyerhof pathway for glycolysis and gluconeogenesis. Complete oxidation of organic substrates could be enabled by the complete TCA cycle. Genomic analysis found all major components of the electron transfer chain necessary for energy generation via oxidative phosphorylation. Autotrophic CO2 fixation could be performed through the Wood-Ljungdahl pathway. Multiple oxygen detoxification systems were identified in the genome. Taking into account the metabolic activity and genomic analysis, the traits of the novel isolate broaden our understanding of active sulfate reduction and associated metabolism beyond strictly anaerobic niches. PMID- 27222220 TI - Seed biopriming with plant growth promoting rhizobacteria: a review. AB - Beneficial microbes are applied to the soil and plant tissues directly or through seed inoculation, whereas soil application is preferred when there is risk of inhibitors or antagonistic microbes on the plant tissues. Insufficient survival of the microorganisms, hindrance in application of fungicides to the seeds and exposure to heat and sunlight in subsequent seed storage in conventional inoculation methods force to explore appropriate and efficient bacterial application method. Seed priming, where seeds are hydrated to activate metabolism without actual germination followed by drying, increases the germination, stand establishment and stress tolerance in different crops. Seed priming with living bacterial inoculum is termed as biopriming that involves the application of plant growth promoting rhizobacteria. It increases speed and uniformity of germination; also ensures rapid, uniform and high establishment of crops; and hence improves harvest quality and yield. Seed biopriming allows the bacteria to enter/adhere the seeds and also acclimatization of bacteria in the prevalent conditions. This review focuses on methods used for biopriming, and also the role in improving crop productivity and stress tolerance along with prospects of this technology. The comparison of methods being followed is also reviewed proposing biopriming as a promising technique for application of beneficial microbes to the seeds. PMID- 27222221 TI - Biogeography of planktonic and coral-associated microorganisms across the Hawaiian Archipelago. AB - Factors driving the distribution of marine microorganisms are widely debated and poorly understood. Recent studies show that free-living marine microbes exhibit geographical patterns indicative of limited dispersal. In contrast, host associated microbes face a different set of dispersal challenges, and hosts may function as habitat 'islands' for resident microbial populations. Here, we examine the biogeographical distributions of planktonic and adjacent coral associated bacterial communities across the Hawaiian Archipelago, Johnston Atoll (~1400 km southwest of Hawaii) and American Samoa in the Pacific Ocean and investigate the potential underlying processes driving observed patterns. Statistical analyses of bacterial community structure, determined using a small subunit ribosomal RNA gene-based approach, showed that bacterioplankton and coral associated bacterial communities were distinct, and correlated with geographical distance between sites. In addition, biogeographical patterns of bacterial associates paralleled those of their host coral Porites lobata, highlighting the specificity of these associations and the impact that host dispersal may have on bacterial biogeography. Planktonic and coral-associated bacterial communities from distant Johnston Atoll were shown to be connected with communities from the center of the Hawaiian Archipelago, a pattern previously observed in fish and invertebrates. No significant correlations were detected with habitat type, temperature or depth. However, non-distance-based geographical groupings were detected, indicating that, in addition to dispersal, unidentified environmental factors also affected the distributions of bacterial communities investigated here. PMID- 27222222 TI - Characterising the microbiome of Corallina officinalis, a dominant calcified intertidal red alga. AB - The living prokaryotic microbiome of the calcified geniculate (articulated) red alga, Corallina officinalis from the intertidal seashore is characterised for the first time based on the V6 hypervariable region of 16S rRNA. Results revealed an extraordinary diversity of bacteria associated with the microbiome. Thirty-five prokaryotic phyla were recovered, of which Proteobacteria, Cyanobacteria, Bacteroidetes, Actinobacteria, Planctomycetes, Acidobacteria, Verrucomicrobia, Firmicutes and Chloroflexi made up the core microbiome. Unclassified sequences made up 25% of sequences, suggesting insufficient sampling of the world's oceans/macroalgae. The greatest diversity in the microbiome was on the upper shore, followed by the lower shore then the middle shore, although the microbiome community composition did not vary between shore levels. The C. officinalis core microbiome was broadly similar in composition to those reported in the literature for crustose coralline algae (CCAs) and free-living rhodoliths. Differences in relative abundance of the phyla between the different types of calcified macroalgal species may relate to the intertidal versus subtidal habit of the taxa and functionality of the microbiome components. The results indicate that much work is needed to identify prokaryotic taxa, and to determine the nature of the relationship of the bacteria with the calcified host spatially, temporally and functionally. PMID- 27222223 TI - Deciphering endophyte behaviour: the link between endophyte biology and efficacious biological control agents. AB - Endophytes associate with the majority of plant species found in natural and managed ecosystems. They are regarded as extremely important plant partners that provide improved stress tolerance to the host compared with plants that lack this symbiosis. Fossil records of endophytes date back more than 400 million years, implicating these microorganisms in host plant adaptation to habitat transitions. However, it is only recently that endophytes, and their bioactive products, have received meaningful attention from the scientific community. The benefits some endophytes can confer on their hosts include plant growth promotion and survival through the inhibition of pathogenic microorganisms and invertebrate pests, the removal of soil contaminants, improved tolerance of low fertility soils, and increased tolerance of extreme temperatures and low water availability. Endophytes are extremely diverse and can exhibit many different biological behaviours. Not all endophyte technologies have been successfully commercialised. Of interest in the development of the next generation of plant protection products is how much of this is due to the biology of the particular endophytic microorganism. In this review, we highlight selected case studies of endophytes and discuss their lifestyles and behavioural traits, and discuss how these factors contribute towards their effectiveness as biological control agents. PMID- 27222224 TI - Intraspecific competition between ectomycorrhizal Pisolithus microcarpus isolates impacts plant and fungal performance under elevated CO2 and temperature. AB - Root systems are simultaneously colonized by multiple individuals of mycorrhizal fungi. Intraspecific competitive interactions between fungal isolates are likely to affect both fungal and plant performance and be influenced by abiotic factors. Here, we assessed the impact of intraspecific competition between three Pisolithus microcarpus isolates on the establishment of, and benefit derived from, symbioses with Eucalyptus grandis seedlings. We investigated the outcomes of competition under ambient and elevated temperature and CO2 concentration ([CO2]) in a factorial design. We observed a reduction in mycelium growth, mycorrhiza formation and seedling mass when two P. microcarpus isolates were co inoculated on a single E. grandis seedling. Isolates invested more in mycelium than in mycorrhizas in the presence of a competitor. All isolates responded negatively to elevated [CO2] and positively to elevated temperature, which led to no changes on the outcomes of the interactions with changing conditions. However, the presence of a competitor hindered the positive response of P. microcarpus isolates to warming, which resulted in larger negative effects of competition under elevated temperature than under ambient conditions. Our study highlights the need to consider how competition affects individual fungal responses as well as plant performance when trying to predict the impacts of climate change. PMID- 27222226 TI - A new benzimidazole based covalent organic polymer having high energy storage capacity. AB - We report the synthesis of a new benzimidazole-based covalent organic polymer (TpDAB) via solvothermal Schiff base condensation between 1,3,5 triformylphloroglucinol (Tp) and 3,3'-diaminobenzidine (DAB). TpDAB showed high energy storage capacity with a specific capacitance of 335 F g(-1) at 2 mV s(-1) scan rate and good cyclic stability with 93% retention of its initial specific capacitance after 1000 cycles. PMID- 27222225 TI - Perceptual conflict during sensorimotor integration processes - a neurophysiological study in response inhibition. AB - A multitude of sensory inputs needs to be processed during sensorimotor integration. A crucial factor for detecting relevant information is its complexity, since information content can be conflicting at a perceptual level. This may be central to executive control processes, such as response inhibition. This EEG study aims to investigate the system neurophysiological mechanisms behind effects of perceptual conflict on response inhibition. We systematically modulated perceptual conflict by integrating a Global-local task with a Go/Nogo paradigm. The results show that conflicting perceptual information, in comparison to non-conflicting perceptual information, impairs response inhibition performance. This effect was evident regardless of whether the relevant information for response inhibition is displayed on the global, or local perceptual level. The neurophysiological data suggests that early perceptual/ attentional processing stages do not underlie these modulations. Rather, processes at the response selection level (P3), play a role in changed response inhibition performance. This conflict-related impairment of inhibitory processes is associated with activation differences in (inferior) parietal areas (BA7 and BA40) and not as commonly found in the medial prefrontal areas. This suggests that various functional neuroanatomical structures may mediate response inhibition and that the functional neuroanatomical structures involved depend on the complexity of sensory integration processes. PMID- 27222227 TI - Parasitic infection alters the physiological response of a marine gastropod to ocean acidification. AB - Increased hydrogen ion concentration and decreased carbonate ion concentration in seawater are the most physiologically relevant consequences of ocean acidification (OA). Changes to either chemical species may increase the metabolic cost of physiological processes in marine organisms, and reduce the energy available for growth, reproduction and survival. Parasitic infection also increases the energetic demands experienced by marine organisms, and may reduce host tolerance to stressors associated with OA. This study assessed the combined metabolic effects of parasitic infection and OA on an intertidal gastropod, Zeacumantus subcarinatus. Oxygen consumption rates and tissue glucose content were recorded in snails infected with one of three trematode parasites, and an uninfected control group, maintained in acidified (7.6 and 7.4 pH) or unmodified (8.1 pH) seawater. Exposure to acidified seawater significantly altered the oxygen consumption rates and tissue glucose content of infected and uninfected snails, and there were clear differences in the magnitude of these changes between snails infected with different species of trematode. These results indicate that the combined effects of OA and parasitic infection significantly alter the energy requirements of Z. subcarinatus, and that the species of the infecting parasite may play an important role in determining the tolerance of marine gastropods to OA. PMID- 27222228 TI - Regulation of two motor patterns enables the gradual adjustment of locomotion strategy in Caenorhabditis elegans. AB - In animal locomotion a tradeoff exists between stereotypy and flexibility: fast long-distance travelling (LDT) requires coherent regular motions, while local sampling and area-restricted search (ARS) rely on flexible movements. We report here on a posture control system in C. elegans that coordinates these needs. Using quantitative posture analysis we explain worm locomotion as a composite of two modes: regular undulations versus flexible turning. Graded reciprocal regulation of both modes allows animals to flexibly adapt their locomotion strategy under sensory stimulation along a spectrum ranging from LDT to ARS. Using genetics and functional imaging of neural activity we characterize the counteracting interneurons AVK and DVA that utilize FLP-1 and NLP-12 neuropeptides to control both motor modes. Gradual regulation of behaviors via this system is required for spatial navigation during chemotaxis. This work shows how a nervous system controls simple elementary features of posture to generate complex movements for goal-directed locomotion strategies. PMID- 27222229 TI - Overcoming cetuximab resistance in Ewing's sarcoma by inhibiting lactate dehydrogenase-A. AB - Ewing's sarcoma, the second most common type of malignant bone tumor, generally occurs in children and young adults. The current treatment of Ewing's sarcoma comprises systemic anti-cancer chemotherapy with complete surgical resection. However, the majority of patients with Ewing's sarcoma develop resistance to chemotherapy. The present study revealed an oncogenic role of lactate dehydrogenase-A (LDHA) in the resistance of Ewing's sarcoma to cetuximab. LDHA was shown to be upregulated at the protein and mRNA level in cetuximab-resistant Ewing's sarcoma tissues and a cell line. In addition, a link between LDHA-induced glycolysis and cetuximab resistance in Ewing's sarcoma cells was revealed. Of note, inhibition of LDHA by either small interfering RNA or LDHA inhibitor oxamate significantly re-sensitized cetuximab-resistant cells to cetuximab. Combined treatment with LDHA inhibitor and cetuximab synergistically reduced the viability of cetuximab-resistant cells through the suppression of LDHA. The present study revealed a novel mechanism of cetuximab resistance from the perspective of cancer-cell metabolism and provided a sensitization approach, which may aid in the development of anti-chemoresistance strategies for the treatment of cetuximab-resistant Ewing's sarcoma. PMID- 27222230 TI - Expression of Sam68 Correlates With Cell Proliferation and Survival in Epithelial Ovarian Cancer. AB - Src associated in mitosis, 68 kDa (Sam68) is a KH domain RNA-binding protein that belongs to the signal transduction and activation of RNA family. It is a multifunctional protein known to regulate cellular signal transduction, transcription, RNA metabolism, proliferation, and apoptosis, thus implicated in tumor growth. Herein, we investigated the clinical significance of Sam68 in human epithelial ovarian cancer (EOC). Western blot and immunohistochemical staining demonstrated that Sam68 expression was upregulated in EOC tissues and cell lines. Statistical analysis showed that high expression of Sam68 correlated with poor prognosis of patients with EOC. In vitro, serum starvation-refeeding experiment was primarily performed to confirm that Sam68 participated in the cell cycle progression of EOC cell lines. Then knocking down Sam68 level with small interfering RNA, cell cycle was arrested at G1 phase and cell proliferation impaired. Furthermore, we demonstrated that the antiproliferative effect of silencing Sam68 in EOC cells was associated with the upregulation of cyclin dependent kinase inhibitors p21Cip1 and p27Kip1, along with the downregulation of p-FOXO3a, p-Akt, and p-GSK-3beta. Taken together, our findings uncovered that Sam68 played an important role in promoting the proliferation of human ovarian cancer, thereby might be a novel therapeutic target for EOC. PMID- 27222231 TI - PI3K/Akt Activated by GPR30 and Src Regulates 17beta-Estradiol-Induced Cultured Immature Boar Sertoli Cells Proliferation. AB - Sertoli cell (SC) is a key element in the process of spermatogenesis. Accumulating research show that estrogen plays an important role in regulating boar SC proliferation. However, it is unclear whether phosphatidylinositol-4,5 bisphosphate 3-kinase/protein kinase B (PI3K/Akt) is involved in this process. In the present study, the role of PI3K/Akt on the 17beta-estradiol-induced piglet SC proliferation was explored. In addition, we also explained the roles of G-protein coupled estrogen receptor (GPR30) and Sarcoma protein (Src) in this process. Our study demonstrated that, 17beta-estradiol induced activation of PI3K in a time dependent manner. Both G-15 (an antagonist of GPR30, 0.1 MUmol/L) and PP2 (an inhibitor of Src, 2.0 MUmol/L) inhibited 17beta-estradiol-induced activation of PI3K, reduced SC proliferation, and decreased messenger RNA (mRNA) and protein expression of S-phase kinase-associated protein 2 (Skp2). We also found that 17beta-estradiol induced activation of Akt in a time-dependent manner. Both LY294002 (an inhibitor of PI3K) and 10-DEBC (an inhibitor of Akt) significantly reduced 17beta-estradiol-induced SC proliferation and reduced mRNA and protein expression of Skp2. In addition, LY294002 inhibited 17beta-estradiol-induced activation of Akt. The results indicated that 17beta-estradiol regulates SC proliferation by activating PI3K/Akt. Both GPR30 and Src are involved in 17beta estradiol-induced phosphorylation of PI3K/Akt. Activation of PI3K/Akt enhances the expression of Skp2, which promotes SC proliferation. PMID- 27222232 TI - Endometrial BCL6 Overexpression in Eutopic Endometrium of Women With Endometriosis. AB - The objective of this study was to examine B-cell CLL/lymphoma 6 (BCL6) expression in human eutopic endometrium across the menstrual cycle in women with and without endometriosis and to establish a cutoff for future studies. This design was a series of case-control studies in tertiary University teaching hospitals. We examined BCL6 expression by messenger RNA and immunohistochemically in prospectively collected samples in both the proliferative (P) and the secretory phases. BCL6 is minimally increased in the mid-secretory phase of the menstrual cycle compared to the P phase in normal patients. BCL6 protein expression was significantly higher in the secretory phase of patients with endometriosis (n = 29) versus fertile controls without endometriosis at laparoscopy (n = 20; P < .0001). Normal fertile controls (n = 28) recruited for endometrial biopsy also had low levels of secretory phase BCL6 expression compared to women with unexplained infertility (UI; n = 119). A receiving operator characteristic analysis of these data revealed an area under the curve of 94% (95% confidence interval 85%-100%; P < .0001) with an HSCORE cutoff of 1.4 to differentiate cases with and without endometriosis. Using this cutoff value, BCL6 was positive in 88% of cases with UI. Laparoscopic examination of a subset of 65 patients confirmed abnormalities in 98% of cases; 61 (93.8%) were found to have endometriosis, 3 (4.6%) with hydrosalpinx, and 1 (1.5%) with a normal pelvis. These data suggest that BCL6 is a promising candidate as a single diagnostic biomarker for detection of endometriosis in women with otherwise UI and may be associated with endometrial dysfunction, including progesterone resistance. PMID- 27222233 TI - PRL-3 Is Involved in Estrogen- and IL-6-Induced Migration of Endometrial Stromal Cells From Ectopic Endometrium. AB - OBJECTIVE: To investigate the role of phosphatase of regenerating liver-3 (PRL-3) in the 17beta-estradiol (E2)- and interleukin 6 (IL-6)-induced migration of endometrial stromal cells (ESCs) from ectopic endometrium. METHODS: Ectopic endometrial tissues were collected from patients with endometriosis, and PRL-3 expression in ectopic and eutopic endometrium was examined by immunohistochemistry. Endometrial stromal cells isolated from ectopic endometrium were treated with E2, progesterone (P), IL-6, or sodium orthovanadate (Sov) to inhibit PRL-3. Total RNA and protein were extracted from ESCs after treatment for quantitative real-time polymerase chain reaction and Western blot analyses. Cell migration was assessed using a scratch wound assay. RESULTS: Phosphatase of regenerating liver 3 protein was highly expressed in the endometrial glandular cells (EGCs) and ESCs in ectopic endometrium, whereas its weak expression was observed only in EGCs in eutopic endometrium. Both E2 and IL-6 treatment significantly increased PRL-3 messenger RNA and protein expression, and P treatment significantly inhibited PRL-3 expression. However, E2-induced PRL-3 expression in ESCs from ectopic endometrium was significantly blocked by IL-6 antibody. Moreover, E2- and IL-6-enhanced cell migration was completely abrogated by Sov treatment. Furthermore, Sov treatment could significantly promote PTEN expression but inhibit E2- and IL-6-induced p-AKT activation. CONCLUSION: Phosphatase of regenerating liver 3 plays a key role in the E2- and IL-6-induced migration of ESCs from ectopic endometrium, a process that is involved in the PTEN-AKT signaling pathway. PMID- 27222235 TI - Perceived barriers towards healthy eating and their association with fruit and vegetable consumption. AB - Background: Improving dietary intakes is a key public health target. Perceived barriers to healthy eating (PBHE) are an important component of the Health Belief Model which aims to understand why individuals do not adopt preventive health measures. This study investigates the relationship between PBHE and reported fruit and vegetable (F&V) consumption. Methods: Data from the Scottish Health Survey 2008-11 (n = 8319) for PBHE and self-reported F&V consumption were used in Probit regression models to test the association between meeting the 400 g per day F&V recommendation and PBHE. Results: Regression models show women who reported a lack of cooking skills were 10.4% less likely to meet the F&V recommendations (P = 0.001). Not liking the taste of healthy foods or finding them too boring (10.2%, P = 0.022), preparation time (5.6%, P = 0.020) or willpower (3.0%, P = 0.021) were also significant. For men, reporting not liking the taste of healthy foods or finding them too boring (6.8%, P = 0.02) was the only significant result. Price, a commonly reported PBHE, was not significantly associated with F&V consumption. Conclusions: Not all commonly reported perceived barriers to healthy eating are significantly associated with meeting the recommended F&V intake. PMID- 27222234 TI - Naunyn-Schmiedeberg's Archives of Pharmacology under new editorship: change and continuity. PMID- 27222236 TI - Impact of maternal and paternal smoking on birth outcomes. AB - Background: The adverse effects of maternal and paternal smoking on child health have been studied. However, few studies demonstrate the interaction effects of maternal/paternal smoking, and birth outcomes other than birth weight have not been evaluated. The present study examined individual effects of maternal/paternal smoking and their interactions on birth outcomes. Methods: A follow-up hospital-based study from pregnancy to delivery was conducted from 1997 to 2010 with parents and newborn infants who delivered at a large hospital in Hamamatsu, Japan. The relationships between smoking and growth were evaluated with logistic regression. Results: The individual effects of maternal smoking are related to low birth weight (LBW), short birth length and small head circumference. The individual effects of paternal smoking are related to short birth length and small head circumference. In the adjusted model, both parents' smoking showed clear associations with LBW (odds ratio [OR] = 1.64, 95% confidence interval [CI] 1.18-2.27) and short birth length (-1 standard deviation [SD] OR = 1.38, 95% CI 1.07-1.79; -2 SD OR = 2.75, 95% CI 1.84-4.10). Conclusions: Maternal smoking was significantly associated with birth weight and length, but paternal smoking was not. However, if both parents smoked, the risk of shorter birth length increased. PMID- 27222237 TI - Perceived barriers to partner notification among sexually transmitted infection clinic patients, Cape Town, South Africa. AB - Background: Public health approaches to sexually transmitted infection (STI) prevention in resource-limited countries rely on patients to self-notify sex partners of their STI. However, a majority of partners go uninformed and remain untreated and infectious. Methods: Anonymous surveys collected from 776 men and women receiving STI clinic services in Cape Town, South Africa. Results: Half of patients surveyed intended to inform their partners, while half did not intend to notify partners. Women were more likely than men to intend to notify their partners. Patients who completed formal education were also more likely to indicate intentions to notify partners. There were no associations between numbers of partners patients had or partner types with intentions to notify partners. Among both men and women, concerns about adverse partner reactions were associated with intentions not to notify partners. Multivariable analyses stratified by gender and controlling for confounds showed that intentions to notify partners were significantly related to men's concerns that their partner could react violently against them and women's concerns that their partner may leave them and refuse to see them again. Conclusions: Interventions that assist patients to develop strategies to safely inform their partners are needed to increase patient-initiated partner notification. PMID- 27222238 TI - Poverty and health-related quality of life of people living in Hong Kong: comparison of individuals from low-income families and the general population. AB - Background: To assess health-related quality of life (HRQOL) among Chinese adults from low-income households in Hong Kong, and to explore any threshold of household income that impaired HRQOL. Methods: A cross-sectional analysis was conducted on 298 adults from low-income families when they enrolled into a cohort study between 2012 and 2014. HRQOL was measured by the 12-item Short-Form Health Survey-version 2 (SF-12v2). Their mean SF-12v2 subscale and summary scores were compared with those of 596 age-sex-matched subjects randomly selected from a database of 2763 adults from the Hong Kong general population (ratio = 1:2). Multiple linear regressions were conducted to determine any association between monthly household income and HRQOL. Results: Subjects from low-income households had significantly lower SF-12v2 bodily pain, general health, vitality and physical component summary (PCS) scores than the age-sex matched subjects from the general population. Subgroup analysis showed that a household income <50% of the median monthly household income in Hong Kong (HK$10 000 ~ US$1290, i.e. poverty line in Hong Kong) was independently associated with poorer PCS and mental component summary (MCS) scores after adjustment for socio-demographics and co-morbidities. Conclusion: Chinese adults from low-income households had poorer HRQOL, and <50% of the median monthly household income seems to be the threshold for impairment of both physical and mental HRQOL. The findings support the current definition of the poverty line. PMID- 27222239 TI - Retrospective case series analysis of characteristics and trends in unintentional pharmaceutical drug poisoning by methadone, opioid analgesics, antidepressants and benzodiazepines in Clark County, NV 2009-13. AB - Background: Poisoning has become the leading cause of injury death in the USA with opioid analgesic involved in more fatal poisonings than any other drug, including cocaine and heroin. The epidemic of prescription drug poisonings is a public health concern. This study aimed to define potential high-risk groups for unintentional prescription drug poisoning by methadone, opioid analgesics, antidepressants or benzodiazepines. Methods: A hospital-based retrospective case series analysis of admissions related to prescription drug poisonings associated with methadone, opioid analgesics, antidepressants or benzodiazepines for hospitals in Clark County, Nevada between 2009 and 2013 was employed. Results: There were 7414 admissions with a primary diagnosis of an unintentional poisoning due to methadone, opioid analgesics, antidepressants or benzodiazepines. Women had the highest rate of admissions particularly in the 45-54 age group. Higher rates of admissions were also found among non-Hispanic whites, single and uninsured populations. There were concerning increases in admissions among 65+ and Native American/Alaskan Native subgroups in 2013. Benzodiazepines and opioid analgesics were the most prevalent drug categories for prescription drug poisoning admissions. Conclusion: Public health professionals can utilize hospital data to identify populations at risk and in need of targeted interventions. PMID- 27222240 TI - Factor associated with risky sexual behaviors among the French general population. AB - Background: Despite prevention programs, a rising incidence of sexually transmitted infections is currently reported in France. Aims: Research factors associated with risky sexual behaviors (RSBs) among the French population. Methods: Subjects aged 15-54 years from the French national survey 'Barometre sante 2010' were included (n = 16 598). RSB was defined as having multiple partners or failure to use condom at first intercourse with a new partner over past 12 months. Factors associated were identified using one logistic regression by gender. Results: The overall RSB prevalence was 9.5%, being higher among men (P < 0.001). Factors associated with RSB for both genders were young age (OR = 1.5), single status (men: OR = 7.1; women: OR = 6.4), homosexual relations (men: OR = 2.0; women: OR = 3.2), low incomes (men: OR = 1.5; women: OR = 1.4), use of cannabis (men: OR = 1.4; women: OR = 3.0). Men-specific factors were history of STI (OR = 2.5) and alcohol drunkenness (OR = 2.2), and women-specific factors history of suicide attempt (OR = 1.6) and history of sexual assault (OR = 1.6). Conclusions: Confirming most of known determinants of RSB, this study also identified some specific risky patterns for whom preventive actions can be developed: multiusers of psychoactive substances, people living with low incomes, women having sex with women or presenting history of psychological vulnerability (suicide attempts, sexually harassed). PMID- 27222241 TI - Perceptions of influenza vaccination during pregnancy in Korean women of childbearing age. AB - The rate of maternal influenza vaccination in Korea is much lower than the general population. We evaluated the influenza vaccination rate during pregnancy and assessed women's perceptions of the influenza vaccine. One thousand women of childbearing age were surveyed from April through May 2014, using a questionnaire about vaccination history, general understanding of influenza vaccination and that examined factors that influence decisions about influenza vaccination. We also conducted an intervention to evaluate potential improvement in vaccination behavior. The influenza vaccination rate during pregnancy was 37.3%. The common reasons listed in support of vaccination included the perception of the risk of influenza infection, recommendations from health care providers, and belief in the effectiveness of the influenza vaccine. The most common reasons for not vaccinating included concern about harmful effects and the lack of recommendation from health care providers. Based on the results of the questionnaire and intervention, it is important to provide accurate information and for health care providers to recommend the influenza vaccine to pregnant women. It is also necessary for the government to encourage women to receive the influenza vaccination as a healthcare policy. PMID- 27222242 TI - Bergamottin isolated from Citrus bergamia exerts in vitro and in vivo antitumor activity in lung adenocarcinoma through the induction of apoptosis, cell cycle arrest, mitochondrial membrane potential loss and inhibition of cell migration and invasion. AB - The objective of the present study was to investigate the in vitro and in vivo anticancer properties of bergamottin, a natural furanocoumarin, against human non small cell lung carcinoma (NSCLC) A549 cells. We also studied its effect on cell proliferation, cell cycle arrest, cell invasion, cell migration as well as cell apoptosis. Antiproliferative activity of bergamottin was estimated by the MTT assay. Phase contrast and fluorescence microscopy as well as flow cytometry using Annexin V-FITC assay were used to study induction of apoptosis by bergamottin in these cells. The effects of bergamottin on cell cycle phase distribution as well as on mitochondrial membrane potential were also demonstrated using flow cytometry. In vitro wound healing assay was used to study the effect of bergamottin on cell migration. The effects of bergamottin on tumor progression were also observed using a nude mouse model. The mice were divided into 4 groups and treated with bergamottin injected intraperitoneally. Bergamottin induced dose dependent as well as time-dependent cytotoxic effects as well as inhibition of colony formation in the A549 cancer cells. Bergamottin also suppressed cancer cell invasion as well as cancer cell migration. Phase contrast microscopy and fluorescence microscopy revealed that bergamottin induced cell shrinkage, chromatin condensation and the cells became rounded and detached from each other. Bergamottin also induced a potent cell cycle arrest at the G2/M phase of the cell cycle. Experiments in mice showed that 25, 50 and 100 mg/kg bergamottin injection reduced the tumor weight from 1.61 g in the phosphate-buffered saline (PBS) treated group (control) to 1.21, 0.42 and 0.15 g in the bergamottin-treated groups, respectively. The results of the present study revealed that bergamottin was able to inhibit lung cancer cell growth both in a cell model and a xenograft mouse model by inducing apoptosis, mitochondrial membrane potential loss, G2/M cell cycle arrest as well as inhibiting cell migration and invasion. PMID- 27222243 TI - In vivo confocal microscopy evaluation of ocular and cutaneous alterations in patients with rosacea. AB - AIMS: The physiopathology of rosacea and the correlation between ocular and cutaneous rosacea remains unclear. This study analysed ocular and cutaneous rosacea with in vivo confocal microscopy (IVCM). METHODS: Thirty-four eyes of 34 patients with confirmed rosacea-associated meibomian gland dysfunction-related evaporative dry eye were enrolled in the study. The ophthalmological investigations included dry eye ocular surface disease index (OSDI), the Schirmer test, tear osmolarity, tear break up time, the Oxford score, infrared meibography for meibomian gland (MG) analysis and IVCM investigation for cornea, MG and skin analysis (cheek, hand). Presences of Demodex in the MG and in the cheek were also investigated. We established scores for quantifying the MG alterations in the MG (IVCM-MG) and cheek (IVCM-Cheek), and scores for Demodex quantification in the MG and cheek (IVCM-MG-Dex and IVCM-Cheek-Dex). RESULTS: IVCM was relevant for analysing the cornea and MG structures and was also suitable for cutaneous analysis. Exposed skin explorations presented the epidermal and dermal layers clearly. In patients with rosacea, the IVCM-MG alteration scores were correlated with IVCM-Cheek (R2=0.27 and p=0.0006) and IVCM-MG-Dex was correlated with IVCM Cheek-Dex (R2=0.70 and p<0.0001). However, no correlation was found between the IVCM-MG or IVCM-Cheek and the break up time, Schirmer, Oxford and osmolarity evaluations. CONCLUSIONS: IVCM could be a safe, effective and reliable tool to quantify alterations of the cornea, MG and cheek glands in patients with rosacea combined with quantification of Demodex infections. As a valuable tool for investigating the pathophysiology of the disease, it could be used to assess the effectiveness of therapy. PMID- 27222244 TI - Comparison of the harmonic focus and the thunderbeat for open thyroidectomy. AB - PURPOSE: An effective method for controlling haemostasis during open thyroidectomy procedures is crucial because of the high risks of haemorrhage and neck haematoma. This study aimed to demonstrate the efficacy of the integrated ultrasonic/bipolar ThunderbeatTM for this procedure. METHODS: This retrospective non-inferiority study compared the ThunderbeatTM and the ultrasonic Harmonic Focus(r) devices in 761 consecutive patients receiving a partial or total open thyroidectomy (with or without neck dissection). The main outcomes were duration of surgery, blood loss, and length of hospitalisation. Secondary outcomes were occurrence of hypocalcaemia, recurrent nerve paralysis, or other post-operative complications. A non-inferiority logistic regression approach was used to evaluate primary outcomes, adjusting for age, gender, body mass index, type of surgery, anaesthesiology score, and indication (benign or malign). RESULTS: The data demonstrated that the Thunderbeat was non-inferior to the Focus in terms of duration of surgery, blood loss, and length of hospital stay. Furthermore, subgroup analyses showed non-inferiority of the Thunderbeat for partial thyroidectomy (all three outcomes), total thyroidectomy (duration of surgery and length of hospitalisation), and total thyroidectomy with neck dissection (length of hospitalisation). In terms of recurrent nerve paralysis and post-operative complications, the Thunderbeat performed at least as well as the Focus; however, no conclusions could be drawn regarding the occurrence of post-operative hypocalcaemia. CONCLUSION: In a cohort of patients that underwent partial or total thyroidectomy, the Thunderbeat appeared to be at least as good as the Harmonic Focus. PMID- 27222245 TI - B-Flow Imaging in Lower Limb Peripheral Arterial Disease and Bypass Graft Ultrasonography. AB - Doppler ultrasonography plays a key role in the diagnosis of peripheral arterial disease, but is often limited by pitfalls that may be overcome by B-flow imaging. Thus far, there is little information on B-flow imaging for the assessment of peripheral arterial disease and bypass grafts in lower limbs. This article describes the authors' early experience with B-flow in the lower extremities. Sixty patients were included among a large cohort of patients routinely referred to the vascular laboratory for peripheral arterial disease and bypass graft assessments. Two experienced vascular sonographers performed all scans, comparing color Doppler ultrasonography with B-flow imaging. All scans were performed using a combination of the 9 L linear and C2-9 curvilinear transducers with the LOGIQ E9 system (GE Healthcare, Waukesha, WI, USA). Our experience indicates that this relatively unexplored technology has the potential to significantly improve peripheral blood flow evaluation. Nevertheless, B-flow imaging is not exempt from limitations and should be considered complementary to color Doppler ultrasonography. PMID- 27222246 TI - Design and Testing of a Single-Element Ultrasound Viscoelastography System for Point-of-Care Edema Quantification. AB - Management of fluid overload in patients with end-stage renal disease represents a unique challenge to clinical practice because of the lack of accurate and objective measurement methods. Currently, peripheral edema is subjectively assessed by palpation of the patient's extremities, ostensibly a qualitative indication of tissue viscoelastic properties. New robust quantitative estimates of tissue fluid content would allow clinicians to better guide treatment, minimizing reactive treatment decision making. Ultrasound viscoelastography (UVE) can be used to estimate strain in viscoelastic tissue, deriving material properties that can help guide treatment. We are developing and testing a simple, low-cost UVE system using a single-element imaging transducer that is simpler and less computationally demanding than array-based systems. This benchtop validation study tested the feasibility of using the UVE system by measuring the mechanical properties of a tissue-mimicking material under large strains. We generated depth dependent creep curves and viscoelastic parameter maps of time constants and elastic moduli for the Kelvin model of viscoelasticity. During testing, the UVE system performed well, with mean UVE-measured strain matching standard mechanical testing with maximum absolute errors <=4%. Motion tracking revealed high correlation and signal-to-noise ratios, indicating that the system is reliable. PMID- 27222247 TI - Home safety assessment and modification to reduce injurious falls in community dwelling older adults: cost-utility and equity analysis. AB - BACKGROUND: This study aimed to improve on previous modelling work to determine the health gain, cost-utility and health equity impacts from home safety assessment and modification (HSAM) for reducing injurious falls in older people. METHODS: The model was a Markov macrosimulation one that estimated quality adjusted life-years (QALYs) gained. The setting was a country with detailed epidemiological and cost data (New Zealand (NZ)) for 2011. A health system perspective was taken and a discount rate of 3% was used (for both health gain and costs). Intervention effectiveness estimates came from a Cochrane systematic review and NZ-specific intervention costs were from a randomised controlled trial. RESULTS: In the 65 years and above age group, the HSAM programme cost a total of US$98 million (95% uncertainty interval (UI) US$65 to US$139 million) to implement nationally and the accrued net health system costs were US$74 million (95% UI: cost saving to US$132 million). Health gains were 34 000 QALYs (95% UI: 5000 to 65 000). The incremental cost-effectiveness ratio (ICER) was US$6000 (95% UI: cost saving to US$13 000), suggesting that HSAM is highly cost-effective. Targeting HSAM only to older people with previous injurious falls and to older people aged 75 years and above were also cost-effective (ICERs=US$1000 and US$11 000, respectively). There was no evidence for differential cost-effectiveness by gender or by ethnicity (Indigenous New Zealanders: Maori vs non-Maori). CONCLUSIONS: As per other studies, this modelling study indicates that the provision of an HSAM intervention produces considerable health gain and is highly cost-effective among older people. Targeting this intervention to older people with previous injurious falls is a promising initial approach before any scale up. TRIAL REGISTRATION NUMBER: ACTRN12609000779279. PMID- 27222249 TI - Population-balance description of shear-induced clustering, gelation and suspension viscosity in sheared DLVO colloids. AB - Application of shear flow to charge-stabilized aqueous colloidal suspensions is ubiquitous in industrial applications and as a means to achieve controlled field induced assembly of nanoparticles. Yet, applying shear flow to a charge stabilized colloidal suspension, which is initially monodisperse and in quasi equilibrium leads to non-trivial clustering phenomena (and sometimes to a gelation transition), dominated by the complex interplay between DLVO interactions and shear flow. The quantitative understanding of these strongly nonequilibrium phenomena is still far from being complete. By taking advantage of a recent shear-induced aggregation rate theory developed in our group, we present here a systematic numerical study, based on the governing master kinetic equation (population-balance) for the shear-induced clustering and breakup of colloids exposed to shear flow. In the presence of sufficiently stable particles, the clustering kinetics is characterized by an initial very slow growth, controlled by repulsion. During this regime, particles are slowly aggregating to form clusters, the reactivity of which increases along with their size growth. When their size reaches a critical threshold, a very rapid, explosive-like growth follows, where shear forces are able to overcome the energy barrier between particles. This stage terminates when a dynamic balance between shear-induced aggregation and cluster breakage is reached. It is also observed that these systems are characterized by a cluster mass distribution that for a long time presents a well-defined bimodality. The model predictions are quantitatively in excellent agreement with available experimental data, showing how the theoretical picture is able to quantitatively account for the underlying nonequilibrum physics. PMID- 27222248 TI - Paradoxical activation of MEK/ERK signaling induced by B-Raf inhibition enhances DR5 expression and DR5 activation-induced apoptosis in Ras-mutant cancer cells. AB - B-Raf inhibitors have been used for the treatment of some B-Raf-mutated cancers. They effectively inhibit B-Raf/MEK/ERK signaling in cancers harboring mutant B Raf, but paradoxically activates MEK/ERK in Ras-mutated cancers. Death receptor 5 (DR5), a cell surface pro-apoptotic protein, triggers apoptosis upon ligation with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or aggregation. This study focused on determining the effects of B-Raf inhibition on DR5 expression and DR5 activation-induced apoptosis in Ras-mutant cancer cells. Using chemical and genetic approaches, we have demonstrated that the B-Raf inhibitor PLX4032 induces DR5 upregulation exclusively in Ras-mutant cancer cells; this effect is dependent on Ras/c-Raf/MEK/ERK signaling activation. PLX4032 induces DR5 expression at transcriptional levels, largely due to enhancing CHOP/Elk1-mediated DR5 transcription. Pre-exposure of Ras-mutated cancer cells to PLX4032 sensitizes them to TRAIL-induced apoptosis; this is also a c-Raf/MEK/ERK-dependent event. Collectively, our findings highlight a previously undiscovered effect of B-Raf inhibition on the induction of DR5 expression and the enhancement of DR5 activation-induced apoptosis in Ras-mutant cancer cells and hence may suggest a novel therapeutic strategy against Ras mutated cancer cells by driving their death due to DR5-dependent apoptosis through B-Raf inhibition. PMID- 27222250 TI - Effect of tethering on the surface dynamics of a thin polymer melt layer. AB - The surface height fluctuations of a layer of low molecular weight (2.2k) untethered perdeuterated polystyrene (dPS) chains adjacent to a densely grafted polystyrene brush are slowed dramatically. Due to the interpenetration of the brush with the layer of "untethered chains" a hydrodynamic continuum theory can only describe the fluctuations when the effective thickness of the film is taken to be that which remains above the swollen brush. The portion of the film of initially untethered chains that interpenetrates with the brush becomes so viscous as to effectively play the role of a rigid substrate. Since these hybrid samples containing a covalently tethered layer at the bottom do not readily dewet, and are more robust than thin layers of untethered short chains on rigid substrates, they provide a route for tailoring polymer layer surface properties such as wetting, adhesion and friction. PMID- 27222251 TI - Recent changes in breast cancer incidence and mortality in Estonia: Transition to the west. AB - Background The aim of this study was to examine breast cancer (BC) incidence and mortality trends in Estonia during recent decades and to compare the pattern of these trends with other selected European countries and regions. We attempt to explain the findings in relation to changes in Estonian society and healthcare system. Methods BC incidence (1985-2012) and mortality (1985-2013) data for Estonia were obtained from the Estonian Cancer Registry and Statistics Estonia. Data for selected European countries were obtained from the EUREG database. Joinpoint regression was used to analyze age-standardized rates in Estonia by age. For international comparison of incidence and mortality rates, we used scatterplot with 95% confidence ellipses and the mortality to incidence ratio. Results The overall BC incidence continues to increase in Estonia, while mortality has been in decline since 2000. Both incidence and mortality trends varied considerably across age groups. Among women aged 60 years and older, BC incidence increased at a rate of nearly 3% per year. Significant decrease in mortality was seen only among women aged 50-59 years. Comparison of scatterplots between countries and regions revealed two clusters in Europe separated along the incidence axis. The correlation between incidence and mortality in Estonia changed its direction in the mid-1990s. Conclusion In recent years, the dynamics of BC burden in Estonia has transitioned towards the high incidence-low mortality type model, which is characteristic to Western, Northern and Southern Europe. Although overall BC incidence is much lower in Estonia than in more affluent European countries, mortality from BC is still relatively high, particularly among elderly women. PMID- 27222252 TI - 11-O-acetylcyathatriol inhibits MAPK/p38-mediated inflammation in LPS-activated RAW 264.7 macrophages and has a protective effect on ethanol-induced gastric injury. AB - The present study investigated the effects of 11-O-acetylcyathatriol, a natural cyathane diterpene, on the release of inflammatory mediators and on the activation of the nuclear factor (NF)-kappaB or the mitogen-activated protein kinase (MAPK) transduction pathways in lipopolysaccharide (LPS)-activated macrophages. MTT was used to evaluate the cytotoxicity. A Griess assay was used to determine the production of nitrous oxide (NO). The levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 were determined using ELISA kits. The protein expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, phosphorylated (p)-extracellular signal-regulated kinase (ERK1/2), p-J-N-terminal kinase (JNK), p-p38 and inhibitor of NFkappaB (IkappaB) alpha were detected using western blot analysis. 11-O-acetylcyathatriol significantly inhibited the overproduction of NO and the release of IL-6, but had no inhibitory effect on the release of TNF-alpha. It also significantly downregulated the high expression levels of iNOS and COX-2 induced by LPS. In addition, it markedly inhibited the phosphorylation of the MAPK/p38 protein, but only exhibited weak inhibition on the phosphorylation of the ERK1/2 and JNK proteins, and the degradation of the IkappaB-alpha protein. The possible protective effect of 11-O-acetylcyathatriol on ethanol-induced gastric injury was also examined using an in vivo animal experiment. Following gavage administration, it showed an important protective effect on ethanol-induced gastric mucosal injury in rats. These results suggested the possibility that the anti-inflammatory effect of 11-O-acetylcyathatriol was predominantly due to the inhibition of iNOS and COX-2 proteins, and may be associated with the MAPK/p38 transduction pathway, but not the NF-kappaB transduction pathway. These findings provide an explanation for the underlying mechanism of anti-inflammatory action of 11-O-acetylcyathatriol, which may assist with its clinical application and future development. PMID- 27222253 TI - Non-hematopoietic effects of endogenous erythropoietin on lean mass and body weight regulation. AB - OBJECTIVE: To investigate the concurrent relationships between human plasma erythropoietin concentrations and energy expenditure (EE), body composition, plasma leptin concentrations, and associations with weight change. METHODS: Plasma to measure erythropoietin and leptin; data for body composition; 24-h EE measured in a whole-room calorimeter; and 75 g oral glucose tolerance testing were available from 109 full-heritage Pima Indians (55% male) from a larger study designed to understand the causes of obesity. Seventy-nine subjects had data for weight at a later visit (mean follow-up = 4.3 +/- 1.9 years) to calculate percent weight change per year. RESULTS: Erythropoietin, adjusted for covariates, correlated with 24-h EE (r = 0.26, P = 0.007), sleeping EE (r = 0.29, P = 0.003), fat-free mass (r = 0.19, P = 0.05), and fat mass (r = 0.27, P = 0.005), but not insulin or glucose measures. The association of erythropoietin with 24-h EE was fully mediated by fat-free mass. Erythropoietin associated with leptin in women (rho = 0.36, P = 0.01), but not in men (P = 0.9), independently from fat mass. The association of erythropoietin with percent weight change per year was in opposing directions (interaction: P = 0.002) in males (r = -0.35, P = 0.02) versus females (r = 0.37, P = 0.02). CONCLUSIONS: Non-hematopoietic endogenous erythropoietin action may be involved in body weight regulation in opposing directions in men and women, i.e., weight loss in men and weight gain in women. PMID- 27222255 TI - Downregulation of lncRNA CASC2 by microRNA-21 increases the proliferation and migration of renal cell carcinoma cells. AB - Several long non-coding RNAs (lncRNAs) have been identified that may have a crucial role in tumor progression and metastasis. The lncRNA cancer susceptibility candidate 2 (CASC2) has previously been reported to act as a tumor suppressor gene in glioma and colorectal cancer. However, the expression and function of CASC2 in renal cell carcinoma (RCC) remains to be elucidated. The present study confirmed that CASC2 was downregulated in human RCC tissues and human RCC cell lines (786-O and A498). Restoration of CASC2 expression via transfection with a pcDNA3.1(+)-CASC2 vector was able to inhibit cell proliferation and migration in 786-O and A498 cells, as compared with in the cells transfected with a pcDNA3.1(+) empty vector. MicroRNA-21 (miR-21) has been reported to be upregulated in human RCC tissues and cell lines, and is associated with the malignant progression of RCC. In the present study, bioinformatics analysis and dual-luciferase reporter assays confirmed that CASC2 was a direct target gene of miR-21. miR-21 was able to decrease the expression of CASC2 in 786 O and A498 cells. Furthermore, overexpression of miR-21 partly abrogated CASC2 mediated inhibition of 786-O and A498 cell proliferation and migration. The present study provides evidence indicating that CASC2 targeted by miR-21 acts as a tumor suppressor in RCC. Therefore, CASC2 may be considered a novel target for the diagnosis and treatment of RCC. PMID- 27222256 TI - Enhanced cadmium efflux and root-to-shoot translocation are conserved in the hyperaccumulator Sedum alfredii (Crassulaceae family). AB - Investigation on the molecular mechanisms of cadmium hyperaccumulation has been mostly focused on members of the Brassicaceae family. Here, we show using hyperaccumulating (HP) and nonhyperaccumulating (NHP) populations of Sedum alfredii (Crassulaceae), that Cd hypertolerance correlates with higher Cd efflux rates and less cadmium accumulation in suspension cells and roots. The heavy metal ATPase HMA2, but not HMA4, was highly expressed in suspension cultures and roots from HP plants compared to NHP cells and plants. Reciprocal grafting also showed that Cd translocation is more efficient in HP plants. These results suggest that cadmium efflux is a conserved mechanism among natural cadmium hyperaccumulator species. PMID- 27222254 TI - Physiological underpinnings in life-history trade-offs in man's most popular selection experiment: the dog. AB - Animal life-history traits fall within a limited ecological space, a continuum referred to as a "slow-fast" life-history axis. Differences of life-history traits are thought to result from trade-offs between behavioral and physiological aspects in each species as mediated by the biotic and abiotic environment, as well as genetic mechanisms. Domestic animals tend to show inverse relationships between body size and life span. Dogs are a good example of this, with smaller dogs having higher mass-specific metabolic rates and longer lifespans compared with larger dogs. Thus, dogs provide a unique system to examine physiological consequences of life-history trade-offs. I have collected data from the literature to explore implications of these trade-offs at several levels of physiological organization including whole-animal, organ systems, and cells. Small dogs tend to have longer lifespans, fewer pups per litter, faster and shorter developmental trajectories, and higher mass-specific metabolic rates, and in general, larger metabolically active organs compared with large dogs. From work on isolated primary fibroblast cells and telomeres of dogs, I show that selection for body size may influence the attributes of cells that shape proliferative cellular rates and rates of telomere shortening. The potential links between body size, and cellular oxidative stress in dogs as they age are discussed. Furthermore, small size in dogs has been linked to concentrations of reduced insulin growth factor-1 (IGF-1) levels in plasma, a possible metabolic advantage that may provide higher resistance to oxidative stress, a parameter essential to increases in lifespan. PMID- 27222260 TI - Newborn Resuscitation Training Programmes Reduce Early Neonatal Mortality. AB - BACKGROUND: Substantial health care resources are expended on standardised formal neonatal resuscitation training (SFNRT) programmes, but their effectiveness has not been proven. OBJECTIVES: To determine whether SFNRT programmes reduce neonatal mortality and morbidity, improve acquisition and retention of knowledge and skills, or change teamwork and resuscitation behaviour. METHODS: We searched CENTRAL, MEDLINE, PREMEDLINE, EMBASE, CINAHL, Web of Science and the Oxford Database of Perinatal Trials, ongoing trials and conference proceedings in April 2015, and included randomised or quasi-randomised trials that reported at least one of our specified outcomes. RESULTS: SFNRT in low- and middle-income countries decreased early neonatal mortality [risk ratio (RR) 0.85 (95% CI 0.75-0.96)]; the number needed to treat for benefit [227 (95% CI 122-1,667; 3 studies, 66,162 participants, moderate-quality evidence)], and 28-day mortality [RR 0.55 (95% CI 0.33-0.91); 1 study, 3,355 participants, low-quality evidence]. Decreasing trends were noted for late neonatal mortality [RR 0.47 (95% CI 0.20-1.11)] and perinatal mortality [RR 0.94 (95% CI 0.87-1.00)], but there were no differences in fresh stillbirths [RR 1.05 (95% CI 0.93-1.20)]. Teamwork training with simulation increased the frequency of teamwork behaviour [mean difference (MD) 2.41 (95% CI 1.72-3.11)] and decreased resuscitation duration [MD -149.54 (95% CI -214.73 to 84.34); low-quality evidence, 2 studies, 130 participants]. CONCLUSIONS: SFNRT in low- and middle-income countries reduces early neonatal mortality, but its effects on birth asphyxia and neurodevelopmental outcomes remain uncertain. Follow-up studies suggest normal neurodevelopment in resuscitation survivors. PMID- 27222261 TI - Outcomes of Vascular Access Care and Surgery Managed by Interventional Nephrologists: A Twelve-Year Experience. AB - BACKGROUND: Optimizing vascular access outcomes is still a challenge, since 30 60% of arteriovenous fistulas fail or do not mature and catheters are widely used in contemporary patients. METHODS: This study reports on strategies and outcomes in a single center in which access planning, surgery and maintenance are managed by a team of nephrologists. We retrospectively analyzed 305 fistulas and 61 grafts created in 270 consecutive patients between 2002 and 2013. RESULTS: The percentage of patients receiving a fistula or graft who initiated hemodialysis with a mature access was 68.6%. Among prevalent patients, 71.7% used a fistula, 15.7% a graft and 12.6% a catheter. Rates of primary failure and revision before cannulation were 14.4 and 1.6% for fistulas vs. 4.9 and 3.3% for grafts. After maturation, complications (1.040 vs. 0.188 per patient-year (py)) and interventions (0.743 vs. 0.066 per py) were greater for grafts than for fistulas (p < 0.001). Secondary patency did not significantly differ between grafts and fistulas (median survival 34.8 vs. 57.3 months, p = 0.36), unless primary failures were excluded from Kaplan-Meier analysis (median survival 34.9 vs. 70.9 months, p = 0.03). CONCLUSIONS: High fistula prevalence, low access-related morbidity and catheter dependence were achieved using individualized strategies, including mid-forearm or perforating vein fistula creation and selective graft placement in high risk patients. Direct involvement of nephrologists throughout all steps of access care can improve access outcomes, by promoting a patient centered approach. PMID- 27222262 TI - The Broader Impact of Friend to Friend (F2F): Effects on Teacher-Student Relationships, Prosocial Behaviors, and Relationally and Physically Aggressive Behaviors. AB - Girls often harm others' social standing by starting rumors about peers or by excluding others from peer group activities, which is called relational aggression. Although relational aggression is not a new phenomenon, there have been relatively few interventions designed to address this, especially for urban ethnic minority girls. The Friend to Friend (F2F) program, developed through an iterative participatory action research process, has proven to be effective in improving targeted relationally aggressive urban girls' social problem-solving knowledge and decreasing levels of relational aggression, with effects being maintained 1 year after treatment. In the current article, we examine the broader effects of the F2F program. Findings suggest that the indicated F2F program has broader effects such as increasing prosocial behaviors, decreasing relational and physical aggression, and improving teacher-student relationships among non targeted boys. In addition, the program demonstrated some effects for non targeted girls including an increase in prosocial behaviors and improved teacher student relationships. Implications for examining the cost-effectiveness of indicated interventions such as F2F are discussed. PMID- 27222263 TI - Sixty seconds on . . . gardening. PMID- 27222264 TI - Current Trends on Antipsychotics: Focus on Asenapine. AB - Over the years, both first- (FGAs) and second-generation antipsychotics (SGAs), continue to gain increasing evidence of being effective in the treatment of psychotic symptoms. Currently, they represent the first-line treatment of schizophrenia and bipolar disorder, although they are widely used in psychotic depression and other clinical conditions, such as agitation and/or behavioural disturbances. Despite representing an indispensable tool for the treatment of severe psychotic disorders, they are widely known to have a number of unwanted side effects that the clinician must be aware of, and handle carefully to provide the patient the best available treatment in the short and long-term. However, even with respect to the long-term use of some of the most effective SGAs, it is imperative for clinicians not to overlook the risk linked to the onset of potentially severe metabolic side effects such as weight gain, dyslipidaemia, insulinresistance and type II diabetes. Asenapine is one of the newest SGAs licenced in Europe for the treatment of manic episodes and in the US for schizophrenia. It belongs to the same class of clozapine, olanzapine and quetiapine, sharing with them a rather complex pharmacological binding profile. In fact, asenapine shows a high affinity for the serotonin (5HT) receptor of the type 2A (5HT2A) and to a lesser extent for the dopamine receptor of the type 2 (D2), similar to other SGAs. Asenapine behaves also as an antagonist at the level of 5HT2C, H1 and alpha2-receptors. Asenapine has been reported to be effective either in monotherapy or in combination with mood stabilers (lithium and valproate) in the treatment of manic or mixed episodes, with a lower propensity to induce, or being followed by, depressive symptoms, when compared to other SGAs. These unique properties may explain the increasing interest towards the use of this drug in mixed states, besides schizophrenia and acute mania. The aim of this paper was at reviewing current data on pharmacological properties and clinical use of asenapine, as well as on possible future indication of this SGA. PMID- 27222265 TI - From Bone Marrow to Cardiac Atrial Appendage Stem Cells for Cardiac Repair: A Review. AB - Traditionally the heart is considered a terminally differentiated organ. However, at the beginning of this century increased mitotic activity was reported in ischemic and idiopathic dilated cardiomyopathy hearts, compared to healthy controls, underscoring the potential of regeneration after injury. Due to the presence of adult stem cells in bone marrow and their purported ability to differentiate into other cell lineages, this cell population was soon estimated to be the most suited candidate for cardiac regeneration. Clinical trials with autologous bone marrow-derived mononuclear cells, using either an intracoronary or direct intramyocardial injection approach consistently showed only minor improvement in global left ventricular ejection fraction. This was explained by their limited cardiomyogenic differentiation potential. To obtain more convincing improvement in cardiac function, based on true myocardial regeneration, the focus of research has shifted towards resident cardiac progenitor cells. Several isolation procedures have been described: the c-kit surface marker was the first to be used, however experimental research has clearly shown that c-kit+ cells only marginally contribute to regeneration post myocardial infarction. Sphere formation was used to isolate the so-called cardiosphere derived cells (CDC), and also in this cell population cardiomyogenic differentiation is a rare event. Recently a new type of stem cells derived from atrial tissue (cardiac atrial stem cells - CASCs) was identified, based on the presence of the enzyme aldehyde dehydrogenase (ALDH). Those cells significantly improve both regional and global LV ejection fraction, based on substantial engraftment and consistent differentiation into mature cardiomyocytes (98%). PMID- 27222266 TI - Adamantane - A Lead Structure for Drugs in Clinical Practice. AB - The adamantane moiety is the structural backbone of numerous compounds and its discovery launched a new field of chemistry studying the approaches to the synthesis as well as the physicochemical and biological properties of organic polyhedral compounds with practical application in the pharmaceutical industry. Adamantane derivatives have proven to be very potent compounds in a wide range of applications from systemic to topical therapy. This review summarizes the currently available adamantane derivatives in clinical practice (amantadine, memantine, rimantadine, tromantadine, adapalene, saxagliptin, vildagliptin), focusing on mechanisms of action, pharmacokinetics, pharmacodynamics and clinical trials. The adamantane-based compounds presented in this manuscript have been approved for a wide spectrum of indications (antivirals, antidiabetics and against Alzheimer's and Parkinson's disease). Each of the compounds proved to be of vital importance in their therapeutic indication for numerous patients worldwide. This review also considers the mechanisms of side effects to deliver a complete perspective on current treatment options. PMID- 27222267 TI - Antimicrobial Compounds from Marine Invertebrates-Derived Microorganisms. AB - It is known that marine invertebrates, including sponges, tunicates, cnidaria or mollusks, host affluent and various communities of symbiotic microorganisms. The microorganisms associated with the invertebrates metabolized various biologically active compounds, which could be an important resource for the discovery and development of potentially novel drugs. In this review, the new compounds with antimicrobial activity isolated from marine invertebrate-derived microorganisms in the last decade (2004-2014) will be presented, with focus on the relevant antimicrobial activities, origin of isolation, and information of strain species. New compounds without antimicrobial activity were not revealed. PMID- 27222268 TI - Tat-ATOX1 inhibits streptozotocin-induced cell death in pancreatic RINm5F cells and attenuates diabetes in a mouse model. AB - Antioxidant 1 (ATOX1) functions as an antioxidant against hydrogen peroxide and superoxide, and therefore may play a significant role in many human diseases, including diabetes mellitus (DM). In the present study, we examined the protective effects of Tat-ATOX1 protein on streptozotocin (STZ)-exposed pancreatic insulinoma cells (RINm5F) and in a mouse model of STZ-induced diabetes using western blot analysis, immunofluorescence staining and MTT assay, as well as histological and biochemical analysis. Purified Tat-ATOX1 protein was efficiently transduced into RINm5F cells in a dose- and time-dependent manner. Additionally, Tat-ATOX1 protein markedly inhibited reactive oxygen species (ROS) production, DNA damage and the activation of Akt and mitogen activated protein kinases (MAPKs) in STZ-exposed RINm5F cells. In addition, Tat-ATOX1 protein transduced into mice pancreatic tissues and significantly decreased blood glucose and hemoglobin A1c (HbA1c) levels as well as the body weight changes in a model of STZ-induced diabetes. These results indicate that transduced Tat-ATOX1 protein protects pancreatic beta-cells by inhibiting STZ-induced cellular toxicity in vitro and in vivo. Based on these findings, we suggest that Tat-ATOX1 protein has potential applications as a therapeutic agent for oxidative stress-induced diseases including DM. PMID- 27222269 TI - Antipsychotics decrease response confidence. AB - Antipsychotics represent the first-choice treatment for schizophrenia. However, the cognitive and emotional pathways through which symptom reduction is achieved have remained unclear. We recently proposed that the induction of doubt is a core mechanism of action of antipsychotics. In the framework of a randomized, double blind, placebo-controlled, crossover design, 39 nonclinical participants filled out a questionnaire tapping into cognitive and emotional changes (Effect of Antipsychotic Medication on Emotion and Cognition-revised (EAMEC-r)) each time they had received one of three substances (haloperidol, placebo, L-dopa). Participants reported more doubt under haloperidol than under L-dopa lending support to the theory that antipsychotics decrease delusional conviction via the reduction of confidence. Key points from this study are: (a) antipsychotics induce doubt, and (b) doubt may represent a core mechanism of action for the reduction of delusional ideas. PMID- 27222270 TI - Mineralocorticoid receptor haplotype moderates the effects of oral contraceptives and menstrual cycle on emotional information processing. AB - RATIONALE: The processing of emotional information is affected by menstrual cycle phase and by the use of oral contraceptives (OCs). The stress hormone cortisol is known to affect emotional information processing via the limbic mineralocorticoid receptor (MR). OBJECTIVES: We investigated in an exploratory study whether the MR genotype moderates the effect of both OC-use and menstrual cycle phase on emotional cognition. METHODS: Healthy premenopausal volunteers (n=93) of West European descent completed a battery of emotional cognition tests. Forty-nine participants were OC users and 44 naturally cycling, 21 of whom were tested in the early follicular (EF) and 23 in the mid-luteal (ML) phase of the menstrual cycle. RESULTS: In MR-haplotype 1/3 carriers, ML women gambled more than EF women when their risk to lose was relatively small. In MR-haplotype 2, ML women gambled more than EF women, regardless of their odds of winning. OC-users with MR haplotype 1/3 recognised fewer facial expressions than ML women with MR-haplotype 1/3. CONCLUSION: MR-haplotype 1/3 carriers may be more sensitive to the influence of their female hormonal status. MR-haplotype 2 carriers showed more risky decision-making. As this may reflect optimistic expectations, this finding may support previous observations in female carriers of MR-haplotype 2 in a naturalistic cohort study. PMID- 27222271 TI - Pharmacokinetics, pharmacodynamics and safety of CEP-26401, a high-affinity histamine-3 receptor antagonist, following single and multiple dosing in healthy subjects. AB - CEP-26401 is a novel orally active, brain-penetrant, high-affinity histamine H3 receptor (H3R) antagonist, with potential therapeutic utility in cognition enhancement. Two randomized, double-blind, placebo-controlled dose escalation studies with single (0.02 to 5 mg) or multiple administration (0.02 to 0.5 mg once daily) of CEP-26401 were conducted in healthy subjects. Plasma and urine samples were collected to investigate CEP-26401 pharmacokinetics. Pharmacodynamic endpoints included a subset of tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and nocturnal polysomnography. Population pharmacokinetic-pharmacodynamic modeling was conducted on one CANTAB and one polysomnography parameter of interest. CEP-26401 was slowly absorbed (median tmax range 3-6 hours) and the mean terminal elimination half-life ranged from 24-60 hours. Steady-state plasma concentrations were achieved within six days of dosing. CEP-26401 exhibits dose- and time-independent pharmacokinetics, and renal excretion is a major elimination pathway. CEP-26401 had a dose-dependent negative effect on sleep, with some positive effects on certain CANTAB cognitive parameters seen at lower concentrations. The derived three compartment population pharmacokinetic model, with first-order absorption and elimination, accurately described the available pharmacokinetic data. CEP-26401 was generally well tolerated up to 0.5 mg/day with most common treatment related adverse events being headache and insomnia. Further clinical studies are required to establish the potential of low-dose CEP-26401 in cognition enhancement. PMID- 27222272 TI - Evaluation of renal cortical thickness by non-contrast-enhanced MR imaging with spatially selective IR pulses: comparison between cirrhotic and non-cirrhotic patients. AB - OBJECTIVE: To compare renal cortical thicknesses between patients with and without cirrhosis with normal renal function based on serum creatinine using non contrast-enhanced steady-state, free precession (SSFP) MRI with spatially selective inversion recovery (IR) pulses and to discuss the clinical implications of measuring renal cortical thickness in patients with cirrhosis. METHODS: 40 patients with and without cirrhosis who had normal renal function based on serum creatinine and underwent non-contrast-enhanced SSFP imaging with spatially selective IR pulses were included. The renal cortical thickness, renal width, renal cortical width ratio, serum creatinine levels and estimated glomerular filtration rates (eGFRs) were compared between cirrhotic and non-cirrhotic groups. RESULTS: The mean renal cortical thickness was significantly lower in the cirrhotic group (3.6 +/- 0.9 mm) than in the non-cirrhotic group (4.9 +/- 0.8 mm; p < 0.001). The mean renal cortical width ratio was significantly lower in the cirrhotic group (0.07 +/- 0.02) than in the non-cirrhotic group (0.10 +/- 0.02; p < 0.001). The mean serum creatinine and mean eGFR did not show significant differences between the two groups. CONCLUSION: Measurement of renal cortical thickness by means of non-contrast-enhanced SSFP MRI with spatially selective IR pulses may help evaluate renal function accurately in patients with cirrhosis, in whom it may be overestimated by serum creatinine and eGFR. ADVANCES IN KNOWLEDGE: (1) The renal corticomedullary junction was clearly depicted by non-contrast enhanced SSFP MRI with spatially selective IR pulses in all patients with and without cirrhosis. (2) The mean renal cortical thickness measured on the optimal SSFP image with spatially selective IR pulses was significantly lower in the cirrhotic group (3.6 +/- 1.0 mm) than in the non-cirrhotic group (4.9 +/- 0.8 mm) (p < 0.001), although the mean eGFR did not show a significant difference between the two groups. PMID- 27222273 TI - In vivo morphological and functional evaluation of the lateral pterygoid muscle: a diffusion tensor imaging study. AB - OBJECTIVE: To explore the feasibility of morphological and functional evaluation of the lateral pterygoid muscle (LPM) by diffusion tensor imaging (DTI) in vivo. METHODS: 30 healthy volunteers underwent DTI with the jaw in the rest position, opening and clenching. Diffusion parameters of the superior head of the LPM (SHLP) and the inferior head of the LPM (IHLP) at different jaw positions were calculated. RESULTS: When the jaw was in the rest position, lambda3 of the SHLP was significantly lower than that of the IHLP; fractional anisotropy (FA) value of the SHLP was significant higher than that of the IHLP. There was no significant difference in lambda1, lambda2 and apparent diffusion coefficient (ADC) value. During jaw opening, there was significant increase of all three eigenvalues and ADC value, and significant decrease of FA value both at the SHLP and IHLP. Clenching caused a significant increase in the ADC and all three eigenvalues, and caused a significant decrease of FA at the SHLP. However, at the IHLP, the variations of all diffusion parameters by clenching in the intercuspal position showed no significance when compared with those at rest. CONCLUSION: The morphological and functional changes of LPM fibres caused by jaw movements could be sensitively detected by DTI which may serve as a new and non-invasive method for simultaneously investigating the functional and morphological features of the LPM during jaw movement. ADVANCES IN KNOWLEDGE: A new application of DTI is proposed for the morphological and functional evaluation of the LPMs. The results show that the significant change of three eigenvalues indicates the activity of the LPM in a specific jaw movement, a finding that shows the potential value of DTI serving as a new and non-invasive method for investigation of the LPM. PMID- 27222275 TI - Orthopaedic and non-orthopaedic applications of a single-energy iterative metal artefact reduction technique and other metal artefact reduction techniques explained. AB - Metal within the CT field of view causes artefact that degrades the diagnostic quality of the processed images. This is related to the high atomic number of most metals and is due to a combination of beam hardening, scatter, edge effects and photon starvation. Both software and hardware metal artefact reduction (MAR) techniques have been developed. Iterative reconstruction software MAR techniques can be applied on raw CT data sets and show improved image quality in the setting of sparse projection data when compared with filtered back-projection methods. Recently, a novel single-energy iterative metal artefact reduction technique (IMART) was released for use with large orthopaedic devices. The aim of this pictorial essay was to demonstrate the usefulness of IMART in the setting of both orthopaedic and non-orthopaedic metallic objects and devices. PMID- 27222274 TI - 123I-MIBG myocardial scintigraphy for the evaluation of Lewy body disease: are delayed images essential? Is visual assessment useful? AB - OBJECTIVE: We performed 123I-meta-iodobenzylguanidine (123I-MIBG) myocardial scintigraphy for the diagnosis of Lewy body disease (LBD) and assessed whether the early heart-to-mediastinum (H/M) ratio was diagnostic and whether visual image analysis was useful. METHODS: Our study included 453 patients with clinically suspected LBD who had undergone 123I-MIBG myocardial scintigraphy. We evaluated semi-quantitative values (early and delayed H/M ratio, washout rate) and performed visual image analysis. The sensitivity, specificity, accuracy, positive-predictive value (PPV) and negative-predictive value (NPV) of both analyses were calculated. RESULTS: The early H/M ratio exhibited the best diagnostic ability. Its overall sensitivity, specificity, accuracy, PPV and NPV were 72.2%, 93.1%, 84.3%, 88.5% and 82.2%, respectively (cut-off value 2.2 or less). However, there was no significant difference from the delayed H/M ratio or the results of visual assessment. CONCLUSION: 123I-MIBG myocardial scintigraphy accurately differentiates between patients with and without LBD and a correct diagnosis can be established based on the early H/M ratio. We also document that visual evaluation of scintigrams is useful. Therefore, patients may benefit from the single performance of the procedure because a correct diagnosis can be obtained early in the disease process and their prognosis and appropriate treatment can be determined. ADVANCES IN KNOWLEDGE: 123I-MIBG myocardial scintigraphy on the early H/M ratio makes it possible to differentiate between patients with LBD and patients without LBD. PMID- 27222276 TI - Intraventricular thrombolysis after endovascular treatment of a ruptured arteriovenous malformation. AB - Intraventricular haemorrhage (IVH) secondary to arteriovenous malformation (AVM) rupture carries significant morbidity and mortality. External ventricular drainage of IVH is frequently complicated by thrombus formation within the ventricular catheter and therefore often unsuccessful at treating hydrocephalus in this setting. Intraventricular administration of recombinant tissue-type plasminogen activator (rtPA) has proved successful in the treatment of spontaneous panventricular haemorrhage. However, usage of rtPA is contraindicated in the setting of a ruptured AVM or aneurysm in which the bleeding source has not been secured. There are only a few reports of intraventricular thrombolysis in the treatment of IVH from AVM rupture. We present the case of successful application of rtPA to treat IVH after endovascularly securing the haemorrhage site of the AVM. Intraventricular thrombolysis remains an option for the treatment of IVH in the setting of AVM rupture and should be considered on a case by-case basis. PMID- 27222277 TI - Inverse psoriasis treated with ustekinumab. AB - Inverse psoriasis is characterised by the involvement of flexural skin folds. This form of psoriasis has distinct clinical and therapeutic features. This report refers to the case of a 48-year-old Caucasian man who was observed in our department, with a clinically and biopsy proven diagnosis of inverse psoriasis. For 2 years, the patient was treated with different combinations of corticosteroids, vitamin D analogues and methotrexate, with no satisfactory response. Given the lack of a clinical response and comorbidities, latent tuberculosis was excluded, and we started treatment with ustekinumab. We chose this biological agent because the patient was a long-distance truck driver and refused the possibility of autoinjections. The patient underwent three ustekinumab injections, which resulted in significant improvement of pruritus, erythaematous lesions and quality of life. PMID- 27222278 TI - Gastropancreatic fistula in a patient with chronic pancreatitis and IPMN. PMID- 27222279 TI - Cough-induced hemiparesis: an unusual manifestation of cord compression. PMID- 27222281 TI - Laparoscopic transgastric resection of a large pedunculated gastric lipoma. AB - Large gastric lipomas are a rare condition. They are often asymptomatic but may present with upper gastrointestinal bleeding or gastric outlet obstruction. We describe the case of a 52-year-old woman with a large gastric lipoma presenting with pain due to intermittent prolapse through the pylorus. The patient was treated using a novel approach of laparoscopic transgastric resection and was discharged on postoperative day 3. She suffered no complication and her histology confirmed a gastric lipoma with clear surgical margins. PMID- 27222280 TI - Eosinophilic cholecystitis with common bile duct stricture: a rare disease. AB - Although the most common cause of cholecystitis is gallstones, other conditions may present as acute cholecystitis. We describe a case of eosinophilic cholecystitis with common bile duct stricture. A 36-year-old woman initially had generalised abdominal pain and peripheral eosinophilia. Diagnostic laparoscopy showed eosinophilic ascites and necrotic nodules on the posterior abdominal wall. She was treated with anthelminthics on presumption of toxacara infection based on borderline positivity of serological tests. She later presented with acute cholecystitis and had a cholecystectomy and choledocotomy. Day 9 T-tube cholangiogram showed irregular narrowing of the distal common bile duct. The patient's symptoms were improved with steroids and the T-tube was subsequently removed. PMID- 27222282 TI - Yield of a second screening colonoscopy 10 years after an initial negative examination in average-risk individuals. AB - BACKGROUND AND AIMS: Current guidelines recommend screening colonoscopy at 10 year intervals in average-risk individuals who had baseline screening colonoscopy (no polyps or only hyperplastic polyps <=5 mm in the recto-sigmoid colon), but the yield of repeat screening at 10 years is unknown. Our aim was to describe the yield of second screening colonoscopy in average-risk individuals performed at least 8 years after a first screening colonoscopy had shown no polyps or only distal hyperplastic polyps <=5 mm in size. METHODS: This was a review of a database for colonoscopies performed at Indiana University Hospital between January 1999 and November 2015. RESULTS: A total of 4463 individuals underwent screening colonoscopy between January 1999 and July 2007, of which 1566 individuals had no polyps, and 334 individuals had only distal hyperplastic polyps <=5 mm; 378 individuals (58.4% female) had follow-up screening at least 8 years after the baseline screening examination, with a mean (+/- standard deviation [SD]) interval of 9.74 years (+/- 1.2 years; range 8-15 years). Mean (+/- SD) age at baseline screening examination was 56.7 years (+/- 5.5 years) and at follow-up screening examination was 66.4 years (+/- 5.6 years). At the second screening, there were 224 patients (59.3%) with at least 1 polyp, including 144 (38.1%) with at least 1 conventional adenoma. The adenoma detection rate at the second screening examination was 36.1% and 56.8% in the groups with no polyp at baseline and with only distal hyperplastic polyps, respectively. There were 15 advanced neoplasms in 13 individuals (3.4%), of which 12 lesions were proximal to the sigmoid colon. There were no cancers at follow-up. CONCLUSIONS: Among individuals aged >=50 years, with normal baseline screening colonoscopy results, the incidence of advanced lesions at a second screening colonoscopy at least 8 years later was comparable to that in baseline screening studies. Our findings support current recommendations for screening at 10-year intervals in average risk individuals. PMID- 27222283 TI - The effect of acidic pH and presence of metals as parameters in establishing a sulfidogenic process in anaerobic reactor. AB - The successful use of anaerobic reactors for bioremediation of acid mine drainage has been shown in systems with neutral pH. However, the choice of an efficient and suitable process for such wastewater must consider the capability of operating at acidic pH and in the presence of metals. This work studies the performance of an anaerobic batch reactor, under conditions of varying initial pH for its efficiencies in sulfate removal and metal precipitation from synthetic acid mine drainage. The chemical oxygen demand/sulfate (COD/SO4(2-)) ratio used was 1.00, with ethanol chosen as the only energy and carbon source. The initial pH of the synthetic drainage was progressively set from 7.0 to 4.0 to make it as close as possible to that of real acid mine drainage. Metals were also added starting with iron, zinc, and finally copper. The effectiveness of sulfate and COD removal from the synthetic acid mine drainage increased as the initial pH was reduced. The sulfate removal increased from 38.5 +/- 3.7% to 52.2 +/- 3%, while the removal of organic matter started at 91.7 +/- 2.4% and ended at 99 +/- 1%. These results indicate that the sulfate reducing bacteria (SRB) community adapted to lower pH values. The metal removal observed was 88 +/- 7% for iron, 98.0 +/- 0.5% for zinc and 99 +/- 1% for copper. At this stage, an increase in the sulfate removal was observed, which reaches up to 82.2 +/- 5.8%. The kinetic parameters for sulfate removal were 0.22 +/- 0.04 h(-1) with Fe, 0.26 +/- 0.04 h(-1) with Fe and Zn and 0.44 +/- 0.04 h(-1) with Fe, Zn, and Cu. PMID- 27222284 TI - Composite HPMC and sodium alginate based buccal formulations for nicotine replacement therapy. AB - Smoking cessation is of current topical interest due to the significant negative health and economic impact in many countries. This study aimed to develop buccal films and wafers comprising HPMC and sodium alginate (SA) for potential use in nicotine replacement therapy via the buccal mucosa, as a cheap but effective alternative to currently used nicotine patch and chewing gum. The formulations were characterised using texture analyser (tensile and hardness, mucoadhesion), scanning electron microscopy, X-ray diffractometry, attenuated total reflection Fourier transform infrared (ATR-FTIR), differential scanning calorimetry (DSC) and swelling capacity. Drug loaded films and wafers were characterised for content uniformity (HPLC) whilst the drug loaded wafers only were further characterised for in vitro drug dissolution. SA modified and improved the functional properties of HPMC at optimum ratio of HPMC: SA of 1.25: 0.75. Generally, both films and wafers (blank and drug loaded) were amorphous in nature which impacted on swelling and mucoadhesive performance. HPMC-SA composite wafers showed a porous internal morphology with higher mucoadhesion, swelling index and drug loading capacity compared to the HPMC-SA composite films which were non porous. The study demonstrates the potential use of composite HPMC-SA wafers in the buccal delivery nicotine. PMID- 27222285 TI - Hypromellose succinate-crosslinked chitosan hydrogel films for potential wound dressing. AB - The objective of this study was to develop novel hydrogel films based on carboxyl modified hypromellose-crosslinked chitosan for potential wound dressing. Hypromellose (HPMC) was grafted with succinic acid to yield hypromellose succinate (HPMCS), and then the reinforced hydrogel films of HPMCS-crosslinked chitosan (HPMCS-CS) were prepared through amide bond formation using 1-ethyl-3-(3 dimethylaminopropyl)carbodiimide (EDC) and N- hydroxysuccinimide (NHS) as a catalyst. Compared to that of blend film, mechanical properties of HPMCS-CS hydrogel films were significantly enhanced both in dry and swollen state. To assess the applicability of HPMCS-CS hydrogel films as wound dressing, the swelling behavior, water vapor transmission rate (WVTR), oxygen permeability, biocompatibility (cytotoxicity and hemolysis), in vitro drug release and bactericidal properties were analyzed. The results indicated that HPMCS-CS hydrogel films with good biocompatibility possess high swelling ratio, proper WVTR, and oxygen permeability, which might accelerate tissue regeneration. Meanwhile, gentamycin sulfate release from drug-loaded HPMCS-CS hydrogel films were sustained, which would help to protect wound from infection. PMID- 27222286 TI - Structural dynamics of a single-chain Fv antibody against (4-hydroxy-3 nitrophenyl)acetyl. AB - Protein structure dynamics are critical for understanding structure-function relationships. An antibody can recognize its antigen, and can evolve toward the immunogen to increase binding strength, in a process referred to as affinity maturation. In this study, a single-chain Fv (scFv) antibody against (4-hydroxy-3 nitrophenyl)acetyl, derived from affinity matured type, C6, was designed to comprise the variable regions of light and heavy chains connected by a (GGGGS)3 linker peptide. This scFv was expressed in Escherichia coli in the insoluble fraction, solubilized in the presence of urea, and refolded by stepwise dialysis. The correctly refolded scFv was purified, and its structural, physical, and functional properties were analyzed using analytical ultracentrifugation, circular dichroism spectrometry, differential scanning calorimetry, and surface plasmon resonance biosensor. Thermal stability of C6 scFv increased greatly upon antigen binding, due to favorable enthalpic contributions. Antigen binding kinetics were comparable to those of the intact C6 antibody. Structural dynamics were analyzed using the diffracted X-ray tracking method, showing that fluctuations were suppressed upon antigen binding. The antigen binding energy determined from the angular diffusion coefficients was in good agreement with that calculated from the kinetics analysis, indicating that the fluctuations detected at single-molecule level are well reflected by antigen binding events. PMID- 27222287 TI - G-protein coupling and nuclear translocation of the human abscisic acid receptor LANCL2. AB - Abscisic acid (ABA), a long known phytohormone, has been recently demonstrated to be present also in humans, where it targets cells of the innate immune response, mesenchymal and hemopoietic stem cells and cells involved in the regulation of systemic glucose homeostasis. LANCL2, a peripheral membrane protein, is the mammalian ABA receptor. We show that N-terminal glycine myristoylation causes LANCL2 localization to the plasmamembrane and to cytoplasmic membrane vesicles, where it interacts with the alpha subunit of a Gi protein and starts the ABA signaling pathway via activation of adenylate cyclase. Demyristoylation of LANCL2 by chemical or genetic means triggers its nuclear translocation. Nuclear enrichment of native LANCL2 is also induced by ABA treatment. Therefore human LANCL2 is a non-transmembrane G protein-coupled receptor susceptible to hormone induced nuclear translocation. PMID- 27222288 TI - Unmasking immune reconstitution inflammatory syndrome: a report of tuberculous epididymo-orchitis mimicking a testicular tumour in a Caucasian AIDS patient. AB - Worldwide, it is estimated that 14.8% of all new tuberculosis cases in adults are attributable to HIV infection. Genitourinary tuberculosis is a known complication and is considered to be a severe form of extrapulmonary tuberculosis. Isolated tuberculous epididymo-orchitis is rare. We report a Caucasian HIV-positive heterosexual male with a clinical diagnosis of testicular tumour for which he underwent a right orchidectomy. Tuberculous epididymo-orchitis was confirmed by histology. In this case, all Immune Reconstitution Inflammatory Syndrome (IRIS) criteria were met. We want to convey the message that in HIV-positive patients presenting with testicular swelling, an infective aetiology should be considered. This will increase the possibility of early diagnosis and proper management. PMID- 27222289 TI - Clinical utility gene card for: Wolfram syndrome. PMID- 27222290 TI - A non-coding variant in the 5' UTR of DLG3 attenuates protein translation to cause non-syndromic intellectual disability. AB - Intellectual disability (ID) is a clinically complex and heterogeneous disorder, which has variable severity and may be associated with additional dysmorphic, metabolic, neuromuscular or psychiatric features. Although many coding variants have been implicated in ID, identification of pathogenic non-coding regulatory variants has only been achieved in a few cases to date. We identified a duplication of a guanine on chromosome X, NC_000023.10:g.69665044dupG 7 nucleotides upstream of the translational start site in the 5' untranslated region (UTR) of the known ID gene DLG3 that encodes synapse-associated protein 102 (SAP102). The dupG variant segregated with affected status in a large multigenerational family with non-syndromic X-linked ID and was predicted to disrupt folding of the mRNA. When tested on blood cells from the affected individuals, DLG3 mRNA levels were not altered, however, DLG3/SAP102 protein levels were. We also showed by dual luciferase reporter assay that the dupG variant interfered with translation. All currently known pathogenic DLG3 variants are predicted to be null, however the dupG variant likely leads to only a modest reduction of SAP102 levels accounting for the milder phenotype seen in this family. PMID- 27222291 TI - The risk of re-identification versus the need to identify individuals in rare disease research. AB - There is a growing concern in the ethics literature and among policy makers that de-identification or coding of personal data and biospecimens is not sufficient for protecting research subjects from privacy invasions and possible breaches of confidentiality due to the possibility of unauthorized re-identification. At the same time, there is a need in medical science to be able to identify individual patients. In particular for rare disease research there is a special and well documented need for research collaboration so that data and biosamples from multiple independent studies can be shared across borders. In this article, we identify the needs and arguments related to de-identification and re identification of patients and research subjects and suggest how the different needs may be balanced within a framework of using unique encrypted identifiers. PMID- 27222292 TI - Identification of variants in MBNL1 in patients with a myotonic dystrophy-like phenotype. AB - The myotonic dystrophies (DMs) are the most common inherited muscular disorders in adults. In most of the cases, the disease is caused by (CTG)n/(CCTG)n repeat expansions (EXPs) in non-coding regions of the genes DMPK (dystrophia myotonica protein kinase) and CNBP (CCHC-type zinc-finger nucleic acid-binding protein). The EXP is transcribed into mutant RNAs, which provoke a common pathomechanism that is characterized by misexpression and mis-splicing. In this study, we screened 138 patients with typical clinical features of DM being negative for EXP in the known genes. We sequenced DMPK and CNBP - associated with DM, as well as CELF1 (CUGBP, Elav-like family member 1) and MBNL1 (muscleblind-like splicing regulator 1) - associated with the pathomechanism of DM, for pathogenic variants, addressing the question whether defects in other genes could cause a DM-like phenotype. We identified variants in three unrelated patients in the MBNL1 gene, two of them were heterozygous missense mutations and one an in-frame deletion of three amino acids. The variants were located in different conserved regions of the protein. The missense mutations were classified as potentially pathogenic by prediction tools. Analysis of MBNL1 splice target genes was carried out for one of the patients using RNA from peripheral blood leukocytes (PBL). Analysis of six genes known to show mis-splicing in the skeletal muscle gave no informative results on the effect of this variant when tested in PBL. The association of these variants with the DM phenotype therefore remains unconfirmed, but we hope that in view of the key role of MBNL1 in DM pathogenesis our observations may foster further studies in this direction. PMID- 27222294 TI - The long N-terminus of the human monocarboxylate transporter 8 is a target of ubiquitin-dependent proteasomal degradation which regulates protein expression and oligomerization capacity. AB - Monocarboxylate transporter 8 (MCT8) equilibrates thyroid hormones between the extra- and the intracellular sides. MCT8 exists either with a short or a long N terminus, but potential functional differences between both variants are yet not known. We, therefore, generated MCT8 constructs which are different in N-terminal length: MCT8(1-613), MCT8(25-613), MCT8(49-613) and MCT8(75-613). The M75G substitution prevents translation of MCT8(75-613) and ensures expression of full length MCT8 protein. The K56G substitution was made to prevent ubiquitinylation. Cell-surface expression, localization and proteasomal degradation were investigated using C-terminally GFP-tagged MCT8 constructs (HEK293 and MDCK1 cells) and oligomerization capacity was determined using N-terminally HA- and C terminally FLAG-tagged MCT8 constructs (COS7 cells). MCT8(1-613)-GFP showed a lower protein expression than the shorter MCT8(75-613)-GFP protein. The proteasome inhibitor lactacystin increased MCT8(1-613)-GFP protein amount, suggesting proteasomal degradation of MCT8 with the long N-terminus. Ubiquitin conjugation of MCT8(1-613)-GFP was found by immuno-precipitation. A diminished ubiquitin conjugation caused by K56G substitution resulted in increased MCT8(1 613)-GFP protein expression. Sandwich ELISA was performed to investigate if the bands at higher molecular weight observed in Western blot analysis are due to MCT8 oligomerization, which was indeed shown. Our data imply a role of the long N terminus of MCT8 as target of ubiquitin-dependent proteasomal degradation affecting MCT8 amount and subsequently oligomerization capacity. PMID- 27222293 TI - Clinical and Molecular Aspects of MBD5-Associated Neurodevelopmental Disorder (MAND). AB - MBD5-associated neurodevelopmental disorder (MAND) is an umbrella term that describes a group of disorders, 2q23.1 deletion syndrome, 2q23.1 duplication syndrome, and MBD5 variants, that affect the function of methyl-binding domain 5 (MBD5) and share a common set of neurodevelopmental, cognitive, and behavioral impairments. This review provides a comprehensive clinical and molecular synopsis of 2q23.1 deletion syndrome. Approaches to diagnosis, genetic counseling, and up to-date management are summarized, followed by a discussion of the molecular and functional role of MBD5. Finally, we also include a brief summary of MBD5 variants that affect function of MBD5 and 2q23.1 duplication syndrome. PMID- 27222295 TI - VLDL-activated cell signaling pathways that stimulate adrenal cell aldosterone production. AB - Aldosterone plays an important role in regulating ion and fluid homeostasis and thus blood pressure, and hyperaldosteronism results in hypertension. Hypertension is also observed with obesity, which is associated with additional health risks, including cardiovascular disease. Obese individuals have high serum levels of very low-density lipoprotein (VLDL), which has been shown to stimulate aldosterone production; however, the mechanisms underlying VLDL-induced aldosterone production are still unclear. Here we demonstrate in human adrenocortical carcinoma (HAC15) cells that submaximal concentrations of angiotensin II and VLDL stimulate aldosterone production in an additive fashion, suggesting the possibility of common mechanisms of action. We show using inhibitors that VLDL-induced aldosterone production is mediated by the PLC/IP3/PKC signaling pathway. Our results suggest that PKC is upstream of the extracellular signal-regulated kinase (ERK) activation previously observed with VLDL. An understanding of the mechanisms mediating VLDL-induced aldosterone production may provide insights into therapies to treat obesity-associated hypertension. PMID- 27222296 TI - Slice Encoding for Metal Artefact Correction in magnetic resonance imaging examinations for radiotherapy planning. AB - BACKGROUND AND PURPOSE: Magnetic resonance (MR) and computed tomography (CT) images are degraded in the presence of metallic implants. We investigate whether SEMAC (Slice Encoding for Metal Artifact Correction) MR is advantageous for radiotherapy (RT) planning. METHODS: Conventional and SEMAC MR protocols were compared (1.5T). A spine fixation device suspended in gelatine, two patients with spine fixation devices and six patients with bilateral hip replacements were scanned with both conventional and SEMAC protocols. In spine patients the visibility of the spinal canal and spinal cord was assessed; in prostate patients, the visibility of the prostate, pelvic structures and the pelvic girdle. RESULTS: The signal loss volume surrounding the spine fixation device was reduced by approximately 20% when the SEMAC protocol was employed, and registration errors were reduced. For spine patients, the spinal canal was completely visible only using the SEMAC protocol. In hip replacement patients, metal artifacts were local; the signal loss extended to the internal surface of the acetabulum in eight implants with conventional protocols, but only in four using SEMAC. CONCLUSIONS: SEMAC MR contributes towards correct co-registration of MR and CT images for RT planning, and is particularly relevant when the TV or OARs are close to implants. PMID- 27222297 TI - Two-dimensional in vivo rectal dosimetry using an endorectal balloon with unfoldable radiochromic film during prostate cancer radiotherapy. AB - BACKGROUND AND PURPOSE: The present study aims to investigate the feasibility of two-dimensional (2D) in vivo rectal dosimetry using an endorectal balloon for the radiotherapy of prostate cancer. MATERIALS AND METHODS: The endorectal balloon was equipped with an unfoldable radiochromic film. The film was unrolled as the balloon was inflated, and rolled as it was deflated. Its mechanical and imaging properties were tested, and the dosimetric effectiveness was evaluated in clinical photon and proton beams. RESULTS: The size of the endorectal balloon including the film was linearly proportional to the volume of water filled in the balloon, and its position could be identified by X-ray radiography. The loss of dose information due to film cutting was within +/-1mm from the cutting line. Applying linear interpolation on cut film, the gamma passing rate was more than 95% for 2%/2mm criteria. The measured dose profiles agreed with the plan within 3% and 4% for the photon and proton beams, respectively. A dose-volume histogram of the anterior rectal wall could be obtained from the measured dose distribution in the balloon, which also agreed well with the plan. CONCLUSIONS: 2D in vivo rectal dosimetry is feasible using the endorectal balloon with a radiochromic film in the radiotherapy of prostate cancer. PMID- 27222298 TI - A Case of Auricular Pseudocyst. AB - BACKGROUND: Auricular pseudocyst is a rare, asymptomatic, cystic-like swelling of the auricle that may pose a diagnostic challenge to the clinician. If inadequately treated, recurrences and ear deformities may ensue. OBJECTIVE: The authors present a case of auricular pseudocyst in a previously healthy 43-year old man. Aetiologies, histology, differential diagnosis, and treatment modalities are discussed. PMID- 27222299 TI - Estimating the risks and benefits of active surveillance protocols for prostate cancer: a microsimulation study. AB - OBJECTIVE: To estimate the increase in prostate cancer mortality (PCM) and the reduction in overtreatment resulting from different active surveillance (AS) protocols, compared with treating men immediately. PATIENTS AND METHODS: We used a microsimulation model (MISCAN-Prostate), with the natural history of prostate cancer based on European Randomized Study of Screening for Prostate Cancer data. We estimated the probabilities of referral to radical treatment while on AS, depending on disease stage, using data from the Johns Hopkins AS cohort. We sampled 10 million men, representative of the US population, and projected the effects of applying AS protocols that differed by time between biopsies and compared these with the effects of treating men immediately. RESULTS: We found that AS with yearly follow-up biopsies for men with low-risk prostate cancer (<= T2a stage and Gleason 6) increases the probability of PCM to 2.6% (1% increase) and reduces overtreatment from 2.5 to 2.1% (18.4% reduction). With biopsies every 3 years after the first year, PCM increases by 2.3% and overtreatment reduces from 2.5 to 1.9% (30.3% reduction). The inclusion of men in the intermediate-risk group (> T2a stage or Gleason 3+4) in AS protocols increases PCM by 2.7% and reduces overtreatment from 2.5 to 2.0% (23.1% reduction). These results may not apply to African-American men. CONCLUSIONS: Offering AS to men with low-risk prostate cancer is relatively safe. Increasing the biopsy interval from yearly to up to every 3 years after the first year will significantly reduce overtreatment among men in the low-risk group, with limited PCM risk. PMID- 27222300 TI - Race, Exclusionary Discipline, and Connectedness to Adults in Secondary Schools. AB - This study examines racial differences in students' connectedness to school adults and considers the possibility that disparities in exclusionary discipline practices may reduce all students' sense of connection to educators, not just those who have been disciplined or are from racial groups overrepresented in out of-school suspensions. Data sources include a self-report survey of secondary school students (n = 29,148) linked to administrative data (n = 107 schools) from a large urban district. Multilevel modeling techniques were used to estimate the relationships between students' racial background, youths' connection to school adults, and school-level racial discipline gaps. Controlling for school racial composition, gender, grade level and other covariates, students of color were significantly less likely to feel connected to school adults than their White peers. Additionally, the racial discipline gap was significantly and negatively associated with connectedness for all students. Results indicate that strategies to improve educational outcomes for youth of color need to attend to relational dynamics between students and school adults. Research findings also suggest that efforts to reduce discipline disparities may improve all students' connectedness. PMID- 27222301 TI - Thermodynamic study of the complexation between Nd(3+) and functionalized diacetamide ligands in solution. AB - A series of amine functionalized ligands, including 2,2' (benzylazanediyl)bis(N,N'-dimethylacetamide) (BnABDMA), 2,2'-azanediylbis(N,N' dimethylacetamide) (ABDMA), and 2,2'-(methylazanediyl)bis(N,N'-dimethylacetamide) (MABDMA), are synthesized for the thermodynamic study of their complexation with Nd(3+) ions. Their complexation in solution is investigated using potentiometry, spectrophotometry, calorimetry, and electrospray ionization mass spectrometry. The results suggest that these ligands act as tridentate ligands. Furthermore, direct comparison between ABDMA and an analogous ether-functionalized ligand, 2,2'-oxybis(N,N'-dimethylacetamide) (TMDGA), showed that the amine functionalized ligand forms thermodynamically stronger complexes with Nd(3+) ions than the ether functionalized ligand. In addition, the amine functionalized ligand can allow the fine-tuning of the binding strength with metal ions via substitution on the central amine N atom with different functional groups, which is not possible for ether functionalized ligands such as TMDGA. PMID- 27222302 TI - Perihematomal Diffusion Restriction in Intracerebral Hemorrhage Depends on Hematoma Volume, But Does Not Predict Outcome. AB - BACKGROUND: Perihematomal diffusion restriction (PDR) is a frequent finding in primary intracerebral hemorrhage (ICH) on diffusion-weighted MRI. Its frequency, associated clinical and imaging findings and impact on clinical outcome are not well understood. METHODS: This is a retrospective single-center analysis of 172 patients with primary ICH who received MRI within 24 h from symptom onset. PDR was defined as a reduction of apparent diffusion coefficient below 550 * 10-6 mm2/s. Multivariate regression analyses were used to assess independent imaging and clinical predictors of PDR. Clinical outcome was assessed using the modified Rankin scale (mRS) at discharge. RESULTS: PDR was present in 88 patients (51.2%). Median PDR volume was 1.1 ml (interquartile range 0.2-4.2). Multivariate analyses identified hematoma volume as the key independent predictor of PDR. The volume of perihematomal edema, lobar hematoma location and low diastolic blood pressure at admission were further predictors. Although the occurrence of PDR correlated with in-hospital mortality (75.0 vs. 43.4%, p < 0.001) and moderately severe to severe disability or death at discharge (mRS >=4; 56.4 vs. 27.8%, p = 0.002), PDR was not an independent predictor of clinical outcome. In contrast, hematoma volume, ventricular extension of hemorrhage and higher age independently predicted an adverse clinical outcome. CONCLUSIONS: PDR is common after primary ICH within 24 h of symptom onset. Hematoma volume was identified as the key predictor of PDR. Although PDR was associated with mortality and severe disability, this effect was confounded by established risk factors. These results do not support a role of early PDR as prognostic factor after ICH independent of hematoma volume. PMID- 27222303 TI - A new family-3 glycoside hydrolase from Penicillium oxalicum BL 3005 catalyzing tyrosol glucosylation to form salidroside. AB - A glycoside hydrolase from Penicillium oxalicum BL 3005 was purified to apparent homogeneity. Its molecular mass was estimated to be 90 kDa by SDS-PAGE. The enzyme was identified to be a new member of family-3 by peptide sequence. High transglycosylation activity was found in the hydrolytic reaction of cellobiose. In the reaction, salidroside (4-hydroxyphenethyl O-beta-d-glucopyranoside) was formed by adding tyrosol as the glycosyl acceptor. The optimum reaction pH and temperature were pH 6.5 and 55 degrees C, respectively. The maximum yield of salidroside was almost 20 g/L. These results indicated that the beta-glucosidase of P. oxalicum can be considered as a very promising catalyst for the synthesis of salidroside. PMID- 27222304 TI - FAM83H and casein kinase I regulate the organization of the keratin cytoskeleton and formation of desmosomes. AB - FAM83H is essential for the formation of dental enamel because a mutation in the FAM83H gene causes amelogenesis imperfecta (AI). We previously reported that the overexpression of FAM83H often occurs and disorganizes the keratin cytoskeleton in colorectal cancer cells. We herein show that FAM83H regulates the organization of the keratin cytoskeleton and maintains the formation of desmosomes in ameloblastoma cells. FAM83H is expressed and localized on keratin filaments in human ameloblastoma cell lines and in mouse ameloblasts and epidermal germinative cells in vivo. FAM83H shows preferential localization to keratin filaments around the nucleus that often extend to cell-cell junctions. Alterations in the function of FAM83H by its overexpression, knockdown, or an AI-causing truncated mutant prevent the proper organization of the keratin cytoskeleton in ameloblastoma cells. Furthermore, the AI-causing mutant prevents desmosomal proteins from being localized to cell-cell junctions. The effects of the AI-causing mutant depend on its binding to and possible inhibition of casein kinase I (CK-1). The suppression of CK-1 by its inhibitor, D4476, disorganizes the keratin cytoskeleton. Our results suggest that AI caused by the FAM83H mutation is mediated by the disorganization of the keratin cytoskeleton and subsequent disruption of desmosomes in ameloblasts. PMID- 27222305 TI - A Bayesian probit model with spatially varying coefficients for brain decoding using fMRI data. AB - Recent advances in human neuroimaging have shown that it is possible to accurately decode how the brain perceives information based only on non-invasive functional magnetic resonance imaging measurements of brain activity. Two commonly used statistical approaches, namely, univariate analysis and multivariate pattern analysis often lead to distinct patterns of selected voxels. One current debate in brain decoding concerns whether the brain's representation of sound categories is localized or distributed. We hypothesize that the distributed pattern of voxels selected by most multivariate pattern analysis models can be an artifact due to the spatial correlation among voxels. Here, we propose a Bayesian spatially varying coefficient model, where the spatial correlation is modeled through the variance-covariance matrix of the model coefficients. Combined with a proposed region selection strategy, we demonstrate that our approach is effective in identifying the truly localized patterns of the voxels while maintaining robustness to discover truly distributed pattern. In addition, we show that localized or clustered patterns can be artificially identified as distributed if without proper usage of the spatial correlation information in fMRI data. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27222306 TI - Dietary fats: debate should consider foods rather than nutrients. PMID- 27222307 TI - Unusual cytological features in multiple myeloma. PMID- 27222308 TI - Effectiveness of after-school interventions at increasing moderate-to-vigorous physical activity levels in 5- to 18-year olds: a systematic review and meta analysis. AB - AIM: Physical activity in children improves cardiovascular, mental, metabolic and skeletal health. Many children fail to meet the national recommendation of at least 60 min per day of moderate-to-vigorous physical activity (MVPA). After school programmes provide an opportunity to engage children in physical activity. This systematic review and meta-analysis examine the effectiveness of after school interventions at increasing MVPA levels in children and adolescents. DESIGN: Systematic review and meta-analyses. DATA SOURCES: A literature search was conducted using MEDLINE, EMBASE and PsychINFO databases from January 1950 to April 2015. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Inclusion criteria Population: participants aged 5-18 years. INTERVENTION: an after-school programme in a school-based setting as the main component of an intervention to increase physical activity levels. OUTCOMES: individual-level measure of time spent in MVPA. STUDY DESIGN: quasi-experimental, pilot, non-randomised or randomised trials. EXCLUSION CRITERIA: conference abstracts, unpublished articles, dissertations and non-English language papers. RESULTS: 1387 records were identified through database searching. After removal of duplicates, there were 748 records. 15 articles met the inclusion criteria for the systematic review. 6 studies were eligible for meta-analysis and the pooled intervention effect at end point follow-up was 4.84 min/day of MVPA (95% CI -0.94 to 10.61). The effectiveness of after-school interventions varied considerably and comparisons between studies limited by different methodological study designs. Subgroup analyses within a small minority of studies revealed significant benefits in overweight/obese children and boys. There was a lack of convincing evidence that interventions based on theories of behaviour change were more effective than those with no underlying theory. CONCLUSIONS: After-school physical activity interventions to date have had mixed effectiveness on increasing MVPA levels. More robust evaluations of extracurricular physical activity interventions are required, particularly studies that use objective assessment of physical activity. PMID- 27222309 TI - Are rolling averages a good way to assess training load for injury prevention? PMID- 27222310 TI - The origin of the abnormal muscle response seen in hemifacial spasm remains controversial. PMID- 27222311 TI - A Novel Pathway-Based Approach Improves Lung Cancer Risk Prediction Using Germline Genetic Variations. AB - BACKGROUND: Although genome-wide association studies (GWAS) have identified many genetic variants that are strongly associated with lung cancer, these variants have low penetrance and serve as poor predictors of lung cancer in individuals. We sought to increase the predictive value of germline variants by considering their cumulative effects in the context of biologic pathways. METHODS: For individuals in the Environment and Genetics in Lung Cancer Etiology study (1,815 cases/1,971 controls), we computed pathway-level susceptibility effects as the sum of relevant SNP variant alleles weighted by their log-additive effects from a separate lung cancer GWAS meta-analysis (7,766 cases/37,482 controls). Logistic regression models based on age, sex, smoking, genetic variants, and principal components of pathway effects and pathway-smoking interactions were trained and optimized in cross-validation and further tested on an independent dataset (556 cases/830 controls). We assessed prediction performance using area under the receiver operating characteristic curve (AUC). RESULTS: Compared with typical binomial prediction models that have epidemiologic predictors (AUC = 0.607) in addition to top GWAS variants (AUC = 0.617), our pathway-based smoking interactive multinomial model significantly improved prediction performance in external validation (AUC = 0.656, P < 0.0001). CONCLUSIONS: Our biologically informed approach demonstrated a larger increase in AUC over nongenetic counterpart models relative to previous approaches that incorporate variants. IMPACT: This model is the first of its kind to evaluate lung cancer prediction using subtype-stratified genetic effects organized into pathways and interacted with smoking. We propose pathway-exposure interactions as a potentially powerful new contributor to risk inference. Cancer Epidemiol Biomarkers Prev; 25(8); 1208 15. (c)2016 AACR. PMID- 27222312 TI - Intermolecular electron transfer states of 1-methyl-3-(N-(1,8 naphthalimidyl)ethyl)imidazolium iodide obtained by constrained density functional theory. AB - Electron transfer (ET) states of 1-methyl-3-(N-(1,8 naphthalimidyl)ethyl)imidazolium iodide are responsible for its photophysics. Investigation of an ET state based on constrained density functional theory (CDFT) revealed that nonradiative decay from the ET excited state is mediated by the interaction of the iodine atom with the 1,8-naphthalimide or the imidazolium group. PMID- 27222313 TI - Inhibition of Rac1 reduces store overload-induced calcium release and protects against ventricular arrhythmia. AB - Rac1 is a small GTPase and plays key roles in multiple cellular processes including the production of reactive oxygen species (ROS). However, whether Rac1 activation during myocardial ischaemia and reperfusion (I/R) contributes to arrhythmogenesis is not fully understood. We aimed to study the effects of Rac1 inhibition on store overload-induced Ca(2+) release (SOICR) and ventricular arrhythmia during myocardial I/R. Adult Rac1(f/f) and cardiac-specific Rac1 knockdown (Rac1(ckd) ) mice were subjected to myocardial I/R and their electrocardiograms (ECGs) were monitored for ventricular arrhythmia. Myocardial Rac1 activity was increased and ventricular arrhythmia was induced during I/R in Rac1(f/f) mice. Remarkably, I/R-induced ventricular arrhythmia was significantly decreased in Rac1(ckd) compared to Rac1(f/f) mice. Furthermore, treatment with Rac1 inhibitor NSC23766 decreased I/R-induced ventricular arrhythmia. Ca(2+) imaging analysis showed that in response to a 6 mM external Ca(2+) concentration challenge, SOICR was induced with characteristic spontaneous intracellular Ca(2+) waves in Rac1(f/f) cardiomyocytes. Notably, SOICR was diminished by pharmacological and genetic inhibition of Rac1 in adult cardiomyocytes. Moreover, I/R-induced ROS production and ryanodine receptor 2 (RyR2) oxidation were significantly inhibited in the myocardium of Rac1(ckd) mice. We conclude that Rac1 activation induces ventricular arrhythmia during myocardial I/R. Inhibition of Rac1 suppresses SOICR and protects against ventricular arrhythmia. Blockade of Rac1 activation may represent a new paradigm for the treatment of cardiac arrhythmia in ischaemic heart disease. PMID- 27222316 TI - Yifuning postpones ovarian aging through antioxidant mechanisms and suppression of the Rb/p53 signal transduction pathway. AB - Yifuning is a traditional Chinese medicine recipe that has been used for many years in China for its effects on treating climacteric syndrome in women. The present study aimed to demonstrate the effects and underlying molecular mechanism of Yifuning on the ovaries of aging rats. Selected aging rats were administered different doses of Yifuning (1.0 or 2.0 g/kg by lavage), and after 6 weeks the rats were sacrificed. The activit of indicators of oxidative stress in the serum were measured. The expression levels of 8-oxo-2'-deoxyguanosine (8-OHDG) and p53 in the ovaries were examined using immunohistochemistry. The expression levels of the corresponding genes and proteins were detected by reverse transcription quantitative polymerase chain reaction and western blotting analyses, respectively. The results indicated that Yifuning significantly prevented ovarian failure, as indicated by improvements in estrous cycling, reproductive organ weights and sex hormone serum levels. Yifuning significantly increased the levels of superoxide dismutase, glutathione peroxidase, catalase and reduced malondialdehyde and hydrogen peroxide levels. Yifuning reduced DNA damage in the ovaries by reducing the expression of 8-OHDG and p53. Treatment with Yifuning significantly reduced the age-induced p19, p53, p21 and Rb activity in the ovaries. The present study demonstrates that Yifuning prevents ovarian failure and the mechanism involved is partly associated with antioxidants and suppression of the Rb/p53 signal transduction pathway. PMID- 27222317 TI - Prognosis of patients with colonic carcinoma before, during and after implementation of complete mesocolic excision. AB - BACKGROUND: The implementation of complete mesocolic excision (CME) for colonic cancer was accompanied by other important changes, including more patients with early diagnosis by screening and the introduction of adjuvant chemotherapy in patients with stage III disease. The contribution of CME remains unclear. METHODS: In this observational study, data from patients with stage I-III colonic carcinoma were analysed by comparing five time intervals: 1978-1984 (pre-CME), 1985-1994 (CME development), 1995-2002 (CME implementation), 2003-2009 (CME) and 2010-2014 (CME), with a special focus on indicators of process and outcome quality. RESULTS: During the observed periods, the median age of patients increased (from 65 to 67 years), there were more right-sided carcinomas (from 17.0 to 32.4 per cent), more stage I disease (from 14.0 to 27.7 per cent) and fewer patients with regional lymph node metastases (from 42.7 to 32.0 per cent). The proportion of patients with pN0 disease and at least 12 examined regional lymph nodes increased (from 84.8 to 100 per cent) as did the R0 resection rate (from 97.0 to 100 per cent). Overall morbidity increased, whereas the in-hospital mortality rate was stable (range 1.8-3.7 per cent). Use of adjuvant chemotherapy in stage III colonic carcinoma increased from 0 to 79 per cent. The improvement in outcome quality was more evident in stage III than in stage I-II tumours. In stage III, the 5-year locoregional recurrence rate decreased from 14.8 to 4.1 per cent (P = 0.046) and the 5-year cancer-related survival rate increased from 61.7 to 80.9 per cent (P = 0.010). CONCLUSION: With CME, the quality indicators of process and outcome quality improved, especially in stage III colonic carcinoma. Adjuvant chemotherapy in stage III and multidisciplinary approaches in patients with metachronous distant metastases contributed to further outcome improvement. PMID- 27222318 TI - Incorporating a 3-dimensional printer into the management of early-stage cervical cancer. AB - We used a 3-dimensional (3D) printer to create anatomical replicas of real lesions and tested its application in cervical cancer. Our study patient decided to undergo radical hysterectomy after seeing her 3D model which was then used to plan and simulate this surgery. Using 3D printers to create patient-specific 3D tumor models may aid cervical cancer patients make treatment decisions. This technology will lead to better surgical and oncological outcomes for cervical cancer patients. J. Surg. Oncol. 2016;114:150-152. (c) 2016 Wiley Periodicals, Inc. PMID- 27222319 TI - Assessing the performance of mental health service facilities for meeting patient priorities and health service responsiveness. AB - The World Health Organisation has defined health service responsiveness as one of the key-objectives of health systems. Health service responsiveness relates to the ability to respond to service users' legitimate expectations on non-medical issues when coming into contact with the services of a healthcare system. It is defined by the areas showing respect for persons and patient orientation. Health service responsiveness is particularly relevant to mental health services, due to the specific vulnerability of mental health patients but also because it matches what mental health patients consider as good quality of care as well as their priorities when seeking healthcare. As (mental) health service responsiveness applies equally to all concerned services it would be suitable as a universal indicator for the quality of services' performance. However, performance monitoring programs in mental healthcare rarely assess health service performance with respect to meeting patient priorities. This is in part due of patient priorities as an outcome being underrepresented in studies that evaluate service provision. The lack of studies using patient priorities as outcomes transmits into evidence based guidelines and subsequently, into underrepresentation of patient priorities in performance monitoring. Possible ways out of this situation include more intervention studies using patient priorities as outcome, considering evidence from qualitative studies in guideline development and developing performance monitoring programs along the patient pathway and on key points of relevance for service quality from a patient perspective. PMID- 27222320 TI - Efficient creation of electron vortex beams for high resolution STEM imaging. AB - The recent discovery of electron vortex beams carrying quantised angular momentum in the TEM has led to an active field of research, exploring a variety of potential applications including the possibility of mapping magnetic states at the atomic scale. A prerequisite for this is the availability of atomic sized electron vortex beams at high beam current and mode purity. In this paper we present recent progress showing that by making use of the Aharonov-Bohm effect near the tip of a long single domain ferromagnetic Nickel needle, a very efficient aperture for the production of electron vortex beams can be realised. The aperture transmits more than 99% of all electrons and provides a vortex mode purity of up to 92%. Placing this aperture in the condenser plane of a state of the art Cs corrected microscope allows us to demonstrate atomic resolution HAADF STEM images with spatial resolution better than 1 Angstrom, in agreement with theoretical expectations and only slightly inferior to the performance of a non vortex probe on the same instrument. PMID- 27222321 TI - Ancestral genomic duplication of the insulin gene in tilapia: An analysis of possible implications for clinical islet xenotransplantation using donor islets from transgenic tilapia expressing a humanized insulin gene. AB - Tilapia, a teleost fish, have multiple large anatomically discrete islets which are easy to harvest, and when transplanted into diabetic murine recipients, provide normoglycemia and mammalian-like glucose tolerance profiles. Tilapia insulin differs structurally from human insulin which could preclude their use as islet donors for xenotransplantation. Therefore, we produced transgenic tilapia with islets expressing a humanized insulin gene. It is now known that fish genomes may possess an ancestral duplication and so tilapia may have a second insulin gene. Therefore, we cloned, sequenced, and characterized the tilapia insulin 2 transcript and found that its expression is negligible in islets, is not islet-specific, and would not likely need to be silenced in our transgenic fish. PMID- 27222322 TI - Selective Chemical Conversion of Sugars in Aqueous Solutions without Alkali to Lactic Acid Over a Zn-Sn-Beta Lewis Acid-Base Catalyst. AB - Lactic acid is an important platform molecule in the synthesis of a wide range of chemicals. However, in aqueous solutions without alkali, its efficient preparation via the direct catalysis of sugars is hindered by a side dehydration reaction to 5-hydroxymethylfurfural due to Bronsted acid, which originates from organic acids. Herein, we report that a previously unappreciated combination of common two metal mixed catalyst (Zn-Sn-Beta) prepared via solid-state ion exchange synergistically promoted this reaction. In water without a base, a conversion exceeding 99% for sucrose with a lactic acid yield of 54% was achieved within 2 hours at 190 degrees C under ambient air pressure. Studies of the acid and base properties of the Zn-Sn-Beta zeolite suggest that the introduction of Zn into the Sn-Beta zeolite sequentially enhanced both the Lewis acid and base sites, and the base sites inhibited a series of side reactions related to fructose dehydration to 5-hydroxymethylfurfural and its subsequent decomposition. PMID- 27222323 TI - Detection of Borrelia burgdorferi sensu stricto in Amblyomma americanum ticks in the southeastern United States: the case of selective compatibility. PMID- 27222324 TI - Candida haemulonii species complex: an emerging species in India and its genetic diversity assessed with multilocus sequence and amplified fragment-length polymorphism analyses. PMID- 27222325 TI - Outbreaks of serotype 4 fowl adenovirus with novel genotype, China. PMID- 27222327 TI - Experimental Trial with a Heat-Shocked Protoscolex Extract as a Vaccine Candidate for Protection Against Hydatid Disease. AB - OBJECTIVE: Cystic echinococcosis is distributed worldwide and is an important public health challenge in many countries. The present study was an experimental trial to use hydatid antigens derived from viable protoscoleces cultivated at 37 and 45 degrees C for 4 h as a vaccine candidate for protection against hydatid infection. METHODS: Balb/c mice were immunized with hydatid antigens extracted from protoscoleces exposed to 37 and 45 degrees C as well as partially purified hydatid antigens containing 30, 60, and 90 ug of heat shock protein 70 administered with or without an adjuvant. RESULTS: Crude antigens from protoscoleces exposed to 37 degrees C conferred non-significant immunity with protection and reduction rates that ranged from 0% to 25% and 77.69% to 98.38%, respectively. In mice receiving crude antigens from protoscoleces exposed to 45 degrees C, the protection and reduction rates ranged from 0% to 66.66% and 94.62% to 98.92%, respectively. The purified antigen from protoscoleces exposed to 45 degrees C conferred significant immunity with absolute protection observed in mice immunized with 60 and 90 ug of the antigen combined with the adjuvant. Immunological parameters (anti-hydatid antibody titer and lymphocyte transformation %) showed a negative correlation with the number of cysts. The assessment of renal and liver functions showed non-significant differences (p>0.05) in comparison with the liver and renal functions of non-immunized mice of the negative control group. CONCLUSION: Purified hydatid antigens containing heat shock protein 70 confer high levels of protection against hydatid infection in mice. PMID- 27222326 TI - Evaluation of the immunogenicity and protective effects of a trivalent chimeric norovirus P particle immunogen displaying influenza HA2 from subtypes H1, H3 and B. AB - The ectodomain of the influenza A virus (IAV) hemagglutinin (HA) stem is highly conserved across strains and has shown promise as a universal influenza vaccine in a mouse model. In this study, potential B-cell epitopes were found through sequence alignment and epitope prediction in a stem fragment, HA2:90-105, which is highly conserved among virus subtypes H1, H3 and B. A norovirus (NoV) P particle platform was used to express the HA2:90-105 sequences from subtypes H1, H3 and B in loops 1, 2 and 3 of the protrusion (P) domain, respectively. Through mouse immunization and microneutralization assays, the immunogenicity and protective efficacy of the chimeric NoV P particle (trivalent HA2-PP) were tested against infection with three subtypes (H1N1, H3N2 and B) of IAV in Madin-Darby canine kidney cells. The protective efficacy of the trivalent HA2-PP was also evaluated preliminarily in vivo by virus challenge in the mouse model. The trivalent HA2-PP immunogen induced significant IgG antibody responses, which could be enhanced by a virus booster vaccination. Moreover, the trivalent HA2-PP immunogen also demonstrated in vitro neutralization of the H3 and B viruses, and in vivo protection against the H3 virus. Our results support the notion that a broadly protective vaccine approach using an HA2-based NoV P particle platform can provide cross-protection against challenge viruses of different IAV subtypes. The efficacy of the immunogen should be further enhanced for practicality, and a better understanding of the protective immune mechanism will be critical for the development of HA2-based multivalent vaccines. PMID- 27222328 TI - Seroprevalance of Leishmaniasis in Dogs from Hatay and Burdur Provinces of Turkey and Northern Cyprus. AB - OBJECTIVE: This study aimed to investigate the seroprevalance of leishmaniasis in dogs from Hatay and Burdur provinces of Turkey and Northern Cyprus. METHODS: Blood was collected from a total of 278 dogs, including 124 from Hatay, 49 from Burdur, and 105 from Northern Cyprus. Dilutions of serum samples were prepared, and the presence of anti-Leishmania antibodies was investigated by indirect fluorescent antibody technique (IFAT). RESULTS: A total of three dogs were found to be seropositive (1.1%), one from Hatay (0.8%) and two from Northern Cyprus (1.9%). Also, one dog (0.4%) from Northern Cyprus was found to be borderline positive. All dogs from Burdur have been identified as seronegative. CONCLUSION: This is the first research on the seroprevalence of the parasite in dogs from Hatay and Burdur. The seropositivity detected in dogs from Hatay and Northern Cyprus demonstrates the presence of the parasite in these regions, and obtained results contribute data on the prevalence of the disease in an epidemiological manner. To obtain more reliable data, it will be useful to conduct studies on wider dog populations and vector sandflies. PMID- 27222329 TI - Prevalence of Ectoparasites of Indigenous Chickens From Dalahu Region, Kermanshah Province, Iran. AB - OBJECTIVE: Ectoparasitism is an important factor associated with the poor production of indigenous chickens. The present study was undertaken to estimate the prevalence and ectoparasite diversity in indigenous chickens of the Dalahu region in the western part of Kermanshah province, Iran. METHODS: A total of 600 indigenous chickens (250 roosters and 350 hens) were randomly examined for the presence of different ectoparasites over the period April to September 2011. Ectoparasites were collected from different parts of chicken body using a hand lens, magnifying glass, and flashlights. The samples were preserved in 70% alcohol and cleared in lactophenol. RESULTS: The overall prevalence of ectoparasites was 52.8% (66% hens and 34.4% roosters) (p<0.001). Mixed infestation was noted in 70.34% of the chickens. The prevalence was significantly higher in young (66.3%) animals compared with older animals (39.33%) (p<0.001). Five species of ectoparasites were identified: Menopon gallinae (35.3%), Menacanthus stramineus (26.7%), Argas persicus (19%), Dermanyssus gallinae (11%), and Echidnophaga gallinacea (the "sticktight flea") (8%). CONCLUSION: The results of the present investigation reveal that ectoparasite infestation is prevalent in this area. Further studies are recommended to evaluate the effects of the ectoparasites on indigenous chicken health and production in the region. PMID- 27222330 TI - Investigation of Entamoeba gingivalis and Trichomonas tenax in Periodontitis or Gingivitis Patients in Kayseri. AB - OBJECTIVE: The aim of this study was to determine the prevalence of Entamoeba gingivalis and Trichomonas tenax in periodontitis and gingivitis patients. METHODS: The study consisted of 107 periodontitis patients and 68 gingivitis patients. Bacterial plaque samples were collected with a curette from the deepest pocket in each quadrant and placed into separate tubes containing sterile 0.9% saline solution. Samples were examined at a magnification of *400 by light microscopy. Cultivation for T. tenax was performed using the same samples, and the cultures were examined after 48 hours. RESULTS: E. gingivalis was present in the samples from 38 periodontitis patients, whereas T. tenax was present in samples from only 3 periodontitis patients. Both E. gingivalis and T. tenax were found together in the samples from 2 periodontitis patients. In total, 22 and 2 gingivitis patients were found to be infected with E. gingivalis and with T. tenax, respectively. Only 1 gingivitis patient was found to be infected with both E. gingivalis and T. tenax. CONCLUSION: In our study, oral protozoa were found in a high percentage in periodontitis and gingivitis patients. We believe that the prevalence of E. gingivalis and T. tenax should be determined via new studies and, in particular, the protection principles should be complied with. PMID- 27222331 TI - Comparative Evaluation of Three Methods (Microscopic Examination, Direct Fluorescent Antibody Assay, and Immunochromatographic Method) for the Diagnosis of Giardia intestinalis From Stool Specimens. AB - OBJECTIVE: The aim of this study was to compare direct microscopic examination, direct fluorescent antibody assay (DFA), and the immunochromatographic method (IK) and identify the best suitable method for the diagnosis of Giardia intestinalis. METHODS: In this study, 25 stool samples that had been diagnosed as being infected with G. intestinalis using the native-Lugol and/or formol-ethyl acetate concentration method and 25 non-parasite-infected samples (the control group) were examined. After microscopic examination of stools, they were kept at 20 degrees C for examination using DFA and IK. Stool samples were studied using DFA (CeLLabs, Crypto/Giardia-Cel IF) and IK (RIDA QUICK, Cryptosporidium/Giardia Combi Dipstick), as per the manufacturers' instructions. RESULTS: In our study, using the DFA method, parasites were detected in all 25 stool samples in which G. intestinalis was diagnosed by direct microscopic examination. Using the IK method, a particular band indicative of the parasite was detected in 24 samples. No parasites were detected in all 25 samples in the control group. CONCLUSION: Thus, when direct microscopic examination is taken as reference, the senstivity and specificity of DFA for the diagnosis of G. intestinalis were found to be 100% each, while those of IK were found to be 96% and 100%, respectively. PMID- 27222332 TI - Cystic Eechinococcosis in Childhood: Five-Years of Experience From a Single Center. AB - OBJECTIVE: To evaluate the clinical data and prognosis of cystic echinococcosis during a 5-year period who were followed by the pediatric clinics. METHODS: Demographic, clinical, laboratory, and prognosis data of 34 patients with cystic echinococcosis obtained between 2009 to 2014 were retrospectively evaluated. Of these, 10 patients were excluded because of incomplete data or failure to follow up. RESULTS: A total of 24 (12 males and 12 females) children were included the study. The mean ages of patients were 11.17 +/- 3.71 (range, 5-17) years. The most common symptoms were abdominal pain (41.7%), cough (16.7%), and fatigue (12.5%). Localization of the parasite in the patients was determined to be as follows: liver (54.2%), lung (33.3%), and intraabdominal (4.2%). Multiorgan involvement was observed in 8.3% of the cases. Indirect hemagglutination test was positive in 13 (54.2%) patients at admission. All patients received treatment with albendazole. Seven patients were treated with puncture-aspiration-injection re-aspiration (PAIR) (29.2%). Open surgery was performed in six patients (24.2%). One patient was treated with both PAIR and open surgery. CONCLUSIONS: Cystic echinococcosis is a serious public health problem in developing countries. Hydatid cyst should be considered in the presence of suspicious radiological and clinical findings in endemic areas. PMID- 27222333 TI - Coexistence of Helicobacter pylori and Intestinal Parasitosis in Children with Chronic Abdominal Pain. AB - OBJECTIVE: The aim of this study was to determine the incidence of coinfection with Helicobacter pylori and intestinal parasitosis in children with chronic abdominal pain (CAP) and to investigate the common risk factors in the development of both infections. METHODS: Ninety patients with CAP were enrolled in this study. Blood samples of each case were screened for human preformed IgG (HpIgG) antibodies, and stool samples were tested for HpSA and also examined for intestinal parasites by direct wet-mount, formalin-ethyl-acetate concentration, and Trichrome staining procedures. Cellophane tape test was used for Enterobius vermicularis. Children tested positive for HpIgG and/or HpSA were accepted as H. pylori positive. The risk factors were compared with a questionnaire. RESULTS: The incidence of Giardia intestinalis was 14.8% in the H. pylori-positive group and was found to be statistically higher than that in the H. pylori-negative group (1.6%). The positivity rates of H. pylori were found to be statistically higher in children attending school and using drinking water from taps. The incidences of parasitosis were significantly higher in children with a low maternal education level and with a history of parasitosis treatment in the family. CONCLUSION: The most common etiologies of CAP in children are H. pylori infection and intestinal parasitosis. Improvement of hygienic conditions would be beneficial in preventing both infections. PMID- 27222334 TI - Endoparasites of the Long-Eared Hedgehog (Hemiechinus auritus) in Zabol District, Southeast Iran. AB - OBJECTIVE: The long-eared hedgehog (Hemiechinus auritus) is a nocturnal animal living in Central and Southeast Iran. However, there are few studies concerning endoparasites, some of which are zoonotic, of the hedgehogs in the north and northwest of Iran. The aim of the present study is to investigate endoparasites in long-eared hedgehogs, living in Zabol district, Southeast Iran. MATERIALS AND METHODS: Stool and blood samples collected from 50 hedgehogs (35 males and 15 females) that were trapped alive were examined with Clayton-Lane flotation and Giemsa staining methods. Furthermore, 10 road-killed hedgehog carcasses were necropsied. The adult parasites were collected and identified under a light microscope. RESULTS: Spirurida eggs in the stool samples and Anaplasma inclusion bodies in red blood cells were determined in 32% and 52% of the samples, respectively. Physaloptera clausa, Mathevotaenia erinacei, Nephridiacanthus major, and Moniliformis moniliformis were identified in the necropsy. CONCLUSION: To the best of our knowledge, ours is the first study concerning endoparasites of long-eared hedgehogs in Iran. Furthermore, M. erinacei was for the first time reported as a parasitic fauna in Iran. PMID- 27222335 TI - Study of Pathophysiological Effects of the Nematode Parasite Eustrongylides sp. on Freshwater Fish Channa punctatus by Hematology, Serum Biochemical, and Histological Studies. AB - OBJECTIVE: The aim of this study was to study the pathophysiological effects on Channa punctatus due to the nematode parasite Eustrongylides sp. METHODS: A total of 250 fish were examined during the period January 2012-2014. Hematological, serum biochemical, histological, and scanning electron microscopic studies were performed on normal and infected hosts to study the effects caused by the nematode. RESULTS: The mean values of red blood corpuscle [RBC] count, hematocrit, and hemoglobin were significantly higher (P<0.01) in noninfected fish, while the values of white blood corpuscle [WBC] count, mean corpuscular volume [MCV], and mean corpuscular hemoglobin [MCH] were significantly higher (P<0.01) in infected fish. In infected fish, the average values of aspartate amminotransferase [AST] (416 UL-1), alanine amminotransferase [ALT] (73.35 UL-1), alkaline phosphatase [ALP] (161.6 mg dl-1), and cholesterol (154.82 mg dl-1) were significantly higher (P<0.01) than those in noninfected fish. Significant differences were also observed in total protein and glucose levels between the infected and noninfected fish. Histological and scanning electron microscopic studies of the host tissues revealed a series of pathological changes and mechanical damage. CONCLUSION: It can be concluded that Eustrongylides sp. has a significant impact on its host and thus the parameters outlined in the present paper may be employed as tools in monitoring the health status of fish in culture practices. PMID- 27222336 TI - Ichthyobodo spp. Infection in Meagre (Argyrosomus regius) from Turkey: Parasitological and Pathological Findings. AB - OBJECTIVE: The aim of this study is to describe the first report of Ichthyobodo spp. infection in meagre (Argyrosomus regius) fry in a marine aquaculture facility in Turkey. METHODS: The material of the study was composed of 30 meagre A. regius in 2-3 g weight taken from the fry adaptation unit of a fish farm in the Aegean Sea. In this study, parasitological and pathological examinations were performed on the meagre. Ichthyobodo spp. was determined on the body surfaces and gills. RESULTS: Pathological examination revealed grayish mucous and erosions between the pin head and lentin over the skin of the examined specimens. Microscopic examinations revealed significant spongiosis, vacuolar degeneration, and hyperplasia in epidermal malpighian cells and hyperplasia in goblet cells. CONCLUSION: In the present study, Ichthyobodo spp. infection was for the first time determined in an alternative cultured meagre in Turkey. PMID- 27222337 TI - Cystic Echinococcosis: One Entity, Two Unusual Locations. AB - We report two cases of cystic echinococcosis at unexpected locations. Patients were a 64-year-old man and 35-year-old woman. A cystic mass was incidentally found between the prostate and seminal vesicles in the male patient, using ultrasonography during a check-up for ischemic coronary disease. The female patient was admitted to the hospital with symptoms of cardiopulmonary disease, but her detailed radiological examination showed a cystic lesion in the interventricular septum of the heart. Both patients were operated, and examinations of the histologic sections revealed cyst walls consistent with echinococcal infection. Attention should be focused on this entity even in endemic areas, and pathologists should be aware of the histologic characteristics of this lesion, to avoid misdiagnosis as a nonspecific cyst. PMID- 27222338 TI - Hydatid Cyst Presenting with Mass That Localized in the Cruris Region. PMID- 27222340 TI - An eight-long non-coding RNA signature as a candidate prognostic biomarker for lung cancer. AB - Cumulative evidence suggests that long non-coding RNAs (lncRNAs) may be good biomarkers in various types of tumors. In the present study, we mined lncRNA expression profiling in 739 lung cancer patients from Gene Expression Omnibus (GEO) datasets. A risk score model was constructed based on the expression data of these eight lncRNAs in the training dataset (GSE30219). The validation for the association was performed in three independent testing sets (GSE31210, GSE37745 and GSE19188). Finally, a set of eight lncRNA genes (AK021595, BC030759, AK000053, AK124307, BC020384, AK022024, CR615992 and AF085995) were identified by the random survival forest algorithm. Using a risk score based on the expression signature of these lncRNAs, we separated the patients into low-risk and high-risk groups with significantly different survival times in the training set. This finding was validated in the other three testing sets. Further study revealed that the eight-lncRNA expression signature was independent of age and gender. Gene Set Enrichment Analysis (GSEA) suggested that lncRNAs were involved in cell cycle and DNA replication signaling pathways. Therefore, the eight lncRNAs may be candidate prognostic biomarkers for lung cancer patients. PMID- 27222341 TI - Ethanol extract of Terminalia chebula fruit protects against UVB-induced skin damage. AB - CONTEXT: The fruit of Terminalia chebula Retz. (Combretaceae) has been used for several therapeutic purposes in Thai folk medicines. Currently, the ethanol extracts containing antioxidant compounds have shown the ability to promote collagen synthesis. OBJECTIVE: This purpose of this work was to study the effects of the ethanol extract from T. chebula fruit on the inhibition of cutaneous photodamage. MATERIALS AND METHODS: The viability of human skin fibroblasts after incubation with T. chebula at concentration 0.5-50 MUg/mL for 24, 48 and 72 h was assessed by using sodium 3'-[(phenyl-amino)-carbonyl]-3,4,tetrazolium-bis(4 methoxy-6-notro)benzene-sulphonic acid hydrate (XTT). The levels of type I procollagen and matrix metalloproteinases (MMP)-1 and MMP-13 produced by UVB irradiated fibroblasts were determined by ELISA. Skin thickness and collagen content caused by long-term UVB irradiation in male ICR mice were determined from haematoxylin and eosin stained tissue sections and spectrophotometric measurement of hydroxyproline. RESULTS: The extract (0.5-50 MUg/mL) had no effect on cell viability or morphology of the human fibroblasts. In vitro studies showed that the T. chebula extract reduced the UVB-induced MMP-1 and MMP-13 expression, whereas an increased production of type I procollagen was observed. In a UVB irradiated animal model, male ICR mice with hair shaved were chronically exposed to UVB which lead to epidermal thickness and loss of hydroxyproline. However, these effects were fully prevented by the topical application of the T. chebula ethanol extract. DISCUSSION AND CONCLUSION: These data suggested that the T. chebula ethanol fruit extract is an efficacious pharmaceutical protectant of skin against photodamage. PMID- 27222342 TI - Fatigue related impairments in oculomotor control are prevented by caffeine. AB - Strenuous exercise can result in an inability of the central nervous system to drive skeletal muscle effectively, a phenomenon known as central fatigue. The impact of central fatigue on the oculomotor system is currently unexplored. Fatigue that originates in the central nervous system may be related to perturbations in the synthesis and metabolism of several neurotransmitters. In this study we examine central fatigue in the oculomotor system after prolonged exercise. The involvement of central neurotransmission was explored by administering caffeine during exercise. Within a double-blind, randomized, repeated measures, crossover design, 11 cyclists consumed a placebo or caffeine solution during 180 min of stationary cycling. Saccadic eye movements were measured using infra-red oculography. Exercise decreased saccade velocity by 8% (placebo trial). This effect was reversed by caffeine, whereby velocity was increased by 11% after exercise. A non-oculomotor perceptual task (global motion processing) was unaffected by exercise. The human oculomotor system is impaired by strenuous exercise of the locomotor system. Caffeine exerts a protective effect on oculomotor control, which could be related to up-regulated central neurotransmission. In addition, cortical processes supporting global motion perception appear to be robust to fatigue. PMID- 27222344 TI - Fasting during the suckling-weaning transient period of rats induces inflammatory gene expression in the adipose tissue and peripheral leukocytes. AB - OBJECTIVE: Nutritional deficiency during developmental stages could be associated with subsequent development of inflammation-related metabolic abnormalities. In this study, we examined the effects of a 3-d fast during the suckling-weaning transient period of rats, and subsequent intake of high-fat-high-sucrose (HF) and low-fat-high-starch (LF) diets in adulthood, on the expression of inflammatory genes in adipose tissue and peripheral leukocytes. METHODS: Male Sprague-Dawley rats were deprived of food for 3 d during the suckling-weaning transient period, and were subsequently fed an HF or LF diet for 14 wk from 17 wk of age. Serum monocyte chemoattractant protein-1 (MCP-1) concentration and mRNA levels of inflammatory genes in mesenteric adipose tissues were assessed at 31 wk of age. The mRNA levels of inflammatory genes at 0 h and 2 h after oral glucose load at 30 wk of age in peripheral leukocytes were measured. RESULTS: Fasting induced circulating MCP-1 protein in rats fed an LF diet but not an HF diet. The HF diet induced high mRNA levels of tumor necrosis factor-alpha, interleukin-1beta, and S100 proteins in peripheral leukocytes at 2 h after glucose load in fasted rats when compared with controls. Expression of CD11c, an activated macrophage marker, was induced in the fasted group given an HF diet during adulthood. CONCLUSIONS: Fasting rats during the suckling-weaning transient period and an HF diet intake during adulthood enhance inflammation by promoting the expression of inflammatory genes in adipose tissue and peripheral leukocytes. PMID- 27222343 TI - NFATc1 supports imiquimod-induced skin inflammation by suppressing IL-10 synthesis in B cells. AB - Epicutaneous application of Aldara cream containing the TLR7 agonist imiquimod (IMQ) to mice induces skin inflammation that exhibits many aspects of psoriasis, an inflammatory human skin disease. Here we show that mice depleted of B cells or bearing interleukin (IL)-10-deficient B cells show a fulminant inflammation upon IMQ exposure, whereas ablation of NFATc1 in B cells results in a suppression of Aldara-induced inflammation. In vitro, IMQ induces the proliferation and IL-10 expression by B cells that is blocked by BCR signals inducing NFATc1. By binding to HDAC1, a transcriptional repressor, and to an intronic site of the Il10 gene, NFATc1 suppresses IL-10 expression that dampens the production of tumour necrosis factor-alpha and IL-17 by T cells. These data indicate a close link between NFATc1 and IL-10 expression in B cells and suggest NFATc1 and, in particular, its inducible short isoform, NFATc1/alphaA, as a potential target to treat human psoriasis. PMID- 27222345 TI - Hyponatremia and decreased bone density in adolescent inpatients diagnosed with anorexia nervosa. AB - OBJECTIVE: Recent studies demonstrated an association between low serum sodium levels and reduced bone density. Patients with anorexia nervosa (AN) are at greater risk for osteoporosis as well as for hyponatremia. The aim of the present study was to assess the association between hyponatremia and bone mineral density (BMD) in a large cohort of adolescent inpatients with AN. METHODS: A historic cohort study of 174 adolescent females (mean age 15.7 +/- 1.8 y) hospitalized because of AN between 2003 and 2013. Demographic and clinical data, including age, psychiatric comorbidity, anthropometric measurements, laboratory tests, and BMD scores were obtained from the patients' medical charts. RESULTS: Mean lumbar spine BMD z-score of the patients was lower than expected in the normal population (mean -1.5 +/- 1.2) and positively correlated with body mass index standard deviation score (r = 0.42, P < 0.0001). Sixty-four participants (36.8%) had at least one episode of hyponatremia during the year preceding the BMD measurement. These participants had a significantly lower lumbar spine BMD z score (-1.8 +/- 1.2 versus -1.3 +/- 1.2, P = 0.01) compared with participants with no hyponatremia. Lumbar spine BMD z-score was also positively correlated with the levels of free triiodothyronine (r = 0.16, P = 0.038), 17 b-estradiol (r = 0.23, P = 0.005), and luteinizing hormone (r = 0.25, P = 0.001), and negatively correlated with cortisol levels (r = 0.33, P < 0.0001). Having at least one episode of hyponatremia, BMI z-score and cortisol levels were identified as independent predictors of BMD z-score (P < 0.001, P < 0.001, and P = 0.034, respectively). CONCLUSIONS: Hyponatremia may be associated with decreased bone density in adolescent females with AN. Additional studies are required to evaluate whether the correction of hyponatremia will improve BMD. PMID- 27222346 TI - Specific clinical signs and symptoms are predictive of clinical course in sporadic Creutzfeldt-Jakob disease. AB - BACKGROUND AND PURPOSE: Akinetic mutism is thought to be an appropriate therapeutic end-point in patients with sporadic Creutzfeldt-Jakob disease (sCJD). However, prognostic factors for akinetic mutism are unclear and clinical signs or symptoms that precede this condition have not been defined. The goal of this study was to identify prognostic factors for akinetic mutism and to clarify the order of clinical sign and symptom development prior to its onset. METHODS: The cumulative incidence of akinetic mutism and other clinical signs and symptoms was estimated based on Japanese CJD surveillance data (455 cases) collected from 2003 to 2008. A proportional hazards model was used to identify prognostic factors for the time to onset of akinetic mutism and other clinical signs and symptoms. RESULTS: Periodic synchronous discharges on electroencephalography were present in the majority of cases (93.5%). The presence of psychiatric symptoms or cerebellar disturbance at sCJD diagnosis was associated with the development of akinetic mutism [hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.14-1.99, and HR 2.15, 95% CI1.61-2.87, respectively]. The clinical course from cerebellar disturbance to myoclonus or akinetic mutism was classified into three types: (i) direct path, (ii) path via pyramidal or extrapyramidal dysfunction and (iii) path via psychiatric symptoms or visual disturbance. CONCLUSIONS: The presence of psychiatric symptoms or cerebellar disturbance increased the risk of akinetic mutism of sCJD cases with probable MM/MV subtypes. Also, there appear to be sequential associations in the development of certain clinical signs and symptoms of this disease. PMID- 27222347 TI - Intercellular and intracellular functions of ceramides and their metabolites in skin (Review). AB - The skin consists of the epidermis, dermis and subcutis. The epidermis is primarily comprised of keratinocytes and is separated into four layers according to the stage of differentiation of the keratinocytes. Corneocytes are terminally differentiated keratinocytes that closely interact with other corneocytes through corneodesmosomes, and synthesize lamellar bodies and the intercellular multilamellar barrier, which protects the body from the external environment. As ceramides are the principal components of lamellar bodies and the multilamellar barrier, it is important to understand the biosynthesis of ceramides and their functions in skin. Ceramides are synthesized by amide bond-mediated interactions between sphingoid bases, long-chain amino alcohols [long-chain base] and fatty acids through a de novo pathway, a sphingomyelin (SM) hydrolysis pathway and a catabolic pathway. The majority of ceramides produced by the de novo pathway form the epidermal barrier. Ceramides used as signaling molecules are synthesized by the SM and catabolic pathways. Synthesized ceramides are released from corneocytes and form the multilamellar barrier. Additionally, ceramides and their metabolites regulate the apoptosis, proliferation and differentiation of skin cells as well as the formation of the skin barrier. Thus, the study of ceramides and their metabolites is crucial to understanding the function and regulation of the skin barrier. PMID- 27222348 TI - Implication of the estrogen receptors GPER, ESR1, ESR2 in post-testicular maturations of equine spermatozoa. AB - Estrogen receptors ESR1, ESR2 and GPER are present on mature ejaculated horse spermatozoa, suggesting these cells as putative targets for estrogens. Indeed, spermatozoa are exposed to high level of estrogens during the transit in the male and female genital tracts but their roles are not investigated. So, we evaluated in vitro the role of 17beta-estradiol during post-testicular maturations: regulation of motility, capacitation and acrosome reaction. Moreover according to the pseudo-seasonal breeder status of the stallion, we analyzed the putative seasonal variations in the presence of ESRs in spermatozoa. We showed that ESRs are more present on stallion sperm during the breeding season. We showed that capacitation and acrosome reaction are independent of estradiol action in horse. Estradiol can weakly modulate the motility and this effect is strictly associated with GPER and not with ESR1 and ESR2. The subcellular localization of GPER in the neck on stallion sperm is coherent with this effect. It seems that estrogens are not major regulators of sperm maturations associated to mare genital tract, so they could act during the epididymal maturations. PMID- 27222349 TI - Beeswax corticosterone implants produce long-term elevation of plasma corticosterone and influence condition. AB - Glucocorticoids can play a critical role in modulating life-history trade-offs. However, studying the effects of glucocorticoids on life-history often requires experimentally elevating plasma glucocorticoid concentrations for several weeks within normal physiological limits and without repeated handling of the animal. Recently, implants made of beeswax and testosterone (T) were shown to have release dynamics superior to some currently available T implants, and these beeswax implants dissolved, eliminating the need to recapture the animal. We evaluated the utility of beeswax implants containing four different dosages of corticosterone (CORT; the primary glucocorticoid in birds) and their effect on several condition indices in a captive colony of zebra finches (Taeniopygia guttata). The three implants with the greatest CORT doses (0.05, 0.1, and 0.5mg) produced spikes in plasma CORT concentrations 20h after treatment, but were within the limits that zebra finches may normally experience. The 0.5mg CORT implant elevated plasma CORT between typical baseline and restraint stress levels reported in other studies of zebra finches for the entire 35day experiment. Birds in the 0.5mg implant group were heavier, had greater furcular fat scores, and had lower hematocrit than birds in the control and other CORT implant groups. Beeswax CORT implants are a low cost method of elevating plasma CORT for a prolonged time. Furthermore, because there is no need to remove these implants at the end of a study, this method may be amenable to studies of free-ranging animals. PMID- 27222350 TI - miR-375 inhibits the invasion and metastasis of colorectal cancer via targeting SP1 and regulating EMT-associated genes. AB - Accumulating evidence has shown that aberrantly expressed microRNAs (miRNAs) are associated with tumor development and progression. Our previous study found that microRNA-375 (miR-375) was downregulated in colorectal cancer (CRC), but little is known concerning the role of miR-375 and the related mechanism in CRC development. The proliferation, invasion and migration effects were investigated by Cell Counting Kit-8 (CCK-8), colony formation and Transwell assays with or without Matrigel. In addition, candidate target genes were screened and validated by luciferase reporter and western blot assays. In addition, western blot analysis was performed to explore the molecular mechanisms associated with epithelial-mesenchymal transition (EMT). It was found that miR-375 inhibited proliferation, invasion and migration in DLD1 and HCT8 cells. In addition, miR 375 negatively regulated Sp1 transcription factor (SP1) protein by directly binding to the 3'-untranslated region (3'-UTR). Furthermore, it was found that miR-375 regulated matrix metalloproteinase 2 (MMP2) and EMT-associated genes, E cadherin, vimentin, snail, N-cadherin and beta-catenin. In conclusion, miR-375 inhibited the proliferation, invasion and migration by directly targeting SP1 and regulating MMP2 and EMT-associated genes. PMID- 27222351 TI - Use of FDSS/MUCell imaging platform for preclinical cardiac electrophysiology safety screening of compounds in human induced pluripotent stem cell-derived cardiomyocytes. AB - FDSS/MUCell is a high-speed acquisition imaging platform (Hamamatsu Ltd., Hamamatsu, Japan) that allows for simultaneous high-throughput reading under controlled conditions. We evaluated the Ca(2+) transients or optical membrane potential changes of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) (iCells) in the presence or absence of 44 pharmacological agents known to interfere with cardiac ion channels (e.g., hERG, IKs, NaV1.5, CaV1.2). We tested two Ca(2+)-sensitive fluorescence dyes (Codex ACTOne(r) and EarlyTox(r)) and a membrane potential dye (FLIPR(r) membrane potential dye). We were able to quantify and report drug-induced early-after depolarizations (EAD) like waveforms, cardiomyocyte ectopic beats and changes in beating rate from a subgroup of pharmacological agents acting acutely (within a 1-hour period). Cardiovascular drugs, such as dofetilide and d,l-sotalol, exhibited EAD-like signals at 3nM and 10MUM, respectively. CNS drugs, such as haloperidol and sertindole, exhibited EAD-like signals and ectopic beats at 30nM and 1MUM, respectively. Other drugs, such as astemizole, solifenacin, and moxifloxacin, exhibited similar arrhythmias at 30nM, 3MUM and 300MUM, respectively. Our data suggest that the membrane potential and intracellular Ca(2+) signal are tightly coupled, supporting the idea that the EAD-like signals reported are the accurate representation of an EAD signal of the cardiac action potential. Finally, the EAD like Ca(2+) signal was well correlated to clinically-relevant concentrations where Torsade de Pointes (TdPs) arrhythmias were noted in healthy volunteers treated orally with some of the compounds we tested, as reported in PharmaPendium(r). PMID- 27222352 TI - Unrealistically pristine air in the Arctic produced by current global scale models. AB - Black carbon aerosol (BCA) in the Arctic has profound impacts on the global climate system through radiation processes. Despite its enormous impacts, current global scale models, powerful tools for estimating overall impact, tend to underestimate the levels of BCA in the Arctic over several seasons. Using a global aerosol transport simulation with a horizontal grid resolution of 3.5 km, we determined that a higher resolution significantly reduced the underestimation of BCA levels in the Arctic, mainly due to an enhancement of the representation of low-pressure and frontal systems. The BCA mass loading in the Arctic simulated with 3.5-km grid resolution was 4.2-times larger than that simulated with coarse (56-km) grid resolution. Our results also indicated that grid convergence had not occurred on both the contrast between the cloud/cloud free areas and the poleward BCA mass flux, despite the use of the 3.5-km grid resolution. These results suggest that a global aerosol transport simulation using kilometre-order or finer grid resolution is required for more accurate estimation of the distribution of pollutants in the Arctic. PMID- 27222353 TI - Screening and identification of the differentially expressed proteins in neonatal rat kidney after partial unilateral ureteral obstruction. AB - Renal fibrosis, considered to be a common consequence of progressive renal disease, involves glomerulosclerosis and/or tubulointerstitial fibrosis. Currently, research is focused on investigating potential mechanisms to prevent or reverse the damage caused by fibrosis. Under the influence of cytokines, chemokines and other signaling molecules, the cellular interactions that regulate the development of interstitial fibrosis are complex. Epithelial-mesenchymal transition (EMT) has emerged as an important pathway leading to the generation of matrix-producing fibroblasts and myofibroblasts in diseased kidneys. The proteomics study compared the protein profiles between the time points of podocyte EMT and tubular cell EMT in a partial unilateral ureteral obstruction (PUUO) model in rats. Proteins isolated from the PUUO group and corresponding sham rat kidney tissues were subjected to 2-D gel electrophoresis and were then identified by mass spectrometry. In total, 43 proteins with differential expression were identified, which were reported to be involved in the regulation of the cytoskeleton and actin, glucose metabolism, cell apoptosis, mitochondrial energy metabolism, oxidative stress and endoplasmic reticulum stress. Electron transfer flavoprotein, beta polypeptide was detected by immunoblot analysis and its mRNA levels were determined in renal tissues. The results demonstrate protein alterations that reflect the pathology of the obstructed kidneys, and thus may aid in understanding the pathogenesis of obstructive nephropathy. PMID- 27222354 TI - Ring Chromosome 9 and Chromosome 9p Deletion Syndrome in a Patient Associated with Developmental Delay: A Case Report and Review of the Literature. AB - Ring chromosomes have been described for all human chromosomes and are typically associated with physical and/or mental abnormalities resulting from a deletion of the terminal ends of both chromosome arms. This report describes the presence of a ring chromosome 9 in a 2-year-old male child associated with developmental delay. The proband manifested a severe phenotype comprising facial dysmorphism, congenital heart defects, and seizures. The child also exhibited multiple cell lines with mosaic patterns of double rings, a dicentric ring and loss of the ring associated with mitotic instability and dynamic tissue-specific mosaicism. His karyotype was 46,XY,r(9)(p22q34)[89]/46,XY,dic r(9; 9)(p22q34;p22q34)[6]/45, XY, 9[4]/47,XY,r(9),+r(9)[1]. However, the karyotypes of his parents and elder brother were normal. FISH using mBAND probe and subtelomeric probes specific for p and q arms for chromosome 9 showed no deletion in any of the regions. Chromosomal microarray analysis led to the identification of a heterozygous deletion of 15.7 Mb from 9p22.3 to 9p24.3. The probable role of the deleted genes in the manifestation of the phenotype of the proband is discussed. PMID- 27222355 TI - Sexuality and Relationships in Young People With Spina Bifida and Their Partners. AB - PURPOSE: Research focusing on sexuality in those living with disabilities, such as spina bifida (SB), has not specifically addressed adolescents and has been largely quantitative in design. Our study qualitatively explored how young people with SB think about and discuss sexuality with their sexual and romantic partners in the context of their disability. METHODS: Participants aged 16-25 years were recruited using purposive sampling from a large urban pediatric rehabilitation center in Toronto, Canada, as well as through a large Spina Bifida and Hydrocephalus Association. Semistructured interviews were conducted in person or by telephone. Inductive coding and descriptive thematic analysis were conducted on verbatim transcripts. RESULTS: There were mixed views on the importance of disclosing their condition to partners. While some participants strongly believed that their disability was important to share with partners, others worried that potential partners would focus on the disability rather than the person. Participants reported challenges about the timing of disclosure, lack of confidence in their abilities to express their sexual needs, and fears of rejection. After disclosure, however, participants often experienced increased confidence in themselves and their relationships. Participants identified a lack of SB-specific sexual education and a desire to learn more from their health care providers. CONCLUSIONS: The findings underscore the importance of empowering young people to become more confident talking about their disability, especially in the context of sexual and romantic relationships. Being able to discuss their abilities, needs and desires could potentially facilitate the development of healthy relationships during their transition to adulthood. PMID- 27222356 TI - Age-Varying Links Between Violence Exposure and Behavioral, Mental, and Physical Health. AB - PURPOSE: To examine age-varying prevalence rates and health implications of weapon-related violence exposure (WRVE) from adolescence to young adulthood (ages 14-30) using time-varying effect modeling. METHODS: Data were from the Add Health study, a longitudinal study of adolescents in the United States (N = 5,103) followed into young adulthood across four assessment waves from age 14-30. RESULTS: WRVE rates varied with age, peaking during mid-to-late adolescence (ages 16-18). Rates were higher for males (vs. females) and African-American youth (vs. white) across nearly all ages. Rates were higher for Hispanic youth (vs. white) during adolescence. WRVE was positively associated with frequent heavy episodic drinking and negatively associated with self-reported general health; these associations were significant during adolescence and early adulthood (ages 15 24). WRVE was positively associated with depressive symptoms. This association remained stable over age and was stronger for females from ages 16-21. The association between violence exposure and decreased general physical health was stronger for white versus African-American youth from ages 15-17, with no significant association observed for African-American youth at any age. CONCLUSIONS: Despite its severity, WRVE is prevalent among U.S. youth during adolescence and young adulthood, particularly among males and African-Americans during mid-to-late adolescence. The associations between WRVE and health were stronger during adolescence and differed by sex and race/ethnicity. This information may assist in the timing and targeting of intervention efforts aimed at interrupting the effects of violence exposure on youth behavioral, mental, and physical health. PMID- 27222357 TI - The heart as an extravascular target of endothelin-1 in particulate matter induced cardiac dysfunction. AB - Exposure to particulate matter air pollution has been causally linked to cardiovascular disease in humans. Several broad and overlapping hypotheses describing the biological mechanisms by which particulate matter exposure leads to cardiovascular disease have been explored, although linkage with specific factors or genes remains limited. These hypotheses may or may not also lead to particulate matter-induced cardiac dysfunction. Evidence pointing to autocrine/paracrine signaling systems as modulators of cardiac dysfunction has increased interest in the emerging role of endothelins as mediators of cardiac function following particulate matter exposure. Endothelin-1, a well-described small peptide expressed in the pulmonary and cardiovascular systems, is best known for its ability to constrict blood vessels, although it can also induce extravascular effects. Research on the role of endothelins in the context of air pollution has largely focused on vascular effects, with limited investigation of responses resulting from the direct effects of endothelins on cardiac tissue. This represents a significant knowledge gap in air pollution health effects research, given the abundance of endothelin receptors found on cardiac tissue and the ability of endothelin-1 to modulate cardiac contractility, heart rate, and rhythm. The plausibility of endothelin-1 as a mediator of particulate matter induced cardiac dysfunction is further supported by the therapeutic utility of certain endothelin receptor antagonists. The present review examines the possibility that endothelin-1 release caused by exposure to PM directly modulates extravascular effects on the heart, deleteriously altering cardiac function. PMID- 27222358 TI - A sacred command of reason? Deceit, deception, and dishonesty in nurse education. AB - Kant (Grounding for the Metaphysics of Morals. Hackett, Indianapolis, 1797) described honesty as 'a sacred command of reason' which should be obeyed at all times and at any cost. This study inquires into the practice of dishonesty, deception, and deceit by universities in the UK in the pursuit of quality indicators such as league table positions, Research Excellence Framework (REF) scores, and student satisfaction survey results. Deception occurs when the metrics which inform these tables and surveys are manipulated to suggest an improvement in quality when, in fact, the raised scores are merely the result of clever strategic planning. Deceit occurs when these manipulated scores are deliberately and knowingly presented as real improvements in research and educational quality. It might be argued that, within the context of the artificial ivory tower world of academe, this is a game played by almost every academic in every higher education institution with no real losers and little wider consequence. However, this study suggests that some of the strategies employed by institutions to improve their scores without directly addressing the issue of quality can, in certain practice-based disciplines such as nursing, result in dire consequences for practitioners and service users. It concludes with a number of suggestions taken from personal experience to resolve the tension between the contractual demands placed on nurse academics by their employers and the moral and practical obligations of their professional body, most notably the use of subversion. The conclusion, contra Kant, is that the most effective strategy against dishonesty and deception is often more dishonesty and deception. PMID- 27222359 TI - Analysis of receptor tyrosine kinase genetics identifies two novel risk loci in GAS6 and PROS1 in Behcet's disease. AB - The TAM kinase (Tyro3, Axl, Mer) and its two ligands (Gas6 and protein S) have been shown to play an important regulatory role in the innate immune response. The present study aimed to investigate whether the tag single-nucleotide polymorphisms (tag SNPs) of these 5 protein-coding genes are associated with Behcet's disease (BD). A two-stage association study was performed in a total of 907 BD patients and 1780 healthy controls. Altogether 32 polymorphisms were tested, using a Sequenom MassARRAY genotyping method in the first stage and a PCR restriction fragment length polymorphism (PCR-RFLP) assay in the replication phase. Real-time PCR was performed to test the relative mRNA expression level of GAS6 and PROS1 from different SNP genotyped healthy individuals. The frequency of the C allele and CC genotype of rs9577873 in GAS6 (Pc = 4.92 * 10(-5), Pc = 1.91 * 10(-5), respectively) and A allele and AA genotype of rs4857037 in PROS1 (Pc = 1.85 * 10(-6), Pc = 4.52 * 10(-7), respectively) were significantly increased in BD. GAS6 expression in CC carriers of rs9577873 was significantly lower than that in CT/TT individuals (P = 0.001). Decreased expression of GAS6 and increased pro inflammatory cytokines (IL-6 and IFN-gamma: P = 4.23 * 10(-4), P = 0.011, respectively) in individuals carrying the CC genotype suggest that the TAM GAS6/PROS1 signal pathway may be involved in the pathogenesis of BD. PMID- 27222360 TI - Risk of early mortality after placement of a temporary-permanent pacemaker. AB - BACKGROUND: Temporary-permanent pacemakers [TPPM] are externally placed permanent generators attached to active fixation transvenous leads. TPPM can be used as an alternative to standard temporary pacing leads when placement of a permanent pacemaker is contraindicated. We sought to determine the incidence and risk factors for early (within 6months) mortality after placement of a TPPM. METHODS: Electronic medical records were used to extract baseline characteristics for 152 patients from Wake Forest Baptist Medical Center who had a TPPM placed between the years 2007 and 2012. Multivariable adjusted Cox proportional hazard models were used to estimate hazard ratios [HR] and 95% confidence intervals [C]) for baseline characteristics [age, sex, race, hypertension, diabetes, heart failure, coronary artery disease, smoking, dyslipidemia, chronic kidney disease [CKD], and indication for pacemaker] on early mortality. RESULTS: Of the 152 patients [mean age 68.9years; 57.2% female; 86.8% white], 45 [29.6%] died within the first 6months after TPPM placement. No deaths occurred as a direct result of TPPM placement, and only 1 patient experienced documented non-fatal complications. Maximum time to PPM from the date of insertion of TPPM was 336days. Using a backward multivariable adjusted hazard regression model, independent risk factors for early mortality were pre-existing CKD [HR (95% CI): 2.240 (1.002-5.010) for eGFR 30-59 and 7.645 (3.594-16.263) for eGFR <30 compared to eGFR >60] and history of smoking [HR (95% CI): 2.015 (1.099-3.696)]. Surprisingly, dyslipidemia was protective of early mortality [HR (95%CI): 0.470 (0.240-0.924)]. CONCLUSION: TPPM placement is a safe procedure with rare direct complications. CKD and smoking are predictive of increased risk for early mortality in patients undergoing TPPM placement. PMID- 27222361 TI - A method of undifferenced ambiguity resolution for GPS+GLONASS precise point positioning. AB - Integer ambiguity resolution is critical for achieving positions of high precision and for shortening the convergence time of precise point positioning (PPP). However, GLONASS adopts the signal processing technology of frequency division multiple access and results in inter-frequency code biases (IFCBs), which are currently difficult to correct. This bias makes the methods proposed for GPS ambiguity fixing unsuitable for GLONASS. To realize undifferenced GLONASS ambiguity fixing, we propose an undifferenced ambiguity resolution method for GPS+GLONASS PPP, which considers the IFCBs estimation. The experimental result demonstrates that the success rate of GLONASS ambiguity fixing can reach 75% through the proposed method. Compared with the ambiguity float solutions, the positioning accuracies of ambiguity-fixed solutions of GLONASS-only PPP are increased by 12.2%, 20.9%, and 10.3%, and that of the GPS+GLONASS PPP by 13.0%, 35.2%, and 14.1% in the North, East and Up directions, respectively. PMID- 27222362 TI - Gene cloning, expression, and characterization of a novel beta-mannanase from the endophyte Paenibacillus sp. CH-3. AB - An endophyte with high yield of beta-mannanase, designated as Paenibacillus sp. CH-3, was isolated from black locust (Robinia pseudoacacia) seeds. The beta mannanase gene (manB) has been cloned, expressed, purified, and characterized. With an open reading frame of 984 bp, the manB gene encodes 327 amino acid residues, which belongs to GH family 5. The recombinant beta-mannanase (ManB) has an apparent molecular weight of 50.4 kDa with an optimal activity level at pH 7.0 and 45 degrees C, and it is stable in the range of pH 4-9. By optimizing, the temperature, isopropyl beta-d-thiogalactoside concentration, and induction time were 28 degrees C, 0.05 mM, and 12 H, respectively. The highest activity reached at 1,054.17 U/mL. In addition, ManB had Km values of 7.30, 8.69, and 27.17 mg/mL for locust bean gum (LBG), guar gum, and konjac glucomannan (KGM), respectively. Its catalytic efficiency (kcat /Km ) was 176.31 mL/(mg.Sec) for LBG, 116.69 mL/(mg.Sec) for guar gum, and 115.49 mL/(mg.Sec) for KGM. The products of glucomannans, which were hydrolyzed by ManB, mainly contain mannobiose, mannotetrose, and a higher manno-oligosaccharide. The characteristics of ManB revealed that it could be exploited as an effective additive in the animal feed industry. PMID- 27222363 TI - Intramuscular Venous Malformation in an Infant Masquerading as Recurrent Gonarthritis. PMID- 27222364 TI - Photoresponsive gelators. AB - Low molecular weight gels can be responsive to a range of external stimuli. The use of light as an external stimulus to modify gels is of particular interest for a number of reasons. Light is a non-invasive trigger. For example, using light it is possible to spatially target a specific area of the gel leading to patterned gel surfaces. Here, we review the different approaches that have been used to form low molecular weight gels that respond to light. PMID- 27222365 TI - Thoracic aortic aneurysms due to giant cell aortitis: three cases and review of the literature. AB - We present three cases of thoracic aortic aneurysms caused by giant cell aortitis. Thoracic aortic aneurysms are common and usually related to hypertension, a bicuspid aortic valve or connective tissue diseases such as Marfan syndrome. Our report serves as a reminder that giant cell aortitis is an unusual yet very important cause of thoracic aortic aneurysm. PMID- 27222366 TI - How would a decision to leave the European Union affect medical research and health in the United Kingdom? PMID- 27222367 TI - Clinical characteristics and outcomes of patients with Hodgkin lymphoma with central nervous system involvement: An international multicenter collaboration. AB - Central nervous system (CNS) involvement is rare in patients with Hodgkin lymphoma (HL). Thus, the clinical features and outcomes are not well described. Cases of histologically confirmed CNS HL diagnosed between 1995 and 2015 were retrospectively identified in institutional (n = 7), national (n = 2), and cooperative group (n = 1) databases. We screened 30,781 patients with HL in our combined databases and identified 21 patients meeting eligibility criteria, an estimated frequency of 0.07%. CNS involvement was present at initial diagnosis in 10 patients (48%) and a feature of relapsed/refractory disease in 11 (52%). Among these 11 patients, the median time from initial diagnosis of HL to development of CNS involvement was 1.9 years (range 0.4-6.6) and the median number of prior lines of therapy was 2 (range 1-7). Altogether, treatments included radiation, multiagent systemic chemotherapy, combined modality therapy, and subtotal resection. The overall response rate was 65%. After a median follow-up of 3.6 years (range 0.8-13.2) from diagnosis of CNS HL, the median PFS and OS were 7.6 and 29 months, respectively. CNS involvement as a feature of relapsed/refractory disease was adversely prognostic for both PFS and OS; however, four patients remain alive and free of relapse at 7-78 months follow-up. CNS involvement in HL is exceedingly rare and has a distinct clinical presentation with predilection for parenchymal lesions with dural extension. Around one-quarter of patients, mostly with CNS involvement at initial HL diagnosis, experience prolonged disease free survival. Am. J. Hematol. 91:894-899, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27222368 TI - Shox2 influences mesenchymal stem cell fate in a co-culture model in vitro. AB - Sinoatrial node (SAN) dysfunction is a common cardiovascular problem, and the development of a cell sourced biological pacemaker has been the focus of cardiac electrophysiology research. The aim of biological pacemaker therapy is to produce SAN-like cells, which exhibit spontaneous activity characteristic of the SAN. Short stature homeobox 2 (Shox2) is an early cardiac transcription factor and is crucial in the formation and differentiation of the sinoatrial node (SAN). The present study aimed to improve pacemaker function by overexpression of Shox2 in canine mesenchymal stem cells (cMSCs) to induce a phenotype similar to native pacemaker cells. To achieve this objective, the cMSCs were transfected with lentiviral pLentis-mShox2-red fluorescent protein, and then co-cultured with rat neonatal cardiomyocytes (RNCMs) in vitro for 5-7 days. The feasibility of regulating the differentiation of cMSCs into pacemaker-like cells by Shox2 overexpression was investigated. Reverse transcription-quantitative polymerase chain reaction and western blotting showed that Shox2-transfected cMSCs expressed high levels of T box 3, hyperpolarization-activated cyclic nucleotide-gated cation channel and Connexin 45 genes, which participate in SAN development, and low levels of working myocardium genes, Nkx2.5 and Connexin 43. In addition, Shox2-transfected cMSCs were able to pace RNCMs with a rate faster than the control cells. In conclusion, these data indicate that overexpression of Shox2 in cMSCs can greatly enhance the pacemaker phenotype in a co-culture model in vitro. PMID- 27222369 TI - Perceiving object affordances through visual and linguistic pathways: A comparative study. AB - It is known that both perceiving visual objects and reading object names automatically activate associated motor codes and modulate motor responses. We examined the nature of these motor activation effects for different effectors (hands and feet), and for pictures and words, across the time course of responding. The compatibility effects elicited by objects and words were comparable for the mean effect size, both were larger for slow than for fast responses and the effects were positively correlated across the stimulus types. Our results support an embodied cognition account in which the perception of objects and words automatically activates perceptual simulations of the associated actions, suggesting that objects and words share cognitive and neural mechanisms for accessing motor codes. However, the compatibility effects for objects and words carried over across trials differently: the compatibility effect for words was sensitive to a previous response, while the effect for objects was more immune to such influence. This result suggests a stronger link between objects and actions through a visual pathway than through a linguistic pathway. PMID- 27222376 TI - The dilemma in prioritizing chemicals for environmental analysis: known versus unknown hazards. AB - A major challenge for society is to manage the risks posed by the many chemicals continuously emitted to the environment. All chemicals in production and use cannot be monitored and science-based strategies for prioritization are essential. In this study we review available data to investigate which substances are included in environmental monitoring programs and published research studies reporting analyses of chemicals in Baltic Sea fish between 2000 and 2012. Our aim is to contribute to the discussion of priority settings in environmental chemical monitoring and research, which is closely linked to chemical management. In total, 105 different substances or substance groups were analyzed in Baltic Sea fish. Polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs) were the most studied substances or substance groups. The majority, 87%, of all analyses comprised 20% of the substances or substance groups, whereas 46 substance groups (44%) were analyzed only once. Almost three quarters of all analyses regarded a POP-substance (persistent organic pollutant). These results demonstrate that the majority of analyses on environmental contaminants in Baltic Sea fish concern a small number of already regulated chemicals. Legacy pollutants such as POPs pose a high risk to the Baltic Sea due to their hazardous properties. Yet, there may be a risk that prioritizations for chemical analyses are biased based on the knowns of the past. Such biases may lead to society failing in identifying risks posed by yet unknown hazardous chemicals. Alternative and complementary ways to identify priority chemicals are needed. More transparent communication between risk assessments performed as part of the risk assessment process within REACH and monitoring programs, and information on chemicals contained in consumer articles, would offer ways to identify chemicals for environmental analysis. PMID- 27222377 TI - The Author's Reply: Changing testosterone had no direct effect on HbA1c or weight in diabetic men when TRT was interrupted and then resumed. PMID- 27222378 TI - Spatial localization and distribution of the TMS-related 'hotspot' of the tibialis anterior muscle representation in the healthy and post-stroke motor cortex. AB - Transcranial magnetic stimulation (TMS) is a type of noninvasive brain stimulation used to study corticomotor excitability of the intact and injured brain. Identification of muscle representations in the motor cortex is typically done using a procedure called 'hotspotting', which involves establishing the optimal location on the scalp that evokes a maximum TMS response with minimum stimulator intensity. The purpose of this study was to report the hotspot locations for the tibialis anterior (TA) muscle representation in the motor cortex of healthy and post stroke individuals. A retrospective data analyses from 42 stroke participants and 32 healthy participants was conducted for reporting TMS hotspot locations and their spatial patterns. Single pulse TMS, using a 110mm double cone coil, was used to identify the motor representation of the TA. The hotspot locations were represented as x and y-distances from the vertex for each participant. The mediolateral extent of the loci from the vertex (x-coordinate) and anteroposterior extent of the loci from the vertex (y-coordinate) was reported for each hemisphere: non-lesioned (XNLes, YNLes), lesioned (XLes, YLes) and healthy (XH, YH). We found that the mean hotspot loci for TA muscle from the vertex were approximately: 1.29cm lateral and 0.55cm posterior in the non lesioned hemisphere, 1.25cm lateral and 0.5cm posterior in the lesioned hemisphere and 1.6cm lateral and 0.8cm posterior in the healthy brain. There was no significant difference in the x- and y-coordinates between the lesioned and non-lesioned hemispheres. However, the locations of the XNLes (p=0.01) and XLes (p=0.004) were significantly different from XH. The YNLes and YLes showed no significant differences from YH loci. Analyses of spatial clustering patterns using the Moran's I index showed a negative autocorrelation in stroke participants (NLes: Moran's I=-0.09, p<0.001; Les: Moran's I=-0.14, p=0.002), and a positive autocorrelation in healthy participants (Moran's I=0.16, p<0.001), suggesting that individuals with stroke demonstrated a more dispersed pattern of hotspot locations than healthy individuals. Our results suggest that the hotspot loci show different spatial patterns in healthy and stroke individuals. The hotspot locations from this study has the potential to provide a guideline for optimal stimulation locations for the TA muscle in healthy and post stroke individuals for neuromodulation procedures such as transcranial direct current stimulation. PMID- 27222379 TI - Effects of WR1065 on 6-hydroxydopamine-induced motor imbalance: Possible involvement of oxidative stress and inflammatory cytokines. AB - Over production of reactive oxygen species (ROS) is postulated to be the main contributor in degeneration of nigrostriatal dopaminergic neurons. In this study we investigated the effects of WR1065, a free radical scavenger, on motor imbalance, oxidative stress parameters and inflammatory cytokines in CSF and brain of hemi-parkinsonian rats. Lesion of dopaminergic neurons was done by unilateral infusion of 6-hydroxydopamine into the central region of the substentia nigra pars compacta (SNc) to induce hemi-parkinsonism and motor imbalance in rats. WR1065 (20, 40 and 80MUg/2MUl/rat) was administered three days before 6-OHDA administration. After three weeks behavioral study was performed and then brain and CSF samples were collected to assess tumor necrosis factor (TNFalpha), interlukin (IL-1beta), reduced glutathione (GSH), and malondialdehyde (MDA). WR1065 pre-treatment in rats before receiving 6-OHDA, improved significantly motor impairment and caused reduction of MDA and inflammatory cytokines TNFalpha and IL-1beta levels, while GSH level significantly increased when compared with lesioned rats. Our study indicated that WR1065 could improve 6 OHDA-induced motor imbalance. Furthermore, it decreased lipid peroxidation and inflammatory cytokines and restored the level of GSH up to normal range. We suggest that WR1065 can be proposed as a potential neuroprotective agent in motor impairments of PD. However to prove this hypothesis more clinical trial studies should be done. PMID- 27222380 TI - Directed evolution of Vibrio fischeri LuxR signal sensitivity. AB - LuxR is the core component of Vibrio fischeri quorum sensing. It acts as the transcriptional activator by binding to its cognate signaling molecules 3-oxo hexanoyl-homoserine lactone (3OC6HSL). Although several acyl-HSLs with 3-oxo groups are known to activate LuxR with similar efficiency, acyl-HSLs without 3 oxo groups are very weak inducers. We conducted a round of LuxR directed evolution to acquire LuxR mutants with higher signal sensitivity to octanoyl homoserine lactone (C8HSL). All of the isolated mutants showed increased signal sensitivity to many other acyl-HSLs, including C8HSL, and some to the LuxR antagonist p-coumaroyl-HSL. The evolution of their ligand sensitivity proceeded through the stabilization of the signal-bound state, thereby elevating the effective concentration of LuxR at the ON-state. PMID- 27222382 TI - Connectivity Reveals Sources of Predictive Coding Signals in Early Visual Cortex During Processing of Visual Optic Flow. AB - Superimposed on the visual feed-forward pathway, feedback connections convey higher level information to cortical areas lower in the hierarchy. A prominent framework for these connections is the theory of predictive coding where high level areas send stimulus interpretations to lower level areas that compare them with sensory input. Along these lines, a growing body of neuroimaging studies shows that predictable stimuli lead to reduced blood oxygen level-dependent (BOLD) responses compared with matched nonpredictable counterparts, especially in early visual cortex (EVC) including areas V1-V3. The sources of these modulatory feedback signals are largely unknown. Here, we re-examined the robust finding of relative BOLD suppression in EVC evident during processing of coherent compared with random motion. Using functional connectivity analysis, we show an optic flow dependent increase of functional connectivity between BOLD suppressed EVC and a network of visual motion areas including MST, V3A, V6, the cingulate sulcus visual area (CSv), and precuneus (Pc). Connectivity decreased between EVC and 2 areas known to encode heading direction: entorhinal cortex (EC) and retrosplenial cortex (RSC). Our results provide first evidence that BOLD suppression in EVC for predictable stimuli is indeed mediated by specific high-level areas, in accord with the theory of predictive coding. PMID- 27222381 TI - MicroRNA-224 promotes the sensitivity of osteosarcoma cells to cisplatin by targeting Rac1. AB - Osteosarcoma is the most common primary bone tumour in children and adolescents. Accumulating evidence has shown that microRNAs (miRNAs) participate in the development of almost all types of cancer. Here, we investigated the role of miR 224 in the development and progression of osteosarcoma. We demonstrated that miR 224 was down-regulated in osteosarcoma cell lines and tissues. Lower miR-224 levels were correlated with shorter survivalin osteosarcoma patients. Furthermore, overexpression of miR-224 suppressed osteosarcoma cell proliferation, migration and invasion and contributed to the increased sensitivity of MG-63 cells to cisplatin. We identified Rac1 as a direct target gene of miR-224 in osteosarcoma. Rac1 expression was up-regulated in the osteosarcoma cell lines and tissues, and there was an inverse correlation between Rac1 and miR-224 expression in osteosarcoma tissues. Furthermore, rescuing Rac1 expression decreased the sensitivity of miR-224-overexpressing MG-63 cells to cisplatin. We also demonstrated that ectopic expression of Rac1 promoted the proliferation, migration and invasion of miR-224-overexpressing MG-63 cells. These data suggest that miR-224 plays a tumour suppressor role in the development of osteosarcoma and is related to the sensitivity of osteosarcoma to cisplatin. PMID- 27222383 TI - Artificial dermal templates: A comparative study of NovoSorbTM Biodegradable Temporising Matrix (BTM) and Integra((r)) Dermal Regeneration Template (DRT). AB - BACKGROUND: Artificial dermal templates play an important role in physiologic wound closure after injury. In addition to contributing to stable, durable and flexible wound closure, they provide a scaffold for tissue repair. Several dermal templates are commercially available, with animal-derived Integra((r)) dermal regeneration template perhaps the most widely used. NovoSorbTM Biodegradable Temporising Matrix (BTM) is a fully synthetic alternative that eliminates any risk of cross-species residual antigenicity. In this study, we aimed to compare early response after application of NovoSorbTM BTM with Integra((r)) in terms of temporary wound closure, host cell infiltration, neovascularisation and collagen deposition in a mouse model. METHODS: Twenty athymic nude mice received full thickness skin excision followed by grafting of the dermal template (n=10 NovoSorbTM BTM, n=10 Integra((r))), with the grafts excised and assessed after two weeks. RESULTS: All twenty mice achieved temporary wound closure with no evidence of wound contracture. Microscopically, all twenty grafts became infiltrated with host cells along the entire length of the template, with NovoSorbTM BTM demonstrating a particular abundance of host inflammatory cells. Evidence of new collagen deposition and neovascularisation was observed in both templates, with NovoSorbTM BTM demonstrating a more extensive vascular network at this time point. However, a greater inflammatory response was also observed in the NovoSorbTM BTM grafts at this time point. CONCLUSIONS: In this study, NovoSorbTM BTM demonstrates favourable properties as a dermal template, but further investigation is required to assess the significance of the differing inflammatory and vascular response to its implantation compared with Integra((r)). PMID- 27222384 TI - Synergistic effect of vitamin D and low concentration of transforming growth factor beta 1, a potential role in dermal wound healing. AB - Dermal wound healing, in which transforming growth factor beta 1 (TGFbeta1) plays an important role, is a complex process. Previous studies suggest that vitamin D has a potential regulatory role in TGFbeta1 induced activation in bone formation, and there is cross-talk between their signaling pathways, but research on their effects in other types of wound healing is limited. The authors therefore wanted to explore the role of vitamin D and its interaction with low concentration of TGFbeta1 in dermal fibroblast-mediated wound healing through an in vitro study. Human dermal fibroblasts were treated with vitamin D, TGFbeta1, both, or vehicle, and then the wound healing functions of dermal fibroblasts were measured. To further explore possible mechanisms explaining the synergistic effect of vitamin D and TGFbeta1, targeted gene silencing of the vitamin D receptor was performed. Compared to either factor alone, treatment of fibroblasts with both vitamin D and low concentration of TGFbeta1 increased gene expression of TGFbeta1, connective tissue growth factor, and fibronectin 1, and enhanced fibroblast migration, myofibroblast formation, and collagen production. Vitamin D receptor gene silencing blocked this synergistic effect of vitamin D and TGFbeta1 on both collagen production and myofibroblast differentiation. Thus a synergistic effect of vitamin D and low TGFbeta1 concentration was found in dermal fibroblast mediated wound healing in vitro. This study suggests that supplementation of vitamin D may be an important step to improve wound healing and regeneration in patients with a vitamin D deficiency. PMID- 27222385 TI - Management of stable angina: A commentary on the European Society of Cardiology guidelines. AB - In 2013 the European Society of Cardiology (ESC) released new guidelines on the management of stable coronary artery disease. These guidelines update and replace the previous ESC guidelines on the management of stable angina pectoris, issued in 2006. There are several new aspects in the 2013 ESC guidelines compared with the 2006 version. This opinion paper provides an in-depth interpretation of the ESC guidelines with regard to these issues, to help physicians in making evidence based therapeutic choices in their routine clinical practice. The first new element is the definition of stable coronary artery disease itself, which has now broadened from a 'simple' symptom, angina pectoris, to a more complex disease that can even be asymptomatic. In the first-line setting, the major changes in the new guidelines are the upgrading of calcium channel blockers, the distinction between dihydropyridines and non-dihydropyridine calcium channel blockers, and the presence of important statements regarding the combination of calcium channel blockers with beta-blockers. In the second-line setting, the 2013 ESC guidelines recommend the addition of long-acting nitrates, ivabradine, nicorandil or ranolazine to first-line agents. Trimetazidine may also be considered. However, no clear distinction is made among different second-line drugs, despite different quality of evidence in favour of these agents. For example, the use of ranolazine is supported by strong and recent evidence, while data supporting the use of the traditional agents appear relatively scanty. PMID- 27222386 TI - Occult coronary artery disease in middle-aged sportsmen with a low cardiovascular risk score: The Measuring Athlete's Risk of Cardiovascular Events (MARC) study. AB - BACKGROUND: Most exercise-related cardiac arrests in men aged >=45 years are due to coronary artery disease (CAD). The current sports medical evaluation (SME) of middle-aged sportsmen includes medical history, physical examination and resting and exercise electrocardiography (ECG). We investigated the added value of low dose cardiac computed tomography (CCT) - both non-contrast CT for coronary artery calcium scoring (CACS) and contrast-enhanced coronary CT angiography (CCTA) - in order to detect occult CAD in asymptomatic recreational sportsmen aged >=45 years without known cardiovascular disease. METHODS: Following a normal SME (with resting and bicycle exercise ECG), 318 asymptomatic sportsmen underwent CCT and 300 (94%) had a low European Society of Cardiology Systematic Coronary Risk Evaluation (SCORE) risk. Occult CAD was defined as a CACS >=100 Agatston units (AU) or obstructive (>=50%) luminal stenosis on CCTA. The number needed to screen (NNS) in order to prevent one cardiovascular event within 5 years with statin treatment was estimated. RESULTS: Fifty-two (16.4%, 95% confidence interval (CI): 12.7-20.8%) of 318 participants had a CACS >=100 AU. The CCTA identified an additional eight participants with luminal narrowing >=50% (and a CACS <100 AU). Taken together, CCT identified CAD in 60 (18.9%, 95% CI: 14.9-23.5%) of 318 participants. The 5-year estimated NNS was 183 (95% CI: 144-236) for CACS and 159 (95% CI: 128-201) for CACS combined with CCTA. CONCLUSIONS: Coronary CT detects occult CAD in almost one in five asymptomatic sportsmen aged >=45 years after a normal SME that included resting and bicycle exercise ECG. CACS reveals most of the relevant CAD with limited additional value of contrast-enhanced CCTA. The NNS in order to prevent one cardiovascular event compares favourably to that of other screening tests. PMID- 27222389 TI - The Multifaceted Roles of Adipose Tissue-Therapeutic Targets for Diabetes and Beyond: The 2015 Banting Lecture. AB - The Banting Medal for Scientific Achievement is the highest scientific award of the American Diabetes Association (ADA). Given in memory of Sir Frederick Banting, one of the key investigators in the discovery of insulin, the Banting Medal is awarded annually for scientific excellence, recognizing significant long term contributions to the understanding, treatment, or prevention of diabetes. Philipp E. Scherer, PhD, of the Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, TX, received the prestigious award at the ADA's 75th Scientific Sessions, 5-9 June 2015, in Boston, MA. He presented the Banting Lecture, "The Multifaceted Roles of Adipose Tissue-Therapeutic Targets for Diabetes and Beyond," on Sunday, 7 June 2015.A number of different cell types contribute to the cellular architecture of adipose tissue. Although the adipocyte is functionally making important contributions to systemic metabolic homeostatis, several additional cell types contribute a supportive role to bestow maximal flexibility on the tissue with respect to many biosynthetic and catabolic processes, depending on the metabolic state. These cells include vascular endothelial cells, a host of immune cells, and adipocyte precursor cells and fibroblasts. Combined, these cell types give rise to a tissue with remarkable flexibility with respect to expansion and contraction, while optimizing the ability of the tissue to act as an endocrine organ through the release of many protein factors, critically influencing systemic lipid homeostasis and biochemically contributing many metabolites. Using an example from each of these categories-adiponectin as a key adipokine, sphingolipids as critical mediators of insulin sensitivity, and uridine as an important metabolite contributed by the adipocyte to the systemic pool-I will discuss the emerging genesis of the adipocyte over the past 20 years from metabolic bystander to key driver of metabolic flexibility. PMID- 27222390 TI - Selective Insulin Resistance and the Development of Cardiovascular Diseases in Diabetes: The 2015 Edwin Bierman Award Lecture. AB - The Edwin Bierman Award Lecture is presented in honor of the memory of Edwin L. Bierman, MD, an exemplary scientist, mentor, and leader in the field of diabetes, obesity, hyperlipidemia, and atherosclerosis. The award and lecture recognizes a leading scientist in the field of macrovascular complications and contributing risk factors in diabetes. George L. King, MD, of the Section of Vascular Cell Biology and Complications, Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, MA, received the prestigious award at the American Diabetes Association's 75th Scientific Sessions, 5-9 June 2015, in Boston, MA. He presented the Edwin Bierman Award Lecture, "Selective Insulin Resistance and the Development of Cardiovascular Disease in Diabetes," on Sunday, 7 June 2015.This review is focused on the factors and potential mechanisms that are causing various cardiovascular pathologies. In diabetes, insulin's actions on the endothelium and other vascular cells have significant influence on systemic metabolisms and the development of cardiovascular pathologies. Our studies showed that insulin receptors on the endothelium are important for insulin transport across the endothelial barrier and mediate insulin's actions in muscle, heart, fat, and the brain. Insulin actions on the vascular cells are mediated by two pathways involving the actions of either IRS/PI3K/Akt or Grb/Shc/MAPK. Insulin's activation of IRS/PI3K/Akt results in mostly antiatherogenic actions, as this pathway induces activation of eNOS, the expressions of HO-1 and VEGF, and the reduction of VCAM-1. In contrast, insulin's activation of the Grb/Shc/MAPK pathway mediates the expressions of ET-1 and PAI-1 and migration and proliferation of contractile cells, which have proatherogenic actions. Elevated levels of glucose, free fatty acids, and inflammatory cytokines due to diabetes and insulin resistance selectively inhibit insulin's antiatherogenic actions via the IRS/PI3K/Akt pathway. This review provides evidence to support the importance of insulin actions in preventing cardiovascular pathology that can be selectively inhibited via the IRS/PI3K/Akt cascade in diabetes. PMID- 27222391 TI - A Reevaluation of the Role of the Unfolded Protein Response in Islet Dysfunction: Maladaptation or a Failure to Adapt? AB - Endoplasmic reticulum (ER) stress caused by perturbations in ER homeostasis activates an adaptive response termed the unfolded protein response (UPR) whose function is to resolve ER stress. If unsuccessful, the UPR initiates a proapoptotic program to eliminate the malfunctioning cells from the organism. It is the activation of this proapoptotic UPR in pancreatic beta-cells that has been implicated in the onset of type 2 diabetes and thus, in this context, is considered a maladaptive response. However, there is growing evidence that beta cell death in type 2 diabetes may not be caused by a maladaptive UPR but by the inhibition of the adaptive UPR. In this review, we discuss the evidence for a role of the UPR in beta-cell dysfunction and death in the development of type 2 diabetes and ask the following question: Is beta-cell dysfunction the result of a maladaptive UPR or a failure of the UPR to adequately adapt? The answer to this question is critically important in defining potential therapeutic strategies for the treatment and prevention of type 2 diabetes. In addition, we discuss the potential role of the adaptive UPR in staving off type 2 diabetes by enhancing beta-cell mass and function in response to insulin resistance. PMID- 27222392 TI - Unraveling the Paradox of Selective Insulin Resistance in the Liver: the Brain Liver Connection. PMID- 27222393 TI - A NEET Way to Impair Mitochondrial Function in alpha- and beta-Cells. PMID- 27222394 TI - Glucagon-Like Peptide 1 Receptor Activation and Platelet Function: Beyond Glycemic Control. PMID- 27222395 TI - Linking MTNR1B Variants to Diabetes: The Role of Circadian Rhythms. PMID- 27222396 TI - Targeting AMP Kinase in Myeloid Cells to Reduce Atherosclerosis. PMID- 27222397 TI - DYRK1A: A Promising Drug Target for Islet Transplant-Based Diabetes Therapies. PMID- 27222398 TI - Erratum. Evidence of Extrapancreatic Glucagon Secretion in Man. Diabetes 2016;65:585-597. PMID- 27222400 TI - Comment on Goldsworthy et al. Haploinsufficiency of the Insulin Receptor in the Presence of a Splice-Site Mutation in Ppp2r2a Results in a Novel Digenic Mouse Model of Type 2 Diabetes. Diabetes 2016;65:1434-1446. PMID- 27222401 TI - Taibaiella soli sp. nov., isolated from pine forest soil. AB - A Gram-stain-negative, motile by gliding, non-spore-forming and oval-shaped bacterial strain designated T1-10T was isolated from pine forest soil, and its taxonomic position was investigated using a polyphasic approach. Growth occurred at 10-37 degrees C (optimum, 30 degrees C), at pH 6-7 and in the presence of 0 1 % (w/v) (optimum, 0 %) NaCl. Flexirubin-type pigments were produced. On the basis of 16S rRNA gene sequence similarity, strain T1-10T was assigned to the genus Taibaiella of the phylum Bacteroidetes, and the most closely related species was Taibaiella koreensis THG-DT86T with 97.11 % sequence similarity, but the strain formed an independent lineage in the phylogenetic tree. The genomic DNA G+C content of strain T1-10T was 42.5 mol%. The main cellular fatty acids were iso-C15 : 1 G, iso-C15 : 0 and iso-C17 : 0 3-OH. The only isoprenoid quinone detected in the strain was MK-7, and the major polyamine was homospermidine. The major polar lipids were phosphatidylethanolamine and unidentified aminophospholipids. Strain T1-10T could be distinguished from related species by physiological and biochemical properties. Phenotypic and phylogenetic data supported that strain T1-10T represents a novel species of the genus Taibaiella, for which the name Taibaiella soli sp. nov. is proposed (type strain T1-10T=KCTC 42277T=JCM 31014T). PMID- 27222402 TI - Systemic inflammatory markers as prognostic factors in stage IIA colorectal cancer. AB - BACKGROUND: The aim of this study was to evaluate systemic inflammatory markers as prognostic factors in patients with stage IIA colorectal cancer. METHODS: Among the patients who underwent curative resection for colorectal cancer at Seoul National University Hospital between 2002 and 2010, 1,035 who were classified as postoperative pathologic stage IIA (T3N0M0) were included. Systemic inflammatory markers, such as the neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), platelet-to-lymphocyte ratio (PLR), prognostic nutritional index (PNI), and serum fibrinogen level, were retrospectively reviewed. The patients were divided into two groups according to the cut-off values of the systemic inflammatory markers after receiver operating characteristic (ROC) curve analysis. Survival analysis was performed to identify factors associated with disease-free survival (DFS) and overall survival (OS). RESULTS: Age, American Society of Anesthesiologists (ASA) score, tumor location, number of harvested lymph nodes, venous invasion, perineural invasion, adjuvant treatment and PNI (HR = 1.534, 95%CI: 1.065-2.211, P = 0.022; HR = 1.915, 95%CI: 1.286-2.852, P = 0.001 for DFS and OS, respectively) were independent significant prognostic factors for both DFS and OS. CONCLUSIONS: PNI can be a prognostic marker in stage IIA colorectal cancer. J. Surg. Oncol. 2016;114:216-221. (c) 2016 Wiley Periodicals, Inc. PMID- 27222404 TI - Prevalence of vitamin B-12 deficiency among patients with thyroid dysfunction. AB - Due to the non-specificity of symptoms and possibly severe consequences of untreated vitamin B-12 deficiency, screening is important for at-risk patients to ensure the prompt delivery of treatment. In this review, studies assessing the prevalence of vitamin B-12 deficiency in thyroid dysfunction are evaluated to determine whether regular vitamin B-12 screening is necessary. A literature search was conducted using multiple electronic databases. Only original studies assessing the prevalence of vitamin B-12 deficiency in thyroid dysfunction that reported their findings as percentages of the sample were eligible for inclusion. From a total of 7091 manuscripts generated, 6 were included in this review. The prevalence of vitamin B-12 deficiency in hypothyroidism was reported as 10, 18.6, and 40.5% in three separate studies. The prevalence of deficiency in autoimmune thyroid disease was reported as 6.3, 28, and 55.5% in three studies. The prevalence of vitamin B-12 deficiency in hypothyroidism and autoimmune thyroid disease are reflective of the nutrition status of the population. Autoimmune thyroid disease is also associated with the autoimmune disorders pernicious anemia and atrophic gastritis which may lead to malabsorption of vitamin B-12. Vitamin B-12 screening is recommended upon initial diagnosis with autoimmune thyroid disease and then periodically thereafter. There is not enough evidence to recommend regular screening for patients with hypothyroidism unless the underlying cause is autoimmune thyroid disease. PMID- 27222403 TI - A simple DNA handle attachment method for single molecule mechanical manipulation experiments. AB - Manipulating single molecules and systems of molecules with mechanical force is a powerful technique to examine their physical properties. Applying force requires attachment of the target molecule to larger objects using some sort of molecular tether, such as a strand of DNA. DNA handle attachment often requires difficult manipulations of the target molecule, which can preclude attachment to unstable, hard to obtain, and/or large, complex targets. Here we describe a method for covalent DNA handle attachment to proteins that simply requires the addition of a preprepared reagent to the protein and a short incubation. The handle attachment method developed here provides a facile approach for studying the biomechanics of biological systems. PMID- 27222405 TI - Intake of added sugar in Malaysia: a review. AB - The term 'added sugars' refers to sugars and syrup added to foods during processing or preparation, and sugars and syrups added at the table. Calls to limit the daily intakes of added sugars and its sources arose from evidence analysed by WHO, the American Heart Association and other organizations. The present review examined the best available evidence regarding levels of added sugar consumption among different age and sex groups in Malaysia and sources of added sugars. Information was extracted from food balance sheets, household expenditure surveys, nutrition surveys and published studies. Varying results emerged, as nationwide information on intake of sugar and foods with added sugar were obtained at different times and used different assessment methods. Data from the 2003 Malaysian Adult Nutrition Survey (MANS) using food frequency questionnaires suggested that on average, Malaysian adults consumed 30 grams of sweetened condensed milk (equivalent to 16 grams sugar) and 21 grams of table sugar per day, which together are below the WHO recommendation of 50 grams sugar for every 2000 kcal/day to reduce risk of chronic disease. Published studies suggested that, for both adults and the elderly, frequently consumed sweetened foods were beverages (tea or coffee) with sweetened condensed milk and added sugar. More accurate data should be obtained by conducting population-wide studies using biomarkers of sugar intake (e.g. 24-hour urinary sucrose and fructose excretion or serum abundance of the stable isotope 13C) to determine intake levels, and multiple 24 hour recalls to identify major food sources of added sugar. PMID- 27222406 TI - beta-carotene losses due to handling and cooking in Kenyan leafy vegetables connote no comparative nutritional superiority over kales. AB - African leafy vegetables (ALVs) are known to be high in beta-carotene content and are preferred over kales due to this nutritional superiority. Ten different vegetables were collected from farm and market locations and analyzed for beta carotene content. Cooked vegetables (in single or in combination) as well as solar dried samples were prepared by the community members in the study area in the usual way and without any instruction or conditions given. beta-carotene content was analyzed using a High Performance Liquid Chromatography (HPLC). The results provided new representative beta-carotene content of the fresh, marketed, cooked and dried vegetables without controlling or simulating the household handling or processing methods in a laboratory. While edible portions of kales are relatively inferior as a beta-carotene source as compare to ALVs when in raw form, this is not the case at market place where kales exhibit comparable level of the beta-carotene. As much as 280 MURE/100 g (a dietarily significant amount) can be lost through beta-carotene oxidation before farm-fresh ALVs are sold in the market place with the losses severe in some ALVs and only subtle and relatively lower in kales. Post-cooking, kales had statistically comparable beta carotene content to ALVs save for when compared with purple amaranths and blacknight shade. Due to losses experienced in ALVs, kales are not comparatively inferior vegetables in terms of beta-carotene content. Measures to prevent beta carotene losses in ALVs between the farm and market, during cooking and drying should be instituted in order to benefit from their high beta-carotene content. PMID- 27222407 TI - Nutritional Risk Screening in patients with chronic kidney disease. AB - Knowledge concerning nutritional status of patients with chronic kidney disease (CKD) is limited. Nutritional Risk Screening-2002 (NRS-2002) has been used to evaluate the nutritional aspects of patients according to the recommendation of European Society for Clinical Nutrition and Metabolism. Here we aim to assess the prevalence and characteristics of nutritional risk in CKD patients by using NRS 2002. NRS-2002 scores of 292 CDK patients were recorded in first 24 hours subsequent to their admission to hospital. All patients have never been on dialysis. BMI, weight and various biochemical parameters were also characterized for these patients. Possible correlations between these parameters and NRS-2002 score were investigated. The overall prevalence of nutritional risk was 44.9% (53.6% in CKD stage 4-5 patients and 38.3% in stage 1-3 patients). Statistically significant differences were found in serum Albumin, Haemoglobin B, and lymphocyte counts between patients with or without increased nutritional risk. Under the situation that attending physicians were completely unaware of NRS-2002 scores, only 35.1% of the patients at risk received nutritional support. The nutritional risk status was associated with CKD stages but independent from primary diagnosis type. More attention should be paid to the nutritional status in CKD patients (including early stage patients). We recommended using NRS-2002 for nutritional risk assessment among non-dialysis CKD patients in routine clinical practice. PMID- 27222408 TI - Validation of the Leeds Food Preference Questionnaire in Arabs. AB - The Leeds Food Preference Questionnaire (LFPQ) is a computerised procedure that assesses liking, wanting and relative preferences for shared characteristics of food. This study adapted the LFPQ (LFPQ-A) to assess its cross-cultural validity in an Arab sample by examining its performance for food characteristics of fat (high or low) and taste (sweet or nonsweet), under fasted and fed states. Individual differences in eating behaviour were examined by testing for associations between the LFPQ-A outcomes and subscales of the Three Factor Eating Questionnaire (TFEQ). Thirty healthy males (age: 36.3+/-10.0 years; body mass index: 29.7+/-5.3 kg/m2) participated in the study. All participants attended the laboratory in the morning following an overnight fast, and performed the LFPQ-A under fasted and fed conditions (after a standardised test meal). Results showed that implicit wanting and relative preference for non-sweet foods decreased in the fed compared to the fasted state, whereas scores for sweet foods increased. Explicit liking and explicit wanting were also higher for non-sweet foods in the fasted condition, and decreased to a greater extent in the fed condition compared to a lesser decrease for sweet foods. Scores on all LFPQ-A outcomes for high-fat non-sweet foods were positively associated with TFEQ Disinhibition. Outcome scores for low-fat non-sweet foods were positively associated with TFEQ Restraint. The LFPQ-A showed outcomes that were consistent with studies performed in Western samples, therefore the current study helps to confirm the validity of the LFPQ-A as a measurement of liking and wanting and preference for food among Arabs. PMID- 27222409 TI - Open-labelled observations of language dysfunction in old ischemic stroke patients with aphasia when given plant and marine-based nutrient supplements for 12 weeks. AB - BACKGROUND AND OBJECTIVES: This study aimed to explore the effect of functional foods on aphasia related to a previous ischemic stroke. When stroke-related neurological deficits result in physical dependency and poor selfcare that persists longer than 6 months, full recovery is almost impossible and the patient often requires long-term care. The functional foods, EASE123 and BioBalance#6, include numerous plant and marine-based nutrient supplements that could prove beneficial for such patients. METHODS AND STUDY DESIGN: This open-labelled study included 10 patients diagnosed with prior ischemic stroke and aphasia lasting longer than 6 months. Each patient was administered 6 tablets of EASE123 at 10:30 AM and at 90 minutes before sleeping, and 3 tablets of BioBalance# 6 at 2:30 PM. After a treatment period of 12 weeks, the patients were followed during a 4-week withdrawal period. Functional improvement was assessed by scores and subscores on the Concise Chinese Aphasia Test (CCAT) at weeks 4, 8, 12, and 16. RESULTS: Average total CCAT scores and matching ability improved significantly at weeks 4, 8, 12, and 16 (p<0.05). Simple response scores improved significantly at weeks 8 and 12 (p<0.05). Auditory comprehension improved significantly at weeks 4 and 12 (p<0.05), and reading comprehension, at week 12 (p<0.05). Repetition ability improved significantly at weeks 8, 12, and 16 (p<0.05), and spontaneous writing, at weeks 4, 12, and 16 (p<0.05). CONCLUSIONS: Matching, repetition, and average total CCAT scores improved over the course of the study. Therefore, 6 months after ischemic stroke, EASE123 and BioBalance# 6 administration may improve stroke-related aphasia. PMID- 27222410 TI - Nutritional risk, malnutrition and nutritional support among hospitalized patients in orthopedics/spinal surgery of a Hohhot teaching hospital. AB - The evolution of nutritional status (the prevalence of nutritional risk, malnutrition, overweight and obesity) and the nutritional support of the hospitalized patients from admission to discharge or over a two-week period in orthopedics/ spinal surgery of a teaching hospital in Hohhot were investigated. 432 patients from two wards of the orthopedics/spinal surgery from Jan to Dec 2013, the traditional spinal surgery and the minimally invasive spinal surgery, were selected and detected in this study. The Nutritional Risk Score 2002 (NRS 2002) was used to determine the patients' nutritional status within 48 h after admission and during their hospitalization. The overall prevalence of nutritional risk, malnutrition, overweight and obesity at admission was 11.6%, 12.7%, 35.9% and 7.41%, respectively. Overall, there were 88.0% of the patients who were at nutritional risk received nutritional support, while 14.1% of non-risk patients received a redundant nutritional support. The overall prevalence of nutritional risk changed from 11.6% at admission to 19.4% upon discharge (p<0.05), and the prevalence of malnutrition changed from 12.7% to 20.6% (p<0.05). The prevalence of overweight and obesity, which changed from 35.9% to 31.0% and from 7.41% to 5.79% respectively, didn't experience statistically significant evolution. NRS 2002 was a feasible nutritional risk screening tool for patients in spinal surgery of orthopedics department. Patients' prevalence of nutritional risk and malnutrition increased significantly in spinal surgery of this hospital. Some inappropriate uses of nutritional support were observed in orthopedics/spinal surgery, and nutritional support guidelines or protocols should be promoted by a professional committee. PMID- 27222411 TI - Nutrition status and small intestinal bacterial overgrowth in patients with virus related cirrhosis. AB - Malnutrition and small intestinal bacterial overgrowth (SIBO) is frequently present in patients with liver cirrhosis (LC). However, the direct relationship between SIBO and nutrition status in the LC patients has not been elucidated. The aim of this study was to investigate whether there was an association between nutrition status, evaluated by the subjective global assessment (SGA) and SIBO in patients with Hepatitis B virus (HBV) or hepatitis C virus (HCV) related cirrhosis. A total of 120 patients with HBV or HCV-related cirrhosis and 30 healthy controls were included. Nutritional status was determined according to SGA and anthropometry. All patients and healthy controls underwent a glucose hydrogen breath test for SIBO. The prevalence of malnutrition for the patients with HBV or HCV related cirrhosis ranged 19.4%-60% in China. The highest prevalence of malnutrition was detected by SGA, the lowest by triceps skinfold thickness. The frequency of SIBO was significantly higher in the malnourished (SGA-B/C) than in the well-nourished (SGA-A) patients with HBV or HCV related cirrhosis [41/72 (56.9%) vs 12/48 (25.0%) (p=0.001)]. Univariate analysis showed that SIBO, ascites, and Child-Turcotte-Pugh (CTP) class were associated with malnutrition. Multivariate analysis demonstrated that SIBO [odds ratio (OR) 8.10; p=0.002] and ascites (OR 4.56; p=0.022) were independently associated with the occurrence of malnutrition (SGA-B/C) in the same subjects. SIBO is independently related to the occurrence of malnutrition (SGA-B/C) in patients with HBV or HCV cirrhosis. We deduce that SIBO may play an important role in nutrition status in patients with HBV or HCV cirrhosis. PMID- 27222412 TI - Prevalence of protein-energy wasting (PEW) and evaluation of diagnostic criteria in Japanese maintenance hemodialysis patients. AB - BACKGROUND AND OBJECTIVES: The International Society of Renal Nutrition and Metabolism (ISRNM) has recently recommended the use of the term "protein-energy wasting" (PEW). PEW is a state of malnutrition with decreased body stores of protein and energy fuel in hemodialysis patients and is known as a risk factor for morbidity and mortality. We examined the prevalence of PEW and the characteristics of PEW patients in a hemodialysis center in Japan. METHODS AND STUDY DESIGN: Fifty-nine outpatients undergoing maintenance hemodialysis at Iga City General Hospital were evaluated. We observed their biochemical data, body composition, dietary intake, and the number of steps prospectively. PEW was defined according to ISRNM criteria. RESULTS: Nine patients (15% of total) were diagnosed as having PEW. Among indicators of PEW criteria, the relevance ratios of "reduced muscle mass" and "unintentional low dietary energy intake" were significantly higher in PEW than in non-PEW. The number of steps was lower, and serum levels of glucose and C-reactive protein were higher in PEW. CONCLUSION: About 15% of Japanese hemodialysis patients are estimated to have PEW. Our results suggested that major contributing factors to PEW were reduced muscle mass, unintentional low dietary energy intake, lower amount of exercise, insulin resistance, and chronic inflammation. PMID- 27222413 TI - Short-term consequences of continuous renal replacement therapy on body composition and metabolic status in sepsis. AB - BACKGROUND AND OBJECTIVES: Fluid overload and hypermetabolism frequently occur in sepsis patients in the intensive care unit (ICU) setting. These abnormalities correlate with inflammatory mediators released under stressful conditions. Continuous renal replacement therapy (CRRT) is an extracorporeal life support technology that persistently and stably eliminates overhydration and cytokines. This study investigated the short-term consequence of CRRT on body composition and pattern of energy expenditure. METHODS AND STUDY DESIGN: We prospectively observed 27 sepsis patients in our ICU treated with CRRT. Bioelectrical impedance analysis and indirect calorimetry were determined at admission and before and after CRRT. All parameters considered to affect body composition and metabolic state with short-term CRRT were recorded. We used correlation analysis to evaluate the relationship between the change of nutritional state and other parameters. RESULTS: Patients had a decreased total body water load and an improved metabolic pattern, but the nutritional parameters had no significant change between pre- and post-CRRT. Furthermore, we observed the percentage variation of resting energy expenditure (REE) was positively correlated with intracellular water change (r=0.547, p=0.003) and CRRT duration (r=0.515, p=0.006). A negative correlation was found between the percentage variation of REE and dialysate temperature (r=-0.668, p=0.001). CONCLUSION: These results suggest that short-term CRRT reduces systemic volume in sepsis patients with overhydration and hypermetabolism, but has no significant impact on acute nutritional status. Meanwhile, CRRT may exert its optimum efficiency when accompanied by other medical practices and support methods. PMID- 27222414 TI - Relationship between bone mineral density and alcohol consumption in Korean men: the Fourth Korea National Health and Nutrition Examination Survey (KNHANES), 2008 2009. AB - BACKGROUND AND OBJECTIVES: Drinking is a risk factor of osteoporosis, but controversy surrounds the relationship between alcohol consumption and bone mineral density (BMD). We performed an analysis of the association between alcohol consumption and BMD. METHODS AND STUDY DESIGN: A cross-sectional study was performed including 2421 men, aged 40-93 years, who participated in the fourth Korea National Health and Nutrition Examination Survey in 2008-2009. Alcohol intake was determined by self-administered questionnaires, and BMD was measured by dual energy x-ray absorptiometry. ANOVA was used to determine the relationship between alcohol intake and BMD, and ANCOVA was performed after adjusting for age, body mass index, education, household income, smoking status, calcium intake, physical activity, and serum 25-hydroxyvitamin D levels. RESULTS: BMD increased significantly in the lumbar spine, total femur, and femoral neck with increased alcohol intake (p for trend=0.028, <0.001, <0.001, respectively). However, after adjusting for age, the relation was no longer statistically significant in any of 3 bone sites (lumbar, p for trend=0.606; total femur, p for trend=0.342; femoral neck, p for trend=0.549). Additionally, after adjusting for all other confounders, no significant relationships were reported in the 3 bone sites (lumbar, p for trend=0.451; total femur, p for trend=0.150; femoral neck, p for trend=0.343). In the stratified analysis, there were no significant correlations according to age, smoking status, physical activity or obesity. CONCLUSIONS: After adjusting for age and other confounders, no significant relationship was found between alcohol intake and BMD. PMID- 27222415 TI - Association between perceived stress, alcohol consumption levels and obesity in Koreans. AB - BACKGROUND AND OBJECTIVES: Coping with stress often leads to unhealthy behaviors that can have an impact on the development of obesity. Therefore, this study is investigate the effect of perceived stress level on alcohol consumption habits, as well as the effect of the interaction between alcohol consumption habits and stress level on obesity in Koreans. METHODS AND STUDY DESIGN: We analyzed perceived stress, alcohol consumption habits (alcohol consumption status, quantity, and alcohol use disorders identification test) and the anthropometrics of 6,229 subjects from the Korean National Health and Nutrition Examination Survey. The gender-based differences of the effect of the perceived level of stress on alcohol consumption habits and anthropometric measurements, as well as the interaction of the perceived level of stress and alcohol consumption habits on prevalence or ORs of obesity were analyzed. RESULTS: The subjects with high perceived stress showed higher proportions for unhealthy alcohol consumption habits than those with low perceived stress [ORs (95% CIs)=1.35 (1.19-1.54), 1.95 (1.68-2.26), and 1.87 (1.60-2.19) for alcohol consumption status, alcohol consumption quantity, and alcohol use disorders identification test, respectively]. Men showed significant interactions between the perceived stress and all alcohol consumption habits with respect to obesity [ORs (95% CIs)=1.28 (1.06-1.55), 1.81 (1.52-2.16), and 1.40 (1.17-1.68) for alcohol consumption status, alcohol consumption quantity, and alcohol use disorders identification test, respectively]. Among women, interactions between the perceived stress and alcohol consumption status [ORs (95% CIs)=0.70 (0.60-0.83)] and alcohol consumption quantity [ORs (95% CIs)=0.93 (0.54-1.36)] in relation to obesity were found to be significant. CONCLUSION: Our study demonstrated that the perceived stress influenced alcohol consumption habits that may have impacted obesity. PMID- 27222417 TI - The relationship between obesity indices and serum vitamin D levels in Chinese adults from urban settings. AB - BACKGROUND AND OBJECTIVES: With an increased incidence of obesity in China, this study sought to investigate the correlation between serum 25-hydroxyvitamin D levels and adiposity phenotypes in Chinese adults from urban settings. METHODS AND STUDY DESIGN: A total of 1277 subjects aged 20-82 years old were recruited into this cross-sectional study. Anthropometric parameters and blood biochemistry panels were measured. Statistical analysis using partial correlation, multivariable regression and covariance were performed to assess the impact of obesity parameters on serum 25-hydroxyvitamin D levels. RESULTS: After adjustment for age and gender, serum25-hydroxyvitamin D levels were found to be inversely related to body mass index, waist circumference, waist/hip ratio, body fat, body fat percentage and waist fat to hip fat ratio. In multivariable regression analysis, serum 25-hydroxyvitamin D levels were negatively associated with waist circumference, waist/hip ratio, body fat, body fat percentage and waist fat/hip fat ratio (p<0.05), while there was no correlation with body mass index (p>0.05). After inclusion of body fat, body fat percentage and waist fat to hip fat ratio in one model, only waist fat to hip fat ratio remained significantly associated with serum 25-hydroxyvitamin D levels (p<0.05). The covariance analysis results showed that abdominal obesity subjects had lower serum 25-hydroxyvitamin D levels compared to the counterpart group, as defined by waist circumference or waist/hip ratio (p<0.05). CONCLUSION: Our results affirm the relationship between serum 25 hydroxyvitamin D levels and abdominal obesity, suggesting that adiposity phenotypes were strongly linked to serum 25-hydroxyvitamin D levels. PMID- 27222416 TI - Age-related decline in skeletal muscle mass and function among elderly men and women in Shanghai, China: a cross sectional study. AB - OBJECTIVE: To investigate the relationship of muscle mass and muscle function with age. METHODS AND STUDY DESIGN: The study including 415 participants (aged 60 99 years). Upper (UMM) and lower (LMM) limbs muscle mass and whole body fat free mass (FFM) were measured by bioelectrical impedance analysis. The appendicular skeletal muscle mass (ASM) index (ASM/height2) was calculated. Muscle function was assessed by measuring hand grip strength (HGS) and gait speed. RESULTS: Using ASM index cutoff values we found that higher prevalence of sarcopenia in women than in men (33.5% vs 23.6%, p=0.025). In the upper limb, HGS (beta=-0.809) declined more rapidly with age than did UMM (beta=-0.592) in men, but not in women (beta=-0.389 and beta=-0.486 respectively). In the lower limb, gait speed declined more rapidly than LMM in both men (beta=-0.683 vs beta=-0.442) and women (beta=-1.00 vs beta=-0.461). The variance of UMM explained 28-29% of the variance of HGS, and LMM explained 7-8% of the variance of gait speed in women and men respectively. In addition to the common predictors (BMI and age), the specific predictors were smoking, exercise and education for FFM and ASM, and smoking, drinking and exercise for HGS (p<0.05). CONCLUSIONS: Loss of muscle function is greater than the decline of muscle mass particularly in the upper limbs in men. However, women are more prone to have low muscle mass than the men. Exercise programs need to be designed gender specifically. PMID- 27222418 TI - Factors associated with total mercury concentrations in maternal blood, cord blood, and breast milk among pregnant women in Busan, Korea. AB - This study investigated the concentration of total mercury (THg) in maternal blood, cord blood, and breast milk, and its association with dietary factors. A total of 127 pregnant women in Busan, Korea were recruited. Maternal blood, cord blood, and breast milk were collected at 36 weeks of gestation, at delivery, and at one week after birth, respectively. Information about dietary habits and other factors were obtained from each subject. The mean THg concentrations in maternal blood, cord blood, and breast milk were 3.12+/-1.36 MUg/L, 5.46+/-2.41 MUg/L, and 0.91+/-2.08 MUg/L, respectively. Positive correlations were found between log transformed THg concentrations in maternal blood and cord blood (r=0.829, p<0.001), and between maternal blood and breast milk (r=0.296, p=0.001). Multiple linear regression analysis showed that the log-transformed concentration of THg in maternal blood was positively correlated with fish consumption (beta=0.345, p<0.0001) and negatively correlated with bean consumption (beta=-0.055, p=0.048). Fish consumption (beta=0.482, p<0.0001) and maternal age (beta=0.025, p=0.033) were positively associated with the concentration of THg in cord blood, while negative correlations were found for bean consumption (beta=-0.134, p=0.027) and parity (beta=-0.172, p=0.015). Beef consumption (beta=0.031, p=0.007) was positively associated with log-transformed THg concentrations in breast milk, while negative correlations were found for bean consumption (beta=-0.019, p=0.003) and maternal age (beta=-0.083, p=0.004). Our study found that both the dietary and demographic factors differently affected to THg concentrations among samples of maternal blood, cord blood, and breast milk. PMID- 27222419 TI - Micronutrient powder use and infant and young child feeding practices in an integrated program. AB - Integrated infant and young child feeding (IYCF)/micronutrient powder (MNP) programs are increasingly used to address poor IYCF practices and micronutrient deficiencies in low-income settings; however, little is known about how MNP use may affect IYCF practices. We describe how MNP use was associated with IYCF practices in a pilot program in select districts of Nepal where free MNP for children 6-23 months were added to an existing IYCF platform. Representative cross-sectional surveys were conducted in pilot districts with mothers of eligible children at 3 months (plains ecozone, n=1054) or 15 months (hill ecozone, rural only, n=654) after implementation of an integrated MNP/IYCF program. We used logistic regression to assess how IYCF practices varied by MNP use (none, 1-30, 30-60 sachets). At both time points, consuming 30-60 MNP sachets vs. none was associated with achieving minimum dietary diversity and minimum acceptable diet. In the 3 month survey consuming 30- 60 MNP sachets vs none was also associated with achieving minimum meal frequency and continued breastfeeding at 2 years. In this setting, addition of MNP to an existing platform of IYCF messaging did not appear detrimental to IYCF practices. PMID- 27222420 TI - The effect of socio-demographic variables and dairy use on the intake of essential macro- and micronutrients in 0.5-12-year-old Indonesian children. AB - BACKGROUND AND OBJECTIVES: To study the associations between nutrient intake, dairy intake and socioeconomic variables. METHODS AND STUDY DESIGN: Food consumption data using 24 h recall were collected in 3600 children, aged 0.5 to 12 years old in addition to frequency of dairy use and anthropometric and sociodemographic variables. RESULTS: Overall height for age Z-score (HAZ) and body mass index for age Z-score (BAZ) values (mean+/-SE) were -1.40+/-0.03 and 0.48+/-0.03 respectively, associated with a high prevalence of stunting and thinness in the population. The overall percentage of children not using any dairy products was 71%, and this percentage increased steadily with age. The overall energy intake from dairy was 99+/-3 kcal/capita/day and the overall energy intake from dairy in dairy users was 291+/-7 kcal/day. Dairy use did not differ between boys and girls, but was higher in urban areas, higher if the education of the mother was higher and higher if the mother had a permanent job and if the wealth status of the family was in the upper levels. Nutrient intake after the age of 3 years was inadequate for energy and all nutrients except for protein. The achievement of Recommended Dietary Allowances (RDA) for all nutrients was higher in dairy users compared to non-dairy users, also after correcting for the confounding effect of the higher energy intake (from dairy) and socio-demographic variables. The contribution increased with increasing frequency of dairy use. CONCLUSION: Adequate dairy intake can substantially add to the achievement of RDA in Indonesian children. PMID- 27222421 TI - Estimating dietary micronutrient supply and the prevalence of inadequate intakes from national Food Balance Sheets in the South Asia regiona. AB - Micronutrient deficiencies continue to be a major public health concern worldwide with many South Asian countries suffering a significant proportion of the global burden. A lack of nationally representative data on micronutrient deficiencies hampers sustained action to address the problem. Using data on the national food supply produced by the Food and Agriculture Organisation of the United Nations, and international food composition tables, the present study estimated the prevalence of inadequacy of seven micronutrients (vitamin A, thiamine, riboflavin, folate, vitamin B-12, zinc and calcium) in seven South Asian countries--Bangladesh, India, Iran, Maldives, Nepal, Pakistan and Sri Lanka. The estimated average requirement cut-point method was employed to determine the likelihood of inadequate micronutrient intakes. We report multiple micronutrient inadequacies in the food supply in the region, especially in the low and lower middle income countries. Of the seven micronutrients investigated, calcium had the highest risk levels of inadequacy. Folate, riboflavin, vitamin B-12 and zinc were also deemed to be at high risk of inadequacy, although results differed markedly between countries. Various strategies to combat micronutrient deficiencies are currently underway in these countries. In order to facilitate the implementation of these efforts, the collection of nationally representative nutritional assessment survey data are urgently required to ascertain the true burden of micronutrient malnutrition. PMID- 27222422 TI - Mediterranean diet adherence and risk of multiple sclerosis: a case-control study. AB - BACKGROUND AND OBJECTIVES: We conducted a hospital-based, case-control study to examine the association between Mediterranean diet (MD) and the risk of multiple sclerosis (MS) in Iran. METHODS AND STUDY DESIGN: A total of 70 patients with MS and 142 controls underwent face-to-face interviews in the major neurological clinics of Tehran, Iran. Adherence to a MD was assessed using the 9-unit dietary score, to evaluate the level of conformity of the individual's diet to the Mediterranean dietary pattern. Multivariate logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Higher consumption of fruits (OR=0.28, 95% CI: 0.12-0.63, p-value: 0.002) and vegetables (OR=0.23, 95% CI: 0.10-0.53, p-value: 0.001) were significantly associated with reduced MS risk. In both age adjusted and multivariate adjusted model, the OR of MS decreased significantly in the third as compared to the first tertile of MD score (age adjusted OR: 0.21, 95% CI: 0.06-0.67; p-trend: 0.01, Multivariate adjusted OR: 0.23, 95% CI: 0.06-0.89, p-trend: 0.04). CONCLUSIONS: Our study suggests that a high quality diet assessed by MD may decrease the risk of MS. PMID- 27222423 TI - Personal behaviors including food consumption and mineral supplement use among Japanese adults: a secondary analysis from the National Health and Nutrition Survey, 2003-2010. AB - BACKGROUND AND OBJECTIVES: A daily mineral supplement is useful for those who are at risk of a deficiency. Some Western reports suggest that mineral supplement users have healthy behaviors and are not mineral-deficient. It is unknown whether the same phenomenon is observed in Japan where there is a different dietary culture. The aim of this study was to examine the characteristics of personal behaviors including food consumption nationwide among mineral supplement users from the National Health and Nutrition Survey in Japan 2003-2010. METHODS AND STUDY DESIGN: Data were obtained from 16,275 adults aged 20-59 years who completed sociodemographic, health status, and 1-day household dietary assessments. Supplement users were compared with non-users. Logistic regression models were utilized to identify the characteristics of food consumption and calcium and iron supplement use, using the medium intake group as a reference. RESULTS: Overall, 2.1% and 1.4% of adults reported using calcium supplements and iron supplements, respectively. Calcium supplement users were more likely to be physically active, non-smokers, and eat less fat compared with non-users. Furthermore, they were more likely than non-users to consume a higher intake of calcium from foods such as tea, vegetables, seaweeds, and fruits. Iron supplement users were more likely than non-users to be non-smokers. These individuals tended to have a high intake of seaweeds and fruits. CONCLUSIONS: Japanese adults who had healthier behaviors were more likely to use mineral supplements, especially calcium. Mineral supplement users tended to choose healthy foods such as seaweeds and fruits, without considering their overall mineral consumption. PMID- 27222424 TI - Fast foods--are they a risk factor for functional gastrointestinal disorders? AB - BACKGROUND AND OBJECTIVES: Fast-food consumption has greatly increased in Taiwan. Frequent fast food intake is associated with both allergy and obesity. The aim of this study was to describe fast food habit changes, and to assess the relationship between fast food intake and the risk of functional gastrointestinal disorders (FGIDs) among Taiwanese adolescents. METHODS AND STUDY DESIGN: This analysis used data from the Nutrition and Health Survey in Taiwan (NAHSIT) of high school students conducted in 2011. A total of 2,042 adolescents (12-19 years) completed the questionnaire. The survey included the Rome III criteria for FGIDs, translated into Chinese for adolescents. Respondents with previously diagnosed chronic organic gastrointestinal diseases were excluded from the study. RESULTS: In total, 2,034 children were enrolled. 545 subjects (26.8%) had history of at least one FGID. 88.1% of the subjects reported fast foods consumption. A significantly higher prevalence of FGIDs was noted in adolescents with a history of fast foods consumption, compared with those reported not to have ingested fast foods in the past 30 days (27.6% vs 20.6%, p=0.024). An increased risk of FGIDs in children and adolescents was associated with fast food intake (OR 1.8, 95% CI: 1.78-1.83). CONCLUSIONS: FGIDs were common among Taiwanese adolescents. Fast-food consumption may contribute to a positive association with the development of functional gastrointestinal disorders. Lower fiber intake and more frozen desserts in the diet may be complicit in FGIDs. The findings have public health relevance in regard to the global increase in fast food consumption. PMID- 27222425 TI - Association between salt and hypertension in rural and urban populations of low to middle income countries: a systematic review and meta-analysis of population based studies. AB - BACKGROUND AND OBJECTIVES: The prevalence of hypertension, the greatest contributor to mortality globally, is increasing in low-and-middle income countries (LMICs). In urban regions of LMICs, excessive salt intake is associated with increased risk of hypertension. We aimed to determine whether this is the case in rural regions as well. METHODS AND STUDY DESIGN: We performed a meta analysis of studies in rural and urban areas of LMICs in which the association of salt and hypertension were assessed using multivariable models. RESULTS: We identified 18 studies with a total of 134,916 participants. The prevalence of high salt intake ranged from 21.3% to 89.5% in rural and urban populations. When salt was analysed as a continuous variable, a greater impact of salt on hypertension was found in urban (n=4) (pooled effect size (ES) 1.42, 95% CI 1.19, 1.69) than in rural populations (n=4) (pooled ES 1.07, 95% CI 1.04, 1.10, p for difference <0.001). In studies where salt was analysed continuously, a greater impact of salt on hypertension was observed in lean rural populations (BMI <23 kg/m2) than in non-lean rural populations (BMI >=23 kg/m2, p for difference <0.001). CONCLUSIONS: The prevalence of high salt intake is similar in rural and urban regions. Excessive salt intake has a greater impact on the prevalence of hypertension in urban than rural regions. BMI appears to modify the relationship between salt and hypertension in rural populations. PMID- 27222426 TI - Dietary diversity no longer offsets the mortality risk of hyperhomocysteinaemia in older adults with diabetes: a prospective cohort study. AB - BACKGROUND AND OBJECTIVE: The increased mortality risk of hyperhomocysteinaemia in diabetes may be mitigated by dietary quality. METHODS AND STUDY DESIGN: The Nutrition and Health Survey in Taiwan of 1999-2000 for elders formed this prospective cohort. Baseline health status, diet and anthropometry were documented and plasma homocysteine and biomarkers for B vitamins measured. Participants without diabetes (n=985) were referent for those who had diabetes or developed diabetes until 2006 (n=427). The effect of homocysteine on mortality risk during 1999-2008 was evaluated. RESULTS: Men, smokers and those with poorer physical function had higher homocysteine, but less so with diabetes. Diabetes incidence was unrelated to homocysteine. In hyperhomocysteinaemia (>=15 vs <15 MUmol/L), those with diabetes had an adjusted hazard ratio (HR) (95% CI) for mortality of 1.71 (1.18-2.46); p for interaction between homocysteine and diabetes was 0.005. Without diabetes, but with hyperhomocysteinaemia and a low dietary diversity score (DDS <=4 of 6), where the joint mortality hazard for the greater DDS, (>4) and lower homocysteine (<15) was referent, the HR was 1.80 (1.27-2.54) with significant interaction (p=0.008); by contrast, there was no joint effect with diabetes. The contribution of DDS to mortality mitigation in hyperhomocysteinaemia could not be explained by B group vitamins, even though plasma folate was low in hyperhomocysteinaemic participants. With hyperhomocysteinaemia, heart failure was a major cause of death. CONCLUSIONS: In non-diabetic hyperhomocysteinaemia, a more diverse diet increases survival prospects independent of B group vitamins, but not in hyperhomocysteinaemic diabetes where the cardiomyopathy may be less responsive. PMID- 27222427 TI - Food cravings, food addiction, and a dopamine-resistant (DRD2 A1) receptor polymorphism in Asian American college students. AB - BACKGROUND AND OBJECTIVES: In an era where obesity remains an important public health concern, food addiction has emerged as a possible contributor to obesity. The DRD2 gene is the most studied polymorphism. The aim of this study was to investigate a relationship between food addiction questionnaires, body composition measurements, and a dopamine- resistant receptor polymorphism (DRD2 A1) among Asian Americans. METHODS AND STUDY DESIGN: A total of 84 Asian American college students were recruited. Participants underwent body composition measurement via bioelectrical impedance, answered questionnaires (Food Craving Inventory and Power of Food Scale), and had blood drawn for genotyping (PCR). RESULTS: There was no difference in body composition (BMI, percent body fat) between the A1 (A1A1 or A1A2) and A2 (A2A2) groups. There were statistically significant differences in food cravings of carbohydrates and fast food on the Food Craving Inventory between the A1 and A2 groups (p=0.03), but not for sugar or fat. Among Asian college females, there was also a difference on the Power of Food questionnaire (p=0.04), which was not seen among men. 13 out of 55 women also had >30% body fat at a BMI of 21.4 to 28.5 kg/m2. CONCLUSION: Greater carbohydrate and fast food craving was associated with the DRD2 A1 versus A2 allele among Asian Americans. Further studies examining the ability of dopamine agonists to affect food craving and to reduce body fat in Asian American are warranted. More studies in food addiction among obese Asian Americans are needed with careful definition of obesity, specifically for Asian women. PMID- 27222428 TI - Is jejunostomy output nutrient or waste in short bowel syndrome? Experience from six cases. AB - BACKGROUND AND OBJECTIVES: Certain patients who undergo proximal jejunum resection are unable to undergo primary anastomosis and require exteriorization of the proximal jejunum. These patients usually have major problems with short bowel due to the high output of the stoma. The output of a proximal jejunostomy contains abundant amounts of enzymes and electrolytes. Therefore, it is a feasible approach to re-infuse jejunostomy output to regain homeostasis. To evaluate the effects of proximal jejunostomy output reinfusion into the distal small bowel for patients with short bowel syndrome, and to determine whether reinfusion could avoid long-term parenteral nutrition (PN). METHODS AND STUDY DESIGN: PN was initiated immediately after surgery. When patients started enteral nutrition, we started the proximal jejunostomy output reinfusion protocol. Proximal jejunostomy output reinfusion was performed by the patients, and continued by them after discharge. When proximal jejunostomy output reinfusion could be performed stably, PN was stopped. RESULTS: The median length of the proximal jejunum was 20 cm and of the distal small bowel was 77.5 cm in patients who could stably receive proximal jejunostomy output reinfusion alone. Three patients did not require home PN; they only required PN during hospitalization. Four patients successfully underwent stoma takedown with intestinal anastomosis after 6-7 months without any nutritional or metabolic complications. CONCLUSION: Short bowel syndrome patients with an adequate length of small bowel and functional colon could avoid long-term PN by receiving reinfusion of proximal jejunostomy output into the distal small bowel. PMID- 27222429 TI - Expression and inhibitory role of TIMP-3 in hepatocellular carcinoma. AB - As a member of the tissue inhibitor of metallo-proteinases (TIMP) family, it has been reported that TIMP-3 is involved in human cancer development. However, the function of TIMP-3 in hepatocellular carcinoma (HCC) development is unclear. We aimed to determine the biological role of TIMP-3 in HCC by evaluating the effects of its methylation status and expression on HCC cell function. TIMP-3 expression in HCC tissues was visibly analyzed by immunohistochemistry. Methylation of the TIMP-3 promoter was evaluated by methylation-specific PCR. Effects of TIMP-3 on HCC cell growth, apoptosis, migration, and invasion were examined by transfecting the TIMP-3-expressing plasmid, pCMV6. TIMP-3 was expressed in non-tumorous live tissue, but silenced or downregulated in 60% of HCC cases (P<0.05). Reduced protein expression of TIMP-3 was associated with reduced tumor differentiation (P=0.003) and increased metastatic activity (P=0.005) in HCC cell lines. Promoter methylation contributed to the TIMP-3 inactivation. Overexpression of TIMP-3 in HCC cell lines suppressed cell proliferation, induced apoptosis, and inhibited migration and invasion in vitro. TIMP-3 expression is suppressed by promoter methylation in HCC. This inhibitory protein acts as a functional tumor suppressor by inhibiting HCC cell proliferation, invasion, and migration and by inducing apoptosis and cell cycle arrest at the G2/M phase. PMID- 27222430 TI - A controlled double-duration inducible gene expression system for cartilage tissue engineering. AB - Cartilage engineering that combines competent seeding cells and a compatible scaffold is increasingly gaining popularity and is potentially useful for the treatment of various bone and cartilage diseases. Intensive efforts have been made by researchers to improve the viability and functionality of seeding cells of engineered constructs that are implanted into damaged cartilage. Here, we designed an integrative system combining gene engineering and the controlled release concept to solve the problems of both seeding cell viability and functionality through precisely regulating the anti-apoptotic gene bcl-2 in the short-term and the chondrogenic master regulator Sox9 in the long-term. Both in vitro and in vivo experiments demonstrated that our system enhances the cell viability and chondrogenic effects of the engineered scaffold after introduction of the system while restricting anti-apoptotic gene expression to only the early stage, thereby preventing potential oncogenic and overdose effects. Our system was designed to be modular and can also be readily adapted to other tissue engineering applications with minor modification. PMID- 27222431 TI - Multiyear Survey of Coccidia, Cryptosporidia, Microsporidia, Histomona, and Hematozoa in Wild Quail in the Rolling Plains Ecoregion of Texas and Oklahoma, USA. AB - We developed nested PCR protocols and performed a multiyear survey on the prevalence of several protozoan parasites in wild northern bobwhite (Colinus virginianus) and scaled quail (Callipepla squamata) in the Rolling Plains ecoregion of Texas and Oklahoma (i.e. fecal pellets, bird intestines and blood smears collected between 2010 and 2013). Coccidia, cryptosporidia, and microsporidia were detected in 46.2%, 11.7%, and 44.0% of the samples (n = 687), whereas histomona and hematozoa were undetected. Coccidia consisted of one major and two minor Eimeria species. Cryptosporidia were represented by a major unknown Cryptosporidium species and Cryptosporidium baileyi. Detected microsporidia species were highly diverse, in which only 11% were native avian parasites including Encephalitozoon hellem and Encephalitozoon cuniculi, whereas 33% were closely related to species from insects (e.g. Antonospora, Liebermannia, and Sporanauta). This survey suggests that coccidia infections are a significant risk factor in the health of wild quail while cryptosporidia and microsporidia may be much less significant than coccidiosis. In addition, the presence of E. hellem and E. cuniculi (known to cause opportunistic infections in humans) suggests that wild quail could serve as a reservoir for human microsporidian pathogens, and individuals with compromised or weakened immunity should probably take precautions while directly handling wild quail. PMID- 27222432 TI - Cox process representation and inference for stochastic reaction-diffusion processes. AB - Complex behaviour in many systems arises from the stochastic interactions of spatially distributed particles or agents. Stochastic reaction-diffusion processes are widely used to model such behaviour in disciplines ranging from biology to the social sciences, yet they are notoriously difficult to simulate and calibrate to observational data. Here we use ideas from statistical physics and machine learning to provide a solution to the inverse problem of learning a stochastic reaction-diffusion process from data. Our solution relies on a non trivial connection between stochastic reaction-diffusion processes and spatio temporal Cox processes, a well-studied class of models from computational statistics. This connection leads to an efficient and flexible algorithm for parameter inference and model selection. Our approach shows excellent accuracy on numeric and real data examples from systems biology and epidemiology. Our work provides both insights into spatio-temporal stochastic systems, and a practical solution to a long-standing problem in computational modelling. PMID- 27222433 TI - Histological outcomes of sinus augmentation for dental implants with calcium phosphate or deproteinized bovine bone: a systematic review and meta-analysis. AB - This study compared the histological outcomes of deproteinized bovine bone (DBB) and technically derived calcium phosphate for sinus floor augmentation. MEDLINE, PubMed, Cochrane, EMBASE, and Google Scholar databases were searched until April 2015 with the following key words: dental implants, augmentation/augmented, calcium phosphate/ceramic/tricalcium phosphate, bovine bone/Bio-Oss, deproteinized/anorganic. Randomized controlled trials (RCTs) and two-arm prospective/retrospective studies that used DBB or biphasic calcium phosphate/tricalcium phosphate (BCP/TCP) for sinus augmentation with quantitative results were included. Outcomes were the percentage of new bone formed and percentage of surface contact between the graft material and new bone (bone-to graft contact). Four RCTs and one prospective study were included, with a total of 110 patients and 145 implants. All studies reported the percentage of new vital bone; however, large heterogeneity was present (Q=15.23, P=0.004, I2=73.8%). BCP/TCP was associated with a higher percentage of new bone, but the pooled results did not reach significance (pooled standardized mean difference (SMD)=0.145, 95% confidence interval (CI) -0.488 to 0.778, P=0.654). Only two studies reported bone-to-graft contact, and BCP/TCP was associated with significantly lower bone-to-graft contact (pooled SMD=-0.807, 95% CI -1.276 to 0.337, P=0.001). This meta-analysis does not allow us to conclude superiority of one particular material with respect to histological outcomes. PMID- 27222435 TI - Steroid sulfatase inhibitor DU-14 protects spatial memory and synaptic plasticity from disruption by amyloid beta protein in male rats. AB - Alzheimer's disease (AD) is an age-related mental disorder characterized by progressive loss of memory and multiple cognitive impairments. The overproduction and aggregation of Amyloid beta protein (Abeta) in the brain, especially in the hippocampus, are closely involved in the memory loss in the patients with AD. Accumulating evidence indicates that the Abeta-induced imbalance of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) in the brain plays an important role in the AD pathogenesis and progression. The level of DHEA is elevated, while DHEAS is dramatically decreased in the AD brain. The present study tried to restore the balance between DHEA and DHEAS by using a non steroidal sulfatase inhibitor DU-14, which increases endogenous DHEAS through preventing DHEAS converted back into DHEA. We found that: (1) DU-14 effectively attenuated the Abeta1-42-induced cognitive deficits in spatial learning and memory of rats in Morris water maze test; (2) DU-14 prevented Abeta1-42-induced decrease in the cholinergic theta rhythm of hippocampal local field potential (LFP) in the CA1 region; (3) DU-14 protected hippocampal synaptic plasticity against Abeta1-42-induced suppression of long term potentiation (LTP). These results provide evidence for the neuroprotective action of DU-14 against neurotoxic Abeta, suggesting that up-regulation of endogenous DHEAS by DU-14 could be beneficial to the alleviation of Abeta-induced impairments in spatial memory and synaptic plasticity. PMID- 27222434 TI - Characterization of the T-cell response to Dau c 1, the Bet v 1-homolog in carrot. AB - BACKGROUND: In contrast to other Bet v 1-related food allergens, the major carrot allergen, Dau c 1, has been suggested to induce food allergy independently from Bet v 1. As T cells are crucial in the sensitization process, we sought to characterize the T-cell response to Dau c 1 and its cross-reactivity with Bet v 1. METHODS: Dau c 1-specific T-cell lines (TCL) and clones (TCC) established from PBMC of birch pollen-allergic patients with carrot allergy were analyzed for reactivity to Bet v 1, epitope specificity, allergen-induced cytokine secretion, and expression of integrins alpha4beta7 and alpha4beta1, critical for gut and lung homing, respectively. mRNA expression of GATA3 and Tbet was analyzed in sorted CD3+ CD4+ CFSElow cells proliferating upon stimulation of PBMC with Dau c 1 or Bet v 1. Dau c 1 was incubated with endolysosomal proteases, and the resulting fragments were identified by mass spectrometry. RESULTS: Among 14 distinct T-cell-activating regions, Dau c 1139-153 was recognized by 55% of the patients. Only 6 of 15 (40%) Dau c 1-specific TCL and 9 of 21 (43%) TCC reacted with Bet v 1. Bet v 1-nonreactive TCC were mainly Th1-like and showed a higher expression of the integrin beta7 and a significantly lower expression of the integrin beta1 than Bet v 1-positive TCC. A Th1-like response was also detected in Dau c 1-reactive CD3+ CD4+ CFSElow cells. Full-length Dau c 1 was still detectable after 48 h of endolysosomal degradation. Proteolytic fragments of Dau c 1 matched its T-cell-activating regions. CONCLUSION: Dau c 1 displays several characteristics of sensitizing allergens, namely a major T-cell-activating region, low susceptibility to endolysosomal degradation, and induction of a Bet v 1-independent T-cell response. These cellular insights confirm that the major carrot allergen has a special status among Bet v 1-related food allergens. PMID- 27222436 TI - The effects of transcutaneous vagus nerve stimulation on conditioned fear extinction in humans. AB - A critical component of the treatment for anxiety disorders is the extinction of fear via repeated exposure to the feared stimulus. This process is strongly dependent on successful memory formation and consolidation. Stimulation of the vagus nerve enhances memory formation in both animals and humans. The objective of this study was to assess whether transcutaneous stimulation of the vagus nerve (tVNS) can accelerate extinction memory formation and retention in fear conditioned humans. To assess fear conditioning and subsequent fear extinction, we assessed US expectancy ratings, fear potentiated startle responses and phasic heart rate responses. We conducted a randomized controlled trial in thirty-one healthy participants. After fear conditioning participants were randomly assigned to receive tVNS or sham stimulation during the extinction phase. Retention of extinction memory was tested 24h later. tVNS accelerated explicit fear extinction learning (US expectancy ratings), but did not lead to better retention of extinction memory 24h later. We did not find a differential physiological conditioning response during the acquisition of fear and thus were unable to assess potential effects of tVNS on the extinction of physiological indices of fear. These findings complement recent studies that suggest vagus nerve stimulation could be a promising tool to improve memory consolidation and fear extinction. PMID- 27222437 TI - Validity of self-reported family history of cancer: A systematic literature review on selected cancers. AB - Evidence regarding validity of self-reported family history of cancer (FHC) has been reviewed only for breast, colorectal, prostate, ovarian, endometrial and uterine cancer. We aimed to systematically review studies assessing validity of self-reported family history for the remaining cancer sites. We searched the Medline database for relevant studies published by January 2016. We extracted information on the study design and the positive predictive value (PPV) of self reported FHC, defined as the proportion of reported cancer diagnoses among relatives that was confirmed by a reference standard (as a measure of over reporting). We also extracted information on sensitivity of self-reported FHC (as a measure of underreporting). Overall, 21 studies were included that provided information on the PPV of self-reported FHC for relevant cancers and four studies also provided information on sensitivity. The PPV was highest (mostly >70%) for pancreatic, lung, thyroid and urinary system cancers and for leukemia and lymphoma, while it was lowest for stomach and liver cancer. Sensitivity was highest (>70%) for pancreatic cancer, lung cancer, brain cancer, melanoma, leukemia and lymphoma. For several cancers, sample sizes were low and the number of studies limited, particularly regarding sensitivity of self-reported FHC. In conclusion, for some cancers (e.g., pancreatic cancer, lung cancer, leukemia, lymphoma) self-reported FHC can be considered sufficiently valid to be useful, for example, in preventive counseling. For several cancers, it is not sufficiently studied or the pattern is inconsistent. This needs to be taken into account when using self-reported information about FHC in clinical practice or epidemiological research. PMID- 27222438 TI - The protein PprI provides protection against radiation injury in human and mouse cells. AB - Severe acute radiation injuries are both very lethal and exceptionally difficult to treat. Though the radioresistant bacterium D. radiodurans was first characterized in 1956, genes and proteins key to its radioprotection have not yet to be applied in radiation injury therapy for humans. In this work, we express the D. radiodurans protein PprI in Pichia pastoris yeast cells transfected with the designed vector plasmid pHBM905A-pprI. We then treat human umbilical endothelial vein cells and BALB/c mouse cells with the yeast-derived PprI and elucidate the radioprotective effects the protein provides upon gamma irradiation. We see that PprI significantly increases the survival rate, antioxidant viability, and DNA-repair capacity in irradiated cells and decreases concomitant apoptosis rates and counts of damage-indicative gammaH2AX foci. Furthermore, we find that PprI reduces mortality and enhances bone marrow cell clone formation and white blood cell and platelet counts in irradiated mice. PprI also seems to alleviate pathological injuries to multiple organs and improve antioxidant viability in some tissues. Our results thus suggest that PprI has crucial radioprotective effects on irradiated human and mouse cells. PMID- 27222439 TI - Maternal and offspring outcomes in women with intellectual and developmental disabilities: a population-based cohort study. AB - OBJECTIVE: To compare the risks for adverse maternal and offspring outcomes in women with and without intellectual and developmental disabilities. DESIGN: Population-based cohort study. SETTING: Ontario, Canada. POPULATION: Singleton obstetrical deliveries to 18- to 49-year-old women with and without intellectual and developmental disabilities (n = 3932 in the exposed cohort, n = 382 774 in the unexposed cohort; 2002-2011 fiscal years). METHODS: Women with intellectual and developmental disabilities were identified based on diagnoses in health administrative data or receipt of disability income support. The unexposed cohort comprised women without intellectual and developmental disabilities. Modified Poisson regression was used to compute adjusted relative risks (aRR) and 95% confidence intervals (CI) comparing the two cohorts. MAIN OUTCOME MEASURES: Primary maternal outcomes were: gestational diabetes, gestational hypertension, pre-eclampsia, eclampsia, and venous thromboembolism. Primary offspring outcomes were: preterm birth, small for gestational age, and large for gestational age. RESULTS: The exposed cohort, compared with the unexposed cohort, had increased risks for pre-eclampsia (aRR 1.47, 95% CI 1.11-1.93) and venous thromboembolism (aRR 1.60, 95% CI 1.17-2.19). Their offspring had increased risks for preterm birth (aRR 1.63, 95% CI 1.47-1.80) and small for gestational age (aRR 1.35, 95% CI 1.25-1.45). CONCLUSIONS: These findings suggest that there is a need to address modifiable risk factors for adverse outcomes among women with intellectual and developmental disabilities prior to and during pregnancy. Moreover, there is a need to enhance monitoring for maternal and offspring complications in this population. TWEETABLE ABSTRACT: Large cohort study: intellectual and developmental disabilities predispose women/babies to adverse outcomes. PMID- 27222441 TI - Building emotion categories: Children use a process of elimination when they encounter novel expressions. AB - Recent research has indicated that language provides an important contribution to adults' conceptions of emotional expressions and their associated categories, but how language influences children's expression category acquisition has yet to be explored. Across two studies, we provide evidence that when preschoolers (2 4years) encounter a novel label, they use a process of elimination to match it with its expected expression. Children successfully used a process of elimination to match a single expression to one of several labels (Study 1) and to match a single label to one of several expressions (Study 2). These data highlight one possible mechanism that children may use to learn about the expressions they encounter and may shed light on the ways in which children's expression categories are constructed. PMID- 27222440 TI - Comparative Mitochondrial Genome Analysis of Eligma narcissus and other Lepidopteran Insects Reveals Conserved Mitochondrial Genome Organization and Phylogenetic Relationships. AB - In this study, we sequenced the complete mitochondrial genome of Eligma narcissus and compared it with 18 other lepidopteran species. The mitochondrial genome (mitogenome) was a circular molecule of 15,376 bp containing 13 protein-coding genes (PCGs), 22 transfer RNA (tRNA) genes, two ribosomal RNA (rRNA) genes and an adenine (A) + thymine (T) - rich region. The positive AT skew (0.007) indicated the occurrence of more As than Ts. The arrangement of 13 PCGs was similar to that of other sequenced lepidopterans. All PCGs were initiated by ATN codons, except for the cytochrome c oxidase subunit 1 (cox1) gene, which was initiated by the CGA sequence, as observed in other lepidopterans. The results of the codon usage analysis indicated that Asn, Ile, Leu, Tyr and Phe were the five most frequent amino acids. All tRNA genes were shown to be folded into the expected typical cloverleaf structure observed for mitochondrial tRNA genes. Phylogenetic relationships were analyzed based on the nucleotide sequences of 13 PCGs from other insect mitogenomes, which confirmed that E. narcissus is a member of the Noctuidae superfamily. PMID- 27222442 TI - Length matters: Improved high field EEG-fMRI recordings using shorter EEG cables. AB - BACKGROUND: The use of concurrent EEG-fMRI recordings has increased in recent years, allowing new avenues of medical and cognitive neuroscience research; however, currently used setups present problems with data quality and reproducibility. NEW METHOD: We propose a compact experimental setup for concurrent EEG-fMRI at 4T and compare it to a more standard reference setup. The compact setup uses short EEG cables connecting to the amplifiers, which are placed right at the back of the head RF coil on a form-fitting extension force locked to the patient MR bed. We compare the two setups in terms of sensitivity to MR-room environmental noise, interferences between measuring devices (EEG or fMRI), and sensitivity to functional responses in a visual stimulation paradigm. RESULTS: The compact setup reduces the system sensitivity to both external noise and MR-induced artefacts by at least 60%, with negligible EEG noise induced from the mechanical vibrations of the cryogenic cooling compression pump. COMPARISON WITH EXISTING METHODS: The compact setup improved EEG data quality and the overall performance of MR-artifact correction techniques. Both setups were similar in terms of the fMRI data, with higher reproducibility for cable placement within the scanner in the compact setup. CONCLUSIONS: This improved compact setup may be relevant to MR laboratories interested in reducing the sensitivity of their EEG-fMRI experimental setup to external noise sources, setting up an EEG-fMRI workplace for the first time, or for creating a more reproducible configuration of equipment and cables. Implications for safety and ergonomics are discussed. PMID- 27222443 TI - pH-sensitive pHluorins as a molecular sensor for in situ monitoring of enzyme catalyzed prodrug activation. AB - This work examines the feasibility of using a pH-sensitive fluorescent protein as a molecular reporter for enzyme-catalyzed prodrug activation reaction. Specifically, a ratiometric pHluorins was examined for detection of the activity of horseradish peroxidase (HRP) for the activation of indole-3-acetic acid. The pHluorins and HRP were conjugated chemically, forming a biocatalyst with a self reporting function. Results showed that the characteristic fluorescence intensity ratio of the conjugate shifted from 1.47 to 1.40 corresponding to the progress of the prodrug activation reaction. The effectiveness of applying the conjugate for inhibition of the growth of Bcap-37 cells was also demonstrated simultaneously with reaction monitoring. The results reveal a very promising approach to realizing in situ monitoring of enzyme activities based on pH shifting for enzyme based prodrug therapy applications. PMID- 27222444 TI - Grade-Level Differences in Future-Oriented Self-Concept During Early Adolescence: Potential Relevance to School Nursing. AB - The middle school and early high school years are a time of significant development, including an increasing ability to envision oneself in the future. Little is known about how adolescents' future-oriented self-concept (i.e., possible selves) differs across grade levels, although this knowledge may aid in establishing rapport with students and building effective health promotion and risk reduction interventions. Therefore, this study explored grade-level differences in hoped for and feared possible selves in a sample of sixth- to ninth-grade students (n = 2,498; M age = 12.72, SD = 1.15; 51.3% female). Findings suggest that adolescents list a variety of possible selves, and the content differs according to grade level. These findings offer helpful insight for intervention work aimed at improving student outcomes and preventing risk behavior. Understanding what adolescents hope and fear for themselves in the future may be particularly beneficial for school nurses in identifying the unique challenges students experience and tailoring health promotion efforts. PMID- 27222445 TI - Safety risks associated with physical interactions between patients and caregivers during treatment and care delivery in Home Care settings: A systematic review. AB - OBJECTIVES: To explore the safety risks associated with physical interactions between patients and caregivers during treatment and care delivery in Home Care settings. DESIGN: Seven-stage framework from the PRISMA statement for research question, eligibility (definition), search, identification of relevant papers from title and abstract, selection and retrieval of papers, appraisal and synthesis. DATA SOURCES: British Nursing Index (BNI), Allied and Complementary Medicine Database (AMED), Applied Social Sciences Index and Abstracts (ASSIA), Cinahl, Cochrane Library, Embase, Ergonomics Abstracts, Health Business Elite, Health Management Information Consortium (HMIC), Medline, PsycInfo, Scopus, Social Care online, Social Science Citation Index. REVIEW METHODS: The included references (n=42) were critically appraised using a modified version of Downs and Black checklist and the Mixed Methods Appraisal Tool. RESULTS: The risk factors are reported using the modified model of human factors of health care in the home to represent the roles of both patients and caregivers in the system. The results are grouped as environment (health policy, physical and social), artefacts (equipment and technology), tasks (procedures and work schedules) and care recipient/provider. These include permanent and temporary building design and access, communication and lone working, provision of equipment and consumables, and clinical tasks. The topics with strong evidence from at least 2 papers relate to risks associated with awkward working positions, social environment issues (additional tasks and distractions), abuse and violence, inadequate team (peer) support, problems with workload planning, needle stick injuries and physical workload (moving and handling patients). CONCLUSIONS: As home care increases, there is a need to ensure the safety of both patients and caregivers with an understanding of the physical interactions and tasks to manage safety risks and plan safer care delivery systems. PMID- 27222446 TI - Using TwitterTM to drive research impact: A discussion of strategies, opportunities and challenges. AB - Researchers have always recognised the importance of disseminating the findings of their work, however, recently the need to proactively plan and drive the impact of those findings on the wider society has become a necessity. Firstly, this is because funders require evidence of return from investment and secondly and crucially because national research assessments are becoming powerful determinants of future funding. In research studies associated with nursing, impact needs to be demonstrated by showing the effect on a range of stakeholders including service users, patients, carers, the nursing workforce and commissioners. Engaging these groups is a well-known challenge influenced by lack of access to academic journals, lack of time to read long complex research papers and lack of opportunities to interact directly with the researchers. This needs to be addressed urgently to enable nursing research to increase the impact that it has on health delivery and the work of clinical practitioners. Social media is potentially a novel way of enabling research teams to both communicate about research as studies progress and to disseminate findings and research funders are increasingly using it to publicise information about research programmes and studies they fund. A search of the healthcare literature reveals that advice and guidance on the use of social media for research studies is not well understood or exploited by the research community. This paper, therefore, explores how using social networking platforms, notably TwitterTM offers potential new ways for communicating research findings, accessing diverse and traditionally hard-to reach audiences, knowledge exchange at an exponential rate, and enabling new means of capturing and demonstrating research impact. The paper discusses approaches to initiate the setup of social networking platforms in research projects and considers the practical challenges of using TwitterTM in nursing and healthcare research. The discussion is illuminated with examples from our current research. In summary, we suggest that the use of social media micro-blogging platforms is a contemporary, fast, easy and cost effective way to augment existing ways of disseminating research which helps drive impact. PMID- 27222447 TI - The daily relationships between staffing, safety perceptions and personality in hospital nursing: A longitudinal on-line diary study. AB - BACKGROUND: The association between poor staffing conditions and negative patient safety consequences is well established within hospital nursing. However, many studies have been limited to nurse population level associations, and have used routine data to examine relationships. As a result, it is less clear how these relationships might be manifested at the individual nurse level on a day-to-day basis. Furthermore, personality may have direct and moderating roles in terms of work environment and patient safety associations, but limited research has explored personality in this context. OBJECTIVE: To further our understanding of these associations, this paper takes a within-person approach to examine nurses' daily perceptions of staffing and patient safety. In addition, we explore the potential role of personality factors as moderators of daily level associations. METHOD: We recruited eighty-three hospital nurses from three acute NHS Trusts in the UK between March and July 2013. Nurses completed online end-of-shift diaries over three-five shifts which collected information on perceptions of staffing, patient-nurse ratio and patient safety (perceptions of patient safety, ability to act as a safe practitioner, and workplace cognitive failure). Personality was also assessed within a baseline questionnaire. Data were analysed using hierarchical linear modelling, and moderation effects of personality factors were examined using simple slopes analyses, which decomposed relationships at high and low levels of the moderator. RESULTS: On days when lower patient-nurse ratios were indicated, nurses reported being more able to act as a safe practitioner (p=.011) and more favourable perceptions of patient safety (p=<.001). Additionally, when staffing was perceived more favourably, nurses reported being more able to act as a safe practitioner (p=<.001), more favourable perceptions of patient safety (p=<.001) and experienced less workplace cognitive failure (p=<.001). Conscientiousness and emotional stability emerged as key moderators of daily level associations between staffing and patient safety variables, with many relationships differing at high and low levels of these personality factors. CONCLUSION: The findings elucidate the potential mechanisms by which patient safety risks arise within hospital nursing, and suggest that nurses may not respond to staffing conditions in the same way, dependent upon personality. Further understanding of these relationships will enable staff to be supported in terms of work environment conditions on an individual basis. PMID- 27222448 TI - Research letter: Metasynthesis - Fairy tale of a nursing sleeping beauty. PMID- 27222449 TI - A multi-centre study of interactional style in nurse specialist- and physician led Rheumatology clinics in the UK. AB - BACKGROUND: Nurse-led care is well established in Rheumatology in the UK and provides follow-up care to people with inflammatory arthritis including treatment, monitoring, patient education and psychosocial support. AIM: The aim of this study is to compare and contrast interactional style with patients in physician-led and nurse-led Rheumatology clinics. DESIGN: A multi-centre mixed methods approach was adopted. SETTINGS: Nine UK Rheumatology out-patient clinics were observed and audio-recorded May 2009-April 2010. PARTICIPANTS: Eighteen practitioners agreed to participate in clinic audio-recordings, researcher observations, and note-taking. Of 9 nurse specialists, 8 were female and 5 of 9 physicians were female. Eight practitioners in each group took part in audio recorded post-clinic interviews. All patients on the clinic list for those practitioners were invited to participate and 107 were consented and observed. In the nurse specialist cohort 46% were female; 71% had a diagnosis of Rheumatoid Arthritis (RA). The physician cohort comprised 31% female; 40% with RA and 16% unconfirmed diagnosis. Nineteen (18%) of the patients observed were approached for an audio-recorded telephone interview and 15 participated (4 male, 11 female). METHODS: Forty-four nurse specialist and 63 physician consultations with patients were recorded. Roter's Interactional Analysis System (RIAS) was used to code this data. Thirty-one semi-structured interviews were conducted (16 practitioner, 15 patients) within 24h of observed consultations and were analyzed using thematic analysis. RESULTS: RIAS results illuminated differences between practitioners that can be classified as 'socio-emotional' versus 'task-focussed'. Specifically, nurse specialists and their patients engaged significantly more in the socio-emotional activity of 'building a relationship'. Across practitioners, the greatest proportion of 'patient initiations' were in 'giving medical information' and reflected what patients wanted the practitioner to know rather than giving insight into what patients wanted to know from practitioners. Interviews revealed that continuity of practitioner was highly valued by patients as offering the benefits of an established relationship and of emotional support beyond that of the clinical encounter. This fostered familiarity not only with their particular medical history, but also their individual personal circumstances, and this encouraged patient participation. In contrast, practitioners (mis)perceived waiting times to have a greater impact on patient satisfaction. However, practitioner interviews also revealed that clinic structure is often outside of the practitioner control and can undermine the possibility of maintaining patient-practitioner continuity. CONCLUSIONS: This research enhances understanding of nurse specialist consultation styles in Rheumatology, specifically the value of their socio-emotional communication skills to enhance patient participation. PMID- 27222450 TI - Heparin versus 0.9% sodium chloride intermittent flushing for the prevention of occlusion in long term central venous catheters in infants and children: A systematic review. AB - BACKGROUND: Around the world, guidelines and clinical practice for the prevention of complications associated with central venous catheters (CVC) vary greatly. To prevent occlusion, most institutions recommend the use of heparin when the CVC is not in use. However, there is debate regarding the need for heparin and evidence to suggest normal saline may be as effective. The use of heparin is not without risk, may be unnecessary and is also associated with increased costs. OBJECTIVES: To assess the clinical effects (benefits and harms) of heparin versus normal saline to prevent occlusion in long-term central venous catheters in infants, children and adolescents. DESIGN: A Cochrane systematic review of randomised controlled trials was undertaken. DATA SOURCES: The Cochrane Vascular Group Specialised Register (including MEDLINE, CINAHL, EMBASE and AMED) and the Cochrane Register of Studies were searched. Hand searching of relevant journals and reference lists of retrieved articles was also undertaken. REVIEW METHODS: Data were extracted and appraisal undertaken. We included studies that compared the efficacy of normal saline with heparin to prevent occlusion. We excluded temporary CVCs and peripherally inserted central catheters. Rate ratios per 1000 catheter days were calculated for two outcomes, occlusion of the CVC, and CVC associated blood stream infection. RESULTS: Three trials with a total of 245 participants were included in this review. The three trials directly compared the use of normal saline and heparin. However, between studies, all used different protocols with various concentrations of heparin and frequency of flushes. The quality of the evidence ranged from low to very low. The estimated rate ratio for CVC occlusion per 1000 catheter days between the normal saline and heparin group was 0.75 (95% CI 0.10 to 5.51, two studies, 229 participants, very low quality evidence). The estimated rate ratio for CVC-associated blood stream infection was 1.48 (95% CI 0.24 to 9.37, two studies, 231 participants; low quality evidence). CONCLUSIONS: It remains unclear whether heparin is necessary for CVC maintenance. More well-designed studies are required to understand this relatively simple, but clinically important question. Ultimately, if this evidence were available, the development of evidenced-based clinical practice guidelines and consistency of practice would be facilitated. PMID- 27222451 TI - Patient satisfaction, stress and burnout in nursing personnel in emergency departments: A cross-sectional study. AB - BACKGROUND: Patient satisfaction is considered a measure of the status of the interaction between health- care professionals and service users. The level of this measure indicates the quality of the care received. Burnout is a common phenomenon in nursing professionals and it is a response to the chronic occupational stress. Different studies have shown a link between patient satisfaction and stress and burnout syndrome experienced by nursing personnel in various hospital units. OBJECTIVES: The main objective of this study was to analyze the associations between patients' satisfaction with emergency services and perception of work stress and burnout by the nursing professionals who looked after these patients at a group level. DESIGN: The study followed a descriptive and cross-sectional design; the data were collected by means of questionnaires. SETTING: Emergency services at two general hospitals in Murcia (Spain). PARTICIPANTS: Two samples, one formed of emergency service nursing professionals (n=148) and the other formed by patients (n=390), who were grouped in 48 units of analysis. METHODS: To evaluate perception of stress and burnout of the nursing personnel, we used the Spanish adaptation of the Nursing Stress Scale for hospital emergency nursing personnel, and the Spanish adaptation of the Maslach Burnout Inventory, respectively. A Spanish adaptation of the La Monica-Obsert Patient Satisfaction Scale was used to define the patients' feelings about their nursing care. Moreover, some socio-demographic variables and the length of stay in the emergency unit were included in the protocol. Before statistical analysis, the data were collated at a group level. The intraclass correlation coefficients and the Average Deviation Index support the aggregation of these data at a unit level. RESULTS: Neither perception of stress nor the various elements of burnout experienced by nursing staff were related to patients' levels of satisfaction. We observed a significant and positive association between stress perception among the nurses and two of the burnout dimensions, namely emotional exhaustion and cynicism. The length of stay of the patients in the emergency department was negatively related to the frequency of nurses experiencing perceived stress as well as the burnout dimension of cynicism. CONCLUSIONS: No significant association was observed between experiences of stress and burnout dimensions by nursing professionals and the satisfaction with care received reported by their patients. These findings could be explained by the professional and organizational characteristics of the unit. Finally, the limitations and implications of the study are discussed, as well as future research questions related to research of the associations between occupational stress, burnout and patient satisfaction. PMID- 27222452 TI - Relationships between perineal pain and postpartum depressive symptoms: A prospective cohort study. AB - BACKGROUND: The relationship between concurrent or previous postnatal pain and depressive symptoms remains controversial. To the best of our knowledge, no previous study has used validated measures and multiple scales to evaluate perineal pain, or examined its relationship with depressive symptoms during the postpartum period. OBJECTIVES: We investigated the association between pain and previous postnatal pain with depression during the 6-month postpartum period, and the influence of previous postnatal depressive symptoms. DESIGN: A prospective cohort study design was used. SETTING: Maternity unit of a medical center. PARTICIPANTS: This study included 432 participants; data regarding demographic characteristics, perineal pain, and any pain and depression during the 6-month postpartum period were collected. METHODS: Pain and depressive symptoms were measured using the Short Form-McGill Pain Questionnaire and Center for Epidemiologic Studies Depression Scale, respectively. A generalized estimating equation was used to examine factors associated with postpartum depression. RESULTS: After adjusting for covariates, women who had perineal pain at 4-6 weeks postpartum showed an increased risk for depression at 4-6 weeks (risk ratio [RR]: 1.9, 95% confidence limits [CL]: 1.2, 3.2) and 6 months (RR: 1.9, 95% CL: 1.1, 3.3) compared to those with no perineal pain. Perineal pain severity, 4-6 weeks postpartum, also predicted depressive symptoms at 6 months postpartum (beta=0.63, p=0.02). Any pain intensity score at 3-5 days postpartum predicted depression at 3 months (beta=0.01, p=0.04). Women with high depression scores at 3-5 days had a two- or three-fold higher risk for depression at 4-6 weeks and 3 and 6 months, respectively, compared to those with low depression scores (RR: 3.5, 95% CL: 2.2, 5.4; RR: 2.2, 95% CL: 1.3, 3.4; and RR: 2.8, 95% CL: 1.7, 4.8, respectively). CONCLUSIONS: Our study provides robust evidence that perineal pain 4-6 weeks postpartum is associated with depressive symptoms 4-6 weeks and 6 months postpartum; pain at 3-5 days postpartum predicts depressive symptoms at 3 months postpartum; and previous postnatal depressive symptoms, particularly depressive symptoms 3-5 days postpartum, predict depressive symptoms during the 6-month postpartum period. PMID- 27222453 TI - Epidemiology and neonatal pain management of heelsticks in intensive care units: EPIPPAIN 2, a prospective observational study. AB - BACKGROUND: Heelstick is the most frequently performed skin-breaking procedure in the neonatal intensive care units (NICUs). There are no large multicenter studies describing the frequency and analgesic approaches used for heelsticks performed in NICUs. OBJECTIVES: To describe the frequency of heelsticks and their analgesic management in newborns in the NICU. To determine the factors associated with the lack of specific preprocedural analgesia for this procedure. DESIGN: EPIPPAIN 2 (Epidemiology of Procedural PAin In Neonates) is a descriptive prospective epidemiologic study. SETTING: All 16 NICUs in the Paris region in France. PARTICIPANTS: All newborns in the NICU with a maximum corrected age of 44 weeks +6 days of gestation on admission who had at least one heelstick during the study period were eligible for the study. The study included 562 newborns. METHODS: Data on all heelsticks and their corresponding analgesic therapies were prospectively collected. The inclusion period lasted six weeks, from June 2, 2011 to July 12, 2011. Newborns were followed from their admission to the 14th day of their NICU stay or discharge, whichever occurred first. RESULTS: The mean (SD) gestational age was 33.3 (4.4) weeks and duration of participation was 7.5 (4.4) days. The mean (SD; range) of heelsticks per neonate was 16.0 (14.4; 1-86) during the study period. Of the 8995 heelsticks studied, 2379 (26.4%) were performed with continuous analgesia, 5236 (58.2%) with specific preprocedural analgesia. Overall, 6764 (75.2%) heelsticks were performed with analgesia (continuous and/or specific). In a multivariate model, the increased lack of preprocedural analgesia was associated with female sex, term birth, high illness severity, tracheal or noninvasive ventilation, parental absence and use of continuous sedation/analgesia. CONCLUSIONS: Heelstick was very frequently performed in NICUs. Although, most heelsticks were performed with analgesia, this was not systematic. The high frequency of this procedure and the known adverse effects of repetitive pain in neonates should encourage the search of safe and effective strategies to reduce their number. PMID- 27222455 TI - Sleep and health-related quality of life in pregnant women: Actigraphic and questionnaire survey. PMID- 27222454 TI - How do patients' values influence heart failure self-care decision-making?: A mixed-methods systematic review. AB - BACKGROUND: Values are central to ethical and effective nursing and health care. However, in relation to heart failure, an extremely common and burdensome syndrome, the role that patients' values have in influencing self-care is poorly understood. METHODS: A mixed methods systematic review was conducted using a critical meta-narrative synthesis approach to synthesizing qualitative and qualitized data. Nine databases were searched (14 March 2014). To be included in the review, studies had to contain data on heart failure patients' values and self-care behaviors, include adults aged >=18 years with symptomatic heart failure, and be published >=2000 as full articles or theses. Study quality was assessed using a mixed-methods appraisal tool. FINDINGS: Of 6467 citations identified, 54 studies were included (30 qualitative, 8 mixed methods, and 16 quantitative; 6045 patients, 38 lay caregivers, and 96 health care professionals). The synthesis identified multiple bi-directional interactions between heart failure, patients' values, and self-care. Patients are motivated by self-related and other-related values. Self-related values are tied directly to intimate personal feelings (self-direction, pleasure, and being healthy) or related to individuals' life circumstances (maintaining a healthy lifestyle and financial balance). Other-related values, which are fundamentally socially-based, are related to benefits received from society (social recognition and socialization) and social obligations (responsibility, observing traditions, and obedience). For each decision, several values are involved; some are incompatible and some are in conflict. Patients make their self-care decision based on the values they prioritize and those that are blocked. CONCLUSION: Values are integral to how patients approach and undertake HF self-care. These values both affect and respond to this self-care and the severity of HF symptoms. Values extend to those relating to the self and others and incorporate a range of personal, life, and social dimensions. Values cannot be assumed to be fixed, normative or similar to those held by nurses and other health professionals. Future interventions to improve HF self-care must address and respond to the complexity of patients' values and how they influence patient behavior in undertaking heart failure self-care. PMID- 27222456 TI - The PaArticular Scales - A new outcome measure to quantify the impact of joint contractures on activities and participation in individuals in geriatric care: Development and Rasch analysis. AB - BACKGROUND: Joint contractures are frequent conditions in individuals in geriatric care settings and are associated with activity limitations and participation restrictions. As such, relevant intervention programs should address these aspects, and the effectiveness of such programs should be determined by assessing improvement in activities and participation. However, no patient-centred and psychometrically sound outcome measures for this purpose are available so far. OBJECTIVES: The objectives of this study were to develop and to validate a new outcome measure, the PaArticular Scales, to quantify activities and participation in older individuals with joint contractures. Specific aims were (A) to operationalize the content of an International Classification of Functioning, Disability and Health-based standard set towards meaningful questions and to combine them to a questionnaire and (B) to assess the psychometric properties of the developed questionnaire, in detail to evaluate test-retest reliability, objectivity, internal consistency reliability and criterion validity. DESIGN: Operationalization was reached by an expert consensus conference and a subsequent expert Delphi survey. Psychometric properties were assessed in a cross-sectional study. SETTINGS: Nursing homes, geriatric rehabilitation facilities. PARTICIPANTS: 23 experts (nurses, physicians, physical and occupational therapists) participated in the consensus conference and the Delphi survey. A total of 191 individuals with joint contractures (as confirmed by physician, nurse or physical therapist) between 65 and 102 years, living in nursing homes or as patients in geriatric rehabilitation were enrolled in the cross-sectional study. METHODS: Rasch Partial Credit Modelling. RESULTS: The consensus conference and Delphi survey resulted in a questionnaire with 86 items of the International Classification of Functioning, Disability and Health. Test retest-reliability among those was acceptable (Cohen's weighted kappa: 0.779). The Rasch analysis revealed two independent interval-scaled scales with 24 items for the Activities scale and 11 items for the Participation scale with high internal consistency reliability. Cronbach's alpha was 0.96 for the Activities scale and 0.92 for the Participation scale. Criterion validity was -0.40 and 0.30 for the Activities scale and for the Participation scale, respectively. CONCLUSIONS: The PaArticular Scales, a new patient-centred and psychometric sound outcome measures to comprehensively assess the impact of joint contractures in geriatric care, are available now. These developed scales will serve as primary outcomes in a scheduled evaluation of a complex intervention to improve participation and quality of life in nursing home residents with joint contractures. PMID- 27222457 TI - Parent education interventions designed to support the transition to parenthood: A realist review. AB - BACKGROUND: Public health nurses use parent education programmes to support individuals' transition to parenthood. A wide array of these programmes exists; however, the approach must be accommodated by resources available in a publicly funded system. For example, some new-parent education approaches use 1:1 home visiting (with a nurse or trained lay-home visitor) but the costs of this intensive approach can be prohibitive. Because of this limitation there is an interest in identifying effective and efficient new parent educational approaches that can realistically be provided at a universal level. Unfortunately, there is a lack of high-quality evaluation identifying programmes or educational processes that meet these criteria. OBJECTIVES: To identify potentially effective new parenting education interventions that could be implemented at a population level during the transition to parenthood period. DESIGN: Realist synthesis. DATA SOURCES: Medline, CINAHL, ERIC, PsycINFO, Sociological Abstracts, grey literature. REVIEW METHODS: A realist review method generated a total of 72 papers that were used to inform the results. A three-pronged approach was used incorporating an initial search (6), a database search using applicable keywords and MeSH headings (58), and review of literature identified by advisory group (8 grey literature). An 'implementation chain' was developed to outline the overall logic and process behind parent education interventions and to guide the analysis. RESULTS: Seventy-two papers informed this review: 13 systematic reviews/meta-analyses, 34 intervention studies, 9 opinion papers, 8 programme reviews, and 8 grey literature reports. There was no compelling evidence to suggest that a single educational programme or delivery format was effective at a universal level. Some inherent issues were identified. For example, adult learning principles were overlooked and theories of parent-child interaction were not in evidence. No direct links between universal new-parent education programmes and child development outcomes were established. Programme reach and attrition were key challenges. Programme evaluation criteria were inconsistent, with an over-reliance on parent satisfaction or self-reported intention to change behaviour. There was evidence that effective facilitators helped increase parents' perceived satisfaction with programmes. CONCLUSIONS: It is unlikely that a single standardized format or programme will meet all the specific learning needs of parents. Multiple approaches that will allow people to access information or education at a time and in a format that suits them may be of value. The importance of the transition to parenthood and its impact on parent and child wellbeing warrant careful consideration of current programming and careful evaluation of future initiatives. PMID- 27222458 TI - Nurses' 'worry' as predictor of deteriorating surgical ward patients: A prospective cohort study of the Dutch-Early-Nurse-Worry-Indicator-Score. AB - BACKGROUND: Nurses' 'worry' is used as a calling criterion in many Rapid Response Systems, however it is valued inconsistently. Furthermore, barriers to call the Rapid Response Team can cause delay in escalating care. The literature identifies nine indicators which trigger nurses to worry about a patient's condition. OBJECTIVES: The objective of this study is to determine the significance of nurses' 'worry' and/or indicators underlying 'worry' to predict unplanned Intensive-Care/High-Dependency-Unit admission or unexpected mortality among surgical ward patients. DESIGN: A prospective cohort study. SETTINGS: A 500-bed tertiary University affiliated teaching hospital. PARTICIPANTS: Adult, native speaking surgical patients, admitted to three surgical wards (traumatology, vascular- and abdominal/oncological surgery). We excluded patients with a non-ICU policy or with no curative treatment. Mentally incapacitated patients were also excluded. METHODS: We developed a new clinical assessment tool, the Dutch-Early Nurse-Worry-Indicator-Score (DENWIS) based on signs underlying 'worry'. Nurses systematically scored their 'worry' and the DENWIS once per shift or at any moment of 'worry'. DENWIS measurements were linked to routinely measured vital signs. The composite endpoint was unplanned Intensive-Care/High-Dependency-Unit admission or unexpected mortality. The DENWIS-indicators were included in a univariate and multivariate logistic regression analysis, subsequently inserting 'worry' and the Early Warning Score into the model. We calculated the area under the receiver-operating characteristics curve. RESULTS: In 3522 patients there were 102 (2.9%) patients with unplanned Intensive Care Unit/High Dependency Unit admissions or unexpected mortality. 'Worry' (0.81) and the DENWIS-model (0.85) had a lower area under the receiver-operating characteristics curve than the Early Warning Score (0.86). Adding 'worry' and the Early Warning Score to the DENWIS-model resulted in higher areas under the receiver operating characteristics curves (0.87 and 0.91, respectively) compared with the Early Warning Score only based on vital signs. CONCLUSIONS: In this single-center study we showed that adding the Early Warning Score based on vital signs to the DENWIS indicators improves prediction of unplanned Intensive-Care/High-Dependency-Unit admission or unexpected mortality. PMID- 27222459 TI - The effectiveness of manual-guided, problem-solving-based self-learning programme for family caregivers of people with recent-onset psychosis: A randomised controlled trial with 6-month follow-up. AB - BACKGROUND: Family intervention for psychotic disorders is an integral part of psychiatric treatment with positive effects on patients' mental state and relapse rate. However, the effect of such family-based intervention on caregivers' psychological distress and well-being, especially in non-Western countries, has received comparatively much less attention. OBJECTIVES: To test the effects of guided problem-solving-based manual-guided self-learning programme for family caregivers of adults with recent-onset psychosis over a 6-month period of follow up, when compared with those in usual family support service. DESIGN: A single centre randomised controlled trial, which was registered at ClinicalTrials.gov (NCT02391649), with a repeated-measures, two-arm (parallel-group) design. SETTINGS: One main psychiatric outpatient clinic in the New Territories of Hong Kong. PARTICIPANTS: A random sample of 116 family caregiverss of adult outpatients with recent-onset psychosis. METHODS: Following pre-test measurement, caregivers were assigned randomly to one of two study groups: a 5-month self help, problem-solving-based manual-guided self-learning (or bibliotherapy) programme (in addition to usual care), or usual family support service only. Varieties of patient and caregiver health outcomes were assessed and compared at baseline and at 1-week and 6-month post-intervention. RESULTS: One hundred and eleven (96%) caregivers completed the 6-month follow-up (two post-tests); 55 of them (95%) completed >=4 modules and attended >=2 review sessions (i.e., 75% of the intervention). The family participants' mean age was about 38 years and over 64% of them were female and patient's parent or spouse. Multivariate analyses of variance indicated that the manual-guided self-learning group reported significantly greater improvements than the usual care group in family burden [F(1,110)=6.21, p=0.006] and caregiving experience [F(1,110)=6.88, p=0.0004], and patients' psychotic symptoms [F(1,110)=6.25, p=0.0003], functioning [F(1,110)=7.01, p=0.0005] and number of hospitalisations [F(1,110)=5.71, p=0.005] over 6-month follow-up. CONCLUSIONS: Problem-solving-based, manual-guided self learning programme for family caregivers of adults with recent-onset psychosis can be an effective self-help programme and provide medium-term benefits to patients' and caregivers' mental health and duration of patients' re hospitalisations. PMID- 27222461 TI - The burden of diarrhea in the intensive care unit (ICU-BD). A survey and observational study of the caregivers' opinions and workload. AB - BACKGROUND: Diarrhea as a common complication affects 14% patients in our intensive care unit. Risk factors for diarrhea and its clinical consequences for patients are well known, but the impact of diarrhea on caregivers' workload remains undocumented. OBJECTIVES: This study aims at establishing the impact of diarrhea on costs and human burden in intensive care unit caregivers. DESIGN: A survey and observational study. SETTINGS: A mixed 36-bed medical and surgical intensive care unit. PARTICIPANTS: All intensive care unit caregivers (nurses and nursing aides). METHODS: A questionnaire was designed by a multidisciplinary team and completed by intensive care unit caregivers analyzing the clinical and human impact of diarrhea on their workload. Time measurements for the management of liquid stools were performed. Human related costs of diarrhea were analyzed according to caregivers' years of clinical experience. RESULTS: Questionnaires were completed by 146 of 204 intensive care unit caregivers (75% nurses; 73% nursing aides). Dealing with diarrhea patients is a painful aspect of their work (69% nurses) with tiredness as main feeling and a source of conflict or misunderstanding among caregivers. The mean time measurement for managing one liquid stool in 50 diarrhea episodes was 17min and 33s, involving an average of 1.4 nurses and 0.8 nursing aides. Average human resources cost burden was 26.60 CHF per liquid stool. CONCLUSION: Dealing with diarrhea increases workload for intensive care unit caregivers with consequences on their well-being. Human related costs of diarrhea are substantial and highlight the economic burden of diarrhea episodes in the intensive care unit. A multidisciplinary approach and specific protocols could positively impact the burden of diarrhea in the intensive care unit. TRIAL REGISTRATION: Clinical Trials gov NCT01922570. PMID- 27222460 TI - Skin antiseptics in venous puncture site disinfection for preventing blood culture contamination: A Bayesian network meta-analysis of randomized controlled trials. AB - OBJECTIVE: To compare the efficacy of several antiseptics in decreasing the blood culture contamination rate. DESIGN: Network meta-analysis. DATA SOURCE: Electronic searches of PubMed and Embase were conducted up to November 2015. Only randomized controlled trials or quasi-randomized controlled trials were eligible. We applied no language restriction. A comprehensive review of articles in the reference lists was also accomplished for possible relevant studies. REVIEW METHODS: Relevant studies evaluating efficacy of different antiseptics in venous puncture site for decreasing the blood culture contamination rate were included. The data were extracted from the included randomized controlled trials by two authors independently. The risk of bias was evaluated using Detsky scale by two authors independently. We used WinBUGS1.43 software and statistic model described by Chaimani to perform this network meta-analysis. Then graphs of statistical results of WinBUGS1.43 software were generated using 'networkplot', 'ifplot', 'netfunnel' and 'sucra' procedure by STATA13.0. Odds ratio and 95% confidence intervals were assessed for dichotomous data. A probability of p less than 0.05 was considered to be statistically significant. Compared with ordinary meta analyses, this network meta-analysis offered hierarchies for the efficacy of different antiseptics in decreasing the blood culture contamination rate. RESULTS: Seven randomized controlled trials involving 34,408 blood samples were eligible for the meta-analysis. No significant difference was found in blood culture contamination rate among different antiseptics. No significant difference was found between non-alcoholic antiseptics and alcoholic antiseptics, alcoholic chlorhexidine and povidone iodine, chlorhexidine and iodine compounds, povidone iodine and iodine tincture in this aspect, respectively. CONCLUSIONS: Different antiseptics may not affect the blood culture contamination rate. Different intervals between the skin disinfection and the venous puncture, the different settings (emergency room, medical wards, and intensive care units) and the performance of the phlebotomy may affect the blood culture contamination rate. PMID- 27222462 TI - Giving voice to quality and safety matters at board level: A qualitative study of the experiences of executive nurses working in England and Wales. AB - BACKGROUND: Recent reports into egregious failing in the quality and safety of healthcare in the UK have focussed on the ability of executive boards to discharge their duties effectively. Inevitably the role of executive nurses, whose remit frequently includes responsibility for quality and safety, has become the object of increased scrutiny. However, limited evidence exists about the experiences of the UK's most senior nurses of working at board level. OBJECTIVE: We aimed to generate empirical evidence on the experiences of executive nurses working at board level in England and Wales. We posed two research questions: What are the experiences of nurse executives working at board level? What strategies and/or processes do nurse executives deploy to ensure their views and concerns about quality and safety are taken into account at board level? DESIGN: Qualitative interviews using semi-structured interviews. SETTING: NHS England and Wales. PARTICIPANTS: Purposive sample of 40 executive board nurses. METHODS: Semi structured interviews followed by a process of thematic data analysis using NVivo10 and feedback on early findings from participants. RESULTS: Our findings are presented under three headings: the experiences of executive nurses working with supportive, engaged boards; their experiences of being involved with unsupportive, avoidant boards with a poor understanding of safety, quality and the executive nursing role and the strategies deployed by executive nurses to ensure that the nursing voice was heard at board. Two prominent and interrelated discursive strategies were used by executive nurses - briefing and building relationships and preparing and delivering a credible case. Considerable time and effort were invested in these strategies which were described as having significant impact on individual board members and collective board decision making. These strategies, when viewed through the lens of the concept of "groupthink", can be seen to protect executive nurses from accusations by board colleagues of disloyalty whislt also actively restricting the development of "groupthink" within the board. Another finding of note was that executive boards may not be permanently fixed as either unsupportive or supportive as participants described how certain boards that were initially unsupportive adopted a more supportive attitude towards matters of safety and quality. CONCLUSIONS: These highly positioned nurses can provide invaluable advice and support to boards around matters of quality and safety. However, the work of nurse executives remains an under-research area and more work is needed to better understand the ebb and flow of power and influence at play within hospital boards. PMID- 27222463 TI - Dressing and securement for central venous access devices (CVADs): A Cochrane systematic review. AB - OBJECTIVES: To compare the available dressing and securement devices for central venous access devices (CVADs). DESIGN: Systematic review of randomised controlled trials. DATA SOURCES: Cochrane Wounds Group Specialised Register, the Cochrane Central Register of Controlled Trials, the Database of Abstracts of Reviews and of Effects, NHS Economic Evaluation Database, Ovid MEDLINE, CINAHL, EMBASE, clinical trial registries and reference lists of identified trials. REVIEW METHODS: Studies evaluated the effects of dressing and securement devices for CVADs. All types of CVADs were included. Outcome measures were CVAD-related bloodstream infection, CVAD tip colonisation, entry and exit site infection, skin colonisation, skin irritation, failed CVAD securement, dressing condition and mortality. We used standard methodological approaches as expected by The Cochrane Collaboration. RESULTS: We included 22 studies involving 7436 participants comparing nine different types of securement device or dressing. All included studies were at unclear or high risk of performance bias due to the different appearances of the dressings and securement devices. It is unclear whether there is a difference in the rate of CVAD-related bloodstream infection between securement with gauze and tape and standard polyurethane (RR 0.64, 95% CI 0.26 to 1.63, low quality evidence), or between chlorhexidine gluconate-impregnated dressings and standard polyurethane (RR 0.65, 95% CI 0.40 to 1.05, moderate quality evidence). There is high quality evidence that medication-impregnated dressings reduce the incidence of CVAD-related bloodstream infection relative to all other dressing types (RR 0.60, 95% CI 0.39 to 0.93). There is moderate quality evidence that chlorhexidine gluconate-impregnated dressings reduce the frequency of CVAD-related bloodstream infection per 1000 patient days compared with standard polyurethane dressings (RR 0.51, 95% CI 0.33 to 0.78). There is moderate quality evidence that catheter tip colonisation is reduced with chlorhexidine gluconate-impregnated dressings compared with standard polyurethane dressings (RR 0.58, 95% CI 0.47 to 0.73), but the relative effects of gauze and tape and standard polyurethane are unclear (RR 0.95, 95% CI 0.51 to 1.77, very low quality evidence). CONCLUSIONS: Medication-impregnated dressing products reduce the incidence of CVAD-related bloodstream infection relative to all other dressing types. There is some evidence that chlorhexidine gluconate-impregnated dressings, relative to standard polyurethane dressings, reduce CVAD-related bloodstream infection for the outcomes of frequency of infection per 1000 patient days, risk of catheter tip colonisation and possibly risk of CVAD-related bloodstream infection. Most studies were conducted in intensive care unit settings. More, high quality research is needed regarding the relative effects of dressing and securement products for CVADs. PMID- 27222464 TI - The effects of patient-professional partnerships on the self-management and health outcomes for patients with chronic back pain: A quasi-experimental study. AB - BACKGROUND: Self-management may be a lifelong task for patients with chronic back pain. Research suggests that chronic pain self-management programmes have beneficial effects on patients' health outcome. Contemporary pain management theories and models also suggest that a good patient-professional partnership enhances patients' ability to self-manage their condition. OBJECTIVES: (1) To investigate whether there is a reciprocal relationship between self-management of chronic back pain and health-related quality of life (HRQoL); (2) to examine the impact of a good patient-professional partnership on HRQoL, either directly, or indirectly via change in the ability to self-manage pain. DESIGN AND SETTING: This quasi-experimental study was designed to take place during routine service appointments and conducted in a community-based pain management service in the United Kingdom. A patient-professional partnership was established in which patients were actively involved in setting up goals and developing individualised care plans. Through this, health professionals undertook patients' health needs assessment, collaborated with patients to identify specific problems, provided written materials and delivered individualised exercise based on patients' life situation. Patients were recruited following initial consultation and followed up three months later. PARTICIPANTS: A total of 147 patients (65% female) with a mean age of 48 years (standard deviation (SD): 14 years) were enrolled in the study. Of these, 103 subjects completed the study. Patients were included if they were aged 18 and over, suffered from chronic back pain, had opted in to the clinic and had sufficient ability to read and understand English. Patients were excluded if they opted out this service after the initial assessment, suffered from malignant pain or required acute medical interventions for their pain relief. METHODS: Self-reported measures of HRQoL, patient-professional partnerships and self-management ability were collected at baseline and three months later. Pathways proposed were depicted using structural equation modelling. RESULTS: There was no association between patients' self-management ability and HRQoL at baseline. However, a positive direct effect was detected at three months (-0.38, p<0.01). A patient-professional partnership was not found to be beneficial for patients' HRQoL through a direct pathway, but via an indirect pathway where self-management was a mediator (-19.09, p<0.01). CONCLUSIONS: This study suggests that the increase in patients' self-management ability may lead to improvement in HRQoL after pain management support provided in a partnership with health professionals. A good patient-professional partnership appears to be beneficial as an augmentation to self-management practice for patients with chronic back pain. PMID- 27222465 TI - Effects of Substrate Size and Orientation on Quadrupedal Gait Kinematics in Mouse Lemurs (Microcebus murinus). AB - As the smallest living primate, the mouse lemur is a suitable model for reconstructing the locomotor mechanisms by which primate ancestors might have responded to the challenges of an arboreal environment. In this study, we tested the effects of substrate diameter and orientation on quadrupedal gait kinematics in mouse lemurs (Microcebus murinus). Mouse lemurs highly preferred asymmetrical to symmetrical gaits as they moved across a flat board and poles of three diameters (2.5, 1.0, and 0.5 cm), set at horizontal, 30 degrees inclined, and 30 degrees declined orientations. During symmetrical gaits, mouse lemurs used diagonal sequence walking and ambling gaits on the same substrates and at the same duty factors for which some similarly sized nonprimate mammals use lateral sequence gaits, suggesting that reliance on diagonal sequence walking in primates may not be explicitly a response to body size relative to substrate diameter. When using asymmetrical gaits, kinematic adjustments to small diameter and/or nonhorizontal substrates included a preference for transverse gallops over other gaits, the avoidance of whole-body suspensions, increases in limb contact duration, and increases in the time interval between the landing of trailing and leading limbs. All of these adjustments are consistent with increasing locomotor stability by dampening center of mass movements and reducing the forces imparted to the substrate. Like mouse lemurs, small-bodied ancestral primates likely used symmetrical gaits occasionally, but more frequently used asymmetrical gaits that were adjusted in response to challenging substrates. Therefore, asymmetrical gait dynamics should be incorporated into hypotheses addressing early primate locomotor evolution. PMID- 27222466 TI - Transcriptome Analysis Reveals a Signature Profile for Tick-Borne Flavivirus Persistence in HEK 293T Cells. AB - Tick-borne flaviviruses (TBFVs) cause febrile illnesses, which may progress to severe encephalitis and/or death in humans globally. Most people who recover from severe acute disease suffer from debilitating neurological sequelae, which may be due to viral persistence, infection-induced neurological cell damage, host response, or some combination of these. Acute TBFV infection of human embryonic kidney (HEK) 293T cells in vitro results in the death of >95% of infected cells by day 5. However, replacing cell growth medium allows surviving cells to repopulate and become persistently infected for extended periods of time. The mechanisms responsible for initiation and maintenance of viral persistence remain vague. We subjected the HEK 293T cell transcriptome to deep sequencing to identify genes differentially expressed during acute infection and persistent infection. A total of 451 genes showed unique significant differential expression levels in persistently infected cells relative to the acute phase of infection. Ingenuity Pathway Analysis results suggested that the expression of prosurvival oncogenes AKT2 and ERBB2 was upregulated in persistently infected cells, whereas proapoptotic genes, such as Bad and the beta interferon 1 (IFN-beta1) gene, were downregulated. Genes encoding antiviral cytokines such as the CCL5, tumor necrosis factor alpha (TNF-alpha), and CXCL10 genes were upregulated during the acute phase, but the same genes were relatively quiescent in persistently infected cells. Exogenous induction of apoptosis demonstrated that persistently infected cells were resistant to apoptosis in a dose-dependent manner. In summary, the differential transcriptome profiles of acute-phase compared to persistently infected HEK 293T cells demonstrated an evasion of apoptosis, which may be critical for a chronic TBFV infection state. These results provide a basis for further study of the mechanisms of TBFV persistence. IMPORTANCE: Tick-borne flaviviruses (TBFVs) cause life-threatening encephalitic disease in humans worldwide. Some people who recover from severe disease may suffer prolonged neurological symptoms due to either virus- or host response-induced cell damage or a combination of the two that are linked to viral persistence. By examining the genes that are significantly differentially expressed in acute TBFV infection versus persistent TBFV infection, we may be able to find the molecular basis of viral persistence. Here we used deep sequencing of the host cell transcriptome to discover that the expression levels of prosurvival genes were upregulated in persistently infected cells relative to acute TBFV infections whereas the expression levels of genes that promote programmed cell death were downregulated. In addition, persistently infected cells were also resistant to exogenous chemical induction of cell death, in a dose-dependent manner, compared to uninfected cells. Our results pave the way for further studies aimed at understanding the precise mechanisms of TBFV persistence. PMID- 27222467 TI - Insights into CO2 Fixation Pathway of Clostridium autoethanogenum by Targeted Mutagenesis. AB - The future sustainable production of chemicals and fuels from nonpetrochemical resources and reduction of greenhouse gas emissions are two of the greatest societal challenges. Gas fermentation, which utilizes the ability of acetogenic bacteria such as Clostridium autoethanogenum to grow and convert CO2 and CO into low-carbon fuels and chemicals, could potentially provide solutions to both. Acetogens fix these single-carbon gases via the Wood-Ljungdahl pathway. Two enzyme activities are predicted to be essential to the pathway: carbon monoxide dehydrogenase (CODH), which catalyzes the reversible oxidation of CO to CO2, and acetyl coenzyme A (acetyl-CoA) synthase (ACS), which combines with CODH to form a CODH/ACS complex for acetyl-CoA fixation. Despite their pivotal role in carbon fixation, their functions have not been confirmed in vivo By genetically manipulating all three CODH isogenes (acsA, cooS1, and cooS2) of C. autoethanogenum, we highlighted the functional redundancies of CODH by demonstrating that cooS1 and cooS2 are dispensable for autotrophy. Unexpectedly, the cooS1 inactivation strain showed a significantly reduced lag phase and a higher growth rate than the wild type on H2 and CO2 During heterotrophic growth on fructose, the acsA inactivation strain exhibited 61% reduced biomass and the abolishment of acetate production (a hallmark of acetogens), in favor of ethanol, lactate, and 2,3-butanediol production. A translational readthrough event was discovered in the uniquely truncated (compared to those of other acetogens) C. autoethanogenum acsA gene. Insights gained from studying the function of CODH enhance the overall understanding of autotrophy and can be used for optimization of biotechnological production of ethanol and other commodities via gas fermentation. IMPORTANCE: Gas fermentation is an emerging technology that converts the greenhouse gases CO2 and CO in industrial waste gases and gasified biomass into fuels and chemical commodities. Acetogenic bacteria such as Clostridium autoethanogenum are central to this bioprocess, but the molecular and genetic characterization of this microorganism is currently lacking. By targeting all three of the isogenes encoding carbon monoxide dehydrogenase (CODH) in C. autoethanogenum, we identified the most important CODH isogene for carbon fixation and demonstrated that genetic inactivation of CODH could improve autotrophic growth. This study shows that disabling of the Wood-Ljungdahl pathway via the inactivation of acsA (encodes CODH) significantly impairs heterotrophic growth and alters the product profile by abolishing acetate production. Moreover, we discovered a previously undescribed mechanism for controlling the production of this enzyme. This study provides valuable insights into the acetogenic pathway and can be used for the development of more efficient and productive strains for gas fermentation. PMID- 27222468 TI - Staphylococcus aureus Protein A Mediates Interspecies Interactions at the Cell Surface of Pseudomonas aeruginosa. AB - While considerable research has focused on the properties of individual bacteria, relatively little is known about how microbial interspecies interactions alter bacterial behaviors and pathogenesis. Staphylococcus aureus frequently coinfects with other pathogens in a range of different infectious diseases. For example, coinfection by S. aureus with Pseudomonas aeruginosa occurs commonly in people with cystic fibrosis and is associated with higher lung disease morbidity and mortality. S. aureus secretes numerous exoproducts that are known to interact with host tissues, influencing inflammatory responses. The abundantly secreted S. aureus staphylococcal protein A (SpA) binds a range of human glycoproteins, immunoglobulins, and other molecules, with diverse effects on the host, including inhibition of phagocytosis of S. aureus cells. However, the potential effects of SpA and other S. aureus exoproducts on coinfecting bacteria have not been explored. Here, we show that S. aureus-secreted products, including SpA, significantly alter two behaviors associated with persistent infection. We found that SpA inhibited biofilm formation by specific P. aeruginosa clinical isolates, and it also inhibited phagocytosis by neutrophils of all isolates tested. Our results indicate that these effects were mediated by binding to at least two P. aeruginosa cell surface structures-type IV pili and the exopolysaccharide Psl that confer attachment to surfaces and to other bacterial cells. Thus, we found that the role of a well-studied S. aureus exoproduct, SpA, extends well beyond interactions with the host immune system. Secreted SpA alters multiple persistence-associated behaviors of another common microbial community member, likely influencing cocolonization and coinfection with other microbes. IMPORTANCE: Bacteria rarely exist in isolation, whether on human tissues or in the environment, and they frequently coinfect with other microbes. However, relatively little is known about how microbial interspecies interactions alter bacterial behaviors and pathogenesis. We identified a novel interaction between two bacterial species that frequently infect together-Staphylococcus aureus and Pseudomonas aeruginosa We show that the S. aureus-secreted protein staphylococcal protein A (SpA), which is well-known for interacting with host targets, also binds to specific P. aeruginosa cell surface molecules and alters two persistence associated P. aeruginosa behaviors: biofilm formation and uptake by host immune cells. Because S. aureus frequently precedes P. aeruginosa in chronic infections, these findings reveal how microbial community interactions can impact persistence and host interactions during coinfections. PMID- 27222469 TI - Should Pneumococcal Vaccines Eliminate Nasopharyngeal Colonization? AB - Streptococcus pneumoniae remains an important human pathogen. For more than 100 years, there have been vaccine efforts to prevent pneumococcal infection. The pneumococcal conjugate vaccines have significantly reduced invasive disease. However, these vaccines have changed pneumococcal ecology within the human nasopharynx. We suggest that elimination of the pneumococcus from the human nasopharynx can have consequences that should be considered as the next generation of pneumococcal vaccines is developed. PMID- 27222470 TI - Deletion of nuoG from the Vaccine Candidate Mycobacterium bovis BCG DeltaureC::hly Improves Protection against Tuberculosis. AB - The current tuberculosis (TB) vaccine, Mycobacterium bovis Bacillus Calmette Guerin (BCG), provides insufficient protection against pulmonary TB. Previously, we generated a listeriolysin-expressing recombinant BCG strain, which to date has successfully completed phase I and phase IIa clinical trials. In an attempt to further improve efficacy, we deleted the antiapoptotic virulence gene nuoG, encoding NADH dehydrogenase 1 subunit G, from BCG DeltaureC::hly In vitro, deletion of nuoG unexpectedly led to strongly increased recruitment of the autophagosome marker LC3 to the engulfed vaccine, suggesting that nuoG also affects xenophagic pathways. In mice, BCG DeltaureC::hly DeltanuoG vaccination was safer than BCG and improved protection over that of parental BCG DeltaureC::hly, significantly reducing TB load in murine lungs, ameliorating pulmonary pathology, and enhancing immune responses. Transcriptome analysis of draining lymph nodes after vaccination with either BCG DeltaureC::hly or BCG DeltaureC::hly DeltanuoG demonstrated earlier and stronger induction of immune responses than that with BCG SSI and suggested upregulation of inflammasome activation and interferon-induced GTPases. In summary, BCG DeltaureC::hly DeltanuoG is a promising next-generation TB vaccine candidate with excellent efficacy and safety. IMPORTANCE: Autophagy and apoptosis are fundamental processes allowing cells to degrade their components or kill themselves, respectively. The immune system has adopted these mechanisms to eliminate intracellular pathogens. Residing in host cells, the causative agent of tuberculosis, Mycobacterium tuberculosis, has evolved strategies to set cellular programs of autophagy and apoptosis "on hold." The mycobacterial gene nuoG was found to prevent host cell apoptosis. We have deleted nuoG in the live vaccine candidate BCG DeltaureC::hly, which is in phase II clinical development, to leave cellular apoptosis "on go" upon immunization. In preclinical models, this strategy boosted immunity and improved protection from M. tuberculosis infection. Unexpectedly, we obtained compelling evidence that mycobacterial nuoG facilitates inhibition of autophagic pathways, suggesting a new role for this gene in the host-pathogen interplay in tuberculosis. PMID- 27222472 TI - Author Correction for Hyman et al., Evaluation of a Fully Automated Research Prototype for the Immediate Identification of Microorganisms from Positive Blood Cultures under Clinical Conditions. PMID- 27222471 TI - Antagonism of the Sodium-Potassium ATPase Impairs Chikungunya Virus Infection. AB - Chikungunya virus (CHIKV) is a reemerging alphavirus that has caused epidemics of fever, arthralgia, and rash worldwide. There are currently no licensed vaccines or antiviral therapies available for the prevention or treatment of CHIKV disease. We conducted a high-throughput, chemical compound screen that identified digoxin, a cardiac glycoside that blocks the sodium-potassium ATPase, as a potent inhibitor of CHIKV infection. Treatment of human cells with digoxin or a related cardiac glycoside, ouabain, resulted in a dose-dependent decrease in infection by CHIKV. Inhibition by digoxin was cell type-specific, as digoxin treatment of either murine or mosquito cells did not diminish CHIKV infection. Digoxin displayed antiviral activity against other alphaviruses, including Ross River virus and Sindbis virus, as well as mammalian reovirus and vesicular stomatitis virus. The digoxin-mediated block to CHIKV and reovirus infection occurred at one or more postentry steps, as digoxin inhibition was not bypassed by fusion of CHIKV at the plasma membrane or infection with cell surface-penetrating reovirus entry intermediates. Selection of digoxin-resistant CHIKV variants identified multiple mutations in the nonstructural proteins required for replication complex formation and synthesis of viral RNA. These data suggest a role for the sodium potassium ATPase in promoting postentry steps of CHIKV replication and provide rationale for modulation of this pathway as a broad-spectrum antiviral strategy. IMPORTANCE: Mitigation of disease induced by globally spreading, mosquito-borne arthritogenic alphaviruses requires the development of new antiviral strategies. High-throughput screening of clinically tested compounds provides a rapid means to identify undiscovered, antiviral functions for well-characterized therapeutics and illuminate host pathways required for viral infection. Our study describes the potent inhibition of Chikungunya virus and related alphaviruses by the cardiac glycoside digoxin and demonstrates a function for the sodium-potassium ATPase in Chikungunya virus infection. PMID- 27222473 TI - A phase 2, multicenter study investigating ofatumumab and bendamustine combination in patients with untreated or relapsed CLL. AB - The purpose of this study is to assess the safety and efficacy of the combination of ofatumumab and bendamustine in patients with previously untreated or relapsed chronic lymphocytic leukemia. Patients received IV ofatumumab (cycle 1: 300 mg day 1 and 1,000 mg day 8; cycles 2-6: 1,000 mg on day 1 every 28 days) and IV bendamustine 90 mg m(-2) (previously untreated) or 70 mg m(-2) (relapsed) on days 1 and 2 of each 28-day cycle, for up to 6 cycles. Forty-four previously untreated and 53 relapsed patients were enrolled. Median age was 62.5 years (previously untreated) and 68 years (relapsed); relapsed patients had received a median of 1 (range 1-11) prior therapy. The investigator-assessed overall response rate was 95% (43% complete response [CR]) for the previously untreated, and 74% (11% CR) for the relapsed patients. The regimen was well tolerated with 89% (previously untreated) and 85% (relapsed patients) receiving all 6 cycles. No unexpected toxicities were reported. Grade 3/4 events occurred in 57% of previously untreated, and 72% of relapsed patients. At ~29 months' follow-up, the median progression-free survival (PFS) was not reached for the previously untreated population, and the 28-month PFS estimate was 72.3%. The median PFS for the relapsed population was 22.5 months (95% CI: 14.0-27.3 months). The combination of ofatumumab and bendamustine was well tolerated and effective in these previously untreated or relapsed populations. Am. J. Hematol. 91:900-906, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27222474 TI - [Intensive care unit-acquired muscular weakness: A problem with a single solution?]. PMID- 27222475 TI - Genetic polymorphism of the Nrf2 promoter region is associated with vitiligo risk in Han Chinese populations. AB - The nuclear factor erythroid-derived two-like 2-antioxidant response element (Nrf2-ARE) pathway and its downstream antioxidant enzyme heme oxygenase-1 (HMOX1 or HO-1) play essential roles in H2 O2 -induced oxidative damage in human melanocytes. However, the link between Nrf2 promoter polymorphisms and susceptibility to oxidative stress-related diseases such as vitiligo is unknown. This study evaluated the association of the Nrf2 and HO-1 genes polymorphisms with vitiligo susceptibility. In this case-control study of 1136 Han Chinese vitiligo patients and 1200 controls, Nrf2 (rs35652124 and rs6721961) and HO-1 (rs2071746) genes were genotyped by PCR-restriction fragment length polymorphism analysis. Overall, a significantly decreased risk of vitiligo was found to be associated with Nrf2 rs35652124 CC and combined (CT+CC) genotypes [odds ratio (OR) 0.64, 95% confidence interval (CI) 0.50-0.83 and OR, 0.84, 95% CI 0.71-0.99, respectively], as well as among subgroups: female, onset age <=20 and never smoker. We subsequently found that Nrf2 rs35652124 C allele had higher transcriptional activity in the luciferase reporter assay compared with Nrf2 rs35652124 T allele. Furthermore, we investigated serum HO-1 activity was associated with the rs35652124 CT+CC genotype and lower in patients than in controls (P = 0.024). Logistic regression analysis showed a dose-response relationship between lower vitiligo risk and increased HO-1 activity in rs35652124 CT+CC genotype carriers (Ptrend < 0.05). These findings indicate that the C allele of rs35652124 located in the promoter region of Nrf2 gene is associated with protective effect on vitiligo in a Han Chinese population. PMID- 27222476 TI - CXCR2 and CXCL4 regulate survival and self-renewal of hematopoietic stem/progenitor cells. AB - The regulation of hematopoietic stem cell (HSC) survival and self-renewal within the bone marrow (BM) niche is not well understood. We therefore investigated global transcriptomic profiling of normal human HSC/hematopoietic progenitor cells [HPCs], revealing that several chemokine ligands (CXCL1-4, CXCL6, CXCL10, CXCL11, and CXCL13) were upregulated in human quiescent CD34(+)Hoescht(-)Pyronin Y(-) and primitive CD34(+)38(-), as compared with proliferating CD34(+)Hoechst(+)Pyronin Y(+) and CD34(+)38(+) stem/progenitor cells. This suggested that chemokines might play an important role in the homeostasis of HSCs. In human CD34(+) hematopoietic cells, knockdown of CXCL4 or pharmacologic inhibition of the chemokine receptor CXCR2, significantly decreased cell viability and colony forming cell (CFC) potential. Studies on Cxcr2(-/-) mice demonstrated enhanced BM and spleen cellularity, with significantly increased numbers of HSCs, hematopoietic progenitor cell-1 (HPC-1), HPC-2, and Lin(-)Sca 1(+)c-Kit(+) subpopulations. Cxcr2(-/-) stem/progenitor cells showed reduced self renewal capacity as measured in serial transplantation assays. Parallel studies on Cxcl4 demonstrated reduced numbers of CFC in primary and secondary assays following knockdown in murine c-Kit(+) cells, and Cxcl4(-/-) mice showed a decrease in HSC and reduced self-renewal capacity after secondary transplantation. These data demonstrate that the CXCR2 network and CXCL4 play a role in the maintenance of normal HSC/HPC cell fates, including survival and self renewal. PMID- 27222478 TI - Therapeutic effect of JAK1/2 blockade on the manifestations of hemophagocytic lymphohistiocytosis in mice. AB - Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome, characterized by severe hyperinflammation and immunopathological manifestations in several tissues. These features result from organ infiltration by overactivated CD8 T-cells and macrophages, which produce high levels of pro inflammatory cytokines, such as IFN-gamma, TNF-alpha, IL-6, and IL-18. Recently, several Janus kinase 1/2 (JAK1/2) inhibitors, such as ruxolitinib, have been developed as immunosuppressive agents. They have proven beneficial effects in the treatment of myeloproliferative disorders and inflammatory conditions. To determine whether pharmacological inhibition of the JAK1/2 not only prevents the onset of HLH immunopathology but also is effective against existing HLH, cytotoxicity-impaired Prf1(-/-) and Rab27a(-/-) mice with full-blown HLH syndrome were treated with a clinically relevant dose of ruxolitinib. In vivo, ruxolitinib treatment suppressed signal transducer and activator of transcription 1 activation and led to recovery from HLH manifestations in both murine models. In the Prf1(-/-) mice, these beneficial effects were evidenced by a greater survival rate, and in both murine models, they were evidenced by the correction of blood cytopenia and a rapid decrease in serum IL-6 and TNF-alpha levels. During ruxolitinib treatment, liver tissue damage receded concomitantly with a decrease in the number of infiltrating inflammatory macrophages and an increase in the number of alternatively activated macrophages. In Rab27a(-/-) mice, central nervous system involvement was significantly reduced by ruxolitinib therapy. Our findings demonstrate that clinically relevant doses of the JAK1/2 inhibitor ruxolitinib suppresses the harmful consequences of macrophage overactivation characterizing HLH in 2 murine models. The results could be readily translated into the clinic for the treatment of primary, and perhaps even secondary, forms of HLH. PMID- 27222479 TI - Speed bumps on the road to a chemotherapy-free world for lymphoma patients. AB - With the increasing number of targeted agents for the treatment of patients with lymphoid malignancies comes the promise of safe and effective chemotherapy-free treatment strategies. A number of single agents, such as ibrutinib and idelalisib, have demonstrated impressive efficacy with a favorable toxicity profile. The observations that most responses are, however, partial and treatment duration is indefinite have stimulated interest in combinations of these agents with chemotherapy as well as with each other. Despite the promise of this approach, several recent trials of combinations of agents have been terminated as the result of life-threatening and fatal complications. Such outcomes have generated a cautionary note of the potential for unforeseen adverse effects that challenge drug development and mitigate against the empiric combination of such drugs outside of a clinical trial setting. PMID- 27222477 TI - Peri-alloHCT IL-33 administration expands recipient T-regulatory cells that protect mice against acute GVHD. AB - During allogeneic hematopoietic cell transplantation (alloHCT), nonhematopoietic cell interleukin-33 (IL-33) is augmented and released by recipient conditioning to promote type 1 alloimmunity and lethal acute graft-versus-host disease (GVHD). Yet, IL-33 is highly pleiotropic and exhibits potent immunoregulatory properties in the absence of coincident proinflammatory stimuli. We tested whether peri alloHCT IL-33 delivery can protect against development of GVHD by augmenting IL 33-associated regulatory mechanisms. IL-33 administration augmented the frequency of regulatory T cells (Tregs) expressing the IL-33 receptor, suppression of tumorigenicity-2 (ST2), which persist following total body irradiation. ST2 expression is not exclusive to Tregs and IL-33 expands innate immune cells with regulatory or reparative properties. However, selective depletion of recipient Foxp3(+) cells concurrent with peri-alloHCT IL-33 administration accelerated acute GVHD lethality. IL-33-expanded Tregs protected recipients from GVHD by controlling macrophage activation and preventing accumulation of effector T cells in GVHD-target tissue. IL-33 stimulation of ST2 on Tregs activates p38 MAPK, which drives expansion of the ST2(+) Treg subset. Associated mechanistic studies revealed that proliferating Tregs exhibit IL-33-independent upregulation of ST2 and the adoptive transfer of st2(+) but not st2(-) Tregs mediated GVHD protection. In total, these data demonstrate the protective capacity of peri alloHCT administration of IL-33 and IL-33-responsive Tregs in mouse models of acute GVHD. These findings provide strong support that the immunoregulatory relationship between IL-33 and Tregs can be harnessed therapeutically to prevent GVHD after alloHCT for treatment of malignancy or as a means for tolerance induction in solid organ transplantation. PMID- 27222481 TI - Matrix metalloproteinase (MMP) -2, -7 and -9 promoter polymorphisms in colorectal cancer in ethnic Kashmiri population - A case-control study and a mini review. AB - Matrix metalloproteinases (MMPs) are proteolytic enzymes that play a pivotal role in the transformation and progression of tumors at all stages, especially during the invasion and metastasis. The aim of this study was to determine the genetic association of MMP2, MMP7 and MMP9 promoter polymorphisms with colorectal cancer (CRC) susceptibility and development risk in ethnic Kashmiri population. The genotype frequencies of MMP2-1306C/T, MMP7-181A/G and MMP9-1562C/T SNPs were compared between 142 CRC patients and 184 healthy controls by using PCR-RFLP method. The association between all the three MMP promoter polymorphisms and the modulation of risk of CRC was found to be significant (p<=0.05). The heterozygous genotype (CT) of MMP2-1306C/T SNP and variant genotype (GG) of MMP7-181A/G SNP showed a significant association with decreased risk for the development of CRC [OR, 0.61 (95%CI, 0.37-1.01); p=0.05 and OR, 0.43 (95%CI, 0.20-0.90); p=0.02, respectively] whereas the heterozygous genotype (CT) of MMP9-1562C/T SNP showed a significant association with increased risk for the development of colorectal cancer [OR, 1.88 (95%CI, 1.11-3.18); p=0.02]. Further, the less common MMP9-1562T allele was found to be significantly associated with an increased risk of colorectal cancer [OR, 1.74 (95%CI, 1.15-2.62); p=0.007]. Our results suggest that these MMP2, MMP7 and MMP9 promoter polymorphisms play a role as one of the key modulators of the risk of developing colorectal cancer in Kashmiri population. PMID- 27222480 TI - Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. AB - Daratumumab targets CD38-expressing myeloma cells through a variety of immune mediated mechanisms (complement-dependent cytotoxicity, antibody-dependent cell mediated cytotoxicity, and antibody-dependent cellular phagocytosis) and direct apoptosis with crosslinking. These mechanisms may also target nonplasma cells that express CD38, which prompted evaluation of daratumumab's effects on CD38 positive immune subpopulations. Peripheral blood (PB) and bone marrow (BM) from patients with relapsed/refractory myeloma from 2 daratumumab monotherapy studies were analyzed before and during therapy and at relapse. Regulatory B cells and myeloid-derived suppressor cells, previously shown to express CD38, were evaluated for immunosuppressive activity and daratumumab sensitivity in the myeloma setting. A novel subpopulation of regulatory T cells (Tregs) expressing CD38 was identified. These Tregs were more immunosuppressive in vitro than CD38 negative Tregs and were reduced in daratumumab-treated patients. In parallel, daratumumab induced robust increases in helper and cytotoxic T-cell absolute counts. In PB and BM, daratumumab induced significant increases in CD8(+):CD4(+) and CD8(+):Treg ratios, and increased memory T cells while decreasing naive T cells. The majority of patients demonstrated these broad T-cell changes, although patients with a partial response or better showed greater maximum effector and helper T-cell increases, elevated antiviral and alloreactive functional responses, and significantly greater increases in T-cell clonality as measured by T-cell receptor (TCR) sequencing. Increased TCR clonality positively correlated with increased CD8(+) PB T-cell counts. Depletion of CD38(+) immunosuppressive cells, which is associated with an increase in T-helper cells, cytotoxic T cells, T-cell functional response, and TCR clonality, represents possible additional mechanisms of action for daratumumab and deserves further exploration. PMID- 27222482 TI - Screening and functional analysis of differentially expressed genes in chronic glomerulonephritis by whole genome microarray. AB - BACKGROUND: Chronic glomerulonephritis (CGN) is the most common form of the glomerular disease with unclear molecular mechanisms, which related to immune mediated inflammatory diseases. The aim of this study was to characterize differentially expressed genes in the normal and adriamycin-induced CGN rats by microarray analysis, and to determine the potential molecular mechanisms of CGN pathogenesis. METHODS: For the gene expression analysis, fresh glomerular tissues from both normal and adriamycin treated rats (n=4, respectively) were collected. Total RNA was extracted and subjected to Agilent Rat 4*44 K whole genome microarray. KEGG, Gene Ontology (GO) analyze, LIMMA, String and Cytoscape software were applied to screen and analyze differentially regulated genes. In addition, the Real-time polymerase chain reaction (RT-PCR) was performed to verify the selected genes. RESULTS: 2334 differentially regulated genes were identified including 1294 up-regulated genes and 1040 down-regulated genes. According to the results of Generank, String and Cytoscape analyses, 27 genes may be key controlled genes in the pathogenesis of CGN, including 14 up-regulated genes (Fos, Myc, Kng1, Rac2, Pik3r1, Egr1, Icam1, Syk, Anxa1, Lgals3, Ptprc, Runx1, Itgb7, Ccl6) and 13 down-regulated genes (Aldh2, Dpyd, Mthfd1, Gldc, Ppar alpha, Igf1, Pomc, Oas1a, Gsr, Acox1, Cyp1a1, Ugt2b15, Hsd3b6), which primarily contribute to biological processes such as, cell cycle, cell proliferation, inflammatory response, immune response, metabolic process, and so on. Fos and Syk were considered as potent hub genes. CONCLUSIONS: Global gene expression profile analysis showed that the molecular mechanism of CGN pathogenesis may be related to the promotion of cell cycle and mitosis, dysregulation of cytokine secretion and disordered inflammatory response as well as abnormal metabolism. PMID- 27222483 TI - Construction of synergy networks from gene expression data related to disease. AB - A few methods have been developed to determine whether genes collaborate with each other in relation to a particular disease using an information theoretic measure of synergy. Here, we propose an alternative definition of synergy and justify that our definition improves upon the existing measures of synergy in the context of gene interactions. We use this definition on a prostate cancer data set consisting of gene expression levels in both cancerous and non-cancerous samples and identify pairs of genes which are unable to discriminate between cancerous and non-cancerous samples individually but can do so jointly when we take their synergistic property into account. We also propose a very simple yet effective technique for computation of conditional entropy at a very low cost. The worst case complexity of our method is O(n) while the best case complexity of a state-of-the-art method is O(n(2)). Furthermore, our method can also be extended to find synergistic relation among triplets or even among a larger number of genes. Finally, we validate our results by demonstrating that these findings cannot be due to pure chance and provide the relevance of the synergistic pairs in cancer biology. PMID- 27222484 TI - Hypothesis: Paroxetine, a G Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitor Reduces Morbidity and Mortality in Patients With Heart Failure. AB - The hypothesis that paroxetine decreases morbidity and mortality in patients with heart failure (HF) is plausible but unproven. Basic research demonstrates that inhibition of G protein-coupled receptor kinase 2 (GRK2) both in vitro and in vivo in the myocardium may be beneficial. G protein-coupled receptor kinase 2 antagonism is purported to exert cardioprotective effects immediately following myocardial injury by blunting toxic overstimulation on a recently injured heart. In addition, chronic overexpression of GRK2 inhibits catecholamine induction of vital positive chronotropic and ionotropic effects required to preserve cardiac output leading to worsening of congestive HF. In cardiac-specific GRK2 conditional knockout mice, there is significant improvement in left ventricular wall thickness, left ventricular end-diastolic diameter (LVEDD), and ejection fraction (EF) compared to controls. Paroxetine is a selective serotonin reuptake inhibitor which was recently shown to have the ability to directly inhibit GRK2 both in vitro and in vivo. At physiologic temperatures, paroxetine inhibits GRK2 dependent phosphorylation of an activated G-protein-coupled receptor with a half maximal inhibitory concentration of 35 micromoles, a substantially greater affinity than for other G protein-coupled receptor kinases. In a randomized trial in mice with systolic HF and depressed EF postmyocardial infarction, those treated with paroxetine had a 30% increase in EF, improved contractility, and LVEDD and wall thickness compared to those treated with medical therapy alone. While further basic research may continue to elucidate plausible mechanisms of benefit and observational studies will contribute important relevant information, large scale randomized trials designed a priori to do so are necessary to test the hypothesis. PMID- 27222485 TI - Concluding remarks: progress toward the design of solid catalysts. AB - The 2016 Faraday Discussion on the topic "Designing New Heterogeneous Catalysts" brought together a group of scientists and engineers to address forefront topics in catalysis and the challenge of catalyst design-which is daunting because of the intrinsic non-uniformity of the surfaces of catalytic materials. "Catalyst design" has taken on a pragmatic meaning which implies the discovery of new and better catalysts on the basis of fundamental understanding of the catalyst structure and performance. The presentations and discussion at the meeting illustrate the rapid progress in this understanding linked with improvements in spectroscopy, microscopy, theory, and catalyst performance testing. The following text includes a statement of recurrent themes in the discussion and examples of forefront science that evidences progress toward catalyst design. PMID- 27222486 TI - Design strategies to address the effect of hydrophobic epitope on stability and in vitro assembly of modular virus-like particle. AB - Virus-like particles (VLPs) and capsomere subunits have shown promising potential as safe and effective vaccine candidates. They can serve as platforms for the display of foreign epitopes on their surfaces in a modular architecture. Depending on the physicochemical properties of the antigenic modules, modularization may affect the expression, solubility and stability of capsomeres, and VLP assembly. In this study, three module designs of a rotavirus hydrophobic peptide (RV10) were synthesized using synthetic biology. Among the three synthetic modules, modularization of the murine polyomavirus VP1 with a single copy of RV10 flanked by long linkers and charged residues resulted in the expression of stable modular capsomeres. Further employing the approach of module titration of RV10 modules on each capsomere via Escherichia coli co-expression of unmodified VP1 and modular VP1-RV10 successfully translated purified modular capomeres into modular VLPs when assembled in vitro. Our results demonstrate that tailoring the physicochemical properties of modules to enhance modular capsomeres stability is achievable through synthetic biology designs. Combined with module titration strategy to avoid steric hindrance to intercapsomere interactions, this allows bioprocessing of bacterially produced in vitro assembled modular VLPs. PMID- 27222487 TI - Poor biofilm-forming ability and long-term survival of invasive Salmonella Typhimurium ST313. AB - Salmonella enterica serovar Typhimurium, an enteric pathogen that causes a self limiting gastroenteritis, forms biofilms on different surfaces. In sub-Saharan Africa, Salmonella Typhimurium of a novel sequence type (ST) 313 was identified and produces septicemia in the absence of gastroenteritis. No animal reservoir has been identified, and it is hypothesized that transmission occurs via human to human. In this study, we show that invasive Salmonella Typhimurium ST313 strains from Mali are poor biofilm producers compared to Salmonella Typhimurium ST19 strains, which are found worldwide and are known to be associated with gastroenteritis. We evaluated biofilms using crystal violet staining, examination of the red, dry and rough morphotype, pellicle formation and a continuous flow system. One month-old Salmonella Typhimurium ST19 colonies survived in the absence of exogenous nutrients and were highly resistant to sodium hypochlorite treatment compared to Salmonella Typhimurium ST313. This study for the first time demonstrates the comparative biofilm-forming ability and long-term survival of clinical Salmonella Typhimurium ST19 and ST313 isolates. Salmonella Typhimurium ST19 strains are strong biofilm producers and can survive desiccation compared to Salmonella Typhimurium ST313 that form weak biofilms and survive poorly following desiccation. Our data suggest that like Salmonella Typhi, Salmonella Typhimurium ST313 lack mechanisms that allow it to persist in the environment. PMID- 27222488 TI - Type D personality is related to severity of acute coronary syndrome in patients with recurrent cardiovascular disease. AB - OBJECTIVES: To investigate the relationship between Type D (distressed) personality and cardiac biomarkers of disease severity in patients with acute coronary syndrome. To identify potential mechanisms behind the effect of Type D personality on cardiovascular disease (CVD). DESIGN: Cross-sectional. METHODS: Patients (N = 215) with acute coronary syndrome completed a survey including a measure of Type D personality. Blood samples including a lipid profile and cardiac enzymes were taken within 3 days after the cardiovascular event. Data were analysed using simple correlations, multiple regressions, and mediation analyses. RESULTS: Type D personality was more predictive of severity of the acute coronary syndrome among patients with previous CVD compared to patients without previous CVD. Among patients with previous CVD, Type D personality was associated with the presence of ST elevation (R(2) =.07) and more damage to the myocardium as indicated by higher troponin-I (R(2) = .05) and myoglobin (R(2) = .07) levels. These effects were independent from demographics, CV risk factors, and depression. Lower HDL cholesterol levels mediated the relationship between Type D personality and disease severity (Kappa(2) = .12 [95% CI 0.02, 0.28]) for myoglobin and Kappa(2) = .08 [95% CI 0.01, 0.21] for troponin-I). CONCLUSION: Type D personality was related to a worse lipid profile and more severe acute coronary syndrome in patients with previous history of CVD. Given the strong relationship between disease severity and subsequent mortality, these results suggest that severity of the myocardial infarction may be a potential mechanism explaining increased mortality in Type D patients with recurrent CVD. Statement of contribution What is already known on this subject? Type D personality has been related to worse outcomes in cardiac patients. However, recent studies show mixed results, suggesting the need to clarify potential mechanisms. What does this study add? Type D personality is related to severity of acute coronary syndrome in patients with previous history of cardiovascular disease. This effect is partially accounted for by lower HDL levels in Type D patients. Disease severity is a potential mechanism by which Type D personality may affect cardiovascular health of patients with recurrent CVD. PMID- 27222489 TI - Extended spectrum beta-lactamase producing Enterobacteriaceae causing bloodstream infections in rural Ghana, 2007-2012. AB - BACKGROUND: High prevalence of Extended Spectrum Beta-Lactamase (ESBL) producing Enterobacteriaceae threatens treatment options for invasive bloodstream infections in sub-Saharan Africa. OBJECTIVES: To explore the frequency and genotype distribution of ESBL producing Enterobacteriaceae causing bloodstream infections in a primary health care setting in rural Ghana. METHODS: Blood cultures from all patients with fever >=38 degrees C within 24h after admission (community-acquired) and from all neonates with suspected neonatal sepsis (hospital-acquired) were obtained. ESBL-producing isolates were characterized by combined disc test and by amplifying the blaCTX-M, blaTEM and blaSHV genes. Multilocus sequence typing (MLST) was performed for all ESBL-producing Klebsiella pneumoniae and Escherichia coli isolates, and all K. pneumoniae isolates were differentiated by pulsed-field gel electrophoresis (PFGE). RESULTS: Among 426 Enterobacteriaceae isolated from blood cultures, non-typhoid Salmonella (n=215, 50.8%), S. Typhi (n=110, 26.0%), E. coli (n=50, 11.8%) and K. pneumoniae (n=41, 9.7%) were the most frequent. ESBL-producing isolates were restricted to the CTX M-15 genotype and the species K. pneumoniae (n=34, 82.9%), Enterobacter cloacae complex (n=2, 66.7%) and E. coli (n=5, 10.0%). The rates of ESBL-producers in K. pneumoniae were 55.6% and 90.6% in community-acquired and neonatal bloodstream infections, respectively. MLST and PFGE analysis identified four outbreak clusters among neonates. CONCLUSIONS: Considering the rural primary health care study setting, the high proportion of ESBL-producing Klebsiella pneumoniae is worrisome and might be devastating in the absence of second line antibiotics. Therefore, enhanced diagnostic laboratories for surveillance purposes and sustainable hospital hygiene measures must be considered to prevent further spread of multidrug resistant bacteria within rural communities. PMID- 27222490 TI - When Average Is Not Good Enough: Students With Learning Disabilities at Selective, Private Colleges. AB - Adolescents with learning disabilities disproportionately come from lower socioeconomic status backgrounds, show normative deficits in academic skills, and attend 2-year, public colleges instead of 4-year institutions. However, students with learning disabilities are well represented at the United States' most expensive and selective postsecondary institutions. We examined the psychoeducational functioning of students receiving accommodations for learning disabilities at a private, selective, liberal arts college. We also determined whether students had objective evidence supporting their disability diagnoses and academic accommodations. Most students showed above-average cognitive abilities, average academic skills, and no evidence of impairment. Although nearly all students reported academic problems, most lacked objective evidence of academic difficulties prior to college as well as relative or normative deficits in broad academic skills or fluency. Results indicate a need for greater reliance on objective, multimethod/multi-informant data in the diagnostic process. Results also highlight limitations in the current professional guidelines for documentation decision making in higher education. PMID- 27222491 TI - Effects of Obstetric Complications on Adolescent Postpartum Contraception and Rapid Repeat Pregnancy. AB - STUDY OBJECTIVE: To determine whether complications during pregnancy or at delivery influence postpartum contraception choices and rapid repeat pregnancy rates in adolescent women. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: This retrospective cohort study included 321 adolescents delivering at UMASS Memorial Healthcare. Complications during pregnancy and delivery along with subsequent contraception use were investigated. Postpartum contraception choice (long-acting reversible contraception [LARC] vs non-LARC) at either delivery, hospitalization discharge, or at postpartum outpatient appointment, and rapid repeat pregnancy rate (pregnancy confirmed within 12 months of index delivery), were analyzed according to pregnancy complications. Comparisons were made with chi2 and Fisher exact tests for categorical variables, and with Wilcoxon rank sum test for continuous variables. RESULTS: Of the study population, 27.7% (n = 89/321) used LARC in the postpartum period. The LARC and non-LARC patient populations differed significantly regarding history of abortion (P = .029), with no differences in obstetric complications between the groups. Of the population, 16.6% (n = 53/320) became pregnant again within 1 year of their index delivery. Those with a rapid repeat pregnancy had significantly increased gravidity (P = .002), parity (P = .003), number of previous spontaneous or therapeutic abortions (P = .026); they were also more like to have nonlive birth as a complication (P = .028), compared with those without repeat pregnancy. No other obstetrical complications were statistically significantly different between the compared groups. CONCLUSION: Obstetrical complications seem to have little effect on postpartum contraception choice or repeat pregnancy rate with the notable exception of nonlive birth being associated with rapid repeat pregnancy. PMID- 27222492 TI - Weight loss does not improve birth rate in obese women with infertility, study shows. PMID- 27222493 TI - The effects of intravenous lipid emulsion on hemodynamic recovery and myocardial cell mitochondrial function after bupivacaine toxicity in anesthetized pigs. AB - Local anesthetic toxicity is thought to be mediated partly by inhibition of cardiac mitochondrial function. Intravenous (i.v.) lipid emulsion may overcome this energy depletion, but doses larger than currently recommended may be needed for rescue effect. In this randomized study with anesthetized pigs, we compared the effect of a large dose, 4 mL/kg, of i.v. 20% Intralipid(r) ( n = 7) with Ringer's acetate ( n = 6) on cardiovascular recovery after a cardiotoxic dose of bupivacaine. We also examined mitochondrial respiratory function in myocardial cell homogenates analyzed promptly after needle biopsies from the animals. Bupivacaine plasma concentrations were quantified from plasma samples. Arterial blood pressure recovered faster and systemic vascular resistance rose more rapidly after Intralipid than Ringer's acetate administration ( p < 0.0001), but Intralipid did not increase cardiac index or left ventricular ejection fraction. The lipid-based mitochondrial respiration was stimulated by approximately 30% after Intralipid ( p < 0.05) but unaffected by Ringer's acetate. The mean (standard deviation) area under the concentration-time curve (AUC) of total bupivacaine was greater after Intralipid (105.2 (13.6) mg.min/L) than after Ringer's acetate (88.1 (7.1) mg.min/L) ( p = 0.019). After Intralipid, the AUC of the lipid-un-entrapped bupivacaine portion (97.0 (14.5) mg.min/L) was 8% lower than that of total bupivacaine ( p < 0.0001). To conclude, 4 mL/kg of Intralipid expedited cardiovascular recovery from bupivacaine cardiotoxicity mainly by increasing systemic vascular resistance. The increased myocardial mitochondrial respiration and bupivacaine entrapment after Intralipid did not improve cardiac function. PMID- 27222494 TI - Evaluating the Quality of Website Information of Private-Practice Clinics Offering Cell Therapies in Japan. AB - BACKGROUND: Although the safety and effectiveness of stem cell therapies are yet to be proven, recent studies show that such therapies are being advertised with some questionable marketing techniques to effect positive portrayal of the therapies on the webpages of private-practice clinics to sell their therapies worldwide. In such context, those clinics communicate directly with consumers (patients and their family members) via the clinics' websites. Meanwhile, the Health Science Council at the Ministry of Health, Labour, and Welfare (MHLW) in Japan has pointed out noncompliance of some local clinics with the provisions concerning medical advertising in the Medical Care Act in the past. However, locally little is known about the current status of those clinics including the quality of their webpage information disseminated. OBJECTIVE: To evaluate the quality of website information of private-practice clinics offering cell therapies in Japan. METHODS: Twenty-four websites with 77 treatments from the Google search were identified for evaluation. The following three exploratory analyses were performed: first in order to ascertain web-based portrayal of private-practice clinics offering cell therapies, a descriptive analysis was conducted using a coding frame; second we evaluated the quality of the target website information from the viewpoint of the level of consideration taken for patients and their family members, using 10 quality criteria ("the Minimum Standard") from the e-Health Code of Ethics 2.0; third we counted and coded expressions that matched set categories for "name-dropping" and "personalized medicine" in the information posted on these websites. RESULTS: Analysis on the treatments (N=77) revealed 126 indications (multiple response): the top three indications were "cancer," "skin-rejuvenation/antiaging/anti-skin aging," and "breast augmentation/buttock augmentation." As for the portrayal of treatment risks and benefits, 78% (60/77) of treatments were mentioned with "benefits," whereas 77% (59/77) of treatments were mentioned with "risks." As for the source(s) cited for the discussions of treatment risks and benefits, no treatment quoted an expert's opinion for the risks, whereas 7% (6/77) treatments quoted external sources for the benefits. As for the results with e-Health Code of Ethics 2.0, not a single clinic fulfilled all the 10 criteria; 63% (15/24) of the clinics was found exercising "name-dropping," and 21% (5/24) of the clinics mentioned expressions related to "personalized medicine" on their websites. CONCLUSIONS: Our website content analyses confirmed the following: (1) the clinics mentioned the risks or benefits of the treatments with hardly any scientific citations, (2) the way the website information was disseminated was inappropriate for patients and their families, and (3) many websites seemed to be using marketing techniques in order to draw patients' interests or attentions. It is important that more similar studies are undertaken globally to enable an orchestrated regulatory approach toward private-practice clinics. PMID- 27222495 TI - A Case Study of an Adolescent With Health Anxiety and OCD, Treated Using CBT: Single-Case Experimental Design. AB - PROBLEM: The sparse research evidence base for adolescents with health anxiety proposes a challenge in the treatment of such mental health difficulties. Similarities are drawn between health anxiety and obsessive-compulsive disorder (OCD) in terms of their development and maintenance. The literature is reviewed and discussed in relation to the referral, assessment, formulation, cognitive behavioral intervention, and treatment outcome. METHODS: The case of an adolescent girl (aged 15 years) who presented with significant levels of health anxiety and OCD is described. An adult cognitive behavioral model of health anxiety was adapted and integrated with evidence-based cognitive behavioral therapy (CBT) for children and adolescents with OCD. These models were used to collaboratively conceptualize the young person's presenting difficulties. A single-case experimental design was employed to assess the effectiveness of the intervention. FINDINGS AND CONCLUSION: Routine outcome measures demonstrated the effectiveness of the OCD intervention, and the need for further research in health anxiety in young people, including the development of disorder and age specific measures. The implications for the use of CBT to treat health anxiety for young people are discussed. PMID- 27222496 TI - Repeated invasions into the twilight zone: evolutionary origins of a novel assemblage of fishes from deep Caribbean reefs. AB - Mesophotic and deeper reefs of the tropics are poorly known and underexplored ecosystems worldwide. Collectively referred to as the 'twilight zone', depths below ~30-50 m are home to many species of reef fishes that are absent from shallower depths, including many undescribed and endemic species. We currently lack even a basic understanding of the diversity and evolutionary origins of fishes on tropical mesophotic reefs. Recent submersible collections in the Caribbean have provided new specimens that are enabling phylogenetic reconstructions that incorporate deep-reef representatives of tropical fish genera. Here, we investigate evolutionary depth transitions in the family Gobiidae (gobies), the most diverse group of tropical marine fishes. Using divergence-time estimation coupled with stochastic character mapping to infer the timing of shallow-to-deep habitat transitions in gobies, we demonstrate at least four transitions from shallow to mesophotic depths. Habitat transitions occurred in two broad time periods (Miocene, Pliocene-Pleistocene), and may have been linked to the availability of underutilized niches, as well as the evolution of morphological/behavioural adaptations for life on deep reefs. Further, our analysis shows that at least three evolutionary lineages that invaded deep habitats subsequently underwent speciation, reflecting another unique mode of radiation within the Gobiidae. Lastly, we synthesize depth distributions for 95 species of Caribbean gobies, which reveal major bathymetric faunal breaks at the boundary between euphotic and mesophotic reefs. Ultimately, our study is the first rigorous investigation into the origin of Caribbean deep-reef fishes and provides a framework for future studies that utilize rare, deep-reef specimens. PMID- 27222497 TI - A Case of Drug-induced Cutaneous Toxicity Observed in Cynomolgus Monkeys. AB - The purpose of this article is to describe a case of drug-induced cutaneous toxicity observed in cynomolgus monkeys and to introduce approaches attempted in order to elucidate mechanisms. The test article was a small molecule with a ubiquitously distributed target, especially in rapidly dividing cells, and which modulated cell cycle regulation. After 7 consecutive days of oral dosing, animals developed multifocal skin lesions. The lesions were characterized clinically by vesicles and scabs formation and were distributed mainly in thin-skinned areas of the body including the cheek, chest, abdomen, and inner limbs. Microscopically, the lesions were confirmed as epidermal vesicle formation and ulceration. Immunohistochemical staining revealed that the levels within the epidermis where separation (vesicle formation) occurred were not consistent. The differential diagnoses for vesicular skin lesions and our efforts to elucidate the mechanism of toxicity using in-house database searches and immunohistochemistry are discussed. To the best of our knowledge, similar cutaneous toxicity has not been reported previously, although there are reports of other types of cutaneous toxicities. Understanding the mechanisms of the toxicity is very important when assessing human relevancy during drug development. Our investigative approach can be utilized when unusual skin toxicities are observed in the future. PMID- 27222498 TI - Corrigendum. PMID- 27222500 TI - The Role of Narcissism in Aggression and Violence: A Systematic Review. AB - It has long been hypothesized that feelings of inferiority or low self-esteem lead individuals to aggress against those they view as being threatening. However, recent studies suggest that it is not just the level of self-esteem but stability that is relevant to understanding this process. As such, researchers have looked to related constructs, such as narcissism, in trying to understand aggressive behaviors. Narcissism is characterized by a dissociation between an unconscious sense of inadequacy and a conscious feeling of superiority. A large number of studies examining the relationship between narcissism and violence have recently been published within both clinical and student populations. This review aimed to systematically collate the findings of such studies and integrate them within current theories of violence. Electronic literature databases such as Web of Science, MEDLINE, PsychINFO, EMBASE, Cochrane databases, and LexisNexis (legal database) were searched to identify studies examining the relationship between narcissism and violence. Twenty articles were included in this review, describing 25 separate samples. Findings suggest that narcissism is relevant in understanding aggression and violence. This was consistent across both clinical and nonclinical populations and therefore does not appear to be an artifact of studying either very violent or student samples. Evidence from student samples strongly supported the association between narcissism and aggression following an ego threat, while studies using clinical samples did not examine the effect of an ego threat. These findings may have an impact on how we understand, predict, and reduce violence. PMID- 27222499 TI - Morbidity and mortality of people who live close to municipal waste landfills: a multisite cohort study. AB - BACKGROUND: The evidence on the health effects related to residing close to landfills is controversial. Nine landfills for municipal waste have been operating in the Lazio region (Central Italy) for several decades. We evaluated the potential health effects associated with contamination from landfills using the estimated concentration of hydrogen sulphide (H2S) as exposure. METHODS: A cohort of residents within 5 km of landfills was enrolled (subjects resident on 1 January 1996 and those who subsequently moved into the areas until 2008) and followed for mortality and hospitalizations until 31 December 2012. Assessment of exposure to the landfill (H2S as a tracer) was performed for each subject at enrolment, using a Lagrangian dispersion model. Information on several confounders was available (gender, age, socioeconomic position, outdoor PM10 concentration, and distance from busy roads and industries). Cox regression analysis was performed [Hazard Ratios (HRs), 95% confidence intervals (CIs)]. RESULTS: The cohort included 242 409 individuals. H2S exposure was associated with mortality from lung cancer and respiratory diseases (e.g. HR for increment of 1 ng/m(3) H2S: 1.10, 95% CI 1.02-1.19; HR 1.09, 95% CI 1.00-1.19, respectively). There were also associations between H2S and hospitalization for respiratory diseases (HR = 1.02, 95% CI 1.00-1.03), especially acute respiratory infections among children (0-14 years) (HR = 1.06, 95% CI 1.02-1.11). CONCLUSIONS: Exposure to H2S, a tracer of airborne contamination from landfills, was associated with lung cancer mortality as well as with mortality and morbidity for respiratory diseases. The link with respiratory disease is plausible and coherent with previous studies, whereas the association with lung cancer deserves confirmation. PMID- 27222501 TI - State-level and community-level salt reduction initiatives: a systematic review of global programmes and their impact. AB - BACKGROUND: High-salt diets are linked to elevated blood pressure, a major risk factor for cardiovascular diseases, particularly stroke. State and community salt reduction strategies may complement nationally led initiatives and contribute to achieving global salt reduction targets. We aim to systematically review such interventions and document reported impact where programmes have been evaluated. METHODS: Electronic databases were searched up to June 2015 using terms 'salt' or 'sodium' and 'state' and 'community' in combination with 'campaign', 'initiative', 'project', 'strategy', 'intervention' or 'programme'. Data from evaluated and unevaluated interventions were included. Studies were analysed in relation to intervention components and outcome measures and appraised for quality using a Cochrane Risk-of-Bias Tool. RESULTS: 39 state and community programmes were identified. Settings varied from whole communities (n=23), state owned buildings (n=5), schools (n=7), workplaces (n=3) and correctional facilities (n=1). Strategies included nutrition education programmes, public education campaigns, changes to the food environment, other 'novel' approaches and multifaceted approaches. Of the 28 studies that evaluated intervention effectiveness, significant reductions were observed in terms of salt intake from dietary assessment (n=7), urinary sodium excretion (n=8), blood pressure (n=11) and sodium in foods (n=9). Six studies reported positive changes in consumer knowledge, attitudes and behaviours. All but two studies had some methodological limitations. CONCLUSIONS: State and community salt reduction programmes may be effective in a range of settings but more robust evaluation methods are needed. Scaling up these efforts in coordination with national initiatives could provide the most effective and sustainable approach to reducing population salt intake. PMID- 27222502 TI - Dynamic Changes in Renal Function Are Associated With Major Cardiovascular Events in Patients With Type 2 Diabetes. AB - OBJECTIVE: The pattern of renal function decline prior to cardiovascular (CV) events in type 2 diabetes is not well known. Our aim was to describe the association between renal function trajectories and the occurrence of a CV event. RESEARCH DESIGN AND METHODS: We considered patients with type 2 diabetes from the SURDIAGENE (Survie, Diabete de type 2 et Genetique) study (discovery cohort) and the DIABHYCAR (Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril) study (replication cohort). Global patterns of estimated glomerular filtration rate (eGFR) (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) and serum creatinine (SCr) prior to a major CV event (MACE) or last update were determined using a linear mixed effects model and annual individual slopes computed by simple linear regression. RESULTS: In the 1,040 participants of the discovery cohort, establishment of global patterns including 22,227 SCr over 6.3 years of follow-up showed an annual eGFR decline and an annual SCr increase that were significantly greater in patients with MACE compared with patients without (-3.0 and -1.7 mL/min/1.73 m(2)/year and +10.7 and +4.0 MUmol/L/year, respectively; P < 0.0001 for both). Median annual individual slopes were also significantly steeper in patients with MACE, and adjusted risk of MACE was 4.11 times higher (3.09-5.45) in patients with rapid decline in eGFR (change less than -5 mL/min/1.73 m(2)/year). Consideration of renal function trajectories provided significant additive information helping to explain the occurrence of MACE for both SCr and eGFR (PIDI < 0.0001 and P = 0.0005, respectively). These results were confirmed in the replication cohort. CONCLUSIONS: Renal function decline was associated with a higher risk of MACE. The pattern of renal function decline, beyond baseline kidney function, is an independent factor of CV risk. PMID- 27222503 TI - Nonalcoholic Fatty Liver Disease Is Associated With Ventricular Arrhythmias in Patients With Type 2 Diabetes Referred for Clinically Indicated 24-Hour Holter Monitoring. AB - OBJECTIVE: Recent studies have suggested that nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of heart rate-corrected QT interval prolongation and atrial fibrillation in patients with type 2 diabetes. Currently, no data exist regarding the relationship between NAFLD and ventricular arrhythmias in this patient population. RESEARCH DESIGN AND METHODS: We retrospectively analyzed the data of 330 outpatients with type 2 diabetes without preexisting atrial fibrillation, end-stage renal disease, or known liver diseases who had undergone 24-h Holter monitoring for clinical reasons between 2013 and 2015. Ventricular arrhythmias were defined as the presence of nonsustained ventricular tachycardia (VT), >30 premature ventricular complexes (PVCs) per hour, or both. NAFLD was diagnosed by ultrasonography. RESULTS: Compared with patients without NAFLD, those with NAFLD (n = 238, 72%) had a significantly higher prevalence of >30 PVCs/h (19.3% vs. 6.5%, P < 0.005), nonsustained VT (14.7% vs. 4.3%, P < 0.005), or both (27.3% vs. 9.8%, P < 0.001). NAFLD was associated with a 3.5-fold increased risk of ventricular arrhythmias (unadjusted odds ratio [OR] 3.47 [95% CI 1.65-7.30], P < 0.001). This association remained significant even after adjusting for age, sex, BMI, smoking, hypertension, ischemic heart disease, valvular heart disease, chronic kidney disease, chronic obstructive pulmonary disease, serum gamma-glutamyltransferase levels, medication use, and left ventricular ejection fraction (adjusted OR 3.01 [95% CI 1.26-7.17], P = 0.013). CONCLUSIONS: This is the first observational study to show that NAFLD is independently associated with an increased risk of prevalent ventricular arrhythmias in patients with type 2 diabetes. PMID- 27222504 TI - Evaluating the Quality of Comprehensive Cardiometabolic Care for Patients With Type 2 Diabetes in the U.S.: The Diabetes Collaborative Registry. PMID- 27222505 TI - Eating Behavior, Low-Frequency Functional Mutations in the Melanocortin-4 Receptor (MC4R) Gene, and Outcomes of Bariatric Operations: A 6-Year Prospective Study. AB - OBJECTIVE: Data on the effects of eating behavior and genetics on outcomes of gastrointestinal surgery for diabesity have been sparse, often flawed, and controversial. We aimed to assess long-term outcomes of bariatric operations in patients characterized for eating behavior and rare mutations in the melanocortin 4 receptor (MC4R) gene, which is strongly implicated in energy balance. RESEARCH DESIGN AND METHODS: Between 1996 and 2005, 1,264 severely obese Swiss patients underwent current laparoscopic adjustable gastric banding, gastroduodenal bypass, or a hybrid operation. Of these, 872 patients were followed for a minimum of 6 years and were screened for MC4R mutations. Using regression models, we studied relationships between eating behavior and MC4R mutations and postoperative weight loss, complications, and reoperations after 6 years. RESULTS: At baseline, rare functional MC4R mutation carriers exhibited a significantly higher prevalence of binge eating disorder (BED) or loss-of-control eating independent of age, sex, and BMI. Six years after bariatric surgery, the mutation carriers had more major complications than wild-type subjects independent of age, baseline BMI, sex, operation type, and weight loss. Furthermore, high baseline BMI, male sex, BED, and functional MC4R mutations were independent predictors of higher reoperation rates. CONCLUSIONS: Sequencing of MC4R and eating typology, combined with stratification for sex and baseline BMI, might significantly improve patient allocation to banding or bypass operations for diabesity as well as reduce both complication and reoperation rates. PMID- 27222506 TI - Continuous Glucose Sensor Survival and Accuracy Over 14 Consecutive Days. PMID- 27222507 TI - Impact of Twin Gestation and Fetal Sex on Maternal Risk of Diabetes During and After Pregnancy. PMID- 27222509 TI - HbA1c-Based Classification Reveals Epidemic of Diabetes and Prediabetes in Vietnam. PMID- 27222508 TI - Predisposing Factors for Any and Major Hypoglycemia With Saxagliptin Versus Placebo and Overall: Analysis From the SAVOR-TIMI 53 Trial. AB - OBJECTIVE: To analyze the impact of adding saxagliptin versus placebo on the risk for hypoglycemia and to identify predictors of any and major hypoglycemia in patients with type 2 diabetes included in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) study. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes (n = 16,492) were randomized to saxagliptin or placebo and followed for a median of 2.1 years. Associations between any hypoglycemia (symptomatic or glucose measurement <54 mg/dL) or major hypoglycemia (requiring extended assistance) and patient characteristics overall and by treatment allocation were studied. RESULTS: At least one hypoglycemic event was reported in 16.6% of patients, and 1.9% reported at least one major event. Patients allocated to saxagliptin versus placebo experienced higher rates of any (hazard ratio [HR] 1.16 [95% CI 1.08, 1.25]; P < 0.001) or major (HR 1.26 [1.01, 1.58]; P = 0.038) hypoglycemia. Hypoglycemia rates (any or major) were increased with saxagliptin in patients taking sulfonylureas (SURs) but not in those taking insulin. Rates were increased with saxagliptin in those with baseline HbA1c <=7.0% and not in those with baseline HbA1c >7.0%. Multivariate analysis of the overall population revealed that independent predictors of any hypoglycemia were as follows: allocation to saxagliptin, long duration of diabetes, increased updated HbA1c, macroalbuminuria, moderate renal failure, SUR use, and insulin use. Predictors of major hypoglycemia were allocation to saxagliptin, advanced age, black race, reduced BMI, long duration of diabetes, declining renal function, microalbuminuria, and use of short-acting insulin. Among SURs, glibenclamide was associated with increased risk of major but not any hypoglycemia. CONCLUSIONS: The identification of patients at risk for hypoglycemia can guide physicians to better tailor antidiabetic therapy. PMID- 27222510 TI - Prandial Options to Advance Basal Insulin Glargine Therapy: Testing Lixisenatide Plus Basal Insulin Versus Insulin Glulisine Either as Basal-Plus or Basal-Bolus in Type 2 Diabetes: The GetGoal Duo-2 Trial. AB - OBJECTIVE: To provide evidence-based options on how to intensify basal insulin, we explored head-to-head prandial interventions in overweight patients with type 2 diabetes inadequately controlled on basal insulin glargine with or without 1-3 oral antidiabetic agents (OADs). RESEARCH DESIGN AND METHODS: Patients were randomized to lixisenatide once daily or insulin glulisine given once or thrice daily, added to glargine, with or without metformin, if HbA1c remained >=7 to <=9% (>=53 to <=75 mmol/mol) after 12 weeks of glargine optimization with OADs other than metformin stopped at the start of optimization. Coprimary end points at 26 weeks were 1) noninferiority (95% CI upper bound <0.4% [<4.4 mmol/mol]) in HbA1c reduction with lixisenatide versus glulisine once daily, and either 2a) noninferiority in HbA1c reduction for lixisenatide versus glulisine thrice daily or 2b) superiority in body weight change for lixisenatide versus glulisine thrice daily. Fasting and postprandial plasma glucose, composite efficacy/safety end points, and adverse events were also assessed. RESULTS: Baseline characteristics were similar between arms (n = 298, diabetes and basal insulin duration of 12.2 and 3.2 years, respectively; BMI 32.2 kg/m(2)). HbA1c improved from 8.5% to 7.9% (69 to 63 mmol/mol) with glargine optimization and further to 7.2%, 7.2%, and 7.0% (55, 55, and 53 mmol/mol) with lixisenatide and glulisine once daily and thrice daily, respectively; all coprimary end points were met. Symptomatic hypoglycemia and body weight were lower in lixisenatide versus glulisine patients. More gastrointestinal events occurred with lixisenatide. CONCLUSIONS: Short-acting glucagon-like peptide-1 receptor agonists as add-on to basal insulin may become a preferred treatment intensification option, attaining meaningful glycemic targets with fewer hypoglycemic events without weight gain versus basal plus or basal-bolus in uncontrolled basal insulin-treated type 2 diabetes. PMID- 27222511 TI - HDL Cholesterol as a Residual Risk Factor for Vascular Events and All-Cause Mortality in Patients With Type 2 Diabetes. AB - OBJECTIVE: To evaluate whether low HDL cholesterol (HDL-c) levels are a risk factor for cardiovascular disease and mortality in patients with type 2 diabetes and whether it remains a residual risk factor when attaining low LDL cholesterol (LDL-c) treatment goals or when LDL-c is treated with intensive lipid-lowering therapy. RESEARCH DESIGN AND METHODS: We performed a prospective cohort study of 1,829 patients with type 2 diabetes included in the Second Manifestations of ARTerial disease (SMART) cohort. Cox proportional hazard models were used to evaluate the risk of HDL-c on cardiovascular events and all-cause mortality. Analyses were performed in strata of LDL-c levels (<2.0, 2.0-2.5, and >2.5 mmol/L) and lipid-lowering therapy intensity and were adjusted for age, sex, BMI, smoking, alcohol, LDL-c, triglycerides, systolic blood pressure, estimated glomerular filtration rate, glucose, and HbA1c. RESULTS: A total of 335 new cardiovascular events and 385 deaths occurred during a median follow-up of 7.0 years (interquartile range 3.9-10.4). No relation was found between plasma HDL-c and cardiovascular events (hazard ratio [HR] 0.97, 95% CI 0.93-1.01) or all-cause mortality (HR 0.99, 95% CI 0.96-1.03). Subgroup analysis supported effect modification by plasma LDL-c levels. In patients with LDL-c levels <2.0 mmol/L, higher HDL-c was related to higher risk for all-cause mortality (HR 1.14, 95% CI 1.07-1.21). Higher HDL-c was also related to higher risk for cardiovascular events in patients with LDL-c levels <2.0 mmol/L (HR 1.10, 95% CI 1.07-1.21) in contrast to patients with LDL-c levels between 2.0 and 2.5 mmol/L (HR 0.85, 95% CI 0.75-0.95) and >2.5 mmol/L (HR 0.96, 95% CI 0.91-1.00). CONCLUSIONS: In high risk patients with type 2 diabetes with LDL-c levels <2.0 mmol/L, higher HDL-c at baseline is unexpectedly related to a higher risk for cardiovascular events and all-cause mortality in contrast to high-risk patients with type 2 diabetes with LDL-c levels between 2.0 and 2.5 mmol/L. PMID- 27222512 TI - Evaluating Technical Efficiency of Nursing Care Using Data Envelopment Analysis and Multilevel Modeling. AB - Data envelopment analysis (DEA) is an advantageous non-parametric technique for evaluating relative efficiency of performance. This article describes use of DEA to estimate technical efficiency of nursing care and demonstrates the benefits of using multilevel modeling to identify characteristics of efficient facilities in the second stage of analysis. Data were drawn from LTCFocUS.org, a secondary database including nursing home data from the Online Survey Certification and Reporting System and Minimum Data Set. In this example, 2,267 non-hospital-based nursing homes were evaluated. Use of DEA with nurse staffing levels as inputs and quality of care as outputs allowed estimation of the relative technical efficiency of nursing care in these facilities. In the second stage, multilevel modeling was applied to identify organizational factors contributing to technical efficiency. Use of multilevel modeling avoided biased estimation of findings for nested data and provided comprehensive information on differences in technical efficiency among counties and states. PMID- 27222513 TI - Concurrent elevation of CO2, O3 and temperature severely affects oil quality and quantity in rapeseed. AB - Plant oil is an essential dietary and bio-energy resource. Despite this, the effects of climate change on plant oil quality remain to be elucidated. The present study is the first to show changes in oil quality and quantity of four rapeseed cultivars in climate scenarios with elevated [CO2], [O3] and temperature (T) combined and as single factors. The combination of environmental factors resembled IPCC's 'business as usual' emission scenario predicted for late this century. Generally, the climate scenarios reduced the average amounts of the six fatty acids (FAs) analysed, though in some treatments single FAs remained unchanged or even increased. Most reduced was the FA essential for human nutrition, C18:3-omega3, which decreased by 39% and 45% in the combined scenarios with elevated [CO2]+T+[O3] and [CO2]+T, respectively. Average oil content decreased 3-17%. When [CO2] and T were elevated concurrently, the seed biomass was reduced by half, doubling the losses in FAs and oil content. This corresponded to a 58% reduction in the oil yield per hectare, and C18:3-omega3 decreased by 77%. Furthermore, the polyunsaturated FAs were significantly decreased. The results indicate undesirable consequences for production and health benefits of rapeseed oil with future climate change. The results also showed strong interactive effects of CO2, T and O3 on oil quality, demonstrating why prediction of climate effects requires experiments with combined factors and should not be based on extrapolation from single factor experiments. PMID- 27222514 TI - Discovery, structure, function, and applications of cyclotides: circular proteins from plants. AB - Cyclotides are plant-derived cyclic peptides that have a head-to-tail cyclic backbone and three conserved disulphide bonds that form a cyclic cystine knot motif. They occur in plants from the Violaceae, Rubiaceae, Cucurbitaceae, Fabaceae, and Solanaceae families, typically with 10-100 cyclotides in a given plant species, in a wide range of tissues, including flowers, leaves, stems, and roots. Some cyclotides are expressed in large amounts (up to 1g kg(-1) wet plant weight) and their natural function appears to be to protect plants from pests or pathogens. This article provides a brief overview of their discovery, distribution in plants, and applications. In particular, their exceptional stability has led to their use as peptide-based scaffolds in drug design applications. They also have potential as natural 'ecofriendly' insecticides, and as protein engineering frameworks. PMID- 27222515 TI - HOX13 proteins: the molecular switcher in Hoxd bimodal regulation. AB - The striking correlation between the genomic arrangement of Hox genes and their temporal and spatial pattern of expression during embryonic development has been a source of fascination since its discovery. This correspondence has been used as a privileged example in the investigation of the connection between genomic architecture and function. In this issue of Genes & Development, Beccari and colleagues (pp. 1172-1186) make a big step forward in understanding Hox gene regulation during limb development by showing the pivotal role of HOXA13 and HOXD13 proteins in the transition from a proximal to a distal type of Hoxd transcriptional regulation. PMID- 27222518 TI - Corrigendum: In vivo investigation of the transcription, processing, endonucleolytic activity, and functional relevance of the spatial distribution of a plant miRNA. PMID- 27222520 TI - Family Support and Preparation for Future Care Needs Among Urban Chinese Baby Boomers. AB - Objectives: Little is reported about the family's role in preparation for future care (PFC) before the onset of care needs. The primary aim was to examine the relationships between PFC and different types of family support exchanged with generations both above and below. Method: Path analysis was conducted on 516 Chinese baby boomers aged 45-65 to examine the associations between PFC (care expectation, awareness, information gathering, and decision making) and 4 types of family support (instrumental support, financial assistance, information and appraisal, and emotional support) when the covariates were controlled for. Results: The current planning status and planning paths are consistent with those of the U.S. and European populations. Providing instrumental support to a parent was positively associated with awareness of care needs. Providing emotional support to a child was negatively associated with information gathering. In general, receiving support from a child facilitated PFC. Although those receiving emotional support from an adult child had less awareness of care needs, they displayed more information gathering. Discussion: The role of family support in PFC is more subtle than simply increasing and decreasing resource volumes. Future research is needed to better understand this complexity. PMID- 27222519 TI - Comparison of safety and efficacy of laparoscopic pyelolithotomy versus percutaneous nephrolithotomy in patients with large renal pelvic stones: a meta analysis. AB - To compare percutaneous nephrolithotomy (PCNL) and laparoscopic pyelolithotomy (LP) for surgical management for large (>2 cm) renal stones. We searched MEDLINE, Cochrane, and EMBASE databases until March 11, 2015, using the following search terms: renalpelvic stone, percutaneous nephrolithotomy, laparoscopic pyelolithotomy. Randomized controlled and prospective and retrospective two-armed studies were included. Sensitivity analysis and assessment of the quality of the included studies and publication bias were performed. Nine studies were included in the study with a patient population of 622. The studies were homogeneous with respect to the primary end point of stone-free rate, but were heterogeneous with respect to operation time, length of hospital stay, and blood loss. A higher percentage of patients who received LP remained stone-free following surgery compared with patients who were treated with PCNL (p=0.001). However, the mean operation time was longer for patients with LP than for those treated with PCNL (p=0.002). There was no difference between procedures with regard to length of hospital stay or blood loss (p>=0.071). Sensitivity and quality analysis indicated that the data are reliable and the included studies are of good quality. No publication bias was observed. The study suggests that both procedures are effective and safe for removing large renal stones. However, LP may be more efficacious than PCNL in treating large kidney stones. PMID- 27222517 TI - Asf1 facilitates dephosphorylation of Rad53 after DNA double-strand break repair. AB - To allow for sufficient time to repair DNA double-stranded breaks (DSBs), eukaryotic cells activate the DNA damage checkpoint. In budding yeast, Rad53 (mammalian Chk2) phosphorylation parallels the persistence of the unrepaired DSB and is extinguished when repair is complete in a process termed recovery or when the cells adapt to the DNA damage checkpoint. A strain containing a slowly repaired DSB does not require the histone chaperone Asf1 to resume cell cycle progression after DSB repair. When a second, rapidly repairable DSB is added to this strain, Asf1 becomes required for recovery. Recovery from two repairable DSBs also depends on the histone acetyltransferase Rtt109 and the cullin subunit Rtt101, both of which modify histone H3 that is associated with Asf1. We show that dissociation of histone H3 from Asf1 is required for efficient recovery and that Asf1 is required for complete dephosphorylation of Rad53 when the upstream DNA damage checkpoint signaling is turned off. Our data suggest that the requirements for recovery from the DNA damage checkpoint become more stringent with increased levels of damage and that Asf1 plays a histone chaperone independent role in facilitating complete Rad53 dephosphorylation following repair. PMID- 27222521 TI - Concise argument-wellbeing, collective responsibility and ethical capitalism. PMID- 27222516 TI - Noncanonical views of homology-directed DNA repair. AB - DNA repair is essential to maintain genomic integrity and initiate genetic diversity. While gene conversion and classical nonhomologous end-joining are the most physiologically predominant forms of DNA repair mechanisms, emerging lines of evidence suggest the usage of several noncanonical homology-directed repair (HDR) pathways in both prokaryotes and eukaryotes in different contexts. Here we review how these alternative HDR pathways are executed, specifically focusing on the determinants that dictate competition between them and their relevance to cancers that display complex genomic rearrangements or maintain their telomeres by homology-directed DNA synthesis. PMID- 27222522 TI - Parental enhancement and symmetry of power in the parent-child relationship. AB - Many instances of parental enhancement are objectionable on egalitarian grounds because they unnecessarily amplify one kind of asymmetry of power between parents and children. Because children have full moral status, we ought to seek egalitarian relationships with them. Such relationships are compatible with asymmetries of power only to the extent to which the asymmetry is necessary for (1) advancing the child's level of advantage up to what justice requires or (2) instilling in the child morally required features. This is a ground to oppose parental enhancements whose purpose is either to merely satisfy parents' preferences or to confer on the child advantages above and beyond what the child is owed by justice. PMID- 27222523 TI - BMA end-of-life care and physician-assisted dying project. PMID- 27222524 TI - Early Rivaroxaban Use After Cardioembolic Stroke May Not Result in Hemorrhagic Transformation: A Prospective Magnetic Resonance Imaging Study. AB - BACKGROUND AND PURPOSE: Early anticoagulation after cardioembolic stroke remains controversial because of the potential for hemorrhagic transformation (HT). We tested the safety and feasibility of initiating rivaroxaban <=14 days after cardioembolic stroke/transient ischemic attack. METHODS: A prospective, open label study of patients with atrial fibrillation treated with rivaroxaban <=14 days of transient ischemic attack or ischemic stroke (National Institute of Health Stroke Scale <9). All patients underwent magnetic resonance imaging <24 hours of rivaroxaban initiation and day 7. The primary end point was symptomatic HT at day 7. RESULTS: Sixty patients (mean+/-SD age 71+/-19 years, 82% stroke/18% transient ischemic attack) were enrolled. Median (interquartile range) time from onset to rivaroxaban was 3 (5) days. At treatment initiation, median National Institute of Health Stroke Scale was 2 (4), and median diffusion-weighted imaging volume was 7.9 (13.7) mL. At baseline, HT was present in 25 (42%) patients (hemorrhagic infarct [HI]1=19, HI2=6). On follow-up magnetic resonance imaging, no patients developed symptomatic HT. New asymptomatic HI1 developed in 3 patients, and asymptomatic progression from HI1 to HI2 occurred in 5 patients; otherwise, HT remained unchanged at day 7. CONCLUSIONS: These data support the safety of rivaroxaban initiation <=14 days of mild-moderate cardioembolic stroke/transient ischemic attack. Magnetic resonance imaging evidence of petechial HT, which is common, does not appear to increase the risk of symptomatic HT. PMID- 27222525 TI - Insulin Resistance Intervention After Stroke Trial of Pioglitazone: Is This Perhaps the End of the Beginning? PMID- 27222526 TI - Smoking-Thrombolysis Relationship Depends on Ischemic Stroke Subtype. AB - BACKGROUND AND PURPOSE: The relationship between smoking and the outcome in patients received thrombolysis is undetermined. The outcome could be influenced by different stroke subtypes. This study aimed to explore whether smoking had any impact on the outcome in patients with stroke of different subtypes who received intravenous thrombolysis. METHODS: All patients who received intravenous thrombolysis within 4.5 hours after symptom onset from the Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China (TIMS-China) database were eligible to be entered into this analysis. Smokers were considered if they smoked at least 1 cigarette/d for >6 months before stroke. Ischemic stroke subtype was classified by using the Trial of Org 10172 in Acute Stroke Treatment criteria. Outcome measurements included post-intravenous thrombolysis symptomatic intracranial hemorrhage within 7 days, mortality, and functional independence at 90 days. The relationship between smoking and thrombolysis was analyzed by using univariate and multivariate logistic regression models. RESULTS: Of 1118 patients enrolled, we identified 454 smokers and 664 nonsmokers. After stratifying for ischemic stroke subtypes, multivariate analysis revealed a significant relationship between smoking and functional independence in patients with noncardioembolism stroke subtypes (large artery atherosclerosis: odds ratio [OR], 1.452; 95% confidence interval [CI], 1.053-2.264; small artery occlusion: OR, 4.275; 95% CI, 1.098-16.649; other: OR, 3.120; 95% CI, 1.162-8.373). Furthermore, smoking was specially related to lower rates of symptomatic intracranial hemorrhage (OR, 0.316; 95% CI, 0.120-0.832) and mortality (OR, 0.272; 95% CI, 0.128-0.577) in patients with large artery atherosclerosis subtype. CONCLUSIONS: In patients treated with intravenous thrombolysis, smoking could be related to a better chance of functional independence if their subtype of stroke was noncardioembolic, and a lower risk of symptomatic intracranial hemorrhage and mortality in those with large artery atherosclerosis. PMID- 27222527 TI - Nocturnal Desaturation in the Stroke Unit Is Associated With Wake-Up Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Wake-up stroke (WUS) represents a quarter of all ischemic strokes and may be a specific subgroup. Nocturnal desaturation secondary to sleep disordered breathing is an independent risk factor for stroke, but the association between nocturnal desaturation and WUS remains unclear. We investigated the relationship between nocturnal desaturation using oxygen desaturation index and WUS in patients with acute stroke in the stroke unit. METHODS: A total of 298 patients admitted for acute ischemic stroke to the stroke unit between July 2013 and May 2015 were enrolled. The oxygen desaturation index was calculated using pulse oximetry data sampled every 1 minute during 9 hours on the first night (10:00 pm-7:00 am) of the stroke unit admission, and nocturnal desaturation was defined as an oxygen desaturation index of 5 at least per hour. We compared the clinical characteristics and nocturnal desaturations between patients with and without WUS. RESULTS: Among all patients (age, 67.7+/-12.6 years; male, 54.4%), 26.5% patients had WUS. The proportion of nocturnal desaturation was significantly greater in patients admitted with WUS (29.1% versus 12.3%, P=0.001). The age, sex, risk factors except for hyperlipidemia, stroke severity, and stroke mechanisms were similar between the 2 groups. After adjustment for covariates, it was found that nocturnal desaturation was significantly more common in the WUS group (odds ratio, 3.25; 95% confidence interval, 1.63-6.46). CONCLUSIONS: Nocturnal desaturation was more frequently observed in patients admitted with WUS during the first night in the stroke unit. This suggests that nocturnal desaturation is a possible modifiable risk factor for the occurrence of WUS. PMID- 27222528 TI - Sunflower seed allergy. AB - Sunflower seeds are a rare source of allergy, but several cases of occupational allergies to sunflowers have been described. Sunflower allergens on the whole, however, still await precise and systematic description. We present an interesting case of a 40-year-old male patient, admitted to hospital due to shortness of breath and urticaria, both of which appeared shortly after the patient ingested sunflower seeds. Our laryngological examination revealed swelling of the pharynx with retention of saliva and swelling of the mouth and tongue. During diagnostics, 2 months later, we found that skin prick tests were positive to mugwort pollen (12/9 mm), oranges (6/6 mm), egg protein (3/3 mm), and hazelnuts (3/3 mm). A native prick by prick test with sunflower seeds was strongly positive (8/5 mm). Elevated concentrations of specific IgE against weed mix (inc. lenscale, mugwort, ragweed) allergens (1.04 IU/mL), Artemisia vulgaris (1.36 IU/mL), and Artemisia absinthium (0.49 IU/mL) were found. An ImmunoCap ISAC test found an average level of specific IgE against mugwort pollen allergen component Art v 1 - 5,7 ISU-E, indicating an allergy to mugwort pollen and low to medium levels of specific IgE against lipid transfer proteins (LTP) found in walnuts, peanuts, mugwort pollen, and hazelnuts. Through the ISAC inhibition test we proved that sunflower seed allergen extracts contain proteins cross-reactive with patients' IgE specific to Art v 1, Art v 3, and Jug r 3. Based on our results and the clinical pattern of the disease we confirmed that the patient is allergic to mugwort pollen and that he had an anaphylactic reaction as a result of ingesting sunflower seeds. We suspected that hypersensitivity to sunflower LTP and defensin-like proteins, both cross-reactive with mugwort pollen allergens, were the main cause of the patient's anaphylactic reaction. PMID- 27222529 TI - What is nature capable of? Evidence, ontology and speculative medical humanities. AB - Expanding on the recent call for a 'critical medical humanities' to intervene in questions of the ontology of health, this article develops a what we call a 'speculative' orientation to such interventions in relation to some of the ontological commitments on which contemporary biomedical cultures rest. We argue that crucial to this task is an approach to ontology that treats it not as a question of first principles, but as a matter of the consequences of the images of nature that contemporary biomedical research practices espouse when they make claims to evidence, as well as the possible consequences of imagining different worlds in which health and disease processes partake. By attending to the implicit ontological assumptions involved in the method par excellence of biomedical research, namely the randomised controlled trial (RCT), we argue that the mechanistic ontology that tacitly informs evidence-based biomedical research simultaneously authorises a series of problematic consequences for understanding and intervening practically in the concrete realities of health. As a response, we develop an alternative ontological proposition that regards processes of health and disease as always situated achievements. We show that, without disqualifying RCT-based evidence, such a situated ontology enables one to resist the reduction of the realities of health and disease to biomedicine's current forms of explanation. In so doing, we call for medical humanities scholars to actively engage in the speculative question of what nature may be capable of. PMID- 27222530 TI - Impact of human galectin-1 binding to saccharide ligands on dimer dissociation kinetics and structure. AB - Endogenous lectins can control critical biological responses, including cell communication, signaling, angiogenesis and immunity by decoding glycan-containing information on a variety of cellular receptors and the extracellular matrix. Galectin-1 (Gal-1), a prototype member of the galectin family, displays only one carbohydrate recognition domain and occurs in a subtle homodimerization equilibrium at physiologic concentrations. Such equilibrium critically governs the function of this lectin signaling by allowing tunable interactions with a preferential set of glycosylated receptors. Here, we used a combination of experimental and computational approaches to analyze the kinetics and mechanisms connecting Gal-1 ligand unbinding and dimer dissociation processes. Kinetic constants of both processes were found to differ by an order of magnitude. By means of steered molecular dynamics simulations, the ligand unbinding process was followed monitoring water occupancy changes. By determining the water sites in a carbohydrate binding place during the unbinding process, we found that rupture of ligand-protein interactions induces an increase in energy barrier while ligand unbinding process takes place, whereas the entry of water molecules to the binding groove and further occupation of their corresponding water sites contributes to lowering of the energy barrier. Moreover, our findings suggested local asymmetries between the two subunits in the dimer structure detected at a nanosecond timescale. Thus, integration of experimental and computational data allowed a more complete understanding of lectin ligand binding and dimerization processes, suggesting new insights into the relationship between Gal-1 structure and function and renewing the discussion on the biophysics and biochemistry of lectin-ligand lattices. PMID- 27222531 TI - Development of a multifunctional aminoxy-based fluorescent linker for glycan immobilization and analysis. AB - Glycan arrays have become a technique of choice to screen glycan-protein interactions in a high-throughput manner with high sensitivity and low sample consumption. Here, the synthesis of a new multifunctional fluorescent linker for glycan labeling via aminoxy ligation and immobilization is described; the linker features a fluorescent naphthalene group suitable for highly sensitive high performance liquid chromatography-based purification and an azido- or amino modified pentanoyl moiety for the immobilization onto solid supports. Several glycoconjugates displaying small sugar epitopes via chemical or chemoenzymatic synthesis were covalently attached onto a microarray support and tested with lectins of known carbohydrate binding specificity. The glycan library was extended using glycosyltransferases (e.g. galactosyl-, sialyl- and fucosyltransferases); the resulting neoglycoconjugates, which are easily detected by mass spectrometry, mimic antennal elements of N- and O-glycans, including ABH blood group epitopes and sialylated structures. Furthermore, an example natural plant N-glycan containing core alpha1,3-fucose and beta1,2-xylose was also successfully conjugated to the fluorescent linker, immobilized and probed with lectins as well as antihorseradish peroxidase. These experiments validate our linker as being a potentially valuable tool to study glycozyme and lectin specificities, sensitive enough to allow purification of natural glycans. PMID- 27222532 TI - Refinement of screening for familial pancreatic cancer. AB - OBJECTIVE: Surveillance programmes are recommended for individuals at risk (IAR) of familial pancreatic cancer (FPC) to detect early pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC). However, the age to begin screening and the optimal screening protocol remain to be determined. METHODS: IAR from non-CDKN2A FPC families underwent annual screening by MRI with endoscopic ultrasonography (EUS) in board-approved prospective screening programmes at three tertiary referral centres. The diagnostic yield according to age and different screening protocols was analysed. RESULTS: 253 IAR with a median age of 48 (25-81) years underwent screening with a median of 3 (1-11) screening visits during a median follow-up of 28 (1-152) months. 134 (53%) IAR revealed pancreatic lesions on imaging, mostly cystic (94%), on baseline or follow-up screening. Lesions were significantly more often identified in IAR above the age of 45 years (p<0.0001). In 21 IAR who underwent surgery, no significant lesions (PDAC, pancreatic intraepithelial neoplasia (PanIN) 3 lesions, high-grade intraductal papillary mucinous neoplasia (IPMN)) were detected before the age of 50 years. Potentially relevant lesions (multifocal PanIN2 lesions, low/moderate-grade branch-duct IPMNs) occurred also significantly more often after the age of 50 years (13 vs 2, p<0.0004). The diagnostic yield of potentially relevant lesions was not different between screening protocols using annual MRI with EUS (n=98) or annual MRI with EUS every 3rd year (n=198) and between IAR screened at intervals of 12 months (n=180) or IAR that decided to be screened at >=24 months intervals (n=30). CONCLUSIONS: It appears safe to start screening for PDAC in IAR of non-CDKN2a FPC families at the age of 50 years. MRI-based screening supplemented by EUS at baseline and every 3rd year or when changes in MRI occur appears to be efficient. PMID- 27222533 TI - Stress-activated miR-21/miR-21* in hepatocytes promotes lipid and glucose metabolic disorders associated with high-fat diet consumption. AB - OBJECTIVE: miR-21 is an oncomir highly upregulated in hepatocellular carcinoma and in early stages of liver diseases characterised by the presence of steatosis. Whether upregulation of miR-21 contributes to hepatic metabolic disorders and their progression towards cancer is unknown. This study aims at investigating the role of miR-21/miR-21* in early stages of metabolic liver disorders associated with diet-induced obesity (DIO). DESIGN: Constitutive miR-21/miR-21* knockout (miR21KO) and liver-specific miR-21/miR-21* knockout (LImiR21KO) mice were generated. Mice were then fed with high-fat diet (HFD) and alterations of the lipid and glucose metabolism were investigated. Serum and ex vivo explanted liver tissue were analysed. RESULTS: Under normal breeding conditions and standard diet, miR-21/miR-21* deletion in mice was not associated with any detectable phenotypic alterations. However, when mice were challenged with an obesogenic diet, glucose intolerance, steatosis and adiposity were improved in mice lacking miR-21/miR-21*. Deletion of miR-21/miR-21* specifically in hepatocytes led to similar improvements in mice fed an HFD, indicating a crucial role for hepatic miR-21/miR-21* in metabolic disorders associated with DIO. Further molecular analyses demonstrated that miR-21/miR-21* deletion in hepatocytes increases insulin sensitivity and modulates the expression of multiple key metabolic transcription factors involved in fatty acid uptake, de novo lipogenesis, gluconeogenesis and glucose output. CONCLUSIONS: Hepatic miR-21/miR-21* deficiency prevents glucose intolerance and steatosis in mice fed an obesogenic diet by altering the expression of several master metabolic regulators. This study points out miR-21/miR-21* as a potential therapeutic target for non alcoholic fatty liver disease and the metabolic syndrome. PMID- 27222535 TI - Perspectives on patienthood, practitioners and pedagogy. PMID- 27222534 TI - In vivo evidence for ribavirin-induced mutagenesis of the hepatitis E virus genome. AB - OBJECTIVE: Hepatitis E virus (HEV) infection can take chronic courses in immunocompromised patients potentially leading to liver cirrhosis and liver failure. Ribavirin (RBV) is currently the only treatment option for many patients, but treatment failure can occur which has been associated with the appearance of a distinct HEV polymerase mutant (G1634R). Here, we performed a detailed analysis of HEV viral intrahost evolution during chronic hepatitis E infections. DESIGN: Illumina deep sequencing was performed for the detection of intrahost variation in the HEV genome of chronically infected patients. Novel polymerase mutants were investigated in vitro using state-of-the-art HEV cell culture models. RESULTS: Together, these data revealed that (1) viral diversity differed markedly between patients but did not show major intraindividual short term variations in untreated patients with chronic hepatitis E, (2) RBV therapy was associated with an increase in viral heterogeneity which was reversible when treatment was stopped, (3) the G1634R mutant was detectable as a minor population prior to therapy in patients who subsequently failed to achieve a sustained virological response to RBV therapy and (4) in addition to G1634R further dominant variants in the polymerase region emerged, impacting HEV replication efficiency in vitro. CONCLUSIONS: In summary, this first investigation of intrahost HEV population evolution indicates that RBV causes HEV mutagenesis in treated patients and that an emergence of distinct mutants within the viral population occurs during RBV therapy. We also suggest that next-generation sequencing could be useful to guide personalised antiviral strategies. PMID- 27222536 TI - Controlling for Phylogenetic Relatedness and Evolutionary Rates Improves the Discovery of Associations Between Species' Phenotypic and Genomic Differences. AB - The growing number of sequenced genomes allows us now to address a key question in genetics and evolutionary biology: which genomic changes underlie particular phenotypic changes between species? Previously, we developed a computational framework called Forward Genomics that associates phenotypic to genomic differences by focusing on phenotypes that are independently lost in different lineages. However, our previous implementation had three main limitations. Here, we present two new Forward Genomics methods that overcome these limitations by (1) directly controlling for phylogenetic relatedness, (2) controlling for differences in evolutionary rates, and (3) computing a statistical significance. We demonstrate on large-scale simulated data and on real data that both new methods substantially improve the sensitivity to detect associations between phenotypic and genomic differences. We applied these new methods to detect genomic differences involved in the loss of vision in the blind mole rat and the cape golden mole, two independent subterranean mammals. Forward Genomics identified several genes that are enriched in functions related to eye development and the perception of light, as well as genes involved in the circadian rhythm. These new Forward Genomics methods represent a significant advance in our ability to discover the genomic basis underlying phenotypic differences between species. Source code: https://github.com/hillerlab/ForwardGenomics/. PMID- 27222537 TI - Protection against HPV-16-Associated Tumors Requires the Activation of CD8+ Effector Memory T Cells and the Control of Myeloid-Derived Suppressor Cells. AB - Active anticancer immunotherapeutic approaches have been shown to induce cellular or humoral immune responses in patients, but, thus far, the observed outcomes did not ensure their recommendation for clinical use. The induction of tumor-specific CD8(+) T cells, although required for the clearance of most solid tumors, was shown to be insufficient for the development of a successful immunotherapeutic approach. The suppressive immune environment triggered by tumors, including the expansion of myeloid-derived suppressor cells (MDSC), is detrimental to the development of antitumor immune responses and precludes the generation of more promising clinical outcomes. In this work, we characterized the CD8(+) T-cell population specifically involved in the control of tumor growth and the role of MDSCs after administration of an antitumor therapeutic DNA vaccine targeting human papillomavirus type 16 (HPV-16)-associated tumors. Activation of cytotoxic high-avidity CD8(+) T cells with an effector memory phenotype was found in mice grafted with tumor cells expressing the HPV-16 oncoproteins. In addition, MDSC antibody depletion further enhanced the immunotherapeutic effects of the vaccine, resulting in the complete eradication of tumor cells. Collectively, the current results indicate that the simultaneous control of MDSCs and activation of high avidity tumor-specific effector memory CD8(+) T cells are key features for tumor protection by immunotherapeutic approaches and deserve further testing under clinical conditions. Mol Cancer Ther; 15(8); 1920-30. (c)2016 AACR. PMID- 27222542 TI - Maria Gordon Buse, MD: A Family Affair Through Six Decades of Diabetes Discovery. PMID- 27222538 TI - The Mitogen-Activated Protein Kinase Pathway Facilitates Resistance to the Src Inhibitor Dasatinib in Thyroid Cancer. AB - Advanced stages of papillary and anaplastic thyroid cancer represent a highly aggressive subset, in which there are currently few effective therapies. We and others have recently demonstrated that c-SRC is a key mediator of growth, invasion, and metastasis, and therefore represents a promising therapeutic target in thyroid cancer. However, clinically, Src inhibitor efficacy has been limited, and therefore further insights are needed to define resistance mechanisms and determine rational combination therapies. We have generated four thyroid cancer cell lines with a greater than 30-fold increase in acquired resistance to the Src inhibitor dasatinib. Upon acquisition of dasatinib resistance, the two RAS-mutant cell lines acquired the c-SRC gatekeeper mutation (T341M), whereas the two BRAF mutant cell lines did not. Accordingly, Src signaling was refractory to dasatinib treatment in the RAS-mutant dasatinib-resistant cell lines. Interestingly, activation of the MAPK pathway was increased in all four of the dasatinib resistant cell lines, likely due to B-Raf and c-Raf dimerization. Furthermore, MAP2K1/MAP2K2 (MEK1/2) inhibition restored sensitivity in all four of the dasatinib-resistant cell lines, and overcame acquired resistance to dasatinib in the RAS-mutant Cal62 cell line, in vivo Together, these studies demonstrate that acquisition of the c-SRC gatekeeper mutation and MAPK pathway signaling play important roles in promoting resistance to the Src inhibitor dasatinib. We further demonstrate that up-front combined inhibition with dasatinib and MEK1/2 or ERK1/2 inhibitors drives synergistic inhibition of growth and induction of apoptosis, indicating that combined inhibition may overcome mechanisms of survival in response to single-agent inhibition. Mol Cancer Ther; 15(8); 1952-63. (c)2016 AACR. PMID- 27222539 TI - Chemogenomics and orthology-based design of antibiotic combination therapies. AB - Combination antibiotic therapies are being increasingly used in the clinic to enhance potency and counter drug resistance. However, the large search space of candidate drugs and dosage regimes makes the identification of effective combinations highly challenging. Here, we present a computational approach called INDIGO, which uses chemogenomics data to predict antibiotic combinations that interact synergistically or antagonistically in inhibiting bacterial growth. INDIGO quantifies the influence of individual chemical-genetic interactions on synergy and antagonism and significantly outperforms existing approaches based on experimental evaluation of novel predictions in Escherichia coli Our analysis revealed a core set of genes and pathways (e.g. central metabolism) that are predictive of antibiotic interactions. By identifying the interactions that are associated with orthologous genes, we successfully estimated drug-interaction outcomes in the bacterial pathogens Mycobacterium tuberculosis and Staphylococcus aureus, using the E. coli INDIGO model. INDIGO thus enables the discovery of effective combination therapies in less-studied pathogens by leveraging chemogenomics data in model organisms. PMID- 27222543 TI - Metabolic Surgery for Type 2 Diabetes: Changing the Landscape of Diabetes Care. PMID- 27222544 TI - Metabolic Surgery in the Treatment Algorithm for Type 2 Diabetes: A Joint Statement by International Diabetes Organizations. AB - BACKGROUND: Despite growing evidence that bariatric/metabolic surgery powerfully improves type 2 diabetes (T2D), existing diabetes treatment algorithms do not include surgical options. AIM: The 2nd Diabetes Surgery Summit (DSS-II), an international consensus conference, was convened in collaboration with leading diabetes organizations to develop global guidelines to inform clinicians and policymakers about benefits and limitations of metabolic surgery for T2D. METHODS: A multidisciplinary group of 48 international clinicians/scholars (75% nonsurgeons), including representatives of leading diabetes organizations, participated in DSS-II. After evidence appraisal (MEDLINE [1 January 2005-30 September 2015]), three rounds of Delphi-like questionnaires were used to measure consensus for 32 data-based conclusions. These drafts were presented at the combined DSS-II and 3rd World Congress on Interventional Therapies for Type 2 Diabetes (London, U.K., 28-30 September 2015), where they were open to public comment by other professionals and amended face-to-face by the Expert Committee. RESULTS: Given its role in metabolic regulation, the gastrointestinal tract constitutes a meaningful target to manage T2D. Numerous randomized clinical trials, albeit mostly short/midterm, demonstrate that metabolic surgery achieves excellent glycemic control and reduces cardiovascular risk factors. On the basis of such evidence, metabolic surgery should be recommended to treat T2D in patients with class III obesity (BMI >=40 kg/m(2)) and in those with class II obesity (BMI 35.0-39.9 kg/m(2)) when hyperglycemia is inadequately controlled by lifestyle and optimal medical therapy. Surgery should also be considered for patients with T2D and BMI 30.0-34.9 kg/m(2) if hyperglycemia is inadequately controlled despite optimal treatment with either oral or injectable medications. These BMI thresholds should be reduced by 2.5 kg/m(2) for Asian patients. CONCLUSIONS: Although additional studies are needed to further demonstrate long term benefits, there is sufficient clinical and mechanistic evidence to support inclusion of metabolic surgery among antidiabetes interventions for people with T2D and obesity. To date, the DSS-II guidelines have been formally endorsed by 45 worldwide medical and scientific societies. Health care regulators should introduce appropriate reimbursement policies. PMID- 27222545 TI - Epidemiology of Diabetes-Status of a Pandemic and Issues Around Metabolic Surgery. AB - The number of people with diabetes worldwide has more than doubled during the past 20 years. One of the most worrying features of this rapid increase is the emergence of type 2 diabetes in children, adolescents, and young adults. Although the role of traditional risk factors for type 2 diabetes, such as genetic, lifestyle, and behavioral risk factors, has been given attention, recent research has focused on identifying the contributions of epigenetic mechanisms and the effect of the intrauterine environment. Epidemiological data predict an inexorable and unsustainable increase in global health expenditure attributable to diabetes, so disease prevention should be given high priority. An integrated approach is needed to prevent type 2 diabetes and must recognize its heterogeneity. Future research needs to be directed at improved understanding of the potential role of determinants, such as the maternal environment and other early life factors, as well as changing trends in global demography, to help shape disease prevention programs. Equally important is a better understanding of the role of metabolic surgery in helping to address the management both of persons with type 2 diabetes and of those persons in the community who are at higher risk for type 2 diabetes, particularly in emerging nations where the diabetes epidemic is in full flight. PMID- 27222546 TI - Roles of the Gut in Glucose Homeostasis. AB - The gastrointestinal tract plays a major role in the regulation of postprandial glucose profiles. Gastric emptying is a highly regulated process, which normally ensures a limited and fairly constant delivery of nutrients and glucose to the proximal gut. The subsequent digestion and absorption of nutrients are associated with the release of a set of hormones that feeds back to regulate subsequent gastric emptying and regulates the release of insulin, resulting in downregulation of hepatic glucose production and deposition of glucose in insulin sensitive tissues. These remarkable mechanisms normally keep postprandial glucose excursions low, regardless of the load of glucose ingested. When the regulation of emptying is perturbed (e.g., pyloroplasty, gastric sleeve or gastric bypass operation), postprandial glycemia may reach high levels, sometimes followed by profound hypoglycemia. This article discusses the underlying mechanisms. PMID- 27222547 TI - Mechanisms of Diabetes Improvement Following Bariatric/Metabolic Surgery. AB - More than 20 years ago, Pories et al. published a seminal article, "Who Would Have Thought It? An Operation Proves to Be the Most Effective Therapy for Adult Onset Diabetes Mellitus." This was based on their observation that bariatric surgery rapidly normalized blood glucose levels in obese people with type 2 diabetes mellitus (T2DM), and 10 years later, almost 90% remained diabetes free. Pories et al. suggested that caloric restriction played a key role and that the relative contributions of proximal intestinal nutrient exclusion, rapid distal gut nutrient delivery, and the role of gut hormones required further investigation. These findings of T2DM improvement/remission after bariatric surgery have been widely replicated, together with the observation that bariatric surgery prevents or delays incident T2DM. Over the ensuing two decades, important glucoregulatory roles of the gastrointestinal (GI) tract have been firmly established. However, the physiological and molecular mechanisms underlying the beneficial glycemic effects of bariatric surgery remain incompletely understood. In addition to the mechanisms proposed by Pories et al., changes in bile acid metabolism, GI tract nutrient sensing and glucose utilization, incretins, possible anti-incretin(s), and the intestinal microbiome are implicated. These changes, acting through peripheral and/or central pathways, lead to reduced hepatic glucose production, increased tissue glucose uptake, improved insulin sensitivity, and enhanced beta-cell function. A constellation of factors, rather than a single overarching mechanism, likely mediate postoperative glycemic improvement, with the contributing factors varying according to the surgical procedure. Thus, different bariatric/metabolic procedures provide us with experimental tools to probe GI tract physiology. Embracing this approach through the application of detailed phenotyping, genomics, metabolomics, and gut microbiome studies will enhance our understanding of metabolic regulation and help identify novel therapeutic targets. PMID- 27222548 TI - Clinical Outcomes of Metabolic Surgery: Efficacy of Glycemic Control, Weight Loss, and Remission of Diabetes. AB - Since the 2007 Diabetes Surgery Summit in Rome, Italy, and the subsequent publishing of the world's first guidelines for the surgical treatment of type 2 diabetes (T2D), much new evidence regarding the efficacy and safety of metabolic surgery has emerged. Additional observational cohort studies support the superior effects of surgery over medical treatment with respect to glycemic control, weight loss, and even reduction in mortality and microvascular complications associated with T2D. Furthermore, new safety data suggest that the perioperative morbidity and mortality of metabolic surgery (5% and 0.3%, respectively) are now similar to that of common low-risk procedures, such as cholecystectomy and hysterectomy. The largest advance, however, has been the completion of 11 randomized controlled trials from around the globe that compare surgery with medical treatment of T2D. These studies with follow-up duration of 1-5 years involve nearly 800 patients without surgical mortality and with major complication rates of less than 5% and a reoperation rate of 8%. All but 1 of the 11 randomized controlled trials have shown the superiority of surgery over medical management at achieving remission or glycemic improvement. Surgery was also superior to medical treatment with respect to improving cardiovascular risk factors, such as weight loss and dyslipidemia, while reducing medication burden. This new efficacy and safety evidence should help guide physicians across the globe to the appropriate use of surgery as an effective treatment for patients suffering from T2D and obesity. PMID- 27222549 TI - Clinical Outcomes of Metabolic Surgery: Microvascular and Macrovascular Complications. AB - Understanding of the long-term clinical outcomes associated with bariatric surgery has recently been advanced. Research related to the sequelae of diabetes in particular, long-term microvascular and macrovascular complications-in patients who undergo weight-loss surgery is imperative to this pursuit. While numerous randomized control trials have assessed glucose control with bariatric surgery compared with intensive medical therapy, bariatric surgery outcome data relating to microvascular and macrovascular complications have been limited to observational studies and nonrandomized clinical trials. As a result, whether bariatric surgery is associated with a long-term reduction in microvascular and macrovascular complications when compared with current intensive glycemic control therapy cannot be determined because the evidence is insufficient. However, the consistent salutary effects of bariatric surgery on diabetes remission and glycemic improvement support the opportunity (and need) to conduct high-quality studies of bariatric surgery versus intensive glucose control. This review provides relevant background information related to the treatment of diabetes, hyperglycemia, and long-term complications; reports clinical findings (to date) with bariatric surgery; and identifies ongoing research focusing on long-term vascular outcomes associated with bariatric surgery. PMID- 27222550 TI - Bariatric/Metabolic Surgery to Treat Type 2 Diabetes in Patients With a BMI <35 kg/m2. AB - OBJECTIVE: Global usage of bariatric surgery has been dictated for the past quarter century by National Institutes of Health recommendations restricting these operations to individuals with a BMI >=35 kg/m(2). Strong evidence now demonstrates that bariatric procedures markedly improve or cause remission of type 2 diabetes mellitus (T2DM), in part through weight-independent mechanisms, and that baseline BMI does not predict surgical benefits on glycemic or cardiovascular outcomes. This impels consideration of such operations as "metabolic surgery," which is used expressly to treat T2DM, including among patients with a BMI <35 kg/m(2) who constitute the majority of people with diabetes worldwide. Here, we review available evidence to inform that consideration. RESULTS: A meta-analysis of the 11 published randomized clinical trials (RCTs) directly comparing bariatric/metabolic surgery versus a variety of medical/lifestyle interventions for T2DM provides level 1A evidence that surgery is superior for T2DM remission, glycemic control, and HbA1c lowering. Importantly, this is equally true for patients whose baseline BMI is below or above 35 kg/m(2). Similar conclusions derive from meta-analyses of high-quality nonrandomized prospective comparisons. Meta-analysis of all pertinent published studies indicates that T2DM remission rates following bariatric/metabolic surgery are comparable above and below the 35 kg/m(2) BMI threshold. The safety, antidiabetes durability, and benefits on other cardiovascular risk factors from bariatric/metabolic surgery appear roughly comparable among patients with a BMI below or above 35 kg/m(2). Further studies are needed to extend long-term findings and measure "hard" macrovascular/microvascular outcomes and mortality in RCTs. CONCLUSIONS: Extant data, including level 1A evidence from numerous RCTs, support new guidelines from the 2nd Diabetes Surgery Summit that advocate for the consideration of bariatric/metabolic surgery as one option, along with lifestyle and medical therapy, to treat T2DM among patients with a BMI <35 kg/m(2). PMID- 27222551 TI - Bariatric Surgery: A Potential Treatment for Type 2 Diabetes in Youth. AB - Type 2 diabetes, once referred to as "adult-onset" diabetes, has now emerged as a formidable threat to the health of obese adolescents. Although there is growing evidence regarding the epidemiology of type 2 diabetes in youth and its multisystem health consequences, treatment options have lagged and progression of disease occurs even with aggressive medical therapy. Increasing interest in the application of bariatric surgery for adolescents with type 2 diabetes has evolved in part because of the evidence demonstrating improvement or remission in many adults with diabetes after surgery. Here, we review the burden of type 2 diabetes in youth including its associated complications, discuss the outcomes and complications of bariatric surgery in adolescents with diabetes, and conclude with recommendations for future research and options for refinement of the use of bariatric surgery in this patient population. PMID- 27222552 TI - Bariatric Surgery in Obese Patients With Type 1 Diabetes. AB - OBJECTIVE: There is a paucity of data on the impact of bariatric surgery in type 1 diabetes (T1D). The aim of this review was to quantify the overall effects of bariatric surgery in obese patients with T1D. METHODS: We searched PubMed, Scopus, ISI Web of Knowledge, and Google Scholar from their inception to December 2015 to identify all relevant studies of bariatric surgery in adult obese patients with T1D. RESULTS: The review included 17 studies with 107 individuals, including 10 case series and 7 case reports. Overall, the dominant procedure was gastric bypass (n = 70; 65%). All studies reported a significant reduction in excess weight. A significant reduction in weight-adjusted daily insulin requirements was shown in all case series except one. Pooled mean +/- SD of pre- and postoperative glycated hemoglobin (HbA1c) for the entire cohort with available data (n = 96) was 8.4 +/- 1.3% and 7.9 +/- 1.1%, respectively (P = 0.01). In addition to common postoperative complications, profound glycemic changes (diabetic ketoacidosis and hypoglycemia) and gastrointestinal dysmotility symptoms (prolonged ileus and acute gastric remnant dilation) have been reported. No surgical mortality was reported. CONCLUSIONS: Bariatric surgery leads to significant weight loss in severely obese patients with T1D and results in a significant improvement in insulin requirements and glycemic status. The favorable metabolic effects of bariatric surgery may facilitate medical management of and cardiovascular risk reduction in T1D in the setting of severe obesity. Diabetic ketoacidosis and hypoglycemia are potentially serious complications. Short-term results of bariatric surgery in patients with T1D are encouraging, but larger and longer-term studies are needed. PMID- 27222553 TI - Ethnic Considerations for Metabolic Surgery. AB - Obesity and diabetes represent twin health concerns in the developed world. Metabolic surgery has emerged as an established and enduring treatment for both obesity and diabetes. As the burden of obesity and diabetes varies upon the basis of ethnicity, it is also apparent that there may be differences for indications and outcomes for different ethnic groups after metabolic surgery. Whereas there appears to be evidence for variation in weight loss and complications for different ethnic groups, comorbidity remission particularly for diabetes appears to be free of ethnic disparity after metabolic surgery. The impacts of access, biology, culture, genetics, procedure, and socioeconomic status upon metabolic surgery outcomes are examined. Further refinement of the influence of ethnicity upon metabolic surgery outcomes is likely imminent. PMID- 27222554 TI - Identifying Barriers to Appropriate Use of Metabolic/Bariatric Surgery for Type 2 Diabetes Treatment: Policy Lab Results. AB - Despite increasing recognition of the efficacy, safety, and cost-effectiveness of bariatric/metabolic surgery in the treatment of type 2 diabetes, few patients who may be appropriate candidates and may benefit from this type of surgery avail themselves of this treatment option. To identify conceptual and practical barriers to appropriate use of surgical procedures, a Policy Lab was hosted at the 3rd World Congress on Interventional Therapies for Type 2 Diabetes on 29 September 2015. Twenty-six stakeholders participated in the Policy Lab, including academics, clinicians, policy-makers, industry leaders, and patient representatives. Participants were provided with a summary of available evidence about the cost-effectiveness of bariatric/metabolic surgery and the costs of increasing the use of bariatric/metabolic surgery, using U.K. and U.S. scenarios as examples of distinct health care systems. There was widespread agreement among this group of stakeholders that bariatric/metabolic surgery is a legitimate and cost-effective approach to the treatment of type 2 diabetes in obese patients. The following four building blocks were identified to facilitate policy changes: 1) communicating the scale of the costs and harms associated with rising prevalence of type 2 diabetes; 2) properly articulating the role of bariatric/metabolic surgery for certain population groups; 3) identifying new funding sources for bariatric/metabolic surgery; and 4) incorporating bariatric/metabolic surgery into the appropriate clinical pathways. Although more research is needed to identify specific clinical scenarios for the prioritization of bariatric/metabolic surgery, the case appears to be strong enough to engage relevant policy-makers and practitioners in a concerted discussion of how to better use metabolic surgical resources in conjunction with other interventions in good diabetes practice. PMID- 27222555 TI - Erratum. A Randomized Controlled Trial of Cognitive Behavioral Therapy for Adherence and Depression (CBT-AD) in Patients With Uncontrolled Type 2 Diabetes. Diabetes Care 2014;37:625-633. PMID- 27222557 TI - Comment on Sjoholm et al. Weight Change-Adjusted Effects of Gastric Bypass Surgery on Glucose Metabolism: 2- and 10-Year Results From the Swedish Obese Subjects (SOS) Study. Diabetes Care 2016;39:625-631. PMID- 27222559 TI - Comment on American Diabetes Association. Approaches to Glycemic Treatment. Sec. 7. In Standards of Medical Care in Diabetes-2016. Diabetes Care 2016;39(Suppl. 1):S52-S59. PMID- 27222558 TI - Response to Comment on Sjoholm et al. Weight Change-Adjusted Effects of Gastric Bypass Surgery on Glucose Metabolism: 2- and 10-Year Results From the Swedish Obese Subjects (SOS) Study. Diabetes Care 2016;39:625-631. PMID- 27222560 TI - Response to Comment on American Diabetes Association. Approaches to Glycemic Treatment. Sec. 7. In Standards of Medical Care in Diabetes-2016. Diabetes Care 2016;39(Suppl. 1):S52-S59. PMID- 27222561 TI - Nebulised hypertonic saline may be less effective than previously reported in reducing hospital length of stay and admission rate in acute bronchiolitis. PMID- 27222563 TI - Science and Culture: High-tech tries to reveal artistic motivations. PMID- 27222564 TI - Inner Workings: Ancient teeth reveal clues about microbiome evolution. PMID- 27222567 TI - Janvier et al (J Infect Dis 2015; 212:1208-9). PMID- 27222568 TI - Yen et al (J Infect Dis 2012; 206:41-8). PMID- 27222566 TI - Improving our fundamental understanding of the role of aerosol-cloud interactions in the climate system. AB - The effect of an increase in atmospheric aerosol concentrations on the distribution and radiative properties of Earth's clouds is the most uncertain component of the overall global radiative forcing from preindustrial time. General circulation models (GCMs) are the tool for predicting future climate, but the treatment of aerosols, clouds, and aerosol-cloud radiative effects carries large uncertainties that directly affect GCM predictions, such as climate sensitivity. Predictions are hampered by the large range of scales of interaction between various components that need to be captured. Observation systems (remote sensing, in situ) are increasingly being used to constrain predictions, but significant challenges exist, to some extent because of the large range of scales and the fact that the various measuring systems tend to address different scales. Fine-scale models represent clouds, aerosols, and aerosol-cloud interactions with high fidelity but do not include interactions with the larger scale and are therefore limited from a climatic point of view. We suggest strategies for improving estimates of aerosol-cloud relationships in climate models, for new remote sensing and in situ measurements, and for quantifying and reducing model uncertainty. PMID- 27222576 TI - Proton-hydride tautomerism in hydrogen evolution catalysis. AB - Efficient generation of hydrogen from renewable resources requires development of catalysts that avoid deep wells and high barriers. Information about the energy landscape for H2 production can be obtained by chemical characterization of catalytic intermediates, but few have been observed to date. We have isolated and characterized a key intermediate in 2e(-) + 2H(+) -> H2 catalysis. This intermediate, obtained by treatment of Cp*Rh(bpy) (Cp*, eta(5) pentamethylcyclopentadienyl; bpy, kappa(2)-2,2'-bipyridyl) with acid, is not a hydride species but rather, bears [eta(4)-Cp*H] as a ligand. Delivery of a second proton to this species leads to evolution of H2 and reformation of eta(5)-Cp* bound to rhodium(III). With suitable choices of acids and bases, the Cp*Rh(bpy) complex catalyzes facile and reversible interconversion of H(+) and H2. PMID- 27222577 TI - Phosphoinositide 5- and 3-phosphatase activities of a voltage-sensing phosphatase in living cells show identical voltage dependence. AB - Voltage-sensing phosphatases (VSPs) are homologs of phosphatase and tensin homolog (PTEN), a phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2] and phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] 3-phosphatase. However, VSPs have a wider range of substrates, cleaving 3-phosphate from PI(3,4)P2 and probably PI(3,4,5)P3 as well as 5-phosphate from phosphatidylinositol 4,5 bisphosphate [PI(4,5)P2] and PI(3,4,5)P3 in response to membrane depolarization. Recent proposals say these reactions have differing voltage dependence. Using Forster resonance energy transfer probes specific for different PIs in living cells with zebrafish VSP, we quantitate both voltage-dependent 5- and 3 phosphatase subreactions against endogenous substrates. These activities become apparent with different voltage thresholds, voltage sensitivities, and catalytic rates. As an analytical tool, we refine a kinetic model that includes the endogenous pools of phosphoinositides, endogenous phosphatase and kinase reactions connecting them, and four exogenous voltage-dependent 5- and 3 phosphatase subreactions of VSP. We show that apparent voltage threshold differences for seeing effects of the 5- and 3-phosphatase activities in cells are not due to different intrinsic voltage dependence of these reactions. Rather, the reactions have a common voltage dependence, and apparent differences arise only because each VSP subreaction has a different absolute catalytic rate that begins to surpass the respective endogenous enzyme activities at different voltages. For zebrafish VSP, our modeling revealed that 3-phosphatase activity against PI(3,4,5)P3 is 55-fold slower than 5-phosphatase activity against PI(4,5)P2; thus, PI(4,5)P2 generated more slowly from dephosphorylating PI(3,4,5)P3 might never accumulate. When 5-phosphatase activity was counteracted by coexpression of a phosphatidylinositol 4-phosphate 5-kinase, there was accumulation of PI(4,5)P2 in parallel to PI(3,4,5)P3 dephosphorylation, emphasizing that VSPs can cleave the 3-phosphate of PI(3,4,5)P3. PMID- 27222578 TI - Typhoid toxin provides a window into typhoid fever and the biology of Salmonella Typhi. AB - Salmonella Typhi is the cause of typhoid fever, a disease that has challenged humans throughout history and continues to be a major public health concern. Unlike infections with most other Salmonellae, which result in self-limiting gastroenteritis, typhoid fever is a life-threatening systemic disease. Furthermore, in contrast to most Salmonellae, which can infect a broad range of hosts, S. Typhi is a strict human pathogen. The unique features of S. Typhi pathogenesis and its stringent host specificity have been a long-standing puzzle. The discovery of typhoid toxin not only has provided major insight into these questions but also has offered unique opportunities to develop novel therapeutic and prevention strategies to combat typhoid fever. PMID- 27222579 TI - Search for supersolidity in solid 4He using multiple-mode torsional oscillators. AB - In 2004, Kim and Chan (KC) reported a decrease in the period of torsional oscillators (TO) containing samples of solid (4)He, as the temperature was lowered below 0.2 K [Kim E, Chan MHW (2004) Science 305(5692):1941-1944]. These unexpected results constituted the first experimental evidence that the long predicted supersolid state of solid (4)He may exist in nature. The KC results were quickly confirmed in a number of other laboratories and created great excitement in the low-temperature condensed-matter community. Since that time, however, it has become clear that the period shifts seen in the early experiments can in large part be explained by an increase in the shear modulus of the (4)He solid identified by Day and Beamish [Day J, Beamish J (2007) Nature 450(7171):853 856]. Using multiple-frequency torsional oscillators, we can separate frequency dependent period shifts arising from changes in the elastic properties of the solid (4)He from possible supersolid signals, which are expected to be independent of frequency. We find in our measurements that as the temperature is lowered below 0.2 K, a clear frequency-dependent contribution to the period shift arising from changes in the (4)He elastic properties is always present. For all of the cells reported in this paper, however, there is always an additional small frequency-independent contribution to the total period shift, such as would be expected in the case of a transition to a supersolid state. PMID- 27222580 TI - Cellular folding pathway of a metastable serpin. AB - Although proteins generally fold to their thermodynamically most stable state, some metastable proteins populate higher free energy states. Conformational changes from metastable higher free energy states to lower free energy states with greater stability can then generate the work required to perform physiologically important functions. However, how metastable proteins fold to these higher free energy states in the cell and avoid more stable but inactive conformations is poorly understood. The serpin family of metastable protease inhibitors uses large conformational changes that are downhill in free energy to inhibit target proteases by pulling apart the protease active site. The serpin antithrombin III (ATIII) targets thrombin and other proteases involved in blood coagulation, and ATIII misfolding can thus lead to thrombosis and other diseases. ATIII has three disulfide bonds, two near the N terminus and one near the C terminus. Our studies of ATIII in-cell folding reveal a surprising, biased order of disulfide bond formation, with early formation of the C-terminal disulfide, before formation of the N-terminal disulfides, critical for folding to the active, metastable state. Early folding of the predominantly beta-sheet ATIII domain in this two-domain protein constrains the reactive center loop (RCL), which contains the protease-binding site, ensuring that the RCL remains accessible. N-linked glycans and carbohydrate-binding molecular chaperones contribute to the efficient folding and secretion of functional ATIII. The inability of a number of disease-associated ATIII variants to navigate the folding reaction helps to explain their disease phenotypes. PMID- 27222581 TI - Molecular tandem repeat strategy for elucidating mechanical properties of high strength proteins. AB - Many globular and structural proteins have repetitions in their sequences or structures. However, a clear relationship between these repeats and their contribution to the mechanical properties remains elusive. We propose a new approach for the design and production of synthetic polypeptides that comprise one or more tandem copies of a single unit with distinct amorphous and ordered regions. Our designed sequences are based on a structural protein produced in squid suction cups that has a segmented copolymer structure with amorphous and crystalline domains. We produced segmented polypeptides with varying repeat number, while keeping the lengths and compositions of the amorphous and crystalline regions fixed. We showed that mechanical properties of these synthetic proteins could be tuned by modulating their molecular weights. Specifically, the toughness and extensibility of synthetic polypeptides increase as a function of the number of tandem repeats. This result suggests that the repetitions in native squid proteins could have a genetic advantage for increased toughness and flexibility. PMID- 27222582 TI - Lassoing saddle splay and the geometrical control of topological defects. AB - Systems with holes, such as colloidal handlebodies and toroidal droplets, have been studied in the nematic liquid crystal (NLC) 4-cyano-4'-pentylbiphenyl (5CB): Both point and ring topological defects can occur within each hole and around the system while conserving the system's overall topological charge. However, what has not been fully appreciated is the ability to manipulate the hole geometry with homeotropic (perpendicular) anchoring conditions to induce complex, saddle like deformations. We exploit this by creating an array of holes suspended in an NLC cell with oriented planar (parallel) anchoring at the cell boundaries. We study both 5CB and a binary mixture of bicyclohexane derivatives (CCN-47 and CCN 55). Through simulations and experiments, we study how the bulk saddle deformations of each hole interact to create defect structures, including an array of disclination lines, reminiscent of those found in liquid-crystal blue phases. The line locations are tunable via the NLC elastic constants, the cell geometry, and the size and spacing of holes in the array. This research lays the groundwork for the control of complex elastic deformations of varying length scales via geometrical cues in materials that are renowned in the display industry for their stability and easy manipulability. PMID- 27222583 TI - Single-cell twitching chemotaxis in developing biofilms. AB - Bacteria form surface-attached communities, known as biofilms, which are central to bacterial biology and how they affect us. Although surface-attached bacteria often experience strong chemical gradients, it remains unclear whether single cells can effectively perform chemotaxis on surfaces. Here we use microfluidic chemical gradients and massively parallel automated tracking to study the behavior of the pathogen Pseudomonas aeruginosa during early biofilm development. We show that individual cells can efficiently move toward chemoattractants using pili-based "twitching" motility and the Chp chemosensory system. Moreover, we discovered the behavioral mechanism underlying this surface chemotaxis: Cells reverse direction more frequently when moving away from chemoattractant sources. These corrective maneuvers are triggered rapidly, typically before a wayward cell has ventured a fraction of a micron. Our work shows that single bacteria can direct their motion with submicron precision and reveals the hidden potential for chemotaxis within bacterial biofilms. PMID- 27222584 TI - Analysis of complex neural circuits with nonlinear multidimensional hidden state models. AB - A universal need in understanding complex networks is the identification of individual information channels and their mutual interactions under different conditions. In neuroscience, our premier example, networks made up of billions of nodes dynamically interact to bring about thought and action. Granger causality is a powerful tool for identifying linear interactions, but handling nonlinear interactions remains an unmet challenge. We present a nonlinear multidimensional hidden state (NMHS) approach that achieves interaction strength analysis and decoding of networks with nonlinear interactions by including latent state variables for each node in the network. We compare NMHS to Granger causality in analyzing neural circuit recordings and simulations, improvised music, and sociodemographic data. We conclude that NMHS significantly extends the scope of analyses of multidimensional, nonlinear networks, notably in coping with the complexity of the brain. PMID- 27222585 TI - Enhanced thermopower in ZnO two-dimensional electron gas. AB - Control of dimensionality has proven to be an effective way to manipulate the electronic properties of materials, thereby enabling exotic quantum phenomena, such as superconductivity, quantum Hall effects, and valleytronic effects. Another example is thermoelectricity, which has been theoretically proposed to be favorably controllable by reducing the dimensionality. Here, we verify this proposal by performing a systematic study on a gate-tuned 2D electron gas (2DEG) system formed at the surface of ZnO. Combining state-of-the-art electric-double layer transistor experiments and realistic tight-binding calculations, we show that, for a wide range of carrier densities, the 2DEG channel comprises a single subband, and its effective thickness can be reduced to [Formula: see text] 1 nm at sufficiently high gate biases. We also demonstrate that the thermoelectric performance of the 2DEG region is significantly higher than that of bulk ZnO. Our approach opens up a route to exploit the peculiar behavior of 2DEG electronic states and realize thermoelectric devices with advanced functionalities. PMID- 27222586 TI - High Ki67/BCL2 index is associated with worse outcome in early stage breast cancer. AB - AIMS: Breast cancers are heterogeneous, making it essential to recognise several biomarkers for cancer outcome predictions. Ki67 proliferation index and B cell lymphoma 2 (BCL2) proteins are widely used as prognostic indicators in many types of malignancies. While Ki67 is a marker of normal or tumour cell proliferation, BCL2 plays a central role in antiproliferative activities. A combination of these two biomarkers with contrary purposes can provide enhanced prognostic accuracy than an analysis using a single biomarker. METHODS: We evaluated Ki67 and BCL2 expression with 203 cases of breast cancer. The relative expression of each biomarker named as Ki67/BCL2 index was divided into two groups (low vs high) with the use of area under receiver operating characteristic curves. RESULTS: There were significant correlations between Ki67/BCL2 index and clinicopathological findings such as age, tumour stage, size and necrosis, histological grade, extensive intraductal component, lymphatic and vascular invasion, oestrogen receptor, progesterone receptor, human epithelial growth factor receptor 2 and p53 expression (all p<0.05). In univariate and multivariate analyses, high Ki67/BCL2 index correlated with shorter disease-free survival and overall survival in patients with early stage invasive ductal carcinoma (all p<0.05). CONCLUSIONS: The Ki67/BCL2 index should be considered as a prognostic predictor in patients with early stage invasive ductal carcinoma. PMID- 27222588 TI - The hospital drawings of Barbara Hepworth. PMID- 27222587 TI - Gastric adenocarcinoma: the role of Helicobacter pylori in pathogenesis and prevention efforts. AB - Gastric cancer is the third most common cause of cancer deaths in the world, prompting high-risk countries like South Korea and Japan to establish nationwide screening programmes. Helicobacter pylori is linked to the majority of gastric adenocarcinoma cases and to the vast majority of non-cardia gastric adenocarcinomas. Several studies have demonstrated the effectiveness of 'test-and treat' programmes for H. pylori infection to prevent gastric cancer in high-risk populations. While this strategy has gained momentum, providers in low-risk developed countries may be unaware of the risk individual patients face, particularly those who have emigrated from high-risk regions and members of economically disadvantaged minority groups. Rapidly evolving science in recent years has made it difficult for clinicians to keep up with the current best practices. This article reviews the epidemiology of H. pylori and gastric cancer, screening and diagnostic tests and the current treatment regimens for clinicians. PMID- 27222589 TI - Foxa2 and Hif1ab regulate maturation of intestinal goblet cells by modulating agr2 expression in zebrafish embryos. AB - Mammalian anterior gradient 2 (AGR2), an endoplasmic reticulum (ER) protein disulfide-isomerase (PDI), is involved in cancer cell growth and metastasis, asthma and inflammatory bowel disease (IBD). Mice lacking Agr2 exhibit decreased Muc2 protein in intestinal goblet cells, abnormal Paneth cell development, ileitis and colitis. Despite its importance in cancer biology and inflammatory diseases, the mechanisms regulating agr2 expression in the gastrointestinal tract remain unclear. In the present study, we investigated the mechanisms that control agr2 expression in the pharynx and intestine of zebrafish by transient/stable transgenesis, coupled with motif mutation, morpholino knockdown, mRNA rescue and ChIP. A 350 bp DNA sequence with a hypoxia-inducible response element (HRE) and forkhead-response element (FHRE) within a region -4.5 to -4.2 kbp upstream of agr2 directed EGFP expression specifically in the pharynx and intestine. No EGFP expression was detected in the intestinal goblet cells of Tg(HREM:EGFP) or Tg(FHREM:EGFP) embryos with mutated HRE or FHRE, whereas EGFP was expressed in the pharynx of Tg(HREM:EGFP), but not Tg(FHREM:EGFP), embryos. Morpholino knockdown of foxa1 (forkhead box A1) reduced agr2 levels in the pharynx, whereas knockdown of foxa2 or hif1ab decreased intestinal agr2 expression and affected the differentiation and maturation of intestinal goblet cells. These results demonstrate that Foxa1 regulates agr2 expression in the pharynx, whereas both Foxa2 and Hif1ab control agr2 expression in intestinal goblet cells to regulate maturation of these cells. PMID- 27222590 TI - Complexin splits the membrane-proximal region of a single SNAREpin. AB - Complexin (Cpx) is thought to be a major regulator of soluble N-ethylmaleimide sensitive factor-attachment protein receptor (SNARE)-dependent membrane fusion. Although the inhibition of membrane fusion by Cpx has been frequently reported, its structural basis has been elusive and an anticipated disruption of the SNARE core has never been observed. In the present study, to mimic the natural environment, we assembled a single SNAREpin between two nanodisc membrane patches. Single-molecule FRET (smFRET) detects a large conformational change, specifically at the C-terminal half, whereas no conformational change is observed at the N-terminal half. Our results suggest that Cpx splits the C-terminal half of the SNARE core at least 10 A (1 A=0.1 nm), whereby inhibiting further progression of SNARE zippering and membrane fusion. PMID- 27222592 TI - Systolic flow displacement using 3D magnetic resonance imaging in an experimental model of ascending aorta aneurysm: impact of rheological factors. AB - OBJECTIVES: The impact of systolic flow displacement on the development and progression of ascending aorta dilatation in aortic valve disease is a matter of controversy. Our objective was to study the association between rheological stimuli and development of aortic dilatation in a large animal model of supravalvular aortic stenosis and eccentric flow. METHODS: Twenty-four pigs weighing 10-14 kg were randomly allocated (ratio 2:1) to either restrictive ascending aortic banding or sham operation. Aortic diameter and systolic flow displacement were assessed by three-dimensional phase-contrast magnetic resonance imaging at 6 and 18 weeks after surgery. Twenty pigs (n = 14, banded vs n = 6, sham) completed full imaging protocol and were included in the analysis. After the last follow-up, a subset of 14 animals was sacrificed for histological analysis. RESULTS: All banded animals developed significant progressive aortic dilatation both at 6 and 18 weeks, compared with sham-operated pigs: 34.3 +/- 4.8 vs 21.4 +/- 2.7 mm at 6 weeks (P < 0.001); and 50.0 +/- 8.4 vs 38.0 +/- 8.3 mm at 18 weeks (P = 0.002). The peak gradient at 6 weeks showed a trend to positively correlate with aortic diameter at 18 weeks (R = 0.50, P = 0.06), whereas the systolic flow displacement at 6 weeks correlated better with aortic diameter at 18 weeks (R = 0.59, P = 0.02). The aortic wall thickness was significantly decreased in the anterior aortic section in banded, compared with sham-operated, pigs (1.5 +/- 0.4 vs 2.0 +/- 0.1 mm, respectively; P = 0.03). In addition, banded pigs showed a higher degree of cystic medial necrosis and elastin fibre fragmentation, compared with sham-operated animals. CONCLUSIONS: In this preclinical model of supravalvular aortic stenosis and eccentric flow, we found that systolic flow displacement at earlier stages is positively correlated with the degree of aortic dilatation during follow-up as assessed by three-dimensional phase-contrast magnetic resonance imaging. If our findings are confirmed in further studies, this imaging parameter might be useful to identify those subjects with aortic valve disease who are at risk of developing aortic dilatation at a later stage. PMID- 27222594 TI - Segment-specific regulation of epididymal gene expression. AB - The epididymis is necessary for post-testicular sperm maturation. During their epididymal transit, spermatozoa gain ability for progressive movement and fertilization. The epididymis is composed of several segments that have distinct gene expression profiles that enable the establishment of the changing luminal environment required for sperm maturation. The epididymal gene expression is regulated by endocrine, lumicrine, and paracrine factors in a segment-specific manner. Thus, in addition to its importance for male fertility, the epididymis is a valuable model tissue for studying the regulation of gene expression. This review concentrates on recent advances in understanding the androgen, small RNA, and epigenetically mediated regulation of segment-specific gene expression in the epididymis. PMID- 27222593 TI - Evaluation of the association between Hospital Survey on Patient Safety Culture (HSOPS) measures and catheter-associated infections: results of two national collaboratives. AB - BACKGROUND: The Agency for Healthcare Research and Quality (AHRQ) has funded national collaboratives using the Comprehensive Unit-based Safety Program to reduce rates of two catheter-associated infections-central-line-associated bloodstream infection (CLABSI) and catheter-associated urinary tract infection (CAUTI), using evidence-based intervention bundles to improve technical aspects of care and socioadaptive approaches to foster a culture of safety. OBJECTIVE: Examine the association between hospital units' results for the Hospital Survey on Patient Safety Culture (HSOPS) and catheter-associated infection rates. METHODS: We analysed data from two prospective cohort studies from acute-care intensive care units (ICUs) and non-ICUs participating in the AHRQ CLABSI and CAUTI collaboratives. National Healthcare Safety Network catheter-associated infections per 1000 catheter-days were collected at baseline and quarterly postimplementation. The HSOPS was collected at baseline and again 1 year later. Infection rates were modelled using multilevel negative binomial models as a function of HSOPS components over time, adjusted for hospital-level characteristics. RESULTS: 1821 units from 1079 hospitals (CLABSI) and 1576 units from 949 hospitals (CAUTI) were included. Among responding units, infection rates declined over the project periods (by 47% for CLABSI, by 23% for CAUTI, unadjusted). No significant associations were found between CLABSI or CAUTI rates and HSOPS measures at baseline or over time. CONCLUSIONS: We found no association between results of the HSOPS and catheter-associated infection rates when measured at baseline and postintervention in two successful large national collaboratives focused on prevention of CLABSI and CAUTI. These results suggest that it may be possible to improve CLABSI and CAUTI rates without making significant changes in safety culture, particularly as measured by instruments like HSOPS. PMID- 27222595 TI - Synthesis and reception of prostaglandins in corpora lutea of domestic cat and lynx. AB - Felids show different reproductive strategies related to the luteal phase. Domestic cats exhibit a seasonal polyoestrus and ovulation is followed by formation of corpora lutea (CL). Pregnant and non-pregnant cycles are reflected by diverging plasma progesterone (P4) profiles. Eurasian and Iberian lynxes show a seasonal monooestrus, in which physiologically persistent CL (perCL) support constantly elevated plasma P4 levels. Prostaglandins (PGs) represent key regulators of reproduction, and we aimed to characterise PG synthesis in feline CL to identify their contribution to the luteal lifespan. We assessed mRNA and protein expression of PG synthases (PTGS2/COX2, PTGES, PGFS/AKR1C3) and PG receptors (PTGER2, PTGER4, PTGFR), and intra-luteal levels of PGE2 and PGF2alpha Therefore, CL of pregnant (pre-implantation, post-implantation, regression stages) and non-pregnant (formation, development/maintenance, early regression, late regression stages) domestic cats, and prooestrous Eurasian (perCL, pre mating) and metoestrous Iberian (perCL, freshCL, post-mating) lynxes were investigated. Expression of PTGS2/COX2, PTGES and PTGER4 was independent of the luteal stage in the investigated species. High levels of luteotrophic PGE2 in perCL might be associated with persistence of luteal function in lynxes. Signals for PGFS/AKR1C3 expression were weak in mid and late luteal stages of cats but were absent in lynxes, concomitant with low PGF2alpha levels in these species. Thus, regulation of CL regression by luteal PGF2alpha seems negligible. In contrast, expression of PTGFR was evident in nearly all investigated CL of cat and lynxes, implying that luteal regression, e.g. at the end of pregnancy, is triggered by extra-luteal PGF2alpha. PMID- 27222596 TI - Regulation of fibrillins and modulators of TGFbeta in fetal bovine and human ovaries. AB - Fibrillins 1-3 are stromal extracellular matrix proteins that play important roles in regulating TGFbeta activity, which stimulates fibroblasts to proliferate and synthesize collagen. In the developing ovary, the action of stroma is initially necessary for the formation of ovigerous cords and subsequently for the formation of follicles and the surface epithelium of the ovary. FBN3 is highly expressed only in early ovarian development and then it declines. In contrast, FBN1 and 2 are upregulated in later ovarian development. We examined the expression of FBN1-3 in bovine and human fetal ovaries. We used cell dispersion and monolayer culture, cell passaging and tissue culture. Cells were treated with growth factors, hormones or inhibitors to assess the regulation of expression of FBN1-3 When bovine fetal ovarian tissue was cultured, FBN3 expression declined significantly. Treatment with TGFbeta-1 increased FBN1 and FBN2 expression in bovine fibroblasts, but did not affect FBN3 expression. Additionally, in cultures of human fetal ovarian fibroblasts (9-17weeks gestational age), the expression of FBN1 and FBN2 increased with passage, whereas FBN3 dramatically decreased. Treatment with activin A and a TGFbeta family signaling inhibitor, SB431542, differentially regulated the expression of a range of modulators of TGFbeta signaling and of other growth factors in cultured human fetal ovarian fibroblasts suggesting that TGFbeta signaling is differentially involved in the regulation of ovarian fibroblasts. Additionally, since the changes in FBN1-3 expression that occur in vitro are those that occur with increasing gestational age in vivo, we suggest that the fetal ovarian fibroblasts mature in vitro. PMID- 27222597 TI - Androgen receptor and miRNA-126* axis controls follicle-stimulating hormone receptor expression in porcine ovarian granulosa cells. AB - Androgen, which acts via the androgen receptor (AR), plays crucial roles in mammalian ovarian function. Recent studies showed that androgen/AR signaling regulates follicle-stimulating hormone receptor (FSHR) expression in follicles; however, the detailed mechanism underlying this regulation remained unknown. Here, we demonstrate that AR and miR-126* cooperate to inhibit FSHR expression and function in pig follicular granulosa cells (pGCs). In pGCs, overexpression of AR decreased, whereas knockdown increased, FSHR mRNA and protein expression; however, neither manipulation affected FSHR promoter activity. Using a dual luciferase reporter assay, we found that the FSHR gene is a direct target of miR 126*, which inhibits FSHR expression and increases the rate of AR-induced apoptosis in pGCs. Collectively, our data show for the first time that the AR/miR 126* axis exerts synergetic effects in the regulation of FSHR expression and apoptosis in pGCs. Our findings thus define a novel pathway, AR/miR-126*/FSHR, that regulates mammalian GC functions. PMID- 27222599 TI - Effect of Fiber Crimp on the Elasticity of Random Fiber Networks With and Without Embedding Matrices. AB - Fiber networks are assemblies of one-dimensional elements representative of materials with fibrous microstructures such as collagen networks and synthetic nonwovens. The mechanics of random fiber networks has been the focus of numerous studies. However, fiber crimp has been explicitly represented only in few cases. In the present work, the mechanics of cross-linked networks with crimped athermal fibers, with and without an embedding elastic matrix, is studied. The dependence of the effective network stiffness on the fraction of nonstraight fibers and the relative crimp amplitude (or tortuosity) is studied using finite element simulations of networks with sinusoidally curved fibers. A semi-analytic model is developed to predict the dependence of network modulus on the crimp amplitude and the bounds of the stiffness reduction associated with the presence of crimp. The transition from the linear to the nonlinear elastic response of the network is rendered more gradual by the presence of crimp, and the effect of crimp on the network tangent stiffness decreases as strain increases. If the network is embedded in an elastic matrix, the effect of crimp becomes negligible even for very small, biologically relevant matrix stiffness values. However, the distribution of the maximum principal stress in the matrix becomes broader in the presence of crimp relative to the similar system with straight fibers, which indicates an increased probability of matrix failure. PMID- 27222600 TI - Control of Magnetic Bearings for Rotor Unbalance With Plug-In Time-Varying Resonators. AB - Rotor unbalance, common phenomenon of rotational systems, manifests itself as a periodic disturbance synchronized with the rotor's angular velocity. In active magnetic bearing (AMB) systems, feedback control is required to stabilize the open-loop unstable electromagnetic levitation. Further, feedback action can be added to suppress the repeatable runout but maintain closed-loop stability. In this paper, a plug-in time-varying resonator is designed by inverting cascaded notch filters. This formulation allows flexibility in designing the internal model for appropriate disturbance rejection. The plug-in structure ensures that stability can be maintained for varying rotor speeds. Experimental results of an AMB-rotor system are presented. PMID- 27222598 TI - Developmental programming: postnatal estradiol modulation of prenatally organized reproductive neuroendocrine function in sheep. AB - Gestational testosterone (TS) excess, acting via both the androgenic and estrogenic pathways, advances puberty and disrupts the neuroendocrine estradiol (E2) feedback and periovulatory hormonal dynamics in female sheep. These prenatally programmed defects may be subject to postnatal modifications by continued organizational and/or activational effects of steroids. This study investigated (1) the organizational contribution of prenatal estrogen excess and (2) the impact of postnatal exposure to E2 in modulating the effects of prenatal androgen excess (TS and dihydrotestosterone (DHT)) on puberty, neuroendocrine feedback mechanisms, and periovulatory hormonal dynamics in sheep. Pregnant Suffolk sheep were treated with TS, DHT, E2, or E2 plus DHT (ED) from days 30 to 90 of gestation. A subset of the control (C), TS, and DHT female offspring received a constant-release E2 implant postnatally. Findings revealed that (1) prenatal E2-treatment failed to reproduce the neuroendocrine disruptions predicted to be programmed by the estrogenic pathway and (2) prenatal E2D treatment did not adequately replicate the reproductive neuroendocrine defects induced by prenatal TS excess. More importantly, continuous postnatal E2 treatment, while delaying the onset of puberty and reducing the inhibitory effects of E2 on tonic luteinizing hormone (LH) release, failed to amplify the E2 positive feedback and periovulatory defects induced by prenatal TS-treatment. Our results indicate that disruptions in E2-positive feedback mechanisms and periovulatory gonadotropin secretion induced by prenatal TS-treatment are programmed predominantly during the prenatal life with postnatal exposure to E2 excess not contributing further to these disruptions. PMID- 27222601 TI - Search for Compounds with Hypoglycemic Activity in the Series of 1-[2-(1H Tetrazol-5-yl)-R(1)-phenyl]-3-R(2)-phenyl(ethyl)ureas and R(1)-Tetrazolo[1,5 c]quinazolin-5(6H)-ones. AB - Methods of 1-[2-(1H-tetrazol-5-yl)-R(1)-phenyl]-3-R(2)-phenyl(ethyl)ureas and R(1)-tetrazolo[1,5-c]quinazolin-5(6H)-ones synthesis were designed. IR, LC-MS, (1)H NMR, and elemental analysis data evaluated the structure and purity of the obtained compounds. Different products, depending on the reaction conditions, were distinguished and discussed. The preliminary hypoglycemic activity of 36 synthesized compounds was revealed. Docking studies to 11beta-hydroxysteroid dehydrogenase 1, gamma-peroxisome proliferator-activated receptor, and dipeptidyl peptidase-4 were conducted. Eight of these substances were further tested on glucocorticoid-induced insulin resistance models, namely glucose tolerance, oral rapid insulin, and adrenalin tests. One of the most active compounds turned out to be tetrazolo[1,5-c]quinazolin-5(6H)-one 3.1, exceeding the reference drugs Metformin (50 and 200 mg/kg) and Gliclazide (50 mg/kg). PMID- 27222602 TI - Synthesis and Biological Activity of New [1,3]Thiazolo[4,5-d]pyridazin-4(5H) ones. AB - A series of novel 2-(N-pyrrolidino, N-piperidino or N-morpholino)-7-phenyl(alpha furoyl or alpha-thienyl)-[1,3]thiazolo[4,5-d]pyridazinones 10a-c, 14-16a,b was synthesized in 78-87% yields via the reaction of methyl 5-benzoyl(alpha-furoyl or alpha-thienyl)-2-aminosubstituted-thiazol-4-carboxylates 9a-c, 13a-e with hydrazine. These new compounds have been tested for their in vivo analgesic and anti-inflammatory activities. All compounds have been characterized by (1)H-NMR, (13)C-NMR spectroscopy, and liquid chromatography-mass spectrometry. PMID- 27222603 TI - Synthesis and Characterization of Compounds Related to Lisinopril. AB - Lisinopril is a drug of the angiotensin-converting enzyme (ACE) inhibitor class that is primarily used in the treatment of hypertension. During the scale-up of the lisinopril process, one unknown impurity was observed and is identified. The present work describes the origin, synthesis, characterization, and control of this impurity. This paper also describes the synthesis and characterization of three other impurities listed in the European Pharmacopoeia 8.4 (Impurity C, D, and F). PMID- 27222604 TI - Development and Validation of a Stability-Indicating RP-HPLC Method for the Assay of Pristinamycin in Bulk and Tablet Dosage Form. AB - Pristinamycin is an antibiotic used mainly in the treatment of Staphylococcus infections. The aim of this study was to develop a rapid and simple stability indicating RP-HPLC method for the determination of pristinamycin in tablet dosage form. Pristinamycin was eluted on the ACE-5, C18-HL, 250 x 4.6 mm, 5 um analytical column with a mobile phase consisting of 0.2% orthophosphoric acid and acetonitrile 63:37 v/v, pumped at 1.5 ml/min flow rate. The column was maintained at 40 degrees C and 10 MUl of the solutions were injected. UV detection was performed at 206 nm. The procedure separated pristinamycin and its potential degradation products in an overall analysis time of less than 10 min with pristinamycin eluting at about 3 min. The method was validated according to the regulatory guidelines with respect to specificity, precision, accuracy, linearity, and robustness. Forced degradation studies were also performed for pristinamycin bulk drug samples to demonstrate the stability-indicating power of the HPLC method. The % RSD of system precision and method precision was found to be 0.64 and 1.49%, respectively. The procedure provided a linear response over the concentration range 25-150 MUg/ml (r = 0.9998). Finally, the applicability of the method was evaluated in the tablet dosage form as well as in stability samples. PMID- 27222605 TI - Effect of Nicotinamide on the Photolysis of Riboflavin in Aqueous Solution. AB - The photolysis of riboflavin (RF) in aqueous solution in the presence of nicotinamide (NA) by visible light has been studied in the pH range 1.0-12.0 and the various photoproducts have been identified as known compounds. RF has been determined in degraded solutions by a specific multicomponent spectrometric method in the presence of its photoproducts and NA. The second-order rate constants (k 2) for the bimolecular interaction of RF and NA range from 0.54 (pH 1.0) to 9.66 M(-1) min(-1) (pH 12.0). The log k 2-pH profile for the photolysis reaction follows a sigmoid curve showing a gradual increase in the rate of pH due to a change in the ionization behavior of the molecule. The lower rate in the acid region is probably due to protonation of the molecule since the cationic form of RF is less susceptible to photolysis than the neutral form. Similarly, a slowing of the rate in the alkaline region is due to anion formation of the molecule. NA is involved as an electron acceptor during the sequence of reactions and thus enhances the rate of photolysis of RF. Absorption and fluorescence measurements did not provide evidence for the complex formation between the two compounds under the present conditions. PMID- 27222591 TI - 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). PMID- 27222606 TI - High-Performance Liquid Chromatographic and High-Performance Thin-Layer Chromatographic Method for the Quantitative Estimation of Dolutegravir Sodium in Bulk Drug and Pharmaceutical Dosage Form. AB - Simple, sensitive, precise, and specific high-performance liquid chromategraphic (HPLC) and high-performance thin-layer chromatographic (HPTLC) methods for the determination of dolutegravir sodium in bulk drug and pharmaceutical dosage form were developed and validated. In the HPLC method, analysis of the drug was carried out on the ODS C18 column (150 * 4.6 mm, 5 MUm particle size) using a mixture of acetonitrile: water (pH 7.5) in the ratio of 80:20 v/v as the mobile phase at the flow rate 1 mL/min at 260 nm. This method was found to be linear in the concentration range of 5-35 MUg/mL. The peak for dolutegravir sodium was observed at 3.0 +/- 0.1 minutes. In the HPTLC method, analysis was performed on aluminum-backed plates pre-coated with silica gel G60 F254 using methanol: chloroform: formic acid in the proportion of 8:2:0.5 v/v/v as the mobile phase. This solvent system was found to give compact spots for dolutegravir sodium with the Rf value 0.77 +/- 0.01. Densitometric analysis of dolutegravir sodium was carried out in the absorbance mode at 265 nm. Linear regression analysis showed good linearity with respect to peak area in the concentration range of 200-900 ng/spot. The methods were validated for precision, limit of detection (LOD), limit of quantitation (LOQ), accuracy, and specificity. Statistical analysis showed that both of the methods are repeatable and specific for the estimation of the said drug. The methods can be used for routine quality control analysis of dolutegravir sodium. PMID- 27222607 TI - Trace Level Determination of Mesityl Oxide and Diacetone Alcohol in Atazanavir Sulfate Drug Substance by a Gas Chromatography Method. AB - A capillary gas chromatography method with a short run time, using a flame ionization detector, has been developed for the quantitative determination of trace level analysis of mesityl oxide and diacetone alcohol in the atazanavir sulfate drug substance. The chromatographic method was achieved on a fused silica capillary column coated with 5% diphenyl and 95% dimethyl polysiloxane stationary phase (Rtx-5, 30 m x 0.53 mm x 5.0 um). The run time was 20 min employing programmed temperature with a split mode (1:5) and was validated for specificity, sensitivity, precision, linearity, and accuracy. The detection and quantitation limits obtained for mesityl oxide and diacetone alcohol were 5 ug/g and 10 ug/g, respectively, for both of the analytes. The method was found to be linear in the range between 10 ug/g and 150 ug/g with a correlation coefficient greater than 0.999, and the average recoveries obtained in atazanavir sulfate were between 102.0% and 103.7%, respectively, for mesityl oxide and diacetone alcohol. The developed method was found to be robust and rugged. The detailed experimental results are discussed in this research paper. PMID- 27222609 TI - Simultaneous Quantification of Baricitinib and Methotrexate in Rat Plasma by LC MS/MS: Application to a Pharmacokinetic Study. AB - Efficacy assessments using a combination of baricitinib and methotrexate necessitate the development of an analytical method for the determination of both drugs in plasma with precision. A high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous determination of baricitinib and methotrexate in rat plasma. Extraction of baricitinib, methotrexate, and tolbutamide (internal standard; IS) from 50 uL of rat plasma was carried out by protein precipitation with methanol. Chromatographic separation of the analytes was performed on the YMC pack ODS AM (150 mm * 4.6 mm, 5 um) column under gradient conditions with methanol: 2.0 mM ammonium acetate buffer as the mobile phases at a flow rate of 1 mL/min. The precursor ion and product ion transition for both analytes and IS were monitored on a triple quadrupole mass spectrometer, operated with selective reaction monitoring in positive ionization mode. The method was validated over a concentration range of 0.5-250.00 ng/mL for baricitinib and methotrexate. Mean extraction recoveries for baricitinib, methotrexate, and IS of 86.8%, 89.4%, and 91.8% were consistent across low, medium, and high QC levels, respectively. Precision and accuracy at low, medium, and high quality control levels were less than 15% across the analytes. Benchtop, wet, freeze-thaw, and long-term stability were evaluated for both of the analytes. The analytical method was applied to support the pharmacokinetic study of simultaneous estimation of baricitinib and methotrexate in Wistar rats. Assay reproducibility was demonstrated by reanalysis of 18 incurred samples. PMID- 27222608 TI - Development and Validation of a Rapid RP-HPLC-DAD Analysis Method for the Simultaneous Quantitation of Paclitaxel and Lapatinib in a Polymeric Micelle Formulation. AB - A robust and rapid analysis method was developed and validated for the simultaneous assay of paclitaxel (PTX) and lapatinib (LPT) in a polymeric micelle formulation as a novel drug delivery system using high-performance liquid chromatography (HPLC). The assay was performed using the C18 MZ-Analytical Column (5 MUm, 150 * 4.6 mm, OSD-3) which was protected with the C18 pre-column (5 MUm, 4.0 * 4.6 mm, OSD-3). The mobile phase was composed of acetonitrile and water (70/30; V/V) with a flow rate of 0.5 mL/min and detection wavelength of 227 nm. Accuracy was reported as the relative error and was found to be less than 6.8%. The interday assay was evaluated to be 3.22% and 5.76% RSD for PTX and LPT, respectively. The intraday precision was found to be at its maximum value of 5.83% RSD. The limit of detection for both PTX and LPT was found to be 1 ug/mL by means of the newly developed method. The limit of quantitation for PTX and LPT was found to be 5 ug/mL. The calibration curves for both drugs were linear in the concentration range of 5 to 80 MUg/mL. In vitro release for both drugs from the polymeric micelle was evaluated using the newly developed analysis method. PMID- 27222611 TI - Enhanced Permeation of an Antiemetic Drug from Buccoadhesive Tablets by Using Bile Salts as Permeation Enhancers: Formulation Characterization, In Vitro, and Ex Vivo Studies. AB - Buccal bioadhesive bilayer tablets of prochlorperazine maleate were designed and formulated by using buccoadhesive polymers such as hydroxypropylmethyl cellulose, Carbopol 934P, and sodium alginate. Physicochemical characteristics like the uniformity of weight, hardness, thickness, surface pH, drug content, swelling index, microenvironment pH, in vitro drug release, and in vivo buccoadhesion time of the prepared tablets were found to be dependent on the type and composition of the buccoadhesive materials used. The effect of bile salts on the permeation was studied through porcine buccal mucosa and it was found that out of three bile salts incorporated (sodium glycholate, sodium taurocholate, and sodium deoxycholate), sodium glycholate enhanced the permeation rate of prochlorperazine maleate by an enhancement factor of 1.37. PMID- 27222610 TI - Protective Role of Curcumin against N-Nitrosodiethylamine (NDEA)-Induced Toxicity in Rats. AB - The present investigation was aimed at studying the possible role of curcumin against N-nitrosodiethylamine (NDEA)-induced toxicity in albino rats. Administration of NDEA to rats at a concentration of 0.1 mg/ml in drinking water ad libitum for 21 days produced toxicity in them, which was evident from histopathological changes in the rat livers, and increased levels of blood serum enzyme markers, i.e. aspartate transaminase, alanine transaminase, alkaline phosphatase, and lactate dehydrogenase. In addition, the levels of oxidative stress markers like lipid peroxidation (LPO), protein carbonyl (PCC), and glutathione-S-transferase (GST) activity were elevated and the total glutathione (GSH) content was reduced in the livers. The administration of curcumin to rats at concentrations of 10, 20, and 40 mg/ml in drinking water along with 0.1 mg/ml of NDEA for 21 days effectively suppressed NDEA-induced toxicity and also resulted in a dose-dependent reduction in the levels of blood serum enzyme markers (AST, ALT, ALP, and LDH). Moreover, LPO, PCC, and GST activity were reduced and the GSH level was increased upon the administration of curcumin along with NDEA. The results obtained for the comet assay in rat hepatocytes and blood lymphocytes showed a significant dose-dependent decrease in the mean tail length. The micronucleus assay performed on rat hepatocytes also showed a dose-dependent reduction in the frequency of micronucleated cells along with curcumin administration. These results suggest that curcumin has a protective role against NDEA-induced toxicity in albino rats. PMID- 27222612 TI - Formulation Development, Process Optimization, and In Vitro Characterization of Spray-Dried Lansoprazole Enteric Microparticles. AB - This research focuses on the development of enteric microparticles of lansoprazole in a single step by employing the spray drying technique and studies the effects of variegated formulation/process variables on entrapment efficiency and in vitro gastric resistance. Preliminary trials were undertaken to optimize the type of Eudragit and its various levels. Further trials included the incorporation of plasticizer triethyl citrate and combinations of other polymers with Eudragit S 100. Finally, various process parameters were varied to investigate their effects on microparticle properties. The results revealed Eudragit S 100 as the paramount polymer giving the highest gastric resistance in comparison to Eudragit L 100-55 and L 100 due to its higher pH threshold and its polymeric backbone. Incorporation of plasticizer not only influenced entrapment efficiency, but diminished gastric resistance severely. On the contrary, polymeric combinations reduced entrapment efficiency for both sodium alginate and glyceryl behenate, but significantly influenced gastric resistance for only sodium alginate and not for glyceryl behenate. The optimized process parameters were comprised of an inlet temperature of 150 degrees C, atomizing air pressure of 2 kg/cm(2), feed solution concentration of 6% w/w, feed solution spray rate of 3 ml/min, and aspirator volume of 90%. The SEM analysis revealed smooth and spherical shape morphologies. The DSC and PXRD study divulged the amorphous nature of the drug. Regarding stability, the product was found to be stable under 3 months of accelerated and long-term stability conditions as per ICH Q1A(R2) guidelines. Thus, the technique offers a simple means to generate polymeric enteric microparticles that are ready to formulate and can be directly filled into hard gelatin capsules. PMID- 27222613 TI - Localizations of gamma-Actins in Skin, Hair, Vibrissa, Arrector Pili Muscle and Other Hair Appendages of Developing Rats. AB - Six isoforms of actins encoded by different genes have been identified in mammals including alpha-cardiac, alpha-skeletal, alpha-smooth muscle (alpha-SMA), beta cytoplasmic, gamma-smooth muscle (gamma-SMA), and gamma-cytoplasmic actins (gamma CYA). In a previous study we showed the localization of alpha-SMA and other cytoskeletal proteins in the hairs and their appendages of developing rats (Morioka K., et al. (2011) Acta Histochem. Cytochem. 44, 141-153), and herein we determined the localization of gamma type actins in the same tissues and organs by immunohistochemical staining. Our results indicate that the expression of gamma-SMA and gamma-CYA is suggested to be poor in actively proliferating tissues such as the basal layer of the epidermis and the hair matrix in the hair bulb, and as well as in highly keratinized tissues such as the hair cortex and hair cuticle. In contrast, the expression of gamma-actins were high in the spinous layer, granular layer, hair shaft, and inner root sheath, during their active differentiations. In particular, the localization of gamma-SMA was very similar to that of alpha-SMA. It was located not only in the arrector pili muscles and muscles in the dermis, but also in the dermal sheath and in a limited area of the outer root sheath in both the hair and vibrissal follicles. The gamma-CYA was suggested to be co-localized with gamma-SMA in the dermal sheath, outer root sheath, and arrector pili muscles. Sparsely distributed dermal cells expressed both types of gamma-actin. The expression of gamma-actins is suggested to undergo dynamic changes according to the proliferation and differentiation of the skin and hair-related cells. PMID- 27222615 TI - Special Section on Ratcheting. PMID- 27222614 TI - Angiogenic Factor with G-patch and FHA Domain 1 (AGGF1) Expression in Human Vascular Lesions. AB - Angiogenic factor with G-patch and FHA domain 1 (AGGF1) is a novel angiogenic factor that was first described in Klippel-Trenaunay syndrome, a congenital vascular disease associated with capillary and venous malformations. AGGF1, similar to vascular endothelial growth factor (VEGF), has been shown to promote strong angiogenesis in chick embryos in vivo. Blocking AGGF1 expression prevented vessel formation, which suggests AGGF1 is a potent angiogenic factor linked to vascular malformations. So far, AGGF1 expression studies in human vascular lesions have not been performed. Here, we immunohistochemically investigated AGGF1 expression in venous, arteriovenous or capillary malformations, and infantile or congenital hemangioma. We found that AGGF1 was mostly expressed in endothelial cells with plump morphology. Moreover, the majority of mast cells strongly expressed AGGF1. Notwithstanding our incomplete knowledge of the molecular mechanism of AGGF1 in angiogenesis, our results show for the first time that AGGF1 is expressed in plump endothelial cells and mast cells. PMID- 27222616 TI - Prediction of Burst Pressure in Multistage Tube Hydroforming of Aerospace Alloys. AB - Bursting, an irreversible failure in tube hydroforming (THF), results mainly from the local plastic instabilities that occur when the biaxial stresses imparted during the process exceed the forming limit strains of the material. To predict the burst pressure, Oyan's and Brozzo's decoupled ductile fracture criteria (DFC) were implemented as user material models in a dynamic nonlinear commercial 3D finite-element (FE) software, ls-dyna. THF of a round to V-shape was selected as a generic representative of an aerospace component for the FE simulations and experimental trials. To validate the simulation results, THF experiments up to bursting were carried out using Inconel 718 (IN 718) tubes with a thickness of 0.9 mm to measure the internal pressures during the process. When comparing the experimental and simulation results, the burst pressure predicated based on Oyane's decoupled damage criterion was found to agree better with the measured data for IN 718 than Brozzo's fracture criterion. PMID- 27222617 TI - A randomized comparative study of topical versus intravenous tranexamic acid administration in enhanced recovery after surgery (ERAS) total knee replacement. AB - BACKGROUND: The aim of this study was to compare the topical to IV tranexamic acid (TXA) administration of the same dose, given at the same time in patients who underwent TKR using an enhanced recovery after surgery (ERAS) regime. METHODS: Ninety patients were randomized in control group, and IV and topical application groups received 1 g TXA. RESULTS: Blood loss and transfusion requirements in control group were statistically higher compared to both TXA groups (p < 0.05). Length of stay was the same in all groups. CONCLUSIONS: TXA reduced significantly the blood loss and the need for transfusion in ERAS primary unilateral TKR. PMID- 27222618 TI - Reconstructive osteotomy for a malunited medial Hoffa fracture - A feasible salvage option. AB - A 35-year-old male presented with pain and restriction of movements of right knee of 9 months duration. He underwent open reduction and internal fixation for a coronal plane fracture of medial femoral condyle (Hoffa fracture) in another facility 9 months back. Radiological evaluation showed a malunited isolated medial Hoffa fracture. We did an intraarticular osteotomy as a salvage treatment and got a reasonable outcome. This case report analyses the difficulties in the management of this inherently unstable fracture pattern and the technique of intraarticular osteotomy. PMID- 27222619 TI - Liposclerosing myxofibrous tumor: A series of 9 cases and review of the literature. AB - BACKGROUND: Liposclerosing myxofibrous primary bone tumor is a rare benign bone lesion that was characterized by complex mixture of various histological elements. METHODS: We have studied the radiological, clinical and pathological features of nine patients with this disorder. Pain and limping were the main symptoms. RESULTS: Radiographic images typically showed a geographic lytic lesion with thick sclerotic margin, reflecting a pattern of slow growth. Histological sections revealed a polymorphic neoplasia characterized by predominant proliferation of stellate and fusiform cells aimed the myxoid matrix. CONCLUSIONS: These features suggest that the lesion may represent a variant of fibrous dysplasia with a high risk of malignant transformation. PMID- 27222620 TI - EJHS in Constant Progress. PMID- 27222621 TI - Antibiotic Resistance Patterns of Common Gram-negative Uropathogens in St. Paul's Hospital Millennium Medical College. AB - BACKGROUND: The resistance of bacteria causing urinary tract infection (UTI) to commonly prescribed antibiotics is increasing both in developing and developed countries. Resistance has emerged even to more potent antimicrobial agents. This study was undertaken to determine the current antibiotic resistance pattern among common bacterial uropathogens in St.paul's Hospital Millennium Medical College. METHODS: Using cross sectional study design, a total of 217 female and 207 male participants were consecutively recruited. Mid-urine samples were collected from all patients using wide mouthed urine cup. Inoculation was performed onto blood agar and MacConkey agar symoultaniously, and isolated organisms were identified by conventional methods. Antibiotic susceptibility was done by Kirby Bauer disk diffusion method. Thirteen different antibiotics representing different families of antibiotics were tested on all isolated organisms. RESULTS: Of the total 424 samples, 95(22.4%) showed significant growth. Gram negative organisms totaled 85(20.05%), and 10(2.4%) isolates were gram positive. The most frequently isolated gram negative bacterium was E. coli followed by Protues and Klebsiella spp. 53(12.5%), 8(8.4%), and 7(7.4%) respectively. Resistance to Tetracyclin, Ampicilin, Amoxycilin and Nalidixic Acid was more than 70% of all isolates of E.coli strains. There was relatively low resistance rate to Nitrofurantoin, Gentamycin and Trimethoprim-Sulfamethoxazole. However, there was emerging resistance to Ciprofloxacilin and Ceftriaxone especially for common bacteruria. CONCLUSION: In this study setting, resistant rates to Tetracyclin, Ampicilin, Amoxycilin and Nalidixic Acid were high. Since most isolates were sensitive for Nitrofurantoin, Gentamycin and Trimethoprim-Sulfamethoxazole, they are considered as appropriate antimicrobials for empirical treatment for urinary tract infections with the absence of culture and sensitivity setting. Increasing antibiotic resistance trends indicate that it is imperative to rationalize the use of antimicrobials in the community and use these conservatively. PMID- 27222622 TI - Burnout Status at Work among Health Care Professionals in aTertiary Hospital. AB - BACKGROUND: Burnout is a physical, physiological and psychological stress reaction syndrome Caused by long-term exposure to intense work-related emotional and interpersonal pressures. There is no evidence on the issue in Ethiopian setting. METHODS: An institution based cross-sectional study design was conducted on 403 health care providers. Burnout was detected using Copenhagen's burnout inventory tool. Other structured questionnaire on work-related condition and substance use habits was used to collect data. Binary logistic regression was used to identify the associated factors of burnout at work. RESULTS: Of all the study participants, 36.7% scored above the mean level of burnout. Highest prevalence (82.8%) of burnout status was found among nurses. The least prevalence of burnout was observed among laboratory technicians which was 2.8% (n=4). Job insecurity, history of physical illness, low interest in profession, poor relationship status with managers, worry of contracting infection or illness and physical/verbal abuse were found to be predictors of burnout. CONCLUSION: The prevalence of burnout at work was found to be high. The predictors were job insecurity, history of physical illness, low interest in profession, poor relationship status with managers, worry of contracting infection or illness and physical/verbal abuse. PMID- 27222623 TI - Evaluation of the Community Cataract Surgical Services of a University Teaching Hospital Using Cataract Surgical Coverage in Nigeria. AB - BACKGROUND: Cataract is the leading cause of blindness in the world. An efficient and effective cataract surgical service is necessary to reduce the backlog of cataract blindness in the community. This study aims to determine the cataract surgical coverage among individuals aged 50 years and above residing in Esie and Arandun communities. This will serve as a measure of the impact of the cataract intervention programme provided by the University of Ilorin Teaching Hospital, Nigeria. METHODS: The study was a population-based, cross sectional survey conducted from November to December, 2013. Cataract surgical services are provided by the University of Ilorin Teaching Hospital, Nigeria, at Esie and Arandun communities as out-reach centres. Seven hundred and fifty-five individuals aged 50 years and above residing in these communities had basic ocular examination done. RESULTS: Out of the 765 subjects registered, 755(98.7%) were examined. Out of these, 38.4% were males and 61.6% were females. The prevalence of bilateral cataract blindness was 1.6%. The Cataract Surgical Coverage (eyes) at visual acuity < 3/60 for males and females were 52.3% and 51.2% respectively (X2=19.30, p=0.001), while the Cataract Surgical Coverage (person) at visual acuity less < 3/60 for males and females were 80.6% and 68.4% respectively (X2=2.10, p=0.147). CONCLUSION: The Cataract Surgical Coverage was high with a correspondingly low prevalence of cataract blindness in these communities. The availability of cataract surgical services via out-reach programmes bridges the gap between eye care-givers and the community. PMID- 27222624 TI - Types and Indications of Colostomy and Determinants of Outcomes of Patients After Surgery. AB - BACKGROUND: Colostomy is one of the commonest life saving procedures done worldwide with an intention of either decompression of an obstructed colon or diversion of stool. Indications may vary from region to region. Attending morbidity and mortality is significant. the objective of this study was to Determine the common indications and types of colostomy, and outcomes of patients operated at SPHMMC. METHODS: A retrospective medical records of patients, operation log book and nursing records review was done in a two-year period between January 2011 and December 2013 at the College Teaching Hospital, St Paul's Hospital Millennium Medical, Addis Ababa. RESULTS: During the two years, 253 colostomies were done and 219(86.6%) cases used for analysis. Of these, 151(68.9%) were males. Age ranged from 15 to 85 years with a mean of 50.8. Most of the surgeries, 196(89.5%), were done for emergency conditions. The three most common indications were gangrenous sigmoid volvulus, 102(46.6%), colorectal cancers, 46(21.0%, and abdominal injuries, 28(12.8%). The commonest type of colostomy done was Hartman's colostomy, 179(81.7.1%), gangrenous sigmoid volvulus being the predominant indication, 102(57%). Loop colostomy constituted 35(16%) of all the colostomies. Penetrating abdominal injuries was the main indication 15(42.9%). Overall, 157 complications were seen on 106(48.4%) patients. The most common complications were surgical site infection, 51(23.3%), hospital acquired pneumonia, (10.5%), and wound dehiscence, 17(7.8%). The mortality rate was 9.6% (21). CONCLUSION: Gangrenous sigmoid volvulus is the leading indication for colostomy. Mortality and morbidity rates are high. Aggressive resuscitation, early prompt operation and post op close follow-up should be emphasized. PMID- 27222625 TI - Outcome of Induction and Associated Factors among Term and Post-Term Mothers Managed at Jimma University Specialized Hospital: A Two Years' Retrospective Analysis. AB - BACKGROUND: Induction of labor using oxytocin is a routine procedure in obstetrics used for vaginal delivery of gravid uterus. The purpose of this study was to analyze outcome of induction with oxytocin and associated factors among mothers who delivered at term and post-term in Jimma University Specialized Hospital, Southwest Ethiopia. METHODS: A facility based cross-sectional study was conducted on records of 280 laboring mothers who delivered at term and post-term after induction with oxytocin from September 1(st), 2009 to August 31(st), 2011. The data were extracted using checklist and analyzed using SPSS windows version 16.0. The level of significance to declare relationship between the dependent and independent variables was set at p< 0.05. RESULTS: Mean maximum oxytocin levels used until vaginal delivery and at time of diagnosis of failed induction were 55.0 +/- 29.8 and 89.7+/- 11.6 miu/min respectively. Mean time elapsed from initiation of induction with oxytocin to vaginal delivery and till diagnosis of failed induction were 6:10 +/- 3:09 and 9:57+/- 2:01 hours respectively. Failed induction was diagnosed in 21.4% of the mothers. Primigravidity, unfavorable and intermediate Bishop Scores determined at admission were found to be predictors of failed induction. CONCLUSION: High rate of failed induction and high level of oxytocin use were found. Preparation of the cervix before commencing induction in primigravid women is recommended to improve success of induction with the current protocol. PMID- 27222626 TI - Maternal Health Care Services Access Index and Infant Survival in Nigeria. AB - BACKGROUND: Infant mortality rate in Nigeria is among the highest world-wide. Utilization of modern health care facilities during pregnancy and at delivery reduces infant mortality rate. We examined the relationship between Infant Mortality (IM) and Maternal Health Care Services Access Index (MHCI) in Nigeria. METHODS: This cross-sectional study utilized 2013 NDHS data and included women aged 15-49 years (n=12511). MHCI was obtained from information on antenatal visit, antenatal attendance, tetanus toxoid injection during pregnancy, place of delivery and birth attendance. Cox-proportional hazard and Brass models were used for the analysis (alpha=0.05). RESULTS: Mean MHCI was higher among women with lower prevalence of IM. About 5.1% and 3.4% of the women with none and complete MHCI had experienced infant deaths respectively. The hazard of experienced infant deaths was 1.497(1.068-2.098) and 1.466(1.170-1.836) significantly higher among women with no and low MHCI respectively than those with complete MHCI. This pattern was observed when other factors were used as control. The refined IM probability (range=0.0482-0.1102) and IM rates (range=50-119) increased with reduction in the level of MHCI. The IM rate reduces from 119 per 1,000 live births among women whose MHCI score was zero to 50 per 1,000 live births among those with complete MHCI score. CONCLUSION: Infant death was least experienced among women who had complete MHCI. If women optimize utilization of health facility during pregnancy and delivery, infant deaths will reduce in Nigeria. PMID- 27222627 TI - Paediatric Refractive Errors in an Eye Clinic in Osogbo, Nigeria. AB - BACKGROUND: Paediatric ophthalmology is an emerging subspecialty in Nigeria and as such there is paucity of data on refractive errors in the country. This study set out to determine the pattern of refractive errors in children attending an eye clinic in South West Nigeria. METHODS: A descriptive study of 180 consecutive subjects seen over a 2-year period. Presenting complaints, presenting visual acuity (PVA), age and sex were recorded. Clinical examination of the anterior and posterior segments of the eyes, extraocular muscle assessment and refraction were done. The types of refractive errors and their grades were determined. Corrected VA was obtained. Data was analysed using descriptive statistics in proportions, chi square with p value <0.05. RESULTS: The age range of subjects was between 3 and 16 years with mean age = 11.7 and SD = 0.51; with males making up 33.9%.The commonest presenting complaint was blurring of distant vision (40%), presenting visual acuity 6/9 (33.9%), normal vision constituted >75.0%, visual impairment20% and low vision 23.3%. Low grade spherical and cylindrical errors occurred most frequently (35.6% and 59.9% respectively). Regular astigmatism was significantly more common, P <0.001. The commonest diagnosis was simple myopic astigmatism (41.1%). Four cases of strabismus were seen. CONCLUSION: Simple spherical and cylindrical errors were the commonest types of refractive errors seen. Visual impairment and low vision occurred and could be a cause of absenteeism from school. Low-cost spectacle production or dispensing unit and health education are advocated for the prevention of visual impairment in a hospital set-up. PMID- 27222629 TI - Microbiological Safety of Street Vended Foods in Jigjiga City, Eastern Ethiopia. AB - BACKGROUND: Food safety problems are particularly becoming an increasingly serious threat to public health in developing countries. This study was conducted to assess microbiological safety of street vended foods from May to November, 2014 in Jigjiga City. METHODS: A cross-sectional design was used to answer questions concerning the current status of food hygiene and sanitation practire of street food vending sites. Interview and observational assessments were used to collect socio-demographic data about street food venders. One hundred thirty two samples of street foods were aseptically collected from four 'kebeles' of Jigjiga City. Both descriptive and analytical statistical methods were applied. RESULTS: The majority of the street food vendors were women, 120(90.9%), with the average age group of 23-49 years, (42.85%), and 99(66.7%) them were illiterate. The study revealed that 95(72%) of the food samples had pathogenic bacterial contaminations. Three different bacterial species were isolated: E. coli 68(51.5%), S. aureus 85(64.4%) and 26(19.7%) Salmonella species. The highest incidence of S. aureus 23/33(69%) was seen in 'Sambusa'; the highest incidence of E. coli 24/33(73.5%) was observed in 'Pasta', while the highest Salmonella incidence was observed in 'Ades'. CONCLUSION: This study revealed that there is a reasonable gap on food safety knowledge among street food venders. The microbial profile was also higher compared to standards set by the World Health Organization. Due attention should be given by the government to improve knowledge about food safety and the quality standard of street foods sold in the City. PMID- 27222628 TI - Seroprevalence of Human Immunodeficiency Virus, Hepatitis B Virus, Hepatitis C Virus, and Syphilis among Blood Donors at Jigjiga Blood Bank, Eastern Ethiopia. AB - BACKGROUND: Transfusion-transmissible infectious agents such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and Syphilis are among the greatest threats to blood safety for recipients. They are also the leading causes of death and chronic and life-threatening abnormalities. METHODS: A retrospective analysis of consecutive blood donors' records covering the period between January 2010 and December 2014 was conducted to analyze for seroprevalence of HIV, HBV, HCV and syphilis among blood donors aged 17-65 years. The association of these infections with age group, blood group, their co-infection rate and year trends were analyzed. Linear regression analysis was used to determine trends of HIV, HBV, HCV and syphilis infections. Sterile venous anti-coagulated blood was collected from the donors and analyzed using highly sensitive and specific kits. RESULT: From the total of 6827 consecutive blood donors, 963(14.1%) had serological evidence of infection with at least one pathogen and 73(1.07%) had multiple infections. The overall seroprevalence of HIV, HBV, HCV and syphilis was 3.16%, 9.48%, 0.73% and 0.73% respectively. Among those with multiple infections, the most common combinations were HIV-HBV 41/73(56.2%). Blood group "O positive" was the most common with 51.62% followed by "A positive". Moreover, significantly declining trends of HIV, HCV and syphilis seropositivity were observed over the study period. CONCLUSION: A substantial percentage of the blood donors harbour HIV, HBV, HCV and syphilis infections. Strict selection of blood donors and comprehensive screening of donors' blood using standard methods are highly recommended to ensure the safety of blood for recipients. PMID- 27222630 TI - The Promise of E-Platform Technology in Medical Education. AB - Increasing the number as well as improving the capacity and quality of medical professionals to achieve an equitable health care for all is a global priority and a global challenge. In developing countries, which are facing the largest burden of disease, to achieve the above stated objective, there is a big need for more well-trained, competent and dedicated health care providers. Currently, there is a well-documented shortage of trained health workers globally, with the poorest countries having the greatest shortfalls. The time tested, traditional approach of training health care force by importing professionals from overseas is not only prohibitively expensive but also not sufficient to achieve the scale and pace of the required human capacity building. Considering this fact, distance learning programs, which include m-Health as well as other information technology (IT) platforms and tools, can provide unique, timely, cost-effective, easily scalable and valuable opportunities to expand access to training health care manpower in developing countries where the shortage is critical. PMID- 27222631 TI - No Hypertensive Disorder of Pregnancy; No Preeclampsia-eclampsia; No Gestational Hypertension; No Hellp Syndrome. Vascular Disorder of Pregnancy Speaks for All. AB - Hypertensive disorders complicate 5%-10% of pregnancies with increasing incidence mainly due to upward trends in obesity globally. In the last century, several terminologies have been introduced to describe the spectrum of this disease. The current and widely used classification of hypertensive pregnancy disorders was introduced in 1972 and in 1982, but has not been free of controversy and confusion. Unlike other diseases, the existing terminology combines signs and symptoms, but does not describe the underlying pathology of the disease itself. In this commentary, a detailed account is given to vascular disorder of pregnancy (VDP) as an inclusive terminology taking into account the underlying pathology of the disease on affected organs and systems. A simple and uniform classification scheme for VDP is proposed. PMID- 27222632 TI - Sturge Weber Syndrome: An Unusual Case with Multisystem Manifestations. AB - BACKGROUND: Sturge-Weber syndrome (SWS) is a rare congenital neurocutaneous disorder. It is characterized by the presence of facial port wine stains, neurological abnormalities like seizures and mental retardation, ocular disorders, oral involvement and leptomeningeal angiomas. CASE REPORT: A 13-year old boy presented with the chief complaint of swollen, bleeding gums and deposits on the teeth. Detailed medical and dental history, clinical examination and investigations confirmed the diagnosis of Sturge-Weber syndrome. The treatment comprised of a thorough plaque control regimen to reduce the gingival enlargement, and it included oral hygiene instructions, thorough scaling, root planing at regular intervals and plaque index scoring which motivated the patient at each visit. CONCLUSION: This case illustrates that early intervention in a patient with Sturge-Weber syndrome is quintessential because of its associated gingival vascular features and their complicating manifestations. Furthermore, the need for periodic oral examinations and maintenance of good oral hygiene to prevent any complications from the oral vascular lesions has been highlighted. PMID- 27222633 TI - Association of Vogt Koyanagi Harada Syndrome and Seronegative Rheumatoid Arthritis. AB - BACKGROUND: Vogt Koyanagi Harada (VKH) Syndrome is a rarely-seen multi-systemic, autoimmune and inflammatory disease. It observed frequently with neurologic, auditory and skin manifestations and characterized with bilateral, chronic and diffused granulomatous panuveitis. It generally affects women in young-adult period. CASE: A 57 year-old female patient applied to a special center one year ago with a complaint of decrease in the sight acuity of the right eye. The right eye was operated on with cataract diagnosis. Uveitis was developed firstly in the right eye and then in the left eye after the operation. Having complaints about uveitis, tinnitus and hear loss, the patient was diagnosed with VKH syndrome. The pains started to be felt in small hand joints and both of the two ankles. The pains were increasing especially in the mornings and during rest. The duration of morning stiffness was two hours in hand and foot joints. The patient had had lumbar pain with mechanic characteristic for five years. CONCLUSION: Being diagnosed with seronegative rheumatoid arthritis (RA), our case is presented because VKH syndrome is rarely seen in Turkey, and the joint findings are at the forefront. PMID- 27222634 TI - A Study on Electrical Reliability Criterion on Through Silicon Via Packaging. AB - Three-dimensional (3D) structure with through silicon via (TSV) technology is emerging as a key issue in microelectronic packaging industry, and electrical reliability has become one of the main technical subjects for the TSV designs. However, criteria used for TSV reliability tests have not been consistent in the literature, so that the criterion itself becomes a technical argument. To this end, this paper first performed several different reliability tests on the testing packaging with TSV chains, then statistically analyzed the experimental data with different failure criteria on resistance increasing, and finally constructed the Weibull failure curves with parameter extractions. After comparing the results, it is suggested that using different criteria may lead to the same failure mode on Weibull analyses, and 65% of failed devices are recommended as a suitable termination for reliability tests. PMID- 27222635 TI - Terrestrial arthropods of Steel Creek, Buffalo National River, Arkansas. II. Sawflies (Insecta: Hymenoptera: "Symphyta"). AB - BACKGROUND: This is the second in a series of papers detailing the terrestrial arthropods collected during an intensive survey of a site near Steel Creek campground along the Buffalo National River in Arkansas. The survey was conducted over a period of eight and a half months using twelve trap types - Malaise traps, canopy traps (upper and lower collector), Lindgren multifunnel traps (black, green, and purple), pan traps (blue, purple, red, white, and yellow), and pitfall traps - and Berlese-Tullgren extraction of leaf litter. NEW INFORMATION: We provide collection records for 47 species of "Symphyta" (Insecta: Hymenoptera), 30 of which are new state records for Arkansas: (Argidae) Sterictiphora serotina; (Cimbicidae) Abia americana; (Diprionidae) Monoctenus fulvus; (Orussidae) Orussus terminalis; (Pamphiliidae) Onycholyda luteicornis, Pamphilius ocreatus, P. persicum, P. rileyi; (Pergidae) Acordulecera dorsalis, A. mellina, A. pellucida; (Tenthredinidae) Caliroa quercuscoccineae, Empria coryli, Hoplocampa marlatti, Macrophya cassandra, Monophadnoides conspiculatus, Monophadnus bakeri, Nematus abbotii, Neopareophora litura, Pachynematus corniger, Paracharactus rudis, Periclista marginicollis, Pristiphora banski, P. chlorea, Strongylogaster impressata, S. remota, Taxonus epicera, Thrinax albidopictus, T. multicinctus, Zaschizonyx montana; (Xiphydriidae) Xiphydria tibialis. PMID- 27222636 TI - Erratum to: Inhibition of glycolytic enzyme hexokinase II (HK2) suppresses lung tumor growth. AB - [This corrects the article DOI: 10.1186/s12935-016-0280-y.]. PMID- 27222637 TI - Erratum to: Interleukin-1beta-induced reduction of tissue water diffusion in the juvenile rat brain on ADC MRI is not associated with (31)P MRS-detectable energy failure. AB - [This corrects the article DOI: 10.1186/s12950-016-0118-3.]. PMID- 27222638 TI - Erratum to: 'Oral rivaroxaban for Japanese patients with symptomatic venous thromboembolism - the J-EINSTEIN DVT and PE program'. AB - [This corrects the article DOI: 10.1186/s12959-015-0035-3.]. PMID- 27222639 TI - Changes in life expectancy 1950-2010: contributions from age- and disease specific mortality in selected countries. AB - BACKGROUND: Changes of life expectancy over time serve as an interesting public health indicator for medical, social and economic developments within populations. The aim of this study was to quantify changes of life expectancy between 1950 and 2010 and relate these to main causes of death. METHODS: Pollard's actuarial method of decomposing life expectancy was applied to compare the contributions of different age- and disease-groups on life expectancy in 5 year intervals. RESULTS: From the 1960 to 70s on, declines in cardiovascular disease (CVD) mortality play an increasing role in improving life expectancy in many developed countries. During the past decades gains in life expectancy in these countries were mainly observed in age groups >=65 years. A further consistent pattern was that life expectancy increases were stronger in men than in women, although life expectancy is still higher in women. In Japan, an accelerated epidemiologic transition in causes of death was found, with the highest increases between 1950 and 1955. Short-term declines and subsequent gains in life expectancy were observed in Eastern Europe and the former states of the Union of Soviet Socialist Republics (USSR), reflecting the changes of the political system. CONCLUSIONS: Changes of life years estimated with the decomposing method can be directly interpreted and may therefore be useful in public health communication. The development within specific countries is highly sensitive to changes in the political, social and public health environment. PMID- 27222640 TI - Relationship Between Depression and Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia. AB - This article provides an overview of current data on the relationship between depression and lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH), with a focus on pathophysiology and patient management implications. Review of the literature indicated a clear relationship between LUTS secondary to BPH and depression. It is unknown whether this relationship is bidirectional or unidirectional. Depression is associated with the impact of LUTS on quality of life in men with BPH. Research suggests that depression alters the experience of LUTS in this population. Medical and surgical treatments for BPH may impact quality of life and, therefore, depression. Results conflict on the exact nature of the relationship examined, and on the extent to which the relationship may be attributed to physiological factors such as inflammation. Practicing clinicians should consider using a brief self-administered scale to assess for depression in patients with BPH. There is a clear need for additional research to decisively determine the nature of the relationship between LUTS secondary to BPH and depression, as well as the extent to which change in either condition may be affected by the other. PMID- 27222641 TI - Penile Rehabilitation Strategies Among Prostate Cancer Survivors. AB - Despite advances in technical and surgical approaches, erectile dysfunction (ED) remains the most common complication among prostate cancer survivors, adversely impacting quality of life. This article analyzes the concept and rationale of ED rehabilitation programs in prostate cancer patients. Emphasis is placed on the pathophysiology of ED after diagnosis and treatment of prostate cancer to understand the efficacy of rehabilitation programs in clinical practice. Available evidence shows that ED is a transient complication following prostate biopsy and cancer diagnosis, with no evidence to support rehabilitation programs in these patients. A small increase in ED and in the use of phosphodiesterase type 5 (PDE5) inhibitors was reported in patients under active surveillance. Patients should be advised that active surveillance is unlikely to severely affect erectile function, but clinically significant changes in sexual function are possible. Focal therapy could be an intermediate option for patients demanding treatment/refusing active surveillance and invested in maintaining sexual activity. Unlike radical prostatectomy, there is no support for PDE5 inhibitor use to prevent ED after highly conformal external radiotherapy or low dose rate brachytherapy. Despite progress in the understanding of the pathophysiologic mechanisms responsible for ED in prostate cancer patients, the success rates of rehabilitation programs remain low in clinical practice. Alternative strategies to prevent ED appear warranted, with attention toward neuromodulation, nerve grafting, nerve preservation, stem cell therapy, investigation of neuroprotective interventions, and further refinements of radiotherapy dosing and delivery methods. PMID- 27222642 TI - A Review of Transplantation Practice of the Urologic Organs: Is It Only Achievable for the Kidney? AB - Transplantation is a viable treatment option for failure of most major organs. Within urology, transplantation of the kidney and ureter are well documented; however, evidence supporting transplantation of other urologic organs is limited. Failure of these organs carries significant morbidity, and transplantation may have a role in management. This article reviews the knowledge, research, and literature surrounding transplantation of each of the urologic organs. Transplantation of the penis, testicle, urethra, vas deferens, and bladder is discussed. Transplantation attempts have been made individually with each of these organs. Penile transplantation has only been performed once in a human. Testicular transplantation research was intertwined with unethical lucrative pursuits. Interest in urethra, bladder, and vas deferens transplantation has decreased as a result of successful surgical reconstructive techniques. Despite years of effort, transplantations of the penis, testicle, urethra, vas deferens, and bladder are not established in current practice. Recent research has shifted toward techniques of reconstruction, tissue engineering, and regenerative medicine. PMID- 27222644 TI - From the President's Desk: 2015 Updates and a Look Forward. PMID- 27222645 TI - LUGPA Welcomes Membership of Smaller Practices. PMID- 27222643 TI - Diagnosis, Evaluation, and Treatment of Mixed Urinary Incontinence in Women. AB - Mixed urinary incontinence (MUI) is a common clinical problem in the community and hospital setting. The broad definition of the term makes it difficult to diagnose, as well as determine effective treatment strategies. There are no current guidelines recommended for physicians. The estimated prevalence of this condition is approximately 30% in all women with incontinence. It has also been suggested that patients with MUI report more bothersome symptoms than either stress or urge incontinence; approximately 32% of 40- to 64-year-olds with MUI report symptoms of depression. The authors examine the diagnosis, evaluation, and treatment of patients with MUI. PMID- 27222646 TI - Preparing for the Transition to ICD-10 by Chart Reviews of Four Urology Practice Types. PMID- 27222647 TI - Juxta-adrenal Ancient Schwannoma: A Rare Retroperitoneal Tumor. AB - Retroperitoneal schwannoma is a rare tumor that is often misdiagnosed as malignancy due to a concerning appearance on cross-sectional imaging. Pathology and immunohistochemistry form the gold standard for diagnosis; as such, local excision is the treatment of choice for this disease. We present two cases of juxta-adrenal ancient schwannoma that were treated with adrenalectomy and discuss the current literature regarding this entity. PMID- 27222648 TI - Genitourinary Presentation of Tuberculosis. AB - Tuberculosis (TB) is less common in developed countries; however, the incidence of TB-especially resistant strains-is on the rise worldwide. Cases of TB manifesting as urologic complications are rare in the United States. Urologists should be aware of this potential manifestation, especially in patients who have recently immigrated to the United States or have traveled abroad for prolonged periods. Two cases are presented here to illustrate this entity. PMID- 27222649 TI - Long-term Survival From Muscleinvasive Bladder Cancer With Initial Presentation of Symptomatic Cerebellar Lesion: The Role of Selective Surgical Extirpation of the Primary and Metastatic Lesion. AB - A 59-year-old man was diagnosed with urothelial carcinoma involving an isolated cerebellar metastasis after presenting to the emergency department for headache complaints. After selective surgical excision of the symptomatic brain lesion and delayed cystectomy due to intractable hematuria, he survived 11 years without evidence of recurrence or subsequent systemic chemotherapy. He eventually expired after delayed recurrence in the lung, supraclavicular lymph node, and brain. To our knowledge, this is the only case of prolonged survival from urothelial carcinoma after selective surgical extirpation of the primary and metastatic lesion without subsequent systemic chemotherapy. PMID- 27222650 TI - The Comparison of Magnetic Resonance Image-Guided Targeted Biopsy Versus Standard Template Saturation Biopsy in the Detection of Prostate Cancer. PMID- 27222651 TI - Standard and Targeted Biopsy During Follow-up for Active Surveillance. PMID- 27222652 TI - MRI/Ultrasound Fusion Biopsy Versus Standard 12-Core Biopsy. PMID- 27222653 TI - Passive Dynamics Explain Quadrupedal Walking, Trotting, and Tolting. AB - This paper presents a simplistic passive dynamic model that is able to create realistic quadrupedal walking, tolting, and trotting motions. The model is inspired by the bipedal spring loaded inverted pendulum (SLIP) model and consists of a distributed mass on four massless legs. Each of the legs is either in ground contact, retracted for swing, or is ready for touch down with a predefined angle of attack. Different gaits, that is, periodic motions differing in interlimb coordination patterns, are generated by choosing different initial model states. Contact patterns and ground reaction forces (GRFs) evolve solely from these initial conditions. By identifying appropriate system parameters in an optimization framework, the model is able to closely match experimentally recorded vertical GRFs of walking and trotting of Warmblood horses, and of tolting of Icelandic horses. In a detailed study, we investigated the sensitivity of the obtained solutions with respect to all states and parameters and quantified the improvement in fitting GRF by including an additional head and neck segment. Our work suggests that quadrupedal gaits are merely different dynamic modes of the same structural system and that we can interpret different gaits as different nonlinear elastic oscillations that propel an animal forward. PMID- 27222654 TI - Allergen inhalation challenge, refractoriness and the effects of ibuprofen. AB - BACKGROUND: Bronchoprovocation challenges use direct or indirect acting stimuli to induce airflow obstruction. Indirect stimuli either non-allergic/non-IgE mediated (e.g. exercise, mannitol) or allergic/IgE mediated (i.e. allergen) trigger mast cells to release bronchoconstricting mediators (e.g. cysteinyl leukotrienes, histamine). Performing repeat challenges within a short timeframe (e.g. 3 h) with non-allergic indirect stimuli results in a diminished, refractory response to the second challenge that is inhibited by non-steroidal anti inflammatory medications. Cross refractoriness occurs between indirect stimuli. It follows that repeat bronchoprovocation with allergen might exhibit refractoriness that might be altered by ibuprofen. We assessed the response to a second allergen challenge performed 24 h after an initial allergen challenge to determine if the response is refractory. If refractoriness developed, the study aimed to determine whether a single dose of ibuprofen would alter the refractory response to the second allergen challenge. In the absence of a refractory response, the study design allowed for the assessment of the effect of ibuprofen on allergen challenge outcomes, including indices of airway inflammation. METHODS: Thirteen mild atopic asthmatics were enrolled in a randomized, double blind, placebo controlled, cross-over study. Ibuprofen (400 mg) or placebo was administered 1 h prior to the first of two allergen challenges, performed 24 h apart. Blood and sputum eosinophils, airway responsiveness to methacholine and levels of fractional exhaled nitric oxide were assessed before and 7 h after each allergen challenge. All data were log transformed and differences in geometric means were analyzed by paired t-tests. RESULTS: After placebo, early asthmatic responses for the two challenges were not significantly different (p = 0.82). A single 400 mg dose of ibuprofen decreased both the early (p = 0.03; n = 12) and late asthmatic responses (p = 0.03; n = 3). CONCLUSION: Allergen challenges conducted 24 h apart do not exhibit refractoriness. Single dose ibuprofen inhibits early and late asthmatic responses to allergen bronchoprovocation. Ibuprofen should be withheld for at least 24 h prior to investigations utilizing allergen bronchoprovocation. Trial registration clinicaltrials.gov #NCT02327234. PMID- 27222655 TI - Maternal serum but not breast milk IL-5, IL-6, and IL-13 immune markers are associated with scratching among infants. AB - BACKGROUND: Scratching in infants is considered to be related to early development of eczema. Little is known about the effects of maternal immune markers on scratching among infants. The objective is to compare the risks related to maternal serum immune markers (IMs) during pregnancy and IMs in breast milk for the occurrence of scratching in infants at 6 and 12 months of age. METHODS: Pregnant women were recruited in Columbia and Charleston, South Carolina. Blood (median 3 weeks prepartum) and breast milk (3 weeks postpartum) samples were collected. The concentrations of interferon (IFN)-gamma, IFN gamma induced protein 10 (IP-10) (or CXCL10), CCL11, interleukin (IL) 1beta, IL-4, IL 5, IL-6, IL-8 (CXCL8), IL-10, IL-12 (p70), IL-13, transforming growth factor (TGF)-beta1, and immunoglobulin (Ig) A in both maternal serum and whey were assayed using optimized immunoassays. Scratching and skin manifestations were ascertained at 6 and 12 months. Generalized estimating equations were used to estimate relative risks (RRs) of IMs for repeated measurements of scratching, considering intra-individual correlations and adjusting for confounders. RESULTS: Of 178 women, 161 provided blood and 115 breast milk samples. IL-1beta, IL-4, IL 10, IL-12, and CCL11 in maternal serum and whey were not analyzed due to a large proportion of non-detectable values. Infants in the highest tertile of IL-6 and IL-13 in maternal serum were at higher risk of scratching (RR 1.73 and 1.84, respectively; p <= 0.002) compared to infants in the first tertile; similarly, infants born to mothers with high (versus low) levels of serum IL-5 were also at increased risk (RR 1.60, p = 0.002). None of the breast milk IMs studied were associated with scratching. CONCLUSIONS: Scratching but not doctors diagnosed eczema was associated with higher levels of maternal IL-5, IL-6, and IL-13 during pregnancy. Further investigations are necessary to determine how maternal serum IMs influence infants scratching. PMID- 27222656 TI - Persistence of respiratory and inflammatory responses after dermal sensitization to persulfate salts in a mouse model of non-atopic asthma. AB - BACKGROUND: Exposure to ammonium persulfate (AP) has been reported to be the main cause of occupational asthma in hairdressers. The aim of this study is to assess how long the asthmatic response to AP can be induced after dermal sensitization in a mouse model. METHODS: BALB/c mice received dermal applications of AP or dimethylsulfoxide (DMSO) (control) on days 1 and 8. They then received a single nasal instillation (challenge) of AP or saline on days 15, 22, 29, 36, 45, 60 and 90. Respiratory responsiveness to methacholine was measured 24 h after the challenge using a non-specific methacholine provocation test. Pulmonary inflammation was analysed in bronchoalveolar lavage (BAL), and total serum immunoglobulin (Ig) E, IgG1 and IgG2a were measured in serum samples. Histological analysis of lung slides was performed. RESULTS: Mice dermally sensitized and intranasally challenged with AP showed respiratory responsiveness to methacholine as long as 45 days after initial sensitization, as well as increased percentage of neutrophils in BAL compared with the control group. At day 60, dermally sensitized mice still presented bronchial hyperresponsiveness, while the percentage of neutrophils returned to baseline levels similar to those of controls. Total serum IgE increased significantly on day 22 after dermal sensitization. Total serum IgG1 and IgG2a increased from 45 days after dermal sensitization and remained high at 90 days. CONCLUSIONS: Both respiratory responsiveness to methacholine and airway inflammation responses decrease with increasing time between sensitization and challenge. Respiratory responsiveness to methacholine tends to persist longer than inflammation. PMID- 27222658 TI - Erratum to: Safety and feasibility of oral immunotherapy to multiple allergens for food allergy. AB - [This corrects the article DOI: 10.1186/1710-1492-10-1.]. PMID- 27222659 TI - Drillers and mill operators in an open-pit gold mine are at risk for impaired lung function. AB - BACKGROUND: Occupational studies of associations of exposures with impaired lung function in mining settings are built on exposure assessment and far less often on workplace approach, so the aim of this study was to identify vulnerable occupational groups for early lung function reduction in a cohort of healthy young miners. METHODS: Data from annual screening lung function tests in gold mining company in Kyrgyzstan were linked to occupations. We compared per cent predicted forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and FEV1/FVC between occupational groups and tested selected occupations in multivariate regression adjusted for smoking and work duration for the following outcomes: FEV1 < 80 %, FEV1/FVC < 70 % and both. RESULTS: 1550 tests of permanent workers of 41 occupations (mean age 40.5 +/- 9.2 years, 29.8 % never smokers) were included in the analysis. The mean overall VC was 103.0 +/- 12.9 %; FVC 109.1 +/- 13.0 % and FEV1 100.2 +/- 25.9 %. Drillers and smoking food handlers had the lowest FEV1%. In non-smokers, the lowest FEV1 was in drillers (94.9 +/- 11.3 % compared to 115.2 +/- 17.7 % in engineers). Drillers (adjusted odds ratio (OR) 1.53 (95 % confidence interval (CI) 1.11-2.09)) and mill operators (OR 2.01 (1.13-3.57)) were at greater risk of obstructive ventilation pattern (FEV1/FVC < 70 %). CONCLUSIONS: Drilling and mill operations are the highest risk jobs in an open-pit mine for reduced lung function. Occupational medical clinic at site should follow-up workers in these occupations with depth and strongly recommend smoking cessation. PMID- 27222657 TI - Primary immunodeficiencies associated with eosinophilia. AB - BACKGROUND: Eosinophilia is not an uncommon clinical finding. However, diagnosis of its cause can be a dilemma once common culprits, namely infection, allergy and reactive causes are excluded. Primary immunodeficiency disorders (PID) are among known differentials of eosinophilia. However, the list of PIDs typically reported with eosinophilia is small and the literature lacks an inclusive list of PIDs which have been reported with eosinophilia. This motivated us to review the literature for all PIDs which have been described to have elevated eosinophils as this may contribute to an earlier diagnosis of PID and further the understanding of eosinophilia. METHODS: A retrospective PubMed, and Google Scholar search using the terms "eosinophilia" and "every individual PID" as classified by Expert Committee of the International Union of Immunological Societies with the limit of the English language was performed. Results were assessed to capture case(s) which reported eosinophilia in the context of PID conditions. Absolute eosinophil counts (AEC) were retrieved from manuscripts whenever reported. RESULTS: In addition to the typical PID conditions described with eosinophilia, we document that MHC class II deficiency, CD3gamma deficiency, STAT1 deficiency (AD form), Kostmann disease, cyclic neutropenia, TCRalpha deficiency, Papillon-Lefevre syndrome, CD40 deficiency, CD40L deficiency, anhidrotic ectodermal dysplasia with immune deficiency, ataxia-telangiectasia, common variable immunodeficiency disorders (CVID), Blau syndrome, CARD9 deficiency, neonatal onset multisystem inflammatory disease or chronic infantile neurologic cutaneous and articular syndrome (NOMID/CINCA), chronic granulomatous disease, MALT1 deficiency and Roifman syndrome have been noted to have elevated eosinophils. Severe eosinophilia (>5.0 * 10(9)/L) was reported in Omenn syndrome, Wiskott Aldrich syndrome, ADA deficiency, autoimmune lymphoproliferative syndrome, immunodysregulation polyendocrinopathy enteropathy X-linked, STAT3 deficiency, DOCK8 deficiency, CD40 deficiency, MHC II deficiency, Kostmann disease, Papillon Lefevre syndrome, and CVID. CONCLUSIONS: This literature review shows that there is an extensive list of PIDs which have been reported with eosinophilia. This list helps clinicians to consider an extended differential diagnoses when tasked with exclusion of PID as a cause for eosinophilia. PMID- 27222661 TI - The variation in the major constituents of the dried rhizome of Ligusticum chuanxiong (Chuanxiong) after herbal processing. AB - BACKGROUND: Rhizoma Chuanxiong (RC; Chuanxiong), which is the dried rhizome of Ligusticum chuanxiong (Umbelliferae), is commonly used in Chinese medicine (CM) for improving blood circulation and dispersing blood stasis. RC is usually processed before use in clinical practice to enhance its therapeutic efficacy. This study aimed to investigate the temporal variations of the major constituents of RC by HPLC-DAD-MS during herbal processing to investigate the effects of an adjuvant (e.g., wine), steaming vs stir-frying and the optimal processing time. METHODS: An HPLC-DAD-MS method was developed to determine the major constituents of the RC processed by one of the four processing methods, i.e., stir-frying, steaming, stir-frying with rice wine and steaming with rice wine. Processing was conducted over 60 min. Six major compounds, namely ferulic acid, senkyunolide I, senkyunolide H, senkyunolide A, Z-ligustilide and levistolide A, were selected as markers to analyze the effects on the markers' levels of the different processing methods and optimize the processing time. RESULTS: The results indicated that (a) processing with wine had no discernible impact on the amounts of the six chemical markers in RC; (b) the amounts of the major constituents of RC subjected to steam processing were higher than those of the RC subjected to stir-fry processing. CONCLUSION: Among the four different methods evaluated for RC processing, steaming was better and the optimal time for steaming RC was 40 min. PMID- 27222660 TI - The structure and regulation of Cullin 2 based E3 ubiquitin ligases and their biological functions. AB - BACKGROUND: Cullin-RING E3 ubiquitin ligase complexes play a central role in targeting cellular proteins for ubiquitination-dependent protein turnover through 26S proteasome. Cullin-2 is a member of the Cullin family, and it serves as a scaffold protein for Elongin B and C, Rbx1 and various substrate recognition receptors to form E3 ubiquitin ligases. MAIN BODY OF THE ABSTRACT: First, the composition, structure and the regulation of Cullin-2 based E3 ubiquitin ligases were introduced. Then the targets, the biological functions of complexes that use VHL, Lrr-1, Fem1b, Prame, Zyg-11, BAF250, Rack1 as substrate targeting subunits were described, and their involvement in diseases was discussed. A small molecule inhibitor of Cullins as a potential anti-cancer drug was introduced. Furthermore, proteins with VHL box that might bind to Cullin-2 were described. Finally, how different viral proteins form E3 ubiquitin ligase complexes with Cullin-2 to counter host viral defense were explained. CONCLUSIONS: Cullin-2 based E3 ubiquitin ligases, using many different substrate recognition receptors, recognize a number of substrates and regulate their protein stability. These complexes play critical roles in biological processes and diseases such as cancer, germline differentiation and viral defense. Through the better understanding of their biology, we can devise and develop new therapeutic strategies to treat cancers, inherited diseases and viral infections. PMID- 27222662 TI - Systemic manifestations of hepatitis C infection. AB - Chronic hepatitis C (HCV) is a common infection affecting 185 million people worldwide. The most common manifestation of chronic HCV is progressive liver fibrosis, cirrhosis, liver failure and hepatocellular carcinoma. However, several systemic manifestations of HCV have been recognized and reported in the literature. The purpose of this review is to assimilate published literature based on evidence to categorize these extrahepatic manifestations with the likelihood of a causal association with HCV. Exciting recent developments have resulted in simple all oral interferon-free highly effective therapy for HCV. However, this treatment is also expensive and less accessible to most affected individuals as treatment recommendations are based on stage of liver fibrosis. Expanding the scope of HCV therapy to those with extrahepatic manifestations beyond what is currently recommended will significantly reduce the morbidity and mortality in this aging population. PMID- 27222663 TI - Day clinic and inpatient psychotherapy of depression (DIP-D): qualitative results from a randomized controlled study. AB - OBJECTIVE: Depressive disorders are among the most common psychiatric disorders. For severely depressed patients, day clinic and inpatient settings represent important treatment options. However, little is known about patients' perceptions of the different levels of care. This study aimed to obtain an in-depth analysis of depressive patients' experiences of day clinic and inpatient treatment in a combined clinical setting. METHODS: Following a randomized controlled trial comparing day clinic and inpatient psychotherapy for depression (Dinger et al. in Psychother Psychosom 83:194-195, 2014), a sample of depressive patients (n = 35) was invited to participate in a semi-structured interview during an early follow up 4 weeks after discharge. A qualitative analysis of interview transcripts was performed following the principles of constructivist thematic analysis. RESULTS: Following analysis, 1355 single codes were identified from which five main categories and 26 themes were derived for both groups. In regard to patient group integration and skill transfer to everyday life, distinct differences could be observed between the day clinic and inpatient group. CONCLUSION: While adjustment to therapeutic setting and patient group integration seem to be facilitated by inpatient treatment, the day clinical setting appears to promote treatment integration into patients' everyday contexts, aiding treatment-related skill transfer to everyday life as well as alleviating discharge from clinic treatment. Further studies on depressive subject groups in day clinic and inpatient treatment should investigate aspects of group cohesion and treatment integration in relation to therapeutic outcome. PMID- 27222664 TI - Production of a functional cell wall-anchored minicellulosome by recombinant Clostridium acetobutylicum ATCC 824. AB - BACKGROUND: The use of fossil fuels is no longer tenable. Not only are they a finite resource, their use is damaging the environment through pollution and global warming. Alternative, environmentally friendly, renewable sources of chemicals and fuels are required. To date, the focus has been on using lignocellulose as a feedstock for microbial fermentation. However, its recalcitrance to deconstruction is making the development of economic processes extremely challenging. One solution is the generation of an organism suitable for use in consolidated bioprocessing (CBP), i.e. one able to both hydrolyse lignocellulose and ferment the released sugars, and this represents an important goal for synthetic biology. We aim to use synthetic biology to develop the solventogenic bacterium C. acetobutylicum as a CBP organism through the introduction of a cellulosome, a complex of cellulolytic enzymes bound to a scaffold protein called a scaffoldin. In previous work, we were able to demonstrate the in vivo production of a C. thermocellum-derived minicellulosome by recombinant strains of C. acetobutylicum, and aim to develop on this success, addressing potential issues with the previous strategy. RESULTS: The genes for the cellulosomal enzymes Cel9G, Cel48F, and Xyn10A from C. cellulolyticum were integrated into the C. acetobutylicum genome using Allele-Coupled Exchange (ACE) technology, along with a miniscaffoldin derived from C. cellulolyticum CipC. The possibility of anchoring the recombinant cellulosome to the cell surface using the native sortase system was assessed, and the cellulolytic properties of the recombinant strains were assayed via plate growth, batch fermentation and sugar release assays. CONCLUSIONS: We have been able to demonstrate the synthesis and in vivo assembly of a four-component minicellulosome by recombinant C. acetobutylicum strains. Furthermore, we have been able to anchor a minicellulosome to the C. acetobutylicum cell wall by the use of the native sortase system. The recombinant strains display an improved growth phenotype on xylan and an increase in released reducing sugar from several substrates including untreated powdered wheat straw. This constitutes an important milestone towards the development of a truly cellulolytic strain suitable for CBP. PMID- 27222665 TI - Exploring glycoside hydrolases and accessory proteins from wood decay fungi to enhance sugarcane bagasse saccharification. AB - BACKGROUND: Glycoside hydrolases (GHs) and accessory proteins are key components for efficient and cost-effective enzymatic hydrolysis of polysaccharides in modern, biochemically based biorefineries. Currently, commercialized GHs and accessory proteins are produced by ascomycetes. However, the role of wood decay basidiomycetes proteins in biomass saccharification has not been extensively pursued. Wood decay fungi degrade polysaccharides in highly lignified tissues in natural environments, and are a promising enzyme source for improving enzymatic cocktails that are designed for in vitro lignocellulose conversion. RESULTS: GHs and accessory proteins were produced by representative brown- and white-rot fungi, Laetiporus sulphureus and Pleurotus ostreatus, respectively. Concentrated protein extracts were then used to amend commercial enzymatic cocktails for saccharification of alkaline-sulfite pretreated sugarcane bagasse. The main enzymatic activities found in the wood decay fungal protein extracts were attributed to endoglucanases, xylanases and beta-glucosidases. Cellobiohydrolase (CBH) activities in the L. sulphureus and P. ostreatus extracts were low and nonexistent, respectively. The initial glucan conversion rates were boosted when the wood decay fungal proteins were used to replace half of the enzymes from the commercial cocktails. L. sulphureus proteins increased the glucan conversion levels, with values above those observed for the full load of commercial enzymes. Wood decay fungal proteins also enhanced the xylan conversion efficiency due to their high xylanase activities. Proteomic studies revealed 104 and 45 different proteins in the P. ostreatus and L. sulphureus extracts, respectively. The enhancement of the saccharification of alkaline-pretreated substrates by the modified enzymatic cocktails was attributed to the following protein families: GH5- and GH45-endoglucanases, GH3-beta-glucosidases, and GH10-xylanases. CONCLUSIONS: The extracellular proteins produced by wood decay fungi provide useful tools to improve commercial enzyme cocktails that are currently used for the saccharification of alkaline-pretreated lignocellulosic substrates. The relevant proteins encompass multiple glycoside hydrolase families, including the GH5- and GH45-endoglucanases, GH3-beta-glucosidases, and GH10-xylanases. PMID- 27222666 TI - Cellular adhesiveness and cellulolytic capacity in Anaerolineae revealed by omics based genome interpretation. AB - BACKGROUND: The Anaerolineae lineage of Chloroflexi had been identified as one of the core microbial populations in anaerobic digesters; however, the ecological role of the Anaerolineae remains uncertain due to the scarcity of isolates and annotated genome sequences. Our previous metatranscriptional analysis revealed this prevalent population that showed minimum involvement in the main pathways of cellulose hydrolysis and subsequent methanogenesis in the thermophilic cellulose fermentative consortium (TCF). RESULTS: In further pursuit, five high-quality curated draft genomes (>98 % completeness) of this population, including two affiliated with the inaccessible lineage of SBR1031, were retrieved by sequence based multi-dimensional coverage binning. Comparative genomic analyses revealed versatile genetic capabilities for carbohydrate-based fermentative lifestyle including key genes catalyzing cellulose hydrolysis in Anaerolinea phylotypes. However, the low transcriptional activities of carbohydrate-active genes (CAGs) excluded cellulolytic capability as the selective advantage for their prevalence in the community. Instead, a substantially active type VI pili (Tfp) assembly was observed. Expression of the tight adherence protein on the Tfp indicated its function for cellular attachment which was further testified to be more likely related to cell aggregation other than cellulose surface adhesion. Meanwhile, this Tfp structure was found not contributing to syntrophic methanogenesis. Members of the SBR1031 encoded key genes for acetogenic dehydrogenation that may allow ethanol to be used as a carbon source. CONCLUSION: The common prevalence of Anaerolineae in anaerobic digesters should be originated from advantageous cellular adhesiveness enabled by Tfp assembly other than its potential as cellulose degrader or anaerobic syntrophs. PMID- 27222669 TI - Cardiac Involvement in Ankylosing Spondylitis. AB - Ankylosing spondylitis is one of the subgroup of diseases called "seronegative spondyloarthropathy". Frequently, it affects the vertebral colon and sacroiliac joint primarily and affects the peripheral joints less often. This chronic, inflammatory and rheumatic disease can also affect the extraarticular regions of the body. The extraarticular affections can be ophthalmologic, cardiac, pulmonary or neurologic. The cardiac affection can be 2-10% in all patients. Cardiac complications such as left ventricular dysfunction, aortitis, aortic regurgitation, pericarditis and cardiomegaly are reviewed. PMID- 27222668 TI - Disagreement between two common biomarkers of global DNA methylation. AB - BACKGROUND: The quantification of global DNA methylation has been established in epigenetic screening. As more practicable alternatives to the HPLC-based gold standard, the methylation analysis of CpG islands in repeatable elements (LINE-1) and the luminometric methylation assay (LUMA) of overall 5-methylcytosine content in "CCGG" recognition sites are most widely used. Both methods are applied as virtually equivalent, despite the hints that their results only partly agree. This triggered the present agreement assessments. RESULTS: Three different human cell types (cultured MCF7 and SHSY5Y cell lines treated with different chemical modulators of DNA methylation and whole blood drawn from pain patients and healthy volunteers) were submitted to the global DNA methylation assays employing LINE-1 or LUMA-based pyrosequencing measurements. The agreement between the two bioassays was assessed using generally accepted approaches to the statistics for laboratory method comparison studies. Although global DNA methylation levels measured by the two methods correlated, five different lines of statistical evidence consistently rejected the assumption of complete agreement. Specifically, a bias was observed between the two methods. In addition, both the magnitude and direction of bias were tissue-dependent. Interassay differences could be grouped based on Bayesian statistics, and these groups allowed in turn to re-identify the originating tissue. CONCLUSIONS: Although providing partly correlated measurements of DNA methylation, interchangeability of the quantitative results obtained with LINE-1 and LUMA was jeopardized by a consistent bias between the results. Moreover, the present analyses strongly indicate a tissue specificity of the differences between the two methods. PMID- 27222667 TI - Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy. AB - The term epigenetics is defined as heritable changes in gene expression that are not due to alterations of the DNA sequence. In the last years, it has become more and more evident that dysregulated epigenetic regulatory processes have a central role in cancer onset and progression. In contrast to DNA mutations, epigenetic modifications are reversible and, hence, suitable for pharmacological interventions. Reversible histone methylation is an important process within epigenetic regulation, and the investigation of its role in cancer has led to the identification of lysine methyltransferases and demethylases as promising targets for new anticancer drugs. In this review, we describe those enzymes and their inhibitors that have already reached the first stages of clinical trials in cancer therapy, namely the histone methyltransferases DOT1L and EZH2 as well as the demethylase LSD1. PMID- 27222670 TI - Associations of Apolipoprotein A, High-Sensitivity C-Reactive Protein and Fasting Plasma Insulin in Obese Children With and Without Family History of Cardiovascular Disease. AB - BACKGROUND: The worldwide prevalence of childhood obesity has increased from 4.2% to 6.7% during the last two decades. Pediatric obesity is a major health problem, which is dramatically increasing in Greece. A variety of inflammatory variables have been also found to associate with cardiometabolic (CV) risk in obese children. The purpose of this study was to identify and examine the effects of possible CV risk factors in obese and non-obese children with and without family history (FH) of cardiovascular disease (CVD). METHODS: Sixty-eight (68) healthy children and adolescents aged 7 - 13 years participated in the study. Anthropometrical and biochemical indexes were obtained from all children as well as FH of CVD. RESULTS: Systolic blood pressure (SBP), total cholesterol (TC), triglyceride (TG), high-sensitivity C-reactive protein (hsCRP), fasting plasma insulin (FPI) and homeostasis model assessment of insulin resistance (HOMA-IR) levels were found statistically significantly higher in the obese group compared to the non-obese one. High-density lipoprotein (HDL) levels were observed to be statistically significantly lower in the obese children compared to their normal peers. CONCLUSIONS: Apolipoprotein A, hsCRP and FPI levels were significantly higher in the obese children with FH of CVD compared to the ones without FH of CVD. TC and SBP were found to be independently associated with obesity (odds ratio (OR): 1.965, 95% confidence interval (CI): 1.935 - 2.97, P < 0.031 and OR: 1.045, 95% CI: 1.016 - 1.074, P < 0.002, respectively). PMID- 27222671 TI - Oxidative Stress Measurement and Prediction of Epileptic Seizure in Children and Adults With Severe Motor and Intellectual Disabilities. AB - BACKGROUND: The medical care of severe motor and intellectual disabilities (SMID) depends on the empirical medical care. Epileptic seizure specific to SMID is difficult to suppress using anti-epileptic drugs, and its tendency to persist for long periods poses an issue. The present study was undertaken to evaluate the relationship between epileptic seizure in cases with SMID and oxidative stress in the living body by examining endogenous antioxidants, the degree of oxidation (reactive oxygen metabolites (d-ROMs)), and the biological antioxidant potential (BAP) as indicators. METHODS: Target patients were 43 SMID epilepsy patients. Blood was sampled before breakfast and medication. As for the specimen, d-ROMs and BAP were measured using the free radical analyzer. RESULTS: The present study did not reveal any correlation between endogenous antioxidants (albumin) and the frequency of epileptic seizures. On the other hand, d-ROMs were correlated with the frequency of epileptic seizure. In particular, strong correlations between the frequency of epileptic seizures and the d-ROMs/BAP ratio as well as the BAP/d ROMs ratio were noted. CONCLUSIONS: These results indicate that the use of d-ROMs and BAP as biomarkers can provide a tool for predicting the prognosis of epileptic seizures in patients with SMID. PMID- 27222672 TI - Red Cell Distribution Width and Mean Platelet Volume in Patients With Pityriasis Rosea. AB - BACKGROUND: Pityriasis rosea (PR) is an inflammatory skin disorder of unknown etiology. However, it is suggested to be related with the reactivation of human herpes virus 7 (HHV-7) and/or HHV-6. It is sometimes diffucult to distinguish PR from PR-like drug eruptions and other inflammatory disorders, so we need new parameters which are cheap and easy in determining PR. Red blood cell distribution width (RDW) and mean platelet volume (MPV) have been studied as inflammatory markers in recent studies. However, the RDW and MPV in PR patients have not been investigated. This is the first study investigating RDW and MPV parameters in PR. METHODS: This was a retrospective study of 127 patients and 127 healthy controls. MPV, RDW and the other laboratory tests were recorded. RESULTS: RDW levels of patients with PR were significantly lower than those of the controls (13.66 +/- 2.68 and 14.00 +/- 1.39, P < 0.01). The other inflammatory markers such as MPV (9.97 +/- 0.99 and 10.0 +/- 1.06, P = 0.7) and platelet (2.66.29 +/- 62.85 and 277.41 +/- 63.50, P = 0.3) were studied and statistically significant differences were not obtained. There were no significant differences found between the patient group and healthy controls in terms of hemoglobin, hematocrite, C-reactive protein (CRP), sedimentation, mean corpuscular volume (MCV), aspartate aminotransferase (AST), red blood cell (RBC), alanine aminotransferase (ALT), blood urea nitrogen (BUN), and creatinine parameters (P > 0.05). CONCLUSION: RDW can be used as a marker in diagnosing PR. PMID- 27222673 TI - Non-Ergot Dopamine Agonists Do Not Increase the Risk of Heart Failure in Parkinson's Disease Patients: A Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: In recent years, some observational studies suggested that pramipexole, a non-ergot dopamine agonist (DA) used for the treatment of Parkinson's disease (PD), may increase the risk of heart failure (HF). However, the limitations inherent in observational studies made it difficult to determine whether the excess of incident HF was related to the drug or to other determinants. Thus, some concerns remained regarding the increased putative HF risk associated with non-ergot DAs as a class or individually. METHODS: In our meta-analysis, primary endpoint was the risk of incident HF in patients with PD treated with non-ergot DAs compared to those treated with monotherapy with levodopa. Secondary outcome measures were all-cause mortality and cardiovascular events. For these purposes, only randomized controlled trials (RCTs) were considered, provided that they offered complete outcome data pertaining to the incident HF, all-cause mortality and risk of cardiovascular events. Systematic searches were performed in the databases of PubMed, Embase and ClinicalTrial.gov up to May 2015. The effect size was estimated using the pooled relative risk (RR) of non-ergot DAs versus placebo on incident HF as well as on all-cause mortality or cardiovascular events. RESULTS: Six out of 27 RCTs reported at least one case of incident HF; therefore, we included them in the RR estimate, whereas 13 RCTs were included in the meta-analysis for mortality rates and 22 RCTs were included to evaluate cardiovascular events. Treatment with non-ergot DAs did not reveal an increase in the risk of incident HF as compared with the placebo group (pooled RR: 0.95; 95% CI: 0.30 - 2.90; P = 0.893). Similarly, patients treated with non ergot DAs did not show any significant differences compared to controls with regard to all-cause mortality (pooled RR: 0.617; 95% CI: 0.330 - 1.153; P = 0.13) as well as with regard to cardiovascular events (pooled RR: 1.067; 95% CI: 0.663 1.717; P = 0.789). CONCLUSIONS: The use of non-ergot DAs in PD patients was not associated with an increased risk of incident HF, nor was it shown to increase the overall mortality or the risk of cardiovascular events compared to the PD patients taking monotherapy with levodopa alone. However, larger studies are warranted to confirm the cardiovascular safety of non-ergot DAs for PD management. PMID- 27222674 TI - Factor Analysis of Changes in Hemoglobin A1c After 12 Months of Sitagliptin Therapy in Patients With Type 2 Diabetes. AB - BACKGROUND: Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is an effective oral antidiabetic agent as both monotherapy and when combined with insulin. Data from three observational studies performed in patients with type 2 diabetes receiving sitagliptin therapy in the routine clinical setting were integrated to conduct factor analysis of the changes in hemoglobin A1c (HbA1c), body weight, and estimated glomerular filtration rate (eGFR) over 12 months. METHODS: Among patients with type 2 diabetes attending medical institutions affiliated with Kanagawa Physicians Association, those using sitagliptin were followed for 1 year. In the ASSET-K and ASSIST-K studies, patients were managed by diabetologists, while they were managed by non-diabetologists in the ATTEST-K study. Patients were not administered insulin in ASSET-K, whereas insulin was administered in ASSIST-K. HbA1c (National Glycohemoglobin Standardization Program), blood glucose (fasting/postprandial), body weight, and renal function (serum creatinine and eGFR) were the efficacy endpoints. Factor analysis was performed by analysis of variance using the magnitude of the change in HbA1c, body weight, and eGFR after 12 months of sitagliptin therapy as response variables, and the study, sex, and age as explanatory variables. RESULTS: Of 1,327 patients registered in ASSET-K (diabetologists/without insulin), 1,167 patients in ASSIST-K (diabetologists/with insulin), and 530 patients in ATTEST-K (non-diabetologists), statistical analysis was carried out on 1,074, 854, and 411 patients, respectively. There were significant inter-study differences in patient characteristics (complications, duration of diabetes, and baseline HbA1c), the sitagliptin dose, and the use of other antidiabetic agents. HbA1c decreased significantly in all three studies. According to factor analysis, the magnitude of the change in HbA1c over 12 months showed significant inter-study differences and was also significantly influenced by the age, duration of diabetes, and baseline HbA1c. CONCLUSIONS: Comparison of three observational studies identified differences in patient characteristics, treatment of diabetes (use/non-use of insulin), and the level of specialist care (diabetologist/non-diabetologist). Despite such differences, consistent reduction of HbA1c by sitagliptin was demonstrated in all three studies. The patients showing most improvement in HbA1c with sitagliptin therapy were older patients with a short duration of diabetes and high baseline HbA1c level. PMID- 27222675 TI - Current Proportion of Women Receiving Perinatal Psychosocial or Psychological Intervention in Japan. AB - BACKGROUND: In this study, we examined the current status of psychosocial or psychological intervention for women during pregnancy and the postpartum period in Japan. METHODS: We estimated the number of women receiving perinatal psychosocial or psychological intervention in Japan. On December 2015, we requested 2,462 obstetrical facilities that are members of the Japan Association of Obstetricians and Gynecologists (JAOG) to provide information on women who received psychosocial or psychological intervention during pregnancy, the hospitalization period for childbirth and the puerperal 1 month in 2014. A total of 1,305 (53.0%) of the 2,462 obstetrical facilities responded with valid information on a total of 515,373 women, accounting for approximately 52% of all deliveries that occurred in Japan during the study period. RESULTS: The number of women who received psychosocial or psychological intervention during pregnancy, the hospitalization period for childbirth and the puerperal 1 month were 4,843 (0.94%), 4,791 (0.93%) and 3,015 (0.59%), respectively. In total, 8,743 women (1.70%) received psychosocial or psychological intervention in 2014. CONCLUSION: Considering the response rate, the number of women requiring perinatal psychosocial or psychological intervention was estimated to be 16,000 per year in Japan. PMID- 27222676 TI - Normal Pressure Hydrocephalus in a Human Immunodeficiency Virus Type 1 Patient. AB - Normal pressure hydrocephalus (NPH) is a relatively common disease of adulthood characterized by a typical combination of clinical and radiological findings. In this report, we discuss a 54-year-old female presenting with symptoms suggestive of NPH and found to have a history of human immunodeficiency virus (HIV) type 1. She was not treated as she was in denial state and developed NPH as a possible complication. In the literature, there has only been one reported case of HIV type 2 causing NPH; however, no relationship has been properly documented with HIV type 1. These findings bring about a question on whether NPH is associated or a complication of HIV with awareness of this association. Earlier screening of HIV can be done in patients presenting with such symptoms, thus to prevent further progression of its complications. PMID- 27222677 TI - Complex Partial Seizure as a Manifestation of Non-Ketotic Hyperglycemia: The Needle Recovered From Haystack? AB - We present a case of a 75-year-old gentleman with undiagnosed type 2 diabetes mellitus presenting with acute onset expressive dysphasia and right hemi-paresis with no prior history of seizure. He developed clusters of stereotypical complex partial seizures which were refractory to anti-epileptic agents. He was not known to have diabetes and his brain MRI was normal. His random blood sugar measurement on admission to hospital was 30 mmol/L with HbA1c measurement of 14.8%. His seizures terminated completely when his hyperglycemia was corrected with insulin and rehydration therapy. PMID- 27222678 TI - Extramedullary Involvement by Chronic Myelogeneous Leukemia in Five Patients With Unusual Clinicopathologic Features: A Review of the Effectiveness of Tyrosine Kinase Inhibitors. AB - Chronic myelogeneous leukemia (CML) is associated with BCR-ABL1 fusion gene leading to an abnormal tyrosine kinase molecule. The accepted first-line treatment is imatinib mesylate (IM). CML uncommonly occurs in the extramedullary sites at initial presentation or relapse. Here we report five adult patients with CML who developed myeloid sarcoma (MS) while on treatment with IM. A retrospective medical chart analysis was performed to identify CML patients with MS who were diagnosed and treated at the University of Alabama at Birmingham. The age ranged between 21 and 36 years (median: 28.5) with a male to female ratio of 4:1. All of the patients were diagnosed with CML in chronic phase with initial treatment including IM. The median interval period between the initial diagnosis of CML and MS was 27 months (range 7 - 60 months). The sites of extramedullary involvement included lymph nodes (n = 2), central nervous system (n = 2) and hepatobiliary organs (n = 1). All patients were treated with either induction therapy or stem cell transplant (SCT) following the diagnosis of MS. The median survival was 16 months (range 1 - 72 months). The longest survival was observed in a patient who successfully received SCT therapy. IM is frequently used as the first therapeutic choice in new diagnosed CML; however, its penetration and effectiveness in extramedullary tissue is still unclear. The current report also supports the literature with less favorable prognosis of CML in younger individuals. PMID- 27222679 TI - An Influence of the Estimated Glomerular Filtration Rate on Improvement in Metabolic Parameters by Sodium-Glucose Cotransporter 2 Inhibitors. PMID- 27222680 TI - Sensorless Force Sensing for Minimally Invasive Surgery. AB - Robotic minimally invasive surgery (R-MIS) has achieved success in various procedures; however, the lack of haptic feedback is considered by some to be a limiting factor. The typical method to acquire tool-tissue reaction forces is attaching force sensors on surgical tools, but this complicates sterilization and makes the tool bulky. This paper explores the feasibility of using motor current to estimate tool-tissue forces and demonstrates acceptable results in terms of time delay and accuracy. This sensorless force estimation method sheds new light on the possibility of equipping existing robotic surgical systems with haptic interfaces that require no sensors and are compatible with existing sterilization methods. PMID- 27222681 TI - Reconstruction of Extensive Calvarial Exposure After Major Burn Injury in 2 Stages Using a Biodegradable Polyurethane Matrix. AB - OBJECTIVES: To share our experience of an extensive calvarial reconstruction in a severely burn-injured, elderly patient in a 2-stage procedure utilizing a novel biodegradable temporizing matrix (NovoSorb BTM), followed by autograft. MATERIALS AND METHODS: A 66-year-old patient with 75% full-thickness burns, including 7% total body surface area head and neck, with calvarial exposure of approximately 350 cm(2), complicated by acute renal failure and smoke inhalation injury. Exposed calvarium was burred down to diploe and biodegradable temporizing matrix was applied. Over the next 29 days, the biodegradable temporizing matrix integrated by vascular and tissue ingrowth from the diploe. Delamination and grafting occurred, however, at 43 days postimplantation of biodegradable temporizing matrix due to skin graft donor-site constraints. RESULTS: Graft take was complete, yielding a robust and aesthetically pleasing early result (26 days post-graft application). CONCLUSIONS: Biodegradable temporizing matrix offers an additional resource for reconstructive surgeons faced with fragile patients and complex wounds. PMID- 27222682 TI - Cervical Chondrocutaneous Branchial Remnants: A Case Report. PMID- 27222683 TI - Posterior uterine rupture secondary to use of herbs leading to peritonitis and maternal death in a primigravida following vaginal delivery of a live baby in western Uganda: a case report. AB - Uterine rupture is a potentially avoidable complication resulting in poor perinatal and maternal outcomes. This case had a number of unusual features including delivery of a healthy live baby; spontaneous posterior uterine rupture in a primigravida (and unscarred uterus); and delayed presentation with signs of peritonitis and sepsis rather than haemorrhage. A 19-year old primigravida had a vaginal delivery of a live infant at term, reporting having taken herbs to induce labour. She deteriorated and was transferred to our unit where she was found to have reduced consciousness, a distended abdomen and signs of sepsis. At laparotomy there was blood-stained ascites, signs of peritonitis and a posterior lower segment uterine rupture. A sub-total hysterectomy was performed but the patient's condition worsened resulting in maternal death 5 days post-operatively. This case highlights a number of differences in the presentation, management and outcomes of uterine rupture in resource-poor compared to resource-rich countries. PMID- 27222684 TI - Risk factors and distribution of oncogenic strains of human papilloma virus in women presenting for cervical cancer screening in Port Harcourt, Nigeria. AB - INTRODUCTION: Human papilloma virus(HPV) accounts for most cases of cervical cancer with high risk HPV(hrHPV) genotypes largely responsible. The objective is to ascertain the distribution of oncogenic strains of human papilloma virus genotypes and predisposing risk factors in women presenting for cervical cancer screening in Nigeria. METHODS: A cross-sectional study of 80 women who presented for cervical cancer screening. The biodata of the participants, the presence of risk factors to HPV were recorded and hrHPV were identified using PCR technique. The information obtained was processed using the SPSS version 20 software. Results were presented in tables, test of significance and association done using student's t-test and Odds ratio, with P value < 0.05 as significant. RESULTS: The age range of patients was 19-62 years with prevalence of hrHPV of 10%. HrHPV are more in patients with more than one life time sexual partner (OR 1.26,95%CI 0.13 29.99), multiple sexual partners (OR 1.55, 95% CI 0.28-8.70), early coitarche (OR 1.57, 95% CI 0.14-15.00) and previous STI (OR 150, 95%CI 9.53-1979. 62). Four hrHPV genotypes: 16, 18, 31 and 35 were detected. CONCLUSION: HPV genotype 18 was predominant in Port Harcourt, Nigeria. High risk sexual behaviours are associated with acquisition of hrHPV. PMID- 27222685 TI - [Analysis of predictors of malignancy of nodular goiters: about 500 cases]. AB - Thyroid nodules are very common and less than 10% of them are malignant. They pose a serious diagnostic and therapeutic problem with respect to their benign or malignant nature. The study of some clinical and paraclinical factors for presumed malignancy makes it possible to codify appropriate therapeutic strategy. The aim of this study was to investigate predictors of malignancy in nodular goiters and to compare our results with those reported in the literature. This retrospective study consisted of 500 cases of nodular goiter operated in the Department of Otorhinolaryngology (ear, nose and throat or ENT) and Head and Neck Surgery at Avicenne military hospital in Marrakech between 2006 and 2012. The percentage of cancers was 6,8%. The average age of our patients was 46 years, with a sex-ratio of 5 (F/H). The hard nature of the nodule was present in 94,4% of the cases of cancer by palpation; irregular boundaries were present in 64.70% of the cases of cancer. Three nodules were fixed and malignant. Cervical lymphadenopathy were observed in 8 patients, 7 of which had cancer. Ultrasound examination showed hypoechoic appearance in 61,8% of the malignant nodules, with smooth-edges in 88,24% of the cases. Intranodular vascularization was found in 35,3% of the cases of cancers, with microcalcifications in 55,9% of the cases. Perinodular hypoechoic halo was incomplete in 73,5% of the cases of cancer. Our patients were euthyroid in 84,6% of the cases. Predictors of malignancy in nodular goiters were present in our first clinical study: patients over the age of 60 years, hard consistency of nodule, fixity, irregular and poorly defined character by palpation, as well as presence of cervical adenopathy on examination; and echographic features: hypoechoic character, smooth-edges, presence of microcalcifications and visualization of intranodular vascularization with or without peri-nodular vascularization. Although some of these factors are highly predictive of malignancy, only final histology provides certainty of diagnosis. Clinicians should base their clinical practice and patient management on a body of clinical arguments. PMID- 27222687 TI - [Hepatitis B virus genotypes and evolutionary markers in chronic HBsAG patients in Bujumbura]. AB - INTRODUCTION: Hepatitis B virus infection (VHB) is a serious condition which can lead to serious complications, such as cirrhosis and hepato-cellular carcinoma (HCC). HBV genotypes greatly influence its evolution and the effectiveness of treatment. The aim was to evaluate the HBV genotypes and the evolutionary pathways of chronic HBsAG patients. METHODS: A cross-sectional study was conducted at the University Hospital of Kamenge and at the Digestive and liver diseases Center "CEMADIF" between June 2013 and Mai 2014. Genotyping, quantitative assay of HBeAG and HBV DNA levels were determined in the CERBA Laboratory Cergy Pontoise, France. Fibrotest or Fibroscan were used to evaluate fibrosis. RESULTS: In total 33 patients (52,4% were males, median age 38,1) were enrolled. According to evolutionary markers, 112 patients (78,3%) had negative HBeAG. As regards the viral load, 106 patients (74,2%) had viremia lower than 2000UI/ml and minimal fibrosis below 7 kPa according FibroScan. Of these, 13 patients had undetectable HBV DNA (<20UI/ml). The others 37 patients (26,8%) had a viral load higher than 2000UI/ml and, among them, 31 were HBeAg positive(>0,8UI/ml). It was possible to determine genotype in 51 patients who had a high enough viremia to technically enable dosing. These patients had genotype A. CONCLUSION: HBV genotype-A is the most common in Bujumbura. It is associated with HBV inactive carries. PMID- 27222686 TI - Knowledge and prevalence of Human African Trypanosomiasis among residents of Kachia grazing reserve, Kachia local government area, Kaduna state, Nigeria, 2012. AB - INTRODUCTION: Human African Trypanosomiasis (HAT) is a vector borne parasitic disease transmitted to humans by infected tse-tse flies cause morbidity including delayed child mental development. Reports of nuisance and bites from tse-tse flies by residents of Kachia grazing led to the study to determine the knowledge, practices and prevalence of HAT among residents of the grazing reserve. METHODS: We conducted active case search in a cross-sectional study using multi-stage sampling with probability proportionate to size. We administered structured questionnaire on Knowledge, practices relating to HAT prevention and screened for HAT using card agglutination test for Trypanosomiasis (CATT). Knowledge of HAT was scored 0-5 and categorized good (3-5) and poor (0-2) based on score, predisposition to risk of HAT as exposure to >=two risk factors and, a case of HAT as any respondent that tested positive on CATT. We analysed data using Epi info and MS-excel. RESULTS: Of the 300 respondents, mean age 39(+/-17years) interviewed, 56.3% were males, 12.0% had good knowledge of HAT and 76.3% were exposed to HAT risk factors. Prevention practices included clearing of overgrown bushes around houses (99%), use of insecticidal treated nets (75.7%) and protective clothing (41.0%). Males {Odds Ratio [OR] 5.0; 95% Confidence Interval (CI) 1.8 - 13.6}, age above 40 years {OR 5.0; 95% CI 1.1 - 24.4} and family history of HAT {OR 8.7; 95% CI 2.4 - 32.1} were significantly associated with HAT knowledge. None tested positive on CATT. CONCLUSION: Despite poor knowledge of HAT, residents practiced HAT preventive measures and zero HAT prevalence was recorded. PMID- 27222688 TI - [Clinical and bacteriological profile of neonatal bacterial infection at Laquintinie Hospital, Douala (Cameroon)]. AB - INTRODUCTION: The World Health Organization has estimated that the global incidence of neonatal deaths was 2,8 million in 2015, of which 47,6% were due to infections. These infections can affect newborns babies ages 0-1 month through 3 months. METHODS: This is a prospective study conducted from 1 March to 30 June 2015 in the Neonatology service of the Laquintinie Hospital at Douala. All symptomatic newborns with or without anamnestic criteria and all asymptomatic newborns, with at least an infectious risk and a positive blood culture or an abnormal blood count or positive C-reactive protein were included in the study. RESULTS: Of the 310 newborns enrolled in the study, 300 were retained for neonatal infection, corresponding to a total incidence of 96.8%. We performed 104 cultures, of which 25 were positive, corresponding to an incidence of confirmed neonatal infection of 24%. The factors associated with infection were unexplained preterm birth < 35 weeks of amenorrhea (45,1%) and neonatal resuscitation (34,8%). Fever (56%) and neurological disorders (48.8%) were the most frequent clinical symptoms. Gram-negative bacteria were the most frequent germs (56%). Imipenem (95%) and amikacin (66.7%) were the most effective antibiotics. Outcome was favorable in 66,4% of cases and the overall mortality rate was 33,6%. CONCLUSION: This study revealed a high prevalence of neonatal bacterial infection in this Hospital. Bacterial ecology was dominated by Gram-negative bacteria. It was recorded a significant resistance to the most widely used antibiotics and a fairly high mortality. PMID- 27222690 TI - [The problem of the use of Long-Lasting Insecticide Impregnated Mosquito Nets (LLIN) in children less than five years of age in Democratic Republic of Congo]. AB - INTRODUCTION: Malaria is a vector-borne infectious disease caused by parasites, which represents a major public health problem in tropical countries, especially Sub-Saharan Africa. This study aimed to identify the level of LLIN use in children less than 5 years in Mumbunda health zone. METHODS: The crosscutting study was conducted from 25 to 27 October 2013 and involved a random sample of 410 households with at least a child under 5 years. RESULTS: Among households reported owning LLIN, 13.1% (n=54) of respondents reported having used it among children under 5 years and 80.2% to everybody. In 22.0% of cases, respondents cited lack of money as the reason for non-possession of LLIN. This study found that 79.8% of respondents declared having used LLIN to protect themselves against malaria and 66.3% to protect themselves against mosquito biking. LLIN was spread under shade for 24h before being used, for the first time, by 77.9% of the households. The respondents reported (15.3%, n=63) receiving information by the media about the use of mosquito net. Healthcare personnel was the most important source to demonstrate the correct way to use LLIN for 51.2% of the households. CONCLUSION: The success of Roll Back Malaria must necessarily pass through prevention, follow-up and evaluation of the use of impregnated mosquito nets in Mumbunda health zone. PMID- 27222689 TI - Determinants of default to fully completion of immunization among children aged 12 to 23 months in south Ethiopia: unmatched case-control study. AB - INTRODUCTION: Immunization is a cost effective interventions of vaccine preventable disease. There is still, 2.5 million children die by vaccine preventable disease every year in developing countries. In Ethiopia, default to fully completion of child immunization is high and determinants of default to completions are not explored well in the study setting. The aim of the study was to identify determinants of default to fully completion of immunization among children between ages 12 to 23 months in Sodo Zurea District, Southern Ethiopia. METHODS: Community based unmatched case-control study was conducted. Census was done to identify cases and controls before the actual data collection. A total of 344 samples (172 cases and 172 controls) were selected by simple random sampling technique. Cases were children in the age group of 12 to 23 months old who missed at least one dose from the recommended schedule. Bivariable and multivariable binary logistic regression was used to identify the determinant factors. Odds ratio, 95%CI and p - value less than 0.05 was used to measure the presence and strength of the association. RESULTS: Mothers of infants who are unable to read and write (AOR=8.9; 95%CI: 2.4, 33.9) and attended primary school (AOR=4.1; 95% CI:1.4-15.8), mothers who had no postnatal care follow up (AOR=0.4; 95%CI: 0.3, 0.7), good maternal knowledge towards immunization (AOR= 0.5; 95% CI: 0.3, 0.8) and maternal favorable perception towards uses of health institution for maternal and child care (AOR= 0.2; 95% CI: 0.1, 0.6) were significant determinant factors to default to fully completion of immunization. CONCLUSION: Working on maternal education, postnatal care follow up, promoting maternal knowledge and perception about child immunization are recommended measures to mitigate defaults to complete immunization. PMID- 27222691 TI - Preoperative fasting times in elective surgical patients at a referral Hospital in Botswana. AB - INTRODUCTION: Adults and children are required to fast before anaesthesia to reduce the risk of regurgitation and aspiration of gastric contents. However, prolonged periods of fasting are unnecessary and may cause complications. This study was conducted to evaluate preoperative fasting period in our centre and compare it with the ASA recommendations and factors that influence fasting periods. METHODS: This is a cross-sectional study of preoperative fasting times among elective surgical patients. A total numbers of 260 patients were interviewed as they arrived at the reception area of operating theatre using questionnaire. RESULTS: Majority of patients (98.1%) were instructed to fast from midnight. Fifteen patients (5.8%) reported that they were told the importance of preoperative fasting. The mean fasting period were 15.9+/-2.5 h (range 12.0-25.3 h) for solids and 15.3+/-2.3 h (range 12.0-22.0 h) for liquids. The mean duration of fasting was significantly longer for patients operated after midday compared to those operated before midday, p<0.001. CONCLUSION: The mean fasting periods were 7.65 times longer for clear liquid and 2.5 times for solids than the ASA guidelines. It is imperative that the Hospital should establish Preoperative fasting policies and teach the staff who should ensure compliance with guidelines. PMID- 27222692 TI - Pregnancy rate and birth outcomes among women receiving antiretroviral therapy in Burkina Faso: a retrospective cohort study. AB - INTRODUCTION: In Sub-Saharan Africa, few studies reported pregnancy incidence and outcomes in women taking antiretroviral therapy (ART). This survey aims to estimate the incidence and outcomes of pregnancy in a cohort of HIV positive women initiating ART in Bobo-Dioulasso, Burkina Faso. METHODS: We carried out a retrospective cohort study. We selected women in childbearing age initiating ART and followed up in Bobo-Dioulasso teaching hospital between January 2005 and June 2011. The incidence of pregnancies during follow-up was calculated. Childbirth was defined by the expulsion of a fetus after 22 weeks of amenorrhea. Before this term, it is an abortion. Childbirth is said premature if it occurs before 37 weeks of gestation, to term if it occurs between the 38th and the 42nd week. The annual age-standardized fertility rates were calculated using the baseline population from the 2010 demographic and health survey (DHS) in Burkina Faso. RESULTS: A total of 1,763 women of childbearing age under ART were included in the study. They ranged between 18 and 48 years old with a median of 35 years old. A total of 222 pregnancies were observed during 4639 women-years of follow-up, corresponding to an incidence density of 5 pregnancies for 100 women-years (95% CI: 4.2-5.5). Among the 222 pregnancies recorded, 9(4.0%) ended with abortion, 205(92.4%) with childbirth (including 15 premature childbirths); the outcome of 8(3.6%) pregnancies were unknown abortion. Live birth and stillborn rates were 94.0% (193/205) and 6.0% respectively. The standard fertility rate in our cohort was 45 live births for 1,000 women-years. The general decrease in fertility rates was 66.0% among women infected with HIV compared to the overall population. CONCLUSION: This study shows a low pregnancy incidence among women initiating ART as compared to their peers from the general population. Pregnancies that occurred during ART generally end with live births. Care packages for HIV infected women of childbearing age must include reproductive health services to better address this issue. PMID- 27222693 TI - [Vaginal colonization by group B streptococcus among pregnant women in the region of Marrakech]. AB - INTRODUCTION: Group B streptococcus is the main etiological agent of maternal and fetal infections, sepsis and meningitis in the term newborns. The objective is to determine group B streptococcal (GBS) carriage rate in vagina of term pregnant women. METHODS: Vaginal swab was performed prospectively in 275 pregnant women in labor, prior to entering the delivery room over a period of 6 months. RESULTS: Colonization rate was 20.2%. The bearing was variable according to the gestational age, it constitutes 57.5% between 37 and 38 weeks of amenorrhoea. None of the risk factors was statistically predictive for maternal GBS colonization. CONCLUSION: Screening should be performed from 37 weeks of amenorrhoea and, as colonization is intermittent, a negative swab result does not ensure that GBS colonization is eradicate at birth. PMID- 27222694 TI - Optimal Design of Cable-Driven Manipulators Using Particle Swarm Optimization. AB - The design of cable-driven manipulators is complicated by the unidirectional nature of the cables, which results in extra actuators and limited workspaces. Furthermore, the particular arrangement of the cables and the geometry of the robot pose have a significant effect on the cable tension required to effect a desired joint torque. For a sufficiently complex robot, the identification of a satisfactory cable architecture can be difficult and can result in multiply redundant actuators and performance limitations based on workspace size and cable tensions. This work leverages previous research into the workspace analysis of cable systems combined with stochastic optimization to develop a generalized methodology for designing optimized cable routings for a given robot and desired task. A cable-driven robot leg performing a walking-gait motion is used as a motivating example to illustrate the methodology application. The components of the methodology are described, and the process is applied to the example problem. An optimal cable routing is identified, which provides the necessary controllable workspace to perform the desired task and enables the robot to perform that task with minimal cable tensions. A robot leg is constructed according to this routing and used to validate the theoretical model and to demonstrate the effectiveness of the resulting cable architecture. PMID- 27222695 TI - Three-Dimensional Reconstruction of Blood Vessels of the Human Retina by Fractal Interpolation. AB - In this work, data from two-dimensional (2D) images of the human retina were taken as a case study. First, the characteristic data points had been removed using the Douglas-Peucker (DP) method, and subsequently, more data points were added using random fractal interpolation approach, to reconstruct a three dimensional (3D) model of the blood vessel. By visualizing the result, we can see that all the small blood vessels in the human retina are more visible and detailed. This algorithm of 3D reconstruction has the advantage of being fast with calculation time less than 40 s and also can reduce the 3D image storage level on a disk with a reduction ratio between 78% and 96.65%. PMID- 27222696 TI - Implantable Port Devices, Complications and outcome in Pediatric Cancer, a Retrospective Study. AB - BACKGROUND: Peripheral blood vessels, due to availability are used for many years in cancer patients, however in patients with potentially harmful drugs to skin (vesicant drugs) or difficult accessibility to vessels, the use of implantable port (totally implantable venous access port-TIVAP) devices with central vascular access are important. MATERIALS AND METHODS: In this retrospective study, 85 pediatric cancer patients younger than 16 years, with TIVAP implantation, were followed for their complications and outcome. In addition to demographic data, patients' port complications were assessed and compared with published articles. RESULTS: Mean days of implanted port usage were 531 +/- 358 days in all patients. This period was 287 +/-194 days in complicated patients. Complications included as infection (tunnel infection and catheter related blood-stream infection), malfunction and thrombosis, skin erosion, tube avulsion, and tube adhesion to the adjacent vessels were seen in 30.6% of patients. CONCLUSION: According to the published data and this experience, the most common complications in TIVAP are infection and catheter malfunction. It is important to notice that in order to prolong its efficacious life, effective sterilization methods, prevention of clot formation and trauma, are the most useful measures. PMID- 27222697 TI - Effect of Chewing Gum on Oral Mucositis in Children Undergoing Chemotherapy: A Randomized Controlled Study. AB - BACKGROUND: Oral mucositis is an adverse effect of chemotherapy. Type of chemotherapy regimen is the most important factor causing mucositis. Oral mucositis is usually associated with transient decrease in saliva production. The goal was to study effects of gum consumption on oral mucositis in children undergoing chemotherapy. MATERIALS AND METHOD: This randomized controlled trial was done in Amir Kabir Hospital, Arak, Iran. 130 children 5 to 15 years of age were studied. Control group was composed of 65 children who received mucotoxic drugs. Test group was made up of 65 patients received similar drugs in addition to sugar free gums. Patients consumed 6 pieces of gums per day for 15 days. A standardized follow up form and World Health Organization (WHO) grading system for oral mucositis were used for evaluation of patients during 15 days of treatment. RESULTS: Severe oral mucositis occurred in 30 (46%) of 65 patients in the test group and in 26 of 65 (40%) patients in the control group. Difference was not statistically significant (P > 0.05). Rate of mild to moderate mucoitis (grade 1 and 2) was significantly lower in patients who used gums (15 % vs. 35%, P < 0.05). CONCLUSION: Our study showed that stimulation of saliva flow by chewing gum could decrease mild to moderate inflammatory injuries of the oral mucosa during chemotherapy. However, it was not effective to subside severe mucositis. PMID- 27222698 TI - Incidence and Trend of Childhood and Adolescent Cancers in Yazd, Iran. AB - BACKGROUND: Data on childhood and adolescent malignant tumors incidence are skimp in developing countries. In this study, we analyzed the incidence and trend of childhood and adolescent cancers in Yazd city, center of Iran between Jan 2004 and Dec 2013. MATERIAL AND METHODS: The various types of malignant tumors were grouped pursuant to the International Classification for Cancer in Children. To analyze the data, descriptive and illative statistical methods were used. RESULTS: Two hundred twenty-two patients with a malignancy aged less than 18 years were studied with a male to female ratio of 1.36.The mean age of patients was 9.88 (+/-5.7) years. Leukemia with the frequency of 84 (37.8%) and after that lymphoid malignancies with the frequency of 49 (22.1%) were the most common cancers. There was a low range of oscillation in the incidence rate of malignancies during this period of time (P value= 0.081). Malignancies were mostly in males (P value=0.057) but the whole process of malignancy incidence had gone toward the higher rate of incidence in females. Incidence rate of cancers types was steady. Malignancy incidence was 3-7 cases in hundred of thousands except a year of which this incidence rate was estimated 13.4. CONCLUSION: Leukemias and lymphomas were the main cancers in the center of Iran. Childhood and adolescent malignancies may be considerably under-recorded in our province .A childhood and adolescent cancer registry is necessary for exact analysis of these types of malignancies. PMID- 27222699 TI - Clinical Features and Treatment Outcomes of Primary Immune Thrombocytopenic Purpura in Hospitalized Children Under 2-Years Old. AB - BACKGROUND: Immune thrombocytopenic purpura (ITP) is the most prevalent cause of thrombocytopenia in children. Despite the importance of ITP in children under 2 years old, only a few publications are available in the literature.ITP usually presents itself as isolated thrombocytopenia and mucocutaneous bleeding. MATERIALS AND METHODS: This study was conducted on 187 under 2-year-old children diagnosed with ITP and treated at Dr. Sheikh Hospital from 2004 to 2011.In this retrospective study, clinical symptoms, laboratory findings, history of viral infections, vaccination history, and treatment efficacy in children under 2-years old with ITP were investigated.Patients were followed for one year after being discharged from the hospital. RESULTS: The risk of the disease developing into chronic form was higher in older children (0.001). ITP in children under 3-months old was significantly associated with vaccination (p=0.007). There was no significant differences between male and female patients in regards to newly diagnosed ITP, persistent, and chronic disease status (p = 0.21). No significant difference in bleeding symptoms was observed between patients under 3-months old and 3 to 24-months old (p=0.18). CONCLUSION: Infantile ITP respond favorably to treatment. The risk of the disease developing into chronic form is higher in 3-to 24-month-old children compared to under-three-month olds. PMID- 27222700 TI - Evaluation Efficacy of Ferrous Sulfate Therapy on Headaches of 5-15 Years Old Iron Deficient Children with Migraine. AB - BACKGROUND: Some researches have shown the association between iron deficiency and migraine headache in adults. The aim of present study was to evaluate efficacy of ferrous sulfate treatment on migraine headaches of 5-15 years old migraineur children with iron deficiency. MATERIALS AND METHODS: In a quasi- experimental study, monthly frequency, severity, duration and disability of headaches of 5-15 years old migraineur children that prophylactic therapy was indicated in them and had iron deficiency who were referred to Pediatric Neurology Clinic of Shahid Sadoughi University of Medical Sciences, Yazd, Iran between 2013 and 2015 and were treated with 2mg/kg/day topiramate plus 4mg/kg/day of ferrous sulfate for three consecutive months, were evaluated and headache characteristics before and after treatment were compared. RESULTS: In this study, 98 children with mean age of 9.72+/-3.19 were evaluated that 31children (31.6%) had iron deficiency. Monthly frequency (22.89+/-7.18 vs.14.5+/-4.56, P= 0.02), severity score (8.12+/- 1.76 vs. 5.03+/-1.15, P= 0.02) and disability score of headache (38.23+/-10.7vs. 30.12+/-7.46, P= 0.03) were more in children with iron deficiency. Iron therapy was effective in decreasing of monthlyfrequency 22.89+/- 7.18 vs. 10.13+/-4.51, P = 0.001), severity score (8.12+/-1.76 vs. 5.11+/-1.62, P =0.001), duration (2.14+/-1.23 vs.1.14+/-1.01, P= 0.001) and disability score of headache (38.23+/-10.7 vs. 22.87+/-8.65, P= 0.01). CONCLUSION: In children, iron deficiency increased monthly frequency, severity and disability of migraine headache and ferrous sulfate can be used as a safe and effective drug in migraine prophylaxis. PMID- 27222701 TI - Hematological Indices in Children with Non-organic Failure to Thrive: a Case Control Study. AB - BACKGROUND: Non-organic failure to thrive (NFTT) is the most common cause of failure to thrive (FTT) which is attributed to inadequate nutrition due to economic factors or parental neglect . NFTT can lead to a vicious cycle of poor and inadequate eating and severity of anemia. The aim of this study was to determine the hematological indices in children with NFTT. MATERIALS AND METHODS: In a cross sectional case control study, iron status and blood indices of forty five aged 6-60 months children with NFTT were evaluated and compared with 45 healthy control children (with matching of age and sex). RESULTS: In this study, the prevalence of anemia was 48.9% in NFTT compared to 11.4% in the control group (p<0.001). Microcytic anemia was significantly more prevalent among the subjects than the controls (77.8% versus 27.3%; p<0. 001). The serum iron level was 73.2 and 62.8 mcg/dl for the case and control groups (P=0.29). The ferritin level in the study group was 29.8 versus 35.47 ng/ml in the control group (p=0.227). The prevalence of iron deficiency anemia among children with mild, moderate, and severe underweight was 44.4%, 45.5%, and 48%, respectively. The highest prevalence of iron-deficiency anemia was seen between age group of 12 and 24 months (p<0.05). CONCLUSION: Based on the results of this study, a correlation between malnutrition and anemia was found. However, further studies are needed to assess and confirm the current outcomes. PMID- 27222702 TI - Candidiasis in Pediatrics; Identification and In vitro Antifungal Susceptibility of the Clinical Isolates. AB - BACKGROUND: Candida species are normal microflora of oral cavity, vagina, and gastrointestinal tract. They are the third most prevalent cause of pediatric health care-associated bloodstream fungal infection. This study aimed to provide an epidemiological feature of candidiasis and also presents an antifungal susceptibility profile of clinical Candida isolates among children. MATERIALS AND METHODS: During July 2013 to February 2015, 105 patients from different hospitals of Isfahan, Iran, were examined for candidiasis by phenotypic tests. Samples were obtained from nail clippings, blood, thrush, BAL, urine, oropharynx, skin, and eye discharge. The age range of patients was between 18 days to 16 years. Genomic DNA of isolates was extracted and ITS1-5.8SrDNA-ITS2 region was amplified by ITS1 and ITS2 primers. The PCR products were digested using the restriction enzyme MspI. Minimum inhibitory concentration (MICs) was determined using microdilution broth method according to the clinical and laboratory standards institute (CLSI) M27-A3 and M27-S4 documents. RESULTS: Forty-three patients (40.9%) had Candida infection.The most clinical strains were isolated from nail infections (39.5%), and candidemia (13.9%). Candida albicans was the most prevalent species (46.5%). MICs ranges for amphotericin B, fluconazole, and itraconazole were (0.025-0.75 ug/ml), (0.125-16 ug/ml), and (0.094-2 ug/ml), respectively. CONCLUSION: Due to high incidence of Candida infections among children, increasing of fatal infection like candidemia, and emersion of antifungal resistance Candida isolates, early and precise identification of the Candida species and determination of antifungal susceptibility patterns of clinical isolates may lead to better management of the infection. PMID- 27222703 TI - Association Between RFC1 G80A Polymorphism and Acute Lymphoblastic Leukemia: a Review and Meta-Analysis of 10 Studies. AB - BACKGROUND: Evidence indicates RFC1 G80A polymorphism as a risk factor for a number of cancers. Increasing studies have been conducted on the association of RFC1 G80A polymorphism with acute lymphoblastic leukemia (ALL) risk. However, the results were controversial. The aim of the present study was to derive a more precise estimation of the relationship. MATERIALS AND METHOD: PubMed, Embase, Web of Science, Cochrane database, and Google Scholar were searched to get the genetic association studies between RFC1 G80A polymorphism and ALL. All eligible studies for the period up to February 2016 were identified. Subgroup analyses regarding ethnicity were also implemented. All statistical analyses were done with CMA 2.0. RESULTS: A total of ten studies comprising of 2,168 ALL cases and 2,693 healthy controls were included in this meta-analysis. Overall, no significant association was detected for allelic model (OR = 1.029, 95 % CI 0.754 1.405, P=0.000), Dominant model (OR = 1.619, 95 % CI 0.847-3.094, P=0.145), recessive model (OR = 1.169, 95 % CI 10.764-1.790, P=0.429), and homozygote model (OR = 1.288, 95 % CI 0.928-1.788, P=0.130). However, there was an obvious association under the heterozygote model (OR = 1.368, 95 % CI 1.056- 1.772, P=0.018). Also, in the stratified analysis by ethnicity, no significant association of this polymorphism with risk of OC was found in the Asian and Caucasian populations. However, there was not significant heterogeneity between heterozygote genetic model (P = 0.15, I(2) = 33%) in Caucasian. Therefore, we utilized the fixed-effect model to merge OR value. CONCLUSION: Based on the available evidence, no association between RFC1 G80A Polymorphism and ALL risk was observed, even in the subanalysis by ethnicity. The direction of further research should focus not only on the simple relationship of RFC1 G80A Polymorphism and ALL risk, but also on gene-gene and gene-environment interaction. PMID- 27222704 TI - Severe Anemia and Helicobacter Pylori Infection in school age Children; A case reports. AB - BACKGROUND: Iron-deficiency anemia is a widespread public health problem with major consequences for human health especially, children. However, in a fraction of patients an underlying cause is never found during routine investigation. Recent studies have suggested an association between Helicobacter pylori (H. Pylori) infection and iron-deficiency anemia. CASE PRESENTATION: Here is reported four school aged children (two male, two female) with refractory severe iron deficiency anemia associated H. Pylori gastritis. Mean age of the patients was 13.62 years old and they were admitted with chief complaints of abdominal, chest pain weakness, headache and respiratory distress. Mean hemoglobin level in patients was 6.2 g/dl with persistence to iron therapy. After the diagnosis and therapy of H. pylori infection, clinical complaints, hemoglobin level and iron profiles were being normal and they gained weight. CONCLUSION: This study suggests screening of H. pylori infection and appropriate treatment in any case of refractory moderate to severe iron-deficiency anemia, especially with clinical manifestations of gastrointestinal tract in children. PMID- 27222705 TI - Hydrogen sulfide decreases high glucose/palmitate-induced autophagy in endothelial cells by the Nrf2-ROS-AMPK signaling pathway. AB - BACKGROUND: Excessive autophagy induced by extravagant oxidative stress is the main reason for diabetes-induced vascular endothelial cells dysfunction. Hydrogen sulfide (H2S) has anti-oxidative effects but its regulation on excessive autophagy of vascular endothelial cells is unclear. METHODS: In this study, aorta of db/db mice (28 weeks old) and rat aortic endothelial cells (RAECs) treated with 40 mM glucose and 500 MUM palmitate acted as type II diabetic animal and cellular models, respectively, and 100 MUMNaHS was used as an exogenous H2S donor. The apoptosis level was measured by terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL) staining and Hoechst 33342/PI staining. The activities of SOD, CAT and respiratory complexes were also measured. The mRNA levels of SOD and CAT were detected by real-time PCR. AMPK-siRNA was used to detect the effect of AMPK on autophagy. Western blotting was used to detected the protein level. RESULTS: H2S production was decreased (p < 0.05, p < 0.01) both in vitro and in vivo; NaHS treatment rescued this impairment (p < 0.05, p < 0.01). The expression of adhesive proteins was increased (p < 0.05, p < 0.01) both in vitro and in vivo; NaHS attenuated (p < 0.05, p < 0.01) these alterations. NaHS could protect endothelial cells against apoptosis induced by type II diabetes (p < 0.05, p < 0.01). Furthermore, the expressions and activities of SOD and CAT were impaired (p < 0.05, p < 0.01) in endothelial cells of diabetes II; NaHS treatment attenuated (p < 0.05) this impairment. NaHS also increased ATP production (p < 0.05) and activities of respiratory complexes (p < 0.05), and the ratio of p-AMPK to AMPK was also decreased by NaHS (p < 0.01). The level of autophagy in endothelial cells was also decreased (p < 0.05, p < 0.01) by NaHS treatment and AMPK-siRNA treatment. The expression of Nrf2 in the nuclei was increased (p < 0.05) by NaHS treatment. CONCLUSION: Exogenous H2S might protect arterial endothelial cells by suppressing excessive autophagy induced by oxidative stress through the Nrf2-ROS-AMPK signaling pathway. PMID- 27222706 TI - Tyrosine 625 plays a key role and cooperates with tyrosine 630 in MPL W515L induced signaling and myeloproliferative neoplasms. AB - BACKGROUND: Myeloproliferative neoplasms (MPN) are a group of blood cancers that boost normal blood cell production in the bone marrow. Abnormal mutations in stem cells were found accompanying with the occurrence of MPN. It has been shown that MPL mutations (MPL W515L or MPL W515K) were involved in patients with MPN. Since tyrosine residues 625 and 630 mediate normal MPL signaling, whether them affect MPL W515L-induced myeloproliferative neoplasms (MPNs) is unknown. RESULTS: In this study, we further tested their functions in MPL W515L-induced myeloproliferative neoplasms (MPNs) by substituting either or both of them with phenylalanine in MPL W515L (termed as MPL515/625, MPL515/630 and MPL515/625/630, respectively). In vitro, MPL515/630 but not MPL515/625 or MPL515/625/630 retained the ability to induce TPO-independent proliferation and increase colony-forming unit megakaryocytes (CFU-Mk). Accordingly, differential activation of the downstream signaling by four mutants was observed and constitutively active STAT5 or AKT instead of STAT3 partially compensated MPL515/625/630 function. Further support this, STAT5-deficiency impaired MPL W515L-induced CFU-Mk expansion. In vivo, MPL515/630 but not MPL515/625 or MPL515/625/630 induced typical features of MPNs with high WBC and platelet counts, splenomegaly, hepatomegaly and hypercellularity in the bone marrow. Surprisingly, MPL515/625 also caused hypercellularity of bone marrow and splenomegaly without any other significant features. We also observed differential effects of the four mutants on progenitors, myeloid cells and megakaryocytes. CONCLUSIONS: Our studies have revealed distinct features of tyrosine sites 625 and 630 in mediating MPL W515L induced megakaryocyte hyperproliferation and MPNs. Our study also suggests that MPL cytosolic phosphorylated Y625 and flanking amino acids could become targets for pharmacologic inhibition in MPNs. PMID- 27222707 TI - Postoperative pulmonary complications following major elective abdominal surgery: a cohort study. AB - BACKGROUND: Postoperative pulmonary complications (PPC) are an under-reported but major cause of perioperative morbidity and mortality. The aim of this prospective, contemporary, multicentre cohort study of unselected patients undergoing major elective abdominal surgery was to determine the incidence and effects of PPC. METHODS: Data on all major elective abdominal operations performed over a 2-week period in December 2014 were collected in six hospitals. The primary outcome measure of PPC at 7 days was used. Univariate and multivariate analyses were performed to investigate how different factors were associated with PPC and the effects of such complications. RESULTS: Two hundred sixty-eight major elective abdominal operations were performed, and the internal validation showed that the data set was 99 % accurate. Thirty-two (11.9 %) PPC were reported at 7 days. PPC was more common in patients with a history of chronic obstructive pulmonary disease compared to those with no history (26.7 vs. 10.2 %, p < 0.001). PPC was not associated with other patient factors (e.g. age, gender, body mass index or other comorbidities), type/method of operation or postoperative analgesia. The risk of PPC appeared to increase with every additional minute of operating time independent of other factors (odds ratio 1.01 (95 % confidence intervals 1.00-1.02), p = 0.007). PPC significantly increase the length of hospital stay (10 vs. 3 days). Attendance to the emergency department within 30 days (27.3 vs. 10.6 %), 30-day readmission (21.7 vs. 9.9 %) and 30-day mortality (12.5 vs. 0.0 %) was higher in those with PPC. CONCLUSIONS: PPC are common and have profound effects on outcomes. Strategies need to be considered to reduce PPC. PMID- 27222708 TI - Incidence and characteristic analysis of in-hospital falls after anesthesia. AB - BACKGROUND: In-hospital falls may result in serious clinical adverse consequences, but the effects of anesthesia in the occurrence of postoperative falls are still undetermined. Anesthesia may theoretically cause postoperative falls due to the residual pharmacologic and neuromuscular blocking effects of anesthetics. We retrospectively reviewed events of in-hospital falls occurred after anesthesia management to identify the incidence and risk factors of postanesthesia falls. METHODS: We reviewed the postanesthesia visit of patients received anesthesia in the Hualien Buddhist Tzu Chi General Hospital from January 2009 to December 2013. Falls happened within 24 h after anesthesia were recorded. The Poisson regression model was used for simultaneous analysis of the association between incidence proportion of postanesthesia falls and the potential risk factors. RESULTS: A total of 60,796 inpatients received anesthesia management over the past 5 years, and ten patients fell within 24 h after anesthesia. All cases happened in the general wards. Falls occurred more often at the bedside, presence of caregivers, and during the daytime. Patients underwent regional anesthesia, and old age significantly increased the risk of postanesthesia falls, while differences in gender and ASA physical status did not affect the occurrence of postanesthesia falls. CONCLUSIONS: The overall incidence proportion of postanesthesia falls is 1.6 cases per 10,000 patients (95 % CI 0.006 to 0.026 %) over a 24-h observation period. Falls are more commonly happened during the less expected periods after operation and are increased in the elderly and patients received regional anesthesia. This study highlights that more comprehensive clinical practice guidelines for postoperative care should be exercised to prevent the in-hospital falls. PMID- 27222709 TI - From motivation to acceptability: a survey of public attitudes towards organ donation in Denmark. AB - BACKGROUND: Over the past three decades, public attitudes to organ donation have been a subject of numerous studies focusing on donor motivation. Here, we present a fresh approach. We suggest focusing on public acceptability instead of motivation. The point is to understand public attitudes well enough to avoid risking public support for organ transplantation. We conducted the study in Denmark because there have been significant developments in public attitudes to organ donation in this country. In the 1990s, Denmark was a country with very low public support for organ donation and Denmark was the last country in Europe to introduce brain death as a legal criterion of death, whereas today Eurobarometer surveys rate Denmark as one of the European countries with the highest support for deceased organ donation from brain dead donors. METHODS: We conducted a telephone survey in Denmark (N = 1195). A questionnaire was developed on the basis of preceding qualitative studies and pilot testing and included reuse of one item from earlier surveys to facilitate historical comparison. The analysis of the data was carried out using IBM SPSS Statistics 22 and focused on descriptive statistics. RESULTS: A clear majority of 91.9 % are positive or very positive towards organ donation; 85.8 % like the idea of their body being used after their death, 85.0 % is willing to donate their own organs, 82.1 % to donate their tissue and only 2.3 % find that too much has been done to promote organ donation. There is limited support for monetary incentives for organ donation (5.8 %) and presumed consent (30.4 %), while a majority (63.9 %) supports making it mandatory to register a personal decision. Religious self-identification has limited impact on attitudes. CONCLUSIONS: We can identify a shift over the past three decades from marked opposition to organ transplantation to strong support as well as a pattern in the contemporary public attitudes, which can help explain what is central to public acceptability: self-determination. Policies fostering choice are met with a majority of positive attitudes, while presumed consent and monetary incentives are met with more negative attitudes. Our approach calls for comparative studies in other countries to generate a better overall understanding of the conditions of acceptability, which need to be in place to ensure the long term social robustness of organ donation and thereby safeguard this important medical technology. PMID- 27222710 TI - Lack of transmission among healthcare workers in contact with a case of Middle East respiratory syndrome coronavirus infection in Thailand. AB - INTRODUCTION: A hospital-associated outbreak of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) was reported. We aimed to assess the effectiveness of infection control measures among healthcare workers (HCWs) who were exposed to a MERS patient and/or his body fluids in our institute. METHODS: A descriptive study was conducted among HCWs who worked with a MERS patient in Bamrasnaradura Infectious Diseases Institute, Thailand, between 18 June and 3 July 2015. Contacts were defined as HCWs who worked in the patient's room or with the patient's body fluids. Serum samples from all contacts were collected within 14 days of last contact and one month later. Paired sera were tested for detection of MERS-CoV antibodies by using an indirect ELISA. RESULTS: Thirty-eight (88.4 %) of 43 identified contacts consented to enroll. The mean (SD) age was 38.1 (11.1) years, and 79 % were females. The median (IQR) cumulative duration of work of HCWs in the patient's room was 35 (20-165) minutes. The median (IQR) cumulative duration of work of HCWs with the patient's blood or body fluids in laboratory was 67.5 (43.7-117.5) minutes. All contacts reported 100 % compliance with hand hygiene, using N95 respirator, performing respirator fit test, wearing gown, gloves, eye protection, and cap during their entire working period. All serum specimens of contacts tested for MERS-CoV antibodies were negative. CONCLUSIONS: We provide evidence of effective infection control practices against MERS-CoV transmission in a healthcare facility. Strict infection control precautions can protect HCWs. The optimal infection control measures for MERS-CoV should be further evaluated. PMID- 27222711 TI - Stapled versus hand-sewn cervical esophagogastric anastomosis in patients undergoing esophagectomy: A Retrospective Cohort Study. AB - INTRODUCTION: Anastomotic leak is one of the main causes of morbidity following esophageal resection for carcinoma of the esophagus and gastroesophageal junction. We compared hand sewn and stapled cervical esophagogastric anastomotic techniques in terms of postoperative complications. METHODS: All patients who underwent esophagectomy with cervical esophagogastric anastomosis at a single academic center from 2004 to 2014 were included in the study. Both early and late complications were analyzed. RESULTS: 153 patients underwent resection for carcinoma of the esophagus and gastroesophageal junction. Of these 140 patients had esophagectomy with cervical esophagogastric anastomosis. 66 patients underwent a hand sewn anastomosis and 74 patients had a side-to-side stapled anastomosis fashioned. Both groups were comparable with respect to preoperative characteristics. There was no difference in the operative blood loss and T and N stage of the disease. The overall morbidity and mortality was 32.8% and 6.4%, respectively. Overall leak rate was 17%. There was no difference in the leak rates among two groups (12 in the hand-sewn group & 12 in the Stapled stapled group; p = 0.82). The rate of anastomotic stricture was significantly higher for the hand sewn group (16.1% vs 4.3%; p = 0.03) at median follow up of 30 months. CONCLUSION: Both hand sewn and stapled anastomotic techniques are equally effective way of performing a cervical esophagogastric anastomosis. However, patients having anastomotic leak develop anastomotic stricture more often in those having hand-sewn anastomosis compared to stapled anastomosis. PMID- 27222712 TI - Clinical features and outcome of bone and joint infections with streptococcal involvement: 5-year experience of interregional reference centres in the south of France. AB - Streptococcal bone and joint infections are less common than staphylococcal cases. Few studies have reported the cases with well-identified Streptococcus species. Their clinical features and prognosis are not clearly known to date. Moreover, no treatment regimen has yet been clarified. We reviewed the streptococcal bone and joint infection cases managed in our centres from January 2009 to December 2013. We described the epidemiology, clinical and microbiologic characteristics, treatment approach and outcome. Among the 93 cases, 83% of patients were men with a median age of 60 years, and 90% of patients had comorbidities or risk factors. Bacteraemia occurred in 14% of cases. Serious complications occurred in six patients, including severe sepsis (two cases) and infective endocarditis (two cases). Orthopaedic device infections were observed in 35% of cases, including 17 patients with internal osteosynthesis device infection, 14 with prosthetic joint infection and three with vertebral osteosynthesis device infection. The median time between orthopaedic device implantation and onset of infection was 447 days. Fourteen species of Streptococcus were identified, including 97 isolates using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and three isolates using molecular identification. The five most represented species included S. agalactiae (37%), S. dysgalactiae (12%), S. anginosus (11%), S. constellatus (10%) and S. pneumoniae (9%). Streptococci isolates were susceptible to amoxicillin, with the exception of one S. mitis isolate. Remission 1 year after the end of treatment was recorded in 83%. One patient died of infection; eight patients had infections that failed to respond to treatment; and seven patients experienced relapse. Twenty patients (22%) had an unfavourable functional outcome, including 19 amputations and one arthrodesis. Five significant prognostic factors associated with an unfavourable clinical outcome were identified, including peripheral neuropathy (p 0.009), peripheral arterial disease (p 0.019), diabetes mellitus (p 0.031), location in the femur (p 0.0036), location in the foot (p 0.0475), osteitis without an orthopaedic device (p 0.041) and infection caused by S. dysgalactiae (p 0.020). The rate of poor outcomes remains high despite the low number of Streptococcus isolates resistant to antibiotics. Some prognostic factors, such as the presence of S. dysgalactiae, are associated with an unfavourable clinical outcome. Antibiotic regimens of streptococcal bone and joint infections are not standardized and need to be further investigated. PMID- 27222713 TI - Noncontiguous finished genome sequence and description of Bacillus testis strain SIT10 sp. nov. AB - Bacillus testis strain SIT10 (= CSUR P1492 = DSMZ 101190) is the new type strain collected from stool from a 2-year-old boy from Senegal during a culturomics study. This Gram-positive bacterium is a facultative anaerobic rod and a member of the Bacillaceae family. We describe here the features of this bacterium, together with the complete genome sequence and annotation. The 3 987 349 bp long genome (one chromosome but no plasmid) with 42.8% GC content contains 4005 protein-coding and 171 sRNA genes, including 19 5S rRNA gene, 15 16S rRNA genes and ten 23S rRNA genes. PMID- 27222714 TI - High prevalence of toxic shock syndrome toxin-producing epidemic methicillin resistant Staphylococcus aureus 15 (EMRSA-15) strains in Kuwait hospitals. AB - This study characterized EMRSA-15 isolates obtained from patients in Kuwait hospitals for their genotypic relatedness, antibiotic resistance and carriage of virulence genes using pulsed-field gel electrophoresis (PFGE), coagulase serotyping, SCCmec subtyping, spa typing, multilocus sequence typing and DNA microarray. The isolates were resistant to trimethoprim (75.6%), ciprofloxacin (29.7%), erythromycin and clindamycin (24.3%), tetracycline (19.0%), and gentamicin and kanamycin (21.6%). All 37 isolates belonged to sequence type (ST) 22, coagulase type XI, three PFGE types and eight subtypes, ten spa types including t223 (51.3%), t852 (13.5%), t032 (8.1%), t790 (8.1%), t3107 (5.4%) and one each of t309, t2251, t3935, t5708 and t5983. Twenty-six isolates (70.2%) carried SCCmec IVa, eight isolates carried SCCmec IV and three isolates carried SCCmec IVh. All isolates carried agr1, cap5 and egc gene cluster (seg, sei, selm, seln, selo, and selu). tst (toxic shock syndrome toxin) was detected in 23 isolates. Eight isolates (21.6%) were positive for Panton-Valentine leukocidin (PVL). Genotypic analysis revealed that 62.1% of the isolates comprising ST22-IVa t223 (51.3%) and ST22-IVa-t309/t2251/t3935/t5708 (10.8%) were CC22-[tst1(+)] UK EMRSA-15/Middle Eastern variant, 21.6% were CC22-PVL(+) EMRSA-15 variant and 16.2% were CC22-UK EMRSA-15/Barnim clone. These results show that the tst1 positive-ST22-IVa-t223 (Middle Eastern variant) and the CC22-PVL(+) EMRSA-15 variant were the dominant EMRSA-15 variants in Kuwait hospitals. PMID- 27222715 TI - MALDI-TOF MS contribution to diagnosis of melioidosis in a nonendemic country in three French travellers. AB - Melioidosis is an endemic disease in Southeast Asia and northern Australia. An increasing number of cases are being reported in nonendemic countries, making the diagnosis less obvious. We discuss the identification of Burkholderia pseudomallei using matrix-assisted desorption ionization-time of flight mass spectrometry on the occasion of recent cases of imported melioidosis in French travellers. PMID- 27222716 TI - Whole genome sequencing for deciphering the resistome of Chryseobacterium indologenes, an emerging multidrug-resistant bacterium isolated from a cystic fibrosis patient in Marseille, France. AB - We decipher the resistome of Chryseobacterium indologenes MARS15, an emerging multidrug-resistant clinical strain, using the whole genome sequencing strategy. The bacterium was isolated from the sputum of a hospitalized patient with cystic fibrosis in the Timone Hospital in Marseille, France. Genome sequencing was done with Illumina MiSeq using a paired-end strategy. The in silico analysis was done by RAST, the resistome by the ARG-ANNOT database and detection of polyketide synthase (PKS) by ANTISMAH. The genome size of C. indologenes MARS15 is 4 972 580 bp with 36.4% GC content. This multidrug-resistant bacterium was resistant to all beta-lactams, including imipenem, and also to colistin. The resistome of C. indologenes MARS15 includes Ambler class A and B beta-lactams encoding bla CIA and bla IND-2 genes and MBL (metallo-beta-lactamase) genes, the CAT (chloramphenicol acetyltransferase) gene and the multidrug efflux pump AcrB. Specific features include the presence of an urease operon, an intact prophage and a carotenoid biosynthesis pathway. Interestingly, we report for the first time in C. indologenes a PKS cluster that might be responsible for secondary metabolite biosynthesis, similar to erythromycin. The whole genome sequence analysis provides insight into the resistome and the discovery of new details, such as the PKS cluster. PMID- 27222717 TI - Emergence of NDM-1 and OXA-72 producing Acinetobacter pittii clinical isolates in Lebanon. AB - Acinetobacter spp. have emerged as global opportunistic pathogen causing a wide range of infections. Emergence of carbapenem resistance in these organisms is a matter of great concern. We report here the first detection of Acinetobacter pittii clinical isolates in Lebanon carrying either the bla NDM-1 or the bla OXA 72 gene. PMID- 27222718 TI - Multidrug-resistant tuberculosis outbreak in an Italian prison: tolerance of pyrazinamide plus levofloxacin prophylaxis and serial interferon gamma release assays. AB - The optimal treatment for latent tuberculosis infection (LTBI) in subjects exposed to multidrug-resistant (MDR) tuberculosis (TB) remains unclear, and the change in response of the QuantiFERON-TB Gold In-Tube (QTB-IT) test during and after treatment is unknown. Between May 2010 and August 2010, 39 prisoners at the 'Casa Circondariale' of Modena, Italy, were exposed to a patient with active pulmonary MDR TB. All contacts were tested with the tuberculin skin test and QTB IT. Upon exclusion of active TB, subjects positive to both tests were offered 6 months' treatment with pyrazinamide (PZA) and levofloxacin (LVX). QTB-IT testing was repeated at 3 and 6 months after initial testing in all subjects who were offered LTBI treatment. Seventeen (43.5%) of 39 subjects tested positive to both tuberculin skin test and QTB-IT test, and 12 (70.5%) agreed to receive therapy with PZA and LVX at standard doses. Only five (41.6%) of 12 subjects completed 6 months' treatment. Reasons for discontinuation were asymptomatic hepatitis, gastritis and diarrhoea. The QTB-IT values decreased in all subjects who completed the treatment, in two (33%) of six of those who received treatment for less than 3 months and in one (50%) of two patients who discontinued therapy after 3 months. The QTB-IT test results never turned negative. Despite the small number of subjects, the study confirmed that PZA plus LVX is a poorly tolerated option for MDR LTBI treatment. We observed a large degree of variation in the results of the QTB-IT test results among participants. The study confirmed that the interferon gamma release assay is not a reliable tool for monitoring the treatment of MDR LTBI in clinical practice. PMID- 27222719 TI - Isolation of new species "Peptoniphilus phoceensis" from human gut. AB - Taxonogenomics coupled with culturomics leads to descriptions of new bacteria. Thanks to this strategy, we report the main characteristics of "Peptoniphilus phoceensis" strain SIT15, a new bacterium isolated from a stool sample of a 1 year-old healthy Senegalese boy. PMID- 27222720 TI - "Bariatricus massiliensis" as a new bacterial species from human gut microbiota. AB - We report here the main phenotypic characteristics of "Bariatricus massiliensis" strain AT12 (CSUR P2179), isolated from the stool of a 58-year-old woman who underwent bariatric surgery. PMID- 27222721 TI - Experiences from a pilot study on how to conduct a qualitative multi-country research project regarding use of antibiotics in Southeast Europe. AB - BACKGROUND: In 2014, a qualitative multi-country research project was launched to study the reasons behind the high use of antibiotics in regions of Southeast Europe by using previously untrained national interviewers (who were engaged in other antibiotic microbial resistance-related investigations) to conduct qualitative interviews with local patients, physicians and pharmacists. Little knowledge exists about how to implement qualitative multi-country research collaborations involving previously untrained local data collectors. The aim of this paper was therefore to contribute to the knowledge regarding how to conduct these types of research projects by evaluating a pilot study of the project. METHODS: Local data collectors conducted the study according to a developed protocol and evaluated the study with the responsible researcher-team from University of Copenhagen. The pilot study focused on 'local ownership', 'research quality' and 'feasibility' with regard to successful implementation and evaluation. The evaluation was achieved by interpreting 'Skype' and 'face to face' meetings and email correspondence by applying 'critical common sense'. RESULTS: Local data collectors achieved a sense of joint ownership. Overall, the protocol worked well. Several minor challenges pertaining to research quality and feasibility were identified, in particular obtaining narratives when conducting interviews and recruiting patients for the study. Furthermore, local data collectors found it difficult to allocate sufficient time to the project. Solutions were discussed and added to the protocol. CONCLUSIONS: Despite the challenges, it was possible to achieve an acceptable scientific level of research when conducting qualitative multi-country research collaboration under the given circumstances. Specific recommendations to achieve this are provided by the authors. PMID- 27222722 TI - A survey of FLS2 genes from multiple citrus species identifies candidates for enhancing disease resistance to Xanthomonas citri ssp. citri. AB - Pathogen-associated molecular patterns (PAMPs)-triggered immunity (PTI) is an important component of plant innate immunity. In a previous study, we showed that the PAMP flg22 from Xanthomonas citri ssp. citri (Xflg22), the causal agent of citrus canker, induced PTI in citrus, which correlated with the observed levels of canker resistance. Here, we identified and sequenced two bacterial flagellin/flg22 receptors (FLS2-1 and FLS2-2) from 'Duncan' grapefruit (Citrus paradisi, CpFLS2-1 and CpFLS2-2) and 'Sun Chu Sha' mandarin (C. reticulata, CrFLS2-1 and CrFLS2-2). We were able to isolate only one FLS2 from 'Nagami' kumquat (Fortunella margarita, FmFLS2-1) and gene flanking sequences suggest a rearrangement event that resulted in the deletion of FLS2-2 from the genome. Phylogenetic analysis, gene structure and presence of critical amino acid domains all indicate we identified the true FLS2 genes in citrus. FLS2-2 was more transcriptionally responsive to Xflg22 than FLS2-1, with induced expression levels higher in canker-resistant citrus than in susceptible ones. Interestingly, 'Nagami' kumquat showed the highest FLS2-1 steady-state expression levels, although it was not induced by Xflg22. We selected FmFLS2-1, CrFLS2-2 and CpFLS2 2 to further evaluate their capacity to enhance bacterial resistance using Agrobacterium-mediated transient expression assays. Both FmFLS2-1 and CrFLS2-2, the two proteins from canker-resistant species, conferred stronger Xflg22 responses and reduced canker symptoms in leaves of the susceptible grapefruit genotype. These two citrus genes will be useful resources to enhance PTI and achieve resistance against canker and possibly other bacterial pathogens in susceptible citrus types. PMID- 27222723 TI - Image denoising in bidimensional empirical mode decomposition domain: the role of Student's probability distribution function. AB - Hybridisation of the bi-dimensional empirical mode decomposition (BEMD) with denoising techniques has been proposed in the literature as an effective approach for image denoising. In this Letter, the Student's probability density function is introduced in the computation of the mean envelope of the data during the BEMD sifting process to make it robust to values that are far from the mean. The resulting BEMD is denoted tBEMD. In order to show the effectiveness of the tBEMD, several image denoising techniques in tBEMD domain are employed; namely, fourth order partial differential equation (PDE), linear complex diffusion process (LCDP), non-linear complex diffusion process (NLCDP), and the discrete wavelet transform (DWT). Two biomedical images and a standard digital image were considered for experiments. The original images were corrupted with additive Gaussian noise with three different levels. Based on peak-signal-to-noise ratio, the experimental results show that PDE, LCDP, NLCDP, and DWT all perform better in the tBEMD than in the classical BEMD domain. It is also found that tBEMD is faster than classical BEMD when the noise level is low. When it is high, the computational cost in terms of processing time is similar. The effectiveness of the presented approach makes it promising for clinical applications. PMID- 27222724 TI - Editorial: "This special issue brings together work across these many facets of decision support technology for person-centred healthcare and gives a snapshot of some of the latest research in this area.". PMID- 27222725 TI - Non-invasive, home-based electroencephalography hypoglycaemia warning system for personal monitoring using skin surface electrodes: a single-case feasibility study. AB - AIMS: Hypoglycaemia unawareness is a common condition associated with increased risk of severe hypoglycaemia. The purpose of the authors' study was to develop a simple to use, home-based and non-invasive hypoglycaemia warning system based on electroencephalography (EEG), and to demonstrate its use in a single-case feasibility study. METHODS: A participant with type 1 diabetes forms a single person case study where blood sugar levels and EEG were recorded. EEG was recorded using skin surface electrodes placed behind the ear located within the T3 region by the participant in the home. EEG was analysed retrospectively to develop an algorithm which would trigger a warning if EEG changes associated with hypoglycaemia onset were detected. RESULTS: All hypoglycaemia events were detected by the EEG hypoglycaemia warning algorithm. Warnings were triggered with blood glucose concentration levels at or below 4.2 mmol/l in this participant and no warnings were issued when in euglycaemia. CONCLUSION: The feasibility of a non invasive EEG-based hypoglycaemia warning system for personal monitoring in the home has been demonstrated in a single case study. The results suggest that further studies are warranted to evaluate the system prospectively in a larger group of participants. PMID- 27222726 TI - Bridging the gap between real-life data and simulated data by providing a highly realistic fall dataset for evaluating camera-based fall detection algorithms. AB - Fall incidents are an important health hazard for older adults. Automatic fall detection systems can reduce the consequences of a fall incident by assuring that timely aid is given. The development of these systems is therefore getting a lot of research attention. Real-life data which can help evaluate the results of this research is however sparse. Moreover, research groups that have this type of data are not at liberty to share it. Most research groups thus use simulated datasets. These simulation datasets, however, often do not incorporate the challenges the fall detection system will face when implemented in real-life. In this Letter, a more realistic simulation dataset is presented to fill this gap between real-life data and currently available datasets. It was recorded while re-enacting real life falls recorded during previous studies. It incorporates the challenges faced by fall detection algorithms in real life. A fall detection algorithm from Debard et al. was evaluated on this dataset. This evaluation showed that the dataset possesses extra challenges compared with other publicly available datasets. In this Letter, the dataset is discussed as well as the results of this preliminary evaluation of the fall detection algorithm. The dataset can be downloaded from www.kuleuven.be/advise/datasets. PMID- 27222727 TI - Flexible quality of service model for wireless body area sensor networks. AB - Wireless body area sensor networks (WBASNs) are becoming an increasingly significant breakthrough technology for smart healthcare systems, enabling improved clinical decision-making in daily medical care. Recently, radio frequency ultra-wideband technology has developed substantially for physiological signal monitoring due to its advantages such as low-power consumption, high transmission data rate, and miniature antenna size. Applications of future ubiquitous healthcare systems offer the prospect of collecting human vital signs, early detection of abnormal medical conditions, real-time healthcare data transmission and remote telemedicine support. However, due to the technical constraints of sensor batteries, the supply of power is a major bottleneck for healthcare system design. Moreover, medium access control (MAC) needs to support reliable transmission links that allow sensors to transmit data safely and stably. In this Letter, the authors provide a flexible quality of service model for ad hoc networks that can support fast data transmission, adaptive schedule MAC control, and energy efficient ubiquitous WBASN networks. Results show that the proposed multi-hop communication ad hoc network model can balance information packet collisions and power consumption. Additionally, wireless communications link in WBASNs can effectively overcome multi-user interference and offer high transmission data rates for healthcare systems. PMID- 27222728 TI - Privacy preserving data publishing of categorical data through k-anonymity and feature selection. AB - In healthcare, there is a vast amount of patients' data, which can lead to important discoveries if combined. Due to legal and ethical issues, such data cannot be shared and hence such information is underused. A new area of research has emerged, called privacy preserving data publishing (PPDP), which aims in sharing data in a way that privacy is preserved while the information lost is kept at a minimum. In this Letter, a new anonymisation algorithm for PPDP is proposed, which is based on k-anonymity through pattern-based multidimensional suppression (kPB-MS). The algorithm uses feature selection for reducing the data dimensionality and then combines attribute and record suppression for obtaining k anonymity. Five datasets from different areas of life sciences [RETINOPATHY, Single Proton Emission Computed Tomography imaging, gene sequencing and drug discovery (two datasets)], were anonymised with kPB-MS. The produced anonymised datasets were evaluated using four different classifiers and in 74% of the test cases, they produced similar or better accuracies than using the full datasets. PMID- 27222730 TI - Use of adaptive hybrid filtering process in Crohn's disease lesion detection from real capsule endoscopy videos. AB - The aim of this Letter is to present a new capsule endoscopy (CE) image analysis scheme for the detection of small bowel ulcers that relate to Crohn's disease. More specifically, this scheme is based on: (i) a hybrid adaptive filtering (HAF) process, that utilises genetic algorithms to the curvelet-based representation of images for efficient extraction of the lesion-related morphological characteristics, (ii) differential lacunarity (DL) analysis for texture feature extraction from the HAF-filtered images and (iii) support vector machines for robust classification performance. For the training of the proposed scheme, namely HAF-DL, an 800-image database was used and the evaluation was based on ten 30-second long endoscopic videos. Experimental results, along with comparison with other related efforts, have shown that the HAF-DL approach evidently outperforms the latter in the field of CE image analysis for automated lesion detection, providing higher classification results. The promising performance of HAF-DL paves the way for a complete computer-aided diagnosis system that could support the physicians' clinical practice. PMID- 27222729 TI - Relevance of health level 7 clinical document architecture and integrating the healthcare enterprise cross-enterprise document sharing profile for managing chronic wounds in a telemedicine context. AB - The number of patients with complications associated with chronic diseases increases with the ageing population. In particular, complex chronic wounds raise the re-admission rate in hospitals. In this context, the implementation of a telemedicine application in Basse-Normandie, France, contributes to reduce hospital stays and transport. This application requires a new collaboration among general practitioners, private duty nurses and the hospital staff. However, the main constraint mentioned by the users of this system is the lack of interoperability between the information system of this application and various partners' information systems. To improve medical data exchanges, the authors propose a new implementation based on the introduction of interoperable clinical documents and a digital document repository for managing the sharing of the documents between the telemedicine application users. They then show that this technical solution is suitable for any telemedicine application and any document sharing system in a healthcare facility or network. PMID- 27222731 TI - Automated integration of wireless biosignal collection devices for patient centred decision-making in point-of-care systems. AB - The proper acquisition of biosignals data from various biosensor devices and their remote accessibility are still issues that prevent the wide adoption of point-of-care systems in the routine of monitoring chronic patients. This Letter presents an advanced framework for enabling patient monitoring that utilises a cloud computing infrastructure for data management and analysis. The framework introduces also a local mechanism for uniform biosignals collection from wearables and biosignal sensors, and decision support modules, in order to enable prompt and essential decisions. A prototype smartphone application and the related cloud modules have been implemented for demonstrating the value of the proposed framework. Initial results regarding the performance of the system and the effectiveness in data management and decision-making have been quite encouraging. PMID- 27222732 TI - Future perspectives toward the early definition of a multivariate decision support scheme employed in clinical decision making for senior citizens. AB - Recent neuroscientific studies focused on the identification of pathological neurophysiological patterns (emotions, geriatric depression, memory impairment and sleep disturbances) through computerised clinical decision-support systems. Almost all these research attempts employed either resting-state condition (e.g. eyes-closed) or event-related potentials extracted during a cognitive task known to be affected by the disease under consideration. This Letter reviews existing data mining techniques and aims to enhance their robustness by proposing a holistic decision framework dealing with comorbidities and early symptoms' identification, while it could be applied in realistic occasions. Multivariate features are elicited and fused in order to be compared with average activities characteristic of each neuropathology group. A proposed model of the specific cognitive function which may be based on previous findings (a priori information) and/or validated by current experimental data should be then formed. So, the proposed scheme facilitates the early identification and prevention of neurodegenerative phenomena. Neurophysiological semantic annotation is hypothesised to enhance the importance of the proposed framework in facilitating the personalised healthcare of the information society and medical informatics research community. PMID- 27222734 TI - Why decision support systems are important for medical education. AB - During the last decades, the inclusion of digital tools in health education has rapidly lead to a continuously enlarging digital era. All the online interactions between learners and tutors, the description, creation, reuse and sharing of educational digital resources and the interlinkage between them in conjunction with cheap storage technology has led to an enormous amount of educational data. Medical education is a unique type of education due to accuracy of information needed, continuous changing competences required and alternative methods of education used. Nowadays medical education standards provide the ground for organising the educational data and the paradata. Analysis of such education data through education data mining techniques is in its infancy, but decision support systems (DSSs) for medical education need further research. To the best of our knowledge, there is a gap and a clear need for identifying the challenges for DSSs in medical education in the era of medical education standards. Thus, in this Letter the role and the attributes of such a DSS for medical education are delineated and the challenges and vision for future actions are identified. PMID- 27222733 TI - Predicting asthma exacerbations employing remotely monitored adherence. AB - This Letter investigated the efficacy of a decision-support system, designed for respiratory medicine, at predicting asthma exacerbations in a multi-site longitudinal randomised control trial. Adherence to inhaler medication was acquired over 3 months from patients with asthma employing a dose counter and a remote monitoring adherence device which recorded participant's inhaler use: n = 184 (23,656 audio files), 61% women, age (mean +/- sd) 49.3 +/- 16.4. Data on occurrence of exacerbations was collected at three clinical visits, 1 month apart. The relative risk of an asthma exacerbation for those with good and poor adherence was examined employing a univariate and multivariate modified Poisson regression approach; adjusting for age, gender and body mass index. For all months dose counter adherence was significantly (p < 0.01) higher than remote monitoring adherence. Overall, those with poor adherence had a 1.38 +/- 0.34 and 1.42 +/- 0.39 (remotely monitored) and 1.25 +/- 0.32 and 1.18 +/- 0.31 (dose counter) higher relative risk of an exacerbation in model 1 and model 2, respectively. However, this was not found to be statistically significantly different. Remotely monitored adherence holds important clinical information and future research should focus on refining adherence and exacerbation measures. Decision-support systems based on remote monitoring may enhance patient-physician communication, possibly reducing preventable adverse events. PMID- 27222735 TI - Diagnostic measure to quantify loss of clinical components in multi-lead electrocardiogram. AB - In this Letter, a novel principal component (PC)-based diagnostic measure (PCDM) is proposed to quantify loss of clinical components in the multi-lead electrocardiogram (MECG) signals. The analysis of MECG shows that, the clinical components are captured in few PCs. The proposed diagnostic measure is defined as the sum of weighted percentage root mean square difference (PRD) between the PCs of original and processed MECG signals. The values of the weight depend on the clinical importance of PCs. The PCDM is tested over MECG enhancement and a novel MECG data reduction scheme. The proposed measure is compared with weighted diagnostic distortion, wavelet energy diagnostic distortion and PRD. The qualitative evaluation is performed using Spearman rank-order correlation coefficient (SROCC) and Pearson linear correlation coefficient. The simulation result demonstrates that the PCDM performs better to quantify loss of clinical components in MECG and shows a SROCC value of 0.9686 with subjective measure. PMID- 27222736 TI - Passive wireless tags for tongue controlled assistive technology interfaces. AB - Tongue control with low profile, passive mouth tags is demonstrated as a human device interface by communicating values of tongue-tag separation over a wireless link. Confusion matrices are provided to demonstrate user accuracy in targeting by tongue position. Accuracy is found to increase dramatically after short training sequences with errors falling close to 1% in magnitude with zero missed targets. The rate at which users are able to learn accurate targeting with high accuracy indicates that this is an intuitive device to operate. The significance of the work is that innovative very unobtrusive, wireless tags can be used to provide intuitive human-computer interfaces based on low cost and disposable mouth mounted technology. With the development of an appropriate reading system, control of assistive devices such as computer mice or wheelchairs could be possible for tetraplegics and others who retain fine motor control capability of their tongues. The tags contain no battery and are intended to fit directly on the hard palate, detecting tongue position in the mouth with no need for tongue piercings. PMID- 27222737 TI - Thickness estimation of the subcutaneous fat using coaxial probe. AB - In this Letter, a non-invasive method for thickness estimation of the subcutaneous fat layer of abdominal wall is presented by using a coaxial probe. Fat layer has the highest impact on the averaged attenuation parameter of the abdominal wall due to its high thickness and low permittivity. The abdominal wall is modelled as a multi-layer medium and an analytical model for the probe is derived by calculation of its aperture admittance facing to this multi-layer medium. The performance of this model is then validated by a numerical simulation using finite-difference-time-domain (FDTD) analysis. Simulation results show the high impact of the probe dimension and fat layer thickness on the sensitivity of the measured permittivity. The authors further investigate this sensitivity by statistical analysis of the permittivity variations. Finally, measuring in different locations relative to the body surface is presented as a solution to estimate the fat layer thickness in the presence of uncertainty of model parameters. PMID- 27222738 TI - Anthracnose of lucky bamboo Dracaena sanderiana caused by the fungus Colletotrichum dracaenophilum in Egypt. AB - Dracaena sanderiana, of the family Liliaceae, is among the ornamental plants most frequently imported into Egypt. Typical anthracnose symptoms were observed on the stems of imported D. sanderiana samples. The pathogen was isolated, demonstrated to be pathogenic based on Koch's rule and identified as Colletotrichum dracaenophilum. The optimum temperature for its growth ranges from 25 to 30 degrees C, maintained for 8 days. Kemazed 50% wettable powder (WP) was the most effective fungicide against the pathogen, as no fungal growth was observed over 100 ppm. The biocontrol agents Trichoderma harzianum and Trichoderma viride followed by Bacillus subtilis and Bacillus pumilus caused the highest reduction in fungal growth. To the best of our knowledge, this report describes the first time that this pathogen was observed on D. sanderiana in Egypt. PMID- 27222739 TI - Design of efficient circularly symmetric two-dimensional variable digital FIR filters. AB - Circularly symmetric two-dimensional (2D) finite impulse response (FIR) filters find extensive use in image and medical applications, especially for isotropic filtering. Moreover, the design and implementation of 2D digital filters with variable fractional delay and variable magnitude responses without redesigning the filter has become a crucial topic of interest due to its significance in low cost applications. Recently the design using fixed word length coefficients has gained importance due to the replacement of multipliers by shifters and adders, which reduces the hardware complexity. Among the various approaches to 2D design, transforming a one-dimensional (1D) filter to 2D by transformation, is reported to be an efficient technique. In this paper, 1D variable digital filters (VDFs) with tunable cut-off frequencies are designed using Farrow structure based interpolation approach, and the sub-filter coefficients in the Farrow structure are made multiplier-less using canonic signed digit (CSD) representation. The resulting performance degradation in the filters is overcome by using artificial bee colony (ABC) optimization. Finally, the optimized 1D VDFs are mapped to 2D using generalized McClellan transformation resulting in low complexity, circularly symmetric 2D VDFs with real-time tunability. PMID- 27222740 TI - Oxidative stress during erythropoietin hyporesponsiveness anemia at end stage renal disease: Molecular and biochemical studies. AB - Inflammation and oxidative stress are two faces of one coin in end stage renal disease patients (ESRD) on maintenance hemodialysis. Their interconnection induces anemia complicated with erythropoietin hyporesponsiveness. The biochemical bases behind the resistance to erythropoietin therapy with frequent hemoglobinemia, oxidative stress and iron status have not been fully understood. Here two equal groups (40 patients each) of responders and non-responders to recombinant human erythropoietin therapy (higher than 300 IU/kg/wk of epoetin) were investigated. Hematological and biochemical analyses of collected blood and serum samples were performed along with serum electrophoretic protein footprinting. The leukocytic DNA fragmentation was used to evaluate the degree of oxidative insult. The good responders showed lower erythrocyte malondialdehyde (E MDA) level and less DNA fragmentation of circulating leukocytes than poor responders with elevated hemoglobin, albumin, A/G ratio, total iron, and ferritin levels. Contrariwise, lower erythrocyte superoxide dismutase (E-SOD) and catalase activities in EPO poor responder group were noticed. Neither other serum constituents nor electrophoretic protein pattern showed any difference between the two groups. There were higher levels of inflammatory markers, interleukin-6 (IL6) and C-reactive protein (CRP) in EPO poor responder than good responder. The negative correlations between Hb and both IL6 and CRP levels in the present data remotely indicate a positive correlation between inflammatory markers and severity of anemia. A direct correlation between Hb and antioxidant enzymes (E SOD and catalase) was noticed, while inverse correlation with E-MDA was recorded. The study proved that oral supplementation of vitamin C to ESRD patients might mitigate the previously elevated serum MDA level in these patients. PMID- 27222741 TI - Short-term bulk energy storage system scheduling for load leveling in unit commitment: modeling, optimization, and sensitivity analysis. AB - Energy storage systems (ESSs) have experienced a very rapid growth in recent years and are expected to be a promising tool in order to improving power system reliability and being economically efficient. The ESSs possess many potential benefits in various areas in the electric power systems. One of the main benefits of an ESS, especially a bulk unit, relies on smoothing the load pattern by decreasing on-peak and increasing off-peak loads, known as load leveling. These devices require new methods and tools in order to model and optimize their effects in the power system studies. In this respect, this paper will model bulk ESSs based on the several technical characteristics, introduce the proposed model in the thermal unit commitment (UC) problem, and analyze it with respect to the various sensitive parameters. The technical limitations of the thermal units and transmission network constraints are also considered in the model. The proposed model is a Mixed Integer Linear Programming (MILP) which can be easily solved by strong commercial solvers (for instance CPLEX) and it is appropriate to be used in the practical large scale networks. The results of implementing the proposed model on a test system reveal that proper load leveling through optimum storage scheduling leads to considerable operation cost reduction with respect to the storage system characteristics. PMID- 27222742 TI - Application of waste bulk moulded composite (BMC) as a filler for isotactic polypropylene composites. AB - The aim of this study was to produce isotactic polypropylene based composites filled with waste thermosetting bulk moulded composite (BMC). The influence of BMC waste addition (5, 10, 20 wt%) on composites structure and properties was investigated. Moreover, additional studies of chemical treatment of the filler were prepared. Modification of BMC waste by calcium stearate (CaSt) powder allows to assess the possibility of the production of composites with better dispersion of the filler and more uniform properties. The mechanical, processing, and thermal properties, as well as structural investigations were examined by means of static tensile test, Dynstat impact strength test, differential scanning calorimetry (DSC), wide angle X-ray scattering (WAXS), melt flow index (MFI) and scanning electron microscopy (SEM). Developed composites with different amounts of non-reactive filler exhibited satisfactory thermal and mechanical properties. Moreover, application of the low cost modifier (CaSt) allows to obtain composites with better dispersion of the filler and improved processability. PMID- 27222743 TI - A novel phytase characterized by thermostability and high pH tolerance from rice phyllosphere isolated Bacillus subtilis B.S.46. AB - In this study, an extracellular alkali-thermostable phytase producing bacteria, Bacillus subtilis B.S.46, were isolated and molecularly identified using 16S rRNA sequencing. Response surface methodology was applied to study the interaction effects of assay conditions to obtain optimum value for maximizing phytase activity. The optimization resulted in 137% (4.627 U/mL) increase in phytase activity under optimum condition (56.5 degrees C, pH 7.30 and 2.05 mM sodium phytate). The enzyme also showed 60-73% of maximum activity at wide ranges of temperature (47-68 degrees C), pH (6.3-8.0) and phytate concentration (1.40-2.50 mM). The partially purified phytase demonstrated high stability over a wide range of pH (6.0-10.0) after 24 h, retaining 85% of its initial activity at pH 6 and even interestingly, the phytase activity enhanced at pH 8.0-10.0. It also exhibited thermostability, retaining about 60% of its original activity after 2 h at 60 degrees C. Cations such as Ca(2+) and Li(+) enhanced the phytase activity by 10-46% at 1 mM concentration. The phytase activity was completely inhibited by Cu(2+), Mg(2+), Fe(2+), Zn(2+), Hg(2+) and Mn(2+) and the inhibition was in a dose dependent manner. B. subtilis B.S.46 phytase had interesting characteristics to be considered as animal feed additive, dephytinization of food ingredients, and bioremediation of phosphorous pollution in the environment. PMID- 27222745 TI - Water management in Egypt for facing the future challenges. AB - The current water shortage in Egypt is 13.5 Billion cubic meter per year (BCM/yr) and is expected to continuously increase. Currently, this water shortage is compensated by drainage reuse which consequently deteriorates the water quality. Therefore, this research was commenced with the objective of assessing different scenarios for 2025 using the Water Evaluation and Planning (WEAP) model and by implementing different water sufficiency measures. Field data were assembled and analyzed, and different planning alternatives were proposed and tested in order to design three future scenarios. The findings indicated that water shortage in 2025 would be 26 BCM/yr in case of continuation of current policies. Planning alternatives were proposed to the irrigation canals, land irrigation timing, aquatic weeds in waterways and sugarcane areas in old agricultural lands. Other measures were suggested to pumping rates of deep groundwater, sprinkler and drip irrigation systems in new agricultural lands. Further measures were also suggested to automatic daily surveying for distribution leak and managing the pressure effectively in the domestic and industrial water distribution systems. Finally, extra measures for water supply were proposed including raising the permitted withdrawal limit from deep groundwater and the Nubian aquifer and developing the desalination resource. The proposed planning alternatives would completely eliminate the water shortage in 2025. PMID- 27222744 TI - Antiviral treatment prioritization in HCV-infected patients with extrahepatic manifestations - An Egyptian perspective. AB - Egypt, the single country with highest incidence of HCV infection in the world, has embarked on a government-sponsored mass treatment program using several combinations of DAAs. Recognizing the importance of extrahepatic manifestations, independently of the hepatic, a subcommittee was assigned to develop national guidelines for respective prioritizing indications and protocols. It evaluated the benefit of treating patients with different extrahepatic manifestations, and reviewed relevant clinical trials and guidelines concerning DAA combinations available in Egypt. The latter included Sofosbuvir plus either peg-interferon, Simeprevir, Ledipasvir or daclatasvir, and the Viekera family comprising paritaprevir/ritonavir + ombitasvir with (GT-1) or without (GT-4) Dasabuvir. Any of these protocols may be used with or without Ribavirin according to indication. A blueprint was subjected to peer debate in dedicated workshops in two national meetings and subsequently to an online professional review, eventually leading to a final report that was adopted by the health authorities. Seven compelling and 10 optional indications were identified for treating patients with predominantly extrahepatic manifestations. The former include kidney disease at different stages, cryoglobulinemic vasculitis and non-Hodgkin lymphoma. Selected treatment protocols, were encoded and their use was prioritized on the basis of evidence of efficacy and safety. We concluded that any of the studied protocols may be used, preferably with ribavirin, for 12-week treatment in all patients with extrahepatic manifestations without cirrhosis and with eGFR above 30 ml/min/1.73 sqm. Ribavirin should be included in protocols for treating patients with compensated cirrhosis. Daclatasvir-based protocols are recommended for decompensated cirrhosis, while the Viekera family is recommended in patients with eGFR < 30 ml/min/1.73 sqm, including those on dialysis. In kidney-transplanted patents, caution is due to avoidance of the pharmacokinetic interaction with the Cytochrome-P450 enzyme system, in-between immunosuppressive agents and most DAAs, particularly the Viekera family. PMID- 27222746 TI - The mitigative effect of Raphanus sativus oil on chromium-induced geno- and hepatotoxicity in male rats. AB - To study the impact of radish oil on the possible genotoxic and hepatotoxic effects of hexavalent chromium, male rats were divided into 4 groups. Group 1 served as control, group 2 received radish oil at the recommended human therapeutic dose (0.07 mL/kg) by gavage, group 3 received sodium dichromate dihydrate (SDD) 520 mg/L in drinking water, and group 4 received both SDD and radish oil as previously mentioned in groups 2 and 3. All treatments were continued for six months. The results revealed that chromium exposure promoted oxidative stress with a consequently marked hepatic histopathological alterations, increased serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities, alfa fetoprotein (AFP) levels, and micronucleated erythrocytes (MNE) % in peripheral blood. Moreover, COMET assay of hepatic DNA revealed that SDD exposure significantly decreased the intact cells %, head diameter, and head DNA % compared to control, indicating DNA damage. However, radish oil co-administration with SDD resulted in marked amendment in the altered parameters as detected by improved liver function markers (ALT and ALP) and AFP level, decreased lipid peroxidation, increased antioxidant markers, inhibited hepatic DNA damage and restored the hepatic histology by preventing the appearance of the altered hepatocytes' foci and decreasing chromium induced histopathological lesions. It could be concluded that radish oil was able to provide a convergent complete protection against the geno- and hepatotoxicity of chromium by its potent antioxidant effect. PMID- 27222747 TI - Nanostructured lipid carriers for oral bioavailability enhancement of raloxifene: Design and in vivo study. AB - The objective of present work was to utilize potential of nanostructured lipid carriers (NLCs) for improvement in oral bioavailability of raloxifene hydrochloride (RLX). RLX loaded NLCs were prepared by solvent diffusion method using glyceryl monostearate and Capmul MCM C8 as solid lipid and liquid lipid, respectively. A full 3(2) factorial design was utilized to study the effect of two independent parameters namely solid lipid to liquid lipid ratio and concentration of stabilizer on the entrapment efficiency of prepared NLCs. The statistical evaluation confirmed pronounced improvement in entrapment efficiency when liquid lipid content in the formulation increased from 5% w/w to 15% w/w. Solid-state characterization studies (DSC and XRD) in optimized formulation NLC-8 revealed transformation of RLX from crystalline to amorphous form. Optimized formulation showed 32.50 +/- 5.12 nm average particle size and -12.8 +/- 3.2 mV zeta potential that impart good stability of NLCs dispersion. In vitro release study showed burst release for initial 8 h followed by sustained release up to 36 h. TEM study confirmed smooth surface discrete spherical nano sized particles. To draw final conclusion, in vivo pharmacokinetic study was carried out that showed 3.75-fold enhancements in bioavailability with optimized NLCs formulation than plain drug suspension. These results showed potential of NLCs for significant improvement in oral bioavailability of poorly soluble RLX. PMID- 27222748 TI - Experimental investigation of bioethanol liquid phase dehydration using natural clinoptilolite. AB - An experimental study of bioethanol adsorption on natural Iranian clinoptilolite was carried out. Dynamic breakthrough curves were used to investigate the best adsorption conditions in bioethanol liquid phase. A laboratory setup was designed and fabricated for this purpose. In order to find the best operating conditions, the effect of liquid pressure, temperature and flow rate on breakthrough curves and consequently, maximum ethanol uptake by adsorbent were studied. The effects of different variables on final bioethanol concentration were investigated using Response Surface Methodology (RSM). The results showed that by working at optimum condition, feed with 96% (v/v) initial ethanol concentration could be purified up to 99.9% (v/v). In addition, the process was modeled using Box-Behnken model and optimum operational conditions to reach 99.9% for final ethanol concentration were found equal to 10.7 degrees C, 4.9 bar and 8 mL/min for liquid temperature, pressure and flow rate, respectively. Therefore, the selected natural Iranian clinoptilolite was found to be a promising adsorbent material for bioethanol dehydration process. PMID- 27222749 TI - Analysis of thin plates with holes by using exact geometrical representation within XFEM. AB - This paper presents analysis of thin plates with holes within the context of XFEM. New integration techniques are developed for exact geometrical representation of the holes. Numerical and exact integration techniques are presented, with some limitations for the exact integration technique. Simulation results show that the proposed techniques help to reduce the solution error, due to the exact geometrical representation of the holes and utilization of appropriate quadrature rules. Discussion on minimum order of integration order needed to achieve good accuracy and convergence for the techniques presented in this work is also included. PMID- 27222750 TI - In vitro assessment of pharmaceutical potential of ethosomes entrapped with terbinafine hydrochloride. AB - The present study investigates the entrapment of terbinafine hydrochloride (TH) in ethosomal vesicles via unsonicated and sonication method. Carbopol 934P was incorporated in the best formulation, F6, obtained by sonication method. The formulated ethosomal gel obtained as such i.e. F6(*) was exploited to achieve a zero order release profile of TH. The composition includes phospholipid, ethanol and propylene glycol. Drug entrapment efficiency (DEE), in-vitro and ex-vivo drug diffusion studies, FT-IR and stability studies of the prepared ethosomes were investigated. The size and shape of F6 ethosomes vesicles were characterized by SEM. In-vitro drug release studies were performed using sigma dialysis membrane in phosphate buffer, pH 7.4 for 12 h while drug content was determined by HPLC. DEE was ranked from 55.33 +/- 1.32% to 69.11 +/- 2.11%. Highest DEE was seen with F6 ethosomal formulation with a vesicle size of 248 +/- 1.02 nm. FT-IR studies confirmed that there was no chemical interaction between drug and excipients used in the formulation. Ex-vivo result suggested that drug diffusion observed after 12 h from F6(*) and marketed cream (MR) formulations was 74.01 +/- 0.62% and 61.45 +/- 0.86%, respectively. The results of similarity factor (f 2 values) for MR and F6(*) ethosomal gel were 85.14 and 42.63, respectively. It revealed that F6(*) showed dissimilar dissolution profiles. Transdermal flux value for F6(*) and MR was found to be 144.61 +/- 1.28 MUg/cm(2)/h and 121.6 +/- 1.16 MUg/cm(2)/h, respectively. This study disclosed that F6(*) resides at targeted site for a relatively longer period of time thereby signifying the improved patient compliance. PMID- 27222751 TI - Metallurgical and mechanical properties of laser welded high strength low alloy steel. AB - The study aimed at investigating the microstructure and mechanical properties of Neodymium-Doped Yttrium Aluminum Garnet (Nd:YAG) laser welded high strength low alloy (HSLA) SA516 grade 70 boiler steel. The weld joint for a 4 mm thick plate was successfully produced using minimum laser power of 2 kW by employing a single pass without any weld preheat treatment. The micrographs revealed the presence of martensite phase in the weld fusion zone which could be due to faster cooling rate of the laser weldment. A good correlation was found between the microstructural features of the weld joints and their mechanical properties. The highest hardness was found to be in the fusion zone of cap region due to formation of martensite and also enrichment of carbon. The hardness results also showed a narrow soft zone at the heat affected zone (HAZ) adjacent to the weld interface, which has no effect on the weld tensile strength. The yield strength and ultimate tensile strength of the welded joints were 338 MPa and 549 MPa, respectively, which were higher than the candidate metal. These tensile results suggested that the laser welding process had improved the weld strength even without any weld preheat treatment and also the fractography of the tensile fractured samples showed the ductile mode of failure. PMID- 27222753 TI - Fabrication of electrospun nanofibres of BCS II drug for enhanced dissolution and permeation across skin. AB - The present work reports preparation of irbesartan (IBS) loaded nanofibre mats using electrospinning technique. The prepared nanofibres were characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction analysis, in vitro diffusion and ex vivo skin permeation studies. FTIR studies revealed chemical compatibility of IBS and polyvinyl pyrrolidine (PVP K-30). SEM images confirmed formation of nanofibres wherein IBS existed in amorphous form as revealed by DSC and XRD analyses. The prepared nanofibre mats of IBS were found to be superior to IBS loaded as cast films when analysed for in vitro IBS release and ex vivo skin permeation studies since the flux of IBS loaded nanofibres was 17 times greater than as cast film. The improvement in drug delivery kinetics of IBS loaded nanofibres could be attributed to amorphization with reduction in particle size of IBS, dispersion of IBS at molecular level in PVP matrix and enormous increase in the surface area for IBS release due to nanonization. Thus transdermal patch of IBS loaded nanofibres can be considered as an alternative dosage form in order to improve its biopharmaceutical properties and enhance therapeutic efficacy in hypertension. PMID- 27222752 TI - An eco-friendly dyeing of woolen yarn by Terminalia chebula extract with evaluations of kinetic and adsorption characteristics. AB - In the present study Terminalia chebula was used as an eco-friendly natural colorant for sustainable textile coloration of woolen yarn with primary emphasis on thermodynamic and kinetic adsorption aspects of dyeing processes. Polyphenols and ellagitannins are the main coloring components of the dye extract. Assessment of the effect of pH on dye adsorption showed an increase in adsorption capacity with decreasing pH. Effect of temperature on dye adsorption showed 80 degrees C as optimum temperature for wool dyeing with T. chebula dye extract. Two kinetic equations, namely pseudo first-order and pseudo second-order equations, were employed to investigate the adsorption rates. Pseudo second-order model provided the best fit (R (2) = 0.9908) to the experimental data. The equilibrium adsorption data were fitted by Freundlich and Langmuir isotherm models. The adsorption behavior accorded well (R (2) = 0.9937) with Langmuir isotherm model. Variety of eco-friendly and sustainable shades were developed in combination with small amount of metallic mordants and assessed in terms of colorimetric (CIEL(*) a (*) b (*) and K/S) properties measured using spectrophotometer under D65 illuminant (10 degrees standard observer). The fastness properties of dyed woolen yarn against light, washing, dry and wet rubbing were also evaluated. PMID- 27222754 TI - Association between single nucleotide polymorphism in miR-499, miR-196a2, miR 146a and miR-149 and prostate cancer risk in a sample of Iranian population. AB - MicroRNAs (miRNAs) play an important role in regulating gene expression at the post-transcriptional level and are involved in numerous physiological processes. Accumulating evidence suggests that single-nucleotide polymorphisms (SNPs) in human miRNA genes may affect miRNA biogenesis pathway and influence the susceptibility to several diseases such as cancer. The present study aimed to evaluate the impact of miR-499 rs3746444, miR-196a2 rs11614913, miR-149 rs2292832, and miR-146a rs2910164 polymorphisms on prostate cancer (PCa) risk in a sample of Iranian population. This case-control study was done on 169 patients with pathologically confirmed PCa and 182 benign prostatic hyperplasia (BPH). The genotyping assays were done using T-ARMS-PCR or PCR-RFLP methods. The findings indicated that CC genotype of miR-499 rs3746444 polymorphism increased the risk of PCa (OR = 1.76, 95% CI = 1.12-2.79, P = 0.019) compared to TT genotype. No statistically significant association was found between miR-196a2 rs11614913, miR 149 rs2292832, and miR-146a rs2910164 polymorphisms and PCa risk. In summary, the findings indicated that miR-499 rs3746444 polymorphism increased the risk of PCa in an Iranian population. Further studies with larger sample sizes and different ethnicities are necessary to verify the findings of the present study. PMID- 27222755 TI - Phytochemistry, biological activities and potential of annatto in natural colorant production for industrial applications - A review. AB - Bixa orellana commonly known as annatto is one of the oldest known natural dye yielding plants native to Central and South America. Various parts of annatto have been widely used in the traditional medical system for prevention and treatment of a wide number of health disorders. The plethora of traditional uses has encouraged researchers to identify and isolate phytochemicals from all parts of this plant. Carotenoids, apocarotenoids, terpenes, terpenoids, sterols, and aliphatic compounds are main compounds found in all parts of this plant and are reported to exhibit a wide range of pharmacological activities. In recent years annatto has received tremendous scientific interest mainly due to the isolation of yellow-orange natural dye from its seeds which exhibits high biodegradability, low toxicity, and compatibility with the environment. Considerable research work has already been done and is currently underway for its applications in food, textile, leather, cosmetic, solar cells, and other industries. The present review provides up-to-date systematic and organized information on the traditional usage, phytochemistry and pharmacology of annatto. It also highlights its non food industrial applications in order to bring more interest on this dye plant, identifies the existing gaps and provides potential for future studies. Studies reported in this review have demonstrated that annatto holds a great potential for being exploited as source of drugs and a potential natural dye. However, further efforts are required to identify extract biomolecules and their action mechanisms in exhibiting certain biological activities in order to understand the full phytochemical profile and the complex pharmacological effects of this plant. PMID- 27222756 TI - A review on multicomponent seismology: A potential seismic application for reservoir characterization. AB - Searching for hydrocarbon reserves in deep subsurface is the main concern of wide community of geophysicists and geoscientists in petroleum industry. Exploration seismology has substantially contributed to finding and developing giant fields worldwide. The technology has evolved from two to three-dimensional method, and later added a fourth dimension for reservoir monitoring. Continuous depletion of many old fields and the increasing world consumption of crude oil pushed to consistently search for techniques that help recover more reserves from old fields and find alternative fields in more complex and deeper formations either on land and in offshore. In such environments, conventional seismic with the compressional (P) wave alone proved to be insufficient. Multicomponent seismology came as a solution to most limitations encountered in P-wave imaging. That is, recording different components of the seismic wave field allowed geophysicists to map complex reservoirs and extract information that could not be extracted previously. The technology demonstrated its value in many fields and gained popularity in basins worldwide. In this review study, we give an overview about multicomponent seismology, its history, data acquisition, processing and interpretation as well as the state-of the-art of its applications. Recent examples from world basins are highlighted. The study concludes that despite the success achieved in many geographical areas such as deep offshore in the Gulf of Mexico, Western Canada Sedimentary Basin (WCSB), North Sea, Offshore Brazil, China and Australia, much work remains for the technology to gain similar acceptance in other areas such as Middle East, East Asia, West Africa and North Africa. However, with the tremendous advances reported in data recording, processing and interpretation, the situation may change. PMID- 27222757 TI - Stiffening of short small-size circular composite steel-concrete columns with shear connectors. AB - An experimental program was conducted to investigate the effect of shear connectors' distribution and method of load application on load-displacement relationship and behavior of thin-walled short concrete-filled steel tube (CFT) columns when subjected to axial load. The study focused on the compressive strength of the CFT columns and the efficiency of the shear stud in distribution of the load between the concrete core and steel tube. The study showed that the use of shear connectors enhanced slightly the axial capacity of CFT columns. It is also shown that shear connectors have a great effect on load distribution between the concrete and steel tubes. PMID- 27222758 TI - Transdermal delivery of Diltiazem HCl from matrix film: Effect of penetration enhancers and study of antihypertensive activity in rabbit model. AB - The present investigation focused on the development of Diltiazem HCl (DTH) matrix film and its characterization by in-vitro, ex-vivo and in-vivo methods. Films were prepared by solvent casting method by taking different ratios of hydroxypropyl methylcellulose K4M (HPMC K4M) and Eudragit RS100. Various parameters of the films were analyzed such as mechanical property using tensile tester, interaction study by Fourier transform infrared spectroscopy (FTIR) and Thermogravimetric analysis (TGA), in-vitro drug release through cellulose acetate membrane, ex-vivo permeation study using abdominal skin of rat employing Franz diffusion cell, and in-vivo antihypertensive activity using rabbit model. The FTIR studies confirmed the absence of interaction between DTH and selected polymers. Thermal analysis showed the shifting of endothermic peak of DTH in film, indicating the dispersion of DTH in molecular form throughout the film. Incorporation of 1,8-cineole showed highest flux (89.7 MUg/cm(2)/h) of DTH compared to other penetration enhancers such as capsaicin, dimethyl sulfoxide (DMSO), and N-methyl pyrrolidone (NMP). Photomicrographs of histology study on optimized formulation (DF9) illustrated disruption of stratum corneum (SC) supporting the ex-vivo results. The in-vivo antihypertensive activity results demonstrated that formulation DF9 was effective in reducing arterial blood pressure in normotensive rabbits. SEM analysis of films kept for stability study (40 +/- 2 degrees C/75% +/- 5%RH for 3 months) revealed the formation of drug crystals which may be due to higher temperature. The findings of the study provide a better alternative dosage form of DTH for the effective treatment of hypertension with enhanced patient compliance. PMID- 27222759 TI - Comparative evaluation of passive, active, and passive-active distraction techniques on pain perception during local anesthesia administration in children. AB - Local anesthesia forms the backbone of pain control techniques and is necessary for a painless dental procedure. Nevertheless, administering a local anesthetic injection is among the most anxiety-provoking procedures to children. This study was performed to compare the efficacy of different distraction techniques (passive, active, and passive-active) on children's pain perception during local anesthesia administration. A total of 90 children aged four to nine years, requiring inferior alveolar nerve block for primary molar extraction, were included in this study and randomly divided into three groups according to the distraction technique employed during local anesthesia administration. Passive distraction group: the children were instructed to listen to a song on headphones; Active distraction group: the children were instructed to move their legs up and down alternatively; and Passive-active distraction group: this was a combination between both techniques. Pain perception during local anesthesia administration was evaluated by the Sounds, Eyes, and Motor (SEM) scale and Wong Baker FACES(r) Pain Rating Scale. There was an insignificant difference between the three groups for SEM scale and Wong Baker FACES Pain Rating Scale at P = 0.743 and P = 0.112 respectively. The examined distraction techniques showed comparable results in reducing pain perception during local anesthesia administration. PMID- 27222760 TI - The Direct and Indirect Effects of Paliperidone Extended-release on Depressive Symptoms in Schizoaffective Disorder: A Path Analysis. AB - BACKGROUND: This analysis evaluates improvement in symptoms of depression in patients with schizoaffective disorder administered oral paliperidone extended release by accounting for the magnitude of direct and indirect (changes in negative and positive symptoms and worsening of extrapyramidal symptoms) treatment effects on depressive symptoms. METHODS: Data for this post hoc analysis were drawn from two six-week, randomized, placebo-controlled studies of paliperidone extended-release versus placebo in adult subjects with schizoaffective disorder (N=614; NCT00412373, NCT00397033). Subjects with baseline 17-item Hamilton Rating Scale for Depression scores of 16 or greater were included. Structural equation models (path analyses) were used to separate total effects into direct and indirect effects on depressive symptoms. Change from baseline in 17-item Hamilton Rating Scale for Depression score at the Week 6 end point was the dependent variable; changes in Positive and Negative Syndrome Scale positive and negative factors and Simpson-Angus Scale (to evaluate extrapyramidal symptoms) scores were independent variables. RESULTS: At baseline, 332 of 614 (54.1%) subjects had a 17-item Hamilton Rating Scale for Depression score of 16 or greater. Path analysis determined that up to 26.4 percent of the paliperidone extended-release versus placebo effect on depressive symptoms may be attributed to a direct treatment effect, and 45.8 percent and 28.4 percent were mediated indirectly through improvements on positive and negative symptoms, respectively. No effects were identified as mediated through extrapyramidal symptoms changes (-0.7%). CONCLUSION: RESULTS of this analysis suggest that paliperidone's effect on depressive symptoms in subjects with schizoaffective disorder participating in two six-week, randomized, placebo-controlled studies is mediated through indirect effects (e.g., positive and negative symptom changes) and a direct treatment effect. PMID- 27222761 TI - Sinus Node Dysfunction After Acute Lithium Treatment at Therapeutic Levels. AB - Lithium carbonate (lithium) has been used extensively for the treatment of a variety of psychiatric conditions. It requires close monitoring of serum concentration due to its narrow therapeutic window. Cardiac toxicity range from asymptomatic electrocardiographic changes to fatal arrhythmias may occur even at the therapeutic levels. We report a case of psychiatric inpatient who developed asymptomatic severe bradycardia most likely related to sinus node dysfunction due to acute lithium treatment at therapeutic level. After withdrawal of lithium, a time sequential improvement of severe bradycardia examined by repeated electrocardiogram, including Holter monitoring, suggested a relationship between the lithium toxicity and sinus node dysfunction. Other factors such as baseline sinus bradycardia and lower limit of normal thyroid function might be associated with severe bradycardia. This case emphasizes the need, when prescribing lithium, for clinicians to regularly monitor their patients' electrocardiogram and serum lithium levels to prevent serious or fatal complications, such as cardiac arrest. PMID- 27222763 TI - Accountable Care Organizations and Professional Liability Risk. PMID- 27222762 TI - Probable Nootropicinduced Psychiatric Adverse Effects: A Series of Four Cases. AB - The misuse of nootropics-any substance that may alter, improve, or augment cognitive performance, mainly through the stimulation or inhibition of certain neurotransmitters-may potentially be dangerous and deleterious to the human brain, and certain individuals with a history of mental or substance use disorders might be particularly vulnerable to their adverse effects. We describe four cases of probable nootropic-induced psychiatric adverse effects to illustrate this theory. To the best of our knowledge this has not been previously reported in the formal medical literature. We briefly describe the most common classes of nootropics, including their postulated or proven methods of actions, their desired effects, and their adverse side effects, and provide a brief discussion of the cases. Our objective is to raise awareness among physicians in general and psychiatrists and addiction specialists in particular of the potentially dangerous phenomenon of unsupervised nootropic use among young adults who may be especially vulnerable to nootropics' negative effects. PMID- 27222764 TI - Appearances may be deceiving. PMID- 27222765 TI - Development of poorly differentiated invasive squamous cell carcinoma in giant Bowen's disease: a case report with dermatoscopy. AB - Bowen's disease (BD) is an in situ form of squamous cell carcinoma (SCC), often occurring in the chronically UV-damaged skin of elderly people. The risk of progression of BD to invasive SCC varies between 3% and 5%, and one-third of invasive tumors may metastasize. Herein we discuss the dermatoscopic findings of a case of giant Bowen's disease, which progressed to poorly differentiated invasive SCC. PMID- 27222766 TI - Hypertrophic lichen planus versus prurigo nodularis: a dermoscopic perspective. AB - BACKGROUND: Hypertrophic lichen planus (HLP) classically involves shin and ankles and is characterized by hyperkeratotic plaques and nodules. Prurigo nodularis (PN) is a chronic neurodermatitis that presents with intensely pruritic nodules. Histopathology of HLP and PN demonstrate epidermal hyperplasia, hypergranulosis, and compact hyperkeratosis. The dermis shows vertically arranged collagen fibers and an increased number of fibroblasts and capillaries in both conditions. Moreover, basal cell degeneration is confined to the tips of rete ridges, and band-like infiltration is conspicuously absent in HLP. Therefore, both conditions mimic each other clinically, which makes diagnosis difficult. Hence, there is a need for a diagnostic technique to differentiate both conditions. OBJECTIVE: To evaluate dermoscopic patterns in HLP and PN and to study these patterns histopathologically. MATERIALS AND METHODS: The study was conducted at S. Nijalingappa Medical College in Bagalkot. It was an observational case series study. Ethical clearance and informed consent was obtained. A Dermlite 3 dermoscope (3Gen, San Juan Capistrano, CA, USA) attached to a Sony Cyber Shot camera DSC-W800 (Sony Electronics Inc., San Diego, California, USA) was employed. Histopathology was done to confirm the diagnosis. RESULTS: There were 10 patients each with HLP and PN. HLP was seen in 8 males and 2 females. PN was observed in 7 females and 3 males. Dermoscopy of HLP demonstrated pearly white areas and peripheral striations (100%), gray-blue globules (60%), comedo-like openings (30%), red dots (40%), red globules (10%), brownish-black globules (30%), and yellowish structures (90%). In PN, red dots (70%), red globules (60%), and pearly white areas with peripheral striations (100%) were observed under dermoscopy. CONCLUSION: Both HLP and PN demonstrated specific dermoscopic patterns which can be demonstrated on histopathologic findings. The authors propose that these patterns are hallmarks of each condition. Thus, dermoscopy is a good diagnostic tool in the differentiation of HLP and PN. PMID- 27222767 TI - Two adjacent individual fibroepithelioma of Pinkus of the umbilicus-one pink, one pigmented-a case report and review of the literature. AB - We present a unique case of separate and independent adjacent fibroepitheliomas of Pinkus (FeP) arising from the umbilicus in an 83-year-old man. Of further interest, one is pigmented and the other nonpigmented. Clinical, dermatoscopic and histopathological images are provided. A review of the published literature is undertaken to attempt to assess the incidence of pigmented versus nonpigmented FeP. Of 24 published FeP cases, 10 (41.7%) have been pigmented. Thus to date pigmented FeP comprise approaching one-half of all reported cases. PMID- 27222768 TI - Diet and acne: an exploratory survey study of patient beliefs. AB - BACKGROUND: In the past, medical literature reflected that diet was not a proven cause of acne. However, studies in recent years have substantiated a link between certain dietary factors and acne. It is unclear whether patients are aware of recent research findings. OBJECTIVES: Acne patients were surveyed to explore beliefs regarding the link between diet and acne, to determine whether these beliefs translated into behavior change and to identify health information sources. PATIENTS/METHODS: Upon Institutional Review Board (IRB) approval, surveys were administered to 50 acne patients at an academic dermatology clinic in 2014, with 49 completed in full and included in this analysis. RESULTS: Ninety two percent of respondents believed that diet could affect acne. Seventy-one percent attempted to change their diet to improve acne. Seventy-one percent believed acne to be caused by fried or greasy foods, although chocolate (53%), dairy (47%), and soda drinks (35%) were highly implicated. Patients obtained information from Google searches (49%), dermatologists (43%), family members and TV (41% each), and medical websites (31%). CONCLUSIONS: In this exploratory study, patients reported utilizing a diversity of information sources, a majority from the Internet. In those surveyed, there was a persistence of long-held belief that fried/greasy foods and chocolate may serve as acne triggers, and less belief in trigger foods supported by recent research, including refined carbohydrates and sugar. Given the multiplicity of beliefs and utilized sources among acne patients in our survey, there is a need to establish up-to-date and reliable methods to educate patients on diet and acne. PMID- 27222769 TI - Chronology of lichen planus-like keratosis features by dermoscopy: a summary of 17 cases. AB - Dermoscopic findings for 17 cases of lichen planus-like keratosis (LPLK) were chronologically evaluated. Three males and 14 females were included in the study and the ages ranged from 43 to 85 years (median 65 years). Three cases were diagnosed based on stereotypical dermoscopic findings, while the other 14 cases were histopathologically diagnosed as LPLK. Dermoscopy photographs were divided into four groups depending on the number of days (D) from the initial visit: 1) D = 0 (initial visit or biopsy day); 2) D = 61 to 180; 3) D = 181 to 270; 4) D = 271 to 360. Dermoscopic findings, described as light brown pseudonetwork, pinkish area, gray pseudonetwork, annular granular structures, and blue-gray fine dots, were evaluated at every visit to the hospital. Initial dermoscopy features included light brown pseudonetworks due to residual solar lentigo and overlapping pinkish areas attributed to lichenoid inflammation. Annular granular structures and gray pseudonetwork appeared to be the main features of the regressing stage; these features seemed to progress to "blue-gray fine dots" in the late regressing stage. Blue-gray dots or globules reflecting melanophages, the hallmark dermoscopic features of LPLK, were believed to resolve in approximately one to two years. Based on the clinical and dermoscopic observations, we have specified five stages of evolution of LPLK, namely 1) pre-existing solar lentigo, 2) early inflammatory stage, 3) early regressing stage, 4) regressing stage, and 5) late regressing stage. The limitations of the study are that this is a small-sized, retrospective, observational study and that ethnicity of participants is limited to Japanese patients with skin phototype III. PMID- 27222770 TI - Spitz/Reed nevi: a review of clinical-dermatoscopic and histological correlation. AB - BACKGROUND: Spitz/Reed nevi are melanocytic lesions that may mimic melanoma at clinical, dermatoscopic and histopathological levels. Management strategies of these lesions remain controversial. OBJECTIVES: We aim a correlation among clinical-dermatoscopic and histological features of a series of Spitz/Reed nevi diagnosed during 7 years at the Department of Dermatology. METHODS: Clinical, dermatoscopic and histological features of Spitz/Reed nevi diagnosed at our tertiary hospital from 2008 to 2014 were reviewed in order to seek correlation. RESULTS: All described dermatoscopic patterns for Spitz/Reed nevi were found among the 47 enrolled patients; starburst and atypical/multicomponent patterns prevailed (57.4%). Reticular pattern predominated among children younger than 12 years, whereas homogeneous pattern was more frequent in patients older than 12 years, although these differences were not statistically significant (P=0.785). Among histological atypical lesions, all dermatoscopic patterns were represented, but the atypical/multicomponent predominated (56.3%). Two out of 11 dermatoscopically atypical lesions did not show histopathological counterpart. CONCLUSIONS: The excision of Spitz/Reed nevi in adults is supported, given the inability to accurately predict those with histopathological atypia, based on clinical and dermatoscopic features, which may raise concern about malignancy. PMID- 27222771 TI - Time to reconsider Spitzoid neoplasms? AB - BACKGROUND: Spitzoid neoplasms may pose significant diagnostic problems because in a fraction of them it is quite difficult or impossible to establish if they are benign or malignant lesions. An extraordinarily large number of studies have been made in attempts to solve this problem; regrettably, the histological criteria proposed and the various special sophisticated techniques employed have proven to be ineffective in making this distinction with confidence. OBJECTIVES: To explore the possible causes for this diagnostic failure and an attempt to identify the source of this problem. METHOD: A historical and technical analysis of the specialized literature is performed, critically evaluating the main points of this controversial topic. RESULTS: The reasons for the diagnostic failure in Spitzoid neoplasms are not clear but could be the result of inappropriate conceptual representation. The analysis of available data and a rational review of old and new assumptions and concepts may suggest a different representation for Spitzoid neoplasms: Spitz nevus, atypical Spitz tumor and Spitzoid melanoma, rather than being three different tumors that are difficult or impossible to distinguish with assurance, could be viewed as one unique entity, Spitz tumor (ST). This tumor is a low-grade malignant neoplasm, in which the amount of intrinsic risk is variable, ranging from very low to high (ST1, ST2, ST3), and malignant potential could be estimated. CONCLUSIONS: The proposed alternative representation of Spitzoid neoplasms as a unique tumor may help in overcoming the difficulty in diagnosis of these tumors. PMID- 27222772 TI - Condylomata lata on the ankle: an unusual location. AB - A 43-year-old Japanese man presented with reddish nodules on the ankle. The nodules had a yellowish crust and eroded surface. Dermoscopy revealed red to milky-red globules at the periphery and some glomerular vessels in the center and a whitish-pink network, which corresponded to capillary dilatation in the papillary dermis and prominent acanthosis, respectively. These structures were surrounded by a yellowish peripheral structureless area and multiple white, small, round structures in the center, corresponding to the macerated horny layer and keratin plugs. Blood samples were positive for rapid plasma reagin (1:64), Treponema pallidum hemagglutination assay (1:20480), and fluorescent treponemal antibody-absorption (1:1280). A lesional skin biopsy specimen showed irregular acanthosis and papillomatosis. The Warthin-Starry and anti-Treponema pallidum antibody stains on the biopsy specimen revealed many spirochetes in the lower epidermis and the papillary dermis. A diagnosis of secondary syphilis with condylomata lata was made. After one week of treatment with oral benzylpenicillin benzathine hydrate (Bicillin((r)) G granules 400,000 units; Banyu Pharmaceutical Co., Ltd, Tokyo, Japan), 1.6 million units (U) daily, the ankle lesions had resolved with a small ulcer and pigmentation. Although syphilis is a relatively common disease, this case study reports an unusual presentation as well as dermoscopy findings. PMID- 27222773 TI - Dermoscopy: a useful auxiliary tool in the diagnosis of type 1 segmental Darier's disease. AB - Type 1 segmental Darier's disease is a blaschkolinear variant of Darier's disease resulting from a postzygotic mosaicism. Since it usually lacks diagnostic clues typical of the generalized form, including positive family history of the disease, nail and mucosal abnormalities, and/or acral involvement, its distinction from other acquired inflammatory blaschkolinear dermatoses may often be quite challenging, thus requiring histopathological examination to reach a definitive diagnosis. We report a case of type 1 segmental Darier's disease with its dermoscopic findings in order to show the usefulness of dermoscopy in assisting the noninvasive identification of this condition. PMID- 27222774 TI - Scedosporium apiospermum and S. prolificans mixed disseminated infection in a lung transplant recipient: An unusual case of long-term survival with combined systemic and local antifungal therapy in intensive care unit. AB - Infections due Scedosporium spp. in lung transplant recipients are associated with disseminated disease with high mortality rates. The adjunctive local antifungal therapy may be a useful option when systemic treatment is insufficient and/or surgery is not feasible. We present a case of mixed disseminated infection due Scedosporium apiospermum and S. prolificans in a lung transplant recipient. Combined local and systemic antifungal therapy provided an unusual long-term survival in the intensive care unit. PMID- 27222775 TI - Sarcoidosis patient with lupus pernio and infliximab-induced myositis: Response to Acthar gel. AB - Infliximab is an effective treatment for sarcoidosis patients with persistent disease despite glucocorticoids and immunosuppressive therapy. Patients receiving infliximab can experience side effects, inducing an autoimmune reaction. Treatment is unclear for sarcoidosis patients who develop autoimmune reactions to infliximab. We report a case of a patient with advanced sarcoidosis who developed a myositis type reaction to infliximab characterized by diffuse muscle achiness and weakness and marked elevations in serum creatinine phosphokinase (CPK) and aldolase. Manifestations of sarcoidosis and myositis improved after Acthar treatment. This is the first report of successful treatment with Acthar in a patient with advanced sarcoidosis with an autoimmune reaction to infliximab. PMID- 27222776 TI - Unusual mode of presentation of intrathoracic bronchogenic cyst: A double location. AB - A 63 year old woman presenting chronic back pain and neuralgia had abnormal shadow on chest radiograph. She has a history of pulmonary tuberculosis treated in 1977. The chest-CT scan showed a soft tissue mass in the lower lobe of the right lung and a cystic mass in the paravertebral region. The patient had right lower lobectomy and complete excision of a paraoesophageal cyst. Both masses were bronchogenic cysts at histology. The patient had an uneventful discharge the seventh postoperative day. After 4 years and 7 months of follow-up with CT-scann, the patient was free of symptoms with no evidence of recurrent disease. PMID- 27222777 TI - Chronic cough with normal sweat chloride: Phenotypic descriptions of two rare cystic fibrosis genotypes. AB - While our understanding of cystic fibrosis genetics has expanded in recent decades, the genetics and clinical manifestations of the disease remains highly heterogeneous. Diagnosis of CF in non-classical mutations remains a clinical challenge. We describe the clinical presentation of two patients with chronic cough found to have normal sweat chlorides. We discuss the subsequent evaluation that lead to the diagnosis of two rare CF mutations. We briefly discuss the use of the expanded 106-panel of CF mutations (homozygous 3849 + 10 kb C > T), and the role of whole CFTR gene sequencing (heterozygous c.2752-26 A > G/5T). PMID- 27222778 TI - Sclerosing hemangioma of the lung showing strong FDG avidity on PET scan: Case report and review of the current literature. AB - Sclerosing Hemangioma is a rare lung tumor with polymorphic histologic features that usually occurs in middle aged women. Based on many immunohistochemical and ultrastructural studies, it is most probably derived from undifferentiated respiratory epithelial cells. Symptoms are usually due to enlargement of the tumor and compression of the surrounding tissues. Occurrence of multiple lesions or metastasis is extremely rare although some authors consider sclerosing hemangioma as a potentially low grade malignancy tumor. It usually presents with low to moderate uptake on FDG PET imaging. We present a case of sclerosing hemangioma with strong FDG avidity on PET scan in a 41 year old lady with history of haemoptysis. A full review of the literature on this topic was performed. PMID- 27222779 TI - Pleural haemangioma: A rare cause of recurrent pleural effusion. AB - A middle aged female presented with recurrent unilateral pleural effusion. Thoracoscopy revealed a vascular tumor in the apical region of pleural cavity arising from the chest wall. Biopsy from the tumor showed features of pleural hemangioma. She was successfully managed by surgical excision of the tumor. The case is being presented because of its rarity. PMID- 27222780 TI - IgG4-related disease presenting as a lung mass and weight loss: Case report and review of the literature. AB - We describe a case of IgG4-related lung disease presenting as a lung mass with associated weight loss. IgG4-related disease is a systemic sclerosing disorder that causes fibrotic, often tumor-like manifestations that variably effect different organ systems. The clinical presentation of IgG4-related disease is protean. Timely recognition and diagnosis requires awareness on the part of clinicians and pathologists to the variable manifestations of this newly recognized disorder. We offer a concise review of the pulmonary manifestations, diagnosis and treatment of IgG4-related lung disease. PMID- 27222781 TI - The inter-connection between fibrosis and microvascular remodeling in idiopathic pulmonary fibrosis: Reality or just a phenomenon. AB - BACKGROUND: Idiopathic pulmonary fibrosis is the most frequent interstitial disease with the worst prognosis. It is characterized by an uncontrolled fibrosis which is difficult to manage. The pathogenesis of this disease remains unclear with many theories resulting in multiple target therapies. The relation between fibrosis and vascular remodeling has been debated in the literature with different results that may seem contradictory. AIM: We target to evaluate the connection between fibrosis and vascular remodeling in usual interstitial pneumonia. MATERIAL AND METHODS: 26 cases of idiopathic pulmonary fibrosis were reviewed by 2 pathologists and the diagnosis of UIP was retained according to the American Thoracic Society's criteria. Fibrotic changes and vascular remodeling were evaluated blindly. The fibrotic changes were classified as severe, intermediate and mild. Vascular occlusion was graded in 4 grades extending from medial hypertrophy (grade 1) to plexiform lesions of the vascular wall (grade 4). RESULTS: We noticed that severe degrees of fibrosis were correlated with severe grades of vascular obstruction. In fact, our 26 cases were classified as severe fibrosis in 11 cases with grade IV vascular lesions in 6 cases, intermediate fibrosis in 12 cases with grade II vascular lesions in 8 cases and mild fibrosis in 3 cases with grade I vascular lesions in all cases. CONCLUSION: Many theories have been reported concerning the UIP's pathogenesis. Recently, many authors reported that the primum movens of these lesions was an epithelial/endothelial injury which induces uncontrolled fibrosis and microvascular remodeling using different pathways. This puts emphasis on the necessity of multi-target therapies in order to improve the management of this fatal disease. PMID- 27222782 TI - Management of an elderly patient with respiratory failure due to double aortic arch. AB - Vascular rings are congenital malformations of the aortic arch. A double aortic arch (DAA), the most common type of vascular ring, results from the failure of the fourth embryonic branchial arch to regress, leading to an ascending aorta that divides into a left and right arch that fuse together to completely encircle the trachea and esophagus. The subsequent DAA causes compressive effects on the trachea and esophagus that typically manifests in infancy or early childhood. Adult presentations, particularly in the elderly, are exceedingly rare. Historically such patients have a long-standing history of dyspnea on exertion and dysphagia, with many assumed to have obstructive lung or intrinsic cardiac disease. We describe a case of an elderly woman who presented with respiratory failure due to DAA. In her case, surgery was not feasible and we describe our experience with airway stenting. PMID- 27222783 TI - Gastroesophageal reflux and idiopathic pulmonary fibrosis: A long term relationship. AB - Idiopathic pulmonary fibrosis (IPF) is a dreaded disease of uncertain etiology and no available cure. It is still unclear if a causal relationship exists between gastro-esophageal reflux (GER) and IPF, but studies have shown an increased prevalence of acid reflux in patients with IPF. We describe a patient with achalasia and GER who went on to develop IPF. She underwent a rapidly worsening course punctuated by acute exacerbations of IPF, despite best efforts to manage the acid GER. We also reviewed the literature on the role of GER in the etiology and progression of IPF and the impact of antireflux measures on its course. PMID- 27222784 TI - Immunomodulatory effect of macrolides: At what cost? AB - We present the case of a 60-year old female patient, with a 10 year history of non-CF bronchiectasis and use of macrolides as maintenance immunomodulatory treatment, who was diagnosed with macrolide-resistant Mycobacterium avium complex lung disease. Macrolides' immunomodulatory effect is appealing for non- CF bronchiectasis patients, hiding a high risk for resistance emergence. PMID- 27222785 TI - Possible role of anti-SSA/Ro antibodies in the pathogenesis of pulmonary hypertension. AB - INTRODUCTION: There are many different causes of pulmonary hypertension and the pathogenesis of the disease is still being elucidated. Although they are not the most common, autoimmunity and inflammation have been identified as possible causes. No one autoantibody has been identified as the definite cause of pulmonary hypertension. We present a rare association of anti-SSA/Ro antibodies and isolated pulmonary hypertension. CASE PRESENTATION: A 53 year old African American female presented with abdominal pain, nausea, weight loss, dyspnea and fatigue. Upon further exam she was found to have high titers of antinuclear antibodies and anti-SSA/Ro antibodies. This antibody profile would typically be suggestive of Sjogren's Syndrome, which is characterized by dry eyes and poor salivary gland function. However, since this patient did not have any symptoms consistent with the disease a diagnosis of Sjogren's Syndrome could not be made. A combination of laboratory, imaging and diagnostic studies were done that revealed a final diagnosis of pulmonary hypertension. CONCLUSION: It is known that pulmonary hypertension has association with autoimmune diseases, however no clear markers yet exist. Anti-SSA/Ro antibodies have been rarely described in cases of pulmonary disease, and less so in pulmonary hypertension. This case describes a unique association between isolated pulmonary hypertension and anti SSA/Ro antibody, thereby illustrating the need to investigate this autoantibody and others in the pathogenesis of autoimmune pulmonary hypertension. PMID- 27222786 TI - Phenytoin induced Steven-Johnson syndrome and bronchiolitis obliterans - case report and review of literature. AB - Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are both rare but serious idiosyncratic drug reactions characterized by diffuse muco-epidermoid injury and high mortality. Keratinocytes in both skin and mucous membranes (including eyes, mouth and genitalia) are injured resulting in a diffuse maculopapular rash, blistering lesions and epithelial detachment with minimal force (Nikolsky's sign). SJS is typically diagnosed when less than 10% of the skin surface is involved and the term TEN is used in cases with more than 30% involvement. Respiratory involvement in SJS-TEN is common with 30-50% of cases demonstrating respiratory epithelial sloughing with severe short and long term complications. Patients who survive SJS-TEN are often left with impaired respiratory function and bronchiolitis obliterans. Cases of bronchiolitis obliterans with SJS/TEN have been very rarely reported. We report a case of phenytoin induced SJS/TEN followed by severe bronchiolitis obliterans in an adult patient. The presentation, pathophysiology and management of SJS/TEN related bronchiolitis obliterans is also reviewed. PMID- 27222787 TI - Malignant pleural mesothelioma in a 17-year old boy: A case report and literature review. AB - BACKGROUND: Malignant pleural mesothelioma is a rare, invasive and often fatal neoplasm that develops in the thin layer of tissue surrounding the lungs known as the pleura. Although rare, mesotheliomas do occur in the young; their characteristics are distinct from those of older patients. CASE PRESENTATION: This is a case report of a 17-year-old boy who had moderate dyspnea, cough, right sided pleuritic chest pain, fever, headache and no weight loss. Physical examination showed a right pleural effusion and chest roentgenograms revealed a homogenous opacity on lower right hemithorax. Biochemical analysis of pleural fluid showed hemorrhagic/turbid effusion compatible with exudate. It was initially treated as an empyema. The pleural fluid culture was negative. Adenosine deaminase level was 34.3 U/L (admission) and 19.02 U/L (two weeks after). Pleural fluid smear and culture for Mtb were negative. During the open pleural biopsy, thickened pleura and multiple pale yellow nodules in the lung were observed. The histopathological report was compatible with malignant pleural mesothelioma. With this diagnosis, a chemotherapy regimen with cisplatin was initiated. After two cycles, the patient had no clinical and radiological improvement. The patient is currently under regular follow up. CONCLUSION: MPM is rare in young adults and its clinical presentation makes it different from mesothelioma in elderly patients, so it will be necessary to identify the new risk factors that can identify these patients. PMID- 27222788 TI - Predominant diffuse ground glass opacity in both lung fields: A case of sarcoidosis with atypical CT findings. AB - Sarcoidosis can cause fatal diffuse lung fibrosis in the end stage, so its early diagnosis and treatment can prevent the progression of fibrosis. Predominant ground glass opacity on high-resolution CT (HRCT) scans is a rare presentation of sarcoidosis. We report the case of a patient who presented with very few symptoms and signs of sarcoidosis; HRCT revealed large-scale ground glass opacity and minor lymphadenopathy. Bronchoalveolar lavage fluid contained turbid liquid. Sarcoidosis could be confirmed only based on pathological examination of the resected tissue. The patient was administrated prednisone at 40 mg/d orally with tapering of the dose. Lung HRCT scans taken 6 months after the prednisone treatment showed ablation of the ground glass opacity. This case report sheds light on an atypical HRCT presentation of sarcoidosis; the findings here will be useful for the early diagnosis of sarcoidosis and prevention of fatal complications. PMID- 27222789 TI - A severe case of acute exogenous lipoid pneumonia treated with systemic corticosteroid. AB - Acute exogenous lipoid pneumonia is a rare disorder in adults. A treatment of choice for lipoid pneumonia has not been established, and systemic corticosteroid use remains controversial. We report the case of a 32-year-old man with schizophrenia who presented with kerosene-induced acute exogenous lipoid pneumonia that was treated with a systemic corticosteroid. In this case, supportive therapy did not improve the patient's condition, so systemic corticosteroid therapy was commenced four days after he ingested the kerosene. After corticosteroid commencement, the patient's symptoms and hypoxia improved within a few days. Although some radiological characteristics of this disorder have been reported previously, the process of radiological improvement of exogenous lipoid pneumonia is not well known. In this case, computed tomography findings changed dramatically after corticosteroid therapy was initiated. Extensive bilateral consolidations that were observed on admission improved. Although pneumatoceles developed two weeks after corticosteroid commencement, they were nearly gone after two months of the treatment. While corticosteroid therapy is not suitable for all cases, it should be considered for severe or refractory cases. PMID- 27222790 TI - A case of familial hot tub lung. AB - Hot tub lung is a lung disease caused by Mycobacterium avium complex. We report the first case of familial hot tub lung appearing simultaneously in a husband and wife. Our case supports the consideration that hot tub lung is a hypersensitivity pneumonitis rather than an infectious lung disease. It also suggests that the state of hot tub lung changes seasonally depending on temperature variations, in a manner similar to summer-type hypersensitivity pneumonitis. This case demonstrates similarities between hot tub lung and summer-type hypersensitivity pneumonitis in regards to familial occurrence and seasonal changes in the disease state. PMID- 27222791 TI - Diffuse cystic lung disease due to pulmonary metastasis of colorectal carcinoma. AB - The diffuse cystic lung diseases (DCLDs) are a pathophysiologically heterogeneous processes characterized by the presence of multiple thin-walled, air-filled spaces within the pulmonary parenchyma. The most common causes of DCLD are lymphangioleiomyomatosis (LAM) and pulmonary Langerhans cell histiocytosis (PLCH). DCLD develops rarely as a result of malignancy, typically secondary to metastases from peripheral sarcomas and mesenchymal tumors. DCLD have also been reported in a variety of other metastatic disease such as adenocarcinoma. Our case describes a patient with DCLD as a result of metastatic colorectal adenocarcinoma. PMID- 27222792 TI - Tracheomegaly and tracheosephagial fistula following mechanical ventilation: A case report and review of the literature. AB - Postintubation Tracheoesophageal fistula (TEF) is a rare complication. Acquired TEF most commonly occurred following prolonged mechanical ventilation with an endotracheal or tracheostomy tube, cuff-related tracheal injury, post-intubation injury. We present a case of both tracheomegaly and tracheosephagial fistula following mechanical ventilation for 15 days, in the light of the literature. PMID- 27222793 TI - Successful management of acute respiratory failure with noninvasive mechanical ventilation after drowning, in an epileptic-patient. AB - Sea drowning is a common cause of accidental death worldwide. Respiratory complications such as acute pulmonary oedema, which is often complicated by acute respiratory distress syndrome, is often seen. Noninvasive ventilation is already widely used as a first approach to treat acute respiratory failure resulting from multiple diseases. We report a case of a 45 year old man with a history of epilepsy, motor and mental handicap who developed acute respiratory failure secondary to sea water drowning after an epileptic crisis. We illustrate successful and rapid management of this case with noninvasive ventilation. We emphasize the advantages and limitations of using noninvasive ventilation to treat acute respiratory failure due to sea water drowning syndrome. PMID- 27222794 TI - A brain stress test: Cerebral perfusion during memory encoding in mild cognitive impairment. AB - Arterial spin labeled perfusion magnetic resonance imaging (ASL MRI) provides non invasive quantification of cerebral blood flow, which can be used as a biomarker of brain function due to the tight coupling between cerebral blood flow (CBF) and brain metabolism. A growing body of literature suggests that regional CBF is altered in neurodegenerative diseases. Here we examined ASL MRI CBF in subjects with amnestic mild cognitive impairment (n = 65) and cognitively normal healthy controls (n = 62), both at rest and during performance of a memory-encoding task. As compared to rest, task-enhanced ASL MRI improved group discrimination, which supports the notion that physiologic measures during a cognitive challenge, or "stress test", may increase the ability to detect subtle functional changes in early disease stages. Further, logistic regression analysis demonstrated that ASL MRI and concomitantly acquired structural MRI provide complementary information of disease status. The current findings support the potential utility of task enhanced ASL MRI as a biomarker in early Alzheimer's disease. PMID- 27222795 TI - Structural and functional brain abnormalities place phenocopy frontotemporal dementia (FTD) in the FTD spectrum. AB - PURPOSE: 'Phenocopy' frontotemporal dementia (phFTD) patients may clinically mimic the behavioral variant of FTD (bvFTD), but do not show functional decline or abnormalities upon visual inspection of routine neuroimaging. We aimed to identify abnormalities in gray matter (GM) volume and perfusion in phFTD and to assess whether phFTD belongs to the FTD spectrum. We compared phFTD patients with both healthy controls and bvFTD patients. MATERIALS & METHODS: Seven phFTD and 11 bvFTD patients, and 20 age-matched controls underwent structural T1-weighted magnetic resonance imaging (MRI) and 3D pseudo-continuous arterial spin labeling (pCASL) at 3T. Normalized GM (nGM) volumes and perfusion, corrected for partial volume effects, were quantified regionally as well as in the entire supratentorial cortex, and compared between groups taking into account potential confounding effects of gender and scanner. RESULTS: PhFTD patients showed cortical atrophy, most prominently in the right temporal lobe. Apart from this regional atrophy, GM volume was generally not different from either controls or from bvFTD. BvFTD however showed extensive frontotemporal atrophy. Perfusion was increased in the left prefrontal cortex compared to bvFTD and to a lesser extent to controls. CONCLUSION: PhFTD and bvFTD show overlapping cortical structural abnormalities indicating a continuum of changes especially in the frontotemporal regions. Together with functional changes suggestive of a compensatory response to incipient pathology in the left prefrontal regions, these findings are the first to support a possible neuropathological etiology of phFTD and suggest that phFTD may be a neurodegenerative disease on the FTD spectrum. PMID- 27222796 TI - Cerebral metabolism and perfusion in MR-negative individuals with refractory focal epilepsy assessed by simultaneous acquisition of (18)F-FDG PET and arterial spin labeling. AB - The major challenge in pre-surgical epileptic patient evaluation is the correct identification of the seizure onset area, especially in MR-negative patients. In this study, we aimed to: (1) assess the concordance between perfusion, from ASL, and metabolism, from (18)F-FDG, acquired simultaneously on PET/MR; (2) verify the utility of a statistical approach as supportive diagnostic tool for clinical readers. Secondarily, we compared (18)F-FDG PET data from the hybrid PET/MR system with those acquired with PET/CT, with the purpose of validate the reliability of (18)F-FDG PET/MR data. Twenty patients with refractory focal epilepsy, negative MR and a defined electro-clinical diagnosis underwent PET/MR, immediately followed by PET/CT. Standardized uptake value ratio (SUVr) and cerebral blood flow (CBF) maps were calculated for PET/CT-PET/MR and ASL, respectively. For all techniques, z-score of the asymmetry index (zAI) was applied for depicting significant Right/Left differences. SUVr and CBF images were firstly visually assessed by two neuroimaging readers, who then re-assessed them considering zAI for reaching a final diagnosis. High agreement between (18)F FDG PET/MR and ASL was found, showing hypometabolism and hypoperfusion in the same hemisphere in 18/20 patients, while the remaining were normal. They were completely concordant in 14/18, concordant in at least one lobe in the remaining. zAI maps improved readers' confidence in 12/20 and 15/20 patients for (18)F-FDG PET/MR and ASL, respectively. (18)F-FDG PET/CT-PET/MR showed high agreement, especially when zAI was considered. The simultaneous metabolism-perfusion acquisition provides excellent concordance on focus lateralisation and good concordance on localisation, determining useful complementary information. PMID- 27222798 TI - Mitigating bit flips or single event upsets in epilepsy neurostimulators. AB - OBJECTIVES: The objective of this study was to review software errors known as single event upsets (SEUs) or bit flips due to cosmic rays in epilepsy neurostimulators. MATERIALS AND METHODS: A case report of a single event upset or bit flip is discussed; device manufacturers and publicly available data were queried for both incidence and types of error as well as strategies of software error mitigation. RESULTS: Neurostimulators, like other implanted devices such as pacemakers, are prone to single event upsets. Strategies for SEU mitigation are reviewed. CONCLUSIONS: Cosmic radiation can threaten RAM and settings of neurostimulators; neuromodulation teams and device designers need to take this threat into account when designing multifunctional neuromodulation systems. PMID- 27222797 TI - The volumetric and shape changes of the putamen and thalamus in first episode, untreated major depressive disorder. AB - Previous MRI studies confirmed abnormalities in the limbic-cortical-striatal pallidal-thalamic (LCSPT) network or limbic-cortico-striatal-thalamic-cortical (LCSTC) circuits in patients with major depressive disorder (MDD), but few studies have investigated the subcortical structural abnormalities. Therefore, we sought to determine whether focal subcortical grey matter (GM) changes might be present in MDD at an early stage. We recruited 30 first episode, untreated patients with major depressive disorder (MDD) and 26 healthy control subjects. Voxel-based morphometry was used to evaluate cortical grey matter changes, and automated volumetric and shape analyses were used to assess volume and shape changes of the subcortical GM structures, respectively. In addition, probabilistic tractography methods were used to demonstrate the relationship between the subcortical and the cortical GM. Compared to healthy controls, MDD patients had significant volume reductions in the bilateral putamen and left thalamus (FWE-corrected, p < 0.05). Meanwhile, the vertex-based shape analysis showed regionally contracted areas on the dorsolateral and ventromedial aspects of the bilateral putamen, and on the dorsal and ventral aspects of left thalamus in MDD patients (FWE-corrected, p < 0.05). Additionally, a negative correlation was found between local atrophy in the dorsal aspects of the left thalamus and clinical variables representing severity. Furthermore, probabilistic tractography demonstrated that the area of shape deformation of the bilateral putamen and left thalamus have connections with the frontal and temporal lobes, which were found to be related to major depression. Our results suggested that structural abnormalities in the putamen and thalamus might be present in the early stages of MDD, which support the role of subcortical structure in the pathophysiology of MDD. Meanwhile, the present study showed that these subcortical structural abnormalities might be the potential trait markers of MDD. PMID- 27222799 TI - Combined variants in reading epilepsy; coexisting anterior and posterior variants camouflaged as heat cramps where the patient finds his own diagnosis searching the internet. AB - Reading epilepsy is a form of reflex-induced seizures. Two entities are postulated as part of a clinical spectrum; one anterior variant with jaw jerks and orofacial myoclonia and another posterior variant with visual symptoms and alexia or dyslexia. We present a case with suggestible evidence of both conditions coexisting within the same patient, a finding that, to our knowledge, has not been previously reported. The diagnosis in this specific case was contributed to by the patient searching the internet. PMID- 27222800 TI - High-quality draft genome sequence of Enterobacter sp. Bisph2, a glyphosate degrading bacterium isolated from a sandy soil of Biskra, Algeria. AB - Enterobacter sp. strain Bisph2 was isolated from a sandy soil from Biskra, Algeria and exhibits glyphosate-degrading activity. Multilocus sequence analysis of the 16S rRNA, rpoB, hsp60, gyrB and dnaJ genes demonstrated that Bisph2 might be a member of a new species of the genus Enterobacter. Genomic sequencing of Bisph2 was used to better clarify the relationships among Enterobacter species. Annotation and analysis of the genome sequence showed that the 5.535.656 bp genome of Enterobacter sp. Bisph2 consists in one chromosome and no detectable plasmid, has a 53.19% GC content and 78% of genes were assigned a putative function. The genome contains four prophages of which 3 regions are intact and no CRISPER was detected. The nucleotide sequence of this genome was deposited into DDBJ/EMBL/GenBank under the accession JXAF00000000. PMID- 27222801 TI - Genome-wide functional annotation of Phomopsis longicolla isolate MSPL 10-6. AB - Phomopsis seed decay of soybean is caused primarily by the seed-borne fungal pathogen Phomopsis longicolla (syn. Diaporthe longicolla). This disease severely decreases soybean seed quality, reduces seedling vigor and stand establishment, and suppresses yield. It is one of the most economically important soybean diseases. In this study we annotated the entire genome of P. longicolla isolate MSPL 10-6, which was isolated from field-grown soybean seed in Mississippi, USA. This study represents the first reported genome-wide functional annotation of a seed borne fungal pathogen in the Diaporthe-Phomopsis complex. The P. longicolla genome annotation will enable research into the genetic basis of fungal infection of soybean seed and provide information for the study of soybean-fungal interactions. The genome annotation will also be a valuable resource for the research and agricultural communities. It will aid in the development of new control strategies for this pathogen. The annotations can be found from: http://bioinformatics.towson.edu/phomopsis_longicolla/download.html. NCBI accession number is: AYRD00000000. PMID- 27222802 TI - Complete genome sequence of Erysipelothrix rhusiopathiae strain GXBY-1 isolated from acute swine erysipelas outbreaks in south China. AB - Erysipelothrix rhusiopathiae (E. rhusiopathiae) is an important pathogenic microorganism affecting swine industry. Here, we report the finished annotated genome sequence of E. rhusiopathiae GXBY-1, isolated from acute swine erysipelas in Binyang County, Guangxi, China. The GXBY-1 strain, which exhibits high pathogenicity for swine, contains 1,876,490 bp with G + C content of 36.50%, and contains 1734 protein-coding genes, 57 tRNAs and 27 rRNAs. The nucleotide sequence of this genome was deposited into GenBank under the accession CP014861. PMID- 27222803 TI - Peeping into genomic architecture by re-sequencing of Ochrobactrum intermedium M86 strain during laboratory adapted conditions. AB - Advances in de novo sequencing technologies allow us to track deeper insights into microbial genomes for restructuring events during the course of their evolution inside and outside the host. Bacterial species belonging to Ochrobactrum genus are being reported as emerging, and opportunistic pathogens in this technology driven era probably due to insertion and deletion of genes. The Ochrobactrum intermedium M86 was isolated in 2005 from a case of non-ulcer dyspeptic human stomach followed by its first draft genome sequence in 2009. Here we report re-sequencing of O. intermedium M86 laboratory adapted strain in terms of gain and loss of genes. We also attempted for finer scale genome sequence with 10 times more genome coverage than earlier one followed by comparative evaluation on Ion PGM and Illumina MiSeq. Despite their similarities at genomic level, lab adapted strain mainly lacked genes encoding for transposase protein, insertion elements family, phage tail-proteins that were not detected in original strain on both chromosomes. Interestingly, a 5 kb indel was detected in chromosome 2 that was absent in original strain mapped with phage integrase gene of Rhizobium spp. and may be acquired and integrated through horizontal gene transfer indicating the gene loss and gene gain phenomenon in this genus. Majority of indel fragments did not match with known genes indicating more bioinformatic dissection of this fragment. Additionally we report genes related to antibiotic resistance, heavy metal tolerance in earlier and re-sequenced strain. Though SNPs detected, there did not span urease and flagellar genes. We also conclude that third generation sequencing technologies might be useful for understanding genomic architecture and re-arrangement of genes in the genome due to their ability of larger coverage that can be used to trace evolutionary aspects in microbial system. PMID- 27222804 TI - Striatal transcriptome analysis of a congenic mouse line (chromosome 11: 50-60Mb) exhibiting reduced methamphetamine sensitivity. AB - Addiction to psychostimulants such as Methamphetamine (MA) is a significant public health issue in the United States and currently, there are no FDA approved pharmacological interventions. Previously, using short term-selected mouse lines for high and low MA sensitivity that were derived from an F2 cross between C57BL/6J (B6) and DBA/2J (D2) strains, we identified a quantitative trait locus (QTL) on chromosome (chr) 11 that influenced sensitivity to MA-induced locomotor activity (D2 < B6). Using interval-specific murine congenic lines containing various D2 allelic segments on a B6 background, we fine mapped the QTL to a 206 kb critical interval on chromosome 11. To investigate the neurobiological mechanism by which this QTL decreases MA sensitivity, we conducted transcriptome analysis in a 10 Mb congenic mouse (chromosome 11: 50-60 Mb) on whole-striatum brain tissue punches compared to wild-type B6 littermate controls [1]. The data from this study can be found in the NCBI Gene Expression Omnibus (GSE66366). PMID- 27222805 TI - Identification of myogenic regulatory genes in the muscle transcriptome of beltfish (Trichiurus lepturus): A major commercial marine fish species with robust swimming ability. AB - The beltfish (Trichiurus lepturus) is considered as one of the most economically important marine fish in East Asia. It is a top predator with a robust swimming ability that is a good model to study muscle physiology in fish. In the present study, we used Illumina sequencing technology (NextSeq500) to sequence, assemble and annotate the muscle transcriptome of juvenile beltfish. A total of 57,509,280 clean reads (deposited in NCBI SRA database with accession number of SRX1674471) were obtained from RNA sequencing and 26,811 unigenes (with N50 of 1033 bp) were obtained after de novo assembling with Trinity software. BLASTX against NR, GO, KEGG and eggNOG databases show 100%, 49%, 31% and 96% annotation rate, respectively. By mining beltfish muscle transcriptome, several key genes which play essential role on regulating myogenesis, including pax3, pax7, myf5, myoD, mrf4/myf6, myogenin and myostatin were identified with a low expression level. The muscle transcriptome of beltfish can provide some insight into the understanding of genome-wide transcriptome profile of teleost muscle tissue and give useful information to study myogenesis in juvenile/adult fish. PMID- 27222807 TI - Transcriptome of the freshwater amphipod Gammarus pulex hepatopancreas. AB - So far, ecotoxicological studies used biomarkers of exposure or of effects in order to investigate the impacts of contaminated areas on biota (Peakall, 1994 [6]). However, although these results are important in the ecotoxicological risk assessment, biomarkers are very specific and only provide information on the biological processes or physiological pathways targeted by the biomarkers experimenters choose to test (Monsinjon and Knigge, 2007 [5]). In recent years, proteomics have become a major tool in ecotoxicology, as they provide a global insight into the mechanism of action of pollutants without the need of hypothesis testing or any preconception on the biological processes likely impacted (Gismondi et al., 2015; Trapp et al., 2015 [7]; Truebano, 2016 [8]). However, the analysis of proteomic results is often limited due to the lack of database, especially for non-model organisms, such as Gammarus sp, commonly used as biological model in ecotoxicology (Sornom et al., 2012 [11]; Vellinger et al., 2013 [9]; Gismondi and Thome, 2014 [1]; Lebrun et al., 2014 [3]). Here, we performed Illumina HiSeq sequencing to total RNA isolated from the hepatopancreas (i.e. detoxification tissue) of Gammarus pulex males and females coming from uncontaminated river and contaminated river (e.g. PCB, benzo(a)pyrene). Approximately 290 M paired-end reads were assembled, filtered and sorted into 39,801 contigs whose 10.878 were similar of proteins available in databases. The assembled contigs could represent a reference hepatopancreas transcriptome for G. pulex, and constitute an important resource for future investigations on the impacts of pollutants on invertebrate biota, since it would improve the understanding of the mechanisms of action involved in toxicity. In addition, the hepatopancreas transcriptome will also allow the identification of new potential biomarkers for the ecotoxicological risk assessments. Assembled contigs were deposited in the European Nucleotide Archive under the BioProject number PRJEB13055, with accession numbers FJVI01000001-FJVI01039801. PMID- 27222806 TI - Sequence analysis of pfcrt and pfmdr1 genes and its association with chloroquine resistance in Southeast Indian Plasmodium falciparum isolates. AB - BACKGROUND: Due to the widespread resistance of Plasmodium falciparum to chloroquine drug, artemisinin-based combination therapy (ACT) has been recommended as the first-line treatment. This study aims to evaluate the extent of chloroquine resistance in P. falciparum infection after the introduction of ACT. This study was carried out based on the mutation analysis in P. falciparum chloroquine resistant transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes. Identification of these molecular markers plays a significant role in monitoring and assessment of drug resistance as well as in designing an effective antimalarial drug policy in India. METHODS: Sixty blood samples were collected from patients infected with P. falciparum from JIPMER, Puducherry and MKCG Medical College, Odisha. Polymerase chain reaction-restriction fragment length polymorphism was performed, targeting the point mutation of K76T in pfcrt and N86Y in pfmdr1 gene. The PCR products were sequenced, genotyped and further analysed for amino acid changes in these codons. RESULTS: The frequency of pfcrt mutation at 76th position was dominant for mutant T allele with 56.7% and wild type K, 43.3%. Majority of pfmdr1 86 allele were wild type, with N (90%) and mutant, Y (10%). Additionally, we found three haplotypes for CQ resistance, SVMNT, CVIET and CVIKT in association with the pfcrt gene. However, a poorly studied SNP in pfmdr1 gene (Y184F) associated with CQ resistance showed high frequency (70%) in P. falciparum isolates. CONCLUSIONS: The point mutation K76T of pfcrt is high in P. falciparum suggesting a sustained high CQ resistance even after five years of the introduction of ACTs for antimalarial therapy. The present study suggests a strong association of CQ resistance with pfcrt T76, but not with the pfmdr1 Y86 mutation. However, sequence analysis showed that Y184F mutation on pfmdr1 gene was found to be associated with high resistance. Also, a new pfcrt haplotype 'CVIKT' associated with CQ resistance was found to be present in Indian strains of P. falciparum. The data obtained from this study helps in continuous monitoring of drug resistance in malaria and also suggests the need for careful usage of CQ in Plasmodium vivax malarial treatment. PMID- 27222808 TI - Expression of microRNAs in HPV negative tonsil cancers and their regulation of PDCD4. AB - Global rates of tonsil cancer have been increasing since the turn of the millennia, however we still have a limited understanding of the genes and pathways which control this disease. This array dataset which is linked to our publication (Zhang et al., 2015) describes the profiling of human miRNAs in tonsil and normal adjacent tissues. With this dataset, we identified a list of microRNA (miRNA) which were highly over represented in tonsil cancers and showed that several miRNAs were able to regulate the tumour suppressor PDCD4 in a temporal manner. The dataset has been deposited into Gene Expression Omnibus (GSE75630). PMID- 27222809 TI - Identification of CELF1 RNA targets by CLIP-seq in human HeLa cells. AB - The specific interactions between RNA-binding proteins and their target RNAs are an essential level to control gene expression. By combining ultra-violet cross linking and immunoprecipitation (CLIP) and massive SoliD sequencing we identified the RNAs bound by the RNA-binding protein CELF1, in human HeLa cells. The CELF1 binding sites deduced from the sequence data allow characterizing specific features of CELF1-RNA association. We present therefore the first map of CELF1 binding sites in human cells. PMID- 27222810 TI - Microarray data analyses of yeast RNA Pol I subunit RPA12 deletion strain. AB - The ribosomal RNA (rRNA) biosynthesis is the most energy consuming process in all living cells and the majority of total transcription activity is dedicated for synthesizing rRNA. The cells may adjust the synthesis of rRNA with the availability of resources. rRNA is mainly synthesized by RNA polymerase I that is composed of 14 subunits. Deletion of RPA12, 14, 39 and 49 are viable. RPA12 is a very small protein (13.6 kDa), and the amount of protein in the cells is very high (12,000 molecules per cell), but the role of this protein is unknown in other cellular metabolic processes (Kulak et al., 2014 [1]). RPA12 consists of two zinc-binding domains and it is required for the termination of rRNA synthesis (Mullem et al., 2002 [2]). Deletions of RPA12 in Saccharomyces cerevisiae and Schizosaccharomyces pombe cause a conditional growth defect (Nogi et al., 1993 [3]). In S. pombe, C-terminal deletion behaves like wild-type (Imazawa et al., 2001 [4]). This prompted us to investigate in detail the physiological role of RPA12 in S. cerevisiae, we performed the microarray of rpa12 ? strain and deposited into Gene Expression Omnibus under GSE68731. The analysis of microarray data revealed that the expression of major cellular metabolism genes is high. The amino acid biosynthesis, nonpolar lipid biosynthesis and glucose metabolic genes are highly expressed. The analyses also revealed that the rpa12 ? cells have an uncontrolled synthesis of cell metabolites, so RPA12 could be a master regulator for whole cellular metabolism. PMID- 27222811 TI - Copy number analysis of the low-copy repeats at the primate NPHP1 locus by array comparative genomic hybridization. AB - Array comparative genomic hybridization (aCGH) has been widely used to detect copy number variants (CNVs) in both research and clinical settings. A customizable aCGH platform may greatly facilitate copy number analyses in genomic regions with higher-order complexity, such as low-copy repeats (LCRs). Here we present the aCGH analyses focusing on the 45 kb LCRs [1] at the NPHP1 region with diverse copy numbers in humans. Also, the interspecies aCGH analysis comparing human and nonhuman primates revealed dynamic copy number transitions of the human 45 kb LCR orthologues during primate evolution and therefore shed light on the origin of complexity at this locus. The original aCGH data are available at GEO under GSE73962. PMID- 27222812 TI - Whole transcriptome expression analysis and comparison of two different strains of Plasmodium falciparum using RNA-Seq. AB - The emergence and distribution of drug resistance in malaria are serious public health concerns in tropical and subtropical regions of the world. However, the molecular mechanism of drug resistance remains unclear. In the present study, we performed a high-throughput RNA-Seq to identify and characterize the differentially expressed genes between the chloroquine (CQ) sensitive (3D7) and resistant (Dd2) strains of Plasmodium falciparum. The parasite cells were cultured in the presence and absence of CQ by in vitro method. Total RNA was isolated from the harvested parasite cells using TRIzol, and RNA-Seq was conducted using an Illumina HiSeq 2500 sequencing platform with paired-end reads and annotated using Tophat. The transcriptome analysis of P. falciparum revealed the expression of ~ 5000 genes, in which ~ 60% of the genes have unknown function. Cuffdiff program was used to identify the differentially expressed genes between the CQ-sensitive and resistant strains. Here, we furnish a detailed description of the experimental design, procedure, and analysis of the transcriptome sequencing data, that have been deposited in the National Center for Biotechnology Information (accession nos. PRJNA308455 and GSE77499). PMID- 27222813 TI - The complete mitochondrial genome of the Antarctic stalked jellyfish, Haliclystus antarcticus Pfeffer, 1889 (Staurozoa: Stauromedusae). AB - In present study, the complete mitogenome sequence of the Antarctic stalked jellyfish, Haliclystus antarcticus Pfeffer (Staurozoa: Stauromedusae) has been sequenced by next-generation sequencing method. The assembled mitogenome comprises of 15,766 bp including 13 protein coding genes, 7 transfer RNAs, and 2 ribosomal RNA genes. The overall base of Antarctic stalked jellyfish constitutes of 26.5% for A, 19.6% for C, 19.8% for G, 34.1% for T and show 90% identity to Sessile Jelly, Haliclystus sanjuanensis, in the northeastern Pacific Ocean. The complete mitogenome of the Antarctic stalked jellyfish, contributes fundamental and significant DNA molecular data for further phylogeography and evolutionary analysis for seahorse phylogeny. The complete sequence was deposited in DBBJ/EMBL/GenBank under accession number KU947038. PMID- 27222814 TI - Draft genome sequence of the docosahexaenoic acid producing thraustochytrid Aurantiochytrium sp. T66. AB - Thraustochytrids are unicellular, marine protists, and there is a growing industrial interest in these organisms, particularly because some species, including strains belonging to the genus Aurantiochytrium, accumulate high levels of docosahexaenoic acid (DHA). Here, we report the draft genome sequence of Aurantiochytrium sp. T66 (ATCC PRA-276), with a size of 43 Mbp, and 11,683 predicted protein-coding sequences. The data has been deposited at DDBJ/EMBL/Genbank under the accession LNGJ00000000. The genome sequence will contribute new insight into DHA biosynthesis and regulation, providing a basis for metabolic engineering of thraustochytrids. PMID- 27222815 TI - Identification of novel splice site mutation IVS9 + 1(G > A) and novel complex allele G355R/R359X in Type 1 Gaucher patients heterozygous for mutation N370S. AB - Gaucher disease is an autosomal recessive lysosomal storage disorder resulting from deficient glucocerebrosidase activity. More than 350 mutations that cause Gaucher disease have been described to date. Novel mutations can potentially provide insight into the glucocerebrosidase structure-function relationship and biochemical basis of the disease. Here, we report the identification of two novel mutations in two unrelated patients with type I (non-neuronopathic) Gaucher disease: 1) a splice site mutation IVS9 + 1G > A; and (2) a complex allele (cis) G355R/R359X. Both patients have a common N370S mutation in the other allele. The splice site mutation results from an intronic base substitution (G to A, c.1328 + 1, g.5005) at the donor splice site of exon and intron 9. The complex allele results from two point mutations in exon 8 of glucocerebrosidase (G to C at c.1180, g.4396, and T to C at c. 1192, g.4408) substituting glycine by arginine (G355R) and arginine by a premature termination (R359X), respectively. In order to demonstrate that G355R/R359X are in cis arrangement, PCR-amplified glucocerebrosidase exon 8 genomic DNA from the patient was cloned into the vector pJET1.2 in Escherichia coli TOP10(r) strain. Out of the 15 clones that were sequence analyzed, 10 contained the normal allele sequence and 5 contained the complex allele G355R/R359X sequence showing both mutations in cis arrangement. Restriction fragment length polymorphism analysis using Hph1 restriction endonuclease digest was established for the IVS9 + 1G > A mutation for confirmation and efficient identification of this mutation in future patients. Past literature suggests that mutations affecting splicing patterns of the glucocerebrosidase transcript as well as mutations in Gaucher complex alleles are detrimental to enzyme activity. However, compound heterozygosity with N370S, a mild mutation, will lead to a mild phenotype. The cases reported here support these past findings. PMID- 27222816 TI - MMP3 and TIMP2 gene variants as predisposing factors for Achilles tendon pathologies: Attempted replication study in a British case-control cohort. AB - Variants within the MMP3 (rs679620) and TIMP2 (rs4789932) genes have been associated with the risk of Achilles tendon pathology (ATP) in populations from South Africa and Australia. This study aimed to determine whether these variants were associated with the risk of ATP in British Caucasians. We recruited 118 cases with ATP, including a subset of 25 individuals with Achilles tendon rupture (RUP) and 131 controls. DNA samples were isolated from saliva and genotyped using qPCR. For the TIMP2 rs4789932 variant we found a significant (p = 0.038) difference in the genotype distribution frequency between males with ATP (CC, 39.4%; CT, 43.7%; TT, 16.9%) compared to male controls (CC, 20.7%; CT, 59.8%; TT, 19.5%). We also observed a difference in the TIMP2 rs4789932 genotype distribution between males with rupture compared to male controls (p = 0.038). The MMP3 rs679620 GG genotype was found to be overrepresented in the Achilles tendon rupture (RUP) group (AA, 24.0%; AG, 32.0%; GG, 44.0%) compared to controls (AA, 26.7%; AG, 54.2%; GG, 19.1%). In conclusion, the CT genotype of the TIMP2 rs4789932 variant was associated with lower risk of ATP in males. Furthermore, while we revealed differences for both variants in genotype distribution between the RUP and control groups, the sample size of the RUP group was small and confirmation would be required in additional cohorts. Finally, although both the TIMP2 rs4789932 and MMP3 rs679620 variants tentatively associated with ATP, there were differences in the direction of association compared to earlier work. PMID- 27222817 TI - Association of G894T eNOS, 4G/5G PAI and T1131C APOA5 polymorphisms with susceptibility to myocardial infarction in Morocco. AB - BACKGROUND: Myocardial infarction (MI) is a common multifactorial disease. Numerous studies have found that genetic plays an essential role in MI occurrence. The main objective of our case-control study is to explore the association of G894T eNOS (rs1799983), 4G/5G PAI (rs1799889) and T1131C APOA5 (rs662799) polymorphisms with MI susceptibility in the Moroccan population. METHODS AND RESULTS: 118 MI patients were recruited vs 184 healthy controls. DNA samples were genotyped by PCR-RFLP method using MboI, BslI and MseI restriction enzymes respectively for the G894T eNOS, 4G/5G PAI and T1131C APOA5 polymorphisms. Our results show that the G894T eNOS was significantly associated with increased risk of MI under the three genetic transmission models (dominant: OR = 1.64, 95% CI = 1.05-2.58, P = 0.003; recessive: OR = 2.15, 95% CI = 0.74 6.16, P = 0.03; additive: OR = 1.54, 95% CI = 1.06-2.23, P = 0.001). The T1131C APOA5 polymorphism was associated to MI risk in recessive and additive models (OR = 1.53, 95% CI = 0.72-3.2, P = 0.04 and OR = 1.78, 95% CI = 1.26-2.51, P = 0.03 respectively). For the 4G/5G PAI variant, even the cases and controls groups were not in Hardy-Weinberg Equilibrium (HWE), the dominant and additive models show a statistically significant association with MI risk (OR = 7.96, 95%CI = 3.83 16.36, P = 0.01 and OR = 1.96, 95% CI = 1.4-2.72, P = 0.03 respectively). CONCLUSION: Our results suggest that G894T eNOS and T1131C APOA5 polymorphisms may be considered as genetic markers of MI among the Moroccan population. Further studies including larger sample sizes and exploring more genetic associations are needed to confirm our results and to better understand the susceptibility to MI. PMID- 27222818 TI - Nucleotide polymorphisms and protein structure changes in the Fg16 gene of Fusarium graminearum sensu stricto. AB - Fusarium graminearum is one of the most important causes of wheat scab in different parts of the world. This fungus is able to produce widespread trichothecene mycotoxins such as nivalenol (NIV) and deoxynivalenol (DON) which are harmful for both human and animals. The Fg16 target is located in chromosome 1 of the F. graminearum genome coding for a hypothetical protein whose function is not yet known. The Fg16 gene is involved in lipid biosynthesis and leads to sexual development during colonization in wheat stalks. This gene is used to detect F. graminearum and determine the lineage of F. graminearum complex species. In the present study, polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and DNA sequencing methods were employed in screening for genetic variation in 172 F. graminearum s.s. isolates. The PCR reaction forced the amplification of 410-bp fragments of Fg16. Two single nucleotide polymorphisms (T82C and A352T) and one amino acid exchange (C65S) with three patterns (TA/TA, CT/CT and TA/CT genotypes) were found in the Fg16 gene fragment. Two haplotypes, 1A and 1B, were identified within F. graminearum s.s. populations in northern and western regions of Iran. Two different secondary structures of protein were predicted for CT/CT and TA/CT genotypes of Fg16 gene. The average diversity levels detected were relatively high (He: 0.3238; Heu: 0.334; Ho: 0.2894; mean PIC: 0.514; mean Shannon's information index: 0.4132; mean number of alleles per locus: 1.473). On the basis of the obtained results, it was revealed that the Fg16 gene had a high degree of polymorphism that can be considered for future control programming strategies and thus the associations between the SSCP patterns with different traits of F. graminearum such as wheat colonization, perithecium formation on stalk tissues and lineage discrimination should be investigated. PMID- 27222819 TI - Relationship between MTHFR C677T and A1298C gene polymorphisms and complications of type 2 diabetes mellitus in an Emirati population. AB - PURPOSE: Type 2 diabetes mellitus (T2DM) is the most common form of diabetes with clinical consequences giving rise to chronic multiple organ complications. Methylenetetrahydrofolate reductase (MTHFR) polymorphisms are genetic variations that have been linked to T2DM, and micro/macrovascular complications. The link between MTHFR and T2DM however is strongly dependent on the ethnic group studied. The objective of this study was to investigate the possible association between two MTHFR polymorphisms (C677T and A1298C) and T2DM and specifically examine if there are any associations with clinical and demographic characteristics among patients in the United Arab Emirates (UAE). METHODS: The study included 169 T2DM patients and 209 healthy controls. Genomic DNA was isolated and genotyped using TaqMan real-Time PCR assays for the MTHFR C677T and A1298C polymorphisms. RESULTS: There were no significant differences in genotype and haplotype distributions observed between groups. A significant association was observed between the C677T polymorphism and history of cerebrovascular accident (CVA) (p = 0.0330), history of nephropathy (p = 0.0280) and levels of LDL cholesterol (p = 0.0409). Also, the A1298C polymorphism was associated with hypertriglyceridemia (p = 0.0305) in T2DM patients. CONCLUSION: These findings demonstrate that the MTHFR gene polymorphisms are not related to T2DM in the Emirati population. However, these polymorphisms can be used as risk markers for CVA, nephropathy, high LDL cholesterol and triglycerides in T2DM patients and allow timely treatment. PMID- 27222821 TI - Fabrication of molecular tension probes. AB - A unique bioluminescent imaging probe is introduced for illuminating molecular tension appended by protein-protein interactions (PPIs) of interest. A full length luciferase is sandwiched between two proteins of interest via minimal flexible linkers. The ligand-activated PPIs append intramolecular tension to the sandwiched luciferase, boosting or dropping the enzymatic activity in a quantitative manner. This method guides construction of a new lineage of bioassays for determining molecular tension appended by ligand-activated PPIs. The summary of the method is: *Molecular tension appended by protein-protein interactions (PPI) is visualized with a luciferase.*Estrogen activities are quantitatively illuminated with the molecular tension probes.*Full-length Renilla luciferase enhances the optical intensities after bending by PPI. PMID- 27222820 TI - Isolation and analysis of sugar nucleotides using solid phase extraction and fluorophore assisted carbohydrate electrophoresis. AB - The building blocks of simple and complex oligosaccharides, termed sugar nucleotides, are often overlooked for their role in metabolic diseases and may hold the key to the underlying disease pathogenesis. Multiple reasons may account for the lack of analysis and quantitation of these sugar nucleotides, including the difficulty in isolation and purification as well as the required expensive instrumentation such as a high performance liquid chromatography (HPLC), mass spectrometer, or capillary electrophoresis. We have established a simple yet effective way to purify and quantitate sugar nucleotides using solid phase extraction (SPE) chromatography combined with fluorophore assisted carbohydrate electrophoresis (FACE). The simplicity of use, combined with the ability to run multiple samples at one time, give this technique a distinct advantage over the established methods for isolation and analysis of sugar nucleotides from cell culture models. *Sugar nucleotides can be easily purified with solid phase extraction chromatography.*FACE can be used to analyze multiple nucleotide sugar extracts with a single run.*The proposed method is simple, affordable, and uses common everyday research labware. PMID- 27222822 TI - Design and construction of a low-cost nose poke system for rodents. AB - Operant behavioral tasks for animals have long been used to probe the function of multiple brain regions (i.e., understanding the role of dopamine in electrical brain stimulation reward [1], or determining the rewarding properties of feeding oriented brain pathways [2]). The recent development of tools and techniques has opened the door to refine the answer to these same questions with a much higher degree of specificity and accuracy, both in biological and spatial-temporal terms [3], [4]. A variety of systems designed to test operant behavior are now commercially available, but have prohibitive costs. Here, we provide a low-cost alternative to a nose poke system for mice. Adapting a freely available sketch for ARDUINO boards, in combination with an in-house built PVC box and inexpensive electronic material we constructed a four-port nose poke system that detects and counts port entries. To verify the applicability and validity of our system we tested the behavior of DAT-CRE transgenic mice injected with an adeno-associated virus to express ChannelRhodopsin 2 in the Ventral tegmental area (VTA) and used the BNC output to drive a blue laser coupled to a fiber implanted above the VTA. Over 6 days, mice perform as it has been reported previously [5] exhibiting a remarkable preference for the port that triggers optogenetic stimulation of VTA dopamine neurons. *We provide a low cost alternative to commercially available nose poke system.*Our custom made apparatus is open source and TTL compatible.*We validate our system with optogenetic self-stimulation of dopamine neurons. PMID- 27222823 TI - Analytical methodologies based on LC-MS/MS for monitoring selected emerging compounds in liquid and solid phases of the sewage sludge. AB - In this work, two analytical methodologies based on liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) were developed for quantification of emerging pollutants identified in sewage sludge after a previous wide-scope screening. The target list included 13 emerging contaminants (EC): thiabendazole, acesulfame, fenofibric acid, valsartan, irbesartan, salicylic acid, diclofenac, carbamazepine, 4-aminoantipyrine (4-AA), 4-acetyl aminoantipyrine (4-AAA), 4 formyl aminoantipyrine (4-FAA), venlafaxine and benzoylecgonine. The aqueous and solid phases of the sewage sludge were analyzed making use of Solid-Phase Extraction (SPE) and UltraSonic Extraction (USE) for sample treatment, respectively. The methods were validated at three concentration levels: 0.2, 2 and 20 MUg L(-1) for the aqueous phase, and 50, 500 and 2000 MUg kg(-1) for the solid phase of the sludge. In general, the method was satisfactorily validated, showing good recoveries (70-120%) and precision (RSD < 20%). Regarding the limit of quantification (LOQ), it was below 0.1 MUg L(-1) in the aqueous phase and below 50 MUg kg(-1) in the solid phase for the majority of the analytes. The method applicability was tested by analysis of samples from a wider study on degradation of emerging pollutants in sewage sludge under anaerobic digestion. The key benefits of these methodologies are: * SPE and USE are appropriate sample procedures to extract selected emerging contaminants from the aqueous phase of the sewage sludge and the solid residue. * LC-MS/MS is highly suitable for determining emerging contaminants in both sludge phases. * Up to our knowledge, the main metabolites of dipyrone had not been studied before in sewage sludge. PMID- 27222824 TI - Ultra-high-pressure liquid chromatography tandem mass spectrometry method for the determination of 9 organophosphate flame retardants in water samples. AB - Few methods are available for comprehensive organophosphate flame retardants (PFRs) detection in water and wastewater. Gas chromatography has been employed previously, but this approach is less selective, not amenable for use with deuterated standards and can suffer unfavorable fragmentation. Ultra-high pressure liquid chromatography tandem mass spectrometry (UHPLC-QqQ-MS/MS) has become the most promising platform, already applied successfully for analysis of selected PFRs in some environmental matrices like water and wastewater. However, the presence of some interferences from the dissolvent, the equipment and the used materials should be taken into account. The procedure involves: *The first determination of PFRs by UHPLC-QqQ-MS/MS using a trap column to distinguish the interferences coming from the instrument and mobile phases.*The optimization of the LC separation to distinguish all target compounds and their interferences.*This method coupled to a solid-phase extraction (SPE) improve the detection and quantification of PFRs. PMID- 27222825 TI - Integrated modelling of crop production and nitrate leaching with the Daisy model. AB - An integrated modelling strategy was designed and applied to the Soil-Vegetation Atmosphere Transfer model Daisy for simulation of crop production and nitrate leaching under pedo-climatic and agronomic environment different than that of model original parameterisation. The points of significance and caution in the strategy are: *Model preparation should include field data in detail due to the high complexity of the soil and the crop processes simulated with process-based model, and should reflect the study objectives. Inclusion of interactions between parameters in a sensitivity analysis results in better account for impacts on outputs of measured variables.*Model evaluation on several independent data sets increases robustness, at least on coarser time scales such as month or year. It produces a valuable platform for adaptation of the model to new crops or for the improvement of the existing parameters set. On daily time scale, validation for highly dynamic variables such as soil water transport remains challenging. *Model application is demonstrated with relevance for scientists and regional managers. The integrated modelling strategy is applicable for other process-based models similar to Daisy. It is envisaged that the strategy establishes model capability as a useful research/decision-making, and it increases knowledge transferability, reproducibility and traceability. PMID- 27222826 TI - Transfection of insect cell in suspension for efficient baculovirus generation. AB - Baculovirus (BV) mediated insect cell expression system utilizes transfection as a first step to introduce recombinant baculovirus DNA into insect cells. Many labs are still relying on the conventional liposome based transfection method in adherent culture. Here we describe a more efficient method that can replace the existing method. This method is economical and does not require any special adjustment in existing labs. *An innovative method of transfecting insect cells in suspension using polyethyleneimine (PEI) is described here.*The beauty of this method is minimal intermediate manipulation of culture during transfection and virus generation.*The method significantly reduces the chances of cross contamination of viruses while handling multiple targets and constructs as well as the other microbial contamination. PMID- 27222827 TI - Anti-proliferative and apoptotic effects of Ziziphus Jujube on cervical and breast cancer cells. AB - OBJECTIVE: Ziziphus Jujube (Jujube) plant has exhibited numerous medicinal and pharmacological properties including antioxidant and anti-inflammatory effects. This study was carried out to investigate its anti-cancer and pro-apoptotic abilities in human cervical and breast cancer cells in vitro. MATERIALS AND METHODS: The cervical OV2008 and breast MCF-7 cancer cells were incubated with different concentrations of Jujube aqueous extraction (0-3 mg/ml) for various times (0-72 h). Cell viability was assessed by Trypan Blue and 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The expression of two apoptosis-related genes in treated cells evaluated by quantitative Real Time -PCR analysis. RESULTS: Jujube significantly inhibited cancer cell viability in a dose- and time- dependent manner. Herb-induced apoptosis was associated with enhanced expression of Bax and decreased Bcl2 gene leading eventually to a time dependent six fold increase in the Bax/Bcl-2 ratio. CONCLUSION: These results indicated that Jujube may be a natural potential and promising agent to prevent or treat human cancers. PMID- 27222829 TI - Functional dyspepsia: A new approach from traditional Persian medicine. AB - OBJECTIVE: One of the most common global disorders is related to gastrointestinal system. Functional dyspepsia (FD) defined as upper abdominal pain and discomfort in the absence of organic ailments is a prevalent disease without any confirmed medication. The purpose of this study was to find gastric disorders which might be coincidental to FD based on traditional Persian medicine (TPM). MATERIALS AND METHODS: We searched the main textbooks of TPM including Al-Havi (by Rhazes), Canon of medicine (by Avicenna), ZakhireKhawrazmshahi (by Ismail Jorjani), Moalijat-e Aghili and Makhzan Al-adviya (by Mohammad Hosein AghiliShirazi), and ExirAzam (by Hakim Azam Khan). Also, we searched Pubmed, Scopus, Science Direct, Medline, scientific information database (SID), Iranmedex and Google Scholar from 1980 to 1 August 2014 for dyspepsia, gastrointestinal disease, traditional Persian medicine, and gastric dystemperaments. RESULTS: There is no equivalent term for FD in traditional Persian medicine although similar signs and symptoms are visible in terms like simple cold dystemperament of stomach, indigestion, and digestion debility in TPM sources. Some treatments mentioned in TPM have shown promising results in the current experimental tests. CONCLUSION: Finding these similarities in complementary and alternative medicine (CAM) textbooks may lead to discovering new remedies for this widespread disease. PMID- 27222828 TI - Immunosuppressive, anti-inflammatory and anti-cancer properties of triptolide: A mini review. AB - OBJECTIVE: Triptolide, the active component of Tripterygium wilfordii Hook F has been used to treat autoimmune and inflammatory conditions for over two hundred years in traditional Chinese medicine. However, the processes through which triptolide exerts immunosuppression and anti-inflammation are not understood well. In this review, we discuss the autoimmune disorders and inflammatory conditions that are currently treated with triptolide. Triptolide also possesses anti-tumorigenic effects. We discuss the toxicity of various triptolide derivatives and offer suggestions to improve its safety. This study also examines the clinical trials that have investigated the efficacy of triptolide. Our aim is to examine the mechanisms that are responsible for the immunosuppressive, anti inflammatory, and anti-cancer effects of triptolide. MATERIALS AND METHODS: The present review provides a comprehensive summary of the literature with respect to the immunosuppressive, anti-inflammatory, and anti-cancer properties of triptolide. RESULTS: Triptolide possesses immunosuppressive, anti-inflammatory, and anti-cancer effects. CONCLUSION: Triptolide can be used alone or in combination with existing therapeutic modalities as novel treatments for autoimmune disorders, cancers, and for immunosuppression. PMID- 27222830 TI - Teratogenic effect of Lippia citriodora leaves aqueous extract in mice. AB - OBJECTIVE: Safety of Lippia citriodora, as a herbal remedy, in pregnancy has not yet been evaluated. This study aimed to identify the effect of L. citriodora aqueous extract on pregnancy outcome in mice. MATERIALS AND METHODS: Timed pregnant mice received doses of 0.5 g/kg/day L. citriodora aqueous extract or the vehicle control during organogenesis, intraperitoneally. Maternal body weights were measured throughout the pregnancy. The litters were examined for external malformations and skeletal abnormalities. Fetuses were stained with Alizarin red S and Alcian blue. RESULTS: There were no significant differences in mean maternal weight gain during pregnancy between groups. Also, no significant differences were observed in mean number of implantation, live and resorbed fetuses between control and treated groups. The prevalence of all types of deformity was low and similar to control group (%1.11). CONCLUSION: The results of this study show that moderate consumption of L. citriodora as an infusion or tea appears to be safe to be used during pregnancy and does not have toxic effects on development of mouse embryo. PMID- 27222831 TI - Hepatoprotective effect of Rosa canina fruit extract against carbon tetrachloride induced hepatotoxicity in rat. AB - OBJECTIVE: The present study was conducted to investigate the hepatoprotective activity of hydro-ethanolic fruit extract of Rosa canina (R. canina) against carbon tetrachloride (CCl4)-induced hepatotoxicity in rats. MATERIALS AND METHODS: Male Wistar albino rats were randomly divided into six groups of 8 animals of each, including control, toxic (CCl4), R. canina 250, 500, and 750 mg/kg + CCl4 and R. canina 750 mg/kg alone. R. canina (p.o., daily) and CCl4 (1 ml/kg twice a week, 50% v/v in olive oil, i.p.) were administered to animals for six weeks. Serum analysis was performed to assay the levels of aspartate aminotransferase (AST), alanine amino transaminase (ALT), alkaline phosphatase (ALP), albumin (ALB), total protein (TP) and malondialdehyde (MDA). Biochemical observations were also supplemented with histopathological examination (haematoxylin and eosin staining) of liver section. RESULTS: Hepatotoxicity was evidenced by considerable increase in serum levels of AST, ALT, ALP, and lipid peroxidation (MDA) and decrease in levels of ALB and TP. Injection of CCL4 also induced congestion in central vein, and lymphocyte infiltration. Treatment with hydro-alcoholic fruit extract of R. canina at doses of 500 and 750 mg/kg significantly reduced CCl4-elevated levels of ALT, AST, ALP and MDA (p<0.01). The extract also increased the serum levels of ALB and TP compared to CCl4 group (p<0.01) at the indicated dose Histopathological studies supported the biochemical finding. CONCLUSION: Our finding indicated hepatoprotective effects of the hydro-alcoholic fruit extract of R. canina on CCl4-induced hepatic damage in rats and suggested that these effects may be produced through reducing oxidative stress. PMID- 27222832 TI - Beneficial effect of Boswellia serrata gum resin on spatial learning and the dendritic tree of dentate gyrus granule cells in aged rats. AB - OBJECTIVE: The hippocampal formation, particularly the dentate gyrus (DG), shows age-related morphological changes that could cause memory decline. It is indicated that Boswellia resins attenuates memory deficits and the major component of Boswellia serrata (Bs) gum resin, beta boswellic acid increased neurite outgrowth and branching in hippocampal neurons. This study was designed to investigate the effect of Boswellia treatment on spatial learning performance and the morphology of dentate granule cells in aged rats. MATERIALS AND METHODS: Sixteen male Wistar rats (24 months old) were divided into experimental and control groups. Experimental group was intragastrically administered with the aqueous extract of Bs (100 mg/kg/d for 8 weeks) and control group received a similar volume of water. Spatial learning performance of rats was tested using Morris water maze task. At the end of experiment, the brain was removed and the right hippocampus was serially sectioned for morphometric analysis. The Cavalieri principle was employed to estimate the volume of the DG. A quantitative Golgi study was used to analyze the dendritic trees of dentate granule cells. RESULTS: Chronic treatment with Bs improved spatial learning capability during the three acquisition days. Comparisons also revealed that Bs-treated aged rat had greater DG with increased dendritic complexity in the dentate granule cells than control rats. Hippocampal granule cells of Bs-treated aged rats had more dendritic segments, larger arbors, more numerical branching density and more dendritic spines in comparison to control animals. CONCLUSION: This study provided a neuro anatomical basis for memory improvement due to chronic treatment with Bs. PMID- 27222833 TI - Effects of berberine on acquisition and reinstatement of morphine-induced conditioned place preference in mice. AB - OBJECTIVE: It has been shown that berberine, a major component of Berberis vulgaris extract, modulates the activity of several neurotransmitter systems including dopamine (Da) and N-methyl-D-aspartate (NMDA) contributing to rewarding and reinforcing effects of morphine. Drug craving and relapsing even after a long time of abstinence therapy are the most important problems of addiction. In the present study, we investigated the alleviating effects of berberine on the acquisition and reinstatement of morphine-induced conditioned place preference (CPP) in mice. MATERIALS AND METHODS: In male NMRI mice, the acquisition of CPP was established by 40 mg/kg of morphine sulphate injection and extinguished after the extinction training and reinstated by a 10 mg/kg injection of morphine. The effects of different doses of berberine (5, 10, and 20 mg/kg) on the acquisition and reinstatement induced by morphine were evaluated in a conditioned place preference test. RESULTS: The results showed that intraperitoneal administration of berberine (5, 10, and 20 mg/kg) did not induce conditioned appetitive or aversive effects. Injection of berberine (10 and 20 mg/kg) 2 h before the morphine administration reduced acquisition of morphine-induced CPP. In addition, same doses of berberine significantly prevented the reinstatement of morphine induced CPP. CONCLUSION: These results suggest that berberine can reduce the acquisition and reinstatement of morphine-induced conditioned place preference and may be useful in treatment of morphine addiction. PMID- 27222834 TI - Effect of Coriandrum sativum hydroalcoholic extract and its essential oil on acetic acid- induced acute colitis in rats. AB - OBJECTIVE: The aim of this study was to determine the protective effects of Coriandrum sativum on acetic acid-inducedcolitis in rats. C. sativum (Coriander) has long been used in Iranian traditional medicine and its use as an anti inflammatory agent is still common in some herbal formulations. MATERIALS AND METHODS: Colitis was induced by intra-rectal administration of 2ml acetic acid 4% in fasted male Wistar rats. Treatment was carried out using three increasing doses of extract (250, 500, 1000 mg/kg) and essential oil (0.25, 0.5, 1 ml/kg) of coriander started 2 h before colitis induction and continued for a five-day period. Colon biopsies were taken for weighting, macroscopic scoring of injured tissue, histopathological examination and measuring myeloperoxidase (MPO) activity. RESULTS: Colon weight was decreased in the groups treated with extract (500 and 1000 mg/kg) and essential oil (0.5 ml/kg) compared to the control group. Regarding MPO levels, ulcer severity and area as well as the total colitis index, same results indicating meaningful alleviation of colitis was achieved after treatment with oral extract and essential oil. CONCLUSION: Since the present experiment was made by oral fractions of coriander thus the resulting effects could be due to both the absorption of the active ingredients and/or the effect of non-absorbable materials on colitis after reaching the colon. In this regard, we propose more toxicological and clinical experiments to warranty its beneficial application in human inflammatory bowel diseases. PMID- 27222835 TI - Antifungal activity of essential oils from Iranian plants against fluconazole resistant and fluconazole-susceptible Candida albicans. AB - OBJECTIVE: The purpose of this study was to assay the antifungal activity of selected essential oils obtained from plants against both fluconazole (FLU) resistant and FLU-susceptible C. albicans strains isolated from HIV positive patients with oropharyngeal candidiasis (OPC). MATERIALS AND METHODS: The essential oils were obtained by hydrodistillation method from Myrtus communis (My. communis), Zingiber officinale roscoe (Z. officinale roscoe), Matricaria chamomilla (Ma. chamomilla), Trachyspermum ammi (T. ammi) and Origanum vulgare (O. vulgare). The susceptibility test was based on the M27-A2 methodology. The chemical compositions of the essential oils were obtained by gas chromatography- mass spectroscopy (GC-MS). RESULTS: In GC-MS analysis, thymol (63.40%), linalool (42%), alpha-pinene (27.87%), alpha-pinene (22.10%), and zingiberene (31.79%) were found to be the major components of T. ammi, O. vulgare, My. communis, Ma. chamomilla and Z. officinale roscoe, respectively. The results showed that essential oils have different levels of antifungal activity. O. vulgare and T. ammi essential oils were found to be the most efficient (P<0.05). The main finding was that the susceptibilities of FLU-resistant C. albicans to essential oils were higher than those of the FLU-susceptible yeasts. CONCLUSION: Results of this study indicated that the oils from medicinal plants could be used as potential anti FLU-resistant C. albicans agents. PMID- 27222837 TI - Antiplasmodial, antioxidant and immunomodulatory activities of ethanol extract of Vernonia amygdalina del. Leaf in Swiss mice. AB - OBJECTIVE: Vernonia amygdalina (V. amygdalina) leaf is locally employed in the Southern region of Nigeria in the treatment of malaria infection. This study evaluated the in vivo antiplasmodial, antioxidant and immunomodulatory effect of ethanol extract of V. amygdalina leaf. MATERIALS AND METHODS: The active principles of the dried leaf were extracted with ethanol. For quality validation, chemical finger-print of the extract was performed through high performance thin layer chromatography (HPTLC). The extract was assessed for antiplasmodial activity by the standard four-day suppressive test on Plasmodium berghei (ANKA) infected male Swiss mice (six weeks old) placed into five groups of six animals each. RESULT: The absorption spectra from the HPTLC revealed several peaks suggesting presence of some bioactive compounds. Results from the in vivo study showed that the ethanol extract of the plant leaf was significantly active against P. berghei in a dose-dependent manner with the minimum and maximum activity observed in the mice treated orally with 100mg/kg (% inhibition of 23.7%) and 1000 mg/kg (% inhibition of 82.3 %) of the extract, respectively, on day four of the study. There was also a dose-dependent decrease (p<0.05) in some oxidative stress indices including nitric oxide and lipid peroxidation levels in the extract treated groups as against the non-treated infected group which had high levels of these parameters. The pro-inflammatory cytokines (TNF-alpha and IFN-gamma) levels were also considerably low in the extract treated groups relative to the non-treated infected group. CONCLUSION: The results suggest that ethanol extract of V. amygdalina leaf was active, with some immunomodulatory effect, against P . berghei infection. PMID- 27222836 TI - The effects of different fractions of Coriandrum sativum on pentylenetetrazole induced seizures and brain tissues oxidative damage in rats. AB - OBJECTIVE: In the present work, the effects of different fractions of Coriandrum sativum (C. sativum), on pentylenetetrazole (PTZ)-induced seizures and brain tissues oxidative damage were investigated in rats. MATERIALS AND METHODS: The rats were divided into the following groups: (1) vehicle, (2) PTZ (90 mg/kg), (3) water fraction (WF) of C. sativum (25 and 100 mg/kg), (4) n-butanol fraction (NBF) of C. sativum (25 and 100 mg/kg), and (5) ethyl acetate fraction (EAF) of C. sativum (25 and 100 mg/kg). RESULTS: The first generalized tonic-clonic seizures (GTCS) latency in groups treated with 100 mg /kg of WF or EAF was significantly higher than that of PTZ group (p<0.01). In contrast to WF, the EAF and NBF were not effective in increasing the first minimal clonic seizure (MCS) latency. Malondialdehyde (MDA) levels in both cortical and hippocampal tissues of PTZ group were significantly higher than those of control animals (p<0.001). Pretreatment with WF, NBF, or EAF resulted in a significant reduction in the MDA levels of hippocampi (p<0.01 - p<0.001). Following PTZ administration, a significant reduction in total thiol groups was observed in the brain tissues (p<0.05). Pretreatment with WF and NBF significantly elevated thiol concentrations in cortical and hippocampal tissues, respectively (p<0.05). CONCLUSION: The present study showed that different fractions of C. sativum possess antioxidant activity in the brain and WF and EAF of this plant have anticonvulsant effects. PMID- 27222838 TI - Hepatoprotective activity of Mammea africana ethanol stem bark extract. AB - OBJECTIVE: The stem bark of Mammea africana Sabine (Guttiferae), (M. africana) a common plant that has been traditionally used to treat various diseases and ailments was evaluated for hepatoprotective potentials against paracetamol induced liver injury in rats. MATERIALS AND METHODS: The hepatoprotective effect of the stem bark extract (30-90 mg/kg) was evaluated by the assay of liver function parameters, namely total and direct bilirubin, serum protein and albumin, total cholesterol, alanine aminotransaminase (ALT), aspartate aminotransaminase (AST), and alkaline phosphatase activities (ALP), antioxidant enzymes: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH) and histopathological study of the liver. RESULTS: Administration of the stem bark extract caused a significant (p<0.05 - 0.001) dose-dependent reduction of high levels of liver enzymes (ALT, AST and ALP), total cholesterol, direct and total bilirubin as well as elevation of serum levels of total protein, albumin and antioxidant enzymes (SOD, CAT, GPx and GSH). Histology of the liver sections of extract and silymarin-treated animals showed reductions in the pathological features compared to the paracetamol-treated animals. The chemical pathological changes were consistent with histopathological observations suggesting marked hepatoprotective effect of the stem bark extract of M. africana. CONCLUSION: The results show that the stem bark extract of M. africana has hepatoprotective potential which may be due to its antioxidant activity. PMID- 27222839 TI - A scalable method for the production of high-titer and high-quality adeno associated type 9 vectors using the HSV platform. AB - Recombinant adeno-associated vectors based on serotype 9 (rAAV9) have demonstrated highly effective gene transfer in multiple animal models of muscular dystrophies and other neurological indications. Current limitations in vector production and purification have hampered widespread implementation of clinical candidate vectors, particularly when systemic administration is considered. In this study, we describe a complete herpes simplex virus (HSV)-based production and purification process capable of generating greater than 1 * 10(14) rAAV9 vector genomes per 10-layer CellSTACK of HEK 293 producer cells, or greater than 1 * 10(5) vector genome per cell, in a final, fully purified product. This represents a 5- to 10-fold increase over transfection-based methods. In addition, rAAV vectors produced by this method demonstrated improved biological characteristics when compared to transfection-based production, including increased infectivity as shown by higher transducing unit-to-vector genome ratios and decreased total capsid protein amounts, shown by lower empty-to-full ratios. Together, this data establishes a significant improvement in both rAAV9 yields and vector quality. Further, the method can be readily adapted to large-scale good laboratory practice (GLP) and good manufacturing practice (GMP) production of rAAV9 vectors to enable preclinical and clinical studies and provide a platform to build on toward late-phases and commercial production. PMID- 27222840 TI - RD-MolPack technology for the constitutive production of self-inactivating lentiviral vectors pseudotyped with the nontoxic RD114-TR envelope. AB - To date, gene therapy with transiently derived lentivectors has been very successful to cure rare infant genetic diseases. However, transient manufacturing is unfeasible to treat adult malignancies because large vector lots are required. By contrast, stable manufacturing is the best option for high-incidence diseases since it reduces the production cost, which is the major current limitation to scale up the transient methods. We have previously developed the proprietary RD2 MolPack technology for the stable production of second-generation lentivectors, based on the RD114-TR envelope. Of note, opposite to vesicular stomatitis virus glycoprotein (VSV-G) envelope, RD114-TR does not need inducible expression thanks to lack of toxicity. Here, we present the construction of RD2- and RD3-MolPack cells for the production of self-inactivating lentivectors expressing green fluorescent protein (GFP) as a proof-of-concept of the feasibility and safety of this technology before its later therapeutic exploitation. We report that human T lymphocytes transduced with self-inactivating lentivectors derived from RD3 MolPack cells or with self-inactivating VSV-G pseudotyped lentivectors derived from transient transfection show identical T-cell memory differentiation phenotype and comparable transduction efficiency in all T-cell subsets. RD MolPack technology represents, therefore, a straightforward tool to simplify and standardize lentivector manufacturing to engineer T-cells for frontline immunotherapy applications. PMID- 27222841 TI - Vascular composition data supporting the role of N-3 polyunsaturated fatty acids in the prevention of cardiovascular disease events. AB - N-3 polyunsaturated fatty acids (PUFAs) are thought to have protective effects against cardiovascular disease. Here, we report the relationship between serum PUFA concentrations and plaque composition, as evaluated by virtual histology intravascular ultrasound (VH-IVUS). Consecutive patients (n=61) who underwent percutaneous coronary intervention (PCI) were pre-operatively examined using VH IVUS to assess the composition of culprit plaques. Gray-scale IVUS and VH-IVUS data of fibrous, fibro-fatty, necrotic core, and dense calcium regions of plaques were estimated at the minimal luminal area sites of culprit lesions. Serum levels of high-sensitivity C-reactive protein (hsCRP) and PUFAs, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA), were compared between patients with (ACS, n=27) and without acute coronary syndrome (non-ACS, n=34) before PCI. Multiple logistic regression analysis of the data showed that EPA/AA under the median was more highly associated with ACS than hsCRP over the median. In addition, EPA/AA was negatively correlated with the percentage of fibrous plaque regions and EPA/AA and DHA/AA were positively correlated with the percentage of dense calcium regions in plaques. Furthermore, the correlation index of EPA/AA was the most highly (R=0.513) correlated with the percentage of dense calcium regions in plaques. PMID- 27222842 TI - Data on dimer formation between importin alpha subtypes. AB - This article describes data related to the research article titled "Functional characterization of importin alpha8 as a classical nuclear localization signal receptor" [1]. A GST pull-down assay showed that both importin alpha1 and alpha8, which are classical nuclear localization signal (cNLS) receptors, can form a dimer with importin alpha6, alpha7, or alpha8. Importin alpha8 has higher dimer forming ability than importin alpha1. In addition, our data show that either importin alpha1 or importin alpha8 can form a heterodimer with importin alpha3, which exists in a preformed complex with cNLS substrates such as the conventional SV40TNLS or the p53 protein, resulting in the release of the cNLS substrates from importin alpha3. PMID- 27222843 TI - Data on four criteria for targeting the placement of conservation buffers in agricultural landscapes. AB - Four criteria are generally used to prioritize agricultural lands for placing conservation buffers. The criteria include soil erodibility, hydrological sensitivity, wildlife habitat, and impervious surface rate that capture conservation buffers' benefits in reducing soil erosion, controlling runoff generation, enhancing wildlife habitat, and mitigating stormwater impacts, respectively. This article describes the data used to derive the values of those attributes and a scheme to classify the values in multi-criteria analysis of conservation buffer placement in "Choosing between alternative placement strategies for conservation buffers using borda count" [1]. PMID- 27222844 TI - Data on polyphenols and biological activity analyses of an Andean tomato collection and their relationships with tomato traits and geographical origin. AB - Data provide information about a tomato collection composed of accessions from the Andean Valley, commercial accessions and wild species. Antioxidant metabolites were measured in mature fruits of this collection, and their biological activities were assessed by both in vitro and in vivo methods. In this work, the parameters used to identify and quantify polyphenols compounds in tomato fruit by liquid chromatography coupled to diode array detector and quadrupole time of flight mass spectrometer are described. Moreover, data supporting a procedure to characterize the properties of tomato fruits to revert death by thermal stress in Caenorhabditis elegans are explained in detail. Lastly, principal component analysis and hierarchical cluster analysis of metabolites composition, antioxidant activities (in vivo and in vitro), tomato traits and geographical origin of the tomatoes collection are shown. The data presented here are related to the research article entitled "Hydrophilic antioxidants from Andean Tomato Landraces assessed by their bioactivities in vitro and in vivo" [1]. PMID- 27222845 TI - Data on macrophage mediated muscle transfection upon delivery of naked plasmid DNA with block copolymers. AB - The data contains 14 figures supporting the research article "Horizontal gene transfer from macrophages to ischemic muscles upon delivery of naked DNA with Pluronic block copolymers" [1]. The data explains the surgical procedure and histological characterization of Murine Hind Limb Ischemia. The data also shows the kinetics of luciferase gene expression, spread of GFP expression through muscle and the colocalization of GFP with cellular markers in ischemic muscles injected with pDNA alone or pDNA/Pluronic. Finally the data shows the effect of Pluronic Block Copolymer to enhance total gene expression (cmv-promoter driven luciferase gene) in coculture of DNA transfected MOs with muscle cells. PMID- 27222846 TI - Data on mitochondrial function in skeletal muscle of old mice in response to different exercise intensity. AB - Endurance exercise is securely linked to muscle metabolic adaptations including enhanced mitochondrial function ("Effects of exercise on mitochondrial oxygen uptake and respiratory enzyme activity in skeletal muscle" [1], "Effects of exercise on mitochondrial content and function in aging human skeletal muscle" [2]). However, the link between exercise intensity and mitochondrial function in aging muscle has not been fully investigated. In order to understand how strenuous exercise affects mitochondrial function in aged mice, male C57BL/6 mice at age 24 months were randomly assigned to 3 groups: non-exercise (NE), low intensity (LE) and high-intensity treadmill exercise group (HE). Mitochondrial complex activity and respiration were measured to evaluate mitochondrial function in mouse skeletal muscle. The data described here are related to the research article entitled "Strenuous exercise induces mitochondrial damage in skeletal muscle of old mice" [3]. PMID- 27222847 TI - Digital data of quality control strains under general deposit at Microbial Culture Collection (MCC), NCCS, Pune, India: A bioinformatics approach. AB - A total of 13 short DNA sequences of quality control strains (MCC 2052, MCC 2077, MCC 2078, MCC 2080, MCC 2309, MCC 2322, MCC 2408, MCC 2409, MCC 2412, MCC 2413, MCC 2415, MCC 2483 and MCC 2515) were retrieved from NCBI BioSample database and generated quick response (QR) codes for sequences. 16S rRNA was used for creation of Chaose Game representation (CGR), Chaose Game Representation of Frequencies (FCGR) and measurement of GC percentage. Digital data in the form of QR codes, CGR, FCGR and GC plot would be useful for identification, visual comparison and evaluation of newly isolated strains with quality control strains. The digital data of QR codes, CGR, FCGR and GC content all the quality control strains are made available to users through this paper. This generated digital data helps to evaluate and compare newly isolated strains, less laborious and avoid misinterpretation of newly isolated species. PMID- 27222848 TI - Data for analysis of mannose-6-phosphate glycans labeled with fluorescent tags. AB - Mannose-6-phosphate (M-6-P) glycan plays an important role in lysosomal targeting of most therapeutic enzymes for treatment of lysosomal storage diseases. This article provides data for the analysis of M-6-P glycans by high-performance liquid chromatography (HPLC) and matrix-assisted laser desorption/ionization time of-flight (MALDI-TOF) mass spectrometry. The identities of M-6-P glycan peaks in HPLC profile were confirmed by measuring the masses of the collected peak eluates. The performances of three fluorescent tags (2-aminobenzoic acid [2-AA], 2-aminobenzamide [2-AB], and 3-(acetyl-amino)-6-aminoacridine [AA-Ac]) were compared focusing on the analysis of bi-phosphorylated glycan (containing two M-6 Ps). The bi-phosphorylated glycan analysis is highly affected by the attached fluorescent tag and the hydrophilicity of elution solvent used in HPLC. The data in this article is associated with the research article published in "Comparison of fluorescent tags for analysis of mannose-6-phosphate glycans" (Kang et al., 2016 [1]). PMID- 27222849 TI - Data on true tRNA diversity among uncultured and bacterial strains. AB - Complete genome sequences of two uncultured archaea (BX649197 and CR937008) and 10 uncultured bacteria (AC160099, FP245538-FP245540, FP312972, FP312974-75, FP312977, FP312985 and NZ_JPJG01000067) were used for creation of digital data of tRNA. tRNAscan-SE and ENDMEMO GC calculating tools were used for detection of tRNA, drawing their structures and calculation of GC percent. Seven archaeal and 48 bacterial tRNA were detected from above 12 sequences. Four archaeal and 30 bacterial tRNA showed cove score more than 20% are called as true tRNA. Three tRNA of uncultured bacteria (AC160099) has the presence of the variable loop. The tRNA of FP245540, FP245575, FP245577 and FP245585 has one variable loop each. The true tRNA of archaea were Alanine, Arginine and Cysteine-type tRNA, while the majority of bacteria true tRNA classified as Alanine, Glutamic acid, Isoleucine, Leucine, Methionine, Phenylalanine, Proline and Valine-type tRNA with cove score ranged from 70% to 97.15%. Archaeal and bacterial have GC content approximately 43% and 34.7-63.3% respectively. Archaeal tRNA has 60.4-64.2% GC content. Similarly, bacterial tRNA contributed 49.3-66.3% GC content to the total GC content. This generated data is useful for studies on diversity of tRNA among prokaryotes. PMID- 27222851 TI - Data on the cost effective surface sterilization method for C.carandas (L.) seeds and callus induction from aseptic seedling. AB - Surface sterilization of explant is an important and most sensitive step in plant tissue culture. Inappropriate concentrations of sterilants have lethal effect in cell division and it restricts growth and development of explant. Therefore, suitable concentration, combinations and duration of exposure of sterilant is essential to raise in vitro cultures successfully. This data demonstrates use of various sterilizing agents for aseptic plantlet germination from seed of Carissa carandas (Apocynaceae). The present dataset provides information in support of cost-effective explant sterilization potential of benzalkonium chloride containing commercial bleach (Lizol) and its comparison with traditionally used surface sterilants in plant tissue culture i.e. 0.1% HgCl2 alone and in combination with 70% alcohol. The data on callogenic response using MS medium supplemented with plant growth regulators is also shared. PMID- 27222852 TI - CO2 and O2 solubility and diffusivity data in food products stored in data warehouse structured by ontology. AB - This data article contains values of oxygen and carbon dioxide solubility and diffusivity measured in various model and real food products. These data are stored in a public repository structured by ontology. These data can be retrieved through the @Web tool, a user-friendly interface to capitalise and query data. The @Web tool is accessible online at http://pfl.grignon.inra.fr/atWeb/. PMID- 27222853 TI - Data on sulforaphane treatment mediated suppression of autoreactive, inflammatory M1 macrophages. AB - Any chronic, inflammatory, autoimmune disease (e.g. arthritis) associated pathogenesis directs uncontrolled accumulation of both soluble forms of collagens in the synovial fluids and M1 macrophages around inflamed tissues. Despite of few studies demonstrating efficiency of Sulforaphane (SFN) in suppressing arthritis associated collagen restricted T cells or fibroblasts, its effects on macrophage polarity and plasticity are less understood. Recently, we reported regulation of phenotypic and functional switching by SFN in induced and spontaneously differentiating human monocytes [1]. Here, flow cytometry, western blot and ELISA derived data demonstrated that SFN inhibited in vitro inflammatory responses developed by soluble human collagens (I-IV) induced auto-reactive M1 type monocyte/macrophage model. PMID- 27222850 TI - All cholesterol-lowering interventions are expected to reduce stroke: Confirmatory data from IMPROVE-IT. AB - The relationship of cholesterol with stroke is much less clear than its relationship with myocardial infarction, thus confounding the interpretation of results with cholesterol-lowering trials (Di Napoli et al., 2002) [1], (De Caterina et al., 2010) [2]). IMPROVE-IT data ((Cannon et al. 2015) [3]), showing a 13.3% reduction in total cholesterol at one year in association with a hazard ratio (HR) of 0.i86 for total stroke during the trial, are very closely aligned with the relative risk of 0.90 predicted based on the totality of lipid lowering interventions ((De Caterina et al., 2016) [4]). We here provide the data from the original trials used to construct this meta-analysis, with the now added additional data from IMPROVE-IT, well-fitting the previously found meta regression line. These data are important to predict stroke outcomes in currently ongoing trials now testing PCSK9 or cholesterol ester transfer protein inhibitors. PMID- 27222854 TI - Data on the abundance of the banana weevil Cosmopolites sordidus and of the earwig Euborellia caraibea in bare soil and cover crop plots. AB - The data presented in this article are related to the research article entitled "Cover cropping reduces the abundance of the banana weevil Cosmopolites sordidus but does not reduce its damage to the banana plants" (Carval et al., in press) [1]. This article describes how the abundance of the banana weevil, Cosmopolites sordidus, and the abundance of the earwig Euborellia caraibea were affected by the addition of a cover crop. The field data set is made publicly available to enable critical or extended analyzes. PMID- 27222855 TI - Dataset of mitochondrial genome variants associated with asymptomatic atherosclerosis. AB - This dataset report is dedicated to mitochondrial genome variants associated with asymptomatic atherosclerosis. These data were obtained using the method of next generation pyrosequencing (NGPS). The whole mitochondrial genome of the sample of patients from the Moscow region was analyzed. In this article the dataset including anthropometric, biochemical and clinical parameters along with detected mtDNA variants in patients with carotid atherosclerosis and healthy individuals was presented. Among 58 of the most common homoplasmic mtDNA variants found in the observed sample, 7 variants occurred more often in patients with atherosclerosis and 16 variants occurred more often in healthy individuals. PMID- 27222856 TI - Satellite data for Singapore, Manila and Kuala Lumpur city growth analysis. AB - This data article presents satellite data related to city growth of Singapore, Manila and Kuala Lumpur cities. The data were collected from NASA and USGS websites. A method has been developed for city built-up density from city center to outward till 50 km by using satellite data. These data sets consists three decade Landsat images. A detailed description is given to show how to use this data to produce urban growth maps. The urban growth maps have been used to know the changes and growth pattern in the Southeast Asia Cities. PMID- 27222857 TI - Data on IL-17 production induced by plant lectins. AB - We reported in article da Silva et al. (2016) [2] that ArtinM induces the IL-17 production through interaction with CD4(+) T cells and stimulation of IL-23 and IL-1. Besides ArtinM, other plant lectins (PLs) induce IL-17 production by murine spleen cells. The IL-17 production induced by PLs was evaluated regarding the involvement of IL-23, IL-6, Th1-, and Th2-cytokines. Furthermore, the effect exerted TLR2, TLR4, and CD14 on the PLs' performance in the induction of IL-17 was examined. The current data were compared to the known ArtinM ability to induce Th17 immunity. PMID- 27222858 TI - Ground penetrating radar data used in discovery of the early Christian church of Notre Dame de Baudes near Labastide-du-Temple, France. AB - Data on ground-penetrating radar transect files are provided that support the research presented in "Discovery and Appraisal of the Early Christian Church of Notre Dame de Baudes near Labastide-du-Temple, France" [1]. Data consist of 102 transect files obtained with a GSSI SIR-3000 controller and a 400 MHz center frequency antenna in two grid blocks covering ca. 2700 m(2). The data are distributed raw without post-processing in SEG-Y rev. 1 format (little endian). PMID- 27222859 TI - Dataset of gene cloning and gel filtration chromatography of R-est6. AB - The data presented in this article are connected to the research article entitled "Expression, purification and biochemical characterization of a family 6 carboxylesterase from Methylococcus capsulatus (bath)" (Soni et al., 2016 [1]). The family 6 carboxylesterases are the smallest and display broad substrate specificity. The 1 kb gene encoding, a family 6 carboxylesterase - R-est6, was amplified from the genome of M. capsulatus (bath strain), and showed in the agarose gel. The corresponding purified protein, after overexpression in Escherichia coli, was biochemically studied in the research article (Soni et al., 2016 [1]). R-est6 has hydrophobic patches on the surface so, it is expected to show oligimeric forms. Here, we have confirmed the presence of oligomers by gel filtration chromatography data and the proteins belonging to the different peaks are shown on a SDS-PAGE. PMID- 27222860 TI - Microarray data on altered transcriptional program of Phgdh-deficient mouse embryonic fibroblasts caused by L-serine depletion. AB - Inherent L-Ser deficiency culminates in intrauterine growth retardation, severe malformation of multiple organs particularly the central nervous system, and perinatal or early postnatal death in human and mouse. To uncover the molecular mechanisms underlying the growth-arrested phenotypes of l-Ser deficiency, we compared gene expression profiles of mouse embryonic fibroblasts deficient in 3 phosphoglycerate dehydrogenase (Phgdh), the first enzyme of de novo L-Ser synthetic pathway, between L-Ser-depleted and -supplemented conditions. The datasets (CEL and CHP files) from this study are publicly available on the Gene Expression Omnibus repository (accession number GEO: GSE55687). PMID- 27222861 TI - Data of in vitro synthesized dsRNAs on growth and development of Helicoverpa armigera. AB - The data presented in this article is related to the research article "RNAi of selected candidate genes interrupts growth and development of Helicoverpa armigera" (Chikate et al., 2016) [1]. RNA interference (RNAi) is emerging as a potent insect pest control strategy over current methods and their resistance by pest. In this study we tested 15 different in vitro synthesized dsRNAs for gene silencing in Helicoverpa armigera. These dsRNAs were specific against H. armigera enzymes/proteins such as proteases like trypsins (HaTry2, 3, 4 and 6), chymotrypsin (HaChy4) and cysteine proteases such as cathepsin (HaCATHL); glutathione S-transferases (HaGST1a, 6 and 8); esterases (HaAce4, HaJHE); catalase (HaCAT); super-oxide-dismutase (HaCu/ZnSOD); fatty acid binding protein (HaFabp) and chitin deacetylase (HaCda5b). These dsRNAs were fed to second instar larvae at an optimized dose (60 ug/day) for 3 days separately. Effects of dsRNA feeding were observed in terms of larval mass gain, percentage mortality and phenotypic abnormalities in later developmental stages of H. armigera. These findings might provide potential new candidates for designing sequence-specific dsRNA as pesticide in crop protection. PMID- 27222862 TI - Datasets depicting mobility retardation of NCS proteins observed upon incubation with calcium, but not with magnesium, barium or strontium. AB - In this data article we show the specificity of the Ca(2+)-induced mobility shift in three proteins that belong to the neuronal calcium sensor (NCS) protein family: Hippocalcin, GCAP1 and GCAP2. These proteins did not display a shift in mobility in native gels when incubated with divalent cations other than Ca(2+) - such as Mg(2+), Ba(2+), and Sr(2+), even at 10* concentrations. The data is similar to that obtained with another NCS protein, neurocalcin delta (Viviano et al., 2016, "Electrophoretic Mobility Shift in Native Gels Indicates Calcium dependent Structural Changes of Neuronal Calcium Sensor Proteins", [1]). PMID- 27222863 TI - Data for a direct fibrinolytic metalloproteinase, barnettlysin-I from Bothrops barnetti (barnett(,)s pitviper) snake venom with anti-thrombotic effect. AB - Initial association of platelets after vascular injury is mediated by glycoprotein (GP)Ib-IX-V binding to von Willebrand factor (vWf) immobilized on exposed collagens and eventually leads to thrombus formation. This article provides data about a new P-I class snake venom metalloproteinase (SVMP), barnettlysin-I (Bar-I), purified from the venom of Bothrops barnetti. This Data in Brief manuscript complements the main research article by providing additional data of the biochemical characterization of Bar-I 10.1016/j.bbagen.2015.12.021[1]. PMID- 27222864 TI - Using Behavioral Risk Factor Data as a surveillance tool to monitor the prevalence of initiation, continuation and completion of Human Papilloma Virus vaccination in children. AB - The Human Papilloma Virus ("HPV") is a common sexually transmitted disease that has infected approximately 79 million men and women in the United States alone. A vaccination is available but in order to be effective it must be received prior to becoming sexually active and recipients must complete a three-dose sequence. In this article we explore the predisposing, enabling and need-based factors associated with parents' or guardians' decision to have their child initiate, continue and complete the Human Papilloma Virus (HPV) vaccine. The data file includes 5531 parents and guardians with presumptive knowledge regarding the number of HPV vaccination their child received. Data includes information on the child (e.g. child's age) as well as the adult respondent (e.g. health insurance status). A smaller subset of the dataset along with the code to run the model are supplied with this article. The interpretation of these data can be found in the research article published by the authors in the Journal of Preventive Medicine in 2015 http://dx.doi.org/10.1016/j.ypmed.2016.01.010[1]. PMID- 27222865 TI - Dataset on the mean, standard deviation, broad-sense heritability and stability of wheat quality bred in three different ways and grown under organic and low input conventional systems. AB - An assessment was previously made of the effects of organic and low-input field management systems on the physical, grain compositional and processing quality of wheat and on the performance of varieties developed using different breeding methods ("Comparison of quality parameters of wheat varieties with different breeding origin under organic and low-input conventional conditions" [1]). Here, accompanying data are provided on the performance and stability analysis of the genotypes using the coefficient of variation and the 'ranking' and 'which-won where' plots of GGE biplot analysis for the most important quality traits. Broad sense heritability was also evaluated and is given for the most important physical and quality properties of the seed in organic and low-input management systems, while mean values and standard deviation of the studied properties are presented separately for organic and low-input fields. PMID- 27222866 TI - Validation data for the quantification of the Annonaceous acetogenin annonacin in Rat brain by UPLC-MS/MS. AB - Annonaceous acetogenins (AAGs) are environmental neurotoxins from the fruit pulp of several Annonaceae species, whose consumption was linked to the occurrence of sporadic atypical Parkinsonism with dementia. The quantification of the prototypical AAG annonacin in Rat brain homogenates was performed by UPLC-MS/MS in selected reaction monitoring (SRM) mode, using a triple quadrupole mass analyzer. A natural analog of annonacin was used as an internal standard. Analyzed data set of the analytical validation of this method is presented, including stability of the samples, extraction recovery and matrix effect, supporting the results described in the article "Quantification of the environmental neurotoxin annonacin in Rat brain by UPLC-MS/MS" N. Bonneau, I. Schmitz-Afonso, D. Touboul, A. Brunelle, P. Champy (2016) [1]. PMID- 27222867 TI - Data on photovoltaic power forecasting models for Mediterranean climate. AB - The weather data have a relevant impact on the photovoltaic (PV) power forecast, furthermore the PV power prediction methods need the historical data as input. The data presented in this article concern measured values of ambient temperature, module temperature, solar radiation in a Mediterranean climate. Hourly samples of the PV output power of 960kWP system located in Southern Italy were supplied for more 500 days. The data sets, given in , were used in DOI: 10.1016/j.enconman.2015.04.078, M.G. De Giorgi, P.M. Congedo, M. Malvoni, D. Laforgia (2015) [1] to compare Artificial Neural Networks and Least Square Support Vector Machines. It was found that LS-SVM with Wavelet Decomposition (WD) outperforms ANN method. In DOI: 10.1016/j.energy.2016.04.020, M.G. De Giorgi, P.M. Congedo, M. Malvoni (2016) [2] the same data were used for comparing different strategies for multi-step ahead forecast based on the hybrid Group Method of Data Handling networks and Least Square Support Vector Machine. The predicted PV power values by three models were reported in . PMID- 27222868 TI - Effect of osmolytes on the conformation and aggregation of some amyloid peptides: CD spectroscopic data. AB - Protein misfolding and aggregation are responsible for a large number of diseases called protein conformational diseases or disorders that include Alzheimer's disease, Huntington's diseases, Prion related encephalopathies and type-II diabetes (http://dx.doi.org/10.1038/35041139) (Kopito and Ron, 2000) [1]. A variety of studies have shown that some small organic molecules, known as osmolytes have the ability to stabilize native conformation of proteins and prevent misfolding and aggregation (http://www.la press.com/article.php?article_id=447) (Zhao et al., 2008) [2]. It has been shown that certain short segment or fragment of respective proteins can also form amyloids, and the segments also promote the aggregation in the full-length protein (http://dx.doi.org/10.2174/0929867023369187) (Gazit, 2002) [3]. This article presents circular dichroism spectroscopic data on conformational analysis and effect of osmolytes on Abeta peptide fragments, different lengths of polyglutamine peptide and the amyloidogenic segment of islet amyloid polypeptide. PMID- 27222869 TI - Data set for renal sinus fat volume and visceral adipose tissue volume on computed tomography. AB - Renal sinus fat is partially characteristic of peri-vascular adipose tissue, however, RSF volume (RSFV) is associated with visceral adipose tissue (VATV). Therefore, the ratio of RSFV to VATV (RSFV/VATV ratio) can distinguish the importance of RSF as an extension of VAT versus its perivascular effects. We assessed the association of RSFV/VATV ratio with coronary artery calcification score (CACS) in 189 patients with suspected coronary artery disease. RSFV of the right kidney and VATV were quantified by using image data of unenhanced abdominal CT. CACS were measured on unenhanced ECG-gated CT images. This article contains data on explanatory scheme of how to measure RSFV on unenhanced abdominal CT, CT indication and exclusion criteria of study population, sex-adjusted association between RSFV with risk factors of coronary vascular diseases and metabolic indices, multivariate linear regression analysis with CACS as the dependent variable in the total study population. The data are supplemental to our original research article describing detailed association between RSFV/VATV ratio and CACS including sub-groups analyses classified by the age of 70 "Renal sinus fat volume on computed tomography in middle-aged patients at risk for cardiovascular disease and its association with coronary artery calcification" Murakami et al. [1]. PMID- 27222870 TI - Trajectories and single-particle tracking data of intracellular vesicles loaded with either SNAP-Crb3A or SNAP-Crb3B. AB - Using a combined approach of pulse chase labeling and single-particle tracking of Crb3A or 3B loaded vesicles we collected trajectories of different vesicle population in living podocyte cells and evaluated statistically their different mobility patterns. Differences in their intracellular mobility and in their directed transport correspond well to the role of Crb3A and 3B in renal plasma membrane sorting (Djuric et al., 2016) [1]. PMID- 27222871 TI - Trajectories of microsecond molecular dynamics simulations of nucleosomes and nucleosome core particles. AB - We present here raw trajectories of molecular dynamics simulations for nucleosome with linker DNA strands as well as minimalistic nucleosome core particle model. The simulations were done in explicit solvent using CHARMM36 force field. We used this data in the research article Shaytan et al., 2016 [1]. The trajectory files are supplemented by TCL scripts providing advanced visualization capabilities. PMID- 27222872 TI - Interferon alfa-induced sarcoidosis resolving without drug withdrawal. PMID- 27222873 TI - Encephalocraniocutaneous lipomatosis (Haberland syndrome): A mild case with bilateral cutaneous and ocular involvement. PMID- 27222874 TI - Paraneoplastic microscopic polyangiitis presenting after thymectomy. PMID- 27222875 TI - Hemorrhagic bullous dermatosis caused by warfarin therapy. PMID- 27222876 TI - Familial benign chronic pemphigus (Hailey-Hailey disease) treated with electron beam radiation. PMID- 27222877 TI - Role of topical tranexamic acid in hemostasis of locally advanced basal cell carcinoma. PMID- 27222878 TI - Leg ulcers in systemic lupus erythematosus associated with underlying dystrophic calcinosis and bone infarcts in the absence of antiphospholipid antibodies. PMID- 27222879 TI - An unusual acneiform presentation representing secondary squamous cell carcinoma of the skin. PMID- 27222880 TI - Pigmented eccrine poroma of the palm clinically mimicking a seborrheic keratosis. PMID- 27222881 TI - A new drug with a nasty bite: A case of krokodil-induced skin necrosis in an intravenous drug user. PMID- 27222882 TI - New-onset oral lichen planus and granulomatous cheilitis in a 66-year-old woman. PMID- 27222883 TI - A fatal case of febrile ulceronecrotic Mucha-Habermann disease in a child. PMID- 27222884 TI - A case of leukemia cutis presenting as blue toes in a patient with chronic lymphocytic leukemia. PMID- 27222885 TI - Increasing incidence of leprosy and transmission from armadillos in Central Florida: A case series. PMID- 27222886 TI - Acquired acrodermatitis enteropathica as a presenting sign of celiac disease. PMID- 27222887 TI - Homozygous GNAL mutation associated with familial childhood-onset generalized dystonia. PMID- 27222888 TI - Ceramic Repair Without Hydrofluoric Acid. AB - PURPOSE: To evaluate the bond strength between composite resin and feldspathic ceramic following repair protocols with and without hydrofluoric acid and aging by thermocycling. MATERIALS AND METHODS: Forty-eight glass feldspathic ceramic blocks (8 x 8 x 6 mm) were divided into three groups on the basis of their surface repair treatment: 1. 10% hydrofluoric acid + Signum Ceramic Primer I + Signum Ceramic Primer II (control group); 2. abrasive rubber tips + Signum Ceramic Primer I + Signum Ceramic Primer II (test group); 3. Signum Ceramic Primer I + Signum Ceramic Primer II (negative control group). The treated surface of each block was built up with composite and then sectioned to produce nontrimmed bars (adhesive area = 1 mm2). Half of the bars from each group were aged by 6000 cycles of 30-s immersions in water baths at 5 degrees C and 55 degrees C, with a transfer time of 2 s. The other bars were immediately subjected to microtensile bond strength testing. The mean bond strength for each block was then recorded and submitted to two-way ANOVA and Tukey's test (alpha = 0.05). RESULTS: The aging protocol influenced the bond strength values of all groups (p = 0.000). The non-aged groups submitted to surface treatment protocols 1 (13.1 +/ 2.5 MPa) and 2 (11.5 +/- 5.1 MPa) presented the highest bond strength values. CONCLUSIONS: The interface bond strength of all groups was susceptible to aging. Surface treatment protocol 2, with abrasive rubber tips and no hydrofluoric acid, appeared to be the most promising option, as the resulting bond strength values were similar to those of the control group. PMID- 27222889 TI - Bonding Effectiveness of Luting Composites to Different CAD/CAM Materials. AB - PURPOSE: To evaluate the influence of different surface treatments of six novel CAD/CAM materials on the bonding effectiveness of two luting composites. MATERIALS AND METHODS: Six different CAD/CAM materials were tested: four ceramics - Vita Mark II; IPS Empress CAD and IPS e.max CAD; Celtra Duo - one hybrid ceramic, Vita Enamic, and one composite CAD/CAM block, Lava Ultimate. A total of 60 blocks (10 per material) received various mechanical surface treatments: 1. 600-grit SiC paper; 2. sandblasting with 30-MUm Al2O3; 3. tribochemical silica coating (CoJet). Subsequent chemical surface treatments involved either no further treatment (control), HF acid etching (HF), silanization (S, or HF acid etching followed by silanization (HF+S). Two specimens with the same surface treatment were bonded together using two dual-curing luting composites: Clearfil Esthetic Cement (self-etching) or Panavia SA Cement (self-adhesive). After 1 week of water storage, the microtensile bond strength of the sectioned microspecimens was measured and the failure mode was evaluated. RESULTS: The bonding performance of the six CAD/CAM materials was significantly influenced by surface treatment (linear mixed models, p < 0.05). The luting cement had a significant influence on bond strength for Celtra Duo and Lava Ultimate (linear mixed models, p < 0.05). Mechanical surface treatment significantly influenced the bond strength for Celtra Duo (p = 0.0117), IPS e.max CAD (p = 0.0115), and Lava Ultimate (p < 0.0001). Different chemical surface treatments resulted in the highest bond strengths for the six CAD/CAM materials: Vita Mark II and IPS Empress CAD: S, HF+S; Celtra Duo: HF, HF+S; IPS e.max CAD: HF+S; Vita Enamic: HF+S, S. For Lava Ultimate, the highest bond strengths were obtained with HF, S, HF+S. Failure analysis showed a relation between bond strength and failure type: more mixed failures were observed with higher bond strengths. Mainly adhesive failures were noticed if no further surface treatment was done. The percentage of adhesive failures was higher for CAD/CAM materials with higher flexural strength (Celtra Duo, IPS e.max CAD, and Lava Ultimate). CONCLUSION: The bond strength of luting composites to novel CAD/CAM materials is influenced by surface treatment. For each luting composite, an adhesive cementation protocol can be specified in order to obtain the highest bond to the individual CAD/CAM materials. PMID- 27222890 TI - Editorial: Should the concept of the three-thread faculty member exist in academic dentistry today? PMID- 27222891 TI - Diagnosis and treatment of ankyloglossia: A narrative review and a report of three cases. AB - BACKGROUND: Ankyloglossia or tongue-tie is a congenital oral anomaly with short, tight, and thick lingual frenulum. It may be asymptomatic or can cause movement limitations of the tongue, speech and articulation difficulties, breastfeeding difficulties in neonates, as well as periodontal and malocclusion problems. The etiopathogenesis of ankyloglossia is unknown; it can occur either as a sole anomaly in the vast majority or in association with other craniofacial anomalies. OBJECTIVES: The aims of this paper were (1) to provide a comprehensive review on the criteria for clinical assessment and diagnosis, etiology and inheritance, and the therapeutic options of ankyloglossia; and (2) to demonstrate the treatment of ankyloglossia by means of frenuloplasty in three cases. REVIEW: The available evidence from the literature indicates that among neonates, children, and adults the prevalence of ankyloglossia is low and in some cases remains undiagnosed. The early clinical assessment, diagnosis, and treatment are beneficial for the patients and their mothers. CONCLUSIONS: Frenuloplasty is a safe, quick, effective, and economical method and for this reason the parents should not hesitate towards frenulum release. More clinical studies are needed to confirm the benefits of the surgical interventions and to compare the results with those obtained using nonsurgical therapy or with untreated cases. PMID- 27222892 TI - Operative Management of Splenic Rupture and Hepatic Flexure Injury during Diagnostic Colonoscopy in a Patient with Adenocarcinoma of the Cecum and Pulmonary Embolism. PMID- 27222893 TI - Management of Small Bowel Fistulae. PMID- 27222894 TI - Transgastric Endoscopy and Pancreaticoduodenectomy after Roux-en-Y Gastric Bypass. PMID- 27222895 TI - Metastatic Invasive Lobular Breast Cancer Presenting as Gastric Cancer. PMID- 27222896 TI - Saving Life and Limb: Multidisciplinary Management of Complex Penetrating Trauma. PMID- 27222897 TI - Damage Control Surgery: Not Just for Trauma. PMID- 27222898 TI - Gastric Perforation Associated with Bilateral Inguinal Hernias. PMID- 27222899 TI - THE EUROPEAN ACADEMY OF REHABILITATION MEDICINE SCIENTIFIC PRIZE 2014. PMID- 27222901 TI - The concept of the quasispecies will soon be 50 years old. Introduction. PMID- 27222903 TI - Chemoselectivity and stereoselectivity have been key factors in the development of fine organic synthesis. Introduction. PMID- 27222902 TI - Quasispecies theory has come of age, and regular updates of the concept of mutation. Introduction. PMID- 27222904 TI - Since their identification 40 years ago, natural killer (NK) cells write a never ending story. Introduction. PMID- 27222905 TI - The last decade has seen many exciting new medicines being introduced to the market. Introduction. PMID- 27222906 TI - "Mental Health" Power and Its Effects: A Commentary on Battling Against Inter Faith Relations in Israel. AB - Hakak (2016) provides an opportunity to examine how mental health and therapy systems in the United States operate to maintain current social and political structures. This commentary suggests that practitioners, including family therapists, participate in and support practices that do not serve the interests of marginalized social groups, despite our best intentions. Discourse theory offers a lens through which such practices become visible and thus open to revision. PMID- 27222907 TI - In Memorium: Sister Alice Smitherman. PMID- 27222908 TI - [Professor F.A. Reyn- talented organizer and prominent public figure (on the 150th anniversary)]. PMID- 27222909 TI - [Prevention of postoperative ventral hernias: current state of the art]. PMID- 27222910 TI - Modify workflows and embrace automation to help practices, patients. PMID- 27222911 TI - Nanostructured Black Phosphorus/Ketjenblack-Multiwalled Carbon Nanotubes Composite as High Performance Anode Material for Sodium-Ion Batteries. AB - Sodium-ion batteries are promising alternatives to lithium-ion batteries for large-scale applications. However, the low capacity and poor rate capability of existing anodes for sodium-ion batteries are bottlenecks for future developments. Here, we report a high performance nanostructured anode material for sodium-ion batteries that is fabricated by high energy ball milling to form black phosphorus/Ketjenblack-multiwalled carbon nanotubes (BPC) composite. With this strategy, the BPC composite with a high phosphorus content (70 wt %) could deliver a very high initial Coulombic efficiency (>90%) and high specific capacity with excellent cyclability at high rate of charge/discharge (~1700 mAh g(-1) after 100 cycles at 1.3 A g(-1) based on the mass of P). In situ electrochemical impedance spectroscopy, synchrotron high energy X-ray diffraction, ex situ small/wide-angle X-ray scattering, high resolution transmission electronic microscopy, and nuclear magnetic resonance were further used to unravel its superior sodium storage performance. The scientific findings gained in this work are expected to serve as a guide for future design on high performance anode material for sodium-ion batteries. PMID- 27222912 TI - A novel diarylheptanoid-bearing sesquiterpene moiety from the rhizomes of Alpinia officinarum. AB - A new diarylheptanoid analogue-bearing sesquiterpene moiety, named Alpinisin A, was isolated from the rhizomes of Alpinia officinarum Hance. The new structure was determined by various spectroscopic techniques (1)H-nuclear magnetic resonance ((1)H NMR), (13)C-attached proton test ((13)C-APT), heteronuclear single quantum coherence (HSQC), heteronuclear multiple bond correlation (HMBC), (1)H-(1)H correlation spectroscopy ((1)H-(1)HCOSY), nuclear overhauser effect spectroscopy (NOESY) and high resolution electrospray ionization mass spectrometry (HR-ESI-MS). The compound was tested for cytotoxic activity in vitro against human tumour cell lines (gastric carcinoma cell -7901 (SGC-7901), Michigan Cancer Foundation-7 (MCF-7) and Caski), which showed significant inhibitory effects with IC50 levels of 11.42, 15.14 and 14.78 MUM, respectively. The novel chemical structure characterised with a diarylheptanoid linked to a chain-like sesquiterpenoid should be highlighted. PMID- 27222913 TI - Tube Current Modulation Between Single- and Dual-Energy CT With a Second Generation Dual-Source Scanner: Radiation Dose and Image Quality. AB - OBJECTIVE: The purpose of this study was to compare the effects of tube current modulation between single- and dual-energy CT with a second-generation dual source scanner. MATERIALS AND METHODS: Custom-made elliptic polymethylmethacrylate phantoms for slim and large patients were used. Absorbed radiation dose at the central point of the phantoms was measured with a solid state detector while the phantoms were scanned in single-energy (120 kV) and dual energy (100/Sn140, 80/Sn140, and 140/80 kV) modes with a second-generation dual source CT scanner. Tube current modulation was activated in both modes, and quality reference tube current-time settings of 150, 300, 450, and 600 mAs were selected. Scanning was performed three times under the same conditions, and image noise was evaluated by measuring the SD of CT numbers in four separate regions of three adjacent images of the phantoms. RESULTS: Absorbed dose increased and image noise decreased with an increase in quality reference tube current-time setting when the slim phantom was scanned. For the large phantom, the radiation dose and noise level reached a plateau above quality reference tube current-time settings of 300 mAs for 100/Sn140 kV and 450 mAs for 120 kV. The radiation dose was small and the noise level was large with 80/Sn140 kV compared with that obtained with 120 and 100/Sn140 kV at all quality reference tube current-time settings. CONCLUSION: When a large phantom is scanned with 100/Sn140 kV, exposure demand for tube current modulation exceeds system limits at a lower quality reference tube current-time setting than for scanning 120 kV. PMID- 27222914 TI - Evidences and perspectives in the utilization of CLNA isomers as bioactive compounds in foods. AB - Conjugated alpha linolenic acid (CLNA) isomers are promising lipids owing to their similarities with conjugated linoleic acid (CLA) but exerting their bioactivity at lower doses; some isomers also belong to omega 3 family. This review aims to summarize the state of the art about the utilization of CLNA as a functional ingredient. Indeed, in vitro and in vivo studies reported that CLNA exerted anticancer, anti-inflammatory, anti-obese, and antioxidant activities. However, CLNA has not been tested in humans. These compounds are naturally present in meat and milk fat from ruminants but the highest concentrations are found in vegetable oils. Their incorporation in foodstuffs is one of the most effective strategies to elaborate CLNA-enriched products together with the microbiological production. Lactobacilli, propionibacteria, and bifidobacteria strains have been assayed to produce CLNA isomers but at the current moment there are not high CLNA concentration products elaborated using these strains. Furthermore, it is known that CLNA isomers are highly prone to oxidation when compared with linoleic acid and CLA, but the possible effects of elaboration and storage on high CLNA productsare unknown.The utilization of CLNA as a functional compound still remains a challenge and requires more research to address all of its technological and bioactivity aspects. PMID- 27222915 TI - Liver fat accumulation is associated with circulating PCSK9. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) associates with cardiovascular disease independently of classic risk factors. Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) is secreted by hepatocytes and inhibits the uptake of low-density lipoproteins by targeting the receptor for degradation, and possibly lipogenesis. PCSK9 loss-of-function mutations and anti PCKS9 drugs reduce LDL-cholesterol. AIM: To evaluate whether hepatic fat content is associated with circulating PCSK9. MATERIALS AND METHODS: In 201 consecutive patients biopsied for suspected nonalcoholic steatohepatitis, liver damage was quantified by NAFLD activity score, circulating PCSK9 by ELISA, and hepatic mRNA by qRT-PCR in a subset (n = 76). RESULTS: Circulating PCSK9 was associated with steatosis grade (p = 0.0011), necroinflammation (p < 0.001), ballooning (p = 0.005), and fibrosis stage (p = 0.001). At multivariate analysis, PCSK9 was associated with steatosis grade (p = 0.012), older age and lower BMI, independently of sex, hyperglycemia, and fibrosis/inflammation. Circulating PCSK9 was associated with hepatic expression of SREBP-1c (p = 0.0002) and FAS (p = 0.03). PCSK9 mRNA levels were also correlated with steatosis severity (p = 0.04) and hepatic APOB (p < 0.001), SREBP-1c (p = 0.047) and FAS expression (p = 0.001). CONCLUSIONS: Circulating PCSK9 increases with hepatic fat accumulation and correlates with the severity of steatosis, independently of metabolic confounders and liver damage. Modulation of PCSK9 synthesis and release might be involved in NAFLD pathogenesis. Key Messages Circulating PCSK9 levels increase with hepatic fat accumulation. Circulating PCSK9 levels are associated with increased de novo lipogenesis. Hepatic PCSK9 expression is associated with steatosis severity and activation of lipogenesis. PMID- 27222916 TI - Chloride-Mediated Apoptosis-Inducing Activity of Bis(sulfonamide) Anionophores. AB - Transmembrane anion transport modality is enjoying a renewed interest because of recent advances toward anticancer therapy. Here we show bis(sulfonamides) as efficient receptors for selective Cl(-) ion binding and transport across lipid bilayer membranes. Anion-binding studies by (1)H NMR indicate a logical correlation between the acidity of sulfonamide N-H proton and binding strength. Such recognition is influenced further by the lipophilicity of a receptor during the ion-transport process. The anion-binding and transport activity of a bis(sulfonamide) system are far superior compared to those of the corresponding bis(carboxylic amide) derivative. Fluorescent-based assays confirm the Cl( )/anion antiport as the operational mechanism of the ion transport by bis(sulfonamides). Disruption of ionic homeostasis by the transported Cl(-) ion, via bis(sulfonamide), is found to impose cell death. Induction of a caspase dependent intrinsic pathway of apoptosis is confirmed by monitoring the changes in mitrochondrial membrane potential, cytochrome c leakage, activation of family of caspases, and nuclear fragmentation studies. PMID- 27222917 TI - Isotherm-Based Thermodynamic Models for Solute Activities of Organic Acids with Consideration of Partial Dissociation. AB - Organic acids make up a significant fraction of the organic mass in atmospheric aerosol particles. The calculation of gas-liquid-solid equilibrium partitioning of the organic acid is therefore critical for accurate determination of atmospheric aerosol physicochemical properties and processes such as new particle formation and activation to cloud condensation nuclei. Previously, an adsorption isotherm-based statistical thermodynamic model was developed for capturing solute concentration-activity relationships for multicomponent aqueous solutions over the entire concentration range (Dutcher et al. J. Phys. Chem. C/A 2011, 2012, 2013), with model parameters for energies of adsorption successfully related to dipole-dipole electrostatic forces in solute-solvent and solvent-solvent interactions for both electrolytes and organics (Ohm et al. J. Phys. Chem. A 2015). However, careful attention is needed for weakly dissociating semivolatile organic acids. Dicarboxylic acids, such as malonic acid and glutaric acid are treated here as a mixture of nondissociated organic solute (HA) and dissociated solute (H(+) + A(-)). It was found that the apparent dissociation was greater than that predicted by known dissociation constants alone, emphasizing the effect of dissociation on osmotic and activity coefficient predictions. To avoid additional parametrization from the mixture approach, an expression was used to relate the Debye-Huckel hard-core collision diameter to the adjustable solute solvent intermolecular distance. An improved reference state treatment for electrolyte-organic aqueous mixtures, such as that observed here with partial dissociation, has also been proposed. This work results in predictive correlations for estimation of organic acid and water activities for which there is little or no activity data. PMID- 27222918 TI - Multivariate Statistical Analysis of Cigarette Design Feature Influence on ISO TNCO Yields. AB - The aim of this study is to explore how differences in cigarette physical design parameters influence tar, nicotine, and carbon monoxide (TNCO) yields in mainstream smoke (MSS) using the International Organization of Standardization (ISO) smoking regimen. Standardized smoking methods were used to evaluate 50 U.S. domestic brand cigarettes and a reference cigarette representing a range of TNCO yields in MSS collected from linear smoking machines using a nonintense smoking regimen. Multivariate statistical methods were used to form clusters of cigarettes based on their ISO TNCO yields and then to explore the relationship between the ISO generated TNCO yields and the nine cigarette physical design parameters between and within each cluster simultaneously. The ISO generated TNCO yields in MSS are 1.1-17.0 mg tar/cigarette, 0.1-2.2 mg nicotine/cigarette, and 1.6-17.3 mg CO/cigarette. Cluster analysis divided the 51 cigarettes into five discrete clusters based on their ISO TNCO yields. No one physical parameter dominated across all clusters. Predicting ISO machine generated TNCO yields based on these nine physical design parameters is complex due to the correlation among and between the nine physical design parameters and TNCO yields. From these analyses, it is estimated that approximately 20% of the variability in the ISO generated TNCO yields comes from other parameters (e.g., filter material, filter type, inclusion of expanded or reconstituted tobacco, and tobacco blend composition, along with differences in tobacco leaf origin and stalk positions and added ingredients). A future article will examine the influence of these physical design parameters on TNCO yields under a Canadian Intense (CI) smoking regimen. Together, these papers will provide a more robust picture of the design features that contribute to TNCO exposure across the range of real world smoking patterns. PMID- 27222919 TI - Zika and the Risk of Microcephaly. PMID- 27222920 TI - Tuning the Interfacial Mechanical Behaviors of Monolayer Graphene/PMMA Nanocomposites. AB - The van der Waals (vdW) force dominated interface between graphene and polymer matrix creates weak points in the mechanical sense. Chemical functionalization was expected to be an effective approach in transfer of the outstanding performance of graphene across multiple length scales up to the macroscopic level, due to possible improvements in the interfacial adhesion. However, published works showed the contradiction that improvements, insensitivity, or even worsening of macro-mechanical performance have all been reported in graphene based polymer nanocomposites. Particularly central cause of such discrepancy is the variations in graphene/polymer interfacial chemistry, which is critical in nanocomposites with vast interfacial area. Herein, O3/H2O gaseous mixture was utilized to oxidize monolayer graphene sheet with controlled functionalization degrees. Hydrogen bonds (H bonds) are expected to form between oxidized graphene sheet/poly(methyl methacrylate) (PMMA) at the interface. On the basis of in situ tensile-micro Raman spectroscopy, the impacts of bonding types (vdW and H-bonds) on both key interfacial parameters (such as interfacial shear strength and critical length) and failure modes of graphene/PMMA nanocomposite were clarified for the first time at the microscopic level. Our results show that owing to improved interfacial interaction via H bonds, the interface tends to be stiffening and strengthening. Moreover, the mechanical properties of the functionalized graphene/PMMA interface will be set by the competition between the enhanced interfacial adhesion and the degraded elastic modulus of graphene, which was caused by structural defects in the graphene sheet during the functionalization process and could lead to catastrophic failure of graphene sheets in our experimental observation. Our results will be helpful to design various nanofiller-based nanocomposites with high mechanical performance. PMID- 27222921 TI - Structural and Functional Lung Impairment in Adult Survivors of Bronchopulmonary Dysplasia. AB - RATIONALE: As more preterm infants recover from severe bronchopulmonary dysplasia (BPD), it is critical to understand the clinical consequences of this condition on the lung health of adult survivors. OBJECTIVES: To assess structural and functional lung parameters in young adult BPD survivors and preterm and term control subjects. METHODS: Young adult survivors of BPD (mean age, 24 yr) underwent spirometry, lung volume assessment, transfer factor, lung clearance index, and fractional exhaled nitric oxide measurements, together with high resolution chest computed tomography and cardiopulmonary exercise testing. MEASUREMENTS AND MAIN RESULTS: Twenty-five adult BPD survivors (mean +/- SD gestational age, 26.8 +/- 2.3 wk; birth weight, 866 +/- 255 g), 24 adult prematurely born non-BPD control subjects (gestational age, 30.6 +/- 1.9 wk; birth weight, 1,234 +/- 207 g), and 25 adult term-birth control subjects (gestational age, 38.5 +/- 0.9 wk; birth weight, 3,569 +/- 2,979 g) were studied. Subjects with BPD were more likely to be wakened by cough (odds ratio, 9.7; 95% confidence interval, 1.8-52.6; P < 0.01) or wheeze and breathlessness (odds ratio, 12.2; 95% confidence interval; 1.3-112; P < 0.05) than term control subjects after adjusting for sex and current smoking. Preterm subjects had greater airway obstruction than term subjects. Subjects with BPD had significantly lower values for FEV1 and forced expiratory flow, midexpiratory phase (percent predicted and z-scores), than term control subjects (both P < 0.001). Although non-BPD subjects also had lower spirometric values than term control subjects, none of the differences reached statistical significance. More subjects with BPD (25%) had fixed airflow obstruction than non-BPD (12.5%) and term (0%) subjects (P = 0.004). Both BPD and non-BPD subjects had significantly greater impairment in gas transfer (Kco percent predicted) than term subjects (both P < 0.05). Eighteen (37%) preterm participants were classified as small for gestational age (birth weight below the 10th percentile for gestational age). These subjects had significantly greater impairment in FEV1 (percent predicted values and z-scores) than those born appropriate for gestational age. BPD survivors had significantly more severe radiographic structural lung impairment than non-BPD subjects. Both preterm groups had impaired exercise capacity compared with term control subjects. There was a trend for greater limitation and leg discomfort in BPD survivors. CONCLUSIONS: Adult preterm birth survivors, especially those who developed BPD, continue to experience respiratory symptoms and exhibit clinically important levels of pulmonary impairment. PMID- 27222922 TI - Photoreponsive Hybrid Nanoparticles with Inherent FRET Activity. AB - The photoactivated inherent fluorescence resonance energy transfer (FRET) properties of a hard-and-soft hybrid nanosystem comprising poly(1'-(2 methacryloxyethyl)-3',3'-dimethyl-6-nitrospiro-(2H-1-benzopyran-2,2'-indoline)) co-poly[2-(dimethylamino)ethyl methacrylate] (PSPMA-co-PDMAEMA) random copolymer brushes on silica nanoparticles are described. This unique FRET process is switched on by the simultaneous generation of isomer X and merocyanine (MC), which are bipolar in nature and comprise donor-acceptor dyads, from a single spiropyran (SP) chromophore upon UV irradiation. These X-MC species exhibit sufficient lifetimes to allow the read-out of the FRET process. The phenomenon is gradually switched off because of the thermal relaxation of the bipolar chromophores. This inherent property of the nanoemitters is employed in the development of biosensors of high specificity by monitoring variations in the FRET efficiency and lifetime of the hybrids in the presence of biological substances. More specifically, bovine serum albumin (BSA) augments the formation of MC species and retards the MC photobleaching process, leading to the enhancement of the FRET efficiency and lifetime, respectively. On the other hand, amino acid l-histidine further retards the MC thermal relaxation and prolongs the FRET process. We envisage that this platform opens new perspectives in the development of novel, optical nanosensors for applications in various fields including healthcare products and environmental monitoring. PMID- 27222923 TI - MicroRNA-128-3p impaired water maze learning by suppressing Doublecortin expression in both wild type and Abeta-42 infused mice. AB - MicroRNA-128-3p (miR-128) is a brain-enriched microRNA reported to target Doublecortin (Dcx), a key transcriptional factor during adult neurogenesis. However, the downstream physiological effects of this miR-128-DCX axis remain unclear. Here we demonstrated that miR-128 could suppress Dcx expression by complementally binding to the -849 to -856 region of the 3'UTR of mouse Dcx. During differentiation of neural stem cells, over-expressing miR-128 with a lentivirus system inhibited the up-regulation of Dcx on Day 5, subsequently decreasing the percentage of TuJ+ cells on Day 16. Administration of the lentivirus encoding miR-128 into mouse hippocampi significantly impaired water maze learning after 14days, which could be attenuated when the Dcx-encoding virus was delivered simultaneously. In addition, similar changes including miR-128 up regulation, Dcx down-regulation and learning defects were observed after a 14-day infusion of Abeta-42, which were also partially reversed by over-expressing Dcx. Collectively, the regulation axis from miR-128 to Dcx is critical for hippocampus related contextual learning not only in wild type, but also in mice infused with Abeta-42. PMID- 27222924 TI - Effect of intermittent hypoxia on arcuate nucleus in the leptin-deficient rat. AB - Intermittent hypoxia (IH) is a major pathophysiological consequence of obstructive sleep apnea. Recently, it has been shown that IH results in changes in body energy balance, leptin secretion and concomitant alterations in arcuate nucleus (ARC). In this study, the role of leptin on these changes was investigated in leptin-deficient rats exposed to IH or normoxic control conditions. Body weights, consumatory and locomotor behaviours, and protein signaling in ARC were assessed immediately after IH exposure. Compared to normoxia, IH altered body weight, food intake, locomotor pattern, and the plasma concentration of leptin and angiotensin II in the wild-type rat. However, these changes were not observed in the leptin-deficient rat. Within ARC of wild-type animals, IH increased phosphorylated signal transducer and activator of transcription 3 and pro-opiomelanocortin protein expression, but not in the leptin-deficient rat. The long-form leptin receptor protein expression was not altered following IH in either rat strain. These data suggest that leptin is involved in mediating the alterations to body energy balance and ARC activity following IH. PMID- 27222926 TI - Brain tissue tessellation shows absence of canonical microcircuits. AB - We provide a novel, fast and cheap method for the morphological evaluation of simple 2-D images taken from histological samples. This method, based on computational geometry, leads to a novel kind of "tessellation" of every type of biological picture, in order to locate the zones equipped with very fine-grained differences in the tissue texture, compared with the surrounding ones. As an example, we apply the technique to the evaluation of histological images from brain sections and demonstrate that the cortical layers, rather than being a canonical assembly of homogeneous cells as usually believed, display scattered neuronal micro-clusters equipped with higher activity than the surrounding ones. PMID- 27222925 TI - Novel pathologic findings in patients with Pelizaeus-Merzbacher disease. AB - Pelizaeus-Merzbacher disease (PMD) is an X-linked inherited hypomyelinating disorder caused by mutations in the gene encoding proteolipid protein (PLP), the major structural protein in central nervous system (CNS) myelin. Prior to our study, whether hypomyelination in PMD was caused by demyelination, abnormally thin sheaths or failure to form myelin was unknown. In this study, we compared the microscopic pathology of myelin from brain tissue of 3 PMD patients with PLP1 duplications to that of a patient with a complete PLP1 deletion. Autopsy tissue procured from PMD patients was embedded in paraffin for immunocytochemistry and plastic for electron microscopy to obtain highresolution fiber pathology of cerebrum and corpus callosum. Through histological stains, immunocytochemistry and electron microscopy, our study illustrates unique pathologic findings between the two different types of mutations. Characteristic of the patient with a PLP1 deletion, myelin sheaths showed splitting and decompaction of myelin, confirming for the first time that myelin in PLP1 deletion patients is similar to that of rodent models with gene deletions. Myelin thickness and g-ratios of some fibers, in relation to axon diameter was abnormally thin, suggesting that oligodendrocytes remain metabolically functional and/or are attempting to make myelin. Many fibers showed swollen, progressive degenerative changes to axons in addition to the dissolution of myelin. All three duplication cases shared remarkable fiber pathology including swellings, constriction and/or transection and involution of myelin. Characteristic of PLP1 duplication patients, many axons showed segmental demyelination along their length. Still other axons had abnormally thick myelin sheaths, suggestive of continued myelination. Thus, each type of mutation exhibited unique pathology even though commonality to both mutations included involution of myelin, myelin balls and degeneration of axons. This pathology study describes findings unique to each mutation that suggests the mechanism causing fiber pathology is likewise heterogeneous. PMID- 27222927 TI - Influence of GRIK4 genetic variants on the electroconvulsive therapy response. AB - Several lines of evidence have shown the involvement of the glutamatergic system in the function of electroconvulsive therapy (ECT). In particular, patients with treatment resistant depression (TRD) and chronic depression have lower levels of glutamate/glutamine than controls, and ECT can reverse this deficit. Genetic factors might contribute to modulating the mechanisms underlying ECT. This study aimed to evaluate the relationship between three polymorphisms (rs1954787, rs4936554 and rs11218030) of the glutamate receptor ionotropic kainate 4 (GRIK4) gene and responsiveness to ECT treatment in a sample of one hundred individuals, TRD or depressive Bipolar Disorder patients resistant to pharmacological treatments. The results revealed that GRIK4 variants were significantly associated with the response to ECT. In particular, we found that patients carrying the G allele of the GRIK4 rs11218030 had a significantly poorer response to ECT (p=2.71*10(-4)), showing five times the risk of relapse after ECT compared to the AA homozygotes. Analogously, patients carrying the GG rs1954787 genotype and rs4936554A allele carriers presented a double risk of lack of response after ECT (p=0.013 and p=0.040, respectively). In conclusion, the current study provides new evidence, indicating that some GRIK4 variants modulate the response to ECT in patients with depression resistant to treatment, suggesting a role for kainate receptor modulation. PMID- 27222928 TI - Developmental origins of polycystic ovary syndrome (PCOS), a case control study comparing birth weight in women with PCOS and control group. AB - Evidence from various epidemiological studies and experimental animal studies has linked adverse intrauterine circumstances with health problems in adult life. This field of investigation is known as Developmental Origins of Health and Disease (DOHaD). Studies investigating the relation between developing polycystic ovary syndrome (PCOS) in adulthood and birth weight have yielded inconsistent results: PCOS is described more often in women with low birth weight and high birth weight, while other studies have failed to establish any relation. In this retrospective case-control study, we evaluated whether women diagnosed with PCOS had lower birth weight compared to women with a regular menstrual cycle (controls). Binary logistic regression models were used to analyze the data and correct for known confounders. About 65 women with PCOS and 96 controls were recruited for this purpose. The average birth weight of PCOS women (3357 g) did not differ from the average birth weight of controls (3409 g). Mean age at menarche differed significantly between groups, 13.7 years and 12.8 years (p = 0.006), respectively, for PCOS women and controls. In conclusion, we could not confirm the effect of adverse intrauterine conditions, reflected in birth weight, on developing PCOS. PMID- 27222929 TI - Simple estimation of induced electric fields in nervous system tissues for human exposure to non-uniform electric fields at power frequency. AB - Most results regarding induced current in the human body related to electric field dosimetry have been calculated under uniform field conditions. We have found in previous work that a contact current is a more suitable way to evaluate induced electric fields, even in the case of exposure to non-uniform fields. If the relationship between induced currents and external non-uniform fields can be understood, induced electric fields in nervous system tissues may be able to be estimated from measurements of ambient non-uniform fields. In the present paper, we numerically calculated the induced electric fields and currents in a human model by considering non-uniform fields based on distortion by a cubic conductor under an unperturbed electric field of 1 kV m(-1) at 60 Hz. We investigated the relationship between a non-uniform external electric field with no human present and the induced current through the neck, and the relationship between the current through the neck and the induced electric fields in nervous system tissues such as the brain, heart, and spinal cord. The results showed that the current through the neck can be formulated by means of an external electric field at the central position of the human head, and the distance between the conductor and the human model. As expected, there is a strong correlation between the current through the neck and the induced electric fields in the nervous system tissues. The combination of these relationships indicates that induced electric fields in these tissues can be estimated solely by measurements of the external field at a point and the distance from the conductor. PMID- 27222930 TI - A unique presentation of acute liver failure from herpes simplex virus hepatitis. AB - We present the case of a patient, with history of myelodysplastic syndrome and recent bone marrow transplant, who developed fulminant liver failure secondary to herpes simplex virus (HSV) hepatitis. His presentation was unique, as findings of liver microabscesses on computed tomography scan have not been described previously in this patient population. Despite initial treatment with acyclovir, he continued to deteriorate, and later sensitivities found the HSV strain to be resistant to acyclovir. HSV hepatitis with secondary liver failure is rare and, without appropriate treatment, its mortality is >80%. Early suspicion and immediate therapy are the keys to improve patient survival. PMID- 27222931 TI - Isoform-Selective HDAC Inhibitor Therapy for Transplantation: Are We Ready for HDAC6? PMID- 27222932 TI - Inhibition of Histone Deacetylase 6 Reveals a Potent Immunosuppressant Effect in Models of Transplantation. AB - BACKGROUND: Current transplant immunosuppression regimens have numerous limitations. Recent evidence suggests histone deacetylase inhibitors (HDACis) may represent a class of drug with immunosuppressive properties. This study compares cyclosporin A (CyA) with the pan-HDACi suberoylanilide hydroxamic acid (SAHA) and a novel HDAC6-specific inhibitor (KA1010) in models of alloreactivity. METHODS: Proliferation and mixed lymphocyte reaction (MLR)-based assays were used to determine the immunosuppressive effect of compounds, and a murine model of allogeneic skin transplantation was adopted to assess the in vivo effects of HDAC6 inhibition. RESULTS: KA1010 displayed superior inhibitory effects on the activation of peripheral mononuclear cells using in vitro models of transplantation. In a 1-way MLR, KA1010 (5 MUMU) reduced parent cell proliferation from 92% to 64% (P = 0.001). A 2-way MLR, adopting IFN-gamma production as a marker of alloresponse, resulting in up to 91% reduction. Dose response curves revealed dose-dependent profiles with greater potency of HDACis over CyA (IC50 values of 82.0 nM and 13.4 nM for KA1010 and SAHA).Mice treated with KA1010 displayed no significant features of skin allograft rejection upon histological analysis at 70 days and graft survival of 80% in subjects treated with 160 mg/kg. Immunological assessment, revealed a significant increase in CD4CD25forkhead box P3 regulatory T cells (from 18% to 25%, P = 0.0002) and a corresponding reduction in CD4 T cells (from 58% to 42%, P = 0.0009). CONCLUSIONS: HDAC6 may represent an optimal target for future immunosuppressant therapeutics with a particular role in transplantation. In this article, we have demonstrated a superior immunosuppressive effect of KA1010 over both CyA and SAHA, in the models of allotransplantation adopted. PMID- 27222933 TI - Graft-Derived IL-6 Amplifies Proliferation and Survival of Effector T Cells That Drive Alloimmune-Mediated Vascular Rejection. AB - BACKGROUND: IL-6 is an inflammatory cytokine that controls effector T cell responses but the mechanisms by which it controls allogeneic immune responses and vascular rejection that leads to transplant arteriosclerosis (TA) are poorly understood. METHODS: We have examined the mechanism by which IL-6 contributes to the pathogenesis of vascular rejection and TA using a murine aortic interposition model of vascular rejection. RESULTS: The absence of IL-6 production from artery graft cells reduced the development of vascular rejection and arteriosclerotic thickening. There was no apparent effect of donor-derived IL-6 on endothelial cell integrity or on the intimal accumulation of smooth muscle cells, macrophages, and anti-donor antibodies. However, reduced vascular pathology in IL 6 artery grafts was accompanied by a significant reduction in the accumulation of CD4 and CD8 T cells. Further, the absence of graft-derived IL-6 resulted in a significant decrease in the activation and proliferation of alloreactive CD4 and CD8 T cells after transplantation as well as in a marked increase in cell death of effector T cells. Alloreactive effector T cells that expanded in the absence of IL-6 were also more susceptible to Fas-mediated activation-induced cell death in vitro. Finally, systemic neutralization of IL-6R did not reduce arteriosclerotic thickening but reduced endothelial integrity in allograft arteries, indicating differential effects of specific elimination of IL-6 in graft cells and systemic IL-6 neutralization. CONCLUSIONS: Donor-derived IL-6 amplifies the expansion of allogeneic T cell responses that cause vascular rejection and TA by increasing T cell proliferation and preventing Fas-mediated T cell death. PMID- 27222934 TI - Anti-Angiotensin II Type 1 Receptor and Anti-Endothelial Cell Antibodies: A Cross Sectional Analysis of Pathological Findings in Allograft Biopsies. AB - BACKGROUND: This is a cross-sectional study designed to evaluate the histologic characteristics of graft injury in the presence of anti-angiotensin II type 1 receptor antibody (AT1R-Ab) and anti-endothelial cell antibody (AECA). METHODS: Non-HLA antibody testing was included in the posttransplant evaluation for 70 kidney recipients. Biopsies were performed for cause for 47 patients and as protocol for the remaining 23 patients. Biopsy-proven rejection was defined according to the Banff 2009-2013 criteria. AT1R-Ab was measured on an ELISA platform. Patients were divided into 3 groups based on AT1R-Ab levels (>17, 10 17, and <10 U/ml). AECA was evaluated using an endothelial cell crossmatch (ECXM) in patients whose HLA antibody level was insufficient to cause a positive flow cytometric crossmatch. RESULTS: AT1R-Ab levels were higher in patients diagnosed with antibody mediated rejection compared to those with no rejection (P = 0.004). Glomerulitis (g) and peritubular capillaritis (ptc) scores were independently correlated with increased AT1R-Ab concentrations in the presence or absence of HLA-DSA (P = 0.007 and 0.03 for g scores; p = 0.005 and 0.03 for ptc scores). Patients with a positive ECXM had higher AT1R-Ab levels compared to those with a negative ECXM (P = 0.005). Microcirculation inflammation (MCI = g + ptc score) was higher in patients with a positive ECXM and with AT1R-Ab >17 U/ml, although this did not reach statistical significance (P = 0.07). CONCLUSIONS: The data show an association between non-HLA antibodies detected in the ECXM and AT1R ELISA and microvascular injury observed in antibody mediated rejection. PMID- 27222935 TI - Neurological Complications Involving the Central Nervous System After Allogeneic Hematopoietic Stem Cell Transplantation During a Period of Evolution in Transplant Modalities: A Cohort Analysis. AB - BACKGROUND: Neurological complications (NC) after hematopoietic stem cell transplantation (HSCT) are rare events. The evolution of transplant procedures has resulted in improved survival and has allowed elderly patients or those with comorbidity to receive an HSCT. The risk of NC in these patients has still not been well defined. Therefore, we carried out an observational study to estimate the occurrence and identify the risks associated with NC. METHODS: The study cohort included 452 adult-allogeneic HSCT recipients, transplanted from 1997 to 2012. The median follow up was 1.3 year (0-15.7). A myeloablative regimen was used in 307 patients. Two hundred patients were grafted from matched unrelated donor (MUD), of these, 129 (64.5%) received an in vivo T-cell depletion. RESULTS: Out of 452 patients, 30 (6.6%) developed NC. Infections were the most frequent causes of NC (30%). Overall survival decreased in patients developing NC (P < 0.001). Univariate survival regression on the cumulative incidence of NC identified period of transplant, linear trend between 4-year periods (1997-2012) (P < 0.001), MUD (P < 0.001), and recipient's age (P = 0.034) as significant risk factors. In multivariate analysis, period of transplant (P < 0.001) and MUD (P = 0.004) remained significant independent risk factors. Matched unrelated donor recipients showed a 3.8-fold elevated risk of developing NC. CONCLUSIONS: Analysis highlights a temporal trend of incidence of NC that progressively increased over time and confirms a strong association between donor type and risk of NC. Our observations suggest that, although relatively uncommon, NC after allo HSCT, may become more frequent due to the improved overall survival in recent years. PMID- 27222936 TI - Pair correlations that link the hydrophobic and Hofmeister effects. AB - The Hofmeister effect describes how different ions make solutes more or less hydrophobic. The effect is thought to occur due to structural changes in the solvent induced by the ion's presence, particularly in water. In this study, the structural changes in water due to the presence of ions are investigated by molecular dynamics simulations of various monatomic ions in the SPC/E water model. Structural analyses reveal specific orientations of solvating waters around each of the ions studied. Using a new method, these orientations are quantified by a set of pair correlation functions that describe dipole-ion correlations in structure. These correlations are shown to contribute to the potential of mean force between waters and the ion of interest, and therefore to the free energy of the system. The magnitude of this free energy is found to result in a Hofmeister series for the various ions studied, therefore demonstrating a Hofmeister effect with respect to water's structure that is quantified by pair correlation functions. Most crucially, the pair correlations that lead to this Hofmeister effect also contribute to the hydrophobic effect (the entropy of hydrophobic solvation) [Liu et al., J. Chem. Phys., 2015, 142, 114117], and those which dominate the hydrophobic effect are modulated by an ion's presence, therefore demonstrating a mechanistic link between the two effects. PMID- 27222937 TI - Determination of amino acids in urine of patients with prostate cancer and benign prostate growth. AB - Prostate cancer is the leading type of cancer diagnosed in men. Serum prostate specific antigen levels and digital rectal exam are far from perfect when it comes to differentiation of patients with prostate cancer and benign prostatic hyperplasia. In this study, we attempt to determine whether amino acids can be used as prostate cancer biomarkers. Concentrations of derivatized amino acids and amines were quantified by liquid chromatography tandem mass spectrometry. A total of 100 urine samples from the two groups including samples provided before and after prostate massage were examined quantitatively for amino acid and amine concentrations with 50 urine samples collected from cancer patients and 50 samples from patients diagnosed with benign prostatic hyperplasia. Arginine, homoserine, and proline were more abundant in urine samples of cancer patients compared with arginine, homoserine, and proline levels determined in urine collected from patients with benign growth. We also show that sarcosine is not a definitive indicator of prostate cancer when analyzed in urine samples collected either before or after prostate massage. PMID- 27222938 TI - Metformin, other antidiabetic drugs, and endometrial cancer risk: a nested case control study within Italian healthcare utilization databases. AB - Metformin may reduce the risk of endometrial cancer whereas other drugs for the treatment of type 2 diabetes mellitus appear to increase it, although the evidence is still limited. We investigated this issue using data from a nested case-control study within the healthcare utilization databases of the Lombardy Region, Italy. This study included 376 diabetic women with endometrial cancer and 7485 diabetic controls matched for cases on age, date at cohort entry, and duration of follow-up. We used conditional logistic regression models to estimate the odds ratio (OR) of endometrial cancer in relation to use of antidiabetic drugs, adjusted for the Charlson's comorbidity index, selected medical conditions, prescription of selected drugs, and concomitant use of other antidiabetic drugs. At cohort entry, no significant associations were observed for metformin [OR=0.99, 95% confidence interval (CI) 0.80-1.23], sulfonylureas (OR=1.14, 95% CI 0.91-1.42), insulin (OR=0.72, 95% CI 0.34-1.56), and other antidiabetic drugs (OR=1.21, 95% CI 0.75-1.95). When we considered use during follow-up, a borderline significant excess risk was found for metformin (OR=1.30, 95% CI 1.00-1.70). However, this estimate decreased to 1.07 (95% CI 0.82-1.41) when taking into account BMI using a Monte Carlo sensitivity analysis. No significant associations were found for sulfonylureas (OR=1.16, 95% CI 0.91 1.47), thiazolidinediones (OR=0.77, 95% CI 0.48-1.24), repaglinide (OR=1.32, 95% CI 0.94-1.87), incretins (OR=1.21, 95% CI 0.63-2.32), and insulin (OR=1.19, 95% CI 0.82-1.71). Our data indicate that metformin, insulin, and other antidiabetic drugs did not meaningfully affect the risk of endometrial cancer. PMID- 27222940 TI - A novel method for determining the relation between nasal polyposis and oxidative stress: the thiol/disulphide homeostasis. AB - CONCLUSION: It is thought that oxidative stress may be the major cause of the increase in the oxide thiol form in the study group. The relationship between oxidative stress status and dynamic thiol/disulphide in nasal polyposis now needs to be investigated. OBJECTIVES: The purpose of this study was to evaluate the relation between nasal polyposis and thiol/disulphide homeostasis, used as a marker of oxidative stress, by measuring that exchange using a novel technique. MATERIALS AND METHODS: The study group consisted of 40 patients (mean age = 46.75 +/- 13.92 years) with bilateral nasal polyposis patients admitted to the hospital. The control group consisted of 31 (mean age = 43.20 +/- 5.68 years) age, sex, and body mass index matched healthy subjects. Thiol/disulphide homeostasis concentrations were measured using a newly-developed method (Erel & Neselioglu). RESULTS: Native thiol and total thiol levels were lower in the study group compared to the control group (native thiol = 415.8 +/- 69.1 MUmol/L vs 448.7 +/- 37.5 MUmol/L, p < 0.05; total thiol = 449.02 +/- 72.0 MUmol/L vs 477.28 +/- 44.5 MUmol/L, p < 0.05, respectively). Disulphide level and the disulphide/native thiol and disulphide/total thiol ratios were higher in the study group compared to the control group (disulphide = 16.58 +/- 5.04 MUmol/L vs 14.28 +/- 5.3 MUmol/L, p < 0.05; disulphide/native thiol ratio = 4.07 +/- 1.52% vs 3.14 +/- 1.04%, p < 0.05, disulphide/total thiol ratio = 3.73 +/- 1.23% vs 2.94 +/- 0.92%, p < 0.05, respectively). PMID- 27222939 TI - Lung cancer screening with low-dose spiral computed tomography: evidence from a pooled analysis of two Italian randomized trials. AB - The benefits and harms of lung cancer (LC) screening with low-dose computed tomography (LDCT) are debatable. Positive results from the US National Lung Screening Trial were not evident in the European trials, possibly due to their smaller sample sizes. To address this issue, we conducted a patient-level pooled analysis of two Italian randomized controlled trials. Data from DANTE and MILD trials were combined for a total of 3640 individuals in the LDCT arm and 2909 in the control arm. LC and overall mortality were analyzed using multivariate hazard ratios (HRs) and log-rank tests stratified by study. The median follow-up was 8.2 years, with a total of 30 480 person-years in the LDCT arm and 22 157 in the control arm. A total of 192 patients developed LC in the LDCT arm and 105 in the control arm. Half of the LC cases in the LDCT arm had stage IA or IB cancer, as compared with 21% in the control arm. Overall mortality rates/100 000 person years were 925 in the LDCT arm and 1074 in the control arm, and LC mortality rates were 299 and 357, respectively. The multivariate pooled overall mortality HR was 0.89 (95% confidence interval: 0.74-1.06) and the LC mortality HR was 0.83 (95% confidence interval: 0.61-1.12) for the LDCT arm as compared with the control arm. The present pooled analysis shows a nonsignificant 11% reduction in overall mortality in individuals undergoing LDCT screening as compared with the control arm. A pooled analysis of all European trials would be a useful contribution to assess the real benefit of LDCT screening. PMID- 27222941 TI - No blank cheques. AB - His complaint is always that nurses - or at least their trade unions - are a greedy, ungrateful bunch who never say thank you. So Mr Clarke, thank you for your success in finding an extra L138.5 million to fund this year's pay award and the impact of clinical grading. PMID- 27222942 TI - More cash***. AB - Health Secretary, Kenneth Clarke, has pledged an extra L138.5 million to help cover the cost of the nurses' pay award. PMID- 27222943 TI - Clarke evades talks. AB - Talks between unions and management on clinical grading broke down last week as the Conservative Party assembled in Brighton for their conference. PMID- 27222945 TI - Midwives keep no strike clause. AB - Royal College of Midwives members have voted against abandoning their no strike clause in the first ballot to be held on the subject. PMID- 27222944 TI - ... But mixed reactions. AB - The announcement of extra cash to cover the nurses' pay award was broadly welcomed by health authorities and politicians, but many reactions were marked by fears that the allocation may still be insufficient. PMID- 27222946 TI - Project 2000 guidelines. AB - Health authority managers were issued last week with guidance from the Department of Health on how they should proceed on the implementation of Project 2000. PMID- 27222947 TI - Clarke's enterprise zone. AB - Health Secretary, Kenneth Clarke, delivered a warning to the NHS to be 'more business like' when he addressed the Conservative Party Conference in Brighton last week. PMID- 27222948 TI - Theatre nurses angry over grading exercise. AB - Anger and frustration surfaced last week as theatre nurses met in Harrogate to discuss the latest developments in the clinical grading exercise. PMID- 27222949 TI - Care standards project gets cash boost. AB - Ann Poole, Chief Nursing Officer for the Department of Health announced last week that the Royal College of Nursing's research work on standards of care will receive an extra L183,193 from the Government. PMID- 27222950 TI - RCN Orders recruitment and mobility survey. AB - The Royal College of Nursing has commissioned the Institute of Manpower Studies to carry out an independent survey into the the attitudes of nurses to recruitment, retention and career mobility. PMID- 27222952 TI - [Not Available]. AB - The winners and runners up in Nursing Standard/IHG's Nurse '88 awards gathered in London recently hr a VIP dinner to mark their achievements. Beverly Gratwohl, Mary Knox and Theresa Gregory, winners in each of the three categories were presented with their awards for clinical excellence by Anne Poole, Chief Nursing Officer at the Department of Health. PMID- 27222951 TI - Consultants propose plan for better funding. AB - Consultants in Birmingham claim their skills are not being fully utilised because the regional cash crisis means they have had to cut down on the number of patients they treat. PMID- 27222953 TI - School nurse link for health services. AB - The health of schoolchildren is being left to chance because there is no national policy for school health services, the Health Visitors Association claims. PMID- 27222954 TI - Community care minister? AB - The Society of Family Practitioner Committees has called on the Government to appoint a Minister with a direct responsibility for the implementation of community care. PMID- 27222955 TI - Back to back injury. AB - The results of two compensation claims made by back injured nurses against their employers last week highlight the continuing blight of this injury on the profession. The claims, which resulted in one success and one failure, coincide with the launch of this week's national 'Think Back Week'. PMID- 27222956 TI - Supporting roles. AB - Disaster plans are necessary to help hospitals deal with the victims of a major accident, but there are no rules to help nurses cope with the most difficult moments after a tragedy, a conference heard. PMID- 27222958 TI - Labour priorities for the NHS. AB - Nurses will play a key role in tomorrow's NHS by providing a service which prioritises caring and enabling, says a major new Labour document. PMID- 27222957 TI - On the upward trend. AB - This summer, after five years, the first term of the UK Central Council for Nursing, Midwifery and Health Visiting came to an end. As new members of the Council prepare to take up office, Nursing Standard looks at the past achievements and future priorities of the UKCC. PMID- 27222959 TI - Ageing process on multidisciplinary course. AB - A pioneering multi-disciplinary course on ageing has now started at the Age Concern Institute of Gerontology. PMID- 27222961 TI - Heart disease booklets. AB - A new range of booklets explaining the dangers of high cholesterol and other factors behind heart disease is now available to nurses and patients. PMID- 27222962 TI - MPs give strong backing to AIDS charity. AB - MPs have responded positively to a call to support ACET, the newest AIDS charity in Britain. PMID- 27222960 TI - Raising race consciousness. AB - New initiatives to tackle nursing in Britain's multi-racial and multi-cultural society are being launched by the RCN. PMID- 27222963 TI - Holiday helpers needed. AB - Holiday Helpers, a scheme which provides volunteers to take disabled and elderly people on holiday, is calling out for nurses to accompany the growing number of people wanting to take advantage of the scheme. PMID- 27222964 TI - [Not Available]. AB - Lights, camera, action: - School Nurses on the set at Dulwich hospital. The Health Visitors Association and Royal College of Nursing working together on a video explaining the role of the school nurse. PMID- 27222966 TI - London takes stock of a blood crisis. AB - A regional blood transfusion centre which successfully averted an imminent supply crisis has warned that current donor shortages may cause another emergency. PMID- 27222965 TI - A question of choice. AB - The British Geriatrics Society has told the Government's NHS review that patients must be able to choose where and how they are treated. PMID- 27222967 TI - Community chair. AB - A new Chair of Community Nursing is to be established at the University of Liverpool. PMID- 27222968 TI - Sound and vision. AB - The winner of the 1988 David Scott Blackball Memorial Award received her S600 prize from Junior Health Minister, Edwina Currie. PMID- 27222969 TI - Call for condoms for prisoners. AB - Newly released Government statistics indicate that AIDS and HIV infection are spreading into the heterosexual community. PMID- 27222970 TI - Memorial service. AB - A memorial service for Dame Elizabeth Cockayne, formerly Chief Nursing Officer at the DoH will take place on October 31. PMID- 27222971 TI - Bulletin clinical grading. AB - Over the previous weeks both sides had agreed to visit six different hospitals and see continuing responsibility in action - the issue being who is in overall charge of a ward and whether, as nurses claim, this is sometimes shared between at least two people. For many sisters and charge nurses the result of this discussion would mean the difference between a grade F and a G. PMID- 27222972 TI - Royal liverpool celebrates ten years service. AB - Hundreds of staff, patients, visitors and well wishers, joined in to celebrate the Royal Liverpool Hospital's 10th birthday observed earlier this month. PMID- 27222973 TI - Market research for scottish health service. AB - Public opinion on the Scottish Health Service is to be assessed by two new Government commissioned initiatives. PMID- 27222974 TI - New maternity unit for yorkshire. AB - A major L1 million maternity unit opened its doors to mothers to be in the Yorkshire area recently. PMID- 27222975 TI - Diabetic resource centre for nottinghamshire. AB - Central Nottinghamshire Health Authority has now officially opened its first resource centre for diabetics. PMID- 27222976 TI - Ne Thames and the NHS story. AB - North East Thames Regional Health Authority has produced a colourful wallchart which explains how the NHS works and why it was set up. PMID- 27222977 TI - Senior nurse takes first prize. AB - First prize in this year's 3M Infection Control Awards has gone to John Rogers, Senior Infection Control Nurse at Southampton General Hospital. PMID- 27222978 TI - Consent issue poses new questions. AB - A breast cancer patient who complained to her regional health authority when she learned she had been involved in clinical trials, has been told her consultant acted properly although he did not seek her consent. PMID- 27222980 TI - Peptic ulcer awareness campaign. AB - A new initiative into health education has been launched to increase the public's awareness of peptic ulcer, a disease which currently affects one in ten people. PMID- 27222979 TI - High blood pressure linked to childhood. AB - High blood pressure may have its origins in childhood, according to the results of a new geographical study. PMID- 27222981 TI - Allergic reaction to disinfectant. AB - Hundreds of theatre nurses using the popular disinfectant, [Illegible Word] taraldehyde, are suffering allergic reaction, delegates at the conference heard. PMID- 27222982 TI - Theatre is not nursing, says students' survey. AB - Student nurses still see operating theatres as unfriendly places where little real nursing care takes place, the NATN conference was told. PMID- 27222983 TI - ODAs should be given a key role. AB - Operating department assistants should have a key role beside the operating table and not just in anaesthetic and recovery according to Bernice McFadden-West, member of the Education Committee of the NATN. PMID- 27222984 TI - Down's syndrome test. AB - A new blood test has been developed to detect. Down's syndrome in unborn babies. PMID- 27222985 TI - Beating sleep disturbance. AB - Children with mental handicap wake more frequently at night than most children, leaving their parents exhausted and stressful, surveys have shown. PMID- 27222986 TI - Hope for haemophiliacs. AB - A 25 year old man with haemophilia is the first person in the UK to receive a genetically engineered blood clotting agent, which experts believe will eventually offer haemophiliacs hope of a permanent cure. PMID- 27222987 TI - Cancer helpline AIDS nurses. AB - A new cancer helpline is providing nurses with a mine of information to use to help their patients, a recent survey has revealed. PMID- 27222988 TI - More education for diabetes nurses. AB - Diabetes nurse specialists must press for an advanced education programme or the speciality will never develop, an annual meeting of diabetes nurses heard. PMID- 27222989 TI - Misleading patch tests. AB - Are patch tests for contact sensitivity always reliable? PMID- 27222990 TI - Dietary dangers. AB - Patients receiving anticoagulants should seek medical advice before making major dietary changes, according to doctors in Salford. PMID- 27222991 TI - Masking pain. AB - Non-steroidal anti-inflammatory drugs ( NSAIDs ) may not only contribute to peptic ulceration but also mask the pain which leads to diagnosis. PMID- 27222992 TI - HIV and genital ulcers. AB - Genital ulcers are linked to the spread of HIV infection, according to researchers from the University of Washington. PMID- 27222993 TI - Eye sign. AB - Observing whether patients close their eyes during examination for abdominal pain may help identify those with non- organic disease. PMID- 27222994 TI - The radical. AB - When her colleagues suggested to Gayle Quick that it was about time they had some enrolled nurse representation on the English. National Board, she took the plunge and is now, at 25, the youngest member serving on it. PMID- 27222995 TI - The psychiatric nurse. AB - It is doubtful whether a grandfather has ever before been described as a nurse of the future but Jim McCarthy is 43, has been a milkman, a railway signalman and a lorry driver, and is an 18-stone grandad. RCN Congress delegates may recall him giving the final speech at Brighton this year heralded by Ravel's Bolero. PMID- 27222997 TI - The academic. AB - As a nurse practitioner at the Oxford Nursing Development Unit, Richard McMahon has as good an opportunity as any to develop innovative clinical practice. PMID- 27222996 TI - The midwife. AB - At 30, Amanda Hallums is Acting Head of Maternity Services for Waltham Forest, a position she has reached with unusual speed. Although, in fact, a senior tutor in midwifery at Whipps Cross in Leytonstone, she seems to have assumed the mantle of further responsibility without major problems so far. PMID- 27222998 TI - The political activist. AB - As a member of RCN Council at the age of 28 and one not afraid to speak her mind, Sally Gooch is already a familiar name to many, though she has only just qualified as a health visitor in Tower Hamlets Health Authority. PMID- 27222999 TI - The health visitor. AB - It was Gillian Southall who, at the recent TUC- conference, put forward the Health Visitors Association motion on national food policy which was accepted unanimously. PMID- 27223000 TI - China. AB - Health care in the People's Republic of China emphasises primary health care and disease prevention. It is also an interesting example of a country where two very different types of medicine seem to co-exist peacefully. PMID- 27223001 TI - Choose wisely. AB - Surprisingly little information is available on how to choose the optimal number and mix of nursing staff. PMID- 27223002 TI - A little of what you fancy. AB - Agency nursing is often perceived as 'moonlighting'. However, many nurses are seeing it as a career opportunity in its own right nowadays. PMID- 27223003 TI - Lean on me. AB - Our booklet on the role of the mentor was written to support and encourage newly qualified nurses in their new-found relationship with learner nurses. PMID- 27223004 TI - Haemostasis. PMID- 27223005 TI - The cream of nursing care. AB - Devon has long been a favourite holiday destination for those who enjoy some of the finer things in life; beautiful scenery, a less hurried lifestyle, deserted beaches and those famous, delicious Devon cream teas which seem to beg the description 'naughty but nice'. PMID- 27223006 TI - On unequal terms. AB - Hopelessness, frustration, anger, and even apathy, are all feelings which may be experienced by a nurse working in the primary health care field when reading through the last report of the now disbanded Health Education Council - 'The health divide' ( 1 ). PMID- 27223007 TI - Listings. PMID- 27223008 TI - Intra-aortic balloon pumps. AB - The use of balloon pumps was first established in the late 1960s as a means of providing mechanical support when a patient's circulation is failing. A balloon assists cardiac function by increasing myocardial oxygen supply and demand. PMID- 27223010 TI - Island in the sun. AB - For the last three months of 1987 I was fortunate in having the opportunity of being seconded, through the Overseas Development Administration, to the Government of St Helena. My terms of reference for this secondment were. PMID- 27223009 TI - No one at home. AB - The typical image most I people have of a I homeless person is of a single, middle aged man, Irish or Scottish and a heavy drinker!' This description can be extended to make him someone who skippers (sleeps rough) and lives in a cardboard box, a common but misleading image. My purpose here is to describe the range of homelessness, and, hopefully, stimulate interest. To paint as detailed a picture as possible, I will break with my working practice and describe clients and problems in groups. PMID- 27223011 TI - Flood of tears. AB - Little did Jane Robertson know what was in store when she went to dinner at the Grand Hotel in Khartoum on August 4 after spending two months working out in the dry bushland of Sudan. PMID- 27223014 TI - How to manage examination stress. AB - Examination stress can be managed. Stress management programmes can be developed to meet the needs of individual students with anxiety and concentration problems. PMID- 27223015 TI - Twenty years on. AB - I wonder if you could help me to contact a group of nurses who were in the December 1968 PTS at Crumpsall Hospital (North Manchester Hospital). I have managed to contact six of them, and we are hoping to have a 20 year reunion at the end of January. PMID- 27223016 TI - Parking grief. AB - I have just spent 30 frustrating minutes attempting to remove a 'Don't park here or else!' sticker obliterating my car window. My sin? Leaving the car in a parking space reserved for consultants. PMID- 27223017 TI - Sheffield reunion. AB - Calling all members of the class of December 1968 from the Northern General Hospital, Sheffield. PMID- 27223018 TI - Third world campaign. AB - Your readers may be interested in knowing that VSO will be holding a publicity campaign in Scotland in November and December. The campaign is a chance for people to come and talk to us about the opportunities available to them to work in Third World countries. We have a wide range of interesting and challenging jobs in long-term development in health work. PMID- 27223019 TI - Board decisions. AB - As a newly elected member of the English National Board for Nursing, Midwifery and Health Visiting, it is with regret that I find it necessary to inform my colleagues among the professions of the Board's decision to elect members outside the profession on to the body of the Investigating Committee. This in effect reverses the previous Board's decision upholding the rights of individuals who have been reported for any alleged breach of the UKCC Code of Professional Conduct, to be judged at the investigatory stage by their peers. PMID- 27223020 TI - Fair play. AB - I wish to draw your attention to my experience of grading for nurses. For the last seven years I have been a ward sister of a 'heavy' psychogeriatric ward. For six of those years I was the sister-in-charge. PMID- 27223021 TI - Headhunters. AB - Was it really necessary for the RCN to engage headhunters (Michael Page Partnership: International Recruitment Consultants) to find a General Secretary Designate to succeed Trevor Clay? PMID- 27223022 TI - Software nurse. AB - Within this hospital we are using a software package called Nurse 1, a nursing personnel and ward management tool, and would be interested to hear from any other hospitals using this system. Please contact Mr David Adams, Long Grove Hospital, Horton Lane, Epsom KT19 8PU Tel 03727- 26200 Assistant Director of Nursing Services Long Grove Hospital. PMID- 27223023 TI - Cease fire. AB - As the 'pay off' in the clinical regrading finally arrives, may I make a plea for a return to normal speaking relations among different groups of nurses? PMID- 27223024 TI - Home improvements. AB - Home is quite the wrong word, in many cases, to describe the NHS accommodation that many nurses are forced to occupy because of low pay, high rent, impossible mortgage rates and difficulties in commuting. PMID- 27223025 TI - Wrong grading. AB - Does the fact that the regrading of nurses depends on what a nurse was doing on April 1 have the same significance to you as it does to me? Just who [Illegible word] April fool? As a non nurse with several nurse relations, it seems to me that the powers- that-be have wasted time and energy thinking up a high- faluting and senseless way of regrading nurses. PMID- 27223026 TI - Clouded vision. AB - As someone who classes themselves as being on the 'active' fringe of the RCN, it gives me a certain satisfaction that the future General Secretary of this organisation might take a passing interest in my opinions. PMID- 27223027 TI - A patients' advocate. AB - For listeners to London Broadcasting, watchers of BBC TV's 'Choices' and readers of the Royal College of Nursing Commission's report 'The Health Challenge', Rabbi Julia Neuberger will need no introduction. But her extensive involvement in health matters, and nursing in particular, is less publicised. PMID- 27223028 TI - Directions. AB - Throughout time, accidents, major and minor, have happened. Some involved only one person, others on a devastatingly large scale took their toll on dozens of people. In the last several decades, setting aside the numbers of wars within or between nations, few people, proportionately, could be truly unaware of the increase of violence in heretofore quiet and peaceful communities. PMID- 27223029 TI - Watchdog. AB - Q I have recently secured a post as a non-teaching assistant/ RGN (registered general nurse) at a school for children with learning difficulties. PMID- 27223030 TI - No smoke without fire. AB - Is passive smoking about to become a thing of the past? If an American manufacturer has its way quite possibly. PMID- 27223031 TI - Plight of the navigator. AB - It was a sunny day in Shetland and two senior Royal College of Nursing Officers were waiting for their plane back to the mainland after an exhaustive and most valuable tour of community mental handicap services in the highlands and islands. With a couple of hours to kill, they hired a car and drove out to see the sea. Arms folded across chests and, no doubt, Fingal's Cave blasting out over the in car entertainment system, they sat down to enjoy the sunshine and the view across the bay. PMID- 27223032 TI - Russian doubletalk. AB - Next time the doctor visits your ward on his rounds, don't be surprised if he looks underneath all the beds. PMID- 27223033 TI - A Bogey role. AB - So there she was, poor Megan, (oh come on, we know you all watch Casualty on BBC1) all burned out and weeping on to the shoulder of the department's director (who was about to collapse with a cardiac arrest, but that's another story). PMID- 27223034 TI - RCN sweep stake. AB - While the national press continues to concentrate on nurses' pay and the future of the NHS, Nursing Standard brings you the latest developments on the real debate. PMID- 27223035 TI - Tackling health pests with posters. AB - An eye-catching poster, tackling the subject of lice and scabies is now available, free, to practice nurses, community nurses and health visitors. PMID- 27223037 TI - Heated mattresses for operating tables. AB - A new type of infrared, thermolayer operating table mattress is now available from leading hospital bed manufacturers, Nesbit Evans. PMID- 27223036 TI - 'Green light for new drug. AB - A new drug, aimed at helping people with arthritis and gastric problems, has just received its UK licence. PMID- 27223038 TI - 'See-through' alternative to stitches. AB - A transparent skin closure system, offering additional benefits to other 'Steri Strip' products, is now on the market. According to the manufacturers 3M Health Care, 'Steri-Strip Primaclear' has greater strength and a semi-rigid carrier eliminating curling during application. Contact 3M Health Care, 3M House, Morley Street, Loughborough, Leicestershire LE11 1EP. Tel: 0509 611 611. PMID- 27223039 TI - Giving fat the funny treatment. AB - A new video, showing the reduction of cardiovascular risk in hy-pertensive patients, uses humour to convey its serious message. PMID- 27223040 TI - Cheaper electric controlled beds. AB - An electrically powered surgical bed is the latest addition to the Hoskins range of surgical beds. PMID- 27223041 TI - Community spirit. PMID- 27223042 TI - PM help sought to save national lottery. AB - The Prime Minister is being urged to step in and save the National Health Lottery, which could be outlawed if new proposals go ahead. Mrs Thatcher has already praised the lottery which could raise up to L40 million a year for the NHS. A combination of 100 local lotteries, it was designed to offer prizes of between L50,000 and L200,000 a week. PMID- 27223044 TI - Mp lobbies opposition to regional pay offer. AB - The Scottish National Party has challenged two of the Government's Scottish ministers to oppose the proposed regional pay plan for nurses. PMID- 27223043 TI - Democrat calls for anonymous screening. AB - Archy Kirkwood, Democrat Health, Education and Welfare Convenor, has called for anonymous HIV screening of all blood samples. PMID- 27223045 TI - Health proviso for income support. AB - Health and well-being will be considered when determining whether 16 and 17 year olds are entitled to income support, Social Security Minister Nicholas Scott, has announced. PMID- 27223047 TI - Hyper. PMID- 27223046 TI - * New rules to govern cold weather payments. AB - Social Security Minister Nicholas Scott, has announced that extra cash will be available during cold spells to help certain people pay their heating bills. PMID- 27223048 TI - Laparoscopic Versus Open Hysterectomy for Benign Disease in Women with Giant Uteri (>=1500 g): Feasibility and Outcomes. AB - STUDY OBJECTIVE: To evaluate perioperative outcomes and complications of laparoscopic hysterectomy (LH) in women with giant uteri (>=1.5 kg) compared with open abdominal hysterectomy (AH), which is considered the reference. DESIGN: A retrospective analysis of prospectively collected data (Canadian Task Force Classification II-2). SETTING: An academic research center. PATIENTS: All consecutive women who underwent hysterectomy for uteri weighing >=1500 g (total = 51) between 2000 and 2015 were analyzed. Twenty-seven (53%) patients had been scheduled for the laparoscopic approach (LH), whereas 24 (48%) had been scheduled for AH. INTERVENTIONS: Hysterectomy +/- mono/bilateral salpingo-oophorectomy. MAIN OUTCOME MEASURES: Perioperative details, incidence, severity, and type of complications were analyzed according to surgical approach (AH vs LH). We also evaluated the trends over time in terms of perioperative outcomes. RESULTS: AH was associated with a shorter operative time (97.5 vs 160 minutes, p = .004) compared with LH. Blood loss (200 vs 225 mL, p = .21) and the decrease in postoperative hemoglobin (-1.2 vs -1.1, p = .89) were similar between AH and LH. Intra- and postoperative complications were similar between the 2 groups; however, hospital stay was significantly shorter in the LH group (median = 3 days vs 1 day, p < .001). A significant trend toward a progressive increase in the use of the minimally invasive approach was registered through the years (p = .001). Parallel to this increase, we observed a significant reduction in terms of length of stay. Moreover, a decrease in the total number of complications, mainly because of a decrease in the rate of early minor events, was observed through the years. CONCLUSIONS: Our experience shows that LH can be considered a feasible procedure, even in cases of uteri >=1.5 kg, with significant advantages over open surgery in terms of postoperative hospital stay. PMID- 27223049 TI - Toward the Development of Specific G-Quadruplex Binders: Synthesis, Biophysical, and Biological Studies of New Hydrazone Derivatives. AB - G-Quadruplex-binding compounds are currently perceived as possible anticancer therapeutics. Here, starting from a promising lead, a small series of novel hydrazone-based compounds were synthesized and evaluated as G-quadruplex binders. The in vitro G-quadruplex-binding properties of the synthesized compounds were investigated employing both human telomeric and oncogene promoter G-quadruplexes with different folding topologies as targets. The present investigation led to the identification of potent G-quadruplex stabilizers with high selectivity over duplex DNA and preference for one G-quadruplex topology over others. Among them, selected derivatives have been shown to trap G-quadruplex structures in the nucleus of cancer cells. Interestingly, this behavior correlates with efficient cytotoxic activity in human osteosarcoma and colon carcinoma cells. PMID- 27223050 TI - Crystal Orientation Controlled Photovoltaic Properties of Multilayer GaAs Nanowire Arrays. AB - In recent years, despite significant progress in the synthesis, characterization, and integration of various nanowire (NW) material systems, crystal orientation controlled NW growth as well as real-time assessment of their growth-structure property relationships still presents one of the major challenges in deploying NWs for practical large-scale applications. In this study, we propose, design, and develop a multilayer NW printing scheme for the determination of crystal orientation controlled photovoltaic properties of parallel GaAs NW arrays. By tuning the catalyst thickness and nucleation and growth temperatures in the two step chemical vapor deposition, crystalline GaAs NWs with uniform, pure ?110? and ?111? orientations and other mixture ratios can be successfully prepared. Employing lift-off resists, three-layer NW parallel arrays can be easily attained for X-ray diffraction in order to evaluate their growth orientation along with the fabrication of NW parallel array based Schottky photovoltaic devices for the subsequent performance assessment. Notably, the open-circuit voltage of purely ?111?-oriented NW arrayed cells is far higher than that of ?110?-oriented NW arrayed counterparts, which can be interpreted by the different surface Fermi level pinning that exists on various NW crystal surface planes due to the different As dangling bond densities. All this indicates the profound effect of NW crystal orientation on physical and chemical properties of GaAs NWs, suggesting the careful NW design considerations for achieving optimal photovoltaic performances. The approach presented here could also serve as a versatile and powerful platform for in situ characterization of other NW materials. PMID- 27223051 TI - Organization of the connections between claustrum and cortex in the mouse. AB - The connections between the claustrum and the cortex in mouse are systematically investigated with adeno-associated virus (AAV), an anterograde viral tracer. We first define the boundary and the three-dimensional structure of the claustrum based on a variety of molecular and anatomical data. From AAV injections into 42 neocortical and allocortical areas, we conclude that most cortical areas send bilateral projections to the claustrum, the majority being denser on the ipsilateral side. This includes prelimbic, infralimbic, medial, ventrolateral and lateral orbital, ventral retrosplenial, dorsal and posterior agranular insular, visceral, temporal association, dorsal and ventral auditory, ectorhinal, perirhinal, lateral entorhinal, and anteromedial, posteromedial, lateroposterior, laterointermediate, and postrhinal visual areas. In contrast, the cingulate and the secondary motor areas send denser projections to the contralateral claustrum than to the ipsilateral one. The gustatory, primary auditory, primary visual, rostrolateral visual, and medial entorhinal cortices send projections only to the ipsilateral claustrum. Primary motor, primary somatosensory and subicular areas barely send projections to either ipsi- or contralateral claustrum. Corticoclaustral projections are organized in a rough topographic manner, with variable projection strengths. We find that the claustrum, in turn, sends widespread projections preferentially to ipsilateral cortical areas with different projection strengths and laminar distribution patterns and to certain contralateral cortical areas. Our quantitative results show that the claustrum has strong reciprocal and bilateral connections with prefrontal and cingulate areas as well as strong reciprocal connections with the ipsilateral temporal and retrohippocampal areas, suggesting that it may play a crucial role in a variety of cognitive processes. J. Comp. Neurol. 525:1317-1346, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27223054 TI - How Physicians Get Their Medical Care. PMID- 27223053 TI - Thrombomodulin reduces tumorigenic and metastatic potential of lung cancer cells by up-regulation of E-cadherin and down-regulation of N-cadherin expression. AB - Thrombomodulin (TM) is an endothelial cell membrane protein and plays critical roles in anti-thrombosis, anti-inflammation, vascular endothelial protection, and is traditionally regarded as a "vascular protection god". In recent years, although TM has been reported to be down-regulated in a variety of malignant tumors including lung cancer, the role and mechanism of TM in lung cancer are enigmatic. In this study, we found that induction of TM overexpression by cholesterol-reducing drug atorvastatin significantly diminished the tumorigenic capability of the lung cancer cells. Moreover, we demonstrated that TM overexpression caused G0/G1 phase arrest and markedly reduced the colony forming capability of the cells. Furthermore, overexpression of TM inhibited cell migration and invasion. Consistently, depletion of TM promoted cell growth, reduced the cell population at the G0/G1 phase, and enhanced cell migratory ability. Mechanistic study revealed that TM up-regulated E-cadherin but down regulated N-cadherin expression, resulting in reversal of epithelial-mesenchymal transition (EMT) in the lung cancer cells. Moreover, silencing TM expression led to decreased E-cadherin and increased N-cadherin. Taken together, our study suggests that TM functions as a tumor suppressive protein, providing a conceptual framework for inducing TM overexpression as a sensible strategy and approach for novel anti-lung cancer drug discovery. PMID- 27223052 TI - Proteomic profile of circulating immune complexes in chronic Chagas disease. AB - Immune complexes (ICs) are the direct and real-time products of humoral immune responses. The identification of constituent foreign or autoantigens within ICs might bring new insights into the pathology of infectious diseases. We applied immune complexome analysis of plasma to the study of Chagas disease caused by Trypanosoma cruzi. Twenty seropositive plasma samples including cardiac and/or megacolon determinate patients (n = 11) and indeterminate (n = 9) were analysed along with 10 seronegative individuals to characterize the antigens bound to circulating ICs. We identified 39 T. cruzi antigens and 114 human autoantigens specific to patients with Chagas. Among those antigens, two T. cruzi antigens (surface protease GP63, glucose-6-isomerase) and six human autoantigens (CD180 antigen, ceruloplasmin, fibrinogen beta chain, fibrinogen beta chain isoform 2 preprotein, isoform gamma-A of fibrinogen gamma-chain, serum paraoxonase) were detected in more than 50% of the patients tested. Human isoform short of complement factor H-related protein 2 and trans-sialidase of T. cruzi were more frequently found in the indeterminate (5/9 for both) compared with in the determinate Chagas (0/11, P = 0.046 for human, 1/11, P = 0.0498 for T. cruzi). The immune complexome could illustrate the difference of immune status between clinical forms of chronic Chagas disease. PMID- 27223055 TI - Cues/Tips. PMID- 27223056 TI - Endocrine problems in women. PMID- 27223057 TI - Secondary amenorrhea. PMID- 27223058 TI - Problems+Solutions. AB - Readers are invited to submit questions relating to problem cases. Inquiries will be answered by qualified consultants and replies forwarded by mail promptly. Selected problems and solutions are published every month in this section. PMID- 27223061 TI - ZnO nanowire array growth on precisely controlled patterns of inkjet-printed zinc acetate at low-temperatures. AB - ZnO nanowires have been fabricated through the hydrothermal method on inkjet printed patterns of zinc acetate dihydrate. The silicon substrate used was heated accordingly during the printing period in order to maintain good spatial uniformity of the zinc acetate nanoparticles, responsible for the pattern morphology. Printing more than one pass of precursor ink leads to an increase in seed layer thickness that subsequently alters the density and dimensions of nanowires. It has been demonstrated that with the right inkjet-printing parameters and substrate temperature, ZnO nanowires can be effortlessly fabricated in accordance with the desired pattern variations under low temperature and mild conditions that ensures promising applications in optoelectronic devices. PMID- 27223060 TI - Immunotoxic effects of sodium tungstate dihydrate on female B6C3F1/N mice when administered in drinking water. AB - Tungsten is a naturally occurring, high-tensile strength element that has been used in a number of consumer products. Tungsten has been detected in soil, waterways, groundwater, and human tissue and body fluids. Elevated levels of tungsten in urine were reported for populations exposed to tungstate in drinking water in areas where natural tungsten formations were prevalent. Published reports indicated that sodium tungstate may modulate hematopoiesis, immune cell populations, and immune responses in rodent models. The objective of this study was to assess potential immunotoxicity of sodium tungstate dihydrate (STD), a drinking water contaminant. Female B6C3F1/N mice received 0-2000 mg STD/L in their drinking water for 28 d, and were evaluated for effects on immune cell populations in spleen and bone marrow, and humoral-mediated, cell-mediated, and innate immunity. Three different parameters of cell-mediated immunity were similarly affected at 1000 mg STD/L. T-cell proliferative responses against allogeneic leukocytes and anti-CD3 were decreased 32%, and 21%, respectively. Cytotoxic T-lymphocyte activity was decreased at all effector:target cell ratios examined. At 2000 mg STD/L, the absolute numbers of CD3(+) T-cell progenitor cells in bone marrow were increased 86%, but the alterations in B-lymphocyte and other progenitor cells were not significant. There were no effects on bone marrow DNA synthesis or colony forming capabilities. STD-induced effects on humoral mediated immunity, innate immunity, and splenocyte sub-populations were limited. Enhanced histopathology did not detect treatment-related lesions in any of the immune tissues. These data suggest exposure to STD in drinking water may adversely affect cell-mediated immunity. PMID- 27223062 TI - Reactivation of Smac-mediated apoptosis in chronic lymphocytic leukemia cells: mechanistic studies of Smac mimetic. AB - Dysfunctional apoptotic machinery is a hallmark feature of chronic lymphocytic leukemia (CLL). Accordingly, targeting apoptosis regulators has been proven a rational approach for CLL treatment. We show that CLL lymphocytes express high levels of XIAP, cIAP1, and cIAP2 compared to normal lymphocytes. Smac mimetic, Smac066, designed to bind to BIR3-domain of IAPs, induce apoptosis in primary CLL cells (n=71; p<0.0001), irrespective of prognostic markers. Apoptosis was mediated by diminished levels of IAPs (XIAP-p=0.02; cIAP-p<0.0001) and increased activation of caspases-8,-9,-3. The caspase-cleavage was in direct association with the levels of apoptosis (r2=0.8 for caspases-8,-9,-3). Correlative analysis revealed a direct relationship between reduction in IAPs and degree of apoptosis (r2=0.6 (XIAP); 0.5 (cIAP2)). There was a strong association between apoptosis, IAP-degradation, and concurrent caspase-activation. Pan-caspase inhibitor Z-Vad fmk reversed the degradation of Mcl-1, but not IAPs suggesting that smac066 is selective to IAPs, however, Mcl-1 degradation is through caspase-mediated cleavage. Immunoprecipitation experiments revealed physical interaction between caspase-3 and XIAP that was disrupted by smac066. Importantly, XIAP and cIAP2 were markedly induced in bone-marrow and lymph-node microenvironments, providing a basis for IAP antagonists as anti-tumor agents in CLL. Smac066 synergized with ABT-737, revealing a mechanistic rationale to jointly target BH3 and BIR3 domains. PMID- 27223063 TI - Circulating tumor DNA: a promising biomarker in the liquid biopsy of cancer. AB - Tissue biopsy is the standard diagnostic procedure for cancers and also provides a material for genotyping, which can assist in the targeted therapies of cancers. However, tissue biopsy-based cancer diagnostic procedures have limitations in their assessment of cancer development, prognosis and genotyping, due to tumor heterogeneity and evolution. Circulating tumor DNA (ctDNA) is single- or double stranded DNA released by the tumor cells into the blood and it thus harbors the mutations of the original tumor. In recent years, liquid biopsy based on ctDNA analysis has shed a new light on the molecular diagnosis and monitoring of cancer. Studies found that the screening of genetic mutations using ctDNA is highly sensitive and specific, suggesting that ctDNA analysis may significantly improve current systems of tumor diagnosis, even facilitating early-stage detection. Moreover, ctDNA analysis is capable of accurately determining the tumor progression, prognosis and assisting in targeted therapy. Therefore, using ctDNA as a liquid biopsy may herald a revolution for tumor management. Herein, we review the biology of ctDNA, its detection methods and potential applications in tumor diagnosis, treatment and prognosis. PMID- 27223064 TI - Oncogene FOXK1 enhances invasion of colorectal carcinoma by inducing epithelial mesenchymal transition. AB - Transcriptional factor FOXK1 is a member of the FOX family, involved in the cell growth and metabolism. The higher expression of FOXK1 leads to a variety of diseases and may play an important role in the development of various tumors. However, the role of FOXK1 in the progression of colorectal cancer (CRC) remains unknown. We demonstrated that FOXK1 was overexpressed in 16 types of solid tumor tissues via tissue multi-array (TMA). We found that FOXK1 induced elevated expressions and transactivities of five major oncogenes in CRC. Moreover, the elevated expression of FOXK1 was showed to be correlated with tumor progression and was a significant predictor of overall survival in CRC patients. Furthermore, it was showed that the depletion of FOXK1 expression could inhibit the migratory and invasive abilities of CRC cells. In contrast, ectopic expression of FOXK1 elicited the opposite effects on these phenotypes in vitro. FOXK1 promoted tumor metastasis through EMT program induction. In addition, TGF-beta1 induced FOXK1 expression in a time-dependent pattern and the knockdown of FOXK1 inhibited TGF beta1-induced EMT. In vivo, higher expression of FOXK1 promotes CRC cell invasion and metastasis, and induces EMT in CRC as well. Alltogether, it was concluded that the higher expression of FOXK1 could indicate a poor prognosis in CRC patients since that FOXK1 induces EMT and promotes CRC cell invasion in vitro and in vivo. PMID- 27223065 TI - Prognostic value of preoperative serum lactate dehydrogenase levels for resectable gastric cancer and prognostic nomograms. AB - The present study aimed to evaluate the prognostic significance of preoperative serum lactate dehydrogenase (SLDH) levels for resected gastric cancer and construct prognostic nomograms for risk prediction. The study cohort consisted of 619 patients with D2-resected gastric cancer. The relationship of SLDH levels with clinicopathological features and clinical outcomes was evaluated. Prognostic nomograms were created using identified prognosticators to predict 3-year overall survival (OS) and 3-year disease-free survival (DFS), and bootstrap validation was performed. High SLDH levels were correlated with old age but not depth of invasion or lymph node metastasis. When assessed as a continuous variable, high SLDH levels were independently associated with poor OS and DFS. Internal validation of the developed nomograms revealed good predictive accuracy (bootstrap-corrected concordance indices: 0.77 and 0.75, respectively for prediction of OS and DFS). The preoperative SLDH levels, an identified unfavorable prognosticator, were incorporated into nomograms along with other clinicopathological features to refine the prediction of clinical outcomes for patients with D2-resected gastric cancer. PMID- 27223066 TI - SCD1 is associated with tumor promotion, late stage and poor survival in lung adenocarcinoma. AB - The discovery of Warburg effect opens a new era in anti-cancer therapy. Aerobic glycolysis is regarded as a hallmark of cancer cells and increasing literatures indicates that metabolic changes are critical for the maintenance and progression of cancer cells. Besides aerobic glycolysis, increased fatty acid synthesis is also required for the rapid growth of cancer cells, and is considered as one of the most typical metabolic symbols of cancer either. Thus, targeting fatty acid metabolism may provide a potential avenue for the diagnosis and therapeutic treatment of cancer. In this study, we have identified Sterol-CoA desaturase-1 (SCD1) which is the rate-limiting enzyme of unsaturated fatty acid synthesis, universally and highly expressed in lung adenocarcinoma and was required for the cell proliferation, migration and invasion. Both in vitro and in vivo studies demonstrated that high expression of SCD1 remarkably enhanced the ability of tumor formation and invasion, while knockdown of SCD1 significantly repressed tumorigenesis and induced cell apoptosis. Clinical association study suggested that high expression of SCD1 is more frequently observed in late stage patients and presents poor prognosis. Taken together, our results suggested that SCD1 is a potentially novel biomarker of lung adenocarcinoma, and targeting SCD1 may represent a new anti-cancer strategy. PMID- 27223068 TI - Urine gamma-synuclein as a biomarker for the diagnosis of bladder cancer. AB - Gamma-synuclein (SNCG) is secreted from tumor cells and elevated in the urine of bladder cancer (BCa) patients, however, the diagnostic and prognostic values of urine SNCG for BCa remain unknown. Here, we used enzyme immunoassay and western blotting to measure urine SNCG levels. Patients with BCa or other urological diseases and healthy controls were enrolled at four Chinese hospitals from April 2010 to November 2014. Diagnostic performance was evaluated by analyzing the area under receiver operating characteristic curves (AUROCs). The AUROC was 0.903 +/- 0.019 (95% confidence interval [CI], 0.867 - 0.940) for the test and 0.929 +/- 0.015 (95% CI, 0.901 - 0.958) for the validation cohort. The optimal cutoff value yielded sensitivities of 68.4%, 62.4% and specificities of 97.4%, 97.8% for the test and validation cohort, respectively. Urine SNCG levels were decreased after tumor resection, but were higher in BCa patients with recurrence than those without (P = 0.001). The urine SNCG levels in patients with urological benign diseases were significantly lower than BCa patients (all P < 0.05) but higher than healthy controls (all P < 0.05). Hematuria did not interfere with the SNCG detection by spiking urine specimens with whole blood. Compared with a nuclear matrix-protein-22 assay in an additional cohort excluding hematuria, SNCG showed a similar sensitivity and higher specificity. In summary, our results demonstrated that urine SNCG can discriminate BCa from urinary diseases, and is a useful prognosticator of postsurgical recurrence. PMID- 27223069 TI - Higher methylation intensity induced by EBV LMP1 via NF-kappaB/DNMT3b signaling contributes to silencing of PTEN gene. AB - Phosphatase and tensin homolog (PTEN) is a major tumor suppressor and usually silenced via the deletion, insertion and mutation. We previously discovered its inactivation via aberrant CpG island methylation. Here, we provide further evidence that EBV latent membrane protein 1(LMP1) can induce a higher intensity of DNA methylation at PTEN CpG islands, inactivating PTEN at the cellular and molecular level. Initially, increased methylation intensity of PTEN CpG islands was observed in EBV-infected nasopharyngeal carcinoma (NPC) cells, accompanied by decreased PTEN expression. In NPC tissue samples showing the methylation at PTEN promoter, LMP1 was highly expressed in higher methylation intensity group relative to lower intensity group, and DNA methyltransferase 3b (DNMT3b) expression was positively correlated with LMP1 expression. Moreover, transfection of LMP1 gene into EBV-negative NPC cells demonstrated that LMP1 up-regulated DNMT3b expression, leading to a higher intensity of PTEN CpG island methylation. Mechanistically, computational prediction and luciferase reporter assay identified a functional NF-kappaB binding site on DNMT3b promoter and the mutated NF-kappaB binding site abolished LMP1-mediated DNMT3b activation. Chromatin immunoprecipitation displayed that NF-kappaB p65 subunit constitutively bound to DNMT3b promoter, supporting the activation of DNMT3b by EBV LMP1 via NF-kappaB signaling. Furthermore, the expression level of DNMT3b was observed to be increased in the nuclei of LMP1-expressing NPC cells, and a NF-kappaB inhibitor, PDTC, counteracted LMP1-mediated DNMT3b overexpression. Thus, this study first reports that LMP1-mediated NF-kappaB can up-regulate DNMT3b transcription, thereby leading to relatively higher methylation intensity at PTEN CpG islands, and ultimately silencing major tumor suppressor PTEN. PMID- 27223070 TI - Differential association for N-acetyltransferase 2 genotype and phenotype with bladder cancer risk in Chinese population. AB - BACKGROUND: N-acetyltransferase 2 (NAT2) is involved in both carcinogen detoxification through hepatic N-acetylation and carcinogen activation through local O-acetylation. NAT2 slow acetylation status is significantly associated with increased bladder cancer risk among European populations, but its association in Asian populations is inconclusive. METHODS: NAT2 acetylation status was determined by both single nucleotide polymorphisms (SNPs) and caffeine metabolic ratio (CMR), in a population-based study of 494 bladder cancer patients and 507 control subjects in Shanghai, China. RESULTS: The CMR, a functional measure of hepatic N-acetylation, was significantly reduced in a dose-dependent manner among both cases and controls possessing the SNP-inferred NAT2 slow acetylation status (all P-values<5.0*10-10). The CMR-determined slow N acetylation status (CMR<0.34) was significantly associated with a 50% increased risk of bladder cancer (odds ratio = 1.50, 95% confidence interval = 1.10-2.06) whereas the SNP-inferred slow acetylation statuses were significantly associated with an approximately 50% decreased risk of bladder cancer. The genotype-disease association was strengthened after the adjustment for CMR and was primarily observed among never smokers. CONCLUSIONS: The apparent differential associations for phenotypic and genetic measures of acetylation statuses with bladder cancer risk may reflect dual functions of NAT2 in bladder carcinogenesis because the former only measures the capacity of carcinogen detoxification pathway while the latter represents both carcinogen activation and detoxification pathways. Future studies are warranted to ascertain the specific role of N- and O-acetylation in bladder carcinogenesis, particularly in populations exposed to different types of bladder carcinogens. PMID- 27223071 TI - Percutaneous computed tomography-guided cryoablation for recurrent retroperitoneal soft tissue sarcoma: a study of safety and efficacy. AB - AIMS: To evaluate the use of computed tomography image-guided percutaneous cryoablation for recurrent retroperitoneal soft tissue sarcomas (RPSs). RESULTS: Adverse events were limited to grades 1 and 2, included fever (n = 19), local pain (n = 11), emesis (n = 10), frostbite (n = 6), and nerve injury (n = 1). Fever was more frequent in the large tumor group (15.8%) than in small tumor group (1.9%) (P = 0.008). Median PFS and OS were 37.0 +/- 7.7 months (range, 4-39 months) and 43.0 +/- 5.9 months (range, 6-54 months), respectively. PFS and OS were significantly longer in the small tumor group than in the large tumor group (P = 0.011 and P = 0.015, respectively), but the response rate (82.7% vs. 72.8%, P = 0.240) did not differ significantly. On univariate analysis, tumor size, tumor invasion grade, and distant metastasis were significant prognostic factors for PFS and OS. On multivariate analysis, a tumor size >=10 cm was an independent negative prognostic factor for PFS and OS after cryoablation (HR: 3.98, 95% CI: 1.27-12.50, P = 0.018 and HR: 4.33, 95% CI: 1.41-13.26, P = 0.010, respectively). MATERIALS AND METHODS: Data from 72 patients with recurrent RPSs who underwent percutaneous cryoablation were reviewed retrospectively. The prognostic factors for progression-free survival (PFS), overall survival (OS), and efficacy based on mRECIST criteria were analysis. Adverse events were compared according to tumor size (<10 and >=10 cm). CONCLUSION: Minimally invasive percutaneous cryoablation was safe and efficacious for recurrent RPSs. PMID- 27223072 TI - Comprehensive genomic profiling of IgM multiple myeloma identifies IRF4 as a prognostic marker. AB - Immunoglobulin M multiple myeloma (IgM MM) is an extremely rare subtype of multiple myeloma with a poor clinical outcome. In this study, bone marrow aspirates of MM patients, including two cases of IgM MM, were analyzed by whole exome sequencing and RNA sequencing. Recurrent somatic mutations in the NRAS, KRAS, CCND1, DIS3, and TP53 genes were found in IgM MM and other types of MM, in agreement with previous studies. Overall transcription profiles of IgM and other types of MM clustered together, but separate from normal blood or peripheral plasma cells. Among the differentially expressed genes in IgM MM, IRF4 was highly expressed in IgM as well as in a subset of other types of MM patients. Thus, IRF4 is an independent prognostic factor for general MM patients. Taken together, the somatic mutation and transcriptome profiles support the idea that IgM MM can be classified as an aggressive MM subtype. PMID- 27223073 TI - MicroRNA-138 acts as a tumor suppressor in non small cell lung cancer via targeting YAP1. AB - MicroRNA (miR)-138 was found to have suppressive effects on the growth and metastasis of different human cancers. In this study, we aimed to investigate the regulatory mechanism of miR-138 in non-small cell lung cancer (NSCLC). We applied the Quantitative real-time PCR (qRT-PCR) to detect the miR-138 levels in NSCLC tissues (n=21) and cell lines, Bioinformatical predication, luciferase reporter assay and western blot to identify the target gene of miR-138. We also applied Cell transfection, MTT, transwell, and wound healing assays to reveal the role of miR-138 in NSCLC cell proliferation and malignant transformation. We observed that miR-138 expression level was significantly decreased in NSCLC tissues compared to their matched adjacent normal tissues. It was also downregulated in tissues with poor differentiation, advanced stage or lymph nodes metastasis, as well as in several NSCLC cell lines compared to normal lung epithelial cell. We further identified YAP1 as a direct target gene of miR-138, and observed that the protein level of YAP1 was negatively mediated by miR-138 in NSCLC A549 cells. Moreover, overexpression of miR-138 significantly inhibited A549 cell growth, invasion and migration, while knockdown of miR-138 enhanced such capacities. Further investigation showed that the cell proliferation capacity was higher in the miR-138+YAP1 group, when compared with that in the miR-138 group, suggesting that overexpression of YAP1 rescued the suppressive effects of miR-138 upregulation on NSCLC cell proliferation. However, we found no difference of cell invasion and migration capacities between miR-138+YAP1 group and miR-138 group. Finally, YAP1 was markedly upregulated in NSCLC tissues compared to their marched adjacent normal tissues. Its mRNA levels were reversely correlated with the miR 138 levels in NSCLC tissues. In summary, our study suggests that miR-138 may play a suppressive role in the growth and metastasis of NSCLC cells partly at least by targeting YAP1. PMID- 27223075 TI - A transferrin-target magnetic/fluorescent dual-mode probe significantly enhances the diagnosis of non-small cell lung cancer. AB - To enhance the diagnosis of non-small cell lung cancer (NSCLC), we prepared a dual-modal probe Cy5.5-Tf-Gd-DTPA. Gd-DTPA and near-infrared (NIR) dyes were conjugated to holo-Transferrin (Tf) sequentially, the result of ICP-AES and UV showed 25 Gd ions and 1 Cy5.5 could be loaded per protein, respectively. The calculated longitudinal relaxivity R1 of Cy5.5-Tf-DTPA-Gd was 4.21 mM-1S-1 per Gd while that of Magnevist (Gd-DTPA) was only 4.02 mM-1S-1. Confocal laser scanning microscopy and immunohistochemical analyses revealed that the Cy5.5-Tf-DTPA-Gd was localized and accumulated in cytoplasmic vesicles; the cell toxicity assay showed no apparent toxicity. MR and NIR imaging of mice with subcutaneous H1299 xenografte tumors following intravenous injection of Cy5.5-Tf-DTPA-Gd revealed a strong positive contrast of the tumors, which caused a longer lasting enhancement of the MRI signal and fluorescence signal. Taken together, these studies indicate that Cy5.5-Tf-DTPA-Gd could be a good agent for MR/NIRF dual mode applications to detect both tumor in situ and its metastasis. PMID- 27223074 TI - MLN4924 suppresses neddylation and induces cell cycle arrest, senescence, and apoptosis in human osteosarcoma. AB - Neddylation is a post-translational protein modification process associated with carcinogenesis and cancer development. MLN4924, a pharmaceutical neddylation inhibitor, induces potent anti-cancer effects in multiple types of cancers. In this study, we investigated the effects of MLN4924 on human osteosarcoma (OS). Levels of both NEDD8 activating enzyme E1 (NAE1) and ubiquitin-conjugating enzyme E2M (Ube2M), two critical components of the neddylation pathway, were much higher in OS tissues and cells than in normal osseous tissues and cells. MLN4924 treatment led to DNA damage, reduced cell viability, senescence and apoptosis in OS cells. Moreover, MLN4924 inhibited OS xenograft tumor growth in mice. Mechanistically, MLN4924 blocked the neddylation of cullins and induced accumulation of several tumor-suppressive substrates of Cullin-RING E3 ubiquitin ligases (CRLs), including CDT1, Wee1, p21, p27, Noxa, and p16. These results suggest clinical studies investigating the utility of MLN4924 for the treatment of OS are warranted. PMID- 27223076 TI - Activin B promotes endometrial cancer cell migration by down-regulating E cadherin via SMAD-independent MEK-ERK1/2-SNAIL signaling. AB - High-risk type II endometrial cancers account for ~30% of cases but ~75% of deaths due, in part, to their tendency to metastasize. Histopathological studies of type II endometrial cancers (non-endometrioid, mostly serous) suggest overproduction of activin B and down-regulation of E-cadherin, both of which are associated with reduced survival. Our previous studies have shown that activin B increases the migration of type II endometrial cancer cell lines. However, little is known about the relationship between activin B signaling and E-cadherin in endometrial cancer. We now demonstrate that activin B treatment significantly decreases E-cadherin expression in both a time- and concentration-dependent manner in KLE and HEC-50 cell lines. Interestingly, these effects were not inhibited by knockdown of SMAD2, SMAD3 or SMAD4. Rather, the suppressive effects of activin B on E-cadherin were mediated by MEK-ERK1/2-induced production of the transcription factor SNAIL. Importantly, activin B-induced cell migration was inhibited by forced-expression of E-cadherin or pre-treatment with the activin/TGF-beta type I receptor inhibitor SB431542 or the MEK inhibitor U0126. We have identified a novel SMAD-independent pathway linking enhanced activin B signaling to reduced E-cadherin expression and increased migration in type II endometrial cancer. PMID- 27223077 TI - Everolimus induces Met inactivation by disrupting the FKBP12/Met complex. AB - Inhibition of the mechanistic target of rapamycin (mTOR) is a promising treatment strategy for several cancer types. Rapamycin derivatives such as everolimus are allosteric mTOR inhibitors acting through interaction with the intracellular immunophilin FKBP12, a prolyl isomerase with different cellular functions. Although mTOR inhibitors have significantly improved survival of different cancer patients, resistance and lack of predictive factors of response remain unsolved issues. To elucidate the mechanisms of resistance to everolimus, we evaluated Met activation in everolimus-sensitive/resistant human cancer cells, in vitro and in vivo. Biochemical and computational analyses were performed. Everolimus-resistant cells were xenografted into mice (10/group) and studied for their response to everolimus and Met inhibitors. The statistical significance of the in vitro results was evaluated by Student's t test.Everolimus reduced Met phosphorylation in everolimus-sensitive cells. This event was mediated by the formation of a Met FKBP12 complex, which in turn is disrupted by everolimus. Aberrant Met activation in everolimus-resistant cells and overexpression of wild-type/mutant Met caused everolimus resistance. Pharmacological inhibition and RNA silencing of Met are effective in condition of everolimus resistance (P<0.01). In mice xenografted with everolimus-resistant cells, the combination of everolimus with the Met inhibitor PHA665752 reduced tumor growth and induced a statistically significant survival advantage (combination vs control P=0.0005).FKBP12 binding is required for full Met activation and everolimus can inhibit Met. Persistent Met activation might sustain everolimus resistance. These results identify a novel everolimus mechanism of action and suggest the development of clinical strategies based on Met inhibitors in everolimus-resistant cancers. PMID- 27223078 TI - Predictors of long-term response to abiraterone in patients with metastastic castration-resistant prostate cancer: a retrospective cohort study. AB - We aimed to identify clinical predictors of long-term response to abiraterone (defined as >12 months drug exposure) in a retrospective cohort of metastatic castration-resistant prostate cancer patients treated in post-docetaxel setting at 24 Italian centers. The Cox proportional hazards model was used to analyze the association between clinical features and the duration of drug exposure. Results were expressed as hazard ratios (HR) with associated 95% confidence intervals (CI). A total of 143 patients met the inclusion criteria. Their median age was 73 years, median Gleason score 8 and median abiraterone exposure 20 months. At the univariate analysis, a significant correlation with the duration of abiraterone exposure was found for Gleason score (HR 0.82, 95% CI 0.71-0.96; p=0.012), PSA (HR 1.10, 95% CI 1.03-1.18; p=0.08) and lactic dehydrogenase levels (HR 1.22, 95% CI 1.02-1.46; p=0.027), while the association between lower alkaline phosphatase levels and treatment duration was marginally significant (HR 1.07, 95% CI 0.99 1.16; p=0.074). Only PSA and Gleason score were predictive of long-term treatment duration in the multivariate analysis. No other clinical factors resulted to be predictive of sustained response to abiraterone, including metastatic disease at diagnosis and visceral disease, suggesting that all subgroups of patients may derive a substantial clinical benefit from abiraterone treatment. These findings need to be validated in prospective, larger studies. PMID- 27223079 TI - Future paradigms for precision oncology. AB - Research has exposed cancer to be a heterogeneous disease with a high degree of inter-tumoral and intra-tumoral variability. Individual tumors have unique profiles, and these molecular signatures make the use of traditional histology based treatments problematic. The conventional diagnostic categories, while necessary for care, thwart the use of molecular information for treatment as molecular characteristics cross tissue types.This is compounded by the struggle to keep abreast the scientific advances made in all fields of science, and by the enormous challenge to organize, cross-reference, and apply molecular data for patient benefit. In order to supplement the site-specific, histology-driven diagnosis with genomic, proteomic and metabolomics information, a paradigm shift in diagnosis and treatment of patients is required.While most physicians are open and keen to use the emerging data for therapy, even those versed in molecular therapeutics are overwhelmed with the amount of available data. It is not surprising that even though The Human Genome Project was completed thirteen years ago, our patients have not benefited from the information. Physicians cannot, and should not be asked to process the gigabytes of genomic and proteomic information on their own in order to provide patients with safe therapies. The following consensus summary identifies the needed for practice changes, proposes potential solutions to the present crisis of informational overload, suggests ways of providing physicians with the tools necessary for interpreting patient specific molecular profiles, and facilitates the implementation of quantitative precision medicine. It also provides two case studies where this approach has been used. PMID- 27223080 TI - Pre-clinical efficacy and synergistic potential of the MDM2-p53 antagonists, Nutlin-3 and RG7388, as single agents and in combined treatment with cisplatin in ovarian cancer. AB - Ovarian cancer is the fifth leading cause of cancer-related female deaths. Due to serious side effects, relapse and resistance to standard chemotherapy, better and more targeted approaches are required. Mutation of the TP53 gene accounts for 50% of all human cancers. In the remaining malignancies, non-genotoxic activation of wild-type p53 by small molecule inhibition of the MDM2-p53 binding interaction is a promising therapeutic strategy. Proof of concept was established with the cis imidazoline Nutlin-3, leading to the development of RG7388 and other compounds currently in early phase clinical trials. This preclinical study evaluated the effect of Nutlin-3 and RG7388 as single agents and in combination with cisplatin in a panel of ovarian cancer cell lines. Median-drug-effect analysis showed Nutlin-3 or RG7388 combination with cisplatin was additive to, or synergistic in a p53-dependent manner, resulting in increased p53 activation, cell cycle arrest and apoptosis, associated with increased p21WAF1 protein and/or caspase-3/7 activity compared to cisplatin alone. Although MDM2 inhibition activated the expression of p53-dependent DNA repair genes, the growth inhibitory and pro apoptotic effects of p53 dominated the response. These data indicate that combination treatment with MDM2 inhibitors and cisplatin has synergistic potential for the treatment of ovarian cancer, dependent on cell genotype. PMID- 27223081 TI - Efficacy of epidermal growth factor receptor inhibitors in combination with chemotherapy in advanced non-small cell lung cancer: a meta-analysis of randomized controlled trials. AB - The role of a combination of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and chemotherapy for non-small-cell lung cancer (NSCLC) has not been well established. To clarify this problem, we performed a meta analysis with 15 studies identified from PubMed, EMBASE and the Cochrane Library. We found that the combined regimen had a significant benefit on progression-free survival (PFS) (hazard ratio (HR) = 0.80; 95% CI = 0.71-0.90; P < 0.001) and the objective response rate (ORR) (RR = 1.35; 95% CI = 1.14-1.59; P < 0.001). However, the combined regimen had no significant impact on overall survival (OS) (HR = 0.96; 95% CI = 0.90-1.03; P = 0.25). Subgroup analysis showed significantly higher OS advantages in EGFR mutation positive patients (P = 0.01), never smokers (P = 0.01), Asian patients (P = 0.02), patients receiving second-line treatment (P < 0.001), and those receiving a sequential combination of EGFR-TKIs and chemotherapy (P = 0.005). The combination regimen showed a higher incidence of grade 3-4 toxicities (leucopenia, neutropenia, febrile neutropenia, anemia, rash, fatigue and diarrhea). In summary, the combination of EGFR-TKIs plus chemotherapy in advanced NSCLC achieved a significantly longer PFS and a higher ORR but not longer OS. Well-designed prospective studies are needed to confirm these findings. PMID- 27223082 TI - Tunneling nanotube formation is stimulated by hypoxia in ovarian cancer cells. AB - In this study, we demonstrated that hypoxic conditions stimulated an increase in tunneling nanotube (TNT) formation in chemoresistant ovarian cancer cells (SKOV3, C200).We found that suppressing the mTOR pathway using either everolimus or metformin led to suppression of TNT formation in vitro, verifying TNTs as a potential target for cancer-directed therapy. Additionally, TNT formation was detected in co-cultures including between platinum-resistant SKOV3 cells, between SKOV3 cells and platinum-chemosensitive A2780 cells, and between SKOV3 cells cultured with benign ovarian epithelial (IOSE) cells; these findings indicate that TNTs are novel conduits for malignant cell interactions and tumor cell interactions with other cells in the microenvironment. When chemoresistant C200 and parent chemosensitive A2780 cells were co-cultured, chemoresistant cells displayed a higher likelihood of TNT formation to each other than to chemosensitive malignant or benign epithelial cells. Hypoxia-induced TNT formation represents a potential mechanism for intercellular communication in ovarian cancer and other forms of invasive refractory cancers. PMID- 27223083 TI - Expression of the extracellular sulfatase SULF2 is associated with squamous cell carcinoma of the head and neck. AB - Sulfatase 2 (SULF2), an extracellular sulfatase that alters sulfation on heparan sulfate proteoglycans, is involved in the tumorigenesis and progression of several carcinomas. SULF2 expression has not been evaluated in squamous cell carcinoma of the head and neck (HNSCC). Here we report results of IHC of SULF2 expression in HNSCC tissue. SULF2 was detected in 57% of tumors (n = 40) with a significant increase in intensity and number of stained cells compared to adjacent cancer-free tissue (p-value < 0.01), increasing with cancer stage when comparing stages 1 and 2 to stages 3 and 4 (p-value 0.01). SULF2 was not detected in epithelial cells of cancer-free controls, and expression was independent of patient demographics, tumor location and etiological factors, smoking and HPV infection by p16 IHC analysis. Sandwich ELISA was performed on serum of HNSCC patients (n = 28) and controls (n = 35), and although SULF2 was detectable, no change was observed in HNSCC. Saliva, collected by mouthwash, from HNSCC patients (n = 8) and controls (n = 8) was also tested by ELISA in a preliminary investigation and an increase in SULF2 was observed in HNSCC (p-value 0.041). Overall, this study shows that SULF2 is increased in HNSCC independent of tissue location (oral cavity, oropharynx, larynx and hypopharynx), patient demographics and etiology. Although no change in SULF2 was detected in HNSCC serum, its detection in saliva makes it worthy of further investigation as a potential HNSCC biomarker. PMID- 27223084 TI - Association of miR-608 rs4919510 polymorphism and cancer risk: a meta-analysis based on 13,664 subjects. AB - Single nucleotide polymorphisms (SNPs) in MicroRNAs (miRNAs) are involved in the mechanism of carcinogenesis. Several studies have evaluated the association of rs4919510 SNP in miR-608 with cancer susceptibility in different types of cancer, with inconclusive outcomes. To obtain a more precise estimation, we carried out this meta-analysis through systematic retrieval from the PubMed and Embase database. A total of 10 case-control studies were analyzed with 6,000 cases and 7,664 controls. The results showed that 4919510 SNP in miR-608 was significantly associated with decreased cancer risk only in recessive model (CC vs. GG+GC: OR=0.89, 95% CI: 0.82-0.97, P=0.009). By further stratified analysis, we found that rs4919510 SNP had some relationship with decreased cancer risk in both homozygote model (CC vs. GG: OR=0.59, 95% CI: 0.36-0.96, P=0.034) and dominant model (CG+ CC vs. GG: OR=0.60, 95% CI: 0.37-0.98, P=0.042) in Caucasians but no relationship in any genetic model in Asians. These results indicated that miR-608 rs4919510 polymorphism may contribute to the decreased cancer susceptibility and could be a promising target to forecast cancer risk for clinical practice. However, to further confirm these results, well-designed large scale case-control studies are needed in the future. PMID- 27223085 TI - Variants in human papillomavirus receptor and associated genes are associated with type-specific HPV infection and lesion progression of the cervix. AB - Human papillomavirus (HPV) infects cervical epithelial cells through cellular membrane receptors, and then induces the initiation and progression of cervical cancer. Single nucleotide polymorphisms (SNPs) may impact the susceptibility and outcome of diseases, but it's still unknown whether variant in HPV receptor and associated genes is associated with type-specific HPV infection and cervical lesion progression. We examined 96 SNPs in 8 genes which may participate in the HPV infection process in 875 samples with HPV negative or single HPV16, 18, 52, 58 positive from 3299 cervical exfoliated cell samples, by Illumina BeadXpress VeraCode platform, and analyzed the correlation between the SNPs and type specific HPV infection and cervical lesions progression. We found rs28384376 in EGFR and rs12034979 in HSPG2 significantly correlated to HPV16 infection; rs2575738, rs2575712, rs2575735 in SDC2 and rs6697265 in HSPG2 significantly correlated to HPV18 infection; rs10510097 in FGFR2, rs12718946 in EGFR significantly correlated to HPV52 infection; rs4947972 in EGFR, rs2981451 in FGFR2, rs2575735 in SDC2 significantly correlated to HPV58 infection. And rs3135772, rs1047057 and rs2556537 in FGFR2, rs12034979 in HSPG2, rs16894821 in SDC2 significantly correlated to cervical lesion progression induced by HPV16 infection; rs6697265 and rs6680566 in HSPG2, rs16860426 in ITGA6 by HPV18 infection; rs878949 in HSPG2, rs12718946 and rs12668175 in EGFR by HPV52 infection; no SNP by HPV58 infection. Our findings suggest that HPV receptor and associated gene variants may influence the susceptibilities to HPV type-specific infection and cervical lesion progression, which might have a potential application value in cervical cancer screening and therapy. PMID- 27223086 TI - Periostin promotes tumor angiogenesis in pancreatic cancer via Erk/VEGF signaling. AB - Pancreatic cancer (PaC) consists of a bulk of stroma cells which contribute to tumor progression by releasing angiogenic factors. Recent studies have found that periostin (POSTN) is closely associate with the metastatic potential and prognosis of PaC. The purpose of this study is to determine the role of POSTN in tumor angiogenesis and explore the precise mechanisms. In this study, we used lentiviral shRNA and human recombinant POSTN protein (rPOSTN) to negatively and positively regulate POSTN expression in vitro. We found that increased POSTN expression promoted the tubule formation dependent on human umbilical vein endothelial cells (HUVECs). Moreover, knockdown of POSTN in PaC cells reduced tumor growth and VEGF expression in vivo. In accordance with these observations, we found that Erk phosphorylation and its downstream VEGF expression were upregulated achieved in rPOSTN-treated groups, opposing results were obversed in POSTN-slienced group. Meanwhile, Erk inhibitor SCH772984 significantly decreased VEGF expression as well as tubule formation of HUVECs in rPOSTN-treated PaC cells. Taken together, these findings suggest that POSTN promotes tumor angiogenesis via Erk/VEGF signaling in PaC and POSTN may be a new target for cancer anti-vascular treatment. PMID- 27223087 TI - Tspan5 is an independent favourable prognostic factor and suppresses tumour growth in gastric cancer. AB - Tetraspanins are believed to interact with specific partner proteins forming tetraspanin-enriched microdomains and regulate some aspects of partner protein functions. However, the role of Tspan5 during pathological processes, particularly in cancer biology, remains unknown. Here we report that Tspan5 is significantly downregulated in gastric cancer (GC) and closely associated with clinicopathological features including tumour size and TNM stage. The expression of Tspan5 is inversely correlated with patient overall survival and is an independent prognostic factor in GC. Upregulation of Tspan5 in tumour cells results in inhibition of cell proliferation and colony formation in vitro and suppression of xenograft growth of GC by reducing tumour cell proliferation in vivo. Thus, Tspan5 functions as a tumour suppressor in stomach to control the tumour growth. Mechanistically, Tspan5 inhibits the cell cycle transition from G1 S phase by increasing the expression of p27 and p15 and decreasing the expression of cyclin D1, CDK4, pRB and E2F1. The correlation of Tspan5 expression with the expression of p27, p15, cyclin D1, CDK4, pRB and E2F1 in vivo are also revealed in xenografted tumours. Reconstitution of either cyclin D1 or CDK4 in Tspan5 overexpressing GC cells rescues the inhibitory phenotype produced by Tspan5, suggesting that cyclin D1/CDK4 play a dominant role in mediating the suppression of tumour growth by Tspan5 in GC. Our results suggest that Tspan5 may serve as a prognostic biomarker for predicting outcome of GC patients and provide new insights into the pathogenesis of GC and rational for the development of clinical intervention strategies against GC. PMID- 27223088 TI - The ratio of hemoglobin to red cell distribution width as a novel prognostic parameter in esophageal squamous cell carcinoma: a retrospective study from southern China. AB - BACKGROUND: We propose a novel prognostic parameter for esophageal squamous cell carcinoma (ESCC)-hemoglobin/red cell distribution width (HB/RDW) ratio. Its clinical prognostic value and relationship with other clinicopathological characteristics were investigated in ESCC patients. RESULTS: The optimal cut-off value was 0.989 for the HB/RDW ratio. The HB/RDW ratio (P= 0.035), tumor depth (P = 0.020) and lymph node status (P<0.001) were identified to be an independent prognostic factors of OS by multivariate analysis, which was validated by bootstrap resampling. Patients with a low HB/RDW ratio had a 1.416 times greater risk of dying during follow-up compared with those with a high HB/RDW (95% CI = 1.024-1.958, P = 0.035). MATERIALS AND METHODS: We retrospectively analyzed 362 patients who underwent curative treatment at a single institution between January 2007 and December 2008. The chi-square test was used to evaluate relationships between the HB/RDW ratio and other clinicopathological variables; the Kaplan Meier method was used to analyze the 5-year overall survival (OS); and the Cox proportional hazards models were used for univariate and multivariate analyses of variables related to OS. CONCLUSION: A significant association was found between the HB/RDW ratio and clinical characteristics and survival outcomes in ESCC patients. Based on these findings, we believe that the HB/RDW ratio is a novel and promising prognostic parameter for ESCC patients. PMID- 27223089 TI - FKBP14 overexpression contributes to osteosarcoma carcinogenesis and indicates poor survival outcome. AB - The FK506-binding protein 14 (FKBP14) is a subfamily of immunophilins, has been implicated in various biochemical processes. However, its effects on the primary malignant bone tumor, osteosarcoma, are unclear. Here, we reported that FKBP14 may be an oncogene as it overexpressed in osteosarcoma tissues and cell lines, and FKBP14 expression was correlated with metastases, recurrence, tumor maximum diameter and poor survival time. FKBP14 was associated with the biological pathways including cell cycle, apoptosis and metastasis. Furthermore, we detected FKBP14 knockdown induced cell cycle arrest, apoptosis, invasion and adhesion in vitro. FKBP14 knockdown decreased the protein levels of PCNA, CDK1 and CCNB1 that promotes cell cycle, increased Bax, caspase-3 and caspase-7 protein involved in promoting cell apoptosis, and increased KIF4A expression as well as decreased SMC4 and TMEM33 proteins that contribute to cell invasion and adhesion. In addition, FKBP14 knockdown also caused a significant inhibition in tumor growth in vivo. Then, we found that the protein RhoA was identified as a binding partner of FKBP14. Taken together, FKBP14 may act as an oncogene in osteosarcoma via suppressing apoptosis and promoting invasion and adhesion in osteosarcoma carcinogenesis. FKBP14 may be a prognostic factor and potential target for osteosarcoma treatment. PMID- 27223090 TI - Activated dendritic cells delivered in tissue compatible biomatrices induce in situ anti-tumor CTL responses leading to tumor regression. AB - Dendritic cell (DC) based anti-cancer immunotherapy is well tolerated in patients with advanced cancers. However, the clinical responses seen after adoptive DC therapy have been suboptimal. Several factors including scarce DC numbers in tumors and immunosuppressive tumor microenvironments contribute to the inefficacy of DCs as cellular vaccines. Hence DC based vaccines can benefit from novel methods of cell delivery that would prevent the direct exposure of immune cells to suppressive tumor microenvironments. Here we evaluated the ability of DCs harbored in biocompatible scaffolds (referred to as biomatrix entrapped DCs; beDCs) in activating specific anti-tumor immune responses against primary and post-surgery secondary tumors. Using a preclinical cervical cancer and a melanoma model in mice, we show that single treatment of primary and post-surgery secondary tumors using beDCs resulted in significant tumor growth retardation while multiple inoculations were required to achieve a significant anti-tumor effect when DCs were given in free form. Additionally, we found that, compared to the tumor specific E6/E7 peptide vaccine, total tumor lysate induced higher expression of CD80 and CD40 on DCs that induced increased levels of IFNgamma production upon interaction with host lymphocytes. Remarkably, a strong immunocyte infiltration into the host-implanted DC-scaffold was observed. Importantly, the host-implanted beDCs induced the anti-tumor immune responses in the absence of any stromal cell support, and the biomatrix structure was eventually absorbed into the surrounding host tissue. Collectively, these data indicate that the scaffold-based DC delivery may provide an efficient and safe way of delivering cell-based vaccines for treatment of primary and post-surgery secondary tumors. PMID- 27223092 TI - Utilizing Risk Readmission Assessment Tool for Nonhospice Palliative Care Consults in Heart Failure Patients. AB - BACKGROUND: Heart failure (HF) affects 5.1 million U.S. citizens with approximately half dying within 5 years of diagnosis, but many never receive palliative care consults or interventions. OBJECTIVE: The purpose of this study was to review medical records of patients admitted and readmitted to the hospital with a primary diagnosis of HF, calculate the risk readmission assessment tool (RRAT) score to determine whether the patient was at high risk, and to determine whether a palliative care consult had been initiated. The tool scoring and medical record review were in retrospect of the hospital admission. METHODS: A retrospective analysis was performed on 70 patients with primary diagnosis of HF who were readmitted at least one time during fiscal year 2012. The RRAT score was calculated on index admission. Patients with high risk scores were assessed for palliative care consult. RESULTS: Forty-nine of the 70 patients scored high risk for readmission at their index admission. The other 21 patients scored moderate risk at the index admission but subsequently scored high risk on their second admission. A total of 35 patients received palliative care consults. Only 10 of those patients received palliative care consults on the index admission. CONCLUSION: Many healthcare providers are unsure when to consult nonhospice palliative care (NHPC) teams for patients with chronic diseases. The findings of this study are important, as they suggest an RRAT can assist with identifying patients with HF in need of NHPC consults. PMID- 27223091 TI - Physical Pain and History of Suicidal Behaviors in Alcohol-Dependent Patients Entering Treatment in Poland. AB - BACKGROUND: Individuals with alcohol use disorders have been shown to be at increased risk for suicidal behaviors and chronic pain. OBJECTIVES: The aim of this study was to conduct initial analyses of the association between current physical pain and the likelihood of suicidal behavior history in alcohol dependent patients entering treatment in Poland. METHODS: A sample of 366 (73.5% men and 26.5% women) participants were recruited from alcohol treatment centers in Warsaw, Poland. Information was obtained about a history of lifetime suicidal behavior, past 4-week pain level, demographics, social functioning, childhood abuse, depressive symptoms, severity of alcohol and sleep problems. RESULTS: A total of 118 individuals (32.2%) reported at least one suicidal behavior during their lifetime. In unadjusted analyses, there was a significant association between a history of lifetime suicidal behavior and a moderate or greater experience of physical pain during the last four weeks. Other variables that were significantly associated with suicidal behaviors were: younger age, history of childhood abuse, depressive symptoms, sleep problems, consequences of drinking, and lower social support. In the multivariate logistic regression analysis, only experience of moderate or greater pain, age, and depressive symptoms remained significantly associated with a history of suicidal behavior. CONCLUSIONS: The experience of physical pain is significantly associated with a lifetime history of suicidal behavior in alcohol-dependent patients. Clinicians should be aware of these associations when conducting assessments and treating alcohol use disorders. PMID- 27223093 TI - PLAGL1 epimutation and bladder exstrophy: Coincidence or concurrent etiology? AB - BACKGROUND: The bladder exstrophy-epispadias complex (BEEC) is characterized by a spectrum of genitourinary malformations. Both classical bladder exstrophy and the most severe phenotype, exstrophy of the cloaca, display omphaloceles, a cardinal anomaly of some disorders caused by altered imprinting. Therefore, we hypothesized that BEEC in some patients could occur on the basis of an undiagnosed imprinting disorder. Such altered imprinting is associated with changes in the parent-of-origin-specific DNA methylation. METHODS: We analyzed the DNA methylation of 54 imprinted loci in 23 selected patients with different BEEC subtypes (epispadias n = 1, classical bladder exstrophy n = 10, exstrophy of the cloaca n = 12) using the Infinium HumanMethylation450 BeadChip. A total of 471,722 not imprinted autosomal CpG loci and 891 imprinted CpG loci were investigated. Findings were corroborated by methylation-specific-multiplex ligation-dependent probe amplification (MS-MLPA) and microsatellite analysis. RESULTS: No significant differences in the DNA methylation of the not imprinted and imprinted CpG were observed depending on subtype of BEEC. Nevertheless, in 1 of the 23 patients who displayed a classical bladder exstrophy, we detected hypomethylation of the imprinted PLAGL1 locus in chromosome 6q24. We verified this hypomethylation by MS-MLPA and showed further the methylation loss to be caused most likely by a mosaic epimutation. CONCLUSION: Considering that it is highly unlikely to detect a PLAGL1 epimutation among 23 individuals given the low incidence of this alteration in the population, our observations further support a link between BEEC and imprinting disorders. Birth Defects Research (Part A) 106:724-728, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27223095 TI - Low-grade inflammation is a major contributor of impaired attentional set shifting in obese subjects. AB - Impairment in cognitive flexibility and set shifting abilities has been described in obesity. This alteration is critical as it can interfere with obesity management strategies. Recent evidences suggest that chronic low-grade inflammation may be involved in cognitive deficits associated with obesity, but the potential involvement in reduced flexibility remains unknown. The objective of this study was to assess the contribution of low-grade inflammation, determined by circulating levels of high-sensitivity C-reactive protein (hsCRP), in reduced cognitive flexibility and shifting abilities of obese subjects relatively to a group of non-obese participants. Performance in the intra/extra dimensional set shift (IED) test, extracted from the CANTAB, was assessed in 66 obese subjects and 20 non-obese participants. Obese subjects with concentrations of hsCRP above 5mg/L exhibited reduced performance on the IED test in comparison to obese subjects with lower levels of hsCRP and non-obese participants. This difference was particularly manifest in the number of errors made during the extra-dimensional shift (EDS errors). In contrast, performance before the extra dimensional shift was spared. Linear regression analyses revealed that the association between obesity and IED alterations was significant only when the condition hsCRP >5mg/L was entered in the model. These findings are important as they indicate that, rather than obesity itself, low-grade inflammation represents a major contributor of IED performance in obese subjects. PMID- 27223094 TI - Antidepressant imipramine diminishes stress-induced inflammation in the periphery and central nervous system and related anxiety- and depressive- like behaviors. AB - In order to relieve anxiety and depression accompanying stress, physicians resort to tricyclic antidepressants, such as imipramine. We had previously shown that imipramine reversed stress-induced social avoidance behavior, and down-regulated microglial activation 24days after stress cessation. To further characterize the effects of imipramine on stress induced neuroimmune dysregulation and associated changes in behavior, the aims of this study were to determine if imipramine 1) ameliorated stress-induced inflammation in the periphery and central nervous system, and 2) prevented stress related anxiety- and depressive-like behaviors. C57BL/6 mice were treated with imipramine (15mg/kg) in their drinking water, and exposed to repeated social defeat (RSD). Imipramine attenuated stress-induced corticosterone and IL-6 responses in plasma. Imipramine decreased the percentage of monocytes and granulocytes in the bone marrow and circulation. However, imipramine did not prevent splenomegaly, stress-related increased percentage of granulocytes in this organ, and the production of pro-inflammatory cytokines in the spleen, following RSD. Moreover, imipramine abrogated the accumulation of macrophages in the brain in mice exposed to RSD. Imipramine blocked neuroinflammatory signaling and prevented stress-related anxiety- and depressive like behaviors. These data support the notion that pharmacomodulation of the monoaminergic system, besides exerting anxiolytic and antidepressant effects, may have therapeutic effects as a neuroimmunomodulator during stress. PMID- 27223096 TI - Intestinal infection associated with future onset of an anxiety disorder: Results of a nationally representative study. AB - Recent research involving mice suggests a possible relationship between intestinal infection and future anxiety-like behavior. However, there has been little epidemiological research showing such a connection in humans. This study uses the Medical Expenditure Panel Survey (MEPS) to assess longitudinally the association between intestinal infection and later onset of an anxiety disorder, through a nationally representative sample. Six 2-year panel datasets, each comprised of 5 consecutive rounds, were pooled from 2007 to 2013 to gather records for all respondents 18years of age or older that did not have an anxiety disorder in Round 1 (n=63, 133 people). Within the study sample, there were 2577 individuals with an intestinal infection in Round 1 and 4239 individuals with an anxiety disorder that began in Round 2, 3, 4, or 5. Overall, intestinal infection in Round 1 was associated with a 1.34 (P<0.01) odds ratio of having an anxiety disorder that began in Round 2, 3, 4, or 5. Separate analyses were performed to determine whether the association applied to other infection types, including respiratory infection, urinary tract infection, hepatitis infection, and skin infection. Respiratory infection was associated with a 1.36 (P<0.01) odds ratio of having an anxiety disorder that began in Round 2, 3, 4, or 5; no other infection type showed a significant association. More research on human populations is needed to examine the apparent association and explore potential mechanisms by which gut pathogens might influence anxiety. PMID- 27223097 TI - Aging and inflammation: Directing traffic through physical activity. PMID- 27223099 TI - Sleep Quality and Health-Related Quality of Life in Pregnancy. AB - The aim of this study was to investigate sleep quality and health-related quality of life in pregnancy. In a cross-sectional design, 492 women (292 pregnant and 200 nonpregnant healthy controls) were included in this study between November 2014 and June 2015. Participants completed a survey on sociodemographic characteristics, the Pittsburgh Sleep Quality Index (PSQI), and the European Quality of Life-5 Dimensions (EQ-5D). The PSQI total and EQ-5D scores of pregnant women were significantly worse than the controls (P = .017 and P < .001, respectively). Linear regression analysis showed that only pregnancy status was related to PSQI scores (beta = .117; P = .009). Compared with the first trimester, the risk of poor sleep quality increased 2.11-fold in the second trimester (P = .048) and 1.86-fold in the third trimester (P = .054). Compared with the first trimester, EQ-5D scores significantly decreased in the second (P = .038) and third (P < .001) trimesters. Sleep quality and health-related quality of life of pregnant women were worse than those of nonpregnant healthy controls. Healthcare professionals need to be aware of deteriorations in sleep quality and health-related quality of life of pregnant women. PMID- 27223100 TI - Analysis of recent failures of disease modifying therapies in Alzheimer's disease suggesting a new methodology for future studies. AB - INTRODUCTION: Pharmaceutical companies and the NIH have invested heavily in a variety of potential disease-modifying therapies for Alzheimer's disease (AD) but unfortunately all double-blind placebo-controlled Phase III studies of these drugs have failed to show statistically significant results supporting their clinical efficacy on cognitive measures. These negative results are surprising as most of these medications have the capability to impact the biomarkers which are associated with progression of Alzheimer's disease. Areas covered: This contradiction prompted us to review all study phases of Intravenous Immunoglobulin (IVIG), Bapineuzumab, Solanezumab, Avagacestat and Dimebolin to shed more light on these recent failures. We critically analyzed these studies, recommending seven lessons from these failures which should not be overlooked. Expert commentary: We suggest a new methodology for future treatment research in Alzheimer's disease considering early intervention with more focus on cognitive decline as a screening tool, more sophisticated exclusion criteria with more reliance on biomarkers, stratification of subjects based on the rate of cognitive decline aiming less heterogeneity, and a longer study duration with periodic assessment of cognition and activities of daily living during the study and also after a washout period. PMID- 27223098 TI - NPR-9, a Galanin-Like G-Protein Coupled Receptor, and GLR-1 Regulate Interneuronal Circuitry Underlying Multisensory Integration of Environmental Cues in Caenorhabditis elegans. AB - C. elegans inhabit environments that require detection of diverse stimuli to modulate locomotion in order to avoid unfavourable conditions. In a mammalian context, a failure to appropriately integrate environmental signals can lead to Parkinson's, Alzheimer's, and epilepsy. Provided that the circuitry underlying mammalian sensory integration can be prohibitively complex, we analyzed nematode behavioral responses in differing environmental contexts to evaluate the regulation of context dependent circuit reconfiguration and sensorimotor control. Our work has added to the complexity of a known parallel circuit, mediated by interneurons AVA and AIB, that integrates sensory cues and is responsible for the initiation of backwards locomotion. Our analysis of the galanin-like G-protein coupled receptor NPR-9 in C. elegans revealed that upregulation of galanin signaling impedes the integration of sensory evoked neuronal signals. Although the expression pattern of npr-9 is limited to AIB, upregulation of the receptor appears to impede AIB and AVA circuits to broadly prevent backwards locomotion, i.e. reversals, suggesting that these two pathways functionally interact. Galanin signaling similarly plays a broadly inhibitory role in mammalian models. Moreover, our identification of a mutant, which rarely initiates backwards movement, allowed us to interrogate locomotory mechanisms underlying chemotaxis. In support of the pirouette model of chemotaxis, organisms that did not exhibit reversal behavior were unable to navigate towards an attractant peak. We also assessed ionotropic glutamate receptor GLR-1 cell-specifically within AIB and determined that GLR-1 fine-tunes AIB activity to modify locomotion following reversal events. Our research highlights that signal integration underlying the initiation and fine-tuning of backwards locomotion is AIB and NPR-9 dependent, and has demonstrated the suitability of C. elegans for analysis of multisensory integration and sensorimotor control. PMID- 27223101 TI - Pd-NHC-Catalyzed Alkynylation of General Aryl Sulfides with Alkynyl Grignard Reagents. AB - Cross-coupling reactions of unactivated aryl sulfides with alkynylmagnesium chloride have been invented to afford 1-aryl-1-alkynes with the aid of a palladium/N-heterocyclic carbene complex. This reaction has by far the widest scope of all transformations utilizing aryl sulfides and alkynes, while known cross-coupling alkynylations of aryl-sulfur electrophiles require activated azaaryl sulfides, thiolactams, or arenesulfonyl chlorides. The alkynylation of aryl sulfides is compatible with typical protecting functional groups. The alkynylation is applied to the synthesis of benzofuran-based fluorescent molecules by taking advantage of characteristic organosulfur chemistry. PMID- 27223102 TI - The relationship between presystolic wave and subclinical left ventricular dysfunction in asymptomatic hypertensive patients. AB - BACKGROUND: The main aim of the current study was to investigate the association between presystolic wave (PSW) and subclinical left ventricular (LV) dysfunction. PATIENTS AND METHODS: A total of 139 patients admitted to the cardiology outpatient clinic with hypertension were consecutively enrolled. The patient population included 79 men and 60 women. The presence of a PSW on the left ventricular outflow tract flow was evaluated in all patients. Subclinical LV dysfunction was defined as the presence of a tissue Doppler-derived myocardial performance index (MPI) of at least 0.5 in the absence of impaired left ventricular ejection fraction (<50%) as evaluated by transthoracic echocardiography. RESULTS: The mean age of the patients was 52+/-10. Patients with PSW had higher MPI (0.44+/-0.13 vs. 0.37+/-0.09, P<0.001), left ventricular mass (LVM) (176+/-45 vs.142+/-33, P<0.001), and LVM index values (92+/-23 vs. 76+/-17, P<0.001) compared with those without PSW. Patients with PSW had a higher prevalence of subclinical LV dysfunction (29 vs. 3.4%, P: 0.008) and LV hypertrophy (22 vs. 2%, P: 0.011). There was a significant correlation with PSW velocity and age (r=0.22, P: 0.04), LVM (r=0.24, P: 0.021), late diastolic mitral annular velocity (r=0.25, P: 0.018), and an inverse correlation with the Em : Am ratio (r=-0.34, P: 0.001). Binary logistic regression analysis indicated the presence of PSW (95% confidence interval 1.3-8.031, odds ratio 3.2, P: 0.012) as an independent determinant of abnormal MPI. CONCLUSION: Assessment of presystolic wave on echocardiography was an independent predictor of subclinical LV dysfunction in patients with hypertension. Attention to the PSW on echocardiography examination might help to identify hypertension patients who could be at risk for developing overt heart failure that has a prognostic impact. PMID- 27223103 TI - Special section: Recent progress in low-frequency dosimetry modeling: from induction to electrostimulation. PMID- 27223104 TI - Changes in Biomass and Quality of Alpine Steppe in Response to N & P Fertilization in the Tibetan Plateau. AB - In the alpine steppe zone on the Central Tibetan Plateau, a large amount of area has been degraded due to natural and artificial factors. N & P fertilization is widely accepted to recover degraded pastures in other regions all over the world. However, it is not clear how alpine steppe communities respond to N & P fertilization, and what is the optimal application rate, in the perspective of forage production. To attempt to explore these questions, in July 2013, two fencing sites were designed in Baingoin County with 12 treatments of different levels of nitrogen (N0: 0; N1: 7.5 g m(-2) yr(-1); N2: 15 g m(-2) yr(-1)) & phosphate (P0: 0; P1: 7.5 gP2O5 m(-2) yr(-1); P2: 15 gP2O5 m(-2) yr(-1); P3: 30 gP2O5 m(-2) yr(-1)). The results indicated N&P addition was capable to ameliorate the quality of the two sites in the Tibetan Plateau steppe. Increasing N application level resulted in significant increment in Gramineae and total biomass in the two sites. P addition significantly improved the quantity of Compositae, total biomass and the biomasss of other species in site II, while it only significantly improved the total biomass in site I. Gramineae was much more sensitive to N-induced changes than P-induced changes, and this indicated N addition was better to ameliorate the quality of plateau steppe than P-induced changes. No strong evidence was found for critical threshold within 15 g N m(-2) yr(-1), and there was decreasing tendency when P addition rate was above 15 g m( 2) yr(-1). N&P has the potential to accelerate soil acidification, which improved the content of available K, likely as a result of nonsignificant correlation between biomass and soil moisture. This work highlights the the tradeoffs that exist in N and P addition in recovering degraded steppe. PMID- 27223105 TI - Fibrous Hydrogels for Cell Encapsulation: A Modular and Supramolecular Approach. AB - Artificial 3-dimensional (3D) cell culture systems, which mimic the extracellular matrix (ECM), hold great potential as models to study cellular processes under controlled conditions. The natural ECM is a 3D structure composed of a fibrous hydrogel that provides both mechanical and biochemical cues to instruct cell behavior. Here we present an ECM-mimicking genetically engineered protein-based hydrogel as a 3D cell culture system that combines several key features: (1) Mild and straightforward encapsulation meters (1) ease of ut I am not so sure.encapsulation of the cells, without the need of an external crosslinker. (2) Supramolecular assembly resulting in a fibrous architecture that recapitulates some of the unique mechanical characteristics of the ECM, i.e. strain-stiffening and self-healing behavior. (3) A modular approach allowing controlled incorporation of the biochemical cue density (integrin binding RGD domains). We tested the gels by encapsulating MG-63 osteoblastic cells and found that encapsulated cells not only respond to higher RGD density, but also to overall gel concentration. Cells in 1% and 2% (weight fraction) protein gels showed spreading and proliferation, provided a relative RGD density of at least 50%. In contrast, in 4% gels very little spreading and proliferation occurred, even for a relative RGD density of 100%. The independent control over both mechanical and biochemical cues obtained in this modular approach renders our hydrogels suitable to study cellular responses under highly defined conditions. PMID- 27223106 TI - Characterization of Electronic Cigarette Aerosol and Its Induction of Oxidative Stress Response in Oral Keratinocytes. AB - In this study, we have generated and characterized Electronic Cigarette (EC) aerosols using a combination of advanced technologies. In the gas phase, the particle number concentration (PNC) of EC aerosols was found to be positively correlated with puff duration whereas the PNC and size distribution may vary with different flavors and nicotine strength. In the liquid phase (water or cell culture media), the size of EC nanoparticles appeared to be significantly larger than those in the gas phase, which might be due to aggregation of nanoparticles in the liquid phase. By using in vitro high-throughput cytotoxicity assays, we have demonstrated that EC aerosols significantly decrease intracellular levels of glutathione in NHOKs in a dose-dependent fashion resulting in cytotoxicity. These findings suggest that EC aerosols cause cytotoxicity to oral epithelial cells in vitro, and the underlying molecular mechanisms may be or at least partially due to oxidative stress induced by toxic substances (e.g., nanoparticles and chemicals) present in EC aerosols. PMID- 27223107 TI - Retraction: The Effect of Social Stress on Chronic Pain Perception in Female and Male Mice. PMID- 27223108 TI - Comparison of Outcomes after Peripheral Blood Haploidentical versus Matched Unrelated Donor Allogeneic Hematopoietic Cell Transplantation in Patients with Acute Myeloid Leukemia: A Retrospective Single-Center Review. AB - Recent studies comparing allogeneic hematopoietic cell transplantation (HCT) using HLA-matched unrelated donors (MUD) versus HLA-haploidentical donors in patients with acute myeloid leukemia (AML) have suggested equivalent outcomes. The graft source used in most studies of haploidentical transplants has been bone marrow. Similar comparisons between MUD and haplo-HCT using peripheral blood as a graft source have not been adequately performed. We reviewed the records of all 52 AML patients who underwent haplo-HCT (using peripheral blood and post transplantation high-dose cyclophosphamide) between January 2010 and August 2015 at our institution and compared their outcomes with 88 patients who had a MUD transplant in the same time frame and were frequency matched (preanalysis) to the haploidentical group for conditioning intensity. Multivariate analysis found no difference in outcomes between the 2 groups with the exception of slower count recovery after haploidentical allografts (HR, .48; 95% CI, .32 to .74 for platelets, and HR, .47; 95% CI, .32 to .71 for neutrophils; P < .001 for both comparisons). Our retrospective analysis, although limited by the small sample size, suggests largely similar outcomes with peripheral blood haploidentical versus MUD transplants for AML. PMID- 27223109 TI - Response of Steroid-Refractory Acute GVHD to alpha1-Antitrypsin. AB - alpha1-Antitrypsin (AAT) is a serine protease inhibitor with anti-inflammatory, antiapoptotic, and immunomodulatory properties. It has therapeutic efficacy in animal models of autoimmune diseases, inflammatory disorders, and transplantation. In a phase I/II open-label single-center study, we administered AAT (Glassia; Baxalta/Kamada, New Ziona, Israel) as salvage therapy to 12 patients with steroid-refractory acute graft-versus-host disease (GVHD). AAT was given i.v. at 2 dose levels over a 15-day course. All patients had grades III or IV GVHD with stage 4 gut involvement. After treatment, plasma AAT levels increased in both cohorts and remained within 2 to 4 mg/mL for the duration of treatment. No clinically relevant toxicities attributable to AAT were observed. GVHD manifestations improved in 8 of 12 patients, and 4 responses were complete. Six patients (50%) were alive at last follow-up (>104 to >820 days). These findings show that AAT is well tolerated and has efficacy in the treatment of steroid-refractory severe acute GVHD. Further studies are warranted. PMID- 27223111 TI - Cumulative, Timing-Specific, and Interactive Models of Residential Mobility and Children's Cognitive and Psychosocial Skills. AB - Residential mobility has received notable attention in the literature, yet there remains limited consensus on how and when mobility is associated with detriments to children's development. Drawing on a nationally representative sample of 19,162 children in the Early Childhood Longitudinal Study followed from kindergarten through eighth grade, this study compared cumulative, timing specific, and interactive models of mobility. Results found that mobility during middle childhood and early adolescence was negatively associated with children's cognitive skills, with short-term effects that dissipated over time. In contrast, associations with psychosocial functioning emerged in relation to early and middle childhood mobility. Effects of residential mobility were robust to more conservative modeling techniques and adjustments for school mobility. PMID- 27223110 TI - Survival Impact of Early Post-Transplant Toxicities in Pediatric and Adolescent Patients Undergoing Allogeneic Hematopoietic Cell Transplantation for Malignant and Nonmalignant Diseases: Recognizing Risks and Optimizing Outcomes. AB - In pediatric and adolescent patients undergoing allogeneic hematopoietic cell transplantation, treatment-related toxicities remain a clinical challenge. A paucity of data investigates the risks for and survival impact of treatment related toxicities in this population. Here the authors assess the relative toxicity of myeloablative, reduced-toxicity, and reduced-intensity conditioning regimens; identify patient-related predictors of post-transplant toxicities; and investigate the impact of early post-transplant toxicities on transplant-related mortality (TRM). In this retrospective study, 164 patients (aged 1 to 22 years) underwent allogeneic stem cell transplantation after busulfan-based conditioning for malignant and nonmalignant diseases between 2000 and 2014. The number of grades III to IV toxicities between days 0 and +30 was calculated for each patient. TRM was calculated to 2 years. Median patient age was 9 years, and median number of toxicities was 3 (range, 0 to 17). The 100-person day incidence of post-transplant toxicities in myeloablative conditioning was not different from the incidence in reduced-toxicity conditioning (13.88 versus 13.59, P = .812). Reduced intensity was less toxic than both myeloablative and reduced toxicity (13.75 versus 8.41, P < .001). Age >= 12 years (.276 with SE = .138, P = .045) and unrelated donor transplant (.318 with SE = 0.113, P = .005) were risk factors for >=3 toxicities. Having >=3 toxicities or a performance score < 90 conferred higher risk of TRM (P = .021). In pediatric and adolescent patients undergoing hematopoietic cell transplantation, reduced-toxicity conditioning was not significantly less toxic than myeloablative conditioning. Additionally, the number of post-transplant toxicities correlated with the risk of mortality. Further investigations to confirm our findings are warranted. PMID- 27223113 TI - Dupilumab, A Monoclonal Antibody for Atopic Dermatitis: A Review of Current Literature. AB - Atopic dermatitis results when aberrant barrier function and immune activation occur within the skin. Standard therapies for atopic dermatitis have fallen short, prompting efforts to discover novel therapeutics for this disease. Of these, dupilumab, a fully human monoclonal antibody that inhibits the actions of both IL-4 and IL-13, has shown the greatest promise. Clinical trials of systemic dupilumab in moderate-to-severe atopic dermatitis have demonstrated marked improvement in patient symptoms, including pruritus and clinically visible disease. Importantly, dupilumab treatment has been correlated with changes in the molecular signature of diseased skin, with reduction of both inflammatory and proliferative markers. Dupilumab recently received US FDA breakthrough therapy designation for atopic dermatitis, with ongoing trials in both adult and pediatric populations. Altogether, dupilumab has shed new light on the pathomechanisms driving atopic dermatitis and is making unprecedented advances towards highly effective control of this debilitating disease. PMID- 27223112 TI - ST2L Transmembrane Receptor Expression: An Immunochemical Study on Endarterectomy Samples. AB - BACKGROUND: ST2 (suppression of tumorigenity) has been described as a receptor for the interleukin-33, a member of the IL-1 family of cytokines. It is associated to coronary artery disease, all-causes mortality and cardiovascular mortality. AIMS: The present study was designed to assess the immunohistochemical expression of the ST2 receptor (ST2L/Il-1R) in atherosclerotic plaques of formalin fixed paraffin-embedded internal carotid arteries of patients with and without cerebro-vascular symptoms. METHODS AND RESULTS: The study involved 41 cases (23 asymptomatic and 18 symptomatic). All the clinical and morphological parameters examined were uniformly distributed between the two groups, with a mild predominance of degree of calcification in asymptomatic cases (p = 0.01). ST2L expression was found to be more evident as a membrane pattern in macrophages when observing carotid atherosclerotic plaques of symptomatic patients, rather than in asymptomatic patients' plaques (77.7% vs 39.1%; p = 0.015), and its expression was particularly remarkable in VI type plaque (AHA). Significantly, ST2L was marked by the endothelium of neoangiogenetic vessels on the shoulder region of the plaque, but not (apart from a few cases) in the endothelium covering the residual lumen of the vessel. CONCLUSIONS: The ST2L immunohistochemical expression was for the first time investigated in a large number of human carotid atherosclerotic plaques, as for its pattern of distribution in the different plaque cell populations. Furthermore, ST2L was particularly remarkable on macrophages, as a membrane pattern, of symptomatic patients' plaque. Considering our data, we hypothesize that ST2L/IL33 axis could drive the mechanism of plaque development and eventually rupture. PMID- 27223114 TI - Nivolumab for Metastatic Melanoma. AB - Melanoma is an aggressive skin cancer with a generally poor prognosis at Stage III-IV disease. Traditionally, metastatic melanoma was treated by surgical resection, when possible, and with systemic chemotherapy. New developments in molecular biology have led to the identification of immune checkpoints which are exploited by malignant cells, allowing them to go undetected by the immune system. Nivolumab (Opdivo(r)) is a human monoclonal antibody which prevents immune inhibition by interacting with PD-1 on tumor cells; thus, increasing tumor specific T cell proliferation. Nivolumab has demonstrated efficacy superior to that of standard chemotherapy and relative safety in clinical trials. Indeed, the outcomes for patients with advanced melanoma are being improved by novel biologic agents such as nivolumab. PMID- 27223115 TI - Trabecular and Cortical Bone of Growing C3H Mice Is Highly Responsive to the Removal of Weightbearing. AB - Genetic make-up strongly influences the skeleton's susceptibility to the loss of weight bearing with some inbred mouse strains experiencing great amounts of bone loss while others lose bone at much smaller rates. At young adulthood, female inbred C3H/HeJ (C3H) mice are largely resistant to catabolic pressure induced by unloading. Here, we tested whether the depressed responsivity to unloading is inherent to the C3H genetic make-up or whether a younger age facilitates a robust skeletal response to unloading. Nine-week-old, skeletally immature, female C3H mice were subjected to 3wk of hindlimb unloading (HLU, n = 12) or served as normal baseline controls (BC, n = 10) or age-matched controls (AC, n = 12). In all mice, cortical and trabecular architecture of the femur, as well as levels of bone formation and resorption, were assessed with MUCT, histomorphometry, and histology. Changes in bone marrow progenitor cell populations were determined with flow cytometry. Following 21d of unloading, HLU mice had 52% less trabecular bone in the distal femur than normal age-matched controls. Reflecting a loss of trabecular tissue compared to baseline controls, trabecular bone formation rates (BFR/BS) in HLU mice were 40% lower than in age-matched controls. Surfaces undergoing osteoclastic resorption were not significantly different between groups. In the mid-diaphysis, HLU inhibited cortical bone growth leading to 14% less bone area compared to age-matched controls. Compared to AC, BFR/BS of HLU mice were 53% lower at the endo-cortical surface and 49% lower at the periosteal surface of the mid-diaphysis. The enriched osteoprogenitor cell population (OPC) comprised 2% of the bone marrow stem cells in HLU mice, significantly different from 3% OPC in the AC group. These data show that bone tissue in actively growing C3H mice is lost rapidly, or fails to grow, during the removal of functional weight bearing-in contrast to the insignificant response previously demonstrated in female young adult C3H mice. Thus, the attributed low sensitivity of the C3H mouse strain to the loss of mechanical signals is not apparent at a young age and this trait therefore does not reflect a genetic regulation throughout the life span of this strain. These results highlight the significance of age in modulating the contribution of genetics in orchestrating bone's response to unloading and that the skeletal unresponsiveness of young adult C3H mice to the loss of weight bearing is not genetically hard-wired. PMID- 27223117 TI - Diet and Mobility in the Corded Ware of Central Europe. AB - Isotopic investigations of two cemetery populations from the Corded Ware Culture in southern Germany reveal new information on the dating of these graves, human diet during this period, and individual mobility. Corded Ware Culture was present across much of temperate Europe ca. 2800-2200 cal. BC and is represented by distinctive artifacts and burial practices. Corded Ware was strongly influenced by the Yamnaya Culture that arose in the steppes of eastern Europe and western Eurasia after 3000 BC, as indicated by recent aDNA research. However, the development of CW on different chronological and spatial scales has to be evaluated. Examination of the CW burials from southern Germany supports an argument for substantial human mobility in this period. Several burials from gravefields and larger samples from two large cemeteries at Lauda-Konigshofen "Wollerspfad" and at Bergheinfeld "Huhnerberg" contributed the human remains for our study of bone and tooth enamel from the Corded Ware Culture. Our results suggest that Corded Ware groups in this region at least were subsisting on a mix of plant and animal foods and were highly mobile, especially the women. We interpret this as indicating a pattern of female exogamy, involving different groups with differing economic strategies. PMID- 27223116 TI - Sequential Washing with Electrolyzed Alkaline and Acidic Water Effectively Removes Pathogens from Metal Surfaces. AB - Removal of pathogenic organisms from reprocessed surgical instruments is essential to prevent iatrogenic infections. Some bacteria can make persistent biofilms on medical devices. Contamination of non-disposable equipment with prions also represents a serious risk to surgical patients. Efficient disinfection of prions from endoscopes and other instruments such as high resolution cameras remains problematic because these instruments do not tolerate aggressive chemical or heat treatments. Herein, we develop a new washing system that uses both the alkaline and acidic water produced by electrolysis. Electrolyzed acidic water, containing HCl and HOCl as active substances, has been reported to be an effective disinfectant. A 0.15% NaCl solution was electrolyzed and used immediately to wash bio-contaminated stainless steel model systems with alkaline water (pH 11.9) with sonication, and then with acidic water (pH 2.7) without sonication. Two bacterial species (Staphylococcus aureus and Pseudomonas aeruginosa) and a fungus (Candida albicans) were effectively removed or inactivated by the washing process. In addition, this process effectively removed or inactivated prions from the stainless steel surfaces. This washing system will be potentially useful for the disinfection of clinical devices such as neuroendoscopes because electrolyzed water is gentle to both patients and equipment and is environmentally sound. PMID- 27223118 TI - Genetic and Environmental Control of Neurodevelopmental Robustness in Drosophila. AB - Interindividual differences in neuronal wiring may contribute to behavioral individuality and affect susceptibility to neurological disorders. To investigate the causes and potential consequences of wiring variation in Drosophila melanogaster, we focused on a hemilineage of ventral nerve cord interneurons that exhibits morphological variability. We find that late-born subclasses of the 12A hemilineage are highly sensitive to genetic and environmental variation. Neurons in the second thoracic segment are particularly variable with regard to two developmental decisions, whereas its segmental homologs are more robust. This variability "hotspot" depends on Ultrabithorax expression in the 12A neurons, indicating variability is cell-intrinsic and under genetic control. 12A development is more variable and sensitive to temperature in long-established laboratory strains than in strains recently derived from the wild. Strains with a high frequency of one of the 12A variants also showed a high frequency of animals with delayed spontaneous flight initiation, whereas other wing-related behaviors did not show such a correlation and were thus not overtly affected by 12A variation. These results show that neurodevelopmental robustness is variable and under genetic control in Drosophila and suggest that the fly may serve as a model for identifying conserved gene pathways that stabilize wiring in stressful developmental environments. Moreover, some neuronal lineages are variation hotspots and thus may be more amenable to evolutionary change. PMID- 27223119 TI - Use of Metabolomics to Trend Recovery and Therapy After Injury in Critically Ill Trauma Patients. AB - IMPORTANCE: Metabolomics is the broad and parallel study of metabolites within an organism and provides a contemporaneous snapshot of physiologic state. Use of metabolomics in the clinical setting may help achieve precision medicine for those who have experienced trauma, where diagnosis and treatment are tailored to the individual patient. OBJECTIVE: To examine whether metabolomics can (1) distinguish healthy volunteers from trauma patients and (2) quantify changes in catabolic metabolites over time after injury. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study with enrollment from September 2014 to May 2015 at an urban, level 1 trauma center. Included in the study were 10 patients with severe blunt trauma admitted within 12 hours of injury with systolic blood pressure less than 90 mm Hg or base deficit greater than 6 mEq/L and 5 healthy volunteers. Plasma samples (n = 35) were obtained on days 1, 3, and 7, and they were analyzed using mass spectrometry. MAIN OUTCOMES AND MEASURES: Principal component analyses, multiple linear regression, and paired t tests were used to select biomarkers of interest. A broad-based metabolite profile comparison between trauma patients and healthy volunteers was performed. Specific biomarkers of interest were oxidative catabolites. RESULTS: Trauma patients had a median age of 45 years and a median injury severity score of 43 (interquartile range, 34-50). Healthy fasting volunteers had a median age of 33 years. Compared with healthy volunteers, trauma patients showed oxidative stress on day 1: niacinamide concentrations were a mean (interquartile range) of 0.95 (0.30-1.45) relative units for trauma patients vs 1.06 (0.96-1.09) relative units for healthy volunteers (P = .02), biotin concentrations, 0.43 (0.27-0.58) relative units for trauma patients vs 1.21 (0.93-1.56) relative units for healthy volunteers (P = .049); and choline concentrations, 0.17 (0.09-0.22) relative units for trauma patients vs 0.21 (0.18-0.22) relative units for healthy volunteers (P = .004). Trauma patients showed lower nucleotide synthesis on day 1: adenylosuccinate concentrations were 0.08 (0.04-0.12) relative units for trauma patients vs 0.15 (0.14-0.17) relative units for healthy volunteers (P = .02) and cytidine concentrations were 1.44 (0.95-1.73) relative units for trauma patients vs 1.74 (1.62-1.98) relative units for healthy volunteers (P = .05). From trauma day 1 to day 7, trauma patients showed increasing muscle catabolism: serine levels increased from 42.03 (31.20-54.95) uM to 79.37 (50.29-106.37) uM (P = .002), leucine levels increased from 69.21 (48.36-99.89) uM to 114.16 (92.89-143.52) uM (P = .004), isoleucine levels increased from 20.43 (10.92-27.41) uM to 48.72 (36.28-64.84) uM (P < .001), and valine levels increased from 122.56 (95.63 140.61) uM to 190.52 (136.68-226.07) uM (P = .004). There was an incomplete reversal of oxidative stress. CONCLUSIONS AND RELEVANCE: Metabolomics can function as a serial, comprehensive, and potentially personalized tool to characterize metabolism after injury. A targeted metabolomics approach was associated with ongoing oxidative stress, impaired nucleotide synthesis, and initial suppression of protein metabolism followed by increased nitrogen turnover. This technique may provide new therapeutic and nutrition targets in critically injured patients. PMID- 27223120 TI - The value of a feasibility study into long-term macrolide therapy in chronic rhinosinusitis. AB - OBJECTIVES: There is currently conflicting level 1 evidence in the use of long term antibiotics for chronic rhinosinusitis without nasal polyps. The primary aim of this feasibility study was to optimise future randomised trial design by assessing recruitment and retention of patients alongside providing preliminary data on symptomatic control. DESIGN: Prospective, multicentre feasibility (cohort) study with all patients receiving macrolide therapy for 12 weeks and a further subsequent 12-week follow-up. Participants received a 12-week course of clarithromycin 250 mg alongside twice daily topical mometasone and nasal douching. Primary outcomes focused on recruitment, retention and compliance. Clinical and quality-of-life outcomes measures were also recorded. SETTING: Patients were prospectively recruited from six UK outpatient clinics. PARTICIPANTS: Adult patients with chronic rhinosinusitis without nasal polyps and no prior endoscopic sinus surgery underwent baseline assessment and then follow up at 3 and 6 months. MAIN OUTCOME MEASURES: Six-month recruitment and retention data. RESULTS: Over 13 months, 55 adults were recruited from five centres. Four patients declined participation. 75% of patients were retained within the study. Dropouts included one medication contraindication, three unable to tolerate medication and 10 not attending full follow-up. Sino Nasal Outcome Test-22 and endoscopic scores showed statistically significant improvement. No other clinical or quality-of-life assessment improvements were seen. CONCLUSION: Retention and recruitment to a trial using long-term clarithromycin to treat chronic rhinosinusitis without nasal polyps is achievable and this data will support a future randomised controlled trial. The study provides vital insight into trial design, thus informing UK research networks and rhinology researchers internationally. PMID- 27223121 TI - Epigenetic regulation of SMARCB1 By miR-206, -381 and -671-5p is evident in a variety of SMARCB1 immunonegative soft tissue sarcomas, while miR-765 appears specific for epithelioid sarcoma. A miRNA study of 223 soft tissue sarcomas. AB - Complete/partial loss of SMARCB1 nuclear-immunopositivity is characteristic of a certain subset of soft tissue sarcomas (STSs). Our previous work showed that oncomiRs-206,-381, and 671-5p could silence the SMARCB1 mRNA and protein expression and that they display significant overexpression in epithelioid sarcomas (ESs). MiR-765 was overexpressed too, but functionally was inactive in the silencing. In the current work, using quantitative PCR, we conducted a miRNA study of 51 ESs, 20 rhabdoid tumors (RTs), 20 synovial sarcomas (SSs), 15 malignant peripheral nerve sheath tumors (MPNSTs), 11 myoepithelial carcinomas (MECs), and 10 extraskeletal myxoid chondrosarcomas (EMCSs) with complete/partial loss of SMARCB1 nuclear immunostain, in contrast to controls (SMARCB1 immunopositive) of 96 STSs, 13 melanomas and 10 sarcomatoid carcinomas. The SMARCB1 genetic status of ESs was determined by MLPA and FISH. A subset of ESs (5/51) showed biallelic deletion of SMARCB1 with no overexpression of any miRNA, suggesting these tumors could be the counterpart of pediatric RT, at least genetically. Another subset (5/51) was genetically either intact or monoallelic deleted with at least threefold overexpression of one of miR-206,-381,-671-5p, suggesting epigenetic regulation only. 39/51 ESs had a biallelic deletion (>20% by FISH and/or by MLPA) but with overexpressed miR-206,-381, and 671-5p, suggesting intratumoral heterogeneity, i.e., both genetic and epigenetic regulation. At least threefold overexpression of one of miR-206,-381, and 671-5p was detected in all MPNSTs, EMCSs, SSs and 7 MCs. Except for ESs, four SSs and one MPNST, there was no event above threefold overexpression of miR-765 among all 195 tested tumors. Our results suggest a general role of miR-206,-381, and 671-5p in SMARCB1 gene silencing of ES, MC, EMCS, MPNST and SS. In the future, miR-765 could possibly be a diagnostic tool for ES because of its 97% specificity and 80% sensitivity. (c) 2016 Wiley Periodicals, Inc. PMID- 27223123 TI - Correcting Misconceptions About the Diagnostic Criteria for Posttraumatic Stress Disorder in DSM-5. PMID- 27223122 TI - Small Molecule APY606 Displays Extensive Antitumor Activity in Pancreatic Cancer via Impairing Ras-MAPK Signaling. AB - Pancreatic cancer has been found with abnormal expression or mutation in Ras proteins. Oncogenic Ras activation exploits their extensive signaling reach to affect multiple cellular processes, in which the mitogen-activated protein kinase (MAPK) signaling exerts important roles in tumorigenesis. Therapies targeted Ras are thus of major benefit for pancreatic cancer. Although small molecule APY606 has been successfully picked out by virtual drug screening based on Ras target receptor, its in-depth mechanism remains to be elucidated. We herein assessed the antitumor activity of APY606 against human pancreatic cancer Capan-1 and SW1990 cell lines and explored the effect of Ras-MAPK and apoptosis-related signaling pathway on the activity of APY606. APY606 treatment resulted in a dose- and time dependent inhibition of cancer cell viability. Additionally, APY606 exhibited strong antitumor activity, as evidenced not only by reduction in tumor cell invasion, migration and mitochondrial membrane potential but also by alteration in several apoptotic indexes. Furthermore, APY606 treatment directly inhibited Ras-GTP and the downstream activation of MAPK, which resulted in the down regulation of anti-apoptotic protein Bcl-2, leading to the up-regulation of mitochondrial apoptosis pathway-related proteins (Bax, cytosolic Cytochrome c and Caspase 3) and of cyclin-dependent kinase 2 and Cyclin A, E. These data suggest that impairing Ras-MAPK signaling is a novel mechanism of action for APY606 during therapeutic intervention in pancreatic cancer. PMID- 27223124 TI - [New drugs for horses and production animals in 2015]. AB - In 2015, four newly developed active pharmaceutical ingredients for horses and food-producing animals were released on the German market for veterinary drug products. These were the bisphosphonate Clodronic Acid (Osphos(r)), the 5 hydroxytryptamine (2A) receptor antagonist Ketanserin (Vulketan(r)), the aminoglycoside antibiotic Paromomycin (Parofor(r)) and the antibiotic Thiamphenicol (TAF Spray(r)) from the fenicole group. With Chlorphenamine, a temporary not available active ingredient was reapproved in a new drug. Furthermore, three veterinary drugs with a new formulation as well as one product with a new strength and two products with a new combination of active pharmaceutical ingredients have been launched. PMID- 27223125 TI - Orexins and receptor OX2R in the gastroenteric apparatus of two teleostean species: Dicentrarchus labrax and Carassius auratus. AB - Orexin A and B peptides and the receptor OX2R were studied in sea bass and goldfish gastroenteric tract by immunoblotting combined with densitometric analysis using NIH Image J software and immunohistochemical techniques. These teleost species present a different gut organization and diverse feeding habits. Immunoblotting experiments showed one band of 16 kDa corresponding to prepro orexin, and one band of 38 kDa corresponding to the OX2R receptor. Immunohistochemical localization of OXA and OXB was observed in the enteric nervous system throughout the gastroenteric tract of both species. OXA and OXB immunoreactive cells were found in the gastric and intestinal regions of sea bass, and were mainly found in the basal region of folds in intestinal bulb, and in the midgut and hindgut of goldfish. The distribution of OX2R was mainly detected in the mucosa of the gastroenteric tract of sea bass and goldfish. This distribution suggests an endocrine action of OXA and OXB in the gastrointestinal tract as well as involvement in the peripheral control of food intake and digestive processes in both species. This study might also serve to determine the productive factors in breeding and as a baseline for future experimental studies on the regulation of the gastroenteric functions in non-mammalian vertebrates. Anat Rec, 299:1121-1129, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27223126 TI - Root filling bond strength using reciprocating file-matched single-cones with different sealers. AB - The aim of the present study was to evaluate the bond strength (BS) of root canal fillings to root dentin using the reciprocating file-matched single-cone or lateral compaction techniques with resin-based and calcium-silicate-based sealers. Maxillary canine roots were prepared and filled using one of the following approaches: Reciproc R40 file and R40 single cone, WaveOne Large file and Large single cone, or ProTaper up to F4 file with lateral compaction. The root filling was performed using AH Plus, Epiphany SE or MTA Fillapex (n = 10). Three 1-mm-thick slices were obtained from each third of each root. Two slices were subjected to a push-out test, and the other slices were prepared for scanning electron microscopy (SEM) to examine the dentin-sealer interface. Data (in MPa) from the push-out tests were analyzed using a two-way ANOVA and Tukey's test (p < 0.05). Failure modes (adhesive, cohesive or mixed) were evaluated at *25 magnification. The single-cone techniques resulted in lower BS values than the lateral compaction technique. For lateral compaction, AH Plus and Epiphany SE showed the highest and lowest BS values, respectively. Slight differences were observed between sealers when the single-cone techniques were used. A tendency to reduce the BS toward the apical third was observed. Adhesive failures were predominant for all experimental conditions. A closer adaption of the filling material on the root dentin was observed for the AH Plus and lateral compaction techniques. The Reciproc and WaveOne techniques were associated with lower BS values than the lateral compaction technique. However, the effect of the root canal filling technique appears to be sealer-dependent. PMID- 27223127 TI - Incidence of dental caries in primary dentition and risk factors: a longitudinal study. AB - The objectives of this prospective, longitudinal, population-based study were to estimate the incidence of dental caries in the primary dentition, identify risk factors and determine the proportion of children receiving dental treatment, through a two-year follow up. The first dental exam was conducted with 381 children aged one to five years, at health centers during immunization campaigns; 184 of them had dental caries and 197 had no caries experience. The second exam was carried out two years later at a nursery or at home with the same individuals who participated in the first exam. The diagnosis of dental caries was performed using the dmft criteria. Parents were interviewed regarding socioeconomic indicators. Descriptive, bivariate and adjusted Poisson regression analyses were performed. Among the 381 children, 234 were reexamined after two years (non exposed: 139; exposed: 95). The overall incidence of dental caries was 46.6%. The greatest incidence of dental caries was found in the group of children with previous caries experience (61.1%). Among the children without dental caries in the first exam, 36.7% exhibited caries in the second exam. The majority of children (72.6%) received no treatment for carious lesions in the two-year interval between examinations. Children with previous dental caries (RR: 1.52, 95%CI: 1.12-2.05) had a greater risk of developing new lesions, compared with the children without previous dental caries. The incidence of dental caries was high and most of children's caries were untreated. Previous caries experience is a risk factor for developing new carious lesions in children. PMID- 27223128 TI - Predictors of clinical outcomes after periodontal treatment of aggressive periodontitis: 12-month randomized trial. AB - Little is known about the factors that may be used in clinical practice to predict the therapeutic response of aggressive periodontitis patients. The aim of this study was to determine predictors of clinical outcomes after non-surgical treatment of aggressive periodontitis. A total of 24 patients (aged 13-26 years) received oral hygiene instructions, as well as subgingival scaling and root planing. Twelve subjects received systemic azithromycin at random. Clinical variables were assessed at baseline, 3, 6, 9, and 12 months. Baseline microbiological assessment was performed by checkerboard DNA-DNA hybridization. Multivariable models used generalized estimating equations. There were significant improvements in the entire sample in regard to pocket depth, clinical attachment level and bleeding on probing. Significant predictors of a reduction in mean pocket depth were: use of azithromycin, non-molar teeth, generalized disease and baseline pocket depth. Absence of plaque predicted a 0.22 mm higher attachment gain, whereas a baseline pocket depth >=7 mm predicted a 1.36 mm higher attachment loss. Azithromycin, plaque, and baseline pocket depth were significant predictors of bleeding on probing. The concomitant presence of all three red complex species predicted a 0.78 mm higher attachment loss. It may be concluded that dental plaque, tooth type, disease extent, baseline pocket depth, and use of azithromycin were significant predictors of the clinical response to treatment for aggressive periodontitis in young individuals. Moreover, the presence of multiple periodontal pathogens may predict challenges in achieving a favorable outcome for aggressive periodontitis. PMID- 27223129 TI - Optimizing light-cured composite through variations in camphorquinone and butylhydroxytoluene concentrations. AB - The use of a free-radical polymerization inhibitor, butylhydroxytoluene (BHT), and a common photo-initiator, camphorquinone (CQ), to reduce polymerization stress in dental composite was investigated in this study. Samples were prepared by mixing Bis-GMA, UDMA, and TEGDMA at a 1:1:1 ratio (wt%), and silanized borosilicate glass fillers at 70 wt% were added to form the composite. Sixteen groups of resin composite were prepared using combinations of four CQ (0.1%, 0.5%, 1.0%, and 1.5%) and four BHT (0.0%, 0.5%, 1.0%, and 1.5%) concentrations. For each group, six properties were tested, including flexural strength (FS), flexural modulus (FM), degree of conversion (DC), contraction stress (CS), stress rate, and gel point (GP). The effects of CQ and BHT combinations on each of these properties were evaluated using two-way analysis of variance (ANOVA) and Fisher's Protected Least Significant Differences test at the 5% significance level. Groups with low CQ and BHT showed moderate values for FS, FM, and CS with a 70% DC. Increasing the BHT concentration caused a decrease in CS and DC with an increase in GP values. Increasing the CQ content led to a steady increase in values for FS and FM. High CQ and BHT combinations showed the most promising values for mechanical properties with low stress values. PMID- 27223130 TI - Sickle cell anemia in Brazil: personal, medical and endodontic patterns. AB - Sickle cell anemia (SCA) is the most prevalent genetic disease worldwide. Recurrent vaso-occlusive infarcts predispose SCA patients to infections, which are the primary causes of morbidly and mortality. This study aimed to evaluate the relationship between SCA and endodontic diseases. Personal information, medical data (hematological indices, virologic testing, blood transfusions, medications received, splenectomy) and information on the need for endodontic treatment were obtained from SCA patients who were registered and followed up by the Fundacao Hemominas, Minas Gerais, Brazil.These data were compared with the need for root canal treatment in SCA patients. One hundred eight patients comprised the studied population, and the rate of the need for endodontic therapy was 10.2%. Among the medical data, a significant difference was observed for eosinophil (p = 0.045) counts and atypical lymphocyte counts (p = 0.036) when the groups (with and without the need for endodontic treatment) were compared. Statistical relevance was observed when comparing the patients with and without the need for root canal therapy concerned eosinophil counts and atypical lymphocyte counts. The differences in statistical medical data, observed between the groups suggest that both parameters are naturally connected to the stimulation of the immune system that can occur in the presence of root canal infections and that can be harmful to SCA individuals. PMID- 27223131 TI - Clinical effect of photodynamic therapy on primary carious dentin after partial caries removal. AB - This study was conducted to assess the clinical effect of photodynamic therapy (PDT) in the decontamination of the deep dentin of deciduous molars submitted to partial removal of carious tissue. After cavity preparation, dentin samples were taken from the pulp wall of nineteen deciduous molars before and after PDT application. Remaining dentin was treated with 0.01% methylene blue dye followed by irradiation with an InGaAlP diode laser (lambda - 660 nm; 40 mW; 120 J/cm2; 120 s). Dentin samples were microbiologically assessed for the enumeration of total microorganisms, Lactobacillus spp. and mutans streptococci. There was no significant difference in the number of colony-forming units (CFU) for any of the microorganisms assessed (p > 0.05). Photodynamic therapy, using 0.01% methylene blue dye at a dosimetry of 120 J/cm2 would not be a viable clinical alternative to reduce bacterial contamination in deep dentin. PMID- 27223132 TI - The effect of smoking on myeloid-related protein-8 and myeloid-related protein 14. AB - The aim of this study was to determine the myeloid-related protein-8 and myeloid related protein-14 levels in the gingival crevicular fluid of smoker patients with generalized aggressive periodontitis (SAgP), smoker patients with chronic periodontitis (SCP), smoker patients with gingivitis (SG-smoker control), non smoker patients with generalized aggressive periodontitis (AgP), non-smoker patients with chronic periodontitis (CP), and non-smoker patients with gingivitis (G-non-smoker control). The periodontal statuses of the patients were determined by periodontal clinical measurements and radiographical evaluations. The levels of myeloid-related protein-8 and myeloid-related protein-14 in the gingival crevicular fluid were assessed using enzyme-linked immuno sorbent assay. The myeloid-related protein-8 and myeloid-related protein-14 levels in the gingival crevicular fluid of patients with generalized aggressive periodontitis (non smoker and smoker) were found to be statistically higher than patients with chronic periodontitis (non-smoker and smoker) and patients with gingivitis (non smoker and smoker). Myeloid-related protein-8 and myeloid-related protein-14 levels of non-smokers were significantly higher than smokers in all types of periodontitis and gingivitis. The decreased myeloid-related protein-8 and myeloid related protein-14 level could have prevented the haemostasis of calcium which plays a significant role in the migration of neutrophiles. Smoking affects myeloid-related protein-8 and myeloid-related protein-14 levels and may inhibit the antimicrobial efficiency against microorganisms. Due to these reasons smoker generalized aggressive periodontitis patients need to be treated in detail and their maintenance durations should be shortened. PMID- 27223133 TI - Enamel and dentine demineralization by a combination of starch and sucrose in a biofilm - caries model. AB - Sucrose is the most cariogenic dietary carbohydrate and starch is considered non cariogenic for enamel and moderately cariogenic for dentine. However, the cariogenicity of the combination of starch and sucrose remains unclear. The aim of this study was to evaluate the effect of this combination on Streptococcus mutans biofilm composition and enamel and dentine demineralization. Biofilms of S. mutans UA159 were grown on saliva-coated enamel and dentine slabs in culture medium containing 10% saliva. They were exposed (8 times/day) to one of the following treatments: 0.9% NaCl (negative control), 1% starch, 10% sucrose, or 1% starch and 10% sucrose (starch + sucrose). To simulate the effect of human salivary amylase on the starch metabolization, the biofilms were pretreated with saliva before each treatment and saliva was also added to the culture medium. Acidogenicity of the biofilm was estimated by evaluating (2 times/day) the culture medium pH. After 4 (dentine) or 5 (enamel) days of growth, biofilms (n = 9) were individually collected, and the biomass, viable microorganism count, and polysaccharide content were quantified. Dentine and enamel demineralization was assessed by determining the percentage of surface hardness loss. Biofilms exposed to starch + sucrose were more acidogenic and caused higher demineralization (p < 0.0001) on either enamel or dentine than those exposed to each carbohydrate alone. The findings suggest that starch increases the cariogenic potential of sucrose. PMID- 27223134 TI - Dental flossing as a diagnostic method for proximal gingivitis: a validation study. AB - This study evaluated the clinical diagnosis of proximal gingivitis by comparing two methods: dental flossing and the gingival bleeding index (GBI). One hundred subjects (aged at least 18 years, with 15% of positive proximal sites for GBI, without proximal attachment loss) were randomized into five evaluation protocols. Each protocol consisted of two assessments with a 10-minute interval between them: first GBI/second floss, first floss/second GBI, first GBI/second GBI, first tooth floss/second floss, and first gum floss-second floss. The dental floss was slid against the tooth surface (TF) and the gingival tissue (GF). The evaluated proximal sites should present teeth with established point of contact and probing depth <= 3mm. One trained and calibrated examiner performed all the assessments. The mean percentages of agreement and disagreement were calculated for the sites with gingival bleeding in both evaluation methods (GBI and flossing). The primary outcome was the percentage of disagreement between the assessments in the different protocols. The data were analyzed by one-way ANOVA, McNemar, chi-square and Tukey's post hoc tests, with a 5% significance level. When gingivitis was absent in the first assessment (negative GBI), bleeding was detected in the second assessment by TF and GF in 41.7% (p < 0.001) and 50.7% (p < 0.001) of the sites, respectively. In the absence of gingivitis in the second assessment (negative GBI), TF and GF detected bleeding in the first assessment in 38.9% (p = 0.004) and 58.3% (p < 0.001) of the sites, respectively. TF and GF appears to be a better diagnostic indicator of proximal gingivitis than GBI. PMID- 27223135 TI - Zika virus infection spread through saliva. PMID- 27223136 TI - Relationship between Sense of Coherence and oral health in adults and elderly Brazilians. AB - The purpose of this study was to investigate the relationship between Sense of Coherence (SOC) and oral health clinical variables (number of teeth present and absence of need for dental prostheses). The sample consisted of 720 adults and elderly Brazilians. The data were collected at home using the SOC-13 scale - a form of clinical examination for the evaluation of oral conditions - and a questionnaire evaluating socioeconomic aspects and the use of dental services. Statistical analysis, both univariate and multivariate, was performed by Poisson regression with robust variance adjustment. The average age of the participants was 60.2 years, and they were predominantly female (57.8%). Among the participants who had a strong SOC, the absence of the need for dental prostheses was 34% higher than among those with a weak SOC, demonstrating a significant difference between the groups (PR = 1.34, 95%CI = 1.06-1.70; p = 0.015). Individuals who had a strong SOC had a 5% higher prevalence of 14 or more existing teeth than those with a weak SOC, which was statistically significant after adjustment for co-factors (PR = 1.05, 95%CI = 1.01-1.11, p = 0.033). A strong personal Sense of Coherence has a beneficial influence on the oral health of adults and older people in Brazil. PMID- 27223137 TI - Fluoride and sodium trimetaphosphate (TMP) release from fluoride varnishes supplemented with TMP. AB - This study assessed fluoride (F) and sodium trimetaphosphate (TMP) release into artificial saliva from varnishes containing 0%, 2.5%, and 5% NaF, supplemented or not with 5% TMP. The varnishes were applied on polyester sheets (n = 8/group), and F and TMP released into artificial saliva were measured for up to 24 hours. The amount of F and TMP released were directly related to NaF and TMP concentrations in the varnishes. The highest F release was seen for 5% NaF and 5% NaF + 5% TMP, whereas 5% TMP released the highest amount of TMP. However, the simultaneous addition of NaF and TMP to varnishes significantly reduced the amount of F and TMP released from the products. PMID- 27223138 TI - Cytotoxicity and genotoxicity of calcium silicate-based cements on an osteoblast lineage. AB - Several calcium silicate-based biomaterials have been developed in recent years, in addition to Mineral Trioxide Aggregate (MTA). The aim of this study was to evaluate the cytotoxicity, genotoxicity and apoptosis/necrosis in human osteoblast cells (SAOS-2) of pure calcium silicate-based cements (CSC) and modified formulations: modified calcium silicate-based cements (CSCM) and three resin-based calcium silicate cements (CSCR1) (CSCR 2) (CSCR3). The following tests were performed after 24 hours of cement extract exposure: methyl-thiazolyl tetrazolium (MTT), apoptosis/necrosis assay and comet assay. The negative control (CT-) was performed with untreated cells, and the positive control (CT+) used hydrogen peroxide. The data for MTT and apoptosis were submitted to analysis of variance and Bonferroni's posttest (p < 0.05), and the data for the comet assay analysis, to the Kruskal-Wallis and Dunn tests (p < 0.05). The MTT test showed no significant difference among the materials in 2 mg/mL and 10 mg/mL concentrations. CSCR3 showed lower cell viability at 10 mg/mL. Only CSC showed lower cell viability at 50 mg/mL. CSCR1, CSCR2 and CSCR3 showed a higher percentage of initial apoptosis than the control in the apoptosis test, after 24 hours exposure. The same cements showed no genotoxicity in the concentration of 2 mg/mL, with the comet assay. CSC and CSCR2 were also not genotoxic at 10 mg/mL. All experimental materials showed viability with MTT. CSC and CSCR2 presented a better response to apoptosis and genotoxicity evaluation in the 10 mg/mL concentration, and demonstrated a considerable potential for use as reparative materials. PMID- 27223139 TI - Drying protocol influence on the bond strength and apical sealing of three different endodontic sealers. AB - The aim of this study was to evaluate the influence of drying protocols (DP) on the apical sealing (AS) and on the bond strength (BS) of teeth filled with different sealers. The root canals of one hundred and fifty-six roots of maxillary canines were prepared with Reciproc rotary files (R50). The teeth were randomly divided into four groups (n = 39), according to the DP: GI-paper points; GII-70% isopropyl alcohol + aspiration with NaviTip points; GIII-95% ethanol + paper points; GIV-EndoVac + paper points. Each group was divided into subgroups, according to the sealer used: AH Plus, Sealapex and MTA Fillapex, using a single cone technique. Evaluation of AS and BS was performed with fluid filtration (FF) and push-out (PO) methods, respectively. The PO test consisted of sectioning the roots, and subjecting a single slice from each third to testing and analysis for failure type. The data was submitted to two-way and three-way variance analysis (ANOVA) and Tukey (alpha = 5%). The AS showed no drying protocol influence. The FF results revealed a statistically significant difference between MTA and Sealapex (p < 0.05) sealers. The BS test values showed that there was no statistical significant difference among the canal thirds (p > 0.05), but that there was such a difference among the sealers (p < 0.05), among the protocols (p < 0.05), and in the interaction between sealers and protocols (p < 0.05). AH Plus revealed the highest BS values among the sealers; the highest BS results for the sealers occurred with the specimens used with isopropyl alcohol, compared with ethanol and EndoVac. PMID- 27223140 TI - Effects of alpha-tocopherol on fracture resistance after endodontic treatment, bleaching and restoration. AB - This study evaluated the effects of 10% alphatocopherol on the fracture resistance of endodontically treated teeth subjected to tooth bleaching with hydrogen peroxide and immediately restored with composite resin. Fifty bovine incisors were selected, including 10 sound teeth that constituted the control group (G1 (C)). The remaining 40 teeth, which were endodontically treated, were divided into four groups (n = 10): G2 (CR), consisting of teeth immediately restored with composite resin; G3 (HP + CR), consisting of teeth subjected to tooth bleaching with 38% hydrogen peroxide and immediately restored with composite resin; G4 (HP + SA + CR), which received treatment similar to that used for G3, but with 10% sodium ascorbate gel applied after the bleaching protocol; and G5 (HP + AT + CR), which was similar to G4 but included 10% alphatocopherol gel as an antioxidant. After 24 h, composite restorations were performed, and teeth were subjected to a fracture resistance test at a speed of 0.5 mm/min in an electromechanical testing machine. The axial force was applied with an angle of incidence of 135 degrees relative to the long axis of the root. Data were subjected to ANOVA and Tukey tests (p = 0.05). G1 exhibited the highest fracture resistance (p < 0.05). No significant differences among the other experimental groups were observed. The 10% sodium ascorbate and 10% alphatocopherol gels did not improve the fracture resistance of endodontically treated teeth subjected to bleaching with 38% hydrogen peroxide. PMID- 27223141 TI - Effective method for the detection of piroxicam in human plasma using HPLC. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used by the general population to alleviate inflammation and pain after oral surgeries. Piroxicam is among the most commonly used NSAIDs and excels in controlling pain, swelling, trismus and other common symptoms of inflammation. This study aimed to evaluate different concentrations of piroxicam and its major metabolite, 5' hydroxypiroxicam, in human plasma samples over time using high performance liquid chromatography (HPLC) after liquid-liquid extraction. Briefly, 10 volunteers participated in this study after approval by the Ethics Committee of Bauru School of Dentistry, Universidade de Sao Paulo - USP, Brazil. Volunteers received a single dose oral of piroxicam (20 mg) and had blood collected at various times following an established protocol. The methodology of liquid-liquid extraction was effective for determining concentrations of piroxicam in plasma using HPLC in 10 out of 10 volunteers while 5'-hydroxypiroxicam was only detected in 2 out of 10 volunteers. PMID- 27223143 TI - Time resolved dosimetry of human brain exposed to low frequency pulsed magnetic fields. AB - An accurate dosimetry is a key issue to understanding brain stimulation and related interaction mechanisms with neuronal tissues at the basis of the increasing amount of literature revealing the effects on human brain induced by low-level, low frequency pulsed magnetic fields (PMFs). Most literature on brain dosimetry estimates the maximum E field value reached inside the tissue without considering its time pattern or tissue dispersivity. Nevertheless a time-resolved dosimetry, accounting for dispersive tissues behavior, becomes necessary considering that the threshold for an effect onset may vary depending on the pulse waveform and that tissues may filter the applied stimulatory fields altering the predicted stimulatory waveform's size and shape. In this paper a time-resolved dosimetry has been applied on a realistic brain model exposed to the signal presented in Capone et al (2009 J. Neural Transm. 116 257-65), accounting for the broadband dispersivity of brain tissues up to several kHz, to accurately reconstruct electric field and current density waveforms inside different brain tissues. The results obtained by exposing the Duke's brain model to this PMF signal show that the E peak in the brain is considerably underestimated if a simple monochromatic dosimetry is carried out at the pulse repetition frequency of 75 Hz. PMID- 27223144 TI - Will Precision Medicine Move Us beyond Race? PMID- 27223142 TI - Alcohol and Cigarette Use Among Warsaw Adolescents: Factors Associated With Risk and Resilience. AB - BACKGROUND: Youth in Poland are at notable risk for substance use. Guided by resiliency theory, we examine if developmental risk and promotive factors are associated with substance abuse risk. OBJECTIVES: We examined the association between adolescent cigarette and alcohol use and related risk and promotive factors including maternal support, neighbors' informal social control, friends' acceptance of substance use, and alcohol and cigarette use by nonparental adults. METHOD: Data were collected from a random sample of 13- to 14-year-old students attending Warsaw middle schools (N = 3029). We used hierarchical regression models and examined compensatory and protective models of resilience, controlling for sociodemograhic factors. RESULTS: Our results indicated that friends' acceptance of substance use and perceived drug use among nonparental adults was associated with increased risk cigarette and alcohol use among youth. We found that maternal support moderated the relationship between friends' acceptance of substance use and cigarette use (protective model of resilience). Thus, mother support buffered the negative effects of friends' acceptance of substance use on youths' cigarette use. Neighbor's informal social control and maternal support were associated with reduced risk of alcohol use (compensatory model of resilience). CONCLUSION: Collectively, results of the study support compensatory and protective models of resilience in a large representative sample of Warsaw adolescents. PMID- 27223145 TI - Considering the Common Good--The View from Seven Miles Up. PMID- 27223146 TI - Factor VIII-Mimetic Function of Humanized Bispecific Antibody in Hemophilia A. AB - BACKGROUND: In patients with severe hemophilia A, standard treatment is regular prophylactic and episodic intravenous infusions of factor VIII. However, these treatments are burdensome, especially for children, and may lead to the formation of anti-factor VIII alloantibodies (factor VIII inhibitors). Emicizumab (ACE910), a humanized bispecific antibody mimicking the cofactor function of factor VIII, was developed to abate these problems. METHODS: We enrolled 18 Japanese patients with severe hemophilia A (with or without factor VIII inhibitors) in an open label, nonrandomized, interindividual dose-escalation study of emicizumab. The patients received subcutaneous emicizumab weekly for 12 weeks at a dose of 0.3, 1.0, or 3.0 mg per kilogram of body weight (cohorts 1, 2, and 3, respectively). The end points were safety and pharmacokinetic and pharmacodynamic profiles. An additional, exploratory end point was the annualized bleeding rate, calculated as 365.25 times the number of bleeding episodes, divided by the number of days in the treatment period as compared with the 6 months before enrollment. RESULTS: Emicizumab was associated with neither serious adverse events nor clinically relevant coagulation abnormalities. Plasma concentrations of emicizumab increased in a dose-dependent manner. Activated partial-thromboplastin times remained short throughout the study. The median annualized bleeding rates in cohorts 1, 2, and 3 decreased from 32.5 to 4.4, 18.3 to 0.0, and 15.2 to 0.0, respectively. There was no bleeding in 8 of 11 patients with factor VIII inhibitors (73%) and in 5 of 7 patients without factor VIII inhibitors (71%). Episodic use of clotting factors to control bleeding was reduced. Antibodies to emicizumab did not develop. CONCLUSIONS: Once-weekly subcutaneous administration of emicizumab markedly decreased the bleeding rate in patients who had hemophilia A with or without factor VIII inhibitors. (Funded by Chugai Pharmaceutical; JapicCTI number, 121934.). PMID- 27223148 TI - CLINICAL PRACTICE. Cryptogenic Stroke. PMID- 27223149 TI - IMAGES IN CLINICAL MEDICINE. Acute Varicocele Revealing Renal Cancer. PMID- 27223150 TI - CASE RECORDS of the MASSACHUSETTS GENERAL HOSPITAL. Case 16-2016. A 31-Year-Old Pregnant Woman with Fever. PMID- 27223147 TI - A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A. AB - BACKGROUND: The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. METHODS: We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites. RESULTS: Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (>=5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00). CONCLUSIONS: Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.). PMID- 27223151 TI - Hemophilia Therapy--Navigating Speed Bumps on the Innovation Highway. PMID- 27223152 TI - Repressing Immunity in Autoimmune Disease. PMID- 27223153 TI - Kidney-Failure Risk Projection for the Living Kidney-Donor Candidate. PMID- 27223154 TI - Kidney-Failure Risk Projection for the Living Kidney-Donor Candidate. PMID- 27223155 TI - Kidney-Failure Risk Projection for the Living Kidney-Donor Candidate. PMID- 27223156 TI - Kidney-Failure Risk Projection for the Living Kidney-Donor Candidate. PMID- 27223157 TI - Postmenopausal Osteoporosis. PMID- 27223158 TI - Postmenopausal Osteoporosis. PMID- 27223159 TI - Postmenopausal Osteoporosis. PMID- 27223160 TI - Postmenopausal Osteoporosis. PMID- 27223161 TI - Physicians and Youth Tackle Football. PMID- 27223162 TI - Physicians and Youth Tackle Football. PMID- 27223163 TI - IMAGES IN CLINICAL MEDICINE. Salmonella enterica Aortitis. PMID- 27223164 TI - A new furanocoumarin from the fruits of Scaevola taccada and antifungal activity against Pythium insidiosum. AB - A new coumarin, scataccanol (1) and 10 known compounds were isolated from the fruits of Scaevola taccada (Gaertn.) Roxb. All compounds were evaluated for antifungal activity against Pythium insidiosum. Compounds 5 and 7 showed strong antifungal activity with minimum inhibitory concentration values of 5 and 10 MUg/mL, respectively. Structural determination of all compounds was accomplished by 1D and 2D-NMR, IR and MS. PMID- 27223165 TI - Mindfulness Self-Care Strategies for Clinicians #316. PMID- 27223166 TI - Interfacial Cohesion and Assembly of Bioadhesive Molecules for Design of Long Term Stable Hydrophobic Nanodrugs toward Effective Anticancer Therapy. AB - The majority of anticancer drugs are poorly water-soluble and thus suffer from rather low bioavailability. Although a variety of delivery carriers have been developed for bioavailability improvement, they are severely limited by low drug loading and undesired side effects. The optimum delivery vehicle would be a biocompatible and biodegradable drug nanoparticle of uniform size with a thin but stable shell, making it soluble, preventing aggregation and enabling targeting. Here, we present a general strategy for the rational design of hydrophobic drug nanoparticles with high drug loading by means of interfacial cohesion and supramolecular assembly of bioadhesive species. We demonstrate that the pathway is capable of effectively suppressing and retarding Ostwald ripening, providing drug nanoparticles with small and uniform size and long-term colloidal stability. The final complex drug nanoparticles provide higher tumor accumulation, negligible toxicity, and enhanced antitumor activity, superior to commercial formulations. Our findings demonstrate that local, on-demand coating of hydrophobic nanoparticles is achievable through cooperation and compromise of interfacial adhesion and assembly. PMID- 27223167 TI - Sampling and Definitions of Placental Lesions: Amsterdam Placental Workshop Group Consensus Statement. AB - CONTEXT: -The value of placental examination in investigations of adverse pregnancy outcomes may be compromised by sampling and definition differences between laboratories. OBJECTIVE: -To establish an agreed-upon protocol for sampling the placenta, and for diagnostic criteria for placental lesions. Recommendations would cover reporting placentas in tertiary centers as well as in community hospitals and district general hospitals, and are also relevant to the scientific research community. DATA SOURCES: -Areas of controversy or uncertainty were explored prior to a 1-day meeting where placental and perinatal pathologists, and maternal-fetal medicine specialists discussed available evidence and subsequently reached consensus where possible. CONCLUSIONS: -The group agreed on sets of uniform sampling criteria, placental gross descriptors, pathologic terminologies, and diagnostic criteria. The terminology and microscopic descriptions for maternal vascular malperfusion, fetal vascular malperfusion, delayed villous maturation, patterns of ascending intrauterine infection, and villitis of unknown etiology were agreed upon. Topics requiring further discussion were highlighted. Ongoing developments in our understanding of the pathology of the placenta, scientific bases of the maternofetoplacental triad, and evolution of the clinical significance of defined lesions may necessitate further refinements of these consensus guidelines. The proposed structure will assist in international comparability of clinicopathologic and scientific studies and assist in refining the significance of lesions associated with adverse pregnancy and later health outcomes. PMID- 27223169 TI - Green care and the consumer. AB - The first step in taking a more responsible attitude to the environment is to put your own house in order by monitoring and thinking carefully about what you buy and how you live. The obstacle for many people is how to buy wisely without it costing the earth - a problem all the more acute for nurses. PMID- 27223170 TI - Nursing the Planet. AB - Healthy people and a healthy environment - which comes first? 'Protecting health' once meant good food, decent housing, enough exercise and an efficient health service. 'Protecting the environment' meant reining in the assaults of industrial society on air, water, land and wildlife. PMID- 27223171 TI - Getting the measure of wounds. AB - A great deal of health profession- MW als' time is spent measuring things. As part of even a fairly short hospital stay, a patient can expect to undergo measurements of weight, blood pressure, urine output, haemoglobin .... The list of possibilities is almost endless. While these measurements are perhaps less frequently employed in tne community setting, they are by no means the prerogative of "hospital practice. PMID- 27223168 TI - Dual PET and Near-Infrared Fluorescence Imaging Probes as Tools for Imaging in Oncology. AB - OBJECTIVE: The purpose of this article is to summarize advances in PET fluorescence resolution, agent design, and preclinical imaging that make a growing case for clinical PET fluorescence imaging. CONCLUSION: Existing SPECT, PET, fluorescence, and MRI contrast imaging techniques are already deeply integrated into the management of cancer, from initial diagnosis to the observation and management of metastases. Combined positron-emitting fluorescent contrast agents can convey new or substantial benefits that improve on these proven clinical contrast agents. PMID- 27223172 TI - Students of destiny. AB - 'Cast your mind back to 4T those early days in nurse training- when you were filled with hope and expectation about your chosen career in nursing. Was there a moment when those expectations were dashed? Or perhaps the process of realisation was gradual. PMID- 27223173 TI - The green care plan. PMID- 27223174 TI - Warm response to regional pay scheme. AB - THE GOVERNMENT'S controversial nurses' regional pay pilot scheme has attracted enthusiastic bidding from health authorities, Nursing Standard discovered last week. PMID- 27223175 TI - Griffiths: announcement expected soon. AB - THE LONG-AWAITED Government response to the Griffiths report on community care is soon to be published, according to indications given by Health Minister David Mellor last week. PMID- 27223176 TI - Health authority accused of racism towards nurse. AB - A STAFF nurse has accused Bexley Health Authority of race discrimination in deciding her clinical grading. PMID- 27223177 TI - Prime minister snubs nurses. AB - THE GOVERNMENT'S White Paper plans came under fire again last week from both the nursing and medical profession. PMID- 27223178 TI - Ozone, CFCs and aerosols. AB - Chlorofluorocarbons (CFCs) are, from the chemist's point of view, unique compounds with very valuable properties. They are inert, cheap and stable. But they also have devastating effects on the environment, destroying the ozone layer and adding to global warming or the greenhouse effect. PMID- 27223179 TI - Copper and common urinary tract organisms. AB - Copper has a history as an inhibitor of fungal and bacterial growth. This property has been utilised in toilet disinfectant blocks and intrauterine contraceptive devices ( 1 ). PMID- 27223180 TI - Raising awareness. AB - Nurses, we are told, should be advocates for health. If this is so, then protection of the environment seems to me to be a natural extension of that role. PMID- 27223181 TI - NHS executive urges strategy on standards. AB - NURSING SHOULD be first in line for a major new quality drive launched by top NHS chief Dun can Nichol. PMID- 27223182 TI - Nurse training reassurance. AB - NEW GOVERNMENT powers will ensure that nurse training continues in self-governing hospitals, Health Secretary Kenneth Clarke said last week. PMID- 27223183 TI - Recommendations on midwives may be rejected. AB - THE GOVERNMENT looks set to reject calls for midwives to be treated as a special case under the new grading structure. PMID- 27223185 TI - Labour pledge on NHS. AB - SHADOW HEALTH Secretary, Robin Cook, has pledged to return self-governing hospitals to district health authority control if Labour wins the next election. PMID- 27223184 TI - [Not Available]. AB - A special balloon race last week symbolically launched a new charity aimed at providing holidays for sick and disabled children. Richard Branson, head of the Virgin Group, launched the National Holiday Fund for Sick and Disabled Children by releasing the last of 5,000 sponsored balloons. The National Holiday Fund, founded by two police officers, aims to brighten the lives of disabled, and chronically or terminally ill children by sending them on dream holidays. Specialist teams, will assess the children and accompany them on holiday. Each of the 5,000 balloons has been sponsored for L1. The sponsor of the balloon which travels the furthest will win L100. PMID- 27223186 TI - Strike call rejected. AB - COHSE DELEGATES last week ruled out industrial action as the way forward in the campaign against the Government's White Paper proposals. PMID- 27223187 TI - Agreement to undertake 'super union' discussions. AB - A POWERFUL new 'super' union comprising members of COHSE, NUPE and NALGO could soon be under discussion. PMID- 27223188 TI - Leadership attacked over clinical grading. AB - COHSE DELEGATES launched a blistering attack on their national leaders last week, accusing them of failing members over clinical grading. PMID- 27223189 TI - Lyofoam in the treatment of open wounds. AB - Lyofoam (Ultra Laboratories Ltd)I consists of open cell polyurethaneI foam sheet, about one centimetre thick. The wound contact side of the dressing is treated by heat and pressure, to form a smooth, non-adherenthydrophilic surface. The untreated reverse side, or outer layer, consists of open cell hydro- phobic foam, with high thermal insulation properties. PMID- 27223190 TI - Nurses honoured in queen's birthday list. AB - The following nurses featured in the Queen's Birthday Honours List. PMID- 27223192 TI - UKCC clears midwife of professional misconduct. AB - A FORMER midwife has been found 'not guilty' of professional misconduct to an allegation that she grossly exaggerated her mileage claims. PMID- 27223191 TI - Success greets campaign. AB - THE HIGHLY successful Enrolled Nurse Campaign launched by Nursing Standard in February of this year has featured successful conferences, innovative meetings and interesting and thought provoking articles by enrolled nurses all over the country. PMID- 27223193 TI - [Not Available]. AB - Around 200 able bodied and wheelchair bound pensioners [illegible word] in Help the Aged's recent Liverpool charity fun run. Mersey Regional Health Authority was among the organisations sponsoring the three-mile, over-60s runaround the city's Sefton Park. PMID- 27223195 TI - Charity rejects cot death claim. AB - A recent theory linking cot death with poisonous gases from PVC mattresses has been dismissed as an 'unproven hypothesis' by a major cot death charity. PMID- 27223196 TI - Easing PMT with magnesium intakes. AB - A daily magnesium supplement can help the ten million women in Britain who suffer from pre-menstrual tension, according to the results of a recent medical trial. PMID- 27223197 TI - Beating cancer with beta carotene intake. AB - A jockey who overcame cancer is urging people to increase their intake of beta carotene in a bid to prevent the disease. PMID- 27223198 TI - Primary nursing video. AB - A new video showing the essence and benefits of primary nursing in practice was launched last week by Leicestershire Health Authority. PMID- 27223199 TI - Getting settled in the North. AB - Trafford Health Authority has recently had some very good news. Bridgewater Hospital - a small but old establishment for psychiatric patients - has just been given the go-ahead for the building of a new hospital. The hospital serves the Trafford area although it is actually situated outside the borough, making access difficult for patients and relatives. PMID- 27223200 TI - The registered mental nurse. AB - It is becoming more and more common for people with a mental illness to be cared for in the community in small mental health units. For this to happen the large old custodial style hospitals are being closed down or have plans for closure in the pipeline. PMID- 27223201 TI - * Pre-registration charge attacked. AB - The decision to charge wouid-be nurses L6 a time for just a pre-registration application has been condemned in Parliament as 'crazy'. PMID- 27223202 TI - * Hospitals to be valued on existing use. AB - All NHS hospitals are to be valued in preparation for the White Paper reforms, the DoH announced last week. PMID- 27223203 TI - * Amendment sought on children's bill. AB - Doctors could be forced to inform parents of advice given to their children about contraceptives and abortions if an amendment to the Children's Bill goes through. PMID- 27223204 TI - * Cattle disease prompts calls for protection. AB - Tighter consumer laws must be introduced to stop the possible spread of a deadly cattle disease to humans, Labour MPs warned last week. PMID- 27223205 TI - * Funding shortfall estimate denied. AB - Health Ministers have denied that the National Health Service is almost half a billion pounds short because the Government got its sums wrong. PMID- 27223206 TI - Listings. AB - National A & E August 5 'Triage in perspective' a study day to be held in the Conference Room, Sharoe Green Hospital, Fulwood, Preston, Lancs. Cost L25. Application forms and further details available from Accident and Emergency Conference Organiser, 49 Portree Drive, Holm- schapel, Cheshire CW4 7JB tel 0477 37671. PMID- 27223207 TI - Whose power? AB - One of the very best things about gaining a certain notoriety is the phone calls and letters I receive and the new people I meet. There are two things that people often say to me. The first is a question, the second a statement. The question goes something like this. 'I'm very interested in the work you do with the homeless. How do I go about it?' The statement is usually versed thus: 'Where I work we wouldn't be allowed to do that.' PMID- 27223212 TI - Attracting students. AB - It is evident that there recruitment crisis in nursing, in addition to the problem of large numbers of student nurses failing to complete their training. My daughter is a student nurse and it is apparent that hospitals and schools of nursing have a great deal of work to do in order to attract and keep young recruits. I would put forward the following points for discussion. PMID- 27223213 TI - Lack of philosophies. AB - On my visits around the United Kingdom I am somewhat concerned about the lack within the majority of district health authorities of set philosophies of care for mental handicap services. Equally, I am amazed that those services which do have a philosophy have not communicated this down to the shop floor staff. PMID- 27223215 TI - Are you an opinionated nurse? AB - Forgive me for taking the lead letter slot in this week's issue but I need your help in introducing a new section in Nursing Standard. If you have a burning desire to put pen to paper about many of the crucial issues facing nursing today then you 're the kind of nurse I want to hear from. PMID- 27223214 TI - Data on day care units. AB - I am the sister of a newly opened day unit for elderly people with mental health problems and I am interested in developing the service for the carers. PMID- 27223216 TI - Hot legs. AB - The recent glorious weather throughout the country brings with it a recurrent and seemingly unresolveable problem. PMID- 27223217 TI - Caseworker community care. AB - With a view of the positive aspects of Griffiths the present and future direction of community care, relating to people with learning difficulties and their families, should be targeted towards a frontline individual approach with the consumer and advocate when appropriate combining specific services according to their needs. PMID- 27223218 TI - Seoul thanks. AB - Having been one of the fortunate nurses from the UK who was privileged to attend the recent 19th Quadrennial ICN Congress at Seoul, South Korea, I feel I must write and comment on the wonderful coverage the conference was given in the recent Nursing Standard. PMID- 27223219 TI - Politics and institutions. AB - My attendance at the International Congress of Nurses prevented me from replying to James Smith's letter (Nursing Standard week ending June 10) before now. He criticises the RCN for maintaining that its apolitical position could be compromised were it to sup- I port an Australian resolution at the lCN calling for the [illegible word] of nuclear weapons testing. James Smith also suggests that this stance by the RCN contrasted unfavourably with my efforts to encourage the profession to become more politically aware. PMID- 27223220 TI - Centenary celebrations. AB - King's Cross Hospital, Dundee, celebrates its Centenary this year and it is proposed to make the occasion with a reunion on Saturday, September 23, 1989. PMID- 27223221 TI - Sisters' support group. AB - In 1988 sisters in the Plymouth Hospitals set up a Sisters' Support Group. The aim was to form a peer group where sisters can talk out problems and have discussion with people in the same situations as themselves. PMID- 27223222 TI - The Bill. AB - The RCN Association of Nursing Students 'Bill of Rights' has recently, like many popular publications gone into a second edition. The RCN Council has ratified this new edition which has made minor changes to the original. Since it was first published in 1987, the Bill of Rights has caused much controversy, many people think that it is inappropriate for the RCN to publish such revolutionary material, others think that it is not revolutionary enough. PMID- 27223223 TI - The right stuff. AB - It may seem a little out of place to recall a document calling on the nursing profession to grant some basic rights to its student population, considering the momentous bids for freedom and democracy we've recently seen in other parts of the world. PMID- 27223224 TI - Learning voice. AB - It can be argued that one of the many roles of learner nurses is that of catalysts - individuals, who question the system, who ask how and why. Students are perhaps obligated to ask such questions; it's part of their unwritten contract. Tutorial staff actually encourage such a questioning attitude, believing it to be beneficial both to the student and ward staff. PMID- 27223225 TI - Student project. AB - In May 1988, Mr John Moore, the then Secretary of State for Health and Social Security, gave the nursing profession Government acceptance of Project 2000. In a letter to the chairman of the UKCC ( 1 ) though, Mr Moore stated that 'further work remains to be done in several important areas before final and definitive conclusions can be reached on some of your proposals'. PMID- 27223226 TI - Better to matter than merely count. AB - when at the age of 42 I gave up my accountancy job in a City bank and became a student nurse at one sixth of the salary I upset the material expectations of a lot of people. But it was money, the symbol of security for so many, that was partly the cause of my undoing. PMID- 27223228 TI - Association of nursing students. PMID- 27223227 TI - [Not Available]. AB - The Association of Nursing Students Executive Committee met at RCN headquarters on June 14. Various items were on the agenda including the Government's White Paper on the National Health Service. PMID- 27223229 TI - The microbe file. PMID- 27223230 TI - Electrical and Thermoelectric Transport by Variable Range Hopping in Thin Black Phosphorus Devices. AB - The moderate band gap of black phosphorus (BP) in the range of 0.3-2 eV, along a high mobility of a few hundred cm(2) V(-1) s(-1) provides a bridge between the gapless graphene and relatively low-mobility transition metal dichalcogenides. Here, we study the mechanism of electrical and thermoelectric transport in 10-30 nm thick BP devices by measurements of electrical conductance and thermopower (S) with various temperatures (T) and gate-electric fields. The T dependences of S and the sheet conductance (sigma?) of the BP devices show behaviors of T(1/3) and exp[-(1/T)(1/3)], respectively, where S reaches ~0.4 mV/K near room T. This result indicates that two-dimensional (2D) Mott's variable range hopping (VRH) is a dominant mechanism in the thermoelectric and electrical transport in our examined thin BP devices. We consider the origin of the 2D Mott's VRH transport in our BPs as trapped charges at the surface of the underlying SiO2 based on the analysis with observed multiple quantum dots. PMID- 27223232 TI - Problems+Solutions. AB - Readers are invited to submit questions relating to problem cases. Inquiries will be answered by qualified consultants and replies forwarded by mail promptly. Selected problems and solutions are published every month in this section. PMID- 27223233 TI - Your Dollars or Your Life. PMID- 27223231 TI - Potential benefits of chewing gum for the delivery of oral therapeutics and its possible role in oral healthcare. AB - INTRODUCTION: Over the years, chewing gum has developed from a candy towards an oral health-promoting nutraceutical. This review summarizes evidence for the oral health benefits of chewing gum, emphasizing identification of active ingredients in gum that facilitate prevention and removal of oral biofilm. AREAS COVERED: Chewing of sugar-free gum yields oral health benefits that include clearance of food debris, reduction in oral dryness, increase of biofilm pH and remineralization of enamel. These basic effects of chewing gum are attributed to increased mastication and salivation. Active ingredients incorporated in chewing gums aim to expand these effects to inhibition of extrinsic tooth stain and calculus formation, enhanced enamel remineralization, reduction of the numbers of bacteria in saliva and amount of oral biofilm, neutralization of biofilm pH, and reduction of volatile sulfur compounds. EXPERT OPINION: Evidence for oral-health benefits of chewing gum additives is hard to obtain due to their relatively low concentrations and rapid wash-out. Clinical effects of gum additives are overshadowed by effects of increased mastication and salivation due to the chewing of gum and require daily chewing of gum for prolonged periods of time. Future studies on active ingredients should focus on specifically targeting pathogenic bacteria, whilst leaving the healthy microbiome unaffected. PMID- 27223234 TI - Editor's Mail. AB - The Editor welcomes readers' comments, and selected letters are published each month. Letters must be signed and should be sent to Editor's Mail at the address shown. The journal reserves the right to condense letters if necessary for space. PMID- 27223236 TI - Cues/Tips. PMID- 27223235 TI - The Medical Bookshelf. PMID- 27223237 TI - Pleural effusions. PMID- 27223238 TI - Pleural effusions. PMID- 27223239 TI - The student's dilemma. AB - This section is reserved for commentaries and brief essays dealing with matters of interest to physicians. Material for consideration should not exceed five double-spaced typewritten pages. An honorarium of $75 is offered at the time of publication. Submissions should be addressed to: Editor, POSTGRADUATE MEDICINE, 4530 W 77th St, Minneapolis, MN 55435. PMID- 27223241 TI - Primary Care Digest. PMID- 27223243 TI - Isomers and Energy Landscapes of Perchlorate-Water Clusters and a Comparison to Pure Water and Sulfate-Water Clusters. AB - Hydrated ions are crucially important in a wide array of environments, from biology to the atmosphere, and the presence and concentration of ions in a system can drastically alter its behavior. One way in which ions can affect systems is in their interactions with proteins. The Hofmeister series ranks ions by their ability to salt-out proteins, with kosmotropes, such as sulfate, increasing their stability and chaotropes, such as perchlorate, decreasing their stability. We study hydrated perchlorate clusters as they are strongly chaotropic and thus exhibit different properties than sulfate. In this study we simulate small hydrated perchlorate clusters using a basin-hopping geometry optimization search with empirical potentials. We compare topological features of these clusters to data from both computational and experimental studies of hydrated sulfate ions and draw some conclusions about ion effects in the Hofmeister series. We observe a patterning conferred to the water molecules within the cluster by the presence of the perchlorate ion and compare the magnitude of this effect to that observed in previous studies involving sulfate. We also investigate the influence of the overall ionic charge on the low-energy structures adopted by these clusters. PMID- 27223244 TI - Methemoglobinemia Hemotoxicity of Some Antimalarial 8-Aminoquinoline Analogues and Their Hydroxylated Derivatives: Density Functional Theory Computation of Ionization Potentials. AB - The administration of primaquine (PQ), an essential drug for the treatment and radical cure of malaria, can lead to methemoglobin formation and life-threatening hemolysis for glucose-6-phosphate dehydrogenase deficient patients. The ionization potential (IP, a quantitative measure of the ability to lose an electron) of the metabolites generated by antimalarial 8-aminoquinoline (8-AQ) drugs like PQ has been believed to be correlated in part to this methemoglobinemia hemotoxicity: the lower the IP of an 8-AQ derivative, the higher the concentration of methemoglobin generated. In this work, demethoxylated primaquine (AQ02) was employed as a model, by intensive computation at the B3LYP SCRF(PCM)/6-311++G**//B3LYP/6-31G** level in water, to study the effects of hydroxylation at various positions on the ionization potential. Compared to the parent AQ02, the IPs of AQ02's metabolites hydroxylated at N1', C5, and C7 were lower by 61, 30, and 19 kJ/mol, respectively, while differences in the IP relative to PQ were small for hydroxylation at all other positions. The C6 position, at which the IP of the hydroxylated metabolite was greater than that of AQ02, by 2 kJ/mol, was found to be unique. Several literature and proposed 8-AQ analogues were studied to evaluate substituent effects on their potential to generate methemoglobin, with the finding that hydroxylations at N1' and C5 contribute the most to the potential hemotoxicity of PQ-based antimalarials, whereas hydroxylation at C7 has little effect. Phenoxylation at C5 in PQ-based 8 AQs can block the hydroxylation at C5 and reduce the potential for methemoglobin generation, while -CF3 and chlorines attached to the phenolic ring can further reduce the risk. The H-shift at N1' during the cationization of hydroxylated metabolites of 8-AQs sharply decreased their IPs, but this effect can be significantly reduced by the introduction of an electron-withdrawing group to the quinoline core. The results and this approach may be utilized for the design of safer antimalarial 8-AQ analogues. PMID- 27223245 TI - Scattering and reflection identification in H-scan images. AB - Medical ultrasound imaging scanners typically display the envelope of the reflected signal on a log scale. The properties of this image and speckle patterns from collections of scatterers have a number of well-known disadvantages. One is the inability to differentiate between different scatterers that may have fundamentally different frequency-dependent scattering cross sections. This study proposes a framework for characterizing scattering behavior and visualizing the results as color coding of the B-scan image. The methodology matches a model of pulse-echo formation from typical situations to the mathematics of Gaussian weighted Hermite functions. The results show an ability to reveal some of the information otherwise hidden in the conventional envelope display, and can be generalized to more conventional bandlimited pulse functions. This new class of images is termed H-scan where 'H' stands for 'Hermite' or 'hue' to distinguish it from conventional B-scan format. PMID- 27223246 TI - SiC Nanowires with Tunable Hydrophobicity/Hydrophilicity and Their Application as Nanofluids. AB - In this paper, several methods including HF, NaOH, TEOS, and PVP treatment were adopted to modify the wettability of silicon carbide (SiC) nanowires switching from hydrophobic to hydrophilic. The phase and microstructure investigated by XRD, FT-IR, XPS, TGA, SEM, and TEM demonstrated SiC nanowires switching from hydrophobic to hydrophilic due to the surface-tethered hydrophilic layer as well as increasing interspace between nanowires. Besides this, SiC nanowires with hydrophilicity may effectively improve the thermal conductivity of a fluid. The thermal conductivity of aqueous SiC nanowires after TEOS treatment with just 0.3 vol % was remarkably improved up to ca. 13.0%. PMID- 27223247 TI - Effects of new ways of working on work hours and work location, health and job related outcomes. AB - New ways of working (NWW) is a type of work organization that is characterized by temporal and spatial flexibility, often combined with extensive use of information and communication technologies (ICT) and performance-based management. In a three-wave intervention study, we examined the effects of NWW on both the organization of work (changes in control over time and place of work; working hours and work location; and other key job characteristics), and on employees' outcomes (work-nonwork balance; health and well-being; and job-related outcomes). We applied a quasi-experimental design within a large Dutch financial company (N = 2,912). We studied an intervention group (n = 2,391) and made comparisons with a reference group (n = 521). There were three study waves: (i) one/two months before, and (ii) 4 months and (iii) 10 months after implementation of NWW. Repeated measures analyses of covariance (involving 361 participants from the intervention group and 80 participants from the reference group) showed a large and significant shift from hours worked at the office to hours worked at home after implementation of NWW. Accordingly, commuting time was reduced. Employees remained working on week days and during day time. Psychosocial work characteristics, work-nonwork balance, stress, fatigue, and job-related outcomes remained favourable and largely unaffected, but the health score in the intervention group decreased (medium effect). These findings suggest that the implementation of NWW does not necessarily lead to changes in psychosocial work characteristics, well-being or job-related outcomes. PMID- 27223248 TI - ActikerallTM (5-Fluorouracil 0.5% and Salicylic Acid 10%) Topical Solution for Patient-directed Treatment of Actinic Keratoses. AB - Actinic keratosis (AK), a common cutaneous lesion with the potential to transform into squamous cell carcinoma, has traditionally been treated with ablative and/or surgical procedures. Recently, a topical formulation combining 0.5% 5 fluorouracil with 10% salicylic acid (5-FU-SA) was introduced in Europe under the trade name ActikerallTM for the treatment of grade I/II AKs. In a single randomized phase III trial, 5-FU-SA was shown to be superior to diclofenac 3% gel in hyaluronic acid, as measured by the histological clearance of one defined lesion (72% vs. 59.1%) and by complete clinical clearance (55.4% vs. 32.0%). 5-FU SA should be applied once daily to a total area of up to 25 cm(2), which may include the lesion(s) and a small area of surrounding skin (rim of healthy skin should not exceed 0.5 cm), for up to 12 weeks. The most common side effects are local inflammation and pruritus at the application site, and no serious adverse effects have been reported to date. Now commercially available in Canada, 5-FU-SA represents a patientapplied therapeutic option for the treatment of both overt and subclinical AKs. PMID- 27223249 TI - DSM-5 Update in Psychodermatology. AB - Up to a third of dermatology outpatients have a significant psychiatric issue complicating their skin complaint. Although the ideal would frequently involve psychiatric assessment, those with comorbid mental illness often refuse psychiatric referral. As a result, it is imperative that dermatologists be mindful of psychiatric comorbidity in their patients and comfortable with the fundamentals of psychodermatologic diagnosis and therapy. This update summarizes current concepts, relevance, and therapeutics in psychodermatology, including aspects pertinent to depression, anxiety, obsessive-compulsive, impulse-control, and delusional disorders as described in the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5, published in 2013 by the American Psychiatric Association). PMID- 27223250 TI - Black cohosh inhibits 17beta-estradiol-induced cell proliferation of endometrial adenocarcinoma cells. AB - This study was conducted to investigate the effect of black cohosh (BC) extract on the proliferation and apoptosis of Ishikawa cells. Ishikawa human endometrial adenocarcinoma cells were treated with or without BC (1, 5, 10 and 25 MUM) and cell proliferation and cytotoxicity were measured by CCK-8 assays and flow cytometry analysis. Additionally, Ishikawa cells were treated with 17beta estradiol (E2), E2 + progesterone and E2 + BC (5 and 10 MUM) and the effect of BC and progesterone on E2-induced cell proliferation was analyzed. BC decreased the proliferation of Ishikawa cells at a dose-dependent rate compared with the control group (p < 0.05). The proliferation of Ishikawa cells increased in the presence of E2, whereas the subsequent addition of progesterone or BC decreased proliferation to the level of the control group (p < 0.05). The inhibitory effect of BC on E2-induced cell proliferation was greater than the inhibitory effect of progesterone. In conclusion, BC induces apoptosis in Ishikawa cells and suppresses E2-induced cell proliferation in Ishikawa cells. BC could be considered a candidate co-treatment agent of estrogen-dependent tumors, especially those involving endometrial cells. PMID- 27223251 TI - Photoresponsive Polysaccharide-Based Hydrogels with Tunable Mechanical Properties for Cartilage Tissue Engineering. AB - Photoresponsive hydrogels were obtained by coordination of alginate-acrylamide hybrid gels (AlgAam) with ferric ions. The photochemistry of Fe(III)-alginate was used to tune the chemical composition, mechanical properties, and microstructure of the materials upon visible light irradiation. The photochemical treatment also induced changes in the swelling properties and transport mechanism in the gels due to the changes in material composition and microstructure. The AlgAam gels were biocompatible and could easily be dried and rehydrated with no change in mechanical properties. These gels showed promise as scaffolds for cartilage tissue engineering, where the photochemical treatment could be used to tune the properties of the material and ultimately change the growth and extracellular matrix production of chondrogenic cells. ATDC5 cells cultured on the hydrogels showed a greater than 2-fold increase in the production of sulfated glycosaminoglycans (sGAG) in the gels irradiated for 90 min compared to the dark controls. Our method provides a simple photochemical tool to postsynthetically control and adjust the chemical and mechanical environment in these gels, as well as the pore microstructure and transport properties. By changing these properties, we could easily access different levels of performance of these materials as substrates for tissue engineering. PMID- 27223252 TI - Multi-polydioxanone (PDO) scaffold for forehead wrinkle correction: A pilot study. AB - BACKGROUND: Forehead wrinkles are the result of contracture of the frontalis muscle and the skin aging process. Currently, hyaluronic acid filler and botulinum toxin are the main materials used for correction of these wrinkles. In addition, polydioxanone (PDO) thread has also been applied for this treatment. OBJECTIVE: In order to evaluate the efficacy and safety of multi-PDO scaffold in animal and human skin, we tested PDO insertion in rat and mini-pig models and human volunteers with forehead wrinkles. METHODS: A stent-shaped multi-PDO scaffold was inserted under the panniculus carnosus of rat dorsal skin and the subcutaneous layer of mini-pig dorsal skin and forehead wrinkles in three human volunteers. RESULTS: Histological analysis at 12 weeks revealed evidence of de novo collagen synthesis, which was consistent with clinical results on photo evaluation. CONCLUSION: Stent-shaped multi-PDO scaffolds may be another effective and safe treatment modality for reduction of forehead wrinkles. PMID- 27223253 TI - High Affinity Agonists of the Neuropeptide Y (NPY) Y4 Receptor Derived from the C Terminal Pentapeptide of Human Pancreatic Polypeptide (hPP): Synthesis, Stereochemical Discrimination, and Radiolabeling. AB - The diastereomeric mixture of d/l-2,7-diaminooctanedioyl-bis(YRLRY-NH2) (BVD-74D, 2) was described in the literature as a high affinity Y4 receptor agonist. Here we report on the synthesis and pharmacological characterization of the pure diastereomers (2R,7R)- and (2S,7S)-2 and a series of homo- and heterodimeric analogues in which octanedioic acid was used as an achiral linker. To investigate the role of the Arg residues, one or two arginines were replaced by Ala. Moreover, N(omega)-(6-aminohexylaminocarbonyl)Arg was introduced as an arginine replacement (17). (2R,7R)-2 was superior to (2S,7S)-2 in binding and functional cellular assays and equipotent with 17. [(3)H]Propionylation of one amino group in the linker of (2R,7R)-2 or at the primary amino group in 17 resulted in high affinity Y4R radioligands ([(3)H]-(2R,7R)-10, [(3)H]18) with subnanomolar Kd values. PMID- 27223254 TI - Chloride anion transporters inhibit growth of methicillin-resistant Staphylococcus aureus (MRSA) in vitro. AB - A series of aminopyrrolic receptors were tested as anion transporters using POPC liposome model membranes. Many were found to be effective Cl(-) transporters and to inhibit clinical strains of Staphylococcus aureus growth in vitro. The best transporters proved effective against the methicillin-resistant Staphylococcus aureus (MRSA) strains, Mu50 and HP1173. Tris-thiourea tren-based chloride transporters were also shown to inhibit the growth of S. aureus in vitro. PMID- 27223255 TI - MBL, P2X7, and SLC11A1 gene polymorphisms in patients with oropharyngeal tularemia. AB - CONCLUSION: A significant association was found of oropharyngeal tularemia with SLC11A1 allele polymorphism (INT4 G/C) and MBL2 C + 4T (P/Q). These results indicate C allele and Q allele might be a risk factor for the development of oropharyngeal tularemia. AIM: This study aimed to investigate the relationship of SLC11A1, MBL, and P2X7 gene polymorphism with oropharyngeal tularemia. METHODS: The study included totally 120 patients who were diagnosed with oropharyngeal tularemia. Frequencies of polymorphisms in the following genes were analyzed both in the patient and control groups in the study: SLC11A1 (5'(GT)n Allele 2/3, Int4 G/C, 3' UTR, D543N G/A), MBL (MBL2 C + 4T (P/Q), and P2X7 (-762 C/T and 1513 A/C). RESULTS: Among all polymorphisms that were investigated in this study, SLC11A1 gene showed a significance in the distriburtion of polymorphism allelle frequency at the INT4 region. Frequency of C allele was 54 (28%) in patients with oropharyngeal tularemia, and 31 (13%) in the control group (p = 0.006 and OR = 1.96 (1.21-3.20)). An association was detected between MBL2 C + 4T (P/Q) gene polymorphism and oropharyngeal tularemia (p < 0.005 and OR = 0.30 (0.19-0.48)). No significant relation was found between P2X7 (-762 C/T and 1513 A/C) gene polymorphism and oropharyngeal tularemia in this study (p > 0.05). PMID- 27223256 TI - How does reading direction modulate perceptual asymmetry effects? AB - Left-side bias effects refer to a bias towards the left side of the stimulus/space in perceptual/visuospatial judgments, and are argued to reflect dominance of right hemisphere processing. It remains unclear whether reading direction can also account for the bias effect. Previous studies comparing readers of languages read from left to right with those read from right to left (e.g., French vs. Hebrew) have obtained inconsistent results. As a language that can be read from left to right or from right to left, Chinese provides a unique opportunity for a within-culture examination of reading direction effects. Chinese participants performed a perceptual judgment task (with both face and Chinese character stimuli; Experiment 1) and two visuospatial attention tasks (the greyscales and line bisection tasks; Experiment 2) once before and once after a reading task, in which they read Chinese passages either from left to right or from right to left for about 20 min. After reading from right to left, participants showed significantly reduced left-side bias in Chinese character perceptual judgments but not in the other three tasks. This effect suggests that the role of reading direction on different forms of left-side bias may differ, and its modulation may be stimulus-specific. PMID- 27223257 TI - Mediation of the malignant biological characteristics of gastric cancer cells by the methylated CpG islands in RNF180 DNA promoter. AB - We previously demonstrated that the methylation of ring finger protein 180 (RNF180) DNA promoter was specific to gastric cancer tissues. We reported that four hypermethylated CpG islands, namely, CpG-116, CpG-80, CpG+97, and CpG+102, in RNF180 promoter were significantly associated with the postoperative overall survival of gastric cancer patients. Correlation analysis revealed that the methylated status of CpG islands was significantly associated with the lymph node metastasis of gastric cancer. We formulated four types of MGC-803 cells with the specific demethylation of one of the four CpG islands through vector transfection method. Conventional detections for the biological characteristics of cancer cells showed that 1) the methylation of CpG+102 island in RNF180 DNA promoter could remarkably influence the comprehensively malignant biological characteristics of gastric cancer cells, including their proliferation, invasion, cell cycle, anti-apoptosis, and tumorigenicity. 2) The CpG+97 island, in addition to the CpG+102 island, should be considered as the other key methylated locus in RNF180 DNA promoter to mediate the malignant biological characteristics of gastric cancer cells. The methylated status of the key CpG islands of RNF180 DNA promoter may be used to predict the variations of the malignant biological characteristics of gastric cancer cells. The proposed method is a promising molecular therapy for gastric cancer. PMID- 27223258 TI - Soluble Toll-like receptor 4 is a potential serum biomarker in non-small cell lung cancer. AB - This study investigated the clinical significance of serum soluble Toll-like receptor 4 (sTLR4) in non-small cell lung cancer (NSCLC). A total of 54 NSCLC patients and 13 healthy volunteers were enrolled from January 2012 to December 2013. The patients with NSCLC were characterized by significantly higher serum levels of sTLR4 compared with those in healthy controls (P < 0.01). A positive correlation between serum sTLR4 and tumor stage was found in patients with stages I-III NSCLC. However, serum sTLR4 in patients with metastatic NSCLC was significantly decreased compared with those with stage III NSCLC (P < 0.05). Furthermore, low serum sTLR4 was identified as a prognostic marker for poor survival of early-stage NSCLC patients who received surgical resection. In conclusion, our present study identified sTLR4 as a potential serum biomarker of NSCLC. PMID- 27223259 TI - The BRG1 chromatin remodeling enzyme links cancer cell metabolism and proliferation. AB - Cancer cells reprogram cellular metabolism to meet the demands of growth. Identification of the regulatory machinery that regulates cancer-specific metabolic changes may open new avenues for anti-cancer therapeutics. The epigenetic regulator BRG1 is a catalytic ATPase for some mammalian SWI/SNF chromatin remodeling enzymes. BRG1 is a well-characterized tumor suppressor in some human cancers, but is frequently overexpressed without mutation in other cancers, including breast cancer. Here we demonstrate that BRG1 upregulates de novo lipogenesis and that this is crucial for cancer cell proliferation. Knockdown of BRG1 attenuates lipid synthesis by impairing the transcription of enzymes catalyzing fatty acid and lipid synthesis. Remarkably, exogenous addition of palmitate, the key intermediate in fatty acid synthesis, rescued the cancer cell proliferation defect caused by BRG1 knockdown. Our work suggests that targeting BRG1 to reduce lipid metabolism and, thereby, to reduce proliferation, has promise for epigenetic therapy in triple negative breast cancer. PMID- 27223260 TI - BET bromodomain-mediated interaction between ERG and BRD4 promotes prostate cancer cell invasion. AB - Prostate cancer (PCa) that becomes resistant to hormone castration and next generation androgen receptor (AR)-targeted therapies, called castration-resistant prostate cancer (CRPC), poses a significant clinical challenge. A better understanding of PCa progression and key molecular mechanisms could bring novel therapies to light. One potential therapeutic target is ERG, a transcription factor aberrantly up-regulated in PCa due to chromosomal rearrangements between androgen-regulated gene TMPRSS2 and ERG. Here we show that the most common PCa associated truncated ERG T1-E4 (ERGDelta39), encoded by fusion between TMPRSS2 exon 1 and ERG exon 4, binds to bromodomain-1 (BD1) of bromodomain containing protein 4 (BRD4), a member of the bromodomain and extraterminal domain (BET) family. This interaction is partially abrogated by BET inhibitors JQ1 and iBET762. Meta-analysis of published ERG (T1-E4) and BRD4 chromatin immunoprecipitation-sequencing (ChIP-seq) data demonstrates overlap in a substantial portion of their binding sites. Gene expression profile analysis shows some ERG-BRD4 co-target genes are upregulated in CRPC compared to hormone naive counterparts. We provide further evidence that ERG-mediated invasion of PCa cells was significantly enhanced by an acetylation-mimicking mutation in ERG that augments the ERG-BRD4 interaction. Our findings reveal that PCa-associated ERG can interact and co-occupy with BRD4 in the genome, and suggest this druggable interaction is critical for ERG-mediated cell invasion and PCa progression. PMID- 27223261 TI - Overexpression of EZH2 is associated with the poor prognosis in osteosarcoma and function analysis indicates a therapeutic potential. AB - Osteosarcoma is a primary malignant bone tumor that has a poor prognosis due to local recurrence, metastasis, and chemotherapy resistance. Therefore, there is an urgent need to develop novel potential therapeutic targets for osteosarcoma. Enhancer of zeste homologue 2 (EZH2) is a member of the polycomb group of proteins, which has important functions in epigenetic silencing and cell cycle regulation. Overexpression of EZH2 has been found in several malignancies, however, its expression and the role of EZH2 in osteosarcoma is largely unknown. In this study, we examined EZH2 expression by immunohistochemistry in a large series of osteosarcoma tissues in association with tumor characteristics and patient outcomes. EZH2 expression was also analyzed in a microarray dataset of osteosarcoma. Results showed that higher expression of EZH2 was significantly associated with more aggressive tumor behavior and poor patient outcomes of osteosarcoma. We subsequently investigated the functional and therapeutic relevance of EZH2 as a target in osteosarcoma. Immunohistochemical analysis indicated that EZH2 expression was significantly associated with more aggressive tumor behavior and poorer patient outcomes of osteosarcoma. EZH2 silencing by siRNA inhibited osteosarcoma cell growth, proliferation, migration, and invasion. Moreover, suppression of EZH2 attenuated cancer stem cell functions. Similar results were observed in osteosarcoma cells treated with EZH2 specific inhibitor 3-deazaneplanocin A (DZNep), which exhausted cellular levels of EZH2. These results suggest that EZH2 is critical for the growth and metastasis of osteosarcoma, and an epigenetic therapy that pharmacologically targets EZH2 via specific inhibitors may constitute a novel approach to the treatment of osteosarcoma. PMID- 27223262 TI - Enhanced anti-tumor activity and cytotoxic effect on cancer stem cell population of metformin-butyrate compared with metformin HCl in breast cancer. AB - Metformin, which is a drug commonly used to treat type 2 diabetes, has shown anti tumor effects in numerous experimental, epidemiologic, observational, and clinical studies. Here, we report a new metformin derivative, metformin-butyrate (MFB). Compared to metformin-HCl, it more potently activates AMPK, inhibits mTOR, and impairs cell cycle progression at S and G2/M phases. Moreover, MFB inhibits the mammosphere formation of breast cancer cells and shows cytotoxic effects against CD44+CD24-/low populations in vitro and in vivo, indicating that it might have preferential effects on the cancer stem cell population. MFB showed synergistic cytotoxicity with docetaxel and cisplatin, and MFB pretreatment of breast cancer cells prior to their injection into the mammary fat pads of mice significantly decreased the obtained xenograft tumor volumes, compared with untreated or metformin-pretreated cells. Overall, MFB showed greater anti neoplastic activity and greater efficacies in targeting the G2/M phase and breast cancer stem cell population, compared to metformin-HCl. This suggests that MFB may be a promising therapeutic agent against aggressive and resistant breast cancers. PMID- 27223263 TI - Targeting DNA repair with aphidicolin sensitizes primary chronic lymphocytic leukemia cells to purine analogs. AB - Purine analogs are among the most effective chemotherapeutic drugs for the treatment of chronic lymphocytic leukemia (CLL). However, chemoresistance and toxicity limit their clinical use. Here, we report that the DNA polymerase inhibitor aphidicolin, which displayed negligible cytotoxicity as a single agent in primary CLL cells, markedly synergizes with fludarabine and cladribine via enhanced apoptosis. Importantly, synergy was recorded regardless of CLL prognostic markers. At the molecular level, aphidicolin enhanced purine analog induced phosphorylation of p53 and accumulation of gammaH2AX, consistent with increase in DNA damage. In addition, aphidicolin delayed gammaH2AX disappearance that arises after removal of purine analogs, suggesting that aphidicolin causes an increase in DNA damage by impeding DNA damage repair. Similarly, aphidicolin inhibited UV-induced DNA repair known to occur primarily through the nucleotide excision repair (NER) pathway. Finally, we showed that fludarabine induced nuclear import of XPA, an indispensable factor for NER, and that XPA silencing sensitized cell lines to undergo apoptosis in response to fludarabine. Together, our data indicate that aphidicolin potentiates the cytotoxicity of purine analogs by inhibiting a DNA repair pathway that involves DNA polymerases, most likely NER, and provide a rationale for manipulating it to therapeutic advantage. PMID- 27223264 TI - H19 long noncoding RNA alters trophoblast cell migration and invasion by regulating TbetaR3 in placentae with fetal growth restriction. AB - Fetal growth restriction (FGR) is a well-recognized risk factor for perinatal mortality and morbidity, as well as neurodevelopmental impairment and adulthood onset disorders. Here we report that the H19 long noncoding RNA (lncRNA) is significantly decreased in placentae from pregnancies with FGR. Downregulation of H19 leads to reduced migration and invasion of extravillous trophoblast (EVT) cells in vitro. This is consistent with reduced trophoblast invasion that has been observed in FGR. Genome-scale transcriptome profiling of EVT cells reveals significantly decreased expression of the type III TGF-beta receptor (TbetaR3) following H19 knockdown. Decreased TbetaR3 expression is also seen in FGR placentae. TbetaR3 repression decreases EVT cell migration and invasion, owing to impaired TGF-beta signaling through a non-canonical TGF-beta signaling pathway. Further, we identify TbetaR3 as a novel regulatory target of microRNA let-7. We propose that dysregulation of this newly identified H19/TbetaR3-mediated regulatory pathway may contribute to the molecular mechanism of FGR. Our findings are the first to show a lncRNA-based mechanism of FGR, holding promise for the development of novel predictive, diagnostic, and therapeutic modalities for FGR. PMID- 27223265 TI - Selective inhibition of p97 by chlorinated analogues of dehydrocurvularin. AB - The ATPase p97 is a ubiquitin targeted segregase that uses the energy of ATP binding and hydrolysis to extract ubiquitylated substrates from biological membranes, from other proteins, or from protein complexes to carry out myriad tasks in eukaryotes. Increased p97 activity has been linked to a poor prognosis in cancer patients, making p97 an anti-neoplastic target. In the present study, we show that dehydrocurvularin (DHC) and its chlorinated variants are covalent inhibitors of p97, interfering with its ATPase activity. Interestingly, cellular studies revealed both DHC and its monochloro analogue interfere with both the proteasome and p97, whereas its dichloro analogue showed p97 specificity. PMID- 27223266 TI - Time for a Change: College Students' Preference for Technology-Mediated Versus Face-to-Face Help for Emotional Distress. AB - BACKGROUND: Even with recent advances in psychological treatments and mobile technology, online computerized therapy is not yet popular. College students, with ubiquitous access to technology, experiencing high distress, and often nontreatment seekers, could be an important area for online treatment dissemination. Finding ways to reach out to college students by offering psychological interventions through technology, devices, and applications they often use, might increase their engagement in treatment. INTRODUCTION: This study evaluates college students' reported willingness to seek help for emotional distress through novel delivery mediums, to play computer games for learning emotional coping skills, and to disclose personal information online. We also evaluated the role of ethnicity and level of emotional distress in help-seeking patterns. METHODS: A survey exploring our domains of interest and the Mental Health Inventory ([MHI] as mental health index) were completed by 572 students (mean age 18.7 years, predominantly Asian American, female, and freshmen in college). RESULTS: More participants expressed preference for online versus face to-face professional help. We found no relationship between MHI and help-seeking preference. A third of participants were likely to disclose at least as much information online as face-to-face. Ownership of mobile technology was pervasive. Asian Americans were more likely to be nontreatment seekers than Caucasians. Most participants were interested in serious games for emotional distress. DISCUSSION: Our results suggest that college students are very open to creative ways of receiving emotional help such as playing games and seeking emotional help online, suggesting a need for online evidence-based treatments. PMID- 27223267 TI - [Perioperative pain therapy in dogs and cats - an overview]. AB - Undermanaged pain leads to negative systemic effects that may greatly disturb our patients' welfare. Therefore, a pain assessment tool should be routinely implemented into clinical practice. Validated pain assessment tools are available for dogs and cats. Advanced analgesic therapy follows the principle of a multimodal approach. This means that different analgesic drugs, which act on different targets within the nociceptive pathway, are combined to achieve the desired analgesic effects. In addition to opioids, nonsteroidal anti-inflammatory drugs and local anaesthetics, alpha2-receptor-agonists, ketamine and gabapentin as well as different nonpharmacologic analgesic techniques are used within the framework of a multimodal analgesic plan. PMID- 27223268 TI - Control of Coherences and Optical Responses of Pigment-Protein Complexes by Plasmonic Nanoantennae. AB - The key for light-harvesting in pigment-protein complexes are molecular excitons, delocalized excited states comprising a superposition of excitations at different molecular sites. There is experimental evidence that the optical response due to such excitons can be largely affected by plasmonic nanoantennae. Here we employ a multiscale approach combining time-dependent density functional theory and polarizable classical models to study the optical behavior of the LH2 complex present in bacteria when interacting with a gold nanorod. The simulation not only reproduces the experiments but also explains their molecular origin. By tuning the chromophoric unit and selectively switching on/off the excitonic interactions, as well as by exploring different setups, we clearly show that the dramatic enhancement in the optical response, unexpectedly, is not accompanied by changes in the coherences. Instead polarization effects are dominant. These results can be used to design an optimal control of the light-harvesting process through plasmonic nanoantennae. PMID- 27223269 TI - Hydrogen on silicene: like or unlike graphene? AB - Hydrogenation of free-standing silicene, the two-dimensional allotrope of silicon, is investigated in detail using first-principles methods and compared with the adsorption of H atoms on graphene. Similarly to graphene, chemisorption of a single H atom on silicene induces the formation of a semilocalized state around the adatom, a sharp peak in the density of states at the Fermi level which acts as a strong resonant scatterer for charge carriers. This state hosts an unpaired electron, the itinerant electron of the resonating valence bond picture which primarily resides on the "majority" sublattice and biases the reactivity towards specific lattice positions. Contrary to graphene, sticking of hydrogen atoms is barrierless, on both the pristine and the hydrogenated surface. As a consequence, hydrogen adsorption on silicene is expected to proceed randomly under typical laboratory conditions, and preferential binding to form balanced dimers (or clusters) only occurs when thermodynamic equilibrium conditions prevail. The absence of clustering can be experimentally confirmed using scanning tunneling microscopy techniques since simulated imaging shows that the investigated structures provide distinguishable features that should allow their easy identification, if present on the surface. Overall, our findings can be rationalized by the fact that in silicene pi bonds are weaker and the lattice is softer than in graphene and suggest that in silicene adatoms may severely limit carrier mobility. PMID- 27223270 TI - How the newborn centriole becomes a mother. PMID- 27223272 TI - Why do Fire Ground Duties Trigger Sudden Cardiac Events in Firefighters? PMID- 27223271 TI - Peripheral Blood Flow Regulation in Human Obesity and Metabolic Syndrome. PMID- 27223273 TI - Pre-Drinking Behavior of Young Heavy Drinkers. AB - BACKGROUND: Pre-drinking has been linked to subsequent heavy drinking and the engagement in multiple risky behaviors. OBJECTIVES: The present study examined a group of adolescents who recently had a "big night out" to determine whether there were differences in their pre-drinking behavior based on age, gender, geographic location, and social setting. METHODS: Participants (n = 351, aged 16 19) representing the heaviest 20-25% of drinkers in their age group were recruited using nonrandom sampling from metropolitan (Melbourne, Sydney, Perth) or regional (Bunbury) locations across Australia and administered a survey by a trained interviewer. RESULTS: Almost half the sample pre-drank (n = 149), most commonly at a friend's house. Those aged 18-19 were more likely to pre-drink, and did so at higher quantities compared to their younger counterparts. Males and females reported similar pre-drinking duration, quantity and amount spent on alcohol. Compared to those in cities, regional participants consumed greater quantities over longer periods of time. Two-thirds of participants consumed alcohol in excess of national guidelines during their pre-drinking session. These participants were more likely to nominate price as a motivation to pre-drink and were less likely to report that someone else provided them alcohol. CONCLUSIONS: This study sheds light on the pre-drinking habits of a population of young risky drinkers, and highlights the need for policy makers to address this form of drinking to reduce alcohol-related harm among young people. PMID- 27223274 TI - Investigation of assumptions underlying current safety guidelines on EM-induced nerve stimulation. AB - An intricate network of a variety of nerves is embedded within the complex anatomy of the human body. Although nerves are shielded from unwanted excitation, they can still be stimulated by external electromagnetic sources that induce strongly non-uniform field distributions. Current exposure safety standards designed to limit unwanted nerve stimulation are based on a series of explicit and implicit assumptions and simplifications. This paper demonstrates the applicability of functionalized anatomical phantoms with integrated coupled electromagnetic and neuronal dynamics solvers for investigating the impact of magnetic resonance exposure on nerve excitation within the full complexity of the human anatomy. The impact of neuronal dynamics models, temperature and local hot spots, nerve trajectory and potential smoothing, anatomical inhomogeneity, and pulse duration on nerve stimulation was evaluated. As a result, multiple assumptions underlying current safety standards are questioned. It is demonstrated that coupled EM-neuronal dynamics modeling involving realistic anatomies is valuable to establish conservative safety criteria. PMID- 27223275 TI - New Casbane and Cembrane Diterpenoids from an Okinawan Soft Coral, Lobophytum sp. AB - A new rare casbane-type diterpenoid 1 and two new cembrane diterpenoids 2, 3 were isolated from an Okinawan soft coral, Lobophytum sp., together with four known cembrane diterpenoids 4-7. Their structures were elucidated by extensive analysis of spectroscopic data (1D and 2D NMR, IR, and MS) and a molecular modeling study. The new isolates showed weak anti-bacterial activity, mild cytotoxicity against HCT116 cells, and anti-inflammatory effect in LPS/IFN-gamma-stimulated RAW 264.7 macrophage cells. PMID- 27223276 TI - Synthesis and p38 Inhibitory Activity of Some Novel Substituted N,N'-Diarylurea Derivatives. AB - We have identified a novel series of substituted N,N'-diarylurea p38alpha inhibitors. The inhibitory activity of the target compounds against the enzyme p38alpha, MAPKAPK2 in BHK cells, TNF-alpha release in LPS-stimulated THP-1 cells and p38alpha binding experiments were tested. Among these compounds, 25a inhibited the p38alpha enzyme with an IC50 value of 0.47 nM and a KD value of 1.54 * 10(-8) and appears to be the most promising one in the series. PMID- 27223277 TI - A Novel Technique to Detect EGFR Mutations in Lung Cancer. AB - Epidermal growth factor receptor (EGFR) gene mutations occur in multiple human cancers; therefore, the detection of EGFR mutations could lead to early cancer diagnosis. This study describes a novel EGFR mutation detection technique. Compared to direct DNA sequencing detection methods, this method is based on allele-specific amplification (ASA), recombinase polymerase amplification (RPA), peptide nucleic acid (PNA), and SYBR Green I (SYBR), referred to as the AS-RPA PNA-SYBR (ARPS) system. The principle of this technique is based on three continuous steps: ASA or ASA combined with PNA to prevent non-target sequence amplification (even single nucleotide polymorphisms, SNPs), the rapid amplification advantage of RPA, and appropriate SYBR Green I detection (the samples harboring EGFR mutations show a green signal). Using this method, the EGFR 19Del(2) mutation was detected in 5 min, while the EGFR L858R mutation was detected in 10 min. In this study, the detection of EGFR mutations in clinical samples using the ARPS system was compatible with that determined by polymerase chain reaction (PCR) and DNA sequencing methods. Thus, this newly developed methodology that uses the ARPS system with appropriate primer sets is a rapid, reliable, and practical way to assess EGFR mutations in clinical samples. PMID- 27223278 TI - Gibberellic Acid: A Key Phytohormone for Spikelet Fertility in Rice Grain Production. AB - The phytohormone gibberellic acid (GA) has essential signaling functions in multiple processes during plant development. In the "Green Revolution", breeders developed high-yield rice cultivars that exhibited both semi-dwarfism and altered GA responses, thus improving grain production. Most studies of GA have concentrated on germination and cell elongation, but GA also has a pivotal role in floral organ development, particularly in stamen/anther formation. In rice, GA signaling plays an important role in spikelet fertility; however, the molecular genetic and biochemical mechanisms of GA in male fertility remain largely unknown. Here, we review recent progress in understanding the network of GA signaling and its connection with spikelet fertility, which is tightly associated with grain productivity in cereal crops. PMID- 27223279 TI - The Role of Proanthocyanidins Complex in Structure and Nutrition Interaction in Alfalfa Forage. AB - Alfalfa (Medicago sativa L.) is one of the main forages grown in the world. Alfalfa is a winter hardy, drought tolerant, N-fixing legume with a good longevity, high yield, high nutrient levels, high digestibility, unique structural to non-structural components ratio, high dry matter intake, and high animal productivity per hectare. However, its main limitation is its excessively rapid initial rate of protein degradation in the rumen, which results in pasture bloat and inefficient use of protein with consequent excessive excretions of nitrogen into the environment. Proanthocyanidins are secondary plant metabolites that can bind with protein and thereby reduce the rate and extent of ruminal protein degradation. However, these secondary metabolites do not accumulate in alfalfa. This review aims to firstly describe the events involved in the rapid release of protein from alfalfa and its effect on ruminant nutrition, environmental pollution, and pasture bloat; secondly, to describe occurrence, structure, functions and benefits of moderate amounts of proanthocyanidin; and finally, to describe the development of alfalfa which accumulates moderate amounts of proanthocyanidins. The emphasis of this review focuses on the role of proanthocyanidins compounds in structure and nutrition interaction in ruminant livestock systems. PMID- 27223280 TI - Analysis of 2-(2-Phenylethyl)chromones by UPLC-ESI-QTOF-MS and Multivariate Statistical Methods in Wild and Cultivated Agarwood. AB - Agarwood is the fragrant resinous material mainly formed from species of Aquilaria. 2-(2-phenylethyl)chromones, especially the highly oxidized 5,6,7,8 tetrahydro-2-(2-phenylethyl)chromones, are the main representative compounds from agarwood. It is important to determine whether agarwood in trade is from cultivated trees or natural trees in the Convention on the International Trade in Endangered Species (CITES). We characterized the 2-(2-phenylethyl)chromones in agarwood by ultra-performance liquid chromatography coupled with electrospray ionization mass spectrometry (UPLC-ESI-QTOF-MS) and differentiated wild from cultivated agarwood by metabolomic analysis. A total of 141 chromones including 50 potentially new compounds were evaluated as belonging to four structural classes (unoxidized 2-(2-phenylethyl)chromones, 5,6,7,8-tetrahydro-2-(2 phenylethyl)-chromones, bi-2-(2-phenylethyl)chromones, and tri-2-(2 phenylethyl)chromones). The metabolic difference between wild and cultivated agarwood was analyzed by component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA). Fourteen markers of metabolisms in wild and cultivated agarwood were constructed (e.g., 6,7-dimethoxy-2-(2 phenylethyl)chromone, 6,8-dihydroxy-2-(2-phenylethyl)chromone, 6-methoxy-2-(2 phenylethyl)chromone, etc.). These results indicated that UPLC-ESI-QTOF-MS-based metabonomics analysis in agarwood may be useful for distinguishing wild agarwood from cultivated agarwood. PMID- 27223282 TI - Cold-Induced Browning Dynamically Alters the Expression Profiles of Inflammatory Adipokines with Tissue Specificity in Mice. AB - Cold exposure or beta3-adrenoceptor agonist treatment induces the adipose tissues remodeling, relevant for beige adipogenesis within white adipose tissue (WAT). It remains unclear whether this process influences inflammatory adipokines expression in adipose tissues. We determine the temporal profile of cold or beta3 adrenoceptor agonist (CL316,243)-induced changes in the expression of inflammatory adipokines in adipose tissues in mice or primary mice adipocytes. Male C57BL/6J mice at eight weeks old were exposed to 4 degrees C for 1-5 days. Interscapular brown adipose tissue (iBAT), inguinal subcutaneous WAT (sWAT) and epididymal WAT (eWAT) were harvested for gene and protein expression analysis. In addition, cultured primary mice brown adipocyte (BA) and white adipocyte (WA) treated with or without CL316,243 were harvested for gene expression analysis. The inflammatory adipokines expressed significantly higher in WAT than BAT at baseline. They were rapidly changed in iBAT, while down-regulated in sWAT and up regulated in eWAT during the cold acclimation. Upon CL316,243 treatment, detected inflammatory adipokines except Leptin were transiently increased in both BA and WA. Our in vivo and in vitro data demonstrate that the browning process alters the inflammatory adipokines expression in adipose tissues, which is acutely responded to in iBAT, dynamically decreased in sWAT whilst increased in eWAT for compensation. PMID- 27223284 TI - Compact SPAD-Based Pixel Architectures for Time-Resolved Image Sensors. AB - This paper reviews the state of the art of single-photon avalanche diode (SPAD) image sensors for time-resolved imaging. The focus of the paper is on pixel architectures featuring small pixel size (<25 MUm) and high fill factor (>20%) as a key enabling technology for the successful implementation of high spatial resolution SPAD-based image sensors. A summary of the main CMOS SPAD implementations, their characteristics and integration challenges, is provided from the perspective of targeting large pixel arrays, where one of the key drivers is the spatial uniformity. The main analog techniques aimed at time-gated photon counting and photon timestamping suitable for compact and low-power pixels are critically discussed. The main features of these solutions are the adoption of analog counting techniques and time-to-analog conversion, in NMOS-only pixels. Reliable quantum-limited single-photon counting, self-referenced analog-to digital conversion, time gating down to 0.75 ns and timestamping with 368 ps jitter are achieved. PMID- 27223281 TI - Circulating MicroRNAs as Biomarkers in Biliary Tract Cancers. AB - Biliary tract cancers (BTCs) are a group of highly aggressive malignant tumors with a poor prognosis. The current diagnosis is based mainly on imaging and intraoperative exploration due to brush cytology havinga low sensitivity and the standard markers, such as carcinoembryonic antigen (CEA) and carbohydrate 19-9 (CA19-9), not having enough sensitivity nor specificity to be used in a differential diagnosis and early stage detection. Thus, better non-invasive methods that can distinguish between normal and pathological tissue are needed. MicroRNAs (miRNAs) are small, single-stranded non-coding RNA molecules of ~20-22 nucleotides that regulate relevant physiological mechanisms and can also be involved in carcinogenesis. Recent studies have demonstrated that miRNAs are detectable in multiple body fluids, showing great stability, either free or trapped in circulating microvesicles, such as exosomes. miRNAs are ideal biomarkers that may be used in screening and prognosis in biliary tract cancers, aiding also in the clinical decisions at different stages of cancer treatment. This review highlights the progress in the analysis of circulating miRNAs in serum, plasma and bile as potential diagnostic and prognostic markers of BTCs. PMID- 27223285 TI - Domotics Project Housing Block. AB - This document develops the study of an implementation project of a home automation system in a housing placed in the town of Galapagar, Madrid. This house, which is going to be occupied by a four-member family, consists of 67 constructed square meters distributed in lounge, kitchen, three bedrooms, bath, bathroom and terrace, this being a common arrangement in Spain. Thus, this study will allow extracting conclusions about the adequacy of the home automation in a wide percentage of housing in Spain. In this document, three house automation proposals are developed based on the requirements of the client and the different home automation levels that the Spanish House and Building Automation Association has established, besides two parallel proposals relating to the safety and the technical alarms. The mentioned proposed systems are described by means of product datasheets and descriptions, distribution plans, measurements, budgets and flow charts that describe the functioning of the system in every case. An evaluation of each system is included, based on other studies conclusions on this matter, where expected energy savings from each design, depending on the current cost of lighting, water and gas, as well as the expected economic amortization period is evaluated. PMID- 27223286 TI - Atmospheric and Fog Effects on Ultra-Wide Band Radar Operating at Extremely High Frequencies. AB - The wide band at extremely high frequencies (EHF) above 30 GHz is applicable for high resolution directive radars, resolving the lack of free frequency bands within the lower part of the electromagnetic spectrum. Utilization of ultra wideband signals in this EHF band is of interest, since it covers a relatively large spectrum, which is free of users, resulting in better resolution in both the longitudinal and transverse dimensions. Noting that frequencies in the millimeter band are subjected to high atmospheric attenuation and dispersion effects, a study of the degradation in the accuracy and resolution is presented. The fact that solid-state millimeter and sub-millimeter radiation sources are producing low power, the method of continuous-wave wideband frequency modulation becomes the natural technique for remote sensing and detection. Millimeter wave radars are used as complementary sensors for the detection of small radar cross section objects under bad weather conditions, when small objects cannot be seen by optical cameras and infrared detectors. Theoretical analysis for the propagation of a wide "chirped" Frequency-Modulated Continuous-Wave (FMCW) radar signal in a dielectric medium is presented. It is shown that the frequency dependent (complex) refractivity of the atmospheric medium causes distortions in the phase of the reflected signal, introducing noticeable errors in the longitudinal distance estimations, and at some frequencies may also degrade the resolution. PMID- 27223283 TI - Prodrug Strategies for Paclitaxel. AB - Paclitaxel is an anti-tumor agent with remarkable anti-tumor activity and wide clinical uses. However, it is also faced with various challenges especially for its poor water solubility and low selectivity for the target. To overcome these disadvantages of paclitaxel, approaches using small molecule modifications and macromolecule modifications have been developed by many research groups from all over the world. In this review, we discuss the different strategies especially prodrug strategies that are currently used to make paclitaxel more effective. PMID- 27223287 TI - Wireless Sensor Array Network DoA Estimation from Compressed Array Data via Joint Sparse Representation. AB - A compressive sensing joint sparse representation direction of arrival estimation (CSJSR-DoA) approach is proposed for wireless sensor array networks (WSAN). By exploiting the joint spatial and spectral correlations of acoustic sensor array data, the CSJSR-DoA approach provides reliable DoA estimation using randomly sampled acoustic sensor data. Since random sampling is performed at remote sensor arrays, less data need to be transmitted over lossy wireless channels to the fusion center (FC), and the expensive source coding operation at sensor nodes can be avoided. To investigate the spatial sparsity, an upper bound of the coherence of incoming sensor signals is derived assuming a linear sensor array configuration. This bound provides a theoretical constraint on the angular separation of acoustic sources to ensure the spatial sparsity of the received acoustic sensor array signals. The Cram e ' r-Rao bound of the CSJSR-DoA estimator that quantifies the theoretical DoA estimation performance is also derived. The potential performance of the CSJSR-DoA approach is validated using both simulations and field experiments on a prototype WSAN platform. Compared to existing compressive sensing-based DoA estimation methods, the CSJSR-DoA approach shows significant performance improvement. PMID- 27223288 TI - A Task-Centric Cooperative Sensing Scheme for Mobile Crowdsourcing Systems. AB - In a densely distributed mobile crowdsourcing system, data collected by neighboring participants often exhibit strong spatial correlations. By exploiting this property, one may employ a portion of the users as active participants and set the other users as idling ones without compromising the quality of sensing or the connectivity of the network. In this work, two participant selection questions are considered: (a) how to recruit an optimal number of users as active participants to guarantee that the overall sensing data integrity is kept above a preset threshold; and (b) how to recruit an optimal number of participants with some inaccurate data so that the fairness of selection and resource conservation can be achieved while maintaining sufficient sensing data integrity. For question (a), we propose a novel task-centric approach to explicitly exploit data correlation among participants. This subset selection problem is regarded as a constrained optimization problem and we propose an efficient polynomial time algorithm to solve it. For question (b), we formulate this set partitioning problem as a constrained min-max optimization problem. A solution using an improved version of the polynomial time algorithm is proposed based on (a). We validate these algorithms using a publicly available Intel-Berkeley lab sensing dataset and satisfactory performance is achieved. PMID- 27223289 TI - A Review of Distributed Optical Fiber Sensors for Civil Engineering Applications. AB - The application of structural health monitoring (SHM) systems to civil engineering structures has been a developing studied and practiced topic, that has allowed for a better understanding of structures' conditions and increasingly lead to a more cost-effective management of those infrastructures. In this field, the use of fiber optic sensors has been studied, discussed and practiced with encouraging results. The possibility of understanding and monitor the distributed behavior of extensive stretches of critical structures it's an enormous advantage that distributed fiber optic sensing provides to SHM systems. In the past decade, several R & D studies have been performed with the goal of improving the knowledge and developing new techniques associated with the application of distributed optical fiber sensors (DOFS) in order to widen the range of applications of these sensors and also to obtain more correct and reliable data. This paper presents, after a brief introduction to the theoretical background of DOFS, the latest developments related with the improvement of these products by presenting a wide range of laboratory experiments as well as an extended review of their diverse applications in civil engineering structures. PMID- 27223290 TI - Sleep Monitoring Based on a Tri-Axial Accelerometer and a Pressure Sensor. AB - Sleep disorders are a common affliction for many people even though sleep is one of the most important factors in maintaining good physiological and emotional health. Numerous researchers have proposed various approaches to monitor sleep, such as polysomnography and actigraphy. However, such approaches are costly and often require overnight treatment in clinics. With this in mind, the research presented here has emerged from the question: "Can data be easily collected and analyzed without causing discomfort to patients?" Therefore, the aim of this study is to provide a novel monitoring system for quantifying sleep quality. The data acquisition system is equipped with multimodal sensors, including a three axis accelerometer and a pressure sensor. To identify sleep quality based on measured data, a novel algorithm, which uses numerous physiological parameters, was proposed. Such parameters include non-REM sleep time, the number of apneic episodes, and sleep durations for dominant poses. To assess the effectiveness of the proposed system, three participants were enrolled in this experimental study for a duration of 20 days. From the experimental results, it can be seen that the proposed monitoring system is effective for quantifying sleep quality. PMID- 27223291 TI - An Improved Measurement Method for the Strength of Radiation of Reflective Beam in an Industrial Optical Sensor Based on Laser Displacement Meter. AB - An optical sensor such as a laser range finder (LRF) or laser displacement meter (LDM) uses reflected and returned laser beam from a target. The optical sensor has been mainly used to measure the distance between a launch position and the target. However, optical sensor based LRF and LDM have numerous and various errors such as statistical errors, drift errors, cyclic errors, alignment errors and slope errors. Among these errors, an alignment error that contains measurement error for the strength of radiation of returned laser beam from the target is the most serious error in industrial optical sensors. It is caused by the dependence of the measurement offset upon the strength of radiation of returned beam incident upon the focusing lens from the target. In this paper, in order to solve these problems, we propose a novel method for the measurement of the output of direct current (DC) voltage that is proportional to the strength of radiation of returned laser beam in the received avalanche photo diode (APD) circuit. We implemented a measuring circuit that is able to provide an exact measurement of reflected laser beam. By using the proposed method, we can measure the intensity or strength of radiation of laser beam in real time and with a high degree of precision. PMID- 27223292 TI - myBlackBox: Blackbox Mobile Cloud Systems for Personalized Unusual Event Detection. AB - We demonstrate the feasibility of constructing a novel and practical real-world mobile cloud system, called myBlackBox, that efficiently fuses multimodal smartphone sensor data to identify and log unusual personal events in mobile users' daily lives. The system incorporates a hybrid architectural design that combines unsupervised classification of audio, accelerometer and location data with supervised joint fusion classification to achieve high accuracy, customization, convenience and scalability. We show the feasibility of myBlackBox by implementing and evaluating this end-to-end system that combines Android smartphones with cloud servers, deployed for 15 users over a one-month period. PMID- 27223293 TI - Integrated Navigation System Design for Micro Planetary Rovers: Comparison of Absolute Heading Estimation Algorithms and Nonlinear Filtering. AB - This paper provides algorithms to fuse relative and absolute microelectromechanical systems (MEMS) navigation sensors, suitable for micro planetary rovers, to provide a more accurate estimation of navigation information, specifically, attitude and position. Planetary rovers have extremely slow speed (~1 cm/s) and lack conventional navigation sensors/systems, hence the general methods of terrestrial navigation may not be applicable to these applications. While relative attitude and position can be tracked in a way similar to those for ground robots, absolute navigation information is hard to achieve on a remote celestial body, like Moon or Mars, in contrast to terrestrial applications. In this study, two absolute attitude estimation algorithms were developed and compared for accuracy and robustness. The estimated absolute attitude was fused with the relative attitude sensors in a framework of nonlinear filters. The nonlinear Extended Kalman filter (EKF) and Unscented Kalman filter (UKF) were compared in pursuit of better accuracy and reliability in this nonlinear estimation problem, using only on-board low cost MEMS sensors. Experimental results confirmed the viability of the proposed algorithms and the sensor suite, for low cost and low weight micro planetary rovers. It is demonstrated that integrating the relative and absolute navigation MEMS sensors reduces the navigation errors to the desired level. PMID- 27223294 TI - Antifungal Effect of Henna against Candida albicans Adhered to Acrylic Resin as a Possible Method for Prevention of Denture Stomatitis. AB - Denture stomatitis is a very common disease affecting the oral mucosa of denture wearers. The aim of this study was to measure the antifungal effect of henna against Candida albicans adhered to acrylic resin as a possible method for prevention of denture stomatitis. One-hundred-eighty acrylic plates were prepared of heat-cured acrylic denture resin. The specimens were divided into six groups of 30 samples each. The first group was only polymer and monomer following the conventional manufacturer instruction for processing complete dentures. The other five groups were processed by adding different concentration of Yamani henna powder (Harazi) to the polymer in a concentration of henna: polymer 1%, 2.5%, 5%, 7.5% and 10%, respectively. Samples were incubated in artificial saliva rich with Candida albicans at 37 degrees C, and the effect of henna on Candida albicans was evaluated in two different methods: semi-quantitative slide count and a culture-based quantitative assay (quantitative). Variation in the number of live Candida was observed with the increase in the concentration of Yamani henna powder. It was observed that the variation in live Candida, between control group and group B (concentration of Yamani henna powder was 1%), was statistically significant with a p-value of 0.0001. Similarly, variations in live Candida were significant, when the concentration of powder was 7.5% or 10% in contrast with control group and p-values were 0.0001 and 0.001 respectively. Adding henna to acrylic resin denture could be effective in controlling Candida albicans proliferation on the denture surface; however, its effects on the physical properties of acrylic resin denture need further studies. PMID- 27223295 TI - Association of Children's Urinary CC16 Levels with Arsenic Concentrations in Multiple Environmental Media. AB - Arsenic exposure has been associated with decreased club cell secretory protein (CC16) levels in adults. Further, both arsenic exposure and decreased levels of CC16 in childhood have been associated with decreased adult lung function. Our objective was to determine if urinary CC16 levels in children are associated with arsenic concentrations in environmental media collected from their homes. Yard soil, house dust, and tap water were taken from 34 homes. Urine and toenail samples were collected from 68 children. All concentrations were natural log transformed prior to data analysis. There were associations between urinary CC16 and arsenic concentration in soil (b = -0.43, p = 0.001, R2 = 0.08), water (b = 0.22, p = 0.07, R2 = 0.03), house dust (b = -0.37, p = 0.07, R2 = 0.04), and dust loading (b = -0.21, p = 0.04, R2 = 0.04). In multiple analyses, only the concentration of arsenic in soil was associated with urinary CC16 levels (b = 0.42, p = 0.02, R2 = 0.14 (full model)) after accounting for other factors. The association between urinary CC16 and soil arsenic may suggest that localized arsenic exposure in the lungs could damage the airway epithelium and predispose children for diminished lung function. Future work to assess this possible mechanism should examine potential associations between airborne arsenic exposures, CC16 levels, lung function, and other possible confounders in children in arsenic-impacted communities. PMID- 27223296 TI - Aerosol Transmission of Filoviruses. AB - Filoviruses have become a worldwide public health concern because of their potential for introductions into non-endemic countries through international travel and the international transport of infected animals or animal products. Since it was first identified in 1976, in the Democratic Republic of Congo (formerly Zaire) and Sudan, the 2013-2015 western African Ebola virus disease (EVD) outbreak is the largest, both by number of cases and geographical extension, and deadliest, recorded so far in medical history. The source of ebolaviruses for human index case(s) in most outbreaks is presumptively associated with handling of bush meat or contact with fruit bats. Transmission among humans occurs easily when a person comes in contact with contaminated body fluids of patients, but our understanding of other transmission routes is still fragmentary. This review deals with the controversial issue of aerosol transmission of filoviruses. PMID- 27223297 TI - N-Glycans on the Rift Valley Fever Virus Envelope Glycoproteins Gn and Gc Redundantly Support Viral Infection via DC-SIGN. AB - Rift Valley fever is a mosquito-transmitted, zoonotic disease that infects humans and ruminants. Dendritic cell specific intercellular adhesion molecule 3 (ICAM-3) grabbing non-integrin (DC-SIGN) acts as a receptor for members of the phlebovirus genus. The Rift Valley fever virus (RVFV) glycoproteins (Gn/Gc) encode five putative N-glycan sequons (asparagine (N)-any amino acid (X)-serine (S)/threonine (T)) at positions: N438 (Gn), and N794, N829, N1035, and N1077 (Gc). The N glycosylation profile and significance in viral infection via DC-SIGN have not been elucidated. Gc N-glycosylation was first evaluated by using Gc asparagine (N) to glutamine (Q) mutants. Subsequently, we generated a series of recombinant RVFV MP-12 strain mutants, which encode N-to-Q mutations, and the infectivity of each mutant in Jurkat cells stably expressing DC-SIGN was evaluated. Results showed that Gc N794, N1035, and N1077 were N-glycosylated but N829 was not. Gc N1077 was heterogeneously N-glycosylated. RVFV Gc made two distinct N-glycoforms: "Gc-large" and "Gc-small", and N1077 was responsible for "Gc-large" band. RVFV showed increased infection of cells expressing DC-SIGN compared to cells lacking DC-SIGN. Infection via DC-SIGN was increased in the presence of either Gn N438 or Gc N1077. Our study showed that N-glycans on the Gc and Gn surface glycoproteins redundantly support RVFV infection via DC-SIGN. PMID- 27223298 TI - Experimental Infection of Calves by Two Genetically-Distinct Strains of Rift Valley Fever Virus. AB - Recent outbreaks of Rift Valley fever in ruminant livestock, characterized by mass abortion and high mortality rates in neonates, have raised international interest in improving vaccine control strategies. Previously, we developed a reliable challenge model for sheep that improves the evaluation of existing and novel vaccines in sheep. This sheep model demonstrated differences in the pathogenesis of Rift Valley fever virus (RVFV) infection between two genetically distinct wild-type strains of the virus, Saudi Arabia 2001 (SA01) and Kenya 2006 (Ken06). Here, we evaluated the pathogenicity of these two RVFV strains in mixed breed beef calves. There was a transient increase in rectal temperatures with both virus strains, but this clinical sign was less consistent than previously reported with sheep. Three of the five Ken06-infected animals had an early-onset viremia, one day post-infection (dpi), with viremia lasting at least three days. The same number of SA01-infected animals developed viremia at 2 dpi, but it only persisted through 3 dpi in one animal. The average virus titer for the SA01 infected calves was 1.6 logs less than for the Ken06-infected calves. Calves, inoculated with either strain, seroconverted by 5 dpi and showed time-dependent increases in their virus-neutralizing antibody titers. Consistent with the results obtained in the previous sheep study, elevated liver enzyme levels, more severe liver pathology and higher virus titers occurred with the Ken06 strain as compared to the SA01 strain. These results demonstrate the establishment of a virulent challenge model for vaccine evaluation in calves. PMID- 27223300 TI - Factors That Improve RT-QuIC Detection of Prion Seeding Activity. AB - Rapid and sensitive detection of prions is important in managing prion diseases. The real-time quaking-induced conversion (RT-QuIC) assay for prion seeding activity has been applied to many prion diseases and provides for specific antemortem diagnostic testing. We evaluated RT-QuIC's long-term consistency and varied multiple reaction parameters. Repeated assays of a single scrapie sample using multiple plate readers and recombinant prion protein (rPrP(Sen)) substrates gave comparable results. N-terminal truncated hamster rPrP(Sen) (residues 90-231) hastened both prion-seeded and prion-independent reactions but maintained a clear kinetic distinction between the two. Raising temperatures or shaking speeds accelerated RT-QuIC reactions without compromising specificity. When applied to nasal brushings from Creutzfeldt-Jakob disease patients, higher temperatures accelerated RT-QuIC kinetics, and the use of hamster rPrP(Sen) (90-231) strengthened RT-QuIC responses. Elongation of shaking periods reduced scrapie seeded reaction times, but continuous shaking promoted false-positive reactions. Furthermore, pH 7.4 provided for more rapid RT-QuIC reactions than more acidic pHs. Additionally, we show that small variations in the amount of sodium dodecyl sulfate (SDS) significantly impacted the assay. Finally, RT-QuIC performed in multiplate thermoshakers followed by fluorescence readings in separate plate readers enhanced assay throughput economically. Collectively, these results demonstrate improved speed, efficacy and practicality of RT-QuIC assays and highlight variables to be optimized for future applications. PMID- 27223301 TI - Deletion of A44L, A46R and C12L Vaccinia Virus Genes from the MVA Genome Improved the Vector Immunogenicity by Modifying the Innate Immune Response Generating Enhanced and Optimized Specific T-Cell Responses. AB - MVA is an attenuated vector that still retains immunomodulatory genes. We have previously reported its optimization after deleting the C12L gene, coding for the IL-18 binding-protein. Here, we analyzed the immunogenicity of MVA vectors harboring the simultaneous deletion of A44L, related to steroid synthesis and A46R, a TLR-signaling inhibitor (MVADeltaA44L-A46R); or also including a deletion of C12L (MVADeltaC12L/DeltaA44L-A46R). The absence of biological activities of the deleted genes in the MVA vectors was demonstrated. Adaptive T-cell responses against VACV epitopes, evaluated in spleen and draining lymph-nodes of C57Bl/6 mice at acute/memory phases, were of higher magnitude in those animals that received deleted MVAs compared to MVAwt. MVADeltaC12L/DeltaA44L-A46R generated cellular specific memory responses of higher quality characterized by bifunctionality (CD107a/b+/IFN-gamma+) and proliferation capacity. Deletion of selected genes from MVA generated innate immune responses with higher levels of determining cytokines related to T-cell response generation, such as IL-12, IFN gamma, as well as IL-1beta and IFN-beta. This study describes for the first time that simultaneous deletion of the A44L, A46R and C12L genes from MVA improved its immunogenicity by enhancing the host adaptive and innate immune responses, suggesting that this approach comprises an appropriate strategy to increase the MVA vaccine potential. PMID- 27223302 TI - Effect of Chocolate and Yerba Mate Phenolic Compounds on Inflammatory and Oxidative Biomarkers in HIV/AIDS Individuals. AB - Flavonoids in cocoa and yerba mate have a beneficial role on inflammation and oxidative disorders. Their effect on HIV individuals has not been studied yet, despite the high cardiovascular risk of this population. This study investigated the role of cocoa and yerba mate consumption on oxidative and inflammatory biomarkers in HIV+ individuals. A cross-over, placebo-controlled, double-blind, randomized clinical trial was conducted in 92 individuals on antiretroviral therapy for at least six months and at viral suppression. Participants were randomized to receive either 65 g of chocolate or chocolate-placebo or 3 g of yerba mate or mate-placebo for 15 days each, alternating by a washout period of 15 days. At baseline, and at the end of each intervention regimen, data regarding anthropometry, inflammatory, oxidative and immunological parameters were collected. High-sensitivity C-reactive protein, fibrinogen, lipid profile, white blood cell profile and thiobarbituric acid reactive substances were assessed. There was a difference between mean concentrations of HDL-c (ANOVA; p <= 0.05) among the different regimens: dark chocolate, chocolate-placebo, yerba mate and mate-placebo. When a paired Student t-test was used for comparisons between mean HDL-c at baseline and after each regimen, the mean concentration of HDL-c was higher after supplementation with dark chocolate (p = 0.008). PMID- 27223299 TI - Hepatitis C Virus Infection Induces Autophagy as a Prosurvival Mechanism to Alleviate Hepatic ER-Stress Response. AB - Hepatitis C virus (HCV) infection frequently leads to chronic liver disease, liver cirrhosis and hepatocellular carcinoma (HCC). The molecular mechanisms by which HCV infection leads to chronic liver disease and HCC are not well understood. The infection cycle of HCV is initiated by the attachment and entry of virus particles into a hepatocyte. Replication of the HCV genome inside hepatocytes leads to accumulation of large amounts of viral proteins and RNA replication intermediates in the endoplasmic reticulum (ER), resulting in production of thousands of new virus particles. HCV-infected hepatocytes mount a substantial stress response. How the infected hepatocyte integrates the viral induced stress response with chronic infection is unknown. The unfolded protein response (UPR), an ER-associated cellular transcriptional response, is activated in HCV infected hepatocytes. Over the past several years, research performed by a number of laboratories, including ours, has shown that HCV induced UPR robustly activates autophagy to sustain viral replication in the infected hepatocyte. Induction of the cellular autophagy response is required to improve survival of infected cells by inhibition of cellular apoptosis. The autophagy response also inhibits the cellular innate antiviral program that usually inhibits HCV replication. In this review, we discuss the physiological implications of the HCV induced chronic ER-stress response in the liver disease progression. PMID- 27223303 TI - Impact of a High-Fat or High-Fiber Diet on Intestinal Microbiota and Metabolic Markers in a Pig Model. AB - To further elaborate interactions between nutrition, gut microbiota and host health, an animal model to simulate changes in microbial composition and activity due to dietary changes similar to those in humans is needed. Therefore, the impact of two different diets on cecal and colonic microbial gene copies and metabolic activity, organ development and biochemical parameters in blood serum was investigated using a pig model. Four pigs were either fed a low-fat/high fiber (LF), or a high-fat/low-fiber (HF) diet for seven weeks, with both diets being isocaloric. A hypotrophic effect of the HF diet on digestive organs could be observed compared to the LF diet (p < 0.05). Higher gene copy numbers of Bacteroides (p < 0.05) and Enterobacteriaceae (p < 0.001) were present in intestinal contents of HF pigs, bifidobacteria were more abundant in LF pigs (p < 0.05). Concentrations of acetate and butyrate were higher in LF pigs (p < 0.05). Glucose was higher in HF pigs, while glutamic pyruvic transaminase (GPT) showed higher concentrations upon feeding the LF diet (p < 0.001). However, C-reactive protein (CRP) decreased with time in LF pigs (p < 0.05). In part, these findings correspond to those in humans, and are in support of the concept of using the pig as human model. PMID- 27223304 TI - Cardiovascular, Metabolic Effects and Dietary Composition of Ad-Libitum Paleolithic vs. Australian Guide to Healthy Eating Diets: A 4-Week Randomised Trial. AB - (1) BACKGROUND: The Paleolithic diet is popular in Australia, however, limited literature surrounds the dietary pattern. Our primary aim was to compare the Paleolithic diet with the Australian Guide to Healthy Eating (AGHE) in terms of anthropometric, metabolic and cardiovascular risk factors, with a secondary aim to examine the macro and micronutrient composition of both dietary patterns; (2) METHODS: 39 healthy women (mean +/- SD age 47 +/- 13 years, BMI 27 +/- 4 kg/m2) were randomised to either the Paleolithic (n = 22) or AGHE diet (n = 17) for four weeks. Three-day weighed food records, body composition and biochemistry data were collected pre and post intervention; (3) RESULTS: Significantly greater weight loss occurred in the Paleolithic group (-1.99 kg, 95% CI -2.9, -1.0), p < 0.001). There were no differences in cardiovascular and metabolic markers between groups. The Paleolithic group had lower intakes of carbohydrate (-14.63% of energy (E), 95% CI -19.5, -9.7), sodium (-1055 mg/day, 95% CI -1593, -518), calcium (-292 mg/day 95% CI -486.0, -99.0) and iodine (-47.9 MUg/day, 95% CI 79.2, -16.5) and higher intakes of fat (9.39% of E, 95% CI 3.7, 15.1) and beta carotene (6777 MUg/day 95% CI 2144, 11410) (all p < 0.01); (4) CONCLUSIONS: The Paleolithic diet induced greater changes in body composition over the short-term intervention, however, larger studies are recommended to assess the impact of the Paleolithic vs. AGHE diets on metabolic and cardiovascular risk factors in healthy populations. PMID- 27223305 TI - The MYC 3' Wnt-Responsive Element Drives Oncogenic MYC Expression in Human Colorectal Cancer Cells. AB - Mutations in components of the Wnt/beta-catenin signaling pathway drive colorectal cancer (CRC) by deregulating expression of downstream target genes including the c-MYC proto-oncogene (MYC). The critical regulatory DNA enhancer elements that control oncogenic MYC expression in CRC have yet to be fully elucidated. In previous reports, we correlated T-cell factor (TCF) and beta catenin binding to the MYC 3' Wnt responsive DNA element (MYC 3' WRE) with MYC expression in HCT116 cells. Here we used CRISPR/Cas9 to determine whether this element is a critical driver of MYC. We isolated a clonal population of cells that contained a deletion of a single TCF binding element (TBE) within the MYC 3' WRE. This deletion reduced TCF/beta-catenin binding to this regulatory element and decreased MYC expression. Using RNA-Seq analysis, we found altered expression of genes that regulate metabolic processes, many of which are known MYC target genes. We found that 3' WRE-Mut cells displayed a reduced proliferative capacity, diminished clonogenic growth, and a decreased potential to form tumors in vivo. These findings indicate that the MYC 3' WRE is a critical driver of oncogenic MYC expression and suggest that this element may serve as a therapeutic target for CRC. PMID- 27223306 TI - Effect of Different Broad Waveband Lights on Membrane Lipids of a Cyanobacterium, Synechococcus sp., as Determined by UPLC-QToF-MS and Vibrational Spectroscopy. AB - Differential profile of membrane lipids and pigments of a Synechococcus sp. cyanobacterial strain cells exposed to blue, green, red and white light are determined by means of liquid chromatography and mass spectrometry or diode array detection. Raman and ATR-IR spectra of intact cells under the diverse light wavebands are also reported. Blue light cells exhibited an increased content of photosynthetic pigments as well as specific species of membrane glycerolipids as compared to cells exposed to other wavebands. The A630/A680 ratio indicated an increased content of phycobilisomes (PBS) in the blue light-exposed cells. Some differences in the protein conformation between the four light waveband-exposed cells were deduced from the variable absorbance at specific wavenumbers in the FT Raman and ATR-FTIR spectra, in particular bands assigned to amide I and amide II. Bands from 1180 to 950 cm(-1) in the ATR-FTIR spectrum suggest degraded outer membrane polysaccharide in the blue light-exposed cells. PMID- 27223307 TI - Comparative analysis of ampoules and vials in sterile and conventional packaging as to microbial load and sterility test. AB - OBJECTIVE: To compare sterility and microbial (bacteria and fungi) load in the outer part of hyperbaric bupivacaine (Neocaina(r)) in ampoule and bupivacaine in vial, in conventional and sterile pack formulations. METHODS: The sterile packs were divided into two groups: G1 (n=16) with ampoules and G2 (n=16) with vials. Conventional formulations were divided into two groups, being G3 (n=16) with ampoules and G4 (n=16) with vials. The ampoules and vials were opened and had their content drawn. The empty bottles were then placed in sterile plastic bags and sent for analysis of microbial load (bacteria and fungi) and sterility testing. Data were analyzed using the chi2 test with Yates correction, and 95% confidence interval. RESULTS: G1 and G2 showed no bacterial growth when compared to conventional groups (p<0.001). The most common agent in conventional microbiological samples was Staphylococcus aureus. There was no fungal growth in both groups. CONCLUSION: The use of (sterile pack) reduces the microbial load of bottles, and would decrease the chance of exposure to potential contamination of the anesthetic solution. OBJETIVO: Comparar a esterilidade e a carga microbiana (bacterias e fungos) da parte externa dos frascos de envasamento de bupivacaina hiperbarica (Neocaina(r)) em ampola e bupivacaina em frasco-ampola das apresentacoes convencional e esteril (sterile pack). METODOS: As apresentacoes estereis (sterile pack) foram distribuidas em dois grupos, sendo que o G1 (n=16) continha as ampolas e o G2 (n=16), os frascos-ampola. As apresentacoes convencionais foram distribuidas em dois grupos, a saber G3 (n=16) com as ampolas e G4 (n=16) com os frascos-ampola. As ampolas e os frascos-ampolas eram abertos e tinham seu conteudo aspirado. Os frascos vazios eram, entao, acondicionados em sacos plasticos estereis e enviados para analise quanto a carga microbiana (bacterias e fungos), bem como para o teste de esterilidade. Os dados foram analisados por meio do teste chi2 com correcao Yates com intervalo de confianca de 95%. RESULTADOS: Os grupos G1 e G2 nao apresentaram crescimento bacteriano quando comparado aos grupos convencionais (p<0,001). O microbiano mais comum nas amostras convencionais foi o Staphylococcus aureus. Nao houve crescimento de fungos em nenhum dos grupos. CONCLUSAO: O uso de embalagens estereis (sterile pack) diminui a carga microbiana dos frascos de envasamentos, o que diminuiria a chance de exposicao a uma potencial contaminacao da solucao anestesica. PMID- 27223308 TI - Ovarian hyperstimulation syndrome in a spontaneous singleton pregnancy. AB - The ovarian hyperstimulation syndrome is the combination of increased ovarian volume, due to the presence of multiple cysts and vascular hyperpermeability, with subsequent hypovolemia and hemoconcentration. We report a case of spontaneous syndrome in a singleton pregnancy. This was a spontaneous pregnancy with 12 weeks of gestational age. The pregnancy was uneventful until 11 weeks of gestational age. After that, the pregnant woman complained of progressive abdominal distention associated with abdominal discomfort. She did not report other symptoms. In the first trimester, a routine ultrasonography showed enlarged ovaries, multiples cysts and ascites. Upon admission, the patient was hemodynamically stable, her serum beta-hCG was 24,487mIU/mL, thyroid-stimulating hormone was 2.2uUI/mL and free T4 was 1.8ng/dL. All results were within normal parameters. However, levels of estradiol were high (10,562pg/mL). During hospitalization, she received albumin, furosemide and prophylactic dose of enoxaparin. The patient was discharged on the sixth hospital day. RESUMO A sindrome de hiperestimulacao ovariana e a combinacao do aumento dos ovarios, devido a presenca de multiplos cistos e de hiperpermeabilidade vascular, com subsequente hipovolemia e hemoconcentracao. Relata-se um caso de sindrome espontanea em uma gestacao unica. Trata-se de gravidez espontanea com 12 semanas de idade gestacional. A gravidez ocorreu sem intercorrencias ate 11 semanas de idade gestacional. Apos, a gestante passou a se queixar de distensao abdominal progressiva, associada com desconforto abdominal. A paciente nao relatava outros sintomas. A ultrassonografia de rotina no primeiro trimestre mostrou ovarios aumentados com multiplos cistos e ascite. No momento da internacao, a paciente apresentava-se hemodinamicamente estavel, com beta-hCG serico de 24.487mUI/mL, hormonio estimulante da tireoide de 2,2uUI/m e T4 livre de 1,8ng/dL, ou seja, valores dentro dos parametros normais. Porem, os niveis de estradiol estavam elevados (10.562pg/mL). Durante a internacao, a paciente recebeu albumina, furosemida e enoxaparina profilatica. A alta hospitalar ocorreu no sexto dia de internacao. PMID- 27223309 TI - Old-and With Severe Heart Failure: Telemonitoring by Using Digital Pen Technology in Specialized Homecare: System Description, Implementation, and Early Results. AB - Telehealth programs for heart failure have been studied using a variety of techniques. Because currently a majority of the elderly are nonusers of computers and Internet, we developed a home telehealth system based on digital pen technology. Fourteen patients (mean age, 84 years [median, 83 years]) with severe heart failure participated in a 13-month pilot study in specialized homecare. Participants communicated patient-reported outcome measures daily using the digital pen and health diary forms, submitting a total of 3 520 reports. The reports generated a total of 632 notifications when reports indicated worsening health. Healthcare professionals reviewed reports frequently, more than 4700 times throughout the study, and acted on the information provided. Patients answered questionnaires and were observed in their home environment when using the system. Results showed that the technology was accepted by participants: patients experienced an improved contact with clinicians; they felt more compliant with healthcare professionals' advice, and they felt more secure and more involved in their own care. Via the system, the healthcare professionals detected heart failure-related deteriorations at an earlier stage, and as a consequence, none of the patients were admitted into hospital care during the study. PMID- 27223310 TI - Increasing patient involvement in the diabetic foot pathway: a pilot randomized controlled trial. AB - AIMS: This pilot study aimed to explore whether the use of an intervention to increase shared decision-making (Decision Navigation) increased decision self efficacy and foot-treatment adherence in patients with a diabetic foot ulcer. METHODS: Fifty-six patients with a diabetic foot ulcer were randomized to receive Decision Navigation (N = 30) or usual care (N = 26). Primary outcomes included decision self-efficacy, adherence to foot treatment as reported by the participant and adherence to foot treatment as reported by the clinician. Secondary outcomes included foot ulcer healing rate, health-related quality of life, decision conflict and decision regret. RESULTS: Despite participants rating Decision Navigation as very helpful, mixed analyses of variance revealed no differences in decision self-efficacy or adherence between those receiving Decision Navigation and those receiving usual care. There were no differences between groups with regards to the secondary outcomes, with the exception of decision conflict which increased over time (12 weeks) for those receiving Decision Navigation. CONCLUSIONS: An intervention that facilitated patient involvement in treatment decisions did not have any impact on decisional confidence or adherence to foot treatment. This does not provide support for the suggestion that personalized care can improve health-related outcomes at this progressed stage of the patient's disease trajectory. We suggest that the diabetic foot population may benefit from interventions aimed at increasing motivation to engage with care pathways, centred on challenging personal controllability beliefs. PMID- 27223311 TI - Of Mosquito Nets and Condoms: The Zika Virus Challenge. PMID- 27223313 TI - The Mismeasure of Health Disparities. PMID- 27223312 TI - Lead Poisoning: Focusing on the Fix. PMID- 27223314 TI - What Is "Informatics"? PMID- 27223315 TI - Public Health Acts to Detect, Respond to, and Prevent the Latest Public Health Threat-Zika Virus Disease. PMID- 27223316 TI - Improving Community-Based Breastfeeding Support: The Role of Local Health Departments. PMID- 27223317 TI - Trends in Overweight/Obesity Prevalence Among Children May Mislead Public Health Efforts. PMID- 27223318 TI - History of Diseases on Death Certificates. PMID- 27223319 TI - Instituting Dark-Colored Cover to Improve Central Space Use Within Guinea Pig Enclosure. AB - Domestic guinea pigs (Cavia aperea f. porcellus) in laboratories have been shown to actively avoid the centers of their cages. This experiment tested a novel, dark-colored "shader" placed over the central portion of a cage. Based on the observed behavior of wild guinea pig species, it was hypothesized that utilization of the central portion of the cage would increase when the shader was present. Eleven male and 11 female albino, 3-week-old Hartley guinea pigs (Crl:HA) experienced the control and treatment conditions in a crossover study design. They spent more time in central cage sections when the shader was present and spent more time in and around the food hopper when the shader was absent (p < .001). Differences between sexes included increased inactivity in males versus females (p < .05) and a difference in time spent in a corner section of the cage (p < .001), likely associated with location in the room. We concluded that the presence of a shader increased utilization of cage space, which appeared to provide a similar increase in space utilization as structural enrichments. PMID- 27223320 TI - Fluorescent 2-Aminopyridine Nucleobases for Triplex-Forming Peptide Nucleic Acids. AB - Development of new fluorescent peptide nucleic acids (PNAs) is important for fundamental research and practical applications. The goal of this study was the design of fluorogenic nucleobases for incorporation in triplex-forming PNAs. The underlying design principle was the use of a protonation event that accompanied binding of a 2-aminopyridine (M) nucleobase to a G-C base pair as an on switch for a fluorescence signal. Two fluorogenic nucleobases, 3-(1-phenylethynyl)-M and phenylpyrrolo-M, were designed, synthesized and studied. The new M derivatives provided modest enhancement of fluorescence upon protonation but showed reduced RNA binding affinity and quenching of fluorescence signal upon triple-helix formation with cognate double-stranded RNA. Our study illustrates the principal challenges of design and provides guidelines for future improvement of fluorogenic PNA nucleobases. The 3-(1-phenylethynyl)-M may be used as a fluorescent nucleobase to study PNA-RNA triple-helix formation. PMID- 27223321 TI - Untold Story. PMID- 27223322 TI - Body Dysmorphic Disorder in aesthetic rhinoplasty: Validating a new screening tool. AB - OBJECTIVES/HYPOTHESIS: To validate a new screening tool for body dysmorphic disorder (BDD) in patients seeking aesthetic rhinoplasty. STUDY DESIGN: We performed a prospective instrument validation study in an academic rhinology clinic. METHODS: The Body Dysmorphic Disorder Questionnaire-Aesthetic Surgery (BDDQ-AS) is a seven-item short questionnaire validated in 116 patients undergoing aesthetic rhinoplasty. Screening was positive if the patient acknowledged on the BDDQ-AS that he/she was concerned about their appearance (question 1 = yes) AND preoccupied with these concerns (question 2 = yes) AND that these concerns caused at least moderate distress or impairment in different domains of daily life (question 3 or 4 or 5 or 6 >= 3 or question 7 = yes). Construct validity was assessed by comparing the BDDQ-AS to the Sheehan Disability Scale and the Derriford Appearance Scale-59. To determine concurrent validity, the BDDQ-AS was compared to the Yale-Brown Obsessive Compulsive Scale Modified for BDD. Finally, the predictive value of the BDDQ-AS on satisfaction 12 months after rhinoplasty was evaluated using a visual analogue scale and the Rhinoplasty Outcome Evaluation. RESULTS: Reliability of the BDDQ-AS was adequate, with Cronbach alpha = .83 for rhinoplasty patients and .84 for controls. Sensitivity was 89.6% and specificity 81.4%. BDDQ-AS-positive patients (n = 55) were more impaired in daily life and experienced more appearance-related distress and dysfunction compared to BDDQ-AS-negative patients. Moreover, they had more severe BDD symptoms. Finally, BDDQ-AS-positive patients were less satisfied after surgery compared to BDDQ-AS-negative patients. CONCLUSIONS: We hereby validated a new screening tool for BDD in an aesthetic rhinoplasty population. LEVEL OF EVIDENCE: 3b. Laryngoscope, 126:1739-1745, 2016. PMID- 27223323 TI - Adenosine diphosphate restricts the protein remodeling activity of the Hsp104 chaperone to Hsp70 assisted disaggregation. AB - Hsp104 disaggregase provides thermotolerance in yeast by recovering proteins from aggregates in cooperation with the Hsp70 chaperone. Protein disaggregation involves polypeptide extraction from aggregates and its translocation through the central channel of the Hsp104 hexamer. This process relies on adenosine triphosphate (ATP) hydrolysis. Considering that Hsp104 is characterized by low affinity towards ATP and is strongly inhibited by adenosine diphosphate (ADP), we asked how Hsp104 functions at the physiological levels of adenine nucleotides. We demonstrate that physiological levels of ADP highly limit Hsp104 activity. This inhibition, however, is moderated by the Hsp70 chaperone, which allows efficient disaggregation by supporting Hsp104 binding to aggregates but not to non aggregated, disordered protein substrates. Our results point to an additional level of Hsp104 regulation by Hsp70, which restricts the potentially toxic protein unfolding activity of Hsp104 to the disaggregation process, providing the yeast protein-recovery system with substrate specificity and efficiency in ATP consumption. PMID- 27223324 TI - PHF13 is a molecular reader and transcriptional co-regulator of H3K4me2/3. AB - PHF13 is a chromatin affiliated protein with a functional role in differentiation, cell division, DNA damage response and higher chromatin order. To gain insight into PHF13's ability to modulate these processes, we elucidate the mechanisms targeting PHF13 to chromatin, its genome wide localization and its molecular chromatin context. Size exclusion chromatography, mass spectrometry, X ray crystallography and ChIP sequencing demonstrate that PHF13 binds chromatin in a multivalent fashion via direct interactions with H3K4me2/3 and DNA, and indirectly via interactions with PRC2 and RNA PolII. Furthermore, PHF13 depletion disrupted the interactions between PRC2, RNA PolII S5P, H3K4me3 and H3K27me3 and resulted in the up and down regulation of genes functionally enriched in transcriptional regulation, DNA binding, cell cycle, differentiation and chromatin organization. Together our findings argue that PHF13 is an H3K4me2/3 molecular reader and transcriptional co-regulator, affording it the ability to impact different chromatin processes. PMID- 27223325 TI - NOVA2-mediated RNA regulation is required for axonal pathfinding during development. AB - The neuron specific RNA-binding proteins NOVA1 and NOVA2 are highly homologous alternative splicing regulators. NOVA proteins regulate at least 700 alternative splicing events in vivo, yet relatively little is known about the biologic consequences of NOVA action and in particular about functional differences between NOVA1 and NOVA2. Transcriptome-wide searches for isoform-specific functions, using NOVA1 and NOVA2 specific HITS-CLIP and RNA-seq data from mouse cortex lacking either NOVA isoform, reveals that NOVA2 uniquely regulates alternative splicing events of a series of axon guidance related genes during cortical development. Corresponding axonal pathfinding defects were specific to NOVA2 deficiency: Nova2-/- but not Nova1-/- mice had agenesis of the corpus callosum, and axonal outgrowth defects specific to ventral motoneuron axons and efferent innervation of the cochlea. Thus we have discovered that NOVA2 uniquely regulates alternative splicing of a coordinate set of transcripts encoding key components in cortical, brainstem and spinal axon guidance/outgrowth pathways during neural differentiation, with severe functional consequences in vivo. PMID- 27223326 TI - The postsynaptic t-SNARE Syntaxin 4 controls traffic of Neuroligin 1 and Synaptotagmin 4 to regulate retrograde signaling. AB - Postsynaptic cells can induce synaptic plasticity through the release of activity dependent retrograde signals. We previously described a Ca(2+)-dependent retrograde signaling pathway mediated by postsynaptic Synaptotagmin 4 (Syt4). To identify proteins involved in postsynaptic exocytosis, we conducted a screen for candidates that disrupted trafficking of a pHluorin-tagged Syt4 at Drosophila neuromuscular junctions (NMJs). Here we characterize one candidate, the postsynaptic t-SNARE Syntaxin 4 (Syx4). Analysis of Syx4 mutants reveals that Syx4 mediates retrograde signaling, modulating the membrane levels of Syt4 and the transsynaptic adhesion protein Neuroligin 1 (Nlg1). Syx4-dependent trafficking regulates synaptic development, including controlling synaptic bouton number and the ability to bud new varicosities in response to acute neuronal stimulation. Genetic interaction experiments demonstrate Syx4, Syt4, and Nlg1 regulate synaptic growth and plasticity through both shared and parallel signaling pathways. Our findings suggest a conserved postsynaptic SNARE machinery controls multiple aspects of retrograde signaling and cargo trafficking within the postsynaptic compartment. PMID- 27223327 TI - A bend, flip and trap mechanism for transposon integration. AB - Cut-and-paste DNA transposons of the mariner/Tc1 family are useful tools for genome engineering and are inserted specifically at TA target sites. A crystal structure of the mariner transposase Mos1 (derived from Drosophila mauritiana), in complex with transposon ends covalently joined to target DNA, portrays the transposition machinery after DNA integration. It reveals severe distortion of target DNA and flipping of the target adenines into extra-helical positions. Fluorescence experiments confirm dynamic base flipping in solution. Transposase residues W159, R186, F187 and K190 stabilise the target DNA distortions and are required for efficient transposon integration and transposition in vitro. Transposase recognises the flipped target adenines via base-specific interactions with backbone atoms, offering a molecular basis for TA target sequence selection. Our results will provide a template for re-designing mariner/Tc1 transposases with modified target specificities. PMID- 27223328 TI - NOVA regulates Dcc alternative splicing during neuronal migration and axon guidance in the spinal cord. AB - RNA-binding proteins (RBPs) control multiple aspects of post-transcriptional gene regulation and function during various biological processes in the nervous system. To further reveal the functional significance of RBPs during neural development, we carried out an in vivo RNAi screen in the dorsal spinal cord interneurons, including the commissural neurons. We found that the NOVA family of RBPs play a key role in neuronal migration, axon outgrowth, and axon guidance. Interestingly, Nova mutants display similar defects as the knockout of the Dcc transmembrane receptor. We show here that Nova deficiency disrupts the alternative splicing of Dcc, and that restoring Dcc splicing in Nova knockouts is able to rescue the defects. Together, our results demonstrate that the production of DCC splice variants controlled by NOVA has a crucial function during many stages of commissural neuron development. PMID- 27223330 TI - Association of Exercise Capacity with Physical Functionality and Various Aspects of Fatigue in Patients with Coronary Artery Disease. AB - The aim of this study was to examine associations between exercise capacity indexed as the metabolic equivalent of the task-and various aspects of subjective fatigue, physical functionality, and depression in patients with coronary artery disease. A cross-sectional design was used. Patients with stable coronary artery disease (N = 240) underwent an exercise stress test and completed self-report assessments of depression, subjective physical limitations, vital exhaustion, and the impact of fatigue on physical, social, and cognitive functions. Associations between exercise capacity and these self-report variables were assessed using bivariate correlations and a series of multivariate regressions. Exercise capacity was negatively associated with vital exhaustion, physical limitations, and impact of fatigue on physical and social functioning but not on cognitive functioning. There was a marginal association between exercise capacity and depression. The associations between exercise capacity and fatigue remained significant even after controlling for effects of age, body mass index, gender, education, and comorbid diabetes mellitus. The main conclusion of the study is that in patients with coronary artery disease, exercise capacity has the strongest predictability for physical fatigue, but, importantly, it also independently predicts the feeling of loss of energy and malaise. PMID- 27223329 TI - Structure of a Holliday junction complex reveals mechanisms governing a highly regulated DNA transaction. AB - The molecular machinery responsible for DNA expression, recombination, and compaction has been difficult to visualize as functionally complete entities due to their combinatorial and structural complexity. We report here the structure of the intact functional assembly responsible for regulating and executing a site specific DNA recombination reaction. The assembly is a 240-bp Holliday junction (HJ) bound specifically by 11 protein subunits. This higher-order complex is a key intermediate in the tightly regulated pathway for the excision of bacteriophage lambda viral DNA out of the E. coli host chromosome, an extensively studied paradigmatic model system for the regulated rearrangement of DNA. Our results provide a structural basis for pre-existing data describing the excisive and integrative recombination pathways, and they help explain their regulation. PMID- 27223331 TI - Chronic behavior disturbance and neurocognitive deficits in neuro-Behcet's disease: a case study. AB - Behcet's disease is a vasculitis and multisystem inflammatory syndrome. Neurological abnormalities occur in a subset of patients. This report presents a case of neuro-Behcet's disease characterized by an initial onset of behavior changes prior to diagnosis, which evolved into a chronic behavioral syndrome. Neuroimaging investigations revealed progressive periventricular white matter and brainstem atrophy and lesions in the basal ganglia and deep white matter tracts, while neuropsychological investigations revealed reductions in information processing, executive functioning, and memory. The case indicates that behavior changes may be the first symptoms to emerge in Behcet's, before other defining features of the disease. PMID- 27223332 TI - First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) mutation positive (M+) non small cell lung cancer (NSCLC) is emerging as an important subtype of lung cancer comprising 10% to 15% of non-squamous tumours. This subtype is more common in women than men and is less associated with smoking. OBJECTIVES: To assess the clinical effectiveness of single -agent or combination EGFR therapies used in the first-line treatment of people with locally advanced or metastatic EGFR M+ NSCLC compared with other cytotoxic chemotherapy (CTX) agents used alone or in combination, or best supportive care (BSC). The primary outcome was overall survival. Secondary outcomes included progression-free survival, response rate, toxicity, and quality of life. SEARCH METHODS: We conducted electronic searches of the the Cochrane Register of Controlled Trials (CENTRAL) (2015, Issue 6), MEDLINE (1946 to 1 June 2015), EMBASE (1980 to 1 June 2015), and ISI Web of Science (1899 to 1 June 2015). We also searched the conference abstracts of the American Society for Clinical Oncology and the European Society for Medical Oncology (1 June 2015); Evidence Review Group submissions to the National Institute for Health and Care Excellence; and the reference lists of retrieved articles. SELECTION CRITERIA: Parallel randomised controlled trials comparing EGFR-targeted agents (alone or in combination with cytotoxic agents or BSC) with cytotoxic chemotherapy (single or doublet) or BSC in chemotherapy-naive patients with locally advanced or metastatic (stage IIIB or IV) EGFR M+ NSCLC unsuitable for treatment with curative intent. DATA COLLECTION AND ANALYSIS: Two review authors independently identified articles, extracted data, and carried out the 'Risk of bias' assessment. We conducted meta-analyses using a fixed-effect model unless there was substantial heterogeneity, in which case we also performed a random-effects analysis as a sensitivity analysis. MAIN RESULTS: Nineteen trials met the inclusion criteria. Seven of these exclusively recruited people with EGFR M+ NSCLC; the remainder recruited a mixed population and reported results for people with EGFR M+ NSCLC as subgroup analyses. The number of participants with EGFR M+ tumours totalled 2317, of whom 1700 were of Asian origin.Overall survival (OS) data showed inconsistent results between the included trials that compared EGFR-targeted treatments against cytotoxic chemotherapy or placebo.Erlotinib was the intervention treatment used in eight trials, gefitinib in seven trials, afatinib in two trials, and cetuximab in two trials. The findings of one trial (FASTACT 2) did report a statistically significant OS gain for participants treated with erlotinib plus cytotoxic chemotherapy when compared to cytotoxic chemotherapy alone, but this result was based on a small number of participants (n = 97). For progression-free survival (PFS), a pooled analysis of 3 trials (n = 378) demonstrated a statistically significant benefit for erlotinib compared with cytotoxic chemotherapy (hazard ratio (HR) 0.30; 95% confidence interval (CI) 0.24 to 0.38).In a pooled analysis with 491 participants administered gefitinib, 2 trials (IPASS and NEJSG) demonstrated a statistically significant PFS benefit of gefitinib compared with cytotoxic chemotherapy (HR 0.39; 95% CI 0.32 to 0.48).Afatinib (n = 709) showed a statistically significant PFS benefit when compared with chemotherapy in a pooled analysis of 2 trials (HR 0.42; 95% CI 0.34 to 0.53).Commonly reported grade 3/4 adverse events for afatinib, erlotinib, and gefitinib monotherapy were rash and diarrhoea. Myelosuppression was consistently worse in the chemotherapy arms, fatigue and anorexia were also associated with some chemotherapies.No statistically significant PFS or OS benefit for cetuximab plus cytotoxic chemotherapy (n = 81) compared to chemotherapy alone was reported in either of the two trials.Six trials reported on quality of life and symptom improvement using different methodologies. For each of erlotinib, gefitinib, and afatinib, 2 trials showed improvement in one or more indices for the tyrosine kinase inhibitor (TKI) compared to chemotherapy.The quality of evidence was high for the comparisons of erlotinib and gefitinib with cytotoxic chemotherapy and for the comparison of afatinib with cytotoxic chemotherapy. AUTHORS' CONCLUSIONS: Erlotinib, gefitinib, and afatinib are all active agents in EGFR M+ NSCLC patients, and demonstrate an increased tumour response rate and prolonged progression-free survival compared to cytotoxic chemotherapy. We also found a beneficial effect of the TKI compared to cytotoxic chemotherapy. However, we found no increase in overall survival for the TKI when compared with standard chemotherapy. Cytotoxic chemotherapy is less effective in EGFR M+ NSCLC than erlotinib, gefitinib, or afatinib and is associated with greater toxicity. There were no data supporting the use of monoclonal antibody therapy. PMID- 27223333 TI - Alkyne-Modulated Surface-Enhanced Raman Scattering-Palette for Optical Interference-Free and Multiplex Cellular Imaging. AB - The alkyne tags possess unique interference-free Raman emissions but are still hindered for further application in the field of biochemical labels due to its extremely weak spontaneous Raman scattering. With the aid of computational chemistry, herein, an alkyne-modulated surface-enhanced Raman scattering (SERS) palette is constructed based on rationally designed 4-ethynylbenzenethiol derivatives for spectroscopic signature, Au@Ag core for optical enhancement and an encapsulating polyallylamine shell for protection and conjugation. Even for the pigment rich plant cell (e.g., pollen), the alkyne-coded SERS tag can be highly discerned on two-dimension distribution impervious to strong organic interferences originating from resonance-enhanced Raman scattering or autofluorescence. In addition, the alkynyl-containing Raman reporters contribute especially narrow emission, band shift-tunable (2100-2300 cm(-1)) and tremendously enhanced Raman signals when the alkynyl group locates at para position of mercaptobenzene ring. Depending on only single Raman band, the suggested alkyne-modulated SERS-palette potentially provides a more effective solution for multiplex cellular imaging with vibrant colors, when the hyperspectral and fairly intense optical noises originating from lower wavenumber region (<1800 cm(-1)) are inevitable under complex ambient conditions. PMID- 27223335 TI - Handwriting performance versus arm forward reach and grasp abilities among post stroke patients, a case-control study. AB - BACKGROUND: Evidence-based studies regarding deficits in handwriting performance relative to hand reaching and grasping after a stroke are lacking. OBJECTIVE: To evaluate the extent of damage to handwriting skills compared to arm reach and grasp task among post-stroke patients. METHODS: Eighteen patients and 19 healthy subjects were recruited to this case-control study. Patients were evaluated 15.2 days (+/-6.5) after the stroke using a Computerized Penmanship Evaluation Tool, surface Electromyography and Fugl-Meyer assessment. This study compared motor deficits in hand reaching and grasping and in handwriting between stroke patients and healthy subjects. Damage to handwriting performance relative to hand reaching and grasping skills was also evaluated. RESULTS: Significant differences were found between groups in handwriting performance (p < 0.05). The performance of the trapezius, biceps, and triceps muscles can predict 63.5% of the variance in the ability to write a short sentence (p < 0.023). Pen pressure can predict 74.9% of the hand motor performance from Fugl-Meyer assessment (p < 0.05). Handwriting was more damaged than was the pattern of activation of the proximal muscles of the shoulder and arm (p < 0.05). FM scores were highly, negatively correlated with the in-air writing time across tasks (r = -0.819, p < 0.004). CONCLUSIONS: This study confirms the clinical observation that dexterity skills are more damaged than are arm forward reach after a stroke. However, these differences in motor performance were not significant in mildly disabled patients, demonstrating the feasibility of handwriting rehabilitation in these patients. Therefore, we modestly recommend focusing on handwriting rehabilitation of the hemiparetic upper extremity in mildly impaired patients after a stroke. PMID- 27223334 TI - Prospective study of pregnancy and newborn outcomes in mothers with West nile illness during pregnancy. AB - BACKGROUND: A previous case report of West Nile virus (WNV) illness during pregnancy suggested that WNV could be a cause of congenital defects. We performed a prospective, longitudinal cohort study of pregnant women with WNV illness to increase our knowledge of the effects of WNV illness during pregnancy. METHODS: Participants were enrolled in 2005 to 2008 from pregnant women with serologically confirmed WNV illness reported to the Centers for Disease Control and Prevention. Comparison was made to WNV-uninfected women, matched on maternal age and enrollment month. Pregnancy and newborn data were collected; cord blood WNV serology was obtained. Pediatric exams and the Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III) were performed. RESULTS: Twenty eight WNV-infected mothers and 25 WNV-uninfected mothers participated. Maternal demographics were similar except for a higher rate of planned pregnancies, education, and household income in the WNV-uninfected mothers. There were no differences in pregnancy and delivery characteristics except that infected mothers had a higher incidence of febrile illnesses and used more medications. Birth weight, length, head circumference, and rate of congenital malformations were similar in babies born to WNV-infected and -uninfected mothers. Follow-up physical exams were generally normal. The Bayley-III assessments, available for 17 children born to mothers with WNV illness, showed performance at or above age level across domains. CONCLUSION: The risk for adverse pregnancy and newborn outcomes in women experiencing WNV illness in pregnancy appears to be low, but future studies with larger numbers are needed to rule out a small risk. Birth Defects Research (Part A) 106:716-723, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27223336 TI - Structural Basis for Bulky-Adduct DNA-Lesion Recognition by the Nucleotide Excision Repair Protein Rad14. AB - Heterocyclic aromatic amines react with purine bases and result in bulky DNA adducts that cause mutations. Such structurally diverse lesions are substrates for the nucleotide excision repair (NER). It is thought that the NER machinery recognises and verifies distorted DNA conformations, also involving the xeroderma pigmentosum group A and C proteins (XPA, XPC) that act as a scaffold between the DNA substrate and several other NER proteins. Here we present the synthesis of DNA molecules containing the polycyclic, aromatic amine C8-guanine lesions acetylaminophenyl, acetylaminonaphthyl, acetylaminoanthryl, and acetylaminopyrenyl, as well as their crystal structures in complex with the yeast XPA homologue Rad14. This work further substantiates the indirect lesion detection mechanism employed by the NER system that recognises destabilised and deformable DNA structures. PMID- 27223337 TI - Exon capture optimization in amphibians with large genomes. AB - Gathering genomic-scale data efficiently is challenging for nonmodel species with large, complex genomes. Transcriptome sequencing is accessible for organisms with large genomes, and sequence capture probes can be designed from such mRNA sequences to enrich and sequence exonic regions. Maximizing enrichment efficiency is important to reduce sequencing costs, but relatively few data exist for exon capture experiments in nonmodel organisms with large genomes. Here, we conducted a replicated factorial experiment to explore the effects of several modifications to standard protocols that might increase sequence capture efficiency for amphibians and other taxa with large, complex genomes. Increasing the amounts of c0 t-1 repetitive sequence blocker and individual input DNA used in target enrichment reactions reduced the rates of PCR duplication. This reduction led to an increase in the percentage of unique reads mapping to target sequences, essentially doubling overall efficiency of the target capture from 10.4% to nearly 19.9% and rendering target capture experiments more efficient and affordable. Our results indicate that target capture protocols can be modified to efficiently screen vertebrates with large genomes, including amphibians. PMID- 27223338 TI - MRI Findings of Injury to the Longus Colli Muscle in Patients With Neck Trauma. AB - OBJECTIVE: The longus colli muscle (LCM) forms the bulk of the deep flexor muscles of the neck. To our knowledge, very little information on the effects of trauma on this muscle group has been published. We describe MRI findings related to injury of the LCM in patients with a history of neck trauma. MATERIALS AND METHODS: A radiology department database was searched to identify patient medical records from 2008 to 2013 that included the keywords "longus colli" and "deep flexors." Patients with fractures and ligament injuries were excluded. Patients with other obvious large soft-tissue injuries and nontraumatic conditions were also omitted. A total of 12 patients met the inclusion criterion of having an isolated or predominant injury to the LCM. Five patients had been involved in a motor vehicle accident, and seven patients had fallen. Eleven patients had undergone a CT examination before MRI was performed. RESULTS: No fractures were noted on CT. MRI examinations of the cervical spine were obtained for the following reasons: for increased prevertebral soft-tissue swelling noted on a CT scan plus neck pain (n = 6), for neck pain only (n = 4), or as part of a routine protocol for assessment of obtunded patients (n = 2). Eight of the 12 patients had isolated injury to the LCM. The remaining four patients also had minor injuries to the other neck muscles. The MR image showed swelling and T2 hyperintensity in the LCM and revealed free fluid in the prevertebral space. CONCLUSION: Isolated injury to the LCM may occur in neck injuries. The MRI findings indicating such injury include increased T2 signal, swelling of the muscle, and the presence of prevertebral fluid. PMID- 27223339 TI - Quantifying the Heterogeneous Dynamics of a Simulated Dipalmitoylphosphatidylcholine (DPPC) Membrane. AB - Heterogeneity of dynamics plays a vital role in membrane function, but the methods for quantifying this heterogeneity are still being developed. Here we examine membrane dynamical heterogeneity via molecular simulations of a single component dipalmitoylphosphatidylcholine (DPPC) lipid bilayer using the MARTINI force field. We draw upon well-established analysis methods developed in the study of glass-forming fluids and find significant changes in lipid dynamics between the fluid (Lalpha), and gel (Lbeta) phases. In particular, we distinguish two mobility groups in the more ordered Lbeta phase: (i) lipids that are transiently trapped by their neighbors and (ii) lipids with displacements on the scale of the intermolecular spacing. These distinct mobility groups spatially segregate, forming dynamic clusters that have characteristic time (1-2 MUs) and length (1-10 nm) scales comparable to those of proteins and other biomolecules. We suggest that these dynamic clusters could couple to biomolecules within the membrane and thus may play a role in many membrane functions. In the equilibrium membrane, lipid molecules dynamically exchange between the mobility groups, and the resulting clusters are not associated with a thermodynamic phase separation. Dynamical clusters having similar characteristics arise in many other condensed phase materials, placing membranes in a broad class of materials with strong intermolecular interactions. PMID- 27223340 TI - The Social and Emotional Lives of Overweight, Obese, and Severely Obese Children. AB - This study examines inter- and intrapersonal problems associated with being overweight among one thousand one hundred sixty-four 6- to 7-year-olds (49% boys) in 29 rural schools. Socioemotional data include child self-reports, peer sociometrics, and teacher reports. Results support the hypothesis that children with weight problems struggle socially and emotionally, and extend current understanding of child obesity by demonstrating that problems appear early, are evident in a community sample, can be identified using standard sociometric methods, and are worse among children with severe obesity. Sociometric status difference between levels of obesity were also found. Although obese children were neglected by peers, severely obese children were rejected. PMID- 27223342 TI - Different prognostic roles of tumor suppressor gene BAP1 in cancer: A systematic review with meta-analysis. AB - Biallelic inactivation of the tumor suppressor gene BRCA1-associated protein 1 (BAP1) has been demonstrated in several cancers, but its prognostic role has not been completely explained. We aimed to investigate the risk associated with loss of BAP1 (BAP1-) for all-cause mortality, cancer-specific mortality and recurrence of disease in subjects with cancer. PubMed and SCOPUS were searched from database inception until 09/15/2015 without language restrictions. Prospective studies reporting data on prognostic parameters in subjects with cancer, comparing participants with presence of BAP1 (BAP1+) vs. BAP1- were included. Data were summarized using risk ratios (RR) for number of deaths/recurrences and hazard ratios (HR) for time-dependent risk related to BAP1- adjusted for potential confounders. From 261 hits, 12 studies (including 13 cohorts) with 3,447 participants (BAP1-: n = 697; BAP1+: n = 2,750), with a median follow-up over 60 months, were meta-analyzed. Compared to BAP1+, BAP1- significantly increased all cause mortality, cancer-specific mortality and risk of recurrence in all the tumor types analyzed, except for mesothelioma, in which the presence of BAP1 mutations correlates with a better prognosis. Furthermore, we demonstrated that BAP1 mutated colorectal and renal carcinomas are associated with high-tumor grading (P < 0.0001), and that BAP1 mutated is more common in women than in men (P < 0.0001). In conclusion, on the basis of our meta-analysis, we have demonstrated a peculiar role of BAP1 in influencing the prognosis in cancer. Thus, BAP1 could be considered as an important potential target for personalized medicine. (c) 2016 Wiley Periodicals, Inc. PMID- 27223341 TI - Habitual Alcohol Seeking: Neural Bases and Possible Relations to Alcohol Use Disorders. AB - Loss of flexible control over alcohol use may contribute to the development of alcohol use disorders. An increased contribution of response habits to alcohol related behaviors may help explain this loss of control. Focusing on data from outcome devaluation and Pavlovian-instrumental transfer procedures, we review evidence for loss of goal-directed control over alcohol seeking and consumption drawing from both preclinical findings and clinical data where they exist. Over the course of extended alcohol self-administration and exposure, the performance of alcohol-seeking responses becomes less sensitive to reduction in the value of alcohol and more vulnerable to the influences of alcohol-predictive stimuli. These behavioral changes are accompanied by a shift in the corticostriatal circuits that control responding from circuits centered on the dorsomedial to those centered on the dorsolateral striatum. These changes in behavioral and neural control could help explain failures to abstain from alcohol despite intention to do so. Understanding and ultimately ameliorating these changes will aid development of more effective treatment interventions. PMID- 27223343 TI - Monolayer Single-Crystal 1T'-MoTe2 Grown by Chemical Vapor Deposition Exhibits Weak Antilocalization Effect. AB - Growth of transition metal dichalcogenide (TMD) monolayers is of interest due to their unique electrical and optical properties. Films in the 2H and 1T phases have been widely studied but monolayers of some 1T'-TMDs are predicted to be large-gap quantum spin Hall insulators, suitable for innovative transistor structures that can be switched via a topological phase transition rather than conventional carrier depletion [ Qian et al. Science 2014 , 346 , 1344 - 1347 ]. Here we detail a reproducible method for chemical vapor deposition of monolayer, single-crystal flakes of 1T'-MoTe2. Atomic force microscopy, Raman spectroscopy, X-ray photoelectron spectroscopy, and transmission electron microscopy confirm the composition and structure of MoTe2 flakes. Variable temperature magnetotransport shows weak antilocalization at low temperatures, an effect seen in topological insulators and evidence of strong spin-orbit coupling. Our approach provides a pathway to systematic investigation of monolayer, single crystal 1T'-MoTe2 and implementation in next-generation nanoelectronic devices. PMID- 27223345 TI - Conflicting images. AB - Demographic trends have placed school leavers with the right qualifications in the happy position of being able to pick and choose their career paths. PMID- 27223346 TI - Handwashing hygiene could save millions. AB - BETTER NURSE handwashing hygiene could help slash up to L36 million a year from NHS spending, a new report declared last week. PMID- 27223347 TI - Same day HIV test service. AB - A NEW HIV testing service, which gives patients their results within hours, is now available in London. PMID- 27223344 TI - Analytical validity of a microRNA-based assay for diagnosing indeterminate thyroid FNA smears from routinely prepared cytology slides. AB - BACKGROUND: The majority of thyroid nodules are diagnosed using fine-needle aspiration (FNA) biopsies. The authors recently described the clinical validation of a molecular microRNA-based assay, RosettaGX Reveal, which can diagnose thyroid nodules as benign or suspicious using a single stained FNA smear. This paper describes the analytical validation of the assay. METHODS: More than 800 FNA slides were tested, including slides stained with Romanowsky-type and Papanicolaou stains. The assay was examined for the following features: intranodule concordance, effect of stain type, minimal acceptable RNA amounts, performance on low numbers of thyroid cells, effect of time since sampling, and analytical sensitivity, specificity, and reproducibility. RESULTS: The assay can be run on FNA slides for which as little as 1% of the cells are thyroid epithelial cells or from which only 5 ng of RNA have been extracted. Samples composed entirely of blood failed quality control and were not classified. Stain type did not affect performance. All slides were stored at room temperature. However, the length of time between FNA sampling and processing did not affect assay performance. There was a high level of concordance between laboratories (96%), and the concordance for slides created from the same FNA pass was 93%. CONCLUSIONS: The microRNA-based assay was robust to various physical processing conditions and to differing sample characteristics. Given the assay's performance, robustness, and use of routinely prepared FNA slides, it has the potential to provide valuable aid for physicians in the diagnosis of thyroid nodules. Cancer Cytopathol 2016;124:711-21. (c) 2016 Rosetta Genomics. Cancer Cytopathology published by Wiley Periodicals, Inc. on behalf of American Cancer Society. PMID- 27223349 TI - DoH ministerial changes announced. AB - NEW MINISTERIAL responsibilities at the Department of Health were announced last week by Health Secretary Kenneth Clarke. PMID- 27223348 TI - Recruitment ad blitz welcomed. AB - THE LATEST phase of the Government's recruitment and retention campaign for nurses, which is being launched this week with TV commercials and press advertisements, has had an encouraging response from professional organisations. PMID- 27223350 TI - Child dangers at floor-level. AB - COMMUNITY NURSES called for a health education drive last week after a disturbing new report revealed 'potential horrors' lurking at child-level in homes around the country. PMID- 27223351 TI - [Not Available]. AB - Nurse Shane Snape, who has AIDS and works as HIV training officer for NW Thames, met Margaret Thatcher last week [Illegible Word] she visited Mildmay Mission Hospital, east London. PMID- 27223352 TI - Blaze destroys wards. AB - MORE THAN 100 patients, many with heart, conditions, had to be rushed to safety when fire broke out at a Reading hospital last week. PMID- 27223353 TI - Big demand for midland bank creche facilities. AB - DOZENS OF health authorities have so far bent the ear of 'the listening bank' in response to proposals for joint creches throughout the country. PMID- 27223354 TI - Papworth hit by staff and facilities shortages. AB - PATIENTS AT the renowned Papworth Hospital are missing the chance of vital transplant surgery because of a short age of facilities, it was claimed last week. PMID- 27223355 TI - Care budgets could suffer from negligence claims. AB - PATIENT CARE will suffer from Government's decision to make health authorities pay for doctors' negligence, districts warned last week. PMID- 27223356 TI - Welsh Office plans attacked. AB - WELSH NURSING unions have attacked Government plans to accelerate the White Paper programme in the Principality. PMID- 27223357 TI - Staff nurses claim sex discrimination in grading. AB - FOUR WOMEN nurses have accused a London hospital of sex discrimination in deciding their clinical grading. PMID- 27223359 TI - Professionals undermined by patients with HIV/AIDS. AB - MOST PEOPLE who are HIV positive have more information about the condition than the nurses and doctors who care for them, AIDS nurses have been told. PMID- 27223360 TI - AIDS campaigns defended. AB - NEW EVIDENCE of growing public awareness about AIDS and HIV infection has been revealed. PMID- 27223358 TI - [Not Available]. AB - Looking optimistic: a cheerful Welsh Minister Ian Grist meets members of the RCN Welsh Board to discuss the implications of the Government's White Paper, 'Working for Patients'. Later the Welsh Office came under attack from nursing unions. PMID- 27223361 TI - [Not Available]. AB - Lady Caroline Cox received a cheque for L10,000 last week from the Royal National Pension Fund for Nurses as a donation to If Trevor Clay Scholarship Fund. Handing over the cheque is RNPFN's General Manager, Victor West. The Fund, which aims to help nurses undertake projects and study to extend knowledge and develop skills, has so far reached L80,000 and hopes to reach six figures by the time the RCN General Secretary retires at the end of September. Donations have been received from places as diverse as national clearing banks and retired nurses - one cheque for L30 was received from residents of the RCN's Sobell Court home in Henfield. PMID- 27223362 TI - BBC and king's fund link up on video for carers. AB - A SPECIAL video pack for in formal carers, produced by the BBC and the King's Fund, is now on offer to carers' groups. PMID- 27223363 TI - Voluntary bodies move to protect children. AB - THE GOVERNMENT has announced a L60,000 drive to prevent sex offenders obtaining jobs involving children. PMID- 27223365 TI - Audiology services face major service overload. AB - Practice nurses could be caught in a service overload after a Government plan to introduce fast community hearing services. PMID- 27223364 TI - Baby milk ban. AB - Midwives have welcomed a new Government code which bans health' authorities from accepting or distributing free samples of baby milk. PMID- 27223366 TI - GPs unsure on treatment of pre-menstrual syndrome. AB - More than 50 per cent of family doctors have difficulty treating women with pre menstrual syndrome, a new survey revealed last week. PMID- 27223367 TI - Typhoid resort alert. AB - Travellers must adopt essential hygiene precautions before visiting typhoid-hit Salou in Spain, Scottish Health Minister Michael Forsyth warned last week. PMID- 27223368 TI - Smear test programme's ineffectiveness attacked. AB - Nurses should run new cervical screening services in a bid to boost disturbingly low uptake levels, a major report declared last week. PMID- 27223370 TI - Good comrades? AB - As the 'For Sale' signs go up at the Health Visitors Association headquarters in south London, there is growing speculation on the outcome of the HVA's search for a partner. PMID- 27223371 TI - Acute illness and AIDS. AB - Long-lasting acute illness during seroconversion to HIV may determine the subsequent course of the disease, according to researchers from Denmark. PMID- 27223373 TI - Blood and crohn's recurrence. AB - Perioperative blood transfusion may reduce the recurrence rate of small bowel Crohn's disease. PMID- 27223372 TI - Fungal nail infections. AB - A new treatment for fungal nail infections is proving safe and effective and could soon be available for use by GPs. PMID- 27223375 TI - Improving breast screening take up. AB - Sending pre-allocated appointments for breast screening achieves a higher response rate than open appointments. PMID- 27223374 TI - Treating otitis media. AB - Myringotomy is not adequate therapy for otitis media in infancy, researchers from Israel have found. PMID- 27223376 TI - * Health, holidays and bitter battles. AB - It seemed such an innocent question: 'And where are you going on holiday this year, Secretary of State?' Startled for just a second, Kenneth Clarke, straight faced, replied: 'Eastern Turkey!'. On the basis of which we can be certain the Health Secretary will not venture anywhere near Eastern Turkey. PMID- 27223377 TI - From bath to basingstoke. AB - Those among us who are keen readers perhaps better equate this lovely part of the country with the characters and lives of Thomas Hardy's heroes and heroines. But the countryside and the towns and villages have greatly changed since Tess of the d'Urberville's day. PMID- 27223378 TI - Listings. AB - Nursing Standard's listings section is a completely free service for its readers. To ensure maximum publicity for any event connected with your of ession, be sure to let us ow so that it can be in- [Illegible word] in our exhaustive nationwide guide to what's on in nursing. PMID- 27223379 TI - A new approach back injury. AB - Ergonomics is the study of people at work. Its focus is the capabilities and limitations of people, both mental and physical, and how these 'match' with their work. Where there is a 'mismatch', problems occur ( Figure 1 ). PMID- 27223380 TI - Nurse teacher's pay award. AB - If my colleagues in nurse education throughout the country could see the above headline they would ask 'which pay award?'. PMID- 27223381 TI - Schizophrenia theories. AB - Christopher Bassett's [illegible word] the history of schizophrenia (Nursing Standard week ending July 15) was - although interesting - flawed by the the omission of vital, relevant detail and relied wholly upon the 'medical model'. PMID- 27223382 TI - Asthma advice. AB - In the past few months two of my friend's children have been told that they are suffering from asthma. PMID- 27223383 TI - Infant deaths and overfeeding. AB - I read with interest Catherine Milne's article on sudden infant death syndrome in Nursing Standard (week ending, July 8). But I disagree with her opinion of there being no single cause -I am inclined to believe there is - that being 'over feeding'. PMID- 27223384 TI - ENB onus and responsibility. AB - I recently applied for the English National Board course 'Care of the Elderly'. I had to attend a formal interview (which was a surprise) at which the senior tutor kept repeating the fact that it was my responsibility to attend post- registration courses as re the UKCC Code of 'Professional Conduct. PMID- 27223385 TI - Epilepsy self-help information. AB - I have become involved in the setting up of an epilepsy self- help group in the town of Tiverton. Because of my experience over many years as the mother of two daughters who both suffer from chronic epilepsy I have been asked to be an adviser to other parents of newly diagnosed children. PMID- 27223386 TI - Council election - welsh section. AB - It is regretted that two dates quoted in the details of Margaret Savage were incorrect. These should have read. PMID- 27223387 TI - Support nestle boycott! AB - I would like to urge readers of Nursing Standard to support the boycott of Nestle by not [illegible word] Nescafe brands of coffee. PMID- 27223389 TI - The breast may be best but ... AB - A spokesman for Nestle replies: 'We accept that breast feeding is best but acknowledge that it is not alway possible. We supply infant formula in response to reguests from doctors at the hospitals concerned and take the view that doctors and nurses in Third World hospitals facing day to day realities, know more than a pressure group in Britain. PMID- 27223388 TI - Nurse educators and pay. AB - As reported in the Nursing Standard (week ending July 29) nurse educators have been informed of their new scale. PMID- 27223390 TI - Watchdog. AB - Q >I have recently commenced an English National Board course in Orthopaedics (No 219), as a post-basic student. Part of the course requires us to complete a research study of our own choice. PMID- 27223391 TI - Chewing the carpet. AB - A word of warning to nurses involved in pet therapy. PMID- 27223392 TI - A load of bull. AB - It was with slightly raised eyebrows that we read Today's report about a health authority employing Spanish nurses to beat the UK skills shortage. PMID- 27223393 TI - The lab report. PMID- 27223394 TI - Desperate, dan. AB - The Department of Health's comical nurse recruitment campaign is, we hear, looking to use comics to recruit nurses. PMID- 27223395 TI - The risks of lifts. AB - [[illegible word] I am sitting at home, off work with [illegible word] a backache suffered after only three days into my elderly care placement, pondering on the effect of the pressure of time on my lifting technique, the unreality of my training in lifting and whether indeed I ought to be lifting anybody at all. PMID- 27223399 TI - The microbe file. PMID- 27223401 TI - In vitro selection of antibiotic-binding aptamers. AB - Despite its wide applicability the selection of small molecule-binding RNA aptamers with high affinity binding and specificity is still challenging. We will present here a protocol which allows the in vitro selection of antibiotic-binding aptamers which turned out to be important building blocks for the design process of synthetic riboswitches. The presented methods will be compared with alternative in vitro selection protocols. A detailed note section will point out useful tips and pitfalls. PMID- 27223400 TI - Efficacy and safety of growth hormone treatment in children with short stature: the Italian cohort of the GeNeSIS clinical study. AB - PURPOSE: We examined auxological changes in growth hormone (GH)-treated children in Italy using data from the Italian cohort of the multinational observational Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) of pediatric patients requiring GH treatment. METHODS: We studied 711 children (median baseline age 9.6 years). Diagnosis associated with short stature was as determined by the investigator. Height standard deviation score (SDS) was evaluated yearly until final or near-final height (n = 78). Adverse events were assessed in all GH-treated patients. RESULTS: The diagnosis resulting in GH treatment was GH deficiency (GHD) in 85.5 % of patients, followed by Turner syndrome (TS 6.6 %). Median starting GH dose was higher in patients with TS (0.30 mg/kg/week) than patients with GHD (0.23 mg/kg/week). Median (interquartile range) GH treatment duration was 2.6 (0.6-3.7) years. Mean (95 % confidence interval) final height SDS gain was 2.00 (1.27-2.73) for patients with organic GHD (n = 18) and 1.19 (0.97-1.40) for patients with idiopathic GHD (n = 41), but lower for patients with TS, 0.37 (-0.03 to 0.77, n = 13). Final height SDS was > 2 for 94 % of organic GHD, 88 % of idiopathic GHD and 62 % of TS patients. Mean age at GH start was lower for organic GHD patients, and treatment duration was longer than for other groups, resulting in greater mean final height gain. GH related adverse events occurred mainly in patients diagnosed with idiopathic GHD. CONCLUSIONS: Data from the Italian cohort of GeNeSIS showed auxological changes and safety of GH therapy consistent with results from international surveillance databases. PMID- 27223402 TI - Imaging flow cytometry for phytoplankton analysis. AB - This review highlights the concepts and instrumentation of imaging flow cytometry technology and in particular its use for phytoplankton analysis. Imaging flow cytometry, a hybrid technology combining speed and statistical capabilities of flow cytometry with imaging features of microscopy, is rapidly advancing as a cell imaging platform that overcomes many of the limitations of current techniques and contributed significantly to the advancement of phytoplankton analysis in recent years. This review presents the various instrumentation relevant to the field and currently used for assessment of complex phytoplankton communities' composition and abundance, size structure determination, biovolume estimation, detection of harmful algal bloom species, evaluation of viability and metabolic activity and other applications. Also we present our data on viability and metabolic assessment of Aphanizomenon sp. cyanobacteria using Imagestream X Mark II imaging cytometer. Herein, we highlight the immense potential of imaging flow cytometry for microalgal research, but also discuss limitations and future developments. PMID- 27223404 TI - Behavior of Bubble Interfaces Stabilized by Particles of Different Densities. AB - Stability of bubbles laden with particles of different densities was investigated. Capillary-held bubbles were produced and coated with particles across the density range of 1.2-3.6 g.cm(-3). The materials used were poly(methyl methacrylate) (PMMA), glass, and anatase. The interaction of the bubbles, once brought into contact, was monitored using high-speed video recording. Visual inspection indicated that denser particles were more easily displaced during the contact of the bubbles and therefore the PMMA particles provided a particle barrier more resistant to coalescence. The coalescence events yielded information on the surface properties of the bubble and the detachment of particles. The attached particles commonly dampen the oscillation of the coalesced bubbles through viscous drag and change in the surface properties (e.g., area-exclusion principle). The dampening of the oscillation generally leads to a reduced mass of particles detaching from the bubble surface. It was found that the different materials investigated did not offer clear evidence of the effect of particle detachment on the bubble surface properties in the present systems. On the other hand, the detachment of different particle materials seemed to be consistent with one another when comparing the attachment and detachment forces exerted on the particles based on their density, size, and hydrophobicity. It was concluded that particles of lower density are more effective in stabilizing interfaces, and thus particle density is an important parameter in the selection of materials for the handling of dispersions. PMID- 27223405 TI - Rebuttal to Dr. Andrew and Dr. Keller letter to the Editor on "Juvenile animal studies in oncology medicines for children". PMID- 27223403 TI - Single-molecule sorting of DNA helicases. AB - DNA helicases participate in virtually all aspects of cellular DNA metabolism by using ATP-fueled directional translocation along the DNA molecule to unwind DNA duplexes, dismantle nucleoprotein complexes, and remove non-canonical DNA structures. Post-translational modifications and helicase interacting partners are often viewed as determining factors in controlling the switch between bona fide helicase activity and other functions of the enzyme that do not involve duplex separation. The bottleneck in developing a mechanistic understanding of human helicases and their control by post-translational modifications is obtaining sufficient quantities of the modified helicase for traditional structure-functional analyses and biochemical reconstitutions. This limitation can be overcome by single-molecule analysis, where several hundred surface tethered molecules are sufficient to obtain a complete kinetic and thermodynamic description of the helicase-mediated substrate binding and rearrangement. Synthetic oligonucleotides site-specifically labeled with Cy3 and Cy5 fluorophores can be used to create a variety of DNA substrates that can be used to characterize DNA binding, as well as helicase translocation and duplex unwinding activities. This chapter describes "single-molecule sorting", a robust experimental approach to simultaneously quantify, and distinguish the activities of helicases carrying their native post-translational modifications. Using this technique, a DNA helicase of interest can be produced and biotinylated in human cells to enable surface-tethering for the single-molecule studies by total internal reflection fluorescence microscopy. The pool of helicases extracted from the cells is expected to contain a mixture of post-translationally modified and unmodified enzymes, and the contributions from either population can be monitored separately, but in the same experiment providing a direct route to evaluating the effect of a given modification. PMID- 27223406 TI - Bioaccumulation Dynamics of Arsenate at the Base of Aquatic Food Webs. AB - Periphyton is an important food source at the base of freshwater ecosystems that tends to bioconcentrate trace elements making them trophically available. The potential for arsenic-a trace element of particular concern due to its widespread occurrence, toxicity, and carcinogenicity-to bioconcentrate in periphyton and thus be available to benthic grazers is less well characterized. To better understand arsenate bioaccumulation dynamics in lotic food webs, we used a radiotracer approach to characterize accumulation in periphyton and subsequent trophic transfer to benthic grazers. Periphyton bioconcentrated As between 3,200 9,700-fold (dry weight) over 8 days without reaching steady state, suggesting that periphyton is a major sink for arsenate. However, As-enriched periphyton as a food source for the mayfly Neocloeon triangulifer resulted in negligible As accumulation in a full lifecycle exposure. Additional studies estimate dietary assimilation efficiency in several primary consumers ranging from 22% in the mayfly N. triangulifer to 75% in the mayfly Isonychia sp. X-ray fluorescence mapping revealed that As was predominantly associated with iron oxides in periphyton. We speculate that As adsorption to Fe in periphyton may play a role in reducing dietary bioavailability. Together, these results suggest that trophic movement of As in lotic food webs is relatively low, though species differences in bioaccumulation patterns are important. PMID- 27223407 TI - Evaluation of biomarkers for ulcerative colitis comparing two sampling methods: fecal markers reflect colorectal inflammation both macroscopically and on a cellular level. AB - OBJECTIVE: Simple, objective and inexpensive tools for the assessment of mucosal inflammation in ulcerative colitis (UC) are highly desirable. The aim of this study was to evaluate a broad spectrum of activity markers comparing two sampling methods: fecal samples and the mucosal patch technique. METHODS: Twenty patients with active UC and 14 healthy controls were characterized by means of clinical indices and endoscopy together with histology and immunohistochemistry on colorectal sections. Neutrophil myeloperoxidase (MPO), calprotectin, eosinophil cationic protein (ECP), eosinophil protein X (EPX/EDN) and IL-1beta were analyzed in fecal samples and rectal fluid collected by the patch technique. Nitric oxide (NO) was analyzed in rectal gas samples. Expression of activity markers on colorectal neutrophils and eosinophils were analyzed by flow cytometry. RESULTS: All fecal and patch markers were increased in UC patients compared with healthy controls. Fecal markers and the level of neutrophil activation correlated to disease activity, whereas patch markers did not. The best markers in terms of discriminative power were fecal MPO and IL-1beta. Fecal marker levels were related to sigmoidal histology scores and to neutrophil number and activation. Patch markers were related to rectal inflammation only. CONCLUSIONS: The levels of inflammation markers in feces and patch fluid distinctly reflected active inflammation in UC. The degree of disease activity was however best assessed by fecal markers, particularly MPO and IL-1beta. Fecal markers reflect colorectal inflammation both macroscopically and on a cellular level, and may be useful for the evaluation of subclinical inflammation. The applicability of patch markers is restricted to rectal inflammation. PMID- 27223408 TI - Biotechnological applications of quorum quenching enzymes. AB - Numerous bacteria use quorum sensing (QS) to synchronize their behavior and monitor their population density. They use signaling molecules known as autoinducers (AI's) that are synthesized and secreted into their local environment to regulate QS-dependent gene expression. Among QS-regulated pathways, biofilm formation and virulence factor secretion are particularly problematic as they are involved in surface-attachment, antimicrobial agent resistance, toxicity, and pathogenicity. Targeting QS represents a promising strategy to inhibit undesirable bacterial traits. This strategy, referred to as quorum quenching (QQ), includes QS-inhibitors and QQ enzymes. These approaches are appealing because they do not directly challenge bacterial survival, and consequently selection pressure may be low, yielding a lower occurrence of resistance. QQ enzymes are particularly promising because they act extracellularly to degrade AI's and can be used in catalytic quantities. This review draws an overview of QQ enzyme related applications, covering several economically important fields such as agriculture, aquaculture, biofouling and health issues. Finally, the possibility of resistance mechanism occurrence to QQ strategies is discussed. PMID- 27223409 TI - Activators and repressors: A balancing act for X-inactivation. AB - In early female embryos X-chromosome inactivation occurs concomitant with up regulation of the non-coding RNA, Xist, on the future inactive X-chromosome. Up regulation of Xist and coating of the future inactive X is sufficient to induce silencing. Therefore unlocking the mechanisms of X-chromosome inactivation requires thorough understanding of the transcriptional regulators, both activators and repressors, which control Xist. Mouse pluripotent embryonic stem cells, which have two active X chromosomes, provide a tractable ex vivo model system for studying X-chromosome inactivation, since this process is triggered by differentiation signals in these cultured cells. Yet there are significant discrepancies found between ex vivo analyses in mouse embryonic stem cells and in vivo studies of early embryos. In this review we elaborate on potential models of how Xist is up regulated on a single X chromosome in female cells and how ex vivo and in vivo analyses enlighten our understanding of the activators and repressors that control this non-coding RNA gene. PMID- 27223411 TI - Study of 1550nm Erbium Glass Laser Fractional non-ablative treatment of photoaging: Comparative clinical effects, histopathology, electron microscopy and immunohistochemistry. AB - BACKGROUND: Non-ablative fractional lasers have been effectively used in skin rejuvenation. OBJECTIVES: Evaluate the efficacy of 1550 nm Erbium Glass Laser for facial rejuvenation through the correlation of clinical evaluation and histopathology, immunohistochemistry and electron microscopy analysis. METHODS: Fifteen subjects (average age 56.4 years old, skin types II-III) with mild to moderate photodamage were submitted to biopsies and 3 facial treatments. Data from the photo assessments and the wrinkles improvement were analyzed 4 months after the treatments. The biopsy skins were fixed in neutral buffered formalin before paraffin embedding, and hematoxylin and eosin stained. The histomorphometric quantification of collagen and elastic fibers; intercellular adhesion molecule 1 expression by immunohistochemistry; and analysis of cell cycle phases, the electrical potential of the mitochondrial and IL- 1, CD34, TGF beta and caspase-3 expression by flow cytometry were analyzed. RESULTS: After 4 months of treatment, collagen fibers had increased by 6.68%, and ICAM-1 by 4.47% in vessel area. Significantly enhanced IL-1 and TGF-beta receptor expression were identified after treatment. Proliferative responses and non-apoptosis-dependent caspase-3 activity were both observed in the cell after dermal treatment. CONCLUSION: The histopathology, immunohistochemistry and electron microscopy showed an improvement compatible to the clinical effectiveness after 4 months. PMID- 27223412 TI - [In Process Citation]. PMID- 27223413 TI - [Ulcerative colitis]. AB - Ulcerative colitis is an immunologic disorder of the intestine which involves the mucosa and sometimes the submucosa. It has a chronic relapsing course, affects the colon and occasionally the terminal ileum. This so called backwash ileitis is overall very rare and of limited clinical importance. Usually the inflammation starts in the rectum and may extend in a proximal and continuous fashion to the rest of the colon. Symptoms consist of frequent loose bloody stools, cramps and weight loss. It is important and frequently neglected that patients especially (but not exclusively) with a limited degree of colonic involvement up to the splenic flexure are treated topically with mesalamine and budesonid or hydrocortisone by suppository, enema or foam. In case of more severe colitis oral mesalamine, systemic corticosteroids and other immunosupressors should be added to the therapy. PMID- 27223415 TI - [Reasons for General Practitioner Shortage - a Comparison Between France and Switzerland]. AB - BACKGROUND AND OBJECTIVES: Both France and Switzerland face a general practitioner (GP) shortage. What differences or parallels exist between the two countries with regard to the causes for this shortage? What conclusions might be drawn from a systematic comparison? METHODS: Literature review with qualitative and semi-quantitative content analysis. RESULTS: Parallels exist in the comparing categories work contents, working structure, income and social status, medical school formation, private life, psychological motives. Differences are found in the categories biography and social selection, medical socialisation, residency. In Switzerland, residency is not uniformly structured, rarely institutionally organised and contains only few elements specific to general medicine. In France, medical socialisation not only exalts the specialists, but also strongly devaluates the GPs. CONCLUSIONS: By systematic analysis and comparison of both countries' pertinent literature, France and Switzerland can deepen their understanding of GP shortage. This paper identifies possible fields of action from medical school through residency up to workplace conditions that are pivotal in addressing the shortage of GPs. PMID- 27223416 TI - [Benzodiazepine Dependency in the Elderly: How to Deal with it]. AB - Benzodiazepine/hypnotic abuse and dependency increase with advanced age. Especially in the elderly, severe adverse events accompany the regular intake of these substances. Sedation, cognitive and psychomotor effects, falls, accidents and injuries are very frequent. The withdrawal of the medication is often associated with major complications. Therefore, prevention is important. These substances should not be prescribed against minor sleep and anxiety disorders and their use should not be restricted to 3-4 weeks. Withdrawal symptoms can include insomnia, anxiety, memory and concentration impairments, ataxia, and in severe states psychotic symptoms, delirium and epileptic seizures. Discontinuation treatment starts with primary-care practitioners, who are still the main prescribers. Long-lasting dependency, on the other hand, often needs in-patient treatment. PMID- 27223417 TI - [Testicular Cancer: Diagnostics, Therapy and Follow Up]. AB - Germ cell tumours represent a rare malignancy that affects mostly young men between 15 and 40 years of age. In approximately 50 % of the cases pure seminoma is found, 50 % non-seminomas are divided into hetrogenous subgroups. The initial therapeutic step usually is orchiectomy, further procedures are defined by histology, clinical staging and risk profile.Therpeutical options consist in active surveillance, radiotherapy or chemotherapy. Stage I shows a cure rate of almost 100 %but even in metastatic stages more then 80 % of all patients can be cured. However they must remain in a close longterm followup during which especially cardiovascular risk factors have to be monitored. PMID- 27223418 TI - [Stroke from the Perspective of Neurologists (Part 3): Update in the Secondary Prevention]. AB - In this third edition the secondary prevention of stroke will be discussed. After the acute phase in which recanalization of an occluded brain artery is in the focus, the risks for a recurrent stroke have to be minimized and rehabilitation should be started. A systematic workup, an extended evaluation of (non-) modifiable risk factors and the clinical-radiological findings are the source of an effective preventive therapy. Risk assessment of the major risk factors such as arterial hypertension, atrial fibrillation, diabetes and dyslipidemia is established. The obstructive sleep apnea syndrome and the complex atheromatosis with a complex structure are independent risk factors for stroke. The search for an etiology is usually a definition of probabilities. The most probable cause of stroke is assumed. PMID- 27223419 TI - [How Does one Avoid Micturition? A Question That not Only Children ask]. AB - We report the history of a 53-year-old kiosk woman who presented with acute urinary retention. The diagnosis of an underactive bladder could be established, which can emerge when the bladder is chronically overstretched, which, in her case, was due to long phases without micturition due to her obligation to care for the kiosk. Despite therapeutic approaches with myocholine and sacral neuromodulation the hypercapacity of the bladder remained. The therapy still consists of a suprapubic cystostomy. PMID- 27223420 TI - [Metformin has no effect on median birth weight score in pregnant non-diabetic women with BMI >35]. PMID- 27223424 TI - Suppression of endogenous lipogenesis induces reversion of the malignant phenotype and normalized differentiation in breast cancer. AB - The correction of specific signaling defects can reverse the oncogenic phenotype of tumor cells by acting in a dominant manner over the cancer genome. Unfortunately, there have been very few successful attempts at identifying the primary cues that could redirect malignant tissues to a normal phenotype. Here we show that suppression of the lipogenic enzyme fatty acid synthase (FASN) leads to stable reversion of the malignant phenotype and normalizes differentiation in a model of breast cancer (BC) progression. FASN knockdown dramatically reduced tumorigenicity of BC cells and restored tissue architecture, which was reminiscent of normal ductal-like structures in the mammary gland. Loss of FASN signaling was sufficient to direct tumors to a reversed phenotype that was near normal when considering the development of polarized growth-arrested acinar-like structure similar to those formed by nonmalignant breast cells in a 3D reconstituted basement membrane in vitro. This process, in vivo, resulted in a low proliferation index, mesenchymal-epithelial transition, and shut-off of the angiogenic switch in FASN-depleted BC cells orthotopically implanted into mammary fat pads. The role of FASN as a negative regulator of correct breast tissue architecture and terminal epithelial cell differentiation was dominant over the malignant phenotype of tumor cells possessing multiple cancer-driving genetic lesions as it remained stable during the course of serial in vivo passage of orthotopic tumor-derived cells. Transient knockdown of FASN suppressed hallmark structural and cytosolic/secretive proteins (vimentin, N-cadherin, fibronectin) in a model of EMT-induced cancer stem cells (CSC). Indirect pharmacological inhibition of FASN promoted a phenotypic switch from basal- to luminal-like tumorsphere architectures with reduced intrasphere heterogeneity. The fact that sole correction of exacerbated lipogenesis can stably reprogram cancer cells back to normal-like tissue architectures might open a new avenue to chronically restrain BC progression by using FASN-based differentiation therapies. PMID- 27223425 TI - Moderate and strong static magnetic fields directly affect EGFR kinase domain orientation to inhibit cancer cell proliferation. AB - Static magnetic fields (SMFs) can affect cell proliferation in a cell-type and intensity-dependent way but the mechanism remains unclear. At the same time, although the diamagnetic anisotropy of proteins has been proposed decades ago, the behavior of isolated proteins in magnetic fields has not been directly observed. Here we show that SMFs can affect isolated proteins at the single molecular level in an intensity-dependent manner. We found that Epidermal Growth Factor Receptor (EGFR), a protein that is overexpressed and highly activated in multiple cancers, can be directly inhibited by SMFs. Using Liquid-phase Scanning Tunneling Microscopy (STM) to examine pure EGFR kinase domain proteins at the single molecule level in solution, we observed orientation changes of these proteins in response to SMFs. This may interrupt inter-molecular interactions between EGFR monomers, which are critical for their activation. In molecular dynamics (MD) simulations, 1-9T SMFs caused increased probability of EGFR in parallel with the magnetic field direction in an intensity-dependent manner. A superconducting ultrastrong 9T magnet reduced proliferation of CHO-EGFR cells (Chinese Hamster Ovary cells with EGFR overexpression) and EGFR-expressing cancer cell lines by ~35%, but minimally affected CHO cells. We predict that similar effects of magnetic fields can also be applied to some other proteins such as ion channels. Our paper will help clarify some dilemmas in this field and encourage further investigations in order to achieve a better understanding of the biological effects of SMFs. PMID- 27223426 TI - Platelet factor 4 is produced by subsets of myeloid cells in premetastatic lung and inhibits tumor metastasis. AB - Bone marrow-derived myeloid cells can form a premetastatic niche and provide a tumor-promoting microenvironment. However, subsets of myeloid cells have also been reported to have anti-tumor properties. It is not clear whether there is a transition between anti- and pro- tumor function of these myeloid cells, and if so, what are the underlying molecular mechanisms. Here we report platelet factor 4 (PF4), or CXCL4, but not the other family members CXCL9, 10, and 11, was produced at higher levels in the normal lung and early stage premetastatic lungs but decreased in later stage lungs. PF4 was mostly produced by Ly6G+CD11b+ myeloid cell subset. Although the number of Ly6G+CD11b+ cells was increased in the premetastatic lungs, the expression level of PF4 in these cells was decreased during the metastatic progression. Deletion of PF4 (PF4 knockout or KO mice) led an increased metastasis suggesting an inhibitory function of PF4. There were two underlying mechanisms: decreased blood vessel integrity in the premetastatic lungs and increased production of hematopoietic stem/progenitor cells (HSCs) and myeloid derived suppressor cells (MDSCs) in tumor-bearing PF4 KO mice. In cancer patients, PF4 expression levels were negatively correlated with tumor stage and positively correlated with patient survival. Our studies suggest that PF4 is a critical anti-tumor factor in the premetastatic site. Our finding of PF4 function in the tumor host provides new insight to the mechanistic understanding of tumor metastasis. PMID- 27223427 TI - Pharmacometabolomics study identifies circulating spermidine and tryptophan as potential biomarkers associated with the complete pathological response to trastuzumab-paclitaxel neoadjuvant therapy in HER-2 positive breast cancer. AB - Defining biomarkers that predict therapeutic effects and adverse events is a crucial mandate to guide patient selection for personalized cancer treatments. In the present study, we applied a pharmacometabolomics approach to identify biomarkers potentially associated with pathological complete response to trastuzumab-paclitaxel neoadjuvant therapy in HER-2 positive breast cancer patients. Based on histological response the 34 patients enrolled in the study were subdivided into two groups: good responders (n = 15) and poor responders (n = 19). The pre-treatment serum targeted metabolomics profile of all patients were analyzed by liquid chromatography tandem mass spectrometry and the differences in the metabolomics profile between the two groups was investigated by multivariate partial least squares discrimination analysis. The most relevant metabolites that differentiate the two groups of patients were spermidine and tryptophan. The Good responders showed higher levels of spermidine and lower amounts of tryptophan compared with the poor responders (p < 0.001, q < 0.05). The serum level of these two metabolites identified patients who achieved a pathological complete response with a sensitivity of 90% [0.79-1.00] and a specificity of 0.87% [0.67-1.00]. These preliminary results support the role played by the individual patients' metabolism in determining the response to cancer treatments and may be a useful tool to select patients that are more likely to benefit from the trastuzumab paclitaxel treatment. PMID- 27223429 TI - Plasma microRNA panels to diagnose pancreatic cancer: Results from a multicenter study. AB - Biomarkers for the early diagnosis of pancreatic cancer (PC) are urgent needed. Plasma microRNAs (miRNAs) might be used as biomarkers for the diagnosis of cancer. We analyzed 361 plasma samples from 6 surgical centers in China and performed machine learning approach. We gain insight of the association between the aberrant plasma miRNA expression and pancreatic disease. 671 microRNAs were screened in the discovery phase and 33 microRNAs in the training phase and 13 microRNAs in the validation phase. After the discovery phase and training phase, 2 diagnostic panels were constructed comprising 3 microRNAs in panel I (miR-486 5p, miR-126-3p, miR-106b-3p) and 6 microRNAs in panel II (miR-486-5p, miR-126-3p, miR-106b-3p, miR-938, miR-26b-3p, miR-1285). Panel I and panel II had high accuracy for distinguishing pancreatic cancer from chronic pancreatitis (CP) with area under the curve (AUC) values of 0.891 (Standard Error (SE): 0.097) and 0.889 (SE: 0.097) respectively, in the validation phase. Additionally, we demonstrated that the diagnostic value of the panels in discriminating PC from CP were comparable to that of carbohydrate antigen 19-9 (CA 19-9) 0.775 (SE: 0.053) (P = 0.1 for both). This study identified 2 diagnostic panels based on microRNA expression in plasma with the potential to distinguish PC from CP. These patterns might be developed as biomarkers for pancreatic cancer. PMID- 27223428 TI - Radiation-enhanced therapeutic targeting of galectin-1 enriched malignant stroma in triple negative breast cancer. AB - Currently there are no FDA approved targeted therapies for Triple Negative Breast Cancer (TNBC). Ongoing clinical trials for TNBC have focused primarily on targeting the epithelial cancer cells. However, targeted delivery of cytotoxic payloads to the non-transformed tumor associated-endothelium can prove to be an alternate approach that is currently unexplored. The present study is supported by recent findings on elevated expression of stromal galectin-1 in clinical samples of TNBC and our ongoing findings on stromal targeting of radiation induced galectin-1 by the anginex-conjugated arsenic-cisplatin loaded liposomes using a novel murine tumor model. We demonstrate inhibition of tumor growth and metastasis in response to the multimodal nanotherapeutic strategy using a TNBC model with orthotopic tumors originating from 3D tumor tissue analogs (TTA) comprised of tumor cells, endothelial cells and fibroblasts. The 'rigorous' combined treatment regimen of radiation and targeted liposomes is also shown to be well tolerated. More importantly, the results presented provide a means to exploit clinically relevant radiation dose for concurrent receptor mediated enhanced delivery of chemotherapy while limiting overall toxicity. The proposed study is significant as it falls in line with developing combinatorial therapeutic approaches for stroma-directed tumor targeting using tumor models that have an appropriate representation of the TNBC microenvironment. PMID- 27223430 TI - Tailored multimodality therapy guided by a two-step decision making process for head-and-neck cancer of unknown primary. AB - BACKGROUND: There is no consensus on the treatment of head-and-neck cancer of unknown primary (HNCUP). The objective of this study is to report our single institution's experience of a tailored multimodality therapy guided by a two-step decision making process. MATERIALS AND METHODS: From January 2007 to November 2013, 92 consecutive patients of HNCUP were treated. 77 patients were treated according the process above, 24 were treated by radiotherapy to the nasopharyngeal site, 7 received neck dissection and radiotherapy to other putative mucosal site, 30 were treated by neck dissection alone, and 16 received neck dissection followed by radiotherapy to the neck. SPSS 20.0 software was used for statistical analysis. RESULTS: After a median follow-up of 34 months, the 3 year overall survival rate was 84.5%. The 3-year mucosal control rate, neck control rate, distant metastasis-free survival rate and disease-free survival rate were 80.9%, 76.2%, and 92.0%, respectively. Of the 24 patients treated as putative nasopharyngeal carcinoma, no primary emerged from any site. Primary tumor emerged in 14 patients, and no primary emerged in the 31 patients treated with putative site radiation (3-year mucosal control rate: 100% vs. 67.9%, p = 0.010). Of the 46 patients treated with neck dissection with/without postoperative radiation, 14 developed neck recurrence, and patients without postoperative radiation suffered more ipsilateral neck recurrence. CONCLUSIONS: The two-step decision-making process seem to be reasonable in treating Chinese HNCUP patients. However, this results need to be prospectively validated. PMID- 27223431 TI - Zoledronic acid impairs stromal reactivity by inhibiting M2-macrophages polarization and prostate cancer-associated fibroblasts. AB - Zoledronic acid (ZA) is a biphosphonate used for osteoporosis treatment and also proved to be effective to reduce the pain induced by bone metastases when used as adjuvant therapy in solid cancers. However, it has been recently proposed that ZA could have direct anti-tumour effects, although the molecular mechanism is unknown. We herein unravel a novel anti-tumour activity of ZA in prostate cancer (PCa), by targeting the pro-tumorigenic properties of both stromal and immune cells. Particularly, we demonstrate that ZA impairs PCa-induced M2-macrophages polarization, reducing their pro-invasive effect on tumour cells and their pro angiogenic features. Crucially, ZA administration reverts cancer associated fibroblasts (CAFs) activation by targeting the mevalonate pathway and RhoA geranyl-geranylation, thereby impairing smooth muscle actin-alpha fibers organization, a prerequisite of fibroblast activation. Moreover, ZA prevents the M2 macrophages-mediated activation of normal fibroblast, highlighting the broad efficacy of this drug on tumour microenvironment. These results are confirmed in a metastatic xenograft PCa mouse model in which ZA-induced stromal normalization impairs cancer-stromal cells crosstalk, resulting in a significant reduction of primary tumour growth and metastases. Overall these findings reinforce the efficacy of ZA as a potential therapeutic approach to reduce cancer aggressiveness, by abrogating the supportive role of tumour microenvironment. PMID- 27223432 TI - Morphoproteomics and biomedical analytics confirm the mTORC2/Akt pathway as a resistance signature and activated ERK and STAT3 as concomitant prosurvival/antiapoptotic pathways in metastatic renal cell carcinoma (RCC) progressing on rapalogs: pathogenesis and therapeutic options. AB - BACKGROUND: It has been proposed that resistance to rapalog therapies in renal cell carcinoma (RCC) is due to adaptive switching from mammalian target of rapamycin complex 1 (mTORC1) to mTORC2. OBJECTIVE: To combine phosphoprotein staining and applied biomedical analytics to investigate resistance signatures in patients with metastatic RCC progressing on rapalog therapies. DESIGN: We applied morphoproteomic analysis to biopsy specimens from nine patients with metastatic RCC who continued to show clinical progression of their tumors while being treated with a rapalog. RESULTS: In patients who were on temsirolimus or everolimus at the time of biopsy, a moderate to strong expression of phosphorylated (p)-mTOR (Ser 2448) in the nuclear compartment with concomitant expression of p-Akt (Ser 473) confirmed the mTORC2 pathway. Concomitant moderate to strong nuclear expression of p-ERK 1/2 (Thr202/Tyr204) and p-STAT3 (Tyr705) was confirmed. Histopathologic changes of hypoxic-type coagulative necrosis in 5 cases as well as identification of insulin-like growth factor-1 receptor (IGF-1R) expression and histone methyltransferase EZH2 in all tumors studied suggested that hypoxia also contributed to the resistance signature. Biomedical analytics provided insight into therapeutic options that could target such adaptive and pathogenetic mechanisms. CONCLUSIONS: Morphoproteomics and biomedical analytics confirm mTORC2/Akt as a resistance signature to rapalog therapy in metastatic RCC and demonstrate activation of the prosurvival ERK and STAT3 pathways and involvement of hypoxic pathways that contribute to pathogenesis of such adaptive resistance. These results highlight the need for a novel combinatorial therapeutic approach in metastatic RCC progressing on rapalogs. PMID- 27223433 TI - Tumor-tropic endothelial colony forming cells (ECFCs) loaded with near-infrared sensitive Au nanoparticles: A "cellular stove" approach to the photoablation of melanoma. AB - In the photothermal treatments (PTs) of tumor, the localization of a high number of near-infrared (NIR) absorbing gold nanoparticles in the tumor mass is still a challenging issue. Here, we propose a promising strategy to deliver therapeutic chitosan-coated gold nanoparticles to tumor cells as hidden cargo of Endothelial Colony Forming Cells (ECFCs) endowed with an innate tumor-tropism. Remarkably, ECFC gold enrichement doesn't affect cell viability and preserves the endothelial lineage characteristics such as capillary morphogenesis and cell migration. We demonstrate that heavily Au-doped ECFCs are able to efficiently warm up the tumor environment, and kill the cancer cells via hyperthermic heating both in vitro as well as in vivo. Thus, we show an excellent thermotransductive property of gold enriched ECFCs and their capability to kill melanoma cells at moderate NIR light intensities. PMID- 27223435 TI - Reactive oxygen species formation and bystander effects in gradient irradiation on human breast cancer cells. AB - Ionizing radiation (IR) in cancer radiotherapy can induce damage to neighboring cells via non-targeted effects by irradiated cells. These so-called bystander effects remain an area of interest as it may provide enhanced efficacy in killing carcinomas with minimal radiation. It is well known that reactive oxygen species (ROS) are ubiquitous among most biological activities. However, the role of ROS in bystander effects has not been thoroughly elucidated. We hypothesized that gradient irradiation (GI) has enhanced therapeutic effects via the ROS-mediated bystander pathways as compared to uniform irradiation (UI). We evaluated ROS generation, viability, and apoptosis in breast cancer cells (MCF-7) exposed to UI (5 Gy) or GI (8-2 Gy) in radiation fields at 2, 24 and 48 h after IR. We found that extracellular ROS release induced by GI was higher than that by UI at both 24 h (p < 0.001) and 48 h (p < 0.001). More apoptosis and less viability were observed in GI when compared to UI at either 24 h or 48 h after irradiation. The mean effective doses (ED) of GI were ~130% (24 h) and ~48% (48 h) higher than that of UI, respectively. Our results suggest that GI is superior to UI regarding redox mechanisms, ED, and toxic dosage to surrounding tissues. PMID- 27223434 TI - Inhibition of FGF/FGFR autocrine signaling in mesothelioma with the FGF ligand trap, FP-1039/GSK3052230. AB - Fibroblast growth factor (FGF) ligand-dependent signaling has a fundamental role in cancer development and tumor maintenance. GSK3052230 (also known as FP-1039) is a soluble decoy receptor that sequesters FGFs and inhibits FGFR signaling. Herein, the efficacy of this molecule was tested in models of mesothelioma, a tumor type shown to express high levels of FGF2 and FGFR1. GSK3052230 demonstrated antiproliferative activity across a panel of mesothelioma cell lines and inhibited growth of tumor xenografts in mice. High expression of FGF2 and FGFR1 correlated well with response to FGF pathway inhibition. GSK3052230 inhibited MAPK signaling as evidenced by decreased phospho-ERK and phospho-S6 levels in vitro and in vivo. Additionally, dose-dependent and statistically significant reductions in tumor vessel density were observed in GSK3052230 treated tumors compared to vehicle-treated tumors. These data support the role of GSK3052230 in effectively targeting FGF-FGFR autocrine signaling in mesothelioma, demonstrate its impact on tumor growth and angiogenesis, and provide a rationale for the current clinical evaluation of this molecule in mesothelioma patients. PMID- 27223436 TI - Lnc-CC3 increases metastasis in cervical cancer by increasing Slug expression. AB - Although screening has reduced mortality rates, metastasis still results in poor survival and prognosis in cervical cancer patients. We compared cervical cancer ESTs libraries with other ESTs libraries to identify candidate genes and cloned a novel cervical cancer-associated lncRNA, lnc-CC3. Overexpression of lnc-CC3 promoted migration and invasion by SiHa cervical cancer cells in vitro and in vivo, increased Slug expression, and reduced the expression of the epithelial cell marker E-cadherin. Conversely, lnc-CC3 knockdown altered SiHa cell morphology and increased the expression of E-cadherin, thereby suppressing migration and invasion. These results suggest lnc-CC3 may be a useful marker of metastasis in cervical cancer. PMID- 27223438 TI - MicroRNA-613 inhibits cell growth, migration and invasion of papillary thyroid carcinoma by regulating SphK2. AB - MicroRNAs (miRNAs) have emerged as important gene regulators and are recognized as key players in carcinogenesis. In this study, we investigated the biological function and mechanism of miR-613 in the regulation of papillary thyroid cancer (PTC) development. We found that miR-613 was downregulated in PTC cell lines and tissues, and overexpression of miR-613 significantly suppressed PTC cell growth, migration and invasion in vitro and inhibited tumor growth in vivo. We identified the gene for sphingosine kinase 2 (SphK2) as a direct target of miR-613. Overexpression of miR-613 significantly repressed SphK2 expression by directly targeting its 3'-untranslated regions (3'-UTR) and restoration of SphK2 reversed the inhibitory effects of miR-613 on PTC cell growth and invasion. Taken together, our results indicated that miR-613 functions as a tumor suppressor in PTC and its suppressive effect is mediated by repressing SphK2 expression. PMID- 27223437 TI - Establishment of a multimarker qPCR panel for the molecular characterization of circulating tumor cells in blood samples of metastatic breast cancer patients during the course of palliative treatment. AB - BACKGROUND: Circulating tumor cells (CTC) are discussed to be an ideal surrogate marker for individualized treatment in metastatic breast cancer (MBC) since metastatic tissue is often difficult to obtain for repeated analysis. We established a nine gene qPCR panel to characterize the heterogeneous CTC population in MBC patients including epithelial CTC, their receptors (EPCAM, ERBB2, ERBB3, EGFR) CTC in Epithelial-Mesenchymal-Transition [(EMT); PIK3CA, AKT2), stem cell-like CTC (ALDH1) as well as resistant CTC (ERCC1, AURKA] to identify individual therapeutic targets. RESULTS: At TP0, at least one marker was detected in 84%, at TP1 in 74% and at TP2 in 79% of the patients, respectively. The expression of ERBB2, ERBB3 and ERCC1 alone or in combination with AURKA was significantly associated with therapy failure. ERBB2 + CTC were only detected in patients not receiving ERBB2 targeted therapies which correlated with no response. Furthermore, patients responding at TP2 had a significantly prolonged overall-survival than patients never responding (p = 0.0090). PATIENTS AND METHODS: 2 * 5 ml blood of 62 MBC patients was collected at the time of disease progression (TP0) and at two clinical staging time points (TP1 and TP2) after 8 12 weeks of chemo-, hormone or antibody therapy for the detection of CTC (AdnaTest EMT-2/StemCell SelectTM, QIAGEN Hannover GmbH, Germany). After pre amplification, multiplex qPCR was performed. Establishment was performed using various cancer cell lines. PTPRC (Protein tyrosine phosphatase receptor type C) and GAPDH served as controls. CONCLUSIONS: Monitoring MBC patients using a multimarker qPCR panel for the characterization of CTC might help to treat patients accordingly in the future. PMID- 27223439 TI - MET exon 14 skipping defines a unique molecular class of non-small cell lung cancer. AB - PURPOSE: Recurrent MET exon 14 splicing has been revealed in lung cancers and is a promising therapeutic target. Because we have limited knowledge about the natural history of MET mutant tumors, the current study was aiming to determine the clinical and pathological characteristics in non-small cell lung cancers (NSCLC). RESULTS: Twenty-three patients (1.3%) were positive for MET exon 14 skipping. Patients with MET exon 14 skipping displayed unique characteristics: female, non-smokers, earlier pathology stage and older age. MET exon 14 skipping indicated an early event as other drivers in lung cancer, while MET copy number gain was more likely a late event in lung cancer. Overall survival (OS) of patients harboring MET exon 14 skipping was longer than patients with KRAS mutation. Almost four-fifths of the lung tumors with MET exon 14 skipping had EGFR and/or HER2 gene copy number gains. EGFR inhibitor showed moderate antitumor activity in treatment of a patient harboring MET exon 14 skipping. PATIENTS AND METHODS: From October 2007 to June 2013, we screened 1770 patients with NSCLC and correlated MET status with clinical pathologic characteristics and mutations in EGFR, KRAS, BRAF, HER2, and ALK. Quantitative Real-Time PCR was used to detect MET gene copy number gain. Immunohistochemistry (IHC) was also performed to screen MET exon 14 skipping. Clinicopathological characteristics and survival information were analyzed. CONCLUSIONS: MET exon 14 skipping was detected in 1.3% (23/1770) of the Chinese patients with NSCLC. MET exon 14 skipping defined a new molecular subset of NSCLC with identifiable clinical characteristics. The therapeutic EGFR inhibitors might be an alternative treatment for patients with MET mutant NSCLC. PMID- 27223440 TI - Characteristics and survival of patients with metachronous or synchronous double primary malignancies: breast and thyroid cancer. AB - BACKGROUND: Clinical experiences suggest that breast cancer (BC) and thyroid cancer (TC) occur metachronously or synchronously in a patient more frequently than it would by chance. This study was conducted to investigate the clinicopathological characteristics and survival of these double primary malignancies. METHODS: 18732 patients with first primary BC and 12877 female patients with first primary TC were performed in this retrospective case controlled study. The control groups were matched with both age at diagnosis and time of surgery (+/-2 years). The clinicopathological factors, Overall survival (OS), and HRs were evaluated by SPSS. RESULTS: There were 91(0.49%) BC patients developed metachronous second primary TC (B-T group), and 117 (0.91%) TC patients developed metachronous second primary BC (T-B group).The expression of estrogen and progesterone receptors, and the value of Ki-67, were significantly higher in the B-T group than control. The median value of thyroid globulin antibody (TGAb) and thyroid peroxidase antibody (TPOAb) were higher in T-B group than control (p <0.05). The duration before second primary cancer was shorter for the B-T group than the T-B group (4.09 years vs. 5.82 years, p<0.001). B-T group patients showed poorer survival than BC only patients (p=0.044). CONCLUSIONS: In general, the overall risk of the occurrence of a second primary TC or BC elevated highly in patients with BC or TC. Detailed mechanisms need to be studied to explore the association between these two cancers. Early detection and effective prevention for the first primary BC or TC patients are necessities for reducing the incidence of the second primary cancer and improving the OS. PMID- 27223441 TI - Ben's 97 Years and 80 Megabytes of Wisdom. PMID- 27223442 TI - Doctor to Doctor. PMID- 27223443 TI - Problems+Solutions. AB - Readers are invited to submit questions relating to problem cases. Inquiries will be answered by qualified consultants and replies forwarded by mail promptly. Selected problems and solutions are published every month in this section. PMID- 27223444 TI - The Medical Bookshelf. PMID- 27223445 TI - The Three-Decade Syndrome. PMID- 27223446 TI - Medical writing. AB - This section is reserved for commentaries and brief essays dealing with matters of interest to physicians. Material for consideration should not exceed five double-spaced typewritten pages. An honorarium of $75 is offered at the time of publication. Submissions should be addressed to: Editor, postgraduate medicine, 4530 W 77th St, Minneapolis, MN 55435. PMID- 27223447 TI - Medical Mnemonics. PMID- 27223448 TI - Exercise and fitness. PMID- 27223449 TI - Medical clearance for vigorous exercise. PMID- 27223450 TI - Cardiac tamponade without pulsus paradoxus. PMID- 27223452 TI - Cues/Tips. PMID- 27223453 TI - Primary Care Digest. PMID- 27223455 TI - Isolated Nodal Failure after Stereotactic Body Radiotherapy for Lung Cancer: The Role for Salvage Mediastinal Radiotherapy. AB - INTRODUCTION: Isolated nodal failure (INF) without synchronous local or distant failure is an uncommon occurrence after stereotactic body radiation therapy (SBRT) for lung cancer. Here we review the natural history and patterns of failure after post-SBRT INF with or without salvage mediastinal radiotherapy (SvRT). METHODS: Patients treated with SBRT for non-small cell lung cancer with definitive intent were identified. Patients who experienced hilar or mediastinal INF without synchronous distant, lobar, or local failure were included and grouped according to the use of SvRT. The rates of subsequent locoregional control, distant metastases, progression-free survival (PFS), and overall survival were assessed. RESULTS: Of 797 patients treated with definitive SBRT, 24 (3%) experienced INF and 15 (63%) received SvRT. The most common SvRT regimen (53%) was 45 Gy in 15 fractions. The median follow-up after INF was 11.3 months for survivors. There were no grade 3 or higher toxicities after SvRT. The 1-year Kaplan-Meier PFS and overall survival estimates were 33% and 56% for patients not receiving radiotherapy and 75% and 73% with SvRT. After SvRT, the rate of locoregional control at 1 year was 84.4%. Crude rates of distant failure were 20.0% with SvRT and 22.2% with no radiotherapy. Of the 13 deaths observed, five (38%) were related to distant progression of lung cancer, four (31%) to comorbidities, three (23%) to mediastinal progression, and one (8%) to an unknown cause. CONCLUSIONS: INF is uncommon after SBRT. Despite the significant comorbidities of this population, intrathoracic progression remains a contributor to morbidity and mortality. SVRT for INF is well tolerated and may improve PFS. PMID- 27223456 TI - cMET Exon 14 Skipping: From the Structure to the Clinic. AB - The abnormal stimulation of the multiple signal transduction pathways downstream of the receptor tyrosine kinase mesenchymal-epithelial transition factor (cMET) promotes cellular transformation, tumor motility, and invasion. Therefore, cMET has been the focus of prognostic and therapeutic studies in different tumor types, including non-small cell lung cancer. In particular, several cMET inhibitors have been developed as innovative therapeutic candidates and are currently under investigation in clinical trials. However, one of the challenges in establishing effective targeted treatments against cMET remains the accurate identification of biomarkers for the selection of responsive subsets of patients. Recently, splice site mutations have been discovered in cMET that lead to the skipping of exon 14, impairing the breakdown of the receptor. Patients with NSCLC who are carrying this splice variant typically overexpress the cMET receptor and show a response to small molecule inhibitors of cMET. Here, we review the main differences at the structural level between the wild-type and the splice variants of cMET and their influence on cMET signaling. We clarify the reason why this variant responds to small molecule inhibitors and their prognostic/predictive role. PMID- 27223457 TI - A Proposal for Combination of Lymph Node Ratio and Anatomic Location of Involved Lymph Nodes for Nodal Classification in Non-Small Cell Lung Cancer. AB - INTRODUCTION: The current pathologic nodal classification (pN) based on anatomic location of involved lymph nodes (LNs) is unsatisfactory in distinguishing heterogeneous pN1 or pN2 non-small cell lung cancer (NSCLC). For the first time we comprehensively compared the prognostic significance of the number of positive LNs (nN), the ratio of the number of positive to removed LNs (LN ratio [LNR]), the combination of pN and nN (pN-nN), the combination of pN and LNR (pN-LNR), and pN to identify a superior classification. METHODS: We identified 700 patients with pN1 (n = 203) or pN2 (n = 497) NSCLC. We classified the patients into four nN categories (nN1, nN2, nN3-6, and nN>=7), four pN-nN categories (pN1-nN1-2, pN1 nN>=3, pN2-nN1-6, and pN2-nN>=7); four LNR categories (LNR<=0.05, 0.1>=LNR>0.05, 0.4>=LNR>0.1, and LNR>0.4), and four pN-LNR categories (pN1-LNR<0.1, pN1 LNR>=0.1, pN2-LNR<0.4, and pN2-LNR>=0.4). The log-rank test was used to analyze differences among groups, and Cox regression was used to evaluate relationships between each classification and survival. RESULTS: In adjusted analyses, pN-LNR was an independent prognostic factor for patients with pN1 or pN2 NSCLC, as were pN-nN, LNR, nN, and pN. pN-LNR was prognostically superior to the other four classifications. Postoperative radiotherapy (PORT) was an independent prognostic factor for pN2 NSCLC. Analyses stratified by LNR showed that PORT did not improve survival in patients with pN2-LNR<0.14 NSCLC, whereas significantly improved survival times in pN2-LNR>=0.14 NSCLC. CONCLUSIONS: We propose a potential revised nodal classification, pN-LNR, to further stratify patients with pN1 or pN2 NSCLC into subgroups so as to more precisely predict survival and help tailor individualized postoperative treatment. PMID- 27223458 TI - Patients with a Previous History of Malignancy Undergoing Lung Cancer Screening: Clinical Characteristics and Radiologic Findings. AB - INTRODUCTION: The aim of this study was to describe the clinical characteristics and radiologic findings in patients with a previous history of malignancy who underwent computed tomography (CT) screening for lung cancer. METHODS: Patients with a previous history of malignancy and a life expectancy of at least 5 years who were referred for lung cancer screening between May 2, 2011, and September 24, 2014, were included. CT scan features assessed included nodule size, morphologic features, and number. The Lung-CT Reporting and Data System scoring system was retrospectively applied to all studies. RESULTS: A total of 139 patients were studied (mean age of 66 years and median smoking history of 50 pack years). All had a previous history of cancer, most often breast cancer (60 patients [43%]), head or neck cancer (26 patients [19%]), and lung cancer (16 patients [12%]). Of these patients, 42 (30%) had a positive screening study result. Lung cancer was diagnosed in seven patients (5%), and a radiation-induced chest wall sarcoma was diagnosed in one patient (1%); 42 patients (30%) had a positive chest CT scan per the National Comprehensive Cancer Network lung cancer screening nodule follow-up algorithm. CONCLUSION: The rate of diagnosis of lung cancer in our patient population is higher than in several previously published studies. Smokers with a history of malignancy may be a group at particularly high risk for the development of subsequent lung cancer. PMID- 27223459 TI - The combination of Everolimus with Verapamil reduces ovarian weight and vascular permeability on ovarian hyperstimulation syndrome: a preclinical experimental randomized controlled study. AB - The efficacy of pathways inhibition and the combined effect of Everolimus (mTOR inhibitor) and Verapamil (CYP3A inhibitor) in ovarian hyperstimulation syndrome (OHSS) need to be tested. Therefore, the impact of a leucotriene receptor antagonist, an anticoagulant, a GnRH antagonist as well as Everolimus plus Verapamil (at various doses and days of administration) on an OHSS rat model was tested. Sixty three female Wistar rats were randomly divided into seven groups. The control group received saline, while the OHSS group received rec-FSH for four consecutive days. The other five groups received rec-FSH for four days and Montelukast daily, Heparin daily, GnRH antagonist daily, Everolimus plus Verapamil in the last two days (half days group) and Everolimus plus Verapamil (half dose group) daily, respectively. All groups received also hCG at the fifth day. Significantly reduced ovarian weight was observed in the Everolimus plus Verapamil groups (half days and half-dose groups) and the Montelukast group compared to the OHSS group (p = 0.001 and p = 0.001, respectively). The vascular permeability was significantly reduced in the Everolimus plus Verapamil group (half dose group) and the GnRH antagonist group compared to the OHSS group (p < 0.001 and p = 0.011, respectively). However, estradiol and progesterone levels did not differ significantly between the groups. Studying the inhibition of different pathways, we concluded that the co-administration of Everolimus and Verapamil (at half dose) is beneficial for reducing ovarian weight and vascular permeability in an OHSS animal model. PMID- 27223460 TI - Improved Endothelial Function of Endothelial Cell Monolayer on the Soft Polyelectrolyte Multilayer Film with Matrix-Bound Vascular Endothelial Growth Factor. AB - Endothelialization on the vascular implants is of great importance for prevention of undesired postimplantation symptoms. However, endothelial dysfunction of regenerated endothelial cell (EC) monolayer has been frequently observed, leading to severe complications, such as neointimal hyperplasia, late thrombosis, and neoatherosclerosis. It has significantly impeded long-term success of the therapy. So far, very little attention has been paid on endothelial function of EC monolayer. Bioinspired by the microenvironment of the endothelium in a blood vessel, this study described a soft polyelectrolyte multilayer film (PEM) through layer-by-layer assembly of poly(l-lysine) (PLL) and hyaluronan (HA). The (PLL/HA) PEM was chemically cross-linked and further incorporated with vascular endothelial growth factor. It demonstrated that this approach could promote EC adhesion and proliferation, further inducing formation of EC monolayer. Further, improved endothelial function of the EC monolayer was achieved as shown with the tighter integrity, higher production of nitric oxide, and expression level of endothelial function related genes, compared to EC monolayers on traditional substrates with high stiffness (e.g., glass, tissue culture polystyrene, and stainless steel). Our findings highlighted the influence of substrate stiffness on endothelial function of EC monolayer, giving a new strategy in the surface design of vascular implants. PMID- 27223461 TI - Directed electrostatic activation in enantioselective organocatalytic cyclopropanation reactions: a computational study. AB - Cyclopropane rings are versatile building blocks in organic chemistry. Their synthesis, by the reaction of sulfur ylides with alpha,beta-unsaturated carbonyl compounds, has recently aroused renewed interest after the discovery of efficient catalysis by using (S)-indoline-2-carboxylic acid. In order to rationalize the behavior of this catalyst, MacMillan proposed a directed electrostatic activation (DEA) mechanism, in which the negative carboxylate group interacts with the positive thionium moiety, thus reducing the activation energy and increasing the reaction rate. More recently, Mayr refuted some of MacMillan conclusions, but accepted the DEA mechanism as a justification for the experimental high reaction rates. In contrast, our results indicate that the selectivity obtained in the process seems to result from several strong hydrogen bond interactions between the two reacting species, while no strong evidence for a DEA mechanism was found. We also concluded that the hydrogen bonds don't improve the reaction rate by lowering the activation energy of the rate-determining step, but can do it by promoting efficient reaction trajectories due to long-range complexation of the reagents. Finally, our results confirm that the cyclopropanation reaction occurs by a two-step mechanism, and that the overall enantioselectivity depends on the relative energies of the two steps, averaged by the relative populations of the iminium intermediates that are initially formed in the reaction. PMID- 27223462 TI - One-Pot Copper(I)-Catalyzed Ligand/Base-Free Tandem Cyclooxidative Synthesis of Quinazolinones. AB - A novel and efficient Cu(I)-catalyzed ligand- and base-free multipathway domino strategy has been developed for the synthesis of 2-substituted quinazolinones. The reaction utilizes 2-bromobenzamide and multiform substrates such as aldehydes, alcohols, and methyl arenes for a one-pot protocol, whereas TMSN3 is used as a nitrogen source. A wide range of substrate scope, functional group tolerance, and operational simplicity are synthetically useful features. PMID- 27223463 TI - Low-frequency electrical dosimetry: research agenda of the IEEE International Committee on Electromagnetic Safety. AB - This article treats unsettled issues in the use of numerical models of electrical dosimetry as applied to international limits on human exposure to low-frequency (typically < 100 kHz) electromagnetic fields and contact current. The perspective in this publication is that of Subcommittee 6 of IEEE-ICES (International Committee on Electromagnetic Safety) Technical Committee 95. The paper discusses 25 issues needing attention, fitting into three general categories: induction models; electrostimulation models; and human exposure limits. Of these, 9 were voted as 'high priority' by members of Subcommittee 6. The list is presented as a research agenda for refinements in numerical modeling with applications to human exposure limits. It is likely that such issues are also important in medical and electrical product safety design applications. PMID- 27223466 TI - [New drugs for small animals in 2015]. AB - In 2015, four active pharmaceutical ingredients were released on the German market for small animals. These were the calcium-channel blocker Amlodipine (Amodip(r)), the benzodiazepine Diazepam (Ziapam(r)), the allylamine antifungal agent Terbinafine (Osurnia(r)) and the loop diuretic Torasemide (UpCard(r)). One substance has been authorized for an additional species. The triazole antifungal drug Itraconazole (Fungitraxx(r)) is now authorized for use in ornamental birds. PMID- 27223465 TI - Fatigue following Acute Q-Fever: A Systematic Literature Review. AB - BACKGROUND: Long-term fatigue with detrimental effects on daily functioning often occurs following acute Q-fever. Following the 2007-2010 Q-fever outbreak in the Netherlands with over 4000 notified cases, the emphasis on long-term consequences of Q-fever increased. The aim of this study was to provide an overview of all relevant available literature, and to identify knowledge gaps regarding the definition, diagnosis, background, description, aetiology, prevention, therapy, and prognosis, of fatigue following acute Q-fever. DESIGN: A systematic review was conducted through searching Pubmed, Embase, and PsycInfo for relevant literature up to 26th May 2015. References of included articles were hand searched for additional documents, and included articles were quality assessed. RESULTS: Fifty-seven articles were included and four documents classified as grey literature. The quality of most studies was low. The studies suggest that although most patients recover from fatigue within 6-12 months after acute Q fever, approximately 20% remain chronically fatigued. Several names are used indicating fatigue following acute Q-fever, of which Q-fever fatigue syndrome (QFS) is most customary. Although QFS is described to occur frequently in many countries, a uniform definition is lacking. The studies report major health and work-related consequences, and is frequently accompanied by nonspecific complaints. There is no consensus with regard to aetiology, prevention, treatment, and prognosis. CONCLUSIONS: Long-term fatigue following acute Q-fever, generally referred to as QFS, has major health-related consequences. However, information on aetiology, prevention, treatment, and prognosis of QFS is underrepresented in the international literature. In order to facilitate comparison of findings, and as platform for future studies, a uniform definition and diagnostic work-up and uniform measurement tools for QFS are proposed. PMID- 27223464 TI - miR-190 Enhances HIF-Dependent Responses to Hypoxia in Drosophila by Inhibiting the Prolyl-4-hydroxylase Fatiga. AB - Cellular and systemic responses to low oxygen levels are principally mediated by Hypoxia Inducible Factors (HIFs), a family of evolutionary conserved heterodimeric transcription factors, whose alpha- and beta-subunits belong to the bHLH-PAS family. In normoxia, HIFalpha is hydroxylated by specific prolyl-4 hydroxylases, targeting it for proteasomal degradation, while in hypoxia the activity of these hydroxylases decreases due to low oxygen availability, leading to HIFalpha accumulation and expression of HIF target genes. To identify microRNAs required for maximal HIF activity, we conducted an overexpression screen in Drosophila melanogaster, evaluating the induction of a HIF transcriptional reporter. miR-190 overexpression enhanced HIF-dependent biological responses, including terminal sprouting of the tracheal system, while in miR-190 loss of function embryos the hypoxic response was impaired. In hypoxic conditions, miR-190 expression was upregulated and required for induction of HIF target genes by directly inhibiting the HIF prolyl-4-hydroxylase Fatiga. Thus, miR-190 is a novel regulator of the hypoxia response that represses the oxygen sensor Fatiga, leading to HIFalpha stabilization and enhancement of hypoxic responses. PMID- 27223467 TI - Is Pertussis Infection Neglected in China? Evidence from a Seroepidemiology Survey in Zhejiang, an Eastern Province of China. AB - BACKGROUND: The resurgence of pertussis has occurred in many countries. However, the epidemiological profiles of pertussis cannot be well understood by the current surveillance system in China. This study was designed to investigate the age specific serologic evidence of antibodies against pertussis, and to offer information regarding the existence of pertussis infection in Zhejiang Province, China. METHODS: A cross-sectional serosurvey was carried out in 6 counties of Zhejiang Province during September and October of 2014. The immunoglobulin G pertussis toxin (IgG-PT) levels were measured quantitatively with a commercially available enzyme-linked immunosorbent assay (ELISA). The antibody activities were expressed in the Food and Drug Administration (FDA)-U/ml and a level >=30 FDA U/ml was considered seropositive. An IgG-PT >80 FDA-U/ml indicated recent pertussis infection if the patient had not received immunization with the pertussis vaccine within the last year. RESULTS: The mean IgG-PT seropositivity rate among the 2107 subjects was 33.32% with a geometric mean concentration of 17.73 (95% confidence interval: 16.90-18.60) FDA-U/ml. The difference in the seropositivity rates reached significant means among the different age groups (waldchi2 = 198.41, P<0.0005), and children aged 3 years had the highest percentage (63.24%) of undetectable IgG-PT level. Of the 1707 subjects >=3 years of age, 169 (9.90%) had evidence of a recent infection. The highest proportion of IgG-PT levels >=80 FDA-U/ml was found in >=60 years age group followed by 11-15 and 16-25 years age groups. CONCLUSIONS: This study indicates the rather lower IgG-PT level sustained 1 year after the acellular pertussis vaccine booster dose, and substantial proportion of population susceptibility to pertussis in Zhejiang Province, China. Moreover, pertussis infection is not uncommon; it was estimated that 10% of subjects were recently infected approximately within the last 100 days. We highly suggest that the surveillance capacity should be strengthened and consider introducing booster dose that protect against pertussis in 6 years old children. PMID- 27223468 TI - Correction: Exploring Early Micronutrient Deficiencies in Rainbow Trout (Oncorhynchus mykiss) by Next-Generation Sequencing Technology - From Black Box to Functional Genomics. AB - [This corrects the article DOI: 10.1371/journal.pone.0069461.]. PMID- 27223469 TI - Multifunctional microbeads for drug delivery in TACE. AB - INTRODUCTION: Transarterial chemoembolization (TACE) is the standard treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC). Microbeads used to embolize tumor vasculature have recently been designed to deliver a therapeutic drug to the tumor site. Increasing the functionality of microbeads for TACE has the potential to improve therapy by accomplishing multiple, beneficial tasks with one system. AREAS COVERED: Microbead functions beyond embolization and drug delivery that could be highly advantageous include detection and tracking with imaging, targeting, degradation, and the delivery of multiple therapeutics or combination therapies. This review covers the concepts of TACE for treatment of HCC, the need for controlled delivery systems and the use of drug-eluting beads. Shortcomings of the current technology and the current approaches to improve materials used as embolic microbeads are discussed. Relevant studies aimed to enhance microbead visibility, targetability, degradability, and the use of multiple therapeutics or combination therapies are reviewed. EXPERT OPINION: The incorporation of nanoparticles that possess desirable properties into the microbead matrix is a suitable method of creating multifunctional microbeads. The development of these 'nano-on-micro' systems is a promising approach to improve TACE therapy and may lead to improved treatment. PMID- 27223471 TI - Plasma Levels of the Interleukin-1-Receptor Antagonist Are Lower in Women with Gestational Diabetes Mellitus and Are Particularly Associated with Postpartum Development of Type 2 Diabetes. AB - Diabetes mellitus is a group of diseases characterized by chronic hyperglycemia. Women who develops hyperglycemia for the first time during pregnancy receive the diagnosis gestational diabetes mellitus (GDM). Presently, there is no consensus about the diagnostic criteria for GDM. A majority of these women subsequently develop postpartum overt diabetes making it important to identify these patients as early as possible. In this study we investigated if plasma levels of the interleukin-1 receptor antagonist (IL-1Ra), an endogenous inhibitor of IL-1 signaling, can be used as a complementary biomarker for diagnosing GDM and predicting postpartum development of overt diabetes mellitus. Patients participating in this study (n = 227) were diagnosed with their first GDM 2004 2013 at Lund University Hospital, Lund, Sweden. Healthy pregnant volunteers (n = 156) were recruited from women's welfare centers in the same region 2014-2015. Levels of IL-1Ra and C-peptide were analyzed in ethylenediaminetetraacetic acid (EDTA)-plasma or serum using enzyme linked immunosorbent assay (ELISA). GDM patients had significantly lower levels of IL-1Ra than the control group (p = 0.012). In addition, GDM patients that had developed impaired glucose tolerance (IGT) or type 2 diabetes mellitus postpartum had significantly lower levels of IL 1Ra, and significantly higher levels of C-peptide than GDM patients that had not developed diabetes mellitus postpartum (p = 0.023) and (p = 0.0011) respectively. An inverse correlation was found between IL-1Ra and serum C-peptide levels in the control group (rs = -0.31 p = 0.0001). Our results show that IL-1Ra might be included in a future panel of biomarkers, both for diagnosing GDM to complement blood glucose, and also identifying GDM patients that are at risk of developing type 2 diabetes mellitus postpartum. However, the ROC curve analysis provided a sensitivity of 52.2% and specificity of 67.1%, which nonetheless may not be sufficient enough to use IL-1Ra as a sole biomarker. PMID- 27223470 TI - Identification of beta-Dystrobrevin as a Direct Target of miR-143: Involvement in Early Stages of Neural Differentiation. AB - Duchenne Muscular Dystrophy, a genetic disorder that results in a gradual breakdown of muscle, is associated to mild to severe cognitive impairment in about one-third of dystrophic patients. The brain dysfunction is independent of the muscular pathology, occurs early, and is most likely due to defects in the assembly of the Dystrophin-associated Protein Complex (DPC) during embryogenesis. We have recently described the interaction of the DPC component beta-dystrobrevin with members of complexes that regulate chromatin dynamics, and suggested that beta-dystrobrevin may play a role in the initiation of neuronal differentiation. Since oxygen concentrations and miRNAs appear as well to be involved in the cellular processes related to neuronal development, we have studied how these factors act on beta-dystrobrevin and investigated the possibility of their functional interplay using the NTera-2 cell line, a well-established model for studying neurogenesis. We followed the pattern of expression and regulation of beta-dystrobrevin during the early stages of neuronal differentiation induced by exposure to retinoic acid (RA) under hypoxia as compared with normoxia, and found that beta-dystrobrevin expression is regulated during RA-induced differentiation of NTera-2 cells. We also found that beta-dystrobrevin pattern is delayed under hypoxic conditions, together with a delay in the differentiation and an increase in the proliferation rate of cells. We identified miRNA-143 as a direct regulator of beta-dystrobrevin expression, demonstrated that beta-dystrobrevin is expressed in the nucleus and showed that, in line with our previous in vitro results, beta dystrobrevin is a repressor of synapsin I in live cells. Altogether the newly identified regulatory pathway miR-143/beta-dystrobrevin/synapsin I provides novel insights into the functions of beta-dystrobrevin and opens up new perspectives for elucidating the molecular mechanisms underlying the neuronal involvement in muscular dystrophy. PMID- 27223473 TI - Forest Owners' Response to Climate Change: University Education Trumps Value Profile. AB - Do forest owners' levels of education or value profiles explain their responses to climate change? The cultural cognition thesis (CCT) has cast serious doubt on the familiar and often criticized "knowledge deficit" model, which says that laypeople are less concerned about climate change because they lack scientific knowledge. Advocates of CCT maintain that citizens with the highest degrees of scientific literacy and numeracy are not the most concerned about climate change. Rather, this is the group in which cultural polarization is greatest, and thus individuals with more limited scientific literacy and numeracy are more concerned about climate change under certain circumstances than those with higher scientific literacy and numeracy. The CCT predicts that cultural and other values will trump the positive effects of education on some forest owners' attitudes to climate change. Here, using survey data collected in 2010 from 766 private forest owners in Sweden and Germany, we provide the first evidence that perceptions of climate change risk are uncorrelated with, or sometimes positively correlated with, education level and can be explained without reference to cultural or other values. We conclude that the recent claim that advanced scientific literacy and numeracy polarizes perceptions of climate change risk is unsupported by the forest owner data. In neither of the two countries was university education found to reduce the perception of risk from climate change. Indeed in most cases university education increased the perception of risk. Even more importantly, the effect of university education was not dependent on the individuals' value profile. PMID- 27223472 TI - Targeting Serglycin Prevents Metastasis in Murine Mammary Carcinoma. AB - In hematopoietic cells, serglycin proteoglycans mainly contribute to proper storage and secretion of inflammatory mediators via their negatively charged glycosaminoglycans. Serglycin proteoglycans are also expressed in cancer cells where increased expression has been linked to poor prognosis. However, the serglycin-dependent mediators promoting cancer progression remain to be determined. In the present study we report that genetic ablation of serglycin proteoglycan completely blocks lung metastasis in the MMTV-PyMT-driven mouse breast cancer model, while serglycin-deficiency did not affect primary tumour growth or number of mammary tumours. Although E-cadherin expression was higher in the serglycin-deficient primary tumour tissue, indicating reduced invasiveness, serglycin-deficient tumour cells were still detected in the circulation. These data suggest that serglycin proteoglycans play a role in extravasation as well as colonization and growth of metastatic cells. A microarray expression analysis and functional annotation of differentially expressed genes identified several biological pathways where serglycin may be important. Our results suggest that serglycin and serglycin-dependent mediators are potential drug targets to prevent metastatic disease/dissemination of cancer. PMID- 27223475 TI - Parameters for the RM1 Quantum Chemical Calculation of Complexes of the Trications of Thulium, Ytterbium and Lutetium. AB - The RM1 quantum chemical model for the calculation of complexes of Tm(III), Yb(III) and Lu(III) is advanced. Subsequently, we tested the models by fully optimizing the geometries of 126 complexes. We then compared the optimized structures with known crystallographic ones from the Cambridge Structural Database. Results indicate that, for thulium complexes, the accuracy in terms of the distances between the lanthanide ion and its directly coordinated atoms is about 2%. Corresponding results for ytterbium and lutetium are both 3%, levels of accuracy useful for the design of lanthanide complexes, targeting their countless applications. PMID- 27223474 TI - Relationship between Proton Magnetic Resonance Spectroscopy of Frontoinsular Gray Matter and Neurodevelopmental Outcomes in Very Low Birth Weight Children at the Age of 4. AB - Very low birth weight is associated with long term neurodevelopmental complications. Macroscopic brain abnormalities in prematurity survivors have been investigated in several studies. However, there is limited data regarding local cerebral metabolic status and neurodevelopmental outcomes. The purpose of this study was to characterize the relationship between proton magnetic resonance spectra in basal ganglia, frontal white matter and frontoinsular gray matter, neurodevelopmental outcomes assessed with the Leiter scale and the Developmental Test of Visual Perception and selected socioeconomic variables in a cohort of very low birth weight children at the age of four. Children were divided in three groups based on the severity of neurodevelopmental impairment. There were no differences in spectroscopy in basal ganglia and frontal white matter between the groups. Lower concentrations of N-acetylaspartate (NAA), choline (Cho) and myoinositol (mI) were observed in the frontoinsular cortex of the left hemisphere in children with neurodevelopmental impairment compared to children with normal neurodevelopmental outcomes. Higher parental education, daycare attendance and breastfeeding after birth were associated with more favorable neurodevelopmental prognosis, whereas rural residence was more prevalent in children with moderate and severe impairment. Our study demonstrates the role of long term neurometabolic disruption in the left frontoinsular cortex and selected socioeconomic variables in determination of neurodevelopmental prognosis in prematurity survivors. PMID- 27223478 TI - SERS of Individual Nanoparticles on a Mirror: Size Does Matter, but so Does Shape. AB - Coupling noble metal nanoparticles by a 1 nm gap to an underlying gold mirror confines light to extremely small volumes, useful for sensing on the nanoscale. Individually measuring 10 000 of such gold nanoparticles of increasing size dramatically shows the different scaling of their optical scattering (far-field) and surface-enhanced Raman emission (SERS, near-field). Linear red-shifts of the coupled plasmon modes are seen with increasing size, matching theory. The total SERS from the few hundred molecules under each nanoparticle dramatically increases with increasing size. This scaling shows that maximum SERS emission is always produced from the largest nanoparticles, irrespective of tuning to any plasmonic resonances. Changes of particle facet with nanoparticle size result in vastly weaker scaling of the near-field SERS, without much modifying the far field, and allows simple approaches for optimizing practical sensing. PMID- 27223476 TI - Molecular Epidemiology and Clinical Impact of Acinetobacter calcoaceticus baumannii Complex in a Belgian Burn Wound Center. AB - Multidrug resistant Acinetobacter baumannii and its closely related species A. pittii and A. nosocomialis, all members of the Acinetobacter calcoaceticus baumannii (Acb) complex, are a major cause of hospital acquired infection. In the burn wound center of the Queen Astrid military hospital in Brussels, 48 patients were colonized or infected with Acb complex over a 52-month period. We report the molecular epidemiology of these organisms, their clinical impact and infection control measures taken. A representative set of 157 Acb complex isolates was analyzed using repetitive sequence-based PCR (rep-PCR) (DiversiLab) and a multiplex PCR targeting OXA-51-like and OXA-23-like genes. We identified 31 rep PCR genotypes (strains). Representatives of each rep-type were identified to species by rpoB sequence analysis: 13 types to A. baumannii, 10 to A. pittii, and 3 to A. nosocomialis. It was assumed that isolates that belonged to the same rep type also belonged to the same species. Thus, 83.4% of all isolates were identified to A. baumannii, 9.6% to A. pittii and 4.5% to A. nosocomialis. We observed 12 extensively drug resistant Acb strains (10 A. baumannii and 2 A. nosocomialis), all carbapenem-non-susceptible/colistin-susceptible and imported into the burn wound center through patients injured in North Africa. The two most prevalent rep-types 12 and 13 harbored an OXA-23-like gene. Multilocus sequence typing allocated them to clonal complex 1 corresponding to EU (international) clone I. Both strains caused consecutive outbreaks, interspersed with periods of apparent eradication. Patients infected with carbapenem resistant A. baumannii were successfully treated with colistin/rifampicin. Extensive infection control measures were required to eradicate the organisms. Acinetobacter infection and colonization was not associated with increased attributable mortality. PMID- 27223479 TI - Use of Telemedicine for Management of Diabetes in Correctional Facilities. AB - BACKGROUND: Prisoners can have difficulty obtaining subspecialty consultations. Telemedicine is used to provide diabetes consultations for residents of correctional facilities from our diabetes center. Telemedicine helps improve access to endocrinologists at reduced cost, but little outcome data are available. METHODS: A retrospective chart review of prisoners from 15 correctional facilities who received televisits for diabetes from 2011 to 2014 was performed. Demographic information, complications, medications, blood pressure, and laboratory results were collected. RESULTS: At baseline (n = 106), mean age was 44 years, duration of diabetes was 15 years, 44% had type 1 diabetes, and all were male. Only 64 of the participants had >=2 video consultations; 58/64 had follow-up HbA1c results; and 53/58 were insulin requiring. Mean initial HbA1c was 9.3% with an average decrease of 0.5% from initial to final visit (a mean of 3.6 televisits). Patients with an initial HbA1c >9% (n = 28) had an average drop of 1.3%. Twenty-two subjects had initial elevated blood pressure; 20/22 (91%) were prescribed angiotensin-converting enzyme-inhibitors (ACE-I)/angiotensin II receptor blockers (ARB); and 15 of these 20 (75%) had a final blood pressure <140/90 mm Hg over a mean of 3.3 televisits. 17/20 with high low-density lipoprotein (LDL) were treated with statin drugs; 15/17 (88%) had improved LDL on follow-up. Follow-up was limited by prisoner availability or visit cancellation by prison facility. CONCLUSION: Improvements in glycemic, blood pressure, and lipid control for prisoners with diabetes can be achieved with teleconsultations to correctional institutions. Given the high costs of transporting prisoners to healthcare facilities, telemedicine should be considered to help improve diabetes care for this vulnerable population. PMID- 27223480 TI - CO adsorption on the GaPd(1[combining macron]1[combining macron]1[combining macron]) surface: a comparative DFT study using different functionals. AB - CO adsorption on the polar (1[combining macron]1[combining macron]1[combining macron]) surface of the intermetallic compound GaPd is examined within ab initio methods using an all-electron full-potential electronic structure approach. Comparison between the PW-LDA, GGA-PBE, GGA-RPBE, GGA-revPBE, and hybrid HSE06 functionals is considered through bulk, clean surface and CO adsorption calculations. The choice of the functional is found to have a strong influence in the description of single CO adsorption on the surface model proposed in literature. As expected from the so called "CO adsorption puzzle", differences in the obtained results demonstrate that classic LDA and PBE functionals can only partially describe the complex CO adsorption bonding scenario on a surface containing transition metal elements (in this case Pd atoms), where the energies of the substrate-adsorbate electronic states are shifted, yielding important differences in the absolute values of the adsorption energies, vibrational frequencies and surface-adsorbate interaction. So far the hybrid functional HSE06 correctly retrieves all the tendencies observed experimentally as confirmed by comparing our first-principles results to experimental findings. PMID- 27223481 TI - Selenium-Containing Phycocyanin from Se-Enriched Spirulina platensis Reduces Inflammation in Dextran Sulfate Sodium-Induced Colitis by Inhibiting NF-kappaB Activation. AB - Selenium (Se) plays an important role in fine-tuning immune responses. Inflammatory bowel disease (IBD) involves hyperresponsive immunity of the digestive tract, and a low Se level might aggravate IBD progression; however, the beneficial effects of natural Se-enriched diets on IBD remain unknown. Previously, we developed high-yield Se-enriched Spirulina platensis (Se-SP) as an excellent organic nutritional Se source. Here we prepared Se-containing phycocyanin (Se-PC) from Se-SP and observed that Se-PC administration effectively reduced the extent of colitis in mouse induced by dextran sulfate sodium. Supplementation with Se-PC resulted in significant protective effects, including mitigation of body weight loss, bloody diarrhea, and colonic inflammatory damage. The anti-inflammatory effects of Se-PC supplementation were found to involve modulation of cytokines, including IL-6, TNF-alpha, MCP-1, and IL-10. Mechanistically, Se-PC inhibited the activation of macrophages by suppressing the nuclear translocation of NF-kappaB, which is involved in the transcription of these pro-inflammatory cytokines. These results together suggest potential benefits of Se-PC as a functional Se supplement to reduce the symptoms of IBD. PMID- 27223482 TI - Antinociceptive properties of shikonin: in vitro and in vivo studies. AB - Shikonin possess a diverse spectrum of pharmacological properties in multiple therapeutic areas. However, the nociceptive effect of shikonin is not largely known. To investigate the antinociceptive potential of shikonin, panel of GPCRs, ion channels, and enzymes involved in pain pathogenesis were studied. To evaluate the translation of shikonin efficacy in vivo, it was tested in 3 established rat pain models. Our study reveals that shikonin has significant inhibitory effect on pan sodium channel/N1E115 and NaV1.7 channel with half maximal inhibitory concentration (IC50) value of 7.6 MUmol/L and 6.4 MUmol/L, respectively, in a cell-based assay. Shikonin exerted significant dose dependent antinociceptive activity at doses of 0.08%, 0.05%, and 0.02% w/v in pinch pain model. In mechanical hyperalgesia model, dose of 10 and 3 mg/kg (intraperitoneal) produced dose-dependent analgesia and showed 67% and 35% reversal of hyperalgesia respectively at 0.5 h. Following oral administration, it showed 39% reversal at 30 mg/kg dose. When tested in first phase of formalin induced pain, shikonin at 10 mg/kg dose inhibited paw flinching by ~71%. In all studied preclinical models, analgesic effect was similar or better than standard analgesic drugs. The present study unveils the mechanistic role of shikonin on pain modulation, predominantly via sodium channel modulation, suggesting that shikonin could be developed as a potential pain blocker. PMID- 27223483 TI - Molecular-Directed Treatment of Differentiated Thyroid Cancer: Advances in Diagnosis and Treatment. AB - IMPORTANCE: Thyroid cancer incidence is increasing, and when fine-needle aspiration biopsy results are cytologically indeterminate, the diagnosis is often still established only after thyroidectomy. Molecular marker testing may be helpful in guiding patient-oriented and tailored management of thyroid nodules and thyroid cancer. OBJECTIVE: To summarize available data on the use of molecular testing to improve the diagnosis and prognostication of thyroid cancer. EVIDENCE REVIEW: A MEDLINE review was conducted using the primary search terms molecular, thyroid cancer, thyroid nodule, and gene expression classifier in search strings. Articles were restricted to those published between January 1, 2010, and June 1, 2015, inclusive of adult humans, and reported in the English language only. FINDINGS: Of 867 titles screened, 67 articles were further identified for review of the full text. The 2 most studied molecular marker testing techniques for indeterminate thyroid nodules include gene expression classifier analysis and evaluation for somatic mutations or rearrangements that are commonly found in thyroid cancer (7-gene panel). Nodules with benign results on gene expression classifier analysis can be associated with less than a 5% risk of cancer and may be observed, while nodules with positive results on the 7-gene panel may have a higher risk of cancer (80%-100%) and definitive surgery can be recommended. However, cancer prevalence and geographic variations in histologic subtypes may affect accuracy and clinical applicability of both tests. Molecular marker tests such as ThyroSeq version 2.1 are more comprehensive, but they need further validation. Preoperative risk stratification using molecular markers also may be used to better define the optimal extent of thyroidectomy for patients with thyroid cancer. CONCLUSIONS AND RELEVANCE: Molecular markers potentially can augment the diagnostic specificity of fine-needle aspiration biopsy to better differentiate cytologically indeterminate nodules that can be safely observed from cytologically indeterminate nodules that may be associated with differentiated thyroid cancer. Long-term follow-up data are still needed; in the end, patient preference regarding the relative risks and benefits of molecular testing is at the crux of decision making. PMID- 27223484 TI - Low skeletal muscle mass index is associated with function and nutritional status in residents in a Turkish nursing home. AB - INTRODUCTION: To determine the prevalence of low muscle mass (LMM) and the relationship between LMM with functional and nutritional status as defined using the LMM evaluation method of European Working Group on Sarcopenia in Older People (EWGSOP) criteria among male residents in a nursing home. METHODS: Male residents aged >60 years of a nursing home located in Turkey were included in our study. Their body mass index (BMI) kg/m2, skeletal muscle mass (SMM-kg) and skeletal muscle mass index (SMMI-kg/m2) were calculated. The participants were regarded as having low SMMI if they had SMMI <9.2 kg/m2 according to our population specific cut-off point. Functional status was evaluated with Katz activities of daily living (ADL) and Lawton Instrumental Activities of Daily Living (IADL). Nutritional assessment was performed using the Mini Nutritional Assessment (MNA). The number of drugs taken and chronic diseases were recorded. RESULTS: One hundred fifty-seven male residents were enrolled into the study. Their mean age was 73.1 +/- 6.7 years with mean ADL score of 8.9 +/- 2.0 and IADL score of 8.7 +/- 4.6. One hundred twelve (71%) residents were aged >70 years. Thirty-five men (23%) had low SMMI in group aged >60 years, and twenty-eight subjects (25%) in the group aged >70 years. MNA scores were significantly lower in residents with low SMMI compared with having normal SMMI (17.1 +/- 3.4 versus 19.6 +/- 2.5, p = 0.005). BMI was significantly lower in the residents with low SMMI compared with normal SMMI (19.6 +/- 2.7 versus 27.1 +/- 4.1, p< 0.001). ADL scores were significantly different between residents with low SMMI and normal SMMI in those aged >70 years (8.1 +/- 2.6 versus 9.1 +/- 1.6, p = 0.014). In regression analyses, the only factor associated with better functional status was the lower age (p = 0.04) while the only factor associated with better nutrition was higher SMMI (p = 0.01). CONCLUSIONS: Low SMMI detected by LMM evaluation method of EWGSOP criteria is prevalent among male nursing home residents. There is association of low SMMI with nutritional status and probably with functional status within the nursing home setting using the EWGSOP criteria with Turkish normative reference cut-off value. PMID- 27223485 TI - Screening for germline BRCA1, BRCA2, TP53 and CHEK2 mutations in families at-risk for hereditary breast cancer identified in a population-based study from Southern Brazil. AB - In Brazil, breast cancer is a public health care problem due to its high incidence and mortality rates. In this study, we investigated the prevalence of hereditary breast cancer syndromes (HBCS) in a population-based cohort in Brazils southernmost capital, Porto Alegre. All participants answered a questionnaire about family history (FH) of breast, ovarian and colorectal cancer and those with a positive FH were invited for genetic cancer risk assessment (GCRA). If pedigree analysis was suggestive of HBCS, genetic testing of the BRCA1, BRCA2, TP53, and CHEK2 genes was offered. Of 902 women submitted to GCRA, 214 had pedigrees suggestive of HBCS. Fifty of them underwent genetic testing: 18 and 40 for BRCA1/BRCA2 and TP53 mutation screening, respectively, and 7 for CHEK2 1100delC testing. A deleterious BRCA2 mutation was identified in one of the HBOC probands and the CHEK2 1100delC mutation occurred in one of the HBCC families. No deleterious germline alterations were identified in BRCA1 or TP53. Although strict inclusion criteria and a comprehensive testing approach were used, the suspected genetic risk in these families remains unexplained. Further studies in a larger cohort are necessary to better understand the genetic component of hereditary breast cancer in Southern Brazil. PMID- 27223486 TI - Antigenotoxicity and antimutagenicity of ethanolic extracts of Brazilian green propolis and its main botanical source determined by the Allium cepa test system. AB - Brazilian green propolis is a resinous substance prepared by bees from parts of the plant Baccharis dracunculifolia. As it possess several biological properties, this work assessed the cytotoxic/anticytotoxic, genotoxic/antigenotoxic and mutagenic/antimutagenic potential of ethanolic extracts of Brazilian green propolis (EEGP) and of B. dracunculifolia (EEBD), by means of the Allium cepa test system. The effects were evaluated by assessing the chromosomal aberrations (CA) and micronuclei (MN) frequencies on meristematic and F1 generation cells from onion roots. Chemical analyses performed with the extracts showed differences in flavonoid quality and quantity. No genotoxic or mutagenic potential was detected, and both extracts were capable of inhibiting cellular damage caused by methyl methanesulfonate (MMS) treatment, reducing the frequencies of CA and MN. By these data, we can infer that, independent of their flavonoid content, the extracts presented a protective effect in A. cepa cells against the clastogenicity of MMS. PMID- 27223487 TI - Early-onset breast cancer patients in the South and Southeast of Brazil should be tested for the TP53 p.R337H mutation. AB - Germline TP53 mutations are associated with Li-Fraumeni syndrome (LFS), a disease that predisposes carriers to a wide variety of early onset tumors. In southern and southeastern Brazil, a high frequency of a germline TP53 mutation, p.R337H, was diagnosed in 0,3% of the population due to a founder effect. Carriers are at risk for developing cancer but the penetrance is lower than in typical DNA binding domain mutations. To date, only a few families were detected and diagnosis of carriers remains a challenge. Therefore, the inclusion of additional criteria to detect p.R337H carriers is necessary for the Brazilian population. We assessed the A.C. Camargo Cancer Center Oncogenetics Department database in search of common characteristics associated with p.R337H families that did not fulfill LFS/LFL clinical criteria. Among 42 p.R337H families, three did not meet any LFS/LFL criteria. All cases were young female patients with breast cancer diagnosed before age 45 and with no family history of LFS linked-cancers. Our results suggest that screening for the germline TP53 p.R337H mutation should be indicated, along with BRCA1 and BRCA2 genetic testing, for this group of patients, especially in the South and Southeast of Brazil. PMID- 27223488 TI - Prevalence of Cafe-au-Lait Spots in children with solid tumors. AB - Cafe-au-lait maculae (CALM) are frequently observed in humans, and usually are present as a solitary spot. Multiple CALMs are present in a smaller fraction of the population and are usually associated with other congenital anomalies as part of many syndromes. Most of these syndromes carry an increased risk of cancer development. Previous studies have indicated that minor congenital anomalies may be more prevalent in children with cancer. We investigated the prevalence of CALMs in two samples of Brazilian patients with childhood solid tumors, totaling 307 individuals. Additionally, 176 school children without diagnosis of cancer, or of a cancer predisposing syndrome, were investigated for the presence of CALMs. The prevalence of solitary CALM was similar in both study groups (18% and 19%) and also in the group of children without cancer. Multiple CALMs were more frequently observed in one of the study groups (Z = 2.1). However, when both groups were analyzed together, the significance disappeared (Z = 1.5). The additional morphological abnormalities in children with multiple CALMs were analyzed and compared to the findings observed in the literature. The nosologic entities associated with CALMs are reviewed. PMID- 27223489 TI - The Development of the Study of Hereditary Cancer in South America. PMID- 27223490 TI - Exposure to Community Violence and Sexual Behaviors Among African American Youth: Testing Multiple Pathways. AB - African American youth bear a disproportionate burden of sexually transmitted infections. A growing number of studies document that youth exposure to community violence and sexual behaviors are highly correlated. Despite such growing evidence, only a few studies have empirically tested conceptually driven pathways that may account for such relationships. This study seeks to address that gap by exploring multiple pathways linking exposure to community violence and youth sexual behaviors. Using an existing sample of 563 African American youth attending high school, we examined whether possible links between exposure to community violence and sexual activity, sexual risk behaviors were mediated by aggression, low student-teacher connectedness, and negative peer norms. Major findings indicated indirect relationships between exposures to community violence and both sexual activity and risky sex, mediated by aggression and negative peer norms with no significant differences based on gender or socioeconomic status. Overall findings also indicated a significant indirect effect of aggression to risky sex via negative peer norms and from community violence to risky peer norms via aggression. By illuminating ways that community violence, aggression, peer norms, and sexual behaviors are dynamically interrelated, these findings have significant implications for future research and intervention initiatives aimed at addressing the different pathways. PMID- 27223491 TI - Isolated Placental Inflammation and Vasculopathy: Clinical Implications in the Extremely Low Birth Weight Infants. AB - : The predictive values of placental histopathologies are compromised by a non segregation of common anomalies. The effects of isolated pure placental inflammation (PI) and vasculopathy-coagulopathy (PV) were compared with normal (NL) placentas in extremely premature infants (ELBW, birth weight < 1000 g). PI infants required lower peak inspiratory pressure on day 3. More infants in PV were oxygen dependence on day 28. PV had an increased risk of intraventricular periventricular hemorrhage (IVH, OR 4.9, 95% CI 1-24.7, p = 0.05). NL infants were unexposed to PPROM or maternal hypertension, had highest requirement for surfactant, did not develop IVH and periventricular leukomalacia (PVL) and none of them were Caucasian. CONCLUSIONS: In ELBW infants (1) pure placental vasculopathy-coagulopathy is a risk factor for IVH, (2) a non- pathological intrauterine environment is nonconducive to IVH and PVL, (3) pure placental inflammation is protective for acute pulmonary disease, (4) Caucasian mothers are more susceptible to adverse intrauterine environment. PMID- 27223492 TI - Why intra-epidermal electrical stimulation achieves stimulation of small fibres selectively: a simulation study. AB - The in situ electric field in the peripheral nerve of the skin is investigated to discuss the selective stimulation of nerve fibres. Coaxial planar electrodes with and without intra-epidermal needle tip were considered as electrodes of a stimulator. From electromagnetic analysis, the tip depth of the intra-epidermal electrode should be larger than the thickness of the stratum corneum, the electrical conductivity of which is much lower than the remaining tissue. The effect of different radii of the outer ring electrode on the in situ electric field is marginal. The minimum threshold in situ electric field (rheobase) for free nerve endings is estimated to be 6.3 kV m(-1). The possible volume for electrostimulation, which can be obtained from the in situ electric field distribution, becomes deeper and narrower with increasing needle depth, suggesting that possible stimulation sites may be controlled by changing the needle depth. The injection current amplitude should be adjusted when changing the needle depth because the peak field strength also changes. This study shows that intra-epidermal electrical stimulation can achieve stimulation of small fibres selectively, because Abeta-, Adelta-, and C-fibre terminals are located at different depths in the skin. PMID- 27223495 TI - Patient Access to Physician Notes Is Gaining Momentum. PMID- 27223493 TI - Long-term follow-up of amitriptyline treatment for idiopathic cough. AB - OBJECTIVES/HYPOTHESIS: To evaluate short- and long-term treatment outcomes of amitriptyline for idiopathic cough. STUDY DESIGN: Retrospective chart review and anonymous survey of a patient cohort. METHODS: We evaluated a cohort of adults treated for cough at the Duke Voice Care Center with amitriptyline over a 2- to 3 year period. We characterized demographics, symptoms, treatment variability, and treatment effects from chart review and survey responses. We performed univariate analysis comparing cough improvement to age, gender, symptoms of throat irritation, cough duration, concurrent speech therapy, and dosage. RESULTS: Eighty-nine percent were taking the medication at the first clinical follow-up at a mean 2.6 months, and overall, 67% reported >=50% improvement. No statistically significant predictors of cough improvement with medication were identified. At follow-up 2 to 3 years later, overall, 53% reported >=50% improvement, with only 34% of patients still taking amitriptyline. After 2 to 3 years, 65% of patients had titrated the medication to effect, and 33% restarted the medication. Occurrence of side effects was the most frequent reason for stopping the medication. CONCLUSIONS: Amitriptyline can be an effective and well-tolerated part of short- and long-term management of idiopathic cough in adults. Titrating the dose and restarting are often necessary. Larger studies and randomized control trials are needed to better understand the outcomes of using amitriptyline to treat idiopathic cough. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:2758-2763, 2016. PMID- 27223496 TI - Regio- and Enantioselective Sequential Dehalogenation of rac-1,3-Dibromobutane by Haloalkane Dehalogenase LinB. AB - The hydrolytic dehalogenation of rac-1,3-dibromobutane catalyzed by the haloalkane dehalogenase LinB from Sphingobium japonicum UT26 proceeds in a sequential fashion: initial formation of intermediate haloalcohols followed by a second hydrolytic step to produce the final diol. Detailed investigation of the course of the reaction revealed favored nucleophilic displacement of the sec halogen in the first hydrolytic event with pronounced R enantioselectivity. The second hydrolysis step proceeded with a regioselectivity switch at the primary position, with preference for the S enantiomer. Because of complex competition between all eight possible reactions, intermediate haloalcohols formed with moderate to good ee ((S)-4-bromobutan-2-ol: up to 87 %). Similarly, (S)-butane 1,3-diol was formed at a maximum ee of 35 % before full hydrolysis furnished the racemic diol product. PMID- 27223497 TI - Prognostic significance of nestin in primary malignant melanoma of the oral cavity. AB - Several studies have examined the correlation between nestin expression and the degree of tumor invasion in cutaneous melanoma. However, no information has been reported on nestin in primary mucosal melanoma of the head and neck. The present study examined the expression and prognostic significance of nestin in patients with primary mucosal melanoma of the oral cavity. Nestin expression was examined immunohistochemically in 39 patients (six oral melanoma in-situ cases and 33 invasive oral melanoma cases) and analyzed for association with disease progression. Age, sex, anatomic site, stage, level of invasion, regional lymph node metastasis, surgical margin involvement, and treatment modality were also analyzed. In the 33 invasive melanoma cases, invasion depth correlated significantly with prognosis in univariate and multivariate analyses. High intensity nestin staining was observed in 14 of the 33 cases and a high proportion of nestin-positive cells was observed in 16 cases. In stage III oral melanoma cases, nestin expression was not significantly associated with disease progression. However, in stage IV cases, both the intensity and the proportion of nestin expression were significantly associated with disease progression (P=0.022 and 0.005, respectively). In all 33 invasive cases, multivariate analyses showed that both the intensity and the proportion of nestin were significantly associated with a poor prognosis (P=0.014 and 0.009; hazard ratio, 3.59 and 4.05; 95% confidence interval, 1.29-9.98 and 1.42-11.56, respectively). In conclusion, nestin can be a valuable prognostic indicator in the advanced-stage (stage IV) cases of oral mucosal melanoma. PMID- 27223499 TI - Evaluating the quality of care. AB - All nurses strive to give good quality care, don't they? But how do you actually measure the quality of care being given? Measuring the amount of care is one thing, but assessing its quality is quite another, and presents more of a challenge. PMID- 27223500 TI - Seeking the right reforms. AB - Preaching to the converted can be a tremendous morale boost. The audience is, predictably, in the main, on your side and you are assured of an ovation or at least a good deal of hand clapping. PMID- 27223501 TI - Complaints procedure 'should be made simpler'. AB - Complaining about the care and treatment they receive should be made much simpler for patients, the Association of Community Health Councils (ACHC) for England and Wales claimed last week. PMID- 27223498 TI - BRAF inhibitor and stereotactic radiosurgery is associated with an increased risk of radiation necrosis. AB - We retrospectively compared the outcomes and toxicities of melanoma brain metastases (MBM) patients treated with BRAF inhibitors (BRAFi) and stereotactic radiosurgery (SRS) with SRS alone. We identified 87 patients with 157 MBM treated with SRS alone from 2005 to 2013. Of these, 15 (17.2%) patients with 32 MBM (21.4%) received BRAFi therapy: three (20.0%) before SRS, two (13.3%) concurrent, and 10 (66.7%) after SRS. Overall survival (OS) was compared between cohorts using the product limit method. Intracranial outcomes were compared using cumulative incidence with competing risk for death. Baseline patient characteristics were similar between groups, except for the SRS cohort, which had higher rates of chemotherapy and more recent year of diagnosis. Radiation characteristics, including dose per fraction, total dose, gross tumor volume size, and prescription isodose, were also similar between cohorts. One-year outcomes - OS (64.3 vs. 40.4%, P=0.205), local failure (3.3 vs. 9.6%, P=0.423), and distant intracranial failure (63.9 vs. 65.1%, P=0.450) were not statistically different between the SRS+BRAFi and SRS-alone groups, respectively. The SRS+BRAFi group showed higher rates of radiographic radiation necrosis (RN) (22.2 vs. 11.0% at 1 year, P<0.001) and symptomatic radiation necrosis (SRN) (28.2 vs. 11.1% at 1 year, P<0.001). Multivariable analysis showed that BRAFi predicted an increased risk of both radiographic and SRN. SRS and BRAFi predicted for an increased risk of radiographic and SRN compared with SRS alone. Approaches to mitigate RN for patients receiving SRS and BRAFi should be considered until the clinical trial (http//:www.clinicaltrials.gov: NCT01721603) evaluating this treatment regimen is completed. PMID- 27223502 TI - [Not Available]. AB - More than 200 nurses demonstrated outside London's Middlesex Hospital last week to protest at conditions in nurses' homes run by Bloomsbury Health Authority. PMID- 27223503 TI - Chief nurse role under threat. AB - District Nurse Adviser posts could be radically reduced to part-time or consultancy roles under the NHS White Paper proposals, a document sent to regional nursing officers reveals. PMID- 27223504 TI - Goodwin resigns from HVA post. AB - Shirley Goodwin has resigned as General Secretary of the Health Visitors Association because of overwork. PMID- 27223505 TI - Legal precedent set after lifting injury. AB - A judge's decision to award L157,000 to a back-injured nurse last week could set a worrying precedent, a NUPF officer has warned. PMID- 27223507 TI - Hancock warns of White Paper chaos. AB - Conservatives heard the Government under attack at their Tory Conference last week when RCN General Secretary Christine Hancock launched into the 'unrealistic' timetable for the White Paper proposals that 'could cause chaos'. PMID- 27223506 TI - Camberwell backs down over union duties row. AB - A Royal College of Nursing convenor, who was stopped from carrying out all union duties by management this summer, has had her facilities restored. PMID- 27223508 TI - Clarke's speech condemned. AB - Nursing leaders last week condemned Health Secretary Kenneth Clarke for his attack on health professionals in a speech to the Conservative Party Conference in Blackpool. PMID- 27223509 TI - In-fighting must stop. AB - Primary health care teams must stop in-fighting and grasp the lead NHS role, Julia Cumberlege, North West Thames Regional Chairman told a major weekend conference. PMID- 27223510 TI - Call for flexibility to cater for everyone. AB - Continuing education for the future must meet the needs of every individual practitioner and not be confined to clinical courses for ten students seconded by their employers, according to Dr Christopher Maggs, Senior Research Fellow at the West London Institute. PMID- 27223511 TI - [Not Available]. AB - First aid books, ambulances and other health images are hidden among the smiling faces on these colourful Christmas cards produced by the Nicaragua Health Fund. Packs of six are available at &1.95 (plus 25p postage and packaging) from 83 Margaret Street. London WIN 7HB. PMID- 27223512 TI - Rediscovering basic values. AB - The profession is facing a new era with a rediscovery of the basic values in nursing' according to Professor Penny Prophit of the University of Edinburgh. PMID- 27223513 TI - ENB proposals opposed. AB - Crucial changes were 'sprung' on midwives and their views were overruled at a closed session of the English National Board, it was claimed last week. PMID- 27223516 TI - Fear over community nurse numbers. AB - English National Board members have criticised the Department of Health for delivering a 'bland' and 'worrying' response to a letter setting out their concerns for community nursing. PMID- 27223514 TI - HA forced to honour pledge. AB - A health authority which tried to renege on its pledge to send nurses and midwives on a health visiting course has been forced to honour its promise. PMID- 27223518 TI - Poll confirms sympathy for nurses. AB - Most people consider nurses are still poorly paid, a nationwide survey revealed last week. PMID- 27223517 TI - Elderly's needs ignored. AB - Elderly people in care are often treated as if they have arrived from outer space, a nurse claimed last week. PMID- 27223519 TI - [Not Available]. AB - Making the point: Shadow Health Minister Harriet Harman (right) shared a platform with new RCN General Secretary' Christine Hancock at the recent labour Party conference. Both emphasised the importance of illness prevention. PMID- 27223520 TI - Alarming staff mortality rates. AB - The NHS is not paying enough attention to the health needs of its own staff, a study comparing the mortality of male health workers with the general population has revealed. PMID- 27223522 TI - Malaria outbreak hits refugees. AB - Hong Kong Health officials in Hong Kong have revealed that the colony is fighting an outbreak of malaria among the Vietnamese boat people - 255 cases have been diagnosed. PMID- 27223523 TI - Measles fear rampant. AB - Canada is facing one of the most serious outbreaks of measles in the past ten years. Public health officials are warning parents and family doctors to ensure children are vaccinated against the disease. PMID- 27223524 TI - Law change forcing lay-offs in the States. AB - United States Rural clinics in New' Mexico, are laying off community nurse practitioners because they cannot afford to pay them. PMID- 27223527 TI - Ballot proceeds despite management refusal. AB - Nurses and patients queued at the gates of a Sheffield Hospital last week to cast their votes in a ballot on opting out following management's refusal to permit it. PMID- 27223525 TI - Slighted organisation boycotts hospital. AB - Denmark The Danish Nurses' Organisation is boycotting a private hospital - the Privathospitalet Kobenhaven - because it has refused to negotiate employment terms with the Organisation. PMID- 27223528 TI - Nurses' role not recognised. AB - Both Sir Roy Griffiths and Kenneth Clarke have failed to recognise the unique skills nurses can contribute to caring for elderly people, the Royal College of Nursing has claimed. PMID- 27223530 TI - ThackrayCare launches new vaginal speculum. AB - ThackrayCare has launched a new disposable vaginal speculum, made from strong, sterile plastic. PMID- 27223531 TI - BritCair taken over by American multinational. AB - American pharmaceutical company, Merck & Co Inc, has taken over BritCair, the UK wound dressings company. PMID- 27223532 TI - Mobile and compact mammography unit. AB - A new purpose-built mammography unit, suitable for use in mobile clinics or screening centres, has been produced by Medical X-Ray Supplies Limited. PMID- 27223533 TI - Disposal review. AB - All clinical waste must be placed in a yellow plastic bag and taken to an incinerator capable of maintaining a temperature that will ensure its complete destruction, new disposal guidelines insist. PMID- 27223534 TI - Parents need nurse's presence. AB - A nurse should always be present when parents are told their newborn baby needs surgical treatment, a conference on neonatal care heard last week. PMID- 27223535 TI - Nurses to take lead. AB - Practice nurses are to take lead roles in a newly proposed family cardiovascular disease prevention programme, a major anticipatory care conference has learned. PMID- 27223536 TI - Handling of babies under question. AB - Neonatal nurses may be handling sick babies far more frequently than is actually necessary, research at a Nottingham hospital shows. PMID- 27223537 TI - Code set to tackle excessive hours. AB - Overworked theatre nurses have been urged to use the Code of Professional Conduct when they are asked to work excessive hours because of staff shortages and standby duty. PMID- 27223538 TI - Staffing problems affect NHS service provision. AB - The NHS will not be able to offer a high standard of service to patients if the quality of life for its staff is poor, David Poole, Chief Nursing Officer for North Bedfordshire Health Authority told the conference. PMID- 27223540 TI - Offers of help during disasters need prioritising, managers warned. AB - A theatre nursing officer who has worked at a Belfast 'front line' hospital for 20 years, said this week that her hardest job is turning down immediate offers of help from other nurses during major disasters. PMID- 27223539 TI - Nurses require 'freedom and autonomy'. AB - Nurses need freedom and autonomy within hierarchical structures if they are to safeguard the interests of patients and exercise professional accountability, a theatre nurse teacher has argued. PMID- 27223541 TI - Zidovudine and dementia. AB - AIDS dementia complex may be prevented by treatment with antiviral agents. PMID- 27223542 TI - Sedation in critically ill patients. AB - Propofol is a satisfactory agent for sedation in critically ill patients, according to researchers. PMID- 27223543 TI - Lyme disease awareness. AB - Greater awareness by clinicians and identification of risk groups is needed to ensure treatment of Lyme disease. PMID- 27223544 TI - Smoking and colonisation. AB - Cigarette smoke has a causal effect on the meningococcal colonisation of the nasopharynx, researchers say. PMID- 27223546 TI - Profit without loss. AB - With cost effectiveness a key word on managers' lips, one increasingly attractive incentive for those on the lookout for a saving is having staff salaries paid by a private company. PMID- 27223545 TI - Relaxation in hypertension. AB - Hypotensive drug therapy may be withdrawn or reduced if relaxation techniques are used to control mild hypertension. PMID- 27223547 TI - A testing dilemma. AB - Government plans for anonymous HIV testing in 20 health districts could face a challenge in the courts, it was claimed last week. PMID- 27223548 TI - Identifying and protecting patients who may get pressure sores. AB - Most people regard pressure sores as an obvious sign of neglect, either by the patient involved, or his nurses. This perception can lead to litigation against nursing and medical staff ( 1 ) and there is no doubt that professional neglect can, at times, be the main cause of a pressure sore. Such neglect may, of course, be blamed on a lack of resources - principally in the shape of skilled nurses and of special equipment. PMID- 27223549 TI - A complete guide to what's on in nursing nationwide. PMID- 27223550 TI - Interprofessional Consultation Interprofessional consultation D Steinberg Blackwell Scientific 134pp L15.95 0-632-02232-3. AB - Interprofessional Consultationfits awkwardly into whatever pigeonhole you place it. It can be called neither a 'guide' to consultation, although it probably is as near to a guide as the reader is likely to find in this particular area, nor 'an academic textbook about consultation', although, again, it meets the necessary criteria to be called just that. So, what is it? PMID- 27223551 TI - Communicating with medical patients Communicating with medical patients Stewart M and Roter D , SAGE Publications 286pp L14.50 0-8039-3217-0. AB - Moira Stewart and Debra Roter present their reading audience with a comprehensive manual which covers the components of communication between both the doctors and their patients or clients. PMID- 27223553 TI - Diagnosing diabetes. AB - Congratulations on the new format of Nursing Standard. I hope your readership will continue to grow as a result of the new image. PMID- 27223554 TI - No concern for the cap? AB - With reference to the letter from the nurse at St George's Hospital ( The cap fits', Letters, Nursing Standard week ending October 10), I would like to point out that the belief that West Cumbrian nurses are defying the management decision regarding caps is mistaken. PMID- 27223555 TI - New member for Wales. AB - May I through your columns, thank all members of the Royal College of Nursing who voted in my successful application to become a member of Council for Wales. PMID- 27223556 TI - Follow up study. AB - I would like to contact all Registered Nurses who undertook a shortened course for graduates at the Queen Elizabeth School of Nursing, Birmingham. This is to enable me to evaluate the course and conduct a follow up study of career pathways after qualification. PMID- 27223558 TI - Fast suggestions. AB - I work in an independent hospital in Golders Green, London, which still fasts patients nil by mouth from twelve midnight who are going to theatre on the afternoon list. PMID- 27223557 TI - Primary concern. AB - Have you ever had deja vu? Remember the nursing process? Years ago both the UKCC and the Department of Health took this on board and urged its implementation. As a result, there was, and still is, a tremendous amount of resistance and misunderstanding of the issue. When change is perceived as being forced on nurses from the top down then inevitably they will resist. PMID- 27223559 TI - Crossword. PMID- 27223560 TI - Independent sector philosphy. AB - In answer to your article on NHS nursing homes ('NHS homes backed', Nursing Standard week ending 10th October), I would like to comment on the results of the survey, that people are happier in NHS nursing homes than hospitals, also applies to nursing homes in the independent sector. PMID- 27223561 TI - Points of view. AB - Dear Ken Last time I wrote my column, I discussed the problems of recruiting and retaining nurses. I have this idea that we wouldn't have to worry about recruiting nurses (despite demographic changes and the all-fired panic to create the support worker) if we actually tackled the reasons why nurses leave nursing in the first place. PMID- 27223562 TI - Half-baked sincerity. AB - Most people are convinced that the latest Government proposals will not reverse the deterioration in the National Health Service or improve the health status of the people in this country. To debate the proposals in order to arrive at a conclusion is futile, for they are so complex and based on so much of the unknown that contributors to the debate all start out with a different perception of what is proposed and thus waste time and energy. PMID- 27223564 TI - Introduction to the Ethos of Nursing Introduction to the Ethos of Nursing J Mellish Butterworths 196pp L11.50 0-409-1007-2. AB - In exploring the characteristics which contribute to the development of a profession such as nursing, the author has to be complimented on the international flavour of this useful book. From a strongly researched historical perspective the reader is taken through the development of nursing in South Africa, Europe and the USA, touching not only on general nursing but the many specialties which have flourished in the latter years of this century. PMID- 27223565 TI - Further Research for Nursing Further Research for Nursing Clark J Macleod Hockey L , editors Scutari 180pp L7.50 1-871364-14-0. AB - Jill Macleod Clark and Lisbeth Hockey present us with the successor to the now ten-year-old Research for Nursing, but with some notable differences: a panel of contributors and very specific issues addressed. The latter makes the book particularly useful. PMID- 27223566 TI - Community Psychiatric Nursing Pollock LC Scutari 244pp L13.75 1-781364-18-3. AB - Community Psychiatric Nursing: Myth and Reality by Linda Pollock is a very wellcome addition to the subject's body of literature. It is a study based on the evaluation of two community psychiatric nursing (CPN) services, firstly 'to provide qualitative information about the process of community nursing' and secondly in relation to the patients' and families response to this service to provide outcome information'. PMID- 27223567 TI - How to Make Nursing Diagnosis Work How to Make Nursing Diagnosis Work Appleton & Lange 348pp L38.45 0-8385-1608-4. AB - We understand from the editor, Emmy Miller, and her nine contributors that this book was borne out of their experiences, excitement and challenges of trying to make nursing diagnosis work in clinical practice. Nursing diagnoses are said to describe actual or potential health problems which nurses, by virtue of their education and experience, are able and ' licensed to treat. PMID- 27223568 TI - Comprehensive coronary care Comprehensive coronary care N Jowett D Thompson Scutari 388pp L18.50 1-871364-05-1. AB - Comprehensive Coronary Care has a joint ' medical and nursing authorship, a I refreshing approach which I warmly welcome. The logical format incorporates topics which are not always so extensively covered in other cardiology textbooks. The integrated approach is particularly noticeable in the sections on rehabilitation and risk-factor modification. Perhaps one could take issue with the statement that the majority of patients who present have no identifiable risk factors; indeed, the initial findings from the British Regional Heart Study would appear to dispute this. PMID- 27223569 TI - Understanding Medical Immunology, 2nd edition Understanding Medical Immunology, 2nd edition E Kirkwood C Lewis Wiley 180pp L12.50 0-471-91577-7. AB - Immunology is a subject dreaded by many staff nurses and students almost as much as neurology. Therefore, any good contribution towards rectifying this state of affairs is to be welcomed. Understanding Medical Immunology is the well presented, revised and expanded second edition of a fairly popular book published six years ago. PMID- 27223571 TI - 2 Skeletal System and Muscular System Riddle J T E Skeletal System and Muscular System 150pp 0-443-03935-6. AB - As with the other books in the series, Book 2, centering on the skeletal and muscular systems, carries easy-to-follow line drawings which are clear enough to facilitate group work without the need for numerous copies. It gives students an inexpensive learning aid that may challenge small groups of learner nurses to assess themselves with immediate feedback on the correct answers. PMID- 27223570 TI - The Structure of the Body and Immunological Disease Riddle J T E Churchill Livingstone L3.95 The Structure of the Body and Immunological Disease 130pp 0-443 03501-6. AB - The first of the Nursing Care Studies concentrates on the topic areas of the structure of the body: cells, tissues, skin ' and immunological disorders. With contributions from many clinical nurse teachers and a consultant physician from Glasgow, the multiple choice style of questions (MCQs) should prove to be a good revision aid for students as well as an aide-memoire for post-basic staff and a teaching aid for nurse tutors. PMID- 27223573 TI - 5 Nervous System and the Special Senses Riddle J T E Nervous System and the Special Senses 128pp 0-443-03938-0. AB - Acute suppurative otitis media, convergent strabismus, retinal detachment, cataract, head injury, epilepsy and rehabilitation following cerebrovascular accident are combined in Book 5 to cover the nervous system and the special senses. PMID- 27223574 TI - 6 Endocrine System and Reproductive System Riddle J T E Endocrine System and Reproductive System 138PP 0-443-03939-9. AB - I Concluding her revision aids series, Janet Riddle explores the endocrine and reproductive systems with studies of diabetes, hypothyroidism, hysterectomy, subfertility, pregnancy and labour, the postnatal care of mother and baby, and prostatic hypertrophy. Again, however, an opportunity for education is missed with the omissions of societies and associations. even this is inconsistent as the epilepsy study (Book 5) lists relevant societies; in Book 6 the diabetes study leaves out the British Diabetic Association. PMID- 27223575 TI - 4 Digestive System and Urinary System Riddle J T E Digestive System and Urinary System 124pp 0-443-03937-2. AB - My concern with multiple choice question and answer books is the increasingly small number of schools of nursing which use MCQs during their courses and at final examinations. With the introduction of Project 2000 (or P2K as I'm told (now!) and continuous assessment, wonder if MCQs will be pushed further into the distant annals of nurse education. This, however, is opposed by the series' modular approach to biological systems which can only complement modular nurse training. At only L3-95, the books must appeal to nearly all learner nurses, including those on combined BSc/RGN courses - although perhaps the MCQ format may appear a little unrelated to their degree course. PMID- 27223576 TI - Effect of macrophages on in vitro corrosion behavior of magnesium alloy. AB - The influence of cells on the corrosion behavior of biomedical magnesium alloy is an important but less studied topic, which is helpful for understanding the inconsistent corrosion rates between in vitro and in vivo experiments. In this work, macrophages were directly cultured on Mg-2.1Nd-0.2Zn-0.5Zr (wt %, abbreviated as JDBM) alloy surface for 72 or 168 hours. Macrophages retained good viability and the generation of reactive oxygen species (ROS) was greatly promoted on the alloy. Weight loss, Mg(2+) concentration, and cross-section observation results demonstrated that macrophages accelerated the in vitro corrosion of JDBM. The coverage of cell body did not affect the local thickness of corrosion product layer. The corrosion product layer had a porous inner Mg(OH)2 layer and a dense outer layer mainly composed of O, P, Mg, and Ca. The uniform acceleration of JDBM corrosion was attributed to the omnidirection diffusion of ROS from macrophages. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2476-2487, 2016. PMID- 27223577 TI - Staffing in Ontario's Long-Term Care Homes: Differences by Profit Status and Chain Ownership. AB - Ontario has the highest proportion of for-profit nursing homes in Canada. These facilities, which are known in Ontario as long-term care (LTC) homes, offer 24 hour custodial as well as nursing care to individuals who cannot live independently. Increasingly, they are also operating as members of multi-facility chains. Using longitudinal data (1996-2011) from the Residential Care Facilities Survey (n = 627), our analysis revealed discernible differences in staffing levels by profit status and chain affiliation. We found for-profit LTC homes - especially those owned by a chain organization - provided significantly fewer hours of care, after adjusting for variation in the residents' care needs. Findings from this study offer new information on the impact of organizational structure on staffing levels in Ontario's LTC homes and have implications for other jurisdictions where a growing presence of private, chain-affiliated operators has been observed. PMID- 27223578 TI - Normalization of Neglect: A Grounded Theory of RNs' Experiences as Family Caregivers of Hospitalized Seniors. AB - Often older people, while maintaining a level of independence, rely on family members to provide care and assistance. Caregivers who are also registered nurses (RNs) may provide a different perspective around the experience when their older relative is admitted to acute care. The aim of our research was to investigate and develop theory regarding nursing care provision as described by RNs, who were family caregivers to older adults, when that older adult was admitted to acute care. Over a six-month period in 2011, RNs meeting this criterion (n = 12) were interviewed individually. We identified two central categories: "Culture of Neglect" and "Vigil by the Bedside". The core category "Normalization of Neglect" was identified as the theory, grounded in the data the participants provided which described a culture of neglect that had normalized poor nursing care. These findings highlight the issue of neglect and abuse, and further investigation is warranted. PMID- 27223579 TI - Experience de frequentation des lieux publics par des personnes agees ayant subi un TCC en presence d'un accompagnateur-citoyen: projet pilote. AB - This pilot project aims to test and see the relevance of the direct observation method to collect data on the barriers and facilitators to attending public places by seniors with TBI. The study is based on the conceptual framework VADA WHO which focuses on the development of friendly built and technological environments for seniors. Three elderly people participated in the study, recruited from an ongoing project, The Citizen Intervention in Community Living (APIC), in the presence of their personalized attendant. The study shows the feasibility of the method in terms of its acceptability and resources mobilized. It shows its relevance to access additional data that would have been difficult to obtain using others methods (e.g., semi-structured interview), such as the identification of the strategies used by the participants to address the obstacles encountered (avoidance, travel planning, use of physical and preventative support of the personalized attendant). PMID- 27223580 TI - Autologous platelet-rich plasma for treating chronic wounds. AB - BACKGROUND: Autologous platelet-rich plasma (PRP) is a treatment that contains fibrin and high concentrations of growth factors with the potential to improve the healing of chronic wounds. This is the first update of a review first published in 2012. OBJECTIVES: To determine whether autologous PRP promotes the healing of chronic wounds. SEARCH METHODS: In June 2015, for this first update, we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library): Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; and EBSCO CINAHL. We also searched for ongoing and unpublished clinical trials in the WHO International Clinical Trials Registry Platform (ICTRP) (searched January 2015). We did not impose any restrictions with respect to language, date of publication, or study setting. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared autologous PRP with placebo or alternative treatments for any type of chronic wound in adults. We did not apply any date or language restrictions. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology, including two reviewers independently selecting studies for inclusion, extracting data, and assessing risk of bias. MAIN RESULTS: The search identified one new RCT, making a total of 10 included RCTs (442 participants, 42% women). The median number of participants per RCT was 29 (range 10 to 117). Four RCTs recruited people with a range of chronic wounds; three RCTs recruited people with venous leg ulcers, and three RCTs considered foot ulcers in people with diabetes. The median length of treatment was 12 weeks (range 8 to 40 weeks).It is unclear whether autologous PRP improves the healing of chronic wounds generally compared with standard treatment (with or without placebo) (risk ratio (RR) 1.19, 95% confidence interval (CI) 0.95 to 1.50; I(2) = 27%, low quality evidence, 8 RCTs, 391 participants). Autologous PRP may increase the healing of foot ulcers in people with diabetes compared with standard care (with or without placebo) (RR 1.22, 95% CI 1.01 to 1.49; I(2) = 0%, low quality evidence, 2 RCTs, 189 participants). It is unclear if autologous PRP affects the healing of venous leg ulcers (RR 1.02, 95% CI 0.81 to 1.27; I(2) = 0% ). It is unclear if there is a difference in the risk of adverse events in people treated with PRP or standard care (RR 1.05, 95% CI 0.29 to 3.88; I(2) = 0%, low quality evidence from 3 trials, 102 participants). AUTHORS' CONCLUSIONS: PRP may improve the healing of foot ulcers associated with diabetes, but this conclusion is based on low quality evidence from two small RCTs. It is unclear whether PRP influences the healing of other chronic wounds. The overall quality of evidence of autologous PRP for treating chronic wounds is low. There are very few RCTs evaluating PRP, they are underpowered to detect treatment effects, if they exist, and are generally at high or unclear risk of bias. Well designed and adequately powered clinical trials are needed. PMID- 27223581 TI - Association Between Dentist-Dental Hygienist Communication and Dental Treatment Outcomes. AB - Communication between physician and patient is critical in all fields of medicine, and various types of communication exist in healthcare settings. Cooperation among healthcare professionals is thought to be essential in providing high-quality services. Dental hygienists are key team members in the provision of dental care, and are known to play an important role in the health of their patients. This study aimed to determine the effect of communication between dentists and hygienists on patient satisfaction. Study subjects were dentists, patients, and dental hygienists, and we examined how dentist-dental hygienist communication affected patient outcome indices. A significant difference was observed only for satisfaction in terms of meeting expectations (p = 0.035). Results for patient satisfaction indicated significant differences in explanatory behavior in dentist-dental hygienist evaluations (p = 0.001). The results showed improved health and reduced fear, indicating significant differences for the dentist-dental hygienist evaluations in explanation behavior (p = 0.016). Our evaluation of the effects of dentist-dental hygienist communication on patient outcomes indicated a significant correlation, suggesting that inter-professional communication in the field of dentistry affects patient satisfaction. PMID- 27223582 TI - Frizzled with age: an opportunity for 'gerontological medicine'. PMID- 27223583 TI - Seasonal changes in hepatocytic lipid droplets, glycogen deposits, and rough endoplasmic reticulum along the natural breeding cycle of female ohrid trout (Salmo letnica Kar.)-A semiquantitative ultrastructural study. AB - This study on wild female Ohrid trout was primarily designed to provide a general overview of the breeding cycle influence upon selected aspects of hepatocytes. According with a semiquantitatively evaluation, some of these cell's structural compartments change during the breeding cycle. Structural modifications were disclosed in the relative occurrence of lipid, glycogen, and RER content during breeding cycle. The relative amount of lipid deposits in the hepatocytes was much greater in previtellogenesis, and decreased postspawning. So, while the seasonal changes in RER were positively related with the ovary maturation status, those of the lipid droplets followed an opposite trend. The hepatocytic glycogen occurred rarely, mainly in late-vitellogenesis and spawning, suggesting that in this species such kind of energy storage is comparatively unimportant. Lipid accumulation and later usage is, probably, the relevant biochemical pathway for Ohrid trout in the wild. While glycogen and RER contents were positively correlated with the gonadosomatic index, lipids were negatively correlated. Additionally, glycogen inclusions were positively correlated with the plasma estradiol levels. When comparing seasonal patterns from wild Ohrid trout with those from well-studied rainbow and brown trout (specimens studied were from aquaculture), there are contradicting results as to lipid and glycogen reserves, and also as to RER loads. The differences among the mentioned trout can result from intrinsic interspecies differences or may be associated with natural feeding conditions versus feeding with commercially prepared diets, or other factors. This study offers new data useful as standard to access liver pathology in wild and aquacultured Ohrid trout. Microsc. Res. Tech. 79:700-706, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27223585 TI - [Histopathology of interstitial lung diseases]. AB - Diffuse interstitial lung disorders include more than 200 different syndroms affecting the space between epithelial basal membrane and endothelial cells. Histopathological investigation of the lung tissue is one of the crucial parts of the multidisciplinary team approach for the investigation of these disorders. The aim of this review is a brief characterization of the pattern of the main subtypes of lung tissue damage. PMID- 27223584 TI - Preschoolers' Preference for Syntactic Complexity Varies by Socioeconomic Status. AB - Two experiments investigated whether 4- and 5-year-old children choose to learn from informants who use more complex syntax (passive voice) over informants using more simple syntax (active voice). In Experiment 1 (N = 30), children viewed one informant who consistently used the passive voice and another who used active voice. When learning novel words from the two informants, children were more likely to endorse information from the passive informant. Experiment 2 (N = 32) explored whether preference for the passive informant varied by socioeconomic status (SES; eligibility for free/reduced lunch). Although higher SES children selectively preferred the passive informant, lower SES children preferred the active informant. Explanations are discussed for why SES might moderate children's sensitivity to syntactic complexity when choosing from whom to learn. PMID- 27223586 TI - [Idiopatic pulmonary fibrosis - news in multidisciplinary diagnostic and therapeutic approaches]. AB - Idiopathic pulmonary fibrosis (IPF) is a primary fibrosing pulmonary process. Due to the ineffectiveness of current therapeutic strategies and unfavorable prognosis, IPF is the most serious example of idiopathic interstitial lung diseases (ILD). Etiology and pathogenesis of this disorder have not been fully clarified yet; but it is anticipated, that the fibroproliferation is caused by the imbalance of reparative and immunologic processes in the genetically predisposed patients. Radiologically and histopathologically, IPF is characterized by specific pattern called usual interstitial pneumonia (UIP), however, this pattern is not fully typical in all cases, and, moreover, it could be seen in other ILD's, e.g. chronic hypersensitivity pneumonitis, asbestosis, autoimmune connective tissue diseases and many others as well. The final diagnosis of IPF is a consensual result of multidisciplinary team composed of pulmologist, pathologist and radiologist. IPF was an incurable disease with prognosis worse than cancer till the year 2011, when antifibrotic drugs decelerating a progression of this disease have been introduced. Earlier and correct diagnosis of IPF is the most important issue for the patients because they could be effectively treated and thus, prolonging their survival as much as possible. PMID- 27223587 TI - [Differential diagnosis of granulomatous lung diseases]. AB - Brief review of histopathology of non-tumor pulmonary diseases with nodular or granulomatous morphology. Differential diagnosis of infections, sarcoidosis, vasculitides with a granulomatous component and selected pneumoconioses is presented. PMID- 27223588 TI - [Interstitial lung diseases associated with smoking]. AB - There are many different interstitial lung diseases associated with smoking. This short review describes officially recognized disorders (desquamative interstitial pneumonia, respiratory bronchiolitis and pulmonary Langerhans'cells histiocytosis) and entities with uncertain relationship to smoking, which have recently been published in the literature. Histopathological pictures and differential diagnosis of smoking-related diseases of the lungs are discussed. PMID- 27223589 TI - [In Process Citation]. PMID- 27223590 TI - [Non-traumatic arteriovenous malformation of the spleen with fatal hemorrhage]. AB - From the medical point of view, splenic rupture developed either as a result of traumatic injury or as a result of any type of splenic disease represents a very severe and life-threatening condition. We describe the case of a 65-year old man without any obvious traumatic injury who was hospitalised because of left abdominal pain. Investigations performed at admission to the hospital (RTG, USG) failed to indicate any signs of intraabdominal bleeding. However, the patient died suddenly after 24 hours of hospitalisation. At autopsy massive intraabdominal bleeding was found. It was caused by rupture of splenic intraparenchymal hematoma developed as a result of an arteriovenous malformation in the lower pole of the spleen. This case shows the necessity of knowledge of all circumstances of death as well as the necessity of consistent histological investigation of the spleen in such cases. PMID- 27223591 TI - [In Process Citation]. PMID- 27223592 TI - [Meningothelial hamartoma of the scalp. A case report]. AB - We report the case of a 34-year - old male with meningothelial hamartoma. The patient had a subcutaneous tumor of the scalp, clinically diagnosed as a lipoma. Histologically, the tumor consisted of mature connective tissue elements, adipose tissue, blood vessels and clusters of cuboidal or polygonal cells with scant eosinophilic or amphophilic cytoplasm and regular nuclei. Mitoses were absent. Immunohistochemically, these cells showed diffuse positivity for vimentin, epithelial membrane antigen (EMA) and progesterone receptors. Other markers examined, including alpha-smooth muscle actin, CD34, desmin, cytokeratin AE1/AE3, cytokeratin CAM 5.2, alpha-inhibin, estrogen receptors, synaptophysin, chromogranin A and S100 protein, were negative. Meningothelial hamartoma is a rare benign lesion known under many synonyms and the exact number of reported cases is difficult to establish. PMID- 27223593 TI - MRI Evaluation of Femoroacetabular Impingement After Hip Preservation Surgery. AB - OBJECTIVE: This article reviews the surgical treatment options for femoroacetabular impingement (FAI), including labral repair and osteochondroplasty, and the expected postoperative appearance on MRI. Complications, including residual osseous deformities, chondral injury, adhesions, femoral neck stress fractures, osteonecrosis, instability, malpositioned suture anchors, and infection, will also be discussed. CONCLUSION: Knowledge of the surgical treatment of FAI can assist in improving our understanding of the expected postoperative MRI appearance and in evaluating surgical complications. PMID- 27223594 TI - Patients with KCNJ11-related diabetes frequently have neuropsychological impairments compared with sibling controls. AB - AIMS: KCNJ11-related diabetes is the most common form of permanent neonatal diabetes and has been associated with a spectrum of neurodevelopmental problems. We compared neurodevelopmental outcomes in patients with KCNJ11 mutations and their sibling controls. METHODS: Through our Monogenic Diabetes Registry (http://monogenicdiabetes.uchicago.edu/), we evaluated 23 patients with KCNJ11 mutations with (n = 9) and without (n = 14) global developmental delay successfully treated with sulfonylurea and 20 healthy sibling controls, using a battery of targeted neuropsychological and behavioural assessments with scaled scores that are comparable across a wide range of ages. RESULTS: Patients with KCNJ11-related diabetes without global developmental delay had significant differences compared with sibling controls on a range of assessments including IQ, measures of academic achievement and executive function. KCNJ11 patients with global delay exhibited significant differences in behavioural symptoms with a tendency to avoid social contact and displayed a reduced ability to adapt to new circumstances. Parents reported more immature behaviour, gross mood swings, bizarre thoughts, other unusual and severe behaviours, and there were also significant deficits in all subdomains of daily living skills. CONCLUSIONS: This series represents the largest and most comprehensive study of neuropsychological and behavioural dysfunction of individuals with KCNJ11 diabetes and is the first to compare outcome with sibling controls. Our data demonstrate the variety of neurodevelopmental problems seen in those with KCNJ11 mutations, even in those without recognized global developmental delays. These data can be used to counsel families and guide structured neurodevelopmental assessments and treatments based on the initial genetic diagnosis in patients with neonatal diabetes. PMID- 27223595 TI - Buprenorphine compared with methadone to treat pregnant women with opioid use disorder: a systematic review and meta-analysis of safety in the mother, fetus and child. AB - AIMS: To assess the safety of buprenorphine compared with methadone to treat pregnant women with opioid use disorder. METHODS: We searched PubMed, Embase and the Cochrane Library from inception to February 2015 for randomized controlled trials (RCT) and observational cohort studies (OBS) that compared buprenorphine with methadone for treating opioid-dependent pregnant women. Two reviewers assessed independently the titles and abstracts of all search results and full texts of potentially eligible studies reporting original data for maternal/fetal/infant death, preterm birth, fetal growth outcomes, fetal/congenital anomalies, fetal/child neurodevelopment and/or maternal adverse events. We ascertained each study's risk of bias using validated instruments and assessed the strength of evidence for each outcome using established methods. We computed effect sizes using random-effects models for each outcome with two or more studies. RESULTS: Three RCTs (n = 223) and 15 cohort OBSs (n = 1923) met inclusion criteria. In meta-analyses using unadjusted data and methadone as comparator, buprenorphine was associated with lower risk of preterm birth [RCT risk ratio (RR) = 0.40, 95% confidence interval (CI) = 0.18, 0.91; OBS RR = 0.67, 95% CI = 0.50, 0.90], greater birth weight [RCT weighted mean difference (WMD) = 277 g, 95% CI = 104, 450; OBS WMD = 265 g, 95% CI = 196, 335] and larger head circumference [RCT WMD = 0.90 cm, 95% CI = 0.14, 1.66; OBS WMD = 0.68 cm, 95% CI = 0.41, 0.94]. No treatment differences were observed for spontaneous fetal death, fetal/congenital anomalies and other fetal growth measures, although the power to detect such differences may be inadequate due to small sample sizes. CONCLUSIONS: Moderately strong evidence indicates lower risk of preterm birth, greater birth weight and larger head circumference with buprenorphine treatment of maternal opioid use disorder during pregnancy compared with methadone treatment, and no greater harms. PMID- 27223596 TI - Schizophrenia as a mimic of behavioral variant frontotemporal dementia. AB - Recently, the diagnostic criteria for the behavioral variant of frontotemporal dementia were revised. Although these criteria offer a relatively high sensitivity, their specificity is yet unknown. We describe a 54-year-old woman fulfilling criteria for both late-onset schizophrenia and probable behavioral variant frontotemporal dementia. Following an initial presentation with psychosis, she developed progressive apathy, compulsiveness, and executive dysfunction. Moreover, bilateral frontotemporal hypometabolism was seen on [(18)F]fludeoxyglucose-positron emission tomography. A post-mortem diagnosis of schizophrenia was established, given the clinical picture combined with the pathological exclusion of a neurodegenerative cause. Our case suggests that patients with other brain disorders may meet the current diagnostic criteria for probable frontotemporal dementia. Further clinicopathological validation of these criteria is needed to determine their exact specificity. PMID- 27223597 TI - Cellular and molecular mechanisms regulating neuronal growth by brain-derived neurotrophic factor. AB - Brain-derived neurotrophic factor (BDNF) and its receptors TrkB and p75 regulate dendritic and axonal growth during development and maintenance of the mature nervous system; however, the cellular and molecular mechanisms underlying this process are not fully understood. In recent years, several advances have shed new light on the processes behind the regulation of BDNF-mediated structural plasticity including control of neuronal transcription, local translation of proteins, and regulation of cytoskeleton and membrane dynamics. In this review, we summarize recent advances in the field of BDNF signaling in neurons to induce neuronal growth. (c) 2016 Wiley Periodicals, Inc. PMID- 27223598 TI - Reliability of Pressure Ulcer Rates: How Precisely Can We Differentiate Among Hospital Units, and Does the Standard Signal-Noise Reliability Measure Reflect This Precision? AB - Hospital performance reports often include rankings of unit pressure ulcer rates. Differentiating among units on the basis of quality requires reliable measurement. Our objectives were to describe and apply methods for assessing reliability of hospital-acquired pressure ulcer rates and evaluate a standard signal-noise reliability measure as an indicator of precision of differentiation among units. Quarterly pressure ulcer data from 8,199 critical care, step-down, medical, surgical, and medical-surgical nursing units from 1,299 US hospitals were analyzed. Using beta-binomial models, we estimated between-unit variability (signal) and within-unit variability (noise) in annual unit pressure ulcer rates. Signal-noise reliability was computed as the ratio of between-unit variability to the total of between- and within-unit variability. To assess precision of differentiation among units based on ranked pressure ulcer rates, we simulated data to estimate the probabilities of a unit's observed pressure ulcer rate rank in a given sample falling within five and ten percentiles of its true rank, and the probabilities of units with ulcer rates in the highest quartile and highest decile being identified as such. We assessed the signal-noise measure as an indicator of differentiation precision by computing its correlations with these probabilities. Pressure ulcer rates based on a single year of quarterly or weekly prevalence surveys were too susceptible to noise to allow for precise differentiation among units, and signal-noise reliability was a poor indicator of precision of differentiation. To ensure precise differentiation on the basis of true differences, alternative methods of assessing reliability should be applied to measures purported to differentiate among providers or units based on quality. (c) 2016 The Authors. Research in Nursing & Health published by Wiley Periodicals, Inc. PMID- 27223599 TI - Facile Probe Design: Fluorescent Amphiphilic Nucleic Acid Probes without Quencher Providing Telomerase Activity Imaging Inside Living Cells. AB - Nowadays, the probe with fluorophore but no quencher is promising for its simple preparation, environmental friendliness, and wide application scope. This study designs a new amphiphilic nucleic acid probe (ANAP) based on aggregation-caused quenching (ACQ) effect without any quencher. Upon binding with targets, the dispersion of hydrophobic part (conjugated fluorene, CF) in ANAP is enhanced as a signal-on model for proteins, nucleic acids, and small molecules detection or the aggregation of CF is enhanced as a signal-off model for ion detection. Meanwhile, because of the high specificity of ANAP, a one-step method is developed powerfully for monitoring the telomerase activity not only from the cell extracts but also from 50 clinic urine samples (positive results from 45 patients with bladder cancer and negative results from 5 healthy people). ANAPs can also readily enter into cells and exhibit a good performance for distinguishing natural tumor cells from the tumor cells pretreated by telomerase-related drugs or normal cells. In contrast to our previous results ( Anal. Chem. 2015 , 87 , 3890 - 3894 ), the present CF is a monomer which is just the structure unit of the previous fluorescent polymer. Since the accurate molecular structure and high DNA/CF ratio of the present CF, these advanced experiments obtain an easier preparation of probes, an improved sensitivity and specificity, and broader detectable targets. PMID- 27223601 TI - Does the brain listen to the gut? AB - Transplanting gut bacteria from one mouse strain to another can override genetics and change behavior. PMID- 27223600 TI - A simple and efficient method for generating high-quality recombinant Mical enzyme for in vitro assays. AB - We have recently identified a new family of multidomain oxidoreductase (redox) enzymes, the MICALs, that directly regulate the actin cytoskeletal elements necessary for the morphology, motility, and trajectory of cells. Our genetic assays reveal that Mical is both necessary and sufficient for actin organization and cellular effects in vivo and our biochemical assays with purified Mical protein reveal that Mical utilizes its redox activity to directly disassemble actin filaments. These results identify Mical proteins as novel actin disassembly factors and uncover a redox signaling mechanism that directly regulates the actin cytoskeleton. These results have also set the stage for in-depth characterization of the Mical enzyme. However, it has been difficult to obtain sufficient amounts of highly-pure Mical protein to conduct further biochemical, structural, imaging, catalytic, and other high-precision studies. Herein, we describe a means for expressing high levels of soluble recombinant Mical protein in bacteria. Likewise, we have designed a new purification strategy that enables the rapid and efficient purification of milligram quantities of highly-pure and >99% active Mical protein. This new strategy for generating large amounts of highly-pure and active Mical protein will aid research objectives designed to characterize the biochemical, enzymology, and structural biology of Mical and its effects on actin filament dynamics. PMID- 27223602 TI - Stimulation of Fe(II) Oxidation, Biogenic Lepidocrocite Formation, and Arsenic Immobilization by Pseudogulbenkiania Sp. Strain 2002. AB - An anaerobic nitrate-reducing Fe(II)-oxidizing bacterium, Pseudogulbenkiania sp. strain 2002, was used to investigate As immobilization by biogenic Fe oxyhydroxides under different initial molar ratios of Fe/As in solutions. Results showed that Fe(II) was effectively oxidized, mainly forming lepidocrocite, which immobilized more As(III) than As(V) without changing the redox state of As. When the initial Fe/As ratios were kept constant, higher initial Fe(II) concentrations immobilized more As with higher Asimmobilized/Feprecipitated in biogenic lepidocrocite. EXAFS analysis showed that variations of initial Fe(II) concentrations did not change the As-Fe complexes (bidentate binuclear complexes ((2)C)) with a fixed As(III) or As(V) initial concentration of 13.3 MUM. On the other hand, variations in initial As concentrations but fixed Fe(II) initial concentration induced the co-occurrence of bidentate binuclear and bidentate mononuclear complexes ((2)E) and bidentate binuclear and monodentate mononuclear complexes ((1)V) for As(III) and As(V)-treated series, respectively. The coexistence of (2)C and (2)E complexes (or (2)C and (1)V complexes) could contribute to higher As removal in experimental series with higher initial Fe(II) concentrations at the same initial Fe/As ratio. Simultaneous removal of soluble As and nitrate by anaerobic nitrate-reducing Fe(II)-oxidizing bacteria provides a feasible approach for in situ remediation of As-nitrate cocontaminated groundwater. PMID- 27223603 TI - Stability Limit of Water by Metastable Vapor-Liquid Equilibrium with Nanoporous Silicon Membranes. AB - Liquid can sustain mechanical tension as its pressure drops below the vapor liquid coexistence line and becomes less than zero, until it reaches the stability limit-the pressure at which cavitation inevitably occurs. For liquid water, its stability limit is still a subject of debate: the results obtained by researchers using a variety of techniques show discrepancies between the values of the stability limit and its temperature dependence as temperature approaches 0 degrees C. In this work, we present a study of the stability limit of water by the metastable vapor-liquid equilibrium (MVLE) method with nanoporous silicon membranes. We also report on an experimental system which enables tests of the temperature dependence of the stability limit with MVLE. The stability limit we found increases monotonically (larger tension) as temperature approaches 0 degrees C; this trend contradicts the centrifugal result of Briggs but agrees with the experiments by acoustic cavitation. This result confirms that a quasi static method can reach stability values similar to that from the dynamic stretching technique, even close to 0 degrees C. Nevertheless, our results fall in the range of ~ -20 to -30 MPa, a range that is consistent with the majority of experiments but is far less negative than the limit obtained in experiments involving quartz inclusions and that predicted for homogeneous nucleation. PMID- 27223604 TI - A case of motor neuropathy after cryolipolysis of the arm. AB - Cryolipolysis treatment is a non-invasive option for localized fat reduction without damaging the surrounding tissue. Clinical studies about cryolipolysis show various side effects, including temporary erythema, bruising, and transient numbness. But, no reports are available on motor nerve malfunction after cryolipolysis. A 24-year-old female received cryolipolysis treatment on abdomen, both arms. After 10 days, patient complained of weakness and inability to lift heavy objects. Symptoms continued for 6 months, and fully recovered without treatment. Thus, we report a case of motor neuropathy after cryolipolysis, which is a rare complication of cryolipolysis. PMID- 27223605 TI - High specific genotyping method using short target probe and helper probe. AB - Differentiating 1-bp differences using real-time PCR often leads to false positive results. Therefore, we developed a fluorescence melting curve analysis (FMCA) method with a short target probe and helper probe labeled with a fluorophore and quencher, respectively. This fluorophore and quencher were designed to be near each other when the probes were hybridized to template DNA. The target probe was designed with a shorter length to facilitate a dramatic shift in melting temperature (Tm) upon encountering mismatched hybridization. In FMCA, when the temperature approached the target probe Tm, the target probe would begin to denature from the template DNA, and at the target probe Tm, the fluorescence signal increased markedly. Here, we examined 1-bp differences using the developed method with mitochondrial DNA from Larimichthys polyactis and Larimichthys crocea. Application of this method permitted specific genotype identification for all cases with no cross-reactivity, even when both templates were added to the same tube. PMID- 27223606 TI - Post-Transcriptional Regulation of the GASC1 Oncogene with Active Tumor-Targeted siRNA-Nanoparticles. AB - Basal-like breast cancer (BLBC) accounts for the most aggressive types of breast cancer, marked by high rates of relapse and poor prognoses and with no effective clinical therapy yet. Therefore, investigation of new targets and treatment strategies is more than necessary. Here, we identified a receptor that can be targeted in BLBC for efficient and specific siRNA mediated gene knockdown of therapeutically relevant genes such as the histone demethylase GASC1, which is involved in multiple signaling pathways leading to tumorigenesis. Breast cancer and healthy breast cell lines were compared regarding transferrin receptor (TfR) expression via flow cytometry and transferrin binding assays. Nanobioconjugates made of low molecular weight polyethylenimine (LMW-PEI) and transferrin (Tf) were synthesized to contain a bioreducible disulfide bond. siRNA complexation was characterized by condensation assays and dynamic light scattering. Cytotoxicity, transfection efficiency, and the targeting specificity of the conjugates were investigated in TfR positive and negative healthy breast and breast cancer cell lines by flow cytometry, confocal microscopy, RT-PCR, and Western blot. Breast cancer cell lines revealed a significantly higher TfR expression than healthy breast cells. The conjugates efficiently condensed siRNA into particles with 45 nm size at low polymer concentrations, showed no apparent toxicity on different breast cancer cell lines, and had significantly greater transfection and gene knockdown activity on mRNA and protein levels than PEI/siRNA leading to targeted and therapeutic growth inhibition post GASC1 knockdown. The synthesized nanobioconjugates improved the efficiency of gene transfer and targeting specificity in transferrin receptor positive cells but not in cells with basal receptor expression. Therefore, these materials in combination with our newly identified siRNA sequences are promising candidates for therapeutic targeting of hard-to-treat BLBC and are currently further investigated regarding in vivo targeting efficacy and biocompatibility. PMID- 27223607 TI - Women are Warmer but No Less Assertive than Men: Gender and Language on Facebook. AB - Using a large social media dataset and open-vocabulary methods from computational linguistics, we explored differences in language use across gender, affiliation, and assertiveness. In Study 1, we analyzed topics (groups of semantically similar words) across 10 million messages from over 52,000 Facebook users. Most language differed little across gender. However, topics most associated with self identified female participants included friends, family, and social life, whereas topics most associated with self-identified male participants included swearing, anger, discussion of objects instead of people, and the use of argumentative language. In Study 2, we plotted male- and female-linked language topics along two interpersonal dimensions prevalent in gender research: affiliation and assertiveness. In a sample of over 15,000 Facebook users, we found substantial gender differences in the use of affiliative language and slight differences in assertive language. Language used more by self-identified females was interpersonally warmer, more compassionate, polite, and-contrary to previous findings-slightly more assertive in their language use, whereas language used more by self-identified males was colder, more hostile, and impersonal. Computational linguistic analysis combined with methods to automatically label topics offer means for testing psychological theories unobtrusively at large scale. PMID- 27223608 TI - Intraocular pressure fluctuations of growing chick eyes are suppressed in constant light conditions. AB - We report measurements of intraocular pressure (IOP) in growing domestic chicks at 12 h intervals, with three different lighting conditions. One group of chicks was raised in 12 h light and 12 h darkness (N), another in constant light (CL), and the third group was initially exposed to CL for three weeks then returned to N for either one week or four weeks (CLN). Pressures were measured in the middle of the light and dark periods (noon and midnight) for N and CLN birds, and at corresponding 12 h intervals for CL birds (also noon and midnight). The IOP of N chicks fluctuated from a light period average value of 25 mm Hg ( +/-1.3 SD), to a dark period average value of 17.5 mm Hg ( +/-1.1 SD mm Hg; P < 0.0001). These pressures were established by 4 days of age. At 7 weeks, (N) IOP continued to fluctuate: light values were 21.7 mm Hg (+/-1.2 SD), and dark values were 18.3 mm Hg ( +/-0.7 SD). The IOP of CL birds did not fluctuate, remaining steady at 17 mm Hg ( +/-1.4 SD). Chicks exposed to CL for 3 weeks required more than one week in N to re-establish (N) IOP values. We conclude that IOP fluctuates in hatchling chicks under N light conditions, that fluctuation is suppressed in CL light conditions, and that IOP recovery from 3 weeks suppression in CL requires more than one week in N light conditions. PMID- 27223609 TI - Recombinant Forms of Leishmania amazonensis Excreted/Secreted Promastigote Surface Antigen (PSA) Induce Protective Immune Responses in Dogs. AB - Preventive vaccination is a highly promising strategy for interrupting leishmaniasis transmission that can, additionally, contribute to elimination. A vaccine formulation based on naturally excreted secreted (ES) antigens was prepared from L. infantum promastigote culture supernatant. This vaccine achieved successful results in Phase III trials and was licensed and marketed as CaniLeish. We recently showed that newly identified ES promastigote surface antigen (PSA), from both viable promastigotes and axenically-grown amastigotes, represented the major constituent and the highly immunogenic antigen of L. infantum and L. amazonensis ES products. We report here that three immunizations with either the recombinant ES LaPSA-38S (rPSA) or its carboxy terminal part LaPSA-12S (Cter-rPSA), combined with QA-21 as adjuvant, confer high levels of protection in naive L. infantum-infected Beagle dogs, as checked by bone marrow parasite absence in respectively 78.8% and 80% of vaccinated dogs at 6 months post-challenge. The parasite burden in infected vaccinated dogs was significantly reduced compared to placebo group, as measured by q-PCR. Moreover, our results reveal humoral and cellular immune response clear-cut differences between vaccinated and control dogs. An early increase in specific IgG2 antibodies was observed in rPSA/QA-21- and Cter-rPSA/QA-21-immunized dogs only. They were found functionally active in vitro and were highly correlated with vaccine protection. In vaccinated protected dogs, IFN-gamma and NO productions, as well as anti leishmanial macrophage activity, were increased. These data strongly suggest that ES PSA or its carboxy-terminal part, in recombinant forms, induce protection in a canine model of zoonotic visceral leishmaniasis by inducing a Th1-dominant immune response and an appropriate specific antibody response. These data suggest that they could be considered as important active components in vaccine candidates. PMID- 27223610 TI - Neutrophil Attack Triggers Extracellular Trap-Dependent Candida Cell Wall Remodeling and Altered Immune Recognition. AB - Pathogens hide immunogenic epitopes from the host to evade immunity, persist and cause infection. The opportunistic human fungal pathogen Candida albicans, which can cause fatal disease in immunocompromised patient populations, offers a good example as it masks the inflammatory epitope beta-glucan in its cell wall from host recognition. It has been demonstrated previously that beta-glucan becomes exposed during infection in vivo but the mechanism behind this exposure was unknown. Here, we show that this unmasking involves neutrophil extracellular trap (NET) mediated attack, which triggers changes in fungal cell wall architecture that enhance immune recognition by the Dectin-1 beta-glucan receptor in vitro. Furthermore, using a mouse model of disseminated candidiasis, we demonstrate the requirement for neutrophils in triggering these fungal cell wall changes in vivo. Importantly, we found that fungal epitope unmasking requires an active fungal response in addition to the stimulus provided by neutrophil attack. NET-mediated damage initiates fungal MAP kinase-driven responses, particularly by Hog1, that dynamically relocalize cell wall remodeling machinery including Chs3, Phr1 and Sur7. Neutrophil-initiated cell wall disruptions augment some macrophage cytokine responses to attacked fungi. This work provides insight into host-pathogen interactions during disseminated candidiasis, including valuable information about how the C. albicans cell wall responds to the biotic stress of immune attack. Our results highlight the important but underappreciated concept that pattern recognition during infection is dynamic and depends on the host-pathogen dialog. PMID- 27223611 TI - The Pharmacochaperone Activity of Quinine on Bitter Taste Receptors. AB - Bitter taste is one of the five basic taste sensations which is mediated by 25 bitter taste receptors (T2Rs) in humans. The mechanism of bitter taste signal transduction is not yet elucidated. The cellular processes underlying T2R desensitization including receptor internalization, trafficking and degradation are yet to be studied. Here, using a combination of molecular and pharmacological techniques we show that T2R4 is not internalized upon agonist treatment. Pretreatment with bitter agonist quinine led to a reduction in subsequent quinine mediated calcium responses to 35 +/- 5% compared to the control untreated cells. Interestingly, treatment with different bitter agonists did not cause internalization of T2R4. Instead, quinine treatment led to a 2-fold increase in T2R4 cell surface expression which was sensitive to Brefeldin A, suggesting a novel pharmacochaperone activity of quinine. This phenomenon of chaperone activity of quinine was also observed for T2R7, T2R10, T2R39 and T2R46. Our results suggest that the observed action of quinine for these T2Rs is independent of its agonist activity. This study provides novel insights into the pharmacochaperone activity of quinine and possible mechanism of T2R desensitization, which is of fundamental importance in understanding the mechanism of bitter taste signal transduction. PMID- 27223612 TI - EEG Asymmetry and ERN: Behavioral Outcomes in Preschoolers. AB - Research has documented reciprocal influences between approach-related and inhibition-related neural activity in adults. However, associations between neural systems of approach and inhibition have not been tested in children. It is thus unclear whether these links are present early in life and whether associations between neural systems of approach and inhibition have long-term behavioral consequences. To address these gaps in the literature, we used electroencephalography (EEG) to examine associations between approach-related neural activity (i.e., hemispheric asymmetry) and inhibition-related neural activity (i.e., error-related negativity [ERN]) in preschool-aged children. Furthermore, we explored whether interactions between asymmetry and ERN predicted social inhibition, a precursor to anxiety problems, or symptoms of Attention Deficit Hyperactivity Disorder (ADHD) six months later. Similar to research on adults, greater left asymmetry (i.e., greater approach-related neural activity) was correlated with reduced ERN amplitude (i.e., weaker inhibition-related neural activity). The interactive effect of asymmetry and ERN amplitude did not predict ADHD symptoms, but did predict social inhibition. When ERN was greater, less left asymmetry was associated with higher levels of social inhibition. Results were most prominent at parietal EEG sites. Implications for understanding the development of the overlap in neural systems of approach and inhibition are discussed. PMID- 27223613 TI - Exome Sequencing of a Pedigree Reveals S339L Mutation in the TLN2 Gene as a Cause of Fifth Finger Camptodactyly. AB - Camptodactyly is a digit deformity characterized by permanent flexion contracture of one or both fifth fingers at the proximal interphalangeal joints. Though over 60 distinct types of syndromic camptodactyly have been described, only one disease locus (3q11.2-q13.12) for nonsyndromic camptodactyly has been identified. To identify the genetic defect for camptodactyly in a four-generation Chinese Han family, exome and Sanger sequencings were conducted and a missense variant, c.1016C>T (p.S339L), in the talin 2 gene (TLN2) was identified. The variant co segregated with disease in the family and was not observed in 12 unaffected family members or 1,000 normal controls, suggesting that p.S339L is a pathogenic mutation. Two asymptomatic carriers in the family indicated incomplete penetrance or more complicated compensated mechanism. Most of p.S339L carriers also have relatively benign cardiac phenotypes. Expression of wild and mutant TLN2 in HEK293 cells suggested the predominant localization in cytoplasm. Our data suggest a potential molecular link between TLN2 and camptodactyly pathogenesis. PMID- 27223614 TI - Monitoring the Growth of an Orthotopic Tumour Xenograft Model: Multi-Modal Imaging Assessment with Benchtop MRI (1T), High-Field MRI (9.4T), Ultrasound and Bioluminescence. AB - BACKGROUND: Research using orthotopic and transgenic models of cancer requires imaging methods to non-invasively quantify tumour burden. As the choice of appropriate imaging modality is wide-ranging, this study aimed to compare low field (1T) magnetic resonance imaging (MRI), a novel and relatively low-cost system, against established preclinical techniques: bioluminescence imaging (BLI), ultrasound imaging (US), and high-field (9.4T) MRI. METHODS: A model of colorectal metastasis to the liver was established in eight mice, which were imaged with each modality over four weeks post-implantation. Tumour burden was assessed from manually segmented regions. RESULTS: All four imaging systems provided sufficient contrast to detect tumours in all of the mice after two weeks. No significant difference was detected between tumour doubling times estimated by low-field MRI, ultrasound imaging or high-field MRI. A strong correlation was measured between high-field MRI estimates of tumour burden and all the other modalities (p < 0.001, Pearson). CONCLUSION: These results suggest that both low-field MRI and ultrasound imaging are accurate modalities for characterising the growth of preclinical tumour models. PMID- 27223615 TI - Crystal Structures of Putative Sugar Kinases from Synechococcus Elongatus PCC 7942 and Arabidopsis Thaliana. AB - The genome of the Synechococcus elongatus strain PCC 7942 encodes a putative sugar kinase (SePSK), which shares 44.9% sequence identity with the xylulose kinase-1 (AtXK-1) from Arabidopsis thaliana. Sequence alignment suggests that both kinases belong to the ribulokinase-like carbohydrate kinases, a sub-family of FGGY family carbohydrate kinases. However, their exact physiological function and real substrates remain unknown. Here we solved the structures of SePSK and AtXK-1 in both their apo forms and in complex with nucleotide substrates. The two kinases exhibit nearly identical overall architecture, with both kinases possessing ATP hydrolysis activity in the absence of substrates. In addition, our enzymatic assays suggested that SePSK has the capability to phosphorylate D ribulose. In order to understand the catalytic mechanism of SePSK, we solved the structure of SePSK in complex with D-ribulose and found two potential substrate binding pockets in SePSK. Using mutation and activity analysis, we further verified the key residues important for its catalytic activity. Moreover, our structural comparison with other family members suggests that there are major conformational changes in SePSK upon substrate binding, facilitating the catalytic process. Together, these results provide important information for a more detailed understanding of the cofactor and substrate binding mode as well as the catalytic mechanism of SePSK, and possible similarities with its plant homologue AtXK-1. PMID- 27223616 TI - Zebras and Biting Flies: Quantitative Analysis of Reflected Light from Zebra Coats in Their Natural Habitat. AB - Experimental and comparative evidence suggests that the striped coats of zebras deter biting fly attack, but the mechanisms by which flies fail to target black and-white mammals are still opaque. Two hypotheses have been proposed: stripes might serve either to defeat polarotaxis or to obscure the form of the animal. To test these hypotheses, we systematically photographed free-living plains zebras in Africa. We found that black and white stripes both have moderate polarization signatures with a similar angle, though the degree (magnitude) of polarization in white stripes is lower. When we modeled the visibility of these signals from different distances, we found that polarization differences between stripes are invisible to flies more than 10 m away because they are averaged out by the flies' low visual resolution. At any distance, however, a positively polarotactic insect would have a distinct signal to guide its visual approach to a zebra because we found that polarization of light reflecting from zebras is higher than from surrounding dry grasses. We also found that the stripes themselves are visible to flies at somewhat greater distances (up to 20 m) than the polarization contrast between stripes. Together, these observations support hypotheses in which zebra stripes defeat visually guided orienting behavior in flies by a mechanism independent of polarotaxis. PMID- 27223618 TI - Using Simulation to Prepare Nursing Students for Professional Roles. AB - The current job market for nurses is variable and although there remains a projected shortage of nurses for the future, availability of entry-level positions has changed. This mixed-methods pilot study describes the successful use of simulated role-play to prepare senior nursing students (N = 66) for competitive job markets. The simulation laboratory was set up as a human resource department. The students and interviewers were evaluated by surveys. The majority of students rated the experience high for understanding interviews and assisting them with readiness for interviews. Qualitative results revealed themes of nervousness, confidence, and readiness. Interviewers also discussed student nervousness and the benefits of simulated interviews. These results affirmed that the overall learning outcome of the experience was positive and can assist in promoting professional role transition. The project will continue to be implemented, and it will be extended to graduate students in the future. PMID- 27223617 TI - Loss of GltB Inhibits Biofilm Formation and Biocontrol Efficiency of Bacillus subtilis Bs916 by Altering the Production of gamma-Polyglutamate and Three Lipopeptides. AB - AIMS: This study examined the contribution of GltB on biofilm formation and biocontrol efficiency of B. subtilis Bs916. METHODS AND RESULTS: The gltB gene was identified through a biofilm phenotype screen and a bioinformatics analysis of serious biofilm formation defects, and then a gltB single knockout mutant was constructed using homologous recombination. This mutant demonstrated severe deficits in biofilm formation and colonisation along with significantly altered production ofgamma-polyglutamate (gamma-PGA) and three lipopeptide antibiotics (LPs) as measured by a transcriptional analysis of both the wild type B. subtilis Bs916 and the gltB mutant. Consequently, the mutant strain retained almost no antifungal activity against Rhizoctonia solani and exhibited decreased biocontrol efficiency against rice sheath blight. Very few gltB mutant cells colonised the rice stem, and they exhibited no significant nutrient chemotaxis compared to the wild type B. subtilis Bs916. The mechanism underlying these deficits in the gltB mutant appears to be decreased significantly in production of gamma-PGA and a reduction in the production of both bacillomycin L and fengycin. Biofilm restoration of gltB mutant by additiongamma-PGA in the EM medium demonstrated that biofilm formation was able to restore significantly at 20 g/L. CONCLUSIONS: GltB regulates biofilm formation by altering the production ofgamma-PGA, the LPs bacillomycin L and fengcin and influences bacterial colonisation on the rice stem, which consequently leads to poor biocontrol efficiency against rice sheath blight. SIGNIFICANCE AND IMPACT OF STUDY: This is the first report of a key regulatory protein (GltB) that is involved in biofilm regulation and its regulation mechanism and biocontrol efficiency by B. subtilis. PMID- 27223619 TI - Does Ramadan Fasting Affect Fatigue in Nurses? AB - The purpose of this study was to evaluate the effect of Ramadan fasting on fatigue in nurses. The study was conducted between June 19 and July 27, 2014, with a descriptive design. This study was completed with 99 nurses working in a public hospital in the city of Gaziantep located in the Southeastern Anatolia Region of Turkey. The data of the study were collected by using a questionnaire and the Piper Fatigue Scale. The Piper Fatigue Scale includes 4 subscale/dimensional scores and total fatigue scores. Higher scores indicate more fatigue. Statistical significance levels were set at P < .05. It was determined that the fatigue subscale and total mean scores of nurses increased in a statistically significant manner except for the affective subscale after the month of Ramadan (P < .05). In addition, it was found that the fatigue mean scores of those, who were working for 0 to 4 years, were employed in surgery units, and evaluated their health as bad, were higher (P > .05). The Ramadan fasting increased fatigue levels of nurses. Therefore, it is of vital importance to evaluate fatigue levels of nurses especially in the month of Ramadan and take the necessary precautions in terms of patient and personnel safety. PMID- 27223620 TI - ALD Zn(O,S) Thin Films' Interfacial Chemical and Structural Configuration Probed by XAS. AB - The ability to precisely control interfaces of atomic layer deposited (ALD) zinc oxysulfide (Zn(O,S)) buffer layers to other layers allows precise tuning of solar cell performance. The O K- and S K-edge X-ray absorption near edge structure (XANES) of ~2-4 nm thin Zn(O,S) films reveals the chemical and structural influences of their interface with ZnO, a common electrode material and diffusion barrier in solar cells. We observe that sulfate formation at oxide/sulfide interfaces is independent of film composition, a result of sulfur diffusion toward interfaces. Leveraging sulfur's diffusivity, we propose an alternative ALD process in which the zinc precursor pulse is bypassed during H2S exposure. Such a process yields similar results to the nanolaminate deposition method and highlights mechanistic differences between ALD sulfides and oxides. By identifying chemical species and structural evolution at sulfide/oxide interfaces, this work provides insights into increasing thin film solar cell efficiencies. PMID- 27223621 TI - Predictors of Clinical Outcome after Prostate Artery Embolization with Spherical and Nonspherical Polyvinyl Alcohol Particles in Patients with Benign Prostatic Hyperplasia. AB - Purpose To assess predictors of outcome after prostate artery embolization (PAE) for benign prostatic hyperplasia with spherical particle polyvinyl alcohol (sPVA) and compare outcomes with the use of nonspherical particle polyvinyl alcohol (nsPVA). Materials and Methods This was a single-center retrospective institutional review board-approved study conducted from 2009 to 2015 in patients undergoing PAE with sPVA (n = 186; mean age +/- standard deviation, 65.5 years +/ 7.7) and nsPVA (n = 300; mean age, 65.3 years +/- 7.6). The two cohorts were compared and analyzed for predictors of outcome with a Cox proportional hazards model and linear regression. Post-PAE prostate ischemia was measured with contrast material-enhanced magnetic resonance (MR) imaging in 23 patients with nsPVA and 25 patients with sPVA. The 24-hour post-PAE prostate-specific antigen (PSA) level was registered in 133 patients with sPVA. Prognostic values of MR imaging and PSA levels 24 hours after PAE were assessed with Cox and random effects regressions. Results Predictors of clinical failure were older age (age over 65 years, P = .002), unilateral procedure (P = .002), and higher baseline International Prostate Symptom Score (IPSS, P = .033). Adjusted hazard ratio for clinical failure of sPVA was 1.273 (P = .16). Acute urinary retention was a predictor of lower IPSS after PAE (P = .002). The mean proportion of prostate ischemia was 11% with sPVA and 10% with nsPVA (P = .65). Lower IPSS after PAE was associated with a higher proportion of prostate ischemia (P = .009). Patients with a PSA level of at least 75 ng/mL (75 MUg/L) 24 hours after PAE had a greater decrease in IPSS (P = .01). Prostate ischemic volume and PSA level 24 hours after PAE were correlated (Pearson r = 0.64, P = .014). Conclusion Clinical outcome was similar after PAE with sPVA and nsPVA. Younger age (up to 65 years), bilateral PAE, lower baseline IPSS, and acute urinary retention were predictors of better clinical outcome. The PSA level 24 hours after PAE correlated with prostate ischemia, and both correlated with clinical outcome. ((c)) RSNA, 2016. PMID- 27223623 TI - Dermatoglyphics and Cheiloscopy as Key Tools in Resolving the Genetic Correlation of Inheritance Patterns in Cleft Lip and Palate Patients: An Assessment of 160 Patients. AB - OBJECTIVE: The objective of this study was to correlate dermatoglyphics and cheiloscopy with genetic inheritance in cleft lip and cleft palate patients. DESIGN AND SETTING: This was a case-control study to look for asymmetry in finger and lip print patterns. All of the participants were divided into two equal groups (40 mothers and 40 fathers in each group). The data were analyzed by three evaluators who were blind to the study to avoid any chances of error. PATIENTS/PARTICIPANTS: A sample of 160 sporadic participants were identified and evaluated. Group A was composed of 80 healthy parents not affected by cleft lip and cleft palate but had at least one child born with nonsyndromic cleft. Group B consisted of 80 healthy parents not affected by cleft lip and cleft palate and had healthy children without cleft lip and cleft palate. MAIN OUTCOME MEASURES: Main outcome measures were marked dermatoglyphic asymmetry and specific lip print pattern in the study group. RESULTS: We found marked asymmetry in various fingerprints and specific type II and type III lip print in the study group when compared with the control group. It was observed that groove count on the lip was significantly more frequent in study group parents. CONCLUSION: Our study determined that there is a significant correlation between increased dermatoglyphic asymmetry and specific type II and type III lip print pattern in parents of children born with cleft. This could act as an important screening marker for the prediction of cleft lip and cleft palate inheritance. PMID- 27223622 TI - Programmatic Management of Drug-Resistant Tuberculosis: An Updated Research Agenda. AB - INTRODUCTION: There are numerous challenges in delivering appropriate treatment for multidrug-resistant tuberculosis (MDR-TB) and the evidence base to guide those practices remains limited. We present the third updated Research Agenda for the programmatic management of drug-resistant TB (PMDT), assembled through a literature review and survey. METHODS: Publications citing the 2008 research agenda and normative documents were reviewed for evidence gaps. Gaps were formulated into questions and grouped as in the 2008 research agenda: Laboratory Support, Treatment Strategy, Programmatically Relevant Research, Epidemiology, and Management of Contacts. A survey was distributed through snowball sampling to identify research priorities. Respondent priority rankings were scored and summarized by mean. Sensitivity analyses explored weighting and handling of missing rankings. RESULTS: Thirty normative documents and publications were reviewed for stated research needs; these were collapsed into 56 research questions across 5 categories. Of more than 500 survey recipients, 133 ranked priorities within at least one category. Priorities within categories included new diagnostics and their effect on improving treatment outcomes, improved diagnosis of paucibacillary and extra pulmonary TB, and development of shorter, effective regimens. Interruption of nosocomial transmission and treatment for latent TB infection in contacts of known MDR-TB patients were also top priorities in their respective categories. Results were internally consistent and robust. DISCUSSION: Priorities retained from the 2008 research agenda include shorter MDR TB regimens and averting transmission. Limitations of recent advances were implied in the continued quest for: shorter regimens containing new drugs, rapid diagnostics that improve treatment outcomes, and improved methods of estimating burden without representative data. CONCLUSION: There is continuity around the priorities for research in PMDT. Coordinated efforts to address questions regarding shorter treatment regimens, knowledge of disease burden without representative data, and treatment for LTBI in contacts of known DR-TB patients are essential to stem the epidemic of TB, including DR-TB. PMID- 27223624 TI - Effects of Infant Cleft Lip on Adult Gaze and Perceptions of "Cuteness". AB - OBJECTIVE: Early mother-infant interactions are impaired in the context of infant cleft lip and are associated with adverse child psychological outcomes, but the nature of these interaction difficulties is not yet fully understood. The aim of this study was to explore adult gaze behavior and cuteness perception, which are particularly important during early social exchanges, in response to infants with cleft lip, in order to investigate potential foundations for the interaction difficulties seen in this population. METHODS: Using an eye tracker, eye movements were recorded as adult participants viewed images of infant faces with and without cleft lip. Participants also rated each infant on a scale of cuteness. RESULTS: Participants fixated significantly longer on the mouths of infants with cleft lip, which occurred at the expense of fixation on eyes. Severity of cleft lip was associated with the strength of fixation bias, with participants looking even longer at the mouths of infants with the most severe clefts. Infants with cleft lip were rated as significantly less cute than unaffected infants. Men rated infants as less cute than women overall but gave particularly low ratings to infants with cleft lip. CONCLUSIONS: Results demonstrate that the limited disturbance in infant facial configuration of cleft lip can significantly alter adult gaze patterns and cuteness perception. Our findings could have important implications for early interactions and may help in the development of interventions to foster healthy development in infants with cleft lip. PMID- 27223625 TI - Computer-Assisted Virtual Planning for Surgical Guide Manufacturing and Internal Distractor Adaptation in the Management of Midface Hypoplasia in Cleft Patients. AB - We are reporting the treatment of severe maxillary hypoplasia in two patients with unilateral cleft lip and palate by using a specific approach combining the Le Fort I distraction osteogenesis technique coupled with computer-aided design/computer-aided manufacturing customized surgical guides and internal distractors based on virtual computational planning. This technology allows for the transfer of the virtual planned reconstruction to the operating room by using custom patient-specific implants, surgical splints, surgical cutting guides, and surgical guides to plate or distractor adaptation. PMID- 27223626 TI - A Standard Set of Outcome Measures for the Comprehensive Appraisal of Cleft Care. AB - Care of the patient with cleft lip and/or palate remains complex. Prior attempts at aggregating data to study the effectiveness of specific interventions or overall treatment protocols have been hindered by a lack of data standards. There exists a critical need to better define the outcomes-particularly those that matter most to patients and their families-and to standardize the methods by which these outcomes will be measured. This report summarizes the recommendations of an international, multidisciplinary working group with regard to which outcomes a typical cleft team could track, how those outcomes could be measured and recorded, and what strategies may be employed to sustainably implement a system for prospective data collection. It is only by agreeing on a common, standard set of outcome measures for the comprehensive appraisal of cleft care that intercenter comparisons can become possible. This is important for quality improvement endeavors, comparative effectiveness research, and value-based health care reform. PMID- 27223627 TI - Investigation of the mechanisms of neuroprotection mediated by Ro5-4864 in brain injury. AB - Increasing evidence has established the involvement of the 18-kDa translocator protein (TSPO) in the process of mitochondrial membrane permeabilization and subsequent apoptosis through modulation of the mitochondrial permeability transition pore. Recent studies have shown that treatment with Ro5-4864, a TSPO ligand, resulted in a neuroprotective effect in traumatic brain injury. Yet, the nature of this effect remained uncertain as mature neurons are considered to be lacking the TSPO protein. In order to investigate the mechanism of Ro5-4864 mediated neuroprotection, the neuro-inflammatory and neurosteroid response to cortical injury was tested in sham-operated, vehicle, cyclosporine A (CsA) and Ro5-4864-treated rats. As anticipated, the levels of interleukin 1beta and tumor necrosis factor alpha, as well as the astrocyte and microglia cellular density in the injured area were all decreased by CsA in comparison with the vehicle group. By contrast, no visible effect could be observed in Ro5-4864-treated animals. None of the groups showed any significant difference with any other in respect with the expression of brain-derived neurotrophic factor. Double immunofluorescence staining with NeuN and TSPO confirmed the absence of TSPO in native neurons though showed clear evidence of co-localization of TSPO in the cytoplasm of NeuN-stained injured neurons. Altogether, this study shows that the neuronal protection mediated by Ro5-4864 in brain injury cannot be solely attributed to an indirect effect of the ligand on glial TSPO but may also represent the consequence of the modulation of upregulated TSPO in injured neurons. This observation may be of importance for future pharmacological research in neurotrauma. PMID- 27223628 TI - Block design enhances classification of 3D reach targets from electroencephalographic signals. AB - To date, decoding accuracy of actual or imagined pointing movements to targets in 3D space from electroencephalographic (EEG) signals has remained modest. The reason may pertain to the fact that these movements activate essentially the same neural networks. In this study, we aimed at testing whether repetitive pointing movements to each of the targets promotes the development of segregated neural patterns, resulting in enhanced decoding accuracy. Six human subjects generated slow or fast repetitive pointing movements with their right dominant arm to one of five targets distributed in 3D space, followed by repetitive imagery of movements to the same target or to a different target. Nine naive subjects generated both repetitive and non-repetitive slow actual movements to each of the five targets to test the effect of block design on decoding accuracy. In order to assure that base line drift and low frequency motion artifacts do not contaminate the data, the data were high-pass filtered in 4-30Hz, leaving out the delta and gamma band. For the repetitive trials, the model decoded target location with 81% accuracy, which is significantly higher than chance level. The average decoding rate of target location was only 30% for the non-repetitive trials, which is not significantly different than chance level. A subset of electrodes, mainly over the contralateral sensorimotor areas, was found to provide most of the discriminative features for all tested conditions. Time proximity between trained and tested blocks was found to enhance decoding accuracy of target location both by target non-specific and specific mechanisms. Our findings suggest that movement repetition promotes the development of distinct neural patterns, presumably by the formation of target-specific kinesthetic memory. PMID- 27223629 TI - Activity of muscarinic, galanin and cannabinoid receptors in the prodromal and advanced stages in the triple transgenic mice model of Alzheimer's disease. AB - Neurochemical alterations in Alzheimer's disease (AD) include cholinergic neuronal loss in the nucleus basalis of Meynert (nbM) and a decrease in densities of the M2 muscarinic receptor subtype in areas related to learning and memory. Neuromodulators present in the cholinergic pathways, such as neuropeptides and neurolipids, control these cognitive processes and have become targets of research in order to understand and treat the pathophysiological and clinical stages of the disease. This is the case of the endocannabinoid and galaninergic systems, which have been found to be up-regulated in AD, and could therefore have a neuroprotective role. In the present study, the functional coupling of Gi/o protein-coupled receptors to GalR1, and the CB1 receptor subtype for endocannabinoids were analyzed in the 3xTg-AD mice model of AD. In addition, the activity mediated by Gi/o protein-coupled M2/4 muscarinic receptor subtypes was also analyzed in brain areas involved in anxiety and cognition. Thus, male mice were studied at 4 and 15months of age (prodromal and advanced stages, respectively) and compared to age-matched non-transgenic (NTg) mice (adult and old, respectively). In 4-month-old 3xTg-AD mice, the [(35)S]GTPgammaS binding stimulated by galanin was significantly increased in the hypothalamus, but a decrease of functional M2/4 receptors was observed in the posterior amygdala. The CB1 cannabinoid receptor activity was up-regulated in the anterior thalamus at that age. In 15-month-old 3xTg-AD mice, muscarinic receptor activity was found to be increased in motor cortex, while CB1 activity was decreased in nbM. No changes were found in GalR1-mediated activity at this age. Our results provide further evidence of the relevance of limbic areas in the prodromal stage of AD, the profile of which is characterized by anxiety. The up-regulation of galaninergic and endocannabinoid systems support the hypothesis of their neuroprotective roles, and these are established prior to the onset of clear clinical cognitive symptoms of the disease. PMID- 27223630 TI - Probucol inhibits neural cell apoptosis via inhibition of mTOR signaling pathway after spinal cord injury. AB - Autophagy plays an essential role in neurodevelopment, axonal guidance, neuropathic pain remission, and neuronal survival. Inhibiting the mammalian target of rapamycin (mTOR) signaling pathway can induce the occurrence of autophagy. In this study, we initially detected the effect of probucol on autophagy after spinal cord injury (SCI) by intraperitoneally injecting spinal cord-injured rats with probucol for 7days. The levels of Beclin1 and LC3B were evidently enhanced at 7days post-operation. However, the increase in the phosphorylated AMP-activated protein kinase (AMPK) protein and the decrease in ribosomal protein S6 kinase p70 subtype (p70S6K) phosphorylation level simultaneously occurred after SCI. Moreover, the expression levels of apoptosis related proteins of Caspase-3, Caspase-9, and Bax were significantly reduced. Immunofluorescence results indicated that the expression of Caspase-3 protein was evidently decreased and that of Beclin-1 protein was increased by probucol. Nissl staining and Basso, Beattie, and Bresnahan scores showed that the quantity and function of motor neurons were visibly preserved by probucol after SCI. This study showed that probucol inhibited the mTOR signaling pathway to induce autophagy, reduce neural cell apoptosis and promote recovery of neurological function after SCI. PMID- 27223631 TI - Polymorphisms on IFNG, IL12B and IL12RB1 genes and paracoccidioidomycosis in the Brazilian population. AB - Paracoccidioidomycosis (PCM) is a systemic chronic mycosis, endemic in Latin America, especially Brazil, and is the eighth leading cause of death among chronic and recurrent infectious diseases. PCM infection is characterized by the presence of Th1 immune response; the acute form, by a mixed Th2/Th9, while the chronic form is characterized by Th17/Th22 profiles. The occurrence and severity of human PCM may also be associated with genetic factors such as single nucleotide polymorphisms (SNP) on cytokines encoding genes. We investigated the association between these polymorphisms and the different clinical forms of PCM. We included 156 patients with PCM (40 with the acute form, 99 with the chronic multifocal and 17 with the chronic unifocal form) and assayed their DNA samples for IFNG +874 T/A SNP by PCR-ARMS (Amplification Refractory Mutational System), IL12B +1188 A/C SNP on 3' UTR and IL12RB1 641 A/G SNP on exon 7 by PCR-RFLP (Restriction Fragment Length Polymorphism). We found similar genotypic and allelic frequencies of the investigated SNPs among the clinical forms of PCM. Considering male patients, the IL12RB1 641 AA genotype was more frequent in the chronic multifocal form while heterozygosis was in the chronic unifocal form of PCM (p=0.048). Although our data suggest that the AA genotype (IL12RB1) may be associated with the more disseminated chronic disease, more patients of the chronic unifocal PCM group need to be analyzed as well as the secretion patterns of IFN-gamma combined with the IL-12Rbeta1 expression for a better comprehension of this association. PMID- 27223632 TI - Spread of the newly emerging infectious laryngotracheitis viruses in Australia. AB - Infectious laryngotracheitis (ILT) is a significant viral disease of chickens in many countries around the globe. In this report the status of ILT in Australia has been used as a model to evaluate the evolution of the ILT viruses (ILTVs). Due to its geographical isolation, Australia harbored a distinct lineage of ILT viruses (ILTV) up to 2007. However examination of the ILT viruses (ILTV) involved in outbreaks between 2007 and 2009 has revealed that many of the outbreaks were caused by two new viral genotypes, class 8 and class 9. These two recombinant viruses were found to emerge as a result of recombination between previously existing live vaccine strains (SA2 and A20), and another live vaccine strain (Serva) introduced into the country in 2007. The new recombinant ILTVs were also shown to possess significantly higher virulence and replication capacity compared with a previously predominant ILTV, class 2. In the current study, examination of a large number of ILTVs isolated from outbreaks between 2009 and 2015 revealed the emergence of yet another recombinant virus (class 10) that appears to have become a predominant genotype in New South Wales. In Victoria however, the recombinant class 9 gradually became the predominant virus, replacing class 2. Therefore, there was an unusual pattern in geographical spread of the newly emerged viruses in different states of the country. These results suggest that ILTV is fast evolving towards a greater transmissibility and therefore greater capacity to spread into ILTV-free areas. PMID- 27223633 TI - Phylodynamics of DENV-1 reveals the spatiotemporal co-circulation of two distinct lineages in 2013 and multiple introductions of dengue virus in Goias, Brazil. AB - Dengue virus type 1 (DENV-1) was the first serotype introduced in Brazil, during in the 1980s. Since then, this virus has spread in the Brazilian territory, causing several outbreaks. In 2013 the highest number of dengue cases was notified, when compared to the previous years in Brazil, and the state of Goias reported over 160 thousand cases. In this study, we aimed to present the Phylodynamics of DENV-1 isolates from the state of Goias, Brazil, during 2013 outbreak, based on the envelope gene (E) sequences. Phylogenetic analysis revealed that Brazilian DENV-1 isolates are grouped together with viruses from genotype V in two distinct lineages (lineage I and lineage II) reflecting co circulation. Phylogeographic analyses showed that these lineages were introduced in different moments in Goias, Brazil, using distinct routes, likely originated from the Caribbean. Lineage I was first introduced coming from Rio de Janeiro (2007-2012), followed by the introduction from Argentina (2010-2013). Lineage II was introduced in a single moment from Rio de Janeiro and this clade has existed since 2007-2010. The different viral introduction events demonstrate the viral dispersion process with neighboring regions, which is essential for the maintenance of outbreaks and introduction of new emerging viruses. In conclusion, obtained data reveals the importance of continuous molecular surveillance of this virus in different regions, providing a better understanding of DENV-1 circulation, considering the evolutionary and virus spread patterns. PMID- 27223634 TI - Human T-lymphotropic virus types 1 and 2 are rare among intravenous drug users in Eastern Europe. AB - BACKGROUND: In Europe, human T-lymphotropic virus (HTLV) type 2 mainly occurs among intravenous drug users (IDUs) with prevalence up to 15% and HTLV-1 among general population with prevalence <1%. However, there is no data regarding the prevalence of HTLV-1 or HTLV-2 in Eastern European IDUs population where HIV prevalence is relatively high. We aimed to determine the prevalence and genotypes of HTLV-1/HTLV-2 among IDUs and healthy volunteers in Estonia. METHODS: The study included 345 IDUs and 138 healthy volunteers. The presence of HTLV-1/HTLV-2 was determined by nested PCR; positive and negative controls were used in every PCR run. RESULTS: The analysed IDUs resembled the IDUs of HIV epidemic in Estonia: mainly male (79%) with median age of 30years (interquartile range [IQR] 25-34), and prolonged duration of intravenous drug usage (11years; IQR 7-14). The prevalence exposure to blood-borne viral infections was high - 50% were HIV positive, 88% hepatitis C positive, 67% hepatitis B positive. Of IDUs, 64% reported receptive needle sharing in the past and 18% at least once a month during last six months. None of the IDUs carried HTLV-1 but there was a case of HTLV-2 (prevalence 0.3%; 95% CI 0.1-1.6). All healthy volunteers were HTLV-1 and HTLV-2 PCR negative. CONCLUSION: This is the first study investigating the prevalence of HTLV-1/HTLV-2 among high risk population and healthy volunteers in Eastern European region. Our results suggest that despite other widely spread blood-borne infections (e.g. HIV, HBV, HCV) HTLV-1 and HTLV-2 are rare among IDUs in Estonia. PMID- 27223636 TI - Diagnosis of sessile serrated adenomas/polyps with image-enhanced endoscopy: a systematic review and meta-analysis. AB - BACKGROUND AND STUDY AIMS: Distinguishing sessile serrated adenomas/polyps (SSA/Ps) from non-neoplastic tissue may be challenging when white-light endoscopy (WLE) is used. Image-enhanced endoscopy (IEE) has shown accuracy in differentiating adenomas from hyperplastic polyps. The aim of this systematic review and meta-analysis was to evaluate the utility of IEE in diagnosis of SSA/Ps. METHODS: Studies were eligible if: they included patients undergoing colonoscopy with an endoscopy-based image-enhancement modality; endoscopic diagnoses, including SSA/P, were based on the appearance of polyps at IEE; and the corresponding histologic diagnoses of polyps were provided. The primary outcome was sensitivity of IEE for SSA/Ps differentiated from non-neoplastic lesions (primary convention) and differentiated from all non-SSA/P lesions, including adenomas (secondary convention). RESULTS: 13 studies met inclusion criteria. Sensitivity ranged from 38 % to 100 % but sensitivity >= 90 % was seen in 4 of 10 narrow band imaging (NBI) or magnification-NBI studies. Pooled sensitivities for discriminating SSA/Ps from non-neoplastic lesions were 80 % for magnification-NBI, 60 % for NBI, 49 % for autofluorescence, and 47 % for flexible spectral imaging color enhancement. In head-to-head comparisons with WLE, NBI (89 % vs. 75 %) and magnification-NBI (78 % vs. 63 %) demonstrated significantly greater sensitivity, while autofluorescence imaging (56 % vs. 66 %), flexible spectral imaging color enhancement (100 % vs. 100 %), and high-resolution endomicroscopy (88 % vs. 100 %) did not. CONCLUSION: IEE currently cannot be recommended as a diagnostic tool for SSA/P. While NBI studies showed promise, more IEE studies employing validated SSA/P criteria in well-defined polyp populations are needed. IEE studies assessing SSA/P detection rates at colonoscopy are also needed. PMID- 27223635 TI - Cataract secondary to self-inflicted blunt trauma in children with autism spectrum disorder. AB - We report 3 cases of bilateral cataract secondary to self-inflicted blunt eye trauma in children with autism spectrum disorder (ASD). All 3 children hit their foreheads, orbits, or globes repeatedly for long periods of time and developed cataracts. Clinicians must be aware of this phenomenon to diagnose ocular pathology early and to provide adequate education, counseling, and services to affected patients and their families and to put appropriate postoperative care mechanisms in place to prevent permanent ocular damage. PMID- 27223637 TI - Video Telementoring to Accelerate Learning of New Surgical Techniques. PMID- 27223638 TI - Microbes and healthful longevity. PMID- 27223639 TI - Non-equilibrium control of complex solids by nonlinear phononics. AB - We review some recent advances in the use of optical fields at terahertz frequencies to drive the lattice of complex materials. We will focus on the control of low energy collective properties of solids, which emerge on average when a high frequency vibration is driven and a new crystal structure induced. We first discuss the fundamentals of these lattice rearrangements, based on how anharmonic mode coupling transforms an oscillatory motion into a quasi-static deformation of the crystal structure. We then discuss experiments, in which selectively changing a bond angle turns an insulator into a metal, accompanied by changes in charge, orbital and magnetic order. We then address the case of light induced non-equilibrium superconductivity, a mysterious phenomenon observed in some cuprates and molecular materials when certain lattice vibrations are driven. Finally, we show that the dynamics of electronic and magnetic phase transitions in complex-oxide heterostructures follow distinctly new physical pathways in case of the resonant excitation of a substrate vibrational mode. PMID- 27223641 TI - Colchicine to Reduce Atrial Fibrillation in the Postoperative Period of Myocardial Revascularization. AB - BACKGROUND: The high prevalence of atrial fibrillation (AF) in the postoperative period of myocardial revascularization surgery increases morbidity and mortality. OBJECTIVE: To assess the efficacy of colchicine to prevent AF in the postoperative period of myocardial revascularization surgery, the impact of AF on hospital length of stay and death, and to identify its risk factors. METHODS: Between May 2012 and November 2013, 140 patients submitted to myocardial revascularization surgery were randomized, 69 to the control group and 71 to the colchicine group. Colchicine was used at the dose of 1 mg orally, twice daily, preoperatively, and of 0.5 mg, twice daily, until hospital discharge. A single dose of 1 mg was administered to those admitted 12 hours or less before surgery. RESULTS: The primary endpoint was AF rate in the postoperative period of myocardial revascularization surgery. Colchicine group patients showed no reduction in AF incidence as compared to control group patients (7.04% versus 13.04%, respectively; p = 0.271). There was no statistically significant difference between the groups regarding death from any cause rate (5.6% versus 10.1%; p = 0,363) and hospital length of stay (14.5 +/- 11.5 versus 13.3 +/- 9.4 days; p = 0.490). However, colchicine group patients had a higher infection rate (26.8% versus 8.7%; p = 0.007). CONCLUSION: The use of colchicine to prevent AF after myocardial revascularization surgery was not effective in the present study. Brazilian Registry of Clinical Trials number RBR-556dhr. PMID- 27223642 TI - Trends in Mortality Rate from Cardiovascular Disease in Brazil, 1980-2012. AB - BACKGROUND: Studies have questioned the downward trend in mortality from cardiovascular diseases (CVD) in Brazil in recent years. OBJECTIVE: to analyze recent trends in mortality from ischemic heart disease (IHD) and stroke in the Brazilian population. METHODS: Mortality and population data were obtained from the Brazilian Institute of Geography and Statistics and the Ministry of Health. Risk of death was adjusted by the direct method, using as reference the world population of 2000. We analyzed trends in mortality from CVD, IHD and stroke in women and men in the periods of 1980-2006 and 2007-2012. RESULTS: there was a decrease in CVD mortality and stroke in women and men for both periods (p < 0.001). Annual mortality variations for periods 1980-2006 and 2007-2012 were, respectively: CVD (total): -1.5% and -0.8%; CVD men: -1.4% and -0.6%; CVD women: 1.7% and -1.0%; DIC (men): -1.1% and 0.1%; stroke (men): -1.7% and -1.4%; DIC (women): -1.5% and 0.4%; stroke (women): -2.0% and -1.9%. From 1980 to 2006, there was a decrease in IHD mortality in men and women (p < 0.001), but from 2007 to 2012, changes in IHD mortality were not significant in men [y = 151 + 0.04 (R2 = 0.02; p = 0.779)] and women [y = 88-0.54 (R2 = 0.24; p = 0.320). CONCLUSION: Trend in mortality from IHD stopped falling in Brazil from 2007 to 2012. PMID- 27223643 TI - Fractal Dimension in Quantifying Experimental-Pulmonary-Hypertension-Induced Cardiac Dysfunction in Rats. AB - BACKGROUND: Right-sided heart failure has high morbidity and mortality, and may be caused by pulmonary arterial hypertension. Fractal dimension is a differentiated and innovative method used in histological evaluations that allows the characterization of irregular and complex structures and the quantification of structural tissue changes. OBJECTIVE: To assess the use of fractal dimension in cardiomyocytes of rats with monocrotaline-induced pulmonary arterial hypertension, in addition to providing histological and functional analysis. METHODS: Male Wistar rats were divided into 2 groups: control (C; n = 8) and monocrotaline-induced pulmonary arterial hypertension (M; n = 8). Five weeks after pulmonary arterial hypertension induction with monocrotaline, echocardiography was performed and the animals were euthanized. The heart was dissected, the ventricles weighed to assess anatomical parameters, and histological slides were prepared and stained with hematoxylin/eosin for fractal dimension analysis, performed using box-counting method. Data normality was tested (Shapiro-Wilk test), and the groups were compared with non-paired Student t test or Mann Whitney test (p < 0.05). RESULTS: Higher fractal dimension values were observed in group M as compared to group C (1.39 +/- 0.05 vs. 1.37 +/- 0.04; p < 0.05). Echocardiography showed lower pulmonary artery flow velocity, pulmonary acceleration time and ejection time values in group M, suggesting function worsening in those animals. CONCLUSION: The changes observed confirm pulmonary-arterial-hypertension-induced cardiac dysfunction, and point to fractal dimension as an effective method to evaluate cardiac morphological changes induced by ventricular dysfunction. PMID- 27223644 TI - Carlos Chagas Discoveries as a Drop Back to Scientific Construction of Chronic Chagas Heart Disease. AB - The scientific construction of chronic Chagas heart disease (CCHD) started in 1910 when Carlos Chagas highlighted the presence of cardiac arrhythmia during physical examination of patients with chronic Chagas disease, and described a case of heart failure associated with myocardial inflammation and nests of parasites at autopsy. He described sudden cardiac death associated with arrhythmias in 1911, and its association with complete AV block detected by Jacquet's polygraph as Chagas reported in 1912. Chagas showed the presence of myocardial fibrosis underlying the clinical picture of CCHD in 1916, he presented a full characterization of the clinical aspects of CCHD in 1922. In 1928, Chagas detected fibrosis of the conductive system, and pointed out the presence of marked cardiomegaly at the chest X-Ray associated with minimal symptomatology. The use of serological reaction to diagnose CCHD was put into clinical practice in 1936, after Chagas' death, which along with the 12-lead ECG, revealed the epidemiological importance of CCHD in 1945. In 1953, the long period between initial infection and appearance of CCHD was established, whereas the annual incidence of CCHD from patients with the indeterminate form of the disease was established in 1956. The use of heart catheterization in 1965, exercise stress testing in 1973, Holter monitoring in 1975, Electrophysiologic testing in 1973, echocardiography in 1975, endomyocardial biopsy in 1981, and Magnetic Resonance Imaging in 1995, added to the fundamental clinical aspects of CCHD as described by Carlos Chagas. PMID- 27223645 TI - Association of oligodendrocytes differentiation regulator gene DUSP15 with autism. AB - OBJECTIVES: Autism is a pervasive neurodevelopmental disorder with high heritability. Genetic factors play crucial roles in the aetiology of autism. Dual specificity phosphatase 15 (DUSP15) has been recognised as a key regulator gene for oligodendrocytes differentiation. A previous study detected one de novo missense variant (p.Thr107Met) with probable deleterious function in exon 6 of DUSP15 among patients with autism. Therefore, we sequenced this mutation in autistic children and performed an association analysis between DUSP15 polymorphisms and autism. METHODS: We performed a case-control study between 255 children affected with autism and 427 healthy controls. Four tag-single nucleotide polymorphisms (SNPs) were selected. These SNPs and the previously reported mutation in exon 6 of DUSP15 were genotyped via Sanger sequencing. RESULTS: Our results showed that rs3746599 was significantly associated with autism under allelic, additive and dominant models, respectively (chi2 = 9.699, P = 0.0018; chi2 = 16.224, P = 0.001; chi2 = 7.198, P = 0.007). The association remained significant after Bonferroni correction and permutation tests (n = 10,000). We did not detect the missense variant p.Thr107Met reported in previous studies. However, a de novo missense variant of DUSP15 (p.Ala56Thr) with a probable disease-causing effect was detected in one autistic child while absent in healthy controls. CONCLUSIONS: Our findings initially suggest that DUSP15 might be a susceptibility gene for autism in Chinese Han population. PMID- 27223646 TI - The Usability and Acceptability of an Adolescent mHealth HIV/STI and Drug Abuse Preventive Intervention in Primary Care. AB - Human Immunodeficiency Virus (HIV)/sexually transmitted infection (STI) risk behaviors among adolescents remain significant public health concerns. Shifts in policy and advances in technology provide opportunities for researchers and clinicians to deliver and evaluate mobile-health (mHealth) prevention programs in primary care, however, research is limited. This study assessed the usability and acceptability of Storytelling 4 Empowerment-a mHealth HIV/STI and drug abuse preventive intervention app-among adolescents in primary care. Informed by principles of community-based participatory research, we recruited a purposive sample of 30 adolescents from a youth-centered community health care clinic in Southeast Michigan. The study sample is primarily African American and female. Adolescents who participated in the Storytelling 4 Empowerment intervention assessed its usability and acceptability, and self-reported their HIV/STI risk behaviors. We used a multiple-methods approach. Adolescents reported high acceptability of the content, process, and format of Storytelling 4 Empowerment, as evidenced by qualitative data and mean scores from the Session Evaluation Form for the HIV/STI and Alcohol/Drug content, overall Storytelling 4 Empowerment intervention, and Client Satisfaction Questionnaire-8. Findings indicate that Storytelling 4 Empowerment is acceptable among adolescents in primary care. A next step is to examine the effect of Storytelling 4 Empowerment on adolescent sexual risk and drug use behaviors and HIV/STI testing. PMID- 27223647 TI - Which are the most common thrombophilic genetic nucleotide polymorphisms in infertile women undergoing an IVF cycle? AB - INTRODUCTION: Thrombophilia is considered one of the causes of infertility, especially after repeated failures of IVF techniques. The aim of this work is to evaluate the incidence of thrombophilia in women who underwent IVF cycles and assess the outcome of the techniques. METHODS: In vivo study. The study sample was composed of 262 women undergoing a fresh cycle of in vitro fertilization (IVF) cycle of Intracytoplasmatic Sperm Injection (ICSI) from July 2012 to December 2014 in the Center of Physiopathology of Human Reproduction. Amongst these patients, we have selected 96 patients with indication for thrombophilia screening. RESULTS: Thrombophilia screening detects that only 8% (n = 8) of the patients was negative to all the studied mutations, while the remaining 92% (n = 88) was positive to at least one mutation. The most common mutations were MTHFR gene (C677T) (91,84%), ACE gene (54,88%) and PAI-1 gene (69,44%). CONCLUSION: Our results showed an increased frequency of genetic nucleotide polymorphisms in women reporting failures in IVF techniques. Differently from scientific literature data, in our work, the most frequent mutation affects the enzyme gene MTHFR, particularly the C667T mutation; on the other side, mutations of factor V and II are less common. PMID- 27223648 TI - Yielding the yield-stress analysis: a study focused on the effects of elasticity on the settling of a single spherical particle in simple yield-stress fluids. AB - The sedimentation of a single particle in materials that exhibit simultaneously elastic, viscous and plastic behavior is examined in an effort to explain phenomena that contradict the nature of purely yield-stress materials. Such phenomena include the loss of the fore-and-aft symmetry with respect to an isolated settling particle under creeping flow conditions and the appearance of the "negative wake" behind it. Despite the fact that similar observations have been reported in studies involving viscoelastic fluids, researchers conjectured that thixotropy is responsible for these phenomena, as the aging of yield-stress materials is another common feature. By means of transient calculations, we study the effect of elasticity on both the fluidized and the solid phase. The latter is considered to behave as an ideal Hookean solid. The material properties of the model are determined under the isotropic kinematic hardening framework via Large Amplitude Oscillatory Shear (LAOS) measurements. In this way, we are able to predict accurately the unusual phenomena observed in experiments with simple yield-stress materials, irrespective of the appearance of slip on the particle surface. Viscoelasticity favors the formation of intense shear and extensional stresses downstream of the particle, significantly changing the entrapment mechanism in comparison to that observed in viscoplastic fluids. Therefore, the critical conditions under which the entrapment of the particle occurs deviate from the well-known criterion established theoretically by Beris et al. (1985) and verified experimentally by Tabuteau et al. (2007) for similar materials under conditions that elastic effects are negligible. Our predictions are in quantitative agreement with published experimental results by Holenberg et al. (2012) on the loss of the fore-aft symmetry and the formation of the negative wake in Carbopol with well-characterized rheology. Additionally, we propose simple expressions for the Stokes drag coefficient, as a function of the gravity number, Yg (related to the Bingham number), for different levels of elasticity and for its critical value, under which entrapment of particles occurs. These criteria are in agreement with the results found in the recent work by Ahonguio et al. (2014). Finally, we propose a method to quantify experimentally the elastic effects in viscoplastic particulate systems. PMID- 27223649 TI - Unraveling Site-Specific and Combinatorial Histone Modifications Using High Resolution Mass Spectrometry in Histone Deacetylase Mutants of Fission Yeast. AB - Histone deacetylases (HDACs) catalyze the removal of acetylation marks from lysine residues on histone and nonhistone substrates. Their activity is generally associated with essential cellular processes such as transcriptional repression and heterochromatin formation. Interestingly, abnormal activity of HDACs has been reported in various types of cancers, which makes them a promising therapeutic target for cancer treatment. In the current study, we aim to understand the mechanisms underlying the function of HDACs using an in-depth quantitative analysis of changes in histone acetylation levels in Schizosaccharomyces pombe (S. pombe) lacking major HDAC activities. We employed a targeted quantitative mass spectrometry approach to profile changes of acetylation and methylation at multiple lysine residues on the N-terminal tail of histones H3 and H4. Our analyses identified a number of histone acetylation sites that are significantly affected by S. pombe HDAC mutations. We discovered that mutation of the Class I HDAC known as Clr6 causes a major increase in the abundance of triacetylated H4 molecules at K5, K8, and K12. A clr6-1 hypomorphic mutation also increased the abundance of multiple acetyl-lysines in histone H3. In addition, our study uncovered a few crosstalks between histone acetylation and methylation upon deletion of HDACs Hos2 and Clr3. We anticipate that the results from this study will greatly improve our current understanding of the mechanisms involved in HDAC mediated gene regulation and heterochromatin assembly. PMID- 27223650 TI - Serological based monitoring of a cohort of patients with chronic Chagas disease treated with benznidazole in a highly endemic area of northern Argentina. AB - This study aimed to evaluate well-documented diagnostic antigens, named B13, 1F8 and JL7 recombinant proteins, as potential markers of seroconversion in treated chagasic patients. Prospective study, involving 203 patients treated with benznidazole, was conducted from endemic areas of northern Argentina. Follow-up was possible in 107 out of them and blood samples were taken for serology and PCR assays before and 2, 3, 6, 12, 24 and 36 months after treatment initiation. Reactivity against Trypanosoma cruzi lysate and recombinant antigens was measured by ELISA. The rate of decrease of antibody titers showed nonlinear kinetics with an abrupt drop within the first three months after initiation of treatment for all studied antigens, followed by a plateau displaying a low decay until the end of follow-up. At this point, anti-B13, anti-1F8 and anti-JL7 titers were relatively close to the cut-off line, while anti-T. cruzi antibodies still remained positive. At baseline, 60.8% (45/74) of analysed patients tested positive for parasite DNA by PCR and during the follow-up period in 34 out of 45 positive samples (75.5%) could not be detected T. cruzi DNA. Our results suggest that these antigens might be useful as early markers for monitoring antiparasitic treatment in chronic Chagas disease. PMID- 27223651 TI - Primary dengue haemorrhagic fever in patients from northeast of Brazil is associated with high levels of interferon-beta during acute phase. AB - Dengue is an acute febrile disease caused by the mosquito-borne dengue virus (DENV) that according to clinical manifestations can be classified as asymptomatic, mild or severe dengue. Severe dengue cases have been associated with an unbalanced immune response characterised by an over secretion of inflammatory cytokines. In the present study we measured type I interferon (IFN I) transcript and circulating levels in primary and secondary DENV infected patients. We observed that dengue fever (DF) and dengue haemorrhagic fever (DHF) patients express IFN-I differently. While DF and DHF patients express interferon alpha similarly (52,71 +/- 7,40 and 49,05 +/- 7,70, respectively), IFN- beta were associated with primary DHF patients. On the other hand, secondary DHF patients were not able to secrete large amounts of IFN- beta which in turn may have influenced the high-level of viraemia. Our results suggest that, in patients from our cohort, infection by DENV serotype 3 elicits an innate response characterised by higher levels of IFN- beta in the DHF patients with primary infection, which could contribute to control infection evidenced by the low-level of viraemia in these patients. The present findings may contribute to shed light in the role of innate immune response in dengue pathogenesis. PMID- 27223652 TI - Control programme for cystic echinococcosis in Uruguay. AB - Cystic echinococcosis is a highly endemic parasitic zoonosis that is present in the Southern Cone countries of America. For several decades, various prevention and control programmes have been implemented in different countries and regions, with varying results. In Uruguay, a new control programme was implemented in 2006 that employed new strategies for canine diagnosis and treatment, dog population control, diagnosis in humans, epidemiological surveillance, and health education, including community participation. The control programme in Uruguay addresses the control and surveillance of the disease from a holistic perspective based on Primary Health Care, which has strengthened the community's participation in developing and coordinating activities in an interdisciplinary manner. Similarly, the control programme that is currently implemented is based on a risk-focused approach. The surveillance and control measures were focused on small villages and extremely poor urban areas. In this study, the strategies used and the results obtained from 2008-2013 are analysed and discussed. PMID- 27223653 TI - Experimental infection of Rio Mamore hantavirus in Sigmodontinae rodents. AB - This study shows an experimental spillover infection of Sigmodontinae rodents with Rio Mamore hantavirus (RIOMV). Necromys lasiurus and Akodon sp were infected with 103 RNA copies of RIOMV by intraperitoneal administration. The viral genome was detected in heart, lung, and kidney tissues 18 days after infection (ai), and viral excretion in urine and faeces began at four and six ai, respectively. These results reveal that urine and faeces of infected rodents contain the virus for at least 18 days. It is possible that inhaled aerosols of these excreta could transmit hantavirus to humans and other animals. PMID- 27223654 TI - A non-enteric adenovirus A12 gastroenteritis outbreak in Rio de Janeiro, Brazil. AB - A gastroenteritis outbreak that occurred in 2013 in a low-income community in Rio de Janeiro was investigated for the presence of enteric viruses, including species A rotavirus (RVA), norovirus (NoV), astrovirus (HAstV), bocavirus (HBoV), aichivirus (AiV), and adenovirus (HAdV). Five of nine stool samples (83%) from patients were positive for HAdV, and no other enteric viruses were detected. Polymerase chain reaction products were sequenced and subjected to phylogenetic analysis, which revealed four strains and one strain of non-enteric HAdV-A12 and HAdV-F41, respectively. The HAdV-A12 nucleotide sequences shared 100% nucleotide similarity. Viral load was assessed using a TaqMan real-time PCR assay. Stool samples that were positive for HAdV-A12 had high viral loads (mean 1.9 X 107 DNA copies/g stool). All four patients with HAdV-A12 were < 25 months of age and had symptoms of fever and diarrhoea. Evaluation of enteric virus outbreaks allows the characterisation of novel or unique diarrhoea-associated viruses in regions where RVA vaccination is routinely performed. PMID- 27223655 TI - Leprosy in children and adolescents under 15 years old in an urban centre in Brazil. AB - This original study describes the intra-urban distribution of cases of leprosy in residents under 15 years old in Salvador, Bahia, Brazil; the study also identifies the environment in which Mycobacterium leprae is being transmitted. The cases were distributed by operational classification, clinical forms, type of contact and the addresses were geo-referenced by neighborhood. Between 2007 and 2011, were reported 145 cases of leprosy in target population living in Salvador, corresponding to detection rates of 6.21, 6.14, 5.58, 5.41 and 6.88/100,000 inhabitants, respectively. The spatial distribution of the disease was focal. Of the 157 neighborhoods of Salvador, 44 (28.6%) notified cases of leprosy and in 22 (50%) of these were detected more than 10 cases per 100,000 inhabitants. The infectious forms were found in 40% of cases. Over 90% of cases had been living in Salvador for more than five years. Overall, 52.6% reported having had contact with another infected individual inside the household and 25% in their social circle. In Salvador, M. leprae transmission is established. The situation is a major concern, since transmission is intense at an early age, indicating that this endemic disease is expanding and contacts extend beyond individual households. PMID- 27223656 TI - On the computation of a retina resistivity profile for applications in multi scale modeling of electrical stimulation and absorption. AB - This study proposes a methodology for computationally estimating resistive properties of tissue in multi-scale computational models, used for studying the interaction of electromagnetic fields with neural tissue, with applications to both dosimetry and neuroprosthetics. Traditionally, models at bulk tissue- and cellular-level scales are solved independently, linking resulting voltage from existing resistive tissue-scale models as extracellular sources to cellular models. This allows for solving the effects that external electric fields have on cellular activity. There are two major limitations to this approach: first, the resistive properties of the tissue need to be chosen, of which there are contradicting measurements in literature; second, the measurements of resistivity themselves may be inaccurate, leading to the mentioned contradicting results found across different studies. Our proposed methodology allows for constructing computed resistivity profiles using knowledge of only the neural morphology within the multi-scale model, resulting in a practical implementation of the effective medium theory; this bypasses concerns regarding the choice of resistive properties and accuracy of measurement setups. A multi-scale model of retina is constructed with an external electrode to serve as a test bench for analyzing existing and resulting resistivity profiles, and validation is presented through the reconstruction of a published resistivity profile of retina tissue. Results include a computed resistivity profile of retina tissue for use with a retina multi-scale model used to analyze effects of external electric fields on neural activity. PMID- 27223657 TI - Perspectives of Suicide Bereaved Individuals on Military Suicide Decedents' Life Stressors and Male Gender Role Stress. AB - The objective of this study was to pilot the newly developed Male Gender Role Stressor Inventory (MGRSI) in military suicide bereaved (i.e., decedents' family members and significant others) and to determine the association between Male Gender Role Stress (MGRS) and other life stressors observed by survivors. Sixty five survivors attending a national survivor seminar completed original surveys, reporting demographic information about themselves and the decedent and observations of the decedent's life stressors during the 1-month and 1-year periods prior to death. The MGRSI obtained acceptable internal reliability (alpha = .76) and indicated that factors including honor, strength, and achievement were the most commonly reported sources of MGRS. Correlational and regression analyses revealed that legal- and trauma-related stressors 1 month prior to suicide were significantly associated with MGRSI score. MGRS may contribute to a better understanding of military male suicide. The Department of Defense and the Veterans Administration may benefit from suicide prevention programs targeting rigid male gender role beliefs and male-specific stressors. PMID- 27223659 TI - Doctor to Doctor. PMID- 27223660 TI - Readers' Forum. PMID- 27223658 TI - Hydrophilic trans-Cyclooctenylated Noncanonical Amino Acids for Fast Intracellular Protein Labeling. AB - Introduction of bioorthogonal functionalities (e.g., trans-cyclooctene-TCO) into a protein of interest by site-specific genetic encoding of non-canonical amino acids (ncAAs) creates uniquely targetable platforms for fluorescent labeling schemes in combination with tetrazine-functionalized dyes. However, fluorescent labeling of an intracellular protein is usually compromised by high background, arising from the hydrophobicity of ncAAs; this is typically compensated for by hours-long washout to remove excess ncAAs from the cellular interior. To overcome these problems, we designed, synthesized, and tested new, hydrophilic TCO-ncAAs. One derivative, DOTCO-lysine was genetically incorporated into proteins with good yield. The increased hydrophilicity shortened the excess ncAA washout time from hours to minutes, thus permitting rapid labeling and subsequent fluorescence microscopy. PMID- 27223662 TI - Frontiers of gallstone therapy. PMID- 27223661 TI - Gallstone problems. PMID- 27223664 TI - Gallstones. PMID- 27223665 TI - Evaluation of type II thyroplasty on phonatory physiology in an excised canine larynx model. AB - OBJECTIVES/HYPOTHESIS: Type II thyroplasty is an alternative treatment for spasmodic dysphonia, addressing hyperadduction by incising and lateralizing the thyroid cartilage. We quantified the effect of lateralization width on phonatory physiology using excised canine larynges. METHODS: Normal closure, hyperadduction, and type II thyroplasty (lateralized up to 5 mm at 1-mm increments with hyperadducted arytenoids) were simulated in excised larynges (N = 7). Aerodynamic, acoustic, and videokymographic data were recorded at three subglottal pressures relative to phonation threshold pressure (PTP). One-way repeated measures analysis of variance assessed effect of condition on aerodynamic parameters. Random intercepts linear mixed effects models assessed effects of condition and subglottal pressure on acoustic and videokymographic parameters. RESULTS: PTP differed across conditions (P < .001). Condition affected percent shimmer (P < .005) but not percent jitter. Both pressure (P < .03) and condition (P < .001) affected fundamental frequency. Pressure affected vibratory amplitude (P < .05) and intrafold phase difference (P < .05). Condition affected phase difference between the vocal folds (P < .001). CONCLUSIONS: Hyperadduction increased PTP and worsened perturbation compared to normal, with near normal physiology restored with 1-mm lateralization. Further lateralization deteriorated voice quality and increased PTP. Acoustic and videokymographic results indicate that normal physiologic relationships between subglottal pressure and vibration are preserved at optimal lateralization width, but then degrade with further lateralization. The 1-mm optimal width observed here is due to the small canine larynx size. Future human trials would likely demonstrate a greater optimal width, with patient-specific value potentially determined based on larynx size and symptom severity. LEVEL OF EVIDENCE: NA Laryngoscope, 2016 127:396-404, 2017. PMID- 27223666 TI - Exploratory Phase II Trial to Evaluate the Safety and the Antiepileptic Effect of Pitolisant (BF2.649) in Refractory Partial Seizures, Given as Adjunctive Treatment During 3 Months. AB - BACKGROUND: Pitolisant (BF2.649) is a nonimidazole histamine 3 receptor antagonist. In previous animal studies, it has been shown that pitolisant might be helpful in chronic seizure treatment of both partial and generalized epilepsies. The present study is a multicenter, national, pragmatic, noncomparative, open-label, exploratory phase II trial. It is the first reported study of the clinical effects of pitolisant in human epilepsy. OBJECTIVE: The goal of this trial was to explore the antiepileptic effect of 3 different doses of pitolisant (20, 30, and 40 mg once daily) in patients presenting partial seizure onset despite therapy with adequate dose of 1 to 3 appropriate antiepileptic drugs. METHODS: The study has been conducted in 6 study sites in France between 2005 and 2006. The primary end point was the proportion of responders having a seizure rate decrease by at least 50%. A larger clinical trial could be started according to the results. An interim analysis was planned in the protocol to decide if the study should be continued or not according to the efficacy and safety results. Descriptive statistics were used for the analysis. RESULTS: An initial goal of 40 patients included had been planned; 23 were finally included. Pitolisant was well tolerated and achieved a clinical response in one third of patients after 3 months of treatment. CONCLUSIONS: Despite encouraging data, there is no evidence for the efficacy of the drug for the regimen that was used, but no firm conclusions can be drawn because the number of included subject was small and the study was not placebo controlled. PMID- 27223667 TI - Donepezil as Add-on Treatment for Resistant Obsessive-Compulsive Disorder: Retrospective Case Series. AB - Obsessive-compulsive disorder (OCD) is one of the most common and disabling psychiatric disorders. Treatment with serotonin selective reuptake inhibitors (SSRIs) shows significant improvement; however, residual symptoms remain in most patients despite continued adequate OCD treatment. For patients exhibiting partial or no response to multiple SSRIs, augmentation strategies are usually recommended. Here, we introduce a retrospective consecutive sample of aged patients with resistant OCD treated with donepezil augmentation to regular pharmacotherapy. METHODS: Ten patients (5 males, 5 females; mean [SD] age, 63.8 [7.5] years), suffering from resistant OCD, were openly treated with donepezil 10 mg/d as add-on. Efficacy was assessed at baseline and after 8 weeks of treatment using the Yale-Brown Obsessive Compulsive Scale, Clinical Global Impression Severity, and Clinical Global Impression-Improvement. RESULTS: The treatment was generally well tolerated without adverse events. In all patients, mean (SD) Yale Brown Obsessive Compulsive Scale scores diminished from 27.3 (4.3) points at baseline to 16.9 (4.5) points at week 8 (P < 0.0001). Mean (SD) Clinical Global Impression-Severity scores diminished from 5.5 (0.7) points to 3.1 (1.0) points, (P < 0.001). According to Clinical Global Impression-Improvement, 7 patients demonstrated "very much" or "much" improvement and 3 patients did not demonstrate any improvement. CONCLUSIONS: Donepezil was a well-tolerated add-on to regular pharmacotherapy in treatment-resistant OCD patients in this small cases series. Donepezil could be a promising optional therapy for patients suffering from resistant OCD, but further randomized controlled studies are necessary. PMID- 27223668 TI - Efficacy and Safety of Levosulpiride Versus Haloperidol Injection in Patients With Acute Psychosis: A Randomized Double-Blind Study. AB - BACKGROUND: Injectable antipsychotics are frequently required for controlling agitation and aggression in acute psychosis. No study has examined the use of injectable levosulpiride for this indication. OBJECTIVE: To compare the efficacy and safety of injectable levosulpiride and haloperidol in patients with acute psychosis. METHODS: This was a randomized, double-blind, parallel-group study in which 60 drug-naive patients having acute psychosis were randomly assigned to receive either intramuscular haloperidol (10-20 mg/d) or levosulpiride (25-50 mg/d) for 5 days. All patients were rated on Brief Psychiatric Rating Scale (BPRS), Overt Agitation Severity Scale (OASS), Overt Aggression Scale-Modified (OAS-M) scores, Simpson Angus Scale (SAS), and Barnes Akathisia Rating Scale (BARS). RESULTS: Repeated-measures ANOVA for BPRS scores showed significant effect of time (P < 0.001) and a trend toward greater reduction in scores in haloperidol group as shown by group * time interaction (P = 0.076). Repeated measures ANOVA for OASS showed significant effect of time (P < 0.001) but no group * time interaction. Repeated-measures ANOVA for OAS-M scores showed significant effect of time (P < 0.001) and greater reduction in scores in haloperidol group as shown by group * time interaction (P = 0.032). Lorazepam requirement was much lower in haloperidol group as compared with those receiving levosulpiride (P = 0.022). Higher rates of akathisia and extrapyramidal symptoms were noted in the haloperidol group. CONCLUSIONS: Haloperidol was more effective than levosulpiride injection for psychotic symptoms, aggression, and severity of agitation in acute psychosis, but extrapyramidal adverse effects were less frequent with levosulpiride as compared with those receiving haloperidol. PMID- 27223669 TI - One-Pot Synthesis of alpha-Amino Acids through Carboxylation of Ammonium Ylides with CO2 Followed by Alkyl Migration. AB - A simple, yet powerful protocol for alpha-amino acid synthesis using carbon dioxide (CO2) was developed. alpha-Amino silanes could undergo four successive reactions (formation of ammonium salt, carboxylation, esterification, and 2,3- or 1,2-Stevens rearrangement) in the presence of allylic or benzylic halides under a CO2 atmosphere (1 atm). It is noteworthy that carboxylation at the position adjacent to a nitrogen atom proceeded via an ammonium ylide intermediate under mild conditions. PMID- 27223670 TI - Super elongation complex contains a TFIIF-related subcomplex. AB - Super elongation complex (SEC) belongs to a family of RNA polymerase II (Pol II) elongation factors that has similar properties as TFIIF, a general transcription factor that increases the transcription elongation rate by reducing pausing. Although SEC has TFIIF-like functional properties, it apparently lacks sequence and structural homology. Using HHpred, we find that SEC contains an evolutionarily related TFIIF-like subcomplex. We show that the SEC subunit ELL interacts with the Pol II Rbp2 subunit, as expected for a TFIIF-like factor. These findings suggest a new model for how SEC functions as a Pol II elongation factor and how it suppresses Pol II pausing. PMID- 27223672 TI - Load Sharing Among Collateral Ligaments, Articular Surfaces, and the Tibial Post in Constrained Condylar Knee Arthroplasty. AB - The normal knee joint maintains stable motion during activities of daily living. After total knee arthroplasty (TKA), stability is achieved by the conformity of the bearing surfaces of the implant components, ligaments, and constraint structures incorporated in the implant design. The large, rectangular tibial post in constrained condylar knee (CCK) arthroplasty, often used in revision surgery, provides added stability, but increases susceptibility to polyethylene wear as it contacts the intercondylar box on the femoral component. We examined coronal plane stability to understand the relative contributions of the mechanisms that act to stabilize the CCK knee under varus-valgus loading, namely, load distribution between the medial and lateral condyles, contact of the tibial post with the femoral intercondylar box, and elongation of the collateral ligaments. A robot testing system was used to determine the joint stability in human cadaveric knees as described by the moment versus angular rotation behavior under varus valgus moments at 0 deg, 30 deg, and 90 deg of flexion. The angular rotation of the CCK knee in response to the physiological moments was limited to <=1.5 deg. The primary stabilizing mechanism was the redistribution of the contact force on the bearing surfaces. Contact between the tibial post and the femoral box provided a secondary stabilizing mechanism after lift-off of a condyle had occurred. Collateral ligaments provide limited stability because little ligament elongation occurred under such small angular rotations. Compressive loads applied across the knee joint, such as would occur with the application of muscle forces, enhanced the ability of the bearing surfaces to provide resisting internal varus valgus moment and, thus, reduced the exposure of the tibial post to the external varus-valgus loads. Our results suggest that the CCK stability can be refined by considering both the geometry of the bearing surfaces and the contacting geometry between the tibial post and femoral box. PMID- 27223673 TI - The International Telecommunications Union and Telemedicine. PMID- 27223671 TI - Emerging immunotherapies for glioblastoma. AB - INTRODUCTION: Immunotherapy for brain cancer has evolved dramatically over the past decade, owed in part to our improved understanding of how the immune system interacts with tumors residing within the central nervous system (CNS). Glioblastoma (GBM), the most common primary malignant brain tumor in adults, carries a poor prognosis (<15 months) and only few advances have been made since the FDA's approval of temozolomide (TMZ) in 2005. Importantly, several immunotherapies have now entered patient trials based on promising preclinical data, and recent studies have shed light on how GBM employs a slew of immunosuppressive mechanisms that may be targeted for therapeutic gain. Altogether, accumulating evidence suggests immunotherapy may soon earn its keep as a mainstay of clinical management for GBM. AREAS COVERED: Here, we review cancer vaccines, checkpoint inhibitors, adoptive T-cell immunotherapy, and oncolytic virotherapy. EXPERT OPINION: Checkpoint blockade induces antitumor activity by preventing negative regulation of T-cell activation. This platform, however, depends on an existing frequency of tumor-reactive T cells. GBM tumors are exceptionally equipped to prevent this, occupying low levels of antigen expression and elaborate mechanisms of immunosuppression. Therefore, checkpoint blockade may be most effective when used in combination with a DC vaccine or adoptively transferred tumor-specific T cells generated ex vivo. Both approaches have been shown to induce endogenous immune responses against tumor antigens, providing a rationale for use with checkpoint blockade where both primary and secondary responses may be potentiated. PMID- 27223674 TI - Malignant Peripheral Nerve Sheath Tumor of the Jugular Foramen. PMID- 27223675 TI - Prognostic and Evolutive Factors of Tinnitus Triggered by Sudden Sensorineural Hearing Loss. AB - INTRODUCTION: The association between sudden sensorineural hearing loss (SSNHL) and tinnitus is frequent. Its correlation with the auditory prognosis remains controversial. The objective of the study is to evaluate tinnitus of which onset is concurrent with SSNHL and analyze it as a prognostic factor and its correlation with hearing recovery. MATERIALS AND METHODS: A prospective cohort study was conducted with 30 patients with SSNHL. Serial audiometry was performed and the Tinnitus Handicap Inventory (THI) was applied at the initial consultation and after treatment. RESULTS: Tinnitus had an incidence of 93.3%, with an initial mean THI of 63.6%. The mean decrease in THI was significant in all scale domains. However, there was no statistically significant difference between the degrees of tinnitus and hearing loss, as well as between hearing recovery percentage in relation to the degree of tinnitus. The correlation of THI gain with the hearing recovery rate was negative (the greater the decrease in the level of tinnitus discomfort, the greater the hearing recovery rate), being significant only in the emotional domain of THI, but showing a poor correlation. DISCUSSION: There was a reduction in the level of tinnitus discomfort, as measured by THI, after treatment of SSNHL. There is a correlation between tinnitus and hearing improvement in patients with SSNHL only in the emotional domain of THI, but this correlation is considered poor. The degree of tinnitus severity as measured by THI was not proportional to the hearing loss and is not a prognostic factor for hearing improvement. PMID- 27223676 TI - Functional Testing of Subcutaneous Piezoelectrically Actuated Hearing Aid: Comparison With BAHA and Potential for Treating Single-sided Deafness. AB - OBJECTIVE: To compare the performance of a subcutaneous piezoelectrically actuated hearing aid (SPAHA) with the bone-anchored hearing aid (BAHA) and assess its effectiveness as a treatment option for conductive loss and single-sided deafness (SSD). BACKGROUND: To validate the use of the SPAHA as a bone conduction implant, its performance was compared with a widely used bone conduction implant, the BAHA. Maximum dynamic range, power consumed to deliver standard speech signals and total harmonic distortion (THD) was assessed. The transcranial attenuation was also measured to assess the SPAHA's potential to treat SSD. METHOD: Functional testing of the SPAHA and BAHA was conducted using cadaver heads. Ipsilateral and contralateral promontory velocity and the power consumption by the devices were measured at 111 different frequencies in the range of 200 to 9600 Hz. Performance metrics were derived from these measurements. RESULT: The maximum dynamic range for SPAHA was within 10 dB of that of BAHA. The THD for the SPAHA was at most 3%, slightly better than the BAHA. The power consumption by the SPAHA, whereas highly variable, was not statistically different than that of the BAHA. Transcranical attenuation in case of SPAHA was 5 to 10 dB across the measured frequency range. CONCLUSION: From observed dynamic range and THD, the speech quality delivered by the SPAHA should equal or exceed that delivered by the BAHA. To attain equivalent hearing sensation at lower frequencies, the drive voltage for SPAHA would have to be significantly higher than that for BAHA. For typical speech inputs the power consumption requirements of the SPAHA should be roughly equal to those of the BAHA. Given its performance at high frequencies, the SPAHA seems well-suited to treating SSD. PMID- 27223677 TI - Sudden Pediatric Hearing Loss: Comparing the Results of Combined Treatment (Intratympanic Dexamethasone and Systemic Steroids) With Systemic Steroid Treatment Alone. AB - OBJECTIVE: The aim of the present study was to compare hearing improvements obtained with combined intratympanic and systemic steroid therapy, and systemic steroid therapy alone in pediatric patients with idiopathic sudden sensorineural hearing loss (SSHL). STUDY DESIGN: Retrospective. SETTING: Tertiary referral hospital. PATIENTS: Pediatric patients with SSHL. INTERVENTIONS: The patients were divided into two groups, based on the method of steroid administration: Group 1 (systemic therapy group, n = 23) was treated with oral methylprednisolone alone whereas Group 2 (combination therapy group, n = 26) was treated with combination of oral methylprednisolone and intratympanic dexamethasone injections. MAIN OUTCOME MEASURES: Pre- and post-treatment audiograms were compared with pure-tone averages (PTAs) in each group. Two treatment groups were also compared. The final hearing assessment was performed 4 weeks after completion of the treatment. RESULTS: The mean PTAs before and after the treatment were 61.86 +/- 23.99 and 42.65 +/- 32.69 dB in Group 1 (p = 0.001), and 70.07 +/- 29.74 and 38.85 +/- 32.28 dB in Group 2 (p = 0.001). Pure-tone gain was 20.00 +/- 15.02 dB in Group 1, and 31.69 +/- 28.29 dB in Group 2. Comparison of two groups for post-treatment PTA and pure-tone gains did not yield any statistically significant differences (p = 0.388 and p = 0.132, respectively). CONCLUSION: Significant hearing improvement may be obtained with use of systemic steroids alone, or simultaneous administration of systemic and intratympanic steroids in pediatric patients with SSHL. Although we did not have a control group, two treatment options appear to offer similar hearing improvements in the pediatric age group higher than the rates obtained with placebo when previous studies in the literature are taken into account. PMID- 27223678 TI - Omics of Brucella: Species-Specific sRNA-Mediated Gene Ontology Regulatory Networks Identified by Computational Biology. AB - Brucella is an intracellular bacterium that causes the zoonotic infectious disease, brucellosis. Brucella species are currently intensively studied with a view to developing novel global health diagnostics and therapeutics. In this context, small RNAs (sRNAs) are one of the emerging topical areas; they play significant roles in regulating gene expression and cellular processes in bacteria. In the present study, we forecast sRNAs in three Brucella species that infect humans, namely Brucella melitensis, Brucella abortus, and Brucella suis, using a computational biology analysis. We combined two bioinformatic algorithms, SIPHT and sRNAscanner. In B. melitensis 16M, 21 sRNA candidates were identified, of which 14 were novel. Similarly, 14 sRNAs were identified in B. abortus, of which four were novel. In B. suis, 16 sRNAs were identified, and five of them were novel. TargetRNA2 software predicted the putative target genes that could be regulated by the identified sRNAs. The identified mRNA targets are involved in carbohydrate, amino acid, lipid, nucleotide, and coenzyme metabolism and transport, energy production and conversion, replication, recombination, repair, and transcription. Additionally, the Gene Ontology (GO) network analysis revealed the species-specific, sRNA-based regulatory networks in B. melitensis, B. abortus, and B. suis. Taken together, although sRNAs are veritable modulators of gene expression in prokaryotes, there are few reports on the significance of sRNAs in Brucella. This report begins to address this literature gap by offering a series of initial observations based on computational biology to pave the way for future experimental analysis of sRNAs and their targets to explain the complex pathogenesis of Brucella. PMID- 27223679 TI - Optimizing the Multivalent Binding of the Bacterial Lectin LecA by Glycopeptide Dendrimers for Therapeutic Purposes. AB - Bacterial lectins are nonenzymatic sugar-binding proteins involved in the formation of biofilms and the onset of virulence. The weakness of individual sugar-lectin interactions is compensated by the potentially large number of simultaneous copies of such contacts, resulting in high overall sugar-lectin affinities and marked specificities. Therapeutic compounds functionalized with sugar residues can compete with the host glycans for binding to lectins only if they are able to take advantage of this multivalent binding mechanism. Glycopeptide dendrimers, featuring treelike topologies with sugar moieties at their leaves, have already shown great promise in this regard. However, optimizing the dendrimers' amino acid sequence is necessary to match the dynamics of the lectin active sites with that of the multivalent ligands. This work combines long-time-scale coarse-grained simulations of dendrimers and lectins with a reasoned exploration of the dendrimer sequence space in an attempt to suggest sequences that could maximize multivalent binding to the galactose specific bacterial lectin LecA. These candidates are validated by simulations of mixed dendrimer/lectin solutions, and the effects of the dendrimers on lectin dynamics are discussed. This approach is an attractive first step in the conception of therapeutic compounds based on the dendrimer scaffold and contributes to the understanding of the various classes of multivalency that underpin the ubiquitous "sugar code". PMID- 27223680 TI - MicroRNA-197 Mediates the Overgrowth and Anti-Apoptotic Effects by Downregulating Insulin-Like Growth Factor-Binding Protein-3 During Nephroblastoma Tumorigenesis. AB - MiR-197 is frequently upregulated to induce a series of oncogenic effects, which is closely associated with poor survival and prognosis of multiple malignancies. However, the roles of miR-197 in tumorigenesis and the detailed molecular mechanism in Wilms tumor (WT) have rarely been reported. This study aimed to evaluate the expression of miR-197 in WT in vivo and the potential effects of miR 197 on the proliferation and apoptosis in SK-NEP-1 cells. A total of 15 patients with a pathologically confirmed diagnosis of WT and 15 paraneoplastic controls were enrolled. Real-time quantitative PCR (RT-qPCR) identified the upregulation of miR-197 and downregulation of insulin-like growth factors binding protein 3 (IGFBP3) in WT tissues in comparison with adjacent normal tissue (p < 0.001). CCK 8 and flow cytometry assay found that inhibition of miR-197 caused a significantly reduced proliferation along with a dramatically enhanced apoptosis of SK-NEP-1 cells (p < 0.01). IGFBP3 was overexpressed in SK-NEP-1 cells by pEGFP C1-IGFBP3 plasmid transfection. Overexpression of IGFBP3 suppressed the proliferation and induced the apoptosis of SK-NEP-1 cells (p < 0.01). Further study detected the decreased IGFBP3 expression with miR-197 mimics SK-NEP-1 cells and increased IGFBP3 expression with miR-197 inhibitor SK-NEP-1 cells compared with mock (p < 0.01). Dual luciferase reporter assay revealed a direct interaction between miR-197 and 3'-UTR site of IGFBP3. Overall, the above results indicated that miR-197 targeted IGFBP3 to induce the overgrowth and anti apoptotic effects of WT cells, which could promote nephroblastoma tumorigenesis. Therefore, miR-197 may be further assessed as a potential target for the treatment of WT. PMID- 27223681 TI - Opioid Pharmacokinetics #307. PMID- 27223683 TI - Uterine leiomyosarcoma - incidence, treatment, and the impact of morcellation. A nationwide cohort study. AB - INTRODUCTION: The risk of morcellation of occult uterine leiomyosarcomas (LMS) during laparoscopic procedures has been under scrutiny over recent years. The objective of this study was to assess the operative treatment performed in women with uterine LMS in Norway in 2000-2012, including the number of morcellated LMS. MATERIAL AND METHODS: Retrospective nationwide cohort study. The study participants were all women with histopathologically verified uterine LMS in Norway during 2000-2012. The data were collected from the Cancer Registry of Norway, National Patient Registry and medical records. RESULTS: There were 212 women diagnosed with uterine LMS in Norway in 2000-2012. Mean age at time of diagnosis was 58.1 years (SD +/- 12.5). The most frequent symptom in women suffering from LMS was abnormal uterine bleeding [110/212 (51.9%)]. LMS was histopathologically verified in 49/212 (23.1%) preoperatively. In 48/212 (22.6%), a malignant condition was suspected and they were treated accordingly. In 115/212 (54.2%), malignancy was not suspected at time of surgery and the women were treated according to the treatment protocol for fibroids. In only four patients was tissue retrieval by power morcellation conducted, accounting for 1.9% of all LMS cases. CONCLUSIONS: In more than 50% of women suffering from LMS, a malignant diagnosis was not confirmed or suspected prior to surgery. In our material, power morcellation of LMS has not lead to reduced survival. We suggest that power morcellators may be used in surgical treatment of selected cases of premenopausal women with symptomatic, presumed benign uterine leiomyomas. PMID- 27223684 TI - Using Health Information Technology to Foster Engagement: Patients' Experiences with an Active Patient Health Record. AB - Personal health records (PHRs) typically employ "passive" communication strategies, such as non-personalized medical text, rather than direct patient engagement in care. Currently there is a call for more active PHRs that directly engage patients in an effort to improve their health by offering elements such as personalized medical information, health coaches, and secure messaging with primary care providers. As part of a randomized clinical trial comparing "passive" with "active" PHRs, we explore patients' experiences with using an "active" PHR known as HealthTrak. The "passive" elements of this PHR included problem lists, medication lists, information about patient allergies and immunizations, medical and surgical histories, lab test results, health reminders, and secure messaging. The active arm included all of these elements and added personalized alerts delivered through the secure messaging platform to patients for services coming due based on various demographic features (including age and sex) and chronic medical conditions. Our participants were part of the larger clinical trial and were eligible if they had been randomized to the active PHR arm, one that included regular personalized alerts. We conducted focus group discussions on the benefits of this active PHR for patients who are at risk for cardiovascular disease. Forty-one patients agreed to participate and were organized into five separate focus group sessions. Three main themes emerged from the qualitatively analyzed focus groups: participants reported that the active PHR promoted better communication with providers; enabled them to more effectively partner with their providers; and helped them become more proactive about tracking their health information. In conclusion, patients reported improved communication, partnership with their providers, and a sense of self management, thus adding insights for PHR designers hoping to address low adoption rates and other patient barriers to the development and use of the technology. PMID- 27223685 TI - Glutathione maintenance is crucial for survival of melanocytes after exposure to rhododendrol. AB - Rhododendrol is a phenolic compound that shows a tyrosinase-dependent toxicity for melanocytes and occasionally induces a vitiligo-like skin depigmentation. The post-tyrosinase mechanisms determining melanocyte death or survival, however, are far from clear. Here, we find that rhododendrol treatment leads to a reduction in the levels of cellular glutathione but also induces a cellular antioxidant response that eventually increases glutathione levels. We further find that rhododendrol toxicity is enhanced when glutathione levels are experimentally reduced and alleviated when glutathione levels are increased. Hence, it appears that the size of the preexisting glutathione pool along with the capacity to supply glutathione via the antioxidant response determines whether melanocytes survive or die after rhododendrol exposure. It is conceivable, therefore, that rhododendrol-induced leukoderma depends on the capacity to maintain appropriate glutathione levels and that enhancement of glutathione levels may preserve a patient's melanocytes and potentially help in repigmentation. PMID- 27223686 TI - Nationwide survey of Helicobacter pylori treatment for children and adolescents in Japan. AB - BACKGROUND: To prevent gastric cancer, a test-and-treat strategy for Helicobacter pylori has been proposed. This retrospective study assessed the clinical features, efficacy and safety of treatment for H. pylori infection in children and adolescents. METHODS: Questionnaires concerning the clinical features and treatment of H. pylori in children and adolescents were sent to doctors in 2013. It included questions on patient background, H. pylori-associated disease, first- and second-line treatment, success or failure of eradication, resistance to antibiotics, and occurrence of adverse events. In 2014, serious adverse events associated with treatment were analyzed. RESULTS: Invitation letters and questionnaires were sent to 1097 doctors, of whom 409 (37.3%) participated. Finally, 332 patients (mean age, 11.6 +/- 3.4 years; male, n = 200) treated from 1997 to 2013 were analyzed. H. pylori-associated gastritis, iron deficiency anemia, and duodenal ulcer occurred most frequently. Success rates for first- and second-line treatments were 73.1% and 79.6%, respectively. Seventy-six H. pylori strains were analyzed for resistance to amoxicillin (AMPC) and clarithromycin (CAM), and 64 were analyzed for resistance to metronidazole (MNZ). CAM resistance was most frequent, occurring in 43.4% of patients; that of MNZ was 21.9%. Adverse events were observed in 13.8% of cases. In total, 587 cases of H. pylori infection were analyzed and no serious adverse events were observed. CONCLUSIONS: Treatment for H. pylori in children and adolescents is safe, but further studies on treatment regimens should be conducted to improve eradication rates and monitor increasing CAM resistance. PMID- 27223688 TI - Quantitative Nonlinear Contrast-Enhanced Ultrasound of the Breast. AB - OBJECTIVE: Breast cancer is the most frequent type of cancer among women (25% of all cancers). The angiogenic process that fuels the growth of tumors is a potential early indicator for differentiating between malignant and benign tumors. Recently, the use of microbubble-based contrast agents combined with ultrasound has allowed the development of contrast agent-specific imaging modes that provide visualization of tumor neovascularity. CONCLUSION: Contrast-enhanced Doppler, harmonic, and subharmonic imaging are some of the imaging modes that have been investigated for visualizing and quantifying the vascularity in breast tumors. PMID- 27223689 TI - The Effects of Music Intervention on Sleep Quality in Community-Dwelling Elderly. AB - OBJECTIVES: To examine the effects of music intervention on sleep quality in community-dwelling elderly people. DESIGN: Two-armed randomized controlled trial. SETTINGS: Four urban communities in Xi'an, China. PARTICIPANTS: People aged 60 years or older with poor sleep quality (Pittsburgh Sleep Quality Index [PSQI] score >7). INTERVENTIONS: All participants received one sleep hygiene education session and biweekly telephone calls. Each participant in the intervention group received an MP3 player with a music database. The participants selected the preferred music and listened for 30-45 minutes per night for 3 months. OUTCOME MEASURES: Sleep quality, the main study outcome, was measured by PSQI at baseline, 1 month, 2 months, and 3 months. RESULTS: Sixty-four elderly people with a mean age of 69.38 +/- 5.46 years were randomly assigned to the control group (n = 32) or the intervention group (n = 32). All participants completed the study, and none reported discomfort related to the music intervention. The intervention group demonstrated continuous improvements in sleep quality, with a global PSQI score of 13.53 at baseline, 9.28 at 1 month, 8.28 at 2 months, and 7.28 at 3 months. Although the global PSQI score in the control group also decreased from 12.26 at baseline to 8.72 at 3 months, the intervention group achieved greater improvements at each measurement (all p < 0.05). Repeated measures analysis of variance revealed significant group-by-time interaction effects in global PSQI score and three component scores: sleep latency, sleep efficiency, and daytime dysfunction (all p < 0.05). CONCLUSION: Music is a safe and effective nonpharmacological intervention for improving the sleep quality of community-dwelling elderly people, especially in improving sleep latency, sleep efficiency, and daytime dysfunction. PMID- 27223690 TI - Pyoverdin cheats fail to invade bacterial populations in stationary phase. AB - Microbes engage in cooperative behaviours by producing and secreting public goods, the benefits of which are shared among cells, and are therefore susceptible to exploitation by nonproducing cheats. In nature, bacteria are not typically colonizing sterile, rich environments in contrast to laboratory experiments, which involve inoculating sterile culture with few bacterial cells that then race to fill the available niche. Here, we study the potential implications of this difference, using the production of pyoverdin, an iron scavenging siderophore that acts as a public good in the bacteria Pseudomonas aeruginosa. We show that (1) nonproducers are able to invade cultures of producers when added at the start of growth or during early exponential growth phase, but not during late exponential or stationary phase; (2) the producer strain does not produce pyoverdin in the late exponential and stationary phases and so is not paying the cost of cooperating during those phases. These results suggest that whether a nonproducing mutant can invade will depend upon when the mutation arises, as well as the population structure, and raise a potential difficulty with the use of antimicrobial treatment strategies that propose to exploit the invasive abilities of cheats. PMID- 27223687 TI - Face Detection and the Development of Own-Species Bias in Infant Macaques. AB - In visually complex environments, numerous items compete for attention. Infants may exhibit attentional efficiency-privileged detection, attention capture, and holding-for face-like stimuli. However, it remains unknown when these biases develop and what role, if any, experience plays in this emerging skill. Here, nursery-reared infant macaques' (Macaca mulatta; n = 10) attention to faces in 10 item arrays of nonfaces was measured using eye tracking. With limited face experience, 3-week-old monkeys were more likely to detect faces and looked longer at faces compared to nonfaces, suggesting a robust face detection system. By 3 months, after peer exposure, infants looked faster to conspecific faces but not heterospecific faces, suggesting an own-species bias in face attention capture, consistent with perceptual attunement. PMID- 27223691 TI - Mediation of buprenorphine analgesia by a combination of traditional and truncated mu opioid receptor splice variants. AB - Buprenorphine has long been classified as a mu analgesic, although its high affinity for other opioid receptor classes and the orphanin FQ/nociceptin ORL1 receptor may contribute to its other actions. The current studies confirmed a mu mechanism for buprenorphine analgesia, implicating several subsets of mu receptor splice variants. Buprenorphine analgesia depended on the expression of both exon 1-associated traditional full length 7 transmembrane (7TM) and exon 11-associated truncated 6 transmembrane (6TM) MOR-1 variants. In genetic models, disruption of delta, kappa1 or ORL1 receptors had no impact on buprenorphine analgesia, while loss of the traditional 7TM MOR-1 variants in an exon 1 knockout (KO) mouse markedly lowered buprenorphine analgesia. Loss of the truncated 6TM variants in an exon 11 KO mouse totally eliminated buprenorphine analgesia. In distinction to analgesia, the inhibition of gastrointestinal transit and stimulation of locomotor activity were independent of truncated 6TM variants. Restoring expression of a 6TM variant with a lentivirus rescued buprenorphine analgesia in an exon 11 KO mouse that still expressed the 7TM variants. Despite a potent and robust stimulation of (35) S-GTPgammaS binding in MOR-1 expressing CHO cells, buprenorphine failed to recruit beta-arrestin-2 binding at doses as high as 10 uM. Buprenorphine was an antagonist in DOR-1 expressing cells and an inverse agonist in KOR-1 cells. Buprenorphine analgesia is complex and requires multiple mu receptor splice variant classes but other actions may involve alternative receptors. PMID- 27223692 TI - Synthetic B-Cell Epitopes Eliciting Cross-Neutralizing Antibodies: Strategies for Future Dengue Vaccine. AB - Dengue virus (DENV) is a major public health threat worldwide. A key element in protection from dengue fever is the neutralising antibody response. Anti-dengue IgG purified from DENV-2 infected human sera showed reactivity against several peptides when evaluated by ELISA and epitope extraction techniques. A multi-step computational approach predicted six antigenic regions within the E protein of DENV-2 that concur with the 6 epitopes identified by the combined ELISA and epitope extraction approach. The selected peptides representing B-cell epitopes were attached to a known dengue T-helper epitope and evaluated for their vaccine potency. Immunization of mice revealed two novel synthetic vaccine constructs that elicited good humoral immune responses and produced cross-reactive neutralising antibodies against DENV-1, 2 and 3. The findings indicate new directions for epitope mapping and contribute towards the future development of multi-epitope based synthetic peptide vaccine. PMID- 27223693 TI - Temporal Dynamics and Spatial Patterns of Aedes aegypti Breeding Sites, in the Context of a Dengue Control Program in Tartagal (Salta Province, Argentina). AB - BACKGROUND: Since 2009, Fundacion Mundo Sano has implemented an Aedes aegypti Surveillance and Control Program in Tartagal city (Salta Province, Argentina). The purpose of this study was to analyze temporal dynamics of Ae. aegypti breeding sites spatial distribution, during five years of samplings, and the effect of control actions over vector population dynamics. METHODOLOGY/PRINCIPAL FINDINGS: Seasonal entomological (larval) samplings were conducted in 17,815 fixed sites in Tartagal urban area between 2009 and 2014. Based on information of breeding sites abundance, from satellite remote sensing data (RS), and by the use of Geographic Information Systems (GIS), spatial analysis (hotspots and cluster analysis) and predictive model (MaxEnt) were performed. Spatial analysis showed a distribution pattern with the highest breeding densities registered in city outskirts. The model indicated that 75% of Ae. aegypti distribution is explained by 3 variables: bare soil coverage percentage (44.9%), urbanization coverage percentage(13.5%) and water distribution (11.6%). CONCLUSIONS/SIGNIFICANCE: This results have called attention to the way entomological field data and information from geospatial origin (RS/GIS) are used to infer scenarios which could then be applied in epidemiological surveillance programs and in the determination of dengue control strategies. Predictive maps development constructed with Ae. aegypti systematic spatiotemporal data, in Tartagal city, would allow public health workers to identify and target high-risk areas with appropriate and timely control measures. These tools could help decision-makers to improve health system responses and preventive measures related to vector control. PMID- 27223694 TI - Type I Interferons Direct Gammaherpesvirus Host Colonization. AB - Gamma-herpesviruses colonise lymphocytes. Murid Herpesvirus-4 (MuHV-4) infects B cells via epithelial to myeloid to lymphoid transfer. This indirect route entails exposure to host defences, and type I interferons (IFN-I) limit infection while viral evasion promotes it. To understand how IFN-I and its evasion both control infection outcomes, we used Mx1-cre mice to tag floxed viral genomes in IFN-I responding cells. Epithelial-derived MuHV-4 showed low IFN-I exposure, and neither disrupting viral evasion nor blocking IFN-I signalling markedly affected acute viral replication in the lungs. Maximising IFN-I induction with poly(I:C) increased virus tagging in lung macrophages, but the tagged virus spread poorly. Lymphoid-derived MuHV-4 showed contrastingly high IFN-I exposure. This occurred mainly in B cells. IFN-I induction increased tagging without reducing viral loads; disrupting viral evasion caused marked attenuation; and blocking IFN-I signalling opened up new lytic spread between macrophages. Thus, the impact of IFN-I on viral replication was strongly cell type-dependent: epithelial infection induced little response; IFN-I largely suppressed macrophage infection; and viral evasion allowed passage through B cells despite IFN-I responses. As a result, IFN I and its evasion promoted a switch in infection from acutely lytic in myeloid cells to chronically latent in B cells. Murine cytomegalovirus also showed a capacity to pass through IFN-I-responding cells, arguing that this is a core feature of herpesvirus host colonization. PMID- 27223695 TI - An Integrated View of Whole-Tree Hydraulic Architecture. Does Stomatal or Hydraulic Conductance Determine Whole Tree Transpiration? AB - Hydraulic conductance exerts a strong influence on many aspects of plant physiology, namely: transpiration, CO2 assimilation, growth, productivity or stress response. However we lack full understanding of the contribution of root or shoot water transport capacity to the total water balance, something which is difficult to study in trees. Here we tested the hypothesis that whole plant hydraulic conductance modulates plant transpiration using two different seedlings of citrus rootstocks, Poncirus trifoliata (L.) Raf. and Cleopatra mandarin (Citrus reshni Hort ex Tan.). The two genotypes presented important differences in their root or shoot hydraulic conductance contribution to whole plant hydraulic conductance but, even so, water balance proved highly dependent on whole plant conductance. Further, we propose there is a possible equilibrium between root and shoot hydraulic conductance, similar to that between shoot and root biomass production, which could be related with xylem anatomy. PMID- 27223696 TI - Soluble Toll-Like Receptors 2 and 4 in Cerebrospinal Fluid of Patients with Acute Hydrocephalus following Aneurysmal Subarachnoid Haemorrhage. AB - BACKGROUND: Toll-like receptor (TLR) signalling begins early in subarachnoid haemorrhage (SAH), and plays a key role in inflammation following cerebral aneurysm rupture. Available studies suggest significance of endogenous first-line blockers of a TLR pathway-soluble TLR2 and 4. METHODS: Eighteen patients with SAH and acute hydrocephalus underwent endovascular coiling and ventriculostomy; sTLR2 and 4 levels were assayed in cerebrospinal fluid (CSF) collected on post-SAH days 0-3, 5, and 10-12. Release kinetics were defined. CSF levels of sTLR2 and 4 were compared with a control group and correlated with the clinical status on admission, the findings on imaging, the degree of systemic inflammation and the outcome following treatment. RESULTS: None of study group showed detectable levels of sTLR2 and 4 on post-SAH day 0-3. 13 patients showed increased levels in subsequent samples. In five SAH patients sTLR2 and 4 levels remained undetectable; no distinctive features of this group were found. On post-SAH day 5 the strongest correlation was found between sTLR2 level and haemoglobin level on admission (cc = -0.498, P = 0.037). On post-SAH day 10-12 the strongest correlation was revealed between sTLR2 and treatment outcome (cc = -0.501, P = 0.076). Remaining correlations with treatment outcome, status at admission, imaging findings and inflammatory markers on post-SAH day 5 and 10-12 were negligible or low (-0.5 <= cc <= 0.5). CONCLUSIONS: In the majority of cases, rupture of a cerebral aneurysm leads to delayed release of soluble TLR forms into CSF. sTLR2 and 4 seem to have minor role in human post-SAH inflammation due to delayed release kinetics and low levels of these protein. PMID- 27223697 TI - The Effects of Disturbance on Hypothalamus-Pituitary-Thyroid (HPT) Axis in Zebrafish Larvae after Exposure to DEHP. AB - Di-(2-ethylhexyl) phthalate (DEHP) has the potential to disrupt the thyroid endocrine system, but the underlying mechanism is unknown. In this study, zebrafish (Danio rerio) embryos were exposed to different concentrations of DEHP (0, 40, 100, 200, 400 MUg/L) from 2 to 168 hours post fertilization (hpf). Thyroid hormones (THs) levels and transcriptional profiling of key genes related to hypothalamus-pituitary-thyroid (HPT) axis were examined. The result of whole body thyroxine (T4) and triiodothyronine (T3) indicated that the thyroid hormone homeostasis was disrupted by DEHP in the zebrafish larvae. After exposure to DEHP, the mRNA expressions of thyroid stimulating hormone (tshbeta) and corticotrophin releasing hormone (crh) genes were increased in a concentration dependent manner, respectively. The expression level of genes involved in thyroid development (nkx2.1 and pax8) and thyroid synthesis (sodium/iodide symporter, nis, thyroglobulin, tg) were also measured. The transcripts of nkx2.1 and tg were significantly increased after DEHP exposure, while those of nis and pax8 had no significant change. Down-regulation of uridinediphosphate-glucuronosyl transferase (ugt1ab) and up-regulation of thyronine deiodinase (dio2) might change the THs levels. In addition, the transcript of transthyretin (ttr) was up regulated, while the mRNA levels of thyroid hormone receptors (tralpha and trbeta) remained unchanged. All the results demonstrated that exposure to DEHP altered the whole-body thyroid hormones in the zebrafish larvae and changed the expression profiling of key genes related to HPT axis, proving that DEHP induced the thyroid endocrine toxicity and potentially affected the synthesis, regulation and action of thyroid hormones. PMID- 27223700 TI - Nursing in Newcastle. AB - Newcastle has only one district - but it is a very large one. Each of the seven units handles a budget which might serve a whole district elsewhere. The scale of services, so far, has been maintained. 'Basically, we have been able to consolidate and mark time,' reports Len Fenwick, general manager of the L30 million Freeman Hospital unit, although it is unlikely this miracle will long continue. PMID- 27223698 TI - Consumer Preferences for Written and Oral Information about Allergens When Eating Out. AB - BACKGROUND: Avoiding food allergens when eating outside the home presents particular difficulties for food allergic (FA) and intolerant (FI) consumers and a lack of allergen information in restaurants and takeaways causes unnecessary restrictions. Across Europe, legislation effective from December 2014, aims to improve allergen information by requiring providers of non-prepacked foods to supply information related to allergen content within their foods. METHODS: Using in-depth interviews with 60 FA/FI adults and 15 parents/carers of FA/FI children, we aimed to identify FA/FI consumers' preferences for written and/or verbal allergen information when eating out or ordering takeaway food. RESULTS: A complex and dynamic set of preferences and practices for written and verbal allergen information was identified. Overwhelmingly, written information was favoured in the first instance, but credible personal/verbal communication was highly valued and essential to a good eating out experience. Adequate written information facilitated implicit trust in subsequent verbal information. Where written information was limited, FA/FIs depended on social cues to assess the reliability of verbal information resources, and defaulted to tried and tested allergen avoidance strategies when these were deemed unreliable. CONCLUSION: Understanding the subtle negotiations and difficulties encountered by FA/FIs when eating out can serve as a guide for legislators and food providers; by encouraging provision of clear written and verbal allergen information, and training of proactive, allergen-aware staff. This, in tandem with legal requirements for allergen information provision, paves the way for FA/FIs to feel more confident in eating out choices; and to experience improved eating out experiences. PMID- 27223699 TI - Testing of the European Union exposure-response relationships and annoyance equivalents model for annoyance due to transportation noises: The need of revised exposure-response relationships and annoyance equivalents model. AB - An in situ survey was performed in 8 French cities in 2012 to study the annoyance due to combined transportation noises. As the European Commission recommends to use the exposure-response relationships suggested by Miedema and Oudshoorn [Environmental Health Perspective, 2001] to predict annoyance due to single transportation noise, these exposure-response relationships were tested using the annoyance due to each transportation noise measured during the French survey. These relationships only enabled a good prediction in terms of the percentages of people highly annoyed by road traffic noise. For the percentages of people annoyed and a little annoyed by road traffic noise, the quality of prediction is weak. For aircraft and railway noises, prediction of annoyance is not satisfactory either. As a consequence, the annoyance equivalents model of Miedema [The Journal of the Acoustical Society of America, 2004], based on these exposure response relationships did not enable a good prediction of annoyance due to combined transportation noises. Local exposure-response relationships were derived, following the whole computation suggested by Miedema and Oudshoorn [Environmental Health Perspective, 2001]. They led to a better calculation of annoyance due to each transportation noise in the French cities. A new version of the annoyance equivalents model was proposed using these new exposure-response relationships. This model enabled a better prediction of the total annoyance due to the combined transportation noises. These results encourage therefore to improve the annoyance prediction for noise in isolation with local or revised exposure-response relationships, which will also contribute to improve annoyance modeling for combined noises. With this aim in mind, a methodology is proposed to consider noise sensitivity in exposure-response relationships and in the annoyance equivalents model. The results showed that taking into account such variable did not enable to enhance both exposure-response relationships and the annoyance equivalents model. PMID- 27223702 TI - [Not Available]. AB - The RCN played April Fool on thousands of readers by placing this advert in the national newspapers. But the laugh, if there was one, was on the Health Minister. PMID- 27223701 TI - Where have all the women gone? AB - The women's movement must have missed nursing completely. Here we are in 1988 and still there are but a handful of women occupying management roles within a largely female dominated profession. PMID- 27223703 TI - Limited amendments to controversial Alton Bill. AB - David Alton's controversial Abortion Bill received two amendments allowing terminations be be performed in some cases of handicap, rape, and incest, when it passed through the Commons committee stage. PMID- 27223704 TI - HA study reveals variety in performance. AB - The latest performance indicators compiled from Health Authority statistics by the Government have shown that while there have been improvements in efficiency by a number of specialities, there are still considerable discrepancies in performance between districts. PMID- 27223705 TI - Too many men in ruling bodies. AB - Nursing organisations are demanding that health authorities should pay urgent attention to the mechanism whereby employees can take time off for statutory body duties. PMID- 27223706 TI - AIDS Nurses to be better protected. AB - HIV-positive nurses will be better protected at work after last week's publication of guidelines drawn up by the Government's Expert Advisory Group on Acquired Immune Deficiency Syndrome. PMID- 27223707 TI - RCN Questions manpower back to nursing figures. AB - The Royal College of Nursing is putting down a Parliamentary question to try to establish flow the Government's estimate of the number of nurses who might be attracted back to nursing has come to less than half of the College's own figure. PMID- 27223708 TI - Nursing's image must improve, says minister. AB - The image of nursing has to be improved if school leavers are to be attracted to the profession, the Scottish Health Minister emphasised last week. PMID- 27223709 TI - Government considers pay recommendations. AB - The issue of nurses' pay will again come into the limelight in the next few weeks, as the Government deliberates on the recommendations contained in the pay Review Body report. PMID- 27223710 TI - A unique course in caring. AB - A unique post graduate and post qualification course in care of people with a mental handicap will start in the University of Hull in October. PMID- 27223711 TI - Brave nurse saves patient from flames. AB - A nurse's 'extremely professional' response to an outbreak of fire on her ward has won the commendation of her UGM. PMID- 27223712 TI - Bradford DHA guilty of discrimination. AB - Bradford District Health Authority has been found guilty of racial discrimination against a Mauritian charge nurse when it promoted a less qualified white ward sister and transferred him to a less prestigious position. PMID- 27223713 TI - Campaigners team up to promote safety at work. AB - The Nursing Standard's What a ' Waste campaign for work injured nurses has found a powerful ally in the shape of a new political crusade to stop the rapid deterioration in health and safety at Britain's workplaces. PMID- 27223714 TI - Eminent nurse dies. AB - Nurses on the Channel Islands will be sorry to hear of the death of Emma Ferbrache in the Princess Elizabeth Hospital, Guernsey, aged 82 years. PMID- 27223715 TI - Passing on the word. AB - Donor card carriers are being urged by a 5500,000 DHSS publicity campaign to tell relatives and friends of their wish to help others after their death. PMID- 27223716 TI - Efficiency drive damages services. AB - National Health Service ties with the community are being damaged by the attempts of general managers to improve efficiency, says a report from the Association of Community Health Councils for England and Wales. PMID- 27223717 TI - Joining forces for the mentally handicapped. AB - A Scottish project to train together nurses and social workers working with the mentally handicapped has been welcomed by the profession. PMID- 27223719 TI - Dramatic rise in children at risk. AB - New statistics which spell out the harsh realities of life for many thousands of Britain's children are revealed in the National Children's Homes' fifth annual fact file 'Children in [Illegible word]'. PMID- 27223718 TI - Funding cancer home care. AB - Cancer Relief Macmillan Fund is to donate a total of 5300,000 over the next three years to St Christopher's Hospice in Sydenham. The grant will be used to fund home care nurses from St Christopher's, where Britain's first home care team for people suffering from cancer was developed in 1969. PMID- 27223721 TI - It's on the cards for student benefits. AB - Student nurses will for the first time be able to apply for student discount cards giving them all the benefits open to others in further education, thanks to the efforts of the RCN's Association of Nursing Students. PMID- 27223722 TI - Successful innovative computer course. AB - The Royal College of Nursing's first course to introduce managers to the use of computers in health care has been declared a success, and demand is such that more are in the pipeline. PMID- 27223723 TI - Scottish board workshops on effects of griffiths community report. AB - Concern at the possible effects of the Griffiths report on community care in Scotland have resulted in the RCN Scottish Board setting up workshops for members. PMID- 27223724 TI - Nationwide survey on how comunity nurses gather data. AB - District nurses are working under increasing pressure in the community, but lack hard information to prove excessive workload levels. For this reason a newly established RCN District Nurses steering group is to conduct a national survey on how nurses gather data. At its first meeting, the group concluded that the means of collecting information as evidence of high workload varied widely around the country. Without that hard evidence, nurses would not be able to convince general managers of the need for more staff and little could be achieved. PMID- 27223725 TI - Paper clarifies accountability in nursing profession. AB - The nurse's professional accountability and her code of conduct can be a 'very powerful force' to protect the interests of patients, says the author of a new College discussion paper. Called Accountability in Nursing, the paper has been produced by the RCN Professional Services Committee to stimulate debate and help resolve what it sees as a complex issue. PMID- 27223726 TI - Poll tax unfair and unjust. AB - Last week saw the launch of a major petition opposing the Government's poll tax legislation, only days before the introduction of the new social security system two policies that nurses believe will worsen deprivation in the community. PMID- 27223727 TI - Will storm clouds gather at brighton? AB - Just about every major issue affecting nurses and nursing will come under the spotlight at this year's RCN Congress, to be held in Brighton between May 23 and May 27. PMID- 27223728 TI - AIDS fellowships awarded to scottish nurses. AB - Three Scottish nurses hove been awarded fellowships to study the support and care of AIDS or HIV infected patients. PMID- 27223729 TI - [Not Available]. AB - The Duchess of York unveiled a commemorative plaque at Leavesden Hospital at Abbots Langley in Hertfordshire when she visited residents and staff there recently. PMID- 27223730 TI - Opposition to edinburgh closures. AB - A proposal to close Beechmount Hospital in Edinburgh has met with opposition from local organisations, despite reassurances from Lothian Health Board. PMID- 27223731 TI - Health authority backs worthing retraining scheme. AB - A successful three-month 'back to nursing' course has now won official funding from its District Health Authority, after existing for 18 months on a Manpower Services Commission grant. PMID- 27223732 TI - Midwives highlight berkshire shortages. AB - The headline grabbing story of a Health Authority's failed attempt find intensive care facilities for premature baby twins at 25 hospitals could well be repeated due to critical shortages of staff, the Royal College of Midwives has warned. PMID- 27223733 TI - Directions. AB - 'Nearly ten years ago, my author, a noted venereologist, suggested that I bring the new edition notes to his office at the clinic. The clinic entrances were quite privately located, away from the main entrance and streams of outpatients and visitors. The separate entrance signs - Women and Men - brought a moment's hesitation (I wasn't certain as to which housed the author) but I headed for the one where I knew I'd have no problem entering. A nurse acting as receptionist came to me immediately, and asked if she could help. I gave my name and asked to see Dr Author whereupon I was pulled aside and, in the most courteous and understanding way, quietly told 'Just give me your number, we don't use names in this department.' PMID- 27223735 TI - Creche barrier. AB - The Budget on March 15 did nothing to change Government policy on taxing subsidies made by employers for creches. The difference between the real cost of providing a place and the subsidised cost to the employee, is still seen as a 'tax deductible benefit' and the employee is duly taxed. PMID- 27223734 TI - New portfolio listings. PMID- 27223736 TI - Peach speech. AB - The national papers, as well as the nursing press, homed in last week on the DHSS's doubling of its nurse recruitment budget, announced in a speech by Len Peach, Chief Executive of the NHS Management Board. PMID- 27223738 TI - Practice nurses in cancer frontline. AB - British practice nurses will play a major part in evaluating the European week against cancer in May, it was announced at a recent practice nurse conference. PMID- 27223739 TI - Activities nurses promote their work. AB - A group of activities nurses wanting to give support to others working in the field and promote the benefits of their work are now meeting regularly and hope eventually to set up a special interest group. PMID- 27223740 TI - Vitamin E May Ease periods. AB - Women with premenstrual syndrome (PMS) are being urged to take natural vitamin E supplements after research from America showed that this could help their symptoms. PMID- 27223742 TI - Coming to terms with neonatal deaths. AB - Nurses and midwives are easing the pain for parents who have had a stillbirth or neonatal death by becoming involved with the self-help organisation SANDS. PMID- 27223741 TI - Running the risks of obesity. AB - Middle aged manual workers who don't smoke are more likely to be overweight, a British Regional Heart Study has shown. PMID- 27223743 TI - Help wanted for screening hotline. AB - The Women's National Cancer Control Campaign is looking for a nurse to man its planned cervical screening hot line. PMID- 27223744 TI - AIDS Admissions drop on home care option. AB - The number of hospital admissions of people with Acquired Immune Deficiency Syndrome or HIV infection has fallen since nurses at St Mary's Hospital, London, began offering patients the choice of hospital or home care. PMID- 27223746 TI - Sober advice on alcohol. AB - A primary health care strategy aimed at cutting alcohol consumption is currently being piloted by the HEA in the south west of England. PMID- 27223745 TI - Clinical trials on point of exposure. AB - Clinical trials of a syringe and needle set where the point need be exposed only at the time of injection are to be carried out by the Department of Health. PMID- 27223747 TI - Information is needed to aid antibiotic prescribing. AB - Information which allows [Illegible Word] prescribing of [Illegible Word] can be collected easily and cheaply, according to Bob Spencer, consultant bacteriologist at the Royal Hallamshire Hospital, Sheffield. PMID- 27223748 TI - Support for self advocacy. AB - Users of mental health services who are involved in self- advocacy groups seem to require fewer admissions to hospital, according to Ian Mooney, community worker for the Nottingham Patient Council Support Group (NPCSG). PMID- 27223749 TI - Incontinence problems of MS patients. AB - Incontinence in people who have multiple sclerosis is fraught with unusual problems that require special attention, delegates at a recent incontinence study day heard. PMID- 27223750 TI - No extended HV service. AB - There is little call for evening, weekend and night health visiting services either from health visitors, health authorities or clients, according to a survey from Barnet HA. PMID- 27223751 TI - Mental handicap reading. AB - Adults with a mental handicap who can read often fail to understand what they are reading, according to a study carried out at a London hospital and two adult training centres. PMID- 27223752 TI - Visual defects. AB - Visual defects in pre-school children are usually detected by family and friends, not by health care workers, according to a British study. PMID- 27223753 TI - Soya milk trials. AB - Substituting soya milk for cows' milk in the diets of children under one year old does not reduce the risk of allergic disease, according to the latest in a series of trials on food and allergy. PMID- 27223754 TI - Smoking problems less important. AB - Nurses are less likely to acknowledge the importance of smoking as a health issue after one year's training than at the beginning, a new report has shown. PMID- 27223755 TI - Watchdog. AB - Q Can you please clear up a point or two for me? I have been asked by members if they choose to opt out of the National Health Service superannuation scheme, will they still be entitled to SERPS (State Earnings Related Pension Scheme)? PMID- 27223756 TI - In safe keeping. AB - Hospitals are dangerous places to work in. Ionising radiation, dangerous substances, such as cytotoxic drugs and medical gases, are part and parcel of the working environment. Since 1978, the RCN has been running courses for health and safety reps to enable them to represent RCN members on all matters connected with their health, safety and welfare at work. PMID- 27223757 TI - Dysphasia - how to help. AB - Information on dysphasia, and other acquired neurological speech disorders, is rarely part of nurses' training. So, even the best-intentioned nurses can be ignorant of the best ways to get round patients' difficulties. PMID- 27223758 TI - Burns. PMID- 27223760 TI - Gall stones. AB - Acute cholecystitis is the third commonest cause of referral to acute surgical wards ( Webb 1988 ), and in 90 per cent of patients is associated with gallstones ( Summerfield 1987 ). PMID- 27223759 TI - Healthy alternatives. AB - The public view of AIDS is a gloomy one: AIDS is synonymous with death. Conventional medicine has only supportive or experimental treatment to offer at present, so it is not surprising that people are looking to alternative forms of therapy. Not all approaches will suit all people - there is no universal panacea but most of the techniques being used are simple to learn and teach. PMID- 27223761 TI - Promoting continence. AB - Information about incontinence has never been more accessible. Many chemist shops now openly display pamphlets and aids relating to incontinence, the subject has been widely discussed in women's magazines and in the media generally, self referral clinics are available in some areas and classified newspaper advertisements offer a range of aids and equipment, from rubber sheets to plastic pants. PMID- 27223762 TI - Money matters. AB - Why is money always the topic of conversation whenever the plight of nurses is discussed? Some news articles make nurses out to be money-grabbing individuals with no sense of loyalty or sensitivity. The Government is no better, Tony Newton, on Newsnight recently, directed his speech only on the statutory pay review body when commenting on the forthcoming strike. In the eyes of many nurses the crisis in the National Health Service concerns not only pay, but predominantly the standard of care that they are able to provide. Nurses are leaving in droves because they are unable to provide adequate and acceptable levels of basic nursing care. PMID- 27223763 TI - A complete guide to what's on in nursing nationwide. PMID- 27223764 TI - Clinical grading - a new deal for nurses. AB - Anew clinical grading structure is all set to fall into place, as soon as the Pay Review Body's latest report has been dealt with by the Government. It is something the profession has wanted for many years. PMID- 27223765 TI - Norway. AB - Norwegian nurses have been staging sporadic strikes in response to a proposed wage freeze by the government for the whole country. It intends to limit wage increases for everyone to five per cent, although inflation is running at just under seven per cent. The good news for nurses is that they, together with teachers, are now exempt from the wage restrictions and can carry out their own negotiations. PMID- 27223766 TI - Nigeria. AB - The use of oral rehydration salts - given out by nurses to mothers in the Third World - is being questioned by Nigeria's Federal Health Minister. The World Health Organisation has made efforts to distribute its own brand of salts, to cut down the millions of deaths caused by dehydration - the most serious consequence of infant diarrhoea. 'With advice from a nurse, any mother can administer this life-saving solution.' PMID- 27223767 TI - Panama. AB - Political unrest in Panama City has resulted in health staff and riot police coming into direct conflict. When 200 nurses, doctors and ancillary staff refused to break up a protest in front of the state Social Security Hospital, they were fired on with birdshot, tear gas and water cannon. PMID- 27223769 TI - Switzerland. AB - WHO has chosen its 40th anniversary on April 7 as a day to 'stimulate national action for health development'. The operation, centred in Switzerland, has produced a kit to spread information on topics such as 'preventable threats to health' and 'insects and health'. PMID- 27223768 TI - Angola. AB - Nurses in the Angolan war zone have a daunting workload, as the more experienced staff are required to undertake limb amputations and other surgery. There is a chronic shortage of medical supplies, orders for drugs and some surgical equipment taking four months to arrive. PMID- 27223770 TI - Australia. AB - At a major hospital in Sydney, a vote has been taken by surgeons to carry out AIDS tests on all casualty victims needing surgery, before operating. PMID- 27223771 TI - United states. AB - New legislation currently proposed in the USA under the Medicare Catastrophic Loss Prevention Act could greatly improve the level of health care available to the poorest Americans, particularly those without any health insurance. A $10 billion annual programme will not be financed by an official increase in taxes, but by an increase in Medicare Part B payments by the elderly. PMID- 27223772 TI - Foreign round up. PMID- 27223773 TI - Cheap exercise. AB - Could it be known that the West Essex Branch of the Royal College of Nursing formally withdraws from the competition to see which branch collects the most signatures in the College's petition to call for fully funding of the NHS? PMID- 27223774 TI - Who's first. AB - I would like to dispute the report (Nursing Standard week ending March 19) that Kingston & Esher Health Authority have appointed the NHS's first ever adviser on safe lifting and handling of patients. PMID- 27223775 TI - Nurses are high risk group. AB - I am the RCN observer to the Medical Council of Alcoholism Education and Public Health Committee and a Charge Nurse at a Sub-Regional Alcohol Treatment Service. I disagree with the comment you reported, that nurses are not a high-risk group in respect of alcohol-related problems. PMID- 27223776 TI - Imbalanced statement. AB - I do wish that unidentified RCN 'spokesmen' could be reminded that 'off the cuff statements' can be harmful to our profession. PMID- 27223777 TI - Any questions. AB - The South Oxfordshire Branch extend our thanks to Trevor Clay for taking part as a panel member on the BBC Radio 4 Any Questions programme, broadcast from the John Rat-cliffe Hospital, Oxford on March 18. PMID- 27223778 TI - Take advice on personal pensions. AB - Immediately after Easter, employed people will be asked to consider taking out 'personal pensions', following major changes in legislation governing pensions provision. It will become illegal to make membership of an occupational pension scheme a condition of employment. Some nurses are already outside occupational pension schemes, for one reason or another. The majority, who are in National Health Service scheme, will have the option of giving up their occupational pension and either relying on SERPS (State Earnings Related Scheme) or taking out a personal pension. PMID- 27223779 TI - The value of rule 12. AB - Once again the seemingly never-ending value and validity of Rule 12 has been questioned. Should the RCN, as a professional body, represent its members with the 'rule' that they will not take 'strike' action? PMID- 27223780 TI - ILL informed. AB - In reply to Mr David Nunn's confused and ill-informed letter (Nursing Standard, April 2), I would like to correct him on the following points. PMID- 27223782 TI - Flying colours. AB - Windswept Sussex on a chill Spring morning and the life of a flying nurse seems far from glamorous. Yet it is what Jennifer Wright has worked towards from the age of 18. PMID- 27223781 TI - Aiming high. AB - David Jones took up his job as Chief Executive of the English National Board for Nursing, Midwifery and Health Visiting on March 1 last year. PMID- 27223788 TI - Levy for poaching NHS nurses refused. AB - Demands for a levy on private and foreign health organisations which 'poach' NHS trained nurses have been rejected by the Government. But ministers have been reminded that growing numbers of nurses are leaving to work overseas as well as [Illegible Word] to the private sector. PMID- 27223789 TI - Government will aid cleveland inquiry costs. AB - Health Minister, Tony Newton, has announced the allocation of L600,000 to the Northern Regional Health Authority and Cleveland County Council to contribute towards the cost of the Cleveland child abuse inquiry. PMID- 27223791 TI - Conditions set out on manual records. AB - Proposals setting out the conditions under which people may see manual records held on them by local authority social services departments in England and Wales have been issued by the DHSS. PMID- 27223790 TI - Minister confirms increase in CPN staff. AB - The number of community psychiatric nurses in England more than doubled in a period of just five years, according to Health Minister, Tony Newton. Between 1981 and 1986 the total leapt from 1,083 to 2,532 - an increase of 134 per cent. PMID- 27223792 TI - New director for breast screening service. AB - Parliamentary Under Secretary of State for Wales, Ian Grist, has announced the appointment of a director to organise the breast screening service throughout the principality. PMID- 27223794 TI - Dancing to a different tune. AB - Vigils, petitions and action groups to save the NHS might have been novel ideas once, but in recent weeks they seem to have been two a penny. PMID- 27223793 TI - Tougher curbs on alcohol sales rejected. AB - Commons calls to impose tougher curbs on alcohol sales in the wake of international evidence of a link with oral cancer have been flatly rejected by the Government. PMID- 27223795 TI - Watery evidence. AB - 'Look before you leap' is the embarrassing lesson some avid school children learned last week. PMID- 27223796 TI - Green for go. AB - Dental research shows that as many as four in ten people are neurotic about bad breath, believing people shun them because of their halitosis. PMID- 27223797 TI - Pressed for space. AB - Are you wondering why there was a lowering of the pitch in the famous 'NHS - to fund or not to fund' debate a few weeks back? You are probably not, but if we are to believe the Fleet Street hacks, there have been fewer accounts than normal about what actually happened to John Moore and Tony Newton in a certain committee room where the Social Services Select Committee report on the NHS was being discussed. PMID- 27223798 TI - What a rack-et. AB - A design and marketing company in Shropshire has decided that the latest addition to the home that has everything is an item that everyone's granny had a couple of generations ago. PMID- 27223799 TI - Bednapped. AB - Things in the health service are bad, with cut backs and so on but spare a thought for the poor patients in Eire who can't even call their bed their own. PMID- 27223800 TI - Easy insertion catheter. PMID- 27223801 TI - Compact portable home nebuliser. AB - A new portable home nebuliser has been launched by DeVilbiss, manufacturers of the 'Pulmo-Aide' nebuliser. PMID- 27223802 TI - Softer approach from new catheter. AB - A new catheter for peripheral vein access which softens once in place has been launched by Becton Dickinson. PMID- 27223803 TI - Uniform company has designs on UK market. AB - The Netherlands uniform company, Borchlo Holdings BV, has formed a new company based in Nottingham. Stronghold Image Wear Limited will be tackling the British market and introducing continental designs and fabrics, says the company. PMID- 27223804 TI - Datacard range is identifying a need. AB - DataCard has launched a new range of machines for processing plastic identification cards. PMID- 27223806 TI - Safer bathing in prize style. AB - The Appollo bath, a new product 1 from a British company, recently won an award for innovation at ; Europe's largest international fair for the construction industry. PMID- 27223805 TI - Stoma care expansion. AB - A new stoma care company offering new products is being set up in Billinghurst, Sussex. PMID- 27223807 TI - Hyper active. PMID- 27223808 TI - Population Genetic Structure, Abundance, and Health Status of Two Dominant Benthic Species in the Saba Bank National Park, Caribbean Netherlands: Montastraea cavernosa and Xestospongia muta. AB - Saba Bank, a submerged atoll in the Caribbean Sea with an area of 2,200 km2, has attained international conservation status due to the rich diversity of species that reside on the bank. In order to assess the role of Saba Bank as a potential reservoir of diversity for the surrounding reefs, we examined the population genetic structure, abundance and health status of two prominent benthic species, the coral Montastraea cavernosa and the sponge Xestospongia muta. Sequence data were collected from 34 colonies of M. cavernosa (nDNA ITS1-5.8S-ITS2; 892 bp) and 68 X. muta sponges (mtDNA I3-M11 partition of COI; 544 bp) on Saba Bank and around Saba Island, and compared with published data across the wider Caribbean. Our data indicate that there is genetic connectivity between populations on Saba Bank and the nearby Saba Island as well as multiple locations in the wider Caribbean, ranging in distance from 100s-1000s km. The genetic diversity of Saba Bank populations of M. cavernosa (pi = 0.055) and X. muta (pi = 0.0010) was comparable to those in other regions in the western Atlantic. Densities and health status were determined along 11 transects of 50 m2 along the south-eastern rim of Saba Bank. The densities of M. cavernosa (0.27 ind. m-2, 95% CI: 0.12 0.52) were average, while the densities of X. muta (0.09 ind. m-2, 95% CI: 0.02 0.32) were generally higher with respect to other Caribbean locations. No disease or bleaching was present in any of the specimens of the coral M. cavernosa, however, we did observe partial tissue loss (77.9% of samples) as well as overgrowth (48.1%), predominantly by cyanobacteria. In contrast, the majority of observed X. muta (83.5%) showed signs of presumed bleaching. The combined results of apparent gene flow among populations on Saba Bank and surrounding reefs, the high abundance and unique genetic diversity, indicate that Saba Bank could function as an important buffer for the region. Either as a natural source of larvae to replenish genetic diversity or as a storehouse of diversity that can be utilized if needed for restoration practices. PMID- 27223809 TI - Varenicline in smokers with diabetes: A pooled analysis of 15 randomized, placebo controlled studies of varenicline. AB - AIMS/INTRODUCTION: Stopping smoking deserves high priority in preventing complications of diabetes; however, only sparse data are available regarding the efficacy of pharmacotherapy in smokers with diabetes. We assessed the efficacy and safety of varenicline in smokers with diabetes who participated in 15 double blind, randomized, placebo-controlled studies. MATERIALS AND METHODS: This retrospective pooled analysis included data from smokers of >=10 cigarettes per day with diabetes. Participants received varenicline 1 mg b.i.d. or placebo for 12 weeks. We examined carbon monoxide-confirmed continuous abstinence rates (CARs) for weeks 9-12, 9-24 and 9-52, and compared safety in participants with and without diabetes. RESULTS: Of 6,771 participants, 323 had diabetes (varenicline n = 162; placebo n = 161). Week 9-12 CAR was higher with varenicline than placebo (43.8% vs 24.8%; odds ratio 2.36, 95% CI 1.47-3.79), as was week 9 24 CAR (27.5% vs 14.4%; odds ratio 2.25, 95% CI 1.27-4.00). Week 9-52 CAR was 18.4% for varenicline and 10.1% for placebo (odds ratio 2.00, 95% CI 0.90-4.49). The most commonly-reported adverse events in participants with diabetes for varenicline vs placebo were: nausea (27.2% vs 8.1%); headache (9.3% vs 9.9%); and insomnia (8.6% vs 5.6%), incidences that were similar in participants without diabetes (29.6% vs 9.7%; 13.4% vs 10.9%; and 11.4% vs 7.1%, respectively). Weight gain in quitters with diabetes (1.7 kg) was similar to that of those without diabetes (2.1 kg). CONCLUSIONS: Varenicline was an effective and well-tolerated aid for smoking cessation in individuals with diabetes. Safety was comparable with participants without diabetes. PMID- 27223810 TI - Global Synthesis of Drought Effects on Maize and Wheat Production. AB - Drought has been a major cause of agricultural disaster, yet how it affects the vulnerability of maize and wheat production in combination with several co varying factors (i.e., phenological phases, agro-climatic regions, soil texture) remains unclear. Using a data synthesis approach, this study aims to better characterize the effects of those co-varying factors with drought and to provide critical information on minimizing yield loss. We collected data from peer reviewed publications between 1980 and 2015 which examined maize and wheat yield responses to drought using field experiments. We performed unweighted analysis using the log response ratio to calculate the bootstrapped confidence limits of yield responses and calculated drought sensitivities with regards to those co varying factors. Our results showed that yield reduction varied with species, with wheat having lower yield reduction (20.6%) compared to maize (39.3%) at approximately 40% water reduction. Maize was also more sensitive to drought than wheat, particularly during reproductive phase and equally sensitive in the dryland and non-dryland regions. While no yield difference was observed among regions or different soil texture, wheat cultivation in the dryland was more prone to yield loss than in the non-dryland region. Informed by these results, we discuss potential causes and possible approaches that may minimize drought impacts. PMID- 27223811 TI - An Empirical Analysis of Rural-Urban Differences in Out-Of-Pocket Health Expenditures in a Low-Income Society of China. AB - OBJECTIVE: The paper examines whether out-of-pocket health care expenditure also has regional discrepancies, comparing to the equity between urban and rural areas, and across households. METHOD: Sampled data were derived from Urban Household Survey and Rural Household Survey data for 2011/2012 for Anhui Province, and 11049 households were included in this study. The study compared differences in out-of-pocket expenditure on health care between regions (urban vs. rural areas) and years (2011 vs. 2012) using two-sample t-test, and also investigated the degree of inequality using Lorenz and concentration curves. RESULT: Approximately 5% and 8% of total household consumption expenditure was spent on health care for urban and rural populations, respectively. In 2012, the wealthiest 20% of urban and rural population contributed 49.7% and 55.8% of urban and rural total health expenditure respectively, while the poorest 20% took only 4.7% and 4.4%. The concentration curve for out-of-pocket expenditure in 2012 fell below the corresponding concentration curve for 2011 for both urban and rural areas, and the difference between curves for rural areas was greater than that for urban areas. CONCLUSION: A substantial and increasing gap in health care expenditures existed between urban and rural areas in Anhui. The health care financing inequality merits ample attention, with need for policymaking to focus on improving the accessibility to essential health care services, particularly for rural and poor residents. This study may provide useful information on low income areas of China. PMID- 27223812 TI - Psychiatric Diagnoses in Individuals with Non-Syndromic Oral Clefts: A Danish Population-Based Cohort Study. AB - BACKGROUND: The aim of this study was to investigate the risk of psychiatric diagnoses in individuals with non-syndromic oral clefts (OC) compared with individuals without OC, including ages from 1 to 76 years. METHODS: Linking four Danish nationwide registers, we investigated the risk of psychiatric diagnoses at Danish psychiatric hospitals during the period 1969-2012 for individuals born with non-syndromic OC in Denmark 1936-2009 compared with a cohort of 10 individuals without OC per individual with OC, matched by sex and birth year. The sample included 8,568 individuals with OC, observed for 247,821 person-years, and 85,653 individuals without OC followed for 2,501,129 person-years. RESULTS: A total of 953 (11.1%) of the individuals with OC (9.6% for cleft lip (CL), 10.8% for cleft lip and palate (CLP) and 13.1% for cleft palate (CP)) and 8,117 (9.5%) in the comparison group had at least one psychiatric diagnosis. Cox proportional hazard regression model revealed that individuals with OC had significantly higher risk of a psychiatric diagnosis (hazard ratio (HR) = 1.19, 95% CI: 1.12 1.28). When examining cleft type, no difference was found for CL (HR = 1.03, 95% CI: 0.90-1.17), but CLP was associated with a small increased risk (HR = 1.13, 95% CI: 1.01-1.26), whereas individuals with CP had the largest increased risk (HR = 1.45, 95% CI: 1.30-1.62). The largest differences were found in schizophrenia-like disorders, mental retardation and pervasive developmental disorders, but we found no increased risk of mood disorders and anxiety-related disorders. CONCLUSION: Individuals with non-syndromic OC had significantly higher risk of psychiatric diagnoses compared with individuals without OC. However, the elevated risk was observed for individuals with CLP and CP but not for individuals with CL and the absolute risk increase was modest. PMID- 27223813 TI - Oral vinorelbine plus cisplatin versus pemetrexed plus cisplatin as first-line treatment of advanced non-squamous non-small-cell lung cancer: cost minimization analysis in 12 European countries. AB - OBJECTIVE: A combination of vinorelbine and cisplatin is a standard treatment in non-small-cell lung cancer; oral vinorelbine is registered in 45 countries. Pemetrexed and cisplatin are recommended in front-line chemotherapy of non squamous non-small-cell lung cancer (NS-NSCLC). The objective of this study was to conduct a cost minimization analysis from the perspective of the national health service (NHS) in each of 12 European countries, based on a randomized phase II study in NS-NSCLC (NAVoTRIAL01), with 100 oral vinorelbine plus cisplatin patients (arm A) and 51 pemetrexed plus cisplatin patients (arm B). RESEARCH DESIGN AND METHODS: Country-specific costs and DRG codes considered included those relating to anticancer drugs, administration settings (out patient/in-patient/at home), serious adverse events (defined as involving hospitalization and considered due to anticancer drugs) and concomitant medications. Relevant costs were calculated based on country-specific reimbursement procedures and official tariffs. MAIN OUTCOME MEASURES: Cost and savings per patient. RESULTS: Using the NHS perspective, savings per patient treated with oral vinorelbine ranged from ?1317 (Denmark) to ?35,001 (Germany). Expressed as percentages, savings per patient treated with oral vinorelbine compared with pemetrexed ranged between 5% (France) and 83% (Czech Republic). Pooled average costs for each treatment arm across the 12 countries resulted in cost savings for payers of ?12,871, favoring oral vinorelbine plus cisplatin. CONCLUSIONS: Given the reported efficacy with both regimens, this pan-European economic analysis provides compelling evidence supporting oral vinorelbine use over pemetrexed for the treatment of NS-NSCLC. Oral vinorelbine provides similar efficacy and an easily manageable safety profile at lower overall cost per patient treated, combined with an easier/more convenient mode of administration. Sensitivity analysis across varied scenarios demonstrated the robustness of the results. The principle weakness of our study was its reliance upon a single small scale study to provide efficacy data, since this is the only study conducted in this specific population of patients. Further large scale trials are needed to confirm these results. PMID- 27223814 TI - Violating instructed human agency: An fMRI study on ocular tracking of biological and nonbiological motion stimuli. AB - Previous studies have shown that beliefs about the human origin of a stimulus are capable of modulating the coupling of perception and action. Such beliefs can be based on top-down recognition of the identity of an actor or bottom-up observation of the behavior of the stimulus. Instructed human agency has been shown to lead to superior tracking performance of a moving dot as compared to instructed computer agency, especially when the dot followed a biological velocity profile and thus matched the predicted movement, whereas a violation of instructed human agency by a nonbiological dot motion impaired oculomotor tracking (Zwickel et al., 2012). This suggests that the instructed agency biases the selection of predictive models on the movement trajectory of the dot motion. The aim of the present fMRI study was to examine the neural correlates of top down and bottom-up modulations of perception-action couplings by manipulating the instructed agency (human action vs. computer-generated action) and the observable behavior of the stimulus (biological vs. nonbiological velocity profile). To this end, participants performed an oculomotor tracking task in an MRI environment. Oculomotor tracking activated areas of the eye movement network. A right hemisphere occipito-temporal cluster comprising the motion-sensitive area V5 showed a preference for the biological as compared to the nonbiological velocity profile. Importantly, a mismatch between instructed human agency and a nonbiological velocity profile primarily activated medial-frontal areas comprising the frontal pole, the paracingulate gyrus, and the anterior cingulate gyrus, as well as the cerebellum and the supplementary eye field as part of the eye movement network. This mismatch effect was specific to the instructed human agency and did not occur in conditions with a mismatch between instructed computer agency and a biological velocity profile. Our results support the hypothesis that humans activate a specific predictive model for biological movements based on their own motor expertise. A violation of this predictive model causes costs as the movement needs to be corrected in accordance with incoming (nonbiological) sensory information. PMID- 27223815 TI - In Situ Generation and Consumption of H2O2 by Bienzyme-Quantum Dots Bioconjugates for Improved Chemiluminescence Resonance Energy Transfer. AB - Exploration of quantum dots (QDs) as energy acceptors revolutionizes the current chemiluminescence resonance energy transfer (CRET), since QDs possess large Stokes shifts and high luminescence efficiency. However, the strong and high concentration of oxidant (typically H2O2) needed for luminol chemiluminescence (CL) reaction could cause oxidative quenching to QDs, thereby decreasing the CRET performance. Here we proposed the use of bienzyme-QDs bioconjugate as the energy acceptor for improved CRET sensing. Two enzymes, one for H2O2 generation (oxidase) and another for H2O2 consumption (horseradish peroxidase, HRP), were bioconjugated onto the surface of QDs. The bienzyme allowed fast in situ cascaded H2O2 generation and consumption, thus alleviating fluorescence quenching of QDs. The nanosized QDs accommodate the two enzymes in a nanometric range, and the CL reaction was confined on the surface of QDs accordingly, thereby amplifying the CL reaction rate and improving CRET efficiency. As a result, CRET efficiency of 30-38% was obtained; the highest CRET efficiency by far was obtained using QDs as the energy acceptor. The proposed CRET system could be explored for ultrasensitive sensing of various oxidase substrates (here exemplified with cholesterol, glucose, and benzylamine), allowing for quantitative measurement of a spectrum of metabolites with high sensitivity and specificity. Limits of detection (LOD, 3sigma) for cholesterol, glucose, and benzylamine were found to be 0.8, 3.4, and 10 nM, respectively. Furthermore, multiparametric blood analysis (glucose and cholesterol) is demonstrated. PMID- 27223816 TI - Innate immunomodulation to trypanosomatid parasite infections. AB - The recognition of invading pathogens by the innate immune system is essential for host protection against human parasites and the initiation of an effective adaptive immune response. Innate immune cells such as macrophages and dendritic cells (DCs) are involved in the first line of defense against protozoan parasites via sensing the invaders through pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs). Activation of macrophages and dendritic cells starts with the interaction between microbial ligands (pathogen-associated molecular patterns - PAMPs) and PRRs, and these activated cells influence the overall immune response. Trypanosomatid PAMPs are sensed by TLRs; for example, TLR2 recognizes alkylacylglycerol and lipophosphoglycan in Trypanosoma cruzi and Leishmania, respectively; TLR2/TLR4 recognize glycoisnositolphospholipids and glycosylphosphatidyl inositol in Trypanosoma species; and TLR9 recognizes genomic DNA in Trypanosoma. TLR signaling includes the recruitment of different adaptor molecules that activate various transcription factors, such as NF-kB, IRF3/7, and MAP kinases, to induce the production of pro-inflammatory cytokines and type I interferons. Moreover, activated macrophages and dendritic cells produce ROS and NOS, which limit pathogen survival, and large amounts of cytokines; additionally, antigen presentation enhances the adaptive immune response. In this review, we highlight the recent findings on PAMP recognition in trypanosomatid infections and the signaling pathways activated by PRRs. PMID- 27223817 TI - High Job Demands and Low Job Control Increase Nurses' Professional Leaving Intentions: The Role of Care Setting and Profit Orientation. AB - We investigated how two types of care setting (home care and nursing home) and type of ownership (for-profit vs. public/non-profit) of geriatric care services interacted in influencing registered nurses' intention to give up their profession. In prior research, employment in for-profit-organizations, high job demands, and low job control were important antecedents of nurses' intent to leave. However, the impact of care setting on these associations was inconclusive. Therefore, we tested a mediated moderation model predicting that adverse work characteristics would drive professional leaving intentions, particularly in for-profit services and in nursing homes. A representative German sample of 304 registered nurses working in 78 different teams participated in our cross-sectional study. As predicted, lower job control and higher job demands were associated with higher professional leaving intentions, and nurses reported higher job demands in public/non-profit care than in for-profit care, and in nursing homes compared to home care. Overall, RNs in nursing homes and home care reported similar intent to leave, but in for-profit settings only, nurses working in nursing homes reported higher professional leaving intentions than did nurses in home care, which was linked to lower job control in the for-profit nursing home setting, supporting mediated moderation. Taken together, our results indicate that the interplay of care setting and type of ownership is important when explaining nurses' intentions to give up their profession. (c) 2016 Wiley Periodicals, Inc. PMID- 27223818 TI - The Type VI Secretion System in Escherichia coli and Related Species. AB - The type VI secretion system (T6SS) is a multiprotein complex widespread in Proteobacteria and dedicated to the delivery of toxins into both prokaryotic and eukaryotic cells. It thus participates in interbacterial competition as well as pathogenesis. The T6SS is a contractile weapon, related to the injection apparatus of contractile tailed bacteriophages. Basically, it assembles an inner tube wrapped by a sheath-like structure and anchored to the cell envelope via a membrane complex. The energy released by the contraction of the sheath propels the inner tube through the membrane channel and toward the target cell. Although the assembly and the mechanism of action are conserved across species, the repertoire of secreted toxins and the diversity of the regulatory mechanisms and of target cells make the T6SS a highly versatile secretion system. The T6SS is particularly represented in Escherichia coli pathotypes and Salmonella serotypes. In this review we summarize the current knowledge regarding the prevalence, the assembly, the regulation, and the roles of the T6SS in E. coli, Salmonella, and related species. PMID- 27223819 TI - Aminoacyl-tRNA Synthetases in the Bacterial World. AB - Aminoacyl-tRNA synthetases (aaRSs) are modular enzymes globally 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 huge structural plasticity related to function and limited idiosyncrasies that are kingdom or even species specific (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 between distant groups such as Gram-positive and Gram-negative Bacteria. The review 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 accumulated in last two decades is reviewed, showing how the field moved from essentially reductionist biology towards more global and integrated approaches. Likewise, the alternative functions of aaRSs and those of aaRS paralogs (e.g., during cell wall 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 pinpointed throughout the review and distinctive characteristics of bacterium like synthetases from organelles are outlined. PMID- 27223821 TI - lambda Recombination and Recombineering. AB - The bacteriophage lambda Red homologous recombination system has been studied over the past 50 years as a model system to define the mechanistic details of how organisms exchange DNA segments that share extended regions of homology. The lambda Red system proved useful as a system to study because recombinants could be easily generated by co-infection of genetically marked phages. What emerged from these studies was the recognition that replication of phage DNA was required for substantial Red-promoted recombination in vivo, and the critical role that double-stranded DNA ends play in allowing the Red proteins access to the phage DNA chromosomes. In the past 16 years, however, the lambda Red recombination system has gained a new notoriety. When expressed independently of other lambda functions, the Red system is able to promote recombination of linear DNA containing limited regions of homology (~50 bp) with the Escherichia coli chromosome, a process known as recombineering. This review explains how the Red system works during a phage infection, and how it is utilized to make chromosomal modifications of E. coli with such efficiency that it changed the nature and number of genetic manipulations possible, leading to advances in bacterial genomics, metabolic engineering, and eukaryotic genetics. PMID- 27223822 TI - Systems Metabolic Engineering of Escherichia coli. AB - Systems metabolic engineering, which recently emerged as metabolic engineering integrated with systems biology, synthetic biology, and evolutionary engineering, allows engineering of microorganisms on a systemic level for the production of valuable chemicals far beyond its native capabilities. Here, we review the strategies for systems metabolic engineering and particularly its applications in Escherichia coli. First, we cover the various tools developed for genetic manipulation in E. coli to increase the production titers of desired chemicals. Next, we detail the strategies for systems metabolic engineering in E. coli, covering the engineering of the native metabolism, the expansion of metabolism with synthetic pathways, and the process engineering aspects undertaken to achieve higher production titers of desired chemicals. Finally, we examine a couple of notable products as case studies produced in E. coli strains developed by systems metabolic engineering. The large portfolio of chemical products successfully produced by engineered E. coli listed here demonstrates the sheer capacity of what can be envisioned and achieved with respect to microbial production of chemicals. Systems metabolic engineering is no longer in its infancy; it is now widely employed and is also positioned to further embrace next generation interdisciplinary principles and innovation for its upgrade. Systems metabolic engineering will play increasingly important roles in developing industrial strains including E. coli that are capable of efficiently producing natural and nonnatural chemicals and materials from renewable nonfood biomass. PMID- 27223820 TI - Human Meningitis-Associated Escherichia coli. AB - Escherichia coli is the most common Gram-negative bacillary organism causing meningitis, and E. coli meningitis continues to be an important cause of mortality and morbidity throughout the world. Our incomplete knowledge of its pathogenesis contributes to such mortality and morbidity. Recent reports of E. coli strains producing CTX-M-type or TEM-type extended-spectrum beta-lactamases create a challenge. Studies using in vitro and in vivo models of the blood-brain barrier have shown that E. coli meningitis follows a high degree of bacteremia and invasion of the blood-brain barrier. E. coli invasion of the blood-brain barrier, the essential step in the development of E. coli meningitis, requires specific microbial and host factors as well as microbe- and host-specific signaling molecules. Blockade of such microbial and host factors contributing to E. coli invasion of the blood-brain barrier is shown to be efficient in preventing E. coli penetration into the brain. The basis for requiring a high degree of bacteremia for E. coli penetration of the blood-brain barrier, however, remains unclear. Continued investigation on the microbial and host factors contributing to a high degree of bacteremia and E. coli invasion of the blood brain barrier is likely to identify new targets for prevention and therapy of E. coli meningitis. PMID- 27223823 TI - Impaired Nrf2 regulation of mitochondrial biogenesis in rostral ventrolateral medulla on hypertension induced by systemic inflammation. AB - Oxidative stress in rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons reside, is involved in the development of hypertension under systemic inflammation. Mitochondrial dysfunction contributes to tissue oxidative stress. In this study, we sought to investigate whether hypertension developed under systemic inflammation is attributable to impaired mitochondrial biogenesis in RVLM. In normotensive Sprague-Dawley rats, intraperitoneal infusion of a low dose Escherichia coli lipopolysaccharide (LPS) for 7 days promoted a pressor response, alongside a decrease in mitochondrial DNA (mtDNA) copy number, reductions in protein expression of nuclear DNA-encoded transcription factors for mitochondrial biogenesis, including mitochondrial transcription factor A (TFAM) and nuclear factor erythroid-derived 2-like 2 (Nrf2), and suppression of nuclear translocation of the phosphorylated Nrf2 (p-Nrf2) in RVLM neurons; all of which were abrogated by treatment with intracisternal infusion of an interleukin-1beta (IL-1beta) blocker, IL-1Ra, or a mobile mitochondrial electron carrier, coenzyme Q10 (CoQ10). Microinjection into RVLM of IL-1beta suppressed the expressions of p Nrf2 and TFAM, and evoked a pressor response; conversely, the Nrf2 inducer, tert butylhydroquinone, lessened the LPS-induced suppression of TFAM expression and pressor response. At cellular level, exposure of neuronal N2a cells to IL-1beta decreased mtDNA copy number, increased protein interaction of Nrf2 to its negative regulator, kelch-like ECH-associated protein 1 (Keap1), and reduced DNA binding activity of p-Nrf2 to Tfam gene. Together these results indicate that defect mitochondrial biogenesis in RVLM neurons entailing redox-sensitive and IL 1beta-dependent suppression of TFAM because of the increase in the formation of Keap1/Nrf2 complex, reductions in nuclear translocation of the activated Nrf2 and its binding to the Tfam gene promoter may underlie hypertension developed under the LPS-induced systemic inflammation. PMID- 27223824 TI - Influence of electron beam irradiation on structural and optical properties of alpha-Ag2WO4 nanoparticles. AB - The influence of 8MeV electron beam irradiation on the structural and optical properties of silver tungstate (alpha-Ag2WO4) nanoparticles synthesized by chemical precipitation method was investigated. The dose dependent effect of electron irradiation was investigated by various characterization techniques such as, X-ray diffraction, scanning electron microscopy, UV-vis absorption spectroscopy, photoluminescence and Raman spectroscopy. Systematic studies confirm that electron beam irradiation induces non-stoichiometry, defects and particle size variation on alpha-Ag2WO4, which in turn results changes in optical band gap, photoluminescence spectra and Raman bands. PMID- 27223825 TI - Primary Air-Liquid Interface Culture of Nasal Epithelium for Nasal Drug Delivery. AB - Nasal drug administration is a promising alternative to oral and parenteral administration for both local and systemic delivery of drugs. The benefits include its noninvasive nature, rapid absorption, and circumvention of first pass metabolism. Hence, the use of an in vitro model using human primary nasal epithelial cells could be key to understanding important functions and parameters of the respiratory epithelium. This model will enable investigators to address important and original research questions using a biologically relevant in vitro platform that mimics the in vivo nasal epithelial physiology. The purpose of this study was to establish, systematically characterize, and validate the use of a primary human nasal epithelium model cultured at the air-liquid interface for the study of inflammatory responses and drug transport and to simultaneously quantify drug effects on ciliary activity. PMID- 27223827 TI - Association of Acute Radiation Syndrome and Rain after the Bombings in Atomic Bomb Survivors. AB - Acute radiation-induced symptoms reported in survivors after the atomic bombings in Hiroshima and Nagasaki have been suspected to be associated with rain that fell after the explosions, but this association has not been evaluated in an epidemiological study that considers the effects of the direct dose from the atomic bombs and other factors. The aim of this study was to evaluate this association using information from a fixed cohort, comprised of 93,741 members of the Life Span Study who were in the city at the time of the bombing. Information on acute symptoms and exposure to rain was collected in surveys conducted by interviewers, primarily in the 1950s. The proportion of survivors developing severe epilation was around 60% at levels of direct radiation doses of 3 Gy or higher and less than 0.2% at levels <0.005 Gy regardless of reported rain exposure status. The low prevalence of acute symptoms at low direct doses indicates that the reported fallout rain was not homogeneously radioactive at a level sufficient to cause a substantial probability of acute symptoms. We observed that the proportion of reported acute symptoms was slightly higher among those who reported rain exposure in some subgroups, however, suggestions that rain was the cause of these reported symptoms are not supported by analyses specific to the known areas of radioactive fallout. Misclassification of exposure and outcome, including symptoms due to other causes and recall bias, appears to be a more plausible explanation. However, the insufficient and retrospective nature of the available data limited our ability to quantify the attribution to those possible causes. PMID- 27223826 TI - Mechanisms Involved in the Development of the Chronic Gastrointestinal Syndrome in Nonhuman Primates after Total-Body Irradiation with Bone Marrow Shielding. AB - In this study, nonhuman primates (NHPs) exposed to lethal doses of total body irradiation (TBI) within the gastrointestinal (GI) acute radiation syndrome range, sparing ~5% of bone marrow (TBI-BM5), were used to evaluate the mechanisms involved in development of the chronic GI syndrome. TBI increased mucosal permeability in the jejunum (12-14 Gy) and proximal colon (13-14 Gy). TBI-BM5 also impaired mucosal barrier function at doses ranging from 10-12.5 Gy in both small intestine and colon. Timed necropsies of NHPs at 6-180 days after 10 Gy TBI BM5 showed that changes in small intestine preceded those in the colon. Chronic GI syndrome in NHPs is characterized by continued weight loss and intermittent GI syndrome symptoms. There was a long-lasting decrease in jejunal glucose absorption coincident with reduced expression of the sodium-linked glucose transporter. The small intestine and colon showed a modest upregulation of several different pro-inflammatory mediators such as NOS-2. The persistent inflammation in the post-TBI-BM5 period was associated with a long-lasting impairment of mucosal restitution and a reduced expression of intestinal and serum levels of alkaline phosphatase (ALP). Mucosal healing in the postirradiation period is dependent on sparing of stem cell crypts and maturation of crypt cells into appropriate phenotypes. At 30 days after 10 Gy TBI-BM5, there was a significant downregulation in the gene and protein expression of the stem cell marker Lgr5 but no change in the gene expression of enterocyte or enteroendocrine lineage markers. These data indicate that even a threshold dose of 10 Gy TBI-BM5 induces a persistent impairment of both mucosal barrier function and restitution in the GI tract and that ALP may serve as a biomarker for these events. These findings have important therapeutic implications for the design of medical countermeasures. PMID- 27223828 TI - Effective Rat Lung Tumor Model for Stereotactic Body Radiation Therapy. AB - Stereotactic body radiation therapy (SBRT) has found an important role in the treatment of patients with non-small cell lung cancer, demonstrating improvements in dose distribution and even tumor cure rates, particularly for early-stage disease. Despite its emerging clinical efficacy, SBRT has primarily evolved due to advances in medical imaging and more accurate dose delivery, leaving a void in knowledge of the fundamental biological mechanisms underlying its activity. Thus, there is a critical need for the development of orthotropic animal models to further probe the biology associated with high-dose-per-fraction treatment typical of SBRT. We report here on an improved surgically based methodology for generating solitary intrapulmonary nodule tumors, which can be treated with simulated SBRT using the X-RAD 225Cx small animal irradiator and Small Animal RadioTherapy (SmART) Plan treatment system. Over 90% of rats developed solitary tumors in the right lung. Furthermore, the tumor response to radiation was monitored noninvasively via bioluminescence imaging (BLI), and complete ablation of tumor growth was achieved with 36 Gy (3 fractions of 12 Gy each). We report a reproducible, orthotopic, clinically relevant lung tumor model, which better mimics patient treatment regimens. This system can be utilized to further explore the underlying biological mechanisms relevant to SBRT and high-dose-per-fraction radiation exposure and to provide a useful model to explore the efficacy of radiation modifiers in the treatment of non-small cell lung cancer. PMID- 27223829 TI - Temporal Responses to X-Radiation Exposure in Spleen in the pKZ1 Mouse Recombination Assay. AB - The in vivo mouse transgenic pKZ1 chromosomal inversion assay is a sensitive assay that responds to very low doses of DNA-damaging agents. pKZ1 inversions are measured as the frequency of cells expressing E. coli beta-galactosidase protein, which can only be produced from an inverted pKZ1 transgene. In previous studies we reported that a single whole-body low dose of 0.01 mGy X rays alone caused an increase in pKZ1 chromosomal inversions in spleen when analyzed 3 days postirradiation, and yet this same dose could protect from high-dose-induced inversions when delivered as a conditioning dose 4 h before or after a 1 Gy challenge dose. In an attempt to explain these results, we performed temporal studies over a wide radiation dose range to determine if the inversion response was temporally different at different doses. pKZ1 mice were irradiated with a single whole-body X-ray dose of 0.01 mGy, 1 mGy or 1 Gy, and spleen sections were then analyzed for pKZ1 inversions at 7 h, 1 day or 7 days after exposure. No change in inversion frequency was observed at the 7 h time point at any dose. At day 1, an increase in inversions was observed in response to the 0.01 mGy dose, whereas a decrease in inversions below sham-treated frequency was observed for the 1 mGy dose. Inversion frequency for both doses returned to sham-treated inversion frequency by day 7. To our knowledge, this is the first reported study to examine the temporal nature of a radiation response spanning a wide dose range, including doses relevant to occupational exposure, and the results are dynamic and dose specific. The results suggest that inversions induced after low dose irradiation are removed by homeostatic mechanisms within a short time frame, and underscore the importance of studying responses over a period of time when interpreting radiation effects. PMID- 27223830 TI - MicroRNAs and Their Impact on Radiotherapy for Cancer. AB - Resistance to radiation is considered to be an important reason for local failure after radiotherapy and tumor recurrence. However, the exact mechanisms of tumor resistance remain poorly understood. Current investigations of microRNAs as potential diagnostic and therapeutic tools for cancer treatment have shown promising results. With respect to radiotherapy resistance and response, there is now emerging evidence that microRNAs modulate key cellular pathways that mediate response to radiation. These data suggest that microRNAs might have significant potential as targets for the development of new therapeutic strategies to overcome radioresistance in cancer. This review summarizes the current literature pertinent to the influence of microRNAs in the response to radiotherapy for cancer treatment, with an emphasis on microRNAs as novel diagnostic and prognostic markers, as well as their potential to alter radiosensitivity. PMID- 27223831 TI - Stimulation of Tetrabromobisphenol A Binding to Soil Humic Substances by Birnessite and the Chemical Structure of the Bound Residues. AB - Studies have shown the main fate of the flame retardant tetrabromobisphenol A (TBBPA) in soils is the formation of bound residues, and mechanisms on it are less-understood. This study investigated the effect of birnessite (delta-MnO2), a naturally occurring oxidant in soils, on the formation of bound residues. (14)C labeled TBBPA was used to investigate the pH dependency of TBBPA bound-residue formation to two soil humic acids (HAs), Elliott soil HA and Steinkreuz soil HA, in the presence of delta-MnO2. The binding of TBBPA and its transformation products to both HAs was markedly increased (3- to 17-fold) at all pH values in the presence of delta-MnO2. More bound residues were formed with the more aromatic Elliott soil HA than with Steinkreuz soil HA. Gel-permeation chromatography revealed a uniform distribution of the bound residues within Steinkreuz soil HA and a nonuniform distribution within Elliott soil HA. (13)C NMR spectroscopy of (13)C-TBBPA residues bound to (13)C-depleted HA suggested that in the presence of delta-MnO2, binding occurred via ester and ether and other types of covalent bonds besides HA sequestration. The insights gained in this study contribute to an understanding of the formation of TBBPA bound residues facilitated by delta-MnO2. PMID- 27223833 TI - Some Additional Considerations Regarding the American Society of Addiction Medicine National Practice Guideline for the Use of Medications in the Treatment of Addiction Involving Opioid Use. PMID- 27223834 TI - Stigmatizing and Misleading Terminology-More. PMID- 27223835 TI - Editor's response to Newman and Gevertz "Stigmatizing and Misleading Terminology More". PMID- 27223836 TI - Measuring Quality of Buprenorphine Care. PMID- 27223837 TI - Treatment Quality for Buprenorphine Care: The Pot at the End of the Rainbow. PMID- 27223839 TI - Society News: ASAM Magazine. PMID- 27223841 TI - Evidence for genistein as a mitochondriotropic molecule. AB - Genistein (4',5,7-trihydroxyisoflavone; C15H10O5), an isoflavone, has been investigated as an anti-cancer agent due to its ability to trigger cell death (both intrinsic and extrinsic apoptotic pathways) in different cancer cells in vitro and in vivo. Furthermore, genistein has been viewed as a mitochondriotropic molecule due to the direct effects this isoflavone induces in mitochondria, such as modulation of enzymatic activity of components of the oxidative phosphorylation system. Apoptosis triggering may also be mediated by genistein through activation of the mitochondria-dependent pathway by a mechanism associated with mitochondrial dysfunction (i.e., disruption of the mitochondrial membrane potential - MMP, release of cytochrome c, activation of the apoptosome, among others). Efforts have been made in order to elucidate how genistein coordinate these biochemical phenomena. Nonetheless, some areas of the mitochondria-associated research (mitochondrial biogenesis, redox biology of mitochondria, and mitochondria-associated bioenergetic parameters) need to be explored regarding the role of genistein as a mitochondria-targeted agent. This is a pharmacologically relevant issue due to the possibility of using genistein as a mitochondria-targeted drug in cases of cancer, neurodegeneration, cardiovascular, and endocrine disease, for example. The present review aims to describe, compare, and discuss relevant data about the effects of genistein upon mitochondria. PMID- 27223840 TI - Travel to Asia and traveller's diarrhoea with antibiotic treatment are independent risk factors for acquiring ciprofloxacin-resistant and extended spectrum beta-lactamase-producing Enterobacteriaceae-a prospective cohort study. AB - Travel to (sub)tropical countries is a well-known risk factor for acquiring resistant bacterial strains, which is especially of significance for travellers from countries with low resistance rates. In this study we investigated the rate of and risk factors for travel-related acquisition of extended spectrum beta lactamase-producing Enterobacteriaceae (ESBL-E), ciprofloxacin-resistant Enterobacteriaceae (CIPR-E) and carbapenem-resistant Enterobacteriaceae. Data before and after travel were collected from 445 participants. Swabs were cultured with an enrichment broth and sub-cultured on selective agar plates for ESBL detection, and on plates with a ciprofloxacin disc. ESBL production was confirmed with the double-disc synergy test. Species identification and susceptibility testing were performed with the Vitek-2 system. All isolates were subjected to ertapenem Etest. ESBL and carbapenemase genes were characterized by PCR and sequencing. Twenty-seven out of 445 travellers (6.1%) already had ESBL-producing strains and 45 of 445 (10.1%) travellers had strains resistant to ciprofloxacin before travel. Ninety-eight out of 418 (23.4%) travellers acquired ESBL-E and 130 of 400 (32.5%) travellers acquired a ciprofloxacin-resistant strain. Of the 98 ESBL-E, predominantly Escherichia coli and predominantly blaCTX-M-15, 56% (55/98) were resistant to gentamicin, ciprofloxacin and co-trimoxazole. Multivariate analysis showed that Asia was a high-risk area for ESBL-E as well as CIPR-E acquisition. Travellers with diarrhoea combined with antimicrobial use were significantly at higher risk for acquisition of resistant strains. Only one carbapenemase-producing isolate was acquired, isolated from a participant after visiting Egypt. In conclusion, travelling to Asia and diarrhoea combined with antimicrobial use are important risk factors for acquiring ESBL-E and CIPR-E. PMID- 27223842 TI - Evaluating clinical mitochondrial respiratory chain enzymes from biopsy specimens presenting skewed probability distribution of activity data. AB - Due to the relative rarity of mitochondrial diseases, generating reference ranges is problematic in evaluation of respiratory chain activities particularly in pediatric cases. We determined the sample distribution of respiratory chain enzyme activities in skeletal muscle biopsies collected from pediatric patients suspected of neuromuscular disorders. Activities of NADH-ubiquinone reductase, NADH-cytochrome c reductase, succinate-cytochrome c reductase; ubiquinol cytochrome c reductase and cytochrome c oxidase activities have log-normal distributions even when confirmed mitochondrial diseases were ruled out. Impact of the log-normal distribution of the respiratory chain enzyme activities on clinical diagnostics is discussed. PMID- 27223843 TI - Directional control of diffusion and swelling in megamolecular polysaccharide hydrogels. AB - Directional control of diffusion and swelling in megamolecular polysaccharide hydrogels is demonstrated by focusing on the anisotropic structures for water absorption. Due to the presence of a layered structure in the hydrogel, the directional control for diffusion parallel to the planar direction and swelling in the lateral direction are possible. PMID- 27223844 TI - Bilayer Cryogel Wound Dressing and Skin Regeneration Grafts for the Treatment of Acute Skin Wounds. AB - In this study, the potential of cryogel bilayer wound dressing and skin regenerating graft for the treatment of surgically created full thickness wounds was evaluated. The top layer was composed of polyvinylpyrrolidone-iodine (PVP-I) cryogel and served as the antiseptic layer, while the bottom regenerative layer was made using gelatin cryogel. Both components of the bilayer showed typical features of a cryogel interconnected macropore network, rapid swelling, high water uptake capacity of about 90%. Both PVP and gelatin cryogel showed high tensile strength of 45 and 10 kPa, respectively. Gelatin cryogel sheets were essentially elastic and could be stretched without any visible deformation. The antiseptic PVP-I layer cryogel sheet showed sustained iodine release and suppressed microbial growth when tested with skin pathogens (zone of inhibition ~2 cm for sheet of 0.9 cm diameter). The gelatin cryogel sheet degraded in vitro in weeks. The gelatin cryogel sheet supported cell infiltration, attachment, and proliferation of fibroblasts and keratinocytes. Microparticles loaded with bioactive molecules (mannose-6-phosphate and human fibrinogen) were also incorporated in the gelatin cryogel sheets for their role in enhancing skin regeneration and scar free wound healing. In vivo evaluation of healing capacity of the bilayer cryogel was checked in rabbits by creating full thickness wound defect (diameter 2 cm). Macroscopic and microscopic observation at regular time intervals for 4 weeks demonstrated better and faster skin regeneration in the wound treated with cryogel bilayer as compared to untreated defect and the repair was comparable to commercial skin regeneration scaffold Neuskin-F. Complete skin regeneration was observed after 4 weeks of implantation with no sign of inflammatory response. Defects implanted with cryogel having mannose-6-phosphate showed no scar formation, while the wound treated with bilayer incorporated with human fibrinogen microparticles showed early signs of skin regeneration; epidermis formation occurred at 2 weeks after implantation. PMID- 27223845 TI - The mucin-degradation strategy of Ruminococcus gnavus: The importance of intramolecular trans-sialidases. AB - We previously identified and characterized an intramolecular trans-sialidase (IT sialidase) in the gut symbiont Ruminococcus gnavus ATCC 29149, which is associated to the ability of the strain to grow on mucins. In this work we have obtained and analyzed the draft genome sequence of another R. gnavus mucin degrader, ATCC 35913, isolated from a healthy individual. Transcriptomics analyses of both ATCC 29149 and ATCC 35913 strains confirmed that the strategy utilized by R. gnavus for mucin-degradation is focused on the utilization of terminal mucin glycans. R. gnavus ATCC 35913 also encodes a predicted IT sialidase and harbors a Nan cluster dedicated to sialic acid utilization. We showed that the Nan cluster was upregulated when the strains were grown in presence of mucin. In addition we demonstrated that both R. gnavus strains were able to grow on 2,7-anyhydro-Neu5Ac, the IT-sialidase transglycosylation product, as a sole carbon source. Taken together these data further support the hypothesis that IT-sialidase expressing gut microbes, provide commensal bacteria such as R. gnavus with a nutritional competitive advantage, by accessing and transforming a source of nutrient to their own benefit. PMID- 27223846 TI - Modeling the cost-effectiveness of ilaprazole versus omeprazole for the treatment of newly diagnosed duodenal ulcer patients in China. AB - OBJECTIVES: To evaluate the cost-effectiveness of 10 mg ilaprazole once-daily vs 20 mg omeprazole once-daily to treat newly-diagnosed duodenal ulcer patients in China. METHODS: A decision tree model was constructed and the treatment impact was projected up to 1 year. The CYP2C19 polymorphism distribution in the Chinese population, the respective cure rates in the CYP2C19 genotype sub-groups, the impact of Duodenal Ulcer (DU) on utility value and drug-related side-effect data were obtained from the literature. The total costs of medications were calculated to estimate the treatment costs based on current drug retail prices in China. Expert surveys were conducted when published data were not available. Probabilistic sensitivity analysis was performed to gauge the robustness of the results. RESULTS: Ilaprazole, when compared with omeprazole, achieved a better overall clinical efficacy. For the overall population, ilaprazole achieved an incremental cost effectiveness ratio (ICER) of Y132 056 per QALY gained. This is less than the WHO recommended threshold of 3-times the average GDP per capita in China (2014). Furthermore, sub-group analysis showed that ilaprazole is cost effective in every province in CYP2C19 hetEM patients and in the most developed provinces in CYP2C19 homEM patients. Probabilistic sensitivity analysis suggests that the results are robust with 97% probability that ilaprozole is considered cost-effective when a threshold of 3-times China's average GDP per capita is considered. LIMITATION: This study didn't have the data of ilaprazole combined with Hp eradication therapy. Caution should be taken when extrapolating these findings to DU patients with an Hp eradication therapy. CONCLUSIONS: The cost effectiveness analysis results demonstrated that ilaprazole would be considered a cost-effective therapy, compared with omeprazole, in Chinese DU patients based on the efficacy projections in various CYP2C19 polymorphism types. PMID- 27223847 TI - Momentary Work Happiness as a Function of Enduring Burnout and Work Engagement. AB - The present study (N = 136) combined global measures with specific, experience based measures to investigate how enduring job burnout and engagement influence the impact of daily work activities on momentary need satisfaction and happiness. We used the day reconstruction method (DRM) to ask employees from various occupations to reconstruct their working days. On the basis of employee work engagement and self-determination theories, we hypothesized that time spent on (a) core work tasks; (b) administrative work tasks; (c) client interactions; (d) interactions with colleagues; and (e) meetings would be negatively related to need satisfaction on the task level for employees high (vs. low) in enduring burnout; and positively related to need satisfaction on the task level for employees high (vs. low) in enduring work engagement. In addition, we predicted that psychological need satisfaction would mediate the relationships between time spent on work tasks and happiness during the tasks. The results of multilevel analyses largely supported these hypotheses. Our findings contribute to the literature by showing how those with high levels of burnout do not manage to satisfy their basic needs through their work, whereas those with high levels of work engagement satisfy their daily needs and stay happy. PMID- 27223848 TI - Nitric oxide inhibitory constituents from the barks of Cinnamomum cassia. AB - Six new compounds including one gamma-butyrolactone, cinncassin A (1), two tetrahydrofuran derivatives, cinncassins B and C (2, 3), two lignans, cinncassins D and E (4, 5), and one phenylpropanol glucoside, cinnacassoside D (6), together with 14 known lignans (7-20) were isolated from the barks of Cinnamomum cassia. The structures of 1-6 were elucidated by extensive 1D and 2D NMR spectroscopic data analysis as well as chemical methods, and the absolute configurations were established by experimental and calculated ECD data. The anti-inflammatory activities of the isolates were evaluated on nitric oxide (NO) production in lipopolysaccharide (LPS)-induced BV-2 microglial cells. Compounds 5, 7, 8, and 15 showed potent inhibition activities with IC50 values of 17.6, 17.7, 18.7, and 17.5MUM, respectively. PMID- 27223849 TI - Kazinol B from Broussonetia kazinoki improves insulin sensitivity via Akt and AMPK activation in 3T3-L1 adipocytes. AB - In this study, we evaluated the insulin-sensitizing effect of flavans purified from Broussonetia kazinoki Siebold (BK) on 3T3-L1 adipocytes. Among the tested compounds, kazinol B enhanced intracellular lipid accumulation, gene expression of proliferator-activated receptorgamma (PPARgamma) and CCAAT/enhancer binding protein-alpha (C/EBPalpha), and consistently induced PPARgamma transcriptional activation. To further investigate the insulin-sensitizing effect of kazinol B, we measured glucose analogue uptake by fully differentiated adipocytes and myotubes. Kazinol B increased 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2 deoxy-d-glucose (2-NBDG) uptake by cells by upregulating the gene expression and translocation of glucose transporter 4 (GLUT-4) into the plasma membrane in adipocytes. Kazinol B stimulated the gene expression and secretion of adiponectin, which is associated with a low risk of types 1 and 2 diabetes mellitus. We also suggested the mechanism of the antidiabetic effect of kazinol B by assaying Akt and AMP-activated protein kinase (AMPK) phosphorylation. In conclusion, kazinol B isolated from BK improved insulin sensitivity by enhancing glucose uptake via the insulin-Akt signaling pathway and AMPK activation. These results suggest that kazinol B might be a therapeutic candidate for diabetes mellitus. PMID- 27223850 TI - New metabolites of acteoside identified by ultra-performance liquid chromatography/quadrupole-time-of-flight MS(E) in rat plasma, urine, and feces. AB - Acteoside, which belongs to the family of phenylethanoid glycosides (PhGs), has extensive biological activities, including strong antioxidant, anti-inflammatory, hepatoprotect, and cell apoptosis regulation. Like other PhGs compounds, the fate of acteoside in the gut for both parent polyphenols and their degradation products, small phenolic acid and aromatic catabolites cannot be ignored. Therefore, in this work, expanded and systematical investigation for metabolism characteristic profiles of acteoside in vivo by ultra-performance liquid chromatography/ quadrupole-time-of-flight and a new MS(E) data collection technology had been studied. This was equivalent to non-slective MS/MS scans and helpful to explore new metabolites. After oral administration of 200mg/kg acteoside, He et al. (2011) a total of 44 metabolites was detected and identified, and 37 of them were reported for the first time. Among them, 35 were parent drug metabolites classified in 14 groups. Owen et al. (2003) Through the comprehensive metabolites study in plasma, urine and feces, acteoside systemical metabolites profiles and characteristics elaborated firstly. The relative content of metabolites research showed that acteoside could exist stably and the process for biotransformation of acteoside in blood keep extreme short time. Pan and Hori (1996) The significant new transformation of isomerization from acteoside to isoacteoside had been firstly found and confirmed. The results of this work provided new information for the clarification of the metabolism of acteoside and rendered a very valuable theoretical basis for the development of novel ideal dosage forms of acteoside in the future. PMID- 27223851 TI - The inhibitory effects of nor-oleanane triterpenoid saponins from Stauntonia brachyanthera towards UDP-glucuronosyltransferases. AB - The inhibition of UDP-glucuronosyltransferases (UGTs) by herbal components might be an important reason for clinical herb-drug interaction (HDI). The inhibitory effects on UGTs via nor-oleanane triterpenoid saponins, which were the bioactive ingredients from Stauntonia brachyanthera, a traditional Chinese folk medicines with highly biological values, were evaluated comprehensively with recombinant UGT isoforms as enzyme source and a nonspecific substrate 4-methylumbelliferone (4-MU) as substrate. The results showed that there are seven compounds, 2, 3, 4, 8, 9, 13 and 14, respectively, exhibited potential inhibitions towards UGT1A1, UGT1A3 and UGT1A10 among all 23 compounds isolated from the plants. The IC50 values were 17.1MUM, 13.5MUM, 9.5MUM, 15.7MUM, 16.3MUM, 1.1MUM, and 0.3MUM, respectively. Data fitting using Dixon and Lineweaver-Burk plots demonstrated that the inhibition of UGT1A10, UGT1A1 and UGT1A3 was best fit to noncompetitive type and competitive, respectively. The inhibition kinetic parameter (Ki) was calculated to be 39MUM, 17MUM, 3.3MUM, 10MUM, 9.3MUM, 0.19MUM, and 0.016MUM, respectively. All these experimental data suggested that HDI might occur when compounds containing herbs were co-administered with drugs which mainly undergo UGTs-mediated metabolism. PMID- 27223853 TI - Spatial and polarity precision of concentric high-definition transcranial direct current stimulation (HD-tDCS). AB - Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique that applies low amplitude current via electrodes placed on the scalp. Rather than directly eliciting a neuronal response, tDCS is believed to modulate excitability-enhancing or suppressing neuronal activity in regions of the brain depending on the polarity of stimulation. The specificity of tDCS to any therapeutic application derives in part from how electrode configuration determines the brain regions that are stimulated. Conventional tDCS uses two relatively large pads (>25 cm(2)) whereas high-definition tDCS (HD-tDCS) uses arrays of smaller electrodes to enhance brain targeting. The 4 * 1 concentric ring HD-tDCS (one center electrode surrounded by four returns) has been explored in application where focal targeting of cortex is desired. Here, we considered optimization of concentric ring HD-tDCS for targeting: the role of electrodes in the ring and the ring's diameter. Finite element models predicted cortical electric field generated during tDCS. High resolution MRIs were segmented into seven tissue/material masks of varying conductivities. Computer aided design (CAD) model of electrodes, gel, and sponge pads were incorporated into the segmentation. Volume meshes were generated and the Laplace equation ([Formula: see text] . (sigma [Formula: see text] V) = 0) was solved for cortical electric field, which was interpreted using physiological assumptions to correlate with stimulation and modulation. Cortical field intensity was predicted to increase with increasing ring diameter at the cost of focality while uni-directionality decreased. Additional surrounding ring electrodes increased uni-directionality while lowering cortical field intensity and increasing focality; though, this effect saturated and more than 4 surround electrode would not be justified. Using a range of concentric HD-tDCS montages, we showed that cortical region of influence can be controlled while balancing other design factors such as intensity at the target and uni-directionality. Furthermore, the evaluated concentric HD-tDCS approaches can provide categorical improvements in targeting compared to conventional tDCS. Hypothesis driven clinical trials, based on specific target engagement, would benefit by this more precise method of stimulation that could avoid potentially confounding brain regions. PMID- 27223854 TI - Relating to Pediatric Dentists. PMID- 27223855 TI - Nonsurgical Correction of Severe Skeletal Class III Malocclusion. PMID- 27223856 TI - What Influences a Pediatric Dentist to Refer to a Particular Orthodontist? PMID- 27223857 TI - Treatment of Chronic Adult Periodontitis in a Patient with Negative Overjet and Multiple Tooth Loss. PMID- 27223858 TI - Accelerated Orthodontics. PMID- 27223859 TI - A "Renewable" Archwire for Uprighting Impacted Lower Second Molars. PMID- 27223860 TI - Double-Ligation Technique for Rotated Teeth. PMID- 27223861 TI - Hypermethylation-Induced Inactivation of the IRF6 Gene as a Possible Early Event in Progression of Vulvar Squamous Cell Carcinoma Associated With Lichen Sclerosus. AB - IMPORTANCE: The molecular mechanism leading to the development of vulvar squamous cell carcinoma (VSCC) from vulvar lichen sclerosus (VLS) is unknown. OBJECTIVE: To assess the possible involvement of the IRF6 tumor-suppressor gene in the development of VSCC from VLS. DESIGN: In laboratories at the University of Ferrara, Ferrara, Italy, IRF6 gene expression and promoter methylation were investigated in paraffin-embedded VSCC and adjacent vulvar intraepithelial neoplasia (VIN) and VLS specimens, in cancer-free VLS (cfVLS) specimens, and in healthy skin specimens by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) analysis and by sequencing of PCR-amplified bisulfite-treated DNA. Methylation-induced dysregulation was assessed by expression of p63, the IRF6-transactivator gene. MAIN OUTCOMES AND MEASURES: IRF6 expression, correlation with promoter methylation and p63 expression, and association with development of VSCC from VLS. RESULTS: Specimens from 60 participating women (1 specimen from each) were analyzed for the study (mean [SD] age, 66.3 [12.1] years): 20 paraffin-embedded specimens of VSCC (patient age, 75.3 [8.3] years) with adjacent VLS lesions, in 5 of which VIN preneoplastic tissue was also present (patient age, 64.3 [15.3] years); 20 cfVLS specimens (patient age, 62.1 [11.4] years) obtained from diagnostic biopsies; and 20 normal skin specimens from noncancer surgical patients (patient age, 61.4 [9.1] years). IRF6 messenger RNA was found to be reduced 4.5-, 2.9-, 6.6-, and 2.2-fold in VLS, VIN, VSCC, and cfVLS specimens, respectively, compared with controls, although p63 was still expressed in all specimens. IRF6 promoter was hypermethylated in 9 (45%) of 20 VLS specimens, 1 (20%) of 5 VIN specimens, 16 (80%) of 20 VSCC specimens, 2 (10%) of 20 cfVLS specimens, and 0 normal skin specimens. CONCLUSIONS AND RELEVANCE: IRF6 dysregulation may be involved in the development of VSCC from VLS. Methylation of the IRF6 promoter may be a marker of cancer risk in patients with VLS. PMID- 27223862 TI - Preventive strategies and potential therapeutic interventions for delirium in sepsis. AB - Delirium is the most frequent and severe clinical presentation of brain dysfunction in critically ill septic patients with an incidence ranging from 9% to 71%. Delirium represents a significant burden for patients and relatives, as well as to the health care system, resulting in higher costs, long-term cognitive impairment and significant risk of death after 6 months. Current interventions for the prevention of delirium typically involve early recognition and amelioration of modifiable risk factors and treatment of underlying conditions that predisposes the individual to delirium. Several pharmacological interventions to prevent and treat delirium have been tested, although their effectiveness remains uncertain, especially in larger and more homogeneous subgroups of ICU patients, like in patients with sepsis. To date, there is inconsistent and conflicting data regarding the efficacy of any particular pharmacological agent, thus substantial attention has been paid to non pharmacological interventions and preventive strategies should be applied to every patient admitted in the ICU. Future trials should be designed to evaluate the impact of these pharmacologic interventions on the prevention and treatment of delirium on clinically relevant outcomes such as length of stay, hospital mortality and long-term cognitive function. The role of specific medications like statins in delirium prevention is also yet to be evaluated. PMID- 27223863 TI - Efficacy and safety of LABA/LAMA fixed-dose combinations approved in the US for the management of COPD. AB - INTRODUCTION: Long-acting beta2-agonists [LABAs] and long-acting muscarinic antagonists [LAMAs]) are primary therapies for chronic obstructive pulmonary disease (COPD). Despite improvements in lung function and patient-reported outcomes (PROs) with these therapies, there is room to optimize outcomes further. Combined use of LABAs and LAMAs is recommended when symptoms are not improved with a single agent, and LABA/LAMA fixed-dose combinations (FDCs) are at the forefront of drug development in COPD. AREAS COVERED: This review focusses on the three LABA/LAMA FDCs (indacaterol/glycopyrrolate(1) [IND/GLY] 27.5/15.6 ug twice daily, umeclidinium/vilanterol [UMEC/VI] 62.5/25 ug once daily and tiotropium/olodaterol [Tio/Olo] 5/5 ug once daily approved in the US. Phase III clinical trials have shown benefits in lung function, dyspnea and health status with FDCs of IND/GLY, UMEC/VI and Tio/Olo versus placebo and monotherapies. Expert commentary: Data from recent studies of three LABA/LAMA combinations, reviewed here, indicate that dual bronchodilation may be beneficial above and beyond both the monotherapies and LABA/ICS combinations, in providing improvements in lung function and PROs for patients with COPD, which may encourage a shift away from the use of ICS in COPD management, in particular for non-exacerbating patients. PMID- 27223864 TI - Reactivity to addictive drugs in the methylazoxymethanol (MAM) model of schizophrenia in male and female rats. AB - OBJECTIVES: Patients with schizophrenia often suffer comorbid substance abuse regardless of gender. However, the vast majority of studies are only conducted in male subjects. Therefore, the aim of these experiments is to assess addictive behaviors of both sexes in a neurodevelopmental model of schizophrenia induced by prenatal methylazoxymethanol (MAM) acetate exposure. METHODS: MAM (22 mg/kg) was administered intraperitoneally on gestational day 17. Two studies were performed in the offspring: (1) an alcohol-drinking procedure to assess daily intake of 20% alcohol and relapse-like behavior after a period of forced abstinence; (2) Methamphetamine (METH) intravenous self administration (IVSA) followed by forced abstinence and reinstatement phases. RESULTS: MAM exposure during the prenatal period did not change alcohol drinking regardless of sex. However, MAM females showed higher alcohol consumption in comparison to MAM males. The METH IVSA study revealed only a modest increase of drug consumption in MAM males, while there was no difference between the female groups. Reinstatement data showed no effect of the MAM model in either sex, but suggested increased responding in female rats. CONCLUSIONS: This study suggests that female sex and schizophrenia-like phenotype may work synergistically to enhance alcohol consumption. However, future research is needed to establish paradigms in which these findings would be readily assessed to test anti-addiction treatments. PMID- 27223865 TI - Emerging infectious disease and fast-track publication: when public health gets priority over the formality of scholarly publishing. PMID- 27223866 TI - Abundance of Lutzomyia longipalpis in urban households as risk factor of transmission of visceral leishmaniasis. AB - Urban occurrence of human and canine visceral leishmaniasis (VL) is linked to households with characteristics conducive to the presence of sand flies. This study proposes an ad hoc classification of households according to the environmental characteristics of receptivity to phlebotominae and an entomological study to validate the proposal. Here we describe the phlebotominae population found in intra- and peridomiciliary environments and analyse the spatiotemporal distribution of the VL vector Lutzomyia longipalpis of households receptive to VL. In the region, 153 households were classified into levels of receptivity to VL followed by entomological surveys in 40 of those properties. Kruskal-Wallis verified the relationship between the households' classification and sand fly abundance and Kernel analysis evaluated L. longipalpis spatial distribution: of the 740 sand flies were captured, 91% were L. longipalpis; 82% were found peridomiciliary whilst the remaining 18% were found intradomiciliary. No statistically significant association was found between sandflies and households levels. L. longipalpis counts were concentrated in areas of high vulnerability and some specific households were responsible for the persistence of the infestation. L. longipalpis prevails over other sand fly species for urban VL transmission. The entomological study may help target the surveillance and vector control strategies to domiciles initiating and/or maintaining VL outbreaks. PMID- 27223867 TI - Anopheles darlingi polytene chromosomes: revised maps including newly described inversions and evidence for population structure in Manaus. AB - Salivary gland polytene chromosomes of 4th instar Anopheles darlingi Root were examined from multiple locations in the Brazilian Amazon. Minor modifications were made to existing polytene photomaps. These included changes to the breakpoint positions of several previously described paracentric inversions and descriptions of four new paracentric inversions, two on the right arm of chromosome 3 and two on the left arm of chromosome 3 that were found in multiple locations. A total of 18 inversions on the X (n = 1) chromosome, chromosome 2 (n = 7) and 3 (n = 11) were scored for 83 individuals from Manaus, Macapa and Porto Velho municipalities. The frequency of 2Ra inversion karyotypes in Manaus shows significant deficiency of heterozygotes (p < 0.0009). No significant linkage disequilibrium was found between inversions on chromosome 2 and 3. We hypothesize that at least two sympatric subpopulations exist within the An. darlingi population at Manaus based on inversion frequencies. PMID- 27223868 TI - Functional complementation of Leishmania (Leishmania) amazonensis AP endonuclease gene (lamap) in Escherichia coli mutant strains challenged with DNA damage agents. AB - During its life cycle Leishmania spp. face several stress conditions that can cause DNA damages. Base Excision Repair plays an important role in DNA maintenance and it is one of the most conserved mechanisms in all living organisms. DNA repair in trypanosomatids has been reported only for Old World Leishmania species. Here the AP endonuclease from Leishmania (L.) amazonensis was cloned, expressed in Escherichia coli mutants defective on the DNA repair machinery, that were submitted to different stress conditions, showing ability to survive in comparison to the triple null mutant parental strain BW535. Phylogenetic and multiple sequence analyses also confirmed that LAMAP belongs to the AP endonuclease class of proteins. PMID- 27223870 TI - Survey of numerical electrostimulation models. AB - This paper evaluates results of a survey of electrostimulation models of myelinated nerve. Participants were asked to determine thresholds of excitation for 18 cases involving different characteristics of the neuron, the stimulation waveform, and the electrode arrangement. Responses were received from 7 investigators using 10 models. Excitation thresholds differed significantly among these models. For example, with a 2 ms monophasic stimulus pulse and an electrode/fiber distance of 1 cm, thresholds from the least to greatest value differed by a factor of 8.3; with a 5 MUs pulse, thresholds differed by the factor 3.8. Significant differences in reported simulations point to the need for experimental validation. Additional efforts are needed to develop computational models for unmyelinated C-fibers, A-delta fibers, CNS neurons, and CNS Synapses. PMID- 27223869 TI - ? PMID- 27223871 TI - Fine Needle Aspiration Cytology vs. the Postoperative Histology - the Continuing Need for Multi-Disciplinary Approach? AB - We set out to investigate the concordance rates that were observed between fine needle aspiration cytology (FNA) compared with that of the post operative histology obtained for thyroid nodules over an 8 year period at a large university hospital.A retrospective analysis of 355 cases was conducted; patients operated for hyperthyroidism were excluded for the purposes of this study. We identified malignancy in a total of 101 cases (28%) The chance of malignancy with 2 Thy1 specimens was 5% in this study and 9% was observed in those with a Thy 2 FNA. On the converse, 7% of patient had malignant cytology on FNA though post operative histology turned out to be benign.This therefore highlights the potential for discordance between thyroid FNA cytology and post-operative histology in the assessment of any thyroid nodule and thus reinforcing the need for a multidisciplinary approach in the assessment of all thyroid nodules. PMID- 27223872 TI - Establishing a Proteomics-Based Monocyte Assay To Assess Differential Innate Immune Activation Responses. AB - Innate immune cells are complex systems that can be simultaneously activated in a variety of ways. Common methods currently used to estimate the response of innate immune cells to stimuli are usually biased toward a single mode of activation. The aim of this study was to assess the possibility of designing an assay based on unbiased proteome analysis that would be capable of predicting the complex response of the innate immune system to various challenges. Monocytes were used as representative cells of the innate immune system. The underlying hypothesis was that their proteome response to different activating molecules would reflect the immunogenicity of these molecules. To identify the main modes of response, we treated the human monocytic THP-1 cell line with nine different stimuli. Differentiation and activation were determined to be the two major modes of monocyte response, with PMA causing the strongest differentiation and Pam3CSK4 causing the strongest proinflammatory activation. The established assay was applied to characterize the monocyte response to epidermal growth factor peptide containing isoaspartate, which induced differentiation but not proinflammatory activation. Because of its versatility, robustness, and specificity, this new assay is likely to find a niche among the more established immunological methods. PMID- 27223873 TI - The role of human papillomavirus (HPV)-related stigma on HPV vaccine decision making among college males. AB - OBJECTIVE: The goals of the present study are (1) to identify sociodemographic and psychosocial predictors of human papillomavirus (HPV)-related stigma and (2) to examine the relationship between HPV-related stigma in predicting HPV vaccine decision-making among college males. PARTICIPANTS: Six hundred and eighty college males aged 18-26 from 3 Canadian universities were recruited from September 2013 to April 2014. METHODS: Participants completed a self-report survey assessing HPV related stigma, psychosocial predictors of HPV-related stigma, and HPV vaccine decision-making. The results were analyzed using variance analyses and linear regressions. RESULTS: Ethnicity, province of residence, and perceived severity of HPV were found to significantly influence HPV-related stigma. In addition, HPV related stigma was higher in those unaware of the availability of the HPV vaccine for males. CONCLUSIONS: Promotion efforts should concentrate on Asian minorities and should avoid HPV severity messaging, as these may lead to higher HPV-related stigma, which in turn may act as a barrier to vaccination. PMID- 27223874 TI - Unveiling the electrochemical mechanisms of Li2Fe(SO4)2 polymorphs by neutron diffraction and density functional theory calculations. AB - The quest for new sustainable iron-based positive electrode materials for lithium ion batteries recently led to the discovery of a new family of compounds with the general formula Li2M(SO4)2 with M = transition metal, which presents monoclinic and orthorhombic polymorphs. In terms of electrochemical performances, although both Li2Fe(SO4)2 polymorphs present a similar potential of ~3.8 V vs. Li(+)/Li(0), the associated electrochemical processes drastically differ in terms of polarization and reaction redox mechanisms. We herein provide an explanation to account for such a behavior. While monoclinic Li2Fe(SO4)2 directly transforms into Li1.0Fe(SO4)2 upon oxidation, the orthorhombic counterpart forms a distinct intermediate Li1.5Fe(SO4)2 phase leading to a two-step delithiation process involving an unequal depopulation of the two Li sites pertaining to the structure as deduced by neutron powder diffraction experiments and confirmed by both density functional theory and Bond Valence Energy Landscape calculations. Moreover, to access band gap information, both polymorphs are studied by UV/Vis spectroscopy. Lastly, the possibility of transforming the monoclinic phase to the orthorhombic phase under pressure is explored. PMID- 27223876 TI - Doctor to Doctor. PMID- 27223875 TI - Single-Molecule Force Spectroscopy Reveals Multiple Binding Modes between DOPA and Different Rutile Surfaces. AB - Inspired by marine mussel adhesive systems, numerous 3,4-dihydroxyphenylalanine (DOPA)-containing surface coating materials have been recently designed. It is well known that DOPA has a strong adhesion ability to different kinds of wet surfaces. However, the molecular mechanism of DOPA adhesion remains elusive. Recent biophysical studies of DOPA adhesion by both surface force apparatus (SFA) and atomic force microscopy (AFM) suggest that DOPA can bind to a wide range of surfaces exhibiting diverse chemical properties through different binding mechanisms. Here, using AFM-based single-molecule force spectroscopy, we show that even for chemically well-defined crystal surfaces, DOPA can bind to them by multiple binding modes. The binding forces between DOPA and different rutile TiO2 surfaces can vary within a broad range from 40-800 pN at a pulling speed of 1000 nm s-1 and are largely dependent on the surface properties. Our findings indicate that the local chemical environment can greatly affect DOPA adhesion, and that single-molecule force spectroscopy is a unique tool to reveal the heterogeneity of DOPA adhesion to the same surface. PMID- 27223877 TI - Mothers. PMID- 27223878 TI - Pearls. PMID- 27223879 TI - cme credit Quiz. PMID- 27223880 TI - Walking for health. PMID- 27223882 TI - Induction Therapy for Kidney Transplant Recipients: Do We Still Need Anti-IL2 Receptor Monoclonal Antibodies? AB - Induction therapy with antilymphocyte biological agents is widely used after kidney transplantation, most commonly T lymphocyte-depleting rabbit-derived antithymocyte globulin (rATG) or an IL-2 receptor antagonist (IL2RA). Early randomized trials showed that rATG or IL2RA induction reduces early acute rejection, prompting recommendations by Kidney Disease Improving Global Outcomes that IL2RA induction be used routinely in first-line therapy after kidney transplantation, with lymphocyte-depleting induction reserved for high-risk cases. These studies, however, mainly used outdated maintenance regimens. No large randomized trial has examined the effect of IL2RA or rATG induction versus no induction in patients receiving tacrolimus, mycophenolic acid and steroids. With this triple maintenance therapy, the addition of induction may achieve an absolute risk reduction for acute rejection of only 1-4% in standard-risk patients without improving graft or patient survival. In contrast, rATG induction lowers the relative risk of acute rejection by almost 50% versus IL2RA in patients with high immunological risk. These recent data raise questions about the need for IL2RA in kidney transplantation, as it may no longer be beneficial in standard-risk transplantation and may be inferior to rATG in high-risk situations. Updated evidence-based guidelines are necessary to support clinicians deciding whether and what induction therapy is required for their transplant patients today. PMID- 27223883 TI - The safety and efficacy of endoscopic Zenker's diverticulotomy: A cohort study. AB - OBJECTIVES/HYPOTHESIS: To determine whether the application of laser-assisted techniques for the treatment of Zenker's diverticulum would reduce the failure rate of endoscopic procedures without compromising safety or durability. STUDY DESIGN: Cohort study with long-term follow-up. METHODS: We performed a single institution review of 106 consecutive patients in whom endoscopic laser-assisted diverticulotomy (ELD) or endoscopic stapler-assisted diverticulotomy (ESD) was attempted. The Eating Assessment Tool was collected pre- and postoperatively. Long-term follow-up was conducted on average 2.4 years postoperatively. RESULTS: The decision to use either ELD or ESD was made intraoperatively. An endoscopic procedure was successfully completed in 103 of 106 patients (97.2%). Eighty-three patients underwent ELD, 20 underwent ESD, and only three required use of an open approach. No serious complications occurred. Postoperatively, there was a significant reduction in dysphagia symptoms. At follow-up, most individuals had dysphagia scores within the normal range (69%) and were eating a regular diet (73%). Fourteen patients (14%) required revision. Compared to historical data from our institution for ESD alone, the addition of ELD resulted in a reduction in the failure rate without an increase in serious complications. Recurrence rates and long-term outcomes were equivalent. CONCLUSION: Through careful patient selection, appropriate workup, and judicious use of techniques, it was possible to perform endoscopic surgery in a majority of patients without serious complications. Both approaches resulted in short- and long-term symptom management with high levels of satisfaction. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:2705-2710, 2016. PMID- 27223884 TI - The Development of a Nurse-Led Internet-Based Learning and Self-care Program for Cancer Patients With Symptoms of Anxiety and Depression-A Part of U-CARE. AB - BACKGROUND: Having access to information about the disease and being encouraged to participate in self-care activities may reduce anxiety and depression symptoms in cancer patients. Internet-based interventions may be one way to support effective self-care strategies to improve emotional well-being and health-related quality of life. OBJECTIVE: The aim of this study was to describe the development and acceptance of an Internet-based program intended to support cancer patients with anxiety and depression symptoms. METHODS: A structured collaboration between patients, clinicians, and researchers was used to develop a theory- and evidence based interactive health communication application (IHCA) based on Orem's self care deficit nursing theory with influences from Bandura's social learning theory and psychoeducation. RESULTS: The result is an IHCA described as a Nurse-led, Internet-based Learning and Self-care program that helps patients to perform self care using different types of material in interaction with patients and healthcare staff. The acceptance of the program is consistent with the results of similar studies. CONCLUSIONS: Collaboration between patients, clinicians, and researchers seems to be a fruitful approach in the development of an IHCA aiming to support cancer patients' self-care strategies. Well-designed intervention studies are needed to evaluate the effects of the IHCA. IMPLICATIONS FOR PRACTICE: This article suggests a theoretical foundation for an IHCA and allows researchers and healthcare providers to take part in the discussion regarding format and content of IHCAs. PMID- 27223885 TI - Synthesis of gamma,delta-Unsaturated alpha-Aminoaldehydes Using a Copper Catalyzed Vinylation Reaction Followed by a Claisen Rearrangement. AB - A new method to synthesize gamma,delta-unsaturated alpha-nitrogenated aldehydes in very good yields is described herein. This method involves a copper-coupling reaction between beta-iodoenamide derivatives and allylic alcohols to generate beta-allyloxyenamide derivatives. The latter, when heated, undergo a Claisen rearrangement and form gamma,delta-unsaturated alpha-nitrogenated aldehydes. PMID- 27223887 TI - Correction: Transformed Recombinant Enrichment Profiling Rapidly Identifies HMW1 as an Intracellular Invasion Locus in Haemophilus influenzae. AB - [This corrects the article DOI: 10.1371/journal.ppat.1005576.]. PMID- 27223886 TI - Expression of E-, P- and N-Cadherin and Its Clinical Significance in Cervical Squamous Cell Carcinoma and Precancerous Lesions. AB - Aberrant expression of classical cadherins has been observed in tumor invasion and metastasis, but its involvement in cervical carcinogenesis and cancer progression is not clear. We investigated E-, P- and N-cadherin expression and its significance in cervical squamous cell carcinoma (SCC) and cervical intraepithelial neoplasia (CIN). This retrospective study enrolled 508 patients admitted to Women's Hospital, School of Medicine, Zhejiang University with cervical lesions between January 2006 and December 2010. Immunochemical staining was performed in 98 samples of normal cervical epithelium (NC), 283 of CIN, and 127 of early-stage SCC. The association of cadherin staining with clinical characteristics and survival of the patients was evaluated by univariate and multivariate analysis. We found gradients of decreasing E-cadherin expression and increasing P-cadherin expression from NC through CIN to SCC. Aberrant E-cadherin and P-cadherin expression were significantly associated with clinical parameters indicating poor prognosis and shorter patient survival. Interestingly, we found very low levels of positive N-cadherin expression in CIN and SCC tissues that were not related to CIN or cancer. Pearson chi-square tests showed that E cadherin expression in SCC was inversely correlated with P-cadherin expression (E P switch), and was not correlated with N-cadherin expression. More important, patients with tissues exhibiting an E-P switch in expression had highly aggressive phenotypes and poorer prognosis than those without E-P switch expression. Our findings suggest that E-cadherin and P-cadherin, but not N cadherin staining, might be useful in diagnosing CIN and for predicting prognosis in patients with early-stage SCC. PMID- 27223888 TI - Research Capacity Strengthening in Low and Middle Income Countries - An Evaluation of the WHO/TDR Career Development Fellowship Programme. AB - Between August 2012 and April 2013 the Career Development Fellowship programme of the Special Programme for Research and Training in Tropical Diseases (World Health Organization) underwent an external evaluation to assess its past performance and determine recommendations for future programme development and continuous performance improvement. The programme provides a year-long training experience for qualified researchers from low and middle income countries at pharmaceutical companies or product development partnerships. Independent evaluators from the Swiss Tropical and Public Health Institute and the Barcelona Institute for Global Health used a results-based methodology to review the programme. Data were gathered through document review, surveys, and interviews with a range of programme participants. The final evaluation report found the Career Development Fellowship to be relevant to organizers' and programme objectives, efficient in its operations, and effective in its training scheme, which was found to address needs and gaps for both fellows and their home institutions. Evaluators found that the programme has the potential for impact and sustainability beyond the programme period, especially with the successful reintegration of fellows into their home institutions, through which newly developed skills can be shared at the institutional level. Recommendations included the development of a scheme to support the re-integration of fellows into their home institutions post-fellowship and to seek partnerships to facilitate the scaling-up of the programme. The impact of the Professional Membership Scheme, an online professional development tool launched through the programme, beyond the scope of the Career Development Fellowship programme itself to other applications, has been identified as a positive unintended outcome. The results of this evaluation may be of interest for other efforts in the field of research capacity strengthening in LMICs or, generally, to other professional development schemes of a similar structure. PMID- 27223889 TI - Tunneled Indwelling Catheters for Malignant Ascites #308. PMID- 27223890 TI - Nation Building and Social Signaling in Southern Ontario: A.D. 1350-1650. AB - Pottery is a mainstay of archaeological analysis worldwide. Often, high proportions of the pottery recovered from a given site are decorated in some manner. In northern Iroquoia, late pre-contact pottery and early contact decoration commonly occur on collars-thick bands of clay that encircle a pot and extend several centimeters down from the lip. These decorations constitute signals that conveyed information about a pot's user(s). In southern Ontario the period A.D. 1350 to 1650 witnessed substantial changes in socio-political and settlement systems that included population movement, coalescence of formerly separate communities into large villages and towns, waxing and waning of regional strife, the formation of nations, and finally the development of three confederacies that each occupied distinct, constricted areas. Social network analysis demonstrates that signaling practices changed to reflect these regional patterns. Networks become more consolidated through time ultimately resulting in a "small world" network with small degrees of separation between sites reflecting the integration of communities within and between the three confederacies. PMID- 27223891 TI - CRISPR-Mediated Slamf1Delta/Delta Slamf5Delta/Delta Slamf6Delta/Delta Triple Gene Disruption Reveals NKT Cell Defects but Not T Follicular Helper Cell Defects. AB - SAP (SH2D1A) is required intrinsically in CD4 T cells to generate germinal center responses and long-term humoral immunity. SAP binds to SLAM family receptors, including SLAM, CD84, and Ly108 to enhance cytokine secretion and sustained T cell:B cell adhesion, which both improve T follicular helper (Tfh) cell aid to germinal center (GC) B cells. To understand the overlapping roles of multiple SLAM family receptors in germinal center responses, Slamf1Delta/Delta Slamf5Delta/Delta Slamf6Delta/Delta triple gene disruption (Slamf1,5,6Delta/Delta) mice were generated using CRISPR-Cas9 gene editing to eliminate expression of SLAM (CD150), CD84, and Ly108, respectively. Gene targeting was highly efficient, with 6 of 6 alleles disrupted in 14 of 23 pups and the majority of alleles disrupted in the remaining pups. NKT cell differentiation in Slamf1,5,6Delta/Delta mice was defective, but not completely absent. The remaining NKT cells exhibited substantially increased 2B4 (SLAMF4) expression. Surprisingly, there were no overt defects in germinal center responses to acute viral infections or protein immunizations in Slamf1,5,6Delta/Delta mice, unlike Sh2d1a-/- mice. Similarly, in the context of a competitive environment, SLAM family receptor expressing GC Tfh cell, GC B cell, and plasma cell responses exhibited no advantages over Slamf1,5,6Delta/Delta cells. PMID- 27223892 TI - Cloning, Expression and Biochemical Characterization of Endomannanases from Thermobifida Species Isolated from Different Niches. AB - Thermobifidas are thermotolerant, compost inhabiting actinomycetes which have complex polysaccharide hydrolyzing enzyme systems. The best characterized enzymes of these hydrolases are cellulases from T. fusca, while other important enzymes especially hemicellulases are not deeply explored. To fill this gap we cloned and investigated endomannanases from those reference strains of the Thermobifida genus, which have published data on other hydrolases (T. fusca TM51, T. alba CECT3323, T. cellulosilytica TB100T and T. halotolerans YIM90462T). Our phylogenetic analyses of 16S rDNA and endomannanase sequences revealed that T. alba CECT3323 is miss-classified; it belongs to the T. fusca species. The cloned and investigated endomannanases belong to the family of glycosyl hydrolases 5 (GH5), their size is around 50 kDa and they are modular enzymes. Their catalytic domains are extended by a C-terminal carbohydrate binding module (CBM) of type 2 with a 23-25 residues long interdomain linker region consisting of Pro, Thr and Glu/Asp rich repetitive tetrapeptide motifs. Their polypeptide chains exhibit high homology, interdomain sequence, which don't show homology to each other, but all of them are built up from 3-6 times repeated tetrapeptide motifs) (PTDP-Tc, TEEP-Tf, DPGT-Th). All of the heterologously expressed Man5A enzymes exhibited activity only on mannan. The pH optima of Man5A enzymes from T. halotolerans, T. cellulosilytica and T. fusca are slightly different (7.0, 7.5 and 8.0, respectively) while their temperature optima span within the range of 70-75 degrees C. The three endomannanases exhibited very similar kinetic performances on LBG-mannan substrate: 0.9-1.7mM of KM and 80-120 1/sec of turnover number. We detected great variability in heat stability at 70 degrees C, which was influenced by the presence of Ca2+. The investigated endomannanases might be important subjects for studying the structure/function relation behind the heat stability and for industrial applications to hemicellulose degradation. PMID- 27223893 TI - Preliminary Proteomic Analysis of A549 Cells Infected with Avian Influenza Virus H7N9 and Influenza A Virus H1N1. AB - A newly emerged H7N9 influenza virus poses high risk to human beings. However, the pathogenic mechanism of the virus remains unclear. The temporal response of primary human alveolar adenocarcinoma epithelial cells (A549) infected with H7N9 influenza virus and H1N1 influenza A virus (H1N1, pdm09) were evaluated using the proteomics approaches (2D-DIGE combined with MALDI-TOF-MS/MS) at 24, 48 and 72 hours post of the infection (hpi). There were 11, 12 and 33 proteins with significant different expressions (P<0.05) at 24, 48 and 72hpi, especially F actin-capping protein subunit alpha-1 (CAPZA1), Ornithine aminotransferase (OAT), Poly(rC)-binding protein 1 (PCBP1), Eukaryotic translation initiation factor 5A-1 (EIF5A) and Platelet-activating factor acetylhydrolaseIb subunit beta (PAFAH1B2) were validated by western-blot analysis. The functional analysis revealed that the differential proteins in A549 cells involved in regulating cytopathic effect. Among them, the down-regulation of CAPZA1, OAT, PCBP1, EIF5A are related to the death of cells infected by H7N9 influenza virus. This is the first time show that the down-regulation of PAFAH1B2 is related to the later clinical symptoms of patients infected by H7N9 influenza virus. These findings may improve our understanding of pathogenic mechanism of H7N9 influenza virus in proteomics. PMID- 27223894 TI - Time Course of Heart Rate Variability Response to PM2.5 Exposure from Secondhand Smoke. AB - PURPOSE: Exposure to secondhand smoke (SHS) has been associated with decreased heart rate variability (HRV). However, the time course of this association is unclear. Therefore, the objective of this study was to investigate the association between 15-240 minute SHS-related fine particulate matter (PM2.5) moving averages and indices of HRV. METHODS: With a panel study design, we used personal monitors to continuously measure PM2.5 and HRV of 35 participants who were exposed to SHS for approximately 6 hours. RESULTS: We observed negative, significant associations between 5-minute HRV indices and 15 minute PM2.5 moving averages and 240 minute PM2.5 moving averages: there was a significant (p<0.01) 7.5% decrease in the 5-minute square root of the mean squared differences of successive normal heart beats associated with (RMSSD), and a significant (p<0.01) 14.7% decrease in the 5-minute high frequency (HF) power associated with the 15 minute PM2.5 moving averages; there was also a significant (p<0.01) 46.9% decrease in the 5-minute RMSSD, and a significant (p<0.01) 77.7% decrease in the 5-minute high frequency (HF) power associated with the 240 minute PM2.5 moving averages. CONCLUSIONS: Our findings that exposure to SHS related PM2.5 was associated with HRV support the hypothesis that SHS can affect the cardiovascular system. The negative associations reported between short and longer term PM2.5 and HRV indicate adverse effects of SHS on the cardiovascular system. PMID- 27223896 TI - The toxicology of heparin reversal with protamine: past, present and future. AB - INTRODUCTION: Unfractionated heparin is a strongly anionic anticoagulant used extensively in medicine to prevent blood clotting. In the case of an emergency bleeding in response to heparin, the protamine sulfate is administered. Despite its extensive clinical use, protamine may produce life-threatening side effects such as systemic hypotension, catastrophic pulmonary vasoconstriction or allergic reactions. Recent studies have demonstrated new organ-specific complications of the heparin reversal with protamine. AREAS COVERED: Past and present knowledge of the mechanisms responsible for the toxicity of protamine and the most promising potential replacements of protamine in the different phases of development. EXPERT OPINION: Despite of the low therapeutic index, protamine is the only registered antidote of heparins. The toxicology of protamine depends on a complex interaction of the high molecular weight, a cationic peptide with the surfaces of the vasculature and blood cells. The mechanisms involve membrane receptors and ion channels targeted by different vasoactive compounds, such as nitric oxide, bradykinin or histamine. Unacceptable side effects of protamine have led to a search for new alternatives: UHRA, LMWP, and Dex40-GTMAC3 are in the preclinical stage; the two other agents (andexanet alfa and PER977) are already in the advanced clinical phases. PMID- 27223895 TI - Acyl-CoA:Diacylglycerol Acyltransferase 1 Expression Level in the Hematopoietic Compartment Impacts Inflammation in the Vascular Plaques of Atherosclerotic Mice. AB - The final step of triacylglycerol synthesis is catalyzed by acyl CoA:diacylglycerol acyltransferases (DGATs). We have previously shown that ApoE-/ Dgat1-/- mice are protected from developing atherosclerosis in association with reduced foam cell formation. However, the role of DGAT1, specifically in myeloid and other hematopoietic cell types, in determining this protective phenotype is unknown. To address this question, we reconstituted the bone marrow of irradiated Ldlr-/-mice with that from wild-type (WT-> Ldlr-/-) and Dgat1-/-(Dgat1-/--> Ldlr /-) donor mice. We noted that DGAT1 in the hematopoietic compartment exerts a sex specific effect on systemic cholesterol homeostasis. However, both male and female Dgat1-/--> Ldlr-/-mice had higher circulating neutrophil and lower lymphocyte counts than control mice, suggestive of a classical inflammatory phenotype. Moreover, specifically examining the aortae of these mice revealed that Dgat1-/--> Ldlr-/-mice have atherosclerotic plaques with increased macrophage content. This increase was coupled to a reduced plaque collagen content, leading to a reduced collagen-to-macrophage ratio. Together, these findings point to a difference in the inflammatory contribution to plaque composition between Dgat1-/--> Ldlr-/-and control mice. By contrast, DGAT1 deficiency did not affect the transcriptional responses of cultured macrophages to lipoprotein treatment in vitro, suggesting that the alterations seen in the plaques of Dgat1-/--> Ldlr-/-mice in vivo do not reflect a cell intrinsic effect of DGAT1 in macrophages. We conclude that although DGAT1 in the hematopoietic compartment does not impact the overall lipid content of atherosclerotic plaques, it exerts reciprocal effects on inflammation and fibrosis, two processes that control plaque vulnerability. PMID- 27223898 TI - Does Personality Have a Different Impact on Self-Rated Distraction, Job Satisfaction, and Job Performance in Different Office Types? AB - This study investigates the joint effect of office type (cell, shared room, open plan, and flex) and personality, measured by the Big Five personality traits, on self-rated measures of distraction, job satisfaction, and job performance (measured by professional efficacy). Regression analyses with interactions between personality and office type were conducted on 1205 participants working in 5 organizations from both the private and public sectors. While few interactions were observed in the cases of professional efficacy and job satisfaction, several were observed between personality traits and office type on the level of distraction reported. Specifically, more emotionally stable participants reported lower distraction, particularly those working in flex offices. Both agreeableness and openness to experience were associated with higher levels of distraction among participants in open-plan compared to cell offices. PMID- 27223897 TI - Retrospective Study of Phospholipase A2 Receptor and IgG Subclasses in Glomerular Deposits in Chinese Patients with Membranous Nephropathy. AB - BACKGROUND AND OBJECTIVES: The research work in the past years showed that detection of phospholipase A2 receptor (PLA2R) antigen and its dominant IgG4 autoantibody in glomerular deposits of patients with membranous nephropathy (MN) was useful for the differentiation between primary MN (PMN) and secondary MN (SMN), but so far such research data from large Chinese patient series is little. Here, we are going to report a research work in a Chinese cohort. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study enrolled 179 patients with PMN, 40 patients with membranous lupus nephritis (LN-MN), 26 patients with hepatitis B virus-associated MN (HBV-MN), 2 patients with malignancy-associated MN (M-MN) and one patient with IgG4-related MN (IgG4-MN). PLA2R and IgG subclasses in glomerular deposits of these patients were examined by immunofluorescence and/or immunohistochemical staining, and the potential value of the above examinations for differential diagnosis of PMN and SMN was evaluated. RESULTS: Glomerular PLA2R deposition was present in 92.2% patients with PMN and 7.7% patients with HBV-MN, but none of the patients with LN-MN. Predominant/codominant IgG4 deposition was found in 93.3% patients with PMN and 11.5% patients with HBV-MN, but none of the patients with LN-MN. The two M-MN patients both had glomerular PLA2R and predominant/codominant IgG4 deposition. The one IgG4-MN patient had deeply staining IgG4 but no PLA2R in glomeruli. CONCLUSIONS: The glomerular PLA2R and predominant/codominant IgG4 deposition is frequently observed in Chinese patients with PMN. Immunofluorescence and immunohistochemical staining of renal biopsy tissue for detection of glomerular PLA2R and IgG subclasses deposition can help to distinguish PMN from LN-MN and most of HBV-MN. PMID- 27223900 TI - Knowledge Translation: Moving Proteomics Science to Innovation in Society. AB - Proteomics is one of the pivotal next-generation biotechnologies in the current "postgenomics" era. Little is known about the ways in which innovative proteomics science is navigating the complex socio-political space between laboratory and society. It cannot be assumed that the trajectory between proteomics laboratory and society is linear and unidirectional. Concerned about public accountability and hopes for knowledge-based innovations, funding agencies and citizens increasingly expect that emerging science and technologies, such as proteomics, are effectively translated and disseminated as innovation in society. Here, we describe translation strategies promoted in the knowledge translation (KT) and science communication literatures and examine the use of these strategies within the field of proteomics. Drawing on data generated from qualitative interviews with proteomics scientists and ethnographic observation of international proteomics conferences over a 5-year period, we found that proteomics science incorporates a variety of KT strategies to reach knowledge users outside the field. To attain the full benefit of KT, however, proteomics scientists must challenge their own normative assumptions and approaches to innovation dissemination-beyond the current paradigm relying primarily on publication for one's scientific peers within one's field-and embrace the value of broader (interdisciplinary) KT strategies in promoting the uptake of their research. Notably, the Human Proteome Organization (HUPO) is paying increasing attention to a broader range of KT strategies, including targeted dissemination, integrated KT, and public outreach. We suggest that increasing the variety of KT strategies employed by proteomics scientists is timely and would serve well the omics system sciences community. PMID- 27223899 TI - New mouse model of acute adult T-cell leukemia generated by transplantation of AKT, BCLxL, and HBZ-transduced T cells. AB - Adult T-cell leukemia/lymphoma (ATL) develops in human T-cell leukemia virus type 1 (HTLV-1) carriers. Although the HTLV-1-encoded HBZ gene is critically involved, HBZ alone is insufficient and additional, cooperative "hits" are required for the development of ATL. Candidate cooperative hits are being defined, but methods to rapidly explore their roles in ATL development in collaboration with HBZ are lacking. Here, we present a new mouse model of acute type ATL that can be generated rapidly by transplanting in vitro-induced T cells that have been retrovirally transduced with HBZ and two cooperative genes, BCLxL and AKT, into mice. Co-transduction of HBZ and BCLxL/AKT allowed these T cells to grow in vitro in the absence of cytokines (Flt3-ligand and interleukin-7), which did not occur with any two-gene combination. Although transplanted T cells were a mixture of cells transduced with different combinations of the genes, tumors that developed in mice were composed of HBZ/BCLxL/AKT triply transduced T cells, showing the synergistic effect of the three genes. The genetic/epigenetic landscape of ATL has only recently been elucidated, and the roles of additional "hits" in ATL pathogenesis remain to be explored. Our model provides a versatile tool to examine the roles of these hits, in collaboration with HBZ, in the development of acute ATL. PMID- 27223902 TI - An arena for caring. AB - If your immediate reaction to this trailer for a new journal AIDS Forum is to groan 'not more AIDS', read on - you are exactly the reader we want. PMID- 27223901 TI - Don't Do Different Things - Do Things Differently! Drug Development in Rare Diseases: The Patient's Perspective. AB - The pharmaceutical industry and regulatory authorities have traditionally made risk-benefit decisions without consulting patients. Today there is a movement to engage the patient in these decisions. This is particularly pertinent for the rare-disease patient population, who have limited access to effective diagnostics and treatments. We argue that their involvement at the earliest point of drug development will lead to more appropriate decision making, and potentially reduce the attrition rate. PMID- 27223903 TI - The silent army. AB - 'Statistics on the staggering amount of people caring for dependants were released last week I by the Office of Population Censuses & Surveys. PMID- 27223904 TI - The second wave. AB - It has now been accepted that the largest growing group in society contracting HIV infection is injecting drug users and their sexual partners. In Edinburgh we have a prime example of what can happen when those who inject, and are HIV positive, share injecting equipment. PMID- 27223906 TI - Protection for community nurses. AB - Nurses injured in patients' homes may be able to sue their health authority for negligence if new proposals go ahead. PMID- 27223905 TI - Call for tax relief on medical insurance. AB - Britain's largest medical insurance company has called for the Government to give tax relief on contributions from the over-65s to encourage them to stay with the scheme. PMID- 27223907 TI - Consensus claim. AB - Massive public debate over funding the NHS has opened the door to market reforms, the latest issue of Public Service Review claims. PMID- 27223909 TI - Salmonella source. AB - The source of the Salmonella Bacteria which poisoned 50 peers and up to 30 House of Lords staff last month has been traced. It was the mayonnaise. PMID- 27223908 TI - Nursing honours. AB - The Queen's Birthday Honours list paid tribute to the work of a number of overseas nurses in addition to the British nurses named in last week's Nursing Standard. The following nurses were also honoured. PMID- 27223910 TI - Peak viewing time for nursing documentaries. AB - A new series of documentaries focusing on the working lives of nurses is to be launched at peak viewing time on the ITV network this week. PMID- 27223911 TI - More effort needed to beat violence. AB - Violence against nurses on NHS premises must be tackled by both management and staff, speakers at two one-day conferences held last week claimed. PMID- 27223912 TI - Radical midwives announce elections. AB - Members of the Association of Radical Midwives will soon be asked to elect extra people to represent their interests, following a decision at their Annual General Meeting on June 11. PMID- 27223913 TI - Support groups for nurses. AB - The responsibility for maintaining health should be a reflection of the basic relationships between the .A. individual and the organisation for which he works. It is in the interest of both parties that reasonable steps are taken to live and work sensibly and not too demandingly'. ( 1 ). PMID- 27223914 TI - Union anger over NHS funding claim. AB - Health service unions have slammed an Oxford University Health Specialist's suggestion that the National Health Service is funded as highly as other western countries when 'efficient' staff costs are taken into account. PMID- 27223916 TI - Nurse exodus continues. AB - Nurses are applying for well paid jobs in America in even greater numbers despite the recent Clinical Grading Review pay awards. PMID- 27223915 TI - Unconsented examinations. AB - Disturbing reports of unconsented vaginal examination of women under general anaesthetic by medical students have been brought to the attention of the Royal College of Nursing Gynaecological Nursing Forum. PMID- 27223917 TI - Poll tax could hasten project 2000. AB - The Government's plan to make student nurses training under the present system pay the full Poll Tax charge may speed the introduction of Project 2000, the RCN has said. PMID- 27223918 TI - HIV-2:The Implications. AB - In 1983, the aetiological agent of AIDS was discovered by French scientists and was termed the 'lym- phadenopathy-associated virus' (LAV) [ 1 ]. A year later, American researchers also described this retrovirus and termed it the 'Human T cell leukemia virus, type III' (HTLV-III) [ 2 ], Both LAV and HTLV-III were the same retrovirus and in 1986, it was agreed that the viruses which can cause AIDS be termed the 'human immunodeficiency viruses' (HIV). PMID- 27223919 TI - Increase in child sexual abuse. AB - New figures released by the NCPCC show a substantial increase in the numbers of children being put on child abuse registers after diagnoses of sexual abuse. PMID- 27223920 TI - More personal services for NHS. AB - Nursing staff will be the powerhouse of a nationwide initiative being launched this week to provide more personalised services for NHS patients. PMID- 27223921 TI - Scottish training scheme for handicap care. AB - Nursing staff in Scotland are to receive special training to enable them to help their mentally handicapped patients achieve their full potential. PMID- 27223922 TI - South Birmingham promote health through theatre. AB - South Birmingham Health Authority will be promoting health through theatre at a special two-day festival this autumn. PMID- 27223923 TI - Waiting list hotline in Wessex. AB - A unique hospital waiting list 'hotline' service has been launched in Wessex. PMID- 27223924 TI - Norwich launch recruitment video. AB - A new recruitment video has been launched to attract male school leavers into nursing. Mr Noel Summers, the Director of the Broadland School of Nursing in Norwich has produced the video, called 'Men in Nursing', to prove to male school leavers that nursing is not a woman only profession. PMID- 27223926 TI - Testing times. AB - Significant issues which health care providers need to address as a matter of urgency have been raised by two announcements, one from the Government, the other from the General Medical Council. Interestingly, both stories 'broke' during the recent RCN Congress - but no mention of them there! PMID- 27223925 TI - Royal visit for Newcastle children's centre. AB - A children's play, help, and health centre set up in a deprived area by local families and officials is to be visited by the Princess Royal. PMID- 27223927 TI - No final solution. AB - As AIDS phobia, coupled with increasing homophobia, surges on with relentless fervour, the latest message from the so-called moral majority is euthanasia for people with AIDS. PMID- 27223928 TI - Hotel style hospital for Cleveland. AB - A L7 million luxury maternity unit has just been opened at South Cleveland Hospital in Middlesbrough. PMID- 27223929 TI - Measle immunisation drive in Wales. AB - Health Authorities in Wales are being urged to raise the level of child measles immunisation. PMID- 27223930 TI - Belfast nurses win computer scholarship. AB - Two Belfast nurses have won scholarships to attend an International Symposium on Nursing Use of Computers and Information at Trinity College, Dublin. PMID- 27223931 TI - Critical response to community care reports. AB - The RCN Society of Mental Handicap Nursing has responded critically to two major reports on the future of community care. PMID- 27223933 TI - Support for stillbirth definition campaign. AB - The RCN has given its backing to a campaign by the Stillbirth and Neonatal Death Society (SANDS) to change the legal definition of stillbirth from 28 to 24 weeks. PMID- 27223932 TI - Importance of pain management stressed. AB - Pain management is the essence of nursing, leading authority Laurel Archer, told nurses at an RCN Welsh Board sunset seminar. PMID- 27223934 TI - Paediatric report launched. AB - The 'Hidden Children' report on the paediatric ward attender system has been officially launched at RCN headquarters. The report has been produced on behalf of a number of organisations, including the RCN and the National Association for the Welfare of Children in Hospital. Lady Jean Lovell-Davis, the Director of NAWCH is pictured seated, with; (from left) Yvonne Mouncer, Deputy Director, National Association of Health Authorities; Jean Rigby, Unit General Manager, paediatrics, Birmingham Children's Hospital; Rosemary Thornes; Roderick MacFaul, and Sue Burr, the RCN Adviser in Peadiatrics. PMID- 27223935 TI - Training support workers. AB - The English National Board decided last week to 'keep an eye' on the training of support workers, but said it is not prepared to commit itself to becoming a validating body for such courses. PMID- 27223937 TI - New test for rare child cancer. AB - Prenatal screening tests will soon be available to women with a family history of devastating childhood cancers, according to scientists from the Institute of Child Health. PMID- 27223939 TI - Baby milk samples to be stopped. AB - Baby milk manufacturers have agreed to stop supplying hospitals with free samples of breast milk substitutes, it was announced last week. PMID- 27223940 TI - Looking at liaison role. AB - Liaison nurses may be widening gaps in services instead of filling them appropriately, the second national meeting of liaison nurses heard last week. PMID- 27223942 TI - Expanding in a new direction. AB - The work of the Alzheimer's Disease Society, the charity which supports people with dementia and their carers, is set to expand following the appointment of its new director, Noreen Miller. PMID- 27223941 TI - Peel report under review. AB - An expert committee is to review the guidelines for the use of foetal material in research, Health Minister Tony Newton announced last week. PMID- 27223943 TI - Quenching thirsts. AB - Elderly people are at risk of becoming dehydrated. Now, new research is developing ways of helping nurses assess dehydration and spot the patients at greatest risk. PMID- 27223945 TI - Suffering a loss. AB - Parents who have suffered the loss of a child should be reassured that their psychosomatic symptoms are not indicative of mental illness. PMID- 27223944 TI - Breaking down the walls... AB - An antibiotic which could act locally has been discovered by researchers in Tel Aviv. PMID- 27223946 TI - Fragmenting gallstones. AB - Lithotripsy using 'second generation' piezo-ceramic systems is effective and safe for treating gallstones, say researchers from London. PMID- 27223947 TI - Advertising alcohol. AB - Television advertisers are failing to direct advertisements for alcohol away from children and adolescents, contrary to the code of practice, researchers from Scotland claim. PMID- 27223948 TI - Hypnotising ulceration. AB - Hypnotherapy may be a useful treatment for some patients with chronic recurrent duodenal ulceration. PMID- 27223949 TI - Same congress. AB - In response to Christopher Basset's letter (Nursing Standard week ending June 11). I was disturbed by his interpretation of the RCN Congress in Brighton - in fact I wonder whether we attended the same congress. PMID- 27223950 TI - Outpatients training. AB - I am very interested in setting up an in-service training programme to meet the needs of nursing staff working within outpatients departments. PMID- 27223951 TI - Seeking aids counsellors. AB - I have recently been appointed AIDS Co-ordinator for Advice and Counselling in this district and would be most interested to hear from any other people with similar backgrounds to my own who hold similar posts. PMID- 27223952 TI - Self advocacy. AB - Being a counsellor, a friend and a spokesperson for the mentally handicapped interested? PMID- 27223953 TI - Shift request. AB - Is there anything particulary wrong with wanting to know what shift you are working in a months time? PMID- 27223954 TI - The other side of the coin. AB - I read with growing interest your articles on the recruitment of student nurses, mainly because if I had seen what I have come to see in seven months of training I would never have entered nurse education. PMID- 27223955 TI - Silence on griffiths. AB - 'Community Care-agenda for action' or Griffiths mark two prompted me to organise a conference, thinking that nurses would need a forum to discuss the issues raised. The fee was L10 per delegate, which is not overly expensive as far as conferences go. But we had such a disappointing response, (only 26 people applied) that it had to be cancelled. PMID- 27223956 TI - Birth research. AB - I am a Student Midwife conducting research called 'Birth Plans; the parents choice.' If any readers have any experience or views of their own I would be most grateful if they could forward it me at; Peterborough Maternity Unit, Alderman's Drive, Peterborough, Cambs. PMID- 27223957 TI - [Not Available]. AB - "we've plenty of Beds, it's Trolleys we're Short of". PMID- 27223958 TI - Covering in surrey. AB - We are compiling a register of SRN/RGNs, plus SENs with some experience of nursing in general practice. PMID- 27223959 TI - Farewell invitation. AB - Mrs Anna Biczo (nee Hauk) will be retiring from Oldham School of Nursing on August [Illegible word] 1988. She began her nursing career in 1951, as a student nurse at North Manchester General Hospital (Crumpsall), then undertook midwifery training in Manchester and Worthing. Following this, she did a Neurosurgical Nursing Course in Edinburgh and returned to North Manchester in 1957. Mrs Biczo has worked in the Oldham School of Nursing since 1965, the last 18 years as Senior Tutor. PMID- 27223960 TI - The romance of Saudi Arabia. AB - The Kingdom of Saudi Arabia occupies much of the Arabian Peninsula, I covering an area of about 830,000 square miles (to put the massive size of the country into perspective, the UK only covers an area of around 94,000 square miles) but the total population is slightly larger than the population of London. PMID- 27223961 TI - Portfolio listings. PMID- 27223962 TI - Directions. AB - That people with mental handicap are educate has been recognised in the United Kingdom for nearly a century and a half. The degree to which the mentally handicapped individual can be educated may depend upon one factor or a combination of several, such as the level or extent of the handicap, the 'educator', the 'environmental determinants' (social, physical and domiciliary) or an associated physical disability. PMID- 27223968 TI - * Praise for no smoking policy. AB - The Royal College of Nursing has been congratulated in the House of Commons for its new 'no smoking' policy. PMID- 27223967 TI - Giving good counsel. AB - When the RCN Congress paid a special tribute to Penny Crawley last month it was to recognise the work she had done to promote and run the College's counselling service, CHAT, and her arguments for an independent service for nurses in all health authorities. PMID- 27223969 TI - Policies to blame for women's poverty. AB - Government policies are to blame for Victorian standards of poverty and ill health among Britain's poorest women, Jo Richardson, Labour's Women's Affairs spokeswoman, stated in the House of Commons. PMID- 27223970 TI - * Fund for disabled officially launched. AB - The Government's Independent Living Fund has been launched by Nicholas Scott, Minister for the Disabled, with a safeguard that payments will not affect entitlement to income support and family credit. PMID- 27223971 TI - Focussing on women's health issues. AB - The Government has announced plans for a one day conference to focus public and medical attention on women's health issues. PMID- 27223972 TI - Commissioners for mental health appointed. AB - Two Commissioners of the Mental Health Commission for Scotland have been appointed by The Queen on the recommendation of Mr Malcolm Rifkind, Secretary of State for Scotland. PMID- 27223973 TI - Expansion of national screening programme. AB - Major expansions of the breast screening programme, including plans for a further 100 centres, with mobile units touring rural areas, are to be announced in Parliament next month. PMID- 27223974 TI - Wheelchair cushion. AB - A lightweight pressure-relief cushion made especially for wheelchairs, is now available from the Danish company Bay Jacobsen. PMID- 27223975 TI - Avoiding balloon pump catheterisation. AB - A cardiac catheter that seeks to avoid one of the complications of catheterisation via balloon pump, has been designed by Datascope Medical. The Percor Stat DL9.5FR catheter has a sheath (through which the catheter is inserted) that measures only 10FR. PMID- 27223976 TI - Power source. AB - A wall-mounted transformer aimed at making diagnostic testing easier is available from Welch Allayn. PMID- 27223977 TI - Mobile first aid kits. AB - A range of first aid kits that can be used in the home, at work or while travelling are now on the market. PMID- 27223978 TI - Diamond studded cloth. AB - A personal cleaning cloth that comes with the added bonus of a pop-up dispenser is now available from the makers of Kleenex. PMID- 27223979 TI - On pins to test nerves. AB - A sterile new pin for testing a patient's neurological response is now on the market. PMID- 27223980 TI - Campaign to lift incontinence taboo. AB - Breaking the silence that surrounds incontinence is the aim of a campaign launched this month in the West Midlands and Tyne Tees. PMID- 27223981 TI - Non-invasive diagnostic system. AB - A new, portable non-invasive vascular diagnostic system is available from PMS (Instruments) Ltd. PMID- 27223982 TI - The sole of the matter. AB - 'Nurse,' the Sister whispered angrily, 'your shoes are too loud.' PMID- 27223983 TI - Down at the waterhole. AB - The Nursing Standard likes to keep you in touch with what is going on, and now we can reveal what happens when one of your colleagues swans off to a symposium. PMID- 27223984 TI - A pizza her mind. AB - It seems that Edwina Currie has finally got the message that people are cheesed off with her chiding them for their unhealthy ways. PMID- 27223986 TI - Well eye'll be! AB - Now girls, some tips to increase the durability of your eye shadow from Mrs Lee de Wet. 'Cream and stick shadows should be set with a light dusting of translucent powder. Use a brush. Powder shadows will last longer if you apply them over a translucent powder base or over a special shadow-fixing powder.' PMID- 27223985 TI - Name that tune... AB - The power of television has once again come to our notice with a piece of research showing that unborn babies can get hooked on soap operas. PMID- 27223987 TI - South Africa. AB - South African nurses earning less than 20,000 Rand a year (approximately L5,000) are set to gain from recently announced tax changes. PMID- 27223989 TI - Chile. AB - The Chilean state health service, which provides free health care on demand, is in a near state of collapse, according to a delegation of British women. PMID- 27223988 TI - United states. AB - A lack of public health nurses has been blamed for a high infant mortality rate in Chicago. PMID- 27223990 TI - Australia. AB - An international trial of a birth control vaccine has shown that it offers protection against pregnancy for up to six months without producing significant side effects. PMID- 27223991 TI - Uganda. AB - A major review of the United Nation's Children's Fund's (UNICEF) immunisation programme in Uganda has revealed an increase in the number of children being vaccinated against infectious diseases. PMID- 27223992 TI - Making music. AB - Gwyn Griffiths is Welsh to the tip of his baton. He speaks Welsh to his cats, conducts a Welsh male voice choir and sits on the RCN Welsh Board. PMID- 27223993 TI - Listings. AB - Nursing Standard's listings section is a completely free service for its readers. To ensure maximum publicity for any event connected with your profession, be sure to let us know so that it can be included in our exhaustive nationwide guide to what's on in nursing. PMID- 27223994 TI - Watchdog. AB - Q I am currently studying for a course in Business Studies. For my final assessment I have to study and discuss the format, membership and current standing of trade unions. In particular, I have to discuss the nurses' unions. PMID- 27223995 TI - Hyper. PMID- 27223996 TI - Feast and famine: Adipose tissue adaptations for healthy aging. AB - Proper adipose tissue function controls energy balance with favourable effects on metabolic health and longevity. The molecular and metabolic asset of adipose tissue quickly and dynamically readapts in response to nutrient fluctuations. Once delivered into cells, nutrients are managed by mitochondria that represent a key bioenergetics node. A persistent nutrient overload generates mitochondrial exhaustion and uncontrolled reactive oxygen species ((mt)ROS) production. In adipocytes, metabolic/molecular reorganization is triggered culminating in the acquirement of a hypertrophic and hypersecretory phenotype that accelerates aging. Conversely, dietary regimens such as caloric restriction or time controlled fasting endorse mitochondrial functionality and (mt)ROS-mediated signalling, thus promoting geroprotection. In this perspective view, we argued some important molecular and metabolic aspects related to adipocyte response to nutrient stress. Finally we delineated hypothetical routes by which molecularly and metabolically readapted adipose tissue promotes healthy aging. PMID- 27223998 TI - Islands in the desert: Species delimitation and evolutionary history of Pseudotetracha tiger beetles (Coleoptera: Cicindelidae: Megacephalini) from Australian salt lakes. AB - The Australian salt lakes are a natural archipelago-like laboratory for investigating evolutionary and population processes. Their environmental conditions have not undergone relevant changes since the aridification of Australia 10-5 million years ago. The genus Pseudotetracha, a group of nocturnal tiger beetles found on these remote salt lakes, includes 20 described species. Recent studies based on molecular markers and cytogenetics hinted at the existence of cryptic species within this group. Here we use various species delimitation algorithms to detect a high number of cryptic and undescribed taxa, and challenge the validity of the taxonomic characters traditionally used for discerning species in this group. Our analyses show that the divergence dates of the clades, between 10 and 5 million years ago, correspond to the period in which Australia was undergoing an aridification process that probably isolated the ancestral Pseudotetracha populations to individual lakes or palaeodrainage basins. This implies an important role of the isolation, produced by the aridification of Australia, in the speciation and divergence of Pseudotetracha, which underwent a remarkable radiation as the populations became geographically restricted. PMID- 27223999 TI - A novel phylogeny of the Gelidiales (Rhodophyta) based on five genes including the nuclear CesA, with descriptions of Orthogonacladia gen. nov. and Orthogonacladiaceae fam. nov. AB - Although the Gelidiales are economically important marine red algae producing agar and agarose, the phylogeny of this order remains poorly resolved. The present study provides a molecular phylogeny based on a novel marker, nuclear encoded CesA, plus plastid-encoded psaA, psbA, rbcL, and mitochondria-encoded cox1 from subsets of 107 species from all ten genera within the Gelidiales. Analyses of individual and combined datasets support the monophyly of three currently recognized families, and reveal a new clade. On the basis of these results, the new family Orthogonacladiaceae is described to accommodate Aphanta and a new genus Orthogonacladia that includes species previously classified as Gelidium madagascariense and Pterocladia rectangularis. Acanthopeltis is merged with Gelidium, which has nomenclatural priority. Nuclear-encoded CesA was found to be useful for improving the resolution of phylogenetic relationships within the Gelidiales and is likely to be valuable for the inference of phylogenetic relationship among other red algal taxa. PMID- 27223997 TI - Fanconi Anemia: A DNA repair disorder characterized by accelerated decline of the hematopoietic stem cell compartment and other features of aging. AB - Fanconi Anemia (FA) is a rare autosomal genetic disorder characterized by progressive bone marrow failure (BMF), endocrine dysfunction, cancer, and other clinical features commonly associated with normal aging. The anemia stems directly from an accelerated decline of the hematopoietic stem cell compartment. Although FA is a complex heterogeneous disease linked to mutations in 19 currently identified genes, there has been much progress in understanding the molecular pathology involved. FA is broadly considered a DNA repair disorder and the FA gene products, together with other DNA repair factors, have been implicated in interstrand cross-link (ICL) repair. However, in addition to the defective DNA damage response, altered epigenetic regulation, and telomere defects, FA is also marked by elevated levels of inflammatory mediators in circulation, a hallmark of faster decline in not only other hereditary aging disorders but also normal aging. In this review, we offer a perspective of FA as a monogenic accelerated aging disorder, citing the latest evidence for its multi factorial deficiencies underlying its unique clinical and cellular features. PMID- 27224000 TI - Hard Cap Espresso Machines in Analytical Chemistry: What Else? AB - A hard cap espresso machine has been used in combination with liquid chromatography with molecular fluorescence detection for the determination of polycyclic aromatic hydrocarbons (PAHs) from contaminated soils and sediments providing appropriate extraction efficiencies and quantitative results. Naphthalene, acenaphthene, fluorene, phenanthrene, anthracene, fluoranthene, pyrene, benz[a]anthracene, chrysene, benz[b]fluoranthene, benz[k]fluoranthene, benz[a]pyrene, dibenz[a,h]anthracene, benz[ghi]perylene, and indeno[1,2,3 cd]pyrene were used as target compounds. It should be mentioned that the pairs benz[a]anthracene-chrysene and dibenz[a,h]anthracene-benz[ghi]perylene peaks coelute under the employed chromatographic conditions; thus, those compounds were determined together. PAHs were extracted from 5.0 g of soil, previously homogenized, freeze-dried, and sieved to 250 MUm, with 50 mL of 40% (v/v) acetonitrile in water at a temperature of 72 +/- 3 degrees C. The proposed procedure is really fast, with an extraction time of 11 s, and it reduces the required amount of organic solvent to do the sample preparation. The obtained limit of detection for the evaluated PAHs was from 1 to 38 MUg kg(-1). Recoveries were calculated using clean soils spiked with 100, 500, 1000, and 2000 MUg kg(-1) PAHs with values ranging from 81 to 121% and good precision with relative standard deviation values lower than 30%. The method was validated using soil and sediment certified reference materials and also using real samples by comparison with ultrasound-assisted extraction, as reference methodology, obtaining statistically comparable results. Thus, the use of hard cap espresso machines in the analytical laboratories offers tremendous possibilities as low cost extraction units for the extraction of solid samples. PMID- 27224001 TI - Association between summer temperature and body weight in Japanese adolescents and children: An ecological analysis. AB - OBJECTIVE: Several experimental studies reported evidence of a negative energy balance at higher temperatures. However, corresponding weight loss has not been noted in clinical practice. This study investigated the geographical association between outdoor temperature and body weight in Japanese adolescents and children. METHODS: An ecological analysis was conducted using prefecture-level data on the mean body weight of Japanese adolescents and children over a 25-year period and Japanese mesh (regional) climatic data on the mean annual temperature, mean daily maximum temperature in August, and mean daily minimum temperature in January were also analyzed. RESULTS: Correlation analysis uncovered a stronger association between weight and the mean daily maximum temperature in August than with other climatic variables. Moreover, multiple regression analysis indicated that height and the mean daily maximum temperature in August were statistically significant predictors of weight. This suggests that geographical differences in weight in Japanese adolescents and children can be explained by the complementary relationship between height-associated weight gain and weight loss caused by summer heat. CONCLUSIONS: Summer temperatures may reduce the proportion of children who are overweight and contribute to geographical differences in body weight in Japanese adolescents and children. Am. J. Hum. Biol. 28:789-795, 2016. (c) 2016Wiley Periodicals, Inc. PMID- 27224002 TI - Role of Narrative Perspective and Modality in the Persuasiveness of Public Service Advertisements Promoting HPV Vaccination. AB - In the context of public service advertisements promoting human papillomavirus (HPV) vaccination, the current research examines 1) the relative persuasiveness of narrative vs. non-narrative messages and 2) the influence of narrative perspective (first- vs. third-person) and modality (text-based vs. audio-based) on message effectiveness. Results of a controlled experiment (N = 121) suggested that both a non-narrative message and a first-person narrative message led to greater perceived risk of getting HPV than a third-person narrative message. There was no difference in risk perception between the non-narrative and first person narrative conditions. These findings were confined to the text-based condition, however. When the messages were audio-based, no differential message effects were detected. The analysis also provided partial evidence for an indirect effect of narrative perspective on intentions to vaccinate against HPV through HPV risk perception. Theoretical and practical implications of the findings are discussed. PMID- 27224004 TI - Guidelines for Burn Care Under Austere Conditions: Introduction to Burn Disaster, Airway and Ventilator Management, and Fluid Resuscitation. PMID- 27224003 TI - Dual-Functional Nanoparticles Targeting CXCR4 and Delivering Antiangiogenic siRNA Ameliorate Liver Fibrosis. AB - The progression of liver fibrosis, an intrinsic response to chronic liver injury, is associated with hepatic hypoxia, angiogenesis, abnormal inflammation, and significant matrix deposition, leading to the development of cirrhosis and hepatocellular carcinoma (HCC). Due to the complex pathogenesis of liver fibrosis, antifibrotic drug development has faced the challenge of efficiently and specifically targeting multiple pathogenic mechanisms. Therefore, CXCR4 targeted nanoparticles (NPs) were formulated to deliver siRNAs against vascular endothelial growth factor (VEGF) into fibrotic livers to block angiogenesis during the progression of liver fibrosis. AMD3100, a CXCR4 antagonist that was incorporated into the NPs, served dual functions: it acted as a targeting moiety and suppressed the progression of fibrosis by inhibiting the proliferation and activation of hepatic stellate cells (HSCs). We demonstrated that CXCR4-targeted NPs could deliver VEGF siRNAs to fibrotic livers, decrease VEGF expression, suppress angiogenesis and normalize the distorted vessels in the fibrotic livers in the carbon tetrachloride (CCl4) induced mouse model. Moreover, blocking SDF 1alpha/CXCR4 by CXCR4-targeted NPs in combination with VEGF siRNA significantly prevented the progression of liver fibrosis in CCl4-treated mice. In conclusion, the multifunctional CXCR4-targeted NPs delivering VEGF siRNAs provide an effective antifibrotic therapeutic strategy. PMID- 27224006 TI - Cost-effectiveness of adding carfilzomib to lenalidomide and dexamethasone in relapsed multiple myeloma from a US perspective. AB - OBJECTIVE: To assess the economic value of carfilzomib (Kyprolis), this study developed the Kyprolis Global Economic Model (K-GEM), which examined from a United States (US) payer perspective the cost-effectiveness of carfilzomib lenalidomide-dexamethasone (KRd) versus lenalidomide-dexamethasone (Rd) in relapsed multiple myeloma (RMM; 1-3 prior therapies) based on results from the phase III ASPIRE trial that directly compared these regimens. METHODS: A partitioned survival model that included three health states of progression-free (on or off treatment), post-progression, and death was developed. Using ASPIRE data, the effect of treatment regimens as administered in the trial was assessed for progression-free survival and overall survival (OS). Treatment effects were estimated with parametric regression models adjusting for baseline patient characteristics and applied over a lifetime horizon. US Surveillance, Epidemiology and End Results (1984-2014) registry data were matched to ASPIRE patients to extrapolate OS beyond the trial. Estimated survival was adjusted to account for utilities across health states. The K-GEM considered the total direct costs (pharmacy/medical) of care for patients treated with KRd and Rd. RESULTS: KRd was estimated to be more effective compared to Rd, providing 1.99 life year and 1.67 quality-adjusted life year (QALY) gains over the modeled horizon. KRd treated patients incurred $179,393 in total additional costs. The incremental cost-effectiveness ratio (ICER) was $107,520 per QALY. LIMITATIONS: Extrapolated survival functions present the greatest uncertainty in the modeled results. Utilities were derived from a combination of sources and assumed to reflect how US patients value their health state. CONCLUSIONS: The K-GEM showed KRd is cost effective, with an ICER of $107,520 per QALY gained against Rd for the treatment of patients with RMM (1-3 prior therapies) at a willingness-to-pay threshold of $150,000. Reimbursement of KRd for patients with RMM may represent an efficient allocation of the healthcare budget. PMID- 27224005 TI - Global TLR2 and 4 deficiency in mice impacts bone resorption, inflammatory markers and atherosclerosis to polymicrobial infection. AB - Toll-like-receptors (TLRs) play a significant role in the generation of a specific innate immune response against invading pathogens. TLR2 and TLR4 signaling contributes to infection-induced inflammation in periodontal disease (PD) and atherosclerosis. Observational studies point towards a relationship between PD and atherosclerosis, but the role of TLR2 and TLR4 in the recognition of multiple oral pathogens and their modulation of host response leading to atherosclerosis are not clear. We evaluated the role of TLR2 and TLR4 signaling in the induction of both PD and atherosclerosis in TLR2-/- and TLR4-/- mice to polymicrobial infection with periodontal pathogens Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, and Fusobacterium nucleatum. Polybacterial infections have established gingival colonization in TLR2-/- and TLR4-/- mice and induction of a pathogen-specific immunoglobulin G immune response. But TLR deficiency dampened accelerated alveolar bone resorption and intrabony defects, indicating a central role in infection-induced PD. Periodontal bacteria disseminated from gingival tissue to the heart and aorta through intravascular dissemination; however, there was no increase in atherosclerosis progression in the aortic arch. Polybacterial infection does not alter levels of serum risk factors such as oxidized low-density lipoprotein, nitric oxide, and lipid fractions in both mice. Polymicrobial-infected TLR2-/- mice demonstrated significant levels (P < 0.05 to P < 0.01) of T helper type 2 [transforming growth factor-beta1 , macrophage inflammatory protein-3alpha, interleukin-13 (IL-13)] and T helper type 17 (IL-17, IL-21, IL-22, IL-23) splenic T-cell cytokine responses. Increased heat-shock protein expression, hspa1a for Hsp 70, was observed for both TLR2-/- and TLR4-/- mice. This study supports a role for TLR2 and TLR4 in PD and atherosclerosis, corroborating an intricate association between two inflammatory diseases. PMID- 27224007 TI - Optimisation of vectorisation property: A comparative study for a secondary amphipathic peptide. AB - RNA interference provides a powerful technology for specific gene silencing. Therapeutic applications of small interfering RNA (siRNA) however require efficient vehicles for stable complexation and intracellular delivery. In order to enhance their cell delivery, short amphipathic peptides called cell penetrating peptides (CPPs) have been intensively developed for the last two decades. In this context, the secondary amphipathic peptide CADY has shown to form stable siRNA complexes and to improve their cellular uptake independent of the endosomal pathway. In the present work, we have described the parameters influencing CADY nanoparticle formation (buffers, excipients, presence of serum, etc.), and have followed in details the CPP:siRNA self-assembly. Once optimal conditions were determined, we have compared the ability of seven different CADY analogues to form siRNA-loaded nanoparticles compared to CADY:siRNA. First of all, we were able to show by biophysical methods that structural polymorphism (alpha-helix) is an important prerequisite for stable nanoparticle formation independently of occurring sequence mutations. Luciferase assays revealed that siRNA complexed to CADY-K (shorter version) shows better knock-down efficiency on Neuro2a-Luc(+) and B16-F10-Luc(+) cells compared to CADY:siRNA. Altogether, CADY K is an ideal candidate for further application especially with regards to ex vivo or in vivo applications. PMID- 27224008 TI - Suppression of protein inactivation during freezing by minimizing pH changes using ionic cryoprotectants. AB - Freezing and lyophilization are often used for stabilization of biomolecules; however, this sometimes results in partial degradation and loss of biological function in these molecules. In this study we examined the effect of freezing induced acidity changes on denaturation of the model enzyme haloalkane dehalogenase under various experimental conditions. The effective local pH of frozen solutions is shown to be the key causal factor in protein stability. To preserve the activity of frozen-thawed enzymes, acidity changes were prevented by the addition of an ionic cryoprotectant, a compound which counteracts pH changes during freezing due to selective incorporation of its ions into the ice. This approach resulted in complete recovery of enzyme activity after multiple freeze thaw cycles. We propose the utilization of ionic cryoprotectants as a new and effective cryopreservation method in research laboratories as well as in industrial processes. PMID- 27224009 TI - Painful Cutaneous Nodule of the Jawline. PMID- 27224010 TI - Transforming phylogenetic networks: Moving beyond tree space. AB - Phylogenetic networks are a generalization of phylogenetic trees that are used to represent reticulate evolution. Unrooted phylogenetic networks form a special class of such networks, which naturally generalize unrooted phylogenetic trees. In this paper we define two operations on unrooted phylogenetic networks, one of which is a generalization of the well-known nearest-neighbor interchange (NNI) operation on phylogenetic trees. We show that any unrooted phylogenetic network can be transformed into any other such network using only these operations. This generalizes the well-known fact that any phylogenetic tree can be transformed into any other such tree using only NNI operations. It also allows us to define a generalization of tree space and to define some new metrics on unrooted phylogenetic networks. To prove our main results, we employ some fascinating new connections between phylogenetic networks and cubic graphs that we have recently discovered. Our results should be useful in developing new strategies to search for optimal phylogenetic networks, a topic that has recently generated some interest in the literature, as well as for providing new ways to compare networks. PMID- 27224011 TI - Emerging Drug Use Trends in Kelantan, Malaysia. AB - The primarily rural and agrarian Kelantan province of Malaysia has high rates of drug use and is characterized by unique sociocultural factors. Combining qualitative and ethnographic methods, we investigated drug use and treatment needs of people who use drugs (PWUD) in rural areas of Kelantan. In February 2014, field visits, participant observation, and focus group discussions (FGDs) with 27 active PWUD were conducted in rural areas surrounding the capital city of Kelantan. The findings indicate a high prevalence of opiate and amphetamine type stimulants (ATS) use in these areas. FGD participants reported initiating drug use at early ages due to peer influences, to relieve boredom, to cope with problems, and a high saturation of villages with other PWUD was reported as a major contributor to their own continued drug use. They reported a trend of drug use initiation at younger ages and increased drug use among females. Participants were interested in treatment; however, their limited knowledge about treatment options and perceived limited availability of services were barriers to treatment seeking. Easy access to drugs, primarily from Thailand and facilitated by the use of mobile phones, resulted in an expanding prevalence of drug use that underscores the need to bolster education and prevention efforts and accessibility of treatment services in Kelantan. PMID- 27224012 TI - An acute gastroenteritis outbreak caused by GII.17 norovirus in Jiangsu Province, China. AB - Noroviruses are a common cause of acute gastroenteritis around the world; however, reports of outbreaks caused by GII.17 norovirus are rare. An outbreak caused by GII.17 norovirus in a senior high school in Wuxi, Jiangsu Province, China is reported here. An epidemiological investigation, pathogen detection, and case-control study were performed. Epidemiological data combined with the epidemic curve indicated that this outbreak was a point source type initially, followed by secondary transmission. The first case was identified as most likely the source of the outbreak. Risk analysis showed exposure to patients and sharing a communal water cooler to be associated with the spread of infection. Sequence analysis of GII-positive samples confirmed that the norovirus GII.17 variant was the etiological agent of this outbreak. PMID- 27224013 TI - A Chimeric Pneumovirus Fusion Protein Carrying Neutralizing Epitopes of Both MPV and RSV. AB - Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are paramyxoviruses that are responsible for substantial human health burden, particularly in children and the elderly. The fusion (F) glycoproteins are major targets of the neutralizing antibody response and studies have mapped dominant antigenic sites in F. Here we grafted a major neutralizing site of RSV F, recognized by the prophylactic monoclonal antibody palivizumab, onto HMPV F, generating a chimeric protein displaying epitopes of both viruses. We demonstrate that the resulting chimeric protein (RPM-1) is recognized by both anti-RSV and anti-HMPV F neutralizing antibodies indicating that it can be used to map the epitope specificity of antibodies raised against both viruses. Mice immunized with the RPM-1 chimeric antigen generate robust neutralizing antibody responses to MPV but weak or no cross-reactive recognition of RSV F, suggesting that grafting of the single palivizumab epitope stimulates a comparatively limited antibody response. The RPM-1 protein provides a new tool for characterizing the immune responses resulting from RSV and HMPV infections and provides insights into the requirements for developing a chimeric subunit vaccine that could induce robust and balanced immunity to both virus infections. PMID- 27224014 TI - The Role of microRNAs in Animal Cell Reprogramming. AB - Our concept of cell reprogramming and cell plasticity has evolved since John Gurdon transferred the nucleus of a completely differentiated cell into an enucleated Xenopus laevis egg, thereby generating embryos that developed into tadpoles. More recently, induced expression of transcription factors, oct4, sox2, klf4, and c-myc has evidenced the plasticity of the genome to change the expression program and cell phenotype by driving differentiated cells to the pluripotent state. Beyond these milestone achievements, research in artificial cell reprogramming has been focused on other molecules that are different than transcription factors. Among the candidate molecules, microRNAs (miRNAs) stand out due to their potential to control the levels of proteins that are involved in cellular processes such as self-renewal, proliferation, and differentiation. Here, we review the role of miRNAs in the maintenance and differentiation of mesenchymal stem cells, epimorphic regeneration, and somatic cell reprogramming to induced pluripotent stem cells. PMID- 27224015 TI - Eggs as a Suitable Tool for Species Diagnosis of Causative Agents of Human Diphyllobothriosis (Cestoda). AB - BACKGROUND: Tapeworms of the order Diphyllobothriidea are parasites of tetrapods and several species may infect man and cause neglected human disease called diphyllobothriosis. Identification of human-infecting diphyllobothriid cestodes is difficult because of their morphological uniformity, which concerns also their eggs in stool samples. METHODS: In the present study, we analysed by far the largest dataset of more than 2,000 eggs of 8 species of diphyllobothriid cestodes that may infect humans, including the most frequent human parasites Diphyllobothrium latum, D. nihonkaiense and Adenocephalus pacificus (syn. Diphyllobothrium pacificum). Size (length, width and length/width ratio) and the surface of the egg shell from naturally and experimentally infected hosts were studied using light and scanning electron microscopy. RESULTS: A high degree of intraspecific and host-related size variability has been detected, but combination of morphometrical and ultrastructural data made it possible to distinguish all of the studied species, including otherwise quite similar eggs of the 3 most common species infecting man, i.e. D. latum, D. nihonkaiense and D. dendriticum. The surface of all marine species is covered by numerous deep pits with species-specific density, whereas the surface of freshwater species is smooth or with isolated shallow hollows or wrinkles. PMID- 27224016 TI - Surface-enhanced Raman scattering of coumarin 343 on silver colloidal nanoparticles. AB - Surface-enhanced Raman scattering (SERS) of coumarin 343 (C343) adsorbed on silver colloidal nanoparticles reduced by sodium citrate was investigated and the surface adsorption geometry of C343 on Ag was sought by optimizing C343-Ag complexes for neutral and deprotonated C343 molecules in the DFT simulations. The SERS of C343 showed a number of spectral changes upon solution pH change. We found that deprotonated C343 adsorbs on the Ag nanoparticles through the carboxylate group keeping a perpendicular geometry to the surface. When protonated, the adsorption geometry of C343 is changed into more or less flat to the surface as the cyclic ester group becomes a preferred surface adsorption site. PMID- 27224019 TI - Intra-amygdala microinfusion of neuropeptide S attenuates neuropathic pain and suppresses the response of spinal microglia and astrocytes after spinal nerve ligation in rats. AB - The amygdala circuitry and neuropeptide S (NPS) have been shown to play an important role in the pain modulation. However, the alleviative effect of NPS in amygdala on neuropathic pain (NP) is not fully understood. Here, we demonstrate a possibility that the intra-amygdala microinfusion of NPS attenuates NP symptoms and suppresses the response of spinal microglia and astrocytes after spinal nerve injury. Spinal nerve ligation (SNL) in rats resulted in a striking decline in level of NPS and density of NPS-immunopositive cells in amygdala. SNL rats randomly received chronic bilateral microinjections of NPS (1, 10 and 100pmol/side) or saline into the amygdala via cannulas on days 3, 6, 9, 12, 15 and 18 post-surgery. Chronic treatment with NPS increased thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT) on day 11-21 post-SNL. The simultaneous treatment with SHA68 as non-peptide NPS receptor antagonist decreased the TWL and MWT, and reversed the inhibitory effects of NPS in SNL rats. NPS also significantly attenuated immunoreactivities of ionized calcium binding adapter molecule 1 and glial fibrillary acidic protein for microglia and astrocytes. Furthermore, the elevated levels of inflammatory mediators and expressions of nuclear factor kappaB p65 and CX3C chemokine receptor 1 due to SNL were significantly attenuated by NPS in amygdala. These effects of NPS were also counteracted by SHA 68. SHA 68 per se deteriorated the symptom of NP and the response of spinal microglia and astrocytes in SNL rats. Our study identified a protective role for NPS in amygdala against the development of NP, possibly attributing to its anti-inflammatory activity and inhibition of spinal microglia and astrocytes. PMID- 27224017 TI - A Disintegrin and Metalloproteinase10 (ADAM10) Regulates NOTCH Signaling during Early Retinal Development. AB - ADAM10 and ADAM17 are two closely related members of the ADAM (a disintegrin and metalloprotease) family of membrane-bound sheddases, which proteolytically cleave surface membrane proteins. Both ADAM10 and ADAM17 have been implicated in the proteolytic cleavage of NOTCH receptors and as such regulators of NOTCH signaling. During retinal development, NOTCH signaling facilitates retinal neurogenesis by maintaining progenitor cells in a proliferative state and by mediating retinal cell fates. However, the roles of ADAM10 and ADAM17 in the retina are not well defined. In this study, we set out to clarify the roles of ADAM10 and ADAM17 during early retinal development. The retinal phenotype of conditionally abated Adam17 retinae (Adam17 CKO) did not differ from the controls whereas conditionally ablated Adam10 retinae (Adam10 CKO) exhibited abnormal morphogenesis characterized by the formation of rosettes and a loss of retinal laminae phenotypically similar to morphological abnormalities identified in mice with retinal NOTCH signaling deficiency. Additionally, Adam10 CKO retinae exhibited abnormal neurogenesis characterized by fewer proliferating progenitor cells and greater differentiation of early photoreceptors and retinal ganglion cells. Moreover, constitutive activation of the NOTCH1-intracellular domain (N1 ICD) rescued Adam10 CKO abnormal neurogenesis, as well as abnormal retinal morphology by maintaining retinal cells in the progenitor state. Collectively these findings provide in vivo genetic evidence that ADAM10, and not ADAM17, is indispensable for proper retinal development as a regulator of NOTCH signaling. PMID- 27224020 TI - Anxiolytic effect of the GPR103 receptor agonist peptide P550 (homolog of neuropeptide 26RFa) in mice. Involvement of neurotransmitters. AB - The GPR103 receptor is a G protein-coupled receptor, which plays a role in several physiological functions. However, the role of the GPR103 receptor in anxiety has not been clarified. The first aim of our study was to elucidate the involvement of the GPR103 receptor in anxious behavior. Mice were treated with peptide P550, which is the mouse homolog of neuropeptide 26RFa and has similar activity for the GPR103 receptor as neuropeptide 26RFa. The anxious behavior was investigated using an elevated plus-maze paradigm. The second aim of our study was to investigate the underlying neurotransmissions. Accordingly, mice were pretreated with a nonselective muscarinic acetylcholine receptor antagonist, atropine, a gamma-aminobutyric acid subunit A (GABAA) receptor antagonist, bicuculline, a non-selective 5-HT2 serotonergic receptor antagonist, cyproheptadine, a mixed 5-HT1/5-HT2 serotonergic receptor antagonist, methysergide, a D2, D3, D4 dopamine receptor antagonist, haloperidol, a nonselective alpha-adrenergic receptor antagonist, phenoxybenzamine and a nonselective beta-adrenergic receptor antagonist, propranolol. Our results demonstrated that peptide P550 reduces anxious behavior in elevated plus maze test in mice. Our study shows also that GABAA-ergic, alpha- and beta-adrenergic transmissions are all involved in this action, whereas 5-HT1 and 5-HT2 serotonergic, muscarinic cholinergic and D2, D3, D4 dopaminergic mechanisms may not be implicated. PMID- 27224021 TI - Development of Acquired Immunity following Repeated Respiratory Syncytial Virus Infections in Cotton Rats. AB - Respiratory syncytial virus (RSV) infections occur every year worldwide. Most infants are infected with RSV by one year of age and are reinfected because immune responses after the first infection are too weak to protect against subsequent infections. In the present study, immune responses against RSV were investigated in order to obtain a better understanding of repetitive RSV infections in cotton rats. No detectable neutralizing antibody (NT) was developed after the first infection, and the second infection was not prevented. The results of histological examinations revealed severe inflammation, viral antigens were detected around bronchial epithelial cells, and infectious viruses were recovered from lung homogenates. Following the second infection neutralizing antibodies were significantly elevated, and CD8+ cells were activated in response to RSV-F253-265. No viral antigens was detected thereafter in lung tissues and infectious viruses were not recovered. Similar results were obtained in the present study using the subgroups A and B. These results support the induction of humoral and cellular immune responses following repetitive infections with RSV; however, these responses were insufficient to eliminate viruses in the first and second infections. PMID- 27224022 TI - Role of implant configurations supporting three-unit fixed partial denture on mandibular bone response: biological-data-based finite element study. AB - Implant-supported fixed partial denture with cantilever extension can transfer the excessive load to the bone around implants and stress/strain concentration potentially leading to bone resorption. This study investigated the effects of implant configurations supporting three-unit fixed partial denture (FPD) on the stress and strain distribution in the peri-implant bone by combining clinically measured time-dependent loading data and finite element (FE) analysis. A 3 dimensional mandibular model was constructed based on computed tomography (CT) images. Four different configurations of implants supporting 3-unit FPDs, namely three implant-supported FPD, conventional three-unit bridge FPD, distal cantilever FPD and mesial cantilever FPD, were modelled. The FPDs were virtually inserted to the molar area in the mandibular FE models. The FPDs were loaded according to time-dependent in vivo-measured 3-dimensional loading data during chewing. The von Mises stress (VMS) and equivalent strain (EQS) in peri-implant bone regions were evaluated as mechanical stimuli. During the chewing cycles, the regions near implant necks and bottom apexes experienced high VMS and EQS than the middle regions in all implant-supported FPD configurations. Higher VMS and EQS values were also observed at the implant neck region adjacent to the cantilever extension in the cantilevered configurations. The patient-specific dynamic loading data and CT-based reconstruction of full 3D mandibular allowed us to model the biomechanical responses more realistically. The results provided data for clinical assessment of implant configuration to improve longevity and reliability of the implant-supported FPD restoration. PMID- 27224023 TI - Performance of Bio-Rad and Limiting Antigen Avidity Assays in Detecting Recent HIV Infections Using the Quebec Primary HIV-1 Infection Cohort. AB - BACKGROUND: Accurate and practical biologic tools to estimate HIV incidence is crucial to better monitor the epidemic and evaluate the effectiveness of HIV prevention and treatment programs. METHODS: We evaluated two avidity assays to measure recent HIV infection: the Sedia HIV-1 LAg-Avidity EIA (Sedia Biosciences, Portland) and the Centers for Disease Control and Prevention (CDC)-modified Bio Rad-Avidity assay (Bio-Rad Laboratories, Mississauga, ON). Longitudinal specimens (n = 473) obtained from 123 treatment-naive seroconverted individuals enrolled in the Primary HIV-1 Infection (PHI) cohort of Quebec were used to determine the average time an individual is considered to be recently infected (mean duration of recent infection; MDRI), for the two avidity assays alone and in combination using a nonparametric survival method analysis. A total of 420 specimens from individuals with established HIV infection (90 individuals from the PHI cohort of Quebec and 330 individuals from the Laboratoire de sante publique du Quebec (LSPQ) serobank) were also tested to investigate false recency rate (FRR). RESULTS: The CDC-modified Bio-Rad-Avidity gave an estimated MDRI of 234 days (95% CI 220-249) at the avidity index cutoff of 30% while the Sedia-LAg-Avidity assay gave an estimated MDRI of 120 days (95% CI 109-132) at the normalized optical density (ODn) cutoff of 1.5. The FRR among individuals with established HIV infection was 10.2% (7.5%-13.5%) with the CDC-modified Bio-Rad-Avidity assay as compared to 6.0% (3.9%-8.7%) with the Sedia-LAg-Avidity assay. When optimizing a multiassay algorithm (MAA) that includes sequentially the CDC-modified Bio-Rad Avidity assay then the Sedia-LAg-Avidity assay EIA (avidity index/ODn: 30%/1.7), the MDRI was 136 days (95% CI 123-148) and the FRR, 3.3% (95% CI 1.8-5.6). CONCLUSION: Multiassay algorithms that include the CDC-modified Bio-Rad-Avidity assay and the Sedia-LAg-Avidity assay performed better than each avidity assay alone. Such 2-assay algorithm that starts with the CDC-modified Bio-Rad-Avidity assay followed by the Sedia-LAg-Avidity assay allowed a better classification of HIV-1 infections. PMID- 27224024 TI - Factors that impact health-related quality of life over time for individuals with head and neck cancer. AB - OBJECTIVES/HYPOTHESIS: To identify sociodemographic, behavioral, and clinical factors associated with health-related quality of life (HRQOL) for head and neck cancer (HNC) patients over time. STUDY DESIGN: A population-based longitudinal cohort study. METHODS: Newly diagnosed HNC patients (N = 587) were administered the Functional Assessment of Cancer Therapy-Head and Neck questionnaire at baseline (median 3 months postdiagnosis) and two follow-up assessments (median 22 and 42 months). Linear mixed-effect models were used with backward variable selection to identify factors associated with HRQOL over time (P < .05). Adjusted means reported at 2 years postdiagnosis. RESULTS: African Americans reported better Functional Well-Being than whites (mean of 20.01 vs. 18.53) and fewer HNC symptoms over time. Older patients (75+ years) reported better HRQOL than younger patients (< 50 years). Current tobacco use compared to no tobacco use had worse Physical (20.20 vs. 21.50), Emotional (17.55 vs. 19.06), Social (21.28 vs. 22.88), and Functional (17.32 vs. 19.29) Well-Being and more HNC symptoms (21.50 vs. 23.71). Radiation therapy was associated with worse Physical and Functional Well-Being and more head and neck symptoms over time, but HRQOL was similar to those who were not irradiated by 2 to 4 years postdiagnosis. CONCLUSION: This study identified key factors for individuals at risk for poorer HRQOL that may help clinicians and caregivers find solutions to address these decrements. Smoking cessation programs can be encouraged for survivors who use tobacco. Psychological and social support and medications may help for dealing with emotional distress and dealing with the physical symptoms from treatment. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:2718-2725, 2016. PMID- 27224026 TI - Canine and incisor microwear in pitheciids and Ateles reflects documented patterns of tooth use. AB - OBJECTIVES: Platyrrhine species differ in the extent to and the manner in which they use their incisors and canines during food ingestion. For example, Ateles uses its anterior teeth to process mechanically nondemanding soft fruits, while the sclerocarp-harvesting pitheciids rely extensively on these teeth to acquire and process more demanding foods. Pitheciids themselves vary in anterior tooth use, with the pitheciines (Cacajao, Chiropotes, and Pithecia) noted to use their robust canines in a variety of ways to predate seeds, while Callicebus, which rarely predates seeds, uses its incisors and exceptionally short canines to scrape tough mesocarp from fruits. To investigate the relationship between tooth use and dental wear, microwear textures were investigated for the anterior teeth of these five genera of platyrrhine primates. METHODS: Using a white light confocal microscope, 12 microwear texture attributes that reflect feature size, anisotropy, density, and complexity were recorded from high-resolution epoxy casts of the incisors and canines of adult wild-collected Brazilian specimens of Ateles, Callicebus, Cacajao, Chiropotes, and Pithecia. RESULTS: Pitheciine canines tend to have deep microwear features and complex, anisotropic microwear textures, while Ateles anterior teeth tend to have very small features, low feature density, and less complex and anisotropic surfaces. Callicebus incisor and canine microwear is generally intermediate in size and complexity between those extremes. CONCLUSIONS: These findings align with expectations from reported field observations of tooth use and illustrate the potential for using microwear texture analysis to infer patterns of anterior tooth use in extinct primates. Am J Phys Anthropol 161:6-25, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27224025 TI - Performance Evaluation of the Becton Dickinson FACSPrestoTM Near-Patient CD4 Instrument in a Laboratory and Typical Field Clinic Setting in South Africa. AB - BACKGROUND: The BD-FACSPrestoTM CD4 is a new, point-of-care (POC) instrument utilising finger-stick capillary blood sampling. This study evaluated its performance against predicate CD4 testing in South Africa. METHODS: Phase-I testing: HIV+ patient samples (n = 214) were analysed on the PrestoTM under ideal laboratory conditions using venous blood. During Phase-II, 135 patients were capillary-bled for CD4 testing on FACSPrestoTM, performed according to manufacturer instruction. Comparative statistical analyses against predicate PLG/CD4 method and industry standards were done using GraphPad Prism 6. It included Bland-Altman with 95% limits of agreement (LOA) and percentage similarity with coefficient of variation (%CV) analyses for absolute CD4 count (cells/MUl) and CD4 percentage of lymphocytes (CD4%). RESULTS: In Phase-I, 179/217 samples yielded reportable results with PrestoTM using venous blood filled cartridges. Compared to predicate, a mean bias of 40.4+/-45.8 (LOA of 49.2 to 130.2) and %similarity (%CV) of 106.1%+/-7.75 (7.3%) was noted for CD4 absolute counts. In Phase-2 field study, 118/135 capillary-bled PrestoTM samples resulted CD4 parameters. Compared to predicate, a mean bias of 50.2+/-92.8 (LOA of -131.7 to 232) with %similarity (%CV) 105%+/-10.8 (10.3%), and 2.87+/-2.7 (LOA of -8.2 to 2.5) with similarity of 94.7+/-6.5% (6.83%) noted for absolute CD4 and CD4% respectively. No significant clinical differences were indicated for either parameter using two sampling methods. CONCLUSION: The PrestoTM produced remarkable precision to predicate methods, irrespective of venous or capillary blood sampling. A consistent, clinically insignificant over-estimation (5-7%) of counts against PLG/CD4 and equivalency to FACSCountTM was noted. Further field studies are awaited to confirm longer-term use. PMID- 27224028 TI - Gadolinium in Humans: A Family of Disorders. AB - OBJECTIVE: The literature informs us that gadolinium can cause health issues. At least four major gadolinium disorders, including the two well-recognized nephrogenic systemic fibrosis and severe acute adverse event, have been identified. CONCLUSION: We propose naming the histopathologically proven presence of gadolinium in brain tissue "gadolinium storage condition," and we describe a new entity that represents symptomatic deposition of gadolinium in individuals with normal renal function, for which we propose the designation "gadolinium deposition disease." PMID- 27224027 TI - Effect of Atmospheric-Pressure Cold Plasma on Pathogenic Oral Biofilms and In Vitro Reconstituted Oral Epithelium. AB - Considering the ability of atmospheric-pressure cold plasma (ACP) to disrupt the biofilm matrix and rupture cell structure, it can be an efficient tool against virulent oral biofilms. However, it is fundamental that ACP does not cause damage to oral tissue. So, this study evaluated (1) the antimicrobial effect of ACP on single- and dual-species biofilms of Candida albicans and Staphylococcus aureus as well as (2) the biological safety of ACP on in vitro reconstituted oral epithelium. Standardized cell suspensions of each microorganism were prepared for biofilm culture on acrylic resin discs at 37 degrees C for 48 hours. The biofilms were submitted to ACP treatment at 10 mm of plasma tip-to-sample distance during 60 seconds. Positive controls were penicillin G and fluconazole for S. aureus and C. albicans, respectively. The biofilms were analyzed through counting of viable colonies, confocal laser scanning microscopy, scanning electron microscopy and fluorescence microscopy for detection of reactive oxygen species. The in vitro reconstituted oral epithelium was submitted to similar ACP treatment and analyzed through histology, cytotoxocity test (LDH release), viability test (MTT assay) and imunnohistochemistry (Ki67 expression). All plasma-treated biofilms presented significant log10 CFU/mL reduction, alteration in microorganism/biofilm morphology, and reduced viability in comparison to negative and positive controls. In addition, fluorescence microscopy revealed presence of reactive oxygen species in all plasma-treated biofilms. Low cytotoxicity and high viability were observed in oral epithelium of negative control and plasma group. Histology showed neither sign of necrosis nor significant alteration in plasma treated epithelium. Ki67-positive cells revealed maintenance of cell proliferation in plasma-treated epithelium. Atmospheric-pressure cold plasma is a promissing approach to eliminate single- and dual-species biofilms of C. albicans and S. aureus without having toxic effects in oral epithelium. PMID- 27224029 TI - The Lymphatic Endothelial mCLCA1 Antibody Induces Proliferation and Growth of Lymph Node Lymphatic Sinuses. AB - Lymphocyte- and leukocyte-mediated lymph node (LN) lymphatic sinus growth (lymphangiogenesis) is involved in immune responses and in diseases including cancer and arthritis. We previously discovered a 10.1.1 Ab that recognizes the lymphatic endothelial cell (LEC) surface protein mCLCA1, which is an interacting partner for LFA1 and Mac-1 that mediates lymphocyte adhesion to LECs. Here, we show that 10.1.1 Ab treatment specifically induces LEC proliferation, and influences migration and adhesion in vitro. Functional testing by injection of mice with 10.1.1 Ab but not control hamster Abs identified rapid induction of LN LEC proliferation and extensive lymphangiogenesis within 23 h. BrdU pulse-chase analysis demonstrated incorporation of proliferating LYVE-1-positive LEC into the growing medullary lymphatic sinuses. The 10.1.1 Ab-induced LN remodeling involved coordinate increases in LECs and also blood endothelial cells, fibroblastic reticular cells, and double negative stroma, as is observed during the LN response to inflammation. 10.1.1 Ab-induced lymphangiogenesis was restricted to LNs, as mCLCA1-expressing lymphatic vessels of the jejunum and dermis were unaffected by 23 h 10.1.1 Ab treatment. These findings demonstrate that 10.1.1 Ab rapidly and specifically induces proliferation and growth of LN lymphatic sinuses and stroma, suggesting a key role of mCLCA1 in coordinating LN remodeling during immune responses. PMID- 27224030 TI - Infantile Pain Episodes Associated with Novel Nav1.9 Mutations in Familial Episodic Pain Syndrome in Japanese Families. AB - Painful peripheral neuropathy has been correlated with various voltage-gated sodium channel mutations in sensory neurons. Recently Nav1.9, a voltage-gated sodium channel subtype, has been established as a genetic influence for certain peripheral pain syndromes. In this study, we performed a genetic study in six unrelated multigenerational Japanese families with episodic pain syndrome. Affected participants (n = 23) were characterized by infantile recurrent pain episodes with spontaneous mitigation around adolescence. This unique phenotype was inherited in an autosomal-dominant mode. Linkage analysis was performed for two families with 12 affected and nine unaffected members, and a single locus was identified on 3p22 (LOD score 4.32). Exome analysis (n = 14) was performed for affected and unaffected members in these two families and an additional family. Two missense variants were identified: R222H and R222S in SCN11A. Next, we generated a knock-in mouse model harboring one of the mutations (R222S). Behavioral tests (Hargreaves test and cold plate test) using R222S and wild-type C57BL/6 (WT) mice, young (8-9 weeks old; n = 10-12 for each group) and mature (36 38 weeks old; n = 5-6 for each group), showed that R222S mice were significantly (p < 0.05) more hypersensitive to hot and cold stimuli than WT mice. Electrophysiological studies using dorsal root ganglion neurons from 8-9-week-old mice showed no significant difference in resting membrane potential, but input impedance and firing frequency of evoked action potentials were significantly increased in R222S mice compared with WT mice. However, there was no significant difference among Nav1.9 (WT, R222S, and R222H)-overexpressing ND7/23 cell lines. These results suggest that our novel mutation is a gain-of-function mutation that causes infantile familial episodic pain. The mouse model developed here will be useful for drug screening for familial episodic pain syndrome associated with SCN11A mutations. PMID- 27224032 TI - New Water Vapor Barrier Film Based on Lamellar Aliphatic-Monoamine-Bridged Polysilsesquioxane. AB - Siloxane-based hybrid lamellar materials with ordered nanostructure units paralleling to the substrate have been widely used for water vapor barrier. However, it is very difficult to control the orientation of the lamellar units at molecular level. In this Research Article, a new lamellar bridged polysilsesquioxane (BPSQ) film, whose voids between lamellae were filled by pendant alkyl chains in the organic bridge, was prepared via the stoichiometric reaction between 3-glycidoxypropyltrimethoxysilane and aliphatic monoamine at 60 degrees C without catalyst. Experimental evidence obtained from FT-IR, MS, NMR, and GIXRD techniques suggested that the as-prepared BPSQ films were constructed by lamellar units with disordered orientation. Nonetheless, they possessed satisfactory water vapor barrier performance for potassium dihydrogen phosphate (KDP) and deuterated potassium dihydrogen phosphate (DKDP) optical crystals, and the water vapor transmission rate through BPSQ film with thickness of 25 MUm was as low as 20.3 g.m(-2).d(-1). Those results proved that filling the voids between molecular lamellae with alkyl chains greatly weakened the effect of lamellar unit orientation on the vapor barrier property of BPSQ film. PMID- 27224031 TI - SUMO-Modification of the La Protein Facilitates Binding to mRNA In Vitro and in Cells. AB - The RNA-binding protein La is involved in several aspects of RNA metabolism including the translational regulation of mRNAs and processing of pre-tRNAs. Besides its well-described phosphorylation by Casein kinase 2, the La protein is also posttranslationally modified by the Small Ubiquitin-like MOdifier (SUMO), but the functional outcome of this modification has not been defined. The objective of this study was to test whether sumoylation changes the RNA-binding activity of La. Therefore, we established an in vitro sumoylation assay for recombinant human La and analyzed its RNA-binding activity by electrophoretic mobility shift assays. We identified two novel SUMO-acceptor sites within the La protein located between the RNA recognition motif 1 and 2 and we demonstrate for the first time that sumoylation facilitates the RNA-binding of La to small RNA oligonucleotides representing the oligopyrimidine tract (TOP) elements from the 5' untranslated regions (UTR) of mRNAs encoding ribosomal protein L22 and L37 and to a longer RNA element from the 5' UTR of cyclin D1 (CCND1) mRNA in vitro. Furthermore, we show by RNA immunoprecipitation experiments that a La mutant deficient in sumoylation has impaired RNA-binding activity in cells. These data suggest that modulating the RNA-binding activity of La by sumoylation has important consequences on its functionality. PMID- 27224033 TI - Nonuniform Deposition of Pressurized Metered-Dose Aerosol in Spacer Devices. AB - BACKGROUND: Pressurized metered-dose inhalers (pMDIs) are commonly used to administer medication to patients suffering from chronic lower respiratory tract diseases such as asthma. Inhaling medication directly from a pMDI can prove difficult for some patients and, as a result, add-on devices (or spacers) have been designed to aid in the delivery of medication. Although spacers increase the percentage of medication that reaches the patient, medication will also nonsymmetrically deposit on the walls of the device and will be lost to the device itself. METHODS: The deposition of medication, salbutamol sulfate, within a large- and a small-volume spacer, has been studied through an experimental and numerical analysis. Experiments were conducted at inspiratory flow rates ranging from 30 to 60 L/min. The amount of deposition of the medication on the walls of the spacer was quantified through an application of spectrophotometry. Computational fluid dynamics was used to quantify the deposition numerically. Simulations were conducted by implementing mean flow and turbulent tracking of particles using unsteady Reynolds-averaged Navier-Stokes (URANS) equations with a shear stress transport turbulence model. Regions of deposition are of interest, as well as how the method of deposition varied for different inhalation flow rates. RESULTS AND CONCLUSIONS: The deposition of salbutamol sulfate in the Volumatic(r) and OptiChamber(r) spacers was found to be greater in the lower half as opposed to the upper half of the spacer due to a downward spray angle. With an increased flow rate, these spacers demonstrated a slight increase in medication delivered to the inline filter, which is analogous to that reaching the patient, and an increase in distal deposition. For the numerical analysis, the results indicated that inertial impaction is the most likely method of deposition for the Volumatic spacer, and turbulence is more likely to cause deposition in the OptiChamber spacer. PMID- 27224034 TI - Quantum and classical dynamics of H + CaCl(X (2)Sigma(+)) -> HCl + Ca((1)S) reaction and vibrational energy levels of the HCaCl complex. AB - We carried out accurate quantum wave packet as well as quasi-classical trajectory (QCT) calculations for H + CaCl (nui = 0, ji = 0) reaction occurring on an adiabatic ground state using the recent ab initio potential energy surface to obtain the quantum and QCT reaction probabilities for several partial waves (J = 0, 10, and 20) as well as state resolved QCT integral and differential cross sections. The complete list of vibrational energy levels supported by the intermediate HCaCl complex is also obtained using the Lanczos algorithm. The QCT reaction probabilities show excellent agreement with the quantum ones except for the failure in reproducing the highly oscillatory resonance structure. Despite the fact that the reaction is exothermic and the existence of a barrier that is energetically lower than the bottom of the reactant valley, the reaction probability for J = 0 shows threshold-like behavior and the reactivity all through the energies is very low (<0.1). The dynamical features at two different energy regions (<0.35 eV and >0.35 eV) are found to be different drastically from each other. The analyses of these results suggest that the reaction is governed by one of the two different types of reaction mechanism, one is the direct mechanism at the high energy region and the other is the indirect mechanism at the low energy region by which the reaction proceeds through the long-lived intermediate complex followed by a statistical dissociation into asymptotic channels. PMID- 27224035 TI - Reconstruction of foot and ankle defects with a superthin innervated anterolateral thigh perforator flap. AB - BACKGROUND: An anterolateral thigh (ALT) perforator flap can be thinned to an extent to which it is vascularised only by the subdermal plexus. This study presents an innervated flap thinning technique and its application for dorsal foot and ankle resurfacing. METHODS: A superthin innervated ALT perforator flap was used to repair the dorsal foot and ankle of 12 patients. The perforators were classified according to their variations in the adipose layer, and the corresponding microdissection technique was then applied. The branch of the lateral femoral cutaneous nerve and its accompanying vessels were adopted to construct a sensory flap. RESULTS: The flap thickness before defatting, which was measured immediately after flap elevation, ranged from 25-45 mm. The average flap thickness after defatting was 4.55 mm (range = 3-6 mm). A total of 11 flaps completely survived, and one flap presented superficial necrosis within a small area (2 cm *2 cm) in the distal part of the flap. No further flap revision or defatting procedures were required for these patients during an average follow-up period of 16.5 months (range = 10-24 months). In the transferred flap, protective sensibility existed in all cases, and the static two-point discrimination was 13 16 mm. CONCLUSIONS: The superthin innervated ALT perforator flap may be considered as an ideal strategy for foot and ankle reconstruction. PMID- 27224036 TI - Transfusion-Free Calvarial Vault Reconstruction Using Multimodal Blood Conservation Strategies in Two Pediatric Jehovah's Witness Patients With Craniosynostosis. AB - Transfusion-free surgery for the Jehovah's Witness patient has been described, but there are few reports in pediatric patients undergoing major elective surgery. We present 2 patients of the Jehovah's Witness faith affected with craniosynostosis who underwent transfusion-free calvarial vault reconstructions using several blood conservation approaches, including the use of antifibrinolytic epsilon-aminocaproic acid. PMID- 27224037 TI - A Technique to Allow Prone Positioning in the Spine Surgery Patient With Unstable Spine Fracture and Flail Segment Rib Fractures. AB - Two patients with unstable thoracic spine and flail segment rib fractures initially failed prone positioning on a Jackson spinal table used for posterior spinal instrumentation and fusion surgery. Both patients experienced rapid hemodynamic collapse. We developed a solution using the anterior portions of a thoracolumbosacral orthosis brace as chest supports to use during prone positioning, allowing both patients to undergo uncomplicated posterior spinal instrumentation and fusion surgeries with greater hemodynamic stability. PMID- 27224038 TI - ImpellaTM Left Ventricular Assist Device for Acute Peripartum Cardiomyopathy After Cesarean Delivery. AB - Peripartum cardiomyopathy is a rare form of heart failure with significant perioperative implications. In this case report, we describe a 34-year-old gravida 5, parity 3, patient who was admitted for an elective cesarean delivery. During the delivery, the patient developed sudden cardiac arrest and was emergently intubated in the operating room. An emergent transesophageal echocardiogram revealed a left ventricular ejection fraction of 10% with global biventricular hypokinesis. Urgent multidisciplinary consultations led to the rapid implementation of the ImpellaTM 2.5 for ventricular support. The patient recovered ventricular function within 4 days and recovered to baseline function. PMID- 27224039 TI - Ventriculoperitoneal Shunt Insertion Under Monitored Anesthesia Care in a Patient With Severe Pulmonary Hypertension. AB - A 32-year-old man with severe pulmonary arterial hypertension and Eisenmenger syndrome secondary to congenital ventricular septal defects presented for ventriculoperitoneal shunt insertion. Consultation between surgical and anesthesia teams acknowledged the extreme risk of performing this case, but given ongoing symptoms related to increased intracranial pressure from a large third ventricle colloid cyst, the case was deemed urgent. After a full discussion with the patient, including an explanation of anesthetic expectations and perioperative risks, the case was performed under monitored anesthesia care. Anesthetic management included high-flow nasal cannula oxygen with capnography and arterial blood pressure monitoring, dexmedetomidine infusion, boluses of midazolam and ketamine, and local anesthetic infiltration of the cranial and abdominal incisions as well as the catheter track. Hemodynamic support was provided with an epinephrine infusion, small vasopressin boluses, and inhaled nitric oxide. The patient recovered without any significant problems and was discharged home on postoperative day 3. PMID- 27224040 TI - Migration of a Central Venous Catheter in a Hemodialysis Patient Resulted in Left Atrial Perforation and Thrombus Formation Requiring Open Heart Surgery. AB - Central venous catheterization is widely used in patients on hemodialysis. A rare complication associated with the clinical use of central venous catheters is perforation of the heart or major vessels. We report a case of inadvertent perforation of the left atrium and thrombosis after the placement of a hemodialysis catheter in the right internal jugular vein. In such cases, surgical removal of the central venous catheter from perforation sites in the heart and vessel walls poses anesthetic challenges because of the high risk of pneumothorax, hemorrhage, arrhythmias, thrombosis, and death. PMID- 27224041 TI - Intraoperative Autotriggered Pressure Support Ventilation Resistant to Increased Flow Trigger Threshold. AB - Oscillations from cardiac pulsations are normally transmitted to mediastinal structures without any consequence. Autotriggering (AT) of mechanical ventilation occurs when an inspiratory trigger, typically negative inspiratory flow in anesthesia ventilators, is met in the absence of patient effort. AT can lead to respiratory alkalosis, opioid overdose, prolonged mechanical ventilation, and lung hyperinflation. This entity has been reported in both critical care and operating room environments. Increasing the flow trigger usually resolves AT in all cases. We report a case of AT that failed to respond to increasing the flow trigger threshold to its maximal value on the GE Datex-Ohmeda Avance S5(r) anesthesia station. PMID- 27224042 TI - Does clinician continuity influence hearing aid outcomes? AB - OBJECTIVE: To evaluate whether clinician continuity is associated with successful hearing aid outcomes. DESIGN: A prospective cohort study. Clinician continuity was defined as occurring when a patient was cared for by the same clinician for the hearing assessment, hearing aid selection process, hearing aid fitting and programming, and subsequent hearing aid fine tuning appointments. The hearing aid outcome measures included self-reported hearing aid use, benefit and satisfaction as well as self-reported handling skills and problems experienced with hearing aids. STUDY SAMPLE: Four hundred and sixty-eight adult hearing aid users (mean age 73.9 years +/-10.9) and 26 qualified audiologists (mean age 34 years +/-6.34) recruited from a single hearing clinic in Perth, Western Australia. RESULTS: There were no significant differences in hearing aid outcomes between participants who experienced clinician continuity and those who did not. CONCLUSIONS: Within a controlled practice setting, hearing aid outcomes may not be adversely effected if services are provided by more than one clinician. PMID- 27224043 TI - Holbrook Edwin Kohrt-In memoriam. PMID- 27224044 TI - The Pharmacological Effects and Mechanism of Tripterygium wilfordii Hook F in Central Nervous System Autoimmunity. AB - OBJECTIVE: Extracts of the Chinese herb Tripterygium wilfordii Hook F (TwHF) have potent anti-inflammatory functions and are widely used to treat rheumatoid arthritis and Crohn's disease. They have also been considered as potential drugs in the treatment of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. METHODS: A systematic search of MEDLINE, EMBASE, PubMed, and the China National Knowledge Infrastructure (CNKI) was performed. We reviewed many Chinese- and English-language articles. RESULTS: Recent studies have indicated that TwHF extracts, such as triptolide and tripchlorolide, are able to attenuate progression of this neuroimmunologic disorder because of their immunoregulatory, neurotrophic, and neuroprotective effects, but use of these extracts is often accompanied by acute and chronic toxicity. CONCLUSIONS: This review systematically summarizes the effects, safety consideration, and molecular mechanisms of action of TwHF extracts with regard to their inhibition of microglia activation, T cell functions, and transcriptional activation of nuclear factor (NF)-kappaB signaling. PMID- 27224045 TI - Lewis Acid Catalyzed Regiospecific Cross-Dehydrative Coupling Reaction of 2 Furylcarbinols with beta-Keto Amides or 4-Hydroxycoumarins: A Route to Furyl Enols. AB - Lewis acid catalyzed directly dehydrative carbon-carbon bond formation reaction of 2-furylcarbinols with beta-keto amides provides a straightforward method for regioselective synthesis of (Z)-furyl enols. Moreover, this Lewis acid catalyzed cross-coupling reaction can be extended to an interesting heterocyclic version featuring a functionalized 3-furyl-4-hydroxycoumarin synthesis. PMID- 27224047 TI - In vivo recombination efficiency of two site-specific recombination systems, VCre/VloxP and SCre/SloxP, in medaka (Oryzias latipes). AB - The present study delineates the in vivo efficiency of two site-specific recombination systems, VCre/VloxP and SCre/SloxP, in medaka (Oryzias latipes). VCre, SCre, and Cre RNA was microinjected into fertilized medaka eggs belonging to three transgenic lines harboring VloxP, SloxP, and loxP cassette. VCre induced site-specific recombination specifically at VloxP sequence and SCre at SloxP sequence without any cross-reactivity. These findings provide two novel alternative recombination systems in vivo in addition to the existing Cre/loxP and Flp/FRT systems, thus enabling sophisticated gene expression in model organisms. PMID- 27224046 TI - Disparate Modes of Evolution Shaped Modern Prion (PRNP) and Prion-Related Doppel (PRND) Variation in Domestic Cattle. AB - Previous investigations aimed at determining whether the mammalian prion protein actually facilitates tangible molecular aspects of either a discrete or pleiotropic functional niche have been debated, especially given the apparent absence of overt behavioral or physiological phenotypes associated with several mammalian prion gene (PRNP) knockout experiments. Moreover, a previous evaluation of PRNP knockout cattle concluded that they were normal, suggesting that the bovine prion protein is physiologically dispensable. Herein, we examined the frequency and distribution of nucleotide sequence variation within the coding regions of bovine PRNP and the adjacent Doppel (PRND) gene, a proximal paralogue to PRNP on BTA13. Evaluation of PRND variation demonstrated that the gene does not depart from a strictly neutral model of molecular evolution, and would therefore not be expected to influence tests of selection within PRNP. Collectively, our analyses confirm that intense purifying selection is indeed occurring directly on bovine PRNP, which is indicative of a protein with an important role. These results suggest that the lack of observed fitness effects may not manifest in the controlled environmental conditions used to care for and raise PRNP knockout animals. PMID- 27224048 TI - Adolescent self-harm and risk factors. AB - OBJECTIVE: This study aims to define the characteristics of adolescents who have engaged in self-harm behavior and ascertain the risk factors. METHODS: From January 2013 to January 2014, 4,176 adolescents from senior middle schools in Linyi, China, were administered four questionnaire surveys to ascertain the following: incidence of self-harm behavior regarding the frequency of different self-harm behaviors by group (never/one to five times/greater than five times in the last 6 months) and then comparing the self-harm behavior of the different subgroups; symptom self-check, comparing the differences between the adolescents with self-harm behavior and without in nine subscales (somatization, obsessive compulsive symptoms, interpersonal sensitivity, depression, anxiety, hostility, fear, paranoid, and psychosis); Adolescent Self-Rating Life Events Check List scores; and Egna Minnenav Barndoms Uppfostran (EMBU) scores. Multivariate logistic regression analysis was used to determine the risk factors of self-harm in adolescents. RESULTS: The incidence of adolescent self-harm was 27.60%; the occurrence of adolescent self-harm was closely related to their mental health status, stressful life events, and EMBU. Being female, an urban student, or an only child; having poor school performance or experiences of stressful life events, harsh parenting styles, or excessive interference; and poor mental health were the risk factors for adolescent self-harm. CONCLUSIONS: The incidence of adolescent self-harm was high, and their mental health status, stressful life events, and EMBU affected the occurrence of adolescent self-harm, which is an issue that needs greater attention. PMID- 27224049 TI - MAOD Determined in a Single Supramaximal Test: a Study on the Reliability and Effects of Supramaximal Intensities. PMID- 27224050 TI - Reconciling Biodiversity Conservation and Widespread Deployment of Renewable Energy Technologies in the UK. AB - Renewable energy will potentially make an important contribution towards the dual aims of meeting carbon emission reduction targets and future energy demand. However, some technologies have considerable potential to impact on the biodiversity of the environments in which they are placed. In this study, an assessment was undertaken of the realistic deployment potential of a range of renewable energy technologies in the UK, considering constraints imposed by biodiversity conservation priorities. We focused on those energy sources that have the potential to make important energy contributions but which might conflict with biodiversity conservation objectives. These included field-scale solar, bioenergy crops, wind energy (both onshore and offshore), wave and tidal stream energy. The spatially-explicit analysis considered the potential opportunity available for each technology, at various levels of ecological risk. The resultant maps highlight the energy resource available, physical and policy constraints to deployment, and ecological sensitivity (based on the distribution of protected areas and sensitive species). If the technologies are restricted to areas which currently appear not to have significant ecological constraints, the total potential energy output from these energy sources was estimated to be in the region of 5,547 TWh/yr. This would be sufficient to meet projected energy demand in the UK, and help to achieve carbon reduction targets. However, we highlight two important caveats. First, further ecological monitoring and surveillance is required to improve understanding of wildlife distributions and therefore potential impacts of utilising these energy sources. This is likely to reduce the total energy available, especially at sea. Second, some of the technologies under investigation are currently not deployed commercially. Consequently this potential energy will only be available if continued effort is put into developing these energy sources/technologies, to enable realisation of their full potential. PMID- 27224051 TI - Novel Hypomorphic Alleles of the Mouse Tyrosinase Gene Induced by CRISPR-Cas9 Nucleases Cause Non-Albino Pigmentation Phenotypes. AB - Tyrosinase is a key enzyme in melanin biosynthesis. Mutations in the gene encoding tyrosinase (Tyr) cause oculocutaneous albinism (OCA1) in humans. Alleles of the Tyr gene have been useful in studying pigment biology and coat color formation. Over 100 different Tyr alleles have been reported in mice, of which ~24% are spontaneous mutations, ~60% are radiation-induced, and the remaining alleles were obtained by chemical mutagenesis and gene targeting. Therefore, most mutations were random and could not be predicted a priori. Using the CRISPR-Cas9 system, we targeted two distinct regions of exon 1 to induce pigmentation changes and used an in vivo visual phenotype along with heteroduplex mobility assays (HMA) as readouts of CRISPR-Cas9 activity. Most of the mutant alleles result in complete loss of tyrosinase activity leading to an albino phenotype. In this study, we describe two novel in-frame deletion alleles of Tyr, dhoosara (Sanskrit for gray) and chandana (Sanskrit for sandalwood). These alleles are hypomorphic and show lighter pigmentation phenotypes of the body and eyes. This study demonstrates the utility of CRISPR-Cas9 system in generating domain-specific in frame deletions and helps gain further insights into structure-function of Tyr gene. PMID- 27224052 TI - Can Word Puzzles be Tailored to Improve Different Dimensions of Verbal Fluency? A Report of an Intervention Study. AB - Verbal fluency is commonly used as a proxy measure of executive functioning, as it involves cognitive flexibility, working memory, and inhibitory control. Previous research has demonstrated that crosswords can be a useful means of improving verbal fluency, results consistent with the cognitive reserve hypothesis; the form of verbal fluency affected has, however, differed across studies. The present study sought to assess the extent to which it was possible to target phonemic (PVF) and semantic verbal fluency (SVF) separately through word puzzles designed to focus on semantic/thematic and structural clues respectively. Fifty-three university students were randomly assigned to one of three groups: semantic/thematic, structural, or a daily diary control group. They were assessed on PVF and SVF at baseline, and immediately following a four-week intervention. Age, sex, and depression scores were controlled for. A 2 * 3 mixed ANCOVA showed that the structural group improved significantly more in PVF during the intervention period than did the semantic/thematic or control groups, with the improvement linked to improved switching performance. The effect size was large. No significant difference in improvement in SVF emerged, although the effect size was moderate. The findings support the notion that it is possible to improve specific forms of verbal fluency through tailored brief word-puzzle interventions. PMID- 27224054 TI - Simulation of Temperature-Dependent Charge Transport in Organic Semiconductors with Various Degrees of Disorder. AB - Different trends in the temperature dependence of the mobility can be observed in organic semiconductors, which constitutes a serious challenge for theoretical approaches. In this work, we apply an atomistic bottom-up simulation for the calculation of temperature-dependent mobilities of a broad selection of materials, ranging from single crystal to amorphous solid. We evaluate how well the method is able to distinguish temperature dependences of different materials and how the findings relate to experimental observations. The applied method is able to cover the full range of temperature dependencies from activated transport in amorphous materials to band-like transport in crystals. In well-characterized materials, we find good agreement with the experiment and a band-like temperature dependence. In less-ordered materials, we find discrepancies from the experiment that indicated that experimentally studied materials possess a higher degree of disorder than do the simulated defect-free morphologies. PMID- 27224053 TI - Risk of Allergic Rhinitis, Allergic Conjunctivitis, and Eczema in Children Born to Mothers with Gum Inflammation during Pregnancy. AB - PURPOSE: Despite links between maternal and child health status, evidence on the association between gum infection in pregnant mothers and childhood allergies is scarce. We aim to evaluate the risk of developing allergy in children born to periodontal mothers in a nationwide study. METHODS: We conducted a 9-year population-based, retrospective cohort study using Taiwan's National Health Insurance database. A study cohort of 42,217 newborns born to mothers with periodontal disease during pregnancy was identified in 2001 and matched with 42,334 babies born to mothers without any infection (control) by mother's age at delivery and baby sex. With a follow-up period from 2001 to 2010, we observed the incidence of allergic rhinitis (AR), allergic conjunctivitis (AC), and eczema in these children. Cox proportional hazards regression models were performed with premature deaths as competing risk for the estimation of allergic disease risks. RESULTS: Nine-year cumulative incidences were the highest among children born to periodontal mothers; they reached 46.8%, 24.2%, and 40.4% (vs. 39.5%, 18.3% and 34.8% in control) for AR, AC, and eczema, respectively. Our results showed moderately increased risks for the allergies in children born to periodontal mothers relative to their matched non-inflammatory control (adjusted HRs: 1.17, 95% CI: 1.15-1.20; 1.27, 1.24-1.31; 1.14, 1.12-1.17, respectively). Because the impact of food consumption and living environment cannot be considered using insurance data, we attempted to control it by adjusting for parental income and mother's residential area. CONCLUSIONS: Overall cumulative incidence and risks of children born to periodontal mothers for AR, AC, and eczema are significantly higher than those born to non-inflammatory mothers. Gum infection in women during pregnancy is an independent risk factor for allergic diseases in children, thus its intergenerational consequences should be considered in gestational care. PMID- 27224055 TI - Formation and Stabilization of Environmentally Persistent Free Radicals Induced by the Interaction of Anthracene with Fe(III)-Modified Clays. AB - Environmentally persistent free radicals (EPFRs) are occasionally detected in Superfund sites but the formation of EPFRs induced by polycyclic aromatic hydrocarbons (PAHs) is not well understood. In the present work, the formation of EPFRs on anthracene-contaminated clay minerals was quantitatively monitored via electron paramagnetic resonance (EPR) spectroscopy, and surface/interface-related environmental influential factors were systematically explored. The obtained results suggest that EPFRs are more readily formed on anthracene-contaminated Fe(III)-montmorillonite than in other tested systems. Depending on the reaction condition, more than one type of organic radicals including anthracene-based radical cations with g-factors of 2.0028-2.0030 and oxygenic carbon-centered radicals featured by g-factors of 2.0032-2.0038 were identified. The formed EPFRs are stabilized by their interaction with interlayer surfaces, and such surface bound EPFRs exhibit slow decay with 1/e-lifetime of 38.46 days. Transformation pathway and possible mechanism are proposed on the basis of experimental results and quantum mechanical simulations. Overall, the formation of EPFRs involves single-electron-transfer from anthracene to Fe(III) initially, followed by H2O addition on formed aromatic radical cation. Because of their potential exposure in soil and atmosphere, such clay surface-associated EPFRs might induce more serious toxicity than PAHs and exerts significant impacts on human health. PMID- 27224057 TI - Looking to Learn: The Effects of Visual Guidance on Observational Learning of the Golf Swing. AB - Skilled performers exhibit more efficient gaze patterns than less-skilled counterparts do and they look more frequently at task-relevant regions than at superfluous ones. We examine whether we may guide novices' gaze towards relevant regions during action observation in order to facilitate their learning of a complex motor skill. In a Pre-test-Post-test examination of changes in their execution of the full golf swing, 21 novices viewed one of three videos at intervention: i) a skilled golfer performing 10 swings (Free Viewing, FV); ii) the same video with transient colour cues superimposed to highlight key features of the setup (Visual Guidance; VG); iii) or a History of Golf video (Control). Participants in the visual guidance group spent significantly more time looking at cued areas than did the other two groups, a phenomenon that persisted after the cues had been removed. Moreover, the visual guidance group improved their swing execution at Post-test and on a Retention test one week later. Our results suggest that visual guidance to cued areas during observational learning of complex motor skills may accelerate acquisition of the skill. PMID- 27224058 TI - Immune checkpoint inhibitors in malignant pleural mesothelioma: promises and challenges. PMID- 27224056 TI - Spectrum and Frequency of the GJB2 Gene Pathogenic Variants in a Large Cohort of Patients with Hearing Impairment Living in a Subarctic Region of Russia (the Sakha Republic). AB - Pathogenic variants in the GJB2 gene, encoding connexin 26, are known to be a major cause of hearing impairment (HI). More than 300 allelic variants have been identified in the GJB2 gene. Spectrum and allelic frequencies of the GJB2 gene vary significantly among different ethnic groups worldwide. Until now, the spectrum and frequency of the pathogenic variants in exon 1, exon 2 and the flanking intronic regions of the GJB2 gene have not been described thoroughly in the Sakha Republic (Yakutia), which is located in a subarctic region in Russia. The complete sequencing of the non-coding and coding regions of the GJB2 gene was performed in 393 patients with HI (Yakuts-296, Russians-51, mixed and other ethnicities-46) and in 187 normal hearing individuals of Yakut (n = 107) and Russian (n = 80) populations. In the total sample (n = 580), we revealed 12 allelic variants of the GJB2 gene, 8 of which were recessive pathogenic variants. Ten genotypes with biallelic recessive pathogenic variants in the GJB2 gene (in a homozygous or a compound heterozygous state) were found in 192 out of 393 patients (48.85%). We found that the most frequent GJB2 pathogenic variant in the Yakut patients was c.-23+1G>A (51.82%) and that the second most frequent was c.109G>A (2.37%), followed by c.35delG (1.64%). Pathogenic variants s.35delG (22.34%), c.-23+1G>A (5.31%), and c.313_326del14 (2.12%) were found to be the most frequent among the Russian patients. The carrier frequencies of the c. 23+1G>A and s.109G>A pathogenic variants in the Yakut control group were 10.20% and 2.80%, respectively. The carrier frequencies of s.35delG and c.101T>C were identical (2.5%) in the Russian control group. We found that the contribution of the GJB2 gene pathogenic variants in HI in the population of the Sakha Republic (48.85%) was the highest among all of the previously studied regions of Asia. We suggest that extensive accumulation of the c.-23+1G>A pathogenic variant in the indigenous Yakut population (92.20% of all mutant chromosomes in patients) and an extremely high (10.20%) carrier frequency in the control group may indicate a possible selective advantage for the c.-23+1G>A carriers living in subarctic climate. PMID- 27224060 TI - Measurement and simulation of unmyelinated nerve electrostimulation: Lumbricus terrestris experiment and numerical model. AB - The electrostimulation excitation threshold of a nerve depends on temporal and frequency parameters of the stimulus. These dependences were investigated in terms of: (1) strength-duration (SD) curve for a single monophasic rectangular pulse, and (2) frequency dependence of the excitation threshold for a continuous sinusoidal current. Experiments were performed on the single-axon measurement setup based on Lumbricus terrestris having unmyelinated nerve fibers. The simulations were performed using the well-established SENN model for a myelinated nerve. Although the unmyelinated experimental model differs from the myelinated simulation model, both refer to a single axon. Thus we hypothesized that the dependence on temporal and frequency parameters should be very similar. The comparison was made possible by normalizing each set of results to the SD time constant and the rheobase current of each model, yielding the curves that show the temporal and frequency dependencies regardless of the model differences. The results reasonably agree, suggesting that this experimental setup and method of comparison with SENN model can be used for further studies of waveform effect on nerve excitability, including unmyelinated neurons. PMID- 27224059 TI - Localized Irradiation of Cell Membrane by Auger Electrons Is Cytotoxic Through Oxidative Stress-Mediated Nontargeted Effects. AB - AIMS: We investigated whether radiation-induced nontargeted effects are involved in the cytotoxic effects of anticell surface monoclonal antibodies labeled with Auger electron emitters, such as iodine 125 (monoclonal antibodies labeled with (125)I [(125)I-mAbs]). RESULTS: We showed that the cytotoxicity of (125)I-mAbs targeting the cell membrane of p53(+/+) HCT116 colon cancer cells is mainly due to nontargeted effects. Targeted and nontargeted cytotoxicities were inhibited in vitro following lipid raft disruption with Methyl-beta-cyclodextrin (MBCD) or filipin or use of radical oxygen species scavengers. (125)I-mAb efficacy was associated with acid sphingomyelinase activation and modulated through activation of the AKT, extracellular signal-related kinase 1/2 (ERK1/2), p38 kinase, c-Jun N terminal kinase (JNK) signaling pathways, and also of phospholipase C-gamma (PLC gamma), proline-rich tyrosine kinase 2 (PYK-2), and paxillin, involved in Ca(2+) fluxes. Moreover, the nontargeted response induced by directing 5-[(125)I]iodo-2' deoxyuridine to the nucleus was comparable to that of (125)I-mAb against cell surface receptors. In vivo, we found that the statistical significance of tumor growth delay induced by (125)I-mAb was removed after MBCD treatment and observed oxidative DNA damage beyond the expected Auger electron range. These results suggest the involvement of nontargeted effects in vivo also. INNOVATION: Low energy Auger electrons, such as those emitted by (125)I, have a short tissue range and are usually targeted to the nucleus to maximize their cytotoxicity. In this study, we show that targeting the cancer cell surface with (125)I-mAbs produces a lipid raft-mediated nontargeted response that compensates for the inferior efficacy of non-nuclear targeting. CONCLUSION: Our findings describe the mechanisms involved in the efficacy of (125)I-mAbs targeting the cancer cell surface. Antioxid. Redox Signal. 25, 467-484. PMID- 27224061 TI - FISICO: Fast Image SegmentatIon COrrection. AB - BACKGROUND AND PURPOSE: In clinical diagnosis, medical image segmentation plays a key role in the analysis of pathological regions. Despite advances in automatic and semi-automatic segmentation techniques, time-effective correction tools are commonly needed to improve segmentation results. Therefore, these tools must provide faster corrections with a lower number of interactions, and a user independent solution to reduce the time frame between image acquisition and diagnosis. METHODS: We present a new interactive method for correcting image segmentations. Our method provides 3D shape corrections through 2D interactions. This approach enables an intuitive and natural corrections of 3D segmentation results. The developed method has been implemented into a software tool and has been evaluated for the task of lumbar muscle and knee joint segmentations from MR images. RESULTS: Experimental results show that full segmentation corrections could be performed within an average correction time of 5.5+/-3.3 minutes and an average of 56.5+/-33.1 user interactions, while maintaining the quality of the final segmentation result within an average Dice coefficient of 0.92+/-0.02 for both anatomies. In addition, for users with different levels of expertise, our method yields a correction time and number of interaction decrease from 38+/-19.2 minutes to 6.4+/-4.3 minutes, and 339+/-157.1 to 67.7+/-39.6 interactions, respectively. PMID- 27224063 TI - Bird Responses to Lowland Rainforest Conversion in Sumatran Smallholder Landscapes, Indonesia. AB - Rapid land-use change in the tropics causes dramatic losses in biodiversity and associated functions. In Sumatra, Indonesia, lowland rainforest has mainly been transformed by smallholders into oil palm (Elaeis guineensis) and rubber (Hevea brasiliensis) monocultures, interspersed with jungle rubber (rubber agroforests) and a few forest remnants. In two regions of the Jambi province, we conducted point counts in 32 plots of four different land-use types (lowland rainforest, jungle rubber, rubber plantation and oil palm plantation) as well as in 16 nearby homegardens, representing a small-scale, traditional agricultural system. We analysed total bird abundance and bird abundance in feeding guilds, as well as species richness per point count visit, per plot, and per land-use system, to unveil the conservation importance and functional responses of birds in the different land-use types. In total, we identified 71 species from 24 families. Across the different land-use types, abundance did not significantly differ, but both species richness per visit and per plot were reduced in plantations. Feeding guild abundances between land-use types were variable, but homegardens were dominated by omnivores and granivores, and frugivorous birds were absent from monoculture rubber and oil palm. Jungle rubber played an important role in harbouring forest bird species and frugivores. Homegardens turned out to be of minor importance for conserving birds due to their low sizes, although collectively, they are used by many bird species. Changes in functional composition with land-use conversion may affect important ecosystem functions such as biological pest control, pollination, and seed dispersal. In conclusion, maintaining forest cover, including degraded forest and jungle rubber, is of utmost importance to the conservation of functional and taxonomic bird diversity. PMID- 27224062 TI - SDCCAG8 Interacts with RAB Effector Proteins RABEP2 and ERC1 and Is Required for Hedgehog Signaling. AB - Recessive mutations in the SDCCAG8 gene cause a nephronophthisis-related ciliopathy with Bardet-Biedl syndrome-like features in humans. Our previous characterization of the orthologous Sdccag8gt/gt mouse model recapitulated the retinal-renal disease phenotypes and identified impaired DNA damage response signaling as an underlying disease mechanism in the kidney. However, several other phenotypic and mechanistic features of Sdccag8gt/gt mice remained unexplored. Here we show that Sdccag8gt/gt mice exhibit developmental and structural abnormalities of the skeleton and limbs, suggesting impaired Hedgehog (Hh) signaling. Indeed, cell culture studies demonstrate the requirement of SDCCAG8 for ciliogenesis and Hh signaling. Using an affinity proteomics approach, we demonstrate that SDCCAG8 interacts with proteins of the centriolar satellites (OFD1, AZI1), of the endosomal sorting complex (RABEP2, ERC1), and with non muscle myosin motor proteins (MYH9, MYH10, MYH14) at the centrosome. Furthermore, we show that RABEP2 localization at the centrosome is regulated by SDCCAG8. siRNA mediated RABEP2 knockdown in hTERT-RPE1 cells leads to defective ciliogenesis, indicating a critical role for RABEP2 in this process. Together, this study identifies several centrosome-associated proteins as novel SDCCAG8 interaction partners, and provides new insights into the function of SDCCAG8 at this structure. PMID- 27224064 TI - Episiotomy and its relationship to various clinical variables that influence its performance. AB - OBJECTIVE: to understand the episiotomy rate and its relationship with various clinical variables. METHOD: a descriptive, cross-sectional, analytic study of 12,093 births in a tertiary hospital. VARIABLES: Parity, gestational age, start of labor, use of epidural analgesia, oxytocin usage, position during fetal explusion, weight of neonate, and completion of birth. The analysis was performed with SPSS 19.0. RESULTS: the global percentage of episiotomies was 50%. The clinical variables that presented a significant association were primiparity (RR=2.98), gestational age >41 weeks (RR=1.2), augmented or induced labor (RR=1.33), epidural analgesia use (RR=1,95), oxytocin use (RR=1.58), lithotomy position during fetal expulsion (RR=6.4), and instrumentation (RR=1.84). Furthermore, maternal age >=35 years (RR=0.85) and neonatal weight <2500 g (RR=0.8) were associated with a lower incidence of episiotomy. CONCLUSIONS: episiotomy is dependent on obstetric interventions performed during labor. If we wish to reduce the episiotomy rate, it will be necessary to bear in mind these risk factors when establishing policies for reducing this procedure. PMID- 27224065 TI - Excimer laser phototherapeutic keratectomy in conjunction with mitomycin C in corneal macular and granular dystrophies. AB - PURPOSE: To evaluate the visual outcomes, recurrence patterns, safety, and efficacy of excimer laser phototherapeutic keratectomy (PTK) in conjunction with mitomycin C (MMC) for corneal macular and granular diystrophies. METHODS: The patients were divided into two groups. Group 1 included patients with macular corneal dystrophy (MCD) that caused superficial corneal plaque opacities, and Group 2 included patients with granular corneal dystrophy (GCD). Patients in both groups were pre-, peri-, and postoperatively evaluated. The groups were compared in terms of uncorrected visual acuity (VA), best spectacle-corrected VA, presence of mild or significant recurrence, and time of recurrence. RESULTS: Eighteen eyes (nine with MCD and nine with GCD) of 18 patients (10 men and eight women) were included. PTK was performed for each eye that was included in this study. The mean ablation amount was 117.8 +/- 24.4 um and 83.5 +/- 45.7 um in MCD and GCD, respectively, (p=0.18). The postoperative improvement of the mean VA was similar between the two groups before recurrences (p>0.43) and after recurrences (p>0.71). There were no statistically significant differences in the recurrence rate and the recurrence-free period for any recurrence type. CONCLUSION: PTK was an effective, safe, and minimally invasive procedure for patients with MCD and GCD. PTK in conjunction with MMC was similarly effective for both groups in terms of recurrence and visual outcomes. PMID- 27224066 TI - Short-term visual performance of soft multifocal contact lenses for presbyopia. AB - PURPOSE: To compare visual acuity (VA), contrast sensitivity, stereopsis, and subjective visual performance of Acuvue(r) Oasys(r) for Presbyopia (AOP), Air Optix(r) Aqua Multifocal (AOMF), and Air Optix(r) Aqua Single Vision (AOSV) lenses in patients with presbyopia. METHODS: A single-blinded crossover trial was conducted. Twenty patients with mild presbyopia (add <=+1.25 D) and 22 with moderate/severe presbyopia (add >=+1.50 D) who wore lenses bilaterally for 1 h, with a minimum overnight washout period between the use of each lens. Measurements included high- and low-contrast visual acuity (HCVA and LCVA, respectively) at a distance, contrast sensitivity (CS) at a distance, HCVA at intermediate (70 cm) and near (50 cm & 40 cm) distances, stereopsis, and subjective questionnaires regarding vision clarity, ghosting, overall vision satisfaction, and comfort. The test variables were compared among the lens types using repeated-measures ANOVA. RESULTS: Distance variables (HCVA, LCVA, and CS) were significantly worse with multifocal lens than with AOSV lens (p<=0.008), except for AOMF lens in the mild presbyopia group in which no significant difference was observed (p>0.05). Multifocal lenses had significantly greater HCVA at 40 cm than AOSV lens (p<=0.026). AOMF lens had greater intermediate HCVA than AOP lens (p<0.03). AOP lens demonstrated greater improvements in stereopsis than AOMF and AOSV lens in the moderate/severe presbyopia group (p<=0.03). Few significant differences in subjective variables were observed, with no significant difference in the overall vision satisfaction observed between lens types (p>0.05). The proportions of patients willing to buy AOSV, AOMF, and AOP lenses were 20%, 40%, and 50%, respectively, in the mild presbyopia group and 14%, 32%, and 23%, respectively, in the moderate/severe presbyopia group; however, these differences were not statistically significant (p>=0.159). CONCLUSIONS: Further development of multifocal lenses is required before significant advantages of multifocal lenses over single vision lens are observed in patients with presbyopia. PMID- 27224067 TI - Retinal nerve fiber layer, ganglion cell complex, and choroidal thicknesses in migraine. AB - PURPOSE: To evaluate the thicknesses of the peripapillary retinal nerve fiber layer (RNFL), ganglion cell complex (GCL), and choroid layer using spectral domain optical coherence tomography (SD-OCT) for investigating the effects of vascular changes on the eye and optic nerve in patients who have migraine with aura. METHODS: Forty-five patients who had migraine with aura (migraine group) and 45 healthy individuals (control group) were enrolled in the study. Age, gender, duration after migraine diagnosis, intraocular pressure, and axial length measurements were recorded in each case. RNFL, GCL, and choroid layer thicknesses were measured using SD-OCT in all participants. RESULTS: The mean age was 36.1 +/ 6.7 (20-45) years in the migraine group and 35.7 +/- 8.6 (19-45) years in the control group. There was no significant difference in the RNFL thicknesses of the temporal and nasal quadrants (p >0.05). The RNFL thicknesses of the superior and inferior quadrants were significantly lower in the migraine group compared with those in the control group (p =0.001, p <0.01, respectively). Measurements for the superior and inferior GCL were not significantly different between the groups (p >0.05). Subfoveal, temporal, and nasal choroidal thickness measurements at 500 um, 1000 um, and 1500 um were significantly lower in the migraine group than in the control group (p =0.001; p <0.01, respectively). CONCLUSIONS: Compared with the controls, the RNFL and choroid layer were determined to be thinner in patients who had chronic migraine with aura. PMID- 27224068 TI - Descriptive analysis of the type and design of contact lenses fitted according to keratoconus severity and morphology. AB - PURPOSE: Keratoconus is characterized by bilateral asymmetrical corneal ectasia that leads to inferior stromal thinning and corneal protrusion. There is currently a lack of consensus regarding the most efficacious method for fitting contact lenses in patients with keratoconus, given the various topographical patterns and evolution grades observed in affected populations. The purpose of the present study was to evaluate the association between keratoconus evolution grade and topography pattern and the type and design of fitted contact lens. METHODS: We performed a retrospective analysis of contact lenses fitted in a total of 185 patients with keratoconus (325 eyes). Keratoconus was classified as either grade I, II, III, or IV based on keratometry and cone morphology (nipple, oval, globus, or indeterminate) results. RESULTS: A total of 325 eyes were evaluated in the present study. Of the 62 eyes classified as grade I, 66.1% were fitted with monocurve contact lenses. Of the 162 eyes classified as grade I and II, 51%, 30%, and 19% were fitted with adapted monocurve rigid gas-permeable contact lenses (RGPCL), bicurve lenses, and others lens types, respectively. Bicurve lenses were fitted in 52.1% and 62.2% of eyes classified as grade III and IV, respectively. Of the eyes classified as grade III and IV, monocurve and bicurve RGPCL were fitted in 26% and 55%, respectively. In eyes with oval keratoconus, 45%, 35%, and 20% were fitted with monocurve lenses, bicurve lenses, and other lens types, respectively. In eyes with round cones (nipple morphology), 55%, 30%, and 15% were fitted with bicurve lenses, monocurve lenses, and other lens types, respectively. CONCLUSION: Monocurve RGPCL were most frequently fitted in patients with mild to moderate keratoconus and oval cones morphology, while bicurve lenses were more frequently fitted in patients with severe and advanced keratoconus. This was probably because bicurve lenses are more appropriate for round cones due to increased corneal asphericity. PMID- 27224069 TI - Initial experience with ocriplasmin in the treatment of vitreomacular traction. AB - This study aimed to report the clinical and structural outcomes of intravitreal ocriplasmin in the treatment of vitreomacular interface disorders in two tertiary centers in Brazil. A retrospective study was performed by reviewing medical records and spectral domain optical coherence tomography (SD-OCT) findings of seven patients who were treated with a single ocriplasmin injection. A total of 57.14% of patients achieved resolution of vitreomacular traction as evidenced by SD-OCT. Regarding our functional results, 87.71% maintained or improved visual acuity after follow-up. To the best of our knowledge, this is the first study reporting initial results of ocriplasmin therapy in Brazil. PMID- 27224070 TI - Intraocular straylight before and after low myopic photorefractive keratectomy with and without mitomycin C. AB - PURPOSE: To evaluate ocular straylight before and after photorefractive keratectomy (PRK) for low myopia with and without topical mitomycin (MMC) treatment. METHODS: Patients who underwent PRK for low myopia were enrolled into the study. PRK without MMC was performed in 21 eyes (12 patients), whereas PRK with topical 0.02% MMC was performed in 25 eyes (14 patients). Both groups were treated using the NIDEK EC5000 excimer laser. Measurements were performed using the C-Quant straylight meter preoperatively and at two and four months postoperatively. RESULTS: The mean patient age was 30 +/- 4 years, and the mean spherical equivalent refractive error was -2.2 +/- 0.75 D. The mean preoperative intraocular straylight values were 1.07 +/- 0.10 in the PRK without MMC group and 1.07 +/- 0.11 log(s) in the PRK with topical MMC group. At two months after surgery, there was a decrease in mean intraocular straylight values in both groups. However, a significant difference was only reached in the PRK with MMC group [0.98 +/- 0.09 log(s), p=0.002] compared with preoperative values, which was likely due to a greater scatter of measurements in the PRK without MMC group [1.03 +/- 0.13 log(s), p=0.082]. At four months postoperatively, ocular straylight values were not significantly different compared with those at baseline in either the PRK without MMC group [1.02 +/- 0.14 log(s), p=0.26] or in the PRK with topical MMC group [1.02 +/- 0.11 log(s), p=0.13]. CONCLUSION: PRK for low myopia decreases ocular straylight, and MMC application further reduces straylight in the early postoperative period. However, ocular straylight values do not significantly differ at four months after surgery compared with those at baseline. PMID- 27224071 TI - The effects of delivery type and gender on intraocular pressure and central corneal thickness in newborns. AB - PURPOSE: To analyze intraocular pressure (IOP) and central corneal thickness (CCT) in newborns during the first 12 h of life. METHODS: Forty-three newborns born by vaginal delivery (VD) and 30 newborns born by cesarean section (CS) were evaluated. IOP and CCT were measured using Tono-Pen and handheld pachymeter, respectively, at both the 5th minute after delivery and at the 12th h of life. RESULTS: The mean IOP for the VD group was significantly higher than that of the CS group at both the 5th minute and 12th h (p =0.042 and p =0.018, respectively). In both groups, the IOP decreased by the 12th h, but the decrease was only significant for the CS group (p =0.020). The decrease in CCT over the 12 h was significant for both groups (p <0.001). In the VD and CS groups, the IOP values of the males were significantly higher than those of the females at the fifth minute only (p =0.024 and p =0.043, respectively). No other values were significantly different between the genders. CONCLUSIONS: Newborn IOP is affected by the mode of delivery and gender. A higher IOP was found in vaginally delivered newborns than in CS newborns for at least 12 h postpartum. CCT showed a significant decline within 12 h. Male newborns have significantly higher IOP values in the first minutes of life. PMID- 27224072 TI - Treatment success of laser therapy for retinopathy of prematurity in referred and non-referred patients. AB - PURPOSE: Comparison of laser therapy (LT) outcomes in patients with retinopathy of prematurity (ROP) followed up in our clinic and referred from other centers. METHODS: Medical records of 1,856 ROP patients were retrospectively evaluated, and a total of 128 patients who underwent LT were included in the study. The study population was divided into the following two groups: patients who were followed up and treated in our clinic (group 1, N=45) and patients who were referred to our clinic from other centers (group 2, N=83). Data regarding birth weight, sex, gestational age, postnatal treatment time, disease localization, and stage were analyzed and compared between the two groups. Treatment success was defined by anatomic success 6 months after treatment. RESULTS: Patients in the referred group presented with a more advanced disease (p<0.01), a lower treatment success rate (p=0.01), and a longer time interval between diagnosis and LT (p=0.04). CONCLUSIONS: The treatment success rate of ROP was significantly lower in referred patients because of the potential delay in LT and more advanced disease at the time of treatment initiation. PMID- 27224073 TI - Cognitive performance of primary open-angle glaucoma and normal-tension glaucoma patients. AB - PURPOSE: To assess cognitive performance differences among primary open-angle glaucoma (POAG) patients, normal-tension glaucoma (NTG) patients, and healthy control (C) subjects. METHODS: A total of 60 participants (20 POAG, 20 NTG, and 20 C subjects) were included in this study. A detailed ophthalmologic examination was performed on all participants. A spectral domain-optical coherence tomography (SD-OCT) system was used to measure the ganglion cell-inner plexiform layer (GC IPL) and retinal nerve fiber layer (RNFL) thicknesses. To assess the cognitive performance of all participants, detailed neurological examinations, including the mini-mental state examination (MMSE), were performed by the same neurologist. RESULTS: There were no significant differences among the groups in terms of age (p =0.348) or gender (p =0.935). The mean RNFL thicknesses were significantly different among the groups (85.2 +/- 14.7, 76.8 +/- 10.3, and 91.4 +/- 7.7 um in the POAG, NTG, and C subjects, respectively; p <0.001). The mean GC-IPL thicknesses were 77.5 +/- 9.7 um in the POAG group, 73.4 +/- 7.8 um in the NTG group, and 78.8 +/- 3.8 um in the C group. Differences among the groups were not statistically significant (p =0.085). MMSE scores were 26.1 +/- 1.4, 25.7 +/- 2.3, and 28.8 +/- 0.9 in the POAG, NTG, and C groups, respectively. There were significant differences among the three groups (p <0.001). Specifically, there were significant differences between the NTG and C groups (p <0.001), and between the POAG and C groups (p =0.001). There was no significant difference between the POAG and NTG groups (p =0.595). CONCLUSIONS: There appear to be similar risk factors in glaucoma and neurodegenerative disorders that cause deterioration in cognitive performance. Comparing the low MMSE scores of the POAG and NTG patients with the scores of healthy C participants supports our hypothesis. Consequently, it is recommended that a neurologist should also examine glaucoma patients. PMID- 27224074 TI - Lacrimal gland primary acinar cell culture: the role of insulin. AB - PURPOSE: The goal of the present study was to establish a protocol for primary culture of lacrimal gland acinar cells (LGACs) and to assess the effect of adding insulin to the culture media. METHODS: LGACs were isolated and cultured from lacrimal glands of Wistar male rats. The study outcomes included cell number, viability, and peroxidase release over time and in response to three concentrations of insulin (0.5, 5.0, and 50.0 MUg/mL). RESULTS: In LGAC primary culture, cells started to form clusters by day 3. There was a time-response pattern of peroxidase release, which rose by day 6, in response to carbachol. Culture viability lasted for 12 days. An insulin concentration of 5.0 MUg/mL in the culture medium resulted in higher viability and secretory capacity. CONCLUSIONS: The present method simplifies the isolation and culture of LGACs. The data confirmed the relevance of adding insulin to maintain LGACs in culture. PMID- 27224075 TI - Isolated posterior scleritis associated with tuberculosis. AB - Ocular tuberculosis (TB) is considered to be rare, although its incidence has varied widely over time and in different populations. Latent TB is diagnosed when a person is infected with Mycobacterium tuberculosis but does not have active TB. During the last decade, interferon-gamma release assay tests have been developed that allow identification of patients with latent TB infection with better specificity than the tuberculin skin test and can differentiate between infection and prior vaccination. Although rare, tuberculous scleritis should be considered in the differential diagnosis of posterior scleritis. Here we describe a patient with posterior scleritis and severe visual loss associated with latent TB without uveitis, anterior scleritis, keratitis, or any other previous ocular disease history. The patient responded well to a combined treatment of antitubercular therapy and oral corticosteroids. PMID- 27224076 TI - Dexamethasone 0.7 mg implants in the management of pseudophakic cystoid macular edema. AB - Pseudophakic cystoid macular edema (PCME) is a common complication following cataract surgery. Although majority of patients with PCME remain asymptomatic, it remains an important cause of vision loss after cataract surgery. The pathogenesis of PCME remains unclear, but most authors agree that inflammation plays a major role in its development. There is no standard algorithm for treatment procedures for PCME. A biodegradable 0.7 mg dexamethasone intravitreal implant can be used to deliver medication into the posterior segment of eyes. This drug acts on all inflammatory mediators and has been approved for the treatment of macular abnormalities secondary to retinal vein occlusion and for non-infectious posterior uveitis. In this case series, we report six patients who presented with PCME and were treated with a 0.7 mg dexamethasone intravitreal implant. Favorable anatomical outcomes were demonstrated by spectral domain optical coherence tomography images. PMID- 27224077 TI - Assessment of surgical outcomes of limbal transplantation using simple limbal epithelial transplantation technique in patients with total unilateral limbal deficiency. AB - This study aimed to evaluate the effectiveness of the novel simple limbal epithelial transplantation (SLET) technique, which reduces the risk of iatrogenic limbal stem cell deficiency in the donor eye. Four patients with total unilateral limbal stem cell deficiency received a limbal graft, measuring 4 mm * 2 mm, from the contralateral healthy eye in a single surgical procedure. The graft was divided into 10-20 pieces and distributed on the corneal surface. At 6-month follow-up, a completely avascular corneal epithelial surface was obtained in two patients, and there was improvement in visual acuity in one patient. The limbal grafts did not adhere to the cornea in one patient. No serious complications related to the surgery were observed in this study. PMID- 27224078 TI - Bilateral acute depigmentation of the iris: a case report. AB - Bilateral acute depigmentation of the iris (BADI) is a new clinical entity of unknown etiology and is characterized by bilateral, symmetrical, and simultaneous depigmentation of the iris with focal or diffuse stromal atrophy; this condition generally has a good prognosis. We present a case of a 26-year-old woman who noted a spontaneous change in the iris color in both eyes in the last 2 months. The ophthalmological findings were atrophy of the iris stroma and pigmentation of the trabecular meshwork, without affecting the pigmented epithelium of the iris. Her intraocular pressure was normal and the visual acuity was 20/20 in both eyes. PMID- 27224079 TI - Methylene blue-related corneal edema and iris discoloration. AB - We report the case of a 70-year-old female patient who developed corneal edema and iris discoloration following the inadvertent use of 1% methylene blue instead of 0.025% trypan blue to stain the anterior capsule during cataract phacoemulsification surgery. Copious irrigation was performed upon realization of incorrect dye use. Corneal edema and iris discoloration developed during the early postoperative period and persisted at 24-months follow-up. However, keratoplasty was not required. The intracameral use of 1% methylene blue has a cytotoxic effect on the corneal endothelium and iris epithelium. Copious irrigation for at least 30 min using an anterior chamber maintainer may improve outcomes. PMID- 27224080 TI - Panophthalmitis with orbital cellulitis following glaucoma drainage implant surgery in a pediatric patient. AB - Here we report a case of childhood glaucoma refractory to angle and trabeculectomy surgery. The patient was treated with an AhmedTM drainage implant that was subsequently complicated by rapid-onset panophthalmitis and orbital cellulitis. Intravenous and intravitreal antibiotic therapy was initiated and the drainage tube was removed. The infectious process resolved within 3 weeks; however, phthisis bulbi developed subsequently. PMID- 27224081 TI - Herpes zoster ophthalmicus and varicella zoster virus vasculopathy. AB - Herpes zoster (HZ) corresponds to the reactivation of varicella zoster virus (VZV). Among adults, the ophthalmic division of the trigeminal nerve is one of the most common sites of involvement. Vasculopathy caused by HZ is associated with significant morbidity and mortality, affecting structures such as the brain, which can lead to stroke. In this review, we analyzed the epidemiological and clinical aspects of the vascular involvement of VZV, focusing on the peculiarities of its association with ocular HZ. A review of the available literature indicated that ocular involvement of HZ was a risk factor for vasculopathy after adjusting for age, sex, body mass index, smoking, indicators of metabolic syndrome, and vascular and heart diseases. Considering the severity of this complication, vascular disease mediated by VZV requires early diagnosis and aggressive treatment. Finally, the anti-HZ vaccine has been recommended as a prophylactic measure in the elderly, but it should be used with caution in immunocompromised individuals. PMID- 27224082 TI - Comment on: "measurement and clinical implications of choroidal thickness in patients with inflammatory bowel disease". PMID- 27224083 TI - Evaluation of a simulation tool in ophthalmology: application in teaching funduscopy. PMID- 27224084 TI - Acquired restrictive strabismus in infancy associated with neurofibromatosis type 2. PMID- 27224085 TI - What is plagiarism after all? PMID- 27224086 TI - Two-Site Evaluation of the Repeatability and Precision of an Automated Dual Column Hydrogen/Deuterium Exchange Mass Spectrometry Platform. AB - Hydrogen/deuterium exchange coupled with mass spectrometry (HDX-MS) is an information-rich biophysical method for the characterization of protein dynamics. Successful applications of differential HDX-MS include the characterization of protein-ligand binding. A single differential HDX-MS data set (protein +/- ligand) is often comprised of more than 40 individual HDX-MS experiments. To eliminate laborious manual processing of samples, and to minimize random and gross errors, automated systems for HDX-MS analysis have become routine in many laboratories. However, an automated system, while less prone to random errors introduced by human operators, may have systematic errors that go unnoticed without proper detection. Although the application of automated (and manual) HDX MS has become common, there are only a handful of studies reporting the systematic evaluation of the performance of HDX-MS experiments, and no reports have been published describing a cross-site comparison of HDX-MS experiments. Here, we describe an automated HDX-MS platform that operates with a parallel, two trap, two-column configuration that has been installed in two remote laboratories. To understand the performance of the system both within and between laboratories, we have designed and completed a test-retest repeatability study for differential HDX-MS experiments implemented at each of two laboratories, one in Florida and the other in Spain. This study provided sufficient data to do both within and between laboratory variability assessments. Initial results revealed a systematic run-order effect within one of the two systems. Therefore, the study was repeated, and this time the conclusion was that the experimental conditions were successfully replicated with minimal systematic error. PMID- 27224087 TI - Transcranial brain stimulation: closing the loop between brain and stimulation. AB - PURPOSE OF REVIEW: To discuss recent strategies for boosting the efficacy of noninvasive transcranial brain stimulation to improve human brain function. RECENT FINDINGS: Recent research exposed substantial intra- and inter-individual variability in response to plasticity-inducing transcranial brain stimulation. Trait-related and state-related determinants contribute to this variability, challenging the standard approach to apply stimulation in a rigid, one-size-fits all fashion. Several strategies have been identified to reduce variability and maximize the plasticity-inducing effects of noninvasive transcranial brain stimulation. Priming interventions or paired associative stimulation can be used to 'standardize' the brain-state and hereby, homogenize the group response to stimulation. Neuroanatomical and neurochemical profiling based on magnetic resonance imaging and spectroscopy can capture trait-related and state-related variability. Fluctuations in brain-states can be traced online with functional brain imaging and inform the timing or other settings of transcranial brain stimulation. State-informed open-loop stimulation is aligned to the expression of a predefined brain state, according to prespecified rules. In contrast, adaptive closed-loop stimulation dynamically adjusts stimulation settings based on the occurrence of stimulation-induced state changes. SUMMARY: Approaches that take into account trait-related and state-related determinants of stimulation-induced plasticity bear considerable potential to establish noninvasive transcranial brain stimulation as interventional therapeutic tool. PMID- 27224088 TI - A new neuroinformatics approach to personalized medicine in neurology: The Virtual Brain. AB - PURPOSE OF REVIEW: An exciting advance in the field of neuroimaging is the acquisition and processing of very large data sets (so called 'big data'), permitting large-scale inferences that foster a greater understanding of brain function in health and disease. Yet what we are clearly lacking are quantitative integrative tools to translate this understanding to the individual level to lay the basis for personalized medicine. RECENT FINDINGS: Here we address this challenge through a review on how the relatively new field of neuroinformatics modeling has the capacity to track brain network function at different levels of inquiry, from microscopic to macroscopic and from the localized to the distributed. In this context, we introduce a new and unique multiscale approach, The Virtual Brain (TVB), that effectively models individualized brain activity, linking large-scale (macroscopic) brain dynamics with biophysical parameters at the microscopic level. We also show how TVB modeling provides unique biological interpretable data in epilepsy and stroke. SUMMARY: These results establish the basis for a deliberate integration of computational biology and neuroscience into clinical approaches for elucidating cellular mechanisms of disease. In the future, this can provide the means to create a collection of disease-specific models that can be applied on the individual level to personalize therapeutic interventions. VIDEO ABSTRACT. PMID- 27224089 TI - Assembly of Double-Hydrophilic Block Copolymers Triggered by Gadolinium Ions: New Colloidal MRI Contrast Agents. AB - Mixing double-hydrophilic block copolymers containing a poly(acrylic acid) block with gadolinium ions in water leads to the spontaneous formation of polymeric nanoparticles. With an average diameter near 20 nm, the nanoparticles are exceptionally stable, even after dilution and over a large range of pH and ionic strength. High magnetic relaxivities were measured in vitro for these biocompatible colloids, and in vivo magnetic resonance imaging on rats demonstrates the potential utility of such polymeric assemblies. PMID- 27224091 TI - Coming in Postgraduate Medicine. PMID- 27224090 TI - En Bloc Liver Kidney Transplantation Using Donor Splenic Artery as Inflow to the Kidney: Report of Two Cases. AB - The number of simultaneous liver-kidney transplants has been increasing. This surgery is associated with an increased risk of complications, longer duration of surgery and longer ischemia time for the renal allograft. Two patients listed for liver-kidney transplant at our center underwent en bloc combined liver-kidney transplantation using donor splenic artery as inflow. Patient 1 previously underwent cardiac catheterization that was complicated by a bleeding pseudoaneurysm of the right external iliac artery that required endovascular stenting of the external iliac artery and embolization of the inferior epigastric artery. Patient 2 was on vasopressor support and continuous renal replacement therapy at the time of transplant. In this paper, we described a novel technique of en bloc liver-kidney transplant with simultaneous reperfusion of both allografts using the donor splenic artery for renal inflow. This technique is useful for decreasing cold ischemia time and total operative time by simultaneous reperfusion of both allografts. It is a useful technical variant that can be used in patients with severe disease of the iliac arteries. PMID- 27224093 TI - What's Happening in Medicine! PMID- 27224092 TI - Problems/Solutions. AB - Readers are invited to submit questions relating to problem cases. Inquiries will be answered by qualified consultants and replies forwarded by mail promptly. Selected problems and solutions are published every month in this section. PMID- 27224095 TI - Washington Report on Health. PMID- 27224096 TI - Meetings and Courses. PMID- 27224097 TI - Tongue Cancer. PMID- 27224099 TI - The Medical Muse. PMID- 27224098 TI - Editor's Mail. PMID- 27224101 TI - Your Investments. PMID- 27224103 TI - A time for decisions. AB - 'The Government can no longer ignore the fact that there are major problems with the implementation of clinical grading. PMID- 27224102 TI - Therapeutic Index. PMID- 27224104 TI - Ten commandments. AB - The International Department of I the Royal College of Nursing offers a comprehensive advisory service for those members who wish to travel overseas. The number of people seeking such help and advice has increased over the past two years. This could be due to the increased number of advertisements for posts overseas, because of the seemingly world-wide shortage of nurses. PMID- 27224105 TI - Low grades indicated from leaked figures. AB - Leaked district health authority grading figures for nurses and health visitors show considerable cause for concern, the Confederation of Health Service Employees said this week. PMID- 27224106 TI - Midwife struck off professional register. AB - A midwife who was suspended after taking a critically ill mother to hospital in her own car has been found guilty of professional misconduct and struck off the professional register. PMID- 27224107 TI - More doubts over funding. AB - Staff and management side were due to meet again this week as concern resurfaces about the implementation of clinical grading and the amount of money available to fund the exercise. PMID- 27224108 TI - Revised position. AB - The Royal College of Nursing has revised arrangements for the appointment of a new General Secretary Designate, and the position will be re-advertised in the week beginning October 3. PMID- 27224109 TI - Accountability guidance. AB - New guidance for nurses on the issue of professional account ability is soon to be released by the UK Central Council for Nursing, Midwifery and Health Visiting, nurses at the first International Orthopaedic Conference were told. PMID- 27224110 TI - Back pain awareness week launched. AB - Back injured nurses should pressure employers into improving conditions through their insurers, Lord Joseph, President of the National Back Pain Association, said last week. PMID- 27224111 TI - Study reveals information gap. AB - One mother in five does not receive enough information from health care professionals during pregnancy, labour, and delivery', a new study has revealed. PMID- 27224112 TI - Cancer nursing degree. AB - Nurses specialising in the care of cancer patients will soon be able to take a Master of Science Degree in Cancer Nursing. PMID- 27224113 TI - A unique challenge. AB - The Kingdom of Saudi Arabia is rich in culture and tradition. To the nurse contemplating a working experience there, it brings many varying and unique challenges, both in professional and personal terms. PMID- 27224114 TI - Using cancer patients' trust. AB - Nurses must take full advantage of the trust that cancer patients place in them, Edwina Currie, Junior Health Minister, told the Fifth International Cancer Conference. PMID- 27224115 TI - Broadmoor balloted. AB - Nurses at Broadmoor Special Hospital are being balloted on whether to accept an offer of a L200 locality allowance and an increase in housing from the Department of Health. PMID- 27224116 TI - Indefinite strike action hits maudsley hospital. AB - Nurses at Maudsley Psychiatric Hospital in London began [illegible word] industrial action last week in protest at the Government's failure to commit itself to fund the full cost of the nurses' pay award. PMID- 27224117 TI - NHS report set to stir up debate. AB - The RCN aims to make the report of its Commission on the NHS, launched last week, the centre of major political, professional and public debate over the coming months. PMID- 27224119 TI - Unions accept call for health charter. AB - Delegates at the Trade Union Congress in Bournemouth unanimously passed a motion proposing a 'Charter for Health', which calls for I the full funding of the nurses' pay award and an urgent injection of cash into the NHS. PMID- 27224118 TI - Opportunities in canada. AB - Canada has a bad reputation as far as visas go. Lots of people want to work there, but few are granted the chance. PMID- 27224120 TI - Concern mounts over neonatal icu services. AB - A recently published survey into nationwide neonatal intensive care shortages is expected to show that a disturbingly high number of premature babies are not receiving hospital care. PMID- 27224122 TI - [Not Available]. PMID- 27224121 TI - For the record. AB - Nurses' and health visitors' organisations are alarmed at the possibility that nurses will not be allowed to decide whether patients are allowed to see their records. PMID- 27224123 TI - Northern lifestyles no better, no worse. AB - A comprehensive survey has shown that despite the adverse publicity they have received in recent years, Northerners have very similar health habits to the rest of the country. PMID- 27224124 TI - Satisfaction survey at bloomsbury. AB - A new computer-based patient satisfaction survey is being developed for health authorities around the country to use. PMID- 27224125 TI - South western RHA in concrete cancer claim. AB - A regional health authority is claiming compensation from the builders of a hospital it is having to replace because of 'concrete cancer'. PMID- 27224126 TI - Glaswegian ahead in cash cycle. AB - A young cyclist who suffered serious head injuries following an accident three years ago aims to repay the nurses who put him on the road to recovery. PMID- 27224127 TI - Memorable reception for retiring scottish board secretary. AB - The Royal College of Nursing Scottish Board marked the retirement of Elizabeth McLaren, the Board's Secretary, with a memorable reception last week. PMID- 27224128 TI - Ans recruitment drive. AB - The RCN Association of Nursing Students wants branch activists to help with them with their biggest recruitment drive this year. PMID- 27224129 TI - Nl board to host major conference. AB - The RCN Northern Ireland Board is holding a major conference to mark the completion I of the refurbishment and extention of its headquarters' educational facilities. PMID- 27224130 TI - OH management conference. AB - The Occupational Health Managers Forum is holding its 10th annual conference and exhibition on September 21 in London. PMID- 27224132 TI - The best of the west. AB - A s many as 70 per cent of the / I nurses who leave the UK for the United States apply fora'green w 1 card', or permanent work permit once their temporary visas expire. PMID- 27224131 TI - Clinical grading. AB - Yorkshire Region reported that despite the mail problems the information from their districts was all coming in and that they would be able to work out manpower projections and provisional costing in time. It was a rapid process to work out the cost having received the figures from the districts, a spokesman said, and it should have been completed by the end of last week. PMID- 27224133 TI - Arrive, assess, advise. AB - There are few fields of nursing where the 'search for health needs' is made an explicit responsibility of nurses. In many specialities health needs are presented to nurses on a plate and nurses are able to leap straight in and meet them. Health visiting claims searching for health needs as its own because it is one of the four principles of health visiting set down by the Council for the Education and Training of Health Visitors (1977) . However, it is a principle that rightly belongs to all nurses. PMID- 27224134 TI - Denmark. AB - The waiting list problem in Denmark has caused a rapid growth in the Danish private health insurance industry, according to a report by the Office of Health Economics. PMID- 27224135 TI - Ethiopia. AB - Large numbers of civilian casualties in Tigray have led to further requests for medical assistance. PMID- 27224136 TI - Australia. AB - Nurses at the Royal Melbourne Hospital in Victoria are going to jail rather than pay parking fines. PMID- 27224137 TI - United states. AB - The Association of Operating Room Nurses has stood behind other US nursing organisations in condemning the idea of introducing a registered care technologist to cope with nursing shortages. PMID- 27224138 TI - Netherlands. AB - Thousands of nurses all over the Netherlands are currently taking part in a quality assurance project backed by the government. PMID- 27224139 TI - Taxing time. AB - The summer recess is in full swing, with MPs either back in their constituencies or taking their summer holidays. PMID- 27224141 TI - Coronary care outcomes. AB - Strategies for preparing patients for self care following myocardial infarction may need to be adjusted in view of the short in-patient stay. PMID- 27224140 TI - Vaccine progress. AB - Giving antibody/antigen complexes may enhance the action of a vaccine against human immunodeficiency virus (HIV). PMID- 27224142 TI - Drug attitudes. AB - Nurses show positive attitudes to colleagues who are substance abusers, according to research from Oregon. PMID- 27224143 TI - Skin cancer antibody tests. AB - It may soon be possible to prevent malignant melanomas metastasising, according to researchers in Australia. PMID- 27224144 TI - Collaboration needed. AB - More extensive facilities than those available in joint assessment units are needed for the management of elderly psychiatry patients. PMID- 27224145 TI - Ultrasound stethoscope warning. AB - Primary health care teams have been warned not to let themselves be 'seduced' by the apparent attractions of cheap and portable ultrasound scanners. Delegates at the 13th International Gastroenterology Conference in Rome were told that the notion of the 'ultrasound stethoscope' was superficially attractive by an international working party which has studied it for two years. PMID- 27224146 TI - Holistic orthopaedic nursing. AB - Primary nursing seems significantly to improve levels of patient and staff satisfaction, the RCN Orthopaedic Nursing Conference heard last week. PMID- 27224147 TI - Pre-hospital treatment available for coronary patients. AB - A new blood clot dissolving agent which is easier to administer than traditional treatment with streptokinase may save the lives of thousands of coronary patients. PMID- 27224148 TI - Shame makes women hide post-natal depression. AB - Women who suffer from postnatal depression are likely to have been competent and successful before their pregnancy and often try to hide their condition from nurses and midwives, a conference was told. PMID- 27224149 TI - Psychological care emphasised. AB - The mental health needs of the physically ill require greater attention from nurses, a conference on cancer care heard. PMID- 27224151 TI - Concern voiced over hepatitis b danger. AB - Over 1,300 nurses from across the world packed the annual conference of the European Dialysis and Transplant Nurses Association last week. PMID- 27224150 TI - RCN general secretary backs patient centred cancer care. AB - The development of patient centred cancer care would extend the nurse's role and improve quality and efficiency, Trevor Clay, General Secretary of the Royal College of Nursing, said last week. PMID- 27224152 TI - Opinions on time questioned. AB - Nurses' assumptions about how they spend their time are not always reliable and can limit their ability to explore alternative management strategies, Glynis Markham, Director of Nursing Services at the Royal Marsden Hospital, told the International Cancer Conference. PMID- 27224154 TI - Third world aid. AB - Last month two major disasters highlighted the Third World's continuing need of the skills that western nurses have to offer. PMID- 27224153 TI - Poles apart in health crisis. AB - How would you feel if you had to use an adult catheter for a small child and the shortage of analgesics made it difficult even to do anything for the pain this would cause? PMID- 27224155 TI - Care of the elderly has its rewards. AB - Nursing the elderly is often seen as fit only for those who are unskilled or professionally underdeveloped. This unenlightened view leads to nurses working in this challenging area being looked down on by their colleagues outside the speciality. It is time these attitudes were changed. While it has been recognised that a new form of care is needed for our elderly, we still have a long way to go to educate not only those outside this speciality, but also many nurses involved in working with the elderly. What, then, are some of the too often unrecognised, special qualities that are necessary in the elderly care nurse? PMID- 27224156 TI - Listings. AB - Nursing Standard's listings section is a completely free service for its readers. To ensure maximum publicity for any event connected with your profession, be sure to let us know so that it can be included in our exhaustive nationwide guide to what's on in nursing. PMID- 27224157 TI - Equal to the challenge. AB - People with learning difficulties may also exhibit additional behaviours which present a serious challenge to service providers and their staff. PMID- 27224158 TI - Plymouth ho! AB - Plymouth Health Authority, way down in the south west, is somewhat isolated. But that's not to say that it's a backwater where innovation is a dirty word. PMID- 27224159 TI - Endocrine system the pituitary gland. AB - The body is under control of two very different systems which function in different ways but whose actions compliment each other. The nervous system provides a rapid response to the information it receives. In contrast, the endocrine system functions more slowly. PMID- 27224160 TI - The nursing shop. AB - Recruitment to the nursing profession is falling, and falling quite markedly. Unless something drastic is done, the standards of nursing care in our hospitals is likely to drop. PMID- 27224161 TI - Limb amputation. AB - Amputation of the lower limb is necessary for a variety of reasons, such as ischaemia, trauma and malignant disease. For the patient, who may be elderly, the need to amputate is an enormous shock and requires a great [Illegible Word] of adjustment. PMID- 27224162 TI - Hydrotherapy. AB - Hippocrates (460- 375BC) used hot and cold water in treating diseases. The term hydrotherapy is derived from the Greek Hydor meaning water, and Therapeia meaning healing. PMID- 27224163 TI - Treating rabies. AB - Rabies was first reported by Aristotle over 2,000 years ago and has plagued man ever since. Little has been done to provide adequate treatment once the symptoms have appeared. Therefore the battle against rabies involves health education and prophylaxis, although during the incubation period rabies is treatable. The incubation period of this communicable disease can range from ten days to six months but may be as long as two years. The length of the incubation period is determined by the proximity and severity of the bite, to the brain. PMID- 27224164 TI - Renal diet. AB - Aim of diet in renal disease Diet in renal disease is aimed at treating abnormal body biochemistry and symptoms of uraemia while maintaining optimal nutrition to preserve body mass. The abnormalities in biochemistry and the physical signs vary to some extent from person to person and with the type of renal disease present( l ). PMID- 27224165 TI - Learning can be 'fun'. AB - In January 1988 Doncaster Nurse Education Department recommenced nurse training with its brand new Curriculum for General Nurses. A modular system of education, with an impressive depth and width for prospective candidates to get their teeth into; one which we hope will eventually lead them towards autonomy within the profession. PMID- 27224170 TI - How to pass exams on the run. AB - Yes, dear friends of my youth, it is I - he who left school with two 'O' levels, o music CSE [Illegible Word] a budgerigar; consolidating this by failing his SRN three times, finally getting on the only refresher course in England and passing in October 1979- the very last occasion to take an SRN for the fourth time. Have I got a cheek to write about passing exams? These experiences hove had their effect! I come to academic life late and have developed a hectic domestic, social and professional life meanwhile. PMID- 27224171 TI - Just desserts. AB - I have been in the nursing profession for 22 years, starting as a 16 year old cadet nurse. I have been employed in my present post as an enrolled nurse on night duty for the past 13 years, regularly in charge of a high dependency surgical ward. After attending my recent interview for clinical grading and accompanying one of my fellow enrolled nurses as an observer, I find it hard to describe how I felt on leaving the interviews: disappointed, angry and disgusted with the profession. Am I to consider myself lucky and be eternally grateful if I am given a D grade when I have done the same job as a staff nurse for the past 13 years? Having super-. vised trained and untrained I staff and taught trained and untrained junior and senior staff, imagine my dismay. At my interview, I was informed that I have been supervised for all these years, that supervision being a night sister at the end of a telephone via a bleep. I may add that the night sister is covering for up to six wards. When the clinical grading structure was announced, I, like many enrolled nurses, thought at last we were going to be rewarded for the job we do, not what management would like us to do. But now as the euphoria dies and the real nightmare emerges, it would seem that we are going to be downtrodden again. Experi- ence, service and loyalty count for nothing. I fail to see how the answers to 16 questions only can give a fair and equal account of the job you do and the responsibilities involved in the post you hold. PMID- 27224172 TI - Ready for battle. AB - As a newly elected member of the English National Board, I would like to thank my fellow nurses, friends and colleagues who voted for me. PMID- 27224173 TI - Work injured nurses group. AB - The Work Injured Nurses Group (WING) was started as the RCN Back Group by one of the RCN solicitors, who was very concerned about the social isolation and lack of [Illegible word] available for nurses following injury. PMID- 27224174 TI - Dissent and resentment. AB - Referring to the clinical grading structure which has been hailed as the all embracing answer to nurses' pay, its anomalies and discrepancies are set to produce dissension and resentment in nursing in the years to come. (Witness the arguments and discussion going on at the moment right to the highest levels.). PMID- 27224175 TI - Group formation. AB - I am co-ordinating the formation of a practice nurses' group for the Walsall area. Our inaugural meeting will be in October. Any practice nurse who would like more information please contact me at the following address. PMID- 27224176 TI - Reminder. AB - We would like to take this opportunity to remind friends, old and new, of Hartlepool branch of the RCN 7th International conference/exhibition (in collaboration with Nursing Standard), to be held on Thursday October 27 1988, in the Civic Centre, Hartlepool. Application forms will be issued with RCN newsline and in Nursing Standard or are available from us c/o Ward 6, Hartlepool General Hospital, Hartlepool. PMID- 27224177 TI - Premature sentiments. AB - While I found myself nodding in agreement with the sentiments of your editorial (Nursing Standard August 20, 1988), aren't you 'jumpinq the qun' just a little? PMID- 27224178 TI - The write stuff. AB - To most writers the rejection slip plays an uncomfortably large part in the mail delivery. But there are not many who are actually approached by a publisher to write a particular novel before they have ever tried their hand at this kind of work. PMID- 27224179 TI - A taste for adventure. AB - Emir O'Sullivan has been recruiting nurses for the new London Welbeck Hospital. If the hospital director was looking for someone with a varied nursing background to do this recruiting job, he found the right person in Emir O'Sullivan. PMID- 27224180 TI - Directions. AB - Your mother is coming along very well,' the houseman assured the two middle aged women. 'She's cheerful, cooperative and as good as a lamb.' The women turned, looked at each other and the elder in the most serious manner whispered, 'Now I know she's ill!' PMID- 27224181 TI - Watchdog. AB - We are a group of nurses working on an Ear, Nose and Throat ward and hold the Midland Institute Diploma of Otorhinocology. Our managers have always encouraged the staff to obtain this diploma. We were granted half-day release to the Queen Elizabeth Hospital, Birmingham, for lectures, and the Diploma was presented at the annual prizegiving. PMID- 27224182 TI - League facing relegation. AB - We are quite sure the buzzword 'demography' has already entered your tea-break banter, but for the uninitiated, it refers to the impending drastic shortage of qualified school leavers entering the health service. The word should be accompanied by a knowing look, a sharp intake of breath, and a slow nodding of the head. PMID- 27224183 TI - Paper chase. PMID- 27224184 TI - Spaced out cereal. AB - At last it can be revealed! Our Edwina's so hyperactive because she's high on LSD! PMID- 27224185 TI - Burgers off. AB - The latest scapegoat for all of society's ills has now been pinned down. Junk food is the culprit. Two British nutritio- nalists, Dr Damien Downing and Mr Ian Stokes say they have found a link between teenager's consumption of junk food and soft drinks and the rise in soccer hooliganism. PMID- 27224187 TI - The lab report. PMID- 27224186 TI - Horsing around. AB - Doctor Doctor! This patient is feeling a little horse. PMID- 27224189 TI - Adhesive skin closure. AB - A new adhesive skin closure from 3M Health Care comes with a semi-rigid carrier delivery system. PMID- 27224188 TI - Extended role models. AB - It may seem that all the world and his dog has been swept up in the media storm over the clinical grading review. PMID- 27224190 TI - Child restraints in cars. AB - An educational video, which portrays the dangers children face when they are not properly restrained in cars, is now available on loan from Britax Excelsior. PMID- 27224191 TI - Lightweight aluminium wheelchair. AB - A new lightweight wheelchair, specially constructed to give increased mobility and easy use, is now on the market. PMID- 27224192 TI - Medicinal berry in tablet form. AB - A medicinal berry, to which people in China, Russia and Sweden already attribute a wide range of healing properties, is now available in the UK. PMID- 27224193 TI - Women's shoes for all day wear. AB - The shoe retailers Olivers and Timpson are now marketing shoes for women who are on their feet all day. PMID- 27224194 TI - Pulse oximeter with extended memory. AB - A new pulse oximeter featuring a powerful memory capacity and a programmable alarm system is now available from DeVilbiss Health Care. PMID- 27224196 TI - Hyper active. PMID- 27224195 TI - Converting the faithful. AB - As many enrolled nurses know only too well, conversion course places are as scarce as water in the desert. There are plenty of courses available now, but with the imposed tutor/student ratio of 1:10, and the high number of people wanting to do the course, places are very rare indeed. PMID- 27224197 TI - An equal opportunity. AB - Anybody thinking about nursing in Saudi Arabia cannot fail to notice that every piece of literature on the Kingdom refers to the cultural difference and how much there is to be gained from experiencing it. PMID- 27224198 TI - Going dutch. AB - When Els Keane left her native Holland more than 20 years ago to practise as a qualified nurse in this country, she found there were some major differences to contend with. PMID- 27224199 TI - Nursing stateside. AB - Nursing in the United States is looking better and better for United Kingdom nurses, with recruitment drives by American nurse agencies becoming commonplace and short-term contracts allowing nurses to make a commitment with a time limit on it. PMID- 27224200 TI - Commission of graduates of foreign nursing schools. AB - Before you can work in the US you must prove to the State Nursing Boards that you are competent. For all states except California, Florida and Arkansas, this entails sitting the CGFNS exam. PMID- 27224201 TI - Active implantable medical device EMI assessment for wireless power transfer operating in LF and HF bands. AB - The electromagnetic interference (EMI) imposed on active implantable medical devices by wireless power transfer systems (WPTSs) is discussed based upon results of in vitro experiments. The purpose of this study is to present comprehensive EMI test results gathered from implantable-cardiac pacemakers and implantable cardioverter defibrillators exposed to the electromagnetic field generated by several WPTSs operating in low-frequency (70 kHz-460 kHz) and high frequency (6.78 MHz) bands. The constructed in vitro experimental test system based upon an Irnich's flat torso phantom was applied. EMI test experiments are conducted on 14 types of WPTSs including Qi-compliant system and EV-charging WPT system mounted on current production EVs. In addition, a numerical simulation model for active implantable medical device (AIMD) EMI estimation based on the experimental test system is newly proposed. The experimental results demonstrate the risk of WPTSs emitting intermittent signal to affect the correct behavior of AIMDs when operating at very short distances. The proposed numerical simulation model is applicable to obtain basically the EMI characteristics of various types of WPTSs. PMID- 27224202 TI - Staphylococcus aureus Regulatory RNAs as Potential Biomarkers for Bloodstream Infections. AB - Staphylococcus aureus is a commensal bacterium and pathogen. Identifying biomarkers for the transition from colonization to disease caused by this organism would be useful. Several S. aureus small RNAs (sRNAs) regulate virulence. We investigated presence and expression of 8 sRNAs in 83 S. aureus strains from 42 patients with sepsis or septic shock and 41 asymptomatic colonized carriers. Small pathogenicity island sRNAs sprB and sprC were clade specific. Six sRNAs had variable expression not correlated with clinical status. Expression of RNAIII was lower in strains from septic shock patients than in strains from colonized patients. When RNAIII was associated with expression of sprD, colonizing strains could be discriminated from strains in patients with bloodstream infections, including patients with sepsis and septic shock. Isolates associated with colonization might have sRNAs with target expression different from those of disease isolates. Monitoring expression of RNAIII and sprD could help determine severity of bloodstream infections. PMID- 27224203 TI - Femtosecond-Laser-Pulse Characterization and Optimization for CARS Microscopy. AB - We present a simple method and its experimental implementation to determine the pulse durations and linear chirps of the pump-and-probe pulse and the Stokes pulse in a coherent anti-Stokes Raman scattering microscope at sample level without additional autocorrelators. Our approach exploits the delay line, ubiquitous in such microscopes, to perform a convolution of the pump-and-probe and Stokes pulses as a function of their relative delay and it is based on the detection of the photons emitted from an appropriate non-linear sample. The analysis of the non-resonant four-wave-mixing and sum-frequency-generation signals allows for the direct retrieval of the pulse duration on the sample and the linear chirp of each pulse. This knowledge is crucial in maximizing the spectral-resolution and contrast in CARS imaging. PMID- 27224204 TI - Culture and group-based emotions: could group-based emotions be dialectical? AB - Group-based emotions are experienced when individuals are engaged in emotion provoking events that implicate the in-group. This research examines the complexity of group-based emotions, specifically a concurrence of positive and negative emotions, focusing on the role of dialecticism, or a set of folk beliefs prevalent in Asian cultures that views nature and objects as constantly changing, inherently contradictory, and fundamentally interconnected. Study 1 found that dialecticism is positively associated with the complexity of Chinese participants' group-based emotions after reading a scenario depicting a positive intergroup experience. Study 2 found that Chinese participants experienced more complex group-based emotions compared with Dutch participants in an intergroup situation and that this cultural difference was mediated by dialecticism. Study 3 manipulated dialecticism and confirmed its causal effect on complex group-based emotions. These studies also suggested the role of a balanced appraisal of an intergroup situation as a mediating factor. PMID- 27224205 TI - A Detailed Analysis of the Morphology of Fibrils of Selectively Mutated Amyloid beta (1-40). AB - A small library of rationally designed amyloid beta [Abeta(1-40)] peptide variants is generated, and the morphology of their fibrils is studied. In these molecules, the structurally important hydrophobic contact between phenylalanine 19 (F19) and leucine 34 (L34) is systematically mutated to introduce defined physical forces to act as specific internal constraints on amyloid formation. This Abeta(1-40) peptide library is used to study the fibril morphology of these variants by employing a comprehensive set of biophysical techniques including solution and solid-state NMR spectroscopy, AFM, fluorescence correlation spectroscopy, and XRD. Overall, the findings demonstrate that the introduction of significant local physical perturbations of a crucial early folding contact of Abeta(1-40) only results in minor alterations of the fibrillar morphology. The thermodynamically stable structure of mature Abeta fibrils proves to be relatively robust against the introduction of significantly altered molecular interaction patterns due to point mutations. This underlines that amyloid fibril formation is a highly generic process in protein misfolding that results in the formation of the thermodynamically most stable cross-beta structure. PMID- 27224206 TI - Pheomelanin in the secondary sexual characters of male parasitoid wasps (Hymenoptera: Pteromalidae). AB - The occurrence and distribution of eumelanin and pheomelanin, the most prevalent biological pigments, has been rarely investigated in insects. Particularly yellowish to brownish body parts, which in many vertebrates are associated with pheomelanin, are visible in many insects but their chemical nature was rarely examined to a similar detail. Here, by using Dispersive Raman spectroscopy analysis, we found both eumelanin and pheomelanin in different body parts of male parasitoid wasps of three species of the genus Mesopolobus (Hymenoptera: Pteromalidae), which are known to have species-specific spots and coloured stripes on the legs and/or antennae which are displayed to females during courtship. We found a strong eumelanin signal in the antennal clava of all studied Mesopolobus species and in the circular black spot or callosity and the triangular black projection on the outer apical angle of the typically expanded middle tibia of Mesopolobus tibialis and Mesopolobus xanthocerus. Eumelanin was also the predominant pigment in the black thorax of Mesopolobus and other members of the family. Pheomelanin, on the other hand, was detected as predominant only in certain body parts of M. tibialis and M. xanthocerus, precisely in a very narrow, longitudinal brownish stripe on the middle femur and, only in M. tibialis, in a brownish oval-longitudinal stripe on the middle tibia. The two melanin types co-occurred in most pigmented areas, but more often one is clearly predominant relative to the other, according to the variation of Raman signal intensity of their signature peaks. A further tibial yellowish-orange stripe present in both these species did not include melanins of any type. Pheomelanin, could be more widespread than previously known in insects. A convergent evolution of melanin-based male sexual ornaments between vertebrates (e.g. bird feathers) and wasps can be suggested, opening to a new line of comparative evolutionary studies. PMID- 27224208 TI - Association of ADIPOQ single nucleotide polymorphisms with the risk of intracranial atherosclerosis. AB - BACKGROUND: The genetic mechanism of the racial distribution difference of intracranial atherosclerosis (ICAS) is unclear. The single nucleotide polymorphisms (SNPs) may be associated with different genetic susceptibility to ICAS. At present, the correlation between ADIPOQ gene SNPs and the risk of ICAS remains unknown. METHODS: Continuous inpatients were selected and divided into ICAS group and control group. Computed tomography angiography was performed to observe intracranial arteries. ADIPOQ SNPs were detected using the ligase detection reaction-PCR. The correlation between the identified SNPs and ICAS was determined using the binary logistic regression analysis. RESULTS: This study contained 602 patients in total, including 199 ICAS and 403 control cases. The binary logistic regression analysis showed that the AG/AA genotype of the rs2241767 (OR = 2.242, 95% CI: 1.037-4.878, P = 0.040) and the AG/GG genotype of the rs182052 (OR = 1.822, 95% CI: 1.111-2.987, P = 0.017) were closely related to the risk of ICAS after adjusting for conventional cardiovascular risk factors. The haploid analysis results indicated that the incidence of the A-G haplotype of the rs2241767 and rs182052 was higher in the ICAS group than in the control group (P = 0.026). CONCLUSIONS: The SNPs of the ADIPOQ gene are closely related to increased risk of ICAS in Chinese Han population. PMID- 27224209 TI - ENDEMIC ORTHOPOXVIRUS CIRCULATING IN PROCYONIDS IN MEXICO. AB - Limited serosurveillance studies suggested that orthopoxviruses (OPXV) are widespread in the US (e.g., Raccoonpox virus, Skunkpox virus, Volepox virus) and Brazil (Vaccinia virus); however, their animal reservoir(s) remain unconfirmed. Mexican mammal diversity includes several species related to those in which evidence for OPXV infections has been found (Oryzomys, Peromyscus, Microtus, and Procyonidae). The presence of these groups of mammals in Mexico and the evidence of their possible involvement in the maintenance of OPXV in nature suggest the same or similar OPXV are circulating in Mexico. We tested 201 sera from 129 procyonids via modified enzyme-linked immunosorbent assay (ELISA) and Western blot (WB) to estimate OPXV antibody prevalence in these animals. We detected a prevalence of 16.67% in Nasua narica (white-nosed coati), 35% in Procyon lotor (raccoon), and 30.4% in Bassariscus astutus (ring-tailed cat) when tested by either ELISA or WB. Western blot results presented protein bands consistent with the size of some OPXV immunodominant bands (14, 18, 32, 36, and 62 kDa). These results support the hypothesis that OPXV circulate in at least three genera of Procyonidae in Central and Southeast Mexico. PMID- 27224207 TI - Pharmacological blockade of the calcium plateau provides neuroprotection following organophosphate paraoxon induced status epilepticus in rats. AB - Organophosphate (OP) compounds which include nerve agents and pesticides are considered chemical threat agents. Currently approved antidotes are crucial in limiting OP mediated acute mortality. However, survivors of lethal OP exposure exhibit delayed neuronal injury and chronic behavioral morbidities. In this study, we investigated neuroprotective capabilities of dantrolene and carisbamate in a rat survival model of paraoxon (POX) induced status epilepticus (SE). Significant elevations in hippocampal calcium levels were observed 48-h post POX SE survival, and treatment with dantrolene (10mg/kg, i.m.) and carisbamate (90mg/kg, i.m.) lowered these protracted calcium elevations. POX SE induced delayed neuronal injury as characterized by Fluoro Jade C labeling was observed in critical brain areas including the dentate gyrus, parietal cortex, amygdala, and thalamus. Dantrolene and carisbamate treatment provided significant neuroprotection against delayed neuronal damage in these brain regions when administered one-hour after POX-SE. These results indicate that dantrolene or carisbamate could be effective adjuvant therapies to the existing countermeasures to reduce neuronal injury and behavioral morbidities post OP SE survival. PMID- 27224211 TI - Prevalence and Distribution of Vibrio spp. in Wild Aquatic Birds of the Southern Caribbean Sea, Venezuela, 2011-12. AB - Vibrio spp. are associated with waterbirds mainly in temperate latitudes. We evaluated the prevalence and distribution of Vibrio spp. from fecal samples of resident and migratory aquatic birds collected during October 2011 and March 2012 at two coastal sites in the tropical southern Caribbean Sea. We amplified DNA by PCR in 40% of samples, resulting in 47% and 36% estimated prevalence for resident and migratory birds in Cuare Wildlife Refuge, and 33% and 44% in Margarita Island, respectively. We found nontoxigenic Vibrio cholerae in Cuare Wildlife Refuge with a higher prevalence in resident birds (18%). Our PCR results for Vibrio and V. cholerae were not significantly different between sites or bird migratory status. The 16S rRNA phylogenetic analysis sequences from fecal samples from Cuare Wildlife Refuge were highly similar to V. cholerae and Vibrio vulnificus , whereas sequences from Margarita Island samples formed clusters with species related to the Harveyi clade. Our findings indicate that several species of Vibrio are common in aquatic birds along the southern Caribbean Sea and contribute to our understanding of the role of birds as possible reservoirs of potentially pathogenic bacteria. PMID- 27224210 TI - COMPLETE GENOMIC SEQUENCE OF VIRULENT PIGEON PARAMYXOVIRUS IN LAUGHING DOVES (STREPTOPELIA SENEGALENSIS) IN KENYA. AB - Following mass deaths of Laughing Doves (Streptopelia senegalensis) in different localities throughout Kenya, internal organs obtained during necropsy of two moribund birds were sampled and analyzed by next generation sequencing. We isolated the virulent strain of pigeon paramyxovirus type-1 (PPMV-1), PPMV1/Laughing Dove/Kenya/Isiolo/B2/2012, which had a characteristic fusion gene motif (110)GGRRQKRF(117). We obtained a partial full genome of 15,114 nucleotides. The phylogenetic relationship based on the fusion gene and genomic sequence grouped our isolate as class II genotype VI, a group of viruses commonly isolated from wild birds but potentially lethal to Chickens ( Gallus gallus domesticus ). The fusion gene isolate clustered with PPMV-I strains from pigeons (Columbidae) in Nigeria. The complete genome showed a basal and highly divergent lineage to American, European, and Asian strains, indicating a divergent evolutionary pathway. The isolated strain is highly virulent and apparently species-specific to Laughing Doves in Kenya. Risk of transmission of such a strain to poultry is potentially high whereas the cyclic epizootic in doves is a threat to conservation of wild Columbidae in Kenya. PMID- 27224212 TI - Fusobacterium necrophorum in North American Bighorn Sheep ( Ovis canadensis ) Pneumonia. AB - Fusobacterium necrophorum has been detected in pneumonic bighorn sheep (BHS; Ovis canadensis ) lungs, in addition to the aerobic respiratory pathogens Mannheimia haemolytica , Bibersteinia trehalosi , Pasteurella multocida , and Mycoplasma ovipneumoniae . Similar to M. haemolytica , F. necrophorum produces a leukotoxin. Leukotoxin-induced lysis and degranulation of polymorphonuclear leukocytes (PMNs) and macrophages are responsible for acute inflammation and lung tissue damage characteristic of M. haemolytica -caused pneumonia. As one approach in elucidating the role of F. necrophorum in BHS pneumonia, we determined the frequency of the presence of F. necrophorum in archived pneumonic BHS lung tissues, and susceptibility of BHS leukocytes to F. necrophorum leukotoxin. A species-specific PCR assay detected F. necrophorum in 37% of pneumonic BHS lung tissues (total tested n=70). Sequences of PCR amplicons were similar to the less virulent F. necrophorum subsp. funduliforme. Fusobacterium necrophorum leukotoxin exhibited cytotoxicity to BHS PMNs and peripheral blood mononuclear cells. As with the M. haemolytica leukotoxin, F. necrophorum leukotoxin was more toxic to BHS PMNs than domestic sheep PMNs. It is likely that F. necrophorum enters the lungs after M. haemolytica and other aerobic respiratory pathogens enter the lungs and initiate tissue damage, thereby creating a microenvironment that is conducive for anaerobic bacterial growth. In summary, Fusobacterium leukotoxin is highly toxic for BHS leukocytes; however, based on the PCR findings, it is unlikely to play a direct role in the development of BHS pneumonia. PMID- 27224213 TI - Blood and Plasma Biochemistry Reference Intervals for Wild Juvenile American Alligators ( Alligator mississippiensis ). AB - : American alligators ( Alligator mississippiensis ) are one of the most studied crocodilian species in the world, yet blood and plasma biochemistry information is limited for juvenile alligators in their northern range, where individuals may be exposed to extreme abiotic and biotic stressors. We collected blood samples over a 2-yr period from 37 juvenile alligators in May, June, and July to establish reference intervals for 22 blood and plasma analytes. We observed no effect of either sex or blood collection time on any analyte investigated. However, our results indicate a significant correlation between a calculated body condition index and aspartate aminotransferase and creatine kinase. Glucose, total protein, and potassium varied significantly between sampling sessions. In addition, glucose and potassium were highly correlated between the two point-of care devices used, although they were significantly lower with the i-STAT 1 CG8+ cartridge than with the Vetscan VS2 Avian/Reptile Rotor. The reference intervals presented herein should provide baseline data for evaluating wild juvenile alligators in the northern portion of their range. PMID- 27224214 TI - Survey of Feral Swine ( Sus scrofa ) Infection with the Agent of Chagas Disease ( Trypanosoma cruzi ) in Texas, 2013-14. AB - : Feral swine ( Sus scrofa ) are an invasive species and reservoir of numerous zoonotic pathogens in the US, and Texas leads the nation in the estimated population size of feral hogs. Texas also harbors enzootic transmission cycles of the protozoan parasite Trypanosoma cruzi , agent of Chagas disease. Given previous evidence that swine can serve as reservoirs of T. cruzi in Latin America and new evidence of triatomines (kissing bugs) feeding on swine in Texas, we measured the prevalence of T. cruzi infection in feral swine in Texas. From 2013 to 2014, we sampled blood and/or cardiac tissue from 78 feral swine across 14 Texas counties (seven with and seven without prior documentation of kissing bug occurrence) and used PCR and histopathology to detect T. cruzi infection. We determined an overall infection prevalence of 6% (3 of 54) based on PCR evaluation of cardiac tissue, and no blood samples were positive (n=72). All three positive pigs were from counties where kissing bugs are documented. No T. cruzi amastigotes were noted on histopathology (n=54). Sarcocysts were observed in 10 (18%) of the samples, five of which also had mild focal areas of degeneration and inflammatory cell infiltration. Eco-epidemiologic investigations can provide an assessment of contributions of feral hogs to maintenance of T. cruzi across a landscape to help protect human and animal health. PMID- 27224215 TI - Rethinking the HIV-exposed, uninfected child: epidemiologic perspectives. PMID- 27224216 TI - The Data Box and Within-Subject Analyses: A Comment on Nesselroade and Molenaar (2016). AB - Nesselroade and Molenaar suggest that it is the relationships between latent variables within subjects that are invariant across subjects and thus the appropriate unit of analysis. We disagree and take the view that between-factor correlations may differ systematically across subjects. Further, individual differences in these correlations may be an important source of information about each unique individual. Following from this premise, analyses of consistencies and differences between subjects of the within-subject pattern of interfactor correlations is a step toward an integrative science of behavior. We give several examples demonstrating how this approach has the potential to yield novel insights into personality functioning. PMID- 27224217 TI - Autophagy guarantees stemness of muscle stem cells by maintaining quiescence. PMID- 27224218 TI - Gel-Free/Label-Free Proteomic Analysis of Endoplasmic Reticulum Proteins in Soybean Root Tips under Flooding and Drought Stresses. AB - Soybean is a widely cultivated crop; however, it is sensitive to flooding and drought stresses. The adverse environmental cues cause the endoplasmic reticulum (ER) stress due to accumulation of unfolded or misfolded proteins. To investigate the mechanisms in response to flooding and drought stresses, ER proteomics was performed in soybean root tips. The enzyme activity of NADH cytochrome c reductase was two-fold higher in the ER than other fractions, indicating that the ER was isolated with high purity. Protein abundance of ribosomal proteins was decreased under both stresses compared to control condition; however, the percentage of increased ribosomes was two-fold higher in flooding compared to drought. The ER proteins related to protein glycosylation and signaling were in response to both stresses. Compared to control condition, calnexin was decreased under both stresses; however, protein disulfide isomerase-like proteins and heat shock proteins were markedly decreased under flooding and drought conditions, respectively. Furthermore, fewer glycoproteins and higher levels of cytosolic calcium were identified under both stresses compared to control condition. These results suggest that reduced accumulation of glycoproteins in response to both stresses might be due to dysfunction of protein folding through calnexin/calreticulin cycle. Additionally, the increased cytosolic calcium levels induced by flooding and drought stresses might disturb the ER environment for proper protein folding in soybean root tips. PMID- 27224219 TI - Patterns of directional asymmetry in the pelvis and pelvic canal. AB - OBJECTIVES: The human pelvis is unique among modern taxa for supporting both parturition of large brained young and obligate bipedalism. Though much work has focused on pelvic development and variation, little work has explored the presence or absence of asymmetry in the pelvis despite well-known patterns of asymmetry in other skeletal regions. This study investigated whether patterns of directional asymmetry (DA) could be observed in the pelvis or pelvic canal. METHODS: Seventeen bilaterally paired osteometric measurements of the os coxae (34 measures in total) were taken from 128 skeletons (female n = 65, male n = 63) from recent human populations in five geographic regions. Paired sample t-tests and Mann-Whitney U-tests were used to investigate DA. RESULTS: Results from a pooled sample of all individuals showed that the pelvis exhibited a left-bias in DA. In contrast, the pelvic canal exhibited a pattern in which the anterior canal exhibited a right-bias and the posterior canal exhibited a left-bias. Neither sex nor populational differences in DA were observed in the pelvis or pelvic canal. CONCLUSIONS: The varying patterns of asymmetry uncovered here accord with prior work and may indicate that loading from the trunk and legs place differing stresses on the pelvis and canal, yielding these unequal asymmetries. However, this is speculative and the possible influence of genetics, biomechanics, and nutritional status on the development of pelvic and canal asymmetries presents a rich area for future study. Additionally, the potential influence of pelvic canal asymmetry on obstetric measures of pelvic capacity merits future research. Am. J. Hum. Biol. 28:804-810, 2016. (c) 2016Wiley Periodicals, Inc. PMID- 27224220 TI - Reproducibility of an in-laboratory test meal to assess ad libitum energy intake in adolescents with obesity. AB - AIM: The aim of the present work was to test the reproducibility of a personalized in-laboratory ad libitum buffet meal in assessing energy and macronutrient intake in obese adolescents. METHODS: Twelve 13.5 +/- 1.5 years old obese adolescent girls were asked to complete three identical experimental sessions during which an ad libitum buffet meal was presented at lunch time. The buffet was personalized based on food preference questionnaires, presented usually consumed food items and excluded preferred foods. Total energy intake and the energy ingested derived from each macronutrient were assessed by investigators using the Bilnuts nutritional software. RESULTS: Mean body mass was 87.0 +/- 13.7 kg and mean BMI was 32.2 +/- 4.9 kg/m(2). Mean FM percentage was 39.1 +/- 4.4% and FFM was 50.6 +/- 7.7 kg. There was no significant difference between total energy intake, the percentage of intake related to fat, protein or Carbohydrates (CHO) between the three sessions. The Intraclass Correlations (ICC) observed for total energy intake was 0.99. ICC for Protein, Fat and CHO were 0.38; 0.96 and 0.81 respectively. The Bland & Altman visual analysis revealed an important agreement between meals. CONCLUSION: The proposed personalized in laboratory ad libitum test meal produces is a reproducible methods to assess energy and macronutrients intake in obese adolescent girls. PMID- 27224221 TI - Beak-Like Extension of the Pancreatic Uncinate Process on MDCT: Is It Hyperplasia or Movement? AB - OBJECTIVE: We aimed to evaluate the pancreatic uncinate process with a beak-like extension (BLE) beyond the left border of the superior mesenteric artery, to define the cause of BLE, and to differentiate BLE from hyperplasia. METHODS: We retrospectively reviewed 1042 triple-phase contrast-enhanced multidetector-row computed tomography (3P-CE-MDCT) examinations of 500 patients. Finally, 38 patients (28 men, 10 women; mean age, 66 years) with 140 3P-CE-MDCT images showing BLE were studied regarding BLE size, contour, and cause. The superior mesenteric artery position was also evaluated. RESULTS: Beak-like extensions were found in 7.6% of patients. Most were caused by movement of the small bowel mesentery (n = 21, 55%), with deviation of mesenteric vessels or mass effect from expanded adjacent organs (n = 3, 8%). Seven patients (18.5%) had true hyperplasia. CONCLUSIONS: Beak-like extension is caused by movement of the small bowel mesentery with deviation of mesenteric vessels or by adjacent organ expansion. Beak-like extension closely mimics other pathology on nonenhanced MDCT. PMID- 27224222 TI - Radiologic and Clinicopathologic Findings of Inflammatory Myofibroblastic Tumor. AB - PURPOSE: The aim of the study was to describe the clinical, radiographic, and pathologic features of inflammatory myofibroblastic tumor (IMT) to enhance the recognition of this rare disease. MATERIALS AND METHODS: The clinical, imaging, and pathologic findings were retrospectively reviewed in 54 patients with IMT lesions, which were conformed by biopsy or surgical pathology. Of 54 patients, 51 had preoperative computed tomography (CT) examination and 13 had preoperative magnetic resonance imaging records. RESULTS: The clinical appearances of these 54 patients had some relationship with the locations of lesions. Of 54 IMT patients, 87.0% cases (47/54) had solitary lesion. The mean long diameter of the lesions located at the sites of chest, abdomen, and pelvic regions was bigger than that of other locations (F = 3.025, P = 0.038). On plain CT images, soft tissue mass was found in all IMT lesions, except for 3 lesions that arose in the intestine tract, appearing as focal or diffuse thickening in the bowel wall. After contrast administration, all lesions were persistently enhanced; 72.7% cases (24/33) demonstrated heterogeneous enhancement with various cystic regions. Comparing the CT features with different anatomic lesions, ill-defined margin on the plain CT images and calcification were seen more frequently in the lesions of the head and neck (P = 0.010 and 0.035); however, the other radiological findings had no significant differences (all P > 0.05). Twelve of 51 IMT patients showed invasion into adjacent structures. On magnetic resonance imaging, 92.3% lesions (12/13) showed soft tissue masses demonstrating isointense to hypointense contrast compared with skeletal muscle on T1-weighted images and heterogeneously high signals on T2-weighted images; 85.7%(6/7) of lesions were heterogeneously enhanced with cystic changes. Immunohistochemistry showed that the percentage of positive staining for SMA, vimentin, anaplastic lymphoma kinase, CD68, CD34, CD99, B-cell lymphoma/leukemia-2, cytokeratin, Desmin, and S-100 protein were 88.9%, 87.0%, 44.4%, 59.3%, 53.7%, 29.6%, 42.6%, 28.5%, 13.0%, and 24.1%, respectively. CONCLUSIONS: Inflammatory myofibroblastic tumor can involve any part of the body, and the clinical and radiological appearances are various owing to different anatomic sites. An ill-defined soft tissue mass heterogeneous enhancement with or without invasion into adjacent structures on computed tomographic or magnetic resonance images and positive staining for SMA and vimentin on immunohistochemical examination could suggest the diagnosis. PMID- 27224223 TI - Lesion Size and Iodine Quantification to Distinguish Low-Grade From High-Grade Clear Cell Renal Cell Carcinoma Using Dual-Energy Spectral Computed Tomography. AB - OBJECTIVE: The aim of this study was to assess the utility of lesion size and iodine quantification using dual-energy spectral computed tomography to distinguish between low-grade and high-grade clear cell renal cell carcinomas (ccRCCs). METHODS: Spectral parameters of 75 patients with pathologically proven ccRCCs who underwent preoperative dual-energy spectral computed tomography examinations were divided into low-grade and high-grade groups. Independent sample t test, receiver operating characteristic curve analysis, and Spearman rank correlation were analyzed. RESULTS: The lesion size was significantly smaller, and spectral parameters were significantly higher in the low-grade ccRCC. The significant correlation (r = -0.412, P < 0.001) by the Spearman rank correlation was between the normalized iodine concentration and lesion size. The receiver operating characteristic analysis demonstrated that 0.710 was the optimal cutoff value, which yielded the following: sensitivity, 97.6%; specificity, 97.1%; positive predictive value, 97.6%; negative predictive value, 97.1%; and accuracy, 97.3%. CONCLUSIONS: Iodine quantification can play an important role in distinguishing low-grade from high-grade ccRCC. PMID- 27224224 TI - Low-Contrast and Low-Radiation Dose Protocol in Cardiac Computed Tomography: Usefulness of Low Tube Voltage and Knowledge-Based Iterative Model Reconstruction Algorithm. AB - OBJECTIVE: This study aimed to evaluate the feasibility of a low contrast, low radiation dose protocol of 80-peak kilovoltage (kVp) with prospective electrocardiography-gated cardiac computed tomography (CT) using knowledge-based iterative model reconstruction (IMR). METHODS: Thirty patients underwent an 80 kVp prospective electrocardiography-gated cardiac CT with low-contrast agent (222 mg iodine per kilogram of body weight) dose. We also enrolled 30 consecutive patients who were scanned with a 120-kVp cardiac CT with filtered back projection using the standard contrast agent dose (370-mg iodine per kilogram of body weight) as a historical control group. We evaluated the radiation dose for the 2 groups. The 80-kVp images were reconstructed with filtered back projection (protocol A), hybrid iterative reconstruction (HIR, protocol B), and IMR (protocol C). We compared CT numbers, image noise, and contrast-to-noise ratio among 120-kVp protocol, protocol A, protocol B, and protocol C. In addition, we compared the noise reduction rate between HIR and IMR. Two independent readers compared image contrast, image noise, image sharpness, unfamiliar image texture, and overall image quality among the 4 protocols. RESULTS: The estimated effective dose (ED) of the 80-kVp protocol was 74% lower than that of the 120-kVp protocol (1.4 vs 5.4 mSv). The contrast-to-noise ratio of protocol C was significantly higher than that of protocol A. The noise reduction rate of IMR was significantly higher than that of HIR (P < 0.01). There was no significant difference in almost all qualitative image quality between 120-kVp protocol and protocol C except for image contrast. CONCLUSIONS: A 80-kVp protocol with IMR yields higher image quality with 74% decreased radiation dose and 40% decreased contrast agent dose as compared with a 120-kVp protocol, while decreasing more image noise compared with the 80-kVp protocol with HIR. PMID- 27224225 TI - Multivariate Analysis of Pleural Invasion of Peripheral Non-Small Cell Lung Cancer-Based Computed Tomography Features. AB - OBJECTIVE: The aim of this study was to comprehensively analyze computed tomography features to improve the diagnostic accuracy of visceral pleural invasion of peripheral non-small cell lung cancer. METHODS: The computed tomography features of 205 non-small cell lung cancer patients were retrospectively studied. The lesion's relation to the pleura was classified into 5 grades. A multivariate logistic regression analysis was conducted to identify independent factors predicting pleural invasion. RESULTS: The multivariate logistic regression analysis showed that sex (odds ratio [OR], 1.822; P = 0.080), pleural indentation (OR, 4.111; P < 0.001), tumor density (OR, 2.735; P = 0.008), and distance between the lesion and pleura (OR, 1.981; P = 0.048) were independent predictors of pleural invasion. A patient with a score of 10.6 had an 80% risk of pleural invasion, whereas a score lower than 2 was associated with a lower (20%) risk of pleural invasion. CONCLUSIONS: Comprehensive consideration of these factors of pleural indentation, sex, tumor density, and distance between the lesion and pleura might improve the diagnosis of pleural invasion. PMID- 27224226 TI - Dual-Energy CT Characteristics of Parathyroid Adenomas on 25-and 55-Second 4D-CT Acquisitions: Preliminary Experience. AB - OBJECTIVE: The objective of this study was to compare the dual-energy computed tomography (CT) characteristics of parathyroid adenomas (PAs), thyroid tissue, and lymph nodes (LNs) and assess whether the spectral information can improve distinction of these tissues. METHODS: Dual-energy CT scans from 20 patients with pathologically proven PAs were retrospectively evaluated, identifying 19 eligible PAs and region of interest analysis used for spectral characterization. RESULTS: There was a significant difference in multiple spectral parameters between PAs, LNs, and the thyroid gland (P < 0.05-0.0001). The greatest difference in spectral characteristics of PAs compared with that of LNs was on the 25-second acquisition, whereas the 55-second acquisition was better for distinguishing PAs from the thyroid gland. CONCLUSIONS: Four-dimensional CT acquired in dual-energy CT mode has the potential to further enhance diagnostic accuracy for PA identification on individual phases of the perfusion study. PMID- 27224227 TI - Accelerated Brain Atrophy on Serial Computed Tomography: Potential Marker of the Progression of Alzheimer Disease. AB - OBJECTIVE: The aim of this study was to validate computed tomography (CT)-based longitudinal markers of the progression of Alzheimer disease (AD). MATERIALS AND METHODS: We retrospectively studied 33 AD patients and 39 nondemented patients with other neurological illnesses (non-AD) having 4 to 12 CT examinations of the head, with over a mean (SD) of 3.9 (1.7) years. At each time point, we applied an automatic software to measure whole brain, cerebrospinal fluid, and intracranial space volumes. Longitudinal measures were then related to disease status and time since the first scan using hierarchical models. RESULTS: Absolute brain volume loss accelerated for non-AD patients by 0.86 mL/y (95% confidence interval [CI], 0.64-1.08 mL/y) and 1.5* faster, that is, 1.32 mL/y (95% CI, 1.09-1.56 mL/y) for AD patients (P = 0.006). In terms of brain volume normalized to intracranial space, the acceleration in atrophy rate for non-AD patients was 0.0578%/y (95% CI, 0.0389%/y to 0.0767%/y), again 1.5* faster, that is, 0.0919%/y (95% CI, 0.0716%/y to 0.1122%/y) for AD patients (P = 0.017). This translates to an increase in atrophy rate from 0.5% to 1.4% in AD versus to 1.1% in non-AD group after 10 years. CONCLUSIONS: Brain volumetry on CT reliably detected accelerated volume loss in AD and significantly lower acceleration factor in age-matched non AD patients, leading to the possibility of its use to monitor the progression of cognitive decline and dementia. PMID- 27224228 TI - The Initial Exploration of Adamkiewicz Artery Computed Tomographic Angiography With Monochromatic Reconstruction of Gemstone Spectral Imaging. AB - OBJECTIVE: The study aimed to explore whether optimal monochromatic reconstruction can improve the depiction of the Adamkiewicz artery (AKA) on gemstone spectral computed tomographic angiography (GSCTA) compared with the polychromatic reconstruction protocol. METHODS: The prospective study was approved by the ethics committee, and written informed consent was obtained from each patient. The 58 consecutive patients suspected of aortic aneurysm or dissection underwent aortic GSCTA. All images were reconstructed with both polychromatic (group A) and optimal monochromatic (group B) protocol. The CT values of the descending aorta and muscle, background noise, and the contrast-to noise ratio were measured and calculated. With the criterion standard display of AKA, characteristic hairpin curve sign, 2 blinded radiologists analyzed data independently with the paired samples t, chi, and Mann-Whitney U test. RESULTS: The CT value of the descending aorta and the contrast-to-noise ratio of group B were significantly superior to group A (t = 12.7, P < 0.01; t = 15.2, P < 0.01). The visual rate of AKA (94.8%) in group B was significantly higher (chi = 4.2, P = 0.04) than group A (82.8%). Using a 5-point scale to assess, the score of the visualization efficiency of group B (226) was significantly higher (Z = -2.4, P = 0.02) than group A (192). CONCLUSIONS: The optimal monochromatic reconstruction for GSCTA can improve the visualization efficiency and quality of the AKA compared with the polychromatic reconstruction protocol. PMID- 27224229 TI - A Liver Phantom Study: CT Radiation Dose Reduction and Different Image Reconstruction Algorithms Affect Diagnostic Quality. AB - OBJECTIVE: The aim of this study was to evaluate whether iterative reconstruction techniques for different dose levels and/or reduction of tube potential can increase liver lesion detectability. METHODS: An anthropomorphic liver phantom was scanned at different dose levels (CTDIvol 15 mGy, 7.5 mGy, 5 mGy, and 2.6 mGy) and tube potential levels (120 kV, 100 kV, and 80 kV). Images were reconstructed with the following algorithms: filtered back projection (FBP), adaptive statistical iterative reconstruction (ASiR) 40%, and a model-based iterative reconstruction (Veo). The presence or absence of lesions was assessed independently on a 4-point scale by 4 readers. The areas under the receiver operating characteristic curve were calculated. RESULTS: Veo improved detectability of hyperdense liver lesions compared with both FBP and ASiR 40% at most dose levels (15 mGy, 7.5 mGy, and 5 mGy with P < 0.05). Veo also improved detectability at reduced tube potential compared with FBP (120 kV, 100 kV, and 80 kV at 5 mGy with P < 0.05) and ASiR 40% (120 kV and 100 kV at 5 mGy with P < 0.05). For ASiR 40%, the area under the receiver operating characteristic curve was significantly larger compared with FBP only at dose levels 7.5 mGy and 2.6 mGy at 120 kV. In general, the reduction of tube potential reduced the lesion detectability. CONCLUSIONS: This study shows that iterative reconstruction algorithms, in particular Veo, improve lesion detectability in a liver phantom. However, a too aggressive dose reduction may result in poorer image quality. Results considering different tube potentials diverged, thus careful consideration is necessary upon tube potential reduction. PMID- 27224230 TI - Computed Tomography Perfusion of Prostate Cancer: Diagnostic Value of Quantitative Analysis. AB - OBJECTIVE: The aim of the study was to assess the diagnostic value of computed tomography perfusion (CTp) of prostate in distinguishing between normal tissue and malignant lesion by using quantitative threshold values of CTp parameters. MATERIALS AND METHODS: Sixty-one consecutive men with indication for radical prostatectomy were prospectively enrolled. All patients were intravenously injected with 80-mL bolus of nonionic iodinated contrast medium during cine-mode acquisition protocol. Perfusion data sets were analyzed by a dedicated software system and values for each of the 4 CTp parameters (blood volume, blood flow, mean transit time, and permeability surface-area product measurements) were recorded. Receiver operating characteristic curves were calculated to find which CTp parameter and which cutoff value might reveal the best diagnostic accuracy. Histopathology was used as reference standard. RESULTS: Statistical correlation between radiological and pathological results was performed on 48 patients using 3456 segmented squares. Blood volume and permeability surface revealed the best diagnostic accuracy for differentiating between malignant and benign squares, with cutoff values of 6.1 and 16.5, respectively, and a sensitivity of 84.8% and 81.8%, respectively. All parameters showed also a high negative predictive value: 97.1% for blood volume and 95.4% for permeability surface. CONCLUSIONS: Blood volume and permeability surface are the 2 CTp parameters with the highest diagnostic accuracy in differentiating between normal tissue and prostatic neoplasia. Due to the extremely high negative predictive value, they are particularly valuable in excluding the presence of cancer and thus resulting potentially useful in assessing cancer response to adjuvant therapy. PMID- 27224231 TI - Apparent Diffusion Coefficient and Dynamic Contrast-Enhanced Magnetic Resonance Imaging in Pancreatic Cancer: Characteristics and Correlation With Histopathologic Parameters. AB - OBJECTIVE: To clarify diffusion and perfusion abnormalities and evaluate correlation between apparent diffusion coefficient (ADC), MR perfusion and histopathologic parameters of pancreatic cancer (PC). METHODS: Eighteen patients with PC underwent diffusion-weighted imaging and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Parameters of DCE-MRI and ADC of cancer and non-cancerous tissue were compared. Correlation between the rate constant that represents transfer of contrast agent from the arterial blood into the extravascular extracellular space (K, volume of the extravascular extracellular space per unit volume of tissue (Ve), and ADC of PC and histopathologic parameters were analyzed. RESULTS: The rate constant that represents transfer of contrast agent from the extravascular extracellular space into blood plasma, K, tissue volume fraction occupied by vascular space, and ADC of PC were significantly lower than nontumoral pancreases. Ve of PC was significantly higher than that of nontumoral pancreas. Apparent diffusion coefficient and K values of PC were negatively correlated to fibrosis content and fibroblast activation protein staining score. Fibrosis content was positively correlated to Ve. CONCLUSION: Apparent diffusion coefficient values and parameters of DCE-MRI can differentiate PC from nontumoral pancreases. There are correlations between ADC, K, Ve, and fibrosis content of PC. Fibroblast activation protein staining score of PC is negatively correlated to ADC and K. Apparent diffusion coefficient, K, and Ve may be feasible to predict prognosis of PC. PMID- 27224232 TI - Primary Extremity Liposarcoma: MRI Features, Histopathology, and Clinical Outcomes. AB - OBJECTIVE: This study aimed to describe magnetic resonance imaging (MRI) features of extremity liposarcoma (LPS) subtypes, correlating with histopathology and clinical outcomes. METHODS: In this retrospective study, we included 125 patients (80 men, 45 women; mean age, 53 years) with extremity LPS [23 atypical lipomatous tumor (ALT), 9 dedifferentiated (DDLPS), 70 myxoid (MLPS), 23 pleomorphic (PLPS)]. Pretreatment MRI of primary tumors in 56 patients (10 ALT, 4 DDLPS, 28 MLPS, 14 PLPS) was reviewed. RESULTS: All subtypes were predominantly T1 isointense relative to skeletal muscle (DDLPS = 3/4, MLPS = 28/28, PLPS = 13/14) and T2 hyperintense (ALT = 10/10, DDLPS = 3/4, MLPS = 28/28, PLPS = 14/14) except for ALT which were T1 hyperintense (8/10). Within MLPS, high grade was associated with unencapsulated margins (P = 0.05) and solid, nodular enhancement (P < 0.0001). Peritumoral edema (P = 0.03) and T2 heterogeneity (P = 0.05) predicted pulmonary (rather than extrapulmonary) metastases in MLPS. Tumor subtype correlated with mortality (P = 0.04). CONCLUSIONS: The MRI features can help to distinguish between extremity LPS subtypes, and can predict histopathologic grade and metastatic pattern in myxoid LPS. PMID- 27224233 TI - Retrospective Assessment of Histogram-Based Diffusion Metrics for Differentiating Benign and Malignant Endometrial Lesions. AB - OBJECTIVE: Our study aimed to retrospectively evaluate the utility of volumetric histogram-based diffusion metrics in differentiating benign from malignant endometrial abnormalities. METHODS: A total of 54 patients underwent pelvic magnetic resonance imaging with diffusion-weighted imaging before endometrial tissue diagnosis. Two radiologists placed volumes of interest on the apparent diffusion coefficient (ADC) map encompassing the entire endometrium and focal endometrial lesions. The mean ADC, percentile ADC values, kurtosis, skewness, and entropy of ADC were compared between benign and malignant abnormalities. RESULTS: In premenopausal patients, significant independent predictors of malignancy were whole-endometrium analysis for R1, 10th to 25th ADC percentile (P = 0.012); whole endometrium analysis for R2, mean ADC (P = 0.001) and skewness (P = 0.004); focal lesion analysis for R1, skewness (P = 0.045); focal lesion analysis for R2, 10th to 25th ADC percentile (P <= 0.0001). The area under the curve for malignancy was 90.0% to 97.3% and 76.1% to 77.3% for the more and less experienced radiologists, respectively. In postmenopausal patients, the only significant difference was kurtosis using whole-endometrium analysis for R1 (P = 0.042). CONCLUSIONS: Volumetric ADC histogram metrics may help radiologists assess the risk of malignancy in endometrial abnormalities on magnetic resonance imaging in premenopausal patients. PMID- 27224234 TI - Evaluation of Lung Radiofrequency Ablation With Dual-Energy Computed Tomography: Analysis of Tumor Composition and Lung Perfusion. AB - OBJECTIVE: The aim of this study was to evaluate radiofrequency ablation (RFA) of lung tumors with dual-energy computed tomography while focusing on tumor composition and lung perfusion. METHODS: The 36 tumors in 25 patients were included. Dual-energy computed tomography was performed before RFA and at 2 days and 1, 3, and 6 months thereafter. The effective atomic number (Zeff) of the tumors before RFA was compared with the Zeff at each follow-up using the paired t test. Lung perfusion was evaluated by iodine map images. When decreased perfusion was suspected after RFA, lung perfusion scintigraphy was performed. RESULTS: The mean Zeff of the tumors significantly (P < 0.001) decreased at each follow-up, compared with that before RFA. Lung perfusion in the parenchyma peripheral to the tumors appeared to decrease at 2 days in 9 tumors, which was confirmed by scintigraphy in 7 tumors. CONCLUSIONS: Dual-energy computed tomography was useful by providing additional information on tumor composition and lung perfusion. PMID- 27224235 TI - Iterative Reconstruction Results in Larger Computed Tomography Measurements of Iliofemoral Artery Diameter in Patients Referred for Transcatheter Aortic Valve Replacement. AB - OBJECTIVES: We hypothesized that improved iterative reconstruction increases image quality and reduces artifacts for iliofemoral artery computed tomography imaging in patients referred for transcatheter aortic valve replacement (TAVR). METHODS: We examined 56 consecutive patients undergoing computed tomography for possible TAVR and compared image quality and iliofemoral artery size between adaptive statistical iterative reconstructions (ASIRs) and improved model-based iterative reconstructions (MBIRs). RESULTS: Model-based iterative reconstruction (vs ASIR) was associated with improved (P < 0.001 for each) image quality (3.4 +/ 0.8 vs 2.8 +/- 1.0), beam hardening (3.5 +/- 0.8 vs 3.0 +/- 1.1), and wall definition (3.6 +/- 0.6 vs 3.1 +/- 0.8). Image signal-to-noise ratios (20.4 +/- 10.1 vs 13.7 +/- 6.6, P < 0.001) were also increased with MBIR as compared with ASIR. Mean iliofemoral artery size was larger using MBIR compared with ASIR (left, 7.7 +/- 1.5 vs 7.4 +/- 1.7 mm, P < 0.001; right, 7.8 +/- 1.2 vs 7.4 +/- 1.5 mm, P = 0.008). CONCLUSIONS: In patients referred for TAVR, improved MBIR resulted in higher image quality, reduced artifacts, and larger iliofemoral artery diameters compared with standard iterative reconstructions. PMID- 27224236 TI - Randomness in Sequence Evolution Increases over Time. AB - The second law of thermodynamics states that entropy, as a measure of randomness in a system, increases over time. Although studies have investigated biological sequence randomness from different aspects, it remains unknown whether sequence randomness changes over time and whether this change consists with the second law of thermodynamics. To capture the dynamics of randomness in molecular sequence evolution, here we detect sequence randomness based on a collection of eight statistical random tests and investigate the randomness variation of coding sequences with an application to Escherichia coli. Given that core/essential genes are more ancient than specific/non-essential genes, our results clearly show that core/essential genes are more random than specific/non-essential genes and accordingly indicate that sequence randomness indeed increases over time, consistent well with the second law of thermodynamics. We further find that an increase in sequence randomness leads to increasing randomness of GC content and longer sequence length. Taken together, our study presents an important finding, for the first time, that sequence randomness increases over time, which may provide profound insights for unveiling the underlying mechanisms of molecular sequence evolution. PMID- 27224238 TI - Ovoid Palatal Patch in Dermatomyositis: A Novel Finding Associated With Anti TIF1gamma (p155) Antibodies. PMID- 27224237 TI - A new approach to detect early lung functional impairment in very light smokers. AB - PURPOSE: The aim of our study is to investigate if lung carbon monoxide diffusing capacity (DLCO) measured during effort is able to detect early respiratory functional impairment. METHODS: We enrolled 25 very light smokers and 20 healthy non smokers. Subjects underwent plethysmography, DLCO (single breath technique) and calculated effective pulmonary blood flow (Qc) by rebreathing method. During exercise by cycle ergometer (duration 10+/-2min; recovery 11+/-3min) DLCO and Qc were calculated at 25% and 50% of theoretical maximum workload. RESULTS: At baseline lung function and Qc did not differ between groups. DLCO and DLCO/Qc measured during exercise were significantly greater in non smokers (p<0.001); Qc was not statistically different. In very light smokers, DLCO, DLCO/Qc measured during exercise significantly correlated with the number of pack years (r=-0.60 p<0.001; r=-0.58 p<0.05; r=-0.55 p<0.05, respectively). CONCLUSIONS: In very light smokers there is lung function impairment and our data show that DLCO during exercise may reveal this underlying early damage. PMID- 27224239 TI - Coptis chinensis Franch. extract up-regulate type I helper T-cell cytokine through MAPK activation in MOLT-4 T cell. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The dried rhizome of Coptis chinensis Franch. (Huanglian) has been widely used in Asian traditional medicine. It was already known that Coptis chinensis Franch. rhizome has various pharmacological properties including its anti-oxidant, anti-cancer, and anti-inflammatory activity. AIM OF THE STUDY: To evaluate the immune-enhancement effect of the Coptis chinensis Franch. rhizome extract on helper T cells and its signaling mechanism. MATERIALS AND METHODS: MOLT-4 human T cell line was used to investigate the effect of the Coptis chinensis Franch. rhizome extract. Cell viability was measured by the MTT assay and cytokine expression level was analyzed by ELISA and qRTPCR. MAPKs signal molecule's activation level was detected by immunoblotting. RESULTS: The expression of IFN-gamma, a cytokine of type I helper T (Th1) cell, increased; however, IL-4 was not affected by the Coptis chinensis Franch. rhizome extract. Other Th1 cytokines, such as IL-1beta, IL-2, and IL-6, also increased. These data suggest that the Coptis chinensis Franch. rhizome extract activates MOLT-4 cell to Th1 cell, not type II helper T cell. Furthermore, the Coptis chinensis Franch. rhizome extract activates the Mitogen-activated protein kinase (MAPKs) signaling pathways. CONCLUSION: The results obtained from this study suggest that the Coptis chinensis Franch. rhizome extract should be used as an immune enhancer in anti-inflammatory medicine, adjuvant materials, and as a supplement to treat weakened immune system. PMID- 27224240 TI - Xiaotan Sanjie decoction inhibits angiogenesis in gastric cancer through Interleukin-8-linked regulation of the vascular endothelial growth factor pathway. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Interleukin-8 (IL-8) as a pro-angiogenic factor is strongly associated with gastric cancer metastasis. Xiaotan Sanjie (XTSJ) decoction is an empirical compound prescription based on the phlegm theory of traditional Chinese medicine. Previous studies have shown that XTSJ decoction decreases IL-8 level and formation of vasculogenic mimicry of gastric cancer. AIM OF THE STUDY: To investigate the link between Xiaotan Sanjie (XTSJ) decoction and IL-8 regulation in the angiogenesis of gastric cancer. MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVECs) were co-cultured with SGC-7901 human gastric cancer cells and exposed to serum samples containing XTSJ decoction and/or IL-8 (1.0ng/mL). The canalization and migration capacities were evaluated by tube formation and transwell migration assay. Protein (immunofluorescence and Western blot) and mRNA (qPCR) expressions were measured in 24-h-cultured HUVECs for vascular endothelial growth factor-A (VEGF-A), vascular endothelial growth factor receptor (VEGFR)-1, and VEGFR-2. RESULTS: IL-8 significantly promoted and XTSJ decoction inhibited HUVEC tube formation and migration. Links between IL-8 regulation and XTSJ decoction were found in tube formation and migration assays. IL-8 upregulated and XTSJ decoction downregulated VEGF-A, VEGFR-1, and VEGFR-2 protein levels. XTSJ decoction inhibited IL-8-induced VEGF-A and VEGFR-1 protein expressions. Similarly, IL-8 promoted VEGF-A, VEGFR-1, and VEGFR-2 mRNA levels; however, XTSJ decoction inhibited only VEGF-A mRNA. Interestingly, XTSJ decoction inhibited IL-8-induced VEGFR-1 and VEGFR-2 mRNA expression. CONCLUSION: XTSJ decoction might inhibit angiogenesis in gastric cancer through IL-8-linked regulation of the VEGF pathway. PMID- 27224241 TI - Functional proteomic analysis revels that the ethanol extract of Annona muricata L. induces liver cancer cell apoptosis through endoplasmic reticulum stress pathway. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Annona muricata L. is used to treat cancer in some countries. Extracts of Annona muricata have been shown to cause apoptosis of various cancer cells in vitro, and inhibit tumor growth in vivo in animal models. However, the molecular mechanisms underlying its anti-cancer and apoptotic effects of the herb remain to be explored. AIM OF STUDY: The study investigated the molecular mechanisms underlying liver cancer cell apoptosis triggered by the ethanol extract of leaves of Annona muricata L. MATERIALS AND METHODS: Liver cancer HepG2 cells were used as experimental model. MTT assay was employed to evaluate cell viability. Flow cytometry and TUNEL assays were performed to confirm apoptosis. We employed functional proteomic analysis to delineate molecular pathways underlying apoptosis triggered by the herbal extract. RESULTS: We showed that the extract was able to reduce viability and trigger apoptosis of the cancer cells. Proteomic analysis identified 14 proteins associated with the extract-elicited apoptosis, which included the increased expression levels of HSP70, GRP94 and DPI-related protein 5. Western blot analysis confirmed that the extract did up-regulated the protein levels of HSP70 and GRP94. Results from bioinformatic annotation pulled out two molecular pathways for the extract, which, notably, included endoplasmic reticulum (ER) stress which was evidenced by the up-regulation of HSP70, GRP94 and PDI-related protein 5. Further examinations of typical protein signaling events in ER stress using western blot analysis have shown that the extract up-regulated the phorsphorelation of PERK and eIF2alpha as well as the expression level of Bip and CHOP. CONCLUSION: Our results indicate that the ethanol extract of leaves of Annona muricata L. causes apoptosis of liver cancer cells through ER stress pathway, which supports the ethnomedicinal use of this herb as an alternative or complementary therapy for cancer. PMID- 27224242 TI - Poncirin and its metabolite ponciretin attenuate colitis in mice by inhibiting LPS binding on TLR4 of macrophages and correcting Th17/Treg imbalance. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The fruit of Poncirus trifoliate, which contains poncirin as a main constituent, is frequently used in the traditional Chinese medicine for inflammation, asthma, and infection diseases. AIM OF THE STUDY: To examine anti-colitic effects of poncirin and ponciretin, a metabolite of poncirin by gut microbiota. MATERIALS AND METHODS: Colitis was induced in mice by the intrarectal injection of 2,4,6-trinitrobenzenesulfonic acid (TNBS). Inflammatory markers were analyzed by enzyme-linked immunosorbent assay, immunoblotting, quantitative polymerase chain reaction, confocal microscopy, and flow cytometry. Peritoneal macrophages were isolated from mice stimulated with 4% thioglycolate. RESULTS: Poncirin was metabolized to ponciretin in vitro and in vivo by gut microbiota of mice. Orally administered poncirin and ponciretin suppressed TNBS induced colitis in mice: these inhibited colon shortening, myeloperoxidase activity, NF-kappaB activation, and Th17 cell differentiation, but increased occludin, claudin-1, and ZO-1 expressions and Treg cell differentiation. Poncirin and ponciretin suppressed the differentiation of splenocytes into Th17 cells and expression of IL-17 and Foxp3 in vitro, as well as the activation of macrophages stimulated with lipopolysaccharide (LPS) by inhibiting the binding of LPS on TLR4 of macrophages. These increased the differentiation of splenocytes into Treg cells. The ant-inflammatory effect of ponciretin was superior to that of poncirin. CONCLUSION: Orally administered poncirin is metabolized to ponciretin by gut microbiota and poncirin and ponciretin attenuates colitis by suppressing NF-kappaB activation through the inhibition of LPS binding on macrophages and correcting Th17/Treg cell imbalance. PMID- 27224243 TI - Huangkui capsule, an extract from Abelmoschus manihot (L.) medic, improves diabetic nephropathy via activating peroxisome proliferator-activated receptor (PPAR)-alpha/gamma and attenuating endoplasmic reticulum stress in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Abelmoschus manihot (L.) medic (AM) is a natural medicinal plant used for the treatment of chronic kidney disease (CKD) in China. Huangkui capsule (HKC), an extract from AM, has been proved clinically effective in improving renal inflammation and glomerular injury in CKD. However, the mechanisms of HKC are still not fully understood. AIM OF THE STUDY: Peroxisome proliferator-activated receptor (PPAR)-alpha/gamma dual agonists have the potential to be used as therapeutic agents for the treatment of type 2 diabetes and diabetic nephropathy (DN). This study evaluated the function of Huangkui capsule (HKC), an extract from Abelmoschus manihot (L.) medic (AM), as a dual agonist for PPARalpha/gamma and investigated its anti-DN effects in a DN rat model. MATERIALS AND METHODS: ChIP and reporter gene assays were performed and the expression of PPARalpha/gamma target genes was monitored to examine the ability of HKC to activate PPARalpha/gamma. DN was induced in male Sprague-Dawley rats via unilateral nephrectomy and intraperitoneal injection of streptozotocin. HKC was administered to the diabetic nephropathy rats at three different doses: high dose HKC (300mg/kg/d); middle dose HKC (175mg/kg/d); and low dose HKC (75mg/kg/d). Irbesartan (4mg/kg/d body weight) was used as a positive control. Following 12 weeks' treatment, we measured general status, renal morphological appearance, proteinuria, blood biochemical parameters, and glomerular morphological changes. The expression of collagen IV, TGFbeta, TNFalpha and IL-6 in renal tissue was evaluated. Endoplasmic reticulum (ER) stress in renal tissue was also analyzed. RESULTS: HKC enhanced the transcriptional activity of PPARalpha and PPARgamma in cultured cells, livers and kidneys of DN rats, and it reduced serum triglyceride and cholesterol levels and fat in livers of DN rats. Furthermore, HKC reduced the expressions of inflammatory genes in kidneys of DN rats. Strikingly, HKC reduced ER stress and c-Jun NH2-terminal kinase activation in the liver and kidney of DN rats and subsequently improved renal injury. CONCLUSIONS: Our results show that HKC improved lipid metabolic disorders by activating PPARalpha/gamma and attenuating ER stress. HKC could dose-dependently ameliorate renal inflammation and glomerular injury in DN rats. These results suggest that HKC has potential as an anti-DN agent for the treatment of DN in humans. PMID- 27224244 TI - New halogenated constituents from Mangifera zeylanica Hook.f. and their potential anti-cancer effects in breast and ovarian cancer cells. AB - ETHNOPHARMACOLOGICAL RELEVENCE: Mangifera zeylanica Hook.f. (Anacardiaceae) is a plant endemic to Sri Lanka. Its bark has been used in traditional and Ayurvedic medicine for the treatment of various diseases including some cancers. AIM OF THE STUDY: This study was planned to isolate and identify potentially cytotoxic compounds from the bark of M. zeylanica, which may have contributed to its ethno pharmacological use in the treatment of cancer. MATERIALS AND METHODS: The chloroform extract of M. zeylanica bark which is cytotoxic to breast and ovarian cancer cells was fractionated using column chromatography and preparative reversed phase high performance liquid chromatography to isolate four compounds. Structures of the isolated compounds were elucidated by means of (1)H- and (13)C NMR spectroscopy, and mass spectrometric techniques. Cytotoxic potential of the isolated compounds was tested in MDA-MB-231 (triple negative breast cancer), MCF 7 (estrogen receptor positive breast cancer), SKOV-3 (ovarian epithelial cancer) and MCF-10A (normal mammary epithelial) cells by SRB assay. Human cancer drug target real-time PCR array was carried out to analyze regulation of possible cancer drug target genes in compound 2 treated triple negative breast cancer cells. DPPH radical scavenging and caspase 3 and 7 induction in response to isolated compounds were also studied. RESULTS: Two new halogenated compounds, bromomangiferic acid (1), and chloromangiferamide (2) along with two known compounds quercetin (3), and catechin (4), were isolated from the bark of Mangifera zeylanica for the first time. Interestingly, chloromangiferamide showed cytotoxicity only to triple negative breast cancer cells [IC50:73.19+/-0.87uM (24h), 56.29+/-0.86uM (48h)] with no cytotoxicity to other two cancer cell lines or to normal mammary epithelial cells. Quercetin and catechin were cytotoxic to all three cancer cell lines while bromomangiferic acid had no effect. Chloromangiferamide significantly regulated expression of genes associated with apoptosis, drug metabolism, cell cycle, receptor tyrosine kinase signaling, protein kinases, histone deacetylases, growth factors and receptors, topoisomerases, PI-3 kinases and phosphatases in triple negative breast cancer cells. CONCLUSION: Selective cytotoxic activity in triple negative breast cancer cells and regulation of some cancer drug target genes by chloromangiferamide indicate that it can be used to develop a potential chemotherapeutic agent for triple negative breast cancer cells. PMID- 27224245 TI - Von Willebrand Factor Gene Variants Associate with Herpes simplex Encephalitis. AB - Herpes simplex encephalitis (HSE) is a rare complication of Herpes simplex virus type-1 infection. It results in severe parenchymal damage in the brain. Although viral latency in neurons is very common in the population, it remains unclear why certain individuals develop HSE. Here we explore potential host genetic variants predisposing to HSE. In order to investigate this we used a rat HSE model comparing the HSE susceptible SHR (Spontaneously Hypertensive Rats) with the asymptomatic infection of BN (Brown Norway). Notably, both strains have HSV-1 spread to the CNS at four days after infection. A genome wide linkage analysis of 29 infected HXB/BXH RILs (recombinant inbred lines-generated from the prior two strains), displayed variable susceptibility to HSE enabling the definition of a significant QTL (quantitative trait locus) named Hse6 towards the end of chromosome 4 (160.89-174Mb) containing the Vwf (von Willebrand factor) gene. This was the only gene in the QTL with both cis-regulation in the brain and included several non-synonymous SNPs (single nucleotide polymorphism). Intriguingly, in human chromosome 12 several SNPs within the intronic region between exon 43 and 44 of the VWF gene were associated with human HSE pathogenesis. In particular, rs917859 is nominally associated with an odds ratio of 1.5 (95% CI 1.11-2.02; p value = 0.008) after genotyping in 115 HSE cases and 428 controls. Although there are possibly several genetic and environmental factors involved in development of HSE, our study identifies variants of the VWF gene as candidates for susceptibility in experimental and human HSE. PMID- 27224246 TI - Clinical pharmacology and efficacy of rotigotine (Neupro(r) patch) in the treatment of restless leg syndrome. AB - INTRODUCTION: Restless legs syndrome/Willis Ekbom disease (RLS/WED) is a sensorimotor disorder characterized by unpleasant sensations in the legs accompanied by an urge to move them, that typically occurs and tend to worsen in the evening/night or during period of inactivity. Standard medications for RLS/WED are dopamine agonists and calcium channel alpha-2-delta ligands. The clinical spectrum of RLS/WED is very broad, ranging from individuals suffering from the disease during limited periods up to those severely affected, with daily symptoms. In such cases a long-acting drug like rotigotine should be considered. AREAS COVERED: The clinical pharmacology and efficacy of rotigotine was examined to evaluate the evidence supporting its use in RLS/WED. EXPERT OPINION: The rotigotine transdermal patch provides constant delivery of the drug, maintaining a stable plasma concentration over 24 hours by means of a single daily application. Several randomized, double-blind, placebo-controlled trials have demonstrated the efficacy of rotigotine in improving moderate-to-severe RLS/WED symptoms. Rotigotine is generally well tolerated. The most common adverse effects were application-site reactions, dose-dependent, more frequently reported in the first period of treatment. Incidence of augmentation in RLS/WED patients treated with oral dopamine agonists is higher when compared with the use of transdermal rotigotine. PMID- 27224247 TI - Grey Matter Changes Associated with Heavy Cannabis Use: A Longitudinal sMRI Study. AB - Cannabis is the most frequently used illicit drug worldwide. Cross-sectional neuroimaging studies suggest that chronic cannabis exposure and the development of cannabis use disorders may affect brain morphology. However, cross-sectional studies cannot make a conclusive distinction between cause and consequence and longitudinal neuroimaging studies are lacking. In this prospective study we investigate whether continued cannabis use and higher levels of cannabis exposure in young adults are associated with grey matter reductions. Heavy cannabis users (N = 20, age baseline M = 20.5, SD = 2.1) and non-cannabis using healthy controls (N = 22, age baseline M = 21.6, SD = 2.45) underwent a comprehensive psychological assessment and a T1- structural MRI scan at baseline and 3 years follow-up. Grey matter volumes (orbitofrontal cortex, anterior cingulate cortex, insula, striatum, thalamus, amygdala, hippocampus and cerebellum) were estimated using the software package SPM (VBM-8 module). Continued cannabis use did not have an effect on GM volume change at follow-up. Cross-sectional analyses at baseline and follow-up revealed consistent negative correlations between cannabis related problems and cannabis use (in grams) and regional GM volume of the left hippocampus, amygdala and superior temporal gyrus. These results suggests that small GM volumes in the medial temporal lobe are a risk factor for heavy cannabis use or that the effect of cannabis on GM reductions is limited to adolescence with no further damage of continued use after early adulthood. Long-term prospective studies starting in early adolescence are needed to reach final conclusions. PMID- 27224248 TI - Epicatechin-3-gallate reverses TGF-beta1-induced epithelial-to-mesenchymal transition and inhibits cell invasion and protease activities in human lung cancer cells. AB - Epithelial-to-mesenchymal transition (EMT) and invasion potential have been considered as essential factors in cancer metastasis, which is the major cause of cancer death. EMT is a multi-step process that involves gain invasion, cytoskeleton change, cell adhesion, and proteolytic extracellular matrix degradation. Epicatechin-3-gallate (ECG), which is a natural polyphenolic component of green tea, elicits several antioxidant and anti-inflammatory effects. However, the effects of ECG on cancer invasion and EMT of human lung carcinoma remain unknown. We provided molecular evidence supporting the anti metastatic effect of ECG. This compound suppressed the invasion (P < 0.001) of highly metastatic A549 cells by reducing the activities of matrix metalloproteinase-2 (P < 0.001) and urokinasetype plasminogen activator (P < 0.001). ECG also reversed the transforming growth factor (TGF)-beta1-induced EMT and upregulated epithelial markers, such as E-cadherin. Conversely, ECG inhibited mesenchymal markers, such as fibronectin and p-FAK. The subcutaneous inoculation of this compound also inhibited the tumor growth of the A549 cells in vivo. Therefore, ECG may be used as an anti-cancer and anti-invasion agent for the adjuvant treatment and metastasis control of human lung cancer cells. ECG may also be administered as an effective chemopreventive agent against TGF-beta1 induced EMT. PMID- 27224249 TI - Sphingosine-1-Phosphate Receptor 2 Regulates Proinflammatory Cytokine Production and Osteoclastogenesis. AB - Sphingosine-1-phosphate receptor 2 (S1PR2) couples with the Gi, Gq, and G12/13 group of proteins, which modulate an array of cellular signaling pathways and affect immune responses to multiple stimuli. In this study, we demonstrated that knockdown of S1PR2 by a specific S1PR2 shRNA lentiviral vector significantly inhibited IL-1beta, IL-6, and TNF-alpha protein levels induced by oral pathogen Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) in murine bone marrow-derived monocytes and macrophages (BMMs) compared with controls. In addition, knockdown of S1PR2 by the S1PR2 shRNA lentiviral vector suppressed p PI3K, p-ERK, p-JNK, p-p38, and p-NF-kappaBp65 protein expressions induced by A. actinomycetemcomitans. Furthermore, bone marrow cells treated with the S1PR2 shRNA lentiviral vector inhibited osteoclastogenesis induced by RANKL compared with controls. The S1PR2 shRNA suppressed the mRNA levels of six osteoclastogenic factors including nuclear factor of activated T-cells cytoplasmic calcineurin dependent 1 (NFATc1), cathepsin K (Ctsk), acid phosphatase 5 (Acp5), osteoclast associated receptor (Oscar), dendritic cells specific transmembrane protein (Dcstamp), and osteoclast stimulatory transmembrane protein (Ocstamp) in bone marrow cells. We conclude that S1PR2 plays an essential role in modulating proinflammatory cytokine production and osteoclastogenesis. Blocking S1PR2 signaling might be a novel therapeutic strategy to treat inflammatory bone loss diseases. PMID- 27224250 TI - Role of Fibroblast Growth Factor-5 on the Proliferation of Human Tonsil-Derived Mesenchymal Stem Cells. AB - Human mesenchymal stem cells (MSCs) are a promising tool for therapeutic applications in cell-based therapy and regenerative medicine, and MSCs from the human palatine tonsils have recently been used as a new tissue source. However, the understanding of the proliferation and differentiation capacity of tonsil derived MSCs (T-MSCs) is limited. In this study, we compared the proliferative potential of T-MSCs with those of bone marrow MSCs (BM-MSCs) and adipose tissue derived MSCs (A-MSCs). Additionally, we investigated the underlying mechanism of T-MSC function. We showed that T-MSCs proliferated faster than A-MSCs and BM-MSCs in methylthiazolyl diphenyl-tetrazolium (MTT) assays, cell count assays, and cell cycle distribution analyses. DNA microarray and real-time PCR analyses revealed that the expression of fibroblast growth factor-5 (FGF5) was significantly elevated in T-MSCs compared with those in A-MSCs and BM-MSCs. Cell growth curves showed a difference in cell growth between untreated cells and siFGF5-treated T MSCs. The administration of recombinant human FGF5 (rhFGF5) to the cells transfected with siFGF5 led to a significant increase in the proliferation rates. The administration of rhFGF5 to T-MSCs led to an increase in the levels of phosphorylated ERK1/2. However, treatment with siFGF5 resulted in an overall decrease in the level of phosphorylated ERK1/2. The osteogenic differentiation of T-MSCs was reduced following siFGF5 transfection, and it recovered to near-normal levels when rhFGF5 was added. These findings indicate that T-MSCs show significantly higher proliferative potential compared with those of BM-MSCs and A MSCs. FGF5 facilitates cell proliferation through ERK1/2 activation, and it influences the osteogenic differentiation of T-MSCs. PMID- 27224252 TI - A One Health Message about Bats Increases Intentions to Follow Public Health Guidance on Bat Rabies. AB - Since 1960, bat rabies variants have become the greatest source of human rabies deaths in the United States. Improving rabies awareness and preventing human exposure to rabid bats remains a national public health priority today. Concurrently, conservation of bats and the ecosystem benefits they provide is of increasing importance due to declining populations of many bat species. This study used a visitor-intercept experiment (N = 521) in two U.S. national parks where human and bat interactions occur on an occasional basis to examine the relative persuasiveness of four messages differing in the provision of benefit and uncertainty information on intentions to adopt a rabies exposure prevention behavior. We found that acknowledging benefits of bats in a risk message led to greater intentions to adopt the recommended rabies exposure prevention behavior without unnecessarily stigmatizing bats. These results signify the importance of communicating benefits of bats in bat rabies prevention messages to benefit both human and wildlife health. PMID- 27224253 TI - Alternate Routes of Administration among Prescription Opioid Misusers and Associations with Sexual HIV Transmission Risk Behaviors. AB - Literature suggests that young adult prescription opioid misusers who are using alternate routes of administration (e.g., snorting, injecting) may be engaging in sexual and non-sexual HIV risk behaviors. This study examines demographics, substance use, sexual risk behavior, and health and social problems associated with alternate routes of administration of prescription opioids among a sample of young adult prescription opioid misusers. Data are drawn from baseline assessments from a behavioral intervention trial. Eligible participants were ages 18-39, and reported recent (past 90 days) heterosexual sex, and recent and regular substance use and attendance at large, recognized local nightclubs. The analyses include 446 racially/ethnically diverse participants. In bivariate regression models, compared to those who did not, participants reporting alternate routes of administration (n = 209) were more likely to be White (p < 0.025) and report group sex participation history (p = 0.002), sex with an injection drug user (p = 0.003), sexual victimization history (p = 0.003), and severe mental distress (p < 0.000). White race, group sex participation history, and severe mental distress remained significant in the multivariate model. Alternate routes of administration of prescription opioids are associated with sexual HIV transmission risk behaviors. Early prevention and intervention efforts that address sexual and non-sexual HIV risk behaviors are warranted. PMID- 27224254 TI - Metabolic Enzymes of Cocaine Metabolite Benzoylecgonine. AB - Cocaine is one of the most addictive drugs without a U.S. Food and Drug Administration (FDA)-approved medication. Enzyme therapy using an efficient cocaine-metabolizing enzyme is recognized as the most promising approach to cocaine overdose treatment. The actual enzyme, known as RBP-8000, under current clinical development for cocaine overdose treatment is our previously designed T172R/G173Q mutant of bacterial cocaine esterase (CocE). The T172R/G173Q mutant is effective in hydrolyzing cocaine but inactive against benzoylecgonine (a major, biologically active metabolite of cocaine). Unlike cocaine itself, benzoylecgonine has an unusually stable zwitterion structure resistant to further hydrolysis in the body and environment. In fact, benzoylecgonine can last in the body for a very long time (a few days) and, thus, is responsible for the long term toxicity of cocaine and a commonly used marker for drug addiction diagnosis in pre-employment drug tests. Because CocE and its mutants are all active against cocaine and inactive against benzoylecgonine, one might simply assume that other enzymes that are active against cocaine are also inactive against benzoylecgonine. Here, through combined computational modeling and experimental studies, we demonstrate for the first time that human butyrylcholinesterase (BChE) is actually active against benzoylecgonine, and that a rationally designed BChE mutant can not only more efficiently accelerate cocaine hydrolysis but also significantly hydrolyze benzoylecgonine in vitro and in vivo. This sets the stage for advanced studies to design more efficient mutant enzymes valuable for the development of an ideal cocaine overdose enzyme therapy and for benzoylecgonine detoxification in the environment. PMID- 27224255 TI - Asthma-like Features and Clinical Course of Chronic Obstructive Pulmonary Disease. An Analysis from the Hokkaido COPD Cohort Study. AB - RATIONALE: Some patients with chronic obstructive pulmonary disease (COPD) have asthma-like features, such as significant bronchodilator reversibility, blood eosinophilia, and/or atopy, even if they are not clinically diagnosed as having asthma. However, the clinical significance of asthma-like features overlapping with COPD remains unclear. OBJECTIVES: The aim of this study was to assess the effect of asthma-like features on the clinical course of patients with COPD who were adequately treated and followed-up over 10 years. METHODS: A total of 268 patients with COPD who had been clinically considered as not having asthma by respiratory specialists were included in this study. The asthma-like features included in this study were bronchodilator reversibility (DeltaFEV1, >=12% and >=200 ml), blood eosinophilia (>=300 cells/MUl), and atopy (positive specific IgE for any inhaled antigen). The annual changes in post-bronchodilator FEV1 and COPD exacerbations were monitored during the first 5 years, and mortality was followed during the entire 10 years of the study. MEASUREMENTS AND MAIN RESULTS: Fifty seven subjects (21%) had bronchodilator reversibility, 52 (19%) had blood eosinophilia, and 67 (25%) had atopy. Subjects with blood eosinophilia had significantly slower annual post-bronchodilator FEV1 decline; bronchodilator reversibility and atopy did not affect the annual post-bronchodilator FEV1 decline, and none of the asthma-like features was associated with development of COPD exacerbation. Even if subjects had two or more asthma-like features, they displayed annual post-bronchodilator FEV1 declines and exacerbation rates similar to those of subjects with one or zero asthma-like features, as well as a lower 10 year mortality rate (P = 0.02). CONCLUSIONS: The presence of asthma-like features was associated with better clinical course in patients with COPD receiving appropriate treatment. PMID- 27224256 TI - Metastatic malignant struma ovarii with coexistence of Hashimoto's thyroiditis. AB - Struma ovarii is a rare ovarian teratoma characterized by the presence of thyroid tissue as the major component. Malignant transformation of the thyroidal component (malignant struma ovarii) has been reported in approximately 5% of struma ovarii. The management and follow-up of this unusual disease remain controversial. We report the case of a woman with a history of autoimmune thyroiditis and a previous resection of a benign struma ovarii that underwent hystero-annexiectomy for malignant struma ovarii with multiple papillary thyroid cancer foci and peritoneal involvement. Total thyroidectomy and subsequent radioiodine treatment lead to complete disease remission after 104 months of follow-up. The diagnosis and natural progression of malignant struma ovarii are difficult to discern, and relapses can occur several years after diagnosis. A multidisciplinary approach is mandatory; after surgical excision of malignant struma, thyroidectomy in combination with (131)I therapy should be considered after risk stratification in accordance with a standard approach in differentiated thyroid cancer patients. LEARNING POINTS: Malignant struma ovarii is a rare disease; diagnosis is difficult and management is not well defined.Predominant sites of metastasis are adjacent pelvic structures.Thyroidectomy and (131)I therapy should be considered after risk stratification in accordance with standard approaches in DTC patients. PMID- 27224257 TI - Medial thigh lift in post-bariatric patients: Our encouraging experience. AB - BACKGROUND: A high rate of postoperative complications following inner thigh lift is reported in the medical literature. The authors present the results of a study on the validity of inner thigh contouring, with liposuction and concomitant skin excision, in postbariatric patients. METHODS: This study examined the charts of 46 postbariatric female patients, who underwent medial thigh lift with a 'T' scar technique and concomitant liposuction, between February 2010 and February 2013. Complications were recorded. A questionnaire was administered to the patients at the 1-year follow-up visit. Preoperative and 1-year postoperative photographs were compared, superimposed, and analysed. RESULTS: This study did not observe major systemic complications, haematoma, seroma, infection, skin necrosis, lymphoceles, or lymphoedema. Minor complications were three cases of wound dehiscence and two cases of deepithelialisation. At the 1-year follow-up visit, caudal scar migration, genital distortion, recurrent ptosis, or deformity of the inner thigh contour were not observed. Questionnaires and a comparison of pre- and 1-year postoperative pictures showed encouraging results. CONCLUSIONS: The medial thigh lift technique described and assessed in this article is a straightforward surgical procedure, with considerable functional and aesthetic results. Liposuction, early mobilisation, and appropriate postoperative management are pivotal to reduce postoperative downtime and complications. PMID- 27224259 TI - Low Six4 and Six5 gene dosage improves dystrophic phenotype and prolongs life span of mdx mice. AB - Muscle regeneration is an important process for skeletal muscle growth and recovery. Repair of muscle damage is exquisitely programmed by cellular mechanisms inherent in myogenic stem cells, also known as muscle satellite cells. We demonstrated previously the involvement of homeobox transcription factors, SIX1, SIX4 and SIX5, in the coordinated proliferation and differentiation of isolated satellite cells in vitro. However, their roles in adult muscle regeneration in vivo remain elusive. To investigate SIX4 and SIX5 functions during muscle regeneration, we introduced knockout alleles of Six4 and Six5 into an animal model of Duchenne Muscular Dystrophy (DMD), mdx (Dmd(mdx) /Y) mice, characterized by frequent degeneration-regeneration cycles in muscles. A lower number of small myofibers, higher number of thick ones and lower serum creatine kinase and lactate dehydrogenase activities were noted in 50-week-old Six4(+/-) 5(+/-) Dmd(mdx) /Y mice than Dmd(mdx) /Y mice, indicating improvement of dystrophic phenotypes of Dmd(mdx) /Y mice. Higher proportions of cells positive for MYOD1 and MYOG (markers of regenerating myonuclei) and SIX1 (a marker of regenerating myoblasts and newly regenerated myofibers) in 12-week-old Six4(+/-) 5(+/-) Dmd(mdx) /Y mice suggested enhanced regeneration, compared with Dmd(mdx) /Y mice. Although grip strength was comparable in Six4(+/-) 5(+/-) Dmd(mdx) /Y and Dmd(mdx) /Y mice, treadmill exercise did not induce muscle weakness in Six4(+/-) 5(+/-) Dmd(mdx) /Y mice, suggesting higher regeneration capacity. In addition, Six4(+/-) 5(+/-) Dmd(mdx) /Y mice showed 33.8% extension of life span. The results indicated that low Six4 and Six5 gene dosage improved dystrophic phenotypes of Dmd(mdx) /Y mice by enhancing muscle regeneration, and suggested that SIX4 and SIX5 are potentially useful de novo targets in therapeutic applications against muscle disorders, including DMD. PMID- 27224258 TI - Serologic screening of United States blood donors for Babesia microti using an investigational enzyme immunoassay. AB - BACKGROUND: The tick-borne pathogen Babesia microti has become recognized as the leading infectious risk associated with blood transfusion in the United States, yet no Food and Drug Administration-licensed screening tests are currently available to mitigate this risk. The aim of this study was to evaluate the performance of an investigational enzyme immunoassay (EIA) for B. microti as a screening test applied to endemic and nonendemic blood donor populations. STUDY DESIGN AND METHODS: The study aimed to test 20,000 blood donors from areas of the United States considered endemic for B. microti and 10,000 donors from a nonendemic area with the investigational B. microti EIA. Repeat-reactive samples were retested by polymerase chain reaction (PCR), blood smear, immunofluorescent assay (IFA), and immunoblot assay. In parallel, serum samples from symptomatic patients with confirmed babesiosis were tested by EIA, IFA, and immunoblot assays. RESULTS: A total of 38 of 13,757 (0.28%) of the donors from New York, 7 of 4583 (0.15%) from Minnesota, and 11 of 8363 (0.13%) from New Mexico were found repeat reactive by EIA. Nine of the 56 EIA repeat-reactive donors (eight from New York and one from Minnesota) were positive by PCR. The specificity of the assay in a nonendemic population was 99.93%. Among IFA-positive clinical babesiosis patients, the sensitivity of the assay was 91.1%. CONCLUSION: The B. microti EIA detected PCR-positive, potentially infectious blood donors in an endemic population and exhibited high specificity among uninfected and unexposed individuals. The EIA promises to provide an effective tool for blood donor screening for B. microti in a format amenable to high-throughput and cost effective screening. PMID- 27224261 TI - Transitions in the Molecular Configuration and Aggregates for Mixtures of a Star Shaped Hexameric Cationic Surfactant and a Monomeric Anionic Surfactant. AB - A hexameric cationic ammonium surfactant (PAHB), in which six amphiphilic moieties were connected by a star-shaped spacer group, adopted star-shaped, claw like, and pyramid-like molecular configurations in aqueous solution, depending on the concentration. Herein, we studied the effect of adding sodium dodecyl sulfate (SDS) on the configuration and aggregation behavior of PAHB. Taking these three configurations of PAHB as initial states, the addition of SDS caused transitions of the star-shaped and claw-like configurations into a pyramid-like configuration, whilst the pyramid-like configuration remained unchanged. Moreover, the SDS/PAHB aggregates experienced transition from small spheres to large spherical fingerprint-like aggregates, no matter the initial state of PAHB. Molecular packing in the aggregates was also studied. These results have improved our understanding about the cooperative interactions between star-shaped oligomeric surfactants and monomeric surfactants, which should guide future applications of this unique type of surfactant. PMID- 27224260 TI - Dual-Energy CT for Quantification of Urinary Stone Composition in Mixed Stones: A Phantom Study. AB - OBJECTIVE: The purpose of this study was to assess the feasibility of using dual energy CT to accurately quantify uric acid and non-uric acid components in urinary stones of mixed composition. MATERIALS AND METHODS: A total of 24 urinary stones were analyzed with micro CT to serve as the reference standard for uric acid and non-uric acid composition. These stones were placed in water phantoms to simulate body attenuation of slim to obese adults and scanned with a third generation dual-source CT scanner by use of dual-energy modes adaptively selected on the basis of phantom size. CT number ratio, which is distinct for different materials, was calculated for each pixel of the stones. Each pixel was then classified as uric acid and non-uric acid by comparison of the CT number ratio with preset thresholds ranging from 1.10 to 1.70. Minimal, maximal, and root-mean square errors were calculated by comparing composition with the reference standard, and the threshold with the minimal root-mean-square error was determined. A paired t test was performed to compare the stone composition determined with dual-energy CT with the reference standard obtained with micro CT. RESULTS: The optimal CT number ratio threshold ranged from 1.27 to 1.55, dependent on phantom size. The root-mean-square error ranged from 9.60% to 12.87% across all phantom sizes. Minimal absolute error ranged from 0.04% to 1.24% and maximal absolute error from 22.05% to 35.46%. Dual-energy CT and the reference micro CT did not differ significantly on uric acid and non-uric acid composition (paired t test, p = 0.20-0.96). CONCLUSION: Accurate quantification of uric acid and non-uric acid composition in mixed stones is possible with dual-energy CT. PMID- 27224262 TI - c-Rel is Required for the Induction of pTregs in the Eye but Not in the Gut Mucosa. AB - Regulatory T (Treg) cells play an integral role in maintaining immune homeostasis and preventing autoimmune diseases. Forkhead box P3 expression marks the commitment of progenitor cells to the Treg lineage. Although the essential function of the nuclear factor (NF)-kappaB family transcription factor c-Rel in the regulation of natural Treg cells has been firmly established, little is known about whether c-Rel is involved in the in vivo generation of peripheral Treg cells (pTregs), which develop from mature CD4+ conventional T cells outside of the thymus. We sought to answer this question through the induction of pTregs in the eye and gut mucosa using ovalbumin-specific T cell receptor transgenic mice that do or do not express c-Rel. Our results showed that Tregs can be induced in the eye in a c-Rel-dependent manner when immune-mediated inflammation occurs. However, c-Rel is dispensable for the induction of pTregs in the gut mucosa after oral antigen administration. Thus, c-Rel may play distinct roles in regulating the development of pTregs in different organs. Abbreviations ACAID: Anterior Chamber-Associated Immune Deviation; ATF: activating transcription factor; CREB: cAMP responsive element-binding protein; DMEM: Dulbecco minimum essential medium; HBSS: Hanks Balanced Salt Solution; NFAT: Nuclear Factor of Activated T cells; PBS: Phosphate-buffered saline; PE: Phycoerythrin; WT: wild type. PMID- 27224263 TI - Functional Expression of FSH Receptor in Endometriotic Lesions. AB - CONTEXT: FSH receptor (FSHR), besides being expressed in gonads, is also expressed in some extragonadal tissues at low levels. OBJECTIVE: We examined the functional expression of FSHR in different types of endometriotic lesions. DESIGN: Extensive studies were carried out to detect functional FSHR expression and FSH-stimulated estrogen production in ovarian endometriomas and recto-vaginal endometriotic nodules (RVEN). Normal endometrium, ovary, and myometrium tissues from nonpregnant cycling women served as controls. SETTINGS: This laboratory based study was carried out on tissue specimens from patients with endometriosis and healthy donors. RESULTS: Endometriotic lesions and normal secretory-phase endometrium showed FSHR expression at both mRNA and protein level. RVEN and ovarian endometrioma demonstrated up-regulated CYP19A1, dependent on the activation of CYP19A1 proximal promoter II. Estrogen receptor-beta (ESR2) expression was significantly increased in RVEN vs normal endometrium. Recombinant human FSH stimulation of RVEN explants significantly increased estradiol production and CYP19A1 and ESR2 expression. FSHR was up-regulated in recombinant human FSH-stimulated endometrial and decidualized stromal cells with increased CYP19A1 expression. CONCLUSIONS: We described a novel functional FSHR expression, where FSH-stimulated CYP19A1 expression and estrogen production in RVEN are demonstrated. This locally FSH-induced estrogen production may contribute to the pathology, development, progression, and severity of RVEN. PMID- 27224264 TI - IL-17A Exacerbates Fibrosis by Promoting the Proinflammatory and Profibrotic Function of Orbital Fibroblasts in TAO. AB - CONTEXT: The development of thyroid-associated ophthalmopathy (TAO) is associated with self-immune dysfunction. Recent findings in TAO and Graves' disease indicate that IL-17A may also be involved in the autoimmunity of TAO. OBJECTIVE: We sought to investigate the pathogenic function of IL-17A-producing T cells in TAO. DESIGN/SETTING/PARTICIPANTS: Blood samples and orbital fibroblasts (OFs) were collected from TAO patients and healthy subjects. MAIN OUTCOME MEASURES: Flow cytometry, real-time PCR, cytokine-specific ELISA, and Western blotting were performed. RESULTS: Here, we showed a significantly higher proportion of IL-17A producing T cells in TAO patients and the recruitment of both CD4(+) and CD8(+) T cells in TAO orbits. TAO orbital tissues expressed more IL-17A receptor, IL-17A, and its related cytokines, with severe fibrotic change compared with normal controls. Furthermore, we validated that IL-17A could enhance the proinflammatory function of OFs and stimulate the production of extracellular matrix proteins in OFs but not eyelid fibroblasts. The mechanisms involved in this enhancement mainly relied on MAPK activation. Finally, we observed that the deubiquitinase inhibitor vialinin A could down-regulate retinoic acid receptor-related orphan receptor-gammat expression and decrease IL-17A level in TAO patients. CONCLUSION: Our observations illustrate the potential pathogenic role of IL-17A-producing T cells in the inflammatory response and fibrosis of TAO. The effect of vialinin A on the reduction of retinoic acid receptor-related orphan receptor-gammat level implicates its potential role as a novel therapeutic agent for TAO and other autoimmune disorders in the future. PMID- 27224265 TI - Subjective food intake ability related to oral health-related quality of life and psychological health. AB - Reduced food intake ability can restrict an individual's choice of foods and might have a significant impact on the individual's quality of life and mental health. The aim of this study was to evaluate the correlations between self reported masticatory ability and oral health-related quality of life (OHRQOL) and psychological health. The study included 72 (26 men, 46 women) adults with a mean age of 26.4 +/- 8.6 years. Each participant completed the key subjective food intake ability (KFIA) test for five key foods, the Korean version of the Oral Health Impact Profile-14 (OHIP-14K) and three questionnaires for measuring anxiety, depression and self-esteem. The participants were distributed into two groups by sex (a mean age of 23.9 +/- 5.2 for men and 27.9 +/- 9.8 for women) and by the median KFIA score. There were no significant differences in any of the variables according to sex. Thirty-two participants (12 men, 20 women) in the lower KFIA group had a higher total OHIP-14K (P < 0.001) and depression level (P < 0.05) than the 40 participants (14 men, 26 women) in the higher KFIA group. As the KFIA decreased, OHRQOL worsened (P < 0.001) and depression increased (P < 0.05). Participants with lower KFIA scores were more than 4.3 times as likely as to have a poor OHRQOL than the reference group (odds ratio, 4.348; 95% confidence interval, 1.554-12.170, P < 0.01). Lower subjective food intake ability is associated with a poor oral health-related quality of life and higher depression level. PMID- 27224266 TI - Liquid Chromatography-Electrospray Ionization Mass Spectrometry Analysis of Limonoids and Flavonoids in Seeds of Grapefruits, Other Citrus Species, and Dietary Supplements. AB - A selective UHPLC-DAD-QToF-MS method was developed to screen grapefruit seeds, and the seeds of other Citrus species for limonoid aglycones, acids, glucosides, and flavonoids. These classes of compounds were identified in positive and negative ion modes over a mass-to-charge range from 100-1500. Accurate mass values, elution times, and fragmentation patterns obtained by QToF-mass spectrometry were used to identify or tentatively characterize the compounds detected in the sample of this study. Limonin was the major limonoid in most of the seeds of Citrus species, followed by nomilin. This analytical method was successfully applied for the analysis of commercial extracts and dietary supplements claiming to contain grapefruit seed extract, or extracts made from the seed and other fruit parts such as the peel or pulp. Many commercial products contained large numbers of flavonoids, indicating the use of peel, pulp, or seed coat. This method also permitted detection of synthetic preservatives such as benzethonium chloride, methylparaben, and triclosan in commercial grapefruit seed extract products. Out of the 17 commercial products analyzed, two contained the synthetic antimicrobial agent benzethonium chloride. PMID- 27224267 TI - Antileishmanial Activity of a Calophyllum brasiliense Leaf Extract. AB - Calophyllum brasiliense (Clusiaceae) is a tree that grows mainly in the Atlantic Forest in Brazil. Its leaves possess antibacterial activity, cytotoxic activity against certain tumor cell lines, and antimicrobial activity in BALB/c mice infected with Leishmania (Leishmania) amazonensis.Aiming to identify ultrastructural changes and DNA fragmentation in Leishmania (Viannia) braziliensis, promastigotes were treated with a concentration of the dichloromethane extract and coumarin (-) mammea A/BB from C. brasiliense leaves that inhibited 50 % of the parasites (IC50), and were evaluated by transmission and scanning electron microscopy. Ultrastructural changes showed different levels of mitochondrial alterations, including mitochondrial swelling and a reduction in the density of the mitochondrial matrix. Induced DNA fragmentation, as observed by TUNEL, suggested that the extract and coumarin (-) mammea A/BB induced apoptosis-like cell death. These results suggest that the combination of C. brasiliense extract and coumarin (-) mammea A/BB can be considered a promising candidate for the development of new antiprotozoal agents, because of its significant leishmanicidal activity. PMID- 27224268 TI - A Ring-D-Seco-Tetranortriterpenoid from Seeds of Carapa procera Active against Breast Cancer Cell Lines. AB - The seeds of Carapa procera are exploited extensively in West African ethnopharmacy for the treatment of several pathologies, including inflammation. They also are effective as insect antifeedants and as a mosquito repellent. With the aim of identifying bioactive principles, an ethyl acetate extract of the defatted seeds was made and fractionated. Two principle compounds were isolated. One of these, 5,6-dehydro-7-deacetoxy-7-oxogedunin (1), while known from another genus of the Meliaceae, is newly identified from the genus Carapa and its X-ray structure is described for the first time. In addition, 1 displayed strong anti clonogenic activity at 10 uM. The other compound, mexicanolide (2), is known from this species and showed neither cytotoxicity nor anti-clonogenicity. These differences in efficacy are discussed in relation to known structure-activity relationships of limonoids. PMID- 27224269 TI - Matrix Effect on the Spray Drying Nanoencapsulation of Lippia sidoides Essential Oil in Chitosan-Native Gum Blends. AB - Essential oils have many applications in the pharmaceutical, chemical, and food fields, however, their use is limited to the fact that they are very labile, requiring their a priori encapsulation, aiming to preserve their properties.This work reports on the preparation of chitosan-gum nanoparticles loaded with thymol containing Lippia sidoides essential oil, using exudates of Anacardium Occidentale (cashew gum), Sterculia striata (chicha gum), and Anadenanthera macrocarpa trees (angico gum). Nanoparticles were produced by spray drying an emulsion of L. sidoides essential oil and aqueous solution of gums with different chitosan : gum ratios. Samples were characterized by FTIR and UV/VIS spectroscopy, particle size, volume distribution, and zeta potential. The FTIR spectrum showed the main signals of chitosan and the gums. Data obtained revealed that the samples had sizes in the nano range, varying from 17 nm to 800 nm. The zeta potential varied from + 30 mV to - 40 mV. Nanoparticle loading values varied from 6.7 % to 15.6 %, with an average encapsulating efficiency of 62 %, where the samples with high ratios of cashew gum and chicha gum presented high oil loading values. The data revealed that both the chitosan : gum ratio and polysaccharide characteristics play major roles in nanoencapsulation processes. PMID- 27224270 TI - Arctigenin Attenuates Learning and Memory Deficits through PI3k/Akt/GSK-3beta Pathway Reducing Tau Hyperphosphorylation in Abeta-Induced AD Mice. AB - Arctigenin is a phenylpropanoid dibenzylbutyrolactone lignan compound possessing antitumor, anti-inflammatory, anti-influenza, antioxidant, antibacterial, and hypoglycaemic activities. Our previous study demonstrated that arctigenin exerts neuroprotective effects both in vitro and in vivo in a Parkinson's disease model. However, the exact mechanism through which arctigenin improves amyloid beta induced memory impairment by inhibiting the production of the hyperphosphorylated tau protein is unknown. Amyloid beta1-42 was slowly administered via the intracerebroventricular route in a volume of 3 uL (~ 410 pmmol/mouse) to mice. The mice were administered arctigenin (10, 40, or 150 mg/kg) or vehicle starting from the second day after amyloid beta1-42 injection to the end of the experiment. Behavioural tests were performed from days 9 to 15. On day 16 after the intracerebroventricular administration of amyloid beta1-42, the mice were sacrificed for biochemical analysis. Arctigenin (10-150 mg/kg) significantly attenuated the impairment of spontaneous alternation behaviours in the Y-maze task, decreased the escape latency in the Morris water maze test, and increased the swimming times and swimming distances to the platform located in the probe test. Arctigenin attenuated the level of phosphorylated tau at the Thr-181, Thr 231, and Ser-404 sites in the hippocampus, and increased the phosphorylation levels of phosphatidylinositol-3-kinase, threonine/serine protein kinase B, and glycogen synthase kinase-3beta. Arctigenin effectively provides protection against learning and memory deficits and in inhibits hyperphosphorylated tau protein expression in the hippocampus. The possible mechanism may occur via the phosphatidylinositol-3-kinase/protein kinase B-dependent glycogen synthase kinase 3beta signalling pathway. PMID- 27224271 TI - Gamma-Terpinene Modulation of LPS-Stimulated Macrophages is Dependent on the PGE2/IL-10 Axis. AB - Gamma-terpinene is a monoterpene present in the essential oils of several plants, including those from the Eucalyptus genus. This molecule was recently described as anti-inflammatory and microbiocidal, but little is known about the mechanisms behind its effects. The aim of the present study was to investigate the effect of gamma-terpinene on the lipopolysaccharide-induced production of cytokines by murine peritoneal macrophages. Gamma-terpinene treatment was found to reduce the production of proinflammatory cytokines, such as interleukin-1beta and interleukin-6, and enhance that of the anti-inflammatory cytokine interleukin-10. This was accompanied by increased levels of the enzyme cycloxygenase-2 and its product, the lipid mediator prostaglandin E2. Inhibition of cycloxygenase-2 with nimesulide abolished the potentiating effect of gamma-terpinene on interleukin-10 production. Moreover, nimesulide treatment also abrogated the inhibitory effect of gamma-terpinene on interleukin-1beta and interleukin-6. Furthermore, in macrophages from mice deficient in the interleukin-10 gene, gamma-terpinene failed to inhibit interleukin-1beta and interleukin-6 production. These results suggest that this monoterpene promotes the prostaglandin E2/interleukin-10 axis, which inhibits the production of these proinflammatory cytokines. PMID- 27224272 TI - Pregnane Glycosides from Cynanchum marnierianum Stimulate GLP-1 Secretion in STC 1 Cells. AB - In the framework of the search for natural glucagon-like peptide-1 secretagogues, the bioassay-guided fractionation of the ethanolic extract from Cynanchum marnierianum led to the isolation of two new pregnane glycosides named marnieranosides A (1) and B (2). The structures were determined based on spectroscopic data and were established as 12beta,20 S-O-dibenzoyl-pregn-6-en 5alpha,8beta,14beta,17beta-tetraol-3-O-beta-D-oleandropyranosyl-(1 -> 4)-beta-D cymaropyranoside (1) and 12beta,20R-O-dibenzoyl-pregn-6-en-5alpha,8beta,14beta triol-3-O-beta-D-oleandropyranosyl-(1 -> 4)-beta-D-canaropyranosyl-(1 -> 4)-beta D-cymaropyranoside (2). They present structural analogies to pregnanes previously described in species known for their appetite suppressant and antihyperglycemic effects, such as P57 from Hoodia gordonii. Lupeol (3), a known dipeptidyl peptidase-4 inhibitor, and the insulinomimetic kaempferol-3-O-neohesperidoside (4) were also identified in C. marnierianum. In an in vitro assay on secretin tumor cell line-1 cells, compounds 1, 2, and P57 were found to stimulate the secretion of GLP-1 by 130 % (all tested at 100 uM). These results suggest that C. marnierianum could be of great interest in the treatment of type 2 diabetes, and that pregnane derivatives should be partly responsible via the stimulation of glucagon-like peptide-1 secretion. PMID- 27224273 TI - Immunmodulatory and Antiproliferative Properties of Rhodiola Species. AB - The traditional medicines of Asia and Europe have long used various Rhodiola species, which are endemic to the subarctic areas of the northern hemisphere, as tonic, adaptogen, antidepressant, and anti-inflammatory drugs. In order to establish the therapeutic uses of these plants in modern medicine, the pharmacological effects of Rhodiola sp. have been widely studied. Indeed, the most amply researched species, Rhodiola rosea, has been shown to possess antioxidant, adaptogenic, antistress, antimicrobial, immunomodulatory, angiomodulatory, and antitumoral effects. Salidroside (p-hydroxyphenethyl-beta-D glucoside), a major compound in Rhodiola, seems to be responsible for many of the effects observed with Rhodiola extracts.The aim of this paper is to review the pharmacological effects not only of various Rhodiola species, mainly R. rosea along with Rhodiola imbricata, Rhodiola algida, and Rhodiola crenulata, but also of salidroside, focusing especially on its antioxidant, immunomodulatory, antitumoral, and antiproliferative activities, as well as to describe their therapeutic significance in disease management. Although previous pharmacological studies have established a scientific basis for possible therapeutic uses of Rhodiola extracts and salidroside, high-quality, randomized, controlled clinical trials are still needed. PMID- 27224274 TI - Medicinal Plants and Natural Products as Potential Sources for Antiparkinson Drugs. AB - Parkinson's disease is a progressive neurodegenerative dysfunction characterized by the loss of pigmented dopaminergic neurons of the nigrostriatal system with a consequent dopamine decrease. The reduction of dopamine levels produces neuronal damage, depigmentation of the substantia nigra, and the presence of intracellular inclusions in dopaminergic neurons. Treatments for Parkinson's disease aim for improving these motor symptoms by increasing the dopaminergic signal in the striatum with levodopa in combination with enzyme inhibitors or anticholinergic drugs. Nevertheless, natural products can act as neuroprotective agents by reducing the progression of the disease and the inflammatory process.In the present review, we have compiled data on the principal medicinal plants and natural products as potential antiparkinsonian agents. They act by different mechanisms, such as the inhibition of alpha-synuclein condensation, reduction of oxidative stress and neuro-inflammation, increase of dopaminergic neurons survival, or the blockade of the A2 A receptor. PMID- 27224275 TI - Conductivities of epidermis, dermis, and subcutaneous tissue at intermediate frequencies. AB - Novel data for the conductivities of the tissues composing the skin, which are the epidermis, dermis and subcutaneous tissue, were obtained at intermediate frequencies by in vitro measurement. The conductivity of the epidermis was determined from those of the dermis and bulk skin. The conductivities of the dermis and subcutaneous tissue were almost constant from 10 kHz to 1 MHz. On the other hand, a frequency dependence was observed for the epidermis; the conductivity decreases with decreasing frequency. It was found that the conductivity of bulk skin is not determined by that of the dermis but by that of the epidermis. The presented data are expected to contribute to the assessment of safety and to the research and development of medical applications. PMID- 27224276 TI - Early commencement of physical therapy in the acute phase following elective lower limb arthroplasty produces favorable outcomes: a systematic review and meta analysis examining allied health service models. AB - BACKGROUND: Temporal and dose-response relationships between allied health (AH) and recovery in the acute phase following lower limb (LL) arthroplasty are unclear. This systematic review investigates whether early commencement, additional therapy and/or weekend AH affects length of stay (LOS) and patient outcomes in the acute phase following LL arthroplasty. METHODS: Electronic databases were searched in February 2015. Studies were included if they evaluated any of the following aspects of AH for adults following LL arthroplasty in the acute phase: Early compared to later therapy commencement; Additional therapy; or a 6- or 7-day service compared to a lesser service. RESULTS: Twenty-four studies met the inclusion criteria, of which 19 investigated effects of physical therapy (PT) alone. Earlier PT reduced LOS (WMD = -1.23 days; 95% CI, -2.16 to -0.30) and resulted in higher probability of discharge directly home (relative risk = 1.45; 95% CI, 1.26-1.67). Addition of weekend PT reduced LOS (WMD = -1.04 days; 95% CI, -1.66 to -0.41) and improved function (SMD = 0.37; 95% CI, 0.02-0.73). Increasing PT from once to twice daily did not affect LOS (WMD = -0.35 days; 95% CI, -0.96 0.26) or function (SMD = 0.31; 95% CI, -0.06-0.71). DISCUSSION: Early PT commencement and a weekend service may produce favorable outcomes following LL arthroplasty when baseline LOS is 4 days or more. Redistributing PT resources to commence as early as day of surgery regardless of weekday may accelerate postoperative recovery. Current, high quality research is needed to confirm these findings. PMID- 27224278 TI - Zika epidemic and social inequalities: Brazil and its fate. PMID- 27224277 TI - Deciphering the Molecular Variations of Pine Wood Nematode Bursaphelenchus xylophilus with Different Virulence. AB - Bursaphelenchus xylophilus is the causative agent of pine wilt disease which has caused huge economic losses in many countries. It has been reported that two forms of pine wood nematodes existed in its native region, i.e., with strong virulence and weak virulence. However, little is known about the molecular differences between the two forms. To better understand their molecular variations, transcriptome and genome sequences of three strongly virulent and one weakly virulent strains were analyzed. We found 238 transcripts and 84 exons which showed notable changes between the two virulent forms. Functional analyses of both differentially expressed transcripts and exons indicated that different virulence strains showed dissimilar nematode growth, reproduction, and oxidoreductase activities. In addition, we also detected a small number of exon skipping events in B. xylophilus. Meanwhile, 117 SNPs were identified as potential genetic markers in distinguishing the two forms. Four of them were further proved to have undergone allele specific expressions and possibly interrupted the target site of evolutionary conserved B. xylophilus miR-47. These particular SNPs were experimentally verified by including eight additional strains to ensure the validity of our sequencing results. These results could help researchers to better diagnose nematode species with different virulence and facilitate the control of pine wilt disease. PMID- 27224279 TI - Mistreatment in an academic setting and medical students' perceptions about their course in Sao Paulo, Brazil: a cross-sectional study. AB - CONTEXT AND OBJECTIVE: High prevalence of mistreatment among medical students has been described in the worldwide literature since the 1980s. However, studies addressing the severity and recurrence of victimization and its effects on students' perceptions of their medical course are scarce. This study had the aim of estimating the prevalence of exposure to mistreatment that was considered to be severe and recurrent and its association with medical students' perceptions about their medical course. METHODS: A cross-sectional study was conducted in a medical school in Sao Paulo, Brazil. Three hundred and seventeen students from the first to the sixth year answered the online questionnaire. RESULTS: High prevalence of mistreatment during the course was found. Two thirds of the students considered the episodes to be severe, and around one third reported experiencing recurrent victimization. Occurences of mistreatment that the students considered to be severe were correlated with feeling overloaded and wanting to abandon the medical course. CONCLUSIONS: Occurrences of mistreatment within the academic environment are frequent in Brazil. The results suggest that mistreatment that was considered to be severe might negatively affect students' perceptions about their course. PMID- 27224280 TI - Impact of health research on advances in knowledge, research capacity-building and evidence-informed policies: a case study on maternal mortality and morbidity in Brazil. AB - CONTEXT AND OBJECTIVE: National health research systems aim to generate high quality knowledge so as to maintain and promote the population's health. This study aimed to analyze the impact of maternal mortality/morbidity research funded by the Brazilian Ministry of Health and institutional partners, on the dimensions: advancing in knowledge, research capacity-building and informing decision-making, within the framework of the Canadian Academy of Health Sciences. DESIGN AND SETTING: Descriptive study based on secondary data, conducted at a public university. METHODS: The advancing in knowledge dimension was estimated from the principal investigators' publication counts and h-index. Data on research capacity-building were obtained from the Ministry of Health's information system. The informing decision-making dimension was analyzed from citations in Stork Network (Rede Cegonha) documents. RESULTS: Between 2002 and 2010, R$ 21.6 million were invested in 128 maternal mortality/morbidity projects. Over this period, the principal investigators published 174 articles, resulting in an h-index of 35, thus showing progress in the advancing in knowledge dimension. Within the research capacity-building dimension, training of 71 students (undergraduate/postgraduate) was observed. Progress in the informing decision-making dimension was modest: 73.5% of the 117 citations in the Stork Network documents were institutional documents and norms. One of the projects funded, the 2006/7 National Demography and Health Survey, was cited in program documents. CONCLUSION: Impacts were shown in the advancing in knowledge and research capacity-building dimensions. The health research system needs to incorporate research for evidence-informed policies. PMID- 27224281 TI - Prevalence of high blood pressure measured in the Brazilian population, National Health Survey, 2013. AB - CONTEXT AND OBJECTIVE: High blood pressure (hypertension) is the most frequent cause of morbidity and a major risk factor for cardiovascular complications. The aim here was to describe the prevalence of blood pressure greater than or equal to 140/90 mmHg in the adult Brazilian population and federal states, along with self-reported information about previous medical diagnoses of hypertension, use of medication and medical care for hypertension control. DESIGN AND SETTING: Cross-sectional study analyzing information from the National Health Survey of 2013, relating to Brazil and its federal states. METHODS: The sample size was estimated as 81,254 households and information was collected from 64,348 households. The survey consisted of interviews, physical and laboratory measurements. Systolic blood pressure was considered to be high when it was >= 140 mmHg and diastolic blood pressure, >= 90 mmHg. RESULTS: It was found that 22.8% of the population has blood pressure measurements >= 140/90 mmHg. The proportion was higher among men than among women: 25.8% versus 20.0%. The frequency increased with age, reaching 47.1% in individuals over 75 years and was highest in the southeast and south. 43.2% reported previous medical diagnoses of hypertension and, of these, 81.4% reported using medication for hypertension and 69.6%, going to the doctor within the past year for pressure monitoring, thus showing regular medical follow-up. CONCLUSION: These results are important for supporting measures for preventing and treating hypertension in Brazil, with the aim of achieving the World Health Organization's goal of reducing hypertension by 25% over the next decade. PMID- 27224282 TI - Reduced or modified dietary fat for preventing cardiovascular disease. AB - BACKGROUND: Reduction and modification of dietary fats have differing effects on cardiovascular risk factors (such as serum cholesterol), but their effects on important health outcomes are less clear. OBJECTIVE: To assess the effect of reduction and/or modification of dietary fats on mortality, cardiovascular mortality, cardiovascular morbidity and individual outcomes including myocardial infarction, stroke and cancer diagnoses in randomised clinical trials of at least 6 months duration. METHODS: SEARCH METHODS: For this review update, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline and Embase, were searched through to June 2010. References of Included studies and reviews were also checked. SELECTION CRITERIA: Trials fulfilled the following criteria: 1) randomized with appropriate control group, 2) intention to reduce or modify fat or cholesterol intake (excluding exclusively omega-3 fat interventions), 3) not multi factorial, 4) adult humans with or without cardiovascular disease, 5) intervention at least six months, 6) mortality or cardiovascular morbidity data available. DATA COLLECTION AND ANALYSIS: Participant numbers experiencing health outcomes in each arm were extracted independently in duplicate and random effects meta-analyses, meta-regression, sub-grouping, sensitivity analyses and funnel plots were performed. MAIN RESULTS: This updated review suggested that reducing saturated fat by reducing and/or modifying dietary fat reduced the risk of cardiovascular events by 14% (RR 0.86, 95% CI 0.77 to 0.96, 24 comparisons, 65,508 participants of whom 7% had a cardiovascular event, I2 50%). Subgrouping suggested that this reduction in cardiovascular events was seen in studies of fat modification (not reduction - which related directly to the degree of effect on serum total and LDL cholesterol and triglycerides), of at least two years duration and in studies of men (not of women). There were no clear effects of dietary fat changes on total mortality (RR 0.98, 95% CI 0.93 to 1.04, 71,790 participants) or cardiovascular mortality (RR 0.94, 95% CI 0.85 to 1.04, 65,978 participants). This did not alter with sub-grouping or sensitivity analysis. Few studies compared reduced with modified fat diets, so direct comparison was not possible. AUTHORS' CONCLUSIONS: The findings are suggestive of a small but potentially important reduction in cardiovascular risk on modification of dietary fat, but not reduction of total fat, in longer trials. Lifestyle advice to all those at risk of cardiovascular disease and to lower risk population groups, should continue to include permanent reduction of dietary saturated fat and partial replacement by unsaturates. The ideal type of unsaturated fat is unclear. PMID- 27224283 TI - Long-term non-pharmacological weight loss interventions for adults with type 2 diabetes mellitus. AB - BACKGROUND: Most persons with type 2 diabetes are overweight and obesity worsens the metabolic and physiologic abnormalities associated with diabetes. OBJECTIVE: The objective of this review is to assess the effectiveness of lifestyle and behavioral weight loss and weight control interventions for adults with type 2 diabetes. METHODS: SEARCH METHODS: Studies were obtained from computerized searches of multiple electronic bibliographic databases, supplemented with hand searches of selected journals and consultation with experts in obesity research. SELECTION CRITERIA: Studies were included if they were published or unpublished randomized controlled trials in any language, and examined weight loss or weight control strategies using one or more dietary, physical activity, or behavioral interventions, with a follow-up interval of at least 12 months. DATA COLLECTION AND ANALYSIS: Effects were combined using a random effects model. MAIN RESULTS: The 22 studies of weight loss interventions identified had a 4,659 participants and follow-up of 1 to 5 years. The pooled weight loss for any intervention in comparison to usual care among 585 subjects was 1.7 kg (95 % confidence interval [CI] 0.3 to 3.2), or 3.1% of baseline body weight among 517 subjects. Other main comparisons demonstrated non significant results: among 126 persons receiving a physical activity and behavioral intervention, those who also received a very low calorie diet lost 3.0 kg (95% CI -0.5 to 6.4), or 1.6% of baseline body weight, more than persons receiving a low-calorie diet. Among 53 persons receiving identical dietary and behavioral interventions, those receiving more intense physical activity interventions lost 3.9 kg (95% CI -1.9 to 9.7), or 3.6% of baseline body weight, more than those receiving a less intense or no physical activity intervention. Comparison groups often achieved significant weight loss (up to 10.0 kg), minimizing between-group differences. Changes in glycated hemoglobin generally corresponded to changes in weight and were not significant when between-group differences were examined. No data were identified on quality of life and mortality. AUTHORS CONCLUSIONS: Weight loss strategies using dietary, physical activity, or behavioral interventions produced small between-group improvements in weight. These results were minimized by weight loss in the comparison group, however, and examination of individual study arms revealed that multicomponent interventions including very low calorie diets or low calorie diets may hold promise for achieving weight loss in adults with type 2 diabetes. PMID- 27224284 TI - The role of probiotic bacteria in managing periodontal disease: a systematic review. AB - INTRODUCTION: The frequent recolonization of treated sites by periodontopathogens and the emergence of antibiotic resistance have led to a call for new therapeutic approaches for managing periodontal diseases. As probiotics are considered a new tool for combating infectious diseases, we systematically reviewed the evidences for their effectiveness in the management of periodontitis. AREAS COVERED: An electronic search was performed in the MEDLINE, SCOPUS and Cochrane Library databases up to March 2016 using the terms 'periodontitis', 'chronic periodontitis', 'probiotic(s)', 'prebiotic(s)', 'symbiotic(s)', 'Bifidobacterium and 'Lactobacillus'. Only randomized controlled trials (RCTs) were included in the present study. Analysis of 12 RCTs revealed that in general, oral administration of probiotics improved the recognized clinical signs of chronic and aggressive periodontitis such as probing pocket depth, bleeding on probing, and attachment loss, with a concomitant reduction in the levels of major periodontal pathogens. Continuous probiotic administration, laced mainly with Lactobacillus species, was necessary to maintain these benefits. Expert commentary: Oral administration of probiotics is a safe and effective adjunct to conventional mechanical treatment (scaling) in the management of periodontitis, specially the chronic disease entity. Their adjunctive use is likely to improve disease indices and reduce the need for antibiotics. PMID- 27224285 TI - Diastereoselective and Enantioselective Synthesis of Unsymmetric beta,beta-Diaryl alpha-Amino Acid Esters via Organocatalytic 1,6-Conjugate Addition of para Quinone Methides. AB - A novel strategy based on phase transfer catalysis for the diastereoselective and enantioselective direct assembly of unsymmetric beta,beta-diaryl-alpha-amino acid esters via 1,6-conjugate addition of para-quinone methides and glycine derivatives is described. This protocol also provides an alternative route to the synthetically interesting functionalized chiral tetrahydroisoquinoline and its analogues. PMID- 27224287 TI - A New Dicynodont (Therapsida: Anomodontia) from the Permian of Southern Brazil and Its Implications for Bidentalian Origins. AB - Dicynodonts were a highly successful group of herbivorous therapsids that inhabited terrestrial ecosystems from the Middle Permian through the end of the Triassic periods. Permian dicynodonts are extremely abundant in African deposits, but are comparatively poorly known from the other regions of Gondwana. Here we describe a new South American dicynodont, Rastodon procurvidens gen. et sp. nov., from the Boqueirao farm site of the Rio do Rasto Formation, Parana Basin, Guadalupian/Lopingian of Brazil. Diagnostic features of R. procurvidens include uniquely anteriorly-curved maxillary tusks, well-developed ridges extending from the crista oesophagea anteriorly along the pterygoid rami, strong posterior angulation of the posterior pterygoid rami, and a bulbous, well-developed retroarticular process of the articular. Phylogenetic analysis indicates that R. procurvidens is the earliest and most basal member of Bidentalia, a cosmopolitan clade that includes Permian and Triassic dicynodonts whose dentition is usually reduced to a pair of maxillary tusks. PMID- 27224286 TI - Involvement of TGF-beta1/Smad3 Signaling in Carbon Tetrachloride-Induced Acute Liver Injury in Mice. AB - Transforming growth factor-beta1 (TGF-beta1) is a major factor in pathogenesis of chronic hepatic injury. Carbon tetrachloride (CCl4) is a liver toxicant, and CCl4 induced liver injury in mouse is a classical animal model of chemical liver injury. However, it is still unclear whether TGF-beta1 is involved in the process of CCl4-induced acute chemical liver injury. The present study aimed to evaluate the role of TGF-beta1 and its signaling molecule Smad3 in the acute liver injury induce by CCl4. The results showed that CCl4 induced acute liver injury in mice effectively confirmed by H&E staining of liver tissues, and levels of not only liver injury markers serum ALT and AST, but also serum TGF-beta1 were elevated significantly in CCl4-treated mice, compared with the control mice treated with olive oil. Our data further revealed that TGF-beta1 levels in hepatic tissue homogenate increased significantly, and type II receptor of TGF-beta (TbetaRII) and signaling molecules Smad2, 3, mRNA expressions and Smad3 and phospho-Smad3 protein levels also increased obviously in livers of CCl4-treated mice. To clarify the effect of the elevated TGF-beta1/Smad3 signaling on CCl4-induced acute liver injury, Smad3 in mouse liver was overexpressed in vivo by tail vein injection of Smad3-expressing plasmids. Upon CCl4 treatment, Smad3-overexpressing mice showed more severe liver injury identified by H&E staining of liver tissues and higher serum ALT and AST levels. Simultaneously, we found that Smad3 overexpressing mice treated with CCl4 showed more macrophages and neutrophils infiltration in liver and inflammatory cytokines IL-1beta and IL-6 levels increment in serum when compared with those in control mice treated with CCl4. Moreover, the results showed that the apoptosis of hepatocytes increased significantly, and apoptosis-associated proteins Bax, cytochrome C and the cleaved caspase 3 expressions were up-regulated in CCl4-treated Smad3 overexpressing mice as well. These results suggested that TGF-beta1/Smad3 signaling was activated during CCl4-induced acute liver injury in mice, and Smad3 overexpression aggravated acute liver injury by promoting inflammatory cells infiltration, inflammatory cytokines release and hepatocytes apoptosis. In conclusion, the activation of TGF-beta signaling contributes to the CCl4-induced acute liver injury. Thus, TGF-beta1/Smad3 may serve as a potential target for acute liver injury therapy. PMID- 27224290 TI - Hospital Privileges. PMID- 27224289 TI - Geographic Distribution of Natural Products Produced by the Red Alga Laurencia dendroidea J. Agardh. AB - In order to evaluate the chemical diversity of Laurencia dendroidea J. Agardh, a widely distributed seaweed in Brazilian coast, a phytochemical study was carried out with algae collected from six different locations along the Southeast Brazilian coast. Purified compounds were identified by MS and NMR techniques. The chemical profiles of lipophilic extracts were obtained by GC/MS for each population. In total, 15 compounds were described. The sesquiterpene composition accounted for 49 - 63% of the GC/MS chromatogram area. The discrimination of three chemotypes was done by the use of HCA on GC/MS chromatograms. They were also analyzed by the PCA and, together with peak area analysis, it was possible to discriminate all populations by the main variation of elatol, obtusol, rogiolol, and triquinane. The results revealed the high diversity of sesquiterpene composition among populations of L. dendroidea. Curiously, the within and among population variation of elatol and obtusol suggested a biochemical interplay on the content of these compounds. More studies are necessary to understand the patterns of chemical diversity and compound variation within and among populations of L. dendroidea. PMID- 27224291 TI - Problems+Solutions. AB - Readers are invited to submit questions relating to problem cases. Inquiries will be answered by qualified consultants and replies forwarded by mail promptly. Selected problems and solutions are published every month in this section. PMID- 27224288 TI - 17-DMAG, an HSP90 Inhibitor, Ameliorates Multiple Organ Dysfunction Syndrome via Induction of HSP70 in Endotoxemic Rats. AB - Sepsis is a systemic inflammatory disorder, accompanied with elevated oxidative stress, leading to multiple organ dysfunction syndrome (MODS), and disseminated intravascular coagulation. 17-Dimethylaminoethylamino- 17-demethoxygeldanamycin (17-DMAG), a heat shock protein (HSP) 90 inhibitor, has been reported to possess anti-inflammatory effects. In this study, the beneficial effects of 17-DMAG on lipopolysaccharide (LPS) induced MODS and DIC was evaluated in anesthetized rats. 17-DMAG (5 mg/kg, i.p.) was significantly increased survival rate, and prevented hypotension in LPS (30 mg/kg i.v. infused for 4 h) induced endotoxemia. The elevated levels of alanine aminotransferase (ALT), creatine phosphokinase (CPK), lactate dehydrogenase, creatinine, nitric oxide (NO) metabolites, IL-6, and TNF alpha in LPS-exposed rat plasma were significantly reduced by 17-DMAG. Moreover, 17-DMAG suppressed LPS-induced superoxide anion production and caspase 3 activation in heart tissues. LPS induced the prolongation of prothrombin time, and a pronounced decrease in platelet count, which were improved by 17-DMAG. 17 DMAG markedly induced HSP70 and heme oxygenase (HO)-1, and suppressed inducible nitric oxide synthase (iNOS) and phosphorylated NF-kappaB p65 protein expression in organs 6 h after LPS initiation. Pretreatment with high dose of quercetin (300 mg/kg, i.p.), as an HSP70 inhibitor, reversed the beneficial effects of 17-DMAG on survival rate, plasma levels of ALT, CPK, creatinine, IL-6, and NO metabolites, iNOS induction, and caspase-3 activation in LPS-treated rats. In conclusion, 17-DMAG possesses the anti-inflammatory and antioxidant effects that were proved through LPS-induced acute inflammation, which is associated with induction of HSP70 and HO-1, leading to prevent MODS in sepsis. PMID- 27224292 TI - Editor's Mail. PMID- 27224294 TI - Gait and rotational problems in children. PMID- 27224293 TI - Musculoskeletal disorders in children. PMID- 27224296 TI - Outcomes From the NIH Clinical Research Training Program: A Mentored Research Experience to Enhance Career Development of Clinician-Scientists. AB - PURPOSE: Clinician-scientists are considered an endangered species for many reasons, including challenges with establishing and maintaining a career pipeline. Career outcomes from yearlong medical and dental students' research enrichment programs have not been well determined. Therefore, the authors assessed career and research outcome data from a cohort of participants in the National Institutes of Health (NIH) Clinical Research Training Program (CRTP). METHOD: The CRTP provided a yearlong mentored clinical or translational research opportunity for 340 medical and dental students. Of these, 135 completed their training, including fellowships, from 1997 to January 2014. Data for 130 of 135 were analyzed: time conducting research, types of public funding (NIH grants), and publications from self-reported surveys that were verified via the NIH Research Portfolio Online Reporting Tools Web site and PubMed. RESULTS: Nearly two-thirds (84 of 130) indicated that they were conducting research, and over half of the 84 (approximately one-third of the total cohort) spent more than 25% of time conducting research. Of those 84, over 25% received grant support from the NIH, and those further in their careers published more scholarly manuscripts. CONCLUSIONS: Data suggest that the CRTP helped foster the careers of research oriented medical and dental students as measured by time conducting research, successful competition for federal funding, and the publication of their research. Longer follow-up is warranted to assess the impact of these mentored research experiences. Investments in mentored research programs for health professional students are invaluable to support the dwindling pipeline of biomedical researchers and clinician-scientists. PMID- 27224297 TI - After the "Doc Fix": Implications of Medicare Physician Payment Reform for Academic Medicine. AB - The Medicare Access and CHIP Reauthorization Act (MACRA) introduces incentives for clinicians serving Medicare patients to move away from traditional "fee-for service" and into alternative payment models (APMs) such as accountable care organizations and bundled payment arrangements. Thus, MACRA creates strong reasons for various teaching clinical services to participate in APMs, not only for Medicare patients but for other public and private payers as well. Unfortunately, different APMs may be more or less applicable to the diverse teaching physician roles, academic clinical programs, and patient populations served by medical schools and teaching hospitals. Therefore, this time of transition will complicate the work of academic clinical program leaders endeavoring to sustain the tripartite mission of patient care, health professional education, and research. Nonetheless, payment reforms promoted by MACRA can reward efforts to reinvent medical education to better incorporate value into medical decision making, as well as to give clinical learners the tools and insights needed to recognize their personal financial (and other) conflicts and navigate these to meet their patients' needs. This post-MACRA environment may intensify the need for researchers in academic medicine to stay independent of the short-term financial interests of affiliated clinical institutions. Health sciences scholars must be able to study effectively and speak forcefully regarding the actual benefits, risks, and costs of health care services so that educators and clinicians can identify high-value care and deliver it to their patients. PMID- 27224298 TI - Responding to the Marketplace: Workforce Balance and Financial Risk at Academic Health Centers. AB - Elsewhere in this issue, Welch and Bindman present research demonstrating that academic health centers (AHCs) continue to disproportionately comprise specialists and subspecialist faculty physicians compared with community-based physician groups. This workforce composition has served AHCs well through the years-specialists fuel the clinical engine of the major tertiary and quaternary missions of AHCs, and they also dominate much of the clinical and translational research enterprise. AHCs are not alone-less than one-third of U.S. physicians practice primary care. However, health reform has prompted many health systems to reconsider this configuration. Payers, employers, and policy makers are shifting away from fee-for-service toward value-based care. Large community-based physician groups and their parent health systems appear to be far ahead of AHCs with a more balanced physician workforce. Many are leveraging their emphasis on primary care to participate in population health initiatives, such as accountable care organizations, and some own their own health plans. These approaches largely assume some element of financial risk and require both a more balanced workforce and an infrastructure to accommodate the management of covered lives. It remains to be seen whether AHCs will reconsider their own physician specialty composition to emphasize primary care-and, if they do, whether the traditional academic model, or a more community-based approach, will prevail. PMID- 27224299 TI - A Big Data and Learning Analytics Approach to Process-Level Feedback in Cognitive Simulations. AB - Collecting and analyzing large amounts of process data for the purposes of education can be considered a big data/learning analytics (BD/LA) approach to improving learning. However, in the education of health care professionals, the application of BD/LA is limited to date. The authors discuss the potential advantages of the BD/LA approach for the process of learning via cognitive simulations. Using the lens of a cognitive model of radiograph interpretation with four phases (orientation, searching/scanning, feature detection, and decision making), they reanalyzed process data from a cognitive simulation of pediatric ankle radiography where 46 practitioners from three expertise levels classified 234 cases online. To illustrate the big data component, they highlight the data available in a digital environment (time-stamped, click-level process data). Learning analytics were illustrated using algorithmic computer-enabled approaches to process-level feedback.For each phase, the authors were able to identify examples of potentially useful BD/LA measures. For orientation, the trackable behavior of re-reviewing the clinical history was associated with increased diagnostic accuracy. For searching/scanning, evidence of skipping views was associated with an increased false-negative rate. For feature detection, heat maps overlaid on the radiograph can provide a metacognitive visualization of common novice errors. For decision making, the measured influence of sequence effects can reflect susceptibility to bias, whereas computer-generated path maps can provide insights into learners' diagnostic strategies.In conclusion, the augmented collection and dynamic analysis of learning process data within a cognitive simulation can improve feedback and prompt more precise reflection on a novice clinician's skill development. PMID- 27224300 TI - Town and Gown Differences Among the 100 Largest Medical Groups in the United States. AB - PURPOSE: The authors undertook a study to determine whether large academic and community-based medical groups differ in terms of their financial stake in Medicare Advantage or Medicare Accountable Care Organizations (ACOs) and whether their participation in these alternative payment models is related to their size, specialty mix, and Medicare physician market share in their local area. METHOD: The authors used the 2013 Medicare Data on Provider Practice and Specialty database and a national database of ACOs to conduct a cross-sectional descriptive study of the 100 largest medical groups in the United States. Medical groups were categorized as academic or community based on matches of their name with a list of U.S. medical schools or the results of a series of Internet search procedures. RESULTS: Sixty-eight of the 100 largest groups were academic, and 32 were community based. On average, community-based groups had more than twice the percentage of primary care physicians as academic groups (mean, 38.4%; 95% CI, 34.7%-42.0%; vs. 18.3%; 95% CI, 17.0%-19.6%). Community groups were significantly (P < .001) more likely than academic groups to have a financial stake in a Medicare ACO or Medicare Advantage plan, but this difference was no longer significant when the percentage of primary care physicians in the group was added to the model. CONCLUSIONS: The specialty mix within academic medical groups may hinder their ability to transform themselves into organizations that can manage the financial responsibilities of caring for a patient population through a Medicare ACO or Medicare Advantage. PMID- 27224301 TI - Measuring Diversity of the National Institutes of Health-Funded Workforce. AB - PURPOSE: To measure diversity within the National Institutes of Health (NIH) funded workforce. The authors use a relevant labor market perspective to more directly understand what the NIH can influence in terms of enhancing diversity through NIH policies. METHOD: Using the relevant labor market (defined as persons with advanced degrees working as biomedical scientists in the United States) as the conceptual framework, and informed by accepted economic principles, the authors used the American Community Survey and NIH administrative data to calculate representation ratios of the NIH-funded biomedical workforce from 2008 to 2012 by race, ethnicity, sex, and citizenship status, and compared this against the pool of characteristic individuals in the potential labor market. RESULTS: In general, the U.S. population during this time period was an inaccurate comparison group for measuring diversity of the NIH-funded scientific workforce. Measuring accurately, we found the representation of women and traditionally underrepresented groups in NIH-supported postdoc fellowships and traineeships and mentored career development programs was greater than their representation in the relevant labor market. The same analysis found these demographic groups are less represented in the NIH-funded independent investigator pool. CONCLUSIONS: Although these findings provided a picture of the current NIH-funded workforce and a foundation for understanding the federal role in developing, maintaining, and renewing diverse scientific human resources, further study is needed to identify whether junior- and early-stage investigators who are part of more diverse cohorts will naturally transition into independent NIH-funded investigators, or whether they will leave the workforce before achieving independent researcher status. PMID- 27224302 TI - Bioconcentration of Dissolved Organic Compounds from Oil Sands Process-Affected Water by Medaka (Oryzias latipes): Importance of Partitioning to Phospholipids. AB - The complex mixture of dissolved organics in oil sands process-affected water (OSPW) is acutely lethal to fish at environmentally relevant concentrations, but few bioconcentration factors (BCFs) have been measured for its many chemical species. Japanese medaka (Oryzias latipes) were exposed to 10% OSPW, and measured BCFs were evaluated against predicted BCFs from octanol-water distribution ratios (DOW) and phospholipid membrane-water distribution ratios (DMW). Two heteroatomic chemical classes detected in positive ion mode (SO(+), NO(+)) and one in negative mode (O2(-), also known as naphthenic acids) had the greatest DMW values, as high as 10 000. Estimates of DMW were similar to and correlated with DOW for O(+), O2(+), SO(+), and NO(+) chemical species, but for O2(-) and SO2(-) species the DMW values were much greater than the corresponding DOW, suggesting the importance of electrostatic interactions for these ionizable organic acids. Only SO(+), NO(+), and O2(-) species were detectable in medaka exposed to OSPW, and BCFs for SO(+) and NO(+) species ranged from 0.6 to 28 L/kg, lower than predicted (i.e., 1.4-1.7 * 10(3) L/kg), possibly because of biotransformation of these hydrophobic substances. BCFs of O2(-) species ranged from 0.7 to 53 L/kg, similar to predicted values and indicating that phospholipid partitioning was an important bioconcentration mechanism. PMID- 27224304 TI - Investigation into the effects of high-Z nano materials in proton therapy. AB - High-Z nano materials have been previously shown to increase the amount of dose deposition within the tumour due to an increase in secondary electrons. This study evaluates the effects of high-Z nano materials in combination with protons, and the impact of proton energy, nanoparticle material and concentration. These effects were studied in silico through Monte Carlo simulation and experimentally through a phantom study, with particular attention to macroscale changes to the Bragg peak in the presence of nanoparticles. Three nanoparticle materials were simulated (gold, silver and platinum) at three concentrations (0.01, 0.1 and 6.5 mg ml(-1)) at two clinical proton energies (60 and 226 MeV). Simulations were verified experimentally using Gafchromic film measurements of gold nanoparticles suspended in water at two available high concentrations (5.5 mg ml(-1) and 1.1 mg ml(-1)). A significant change to Bragg peak features was evident, where at 226 MeV and 6.5 mg ml(-1), simulations of gold showed a 4.7 mm longitudinal shift of the distal edge and experimentally at 5.5 mg ml(-1), a shift of 2.2 mm. Simulations showed this effect to be material dependent, where platinum having the highest physical density caused the greatest shift with increasing concentration. A dose enhancement of 6% +/- 0.05 and 5% +/- 0.15 (60 MeV and 226 MeV, respectively) was evident with gold at 6.5 mg ml(-1) to water alone, compared to the 21% +/- 0.53 observed experimentally as dose to film with 5.5 mg ml(-1) of gold nanoparticles suspended in water at 226 MeV. The introduction of nanoparticles has strong potential to enhance dose in proton therapy, however the changes to the Bragg peak distribution that occur with high concentrations need to be accounted for to ensure tumour coverage. PMID- 27224303 TI - Upregulation of Glutaredoxin-1 Activates Microglia and Promotes Neurodegeneration: Implications for Parkinson's Disease. AB - AIMS: Neuroinflammation and redox dysfunction are recognized factors in Parkinson's disease (PD) pathogenesis, and diabetes is implicated as a potentially predisposing condition. Remarkably, upregulation of glutaredoxin-1 (Grx1) is implicated in regulation of inflammatory responses in various disease contexts, including diabetes. In this study, we investigated the potential impact of Grx1 upregulation in the central nervous system on dopaminergic (DA) viability. RESULTS: Increased GLRX copy number in PD patients was associated with earlier PD onset, and Grx1 levels correlated with levels of proinflammatory tumor necrosis factor-alpha (TNF-alpha) in mouse and human brain samples, prompting mechanistic in vitro studies. Grx1 content/activity in microglia was upregulated by lipopolysaccharide (LPS), or TNF-alpha, treatment. Adenoviral overexpression of Grx1, matching the extent of induction by LPS, increased microglial activation; Grx1 silencing diminished activation. Selective inhibitors/probes of nuclear factor kappaB (NF-kappaB) activation revealed glrx1 induction to be mediated by the Nurr1/NF-kappaB axis. Upregulation of Grx1 in microglia corresponded to increased death of neuronal cells in coculture. With a mouse diabetes model of diet-induced insulin resistance, we found upregulation of Grx1 in brain was associated with DA loss (decreased tyrosine hydroxylase [TH]; diminished TH-positive striatal axonal terminals); these effects were not seen with Grx1-knockout mice. INNOVATION: Our results indicate that Grx1 upregulation promotes neuroinflammation and consequent neuronal cell death in vitro, and synergizes with proinflammatory insults to promote DA loss in vivo. Our findings also suggest a genetic link between elevated Grx1 and PD development. CONCLUSION: In vitro and in vivo data suggest Grx1 upregulation promotes neurotoxic neuroinflammation, potentially contributing to PD. Antioxid. Redox Signal. 25, 967-982. PMID- 27224305 TI - Brooding rumination and attentional biases in currently non-depressed individuals: an eye-tracking study. AB - Both rumination and attentional biases have been proposed as key components of the RDoC Negative Valence Systems construct of Loss. Although theorists have proposed that rumination, particularly brooding rumination, should be associated with increased sustained attention to depression-relevant information, it is not clear whether this link would be observed in a non-depressed sample or whether it is specific to brooding versus reflective rumination. To address these questions, the current study examined the link between brooding rumination and attentional biases in a sample of non-depressed individuals (n = 105). Attentional biases were assessed using eye tracking during a passive viewing task in which participants were presented with 2 * 2 arrays of angry, happy, sad, and neutral faces. In line with predictions, higher levels of brooding rumination were associated with greater sustained attention to sad faces and less sustained attention to happy faces. These results remained significant after controlling for participants' prior history of major depression and current nonclinical level of depressive symptoms, suggesting that the link between brooding rumination and attentional biases is at least partially independent of current or past depression. PMID- 27224306 TI - Comparison of Three Efficient Approximate Exact-Exchange Algorithms: The Chain-of Spheres Algorithm, Pair-Atomic Resolution-of-the-Identity Method, and Auxiliary Density Matrix Method. AB - We compare the performance of three approximate methods for speeding up evaluation of the exchange contribution in Hartree-Fock and hybrid Kohn-Sham calculations: the chain-of-spheres algorithm (COSX; Neese , F. Chem. Phys. 2008 , 356 , 98 - 109 ), the pair-atomic resolution-of-identity method (PARI-K; Merlot , P. J. Comput. Chem. 2013 , 34 , 1486 - 1496 ), and the auxiliary density matrix method (ADMM; Guidon , M. J. Chem. Theory Comput. 2010 , 6 , 2348 - 2364 ). Both the efficiency relative to that of a conventional linear-scaling algorithm and the accuracy of total, atomization, and orbital energies are compared for a subset containing 25 of the 200 molecules in the Rx200 set using double-, triple , and quadruple-zeta basis sets. The accuracy of relative energies is further compared for small alkane conformers (ACONF test set) and Diels-Alder reactions (DARC test set). Overall, we find that the COSX method provides good accuracy for orbital energies as well as total and relative energies, and the method delivers a satisfactory speedup. The PARI-K and in particular ADMM algorithms require further development and optimization to fully exploit their indisputable potential. PMID- 27224307 TI - Hydrogenation Driven Conductive Na2Ti3O7 Nanoarrays as Robust Binder-Free Anodes for Sodium-Ion Batteries. AB - We present a general and rational approach to fabricate highly accessible and affordable sodium-ion battery anodes by engineering three-dimensional hydrogenated Na2Ti3O7 nanoarrays supported on flexible Ti substrates. The hydrogenated Na2Ti3O7 nanoarrays exhibit desirable properties for sodium storage, such as high surface area, high electrical conductivity, and Na(+) diffusivity. The as-obtained nanoarrays demonstrate remarkably stable and robust Na-storage performance when tested as binder-free anodes for sodium-ion battery. They can afford a high reversible (desodiation) capacity of 227 mAh g(-1) and retain a capacity of 65 mAh g(-1) over 10,000 continuous cycles at a high rate of 35 C. Therefore, through this synergy of array architecture and hydrogenation, it is possible to engineer numerous anodes that can reversibly store Na(+) ions in a fast and stable manner. PMID- 27224308 TI - A Sensitive and Automatic White Matter Fiber Tracts Model for Longitudinal Analysis of Diffusion Tensor Images in Multiple Sclerosis. AB - Diffusion tensor imaging (DTI) is a sensitive tool for the assessment of microstructural alterations in brain white matter (WM). We propose a new processing technique to detect, local and global longitudinal changes of diffusivity metrics, in homologous regions along WM fiber-bundles. To this end, a reliable and automatic processing pipeline was developed in three steps: 1) co registration and diffusion metrics computation, 2) tractography, bundle extraction and processing, and 3) longitudinal fiber-bundle analysis. The last step was based on an original Gaussian mixture model providing a fine analysis of fiber-bundle cross-sections, and allowing a sensitive detection of longitudinal changes along fibers. This method was tested on simulated and clinical data. High levels of F-Measure were obtained on simulated data. Experiments on cortico spinal tract and inferior fronto-occipital fasciculi of five patients with Multiple Sclerosis (MS) included in a weekly follow-up protocol highlighted the greater sensitivity of this fiber scale approach to detect small longitudinal alterations. PMID- 27224310 TI - Fat embolism showing restriction on diffusion sequence in brain magnetic resonance imaging. PMID- 27224309 TI - Cholesterol-Dependent Phase-Demixing in Lipid Bilayers as a Switch for the Activity of the Phosphoinositide-Binding Cytoskeletal Protein Gelsolin. AB - The lateral distribution of phosphatidylinositol 4,5-bisphosphate (PIP2) in lipid bilayers is affected both by divalent cation-mediated attractions and cholesterol dependent phase demixing. The effects of lateral redistribution of PIP2 within a membrane on PIP2-protein interactions are explored with an N-terminal fragment of gelsolin (NtGSN) that severs actin in a Ca(2+)-insensitive manner. The extent of NtGSN inhibition by PIP2-containing large unilamellar vesicles (LUVs) depends on the lateral organization of the membrane as quantified by an actin-severing assay. At a fixed PIP2 mole fraction, the inhibition is largely enhanced by the segregation of liquid ordered/liquid disordered (Lo/Ld) phases that is induced by altering either cholesterol content or temperature, whereas the presence of Ca(2+) only slightly improves the inhibition. Inhibition of gelsolin induced by demixed LUVs is more effective with decreasing temperature, coincident with increasing membrane order as determined by Laurdan generalized polarization and is reversible as the temperature increases. This result suggests that PIP2 mediated inhibition of gelsolin function depends not only on changes in global concentration but also on lateral distribution of PIP2. These observations imply that gelsolin, and perhaps other PIP2-regulated proteins, can be activated or inactivated by the formation of nanodomains or clusters without changing PIP2 bulk concentration in the cell membrane. PMID- 27224311 TI - Validity and reliability evidence of the questionnaire for illness representation, the impact of epilepsy, and stigma (QIRIS). AB - The objective of this study was to obtain reliability and validity evidence for the questionnaire of illness representation, the impact of epilepsy, and stigma (QIRIS) for use with adolescents and adults in Brazil. QIRIS consists of 14 questions grouped in three domains (attribution of meaning, impact of disease, and stigma) and was applied to 57 adults with epilepsy. QIRIS internal consistency was satisfactory (Cronbach's alpha = 0. 866). Significant and strong correlation was found between issues belonging to the same domain, as expected. Three domains have highly significant and positive correlations with the instrument's total score, indicating evidence of content validity. We conclude that QIRIS has psychometric properties and can facilitate a systematic evaluation of the patient's representation according to a biopsychosocial approach that may contribute to clinical practice based on scientific evidence. PMID- 27224312 TI - Hoarding disorder secondary to pituitary adenoma: a case study. PMID- 27224313 TI - Collateral blood vessels in acute ischemic stroke: a physiological window to predict future outcomes. AB - Collateral circulation is a physiologic pathway that protects the brain against ischemic injury and can potentially bypass the effect of a blocked artery, thereby influencing ischemic lesion size and growth. Several recent stroke trials have provided information about the role of collaterals in stroke pathophysiology, and collateral perfusion has been recognized to influence arterial recanalization, reperfusion, hemorrhagic transformation, and neurological outcomes after stroke. Our current aim is to summarize the anatomy and physiology of the collateral circulation and to present and discuss a comprehensible review of the related knowledge, particularly the effects of collateral circulation on the time course of ischemic injury and stroke severity, as well as imaging findings and therapeutic implications. PMID- 27224316 TI - Cold comfort in NHS winter. AB - No matter how smoothly Goverment may insist that all that can be I done is being done in funding I health care and supporting the NHS, no matter what percentages are circulated to prove that financial allocation and commitment is rising - services continue to be curtailed. PMID- 27224317 TI - Fighting hypothermia. AB - Hypothermia is a complex [Illegible word] with far-reaching effects, even following appropriate management, delegates at a conference organised by the Royal Society of Health heard. PMID- 27224314 TI - Comparison between DNA Detection in Trigeminal Nerve Ganglia and Serology to Detect Cattle Infected with Bovine Herpesviruses Types 1 and 5. AB - Bovine herpesviruses (BoHVs) types 1 (BoHV-1) and 5 (BoHV-5) are alphaherpesviruses of major importance to the bovine production chain. Such viruses are capable of establishing latent infections in neuronal tissues. Infected animals tend to develop a serological response to infection; however, such response-usually investigated by antibody assays in serum-may eventually not be detected in laboratory assays. Nevertheless, serological tests such as virus neutralization (VN) and various enzyme-linked immunosorbent assays (ELISAs) are widely employed to check individual or herd status of BoHV infections. The correlation between detection of antibodies and the presence of viral nucleic acids as indicatives of infection in infected cattle has not been deeply examined. In order to investigate such correlation, 248 bovine serum samples were tested by VN to BoHV-1 and BoHV-5, as well as in a widely employed (though not type-differential) gB ELISA (IDEXX IBR gB X2 Ab Test) in search for antibodies to BoHVs. Immediately after blood withdrawal, cattle were slaughtered and trigeminal ganglia (TG) excised for DNA extraction and viral nucleic acid detection (NAD) by nested PCR. Neutralizing antibodies to BoHV-1 and/or BoHV-5 were detected in 44.8% (111/248) of sera, whereas the gB ELISA detected antibodies in 51.2% (127/248) of the samples. However, genomes of either BoHV-1, BoHV-5, or both, were detected in TGs of 85.9% (213/248) of the animals. These findings reveal that the assays designed to detect antibodies to BoHV-1 and/or BoHV-5 employed here may fail to detect a significant number of latently infected animals (in this study, 35.7%). From such data, it is clear that antibody assays are poorly correlated with detection of viral genomes in BoHV-1 and BoHV-5-infected animals. PMID- 27224315 TI - Time Course of MERS-CoV Infection and Immunity in Dromedary Camels. AB - Knowledge about immunity to Middle East respiratory syndrome coronavirus (MERS CoV) in dromedary camels is essential for infection control and vaccination. A longitudinal study of 11 dam-calf pairs showed that calves lose maternal MERS-CoV antibodies 5-6 months postparturition and are left susceptible to infection, indicating a short window of opportunity for vaccination. PMID- 27224319 TI - Antenatal advances. AB - Antenatal care is gradually becoming more flexible and geared to individual needs, but there is still a long way to go, delegates at a conference on the relevance of antenatal care heard recently. PMID- 27224320 TI - Movement of patients criticised. AB - Fears that the quality of nurse teaching is being affected by the increasing movement of patients between wards were expressed at the English National Board for Nursing, Midwifery and Health Visiting meeting last week. PMID- 27224321 TI - Asian campaign success. AB - Despite initial setbacks, the Asian Mother and Baby Campaign has been proclaimed a success, according to its recent evaluation, with many health authorities now permanently appointing Asian link workers and others expressing interest in the scheme. PMID- 27224322 TI - Occupational health dilemma. AB - Should MRSA (multi resistant staphylococcus glococcus) be vigorously hunted down or ignored? The dilemma was aired recently at a study day held by the Royal College of Nursing's Forum for Occupational Health Nurses in the National Health Service. PMID- 27224323 TI - Implant gives easier vein access. AB - Cystic Fibrosis patients who have the intravenous system 'Port-a-Cath' implanted have easy access to large veins with a reduced risk of infection, according to Fran Duncan, Clinical Nurse Specialist at the Brompton Hospital, speaking at a seminar for CF nurses last week. The device is implanted in the chest wall of the patient and has an 11.4mm diameter membrane throuigh which drugs can be injected. PMID- 27224324 TI - Research awards. AB - Twelve research projects looking into the nursing care of people with HIV in the community are now underway following awards given out last month. The areas to be covered include the problem of dementia in HIV positive people, the cost effectiveness of community care and counselling support systems for drug users, pregnant women, families and carers. PMID- 27224325 TI - New patient assessment method. AB - Individual Patient Profiles is a new form of patient assessment that may take over from the nursing process as the way to plan nursing care. PMID- 27224326 TI - Adapting to stoma care. AB - People recovering from bowel surgery do not necessarily adapt more quickly to having a stoma just because they have access to a stoma care nurse, according to new research. PMID- 27224327 TI - Surgery awareness. AB - Research suggests that one per cent of patients have some degree of awareness during surgery. PMID- 27224328 TI - Not enough painful reports. AB - Nurses documented significantly less than 50 per cent of the pain their patients described, according to an American study of medical, surgical and oncolgy patients. PMID- 27224329 TI - Students prefer cheerful patients. AB - Nursing students prefer caring for patients who are cheerful and communicative, according to new research in the United States. PMID- 27224330 TI - Cot deaths research. AB - New research into cot deaths has revived the theory that poor air circulation in solid sided carry cots, particularly in a badly ventilated room, may be to blame. PMID- 27224331 TI - 'Yuppie' Nurses. AB - The 'Filofax' revolution has finally hit nursing. PMID- 27224332 TI - Specialists one year course. AB - Enrolled nurses working in specialist fields will be able to carry their qualifications through to first level via the ordinary 52 week conversion course, the English National Board for Nursing, Midwifery and Health Visiting has recently decided. PMID- 27224333 TI - Decision to access. AB - The Home Office is to ensure that nurses are involved in deciding whether patient's records should be restricted under the Data Protection Act, despite fears to the contrary. PMID- 27224334 TI - Poor standards. AB - Paediatric intensive care is suffering from years of bad planning, with little provision made for the needs of children, inadequate funding, and chronic difficulties in recruiting and retaining nurses. Speaking at a confer ence of the Royal College of Nursing Society of Paediatric Nursing, Sally Nethercott, Senior Nurse in Paediatrics at Guy's Hospital, said that of the 6,000 children needing intensive care each year, a third were nursed in adult units. PMID- 27224335 TI - Health service is under strain. AB - The health service is 'cracking under the strain of the fiction that it can treat all t he ailments of everybody,' said Trevor Clay, General Secretary of the Royal College of Nursing, last week. PMID- 27224337 TI - Not all doom and gloom. AB - Private nurse agency managers were last week told they were being 'too gloomy' when they said the Project 2000 reforms would create only nurse academics and be too expensive. PMID- 27224336 TI - Nurses on the march. AB - Nurses from several London hospitals took to the streets last Friday, marching in protest at the effects of financial cuts on patient care in the capital. PMID- 27224339 TI - Pub hours concern. AB - Accident and Emergency nurses have reacted with dismay to Government, moves to extend pub licensing hours. PMID- 27224340 TI - Nurse sues for back injury. AB - A nurse who ended up a patient herself after trying to prevent an elderly woman having a fall, told an Old Bailey court, she had not received proper training in lifting heavy patients. PMID- 27224341 TI - Mental issue investigated. AB - Allegations that large numbers of black patients are being wrongly held in mental institutions are being investigated by the Government. PMID- 27224342 TI - Musical therapy. AB - Music and drama sessions for severely mentally handicapped people should be expanded because of their therapeutic effect, according to Jimmy Bond, Senior Nurse Manager at St Ebba's Hospital in Epsom, Surrey where patients are having to pay for their own sessions . PMID- 27224343 TI - Access to personal information. AB - MP Archy Kirkwood has pledged to continue the fight to make non-computerised personal records available to patients. PMID- 27224344 TI - Mental handicap nurses' key role. AB - General managers would ignore the contribution of community mental handicap nurses at their peril and should ensure they use nursing skills fully, said Tony Thompson, Education Officer with the English National Board speaking at a conference in York. PMID- 27224345 TI - Ensure true equality. AB - Health authority officials 'right at the top' should be going out into the community to find out what black and ethnic minority people want from health services, according to Veena Bahl, the Department of Health and Social Security's Advisor on Ethnic Minority Health. PMID- 27224346 TI - Future of education in danger. AB - The future of nurse education could be at risk if the English National Board for Nursing, Midwifery and Health Visiting is denied funds to make up an estimated L2.8 million shortfall next year. PMID- 27224347 TI - Response praised. AB - A terrorist bomb which killed 11 people at a Remembrance Day service in Northern Ireland last week also claimed the lives of three nurses. PMID- 27224348 TI - Residential care homes row. AB - Encouraging patients in the community to live in their own home supported by local authorities denies freedom of choice and would not save money, says the Independent Hospitals Association in evidence to Sir Roy Griffiths review of community care. PMID- 27224349 TI - Mobile screening units called for. AB - More mobile cervical cancer screening units have been called for by the National Federation of Women's Institutes, which is concerned that HAs will not meet the March 1988 Govern ment deadline for computerised call and recall systems. PMID- 27224350 TI - New directory. AB - A directory of acute hospital facilities in the private sector has been compiled by the health insurance group BUPA and will be distributed to over 800 managers in NHS hospitals. PMID- 27224352 TI - Staff shortages are now desperate. AB - The staffing crisis in Scotland's psychiatric and mental illness hospitals was brought forcibly into the spotlight last week when the Mental Welfare Commission for Scotland broke with tradition to issue a public statement criticising conditions in hospitals throughout the country. PMID- 27224351 TI - Theatre travel. AB - A L4,000 travel scholarship is being offered to theatre nurses anywhere in the UK by the Smith and Nephew Foundation. PMID- 27224353 TI - Hoping for mild winter. AB - The statement from an Age Concern spokesman that 'all we can do is to pray we have a mild winter' sums up the knife-edge position faced by many health authorities as they approach the winter period, traditionally a time which sees many elderly deaths from hypothermia. PMID- 27224354 TI - General secretary calls for minimum salary. AB - RCN General Secretary, Trevor Clay, has called for all newly qualified nursing staff to be paid a minimum of L10,000 a year as soon as possible. Speaking at the opening of the College's new South East Thames regional office, Mr Clay emphasised the need to encourage people to move into and remain in the NHS, particularly in such a high cost area. PMID- 27224356 TI - Retiring ruth. AB - Ruth Stewart, Training Officer at the RCN Scottish Board will officially retire at the end of this month, after more than 26 years as a member of the College staff. PMID- 27224355 TI - Mental illness forum ratifies constitution. AB - Focus, the RCN Forum for nurses caring for the elderly mentally ill, ratified its draft constitution last week at a joint RCN Geriatric and Psychiatric Societies conference. Chairman, Les Hardy, Nursing Services Manager (Elderly Services), at Prestwich Hospital in Manchester, said Focus would concentrate on preparing guidelines on the use of restraint on the elderly mentally ill. PMID- 27224357 TI - Papers invited for research conference. AB - Nurse researchers are invited to submit abstracts of papers for presentation at next year's RCN Research Society national conference in Northern Ireland. Abstracts are invited on the conference theme 'To build anew with nursing research' - including issues such as innovations in research design and evaluation, utilisation and teaching of nursing research. PMID- 27224358 TI - Mature nurses help scottish manpower. AB - Hospitals in the Greater Glasgow area see mature nurses as the solution to their future manpower problem. PMID- 27224359 TI - Self preservation for surrey nurses. AB - Self-defence may be a last resort in dealing with violent patients, but many staff like district nurse, Hilary Freeman, now feel they need self-preservation skills at work. PMID- 27224360 TI - Bath nurses get royal awards for dedication. AB - Two Bath nurses have been presented with special awards for their dedication and commitment to their work with the terminally ill. PMID- 27224361 TI - Better education for yorkshire practice nurses. AB - A year long project, backed by the Manpower Services Commission, which aims to provide better education for practice nurses is now nearing completion. PMID- 27224362 TI - Appraisal system developed at hove. AB - The best staff appraisal techniques are simple and easy to understand according to Jacqueline Filkins, Hospital Manager at the Hove General Hospital. PMID- 27224363 TI - Threatened dispute at norwich hospital. AB - Nurses at a mental handicap hospital in Norwich are threatening to go into dispute over plans to appoint staff who are not nurses to patient care manager posts. PMID- 27224364 TI - Decline in london services for the elderly. AB - There has been a marked decline in the provision of caring services for elderly, mentally ill and mentally handicapped people in recent years, according to research carried out in London. PMID- 27224366 TI - Parliament vigil for lambeth nurses. AB - Nurses at St Thomas' Hospital are continuing their campaign against the closure of 137beds, with a week-long vigil outside the Houses of Parliament. Working in shifts of three, nurses stood in Parliament Square each day from 10am until midnight to draw attention to their concern over patient care. PMID- 27224365 TI - Welsh office takes the initiative. AB - The Welsh Office has approved six new projects under its Elderly Initiative Grant Scheme, launched in January this year. PMID- 27224367 TI - Birmingham appeal. AB - An appeal by Birmingham's Queen Elizabeth Hospital for funds to buy equipment for the treatment of burn injuries has received a boost from staff at the nearby private Priory Hospital. PMID- 27224368 TI - Brentwood brochure. AB - Barking, Havering and Brentwood Health Authority has launched a new initiative to help recruit staff into mental handicap services, in the form an information brochure written by professionals in the district. PMID- 27224369 TI - Watchdog. AB - Q I am an Enrolled Nurse/General (EN/G), qualified a year and a half ago and interested in furthering my career. Is there a shortened course for Registered General Nurse (RGN) training - if so to whom do I write initially for details? PMID- 27224370 TI - Directions: Gynaecological nursing. AB - With women's health care a major theme today, the logical view is to look at those who plan, give and evaluate that care and the type and amount of training required to do so. PMID- 27224371 TI - Bitter pills. AB - However long they've been qualified, nurses can usually recite without hesitation the ground rules about drug administration which were hammered home at the outset of their training. The right dosage of the right drug to the right patient at the right time by the right route at the right frequency. If these principles are adhered to by the letter, it's difficult to see how errors can be made. PMID- 27224372 TI - PMS - pre- nenstrual syndrome. AB - The bad news... PMS is controversial. Even today, many doctors - and nurses - dismiss women's complaints as neurotic or exaggerated. Many others fail to consider PMS as a likely cause of puzzling problems in female patients (and their families). PMID- 27224373 TI - Nursing by degrees. AB - What's the point of a degree in nursing? Nursing graduates themselves are apparently in no doubt as to its benefits, although the gap between their ideals and reality can be wide. Their non-graduate peers, however, often remain to be convinced. PMID- 27224374 TI - Given the choice . . . AB - Around 25,000 women a year in this country discover that they have breast cancer. For any woman, the news is devastating and it takes a lot of courage to make the knowledge public. People are still embarrassed by cancer and coping with the sympathy of relatives and friends can be very hard to handle when you're at an emotional low. PMID- 27224375 TI - Know your midwife. AB - Deep in the heart of the Rhondda Valley in South Wales, a team of six midwives is involved in a pioneering pilot study which aims to improve community midwifery services. PMID- 27224377 TI - New homes for old. AB - When Social Services Secretary John Moore delivered his speech to the Conservative Party Conference in Blackpool last month, it contained hints that nurses homes could be a suitable target for greater NHS privatisation. PMID- 27224376 TI - Avoiding Major Surgery. AB - Nurses in the Cardiac Department at King's College Hospital in London have been closely involved in the development of a new procedure for elderly patients severely disabled by aortic valve stenosis but too frail to undergo the rigours of major heart surgery. PMID- 27224378 TI - Extending good health. AB - To move is to live' - that is the message preached by Penny Copple, who founded EXTEND, the charity which trains nurses to help put elderly people back on their feet. And it is a message which comes straight from the heart. For Penny, a former nurse, has personally experienced the healing powers of exercise and movement. PMID- 27224379 TI - Morning after pill curbed by act. AB - The pro Life lobby of MPs in the House of Commons - who are currently making concerted efforts to amend Britain's abortion laws - have received assurances that the controversial 'morning after pill' will not be sold over chemist's counters. PMID- 27224380 TI - NHS savings probed over standards. AB - Chief Executive of the National Health Service Management Board, Len Peach, has been grilled about suggestions that increased savings to the NHS in England through competitive tendering of domestic services were at least partly due to reduced standards. PMID- 27224381 TI - Exemptions from trade union law. AB - The General Secretaries of the Royal College of Nursing, Royal College of Midwives, British Medical Association and other royal medical colleges will be exempt from provisions under new trade union law which would have required them to be elected to office. PMID- 27224382 TI - New moves on community nursing. AB - Major advances in the status of community nurses planned by the Government were expected to be released this week. PMID- 27224383 TI - Agency nurses cheaper than NHS staff. AB - Health Minister Tony Newton has now admitted to MPs that using agency nurses can sometimes be up to 12 per cent cheaper than National Health Service nurses. PMID- 27224389 TI - Cap in hand. AB - How good to read in your Diary column that Nurse Managers are at last listening to nurses. I refer to the Hartlepool decision to restore the use of nurses' caps. We younger nurses not only want a challenging i research-based profession respected by our colleagues, but we also want to keep the traditional aspects of nursing. To most of us that tradition is found not only in providing the highest standards of care but also in the appearance of uniforms. PMID- 27224390 TI - Team spirit. AB - I note with interest the clinical feature - 'Keeping in touch' (week ending October 31) - especially the way the ODA featured therein and because of this I would be grateful for the opportunity to respond on behalf of ODAs. PMID- 27224391 TI - Conference congratulations. AB - Having attended the RCN conference 'In Pursuit of Excellence', I must congratulate the College conference and exhibition organisers for their efforts and Shelagh Murphy in particular for her warm assistance. I attended the conference having won a Royal National Pension Fund For Nurses place. PMID- 27224392 TI - Ensure staff well being. AB - I have recently read the report in Nursing Standard (week ending September 19) of the death of my daughter Elizabeth. PMID- 27224393 TI - Working mother. AB - I read with great interest your articles on 'Back To Nursing' regarding working mothers and the nursing profession. PMID- 27224394 TI - Rape victims. AB - In Nursing Standard (week ending November 7) Police Chief Medical Officer, David McLay is quoted as saying that hospitals are not the ideal place for the examination of rape victims. I assume therefore that he is advocating examination on police premises. PMID- 27224395 TI - Cornerstones. AB - It was with some wonderment and an element of surprise that I read in your Editorial that the RCN has defined the cornerstones of nursing as equity, respect for persons caring (week ending November 7). PMID- 27224396 TI - Missing the point. AB - Concerning the feature 'Abortion - What limit' (Nursing Standard week ending October 31). PMID- 27224397 TI - Strange return. AB - When I stepped back onto a ward for the first time after ten years of bringing up my three children I was lucky that I had been able to attend a three week 'Back To Nursing Course'. PMID- 27224398 TI - Familiar Story. AB - Does this ring any bells? 'Many now complain that after five years' training they enter a profession with no clear career structure... the service cannot cope with the demands now being made on it... it is becoming impossible to keep up our high standards under increasing pressure... the number of cases has increased although the number of staff has stayed the same... the service tends to be taken for granted...' PMID- 27224399 TI - Bold age. AB - The debate about epidurals has long raged in midwifery circles. But now the question is being tackled in research which should help to point the way for future practice. PMID- 27224400 TI - Prize-winning conference. AB - Anyone who's been involved in organising a conference will know what a stressful and expensive - business it can be. PMID- 27224401 TI - Play it again, archy. AB - Children sometimes get hold of the wrong end of the stick - as Liberal MP Archy Kirkwood recently discovered. PMID- 27224402 TI - Obscuring the standard. AB - We've heard a lot recently about 'standards of nursing care'. Standards in stoma care nursing, renal nursing, oncology nursing - there is no limit to the specialities where standards can be set (sorry - talked about, planned, implemented and evaluated). PMID- 27224403 TI - Australia. AB - Nurses working in the Australian outback of the Northern Territory are being urged to fight government cutbacks which will erode their pay, lead to mass resignations and shortages, lower standards and discourage interstate nurses from the area. PMID- 27224404 TI - New zealand. AB - Senior nurses in New Zealand have been advised not to complete a questionnaire distributed to all hospital boards by the country's taskforce which is reviewing hospital and related services. PMID- 27224405 TI - Fiji. AB - Training rural based primary health care nurses in emergency and simple eye care has resulted in a two fold increase in the number of patients receiving cataract treatment in Fiji. PMID- 27224406 TI - Brazil. AB - The city of Sao Paulo in Brazil will host the first Interamerican Symposium on Qualitative Nursing Research next February, which will provide a forum to promote the development of qualitative nursing research. PMID- 27224407 TI - United states. AB - The growing shortage of nurses, a shortage of funds and greater emphasis on primary care in the United States could lead to major cuts in the acute sector. PMID- 27224408 TI - Nursing back to nature. AB - Twenty acres of farmland on windswept and treacherous Teesdale in County Durham may not sound like everyone's idea of bliss - especially when the gales are howling and the snow is beating down. PMID- 27224409 TI - Professional advisory machinery. AB - For too long, nursing has been grieving for Griffiths. This is most clearly seen among that group of staff who saw their budgets disappear, if there were five noughts or more on the end of it. What seems to be slow in coming is the adjustment, rehabilitation and development of a new role which incorporates the change. PMID- 27224410 TI - Listings. AB - Nursing Standard's listings section is a completely free service for its readers. To ensure maximum publicity for any event connected with your profession be sure to let us know so that it can be included in our exhaustive nationwide guide to what's on in nursing. PMID- 27224412 TI - Automatic sterilising ovens. AB - The range of standard automatic sterilising ovens manufactured by R E Pickstone Ltd has been updated and now incorporates four models from 40 to 220 litre capacity with maximum temperatures of 200 degrees Centigrade. PMID- 27224411 TI - Computing a patient form. AB - A new computer form is being used at Milton Keynes General Hospital to process admission and diagnostic procedures in the Accident and Emergency Department. PMID- 27224413 TI - Dressings dispenser. AB - A wall dispenser unit for 3M's new Medipore range of pre-cut surgical dressings is now available. PMID- 27224414 TI - Designer bedpans. AB - A new bedpan for women has been produced and designed, its manufacturers say, 'to overcome the limitations of existing female urinals'. The Lorann Female Bed- pan has an adjustable base to suit different body sizes, and a flexible perineal seal to provide a leak proof contact. Further information' from Medical Resupply UK Ltd, Homewoodgate House, Nov- ington Lane, East Chiltington, Lewes, Sussex, BN7 3AU. PMID- 27224416 TI - Hyper active. PMID- 27224415 TI - Sterile version of leg bag. AB - A sterile version of the Conveen Contoured Leg Bag has been launched by Coloplast, to be used with indwelling catheters. Urine collects evenly in 10 channels, so the bag moulds to the shape of the thigh or calf as it fills. The channels also ensure that there is no noise from the bag as it fills or as the user moves around. The bag has a nonwoven fabric backing which absorbs perspiration. PMID- 27224417 TI - Mortality Risk Associated With Resistant Hypertension Among Women: Analysis from Three Prospective Cohorts Encompassing the Spectrum of Women's Heart Disease. AB - BACKGROUND: Women are at greater risk of developing resistant hypertension (RH) than men, yet scarce data exist on RH-associated outcomes in women. We aimed to determine all-cause mortality risk associated with apparent RH (aRH) among women across the spectrum of underlying coronary disease. MATERIALS AND METHODS: We analyzed data from St. James Women Take Heart (WTH; women without coronary disease at baseline), Women's Ischemia Syndrome Evaluation (women with signs/symptoms of ischemia at baseline), and the INternational VErapamil Trandolapril STudy (INVEST; women with coronary artery disease and hypertension at baseline), totaling 15,108 adult women with no hypertension, non-RH (blood pressure [BP] >=140/90 mmHg on <=2 drugs or BP <140/90 mmHg on 1-3 drugs), or aRH (BP >=140/90 mmHg on >=3 drugs or anyone on >=4 drugs) at baseline. The primary outcome was all-cause mortality. RESULTS: Prevalence of aRH ranged from 0.4% (WTH) to 10.6% (INVEST). Women with aRH, compared to those without, were older, more often black, and more likely to be obese or diabetic. Pooling all cohorts, risk for all-cause death was greater in women with aRH than in women with non-RH (adjusted HR 1.40; 95% CI 1.27-1.55) and women without hypertension (adjusted HR 2.34; 95% CI 1.76-3.11) over a median follow-up of 14.3 years. CONCLUSIONS: aRH prevalence in women varies according to underlying coronary disease, and aRH is associated with a substantial, early, and sustained increased risk of all-cause death. Additional research into early recognition and prevention strategies for RH are needed, especially in black and older women, and those with known cardiovascular risk factors. PMID- 27224418 TI - Trace element contamination and availability in the Fildes Peninsula, King George Island, Antarctica. AB - The Ardley Cove area (located on the Maxwell Bay shoreline, Fildes Peninsula, King George Island, Antarctica) is characterized not only by its high biodiversity, but also by a high density of scientific stations, making it potentially one of the most impacted areas of Antarctica. In order to assess the source, contamination levels, distribution and availability of several trace elements (Cr, Ni, Cu, Zn, As, Pb, Cd and Hg) in and around Maxwell Bay, soil and seawater samples were collected. Soil samples were also collected in the study reference site near the Bellingshausen Dome area, as it lies far from centers of human activity and associated infrastructure. Enrichment factors (EFs) and sequential extractions were also used to assess the degree of contamination and availability of the trace elements under investigation. The results obtained in this study pointed to the existence of several contamination hotspots, mainly related to high levels of Zn, Pb, Cd, Cr and Ni. Comparison of the contaminant distribution patterns with data from earlier studies allowed the identification of anthropogenic sources. Use of the EF approach and sequential extractions confirmed these findings. In particular, higher extraction proportions were obtained for Zn and Pb (68 and 71%, respectively), which were also the same elements where the highest EFs were determined. The results obtained in this study clearly point to human impact on the natural environment in this region of Antarctica and we recommend the implementation of appropriate contamination control and remediation methods. PMID- 27224419 TI - Expression of Genes by Aflatoxigenic and Nonaflatoxigenic Strains of Aspergillus flavus Isolated from Brazil Nuts. AB - The aims of the present study were to monitor the production of aflatoxin B1 (AFB1) and mycelial growth, and to evaluate the expression of genes directly and indirectly involved in the biosynthesis of aflatoxins by Aspergillus flavus isolated from Brazil nuts. Six previously identified A. flavus strains were grown on coconut agar at 25 degrees C for up to 10 days. Mycotoxins were separated by high-performance liquid chromatography and fungal growth was measured daily using the diametric mycelial growth rate. Transcriptional analysis was performed by real-time polymerase chain reaction (PCR) after 2 and 7 d of incubation using specific primers (aflR, aflD, aflP, lipase, metalloprotease, and LaeA). Three (50%) of the six A. flavus isolates produced AFB1 (ICB-1, ICB-12, and ICB-54) and three (50%) were not aflatoxigenic (ICB-141, ICB-161, and ICB-198). Aflatoxin production was observed from d 2 of incubation (1.5 ng/g for ICB-54) and increased gradually with time of incubation until d 10 (15,803.6 ng/g for ICB 54). Almost all A. flavus isolates exhibited a similar gene expression pattern after 2 d of incubation (p > 0.10). After 7 d of incubation, the LaeA (p < 0.05) and metalloprotease (p < 0.05) genes were the most expressed by nonaflatoxigenic strains, whereas aflatoxigenic isolates exhibited higher expression of the aflR (p < 0.05) and aflD genes (p < 0.05). Our results suggest that the expression of aflR and aflD is correlated with aflatoxin production in A. flavus and that overexpression of aflR could affect the transcriptional and aflatoxigenic pattern (ICB-54). Elucidation of the molecular mechanisms that regulate the secondary metabolism of toxigenic fungi may permit the rational silencing of the genes involved and consequently the programmed inhibition of aflatoxin production. Knowledge of the conditions, under which aflatoxin genes are expressed, should contribute to the development of innovative and more cost-effective strategies to reduce and prevent aflatoxin contamination in Brazil nuts. PMID- 27224420 TI - Epoxyeicosatrienoic Acids Regulate Adipocyte Differentiation of Mouse 3T3 Cells, Via PGC-1alpha Activation, Which Is Required for HO-1 Expression and Increased Mitochondrial Function. AB - Epoxyeicosatrienoic acid (EET) contributes to browning of white adipose stem cells to ameliorate obesity/diabetes and insulin resistance. In the current study, we show that EET altered preadipocyte function, enhanced peroxisome proliferation-activated receptor gamma coactivator alpha (PGC-1alpha) expression, and increased mitochondrial function in the 3T3-L1 preadipocyte subjected to adipogenesis. Cells treated with EET resulted in an increase, P < 0.05, in PGC 1alpha and a decrease in mitochondria-derived ROS (MitoSox), P < 0.05. The EET increase in heme oxygenase-1 (HO-1) levels is dependent on activation of PGC 1alpha as cells deficient in PGC-1alpha (PGC-1alpha knockout adipocyte cell) have an impaired ability to express HO-1, P < 0.02. Additionally, adipocytes treated with EET exhibited an increase in mitochondrial superoxide dismutase (SOD) in a PGC-1alpha-dependent manner, P < 0.05. The increase in PGC-1alpha was associated with an increase in beta-catenin, P < 0.05, adiponectin expression, P < 0.05, and lipid accumulation, P < 0.02. EET decreased heme levels and mitochondria-derived ROS (MitoSox), P < 0.05, compared to adipocytes that were untreated. EET also decreased mesoderm-specific transcript (MEST) mRNA and protein levels (P < 0.05). Adipocyte secretion of EET act in an autocrine/paracrine manner to increase PGC 1alpha is required for activation of HO-1 expression. This is the first study to dissect the mechanism by which the antiadipogenic and anti-inflammatory lipid, EET, induces the PGC-1alpha signaling cascade and reprograms the adipocyte phenotype by regulating mitochondrial function and HO-1 expression, leading to an increase in healthy, that is, small, adipocytes and a decrease in adipocyte enlargement and terminal differentiation. This is manifested by an increase in mitochondrial function and an increase in the canonical Wnt signaling cascade during adipocyte proliferation and terminal differentiation. PMID- 27224421 TI - What's Coming Near? The Influence of Dynamical Visual Stimuli on Nociceptive Processing. AB - Objects approaching us may pose a threat, and signal the need to initiate defensive behavior. Detecting these objects early is crucial to either avoid the object or prepare for contact most efficiently. This requires the construction of a coherent representation of our body, and the space closely surrounding our body, i.e. the peripersonal space. This study, with 27 healthy volunteers, investigated how the processing of nociceptive stimuli applied to the hand is influenced by dynamical visual stimuli either approaching or receding from the hand. On each trial a visual stimulus was either approaching or receding the participant's left or right hand. At different temporal delays from the onset of the visual stimulus, a nociceptive stimulus was applied either at the same or the opposite hand, so that it was presented when the visual stimulus was perceived at varying distances from the hand. Participants were asked to respond as fast as possible at which side they perceived a nociceptive stimulus. We found that reaction times were fastest when the visual stimulus appeared near the stimulated hand. Moreover, investigating the influence of the visual stimuli along the continuous spatial range (from near to far) showed that approaching lights had a stronger spatially dependent effect on nociceptive processing, compared to receding lights. These results suggest that the coding of nociceptive information in a peripersonal frame of reference may constitute a safety margin around the body that is designed to protect it from potential physical threat. PMID- 27224422 TI - Loss of N-Cadherin Expression in Tumor Transplants Produced From As+3- and Cd+2 Transformed Human Urothelial (UROtsa) Cell Lines. AB - BACKGROUND: Epithelial to mesenchymal transition is a process in which a cell experiences a loss of epithelial cell characteristics and acquires a more mesenchymal cell phenotype. In cancer, epithelial to mesenchymal transition has been proposed to play an important role during specific stages of tumor progression. The role epithelial to mesenchymal transition and mesenchymal to epithelial transition might play in toxicant-induced urothelial cancer is unknown. METHODS: Real-time PCR, Western blotting, immuno-histochemistry and immuno-fluorescence were used to determine the expression of E- and N-cadherin in the UROtsa parent, the As+3- and Cd+2-transformed cell lines, the spheroids isolated from these cell lines as well as the tumor heterotransplants that were produced by the injection of the transformed cells into immune compromised mice. RESULTS: This study showed that N-cadherin expression was increased in 6 As+3- and 7 Cd+2- transformed cell lines generated from human urothelial cells (UROtsa). The expression varied within each cell line, with 10% to 95% of the cells expressing N-cadherin. Tumors produced from these cell lines showed no expression of the N-cadherin protein. Spheroids which are made up of putative cancer initiating cells produced from these cell lines showed only background expression of N-cadherin mRNA, increased expression of aldehyde dehydrogenase 1 mRNA and produced tumors which did not express N-cadherin. There was no change in the expression of E-cadherin in the tumors, and the tumors formed by all the As+3 and Cd+2-transformed cell lines and cancer initiating cells stained intensely and uniformly for E-cadherin. CONCLUSIONS: The finding that the cells expressing N cadherin gave rise to tumors with no expression of N-cadherin is in agreement with the classical view of epithelial to mesenchymal transition. Epithelial to mesenchymal transition and N-cadherin are associated with dissemination and not with the ability to establish new tumor growth. Mesenchymal to epithelial transition and E-cadherin are viewed as necessary for a cell to establish a new metastatic site. The lack of N-cadherin expression in tumor transplants is consistent with E-cadherin expressing cells "seeding" a site for tumor growth. The study shows that a minority population of cultured cells can be the initiators of tumor growth. PMID- 27224424 TI - Effect of a self-adhesive coating on the load-bearing capacity of tooth-coloured restorative materials. AB - BACKGROUND: The aim of this study was to compare the flexural strength and Vickers hardness of tooth-coloured restorative materials with and without applying a self-adhesive coating for up to 6 months. METHODS: Specimens were prepared from three resin composites (RC), two resin-modified glass-ionomer cements (RM-GIC) and two conventional glass-ionomer cements (CGIC). All materials were tested both with and without applying G-Coat Plus (GCP). Specimens were conditioned in 37 degrees C distilled deionized water for 24 h, and 1, 3 and 6 months. The specimens were strength tested using a four-point bend test jig in a universal testing machine. The broken specimen's halves were used for Vickers hardness testing. Representative specimens were examined under an environmental scanning electron microscope. RESULTS: Data analysis showed that regardless of time and materials, generally the surface coating was associated with a significant increase in the flexural strength of the materials. Applying the GCP decreased the hardness of almost all materials significantly (P < 0.05) and effect of time intervals on hardness was material dependent. CONCLUSIONS: The load-bearing capacity of the restorative materials was affected by applying self adhesive coating and ageing. The CGIC had significantly higher hardness but lower flexural strength than the RM-GIC and RC. PMID- 27224423 TI - The Potential Impact of a Hepatitis C Vaccine for People Who Inject Drugs: Is a Vaccine Needed in the Age of Direct-Acting Antivirals? AB - BACKGROUND AND AIMS: The advent of highly effective hepatitis C (HCV) treatments has questioned the need for a vaccine to control HCV amongst people who inject drugs (PWID). However, high treatment costs and ongoing reinfection risk suggest it could still play a role. We compared the impact of HCV vaccination amongst PWID against providing HCV treatment. METHODS: Dynamic HCV vaccination and treatment models among PWID were used to determine the vaccination and treatment rates required to reduce chronic HCV prevalence or incidence in the UK over 20 or 40 years. Projections considered a low (50% protection for 5 years), moderate (70% protection for 10 years) or high (90% protection for 20 years) efficacy vaccine. Sensitivities to various parameters were examined. RESULTS: To halve chronic HCV prevalence over 40 years, the low, moderate and high efficacy vaccines required annual vaccination rates (coverage after 20 years) of 162 (72%), 77 (56%) and 44 (38%) per 1000 PWID, respectively. These vaccination rates were 16, 7.6 and 4.4 times greater than corresponding treatment rates. To halve prevalence over 20 years nearly doubled these vaccination rates (moderate and high efficacy vaccines only) and the vaccination-to-treatment ratio increased by 20%. For all scenarios considered, required annual vaccination rates and vaccination-to-treatment ratios were at least a third lower to reduce incidence than prevalence. Baseline HCV prevalence had little effect on the vaccine's impact on prevalence or incidence, but substantially affected the vaccination-to treatment ratios. Behavioural risk heterogeneity only had an effect if we assumed no transitions between high and low risk states and vaccinations were targeted or if PWID were high risk for their first year. CONCLUSIONS: Achievable coverage levels of a low efficacy prophylactic HCV vaccine could greatly reduce HCV transmission amongst PWID. Current high treatment costs ensure vaccination could still be an important intervention option. PMID- 27224425 TI - Neurobehavioral radiation mitigation to standard brain cancer therapy regimens by Mn(III) n-butoxyethylpyridylporphyrin-based redox modifier. AB - Combinations of radiotherapy (RT) and chemotherapy have shown efficacy toward brain tumors. However, therapy-induced oxidative stress can damage normal brain tissue, resulting in both progressive neurocognitive loss and diminished quality of life. We have recently shown that MnTnBuOE-2-PyP(5+) (Mn(III)meso-tetrakis(N-n butoxyethylpyridinium -2-yl)porphyrin) rescued RT-induced white matter damage in cranially-irradiated mice. Radiotherapy is not used in isolation for treatment of brain tumors; temozolomide is the standard-of-care for adult glioblastoma, whereas cisplatin is often used for treatment of pediatric brain tumors. Therefore, we evaluated the brain radiation mitigation ability of MnTnBuOE-2 PyP(5+) after either temozolomide or cisplatin was used singly or in combination with 10 Gy RT. MnTnBuOE-2-PyP(5+) accumulated in brains at low nanomolar levels. Histological and neurobehavioral testing showed a drastic decrease (1) of axon density in the corpus callosum and (2) rotorod and running wheel performance in the RT only treatment group, respectively. MnTnBuOE-2-PyP(5+) completely rescued this phenotype in irradiated animals. In the temozolomide groups, temozolomide/ RT treatment resulted in further decreased rotorod responses over RT alone. Again, MnTnBuOE-2-PyP(5+) treatment rescued the negative effects of both temozolomide +/- RT on rotorod performance. While the cisplatin-treated groups did not give similar results as the temozolomide groups, inclusion of MnTnBuOE-2 PyP(5+) did not negatively affect rotorod performance. Additionally, MnTnBuOE-2 PyP(5+) sensitized glioblastomas to either RT +/- temozolomide in flank tumor models. Mice treated with both MnTnBuOE-2-PyP(5+) and radio-/chemo-therapy herein demonstrated brain radiation mitigation. MnTnBuOE-2-PyP(5+) may well serve as a normal tissue radio-/chemo-mitigator adjuvant therapy to standard brain cancer treatment regimens. Environ. Mol. Mutagen. 57:372-381, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27224426 TI - Elongation Factor Tu Prevents Misediting of Gly-tRNA(Gly) Caused by the Design Behind the Chiral Proofreading Site of D-Aminoacyl-tRNA Deacylase. AB - D-aminoacyl-tRNA deacylase (DTD) removes D-amino acids mischarged on tRNAs and is thus implicated in enforcing homochirality in proteins. Previously, we proposed that selective capture of D-aminoacyl-tRNA by DTD's invariant, cross-subunit Gly cisPro motif forms the mechanistic basis for its enantioselectivity. We now show, using nuclear magnetic resonance (NMR) spectroscopy-based binding studies followed by biochemical assays with both bacterial and eukaryotic systems, that DTD effectively misedits Gly-tRNAGly. High-resolution crystal structure reveals that the architecture of DTD's chiral proofreading site is completely porous to achiral glycine. Hence, L-chiral rejection is the only design principle on which DTD functions, unlike other chiral-specific enzymes such as D-amino acid oxidases, which are specific for D-enantiomers. Competition assays with elongation factor thermo unstable (EF-Tu) and DTD demonstrate that EF-Tu precludes Gly-tRNAGly misediting at normal cellular concentrations. However, even slightly higher DTD levels overcome this protection conferred by EF-Tu, thus resulting in significant depletion of Gly-tRNAGly. Our in vitro observations are substantiated by cell-based studies in Escherichia coli that show that overexpression of DTD causes cellular toxicity, which is largely rescued upon glycine supplementation. Furthermore, we provide direct evidence that DTD is an RNA-based catalyst, since it uses only the terminal 2'-OH of tRNA for catalysis without the involvement of protein side chains. The study therefore provides a unique paradigm of enzyme action for substrate selection/specificity by DTD, and thus explains the underlying cause of DTD's activity on Gly-tRNAGly. It also gives a molecular and functional basis for the necessity and the observed tight regulation of DTD levels, thereby preventing cellular toxicity due to misediting. PMID- 27224427 TI - The Regulation of Cytokine Networks in Hippocampal CA1 Differentiates Extinction from Those Required for the Maintenance of Contextual Fear Memory after Recall. AB - We investigated the distinctiveness of gene regulatory networks in CA1 associated with the extinction of contextual fear memory (CFM) after recall using Affymetrix GeneChip Rat Genome 230 2.0 Arrays. These data were compared to previously published retrieval and reconsolidation-attributed, and consolidation datasets. A stringent dual normalization and pareto-scaled orthogonal partial least-square discriminant multivariate analysis together with a jack-knifing-based cross validation approach was used on all datasets to reduce false positives. Consolidation, retrieval and extinction were correlated with distinct patterns of gene expression 2 hours later. Extinction-related gene expression was most distinct from the profile accompanying consolidation. A highly specific feature was the discrete regulation of neuroimmunological gene expression associated with retrieval and extinction. Immunity-associated genes of the tyrosine kinase receptor TGFbeta and PDGF, and TNF families' characterized extinction. Cytokines and proinflammatory interleukins of the IL-1 and IL-6 families were enriched with the no-extinction retrieval condition. We used comparative genomics to predict transcription factor binding sites in proximal promoter regions of the retrieval regulated genes. Retrieval that does not lead to extinction was associated with NF-kappaB-mediated gene expression. We confirmed differential NF-kappaBp65 expression, and activity in all of a representative sample of our candidate genes in the no-extinction condition. The differential regulation of cytokine networks after the acquisition and retrieval of CFM identifies the important contribution that neuroimmune signalling plays in normal hippocampal function. Further, targeting cytokine signalling upon retrieval offers a therapeutic strategy to promote extinction mechanisms in human disorders characterised by dysregulation of associative memory. PMID- 27224429 TI - How much money is spent on vaccines across Western European countries? AB - Prevention programs, particularly vaccinations, remain highly vulnerable to budget cuts because their benefits may not be immediately identifiable. Seven Western European countries were selected (Germany, England, France, Italy, Spain, Sweden and Portugal) constituting a good mix of vaccine procurement modalities, with the objective to document the proportion of healthcare spending devoted to vaccines and its evolution. A data search was performed using the OECD online databases and official national sources from 2008 (2006 for England). No country spent more than 0.5% of its healthcare budget on vaccines. The proportion ranged from 0.25% in Spain (2012) and France (2013) to 0.47% in Germany (2014). Whereas healthcare spending increased in all countries but Spain (with increases ranging from +2.6% per year in France between 2008 and 2013 to +8.1% per year in England between 2006/07 and 2009/10), vaccine spending diminished markedly in Germany ( 6.2% per year from 2008 to 2014), Spain (-6.7% per year from 2008 to 2012) and France (-4.2% per year from 2008 to 2013). Only Sweden (+5.9% per year from 2011 to 2013) and England (+18.9% per year from 2006/07 to 2009/10) increased their spending on vaccines. Vaccination involves relatively low levels of healthcare investment in Western Europe relative to the far-reaching public health benefits that it provides. We found a net trend toward a decrease in such spending in recent years, with the exception of Sweden and England. Vaccination budgets should be preserved or even increased to sustain a life-course approach to immunization with sufficient coverage rates. PMID- 27224428 TI - Synthetic Cannabinoid Use and Descriptive Norms among Collegiate Student Athletes. AB - Synthetic cannabinoids have gained popularity over the past decade, especially among young adults, due to sharing similar psychoactive properties with Tetrahydrocannabinol (THC). A limited number of studies have examined synthetic cannabinoid use among college students but none have examined use exclusively by collegiate student-athletes. The objective of this study was to examine synthetic cannabinoid use among collegiate student-athletes. In the spring of 2013, 3,276 freshmen and transfer collegiate student-athletes from 47 NCAA Division I, II, and III institutions participated in a web-based survey on substance use. Bivariate logistic regression was used to analyze the relationship between collegiate student-athlete characteristics, substance use, and descriptive norms with lifetime use of synthetic cannabinoids. Sixty-two individuals (1.9%) reported lifetime use of synthetic cannabinoids, and 3 (0.1%) reported past-30 day use. Males, current drinkers, and athletes who used hookah and marijuana in the past 30 days were more likely to use synthetic cannabinoids. Peer use of synthetic cannabinoids was estimated to be higher than actual use, and such overestimation was positively associated with personal use of synthetic cannabinoids. Our findings suggest that campaigns addressing normative beliefs should be implemented on college campuses to prevent synthetic cannabinoid use among college students and collegiate student-athletes. PMID- 27224430 TI - Electrochemical properties of seamless three-dimensional carbon nanotubes-grown graphene modified with horseradish peroxidase. AB - Horseradish peroxidase (HRP) was immobilized through sodium dodecyl sulfate (SDS) on the surface of a seamless three-dimensional hybrid of carbon nanotubes grown at the graphene surface (HRP-SDS/CNTs/G) and its electrochemical properties were investigated. Compared with graphene alone electrode modified with HRP via SDS (HRP-SDS/G electrode), the surface coverage of electroactive HRP at the CNTs/G electrode surface was approximately 2-fold greater because of CNTs grown at the graphene surface. Based on the increase in the surface coverage of electroactive HRP, the sensitivity to H2O2 at the HRP-SDS/CNTs/G electrode was higher than that at the HRP-SDS/G electrode. The kinetics of the direct electron transfer from the CNTs/G electrode to compound I and II of modified HRP was also analyzed. PMID- 27224431 TI - Pinprick Testing in Small Fiber Neuropathy: Accuracy and Pitfalls. AB - OBJECTIVES: To assess the sensitivity, specificity, and predictive value of pinprick perception and its concordance with established laboratory measures in small fiber neuropathy. METHODS: Fifty-six patients suspected of SFN underwent detailed evaluation and standardized quantitative sensory and autonomic testing. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value of pinprick sensation were determined. RESULTS: Pinprick perception had relatively consistent results between modalities with moderate sensitivity (70%); combining the testing modalities increased the diagnostic yield. PPV of pinprick approached 89%; however, negative predictive value was 19%. CONCLUSIONS: As a screening tool, pinprick has high PPV for SFN, but many patients are likely to be missed if they report unimpaired subjective perception of pinprick sensation. Multimodal testing is recommended in clinically suspected cases to positively rule out SFN. PMID- 27224432 TI - Frequency of Radiculopathy in Patients With Carpal Tunnel Syndrome and Paracervical Pain. AB - OBJECTIVES: Patients with carpal tunnel syndrome (CTS) and paracervical pain (PCP) are often incorrectly diagnosed with cervical radiculopathy. The objective of the study is to determine how frequently such patients have electrophysiologic evidence of radiculopathy. METHODS: We reviewed charts of patients with clinical features of CTS and at least 1 median nerve conduction parameter showing slowing across the wrist. Patients were divided into those with and without PCP. Radiculopathy was defined electrophysiologically. We assessed group differences in the frequency of radiculopathy and how radiculopathy frequency varied with median nerve entrapment severity. RESULTS: Of 108 patients meeting criteria, 56 had PCP and 52 did not. Eight of 56 patients with PCP and 4 of 52 without pain had cervical radiculopathy (P = 0.36). There was no difference in the frequency of radiculopathy related to the severity of median nerve entrapment (P = 0.64). DISCUSSION: In patients with CTS, PCP is not associated with cervical radiculopathy. Cervical radiculopathy is not more frequent in more severe CTS. PMID- 27224433 TI - Clinical and Electrophysiological Findings in Hereditary Inclusion Body Myopathy Compared With Sporadic Inclusion Body Myositis. AB - OBJECTIVE: To compare the clinical and electrophysiological findings in hereditary inclusion body myopathy (hIBM) and sporadic inclusion body myositis (sIBM) patients. METHODS: We retrospectively identified 8 genetically proven hIBM patients and 1 DNAJB6 myopathy with pathological features of hIBM, and compared their clinical, electromyographic, and serological data with a group of 51 pathologically proven sIBM patients. RESULTS: hIBM patients had a younger mean age of onset (36 vs. 60 years, P = 0.0001). Diagnostic delay was shorter in sIBM (6 vs. 15 years, P = 0.0003). Wrist flexors (P = 0.02), digit flexors (P = 0.01), digit extensors (P = 0.02), and quadriceps (P = 0.008) muscles were more frequently affected in sIBM. Fibrillation potentials were more common in sIBM patients (P = 0.03). Electrical myotonia was found in 4 hIBM patients, not significantly different from sIBM patients (P = 0.45). Creatinine kinase was higher in sIBM patients (799 vs 232, P = 0.03). CONCLUSIONS: sIBM and hIBM seem to have similar electromyographic changes. The combination of clinical, serological, and histopathological findings can guide genetic testing to the final diagnosis. PMID- 27224434 TI - Chronic Myopathy Associated With Anti-Signal Recognition Particle Antibodies Can Be Misdiagnosed As Facioscapulohumeral Muscular Dystrophy. AB - OBJECTIVES: To report cases of chronic autoimmune necrotizing myopathy with anti signal recognition particle antibodies (anti-SRP myopathy) initially misdiagnosed as muscular dystrophy, in particular, facioscapulohumeral muscular dystrophy (FSHD). METHODS: Medical records of patients with anti-SRP myopathy in our institution were retrospectively reviewed. RESULTS: All 6 patients were initially diagnosed with muscular dystrophy because of the long-term clinical course and lack of inflammation on biopsy; 5 were diagnosed with FSHD based on a winged scapula. However, the following features suggested an alternative diagnosis, leading to anti-SRP antibody measurement: (1) lack of family history, (2) lack of facial involvement and asymmetry, (3) prominent dysphagia, and (4) profuse spontaneous activities on needle electromyography. All patients showed improvement with immunomodulating therapy. CONCLUSIONS: Anti-SRP antibody measurement should be considered in patients diagnosed with FSHD if they present with diagnostic hallmarks of anti-SRP myopathy listed above, to avoid oversight of this potentially treatable disorder. PMID- 27224435 TI - A Case of Morvan Syndrome Mimicking Amyotrophic Lateral Sclerosis With Frontotemporal Dementia. AB - INTRODUCTION: Morvan syndrome is a rare autoimmune/paraneoplastic disorder involving antibodies to the voltage-gated potassium channel complex. It is defined by subacute encephalopathy, neuromuscular hyperexcitability, dysautonomia, and sleep disturbance. It may present a diagnostic dilemma when trying to differentiate from amyotrophic lateral sclerosis with frontotemporal dementia. METHODS: A 76-year-old man with a history of untreated prostate adenocarcinoma was evaluated for subacute cognitive decline, diffuse muscle cramps, and hyponatremia. RESULTS: MRI demonstrated atrophy most prominent in the frontal and temporal regions. Electromyography (EMG) demonstrated diffuse myokymia/neuromyotonia. Polysomnography lacked REM and N3 sleep. Paraneoplastic panel detected antibodies to voltage-gated potassium channel complex (CASPR2 subtype). CONCLUSIONS: It is difficult to differentiate between Morvan syndrome and amyotrophic lateral sclerosis with frontotemporal dementia with examination and neuroimaging alone. There may be a link between Morvan syndrome and prostate adenocarcinoma which could help with screening/diagnosis. The authors found that laboratory and neurophysiological tests are indispensable in diagnosing and treating Morvan syndrome. PMID- 27224436 TI - Abnormal Nutritional Factors in Patients Evaluated at a Neuropathy Center. AB - Abnormal concentrations of nutritional factors were found in 24.1% of 187 patients with neuropathy who were newly seen at our academic neuropathy referral center over a 1-year period. All patients presented with sensory axonal or small fiber neuropathy. In 7.3%, they were present in association with at least one other identifiable cause for neuropathy. Elevated levels of pyridoxal phosphate or mercury occurred more frequently than deficiencies in vitamins B1, B12, or B6. The nutritional abnormalities are amenable to correction by dietary intervention. PMID- 27224437 TI - Electrodiagnostic Abnormalities in Tick Paralysis: A Case Report and Review of Literature. AB - OBJECTIVE: To study the electrodiagnostic abnormalities in tick paralysis. METHODS: A 7-year-old girl with acute onset proximal muscle weakness and an engorged dog tick attached to her scalp was evaluated. RESULTS: The routine motor nerve conduction study showed normal compound muscle action potential amplitude. The stimulated jitter analysis of the orbicularis oculi muscle showed normal jitter with no blocking. The quantitative electromyography of the proximal muscles showed decreased mean duration of the motor unit potentials. CONCLUSION: We propose toxin-mediated direct skeletal muscle involvement as one of the reasons for muscle weakness in tick paralysis. PMID- 27224438 TI - Case of Young-Onset Sporadic Amyotrophic Lateral Sclerosis. AB - Amyotrophic lateral sclerosis (ALS) constitutes the main type of motor neuron disease. Familial ALS is characterized by the presence of positive family history and accounts for 10% of ALS cases. Although familial ALS is the main culprit for early-onset disease, there are rare cases of early- or young-onset ALS with negative family history or sporadic ALS. We describe a 23-year-old man with clinical and electrophysiological evidence of probable sporadic ALS according to the revised EI Escorial criteria. Interestingly, brain neuroimaging revealed bilaterally increased T2 signals across corona radiata, posterior limb of the internal capsule, and descending motor tracts in the brainstem and hypointensity rim of the motor cortex on T2-weighted images. Young-onset sporadic ALS may be a distinct nosological entity. The topic is shortly discussed in the light of its genetic and clinical characteristics. PMID- 27224439 TI - Prevalence of Vitamin D Deficiency in Spring and Summer Months in Central Pennsylvania Neuromuscular Clinic: A Study Complementary to the Pilot Study Published in Journal of Clinical Neuromuscular Disease in June 2015 for Fall and Winter Months. PMID- 27224440 TI - Bilateral Femoral Neuropathy After Transurethral Lithotomy in the Lithotomy Position: Report of a Case. PMID- 27224441 TI - What's in the Literature? AB - One of the first questions asked by patients and family members when a diagnosis of amyotrophic lateral sclerosis is made is "what about stem cells?" The term "stem cells" has attractiveness to it, with the assumption that stem cell treatment (stem nerve cells) can replace lost nerve cells. There are perhaps 2 types of stem cell trials, those that are vetted by the Food and Drug Administration and those that have no official oversight and whose results are infrequently published. The issue of the latter was discussed in the last edition of this column. The results of one of the formal stem cell trials now in the United States have been reported. Spinal muscular atrophy is a form of motor neuron disease affecting children and has a genetic cause, which has led to a feasibility study giving antisense oligonucleotides, and the results have also been reported. Biomarkers of amyotrophic lateral sclerosis are being sought, and the presence of neurofilaments is promising. Inflammatory neuropathies are an important group because they are treatable. Intravenous immune globulin is a commonly used agent, but a number of questions persist: one is efficacy among brands, another is the probability of a response, and a third is optimum dosing and taper schedules. A number of recent articles address these issues. The predictive value of single-fiber electromyography in determining which patients with ocular myasthenia will develop generalized disease, the risk of crisis after thymectomy, and 2 papers discussing new forms of congenital myasthenic syndrome are discussed. The risk of brain tumors, quality of life, and the assessment of trunk muscle strength in patients with type 1 myotonic dystrophy is reviewed. An article describing the discovery of mutations in SCN4A as a cause of congenital myopathy is discussed, as is one describing the occurrence of rhabdomyolysis in a group of patients subsequently discovered to have various forms of muscular dystrophy. Finally, articles describing the features of patients with inflammatory myopathies and Jo-1 and either 3-hydroxy-3-methylglutaryl-conezymea reductase or to signal recognition particle antibodies are reviewed. PMID- 27224442 TI - Auto- and allo-epitopes in DQ alloreactive antibodies. AB - PURPOSE OF REVIEW: Significant interest is now focused on deciphering human leukocyte antigen (HLA) epitopes and the utilization of this new knowledge to improve donor-recipient matching in transplantation. A recently introduced concept is the appearance of antibodies against what may be considered as self epitopes, including the introduction of the 'nonself-self paradigm'. RECENT FINDINGS: Common practice in analyzing HLA-DQ antibodies have been to separate between antibodies against the alpha chain and antibodies against the beta chain of the molecule. This is despite the fact that the two chains have to intertwine together to be expressed stably on the cell surface. We have previously provided evidence that this practice is false. We further provide evidence to refute the use of 'self-epitopes' as an immunologically feasible terminology by delineating the historic events leading to today's misconceptions. SUMMARY: The evidence we present supports the need for a change in current practices. HLA-DQ antigens and antibodies should be viewed as combined DQalpha/beta complexes. This will have impact to assigning cPRA value, assigning acceptable and unacceptable antigens, and pave the way to a better understanding of true HLA epitopes as we strive to improve donor--recipient compatibility and minimize generation of de-novo HLA antibodies. PMID- 27224443 TI - Mitochondrial Haplogroups and Risk of Pulmonary Arterial Hypertension. AB - Pulmonary arterial hypertension (PAH) is a serious and often fatal disease. It is a panvasculopathy of the pulmonary microcirculation characterized by vasoconstriction and arterial obstruction due to vascular proliferation and remodeling and ultimately right ventricular failure. Mitochondrial dysfunction is a universal finding in pulmonary vascular cells of patients with PAH, and is mechanistically linked to disease origins in animal models of pulmonary hypertension. Mitochondria have their own circular DNA (mtDNA), which can be subgrouped into polymorphic haplogroup variants, some of which have been identified as at-risk or protective from cardiovascular and/or neurodegenerative diseases. Here, we hypothesized that mitochondrial haplogroups may be associated with PAH. To test this, mitochondrial haplogroups were determined in a cohort of PAH patients and controls [N = 204 Caucasians (125 PAH and 79 controls) and N = 46 African Americans (13 PAH and 33 controls)]. Haplogroup L was associated with a lower rate of PAH as compared to macrohaplogroups N and M. When haplogroups were nested based on ancestral inheritance and controlled for age, gender and race, haplogroups M and HV, JT and UK of the N macro-haplogroup had significantly higher rates of PAH compared to the ancestral L (L0/1/2 and L3) (all p <= 0.05). Overall, the findings suggest that mitochondrial haplogroups influence risk of PAH and that a vulnerability to PAH may have emerged under the selective enrichment of specific haplogroups that occurred with the migration of populations out of Africa. PMID- 27224444 TI - Development of Chemical Probes for Investigation of Salt-Inducible Kinase Function in Vivo. AB - Salt-inducible kinases (SIKs) are promising therapeutic targets for modulating cytokine responses during innate immune activation. The study of SIK inhibition in animal models of disease has been limited by the lack of selective small molecule probes suitable for modulating SIK function in vivo. We used the pan-SIK inhibitor HG-9-91-01 as a starting point to develop improved analogs, yielding a novel probe 5 (YKL-05-099) that displays increased selectivity for SIKs versus other kinases and enhanced pharmacokinetic properties. Well-tolerated doses of YKL-05-099 achieve free serum concentrations above its IC50 for SIK2 inhibition for >16 h and reduce phosphorylation of a known SIK substrate in vivo. While in vivo active doses of YKL-05-099 recapitulate the effects of SIK inhibition on inflammatory cytokine responses, they did not induce metabolic abnormalities observed in Sik2 knockout mice. These results identify YKL-05-099 as a useful probe to investigate SIK function in vivo and further support the development of SIK inhibitors for treatment of inflammatory disorders. PMID- 27224445 TI - Idarucizumab for dabigatran overdose. AB - CONTEXT: An overdose of oral anticoagulants represents a challenging scenario for emergency physicians. Dabigatran, an oral direct thrombin inhibitor, is increasingly used in place of warfarin. The lack of an antidote is a concern in patients who overdose on dabigatran, even though the drug can be eliminated with hemodialysis. Idarucizumab is an antibody fragment that binds dabigatran with high affinity. It reverses the anticoagulant effect of dabigatran within minutes and is approved for the reversal of dabigatran during emergency situations. CASE DETAILS: We describe the use of idarucizumab in the management of a 68-year-old woman who was taking dabigatran 150 mg twice daily and ingested 125 capsules. Despite gastric lavage and administration of activated charcoal within two hours of drug intake, the activated partial thromboplastin time (aPTT) and prothrombin time (PT) remained prolonged. The administration of 5 g of intravenous idarucizumab promptly and completely reversed the anticoagulant activity of dabigatran as assessed by routine and specific coagulation assays (aPTT from to 75 to 26 s, PT from 26 to 11 s and diluted thrombin time from 92 to 27 s). The initially planned emergency hemodialysis was canceled. DISCUSSION: This case highlights the potential use of idarucizumab for the management of massive dabigatran overdoses. PMID- 27224446 TI - Impaired biological response to aspirin in therapeutic hypothermia comatose patients resuscitated from out-of-hospital cardiac arrest. AB - AIM OF THE STUDY: Acute coronary syndrome is one of the main causes of out-of hospital cardiac arrest (OHCA). OHCA patients are particularly exposed to high platelet reactivity (HPR) under aspirin (ASA) treatment. The aim was to evaluate HPR-ASA in therapeutic hypothermia comatose patients resuscitated from OHCA. METHODS AND RESULTS: Twenty-two consecutive patients with OHCA of cardiac origin were prospectively included after therapeutic hypothermia and randomized to receive ASA 100mg per day, either intravenously (n=13) or orally via a gastric tube (n=9). ADP inhibitors (prasugrel or, if contra-indicated, clopidogrel) were administered in the event of angioplasty. HPR-ASA was assessed by light transmission aggregometry (LTA) with arachidonic acid (AA) and by the PFA 100((r)) system with collagen/epinephrine. Clinical, biological and angiographic characteristics were similar in both groups. Using LTA-AA, maximum aggregation intensity was significantly lower in the intravenous group compared to the oral group (15% vs. 29%, respectively; p=0.04). Overall, 10 patients (45%) had HPR-ASA (38% intravenously vs 56% orally; p=0.7). Similarly, closure time was significantly increased in the IV group (277s vs. 155s, respectively; p=0.04). CONCLUSION: This study suggests that impaired response to both intravenous and oral aspirin is frequent in comatose patients resuscitated from OHCA. PMID- 27224447 TI - Prolonged cardiopulmonary resuscitation and outcomes after out-of-hospital cardiac arrest. AB - AIM: It is unclear whether prolonged resuscitation can result in successful outcome following out-of-hospital cardiac arrests (OHCA). We assessed associations between duration of pre-hospital resuscitation on survival and functional outcome following OHCA in patients achieving pre-hospital return of spontaneous circulation (ROSC). METHODS: We included 1316 adult OHCA individuals with pre-hospital ROSC (2005-2011) handled by the largest nationwide ambulance provider in Denmark. Patients were stratified into 0-5, 6-10, 11-15, 16-20, 21-25 and >25min of cardiopulmonary resuscitation (CPR) by emergency medical services until ROSC was achieved. Nursing home admission and diagnosis of anoxic brain damage were measured as proxies of poor neurological/functional outcomes. FINDINGS: Median time from CPR initiation to ROSC was 12min (IQR: 7-18) while 20.4% achieved ROSC after >25min. Overall, 37.5% (494) of the study population achieved 30-day survival. Thirty-day survival was inversely related to minutes of CPR to ROSC: ranging from 59.6% (127/213) for <=5min to 13.8% (19/138) for >25min. If bystander initiated CPR before ambulance arrival, corresponding values ranged from 70.4% (107/152) to 21.8% (12/55). Of 30-day survivors, patients discharged to own home rather than nursing home ranged from 95.0% (124/127) to 84.7% (18/19), respectively. Of 30-day survivors, patients discharged without diagnosis of anoxic brain damage ranged from 98.4% (125/127) to 73.7% (14/19) for corresponding intervals. CONCLUSION: Even those requiring prolonged resuscitation duration prior to ROSC had meaningful survival rates with the majority of survivors able to return to live in own homes. These data suggest that prolonged resuscitation is not futile. PMID- 27224448 TI - Time without ventilation during intubation in neonates as a patient-centred measure of performance. AB - AIMS: Time without ventilation is often much longer than an intubation attempt, yet patient stability relies on effective gas exchange. We argue that in addition to existing performance criteria, intubation performance measures should include interruption to effective ventilation. METHODS: We reviewed video recorded resuscitations of 31 term and preterm newborns that included at least one intubation attempt. Time stamps were recorded at the end of mask ventilation, laryngoscope insertion and removal (laryngoscope duration), and re-commencement of ventilation via mask or endotracheal tube (ETT). Intubation attempts were defined as Successful (subsequent ventilation via ETT), or Failed (ETT incorrectly placed) or Withdrawn (laryngoscope removed before ETT insertion attempt). RESULTS: During intubation, total time without ventilation varied from 31 to 273s, compared to laryngoscope duration of 12-149s. Time without ventilation as Median [min-max] was greater for failed attempts 64 [48-273]s, yet laryngoscope duration was shortest for failed attempts 33 [21-46]s. Time between ceasing ventilation and commencing intubation was 5 [1-46]s suggesting room for improvement during transitions within the procedure. CONCLUSIONS: Time without ventilation is a more physiologically important measure of a resuscitation team's intubation expertise than laryngoscope duration. Since successful attempts took longer than failed attempts, emphasising haste during vocal cord visualisation and tube insertion may reduce success rates. Reducing the time without ventilation at either end of the procedure may be achievable with better team coordination and could be just as important to patient wellbeing as technical precision. PMID- 27224449 TI - Dinosaur: A Refined Open-Source Peptide MS Feature Detector. AB - In bottom-up mass spectrometry (MS)-based proteomics, peptide isotopic and chromatographic traces (features) are frequently used for label-free quantification in data-dependent acquisition MS but can also be used for the improved identification of chimeric spectra or sample complexity characterization. Feature detection is difficult because of the high complexity of MS proteomics data from biological samples, which frequently causes features to intermingle. In addition, existing feature detection algorithms commonly suffer from compatibility issues, long computation times, or poor performance on high-resolution data. Because of these limitations, we developed a new tool, Dinosaur, with increased speed and versatility. Dinosaur has the functionality to sample algorithm computations through quality-control plots, which we call a plot trail. From the evaluation of this plot trail, we introduce several algorithmic improvements to further improve the robustness and performance of Dinosaur, with the detection of features for 98% of MS/MS identifications in a benchmark data set, and no other algorithm tested in this study passed 96% feature detection. We finally used Dinosaur to reimplement a published workflow for peptide identification in chimeric spectra, increasing chimeric identification from 26% to 32% over the standard workflow. Dinosaur is operating-system-independent and is freely available as open source on https://github.com/fickludd/dinosaur . PMID- 27224450 TI - Development of an Assessment to Examine Training of the Hospice Primary Caregiver. AB - BACKGROUND: Key to high-quality care of dying hospice patients at home is whether the hospice provides adequate training so the caregiver can safely care for the patient. OBJECTIVE: The study objective was to develop and validate a survey of hospice training for caregivers to ensure safe, high-quality care in the home setting. DESIGN: Our survey design was cross-sectional. Bereaved respondents of individuals who died at home under the care of hospice were surveyed three to six months postdeath. MEASUREMENTS: Items were developed based on advice of an expert panel, focus groups of hospice caregivers, and literature review, with 12 items developed for testing and examining 8 key processes of care. We examined the validity and reliability of the assessment using factor analysis, correlational analyses, and multivariable modeling. RESULTS: Our sample consisted of 262 primary caregivers (mean age 62.4, 76.7% female, 58.8% non-Hispanic white). Six questions focused on providing the caregiver with information, while another six focused on the training that hospice provided. Based on model fit and Cronbach's alpha, we dropped the information items. The items that examined hospice training demonstrated a one-factor solution and a Cronbach's of 0.90. We examined correlations of the multi-item composite with overall rating of quality of care (0.53), overall distress (0.31), and whether the respondent would recommend this hospice to others (0.49). There were no significant sociodemographic correlates of concerns with training. CONCLUSIONS: Sufficient preliminary reliability and validity warrants further testing of this composite to examine the adequacy of training provided to family members to care safely for the patient. PMID- 27224451 TI - A European Mitochondrial Haplotype Identified in Ancient Phoenician Remains from Carthage, North Africa. AB - While Phoenician culture and trade networks had a significant impact on Western civilizations, we know little about the Phoenicians themselves. In 1994, a Punic burial crypt was discovered on Byrsa Hill, near the entry to the National Museum of Carthage in Tunisia. Inside this crypt were the remains of a young man along with a range of burial goods, all dating to the late 6th century BCE. Here we describe the complete mitochondrial genome recovered from the Young Man of Byrsa and identify that he carried a rare European haplogroup, likely linking his maternal ancestry to Phoenician influenced locations somewhere on the North Mediterranean coast, the islands of the Mediterranean or the Iberian Peninsula. This result not only provides the first direct ancient DNA evidence of a Phoenician individual but the earliest evidence of a European mitochondrial haplogroup, U5b2c1, in North Africa. PMID- 27224452 TI - Ultrafine and Fine Particles and Hospital Admissions in Central Europe. Results from the UFIREG Study. AB - RATIONALE: Evidence of short-term effects of ultrafine particles (UFP) on health is still inconsistent and few multicenter studies have been conducted so far especially in Europe. OBJECTIVES: Within the UFIREG project, we investigated the short-term effects of UFP and fine particulate matter (particulate matter with an aerodynamic diameter less than 2.5 MUm [PM2.5]) on daily cause-specific hospital admissions in five Central and Eastern European cities using harmonized protocols for measurements and analyses. METHODS: Daily counts of cause-specific hospital admissions focusing on cardiovascular and respiratory diseases were obtained for Augsburg and Dresden (Germany), 2011-2012; Chernivtsi (Ukraine), 2013 to March 2014; and Ljubljana (Slovenia) and Prague (Czech Republic), 2012-2013. Air pollution and meteorologic data were measured at fixed monitoring sites in all cities. We analyzed city-specific associations using confounder-adjusted Poisson regression models and pooled the city-specific effect estimates using metaanalysis methods. MEASUREMENTS AND MAIN RESULTS: A 2,750 particles/cm3 increase (average interquartile range across all cities) in the 6-day average of UFP indicated a delayed and prolonged increase in the pooled relative risk of respiratory hospital admissions (3.4% [95% confidence interval, -1.7 to 8.8%]). We also found increases in the pooled relative risk of cardiovascular (exposure average of lag 2-5, 1.8% [0.1-3.4%]) and respiratory (6-d average exposure, 7.5% [4.9-10.2%]) admissions per 12.4 MUg/m3 increase (average interquartile range) in PM2.5. CONCLUSIONS: Our findings indicated delayed and prolonged effects of UFP exposure on respiratory hospital admissions in Central and Eastern Europe. Cardiovascular and respiratory hospital admissions increased in association with an increase in PM2.5. Further multicenter studies are needed using harmonized UFP measurements to draw definite conclusions on health effects of UFP. PMID- 27224453 TI - Optimization of Scat Detection Methods for a Social Ungulate, the Wild Pig, and Experimental Evaluation of Factors Affecting Detection of Scat. AB - Collection of scat samples is common in wildlife research, particularly for genetic capture-mark-recapture applications. Due to high degradation rates of genetic material in scat, large numbers of samples must be collected to generate robust estimates. Optimization of sampling approaches to account for taxa specific patterns of scat deposition is, therefore, necessary to ensure sufficient sample collection. While scat collection methods have been widely studied in carnivores, research to maximize scat collection and noninvasive sampling efficiency for social ungulates is lacking. Further, environmental factors or scat morphology may influence detection of scat by observers. We contrasted performance of novel radial search protocols with existing adaptive cluster sampling protocols to quantify differences in observed amounts of wild pig (Sus scrofa) scat. We also evaluated the effects of environmental (percentage of vegetative ground cover and occurrence of rain immediately prior to sampling) and scat characteristics (fecal pellet size and number) on the detectability of scat by observers. We found that 15- and 20-m radial search protocols resulted in greater numbers of scats encountered than the previously used adaptive cluster sampling approach across habitat types, and that fecal pellet size, number of fecal pellets, percent vegetative ground cover, and recent rain events were significant predictors of scat detection. Our results suggest that use of a fixed width radial search protocol may increase the number of scats detected for wild pigs, or other social ungulates, allowing more robust estimation of population metrics using noninvasive genetic sampling methods. Further, as fecal pellet size affected scat detection, juvenile or smaller-sized animals may be less detectable than adult or large animals, which could introduce bias into abundance estimates. Knowledge of relationships between environmental variables and scat detection may allow researchers to optimize sampling protocols to maximize utility of noninvasive sampling for wild pigs and other social ungulates. PMID- 27224454 TI - Predictors of early breastfeeding cessation among HIV-infected women in Botswana. AB - OBJECTIVE: Infants born to HIV-infected women receiving antiretroviral treatment (ART) can be breastfed through at least 6 months with very low risk of HIV acquisition. We aimed to identify demographic and cultural factors that may influence mothers' willingness to breastfeed for the recommended duration. METHODS: We evaluated factors associated with early cessation of breastfeeding (i.e. before 5 months post-partum) in a randomized clinical trial evaluating different ART regimens used for prevention of mother-to-child transmission during breastfeeding in Botswana. Univariate and multivariable Cox regressions were used to describe predictors of early exclusive BF cessation. RESULTS: Among 677 women who started breastfeeding, the median time to breastfeeding cessation was 178 days (IQR 150-181) and 25.1% weaned early. In multivariable analysis, urban location (aHR = 1.86 95%CI 1.27-2.73; P = 0.002), salaried employment or being a student (aHR = 2.78 95% CI 1.63-4.75; P < 0.001) and infant hospitalisation before weaning (aHR = 2.04 95% CI 1.21-3.45; P = 0.008) were independently and significantly associated with early BF cessation. CONCLUSIONS: Improved support for breastfeeding among employed mothers, especially in urban settings, may allow HIV-infected women who are receiving ART prophylaxis to breastfeed longer. PMID- 27224455 TI - Ethnic differences in inter- and intra-situational blood pressure variation: Comparisons among African-American, Hispanic-American, Asian-American, and European-American women. AB - OBJECTIVES: The purpose of this study was to compare the daily inter- and intra situational ambulatory blood pressure (BP) variation by ethnicity in women. METHODS: The African-American (N = 82; Age = 39.7 + 8.9), Hispanic-American (N = 25; age = 37.5 + 9.4), Asian-American (N = 22; Age = 35.2 + 8.6), and European American (N = 122; Age = 37.2+ 9.4) women in this study all worked in similar positions at two major medical centers in NYC. Each wore an ambulatory monitor during the course of one mid-week workday. Proportional BP changes from work or home to sleep, intra-situational BP variation (standard deviation [SD]) and mean situational BP levels were compared among the groups using ANOVA models. RESULTS: African-American and Asian-American women had significantly smaller proportional work-sleep systolic changes than either European- (P < 0.05) or Hispanic-American (P < 0.05) women, but the Asian-American women's changes tended to be smallest. The variability (SD) of diastolic BP at work was significantly greater among African- and Hispanic-American women compared to Asian- and European-American women (all P < 0.05). African-American women had greater sleep variability than European-American women (P < 0.05). Asian-American women had the highest level of sleep diastolic pressure (all comparisons P < 0.05). CONCLUSIONS: African American and Asian-American women have an attenuated proportional BP decline from waking environments to sleep compared to European-American and Hispanic-American women. Asian-American nocturnal BP may be elevated relative to all other groups. Am. J. Hum. Biol. 28:932-935, 2016. (c) 2016Wiley Periodicals, Inc. PMID- 27224456 TI - Remote Electronic Effects by Ether Protecting Groups Fine-Tune Glycosyl Donor Reactivity. AB - It was established that para-substituted benzyl ether protecting groups affect the reactivity of glycosyl donors of the thioglycoside type with the N iodosuccinimide/triflic acid promoter system. Having electron donating p methoxybenzyl ether (PMB) groups increased the reactivity of the donor in comparison to having electron withdrawing p-chloro (PClB) or p-cyanobenzyl ether (PCNB) protecting groups, which decreased the reactivity of the glycosyl donor relative to the parent benzyl ether (Bn) protected glycosyl donor. These findings were used to perform the first armed-disarmed coupling between two benzylated glucosyl donors by tuning their reactivity. In addition, the present work describes a highly efficient palladium catalyzed multiple cyanation and methoxylation of p-chlorobenzyl protected thioglycosides. The results of this paper regarding both the different electron withdrawing properties of various benzyl ethers and the efficient and multiple protecting group transformations are applicable in general organic chemistry and not restricted to carbohydrate chemistry. PMID- 27224457 TI - Sustainability, Succession, and the Senior Faculty. PMID- 27224458 TI - The Role of Linguistic Modification in Nursing Education. AB - BACKGROUND: English-as-a-second-language (ESL) nursing students fail to graduate from programs at alarming rates. For many of these students, academic failure results from poor performance on multiple choice examinations, which frequently contain linguistic errors. A remedy for these errors is to linguistically modify examination questions. This study assessed the effects of linguistic modification on examination scores. METHOD: Scores of ESL and non-ESL nursing students were compared on an experimental multiple choice examination and a control examination. RESULTS: After exclusion, 67 ESL and 252 non-ESL students completed the experimental examination; 68 ESL and 257 non-ESL students completed the control examination. CONCLUSION: Both ESL and non-ESL students scored higher on the experimental examination than on the control examination. For ESL students, the increase in observed means between the experimental and control examination was 0.6%; for non-ESL students, the increase was 0.48%. [J Nurs Educ. 2016;55(6):309-315.]. PMID- 27224459 TI - Advancing Health Equity Through Student Empowerment and Professional Success: A Statewide Approach. AB - BACKGROUND: A lack of diversity in the nursing workforce nationally has been identified by Oregon state leaders as a factor contributing to health inequity. METHOD: The goal of Advancing Health Equity Through Student Empowerment and Professional Success (HealthE STEPS) is to graduate nursing students from disadvantaged backgrounds to improve health equity within their communities. A comprehensive plan of evidence-based strategies was developed based on social determinants of health and addresses academic socialization, learning support, financial resources, networking, curriculum development, and campus culture. RESULTS: Ninety undergraduate nursing students participated in the program during a 2-year period. Retention of participants was 97% with graduation rates of 94%. First-time licensure pass rates were 82% and 96% of participating graduates employed in a medically underserved community. CONCLUSION: This comprehensive innovative program of evidence-based strategies addresses health equity by developing a diverse nursing workforce to practice in medically underserved communities. [J Nurs Educ. 2016;55(6):316-322.]. PMID- 27224460 TI - Summative Simulated-Based Assessment in Nursing Programs. AB - BACKGROUND: Summative simulated-based assessments are intended to determine students' competence in practice. These assessments need to be carefully designed and implemented especially when the results are used to make high-stakes decisions. METHOD: Critical steps need to be followed to design simulations for summative assessment, ensure the validity of the assessment and reliability of the ratings, and train evaluators. RESULTS: Guidelines for using simulation for assessment in nursing are suggested. The guidelines are based on the literature and the authors' experiences from a project that examined the feasibility of using simulation for determining students' competence in performance at the end of the nursing program. CONCLUSION: Summative simulation-based assessments need to be valid, measuring the knowledge and skills they are intended to, and reliable, with results being reproduced by different evaluators and by the same evaluator at another time. [J Nurs Educ. 2016;55(6):323-328.]. PMID- 27224461 TI - Prelicensure Baccalaureate Nursing Students' Perceptions of Their Development of Clinical Reasoning. AB - BACKGROUND: Establishing a strong foundation for the development of clinical reasoning in nursing students is essential to ensure safe and effective patient care. This study explored prelicensure baccalaureate nursing students' perceptions of their development of clinical reasoning, as well as their perceptions of how it is taught. METHOD: In this phenomenological study, individual semistructured interviews were conducted to gather data related to participants' perceptions of their development of clinical reasoning. Data were analyzed using procedural steps delineated by Giorgi. RESULTS: Data analysis revealed three main themes: Instructor Characteristics, Importance of Clinical Reasoning, and Best Place to Learn Clinical Reasoning. Students recognized how clinical reasoning enhances safe and effective clinical practice and indicated the clinical arena was the most beneficial environment in which to learn clinical reasoning. CONCLUSION: Understanding students' perceptions of learning benefits nurse educators in planning nursing program curricula to enhance and facilitate the development of clinical reasoning. [J Nurs Educ. 2016;55(6):329-335.]. PMID- 27224462 TI - Evaluation Criteria for Nursing Student Application of Evidence-Based Practice: A Delphi Study. AB - BACKGROUND: Core clinical evaluation criteria do not exist for measuring prelicensure baccalaureate nursing students' application of evidence-based practice (EBP) during direct care assignments. The study objective was to achieve consensus among EBP nursing experts to create clinical criteria for faculty to use in evaluating students' application of EBP principles. METHOD: A three-round Delphi method was used. Experts were invited to participate in Web-based surveys. Data were analyzed using qualitative coding and categorizing. Quantitative analyses were descriptive calculations for rating and ranking. RESULTS: Expert consensus occurred in the Delphi rounds. The study provides a set of 10 core clinical evaluation criteria for faculty evaluating students' progression toward competency in their application of EBP. CONCLUSION: A baccalaureate program curriculum requiring the use of Bostwick's EBP Core Clinical Evaluation Criteria will provide a clear definition for understanding basic core EBP competence as expected for the assessment of student learning. [J Nurs Educ. 2016;55(5):336 341.]. PMID- 27224463 TI - Learning About and Benefiting From Peer Review: A Course Assignment for Doctoral Students at Two Different Universities. AB - BACKGROUND: Peer review is an expectation of PhD-prepared nurses but a lack of evidence in the best methods to train students is of concern. METHOD: Guided by the ADDIE (Analysis, Design, Development, Implementation, and Evaluation) model, faculty at two universities developed, implemented, and evaluated a peer review assignment for 22 second-year PhD nursing students. Quantitative and qualitative data were collected and analyzed using descriptive statistics and content analysis. RESULTS: Students reported the process of peer review was beneficial (82%) because it informed their own writing (59%), assisted them to read more critically (73%), and increased their appreciation of the role of peer review in the revision process (77%). Giving constructive feedback was difficult for students, but the feedback they received was helpful. CONCLUSION: Peer review is important to the development of science and an expectation of PhD-prepared nurses. Methods to include peer review in education are needed. [J Nurs Educ. 2016;55(6):342-344.]. PMID- 27224464 TI - Baccalaureate Nursing Students' Attitudes of Prejudice: A Qualitative Inquiry. AB - BACKGROUND: Attitudes of prejudice in nursing students have the potential to impact patient care and ultimately may contribute to culturally based health disparities. The purpose of this study was to describe attitudes of prejudice reported by baccalaureate nursing students. METHOD: Baccalaureate nursing students were recruited through Web networking and e-mailing. Participants responded to a Web-based survey that contained an open-ended item requesting them to describe a time when they held an attitude of prejudice. Qualitative data were coded and analyzed for themes. RESULTS: The majority of participants (N = 50) were women (86%) and White (68%). Qualitative data analysis revealed two major themes: Prejudice Against Obese Individuals, and Prejudice Against Someone of Another Race. Many of the participants had insight that prejudice was wrong and they wanted to change. CONCLUSION: Acknowledging prejudice, as an explicit bias, is an important step toward cultural competence. Teaching strategies focused on addressing explicit and implicit bias are warranted. [J Nurs Educ. 2016;55(6):345 348.]. PMID- 27224465 TI - Where Is the Nursing?: Baccalaureate Nursing Students' Perceptions of Nontraditional Child Health Clinical Placements. AB - BACKGROUND: Nursing students tend to look forward to their child health clinical placement in a hospital setting. However, there has been a shift away from hospital experiences to nontraditional community settings. When students are notified that the clinical settings are in the community, they often are disappointed. However, on completion of the placement, students' preconceptions about the community setting often have been changed positively. METHOD: This qualitative study using focus groups explored the pre- and postperceptions of nursing students in nontraditional clinical placements. RESULTS: The overarching theme was Where Is the Nursing? This theme was underpinned by subthemes of the value of the placement and role (expectations and self-identification as a nurse). CONCLUSION: Participants were able to identify key aspects of nursing (e.g., communication, building relationships), but many of the students did not view these as nursing skills. In addition, some participants had difficulty identifying their roles as nurses. [J Nurs Educ. 2016;55(6):349-352.]. PMID- 27224466 TI - Optimizing the Reflective Observer Role in High-Fidelity Patient Simulation. AB - BACKGROUND: The purpose of this descriptive secondary analysis of qualitative data was to gain insights into the role and opportunities of the reflective observer in high-fidelity patient simulation (HFPS). Although the value of HFPS in nursing education has been documented, the reflective observer role in HFPS may not be used to its potential. METHOD: This secondary data analysis of a broader study included qualitative interviews of those in observer roles (N = 23). This secondary analysis used content analysis to address research questions related to the reflective observer role. RESULTS: Three themes emerged related to using the reflective observer role for self-assessment, peer review and debriefing, and team-focused learning. CONCLUSION: Implications for nursing education, including orienting all HFPS participants to reflective observer roles and opportunities, are addressed. Further study of this important role for both individual and team learning is indicated. [J Nurs Educ. 2016;55(6):353-356.]. PMID- 27224467 TI - Nursing Student Work-Study Internship Program: An Academic Partnership. AB - BACKGROUND: A large northern California-based integrated health system and five universities partnered to conduct an innovative work-study internship program designed to address the education-to-practice gap for nursing students. METHOD: The nursing student work-study intern-ship program provides prelicensure nursing students with a paid internship in the health system. Interns are exposed to the realities of clinical practice and master learned skills working under the supervision of an RN preceptor. RESULTS: Work-study interns reported that participation in the program exposed them to new clinical situations, helped them integrate clinical knowledge and critical thinking skills, improved prioritization and time management skills, and expanded their communication skills within the interprofessional team. Interns cited feeling better equipped to safely and effectively transition into the new graduate role. CONCLUSION: The nursing student work-study program shows how an academic practice partnership can address the education-to-practice gap in an innovative manner. [J Nurs Educ. 2016;55(6):357-359.]. PMID- 27224468 TI - Using Shampoo to Explore Qualitative Research With Undergraduate Students. PMID- 27224469 TI - Efficacy of Short-Term Antiarrhythmic Drugs Use after Catheter Ablation of Atrial Fibrillation-A Systematic Review with Meta-Analyses and Trial Sequential Analyses of Randomized Controlled Trials. AB - BACKGROUND: The efficacy of short-term antiarrhythmic drugs (AADs) use compared with no-AADs prescription after catheter ablation of atrial fibrillation (AF) in preventing atrial arrhythmia recurrence is uncertain. METHODS: We searched PubMed, Embase, and the Cochrane Library through December 2015 to identify randomized controlled trials (RCTs) which evaluated the efficacy of short-term AADs use compared with no-AADs prescription after AF ablation in preventing atrial arrhythmia recurrence. The primary outcome was labeled as early atrial arrhythmia recurrence within 3 months after ablation. Secondary outcome was defined as late recurrence after 3 months of ablation. Random-effects model or fixed-effects model was used to estimate relative risks (RRs) with 95% confidence intervals (CIs). RESULTS: Six RCTs with 2,667 patients were included into this meta-analysis. Compared with no-AADs administration after AF ablation, short-term AADs use was associated with significant reduction of early atrial arrhythmia recurrence (RR, 0.68; 95% CI, 0.52-0.87; p = 0.003). Trial sequential analysis (TSA) showed that the cumulative Z-curve crossed the trial sequential monitoring boundary for benefit, establishing sufficient and conclusive evidence. However, compared with no-AADs prescription, short-term AADs use after AF ablation didn't significantly reduce the risk of late atrial arrhythmia recurrence (RR, 0.92; 95% CI, 0.83-1.03; p = 0.15). TSA supported this result; meanwhile the estimated required information size (1,486 patients) was also met. CONCLUSION: Short-term use of AADs after AF ablation can significantly decrease the risk of early atrial arrhythmia recurrence but not lead to corresponding reduction in risk of late atrial arrhythmia recurrence. PMID- 27224470 TI - Mind the gap: What is driving the survival disparity between the sexes in bladder cancer? PMID- 27224471 TI - The arboviral burden of disease caused by co-circulation and co-infection of dengue, chikungunya and Zika in the Americas. PMID- 27224472 TI - Post-operative morbidity and 1-year outcomes in CO2-laser tonsillotomy versus dissection tonsillectomy. AB - OBJECTIVE: In this study a type of partial tonsil surgery, CO2-laser tonsillotomy, was compared to regular tonsillectomy. The effectiveness and post operative recovery rate of both interventions in adult patients was assessed by using a questionnaire. STUDY DESIGN: Prospective follow-up non-randomized cohort study. METHOD: One hundred and seven adults were included; 46 tonsillectomies and 61 tonsillotomies were performed. Patients in the tonsillectomy group underwent general anaesthesia, while tonsillotomy was performed in an ambulatory setting with local anaesthesia. Post-operative questionnaires were administered by mail after 2 weeks, 6 months, and 1 year to assess recovery rate and symptom recurrence. RESULTS: In total, 72.5% of patients were cured from their initial symptoms after tonsillotomy. Three patients (7.5%) required re-surgery for their initial complaints. After tonsillectomy, 97.2% of patients were cured. Both groups showed equally high satisfaction scores after treatment. Post-operative evaluation after 2 weeks showed a mean pain-intensity score of 5.4 (Visual Analogue Scale 0-10) after tonsillotomy and a mean pain-intensity score of 7.7 after tonsillectomy. The post-operative use of analgesics was twice as long in the tonsillectomy group compared to the tonsillotomy group and the tonsillectomy group required twice as many days for full recovery. After tonsillectomy a higher rate of major post-operative haemorrhage was seen. CONCLUSION: CO2-laser tonsillotomy is associated with a shorter and less painful recovery period. Both surgical methods are equal in terms of long-term satisfaction, although tonsillotomy comes with a higher recurrence rate of mild symptoms. A strict pre operative patient selection for CO2-laser tonsillotomy is necessary. PMID- 27224473 TI - Density and Biomass Estimates by Removal for an Amazonian Crocodilian, Paleosuchus palpebrosus. AB - Direct counts of crocodilians are rarely feasible and it is difficult to meet the assumptions of mark-recapture methods for most species in most habitats. Catch out experiments are also usually not logistically or morally justifiable because it would be necessary to destroy the habitat in order to be confident that most individuals had been captured. We took advantage of the draining and filling of a large area of flooded forest during the building of the Santo Antonio dam on the Madeira River to obtain accurate estimates of the density and biomass of Paleosuchus palpebrosus. The density, 28.4 non-hatchling individuals per km2, is one of the highest reported for any crocodilian, except for species that are temporarily concentrated in small areas during dry-season drought. The biomass estimate of 63.15 kg*km-2 is higher than that for most or even all mammalian carnivores in tropical forest. P. palpebrosus may be one of the World's most abundant crocodilians. PMID- 27224474 TI - Neutrophil CD64 as a Marker of Bacterial Infection in Acute Exacerbations of Chronic Obstructive Pulmonary Disease. AB - Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are responsible for most mortality in patients with chronic obstructive pulmonary disease (COPD) and are caused mainly by bacterial infection. We analyzed and compared neutrophil CD64 expression (using the ratio of CD64 level in neutrophils to that in lymphocytes as an index), serum C-reactive protein (CRP), procalcitonin (PCT) levels, white blood cell (WBC) count, and neutrophil percentage among healthy subjects and patients with stable COPD or AECOPD. Compared with patients with COPD and healthy subjects, patients with AECOPD demonstrated significantly increased CD64 index, CRP, PCT, WBC count, and neutrophil percentage. Interestingly, CD64 index and PCT were both significantly higher in patients with AECOPD with positive bacterial sputum culture than those with negative culture. Furthermore, CD64 index and PCT were positively correlated in AECOPD, and there was also correlation between CD64 index and CRP, WBC, and neutrophil percentage. These data suggest that CD64 index is a relevant marker of bacterial infection in AECOPD. We divided patients with AECOPD into CD64-guided group and conventional treatment group. In CD64-guided group, clinicians prescribed antibiotics based on CD64 index; while in the conventional treatment group, clinicians relied on experience and clinical symptoms to determine the necessity for antibiotics. We found that the efficacy of antibiotic treatment in CD64-guided group was significantly improved compared with the conventional treatment group, including reduction of hospital stays and cost and shortened antibiotic treatment duration. Thus, the CD64 index has important diagnostic and therapeutic implications for antibiotic treatment of patients with AECOPD. PMID- 27224475 TI - Frailty - From concept to clinical practice. AB - Frailty has emerged as a true geriatric syndrome with increasing interest for both basic scientist as well as clinicians. The conceptual frame of a decreased resistance to internal and external stressors shows - when speaking of physical frailty - substantial overlaps to primary sarcopenia, the age-related loss of muscle mass. Consensus for the definition of frailty and sarcopenia is rapidly increasing and ease the path for a common understanding of these syndromes with high impact on functionality, independence and thereby quality of life of older adults. Ageing per se has long been thought to be unalterable and being the major cause for most chronic diseases and frailty. Significant increases in the understanding of cellular senescence now challenge this. Interventions may delay age-related conditions and thus compressing late-life morbidity with positive consequences for public health. Besides pharmacological interventions, lifestyle choices including diet and physical activity can optimize the biology of ageing and extend healthy life span. PMID- 27224476 TI - Combined Effects of Ocean Warming and Acidification on Copepod Abundance, Body Size and Fatty Acid Content. AB - Concerns about increasing atmospheric CO2 concentrations and global warming have initiated studies on the consequences of multiple-stressor interactions on marine organisms and ecosystems. We present a fully-crossed factorial mesocosm study and assess how warming and acidification affect the abundance, body size, and fatty acid composition of copepods as a measure of nutritional quality. The experimental set-up allowed us to determine whether the effects of warming and acidification act additively, synergistically, or antagonistically on the abundance, body size, and fatty acid content of copepods, a major group of lower level consumers in marine food webs. Copepodite (developmental stages 1-5) and nauplii abundance were antagonistically affected by warming and acidification. Higher temperature decreased copepodite and nauplii abundance, while acidification partially compensated for the temperature effect. The abundance of adult copepods was negatively affected by warming. The prosome length of copepods was significantly reduced by warming, and the interaction of warming and CO2 antagonistically affected prosome length. Fatty acid composition was also significantly affected by warming. The content of saturated fatty acids increased, and the ratios of the polyunsaturated essential fatty acids docosahexaenoic- (DHA) and arachidonic acid (ARA) to total fatty acid content increased with higher temperatures. Additionally, here was a significant additive interaction effect of both parameters on arachidonic acid. Our results indicate that in a future ocean scenario, acidification might partially counteract some observed effects of increased temperature on zooplankton, while adding to others. These may be results of a fertilizing effect on phytoplankton as a copepod food source. In summary, copepod populations will be more strongly affected by warming rather than by acidifying oceans, but ocean acidification effects can modify some temperature impacts. PMID- 27224477 TI - Extruding Loops to Make Loopy Globules? PMID- 27224478 TI - When Computer Simulation Excels Experiment. PMID- 27224479 TI - Single Filaments to Reveal the Multiple Flavors of Actin. AB - A number of key cell processes rely on specific assemblies of actin filaments, which are all constructed from nearly identical building blocks: the abundant and extremely conserved actin protein. A central question in the field is to understand how different filament networks can coexist and be regulated. Discoveries in science are often related to technical advances. Here, we focus on the ongoing single filament revolution and discuss how these techniques have greatly contributed to our understanding of actin assembly. In particular, we highlight how they have refined our understanding of the many protein-based regulatory mechanisms that modulate actin assembly. It is now becoming apparent that other factors give filaments a specific identity that determines which proteins will bind to them. We argue that single filament techniques will play an essential role in the coming years as we try to understand the many ways actin filaments can take different flavors and unveil how these flavors modulate the action of regulatory proteins. We discuss different factors known to make actin filaments distinguishable by regulatory proteins and speculate on their possible consequences. PMID- 27224480 TI - Platinum-Based Drugs and DNA Interactions Studied by Single-Molecule and Bulk Measurements. AB - Platinum-containing molecules are widely used as anticancer drugs. These molecules exert cytotoxic effects by binding to DNA through various mechanisms. The binding between DNA and platinum-based drugs hinders the opening of DNA, and therefore, DNA duplication and transcription are severely hampered. Overall, impeding the above-mentioned important DNA mechanisms results in irreversible DNA damage and the induction of apoptosis. Several molecules, including multinuclear platinum compounds, belong to the family of platinum drugs, and there is a body of research devoted to developing more efficient and less toxic versions of these compounds. In this study, we combined different biophysical methods, including single-molecule assays (magnetic tweezers) and bulk experiments (ultraviolet absorption for thermal denaturation) to analyze the differential stability of double-stranded DNA in complex with either cisplatin or multinuclear platinum agents. Specifically, we analyzed how the binding of BBR3005 and BBR3464, two representative multinuclear platinum-based compounds, to DNA affects its stability as compared with cisplatin binding. Our results suggest that single molecule approaches can provide insights into the drug-DNA interactions that underlie drug potency and provide information that is complementary to that generated from bulk analysis; thus, single-molecule approaches have the potential to facilitate the selection and design of optimized drug compounds. In particular, relevant differences in DNA stability at the single-molecule level are demonstrated by analyzing nanomechanically induced DNA denaturation. On the basis of the comparison between the single-molecule and bulk analyses, we suggest that transplatinated drugs are able to locally destabilize small portions of the DNA chain, whereas other regions are stabilized. PMID- 27224481 TI - Chromosome Compaction by Active Loop Extrusion. AB - During cell division, chromosomes are compacted in length by more than a 100 fold. A wide range of experiments demonstrated that in their compacted state, mammalian chromosomes form arrays of closely stacked consecutive ~100 kb loops. The mechanism underlying the active process of chromosome compaction into a stack of loops is unknown. Here we test the hypothesis that chromosomes are compacted by enzymatic machines that actively extrude chromatin loops. When such loop extruding factors (LEF) bind to chromosomes, they progressively bridge sites that are further away along the chromosome, thus extruding a loop. We demonstrate that collective action of LEFs leads to formation of a dynamic array of consecutive loops. Simulations and an analytically solved model identify two distinct steady states: a sparse state, where loops are highly dynamic but provide little compaction; and a dense state, where there are more stable loops and dramatic chromosome compaction. We find that human chromosomes operate at the border of the dense steady state. Our analysis also shows how the macroscopic characteristics of the loop array are determined by the microscopic properties of LEFs and their abundance. When the number of LEFs are used that match experimentally based estimates, the model can quantitatively reproduce the average loop length, the degree of compaction, and the general loop-array morphology of compact human chromosomes. Our study demonstrates that efficient chromosome compaction can be achieved solely by an active loop-extrusion process. PMID- 27224482 TI - Stable Domain Assembly of a Monomolecular DNA Quadruplex: Implications for DNA Based Nanoswitches. AB - In the presence of K(+) ions, the 5'-GGGTGGGTGGGTGGG-3' (G3T) sequence folds into a monomolecular quadruplex with unusually high thermal stability and unique optical properties. In this study we report that although single G3T molecules unfold and fold rapidly with overlapping melting and refolding curves, G3T multimers (G3T units covalently attached to each other) demonstrate highly reproducible hysteretic behavior. We demonstrate that this behavior necessitates full-length tandem G3T monomers directly conjugated to each other. Any modification of the tandem sequences eliminates the hysteresis. The experimentally measured kinetic parameters and equilibrium transition profiles suggest a highly specific two-state transition in which the folding and unfolding of the first G3T monomer is rate-limiting for both annealing and melting processes. The highly reproducible hysteretic behavior of G3T multimers has the potential to be used in the design of heat-stimulated DNA switches or transistors. PMID- 27224483 TI - Simulation of DNA Supercoil Relaxation. AB - Several recent single-molecule experiments observe the response of supercoiled DNA to nicking endonucleases and topoisomerases. Typically in these experiments, indirect measurements of supercoil relaxation are obtained by observing the motion of a large micron-sized bead. The bead, which also serves to manipulate DNA, experiences significant drag and thereby obscures supercoil dynamics. Here we employ our discrete wormlike chain model to bypass experimental limitations and simulate the dynamic response of supercoiled DNA to a single strand nick. From our simulations, we make three major observations. First, extension is a poor dynamic measure of supercoil relaxation; in fact, the linking number relaxes so fast that it cannot have much impact on extension. Second, the rate of linking number relaxation depends upon its initial partitioning into twist and writhe as determined by tension. Third, the extensional response strongly depends upon the initial position of plectonemes. PMID- 27224484 TI - SAXS/SANS on Supercharged Proteins Reveals Residue-Specific Modifications of the Hydration Shell. AB - Water molecules in the immediate vicinity of biomacromolecules, including proteins, constitute a hydration layer characterized by physicochemical properties different from those of bulk water and play a vital role in the activity and stability of these structures, as well as in intermolecular interactions. Previous studies using solution scattering, crystallography, and molecular dynamics simulations have provided valuable information about the properties of these hydration shells, including modifications in density and ionic concentration. Small-angle scattering of x-rays (SAXS) and neutrons (SANS) are particularly useful and complementary techniques to study biomacromolecular hydration shells due to their sensitivity to electronic and nuclear scattering length density fluctuations, respectively. Although several sophisticated SAXS/SANS programs have been developed recently, the impact of physicochemical surface properties on the hydration layer remains controversial, and systematic experimental data from individual biomacromolecular systems are scarce. Here, we address the impact of physicochemical surface properties on the hydration shell by a systematic SAXS/SANS study using three mutants of a single protein, green fluorescent protein (GFP), with highly variable net charge (+36, -6, and -29). The combined analysis of our data shows that the hydration shell is locally denser in the vicinity of acidic surface residues, whereas basic and hydrophilic/hydrophobic residues only mildly modify its density. Moreover, the data demonstrate that the density modifications result from the combined effect of residue-specific recruitment of ions from the bulk in combination with water structural rearrangements in their vicinity. Finally, we find that the specific surface-charge distributions of the different GFP mutants modulate the conformational space of flexible parts of the protein. PMID- 27224486 TI - Reconstitution of Human Ion Channels into Solvent-free Lipid Bilayers Enhanced by Centrifugal Forces. AB - Artificially formed bilayer lipid membranes (BLMs) provide well-defined systems for functional analyses of various membrane proteins, including ion channels. However, difficulties associated with the integration of membrane proteins into BLMs limit the experimental efficiency and usefulness of such BLM reconstitution systems. Here, we report on the use of centrifugation to more efficiently reconstitute human ion channels in solvent-free BLMs. The method improves the probability of membrane fusion. Membrane vesicles containing the human ether-a-go go-related gene (hERG) channel, the human cardiac sodium channel (Nav1.5), and the human GABAA receptor (GABAAR) channel were formed, and the functional reconstitution of the channels into BLMs via vesicle fusion was investigated. Ion channel currents were recorded in 67% of the BLMs that were centrifuged with membrane vesicles under appropriate centrifugal conditions (14-55 * g). The characteristic channel properties were retained for hERG, Nav1.5, and GABAAR channels after centrifugal incorporation into the BLMs. A comparison of the centrifugal force with reported values for the fusion force revealed that a centrifugal enhancement in vesicle fusion was attained, not by accelerating the fusion process but by accelerating the delivery of membrane vesicles to the surface of the BLMs, which led to an increase in the number of membrane vesicles that were available for fusion. Our method for enhancing the probability of vesicle fusion promises to dramatically increase the experimental efficiency of BLM reconstitution systems, leading to the realization of a BLM-based, high throughput platform for functional assays of various membrane proteins. PMID- 27224487 TI - Geometry of the Contact Zone between Fused Membrane-Coated Beads Mimicking Cell Cell Fusion. AB - The fusion of lipid membranes is a key process in biology. It enables cells and organelles to exchange molecules with their surroundings, which otherwise could not cross the membrane barrier. To study such complex processes we use simplified artificial model systems, i.e., an optical fusion assay based on membrane-coated glass spheres. We present a technique to analyze membrane-membrane interactions in a large ensemble of particles. Detailed information on the geometry of the fusion stalk of fully fused membranes is obtained by studying the diffusional lipid dynamics with fluorescence recovery after photobleaching experiments. A small contact zone is a strong obstruction for the particle exchange across the fusion spot. With the aid of computer simulations, fluorescence-recovery-after photobleaching recovery times of both fused and single-membrane-coated beads allow us to estimate the size of the contact zones between two membrane-coated beads. Minimizing delamination and bending energy leads to minimal angles close to those geometrically allowed. PMID- 27224485 TI - Relative Orientation of POTRA Domains from Cyanobacterial Omp85 Studied by Pulsed EPR Spectroscopy. AB - Many proteins of the outer membrane of Gram-negative bacteria and of the outer envelope of the endosymbiotically derived organelles mitochondria and plastids have a beta-barrel fold. Their insertion is assisted by membrane proteins of the Omp85-TpsB superfamily. These proteins are composed of a C-terminal beta-barrel and a different number of N-terminal POTRA domains, three in the case of cyanobacterial Omp85. Based on structural studies of Omp85 proteins, including the five POTRA-domain-containing BamA protein of Escherichia coli, it is predicted that anaP2 and anaP3 bear a fixed orientation, whereas anaP1 and anaP2 are connected via a flexible hinge. We challenged this proposal by investigating the conformational space of the N-terminal POTRA domains of Omp85 from the cyanobacterium Anabaena sp. PCC 7120 using pulsed electron-electron double resonance (PELDOR, or DEER) spectroscopy. The pronounced dipolar oscillations observed for most of the double spin-labeled positions indicate a rather rigid orientation of the POTRA domains in frozen liquid solution. Based on the PELDOR distance data, structure refinement of the POTRA domains was performed taking two different approaches: 1) treating the individual POTRA domains as rigid bodies; and 2) using an all-atom refinement of the structure. Both refinement approaches yielded ensembles of model structures that are more restricted compared to the conformational ensemble obtained by molecular dynamics simulations, with only a slightly different orientation of N-terminal POTRA domains anaP1 and anaP2 compared with the x-ray structure. The results are discussed in the context of the native environment of the POTRA domains in the periplasm. PMID- 27224488 TI - Microtubule Defects Influence Kinesin-Based Transport In Vitro. AB - Microtubules are protein polymers that form "molecular highways" for long-range transport within living cells. Molecular motors actively step along microtubules to shuttle cellular materials between the nucleus and the cell periphery; this transport is critical for the survival and health of all eukaryotic cells. Structural defects in microtubules exist, but whether these defects impact molecular motor-based transport remains unknown. Here, we report a new, to our knowledge, approach that allowed us to directly investigate the impact of such defects. Using a modified optical-trapping method, we examined the group function of a major molecular motor, conventional kinesin, when transporting cargos along individual microtubules. We found that microtubule defects influence kinesin based transport in vitro. The effects depend on motor number: cargos driven by a few motors tended to unbind prematurely from the microtubule, whereas cargos driven by more motors tended to pause. To our knowledge, our study provides the first direct link between microtubule defects and kinesin function. The effects uncovered in our study may have physiological relevance in vivo. PMID- 27224489 TI - Resolving Fast, Confined Diffusion in Bacteria with Image Correlation Spectroscopy. AB - By following single fluorescent molecules in a microscope, single-particle tracking (SPT) can measure diffusion and binding on the nanometer and millisecond scales. Still, although SPT can at its limits characterize the fastest biomolecules as they interact with subcellular environments, this measurement may require advanced illumination techniques such as stroboscopic illumination. Here, we address the challenge of measuring fast subcellular motion by instead analyzing single-molecule data with spatiotemporal image correlation spectroscopy (STICS) with a focus on measurements of confined motion. Our SPT and STICS analysis of simulations of the fast diffusion of confined molecules shows that image blur affects both STICS and SPT, and we find biased diffusion rate measurements for STICS analysis in the limits of fast diffusion and tight confinement due to fitting STICS correlation functions to a Gaussian approximation. However, we determine that with STICS, it is possible to correctly interpret the motion that blurs single-molecule images without advanced illumination techniques or fast cameras. In particular, we present a method to overcome the bias due to image blur by properly estimating the width of the correlation function by directly calculating the correlation function variance instead of using the typical Gaussian fitting procedure. Our simulation results are validated by applying the STICS method to experimental measurements of fast, confined motion: we measure the diffusion of cytosolic mMaple3 in living Escherichia coli cells at 25 frames/s under continuous illumination to illustrate the utility of STICS in an experimental parameter regime for which in-frame motion prevents SPT and tight confinement of fast diffusion precludes stroboscopic illumination. Overall, our application of STICS to freely diffusing cytosolic protein in small cells extends the utility of single-molecule experiments to the regime of fast confined diffusion without requiring advanced microscopy techniques. PMID- 27224490 TI - Angular Approach Scanning Ion Conductance Microscopy. AB - Scanning ion conductance microscopy (SICM) is a super-resolution live imaging technique that uses a glass nanopipette as an imaging probe to produce three dimensional (3D) images of cell surface. SICM can be used to analyze cell morphology at nanoscale, follow membrane dynamics, precisely position an imaging nanopipette close to a structure of interest, and use it to obtain ion channel recordings or locally apply stimuli or drugs. Practical implementations of these SICM advantages, however, are often complicated due to the limitations of currently available SICM systems that inherited their design from other scanning probe microscopes in which the scan assembly is placed right above the specimen. Such arrangement makes the setting of optimal illumination necessary for phase contrast or the use of high magnification upright optics difficult. Here, we describe the designs that allow mounting SICM scan head on a standard patch-clamp micromanipulator and imaging the sample at an adjustable approach angle. This angle could be as shallow as the approach angle of a patch-clamp pipette between a water immersion objective and the specimen. Using this angular approach SICM, we obtained topographical images of cells grown on nontransparent nanoneedle arrays, of islets of Langerhans, and of hippocampal neurons under upright optical microscope. We also imaged previously inaccessible areas of cells such as the side surfaces of the hair cell stereocilia and the intercalated disks of isolated cardiac myocytes, and performed targeted patch-clamp recordings from the latter. Thus, our new, to our knowledge, angular approach SICM allows imaging of living cells on nontransparent substrates and a seamless integration with most patch clamp setups on either inverted or upright microscopes, which would facilitate research in cell biophysics and physiology. PMID- 27224492 TI - Phenotypic Diversity Using Bimodal and Unimodal Expression of Stress Response Proteins. AB - Populations of cells need to express proteins to survive the sudden appearance of stressors. However, these mechanisms may be taxing. Populations can introduce diversity, allowing individual cells to stochastically switch between fast growing and stress-tolerant states. One way to achieve this is to use genetic networks coupled with noise to generate bimodal distributions with two distinct subpopulations, each adapted to a stress condition. Another survival strategy is to rely on random fluctuations in gene expression to produce continuous, unimodal distributions of the stress response protein. To quantify the environmental conditions where bimodal versus unimodal expression is beneficial, we used a differential evolution algorithm to evolve optimal distributions of stress response proteins given environments with sudden fluctuations between low and high stress. We found that bimodality evolved for a large range of environmental conditions. However, we asked whether these findings were an artifact of considering two well-defined stress environments (low and high stress). As noise in the environment increases, or when there is an intermediate environment (medium stress), the benefits of bimodality decrease. Our results indicate that under realistic conditions, a continuum of resistance phenotypes generated through a unimodal distribution is sufficient to ensure survival without a high cost to the population. PMID- 27224491 TI - Emergence of Collagen Orientation Heterogeneity in Healing Infarcts and an Agent Based Model. AB - Spatial heterogeneity of matrix structure can be an important determinant of tissue function. Although bulk properties of collagen structure in healing myocardial infarcts have been characterized previously, regional heterogeneity in infarct structure has received minimal attention. Herein, we quantified regional variations of collagen and nuclear orientations over the initial weeks of healing after infarction in rats, and employed a computational model of infarct remodeling to test potential explanations for the heterogeneity we observed in vivo. Fiber and cell orientation maps were generated from infarct samples acquired previously at 1, 2, 3, and 6 weeks postinfarction in a rat ligation model. We analyzed heterogeneity by calculating the dot product of each fiber or cell orientation vector with every other fiber or cell orientation vector, and plotting that dot product versus distance between the fibers or cells. This analysis revealed prominent regional heterogeneity, with alignment of both fibers and cell nuclei in local pockets far exceeding the global average. Using an agent based model of fibroblast-mediated collagen remodeling, we found that similar levels of heterogeneity can spontaneously emerge from initially isotropic matrix via locally reinforcing cell-matrix interactions. Specifically, cells that sensed fiber orientation at a distance or remodeled fibers at a distance by traction mediated reorientation or aligned deposition gave rise to regionally heterogeneous structures. However, only the simulations in which cells deposited collagen fibers aligned with their own orientation reproduced experimentally measured patterns of heterogeneity across all time points. These predictions warrant experimental follow-up to test the role of such mechanisms in vivo and identify opportunities to control heterogeneity for therapeutic benefit. PMID- 27224493 TI - The changing epidemiology and aetiology of hepatocellular carcinoma from 1969 through 2013 in Alaska Native people. AB - BACKGROUND & AIMS: Alaska Native people have an increased rate of hepatocellular carcinoma compared to the United States population. Viral hepatitis is a risk factor for malignancy and the leading cause of hepatocellular carcinoma in Alaska. With the introduction of hepatitis B immunization in 1982, as well as the emergence of hepatitis C virus in this population, the epidemiology and aetiology of hepatocellular carcinoma in Alaska have changed. METHODS: Using the Alaska Native Tumor Registry, all cases of viral and non-viral hepatocellular carcinoma occurring from 1969 through 2013 were identified and reviewed. Incidence rates per 100 000 population were calculated for hepatocellular carcinoma overall and by aetiological category. RESULTS: One hundred and fifty-two cases of hepatocellular carcinoma were identified in 148 Alaska Native persons. Overall tumour rate was 3.82 per 100 000 and did not change significantly over the study period. Hepatitis B-associated cases decreased significantly over the study period (P = 0.048) and were eliminated in persons under the age of 20. Hepatitis C-associated cases increased significantly (P < 0.001). Undetermined hepatocellular carcinoma rates also decreased (P = 0.034). CONCLUSIONS: Overall hepatocellular carcinoma rates in Alaska Native people remained stable over the study period, but the epidemiology and aetiology are changing. Two decades after routine hepatitis B immunization, the hepatocellular carcinoma age distribution has shifted to cases presenting later in life. This is consistent with an ageing hepatitis B-infected population with no new infected young persons' coming into the population, as well as the emergence of hepatitis C in adults. PMID- 27224494 TI - Impact of the Kohn-Sham Delocalization Error on the 4f Shell Localization and Population in Lanthanide Complexes. AB - The extent of ligand to metal donation bonding and mixing of 4f (and 5d) orbitals with ligand orbitals is studied by Kohn-Sham (KS) calculations for LaX3 (X = F, Cl, Br, I), GdX3, and LuX3 model complexes, CeCl6(2-), YbCp3, and selected lanthanide complexes with larger ligands. The KS delocalization error (DE) is quantified via the curvature of the energy for noninteger electron numbers. The extent of donation bonding and 4f-ligand mixing correlates well with the DE. For Lu complexes, the DE also correlates with the extent of mixing of ligand and 4f orbitals in the canonical molecular orbitals (MOs). However, the localized set of MOs and population analyses indicate that the closed 4f shell is localized. Attempts to create situations where mixing of 4f and ligand orbitals occurs due to a degeneracy of fragment orbitals were unsuccessful. For La(III) and, in particular, for Ce(IV), Hartree-Fock, KS, and coupled cluster singles and doubles calculations are in agreement in that excess 4f populations arise from ligand donation, along with donation into the 5d shell. Likewise, KS calculations for all systems with incompletely filled 4f shells, even those with "optimally tuned" functionals affording a small DE, produce varying degrees of excess 4f populations which may be only partially attributed to 5d polarization. PMID- 27224495 TI - Ichthyosis Prematurity Syndrome: From Fetus to Adulthood. PMID- 27224496 TI - The Role of Nutrition in Frailty: An Overview. AB - Inadequate nutritional intake is an important modifiable risk factor for frailty. Existing evidence supports the importance of adequate dietary quantity and especially quality to ensure sufficient intakes of energy, protein and micronutrients. However, to date no nutritional intervention or supplementation concept has emerged as being effective for the prevention or treatment of frailty. Further research, including specifically the group of frail older persons and those at risk of frailty, and focussing on functional benefits as an outcome, is needed to allow definite recommendations for optimal diet, i.e. food and nutrient intakes, for this population. This article aims to give a short overview on current knowledge concerning the role of nutrition for the prevention and treatment of frailty, while providing readers with references giving an overview for further reading. PMID- 27224497 TI - Construct Validity of Four Frailty Measures in an Older Australian Population: A Rasch Analysis. AB - Individuals identified as frail have been shown to be at an increased risk of adverse health outcomes. However, there is no gold standard frailty measure and frailty status can vary depending on the measure used, suggesting the measures perform differently. Construct validity can be used to assess a measure's performance. This study aimed to examine the construct validity of four frailty measures in an Australian older population using Rasch analysis. Frailty status among the 2087 participants aged 65 years and above from the Australian Longitudinal Study of Ageing (ALSA) was assessed using: frailty phenotype--FP, simplified frailty phenotype--SFP, frailty index--FI, and prognostic frailty score--PFS. Rasch analysis was used to assess the unidimensionality of the measures, which is the extent to which the underlying characteristic of frailty is assessed. The criteria for unidimensionality from principal component analysis of the residuals was when 50% or more of the raw variance was explained by the measures, and less than 5% was unexplained variance. Only FI meet the unidimensionality criteria with 74% of explained variance and 2.1% of unexplained variance. SFP did not show a unidimensional construct with 13.3% of explained variance and 47.1% of unexplained variance. FP and PFS had 39.6%, 18.1% and 46.5%, 8.7% of explained and unexplained variance, respectively. Our findings showed that FI has better construct validity than the other three measures in assessing frailty among the Australian older population. PMID- 27224498 TI - Disseminating a Clinically Effective Physical Activity Program to Preserve Mobility in a Community Setting for Older Adults. AB - BACKGROUND: As the population of older adults continues to increase, the dissemination of strategies to maintain independence of older persons is of critical public health importance. Recent large-scale clinical trial evidence has definitively shown intervention of moderate-intensity physical activity (PA) reduces major mobility disability in at-risk older adults. However, it remains unknown whether structured PA interventions, with demonstrated efficacy in controlled, clinical environments, can be successfully disseminated into community settings to benefit wider populations of older adults. OBJECTIVE: To assess the dissemination of an evidence-based PA program for older adults by evaluating program participation and its impact on mobility, strength and quality of life. SETTING: An urban senior center. PARTICIPANTS: Fifty older adults (71.2 +/- 8 years aged; BMI: 30.1 +/- 7 kg/m2). INTERVENTION: Average of 8.0 +/- 1.8 months of participation in the Fit-4-Life Program, a community-based PA and nutrition counseling intervention. MEASUREMENTS: Mobility (Short Physical Performance Battery (SPPB)), self-reported physical activity (CHAMPS questionnaire), leg strength, grip strength, and quality of life (Quality of Well Being Self-Administered (QWB-SA) scale) were assessed at baseline and follow-up. RESULTS: Mean attendance was 55.8%. Fourteen participants were lost to follow-up. Those who dropped-out engaged in less PA at baseline (78 +/- 108 mins/wk) compared to those who completed follow-up (203 +/- 177 mins/wk, P=0.01). Participants exhibited sustained increases of PA (65 +/- 153 mins/wk, P= 0.08), and there were meaningful improvements in SPPB (0.5 +/- 0.2, P< 0.01), knee extensor strength (2.6 +/- 4.4 kg, P< 0.01) and QWB-SA (0.04 +/- 0.09, P= 0.05). CONCLUSION: The dissemination of a clinically efficacious PA intervention into a community-based setting can improve mobility, strength and quality of life for older adults. This knowledge may be helpful for the design and implementation of larger-scale PA intervention studies designed to preserve mobility in older adults within community-based settings. PMID- 27224499 TI - Systematic Literature Review on the Relationship Between Biomarkers of Sarcopenia and Quality of Life in Older People. AB - Sarcopenia is a multi-faceted geriatric syndrome that is prevalent in the older population. It is an independent risk factor for a variety of devastating health outcomes that threaten the independence of older people. Quality of life is also very important to older people. The objective of this systematic review therefore was to determine the relationship between the biomarkers of sarcopenia (or sarcopenia) and health related quality of life in older people. Systematic searches were done using the electronic databases from MEDLINE and EMBASE. Search terms included sarcopenia, biomarkers of sarcopenia (e.g. muscle mass, grip strength, muscle performance), and health related quality of life. A total of 20 studies were finally included in this review. Only four studies were deemed of good quality. Sarcopenia was associated with poor health related quality of life in both genders from the one cross sectional study defining sarcopenia as per consensus definition. One high quality longitudinal study demonstrated that better physical performance and muscle strength was associated with a slower rate of decline in health related quality of life over six years. Muscle performance and strength were associated with health related quality of life but muscle mass was not in cross-sectional studies. Good quality and longitudinal studies where sarcopenia is defined as per consensus guidelines are required if the impact of the disease on quality of life is to be clarified. PMID- 27224500 TI - Frailty and Drug Use. PMID- 27224501 TI - Measuring the Effect of Carers on Patients' Risk of Adverse Healthcare Outcomes Using the Caregiver Network Score. AB - BACKGROUND: Although caregivers are important in the management of frail, community-dwelling older adults, the influence of different caregiver network types on the risk of adverse healthcare outcomes is unknown. OBJECTIVE: To examine the association between caregiver type and the caregiver network subtest of The Risk Instrument for Screening in the Community (RISC), a five point Likert scale scored from one ("can manage") to five ("absent/liability"). To measure the association between caregiver network scores and the one-year incidence of institutionalisation, hospitalisation and death. DESIGN: Observational cohort study. SETTING AND PARTICIPANTS: Community-dwelling adults, aged >65, attending health centres in Ireland, (n=779). PROCEDURE AND MEASUREMENTS: The caregiver network subtest of the RISC was scored by public health nurses. Caregivers were grouped dichotomously into low-risk (score of one) or high-risk (scores two five). RESULTS: The majority of patients had a primary caregiver (582/779; 75%), most often their child (200/582; 34%). Caregiver network scores were highest, indicating greatest risk, when patients had no recognised primary caregiver and lowest when only a spouse or child was available. Despite this, patients with a caregiver were significantly more likely to be institutionalised than those where none was required or identified (11.5% versus 6.5%, p=0.047). The highest one year incidence of adverse outcomes occurred when state provided care was the sole support; the lowest when private care was the sole support. Significantly more patients whose caregiver networks were scored high-risk required institutionalisation than low-risk networks; this association was strongest for perceived difficulty managing medical domain issues, odds ratio (OR) 3.87:(2.22 6.76). Only perceived difficulty managing ADL was significantly associated with death, OR 1.72:(1.06-2.79). There was no association between caregiver network scores and risk of hospitalisation. CONCLUSION: This study operationalizes a simple method to evaluate caregiver networks. Networks consisting of close family (spouse/children) and those reflecting greater socioeconomic privilege (private supports) were associated with lower incidence of adverse outcomes. Caregiver network scores better predicted institutionalisation than hospitalisation or death. PMID- 27224502 TI - Association between Perceived Ethnic Discrimination and Health: Evidence from the National Latino and Asian American Study (NLAAS). AB - BACKGROUND: The field of aging studies continues to better understand between racial-group health disparities. Previous work provides empirical evidence for a statistical relationship between perceived discrimination and adverse health across all age groups. SPECIFIC AIM: We contribute to the literature by investigating the quantitative relationship between Perceived Ethnic Discrimination (PED), Self-Rated Physical Health (SR-PH), Self-Rated Mental Health (SR-MH), and their combined score (SR-PH-MH). SETTING AND DESIGN: The cross-sectional observational study used data collected between 2002 and 2004 from the National Latino and Asian American Study (n=4,559; average age=41; 54% female; 18% Mexican; 36% Non-Mexican Latinos; 12% Chinese; 31% Non-Chinese Asians). We provide descriptive statistics for those below and at or above age 65. RESULTS: Multivariable linear models adjusting for age, sex, ethnicity, education, body mass index, and neighborhood perception provide evidence that although a small effect, PED explains between-people variance in SR-PH (beta= 0.01; alpha=0.001), SR-MH (beta=-0.03; alpha=0.001), and SR-PH-MH (beta=-0.04; alpha=0.001). CONCLUSIONS: The analysis supports arguments that PED has a non random association with health. As we continue to explore novel measures of frailty, markers of social stress should be considered. PMID- 27224503 TI - Social Determinants of Discharge Outcomes in Older People Admitted to a Geriatric Medicine Ward. AB - The factors determining hospital discharge outcomes in older people are complex. This retrospective study was carried out in an in-patient geriatric ward over a month in 2015 and aimed to explore if self-reported feeling of loneliness and clinical frailty contribute to longer hospital stays or higher rates of readmission to hospital after discharge in the older population. Twenty-two men and twenty-five women (mean age 85.1 years) were assessed. There was a significant multivariate association between both self-reported loneliness (p=0.021) and the Clinical Frailty Scale (p=0.010) with length of stay, after adjusting for age, dementia and living alone. In multivariate analysis, patients who lived alone were more likely to be readmitted to hospital within 30 days (p=0.036). Loneliness, living alone and clinical frailty were associated with adverse discharge outcomes. Lower thresholds for referral to voluntary organisations and for psychosocial interventions in patients who report loneliness or live alone may be beneficial. PMID- 27224504 TI - Higher Physiotherapy Frequency Is Associated with Shorter Length of Stay and Greater Functional Recovery in Hospitalized Frail Older Adults: A Retrospective Observational Study. AB - Extra physiotherapy has been associated with better outcomes in hospitalized patients, but this remains an under-researched area in geriatric medicine wards. We retrospectively studied the association between average physiotherapy frequency and outcomes in hospitalized geriatric patients. High frequency physiotherapy (HFP) was defined as >=0.5 contacts/day. Of 358 eligible patients, 131 (36.6%) received low, and 227 (63.4%) HFP. Functional improvement (discharge versus admission) in the modified Rankin scale was greater in the HFP group (1.1 versus 0.7 points, P<0.001). The mean length of stay (LOS) of the HFP group was 6 days shorter (7 versus 13 days, P<0.001). After adjusting for age, gender, comorbidity (Charlson index), frailty (Clinical Frailty Scale), dementia and acute illness severity, HFP was an independent predictor of functional improvement, shorter LOS and likelihood of being discharged without a formal care package. Prospective research is needed to examine the effect of physiotherapy frequency and intensity in geriatric wards. PMID- 27224505 TI - Resistance Training and Co-supplementation with Creatine and Protein in Older Subjects with Frailty. AB - BACKGROUND: Studies assessing the effects co-supplementation with creatine and protein, along with resistance training, in older individuals with frailty are lacking. OBJECTIVES: This is an exploratory trial from the Pro-Elderly study ("Protein Intake and Resistance Training in Aging") aimed at gathering knowledge on the feasibility, safety, and efficacy of co-supplementation with creatine and protein supplementation, combined with resistance training, in older individuals with frailty. DESIGN: A 14-week, double-blind, randomized, parallel-group, placebo controlled exploratory trial. SETTING, PARTICIPANTS: The subjects were randomly assigned to whey protein and creatine co-supplementation (WHEY+CR) or whey protein supplementation (WHEY) group. All subjects undertook a supervised exercise training program and were assessed at baseline and after 14 weeks. MEASUREMENTS: Muscle function, body composition, blood parameters, and self reported adverse events were assessed. RESULTS: No interaction effects (between group differences) were observed for any dependent variables (p > 0.05 for all). However, there were main time-effects in handgrip (WHEY+CR = 26.65 +/- 31.29; WHEY = 13.84 +/- 14.93 Kg; p = 0.0005), timed-up-and-go (WHEY+CR = -11.20 +/- 9.37; WHEY = -17.76 +/- 21.74 sec; p = 0.006), and timed-stands test (WHEY+CR = 47.50 +/- 35.54; WHEY = 46.87 +/- 24.23 reps; p = 0.0001), suggesting that WHEY+CR and WHEY were similarly effective in improving muscle function. All of the subjects showed improvements in at least two of the three functional tests, regardless of their treatments. Body composition and blood parameters were not changed (p > 0.05). No severe adverse effects were observed. CONCLUSIONS: Co supplementation with creatine and whey protein was well-tolerable and free of adverse events in older subjects with frailty undertaking resistance training. Creatine supplementation did not augment the adaptive effects of resistance training along with whey protein on body composition or muscle function in this population. Clinicaltrials.gov: NCT01890382. PMID- 27224506 TI - The hepatocyte growth factor isoform NK2 activates motogenesis and survival but not proliferation due to lack of Akt activation. AB - Hepatocyte growth factor (HGF) is a pleiotrophic factor involved in cellular proliferation, migration and morphogenesis. HGF is required for normal tissue and organ development during embryogenesis, but in the adult HGF has been demonstrated to drive normal tissue repair and inhibit fibrotic remodeling. HGF has two naturally occurring human isoforms as a result of alternative splicing, NK1 and NK2. While NK1 has been defined as an agonist for HGF receptor, Met, NK2 is defined as a partial Met antagonist. Furthermore, under conditions of fibrotic remodeling, NK2 is still expressed while full length HGF is suppressed. Furthermore, the mechanism by which NK2 partially signals through Met is not completely understood. Here, we investigated the mitogenic, motogenic, and anti apoptotic activities of NK2 compared with full length HGF in primary human bronchial epithelial cells (BEpC) and bovine pulmonary artery endothelial cells (PAEC). In human BEpC, NK2 partial activated Met, inducing Met phosphorylation at Y1234/1235 in the tyrosine-kinase domain but not at Y1349 site in the multifunctional docking domain. Partial phosphorylation of Met by NK2 resulted in activation of MAPK and STAT3, but not AKT. This correlated with motogenesis and survival in a MAPK-dependent manner, but not cell proliferation. Overexpression of a constitutively active AKT complemented NK2 signaling, allowing NK2 to induce cell proliferation. These data indicate that NK2 and HGF drive motogenic and anti apoptotic signaling but only HGF drives cell proliferation by activating AKT pathway signaling. These results have implications for the biological consequences of differential regulation of the two isoforms under pro-fibrotic conditions. PMID- 27224508 TI - Functionalized anatomical models for EM-neuron Interaction modeling. AB - The understanding of interactions between electromagnetic (EM) fields and nerves are crucial in contexts ranging from therapeutic neurostimulation to low frequency EM exposure safety. To properly consider the impact of in vivo induced field inhomogeneity on non-linear neuronal dynamics, coupled EM-neuronal dynamics modeling is required. For that purpose, novel functionalized computable human phantoms have been developed. Their implementation and the systematic verification of the integrated anisotropic quasi-static EM solver and neuronal dynamics modeling functionality, based on the method of manufactured solutions and numerical reference data, is described. Electric and magnetic stimulation of the ulnar and sciatic nerve were modeled to help understanding a range of controversial issues related to the magnitude and optimal determination of strength-duration (SD) time constants. The results indicate the importance of considering the stimulation-specific inhomogeneous field distributions (especially at tissue interfaces), realistic models of non-linear neuronal dynamics, very short pulses, and suitable SD extrapolation models. These results and the functionalized computable phantom will influence and support the development of safe and effective neuroprosthetic devices and novel electroceuticals. Furthermore they will assist the evaluation of existing low frequency exposure standards for the entire population under all exposure conditions. PMID- 27224509 TI - Toxicokinetic and toxicodynamic considerations when deriving health-based exposure limits for pharmaceuticals. AB - The purpose of this paper is to describe the use of toxicokinetic (TK) and toxicodynamic (TD) data in setting acceptable daily exposure (ADE) values and occupational exposure limits (OELs). Use of TK data can provide a more robust exposure limit based on a rigorous evaluation of systemic internal dose. Bioavailability data assist in extrapolating across different routes of exposure to be protective for route-based differences of exposure. Bioaccumulation data enable extrapolation to chronic exposures when the point of departure (PoD) is from a short-term critical study. Applied in the context of chemical-specific adjustment factors (CSAFs), TK data partially replace traditional default adjustment factors for interspecies extrapolation (extrapolation from studies conducted in animals to humans) and intraspecies variability (to account for human population variability). Default adjustments of 10-fold each for interspecies and intraspecies extrapolation are recommended in several guidelines, although some organization recommend other values. Such default factors may overestimate variability for many APIs, while not being sufficiently protective for variability with other APIs. For this reason, the use of chemical specific TK and TD data are preferred. Making full use of existing TK and TD data reduces underlying uncertainties, increases transparency, and ensures that resulting ADEs reflect the best available science. PMID- 27224507 TI - CSF-1 receptor signalling is governed by pre-requisite EHD1 mediated receptor display on the macrophage cell surface. AB - Colony stimulating factor-1 receptor (CSF-1R), a receptor tyrosine kinase (RTK), is the master regulator of macrophage biology. CSF-1 can bind CSF-1R resulting in receptor activation and signalling essential for macrophage functions such as proliferation, differentiation, survival, polarization, phagocytosis, cytokine secretion, and motility. CSF-1R activation can only occur after the receptor is presented on the macrophage cell surface. This process is reliant upon the underlying macrophage receptor trafficking machinery. However, the mechanistic details governing this process are incompletely understood. C-terminal Eps15 Homology Domain-containing (EHD) proteins have recently emerged as key regulators of receptor trafficking but have not yet been studied in the context of macrophage CSF-1R signalling. In this manuscript, we utilize primary bone-marrow derived macrophages (BMDMs) to reveal a novel function of EHD1 as a regulator of CSF-1R abundance on the cell surface. We report that EHD1-knockout (EHD1-KO) macrophages cell surface and total CSF-1R levels are significantly decreased. The decline in CSF-1R levels corresponds with reduced downstream macrophage functions such as cell proliferation, migration, and spreading. In EHD1-KO macrophages, transport of newly synthesized CSF-1R to the macrophage cell surface was reduced and was associated with the shunting of the receptor to the lysosome, which resulted in receptor degradation. These findings reveal a novel and functionally important role for EHD1 in governing CSF-1R signalling via regulation of anterograde transport of CSF-1R to the macrophage cell surface. PMID- 27224510 TI - Cationic Poly(p-phenylene vinylene) Materials as a Multifunctional Platform for Light-Enhanced siRNA Delivery. AB - In this work, a multifunctional platform based on the versatile function of cationic poly(p-phenylene vinylene) (PPV) derivative has been developed for white light-enhanced siRNA delivery in a remote control manner. Conjugated polyelectrolyte PPV, which possesses cationic and amphipathic features, can effectively self-assemble with siRNA and deliver siRNA into living cells. More importantly, PPV can sensitize surrounding oxygen into reactive oxygen species (ROS) upon exposure to white light and disrupt the endosomal membrane, and the resulting enhanced endosomal escape increases the gene silencing ability of siRNA. Besides, due to high fluorescent emission, PPV can also be used to image the siRNA delivery and intracelluar location. Therefore, by taking full advantage of PPV, this strategy provides a new enhanced siRNA delivery in a non-invasive and spatiotemporal photochemical manner. PMID- 27224511 TI - Dieulafoy's disease of the airways: a comprehensive review of a rare entity. PMID- 27224513 TI - Self-harm as a risk factor for inpatient aggression among women admitted to forensic psychiatric care. AB - BACKGROUND: Inpatient aggression among female forensic psychiatric patients has been shown to be associated with self-harm, that is considered to be a historical risk factor for violence. Research on associations between previous or current self-harm and different types of inpatient aggression is missing. AIM: The aim of this register study was to investigate the prevalence of self-harm and the type of inpatient aggression among female forensic psychiatric inpatients, and to study whether the patients' self-harm before and/or during forensic psychiatric care is a risk factor for inpatient aggression. METHODS: Female forensic psychiatric patients (n = 130) from a high security hospital were included. RESULTS: The results showed that 88% of the female patients had self-harmed at least once during their life and 57% had been physically and/or verbally aggressive towards staff or other patients while in care at the hospital. Self harm before admission to the current forensic psychiatric care or repeated self harm were not significantly associated with inpatient aggression, whereas self harm during care was significantly associated with physical and verbal aggression directed at staff. CONCLUSIONS: These results pointed towards self-harm being a dynamic risk factor rather than a historical risk factor for inpatient aggression among female forensic psychiatric patients. Whether self-harm is an individual risk factor or a part of the clinical risk factor 'Symptom of major mental illness' within the HCR-20V3 must be further explored among women. Thus, addressing self-harm committed by female patients during forensic psychiatric care seems to be important in risk assessments and the management of violence, especially in reducing violence against staff in high-security forensic psychiatric services. PMID- 27224512 TI - A TNFR2-Agonist Facilitates High Purity Expansion of Human Low Purity Treg Cells. AB - Regulatory T cells (Treg) are important for immune homeostasis and are considered of great interest for immunotherapy. The paucity of Treg numbers requires the need for ex vivo expansion. Although therapeutic Treg flow-sorting is feasible, most centers aiming at Treg-based therapy focus on magnetic bead isolation of CD4+CD25+ Treg using a good manufacturing practice compliant closed system that achieves lower levels of cell purity. Polyclonal Treg expansion protocols commonly use anti-CD3 plus anti-CD28 monoclonal antibody (mAb) stimulation in the presence of rhIL-2, with or without rapamycin. However, the resultant Treg population is often heterogeneous and pro-inflammatory cytokines like IFNgamma and IL-17A can be produced. Hence, it is crucial to search for expansion protocols that not only maximize ex vivo Treg proliferative rates, but also maintain Treg stability and preserve their suppressive function. Here, we show that ex vivo expansion of low purity magnetic bead isolated Treg in the presence of a TNFR2 agonist mAb (TNFR2-agonist) together with rapamycin, results in a homogenous stable suppressive Treg population that expresses FOXP3 and Helios, shows low expression of CD127 and hypo-methylation of the FOXP3 gene. These cells reveal a low IL-17A and IFNgamma producing potential and hardly express the chemokine receptors CCR6, CCR7 and CXCR3. Restimulation of cells in a pro inflammatory environment did not break the stability of this Treg population. In a preclinical humanized mouse model, the TNFR2-agonist plus rapamycin expanded Treg suppressed inflammation in vivo. Importantly, this Treg expansion protocol enables the use of less pure, but more easily obtainable cell fractions, as similar outcomes were observed using either FACS-sorted or MACS-isolated Treg. Therefore, this protocol is of great interest for the ex vivo expansion of Treg for clinical immunotherapy. PMID- 27224514 TI - Consistent Treatment of Variables and Causation Poses a Challenge for Behavioral Research Methods: A Commentary on Nesselroade and Molenaar (2016). AB - Nesselroade and Molenaar presented the ideographic filter as a proposal for analyzing lawful regularities in behavioral research. The proposal highlights an inconsistency that poses a challenge for behavioral research more generally. One can distinguish a broadly Humean approach from a broadly non-Humean approach as they relate to variables and to causation. Nesselroade and Molenaar rejected a Humean approach to latent variables that characterizes them as nothing more than summaries of their manifest indicators. By contrast, they tacitly accepted a Humean approach to causes characterized as nothing more than summaries of their manifest causal effects. A non-Humean treatment of variables coupled with a Humean treatment of causation creates a theoretical tension within their proposal. For example, one can interpret the same model elements as simultaneously representing both variables and causes. Future refinement of the ideographic filter proposal to address this tension could follow any of a number of strategies. PMID- 27224516 TI - Connecting HIV-1 integration and transcription: a step toward new treatments. AB - Thanks to the current combined antiretroviral therapy (cART), HIV-1 infection has become a manageable although chronic disease. The reason for this lies in the fact that long-lived cellular reservoirs persist in patients on cART. Despite numerous efforts to understand molecular mechanisms that contribute to viral latency, the important question of how and when latency is established remains unanswered. Related to this is the connection between HIV-1 integration and the capacity of the provirus to enter the latent state. In this review, we will give an overview of these nuclear events in the viral life cycle in the light of current therapeutic approaches, which aim to either reactivate the provirus or even excise the proviral DNA from the cellular genome. PMID- 27224515 TI - Comparison of Cox Model Methods in A Low-dimensional Setting with Few Events. AB - Prognostic models based on survival data frequently make use of the Cox proportional hazards model. Developing reliable Cox models with few events relative to the number of predictors can be challenging, even in low-dimensional datasets, with a much larger number of observations than variables. In such a setting we examined the performance of methods used to estimate a Cox model, including (i) full model using all available predictors and estimated by standard techniques, (ii) backward elimination (BE), (iii) ridge regression, (iv) least absolute shrinkage and selection operator (lasso), and (v) elastic net. Based on a prospective cohort of patients with manifest coronary artery disease (CAD), we performed a simulation study to compare the predictive accuracy, calibration, and discrimination of these approaches. Candidate predictors for incident cardiovascular events we used included clinical variables, biomarkers, and a selection of genetic variants associated with CAD. The penalized methods, i.e., ridge, lasso, and elastic net, showed a comparable performance, in terms of predictive accuracy, calibration, and discrimination, and outperformed BE and the full model. Excessive shrinkage was observed in some cases for the penalized methods, mostly on the simulation scenarios having the lowest ratio of a number of events to the number of variables. We conclude that in similar settings, these three penalized methods can be used interchangeably. The full model and backward elimination are not recommended in rare event scenarios. PMID- 27224518 TI - Surveillance of pertussis: methods and implementation. AB - INTRODUCTION: Pertussis or whooping cough is a respiratory disease caused by Bordetella pertussis or, to a lesser extent, by B. parapertussis. Vaccines against pertussis have been widely used for more than 50 years and have led to a significant reduction of morbidity and mortality. However, even in countries with a high vaccine coverage, the disease is still not well controlled. Surveillance is urgently needed. AREAS COVERED: This review summarizes surveillance methods and gives examples that may be used when setting up a surveillance program or analyzing an outbreak. Expert commentary: Pertussis surveillance is urgently required in order to define the burden of disease, to adapt vaccine strategies according to the type of pertussis vaccine used and to follow the evolution of the bacteria. PMID- 27224517 TI - Predictive Factors of Lapatinib and Capecitabine Activity in Patients with HER2 Positive, Trastuzumab-Resistant Metastatic Breast Cancer: Results from the Italian Retrospective Multicenter HERLAPAC Study. AB - BACKGROUND: There are no validated predictive markers for lapatinib and capecitabine in patients with trastuzumab-resistant HER2 positive metastatic breast cancer. METHODS: Data of 148 consecutive patients treated with lapatinib and capecitabine from March 2007 to December 2013 were collected from 13 Italian institutions. Estimates of progression-free survival (PFS) and overall survival (OS) were obtained with the Kaplan-Meier method and compared with logrank test. The association of clinicopathological variables and the outcome was studied by binary logistic regression analysis and Cox proportional hazard analysis. RESULTS: At a median follow-up of 41 months, median PFS and OS were 7 and 21 months, respectively. Patents with a PFS longer than 7 months had a significantly longer OS, compared with patients with a PFS equal to or shorter than 7 months (36 vs 15 months; p<0.001). Multivariate analysis revealed the benefit of lapatinib-based therapy in terms of PFS and OS was significantly associated with time-to-progression (TTP) on prior first-line trastuzumab-based therapy. In particular, each additional month on first-line trastuzumab based therapy was associated with a reduction in hazard of progression and death after the initiation of lapatinib-based therapy of 2% and 4%, respectively. CONCLUSIONS: A longer TTP to first line trastuzumab seems to predict a prolonged PFS and OS with subsequent lapatinib and capecitabine. PMID- 27224519 TI - Polaron Stabilization by Cooperative Lattice Distortion and Cation Rotations in Hybrid Perovskite Materials. AB - Solution-processed organometallic perovskites have rapidly developed into a top candidate for the active layer of photovoltaic devices. Despite the remarkable progress associated with perovskite materials, many questions about the fundamental photophysical processes taking place in these devices, remain open. High on the list of unexplained phenomena are very modest mobilities despite low charge carrier effective masses. Moreover, experiments elucidate unique degradation of photocurrent affecting stable operation of perovskite solar cells. These puzzles suggest that, while ionic hybrid perovskite devices may have efficiencies on par with conventional Si and GaAs devices, they exhibit more complicated charge transport phenomena. Here we report the results from an in depth computational study of small polaron formation, electronic structure, charge density, and reorganization energies using both periodic boundary conditions and isolated structures. Using the hybrid density functional theory, we found that volumetric strain in a CsPbI3 cluster creates a polaron with binding energy of around 300 and 900 meV for holes and electrons, respectively. In the MAPbI3 (MA = CH3NH3) cluster, both volumetric strain and MA reorientation effects lead to larger binding energies at around 600 and 1300 meV for holes and electrons, respectively. Such large reorganization energies suggest appearance of small polarons in organometallic perovskite materials. The fact that both volumetric lattice strain and MA molecular rotational degrees of freedom can cooperate to create and stabilize polarons indicates that in order to mitigate this problem, formamidinium (FA = HC(NH2)2) and cesium (Cs) based crystals and alloys, are potentially better materials for solar cell and other optoelectronic applications. PMID- 27224520 TI - Use of Raman spectroscopy to identify carbon nanotube contamination at an analytical balance workstation. AB - Carbon nanotubes (CNTs) are cylindrical molecules of carbon with diverse commercial applications. CNTs are also lightweight, easily airborne, and have been shown to be released during various phases of production and use. Therefore, as global CNT production increases, so do concerns that CNTs could pose a safety threat to those who are exposed to them. This makes it imperative to fully understand CNT release scenarios to make accurate risk assessments and to implement effective control measures. However, the current suite of direct reading and off-line instrumentation used to monitor the release of CNTs in workplaces lack high chemical specificity, which complicates risk assessments when the sampling and/or measurements are performed at a single site where multiple CNT types are handled in the presence of naturally occurring background particles, or dust. Herein, we demonstrate the utility of Raman spectroscopy to unequivocally identify whether particulate matter collected from a multi-user analytical balance workstation comprised CNTs, as well as, whether the contamination included CNTs that were synthesized by a Ni/Y-catalyzed electric arc method or a Co/Mo-catalyzed chemical vapor deposition method. Identifying the exact CNT type generated a more accurate risk assessment by knowing the metallic impurities involved, and it also led to the identification of the users who handled these CNTs, a review of their handling techniques, and an improved protocol for safely weighing CNTs. PMID- 27224521 TI - Effect of cell membrane permeability protein on porcine oocyte vitrification. AB - BACKGROUND: The discovery of proteins with inherent cell membrane-translocating activity will expand our ability to study and manipulate various intracellular processes in living systems. OBJECTIVE: We investigated the effect of TAT-EGFP (trans-activator of transcription-enhanced green fluorescent protein) intra cellular delivery on the survival and development of mature porcine oocytes after cryopreservasion. MATERIALS AND METHODS: Cumulus-oocyte complexes (COCs) collected from follicles 3 to 6 mm in diameter in abattoir-derived oocytesries of prepubertal gilts were on vitro matured (IVM). After IVM, the oocytes were used for TAT-EGFP delivery test and cryopreservation with and without TAT-EGFP supplementation. Oocyte viability was assayed by staining with fluorescein diacetate. Live oocytes were parthened and cultured in vitro, to assess their ability to be activated and to therefore develop. RESULTS: The results show that the TAT-EGFP was well delivered into the nuclear of the Hela cell and oocytes also. In the medium toxic test, the proportion of viable oocytes in seven groups showed no significance. In vitrification experiments, the viability of oocytes in group supplemented with TAT-EGFP was significantly higher than that in the without TAT-EGFP group and the control groups (27.7%, 90.4%, and 100%, respectively). Among the three groups, the developmental abilities of oocytes in the supplement TAT-EGFP, EGFP and Control groups revealed that the vitrified group had a significantly reduced ability to undergo first cleavage (34.4%, 63.3%, and 69.0%, respectively). CONCLUSION: the supplement of TAT-EGFP protein into vitrification medium does not affect the viability of the oocytes whereas it improved the viability and developmental potential of oocytes after it was vitrified. PMID- 27224522 TI - Cardiac mitochondrial oxidative capacity is partly preserved after cryopreservation with dimethyl sulfoxide. AB - BACKGROUND: Cardiac muscle cryopreservation is a challenge for both diagnostic procedure requiring viable tissues and therapeutic advance in regenerative medicine. Mitochondria are targets of both direct and indirect damages, secondary to congelation per se and/or to cryoprotectant's toxic effects, which participate to diminution of viability and/or functioning of cells after freezing. At the cardiac muscle level, only one study had investigated mitochondrial respiration after cryopreservation. OBJECTIVE: To determine the effect of cryopreservation on mitochondrial respiration of cardiac muscle. MATERIALS AND TMETHODS: We recorded mitochondrial respiration through complexes I, II, III and IV along with mitochondrial coupling in fresh and cryopreserved rat left ventricles samples and assessed difference of the means, correlation and agreement between the measures in all samples. RESULTS: Mitochondrial respiration was partly maintained up to 70% in cryopreserved samples whatever the substrate. A significant correlation was observed between fresh and cryopreserved samples (r = 0.71, p < 0.0001). However, mitochondrial coupling significantly decreased after cryopreservation (- 1.44 +/- 0.15; p < 0.005) suggesting that mitochondrial intactness was not totally preserved by cryopreservation. Further, the fluctuations around the mean difference were wide (-14.06, +5.08 umol/min/g), increasing with respiration rates (p < 0.0001). CONCLUSION: Thus, fresh samples extemporaneous analysis should be preferred when available despite the fact that cryopreservation using DMSO partly protect cardiac mitochondrial respiration and coupling. These data support the interest to further refine cryopreservation methods. PMID- 27224523 TI - Effect of melatonin supplementation on cryopreserved sperm quality in mouse. AB - BACKGROUND: Antioxidants protect spermatozoa against cell damage during cryopreservation. OBJECTIVE: To investigate whether melatonin supplement in the extender may improve the quality of cryopreserved mouse sperm. METHODS: Kunming mice sperm frozen in extender R18S3 (18% (w/v) raffinose and 3% (w/v) skim milk) supplemented with melatonin were thawed and evaluated. RESULTS: Mouse spermatozoa were cryopreserved in the freezing extender R18S3 that contained melatonin at 0, 0.125, 0.25 and 0.5 mg/mL melatonin. The extender without melatonin supplement was associated with increased formation of reactive oxygen species (ROS) and decreased sperm motility. Melatonin supplement at 0.125 mg/mL significantly increased the progressive motility of sperm in comparison to other melatonin concentration or control. The percentage of thawed viable sperm with ROS was lower in the melatonin-treated groups than in untreated group. Melatonin supplement also increased antiapoptotic gene Bcl-xl expression in the thawed sperm. CONCLUSION: Supplement of 0.125 mg/mL melatonin could reduce oxidative damage and apoptosis. PMID- 27224524 TI - Comparative effects of slow freezing and vitrification on cryosurvival of spermatozoa obtained from west African dwarf goat bucks. AB - BACKGROUND: Slow freezing and vitrification are used to improve the viability of spermatozoa from various species but comparative effects of these cryoprotocols have never been evaluated for spermatozoa obtained from West African Dwarf (WAD) goat bucks. OBJECTIVE: This study evaluated the comparative effects of slow freezing and vitrification on the viability of spermatozoa of WAD goat bucks. MATERIALS AND METHODS: Semen samples collected with the aid of artificial vagina were allocated to slow freezing and vitrification protocols and cryopreserved for 30 days in liquid nitrogen. RESULTS: Consistent higher (P<0.05) sperm motility, acrosome integrity, membrane integrity, live sperm, acrosome reaction and capacitation in slow freezing compared to vitrification. Abnormal sperm cells and malondialdehyde (MDA) concentrations reduced (P<0.05) in slow freezing compared to vitrification. Higher (P<0.05) arginase activity was observed in slow freezing compared to vitrification. CONCLUSION: The findings indicated that spermatozoa obtained from WAD goat bucks were better preserved in slow freezing compared to vitrification. PMID- 27224525 TI - Both death receptor and mitochondria mediated apoptotic pathways participated the occurrence of apoptosis in porcine vitrified mii stage oocytes. AB - BACKGROUND: Oocytes vitrification is widely used for cryopreservation of female genetic resources. OBJECTIVE: In order to illuminate the apoptotic pathways of porcine MII stage oocytes after vitrification. MATERIALS AND METHODS: This study used in situ fluorescence staining and RT-PCR to detect the expression levels of some key molecules from death receptor and mitochondria mediated apoptotic pathways. RESULTS: (1) Early stage apoptosis were detected in both PI staining survival oocytes and PI staining dead oocytes. (2) The fluorescence intensity of caspase 8, caspase 9, caspase 3 and pan caspase from vitrified oocytes were 32.03, 16.56, 16.70 and 8.43 respectively, which were much higher than those from fresh oocytes (4.02, 4.83, 4.23 and 3.08, P < 0.05). (3) Not only the genes from death receptor mediated apoptotic pathway, but also from mitochondrial mediated apoptotic pathway were changed greatly. CONCLUSION: The death of porcine vitrified oocytes could be induced by apoptosis, both death receptor and mitochondria mediated apoptotic pathways participated the occurrence of apoptosis in porcine vitrified MII stage oocytes. PMID- 27224526 TI - Dog sperm cryopreservation using one step dilution with glycerol-free tris extender. AB - OBJECTIVE: The present study was to investigate a freezing method using one step dilution with glycerol-free TRIS extender containing 172.2 mM glucose (GFTG). MATERIALS AND METHODS: The sperm pellet from selected ejaculates was resuspended in GFTG at 1*10(8) cells/mL. The semen was cooled for 10, 30, 50 or 70 min in GFTG at 4 degree C and was frozen in LN(2) vapor or in deep freezer (-80 degree C, DF) for 20 min before plunge into LN(2). Post-thaw sperm characteristics were examined. The phosphatidylserine (PS) translocation (Annexin V-FITC) and DNA integrity (TUNEL assay) were assessed using flow cytometry. RESULTS: Progressive motility and viability were significantly higher in 50 and 70 min groups than the other groups (P<0.05). PS translocation index was significantly lower in spermatozoa cooled for 50 or 70 min compared to 10 min (P<0.05). Freezing methods using LN2 vapor showed higher progressive motility than DF method (P<0.05), while viability and DNA fragmentation were not different between two freezing methods. CONCLUSION: Cryopreservation of canine sperm cooled for 50 or 70 min following one step dilution in GFTG yields more viable sperm with lower PS translocation and freezing method using LN(2) vapor is more effective on progressive motility. PMID- 27224527 TI - Cryopreservation on a cryo-plate of Arundina graminifolia protocorms, dehydrated with silica gel and drying beads. AB - BACKGROUND: There are various methods for the cryopreservation of plant material, with each biological specimen potentially requiring protocol optimization to maximize success. OBJECTIVE: The aim of this study is to compare droplet vitrification, encapsulation-dehydration, and the cryo-plate method for cryopreservation of protocorms of the orchid Arundina graminifolia, using silica gel and drying beads as the desiccation materials. MATERIALS AND METHODS: The cryo-plate method included preculture of protocorms, developed from seeds, placed on aluminium cryo-plates and embedded in alginate gel. Cryo-plates were surface dried using sterile filter paper, placed in Petri dishes containing 50 g silica gel or 30 g drying beads in a laminar air-flow cabinet. Specimens on cryo-plates were dehydrated to 25 % moisture content, placed into 2 mL cryotubes and plunged directly into liquid nitrogen for 1 d. RESULTS: For cryopreservation, the cryo plate method, involving dehydration with 30 g drying beads gave the highest regrowth (77 %), followed by the encapsulation-dehydration method with 30 g drying beads (64 % regrowth) and the droplet-vitrification method, following exposure to PVS2 solution for 20 min (33 % regrowth). CONCLUSIONS: Regrowth of cryopreserved protocorms using the cryo-plate method was rapid with the highest survival and regrowth. PMID- 27224528 TI - Melatonin-loaded alginate beads improve cryopreservation of yam (Dioscorea alata and D. cayenensis). AB - BACKGROUND: The cryopreservation of yam is constrained with many challenges. OBJECTIVE: This study tested the effects of melatonin on shoot tips of D. alata and D. cayenensis accessions exposed to water and liquid nitrogen (LN) stresses. MATERIALS AND METHODS: Sucrose pretreatment (0.3 M) was applied for 48 h before cryopreservation. Shoot tips were encapsulated in beads loaded with 0.75 M sucrose, with and without melatonin and desiccated over sterile dry silica gel for 0 - 9 h. RESULTS: The beads moisture content declined from 100% to ~ 13% after 9 h. The 3 h desiccation period without melatonin produced a significantly higher regeneration compared to 6 h and 9 h. Shoot tips with melatonin had significantly higher regeneration after 3 - 6 h desiccation compared to 9 h and the regeneration of all accessions after 6 h was >80%. Regeneration following 6 h desiccation and LN was significantly greater for melatonin-treated shoot tips compared to non-treated ones. CONCLUSION: The results indicate that melatonin significantly increased regeneration from 15% to 35%. PMID- 27224529 TI - The revascularization and follicular survival of mouse ovarian grafts treated with FSH during cryopreservation by vitrification. AB - BACKGROUND: Ovarian cryopreservation by vitrification is a very effective pathway for the preservation of female fertility during radiotherapy and chemotherapy. However, damage of follicles was triggered by cryo-injure during the process of ovarian vitrification and ischemia/reperfusion during the process of ovarian transplantation. Appropriate FSH play important roles in anti-apoptosis and neoangiogenesis during ovarian follicle development. OBJECTIVE: Therefore, the purpose of this study was to investigate the effect of FSH on the revascularization and follicular survival of vitrified-warmed ovarian grafts. MATERIALS AND TMETHODS: Four-week-old C57BL/6J mice with diestrus were used and the ovaries were randomized into the following three groups: fresh control group (FCG), vitrified/warmed group (VCG) and vitrified/warmed group treated with 0.3 IU/mL FSH (FSH-VG) during ovarian vitrification. After warming, the ovaries of the three groups were allotransplanted into the renal capsule of receptor mice. Assessment of follicular quantity was performed by histological analysis. The angiogenesis factors, CD31 and MMP-2, and cell survival factors, PCNA, EdU and survivin were examined by immunohistochemistry and western blot analysis. Angiogenesis was detected by vascular perfusion with the fluorescent dye 2MD-FITC Dextran. RESULTS: The expression of CD31and MMP-2 were not significantly different in either VCG or FSH-VG compared with FCG, but when the ovaries were transplanted 48 hours later, the expression levels of CD31 and MMP-2 were lower for VCG than FCG (P < 0.05) and FSH-VG was not significantly different from FCG. Before transplantation, the expression levels of PCNA and survivin were lower for VCG and FSH-VG than FCG (p < 0.05), but FSH-VG was higher than VCG (p < 0.05). After 48 h of ovarian transplantation, the expression of survivin was lower for VCG than FCG (P < 0.05), but FSH-VG was not significantly different from FCG. In addition, these data were further supported by the results from detecting the 2MD FITC-Dextran and EdU. CONCLUSION: Taken together, supplementation with 0.3 IU/mL FSH during ovarian cryopreservation by vitrification increased the revascularization and follicular survival for mouse ovarian grafts through the up regulated expression of angiogenesis and ovarian survival factors. PMID- 27224531 TI - Vestibular Mast Cell Density in Vulvodynia: A Case-Controlled Study. AB - OBJECTIVES: To identify whether mast cell densities in vulvar biopsies from the vestibule are associated with vulvodynia. METHODS: We enrolled 100 women aged 19 to 59 years with confirmed vulvodynia cases, 100 racially matched controls, and 100 black control women. All had vulvar biopsies performed at the 7 o'clock position of the vestibule, which were then immunostained to detect c-KIT protein. The numbers of c-KIT positive mast cells per *400 magnification field were manually counted, and t tests and logistic regression were used to assess the association with case-control status. RESULTS: Of the biopsies, 235 were adequate samples for c-KIT testing for mast cells. The mast cell density was substantially lower in black control women (13.9 +/- 10.9) in comparison to white control women (22.5 +/- 13.2 p < 0.001): hence the analysis was confined to white cases and racially matched control women. Compared with racially matched controls, cases were younger, more likely to be married, and reported a higher household income. The average number of mast cells per *400 magnification field overall was 19.1 +/ 13.2 (range, 0-62). There was no difference in the mast cell count between racially matched cases (22.4 +/- 13.9 per *400 field) and controls (22.5 +/- 13.2) in either the univariate or multivariable analyses. Within the group of cases, there was no difference in mast cell density based on the presence or absence of a variety of urogenital symptoms. CONCLUSIONS: No difference in mast cell density in biopsies of the vestibule was found between white cases and racially matched controls. Black control women have a lower mast cell density compared with white control women. PMID- 27224530 TI - Discovery of high affinity anti-ricin antibodies by B cell receptor sequencing and by yeast display of combinatorial VH:VL libraries from immunized animals. AB - Ricin is a toxin that could potentially be used as a bioweapon. We identified anti-ricin A chain antibodies by sequencing the antibody repertoire from immunized mice and by selecting high affinity antibodies using yeast surface display. These methods led to the isolation of multiple antibodies with high (sub nanomolar) affinity. Interestingly, the antibodies identified by the 2 independent approaches are from the same clonal lineages, indicating for the first time that yeast surface display can identify native antibodies. The new antibodies represent well-characterized reagents for biodefense diagnostics and therapeutics development. PMID- 27224533 TI - Performance of an Human Papillomavirus Test in Samples From Women With Histopathologically Confirmed Invasive Cervical Cancer. PMID- 27224532 TI - Natural Antibodies to Human Papillomavirus 16 and Recurrence of Vulvar High-Grade Intraepithelial Neoplasia (VIN3). AB - OBJECTIVES: Approximately 30% of women treated for squamous high-grade intraepithelial neoplasia (VIN3), often associated with human papillomavirus (HPV), have recurrent disease. In this study, we assess predictors of recurrence that may provide targets for early prevention or treatment. MATERIALS AND METHODS: Women with VIN3 who participated in a previous population-based case control study with blood and tumor samples completed a follow-up telephone interview an average of 5 years after initial diagnosis. The risk of recurrence was determined by proportional hazards modeling. RESULTS: Women with VIN3 in the follow-up study (n = 65) were similar to women with VIN3 in the parent study (n = 215) with regard to age at primary diagnosis, level of current cigarette smoking (>60%), and lifetime number of partners. We found that 22 (33.8%) of 65 participants had a vulvar recurrence and that 73.4% recurred within 3 years of treatment. Recurrences occurred more often among women with common warts in the decade before diagnosis (hazard ratio [HR] = 2.5, 95% CI = 1.1-5.8) and among those with a previous anogenital cancer (HR = 2.7, 95% CI = 1.2-6.3). Interestingly, recurrence was less frequent among women who mounted a natural antibody response to HPV16 (HR = 0.4, 95% CI = 0.2-0.9). CONCLUSIONS: These data provide strong preliminary evidence that VIN3 recurrence was less frequent among those with HPV16 antibodies. Vaccination with the currently licensed HPV vaccine as part of adjunctive therapy for VIN3 would increase antibody response and may decrease risk of recurrence. Randomized controlled trials are needed to determine whether HPV vaccination is effective against VIN3 recurrence. PMID- 27224535 TI - Freedom of the Press. PMID- 27224534 TI - Neural correlates of autobiographical memory retrieval in children and adults. AB - Autobiographical memory (AM) is a critically important form of memory for life events that undergoes substantial developmental changes from childhood to adulthood. Relatively little is known regarding the functional neural correlates of AM retrieval in children as assessed with fMRI, and how they may differ from adults. We investigated this question with 14 children ages 8-11 years and 14 adults ages 19-30 years, contrasting AM retrieval with semantic memory (SM) retrieval. During scanning, participants were cued by verbal prompts to retrieve previously selected recent AMs or to verify semantic properties of words. As predicted, both groups showed AM retrieval-related increased activation in regions implicated in prior studies, including bilateral hippocampus, and prefrontal, posterior cingulate, and parietal cortices. Adults showed greater activation in the hippocampal/parahippocampal region as well as prefrontal and parietal cortex, relative to children; age-related differences were most prominent in the first 8 sec versus the second 8 sec of AM retrieval and when AM retrieval was contrasted with semantic retrieval. This study is the first to characterise similarities and differences during AM retrieval in children and adults using fMRI. PMID- 27224536 TI - Problems+Solutions. AB - Readers are invited to submit questions relating to problem cases. Inquiries will be answered by qualified consultants and replies forwarded by mail promptly. Selected problems and solutions are published every month in this section. PMID- 27224537 TI - The Medical Bookshelf. AB - Books received are listed as space permits, and those of particular interest to our readers are reviewed. PMID- 27224538 TI - Editor's Mail. AB - The Editor welcomes readers' comments, and selected letters are published each month. Letters must be signed and should be sent to Editor's Mail at the address shown. The journal reserves the right to condense letters if necessary for space. PMID- 27224539 TI - Introduction. PMID- 27224540 TI - cme credit QUIZ. PMID- 27224541 TI - Primary Care Digest. PMID- 27224542 TI - Immunization. AB - A feature of POSTGRADUATE MEDICINE intended for patient use in preventing and treating common health problems. PMID- 27224545 TI - Novel insights into RAD51 activity and regulation during homologous recombination and DNA replication. AB - In this review we focus on new insights that challenge our understanding of homologous recombination (HR) and Rad51 regulation. Recent advances using high resolution microscopy and single molecule techniques have broadened our knowledge of Rad51 filament formation and strand invasion at double-strand break (DSB) sites and at replication forks, which are one of most physiologically relevant forms of HR from yeast to humans. Rad51 filament formation and strand invasion is regulated by many mediator proteins such as the Rad51 paralogues and the Shu complex, consisting of a Shu2/SWS1 family member and additional Rad51 paralogues. Importantly, a novel RAD51 paralogue was discovered in Caenorhabditis elegans, and its in vitro characterization has demonstrated a new function for the worm RAD51 paralogues during HR. Conservation of the human RAD51 paralogues function during HR and repair of replicative damage demonstrate how the RAD51 mediators play a critical role in human health and genomic integrity. Together, these new findings provide a framework for understanding RAD51 and its mediators in DNA repair during multiple cellular contexts. PMID- 27224546 TI - Rac GTPase regulation of 3D invasion in neuroblastomas lacking MYCN amplification. AB - Neuroblastomas are highly invasive tumors that occur in pediatric patients and treatment of invasive disease remains a challenge. The study of cells invading in 3-dimensional (3D) hydrogels has revealed morphologically distinct modes of invasion by which cancer cells adapt to the local tissue environment in order to invade local tissue. Specifically, the small G protein Rac GTPase has been implicated as regulating the elongated/mesenchymal mode of cell invasion. In the present study we demonstrate an inverse association between Rac expression and amplification of MYCN, a well-established prognostic indicator in neuroblastoma. Moreover, the association further tracks with previously described morphological variants of neuroblastoma. Importantly, while MYCN amplification is associated with universally poor prognosis, the clinical course of patients whose tumors lack MYCN amplification are more difficult to predict. Therefore, we analyzed the role that Rac plays in regulating the invasive behavior of neuroblastoma cells lacking MYCN amplification. Using siRNA targeting Rac in single cell suspensions in 3D collagen gels and Rac inhibition of multicellular spheroids (MCS) embedded in collagen gels, we find that the high Rac-expressing lines differ in their morphological response to Rac depletion and inhibition. Live cell imaging of embedded MCS reveals distinct individual and collective modes of invasion between the cell lines. Critically, Rac inhibition blocked both individual and collective invasion in 2 of the 3 high Rac expressing cell lines. Our study suggests that Rac activity may be an important determinant of metastatic capability in subsets of neuroblastoma cells lacking MYCN amplification. PMID- 27224547 TI - Under-response of a PTW-60019 microDiamond detector in the Bragg peak of a 62 MeV/n carbon ion beam. AB - To investigate the linear energy transfer (LET) dependence of the response of a PTW-60019 Freiburg microDiamond detector, its response was compared to the response of a plane-parallel Markus chamber in a 62 MeV/n mono-energetic carbon ion beam. Results obtained with two different experimental setups are in agreement. As recommended by IAEA TRS-398, the response of the Markus chamber was corrected for temperature, pressure, polarity effects and ion recombination. No correction was applied to the response of the microDiamond detector. The ratio of the response of the Markus chamber to the response of the microDiamond is close to unity in the plateau region. In the Bragg peak region, a significant increase of the ratio is observed, which increases to 1.2 in the distal edge region. Results indicate a correlation between the under-response of the microDiamond detector and high LET values. The combined relative standard uncertainty of the results is estimated to be 2.38% in the plateau region and 12% in the distal edge region. These values are dominated by the uncertainty of alignment in the non uniform beam and the uncertainty of range determination. PMID- 27224548 TI - The Monomeric Species of the Regulatory Domain of Tyrosine Hydroxylase Has a Low Conformational Stability. AB - Tyrosine hydroxylase (TyrH) catalyzes the hydroxylation of tyrosine to form 3,4 dihydroxyphenylalanine, the first step in the synthesis of catecholamine neurotransmitters. The protein contains a 159-residue regulatory domain (RD) at its N-terminus that forms dimers in solution; the N-terminal region of RDTyrH (residues 1-71) is absent in the solution structure of the domain. We have characterized the conformational stability of two species of RDTyrH (one containing the N-terminal region and another lacking the first 64 residues) to clarify how that N-terminal region modulates the conformational stability of RD. Under the conditions used in this study, the RD species lacking the first 64 residues is a monomer at pH 7.0, with a small conformational stability at 25 degrees C (4.7 +/- 0.8 kcal mol(-1)). On the other hand, the entire RDTyrH is dimeric at physiological pH, with an estimated dissociation constant of 1.6 MUM, as determined by zonal gel filtration chromatography; dimer dissociation was spectroscopically silent to circular dichroism but not to fluoresecence. Both RD species were disordered below physiological pH, but the acquisition of secondary native-like structure occurs at pHs lower than those measured for the attainment of tertiary native- and compactness-like arrangements. PMID- 27224549 TI - Isotype switching: Mouse IgG3 constant region drives increased affinity for polysaccharide antigens. PMID- 27224550 TI - Methylmercury production in a chronically sulfate-impacted sub-boreal wetland. AB - Increased deposition of atmospheric sulfate exacerbates methylmercury (MeHg) production in freshwater wetlands by stimulating methylating bacteria, but it is unclear how methylation in sub-boreal wetlands is impacted by chronically elevated sulfate inputs, such as through mine discharges. The purpose of our study is to determine how sulfate discharges to wetlands from iron mining activities impact MeHg production. In this study, we compare spatial and temporal patterns in MeHg and associated geochemistry in two wetlands receiving contrasting loads of sulfate. Two orders of magnitude less sulfate in the un impacted wetland create significant differences in acid-volatile sulfide and porewater sulfide; however, dissolved and solid-phase MeHg concentrations and methylation rate potentials (Kmeth) are statistically similar in both wetlands. Permitted mine pumping events flood the sulfate-impacted wetland with very high sulfate waters during the fall. In contrast to observations in sulfate-limited systems, this large input of sulfate to a chronically sulfate-impacted system led to significantly lower potential relative methylation rates, suggesting a predominance of demethylation processes over methylation processes during the sulfate loading. Overall, short-term measurements of methylation and demethylation potential are unrelated to gross measures of long-term MeHg accumulation, indicating a decoupling of short- and long-term process measurements and an overall disequilibrium in the systems. High sulfide accumulation, above ~600-800 MUg l(-1) sulfide, in the sulfate-impacted system lowers long-term MeHg accumulation, perhaps as a result of less bioavailable Hg-S complexes. Although continued research is required to determine how sulfate limited freshwater wetlands might respond to new, large inputs of high-sulfate runoff from mining operations, chronically impacted wetlands do not appear to continually accumulate or produce MeHg at rates different from wetlands unimpacted by mining. PMID- 27224551 TI - Visfatin Triggers the Cell Motility of Non-Small Cell Lung Cancer via Up Regulation of Matrix Metalloproteinases. AB - High levels of visfatin are correlated with worse clinical prognosis of various cancers. Still, the effects and mechanisms of visfatin on progression of non small cell lung cancer (NSCLC) remain unclear. This study revealed that plasma levels of visfatin in patients with NSCLC (585 +/- 287 pg/ml) were significantly (p < 0.01) higher than those in healthy people (142 +/- 61.1 pg/ml). The high level of plasma visfatin was found to be significantly (p < 0.05) correlated with TNM stage, lymph node metastasis and distant metastasis. Visfatin treatment can increase the migration and invasion of NSCLC cells via up-regulation of metalloproteinase-2 (MMP-2) and MMP-9. Both si-MMP-2 and si-MMP-9 attenuated visfatin-induced migration of NSCLC cells. The inhibitor of NF-kappaB, while not ERK1/2, p38-MAPK or PI3K/Akt, can significantly abolish visfatin-induced migration of A549 cells and up-regulation of MMP-2 and MMP-9. Furthermore, visfatin can increase the phosphorylation of IkappaBalpha and p65 and the transcription activities of NF-kappaB in NSCLC cells. ACHP, the inhibitor of IKK beta, blocked visfatin-induced activation of p65 and up-regulation of MMP-2 and MMP-9. Collectively, our data revealed that visfatin can trigger the in vitro migration and invasion of NSCLC cells via up-regulation of MMPs through activation of NF-kappaB. PMID- 27224552 TI - Exercise in Chronic Heart Failure: Anything Left to Learn? PMID- 27224553 TI - HE4 Serum Levels Are Associated with Heart Failure Severity in Patients With Chronic Heart Failure. AB - BACKGROUND: The novel biomarker human epididymis protein 4 (HE4) shows prognostic value in acute heart failure (HF) patients. We measured HE4 levels in patients with chronic heart failure (CHF) and correlated them to HF severity, kidney function, and HF biomarkers, and determined its predictive value. METHODS: Serum HE4 levels in patients (n = 101) with stable CHF with reduced left ventricular ejection fraction (LVEF <45%) from the Vitamin D CHF (VitD-CHF) study (NCT01092130) were compared with those in age- and sex-matched healthy control subjects (n = 58) from the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. RESULTS: HE4 levels were higher in CHF compared with control subjects (69.2 pmol/L [interquartile range 55.6-93.8] vs 56.1 pmol/L [46.6-69.0]; P < .001) and were higher with increasing New York Heart Association functional class. Levels were associated with HF risk factors, including age, gender, diabetes, smoking and N-terminal prohormone of B-type natriuretic peptide (NT proBNP). HE4 demonstrated strong associations with kidney function and HF fibrosis biomarkers. In a multivariable model, we identified creatinine, NT proBNP, galectin-3, high-sensitive troponin T, and smoking as factors associated with HE4. Independently from these factors, HE4 levels predicted death and HF rehospitalization (5-year follow-up, hazard ratio 3.8; confidence interval 1.31 11.1; P = .014). CONCLUSIONS: HE4 levels are increased in CHF, correlate with HF severity and kidney function, and predict HF outcome. PMID- 27224554 TI - The Influence of Hydroxylation on Maintaining CpG Methylation Patterns: A Hidden Markov Model Approach. AB - DNA methylation and demethylation are opposing processes that when in balance create stable patterns of epigenetic memory. The control of DNA methylation pattern formation by replication dependent and independent demethylation processes has been suggested to be influenced by Tet mediated oxidation of 5mC. Several alternative mechanisms have been proposed suggesting that 5hmC influences either replication dependent maintenance of DNA methylation or replication independent processes of active demethylation. Using high resolution hairpin oxidative bisulfite sequencing data, we precisely determine the amount of 5mC and 5hmC and model the contribution of 5hmC to processes of demethylation in mouse ESCs. We develop an extended hidden Markov model capable of accurately describing the regional contribution of 5hmC to demethylation dynamics. Our analysis shows that 5hmC has a strong impact on replication dependent demethylation, mainly by impairing methylation maintenance. PMID- 27224555 TI - Platelet Rich Plasma (PRP) Produces an Atherofibrotic Histophenotype During Craniofacial Bone Repair Due to Changes of Immunohistochemical Expression of Erk1/2, p38alpha/beta, Adiponectin and Elevated Presence of Cells Exhibiting B scavenger Receptor (CD36+). AB - The platelet-extracellular matrix interaction in platelet rich plasma (PRP) through thrombospondin receptor-CD36 induces the secretion of growth factors responsible for cellular proliferation and differentiation during the repair process. Since CD36 also acts as a class B-scavenger-receptor for development of foam-like cells and mitogen-activated kinases, such as Erk1/2 and p38alpha/beta, are important proteins activated by platelet growth factor, the aim of this study was to evaluate the immunohistochemical presence of CD36, Erk1/2, p38alpha/beta during the bone repair treated and non-treated with PRP and to compare these results with the histomorphometry of repair. Simultaneously, the immunopresence of adiponectin was analyzed, which may contribute to osteogenesis at the same time it inhibits fibrosis and impairs adipogenesis and foam cell formation in the medullary area. An artificial bone defect measuring 5*1 mm was produced in the calvaria of 56 Wistar rats. The defects were randomly treated with autograft, autograft+PRP, PRP alone and sham. The animals were euthanized at 2 and 6 weeks post-surgery. Data were analyzed by ANOVA followed by non-parametric test Student Newman-Keuls (p<0.05) for histomorphometric and immunohistochemical interpretation. The results revealed that in specimens that received PRP the immunopositivity for Erk1/2, p38alpha/beta and CD36 proteins increased significantly while the immunohistochemical expression of adiponectin decreased simultaneously. There was also an accentuated reduction of bone matrix deposition and increase of the medullary area represented by fibrosis and/or presence of foam-like cells, which exhibited immunophenotype CD36+adiponectin. The findings of this study suggest that PRP acted as an inhibitor of osteogenesis during the craniofacial bone repair and induced a pathological condition that mimics an atherofibrotic condition. PMID- 27224556 TI - Influence of Aae Autotransporter Protein on Adhesion and Biofilm Formation by Aggregatibacter actinomycetemcomitans. AB - The periodontopathogen Aggregatibacter actinomycetemcomitans colonizes oral cavity by binding to and invading epithelial cells as well as by participating in biofilms formed on hard surfaces. Aae, an autotransporter protein, is implicated in bacterial adhesion to epithelial cells. Due to the multiple functions of bacterial autotransporter proteins, this study aimed to evaluate the role of aae in A. actinomycetemcomitans ability to adhere to both saliva-coated hydroxyapatite (SHA) and biofilm. An aae null mutant was constructed. Its hydrophobic properties as well as its ability to adhere to epithelial cells, SHA and to form biofilm were evaluated and compared with the parental strain, A. actinomycetemcomitans VT1169. The aae null mutant showed reduced hydrophobicity, as well as decreased binding to SHA and biofilm formation compared to the parental strain. These data suggest that aae mediates A. actinomycetemcomitans adhesion to epithelial cells and may be involved in biofilm formation and interaction with adsorbed salivary proteins. PMID- 27224557 TI - Association between Chronic Periodontitis and Oral/Oropharyngeal Cancer. AB - The aim of this case control study was to assess the association between the extent and severity of chronic periodontitis and oral cavity and/or oropharyngeal cancer. The case group comprised 35 patients (mean age 56.1+/-8.4), diagnosed for oral and/or oropharyngeal cancer. The control group comprised 40 individuals (mean age 55.4+/-9.4) without diagnostic of cancer. All individuals were subjected to a periodontal examination, including bleeding on probing, plaque index, gingival index, probing pocket depth (PPD), clinical attachment loss (CAL), and decayed, extracted and filled teeth index (DMFT). The case group had significantly more sites with plaque. GI and BOP had similar values in both groups. The median PPD and CAL values were significantly higher for the case group. Chronic generalized periodontitis was predominant in 80% of patients with oral and/or oropharyngeal cancer. Eighty nine percent of the patients in the case group presented severe chronic periodontitis. There was no significant difference between groups for median values of DMFT. The extent and severity of chronic periodontitis remained as risk indicators for oral cavity and/or oropharyngeal cancer even after the adjustments for traditional confound factors, i.e. smoking and alcohol consumption. PMID- 27224558 TI - Anti-inflammatory and Anti-resorptive Effects of Atorvastatin on Alveolar Bone Loss in Wistar Rats. AB - The aim of this study was to evaluate the anti-inflammatory and anti-resorptive effect of atorvastatin (ATV) in an experimental alveolar bone loss (ABL) model. Wistar rats were subjected to ligature placement around the maxillary second molar for 11 days. The animals received 0.9% saline (2 mL/kg) or ATV (0.3, 3 or 27 mg/kg) daily by gavage. ABL was evaluated by resorption area and histopathological analysis. Serum bone-specific alkaline phosphatase (BALP) activity was also evaluated. Leukogram was performed at 0 h, 6th h, 2nd, 7th and 11th days. Kidney and liver conditions and the body mass variation were analyzed. ATV (3 and 27 mg/kg) inhibited ABL by 39% and 56%, respectively. Histopathological analysis showed that ATV 27 mg/kg prevented ABL and cemental resorption, and inflammatory cell infiltration induced by ligature. ATV (27 mg/kg) prevented serum BALP levels reduction. ATV (27 mg/kg) prevented leukocytosis and did not affect either kidney or liver function nor body mass weight. ATV showed a protecting effect in the ligature-induced periodontitis, without affecting system parameters, by inhibition of inflammatory process and by its anabolic activity on the alveolar bone. PMID- 27224559 TI - Microbiological Seal of Two Types of Tapered Implant Connections. AB - Tapered implant connections have gained wide popularity for being more resistant to fatigue and for promoting a better seal against bacterial infiltration than conventional connections. The aim of this study was to evaluate the bacterial seal at the implant-abutment interface using two Morse taper implant models, by in vitro microbiological analysis. Eleven non-indexed and 11 indexed abutments were selected and connected to their respective implants with a 20 N torque, according to manufacturer's recommendation. Microbiological analysis was carried out using colonies of Escherichia coli transported directly from a culture dish to the prosthetic component. For control, one non-contaminated abutment-implant set from each group (negative control) and one contaminated implant with no abutment (positive control) were used. The specimens were immersed in BHI broth and maintained in an incubator at 37 degrees C for 14 days to assess the development of bacterial contamination. The results revealed that 36.4% (n=4) of the indexed components and 90.9% (n=10) of the non-indexed components allowed bacterial leakage, with significant difference between groups (p=0.0237). In conclusion, both tapered components failed to provide adequate sealing to bacterial leakage, although the indexed type components showed a superior seal compared with non-indexed components. PMID- 27224560 TI - Influence of Piezosurgery on Bone Healing around Titanium Implants: A Histological Study in Rats. AB - The aim of this study was to evaluate histomorphometrically the influence of two techniques of dental implant site preparation on bone healing around titanium implants. Fifteen male Wistar rats (+/-300 g) were used in the study. Each tibia was randomly assigned to receive the implant site preparation either with a conventional drilling technique (control - DRILL group) or with a piezoelectric device (PIEZO group). The animals were sacrificed after 30 days and then the following histomorphometric parameters were evaluated (percentage) separately for cortical and cancellous regions: proportion of mineralized tissue (PMT) adjacent to implant threads (500 MUm adjacent); bone area within the threads (BA) and bone implant contact (BIC). The results demonstrated that there were no statistically significant differences between both groups for cancellous BIC (p>0.05) and cortical PMT (p>0.05). On the other hand, a higher percentage of BA was observed in the PIEZO group in the cortical (71.50+/-6.91 and 78.28+/-4.38 for DRILL and PIEZO groups, respectively; p<0.05) and cancellous regions (9.62+/-4.06 and 19.94+/-14.18 for DRILL and PIEZO groups, respectively; p<0.05). The piezosurgery also showed higher PMT values in the cancellous zone (9.35+/-5.54 and 18.72+/ 13.21 for DRILL and PIEZO groups, respectively; p<0.05). However, the DRILL group presented better results for BIC in cortical region (80.42+/-10.88 and 70.25+/ 16.93 for DRILL and PIEZO groups, respectively; p<0.05). In conclusion, for the implant site preparation, the piezosurgery was beneficial to bone healing rates in the cancellous bone region, while the drill technique produced better results in the cortical bone. PMID- 27224561 TI - Resistance and Stress Finite Element Analysis of Different Types of Fixation for Mandibular Orthognathic Surgery. AB - The aim of this study was to evaluate the stress and dislodgement resistance by finite element analysis of different types of fixation in mandibular orthognathic surgery. A 3D solid finite element model of a hemi-mandible was obtained. A bilateral sagittal split osteotomy was simulated and the distal segment was advanced 5 mm forward. After the adjustment and superimposing of segments, 9 different types of osteosynthesis with 2.0 miniplates and screws were simulated: A, one 4-hole conventional straight miniplate; B, one 4-hole locking straight miniplate; C, one 4-hole conventional miniplate and one bicortical screw; D, one 4-hole locking miniplate and 1 bicortical screws; E, one 6-hole conventional straight miniplate; F, one 6-hole locking miniplate; G, two 4-hole conventional straight miniplates; H, two 4-hole locking straight miniplates; and I, 3 bicortical screws in an inverted-L pattern. In each model, forces simulating the masticatory muscles were applied. The values of stress in the plates and screws were checked. The dislodgement resistance was checked at the proximal segment since the distal segment was stable because of the screen at the occlusal tooth. The regions with the lowest and highest displacement were measured. The offset between the osteotomized segments was verified by millimeter intervals. Inverted L with bicortical screws was the model that had the lowest dislodgment and the model with the lowest tension was the one with two conventional plates. The results suggest that the tension was better distributed in the locking miniplates, but the locking screws presented higher concentration of tension. PMID- 27224562 TI - Parameters Associated with Marginal Bone Loss around Implant after Prosthetic Loading. AB - This study evaluated retrospectively the association among occlusal, periodontal and implant-prosthetic parameters and marginal bone loss (MBL) around implants and survival rate at 5.7 +/-3.2 years of follow-up after prosthetic loading. Eighty-two patients received 164 external hexagon implants. After the standard healing period (3 to 6 months), the implants were restored with single-tooth or up to three splinted crowns. All patients were followed according to a strict maintenance program with regular recalls and clinically evaluated by a calibrated examiner. The MBL measurements taken from standardized radiographs made at permanent crown placement (baseline) and after the last evaluation were calculated considering occlusal, periodontal and implant-prosthetic parameters. Veneer fractures and abutment loosening were not considered failure. Two implants failed during the follow-up period, resulting in a survival rate of 98.8%. Cox regression analyses showed MBL associated with non-working side contacts (p=0.047), inadequate anterior guidance (p=0.001), lateral group guidance involving teeth and implants (p=0.015), periimplant plaque index (p=0.035), prosthetic design (p=0.030) and retention (p=0.006). Inadequate occlusal pattern guide, presence of visible plaque, and cemented and splinted implant-supported restoration were associated with greater MBL around the implant. PMID- 27224563 TI - Anticaries Potential of Low Fluoride Dentifrices Found in The Brazilian Market. AB - Low-fluoride (F) dentifrices (<600 ug F/g) are widely available worldwide, but evidence to recommend the use of such dentifrices, with either regular or improved formulations, is still lacking. Therefore, the aim of this study was to evaluate the anticaries potential of low-F dentifrices found in the Brazilian market, using a validated and tested pH-cycling model. Enamel blocks were selected by surface hardness (SH) and randomized into four treatment groups (n=12): non-F dentifrice (negative control), low-F dentifrice (500 MUg F/g), low F acidulated dentifrice (550 MUg F/g) and 1,100 MUg F/g dentifrice (positive control). The blocks were subjected to pH-cycling regimen for 8 days and were treated 2x/day with dentifrice slurries prepared in water (1:3, w/v). The pH of the slurries was checked, and only the acidulated one had low pH. After the pH cycling, SH was again determined and the percentage of surface hardness loss was calculated as indicator of demineralization. Loosely- and firmly-bound F concentrations in enamel were also determined. The 1,100 MUg F/g dentifrice was more effective than the low-F ones to reduce enamel demineralization and was the only one that differed from the non-F (p<0.05). All F dentifrices formed higher concentration of loosely-bound F on enamel than the non-F (p<0.05), but the 1,100 MUg F/g was the only one that differed from the non-F in the ability to form firmly-bound F. The findings suggest that the low-F dentifrices available in the Brazilian market, irrespective of their formulation, do not have anticaries potential. PMID- 27224564 TI - Bonding Effectiveness of Universal Adhesive to Intracoronal Bleached Dentin Treated with Sodium Ascorbate. AB - This study evaluated the effect of restorative protocol with sodium ascorbate on the shear bond strength (SBS) of a universal adhesive to intracoronal bleached dentin. One hundred-and-twenty bovine dentin fragments were randomly divided into 12 groups (n=10), according to the bleaching procedure (unbleached and bleached) and restorative protocol (no treatment, 10% sodium ascorbate -10SA, 35% sodium ascorbate -35SA and two-step etch-and-rinse -ER or one-step self-etch -SE Scotchbond universal adhesive approaches). Four whitening sessions were performed using 35% hydrogen peroxide. The samples from control groups were kept in relative humidity at 37 degrees C. Immediately after bleaching procedures, the assigned antioxidant solution was applied on dentin and restorative procedures were performed following either the ER or the SE approach. After 24 h, the specimens were subjected to SBS test. Data (MPa) were analyzed by ANOVA and Tukey's test (?=0.05). Lower SBS values were found for bleached specimens (8.54 MPa) compared with those unbleached (12.13 MPa) (p<0.05). The bond strength of the sodium ascorbate-treated groups was higher than those untreated, regardless of the strategy employed (p<0.05). Groups restored without sodium ascorbate showed lower bond strength values for both ER (8.32 MPa) and SE (8.28 MPa) adhesive strategies. The group treated with 10SA submitted to ER approach (10.14 MPa) was similar to untreated groups (p>0.05). It may be concluded that bond strength of composite resin to intracoronal dentin was affected by restorative protocol and reduced by bleaching. PMID- 27224565 TI - Bond Strength of a Bisphenol-A-Free Fissure Sealant With and Without Adhesive Layer under Conditions of Saliva Contamination. AB - Dental sealants are important for prevention of carious lesions, if they have good shear strength. The aim of this study was to evaluate the shear bond strength (SBS) of two sealants to saliva-contaminated and non-contaminated enamel with and without an intermediate adhesive layer underneath the sealant. Ninety flat enamel surfaces from human third molars were randomly assigned to 6 groups (n=15): F (control): Fluroshield(tm) sealant; EWB (control): Embrace(tm) WetBond(tm); SB/F: Single Bond adhesive system + F; SB/EWB, s-SB/F and s-SB/EWB. In the s-SB/F and s-SB/EWB groups, the acid-etched enamel was contaminated with 0.01 mL of fresh human saliva for 20 s. Sealant cylinders were bonded to enamel surface with and without an intermediate adhesive system layer. The shear tests were performed using a universal testing machine (0.5 mm/min). Data were analyzed statistically by Kruskal-Wallis and Mann-Whitney tests (alpha=0.05). F presented higher mean SBS than EWB in all experimental conditions. The lowest SBS mean was obtained for EWB on contaminated enamel (p<0.05). In conclusion, an adhesive system layer should be used prior to sealant placement, in both dry and saliva contaminated enamel. F had the best performance in all experimental conditions. EWB sealant showed very low results, but an adhesive layer underneath the sealant increased its SBS even after salivary contamination. PMID- 27224566 TI - Analysis of the Early Stages and Evolution of Dental Enamel Erosion. AB - The aim of this study was to evaluate by atomic force microscopy (AFM) the early phases and evolution of dental enamel erosion caused by hydrochloric acid exposure, simulating gastroesophageal reflux episodes. Polished bovine enamel slabs (4x4x2 mm) were selected and exposed to 0.1 mL of 0.01 M hydrochloric acid (pH=2) at 37 ?#61472;?#61616;C using five different exposure intervals (n=1): no acid exposure (control), 10 s, 20 s, 30 s and 40 s. The exposed area was analyzed by AFM in 3 regions to measure the roughness, surface area and morphological surface. The data were analyzed qualitatively. Roughness started as low as that of the control sample, Rrms=3.5 nm, and gradually increased at a rate of 0.3 nm/s, until reaching Rrms=12.5 nm at 30 s. After 40 s, the roughness presented increment of 0.40 nm only. Surface area (SA) increased until 20 s, and for longer exposures, the surface area was constant (at 30 s, SA=4.40 MUm2 and at 40 s, SA=4.43 MUm2). As regards surface morphology, the control sample presented smaller hydroxyapatite crystals (22 nm) and after 40 s the crystal size was approximately 60 nm. Short periods of exposure were sufficient to produce enamel demineralization in different patterns and the morphological structure was less affected by exposure to hydrochloric acid over 30 s. PMID- 27224567 TI - Molecular Identification of Cultivable Bacteria From Infected Root Canals Associated With Acute Apical Abscess. AB - The objective of this study was to investigate the bacterial composition present in root canals of teeth associated with acute apical abscess by molecular identification (16S rRNA) of cultivable bacteria. Two hundred and twenty strains isolated by culture from 20 root canals were subjected to DNA extraction and amplification of the 16S rRNA gene (PCR), followed by sequencing. The resulting nucleotide sequences were compared to the GenBank database from the National Center of Biotechnology Information through BLAST. Strains not identified by sequencing were submitted to clonal analysis. The association of microbiological findings with clinical features and the association between microbial species were also investigated. Fifty-nine different cultivable bacteria were identified by 16S rRNA gene sequencing, belonging to 6 phyla, with an average number of 6 species per root canal. Molecular approaches allowed identification of 99% of isolates. The most frequently identified bacteria were Prevotella spp., Pseudoramibacter alactolyticus, Parvimonas micra, Dialister invisus, Filifactor alocis, and Peptostreptococcus stomatis. Positive association was found between Prevotella buccae and Pseudoramibacter alactolyticus and between Parvimonas micra and Prevotella nigrescens (both p<0.05). It was concluded that the microbiota of infected root canals associated with acute apical abscess is diverse and heterogeneous, composed mainly of anaerobic Gram-negative bacteria, with the great majority belonging to the phyla Firmicutes and Bacteroidetes. PMID- 27224568 TI - Ions Release and pH of Calcium Hydroxide-, Chlorhexidine- and Bioactive Glass Based Endodontic Medicaments. AB - This study evaluated pH and release of calcium, sodium and phosphate ions from different medications in human dentin. Fifty premolars were prepared and randomly divided into groups: (CHX) - 2% chlorhexidine gel; (CHX + CH) - CHX + calcium hydroxide PA; (CH) - CH + propylene glycol 600; (NPBG) - experimental niobium phosphate bioactive glass + distilled water; (BG) - bioactive glass (Bio-Gran) + distilled water. The specimens were immersed in deionized water and the pH variations were measured. The quantification of ions in the solutions was made by inductively coupled plasma - atomic emission spectroscopy (ICP/AES) at 10 min, 24 h, 7, 14, 21 and 30 days. The results were analyzed by ANOVA and Tukey's test, with a significance level of 5%. CH had the highest level of calcium ions release at 30 days, while CHX and BG released more sodium ions. BG, NPBG and CHX released a higher amount of phosphate ions. The pH of CH was significantly higher compared with the other groups. CH favored the greatest increase of pH and calcium ions release. The bioactive glasses released more sodium and phosphate ions and presented an alkaline pH immediately and after 30 days. PMID- 27224569 TI - Push-out Bond Strength of Root-end Filling Materials. AB - The aim of this study was to evaluate the bond strength of root-end filling materials. Forty 2-mm-thick slices were obtained from human single-rooted teeth. After root canal preparation using a 1.5 mm diameter cylindrical drill, the dentinal walls were prepared by diamond ultrasonic tip (CVD T0F-2). The specimens were divided according the material (n=10): MTA Angelus (MTAA), MTA Sealer (MTAS, experimental), Sealer 26 (S26) and zinc oxide and eugenol cement (ZOE). The push out test was performed in a mechanical test machine (EMIC DL 2000) at 1 mm/min speed. The failure type was evaluated by stereomicroscopy. The results were subjected to ANOVA and Tukey test, at 5% significance level. MTAA (19.18 MPa), MTAS (19.13 MPa) and S26 (15.91 MPa) showed higher bond strength (p<0.05). ZOE (9.50 MPa) showed the least bond strength values (p<0.05). Adhesive failure was prevalent in all groups, except for ZOE, which showed mixed failures. It was concluded that root-end filling materials MTA Angelus, MTA Sealer and Sealer 26 showed higher bond strength to dentinal walls than zinc oxide and eugenol cement after retrograde preparation. PMID- 27224570 TI - Influence of Blood on the Accuracy of Raypex 5 and Root ZX Electronic Foramen Locators: An In Vivo Study. AB - The aim of this study was to evaluate in vivo the accuracy of the Raypex 5 and Root ZX electronic foramen locators (EFLs) in the presence of blood in the root canal space. Forty single-canal teeth scheduled for extraction were selected. Access cavity was prepared and coronal enlargement was carried out. Approximately two drops of blood were collected by finger prick and injected into the root canal space. The electronic working length (EWL) of each tooth by each device was established twice before (NB group) and after (WB group) injecting blood into the root canal. The tooth was extracted and the actual working length (AWL) was determined. Data were analyzed using McNemar's test. The accuracy rates of Raypex 5 and Root ZX within 0.5 mm in the NB group were 88.9% and 91.5%, with 83.3% and 86.2% in the WB group, respectively. There were no significant differences between the accuracy of each EFL in the two groups (p>0.05). Considering the NB and WB groups, there were no statistically significant differences in the accuracy of the EFLs (p>0.05). The presence of blood in the root canal space did not influence the accuracy of the EFLs. PMID- 27224571 TI - Oral Health in Elders with Parkinson's Disease. AB - This study aimed to evaluate objectively and subjectively the oral health of elders with Parkinson's disease (PD), using clinical oral assessments and the General Oral Health Assessment Index (GOHAI). Subjects included 37 removable prosthesis wearers, 17 with PD (mean age 69.59+/-5.09 years) and 20 without PD (mean age 72.00+/-5.69 years). The objective assessment included an evaluation of oral characteristics, including the number of remaining teeth, decayed, missing and filled teeth (DMFT), visible plaque index (VPI), salivary flow rate and removable prosthesis conditions. The subjective assessment included self perception of oral health collected using the GOHAI index. The number of remaining teeth, DMFT, VPI, salivary flow rate and GOHAI data were compared between the groups using t-tests. Removable prosthesis conditions were analyzed using chi2 tests (p<0.05). There were no group differences in the number of remaining teeth, DMFT, VPI or salivary flow rate (p>0.05). Greater maxillary prosthesis defects were observed in the control group (p=0.037). GOHAI scores were low for the PD group and moderate for controls, yielding a group difference (p=0.04). In conclusion, elders with PD have similar oral health to controls. Although all elders had few remaining teeth, high DMFT and high VPI, PD elders had more negative self-perceptions of their oral health than did the controls. PMID- 27224572 TI - Edentulism, Severe Tooth Loss and Lack of Functional Dentition in Elders: A Study in Southern Brazil. AB - The aim of this study was to estimate self-reported prevalence of edentulism, severe tooth loss and lack of functional dentition in elders, and to identify potential associated factors. A population based cross-sectional study was carried out with 1,451 elders (>=60 years), in Pelotas, RS, Brazil. Crude and adjusted prevalence ratios were estimated using Poisson regressions. The prevalence of edentulism, severe tooth loss and lack of functional dentition was 39.3%, 60.9% and 82.7%, respectively. The factors positively associated with tooth loss in the three-degree severity were sex (females), older individuals, low familial income, low level of schooling and having the last dental visit longer than 24 months ago. The high prevalence of tooth loss in its different degrees of severity and the association with preventable factors highlight the need of programs focused on elders, emphasizing the prevention of tooth loss and need for prosthetic rehabilitation. PMID- 27224573 TI - Surgery Combined with LPRF in Denosumab Osteonecrosis of the Jaw: Case Report. AB - This paper describes two cases in which the use of leucocyte-rich and platelet rich fibrin (LPRF) combined with bone resection did not result in complete tissue response in the treatment of medication-related osteonecrosis of the jaw (MRONJ). It has been recently described in patients receiving subcutaneous administration of RANK-inhibitors, such as Denosumab, and anti-angiogenic drugs, such as Bevacizumab, as observed in our cases. Due to promising results in recent studies, more patients will receive these medications in order to avoid skeletal complications due to metastatic bone disease and, therefore, this scenario has a potential to become a comparable challenge to the bisphosphonate- induced jaw necrosis in the area of Oral and Maxillofacial Surgery. No convincing surgical technique has been described to overcome the non-healing mucosal lesions with exposed bone due to RANK-inhibitor therapy. Based on the findings in the literature and in both cases described herein can be concluded that the use of LPRF should be considered in the treatment of patients with DRONJ. PMID- 27224574 TI - Immediate Desensitization in Teeth Affected by Amelogenesis Imperfecta. AB - The aim of this paper was to describe a clinical case of immediate dental desensitization using a self-etch adhesive system in an adolescent patient diagnosed with amelogenesis imperfecta (AI). AI was associated with severe tooth sensitivity, treated by the application of a universal adhesive system for desensitization of the teeth affected by AI. Reduction of tooth sensitivity was assessed using a visual analog scale during all reevaluations. The technique was effective for reducing tooth sensitivity. It was concluded that the adhesive system for tooth desensitization had an immediate effect and maintained its effectiveness during a 12-month follow-up period. PMID- 27224575 TI - [Imaging Diagnosis of Cardial Chloroma]. PMID- 27224576 TI - Dual-Energy Perfusion-CT in Recurrent Pancreatic Cancer - Preliminary Results. AB - PURPOSE: To evaluate the diagnostic performance of dual energy (DE) perfusion-CT for the differentiation between postoperative soft-tissue formation and tumor recurrence in patients after potentially curative pancreatic cancer resection. MATERIAL AND METHODS: 24 patients with postoperative soft-tissue formation in the conventional regular follow-up CT acquisition after pancreatic cancer resection with curative intent were included prospectively. They were examined with a 64 row dual-source CT using a dynamic sequence of 34 DE acquisitions every 1.5 s (80 ml of iodinated contrast material, 370 mg/ml, flow rate 5 ml/s). Weighted average (linearly blended M0.5) 120kVp-equivalent dual-energy perfusion image data sets were evaluated with a body-perfusion CT tool (see above) for estimating blood flow, permeability, and blood volume. Diagnosis was confirmed by histological study (n = 4) and by regular follow-up. RESULTS: Final diagnosis was local recurrence of pancreatic cancer in 15 patients and unspecific postoperative tissue formation in 9 patients. The blood-flow values for recurrence tissue trended to be lower compared to postoperative tissue formation with 16.6 ml/100 ml/min and 24.7 ml/100 ml/min, respectively for weighted average 120kVp equivalent image data, which was not significant (n.s.) (p = 0.06, significance level 0.05). Permeability- and blood-volume values were only slightly lower in recurrence tissue (n.s.). CONCLUSION: DE perfusion-CT is feasible in patients after pancreatic cancer resection and a promising functional imaging technique. As only a trend for lower perfusion values in local recurrence compared to unspecific postoperative alterations was found, the perfusion differences are not yet sufficient to differentiate between malignancy and unspecific postoperative alterations for this new technique. Further studies and technical improvements are needed to generate reliable data for this clinically highly relevant differentiation. KEY POINTS: * DE Perfusion CT is feasible in patients after pancreatic cancer resection.* While reliable differentiation of unspecific postoperative tissue formation from recurrent malignancy cannot be achieved yet, it is within reach.* DE Perfusion CT has the potential to overcome todays limitations of pure morphological diagnosis of recurrent pancreatic cancer. Citation Format: * Fritz F, Skornitzke S, Hackert T et al. Dual-Energy Perfusion CT in Recurrent Pancreatic Cancer - Preliminary RESULTS. Fortschr Rontgenstr 2016; 188: 559 - 565. PMID- 27224578 TI - [In Process Citation]. PMID- 27224577 TI - [In Process Citation]. PMID- 27224579 TI - [In Process Citation]. PMID- 27224580 TI - [In Process Citation]. PMID- 27224581 TI - [In Process Citation]. PMID- 27224582 TI - [In Process Citation]. PMID- 27224583 TI - [In Process Citation]. PMID- 27224584 TI - [In Process Citation]. PMID- 27224585 TI - [In Process Citation]. PMID- 27224586 TI - [In Process Citation]. PMID- 27224587 TI - This is what 'caring for the carers' looks like. AB - Bereavement affects each of us differently, and few of us can anticipate how we will react when we lose a loved one. We can also never be sure how those around us will be affected, especially younger children experiencing death for the first time. This week's Nursing Standard features a nurse who has developed a service that offers holistic care in the aftermath of death and should serve as a blueprint for commissioners to follow. PMID- 27224588 TI - Framework provides 'fantastic opportunity'. AB - England's chief nursing officer launched her framework for the profession at the RCN headquarters in London - hailing it as a 'fantastic opportunity' to provide a first class service. PMID- 27224589 TI - Researchers receive financial backing for trust staffing study. AB - A two-year study into safe staffing has been backed by L500,000 of government money. PMID- 27224590 TI - Promote benefits of even modest boosts in activity. AB - People who are physically inactive will be targeted in a national campaign to improve the nation's physical fitness and mental health. PMID- 27224591 TI - New NHS access rules could penalise foreign staff. AB - The RCN has criticised a proposal in the Queen's Speech that could lead to foreign nurses who work in the NHS being charged to use its services. PMID- 27224592 TI - NHS looks to nurses with procurement expertise to bag equipment bargains. AB - A new team of nursing professionals has been set up to cut NHS costs by more efficient purchasing of essentials, such as gloves and syringes. PMID- 27224593 TI - Infection control specialist pay should reflect gravity of the threat. AB - Nurses and other professionals working in infectious disease control should be paid more to fight emerging antimicrobial resistance. PMID- 27224594 TI - Burns outreach wins team a Cavell award. AB - Nurses from the Welsh Centre for Burns and Plastic Surgery in Swansea have been honoured with a Cavell Nurses' Trust special achievement award. PMID- 27224597 TI - Lung cancer survey targets survival. AB - Nurses are being asked for their views on how to improve lung cancer survival rates. PMID- 27224596 TI - Tailored plan 'could improve a student's ability to cope'. AB - Universities should develop interventions to boost nursing students' belief in their ability to manage difficult situations, researchers suggest. PMID- 27224598 TI - All new prisoners should receive nurse-supervised assessments. AB - Recommendations from the National Institute for Health and Care Excellence call for every person admitted to prison to receive a healthcare assessment before being allocated a cell. PMID- 27224599 TI - Digging deeper for health benefits. AB - TV presenter Mary Berry swapped the Great British Bake Off tent for the great outdoors at an event promoting the health benefits of gardening. PMID- 27224600 TI - Leadership and efficiency - chief nurse's vision for better outcomes. AB - Better patient outcomes and experience, as well as better use of resources for nurses and patients, are the aspirations of a new NHS England strategy. PMID- 27224601 TI - E-cigarettes are a useful tool in getting people to stop smoking. AB - E-cigarettes have the potential to help radically reduce the incidence of death and disability due to tobacco use, a new study says. PMID- 27224602 TI - Evidence suggests rosacea may be linked to Parkinson's and Alzheimer's disease. AB - Patients who have rosacea are at increased risk of developing dementia, particularly Alzheimer's disease. PMID- 27224603 TI - American death certificates fail to show medical error as possible cause of death. AB - Medical error is the third biggest cause of death in the United States, only exceeded by heart disease and cancer. PMID- 27224604 TI - Yoga may help lessen the debilitating effects of asthma and have lifestyle benefits. AB - There is evidence that yoga could improve the symptoms of asthma and boost quality of life, but the effects on lung function and medication use are uncertain, new research has found. PMID- 27224605 TI - Video calls help prevent long-term memory loss problems after chemotherapy. AB - Long-term memory issues after having chemotherapy could be prevented by cognitive behavioural therapy delivered via video conferencing. PMID- 27224606 TI - Womb cancer. AB - Essential facts About 9,000 women are diagnosed with womb cancer in the UK each year, making it the fourth most common cancer in women. Around 2,000 women die from the disease - also known as uterine cancer - each year. Endometrial cancer, which starts in the lining of the uterus, is the most common type. PMID- 27224607 TI - Empower children to cope with their grief. PMID- 27224608 TI - Watching TV can be a beneficial experience. PMID- 27224609 TI - What price a degree? AB - Let's face it, nurse education is big business for British universities. The lobby group of universities offering nursing degrees, the Council of Deans of health (CoDH), argues that the true cost of nursing degrees is subsidised by their members. PMID- 27224610 TI - Voices - Listen, learn and act now to achieve safe staffing, says Susan Osborne. AB - The latest report from the Public Accounts Committee severely criticises senior health service leaders. PMID- 27224611 TI - If life is a blur. AB - I'd already told the midwife something was wrong, and she'd gone for help. But that was an hour ago. Now I was going downhill fast. PMID- 27224613 TI - Workforce. AB - The Observer newspaper recently reported that the UK is in the throes of a housing crisis. PMID- 27224614 TI - Readers panel - Myth of weekend death rates. AB - Our experts consider a hot topic of the day. PMID- 27224612 TI - Shattering news. AB - When I fear I am becoming clumsy in old age, I take out my smartphone, cradle it in the palm of my hand and admire its pristine glass surfaces. PMID- 27224615 TI - Starting out - I had to see beyond 'fixing' patients and adopt a more holistic approach. AB - When asked about my biggest fear for a nursing career, my answer was 'difficult situations' such as giving bad news and caring for a dying patient. PMID- 27224620 TI - Knee Decide app. AB - Part of a series of free medical apps by Orca Health, Knee Decide provides health professionals with a useful aid in communicating basic knee anatomy to patients. PMID- 27224619 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 27224621 TI - Now is the time to demand change to punishing FtP procedures. AB - Having undergone Nursing and Midwifery Council fitness to practise (FtP) proceedings after raising and escalating concerns, I read with interest your article about nurses facing FtP hearings being 'pushed to breaking point' (analysis, May 11). PMID- 27224622 TI - Expanding our roles is all very well, but we are already overstretched. AB - It was with some concern that I learned of the proposals for nursing roles to be expanded (news, May 18) as part of an initiative to supplement care delivered previously by junior doctors. PMID- 27224623 TI - Health problems have come in wake of contact with chemicals. AB - As a result of working with the chemicals glutaraldehyde and formaldehyde as a theatre nurse some years ago, I believe that I have suffered numerous health problems that resulted in my retirement. PMID- 27224624 TI - Action plan flags opportunities to address health inequalities. AB - We know that health inequalities apply to people with mental health problems who have poorer physical health than the general population. PMID- 27224625 TI - The fight against polio takes a tragic toll, but it must continue. AB - The recent news that seven policemen in Pakistan were killed while guarding polio vaccination workers in Karachi was tragic, especially when we are close to eradicating polio from the only two remaining countries where the virus is considered endemic - Pakistan and Afghanistan. PMID- 27224628 TI - How to administer eye drops and eye ointment. AB - Rationale and key points Eye drops and eye ointment are the mainstay of treatment of ocular conditions. Failure to prioritise administration of these medicines can prolong the condition and may present a risk to the patient's vision. ? Eye drops and eye ointments are used to treat acute and chronic conditions of the eye and surrounding structures. Eye drops must be instilled before applying eye ointment, since the ointment will affect the absorption of the eye drop. ? Nurses require knowledge of the technique, side effects and potential interactions associated with systemically or topically applied medicines to the eye to ensure patient safety and optimum outcomes. 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 this article will change your practice. 2. How you intend to develop your knowledge and skills regarding treatment of ocular conditions. Subscribers can update their reflective accounts at rcni.com/portfolio. PMID- 27224629 TI - Promoting participation of people with dementia in research. AB - Dementia is a neurodegenerative disorder that can have a severe effect on the quality of life of individuals with the condition, and can place considerable strain on informal carers and healthcare systems. Research is required to identify ways to prevent or delay the onset of dementia. The government is committed to dementia research, yet funding for dementia research is eclipsed by funding for research into other conditions. Moreover, dementia research can only progress if individuals with the condition participate in research studies. This article discusses barriers associated with research into dementia and describes a UK government initiative, Join Dementia Research, which supports research participation for people with dementia. PMID- 27224630 TI - Identifying and managing Hymenoptera venom allergy. AB - Hymenoptera venom allergy is an immunoglobulin E (IgE)-mediated hypersensitivity to the venom of insects from the Hymenoptera order and is a common cause of anaphylaxis. A diagnosis of venom allergy is made by taking an accurate medical, family and social history, alongside specific allergy testing. Systemic reactions to Hymenoptera venom occur in a small proportion of the population; these range from mild to life-threatening in severity. Treatment for local reactions involves the use of cold packs, antihistamines, analgesia and topical corticosteroids to help alleviate swelling, pain and pruritus. Venom immunotherapy is the treatment of choice for reducing the incidence of future anaphylactic reactions in individuals who have signs of respiratory obstruction or hypotension. Venom immunotherapy is the most effective treatment in reduction of life-threatening reactions to venom, and can improve quality of life for individuals. Treatment should only be provided by experienced staff who are able to provide emergency care for anaphylaxis and life-threatening episodes. A risk assessment to deliver treatment should be undertaken before treatment is commenced. PMID- 27224631 TI - Polypharmacy: the challenge for nurses. AB - Polypharmacy refers to the prescribing of many medicines for one individual. Polypharmacy is increasingly common as a result of the rise in multimorbidity, use of evidence-based clinical guidelines and care pathways, and a focus on disease prevention. Polypharmacy can be justified and appropriate, but it may also be inappropriate and associated with suboptimal health outcomes and mortality. Polypharmacy is associated with adverse drug events such as drug-drug interactions and adverse drug reactions (ADRs). Taking multiple medicines can adversely affect adherence, resulting in lost opportunities for health gain and wasted medicines. Older people, and particularly those who are frail, are susceptible to the adverse effects of polypharmacy. Medication reviews should be undertaken regularly in older people with polypharmacy. Medicines management systems, research, and education are essential to improve safe practice in the management of polypharmacy. PMID- 27224632 TI - Psychological support. AB - I read the CPD article to improve my knowledge of the psychological needs of people living with cancer. Half of these people (150,000 per year) experience anxiety or depression after a diagnosis of cancer. PMID- 27224633 TI - Workplace matters. AB - Medical settings are fast-paced and busy, so if someone is not pulling their weight, it can have a big effect on the rest of the team and the quality of care being given. What if it is one of your colleagues who is not fulfilling their duties or performing to the required standard? PMID- 27224634 TI - Comfort through the night. AB - When Karen Titchener helped launch an out-of-hours end of life nursing team she saw an opportunity to reduce gaps in the service as well as potential for her own role. PMID- 27224636 TI - Student life - Preserving safety. AB - In addition to providing compassionate care and administering correct treatments, the Nursing and Midwifery Council Code states that nurses must keep patients and the public safe and free from harm. PMID- 27224637 TI - Failed Intussusception Reduction in Children: Correlation Between Radiologic, Surgical, and Pathologic Findings. AB - OBJECTIVE: The objective of this study was to identify causes of irreducible intussusception after contrast enema and to correlate imaging findings with surgical and histopathologic findings. MATERIALS AND METHODS: Between 2005 and 2013, a total of 543 children underwent reduction of intussusception with the use of an enema technique (hereafter referred to as "enema reduction"). The medical records of 72 children (56 boys [mean age, 24.8 months; range, 3.8 months to 10.9 years] and 16 girls [mean age, 14.2 months; range, 1.5 months to 6.9 years) who underwent unsuccessful reduction and were treated surgically were retrospectively analyzed. The data collected included information on the cause of intussusception, the risk factors noted on ultrasound, operative management, outcome, and the length of the hospital stay. The imaging findings for these patients were compared with findings for statistically similar age-matched control subjects. RESULTS: Ultrasound detected 56 of 57 cases of intussusception, but it failed to detect the lead point in three cases and failed to detect ischemic necrosis in seven cases. Positive predictors of failed enema reduction were the presence of a distal mass and observation of the dissecting sign. Of the 72 patients who underwent surgical treatment of intussusception, 26 (36.1%) underwent laparoscopy, 38 (52.8%) underwent laparotomy, and eight (11.1%) underwent conversion from laparoscopy to laparotomy. Surgical reduction was performed in 61.1% of cases, small bowel resection in 19.4%, ileocecectomy in 12.5%, and self-reduction in 69%. Pathologic lead points (noted in 25% of cases) included lymphoid hyperplasia (n = 7), Meckel diverticulum (n = 3), Burkitt lymphoma (n = 3), enteric duplication cyst (n = 2), juvenile polyp (n = 2), and adenovirus appendicitis (n = 1). The length of the hospital stay was significantly longer after laparotomy. CONCLUSION: The distalmost location of the intussusception mass and presence of the dissecting sign on images obtained during contrast enema have a higher positive predictive value for failed reduction. Screening ultrasound decreases the number of unnecessary contrast enemas performed; however, classic pathologic lead points, such as Burkitt lymphoma and Meckel diverticulum, may be difficult to diagnose with the use of ultrasound. Laparotomy and laparoscopy are equally safe and efficacious in reducing intussusception, with the length of the hospital stay after laparoscopy significantly shorter than that noted after laparotomy. Most failed enema reductions are idiopathic, and pathologic lead points are noted in 25% of cases. PMID- 27224638 TI - Presence of a high-flow-mediated constriction phenomenon prior to flow-mediated dilatation in normal weight, overweight, and obese children and adolescents. PMID- 27224639 TI - Electrical Impedance Tomography Visualizes Impaired Ventilation Due to Hemidiaphragmatic Paresis after Interscalene Brachial Plexus Block. PMID- 27224640 TI - Transcranial Doppler to Predict Neurologic Outcome after Mild to Moderate Traumatic Brain Injury. AB - BACKGROUND: To assess the performance of transcranial Doppler (TCD) in predicting neurologic worsening after mild to moderate traumatic brain injury. METHODS: The authors conducted a prospective observational study across 17 sites. TCD was performed upon admission in 356 patients (Glasgow Coma Score [GCS], 9 to 15) with mild lesions on cerebral computed tomography scan. Normal TCD was defined as a pulsatility index of less than 1.25 and diastolic blood flow velocity higher than 25 cm/s in the two middle cerebral arteries. The primary endpoint was secondary neurologic deterioration on day 7. RESULTS: Twenty patients (6%) developed secondary neurologic deterioration within the first posttraumatic week. TCD thresholds had 80% sensitivity (95% CI, 56 to 94%) and 79% specificity (95% CI, 74 to 83%) to predict neurologic worsening. The negative predictive values and positive predictive values of TCD were 98% (95% CI, 96 to 100%) and 18% (95% CI, 11to 28%), respectively. In patients with minor traumatic brain injury (GCS, 14 to 15), the sensitivity and specificity of TCD were 91% (95% CI, 59 to 100%) and 80% (95% CI, 75 to 85%), respectively. The area under the receiver operating characteristic curve of a multivariate predictive model including age and GCS was significantly improved with the adjunction of TCD. Patients with abnormal TCD on admission (n = 86 patients) showed a more altered score for the disability rating scale on day 28 compared to those with normal TCD (n = 257 patients). CONCLUSIONS: TCD measurements upon admission may provide additional information about neurologic outcome after mild to moderate traumatic brain injury. This technique could be useful for in-hospital triage in this context. (Anesthesiology 2016; 125:346-54). PMID- 27224641 TI - Programming Self-Assembly of DNA Origami Honeycomb Two-Dimensional Lattices and Plasmonic Metamaterials. AB - Scaffolded DNA origami has proven to be a versatile method for generating functional nanostructures with prescribed sub-100 nm shapes. Programming DNA origami tiles to form large-scale 2D lattices that span hundreds of nanometers to the micrometer scale could provide an enabling platform for diverse applications ranging from metamaterials to surface-based biophysical assays. Toward this end, here we design a family of hexagonal DNA-origami tiles using computer-aided design and demonstrate successful self-assembly of micrometer-scale 2D honeycomb lattices and tubes by controlling their geometric and mechanical properties including their interconnecting strands. Our results offer insight into programmed self-assembly of low-defect supra-molecular DNA-origami 2D lattices and tubes. In addition, we demonstrate that these DNA-origami hexagon tiles and honeycomb lattices are versatile platforms for assembling optical metamaterials via programmable spatial arrangement of gold nanoparticles (AuNPs) into cluster and superlattice geometries. PMID- 27224642 TI - The UK Lung Cancer Screening Trial: a pilot randomised controlled trial of low dose computed tomography screening for the early detection of lung cancer. AB - BACKGROUND: Lung cancer kills more people than any other cancer in the UK (5-year survival < 13%). Early diagnosis can save lives. The USA-based National Lung Cancer Screening Trial reported a 20% relative reduction in lung cancer mortality and 6.7% all-cause mortality in low-dose computed tomography (LDCT)-screened subjects. OBJECTIVES: To (1) analyse LDCT lung cancer screening in a high-risk UK population, determine optimum recruitment, screening, reading and care pathway strategies; and (2) assess the psychological consequences and the health-economic implications of screening. DESIGN: A pilot randomised controlled trial comparing intervention with usual care. A population-based risk questionnaire identified individuals who were at high risk of developing lung cancer (>= 5% over 5 years). SETTING: Thoracic centres with expertise in lung cancer imaging, respiratory medicine, pathology and surgery: Liverpool Heart & Chest Hospital, Merseyside, and Papworth Hospital, Cambridgeshire. PARTICIPANTS: Individuals aged 50-75 years, at high risk of lung cancer, in the primary care trusts adjacent to the centres. INTERVENTIONS: A thoracic LDCT scan. Follow-up computed tomography (CT) scans as per protocol. Referral to multidisciplinary team clinics was determined by nodule size criteria. MAIN OUTCOME MEASURES: Population-based recruitment based on risk stratification; management of the trial through web-based database; optimal characteristics of CT scan readers (radiologists vs. radiographers); characterisation of CT-detected nodules utilising volumetric analysis; prevalence of lung cancer at baseline; sociodemographic factors affecting participation; psychosocial measures (cancer distress, anxiety, depression, decision satisfaction); and cost-effectiveness modelling. RESULTS: A total of 247,354 individuals were approached to take part in the trial; 30.7% responded positively to the screening invitation. Recruitment of participants resulted in 2028 in the CT arm and 2027 in the control arm. A total of 1994 participants underwent CT scanning: 42 participants (2.1%) were diagnosed with lung cancer; 36 out of 42 (85.7%) of the screen-detected cancers were identified as stage 1 or 2, and 35 (83.3%) underwent surgical resection as their primary treatment. Lung cancer was more common in the lowest socioeconomic group. Short-term adverse psychosocial consequences were observed in participants who were randomised to the intervention arm and in those who had a major lung abnormality detected, but these differences were modest and temporary. Rollout of screening as a service or design of a full trial would need to address issues of outreach. The health economic analysis suggests that the intervention could be cost-effective but this needs to be confirmed using data on actual lung cancer mortality. CONCLUSIONS: The UK Lung Cancer Screening (UKLS) pilot was successfully undertaken with 4055 randomised individuals. The data from the UKLS provide evidence that adds to existing data to suggest that lung cancer screening in the UK could potentially be implemented in the 60-75 years age group, selected via the Liverpool Lung Project risk model version 2 and using CT volumetry-based management protocols. FUTURE WORK: The UKLS data will be pooled with the NELSON (Nederlands Leuvens Longkanker Screenings Onderzoek: Dutch-Belgian Randomised Lung Cancer Screening Trial) and other European Union trials in 2017 which will provide European mortality and cost-effectiveness data. For now, there is a clear need for mortality results from other trials and further research to identify optimal methods of implementation and delivery. Strategies for increasing uptake and providing support for underserved groups will be key to implementation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN78513845. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 40. See the NIHR Journals Library website for further project information. PMID- 27224643 TI - Abdominal Obesity, Race and Chronic Kidney Disease in Young Adults: Results from NHANES 1999-2010. AB - OBJECTIVE: Kidney dysfunction in obesity may be independent of and may precede the development of hypertension and/or diabetes mellitus. We aimed to examine if abdominal obesity is associated with early markers of CKD in a young healthy population and whether these associations differ by race and/or ethnicity. METHODS: We analyzed data from the NHANES 1999-2010 for 6918 young adults ages 20 40 years. Abdominal obesity was defined by gender criteria of waist circumference. CKD markers included estimated glomerular filtration rate and albuminuria >=30 mg/g. Race stratified analyses were done overall and in subgroups with normal blood pressures, normoglycemia and normal insulin sensitivity. Awareness of CKD was assessed in participants with albuminuria. RESULTS: Abdominal obesity was present in over one-third of all young adults and was more prevalent among non-Hispanic blacks (45.4%) versus Mexican-Americans (40.6%) or non-Hispanic whites (37.4%) (P-value = 0.004). Mexican-American young adults with abdominal obesity had a higher odds of albuminuria even among those with normal blood pressure, normal glucose, and normal insulin sensitivity [adjusted odds ratio 4.5; 95% confidence interval (1.6-12.2), p = 0.004]. Less than 5% of young adults with albuminuria of all races and ethnicities had been told they had kidney disease. CONCLUSION: Abdominal obesity in young adults, especially in Mexican-Americans, is independently associated with albuminuria even with normal blood pressures, normoglycemia and normal insulin levels. Greater awareness of CKD is needed to protect this young population from long standing exposure to abdominal obesity and early progressive renal disease. PMID- 27224644 TI - Assessment of a High-Throughput Methodology for the Study of Alloy Oxidation using AlxFeyNi1-x-y Composition Gradient Thin Films. AB - The high-temperature oxidation of multicomponent metal alloys exhibits complex dependencies on composition, which are not fully understood for many systems. Combinatorial screening of the oxidation of many different compositions of a given alloy offers an ideal means for gaining fundamental insights into such systems. We have previously developed a high-throughput methodology for studying AlxFeyNi1-x-y alloy oxidation using ~100 nm thick composition spread alloy films (CSAFs). In this work, we critically assess two aspects of this methodology: the sensitivity of CSAF oxidation behavior to variations in AlxFeyNi1-x-y composition and the differences between the oxidation behavior of ~100 nm thick CSAFs and that of bulk AlxFeyNi1-x-y alloys. This was done by focusing specifically on AlxFe1-x and AlxNi1-x oxidation in dry air at 427 degrees C. Transitions between phenomenologically distinguishable types of oxidation behavior are found to occur over CSAF compositional ranges of <2 at. %. The oxidation of AlxFe1-x CSAFs is found to be very similar to that of bulk AlxFe1-x alloys, but some minor differences between CSAF and bulk behavior are observed for AlxNi1-x oxidation. On the basis of our assessment, high-throughput studies of CSAF oxidation appear to be an effective method for gaining fundamental insights into the composition dependence of the oxidation of bulk alloys. PMID- 27224645 TI - School attendance and daily respiratory symptoms in children: influence of moisture damage. AB - We investigated the effect of weekends and school holidays on the daily frequency and severity of respiratory and other symptoms among children attending schools with (index) or without (reference) moisture damage in Spain, the Netherlands, and Finland. Throughout 1 year, parents of 419 children with a respiratory condition attending index (n=15) or reference (n=10) primary schools completed three symptom diaries. We assessed associations between lower respiratory tract, upper respiratory tract or allergy, and other symptom scores and school day, weekend, or summer holiday using mixed regression models stratified by country and moisture damage. We evaluated interactions between moisture damage and type of day. We combined country-specific estimates (incidence rate ratios [IRRs] and 95% confidence interval [CI]) in meta-analyses. Symptom scores were lower during weekends and holiday. Lower respiratory tract symptoms were statistically significantly less common during holiday with strongest effect in index schools (IRR=0.7; CI=0.6-0.8). Reporting of other symptoms was more reduced during holiday in index (IRR=0.6; CI=0.4-0.9) than in reference (IRR=0.95; CI=0.8-1.2) schools (interaction P<.01). In conclusion, symptoms were less frequent and/or severe during summer holiday and weekends. This pattern was stronger among children attending moisture-damaged schools, suggesting potential improvement in moisture damage-related symptoms during school breaks. PMID- 27224646 TI - Effects of Dietary Fibre (Pectin) and/or Increased Protein (Casein or Pea) on Satiety, Body Weight, Adiposity and Caecal Fermentation in High Fat Diet-Induced Obese Rats. AB - Dietary constituents that suppress appetite, such as dietary fibre and protein, may aid weight loss in obesity. The soluble fermentable dietary fibre pectin promotes satiety and decreases adiposity in diet-induced obese rats but effects of increased protein are unknown. Adult diet-induced obese rats reared on high fat diet (45% energy from fat) were given experimental diets ad libitum for 4 weeks (n = 8/group): high fat control, high fat with high protein (40% energy) as casein or pea protein, or these diets with added 10% w/w pectin. Dietary pectin, but not high protein, decreased food intake by 23% and induced 23% body fat loss, leading to 12% lower final body weight and 44% lower total body fat mass than controls. Plasma concentrations of satiety hormones PYY and total GLP-1 were increased by dietary pectin (168% and 151%, respectively) but not by high protein. Plasma leptin was decreased by 62% on pectin diets and 38% on high pea (but not casein) protein, while plasma insulin was decreased by 44% on pectin, 38% on high pea and 18% on high casein protein diets. Caecal weight and short chain fatty acid concentrations in the caecum were increased in pectin-fed and high pea protein groups: caecal succinate was increased by pectin (900%), acetate and propionate by pectin (123% and 118%, respectively) and pea protein (147% and 144%, respectively), and butyrate only by pea protein (309%). Caecal branched chain fatty acid concentrations were decreased by pectin (down 78%) but increased by pea protein (164%). Therefore, the soluble fermentable fibre pectin appeared more effective than high protein for increasing satiety and decreasing caloric intake and adiposity while on high fat diet, and produced a fermentation environment more likely to promote hindgut health. Altogether these data indicate that high fibre may be better than high protein for weight (fat) loss in obesity. PMID- 27224647 TI - A potential biomarker for fatigue: Oxidative stress and anti-oxidative activity. AB - We sought to determine whether oxidative stress and anti-oxidative activity could act as biomarkers that discriminate patients with chronic fatigue syndrome (CFS) from healthy volunteers at acute and sub-acute fatigue and resting conditions. We calculated the oxidative stress index (OSI) from reactive oxygen metabolites derived compounds (d-ROMs) and the biological antioxidant potential (BAP). We determined changes in d-ROMs, BAP, and OSI in acute and sub-acute fatigue in two healthy groups, and compared their values at rest between patients with CFS (diagnosed by Fukuda 1994 criteria) and another group of healthy controls. Following acute fatigue in healthy controls, d-ROMs and OSI increased, and BAP decreased. Although d-ROMs and OSI were significantly higher after sub-acute fatigue, BAP did not decrease. Resting condition yielded higher d-ROMs, higher OSI, and lower BAP in patients with CFS than in healthy volunteers, but lower d ROMs and OSI when compared with sub-acute controls. BAP values did not significantly differ between patients with CFS and controls in the sub-acute condition. However, values were significantly higher than in the resting condition for controls. Thus, measured of oxidative stress (d-ROMS) and anti oxidative activity (BAP) might be useful for discriminating acute, sub-acute, and resting fatigue in healthy people from patients with CFS, or for evaluating fatigue levels in healthy people. PMID- 27224649 TI - Tailoring the germanene-substrate interactions by means of hydrogenation. AB - Thanks to density functional calculations, the influence of hydrogenation on the interactions between a (2 * 2) germanene layer and a (3 * 3) Al(111) substrate has been investigated. It appears that the Ge-Al inter-atomic distance increases with hydrogen coverage, while the interaction energy and charge transfer between the Ge layer and the Al topmost plane drastically diminish, thus reducing the electrostatic interactions. Moreover, hydrogenation also lowers the electron density at the interface, weakening the chemical interaction between the Ge layer and the Al surface, and opening the door to a possible decoupling of the germanene layer from the Al substrate. PMID- 27224648 TI - Overexpression of L-Type Amino Acid Transporter 1 (LAT1) and 2 (LAT2): Novel Markers of Neuroendocrine Tumors. AB - BACKGROUND: 6-18F-fluoro-L-3,4-dihydroxyphenylalanine (18F-FDOPA) PET is a useful tool in the clinical management of pheochromocytoma (PHEO) and medullary thyroid carcinoma (MTC). 18F-FDOPA is a large neutral amino acid biochemically resembling endogenous L-DOPA and taken up by the L-type amino acid transporters (LAT1 and LAT2). This study was conducted to examine the expression of the LAT system in PHEO and MTC. METHODS: Real-time PCR and Western blot analyses were used to assess LAT1 and LAT2 gene and protein expression in 32 PHEO, 38 MTC, 16 normal adrenal medulla and 15 normal thyroid tissue samples. Immunohistochemistry method was applied to identify the proteins' subcellular localization. RESULTS: LAT1 and LAT2 were overexpressed in both PHEO and MTC by comparison with normal tissues. LAT1 presented a stronger induction than LAT2, and their greater expression was more evident in PHEO (15.1- and 4.1-fold increases, respectively) than in MTC (9.9- and 4.1-fold increases, respectively). Furthermore we found a good correlation between LAT1/2 and GLUT1 expression levels. A positive correlation was also found between urinary noradrenaline and adrenaline levels and LAT1 gene expression in PHEO. The increased expression of LAT1 is also confirmed at the protein level, in both PHEO and MTC, with a strong cytoplasmic localization. CONCLUSIONS: The present study is the first to provide experimental evidence of the overexpression in some NET cancers (such as PHEO or MTC) of L-type amino acid transporters, and the LAT1 isoform in particular, giving the molecular basis to explain the increase of the DOPA uptake seen in such tumor cells. PMID- 27224650 TI - Surface Functionalization of Metals by Alkyl Chains through a Radical Crossover Reaction. AB - Alkyl chains are covalently attached onto metal surfaces by indirect reduction of the bromoalkyl derivative (RBr). This indirect reaction involves the formation (by spontaneous or electrochemical reduction of the 2,6-dimethylbenzenediazonium salt) of a sterically hindered aryl radical that abstracts a Br atom from RBr but does not react with the surface. This crossover reaction furnishes an alkyl radical that reacts with the surface. Starting from 6-bromohexanoic acid, carboxylic functionalized gold surfaces are prepared. "Layer-by-layer" assemblies are built from these surfaces and present some ionic selectivity. PMID- 27224652 TI - Effect of deploying community health assistants on appropriate treatment for diarrhoea, malaria and pneumonia: quasi-experimental study in two districts of Zambia. AB - OBJECTIVE: A critical shortage of human resources for health in Zambia remains a great challenge. In response, the Zambian Ministry of Health developed a national community health assistant (CHA) programme, aiming to create a well-trained and motivated community-based health workforce. This study assessed whether CHAs increased treatment rates for diarrhoea, confirmed malaria or pneumonia in the first programme year. METHODS: This study used a quasi-experimental difference-in difference design, comparing changes in the catchment areas of health posts with CHAs to those without. Baseline and end line household surveys were conducted to measure the proportion of children under 5 years treated for diarrhoea, malaria or pneumonia in the 2 weeks before the survey and immunisation rates and malaria rapid diagnostic test rates. RESULTS: We surveyed 2330 women with children under five from the intervention area and 2314 from comparison areas at baseline and end line. Treatment for diarrhoea, malaria or pneumonia increased by 18.0% (P < 0.01) and 23.5% (P < 0.01) in the intervention and comparison groups, respectively, but DID analysis was not significant (P = 0.27). The proportion of fully immunised children grew by 7.5% in the intervention, but shrank by 7.5% in the comparison group (DID: 0.14; 95% CI 0.12-0.16, P < 0.01). CONCLUSION: Although we observed no significant difference between the intervention and comparison groups in the DID estimates for the primary outcome, there were significant increases after one year in treatment for all three diseases in the intervention group from baseline to end line and in the proportion of fully immunised children. PMID- 27224653 TI - Identifying Talent in Youth Sport: A Novel Methodology Using Higher-Dimensional Analysis. AB - Prediction of adult performance from early age talent identification in sport remains difficult. Talent identification research has generally been performed using univariate analysis, which ignores multivariate relationships. To address this issue, this study used a novel higher-dimensional model to orthogonalize multivariate anthropometric and fitness data from junior rugby league players, with the aim of differentiating future career attainment. Anthropometric and fitness data from 257 Under-15 rugby league players was collected. Players were grouped retrospectively according to their future career attainment (i.e., amateur, academy, professional). Players were blindly and randomly divided into an exploratory (n = 165) and validation dataset (n = 92). The exploratory dataset was used to develop and optimize a novel higher-dimensional model, which combined singular value decomposition (SVD) with receiver operating characteristic analysis. Once optimized, the model was tested using the validation dataset. SVD analysis revealed 60 m sprint and agility 505 performance were the most influential characteristics in distinguishing future professional players from amateur and academy players. The exploratory dataset model was able to distinguish between future amateur and professional players with a high degree of accuracy (sensitivity = 85.7%, specificity = 71.1%; p<0.001), although it could not distinguish between future professional and academy players. The validation dataset model was able to distinguish future professionals from the rest with reasonable accuracy (sensitivity = 83.3%, specificity = 63.8%; p = 0.003). Through the use of SVD analysis it was possible to objectively identify criteria to distinguish future career attainment with a sensitivity over 80% using anthropometric and fitness data alone. As such, this suggests that SVD analysis may be a useful analysis tool for research and practice within talent identification. PMID- 27224654 TI - Massive Shift in Gene Expression during Transitions between Developmental Stages of the Gall Midge, Mayetiola Destructor. AB - Mayetiola destructor is a destructive pest of wheat and has six developmental stages. Molecular mechanisms controlling the transition between developmental stages remain unknown. Here we analyzed genes that were expressed differentially between two successive developmental stages, including larvae at 1, 3, 5, and 7 days, pupae, and adults. A total of 17,344 genes were expressed during one or more of these studied stages. Among the expressed genes, 38-68% were differently expressed between two successive stages, with roughly equal percentages of up- and down-regulated genes. Analysis of the functions of the differentially expressed genes revealed that each developmental stage had some unique types of expressed genes that are characteristic of the physiology at that stage. This is the first genome-wide analysis of genes differentially expressed in different stages in a gall midge. The large dataset of up- and down-regulated genes in each stage of the insect shall be very useful for future research to elucidate mechanisms regulating insect development and other biological processes. PMID- 27224655 TI - Intestinal-type sinonasal adenocarcinomas: The road to molecular diagnosis and personalized treatment. AB - BACKGROUND: Sinonasal intestinal-type adenocarcinomas (ITACs) are epithelial tumors of the nasal cavity and the paranasal sinuses, often related to professional exposure to organic dust, mainly wood or leather. It is a rare cancer. If resectable, surgery is the treatment of choice. Postoperative radiotherapy is often indicated to increase local control. Systemic treatment (chemotherapy, targeted agents, or immunotherapy) of irresectable ITACs and/or metastasized disease is less standardized. METHODS: Articles on ITAC histopathology, molecular profile, and current treatment options of this specific tumor were identified and reviewed, using the electronic databases Pubmed, Medline, Cochrane, and Web of Science. RESULTS: This article reviews what is currently known on the histopathology, tumorigenesis, molecular characteristics, and standardized treatment options of ITAC. CONCLUSION: More translational research is needed to identify druggable targets that may lead to a personalized treatment plan in order to improve long-term outcome in patients with locally advanced and/or metastasized ITAC. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: First-1570, 2016. PMID- 27224656 TI - The Cycloaddition of the Benzimidazolium Ylides with Alkynes: New Mechanistic Insights. AB - New insights concerning the reaction mechanism in the cycloaddition reaction of benzimidazolium ylides to activated alkynes are presented. The proposed pathway leading both to 2-(1H-pyrrol-1-yl)anilines and to pyrrolo[1,2-a]quinoxalin-4(5H) ones involves an opening of the imidazole ring from the cycloaddition product, followed by a nucleophilic attack of the aminic nitrogen to a proximal carbonyl group and the elimination of a leaving group. The mechanistic considerations are fully supported by experimental data, including the XRD resolved structure of the key reaction intermediate. PMID- 27224657 TI - One-Pot Synthesis of Tetraphene and Construction of Expanded Conjugated Aromatics. AB - Acene derivatives as a class of polycyclic aromatic hydrocarbons have attracted considerable interest because of their outstanding semiconductor properties. We developed a one-pot synthesis for fully conjugated tetraphene via a sequence of propargyl-allenyl isomerization, phosphine addition, intramolecular Wittig reactions, and Diels-Alder cyclization reactions. The derivative-conjugated aromatic compounds including carbazole or triphenylamine have been constructed via Pd-catalyzed coupling reaction with dibromotetraphene. These compounds show superior photophysical and electrochemical properties, which make them possible candidates for optoelectronic conjugated materials. PMID- 27224658 TI - Joint association of sleep problems and psychosocial working conditions with registered long-term sickness absence. A Danish cohort study. AB - OBJECTIVES: Sleep problems and adverse psychosocial working conditions are associated with increased risk of long-term sickness absence. Because sleep problems affect role functioning they may also exacerbate any effects of psychosocial working conditions and vice versa. We examined whether sleep problems and psychosocial working conditions interact in their associations with long-term sickness absence. METHODS: We linked questionnaire data from participants to two surveys of random samples of the Danish working population (N=10 752) with registries on long-term sick leave during five years after questionnaire response. We defined sleep problems by self-reported symptoms and/or register data on hypnotics purchases of hypnotics. Psychosocial working conditions included quantitative and emotional demands, influence, supervisor recognition and social support, leadership quality, and social support from colleagues. Using time-to-event models, we calculated hazard ratios (HR) and differences and examined interaction as departure from multiplicativity and additivity. RESULTS: During 40 165 person-years of follow-up, we identified 2313 episodes of long-terms sickness absence. Sleep problems predicted risk of long term sickness absence [HR 1.54, 95% confidence interval (95% CI) 1.38-1.73]. This association was statistically significantly stronger among participants with high quantitative demands and weaker among those with high supervisor recognition (P<0.0001). CONCLUSIONS: High quantitative demands exacerbated the association of sleep problems with risk of long-term sickness absence whereas high supervisor recognition buffered this association. To prevent long-term sickness absence among employees with sleep problems, workplace modifications focusing on quantitative demands and supervisor recognition may be considered. Workplace interventions for these factors may more effectively prevent sickness absence when targeted at this group. The efficacy and effectiveness of such interventions needs to be established in future studies. PMID- 27224659 TI - The Dorsal Root Ganglion as a Therapeutic Target for Chronic Pain. AB - Chronic neuropathic pain is a widespread problem with negative personal and societal consequences. Despite considerable clinical neuroscience research, the goal of developing effective, reliable, and durable treatments has remained elusive. The critical role played by the dorsal root ganglion (DRG) in the induction and maintenance of chronic pain has been largely overlooked in these efforts, however. It may be that, by targeting this site, robust new options for pain management will be revealed. This review summarizes recent advances in the knowledge base for DRG-targeted treatments for neuropathic pain:* Pharmacological options including the chemical targeting of voltage-dependent calcium channels, transient receptor potential channels, neurotrophin production, potentiation of opioid transduction pathways, and excitatory glutamate receptors.* Ablation or modulation of the DRG via continuous thermal radiofrequency and pulsed radiofrequency treatments.* Implanted electrical neurostimulator technologies.* Interventions involving the modification of DRG cellular function at the genetic level by using viral vectors and gene silencing methods. PMID- 27224660 TI - Suppression of MAPKs/NF-kappaB Activation Induces Intestinal Anti-Inflammatory Action of Ginsenoside Rf in HT-29 and RAW264.7 Cells. AB - This study investigated the intestinal anti-inflammatory action of ginsenoside Rf in inflammatory bowel disease (IBD). IBD is a chronic inflammatory disease that affects the intestinal tract. It is associated with elevated levels of various inflammatory mediators, including interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha (TNF-alpha), nitric oxide (NO), and reactive oxygen species (ROS). Ginsenosides, the main active constituents of ginseng, have been reported to exert potent therapeutic effects against diverse diseases. However, ginsenoside Rf treatment for inflammation has not yet been examined. In this study, we evaluated the inhibitory effect of ginsenoside Rf on the inflammatory mediators downstream of p38/NF-kB activation on TNF-alpha-stimulated intestinal epithelial cells (HT-29) and mouse macrophage cells (RAW264.7). Our results showed that ginsenoside Rf significantly reduced the production of IL-1beta, IL-6, TNF-alpha, NO, and ROS, which are most highly activated in IBD. In addition, ginsenoside Rf significantly suppressed TNF-alpha/LPS-induced NF-kappaB transcriptional activity. These results suggest that ginsenoside Rf contains a compound that has potent intestinal anti-inflammatory effects that could be used to treat diseases such as IBD. PMID- 27224661 TI - Sex disparities in use of chemotherapy and survival in patients with advanced bladder cancer. AB - BACKGROUND: Women with advanced bladder cancer have inferior survival compared with men. However, women treated on clinical trials do not appear to have a survival disadvantage. Less frequent administration of systemic chemotherapy in women with advanced bladder cancer may contribute to their inferior survival. METHODS: The authors identified patients diagnosed with stage IV bladder cancer from 1998 through 2010 using the National Cancer Data Base, a national outcomes database that includes 70% of all newly diagnosed cancer cases in the United States. Sex differences in demographics, systemic chemotherapy administration, and overall survival (OS) were compared. RESULTS: A total of 23,981 patients were identified (35% of whom were female). Compared with men, women were older, more likely to be black, and less likely to be insured (P<.01 for all). The Charlson Deyo comorbidity score did not differ between men and women. Women were less likely to receive systemic chemotherapy than men (45% vs 52%; adjusted relative risk, 0.91 [95% confidence interval (95% CI), 0.88-0.94]). Women had a lower median OS compared with men (8.0 months [95% CI, 7.7-8.3 months] vs 9.8 months [95% CI, 9.5-10.0 months]; P<.001). OS remained lower for women on multivariable analysis, even after adjusting for the administration of systemic chemotherapy (hazard ratio for death, 1.11 [95% CI, 1.08-1.15]). CONCLUSIONS: Women are less likely than men to receive systemic chemotherapy for advanced bladder cancer and this difference may partially account for the poorer OS observed in women. However, OS remains lower in women independent of chemotherapy use, and may be related to unmeasured comorbidities, functional status, or tumor biology. Cancer 2016;122:2012-20. (c) 2016 American Cancer Society. PMID- 27224662 TI - Protective effects of BMP-7 against tumor necrosis factor alpha-induced oligodendrocyte apoptosis. AB - Bone morphogenic protein-7 (BMP7) is a multifunctional cytokine with demonstrated neurogenic potential. Oligodendrocytes (OLs) death after spinal cord injury (SCI) contributes to demyelination of spared axons, even leading to a permanent neurological deficit. Therefore, therapeutic approaches to prevent OLs death after SCI should be considered. Since the effects of BMP7 on OLs after injury are largely unknown, we demonstrated the effects of BMP7 on TNF-alpha-induced OLs apoptosis in vitro. The effects of BMP7 on TNF-alpha-induced OLs apoptosis were verified by flow cytometry, spectrophotometry and western blotting on primary cultures from spinal cord of postnatal day 1 (P1) to P2 rats. As shown by flow cytometry, apoptosis rate was 25.6% for the control group, 59.0% for the TNF alpha group, and 33.5% for the BMP7+TNF-alpha group; spectrophotometry showed caspase-3 and caspase-8 activity were significantly increased in the TNF-alpha group than in the control group, and BMP7 could reverse the increase. The involvement of cIAP1 in the protection of BMP7 was determined by western blotting and silencing cIAP1. In summary, our results demonstrated that BMP7 could potently inhibite TNF-alpha-induced OLs apoptosis and identified the cIAP1 expression level, the activity of caspase-3 and caspase-8 as important mediators of OLs survival after cellular stress and cytokine challenge. PMID- 27224663 TI - Therapeutic monitoring of immunosuppressive drugs in pediatric patients: special considerations. PMID- 27224665 TI - Correction: Scoring Tools for the Analysis of Infant Respiratory Inductive Plethysmography Signals. AB - [This corrects the article DOI: 10.1371/journal.pone.0134182.]. PMID- 27224664 TI - Video head impulse in comparison to caloric testing in unilateral vestibular schwannoma. AB - CONCLUSIONS: Although there was a statistically significant relationship between the results of the vHIT and the caloric test, the limited strength of this relationship suggests that, for unilateral vestibular schwannoma (UVS), caloric testing and vHIT may provide complementary information on vestibular function. OBJECTIVE: There is limited information that can be used to determine which of the video head impulse test (vHIT) and caloric test might be better used in the diagnosis and management of UVS. In this study, a group of participants with un operated UVS was studied using both methods. METHODS: The subjects' vestibular function was assessed using the vHIT and caloric testing. Tumour size was quantified using MRI and their balance disturbance assessed using the Jacobsen Dizziness Handicap Inventory (DHI). RESULTS: Twenty of 30 subjects had an abnormal canal paresis according to the Jongkees' criterion (> 0.25); however, only 10/30 had an ipsilesional vHIT gain of <0.79. Canal paresis could be predicted from the ipsilesional and contralesional vHIT gains. Tumour size could also be predicted from the ipsilesional vHIT gain and canal paresis. However, DHI scores could not be predicted from the degree of canal paresis, vHIT gain, or the MRI measures. PMID- 27224666 TI - Optical Properties of Gold Nanoclusters Functionalized with a Small Organic Compound: Modeling by an Integrated Quantum-Classical Approach. AB - Motivated by the growing importance of organometallic nanostructured materials and nanoparticles as microscopic devices for diagnostic and sensing applications, and by the recent considerable development in the simulation of such materials, we here choose a prototype system - para-nitroaniline (pNA) on gold nanoparticles - to demonstrate effective strategies for designing metal nanoparticles with organic conjugates from fundamental principles. We investigated the motion, adsorption mode, and physical chemistry properties of gold-pNA particles, increasing in size, through classical molecular dynamics (MD) simulations in connection with quantum chemistry (QC) calculations. We apply the quantum mechanics-capacitance molecular mechanics method [Z. Rinkevicius et al. J. Chem. Theory Comput. 2014, 10, 989] for calculations of the properties of the conjugate nanoparticles, where time dependent density functional theory is used for the QM part and a capacitance-polarizability parametrization of the MM part, where induced dipoles and charges by metallic charge transfer are considered. Dispersion and short-range repulsion forces are included as well. The scheme is applied to one- and two-photon absorption of gold-pNA clusters increasing in size toward the nanometer scale. Charge imaging of the surface introduces red-shifts both because of altered excitation energy dependence and variation of the relative intensity of the inherent states making up for the total band profile. For the smaller nanoparticles the difference in the crystal facets are important for the spectral outcome which is also influenced by the surrounding MM environment. PMID- 27224667 TI - Phaeoacremonium sphinctrophorum as a Novel Agent of Eumycetoma. PMID- 27224668 TI - Wording Clarification. PMID- 27224669 TI - Formulation and stabilization of norfloxacin in liposomal preparations. AB - A number of liposomal preparations of norfloxacin (NF) containing variable concentrations of phosphatidylcholine (PC) (10.8-16.2mM) have been formulated and an entrapment of NF to the extent of 41.7-56.2% was achieved. The values of apparent first-order rate constants (kobs) for the photodegradation of NF in liposomes (pH7.4) lie in the range of 1.05-2.40*10(-3)min(-1) compared to a value of 8.13*10(-3)min(-1) for the photodegradation of NF in aqueous solution (pH7.4). The values of kobs are a linear function of PC concentration indicating an interaction of PC and NF during the reaction. The second-order rate constant for the photochemical interaction of PC and NF has been determined as 8.92*10(-2)M( 1)min(-1). Fluorescence measurements on NF in liposomes indicate a decrease in fluorescence with an increase in PC concentration as a result of formation of NF( ) species which exhibits poor fluorescence. Dynamic light scattering has shown an increase in the size of NF encapsulated liposomes with an increase in PC concentration. The stabilization of NF in liposomes is achieved by the formation of a charge-transfer complex between NF and PC. PMID- 27224671 TI - A novel homogenization procedure to model the skin layers in LF numerical dosimetry. AB - In this study we focus on the validity of the skin layer currently implemented in up-to-date human-body anatomical models employed in low frequency (LF) numerical dosimetry. Indeed, the several layers of the skin structure, i.e. the stratum corneum (SC), dermis, and epidermis are in these models embedded into a unique fairly-thick (2-3 mm) layer encompassing all of them. While a previous work from the authors showed that for normal-standing (or limb-non-touching) postures a single-layer skin model could conservatively estimate the peak electric field induced in the skin, at least a two-layer skin model comprising of the SC and the remaining skin layers should be used for limb-touching exposure scenarios. This implies notable efforts to discretize the tiny SC layer questioning the validity of current anatomical models. A novel strategy based on the homogenization of the several skin layers has been therefore proposed in order to eliminate the SC from the computational domain opening the doors to future LF magnetic applications even for limb-touching scenarios. PMID- 27224670 TI - Elevated levels of circulating CDH5 and FABP1 in association with human drug induced liver injury. AB - BACKGROUND & AIMS: The occurrence of drug-induced liver injury (DILI) is a major issue in all phases of drug development. To identify novel biomarker candidates associated with DILI, we utilised an affinity proteomics strategy, where antibody suspension bead arrays were applied to profile plasma and serum samples from human DILI cases and controls. METHODS: An initial screening was performed using 4594 randomly selected antibodies, representing 3450 human proteins. Resulting candidate proteins together with proposed DILI biomarker candidates generated a DILI array of 251 proteins for subsequent target analysis and verifications. In total, 1196 samples from 241 individuals across four independent cohorts were profiled: healthy volunteers receiving acetaminophen, patients with human immunodeficiency virus and/or tuberculosis receiving treatment, DILI cases originating from a wide spectrum of drugs, and healthy volunteers receiving heparins. RESULTS: We observed elevated levels of cadherin 5, type 2 (CDH5) and fatty acid-binding protein 1 (FABP1) in DILI cases. In the two longitudinal cohorts, CDH5 was elevated already at baseline. FABP1 was elevated after treatment initiation and seemed to respond more rapidly than alanine aminotransferase (ALT). The elevations were verified in the DILI cases treated with various drugs. In the heparin cohort, CDH5 was stable over time whereas FABP1 was elevated. CONCLUSIONS: These results suggest that CDH5 may have value as a susceptibility marker for DILI. FABP1 was identified as a biomarker candidate with superior characteristics regarding tissue distribution and kinetics compared to ALT but likely with limited predictive value for the development of severe DILI. Further studies are needed to determine the clinical utility of the proposed markers. PMID- 27224672 TI - Hybrid Corannulene-Perylene Dyes: Facile Synthesis and Optoelectronic Properties. AB - Considering the peculiar topology of corannulene and extraordinary optoelectronic properties of perylene dyes, a series of hybrid corannulene-perylene dyes, namely corannulene-fused perylene-3,4-dicarboxylic acid monoimide (PMI) and corannulene fused perylene-3,4,9,10-tetracarboxylic acid diimides (PDIs), were efficiently synthesized by a Suzuki coupling (carbon-carbon bond formation) and subsequent oxidative cyclization and photocyclization, respectively. Single crystal packing demonstrates that the solid state of the corannulene-fused PMI is arranged in back to back antiparallel dimers due to the strong dipole-dipole interactions. Integration of the corannulene unit to the perylene dyes along peri-positions makes the absorption bathochromically-shifted together with a much higher molar extinction coefficient, whereas integration of the corannulene unit to the perylene dyes along bay-positions has a much broader absorption. Strong and broad absorption properties, strong electron-accepting ability, and suitable LUMO levels close to that of [6,6]-phenyl-C61 -butyric acid methyl ester (PCBM) make hybrid corannulene-perylene dyes promising electron-acceptor materials for organic optoelectronic devices. PMID- 27224673 TI - Attenuation of the blood pressure response to exogenous angiotensin I after oral administration of benazepril to healthy adult horses. AB - BACKGROUND: Benazepril has been shown to inhibit circulating angiotensin converting enzyme (ACE) activity in horses but the optimal dosage is unknown. OBJECTIVES: To determine the lowest tested dose of benazepril that results in >=75% attenuation in the response of arterial blood pressure (BP) to exogenous angiotensin I (ANG-I) administration. STUDY DESIGN: Prospective experimental study. METHODS: A total of 5 healthy horses were instrumented for the direct measurement of BP. Each horse received 4 intragastric doses of benazepril (0.5, 1, 2 and 4 mg/kg bwt) with a washout period of 7 days between doses. Prior to and 2, 12 and 24 h after benazepril administration, each horse received intravenous (i.v.) boluses of ANG-I at 20, 60 and 200 ng/kg. Attenuation of the systolic arterial pressure (SBP) response to ANG-I and serum ACE activity were quantified and expressed as percentage of inhibition. RESULTS: There was a significant effect of benazepril dose (P = 0.004) and time (P = 0.004) on the percentage of inhibition of the systolic pressor response to ANG-I. Regardless of benazepril dose, the percentage of inhibition was significantly greater 2 h after administration of benazepril compared with 12 and 24 h. At an ANG-I dose of 20 ng/kg, the percentage of inhibition after administration of benazepril at 1 mg/kg bwt (46.6 +/- 18.9%) was significantly greater than that achieved after 0.5 mg/kg bwt (19 +/- 14%) but not significantly different from that achieved at higher doses of benazepril. Benazepril doses >=1 mg/kg bwt resulted in serum ACE inhibition of at least 90%. MAIN LIMITATIONS: Small sample size and resulting low statistical power. CONCLUSIONS: Attenuation of the rise in SBP in response to ANG I after administration of benazepril is modest in horses despite adequate serum ACE inhibition. A dose of 1 mg/kg bwt would be recommended for future investigations of benazepril for the management of cardiovascular diseases in horses. PMID- 27224674 TI - Evaluation of the acute and sub-chronic oral toxicity of the herbal formula Xiaoer Chaigui Tuire Oral Liquid. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Xiaoer Chaigui Tuire Oral Liquid (XCTOL) is a popular Chinese herbal formula. It is used to treat exogenous fever in children by inducing diaphoresis and clearing interior heat. AIM OF THE STUDY: To evaluate the acute and sub-chronic toxicity of XCTOL in mice and rats, respectively. MATERIALS AND METHODS: In the acute toxicity study, mice were orally administered 100g/kg body weight XCTOL three times a day. General behavior, adverse effects and mortality were recorded for 14 days after treatment. In the sub-chronic toxicity study, rats were orally administered 0, 20 or 80g/kg XCTOL for 30 days. The rats were observed daily for clinical signs and mortality. Body weight changes were measured every three days, and relative organ weights, hematological parameters, urinalysis results, biochemical parameters and pathology were monitored at the end of treatment. After treatment, a 30-day withdrawal study was conducted. RESULTS: In the acute toxicity study, after the mice were administered with 300g/kg (3*100g/kg) XCTOL in the first day, no adverse effects or death were observed in the following 14 days. In the 30-day sub-chronic toxicity study, daily oral administration of 80g/kg XCTOL resulted in significant body weight loss in both male and female rats. In the male rats, the red blood cell distribution width standard deviation (RDW-SD) and red blood cell distribution width coefficient of variability (RDW-CV) in the hematological test and total bilirubin (T-Bil) in the blood biochemistry test were significantly increased (RDW-SD, p<0.01; RDW-CV and T-Bil, p<0.05 vs. the control group). In the female rats, the specific gravity of the urinalysis was significantly increased (p<0.05 vs. the control group). Pathological damage was not observed in the main organs in the 80g/kg group. In the 20g/kg group, the lymphocyte % (LYM%) was significantly increased (p<0.05 the control group) in the female rats. CONCLUSIONS: The maximum-tolerated dose of XCTOL was greater than 300g/kg in mice. The no-observed-adverse-effect-level was between 20 and 80g/kg body weight for 30 days in rats, which is 2.2-8.8 times higher, respectively, than the dose that has already been used in the clinical practice. Therefore, XCTOL at a dose less than 300g/kg in one day or 20g/kg per day for 30 days is considered safe. PMID- 27224675 TI - A one-stage cultivation process for the production of poly-3-(hydroxybutyrate-co hydroxyvalerate) from olive mill wastewater by Haloferax mediterranei. AB - Olive mill wastewater (OMW), a highly polluting waste from the olive oil industry, was utilized as sole carbon source for the production of polyhydroxyalkanoate (PHA) by extremely halophilic Haloferax Mediterranei (H. mediterranei) in a one stage cultivation step. H. mediterranei showed remarkable cell growth and tolerated the inhibitory effect of polyphenols present in medium containing 25% of OMW. H. mediterranei cultivation conditions were optimized in medium containing 15% OMW by investigating several parameters that affect the production of PHA. The highest polymer yield (0.2g/L) and PHA content (43% PHA/cell dry mass) were achieved at 37 degrees C, 170rpm and 22% salt concentration. Analysis of the produced PHA revealed the production of copolyester poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBHV) containing 6.5mol% 3-hydroxyvalerate (3HV). The production of PHBHV was observed without the need for fermentation step or adding external carbon source. The PHBHV displayed reduced melting points at 140.1 degrees C and 154.4 degrees C when compared to homopolymer polyhydroxybutyrate. PMID- 27224676 TI - The Role of Emotion Regulation Difficulties in the Relation Between PTSD Symptoms and the Learned Association Between Trauma-Related and Cocaine Cues. AB - BACKGROUND: PTSD and cocaine dependence frequently co-occur. However, few studies have specifically examined the functional relation between trauma-related distress and cocaine use and none have examined the extent to which PTSD is associated with a learned association between trauma cues and cocaine or the underlying role of emotion regulation difficulties in this relation. OBJECTIVES: Thus, this study used a novel version of the Implicit Association Test (IAT) to examine the relation of PTSD symptoms to the strength of the trauma-cocaine cue association and the role of specific emotion regulation difficulties in this relation. METHODS: A sample of 42 cocaine-dependent inpatients with a history of interpersonal traumatic exposure were recruited. Participants completed a series of questionnaires assessing PTSD symptom severity and emotion regulation difficulties. Participants then completed the IAT. RESULTS: Results revealed a significant indirect relation of PTSD symptom severity to the strength of the trauma-cocaine cue association through the specific emotion regulation dimension of difficulties controlling impulsive behaviors when distressed. Conclusion/Importance: Results build upon extant research suggesting that factors related to emotional responding and regulation may underlie the relation between trauma-cue exposure and responses to cocaine cues among cocaine dependent patients with PTSD. The finding that PTSD symptom severity is associated with the strength of the trauma-cocaine cue association through one particular dimension of emotion regulation difficulties, difficulties controlling impulsive behaviors when distressed, highlight the potential utility of interventions focused on improving emotion regulation and impulse control abilities among trauma-exposed cocaine dependent patients. PMID- 27224677 TI - Effect of multiple alcohol-based hand rub applications on the tensile properties of thirteen brands of medical exam nitrile and latex gloves. AB - Current CDC guidance for the disinfection of gloved hands during the doffing of personal protective equipment (PPE) following the care of a patient with Ebola recommends for multiple applications of alcohol-based hand rub (ABHR) on medical exam gloves. To evaluate possible effects of ABHR applications on glove integrity, thirteen brands of nitrile and latex medical exam gloves from five manufacturers and two different ABHRs were included in this study. A pair of gloves were worn by a test operator and the outside surfaces of the gloves were separately treated with an ABHR for 1-6 applications. Tensile strength and ultimate elongation of the gloves without any ABHR treatments (control gloves) and gloves after 1-6 ABHR applications were measured based on the ASTM D412 standard method. In general, tensile strength decreased with each ABHR application. ABHRs had more effect on the tensile strength of the tested nitrile than latex gloves, while ethanol-based ABHR (EBHR) resulted in lesser changes in tensile strength compared to isopropanol-based ABHR (IBHR). The results show that multiple EBHR applications on the latex gloves and some of the nitrile gloves tested should be safe for Ebola PPE doffing based on the CDC guidance. Appropriate hospital staff practice using ABHR treatment and doffing gloves is recommended to become more familiar with changes in glove properties. PMID- 27224678 TI - Photocatalytic Reactive Oxygen Species Formation by Semiconductor-Metal Hybrid Nanoparticles. Toward Light-Induced Modulation of Biological Processes. AB - Semiconductor-metal hybrid nanoparticles manifest efficient light-induced spatial charge separation at the semiconductor-metal interface, as demonstrated by their use for hydrogen generation via water splitting. Here, we pioneer a study of their functionality as efficient photocatalysts for the formation of reactive oxygen species. We observed enhanced photocatalytic activity forming hydrogen peroxide, superoxide, and hydroxyl radicals upon light excitation, which was significantly larger than that of the semiconductor nanocrystals, attributed to the charge separation and the catalytic function of the metal tip. We used this photocatalytic functionality for modulating the enzymatic activity of horseradish peroxidase as a model system, demonstrating the potential use of hybrid nanoparticles as active agents for controlling biological processes through illumination. The capability to produce reactive oxygen species by illumination on-demand enhances the available peroxidase-based tools for research and opens the path for studying biological processes at high spatiotemporal resolution, laying the foundation for developing novel therapeutic approaches. PMID- 27224679 TI - Female rat transcriptome response to infraorbital nerve transection differs from that of males: RNA-seq. AB - The effects of infraorbital nerve (ION) transection on gene expression in the adult female rat barrel cortex were investigated using RNA sequencing. After a 24 hour survival duration, 28 genes were differentially regulated by ION transection. Differentially expressed genes suggest microglial activity, increased retrograde ciliary transport, and a decrease in inhibition. These changes may be functionally comparable to changes in the male barrel cortex, where changes in genes related to morphology, neuronal activity, and neuronal excitability were observed. However, the patterns in changes in gene expression are vastly different between male and female rats. The results strongly caution against the practice of generalizing data from one sex to both sexes. This cautionary note has potentially profound implications for a range of research lines, including substance abuse and stress, both research domains in which subjects have been predominantly males. Future research needs to employ sex as a classification variable, as sex differences can generally be expected. Future research is also needed to confirm that changes in gene expression observed with RNA-seq correlate with changes in protein expression. J. Comp. Neurol. 525:140 150, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27224680 TI - Determinants of change in body weight and body fat distribution over 5.5 years in a sample of free-living black South African women. AB - OBJECTIVE: To identify socio-demographic and lifestyle determinants of weight gain in a sample of premenopasual black South African (SA) women. METHODS: Changes in body composition (dual-energy X-ray absorptiometry, computerised tomography), socio-economic status (SES) and behavioural/lifestyle factors were measured in 64 black SA women at baseline (27 +/- 8 years) and after 5.5 years. RESULTS: A lower body mass index (BMI) and nulliparity, together with access to sanitation, were significant determinants of weight gain and change in body fat distribution over 5.5 years. In addition, younger women increased their body weight more than their older counterparts, but this association was not independent of other determinants. CONCLUSION: Further research is required to examine the effect of changing SES, as well as the full impact of childbearing on weight gain over time in younger women with lower BMIs. This information will suggest areas for possible intervention to prevent long-term weight gain in these women. PMID- 27224682 TI - Medication Adherence in People With Parkinson Disease. AB - Parkinson disease (PD) is the second most common neurodegenerative disorder in the United States. Because there is no cure for PD currently, pharmacological therapy is the mainstay of PD symptom management. Despite the importance of medication adherence in PD, several studies have reported medication nonadherence and/or suboptimal adherence. This literature review provides an overview of medication adherence issues in people with PD. Articles were identified for this study using computerized database searches and journal hand searches. Of the 72 medication adherence articles reviewed, the following articles were eligible for this review: (a) 10 articles measuring medication adherence in people with PD, (b) four medication adherence intervention articles, and (c) six studies of medication adherence in hospitalized settings. The importance of adherence assessment and strategies in improving medication adherence are discussed with the goal of improving symptom management and clinical outcomes in people with PD. Because medication taking is a complex and multifaceted phenomena, patient centered, theory-driven interventions are needed to improve medication adherence and quality of care and life in people with PD. PMID- 27224681 TI - Physical Activity and Cognitive Function in Older Adults: The Mediating Effect of Depressive Symptoms. AB - Depressive symptoms and social networks may influence the relationship between physical activity and cognition. Using structural equation modeling, depressive symptoms and social networks were examined as mediators between physical activity and cognition in community-dwelling older adults (N = 122), with a range of cognitive abilities (e.g., normal, mild cognitive impairment). The model included age, physical activity, sedentary behavior, sleeping, social networks, depressive symptoms, and cognitive function. A path was observed between physical activity, depressive symptoms, and cognition; specifically, those who were more physically active experienced less depression and better cognitive functioning. No relationship between social networks and cognition was found. This model fits the data well (goodness-of-fit index = .93, adjusted goodness-of-fit index = .90, root mean square error of approximation = .06). Results suggest that physical activity may mitigate depressive symptoms, with beneficial effects on cognitive functioning in both those with and without mild cognitive impairment. Suggestions for managing depression and improving cognitive functioning are provided. PMID- 27224683 TI - Nursing Interventions for Identifying and Managing Acute Dysphagia are Effective for Improving Patient Outcomes: A Systematic Review Update. AB - BACKGROUND: Dysphagia, or difficulty in swallowing, is a serious and life threatening medical condition that affects a significant number of individuals with acute neurological impairment, largely from stroke. Dysphagia is not generally considered a major cause of mortality; however, the complications that result from this medical condition, namely, aspiration pneumonia and malnutrition, are among the most common causes of death in the older adults. METHODS: This is an update of an existing systematic review. The standard systematic review methods of the Joanna Briggs Institute were used. Methods were specified in advance in a published protocol. A wide range of databases were searched for quantitative research articles examining the effectiveness of nursing interventions to identify and manage dysphagia in adult patients with acute neurological dysfunction, published between 2008 and 2013. RESULTS: Four new studies were added in this update, for a total of 15 included studies. Strong evidence was found to show that nurse-initiated dysphagia screening is effective for reducing chest infections in patients with dysphagia (odds ratio [OR] = 0.45, 95% CI [0.33, 0.62], p < .00001). Nurse-initiated dysphagia screening by trained nurses may be effective for detection of dysphagia, and training nurses in dysphagia screening improves the number and accuracy of screens conducted. The presence of formal dysphagia guidelines in a health facility is likely to reduce inpatient deaths (OR = 0.60, 95% CI [0.43, 0.84], p = .003) and chest infections (OR = 0.68, 95% CI [0.51, 0.90], p = .008); however, it does not appear that formal guidelines have an effect on length of stay. CONCLUSIONS: Nurse-initiated dysphagia screening for patients with acute neurological dysfunction is effective for a range of important patient outcomes. The presence of formal guidelines for the identification and management of dysphagia may have a significant effect on serious adverse outcomes such as chest infections and death. Training nurses to conduct dysphagia screening will improve patient outcomes. PMID- 27224684 TI - Swedish Translation and Reliability of the Full Outline of Unresponsiveness Score. AB - BACKGROUND: It is important for patient safety that the patient's level of consciousness is assessed and documented in a structured and reliable manner. The Full Outline of Unresponsiveness (FOUR) score measures the level of consciousness more comprehensively than the coma scales that are commonly used in Sweden. Therefore, there was a need to translate the FOUR score into Swedish and to evaluate its use in a Swedish healthcare context. OBJECTIVES: The aim of this study was to translate the FOUR score into Swedish and to evaluate the reliability of the Swedish version compared with the reliability of the Glasgow Coma Scale (GCS). METHODS: The English version of the FOUR score was translated into Swedish and evaluated in terms of interrater reliability and internal consistency on fictitious patient cases with an advanced high-fidelity patient simulator. Two nurses rated 30 patient cases with the FOUR score and the GCS. Interrater reliability for items was determined by quadratic-weighted kappa and for the total score by intraclass correlation coefficient. Internal consistency was calculated with Cronbach's alpha. RESULTS: The fourth version of the Swedish translation reached consensus in the expert panel. The back-translation was approved by the author of the original FOUR score. Interrater reliability of the Swedish version of the FOUR score was excellent; the weighted kappa was 0.94-1, and intraclass correlation coefficient = .99 (95% CI [0.97, 0.99]), and these were equal to the reliability of the GCS. Cronbach's alpha showed a high degree of internal consistency for the FOUR score (alpha = .92 for rater A and .91 for rater B), which was slightly higher than that for the GCS. CONCLUSIONS: The Swedish version of the FOUR score is equivalent to the original English version and has shown excellent reliability using fictitious patient cases with an advanced patient simulator. PMID- 27224685 TI - A Preoperative, Nurse-Led Intervention Program Reduces Acute Postoperative Delirium. AB - The aim of this study was to evaluate the effect of a preoperative, multidisciplinary intervention program for the prevention of acute postoperative delirium on the incidence and severity in patients who were treated in the intensive care unit after surgery. We studied 122 patients who had been transferred into intensive care unit after surgery at a teaching general hospital in China. The intervention consisted of standardized protocols for the management of risk factors for delirium: education of nursing staff, systematic cognitive caring, maintaining a safe environment, social support, and improving sleep quality. All patients were monitored for signs of delirium after surgery, as measured by the Delirium Detection Score. The Delirium Detection Scores of patients in the intervention cohort after surgery on different time points were less than the scores of patients in the control group on the same point-in-time (p < .01). The severity degree of delirium for patients was less (p < .01) in the intervention group within 24 hours than that in the usual care cohort. This study showed the beneficial effects of a preoperative intervention program focusing on early prevention of delirium in patients before surgery. Systematic and comprehensive interventions could reduce the incidence and severity of delirium. PMID- 27224686 TI - A Comparative Study of Glasgow Coma Scale and Full Outline of Unresponsiveness Scores for Predicting Long-Term Outcome After Brain Injury. AB - PURPOSE: The aim of this study was to compare predictive ability of hospital Glasgow Coma Scale (GCS) scores and scores obtained using a novel coma scoring tool (the Full Outline of Unresponsiveness [FOUR] scale) on long-term outcomes among patients with traumatic brain injury. Preliminary research of the FOUR scale suggests that it is comparable with GCS for predicting mortality and functional outcome at hospital discharge. No research has investigated relationships between coma scores and outcome 12 months postinjury. METHODS: This is a prospective cohort study. Data were gathered on adult patients with traumatic brain injury admitted to urban level I trauma center. GCS and FOUR scores were assigned at 24 and 72 hours and at hospital discharge. Glasgow Outcome Scale scores were assigned at 6 and 12 months. RESULTS: The sample size was n = 107. Mean age was 53.5 (SD = +/-21, range = 18-91) years. Spearman correlations were comparable and strongest among discharge GCS and FOUR scores and 12-month outcome (r = .73, p < .000; r = .72, p < .000). Multivariate regression models indicate that age and discharge GCS were the strongest predictors of outcome. Areas under the curve were similar for GCS and FOUR scores, with discharge scores occupying the largest areas. CONCLUSION: GCS and FOUR scores were comparable in bivariate associations with long-term outcome. Discharge coma scores performed best for both tools, with GCS discharge scores predictive in multivariate models. PMID- 27224687 TI - Amyotrophic lateral sclerosis: A higher than expected incidence in people over 80 years of age. AB - Our objective was to determine the age-specific incidence and clinical epidemiological characteristics of an amyotrophic lateral sclerosis (ALS) cohort of patients in Catalonia (Spain). New cases diagnosed between 1 January 2004 and 31 December 2013 were 41 (20 males and 21 females), with an annual crude incidence rate of 2.7 per 100,000 person-years (95% CI 1.90-3.59). The incidence rate increased with age reaching a peak in the age group of 70-79 years. There was a non-significant decrease in the incidence rate in the group of patients over 80 years (p-value = 0.75) at 17.99 per 100,000 person years (95% CI 7.81 28.17). The percentage of patients over 80 years of age was 29.3% and over age 85 years was 9.8%. The prevalence rate at the end of the study period was 8.38/100,000 of the total population. Mean age at symptom onset was 76.0 years. Onset of symptoms was bulbar or generalized in 36.6% of cases. In conclusion, ALS incidence in Osona is within the range of other countries across Europe. Our results suggest that the age-specific incidence rate of ALS increases with age through the oldest age groups suggesting an age-risk effect to develop the disease. PMID- 27224689 TI - Editor's Mail. AB - The Editor welcomes readers' comments, and selected letters are published each month. Letters must be signed and should be sent to Editor's Mail at the address shown. The journal reserves the right to condense letters if necessary for space. PMID- 27224691 TI - Cues/Tips. PMID- 27224690 TI - Problems+Solutions. AB - Readers are invited to submit questions relating to problem cases. Inquiries will be answered by qualified consultants and replies forwarded by mail promptly. Selected problems and solutions are published every month in this section. PMID- 27224692 TI - Diabetes. AB - AMA Category 1 credit (2 hr), AAFP Prescribed credit (1 hr), and AOA Category 2B credit (1 hr) may be obtained by reading the article beginning on page 118 and submitting the related quiz. The other articles in this group are followed by self-assessment questions. PMID- 27224693 TI - Childhood diabetes. PMID- 27224726 TI - Molecular correlates and prognostic value of tmTNF-alpha expression in colorectal cancer of 5-Fluorouracil-Based Adjuvant Therapy. AB - Transmembrane tumor necrosis factor-alpha (tmTNF-alpha) is known to induce the activation of NF-kappaB to protect tumor cells. Upregulation of tmTNF-alpha leads to resistance to apoptosis and induces drug resistance in breast cancer. However, the expression of tmTNF-alpha in colorectal cancer (CRC) and its association with clinical outcome in CRC have remained unclear. In this study, we examined the tmTNF-alpha expression in CRC by immunohistochemistry and western blotting, assessed the prognostic value of tmTNF-alpha related to the recurrence/metastasis and survival of stage II/III CRC by the Kaplan-Meier survival curve and Cox regression model, and also explored the role of tmTNF-alpha expression on the chemotherapeutic efficacy of 5-Fluorouracil by flow cytometry assay and cell counting kit-8 (CCK-8) in vitro. Overall, we found that 77 (78.6%) out of 98 patients exhibited higher tmTNF-alpha expression in the CRC tissues comparing with the adjacent tissues. The tmTNF-alpha expression was correlated with Differentiation (P = 0.019), TNM stage (P = 0.039), Lymph nodes metastasis (P = 0.024) and Lymphovascular invasion (P = 0.027) but not related with Age (P = 0.617), Gender (P = 0.625), Tumor location (P = 0.138), Perforation/Obstruction (P = 1.000), Depth of invasion (P = 0.327), and microsatellite instability status (P = 0.150). The prognostic analyses showed that high tmTNF-alpha expression patients was significantly associated with decreased Disease-Free Survival (P = 0.0209) and Overall Survival (P = 0.0163). CCK-8 results suggested that the tmTNF alpha influenced the chemotherapeutic effect of 5-Fluorouracil on colon cancer cells. Altogether, these data indicated the stageII/III CRC patients with high tmTNF-alpha expression were more likely to have a worse prognosis than patients with low tmTNF-alpha expression and tmTNF-alpha may influence the chemotherapeutic effect of 5-Fluorouracil. The mechanism for these observations warrants further study. PMID- 27224727 TI - Evaluation of a deterministic grid-based Boltzmann solver (GBBS) for voxel-level absorbed dose calculations in nuclear medicine. AB - To evaluate the 3D Grid-based Boltzmann Solver (GBBS) code ATTILA ((r)) for coupled electron and photon transport in the nuclear medicine energy regime for electron (beta, Auger and internal conversion electrons) and photon (gamma, x ray) sources. Codes rewritten based on ATTILA are used clinically for both high energy photon teletherapy and (192)Ir sealed source brachytherapy; little information exists for using the GBBS to calculate voxel-level absorbed doses in nuclear medicine. We compared DOSXYZnrc Monte Carlo (MC) with published voxel-S values to establish MC as truth. GBBS was investigated for mono-energetic 1.0, 0.1, and 0.01 MeV electron and photon sources as well as (131)I and (90)Y radionuclides. We investigated convergence of GBBS by analyzing different meshes ([Formula: see text]), energy group structures ([Formula: see text]) for each radionuclide component, angular quadrature orders ([Formula: see text], and scattering order expansions ([Formula: see text]-[Formula: see text]); higher indices imply finer discretization. We compared GBBS to MC in (1) voxel-S-value geometry for soft tissue, lung, and bone, and (2) a source at the interface between combinations of lung, soft tissue, and bone. Excluding Auger and conversion electrons, MC agreed within ~5% of published source voxel absorbed doses. For the finest discretization, most GBBS absorbed doses in the source voxel changed by less than 1% compared to the next finest discretization along each phase space variable indicating sufficient convergence. For the finest discretization, agreement with MC in the source voxel ranged from -3% to -20% with larger differences at lower energies (-3% for 1 MeV electron in lung to 20% for 0.01 MeV photon in bone); similar agreement was found for the interface geometries. Differences between GBBS and MC in the source voxel for (90)Y and (131)I were -6%. The GBBS ATTILA was benchmarked against MC in the nuclear medicine regime. GBBS can be a viable alternative to MC for voxel-level absorbed doses in nuclear medicine. However, reconciliation of the differences between GBBS and MC at lower energies requires further investigation of energy deposition cross-sections. PMID- 27224728 TI - Identification of a Minimal Peptide Tag for in Vivo and in Vitro Loading of Encapsulin. AB - The encapsulation of enzymes and other proteins within a proteinaceous shell has been observed in many bacteria and archaea, but the function and utility of many such compartments are enigmatic. Efforts to study these functions have been complicated by the size and complexity of traditional protein compartments. One potential system for investigating the effect of compartmentalization is encapsulin, a large and newly discovered class of protein shells that are typically composed of two proteins: a protomer that assembles into the icosahedral shell and a cargo protein packaged inside. Encapsulins are some of the simplest known protein shell systems and readily self-assemble in vivo. Systematic characterization of the effects of compartmentalization requires the ability to load a wide range of cargo proteins. Here, we demonstrate that foreign cargo can be loaded into the encapsulin from Thermotoga maritima both in vivo and in vitro by fusion of the cargo protein with a short C-terminal peptide present in the native cargo. To facilitate biochemical characterization, we also develop a simple and rapid purification protocol and demonstrate the thermal and pH stability of the shell. Efforts to study the biophysical effects of protein encapsulation have been problematic in complex compartments, but the simplicity of assembling and loading encapsulin makes it an ideal system for future experiments exploring the effects of encapsulation on proteins. PMID- 27224729 TI - A Step-by-Step Guide to Laparoscopic Subtotal Fenestrating Cholecystectomy: A Damage Control Approach to the Difficult Gallbladder. PMID- 27224730 TI - Urbanization effects on the composition and structure of macrophytes communities in a lotic ecosystem of Pernambuco State, Brazil. AB - Population growth in urban areas changes freshwater ecosystems, and this can have consequences for macrophyte communities as can be seen in the municipalities that border the Capibaribe River, Pernambuco, Brazil. This study reports the effects of urbanization on the composition and structure of macrophyte communities in areas along that river. The following urbanized and non-urbanized sampling sites were chosen: Sites 1 and 2 (municipality of Santa Cruz do Capibaribe), Sites 3 and 4 (municipality of Toritama), and Sites 5 and 6 (metropolitan region of Recife). These sites were visited every two months from January to July 2013 to observe seasonal variation (wet and dry seasons). Thirty-one species were identified. Generally, the non-urbanized sites had a higher number of species. Multivariate analyses indicated significant overall differences between urbanized and non-urbanized areas (R = 0.044; p < 0.001) and between seasons (R = 0.018; p < 0.019). Owing to the large variation in physical, chemical, and biological characteristics between urbanized and non-urbanized areas, we found that urbanization significantly influenced the floristic composition and structure of macrophyte communities. PMID- 27224731 TI - Environmental indicators in effluent assessment of rainbow trout (Oncorhynchus mykiss) reared in raceway system through phosphorus and nitrogen. AB - The phosphorus and nitrogen discharge via effluent of intensive trout farming system was quantified through the use of environmental indicators. The nutrient loads, the mass balance, the estimated amount of nutrients in feed and the amount of nutrients converted in fish biomass were calculated based on the concentrations of phosphorus (P) and nitrogen (N) in the feed and in the water. Of the offered feed, 24.75 kg were available as P and 99.00 kg as N, of these, 9.32 kg P (38%) and 29.12 kg N (25%) were converted into fish biomass and 15.43 kg P (62%) and 69.88 kg N (75%) were exported via effluent. The loads and the mass balance show the excessive discharge of nutrients via effluent, corroborated by the feed conversion ratio (2.12:1) due to the low efficiency of feed utilization, therefore, it is proposed the use of this zootechnical parameter as environmental indicator. In addition, feed management practices are not adequate, highlighting the low frequency of feeding during the day, excessive amount and low quality of feed offered. These results demonstrate the need for adequate feed management and the need for careful monitoring of effluent. PMID- 27224732 TI - Antiparasitic drugs: in vitro tests against nematophagous fungi. AB - The use of biological agents has been intensified in recent years against eggs and larvae of gastrointestinal nematodes as an alternative control method in pasture plant health management, with the concomitant use with antiparasitic drugs still occurring. The aim of this study was to test the in vitro activity of the following antiparasitic drugs: Ivermectin and albendazole against the following nematophagous fungi: Paecilomyces fumosoroseus, Paecilomyces lilacinus and Paecilomyces variotii. The agar diffusion test was performed using an initial concentration of 0.0016g/mL of each drug, after solidification of the culture medium containing the drug concentration each nematophagous fungi was inoculated. The results showed that in a concentration of 80MUg/mL, the fungal growth decreased, however, with the concentration of 160MUg/mL, there was no fungal growth in both drugs, compared to the control, which indicates an inhibition in the development of the nematophagous fungi studied when they come in contact with ivermectin and albendazole. PMID- 27224733 TI - Revascularization as Treatment of a Ruptured Fusiform Aneurysm at the Cortical Segment of the Superior Cerebellar Artery: A Case Report and Literature Review. AB - A fusiform aneurysm of the superior cerebellar artery (SCA) is rare and mainly occurs at the proximal segment. A 71-year-old female patient was admitted to our institution with a subarachnoid hemorrhage. Angiography revealed dominance of both SCAs with aplasia of both the posterior inferior cerebellar artery and a fusiform aneurysm at the cortical segment of the left SCA involving the bifurcation site. Bypass connecting the left occipital artery to the inferior branch of the left SCA was performed, followed by trapping and clipping of the proximal and distal parts of the aneurysm, respectively. Blood flow was maintained in a retrograde manner from the inferior branch to the superior branch. She was discharged with no neurologic deficits and continues to be followed up by our department as an outpatient. This is the first report of a treatment method for a fusiform aneurysm located in the cortical segment of the SCA. PMID- 27224734 TI - Rapid Clearance of Lateral Ventricular Hematoma via Frontal Eminence Puncture and Aspiration: A Technical Note. AB - Background Intraventricular extension of a parenchymal hemorrhage is an independent predictor of poor outcome and might be complicated by delayed hydrocephalus. We describe a method for the rapid and effective removal of a lateral ventricular hematoma via catheter-based puncture and aspiration. Methods A catheter-based aspiration of a ventricular hematoma via a frontal eminence (FE) puncture was performed in 10 patients with thalamic and ganglionic hemorrhage perforating into the lateral ventricle. Paralleling the long axis of the lateral ventricle, a flexible silicone catheter was moved anteroposteriorly and rotated simultaneously to facilitate clot aspiration and removal. Computed tomography scans before and after surgery were compared for assessment of ventricular clot volume, Graeb score, and the ventriculocranial ratio (VCR). The Glasgow Coma Scale (GCS) score and Glasgow Outcome Scale (GOS) score were assessed at 14 days and 12 months following surgery, respectively. Results In all 10 patients, catheter-based aspiration resulted in substantial hematoma removal with a clearance rate of 64.9%, a reduced Graeb score by 61.8%, and an elevated GCS score by 52.7%. The procedure was performed safely without occurrence of another hemorrhage, infection, and catheter obstruction in any case. At 12-month follow up, VCR was reduced by 22.5%, no delayed hydrocephalus occurred, and a favorable outcome with an average GOS of 4.6 was observed in this small cohort of patients. Conclusion Catheter-based aspiration of a ventricular hematoma via FE puncture rapidly, efficiently, and safely reduced the clot in the ventricular system, prevented delayed hydrocephalus sufficiently, and produced a favorable outcome. PMID- 27224735 TI - Tuning Curves for Arm Posture Control in Motor Cortex Are Consistent with Random Connectivity. AB - Neuronal responses characterized by regular tuning curves are typically assumed to arise from structured synaptic connectivity. However, many responses exhibit both regular and irregular components. To address the relationship between tuning curve properties and underlying circuitry, we analyzed neuronal activity recorded from primary motor cortex (M1) of monkeys performing a 3D arm posture control task and compared the results with a neural network model. Posture control is well suited for examining M1 neuronal tuning because it avoids the dynamic complexity of time-varying movements. As a function of hand position, the neuronal responses have a linear component, as has previously been described, as well as heterogeneous and highly irregular nonlinearities. These nonlinear components involve high spatial frequencies and therefore do not support explicit encoding of movement parameters. Yet both the linear and nonlinear components contribute to the decoding of EMG of major muscles used in the task. Remarkably, despite the presence of a strong linear component, a feedforward neural network model with entirely random connectivity can replicate the data, including both the mean and distributions of the linear and nonlinear components as well as several other features of the neuronal responses. This result shows that smoothness provided by the regularity in the inputs to M1 can impose apparent structure on neural responses, in this case a strong linear (also known as cosine) tuning component, even in the absence of ordered synaptic connectivity. PMID- 27224736 TI - Prognostic Factors in Emergency Department Patients with Glyphosate Surfactant Intoxication: Point-of-Care Lactate Testing. AB - An increasing number of suicide attempts involve the ingestion of glyphosate surfactant; hence, clinical toxicologists may encounter severe cases of glyphosate surfactant intoxication. In several other clinical conditions, serum lactate is used to predict outcome. We investigated the relationship between lactate levels and 30-day mortality from glyphosate surfactant poisoning. This retrospective analysis involved 232 patients who were admitted to the emergency department after acute glyphosate surfactant poisoning between January 2004 and June 2014. We used a receiver operating characteristic (ROC) curve to define the optimal cut-off point for lactate levels. A Kaplan-Meier 30-day survival curve was then analysed in terms of the defined cut-off level. We used multi-variate Cox proportional hazards regression analysis to determine the risk factors for 30 day mortality. Of the 232 patients, 29 died, yielding a case fatality rate of 12.5%. Lactate was significantly higher in non-survivors (6.5 +/- 3.1 mmol/L) than in survivors (3.3 +/- 2.2 mmol/L; p < 0.001), and elevated lactate was significantly associated with 30-day mortality. The area under the ROC curve of lactate levels was 0.836 [95% confidence interval (CI): 0.716-0.869]. Lactate levels higher than 4.7 mmol/L were associated with increased mortality in multi variable analysis (hazard ratio: 3.2; 95% CI: 1.1-8.7). Besides lactate, age >59 years, corrected QT interval >495 ms and potassium >5.5 mmol/L were independent risk factors for 30-day mortality. Lactate is an independent predictor of 30-day mortality in patients with glyphosate surfactant poisoning. Early measurement of lactate levels may be a simple and practical way to assess the severity of intoxication. PMID- 27224738 TI - Thermo-Electrohydrodynamic Patterning in Nanofilms. AB - To improve the electrically assisted patterning process and create smaller sized features with the higher active surface area, the combined thermocapillary electrohydrodynamic (TC-EHD) instability of liquid nanofilms is considered. First, the 3-D thin film equation is rederived for nonisothermal films and then the influential factors on the dynamics and stability of thin liquid film are found using linear stability (LS) analysis. Nonlinear studies are also conducted to investigate the long-time evolution of the interface using an in-house developed Fortran code employing high order finite difference and adaptive time step solver for the spatial and time derivatives. The number density of pillars (columnar raised structure) formed in 1 MUm(2) area is significantly increased compared to the EHD base-case and nanosized pillars are created due to the thermocapillary effects. Relative interface area increases of up to 18% due to this pattern miniaturization are realized. It is also found that increase in the thermal conductivity ratio of layers changes the mechanism of pattern formation resulting in nonuniform and randomly distributed micro pillars being generated. PMID- 27224737 TI - Talaromyces marneffei laccase modifies THP-1 macrophage responses. AB - Talaromyces (Penicillium) marneffei is an emerging opportunistic pathogen associated with HIV infection, particularly in Southeast Asia and southern China. The rapid uptake and killing of T. marneffei conidia by phagocytic cells along with the effective induction of an inflammatory response by the host is essential for disease control. T. marneffei produces a number of different laccases linked to fungal virulence. To understand the role of the various laccases in T. marneffei, laccase-encoding genes were investigated. Targeted single, double and triple gene deletions of laccases encoding lacA, lacB, and lacC showed no significant phenotypic effects suggesting redundancy of function. When a fourth laccase-encoding gene, pbrB, was deleted in the DeltalacA DeltalacB DeltalacC background, the quadruple mutant displayed delayed conidiation and the conidia were more sensitive to H2O2, sodium dodecyl sulfate (SDS), and antifungal agents than wild-type and other transformants. Conidia of the quadruple mutant showed marked differences in their interaction with the human monocyte cell line, THP-1 such that phagocytosis was significantly higher when compared with the wild-type at one and 2 hours of incubation while the phagocytic index was significantly different from 15 to 120 minutes. In addition, killing of the quadruple mutant by THP-1 cells was more efficient at 2 and 4 hours of incubation. The levels of the proinflammatory cytokines TNF-alpha, IL-1beta and IL-6 from THP-1 cells infected with the quadruple mutant were also significantly increased in comparison with wild-type. The results demonstrate that production of laccases by T. marneffei actually promotes the pathogen's resistance to innate host defenses. PMID- 27224739 TI - Multipolar Electrostatic Energy Prediction for all 20 Natural Amino Acids Using Kriging Machine Learning. AB - A machine learning method called kriging is applied to the set of all 20 naturally occurring amino acids. Kriging models are built that predict electrostatic multipole moments for all topological atoms in any amino acid based on molecular geometry only. These models then predict molecular electrostatic interaction energies. On the basis of 200 unseen test geometries for each amino acid, no amino acid shows a mean prediction error above 5.3 kJ mol(-1), while the lowest error observed is 2.8 kJ mol(-1). The mean error across the entire set is only 4.2 kJ mol(-1) (or 1 kcal mol(-1)). Charged systems are created by protonating or deprotonating selected amino acids, and these show no significant deviation in prediction error over their neutral counterparts. Similarly, the proposed methodology can also handle amino acids with aromatic side chains, without the need for modification. Thus, we present a generic method capable of accurately capturing multipolar polarizable electrostatics in amino acids. PMID- 27224740 TI - Ankylosing spondylitis: beyond genome-wide association studies. AB - PURPOSE OF REVIEW: This article discusses genomic investigations in ankylosing spondylitis (AS) beyond genome-wide association (GWA) studies, but prior to this, genetic variants achieving genome-wide significance will be summarized highlighting key pathways contributing to disease pathogenesis. RECENT FINDINGS: Evidence suggests that disease pathogenesis is attributed to a complex interplay of genetic, environmental and immunological factors. GWA studies have greatly enhanced our understanding of AS pathogenesis by illuminating distinct immunomodulatory pathways affecting innate and acquired immunity, most notably the interleukin-23/interleukin-17 pathway. However, despite the wealth of new information gleaned from such studies, a fraction of the heritability (24.4%) has been explained. This review will focus on investigations beyond GWA studies including copy number variants, gene expression profiling, including microRNA (miRNA), epigenetics, rare variants and gene-gene interactions. SUMMARY: To address the 'missing heritability' and advance beyond GWA studies, a concerted effort involving rethinking of study design and implementation of newer technologies will be required. The coming of age of next-generation sequencing and advancements in epigenetic and miRNA technologies, combined with familial focused investigations using well-characterized cohorts, is likely to reveal some of the hidden genomic mysteries associated with AS. PMID- 27224741 TI - Rare variants, autoimmune disease, and arthritis. AB - PURPOSE OF REVIEW: We review select studies of newly discovered rare variants in autoimmune diseases with a focus on newly described monogenic disorders, rheumatoid arthritis, and systemic lupus erythematosus. RECENT FINDINGS: Two new monogenic syndromes of inflammatory arthritis were discovered using whole exome sequencing: the coatomer subunit alpha syndrome because of rare mutations in coatomer subunit alpha and haploinsufficiency of A20 resulting from rare mutations in TNFAIP3. Targeted exon sequencing identified rare variants in IL2RA and IL2RB associated with rheumatoid arthritis. Rare variants in TREX1 and other genes associated with monogenic interferonopathies are also associated with systemic lupus erythematosus. SUMMARY: Rare genetic variants contribute to the heritability of autoimmunity and provide key insight into both novel and previously implicated immunological pathways that are disrupted in autoimmune diseases. PMID- 27224742 TI - Varicella zoster virus triggers the immunopathology of giant cell arteritis. AB - PURPOSE OF REVIEW: Giant cell arteritis (GCA) is a severe form of vasculitis in the elderly. The recent discovery of varicella zoster virus (VZV) in the temporal arteries and adjacent skeletal muscle of patients with GCA, and the rationale and strategy for antiviral and corticosteroid treatment for GCA are reviewed. RECENT FINDINGS: The clinical features of GCA include excruciating headache/head pain, often with scalp tenderness, a nodular temporal arteries and decreased temporal artery pulsations. Jaw claudication, night sweats, fever, malaise, and a history of polymyalgia rheumatica (aching and stiffness of large muscles primarily in the shoulder girdle, upper back, and pelvis without objective signs of weakness) are common. ESR and CRP are usually elevated. Diagnosis is confirmed by temporal artery biopsy which reveals vessel wall damage and inflammation, with multinucleated giant cells and/or epithelioid macrophages. Skip lesions are common. Importantly, temporal artery biopsies are pathologically negative in many clinically suspect cases. This review highlights recent virological findings in temporal arteries from patients with pathologically verified GCA and in temporal arteries from patients who manifest clinical and laboratory features of GCA, but whose temporal artery biopsies (Bx) are pathologically negative for GCA (Bx negative GCA). Virological analysis revealed that VZV is present in most GCA positive and GCA-negative temporal artery biopsies, mostly in skip areas that correlate with adjacent GCA pathology. SUMMARY: The presence of VZV in Bx positive and Bx-negative GCA temporal arteries indicates that VZV triggers the immunopathology of GCA. However, the presence of VZV in about 20% of temporal artery biopsies from non-GCA postmortem controls also suggests that VZV alone is not sufficient to produce disease. Treatment trials should be performed to determine if antiviral agents confer additional benefits to corticosteroids in both Bx-positive and Bx-negative GCA patients. These studies should also examine whether oral antiviral agents and corticosteroids are as effective as intravenous acyclovir and corticosteroids. Appropriate dosage and duration of treatment also remain to be determined. PMID- 27224743 TI - Proton pump inhibitors and osteoporosis. AB - PURPOSE OF REVIEW: The purpose of the review is to provide an update on recent advances in the evidence based on proton pump inhibitors (PPI) as a possible cause of osteoporosis and osteoporotic fractures. This review focuses, in particular, on new studies published in the last 18 months and a discussion of these findings and how this has influenced our understanding of this association, the clinical impact and the underlying pathophysiology. RECENT FINDINGS: New studies have further strengthened existing evidence linking use of PPIs to osteoporosis. Short-term use does not appear to pose a lower risk than long-term use. There is a continued lack of conclusive studies identifying the pathogenesis. Direct effects on calcium absorption or on osteoblast or osteoclast action cannot at present plausibly explain the mechanism. SUMMARY: The use of PPIs is a risk factor for development of osteoporosis and osteoporotic fractures. However, as the direct pathogenesis remains unclear, specific points of intervention are lacking, other than being vigilant in regard to the indication for prescribing PPIs and to use the lowest effective dose where PPIs cannot be avoided. PMID- 27224744 TI - Hemodynamic Stability to Surface Warming and Cooling During Sustained and Continuous Simulated Hemorrhage in Humans. AB - One in 10 deaths worldwide is caused by traumatic injury, and 30% to 40% of those trauma-related deaths are due to hemorrhage. Currently, warming a bleeding victim is the standard of care due to the adverse effects of combined hemorrhage and hypothermia on survival. We tested the hypothesis that heating is detrimental to the maintenance of arterial pressure and cerebral perfusion during hemorrhage, while cooling is beneficial to victims who are otherwise normothermic. Twenty-one men (31 +/- 9 y) were examined under two separate protocols designed to produce central hypovolemia similar to hemorrhage. Following 15 min of supine rest, 10 min of 30 mm Hg of lower body negative pressure (LBNP) was applied. On separate randomized days, subjects were then exposed to skin surface cooling (COOL), warming (WARM), or remained thermoneutral (NEUT), while LBNP continued. Subjects remained in these thermal conditions for either 40 min of 30 mm Hg LBNP (N = 9), or underwent a continuous LBNP ramp until hemodynamic decompensation (N = 12). Arterial blood pressure during LBNP was dependent on the thermal perturbation as blood pressure was greater during COOL (P >0.001) relative to NEUT and WARM for both protocols. Middle cerebral artery blood velocity decreased (P <0.001) from baseline throughout sustained and continuous LBNP, but the magnitude of reduction did not differ between thermal conditions. Contrary to our hypothesis, WARM did not reduce cerebral blood velocity or LBNP tolerance relative to COOL and NEUT in normothermic individuals. While COOL increased blood pressure, cerebral perfusion and time to presyncope were not different relative to NEUT or WARM during sustained or continuous LBNP. Warming an otherwise normothermic hemorrhaging victim is not detrimental to hemodynamic stability, nor is this stability improved with cooling. PMID- 27224745 TI - Comparison between Focus Harmonic scalpel and other hemostatic techniques in open thyroidectomy: A systematic review and meta-analysis. AB - BACKGROUND: The purpose of this review was to compare the efficacy and surgical outcomes of total thyroidectomy between the Focus Harmonic scalpel (Ethicon, Cincinnati, OH) and other hemostatic procedures. METHODS: An extensive search was conducted using the PubMed and Cochrane databases from January 2008 to October 2014. Operating time, blood loss, pain, complications, and hospital stay were evaluated. RESULTS: When compared with conventional techniques or LigaSure Precise Vessel Sealing System (Medtronic, Minneapolis, MN), the use of the Focus Harmonic scalpel reduced operative time by 22,428 minutes and blood loss by 13,914 mL. Length of hospital stay was significantly shorter in the Focus Harmonic scalpel group with a mean reduction of 0.410 days. CONCLUSION: According to our meta-analysis, when comparing the Focus Harmonic scalpel versus conventional techniques, it seems evident that the use of this device in thyroid surgery is associated with a mean reduction in operating time, blood loss, and hospital stay, without any increase in pain and complications. There was no appreciable difference between the Focus Harmonic scalpel and the LigaSure Precise Vessel Sealing System. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: First-1578, 2016. PMID- 27224747 TI - State of oppression. AB - The NHS White Paper has M won favour with few, it has I faced unanimous opposition from health care organisations. It has been criticised by policy analysts, managers and patients alike. The Government's White Paper, it's said, is the most serious threat ever to Britain's NHS. Some have gone so far as to suggest that the NHS has deliberately been chosen as a test bed for Conservative principles, with services split on political lines. Kenneth Clarke's speech to the Tory Reform Club hinted that self governing hospitals would create politically divided [Illegible word] - on conservative and socialist lines - which would compete for state resources. This issue clearly effects millions of UK citizens who rightly deserve a high profile informed debate on the changes being proposed. PMID- 27224746 TI - The bright side of plasmonic gold nanoparticles; activation of Nrf2, the cellular protective pathway. AB - Plasmonic gold nanoparticles (AuNPs) are widely investigated for cancer therapy, due to their ability to strongly absorb light and convert it to heat and thus selectively destroy tumor cells. In this study we shed light on a new aspect of AuNPs and their plasmonic excitation, wherein they can provide anti-oxidant and anti-inflammatory protection by stimulating the cellular protective Nrf2 pathway. Our study was carried out on cells of the immune system, macrophages, and on skin cells, keratinocytes. A different response to AuNPs was noted in the two types of cells, explained by their distinct uptake profiles. In keratinocytes, the exposure to AuNPs, even at low concentrations, was sufficient to activate the Nrf2 pathway, without any irradiation, due to the presence of free AuNPs inside the cytosol. In contrast, in macrophages, the plasmonic excitation of the AuNPs by a low, non-lethal irradiation dose was required for their release from the constraining vesicles. The mechanism by which AuNPs activate the Nrf2 pathway was studied. Direct and indirect activation were suggested, based on the inherent ability of the AuNPs to react with thiol groups and to generate reactive oxygen species, in particular, under plasmonic excitation. The ability of AuNPs to directly activate the Nrf2 pathway renders them good candidates for treatment of disorders in which the up-regulation of Nrf2 is beneficial, specifically for topical treatment of inflammatory skin diseases. PMID- 27224748 TI - Charter change for support workers? AB - THE ENTIRE membership of the RCN will vote later this year on a proposed Charter change which enables the College's Council to extend membership to support workers. PMID- 27224749 TI - En timetable is too long. AB - HEALTH SECRETARY Kenneth Clarke's definitive statement on Project 2000 provoked concern and disappointment from the English National Board last week. PMID- 27224750 TI - Bursary boost for learner. AB - NURSE EDUCATION received a major boost last week with the announcement of substantial bursaries for learners under Project 2000. The awards compare favourably with the salaries which student nurses currently receive and are well above the grants awarded to ordinary students in higher education. PMID- 27224751 TI - Government health policies attacked on two fronts. AB - ROYAL COLLEGE of Nursing General Secretary', Trevor Clay hit out at the Government on two fronts last week, criticising the exclusion of nurses from the new National Health Service Policy Board and attacking the White Paper on the National Health Service. PMID- 27224752 TI - RCN Council bid for higher subs. AB - ROYAL COLLEGE of Nursing Council has agreed to seek a two stage subscription increase at the Annual General Meeting later this year. PMID- 27224753 TI - RCN convenor banned from union duties. AB - A ROYAL College of Nursing convenor and branch secretary has been stopped from carrying out all union duties by management because of an 'emergency situation' in the unit where she works. PMID- 27224754 TI - Nurses picket DHA meeting. AB - ANGRY NURSES picketed their DHA's meeting last week, claiming two sisters' successful appeals were 'improperly' overturned at the last moment. PMID- 27224755 TI - ENB rejects 'task force' report on training needs. AB - THE ENGLISH National Board warned 'hands off nursing' last week, after a medical college produced its own review of nurse training needs. PMID- 27224756 TI - Managers at fault over grading. AB - RADIOLOGY NURSES may have missed out during the clinical grading review because their managers misunderstood their complex roles, a new survey shows. The survey, which was carried out by Connie Wakley, Chair of the RCN Radiology Nursing Forum, looked at the grades awarded to radiology and cardiology nurses in 170 departments around Britain. PMID- 27224757 TI - [Not Available]. AB - Actor Simon Callow accepted a cheque for L500 on behalf of the Terence Higgins Trust from Fiona Neeson of the RCN Association of Nursing Students. The money was raised at the ANS Ball. They are pictured with David Campbell of Terence Higgins Trust. PMID- 27224758 TI - Student awarded damages. AB - A STUDENT nurse who badly injured her back during a classroom lifting exercise was awarded L140,000 in an out-of- court settlement with her HA. PMID- 27224759 TI - Mental handicap strategy. AB - MORE THAN 70 nurses from Northern Ireland gathered at the RCN in Belfast to hear the province's Chief Nursing Officer, Tony Haughey pledge his full support for the future of mental handicap nursing. PMID- 27224761 TI - Poll tax levy challenged. AB - A SCOTTISH council which is levying the full poll tax on student nurses will be challenged through the courts, COHSE revealed last week. PMID- 27224760 TI - 'Drunken nurse' case gets UKCC hearing. AB - A FORMER nurse appeared before a UKCC professional conduct committee last week accused of being drunk on duty and failing to supervise staff and patients. PMID- 27224763 TI - Preventing accidental deaths in children. AB - Statistics showing accidents are the most common cause of death among children have prompted the Child Accident Prevention Trust to produce an accident prevention guide. PMID- 27224764 TI - Plastic ampoules launched. AB - Nurses who fear cutting their hands as they snap the top from glass ampoules may soon be using a revolutionary plastic alternative. PMID- 27224765 TI - Botulism in yoghurt. AB - At least 18 people were rushed to hospital last week suffering from botulism, the most dangerous form of food contamination. PMID- 27224766 TI - Cot deaths and suffocation. AB - Recent reports stating that up to ten per cent of cot deaths are caused by mothers smothering their children are probably accurate, the RCN's Society of Paediatric Nursing believes. PMID- 27224767 TI - BCG Vaccines halted. AB - Tuberculosis immunisation programmes have ground to a halt in schools across the UK, because the company which supplies the BCG vaccine has run into 'technical difficulties'. PMID- 27224768 TI - Galvanising nurses into action. AB - A major hard-hitting campaign is launched this week by Nursing Standard and Friends of the Earth. Its aim is to ensure a healthier environment for the future. PMID- 27224769 TI - Mental handicap nursing. AB - The face of mental handicap nursing has changed dramatically over the last decade with the move away from institutional care toward a developmental rather than a clinical approach. The larger institutions have been replaced by smaller, more homely units and ordinary houses where 24 hour care is provided by registered mental handicap nurses, experts in developing the potential of individuals. RNMHs now work in a multi-agency system, their fellow professionals being psychologists, social workers as well as staff from other branches of nursing. PMID- 27224770 TI - Nurse '89 Awards. AB - The first annual Nursing Standard/ BUPA Nursing award, which aims to recognise and reward nurses who are promoting and safeguarding high standards of care, closes next week (June 30). PMID- 27224771 TI - Anamolies in pay scales spark MP protest. AB - Anomalies in student midwives' current pay scales have provoked Parliamentary protests from Members of Parliament on both sides of the House of Commons. PMID- 27224772 TI - Britain's pensioners among europe's poorest. AB - Britain's pensioners are among the worst off in Europe, the Labour Party claimed last week, as it unveiled its new health plans for the elderly. PMID- 27224773 TI - * New guidelines for national airline caterers. AB - The Government is to issue new guidelines to prevent food poisoning from airline meals. The proposed action comes in response to recent survey evidence which found contaminated meals served up to passengers. PMID- 27224775 TI - DHAs get manual on maternity surveys. AB - The Government is to issue health authorities with new guidance on mounting maternity patient satisfaction surveys. PMID- 27224774 TI - Clarke raps doctors on white paper reaction. AB - Health Secretary, Kenneth Clarke, has accused the medical profession of a 'knee jerk reaction' in its opposition to Government plans for shaking-up the National Health Service. But he believes an increasing number of individual doctors are voicing support for the proposals. PMID- 27224776 TI - * Air ambulance service needs improving. AB - The air ambulance service needs far greater resources, Labour Member of Parliament, Tam Dalyell told Ministers last week. PMID- 27224778 TI - Soviet union. AB - More than 70 children and eight of their mothers became infected with HIV after a nurse reused contaminated syringes in a Russian hospital, an international AIDS conference has heard. PMID- 27224777 TI - Eire. AB - Forgetful and uninformative nurses are one of the major reasons why Irish patients dread a hospital stay, a hardhitting new report claims. PMID- 27224779 TI - Italy. AB - Italy is recruiting nurses from overseas with an initial batch from the Irish Republic, to tackle what has been described as a [Illegible word] crisis which is paralysing the hospital system. PMID- 27224780 TI - Iceland. AB - Icelandic nurses are spearheading a campaign designed to cut down on the number of accidents in the home, according to a senior nurse manager. PMID- 27224781 TI - Israel. AB - An age-old Arab contraceptive appears to have a sound scientific basis, scientists have discovered. PMID- 27224782 TI - Preventing stroke recurrence. AB - Ticlopidine may be a useful drug in preventing the occurence of stroke, myocardial infarction or vascular death in patients who have had a thromboembolic stroke. PMID- 27224783 TI - Burns prevention. AB - Education is needed to prevent burns in children from ethnic minorities, according to researchers from Birmingham. PMID- 27224784 TI - Pyrexia and epidurals. AB - Women receiving epidural analgesia during labour are at risk of developing pyrexia, researchers from London say. PMID- 27224785 TI - Falling a symptom of the menopause? AB - Forearm fractures in perimenopausal women may be the result of an interaction between osteoporosis and an increase in the tendency to fall. PMID- 27224786 TI - Predicting rejection. AB - Researchers from Newcastle- upon-Tyne have discovered a way of predicting rejection of transplanted organs. PMID- 27224788 TI - Listings. PMID- 27224787 TI - Down by the riverside. AB - Like any inner city area, Riverside Health Authority has contrasting areas of poverty and affluence. Within Riverside there are such flourishing and popular areas as Knights- bridge and Belgravia which contrast so sharply with Earls Court where the population is exceptionally mobile. PMID- 27224789 TI - Medical surgical care plans Medical surgical care plans Holloway N Medical surgical care plans Springhouse 498pp L16.95 0-87434-128-0. AB - By integrating three important themes in nursing: care planning, nursing diagnosis and diagnosis-related groups, Nancy Holloway aims to provide a comprehensive data base for nurses to use daily in planning patient care. While focusing on the adult medical-surgical inpatient, she purports to offer nursing students, educators and experienced clinicians realistic care plans suitable for busy, cost-conscious ward environments. PMID- 27224791 TI - The Medical Assistant, 6th edition M Kinn and E Derge The Medical Assistant, 6th edition W B Saunders 878pp L21.00 0-7216- 1731-X. AB - Written for the American equivalent of nursing auxiliaries, The Medical Assistant: Administrative and Clinical has a logical format, is well illustrated and the information is easy to find because of the additional detailed contents list and index. The UK nursing auxiliary would find two of the three sections relevant. PMID- 27224793 TI - General Health care counselling General Health care counselling R Harris A Ramsay Williams & Wilkins 114pp L15.00 0-86433-047-2. AB - Behaviourism traditionally invokes connotations of a judgemental and controlling attitude, which is perhaps unfashionable in nursing. Nevertheless, many factors in contemporary health care (eg, the concept of 'health promotion' or 'the nursing process') are formed by a desire to change behaviour. PMID- 27224792 TI - Homoeopathy by Ullman Homoeopathy Ullman D Thorsons 272pp L7.99 0-7225-1713-0. AB - As homoeopathy, along with the other complementary therapies, gains in popularity there is a corresponding flurry of books to meet public demand. Many are basic introductions, often aimed at 'self- help' and as such provide a useful service. Beyond this, it's difficult for the more serious reader to find a critical, comprehensive book on homoeopathy. Recommended 'further reading' often suggests homoeopathic classics, written in archaic language, which are either 'quaint' or 'unscientific' depending on your viewpoint. PMID- 27224795 TI - Radiotherapy by S Holmes Radiotherapy Austen Cornish 224pp L6.50 1-870065-05-0. AB - The Lisa Sainsbury Foundation is well known for its work in continuing care. Radiotherapy shows their changing emphasis to oncology education in general. PMID- 27224796 TI - Practical burns management Practical burns management Harvey J Kemble B Lamb Hodder & Stoughton 262pp L9.95 0-340-36997-3. AB - J Harvey Kemble and Brenda Lamb aim to equip staff without a specialist knowledge in the care of burns patients with practical information so that they can give the correct care. The authors cover burns patients ranging from those requiring first aid in an A&E department to those needing admission to an intensive care unit. This seemed to be a very ambitious aim for any book, so I decided to test its claims. PMID- 27224797 TI - Pediatric emergency nursing Pediatric emergency nursing Kelley S J Appleton & Lange 478pp L42.75 0-8385-7790-3. AB - Susan Kelley's intended audience is the paediatric nurse working in an accident and emergency department. She deals with a wide range of subjects from child abuse, sudden infant death syndrome, resuscitation of infants and children, poisoning, trauma and multisystem emergencies and disorders. PMID- 27224798 TI - Nursing ethics, 2nd edition I Thompson K Melia K Boyd Nursing ethics, 2nd edition Churchill Livingstone 270pp L7.95 0-443-03458-3. AB - Without doubt, this excellent book should Illegible word available to all nurses. If ever there was a time when the ethical dimension of hospital life could be left to others, it has long since passed away. New forms of treatment, the emergence of a questioning patient clientele and controversial ideas in health care pushed ethical dilemmas into the routine practice of the modern nurse. PMID- 27224799 TI - Handbook of Enteral and Parenteral Feedings Y Hui Handbook of Enteral and Parenteral Feedings Wiley 994pp L85.00 0-471-85035-7. AB - Since there is a confusing array of enteral and parenteral nutritional formulae currently on the market, it would, in theory at least, seem useful to have a reference book that provides detailed, cross- referenced comparative data on the major available products. Unfortunately, I do not feel that I can recommend this particular text for such a purpose. PMID- 27224800 TI - Drugs Handbook 1988-9, 8th edition P Turner G Volans Drugs Handbook 1988-9, 8th edition Macmillan 182pp L7.95 0-333-46753-1. AB - The eighth edition of Paul Turner and Glyn Volans's popular handbook maintains its familiar format with two main sections. The first lists drugs alphabetically by approved name, each entry accompanied by a brief description of the drugs' action, use and side effects. Guidelines to normal dosage or route of administration are not included. PMID- 27224801 TI - The new faber anatomical atlas A Roberts A Besterman The new faber anatomical atlas Faber 126pp L5.95 0-571-13839-X. AB - A neat and compact text split into two sections: the first 40 pages are given over to line-drawn anatomy plates; the remaining pages, which while not exactly complementing the drawings, give a basic explanation of structure. PMID- 27224802 TI - Special tests Special tests Evans DMD Faber 278pp L3.95 0-571-15205-8. AB - The proof of popularity can sometimes be measured by durability. Here is a book that in its 13th edition has survived 50 years of publication. It was first published in 1939. PMID- 27224803 TI - Signs and symptoms handbook Signs and symptoms handbook Springhouse 484pp L14.75 0-87434-143-4. AB - Springhouse claims that this handbook is a comprehensive review of signs and symptoms of disease, and so it is? It is well-illustrated, alphabetically indexed and, with 79 contributors, obviously well-researched. PMID- 27224804 TI - Musculoskeletal problems Musculoskeletal problems 0-87434-184-1 Springhouse 160pp L11.95. AB - Musculoskeletal Problems reviews the anatomy and physiology of the system, the risk factors, where applicable, and the key signs and symptoms of bone, joint, or muscle disorders as well as musculoskeletal tumours and trauma. PMID- 27224805 TI - Gastrointestinal problems Gastrointestinal problems 0-87434-181-7 Springhouse 160pp L11.95. AB - By the clever use of charts and diagrams, a wealth of material is included in this text. The assessment chapter stresses historytaking, while the chapter on diagnostic tests emphasises patient-teaching. In [Illegible word] to reviewing a number of common conditions, eg, peptic ulceration, colonic cancer, cholecystitis, etc., gastrointestinal emergencies and nutritional disorders are also considered. PMID- 27224806 TI - Revision. AB - The Springhouse series of Nurse Reviews is organised according to the phases of the nursing process and aims to provide nursing solutions for a wide range of patient problems. Each multiauthored American text has different clinical consultants and tries to present the current nursing knowledge and practice for a particular nursing specialty. PMID- 27224808 TI - Pediatric nursing: a study and learning tool Pediatric nursing: a study and learning tool Selkman J Springhouse 144pp L5.75 0-87434-109-4. AB - Janice Selekman divides her work into 14 main sections, ranging from growth and development to chronic life-threatening diseases, thereby covering a wide spectrum of paediatric possibilities. PMID- 27224809 TI - Vascular problems 0-87434-182-5 Vascular problems Springhouse 160pp L11.95. AB - Shock, hypotension and peripheral vascular disease are the three major areas featured. By highlighting such fundamental vascular problems, most of the common disorders are discussed in some detail and in a way that will enhance both understanding and practice. For example, the section on shock deals with all the various types of shock - how they occur, the common features and interventions necessary to prevent deterioration. PMID- 27224810 TI - Shopping hours. AB - I read with some surprise your news feature article titled 'Open all hours' (week ending June 10) as I have always found that one of the 'perks' of my working unsociable hours has been the opportunity to shop when those who work '9-5' cannot. Having free mornings and mid-week days off is surely an advantage not a disadvantage! PMID- 27224811 TI - Smoking viewpoint. AB - I am writing in defence of the numbers of nursing staff who partake in the unsocial habit of smoking. PMID- 27224812 TI - Board disgrace. AB - I read your editorial (Nursing Standard week ending June 4, 1989) with great interest. I agree it is nothing short of disgraceful that there is not a nurse representative on the NHS Policy Board. PMID- 27224814 TI - Care standards. AB - Having recently taken over the management of a nursing home in the independent sector I was pleasantly surprised to find that the registered body, the local health authority, insisted on a wide range of minimum expectable standards. PMID- 27224813 TI - Enrolled role. AB - I have followed with great interest the debate on the future of the enrolled nurse for sometime. PMID- 27224815 TI - Working with the elderly. AB - Having recently completed my training and qualified as an RGN I would like to explain why I have left the health service. PMID- 27224816 TI - Support needed. AB - I have just started working as a support worker in a new nursing home with a view to beginning nurse training. I have been able to witness the benefits a nursing home can offer not only in the experienced gained by me but in the care that can be given to an elderly resident. PMID- 27224817 TI - Rightful owner. AB - We recently moved from Worcester to Crewe and, in the process of emptying one of the removal firm's packing cases, came upon a document which had clearly been left there during someone's earlier removal - a final nursing certificate awarded at Hammersmith Hospital. The certificate was accompanied by an empty envelope bearing the same name as that on the certificate, and an address near Aylesbury. PMID- 27224819 TI - Abortion point. AB - Mrs D Munday claims in your pages (Nursing Standard week ending June 3) the dubious privilege for the organisation the BPAS to perform one third of non NHS abortions. Yet, she denies that the BPAS counselling services channel those who approach them in [Illegible word] direction of the operating theatre of the abortion clinics. Where, then, do they channel them? PMID- 27224818 TI - Paediatric pre-admission. AB - I work as a paediatric ward sister in a busy district general hospital. Together with the hospital play specialist I was recently awarded a research bursary to investigate and implement a pre-admission road show to take out to local schools, playgroups and health clinics so as to give prior knowledge of coming into hospital. We already run a well established weekly pre-admission programme for 'cold admissions' but would now like to expand the remit further. PMID- 27224820 TI - A Special experience. AB - We are regularly reminded of the controversy of the unique nursing ethos of the special hospital nurse through the professional press. Little is complimentary, critics preferring to negate positive issues, concentrating on emotional rhetoric, often with little qualification. PMID- 27224821 TI - 150 Years on. AB - In June 1839, the first patient was admitted to this hospital. To mark the 150th anniversary, a museum has been opened, displaying a wide variety of memorabilia and it is hoped to expand this collection. PMID- 27224823 TI - Babyminder alarm system developed. AB - Huntleigh Technology have introduced an advanced baby monitoring alarm system to help in the fight against cot death. PMID- 27224822 TI - Pocket sized attack alarm launched. AB - A new personal attack alarm has been produced by Static Systems Group Plc. PMID- 27224824 TI - Relaunched baby foods from robinsons'. AB - Robinsons' Baby Foods are relaunching their range of baby juices and have added a new variety. PMID- 27224825 TI - Bath E45 oil for soothing dry skin. AB - Crookes Healthcare Ltd has introduced as part of its E45 range a new dermatological bath for the relief of dry skin. PMID- 27224826 TI - Incontinence management range extended. AB - Vernon-Carus have extended their 'Cumfie' incontinence management range with the addition of three new products. PMID- 27224827 TI - Scholl adds open toe compression hosiery. AB - A new open-toe style of compression hosiery hos now been added to Scholl's comprehensive range. PMID- 27224829 TI - Wide awake. AB - Military scientists would have appeared to have come up with the answer to nursing's problems. PMID- 27224828 TI - Private sector cuts. AB - The marathon hospital waiting-times that some patients are forced to endure have now become part of the great British way of life. So when a new hospital unit opened in Taunton recently, it was no surprise to find that someone quickly managed to get to the front of the queue. PMID- 27224830 TI - Getting it in the neck. AB - Danger - you could be risking a close shave or a brush with death in the bathroom every morning, scientists have warned. PMID- 27224831 TI - If looks could kill. AB - Does this sound like someone you know? 'I am tall, dark, sad-eyed with a mien combining that of a television intellectual and Dracula. I move quite naturally in a way conveyed only by the most swaggering and self-indulgent portraitists...' No? PMID- 27224832 TI - Of this 'N' that. AB - The World Health Organisation seems to have committed a slight faux pas with [Illegible word] latest information technology programme. PMID- 27224833 TI - The lab report. PMID- 27224834 TI - Hyper active. PMID- 27224835 TI - Independent and joint exposure to passive smoking and cooking oil fumes on oral cancer in Chinese women: a hospital-based case-control study. AB - CONCLUSIONS: Passive smoking and COF exposure are independent risk factors for oral cancer in Chinese women, with the multiplicative interactions from combined exposures. Avoiding exposure to environmental tobacco smoke and COF may contribute to the prevention of oral cancer in Chinese women. OBJECTIVE: To evaluate the independent and joint effects of passive smoking and cooking oil fumes (COF) on oral cancer in Chinese women. METHODS: A case-control study was performed including 238 female patients with pathologically confirmed oral cancer and 470 controls as age-matched controls. Face-to-face interviews were conducted based on a structured questionnaire. The effects of passive smoking and COF exposure were analyzed using non-conditional logistic regression models. RESULTS: Passive smoking significantly increased the risk of oral cancer in Chinese women: adjusted ORs were 2.12 (95% CI = 1.11-4.07) for those only exposed before age 18, 1.52 (95% CI = 1.01-2.31) for those only exposed after age 18, and 2.38 (95% CI = 1.47-3.85) for those both exposed before and after age 18. In addition, COF exposure was significantly associated with a risk of oral cancer (adjusted ORs were 1.69 (95% CI = 1.03-2.78) for light exposure and 2.06 (95% CI = 1.21-3.50) for heavy exposure). Furthermore, there was a significantly multiplicative interaction between passive smoking and COF for oral cancer. PMID- 27224836 TI - Percutaneous Image-Guided Musculoskeletal Tumor Treatments. AB - OBJECTIVE: The purpose of this article is to review the current guidelines and recommendations for percutaneous image-guided treatment of musculoskeletal tumors. CONCLUSION: With the ongoing technologic advances, it is essential that the musculoskeletal interventionalist is familiar with the current tools and techniques available for the treatment of soft-tissue and bone tumors. Fortunately, many of these tools are readily available in a standard interventional radiology department and can be easily applied to the musculoskeletal system. PMID- 27224837 TI - The role of emotional maltreatment and looming cognitive style in the development of social anxiety symptoms in late adolescents. AB - BACKGROUND: Social looming constitutes a specific cognitive vulnerability that acts as a danger schema and biases the processing of threat-related information associated with the development of social anxiety disorder. This model characterizes early negative experiences as critical to the formation of looming cognitive style. Furthermore, research has found links between parental emotional abuse and peer victimization and social anxiety. DESIGN: A three-wave longitudinal design was used to analyze the role of parents' emotional abuse and peer victimization in the onset of social anxiety symptoms through the development of this cognitive style. METHODS: The final sample was made up of 307 females and 243 males (Mage = 16.97, SDage = .81). Perceived parents' emotional abuse and peer victimization by participants were measured at Time 1, social looming was measured at Time 1 and 2, and social anxiety symptoms were measured at Times 1, 2, and 3. RESULTS: Parents' emotional abuse and peer victimization were related to social anxiety cross-sectionally. Longitudinally, social looming acted as a mediator in the relationship between parents' emotional abuse and social anxiety. CONCLUSIONS: These findings highlight the need to better understand the mechanisms through which emotional abuse and peer victimization impact social looming and contribute to social anxiety. PMID- 27224838 TI - A new framework for the interpretation of IgE sensitization tests. AB - IgE sensitization tests, such as skin prick testing and serum-specific IgE, have been used to diagnose IgE-mediated clinical allergy for many years. Their prime drawback is that they detect sensitization which is only loosely related to clinical allergy. Many patients therefore require provocation tests to make a definitive diagnosis; these are often expensive and potentially associated with severe reactions. The likelihood of clinical allergy can be semi-quantified from an IgE sensitization test results. This relationship varies though according to the patients' age, ethnicity, nature of the putative allergic reaction and coexisting clinical diseases such as eczema. The likelihood of clinical allergy can be more precisely estimated from an IgE sensitization test result, by taking into account the patient's presenting features (pretest probability). The presence of each of these patient-specific factors may mean that a patient is more or less likely to have clinical allergy with a given test result (post-test probability). We present two approaches to include pretest probabilities in the interpretation of results. These approaches are currently limited by a lack of data to allow us to derive pretest probabilities for diverse setting, regions and allergens. Also, cofactors, such as exercise, may be necessary for exposure to an allergen to result in an allergic reaction in specific IgE-positive patients. The diagnosis of IgE-mediated allergy is now being aided by the introduction of allergen component testing which may identify clinically relevant sensitization. Other approaches are in development with basophil activation testing being closest to clinical application. PMID- 27224839 TI - Ultrasound-Guided Percutaneous Tendon Treatments. AB - OBJECTIVE: The purpose of this article is to review currently available tendon treatments, especially those performed with sonographic guidance. CONCLUSION: Treatments of tendon disease have continued to develop and expand, and multiple therapeutic options have become available, all with varying levels of supportive clinical evidence of their efficacy. The use of ultrasound to direct these treatments improves accuracy and performance by facilitating visualization of the target and relevant adjacent structures. PMID- 27224841 TI - Solution Structure of Turbo-Hauser Base TMPMgCl?LiCl in [D8 ]THF. AB - Turbo-Hauser bases are very useful and highly reactive organometallic reagents in synthesis. Especially TMPMgCl?LiCl 1 (TMP=2,2,6,6-tetramethylpiperidide) is an excellent base for converting a wide range of (hetero)aromatic substrates into highly functionalized compounds with a broad application in organic synthesis. The knowledge of its structure in solution is of essential importance to understand the extraordinary reactivity and selectivity. However, very little is known about the aggregation of this prominent reagent in solution. Herein, we present the THF-solution structure of 1 by employing our newly elaborated DOSY NMR method based on external calibration curves (ECC) with normalized diffusion coefficients. PMID- 27224840 TI - Structure of Quinolinate Synthase from Pyrococcus horikoshii in the Presence of Its Product, Quinolinic Acid. AB - Quinolinic acid (QA) is a common intermediate in the biosynthesis of nicotinamide adenine dinucleotide (NAD(+)) and its derivatives in all organisms that synthesize the molecule de novo. In most prokaryotes, it is formed from the condensation of dihydroxyacetone phosphate (DHAP) and aspartate-enamine by the action of quinolinate synthase (NadA). NadA contains a [4Fe-4S] cluster cofactor with a unique, non-cysteinyl-ligated, iron ion (Fea), which is proposed to bind the hydroxyl group of a postulated intermediate in the last step of the reaction to facilitate a dehydration. However, direct evidence for this role in catalysis has yet to be provided. Herein, we present the structure of NadA in the presence of the product of its reaction, QA. We find that N1 and the C7 carboxylate group of QA ligate to Fea in a bidentate fashion, which is confirmed by Hyperfine Sublevel Correlation (HYSCORE) spectroscopy. This binding mode would place the C5 hydroxyl group of the postulated final intermediate distal to Fea and virtually incapable of coordinating to it. The structure shows that three strictly conserved amino acids, Glu198, Tyr109, and Tyr23, are in close proximity to the bound product. Substitution of these amino acids with Gln, Phe, and Phe, respectively, leads to complete loss of activity. PMID- 27224842 TI - Sugar Sag: Glycation and the Role of Diet in Aging Skin. AB - First described in the context of diabetes, advanced glycation end products (AGEs) are formed through a type of non-enzymatic reaction called glycation. Increased accumulation of AGEs in human tissue has now been associated with end stage renal disease, chronic obstructive pulmonary disease, and, recently, skin aging. Characteristic findings of aging skin, including decreased resistance to mechanical stress, impaired wound healing, and distorted dermal vasculature, can be in part attributable to glycation. Multiple factors mediate cutaneous senescence, and these factors are generally characterized as endogenous (e.g., telomere shortening) or exogenous (e.g., ultraviolet radiation exposure). Interestingly, AGEs exert their pathophysiological effects from both endogenous and exogenous routes. The former entails the consumption of sugar in the diet, which then covalently binds an electron from a donor molecule to form an AGE. The latter process mostly refers to the formation of AGEs through cooking. Recent studies have revealed that certain methods of food preparation (i.e., grilling, frying, and roasting) produce much higher levels of AGEs than water-based cooking methods such as boiling and steaming. Moreover, several dietary compounds have emerged as promising candidates for the inhibition of glycation-mediated aging. In this review, we summarize the evidence supporting the critical role of glycation in skin aging and highlight preliminary studies on dietary strategies that may be able to combat this process. PMID- 27224843 TI - Tavaborole 5% Solution: A Novel Topical Treatment for Toenail Onychomycosis. AB - Onychomycosis is a stubborn fungal infection of the nails that can be difficult to effectively manage. One of the challenges with topical therapies is penetrating the nail plate to reach the site of infection. As the first antifungal in a boron-containing class of drugs with a novel mechanism of action, tavaborole is able to penetrate the nail plate more effectively than ciclopirox and amorolfine lacquers. In Phase II/III clinical trials, tavaborole was shown to be safe and clinically effective. Tavaborole 5% solution was approved by the US FDA for the treatment of toenail onychomycosis in July 2014 and is an important addition to the topical treatment arsenal against this stubborn infection. PMID- 27224845 TI - Aromaticity Competition in Differentially Fused Borepin-Containing Polycyclic Aromatics. AB - This report describes the synthesis and characterization of a series of borepin based polycyclic aromatics bearing two different arene fusions. The borepin synthesis features streamlined Ti-mediated alkyne reduction, leading to Z olefins, followed by direct lithiation and borepin formation. These molecules allow for an assessment of aromatic competition between the fused rings and the central borepin core. Crystallographic, magnetic, and computational studies yielded insights about the aromaticity of novel, differentially fused [b,f]borepins and allowed for comparison to literature compounds. Multiple borepin motifs were also incorporated into polycyclic aromatics with five or six rings in the main backbone, and their properties were also evaluated. PMID- 27224844 TI - Maximum levels of hepatitis C virus lipoviral particles are associated with early and persistent infection. AB - BACKGROUND & AIMS: Hepatitis C virus (HCV) is bound to plasma lipoproteins and circulates as an infectious lipoviral particle (LVP). Experimental evidence indicates that LVPs have decreased susceptibility to antibody-mediated neutralisation and higher infectivity. This study tested the hypothesis that LVPs are required to establish persistent infection, and conversely, low levels of LVP in recent HCV infection increase the probability of spontaneous HCV clearance. METHODS: LVP in non-fasting plasma was measured using the concentration of HCV RNA bound to large >100 nm sized lipoproteins after ex vivo addition of a lipid emulsion, that represented the maximum concentration of LVP (maxi-LVP). This method correlated with LVP in fasting plasma measured using iodixanol density gradient ultracentrifugation. Maxi-LVP was measured in a cohort of 180 HCV participants with recent HCV infection and detectable HCV RNA from the Australian Trial in Acute Hepatitis C (ATAHC) and Hepatitis C Incidence and Transmission Study in prison (HITS-p) cohorts. RESULTS: Spontaneous clearance occurred in 15% (27 of 180) of individuals. In adjusted analyses, low plasma maxi-LVP level was independently associated with spontaneous HCV clearance (<=827 IU/ml; adjusted odds ratio 3.98, 95% CI: 1.02, 15.51, P = 0.047), after adjusting for interferon lambda-3 rs8099917 genotype, estimated duration of HCV infection and total HCV RNA level. CONCLUSIONS: Maxi-LVP is a biomarker for the maximum concentration of LVP in non-fasting samples. Low maxi-LVP level is an independent predictor of spontaneous clearance of acute HCV. PMID- 27224846 TI - Using online social networks to track a pandemic: A systematic review. AB - BACKGROUND: The popularity and proliferation of online social networks (OSNs) have created massive social interaction among users that generate an extensive amount of data. An OSN offers a unique opportunity for studying and understanding social interaction and communication among far larger populations now more than ever before. Recently, OSNs have received considerable attention as a possible tool to track a pandemic because they can provide an almost real-time surveillance system at a less costly rate than traditional surveillance systems. METHODS: A systematic literature search for studies with the primary aim of using OSN to detect and track a pandemic was conducted. We conducted an electronic literature search for eligible English articles published between 2004 and 2015 using PUBMED, IEEExplore, ACM Digital Library, Google Scholar, and Web of Science. First, the articles were screened on the basis of titles and abstracts. Second, the full texts were reviewed. All included studies were subjected to quality assessment. RESULT: OSNs have rich information that can be utilized to develop an almost real-time pandemic surveillance system. The outcomes of OSN surveillance systems have demonstrated high correlations with the findings of official surveillance systems. However, the limitation in using OSN to track pandemic is in collecting representative data with sufficient population coverage. This challenge is related to the characteristics of OSN data. The data are dynamic, large-sized, and unstructured, thus requiring advanced algorithms and computational linguistics. CONCLUSIONS: OSN data contain significant information that can be used to track a pandemic. Different from traditional surveys and clinical reports, in which the data collection process is time consuming at costly rates, OSN data can be collected almost in real time at a cheaper cost. Additionally, the geographical and temporal information can provide exploratory analysis of spatiotemporal dynamics of infectious disease spread. However, on one hand, an OSN-based surveillance system requires comprehensive adoption, enhanced geographical identification system, and advanced algorithms and computational linguistics to eliminate its limitations and challenges. On the other hand, OSN is probably to never replace traditional surveillance, but it can offer complementary data that can work best when integrated with traditional data. PMID- 27224847 TI - The INTEGRATE project: Delivering solutions for efficient multi-centric clinical research and trials. AB - The objective of the INTEGRATE project (http://www.fp7-integrate.eu/) that has recently concluded successfully was the development of innovative biomedical applications focused on streamlining the execution of clinical research, on enabling multidisciplinary collaboration, on management and large-scale sharing of multi-level heterogeneous datasets, and on the development of new methodologies and of predictive multi-scale models in cancer. In this paper, we present the way the INTEGRATE consortium has approached important challenges such as the integration of multi-scale biomedical data in the context of post-genomic clinical trials, the development of predictive models and the implementation of tools to facilitate the efficient execution of postgenomic multi-centric clinical trials in breast cancer. Furthermore, we provide a number of key "lessons learned" during the process and give directions for further future research and development. PMID- 27224849 TI - Progressive multifocal leukoencephalopathy after liver transplantation can have favorable or unfavorable outcome. AB - Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the JC polyomavirus (JCPyV) in immunocompromised patients, including solid organ transplant recipients. We report 2 cases of PML late after liver transplantation (144 and 204 months) and review the few other published cases. The clinical course of PML is characterized by a rapid progressive neurological decline coinciding with the presence of white matter lesions on magnetic resonance images. No direct antiviral therapy is available against the JCPyV. The prognosis is therefore extremely poor. Restoration of the immune response achieved by tapering or ending the immunosuppressive therapy is the basis of treatment in transplanted patients. One of our patients is alive 3 years after diagnosis after total withdrawal of immunosuppressive therapy. The other presented severe rejection when tapering immunosuppression and died 26 months after diagnosis. PMID- 27224848 TI - Risk Factors, Methods, and Timing of Suicide Attempts Among US Army Soldiers. AB - IMPORTANCE: Suicide attempts in the US Army have risen in the past decade. Understanding the association between suicide attempts and deployment, as well as method and timing of suicide attempts, can assist in developing interventions. OBJECTIVE: To examine suicide attempt risk factors, methods, and timing among soldiers currently deployed, previously deployed, and never deployed at the time this study was conducted. DESIGN, SETTING, AND PARTICIPANTS: This longitudinal, retrospective cohort study of Regular Army-enlisted soldiers on active duty from 2004 through 2009 used individual-level person-month records to examine risk factors (sociodemographic, service related, and mental health), method, and time of suicide attempt by deployment status (never, currently, and previously deployed). Administrative data for the month before each of 9650 incident suicide attempts and an equal-probability sample of 153 528 control person-months for other soldiers were analyzed using a discrete-time survival framework. MAIN OUTCOMES AND MEASURES: Suicide attempts and career, mental health, and demographic predictors were obtained from administrative and medical records. RESULTS: Of the 9650 enlisted soldiers who attempted suicide, 86.3% were male, 68.4% were younger than 30 years, 59.8% were non-Hispanic white, 76.5% were high school educated, and 54.7% were currently married. The 40.4% of enlisted soldiers who had never been deployed (n = 12 421 294 person-months) accounted for 61.1% of enlisted soldiers who attempted suicide (n = 5894 cases). Risk among those never deployed was highest in the second month of service (103 per 100 000 person months). Risk among soldiers on their first deployment was highest in the sixth month of deployment (25 per 100 000 person-months). For those previously deployed, risk was highest at 5 months after return (40 per 100 000 person months). Currently and previously deployed soldiers were more likely to attempt suicide with a firearm than those never deployed (currently deployed: OR, 4.0; 95% CI, 2.9-5.6; previously deployed: OR, 2.7; 95% CI, 1.8-3.9). Across deployment status, suicide attempts were more likely among soldiers who were women (currently deployed: OR, 3.4; 95% CI, 3.0-4.0; previously deployed: OR, 1.5; 95% CI, 1.4-1.7; and never deployed: OR, 2.4; 95% CI, 2.3-2.6), in their first 2 years of service (currently deployed: OR, 1.9; 95% CI, 1.5-2.3; previously deployed: OR, 2.2; 95% CI, 1.9-2.7; and never deployed: OR, 3.1; 95% CI, 2.7-3.6), and had a recently received a mental health diagnosis in the previous month (currently deployed: OR, 29.8; 95% CI, 25.0-35.5; previously deployed: OR, 22.2; 95% CI, 20.1-24.4; and never deployed: OR, 15.0; 95% CI, 14.2 16.0). Among soldiers with 1 previous deployment, odds of a suicide attempt were higher for those who screened positive for depression or posttraumatic stress disorder after return from deployment and particularly at follow-up screening, about 4 to 6 months after deployment (depression: OR, 1.4; 95% CI, 1.1-1.9; posttraumatic stress disorder: OR, 2.4; 95% CI, 2.1-2.8). CONCLUSIONS AND RELEVANCE: Identifying the timing and risk factors for suicide attempt in soldiers requires consideration of environmental context, individual characteristics, and mental health. These factors can inform prevention efforts. PMID- 27224850 TI - On the importance of body posture and skin modelling with respect to in situ electric field strengths in magnetic field exposure scenarios. AB - The reference levels and maximum permissible exposure values for magnetic fields that are currently used have been derived from basic restrictions under the assumption of upright standing body models in a standard posture, i.e. with arms laterally down and without contact with metallic objects. Moreover, if anatomical modelling of the body was used at all, the skin was represented as a single homogeneous tissue layer. In the present paper we addressed the possible impacts of posture and skin modelling in scenarios of exposure to a 50 Hz uniform magnetic field on the in situ electric field strength in peripheral tissues, which must be limited in order to avoid peripheral nerve stimulation. We considered different body postures including situations where body parts form large induction loops (e.g. clasped hands) with skin-to-skin and skin-to-metal contact spots and compared the results obtained with a homogeneous single-layer skin model to results obtained with a more realistic two-layer skin representation consisting of a low-conductivity stratum corneum layer on top of a combined layer for the cellular epidermis and dermis. Our results clearly indicated that postures with loops formed of body parts may lead to substantially higher maximum values of induced in situ electric field strengths than in the case of standard postures due to a highly concentrated current density and in situ electric field strength in the skin-to-skin and skin-to-metal contact regions. With a homogeneous single-layer skin, as is used for even the most recent anatomical body models in exposure assessment, the in situ electric field strength may exceed the basic restrictions in such situations, even when the reference levels and maximum permissible exposure values are not exceeded. However, when using the more realistic two-layer skin model the obtained in situ electric field strengths were substantially lower and no violations of the basic restrictions occurred, which can be explained by the current-limiting effect of the low-conductivity stratum corneum layer. PMID- 27224851 TI - Bortezomib for the prevention and treatment of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. AB - Allogeneic hematopoietic stem cell transplantation is the standard treatment for a variety of benign and malignant conditions. However, graft-versus-host disease (GvHD) continues to present a major barrier to the success and wide applicability of this procedure. Although current GvHD prevention and treatment regimens exclusively target T cells, bortezomib, a reversible proteasome inhibitor, possesses unique immune regulatory activities that span a wide variety of cellular processes of T and dendritic cells essential for the development of GvHD. Herein, we review the current understanding of the effects of bortezomib in vitro and in animal models and summarize the clinical data relevant to its use in the prevention and treatment of GvHD. We conclude with an outline of the remaining challenges and opportunities to optimize bortezomib's potential role in this setting. PMID- 27224852 TI - On the threshold conditions for electron beam damage of asbestos amosite fibers in the transmission electron microscope (TEM). AB - Asbestos amosite fibers were investigated to evaluate the damage caused by a transmission electron microscope (TEM) electron beam. Since elemental x-ray intensity ratios obtained by energy dispersive x-ray spectroscopy (EDS) are commonly used for asbestos identification, the impact of beam damage on these ratios was evaluated. It was determined that the magnesium/silicon ratio best represented the damage caused to the fiber. Various tests showed that most fibers have a current density threshold above which the chemical composition of the fiber is modified. The value of this threshold current density varied depending on the fiber, regardless of fiber diameter, and in some cases could not be determined. The existence of a threshold electron dose was also demonstrated. This value was dependent on the current density used and can be increased by providing a recovery period between exposures to the electron beam. This study also established that the electron beam current is directly related to the damage rate above a current density of 165 A/cm2. The large number of different results obtained suggest, that in order to ensure that the amosite fibers are not damaged, analysis should be conducted below a current density of 100 A/cm2. PMID- 27224854 TI - Granule size distributions after twin-screw granulation - Do not forget the feeding systems. AB - The aim of this study was to investigate the influence of qualitatively different powder feeder performances on resulting granule size distributions after twin screw granulation of a highly drug loaded, hydrophobic mixture and a mannitol powder. It was shown that powder feeder related problems usually cannot be identified by trusting in the values given by the feeder. Therefore, a newly developed model for the evaluation of the performance of powder feeders was introduced and it was tried to connect this model to residence time distributions in twin-screw granulation processes. The influence of feeder performances on resulting granule size distributions varied, depending on the applied screw configuration and the used powder. Regarding the hydrophobic and highly drug loaded formulation, which was granulated at an L/S-ratio of 0.5, a pure conveying screw and a medium kneading configuration, consisting of 60 degrees kneading blocks were negatively influenced by poor feeder settings. For optimal settings more narrow distributions could be obtained. For an extensive kneading configuration good and poor settings resulted in mono-modal granule size distributions but were differing in the overall size. Mannitol, a model substance for a liquid sensitive formulation was granulated at an L/S-ratio of 0.075. It was even more important to maintain optimal feeding as mannitol was highly affected by poor feeder performances. Even an extensive kneading configuration could not level the errors in powder feeder performance, resulting in qualitatively different granule size distributions. The results of this study demonstrate the importance of detailed knowledge about applied feeding systems to gain optimal performance in twin-screw granulation. PMID- 27224853 TI - Conformal Nanoencapsulation of Allogeneic T Cells Mitigates Graft-versus-Host Disease and Retains Graft-versus-Leukemia Activity. AB - Allogeneic transplantation of hematopoietic stem cells (HSC) in combination with T cells has a curative potential for hematopoietic malignancies through graft versus-leukemia (GVL) effects, but is often compromised by the notorious side effect of graft-versus-host disease (GVHD) resulting from alloreactivity of the donor T cells. Here, we tested if temporary immunoisolation achieved by conformally encapsulating the donor T cells within a biocompatible and biodegradable porous film (~450 nm in thickness) of chitosan and alginate could attenuate GVHD without compromising GVL. The nanoencapsulation was found not to affect the phenotype of T cells in vitro in terms of size, viability, proliferation, cytokine secretion, and cytotoxicity against tumor cells. Moreover, the porous nature of the nanoscale film allowed the encapsulated T cells to communicate with their environment, as evidenced by their intact capability of binding to antibodies. Lethally irradiated mice transplanted with bone marrow cells (BMCs) and the conformally encapsulated allogeneic T cells exhibited significantly improved survival and reduced GVHD together with minimal liver damage and enhanced engraftment of donor BMCs, compared to the transplantation of BMCs and non-encapsulated allogeneic T cells. Moreover, the conformal nanoencapsulation did not compromise the GVL effect of the donor T cells. These data show that conformal nanoencapsulation of T cells within biocompatible and biodegradable nanoscale porous materials is a potentially safe and effective approach to improve allogeneic HSC transplantation for treating hematological malignancies and possibly other diseases. PMID- 27224855 TI - RNAi mediated IL-6 in vitro knockdown in psoriasis skin model with topical siRNA delivery system based on liquid crystalline phase. AB - Gene therapy by RNA interference (RNAi) is a post-transcriptional silencing process that can suppress the expression of a particular gene and it is a promising therapeutic approach for the treatment of many severe diseases, including cutaneous disorders. However, difficulties related to administration and body distribution limit the clinical use of small interfering RNA (siRNA) molecules. In this study, we proposed to use nanocarriers to enable siRNA application in the topical treatment of skin disorders. A siRNA nanodispersion based on liquid crystalline phase and composed of monoolein (MO), oleic acid (OA) and polyethylenimine (PEI) was developed and its physicochemical properties, efficiency of complexation and carrier/siRNA stability were assessed. Subsequently, cell viability, cellular uptake, in vitro skin irritation test using reconstructed human epidermis (RHE) and in vitro IL-6 knockdown in psoriasis skin model were evaluated. The results showed that the liquid crystalline nanodispersion is a promising topical delivery system for administration of siRNA, being able to overcome the limitations of the route of administration, as well those resulting from the characteristics of siRNA molecules. The formulation was effective at complexing the siRNA, presented high rate of cell uptake (~90%), increased the skin penetration of siRNA in vitro, and did not cause skin irritation compared with Triton-X (a moderate irritant), resulting in a 4-fold higher viability of reconstructed human epidermis and a 15.6-fold lower release of IL-1alpha. A single treatment with the liquid crystalline nanodispersion carrying IL-6 siRNA for 6h was able to reduce the extracellular IL-6 levels by 3.3-fold compared with control treatment in psoriasis skin model. Therefore, liquid crystalline nanodispersion is a suitable nanocarrier for siRNA with therapeutic potential to suppress skin disease specific genes. This study also highlights the applicability of reconstructed skin models in pharmaceutical field to evaluate the performance of delivery systems without the use of animal models. PMID- 27224856 TI - The preparation and characterization of PLG nanoparticles with an entrapped synthetic TLR7 agonist and their preclinical evaluation as adjuvant for an adsorbed DTaP vaccine. AB - The design of safe and potent adjuvants able to enhance and modulate antigen specific immunity is of great interest for vaccine research and development. In the present study, negatively charged poly(lactide-co-glycolide) (PLG) nanoparticles have been combined with a synthetic immunepotentiator molecule targeting the Toll-like receptor 7. The selection of appropriate preparation and freeze-drying conditions resulted in a PLG-based adjuvant with well-defined and stable physico-chemical properties. The adjuvanticity of such nanosystem has later been evaluated in the mouse model with a diphtheria-tetanus-pertussis (DTaP) vaccine, on the basis of the current need to improve the efficacy of acellular pertussis (aP) vaccines. DTaP antigens were adsorbed onto PLG nanoparticles surface, allowing the co-delivery of TLR7a and multiple antigens through a single formulation. The entrapment of TLR7a into PLG nanoparticles resulted in enhanced IgG and IgG2a antibody titers. Notably, the immune potentiator effect of TLR7a was less evident when it was used in not-entrapped form, indicating that co-localization of TLR7a and antigens is required to adequately stimulate immune responses. In conclusion, the rational selection of adjuvants and formulation here described resulted as a highly valuable approach to potentiate and better tailor DTaP vaccine immunogenicity. PMID- 27224857 TI - Short- and Long-term Results of Unroofing and Marsupialization for Adolescent Pilonidal Disease. PMID- 27224859 TI - Emerging of two new subgenotypes of porcine reproductive and respiratory syndrome viruses in Southeast China. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the leading swine pathogens and causes major economic loss to the global swine industry. In this study, a total of 49 PRRSV isolates were collected from different swine herds in seven provinces in Southeast China from 2014 to 2015. All the ORF5 genes and some Nsp2 genes were sequenced. Phylogenetic analysis showed that all the isolates belonged to the North America genotype. Among them, five isolates formed a new subgenotype IV derived from highly pathogenic PRRSV (HP-PRRSV). Six isolates formed subgenotype III, which were closely related to the NADC30 strain in the US. These isolates formed 13 putative N-linked glycosylation site (NGS) patterns based on N30, 33, 34, 35, 44 and 51. There were fewer NGSs of isolates in subgenotype IV than in subgenotype III. This indicates that the two new subgenotypes of PRRSV strains with different NGS patterns were spreading in those regions of China. The genetic diversity should be considered for the control and prevention of this disease. PMID- 27224858 TI - Use, complications, and costs of stereotactic body radiotherapy for localized prostate cancer. AB - BACKGROUND: Stereotactic body radiotherapy (SBRT) for localized prostate cancer has potential advantages over traditional radiotherapies. Herein, the authors compared national trends in use, complications, and costs of SBRT with those of traditional radiotherapies. METHODS: The authors identified men who underwent SBRT, intensity-modulated radiotherapy (IMRT), brachytherapy, and proton beam therapy as primary treatment of prostate cancer between 2004 and 2011 from Surveillance, Epidemiology, and End Results Program (SEER)-Medicare linked data. Temporal trend of therapy use was assessed using the Cochran-Armitage test. Two year outcomes were compared using the chi-square test. Median treatment costs were compared using the Kruskal-Wallis test. RESULTS: A total of 542 men received SBRT, 9647 received brachytherapy, 23,408 received IMRT, and 800 men were treated with proton beam therapy. There was a significant increase in the use of SBRT and proton beam therapy (P<.001), whereas brachytherapy use decreased (P<.001). A higher percentage of patients treated with SBRT and brachytherapy had low-grade cancer (Gleason score <= 6 vs >= 7) compared with individuals treated with IMRT and proton beam therapy (54.0% and 64.2% vs 35.2% and 49.6%, respectively; P<.001). SBRT compared with brachytherapy and IMRT was associated with equivalent gastrointestinal toxicity but more erectile dysfunction at 2-year follow-up (P<.001). SBRT was associated with more urinary incontinence compared with IMRT and proton beam therapy but less compared with brachytherapy (P<.001, respectively). The median cost of SBRT was $27,145 compared with $17,183 for brachytherapy, $37,090 for IMRT, and $54,706 for proton beam therapy (P<.001). CONCLUSIONS: The use of SBRT and proton beam therapy for localized prostate cancer has increased over time. Despite men of lower disease stage undergoing SBRT, SBRT was found to be associated with greater toxicity but lower health care costs compared with IMRT and proton beam therapy. Cancer 2016;122:2496-504. (c) 2016 American Cancer Society. PMID- 27224860 TI - Nebivolol prevents indomethacin-induced gastric ulcer in rats. AB - Gastric ulcer is a very common gastrointestinal disease that may lead to dangerous complications and even death. This study was conducted to evaluate the prophylactic effect of nebivolol against indomethacin [INDO]-induced gastric ulcer. Male Wistar rats were divided into four groups: normal control, ulcer control (INDO only), omeprazole before INDO and nebivolol before INDO. Each rat to receive nebivolol and omeprazole was given the agent orally (by gavage) daily for 10 days prior to induction of ulcer by oral dosing with INDO. Four hours after INDO treatment, all rats were euthanized and their stomachs obtained for measures of gastric acidity, oxidative stress and inflammatory markers, as well as cytoprotective mediators. The results showed that a single oral dose of INDO (100 mg/kg) induced gastric acidity, an ulcer index of 2900 and significantly increased levels of gastric tumor necrosis factor (TNF)-alpha and malondialdehyde (MDA) and significantly decreased levels of gastric prostaglandin E2 (PGE2), glutathione (GSH) and nitric oxide (NO), compared to in normal control counterpart stomachs. Giving nebivolol before INDO corrected the gastric acidity and resulted in a significant increase in GSH, PGE2 and NO and a significant decrease in TNFalpha and MDA gastric levels, compared to ulcer control values. Results obtained with nebivolol were comparable to those with omeprazole; the preventive index in the nebivolol group was 90.7% compared to 94.5% in rats in the omeprazole group. These studies showed that nebivolol provided a valuable role in preventing gastric ulcers induced by INDO and provided a promise for potentially protecting hypertensive patients from experiencing gastric ulcer. Thus, it is possible that, pending further studies, nebivolol could be used for pre-exposure prophylaxis from gastric ulcer in these patients. PMID- 27224861 TI - PEPIS: A Pipeline for Estimating Epistatic Effects in Quantitative Trait Locus Mapping and Genome-Wide Association Studies. AB - The term epistasis refers to interactions between multiple genetic loci. Genetic epistasis is important in regulating biological function and is considered to explain part of the 'missing heritability,' which involves marginal genetic effects that cannot be accounted for in genome-wide association studies. Thus, the study of epistasis is of great interest to geneticists. However, estimating epistatic effects for quantitative traits is challenging due to the large number of interaction effects that must be estimated, thus significantly increasing computing demands. Here, we present a new web server-based tool, the Pipeline for estimating EPIStatic genetic effects (PEPIS), for analyzing polygenic epistatic effects. The PEPIS software package is based on a new linear mixed model that has been used to predict the performance of hybrid rice. The PEPIS includes two main sub-pipelines: the first for kinship matrix calculation, and the second for polygenic component analyses and genome scanning for main and epistatic effects. To accommodate the demand for high-performance computation, the PEPIS utilizes C/C++ for mathematical matrix computing. In addition, the modules for kinship matrix calculations and main and epistatic-effect genome scanning employ parallel computing technology that effectively utilizes multiple computer nodes across our networked cluster, thus significantly improving the computational speed. For example, when analyzing the same immortalized F2 rice population genotypic data examined in a previous study, the PEPIS returned identical results at each analysis step with the original prototype R code, but the computational time was reduced from more than one month to about five minutes. These advances will help overcome the bottleneck frequently encountered in genome wide epistatic genetic effect analysis and enable accommodation of the high computational demand. The PEPIS is publically available at http://bioinfo.noble.org/PolyGenic_QTL/. PMID- 27224862 TI - How do we capture the emergency nurse practitioners' contribution to value in health service delivery? AB - The emergency nurse practitioner is now a well established and respected member of the healthcare team. Evaluation of the role has focused on patient safety, effectiveness and quality of care outcomes. Comparisons of the role continue to focus on cost, with findings based on incomplete and almost impossible to define, recognition of contribution to service delivery by paralleled practitioners. Currently there is no clear definition as to how nurse practitioners contribute to value in health service delivery. Robust and rigorous research needs to be commissioned taking into consideration the unique hybrid nature of the emergency nurse practitioner role and focusing on the value they contribute to health care delivery. PMID- 27224863 TI - Editorial. PMID- 27224864 TI - Society is the Patient. PMID- 27224865 TI - Cues/Tips. PMID- 27224866 TI - Ultrasound flowmetry in clinical practice. PMID- 27224867 TI - Physical properties of Doppler ultrasound. PMID- 27224868 TI - The duck, the desert rat, and the dichotomy. AB - This section is reserved for commentaries and brief essays dealing with matters of interest to physicians. Material for consideration should not exceed five double-spaced typewritten pages. An honorarium of $75 is offered at the time of publication. Submissions should be addressed to: Editor, POSTGRADUATE MEDICINE, 4530 W 77th St, Minneapolis, MN 55435. PMID- 27224869 TI - I lead a double life. AB - This section is reserved for commentaries and brief essays dealing with matters of interest to physicians. Material for consideration should not exceed five double-spaced typewritten pages. An honorarium of $75 is offered at the time of publication. Submissions should be addressed to: Editor, POSTGRADUATE MEDICINE, 4530 W 77th St, Minneapolis, MN 55435. PMID- 27224871 TI - DNA Triplexes-Guided Assembly of G-Quadruplexes for Constructing Label-free Fluorescent Logic Gates. AB - Assembly of G-quadruplexes guided by DNA triplexes in a controlled manner is achieved for the first time. The folding of triplex sequences in acidic conditions brings two separated guanine-rich sequences together and subsequently a G-quadruplex structure is formed in the presence of K(+) . Based on this novel platform, label-free fluorescent logic gates, such as AND, INHIBIT, and NOR, are constructed with ions as input and the fluorescence of a G-quadruplex-specific fluorescent probe NMM as output. PMID- 27224874 TI - Very Small Bandgap pi-Conjugated Polymers with Extended Thienoquinoids. AB - The introduction of quinoidal character to pi-conjugated polymers is one of the effective approaches to reducing the bandgap. Here we synthesized new pi conjugated polymers (PBTD4T and PBDTD4T) incorporating thienoquinoids 2,2' bithiophene-5,5'-dione (BTD) and benzo[1,2-b:4,5-b']dithiophene-2,6-dione (BDTD) as strong electron-deficient (acceptor) units. PBTD4T showed a deep LUMO energy level of -3.77 eV and a small bandgap of 1.28 eV, which are similar to those of the analog using thieno[3,2-b]thiophene-2,5-dione (TTD) (PTTD4T). PBDTD4T had a much deeper LUMO energy level of -4.04 eV and a significantly smaller bandgap of 0.88 eV compared to those of the other two polymers. Interestingly, PBDTD4T showed high transparency in the visible region. The very small bandgap of PBDTD4T can be rationalized by the enhanced contribution of the resonance backbone structure in which the p-benzoquinodimethane skeleton in the BDTD unit plays a crucial role. PBTD4T and PBDTD4T exhibited ambipolar charge transport with more balanced mobilities between the hole and the electron than PTTD4T. We believe that the very small bandgap, i.e., the high near-infrared activity, as well as the well-balanced ambipolar property of the pi-conjugated polymers based on these units would be of particular interest in the fabrication of next-generation organic devices. PMID- 27224873 TI - Programmed death-1 immune checkpoint blockade in the treatment of hematological malignancies. AB - The use of tumor-specific monoclonal antibodies (MAbs) has revolutionize the field of cancer immunotherapy. Although treatment of malignant diseases with MAbs is promising, many patients fail to respond or relapse after an initial response. Both solid tumors and hematological malignancies develop mechanisms that enable them to evade the host immune system by usurping immune checkpoint pathways such as PD-1, PD-2, PDL-1, or PDL-2 (programmed cell death protein-1 or 2 and PD Ligand 1 or 2), which are expressed on activated T cells and on T-regulatory, B cells, natural killers, monocytes, and dendritic cells. One of the most exciting anticancer development in recent years has been the immune checkpoint blockade therapy by using MAbs against immune checkpoint receptor and/or ligands. Anti-PD1 antibodies have been tested in clinical studies that included patients with hematological malignancies and showed remarkable efficacy in Hodgkin lymphoma (HL). In our review, we will focus on the effect of PD-1 activation on hematological malignancies and its role as a therapeutic target. Key messages The programmed death 1 (PD1) immune checkpoint is an important homeostatic mechanism of the immune system that helps in preventing autoimmunity and uncontrolled inflammation in cases of chronic infections. However, PD1 pathway is also operated by a wide variety of malignancies and represents one of the most important mechanisms by which tumor cells escape from the surveillance of the immune system. Blocking of immune checkpoints by the use of monoclonal antibodies opened a new era in the field of cancer immunotherapy. Results from clinical trials are promising, and currently, this approach has been proven effective and safe in patients with solid tumors and hematological malignancies. PMID- 27224872 TI - Associations between body fat distribution, insulin resistance and dyslipidaemia in black and white South African women. AB - AIM: The aim was to examine differences in body fat distribution between premenopausal black and white South African (SA) women and explore the ethnic specific associations with cardiometabolic risk. METHODS: Body composition, using dual-energy X-ray absorptiometry (DXA) and computerised tomography, insulin resistance (HOMA-IR) and lipid levels were assessed in 288 black and 197 white premenopausal SA women. RESULTS: Compared to the white women, black women had less central and more peripheral (lower-body) fat, and lower serum lipid and glucose concentrations, but similar homeostasis models for insulin resistance (HOMA-IR) values. The associations between body fat distribution and HOMA-IR, triglyceride and high-density lipoprotein cholesterol concentrations were similar, while the associations with fasting glucose, total and low-density lipoprotein cholesterol levels differed between black and white women. CONCLUSION: Ethnic differences in body fat distribution are associated, in part, with differences in cardiometabolic risk between black and white SA women. PMID- 27224875 TI - Structure-Based Design of Potent Nicotinamide Phosphoribosyltransferase Inhibitors with Promising in Vitro and in Vivo Antitumor Activities. AB - Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) has the potential to directly limit NAD production in cancer cells and is an effective strategy for cancer treatment. Using a structure-based strategy, we have designed a new class of potent small-molecule inhibitors of NAMPT. Several designed compounds showed promising antiproliferative activities in vitro. (E)-N-(5-((4-(((2-(1H-Indol-3 yl)ethyl)(isopropyl)amino)methyl)phenyl)amino)pentyl)-3-(pyridin-3-yl)acrylamide, 30, bearing an indole moiety, has an IC50 of 25.3 nM for binding to the NAMPT protein and demonstrated promising inhibitory activities in the nanomolar range against several cancer cell lines (MCF-7 GI50 = 0.13 nM; MDA-MB-231 GI50 = 0.15 nM). Triple-negative breast cancer is the most malignant subtype of breast cancer with no effective targeted treatments currently available. Significant antitumor efficacy of compound 30 was achieved (TGI was 73.8%) in an orthotopic MDA-MB-231 triple-negative breast cancer xenograft tumor model. This paper reports promising lead molecules for the inhibition of NAMPT which could serve as a basis for further investigation. PMID- 27224876 TI - Understanding Symptoms and Quality of Life in Patients With Dry Eye Syndrome. AB - Dry eye disease (DED) is one of the most common reasons for patients (particularly those over the age of 50) to seek ophthalmic care. There is a wide array of causes for DED that can induce an alteration of the ocular surface system and determine the chronicity of the disease, including low blink rates (eg, computer use), systemic and topical drugs, autoimmune diseases, contact lens wear, and cataract and refractive surgery. Patients with dry eye experience numerous symptoms that can reduce their productivity and overall quality of life. This article presents the results of a roundtable focused on patients' symptoms. The goal was to better understand the symptoms reported by patients, the possible effects on visual function, the consequences on the quality of life, and the methodologies that can be used to measure and monitor symptoms in clinical practice and in clinical studies. The discrepancies between clinical signs and symptoms reported in some cases are considered in the context of the ocular surface system. PMID- 27224878 TI - Epigenetic mechanisms and associated brain circuits in the regulation of positive emotions: A role for transposable elements. AB - Epigenetic programming and reprogramming are at the heart of cellular differentiation and represent developmental and evolutionary mechanisms in both germline and somatic cell lines. Only about 2% of our genome is composed of protein-coding genes, while the remaining 98%, once considered "junk" DNA, codes for regulatory/epigenetic elements that control how genes are expressed in different tissues and across time from conception to death. While we already know that epigenetic mechanisms are at play in cancer development and in regulating metabolism (cellular and whole body), the role of epigenetics in the developing prenatal and postnatal brain, and in maintaining a proper brain activity throughout the various stages of life, in addition to having played a critical role in human evolution, is a relatively new domain of knowledge. Here we present the current state-of-the-art techniques and results of these studies within the domain of emotions, and then speculate on how genomic and epigenetic mechanisms can modify and potentially alter our emotional (limbic) brain and affect our social interactions. J. Comp. Neurol. 524:2944-2954, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27224877 TI - Prebiotic nut compounds and human microbiota. AB - Nut consumption is clearly related to human health outcomes. Its beneficial effects have been mainly attributed to nut fatty acid profiles and content of vegetable protein, fiber, vitamins, minerals, phytosterols and phenolics. However, in this review we focus on the prebiotics properties in humans of the non-bioaccessible material of nuts (polymerized polyphenols and polysaccharides), which provides substrates for the human gut microbiota and on the formation of new bioactive metabolites and the absorption of that may partly explain the health benefits of nut consumption. PMID- 27224879 TI - Steroid 5alpha-reductase 2 deficiency. AB - Dihydrotestosterone is a potent androgen metabolite formed from testosterone by action of 5alpha-reductase isoenzymes. Mutations in the type 2 isoenzyme cause a disorder of 46,XY sex development, termed 5alpha-reductase type 2 deficiency and that was described forty years ago. Many mutations in the encoding gene have been reported in different ethnic groups. In affected 46,XY individuals, female external genitalia are common, but Mullerian ducts regress, and the internal urogenital tract is male. Most affected males are raised as females, but virilization occurs at puberty, and male social sex develops thereafter with high frequency. Fertility can be achieved in some affected males with assisted reproduction techniques, and adults with male social sex report a more satisfactory sex life and quality of life as compared to affected individuals with female social sex. PMID- 27224880 TI - Return to Work and Multilevel Versus Single-Level Cervical Fusion for Radiculopathy in a Workers' Compensation Setting. AB - STUDY DESIGN: Retrospective comparative cohort study. OBJECTIVE: Examine the impact of multilevel fusion on return to work (RTW) status and compare RTW status after multi- versus single-level cervical fusion for patients with work-related injury. SUMMARY OF BACKGROUND DATA: Patients with work-related injuries in the workers' compensation systems have less favorable surgical outcomes. Cervical fusion provides a greater than 90% likelihood of relieving radiculopathy and stabilizing or improving myelopathy. However, more levels fused at index surgery are reportedly associated with poorer surgical outcomes than single-level fusion. METHODS: Data was collected from the Ohio Bureau of Workers' Compensation (BWC) between 1993 and 2011. The study population included patients who underwent cervical fusion for radiculopathy. Two groups were constructed (multilevel fusion [MLF] vs. single-level fusion [SLF]). Outcomes measures evaluated were: RTW criteria, RTW <1year, reoperation, surgical complication, disability, and legal litigation after surgery. RESULTS: After accounting for a number of independent variables in the regression model, multilevel fusion was a negative predictor of successful RTW status within 3-year follow-up after surgery (OR = 0.82, 95% CI: 0.70-0.95, P <0.05).RTW criteria were met 62.9% of SLF group compared with 54.8% of MLF group. The odds of having a stable RTW for MLF patients were 0.71% compared with the SLF patients (95% CI: 0.61-0.83; P: 0.0001).At 1 year after surgery, RTW rate was 53.1% for the SLF group compared with 43.7% for the MLF group. The odds of RTW within 1 year after surgery for the MLF group were 0.69% compared with SLF patients (95% CI: 0.59-0.80; P: 0.0001).Higher rate of disability after surgery was observed in the MLF group compared with the SLF group (P: 0.0001) CONCLUSION.: Multilevel cervical fusion for radiculopathy was associated with poor return to work profile after surgery. Multilevel cervical fusion was associated with lower RTW rates, less likelihood of achieving stable return to work, and higher rate of disability after surgery. LEVEL OF EVIDENCE: 3. PMID- 27224882 TI - Prolonged Preoperative Opioid Therapy Associated With Poor Return to Work Rates After Single-Level Cervical Fusion for Radiculopathy for Patients Receiving Workers' Compensation Benefits. AB - STUDY DESIGN: Retrospective comparative cohort study. OBJECTIVE: Examine the effect of prolonged preoperative opioid use on return to work (RTW) status after single-level cervical fusion for radiculopathy. SUMMARY OF BACKGROUND DATA: The use of opioids has a dramatic effect in a workers' compensation population. The costs of claims that involved opioids in the management plan are catastrophic particularly for those undergoing spinal surgical procedure. MATERIALS: Data of patients who underwent single-level cervical fusion for radiculopathy and had received opioid prescriptions before surgery were retrospectively collected from Ohio Bureau of Workers' Compensation between 1993 and 2011 after work-related injury. Then, based on opioid use duration, short-term use (STO) group (<3 mo), intermediate-term use (ITO) group (3-6 mo), and long-term use (LTO) group (>6 mo) were constructed. A multivariate logistic regression analysis was used to determine whether successful RTW status was achieved. Chi-square and analysis of variance tests were used to compare other secondary outcomes after surgery. RESULTS: Prolonged preoperative opioid use was a negative predictor of successful RTW status (odds ratio = 0.73; 95% confidence interval: 0.55-0.98; P value: 0.04). Prolonged preoperative opioid use was associated with increasingly lower rates of achieving stable RTW status (P < 0.05) and RTW within 1 year after surgery (P < 0.05). The odds of achieving successful RTW status were 0.49 (0.25 0.94) for ITO, and 0.40 (0.24-0.68) for LTO compared with STO group. The odds of RTW less than 1 year after surgery were 0.43 (0.21-0.88) for ITO and 0.36 (0.21 0.62) for LTO compared with STO group. Prolonged preoperative opioid use was also associated with increasingly higher net medical costs (P < 0.01), and disability benefits awarded after surgery (P < 0.01). CONCLUSION: Prolonged preoperative opioid use was associated with poor functional outcomes after cervical fusion. STO and earlier inclusion of the surgical approach in the management plan may offer better surgical and functional outcomes after cervical fusion. LEVEL OF EVIDENCE: 3. PMID- 27224886 TI - Transcranial random noise stimulation benefits arithmetic skills. AB - Although arithmetic skills are crucial cognitive abilities, numeric competence impairments affect a significant portion of the young population. These problems produce a high socio-economic cost by negatively affecting scholastic and work performance. The parietal cortex is the brain area that is classically associated with numeric processing, but it is still debated whether other cortical areas are involved, and only a few studies tried to directly assess the causal link between brain and this cognitive function by using transcranial random noise stimulation, tRNS. This non-invasive electric stimulation device has been shown to enhance activity in the underlying cortex. We tested three groups of participants with equivalent arithmetic skills - an arithmetic 'screening' was administered. One group was stimulated by tRNS on the frontal lobe, another on the parietal lobe, and a third group was assigned to the placebo condition. During the stimulation, participants performed a subtraction verification task. To investigate long-term effects of tRNS, the task was repeated seven days later without stimulation. Aside previously-tested (familiar) subtractions, in the second experimental session unfamiliar subtractions were also administered. We found that, compared to placebo, parietal and frontal stimulation significantly reduced reaction times immediately, and enhanced accuracy after seven days. This benefit encompassed both familiar and unfamiliar subtractions. These results suggest that modulation of frontal and parietal cortices may ameliorate basic arithmetic skills by benefitting working memory function. This could open new avenues for neuro restorative applications of brain stimulation. PMID- 27224885 TI - Motivated encoding selectively promotes memory for future inconsequential semantically-related events. AB - Neurobiological models of long-term memory explain how memory for inconsequential events fades, unless these happen before or after other relevant (i.e., rewarding or aversive) or novel events. Recently, it has been shown in humans that retrospective and prospective memories are selectively enhanced if semantically related events are paired with aversive stimuli. However, it remains unclear whether motivating stimuli, as opposed to aversive, have the same effect in humans. Here, participants performed a three phase incidental encoding task where one semantic category was rewarded during the second phase. A memory test 24h after, but not immediately after encoding, revealed that memory for inconsequential items was selectively enhanced only if items from the same category had been previously, but not subsequently, paired with rewards. This result suggests that prospective memory enhancement of reward-related information requires, like previously reported for aversive memories, of a period of memory consolidation. The current findings provide the first empirical evidence in humans that the effects of motivated encoding are selectively and prospectively prolonged over time. PMID- 27224887 TI - Mechanisms of Membrane Pore Formation by Amyloidogenic Peptides in Amyotrophic Lateral Sclerosis. AB - Using unbiased atomic-detailed molecular dynamics simulations, the C-terminal fragments of TDP-43 are observed to aggregate and form disordered-toroidal pores in a lipid bilayer. Cytotoxicity of TDP-43 may be inferred from the observation that the membrane pores catalyze lipid flip-flop between bilayer leaflets and conduct water at high rates. PMID- 27224888 TI - Reply: "Unnecessarily Undergeneralizing Data"-Dermatol Surg 2016;775. PMID- 27224889 TI - Primary Horizontal Closure With Suspension Sutures for Infraorbital Defects to Achieve Aesthetically Superior Closure and Prevent Ectropion. PMID- 27224890 TI - Role of the tumor microenvironment in regulating apoptosis and cancer progression. AB - Apoptosis is a gene-directed program that is engaged to efficiently eliminate dysfunctional cells. Evasion of apoptosis may be an important gate to tumor initiation and therapy resistance. Like any other developmental program, apoptosis can be disrupted by several genetic aberrations driving malignant cells into an uncontrolled progression and survival. For its sustained growth, cancer develops in a complex environment, which provides survival signals and rescues malignant cells from apoptosis. Recent studies have clearly shown a wide interaction between tumor cells and their microenvironment, confirming the influence of the surrounding cells on tumor expansion and invasion. These non malignant cells not only intensify tumor cells growth but also upgrade the process of metastasis. The strong crosstalk between malignant cells and a reactive microenvironment is mediated by soluble chemokines and cytokines, which act on tumor cells through surface receptors. Disturbing the microenvironment signaling might be an encouraging approach for patient's treatment. Therefore, the ultimate knowledge of "tumor-microenvironment" interactions facilitates the identification of novel therapeutic procedures that mobilize cancer cells from their supportive cells. This review focuses on cancer progression mediated by the dysfunction of apoptosis and by the fundamental relationship between tumor and reactive cells. New insights and valuable targets for cancer prevention and therapy are also presented. PMID- 27224891 TI - Organ-specific gene modulation: Principles and applications in cancer research. AB - Microarray and next generation sequencing has led to the exploration of correlated gene patterns and their shared functions. Gene modulators are proteins that alter the activity of transcription factors and influence the expression of their target genes. It is assumed that modulators are dependent on transcription factors. Several algorithms have been developed for the detection of gene modulators. On the other hand, it is becoming increasingly evident that modulators play a crucial role in carcinogenesis by interfering with fundamental biologic processes. Therapeutic gene modulation that is based on artificial modification of endogenous gene functions by designer molecules is an exciting new field of investigation. PMID- 27224892 TI - Carbon ion radiotherapy decreases the impact of tumor heterogeneity on radiation response in experimental prostate tumors. AB - OBJECTIVE: To quantitatively study the impact of intrinsic tumor characteristics and microenvironmental factors on local tumor control after irradiation with carbon ((12)C-) ions and photons in an experimental prostate tumor model. MATERIAL AND METHODS: Three sublines of a syngeneic rat prostate tumor (R3327) differing in grading (highly (-H) moderately (-HI) or anaplastic (-AT1)) were irradiated with increasing single doses of either (12)C-ions or 6 MV photons in Copenhagen rats. Primary endpoint was local tumor control within 300 days. The relative biological effectiveness (RBE) of (12)C-ions was calculated from the dose at 50% tumor control probability (TCD50) of photons and (12)C-ions and was correlated with histological, physiological and genetic tumor parameters. RESULTS: Experimental findings demonstrated that (i) TCD50-values between the three tumor sublines differed less for (12)C-ions (23.6-32.9 Gy) than for photons (38.2-75.7 Gy), (ii) the slope of the dose-response curve for each tumor line was steeper for (12)C-ions than for photons, and (iii) the RBE increased with tumor grading from 1.62 +/- 0.11 (H) to 2.08 +/- 0.13 (HI) to 2.30 +/- 0.08 (AT1). CONCLUSION: The response to (12)C-ions is less dependent on resistance factors as well as on heterogeneity between and within tumor sublines as compared to photons. A clear correlation between decreasing differentiation status and increasing RBE was found. (12)C-ions may therefore be a therapeutic option especially in patients with undifferentiated prostate tumors, expressing high resistance against photons. PMID- 27224893 TI - Alcohol Gel Ingestion Among Homeless Eastern and Central Europeans in London: Assessing the Effects on Cognitive Functioning and Psychological Health. AB - BACKGROUND: Intentional consumption of alcohol-based hand gels has been reported especially amongst non-UK national, alcohol dependent, homeless individuals in London. Whilst alcohol misuse is known to be associated with impaired cognitive functioning and mental health problems, the effects of additional ingestion of alcohol gel are unknown. OBJECTIVES: To explore cognitive and psychological functioning in users who intentionally ingest alcohol gel compared with ethyl alcohol only misusers and controls. METHODS: Male, Central and Eastern European alcohol only misusers, (n = 14; mean age 39 years), alcohol gel users (n = 14; mean age 43 years) and controls (n = 12; mean age 31 years) were recruited from a London Homeless Service during 2013/14. Alcohol misusers, alcohol gel users and controls were compared on the Forwards and Backwards Digit Span Test; Block Design test; Retrospective and Prospective Memory Questionnaire (PRMQ) and the Hospital and Anxiety Depression Scale (HADS). RESULTS: Alcohol gel users performed significantly worse on the Block Design task (p < .01) and PRMQ (p < .01) relative to both alcohol only and control groups, and significantly worse on the digit span relative to controls (p = .01). Both alcohol misusing groups scored comparatively on digit span backwards (p < .01), with both groups performing significantly worse than controls. The alcohol gel group reported significantly higher levels of anxiety relative to controls (p = .02). CONCLUSIONS: Whilst there could be constitutional differences between alcohol misusers who additionally abuse alcohol gel, the findings suggest that alcohol gel ingestion may have a greater impact on psychological functioning than traditional alcohol misuse. PMID- 27224894 TI - Structural model of self-care agency in patients with diabetes: A path analysis of the Instrument of Diabetes Self-Care Agency and body self-awareness. AB - AIM: The aim of this study was to examine a causal model of self-care agency by exploring the relationship between the structure of "body self-awareness" and the structure of the Instrument of Diabetes Self-Care Agency (IDSCA). METHODS: The participants were 353 patients with diabetes. The internal consistency of the six items for body self-awareness was examined by calculating the factor structure using principal factor analysis and Cronbach's alpha. In order to examine the relationship between the seven factors in the IDSCA, a path analysis was conducted. RESULTS: With regard to the factor structure, the factor loading of these five items was 0.511-0.743 (alpha = 0.739). In the path analysis, "body self-awareness" was influenced by the "ability to acquire knowledge" and had a direct effect (0.33) on the "motivation to self-manage", while "motivation to self-manage" had an effect (-0.32) on the "ability to self-manage". The Goodness of-Fit Index was 0.974. CONCLUSION: "Body self-awareness" plays a part in the self-care operation process and serves as an intermediary factor to enable the performance of self-care operations by making the most use of self-care agency. Moreover, striking a proper balance between self-management that is focused on the treatment of diabetes and a person's ability for self-management of diabetes was found to be important. PMID- 27224895 TI - Unintended Consequences of Changing the Definition of Posttraumatic Stress Disorder in DSM-5: Critique and Call for Action. PMID- 27224896 TI - Birth defects in infants born to employees of a microelectronics and business machine manufacturing facility. AB - BACKGROUND: Concerns about solvent releases from a microelectronics/business machine manufacturing facility in upstate New York led to interest in the health of former workers, including this investigation of birth defects in children of male and female employees. METHODS: Children born 1983 to 2001 to facility employees were enumerated and matched to New York State's Congenital Malformations Registry. Reported structural birth defects were compared with numbers expected from state rates (excluding New York City), generating standardized prevalence ratios (SPRs). Exposure assessors classified employees as ever/never potentially exposed at the facility to metals, chlorinated hydrocarbons, and other hydrocarbons during windows critical to organogenesis (female workers) or spermatogenesis (male workers). Among workers, adjusted prevalence ratios were generated to evaluate associations between potential exposures and specific birth defects. RESULTS: External comparisons for structural defects were at expectation for infants of male workers (SPR = 1.01; 95% confidence interval [CI], 0.77-1.29; n = 60) and lower for births to female workers (SPR = 0.84; 95% CI, 0.50-1.33; n = 18). Among full-term infants of male workers, ventricular septal defects (VSDs) were somewhat elevated compared with the general population (SPR = 1.58; 95% CI, 0.99-2.39; n = 22). Within the cohort, potential paternal metal exposure was associated with increased VSD risk (adjusted prevalence ratio = 2.70; 95% CI, = 1.09-6.67; n = 7). CONCLUSION: While overall SPRs were near expectation, paternal exposure to metals (primarily lead) appeared to be associated with increased VSD risk in infants. Take-home of occupational exposures, nonoccupational exposures, and chance could not be ruled out as causes. Case numbers for many defects were small, limiting assessment of the role of occupational exposures. Birth Defects Research (Part A) 106:696-707, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27224897 TI - Melasma and Post Inflammatory Hyperpigmentation: Management Update and Expert Opinion. AB - Dyschromia is a leading cause for cosmetic consultation, especially in those with diverse skin types (mixture of ethnicities) and with the rise of non-core and untrained physicians performing cosmetic procedures. Melasma and post inflammatory hyperpigmentation (PIH) account for the majority of cases and are characterized by pigmented macules and patches distributed symmetrically in sun exposed areas of the forehead, cheeks, and chin in melasma, and irregularly in areas of inflammation or an inciting traumatic event with PIH. Treatment is challenging and focused on a variety of mechanisms to stop, hinder, and/or prevent steps in the pigment production (melanocytic hyperactivity) process, breaking down deposited pigment for internal removal or external release, exfoliating cells to enhance turnover, and decreasing inflammation. Topical lightening therapy in combination with sun protection is essential for potential improvement. The most commonly prescribed and researched topical lightening agents are hydroquinone (HQ), azelaic acid (AzA), and retinoids - although only HQ and a triple combination cream (Tri-Luma(r); fluocinolone acetonide 0.01%, HQ 4%, tretinoin 0.05%) are US FDA-approved for "bleaching of hyperpigmented skin" (HQ) and "melasma" (Tri-Luma(r)). Numerous non-HQ brightening/lightening agents, including antioxidant and botanical cosmeceuticals, have recently flooded the market with improvements that claim less irritant potential, as well as avoiding the stigmata associated with HQ agents such as carcinogenesis and cutaneous ochronosis. Combining topical therapy with procedures such as chemical peels, intense pulsed light (IPL), fractional non-ablative lasers or radiofrequency, pigment lasers (microsecond, picosecond, Q-switched), and microneedling, enhances results. With proper treatment, melasma can be controlled, improved, and maintained; alternatively, PIH can be cured in most cases. Herein, we review treatments for both conditions and provide an opinion on proper management for enhanced results. PMID- 27224898 TI - Off-Label Uses of Topical Calcineurin Inhibitors. AB - Topical calcineurin inhibitors (TCIs) have been proposed as an alternative, long term treatment option to topical corticosteroids, without the side effects commonly associated with steroid use. Currently, TCIs are only approved for treatment of atopic dermatitis in patients 2 years of age or older. This article reviews the off-label uses of TCIs and their efficacy in the treatment of cutaneous diseases. Studies show that TCIs may be effective in treating/managing a variety of skin conditions. The strongest evidence based support on clinical outcomes has been reported for allergic contact dermatitis, lichen planus, psoriasis, seborrheic dermatitis and vitiligo. PMID- 27224899 TI - Zeranol induces COX-2 expression through TRPC-3 activation in the placental cells JEG-3. AB - Transient Receptor Potential Channels (TRPs) are commonly expressed in the reproductive tissues in human. Many female reproductive processes have been associated with these TRPs. The mycotoxin zeranol or alpha-zearalanol is derived from fungi in the Fusarium family. Limited exposure to zeranol appears to be safe. In North America, farmers are using synthetic zeranol to promote growth in livestock. As the health risks of exposure to residual zeranol have not been determined, this practice is disallowed in the European Community. In the present study the cellular calcium levels were elevated in JEG-3 cells treated with zeranol at or above 10nM. Subsequent study indicated that expressions of TRP channels were induced. In response to the calcium flow, ERK, P38 and PKCbeta were activated and COX-2 expression was increased. Specific TRP inhibitors were employed to establish the connection between the ion channel activity and COX-2 expression, and TRPC-3 appeared to be the triggering mechanism. Since the involvement of COX-2 is implicated in placental development and parturition, exposure to this mycotoxin poses a potential threat to pregnant women. PMID- 27224900 TI - Electronic structure of p-type perylene monoimide-based donor-acceptor dyes on the nickel oxide (100) surface: a DFT approach. AB - A p-type dye-sensitized solar cell, where the dye injects a hole into the semiconductor, could be combined with a typical Gratzel cell to create an efficient tandem device. However, the current p-type devices suffer from low efficiency. Here, geometries and electronic structures of four perylenemonoimide based dyes () both as free and adsorbed on the NiO(100) semiconductor surface have been investigated to gain a better understanding of the p-type devices. In particular, the electronic transitions relevant to charge transfer between the dye and the surface have been identified. Excitations have been evaluated using the time-dependent DFT calculations, and the roles of frontier orbitals and band edges in transitions have been assessed. The adsorbed dyes can adopt either upright or slightly tilted geometries depending on the structure of the anchoring group and the binding mode of the dye. The adsorption slightly lowers the NiO band gap, from 4.06 eV to 3.90-3.96 eV, depending on the surface-adsorbate system and the band gaps of the dye molecules by 0.1-0.2 eV. Additionally, the adsorption mode of dye moves the LUMO+1 level down by 0.5 eV. The effective mass of charge carrier holes is significantly smaller at the NiO surface than in the bulk indicating the importance of surface conductivity. We also found that the potential drop, i.e. the driving force for charge transfer from NiO to the dye molecule, depends on the adsorption mode of . PMID- 27224901 TI - An improved method for in vitro morphofunctional analysis of mouse dorsal root ganglia. AB - Sensory neurons in dorsal root ganglia (DRGs) are the first-order neurons along the pathway conveying sensory information from the periphery to the central nervous system. The analysis of the morphological and physiological features of these neurons and their alterations in pathology is the necessary prerequisite to understand pain encoding mechanisms. Here, we describe an in vitro procedure for combined morphofunctional analysis of mouse DRGs. Freshly excised DRGs obtained from adult mice were incubated in collagenase to dissolve the ensheathing connective capsule. The degradation of the connective tissue facilitates both access to the neurons by classical recording glass pipettes and the penetration of primary antibodies for immunohistochemical procedures. The entire DRGs were then imaged using a confocal microscope obtaining a fine 3D representation of their cytoarchitecture without requiring tissue sectioning. Thus, our proposed whole-mount preparation represents a flexible in vitro approach for both functional and phenotypic analysis of DRG neurons by at the same time preserving their neuroanatomical relationships. PMID- 27224902 TI - Phytohormone profiling of the sweet orange (Citrus sinensis (L.) Osbeck) leaves and roots using GC-MS-based method. AB - Phytohormones mainly affect plant development and trigger varied responses to biotic and abiotic stresses. The sensitivity of methods used to profile phytohormones is a vital factor that affects the results. We used an improved GC MS-based method in the selective ion-monitoring (SIM) mode to study the phytohormone profiling in citrus tissues. One extraction solvent mixture and two derivatization reagents were used, methyl chloroformate (MCF) and N-Methyl-N (trimethylsilyl) trifluoroacetamide (MSTFA). The method showed a low limit of detection and low limit of quantification with high extraction recovery percentage and reproducibility. Overall, we detected 13 phytohormones belonging to six different groups. Auxins, SAs, tJA, and ABA were detected after derivatization with MCF while cytokinins and GAs were detected after derivatization with MSTFA. Cytokinins, SAs, and gibberellins were found in all tissues while auxins and tJA were observed only in the leaves. ABA was found in leaves and roots, but not in root tips. The method we used is efficient, precise, and appropriate to study citrus phytohormonal profiles to understand their crosstalk and responses to environmental and biological stresses. PMID- 27224903 TI - Parent Discrimination Predicts Mexican-American Adolescent Psychological Adjustment 1 Year Later. AB - This study examined whether Mexican-American parents' experiences with discrimination are related to adolescent psychological adjustment over time. The extent to which associations between parent discrimination and adolescent adjustment vary as a function of parents' ethnic socialization of their children was also examined. Participants included 344 high school students from Mexican or Mexican-American backgrounds (primarily second generation; ages 14-16 at Wave 1) and their primary caregivers who completed surveys in a 2-year longitudinal study. Results revealed that parent discrimination predicted internalizing symptoms and self-esteem among adolescents 1 year later. Additionally, adolescents were more likely to report low self-esteem in relation to parents' increased experiences of discrimination when parents conveyed ethnic socialization messages to them. PMID- 27224904 TI - Forces and moments delivered by novel, thinner PET-G aligners during labiopalatal bodily movement of a maxillary central incisor: An in vitro study. AB - OBJECTIVE: To evaluate whether overloading of teeth can be avoided by utilizing aligners with reduced thicknesses of 0.4 mm or 0.3 mm. MATERIALS AND METHODS: The experimental setup included an acrylic maxillary jaw model with tooth 11 separated and fixed via a 3-D force-moment transducer to a hexapod for experimental movement. Aligners tested were fabricated on duplicate stone models using commercially available polyethylene terephthalate glycol (PET-G) foils with thicknesses between 0.5 and 0.75 mm, and novel 0.4-mm- and 0.3-mm-thick foils. With the test aligner seated, 11 was bodily displaced in a labiopalatal direction in the range of +/-0.25 mm while all six force-and-moment components exerted on this tooth were registered. RESULTS: With the thinnest commercially available 0.5 mm aligner, median forces of -7.89 N and 8.37 N were measured for the maximum 0.25-mm movement of 11 in a labial and palatal direction, respectively. In comparison, force values were 35% and 71% lower for the novel aligners with a thickness of 0.4 mm and 0.3 mm, respectively. CONCLUSIONS: Novel "leveling" aligners with reduced thickness may reduce overloading of individual teeth during aligner therapy. Due to form instability of 0.3-mm aligners, we suggest a novel sequence of 0.4-0.5-0.75 mm for aligner systems using several foil thicknesses for load graduation within single setup steps. This would combine low stiffness of the initial aligner and relatively constant load increases throughout the treatment. PMID- 27224905 TI - Risk of tuberculosis after lung transplantation: the value of pretransplant chest computed tomography and the impact of mTOR inhibitors and azathioprine use. AB - BACKGROUND: It is necessary to determine the incidence and risk factors for tuberculosis (TB), as well as strategies to assess and treat latent tuberculosis infection (LTBI) in lung transplant recipients. METHODS: A retrospective cohort study of 398 lung transplant recipients was performed. Episodes of TB were studied and the incidence rate was calculated. Logistic regression analysis was used to analyze specific variables as potential risk factors for TB. RESULTS: Median follow-up was 558 days (range 1-6636). Six cases (1.5%) of TB were documented in 398 transplant patients. The incidence density of TB was 406.3 cases/10(5) patient-years (95% confidence interval [CI] 164.7-845), which is higher than in the general population (13.10 cases/10(5) person-years). All cases occurred in the period 1993-2006, when the tuberculin skin test (TST) and treatment of LTBI in positive TST patients were not part of the protocol. Pretransplant computed tomography (CT) showed residual lesions in 50% of patients who developed TB, although the TST was negative and the chest radiograph was inconclusive. Multivariate analysis identified the presence of residual lesions in the pretransplant chest CT (odds ratio [OR] 11.5, 95% CI 1.9-69.1, P = 0.008), use of azathioprine (OR 10.6, 95% CI 1.1-99.1, P = 0.038), and use of everolimus (OR 6.7, 95% CI 1.1-39.8, P = 0.036) as independent risk factors for TB. CONCLUSIONS: Residual lesions in the pretransplant chest CTs and the use of azathioprine and mTOR inhibitors are associated with the risk of TB. PMID- 27224906 TI - PredictSNP2: A Unified Platform for Accurately Evaluating SNP Effects by Exploiting the Different Characteristics of Variants in Distinct Genomic Regions. AB - An important message taken from human genome sequencing projects is that the human population exhibits approximately 99.9% genetic similarity. Variations in the remaining parts of the genome determine our identity, trace our history and reveal our heritage. The precise delineation of phenotypically causal variants plays a key role in providing accurate personalized diagnosis, prognosis, and treatment of inherited diseases. Several computational methods for achieving such delineation have been reported recently. However, their ability to pinpoint potentially deleterious variants is limited by the fact that their mechanisms of prediction do not account for the existence of different categories of variants. Consequently, their output is biased towards the variant categories that are most strongly represented in the variant databases. Moreover, most such methods provide numeric scores but not binary predictions of the deleteriousness of variants or confidence scores that would be more easily understood by users. We have constructed three datasets covering different types of disease-related variants, which were divided across five categories: (i) regulatory, (ii) splicing, (iii) missense, (iv) synonymous, and (v) nonsense variants. These datasets were used to develop category-optimal decision thresholds and to evaluate six tools for variant prioritization: CADD, DANN, FATHMM, FitCons, FunSeq2 and GWAVA. This evaluation revealed some important advantages of the category-based approach. The results obtained with the five best-performing tools were then combined into a consensus score. Additional comparative analyses showed that in the case of missense variations, protein-based predictors perform better than DNA sequence-based predictors. A user-friendly web interface was developed that provides easy access to the five tools' predictions, and their consensus scores, in a user-understandable format tailored to the specific features of different categories of variations. To enable comprehensive evaluation of variants, the predictions are complemented with annotations from eight databases. The web server is freely available to the community at http://loschmidt.chemi.muni.cz/predictsnp2. PMID- 27224907 TI - Protective Effect of Guggulipid in High Fat Diet and Middle Cerebral Artery Occlusion (MCAO) Induced Ischemic Cerebral Injury in Rats. AB - AIM: The role of guggulipid was evaluated in high fat diet and middle cerebral artery occlusion (MCAO) induced ischemic cerebral dysfunctions in rats of either sex. MATERIALS AND METHODS: Ethyl acetate extract of guggul known as guggulipid was prepared and administered to rats. Animals were divided into 9 groups, consisting 6 rats, each receiving different treatments per orally for 8 weeks. Control group rats received normal control diet while rest of the other groups animals were fed high fat diet (HFD) for 8 weeks. Cerebral ischemia was induced for 2 h followed by reperfusion for 22 h. Locomotor activity and grip strength tests were performed immediately after 24 h of reperfusion followed by biochemical estimations and histopathology. RESULTS: Locomotor activity and grip strength were significantly decreased in HFD and HFD fed MCAO groups and improved significantly in pretreatment groups. Cerebral infarction, thiobarbituric acid reactive substances (TBARs), nitric oxide and tumor necrosis factor alfa (TNFalpha) levels were increased, pretreatment of guggulipid alone and with aspirin significantly reduced these markers. Reduced glutathione (GSH), superoxide dismutase (SOD) and catalase, levels were decreased but all drug pretreated groups showed significant improvement in those markers. CONCLUSION: Guggulipid demonstrated neuroprotection owing to its hypolipidemic, antioxidant, anti-inflammatory and anti-thrombotic activities but further research is warranted to confirm its role in cerebral ischemia. PMID- 27224908 TI - Methodological Issues in Conducting Pilot Trials in Chronic Pain as Randomized, Double-blind, Placebo-controlled Studies. AB - BACKGROUND: The efficacy of tapentadol extended release (ER) for managing chronic pain has been demonstrated in large-scale, randomized, controlled, phase 3 studies (N=318-1,030) in patients with chronic osteoarthritis (OA) pain, low back pain (LBP), and pain related to diabetic peripheral neuropathy (DPN), which led to registration in many regions, including the United States and Europe. 2 pilot 12-week, randomized, double-blind, placebo-controlled phase 2 studies of tapentadol ER for chronic pain (OA knee pain or LBP, n=91; DPN or peripheral herpetic neuralgia [PHN] pain; n=91) were conducted in Japan. These small exploratory studies were substantially underpowered compared with the registration trials. METHODS: Patients in both studies were randomized (2:1) to tapentadol ER (25-250 mg) or placebo for 12 weeks (<=6-week titration plus maintenance periods). RESULTS: For the primary efficacy endpoint (change in pain intensity from baseline to last week of treatment; last observation carried forward), both studies failed to differentiate between tapentadol ER and placebo; least-squares mean differences (95% confidence intervals) for tapentadol ER vs. placebo were -0.1 (-1.04, 0.80) in the OA/LBP study and -0.1 (-1.10, 0.99) in the DPN/PHN study. More than 80% of patients took concomitant analgesics during these studies. Tapentadol was well tolerated. CONCLUSIONS: Both studies were associated with methodological issues, including populations with different disease entities, small sample sizes, use of concomitant analgesics, and possible placebo effect that may have led to the failure to differentiate between tapentadol ER and placebo. PMID- 27224909 TI - Expression of transmembrane protein 26 (TMEM26) in breast cancer and its association with drug response. AB - We have previously shown that stromal cells desensitize breast cancer cells to the anti-estrogen fulvestrant and, along with it, downregulate the expression of TMEM26 (transmembrane protein 26). In an effort to study the function and regulation of TMEM26 in breast cancer cells, we found that breast cancer cells express non-glycosylated and N-glycosylated isoforms of the TMEM26 protein and demonstrate that N-glycosylation is important for its retention at the plasma membrane. Fulvestrant induced significant changes in expression and in the N glycosylation status of TMEM26. In primary breast cancer, TMEM26 protein expression was higher in ERalpha (estrogen receptor alpha)/PR (progesterone receptor)-positive cancers. These data suggest that ERalpha is a major regulator of TMEM26. Significant changes in TMEM26 expression and N-glycosylation were also found, when MCF-7 and T47D cells acquired fulvestrant resistance. Furthermore, patients who received aromatase inhibitor treatment tend to have a higher risk of recurrence when tumoral TMEM26 protein expression is low. In addition, TMEM26 negatively regulates the expression of integrin beta1, an important factor involved in endocrine resistance. Data obtained by spheroid formation assays confirmed that TMEM26 and integrin beta1 can have opposite effects in breast cancer cells. These data are consistent with the hypothesis that, in ERalpha positive breast cancer, TMEM26 may function as a tumor suppressor by impeding the acquisition of endocrine resistance. In contrast, in ERalpha-negative breast cancer, particularly triple-negative cancer, high TMEM26 expression was found to be associated with a higher risk of recurrence. This implies that TMEM26 has different functions in ERalpha-positive and -negative breast cancer. PMID- 27224910 TI - Epigallocatechin-3-gallate ameliorates radiation-induced acute skin damage in breast cancer patients undergoing adjuvant radiotherapy. AB - There are few effective treatment options for radiation-induced dermatitis in breast cancer patients. We conducted a single-arm trial to tested the hypothesis that topical epigallocatechin-3-gallate (EGCG) is effective against radiation induced dermatitis in breast cancer patients undergoing radiotherapy. Forty-nine patients participated in this study. The patients underwent mastectomy followed by adjuvant radiotherapy. Topical EGCG was applied daily, starting when grade I dermatitis appeared and ending two weeks after radiotherapy. The maximum dermatitis observed during the EGCG treatment was as follows: Grade 1 toxicity, 71.4% (35 patients); grade 2 toxicity, 28.6% (14 patients); there were no patients with grade 3 or 4 toxicity. The majority of the radiation-induced dermatitis was observed 1 week after the end of radiotherapy. EGCG reduced the pain in 85.7% of patients, burning-feeling in 89.8%, itching in 87.8%, pulling in 71.4%, and tenderness in 79.6%. These findings suggest topical EGCG may be an effective treatment for radiation-induced dermatitis and has acceptable toxicity. PMID- 27224911 TI - Increased translocation of antigens to endosomes and TLR4 mediated endosomal recruitment of TAP contribute to nicotine augmented cross-presentation. AB - Cross-presentation by dendritic cells (DCs) requires surface molecules such as lectin, CD40, langerin, heat shock protein, mannose receptor, mediated endocytosis, the endosomal translocation of internalized antigen, and the relocation of transporter associated with antigen processing (TAP). Although the activation of alpha7 nicotinic acetylcholine receptor (alpha7 nAchR) up-regulate surface molecule expression, augment endocytosis, and enhance cross-presentation, the molecular mechanism of alpha7 nAchR activation-increased cross-presentation is still poorly understood. In this study, we investigated the role of mannose receptor in nicotine-increased cross-presentation and the mechanism that endotoxins orchestrating the recruitment of TAP toward endosomes. We demonstrated that nicotine increase the expressiones of mannose receptor and Toll-like receptor 4 (TLR4) via PI3K-Akt-mTOR-p70S6 pathway. Both endosomal translocation of mannose receptor-internalized antigens and TLR4 sig- naling are necessary for nicotine-augmented cross-presentation and cross-priming. Importantly, the recruitment of TAP toward endosomes via TLR4-MyD88-IRAK4 signaling contributes to nicotine-increased cross-presentation and cross-activation of T cells. Thus, these data suggest that increased recruitment of TAP to Ag-containing vesicles contributes to the superior cross-presentation efficacy of alpha7 nAchR activated DCs. PMID- 27224912 TI - Genetic heterogeneity in primary and relapsed mantle cell lymphomas: Impact of recurrent CARD11 mutations. AB - The genetic mechanisms underlying disease progression, relapse and therapy resistance in mantle cell lymphoma (MCL) remain largely unknown. Whole-exome sequencing was performed in 27 MCL samples from 13 patients, representing the largest analyzed series of consecutive biopsies obtained at diagnosis and/or relapse for this type of lymphoma. Eighteen genes were found to be recurrently mutated in these samples, including known (ATM, MEF2B and MLL2) and novel mutation targets (S1PR1 and CARD11). CARD11, a scaffold protein required for B cell receptor (BCR)-induced NF-kappaB activation, was subsequently screened in an additional 173 MCL samples and mutations were observed in 5.5% of cases. Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR-inhibitor ibrutinib and NF-kappaB inhibitor lenalidomide. Genetic alterations acquired in the relapse samples were found to be largely non-recurrent, in line with the branched evolutionary pattern of clonal evolution observed in most cases. In summary, this study highlights the genetic heterogeneity in MCL, in particular at relapse, and provides for the first time genetic evidence of BCR/NF-kappaB activation in a subset of MCL. PMID- 27224913 TI - Dual PI3K- and mTOR-inhibitor PI-103 can either enhance or reduce the radiosensitizing effect of the Hsp90 inhibitor NVP-AUY922 in tumor cells: The role of drug-irradiation schedule. AB - Inhibition of Hsp90 can increase the radiosensitivity of tumor cells. However, inhibition of Hsp90 alone induces the anti-apoptotic Hsp70 and thereby decreases radiosensitivity. Therefore, preventing Hsp70 induction can be a promising strategy for radiosensitization. PI-103, an inhibitor of PI3K and mTOR, has previously been shown to suppress the up-regulation of Hsp70. Here, we explore the impact of combining PI-103 with the Hsp90 inhibitor NVP-AUY922 in irradiated glioblastoma and colon carcinoma cells. We analyzed the cellular response to drug irradiation treatments by colony-forming assay, expression of several marker proteins, cell cycle progression and induction/repair of DNA damage. Although PI 103, given 24 h prior to irradiation, slightly suppressed the NVP-AUY922-mediated up-regulation of Hsp70, it did not cause radiosensitization and even diminished the radiosensitizing effect of NVP-AUY922. This result can be explained by the activation of PI3K and ERK pathways along with G1-arrest at the time of irradiation. In sharp contrast, PI-103 not only exerted a radiosensitizing effect but also strongly enhanced the radiosensitization by NVP-AUY922 when both inhibitors were added 3 h before irradiation and kept in culture for 24 h. Possible reasons for the observed radiosensitization under this drug-irradiation schedule may be a down-regulation of PI3K and ERK pathways during or directly after irradiation, increased residual DNA damage and strong G2/M arrest 24 h thereafter. We conclude that duration of drug treatment before irradiation plays a key role in the concomitant targeting of PI3K/mTOR and Hsp90 in tumor cells. PMID- 27224914 TI - Significant association between decreased ALDH2 activity and increased sensitivity to genotoxic effects in workers occupationally exposed to styrene. AB - ALDH2 is involved in the metabolism of styrene, a widely used industrial material, but no data are available regarding the influence of this enzyme on the metabolic fate as well as toxic effects of this chemical. In this study, we recruited 329 workers occupationally exposed to styrene and 152 unexposed controls. DNA strand breaks, DNA-base oxidation in leukocytes and urinary 8 hydroxydeoxyguanosine (8-OH-dG) were assayed as biomarkers to measure genotoxic effects. Meanwhile, we examined the genetic polymorphisms, including ALDH2, EXPH1, GSTM1, GSTT1 and CYP2E1, and also analyzed the levels of styrene exposure through detecting urinary styrene metabolites and styrene concentration in air. In terms of DNA damage, the three genotoxic biomarkers were significantly increased in exposed workers as compared with controls. And the styrene-exposed workers with inactive ALDH2 *2 allele were subjected to genotoxicity in a higher degree than those with ALDH2 *1/*1 genotype. Also, lower levels of urinary styrene metabolites (MA + PGA) were observed in styrene-exposed workers carrying ALDH2 *2 allele, suggesting slower metabolism of styrene. The polymorphisms of other enzymes showed less effect. These results suggested that styrene metabolism and styrene-induced genotoxicity could be particularly modified by ALDH2 polymorphisms. The important role of ALDH2 indicated that the accumulation of styrene glycoaldehyde, a possible genotoxic intermediate of styrene, could account for the genotoxicity observed, and should be taken as an increased risk of cancer. PMID- 27224915 TI - FOXP2-positive diffuse large B-cell lymphomas exhibit a poor response to R-CHOP therapy and distinct biological signatures. AB - FOXP2 shares partially overlapping normal tissue expression and functionality with FOXP1; an established diffuse large B-cell lymphoma (DLBCL) oncogene and marker of poor prognosis. FOXP2 is expressed in the plasma cell malignancy multiple myeloma but has not been studied in DLBCL, where a poor prognosis activated B-cell (ABC)-like subtype display partially blocked plasma cell differentiation. FOXP2 protein expression was detected in ABC-DLBCL cell lines, and in primary DLBCL samples tumoral FOXP2 protein expression was detected in both germinal center B-cell-like (GCB) and non-GCB DLBCL. In biopsies from DLBCL patients treated with immunochemotherapy (R-CHOP), >= 20% nuclear tumoral FOXP2 positivity (n = 24/158) correlated with significantly inferior overall survival (OS: P = 0.0017) and progression-free survival (PFS: P = 0.0096). This remained significant in multivariate analysis against either the international prognostic index score or the non-GCB DLBCL phenotype (P < 0.05 for both OS and PFS). Expression of BLIMP1, a marker of plasmacytic differentiation that is commonly inactivated in ABC-DLBCL, did not correlate with patient outcome or FOXP2 expression in this series. Increased frequency of FOXP2 expression significantly correlated with FOXP1-positivity (P = 0.0187), and FOXP1 co-immunoprecipitated FOXP2 from ABC-DLBCL cells indicating that these proteins can co-localize in a multi-protein complex. FOXP2-positive DLBCL had reduced expression of HIP1R (P = 0.0348), which is directly repressed by FOXP1, and exhibited distinct patterns of gene expression. Specifically in ABC-DLBCL these were associated with lower expression of immune response and T-cell receptor signaling pathways. Further studies are warranted to investigate the potential functional cooperativity between FOXP1 and FOXP2 in repressing immune responses during the pathogenesis of high-risk DLBCL. PMID- 27224916 TI - ChREBP promotes the differentiation of leukemia-initiating cells to inhibit leukemogenesis through the TXNIP/RUNX1 pathways. AB - Targeting leukemia-initiating cells (LICs) is the key to eradicating leukemia and preventing its relapse. Recent studies have indicated that metabolic regulation may play a critical role in the maintenance of stemness in LICs, although the detailed mechanisms are poorly understood. Herein, we provide intriguing evidence showing that a glucose-responsive transcription factor, carbohydrate responsive element binding protein (ChREBP), served as a tumor suppressor rather than an oncogene, as previously described, to inhibit the development of acute myeloid leukemia by promoting the differentiation of LICs. Using an MLL-AF9-induced murine leukemia model, we demonstrated that the deletion of ChREBP resulted in the blockage of the differentiation of LICs and significantly reduced survival in ChREBP-null leukemic mice. However, ChREBP was not required for the normal repopulation abilities of hematopoietic stem cells. ChREBP promoted leukemia cell differentiation through the direct inhibition of RUNX1 or the transactivation of TXNIP to downregulate the RUNX1 level and ROS generation. Moreover, knockdown of ChREBP in human leukemia THP1 cells led to markedly enhanced proliferation and decreased differentiation upon PMA treatment. Collectively, we unraveled an unexpected role of ChREBP in leukemogenesis, which may provide valuable clues for developing novel metabolic strategies for leukemia treatment. PMID- 27224917 TI - Utility of patient-derived lymphoblastoid cell lines as an ex vivo capecitabine sensitivity prediction model for breast cancer patients. AB - Capecitabine is commonly used in treating breast cancer; however, therapeutic response varies among patients and there is no clinically validated model to predict individual outcomes. Here, we investigated whether drug sensitivity quantified in ex vivo patients' blood-derived cell lines can predict response to capecitabine in vivo. Lymphoblastoid cell lines (LCLs) were established from a cohort of metastatic breast cancer patients (n = 53) who were prospectively monitored during treatment with single agent capecitabine at 2000 mg/m2/day. LCLs were treated with increasing concentrations of 5'-DFUR, a major capecitabine metabolite, to assess patients' ex vivo sensitivity to this drug. Subsequently, ex vivo phenotype was compared to observed patient disease response and drug induced-toxicities. We acquired an independent cohort of breast cancer cell lines and LCLs derived from the same donors from ATCC, compared their sensitivity to 5' DFUR. As seen in the patient population, we observed large inter-individual variability in response to 5'-DFUR treatment in patient-derived LCLs. Patients whose LCLs were more sensitive to 5'-DFUR had a significantly longer median progression free survival (9-month vs 6-month, log rank p-value = 0.017). In addition, this significant positive correlation for 5'-DFUR sensitivity was replicated in an independent cohort of 8 breast cancer cell lines and LCLs derived from the same donor. Our data suggests that at least a portion of the individual sensitivity to capecitabine is shared between germline tissue and tumor tissue. It also supports the utility of patient-derived LCLs as a predictive model for capecitabine treatment efficacy in breast cancer patients. PMID- 27224918 TI - MCT4 as a potential therapeutic target for metastatic gastric cancer with peritoneal carcinomatosis. AB - Monocarboxylate transporters (MCTs) play a major role in up-regulation of glycolysis and adaptation to acidosis. However, the role of MCTs in gastric cancer (GC) is not fully understood. We investigated the potential utilization of a new cancer therapy for GC. We characterized the expression patterns of the MCT isoforms 1, 2, and 4 and investigated the role of MCT in GC through in vitro and in vivo tests using siRNA targeting MCTs. In GC cell lines, MCT1, 2, and 4 were up-regulated with different expression levels; MCT1 and MCT4 were more widely expressed in GC cell lines compared with MCT2. Inhibition of MCTs by siRNA or AR C155858 reduced cell viability and lactate uptake in GC cell lines. The effect of inhibition of MCTs on tumor growth was also confirmed in xenograft models. Furthermore, MCT inhibition in GC cells increased the sensitivity of cells to radiotherapy or chemotherapy. Compared with normal gastric tissue, no significant alterations of expression levels in tumors were identified for MCT1 and MCT2, whereas a significant increase in MCT4 expression was observed. Most importantly, MCT4 was highly overexpressed in malignant cells of acsites and its silencing resulted in reduced tumor cell proliferation and lactate uptake in malignant ascites. Our study suggests that MCT4 is a clinically relevant target in GC with peritoneal carcinomatosis. PMID- 27224919 TI - Radiosensitization by the investigational NEDD8-activating enzyme inhibitor MLN4924 (pevonedistat) in hormone-resistant prostate cancer cells. AB - Salvage radiotherapy (SRT) is the first-line treatment for prostate cancer patients with biochemical recurrence following radical prostatectomy, and new specific radiosensitizers are in urgent need to enhance SRT effect. MLN4924 (also known as Pevonedistat), a specific inhibitor of NEDD8-activating enzyme, has recently entered phase I/II clinical trials in several malignancies. By inhibiting cullin neddylation, MLN4924 inactivates Cullin-RING ligases (CRL), which have been validated as an attractive radiosensitizing target. In our study, we demonstrate that MLN4924 can be used as a potent radiosensitizer in hormone resistant prostate cancer cells. We found that MLN4924 inhibited cullin neddylation and sensitized prostate cancer cells to irradiation (IR). Mechanistically, MLN4924 enhanced IR-induced G2 cell-cycle arrest, by inducing accumulation of WEE1/p21/p27, three well-known CRL substrates. Importantly, siRNA knockdown of WEE1/p21/p27 partially abrogated MLN4924-induced G2 cell-cycle arrest, indicating a causal role of WEE1/p21/p27 in MLN4924-induced radiosensitization. Further mechanistic studies revealed that induction of DNA damage and apoptosis also contributed to MLN4924 radiosensitization in hormone resistant prostate cancer cells. Our findings lay the foundation for future application of MLN4924 as a potential radiosensitizer in hormone refractory prostate cancer (HRPC). PMID- 27224921 TI - Screen-identified selective inhibitor of lysine demethylase 5A blocks cancer cell growth and drug resistance. AB - Lysine demethylase 5A (KDM5A/RBP2/JARID1A) is a histone lysine demethylase that is overexpressed in several human cancers including lung, gastric, breast and liver cancers. It plays key roles in important cancer processes including tumorigenesis, metastasis, and drug tolerance, making it a potential cancer therapeutic target. Chemical tools to analyze KDM5A demethylase activity are extremely limited as available inhibitors are not specific for KDM5A. Here, we characterized KDM5A using a homogeneous luminescence-based assay and conducted a screen of about 9,000 small molecules for inhibitors. From this screen, we identified several 3-thio-1,2,4-triazole compounds that inhibited KDM5A with low MUM in vitro IC50 values. Importantly, these compounds showed great specificity and did not inhibit its close homologue KDM5B (PLU1/JARID1B) or the related H3K27 demethylases KDM6A (UTX) and KDM6B (JMJD3). One compound, named YUKA1, was able to increase H3K4me3 levels in human cells and selectively inhibit the proliferation of cancer cells whose growth depends on KDM5A. As KDM5A was shown to mediate drug tolerance, we investigated the ability of YUKA1 to prevent drug tolerance in EGFR-mutant lung cancer cells treated with gefitinib and HER2+ breast cancer cells treated with trastuzumab. Remarkably, this compound hindered the emergence of drug-tolerant cells, highlighting the critical role of KDM5A demethylase activity in drug resistance. The small molecules presented here are excellent tool compounds for further study of KDM5A's demethylase activity and its contributions to cancer. PMID- 27224920 TI - Antivascular and antitumor properties of the tubulin-binding chalcone TUB091. AB - We investigated the microtubule-destabilizing, vascular-targeting, anti-tumor and anti-metastatic activities of a new series of chalcones, whose prototype compound is (E)-3-(3''-amino-4''-methoxyphenyl)-1-(5'-methoxy-3',4'-methylendioxyphenyl)-2 methylprop-2-en-1-one (TUB091). X-ray crystallography showed that these chalcones bind to the colchicine site of tubulin and therefore prevent the curved-to straight structural transition of tubulin, which is required for microtubule formation. Accordingly, TUB091 inhibited cancer and endothelial cell growth, induced G2/M phase arrest and apoptosis at 1-10 nM. In addition, TUB091 displayed vascular disrupting effects in vitro and in the chicken chorioallantoic membrane (CAM) assay at low nanomolar concentrations. A water-soluble L-Lys-L-Pro derivative of TUB091 (i.e. TUB099) showed potent antitumor activity in melanoma and breast cancer xenograft models by causing rapid intratumoral vascular shutdown and massive tumor necrosis. TUB099 also displayed anti-metastatic activity similar to that of combretastatin A4-phosphate. Our data indicate that this novel class of chalcones represents interesting lead molecules for the design of vascular disrupting agents (VDAs). Moreover, we provide evidence that our prodrug approach may be valuable for the development of anti-cancer drugs. PMID- 27224922 TI - Inhibition of neddylation regulates dendritic cell functions via Deptor accumulation driven mTOR inactivation. AB - Neddylation, a newly identified post-translational modification, is significant for the activity and stability of target proteins. The exact role of neddylation in the pathogenesis of inflammatory bowel disease, specifically those mediated by dendritic cells (DCs), was still rarely reported. Here, we showed that inhibition of neddylation protected mice from mucosal inflammation. Targeting neddylation also inhibited DC maturation characterized by reduced cytokine production, down regulated costimulatory molecules and suppressed capacity in allogeneic T cell stimulation. Additionally, inactivation of neddylation promotes caspase dependent apoptosis of DCs. These phenomena were attributed to the inactivation of mTOR, which was caused by Cullin-1 deneddylation induced Deptor accumulation. Together, our findings revealed that neddylation inhibition suppressed DC functions through mTOR signaling pathway and provided a potential therapeutic opportunity in inflammatory bowel diseases. PMID- 27224923 TI - The FOXG1/FOXO/SMAD network balances proliferation and differentiation of cortical progenitors and activates Kcnh3 expression in mature neurons. AB - Transforming growth factor beta (TGFbeta)-mediated anti-proliferative and differentiating effects promote neuronal differentiation during embryonic central nervous system development. TGFbeta downstream signals, composed of activated SMAD2/3, SMAD4 and a FOXO family member, promote the expression of cyclin dependent kinase inhibitor Cdkn1a. In early CNS development, IGF1/PI3K signaling and the transcription factor FOXG1 inhibit FOXO- and TGFbeta-mediated Cdkn1a transcription. FOXG1 prevents cell cycle exit by binding to the SMAD/FOXO-protein complex. In this study we provide further details on the FOXG1/FOXO/SMAD transcription factor network. We identified ligands of the TGFbeta- and IGF family, Foxo1, Foxo3 and Kcnh3 as novel FOXG1-target genes during telencephalic development and showed that FOXG1 interferes with Foxo1 and Tgfbeta transcription. Our data specify that FOXO1 activates Cdkn1a transcription. This process is under control of the IGF1-pathway, as Cdkn1a transcription increases when IGF1-signaling is pharmacologically inhibited. However, overexpression of CDKN1A and knockdown of Foxo1 and Foxo3 is not sufficient for neuronal differentiation, which is probably instructed by TGFbeta-signaling. In mature neurons, FOXG1 activates transcription of the seizure-related Kcnh3, which might be a FOXG1-target gene involved in the FOXG1 syndrome pathology. PMID- 27224924 TI - TIM-4 is differentially expressed in the distinct subsets of dendritic cells in skin and skin-draining lymph nodes and controls skin Langerhans cell homeostasis. AB - T cell immunoglobulin and mucin-4 (TIM-4), mainly expressed on dendritic cells (DC) and macrophages, plays an essential role in regulating immune responses. Langerhans cells (LC), which are the sole DC subpopulation residing at the epidermis, are potent mediators of immune surveillance and tolerance. However, the significance of TIM-4 on epidermal LCs, along with other cutaneous DCs, remains totally unexplored. For the first time, we discovered that epidermal LCs expressed TIM-4 and displayed an increased level of TIM-4 expression upon migration. We also found that dermal CD207+ DCs and lymph node (LN) resident CD207-CD4+ DCs highly expressed TIM-4, while dermal CD207- DCs and LN CD207-CD4- DCs had limited TIM-4 expressions. Using TIM-4-deficient mice, we further demonstrated that loss of TIM-4 significantly upregulated the frequencies of epidermal LCs and LN resident CD207-CD4+ DCs. In spite of this, the epidermal LCs of TIM-4-deficient mice displayed normal phagocytic and migratory abilities, comparable maturation status upon the stimulation as well as normal repopulation under the inflamed state. Moreover, lack of TIM-4 did not affect dinitrofluorobenzene-induced contact hypersensitivity response. In conclusion, our results indicated that TIM-4 was differentially expressed in the distinct subsets of DCs in skin and skin-draining LNs, and specifically regulated epidermal LC and LN CD207-CD4+ DC homeostasis. PMID- 27224925 TI - Age-specific effects on the prognosis after surgery for gastric cancer: A SEER population-based analysis. AB - Prognosis of age at diagnosis for gastric cancer (GC) has been investigated in a few studies with inconclusive results. To assess the survival of GC across different age groups, we searched the Surveillance, Epidemiology, and End Results (SEER) database (1988-2010) and identified 10,092 patients undergoing gastrectomy. Analyses of the associations between age and 5-year GC-specific survival (GCSS) were carried out using the Kaplan-Meier method and Cox regression model. When the 50-59 year age group was used as reference group, patients younger than 50 years suffered similar survival rates, and the risk of death increased for patients older than 60 years (hazard ratio [HR], 1.11; 95% confidence interval [CI], 1.02-1.20), peaking for ages > 80 years (HR, 1.60; 95% CI, 1.46-1.76). Overall, HRs of 5-year GCSS increased steadily with age, even when age was evaluated as a continuous variable. We assessed the survival differences associated with age between three groups, using the cut-off ages of 30 and 50 years. Compared with the elderly group, a high survival rate was observed in the mid-age group, but not in the youngest group. Stratified analysis for sex, race, tumor site, histology and clinical stage yielded consistent results. This study shows that the prognosis of GC varies with age, and young GC patients appear to have a favorable GCSS after surgical treatment. Further studies are warranted to verify our findings. PMID- 27224927 TI - Efficacy and pregnancy outcomes of laparoscopic single sheet mesh sacrohysteropexy. AB - AIMS: To evaluate outcomes following laparoscopic single sheet mesh sacrohysteropexy for the management of uterine prolapse. METHODS: One hundred and fifty-nine women underwent the procedure between August 2010 and August 2014. One hundred and forty-four patients completed the follow up assessment. At each visit, the prolapse symptoms were assessed using the prolapse quality-of-life (P QOL) questionnaire and objectively with the use of the Pelvic Organ Prolapse Quantification (POPQ) score. The subjective outcomes were also evaluated with the use of the Patient Global Impression of Improvement (PGII) questionnaires. Perioperative complications and further surgery for prolapse were evaluated. Women who conceived following the procedure were evaluated for pregnancy outcomes and prolapse recurrence. RESULTS: Pre-operatively, 85% (135/159) had uterine prolapse >= stage 2. Postoperatively, 95.1% (137/144) of women had anatomical success rate defined as stage 0 uterine descent. Eighty-two percent (118/144) of women reported cure of prolapse symptoms and feeling "much better" or "very much better" on postoperative PGII assessment. Eight women (5%) became pregnant following the laparoscopic sacrohysteropexy- seven had full term pregnancies and one had a miscarriage. Six out of the seven (86%) had stage 0 apical prolapse and PGII of "much better" at 6 months postpartum. One patient had symptomatic prolapse recurrence and underwent perineorrhaphy at 3 years. CONCLUSION: Laparoscopic single sheet mesh sacrohysteropexy is associated with subjective and objective improvement in prolapse symptoms and QoL that is maintained up to 48 months. Laparoscopic sacrohysteropexy can be offered to women desiring future fertility; however, further research is needed to advise on best surgical approach in women of childbearing age. Neurourol. Urodynam. 36:787-793, 2017. (c) 2016 The Authors. Neurourology and Urodynamics Published by Wiley Periodicals, Inc. PMID- 27224926 TI - Deficiency of myeloid-related proteins 8 and 14 (Mrp8/Mrp14) does not block inflammaging but prevents steatosis. AB - The Mrp8 and Mrp14 proteins (calprotectin) accumulate within tissues during aging and may contribute to chronic inflammation. To address this possibility, we evaluated female calprotectin-deficient Mrp14-KO and wild-type (WT) mice at 5 and 24 months of age. However, there was no evidence that age-related inflammation is blunted in KO mice. Inflammation markers were in fact elevated in livers from old KO mice, and microarray analysis revealed more consistent elevation of genes specifically expressed by B-cells and T-cells. Adipose-specific genes, however, were less consistently elevated in aged KO mice, suggesting an anti-steatosis effect of Mrp8/14 deficiency. Consistent with this, genes decreased by the anti steatosis agent SRT1720 were decreased in old KO compared to old WT mice. Expression of lipid metabolism genes was altered in KO mice at 5 months of age, along with genes associated with development, biosynthesis and immunity. These early-age effects of Mrp8/14 deficiency, in the absence of any external stressor, were unexpected. Taken together, our findings demonstrate a pro-steatosis rather than pro-inflammatory role of calprotectin within the aging liver. This appears to reflect a developmental-metabolic phenotype of Mrp14-KO mice that is manifest at a young age in the absence of pro-inflammatory stimuli. PMID- 27224928 TI - The Quadratojugal of Eryops studied by computed tomography and the morphological variability of foramina and canals in the quadratojugal of basal tetrapods. AB - With respect to its large size and abundance, Eryops is an important representative of Permo-Carboniferous basal tetrapods and one of the best-known large temnospondyl amphibians of this period. This taxon forms a significant component of the Early Permian tetrapod fauna of Texas and New Mexico and here we describe a new record of skull remains, the first one from Brushy Creek (30 km northeast of Seymour) in Texas (Petrolia Formation, Wichita Group; Lower Permian lower Artinskian). Our material, found in 2015, consists of a left nasal, a jaw fragment (premaxilla or maxilla), left quadratojugal fragments, and a partial left mandible. We used computed tomography methods (micro-CT) for imaging both internal and external structures, for the first time, for Eryops. The quadratojugal presented here is exceptional compared to all known basal tetrapods in having four different internal foramina. CT data show that these foramina are interconnected by canals within the bone. This indicates that the morphology of the foramina and the course of the canals in the quadratojugal of basal tetrapods are more variable than hitherto thought. Anat Rec, 299:1073-1079, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27224929 TI - Radiation dose distribution in the teeth, maxilla, and mandible of patients with oropharyngeal and nasopharyngeal tumors who were treated with intensity-modulated radiotherapy. AB - BACKGROUND: The purpose of this study was to evaluate the distribution of the intensity-modulated radiotherapy (IMRT) dose delivered to the teeth, maxilla, and mandible. METHODS: The mean dose (Dmean) and maximum dose (Dmax) of radiation for the maxilla, mandible, and teeth of 63 patients with oropharyngeal (n = 44) or nasopharyngeal (n = 19) tumors were retrospectively evaluated. RESULTS: The posterior regions of the mandible received the highest doses, and the teeth received lower doses than the bones (maximum dose, p < .001; average dose, p < .001). The Dmax (p < .001) and Dmean (p < .001) depended on primary tumor location. The superior bones and teeth of patients with nasopharyngeal tumors received more radiation than those of patients with oropharyngeal tumors. CONCLUSION: A dose distribution map was generated based on the estimated doses received, which could allow prediction of the areas most affected by radiation and facilitate further correlations with dental complications after radiotherapy. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: 1708-1716, 2016. PMID- 27224930 TI - Synaptic proteins predict cognitive decline in Alzheimer's disease and Lewy body dementia. AB - INTRODUCTION: Our objective was to compare the levels of three synaptic proteins involved in different steps of the synaptic transmission: Rab3A, SNAP25, and neurogranin, in three common forms of dementia: Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Parkinson's disease dementia. METHODS: A total of 129 postmortem human brain samples were analyzed in brain regional specific manner exploring their associations with morphologic changes and cognitive decline. RESULTS: We have observed robust changes reflecting synaptic dysfunction in all studied dementia groups. There were significant associations between the rate of cognitive decline and decreased levels of Rab3 in DLB in the inferior parietal lobe and SNAP25 in AD in the prefrontal cortex. Of particular note, synaptic proteins significantly discriminated between dementia cases and controls with over 90% sensitivity and specificity. DISCUSSION: Our findings suggest that the proposition that synaptic markers can predict cognitive decline in AD, should be extended to Lewy body diseases. PMID- 27224931 TI - The Effect of Lipid Emulsion on Pharmacokinetics of Bupivacaine in Rats: Long Chain Triglyceride Versus Long- and Medium-Chain Triglyceride. AB - BACKGROUND: Lipid infusions have been proposed to treat local anesthetic-induced cardiac toxicity. This study compared the effects of long-chain triglyceride (LCT) emulsions with those of long- and medium-chain triglyceride (LCT/MCT) emulsions on the pharmacokinetics of bupivacaine in a rat model. METHODS: After administration of intravenous infusion of bupivacaine at 2 mg.kg.min for 5 minutes in Sprague-Dawley (SD) rats, either Intralipid 20%, an LCT emulsion (LCT group, n = 6), or Lipovenoes 20%, an LCT/MCT emulsion (LCT/MCT group, n = 6), was infused at 2mg.kg.min for 5 minutes. The concentrations of total plasma bupivacaine and bupivacaine that were not bound by lipid (lipid unbound) were measured by a liquid chromatography-tandem mass spectrometric method. A 2 compartmental analysis was performed to calculate the lipid-bound percentage of bupivacaine and its pharmacokinetics. RESULTS: In the LCT group, the clearance (15 +/- 2 vs 10 +/- 1 mL.min.kg, P = .003) was higher; the volume of distribution (0.57 +/- 0.10 vs 0.36 +/- 0.11 L.kg, P = .007) and K21 (0.0100 +/- 0.0018 vs 0.0070 +/- 0.0020 min, P = .021, P' = .032) were larger; and the area under the blood concentration-time curve 0 - t; (605 +/- 82 vs 867 +/- 110 mgL.min, P =.001) and the area under the blood concentration-time curve (0 - infinity) (697 +/- 111 vs 991 +/- 121 mgL.min, P =.001) were less, when compared with the LCT/MCT group. CONCLUSIONS: LCT emulsions are more effective than LCT/MCT emulsions in the metabolism of bupivacaine through demonstration of a superior pharmacokinetic profile. PMID- 27224932 TI - The Antiallodynic Effects of Nefopam Are Mediated by the Adenosine Triphosphate Sensitive Potassium Channel in a Neuropathic Pain Model. AB - BACKGROUND: Nefopam hydrochloride is a centrally acting compound that induces antinociceptive and antihyperalgesic properties in neuropathic pain models. Previous reports have shown that activation of adenosine triphosphate (ATP) sensitive and calcium-activated potassium (KATP and KCa2+) channels has antiallodynic effects in neuropathic pain. In the present study, we evaluated the relationship between potassium channels and nefopam to determine whether the antiallodynic effects of nefopam are mediated by potassium channels in a neuropathic pain model. METHODS: Mechanical allodynia was induced by spinal nerve ligation (SNL) in rats, and the paw withdrawal threshold (PWT) was evaluated by the use of von Frey filaments. Nefopam was administered intraperitoneally before or after SNL. We assessed the relationship between nefopam and intrathecal injection of the KCa2+ channel antagonists apamin and charybdotoxin, and the KATP channel blocker glibenclamide to assess their abilities to reverse the antiallodynic effects of nefopam. In addition, we evaluated whether the KATP channel opener pinacidil had antiallodynic effects and promoted the antiallodynic effects of nefopam. RESULTS: Administration of nefopam before and after SNL induced significant antiallodynic effects (P < .01, respectively), which were significantly reduced by glibenclamide (P < .01). Pinacidil improved the antiallodynic effects of nefopam (P < .01); however, apamin and charybdotoxin had little effects on the antiallodynic properties of nefopam. CONCLUSIONS: The antiallodynic effects of nefopam are increased by a KATP channel agonist and reversed by a KATP channel antagonist. These data suggest that the KATP channel is involved in the antiallodynic effects of nefopam in a neuropathic pain model. PMID- 27224935 TI - Moving beyond the rhetoric of patient input in health technology assessment deliberations. AB - At a health system level, the importance of patient and public input into healthcare decision making is well recognised. Patient and public involvement not only provides a mechanism to legitimise decisions, but also contributes to improved translation of these decisions into practice, ultimately leading to better patient outcomes. Recent reviews in the health technology assessment space have identified the need for, and increased use of, patient input through systematic methodologies. Yet, what does this mean in practical terms? This paper outlines both short- and longer-term options for strengthening patient input into health technology assessment deliberations. This is particularly important given the planned reforms in this area and the commitment to public consultation as part of the reform process. PMID- 27224936 TI - [Catheter-associated complications in the horse - diagnosis and treatment in practice]. AB - Venous diseases due to venous catheters have variable symptoms and clinical progress. They comprise perivenous hematoma, periphlebitis, endophlebitis, phlebothrombosis or septic thrombophlebitis. To diagnose venous disease, a clinical examination (possibillity to distend the vein, swelling, pain, increased skin temperature, and any exudation around the injection site) and an ultrasonographic examination (perivenous tissue, venous wall, venous content) of the vein are performed. Treatment of venous diseases depends on the etiology and pathogenesis and combines the use of anticoagulants (heparin, phenprocoumon), anti-inflammatory and analgesic substances (non-steroidal inflammatory drugs) as well as the application of antibiotics depending on the case. For prevention of venous diseases a careful catheter management is important. This includes in particular the adequate selection of the catheter system (long-term catheter made of polyurethane), catheter care and intensive monitoring. This article reviews the different venous diseases, diagnosis and therapeutic measures in a practical manner. PMID- 27224934 TI - A Novel Device for the Evaluation of Hemostatic Function in Critical Care Settings. AB - Major surgical procedures often result in significant intra- and postoperative bleeding. The ability to identify the cause of the bleeding has the potential to reduce the transfusion of blood products and improve patient care. We present a novel device, the Quantra Hemostasis Analyzer, which has been designed for automated, rapid, near-patient monitoring of hemostasis. The Quantra is based on Sonic Estimation of Elasticity via Resonance Sonorheometry, a proprietary technology that uses ultrasound to measure clot time and clot stiffness from changes in viscoelastic properties of whole blood during coagulation. We present results of internal validation and analytical performance testing of the technology and demonstrate the ability to characterize the key functional components of hemostasis. PMID- 27224937 TI - Innovations in interventional pain management of chronic spinal pain. AB - INTRODUCTION: Interventional pain management dates back to 1901, with significant innovations, which include the definition, literature synthesis, pathophysiology, and technical interventions. AREAS COVERED: Interventional pain management and interventional techniques include neural blockade, neural ablative procedures, spinal cord and peripheral nerve stimulation, intrathecal drug delivery systems, minimally invasive lumbar decompression (MILD(r)), percutaneous endoscopic spinal decompression, and regenerative medicine. In addition, advances are also related to the evidence synthesis of comparative effectiveness research. Expert commentary: Multiple innovations in interventional pain management and potential innovations may reduce costs and improve care and outcomes with proper evidence synthesis and application of principles of evidence-based medicine. Innovations in interventional pain management in managing chronic spinal pain depend on extensive research and appropriate evidence synthesis. Innovations should be developed in conjunction with health care policy based on principles of evidence based medicine. PMID- 27224939 TI - Turn-On Fluorogenic and Chromogenic Detection of Small Aromatic Hydrocarbon Vapors by a Porous Supramolecular Host. AB - Benzene, toluene, ethylbenzene, the isomers of xylene, and trimethylbenzene are harmful volatile organic compounds and pose risks to human health and the environment. However, there are currently no effective chemosensors for vapors of these compounds. A porous supramolecular host for turn-on fluorogenic and chromogenic detection of the vapors of small aromatic hydrocarbons is presented. The host was constructed from a naphthalenediimide derivative that was supramolecularly connected to tris(pentafluorophenyl)borane. The amorphous powder form of the host allowed for effective accommodation of vapors of small aromatic hydrocarbons, resulting in a guest-dependent fluorescence emission. Increases in the fluorescence yield of 76-, 46-, and 37-fold were observed with toluene, benzene, and m-xylene, respectively. Negligible responses were obtained with common organic solvents. This simple supramolecular host could be applied as a useful sensor of small aromatic hydrocarbon vapors. PMID- 27224940 TI - Psychopathology and behavior problems in children and adolescents with Williams syndrome: Distinctive relationships with cognition. AB - Several studies have documented the high prevalence of psychopathology and behavior problems in Williams syndrome (WS). However, the links between cognitive development and such symptoms need further clarification. Our study aims to expand current knowledge on levels of behavior problems and its links to cognition in a sample of Brazilian individuals with WS. A total of 25 children and adolescents with WS and their parents participated in this study. The participants' IQs were assessed with the Wechsler Scales of Intelligence (for children or adults) and parental reports of psychopathology/behavior problems were collected using the Child Behavior Checklist (CBCL). The presence of clinically significant attention problems was a main feature in our sample of children and adolescents with WS. In the children, higher IQ scores were found to be significantly associated with less externalizing problems, while in the adolescents cognitive abilities were found to be associated with less internalizing symptoms. These results provide further insight into the links between psychopathology and behavior problems and cognitive abilities in WS, and suggest the need to take age into consideration when analyzing such relationships. PMID- 27224938 TI - Decoding transcriptional enhancers: Evolving from annotation to functional interpretation. AB - Deciphering the intricate molecular processes that orchestrate the spatial and temporal regulation of genes has become an increasingly major focus of biological research. The differential expression of genes by diverse cell types with a common genome is a hallmark of complex cellular functions, as well as the basis for multicellular life. Importantly, a more coherent understanding of gene regulation is critical for defining developmental processes, evolutionary principles and disease etiologies. Here we present our current understanding of gene regulation by focusing on the role of enhancer elements in these complex processes. Although functional genomic methods have provided considerable advances to our understanding of gene regulation, these assays, which are usually performed on a genome-wide scale, typically provide correlative observations that lack functional interpretation. Recent innovations in genome editing technologies have placed gene regulatory studies at an exciting crossroads, as systematic, functional evaluation of enhancers and other transcriptional regulatory elements can now be performed in a coordinated, high-throughput manner across the entire genome. This review provides insights on transcriptional enhancer function, their role in development and disease, and catalogues experimental tools commonly used to study these elements. Additionally, we discuss the crucial role of novel techniques in deciphering the complex gene regulatory landscape and how these studies will shape future research. PMID- 27224941 TI - Evaluation of the impact of 16-dehydropregnenolone on the activity and expression of rat hepatic cytochrome P450 enzymes. AB - 16-dehydropregnenolone (DHP) is a promising novel antihyperlipidemic agent developed and patented by Central Drug Research Institute (CDRI), India. The purpose of the present study was to investigate whether DHP influences the activities and mRNA expression of hepatic drug-metabolizing cytochrome P450 (CYP) enzymes (CYP1A2, CYP2C11, CYP2D2, CYP2E1 and CYP3A1) in Sprague-Dawley (SD) rats. A cocktail suspension of CYP probe substrates which contained caffeine (CYP1A2), tolbutamide (CYP2C11), dextromethorphan (CYP2D2), chlorzoxazone (CYP2E1) and dapsone (CYP3A1) was administered orally on eighth- or fifteenth-day to rats pre treated with DHP intragastrically at a dose of 36 and 72mg/kg for one week and two weeks. The concentrations of probe drugs in plasma were estimated by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Alongside, the effect of DHP on CYPs activity and mRNA expression levels were assayed in isolated rat liver microsomes and by real-time reverse transcription-polymerase chain reaction (RT PCR), respectively. DHP had significant inducing effects on CYP1A2, 2C11, 2D2 and 2E1 with no effect on CYP3A1 in dose- and time-dependent manner, as revealed from the pharmacokinetic profiles of the probe drugs in rats. In-vitro microsomal activities and mRNA expression results were in good agreement with the in-vivo pharmacokinetic results. Collectively, the results unveiled that DHP is an inducer of rat hepatic CYP enzymes. Hence, intense attention should be paid when DHP is co-administered with drugs metabolized by CYP1A2, 2C11, 2D2 and 2E1, which might result in drug-drug interactions and therapeutic failure. PMID- 27224942 TI - Views of HIV-negative partners in heterosexual serodiscordant relationships regarding HIV pre-exposure prophylaxis: a qualitative study. AB - Background: Pre-exposure prophylaxis (PrEP) may be an effective option for HIV prevention among heterosexual serodiscordant couples. However, there are knowledge gaps in social research about PrEP in heterosexual serodiscordant relationships, including motivations and barriers to its use and possible impacts of PrEP uptake on the sexual practices of these couples. The aim of this study was to explore the views of HIV-negative men and women in stable serodiscordant heterosexual relationships about the possible use of PrEP. Methods: Semi structured interviews were used to understand participants' views on the use of PrEP. Interviews were conducted face-to-face or by telephone and transcribed verbatim for thematic analysis. Results: In total, 13 HIV-negative partners were interviewed; six men and seven women. Participants demonstrated a high interest in the use of PrEP for conception. PrEP was also considered an option for general HIV prevention, although men saw more benefits for this use than women. Participants' main concerns around PrEP usage were about cost, efficacy, daily adherence and side-effects. HIV-positive partner support is likely to play a central role for PrEP uptake and adherence. Conclusions: This study is one of the first studies to explore the views of HIV-negative heterosexual partners in serodiscordant relationships around the use of PrEP while trying to conceive, as well as for general HIV prevention. These study results provide new insights for the further development of guidelines governing the use of PrEP for serodiscordant couples. PMID- 27224943 TI - Management of Progressive Myopia. PMID- 27224944 TI - Failed Goniotomy Surgery for Congenital Glaucoma. PMID- 27224945 TI - Hop to It: Add Blue to Your Blues. PMID- 27224946 TI - Use of Anterior Segment Optical Coherence Tomography to Determine the Position of the Horizontal and Vertical Extraocular Muscles. PMID- 27224947 TI - Anterior Segment Optical Coherence Tomography of the Horizontal and Vertical Extraocular Muscles With Measurement of the Insertion to Limbus Distance. AB - PURPOSE: To assess the possibility of determining the insertion distance from the limbus of horizontal and vertical extraocular rectus muscles with anterior segment optical coherence tomography (AS-OCT). METHODS: The right eyes of 46 patients underwent AS-OCT. The horizontal and vertical extraocular rectus muscle insertion distances from the limbus were measured in a masked fashion by two pediatric ophthalmologists. RESULTS: Forty-two lateral rectus, 43 medial rectus, 35 inferior rectus, and 40 superior rectus muscles of the right eyes of 46 patients were included. Insertion to limbus measurements (mean +/- SD) were as follows: lateral rectus = mean 6.8 +/- 0.7 mm, range = 4.8 to 8.4 mm; medial rectus = mean 5.7 +/- 0.8 mm, range = 4.3 to 7.8 mm; inferior rectus = mean 6.0 +/- 0.6 mm, range = 4.8 to 7.0 mm; superior rectus = mean 6.8 +/- 0.6 mm, range = 5.5 to 8.1 mm. The intraobserver and interobserver correlation coefficients for the insertion to limbus measurements of all four rectus muscles exceeded 0.75 (excellent correlation). CONCLUSIONS: The study showed that AS-OCT is capable of imaging all four of the rectus muscle insertions and measuring the insertion to limbus distance, and is the second AS-OCT study to image the superior and inferior rectus muscle insertions. The insertion to limbus measurements between examiners and on repeat measurements were consistent and reproducible. The ability to accurately image extraocular rectus muscle insertions may have future implications for the preoperative procedure planning in patients who have had previous surgery. [J Pediatr Ophthalmol Strabismus. 2016;53(3):141-145.]. PMID- 27224948 TI - Prospective Evaluation of Photoscreeners in the Pseudophakic Eyes of Children. AB - PURPOSE: To compare refractive data of Plusoptix AO9 (Plusoptix, Inc., Atlanta, GA) and Spot (Welch Allyn, Skaneateles Falls, NY) photoscreeners with retinoscopy in pseudophakic eyes of children. METHODS: In this prospective study, patients underwent testing with the Plusoptix and Spot photoscreeners prior to their examination by a pediatric ophthalmologist masked to the results of both photoscreeners. Data including testability and estimated refractions were entered into a Research Electronic Data Capture database for statistical analysis. For bilateral pseudophakia, one randomly selected eye was included in the analysis. RESULTS: Forty-four eyes were included, with a mean age of 7.4 +/- 4.8 years. Refraction was estimated in all eyes using retinoscopy, but a refractive estimate was obtained in only 11.3% (5 of 44) of eyes using the Plusoptix binocularly and 63.6% (28 of 44) of eyes using the Spot. Compared to retinoscopy, the Plusoptix showed a mean difference of -0.80, 0.10, and -0.75 diopters (D) for sphere, cylinder, and spherical equivalent, respectively (P > .05). Comparable values for the Spot were 0.18, -0.26, and 0.05 D, respectively (P > .05). Compared to retinoscopy, the Plusoptix showed a mean absolute difference of 1.30, 0.80, and 1.25 D for sphere, cylinder, and spherical equivalent, respectively (P > .05). Similar values for the Spot were 1.38, 0.88, and 0.97 D, respectively (P > .05). CONCLUSIONS: Refraction was estimated in a higher number of pseudophakic eyes of children using the Spot as compared to the Plusoptix. The Spot may be useful to evaluate myopic shift in pseudophakic eyes of children. [J Pediatr Ophthalmol Strabismus. 2016;53(3):146-149.]. PMID- 27224949 TI - A New Surgical Treatment Option for Chronic Total Oculomotor Nerve Palsy: A Modified Technique for Medial Transposition of Split Lateral Rectus Muscle. AB - PURPOSE: To describe a new surgical modified procedure in patients with chronic total oculomotor nerve palsy and to evaluate the results of this procedure. METHODS: Eight eyes of 6 consecutive patients who underwent strabismus surgery due to chronic total oculomotor nerve palsy were enrolled in the study. The lateral rectus muscle was split into two halves and disinserted from the sclera. The upper half of the muscle was passed under the superior rectus muscle and the inferior half of the muscle was passed under the inferior rectus muscle. The two halves of the muscle were moved to the medial rectus muscle insertion area and were sutured to sclera near the insertion. Additional medial rectus resections were made in the undercorrected patients. RESULTS: The mean age was 21.8 +/- 12.1 years (range: 11 to 42 years). Postoperatively, 4 of 6 patients had stable horizontal deviations; 1 had orthophoria, 2 had 10 prism diopters (PD) of exotropia, and 1 had 10 PD of esotropia. However, 2 cases had 25 and 30 PD of undercorrection. Additional medial rectus resections were made in these undercorrected patients and horizontal deviations reduced to 15 and 20 PD of exotropia, respectively. The mean primary position horizontal deviation, which was 74.1 +/- 10.2 PD before the surgeries, reduced to 10.8 +/- 6.6 PD after the surgeries (P < .001). CONCLUSIONS: The authors described a new and relatively simple modified surgical procedure for the treatment of chronic total ocular nerve palsy and reached satisfactory outcomes. Further studies with larger sample sizes are warranted. [J Pediatr Ophthalmol Strabismus. 2016;53(3):150-154.]. PMID- 27224950 TI - Myectomy of the Extraocular Muscles Without Reattachment as a Surgical Treatment for Horizontal Nystagmus. AB - PURPOSE: To report the comparative clinical findings for two nystagmus procedures in two consecutive case series: the Sinskey anterior extirpation procedure (SAEP) and a modification, myectomy without reattachment (MWR). METHODS: Twenty consecutive patients underwent the SAEP and 19 underwent MWR. The SAEP is a snare assisted unmeasured deep myectomy, whereas MWR is a measured myectomy at posterior Tenon's fascia. All patients underwent comprehensive ophthalmologic and orthoptic examination with infrared videonystagmography. Binocular best corrected visual acuity, nystagmus amplitude, alignment, and versions outcomes were measured. RESULTS: The highest percentage of patients experiencing two or more lines of improvement in distance and near acuity was in the SAEP group, who were younger than 10 years and had no ocular comorbidity (100%). Distance and near acuity improved at least one line in 71% and 86% of patients in the SAEP group and 72% and 61% in the MWR group, respectively. In both groups, patients younger than 10 years had the best acuity gains. Average nystagmus amplitude was reduced 76.3% (SAEP) and 68% (MWR). Horizontal versions were more compromised in the SAEP group and one patient experienced intraoperative orbital bleeding. Patients requiring reoperation for strabismus numbered 5 of 20 (20%) in the SAEP and 3 of 19 (16%) in the MWR groups. CONCLUSIONS: Similar to SAEP, the MWR procedure reduces nystagmus amplitudes and improves visual acuity but with less limitation of versions, risk of intraoperative bleeding, and risk of postoperative strabismus. Data suggest that early surgery (for patients younger than 10 years) can have a greater beneficial effect on postoperative visual acuity. [J Pediatr Ophthalmol Strabismus. 2016;53(3):156-166.]. PMID- 27224951 TI - Comparison of Anisometropia and Refractive Status in Children With Unilateral and Bilateral Congenital Nasolacrimal Duct Obstruction. AB - PURPOSE: To evaluate and compare the refractive state in children diagnosed as having unilateral or bilateral congenital nasolacrimal duct obstruction (CNLDO). This study also compares how the laterality of CNLDO affects the refractive state of the patients. METHODS: This descriptive cross-sectional study includes consecutive children with unilateral and bilateral CNLDO over a period of 1 year. Cycloplegic refraction was performed on each child who presented with CNLDO followed by appropriate plans for treatment. The refractive errors of patients with unilateral and bilateral CNLDO were compared. RESULTS: One hundred sixty-one patients with unilateral CNLDO (mean age: 29 +/- 19.93 months) and 46 with bilateral CNLDO (mean age: 30 +/- 16.21 months) were enrolled from August 2013 to July 2014. The rate of the anisometropia (>= 1 diopters [D] difference between the two eyes) was 13.7% (n = 22) and 8.6% (n = 4) in patients with unilateral and bilateral CNLDO, respectively. Interocular difference was significant in terms of spherical equivalent (P < .01) but not cylindrical refractive error in patients with unilateral CNLDO. Patients with bilateral CNLDO had insignificant interocular differences in terms of spherical equivalent and cylindrical refractive errors (P > .05). CONCLUSIONS: Unilateral CNLDO is associated with statistically significant anisometropia compared to bilateral CNLDO, which predisposes children with unilateral CNLDO to amblyopia. It is vital to perform cycloplegic refraction routinely and counsel parents regarding regular follow ups. [J Pediatr Ophthalmol Strabismus. 2016;53(3):168-172.]. PMID- 27224952 TI - The Impact of the Transition to an Electronic Medical Record on Patient Perceptions in a Pediatric Ophthalmology Practice. AB - PURPOSE: To assess the impact of the transition from traditional paper-based medical records to electronic medical records in a pediatric ophthalmology practice at a tertiary care center. METHODS: A prospective, cross-sectional survey was completed at three time points: 2 weeks prior to (phase 1), 2 weeks after (phase 2), and 3 months after (phase 3) the electronic medical record transition. The survey consisted of 10 Likert-type scaled questions assessing patient satisfaction and two free response questions estimating the wait time, which was completed by patients or parents/guardians whose child/children (younger than 18 years) had an appointment in the pediatric ophthalmology and strabismus clinic. Satisfaction scores and waiting times were compared within each phase and across phases and between different appointment types. RESULTS: A total of 382 surveys were collected: 158 from phase 1, 68 from phase 2, and 156 from phase 3. Overall, patient satisfaction was high at all three time points. Patients' estimates of waiting time compared to actual waiting time were not significantly different at any phase; however, patients' estimates of time spent with the physician were significantly underestimated in phase 1 (20 vs 25 minutes, P = .04) and were correct or overestimated in phase 3. CONCLUSIONS: Patients were satisfied with the service regardless of the use of paper charts or electronic medical records. The electronic medical record system does not seem to improve patients' waiting time, but has a significant impact on the perception of time spent with the physician. [J Pediatr Ophthalmol Strabismus. 2016;53(3):173 178.]. PMID- 27224953 TI - Facilitated Versus Self-guided Training of Non-ophthalmologists for Grading Pre plus and Plus Disease Using Fundus Images for Retinopathy of Prematurity Screening. AB - PURPOSE: Retinopathy of prematurity (ROP) is an important cause of preventable blindness; barriers to screening necessitate novel approaches. Although trained non-ophthalmologists can accurately grade retinal images for ROP, effective training protocols are not established. This study compares the effectiveness of facilitated versus self-guided training of non-ophthalmologists for grading retinal images for pre-plus or plus disease in ROP. METHODS: Forty-eight undergraduate and graduate students were trained to grade retinal images for the presence of pre-plus or plus disease. Students were randomly assigned to one of two training protocols. Both used identical electronic slideshows: one was guided by an in-person facilitator and the other was self-guided. After completing their respective training, students proficient in grading pre-plus and plus disease graded images in a telemedicine screening scenario. Accuracy of grading was compared to the reference standard of clinical examination. RESULTS: Eighty-three percent (40 of 48) of trained students (91% in the facilitated vs 77% in the self guided group, P = .26) were proficient and qualified to grade the ROP telemedicine screening scenario. Median accuracy for grading normal, pre-plus, or plus disease was 69% (70% in the facilitated vs 68% in the self-guided group, P = .91). When considering the designation of pre-plus or plus disease by graders as a screening test for detecting plus disease (confirmed on clinical examination), the median sensitivity and specificity of all students were 95% and 64%, respectively. CONCLUSIONS: Both facilitated and self-guided teaching protocols yielded similar performance in ROP image grading for pre-plus or plus disease. Self-guided training protocols may be adequate to train non-ophthalmologists to grade retinal images for pre-plus and plus disease with high sensitivity. [J Pediatr Ophthalmol Strabismus. 2016;53(3):179-185.]. PMID- 27224954 TI - The Degree of Anisocoria in Pediatric Patients With Horner Syndrome When Compared to Children Without Disease. AB - PURPOSE: To study the magnitude of anisocoria in pediatric patients using the plusoptiX A08 (plusoptiX GmbH, Nuremberg, Germany) photoscreener as compared to a literature review of pediatric patients with known Horner syndrome to determine if anisocoria alone should raise suspicion for the diagnosis. METHODS: The medical records of 592 consecutive patients, neonates to 9 years old, were collected and analyzed. All patients had complete ophthalmic examinations that included photoscreening with the plusoptiX A08. Data included age, pupil sizes, and anisocoria. A complete literature search of documented pupillary size in pediatric patients with the diagnosis of Horner syndrome was performed. This was then compared to the normative pediatric pupil data from the study. RESULTS: Of the 592 children without Horner syndrome, 372 had an anisocoria of 0.1 to 0.5 mm (62.84%), 167 had an anisocoria of 0.6 to 1.2 mm (28.16%), and 21 had an anisocoria of 1.3 mm or greater (3.70%). There was no correlation between increasing age and severity of anisocoria (P = .55). For pediatric patients with a diagnosis of Horner syndrome, the average level of anisocoria was 1.37 mm in room light and 2 mm in darkness. In room light, three children had anisocoria of 0.1 to 0.5 mm (9.4%), 14 had anisocoria of 0.6 to 1.2 mm (43.8%), and 15 had anisocoria of 1.3 mm or greater (46.9%). In darkness, the level of anisocoria increased in 19 patients, causing the first category, 0.1 to 0.5 mm, to include 1 patient (3.1%), the second group to include 5 patients (15.6%), and the last group to include 26 patients (81.3%). Other associated signs/symptoms included ptosis (100%), heterochromia (28.1%), anhidrosis (9.4%), straight hair on affected/curly on unaffected side (9.4%), and neck mass (6.3%). In 37.5% of cases, imaging results were negative and no specific etiology was determined. CONCLUSIONS: In a study of 592 children without Horner syndrome, the average pupillary size increased with age, but the degree of anisocoria remained stable with increasing age. Over half of the children studied had anisocoria up to 0.5 mm (62.84%), but rarely had anisocoria greater than 1.3 mm (3.70%). In children with a diagnosis of Horner syndrome, the majority had anisocoria greater than 1.3 mm, with the discrepancy in pupil size becoming more apparent in low levels of light intensity. Anisocoria greater than 1.3 mm is unlikely to be physiologic in a child; therefore, he or she should be carefully evaluated for other localizing signs, such as ptosis, anhidrosis, and neck mass. [J Pediatr Ophthalmol Strabismus. 2016;53(3):186-189.]. PMID- 27224955 TI - Tubulointerstitial Nephritis and Uveitis Syndrome Associated With Human Papillomavirus Vaccine. PMID- 27224956 TI - Pilomatrixoma of the Eyebrow in an 11-Year-Old Child. PMID- 27224958 TI - Nanocrystal Size-Dependent Efficiency of Quantum Dot Sensitized Solar Cells in the Strongly Coupled CdSe Nanocrystals/TiO2 System. AB - Light absorption and electron injection are important criteria determining solar energy conversion efficiency. In this research, monodisperse CdSe quantum dots (QDs) are synthesized with five different diameters, and the size-dependent solar energy conversion efficiency of CdSe quantum dot sensitized solar cell (QDSSCs) is investigated by employing the atomic inorganic ligand, S(2-). Absorbance measurements and transmission electron microscopy show that the diameters of the uniform CdSe QDs are 2.5, 3.2, 4.2, 6.4, and 7.8 nm. Larger CdSe QDs generate a larger amount of charge under the irradiation of long wavelength photons, as verified by the absorbance results and the measurements of the external quantum efficiencies. However, the smaller QDs exhibit faster electron injection kinetics from CdSe QDs to TiO2 because of the high energy level of CBCdSe, as verified by time-resolved photoluminescence and internal quantum efficiency results. Importantly, the S(2-) ligand significantly enhances the electronic coupling between the CdSe QDs and TiO2, yielding an enhancement of the charge transfer rate at the interfacial region. As a result, the S(2-) ligand helps improve the new size-dependent solar energy conversion efficiency, showing best performance with 4.2-nm CdSe QDs, whereas conventional ligand, mercaptopropionic acid, does not show any differences in efficiency according to the size of the CdSe QDs. The findings reported herein suggest that the atomic inorganic ligand reinforces the influence of quantum confinement on the solar energy conversion efficiency of QDSSCs. PMID- 27224957 TI - Orthogonally Functionalizable Polyurethane with Subsequent Modification with Heparin and Endothelium-Inducing Peptide Aiming for Vascular Reconstruction. AB - Surface coimmobilization modifications of blood-contacting devices with both antithrombogenic moieties and endothelium-inducing biomolecules may create a synergistic effect to improve their performance. However, it is difficult to perform covalent dual-functionalization with both biomolecules on the surface of normally used synthetic polymeric substrates. Herein, we developed and characterized an orthogonally functionalizable polymer, biodegradable elastic poly(ester urethane)urea with disulfide and amino groups (PUSN), which was further fabricated into electropun fibrous scaffolds and surface modified with heparin and endothelial progenitor cells (EPC) recruiting peptide (TPS). The modification effects were assessed through platelet adhesion, EPC, and HUVEC proliferation. Results showed the dual modified PUSN scaffolds demonstrated a synergistic effect of reduced platelet deposition and improved EPC proliferation in vitro study, and demonstrated their potential application in small diameter vascular regeneration. PMID- 27224959 TI - Thermally Conductive-Silicone Composites with Thermally Reversible Cross-links. AB - Thermally conductive-silicone composites that contain thermally reversible cross links were prepared by blending diene- and dienophile-functionalized polydimethylsiloxane (PDMS) with an aluminum oxide conductive filler. This class of thermally conductive-silicones are useful as thermal interface materials (TIMs) within Information Technology (IT) hardware applications to allow rework of valuable components. The composites were rendered reworkable via retro Diels Alder cross-links when temperatures were elevated above 130 degrees C and required little mechanical force to remove, making them advantageous over other TIM materials. Results show high thermal conductivity (0.4 W/m.K) at low filler loadings (45 wt %) compared to other TIM solutions (>45 wt %). Additionally, the adhesion of the material was found to be ~7 times greater at lower temperatures (25 degrees C) and ~2 times greater at higher temperatures (120 degrees C) than commercially available TIMs. PMID- 27224960 TI - Improvement of Charge Collection and Performance Reproducibility in Inverted Organic Solar Cells by Suppression of ZnO Subgap States. AB - Organic solar cells (OSCs) with inverted structure usually exhibit higher power conversion efficiency (PCE) and are more stable than corresponding devices with regular configuration. Indium tin oxide (ITO) surface is often modified with solution-processed low work function metal oxides, such as ZnO, serving as the transparent cathode. However, the defect-induced subgap states in the ZnO interlayer hamper the efficient charge collection and the performance reproducibility of the OSCs. In this work, we demonstrate that suppression of the ZnO subgap states by modification of its surface with an ultrathin Al layer significantly improves the charge extraction and performance reproducibility, achieving PCE of 8.0%, which is ~15% higher than that of a structurally identical control cell made with a pristine ZnO interlayer. Light intensity-dependent current density-voltage characteristic, photothermal deflection spectroscopy, and X-ray photoelectron spectroscopy measurements point out the enhancement of charge collection efficiency at the organic/cathode interface, due to the suppression of the subgap states in the ZnO interlayer. PMID- 27224961 TI - Designing NHC-Copper(I) Dipyridylamine Complexes for Blue Light-Emitting Electrochemical Cells. AB - This study presents the influence of various substituents on the photophysical features of heteroleptic copper(I) complexes bearing both N-heterocyclic carbene (NHC) and dipyridylamine (dpa = dipyridylamine skeleton corresponding to ligand L1) ligands. The luminescent properties have been compared to our recently reported archetypal blue emitting [Cu(IPr)(dpa)][PF6] complex. The choice of the substituents on both ligands has been guided to explore the effect of the electron donor/acceptor and "push-pull" on the emission wavelengths and photoluminescence quantum yields. A selection of the best candidates in terms of their photophysical features were applied for developing the first blue light emitting electrochemical cells (LECs) based on copper(I) complexes. The device analysis suggests that the main concern is the moderate redox stability of the complexes under high applied driving currents, leading to devices with moderate stabilities pointing to a proof-of-concept for further development. Nevertheless, under low applied driving currents the blue emission is stable, showing performance levels competitive to those reported for blue LECs based on iridium(III) complexes. Overall, this work provides valuable guidelines to tackle the design of enhanced NHC copper complexes for lighting applications in the near future. PMID- 27224962 TI - In Situ Fabrication of CoS and NiS Nanomaterials Anchored on Reduced Graphene Oxide for Reversible Lithium Storage. AB - CoS and NiS nanomaterials anchored on reduced graphene oxide (rGO) sheets, synthesized via combination of hydrothermal with sulfidation process, are studied as high-capacity anode materials for the reversible lithium storage. The obtained CoS nanofibers and NiS nanoparticles are uniformly dispersed on rGO sheets without aggregation, forming the sheet-on-sheet composite structure. Such nanoarchitecture can not only facilitate ion/electron transport along the interfaces, but also effectively prevent metal-sulfide nanomaterials aggregation during the lithium reactions. Both the rGO-supported CoS nanofibers (NFs) and NiS nanoparticles (NPs) show superior lithium storage performance. In particular, the CoS NFs-rGO electrodes deliver the discharge capacity as high as 939 mA h g(-1) after the 100th cycle at 100 mA g(-1) with Coulombic efficiency above 98%. This strategy for construction of such composite structure can also synthesize other metal-sulfide-rGO nanomaterials for high-capacity lithium-ion batteries. PMID- 27224963 TI - Large Grained Perovskite Solar Cells Derived from Single-Crystal Perovskite Powders with Enhanced Ambient Stability. AB - In this study, we demonstrate the large grained perovskite solar cells prepared from precursor solution comprising single-crystal perovskite powders for the first time. The resultant large grained perovskite thin film possesses a negligible physical (structural) gap between each large grain and is highly crystalline as evidenced by its fan-shaped birefringence observed under polarized light, which is very different from the thin film prepared from the typical precursor route (MAI + PbI2). PMID- 27224964 TI - Ethics and care for older people approaching the end of life -- symptoms, choices and dilemmas. AB - The provision of high quality care to older people with complex healthcare needs brings a unique set of clinical and ethical issues. This symposium explored a range of challenging topics which often confront clinicians. It aimed to increase knowledge of symptom control in complex conditions, improve confidence in decision-making regarding difficult ethical situations, and to provide a better understanding of how to organise and support end of life care both in the hospital and in the community. PMID- 27224965 TI - Cardiovascular Devices; Reclassification of External Cardiac Compressor; Reclassification of Cardiopulmonary Resuscitation Aids. Final order. AB - The Food and Drug Administration (FDA) is issuing a final order to reclassify external cardiac compressors (ECC) (under FDA product code DRM), a preamendments class III device, into class II (special controls). FDA is also creating a separate classification regulation for a subgroup of devices previously included within this classification regulation, to be called cardiopulmonary resuscitation (CPR) aids, and reclassifying these devices from class III to class II for CPR aids with feedback and to class I for CPR aids without feedback. PMID- 27224966 TI - Americans' Experiences with ACA Marketplace and Medicaid Coverage: Access to Care and Satisfaction: Findings from the Commonwealth Fund Affordable Care Act Tracking Survey, February-April 2016. AB - The fourth wave of the Commonwealth Fund Affordable Care Act Tracking Survey, February--April 2016, finds at the close of the third open enrollment period that the working-age adult uninsured rate stands at 12.7 percent, statistically unchanged from 2015 but significantly lower than 2014 and 2013. Uninsured rates in the past three years have fallen most steeply for low-income adults though remain higher compared to wealthier adults. ACA marketplace and Medicaid coverage is helping to end long bouts without insurance, bridge gaps when employer insurance is lost, and improve access to health care. Sixty-one percent of enrollees who had used their insurance to get care said they would not have been able to afford or access it prior to enrolling. Doctor availability and appointment wait times are similar to those reported by insured Americans overall. Majorities with marketplace or Medicaid coverage continue to be satisfied with their insurance. PMID- 27224967 TI - In reply. PMID- 27224968 TI - In reply. PMID- 27224969 TI - Fostering Informed Choice: Alleviating the Trauma of Genetic Abortions. AB - Each year, thousands of pregnant women learn of fetal abnormalities through prenatal genetic analysis. This discovery--made after a woman has initially declined to exercise her right to abort an unwanted pregnancy-raises the difficult and heart-wrenching question of whether to terminate on genetic grounds. Women considering a genetic abortion rely on information and support from health care providers to assist them in making their choice. Though intended to be objective and nondirective, the support women receive frequently provides them within complete and incomprehensible information having the effect of encouraging them to abort genetically anomalous fetuses. As a result, genetic terminations--which cause severe and long-standing psychological impacts such as pathological grief, depression and post-traumatic stress-are often the result of something other than a fully informed choice.Congress and eleven states have recognized the importance of better informing choice by passing legislation aimed at providing clearer and more balanced information to expectant mothers learning of fetal genetic abnormalities. But existing legislative remedies do not adequately address this problem, and this inadequacy will become more pronounced in future years as increases in access to prenatal genetic analysis further stretch the capabilities of the available support services.This Article describes the unique characteristics of terminations for a fetal abnormality, their troubling and persistent psychological impacts,and the reasons why they will become more common in future years. It then offers proposals for how to reconfigure the prenatal genetic counseling landscape in order to reduce the incidence of genetic terminations based on incomplete or misleading information, thereby alleviating their distinct psychological costs. Its overall objective is to ensure that women learning of prenatal genetic abnormalities have access to complete and comprehensible information prior to making their decision and adequate support whether or not they choose to terminate. PMID- 27224970 TI - Does Matter of A-R-C-G- Matter That Much?: Why Domestic Violence Victims Seeking Asylum Need Better Protection. PMID- 27224971 TI - Reliability of numerical scales used for direct observation of procedural skills. PMID- 27224972 TI - Reply from the Author. PMID- 27224973 TI - Cognitive impairment. PMID- 27224974 TI - INSUFFICIENT EVIDENCE FOR THE USE OF OMEGA 3 SUPPLEMENTS IN TREATING DEPRESSION. PMID- 27224975 TI - WHO CALL ON COUNTRIES TO PROTECT HEALTH FROM CLIMATE CHANGE. PMID- 27224976 TI - WHO/UNICEF REPORT: MALARIA MDG TARGET ACHIEVED AMID SHARP DROP IN CASES AND MORTALITY, BUT 3 BILLION PEOPLE REMAIN AT RISK. PMID- 27224977 TI - Taxonomer: an interactive metagenomics analysis portal for universal pathogen detection and host mRNA expression profiling. AB - BACKGROUND: High-throughput sequencing enables unbiased profiling of microbial communities, universal pathogen detection, and host response to infectious diseases. However, computation times and algorithmic inaccuracies have hindered adoption. RESULTS: We present Taxonomer, an ultrafast, web-tool for comprehensive metagenomics data analysis and interactive results visualization. Taxonomer is unique in providing integrated nucleotide and protein-based classification and simultaneous host messenger RNA (mRNA) transcript profiling. Using real-world case-studies, we show that Taxonomer detects previously unrecognized infections and reveals antiviral host mRNA expression profiles. To facilitate data-sharing across geographic distances in outbreak settings, Taxonomer is publicly available through a web-based user interface. CONCLUSIONS: Taxonomer enables rapid, accurate, and interactive analyses of metagenomics data on personal computers and mobile devices. PMID- 27224978 TI - Allergic Reactions to Metamizole: Immediate and Delayed Responses. AB - BACKGROUND: Pyrazolones are the most common causes of selective nonsteroidal anti inflammatory drug (NSAID) hypersensitivity. We studied a large group of patients with immediate and delayed selective responses to metamizole. METHODS: Patients with suspicion of hypersensitivity to metamizole were evaluated. We verified acetylsalicylic acid tolerance and classified patients as immediate or delayed responders if they showed symptoms less or more than 24 h after metamizole administration. Skin tests were performed and if negative, a basophil activation test (BAT) was performed on immediate responders. If it was negative, we performed a drug provocation test (DPT) with metamizole. RESULTS: A total of 137 patients were included: 132 reacted within 24 h (single NSAID-induced urticaria/angioedema/anaphylaxis; SNIUAA) and 5 after 24 h (single NSAID-induced delayed hypersensitivity reaction; SNIDHR). Most SNIUAA patients developed anaphylaxis (60.60%); for SNIDHR, maculopapular exanthema was the most frequent entity (60%). Skin testing was positive in 62.04% of all cases and BAT in 28% of the SNIUAA patients with negative skin tests. In 5.1% of the cases, DPT with metamizole was needed to establish the diagnosis. In 22.62% of the cases, diagnosis was established by consistent and unequivocal history of repeated allergic episodes in spite of a negative skin test and BAT. CONCLUSIONS: SNIUAA to metamizole is the most frequent type of selective NSAID hypersensitivity, with anaphylaxis being the most common clinical entity. It may occur within 1 h after drug intake. SNIDHR occurs in a very low percentage of cases. The low sensitivity of diagnostic tests may be due to incomplete characterization of the chemical structures of metamizole and its metabolites. PMID- 27224979 TI - Vaginal Prostate Specific Antigen (PSA) Is a Useful Biomarker of Semen Exposure Among HIV-Infected Ugandan Women. AB - The practical feasibility of using prostate specific antigen (PSA) as a biomarker of semen exposure was examined among HIV-infected Ugandan women. Vaginal fluids were obtained with self-collected swabs and a qualitative rapid test (ABAcard(r)p30) was used to detect PSA. Trained laboratory technicians processed samples on-site and positive PSA tests were compared to self-reported unprotected vaginal sex (UVS) in the last 48 h. A total of 77 women submitted 126 samples for PSA testing at up to three study visits. Of these samples, 31 % (n = 39/126) were PSA positive, and 64 % (n = 25/39) of the positive PSA samples were accompanied by self-report of no UVS at the study visit the PSA was collected. There were no reported difficulties with specimen collection, storage, or processing. These findings provide preliminary data on high levels of misreported UVS among HIV infected Ugandan women using practically feasible methods for PSA collection and processing. PMID- 27224980 TI - Effect of Continuing Care for Cocaine Dependence on HIV Sex-Risk Behaviors. AB - Evaluate the effect of continuing care interventions for cocaine use with HIV risk-reduction components on HIV sex-risk. Explore whether cocaine use at treatment initiation interacts with the type of continuing care intervention to affect HIV sex-risk. Cocaine dependent participants (N = 321) were randomized to: (1) Treatment as usual (TAU): intensive outpatient treatment, (2) TAU and telephone monitoring and counseling (TMC), and (3) TAU and TMC plus incentives for participation in telephone contacts (TMC+). Participants in TMC and TMC+ received a brief HIV intervention, with booster sessions as needed. Generalized estimating equations analysis compared TAU, TMC and TMC+ at 6, 12, 18, 24 months post-baseline on the following outcomes: overall HIV sex-risk, number of sexual partners, condom usage, exchange of drugs for sex, exchange of sex for drugs, exchange of money for sex, exchange of sex for money, and crack house visits. Overall sex-risk decreased for all treatment conditions at follow-up, with no treatment main effects. For people with no cocaine use at baseline, TAU experienced greater sex-risk reductions than TMC (p < .01) and TMC+ (p < .001). The three treatment conditions are effective in reducing HIV sex-risk. TMC with HIV risk-reduction components is unnecessary for cocaine-dependent clients who stop using cocaine early in treatment. PMID- 27224981 TI - Isolation and molecular characterization of porcine epidemic diarrhea viruses collected in Japan in 2014. AB - Porcine epidemic diarrhea virus (PEDV) is the etiological agent of porcine epidemic diarrhea (PED), which is threatening the swine industry all over the world. In Japan, although there were no reported PED cases from 2007 to 2012, a large-scale PED outbreak started in 2013, causing severe economic losses. Although several PEDV studies have been conducted in Japan, more PEDV isolates and sequence information are needed to understand the molecular biology and epidemiology of PEDV. Here, we isolated seven Japanese PEDV strains from intestinal tissue samples collected in 2014 and determined the spike gene sequences of 13 Japanese PEDV strains, including the above seven isolates. Phylogenetic analysis shows that all of the strains are genetically distinct from classical Japanese PEDV strains isolated prior to 2013 and can be classified into two different genotypes: 12 strains belong to the North American clade composed of recent highly pathogenic PEDV strains, and the remaining one strain belongs to the so-called insertion deletion (INDEL) clade. These data suggest multiple PEDV invasions from abroad to Japan. Notably, compared to classical Japanese strains, all of the recent Japanese strains have two amino acid substitutions in a known neutralizing epitope. In addition, one of the strains acquired an additional mutation in another neutralizing epitope that is highly conserved among PEDVs, including the classical and recent isolates. Our isolates and findings will be useful for future investigations aimed at understanding, controlling, and preventing PED. PMID- 27224982 TI - Complete genome sequence of a new bipartite begomovirus infecting cotton in the Republic of Benin in West Africa. AB - Here, we report the complete genome sequence of a novel bipartite begomovirus isolated from cotton plants (Gossypium raimondii, Malvaceae) exhibiting light yellow mosaic symptoms. The genome sequence was determined by Illumina DNA sequencing and confirmed by Sanger sequencing of RCA-enriched, cloned circular genomic components. The DNA-A and DNA-B components were each ~2.7 kb in size, and their genome arrangement was characteristic of other Old World bipartite begomoviruses. While the DNA-A component was most closely related to tobacco leaf curl Comoros virus (TbLCKMV) at 80 %, the DNA-B component had as its closet relative soybean chlorotic blotch virus (SbCBV) at 66 %. This previously undescribed begomovirus is herein named "cotton yellow mosaic virus" (CYMV). PMID- 27224983 TI - Coxsackievirus B3 infection induces autophagic flux, and autophagosomes are critical for efficient viral replication. AB - Autophagy is an intrinsic cellular process that can degrade cytoplasmic components. It has been reported that several pathogens hijack this process to facilitate their replication. Coxsackievirus B3 (CVB3), a member of the family Picornaviridae, induces autophagy upon infection. However, the details of CVB3 induced autophagy remain a subject of debate. This study applied a combination of multiple assays for the measurement of autophagy and demonstrated that CVB3 induces a complete autophagic flux. Experiments with infected HEK293A cells revealed that autophagosomes were induced upon CVB3 infection. Most of these autophagosomes were mCherry positive in mCherry-GFP-LC3 cells. Conversely, mCherry-positive autophagosomes were rescued to green positive when treated with the acidification inhibitors chloroquine (CQ) and bafilomycin A1 (BAF), suggesting that autophagosomes fused with late endosomes or lysosomes. The co localization of LC3-positive puncta with lysosome-associated membrane protein 1 (LAMP1) or LysoTracker confirmed that the autophagosomes fused primarily with lysosomes. Interestingly, the disruption of autophagosome formation by 3 methyladenine (3-MA) or ATG5 siRNA treatment during viral infection significantly decreased CVB3 replication. However, inhibitors of lysosomal acidification, fusion, or degradation did not affect viral replication. Therefore, autolysosomes may not be critical for viral replication in vitro. PMID- 27224984 TI - Double-Balloon-Assisted n-Butyl-2-Cyanoacrylate Embolization of Intrahepatic Arterioportal Shunt Prior to Chemoembolization of Hepatocellular Carcinoma. AB - A case of multiple hepatocellular carcinomas with a severe intrahepatic arterioportal shunt that was successfully embolized with n-butyl-2-cyanoacrylate with coaxial double-balloon occlusion prior to transcatheter arterial chemoembolization is presented. A proximal balloon positioned at the proper hepatic artery was used for flow control, and a coaxial microballoon, positioned in the closest of three arterial feeding branches to the arterioportal shunt, was used to control the delivery of n-butyl-2-cyanoacrylate. This coaxial double balloon technique can prevent proximal embolization and distal migration of n butyl-2-cyanoacrylate and enable precise control of the distribution of n-butyl-2 cyanoacrylate. It could also be applicable to n-butyl-2-cyanoacrylate embolization for other than intrahepatic arterioportal shunt. PMID- 27224985 TI - Combined Endovascular Treatment with Distal Radial Artery Coil Embolization and Angioplasty in Steal Syndrome Associated with Forearm Dialysis Fistula. AB - PURPOSE: The present study was performed to define the results of the endovascular treatment with angioplasty and distal radial artery embolization in ischemic steal syndrome associated with forearm arteriovenous accesses. METHOD: The cases referred to our interventional radiology unit with symptoms and physical examination findings suggestive of ischemic steal syndrome were retrospectively evaluated first by Doppler ultrasonography, and then by angiography. Cases with proximal artery stenosis were applied angioplasty, and those with steal syndrome underwent coil embolization to distal radial artery. RESULTS: Of 589 patients who underwent endovascular intervention for dialysis arteriovenous fistulae (AVF)-associated problems, 6 (1.01 %) (5 female, 1 males; mean age 62 (range 41-78) with forearm fistula underwent combined endovascular treatment for steal syndrome. In addition to steal phenomenon, there were stenosis and/or occlusion in proximal radial and/or ulnar artery in 6 patients concurrently. Embolization of distal radial artery and angioplasty to proximal arterial stenoses were performed in all patients. Ischemic symptoms were eliminated in all patients and the AVF were in use at the time of study. In one patient, ischemic symptoms recurring 6 months later were alleviated by repeat angioplasty of ulnar artery. CONCLUSION: In palmar arch steal syndrome affecting forearm fistulae, combined distal radial embolization and angioplasty is also an effective treatment method in the presence of proximal radial and ulnar arterial stenoses and occlusions. PMID- 27224986 TI - Balloon-Assisted Reduction of Transjugular Intrahepatic Portosystemic Shunt (BART) Using Polytetrafluoroethylene Stent-Grafts. PMID- 27224987 TI - Safety and Efficacy of Percutaneous Biliary Covered Stent Placement in Patients with Malignant Biliary Hilar Obstruction; Correlation with Liver Function. AB - PURPOSE: To estimate the safety and efficacy of percutaneous ePTFE-covered biliary stent placement and the relationship between underlying liver function and stent patency in patients with malignant hilar obstruction. MATERIALS AND METHODS: From March 2012 to June 2015, 41 patients [22 females, 19 males; mean age 69.8 (range 34-94) years] with malignant biliary obstruction underwent percutaneous biliary stent placement (31 patients with unilateral, 10 patients with bilateral side-by-side). Cumulative patient survival and stent patency rate curves were derived using the Kaplan-Meier method. A Cox model was used to explore the relationship between liver function and patient survival, and also biliary stent patency. Pearson correlation coefficient was used to analyze the relationship between patient survival and stent patency. RESULTS: Technical success rate was 100 % and clinical success rate was 95 %. During follow-up, four complications occurred (two bilomas and two cases of acute cholecystitis) and were treated successfully with percutaneous drainage. No other complication occurred. Mean serum bilirubin level was 11.34 +/- 7.35 mg/dL before drainage and 5.00 +/- 4.83 mg/dL 2 weeks after stent placement. The median patent survival duration was 147 days (95 % CI, 69.6-224.4 days). The median stent patency duration was 101 days (95 % CI, 70.0-132.0 days). The cumulative stent patency rates at 1, 3, 6, and 12 months were 97, 57.6, 30.3, and 17.0 %, respectively. Child-Pugh score was correlated significantly with patient survival (P = 0.011) and stent patency (P = 0.007). MELD score was correlated significantly with stent patency (P = 0.044). There was a correlation between patient survival and stent patency (r = 0.778, P < 0.001). CONCLUSION: Percutaneous placement of ePTFE covered biliary stent was a safe and an effective method for malignant biliary obstruction. Underlying liver function seemed to be one of the important factors affecting patient survival and stent patency, and stent patency showed statistically significant correlation with patient survival. PMID- 27224988 TI - Next-Generation Sequencing in Salivary Gland Basal Cell Adenocarcinoma and Basal Cell Adenoma. AB - Basal cell adenoma and basal cell adenocarcinoma represent basaloid salivary gland neoplasms that show cyto-morphologic similarity but differ at the histologic level by their invasive qualities, as adenocarcinomas show invasion beyond their capsule, a finding not seen in the adenomas. Due to the low incidence of these tumors, the molecular mechanism underlying their pathogenesis is poorly understood. We sought to further delineate these neoplasms through mutation profiling by targeted next-generation sequencing (NGS). Twenty cases (basal cell adenocarcinoma = 10; basal cell adenoma = 10) were retrospectively selected from a previous analysis. NGS was performed using the Ion AmpliSeqTM Cancer Hotspot Panel v2 (Life Technologies, Carlsbad, CA). The data was analyzed using the Ion Torrent Suite Software (Life Technologies) followed by a laboratory developed pipeline. One of eight cases of basal cell adenocarcinoma had a mutation, which was an activating mutation in PIK3CA (c.3140A>G, p.H1047R). No mutations were detected in the remaining basal cell adenocarcinomas. In the basal cell adenomas, the CTNNB1 p.I35T mutation was identified in three of nine (3/9) cases. A missense mutation in the ATM gene (c.2572T>C, p.F858L) was seen in a basal cell adenoma with an allele frequency of 53 %, raising the possibility of a germline mutation. The overall findings suggest that although there is cytomorphologic similarity, differences exist between these two tumors at the histologic and genetic level. Although the numbers of cases are limited, the aberrations in genes affecting different signaling pathways in the basal cell adenocarcinoma versus the basal cell adenomas suggest that basal cell adenocarcinoma likely arises de novo and not from basal cell adenoma. PMID- 27224989 TI - Anxiety and Depression Symptom Dimensions Demonstrate Unique Relationships with the Startle Reflex in Anticipation of Unpredictable Threat in 8 to 14 Year-Old Girls. AB - There is growing evidence that heightened sensitivity to unpredictability is a core mechanism of anxiety disorders. In adults, multiple anxiety disorders have been associated with a heightened startle reflex in anticipation of unpredictable threat. Child and adolescent anxiety has been linked to an increased startle reflex across baseline, safety, and threat conditions. However, it is unclear whether anxiety in youth is related to the startle reflex as a function of threat predictability. In a sample of 90 8 to 14 year-old girls, the present study examined the association between anxiety symptom dimensions and startle potentiation during a no, predictable, and unpredictable threat task. Depression symptom dimensions were also examined given their high comorbidity with anxiety and mixed relationship with the startle reflex and sensitivity to unpredictability. To assess current symptoms, participants completed the self report Screen for Child Anxiety Related Emotional Disorders and Children's Depression Inventory. Results indicated that social phobia symptoms were associated with heightened startle potentiation in anticipation of unpredictable threat and attenuated startle potentiation in anticipation of predictable threat. Negative mood and negative self-esteem symptoms were associated with attenuated and heightened startle potentiation in anticipation of unpredictable threat, respectively. All results remained significant after controlling for the other symptom dimensions. The present study provides initial evidence that anxiety and depression symptom dimensions demonstrate unique associations with the startle reflex in anticipation of unpredictable threat in children and adolescents. PMID- 27224990 TI - Effects of four nucleoside analogues used as antiviral agents on rat Sertoli cells (SerW3) in vitro. AB - Some nucleoside analogues are used to treat herpes simplex and other viral infections. They are known to impair spermatogenesis, but published data are scarce. We studied the effects of four nucleosides on SerW3 cells, a rat Sertoli cell line. Cells were cultured for 3 days in DMEM supplemented with four different concentrations of each drug. Aciclovir and ganciclovir were added at concentrations of 0.3, 1, 3 and 10 mg/l medium; penciclovir and its prodrug famciclovir were used at higher concentrations (3, 10, 30, 100 mg/l medium). After a culture period of 3 days, we analysed the expression of connexin43, N cadherin and the cytoskeleton protein vimentin by Western blot. Aciclovir caused a clear-cut effect at the highest concentration tested (10 mg/l), which is less than the peak plasma concentration achieved in patients during intravenous therapy with the drug. Connexin43, vimentin and N-cadherin content decreased to 49.8 +/- 17, 44.0 +/- 4 and 75.4 +/- 1.5 % of the control values, respectively (n = 3; mean +/- SD). Similar effects were observed with the prodrug ganciclovir (43.2 +/- 10.8; 54.1 +/- 11.9; 84.4 +/- 10.8 % of controls). Penciclovir caused less pronounced effects at 10 mg/l medium (82.1 +/- 20.6; 90.0 +/- 12.0; 76.5 +/- 17.7 % of controls). Only a slight effect was observed with famciclovir. Even at a 10-fold concentration (100 mg/l), just moderate changes were induced. In summary, we observed clear-cut effects with aciclovir and ganciclovir on Sertoli cells in vitro at therapeutically relevant concentrations and identified connexin43 as the most sensitive marker. PMID- 27224991 TI - [Pharmacovigilance in Germany : It is about time]. AB - BACKGROUND: Pharmacovigilance is defined as the activities relating to the detection, assessment, and prevention of adverse drug reactions (ADRs). Although its beginnings in Germany date back more than 50 years, a stagnation in this field has been observed lately. OBJECTIVES: Different tools of pharmacovigilance will be illustrated and the reasons for its stagnation in Germany will be elucidated. CURRENT DATA: Spontaneous reporting systems are an important tool in pharmacovigilance and are based on reports of ADRs from treating physicians, other healthcare professionals, or patients. Due to several weaknesses of spontaneous reporting systems such as underreporting, media bias, confounding by comorbidity or comedication, and due to the limited quality of the reports, the development of electronic healthcare databases was publicly funded in recent years so that they can be used for pharmacovigilance research. In the US different electronic healthcare databases were merged in a project sponsored by public means resulting in more than 193 million individuals. In Germany the establishment of large longitudinal databases was never conceived as a public duty and has not been implemented so far. Further attempts to use administrative healthcare data for pharmacovigilance purposes are severely restricted by the Code of Social Law (Section 75, Book 10). This situation has led to a stagnation in pharmacovigilance research in Germany. CONCLUSIONS: Without publicly funded large longitudinal healthcare databases and an amendment of Section 75, Book 10, of the Code of Social Law, the use of healthcare data in pharmacovigilance research in Germany will remain a rarity. This could have negative effects on the medical care of the general population. PMID- 27224992 TI - [Erratum to: Standard therapy of tuberculosis]. PMID- 27224993 TI - Topiramate Extended Release: A Review in Epilepsy. AB - Once-daily oral topiramate extended release (USL255; hereafter referred to as topiramate XR) [QUDEXY((r)) XR] is approved in the USA for use as initial monotherapy and adjunctive therapy in patients aged >=2 years with partial-onset seizures (POS) or primary generalized tonic-clonic seizures and as adjunctive therapy in patients aged >=2 years with seizures associated with Lennox-Gastaut syndrome. Compared with twice-daily topiramate immediate release at the same total daily dose, topiramate XR provided bioequivalent exposure, an extended absorption rate (permitting convenient once-daily dosing) and more constant therapeutic plasma concentrations (potentially minimizing topiramate-associated adverse events). Switching between the two formulations did not affect the maintenance of topiramate concentrations. Moreover, the contents of a topiramate XR capsule may be sprinkled on to soft food for patients who have difficulty swallowing. In a multinational phase III study in adults with refractory POS, adjunctive topiramate XR was associated with significantly greater improvements from baseline in weekly median seizure frequency and the proportion of patients achieving a >=50 % reduction in seizure frequency compared with placebo. These benefits were sustained during a 55-week open-label extension study. Adjunctive topiramate XR was generally well tolerated in these studies, with the majority of treatment-emergent adverse events being mild or moderate in intensity. In conclusion, current evidence suggests once-daily topiramate XR extends the treatment options currently available for patients aged >=2 years with epilepsy, with its dosing regimen potentially delivering tolerability and adherence advantages over AEDs that require more frequent administration. PMID- 27224996 TI - Herbs for a hospice. PMID- 27224994 TI - Relationships Between Functional Outcomes and Symptomatic Improvement in Atomoxetine-Treated Adult Patients with Attention-Deficit/Hyperactivity Disorder: Post Hoc Analysis of an Integrated Database. AB - BACKGROUND: Atomoxetine treatment is associated with improvements in functional outcomes in patients with attention-deficit/hyperactivity disorder (ADHD), although relationships between improvements in these outcomes and reductions in ADHD symptoms have not been comprehensively investigated in adults. OBJECTIVES: The aim of this study was to assess relationships between functional outcomes and ADHD symptoms (primary objective), and to assess time courses of changes in functional outcomes from baseline to weeks 10 and 24 (secondary objective). METHODS: We analyzed data pooled from seven Eli Lilly-sponsored placebo controlled trials of atomoxetine in adults with ADHD that had Conners' Adult ADHD Rating Scales-Investigator Rated: Screening Version (CAARS-Inv:SV) total scores and functional outcome data at baseline and at week 10. Two trials also had these data at week 24. Patients were included in these pooled analyses if they had a CAARS-Inv:SV total score at baseline and at one or more post-baseline visits at weeks 10 or 24, or had post-baseline scores that would allow missing scores at weeks 10 or 24 to be imputed. To address the primary objective, changes in functional outcomes during treatment with atomoxetine versus placebo were assessed using last observation carried forward (LOCF) analysis of covariance (ANCOVA) and mixed-effects model repeated measures (MMRM) analysis, and correlations between score changes in CAARS-Inv:SV total and functional outcomes were assessed using Spearman's rank correlation coefficient (r) at weeks 10 and 24. The secondary objective was addressed using MMRM. RESULTS: At baseline, patients generally had moderately severe or worse ADHD symptoms (based on CAARS Inv:SV total scores) and impaired functional outcomes (based on Adult ADHD Quality-of-Life [AAQoL], Behavior Rating Inventory of Executive Function-Adult Version [BRIEF-A], Sheehan Disability Scale [SDS], and 36-item Short-Form Health Survey [SF-36] scores). These baseline characteristics were comparable in the atomoxetine and placebo groups. For atomoxetine versus placebo, statistically significant improvements were detected in AAQoL total and subscores at weeks 10 and 24, and in BRIEF-A Self-Report scores at week 10, but not in BRIEF-A Informant Report or SDS scores at week 10 (no BRIEF-A or SDS data were available at week 24), and not in SF-36 at weeks 10 or 24. All functional improvements were gradual. During treatment with atomoxetine, there were moderate correlations between reductions in CAARS-Inv:SV total scores and increases in AAQoL total and subscores at weeks 10 and 24 (r range -0.58 to -0.39; n = 394-545), and also with reductions in BRIEF-A Self-Report at week 10 (r = 0.49; n = 256). With placebo, moderate correlations were also found between reductions in CAARS-Inv:SV total scores and increases in AAQoL total and subscores at weeks 10 and 24 (r range 0.56 to -0.28; n = 321-542), and with reductions in BRIEF-A Self-Report at week 10 (r = 0.49; n = 271). However, correlations between changes in CAARS-Inv:SV and BRIEF-A Informant at week 10 were low for atomoxetine-treated patients (r = 0.25; n = 65), moderate with placebo (r = 0.42; n = 72), and there were low/no correlations between changes in CAARS-Inv:SV and functional outcome rating scales that are not specific to ADHD; that is, for atomoxetine-treated patients, SDS total r = 0.19 (n = 32 at week 10) and SF-36 r range - 0.20 to -0.01 (n = 51 at week 10, n = 183 at week 24). CONCLUSIONS: Atomoxetine-treated adult patients experienced improvements in functional outcomes (AAQoL and BRIEF-A Self-Report) that correlated with reductions in ADHD symptoms. Although atomoxetine improved both the ADHD symptoms and functional outcomes, the correlation between symptoms and functional outcomes was low to moderate, suggesting that they measure overlapping but different aspects of the disorder. Hence, clinicians should assess not just ADHD symptoms, but also the functional impairments. PMID- 27224995 TI - Improving handoff communication from hospital to home: the development, implementation and evaluation of a personalized patient discharge letter. AB - OBJECTIVE: To develop, implement and evaluate a personalized patient discharge letter (PPDL) to improve the quality of handoff communication from hospital to home. DESIGN: From the end of 2006-09 we conducted a quality improvement project; consisting of a before-after evaluation design, and a process evaluation. SETTING: Four general internal medicine wards, in a 1024-bed teaching hospital in Amsterdam, the Netherlands. PARTICIPANTS: All consecutive patients of 18 years and older, admitted for at least 48 h. INTERVENTIONS: A PPDL, a plain language handoff communication tool provided to the patient at hospital discharge. MAIN OUTCOME MEASURES: Verbal and written information provision at discharge, feasibility of integrating the PPDL into daily practice, pass rates of PPDLs provided at discharge. RESULTS: A total of 141 patients participated in the before-after evaluation study. The results from the first phase of quality improvement showed that providing patient with a PPDL increased the number of patients receiving verbal and written information at discharge. Patient satisfaction with the PPDL was 7.3. The level of implementation was low (30%). In the second phase, the level of implementation improved because of incorporating the PPDL into the electronic patient record (EPR) and professional education. An average of 57% of the discharged patients received the PPDL upon discharge. The number of discharge conversations also increased. CONCLUSION: Patients and professionals rated the PPDL positively. Key success factors for implementation were: education of interns, residents and staff, standardization of the content of the PPDL, integrating the PPDL into the electronic medical record and hospital wide policy. PMID- 27224997 TI - Quantifying beliefs regarding telehealth: Development of the Whole Systems Demonstrator Service User Technology Acceptability Questionnaire. AB - Introduction Telehealth (TH) is a potential solution to the increased incidence of chronic illness in an ageing population. The extent to which older people and users with chronic conditions accept and adhere to using assistive technologies is a potential barrier to mainstreaming the service. This study reports the development and validation of the Whole Systems Demonstrator (WSD) Service User Technology Acceptability Questionnaire (SUTAQ). Methods Questionnaires measuring the acceptability of TH, quality of life, well-being and psychological processes were completed by 478 users of TH. The 22 acceptability items were subject to principal components analysis (PCA) to determine sub-scales. Scale scores, relationships between scales and other patient-reported outcome measures (PROMs), and group differences on scales were utilised to check the reliability and validity of the measure. Results PCAs of SUTAQ items produced six TH acceptability scales: enhanced care, increased accessibility, privacy and discomfort, care personnel concerns, kit as substitution and satisfaction. Significant correlations within these beliefs and between these scales and additional PROMs were coherent, and the SUTAQ sub-scales were able to predict those more likely to refuse TH. Discussion The SUTAQ is an instrument that can be used to measure user beliefs about the acceptability of TH, and has the ability to discriminate between groups and predict individual differences in beliefs and behaviour. Measuring acceptability beliefs of TH users can provide valuable information to direct and target provision of services to increase uptake and maintain use of TH. PMID- 27224998 TI - Effects of diesel exhaust particles on macrophage polarization. AB - BACKGROUND: Exposure to diesel exhaust particles (DEP) has long been associated with increased cardiovascular morbidity and mortality. The development of DEP toxicity seems to be linked to inflammation in which macrophages play a critical role. Macrophages can be polarized into proinflammatory M1 or anti-inflammatory M2 macrophages. The aim of this study was to identify the role of inflammation in DEP-induced toxicity by assessing the effects of DEP on macrophage polarization. METHODS: Monocyte-derived macrophages (Mphi) were stimulated with interferon gamma and lipopolysaccharide or interleukin (IL)-4 to obtain M1 and M2 subtypes, respectively. To test the polarization capacity of DEP, Mphi cells were exposed to DEP and compared to Mphi, M1, and M2. We also studied the effects of DEP on already-polarized M1 or M2. The M1 markers assessed were tumor necrosis factor alpha (TNF-alpha) and IL-1beta, while the M2 markers were the mannose receptor C type 1 (MRC-1) and transglutaminase 2 (TGM2). RESULTS: Western blots revealed a 31 kDa band corresponding to pro-IL-1beta, but only in M1-polarized macrophages. In M1, we also observed an upregulation of TNF-alpha messenger RNA (mRNA) expression. MRC-1 and TGM2 mRNA expression were only significantly enhanced in M2. DEP had no effect on any of the M1/M2 markers assessed. Moreover, DEP were not able to modify the phenotype of already-polarized M1 or M2. CONCLUSION: Mphi incubation with DEP did not have any effect on macrophage polarization, at least on the markers assessed in this study, namely, TNF-alpha/IL-1beta for M1, and MRC 1/TGM2 for M2. Hence, these data argue against an important role of inflammation in DEP-induced vascular toxicity. PMID- 27224999 TI - Protein-losing enteropathy in camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome. AB - BACKGROUND: Camptodactyly-arthropathy-coxa vara-pericarditis (CACP, OMIM: #208250) syndrome is a rare autosomal recessive disease that can be difficult to recognise not only because of its wide clinical variability but also because of its clinical resemblance to juvenile idiopathic arthritis (JIA). PRG4 is the only gene so far known to be associated with CACP syndrome. Children with CACP syndrome lack the glycoprotein lubricin due to recessive mutations in PRG4. Lubricin serves as a lubricant in joints, tendons and visceral cavities (pleural cavity, pericardium) and inhibits synovial proliferation. Children with CACP syndrome suffer from congenital camptodactyly, arthropathy, coxa vara and sometimes pericarditis. This report concerns a child with CACP syndrome complicated by protein-losing enteropathy (PLE), caused by constrictive pericarditis and so contributes to knowledge of the presentation of CACP syndrome. CASE PRESENTATION: A 10- year-old girl with consanguineous parents suffered from congenital camptodactyly and progressive swollen and painful joints. Her father and his sister had similar childhood-onset joint complaints. Laboratory tests showed no signs of inflammation but showed persistent low protein- and IgG- levels, indicating a secondary immunodeficiency. Increased alpha antitrypsin clearance confirmed PLE. Abdominal ultrasound with Doppler showed hepatomegaly and portal hypertension. Echocardiography suggested constrictive pericarditis. However, heart catheterization could not confirm this. Ultrasound and X-ray examination of the joints combined with a puncture of the synovial fluid were performed. These results, combined with the clinical presentation and the consanguinity, suggested CACP syndrome. Due to excessive enteral protein losses, the patient was treated with Cotrimoxazol prophylaxis and immunoglobulin supplements. These supplements were inadequate to achieve normal IgG values. As constrictive pericarditis with subsequent PLE was the best explanation for the excessive IgG losses, pericardiectomy was performed with good results. Genetic testing in our patient was complicated but revealed a pathogenic mutation within the repeat sequence in exon 7 of the PRG4 gene. CONCLUSION: PLE resulting from constrictive pericarditis can be a complication of CACP syndrome. As serious complications can arise from the resulting secondary immunodeficiency, we recommend regular evaluation of clinical symptoms of constrictive pericarditis and PLE in children with CACP syndrome. PMID- 27225000 TI - Analysis of the virulence determination mechanisms in a local Toxoplasma strain (T.gHB1) isolated from central China. AB - Several rhoptry proteins (ROPs) have been confirmed to be critical virulence factors of Toxoplasma gondii strains from North America and Europe. The two active kinases ROP17 and ROP18, and pseudokinase ROP5 were thought to be the key determinants of parasites' virulence in laboratory mice. Given the genetic diversity of Toxoplasma strains from different geographical regions, the virulence determinants in other strains, particularly the ones that are phylogenetically distant to the North American and European strains, are yet to be elucidated. In this study, we sought to examine the contribution of three known virulence factors to the virulence of a type I strain (T.gHB1) isolated from Central China. We deleted ROP17 and ROP18 individually, as well as in combination with GRA7 by the CRISPR-Cas9 system in this local isolate. Subsequent virulence tests in mice indicated that deletion of GRA7, ROP17, or ROP18 in T.gHB1showed similar attenuation in mice as the type I RH strain lacking the corresponding proteins. However, in contrast to the reported double knockouts in RH, double deletions of GRA7 plus ROP17 or GRA7 plus ROP18 in T.gHB1 did not show significant further virulence attenuation compared to the ROP17 or ROP18 single knockouts. These results indicated that GRA7, ROP18 and ROP17 may play different roles in virulence determination in genetically diverse strains of Toxoplasma. PMID- 27225001 TI - A novel PCR-RFLP assay for molecular characterization of Echinococcus granulosus sensu lato and closely related species in developing countries. AB - Cystic echinococcosis, due to Echinococcus granulosus sensu lato (s. l.), currently affects three million people, especially in low-income countries and results in high livestock production loss. DNA-based methods demonstrated genetic variability of E. granulosus s. l., and five species were recognized to belong to the complex, including E. granulosus sensu stricto (s.s) (genotypes G1-G3), Echinococcus equinus (genotype G4), Echinococcus ortleppi (genotype G5), Echinococcus canadensis (genotypes G6-G10), and the lion strain Echinococcus felidis. The characterization of Echinococcus species responsible for human and animal echinococcosis is crucial to adapt the preventive measures against this parasitic disease. The sequencing approach is the gold standard for genotyping assays. Unfortunately, developing countries do not often have access to these techniques. Based on in silico RFLP tools, we described an accurate PCR-RFLP method for Echinococcus spp. characterization. The double digestion with the HaeIII and HinfI restriction enzymes of the PCR product from nad1 gene (1071 bp) led to a clear discrimination between E. granulosus s. l. and most closely related species (Echinococcus shiquicus and Echinococcus multilocularis).Molecular procedures and phylogenetic analysis confirmed the efficiency and the reproducibility of this simple and fast PCR-RFLP method. This technique is proved useful for fresh/unfixed and FF-PET tissues and enables large scale molecular epidemiological screening in developing countries. PMID- 27225003 TI - Erratum to: Successful overwintering of Aedes albopictus in Germany. PMID- 27225002 TI - Morphological and molecular characterization of Myxobolus sheyangensis n. sp. (Myxosporea: Myxobolidae) with intralamellar sporulation in allogynogenetic gibel carp, Carassius auratus gibelio (Bloch) in China. AB - Allogynogenetic gibel carp is one of the most important freshwater cultured species in China. However, myxosporidiosis represents a severe threat to prevent the sustainable development of aquaculture of this species. During the investigation of myxosporean diversity of reared allogynogenetic gibel carp in East China, a new myxosporean with typical characteristics of Myxobolus was found from 169 out of 210 (80.4 %) examined samples, designated as Myxobolus sheyangensis n. sp. by combing comparative analysis of morphological and molecular data. The diagnostic features of this species are reminiscent with Myxobolus pyramidis Chen, 1958 as follows: round or ellipsoidal, grayish white, cyst-like polysporous plasmodia, averaging 219.3 +/- 11.9 (98.7-421.7) * 158.4 +/ 9.7 MUm (79.9-191.8) in size; spores flat-pear shaped in frontal view with tapering anterior and rounded posterior ends and lemon-shaped in sutural view, averaging 11.0 +/- 0.31 (10.5-11.9) * 10.2 +/- 0.25 (9.2-10.7) * 6.3 +/- 0.23 MUm (5.9-6.9) in size; and two equal pyriform polar capsules averaging 5.5 +/- 0.3 (4.5-6.1) * 3.4 +/- 0.26 MUm (2.9-4.0) in size with convergent longitudinal axes and polar filaments wounded in seven to eight coils, perpendicularly to the longitudinal axis of the polar capsules. Spore surface was smooth and two spore valves were symmetrical, with a thin and straight sutural ridge. Occasionally, abnormal spores with typical Henneguya-like caudal appendage and atypical papillary caudal appendage could be observed. The sporogenesis is asynchronous. Histopathological investigation showed that the plasmodia developed inside the capillary network of gill lamellae, belonging to the intralamellar vascular type, and no significant inflammatory responses were provoked by the infection. Homology search by BLAST showed that the newly obtained sequence did not match any available sequences in GenBank. Phylogenetic analysis of the aligned sequences indicated that M. sheyangensis n. sp. positioned in a clade composed of Myxobolus species infecting the gill of several freshwater cyprinid fish. PMID- 27225004 TI - Expression of the Plasmodium berghei actin II gene is controlled by elements in a long genomic region. AB - Plasmodium parasites have two actin isoforms. Actin I is ubiquitously expressed, while the second actin isoform is expressed in the sexual stages and ookinetes. Reverse genetic analysis revealed two phenotypes in parasites lacking the protein: a block in male gametogenesis (exflagellation) and a second phenotype in oocyst development, dependent upon the expression of the gene in female gametocytes. Here, we report that the genetic complementation of two independent mutants lacking actin II does not fully restore wild-type function. Constructs were integrated in the c-rrna locus, previously used for expression of transgenes, in order to determine the dependence of expression on actin II flanking genomic regions. Partial restoration of male gametogenesis was achieved when the transgene contained, in addition to the coding region, 1.2 kb upstream of the actin II open reading frame. Another transgene, which comprised 2.7 kb of actin II 5' flanking regions and the cognate 3' downstream sequence, fully restored exflagellation. However, in both complemented strains, oocyst development was severely impaired compared to the WT. These data suggest that male gametocyte expression of actin II is dependent upon extensive flanking regions, while female expression requires even longer genomic sequences for correct expression of the gene. PMID- 27225005 TI - Sustainability assessment of greenhouse vegetable farming practices from environmental, economic, and socio-institutional perspectives in China. AB - To provide growing population with sufficient food, greenhouse vegetable production has expanded rapidly in recent years in China and sustainability of its farming practices is a major concern. Therefore, this study assessed the sustainability of greenhouse vegetable farming practices from environmental, economic, and socio-institutional perspectives in China based on selected indicators. The empirical data were collected through a survey of 91 farm households from six typical greenhouse vegetable production bases and analysis of environmental material samples. The results showed that heavy fertilization in greenhouse vegetable bases of China resulted in an accumulation of N, P, Cd, Cu, Pb, and Zn in soil, nutrient eutrophication in irrigation water, and high Cd in some leaf vegetables cultivated in acidic soil. Economic factors including decreased crop yield in conventional farming bases, limited and site-dependent farmers' income, and lack of complete implementation of subsidy policies contributed a lot to adoption of heavy fertilization by farmers. Also, socio institutional factors such as lack of unified management of agricultural supplies in the bases operated in cooperative and small family business models and low agricultural extension service efficiency intensified the unreasonable fertilization. The selection of cultivated vegetables was mainly based on farmers' own experience rather than site-dependent soil conditions. Thus, for sustainable development of greenhouse vegetable production systems in China, there are two key aspects. First, it is imperative to reduce environmental pollution and subsequent health risks through integrated nutrient management and the planting strategy of selected low metal accumulation vegetable species especially in acidic soil. Second, a conversion of cooperative and small family business models of greenhouse vegetable bases to enterprises should be extensively advocated in future for the unified agricultural supplies management and improved agricultural extension service efficiency, which in turn can stabilize vegetable yields and increase farmers' benefits. PMID- 27225006 TI - Trace metal contamination in commercial fish and crustaceans collected from coastal area of Bangladesh and health risk assessment. AB - Trace metals contamination in commercial fish and crustaceans have become a great problem in Bangladesh. This study was conducted to determine seven trace metals concentration (Cr, Ni, Cu, Zn, As, Cd, and Pb) in some commercial fishes and crustaceans collected from coastal areas of Bangladesh. Trace metals in fish samples were in the range of Cr (0.15 - 2.2), Ni (0.1 - 0.56), Cu (1.3 - 1.4), Zn (31 - 138), As (0.76 - 13), Cd (0.033 - 0.075), and Pb (0.07 - 0.63 mg/kg wet weight (ww)), respectively. Arsenic (13 mg/kg ww) and Zn (138 mg/kg ww) concentrations were remarkably high in fish of Cox's Bazar due to the interference of uncontrolled huge hatcheries and industrial activities. The elevated concentrations of Cu (400), Zn (1480), and As (53 mg/kg ww) were also observed in crabs of Cox's Bazar which was considered as an absolutely discrepant aquatic species with totally different bioaccumulation pattern. Some metals in fish and crustaceans exceeded the international quality guidelines. Estimated daily intake (EDI) and target cancer risk (TR) revealed high dietary intake of As and Pb, which was obviously a matter of severe public health issue of Bangladeshi coastal people which should not be ignored and concentrate our views to solve this problem with an integrated approaches. Thus, continuous monitoring of these toxic trace elements in seafood and immediate control measure is recommended. PMID- 27225007 TI - Assessment of the effects of the carbamazepine on the endogenous endocrine system of Daphnia magna. AB - In the present study, the endocrine activity of the antiepileptic pharmaceutical carbamazepine (CBZ) in the crustacean Daphnia magna was assessed. To assess the hormonal activity of the drug, we exposed maternal daphnids and embryos to environmental relevant concentrations of CBZ (ranging from 10 to 200 MUg/L) and to mixtures of CBZ with fenoxycarb (FEN; 1 MUg/L). Chronic exposure to CBZ significantly decreased the reproductive output and the number of molts of D. magna at 200 MUg/L. This compound induced the production of male offspring (12 +/ 1.7 %), in a non-concentration-dependent manner, acting as a weak juvenile hormone analog. Results showed that this substance, at tested concentrations, did not antagonize the juvenoid action of FEN. Further, CBZ has shown to be toxic to daphnid embryos through maternal exposure interfering with their normal gastrulation and organogenesis stages but not producing direct embryo toxicity. These findings suggest that CBZ could act as an endocrine disruptor in D. magna as it decreases the reproductive output, interferes with sex determination, and causes development abnormality in offspring. Therefore, CBZ could directly affect the population sustainability. PMID- 27225008 TI - The influence of low-dose cadmium on the laryngeal microstructure and ultrastructure of Pelophylax nigromaculata. AB - Cadmium (Cd) is one of the common heavy metals dispersed throughout the modern environment that disrupts the development of aquatic organisms. Amphibians appear to be particularly vulnerable to this heavy metal contaminant since their eggs and aquatic larvae live in aquatic habitats and have permeable skin. During this critical sensitive period, amphibians live primarily in the water and are thus susceptible to the effects of environmental pollutants in water. Pelophylax nigromaculata completes their laryngeal development from Gosner stage 19 (GS 19, embryonic stage) to GS 46 (metamorphosis stage). To study whether long-term (from GS 19 to GS 46) exposure to low Cd concentrations (0, 4, 8, 16, 32, 64, and 128 MUg/L) affects the development of the larynx in P. nigromaculata, a comparative study of microstructures and ultrastructures of female and male P. nigromaculata larynges was carried out. In histological structure, the larynx was composed of epithelial tissue, skeletal muscle, and hyaline cartilage, and there were no differences between male and female frogs except that males had a larger cross section area than females. In contrast to controls, 64 and 128 MUg/L Cd treatments caused a significant decrease in cross-sectional area, while other treatments showed no significant differences. Under the scanning electron microscope, the surface of the larynx could be seen to be attached to developed and evenly distributed cilia, with no significant differences between young male and female frogs, even among the Cd treatments. Under transmission electron microscopy, developed laryngeal epithelial cells could be observed, with obvious cross striations of skeletal muscle cells and mitochondria distributed around the muscle and skeletal muscle satellite cells. Compared with the control group, mitochondria around the skeletal muscle grew in size and decreased in number in the high-concentration treatment. PMID- 27225009 TI - Effects of copper deficiency and copper toxicity on organogenesis and some physiological and biochemical responses of Scots pine (Pinus sylvestris L.) seedlings grown in hydroculture. AB - The morphological, physiological, and biochemical parameters of 6-week-old seedlings of Scots pine (Pinus sylvestris L.) were studied under deficiency (1.2 nM) and chronic exposure to copper (0.32, 1, 2.5, 5, and 10 MUM CuSO4) in hydroculture. The deposit of copper in the seed allowed the seedlings to develop under copper deficiency without visible disruption of growth. The high sensitivity of Scots pine to the toxic effects of copper was shown, which manifested as a significant inhibition of growth and development. The loss of dominance of the main root and a strong inhibition of lateral root development pointed to a lack of adaptive reorganization of the root system architecture under copper excess. A preferential accumulation of copper in the root and a minor translocation in aerial organs confirmed that Scots pine belongs to a group of plants that exclude copper. Selective impairment in the absorption of manganese was discovered, under both deficiency and excess of copper in the nutrient solution, which was independent of the degree of development of the root system. Following 10 MUM CuSO4 exposure, the absorption of manganese and iron from the nutrient solution was completely suppressed, and the development of seedlings was secured by the stock of these micronutrients in the seed. The absence of signs of oxidative stress in the seedling organs was shown under deficiency and excess of copper, as evidenced by the steady content of malondialdehyde and 4-hydroxyalkenals. Against this background, no changes in total superoxide dismutase activity in the organs of seedlings were revealed, and the increased content of low-molecular-weight antioxidants was observed in the roots under 1 MUM and in the needles under 5 MUM CuSO4 exposures. PMID- 27225011 TI - Headache meets neurology and psychiatry: a framework for diagnosis. AB - This is a case of a very rare progressive disorder which presented with unusual neurological symptoms. Significant diagnostic challenges were experienced. A structured approach to each stage of the case demonstrates a framework to use when considering children with unusual neurological presentations. PMID- 27225012 TI - Comparison of Screening Dilution and Automated Reading for Antinuclear Antibody Detection on HEP2 Cells in the Monitoring of Connective Tissue Diseases. AB - BACKGROUND: Indirect immunofluorescence plays a major role in the detection of antinuclear antibodies (ANAs) and follow-up of their titers in the context of connective tissue diseases. Given the numerous unfavorable features of the conventional manual reading of HEP2 slides (need of time and expert morphologists for the reading, lack of standardization, subjectivity of the interpretation), the biomedical industry has developed automated techniques of slide preparation and microscope reading. METHODS: We collected 49 sera beforehand analyzed by the conventional reading of slides. They were prepared again by QUANTA-Lyser((r)) and reanalyzed in four different conditions: two dilutions of screening (1/40 and 1/80), two different systems of analysis, NOVA View((r)) automated reading (INOVA Diagnostics), then confirmation by the operator, and conventional manual reading by two different qualified operators. The analysis was realized in blind of the first interpretation and clinical diagnosis. The sera were classified in four groups, on the basis of the results of the first analysis: negative sera (titer < 1/160; 11 patients), low positives (titer at 1/160; 18 patients), moderated positives (titers between 1/320 and 1/640; 10 patients), and strong positives (titers between 1/1,280 and 1/2,560; 10 patients). RESULTS: Among the 49 patients, 13 presented a connective tissue disease including 4 systemic scleroderma (SS), 3 rheumatoid arthritis (RA), 2 Goujerot-Sjogren (GS), 2 systemic lupus erythematosus (SLE), 1 polymyositis (PM), 1 Raynaud's syndrome (RS), and 1 CREST syndrome. One patient presented both an SLE and an SS. Regarding the screening dilution, the 1/40 dilution is less specific than the 1/80 dilution for both the systems of analysis (5.6% vs. 16.7% for the manual reading, and 27.8% vs. 50% for the automated reading). It also generates statistically more false positives (P = 0.037 for the conventional analysis and P = 0.003 for the automated system). The automated NOVA View((r)) reading of slides allows a gain in specificity for both dilutions, and also statistically less false positives (P = 0.002 at the 1/40 and P = 0.0006 at the 1/80), and detriment of the sensitivity at the highest dilution (84.6% vs. 92.3% with manual reading). Thus, according to our analysis of 49 sera, the automated NOVA View((r)) system of reading of slides at the dilution 1/80 seems to be a successful condition for the detection of ANAs on HEP2 cells, close to the significance (P = 0.067). CONCLUSION: The automated NOVA View((r)) reading of slides allows saving time, and an improvement in the standardization. Nevertheless, it requires a confirmation by a qualified operator, to interpret mixed patterns in particular. PMID- 27225014 TI - The prevalence of potentially abusive behaviours in family caregiving: findings from a national survey of family carers of older people. AB - BACKGROUND: family caregiving can be both rewarding and fulfilling; however, conflicts can occur in the caregiving relationship, and some family carers may engage in behaviours that could be potentially harmful to the older person for whom them provide care. OBJECTIVE: to determine the prevalence of potentially abusive behaviours towards older people by family carers. DESIGN: a postal cross sectional survey of a nationally representative sample of family carers of community-dwelling older people. SUBJECTS: a randomly selected sample of family carers in receipt of a social welfare payment for the care they provide to a relative aged 65 and older. METHODS: a self-completion questionnaire was posted to 4,000 family carers of older people across Ireland, and a total of 2,311 eligible completed questionnaires were returned, yielding a response rate of 58%. RESULTS: more than a third of family carers (36.8%) reported that they engaged in potentially harmful behaviours towards their older family member in the 3 months prior to the survey. Of those potentially harmful behaviours, a third (35.9%) reported that they engaged in potentially harmful psychological behaviours and 8% reported engaging in potentially harmful physical behaviours. CONCLUSIONS: potentially abusive carer behaviours need to be detected at an early stage so that preventive interventions can be introduced to avert caregiving situations deteriorating into serious cases of elder abuse. PMID- 27225013 TI - PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages - a randomised, double-blind, placebo controlled, international multicentre trial and economic evaluation. AB - BACKGROUND AND OBJECTIVES: Progesterone is essential to maintain a healthy pregnancy. Guidance from the Royal College of Obstetricians and Gynaecologists and a Cochrane review called for a definitive trial to test whether or not progesterone therapy in the first trimester could reduce the risk of miscarriage in women with a history of unexplained recurrent miscarriage (RM). The PROMISE trial was conducted to answer this question. A concurrent cost-effectiveness analysis was conducted. DESIGN AND SETTING: A randomised, double-blind, placebo controlled, international multicentre study, with economic evaluation, conducted in hospital settings across the UK (36 sites) and in the Netherlands (nine sites). PARTICIPANTS AND INTERVENTIONS: Women with unexplained RM (three or more first-trimester losses), aged between 18 and 39 years at randomisation, conceiving naturally and giving informed consent, received either micronised progesterone (Utrogestan((r)), Besins Healthcare) at a dose of 400 mg (two vaginal capsules of 200 mg) or placebo vaginal capsules twice daily, administered vaginally from soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) until 12 completed weeks of gestation (or earlier if the pregnancy ended before 12 weeks). MAIN OUTCOME MEASURES: Live birth beyond 24 completed weeks of gestation (primary outcome), clinical pregnancy at 6-8 weeks, ongoing pregnancy at 12 weeks, miscarriage, gestation at delivery, neonatal survival at 28 days of life, congenital abnormalities and resource use. METHODS: Participants were randomised after confirmation of pregnancy. Randomisation was performed online via a secure internet facility. Data were collected on four occasions of outcome assessment after randomisation, up to 28 days after birth. RESULTS: A total of 1568 participants were screened for eligibility. Of the 836 women randomised between 2010 and 2013, 404 received progesterone and 432 received placebo. The baseline data (age, body mass index, maternal ethnicity, smoking status and parity) of the participants were comparable in the two arms of the trial. The follow-up rate to primary outcome was 826 out of 836 (98.8%). The live birth rate in the progesterone group was 65.8% (262/398) and in the placebo group it was 63.3% (271/428), giving a relative risk of 1.04 (95% confidence interval 0.94 to 1.15; p = 0.45). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Economic analysis suggested a favourable incremental cost-effectiveness ratio for decision making but wide confidence intervals indicated a high level of uncertainty in the health benefits. Additional sensitivity analysis suggested the probability that progesterone would fall within the National Institute for Health and Care Excellence's threshold of L20,000-30,000 per quality-adjusted life-year as between 0.7145 and 0.7341. CONCLUSIONS: There is no evidence that first-trimester progesterone therapy improves outcomes in women with a history of unexplained RM. LIMITATIONS: This study did not explore the effect of treatment with other progesterone preparations or treatment during the luteal phase of the menstrual cycle. FUTURE WORK: Future research could explore the efficacy of progesterone supplementation administered during the luteal phase of the menstrual cycle in women attempting natural conception despite a history of RM. TRIAL REGISTRATION: Current Controlled Trials ISRCTN92644181; EudraCT 2009-011208-42; Research Ethics Committee 09/H1208/44. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 41. See the NIHR Journals Library website for further project information. PMID- 27225015 TI - Corrigenda: Corrigendum to 'The risk of overweight/obesity in mid-life and late life for the development of dementia: a systematic review and meta-analysis of longitudinal studies'. PMID- 27225016 TI - Effectiveness of a hospital-initiated smoking cessation programme: 2-year health and healthcare outcomes. AB - BACKGROUND: Tobacco-related illnesses are leading causes of death and healthcare use. Our objective was to determine whether implementation of a hospital initiated smoking cessation intervention would reduce mortality and downstream healthcare usage. METHODS: A 2-group effectiveness study was completed comparing patients who received the 'Ottawa Model' for Smoking Cessation intervention (n=726) to usual care controls (n=641). Participants were current smokers, >17 years old, and recruited during admission to 1 of 14 participating hospitals in Ontario, Canada. Baseline data were linked to healthcare administrative data. Competing-risks regression analysis was used to compare outcomes between groups. RESULTS: The intervention group experienced significantly lower rates of all cause readmissions, smoking-related readmissions, and all-cause emergency department (ED) visits at all time points. The largest absolute risk reductions (ARR) were observed for all-cause readmissions at 30 days (13.3% vs 7.1%; ARR, 6.1% (2.9% to 9.3%); p<0.001), 1 year (38.4% vs 26.7%; ARR, 11.7% (6.7% to 16.6%); p<0.001), and 2 years (45.2% vs 33.6%; ARR, 11.6% (6.5% to 16.8%); p<0.001). The greatest reduction in risk of all-cause ED visits was at 30 days (20.9% vs 16.4%; ARR, 4.5% (0.4% to 8.7%); p=0.03). Reduction in mortality was not evident at 30 days, but significant reductions were observed by year 1 (11.4% vs 5.4%; ARR 6.0% (3.1% to 9.0%); p<0.001) and year 2 (15.1% vs 7.9%; ARR, 7.3% (3.9% to 10.7%); p<0.001). CONCLUSIONS: Considering the relatively low cost, greater adoption of hospital-initiated tobacco cessation interventions should be considered to improve patient outcomes and decrease subsequent healthcare usage. PMID- 27225017 TI - 'Opt-out' referrals after identifying pregnant smokers using exhaled air carbon monoxide: impact on engagement with smoking cessation support. AB - BACKGROUND: In the UK, free smoking cessation support is available to pregnant women; only a minority accesses this. 'Opt-out' referrals to stop smoking services (SSS) are recommended by UK guidelines. These involve identifying pregnant smokers using exhaled carbon monoxide (CO) and referring them for support unless they object. METHODS: To assess the impact of 'opt-out' referrals for pregnant smokers on SSS uptake and effectiveness, we conducted a 'before after' service development evaluation. In the 6-month 'before' period, there was a routine 'opt-in' referral system for self-reported smokers at antenatal 'booking' appointments. In the 6-month 'after' period, additional 'opt-out' referrals were introduced at the 12-week ultrasound appointments; women with CO>=4 ppm were referred to, and outcome data were collected from, local SSS. RESULTS: Approximately 2300 women attended antenatal care in each period. Before the implementation, 536 (23.4%) women reported smoking at 'booking' and 290 (12.7%) were referred to SSS. After the implementation, 524 (22.9%) women reported smoking at 'booking', an additional 156 smokers (6.8%) were identified via the 'opt-out' referrals and, in total, 421 (18.4%) were referred to SSS. Over twice as many women set a quit date with the SSS after 'opt-out' referrals were implemented (121 (5.3%, 95% CI 4.4% to 6.3%) compared to 57 (2.5%, 95% CI 1.9% to 3.2%) before implementation) and reported being abstinent 4 weeks later (93 (4.1%, 95% CI 3.3% to 4.9%) compared to 46 (2.0%, 1.5% to 2.7%) before implementation). CONCLUSIONS: In a hospital with an 'opt-in' referral system, adding CO screening with 'opt-out' referrals as women attended ultrasound examinations doubled the numbers of pregnant smokers setting quit dates and reporting smoking cessation. PMID- 27225019 TI - Survey of Infection Prevention Best Practices in a University OB/GYN Service: Barriers, Obstacles, and Uncertainties. PMID- 27225018 TI - Danish study of Non-Invasive testing in Coronary Artery Disease (Dan-NICAD): study protocol for a randomised controlled trial. AB - BACKGROUND: Coronary computed tomography angiography (CCTA) is an established method for ruling out coronary artery disease (CAD). Most patients referred for CCTA do not have CAD and only approximately 20-30 % of patients are subsequently referred to further testing by invasive coronary angiography (ICA) or non invasive perfusion evaluation due to suspected obstructive CAD. In cases with severe calcifications, a discrepancy between CCTA and ICA often occurs, leading to the well-described, low-diagnostic specificity of CCTA. As ICA is cost consuming and involves a risk of complications, an optimized algorithm would be valuable and could decrease the number of ICAs that do not lead to revascularization. The primary objective of the Dan-NICAD study is to determine the diagnostic accuracy of cardiac magnetic resonance imaging (CMRI) and myocardial perfusion scintigraphy (MPS) as secondary tests after a primary CCTA where CAD could not be ruled out. The secondary objective includes an evaluation of the diagnostic precision of an acoustic technology that analyses the sound of coronary blood flow. It may potentially provide better stratification prior to CCTA than clinical risk stratification scores alone. METHODS/DESIGN: Dan-NICAD is a multi-centre, randomised, cross-sectional trial, which will include approximately 2,000 patients without known CAD, who were referred to CCTA due to a history of symptoms suggestive of CAD and a low-risk to intermediate-risk profile, as evaluated by a cardiologist. Patient interview, sound recordings, and blood samples are obtained in connection with the CCTA. All patients with suspected obstructive CAD by CCTA are randomised to either stress CMRI or stress MPS, followed by ICA with fractional flow reserve (FFR) measurements. Obstructive CAD is defined as an FFR below 0.80 or as high-grade stenosis (>90 % diameter stenosis) by visual assessment. Diagnostic performance is evaluated as sensitivity, specificity, predictive values, likelihood ratios, and C statistics. Enrolment commenced in September 2014 and is expected to be complete in May 2016. DISCUSSION: Dan-NICAD is designed to assess whether a secondary perfusion examination after CCTA could safely reduce the number of ICAs where revascularization is not required. The results are expected to add knowledge about the optimal algorithm for diagnosing CAD. TRIAL REGISTRATION: Clinicaltrials.gov identifier, NCT02264717 . Registered on 26 September 2014. PMID- 27225020 TI - Mesopic Pelli-Robson contrast sensitivity and MP-1 microperimetry in healthy ageing and age-related macular degeneration. AB - PURPOSE: To determine whether decreasing illumination of the Pelli-Robson contrast sensitivity (CS) chart and MP-1 microperimeter to low mesopic conditions is more sensitive to vision changes occurring with healthy ageing and in early and intermediate age-related macular degeneration (AMD) and whether these mesopic tests can differentiate visual function between healthy older participants with and without AMD risk genotypes. METHODS: Retinal sensitivity was measured in 98 healthy participants (19-85 years) and 21 AMD (AREDS Grade 2/3) patients (73.9 +/ 6.5 years) using the Pelli-Robson CS chart and MP-1 microperimeter under low mesopic and standard illumination. The effect of ageing and AMD on retinal sensitivity was estimated using regression analysis. Healthy older participants (>50 years; n = 24) were genotyped for AMD risk genes CFH and/or ARMS2 and retinal sensitivity was compared between genotypes. RESULTS: With healthy ageing, photopic and mesopic Pelli-Robson CS showed a similar decline (-0.004 log CS/year). In AMD, photopic CS showed a similar decline to healthy ageing (-0.004 log CS/year) while mesopic CS was significantly reduced (-0.007 log CS/year). Both standard and low mesopic microperimetry showed a significant decline (-0.51 and -0.73% contrast/year) with healthy ageing and greater decline (-0.73 and 0.99% contrast/year) with AMD onset. Pelli-Robson CS and microperimetry sensitivity did not differ between AMD risk genotypes in healthy participants. CONCLUSIONS: Mesopic Pelli-Robson CS detects functional deficits before photopic CS in early and intermediate AMD that can be differentiated from ageing. This test can be easily administered in clinical practice and may provide a means for early detection of retinal dysfunction. PMID- 27225021 TI - Influence of different salting processes on the evolution of the volatile metabolites of vacuum-packed fillets of farmed and wild sea bass (Dicentrarchus labrax) stored under refrigeration conditions: a study by SPME-GC/MS. AB - BACKGROUND: Fish shelf-life extension is a topic of great interest. In this study the behaviour of salted and unsalted farmed and wild European sea bass (Dicentrarchus labrax) fillets during storage was analysed through the evolution of their volatile metabolites. Farmed and wild sea bass fillets were brine-salted for 15 or 75 min, or dry-salted, vacuum-packed and stored at 4 degrees C for up to 1 month, and their headspaces were studied by Solid Phase Micro extraction-Gas Chromatography/Mass Spectrometry (SPME-GC/MS). RESULTS: At the same storage time, unsalted wild fillets contained, in general, a higher number and abundance of volatile compounds coming from microbiological or endogenous enzymatic activity than unsalted farmed ones. The more intense the salting, the lower the number and abundance of microbiological spoilage metabolites, especially in wild samples. The appearance of oxidation metabolites only in dry-salted wild samples evidences that this kind of salting provokes a certain oxidation in these samples. CONCLUSIONS: The better performance of farmed than wild fillets suggests that salted farmed fillets, vacuum-packed and stored under refrigeration conditions, could be a successful alternative to diversify the presence of sea bass in the market. (c) 2016 Society of Chemical Industry. PMID- 27225024 TI - Sex, Ethics, and Young People. PMID- 27225022 TI - Transcriptome analysis of Streptococcus pneumoniae treated with the designed antimicrobial peptides, DM3. AB - In our previous studies, we generated a short 13 amino acid antimicrobial peptide (AMP), DM3, showing potent antipneumococcal activity in vitro and in vivo. Here we analyse the underlying mechanisms of action using Next-Generation transcriptome sequencing of penicillin (PEN)-resistant and PEN-susceptible pneumococci treated with DM3, PEN, and combination of DM3 and PEN (DM3PEN). DM3 induced differential expression in cell wall and cell membrane structural and transmembrane processes. Notably, DM3 altered the expression of competence induction pathways by upregulating CelA, CelB, and CglA while downregulating Ccs16, ComF, and Ccs4 proteins. Capsular polysaccharide subunits were downregulated in DM3-treated cells, however, it was upregulated in PEN- and DM3PEN-treated groups. Additionally, DM3 altered the amino acids biosynthesis pathways, particularly targeting ribosomal rRNA subunits. Downregulation of cationic AMPs resistance pathway suggests that DM3 treatment could autoenhance pneumococci susceptibility to DM3. Gene enrichment analysis showed that unlike PEN and DM3PEN, DM3 treatment exerted no effect on DNA-binding RNA polymerase activity but observed downregulation of RpoD and RNA polymerase sigma factor. In contrast to DM3, DM3PEN altered the regulation of multiple purine/pyrimidine biosynthesis and metabolic pathways. Future studies based on in vitro experiments are proposed to investigate the key pathways leading to pneumococcal cell death caused by DM3. PMID- 27225023 TI - Construction of plasmid-free Escherichia coli for the production of arabitol-free xylitol from corncob hemicellulosic hydrolysate. AB - High costs and low production efficiency are a serious constraint to bio-based xylitol production. For industrial-scale production of xylitol, a plasmid-free Escherichia coli for arabitol-free xylitol production from corncob hemicellulosic hydrolysate has been constructed. Instead of being plasmid and inducer dependent, this strain relied on multiple-copy integration of xylose reductase (XR) genes into the chromosome, where their expression was controlled by the constitutive promoter P43. In addition, to minimize the flux from L-arabinose to arabitol, two strategies including low XR total activity and high selectivity of XR has been adopted. Arabitol was significantly decreased using plasmid-free strain which had lower XR total activity and an eight point-mutations of XR with a 27-fold lower enzyme activity toward L-arabinose was achieved. The plasmid-free strain in conjunction with this mutant XR can completely eliminate arabitol formation in xylitol production. In fed-batch fermentation, this plasmid-free strain produced 143.8 g L(-1) xylitol at 1.84 g L(-1) h(-1) from corncob hemicellulosic hydrolysate. From these results, we conclude that this route by plasmid-free E. coli has potential to become a commercially viable process for xylitol production. PMID- 27225025 TI - Tuberculids: cutaneous indicator diseases of Mycobacterium tuberculosis infection in young patients. AB - BACKGROUND: In the past years the incidence of tuberculosis has dropped significantly in most parts of Europe and the presentation of symptomatic tuberculosis cases have become increasingly rare. With the recent influx of refugees in Europe coming from tuberculosis endemic areas like the Middle East and Africa, it is expected that the incidence of tuberculosis will increase. OBJECTIVES: Cutaneous symptoms are important hallmarks that can be of aid for the correct diagnosis of an underlying disease, like tuberculosis. METHODS: We describe 2 young patients with tuberculids, respectively lichen scrofulosorum and papulonecrotic tuberculids, caused by a systemic Mycobacterium tuberculosis infection. RESULTS: Tuberculids are cutaneous immunological reactions triggered by a Mycobacterium tuberculosis infection elsewhere in the body. The three main manifestations of cutaneous tuberculids are: lichen scrofulosorum, papulonecrotic tuberculids and erythema induratum of Bazin. Whereas the latter is more common, the first two presentations are rare. CONCLUSION: It is of importance that clinicians, including dermatologists, are aware of the spectrum of clinical presentations of tuberculosis to halt this destructive and highly contagious disease early in its course. PMID- 27225026 TI - The Sodium-Oxygen/Carbon Dioxide Electrochemical Cell. AB - Electrochemical cells that utilize metals in the anode and an ambient gas as the active material in the cathode blur the lines between fuel cells and batteries. Such cells are under active consideration worldwide because they are considered among the most promising energy storage platforms for electrified transportation. Li-air batteries are among the most actively investigated cells in this class, but long-term challenges, such as CO2 contamination of the cathode gas and electrolyte decomposition, are associated with loss of rechargeability owing to metal carbonate formation in the cathode. Remediation of the first of these problems adds significant infrastructure burdens to the Li-air cell that bring into question its commercial viability. Several recent studies offer contradictory evidence, namely, that the presence of substantial fractions of CO2 in the cathode gas stream can have significant benefits, including increasing the already high specific energy of a Li-O2 cell by as much as 200 %. In this report, we consider electrochemical processes in model Na-O2 /CO2 cells and find that, provided the electrode/electrolyte interfaces are electrochemically stable, such cells are able to deliver both exceptional energy storage capacity and stable long-term charge-discharge cycling behaviors at room temperature. PMID- 27225027 TI - Fabrication of COF-MOF Composite Membranes and Their Highly Selective Separation of H2/CO2. AB - The search for new types of membrane materials has been of continuous interest in both academia and industry, given their importance in a plethora of applications, particularly for energy-efficient separation technology. In this contribution, we demonstrate for the first time that a metal-organic framework (MOF) can be grown on the covalent-organic framework (COF) membrane to fabricate COF-MOF composite membranes. The resultant COF-MOF composite membranes demonstrate higher separation selectivity of H2/CO2 gas mixtures than the individual COF and MOF membranes. A sound proof for the synergy between two porous materials is the fact that the COF-MOF composite membranes surpass the Robeson upper bound of polymer membranes for mixture separation of a H2/CO2 gas pair and are among the best gas separation MOF membranes reported thus far. PMID- 27225029 TI - Watt-level passively Q-switched heavily Er(3+)-doped ZBLAN fiber laser with a semiconductor saturable absorber mirror. AB - A diode-cladding pumped mid-infrared passively Q-switched Er(3+)-doped ZBLAN fiber laser with an average output power of watt-level based on a semiconductor saturable absorber mirror (SESAM) is demonstrated. Stable pulse train was produced at a slope efficiency of 17.8% with respect to launched pump power. The maximum average power of 1.01 W at a repetition rate of 146.3 kHz was achieved with a corresponding pulse energy of 6.9 MUJ, from which the maximum peak power was calculated to be 21.9 W. To the best of our knowledge, the average power and the peak power are the highest in 3 MUm region passively Q-switched fiber lasers. The influence of gain fiber length on the operation regime of the fiber laser has been investigated in detail. PMID- 27225030 TI - Formal [3+2] Cycloaddition of Nitrosoallenes with Carbonyl and Nitrile Compounds to Form Functional Cyclic Nitrones. AB - The synthesis of functional cyclic nitrones via [3+2] cycloadditions of allenamide-derived nitrosoallenes with carbonyl/nitrile compounds, including ketones, esters, and nitriles, is presented herein. Rapid carbon-carbon, carbon oxygen, and carbon-nitrogen bond formations were achieved with in situ prepared nitrosoallenes, and densely substituted oxacyclic and carbocyclic nitrones containing tetrasubstituted carbon centers were successfully synthesized. The spirocyclic nitrone products synthesized from cyclic dicarbonyl compounds underwent the unique skeletal rearrangements to cyclic alpha-ketonitrones. PMID- 27225028 TI - Immunotherapy in glioblastoma: emerging options in precision medicine. AB - Immunotherapy for glioblastoma (GBM) provides a unique opportunity for targeted therapies for each patient, addressing individual variability in genes, tumor biomarkers and clinical profile. As immunotherapy has the potential to specifically target tumor cells with minimal risk to normal tissue, several immunotherapeutic strategies are currently being evaluated in clinical trials in GBM. With the Precision Medicine Initiative being announced in the President's State of the Union Address in 2016, GBM immunotherapy provides a useful platform for changing the landscape in treating patients with difficult disease. PMID- 27225031 TI - Broadband diffuse terahertz wave scattering by flexible metasurface with randomized phase distribution. AB - Suppressing specular electromagnetic wave reflection or backward radar cross section is important and of broad interests in practical electromagnetic engineering. Here, we present a scheme to achieve broadband backward scattering reduction through diffuse terahertz wave reflection by a flexible metasurface. The diffuse scattering of terahertz wave is caused by the randomized reflection phase distribution on the metasurface, which consists of meta-particles of differently sized metallic patches arranged on top of a grounded polyimide substrate simply through a certain computer generated pseudorandom sequence. Both numerical simulations and experimental results demonstrate the ultralow specular reflection over a broad frequency band and wide angle of incidence due to the re distribution of the incident energy into various directions. The diffuse scattering property is also polarization insensitive and can be well preserved when the flexible metasurface is conformably wrapped on a curved reflective object. The proposed design opens up a new route for specular reflection suppression, and may be applicable in stealth and other technology in the terahertz spectrum. PMID- 27225033 TI - UK survey of occupational therapist's and physiotherapist's experiences and attitudes towards hip replacement precautions and equipment. AB - BACKGROUND: Total hip replacement (THR) is one of the most common orthopaedic procedures in the United Kingdom (UK). Historically, people following THR have been provided with hip precautions and equipment such as: raised toilet seats and furniture rises, in order to reduce the risks of dislocation post-operation. The purpose of this study was to determine current practices in the provision of these interventions in the UK for people following primary THR. METHODS: A 27 question, self-administered online survey was developed and distributed to UK physiotherapists and occupational therapists involved in the management of people following primary THR (target respondents). The survey included questions regarding the current practices in the provision of equipment and hip precautions for THR patients, and physiotherapist's and occupational therapist's attitudes towards these practices. The survey was disseminated through print and web based/social media channels. RESULTS: 170 health professionals (87 physiotherapists and 83 occupational therapists), responded to the survey. Commonly prescribed equipment in respondent's health trusts were raised toilet seats (95 %), toilet frames and rails (88 %), furniture raises (79 %), helping hands/grabbers (77 %), perching stools (75 %) and long-handled shoe horns (75 %). Hip precautions were routinely prescribed by 97 % of respondents. Hip precautions were most frequently taught in a pre-operative group (52 % of respondents). Similarly equipment was most frequently provided pre-operatively (61 % respondents), and most commonly by occupational therapists (74 % respondents). There was variability in the advice provided on the duration of hip precautions and equipment from up to 6 weeks post-operatively to life-time usage. CONCLUSIONS: Current practice on hip precautions and provision of equipment is not full representative of clinician's perceptions of best care after THR. Future research is warranted to determine whether and to whom hip precautions and equipment should be prescribed post-THR as opposed to the current 'blanket' provision of equipment and movement restriction provided in UK practice. PMID- 27225032 TI - Characterisation of the DNA sequence specificity, cellular toxicity and cross linking properties of novel bispyridine-based dinuclear platinum complexes. AB - BACKGROUND: The anti-tumour activity of cisplatin is thought to be a result of its capacity to form DNA adducts which prevent cellular processes such as DNA replication and transcription. These DNA adducts can effectively induce cancer cell death, however, there are a range of clinical side effects and drug resistance issues associated with its use. In this study, the biological properties of three novel dinuclear platinum-based compounds (that contain alkane bridging linkers of eight, ten and twelve carbon atoms in length) were characterised to assess their potential as anticancer agents. METHODS: The properties of these compounds were determined using a DNA template containing seven tandem telomeric repeat sequences. A linear amplification reaction was used in combination with capillary electrophoresis to quantify the sequence specificity of DNA adducts formed by these compounds at base pair resolution. The DNA cross-linking ability of these compounds was assessed using denaturing agarose gel electrophoresis and cytotoxicity was determined in HeLa cells using a colorimetric cell viability assay. RESULTS: The dinuclear compounds were found to preferentially form DNA adducts at guanine bases and they exhibited different damage intensity profiles at the telomeric repeat sequences compared to that of cisplatin. The dinuclear compounds were found to exhibit a low level of cytotoxicity relative to cisplatin and their cytotoxicity increased as the linker length increased. Conversely, the interstrand cross-linking efficiency of the dinuclear compounds increased as the linker length decreased and the compound with the shortest alkane linker was six-fold more effective than cisplatin. CONCLUSIONS: Since the bifunctional compounds exhibit variation in sequence specificity of adduct formation and a greater ability to cross-link DNA relative to cisplatin they warrant further investigation towards the goal of developing new cancer chemotherapeutic agents. PMID- 27225034 TI - Use of recombinant porcine beta-defensin 2 as a medicated feed additive for weaned piglets. AB - Post-weaning diarrhoea (PWD) in piglets is associated with colonization of the intestine with bacterial pathogens. In this study, we evaluated the use of recombinant porcine beta-defensin 2 (rpBD2) as a medicated feed additive for weaned piglets. The crude extract from the culture supernatant of rpBD2 expressing Pichia pastoris was used as a medicated feed additive for weaned piglets. Dietary treatments included a positive control (basal diet + antibiotics, designated PC) and three different rpBD2 treatments without antibiotics (basal diet supplemented with 1, 5, or 15 g of crude rpBD2/kg basal diet, designated 1PD, 5PD, and 15PD, respectively). Of all the treatments, 5PD had the greatest impact on the weaned piglets. It increased their body weight, average daily weight gain, average daily feed intake, and intestinal villus height in the duodenum and jejunum, and reduced the incidence of PWD. The diversity of the cecal digesta and mucosa microflora was compared between the weaned piglets in the PC and 5PD groups. Piglets treated with 5PD had lower diversity indices and fewer bacterial pathogens in their cecal digesta and mucosa than the PC group. Our results demonstrate that crude rpBD2 could provide an alternative to the traditional antibiotic feed additives given to weaned piglets. PMID- 27225035 TI - Differentiation of Rat Bone Marrow Mesenchymal Stem Cells Into Neuron-Like Cells In Vitro and Co-Cultured with Biological Scaffold as Transplantation Carrier. AB - BACKGROUND Autograft and allograft transplantation are used to prompt the regeneration of axons after nerve injury. However, the poor self-regeneration caused by the glial scar and growth inhibitory factors after neuronal necrosis limit the efficacy of these methods. The purpose of this study was to develop a new chitosan porous scaffold for cell seeding. MATERIAL AND METHODS The bone marrow mesenchymal stem cells (BMSCs) and tissue-engineered biomaterial scaffold compound were constructed and co-cultured in vitro with the differentiated BMSCs of Wistar rats and chitosan scaffold in a 3D environment. The purity of the third generation BMSCs culture was identified using flow cytometry and assessment of induced neuronal differentiation. The scaffolds were prepared by the freeze drying method. The internal structure of scaffolds and the change of cells' growth and morphology were observed under a scanning electron microscope. The proliferation of cells was detected with the MTT method. RESULTS On day 5 there was a significant difference in the absorbance value of the experimental group (0.549+/-0.0256) and the control group (0.487+/-0.0357) (P>0.05); but on day 7 there was no significant difference in the proliferation of the experimental group (0.751+/-0.011) and the control group and (0.78+/-0.017) (P>0.05). CONCLUSIONS Tissue engineering technology can provide a carrier for cells seeding and is expected to become an effective method for the regeneration and repair of nerve cells. Our study showed that chitosan porous scaffolds can be used for such purposes. PMID- 27225036 TI - Affectionate Touch to Promote Relational, Psychological, and Physical Well-Being in Adulthood: A Theoretical Model and Review of the Research. AB - Throughout the life span, individuals engage in affectionate touch with close others. Touch receipt promotes well-being in infancy, but the impacts of touch in adult close relationships have been largely unexplored. In this article, we propose that affectionate touch receipt promotes relational, psychological, and physical well-being in adulthood, and we present a theoretical mechanistic model to explain why affectionate touch may promote these outcomes. The model includes pathways through which touch could affect well-being by reducing stress and by promoting well-being independent of stress. Specifically, two immediate outcomes of affectionate touch receipt-relational-cognitive changes and neurobiological changes-are described as important mechanisms underlying the effects of affectionate touch on well-being. We also review and evaluate the existing research linking affectionate touch to well-being in adulthood and propose an agenda to advance research in this area. This theoretical perspective provides a foundation for future work on touch in adult close relationships. PMID- 27225037 TI - Beyond Dominance and Competence: A Moral Virtue Theory of Status Attainment. AB - Recognition has grown that moral behavior (e.g., generosity) plays a role in status attainment, yet it remains unclear how, why, and when demonstrating moral characteristics enhances status. Drawing on philosophy, anthropology, psychology, and organizational behavior, I critically review a third route to attaining status: virtue, and propose a moral virtue theory of status attainment to provide a generalized account of the role of morality in status attainment. The moral virtue theory posits that acts of virtue elicit feelings of warmth and admiration (for virtue), and willing deference, toward the virtuous actor. I further consider how the scope and priority of moralities and virtues endorsed by a moral community are bound by culture and social class to affect which moral characteristics enhance status. I end by outlining an agenda for future research into the role of virtue in status attainment. PMID- 27225038 TI - Bad Memory: CD4 T Cell Presensitization Fosters Antibody-Mediated Kidney Transplant Rejection. PMID- 27225039 TI - Calcific Uremic Arteriolopathy Revisited. PMID- 27225040 TI - Denaturation induced aggregation in alpha-crystallin: differential action of chaotropes. AB - alpha-Crystallin is a member of small heat shock proteins and is believed to play an exceptional role in the stability of eye lens proteins. The disruption or denaturation of the protein arrangement or solubility of the crystallin proteins can lead to vision problems including cataract. In the present study, we have examined the effect of chemical denaturants urea and guanidine hydrochloride (GdnHCl) on alpha-crystallin aggregation, with special emphasis on protein conformational changes, unfolding, and amyloid fibril formation. GdnHCl (4 M) induced a 16 nm red shift in the intrinsic fluorescence of alpha-crystallin, compared with 4 nm shift by 8 M urea suggesting a major change in alpha crystallin structure. Circular dichroism analysis showed marked increase in the ellipticity of alpha-crystallin at 216 nm, suggesting gain in beta-sheet structure in the presence of GdnHCl (0.5-1 M) followed by unfolding at higher concentration (2-6 M). However, only minor changes in the secondary structure of alpha-crystallin were observed in the presence of urea. Moreover, 8 anilinonaphthalene-1-sulfonic acid fluorescence measurement in the presence of GdnHCl and urea showed changes in the hydrophobicity of alpha-crystallin. Amyloid studies using thioflavin T fluorescence and congo red absorbance showed that GdnHCl induced amyloid formation in alpha-crystallin, whereas urea induced aggregation in this protein. Electron microscopy studies further confirmed amyloid formation of alpha-crystallin in the presence of GdnHCl, whereas only aggregate-like structures were observed in alpha-crystallin treated with urea. Our results suggest that alpha-crystallin is susceptible to unfolding in the presence of chaotropic agents like urea and GdnHCl. The destabilized protein has increased likelihood to fibrillate. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27225041 TI - Investigation of photoelectrical properties of alpha-Si3N4 nanobelts with surface modifications using first-principles calculations. AB - The structural stability, electronic and optical properties of alpha-Si3N4 nanobelts orientating along the different directions with surface H, F and Cl modifications are investigated using first-principles methods. The stabilities of alpha-Si3N4 nanobelts are greatly affected by the surface modifications and increased in the order of H, Cl and F. All the modified alpha-Si3N4 nanobelts exhibit semiconductor characteristics. The effective masses of nanobelts are mainly affected by their orientations as well as surface modifications. The band gaps of alpha-Si3N4 nanobelts are found to be modulated by surface modifications. The Cl-modified nanobelts result in a smaller band gap than that of H- or F modified ones. The electronic properties of alpha-Si3N4 nanobelts have significantly affected their optical properties. The linear light response ranges are mainly located in the ultraviolet region, where the absorption and refraction of light mainly occur, while the reflection is very weak. As the halogen coverage increases to 100%, the absorption edges of alpha-Si3N4 nanobelts have an obvious red-shift and new dielectric peaks appear. The Cl-modified nanobelts possess higher epsilon2(omega) peaks, lower absorption edges and better photoelectric characteristics than those of H- or F-modified nanobelts. The static optical parameters epsilon(0) and n(0) of 100% Cl-modified alpha-Si3N4 nanobelts are significantly larger than those of other nanobelts, indicating special applications in certain optical components. PMID- 27225042 TI - Modulation of T Cell Activation in Obesity. AB - SIGNIFICANCE: Immune T cells are present in adipose tissues (AT), and the stoichiometry of the different T cell subsets is altered during diet-induced obesity (DIO). T cells contribute to the early steps of AT inflammation during DIO. Recent Advances: Many factors could potentially be responsible for this altered pro-inflammatory versus anti-inflammatory T cell balance. CRITICAL ISSUES: T cells are potentially activated in AT, which vitamin D might contribute to, as will be discussed in this article. In addition, we will review the different possible contributors to T cell activation in AT, such as the CD28 and CD154 T cell costimulatory molecules in AT. FUTURE DIRECTIONS: The potential antigen presentation capacities of adipocytes should be further investigated. Moreover, the properties of these AT resident (or migrating to AT) T cells must be further assessed. Antioxid. Redox Signal. 26, 489-500. PMID- 27225044 TI - Improvement of electrochemical performance of nickel rich LiNi0.6Co0.2Mn0.2O2 cathode active material by ultrathin TiO2 coating. AB - LiNi0.6Co0.2Mn0.2O2 cathode material has been surface-modified by coating with ultrathin TiO2via atomic layer deposition (ALD) technology to improve the electrochemical performance of LiNi0.6Co0.2Mn0.2O2 cathodes for lithium ion batteries. Within the cut-off voltage of 2.5-4.3 V, the coated sample delivers an initial discharge capacity of 187.7 mA h g(-1) at 0.1 C and with a capacity retention about 85.9% after 100 cycles at 1 C, which provides a significant improvement in terms of discharge capacity and cyclability, as compared with those of the bare one. Such enhanced electrochemical performance of the coated sample is ascribed to its high-quality ultrathin coating of amorphous TiO2, which can protect the active material from HF attack, withstand the dissolution of metal ions in the electrode and favor the lithium diffusion of oxide as proved by electrochemical impedance spectroscopy (EIS) tests. TiO2 coating via the ALD process provides a potential approach for battery factories to surface-modify Ni rich electrode materials so as to realize improvements in electrochemical performance. PMID- 27225043 TI - Overground walking training with the i-Walker, a robotic servo-assistive device, enhances balance in patients with subacute stroke: a randomized controlled trial. AB - BACKGROUND: Patients affected by mild stroke benefit more from physiological overground walking training than walking-like training performed in place using specific devices. The aim of the study was to evaluate the effects of overground robotic walking training performed with the servo-assistive robotic rollator (i Walker) on walking, balance, gait stability and falls in a community setting in patients with mild subacute stroke. METHODS: Forty-four patients were randomly assigned to two different groups that received the same therapy in two daily 40 min sessions 5 days a week for 4 weeks. Twenty sessions of standard therapy were performed by both groups. In the other 20 sessions the subjects enrolled in the i Walker-Group (iWG) performed with the i-Walker and the Control-Group patients (CG) performed the same amount of conventional walking oriented therapy. Clinical and instrumented gait assessments were made pre- and post-treatment. The follow up observation consisted of recording the number of fallers in the community setting after 6 months. RESULTS: Treatment effectiveness was higher in the iWG group in terms of balance improvement (Tinetti: 68.4 +/- 27.6 % vs. 48.1 +/- 33.9 %, p = 0.033) and 10-m and 6-min timed walking tests (significant interaction between group and time: F(1,40) = 14.252, p = 0.001; and F(1,40) = 7.883, p = 0.008, respectively). When measured, latero-lateral upper body accelerations were reduced in iWG (F = 4.727, p = 0.036), suggesting increased gait stability, which was supported by a reduced number of falls at home. CONCLUSIONS: A robotic servo assisted i-Walker improved walking performance and balance in patients affected by mild/moderate stroke, leading to increased gait stability and reduced falls in the community. TRIAL REGISTRATION: This study was registered on anzctr.org.au (July 1, 2015; ACTRN12615000681550 ). PMID- 27225045 TI - Purple urine bag syndrome. PMID- 27225046 TI - STATISTICS AND INTELLIGENCE IN DEVELOPING COUNTRIES: A NOTE. AB - The purpose of this study is to assess the relationship between intelligence (or human capital) and the statistical capacity of developing countries. The line of inquiry is motivated essentially by the scarce literature on poor statistics in developing countries and an evolving stream of literature on the knowledge economy. A positive association is established between intelligence quotient (IQ) and statistical capacity. The relationship is robust to alternative specifications with varying conditioning information sets and control for outliers. Policy implications are discussed. PMID- 27225047 TI - Assembling Bare Au Nanoparticles at Positively Charged Templates. AB - In-situ X-ray reflectivity (XRR) and grazing incidence X-ray small-angle scattering (GISAXS) reveal that unfunctionalized (bare) gold nanoparticles (AuNP) spontaneously adsorb to a cationic lipid template formed by a Langmuir monolayer of DPTAP (1,2-dihexadecanoyl-3-trimethylammonium-propane) at vapor/aqueous interfaces. Analysis of the XRR yields the electron density profile across the charged-interfaces along the surface normal showing the AuNPs assemble with vertical thickness comparable to the particle size. The GISAXS analysis indicates that the adsorbed mono-particle layer exhibits short-range in-plane correlations. By contrast, single-stranded DNA-functionalized AuNPs, while attracted to the positively charged surface (more efficiently with the addition of salt to the solution), display less in-plane regular packing compared to bare AuNPs. PMID- 27225048 TI - Randomizing Patients without Consent: Waiver vs Exception from Informed Consent. AB - Cole JB , Ho JD , Biros MH . Randomizing patients without consent: waiver vs exception from informed consent. Prehosp Disaster Med. 2016;31(4):457-458. PMID- 27225049 TI - Inherited catecholaminergic polymorphic ventricular tachycardia due to RYR2 mutation. AB - We report the case of an 11-year-old boy who was diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT). The patient had a medical history of three episodes of syncope. The last episode was cardiac arrest while swimming. After resuscitation using automated external defibrillator, he was placed under cerebral hypothermia, examined for long QT syndrome, and underwent insertion of implantable cardioverter defibrillator. He was subsequently discharged from hospital without any adverse sequelae. The patient was diagnosed with CPVT after detection of ryanodine receptor 2 mutation. His father also carried the same mutation, although he did not have any symptoms nor did he have a history of syncope. We propose that CPVT should be included in the differential diagnosis in children with recurrent episodes of syncope. PMID- 27225050 TI - Disposition and metabolism of TAK-438 (vonoprazan fumarate), a novel potassium competitive acid blocker, in rats and dogs. AB - 1. Following oral administration of [14C]TAK-438, the radioactivity was rapidly absorbed in rats and dogs. The apparent absorption of the radioactivity was high in both species. 2. After oral administration of [14C]TAK-438 to rats, the radioactivity in most tissues reached the maximum at 1-hour post-dose. By 168 hour post-dose, the concentrations of the radioactivity were at very low levels in nearly all the tissues. In addition, TAK-438F was the major component in the stomach, whereas TAK-438F was the minor component in the plasma and other tissues. High accumulation of TAK-438F in the stomach was observed after oral and intravenous administration. 3. TAK-438F was a minor component in the plasma and excreta in both species. Its oxidative metabolite (M-I) and the glucuronide of a secondary metabolite formed by non-oxidative metabolism of M-I (M-II-G) were the major components in the rat and dog plasma, respectively. The glucuronide of M-I (M-I-G) and M-II-G were the major components in the rat bile and dog urine, respectively, and most components in feces were other unidentified metabolites. 4. The administered radioactive dose was almost completely recovered. The major route of excretion of the drug-derived radioactivity was via the feces in rats and urine in dogs. PMID- 27225051 TI - Late preterm birth is a strong predictor of maternal stress later in life: Retrospective cohort study in school-aged children. AB - AIM: The aim of this study was to compare the level of stress in mothers of school-aged children born late preterm and admitted to the intensive care unit (ICU) with the level of maternal stress if a child was born late preterm and not admitted to the ICU as well as if a full-term child was admitted to the ICU. METHODS: In this retrospective cohort study the data were gathered via telephone interview with mothers. The Parenting Stress Index/Short Form was used to determine the level of stress in mothers. Background demographic characteristics, medically relevant variables, and the level of stress were tested using the chi square test and Kruskal-Wallis test. Logistic regression was used in order to identify predictors of significant level of stress. RESULTS: Mothers of late preterm born children who were admitted to the ICU, as well as mothers of late preterm children who were not admitted had higher level of stress compared to mothers of full-term children. Namely, mothers of late preterm born children admitted to the ICU had 18-fold increase in risk for significant level of total stress (OR = 18.09; 95% CI 8.55 to 38.26) while 24-fold greater risk was observed in mothers of late preterm children who were not admitted to the ICU (OR = 24.05; 95% CI 10.66 to 54.26) in comparison to mothers of full-term born children. CONCLUSION: Results indicate that preterm birth and its complications are associated with a higher level of stress in mothers, that persists to school age. PMID- 27225052 TI - Janus-Cube Octasilsesquioxane: Facile Synthesis and Structure Elucidation. AB - A perfect "Janus-cube" octasilsesquioxane, a nanometer-scale Janus particle with two different types of substituents, was synthesized through the cross-coupling of a "half-cube" cyclic sodium siloxanolate with another half-cube cyclic fluorosiloxane. The structure was confirmed by X-ray crystallography to be a Janus cube. The overall synthesis is simple and does not require drastic separation methods compared with previous methods. The synthesis of the Janus cube demonstrates a novel siloxane bond-forming reaction involving the coupling a silanol salt and fluorosilane. The reaction is mild, does not result in acid generation, and could be applied to the construction of other novel siloxane compounds. PMID- 27225053 TI - [Oncological results in high grade prostate cancer treated surgically]. AB - OBJECTIVES: Prostate cancer is considered a tumour with a long natural history. However, its high-risk variants exhibit variable behaviour. We analyse the factors that affect BR and CSS (multivariate, Kaplan Meier). METHODS: From 1997 to 2013, 657 patients were operated of a high-grade prostate cancer (pT2b 7.2%, pT3a 73%, pT3b 18.3%, pT4 1.5%). Gleason score was >=8 in 23% of cases. Percentage of PSMs was 46.1%. Mean follow-up was 113 months (24-192). RESULTS: BR occurred in 36.5%. Patients with Gleason score <8, 31.7% had BR, Gleason >=8 had BR in 48% (p<0.05). PSMs recurrence occurred in 48.9%, whereas 26.1% in NSM (p<0.05). If lymphadenectomy, BR occurred in 48.7%, if not 30.9% (p<0,05). In multivariate analysis, stage, Gleason>=8 and PSMs were independent factors for BR. Treatment of BR was 36.5% radiotherapy, 24.1% HT, and 21.2% both simultaneously. Active surveillance was performed in 13.3%. Disease progression (biochemical or radiological) occurred in 23.5%. CSS was 98.93%, pT4 was the stage with the greatest mortality (10%), followed by pT3b (3.4%), p<0.05. Patients with a Gleason score >=8 accounted for 71% CSM (p<0,05). PSMs and lymphadenectomy didn't have repercussions for survival. In multivariate analysis, Gleason>=8 was independent factor for CSM. CONCLUSIONS: Radical prostatectomy plays an important role in multi-modal approach with good oncological control at medium follow up. Gleason score >=8 was the factor with the greatest effect on CSM. Lymphadenectomy didn't affect CSS. PMID- 27225054 TI - [Usefulness of urodynamics in the treatment of mixed urinary incontinence in women with suburethral slings]. AB - OBJECTIVE: The urodynamic results in suburethral slings (SS), are contradictory. We evaluate a series on patients with stress urinary incontinence (associated or not with bladder hyperactivity) that underwent suburethral slings (SS) operations. METHODS: 42 women (age 62+/-12 years) with urinary incontinence underwent suburethral slings (86% TOT, 12% TVT, 2% others), 36% of them with simultaneous pelvic organ prolapse correction. Medical history and a pre and postsurgery urodynamic studies (according to ICS instructions, except when specified) were performed. RESULTS: After surgery, the improvement of urinary incontinence was lower in patients with previous detrusor hyperactivity (DH) than without DH (60% vs 81 %), and the bladder capacity (BC) was lower (123+/-36 ml) in patients with previous mixed urinary incontinence (MUI) versus no MUI (241+/ 83 ml) (p=0.004). The decrease of BC was higher with previous MUI (184+/-92 ml vs 123+/-36 ml) versus no MUI (240+/-91 ml vs 237+/-78 ml), and the DH was more frequent in previous MUI and DH. There was a significant decrease of maximum flow rate (Qmax) (p=0.000) (although without clinical manifestation), and post void residual urine (p=0.007). We demonstrated a significant increase (p=0.001) of mean urethral resistance (URA): 12+/-9 cm H2O versus 15+/-12 cm H2O (without reaching obstruction range), and an improvement of detrusor contractility (W80 20): (3+/-4 W/m2; vs 6+/-17 W/m2;). CONCLUSION: We demonstrated worst results in MUI in patients with urinary incontinence undergoing SS. The urodynamic study gives a better prognosis reliability in the treatment of female urinary incontinence with SS. PMID- 27225055 TI - [Practical refinaments in simplified laparoscopic pyeloplasty]. AB - OBJECTIVES: Laparoscopic pyeloplasty (LP) is the treatment of choice for ureteropelvic junction obstruction (UPJO). We present the 3-trocars LP technique with several considerations and practical advices. METHODS: Several maneuvers to optimize exposure and simplifying the implementation of the operation were showed. A total of thirteen patients with UPJO and criteria for surgical treatment were included, and were operated using the 3 trocars LP technique. Demographic data, perioperative and follow-up were collected retrospectively. RESULTS: Mean operative time was 132 minutes. No conversion to open surgery was registered and additional trocar insertion was not required. Neither perioperative complications nor postoperative complications were reported. Three patients needed ureteral stenting preoperatively for pain. Five patients required flexible nephroscopy with CO2 for extraction of calyceal stones. The pain was controlled in all cases. CONCLUSIONS: The LP is a feasible and safe technique for the surgical correction of UPJO, and maneuvers presented in this study simplify the procedure and may be applied in other laparoscopic procedures. PMID- 27225057 TI - [Hematologic neoplasms with testicular involvement]. AB - OBJECTIVE: We report two cases of patients with a previous diagnosis of hematologic tumor who present with testicular recurrence, and we carry out a review of the literature regarding the infrequency of this pathology. METHODS: We present a retrospective review of the medical records of two patients diagnosed with hematologic malignancies (acute myelogenous leukemia and multiple myeloma) with occurrence of relapse in the testicle. We reviewed the management and outcome after treatment with bilateral orchiectomy. RESULTS: Case 1: The patient was diagnosed with acute myeloid leukemia and treated with an allogeneic transplant. Two years later, the patient reported an increase in testicular size. The complementary studies lead us to suspect a testicular recurrence that was confirmed after orchiectomy. Currently, the patient awaits the start of a chemotherapy treatment prior to a new allogeneic transplant. Case 2: Patient with the diagnosis of multiple myeloma who started a polychemotherapy treatment without response and underwent allogeneic transplant. After five months with complete remission, there were signs of systemic recurrence, and a study for a new transplant was carried out. During the study, potential testicular recurrence was observed. After a batch of complementary tests, bilateral orchiectomy was performed and the diagnosis was confirmed. Currently, the patient is undergoing an allogeneic transplant protocol after radiotherapy and chemotherapy treatment. CONCLUSIONS: Currently the mortality rate in cases of relapse of hematologic malignancy in the testicle has declined despite the sharp rise in its incidence. This is because of, as in our case, early diagnosis and the combined use of chemotherapy, radiotherapy and surgery. This has been achieved through an interdisciplinary collaboration of urologists, hematologists, oncologists and radiotherapists. PMID- 27225056 TI - The effect of asymptomatic histological prostatitis on sexual function and lower urinary tract symptoms. AB - OBJECTIVE: Prostatitis affects 10-14% of men of all ages and ethnicities. More than 50% of the men experience episodes of prostatitis at one time of their lives. Patients with CP typically have longlasting genitourinary/pelvic pain and obstructive and/or irritative voiding symptoms. Sexual dysfunction and psychological symptoms are frequently added to these symptoms. We also investigated the relationship between sexual functions, and lower urinary system symptoms, and asymptomatic histological prostatitis detected on transrectal ultrasound-guided (TRUS) biopsy performed with the indication of high PSA levels. METHODS: Sixty cases compliant with the study criteria among patients who underwent prostate biopsies between September 2014 and June 2015 with the indication of higher PSA levels were included in the study. All patients were requested to complete IIEF-5 and IPSS forms one day previously. Based on histological analysis of biopsy materials, the patients were allocated into groups of BPH (simple BPH without histological prostatitis) (n:30) and histological chronic prostatitis (combination of BPH and histological prostatitis) (n:30). RESULTS: Mean age of the cases was 65.73+/-5.01 (range, 56 75 yrs) years. PSA levels ranged between 4-15 ng/ml. A statistically significant intergroup difference was not found regarding mean age, BMIs, PSA levels, incidence rates of hypertension and coronary artery disease (p>0.05). Prostate volumes of the HCP group were higher than those of the BPH group , with statistically significant differences (p:0.001; p<0.01). Questionnaire forms of the patients included in the study were statistically evaluated, and mean IPSS score of the HCP group was found to be higher when compared with that of the BPH group, with statistically significant differences. (p:0.016; p<0.05). However mean IIEF score of the BPH group was higher than that of the HCP group, with statistically significant differences (p:0.039; p<0.05). DISCUSSION: These findings suggested the presence of a correlation between chronic inflammation and lower urinary tract symptoms (LUTS). In addition, statistically significant lower IIEF values in patients with histological chronic prostatitis relative to those without suggested negative effects of even asymptomatic inflammation on sexual functions and mechanism of erection. PMID- 27225058 TI - [Clear cell renal cell carcinoma metastasized by a breast ductal carcinoma]. AB - OBJECTIVE: To report a clear cell renal cell carcinoma recipient of a metastasizing ductal carcinoma of the breast: A tumor-to-tumor metastasis. METHODS: A 71 year-old woman with a past history of breast carcinoma, diagnosed 12 years before, underwent a nephrectomy for an incidental kidney mass found in a routine imaging examination. RESULTS: Histological examination revealed foci of ductal carcinoma of the breast in an otherwise typical clear cell renal cell carcinoma of the kidney. Immunohistochemical examination confirmed a metastasis of an infiltrating breast carcinoma to a clear cell renal cell carcinoma (positive to GATA3, hormonal receptors and mamoglobin) in a clear cell renal cell carcinoma (positive to PAX8, CD10 and vimentin). CONCLUSIONS: Awareness of this phenomenon should always be kept in mind by urologist in patients with a known history of a previous malignancy and by pathologists when finding a renal tumor with an unusual or dimorphic morphology. Immunohistochemistry plays an important role to establish the exact diagnosis. PMID- 27225059 TI - [Evolution of urinary lithiasis composition in a Spanish health care area over the last four decades]. AB - OBJECTIVE: To provide an updated epidemiological description of urinary lithiasis in a health area in the Western hemisphere over the past four decades. METHODS: 2704 urinary lithiases analysed in our institution between 1980 and 2015 were retrospectively reviewed. They were analyzed using polarized light microscopy, and in the case this method had questionable results we used X-ray diffraction. The variables collected were the lithiasis chemical composition (oxalates, phosphates, uric acid, infectious, cystine, mixed, other). Regarding the date of the analysis, the series of cases was grouped into four periods (1980-1989, 1990- 1999, 2000-2009, and 2010-2015), and also by sex and age of the patient. RESULTS: The mean age at diagnosis was 48.32 years (49.37 in men vs 46.53 in women, p=0.005). A male predominance was found (58.7%). Throughout the four decades, the involvement of women has progressively diminished compared to men. Of all the lithiases, the most frequent were those composed of oxalates (43.3%), followed by uric acid (16.9%) and infectious types (10.7%). The uric acid and oxalate lithiases were more common in men than in women (67.4% vs. 32.6% and 59.1% vs. 40.9%, respectively, p<0.001), while the lithiasis of infectious origin was more frequent in women than in men (56.3% vs. 43.7%, p<0.001). Throughout the time period, a trend of increasing oxalic lithiases and decreasing uric acid and phosphate lithiases was observed, as well as an increase of infectious lithiases over the past five years. CONCLUSIONS: In our setting, urinary lithiases appear more frequently in males at the end of the fourth decade of life. The most common lithiases are composed of oxalates, and their frequency has increased over time, while uric acid and phosphates lithiases have decreased. PMID- 27225061 TI - Synergistically Enhanced Polysulfide Chemisorption Using a Flexible Hybrid Separator with N and S Dual-Doped Mesoporous Carbon Coating for Advanced Lithium Sulfur Batteries. AB - Because of the outstanding high theoretical specific energy density of 2600 Wh kg(-1), the lithium-sulfur (Li-S) battery is regarded as a promising candidate for post lithium-ion battery systems eligible to meet the forthcoming market requirements. However, its commercialization on large scale is thwarted by fast capacity fading caused by the Achilles' heel of Li-S systems: the polysulfide shuttle. Here, we merge the physical features of carbon-coated separators and the unique chemical properties of N and S codoped mesoporous carbon to create a functional hybrid separator with superior polysulfide affinity and electrochemical benefits. DFT calculations revealed that carbon materials with N and S codoping possess a strong binding energy to high-order polysulfide species, which is essential to keep the active material in the cathode side. As a result of the synergistic effect of N, S dual-doping, an advanced Li-S cell with high specific capacity and ultralow capacity degradation of 0.041% per cycle is achieved. Pushing our simple-designed and scalable cathode to a highly increased sulfur loading of 5.4 mg cm(-2), the Li-S cell with the functional hybrid separator can deliver a remarkable areal capacity of 5.9 mAh cm(-2), which is highly favorable for practical applications. PMID- 27225060 TI - Store-independent modulation of Ca(2+) entry through Orai by Septin 7. AB - Orai channels are required for store-operated Ca(2+) entry (SOCE) in multiple cell types. Septins are a class of GTP-binding proteins that function as diffusion barriers in cells. Here we show that Septin 7 acts as a 'molecular brake' on activation of Orai channels in Drosophila neurons. Lowering Septin 7 levels results in dOrai-mediated Ca(2+) entry and higher cytosolic Ca(2+) in resting neurons. This Ca(2+) entry is independent of depletion of endoplasmic reticulum Ca(2+) stores and Ca(2+) release through the inositol-1,4,5 trisphosphate receptor. Importantly, store-independent Ca(2+) entry through Orai compensates for reduced SOCE in the Drosophila flight circuit. Moreover, overexpression of Septin 7 reduces both SOCE and flight duration, supporting its role as a negative regulator of Orai channel function in vivo. Septin 7 levels in neurons can, therefore, alter neural circuit function by modulating Orai function and Ca(2+) homeostasis. PMID- 27225062 TI - The functional response of bioactive titania-modified three-dimensional Ti-6Al-4V mesh structure toward providing a favorable pathway for intercellular communication and osteoincorporation. AB - The objective of the study is to fundamentally elucidate the biological response of 3D printed mesh structures subjected to plasma electrolytic oxidation process through the study of osteoblast functions. The cellular activity of plasma electrolytic-oxidized mesh structure was explored in terms of cell-to-cell communication involving proliferation, synthesis of extracellular and intracellular proteins, and mineralization. Upon plasma electrolytic oxidation of the mesh structure, a thin layer of bioactive titania with pore size 1-3 um was nucleated on the surface. The combination of microporous bioactive titania and interconnected porous architecture provided the desired pathway for supply of nutrients and oxygen to cells and tissue and a favorable osteogenic microenvironment for tissue on-growth and in-growth, in relation to the unmodified mesh structure. The formation of a confluent layer as envisaged via electron microscopy and quantitative assessment of the expression level of proteins (actin, vinculin, and fibronectin) point toward the determining role of surface-modified mesh structure in modulating osteoblasts functions. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2488-2501, 2016. PMID- 27225063 TI - HCV encephalopathy - an artefact due to medical care? AB - Anti-HCV positive individuals frequently complain about chronic disabling fatigue, mood alterations and deficits in concentration and memory. Several data provide evidence that such alterations are unrelated to hepatitis C virus (HCV) viremia. Thus, merely being exposed to HCV in the past may be sufficient to trigger, but the HCV exposure itself. This commentary reviews the available data upon this topic with special reference to the paper by Lowry and colleagues published in this issue of the Journal of Viral hepatitis. We will carefully discuss scientific reasons, why HCV may be directly involved in the development of neuropsychiatric symptoms independent from ongoing detectable viremia, as suggested by epidemiological data. PMID- 27225064 TI - Maternal Risk Factors for Preterm Birth in Murmansk County, Russia: A Registry Based Study. AB - BACKGROUND: Globally, about 11% of all liveborn infants are preterm. To date, data on prevalence and risk factors of preterm birth (PTB) in Russia are limited. The aims of this study were to estimate the prevalence of PTB in Murmansk County, Northwestern Russia and to investigate associations between PTB and selected maternal factors using the Murmansk County Birth Registry. METHODS: We conducted a registry-based study of 52 806 births (2006-2011). In total, 51 156 births were included in the prevalence analysis, of which 3546 were PTBs. Odds ratios with 95% confidence intervals of moderate-to-late PTB, very PTB and extremely PTB for a range of maternal characteristics were estimated using multinomial logistic regression, adjusting for potential confounders. RESULTS: The overall prevalence of PTB in Murmansk County was 6.9%. Unmarried status, prior PTBs, spontaneous and induced abortions were strongly associated with PTB at any gestational age. Maternal low educational level increased the risk of extremely and moderate-to late PTB. Young (<18 years) or older (>=35 years) mothers, graduates of vocational schools, underweight, overweight/obese mothers, and smokers were at higher risk of moderate-to-late PTB. Secondary education, alcohol abuse, diabetes mellitus, or gestational diabetes were strongly associated with moderate-to-late and very PTB. CONCLUSIONS: The observed prevalence of PTB (6.9%) in Murmansk County, Russia was comparable with data on live PTB from European countries. Adverse prior pregnancy outcomes, maternal low educational level, unmarried status, alcohol abuse, and diabetes mellitus or gestational diabetes were the most common risk factors for PTB. PMID- 27225065 TI - A global * global test for testing associations between two large sets of variables. AB - In high-dimensional omics studies where multiple molecular profiles are obtained for each set of patients, there is often interest in identifying complex multivariate associations, for example, copy number regulated expression levels in a certain pathway or in a genomic region. To detect such associations, we present a novel approach to test for association between two sets of variables. Our approach generalizes the global test, which tests for association between a group of covariates and a single univariate response, to allow high-dimensional multivariate response. We apply the method to several simulated datasets as well as two publicly available datasets, where we compare the performance of multivariate global test (G2) with univariate global test. The method is implemented in R and will be available as a part of the globaltest package in R. PMID- 27225067 TI - The prognostic significance of specific HOX gene expression patterns in ovarian cancer. AB - HOX genes are vital for all aspects of mammalian growth and differentiation, and their dysregulated expression is related to ovarian carcinogenesis. The aim of the current study was to establish the prognostic value of HOX dysregulation as well as its role in platinum resistance. The potential to target HOX proteins through the HOX/PBX interaction was also explored in the context of platinum resistance. HOX gene expression was determined in ovarian cancer cell lines and primary EOCs by QPCR, and compared to expression in normal ovarian epithelium and fallopian tube tissue samples. Statistical analysis included one-way ANOVA and t tests, using statistical software R and GraphPad. The analysis identified 36 of the 39 HOX genes as being overexpressed in high grade serous EOC compared to normal tissue. We detected a molecular HOX gene-signature that predicted poor outcome. Overexpression of HOXB4 and HOXB9 was identified in high grade serous cell lines after platinum resistance developed. Targeting the HOX/PBX dimer with the HXR9 peptide enhanced the cytotoxicity of cisplatin in platinum-resistant ovarian cancer. In conclusion, this study has shown the HOX genes are highly dysregulated in ovarian cancer with high expression of HOXA13, B6, C13, D1 and D13 being predictive of poor clinical outcome. Targeting the HOX/PBX dimer in platinum-resistant cancer represents a potentially new therapeutic option that should be further developed and tested in clinical trials. PMID- 27225066 TI - The stress response paradox: fighting degeneration at the cost of cancer. AB - In the modern research era, sequencing and high-throughput analysis have linked genetic factors with a multitude of disease states. Often times, the same cellular machinery is implicated in several different diseases and has made it challenging to drug a particular disease with minimal pleotropic consequences. It is intriguing to see how different fields of disease research can present such differing views when describing the same biological process, pathway, or molecule. As observations in one field converge with research in another, we gain a more complete picture of a biological system and can accurately assess the feasibility for translational science. As an example discussed here, modulating latent stress response pathways within the cell provides exciting therapeutic potential, however, opposing views have emerged in the fields of degenerative disease and cancer. This at first glance seems logical as suppression of degenerative disease entails maintaining cell viability, while cancer aims to enhance selective senescence and cell death. As both of these disciplines seek novel therapeutic interventions, we should not overlook how scientific biases involving one biological process may impact different disease paradigms. PMID- 27225068 TI - Use of surgical safety checklists in Australian operating theatres: an observational study. AB - INTRODUCTION: The use of surgical safety checklists (SSC) is an intervention aimed at reducing mortality and morbidity. Although the effectiveness of their use in surgery has been studied extensively, little is known about their practical use in Australian hospitals. The aim of this study was to observe and document the use of SSC in Australia. METHODS: This study employed direct observations of checklist use for surgical procedures by trained observers. Medical records were also audited to determine compliance with checklist use and to investigate whether there was any discrepancy between practice (actual care measured by direct observation) and documentation (documented care measured by an audit of records). RESULTS: Among the 11 participating hospitals, overall observed mean completion of the components of the checklist was 27%. Only one hospital used the original World Health Organization checklist. The checklist items most commonly observed to be addressed by the operating theatre staff as noted during observations were: correct patient (99%) and procedure (97%), whether the patient had any allergies (80%), and whether the instrument counts were performed correctly (56%). Findings from the direct observations conflicted with the medical record audit, where there was a higher percentage of completion (86% completion) in comparison to the 27% observed. CONCLUSION: This is the first study of surgical checklist use within Australia. Overall completion was low across the sites included in this study. Compliance data collected from observations differed markedly from reported compliance in medical records. PMID- 27225069 TI - Ribosome-inactivating Proteins from Root Tubers and Seeds of Trichosan-thes kirilowii and Other Trichosanthes Species. AB - Ribosome-inactivating proteins have been isolated from Trichosanthes kirilowii root tubers and seeds, including trichosanthin, karasurin and T 33 from root tubers and trichosanthrip, trichokirin, alpha-kirilowin, beta-kirilowin and trichoanguin from seeds. The aforementioned proteins show structural and functional similarities. Among them trichosanthin is the best known and most intensely studied. Trichosanthin manifests anticancer activity in vitro and in tumor bearing mice against a variety of cancers/cancer cell lines. It also exhibits anti-HIV-1 and anti-HSV-1 activities. Trichosanthin has been found to be useful for treatment of cesarean scar pregnancies and ectopic pregnancy, and for preventing acute rejection of major histocompatibility complex-mismatched mouse skin allograft. Trichosanthin selectively lesions some neurons and thus can be used in neuroscience research. PMID- 27225070 TI - The neuroscience of working memory capacity and training. AB - Working memory - the ability to maintain and manipulate information over a period of seconds - is a core component of higher cognitive functions. The storage capacity of working memory is limited but can be expanded by training, and evidence of the neural mechanisms underlying this effect is accumulating. Human imaging studies and neurophysiological recordings in non-human primates, together with computational modelling studies, reveal that training increases the activity of prefrontal neurons and the strength of connectivity in the prefrontal cortex and between the prefrontal and parietal cortex. Dopaminergic transmission could have a facilitatory role. These changes more generally inform us of the plasticity of higher cognitive functions. PMID- 27225071 TI - Integrated information theory: from consciousness to its physical substrate. AB - In this Opinion article, we discuss how integrated information theory accounts for several aspects of the relationship between consciousness and the brain. Integrated information theory starts from the essential properties of phenomenal experience, from which it derives the requirements for the physical substrate of consciousness. It argues that the physical substrate of consciousness must be a maximum of intrinsic cause-effect power and provides a means to determine, in principle, the quality and quantity of experience. The theory leads to some counterintuitive predictions and can be used to develop new tools for assessing consciousness in non-communicative patients. PMID- 27225072 TI - Neurodegenerative disease: Ever decreasing ripples. PMID- 27225073 TI - Glia: Astrocytic go-betweens. PMID- 27225075 TI - Mitochondrial DNA typing of laser-captured single sperm cells to differentiate individuals in a mixed semen stain. AB - The identification of individuals in a mixture of two semen samples usually involves an analysis of autosomal and Y chromosomal short tandem repeats (STR) which can exclude unrelated individuals but cannot achieve the purpose of individual identification. In sperm cells, there are multiple copies of mitochondrial DNAs (mtDNA) which exhibit genetic polymorphisms in different matrilineal-related individuals. Single-cell capture technology can be applied to obtain some single sperm cells in a mixed semen sample, then polymerase chain reaction can be employed to amplify the mtDNA hypervariable region I (HVR I) from each cell. By pooling the cells with the same HVR I sequence, we can obtain the sufficient nuclear DNA for STR typing. PMID- 27225076 TI - A novel scattering switch-on detection technique for target-induced plasmon coupling based sensing by single-particle optical anisotropy imaging. AB - We reported a novel scattering switch-on detection technique using flash-lamp polarization darkfield microscopy (FLPDM) for target-induced plasmon-coupling based sensing in homogeneous solution. With this method, we demonstrated sub-nM sensitivity for hydrogen sulfide (H2S) detection over a dynamic range of five orders of magnitude. This robust technique holds great promise for applications in toxic environmental pollutants and biological molecules. PMID- 27225077 TI - Reaction Mechanism of Mycobacterium Tuberculosis Glutamine Synthetase Using Quantum Mechanics/Molecular Mechanics Calculations. AB - This paper is devoted to the understanding of the reaction mechanism of mycobacterium tuberculosis glutamine synthetase (mtGS) with atomic detail, using computational quantum mechanics/molecular mechanics (QM/MM) methods at the ONIOM M06-D3/6-311++G(2d,2p):ff99SB//B3LYP/6-31G(d):ff99SB level of theory. The complete reaction undergoes a three-step mechanism: the spontaneous transfer of phosphate from ATP to glutamate upon ammonium binding (ammonium quickly loses a proton to Asp54), the attack of ammonia on phosphorylated glutamate (yielding protonated glutamine), and the deprotonation of glutamine by the leaving phosphate. This exothermic reaction has an activation free energy of 21.5 kcal mol(-1) , which is consistent with that described for Escherichia coli glutamine synthetase (15-17 kcal mol(-1) ). The participating active site residues have been identified and their role and energy contributions clarified. This study provides an insightful atomic description of the biosynthetic reaction that takes place in this enzyme, opening doors for more accurate studies for developing new anti-tuberculosis therapies. PMID- 27225074 TI - Somatostatin-expressing neurons in cortical networks. AB - Somatostatin-expressing GABAergic neurons constitute a major class of inhibitory neurons in the mammalian cortex and are characterized by dense wiring into the local network and high basal firing activity that persists in the absence of synaptic input. This firing provides both GABA type A receptor (GABAAR)- and GABABR-mediated inhibition that operates at fast and slow timescales. The activity of somatostatin-expressing neurons is regulated by brain state, during learning and in rewarded behaviour. Here, we review recent advances in our understanding of how this class of cells can control network activity, with specific reference to how this is constrained by their anatomical and electrophysiological properties. PMID- 27225078 TI - Reality check on reproducibility. PMID- 27225079 TI - Source material. PMID- 27225080 TI - Crunch time. PMID- 27225081 TI - Society must seize control of the antibiotics crisis. PMID- 27225093 TI - Three-person embryos may fail to vanquish mutant mitochondria. PMID- 27225095 TI - Silicon quantum computers take shape in Australia. PMID- 27225094 TI - Next generation of carbon-monitoring satellites faces daunting hurdles. PMID- 27225096 TI - Myriad Genetics embroiled in breast-cancer data fight - again. PMID- 27225097 TI - US law could increase postdoc pay - and shake up research system. PMID- 27225099 TI - Correction. PMID- 27225098 TI - US reviews plan to infect mosquitoes with bacteria to stop disease. PMID- 27225100 TI - 1,500 scientists lift the lid on reproducibility. PMID- 27225101 TI - The secret history of ancient toilets. PMID- 27225102 TI - Medical research: Time to think differently about diabetes. PMID- 27225103 TI - Physics: Invest in neutrino astronomy. PMID- 27225107 TI - Pollution: Spend more on soil clean-up in China. PMID- 27225108 TI - Europe: Shark-fin landing policy aids control. PMID- 27225109 TI - Public health: Use open data to curb Zika virus. PMID- 27225110 TI - Restoration: 'Garden of Eden' unrealistic. PMID- 27225111 TI - Restoration: avoid arbitrary baselines. PMID- 27225112 TI - Harry Kroto (1939-2016). PMID- 27225113 TI - Cell biology: Choreography of protein synthesis. PMID- 27225114 TI - Astrophysics: How black holes restrain old galaxies. PMID- 27225115 TI - Cell biology: Killer enzymes tethered. PMID- 27225117 TI - Evolution: The bigger, the better. PMID- 27225118 TI - Atmospheric science: Unexpected player in particle formation. PMID- 27225119 TI - Tracing haematopoietic stem cell formation at single-cell resolution. AB - Haematopoietic stem cells (HSCs) are derived early from embryonic precursors, such as haemogenic endothelial cells and pre-haematopoietic stem cells (pre HSCs), the molecular identity of which still remains elusive. Here we use potent surface markers to capture the nascent pre-HSCs at high purity, as rigorously validated by single-cell-initiated serial transplantation. Then we apply single cell RNA sequencing to analyse endothelial cells, CD45(-) and CD45(+) pre-HSCs in the aorta-gonad-mesonephros region, and HSCs in fetal liver. Pre-HSCs show unique features in transcriptional machinery, arterial signature, metabolism state, signalling pathway, and transcription factor network. Functionally, activation of mechanistic targets of rapamycin (mTOR) is shown to be indispensable for the emergence of HSCs but not haematopoietic progenitors. Transcriptome data-based functional analysis reveals remarkable heterogeneity in cell-cycle status of pre HSCs. Finally, the core molecular signature of pre-HSCs is identified. Collectively, our work paves the way for dissection of complex molecular mechanisms regulating stepwise generation of HSCs in vivo, informing future efforts to engineer HSCs for clinical applications. PMID- 27225120 TI - Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. AB - Brain metastasis represents a substantial source of morbidity and mortality in various cancers, and is characterized by high resistance to chemotherapy. Here we define the role of the most abundant cell type in the brain, the astrocyte, in promoting brain metastasis. We show that human and mouse breast and lung cancer cells express protocadherin 7 (PCDH7), which promotes the assembly of carcinoma astrocyte gap junctions composed of connexin 43 (Cx43). Once engaged with the astrocyte gap-junctional network, brain metastatic cancer cells use these channels to transfer the second messenger cGAMP to astrocytes, activating the STING pathway and production of inflammatory cytokines such as interferon-alpha (IFNalpha) and tumour necrosis factor (TNF). As paracrine signals, these factors activate the STAT1 and NF-kappaB pathways in brain metastatic cells, thereby supporting tumour growth and chemoresistance. The orally bioavailable modulators of gap junctions meclofenamate and tonabersat break this paracrine loop, and we provide proof-of-principle that these drugs could be used to treat established brain metastasis. PMID- 27225123 TI - A resonant chain of four transiting, sub-Neptune planets. AB - Surveys have revealed many multi-planet systems containing super-Earths and Neptunes in orbits of a few days to a few months. There is debate whether in situ assembly or inward migration is the dominant mechanism of the formation of such planetary systems. Simulations suggest that migration creates tightly packed systems with planets whose orbital periods may be expressed as ratios of small integers (resonances), often in a many-planet series (chain). In the hundreds of multi-planet systems of sub-Neptunes, more planet pairs are observed near resonances than would generally be expected, but no individual system has hitherto been identified that must have been formed by migration. Proximity to resonance enables the detection of planets perturbing each other. Here we report transit timing variations of the four planets in the Kepler-223 system, model these variations as resonant-angle librations, and compute the long-term stability of the resonant chain. The architecture of Kepler-223 is too finely tuned to have been formed by scattering, and our numerical simulations demonstrate that its properties are natural outcomes of the migration hypothesis. Similar systems could be destabilized by any of several mechanisms, contributing to the observed orbital-period distribution, where many planets are not in resonances. Planetesimal interactions in particular are thought to be responsible for establishing the current orbits of the four giant planets in the Solar System by disrupting a theoretical initial resonant chain similar to that observed in Kepler-223. PMID- 27225121 TI - Synchronized mitochondrial and cytosolic translation programs. AB - Oxidative phosphorylation (OXPHOS) is a vital process for energy generation, and is carried out by complexes within the mitochondria. OXPHOS complexes pose a unique challenge for cells because their subunits are encoded on both the nuclear and the mitochondrial genomes. Genomic approaches designed to study nuclear/cytosolic and bacterial gene expression have not been broadly applied to mitochondria, so the co-regulation of OXPHOS genes remains largely unexplored. Here we monitor mitochondrial and nuclear gene expression in Saccharomyces cerevisiae during mitochondrial biogenesis, when OXPHOS complexes are synthesized. We show that nuclear- and mitochondrial-encoded OXPHOS transcript levels do not increase concordantly. Instead, mitochondrial and cytosolic translation are rapidly, dynamically and synchronously regulated. Furthermore, cytosolic translation processes control mitochondrial translation unidirectionally. Thus, the nuclear genome coordinates mitochondrial and cytosolic translation to orchestrate the timely synthesis of OXPHOS complexes, representing an unappreciated regulatory layer shaping the mitochondrial proteome. Our whole-cell genomic profiling approach establishes a foundation for studies of global gene regulation in mitochondria. PMID- 27225122 TI - Suppressing star formation in quiescent galaxies with supermassive black hole winds. AB - Quiescent galaxies with little or no ongoing star formation dominate the population of galaxies with masses above 2 * 10(10) times that of the Sun; the number of quiescent galaxies has increased by a factor of about 25 over the past ten billion years (refs 1-4). Once star formation has been shut down, perhaps during the quasar phase of rapid accretion onto a supermassive black hole, an unknown mechanism must remove or heat the gas that is subsequently accreted from either stellar mass loss or mergers and that would otherwise cool to form stars. Energy output from a black hole accreting at a low rate has been proposed, but observational evidence for this in the form of expanding hot gas shells is indirect and limited to radio galaxies at the centres of clusters, which are too rare to explain the vast majority of the quiescent population. Here we report bisymmetric emission features co-aligned with strong ionized-gas velocity gradients from which we infer the presence of centrally driven winds in typical quiescent galaxies that host low-luminosity active nuclei. These galaxies are surprisingly common, accounting for as much as ten per cent of the quiescent population with masses around 2 * 10(10) times that of the Sun. In a prototypical example, we calculate that the energy input from the galaxy's low-level active supermassive black hole is capable of driving the observed wind, which contains sufficient mechanical energy to heat ambient, cooler gas (also detected) and thereby suppress star formation. PMID- 27225124 TI - A high-temperature ferromagnetic topological insulating phase by proximity coupling. AB - Topological insulators are insulating materials that display conducting surface states protected by time-reversal symmetry, wherein electron spins are locked to their momentum. This unique property opens up new opportunities for creating next generation electronic, spintronic and quantum computation devices. Introducing ferromagnetic order into a topological insulator system without compromising its distinctive quantum coherent features could lead to the realization of several predicted physical phenomena. In particular, achieving robust long-range magnetic order at the surface of the topological insulator at specific locations without introducing spin-scattering centres could open up new possibilities for devices. Here we use spin-polarized neutron reflectivity experiments to demonstrate topologically enhanced interface magnetism by coupling a ferromagnetic insulator (EuS) to a topological insulator (Bi2Se3) in a bilayer system. This interfacial ferromagnetism persists up to room temperature, even though the ferromagnetic insulator is known to order ferromagnetically only at low temperatures (<17 K). The magnetism induced at the interface resulting from the large spin-orbit interaction and the spin-momentum locking of the topological insulator surface greatly enhances the magnetic ordering (Curie) temperature of this bilayer system. The ferromagnetism extends ~2 nm into the Bi2Se3 from the interface. Owing to the short-range nature of the ferromagnetic exchange interaction, the time-reversal symmetry is broken only near the surface of a topological insulator, while leaving its bulk states unaffected. The topological magneto electric response originating in such an engineered topological insulator could allow efficient manipulation of the magnetization dynamics by an electric field, providing an energy-efficient topological control mechanism for future spin-based technologies. PMID- 27225125 TI - Ion-induced nucleation of pure biogenic particles. AB - Atmospheric aerosols and their effect on clouds are thought to be important for anthropogenic radiative forcing of the climate, yet remain poorly understood. Globally, around half of cloud condensation nuclei originate from nucleation of atmospheric vapours. It is thought that sulfuric acid is essential to initiate most particle formation in the atmosphere, and that ions have a relatively minor role. Some laboratory studies, however, have reported organic particle formation without the intentional addition of sulfuric acid, although contamination could not be excluded. Here we present evidence for the formation of aerosol particles from highly oxidized biogenic vapours in the absence of sulfuric acid in a large chamber under atmospheric conditions. The highly oxygenated molecules (HOMs) are produced by ozonolysis of alpha-pinene. We find that ions from Galactic cosmic rays increase the nucleation rate by one to two orders of magnitude compared with neutral nucleation. Our experimental findings are supported by quantum chemical calculations of the cluster binding energies of representative HOMs. Ion-induced nucleation of pure organic particles constitutes a potentially widespread source of aerosol particles in terrestrial environments with low sulfuric acid pollution. PMID- 27225126 TI - The role of low-volatility organic compounds in initial particle growth in the atmosphere. AB - About half of present-day cloud condensation nuclei originate from atmospheric nucleation, frequently appearing as a burst of new particles near midday. Atmospheric observations show that the growth rate of new particles often accelerates when the diameter of the particles is between one and ten nanometres. In this critical size range, new particles are most likely to be lost by coagulation with pre-existing particles, thereby failing to form new cloud condensation nuclei that are typically 50 to 100 nanometres across. Sulfuric acid vapour is often involved in nucleation but is too scarce to explain most subsequent growth, leaving organic vapours as the most plausible alternative, at least in the planetary boundary layer. Although recent studies predict that low volatility organic vapours contribute during initial growth, direct evidence has been lacking. The accelerating growth may result from increased photolytic production of condensable organic species in the afternoon, and the presence of a possible Kelvin (curvature) effect, which inhibits organic vapour condensation on the smallest particles (the nano-Kohler theory), has so far remained ambiguous. Here we present experiments performed in a large chamber under atmospheric conditions that investigate the role of organic vapours in the initial growth of nucleated organic particles in the absence of inorganic acids and bases such as sulfuric acid or ammonia and amines, respectively. Using data from the same set of experiments, it has been shown that organic vapours alone can drive nucleation. We focus on the growth of nucleated particles and find that the organic vapours that drive initial growth have extremely low volatilities (saturation concentration less than 10(-4.5) micrograms per cubic metre). As the particles increase in size and the Kelvin barrier falls, subsequent growth is primarily due to more abundant organic vapours of slightly higher volatility (saturation concentrations of 10(-4.5) to 10(-0.5) micrograms per cubic metre). We present a particle growth model that quantitatively reproduces our measurements. Furthermore, we implement a parameterization of the first steps of growth in a global aerosol model and find that concentrations of atmospheric cloud concentration nuclei can change substantially in response, that is, by up to 50 per cent in comparison with previously assumed growth rate parameterizations. PMID- 27225127 TI - Competitive growth in a cooperative mammal. AB - In many animal societies where hierarchies govern access to reproduction, the social rank of individuals is related to their age and weight and slow-growing animals may lose their place in breeding queues to younger 'challengers' that grow faster. The threat of being displaced might be expected to favour the evolution of competitive growth strategies, where individuals increase their own rate of growth in response to increases in the growth of potential rivals. Although growth rates have been shown to vary in relation to changes in the social environment in several vertebrates including fish and mammals, it is not yet known whether individuals increase their growth rates in response to increases in the growth of particular reproductive rivals. Here we show that, in wild Kalahari meerkats (Suricata suricatta), subordinates of both sexes respond to experimentally induced increases in the growth of same-sex rivals by raising their own growth rate and food intake. In addition, when individuals acquire dominant status, they show a secondary period of accelerated growth whose magnitude increases if the difference between their own weight and that of the heaviest subordinate of the same sex in their group is small. Our results show that individuals adjust their growth to the size of their closest competitor and raise the possibility that similar plastic responses to the risk of competition may occur in other social mammals, including domestic animals and primates. PMID- 27225128 TI - How sexual selection can drive the evolution of costly sperm ornamentation. AB - Post-copulatory sexual selection (PSS), fuelled by female promiscuity, is credited with the rapid evolution of sperm quality traits across diverse taxa. Yet, our understanding of the adaptive significance of sperm ornaments and the cryptic female preferences driving their evolution is extremely limited. Here we review the evolutionary allometry of exaggerated sexual traits (for example, antlers, horns, tail feathers, mandibles and dewlaps), show that the giant sperm of some Drosophila species are possibly the most extreme ornaments in all of nature and demonstrate how their existence challenges theories explaining the intensity of sexual selection, mating-system evolution and the fundamental nature of sex differences. We also combine quantitative genetic analyses of interacting sex-specific traits in D. melanogaster with comparative analyses of the condition dependence of male and female reproductive potential across species with varying ornament size to reveal complex dynamics that may underlie sperm-length evolution. Our results suggest that producing few gigantic sperm evolved by (1) Fisherian runaway selection mediated by genetic correlations between sperm length, the female preference for long sperm and female mating frequency, and (2) longer sperm increasing the indirect benefits to females. Our results also suggest that the developmental integration of sperm quality and quantity renders post-copulatory sexual selection on ejaculates unlikely to treat male-male competition and female choice as discrete processes. PMID- 27225130 TI - Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy. AB - Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis. Abiraterone is metabolized in patients to Delta(4) abiraterone (D4A), which has even greater anti-tumour activity and is structurally similar to endogenous steroidal 5alpha-reductase substrates, such as testosterone. Here, we show that D4A is converted to at least three 5alpha reduced and three 5beta-reduced metabolites in human serum. The initial 5alpha reduced metabolite, 3-keto-5alpha-abiraterone, is present at higher concentrations than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5alpha-reductase inhibitor), 3-keto-5alpha-abiraterone and downstream metabolites were depleted by the addition of dutasteride, while D4A concentrations rose, showing that dutasteride effectively blocks production of a tumour-promoting metabolite and permits D4A accumulation. Furthermore, dutasteride did not deplete the three 5beta-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 5alpha reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy. PMID- 27225131 TI - Access of protective antiviral antibody to neuronal tissues requires CD4 T-cell help. AB - Circulating antibodies can access most tissues to mediate surveillance and elimination of invading pathogens. Immunoprivileged tissues such as the brain and the peripheral nervous system are shielded from plasma proteins by the blood brain barrier and blood-nerve barrier, respectively. Yet, circulating antibodies must somehow gain access to these tissues to mediate their antimicrobial functions. Here we examine the mechanism by which antibodies gain access to neuronal tissues to control infection. Using a mouse model of genital herpes infection, we demonstrate that both antibodies and CD4 T cells are required to protect the host after immunization at a distal site. We show that memory CD4 T cells migrate to the dorsal root ganglia and spinal cord in response to infection with herpes simplex virus type 2. Once inside these neuronal tissues, CD4 T cells secrete interferon-gamma and mediate local increase in vascular permeability, enabling antibody access for viral control. A similar requirement for CD4 T cells for antibody access to the brain is observed after intranasal challenge with vesicular stomatitis virus. Our results reveal a previously unappreciated role of CD4 T cells in mobilizing antibodies to the peripheral sites of infection where they help to limit viral spread. PMID- 27225134 TI - A Medical Editor's Utopia. PMID- 27225132 TI - Illuminating life's building blocks. PMID- 27225135 TI - Histological Changes in the Proximal and Distal Tendon Stumps Following Transection of Achilles Tendon in the Rabbits. AB - OBJECTIVE: To determine tendon stump changes following unrepaired Achilles tendon lacerations in an animal model. STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: King Saud University, Riyadh, Saudi Arabia, from October 2013 to January 2014. METHODOLOGY: Arabbit model was developed and studied tendon retraction and histological changes in the proximal and distal stumps following transection of the Achilles tendon. RESULTS: Over a period of 12 weeks, retraction of the distal tendon stump was minimal (2 - 3 mm). In contrast, retraction of the proximal tendon stump peaked to reach 6 mm at 4 weeks post injury and plateaued to reach 7 - 8 mm at the 12-week interval. CONCLUSION: Following complete transection of the Achilles tendon, tendon retraction correlated with the density of myofibroblast expression within the tendon stump. Further research is needed to investigate the pathophysiology of these findings. PMID- 27225136 TI - Validity of Electrocardiographic QT Interval in Predicting Left Ventricular Diastolic Dysfunction in Patients with Suspected Heart Failure. AB - OBJECTIVE: To determine the validity of electrocardiographic QT interval in predicting left ventricular diastolic dysfunction in patients with suspected heart failure using echocardiogram as the gold standard. STUDY DESIGN: Cross sectional validation study. PLACE AND DURATION OF STUDY: AFIC-NIHD, Rawalpindi, from December 2012 to June 2013. METHODOLOGY: Patients with suspected heart failure undergoing 12-lead electrocardiogram and echocardiography were inducted. All electrocardiograms were analyzed by a single trained reader unaware of the echocardiographic findings. QTc interval was calculated according to the published guidelines. All patients underwent a complete M mode, 2 dimensional, Doppler, and tissue Doppler echocardiography using aiE33 ultrasound system and diastolic dysfunction was calculated. RESULTS: Three hundred patients were studied. Descriptive statistics of age was 61.42 years +/-10.43. Of all the patients 218 patients (72.7%) were male and 82 patients were female (27.3%). Mean QT interval (msec) was 427.29 +/-54.69. One hundred and eighty patients (60.0%) had diastolic dysfunction and 120 patients (40%) had no diastolic dysfunction. The sensitivity of electrocardiographic QTc interval in predicting diastolic dysfunction was 71.11% and specificity was 88.11%. CONCLUSION: Prolonged electrocardiographic QTc interval in patients with suspected heart failure is a useful tool in predicting diastolic dysfunction. PMID- 27225137 TI - Yield and Safety Profile of Ultrasound Guided Fine Needle Aspiration Cytology (FNAC) of Lymph Nodes. AB - OBJECTIVE: To determine the re-biopsy rate, positive yield and safety profile of ultrasound guided fine needle aspiration cytology (FNAC) in cervical lymph nodes in terms of its complications and repeat procedures. STUDY DESIGN: An analytical study. PLACE AND DURATION OF STUDY: Department of Vascular and Interventional Radiology, Dow University Hospital, Dow University of Health Sciences, Karachi, from June to December 2013. METHODOLOGY: Eighty neck swellings, which were found to be lymph nodes on ultrasound, underwent ultrasound guided FNAC, from outpatients. Lymph nodes which were included in the study were those that were not easily palpable, located near major blood vessels, where patient refused of direct palpation and wanted image guided FNAC, those directly sent by physician for image guided FNAC and where blind biopsy remained inconclusive. Patients who refused on explanation or did not give consent were excluded. Complications and repeat biopsy were noted. RESULTS: This study consisted of 80 cases, of which 51 cases (63.75%) were female and 29 cases (36.25%) were male. Repeat biopsy was required in 1 case (1.6%). There were no procedure-related complications. Atotal of 44 cases (55%) revealed evidence suggesting or confirming the existence of tuberculosis. Rest of the others showed other benign lesions, reactive lymphadenopathy and malignancy. CONCLUSION: Ultrasound guided FNAC is a safe procedure with low re-biopsy rate that aids diagnosis. The predominant cause of cervical lymphadenopathy in this study was tuberculous lymphadenitis. PMID- 27225138 TI - Chronic Myeloid Leukemia Blood Inflicted Injury in Cord Derived Wharton's Jelly Mesenchymal Stem Cells. AB - OBJECTIVE: To determine the effects of blood from CML patients on human umbilical cord derived Wharton's jelly mesenchymal stem cells (WJMSCs) for evaluation of their therapeutic potential. STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: Centre for Research in Molecular Medicine, University of Lahore, from September 2013 to December 2014. METHODOLOGY: Possible behavior of WJMSCs in CMLpatients was assessed by culturing these cells in their plasma. WJMSCs at passage 3 were cultured in plasma isolated from 9 CMLpatients as well as 9 normal subjects. Effects on cell viability, proliferation, LDH release, paracrine factors (p38 and p53) and oxidative stress were evaluated. RESULTS: WJMSCs cultured in plasma of CML patients showed decreased viability, slow proliferation, high LDH release, high expression of p38 and p53 and a high oxidative stress compared to normal subjects. CONCLUSION: Stressed environment of CML patients' blood/plasma induced injury to WJMSCs as well as reduced their viability. Effectiveness of these cells for therapeutics of CML is, therefore, likely to be reduced. PMID- 27225139 TI - Effect of Leadership Styles on Job Satisfaction Among Critical Care Nurses in Aseer, Saudi Arabia. AB - OBJECTIVE: To evaluate the effect of transformational and transactional leadership styles of head nurses on the job satisfaction of staff nurses in critical care units (CCU) of a tertiary care hospital. STUDY DESIGN: Cross sectional study. PLACE AND DURATION OF STUDY: Critical care units at Aseer Central Hospital (ACH), Abha, Saudi Arabia, from July to December 2012. METHODOLOGY: The multifactor leadership questionnaire (MLQ-5X) and job satisfaction survey with demographics were used. Staff nurses (N=89) reporting to 8 nurse leaders responded as per the requirements of MLQ-5X and also filled the job satisfaction survey. ANOVA, correlation coefficient (Pearson r) and multiple linear regression were used for analyses. RESULTS: All nurse leaders demonstrated a combination of transactional (TA) and transformational (TF) style of leadership. Nurses working under leaders with a TF style demonstrated significantly (p < 0.05) higher job satisfaction. The operating conditions were related negatively to the style of leadership. Pay, fringe benefits and nature of work were not related to the style of leadership. The nurses were moderately satisfied with their work and 23% of the variation in nurses' job satisfaction could be explained by the head nurses 6 leadership facets with positive effect of professional support, intellectual motivation, management by correction and their laissez faire style. CONCLUSION: The study emphasized the importance of TF style of head nurses for increasing staff nurses' job satisfaction. It is suggested that nurse leaders should be trained in TF style of leadership and provided more support and training for effective management of CCU. PMID- 27225140 TI - Comparison of Outcome of Percutaneous Nephrolithotomy in Adult Versus Paediatric Patients. AB - OBJECTIVE: To compare the outcome of percutaneous nephrolithotomy (PCNL) in terms of operative time, hospital stay, stone clearance, and postoperative complications in adult versus paediatric patients. STUDY DESIGN: Descriptive case series. PLACE AND DURATION OF STUDY: Shifa International Hospital, Islamabad, from January 2010 to December 2013. METHODOLOGY: Aretrospective analysis of 155 patients who underwent PCNL from January 2010 to December 2013. The patients were divided into 2 groups: patients aged <=12 years were included in paedriatic group (A) while patients aged > 12 years were included in adult group (B). The patients were analyzed for age, gender, stone size, operative time, stone clearance, hospital stay, and peroperative and postoperative complications. Data was collected by chart review on specified proforma. RESULTS: One hundred and twenty nine (129) patients including 44 (34.10%) females and 85 (65.89%) males with a mean age of 45.00 +/-1.44 years were adults. Twenty-six palrents with mean age of 9.21 +/-5.70 years, 17 (65.4%) males and 9 (34.6%) females, were included in the paedriatic group. Mean stone size was 2.12 +/-1.01 cm in paedriatic group compared to 2.52 +/-0.77 cm in adult group (p = 0.023). Mean operative time in paedriatic group was 158.8 +/-39.63 minutes compared to 119.34 +/-37.06 minutes in adult group (p < 0.001). Mean hospital stay in paedriatic group was 2.76 +/ 1.14 days compared to 3.12 +/-1.27 days in adult group (p=0.1881). Peroperative stone clearance was in paedriatic group was 93.28 +/-9.23% compared to 90.81 +/ 12.23% in adult groups (p = 0.331). One patient in the adult group developed urosepsis. CONCLUSION: There was no significant difference in outcome of percutaneous nephrolithotomy in terms of hospital stay, stone clearance, and postoperative complications in adult versus paediatric patients. Operative time was significantly shorter in adult cases compared to paedriatic cases. PMID- 27225141 TI - Diagnostic Accuracy of Clinical Methods for Detection of Diabetic Sensory Neuropathy. AB - OBJECTIVE: To determine the accuracy of clinical methods for detection of sensory neuropathy as compared to biothesiometry. STUDY DESIGN: Cross-sectional analytical study. PLACE AND DURATION OF STUDY: 1 Mountain Medical Battalion, Azad Kashmir, from October 2013 to September 2014. METHODOLOGY: Patients with type 2 diabetes were enrolled by convenience sampling. Exclusion criteria included other identifiable causes of neuropathy, extensive ulceration of feet, amputated feet, those on treatment for neuropathy and unwilling patients. Average of 3 vibration perception threshold values measured with a biothesiometer on distal hallux was calculated. Ten gm monofilament was used to examine touch sensation over dorsal surfaces of great toes. Vibration sensation was checked over the tips of great toes using 128Hz tuning fork. Ankle jerks were checked bilaterally. RESULTS: Neuropathy (vibration perception threshold > 25 volts) was present in 34 (21.12%) out of 161 patients and 93 (57.76%) were symptomatic. Measures of diagnostic accuracy for monofilament, tuning fork and ankle jerks were: sensitivity 41.18%, 55.88% and 64.71%; specificity 92.91%, 93.70% and 80.31%; positive predictive value (PPV) 60.87%, 70.37% and 46.81%; negative predictive value (NPV) 85.51%, 88.81% and 89.47%; and, diagnostic accuracy 81.99%, 85.71% and 77.02%, respectively. Values for any 1 positive sign, any 2 positive signs or all 3 positive signs were: sensitivity 35.29%, 14.71% and 32.35%; specificity 81.89%, 93.70% and 99.21%; PPV 34.29%, 38.46% and 91.67%; NPV 82.54%, 80.41% and 84.56%; and, diagnostic accuracy 72.05%, 77.02% and 85.09%, respectively. CONCLUSION: Clinical methods are high accurate and specific diagnosis in picking up symmetric sensory neuropathy in patients with type 2 diabetes, particularly when multiple signs are combined. PMID- 27225142 TI - Frequency of Metabolic Syndrome and Its Components in Patients with Carpal Tunnel Syndrome. AB - OBJECTIVE: To determine the frequency of metabolic syndrome and its components in patients with carpal tunnel syndrome. STUDY DESIGN: Case-series. PLACE AND DURATION OF STUDY: Department of Neurology, Mayo Hospital, Lahore, from January to June 2012. METHODOLOGY: Seventy-five (64 females and 11 males) patients with clinically diagnosed and electrodiagnostically confirmed carpal tunnel syndrome were inducted. Their waist circumference, blood pressure, fasting blood glucose, fasting triglycerides and high density lipoprotein cholesterol levels were recorded. Patients were categorized having metabolic syndrome according to Adult Treatment Panel III criteria, if any 3 were present out of hypertension, elevated fasting triglycerides, reduced high density lipoprotein cholesterol, elevated fasting blood glucose, and elevated waist circumference. RESULTS: Mean age of the patients was 42.04 +/-9.31 years, mean waist circumference was 95.32 +/-9.03 cm, mean systolic blood pressure was 134.13 +/-13.72 mmHg, mean diastolic blood pressure was 89.13 +/-8.83 mmHg, mean fasting blood glucose was 94.35 +/-21.81 mg/dl, mean fasting triglycerides was 177.48 +/-48.69 mg/dl, and mean high density lipoprotein cholesterol was 41.95 +/-11.17 mg/dl. Metabolic syndrome was found in 54 (72%) patients including 9 (16.7%) males and 45 (83.3%) females. Out of 75 patients, 54 (72%) had elevated waist circumference, 52 (69.3%) had elevated blood pressure, 19 (25.3%) had elevated fasting blood glucose, 53 (70.6%) had elevated fasting triglycerides and 54 (72%) had reduced high density lipoprotein cholesterol. Highest frequency of metabolic syndrome was found in age range of 40 - 49 years in both genders. CONCLUSION: Metabolic syndrome is frequently found in the patients with carpal tunnel syndrome. PMID- 27225143 TI - Chronic Bronchitis and Chronic Obstructive Pulmonary Disease (COPD) Among Textile Workers in Karachi, Pakistan. AB - OBJECTIVE: To determine the frequency and predictors of chronic bronchitis and COPD among textile workers in Karachi, Pakistan. STUDY DESIGN: Cross-sectional survey. PLACE AND DURATION OF STUDY: Karachi, Pakistan, from October to December 2009. METHODOLOGY: Male textile workers from 15 mills of Karachi were inducted. Data was collected using American Thoracic Society respiratory questionnaire (ATS DLD-78-a) and spirometry. RESULTS: Out of 372 participants, 29 (7.8%) workers had chronic bronchitis (4, 9.1% aged >=40 years) and 25 (6.7%) had COPD (12, 27.2% aged >=40 years). Workers with chronic bronchitis had significantly decreased lung function compared to the healthy workers. Those reporting severe self perceived dust exposure at work, >= 10 pack years of smoking, uneducated, longer duration of work (>=11 years), and ever smokers were more likely to have chronic bronchitis or COPD. In the multivariate analyses, severe self-perceived dust exposure at work (AOR = 7.4; 95% CI: 1.9, 28.0), family history of respiratory illness/symptoms (AOR = 4.8; 95% CI: 1.1, 20.9) and lack of education (AOR = 4.2; 95% CI: 1.1, 16.9) were significant predictors of chronic bronchitis. Duration of work >=11 years (AOR = 5.5; 95% CI: 1.5, 19.7) and pack years of smoking >=10 years (AOR = 3.5; 95% CI: 1.1, 11.7) were strong predictors for COPD. CONCLUSION: There is a high frequency of chronic bronchitis and COPD among textile workers. Multiple important predictors for prevention are identified. PMID- 27225145 TI - Prevalence of Electrolyte Disorders Among Cases of Diarrhea with Severe Dehydration and Correlation of Electrolyte Levels with Age of the Patients. AB - OBJECTIVE: To find out the prevalence of electrolyte disorders among children with severe dehydration, and to study correlation between age and electrolyte, urea and creatinine levels. STUDY DESIGN: Prospective, analytical study. PLACE AND DURATION OF STUDY: Outdoor and indoor of Fazle-Omar Hospital, Rabwah, Pakistan, from January to December 2012. METHODOLOGY: All patients from birth to 18 years age, presenting with diarrhea and severe dehydration were included in the study. Urea, creatinine and electrolyte levels of all patients included in the study were checked and recorded in the data form with name, age and outcome. The prevalence of electrolyte disorders were ascertained and correlation with age was determined by Pearson's coefficient. RESULTS: At total of 104 patients were included in the study. None of the patients died. Hyperchloremia was the commonest electrolyte disorder (53.8%), followed by hyperkalemia (26.9%) and hypernatremia (17.3%). Hyponatremia, hypokalemia and hypochloremia were present in 10.6%, 7.7%, and 10.6% cases, respectively. Weak negative correlation was found between age and chloride and potassium levels. CONCLUSION: Different electrolyte disorders are common in children with diarrhea-related severe dehydration. PMID- 27225144 TI - Assessment of Gender Dimorphism on Sagittal Cephalometry in Pakistani Population. AB - OBJECTIVE: To determine and compare the cephalometric values among Pakistani males and females using commonly used sagittal skeletal measurements (ANB, Wits appraisal, Beta-angle) and newly developed cephalometric analyses (Yen-angle and W-angle). STUDY DESIGN: Observational, cross-sectional study. PLACE AND DURATION OF STUDY: Orthodontic Department of Baqai Medical University, Karachi, Pakistan, from August to October 2013. METHODOLOGY: Atotal of 209 pre-treatment lateral cephalometric radiographs of orthodontic patients were selected from departmental records, comprised of 92 males and 117 females. Radiographs were traced for measurements of ANB, Wits appraisal, Beta-angle, W-angle and Yen-angle. Patients were categorized into skeletal classes I, II, and III on the basis of performed measurements, incisor classification, and profile recorded from their records. Descriptive analysis was used to obtain median interquartile range in both the genders and Mann-Whitney U-test was used to observe gender dimorphism. RESULTS: Skeletal class II was the most prevalent type of malocclusion. There were no difference in the obtained measurements between males and females except the Wits appraisal and Beta-angle in class II patients, which showed significant difference in values (p < 0.05). CONCLUSION: Pakistani population has no significant different difference in the craniofacial morphology of males and females, with the exception of Wits-appraisal and Beta-angle in class II cases. PMID- 27225129 TI - Genome-wide association study identifies 74 loci associated with educational attainment. AB - Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases. PMID- 27225146 TI - Distal Based Sural Fascio-Cutaneous Flap: A Practical Limb Saviour for Wounds of War and Peace. AB - OBJECTIVE: To determine the effect of mechanism of injury on wound healing, and on the viability and success of distally based sural flap when used for the coverage of defects of lower leg, ankle and foot. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Department of Surgery, Combined Military Hospital, Peshawar and Khariyan, from January 2012 to December 2014. METHODOLOGY: Patients with soft tissue defects over the distal leg, ankle and foot were selected by purposive sampling technique and divided into 2 groups of 19 patients each. Group A(road traffic accidents) and group B (war injuries). Sural fascio cutaneous flap was the reconstructive tool used in all the cases using single technique by the same surgical team; and time for recipient site preparation, size of the defect, graft survival, its healing time and complications, were studied. RESULTS: The mean age of the 38 patients in the study was 28.2 +/-13.4 years. There were 36 male and 2 female patients. The most common site of injury encountered was leg (n=20) followed by foot (n=11) and ankle (n=5). Maximum wound size seen in group A was 10 x 12 cm and in group B was 15 x 38 cm. Recovery was uneventful in 17/19 cases of group Awhile 7/19 in group B and with no graft failure. Superficial epidermolysis was seen in 2 and 8 cases in group A and B respectively while edge necrosis of the flap was observed in group B only (n=4). Healing time on average was 2 to 3 weeks in group A, and 4 to 5 weeks in group B. CONCLUSION: Soft tissue defects of the distal lower extremity as a result of war injuries and road traffic accidents have different dynamics in terms of wound size, time of wound healing, wound complications and functional outcome; but distal based sural flap has promising results in both situations. PMID- 27225147 TI - Frequency of Addictive Habits and its Association with Oral Diseases Among a Cross Section of Indian Police Personnel Connotation. AB - OBJECTIVE: To assess the frequency of adverse addictive habits, specially alcohol and tobacco usage, among police personnel of Bhopal City, Central India and its association with the frequency of oral mucosal lesions and periodontal diseases. STUDY DESIGN: Across-sectional analytical study. PLACE AND DURATION OF STUDY: Bhopal City, Capital of Madhya Pradesh State, Central India, from February to April 2013. METHODOLOGY: All the police personnel posted at various police stations were interviewed and clinically examined. Police personnel who did not cooperate or were not willing, were excluded from the study. Chi-square test was used to analyze categorical variables. RESULTS: Atotal of 781 subjects were interviewed for the various forms of adverse habits, followed by clinical assessment of oral mucosal lesions and periodontal status using WHO 1997 criteria. The mean age of study subjects was 40.58 +/-9.84 years. Usage of tobacco was found among 55% and only 1.3% of subjects consumed alcohol. The prevalence of oral mucosal lesions and periodontal diseases was significantly higher among tobacco users. CONCLUSION: There was high usage of tobacco among police personnel in Bhopal City, India with a detrimental effect on oral health. PMID- 27225149 TI - Ascites in Patients on Maintenance Hemodialysis: Causes, Characteristics and Predicting Factors. AB - OBJECTIVE: To describe the causes, characteristics and factors associated with ascites in patients on maintenance hemodialysis. STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi, from November 2007 to November 2014. METHODOLOGY: All patients on maintenance hemodialysis and age > 16 years with ascites were included. Frequencies and percentages were computed for different categorical variables. Chi-square or Fischer exact test were used to identify factors associated with ascites like frequency of hemodialysis, serum albumin and cardiac ejection fraction (EF). Odds ratios were calculated for associated factors. RESULTS: Ninety patients were included in this study; 55.5% were males. Median age was 33 years. Cause of ascites was nephrogenic in 77.8%, cardiac failure in 16.7%, hypothyroidism in 6.67%, liver cirrhosis in 4.4%, abdominal tuberculosis in 2.2%, and peritoneal carcinomatosis in 1.1% patients. The ascites was severe in 53.3% patients and severity was associated with serum albumin < 2.8 gm/dL(p=0.007) and cardiac EF < 40% (p=0.028). The ascites was low serum ascites albumin gradient (SAAG), high protein type (LSHP) in 60% patients and associated with hemorrhage (p=0.040). High SAAG, high protein (HSHP) ascites, found in 33.3%, was associated with cardiac EF < 40% (p=0.005) and portal hypertension (p=0.048). High SAAG, low protein (HSLP) ascites, seen in 6.7%, was associated with portal hypertension (p=0.006). CONCLUSION: The commonest cause of ascites in hemodialysis dependent patients is nephrogenic followed by cardiac failure. Low serum albumin and low cardiac EF predispose to severe forms of ascites. PMID- 27225148 TI - Bone Turnover Markers for Osteoporosis Status Assessment at Baseline in Postmenopausal Pakistani Females. AB - OBJECTIVE: To assess bone turnover status in osteopenic and osteoporotic postmenopausal females. STUDY DESIGN: Cross-sectional analytical study. PLACE AND DURATION OF STUDY: The Aga Khan University Hospital, Karachi, from January to December 2013. METHODOLOGY: Across-sectional study was conducted on 203 postmenopausal females undergoing bone mineral density testing (BMD) by DXAscan. Patients with clinical history of any disorder or medications affecting bone turnover were excluded. Bone turnover was assessed with osteocalcin and beta-CTx. Data was analyzed by SPSS version 19. RESULTS: Mean age of the participants was 54 +/-4.66 years with a mean BMI of 28.7 +/-5.5 kg/m2. Mean beta-CTx (0.28 +/ 0.24 ng/ml) and osteocalcin (21.5 +/-10.6 ng/ml) levels were within the normal reference range. Subjects were grouped into normal (26.6%), osteopenic (44.8%), and osteoporotic (28.6%) based on the t-scores. Serum levels of osteocalcin and beta-CTx between normal, osteopenic, and osteoporotic groups were not significantly different. beta-CTx was negatively and significantly associated with only lumber spine BMD (r = -0.13, p=0.04). Positive association (< 0.0001) was noted between both markers in normal, osteopenic, and osteoporotic females. However, association of these markers with BMD in the 3 groups were not found. Multivariate linear regression showed a positive and significant effect of BMI on BMD (beta= 0.332, p= < 0.0001). beta-CTx had negative but significant effect on BMD (beta= -0.155, p= 0.018) of postmenopausal women. CONCLUSION: Association between baseline levels of BTM and rate of bone loss is variable and site dependent. beta-CTx correlates better with BMD. However, role of osteocalcin in postmenopausal osteoporosis is uncertain and needs further investigation. PMID- 27225150 TI - Adenoid Cystic Carcinoma of Breast: Clinicopathologic Study of Seven Cases. AB - Adenoid cystic carcinoma (ACC) of the breast is a rare type of tumor. Our objective was to determine the clinicopathologic features of breast ACC. We reviewed slides of breast ACC reported during 12 years. Seven cases were identified. Age ranged from 38 to 59 years (mean = 47 years). Mean tumor size was 2.3 cm (range 1.2 to 4 cm). Histologically, dominant cribriform pattern was seen in 4 cases, solid in 2 and tubular in one case. Mitotic figures ranged from 2 to 22/10 HPFs. Grades I and II were seen in 3 cases each while 1 was grade III. Post surgical tamoxifen given in 3 cases, chemotherapy and radiotherapy in 2 and 1 case, respectively. Follow-up ranged from 12.5 - 138.5 months (mean = 61. 25 months). One patient developed vertebral metastasis. Consistent with published data, this series indicated that ACC-breast has a good prognosis. PMID- 27225151 TI - When A Surgeon Should Retire? AB - The question that when a surgeon should retire has been the subject under discussion since long. In the present era, medical education, knowledge, training, and technology are evolving at a rapid pace. At the other end, age causes decline in physical and cognitive performance. So the older a surgeon is, the more likely that he is remote from his initial education and training in his specialty. Research also proves that the senior surgeons are hesitant to plan for their retirement. So far there is no definitive study matching surgical outcomes to surgeons' age. The author believes that work done in related domains can provide a better understanding of physician aging and cognition issues, and thus can suggest more effective strategies towards continuous professional development and lifelong learning in medicine. PMID- 27225152 TI - Using Elasticated Retractors in Head and Neck Surgeries. AB - Elasticated retractors, a recent advancement in surgical techniques, provide an enhanced and effective way of retraction during head and neck surgeries. These have been used for a number of procedures and are known for their effective retraction and minimizing surgical time span. This article highlights the authors' experience and the pros and cons of this technique. PMID- 27225153 TI - Rare Association of Klippel-Trenaunay Syndrome with Large Pulmonary Embolism and Asymmetrical Emphysematous Bullae. AB - Klippel-Trenaunay syndrome is a rarely encountered congenital disease characterized by a triad of enlarged arteries and veins, limb hypertrophy and capillary malformations. We are presenting an interesting case of a 23-year male who had been previously diagnosed to have Klippel-Trenaunay syndrome. The patient presented with large pulmonary embolism after having undergone laser surgery for varicose veins. The diagnostic chest computed tomography (CT) performed also revealed the co-existence of severe destructive pulmonary parenchymal disease involving large areas of the pulmonary parenchyma and formation of large emphysematous bullae having an asymmetric involvement of the left lung field. The patient was managed with thrombolysis with a bolus fibrinolytic agent and subsequently underwent an inferior vena cava (IVC) filter implantation to prevent further episodes of embolism in the presence of a compromised lung. The association of Klippel-Trenaunay syndrome with recurrent pulmonary embolism and unexplained pulmonary parenchymal disease leading to almost complete destruction of large areas of lung fields is interesting and has never been previously described. PMID- 27225154 TI - Sarcoma-Like Mural Nodule in a Borderline Mucinous Tumour of Ovary. AB - A 37-year female presented with complaint of lower abdominal pain and amenorrhoea to the Military Hospital, Rawalpindi. Ultrasound of pelvis showed a right adnexal cystic lesion. On investigation, CA-125 was raised. Her MRI scan of pelvis revealed a right adnexal mass of fluid intensity measuring 15.2 x 12.9 x 9.2 cm. Right ovarian cystectomy was performed and the specimen was sent for histopathological examination. Grossly, the mass was cystic in appearance and measured 13.5 x 10 x 10 cm. On sectioning, it was unilocular and filled with turbid material. The cyst wall showed multiple papillary structures along with a nodule measuring 1.1 x 1 cm. Microscopically, the sections revealed borderline mucinous tumour with a sarcoma-like mural nodule composed of spindle shaped cells and epulis-like giant cells. Sarcoma-like mural nodules are rare nodules which are associated with mucinous tumours of the ovary. However, they have excellent prognosis and should not be interpreted as malignant. PMID- 27225155 TI - Epignathus Teratoma. AB - An epignathus is an extremely rare form of oropharyngeal teratoma that arises from the oral cavity, most commonly from the palate and is associated with a high mortality, secondary to airway obstruction in the neonatal period. We present a case of epignathus, diagnosed on antenatal ultrasound as teratoma. It was associated with polyhydramnios. The mother had presented with preterm labour at 27 weeks of gestation. Astillborn baby girl with a large epignathus was expelled spontaneously 2 hours after admission. Accurate prenatal diagnosis of the condition can be done by prenatal ultrasound including colour Doppler ultrasound, three dimensional ultrasound and MRI. The patient can be managed by EXIT (ex uterointrapartum treatment) procedure immediately after birth. Alternatively, the airway can be secured initially and a more complicated surgery can be undertaken once the patient is stable. Foetal surgery is another theoretical possibility. PMID- 27225156 TI - Assessment of WT1 Expression as a Marker of Treatment Outcome in Karyotype Normal Acute Myeloid Leukemia Patients in Pakistan. AB - Currently, there is an effort to predict relapse by follow-up monitoring of MRD and subsequently to begin the treatment of the patients during their clinical and hematological remission prior to overt hematological relapse. Expression of WT1 in AML is known to be independently associated with significant inferior response to therapy and short survival outcome. Follow-up monitoring of WT1 gene expression during or after therapy would be a valuable predictive marker for early recurrence or relapse of AML disease. This pilot study evaluated newly diagnosed and post-induction or consolidation chemotherapy of AML patients who were registered with the Oncology Clinics of the Aga Khan University Hospital, Karachi. High WT1 burden (> 5000 copies/ml) in 2 patients was indicative of early recurrence of the disease along with shorter disease-free and overall survival. Low WT1 expression (< 200 copies/ml) in 2 patients after induction and consolidation therapy, respectively, was suggestive of better prognosis. PMID- 27225157 TI - Awareness of Hepatitis 'B' Among People of Khyber Pakhtunkhwa Province of Pakistan. AB - Hepatitis B virus is causing serious health concerns in countries like Pakistan. In Khyber Pakhtunkhwa province, 0.6 milion people were estimated to be infected with this virus in 2008. The authors aimed to assess knowledge regarding vaccination, testing and routes of transmission of hepatitis B virus among people of Khyber Pakhtunkhwa, as such knowledge among masses will help limit the infection. People belonging to 12 different districts of Khyber Pakhtunkhwa province were interviewed over a period of 5 months from October 2013 to February 2014. Apre-tested questionnaire was used and in-person survey of randomly selected 1,938 people was carried out throughout the province. Ninety-nine percent people said they knew about hepatitis B virus and 42% said they had got tested for it too. Out of them, 63.2% knew that a vaccine is available for hepatitis B virus. The proportion of respondents, who said hepatitis B virus can spread by sharing razors, toothbrush, syringes or sexual contact, was 97.94%, 95%, 99.3% and 77%, respectively. Only 28.7% knew, it can also spread vertically from mother to child during childbirth. People were quite aware of the routes of transmission of this disease, but they lacked knowledge regarding vaccination and prevention of this menace. Settings should be set up where routine preventive care and immunization services are provided. PMID- 27225158 TI - Unintentional Injuries In Children: Are Our Homes Safe? AB - Unintentional injuries are a leading cause of death in childhood globally. Injuries lead to emotional trauma and financial burden for children, parents, and society. Here are the frequencies of unintentional injuries in children presented to the emergency and paediatric surgery clinics of the Aga Khan University Hospital, Karachi, Pakistan, from January to December 2012. Aretrospective chart review of children aged 0 day to 14 years presented with falls, burns, foreign body ingestion or inhalation, poisoning, fingers caught in doors, electrocution injuries and drowning, was conducted. Atotal of 165 children were included. Domestic injuries were frequently occurring injuries in our set-up which could be prevented by doing small adjustments to make the home safe for children. PMID- 27225159 TI - Hemorrhagic Pericarditis Leading to Cardiac Tamponade Following Abciximab Therapy. PMID- 27225160 TI - Bilateral Reversible Visual Loss and Noncaseating Granulomata: Rare Manifestations of Tuberculosis. PMID- 27225161 TI - Severe Hyponatremia Presenting as Paraneoplastic Syndrome in a Patient with Small Cell Carcinoma of Gallbladder. PMID- 27225162 TI - Creation and validation of an I-123 FP-CIT template for statistical image analysis using high-resolution SPECT for parkinsonian patients. AB - OBJECTIVE: The aim of this study was to create a new template for the anatomical normalization of I-123 FP-CIT SPECT images of Japanese people to evaluate dopamine transporter binding. METHODS: The subjects consisted of 16 normal control subjects (5 females and 11 males; mean age +/- SD, 51.6 +/- 9.5 years, ranging from 25 to 62 years) and 21 parkinsonian patients (7 females and 14 males; mean age +/- SD, 70.7 +/- 9.4 years, ranging from 49 to 85 years). All normal control subjects and 21 patients with parkinsonism underwent MRI. A total of 148 MBq of I-123 FP-CIT was intravenously injected as a bolus, and a SPECT scan was started 4 h later. Data were analyzed with the Statistical Parametric Mapping 8 (SPM8) software. At first, I-123 FP-CIT SPECT images were co-registered to MRI images and MRI images were normalized to Montreal Neurological Institute (MNI) space using a gray.nii template. Co-registered I-123 FP-CIT SPECT images were normalized using the predetermined normalization parameters for MRI images. Then, anatomically normalized I-123 FP-CIT SPECT images were divided by background counts individually measured using ROIs set on the cerebral cortices. The I-123 FP-CIT template was created by averaging the normalized SPECT images of the 16 normal control subjects. Thereafter, the averaged MRI images of the 16 normal control subjects were also created. RESULTS: A visual inspection revealed that there were no apparent differences between the I-123 FP-CIT images subjected to the two methods of anatomical normalization in normal control subjects. However, a group comparison by a paired t test using SPM8 revealed that the I-123 FP-CIT binding was significantly higher in the substriatal and temporal regions in I-123 FP-CIT images directly normalized with the I-123 FP-CIT template than in those normalized by the predetermined parameters with MRI, while it was higher in the bilateral frontal cortical regions in the latter than in the former images. CONCLUSION: We successfully created an I-123 FP-CIT template for Japanese people. This template is thought to be useful and reliable for the statistical analysis of I-123 FP-CIT images, although some problems exist in the evaluation of parkinsonian patients. The results of a paired t test using SPM suggest that we should use the same normalization method in statistical image analyses. PMID- 27225163 TI - Staff Turnover in Assertive Community Treatment (Act) Teams: The Role of Team Climate. AB - Staff turnover in Assertive Community Treatment (ACT) teams can result in interrupted services and diminished support for clients. This paper examines the effect of team climate, defined as team members' shared perceptions of their work environment, on turnover and individual outcomes that mediate the climate turnover relationship. We focus on two climate dimensions: safety and quality climate and constructive conflict climate. Using survey data collected from 26 ACT teams, our analyses highlight the importance of safety and quality climate in reducing turnover, and job satisfaction as the main mediator linking team climate to turnover. The findings offer practical implications for team management. PMID- 27225165 TI - Cardiac resynchronization therapy in congenital heart disease. AB - Cardiac resynchronization therapy (CRT) is an established treatment option for adult patients suffering heart failure due to idiopathic or ischemic cardiomyopathy associated with electromechanical dyssynchrony. There is limited evidence suggesting similar efficacy of CRT in patients with congenital heart disease (CHD). Due to the heterogeneity of structural and functional substrates, CRT implantation techniques are different with a thoracotomy or hybrid approach prevailing. Efficacy of CRT in CHD seems to depend on the anatomy of the systemic ventricle with best results achieved in systemic left ventricular patients upgraded to CRT from conventional pacing. Indications for CRT in patients with CHD were recently summarized in the Pediatric and Congenital Electrophysiology Society (PACES) and the Heart Rhythm Society (HRS) Expert Consensus Statement on the Recognition and Management of Arrhythmias in Adult Congenital Heart Disease and are presented in the text. PMID- 27225164 TI - Surgical aspects of atrial arrhythmia : Right atrial ablation and anti-arrhythmic surgery in congenital heart disease. AB - BACKGROUND: Atrial arrhythmias are frequently described in congenital heart disease. OBJECTIVES: To provide a surgical perspective of anti-arrhythmic procedures and strategic approaches. METHODS: Discussion of the history of anti arrhythmic treatments in congenital heart disease. RESULTS: Before the advent of the Maze procedure (first published in 1991), surgery mainly focused on patients with Wolff-Parkinson-White syndrome and also on arrhythmias in Ebstein's malformation. Atrial septal defects (ASD) subsequently received more attention, i.e., in terms of atrial arrhythmia in the natural prognosis and the surgically modified course and in terms of surgical versus transcatheter approaches. Based on the background of various atrial arrhythmia mechanisms of ASD, several surgical procedures have been reported, ranging from the bilateral full Maze procedure to simple modification of right atriotomy. The so-called right atrial Maze procedure occupies a special position from the viewpoint of cardiology in acquired heart disease, especially in cases of frequently occurring right heart failure. In hearts with more complex structural abnormalities, a detailed understanding of the conditions to improve overall surgical outcome and develop future "anti-arrhythmic" strategies is necessary. CONCLUSIONS: It is important to precisely specify factors in the individual cases, not only morphological diversity but also technical and strategic variations and their consequences. A variety of anti-arrhythmic surgical procedures are currently available. How and when to use which procedure requires professional insight and cautious clinical decision-making. PMID- 27225167 TI - Predictors of non-vertebral fracture in older Chinese males and females: Mr. OS and Ms. OS (Hong Kong). AB - Clinical risk factors to predict fracture are useful in guiding management of patients with osteoporosis or falls. Clinical predictors may however be population specific because of differences in lifestyle, environment and ethnicity. Four thousand community-dwelling Chinese males and females with average ages of 72.4 and 72.6 years were followed up for incident fractures, with an average of 6.5 and 8.8 years, respectively. Clinical information was collected, and bone mineral density (BMD) measurements were carried out at baseline. Stepwise Cox regression models were used to identify risk factors of nonvertebral fractures, with BMD as covariate. Areas under the receiver-operating characteristic (ROC) curve (AUC) were compared among different risk models. The incidence rates of nonvertebral fractures were 10.3 and 20.5 per 1000 person years in males and females, respectively. In males, age >=80, history of a fall in the past year, fracture history, chronic obstructive pulmonary disease, impaired visual depth perception and low physical health-related quality of life were significant fracture risk factors, independent of BMD. In females, the significant factors were fracture history, low visual acuity and slow narrow walking speed. The clinical risk factors had a significant influence on fracture risk irrespective of osteoporosis status, even having a better risk discrimination than BMD alone, especially in males. The best risk prediction model consisted both BMD and clinical risk factors. Clinical risk factors have additive value to hip BMD in predicting nonvertebral fractures in older Chinese people and may predict them better than BMD alone in older Chinese males. PMID- 27225166 TI - [Congenital heart defects in adulthood : Supraventricular tachycardia]. AB - Supraventricular tachycardia (SVT) based on congenital substrates, such as accessory pathways or dual atrioventricular nodal properties, occur with an increased probability linked to specific congenital heart defects (CHDs). In the literature, the association of Ebstein's anomaly with accessory pathways and with Mahaim fibers is most prominent. Compared with patients with otherwise normal hearts, the clinical relevance of SVT is typically more severe and therefore antiarrhythmia treatment is a necessity in many cases. Diagnostics, pharmaceutical treatment, and interventional therapy of SVT in patients with CHD are often demanding owing to anatomical, hemodynamic, and electro-anatomical peculiarities. The use of antiarrhythmic medication is often limited because of intolerable side effects and a lack of reliability in suppressing arrhythmia relapses in the long term. Within the last 15-20 years catheter ablation has thus become established as the first-choice treatment for SVT, even in patients with CHD. However, rates of success, recurrence, and risks are still inferior to those observed in patients with a normally functioning heart owing to the co-existence of vascular and cardiac anomalies, surgically created alterations, an unusual electro-anatomy, and lower tolerance to hemodynamic changes. Successful treatment in patients with CHDs and SVT requires a deep understanding and knowledge of all the disciplines discussed above and should only be practiced in dedicated centers, as patient numbers are small and therefore experience is limited. PMID- 27225168 TI - [Preclinical and clinical management after mass disaster : Experiences from the train collision in Bad Aibling on 9 February 2016]. AB - Mass casualty incidents (MCI) in this day and age represent a special challenge, which initially require on-site coordination and logistics and then a professional distribution of victims (triage) to surrounding hospitals. Technical, logistical and even specialist errors can impair this flow of events. It therefore seems advisable to make a detailed analysis of every MCI. In this article the railway incident from 9 February 2016 is analyzed taking the preclinical and clinical cirumstances into consideration and conclusions for future management are drawn. As a special entity it could be determined that fixed table units in passenger trains represent a particularly dangerous hazard and in many instances in this analysis led to characteristic abdominal and thoracic injuries. PMID- 27225169 TI - Author's Reply to Parsons: "Cytotoxicity of Oxycodone and Morphine in Human Neuroblastoma and Mouse Motoneuronal Cells: A Comparative Approach". PMID- 27225170 TI - Comment on: "Cytotoxicity of Oxycodone and Morphine in Human Neuroblastoma and Mouse Motoneuronal Cells: A Comparative Approach". PMID- 27225172 TI - Development of a multiple immunoaffinity column for simultaneous determination of multiple mycotoxins in feeds using UPLC-MS/MS. AB - A sensitive and specific immunoaffinity column to clean up and isolate multiple mycotoxins was developed along with a rapid one-step sample preparation procedure for ultra-performance liquid chromatography-tandem mass spectrometry analysis. Monoclonal antibodies against aflatoxin B1, aflatoxin B2, aflatoxin G1, aflatoxin G2, zearalenone, ochratoxin A, sterigmatocystin, and T-2 toxin were coupled to microbeads for mycotoxin purification. We optimized a homogenization and extraction procedure as well as column loading and elution conditions to maximize recoveries from complex feed matrices. This method allowed rapid, simple, and simultaneous determination of mycotoxins in feeds with a single chromatographic run. Detection limits for these toxins ranged from 0.006 to 0.12 ng mL(-1), and quantitation limits ranged from 0.06 to 0.75 ng mL(-1). Concentration curves were linear from 0.12 to 40 MUg kg(-1) with correlation coefficients of R (2) > 0.99. Intra-assay and inter-assay comparisons indicated excellent repeatability and reproducibility of the multiple immunoaffinity columns. As a proof of principle, 80 feed samples were tested and several contained multiple mycotoxins. This method is sensitive, rapid, and durable enough for multiple mycotoxin determinations that fulfill European Union and Chinese testing criteria. PMID- 27225173 TI - Barbell-shaped stir bar sorptive extraction using dummy template molecularly imprinted polymer coatings for analysis of bisphenol A in water. AB - This study reports the development of a novel dummy template molecularly imprinted polymer (MIP)-coated barbell-shaped stir bar. The MIP stir bar coatings were prepared by using 2,2-bis(4-hydroxyphenyl)butane (BPB), 4,4' dihydroxydiphenylmethane (BPF), 4-tert-butylphenol (PTBP), and tetrabromobisphenol A (TBBA) as dummy templates using a capillary in situ polymerization method. Uniform coatings can be prepared controllably. The method is simple, easy, and reproducible. The barbell-shaped stir bar was developed by using medical silicone tubes as wheels. The wheels could be removed and reinstalled when necessary; therefore, the barbell-shaped stir bar was easy to disassemble and reassemble. The novel MIP-coated stir bar showed good selectivity for the target analyte, bisphenol A (BPA). The established method is selective and sensitive with a lower detection limit for BPA of 0.003 MUg/L. The dummy template MIP-coated stir bar is suitable for trace BPA analysis in real environmental water samples without template leakage. The novel stir bar can be used at least 100 times. PMID- 27225174 TI - Identification of a ligand for tumor necrosis factor receptor from Chinese herbs by combination of surface plasmon resonance biosensor and UPLC-MS. AB - Identification of bioactive compounds directly from complex herbal extracts is a key issue in the study of Chinese herbs. The present study describes the establishment and application of a sensitive, efficient, and convenient method based on surface plasmon resonance (SPR) biosensors for screening active ingredients targeting tumor necrosis factor receptor type 1 (TNF-R1) from Chinese herbs. Concentration-adjusted herbal extracts were subjected to SPR binding assay, and a remarkable response signal was observed in Rheum officinale extract. Then, the TNF-R1-bound ingredients were recovered, enriched, and analyzed by UPLC QTOF/MS. As a result, physcion-8-O-beta-D-monoglucoside (PMG) was identified as a bioactive compound, and the affinity constant of PMG to TNF-R1 was determined by SPR affinity analysis (K D = 376 nM). Pharmacological assays revealed that PMG inhibited TNF-alpha-induced cytotoxicity and apoptosis in L929 cells via TNF-R1. Although PMG was a trace component in the chemical constituents of the R. officinale extract, it had considerable anti-inflammatory activities. It was found for the first time that PMG was a ligand for TNF receptor from herbal medicines. The proposed SPR-based screening method may prove to be an effective solution to analyzing bioactive components of Chinese herbs and other complex drug systems. Graphical abstract Scheme of the method based on SPR biosensor for screening and recovering active ingredients from complex herbal extracts and UPLC MS for identifying them. Scheme of the method based on SPR biosensor for screening and recovering active ingredients from complex herbal extracts and UPLC MS for identifying them. PMID- 27225175 TI - An investigation on the chemical structure of nitrogen and sulfur codoped carbon nanoparticles by ultra-performance liquid chromatography-tandem mass spectrometry. AB - A highly fluorescent nitrogen and sulfur codoped carbon nanoparticles (N,S-CNP) sample was obtained by microwave-assisted pyrolysis of citric acid and L cysteine. After being purified by dialysis, the complexity and chemical composition of N,S-CNP were evaluated by ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS) as well as by UPLC coupled with ultraviolet (UV) absorption and fluorescence detection (UPLC-UV/FLD) methods. By using the high-resolution UPLC separation, the N,S-CNP were well fractionated into six fractions within 3.5 min. Based on high-accuracy MS and tandem (MS/MS) analyses, the N,S-CNP species were revealed to display various chemical formulas, including (C12H16N2O7S2) n , (C9H13NO8S) n , (C18H20N2O14S2) n , (C18H20N2O12S2) n , (C9H11NO5S) n , and (C9H11NO7S) n . More importantly, our study disclosed unambiguously for the first time that the N,S-CNP species exist as supramolecular clusters with their individual monomer units linked together through noncovalent bonding forces. By using UPLC-UV/FLD analysis, the spectral characteristics of each N,S-CNP species were revealed. Each individual CNP species possesses its unique absorption and PL properties with absorption bands that are redshifted, whereas its emission bands are blueshifted with its elution order. This work highlights the merit of UPLC-MS together with UPLC-UV/FLD to investigate the chemical composition and the spectral properties of each individual N,S-CNP species. It is anticipated that our proposed methodology will open up a new venue in optimizing experimental conditions for producing specific N,S-CNP species of desired composition. Graphical Abstract Carbon nanoparticles synthesized by microwave-assisted pyrolysis of citric acid and L-cysteine exist as supramolecular clusters with their individual monomer units linked together by noncovalent interactions. PMID- 27225176 TI - Threads for tear film collection and support in quantitative amino acid analysis. AB - The collection of tears for chemical composition analysis is complicated by both the difficulty in sampling the tear film and the relatively low microliter volumes available for analysis. The experiments in this study are focused on the demonstration of a method for determining amino acids from tear samples. Phenol red thread was used to absorptively collect tear fluid for qualitative and quantitative analyses of amino acids in basal, reflex, and emotional tears. The thread is also used as a support for sample preparation followed by elution with a buffer. The phenol red indicator on the thread turns from yellow to red with 15 s tear absorption and allows accurate volume measurement from 100 nL to over 1 MUL. Derivatization of amino acids was performed directly on the thread with primary amine reactive fluorescamine for fluorescence detection. Analyte elution was performed via centrifugation with the thread in a pipet tip suspended in a centrifuge tube. Collected tear eluate was analyzed via capillary electrophoresis with LED-induced fluorescence. Glycine, glutamate, and aspartate were baseline resolved and used for method characterization. Recoveries were at 50 % for a single derivation and elution step but average recoveries near 90 % were found with two-step processing. Glutamate and aspartate are shown to be stable stored on thread for 3 days. Basal, reflex, and emotional tears were analyzed from three subjects showing distinct amino acid profiles for each tear type. The demonstration of this method may facilitate the development of routine tear compositional analysis to assess ocular health. Graphical Abstract Schematic drawing of thread-based tear collection and quantitative analysis. PMID- 27225177 TI - Evaluation of cytotoxicity profile and intracellular localisation of doxorubicin loaded chitosan nanoparticles. AB - In the emerging field of nanomedicine, targeted delivery of nanoparticle encapsulated active pharmaceutical ingredients (API) is seen as a potential significant development, promising improved pharmacokinetics and reduced side effects. In this context, understanding the cellular uptake of the nanoparticles and subsequent subcellular distribution of the API is of critical importance. Doxorubicin (DOX) was encapsulated within chitosan nanoparticles to investigate its intracellular delivery in A549 cells in vitro. Unloaded (CS-TPP) and doxorubicin-loaded (DOX-CS-TPP) chitosan nanoparticles were characterised for size (473 +/- 41 nm), polydispersity index (0.3 +/- 0.2), zeta potential (34 +/- 4 mV), drug content (76 +/- 7 MUM) and encapsulation efficiency (95 +/- 1 %). The cytotoxic response to DOX-CS-TPP was substantially stronger than to CS-TPP, although weaker than that of the equivalent free DOX. Fluorescence microscopy showed a dissimilar pattern of distribution of DOX within the cell, being predominantly localised in the nucleus for free form and in cytoplasm for DOX-CS TPP. Confocal microscopy demonstrated endosomal localisation of DOX-CS-TPP. Numerical simulations, based on a rate equation model to describe the uptake and distribution of the free DOX, nanoparticles and DOX-loaded nanoparticles within the cells and the subsequent dose- and time-dependent cytotoxic responses, were used to further elucidate the API distribution processes. The study demonstrates that encapsulation of the API in nanoparticles results in a delayed release of the drug to the cell, resulting in a delayed cellular response. This work further demonstrates the potential of mathematical modelling in combination with intracellular imaging techniques to visualise and further understand the intracellular mechanisms of action of external agents, both APIs and nanoparticles in cells. PMID- 27225178 TI - Colorimetric assessment of BCR-ABL1 transcripts in clinical samples via gold nanoprobes. AB - Gold nanoparticles functionalized with thiolated oligonucleotides (Au-nanoprobes) have been used in a range of applications for the detection of bioanalytes of interest, from ions to proteins and DNA targets. These detection strategies are based on the unique optical properties of gold nanoparticles, in particular, the intense color that is subject to modulation by modification of the medium dieletric. Au-nanoprobes have been applied for the detection and characterization of specific DNA sequences of interest, namely pathogens and disease biomarkers. Nevertheless, despite its relevance, only a few reports exist on the detection of RNA targets. Among these strategies, the colorimetric detection of DNA has been proven to work for several different targets in controlled samples but demonstration in real clinical bioanalysis has been elusive. Here, we used a colorimetric method based on Au-nanoprobes for the direct detection of the e14a2 BCR-ABL fusion transcript in myeloid leukemia patient samples without the need for retro-transcription. Au-nanoprobes directly assessed total RNA from 38 clinical samples, and results were validated against reverse transcription-nested polymerase chain reaction (RT-nested PCR) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The colorimetric Au-nanoprobe assay is a simple yet reliable strategy to scrutinize myeloid leukemia patients at diagnosis and evaluate progression, with obvious advantages in terms of time and cost, particularly in low- to medium-income countries where molecular screening is not routinely feasible. Graphical abstract Gold nanoprobe for colorimetric detection of BCR-ABL1 fusion transcripts originating from the Philadelphia chromosome. PMID- 27225180 TI - Generation of obese rat model by transcription activator-like effector nucleases targeting the leptin receptor gene. AB - The laboratory rat is a valuable mammalian model organism for basic research and drug discovery. Here we demonstrate an efficient methodology by applying transcription activator-like effector nucleases (TALENs) technology to generate Leptin receptor (Lepr) knockout rats on the Sprague Dawley (SD) genetic background. Through direct injection of in vitro transcribed mRNA of TALEN pairs into SD rat zygotes, somatic mutations were induced in two of three resulting pups. One of the founders carrying bi-allelic mutation exhibited early onset of obesity and infertility. The other founder carried a chimeric mutation which was efficiently transmitted to the progenies. Through phenotyping of the resulting three lines of rats bearing distinct mutations in the Lepr locus, we found that the strains with a frame-shifted or premature stop codon mutation led to obesity and metabolic disorders. However, no obvious defect was observed in a strain with an in-frame 57 bp deletion in the extracellular domain of Lepr. This suggests the deleted amino acids do not significantly affect Lepr structure and function. This is the first report of generating the Lepr mutant obese rat model in SD strain through a reverse genetic approach. This suggests that TALEN is an efficient and powerful gene editing technology for the generation of disease models. PMID- 27225181 TI - Treating the enigmatic "exceptional responders" as patients with undiagnosed diseases. PMID- 27225179 TI - The heterogeneity of islet autoantibodies and the progression of islet failure in type 1 diabetic patients. AB - Type 1 diabetes mellitus is heterogeneous in many facets. The patients suffered from type 1 diabetes present several levels of islet function as well as variable number and type of islet-specific autoantibodies. This study was to investigate prevalence and heterogeneity of the islet autoantibodies and clinical phenotypes of type 1 diabetes mellitus; and also discussed the process of islet failure and its risk factors in Chinese type 1 diabetic patients. A total of 1,291 type 1 diabetic patients were enrolled in this study. Demographic information was collected. Laboratory tests including mixed-meal tolerance test, human leukocyte antigen alleles, hemoglobinA1c, lipids, thyroid function and islet autoantibodies were conducted. The frequency of islet-specific autoantibody in newly diagnosed T1DM patients (duration shorter than half year) was 73% in East China. According to binary logistic regressions, autoantibody positivity, longer duration and lower Body Mass Index were the risk factors of islet failure. As the disease developed, autoantibodies against glutamic acid decarboxylase declined as well as the other two autoantibodies against zinc transporter 8 and islet antigen 2. The decrease of autoantibodies was positively correlated with aggressive beta cell destruction. Autoantibodies can facilitate the identification of classic T1DM from other subtypes and predict the progression of islet failure. As there were obvious heterogeneity in autoantibodies and clinical manifestation in different phenotypes of the disease, we should take more factors into consideration when identifying type 1 diabetes mellitus. PMID- 27225183 TI - Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone. AB - Breast cancer metastatic relapse can occur years after therapy, indicating that disseminated breast cancer cells (BCCs) have a prolonged dormant phase before becoming proliferative. A major site of disease dissemination and relapse is bone, although the critical signals that allow circulating BCCs to identify bone microvasculature, enter tissue, and tether to the microenvironment are poorly understood. Using real-time in vivo microscopy of bone marrow (BM) in a breast cancer xenograft model, we show that dormant and proliferating BCCs occupy distinct areas, with dormant BCCs predominantly found in E-selectin- and stromal cell-derived factor 1 (SDF-1)-rich perisinusoidal vascular regions. We use highly specific inhibitors of E-selectin and C-X-C chemokine receptor type 4 (CXCR4) (SDF-1 receptor) to demonstrate that E-selectin and SDF-1 orchestrate opposing roles in BCC trafficking. Whereas E-selectin interactions are critical for allowing BCC entry into the BM, the SDF-1/CXCR4 interaction anchors BCCs to the microenvironment, and its inhibition induces mobilization of dormant micrometastases into circulation. Homing studies with primary BCCs also demonstrate that E-selectin regulates their entry into bone through the sinusoidal niche, and immunohistochemical staining of patient BMs shows dormant micrometastatic disease adjacent to SDF-1(+) vasculature. These findings shed light on how BCCs traffic within the host, and suggest that simultaneous blockade of CXCR4 and E-selectin in patients could molecularly excise dormant micrometastases from the protective BM environment, preventing their emergence as relapsed disease. PMID- 27225182 TI - Amyloid-beta peptide protects against microbial infection in mouse and worm models of Alzheimer's disease. AB - The amyloid-beta peptide (Abeta) is a key protein in Alzheimer's disease (AD) pathology. We previously reported in vitro evidence suggesting that Abeta is an antimicrobial peptide. We present in vivo data showing that Abeta expression protects against fungal and bacterial infections in mouse, nematode, and cell culture models of AD. We show that Abeta oligomerization, a behavior traditionally viewed as intrinsically pathological, may be necessary for the antimicrobial activities of the peptide. Collectively, our data are consistent with a model in which soluble Abeta oligomers first bind to microbial cell wall carbohydrates via a heparin-binding domain. Developing protofibrils inhibited pathogen adhesion to host cells. Propagating beta-amyloid fibrils mediate agglutination and eventual entrapment of unatttached microbes. Consistent with our model, Salmonella Typhimurium bacterial infection of the brains of transgenic 5XFAD mice resulted in rapid seeding and accelerated beta-amyloid deposition, which closely colocalized with the invading bacteria. Our findings raise the intriguing possibility that beta-amyloid may play a protective role in innate immunity and infectious or sterile inflammatory stimuli may drive amyloidosis. These data suggest a dual protective/damaging role for Abeta, as has been described for other antimicrobial peptides. PMID- 27225184 TI - Up-regulation of miR-31 in human atrial fibrillation begets the arrhythmia by depleting dystrophin and neuronal nitric oxide synthase. AB - Atrial fibrillation (AF) is a growing public health burden, and its treatment remains a challenge. AF leads to electrical remodeling of the atria, which in turn promotes AF maintenance and resistance to treatment. Although remodeling has long been a therapeutic target in AF, its causes remain poorly understood. We show that atrial-specific up-regulation of microRNA-31 (miR-31) in goat and human AF depletes neuronal nitric oxide synthase (nNOS) by accelerating mRNA decay and alters nNOS subcellular localization by repressing dystrophin translation. By shortening action potential duration and abolishing rate-dependent adaptation of the action potential duration, miR-31 overexpression and/or disruption of nNOS signaling recapitulates features of AF-induced remodeling and significantly increases AF inducibility in mice in vivo. By contrast, silencing miR-31 in atrial myocytes from patients with AF restores dystrophin and nNOS and normalizes action potential duration and its rate dependency. These findings identify atrial specific up-regulation of miR-31 in human AF as a key mechanism causing atrial dystrophin and nNOS depletion, which in turn contributes to the atrial phenotype begetting this arrhythmia. miR-31 may therefore represent a potential therapeutic target in AF. PMID- 27225185 TI - Is it Trauma- or Fantasy-based? Comparing dissociative identity disorder, post traumatic stress disorder, simulators, and controls. AB - OBJECTIVE: The Trauma Model of dissociative identity disorder (DID) posits that DID is etiologically related to chronic neglect and physical and/or sexual abuse in childhood. In contrast, the Fantasy Model posits that DID can be simulated and is mediated by high suggestibility, fantasy proneness, and sociocultural influences. To date, these two models have not been jointly tested in individuals with DID in an empirical manner. METHOD: This study included matched groups [patients (n = 33) and controls (n = 32)] that were compared on psychological Trauma and Fantasy measures: diagnosed genuine DID (DID-G, n = 17), DID simulating healthy controls (DID-S, n = 16), individuals with post-traumatic stress disorder (PTSD, n = 16), and healthy controls (HC, n = 16). Additionally, personality-state-dependent measures were obtained for DID-G and DID-S; both neutral personality states (NPS) and trauma-related personality states (TPS) were tested. CONCLUSION: For Trauma measures, the DID-G group had the highest scores, with TPS higher than NPS, followed by the PTSD, DID-S, and HC groups. The DID-G group was not more fantasy-prone or suggestible and did not generate more false memories. Malingering measures were inconclusive. Evidence consistently supported the Trauma Model of DID and challenges the core hypothesis of the Fantasy Model. PMID- 27225187 TI - Erratum to: ACMT Position Statement: Guidance for the Use of Intravenous Lipid Emulsion. PMID- 27225186 TI - Investigating the effect of distance between the teacher and learner on the student perception of a neuroanatomical near-peer teaching programme. AB - PURPOSE: Near-peer teaching (NPT) is a highly valuable resource for the education of medical undergraduates with benefits to the students, teachers themselves, and the faculty. To maximise the effectiveness of such teaching programmes, the aim of this study was to determine how the student learning experience, and underpinning social and cognitive congruencies changes as the learner-teacher distance increases. METHODS: Second-year medical students at the University of Southampton participated in a series of neuroanatomy, extra-curricular revision sessions taught by the third-, fourth-, and fifth-year medical students and junior doctors. The students completed a validated questionnaire after the session rating various aspects of the teaching. RESULTS: Although all teachers delivered sessions that we rated highly with a mean perceived gain in knowledge of 18 % amongst all students, it was found that the third- and fourth-year medical students delivered a session that was rated significantly better than the fifth-year students and junior doctors across all, but one areas of feedback. CONCLUSIONS: We believe that these findings may be explained by the diminishing social and cognitive congruencies shared between learner and teacher with increasing distance. From our results, we hypothesise that graduation is an important threshold, where there is a significant drop in congruencies between the learner and teacher, therefore, having a significant impact on the perception of the NPT session. PMID- 27225188 TI - Expression quantitative trait loci in long non-coding RNA PAX8-AS1 are associated with decreased risk of cervical cancer. AB - Paired box 8 (PAX8) is a crucial nephric-lineage transcription factor, and its aberrant expression has been detected in various types of cancer including Mullerian carcinomas. PAX8 antisense RNA 1 (PAX8-AS1), a potential regulator of PAX8, contains specific single nucleotide polymorphisms (SNPs) that may represent expression quantitative trait loci (eQTLs) for PAX8. In this study, we hypothesized that these eQTLs SNPs in PAX8-AS1 may influence the risk of cervical cancer. A case-control study of 1486 cervical cancer patients and 1536 cancer free controls was conducted to identify the associations between two eQTLs SNPs (rs4848320 and rs1110839) and cervical cancer. Logistic regression analyses revealed that variant allele T of rs4848320 (recessive model: adjusted OR = 0.61, 95 % CI = 0.38-0.97, P = 0.027) and G of rs1110839 (additive model: adjusted OR = 0.88, 95 % CI = 0.79-0.99, P = 0.032) were associated with decreased risk of cervical cancer. Moreover, the haplotype containing variant alleles of the two SNPs significantly decreased the risk of cervical cancer compared to the most frequent haplotype (adjusted OR = 0.82, 95 % CI = 0.70-0.95, P = 0.009). These findings indicate that PAX8 eQTLs SNPs may serve as novel susceptibility markers for cervical cancer. PMID- 27225189 TI - Long-term results of anterior cervical corpectomy and fusion with nano hydroxyapatite/polyamide 66 strut for cervical spondylotic myelopathy. AB - To assess the long-term clinical and radiographic outcomes of anterior cervical corpectomy and fusion (ACCF) with a neotype nano-hydroxyapatite/polyamide 66 (n HA/PA66) strut in the treatment of cervical spondylotic myelopathy (CSM). Fifty patients with CSM who underwent 1- or 2-level ACCF with n-HA/PA66 struts were retrospectively investigated. With a mean follow-up of 79.6 months, the overall mean JOA score, VAS and cervical alignment were improved significantly. At last follow-up, the fusion rate was 98%, and the subsidence rate of the n-HA/PA66 strut was 8%. The "radiolucent gap" at the interface between the n-HA/PA66 strut and the vertebra was further noted to evaluate the osteoconductivity and osseointegration of the strut, and the incidence of it was 62% at the last follow up. Three patients suffered symptomatic adjacent segment degeneration (ASD). No significant difference was detected in the outcomes between 1- and 2-level corpectomy at follow-ups. In conclusion, the satisfactory outcomes in this study indicated that the n-HA/PA66 strut was an effective graft for cervical reconstruction. Moreover, the osteoconductivity and osseointegration of the strut is still need to be optimized for future clinical application owing to the notably presence of "radiolucent gap" in present study. PMID- 27225190 TI - Corepressive function of nuclear receptor coactivator 2 in androgen receptor of prostate cancer cells treated with antiandrogen. AB - BACKGROUND: Recruitment of cofactors in the interaction of the androgen receptor (AR) and AR ligands plays a critical role in determining androgenic/antiandrogenic effects of the AR ligand on signaling, but the functions of key cofactors, including nuclear receptor coactivator (NCOA), remain poorly understood in prostate cancer cells treated with AR ligands. METHODS: We examined prostate cancer cell lines LNCaP and VCaP expressing mutated and wild type ARs, respectively, to clarify the significance of NCOAs in the effect of antiandrogens. Hydroxyflutamide showed antagonistic activity against VCaP and an agonistic effect on LNCaP. Bicalutamide served as an antagonist for both. We analyzed mRNA transcription and protein expression of NCOAs in these cells pretreated with dihydrotestosterone and thereafter treated with the mentioned antiandrogens. Transcriptional silencing of candidate NCOAs and AR was performed using small interfering RNA (siRNA). Cell proliferation was evaluated with MTT assay. RESULTS: LNCaP treated with bicalutamide showed an about four-fold increase in the expression of NCOA2 mRNA compared to those pretreated with dihydrotestosterone alone (P <0.01). In VCaP pretreated with dihydrotestosterone, transcriptions of NCOA2 and NCOA7 were slightly increased with bicalutamide (1.96 and 2.42-fold, respectively) and hydroxyflutamide (1.33-fold in both). With Western blotting, the expression of NCOA2 protein also increased in LNCaP cells treated with bicalutamide compared with that in control cells pretreated with dihydrotestosterone alone. Following silencing with siRNA for NCOA2, PSA levels in media with LNCaP receiving bicalutamide were elevated compared with those in non-silencing controls (101.6 +/- 4.2 vs. 87.8 +/- 1.4 ng/mL, respectively, P =0.0495). In LNCaP cells treated with dihydrotestosterone and bicalutamide, NCOA2 silencing was associated with a higher proliferation activity compared with non silencing control and AR-silencing. CONCLUSION: NCOA2, which has been thought to be recruited as a coactivator, possibly plays a corepressive role in AR of prostate cancer cells when treated with antiandrogens, suggesting its potential as a therapeutic target. PMID- 27225191 TI - Factors associated with emergency department visit within 30 days after discharge. AB - BACKGROUND: Post-discharge care remains a challenge because continuity of care is often interrupted and adverse events frequently occur. Previous studies have focused on early readmission but few have investigated emergency department (ED) visit after discharge. METHODS: This retrospective observational study was conducted between April 2011 and March 2012 in a referral center in Taiwan. Patients discharged from the general medical wards during the study period were analyzed and their characteristics, hospital course, and associated factors were collected. An ED visit within 30 days of discharge was the primary outcome while readmission or death at home were secondary outcomes. RESULTS: There were 799 discharged patients analyzed, including 96 (12 %) with an ED visit of 12.4 days post-discharge and 111 (14 %) with readmissions at 13.3 days post-discharge. Sixty patients were admitted after their ED visit. Underlying chronic illnesses were associated with 72 % of ED visits. By multivariate analysis, Charlson score and the use of naso-gastric tube were independent risk factors for ED visit within 30 days after discharge. CONCLUSIONS: Early ED visit after discharge is as high as 12 %. Patients with chronic illness and those requiring a naso-gastric tube or external biliary drain are at high risk for post-discharge ED visit. PMID- 27225192 TI - A genetic polymorphism affects the risk and prognosis of renal cell carcinoma: association with follistatin-like protein 1 expression. AB - Few single nucleotide polymorphisms (SNPs) associated with the risk of renal cell carcinoma (RCC) have been identified, yet genetic predisposition contributes significantly to this malignancy. We previously showed that follistatin-like 1 (FSTL1) was significantly down-regulated in clear cell RCC (ccRCC), in particular metastatic ccRCC. In the present study, we systemically investigated the associations of the 6 SNPs within FSTL1-coding genomic region with RCC risk and postoperative prognosis. Age- and gender-matched case-control study (417 vs 855) indicated that rs1259293 variant genotype CC was significantly associated with an increased risk of RCC, with an odds ratio of 2.004 (95% confidence internal [CI] = 1.190-3.375). Multivariate Cox regression analysis in 309 of 417 cases showed that rs1259293 genotype (CC vs TT + CT) independently predicted an unfavorable prognosis, with a hazard ratio of 2.531 (95% CI = 1.052-6.086). Expression of FSTL1 was significantly higher in adjacent renal tissues than in tumors, and significantly higher in the tissues with rs1259293 TT genotype than in those with rs1259293 TC+CC genotypes. rs1259293 C allele might generate a CTCF binding site that blocks trans-activation of FSTL1 expression. Our results indicate that rs1259293 is associated with an increased risk and unfavorable postoperative prognosis of RCC, possibly by down-regulating FSTL1 expression in renal tissues. PMID- 27225193 TI - Ethics in rehabilitation: challenges and opportunities to promote research. PMID- 27225194 TI - Cochrane physical and rehabilitation medicine: a new field to bridge between best evidence and the specific needs of our field of competence. PMID- 27225195 TI - An unusual finger injury. PMID- 27225197 TI - Evaluating the impact of a computerized surveillance algorithm and decision support system on sepsis mortality. AB - OBJECTIVE: We created a system using a triad of change management, electronic surveillance, and algorithms to detect sepsis and deliver highly sensitive and specific decision support to the point of care using a mobile application. The investigators hypothesized that this system would result in a reduction in sepsis mortality. METHODS: A before-and-after model was used to study the impact of the interventions on sepsis-related mortality. All patients admitted to the study units were screened per the Institute for Healthcare Improvement Surviving Sepsis Guidelines using real-time electronic surveillance. Sepsis surveillance algorithms that adjusted clinical parameters based on comorbid medical conditions were deployed for improved sensitivity and specificity. Nurses received mobile alerts for all positive sepsis screenings as well as severe sepsis and shock alerts over a period of 10 months. Advice was given for early goal-directed therapy. Sepsis mortality during a control period from January 1, 2011 to September 30, 2013 was used as baseline for comparison. RESULTS: The primary outcome, sepsis mortality, decreased by 53% (P = 0.03; 95% CI, 1.06-5.25). The 30 day readmission rate reduced from 19.08% during the control period to 13.21% during the study period (P = 0.05; 95% CI, 0.97-2.52). No significant change in length of hospital stay was noted. The system had observed sensitivity of 95% and specificity of 82% for detecting sepsis compared to gold-standard physician chart review. CONCLUSION: A program consisting of change management and electronic surveillance with highly sensitive and specific decision support delivered to the point of care resulted in significant reduction in deaths from sepsis. PMID- 27225196 TI - Cigarette Smoking and Chronic Kidney Disease in African Americans in the Jackson Heart Study. AB - BACKGROUND: Controversy exists regarding the association of cigarette smoking and renal dysfunction, particularly among African Americans, who are disproportionately affected by chronic kidney disease; therefore, we evaluated the relationship between cigarette smoking and rapid renal function (RRF) decline in the Jackson Heart Study. METHODS AND RESULTS: Rates of RRF decline were determined among 3648 African American participants enrolled at baseline in the Jackson Heart Study. RRF decline was defined as an absolute decline of estimated glomerular filtration rate of 30% from visit 1 to visit 3. There were 422 current, 659 past, and 2567 never smokers identified at visit 1. After adjustment for age, sex, body mass index, diabetes, hypertension, cholesterol, physical activity, education, alcohol consumption, and prevalent cardiovascular disease, current smokers demonstrated a significantly higher incidence of RRF decline compared with never smokers (incidence rate ratio 1.83, 95% CI 1.31-2.56). Current smokers using 1 to 19 and >=20 cigarettes daily had an increased incidence of RRF decline (incidence rate ratios of 1.75 [95% CI 1.18-2.59] and 1.97 [95% CI 1.17-3.31], respectively). There was a significant, progressive reduction in estimated glomerular filtration rate from visit 1 to visit 3 in current and past smokers compared with never smokers. Finally, current smokers had a 1.38-fold increase in C-reactive protein compared with never smokers, after controlling for covariates. CONCLUSIONS: In a large African American cohort, current cigarette smoking was independently associated with RRF decline in a dose dependent manner. There was also evidence of increased inflammation (C-reactive protein) in current smokers, suggesting a potential mechanism for these relationships. PMID- 27225198 TI - Malfunctioned cardiac resynchronization therapy attributed to acute exacerbation of cardiac sarcoidosis. PMID- 27225199 TI - Diagnostic Value of Antigen-Specific Immunoglobulin E Immunoassays against Ara h 2 and Ara h 8 Peanut Components in Child Food Allergy. AB - BACKGROUND: Peanut allergy is one of the most severe food allergies in children. The diagnostic gold standard is the oral food challenge (OFC). However, OFC has inherent risks and is time consuming. The measurement of specific immunoglobulin E (sIgE) to peanut components in blood detects peanut sensitization, but the decision point predicting allergy is still unclear. The aim of this study was to determine the diagnostic value of these tests for the evaluation of child peanut allergy. METHODS: In this retrospective study, 81 children were referred for peanut allergy. The diagnosis of peanut allergy was based on the clinical context and a positive OFC. Levels of sIgE against whole peanuts or peanut components (Ara h 2 and Ara h 8) were determined by immunoassay. RESULTS: The Ara h 2 sIgE assay has the best negative predictive value (0.93) and positive predictive value (1) at a cutoff of 0.1 kU/l. Ara h 2 sIgE titers can predict the risk of anaphylaxis (<0.44 kU/l, low risk; >14 kU/l, high risk). The Ara h 8 sIgE assay is not able to discriminate peanut-allergic patients but can be used to evaluate possible cross-reactions to birch pollen with a low risk of anaphylaxis. The best diagnostic strategy is to first determine the Ara h 2 sIgE level and, if negative, evaluate Ara h 8 sIgE. CONCLUSIONS: We propose an algorithm for a better use of peanut component sIgE immunoassays that should improve their diagnostic value and avoid unnecessary OFC. PMID- 27225201 TI - Dead or alive? Viability of chytrid zoospores shed from live amphibian hosts. AB - Pathogens vary in virulence and rates of transmission because of many differences in the host, the pathogen, and their environment. The amphibian chytrid fungus, Batrachochytrium dendrobatidis (Bd), affects amphibian hosts differently, causing extinction and population declines in some species but having limited effects on others. Phenotypic differences in zoospore production rates among Bd lineages likely contribute to some of the variation observed among host responses, although no studies have quantified the viability of zoospores shed from live animals. We compared host survivorship, infection intensity, shedding rates, and zoospore viability between 2 species of endangered tropical frogs, Hylomantis lemur and Atelopus zeteki, when exposed to a highly virulent lineage of Bd (JEL 423). We applied a dye to zoospores 30 to 60 min following animal soaks, to estimate shedding rate and proportion of live zoospores shed by different species. The average infection intensity for A. zeteki was nearly 17 times higher (31,455 +/- 10,103 zoospore genomic equivalents [ZGEs]) than that of H. lemur (1832 +/- 1086 ZGEs), and A. zeteki died earlier than H. lemur. The proportion of viable zoospores was ~80% in both species throughout the experiment, although A. zeteki produced many more zoospores, suggesting it may play a disproportionate role in spreading disease in communities where it occurs, because the large number of viable zoospores they produce might increase infection in other species where they are reintroduced. PMID- 27225200 TI - Carbonic anhydrase IX is a marker of hypoxia and correlates with higher Gleason scores and ISUP grading in prostate cancer. AB - BACKGROUND: Carbonic anhydrase IX is a member of alpha-carbonic anhydrases that is preferentially expressed in solid tumors. It enables bicarbonate transport across the plasma membrane, neutralizing intracellular pH and conferring to cancer cells a survival advantage in hypoxic/acidic microenvironments. Overexpression of carbonic anhydrase IX in cancer tissues is regulated by hypoxia inducible factor 1alpha - mediated transcription and the enzyme is considered a marker of tumor hypoxia and poor outcome. The role of carbonic anhydrase IX in prostate cancer has not been fully clarified and controversy has arisen on whether this enzyme is overexpressed in hypoxic prostate cancer tissues. METHODS: We analyzed the expression of carbonic anhydrase IX and hypoxia inducible factor 1alpha in two prostate cancer cell lines, LNCaP and PC-3, and in 110 cancer biopsies, by western blotting and immunocyto/histochemistry. RESULTS: In LNCaP and PC-3 cells, carbonic anhydrase IX was mostly cytoplasmic/nuclear, with very limited membrane localization. Nuclear staining became stronger under hypoxia. When we analyzed carbonic anhydrase IX expression in human prostate cancer biopsies, we found that protein staining positively correlated with hypoxia inducible factor 1alpha and with Gleason pattern and score, as well as with the novel grading system proposed by the International Society of Urological Pathology for prostate cancer. Once more, carbonic anhydrase IX was mainly cytoplasmic in low grade carcinomas, whereas in high grade tumors was strongly expressed in the nucleus of the neoplastic cell. An association between carbonic anhydrase IX expression level and the main clinic-pathological features involved in prostate cancer aggressiveness was identified. CONCLUSIONS: There was a statistically significant association between carbonic anhydrase IX and hypoxia inducible factor 1alpha in prostate cancer tissues, that identifies the enzyme as a reliable marker of tumor hypoxia. In addition, carbonic anhydrase IX expression positively correlated with prostate cancer grading and staging, and with outcome, suggesting that the protein may be an independent prognosticator for the disease. The nuclear translocation of the enzyme in hypoxic cancer cells may epitomize a biological switch of the tumor towards a less favorable phenotype. PMID- 27225202 TI - Emerging coral diseases in Kane'ohe Bay, O'ahu, Hawai'i (USA): two major disease outbreaks of acute Montipora white syndrome. AB - In March 2010 and January 2012, we documented 2 widespread and severe coral disease outbreaks on reefs throughout Kane'ohe Bay, Hawai'i (USA). The disease, acute Montipora white syndrome (aMWS), manifested as acute and progressive tissue loss on the common reef coral M. capitata. Rapid visual surveys in 2010 revealed 338 aMWS-affected M. capitata colonies with a disease abundance of (mean +/- SE) 0.02 +/- 0.01 affected colonies per m of reef surveyed. In 2012, disease abundance was significantly higher (1232 aMWS-affected colonies) with 0.06 +/- 0.02 affected colonies m(-1). Prior surveys found few acute tissue loss lesions in M. capitata in Ka-ne'ohe Bay; thus, the high number of infected colonies found during these outbreaks would classify this as an emerging disease. Disease abundance was highest in the semi-enclosed region of south Kane'ohe Bay, which has a history of nutrient and sediment impacts from terrestrial runoff and stream discharge. In 2010, tagged colonies showed an average tissue loss of 24% after 1 mo, and 92% of the colonies continued to lose tissue in the subsequent month but at a slower rate (chronic tissue loss). The host-specific nature of this disease (affecting only M. capitata) and the apparent spread of lesions between M. capitata colonies in the field suggest a potential transmissible agent. The synchronous appearance of affected colonies on multiple reefs across Kane'ohe Bay suggests a common underlying factor. Both outbreaks occurred during the colder, rainy winter months, and thus it is likely that some parameter(s) associated with winter environmental conditions are linked to the emergence of disease outbreaks on these reefs. PMID- 27225203 TI - Metabolic effects of parasitization by the barnacle Polyascus plana (Cirripedia: Rhizocephala: Sacculinidae) on a grapsid host, Metopograpsus thukuhar. AB - Pathophysiological studies of rhizocephalan infections are rare. We describe differences in the levels of tissue and hemolymph metabolites between Polyascus plana-parasitized and unparasitized individuals of Metopograpsus thukuhar. Crabs were assigned to either a parasitized (carrying at least 1 externa, i.e. a protruding reproductive body) or an unparasitized (not carrying externae and determined to be rootlet-free by a barnacle 18S rRNA-based polymerase chain reaction) group. Quantification of metabolites showed that muscle glycogen levels were significantly lower and hepatopancreas levels were significantly higher in parasitized crabs compared to unparasitized crabs; hepatopancreas triacylglycerol levels were significantly higher and hemolymph levels significantly lower in parasitized hosts, and there was no significant difference in muscle triacylglycerol levels between unparasitized and parasitized animals. Glucose levels in the hepatopancreas, muscle, and hemolymph were all significantly higher in parasitized hosts. Significant levels of glucose, triacylglycerol, and glycogen were present in the barnacle externae. In addition, levels of crustacean hyperglycemic hormone in the sinus glands were not significantly different between unparasitized and parasitized animals. Glucose mobilized from the muscle is likely converted to glycogen and triacylglycerol in the rootlet-infiltrated hepatopancreas of parasitized hosts, and the eyestalk neuroendocrine system appears not to be significantly impaired, in terms of hormone production and storage, by parasitization. PMID- 27225204 TI - Characterization and identification of streptococci from golden pompano in China. AB - Streptococcal infections cause significant mortality and high economic losses in the fish farm industry worldwide, including in the culture of golden pompano Trachinotus ovatus L., a species gaining popularity in China. A total of 9 streptococcal strains were isolated from cage-cultured diseased golden pompano in Beihai, Zhanjing, and Shenzhen, China, between 2012 and 2014. Conventional and rapid identification systems were used to determine that the isolates were Streptococcus agalactiae, S. iniae, and S. dysgalactiae subsp. dysgalactiae. All isolates were gram-positive cocci cells in pairs or short-chain, non-motile, catalase negative, alpha or beta hemolytic cocci. The results of multiplex PCR assays and 16S rRNA BLAST analysis also showed that the beta hemolytic strains were S. agalactiae and S. iniae and the alpha hemolytic strain was S. dysgalactiae subsp. dysgalactiae, respectively. Pathogenicity assays revealed that S. agalactiae (lethal dose [LD50]: 6.38 * 10(4) CFU ml(-1)) was more virulent for golden pompano than S. iniae (LD50: 1.47 * 10(7) CFU ml(-1)) and S. dysgalactiae subsp. dysgalactiae (LD50: 2.57 * 10(6) CFU ml(-1)) when they were challenged by intraperiotoneal (i.p.) injection. The results of antibiotic susceptibility showed that all strains were extremely susceptible to cefradine, erythromycin, and cefotaxime but resistant to gentamicin, penicillin G, novobiocin, neomycin, ciprofloxacin, roxithromycin, furazolidone, enrofloxacin, norfloxacin, kanamycin, ampicillin, tetracycline, and vancomycin This is the first report of a phenomenon of golden pompano coinfection with S. agalactiae and S. iniae, which will contribute to the diagnosis and prevention of streptococcicosis. PMID- 27225205 TI - Frequency and histologic characterization of coelomatic neoplasms in koi Cyprinus carpio koi. AB - Koi carp presenting with coelomatic neoplastic lesions are of growing importance in Switzerland and elsewhere in Europe, as clinical diagnosis is usually difficult and prognosis is usually poor because of late recognition. To gain more information about this condition, between 2008 and 2012, 117 koi diagnosed with coelomatic tumours were included in this study. The nature and growth characteristics of these pathologic tissues were documented. Out of 117 koi, 48.9% (n = 57) were female; the ovary was the most often affected organ (35%, n = 41), and in 62.4% (n =73) of cases, the cells of origin were identified as stromal cells of the sex-cord and the tumours were identified as sex-cord stromal tumours. The characteristics of growth and histology showed that the majority of tumours were malignant. PMID- 27225206 TI - Water temperature affects pathogenicity of different betanodavirus genotypes in experimentally challenged Dicentrarchus labrax. AB - Betanodaviruses are the causative agents of a highly infectious disease of fish known as viral nervous necrosis (VNN). To date, 4 different nervous necrosis virus (NNV) genotypes have been described, but natural reassortant viruses have also been detected, which further increase viral variability. Water temperature plays an important role in determining the appearance and the severity of VNN disease. We assessed the effect of temperature (20 degrees , 25 degrees and 30 degrees C) on mortality and virus load in the brain of European sea bass Dicentrarchus labrax experimentally infected with 4 genetically different betanodaviruses, namely red-spotted grouper NNV (RGNNV), striped jack NNV (SJNNV) and the reassortant strains RGNNV/SJNNV and SJNNV/RGNNV. The RGNNV/SJNNV virus possesses the polymerase gene of RGNNV and the coat protein gene of SJNNV, and vice versa for the SJNNV/RGNNV virus. The obtained results showed that the RGNNV strain is the most pathogenic for juvenile sea bass, but clinical disease and mortality appeared only at higher temperatures. The SJNNV strain is weakly pathogenic for D. labrax regardless of the temperature used, while virus replication was detected in the brain of survivors only at 20 degrees C. Finally, reassortant strains caused low mortality, independent of the temperature used, but the viral load in the brain was strongly influenced by water temperature and the genetic type of the polymerase gene. Taken together, these data show that nodavirus replication in vivo is a composite process regulated by both the genetic features of the viral strain and water temperatures. PMID- 27225207 TI - First outbreak of an infection with infectious spleen and kidney necrosis virus (ISKNV) in ornamental fish in Germany. AB - In 2014, infectious spleen and kidney necrosis virus (ISKNV), a member of the genus Megalocytivirus, was detected for the first time in ornamental fish in Germany. Since 2013, angelfish Pterophyllum spp. originating from Colombia have experienced significant epizootics in a number of German retailers' facilities. The diseased fish showed symptoms such as increased ventilation, swollen gills, and ulcerations of the skin. In 2014, diseased angelfish P. altum and platys Xiphophorus maculatus maintained in the same recirculating system were examined. Histopathological lesions included hypertrophic cells, single-cell necrosis, and an inflammatory infiltration of granulocytes, lymphocytes, and macrophages in liver, spleen, and kidney. Transmission electron microscopy revealed the presence of numerous polygonal viral particles (150 nm in diameter) within the cytoplasm of enlarged cells. A PCR assay for the detection of megalocytiviruses amplified 777 bp of major capsid protein gene that was 100% identical to ISKNV. This is the first report of an ISKNV outbreak in Germany that most probably was introduced by infected angelfish from Colombia. To our knowledge, this is the first report of ISKNV detected in fish imported from South America. Given the lethal nature of megalocytiviruses, proper biosecurity would seem prudent in countries like Germany where these emerging pathogens are not established. PMID- 27225208 TI - Concentration of carp edema virus (CEV) DNA in koi tissues affected by koi sleepy disease (KSD). AB - Carp edema virus (CEV), the causative agent of 'koi sleepy disease' (KSD), appears to be spreading worldwide and to be responsible for losses in koi, ornamental varieties of the common carp Cyprinus carpio. Clinical signs of KSD include lethargic behaviour, swollen gills, sunken eyes and skin alterations and can easily be mistaken for other diseases, such as infection with cyprinid herpesvirus 3 (CyHV-3). To improve the future diagnosis of CEV infection and to provide a tool to better explore the relationship between viral load and clinical disease, we developed a specific quantitative PCR (qPCR) for strains of the virus known to infect koi carp. In samples from several clinically affected koi, CEV specific DNA was present in a range from 1 to 2,046,000 copies, with a mean of 129,982 copies and a median of 45 copies per 250 ng of isolated DNA, but virus DNA could not be detected in all clinically affected koi. A comparison of the newly developed qPCR, which is based on a dual-labelled probe, to an existing end point PCR procedure revealed higher specificity and sensitivity of the qPCR and demonstrated that the new protocol could improve CEV detection in koi. In addition to improved diagnosis, the newly developed qPCR test would be a useful research tool. For example, studies on the pathobiology of CEV could employ controlled infection experiments in which the development of clinical signs could be examined in parallel with a quantitative determination of virus load. PMID- 27225209 TI - Megalocytivirus infection in cultured Nile tilapia Oreochromis niloticus. AB - Megalocytiviruses, such as infectious spleen and kidney necrosis virus (ISKNV), induce lethal systemic diseases in both ornamental and food fish species. In this study, we investigated an epizootic affecting Nile tilapia Oreochromis niloticus cultured in the US Midwest. Diseased fish displayed lethargy, gill pallor, and distension of the coelomic cavity due to ascites. Histopathological examination revealed a severe systemic abundance of intravascular megalocytes that were especially prominent in the gills, kidney, spleen, liver, and intestinal submucosa. Transmission electron microscopic examination revealed abundant intracytoplasmic polygonal virions consistent with iridovirus infection. Comparison of the full-length major capsid protein nucleotide sequences from a recent outbreak with a remarkably similar case that occurred at the same facility many years earlier revealed that both epizootics were caused by ISKNV. A comparison of this case with previous reports suggests that ISKNV may represent a greater threat to tilapia aquaculture than previously realized. PMID- 27225210 TI - Antihelminthic potential of quinacrine and oxyclozanide against gill parasite Microcotyle sebastis in black rockfish Sebastes schlegeli. AB - The aim of this study was to assess the treatment potential of quinacrine and oxyclozanide against Microcotyle sebastis (Monogenea: Polyopisthocotylea) infection in cultured black rockfish Sebastes schlegeli. The oral administration of quinacrine led to a reduction in the mean abundance of M. sebastis infection in all quinacrine-treated groups, and the groups of fish administered quinacrine at 50, 100, and 200 mg kg(-1) for 3 consecutive days showed a parasite mean abundance that was 50 to 30% lower compared to that of the control group, suggesting that quinacrine has a therapeutic potential against M. sebastis. Although oxyclozanide showed a very high in vitro killing activity, in oral administration experiments, only the groups of fish administered 200 mg kg(-1) showed less than 50% mean abundance of M. sebastis compared to the control groups, suggesting that the absorption efficiency of orally administered oxyclozanide might be low in black rockfish and/or that M. sebastis might be less sensitive to orally ingested oxyclozanide. As praziquantel has been the sole therapeutic against M. sebastis infection in Korea for a long time, a broadening of available control measures is advisable in order to reduce the possible emergence of praziquantel-resistant M. sebastis. In our study, although quinacrine and oxyclozanide showed a therapeutic potential against M. sebastis, the treatment efficacy was not high enough to replace praziquantel. Thus, after investigations on the pathological effects and pharmacodynamics, use of quinacrine or oxyclozanide in combination with praziquantel may be considered as a way to prevent praziquantel resistance in M. sebastis. PMID- 27225211 TI - Clinical features and outcome of lupus myocarditis in the Western Cape, South Africa. AB - BACKGROUND: African American ethnicity is independently associated with lupus myocarditis compared with other ethnic groups. In the mixed racial population of the Western Cape, South Africa, no data exists on the clinical features/outcome of lupus myocarditis. OBJECTIVES: The objective of this study was to give a comprehensive description of the clinical features and outcome of acute lupus myocarditis in a mixed racial population. METHODS: Clinical records (between 2008 and 2014) of adult systemic lupus erythematosus (SLE) patients at a tertiary referral centre were retrospectively screened for a clinical and echocardiographic diagnosis of lupus myocarditis. Clinical features, laboratory results, management and outcome were described. Echocardiographic images stored in a digital archive were reanalysed including global and regional left ventricular function. A poor outcome was defined as lupus myocarditis related mortality or final left ventricular ejection fraction (LVEF) <40%. RESULTS: Twenty-eight of 457 lupus patients (6.1%) met inclusion criteria: 92.9% were female and 89.3% were of mixed racial origin. Fifty-three per cent of patients presented within three months after being diagnosed with SLE. Seventy-five per cent had severely active disease (SLE disease activity index >= 12) and 67.9% of patients had concomitant lupus nephritis. Laboratory results included: lymphopenia (69%) and an increased aRNP (61.5%). Treatment included corticosteroids (96%) and cyclophosphamide (75%); 14% of patients required additional immunosuppression including rituximab. Diastolic dysfunction and regional wall motion abnormalities occurred in > 90% of patients. LVEF improved from 35% to 47% (p = 0.023) and wall motion score from 1.88 to 1.5 (p = 0.017) following treatment. Overall mortality was high (12/28): five patients (17.9%) died due to lupus myocarditis (bimodal pattern). Patients who died of lupus myocarditis had a longer duration of SLE (p = 0.045) and a lower absolute lymphocyte count (p = 0.041) at diagnosis. LVEF at diagnosis was lower in patients who died of lupus myocarditis (p = 0.099) and in those with a persistent LVEF < 40% (n = 5; p = 0.046). CONCLUSIONS: This is the largest reported series on lupus myocarditis. The mixed racial population had a similar prevalence, but higher mortality compared with other ethnic groups (internationally published literature). Patients typically presented with high SLE disease activity and the majority had concomitant lupus nephritis. Lymphopenia and low LVEF at presentation were of prognostic significance, associated with lupus myocarditis related mortality or a persistent LVEF < 40%. PMID- 27225212 TI - Hughes syndrome and epilepsy: when to test for antiphospholipid antibodies? AB - Epilepsy and seizures are reported among the neurological manifestations of antiphospholipid syndrome (APS) at a prevalence rate of approximately 8%, which is nearly 10 times the prevalence of epilepsy in the general population. The association of seizures with antiphospholipid antibodies (aPL) is even more significant in the presence of systemic lupus erythematosus (SLE). In this review, we discuss the epidemiological, pathophysiological, laboratory, clinical, and radiological aspects of this association, and derive suggestions on when to consider testing for aPL in epileptic patients and how to manage seizures secondary to APS based on literature data. Epilepsy due to APS should be considered in young patients presenting with seizures of unknown origin. Temporal lobe epilepsy seems to be particularly prevalent in APS patients. The pathogenesis is complex and may not only involve micro-thrombosis, but also a possible immune-mediated neuronal damage. Patients with seizures and positive aPL tend to develop thrombocytopenia and livedo racemosa more frequently compared with those without aPL. Magnetic resonance imaging (MRI) remains the imaging modality of choice in these patients. The presence of SLE and the presence of neurological symptoms significantly correlate with the presence of white matter changes on MRI. In contrast, the correlation between aPL positivity and the presence of white matter changes is very weak. Furthermore, MRI can be normal in more than 30-40% of neuropsychiatric lupus patients with or without aPL. aPL testing is recommended in young patients presenting with atypical seizures and multiple hyper-intensity lesions on brain MRI in the absence of other possible conditions. New MRI techniques can better understand the pathology of brain damage in neuro-APS. The therapeutic management of epileptic APS patients relies on anti-epileptic treatment and anticoagulant agents when there is evidence of a thrombotic event. In the absence of consensual recommendations, the decision of lifelong anticoagulation is discussed on a case-by-case basis. The anti thrombotic benefit of hydroxychloroquine and statins is supported by several studies. PMID- 27225213 TI - Effect of a Flared Renal Stent on the Performance of Fenestrated Stent-Grafts at Rest and Exercise Conditions. AB - PURPOSE: To quantify the hemodynamic impact of a flared renal stent on the performance of fenestrated stent-grafts (FSGs) by analyzing flow patterns and wall shear stress-derived parameters in flared and nonflared FSGs in different physiologic scenarios. METHODS: Hypothetical models of FSGs were created with and without flaring of the proximal portion of the renal stent. Flared FSGs with different dilation angles and protrusion lengths were examined, as well as a nonplanar flared FSG to account for lumbar curvature. Laminar and pulsatile blood flow was simulated by numerically solving Navier-Stokes equations. A physiologically realistic flow rate waveform was prescribed at the inlet, while downstream vasculature was modeled using a lumped parameter 3-element windkessel model. No slip boundary conditions were imposed at the FSG walls, which were assumed to be rigid. While resting simulations were performed on all the FSGs, exercise simulations were also performed on a flared FSG to quantify the effect of flaring in different physiologic scenarios. RESULTS: For cycle-averaged inflow of 2.94 L/min (rest) and 4.63 L/min (exercise), 27% of blood flow was channeled into each renal branch at rest and 21% under exercise for all the flared FSGs examined. Although the renal flow waveform was not affected by flaring, flow within the flared FSGs was disturbed. This flow disturbance led to high endothelial cell activation potential (ECAP) values at the renal ostia for all the flared geometries. Reducing the dilation angle or protrusion length and exercise lowered the ECAP values for flared FSGs. CONCLUSION: Flaring of renal stents has a negligible effect on the time dependence of renal flow rate waveforms and can maintain sufficient renal perfusion at rest and exercise. Local flow patterns are, however, strongly dependent on renal flaring, which creates a local flow disturbance and may increase the thrombogenicity at the renal ostia. Smaller dilation angles, shorter protrusion lengths, and moderate lower limb exercise are likely to reduce the risk of thrombosis in flared geometries. PMID- 27225214 TI - Meta-analysis of Left Subclavian Artery Coverage With and Without Revascularization in Thoracic Endovascular Aortic Repair. AB - PURPOSE: To examine the role of left subclavian artery (LSA) revascularization in thoracic endovascular aortic repair (TEVAR) with LSA coverage. METHODS: A systematic search was conducted to identify all studies providing comparative outcomes with or without LSA revascularization for LSA occlusion during TEVAR. The search included MEDLINE, EMBASE, CINAHL, the Cochrane Central Register of Controlled Trials, the World Health Organization International Clinical Trials Registry, ClinicalTrials.gov, ISRCTN Register, and bibliographic reference lists. The primary outcome parameters were perioperative stroke, spinal cord ischemia (SCI), and mortality. Combined overall effect sizes were calculated using fixed effect or random effects models; results are reported as the odds ratio (OR) and 95% confidence interval (CI). RESULTS: Five observational studies reporting a total of 1161 patients were identified; 444 patients underwent LSA revascularization and the remaining 717 patients did not. LSA revascularization was associated with a similar risk of stroke (OR 0.70, 95% CI 0.43 to 1.14, p=0.15), SCI (OR 0.56, 95% CI 0.28 to 1.10, p=0.09), and mortality (OR 0.87, 95% CI 0.55 to 1.39, p=0.56) compared with no LSA revascularization. CONCLUSION: LSA revascularization was not found to significantly reduce neurologic complications or mortality in patients undergoing TEVAR with coverage of the LSA origin. Randomized clinical trials are required to elucidate the role of routine or selective LSA revascularization in these cases. PMID- 27225215 TI - Enhanced whole exome sequencing by higher DNA insert lengths. AB - BACKGROUND: Whole exome sequencing (WES) has been proven to serve as a valuable basis for various applications such as variant calling and copy number variation (CNV) analyses. For those analyses the read coverage should be optimally balanced throughout protein coding regions at sufficient read depth. Unfortunately, WES is known for its uneven coverage within coding regions due to GC-rich regions or off target enrichment. RESULTS: In order to examine the irregularities of WES within genes, we applied Agilent SureSelectXT exome capture on human samples and sequenced these via Illumina in 2 * 101 paired-end mode. As we suspected the sequenced insert length to be crucial in the uneven coverage of exome captured samples, we sheared 12 genomic DNA samples to two different DNA insert size lengths, namely 130 and 170 bp. Interestingly, although mean coverages of target regions were clearly higher in samples of 130 bp insert length, the level of evenness was more pronounced in 170 bp samples. Moreover, merging overlapping paired-end reads revealed a positive effect on evenness indicating overlapping reads as another reason for the unevenness. In addition, mutation analysis on a subset of the samples was performed. In these isogenic subclones, the false negative rate in the 130 bp samples was almost double to that in the 170 bp samples. Visual inspection of the discarded mutation sites exposed low coverages at the sites flanked by high amplitudes of coverage depth. CONCLUSIONS: Producing longer insert reads could be a good strategy to achieve better uniform read coverage in coding regions and hereby enhancing the effective sequencing yield to provide an improved basis for further variant calling and CNV analyses. PMID- 27225216 TI - Adapting the Get Yourself Tested Campaign to Reach Black and Latino Sexual Minority Youth. AB - BACKGROUND: Culturally appropriate efforts are needed to increase sexually transmitted disease (STD) testing and care among Black and Latino sexual-minority youth, who are at high risk for STDs. Get Yourself Tested, a national testing campaign, has demonstrated success among youth, but it has yet to be assessed for relevance or impact among this population. METHOD: This effort included (1) formative and materials-testing research through focus groups; (2) adaptation of existing Get Yourself Tested campaign materials to be more inclusive of Black and Latino sexual-minority youth; (3) a 3-month campaign in four venues of New York City, promoting STD testing at events and through mobile testing and online and social media platforms; (4) process evaluation of outreach activities; and (5) an outcome evaluation of testing at select campaign venues, using a preexperimental design. RESULTS: During the 3-month campaign period, the number of STD tests conducted at select campaign venues increased from a comparable 3-month baseline period. Although testing uptake through mobile vans remained low in absolute numbers, the van drew a high-prevalence sample, with positivity rates of 26.9% for chlamydia and 11.5% for gonorrhea. This article documents the process and lessons learned from adapting and implementing a local campaign for Black and Latino sexual-minority youth. PMID- 27225218 TI - Policy Help Needed, Experience Required: Preparing Practitioners to Effectively Engage in Policy. AB - OBJECTIVES: There is a shift toward a "health in all policies" approach in public health; however, most practitioners are not equipped with the necessary knowledge or skills to engage in and practice policy. This study explores how public health professionals can become policy practitioners and better engage in the policy process. This article also provides recommendations for training programs on how to increase students' policy-related knowledge and skills. METHOD: We conducted in-depth interviews with 10 public health policy experts in the United States spanning academic, governmental, advocacy, and practice settings. Key informants provided perspectives regarding strengths and skill sets that practitioners need to better position themselves to do policy-relevant work and opportunities for public health programs to improve training. The research team conducted thematic analyses to determine commonality among expert responses. RESULTS: Informants identified a number of strengths and skills that either support or impede practitioners' ability to conduct policy work and proposed recommendations for public health curricula to integrate policy-related coursework or practical experiences to prepare practitioners for policy careers. CONCLUSION: Public health professionals need to become more politically astute to practice and advance public health policy. To facilitate the development of such skills, public health training and pedagogy must integrate policy practice into traditional public health coursework, include new policy-focused courses, and provide opportunities for real-world policy experience. PMID- 27225217 TI - Qualitative Process Evaluation of a Community-Based Culturally Tailored Lifestyle Intervention for Underserved South Asians. AB - Introduction There are few examples of effective cardiovascular disease prevention interventions for South Asians (SAs). We describe the results of a process evaluation of the South Asian Heart Lifestyle Intervention for medically underserved SAs implemented at a community-based organization (CBO) using community-based participatory research methods and a randomized control design (n = 63). Method Interviews were conducted with 23 intervention participants and 5 study staff using a semistructured interview guide focused on participant and staff perceptions about the intervention's feasibility and efficacy. Data were thematically analyzed. Results Intervention success was attributed to trusted CBO setting, culturally concordant study staff, and culturally tailored experiential activities. Participants said that these activities helped increase knowledge and behavior change. Some participants, especially men, found that self-monitoring with pedometers helped motivate increased physical activity. Participants said that the intervention could be strengthened by greater family involvement and by providing women-only exercise classes. Staff identified the need to reduce participant burden due to multicomponent intervention and agreed that the CBO needed greater financial resources to address participant barriers. Conclusion Community-based delivery and cultural adaptation of an evidence-based lifestyle intervention were effective and essential components for reaching and retaining medically underserved SAs in a cardiovascular disease prevention intervention study. PMID- 27225219 TI - Scene Integration Without Awareness: No Conclusive Evidence for Processing Scene Congruency During Continuous Flash Suppression. AB - A recent study showed that scenes with an object-background relationship that is semantically incongruent break interocular suppression faster than scenes with a semantically congruent relationship. These results implied that semantic relations between the objects and the background of a scene could be extracted in the absence of visual awareness of the stimulus. In the current study, we assessed the replicability of this finding and tried to rule out an alternative explanation dependent on low-level differences between the stimuli. Furthermore, we used a Bayesian analysis to quantify the evidence in favor of the presence or absence of a scene-congruency effect. Across three experiments, we found no convincing evidence for a scene-congruency effect or a modulation of scene congruency by scene inversion. These findings question the generalizability of previous observations and cast doubt on whether genuine semantic processing of object-background relationships in scenes can manifest during interocular suppression. PMID- 27225220 TI - When Lightning Strikes Twice: Profoundly Gifted, Profoundly Accomplished. AB - The educational, occupational, and creative accomplishments of the profoundly gifted participants (IQs ? 160) in the Study of Mathematically Precocious Youth (SMPY) are astounding, but are they representative of equally able 12-year-olds? Duke University's Talent Identification Program (TIP) identified 259 young adolescents who were equally gifted. By age 40, their life accomplishments also were extraordinary: Thirty-seven percent had earned doctorates, 7.5% had achieved academic tenure (4.3% at research-intensive universities), and 9% held patents; many were high-level leaders in major organizations. As was the case for the SMPY sample before them, differential ability strengths predicted their contrasting and eventual developmental trajectories-even though essentially all participants possessed both mathematical and verbal reasoning abilities far superior to those of typical Ph.D. recipients. Individuals, even profoundly gifted ones, primarily do what they are best at. Differences in ability patterns, like differences in interests, guide development along different paths, but ability level, coupled with commitment, determines whether and the extent to which noteworthy accomplishments are reached if opportunity presents itself. PMID- 27225221 TI - One for You, One for Me: Humans' Unique Turn-Taking Skills. AB - Long-term collaborative relationships require that any jointly produced resources be shared in mutually satisfactory ways. Prototypically, this sharing involves partners dividing up simultaneously available resources, but sometimes the collaboration makes a resource available to only one individual, and any sharing of resources must take place across repeated instances over time. Here, we show that beginning at 5 years of age, human children stabilize cooperation in such cases by taking turns across instances of obtaining a resource. In contrast, chimpanzees do not take turns in this way, and so their collaboration tends to disintegrate over time. Alternating turns in obtaining a collaboratively produced resource does not necessarily require a prosocial concern for the other, but rather requires only a strategic judgment that partners need incentives to continue collaborating. These results suggest that human beings are adapted for thinking strategically in ways that sustain long-term cooperative relationships and that are absent in their nearest primate relatives. PMID- 27225222 TI - Bioinformatic profiling identifies an immune-related risk signature for glioblastoma. AB - OBJECTIVE: To investigate the local immune status and its prognostic value in glioma. METHODS: A cohort of 297 glioma samples with whole genome microarray expression data from the Chinese Glioma Genome Atlas database were included for discovery. The Cancer Genome Atlas (TCGA) database was used for validation. Principal components analysis and gene set enrichment analysis were used to explore the bioinformatic implication. RESULTS: Distinct local immune status was identified according to histologic grade. Glioblastoma (GBM) exhibited an enhanced immune phenotype compared to lower grade glioma. We profiled the immune related gene set and identified 8 genes (FOXO3, IL6, IL10, ZBTB16, CCL18, AIMP1, FCGR2B, and MMP9) with the greatest prognostic value in GBM. A local immune related risk signature was developed from the genes to distinguish cases as high or low risk of unfavorable prognosis, which could be validated in TCGA database. High-risk patients conferred an enhanced intensity of local immune response compared to low-risk ones. Additionally, the signature exhibited different distribution based on molecular features. The signature had prognostic significance in the stratified cohorts and was identified as an independent prognostic factor for GBM. CONCLUSIONS: We profiled the immune status in glioma and established a local immune signature for GBM, which could independently identify patients with a high risk of reduced survival, indicating the relationship between prognosis and local immune response. PMID- 27225224 TI - Solving the riddle of glioblastoma: The hope for immunotherapy. PMID- 27225223 TI - The APOSTEL recommendations for reporting quantitative optical coherence tomography studies. AB - OBJECTIVE: To develop consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results. METHODS: A panel of experienced OCT researchers (including 11 neurologists, 2 ophthalmologists, and 2 neuroscientists) discussed requirements for performing and reporting quantitative analyses of retinal morphology and developed a list of initial recommendations based on experience and previous studies. The list of recommendations was subsequently revised during several meetings of the coordinating group. RESULTS: We provide a 9-point checklist encompassing aspects deemed relevant when reporting quantitative OCT studies. The areas covered are study protocol, acquisition device, acquisition settings, scanning protocol, funduscopic imaging, postacquisition data selection, postacquisition data analysis, recommended nomenclature, and statistical analysis. CONCLUSIONS: The Advised Protocol for OCT Study Terminology and Elements recommendations include core items to standardize and improve quality of reporting in quantitative OCT studies. The recommendations will make reporting of quantitative OCT studies more consistent and in line with existing standards for reporting research in other biomedical areas. The recommendations originated from expert consensus and thus represent Class IV evidence. They will need to be regularly adjusted according to new insights and practices. PMID- 27225225 TI - Understanding Inpatient Perceptions of Indwelling Urinary Catheters Using the Health Belief Model. AB - Patient interviews using the Health Belief Model framework identified thematic patient perceptions of indwelling urinary catheters and catheter-associated urinary tract infections. Generally, patients perceived catheters as convenient and were unaware of catheter alternatives and risks for infection. Better patient education is needed to reduce urinary catheter use and infections. Infect Control Hosp Epidemiol 2016;37:1098-1100. PMID- 27225226 TI - Definite hereditary hemorrhagic telangiectasia in a 60-year-old black Kenyan woman: a case report. AB - BACKGROUND: Hereditary hemorrhagic telangiectasia is a rare autosomal dominant inherited disease characterized by vascular dysplasia. To the best of our knowledge, we report the first case in the literature of definite hereditary hemorrhagic telangiectasia diagnosed in western Kenya, a resource-limited setting with limited treatment options. CASE PRESENTATION: A 60-year-old black Kenyan woman was admitted 1 year ago to a hospital in western Kenya with an 11-year history of recurrent spontaneous epistaxis. Her physical examination revealed that she had telangiectasias on the tongue and hard palate, severe pallor, and hepatomegaly. A chest radiograph revealed right middle lobe opacity. After a positive saline contrast echocardiography, she underwent contrast-enhanced chest computed tomography, which revealed a large pulmonary arteriovenous malformation and multiple hepatic arteriovenous malformations. Therefore, she fulfilled criteria for definite hereditary hemorrhagic telangiectasia. She was managed with nasal packing, tranexamic acid, oral ferrous sulfate, and blood transfusions, as other treatment options were unavailable in this setting. CONCLUSIONS: This rare case of hereditary hemorrhagic telangiectasia demonstrates that it occurs in an African population and that diagnostic challenges in resource-limited settings can be surmounted. Treatment options remain limited in these settings. PMID- 27225227 TI - Intestinal immunomodulating activity and structural characterization of a new polysaccharide from stems of Dendrobium officinale. AB - A homogeneous polysaccharide fraction (DOP-W3-b) with a high intestinal immunomodulating activity was obtained from the stems of Dendrobium officinale through a bioactivity-guided sequential isolation procedure based on the screening of Peyer's patch-mediated immunomodulating activity. Oral administration experiments of mice showed that DOP-W3-b could effectively regulate intestinal mucosal immune activity by changing intestinal mucosal structures, promoting the secretions of cytokines from Peyer's patches (PPs) and mesenteric lymph nodes (MLNs), and increasing the production of secretory immunoglobulin A (sIgA) in the lamina propria. Structure analysis indicated that DOP-W3-b was composed of mannose and glucose in a molar ratio of 4.5 with a relatively low molecular weight of 1.543 * 10(4) Da, and its repeat unit contained a backbone consisting of beta-(1->4)-d-Manp, beta-(1->4)-d-Glcp and beta-(1->3,6)-d-Manp residues, a branch consisting of beta-(1->4)-d-Manp, beta-(1 >4)-d-Glcp and terminal beta-d-Glcp, and O-acetyl groups attached to O-2 of beta (1->4)-d-Manp. These results suggested that DOP-W3-b was a new polysaccharide with an essential potential for modulating body's immune functions. PMID- 27225228 TI - Location of deuterium sites at operating temperature from neutron diffraction of BaIn0.6Ti0.2Yb0.2O2.6-n(OH)2n, an electrolyte for proton-solid oxide fuel cells. AB - A fundamental understanding of the doping effect on the hydration mechanism and related proton diffusion pathways are keys to the progress of Proton-Solid Oxide Fuel Cell (H(+)-SOFC) technologies. Here, we elucidate the possible interplay between the crystal structure upon hydration and the conductivity properties in a promising perovskite type H(+)-SOFC electrolyte, BaIn0.6Yb0.2Ti0.2O2.6-n(OH)2n. Thermal X-ray and neutron diffractions, neutron time-of-flight scattering along with thermal gravimetric analysis reveal the structural features of BaIn0.6Ti0.2Yb0.2O2.6-n(OH)2n at fuel cell operating temperatures. Between 400 600 degrees C, BaIn0.6Yb0.2Ti0.2O2.6-n(OD)2n (n < 0.042) remains in a disordered perovskite structure with high anisotropies in the form of oblate spheroids for oxygen. At 400 degrees C, the presence of oxygen and proton static disorder is clearly established. Yet, the insertion of mobile protons in 24k sites does not induce long-range structural distortion while facilitating both inter- and intra octahedral proton transfers via quasi-linear O-DO bonds, strong hydrogen bonding, and octahedral tilting. This experimental evidence reveals that the co-doping approach on Ba2In2O5 enhances greatly protonic conductivity levels by enabling a continuous proton diffusion pathway through BaIn0.6Yb0.2Ti0.2O2.6-n(OH)2n. These new insights into the doping effect on the proton-transfer mechanism offer new perspectives for the development of H(+)-SOFC electrolyte materials. PMID- 27225229 TI - Non-genomic action of vitamin D3 on N-methyl-D-aspartate and kainate receptor mediated actions in juvenile gonadotrophin-releasing hormone neurons. AB - Vitamin D is a versatile signalling molecule that plays a critical role in calcium homeostasis. There are several studies showing the genomic action of vitamin D in the control of reproduction; however, the quick non-genomic action of vitamin D at the hypothalamic level is not well understood. Therefore, to investigate the effect of vitamin D on juvenile gonadotrophin-releasing hormone (GnRH) neurons, excitatory neurotransmitter receptor agonists N-methyl-D aspartate (NMDA, 30MUM) and kainate (10MUM) were applied in the absence or in the presence of vitamin D3 (VitaD3, 10nM). The NMDA-mediated responses were decreased by VitaD3 in the absence and in the presence of tetrodotoxin (TTX), a sodium channel blocker, with the mean relative inward current being 0.56+/-0.07 and 0.66+/-0.07 (P<0.05), respectively. In addition, VitaD3 induced a decrease in the frequency of gamma-aminobutyric acid mediated (GABAergic) spontaneous postsynaptic currents and spontaneous postsynaptic currents induced by NMDA application with a mean relative frequency of 0.595+/-0.07 and 0.56+/-0.09, respectively. Further, VitaD3 decreased the kainate-induced inward currents in the absence and in the presence of TTX with a relative inward current of 0.64+/ 0.06 and 0.68+/-0.06, respectively (P<0.05). These results suggest that VitaD3 has a non-genomic action and partially inhibits the NMDA and kainate receptor mediated actions of GnRH neurons, suggesting that VitaD3 may regulate the hypothalamic-pituitary-gonadal (HPG) axis at the time of pubertal development. PMID- 27225230 TI - The discovery of allyltyrosine based tripeptides as selective inhibitors of the HIV-1 integrase strand-transfer reaction. AB - From library screening of synthetic antimicrobial peptides, an O-allyltyrosine based tripeptide was identified to possess inhibitory activity against HIV-1 integrase (IN) exhibiting an IC50 value of 17.5 MUM in a combination 3' processing and strand transfer microtitre plate assay. The tripeptide was subjected to structure-activity relationship (SAR) studies with 28 peptides, incorporating an array of natural and non-natural amino acids. Resulting SAR analysis revealed the allyltyrosine residue was a key feature for IN inhibitory activity whilst incorporation of a lysine residue and extended hydrophilic chains bearing a terminal methyl ester was advantageous. Addition of hydrophobic aromatic moieties to the N-terminal of the scaffold afforded compounds with improved inhibitory activity. Consolidation of these functionalities lead to the development of the tripeptide 96 which specifically inhibited the IN strand transfer reaction with an IC50 value of 2.5 MUM. PMID- 27225232 TI - A palladium-catalyzed intramolecular carbonylative annulation reaction for the synthesis of 4,5-fused tricyclic 2-quinolones. AB - A concise and efficient synthetic route to 4,5-fused tricyclic 2-quinolones through the palladium-catalyzed carbonylative annulation of alkyne-tethered N substituted o-iodoanilines has been developed. This reaction proceeds smoothly under mild reaction conditions and exhibits exceptional tolerance to a variety of functional groups. It has been successfully applied to the efficient synthesis of BI 224436, an HIV integrase inhibitor. PMID- 27225231 TI - Is the General Self-Efficacy Scale a Reliable Measure to be used in Cross Cultural Studies? Results from Brazil, Germany and Colombia. AB - This study evaluated cross-cultural measurement invariance for the General Self efficacy Scale (GSES) in a large Brazilian (N = 2.394) and representative German (N = 2.046) and Colombian (N = 1.500) samples. Initially, multiple-indicators multiple-causes (MIMIC) analyses showed that sex and age were biasing items responses on the total sample (2 and 10 items, respectively). After controlling for these two covariates, a multigroup confirmatory factor analysis (MGCFA) was employed. Configural invariance was attested. However, metric invariance was not supported for five items, in a total of 10, and scalar invariance was not supported for all items. We also evaluated the differences between the latent scores estimated by two models: MIMIC and MGCFA unconstraining the non-equivalent parameters across countries. The average difference was equal to |.07| on the estimation of the latent scores, and 22.8% of the scores were biased in at least .10 standardized points. Bias effects were above the mean for the German group, which the average difference was equal to |.09|, and 33.7% of the scores were biased in at least .10. In synthesis, the GSES did not provide evidence of measurement invariance to be employed in this cross-cultural study. More than that, our results showed that even when controlling for sex and age effects, the absence of control on items parameters in the MGCFA analyses across countries would implicate in bias of the latent scores estimation, with a higher effect for the German population. PMID- 27225233 TI - Enabling higher photoelectrochemical efficiency of TiO2via controlled formation of a disordered shell: an alternative to the hydrogenation process. AB - A simple one-step and low-temperature process was developed to form an amorphous overlayer on the crystalline TiO2 film by atomic layer deposition. This composite structure is beneficial for improved photoelectrochemical efficiency since the as deposited amorphous layer showed unique properties such as local disorder and presence of oxygen vacancies. PMID- 27225234 TI - Morphological description and molecular analyses of Tylodelphys sp. (Trematoda: Diplostomidae) newly recorded from the freshwater fish Gobiomorphus cotidianus (common bully) in New Zealand. AB - Among eyeflukes, Tylodelphys Diesing, 1850 includes diverse species able to infect the eyes, but also the brain, pericardial sac and body cavity of their second intermediate host. While the genus shows a cosmopolitan distribution with 29 nominal species in Africa, Asia, Europe and America, a likely lower research effort has produced two records only for all of Australasia. This study provides the first description of a species of Tylodelphys and the first record for a member of the Diplostomidae in New Zealand. Tylodephys sp. metacercaria from the eyes of Gobiomorphus cotidianus McDowall, 1975 is distinguished from its congeners as being larger in all, or nearly all, metrics than Tylodelphys clavata (von Nordmann, 1832), T. conifera (Mehlis, 1846) and T. scheuringi (Hughes, 1929); whereas T. podicipina Kozicka & Niewiadomska, 1960 is larger in body size, ventral sucker and holdfast sizes and T. ophthalmi (Pandey, 1970) has comparatively a very small pharynx and body spination. Tylodelphys sp. exhibits consistent genetic variation for the 28S rDNA, internal transcribed spacer (ITS) and Cox1 genes, and phylogenetic analyses confirm that it represents an independent lineage, closely related to North American species. Morphological and molecular results together support the distinct species status of Tylodephys sp. metacercaria, the formal description and naming of which await discovery of the adult. Furthermore, the validity of T. strigicola Odening, 1962 is restored, T. cerebralis Chakrabarti, 1968 is proposed as major synonym of T. ophthalmi, and species described solely on the basis of metacercariae are considered incertae sedis, except those for which molecular data already exist. PMID- 27225235 TI - Radiation therapy for primary breast lymphoma in male gynecomastia: a rare case report and review of the literature. AB - Primary breast lymphoma is a rare type of non-Hodgkin lymphoma and usually affects women, although a few cases have been reported in men. Chemotherapy and radiation therapy, or a combination of both, are frequently administered for treatment of primary breast lymphoma, as local control by surgical resection is poor. No standard therapy has been established, and the optimal radiation dose and irradiation field for male patients are unknown. The present report describes a 75-year-old man with bilateral cirrhosis-induced gynecomastia who was diagnosed with primary breast lymphoma; specifically, diffuse large B-cell lymphoma. Because of his hepatic dysfunction, he was treated with radiation therapy alone. Radiation therapy was followed by eight cycles of rituximab monotherapy. Clinical response was good, with no signs of relapse. Clinicians may benefit from knowledge regarding effective treatment of primary breast lymphoma in male patients, which has been rarely reported owing to the low incidence of this condition. The outcome in the present case may help to establish effective treatment guidelines in similar cases. PMID- 27225236 TI - Adherence to hydroxyurea medication by children with sickle cell disease (SCD) using an electronic device: a feasibility study. AB - Adherence to hydroxyurea (HU) is a significant modifying factor in sickle cell vaso-occlusive pain. We conducted a study using an electronic medication container-monitor-reminder device (GlowCapTM) to track adherence and determine whether use of this device affected rates of HU adherence. Subjects were regular attendees to our clinic. They were given a 37-item questionnaire and were asked to use a GlowCap containing HU. When the device cap is opened, it makes a remote "medication taken" record. The device also provides usage reminder in the form of lights and alarm sounds if the cap opening is delayed. Nineteen subjects participated in the survey, and 17 in the intervention phase. Of the 17, 12 had reliable adherence data. Seventeen caregivers of patients and two patients completed the survey. Two most common barriers to adherence identified were lack of reminders and absence of medicine home delivery. The intervention component of this study, which used both the electronic (GlowCap) method and medication possession ratio showed that the median adherence rate for the 12 patients evaluated was 85 %. The GlowCap device accurately kept a record of adherence rates. This device may be an effective tool for increasing HU medication adherence. PMID- 27225237 TI - For Rapid Molecular Detection, Why Not a Whole Genome Approach? PMID- 27225238 TI - Reply to Lesho and Clifford. PMID- 27225239 TI - Impact of Widespread Introduction of Pneumococcal Conjugate Vaccines on Pneumococcal and Nonpneumococcal Otitis Media. AB - BACKGROUND: Pneumococcal conjugated vaccines (PCVs) impact on complex otitis media (OM; including recurrent, nonresponsive, and chronic OM with effusion) was greater than that on simple, acute OM in previous studies. Since complex OM is often a polymicrobial disease, we speculated that reduction of complex OM by PCVs would be associated with reduction of non-pneumococcal OM. METHODS: In a prospective, population-based, active surveillance, all OM episodes submitted for middle ear fluid culture in children <3 years from 2004 through 2015 were included. Three sub-periods were established: pre-PCV, PCV7, and PCV13. Incidence rate ratios (IRRs) comparing the 3 periods were calculated for pneumococcal, nontypable Haemophilus influenzae (NTHi), Moraxella catarrhalis, Streptococcus pyogenes, and culture-negative OM. RESULTS: Overall, 7475 episodes were included. Of all-NTHi cases in the pre-PCV period, 34% were mixed with Streptococcus pneumoniae IRRs (95% confidence interval) comparing the pre-PCV to the PCV13 period were 0.02 (0.01-0.04), 0.12 (0.08-0.20), and 0.18 (0.15-0.21) for PCV7+6A serotypes, 5 additional PCV13 serotypes, and all-pneumococcal OM, respectively; non-PCV13 serotype episodes were not significantly reduced. IRRs for single NTHi, mixed NTHi + S. pneumoniae, and all-NTHi OM were 0.30 (0.25-0.35), 0.18 (0.13 0.24), and 0.25 (0.22-0.29), respectively. Moraxella catarrhalis, S. pyogenes, and culture-negative episodes were also significantly reduced. CONCLUSIONS: Both pneumococcal and non-pneumococcal OM episodes, enriched with complex cases, declined substantially in children <3 years following sequential PCV7/PCV13 introduction. The reduction in non-pneumococcal episodes may be attributed to early OM episodes prevention, resulting in a lower rate of complex, often non pneumococcal OM. PMID- 27225240 TI - Neutralizing Anti-Interferon-Gamma Autoantibody Levels May Not Correlate With Clinical Course of Disease. PMID- 27225241 TI - Marijuana Use Is Not Associated With Progression to Advanced Liver Fibrosis in HIV/Hepatitis C Virus-coinfected Women. AB - BACKGROUND: Marijuana (hereafter "tetrahydrocannabinol [THC]") use has been associated with liver fibrosis progression in retrospective analyses of patients with chronic hepatitis C (HCV). We studied long-term effects of THC on fibrosis progression in women coinfected with human immunodeficiency virus (HIV)/HCV enrolled in the Women's Interagency HIV Study (WIHS). METHODS: Liver fibrosis was categorized according to FIB-4 scores as none, moderate, or significant. THC and alcohol use were quantified as average exposure per week. Associations between THC use and progression to significant fibrosis were assessed using Cox proportional hazards regression. RESULTS: Among 575 HIV/HCV-coinfected women followed for a median of 11 (interquartile range, 6-17) years, 324 (56%) reported no THC use, 141 (25%) less than weekly use, 70 (12%) weekly use, and 40 (7%) daily use at WIHS entry. In univariable analysis, entry FIB-4 score (hazard ratio [HR], 2.26 [95% confidence interval {CI}, 1.88-2.73], P < .001), log HCV RNA (HR, 1.19 [95% CI, 1.02-1.38], P = .02), tobacco use (HR, 1.37 [95% CI, 1.02-1.85], P = .04), CD4(+) count (risk per 100-cell increase: HR, 0.90 [95% CI, .86-.95], P < .001), and log HIV RNA (HR, 1.18 [95% CI, 1.05-1.32], P = .005) were associated with progression to significant fibrosis, as was cumulative alcohol use in follow up (HR, 1.03 [95% CI, 1.02-1.04], P < .001). In multivariable analysis, entry FIB 4, entry CD4(+) count, and cumulative alcohol use remained significant. Cumulative THC use was not associated with fibrosis progression (HR, 1.01 [95% CI, .92-1.10], P = .83). CONCLUSIONS: In this large cohort of HIV/HCV-coinfected women, THC was not associated with progression to significant liver fibrosis. Alcohol use was independently associated with liver fibrosis, and may better predict fibrosis progression in HIV/HCV-coinfected women. PMID- 27225243 TI - Guillain-Barre Syndrome and Zika Virus: Estimating Attributable Risk to Inform Intensive Care Capacity Preparedness. PMID- 27225242 TI - Successful Re-treatment of Hepatitis C Virus in Patients Coinfected With HIV Who Relapsed After 12 Weeks of Ledipasvir/Sofosbuvir. AB - We assessed the efficacy and safety of ledipasvir/sofosbuvir plus ribavirin for 24 weeks in 9 human immunodeficiency virus/hepatitis C virus-coinfected patients who relapsed after receiving 12 weeks of treatment with ledipasvir/sofosbuvir. Eight of 9 (89%) achieved sustained virologic response 12 weeks after the end of treatment. One patient relapsed at posttreatment week 4. These results suggest an effective salvage therapy for patients for whom direct-acting antiviral treatment has failed. CLINICAL TRIALS REGISTRATION: NCT02073656. PMID- 27225244 TI - Reply to Tham et al. PMID- 27225245 TI - How do women with lupus manage fatigue? A focus group study. AB - OBJECTIVE: Half of patients with systemic lupus erythematosus (SLE) consider fatigue to be the most disabling disease symptom. To develop and promote strategies to prevent and control fatigue, this study aimed to describe how women with SLE manage the experience of fatigue. METHODS: Four focus groups were conducted with 27 women with SLE, and data were analyzed by means of framework analysis. Two patient representatives with SLE were part of the investigator team. RESULTS: The analysis revealed three main themes (i.e., learning how to be open about fatigue, learning to listen to the body, and learning to accept fatigue) and six sub-themes (i.e., the search for recognition, legitimization, planning and prioritizing, the body's limits and self-indulgence, adjusting life to comply with resources, and acceptance of dependence). CONCLUSION: Fatigue is the controlling element in everyday life of women with SLE. Patients try to integrate fatigue into their everyday lives by attempting to control it and meet the challenges of structure and planning. This study indicates a need for clinicians to acknowledge patients' fatigue, including supporting patients' own resources, offering information, and conversation about fatigue, as well as involving patients' relatives. PMID- 27225246 TI - Plantar forefoot pressures in psoriatic arthritis-related dactylitis: an exploratory study. AB - Dactylitis is a common feature of psoriatic arthritis (PsA); local physical trauma has been identified as a possible contributing factor. The aim of this study was to explore differences in forefoot plantar pressures in patients with PsA with and without dactylitis and compare to healthy controls. Thirty-six participants were recruited into three groups: group A PsA plus a history of dactylitis; group B PsA, no dactylitis; group C control participants. Forefoot plantar pressures were measured barefoot and in-shoe at the left second and fourth toes and corresponding metatarsophalangeal joints. Temporal and spatial parameters were measured and data from the foot impact scale for rheumatoid arthritis (FIS-RA), EQ5D and health assessment questionnaire (HAQ) were collected. Pressure time integral peak plantar pressure, and contact time barefoot and in-shoe were not significantly different between groups. Temporal and spatial parameters reported no significant differences between groups. ANOVA analysis and subsequent post hoc testing using Games-Howell test yielded significance in FIS-RA scores between both PsA groups versus controls, A p <= 0.0001 and PsA group B p < 0.0001 in the FIS-RA impairment and footwear domain, PsA group A p < 0.03 and PsA group B p <= 0.05 in the FIS-RA activity and participation domain compared to controls. This is the first exploratory study to investigate forefoot plantar pressures in patients with and without historical dactylitis in PsA. FIS-RA scores indicate PsA patients have significant limitations compared to controls, although a history of dactylitis does not appear to worsen patient reported outcomes. PMID- 27225247 TI - Elevated high-mobility group B1 levels in active adult-onset Still's disease associated with systemic score and skin rash. AB - High-mobility group box-1 (HMGB1) is a nuclear protein, and such prototypical damage-associated molecular patterns mediate the immune response in the noninfectious inflammatory response. Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder involved in the dysregulation of innate immunity. We investigated the serum HMGB1 level in patients with AOSD and evaluated its clinical significance. Blood samples were collected from 40 patients with active AOSD and 40 healthy controls (HC). Of the patients with AOSD, follow-up samples were collected from 16 patients after a resolution of AOSD disease activity. Serum HMGB1 levels in patients with AOSD were higher than those of the HC (10.0 +/- 5.85 vs. 5.15 +/- 1.79 ng/mL, p < 0.001). Serum HMGB1 levels were found to be correlated with C-reactive protein (CRP) and the systemic score. The AOSD patient who had a sore throat showed a higher serum HMGB1 level than those patients who did not, and the patient with a skin rash had higher levels than the patients without. In addition, the serum HMGB1 levels were decreased after the resolution of disease activity in the AOSD patients who were followed up. The serum HMGB1 levels were elevated in AOSD patients compared to the HC and were correlated with both CRP and the systemic score. The HMGB1 levels were associated with skin rash and a sore throat in AOSD patients. After the resolution of disease activity, serum HMGB1 levels were found to have decreased. PMID- 27225248 TI - Reflectance confocal microscopy for scarring and non-scarring alopecia real-time assessment. AB - Clinical management of alopecia represents one of the major issues in dermatology. Scalp biopsies are not easily accepted because of the high bleeding and sensitive anatomical area. Trichoscopy is routinely used for diagnosis of alopecia, but in several cases lack to provide sufficient information on the status of the disease. Recently, reflectance confocal microscopy demonstrated its usefulness for the evaluation of several inflammatory skin condition and preliminary reports about alopecia have been proposed in the literature. The aim was to identify the confocal features characterizing scarring and non-scarring alopecia. Reflectance confocal microscopy from 86 patients affected by scarring (28 lichen planopilaris and 9 lupus erythematosus) and non-scarring alopecia (30 androgenic alopecia and 19 alopecia areata), were retrospectively, blinded evaluated. Good concordance between different readers on the confocal criteria has been assessed. Statistical significant features, specific for scarring alopecia and non-scarring alopecia have been identified. In this study, data on reflectance confocal microscopy features useful for the differential diagnosis between scarring and non-scarring alopecia have been identified. Further studies focusing on the use of this non-invasive technique in the therapeutic follow-up and distinction of sub-entities of alopecia are still required. PMID- 27225249 TI - Csk regulates angiotensin II-induced podocyte apoptosis. AB - Increasing data have shown that angiotensin II (Ang II) perpetuates podocyte injury and promotes progression to end-stage kidney disease. The mechanism underlying Ang II-induced podocyte apoptosis has not been established. C-terminal Src kinase (Csk) is a cytoplasmic kinase that interacts with scaffolding proteins involved in cell growth, adhesion, and polarization, and the role of Csk in regulating cellular apoptosis has gradually attracted attention. This study evaluates the role of Csk in Ang II-induced podocyte apoptosis. In vivo, Wistar rats were randomly subjected to a normal saline or Ang II infusion. In vitro, we exposed differentiated mouse podocytes to Ang II. Ang II increased Csk expression and induced podocyte apoptosis, stimulated Csk translocation and binding to Caveolin-1, and stimulated decreased Fyn pY416, increased Fyn pY529, and nephrin dephosphorylation. Csk knockdown prevented Ang II-induced podocyte apoptosis, reduced Fyn kinase inactivation, and increased the interaction between nephrin and the activated form of Fyn, accompanied by a reduced interaction between Csk and Caveolin-1. These findings indicate that Ang II induces podocyte injury via a Csk-dependent pathway. PMID- 27225250 TI - Detergent sclerosants at sub-lytic concentrations induce endothelial cell apoptosis through a caspase dependent pathway. AB - To investigate the apoptotic effects of detergent sclerosants sodium tetradecylsulphate (STS) and polidocanol (POL) on endothelial cells at sub-lytic concentrations. Human umbilical vein endothelial cells (HUVECs) were isolated and labelled with antibodies to assess for apoptosis and examined with confocal microscopy and flow cytometry. Isolated HUVECs viability was assessed using propidium iodide staining. Early apoptosis was determined by increased phosphatidylserine exposure by lactadherin binding. Caspase 3, 8, 9 and Bax activation as well as inhibitory assays with Pan Caspase (Z-VAD-FMK) and Bax (BI 6C9) were assessed to identify apoptotic pathways. Porimin activation was used to assess cell membrane permeability. Cell lysis reached almost 100 % with STS at 0.3 % and with POL at 0.6 %. Apoptosis was seen with both STS and POL at concentrations ranging from 0.075 to 0.15 %. PS exposure increased with both STS and POL and exhibited a dose-dependent trend. Active Caspase 3, 8 and 9 but not Bax were increased in HUVECs stimulated with low concentrations of both STS and POL. Inhibitory assays demonstrated Caspase 3, 8, 9 inhibition at low concentrations (0.075 to 0.6 %) with both STS and POL. Both agents increased the activation of porimin at all concentrations. Both sclerosants induced endothelial cell (EC) apoptosis at sub-lytic concentrations through a caspase-dependant pathway. Both agents induced EC oncosis. PMID- 27225251 TI - Identifying the Complexity of Multiple Risk Factors for Obesity Among Urban Latinas. AB - The prevalence of obesity is rising rapidly among Hispanics/Latinas. We evaluated the prevalence of being obese or overweight and associated risk factors among 630 low-income, Latina women from ambulatory care clinics in Upper Manhattan. Overall, 37 % of the sample was overweight and 41 % of the sample was obese, and yet, almost half of women who are overweight considered their weight "just about right." After adjusting for socio-demographic, behavioral, and biological risk factors, being obese was strongly associated with having hypertension [relative risk ratio (RRR) 3.93, 1.75-8.82], pre-hypertension (RRR 2.59, 1.43-4.67), diabetes (RRR 2.50, 1.21-5.14) and moderate/moderately severe/severe depression (RRR 2.09, 1.03-4.26). Women who reported that finding time was a barrier to physical activity were also more likely to be obese (RRR 1.78, 1.04-3.02). Chronic financial stress was associated with lower risk of being overweight (RRR 0.47, 0.28-0.79) or obese (RRR 0.51, 0.31-0.86), as well as eating out at restaurants (RRR 0.75, 0.62-0.89). Opportunities for intervention relate to understanding cultural factors around perceptions of weight and helping women find the time for physical activity. PMID- 27225252 TI - Health Benefits Mandates and Their Potential Impacts on Racial/Ethnic Group Disparities in Insurance Markets. AB - Addressing racial/ethnic group disparities in health insurance benefits through legislative mandates requires attention to the different proportions of racial/ethnic groups among insurance markets. This necessary baseline data, however, has proven difficult to measure. We applied racial/ethnic data from the 2009 California Health Interview Survey to the 2012 California Health Benefits Review Program Cost and Coverage Model to determine the racial/ethnic composition of ten health insurance market segments. We found disproportional representation of racial/ethnic groups by segment, thus affecting the health insurance impacts of benefit mandates. California's Medicaid program is disproportionately Latino (60 % in Medi-Cal, compared to 39 % for the entire population), and the individual insurance market is disproportionately non-Latino white. Gender differences also exist. Mandates could unintentionally increase insurance coverage racial/ethnic disparities. Policymakers should consider the distribution of existing racial/ethnic disparities as criteria for legislative action on benefit mandates across health insurance markets. PMID- 27225253 TI - Model Validation: Has it's Time Come? PMID- 27225254 TI - Does field independence predict visuo-spatial abilities underpinning human navigation? Behavioural evidence. AB - Field independence (FI) has been defined as the extent to which the individual perceives part of a field as discrete from the surrounding field, rather than embedded in the field. It has been proposed to represent a relatively stable pattern in individuals' predisposition towards information processing. In the present study, we assessed the effect of FI on skills underpinning human navigation. Fifty Healthy individuals took part in this study. FI has been assessed by using the group embedded figures test (GEFT). Participants were also asked to perform several visuo-spatial orientation tasks, including the perspective taking/spatial orientation test (PTSOT), the mental rotation task (MRT) and the vividness task, as well as the Santa Barbara Sense of Direction Scale, a self-reported questionnaire, which has been found to predict environmental spatial orientation ability. We found that performances on the GEFT significantly predicted performances on the PTSOT and the MRT. This result supports the idea that FI predicts human navigation. PMID- 27225255 TI - Multifractal signatures of complexity matching. AB - The complexity matching effect supposes that synchronization between complex systems could emerge from multiple interactions across multiple scales and has been hypothesized to underlie a number of daily-life situations. Complexity matching suggests that coupled systems tend to share similar scaling properties, and this phenomenon is revealed by a statistical matching between the scaling exponents that characterize the respective behaviors of both systems. However, some recent papers suggested that this statistical matching could originate from local adjustments or corrections, rather than from a genuine complexity matching between systems. In the present paper, we propose an analysis method based on correlation between multifractal spectra, considering different ranges of time scales. We analyze several datasets collected in various situations (bimanual coordination, interpersonal coordination, and walking in synchrony with a fractal metronome). Our results show that this method is able to distinguish between situations underlain by genuine statistical matching and situations where statistical matching results from local adjustments. PMID- 27225256 TI - Elimination of blinding trachoma in China: why is further study necessary? PMID- 27225257 TI - A review of trachoma history in China: research, prevention, and control. AB - Trachoma is one of the most widespread blinding eye diseases, which is harmful to human visual health. The efforts to prevent and control trachoma in China can be divided into three periods, i.e., highly epidemic period, research on pathogenesis and control of trachoma, and blinding trachoma elimination and epidemiological evaluation. In 1956, Prof. Feifan Tang and Xiaolou Zhang first discovered and isolated Chlamydia trachomatis, which clarified the cause of trachoma, and kick-started a fresh chapter in trachoma research, prevention, and control around the world. Although, the prevalence of trachoma differed in different areas, the average prevalence once exceeded 50% and was as high as 90% in some areas before and at early liberation of China. Therefore, the government led efforts were made to comprehensively prevent and control trachoma, including development of National Plan for the Prevention and Control of Trachoma, nationwide screening and treatment of trachoma, implementation of National Patriotic Health Campaign and improvement of water supply and lavatories. After decades of effort, China reached the goal of eliminating blinding trachoma in 2015. China has gained remarkable achievements in the prevention and treatment of trachoma, making outstanding contributions toward the goal of eliminating trachoma worldwide. The research, prevention, and control of trachoma in China were reviewed in this paper. PMID- 27225258 TI - Study of infectious conjunctivitis among children in rural areas of Qinghai province. AB - Infectious conjunctivitis is no longer a common eye disease in cities and developed areas, but in remote mountainous regions of China where living conditions are relatively under-developed, the occurrence of infectious conjunctivitis remains a public health issue. Here, we evaluate the ratio of infectious conjunctivitis among primary school students in the rural areas of Xunhua, Huangyuan, and Huzhu Counties in the Qinghai province of China, and report the microorganisms involved in causing infection. Of the 765 eligible primary school students, 694 participated to this study (a response rateof 90.7%), 381 boys and 313 girls, with a mean age of 7.52 years (range 7-9 years). A clinical diagnosis of infectious conjunctivitis was returned for 238 of the 694 children examined. The ratio of infectious conjunctivitis in Xunhua County (46.64%) was higher compared to that in Huangyuan (26.67%; P=0.03) and Huzhu Counties (23.61%; P=0.02). The leading cause of conjunctivitis was bacterial, followed by chlamydial and viral. Our results show that there is a high ratio of infectious conjunctivitis among rural primary school students in Qinghai province. PMID- 27225259 TI - Etiological characteristics of chlamydia trachoma conjunctivitis of Primary Boarding School students in the Qinghai Tibetan area. AB - The aim of this study was to investigate the etiological characteristics of Chlamydia trachomatis conjunctivitis among resident students at primary schools in the Qinghai Tibetan area in order to understand the distribution of C. trachomatis and other pathogenic microorganisms, to detect the isolation rate of infectious pathogens, and to provide an evidence for further targeted efforts in the prevent of sporadic trachoma efforts. From two primary schools in Qinghai Province, ocular samples from 35 students who were clinically diagnosed as trachoma cases and 60 normal controls were obtained by swabbing their upper eyelids and lower conjunctival sacs. Samples were preserved at 4 degrees C and airlifted to Beijing Tongren Hospital within 24 h. Real- time polymerase chain reaction (RT-PCR) was used to screen for C. trachomatis, and nested PCR was used to amplify a fragment of the ompA gene for serotype confirmation. Bacterial cultivation and sensitivity tests were conducted based on the 2015 version of the Clinical and Laboratory Standards Institute. Adenovirus, herpes simplex virus, cytomegalovirus, and Epstein-Barr virus were screened by RT-PCR. Among the 35 students with trachoma, 8 came from the Jianshetang Primary School and 27 came from the Central Primary School. Two novel C. trachomatis B serotypes (GenBank accession numbers KU737520 and KU737521) were detected based on a sequence analysis of the ompA gene. Single C. trachomatis infections accounted for 42.86% (9/21) of the cases, and infections with multiple bacteria, particularly Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis, and Streptococcus pneumoniae, accounted for the remaining 57.14% (12/21). Of the 14 C. trachomatis-negative samples, one was positive for adenoviral infection (serotype D) and 13 were positive for bacterial infections (H. influenzae, M. catarrhalis, S. pneumoniae, S. aureus, streptococci other than S. pneumoniae, Staphylococcus epidermidis, Corynebacterium, and Arthrobacterium). In addition to C. trachomatis, the other bacteria and virus that were detected in the boarding students of primary schools in the Qinghai Tibetan area should be emphasized in trachoma prevention and control. PMID- 27225260 TI - Molecular characteristics of the ompA gene of serotype B Chlamydia trachomatis in Qinghai Tibetan primary school students. AB - To study the molecular characteristics of Chlamydia trachomatis, the major outer membrane protein gene (ompA) of C. trachomatis from primary school students with trachoma residing in the Qinghai Tibetan area was sequenced and compared with the same serotype in GenBank. In Jianshetang Primary School and Galeng Central Primary School in the Galeng Tibetan Township of Qinghai Haidong Sala Autonomous County, scraped samples were collected from the upper tarsal conjunctiva and lower conjunctival sac of both eyes of 45 students with trachoma, stored at 4 degrees C, and transported to Beijing Tongren Hospital by air within 24 h. The samples were screened for C. trachomatis by real-time PCR. The ompA gene from the C. trachomatis-positive samples was amplified by nested PCR. The serotype was confirmed by National Center for Biotechnology Information (NCBI) BLAST search and homology analysis. The entire ompA gene sequence was compared with the corresponding gene sequences of serotype B strains available in GenBank. Of the 45 students aged 6-13 years with trachoma, 26 C. trachomatis-positive students were identified by the initial real-time PCR screening (average age, (9.09+/ 1.63) years; sex ratio, 1.0), accounting for 57.78% (26/45). The cycle threshold values for real-time PCR were 16.79-37.77. Half (13/26) of C. trachomatis positive students had a bacterial copy number of >10(5). The compliance rate of the ompA gene sequences with the C. trachomatis serotype B strains in GenBank was up to 99%. Two novel genetic mutations were found when the ompA gene was compared with those of the 11 serotype B strains in GenBank. The two non-synonymous mutations were located at (i) position 271 in the second constant domain, an adenine (A) to guanine (G) substitution (ACT->GCT), changing the amino acid at position 91 from threonine to alanine (Thr->Ala) in all 26 strains; and (ii) position 887 in the fourth variable domain, a cytosine (C) to thymine (T) substitution (GCA->GTA), changing the amino acid at residue 296 from alanine to valine (Ala->Val) in four of the 26 strains. Six mutations were identified relative to ATCC VR-573. The strains could be divided into two gene clusters according to the mutation at nucleotide position 887: CQZ-1 (China Qinghai Tibetan-1) and CQZ-2 (China Qinghai Tibetan-2). We thus detected two novel serotype B mutant strains of C. trachomatis among study subjects with trachoma. PMID- 27225261 TI - Characteristics of pathogenic microorganisms found in 99 cases of conjunctivitis from the Qinghai Tibetan area. PMID- 27225262 TI - Derivation and application of pluripotent stem cells for regenerative medicine. AB - Pluripotent stem cells (PSCs) are cells that can differentiate into any type of cells in the body, therefore have valuable promise in regenerative medicine of cell replacement therapies and tissue/organ engineering. PSCs can be derived either from early embryos or directly from somatic cells by epigenetic reprogramming that result in customized cells from patients. Here we summarize the methods of deriving PSCs, the various types of PSCs generated with different status, and their versatile applications in both clinical and embryonic development studies. We also discuss an intriguing potential application of PSCs in constructing tissues/organs in large animals by interspecies chimerism. All these emerging findings are likely to contribute to the breakthroughs in biological research and the prosperous prospects of regenerative medicine. PMID- 27225263 TI - The prevalence of chromosomal aberrations associated with myelodysplastic syndromes in China. AB - This study aims to investigate the prevalence and distribution of diverse chromosomal aberrations associated with myelodysplastic syndromes (MDS) in China. Bone marrow samples were collected from multiple cities in China. Metaphase cytogenetic (MC) analysis and fluorescence in situ hybridization (FISH) were initially used to test chromosomal lesions. Affymetrix CytoScan 750 K genechip platform performed a genome-wide detection of chromosomal aberrations. Chromosomal gain was identified in 76 patients; the most prevalent was trisomy 8(17.9 %). New chromosomal gain was detected on chromosome 9, 19p, and X. Chromosomal loss was detected in 101 patients. The most frequent was loss 5q (21.0 %). Some loss and gain were not identified by MC or FISH but identified by genechip. UPD was solely identified by genechip in 51 patients; the most prevalent were UPD 7q (4.94 %) and UPD 17p (4.32 %). Furthermore, complex chromosomal aberrations were detected in 56 patients. In conclusion, Affymetrix CytoScan 750 K genechip was more precise than MC and FISH in detection of cryptic chromosomal aberrations relevant to MDS. Analysis of the prevalence and distribution of diverse chromosomal aberrations in China may improve strategies for MDS diagnosis and therapies. PMID- 27225264 TI - Cytomegalovirus infection in autologous stem cell transplant recipients in the era of rituximab. AB - The incidence of cytomegalovirus (CMV) reactivation/disease after autologous stem cell transplant (ASCT) is much lower than that after allogeneic stem cell transplantation. With the recent use of rituximab during cancer chemotherapy or conditioning regimens prior to transplantation, there has been an increasing concern of opportunistic infections including CMV. In the present study, we reviewed the patients undergoing ASCT from December 2007 to December 2013 to identify those developing CMV reactivation/disease. Out of the 978 patients who underwent ASCT at the Karmanos Cancer Institute, 239 patients were tested for symptomatic CMV reactivation based on clinical suspicion. Of the tested patients, 7/239 (2.9 %) were documented to have CMV reactivation within 90 days of ASCT. The median time to develop CMV viremia was 32 days from transplantation. Of the 239 patients tested, CMV viremia was detected in 3 out of 72 patients who received rituximab as compared to 4 out of 167 patients who did not. Three of these seven viremic patients were treated with anti-viral drugs; viremia resolved in all patients at a median of 24 days. Three patients were found to develop other bacterial and/or fungal infections following CMV viremia. Two of the seven patients died during 1-year follow-up, due to primary disease progression or Candida sepsis. None of the patients developed proven tissue-invasive CMV disease. The study did not evaluate the incidence of asymptomatic CMV infection/reactivation. Despite prior publications based on limited data, rituximab does not appear to contribute to an increased frequency of symptomatic CMV reactivation following ASCT. PMID- 27225265 TI - A new method for quantifying mitochondrial axonal transport. AB - Axonal transport of mitochondria is critical for neuronal survival and function. Automatically quantifying and analyzing mitochondrial movement in a large quantity remain challenging. Here, we report an efficient method for imaging and quantifying axonal mitochondrial transport using microfluidic-chamber-cultured neurons together with a newly developed analysis package named "MitoQuant". This tool-kit consists of an automated program for tracking mitochondrial movement inside live neuronal axons and a transient-velocity analysis program for analyzing dynamic movement patterns of mitochondria. Using this method, we examined axonal mitochondrial movement both in cultured mammalian neurons and in motor neuron axons of Drosophila in vivo. In 3 different paradigms (temperature changes, drug treatment and genetic manipulation) that affect mitochondria, we have shown that this new method is highly efficient and sensitive for detecting changes in mitochondrial movement. The method significantly enhanced our ability to quantitatively analyze axonal mitochondrial movement and allowed us to detect dynamic changes in axonal mitochondrial transport that were not detected by traditional kymographic analyses. PMID- 27225266 TI - Epigenetic and genetic variation in GATA5 is associated with gastric disease risk. AB - Gastric cancer incidence varies considerably among populations, even those with comparable rates of Helicobacter pylori infection. To test the hypothesis that genetic variation plays a role in gastric disease, we assessed the relationship between genotypes and gastric histopathology in a Colombian study population, using a genotyping array of immune-related single nucleotide polymorphisms (SNPs). Two synonymous SNPs (rs6061243 and rs6587239) were associated with progression of premalignant gastric lesions in a dominant-effects model after correction for multiple comparisons (p = 2.63E-07 and p = 7.97E-07, respectively); effect sizes were beta = -0.863 and beta = -0.815, respectively, where beta is an estimate of effect on histopathology scores, which ranged from 1 (normal) to 5 (dysplasia). In our replication cohort, a second Colombian population, both SNPs were associated with histopathology when additively modeled (beta = -0.256, 95 % CI = -0.47, -0.039; and beta = -0.239, 95 % CI = -0.45, 0.024), and rs6587239 was significantly associated in a dominant-effects model (beta = -0.330, 95 % CI = -0.66, 0.00). Because promoter methylation of GATA5 has previously been associated with gastric cancer, we also tested for the association of methylation status with more advanced histopathology scores in our samples and found a significant relationship (p = 0.001). A multivariate regression model revealed that the effects of both the promoter methylation and the exonic SNPs in GATA5 were independent. A SNP-by-methylation interaction term was also significant. This interaction between GATA5 variants and GATA5 promoter methylation indicates that the association of either factor with gastric disease progression is modified by the other. PMID- 27225267 TI - Prevalence and risk factors of bovine tuberculosis in dairy cattle in Eritrea. AB - BACKGROUND: The prevalence of bovine tuberculosis (BTB) in dairy cattle in the three major milk producing regions of Eritrea was assessed by subjecting 15,354 dairy cattle, 50 % of Eritrea's dairy cattle population, to the single intradermal comparative tuberculin test (SICTT). Skin test results were interpreted according to guidelines of the World Organization for Animal Health (OIE) with >4 mm as cutoff in skin thickness increase. In addition, we studied the relation between 'physiological' variables related to pregnancy and lactation, and the variable 'region' on the probability to be skin test positive. RESULTS: The BTB prevalences at animal and herd levels were: 21.5% and 40.9% in Maekel, 7.3% and 10% in Debub, and 0.2% and 1.6% in the Anseba region, respectively. Overall, in the regions included, prevalence was 11.3% (confidence interval (CI) 95% CI, 11.29 - 11.31%) and 17.3% (95% CI, 17.27-17.33%), at animal and herd level, respectively. Considering positive herds only, the animal BTB prevalence was 36.8%, 30.1%, and 1.8%, in Maekel, Debub and Anseba, respectively, and the overall animal prevalence within these herds was 32%. In adult dairy cattle the probability of positive reactivity in the SICTT test was highest in pregnant animals as compared to the other categories. CONCLUSION: This study reports persistent prevalence of BTB as defined by positive SICTT in the dairy sector of Eritrea, especially in the regions of Maekel and Debub that are located in the central highlands of the country. To our understanding this is the first report that has encompassed all the major dairy farms in Eritrea and it will be instrumental in advocating future BTB control programs in the dairy sector. PMID- 27225268 TI - Changes of retinal flow volume after intravitreal injection of bevacizumab in branch retinal vein occlusion with macular edema: a case series. AB - BACKGROUND: Although intravitreal injection of bevacizumab (IVB) is effective for macular edema in patients with branch retinal vein occlusion (BRVO), the changes of retinal hemodynamics remain unclear. We investigated retinal hemodynamic changes in BRVO patients after IVB by performing laser speckle flowgraphy (LSFG). METHODS: In 35 BRVO patients with macular edema, the relative flow volume (RFV) of the retinal artery and vein passing through the optic disc was measured in both the occluded and non-occluded regions of the retina before IVB and 1 month after IVB by LSFG. The ischemic region of retina was measured with the Scion Image program and the severity of retinal ischemia was assessed by dividing the non-perfused area by the disc area. RESULTS: Macular edema improved significantly by 1 month after IVB. The venous RFV ratio showed a significant increase in the non-occluded region at 1 month after IVB. There was a significant negative correlation between the venous RFV ratio and the severity of retinal ischemia in the occluded region. On the other hand, arterial RFV ratio showed no significant change after IVB in either the occluded or non-occluded region. In addition, there was no significant correlation between the arterial RFV ratio and the severity of retinal ischemia in either the occluded or non-occluded region. CONCLUSIONS: These results suggest that an increase of retinal venous outflow after IVB may possibly influence the resolution of macular edema and that the response of venous outflow after IVB depends on the severity of retinal ischemia in the occluded region. PMID- 27225269 TI - Adipose-Derived Stromal Cells from Lipomas: Isolation, Characterisation and Review of the Literature. AB - OBJECTIVE: The aim of this study was to characterize adipose-derived stromal cells (ADSCs) from patients diagnosed with multiple symmetric lipomatosis (MSL) in order to obtain potentially new insights into the pathophysiology, pathogenesis and treatment of this disease. METHODS: Cells from the stromal vascular fraction were analysed by the colony-forming efficiency assay and flow cytometry using standard markers. Moreover, the power of adipogenic plasticity was evaluated. Finally, a literature review was performed from 1982 to 2015 using the US National Institutes of Health's PubMed database. RESULTS: Three European descent patients diagnosed with either MSL type I or II could be identified for analysis. The resulting mean colony-forming efficiency assay was 14.3 +/- 5%. Flow-cytometric analysis of the ADSCs revealed high levels of CD34 (70 +/- 9%), CD45 (37 +/- 13%) and CD73 (55.8 +/- 14%), whereas low levels of CD31 (16.8 +/- 14%) and CD105 (5.8 +/- 0.7%) were detected. Furthermore, ADSCs showed a strong adipogenic potential, which is in line with the literature review. The stem cell pool in lipoma shows several alterations in biological activities, such as proliferation, apoptosis and stemness. CONCLUSIONS: ADSCs from lipoma may be interesting in the application of regenerative medicine. We discuss possible molecular treatment options to regulate their activities at the source of the MSL. PMID- 27225271 TI - Simon Singh: Challenging pseudoscience. PMID- 27225270 TI - The dosimetric impact of implants on the spinal cord dose during stereotactic body radiotherapy. AB - BACKGROUND: The effects of spinal implants on dose distribution have been studied for conformal treatment plans. However, the dosimetric impact of spinal implants in stereotactic body radiotherapy (SBRT) treatments has not been studied in spatial orientation. In this study we evaluated the effect of spinal implants placed in sawbone vertebra models implanted as in vivo instrumentations. METHODS: Four different spinal implant reconstruction techniques were performed using the standard sawbone lumbar vertebrae model; 1. L2-L4 posterior instrumentation without anterior column reconstruction (PI); 2. L2-L4 anterior instrumentation, L3 corpectomy, and anterior column reconstruction with a titanium cage (AIAC); 3. L2-L4 posterior instrumentation, L3 corpectomy, and anterior column reconstruction with a titanium cage (PIAC); 4. L2-L4 anterior instrumentation, L3 corpectomy, and anterior column reconstruction with chest tubes filled with bone cement (AIABc). The target was defined as the spinous process and lamina of the lumbar (L) 3 vertebra. A thermoluminescent dosimeter (TLD, LiF:Mg,Ti) was located on the measurement point anterior to the spinal cord. The prescription dose was 8 Gy and the treatment was administered in a single fraction using a CyberKnife(r) (Accuray Inc., Sunnyvale, CA, USA). We performed two different treatment plans. In Plan A beam interaction with the rod was not limited. In plan B the rod was considered a structure of avoidance, and interaction between the rod and beam was prevented. TLD measurements were compared with the point dose calculated by the treatment planning system (TPS). RESULTS AND DISCUSSION: In plan A, the difference between TLD measurement and the dose calculated by the TPS was 1.7 %, 2.8 %, and 2.7 % for the sawbone with no implant, PI, and PIAC models, respectively. For the AIAC model the TLD dose was 13.8 % higher than the TPS dose; the difference was 18.6 % for the AIABc model. In plan B for the AIAC and AIABc models, TLD measurement was 2.5 % and 0.9 % higher than the dose calculated by the TPS, respectively. CONCLUSIONS: Spinal implants may be present in the treatment field in patients scheduled to undergo SBRT. For the types of implants studied herein anterior rod instrumentation resulted in an increase in the spinal cord dose, whereas use of a titanium cage had a minimal effect on dose distribution. While planning SBRT in patients with spinal reconstructions, avoidance of the rod and preventing interaction between the rod and beam might be the optimal solution for preventing unexpectedly high spinal cord doses. PMID- 27225272 TI - Evaluation of red blood cell distribution width as a prognostic indicator in cats with acquired heart disease, with and without congestive heart failure. AB - Objectives Congestive heart failure secondary to cardiomyopathy is a common manifestation of cardiac disease in cats, carrying a variable prognosis. The objective of this retrospective study was to evaluate the relationship between red blood cell distribution width (RDW) and survival time in feline patients with acquired heart disease with and without congestive heart failure (CHF). Methods Three hundred and forty-nine client-owned cats with echocardiograms and complete blood count, including RDW measurement, performed between March 2006 and December 2011, were included in the study. Patient characteristics, including signalment, hematocrit, RDW, echocardiographic parameters and survival, were recorded. Comparisons between RDW in cats with asymptomatic acquired heart disease and those with CHF were made. Survival was documented and compared at 30 days and 6 months. Results CHF was present in 80 cats and absent in 269 cats. Cats with CHF had an increase in mortality compared with cats without CHF at 30 days and 6 months ( P = 0.007 and P = 0.04, respectively). RDW was not significantly associated with survival in cats with or without CHF at 30 days or 6 months. A significant difference was found between median RDW values in cats with CHF vs cats without CHF (16.3% vs 15.8%; P = 0.02). The median RDW value was significantly higher in cats with unclassified cardiomyopathy compared with cats with other types of cardiomyopathy (16.3% vs 15.8%; P = 0.03). Conclusions and relevance Single RDW values did not predict mortality in cats with acquired heart disease but may be useful in determining if cats have decompensated heart disease and CHF. Human studies indicate that incremental increases in serial RDW measurements are associated with decreased survival; serial RDW measurements in cats may be an area of future study. PMID- 27225273 TI - Iridoschisis and keratoconus in a patient with severe allergic eye disease and compulsive eye rubbing: a case report. AB - BACKGROUND: Iridoschisis is a rare disorder characterized by splitting of the anterior and posterior iris stroma, resulting in disintegrated iris fibrils which float freely in the anterior chamber. We report an exceptional case of bilateral iridoschisis occurring in conjunction with keratoconus and severe allergic eye disease. CASE PRESENTATION: A 24-year-old white man had had periocular contact dermatitis and allergic eye disease from the age of 3 years. He was allergic to grass, animal hair, and pollen and worked grooming horses. He compulsively rubbed his eyes. There was no history of previous blunt trauma to either eye. There were signs of bilateral iridoschisis and keratoconus with allergic conjunctivitis, all of which were more severe in his right eye. An open drainage angle was identified bilaterally on gonioscopy, excluding primary angle closure. There was no evidence of glaucoma in either eye. CONCLUSIONS: There are two previous cases reporting the combination of iridoschisis and keratoconus, but no clear common etiology has been identified. In this case there was no evidence of angle closure but there were signs of allergic conjunctivitis. This amalgamation of signs might be explained on the basis of habitual eye rubbing. Treating the allergic eye disease has attenuated this behavior. PMID- 27225274 TI - 1985, Scientists can't do science alone, they need publics. PMID- 27225275 TI - Whole-transcriptome analysis of differentially expressed genes in the ray florets and disc florets of Chrysanthemum morifolium. AB - BACKGROUND: Chrysanthemum morifolium is one of the most important global cut flower and pot plants, and has been cultivated worldwide. However, limited genomic resources are available and the molecular mechanisms involved in the two morphologically distinct floret developmental cycles in chrysanthemum remain unclear. RESULTS: The transcriptomes of chrysanthemum ray florets, disc florets and leaves were sequenced using Illumina paired-end sequencing technology. In total, 16.9 G reads were assembled into 93,138 unigenes with an average length of 738 bp, of which 44,364 unigenes showed similarity to known proteins in the Swissprot or NCBI non-redundant protein databases. Additionally, 26,320, 22,304 and 13,949 unigenes were assigned to 54 gene ontology (GO) categories, 25 EuKaryotic Orthologous Groups (KOG) categories, and 280 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, respectively. A total of 1863 differentially expressed genes (DEGs) (1210 up-regulated and 653 down-regulated) were identified between ray florets and disc florets, including genes encoding transcription factors and protein kinases. GO and KEGG pathway enrichment analyses were performed on the DEGs to identify differences in the biological processes and pathways between ray florets and disc florets. The important regulatory genes controlling flower development and flower organ determination, as well as important functional genes in the anthocyanin biosynthetic pathway, were identified, of which two leucoanthocyanidin dioxygenase-encoding genes showed specific expression in ray florets. Lastly, reverse transcription quantitative PCR was conducted to validate the DEGs identified in our study. CONCLUSIONS: Comparative transcriptome analysis revealed significant differences in patterns of gene expression and signaling pathways between ray florets and disc florets in Chrysanthemum morifolium. This study provided the first step to understanding the molecular mechanism of the differential development of ray florets and disc florets in chrysanthemum, and also provided valuable genomic resources for candidate genes applicable for the breeding of novel varieties in chrysanthemum. PMID- 27225277 TI - Drug resistant focal epilepsy in a patient with myotonic dystrophy type 2: casual or causal association? PMID- 27225276 TI - Influence of A-21T and C-262T genetic polymorphisms at the promoter region of the catalase (CAT) on gene expression. AB - OBJECTIVE: Catalase (CAT, OMIM: 115500) is one of the major antioxidant enzymes, which plays an important role in the clearance of reactive oxygen species. Three genetic polymorphisms of A-21T (rs7943316), C-262T (rs1001179), and C-844T (rs769214) in the promoter region of the CAT have been reported. It has been suggested that these polymorphisms may alter the recognition sites of transcriptional factors, therefore it might be concluded that these polymorphisms may alter the expression levels of the gene. The aim of the present study is to evaluate the associations between these genetic variations and the CAT mRNA levels in human peripheral blood cells. METHODS: The present study consisted of 47 healthy students of Shiraz University (south-west Iran). Genotypes of the CAT polymorphisms were determined by PCR based method. The quantitative CAT mRNA expression levels were investigated using quantitative real-time PCR. RESULTS: Analysis of variance revealed significant differences between the study genotypes (For A-21T polymorphism: F = 7.45; df = 2, 44; P = 0.002; For C-262T polymorphism: F = 15.17; df = 2, 44; P < 0.001). The studied polymorphisms showed linkage disequilibrium (D' = 1.0, r 2 = 0.1813, chi 2 = 17.03, P < 0.0001). The mRNA levels of CAT in the AC/TT, TC/TC, TC/TT, and TC/TC diplotypes significantly were higher than the mRNA levels in AC/AC diplotype. There was a significant difference between the study genotypes (F = 9.24; df = 5, 41; P < 0.001). The TC/TC and TT/TT diplotypes showed about 2 and 4 folds CAT mRNA levels compared with the AC/AC diplotype. CONCLUSIONS: The present findings indicated that these polymorphisms were significantly associated with the gene expression. PMID- 27225278 TI - A review of recent literature on functional MRI and personal experience in two cases of definite vestibular migraine. AB - The pathophysiology of vestibular migraine (VM) is at present poorly understood. Functional magnetic resonance imaging (fMRI), a technique that measures brain activity by detecting changes associated with blood flow oxygenation, has been used to study neural pathways involved in VM pathophysiology. In this study, we summarize results of previous fMRI studies in VM patients, both during and between vertigo attacks. Moreover, we report our experience in two patients with definite VM, who underwent fMRI during a visual stimulation in a vertigo-free period. Compared with 15 matched healthy controls, fMRI demonstrated activation of brain areas related to integration of visual and vestibular cues (increased activation of the paracentral lobule and bilateral inferior parietal lobule and decreased activation of the left superior frontal gyrus, head of the caudate nucleus, left superior temporal gyrus, left parahippocampal gyrus, and right lingual gyrus). Our results partially confirm those of other authors, reporting increased activation of multimodal association brain areas (BA 40, BA 31/5) and decreased activation of occipital regions In addition, we also found a decreased activation of fronto-temporal areas, such as the parahippocampal region, functionally involved in space memory and navigation. PMID- 27225279 TI - Mobitz type I and II atrioventricular blocks during fingolimod therapy. AB - We investigated patients who showed a second-degree atrioventricular block (S AVB) after the first fingolimod administration. We observed six patients with S AVB, three Mobitz type I, and three type II. Monitoring continued on the second day for all patients. Three patients showed persistence of the S-AVB, with resolution on the second or third day. One patient had a persistent S-AVB up to the fourth day when fingolimod was discontinued. We conclude that Mobitz type II S-AVB is possible during fingolimod therapy. Patients with S-AVB could be monitored until resolution of the S-AVBs, as these may persist several days after the first fingolimod administration. PMID- 27225280 TI - Erratum to: Untargeted metabolomic analysis for the clinical screening of inborn errors of metabolism. PMID- 27225281 TI - Thyroid and parathyroid dysfunction after total laryngectomy in patients with laryngeal carcinoma. AB - The objective of this study is to investigate thyroid and parathyroid functions in patients with laryngeal carcinoma after total laryngectomy with hemithyroidectomy with or without irradiation, and to determine if irradiation when following surgery has an additive effect contributing to either or both glands hypo function. This study included 17 patients with laryngeal squamous cell carcinoma who were subjected to surgery. Nine of them were further justified for postoperative radiotherapy as well. All patients were subjected to Clinical assessment, including adequate history taking and physical examination, to detect the presence of hypothyroidism or hypoparathyroidism. Laboratory assessment of thyroid function included TSH and T4 assay, and parathyroid function included corrected serum calcium and parathormone levels. Eight (48 %) patients were treated with surgery alone, and 9 (52 %) patients received postoperative radiotherapy. In this study, 13 out of the 17 patients (78 %) were found to be hypothyroid and 4 (22 %) were euthyroid, while 7 (42 %) were found to have hypoparathyroidism. The study showed; among the 8 patients who were treated by surgery only, 5 (62.5 %) of them developed hypothyroidism and 3 (37.5 %) were euthyroid and 3 (37.5 %) developed hypoparathyroidism and 5 (62.5 %) were normal. Among the 9 patients who were treated by surgery and radiotherapy, 8 (88.9 %) developed hypothyroidism and 1 (11.1 %) was euthyroid and 4 (44.4 %) developed hypoparathyroidism and 5 (55.6 %) were normal. The study confirms the development of hypothyroidism with or without hypoparathyroidism after total laryngectomy with a higher incidence in those treated by combined surgery and radiotherapy and in supraglottic tumors. PMID- 27225282 TI - A comparison of low versus high radioiodine administered activity in patients with low-risk differentiated thyroid cancer. AB - Post-surgical therapeutic management of differentiated thyroid cancer (DTC) is still a controversial subject. Indeed, there is no consensus on the dose of 131I to be administered, although the current trend towards therapy easing through mini-cures for patients with good prognosis. To confirm the non-inferiority in terms of effectiveness of an ablative mini-cure from 1.11 to 1.85 GBq, over a cure of 3.7 GBq, in patients with DTC operated for low and very low risk. We retrospectively studied 157 patients with very low and low risk DTC, followed in the Nuclear Medicine Department of the Salah Azaiez Institute between 2002 and 2012. These patients had a complementary radioiodine therapy with either low dose (group A) or high dose (group B) with an evaluation at 6 months post treatment and in long-term. The study took place at a referral center. The average age was 42.8 +/- 13.7 years with a female predominance (86.7 %). The DTC papillary represented the most common etiology (95 %) with a predominance of pure papillary (68 %) on the follicular variant (27 %). The first cure evaluation did not show statistically significant difference between the two approaches in terms of therapeutic ablative efficiency (p = 0.13). The overall success rate was 77 % (121/157), with 83 % (54/65) in group A and 72.8 % (67/92) in group B. The likelihood of having a remission from the first cure was 1.83 times greater for patients treated with low doses (OR = 1.83, 95 % CI 0.23-1.29). At the end of follow, we have noted one case of refractory disease. The male gender (adjusted OR = 2.71, 95 % CI 0.51-4.23, p = 0.03), and the baseline Tg >= 10 (ng/ml) (adjusted OR = 3.48, 95 % CI 1.25-9.67, p = 0.01) were significantly independent predictors of successful first cure ablation. The results provide that mini-dose protocol is not less effective for ablation of the thyroid remnant than 3.7 GBq activity. PMID- 27225283 TI - UreA and cagA genes of Helicobacter pylori in Egyptian patients with laryngeal squamous cell carcinoma and benign laryngeal polyps: a cohort study. AB - This work aims to estimate the prevalence of Helicobacter pylori ureA gene and evaluate cagA gene-positive strains in both patients of laryngeal squamous cell carcinoma (LSCC) and those with benign laryngeal polyps. This study included 49 patients confirmed pathologically to have LSCC and 15 patients with benign laryngeal polyps over a period from June 2013 to March 2015. Samples of laryngeal tissue were collected during direct laryngoscope under general anesthesia to be pathologically evaluated followed by analysis for H. pylori detection. Each laryngeal tissue sample was divided into three parts; one for bacteriological examination, the second for pathological examination and the third for PCR to detect both ureA and cagA genes. Out of 49 LSCC samples, 31 (64.6 %) was positive for ureA by PCR. Out of them, 29 samples (93.5 %) were cagA positive. Only three cases (20 %) of the benign laryngeal polyp were ureA positive by PCR and one of them was cagA positive by PCR. By the bacteriological culture, only eight samples (25.8 %) gave growth. All of them were ureA positive and only seven of them were cagA positive. There was a significant association between presence of H. pylori and LSCC as compared to benign laryngeal polyp which may contribute in the pathogenesis of laryngeal carcinoma. These results should be confirmed by further studies over larger number of cases. PMID- 27225284 TI - Effectiveness of Spiritual Components Training on Life Satisfaction of Persian Orphan Adolescents. AB - This study was performed with the purpose of determining the effectiveness of spiritual components training on life satisfaction of Persian orphan adolescents. The study population was from female adolescents of two orphanages located in Kerman, Iran. They were randomly divided into two experimental and two control groups (each group including ten members). The experimental groups were received the spiritual training in ten sessions (spiritual training included components such as image of God, relationship with God, Tawwakul, searching for meaning during difficulties and pain), whereas the control groups were in the waiting list. Life satisfaction questionnaire was completed by one experimental and one control group before the training; and also after it, all four groups filled out the mentioned questionnaire. The analysis of covariance on the results revealed that spiritual components training had a significant positive effect on life satisfaction of the experimental groups in comparison with the control groups. Lastly, discussion, conclusion, some suggestions and directions were indicated. PMID- 27225285 TI - Fibroline: A mobile app for improving the quality of life of young people with fibromyalgia. AB - Fibroline is a mobile application with a self-administered cognitive behavioral treatment for young people with fibromyalgia or chronic widespread pain, designed to reduce pain and other common negative symptoms and improve quality of life. Our aims are to report on the usability and feasibility protocols used to assess the app. Two usability cycles were implemented. A group of patients followed the cognitive behavioral treatment intervention to test its feasibility. Qualitative data were collected and content analyses were conducted. The results demonstrated that the app is error-free, easy to use, liked by the users, and acceptable. PMID- 27225286 TI - Effects and safety of combination therapy with gonadotropin-releasing hormone analogue and growth hormone in girls with idiopathic central precocious puberty: a meta-analysis. AB - PURPOSE: This meta-analysis is to evaluate the effects and safety of the combination therapy for girls with idiopathic central precocious puberty (ICPP). METHODS: Electronic databases were searched for randomized controlled trials (RCTs) and clinical controlled trials (CCTs) that adopted gonadotropin-releasing hormone analogue (GnRHa) therapy and GnRHa plus growth hormone (GH) combination therapy to treat ICPP girls. RESULTS: A total of six RCTs (162 patients) and six CCTs (247 patients) were included. Compared to the GnRHa therapy group, the combination therapy group achieved taller final height (mean difference, MD = 2.81 cm, 95 % CI 1.76-3.87, four CCTs; MD = 4.30 cm, 95 % CI 0.59-8.01, one RCT); greater progression of final height compared with target height (MD = 3.92 cm, 95 % CI 3.12-4.73, four CCTs; MD = 4.00 cm, 95 % CI 1.93-6.07, One RCT) and larger height gains (MD = 3.49 cm, 95 % CI 0.97-6.01, four CCTs; MD = 3.88 cm, 95 % CI 0.15-7.61, one RCT). No severe adverse effects of treatment were reported. CONCLUSION: For ICPP girls, the GnRHa and GH combination therapy had advantages over GnRHa alone on final height and no severe adverse effects were reported. We recommend comprehensive assessment of the individual growth rate, patient compliance, the clinical effects, the height expectations of individual patients and the treatment cost to the family in order to identify the best therapy for individual patients. PMID- 27225287 TI - Generating giant and tunable nonlinearity in a macroscopic mechanical resonator from a single chemical bond. AB - Nonlinearity in macroscopic mechanical systems may lead to abundant phenomena for fundamental studies and potential applications. However, it is difficult to generate nonlinearity due to the fact that macroscopic mechanical systems follow Hooke's law and respond linearly to external force, unless strong drive is used. Here we propose and experimentally realize high cubic nonlinear response in a macroscopic mechanical system by exploring the anharmonicity in chemical bonding interactions. We demonstrate the high tunability of nonlinear response by precisely controlling the chemical bonding interaction, and realize, at the single-bond limit, a cubic elastic constant of 1 * 10(20) N m(-3). This enables us to observe the resonator's vibrational bi-states transitions driven by the weak Brownian thermal noise at 6 K. This method can be flexibly applied to a variety of mechanical systems to improve nonlinear responses, and can be used, with further improvements, to explore macroscopic quantum mechanics. PMID- 27225288 TI - Initial Experience With High-Risk Patients Excluded From Clinical Trials: Safety of Short-Term Anticoagulation After Left Atrial Appendage Closure Device. AB - BACKGROUND: The implantation of left atrial appendage closure device (WATCHMAN, Boston Scientific, Natick, MA) is an alternative option to oral anticoagulation (OAC) for stroke prevention in atrial fibrillation. Patients require short-term OAC after implantation to avoid device thrombosis. The 2 clinical trials that assessed this device excluded patients thought not to be candidates for OAC. As such, little is known about the safety of this strategy in patients with previous major bleeding events. METHODS AND RESULTS: All 20 consecutive patients with history of spontaneous major bleeding while on OAC who had subsequently undergone WATCHMAN device implantation at our institution were included. A newly conceived multidisciplinary Atrial Fibrillation Stroke Prevention Center evaluated patients for candidacy for device implantation and subsequent antithrombotic therapy. The primary outcome was spontaneous major bleeding while receiving short-term postprocedural OAC. Median CHA2DS2-VASc and HAS-BLED scores were 5 (quartiles 5 6) and 5 (quartiles 4-5), respectively. Previous major bleeding events were major gastrointestinal bleeding, intracranial bleeding, spontaneous hemopericardium with cardiac tamponade, and hemarthrosis in 11, 7, 1, and 1 patients, respectively. None of the patients had spontaneous major bleeding during the course of OAC after device implantation. In 1 patient, OAC was discontinued after 40 days because of mechanical fall with head trauma resulting in subdural hematoma with no associated neurological deficits; this was managed conservatively. CONCLUSIONS: With careful multidisciplinary evaluation, a short course of OAC after WATCHMAN device implantation in patients with previous spontaneous major bleeding events is associated with low risk of recurrent spontaneous major bleeding. PMID- 27225289 TI - Sec15 links bud site selection to polarised cell growth and exocytosis in Candida albicans. AB - The exocyst plays a crucial role in the targeting of secretory vesicles to the plasma membrane during exocytosis. It has been shown to be involved in diverse cellular processes including yeast budding. However, the mechanism of the exocyst regulating yeast budding has not been fully elucidated. Here we report a novel interaction between the exocyst component Sec15 and the Ras-family GTPase Rsr1, a master regulator of bud-site-selection system, in the fungus Candida albicans. We present several lines of evidence indicating physical and genetic interaction of Sec15 with Rsr1. In vitro binding assays and co-immunoprecipitation studies showed that Sec15 associated physically with Rsr1. Deletion of RSR1 completely abolished the polarised localisation of Sec15 as well as all the other exocyst components in both yeast and hyphal cells, suggesting a functional interaction between Sec15 and Rsr1. We also show that C. albicans Sec15 interacts directly with the polarity determinant Bem1 and the type V myosin, Myo2. Disruption of the interaction by shutting off SEC15 results in mislocaliztion of Bem1-GFP. These findings highlight the important role of Sec15 in polarised cell growth by providing a direct functional link between bud-site-selection and exocytosis. PMID- 27225291 TI - Clinical efficacy of Trigonella foenum graecum (Fenugreek) and dry cupping therapy on intensity of pain in patients with primary dysmenorrhea. AB - OBJECTIVE: To determine the effificacy and safety of fenugreek seed and dry cupping on intensity of pain in primary dysmenorrhea. METHODS: Sixty patients with primary dysmenorrhea were enrolled in this prospective, open-labeled, randomized, standard-controlled study, conducted in the National Institute of Unani Medicine Hospital between February 2010 and April 2011. In group A (20 cases), 3 g powder of fenugreek seed (3 capsules, 1 g each) was given orally twice daily from day 1 to 3 of menstrual cycle. Group B (20 cases) received the same dose of fenugreek seed as group A along with dry cupping therapy [two 4.2-cm and one 2.5-cm cups (internal diameter)], which was applied below the umbilicus for 15 min on day 1 and day 3 of menstrual cycle for 3 consecutive months. The control group C (20 cases) was given mefenamic acid, 500 mg twice daily, on the same protocol. The reduction in menstrual pain intensity was measured with well validated Visual Analogue Scale and safety of fenugreek seed was evaluated by clinical examination and laboratory investigations. RESULTS: Baseline characteristics and biochemical parameters were comparable and homogenous among all groups (P>0.05). The percentage reduction in lower abdominal pain was 66.89%, 66.49%, and 62.88% in A, B and C groups respectively at the end of the treatment. No adverse drug effects were noticed. CONCLUSION: The fenugreek seed and dry cupping are effificacious, safe, cost effective, and well tolerated. PMID- 27225290 TI - TMEM45B, up-regulated in human lung cancer, enhances tumorigenicity of lung cancer cells. AB - Transmembrane protein 45B (TMEM45B) is a member of TMEMs. Altered expression of TMEMs is frequently observed in a variety of human cancers, but the expression and functional roles of TMEM45B in lung cancer is not reported. In the present study, levels of mRNA expression of TMEM45B in lung cancer tissues were assessed using re-analyzing expression data of The Cancer Genome Atlas (TCGA) lung cancer cohort and real-time PCR analysis on our own cohort. Lung cancer cells, A549 and NCI-H1975, infected with TMEM45B short hairpin RNA were examined in cell proliferation, cell cycle, cell apoptosis, wound-healing, and cell invasion assays as well as mouse xenograft models. Here, we demonstrated that TMEM45B was overexpressed in lung cancer and its expression correlated with overall survival of patients. In addition, silencing of TMEM45B expression reduced cell proliferation in vitro and in vivo, induced cell cycle arrest and cell apoptosis, and blocked cell migration and invasion. Moreover, knockdown of TMEM45B significantly suppressed G1/S transition, induced cell apoptosis, and inhibited cell invasion via regulating the expression of cell cycle-related proteins (CDK2, CDC25A, and PCNA), cell apoptosis-related proteins (Bcl2, Bax, and Cleaved Caspase 3), and metastasis-related proteins (MMP-9, Twist, and Snail), respectively. Thus, TMEM45B is a potential prognostic marker and cancer-selective therapeutic target in lung cancer. PMID- 27225292 TI - Key symptoms selection for two major syndromes diagnosis of Chinese medicine in chronic hepatitis B. AB - OBJECTIVE: To identify key symptoms of two major syndromes in chronic hepatitis B (CHB), which can be the clinical evidence for Chinese medicine (CM) doctors to make decisions. METHODS: Standardization scales on diagnosis for CHB in CM were designed including physical symptoms, tongue and pulse appearance. The total of 695 CHB cases with dampness-heat (DH) syndrome or Pi (Spleen) deficiency (SD) syndrome were collected for feature selection and modeling, another 275 CHB patients were collected in different locations for validation. Key symptoms were selected based on modified information gain (IG), and 5 classifiers were applied to assist with models training and validation. Classification accuracy and area under receiver operating characteristic curves (AUC) were evaluated. RESULTS: (1) Thirteen DH syndrome key symptoms and 13 SD syndrome key symptoms were selected from original 125 symptoms; (2) The key symptoms could achieve similar or better diagnostic accuracy than the original total symptoms; (3) In the validation phase, the key symptoms could identify syndromes effectively, especially in DH syndrome, which average prediction accuracy on 5 classifiers could achieve 0.864 with the average AUC 0.772. CONCLUSION: The selected key symptoms could be simple DH and SD syndromes diagnostic elements applied in clinical directly. (Registration N0.: ChiCTR-DCC-10000759). PMID- 27225294 TI - Is Chinese herbal medicine effective for elderly isolated systolic hypertension? A systematic review and meta-analysis. AB - OBJECTIVE: To study the efficacy of Chinese medicine (CM) on isolated systolic hypertension. METHODS: Seven electronic databases were searched for randomized controlled trials (RCTs) published until August 2015. Subgroup analyses and meta analysis were performed to assess the efficacy and safety of the included studies. RESULTS: A total of 24 studies, including 2,096 patients (1,058 patients in the intervention group and 1,038 in the control group), were evaluated in the final analysis. Compared with a conventional therapy used alone, CM as additional intervention was more effective on systolic blood pressure [mean difference (MD)= 0.66, 95% confidence interval (CI)=(-0.97,-0.36), P<0.00001] and significantly diminished the pulse pressure [MD=-7.49, CI=(-12.69,-2.29), P<0.00001]. However it showed no additional benefit on diastolic blood pressure [MD=1.16, CI=(0.02, 2.29), P=0.87]. Adverse events were not explicitly reported in most RCTs. CONCLUSIONS: CM might be a promising approach for the elderly with isolated systolic hypertension, while the evidence for CM employed alone was insufficient. Considering the inherent limitations of the included studies, larger high-quality RCTs with extensive follow-up should be performed to validate our findings in the future. PMID- 27225295 TI - Astible Rivularis: Bioactive compounds and pharmacological functions. AB - Astilbe rivularis Buch. Ham., a rhizomatous perennial herb of the Saxifragaceae family, has been listed in rare species. In traditional medicine the plant has been used for the treatment of ulcer, bleeding during child birth, inflammation, body ache, diarrhea, and dysentery. This article reviews and analyses the traditional use, pharmacological activities of the corresponding bioactive compounds, and toxicological data on A. rivularis species. A. rivularis has been used across Indian subcontinent to treat various human ailments. Its extract consists of alkaloids, flflavonoids, coumarins and glycosides. These extracts as well as isolated bioactive compounds demonstrated various biological activities including antimicrobial, anti-peptic ulcer, anti-inflflammatory, and antioxidant activity. Toxicological studies of the extract on brine shrimp larvae demonstrated mild toxicity; however no acute toxicity in mice. Although the pharmacological effect of A. rivularis has been poorly explored, the available data validated its use in ethnomedicine. To reveal the cryptic therapeutic potential of the species, research should focus on identifification and mechanistic studies of the bioactive compounds. PMID- 27225293 TI - Effect of Chinese herbal compound Naofucong () on the inflammatory process induced by high glucose in BV-2 cells. AB - OBJECTIVE: To determine the effect of medicated serum of Chinese herbal compound Naofucong (, NFC) on the microglia BV-2 cells viability and the transcription and expression of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) in microglia BV-2 cells to further explore the mechanisms underlying the protective effect of NFC on inflammatory process induced by high glucose. METHODS: The microglia BV-2 cells incubated in vitro were divided into different groups: the control group (25 mmol/L glucose), the model group (75 mmol/L glucose), high glucose media containing different dose medicated serum of NFC. After being cultured for 24 h, changes in IL-6 and TNF-alpha were measured by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. The expression of surface marker CD11b of activated microglia was measured by confocal laser scanning microscope and Western blot. Nuclear factor-kappaB (NF kappaB) p-p65 expression was analyzed by Western blot. RESULTS: The model group obviously increased the expression of microglial surface marker CD11b and NF kappaB p-p65 (all P<0.01), induced a signifificant up-regulation of release and the mRNA expression of IL-6 and TNF-alpha (P<0.01 or P<0.05). The medicated serum of NFC could obviously down-regulate the transcription and expression of surface marker CD11 b and NF-kappaB p-p65 (all P<0.01), and inhibit the mRNA and protein expression (P<0.01 or P<0.05) of inflflammatory cytokines, such as IL-6 and TNF alpha, in microglia BV-2 cells cultured with high glucose for 24 h. CONCLUSIONS: The inhibition of microglial activation and IL-6 and TNF-alpha expression induced by high glucose may at least partly explain NFC therapeutic effects on diabetes associated cognitive decline diseases. Its underlying mechanism could probably be related to the inhibition of NFC on NF-kappaB phosphorylation. PMID- 27225296 TI - Differentiation of preadipocytes and mature adipocytes requires PSMB8. AB - The differentiation of adipocytes is tightly regulated by a variety of intrinsic molecules and also by extrinsic molecules produced by adjacent cells. Dysfunction of adipocyte differentiation causes lipodystrophy, which impairs glucose and lipid homeostasis. Although dysfunction of immunoproteasomes causes partial lipodystrophy, the detailed molecular mechanisms remain to be determined. Here, we demonstrate that Psmb8, a catalytic subunit for immunoproteasomes, directly regulates the differentiation of preadipocytes and additionally the differentiation of preadipocytes to mature adipocytes. Psmb8(-/-) mice exhibited slower weight gain than wild-type mice, and this was accompanied by reduced adipose tissue volume and smaller size of mature adipocytes compared with controls. Blockade of Psmb8 activity in 3T3-L1 cells disturbed the differentiation to mature adipocytes. Psmb8(-/-) mice had fewer preadipocyte precursors, fewer preadipocytes and a reduced ability to differentiate preadipocytes toward mature adipocytes. Our data demonstrate that Psmb8-mediated immunoproteasome activity is a direct regulator of the differentiation of preadipocytes and their ultimate maturation. PMID- 27225297 TI - Large-Scale Production of Large-Size Atomically Thin Semiconducting Molybdenum Dichalcogenide Sheets in Water and Its Application for Supercapacitor. AB - To progress from laboratory research to commercial applications, it is necessary to develop an effective method to prepare large quantities and high-quality of the large-size atomically thin molybdenum dichalcogenides (MoS2). Aqueous-phase processes provide a viable method for producing thin MoS2 sheets using organolithium-assisted exfoliation; unfortunately, this method is hindered by changing pristine semiconducting 2H phase to distorted metallic 1T phase. Recovery of the intrinsic 2H phase typically involves heating of the 1T MoS2 sheets on solid substrates at high temperature. This has restricted and hindered the utilization of 2H phase MoS2 sheets suspensions. Here, we demonstrate that the synergistic effect of the rigid planar structure and charged nature of organic salt such as imidazole (ImH) can be successfully used to produce atomically thin 2H-MoS2 sheets suspension in water. Moreover, lateral size and area of the exfoliated sheet can be up to 50 MUm and 1000 MUm(2), respectively. According to the XPS measurements, nearly 100% of the 2H-MoS2 sheets was successfully prepared. A composite paper supercapacitor using the exfoliated 2H MoS2 and carbon nanotubes delivered a superior volumetric capacitance of ~410 F/cm(3). Therefore, the organic salts-assisted liquid-phase exfoliation has great potential for large-scale production of 2H-MoS2 suspensions for supercapacitor application. PMID- 27225298 TI - Osmosis and thermodynamics explained by solute blocking. AB - A solute-blocking model is presented that provides a kinetic explanation of osmosis and ideal solution thermodynamics. It validates a diffusive model of osmosis that is distinct from the traditional convective flow model of osmosis. Osmotic equilibrium occurs when the fraction of water molecules in solution matches the fraction of pure water molecules that have enough energy to overcome the pressure difference. Solute-blocking also provides a kinetic explanation for why Raoult's law and the other colligative properties depend on the mole fraction (but not the size) of the solute particles, resulting in a novel kinetic explanation for the entropy of mixing and chemical potential of ideal solutions. Some of its novel predictions have been confirmed; others can be tested experimentally or by simulation. PMID- 27225299 TI - Stepwise unfolding of human beta2-microglobulin into a disordered amyloidogenic precursor at low pH. AB - Amyloid fibril formation by human beta2-microglobulin (beta2m) is associated with dialysis-related amyloidosis. In order to understand the mechanism of protein misfolding, it is important to characterize the nature and properties of various intermediates formed during protein unfolding. In this work, we studied the effect of pH change on the unfolding of beta2m using a range of spectroscopic readouts. In order to investigate the local structural changes, we created single tryptophan (W60 and W95) mutants of beta2m. The equilibrium results suggested that in the acid-unfolded state of beta2m at pH 2.5, the W60 residue attains non native local structure whereas the W95 residue becomes more exposed. Our stopped flow kinetic data revealed that beta2m undergoes unfolding in a stepwise manner. Initial unfolding of beta2m involves non-uniform protein expansion with the unpacking of tertiary structure and significant core solvation while maintaining a native-like structure around residue W95. The resolved-phase of unfolding exhibits a timescale of ~500 ms that describes the transition from the native like swollen intermediate to an acid-induced disordered state. Taken together, our results demonstrate that beta2m has a complex pH-induced unfolding mechanism yielding a disordered amyloidogenic precursor comprising both exposed and buried segments. PMID- 27225301 TI - Connective tissue diseases: Targeting type I interferon in systemic lupus erythematosus. PMID- 27225302 TI - Connective tissue diseases: Digital ulcers unaffected by endothelin blockade. PMID- 27225300 TI - Hypoxia, mitochondrial dysfunction and synovial invasiveness in rheumatoid arthritis. AB - Synovial proliferation, neovascularization and leukocyte extravasation transform the normally acellular synovium into an invasive tumour-like 'pannus'. The highly dysregulated architecture of the microvasculature creates a poor oxygen supply to the synovium, which, along with the increased metabolic turnover of the expanding synovial pannus, creates a hypoxic microenvironment. Abnormal cellular metabolism and mitochondrial dysfunction thus ensue and, in turn, through the increased production of reactive oxygen species, actively induce inflammation. When exposed to hypoxia in the inflamed joint, immune-inflammatory cells show adaptive survival reactions by activating key proinflammatory signalling pathways, including those mediated by hypoxia-inducible factor-1alpha (HIF-1alpha), nuclear factor kappaB (NF-kappaB), Janus kinase-signal transducer and activator of transcription (JAK-STAT) and Notch, which contribute to synovial invasiveness. The reprogramming of hypoxia-mediated pathways in synovial cells, such as fibroblasts, dendritic cells, macrophages and T cells, is implicated in the pathogenesis of rheumatoid arthritis and other inflammatory conditions, and might therefore provide an opportunity for therapeutic intervention. PMID- 27225303 TI - Rheumatoid arthritis: Immunosuppressive therapies and cancer risk. PMID- 27225304 TI - Lupus nephritis: Targeting Bcl-2 prevents nephritis in mice. PMID- 27225305 TI - Spondyloarthropathies: Sacroiliac joint radiographic progression - speed and determinants. PMID- 27225306 TI - Vasculitis syndromes: Tocilizumab safe and effective for PMR. PMID- 27225307 TI - Role of ATG10 expression quantitative trait loci in non-small cell lung cancer survival. AB - The aim of this article was to evaluate whether genetic variants in autophagy related genes affect the overall survival (OS) of non-small cell lung cancer (NSCLC) patients. We analyzed 14 single nucleotide polymorphisms (SNPs) in core autophagy-related genes for OS in 1,001 NSCLC patients. Three promising SNPs in ATG10 were subsequently annotated by the expression quantitative trait loci (eQTL) and methylation quantitative trait loci (meQTL) analyses based on Genotype Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. We observed that the variants of rs10514231, rs1864182 and rs1864183 were associated with poor lung cancer survival (HR = 1.33, 95% CI = 1.07-1.65; HR = 1.43, 95% CI = 1.13-1.81; HR = 1.38, 95% CI = 1.14-1.68, respectively) and positively correlated with ATG10 expression (all p < 0.05) from GTEx and TCGA datasets. The elevated expression of ATG10 may predict shorter survival time in lung cancer patients in TCGA dataset (HR = 2.10, 95% CI = 1.33-3.29). Moreover, the variants of rs10514231 and rs1864182 were associated with the increased methylation levels of cg17942617 (meQTL), which in turn contributed to the elevated ATG10 expression and decreased survival time. Further functional assays revealed that ATG10 facilitated lung cancer cell proliferation and migration. Our findings suggest that eQTL/meQTL variations of ATG10 could influence lung cancer survival through regulating ATG10 expression. PMID- 27225308 TI - The significance of droughts for hyporheic dwellers: evidence from freshwater crayfish. AB - Freshwater biodiversity is globally threatened by various factors while severe weather events like long-term droughts may be substantially devastating. In order to remain in contact with the water or stay in a sufficiently humid environment at drying localities, the ability to withstand desiccation by dwelling in the hyporheic zone, particularly through vertical burrowing is crucial. We assessed the ability of three European native and five non-native crayfish as models to survive and construct vertical burrows in a humid sandy-clayey substrate under a simulated one-week drought. Three native species (Astacus astacus, A. leptodactylus, and Austropotamobius torrentium) suffered extensive mortalities. Survival of non-native species was substantially higher while all specimens of Cherax destructor and Procambarus clarkii survived. The native species and Pacifastacus leniusculus exhibited no ability to construct vertical burrows. Procambarus fallax f. virginalis and P. clarkii constructed bigger and deeper burrows than C. destructor and Orconectes limosus. In the context of predicted weather fluctuations, the ability to withstand desiccation through constructing vertical burrows into the hyporheic zone under drought conditions might play a significant role in the success of particular crayfish species, as well as a wide range of further hyporheic-dwelling aquatic organisms in general. PMID- 27225309 TI - Characterizing the malignancy and drug resistance of cancer cells from their membrane resealing response. AB - In this report, we showed that two tumor cell characteristics, namely the malignancy and drug-resistance status can be evaluated by their membrane resealing response. Specifically, membrane pores in a number of pairs of cancer and normal cell lines originated from nasopharynx, lung and intestine were introduced by nano-mechanical puncturing. Interestingly, such nanometer-sized holes in tumor cells can reseal ~2-3 times faster than those in the corresponding normal cells. Furthermore, the membrane resealing time in cancer cell lines exhibiting resistance to several leading chemotherapeutic drugs was also found to be substantially shorter than that in their drug-sensitive counterparts, demonstrating the potential of using this quantity as a novel marker for future cancer diagnosis and drug resistance detection. Finally, a simple model was proposed to explain the observed resealing dynamics of cells which suggested that the distinct response exhibited by normal, tumor and drug resistant cells is likely due to the different tension levels in their lipid membranes, a conclusion that is also supported by direct cortical tension measurement. PMID- 27225310 TI - A novel approach of chemical mechanical polishing for cadmium zinc telluride wafers. AB - A novel approach of chemical mechanical polishing (CMP) is developed for cadmium zinc telluride (CdZnTe or CZT) wafers. The approach uses environment-friendly slurry that consists of mainly silica, hydrogen peroxide, and citric acid. This is different from the previously reported slurries that are usually composed of strong acid, alkali, and bromine methanol, and are detrimental to the environment and operators. Surface roughness 0.5 nm and 4.7 nm are achieved for Ra and peak to-valley (PV) values respectively in a measurement area of 70 * 50 MUm(2), using the developed novel approach. Fundamental polishing mechanisms are also investigated in terms of X-ray photoelectron spectroscopy (XPS) and electrochemical measurements. Hydrogen peroxide dominates the passivating process during the CMP of CZT wafers, indicating by the lowest passivation current density among silica, citric acid and hydrogen peroxide solution. Chemical reaction equations are proposed during CMP according to the XPS and electrochemical measurements. PMID- 27225311 TI - A neuroendocrine role for chemerin in hypothalamic remodelling and photoperiodic control of energy balance. AB - Long-term and reversible changes in body weight are typical of seasonal animals. Thyroid hormone (TH) and retinoic acid (RA) within the tanycytes and ependymal cells of the hypothalamus have been implicated in the photoperiodic response. We investigated signalling downstream of RA and how this links to the control of body weight and food intake in photoperiodic F344 rats. Chemerin, an inflammatory chemokine, with a known role in energy metabolism, was identified as a target of RA. Gene expression of chemerin (Rarres2) and its receptors were localised within the tanycytes and ependymal cells, with higher expression under long (LD) versus short (SD) photoperiod, pointing to a physiological role. The SD to LD transition (increased food intake) was mimicked by 2 weeks of ICV infusion of chemerin into rats. Chemerin also increased expression of the cytoskeletal protein vimentin, implicating hypothalamic remodelling in this response. By contrast, acute ICV bolus injection of chemerin on a 12 h:12 h photoperiod inhibited food intake and decreased body weight with associated changes in hypothalamic neuropeptides involved in growth and feeding after 24 hr. We describe the hypothalamic ventricular zone as a key site of neuroendocrine regulation, where the inflammatory signal, chemerin, links TH and RA signaling to hypothalamic remodeling. PMID- 27225313 TI - Synthesis of trifluoromethylated isoxazoles and their elaboration through inter- and intra-molecular C-H arylation. AB - We report conditions for the preparation of a range of trifluoromethylated isoxazole building blocks through the cycloaddition reaction of trifluoromethyl nitrile oxide. It was found that controlling the rate (and therefore concentration) of the formation of the trifluoromethyl nitrile oxide was Critical for the preferential formation of the desired isoxazole products versus the furoxan dimer. Different conditions were optimised for both aryl- and alkyl substituted alkynes. In addition, the reactivity at the isoxazole 4-position has been briefly explored for these building blocks. Conditions for intermolecular C H arylation, lithiation and electrophile quench, and alkoxylation were all identified with brief substrate scoping that signifies useful tolerance to a range of functionalities. Finally, complementary processes for structural diversification through either intramolecular cyclisation or intermolecular cross coupling were developed. PMID- 27225314 TI - Nature-Inspired Design of Artificial Solar-to-Fuel Conversion Systems based on Copper Phosphate Microflowers. AB - Phosphates play significant roles in plant photosynthesis by mediating electron transportation and furnishing energy for CO2 reduction. Motivated by this, we demonstrate herein an artificial solar-to-fuel conversion system, involving versatile copper phosphate microflowers as template and titanium dioxide nanoparticles as host photocatalyst. The elaborate flowerlike architectures, coupled with a unique proton-reduction cycle from interchangeability of different species of orthophosphate ions, not only offer a 2D nanosheet platform for an optimal heterostructure interface but also effectively augment charge-carrier transfer, thereby contributing to enhanced photoactivity and hydrogen generation. These nature-inspired, phosphate-derived nanocomposites advance the synthesis of a large variety of functional materials, which holds great potential for photochemical, photoelectric and catalytic applications. PMID- 27225316 TI - Prenatal Fish Oil Supplementation and Allergy: 6-Year Follow-up of a Randomized Controlled Trial. AB - BACKGROUND AND OBJECTIVE: Evidence from randomized controlled trials in early infancy suggest that prenatal supplementation with Omega-3 (n-3) long-chain polyunsaturated fatty acids (LCPUFA) reduces the incidence of allergic disease characterized by an immunoglobulin E (IgE) response. We aimed to determine whether protective effects were evident in the 6-year-old offspring of women supplemented with n-3 rich fish oil during pregnancy. METHODS: Six-year follow-up of children (n = 706) with a family history of allergic disease from the Docosahexaenoic Acid to Optimize Mother Infant Outcome (DOMInO) trial. Women were randomly allocated to receive n-3 LCPUFA-rich fish oil capsules (800 mg/d docosahexaenoic acid DHA and 100mg/d eicosapentaenoic acid) or vegetable oil capsules (without n-3 LCPUFA). Allergic disease symptoms including eczema, wheeze, rhinitis, and rhino-conjunctivitis, were assessed using the International Study of Asthma and Allergies in Childhood questionnaire and sensitization to allergens was measured by skin prick test. RESULTS: There was no difference in the percentage of children with any IgE-associated allergic disease between the n 3 LCPUFA and control groups (116/367 [31.5%] vs 106/336 [31.5%]; adjusted relative risk, 1.04; 95% confidence interval, 0.82-1.33; P = .73). There was a reduction in the percentage of children sensitized to house dust mite Dermatophagoides farinae (49/367 [13.4%] vs 68/336 [20.3%]; adjusted relative risk, 0.67, 95% confidence interval, 0.44-1.00; P = .0495). CONCLUSIONS: Prenatal n-3 LCPUFA supplementation did not reduce IgE-associated allergic disease at 6 years of age. Secondary outcomes were suggestive of a protective effect of the intervention on the incidence of D. farinae sensitization. PMID- 27225315 TI - High Frequency of MKRN3 Mutations in Male Central Precocious Puberty Previously Classified as Idiopathic. AB - BACKGROUND/AIMS: Recently, loss-of-function mutations in the MKRN3 gene have been implicated in the etiology of familial central precocious puberty (CPP) in both sexes. We aimed to analyze the frequency of MKRN3 mutations in boys with CPP and to compare the clinical and hormonal features of boys with and without MKRN3 mutations. METHODS: This was a retrospective review of clinical, hormonal and genetic features of 20 male patients with idiopathic CPP evaluated at an academic medical center. The entire coding regions of MKRN3, KISS1 and KISS1R genes were sequenced. RESULTS: We studied 20 boys from 17 families with CPP. All of them had normal brain magnetic resonance imaging. Eight boys from 5 families harbored four distinct heterozygous MKRN3 mutations predicted to be deleterious for protein function, p.Ala162Glyfs*14, p.Arg213Glyfs*73, p.Arg328Cys and p.Arg365Ser. One boy carried a previously described KISS1-activating mutation (p.Pro74Ser). The frequency of MKRN3 mutations among these boys with idiopathic CPP was significantly higher than previously reported female data (40 vs. 6.4%, respectively, p < 0.001). Boys with MKRN3 mutations had typical clinical and hormonal features of CPP. Notably, they had later pubertal onset than boys without MKRN3 abnormalities (median age 8.2 vs. 7.0 years, respectively, p = 0.033). CONCLUSION: We demonstrated a high frequency of MKRN3 mutations in boys with CPP, previously classified as idiopathic, suggesting the importance of genetic analysis in this group. The boys with CPP due to MKRN3 mutations had classical features of CPP, but with puberty initiation at a borderline age. PMID- 27225312 TI - IgE and mast cells in host defense against parasites and venoms. AB - IgE-dependent mast cell activation is a major effector mechanism underlying the pathology associated with allergic disorders. The most dramatic of these IgE associated disorders is the fatal anaphylaxis which can occur in some people who have developed IgE antibodies to otherwise innocuous antigens, such as those contained in certain foods and medicines. Why would such a highly "maladaptive" immune response develop in evolution and be retained to the present day? Host defense against parasites has long been considered the only beneficial function that might be conferred by IgE and mast cells. However, recent studies have provided evidence that, in addition to participating in host resistance to certain parasites, mast cells and IgE are critical components of innate (mast cells) and adaptive (mast cells and IgE) immune responses that can enhance host defense against the toxicity of certain arthropod and animal venoms, including enhancing the survival of mice injected with such venoms. Yet, in some people, developing IgE antibodies to insect or snake venoms puts them at risk for having a potentially fatal anaphylactic reaction upon subsequent exposure to such venoms. Delineating the mechanisms underlying beneficial versus detrimental innate and adaptive immune responses associated with mast cell activation and IgE is likely to enhance our ability to identify potential therapeutic targets in such settings, not only for reducing the pathology associated with allergic disorders but perhaps also for enhancing immune protection against pathogens and animal venoms. PMID- 27225317 TI - Reducing Perinatal Mortality in Nepal Using Helping Babies Breathe. AB - BACKGROUND AND OBJECTIVE: Newborns are at the highest risk of dying around the time of birth, due to intrapartum-related complications. Our study's objective was to improve adherence to the Helping Babies Breathe (HBB) neonatal resuscitation protocol and reduce perinatal mortality by using a quality improvement cycle (QIC) in a tertiary hospital in Nepal. METHODS: The HBB QIC was implemented through a multifaceted approach, including the formation of quality improvement teams; development of quality improvement goals, objectives, and standards; HBB protocol training; weekly review meetings; daily skill checks; use of self-evaluation checklists; and refresher training. A cohort design, including a nested case-control study was used to measure changes in clinical outcomes and adherence to the resuscitation protocol through video recording, before and after implementation of the QIC. RESULTS: The intrapartum stillbirth rate decreased from 9.0 to 3.2 per thousand deliveries, and first-day mortality from 5.2 to 1.9 per thousand live births after intervention, demonstrating a reduction of approximately half in the odds of intrapartum stillbirth (adjusted odds ratio [OR] 0.46, 95% confidence interval [CI] 0.32-0.66) and first-day mortality (adjusted OR 0.51, 95% CI 0.31-0.83). After intervention, the odds of inappropriate use of suction and stimulation decreased by 87% (OR 0.13, 95% CI 0.09-0.17) and 62% (OR 0.38, 95% CI 0.29-0.49), respectively. Before intervention, none of the infants received bag-and-mask ventilation within 1 minute of birth, compared with 83.9% of infants after. CONCLUSIONS: The HBB QIC reduced intrapartum stillbirth and first-day neonatal mortality and led to use of suctioning and stimulation more frequently. The HBB QIC requires further testing in primary settings across Nepal. PMID- 27225318 TI - Imaging of cardiac sarcoidosis. AB - Sarcoidosis is a multisystem inflammatory disease. Cardiac involvement is described in up to 50% of the cases. The disease spectrum is wide and cardiac manifestations ranges from being asymptomatic to heart failure, arrhythmias and sudden cardiac death. The diagnosis of cardiac sarcoidosis can be challenging due to its non-specific nature and the focal involvement of the heart. In this review, we discuss the utility of a stepwise approach with multimodality cardiac imaging in the diagnosis and management of CS. PMID- 27225319 TI - Acute myocardial infarction. AB - Inflammatory processes after myocardial infarction have gained major interest in recent cardiovascular research. It is believed that not only the degree of cell recruitment to the heart plays a pivotal role in the quality of wound healing after myocardial infarction, but also the balance between different types or even subtypes of cells. It is also this balance which is thought to control key processes in tissue repair, such as apoptosis and neoangiogenesis. In this paper, we aim to review imaging strategies (with a special focus on nuclear molecular imaging strategies) that target cells and processes involved in postischemic inflammation and that have a high potential to be translated into clinic or that are already being used and evaluated in humans. PMID- 27225320 TI - Valence Band Splitting on Multilayer MoS2: Mixing of Spin-Orbit Coupling and Interlayer Coupling. AB - Understanding the origin of valence band splitting is important because it governs the unique spin and valley physics in few-layer MoS2. We explore the effects of spin-orbit coupling and interlayer coupling on few-layer MoS2 using first-principles methods. We find spin-orbit coupling has a major contribution to the valence band splitting at K in multilayer MoS2. In double-layer MoS2, the interlayer coupling leads to the widening of the gap between the already spin orbit split states. This is also the case for the bands of the K-point in bulk MoS2. In triple-layer MoS2, the strength of interlayer coupling of the spin-up channel becomes different from that of spin-down at K. This combined with spin orbit coupling results in the band splitting in two main valence bands at K. With the increase of pressure, this phenomenon becomes more obvious with a decrease of main energy gap in the splitting valence bands at the K valley. PMID- 27225321 TI - Use of bait containing triclabendazole against Fasciola gigantica in a herd of captive wild impala (Aepyceros melampus). AB - Although the efficacy of triclabendazole treatment against Fasciola gigantica has been shown before in cattle and buffaloes, there appears to be no published report on the efficacy of triclabendazole in impala or other antelope species. As part of a health monitoring programme at Mulungushi International Conference Centre, Lusaka, Zambia, a coprological examination was undertaken to investigate the helminthological status of captive impala (Aepyceros melampus). Of 39 fresh coprological samples, 46% contained F. gigantica. The source of infection was identified to be a fountain within the grounds of the conference centre. Lymnaea natalensis, collected from the study site, were induced to shed cercariae, and were thus confirmed as the snail intermediate host. In managing this disease, triclabendazole at 6 mg/kg was administered together with the feed bait. Water from the pond was drained; vegetation within it cleared and the pond allowed to dry for 1 week before water was replaced. Three weeks post-treatment, faecal examination revealed that the Fasciola had been cleared. To the best of our knowledge, this is a first case of Fasciola spp. infection reported in captive wild impala in Zambia and provides evidence that triclabendazole may be delivered to free-ranging antelope using medicated bait. PMID- 27225322 TI - Series of Multifluorine Substituted Oligomers for Organic Solar Cells with Efficiency over 9% and Fill Factor of 0.77 by Combination Thermal and Solvent Vapor Annealing. AB - We report the synthesis of a family of multifluorine substituted oligomers and the corresponding polymer that have the same backbones but different conjugation lengths and amounts of fluorine atoms on the backbone. The physical properties and photovoltaic performances of these materials were systematically investigated using optical absorption, charge mobility, atomic force microscopy, transmission electron microscopy, grazing incidence X-ray diffraction, resonant soft X-ray scattering methods, and photovoltaic devices. The power conversion efficiencies (PCEs) based on oligomers were much higher than that in the polymer. Moreover, the devices based on BIT6F and BIT10F, which have an axisymmetric electron deficient difluorobenzothiadiazole as the central unit, gave slightly higher PCEs than those with centrosymmetric electron-rich indacenodithiophene (IDT) as the central unit (BIT4F or BIT8F). Using proper solvent vapor annealing (SVA), particularly using thermal annealing (TA) followed by SVA, the device performance could be significantly improved. Notably, the best PCE of 9.1% with a very high FF of 0.76 was achieved using the medium-sized oligomer BIT6F with the optimized film morphology. This efficiency is the highest value reported for organic solar cells from small-molecules without rhodanine terminal group. More excitingly, devices from the shortest oligomer BIT4F showed an impressively high FF of 0.77 (the highest FF value reported for solution-processed small-molecule organic solar cells). These results indicate that photovoltaic performances of oligomers can be modulated through successive change in chain-length and fluorine atoms, alternating spatial symmetric core, and combined post-treatments. PMID- 27225323 TI - Radiofrequency ablation of atrial tachyarrhythmias in adults with tetralogy of Fallot - predictors of success and outcome. AB - BACKGROUND: Adults with tetralogy of Fallot experience atrial tachyarrhythmias; however, there are a few data on the outcomes of radiofrequency ablation. We examined the characteristics, outcome, and predictors of recurrence of atrial tachyarrhythmias after radiofrequency ablation in tetralogy of Fallot patients. Methods/results Retrospective data were collected from 2004 to 2013. In total, 56 ablations were performed on 37 patients. We identified two matched controls per case: patients with tetralogy of Fallot but no radiofrequency ablation and not known to have atrial tachyarrhythmias. Acute success was 98%. Left atrial arrhythmias increased in frequency over time. The mean follow-up was 41 months; 78% were arrhythmia-free. Number of cardiac surgeries, age, and presence of atrial fibrillation were predictors of recurrence. Lone cavo-tricuspid isthmus dependent flutter reduced the likelihood of atrial fibrillation. Right and left atria in patients with tetralogy of Fallot were larger in ablated cases than controls. NYHA class was worse in cases and improved after ablation; baseline status predicted death. Of matched non-ablated controls, a number of them had atrial fibrillation. These patients were excluded from the case-control study but analysed separately. Most of them had died during follow-up, whereas of the matched ablated cases all were alive and the majority in sinus rhythm. CONCLUSION: Patients with tetralogy of Fallot and atrial tachyarrhythmias have more dilated atria than those without atrial tachyarrhythmias. Radiofrequency ablation improves functional status. Left atrial ablation is more commonly required with repeat procedures. There is a high prevalence of atrial tachyarrhythmias, particularly atrial fibrillation, in patients with tetralogy of Fallot; early radiofrequency ablation may have a protective effect against this. PMID- 27225324 TI - Quasi-freestanding graphene on Ni(111) by Cs intercalation. AB - A possible approach to achieve quasi-freestanding graphene on a substrate for technological purpose is the intercalation of alkali metal atoms. Cs intercalation between graphene and Ni(111) therefore is investigated using density functional theory, incorporating van der Waals corrections. It is known that direct contact between graphene and Ni(111) perturbs the Dirac states. We find that Cs intercalation restores the linear dispersion characteristic of Dirac fermions, which agrees with experiments, but the Dirac cone is shifted to lower energy, i.e., the graphene sheet is n-doped. Cs intercalation therefore decouples the graphene sheet from the substrate except for a charge transfer. On the other hand, the spin polarization of Ni(111) does not extend through the intercalated atoms to the graphene sheet, for which we find virtually spin-degeneracy. PMID- 27225325 TI - Bayesian model selection in logistic regression for the detection of adverse drug reactions. AB - Spontaneous adverse event reports have a high potential for detecting adverse drug reactions. However, due to their dimension, the analysis of such databases requires statistical methods. In this context, disproportionality measures can be used. Their main idea is to project the data onto contingency tables in order to measure the strength of associations between drugs and adverse events. However, due to the data projection, these methods are sensitive to the problem of coprescriptions and masking effects. Recently, logistic regressions have been used with a Lasso type penalty to perform the detection of associations between drugs and adverse events. On different examples, this approach limits the drawbacks of the disproportionality methods, but the choice of the penalty value is open to criticism while it strongly influences the results. In this paper, we propose to use a logistic regression whose sparsity is viewed as a model selection challenge. Since the model space is huge, a Metropolis-Hastings algorithm carries out the model selection by maximizing the BIC criterion. Thus, we avoid the calibration of penalty or threshold. During our application on the French pharmacovigilance database, the proposed method is compared to well established approaches on a reference dataset, and obtains better rates of positive and negative controls. However, many signals (i.e., specific drug-event associations) are not detected by the proposed method. So, we conclude that this method should be used in parallel to existing measures in pharmacovigilance. Code implementing the proposed method is available at the following url: https://github.com/masedki/MHTrajectoryR. PMID- 27225326 TI - Gas barrier properties of bio-inspired Laponite-LC polymer hybrid films. AB - Bio-inspired Laponite (clay)-liquid crystal (LC) polymer composite materials with high clay fractions (>80%) and a high level of orientation of the clay platelets, i.e. with structural features similar to the ones found in natural nacre, have been shown to exhibit a promising behavior in the context of reduced oxygen transmission. Key characteristics of these bio-inspired composite materials are their high inorganic content, high level of exfoliation and orientation of the clay platelets, and the use of a LC polymer forming the organic matrix in between the Laponite particles. Each single feature may be beneficial to increase the materials gas barrier property rendering this composite a promising system with advantageous barrier capacities. In this detailed study, Laponite/LC polymer composite coatings with different clay loadings were investigated regarding their oxygen transmission rate. The obtained gas barrier performance was linked to the quality, respective Laponite content and the underlying composite micro- and nanostructure of the coatings. Most efficient oxygen barrier properties were observed for composite coatings with 83% Laponite loading that exhibit a structure similar to sheet-like nacre. Further on, advantageous mechanical properties of these Laponite/LC polymer composites reported previously give rise to a multifunctional composite system. PMID- 27225327 TI - Triphenylamine-Based Metal-Organic Frameworks as Cathode Materials in Lithium-Ion Batteries with Coexistence of Redox Active Sites, High Working Voltage, and High Rate Stability. AB - Through rational organization of two redox active building block, a triphenylamine-based metal-organic framework (MOF) material, Cu-TCA (H3TCA = tricarboxytriphenyl amine), was synthesized and applied as a cathode active material for the first time in lithium batteries. Cu-TCA exhibited redox activity both in the metal clusters (Cu(+)/Cu(2+)) and organic ligand radicals (N/N(+)) with separated voltage plateaus and a high working potential vs Li/Li(+) up to 4.3 V, comparing with the current commercial LiCoO2 cathode materials. The electrochemical behaviors of this MOF electrode material at different states of charge were carefully studied by cyclic voltammetry, X-ray photoelectron spectroscopy, and photoluminescence techniques. Long cycling stability of this MOF was achieved with an average Coulombic efficiency of 96.5% for 200 cycles at a 2 C rate. Discussing the electrochemical performances on the basis of capacity contributions from the metal clusters (Cu(+)/Cu(2+)) and organic ligands (N/N(+)) proposes an alternative mechanism of capacity loss for the MOF materials used in lithium batteries. This improved understanding will shed light on the designing principle of MOF-based cathode materials for their practical application in battery sciences. PMID- 27225328 TI - Predicting the effects of climate change on population connectivity and genetic diversity of an imperiled freshwater mussel, Cumberlandia monodonta (Bivalvia: Margaritiferidae), in riverine systems. AB - In the face of global climate change, organisms may respond to temperature increases by shifting their ranges poleward or to higher altitudes. However, the direction of range shifts in riverine systems is less clear. Because rivers are dendritic networks, there is only one dispersal route from any given location to another. Thus, range shifts are only possible if branches are connected by suitable habitat, and stream-dwelling organisms can disperse through these branches. We used Cumberlandia monodonta (Bivalvia: Unionoida: Margaritiferidae) as a model species to investigate the effects of climate change on population connectivity because a majority of contemporary populations are panmictic. We combined ecological niche models (ENMs) with population genetic simulations to investigate the effects of climate change on population connectivity and genetic diversity of C. monodonta. The ENMs were constructed using bioclimatic and landscape data to project shifts in suitable habitat under future climate scenarios. We then used forward-time simulations to project potential changes in genetic diversity and population connectivity based on these range shifts. ENM results under current conditions indicated long stretches of highly suitable habitat in rivers where C. monodonta persists; populations in the upper Mississippi River remain connected by suitable habitat that does not impede gene flow. Future climate scenarios projected northward and headwater-ward range contraction and drastic declines in habitat suitability for most extant populations throughout the Mississippi River Basin. Simulations indicated that climate change would greatly reduce genetic diversity and connectivity across populations. Results suggest that a single, large population of C. monodonta will become further fragmented into smaller populations, each of which will be isolated and begin to differentiate genetically. Because C. monodonta is a widely distributed species and purely aquatic, our results suggest that persistence and connectivity of stream-dwelling organisms will be significantly altered in response to future climate change. PMID- 27225329 TI - Electron-phonon coupling in hybrid lead halide perovskites. AB - Phonon scattering limits charge-carrier mobilities and governs emission line broadening in hybrid metal halide perovskites. Establishing how charge carriers interact with phonons in these materials is therefore essential for the development of high-efficiency perovskite photovoltaics and low-cost lasers. Here we investigate the temperature dependence of emission line broadening in the four commonly studied formamidinium and methylammonium perovskites, HC(NH2)2PbI3, HC(NH2)2PbBr3, CH3NH3PbI3 and CH3NH3PbBr3, and discover that scattering from longitudinal optical phonons via the Frohlich interaction is the dominant source of electron-phonon coupling near room temperature, with scattering off acoustic phonons negligible. We determine energies for the interacting longitudinal optical phonon modes to be 11.5 and 15.3 meV, and Frohlich coupling constants of ~40 and 60 meV for the lead iodide and bromide perovskites, respectively. Our findings correlate well with first-principles calculations based on many-body perturbation theory, which underlines the suitability of an electronic band structure picture for describing charge carriers in hybrid perovskites. PMID- 27225330 TI - Synthesis of Novel Chiral Sulfonamide-Bearing 1,2,4-Triazole-3-thione Analogs Derived from D- and L-Phenylalanine Esters as Potential Anti-Influenza Agents. AB - Novel enantiopure 1,2,4-trizole-3-thiones containing a benzensulfonamide moiety were synthesized via multistep reaction sequence starting with D-phenylalanine methyl ester and L-phenylalanine ethyl ester as a source of chirality. The chemical structures of all compounds were characterized by elemental analysis, UV, IR, (1) H NMR, (13) C NMR, 2D NMR (HETCOR), and mass spectral data. All compounds were tested in vitro antiviral activity against a broad variety of DNA and RNA viruses and in vitro cytostatic activity against murine leukemia (L1210), human T-lymphocyte (CEM) and human cervix carcinoma (HeLa) cell lines. Although enantiopure 1,2,4-triazole-3-thione analogs in (R) configuration emerged as promising anti-influenza A H1N1 subtype in Madin Darby canine kidney cell cultures (MDCK), their enantiomers exhibited no activity. Especially compounds , , , , and (EC50 : 6.5, 6.1, 2.4, 1.6, 1.7 MUM, respectively) had excellent activity against influenza A H1N1 subtype compared to the reference drug ribavirin (EC50 : 8.0 MUM). Several compounds have been found to inhibit proliferation of L1210, CEM and HeLa cell cultures with IC50 in the 12-53 MUM range. Compound and in (R) configuration were the most active compounds (IC50 : 12-22 MUM for and IC50 : 19-23 MUM for ). Chirality 28:495-513, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27225331 TI - Physical-Chemical Properties of the Chiral Fungicide Fenamidone and Strategies for Enantioselective Crystallization. AB - Thermodynamic and kinetic parameters are of prime importance for designing crystallization processes. In this article, Preferential Crystallization, as a special approach to carry out enantioselective crystallization, is described to resolve the enantiomers of the chiral fungicide fenamidone. In preliminary investigations the melting behavior and solid-liquid equilibria in the presence of solvents were quantified. The analyses revealed a stable solid phase behavior of fenamidone in the applied solvents. Based on the results obtained, a two-step crystallization route was designed and realized capable of providing highly pure enantiomers. An initial Preferential Crystallization of the racemate was performed prior to crystallizing the target enantiomer preferentially out of the enriched mother liquor. Chirality 28:514-520, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27225332 TI - Aza-Bambusurils En Route to Anion Transporters. AB - Previous calculations of anion binding with various bambusuril analogs predicted that the replacement of oxygen by nitrogen atoms to produce semiaza bambus[6]urils would award these new cavitands with multiple anion binding properties. This study validates the hypothesis by efficient synthesis, crystallography, thermogravimetric analysis and calorimetry. These unique host molecules are easily accessible from the corresponding semithio-bambusurils in a one-pot reaction, which converts a single anion receptor into a potential anion channel. Solid-state structures exhibit simultaneous accommodation of three anions, linearly positioned within the cavity along the main symmetry axis. The ability to hold anions at a short distance of about 4 A is reminiscent of natural chloride channels in E. coli, which exhibit similar distances between their adjacent anion binding sites. The calculated transition-state energy for double anion movement through the channel suggests that although these host-guest complexes are thermodynamically stable they enjoy high kinetic flexibility to render them efficient anion channels. PMID- 27225333 TI - Incidence of and risk factors for glaucoma in lost-to-follow-up normal-tension glaucoma suspect patients. AB - BACKGROUND: To investigate the incidence and risk factors of glaucoma in normal tension glaucoma (NTG) suspect patients who had been lost-to-follow-up for at least 24 months. METHODS: Seventy-two eyes of 72 NTG suspect patients who returned to the hospital after at least 24 months of follow-up loss were enrolled in this study between January 2009 and June 2013. The data were collected retrospectively. The incidence of glaucoma was investigated using a comprehensive glaucoma evaluation in lost-to-follow-up NTG suspect patients. The patients were classified into the glaucoma group, who developed glaucoma during the study period, and the glaucoma suspect group, who did not, to analyse the risk factors for glaucoma. RESULTS: The number of patients who developed glaucoma was 7 (9.7 %) out of the 72 NTG suspect patients who had been mean lost-to-follow-up for 44 months. The rate of progression from suspected to glaucoma was 2.6 %/year. In the glaucoma group, the baseline intraocular pressure (IOP) was 18.43 +/- 2.44 mmHg, and the average retinal nerve fiber layer (RNFL) thickness was 78.14 +/- 7.60 MUm; in the glaucoma suspect group, the baseline IOP was 14.95 +/- 2.47 mmHg, and the average RNFL thickness was 92.55 +/- 7.65 MUm. The study results showed that the glaucoma group had higher baseline IOP and a thinner average RNFL (p = 0.003; p < 0.001). The results of the multivariable logistic regression analysis showed that the risk factors for glaucoma were high baseline IOP (OR = 1.63; p = 0.037) and a thin average RNFL (OR = 0.841; p = 0.004). CONCLUSIONS: The incidence of glaucoma in the lost-to-follow-up NTG suspect patients was 9.7 % for approximately 44 months, at a rate of 2.6 %/year. The risk factors for glaucoma in these patients were high baseline IOP and a thin average RNFL. PMID- 27225334 TI - Pharmacokinetics and Pharmacodynamics of Omarigliptin, a Once-Weekly Dipeptidyl Peptidase-4 (DPP-4) Inhibitor, After Single and Multiple Doses in Healthy Subjects. AB - The pharmacokinetics (PK) and pharmacodynamics (PD) of omarigliptin, a novel once weekly DPP-4 inhibitor, were assessed following single and multiple doses in healthy subjects. Absorption was rapid, and food did not influence single-dose PK. Accumulation was minimal, and steady state was reached after 2 to 3 weeks. Weekly (area under the curve) AUC and Cmax displayed dose proportionality within the dose range studied at steady state. The average renal clearance of omarigliptin was ~2 L/h. DPP-4 inhibition ranged from ~77% to 89% at 168 hours following the last of 3 once-weekly doses over the dose range studied. Omarigliptin resulted in ~2-fold increases in weighted average postprandial active GLP-1. Omarigliptin acts by stabilizing active GLP-1, which is consistent with its mechanism of action as a DPP-4 inhibitor. Administration of omarigliptin was generally well tolerated in healthy subjects, and both the PK and PD profiles support once-weekly dosing. A model-based assessment of QTc interval risk from the single ascending dose study predicted a low risk of QTc prolongation within the likely clinical dose range, a finding later confirmed in a thorough QT trial. PMID- 27225335 TI - Associations of Infant Subcutaneous Fat Mass with Total and Abdominal Fat Mass at School-Age: The Generation R Study. AB - BACKGROUND: Skinfold thickness enables the measurement of overall and regional subcutaneous fatness in infancy and may be associated with total and abdominal body fat in later childhood. We examined the associations of subcutaneous fat in infancy with total and abdominal fat at school-age. METHODS: In a population based prospective cohort study among 821 children, we calculated total subcutaneous fat (sum of biceps, triceps, suprailiacal, and subscapular skinfold thicknesses) and central-to-total subcutaneous fat ratio (sum of suprailiacal and subscapular skinfold thicknesses/total subcutaneous fat) at 1.5 and 24 months. At 6 years, we measured fat mass index (total fat/height(3) ), central-to-total fat ratio (trunk fat/total fat), and android-to-gynoid fat ratio (android fat/gynoid fat) by dual-energy X-ray absorptiometry and preperitoneal fat mass area by abdominal ultrasound. RESULTS: Central-to-total subcutaneous fat ratio at 1.5 months was positively associated with fat mass index and central-to-total fat ratio at 6 years, whereas both total and central-to-total subcutaneous fat ratio at 24 months were positively associated with all childhood adiposity measures. A 1-standard-deviation scores higher total subcutaneous fat at 24 months was associated with an increased risk of childhood overweight (odds ratio 1.70, 95% confidence interval 1.36, 2.12). These associations were weaker than those for body mass index and stronger among girls than boys. CONCLUSIONS: Subcutaneous fat in infancy is positively associated with total and abdominal fat at school-age. Our results also suggest that skinfold thicknesses add little value to estimate later body fat, as compared with body mass index. PMID- 27225336 TI - Dienogest compared with gonadotropin-releasing hormone agonist after conservative surgery for endometriosis. AB - AIM: Although there are various hormone therapies, including gonadotropin releasing hormone agonist, danazol, levonorgestrel-releasing intrauterine system, dienogest, and low-dose estrogen progestin, no consensus opinion has been reached in terms of which medication should be used and for how long it should be administered. We aimed to determine whether dienogest or goserelin is the better postoperative therapy to prevent recurrence of endometriosis. METHODS: A prospective cohort randomized study were conducted, including 198 patients diagnosed as having endometriosis. A total of 111 patients were randomly assigned into two groups: the dienogest-administered group (n = 56) and the goserelin administered group (n = 55). Patients were followed for 24 months after laparoscopic surgery. Those who gave consent but desired no postoperative therapy were assigned to the non-treatment group (n = 79). Recurrence, side-effects, degrees of menstrual pain and chronic pelvic pain measured by the Visual Analogue Scale were compared among the three groups: the dienogest, goserelin, and non treatment groups. RESULTS: No significant difference was observed in the postoperative recurrence rate between the dienogest and goserelin groups. No significant difference was found in the recurrence rate between the goserelin group and non-treatment group; however, a significant difference was found in the recurrence rate between the dienogest group and the non-treatment group (P = 0.027). Menstrual pain and chronic pelvic pain were significantly improved in both treatment groups. Side-effects were markedly observed in the goserelin group as compared with the dienogest group. CONCLUSION: Dienogest is available for prolonged administration of more than 6 months, so it is more useful than goserelin, which is available only for short-term administration. PMID- 27225337 TI - Quantifying benefit-risk preferences for new medicines in rare disease patients and caregivers. AB - BACKGROUND: Rare disease patients and caregivers face uncommon, serious, debilitating conditions often characterised by poor prognosis and limited treatment options. This study aimed to explore what they consider of value when choosing between hypothetical therapeutic options and to quantify both their benefit-risk preferences and the influence of disease context. METHODS: A mixed methods survey with patients and caregivers was conducted in the United Kingdom across a range of rare diseases. Discrete-choice experiments that compared hypothetical treatment profiles of benefits and risks were used to measure respondent preferences across a set of seven attributes related to health outcomes, safety, and process of care. Bespoke questions on current disease management and the joint use of the 12-item WHODAS 2.0 questionnaire and of two Likert scales capturing self- and proxy-assessed disease-induced threat to life and impairment were implemented to describe disease context. Additionally, qualitative insights on the definitions of value and risk were collected from respondents. RESULTS: Final study sample included 721 patients and 152 informal caregivers, across 52 rare diseases. When choosing between hypothetical novel treatments for rare diseases, respondents attributed most importance to drug response, risk of serious side effects, and the ability to conduct usual activities while on treatment. In contrast, attributes related to treatment modalities were the least important. Respondents expressed a willingness to accept risks in hopes of finding some benefit, such as a higher chance of drug response or greater health improvement potential. Increasing disease severity, impairment or disability, and the lack of effective therapeutic options were shown to raise significantly the willingness to gain benefit through increased risk. CONCLUSIONS: This is the first study performing a quantitative discrete choice experiment amongst patients and caregivers across 52 rare conditions. It enables a more detailed understanding of the relationship between disease context, treatment attributes and the degree of risk respondents are willing to take to gain a specific degree of benefit. Researchers of novel therapeutics for rare diseases should be encouraged to invest in preference elicitation studies to generate rigorous patient evidence and specific regulatory guidance should be issued to acknowledge their importance and their use in marketing authorisations. PMID- 27225338 TI - A double-blind randomized clinical trial comparing different doses of magnesium in cardioplegic solution for prevention of atrial fibrillation after coronary artery bypass graft surgery. AB - AIMS: This study aims to compare different doses of magnesium administered via cardioplegic solutions to prevent atrial fibrillation (AF) after coronary artery bypass graft (CABG) surgery. METHODS: A total of 120 patients who were scheduled for elective CABG surgery using cardiopulmonary bypass were enrolled in this double-blind, randomized clinical trial. After fulfilling the inclusion criteria, they were randomly allocated into three groups (A, B, and C). Patients in groups A, B, and C received 60, 80, and 100 mg/kg of magnesium sulfate via cardioplegic solutions during aortic cross-clamp, respectively. Postoperative AF was assessed by continuous ECG monitoring during 3 days after surgery. Also serum magnesium, potassium, and calcium levels were assessed during the study period. RESULTS: The findings revealed significant differences in four point measurements of serum magnesium level after surgery (P<.001). In particular, it was observed that 10 (26.3%) patients in group A, 4 (10%) patients in group B, and 2 (5.4%) patients in group C had AF after surgery. This indicates patients receiving magnesium at doses of 80 and 100 mg/kg had lower rates of AF occurrence than those receiving 60 mg/kg dose of magnesium (P=.02). Additionally, no significant difference was found in serum calcium and potassium concentration between the three groups throughout the study period. CONCLUSION: Magnesium administration via the cardioplegic solution during aortic cross-clamping at doses of 80 and 100 mg/kg can reduce the risk of AF occurrence after CABG compared to the dose of 60 mg/kg. Considering the lower rate of AF incidence and shorter length of ICU stay in patients receiving 100 mg/kg of magnesium, it seems reasonable to administer 100 mg/kg magnesium during aortic cross-clamp to prevent postoperative AF. PMID- 27225339 TI - Loxoprofen-induced interstitial pneumonia: a case report. AB - BACKGROUND: Loxoprofen is a nonsteroidal anti-inflammatory drug used in the treatment of many diseases. However, there are no case reports about loxoprofen induced pneumonia. We have encountered a rare case of loxoprofen-induced pneumonia. CASE PRESENTATION: We report the case of a 71-year-old Japanese woman who was initially treated with loxoprofen for fever. She was admitted to our hospital because of worsening of her symptoms, including fever and dyspnea. Her symptoms improved after treatment with ceftriaxone. Seven days after admission, she again developed high fever. She was again treated with loxoprofen and levofloxacin. However, acute respiratory failure developed after initiation of loxoprofen treatment. Chest computed tomography showed peribronchovascular consolidation. She was diagnosed with loxoprofen-induced pneumonia for which she was administered steroids. After treatment, her dyspnea and radiological findings improved. CONCLUSIONS: The findings in this case report reveal an association between treatment with a nonsteroidal anti-inflammatory drug and pneumonia. This rare case was diagnosed after accidental retreatment with loxoprofen. This is the first report of loxoprofen-induced pneumonia. PMID- 27225340 TI - Whisker experience-dependent mGluR signaling maintains synaptic strength in the mouse adolescent cortex. AB - Sensory experience-dependent plasticity in the somatosensory cortex is a fundamental mechanism of adaptation to the changing environment not only early in the development but also in adolescence and adulthood. Although the mechanisms underlying experience-dependent plasticity during early development have been well documented, the corresponding understanding in the mature cortex is less complete. Here, we investigated the mechanism underlying whisker deprivation induced synaptic plasticity in the barrel cortex in adolescent mice. Layer 4 (L4) to L2/3 excitatory synapses play a crucial role for whisker experience-dependent plasticity in rodent barrel cortex and whisker deprivation is known to depress synaptic strength at L4-L2/3 synapses in adolescent and adult animals. We found that whisker deprivation for 5 days or longer decreased the presynaptic glutamate release probability at L4-L2/3 synapses in the barrel cortex in adolescent mice. This whisker deprivation-induced depression was restored by daily administration of a positive allosteric modulator of the type 5 metabotropic glutamate receptor (mGluR5). On the other hand, the administration of mGluR5 antagonists reproduced the effect of whisker deprivation in whisker-intact mice. Furthermore, chronic and selective suppression of inositol 1,4,5-trisphosphate (IP3 ) signaling in postsynaptic L2/3 neurons decreased the presynaptic release probability at L4 L2/3 synapses. These findings represent a previously unidentified mechanism of cortical plasticity, namely that whisker experience-dependent mGluR5-IP3 signaling in the postsynaptic neurons maintains presynaptic function in the adolescent barrel cortex. PMID- 27225341 TI - Gender difference in the association between food away-from-home consumption and body weight outcomes among Chinese adults. AB - OBJECTIVE: The present study aimed to explore the associations between food away from-home (FAFH) consumption and body weight outcomes among Chinese adults. DESIGN: FAFH was defined as food prepared at restaurants and the percentage of energy from FAFH was calculated. Measured BMI and waist circumference (WC) were used as body weight outcomes. Quantile regression models for BMI and WC were performed separately by gender. SETTING: Information on demographic, socio economic, diet and health parameters at individual, household and community levels was collected in twelve provinces of China. SUBJECTS: A cross-sectional sample of 7738 non-pregnant individuals aged 18-60 years from the China Health and Nutrition Survey 2011 was analysed. RESULTS: For males, quantile regression models showed that percentage of energy from FAFH was associated with an increase in BMI of 0.01, 0.01, 0.01, 0.02, 0.02 and 0.03 kg/m2 at the 5th, 25th, 50th, 75th, 90th and 95th quantile, and an increase in WC of 0.04, 0.06, 0.06, 0.04, 0.06, 0.05 and 0.07 cm at the 5th, 10th, 25th, 50th, 75th, 90th and 95th quantile. For females, percentage of energy from FAFH was associated with 0.01, 0.01, 0.01 and 0.02 kg/m2 increase in BMI at the 10th, 25th, 90th and 95th quantile, and with 0.05, 0.04, 0.03 and 0.03 cm increase in WC at the 5th, 10th, 25th and 75th quantile. CONCLUSIONS: Our findings suggest that FAFH consumption is relatively more important for BMI and WC among males rather than females in China. Public health initiatives are needed to encourage Chinese adults to make healthy food choices when eating out. PMID- 27225342 TI - NES-REBS: A novel nuclear export signal prediction method using regular expressions and biochemical properties. AB - A nuclear export signal (NES) is a protein localization signal, which is involved in binding of cargo proteins to nuclear export receptor, thus contributes to regulate localization of cellular proteins. Consensus sequences of NES have been used to detect NES from protein sequences, but suffer from poor predictive power. Some recent peering works were proposed to use biochemical properties of experimental verified NES to refine NES candidates. Those methods can achieve high prediction rates, but their execution time will become unacceptable for large-scale NES searching if too much properties are involved. In this work, we developed a novel computational approach, named NES-REBS, to search NES from protein sequences, where biochemical properties of experimental verified NES, including secondary structure and surface accessibility, are utilized to refine NES candidates obtained by matching popular consensus sequences. We test our method by searching 262 experimental verified NES from 221 NES-containing protein sequences. It is obtained that NES-REBS runs in 2-3[Formula: see text]mins and performs well by achieving precision rate 47.2% and sensitivity 54.6%. PMID- 27225343 TI - Allergic reactions to meglumine antimoniate while treating cutaneous leishmaniasis. PMID- 27225344 TI - Environmental Effects on Reactive Oxygen Species Detection-Learning from the Phagosome. AB - SIGNIFICANCE: Reactive oxygen species (ROS) fulfill numerous roles in biology ranging from signal transduction to the induction of cell death. To advance our understanding of these sometimes contradictory roles, quantitative, specific, and sensitive ROS measurements are required. RECENT ADVANCES: Several organic or genetically encoded probes were successfully developed for ROS detection. CRITICAL ISSUES: In some cases, ROS production occurs in a harsh environment such as low pH or high concentration of proteases. However, the ROS sensor may be sensitive to such environmental conditions and therefore becomes inaccurate. While the sensitivity of many ROS sensors to pH is known, many other environmental conditions remain unexplored. This article illustrates the interference between ROS sensors and their environment using the phagosome as an example. In the phagosome, pH changes, high concentration of ROS, and the presence of many proteases generate a hostile and rapidly changing environment. FUTURE DIRECTIONS: Difficulties due to cell movement and continuous formation of new phagosomes can be reduced by ratio measurements, if appropriate dyes are identified. For detection in live cells and subcellular locations, fluorescent proteins (FPs) offer several advantages and are used to create biosensors for ROS. Some FPs are directly sensitive to certain ROS as shown here. Although this may compromise their use in an environment with high levels of ROS, it can also be exploited for ROS measurement directly with the FPs themselves. For all types of ROS detection, we suggest a set of basic guidelines for testing the environmental sensitivity of an ROS sensor. Antioxid. Redox Signal. 25, 564-576. PMID- 27225345 TI - Expression of PD-L1 Identifies a Subgroup of More Aggressive Non-Small Cell Carcinomas of the Lung. AB - OBJECTIVES: In light of various trials showing impressive response rates when treating non-small cell lung cancer (NSCLC) patients with anti PD-1/PD-L1 antibodies, the currently equivocal role of PD-L1 expression in NSCLC is in need of further clarification. METHODS: We therefore analyzed the expression of PD-L1 on 293 well-documented NSCLC cases and correlated the results with clinical, histopathological and immunohistochemical characteristics. RESULTS: The expression of PD-L1 on NSCLC was a poor prognostic factor for patients with nodal negative adenocarcinoma (ACA) and, independent of other covariates, in tumors with increased CD8+ tumor-infiltrating lymphocytes (TILs). Expression of PD-L1 was more commonly seen in ACA and in male patients with a past and current smoking history. Finally, PD-L1+ TILs were more often found in squamous and large cell carcinomas. CONCLUSIONS: Should the expression of PD-L1 be on the verge of becoming an additional biomarker for routine diagnostics in NSCLC, our findings will provide important further insight and could contribute towards more effectively stratifying patients. These results may single out certain patient groups with a potential for increased benefit from anti PD-1/PD-L1 treatment strategies and should be considered in future trials. PMID- 27225346 TI - Accuracy of cone beam computed tomography in following simulated autogenous graft resorption in maxillary sinus augmentation procedure: an ex vivo study. AB - OBJECTIVES: Maxillary sinus augmentation is a well-documented procedure with long term success in implant dentistry. Assessing graft volume changes over time is crucial, since resorption remains a major concern. CBCT is commonly employed to assess the quantity and quality of the available bone at the implant receptor site. However, its applicability in following graft volume changes is yet to be determined. The study aimed to assess CBCT accuracy in following simulated graft resorption ex vivo. METHODS: 4 differently sized autogenous bone blocks harvested from the zygomatic buttress were bilaterally placed in the maxillary sinus of 12 human cadavers. The Accuitomo (J Morita, Kyoto, Japan) CBCT system was employed to scan each one of the 4 grafts in each of the 12 cadavers using identical settings. Gold standard graft measurements were obtained using micro-CT. One independent observer assessed the volume of each graft on CBCT images twice. Intraobserver reliability was assessed using Cohen's kappa and one-sample t-test was used to compare CBCT with micro-CT volumetric measurements. RESULTS: The mean micro-CT graft volumes were 97.12 +/- 1.4, 197.32 +/- 3.4, 361.41 +/- 4.2 and 1040.11 +/- 3.2 mm3 for Grafts 1-4, respectively, and the mean CBCT volumes of the corresponding grafts were 115.39 +/- 7.01, 205.97 +/- 9.91, 404.05 +/- 16.81 and 1138.04 +/- 20.98 mm3. CBCT measurements were statistically significantly different from micro-CT measurements (p = 0.001). Intraobserver reliability was good (r = 0.78). CONCLUSIONS: In every case, CBCT overestimated the maxillary graft volume in comparison with micro-CT. However, the measurement differences were limited and might not influence clinical performance. PMID- 27225347 TI - Social perception of morbidity in facial nerve paralysis. AB - BACKGROUND: There are many patient-based and clinician-based scales measuring the severity of facial nerve paralysis and the impact on quality of life, however, the social perception of facial palsy has received little attention. The purpose of this pilot study was to measure the consequences of facial paralysis on selected domains of social perception and compare the social impact of paralysis of the different components. METHOD: Four patients with typical facial palsies (global, marginal mandibular, zygomatic/buccal, and frontal) and 1 control were photographed. These images were each shown to 100 participants who subsequently rated variables of normality, perceived distress, trustworthiness, intelligence, interaction, symmetry, and disability. Statistical analysis was performed to compare the results among each palsy. RESULTS: Paralyzed faces were considered less normal compared to the control on a scale of 0 to 10 (mean, 8.6; 95% confidence interval [CI] = 8.30-8.86) with global paralysis (mean, 3.4; 95% CI = 3.08-3.80) rated as the most disfiguring, followed by the zygomatic/buccal (mean, 6.0; 95% CI = 5.68-6.37), marginal (mean, 6.5; 95% CI = 6.08-6.86), and then temporal palsies (mean, 6.9; 95% CI = 6.57-7.21). Similar trends were seen when analyzing these palsies for perceived distress, intelligence, and trustworthiness, using a random effects regression model. CONCLUSION: Our sample suggests that society views paralyzed faces as less normal, less trustworthy, and more distressed. Different components of facial paralysis are worse than others and surgical correction may need to be prioritized in an evidence-based manner with social morbidity in mind. (c) 2016 Wiley Periodicals, Inc. Head Neck 38:1158 1163, 2016. PMID- 27225348 TI - The performance of risk prediction models for pre-eclampsia using routinely collected maternal characteristics and comparison with models that include specialised tests and with clinical guideline decision rules: a systematic review. AB - BACKGROUND: Risk prediction models may be valuable to identify women at risk of pre-eclampsia to guide aspirin prophylaxis in early pregnancy. OBJECTIVE: To assess the performance of 'simple' risk models for pre-eclampsia that use routinely collected maternal characteristics; compare with 'specialised' models that include specialised tests; and to guideline recommended decision rules. SEARCH STRATEGY: MEDLINE, Embase and PubMed were searched to June 2014. SELECTION CRITERIA: We included studies that developed or validated pre-eclampsia risk models using maternal characteristics with or without specialised tests and reported model performance. DATA COLLECTION AND ANALYSIS: We extracted data on study characteristics; model predictors, validation and performance including area under the curve (AUC), sensitivity and specificity. MAIN RESULTS: We identified 29 studies that developed 70 models including 22 simple models. Studies included 151-9149 women with a pre-eclampsia prevalence of 1.2-9.5%. No single predictor was included in all models. Four simple models were externally validated, with a model using parity, pre-eclampsia history, race, chronic hypertension and conception method to predict early-onset pre-eclampsia achieving the highest AUC (0.76, 95% CI 0.74-0.77). Nine studies comparing simple versus specialized models in the same population reported AUC favouring specialised models. A simple model achieved fewer false positives than a guideline recommended risk factor list, but sensitivity to classify risk for aspirin prophylaxis was not assessed. CONCLUSION: Validated simple pre-eclampsia risk models demonstrate good risk discrimination that can be improved with specialised tests. Further research is needed to determine their clinical value to guide aspirin prophylaxis compared with decision rules. TWEETABLE ABSTRACT: Pre eclampsia risk models using maternal factors show good risk discrimination to guide aspirin prophylaxis. PMID- 27225350 TI - Temporary undernutrition during early gestation, corpora lutea morphometrics, ovarian progesterone secretion and embryo survival in gilts. AB - The present study reports effects of severe undernutrition on luteal function and pregnancy in pigs. Gilts were inseminated and either fasted on Day 10 and 11 after conception (n=11) or fully fed throughout (n=10). Fasting did not affect LH or progesterone pulsatile secretion pattern on Day 11 in samples taken from blood vessels draining an ovary. Ultrasonographic measurements of the size of the corpora lutea did not show any effect of fasting either. However, fasted gilts had 10 to 30% lower systemic progesterone from Day 12 through Day 15 after conception (P<0.05). All gilts farrowed, but fasted gilts had fewer born piglets than fully fed gilts (8.8+/-0.8 vs 10.9+/-0.5 respectively; P<0.05). In conclusion, fasting during embryo elongation can compromise embryonic survival by affecting ovarian function in the days after fasting, without having an immediate effect on LH secretion and progesterone output by the ovaries. PMID- 27225351 TI - The effect of Schisandra chinensis extracts on depression by noradrenergic, dopaminergic, GABAergic and glutamatergic systems in the forced swim test in mice. AB - Schisandra chinensis (Turcz.) Baill., as a Chinese functional food, has been widely used in neurological disorders including insomnia and Alzheimer's disease. The treatment of classical neuropsychiatric disorder depression is to be developed from Schisandra chinensis. The antidepressant-like effects of the Schisandra chinensis extracts (SCE), and their probable involvement in the serotonergic, noradrenergic, dopaminergic, GABAergic and glutamatergic systems were investigated by the forced swim test (FST). Acute administration of SCE (600 mg kg(-1), i.g.), a combination of SCE (300 mg kg(-1), i.g.) and reboxetine (a noradrenalin reuptake inhibitor, 2.5 mg kg(-1), i.p.) or imipramine (a TCA, 2 mg kg(-1), i.p.) reduced the immobility time in the FST. Pretreatment with N-(2 chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4, a selective noradrenergic neurotoxin, 50 mg kg(-1), i.p., 4 days), haloperidol (a non selective D2 receptor antagonist, 0.2 mg kg(-1), i.p.), SCH 23390 (a selective D1 receptor antagonist, 0.03 mg kg(-1), i.p.), bicuculline (a competitive GABA antagonist, 4 mg kg(-1), i.p.) and N-methyl-d-aspartic acid (NMDA, an agonist at the glutamate site, 75 mg kg(-1), i.p.) effectively reversed the antidepressant like effect of SCE (600 mg kg(-1), i.g.). However, p-chlorophenylalanine (pCPA, an inhibitor of 5-HT synthesis, 100 mg kg(-1), i.p., 4 days,) did not eliminate the reduced immobility time induced by SCE (600 mg kg(-1), i.g.). Moreover, the treatments did not change the locomotor activity. Altogether, these results indicated that SCE produced antidepressant-like activity, which might be mediated by the modification of noradrenergic, dopaminergic, GABAergic and glutamatergic systems. PMID- 27225349 TI - A missense mutation in TUBD1 is associated with high juvenile mortality in Braunvieh and Fleckvieh cattle. AB - BACKGROUND: Haplotypes with reduced or missing homozygosity may harbor deleterious alleles that compromise juvenile survival. A scan for homozygous haplotype deficiency revealed a short segment on bovine chromosome 19 (Braunvieh haplotype 2, BH2) that was associated with high juvenile mortality in Braunvieh cattle. However, the molecular genetic underpinnings and the pathophysiology of BH2 remain to be elucidated. RESULTS: The frequency of BH2 was 6.5 % in 8,446 Braunvieh animals from the national bovine genome databases. Both perinatal and juvenile mortality of BH2 homozygous calves were higher than the average in Braunvieh cattle resulting in a depletion of BH2 homozygous adult animals (P = 9.3x10(-12)). The analysis of whole-genome sequence data from 54 Braunvieh animals uncovered a missense mutation in TUBD1 (rs383232842, p.H210R) that was compatible with recessive inheritance of BH2. The availability of sequence data of 236 animals from diverse bovine populations revealed that the missense mutation also segregated at a low frequency (1.7 %) in the Fleckvieh breed. A validation study in 37,314 Fleckvieh animals confirmed high juvenile mortality of homozygous calves (P = 2.2x10(-15)). Our findings show that the putative disease allele is located on an ancestral haplotype that segregates in Braunvieh and Fleckvieh cattle. To unravel the pathophysiology of BH2, six homozygous animals were examined at the animal clinic. Clinical and pathological findings revealed that homozygous calves suffered from chronic airway disease possibly resulting from defective cilia in the respiratory tract. CONCLUSIONS: A missense mutation in TUBD1 is associated with high perinatal and juvenile mortality in Braunvieh and Fleckvieh cattle. The mutation is located on a common haplotype likely originating from an ancient ancestor of Braunvieh and Fleckvieh cattle. Our findings demonstrate for the first time that deleterious alleles may segregate across closed cattle breeds without recent admixture. Homozygous calves suffer from chronic airway disease resulting in poor growth performance and high juvenile mortality. The respiratory manifestations resemble key features of diseases resulting from impaired function of airway cilia. PMID- 27225352 TI - Experiences of Turkish survivors of breast cancer: Neuman systems model perspective. PMID- 27225355 TI - Association Between Hypovitaminosis D in Elderly Women and Long- and Short-Term Mortality-Results from the Osteoporotic Prospective Risk Assessment Cohort. AB - OBJECTIVES: To investigate the association between low vitamin D levels (<50 nmol/L) and 10-year mortality in women aged 75 and older. DESIGN: Prospective with 15 years of follow-up. SETTING: Malmo, Sweden. PARTICIPANTS: Population based cohort of 75-year-old women (N = 1,044). MEASUREMENTS: Serum 25 hydroxyvitamin D (25(OH)D) levels at age 75 (n = 1,011), 80 (n = 642), and 85 (n = 348) were categorized as low (<50 nmol/L), intermediate (50-75 nmol/L) and high (>75 nmol/L) at all ages. Hazard ratios (HRs) for all-cause mortality between ages 75 and 90 were calculated according to 25(OH)D category. RESULTS: Between ages 80 and 90, all-cause mortality (HR = 1.8, 95% confidence interval (CI) = 1.3 2.4, P < .001; adjusted for comorbidities (aHR) = 1.9, 95% CI = 1.4-2.6, P < .001) was significantly higher in women with low 25(OH)D levels than in those with high levels. Osteoporosis had the greatest effect on mortality, but even after excluding women with osteoporotic fracture during the risk of dying associated with low 25(OH)D remained greater (HR = 1.8, 95% CI = 1.2-2.7, P = .002; aHR = 1.7, 95% CI = 1.2-2.5, P = .006). CONCLUSION: In this observational study of women aged 75 and older, 25(OH)D levels of less than 50 nmol/L were associated with greater all-cause mortality for up to 10 years. This difference was at least partially independent of comorbidities and fracture, indicating that low 25(OH)D not only is an indicator of impaired health, but also plays a role in disease outcome. PMID- 27225354 TI - Racial Disparities in Cognitive Performance in Mid- and Late Adulthood: Analyses of Two Cohort Studies. AB - OBJECTIVES: To examine whether the attenuation of racial disparities observed in physical health outcomes at older ages can be extended to cognitive outcomes in mid- and late-life samples. DESIGN: Cross-sectional associations between race and cognitive functioning were examined as a function of age. SETTING: The National Survey of Midlife Development in the United States (MIDUS) and the Washington Heights-Inwood Columbia Aging Project (WHICAP). PARTICIPANTS: Non-Hispanic African American or white individuals aged 40 and older (MIDUS; n = 3875, 10.5% African American) and non-Hispanic African American or white individuals aged 65 and older without a diagnosis of dementia (WHICAP; n = 2,729, 53.8% African American). MEASUREMENTS: Composite scores of executive functioning and episodic memory. RESULTS: Independent of main effects of age, birth cohort, sex, education, and chronic health conditions, significant interactions between age and race indicated that racial disparities in episodic memory and executive functioning were larger at younger than older age in both samples. CONCLUSION: Attenuation of racial inequalities in older age can be extended to cognitive outcomes, which probably reflects selective survival. Research on cognitive disparities or on race-specific causes of cognitive outcomes in old age must incorporate corrections for selective survival if the goal is to identify causal predictors of cognitive outcomes rather than merely statistical predictors. PMID- 27225356 TI - Systematic Review of Prevalence and Predictors of Frailty in Individuals with Human Immunodeficiency Virus. AB - OBJECTIVES: To describe the prevalence and predictors of frailty in individuals with the human immunodeficiency virus (HIV) using systematic review methodology. DESIGN: Review. SETTING: Community. PARTICIPANTS: Older adults with HIV. MEASUREMENTS: Medline, CINAHL, EMBASE, PsychInfo, and PubMed were searched for original observational studies with populations including individuals with HIV in which frailty was assessed using the frailty phenotype or a variant thereof. Studies were examined for frailty prevalence and predictors of the syndrome in those with HIV. RESULTS: Thirteen of 322 citations were included for full review. All demonstrated the presence of frailty in individuals with HIV, with prevalence ranging from 5% to 28.6% depending on population studied. HIV was a risk factor for frailty. Predictors of frailty included older age, comorbidities, diagnosis of acquired immunodeficiency syndrome, and low current CD4(+) cell count. CONCLUSION: HIV appears to be an independent risk factor for frailty, with frailty occurring in individuals with HIV at rates comparable with older individuals without HIV. Heterogeneity in study populations and frailty assessment measures hamper accurate description of the problem. Future longitudinal work with standardized methodology is needed to describe prevalence accurately and confirm predictors. PMID- 27225353 TI - Hospitalizations During a Physical Activity Intervention in Older Adults at Risk of Mobility Disability: Analyses from the Lifestyle Interventions and Independence for Elders Randomized Clinical Trial. AB - OBJECTIVES: To determine whether moderate-intensity physical activity (PA) and health education (HE) are differentially associated with categories of hospitalizations or subgroups of participants. DESIGN: Multicenter randomized controlled trial in which participants were randomized to a PA or HE program for an average of 2.6 years. SETTING: Eight field centers. PARTICIPANTS: Sedentary men and women aged 70-89 with lower extremity physical limitations but able to walk 400-m in 15 minutes or less (N = 1,635). INTERVENTIONS: Structured, moderate intensity PA (n = 818) at a center (2*/wk) and at home (3-4*/wk) that included aerobic, strength, balance, and flexibility training or HE (n = 817) of educational workshops and upper extremity stretching exercises. MEASUREMENTS: All cause inpatient hospitalizations ascertained at 6-month intervals. RESULTS: There were 1,458 hospitalizations (49.1% of PA, 44.4% of HE; risk difference = 4.68%, 95% confidence interval (CI) = -0.18-9.54; hazard ratio (HR) = 1.16, 95% CI = 1.00-1.34). The intervention effect on incident hospitalization did not differ according to race, sex, Short Physical Performance Battery score, age, or history of cardiovascular disease or diabetes mellitus. PA was associated with higher rates of hospitalization in the middle baseline gait speed category, than HE (<0.8 m/s: HR = 0.93, 95% CI = 0.76-1.14; 0.8-1.0 m/s: HR = 1.54, 95% CI = 1.23 1.94; >1.0 m/s: HR = 1.05, 95% CI = 0.67-1.65; interaction P = .005). CONCLUSION: A PA program in older adults at risk for mobility disability did not lead to a different risk of specific types of hospitalizations than a HE program overall. Baseline gait speed may be a marker for risk of hospitalization during a PA intervention, because individuals with moderate baseline gait speed in the PA group had slightly higher rates of hospitalization than those in the HE group. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01072500. PMID- 27225357 TI - Gait Speed as a Guide for Blood Pressure Targets in Older Adults: A Modeling Study. AB - OBJECTIVES: To evaluate the potential for gait speed to inform decisions regarding optimal systolic blood pressure targets in older adults. DESIGN: Forecasting study from 2014 to 2023 using the Cardiovascular Disease Policy Model, a Markov model. SETTING: National Health and Nutrition Examination Survey. PARTICIPANTS: U.S. adults aged 60-94 stratified into fast walking, slow walking, and poor functioning (noncompleters) based on measured gait speed. MEASUREMENTS: Lowering SBP to a target of 140 or 150 mmHg was modeled in persons with (secondary prevention) and without (primary prevention) a history of coronary heart disease or stroke. Based on clinical trials and observational studies, it was projected that slow-walking and poor-functioning participants would have greater noncardiovascular mortality. Myocardial infarctions (MIs), strokes, deaths, cost, and disability-adjusted life years (DALYs) were measured. RESULTS: Regardless of gait speed, it was projected that secondary prevention to a systolic blood pressure (SBP) of 140 mmHg would prevent more events and save more money than secondary prevention to 150 mmHg. Similarly, primary prevention to 140 mmHg in fast-walking adults was projected to prevent events and save money. In slow-walking adults, primary prevention to 150 mmHg was projected to prevent MIs and strokes and save DALYs but was cost saving only in men; intensification to 140 mmHg is of uncertain benefit in slow-walking individuals. Primary prevention in poor-functioning adults to a target of 140 or 150 mmHg SBP is projected to decrease DALYs. CONCLUSION: The most cost-effective SBP target varies according to history of cardiovascular disease and gait speed in persons aged 60-94. These projections highlight the need for better estimates of the benefits and harms of antihypertensive medications in a diverse group of older adults, because the net benefit is sensitive to the characteristics of the population treated. PMID- 27225359 TI - Depressive Symptoms and Orthostatic Hypotension Are Risk Factors for Unexplained Falls in Community-Living Older People. AB - OBJECTIVES: To investigate risk factors for unexplained falls in older community dwelling individuals. DESIGN: Prospective cohort study. SETTING: Community population, Sydney, Australia. PARTICIPANTS: Older adults (N = 529; mean age 79.8 +/- 4.4, 52.2% female). MEASUREMENTS: Participants provided information demographic, medical, and medication characteristics and completed cardiovascular (tilt table test, pulse wave velocity), cognitive, and sensorimotor assessments at baseline. Falls were then recorded in monthly fall diaries for 12 months. Unexplained fallers (UFs) were those who reported falls due to a blackout, dizziness, feeling faint, or "found themselves suddenly on the ground." RESULTS: Of the 523 participants available at follow-up, 238 (45.5%) reported one or more falls; 35 participants fulfilled the definition of UFs. UFs were more likely than balance-related fallers (BFs) (n = 203) and nonfallers (n = 291) to have orthostatic hypotension (39.4%, 20.5% and 22.4%, respectively) and depressive symptoms (24.2%, 10.1%, and 7.9% respectively). More UFs (88.6%) than BFs (70.9%) had injurious falls. A multivariate logistic regression model revealed that depressive symptoms and orthostatic hypotension were significant and independent determinants of UF status. CONCLUSION: Approximately 15% of fallers had unexplained falls, which were more likely to result in injuries. Depressive symptoms and orthostatic hypotension increased the risk of unexplained falls, whereas cognitive deficits and sensorimotor and balance impairments did not. Future research should investigate whether psychotherapy and physical exercise to improve mood and medication reviews and nonpharmacological therapies for the treatment of orthostatic hypotension and depression are effective at reducing the risk of unexplained falls in older people. PMID- 27225360 TI - Are Obese Residents More Likely to Be Admitted to Nursing Homes That Have More Deficiencies in Care? AB - OBJECTIVES: To determine whether obese older adults who qualify for nursing home (NH) placement are as likely as nonobese adults to be admitted to NHs that provide adequate quality of care. DESIGN: Retrospective study. SETTING: NHs in New York State. PARTICIPANTS: Individuals aged 65 and older newly admitted to a NH in New York State in 2006-07. MEASUREMENTS: Total and healthcare-related deficiency citations for each facility were obtained from the Online Survey, Certification, and Reporting file. Bivariate and multivariate regression analyses were used to assess the association between obesity (body mass index (BMI) 30.0 39.9 kg/m(2) ) and morbid obesity (BMI >= 40.0 kg/m(2) ) separately and admission to facilities with more deficiencies. RESULTS: NHs that admitted a higher proportion of morbidly obese residents were more likely to have more deficiencies, whether total or healthcare related. These NHs also had greater odds of having severe deficiencies, or falling in the top quartile ranking of total deficiencies. After sequentially controlling for the choice of facilities within the inspection region, resident characteristics, and facility covariates, the association between morbid obesity and admission to higher-deficiency NHs persisted. CONCLUSION: Residents with morbid obesity were more likely to be admitted to NHs of poorer quality based on deficiency citations. The factors driving these disparities and their impact on the care of obese NH residents require further elucidation. PMID- 27225358 TI - Using an Atrial Fibrillation Decision Support Tool for Thromboprophylaxis in Atrial Fibrillation: Effect of Sex and Age. AB - OBJECTIVES: To assess the appropriateness of oral anticoagulant therapy (OAT) in women and elderly adults, looking for patterns of undertreatment or unnecessary treatment. DESIGN: Retrospective cohort study. SETTING: Primary care practices of an academic healthcare system. PARTICIPANTS: Adults (aged 28-93) with nonvalvular atrial fibrillation (AF) seen between March 2013 and February 2014 (N = 1,585). MEASUREMENTS: Treatment recommendations were made using an AF decision support tool (AFDST) based on projections of quality-adjusted life expectancy calculated using a decision analytical model that integrates individual-specific risk factors for stroke and hemorrhage. RESULTS: Treatment was discordant from AFDST recommended treatment in 45% (326/725) of women and 39% (338/860) of men (P = .02). Although current treatment was discordant from recommended in 35% (89/258) of participants aged 85 and older and in 43% (575/1,328) of those younger than 85 (P = .01), many undertreated elderly adults were receiving aspirin as the sole antithrombotic agent. CONCLUSION: Physicians should understand that female sex is a significant risk factor for AF-related stroke and incorporate this into decision-making about thromboprophylaxis. Treating older adults with aspirin instead of OAT exposes them to significant risk of bleeding with little to no reduction in AF-related stroke risk. PMID- 27225361 TI - Norovirus Infections in Long-Term Care Facilities. AB - Noroviruses have emerged as one of the leading causes of viral gastroenteritis worldwide, affecting community-dwelling and institutionalized older adults. Recent global epidemics present a growing challenge to the healthcare system and to long-term care facilities. Noroviruses spread readily and rapidly through multiple routes (e.g., person-to-person contact, contact with contaminated surfaces, airborne dissemination of vomitus) and thus are able to sustain an epidemic efficiently and successfully. Although norovirus gastroenteritis is a short self-limited illness in healthy immunocompetent individuals, it can result in significant morbidity and mortality in vulnerable compromised persons such as frail elderly persons and older residents of nursing homes. Diagnosis is made by clinical assessment and confirmed primarily by stool evaluation using polymerase chain reaction. Treatment is confined to supportive measures. Public health prevention and control strategies provide guidance regarding surveillance and the necessary steps to curb the clinical effect and spread of norovirus infections in various settings, including long-term care. PMID- 27225362 TI - Randomized Controlled Trial of the Effect of Inspiratory Muscle Training and Incentive Spirometry on Respiratory Muscle Strength, Chest Wall Expansion, and Lung Function in Elderly Adults. PMID- 27225363 TI - Erysipeloid Carcinoma As the Primary Clinical Presentation of a Pulmonary Adenocarcinoma. PMID- 27225365 TI - Adherence to Multiple Medications in Older Adults with Asthma. PMID- 27225364 TI - Transitional Care Outcomes in Older Spanish-English Bilingual Veterans. PMID- 27225366 TI - Therapy-Related Spontaneous Pectoral Muscle Hematoma: A Case Report and Review of the Literature. PMID- 27225367 TI - Quetiapine-Induced Cutaneous Vasculitis: Diagnostic Challenges and Therapeutic Implications. PMID- 27225368 TI - Severe Hyponatremia After Desmopressin Diacetate Arginine Vasopressin Infusion in an Older Woman. PMID- 27225369 TI - Ruptured Huge Internal Iliac Artery Aneurysm in an Elderly Adult. PMID- 27225370 TI - Cutaneous Tumor of the Arm Revealing a Sporadic Burkitt Lymphoma. PMID- 27225371 TI - Decrease in Upright Postural Sway from Open to Closed Eyes: Episodic Memory Impairment Matters, Too. PMID- 27225372 TI - Hepatotoxicity Associated with Donepezil in an Individual Taking Citalopram. PMID- 27225373 TI - Abdominal Epilepsy Associated With Alzheimer's Disease. PMID- 27225374 TI - In response to "Conservative Management of Intentional Massive Dabigatran Overdose". PMID- 27225375 TI - Association Between Hearing Aid Use and Cognitive Decline. PMID- 27225376 TI - Response to Wallhagen and Strawbridge. PMID- 27225377 TI - Protracted Versus New-Onset Delirium: Diagnostic Challenges. PMID- 27225378 TI - Can We Equate All Proton Pump Inhibitors with One Another? PMID- 27225379 TI - Response to Alici. PMID- 27225380 TI - Response to Sumer and Colleagues. PMID- 27225382 TI - From FOX-7 to H-FOX to insensitive energetic materials with hypergolic properties. AB - Nitrogen/halogen rich derivatives, , , , and of FOX-7 (1,1-diamino-2,2 dinitroethene), and H-FOX (1-hydrazinyl-2,2-dinitroethenamine) have been synthesized, characterized and found to exhibit good energetic properties. Compound displays hypergolic properties with commonly utilized fuels such as monomethyl hydrazine (MMH), and hydrazine hydrate (HH), as well as with ethylenediamine (EN), and 1,3-diaminopropane (DAP) showing ignition delay times between 2.5 to 10 ms. Additionally, the hypergolic properties of 4 and 8 were further studied by using ammonia borane as a fuel solubilized in a green ionic liquid, 1-allyl-3-methyl imidazolium dicyanamide, (1 : 1 molar ratio). This is a new role for a derivative of H-FOX. The energetic and physical properties of all the molecules were either measured or calculated. All of materials were characterized by NMR, and infrared spectra, elemental analyses, and differential scanning calorimetry. Single crystal X-ray structural measurements for and were helpful in their confirmation. PMID- 27225384 TI - Nanoemulsions Containing a Coumarin-Rich Extract from Pterocaulon balansae (Asteraceae) for the Treatment of Ocular Acanthamoeba Keratitis. AB - This study describes the incorporation of a coumarin-rich extract from Pterocaulon balansae into nanoemulsions intended for the local treatment of ocular keratitis caused by Acanthamoeba. The n-hexane dewaxed extract of P. balansae was characterized by HPLC/PDA and UPLC/MS. The presence of four major coumarins was detected, where 5-methoxy-6,7-methylenedioxycoumarin was selected as a chemical marker. This extract was then incorporated into nanoemulsions composed of medium chain triglycerides and egg-lecithin, through spontaneous emulsification. Such a procedure yielded the formation of monodisperse nanoemulsions in a sub-300-nm range, regardless of the amount of extract incorporated (1.0-5.0 mg/mL). The amoebicidal activity against Acanthamoeba castellanii was both dose-dependent and incubation time-dependent. A reduction of 95% of trophozoite viability was detected after 24 h of incubation with a nanoemulsion at 1.25 mg/mL of coumarins, being a similar effect detected for chlorhexidine. These results suggest a potential of the formulations developed in this study as a new strategy for the treatment of ocular keratitis caused by Acanthamoeba. PMID- 27225385 TI - Enhanced Anti-Inflammatory Efficacy Through Targeting to Macrophages: Synthesis and In Vitro Evaluation of Folate-Glycine-Celecoxib. AB - As an effective COX-2 inhibitor, celecoxib is widely used in anti-inflammation therapy. However, it may cause cardiovascular risks and renal adverse effects. In the present study, we aimed to construct a celecoxib prodrug with enhanced anti inflammatory efficacy and reduced adverse effects using folate in order to target activated macrophages. Folate-glycine-celecoxib was synthesized and identified by 1H-NMR, MS, and FTIR analyses. The cytotoxicity of folate-glycine-celecoxib was tested on murine macrophage cells (RAW264.7) using thiazolyl blue tetrazolium bromide. Cellular uptake studies were employed to determine targeting ability toward folate receptors via flow cytometry and confocal microscopy. Anti inflammatory efficacy of folate-glycine-celecoxib was investigated by measuring the concentration of LPS-induced nitric oxide (NO). Folate-glycine-celecoxib exhibited lower cytotoxicity than conventional celecoxib, and this conjugate could be targetedly transported into RAW264.7 cells through binding with folate receptors on cell surface. Through targeting to RAW264.7 cells, folate-glycine celecoxib exhibited better effects than equimolar celecoxib in NO inhibition, suggesting greater anti-inflammatory activity. These findings demonstrated that the prodrug folate-glycine-celecoxib had potential to treat inflammatory disease with low cytotoxicity and high targeting ability. PMID- 27225383 TI - Towards correlative super-resolution fluorescence and electron cryo-microscopy. AB - Correlative light and electron microscopy (CLEM) has become a powerful tool in life sciences. Particularly cryo-CLEM, the combination of fluorescence cryo microscopy (cryo-FM) permitting for non-invasive specific multi-colour labelling, with electron cryo-microscopy (cryo-EM) providing the undisturbed structural context at a resolution down to the Angstrom range, has enabled a broad range of new biological applications. Imaging rare structures or events in crowded environments, such as inside a cell, requires specific fluorescence-based information for guiding cryo-EM data acquisition and/or to verify the identity of the structure of interest. Furthermore, cryo-CLEM can provide information about the arrangement of specific proteins in the wider structural context of their native nano-environment. However, a major obstacle of cryo-CLEM currently hindering many biological applications is the large resolution gap between cryo FM (typically in the range of ~400 nm) and cryo-EM (single nanometre to the Angstrom range). Very recently, first proof of concept experiments demonstrated the feasibility of super-resolution cryo-FM imaging and the correlation with cryo EM. This opened the door towards super-resolution cryo-CLEM, and thus towards direct correlation of structural details from both imaging modalities. PMID- 27225386 TI - Bond strengths of brackets bonded to enamel surfaces conditioned with femtosecond and Er:YAG laser systems. AB - The aim of this study was to compare femtosecond and Er:YAG laser systems with regard to enamel demineralization and bracket bond strength. Human-extracted premolars were randomized to three groups (n = 17) depending on the conditioning treatment used for the buccal surfaces: 37 % orthophosphoric acid, Er:YAG laser etching (MSP mode 120 mJ, 10 Hz, 1.2 W), and femtosecond laser etching (0.4 W, 800 nm, 90 fs/pulse, 1 kHz). Metal brackets were bonded with Transbond XT to the conditioned surfaces and light cured for 20 s. The samples were thermocycled (5000 cycles, 5-55 degrees C) and subjected to shear bond strength (SBS) testing using a universal testing machine. Failure types were analyzed under an optical stereomicroscope and SEM. The adhesive remnant index (ARI) was evaluated to assess residual adhesive on the enamel surface. The results revealed no significant differences in SBS between the Er:YAG laser (7.2 +/- 3.3 MPa) and acid etching groups (7.3 +/- 2.7 MPa; p < 0.05), whereas a significant difference was observed between the femtosecond laser etching group (3.3 +/- 1.2 MPa) and the other two groups (p < 0.01). ARI scores were significantly different among the three groups. The results of our study suggest that laser conditioning with an Er:YAG system results in successful etching, similar to that obtained with acid. The sole use of a femtosecond laser system may not provide an adequate bond strength at the bracket-enamel interface. PMID- 27225387 TI - Oncotype-DX recurrence score distribution in breast cancer patients with BRCA1/2 mutations. AB - Oncotype-DX assay has never been validated for BRCA mutation carriers. This study compares the recurrence score (RS) distribution in BRCA-positive breast cancer patients with that of a general population (GP) of patients and reports their outcomes. Eligible patients were BRCA carriers who performed the Oncotype-DX assay. Two sets of databases were cross-linked: BRCA carriers at Rabin Medical Center and Sheba Medical Center with Oncotype-DX tests performed through Clalit Health Services HMO, from 2003 to 2015. Fifty-eight BRCA patients were included (20 BRCA1, 38 BRCA2). The GP included 1020 patients. Compared to the GP, BRCA1 patients were younger, had higher rate of grade three tumors, and higher Ki67. BRCA2 patients had lower PR index, higher rate of grade three tumors, and higher Ki67. Among the GP, 52.9, 37.9, and 9.1 % had low, intermediate, and high risk RS, respectively. Corresponding rates were 15, 35, and 50 % in BRCA1 patients, and 18.4, 52.6, and 29 % in BRCA2 patients. Subgroup analysis revealed a similar RS distribution pattern regardless of the nodal status. Median follow-up was 45 months. Four BRCA patients (7 %) developed disease recurrence. RS of these patients were in the intermediate and low range. All recurrences occurred in chemo-naive patients who had not undergone bilateral oophorectomy. This study revealed significantly different RS distributions between BRCA patients and the GP. RS values shifted toward high and intermediate risk categories. This pattern held regardless of the nodal status and was more pronounced in the BRCA1 group. PMID- 27225388 TI - Lymphovascular invasion is an independent predictor of survival in breast cancer after neoadjuvant chemotherapy. AB - Various prognostic indicators have been investigated in neoadjuvant chemotherapy (NAC)-treated invasive breast cancer (BC). Our study examines if lymphovascular invasion (LVI) is an independent predictor of survival in women receiving NAC. We performed a retrospective analysis in 166 women with operable invasive BC who underwent adriamycin- and taxane-based NAC between 2000 and 2013. The presence of LVI was noted in breast excisions following NAC. Associations between progression free and overall survival and LVI and other clinicopathologic variables were assessed. Median follow-up was 31 months (range 1.4-153 months) with a total of 56 events and 24 deaths from any cause. LVI was found in 74 of 166 patients (45 %). In univariate analysis, the presence of LVI was associated with worse progression-free survival (HR 3.37, 95 % CI 1.87-6.06, p < 0.01) and overall survival (HR 4.35, 95 % CI 1.61-11.79, p < 0.01). In multivariate models adjusting for breast cancer subtype, LVI was significantly associated with a decrease in progression-free survival (HR 3.76, 95 % CI 2.07-6.83, p < 0.01) and overall survival (HR 5.70, 95 % CI 2.08-15.64, p < 0.01). When stratified by subtype, those with hormone receptor or HER2-positive BCs with no LVI had the most favorable progression-free and overall survival. Those with both LVI and triple-negative BC had the worst progression-free and overall survival. LVI is an important prognostic marker and is associated with worse clinical outcome in breast cancer patients receiving NAC. PMID- 27225389 TI - Evaluation of the genetic parameters and mutation analysis of 22 STR loci in the central Chinese Han population. AB - At present, the Han nationality is China's main ethnic group and also the most populous nation in the world. This is a great resource to study microsatellite mutations and for the study of ethnogeny. The aim of this study is to investigate the genetic polymorphisms and mutations of 22 autosomal STR loci in 2475 individuals from Henan province, China. DNA is amplified and genotyped using PowerPlexTM24 system. The gene frequencies, forensic parameters, and the mutation rate of the 22 STR loci are analyzed. A total of 295 alleles are observed in this Henan Han population, and the allelic frequencies ranged from 0.0003 to 0.5036. In order to investigate the genetic relationships between the Henan Han and the other 14 different populations, our present data were compared with previously published data for the same 15 STR loci. The results indicated that the Henan Han had closer genetic relationships the groups including Minnan Han, Maonan, Yi and Guangdong Han groups while the South morocco population, the Moroccan population, the Malay group, and the Uigur stand away from Henan Han. Except of D2S441, D13S317, PentaE, D2S1338, D5S818, TPOX and D19S433, the mutation events are found in the other 15 STR loci. A total of 40 mutation events are observed in the 15 STR loci. The mutation rates are ranged from 0 to 4.85 * 10-3. In this study, 39 mutations are single-step mutations, and only one at FGA comprised two steps. STR mutation is commonly existed in paternity testing, while there are no STR mutation studies of the 22 STR loci in the Henan Han population. It is of great importance in forensic individual discrimination and paternal testing. PMID- 27225390 TI - Lethal ventricular tachycardia triggered after femoral fracture repair in an obese man with insulin-resistant diabetes. AB - An obese man (height, 178 cm; weight, 160 kg; body mass index, 50.5 kg/m2) with a history of recurrent ventricular tachycardia (VT), cardiomyopathy, coronary sclerosis, and insulin-resistant diabetes suffered a right femur fracture in a vehicular accident. His fracture was repaired the following day, but shortly after surgery, his serum potassium (K+) level increased, presumably due to K+ leakage from the injured muscles, leading to persistent VT and death. An autopsy revealed severe cardiac hypertrophy, moderate coronary sclerosis, and histological findings of myocardial hypercontraction, but not myoglobin-related renal failure, pulmonary thrombosis, lipid emboli, or inflammation. The hyperkalemia was not corrected by glucose-insulin infusion and led to the death of the patient due to the preexisting cardiomyopathy, coronary sclerosis, and a predisposition to VT. In addition to the autopsy, the analysis of the clinical course was indispensable for determining the cause of death as hyperkalemia related VT. PMID- 27225391 TI - Identification of canine saliva using mRNA-based assay. AB - A dog saliva analysis in addition to a bite-mark analysis may be important for evidence when a crime involves a dog bite. In this study, the utility of detecting canine saliva-specific mRNAs to identify canine saliva was evaluated. Canine saliva swabs (n = 20), urine swabs (n = 20), body surface swabs (n = 20), whole blood samples (n = 10), human saliva (n = 20), human skin surface swabs (n = 20), and human whole blood (n = 20) were tested. The saliva-specific genes encoding statherin (STATH), carbonic anhydrase VI (CA-VI), and dog allergens (Canf1 and Canf2) were analyzed as candidate genes. Moreover, glyceraldehyde-3 phosphate dehydrogenase (GAPDH) was used as confirmation of canine mRNA extraction. STATH, CA-VI, Canf1, Canf2, and GAPDH mRNAs were detected in 19/20, 1/20, 11/20, 4/20, and 20/20 saliva samples, respectively. The STATH, CA-VI, Canf1, Canf2, and GAPDH mRNAs did not exhibit cross-reactivity with samples of human origin. This mRNA-based assay was also able to detect canine saliva in mock forensic samples. The results of this study indicated that the detection of STATH mRNA is useful for the identification of canine saliva, and GAPDH is a suitable marker for canine mRNA extraction. PMID- 27225392 TI - Post-mortem CT and MR brain imaging of putrefied corpses. AB - INTRODUCTION: Putrefaction of the brain is a challenge to a forensic pathologist because it may lead to considerable organ alterations and restrict documenting reliable autopsy findings. OBJECTIVES: This study aims to present a new and systematic evaluation of possible benefits of post-mortem MR Neuroimaging (1.5 Tesla, sequences: T1w, T2w) in putrefied corpses in comparison to PMCT and autopsy. METHODS: A post-mortem MRI brain examination was conducted on 35 adult, putrefied corpses after performing a whole body CT scan prior to a forensic autopsy. Imaging data and autopsy findings were compared with regard to brain symmetry, gray and white matter junction, ventricular system, basal ganglia, cerebellum, brain stem, and possible pathological findings. RESULTS: At autopsy, a reliable assessment of the anatomical brain structures was often restricted. MR imaging offered an assessment of the anatomical brain structures, even at advanced stages of putrefaction. In two cases, MR imaging revealed pathological findings that were detectable neither by CT scans nor at autopsy. CONCLUSIONS: Post-mortem MR imaging of putrefied brains offers the possibility to assess brain morphology, even if the brain is liquefied. Post-mortem MR imaging of the brain should be considered if the assessment of a putrefied brain is crucial to the evaluation of a forensic autopsy case. PMID- 27225393 TI - Effect of water on the structure of a prototype ionic liquid. AB - The influence of water on the structure of a prototype ionic liquid (IL) 1-octyl 3-methylimidazolium tetrafluoroborate (C8mimBF4) is examined in the IL-rich regime using high-energy X-ray diffraction (HEXRD) and molecular dynamics (MD) simulations. A many-body polarizable force field APPLE&P was developed for C8mimBF4-water mixture. It predicts structure factors of pure IL and IL-water mixture in excellent agreement with the HEXRD experiments. The MD results provide detailed insights into the structural changes from the partial structure factors, 2-D projections of the simulation box and 3-D distribution functions. Water partitioning with IL and its competition with BF4(-) for complexing the imidazolium rings was examined. The added water molecules occupy a diffuse coordination shell around the imidazolium ring but are not present around the alkyl tail. The strong coordination of the fluorine atoms of the BF4(-) anions to the imidazolium ring is not significantly changed by the addition of water. A complementary packing of water and imidazolium around BF4(-) was found. These results are consistent with the very small differences in the average structure between the pure IL and the mixture. PMID- 27225394 TI - Modification of Wide-Band-Gap Oxide Semiconductors with Cobalt Hydroxide Nanoclusters for Visible-Light Water Oxidation. AB - Cobalt-based compounds, such as cobalt(II) hydroxide, are known to be good catalysts for water oxidation. Herein, we report that such cobalt species can also activate wide-band-gap semiconductors towards visible-light water oxidation. Rutile TiO2 powder, a well-known wide-band-gap semiconductor, was capable of harvesting visible light with wavelengths of up to 850 nm, and thus catalyzed water oxidation to produce molecular oxygen, when decorated with cobalt(II) hydroxide nanoclusters. To the best of our knowledge, this system constitutes the first example that a particulate photocatalytic material that is capable of water oxidation upon excitation by visible light can also operate at such long wavelengths, even when it is based on earth-abundant elements only. PMID- 27225395 TI - Cerebrotendinous xanthomatosis, a metabolic disease with different neurological signs: two case reports. AB - Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive inborn error of bile acids synthesis and lipid accumulation caused by a deficiency of the mitochondrial cytochrome P450 sterol 27-hydroxylase enzyme encoded by CYP27A1. Pathogenic variants in CYP27A1 cause elevated cholestanol levels in the body, which leads to a variable clinical presentation that often includes cataracts, intellectual disability, neurological features, tendon xanthomas, and chronic diarrhea. Herein we describe the cases of two unrelated adult CTX patients. Case 1 is a patient with neurological dysfunction, including moderate intellectual disability, cataract of right eye, and xanthomas; Case 2 is a patient with tendon xanthomas without neurological symptoms. Plasma sterols profile obtained from both cases showed higher levels of cholestanol and cholesterol biosynthetic precursors compared to unaffected subjects. Case 1 and Case 2 were homozygous for the c.1263 + 5G > T (p.Leu396Profs29X) and c.1435C > G (p.Arg479Gly) pathogenic variants, respectively, in the CYP27A1 gene. Interestingly, for the first time, Case 2 variant has been identified in a homozygous state. Our results highlight that the sterol profile and genetic analyses are essential to make the diagnosis of CTX and to exclude other dyslipidemias. PMID- 27225396 TI - Cardiac resynchronization therapy for ischemic myopathy. AB - We performed coronary artery grafting, mitral valve plasty, and tricuspid plasty in a 75-year-old man who had double-vessel coronary disease and moderate mitral and tricuspid insufficiency. Preoperative transthoracic echocardiography revealed an ejection fraction of 34% and dyssynchronous wall motion of the septum and free wall. We placed pacing leads on the right ventricular outlet and posterior left ventricular wall for cardiac resynchronization therapy. The dyssynchrony disappeared postoperatively and the New York Heart Association functional class improved from IV to I. PMID- 27225397 TI - Primary dedifferentiated massive mediastinal liposarcoma weighing 5.3 kg. PMID- 27225398 TI - Unusual variant of pulmonary venous atresia. PMID- 27225399 TI - "Open top flask" sign. PMID- 27225400 TI - A spin-liquid with pinch-line singularities on the pyrochlore lattice. AB - The mathematics of gauge theories lies behind many of the most profound advances in physics in the past 200 years, from Maxwell's theory of electromagnetism to Einstein's theory of general relativity. More recently it has become clear that gauge theories also emerge in condensed matter, a prime example being the spin ice materials which host an emergent electromagnetic gauge field. In spin-ice, the underlying gauge structure is revealed by the presence of pinch-point singularities in neutron-scattering measurements. Here we report the discovery of a spin-liquid where the low-temperature physics is naturally described by the fluctuations of a tensor field with a continuous gauge freedom. This gauge structure underpins an unusual form of spin correlations, giving rise to pinch line singularities: line-like analogues of the pinch points observed in spin-ice. Remarkably, these features may already have been observed in the pyrochlore material Tb2Ti2O7. PMID- 27225401 TI - [Tick-borne encephalitis]. AB - Tick-borne encephalitis (TBE) is one of the most important viral infections of the human central nervous system. Approximately 10,000 cases of TBE are referred to hospitals in Europe and Asia each year. The TBE virus (TBEV) is mainly transmitted by tick bites but also occasionally by unpasteurized goat's milk. As in endemic areas on average only 1-3 % of ticks are infected with the TBEV and the clinical manifestation rate is approximately 33 %, only approximately 1 in every 100-300 tick bites leads to disease. The incubation period varies from 5-28 days and typically has a biphasic course of fever. The TBE manifests as meningitis in approximately 50 % of patients, as meningoencephalitis in 40 % and as encephalomyelitis in 10 %. The suspected diagnosis is confirmed by the demonstration of TBEV-specific IgM and IgG antibodies in serum and the presence of elevated cell counts in cerebrospinal fluid. No specific treatment for TBE is known but it can be successfully prevented by active immunization. PMID- 27225402 TI - Clinical Features, Outcomes, and Molecular Characteristics of Community- and Health Care-Associated Staphylococcus lugdunensis Infections. AB - Staphylococcus lugdunensis is a major cause of aggressive endocarditis, but it is also responsible for a broad spectrum of infections. The differences in clinical and molecular characteristics between community-associated (CA) and health care associated (HA) S. lugdunensis infections have remained unclear. We performed a retrospective study of S. lugdunensis infections between 2003 and 2014 to compare the clinical and molecular characteristics of CA and HA isolates. We collected 129 S. lugdunensis isolates in total: 81 (62.8%) HA isolates and 48 (37.2%) CA isolates. HA infections were more frequent than CA infections in children (16.0% versus 4.2%, respectively; P = 0.041) and the elderly (38.3% versus 14.6%, respectively; P = 0.004). The CA isolates were more likely to cause skin and soft tissue infections (85.4% versus 19.8%, respectively; P < 0.001). HA isolates were more frequently responsible for bacteremia of unknown origin (34.6% versus 4.2%, respectively; P < 0.001) and for catheter-related bacteremia (12.3% versus 0%, respectively; P = 0.011) than CA isolates. Fourteen-day mortality was higher for HA infections than for CA infections (11.1% versus 0%, respectively). A higher proportion of the HA isolates than of the CA isolates were resistant to penicillin (76.5% versus 52.1%, respectively; P = 0.004) and oxacillin (32.1% versus 2.1%, respectively; P < 0.001). Two major clonal complexes (CC1 and CC3) were identified. Sequence type 41 (ST41) was the most common sequence type identified (29.5%). The proportion of ST38 isolates was higher for HA than for CA infections (33.3% versus 12.5%, respectively; P = 0.009). These isolates were of staphylococcal cassette chromosome mec element (SCCmec)type IV, V, or Vt. HA and CA S. lugdunensis infections differ in terms of their clinical features, outcome, antibiotic susceptibilities, and molecular characteristics. PMID- 27225403 TI - Rapid Drug Susceptibility Testing of Drug-Resistant Mycobacterium tuberculosis Isolates Directly from Clinical Samples by Use of Amplicon Sequencing: a Proof-of Concept Study. AB - Increasingly complex drug-resistant tuberculosis (DR-TB) is a major global health concern and one of the primary reasons why TB is now the leading infectious cause of death worldwide. Rapid characterization of a DR-TB patient's complete drug resistance profile would facilitate individualized treatment in place of empirical treatment, improve treatment outcomes, prevent amplification of resistance, and reduce the transmission of DR-TB. The use of targeted next generation sequencing (NGS) to obtain drug resistance profiles directly from patient sputum samples has the potential to enable comprehensive evidence-based treatment plans to be implemented quickly, rather than in weeks to months, which is currently needed for phenotypic drug susceptibility testing (DST) results. In this pilot study, we evaluated the performance of amplicon sequencing of Mycobacterium tuberculosis DNA from patient sputum samples using a tabletop NGS technology and automated data analysis to provide a rapid DST solution (the Next Gen-RDST assay). One hundred sixty-six out of 176 (94.3%) sputum samples from the Republic of Moldova yielded complete Next Gen-RDST assay profiles for 7 drugs of interest. We found a high level of concordance of our Next Gen-RDST assay results with phenotypic DST (97.0%) and pyrosequencing (97.8%) results from the same clinical samples. Our Next Gen-RDST assay was also able to estimate the proportion of resistant-to-wild-type alleles down to mixtures of <=1%, which demonstrates the ability to detect very low levels of resistant variants not detected by pyrosequencing and possibly below the threshold for phenotypic growth methods. The assay as described here could be used as a clinical or surveillance tool. PMID- 27225404 TI - Antibodies to the Novel Human Pegivirus 2 Are Associated with Active and Resolved Infections. AB - A novel blood-borne human pegivirus (HPgV), HPgV-2, was recently identified in hepatitis C virus (HCV)-infected individuals and individuals who had received multiple transfusions. Robust serological assays capable of detecting antibodies in HPgV-2-infected individuals are needed to establish global seroprevalence rates and potential disease associations. The two objectives of this study were to determine the utility of mammalian cell-expressed HPgV-2 E2 glycoprotein or bacterium-expressed nonstructural protein 4AB (NS4AB) in detecting past or present infections and to compare the total prevalence (antibody and RNA positive) of HPgV-2 with that of the other human pegivirus, HPgV-1 (GB virus C [GBV-C]). HPgV-2 E2 antibodies were detected in 13 (92.86%) of 14 HPgV-2-viremic cases, and NS4AB antibodies were detected in 8 (57.14%) of 14 cases. The HPgV-2 seroprevalence was significantly higher (P < 0.0001) among HCV-infected individuals (3.31% [24 of 726 samples]) than among non-HCV-infected individuals (0.30% [4 of 1,348 samples]). Of 31 anti-E2-positive samples, 22 had supplemental supporting data; 12 samples were HPgV-2 RNA positive and 10 nonviremic samples were antibody positive for peptides or NS4AB. The total prevalence of HPgV-1 (35.00%) was significantly higher than that of HPgV-2 (1.33%) in all populations tested (P < 0.0001). For HPgV-1, codetection of antibodies to E2 and RNA was infrequent (5.88%). In contrast, antibodies to E2 were detected in most HPgV-2 viremic individuals (92.86%), as is observed among individuals chronically infected with HCV, most of whom are antibody positive for HCV E2. Our studies indicate that HPgV-2 circulates with HCV and displays a profile similar to the serological profile of HCV-infected persons, although the pathogenicity of this virus has yet to be established. PMID- 27225405 TI - Evaluation of the Vitek MS Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry System for Identification of Clinically Relevant Filamentous Fungi. AB - Invasive fungal infections have a high rate of morbidity and mortality, and accurate identification is necessary to guide appropriate antifungal therapy. With the increasing incidence of invasive disease attributed to filamentous fungi, rapid and accurate species-level identification of these pathogens is necessary. Traditional methods for identification of filamentous fungi can be slow and may lack resolution. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has emerged as a rapid and accurate method for identification of bacteria and yeasts, but a paucity of data exists on the performance characteristics of this method for identification of filamentous fungi. The objective of our study was to evaluate the accuracy of the Vitek MS for mold identification. A total of 319 mold isolates representing 43 genera recovered from clinical specimens were evaluated. Of these isolates, 213 (66.8%) were correctly identified using the Vitek MS Knowledge Base, version 3.0 database. When a modified SARAMIS (Spectral Archive and Microbial Identification System) database was used to augment the version 3.0 Knowledge Base, 245 (76.8%) isolates were correctly identified. Unidentified isolates were subcultured for repeat testing; 71/319 (22.3%) remained unidentified. Of the unidentified isolates, 69 were not in the database. Only 3 (0.9%) isolates were misidentified by MALDI-TOF MS (including Aspergillus amoenus [n = 2] and Aspergillus calidoustus [n = 1]) although 10 (3.1%) of the original phenotypic identifications were not correct. In addition, this methodology was able to accurately identify 133/144 (93.6%) Aspergillus sp. isolates to the species level. MALDI-TOF MS has the potential to expedite mold identification, and misidentifications are rare. PMID- 27225406 TI - Impact of Early Detection of Respiratory Viruses by Multiplex PCR Assay on Clinical Outcomes in Adult Patients. AB - Rapid and definitive diagnosis of viral respiratory infections is imperative in patient triage and management. We compared the outcomes for adult patients with positive tests for respiratory viruses at a tertiary care center across two consecutive influenza seasons (winters of 2010-2011 and 2012). Infections were diagnosed by conventional methods in the first season and by multiplex PCR (FilmArray) in the second season. FilmArray decreased the time to diagnosis of influenza compared to conventional methods (median turnaround times of 1.7 h versus 7.7 h, respectively; P = 0.015); FilmArray also decreased the time to diagnosis of non-influenza viruses (1.5 h versus 13.5 h, respectively; P < 0.0001). Multivariate logistic regression found that a diagnosis of influenza by FilmArray was associated with significantly lower odds ratios (ORs) for admission (P = 0.046), length of stay (P = 0.040), duration of antimicrobial use (P = 0.032), and number of chest radiographs (P = 0.005), when controlling for potential confounders. We conclude that the rapid turnaround time, multiplex nature of the test (allowing simultaneous detection of an array of viruses), and superior sensitivity of FilmArray may improve the evaluation and management of patients suspected of having respiratory virus infections. PMID- 27225407 TI - Multiplex Real-Time PCR Assay with High-Resolution Melting Analysis for Characterization of Antimicrobial Resistance in Neisseria gonorrhoeae. AB - Resistance to antibiotics used against Neisseria gonorrhoeae infections is a major public health concern. Antimicrobial resistance (AMR) testing relies on time-consuming culture-based methods. Development of rapid molecular tests for detection of AMR determinants could provide valuable tools for surveillance and epidemiological studies and for informing individual case management. We developed a fast (<1.5-h) SYBR green-based real-time PCR method with high resolution melting (HRM) analysis. One triplex and three duplex reactions included two sequences for N. gonorrhoeae identification and seven determinants of resistance to extended-spectrum cephalosporins (ESCs), azithromycin, ciprofloxacin, and spectinomycin. The method was validated by testing 39 previously fully characterized N. gonorrhoeae strains, 19 commensal Neisseria species strains, and an additional panel of 193 gonococcal isolates. Results were compared with results of culture-based AMR determination. The assay correctly identified N. gonorrhoeae and the presence or absence of the seven AMR determinants. There was some cross-reactivity with nongonococcal Neisseria species, and the detection limit was 10(3) to 10(4) genomic DNA (gDNA) copies/reaction. Overall, the platform accurately detected resistance to ciprofloxacin (sensitivity and specificity, 100%), ceftriaxone (sensitivity, 100%; specificity, 90%), cefixime (sensitivity, 92%; specificity, 94%), azithromycin (sensitivity and specificity, 100%), and spectinomycin (sensitivity and specificity, 100%). In conclusion, our methodology accurately detects mutations that generate resistance to antibiotics used to treat gonorrhea. Low assay sensitivity prevents direct diagnostic testing of clinical specimens, but this method can be used to screen collections of gonococcal isolates for AMR more quickly than current culture-based AMR testing. PMID- 27225408 TI - Serological and Molecular Detection of Senecavirus A Associated with an Outbreak of Swine Idiopathic Vesicular Disease and Neonatal Mortality. AB - We performed a longitudinal field study in a swine breeding herd that presented with an outbreak of vesicular disease (VD) that was associated with an increase in neonatal mortality. Initially, a USDA Foreign Animal Disease (FAD) investigation confirmed the presence of Senecavirus A (SVA) and ruled out the presence of exotic agents that produce vesicular lesions, e.g., foot-and-mouth disease virus and others. Subsequently, serum samples, tonsil swabs, and feces were collected from sows (n = 22) and their piglets (n = 33) beginning 1 week after the onset of the clinical outbreak and weekly for 6 weeks. The presence of SVA RNA was evaluated in all specimens collected by reverse transcriptase quantitative PCR (RT-qPCR) targeting a conserved region of the 5' untranslated region (5'-UTR). The serological response (IgG) to SVA was evaluated by the weekly testing of sow and piglet serum samples on a SVA VP1 recombinant protein (rVP1) indirect enzyme-linked immunosorbent assay (ELISA). The rVP1 ELISA detected seroconversion against SVA in clinically affected and non-clinically affected sows at early stages of the outbreak as well as maternal SVA antibodies in offspring. Overall, the absence of vesicles (gross lesions) in SVA-infected animals and the variability of RT-qPCR results among specimen type demonstrated that a diagnostic algorithm based on the combination of clinical observations, RT qPCR in multiple diagnostic specimens, and serology are essential to ensure an accurate diagnosis of SVA. PMID- 27225409 TI - Use of a Rapid Test for Diagnosis of Dengue during Suspected Dengue Outbreaks in Resource-Limited Regions. AB - Dengue is major public health problem, globally. Timely verification of suspected dengue outbreaks allows for public health response, leading to the initiation of appropriate clinical care. Because the clinical presentation of dengue is nonspecific, dengue diagnosis would benefit from a sensitive rapid diagnostic test (RDT). We evaluated the diagnostic performance of an RDT that detects dengue virus (DENV) nonstructural protein 1 (NS1) and anti-DENV IgM during suspected acute febrile illness (AFI) outbreaks in four countries. Real-time reverse transcription-PCR and anti-DENV IgM enzyme-linked immunosorbent assay were used to verify RDT results. Anti-DENV IgM RDT sensitivity and specificity ranged from 55.3 to 91.7% and 85.3 to 98.5%, respectively, and NS1 sensitivity and specificity ranged from 49.7 to 92.9% and 22.2 to 89.0%, respectively. Sensitivity varied by timing of specimen collection and DENV serotype. Combined test results moderately improved the sensitivity. The use of RDTs identified dengue as the cause of AFI outbreaks where reference diagnostic testing was limited or unavailable. PMID- 27225410 TI - Genomic and Phenotypic Analyses Reveal the Emergence of an Atypical Salmonella enterica Serovar Senftenberg Variant in China. AB - Human infections with Salmonella enterica subspecies enterica serovar Senftenberg are often associated with exposure to poultry flocks, farm environments, or contaminated food. The recent emergence of multidrug-resistant isolates has raised public health concerns. In this study, comparative genomics and phenotypic analysis were used to characterize 14 Salmonella Senftenberg clinical isolates recovered from multiple outbreaks in Shenzhen and Shanghai, China, between 2002 and 2011. Single-nucleotide polymorphism analyses identified two phylogenetically distinct clades of S Senftenberg, designated SC1 and SC2, harboring variations in Salmonella pathogenicity island 1 (SPI-1) and SPI-2 and exhibiting distinct biochemical and phenotypic signatures. Although the two variants shared the same serotype, the SC2 isolates of sequence type 14 (ST14) harbored intact SPI-1 and 2 and hence were characterized by possessing efficient invasion capabilities. In contrast, the SC1 isolates had structural deletion patterns in both SPI-1 and -2 that correlated with an impaired capacity to invade cultured human cells and also the year of their isolation. These atypical SC1 isolates also lacked the capacity to produce hydrogen sulfide. These findings highlight the emergence of atypical Salmonella Senftenberg variants in China and provide genetic validation that variants lacking SPI-1 and regions of SPI-2, which leads to impaired invasion capacity, can still cause clinical disease. These data have identified an emerging public health concern and highlight the need to strengthen surveillance to detect the prevalence and transmission of nontyphoidal Salmonella species. PMID- 27225412 TI - Comparison of Mycobacterial Growth Indicator Tube with Culture on RGM Selective Agar for Detection of Mycobacteria in Sputum Samples from Patients with Cystic Fibrosis. AB - Nontuberculous mycobacteria (NTM) are an important cause of pulmonary disease in patients with cystic fibrosis (CF). A new culture medium (RGM medium) for the isolation of rapidly growing mycobacteria from the sputum of cystic fibrosis patients has recently been reported. The aim of this study was to compare culture of sputum samples on RGM medium with culture using a standard automated liquid culture method. Sputum samples were obtained from 187 distinct patients with CF attending King's College Hospital, London, United Kingdom. Each sample was decontaminated with 3% oxalic acid and inoculated into a mycobacterial growth indicator tube (MGIT) that was monitored for 42 days using the Bactec MGIT 960 instrument. Each sample was also cultured, without decontamination, onto RGM medium, which was incubated for 10 days at 30 degrees C. Mycobacteria were isolated from 28 patients (prevalence, 15%). Mycobacteria were detected in 24 samples (86%) using the MGIT and in 23 samples (82%) using RGM medium (P = 1.00). In this setting, RGM medium showed sensitivity equivalent to that of the MGIT for isolation of NTM from the sputum of patients with CF. RGM medium offers a simple, convenient tool that can be embedded into routine culture methods, allowing the culture of all sputum samples that are submitted from patients with CF. PMID- 27225411 TI - Comparison of Two Widely Used Human Papillomavirus Detection and Genotyping Methods, GP5+/6+-Based PCR Followed by Reverse Line Blot Hybridization and Multiplex Type-Specific E7-Based PCR. AB - GP5+/6+-based PCR followed by reverse line blot hybridization (GP5+/6+RLB) and multiplex type-specific PCR (E7-MPG) are two human papillomavirus (HPV) genotyping methodologies widely applied in epidemiological research. We investigated their relative analytical performance in 4,662 samples derived from five studies in Bhutan, Rwanda, and Mongolia coordinated by the International Agency for Research on Cancer (IARC). A total of 630 samples were positive by E7 MPG only (13.5%), 24 were positive by GP5+/6+RLB only (0.5%), and 1,014 were positive (21.8%) by both methods. Ratios of HPV type-specific positivity of the two tests (E7-MPG:GP5+/6+RLB ratio) were calculated among 1,668 samples that were HPV positive by one or both tests. E7-MPG:GP5+/6+RLB ratios were >1 for all types and highly reproducible across populations and sample types. E7-MPG:GP5+/6+RLB ratios were highest for HPV53 (7.5) and HPV68 (7.1). HPV16 (1.6) and HPV18 (1.7) had lower than average E7-MPG:GP5+/6+RLB ratios. Among E7-MPG positive infections, median mean fluorescence intensity (MFI; a semiquantitative measure of viral load) tended to be higher among samples positive for the same virus type by GP5+/6+RLB than for those negative for the same type by GP5+/6+RLB. Exceptions, however, included HPV53, -59, and -82, for which the chances of being undetected by GP5+/6+RLB appeared to be MFI independent. Furthermore, the probability of detecting an additional type by E7-MPG was higher when another type was already detected by GP5+/6+RLB, suggesting the existence of masking effects due to competition for GP5+/6+ PCR primers. In conclusion, this analysis is not an evaluation of clinical performance but may inform choices for HPV genotyping methods in epidemiological studies, when the relative merits and dangers of sensitivity versus specificity for individual types should be considered, as well as the potential to unmask nonvaccine types following HPV vaccination. PMID- 27225413 TI - A Computationally Designed Serological Assay for Porcine Epidemic Diarrhea Virus. AB - The periodic emergence of new infectious agents and the genetic and antigenic evolution of existing agents necessitate the improvement of technology for the rapid development of diagnostic assays. The porcine epidemic diarrhea virus (PEDV) emerged in the United States in 2013, causing severe economic damage to the pork industry. The primary goal of this study was to develop methods to reduce the lead time for serological assay development. An approach involving the computational prediction of diagnostic targets, followed by a rapid synthesis of antigens, was adopted to achieve this objective. To avoid cross-reactivity with other closely related swine coronaviruses, the N protein sequences of PEDV were analyzed to identify sequences unique to PEDV. The potential antigenicity of the identified sequence was predicted computationally using the Jameson-Wolf method. A sequence with a high antigenic index was rapidly synthesized using an in vitro transcription and translation system to yield the diagnostic antigen. The computationally designed enzyme-linked immunosorbent assay (ELISA) was validated using 169 field sera, whose statuses were determined by a PEDV-specific immunofluorescence assay. Comparison of the computationally designed ELISA to a conventionally developed ELISA, using bacterially expressed N protein, and to the immunofluorescence assay showed a high degree of agreement among the three tests (mean kappa statistic, 0.842). The sensitivity and specificity, compared to the conventionally developed assay, were 90.62 and 95.18, respectively. Therefore, the described approach is useful in reducing the development time for serological assays in the face of an infectious disease outbreak. PMID- 27225414 TI - Systematic analysis of mutation distribution in three dimensional protein structures identifies cancer driver genes. AB - Protein tertiary structure determines molecular function, interaction, and stability of the protein, therefore distribution of mutation in the tertiary structure can facilitate the identification of new driver genes in cancer. To analyze mutation distribution in protein tertiary structures, we applied a novel three dimensional permutation test to the mutation positions. We analyzed somatic mutation datasets of 21 types of cancers obtained from exome sequencing conducted by the TCGA project. Of the 3,622 genes that had >=3 mutations in the regions with tertiary structure data, 106 genes showed significant skew in mutation distribution. Known tumor suppressors and oncogenes were significantly enriched in these identified cancer gene sets. Physical distances between mutations in known oncogenes were significantly smaller than those of tumor suppressors. Twenty-three genes were detected in multiple cancers. Candidate genes with significant skew of the 3D mutation distribution included kinases (MAPK1, EPHA5, ERBB3, and ERBB4), an apoptosis related gene (APP), an RNA splicing factor (SF1), a miRNA processing factor (DICER1), an E3 ubiquitin ligase (CUL1) and transcription factors (KLF5 and EEF1B2). Our study suggests that systematic analysis of mutation distribution in the tertiary protein structure can help identify cancer driver genes. PMID- 27225415 TI - Electrophysiology Alterations in Primary Visual Cortex Neurons of Retinal Degeneration (S334ter-line-3) Rats. AB - The dynamic nature of the brain is critical for the success of treatments aimed at restoring vision at the retinal level. The success of these treatments relies highly on the functionality of the surviving neurons along the entire visual pathway. Electrophysiological properties at the retina level have been investigated during the progression of retinal degeneration; however, little is known about the changes in electrophysiological properties that occur in the primary visual cortex (V1) during the course of retinal degeneration. By conducting extracellular recording, we examined the electrophysiological properties of V1 in S334ter-line-3 rats (a transgenic model of retinal degeneration developed to express a rhodopsin mutation similar to that found in human retinitis pigmentosa patients). We measured the orientation tuning, spatial and temporal frequency tunings and the receptive field (RF) size for 127 V1 neurons from 11 S334ter-3 rats and 10 Long-Evans (LE) rats. V1 neurons in the S334ter-3 rats showed weaker orientation selectivity, lower optimal spatial and temporal frequency values and a smaller receptive field size compared to the LE rats. These results suggest that the visual cognitive ability significantly changes during retinal degeneration. PMID- 27225416 TI - Origin of Structural Transformation in Mono- and Bi-Layered Molybdenum Disulfide. AB - Mono- and multi-layered molybdenum disulfide (MoS2) is considered to be one of the next generation anode materials for rechargeable ion batteries. Structural transformation from trigonal prismatic (2H) to octahedral (1T) upon lithium or sodium intercalation has been in-situ observed experimentally using transmission electron microscope during studies of their electrochemical dynamics processes. In this work, we explored the fundamental mechanisms of this structural transformation in both mono- and bi-layered MoS2 using density functional theory. For the intercalated MoS2, the Li and Na donate their electrons to the MoS2. Based on the theoretical analysis, we confirmed that, for the first time, electron transfer is dominant in initiating this structural transformation, and the results provide an in-depth understanding of the transformation mechanism induced by the electron doping. The critical values of electron concentrations for this structural transformation are decreased with increasing the layer thickness. PMID- 27225417 TI - Long-term survival with surgery for metachronous retroperitoneal lymph node and pancreatic metastases after curative resection of rectal cancer: a case report. AB - BACKGROUND: The possible benefits of the surgical resection of multiple metastases in rare sites from colorectal cancer (CRC) are still unclear. Therefore, more cases are needed to investigate the surgical outcomes of these diseases. A very rare case in which the simultaneous resection of both the metachronous retroperitoneal lymph node and pancreatic metastases from rectal cancer was successfully performed is reported. CASE PRESENTATION: A 68-year-old man had undergone low anterior resection for rectal cancer. Eight months later, computed tomography showed an enlarged lymph node located below the aortic bifurcation and a pancreatic head tumor. Positron emission tomography showed increased focal uptake in these two lesions. With a diagnosis of retroperitoneal lymph node metastasis from rectal cancer and primary pancreatic cancer or pancreatic metastasis from rectal cancer, resection of the enlarged retroperitoneal lymph node and pancreaticoduodenectomy were performed. The pathological examination showed that both resected lesions were metastases from the primary rectal cancer. After the metastasectomy, the patient was given systemic chemotherapy, which was discontinued due to an adverse event. He was then followed up routinely without any medication. Sixty-nine months after the metastasectomy, he is alive without any indication of recurrence. CONCLUSIONS: Thus, even with metastases from CRC located in rare sites, an acceptable outcome can be expected following curative surgical resection in carefully selected patients. Whenever possible, an aggressive surgical approach should be included in the multimodality treatment of metastatic CRC. PMID- 27225418 TI - Taphophobia and 'life preserving coffins' in the nineteenth century. AB - In 1891 the Italian psychiatrist Enrico Morselli (1852-1929) described taphophobia, defining it as an extreme condition of claustrophobia due to the fear of being buried alive. This rare psychopathological phenomenon reflects an ancient fear, and its origin is not known. Taphophobia is closely linked to the problem of apparent death and premature burial. In the nineteenth century, scientists and authors paid particular attention to the issue of apparent death, and special devices (safety coffins) were invented to ensure that premature burial was avoided. Nowadays taphophobia is quite a rare psychiatric disorder; different forms of social anxiety disorders are much more widespread. Its modern equivalent could be the fear of organs harvested from a patient who is still alive. PMID- 27225419 TI - Optimization of Electrospray Ionization by Statistical Design of Experiments and Response Surface Methodology: Protein-Ligand Equilibrium Dissociation Constant Determinations. AB - Electrospray ionization mass spectrometry (ESI-MS) binding studies between proteins and ligands under native conditions require that instrumental ESI source conditions are optimized if relative solution-phase equilibrium concentrations between the protein-ligand complex and free protein are to be retained. Instrumental ESI source conditions that simultaneously maximize the relative ionization efficiency of the protein-ligand complex over free protein and minimize the protein-ligand complex dissociation during the ESI process and the transfer from atmospheric pressure to vacuum are generally specific for each protein-ligand system and should be established when an accurate equilibrium dissociation constant (KD) is to be determined via titration. In this paper, a straightforward and systematic approach for ESI source optimization is presented. The method uses statistical design of experiments (DOE) in conjunction with response surface methodology (RSM) and is demonstrated for the complexes between Plasmodium vivax guanylate kinase (PvGK) and two ligands: 5'-guanosine monophosphate (GMP) and 5'-guanosine diphosphate (GDP). It was verified that even though the ligands are structurally similar, the most appropriate ESI conditions for KD determination by titration are different for each. Graphical Abstract ?. PMID- 27225420 TI - NF-kB2 induces senescence bypass in melanoma via a direct transcriptional activation of EZH2. PMID- 27225421 TI - Relationship Between Femoral Vascular Closure Devices and Short-Term Mortality From 271 845 Percutaneous Coronary Intervention Procedures Performed in the United Kingdom Between 2006 and 2011: A Propensity Score-Corrected Analysis From the British Cardiovascular Intervention Society. AB - BACKGROUND: The impact of vascular closure devices (VCDs) via the femoral arterial access site on short-term mortality in patients undergoing percutaneous coronary intervention is currently unknown. METHODS AND RESULTS: The association between femoral arterial vascular access site management (manual pressure [including external clamp] versus VCD) and 30-day mortality was examined in a national real-world registry of 271 845 patients undergoing percutaneous coronary intervention for elective, non-ST-segment-elevation myocardial infarction and ST segment-elevation myocardial infarction indications in the United Kingdom between 2006 and 2011. Crude and propensity score-corrected analyses were performed using Cox regression, with additional analyses undertaken in clinically relevant subgroups; 40.1% (n=109 001) of subjects were treated with manual pressure and 59.9% (n=162 844) with VCD. Subjects treated with VCD had fewer comorbidities and were less likely to present with ST-segment-elevation myocardial infarction and cardiogenic shock (P<0.001). Crude 30-day mortality was lower in the group treated with VCD compared with manual pressure (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.54-0.61; 1.4% versus 2.4%, log rank P<0.0001), findings that were substantially reduced but persisted after propensity score correction (HR, 0.91; 95% CI, 0.86-0.97; 1.8% versus 2.0% versus P<0.001). A more pronounced association of VCD with a reduction in 30-day mortality was evident in females (HR, 0.85; 95% CI, 0.77-0.94; Pinteraction=0.037), presentation with acute coronary syndrome (HR, 0.88; 95% CI, 0.83-0.94; Pinteraction=0.0027), or recent lysis (HR, 0.63; 95% CI, 0.40-1.01; Pinteraction=0.0001). CONCLUSIONS: When compared with manual pressure, VCD was associated with a minor short-term (30-day) prognostic benefit after propensity score correction in the global population and clinically relevant subgroups. The potential for residual confounding factors impacting on short-term mortality cannot be excluded, despite the study having measured and balanced all recorded confounder factors. PMID- 27225422 TI - Evidence for selection maintaining MHC diversity in a rodent species despite strong density fluctuations. AB - Strong spatiotemporal variation in population size often leads to reduced genetic diversity limiting the adaptive potential of individual populations. Key genes of adaptive variation are encoded by the immune genes of the major histocompatibility complex (MHC) playing an essential role in parasite resistance. How MHC variation persists in rodent populations that regularly experience population bottlenecks remains an important topic in evolutionary genetics. We analysed the consequences of strong population fluctuations on MHC class II DRB exon 2 diversity in two distant common vole (Microtus arvalis) populations in three consecutive years using a high-throughput sequencing approach. In 143 individuals, we detected 25 nucleotide alleles translating into 14 unique amino acid MHC alleles belonging to at least three loci. Thus, the overall allelic diversity and amino acid distance among the remaining MHC alleles, used as a surrogate for the range of pathogenic antigens that can be presented to T-cells, are still remarkably high. Both study populations did not show significant population differentiation between years, but significant differences were found between sites. We concluded that selection processes seem to be strong enough to maintain moderate levels of MHC diversity in our study populations outcompeting genetic drift, as the same MHC alleles were conserved between years. Differences in allele frequencies between populations might be the outcome of different local parasite pressures and/or genetic drift. Further understanding of how pathogens vary across space and time will be crucial to further elucidate the mechanisms maintaining MHC diversity in cyclic populations. PMID- 27225423 TI - Efficiency Enhancement Mechanism for Poly(3, 4 ethylenedioxythiophene):Poly(styrenesulfonate)/Silicon Nanowires Hybrid Solar Cells Using Alkali Treatment. AB - The efficiency enhancement mechanism of the alkali-treated Si nanowire (SiNW) solar cells is discussed and analyzed in detail, which is important to control the useful photovoltaic process. All the results demonstrate that the photovoltaic performance enhancement of alkali-treated SiNW device steps from the formation of the good core-shell heterojunction, which consequently enhances the junction area, promotes fast separating and transporting of electron and hole pairs, and reduces the carrier surface combination. It also indicates that alkali treatment for SiNWs is a promising processing as an economical method for the formation of good core-shell SiNW/polymer heterojunction. PMID- 27225424 TI - A Nanopore-Structured Nitrogen-Doped Biocarbon Electrocatalyst for Oxygen Reduction from Two-Step Carbonization of Lemna minor Biomass. AB - So far, the development of highly active and stable carbon-based electrocatalysts for oxygen reduction reaction (ORR) to replace commercial Pt/C catalyst is a hot topic. In this study, a new nanoporous nitrogen-doped carbon material was facilely designed by two-step pyrolysis of the renewable Lemna minor enriched in crude protein under a nitrogen atmosphere. Electrochemical measurements show that the onset potential for ORR on this carbon material is around 0.93 V (versus reversible hydrogen electrode), slightly lower than that on the Pt/C catalyst, but its cycling stability is higher compared to the Pt/C catalyst in an alkaline medium. Besides, the ORR at this catalyst approaches to a four-electron transfer pathway. The obtained ORR performance can be basically attributed to the formation of high contents of pyridinic and graphitic nitrogen atoms inside this catalyst. Thus, this work opens up the path in the ORR catalysis for the design of nitrogen-doped carbon materials utilizing aquatic plants as starting precursors. PMID- 27225425 TI - MicroRNA-126 contributes to Niaspan treatment induced vascular restoration after diabetic retinopathy. AB - Diabetic retinopathy (DR) is a serious microvascular complication of diabetes and a major cause of blindness in the developing world. Early diabetic retinopathy is characterized by a loss of pericytes and vascular endothelial cells, a breakdown of the blood-retinal barrier, vascular dysfunction and vascular neuroinflammation. However, optimal treatment options and related mechanisms are still unclear. MicroRNA-126 (miR-126) plays a potential role in the pathogenesis in DR, which may regulate VEGF, Ang-1 and VCAM-1 expressions. This study investigated the therapeutic effects and mechanisms of Niaspan treatment of DR in diabetes (DM) rats. DM rats exhibits significantly decreased miR-126 and tight junction Claudin-5/Occludin/ZO-1 genes expression, and increased Blood retinal barrier (BRB) breakdown, retinal apoptosis and VEGF/VEGFR, as well as VCAM-1/CD45 expressions in the retina compared to normal control group. Niaspan treatment significantly improved clinical and histopathological outcomes; decreased the expressions of VEGF/VEGFR, VCAM-1/CD45, apoptosis and BRB breakdown, significantly increased tight junction proteins and Ang-1/Tie-2 expressions, as well as increased retinal miR-126 expression compared to non-treatment diabetic rats. These data are the first to show that Niaspan treatment ameliorates DR through its repair vascular and inhibits inflammatory effects, and also suggest that the miR-126 pathway may contribute to Niaspan treatment induced benefit effects. PMID- 27225427 TI - The decisive role of free water in determining homogenous ice nucleation behavior of aqueous solutions. AB - It is a challenging issue to quantitatively characterize how the solute and pressure affect the homogeneous ice nucleation in a supercooled solution. By measuring the glass transition behavior of solutions, a universal feature of water-content dependence of glass transition temperature is recognized, which can be used to quantify hydration water in solutions. The amount of free water can then be determined for water-rich solutions, whose mass fraction, Xf, is found to serve as a universal relevant parameter for characterizing the homogeneous ice nucleation temperature, the meting temperature of primary ice, and even the water activity of solutions of electrolytes and smaller organic molecules. Moreover, the effects of hydrated solute and pressure on ice nucleation is comparable, and the pressure, when properly scaled, can be incorporated into the universal parameter Xf. These results help establish the decisive role of free water in determining ice nucleation and other relevant properties of aqueous solutions. PMID- 27225426 TI - Budding of Tiger Frog Virus (an Iridovirus) from HepG2 Cells via Three Ways Recruits the ESCRT Pathway. AB - The cellular endosomal sorting complex required for transport (ESCRT) pathway is a multifunctional pathway involved in cell physiological activities. While the majority of RNA viruses bearing L-domains are known to hijack the ESCRT pathway to complete the budding process, the budding of large and complex enveloped DNA viruses, especially iridoviruses, has been rarely investigated. In the present study, we use the tiger frog virus (TFV) as a model to investigate whether iridoviruses are released from host cells through the ESCRT pathway. Inhibition of class E proteins and auxiliary proteins (VPS4A, VPS4B, Tsg101, Alix, and Nedd4.1) reduces extracellular virion production, which preliminarily indicates that the ESCRT pathway is involved in TFV release. The respective interactions of TFV VP031L, VP065L, VP093L with Alix, Tsg101, Nedd4 suggest the underlying molecular mechanism by which TFV gets access to the ESCRT pathway. Co-depletion of Alix, Tsg101, and Nedd4.1 induces a significant reduction in extracellular virion production, which implies the functional redundancy of host factors in TFV budding. Those results are first observation that iridovirus gains access to ESCRT pathway through three ways of interactions between viral proteins and host proteins. Our study provides a better understanding of the budding mechanism of enveloped DNA viruses. PMID- 27225430 TI - A numerical scheme for the early steps of nucleation-aggregation models. AB - In the formation of large clusters out of small particles, the initializing step is called the nucleation, and consists in the spontaneous reaction of agents which aggregate into small and stable polymers called nuclei. After this early step, the polymers are involved in a number of reactions such as polymerization, fragmentation and coalescence. Since there may be several orders of magnitude between the size of a particle and the size of an aggregate, building efficient numerical schemes to capture accurately the kinetics of the reaction is a delicate step of key importance. In this article, we propose a conservative scheme, based on finite volume methods on an adaptive grid, which is capable of simulating well the early steps of the reaction as well as the later chain reactions. PMID- 27225429 TI - An ultra-high density linkage map and QTL mapping for sex and growth-related traits of common carp (Cyprinus carpio). AB - High density genetic linkage maps are essential for QTL fine mapping, comparative genomics and high quality genome sequence assembly. In this study, we constructed a high-density and high-resolution genetic linkage map with 28,194 SNP markers on 14,146 distinct loci for common carp based on high-throughput genotyping with the carp 250 K single nucleotide polymorphism (SNP) array in a mapping family. The genetic length of the consensus map was 10,595.94 cM with an average locus interval of 0.75 cM and an average marker interval of 0.38 cM. Comparative genomic analysis revealed high level of conserved syntenies between common carp and the closely related model species zebrafish and medaka. The genome scaffolds were anchored to the high-density linkage map, spanning 1,357 Mb of common carp reference genome. QTL mapping and association analysis identified 22 QTLs for growth-related traits and 7 QTLs for sex dimorphism. Candidate genes underlying growth-related traits were identified, including important regulators such as KISS2, IGF1, SMTLB, NPFFR1 and CPE. Candidate genes associated with sex dimorphism were also identified including 3KSR and DMRT2b. The high-density and high-resolution genetic linkage map provides an important tool for QTL fine mapping and positional cloning of economically important traits, and improving common carp genome assembly. PMID- 27225428 TI - Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels. AB - Circulating insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome-wide association study [GWAS] and 48 in reported candidate genes). In ~700 men without prostate cancer and two replication cohorts (N ~ 900 and ~9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF-I, IGF-II, IGFBP-2 and IGFBP-3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs. high (>= 7) Gleason grade, localised vs. advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF-II and IGFBP-3, less so for IGF-I. Rs11977526 was associated with high (vs. low) Gleason grade (OR per IGF-II/IGFBP-3 level-raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF-II (~265 ng/mL) on risk of high vs. low grade disease as 1.14 (95% CI: 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker. PMID- 27225431 TI - Species-abundance distributions under colored environmental noise. AB - Natural communities at all spatiotemporal scales are subjected to a wide variety of environmental pressures, resulting in random changes in the demographic rates of species populations. Previous analyses have examined the effects of such environmental variance on the long-term growth rate and time to extinction of single populations, but studies of its effects on the diversity of communities remain scarce. In this study, we construct a new master-equation model incorporating demographic and environmental variance and use it to examine how statistical patterns of diversity, as encapsulated by species-abundance distributions (SADs), are altered by environmental variance. Unlike previous diffusion models with environmental variance uncorrelated in time (white noise), our model allows environmental variance to be correlated at different timescales (colored noise), thus facilitating representation of phenomena such as yearly and decadal changes in climate. We derive an exact analytical expression for SADs predicted by our model together with a close approximation, and use them to show that the main effect of adding environmental variance is to increase the proportion of abundant species, thus flattening the SAD relative to the log series form found in the neutral case. This flattening effect becomes more prominent when environmental variance is more correlated in time and has greater effects on species' demographic rates, holding all other factors constant. Furthermore, we show how our model SADs are consistent with those from diffusion models near the white noise limit. The mathematical techniques we develop are catalysts for further theoretical work exploring the consequences of environmental variance for biodiversity. PMID- 27225432 TI - Whole-grain intake and total, cardiovascular, and cancer mortality: a systematic review and meta-analysis of prospective studies. AB - BACKGROUND: The potential role of whole grain in preventing various mortality outcomes has been inconsistently reported in a wealth of prospective observational studies. OBJECTIVE: We evaluated the relations between whole-grain intake and risks of dying from any cause, cardiovascular disease (CVD), and cancer through a meta-analytic approach. DESIGN: Relevant studies were identified by searching PubMed and EMBASE databases and bibliographies of retrieved full publications. Summary RRs with 95% CIs were calculated with a random-effects model. RESULTS: Thirteen studies on total mortality (104,061 deaths), 12 on CVD mortality (26,352 deaths), and 8 on cancer mortality (34,797 deaths) were included. Three studies reported whole-grain intake, and the remaining studies reported whole-grain product intake. In the dose-response analysis in which the intake of whole-grain products was converted to the amount of whole grain, the summary RRs for an increment in whole-grain intake of 50 g/d were 0.78 (95% CI: 0.67, 0.91) for total mortality, 0.70 (95% CI: 0.61, 0.79) for CVD mortality, and 0.82 (95% CI: 0.69, 0.96) for cancer mortality. A similar reduction was observed for the mortality from ischemic heart disease (RR: 0.68; 95% CI: 0.55, 0.84) but not from stroke (RR: 0.93; 95% CI: 0.54, 1.62). There was evidence of nonlinear associations of whole-grain intake with total (P-nonlinearity < 0.001) and CVD mortality (P-nonlinearity <0.001), but not with cancer mortality (P-nonlinearity = 0.12), with the curves for the associations appearing slightly steeper at lower ranges (<35 g/d) of the intake than at higher ranges. CONCLUSIONS: Our findings suggest significant inverse relations between whole-grain intake and mortality due to any cause, CVD, or cancer. The findings support the recommendation of increasing whole-grain intake to improve public health. PMID- 27225433 TI - Serum caffeine and paraxanthine concentrations and menstrual cycle function: correlations with beverage intakes and associations with race, reproductive hormones, and anovulation in the BioCycle Study. AB - BACKGROUND: Clinicians often recommend limiting caffeine intake while attempting to conceive; however, few studies have evaluated the associations between caffeine exposure and menstrual cycle function, and we are aware of no previous studies assessing biological dose via well-timed serum measurements. OBJECTIVES: We assessed the relation between caffeine and its metabolites and reproductive hormones in a healthy premenopausal cohort and evaluated potential effect modification by race. DESIGN: Participants (n = 259) were followed for <=2 menstrual cycles and provided fasting blood specimens <=8 times/cycle. Linear mixed models were used to estimate associations between serum caffeine biomarkers and geometric mean reproductive hormones, whereas Poisson regression was used to assess risk of sporadic anovulation. RESULTS: The highest compared with the lowest serum caffeine tertile was associated with lower total testosterone [27.9 ng/dL (95% CI: 26.7, 29.0 ng/dL) compared with 29.1 ng/dL (95% CI: 27.9, 30.3 ng/dL), respectively] and free testosterone [0.178 ng/mL (95% CI: 0.171, 0.185 ng/dL) compared with 0.186 ng/mL (95% CI: 0.179, 0.194 ng/dL), respectively] after adjustment for age, race, percentage of body fat, daily vigorous exercise, perceived stress, depression, dietary factors, and alcohol intake. The highest tertiles compared with the lowest tertiles of caffeine and paraxanthine were also associated with reduced risk of anovulation [adjusted RRs (aRRs): 0.39 (95% CI: 0.18, 0.87) and 0.40 (95% CI: 0.18, 0.87), respectively]. Additional adjustment for self-reported coffee intake did not alter the reproductive hormone findings and only slightly attenuated the results for serum caffeine and paraxanthine and anovulation. Although reductions in the concentrations of total testosterone and free testosterone and decreased risk of anovulation were greatest in Asian women, there was no indication of effect modification by race. CONCLUSION: Caffeine intake, irrespective of the beverage source, may be associated with reduced testosterone and improved menstrual cycle function in healthy premenopausal women. PMID- 27225434 TI - Dietary epicatechin intake and 25-y risk of cardiovascular mortality: the Zutphen Elderly Study. AB - BACKGROUND: Prospective cohort studies have shown that the consumption of cocoa and tea is associated with lower risk of cardiovascular diseases (CVDs), and cocoa and tea have been shown to improve CVD risk factors in randomized controlled trials. Cocoa and tea are major dietary sources of the flavan-3-ol epicatechin. OBJECTIVE: We investigated the associations of dietary epicatechin intake with 25-y CVD mortality in elderly Dutch men. DESIGN: We used data from the Zutphen Elderly Study, which was a prospective cohort study of 774 men aged 65-84 y in 1985. Epicatechin intake was estimated 4 times in 15 y with the use of the crosscheck dietary history method. Time-dependent Cox proportional hazards models were used to investigate repeated measures of epicatechin intake in relation to 25-y CVD mortality. RESULTS: Mean intake of epicatechin was 15.2 +/- 7.7 mg/d, and the major dietary sources were tea (51%), apples (28%), and cocoa (7%). During 25 y of follow-up, 329 men died from CVD, 148 died from coronary heart disease (CHD), and 72 men died from stroke. Risk of CHD mortality was 38% lower in men in the top tertile of epicatechin intake than in men in the bottom tertile of epicatechin intake (HR: 0.62; 95% CI: 0.39, 0.98). Epicatechin intake was also significantly associated with 46% lower risk of CVD mortality in men with prevalent CVD (HR: 0.54; 95% CI: 0.31, 0.96) but not in men who were free of CVD. CONCLUSIONS: We show, for the first time to our knowledge, that epicatechin intake is inversely related to CHD mortality in elderly men and to CVD mortality in prevalent cases of CVD. More studies are needed before conclusions can be drawn. PMID- 27225435 TI - Ultra-long-term human salt balance studies reveal interrelations between sodium, potassium, and chloride intake and excretion. AB - BACKGROUND: The intake of sodium, chloride, and potassium is considered important to healthy nutrition and cardiovascular disease risk. Estimating the intake of these electrolytes is difficult and usually predicated on urine collections, commonly for 24 h, which are considered the gold standard. We reported on data earlier for sodium but not for potassium or chloride. OBJECTIVE: We were able to test the value of 24-h urine collections in a unique, ultra-long-term balance study conducted during a simulated trip to Mars. DESIGN: Four healthy men were observed while ingesting 12 g salt/d, 9 g salt/d, and 6 g salt/d, while their potassium intake was maintained at 4 g/d for 105 d. Six healthy men were studied while ingesting 12 g salt/d, 9 g salt/d, and 6 g salt/d, with a re-exposure of 12 g/d, while their potassium intake was maintained at 4 g/d for 205 d. Food intake and other constituents were recorded every day for each subject. All urine output was collected daily. RESULTS: Long-term urine recovery rates for all 3 electrolytes were very high. Rather than the expected constant daily excretion related to daily intake, we observed remarkable daily variation in excretion, with a 7-d infradian rhythm at a relatively constant intake. We monitored 24-h aldosterone excretion in these studies and found that aldosterone appeared to be the regulator for all 3 electrolytes. We report Bland-Altman analyses on the value of urine collections to estimate intake. CONCLUSIONS: A single 24-h urine collection cannot predict sodium, potassium, or chloride intake; thus, multiple collections are necessary. This information is important when assessing electrolyte intake in individuals. PMID- 27225436 TI - Water-loss (intracellular) dehydration assessed using urinary tests: how well do they work? Diagnostic accuracy in older people. AB - BACKGROUND: Water-loss dehydration (hypertonic, hyperosmotic, or intracellular dehydration) is due to insufficient fluid intake and is distinct from hypovolemia due to excess fluid losses. Water-loss dehydration is associated with poor health outcomes such as disability and mortality in older people. Urine specific gravity (USG), urine color, and urine osmolality have been widely advocated for screening for dehydration in older adults. OBJECTIVE: We assessed the diagnostic accuracy of urinary measures to screen for water-loss dehydration in older people. DESIGN: This was a diagnostic accuracy study of people aged >=65 y taking part in the DRIE (Dehydration Recognition In our Elders; living in long-term care) or NU-AGE (Dietary Strategies for Healthy Ageing in Europe; living in the community) studies. The reference standard was serum osmolality, and index tests included USG, urine color, urine osmolality, urine cloudiness, additional dipstick measures, ability to provide a urine sample, and the volume of a random urine sample. Minimum useful diagnostic accuracy was set at sensitivity and specificity >=70% or a receiver operating characteristic plot area under the curve >=0.70. RESULTS: DRIE participants (women: 67%; mean age: 86 y; n = 162) had more limited cognitive and functional abilities than did NU-AGE participants (women: 64%; mean age: 70 y; n = 151). Nineteen percent of DRIE participants and 22% of NU-AGE participants were dehydrated (serum osmolality >300 mOsm/kg). Neither USG nor any other potential urinary tests were usefully diagnostic for water-loss dehydration. CONCLUSIONS: Although USG, urine color, and urinary osmolality have been widely advocated for screening for dehydration in older adults, we show, in the largest study to date to our knowledge, that their diagnostic accuracy is too low to be useful, and these measures should not be used to indicate hydration status in older people (either alone or as part of a wider tranche of tests). There is a need to develop simple, inexpensive, and noninvasive tools for the assessment of dehydration in older people. The DRIE study was registered at www.researchregister.org.uk as 122273. The NU-AGE trial was registered at clinicialtrials.gov as NCT01754012. PMID- 27225437 TI - Physiological and lactation responses of Egyptian dairy Baladi goats to natural thermal stress under subtropical environmental conditions. AB - The objective of this study was to evaluate the impact of thermal stress on milk production and physiological traits of Baladi goats under subtropical Egyptian conditions. Sixty dairy Baladi goats were exposed to three different levels of temperature-humidity index (THI), including low (less than 70), moderate (over 70 and up to 80), and high levels (over 80). The influence of THI on the milk composition and physiological, hematological, and biochemical traits was investigated. Rectal temperature and respiration rate were significantly greater at the higher THI than at low and moderate THI (p = 0.016 and 0.002, respectively). Baladi goats had decreased daily milk yield in a rate of 27.3 and 19.3 % at high THI level, compared with low and moderate THI, respectively (p = 0.031). On the contrary, no significant differences have been reported in protein, fat, and total solids percentages at different THI levels. Total leucocyte count, serum glucose, and total protein were significantly reduced at high THI in comparison with low and moderate THI levels (p = 0.043, 0.001, and 0.001, respectively). However, dairy goats maintained relatively stable estimates for erythrocytes count, hemoglobin, serum triglycerides, cholesterol, catalase, total antioxidant capacity, and triiodothyronine at different THI levels. Our results indicate that dairy Baladi goats can tolerate THI levels up to 80; however, variable reduction in milk yield and few biochemical (serum total protein and glucose) and hematological (leucocytes count) parameters have been reported at a THI level higher than 80. PMID- 27225438 TI - Validation of the thermophysiological model by Fiala for prediction of local skin temperatures. AB - The most complete and realistic physiological data are derived from direct measurements during human experiments; however, they present some limitations such as ethical concerns, time and cost burden. Thermophysiological models are able to predict human thermal response in a wide range of environmental conditions, but their use is limited due to lack of validation. The aim of this work was to validate the thermophysiological model by Fiala for prediction of local skin temperatures against a dedicated database containing 43 different human experiments representing a wide range of conditions. The validation was conducted based on root-mean-square deviation (rmsd) and bias. The thermophysiological model by Fiala showed a good precision when predicting core and mean skin temperature (rmsd 0.26 and 0.92 degrees C, respectively) and also local skin temperatures for most body sites (average rmsd for local skin temperatures 1.32 degrees C). However, an increased deviation of the predictions was observed for the forehead skin temperature (rmsd of 1.63 degrees C) and for the thigh during exercising exposures (rmsd of 1.41 degrees C). Possible reasons for the observed deviations are lack of information on measurement circumstances (hair, head coverage interference) or an overestimation of the sweat evaporative cooling capacity for the head and thigh, respectively. This work has highlighted the importance of collecting details about the clothing worn and how and where the sensors were attached to the skin for achieving more precise results in the simulations. PMID- 27225439 TI - Not All Patients with a Pancreatic Neuroendocrine Tumour Will Benefit from All Approved or Recommended Therapeutic Options: A Real-Life Retrospective Study. AB - BACKGROUND: At least nine therapeutic options are recommended or approved for pancreatic neuroendocrine tumour (pNET). The primary endpoint of this study was to determine the number of therapeutic lines given before death. Secondary endpoints were to determine toxic events as a function of number of therapeutic lines and of time. METHODS: Patients with pNET treated between 1998 and 2010 at our centre were characterised. All therapeutic lines were recorded as well as tumour- or toxic-related deaths. Persistent treatment-related toxicity (PTRT) was defined as: chronic kidney disease, anaemia, thrombocytopenia, neutropenia, severe liver failure, cardiac failure and recurrent sepsis, precluding at least one other therapeutic option or second cancers. RESULTS: Ninety-two patients were analysed. The median follow-up was 7 years. The 1-, 2- and 5-year overall survival rates were 90, 81 and 51%, respectively. After 3 and 5 therapeutic lines, 23 and 50% of patients had died, respectively. After 3 and 5 lines, the frequency of toxic events was 8 and 24%, respectively. Overall, 17 toxic events were observed including 6 treatment-related deaths and 11 PTRT. After 1, 2 and 5 years of treatment, the frequency of toxic events was 6, 9 and 16%, respectively. CONCLUSION: Tumour- and toxic-related deaths as well as PTRT may preclude access to all therapeutic options in patients with pNET. Optimised risk benefit sequence should be investigated. PMID- 27225441 TI - Systemic Besnoitiosis in a Juvenile Roe Deer (Capreolus capreolus). AB - Herein, we report the first incidence of systemic besnoitiosis in a male juvenile roe deer Capreolus capreolus. The animal was found dead in an area where bovine besnoitiosis is endemic and showed cachexia and multiple skin erosions in the metacarpal and metatarsal areas. Moreover, round and elevated white structures suggestive of Besnoitia spp. tissue cysts were also present. Twenty-eight tissue samples from different anatomical locations were collected for microscopic lesion and parasite detection through histopathology and PCR. Immunohistochemistry was performed to confirm Besnoitia-positive reaction in the tissue cysts. In addition, the identity of Besnoitia spp. in PCR-positive tissue samples was also investigated using microsatellite (MS) markers, and the comparison of protein disulphide isomerase gene sequences (BbPDI) of B. besnoiti and B. tarandi isolated from cattle and reindeer, respectively. Besnoitia cysts were detected in the skin (several parts), respiratory and upper digestive tracts, eyes, kidney, liver, testicle, cardiac muscle and lymphoid tissue. Remarkably, the presence of tissue cysts in the brain confirmed the capacity of Besnoitia spp. to form tissue cysts in the central nervous system (CNS). Finally, the Besnoitia species detected showed the same MS genotype as B. besnoiti, and BbPDI sequences from roe deer and two B. besnoiti isolates were genetically identical throughout multiple sequence alignment. Thus, for the first time, there is evidence that roe deer might act as an intermediate host of B. besnoiti. Further molecular analyses and parasite isolations are needed to corroborate these findings. PMID- 27225440 TI - Glucose-6-phosphate dehydrogenase deficiency prevalence and genetic variants in malaria endemic areas of Colombia. AB - BACKGROUND: Glucose 6-phosphate dehydrogenase (G6PD) is an enzyme involved in prevention of cellular oxidative damage, particularly protecting erythrocytes from haemolysis. An estimated 400 million people present variable degrees of inherited G6PD deficiency (G6PDd) which puts them at risk for developing haemolysis triggered by several risk factors including multiple drugs and certain foods. Primaquine (PQ) is a widely used anti-malarial drug that can trigger haemolysis in individuals with G6PDd. Intensification of malaria control programmes worldwide and particularly malaria elimination planning in some regions recommend a more extensive use of PQ and related drugs in populations with different G6PDd prevalence. This a preliminary study to assess the prevalence of G6PDd in representative malaria endemic areas of Colombia by measuring G6PD phonotype and genotypes. METHODS: Volunteers (n = 426) from four malaria endemic areas in Colombia (Buenaventura, Tumaco, Tierralta and Quibdo) were enrolled. Blood samples were drawn to evaluate G6PD enzymatic activity by using a quantitative G6PD test and a subset of samples was analysed by PCR-RFLP to determine the frequency of the three most common G6PD genotypic variants: A-, A+ and Mediterranean. RESULTS: A total of 28 individuals (6.56 %) displayed either severe or intermediate G6PDd. The highest prevalence (3.51 %) was in Buenaventura, whereas G6PDd prevalence was lower (<1 %) in Tierralta and Quibdo. G6PD A alleles were the most frequent (15.23 %) particularly in Buenaventura and Tumaco. Overall, a high frequency of G6PD A- genotype, followed by A+ genotype was found in the analysed population. CONCLUSIONS: G6PDd based on enzymatic activity as well as G6PD A allelic variants were found in malaria-endemic populations on the Pacific coast of Colombia, where most of malaria cases are caused by Plasmodium vivax infections. These infections are treated for 14 days with PQ, however there are no official reports of PQ-induced haemolytic crises. Further assessment of G6PDd prevalence in malaria endemic areas in Colombia is crucial in view of possible mass drug administration for malaria elimination in these regions, as well as implementation of appropriate G6PDd diagnostic methods. PMID- 27225442 TI - Management of the exposed total knee prosthesis, a six-year review. AB - INTRODUCTION: An exposed knee prosthesis is a limb threatening condition. Our unit manages such cases according to a multidisciplinary orthoplastic protocol. Whilst early prosthetic joint infection with dehiscence may be managed by Debridement, Antibiotics and Implant Retention (DAIR) and soft tissue coverage, the majority of these cases are chronic and in our unit are managed by Debridement, Explantation, Antibiotics (spacer and systemic) and Flap (DEAF). PATIENTS AND METHODS: We report our experience of managing 17 of these challenging cases, 16 DEAFs and one DAIR and flap. Outcomes were assessed clinically and using the 36-item Short Form Health Survey (SF-36). RESULTS: The mean time from arthroplasty to presentation in our unit was 19months (range: 0.5 80). Whilst an open knee replacement is by definition 'infected', significant microbiological growth from deep tissue/fluid samples was only detected in 14 patients (82%). Five patients (29.4%) subsequently underwent an amputation. Of these five, three patients were extensor deficient at presentation. At follow-up, health-related quality of life scoring using the Short Form-36 demonstrated poor physical function and highlighted differences in emotional function and pain levels between patients whose limbs were salvaged and patients who underwent amputation. CONCLUSION: An exposed total knee prosthesis is a devastating complication, which despite our multidisciplinary salvage approach, has a high rate (5/17=29%) of amputation in this series. Quality of life in this patient group is poor irrespective of limb salvage. Salvage surgery was associated with worse pain, but better emotional profile than patients with an above knee amputation. PMID- 27225444 TI - Foreign body in the appendix presenting as acute appendicitis: a case report. AB - BACKGROUND: Foreign bodies are a rare cause of appendicitis. In most instances, ingested foreign bodies pass through the alimentary tract asymptomatically. However, those that enter the lumen of the vermiform appendix may not be able to re-enter the colon and may initiate an inflammatory process. We report a case of acute appendicitis induced by an unusual foreign body. CASE PRESENTATION: A 26 year-old Sub-Saharan woman presented with right iliac fossa pain and tenderness. She underwent an open appendectomy which revealed a condom fragment within the appendiceal lumen. A detailed retrospective history confirmed accidental ingestion of the condom 2 weeks prior to onset of symptoms. CONCLUSIONS: Although a rare finding, a variety of foreign bodies can be lodged in the appendix and may instigate an inflammatory process. There is a need to increase awareness of the potential dangers of ingested foreign bodies. PMID- 27225443 TI - Nation-wide epidemiological study of Japanese patients with rare viral myelopathy using novel registration system (HAM-net). AB - BACKGROUND: At least one million people are infected with human T-lymphotropic virus type 1 (HTLV-1) in Japan, a small percentage of whom develop HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) or adult T-cell leukemia/lymphoma (ATLL). Patients with HAM/TSP suffer from progressively worsening myelopathic symptoms, such as motor disability and bladder dysfunction, and may become wheelchair-bound or even bedridden. METHODS: To learn more about this rare, debilitating disease, we established the national registration system "HAM-net" in March 2012. We continuously obtain detailed data from enrolled patients using the registration forms and an annual telephone interview. In this retrospective study, we describe the demographics and clinical histories of 383 registered patients from all over Japan. RESULTS: Patients were diagnosed at a median of 53 years old, long after disease onset at 45. Most (55.3 %) were originally from the southernmost regions, Kyushu and Okinawa. The main initial symptoms were difficulty walking (81.9 %), urinary dysfunction (38.5 %), and lower limb sensory disturbances (13.9 %). Many patients reported frequent leg numbness and leg pain, and the vast majority required medical intervention for urinary symptoms and constipation. A median of 8 years elapsed from the onset of motor symptoms to Osame Motor Disability Score (OMDS) 5 (requiring unilateral support), 12.5 years to OMDS 6 (requiring bilateral support), and 18 years to OMDS 9 (unable to walk). Health Assessment Questionnaire - Disability Index (HAQ DI) tasks related to mobility, as opposed to hand motions, were very difficult for HAM/TSP patients and well-correlated with OMDS. Scores on the MOS 36-Item Short-Form Health Survey (SF-36) indicated that physical functioning was severely impaired in HAM/TSP patients. Patients with a history of blood transfusion (19.1 %) were older and suffered from more severe disability as indicated by their high HAQ-DI scores. Patients with a family history of HAM/TSP (8.4 %) were younger and had relatively mild symptoms given their long disease durations; many (15.6 %) also had a relative with ATLL. CONCLUSIONS: The HAM-net national registration system has been an effective tool for gathering personal and clinical data from HAM/TSP patients scattered throughout Japan. We expect to conduct many retrospective and prospective epidemiological studies using HAM-net in the future. PMID- 27225445 TI - Risk-Taking Attitudes of Patients who Seek Health Care: An Exploratory Approach through Lottery Games. AB - BACKGROUND: The characterization of the risk-taking attitude of individuals may be useful for planning health care interventions. It has been attempted to study expressions of risk-taking attitude and evaluate characteristics of a standard lottery game in a population that seeks health care to elicit these attitudes. METHODS: Multicentric cross-sectional study. Demographic and socioeconomic characteristics, quality of life (EuroQol-5D), and health risk behaviors were collected from 662 users of 23 health centers selected by random sampling. Risk taking attitude was evaluated by means of a self-evaluation scale and two lottery games, (L1 and L2; L2 included the possibility of economic losses). Generalized estimating equations (GEE) explicative models were used to evaluate the variability of risk-taking attitude. RESULTS: Nineteen percent out of interviewed people (CI95%: 15.6-22.6%) expressed a high risk appetite, but only 10.0% (CI95% 7.0 to 13.0) were classified as risk-seeking by L2. It was found association between increased risk appetite and having a better perception of health status (0.110, CI95%: 0,007-0,212) or a higher income (0.010, CI95%: 0.017- 0.123) or smoking status (0.059, CI95%: 0.004- 0.114). Being Spanish was associated with lower risk appetite (-0.105, CI95%: -0.005 --0.205), as being over 65 (-0.031, CI95%:- 0.061- -0.001) or a woman (-0.038, CI95%:-0.064- -0.012). The intraclass correlation coefficient for self-evaluation scale was 0.511 (95% CI: 0.372 to 0.629), 0.571 (95% CI: 0.441 to 0.678) for L1 and 0.349 (95% CI: 0.186-0.493) to L2. CONCLUSIONS: People who seek health care express certain inclination to risk, but this feature is attenuated when methodologies involving losses are used. Risk appetite seems greater in young people, males, people with better health, or more income, and in immigrants. Lottery games such as the proposed ones are a simple and useful tool to estimate individuals' inclination to risk. PMID- 27225447 TI - MoS2 Enhanced T-Phase Stabilization and Tunability Through Alloying. AB - Two-dimensional MoS2 is a promising material for nanoelectronics and catalysis, but its potential is not fully exploited since proper control of its multiple phases (H, T, ZT) and electronic properties is lacking. In this theoretical study, alloying is proposed as a method to stabilize the MoS2 T-phase. In particular, MoS2 is alloyed with another material that is known to exist in a monolayer MX2 T-structure, and we show that the formation energy difference among phases decreases even for low impurity concentrations in MoS2, and a relationship between impurity concentration and alloy band gap is established. This method can be potentially applied to many two-dimensional materials to tune/enhance their electronic properties and stabilities in order to suit the desired application. PMID- 27225446 TI - Early reduced myocardial diastolic function in children and adolescents with type 1 diabetes mellitus a population-based study. AB - BACKGROUND: Reduced diastolic myocardial function is an early sign of diabetic cardiomyopathy. The aim of this study was to test the hypothesis that children and adolescents with type 1 diabetes mellitus (T1D), but without other known complications, have early reduced diastolic myocardial function diagnosed with echocardiographic color tissue Doppler imaging (cTDI). METHODS: cTDI examination was carried out in 173 T1D patients and 62 age-matched controls. The T1D-patients were 8-18 years old with (mean (SD)) diabetes duration of 5.6 (3.4) years and HbA1c of 8.4 (1.3). All were treated with either insulin pumps or 4-6 daily insulin injections. cTDI early (E') and late (A') peak diastolic velocities and systolic peak velocity were measured from the lateral, septal, anterior and posterior mitral annulus and from the lateral tricuspidal annulus. RESULTS: Myocardial diastolic function was reduced in the T1D-patients with higher peak A' velocity and lower E'/A'-ratio in all registrations. Overall mean (SD) mitral E'/A'-ratio was 2.3 (0.5) in T1D and 2.7 (0.6) in the controls (p < 0001). The overall mitral E'/A'-ratio was negative associated with blood pressure (BP) and body mass index (BMI). Stratifying all participants into three groups according to BMI (<25, 25-75, >75 centile, respectively), the T1D had lower E'/A'-values in all stratified groups, except for in the highest BMI-group where both T1D and controls had the lowest E'/A'-ratio. Systolic function did not differ in any of the measurements. There were no associations with sex, diabetes duration, carotid artery intima-media-thickness, vessel elasticity or HbA1c. CONCLUSION: Diabetic children and adolescents using modern intensive insulin treatment had echocardiographic signs of reduced diastolic myocardial function despite short duration of disease. The reduced function was associated with higher BP and higher BMI. PMID- 27225448 TI - Cordycepin Affects Multiple Apoptotic Pathways to Mediate Hepatocellular Carcinoma Cell Death. AB - BACKGROUND: Cordycepin possesses anti-inflammatory, anti-metastatic and anti tumor properties. OBJECTIVE: The present study investigates the anti hepatocellular carcinoma activities of cordycepin in in vitro and in vivo models. METHOD: Cell viability, apoptosis rate, intracellular reactive oxygen species (ROS) level and mitochondrial membrane potential (MMP) were determined by 3-(4,5) dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide bromide assay, annexin V/propidium iodide double staining, 2',7'-dichlorfluorescein-diacetate and 5,5',6,6'-tetrachloro-1,1',3,3' tetraethylbenzimidazolylcarbocyanine iodide (JC 1) staining respectively. The expressions of pro-apoptosis and antiapoptosis proteins were detected by western blot. A PLC/PRL/5-xenografted nude mouse model was applied to further confirm the anti-tumor activities of cordycepin. RESULTS: Cordycepin suppressed cell viability, enhanced apoptotic rate, inhibited cell proliferation and increased cleaved poly (ADP-ribose) polymerase (PARP) level. Apoptotic alteration on mitochondria and abnormal changes on b-cell lymphoma 2 (Bcl-2) and b-cell lymphoma-extra large (Bcl-xL) levels were observed in cordycepin-treated cells. Furthermore, cordycepin suppressed the activation of extracellular signaling-regulated kinase (ERKs) and mammalian target of rapamycin (mTOR) in both PLC/PRF/5 and HepG2 cells. Finally, PLC/PRL/5-xengrafted BALB/c athymic nude mice were performed to confirm cordycepin's anti-tumor action. CONCLUSION: Our finding suggests that the anti-hepatocellular carcinoma properties of cordycepin are related to its modulation of multiple anti-apoptotic and pro-apoptotic pathways. Our study provides an experimental evidence for cordycepin as a rational agent for hepatocellular carcinoma treatment. PMID- 27225449 TI - Cetuximab Immunoliposomes Enhance Delivery of 5-FU to Skin Squamous Carcinoma Cells. AB - BACKGROUND: Topical chemotherapy of skin cancers is a promising strategy for reduction of side effects and for improvement of patient compliance. The combination of the chemotherapeutic 5-fluouracil (5-FU) and the anti- EGFR antibody cetuximab is a strategy to inhibit tumor growth. Their skin penetration, however, is hampered by their high hydrophilicity, which could be improved by encapsulation in delivery systems. Furthermore, it is a challenge to encapsulate hydrophilic drugs. The conjugation of an antibody to a liposome, maintaining its activity, is also a difficult task. OBJECTIVE: Thus, we aimed to develop 5-FU liposomes and cetuximab-conjugated liposomes (immunoliposomes) of 5- FU to improve drug cytotoxicity against skin cancer cells. METHOD: We characterized them by particle size, zeta potential, loading efficiency and antibody integrity. To optimize the loading efficiency of 5-FU, a series of liposomes were prepared, using different methods and drug-to-lipid ratios. RESULTS: Liposomes containing DSPC and Chol at drug-to-lipid ratio 0.1 prepared by the thin lipid hydration method resulted in the best 5-FU encapsulation and were chosen to conjugate with cetuximab. Cetuximab was directly coupled to preformed liposomes using DSPE mPEG2000-Mal as an anchor. In A431 skin carcinoma cells, at 72 h, 5-FU liposomes showed a 5-fold lower IC50 than 5-FU solution. Additionally, 5-FU immunoliposomes resulted in a 4-fold lower cetuximab IC50 than cetuximab solution, demonstrating synergism with a combination index lower than 1 and potential to improve 5-FU and cetuximab cytotoxicity. CONCLUSION: Liposomes and immunoliposomes containing 5-FU were developed and cetuximab remained active as demonstrated in cell culture studies. PMID- 27225450 TI - Rapamycin-loaded Immunoliposomes Functionalized with Trastuzumab: A Strategy to Enhance Cytotoxicity to HER2-positive Breast Cancer Cells. AB - BACKGROUND: Liposomes have been employed to improve pharmacokinetics and reduce side effects of drugs. They can be functionalized with antibodies for targeted delivery. While the monoclonal antibody trastuzumab has been employed in the therapy of HER2-positive breast cancer, the resistance developed during treatment has been reported. Rapamycin could be used in combination with trastuzumab for improved therapeutic response. OBJECTIVE: In this study, we aimed to develop rapamycin-loaded liposomes and immunoliposomes with trastuzumab, characterize them and evaluate their in vitro cytotoxicity. METHOD: Formulations were prepared by the thin film hydration method and immunoliposome was conjugated to antibody by covalent bond. Characterization involved particle size, polydispersity, zeta potential, encapsulation efficiency, functionalization efficiency, DSC and FTIR assays. Cell studies were conducted through the MTT assay. RESULTS: SPC:Chol:DSPE PEG formulation prepared at 1:10 drug to lipid ratio presented high encapsulation efficiency, appropriate particle size, low polydispersity, negative zeta potential and colloidal stability. Rapamycin exhibited intermolecular interactions with lipids and underwent crystallinity reduction. Rapamycin-loaded immunoliposomes were prepared with high trastuzumab functionalization efficiency and antibody stability. Cytotoxicity studies showed that the HER2-positive SK-BR 3 cell line was sensitive to trastuzumab, either as free drug or in the context of immunoliposomes, and is more sensitive to rapamycin than the triple negative MDA-MB-231 cells. For MDA-MB-231, the liposomal rapamycin was more cytotoxic than the free drug. Furthermore, the immunoliposomes showed potent cytotoxicity against SK-BR-3 cells. Finally, rapamycin and trastuzumab exhibited in vitro synergistic effect, particularly through immunoliposomes. CONCLUSION: The formulation developed herein has potential for in vivo evaluation. PMID- 27225451 TI - Preparation and Evaluation of in vitro Self-assembling HSA Nanoparticles for Cabazitaxel. AB - BACKGROUND: A novel formulation for cabazitaxel loaded HSA nanoparticle (Cbz-NPs) with non-crosslinking agent participation was reported in this study. OBJECTIVE: A simple method through unfolding of HSA self-assembling nanoparticle for cabazitaxel (Cbz) overcomes the drawbacks of Cbz with high toxicity, poor solubility and low tissue specificity, and avoids side effects of polysorbate 80 which is commonly used for dissolving Cbz. METHOD: The optimum condition was obtained by Response surface methodology (RSM). The NPs were analyzed by differential scanning calorimetry (DSC) and drug release in vitro was also determined. Furthermore, cytotoxicity, cellular uptake were assessed. RESULTS: The experimental encapsulation efficacy (EE) is 52.95%, which is close to the predicted value of 62.44%, indicating the correct prediction, and the nanoscale sized particles enhanced permeability and retention (EPR) effect. Differential scanning calorimetry (DSC) demonstrates an amorphous state of cabazitaxel-NPs, and a sustained release was found in vitro drug release. Human prostate cancer lines PC3 and Human Lung Cancer line A549 were employed for cytotoxicity study by the MTT test. Single solvent with polysorbate 80 showed serious cytotoxicity with the cell viability of only 80% while no toxicity was found in drug-free nanoparticles. Fluorescence intensity of FITC-HSA nanoparticles encapsulating Cbz increased with the incubation time. The cellular localizatiton of cabazitaxel-NPs was observed by confocal microscopy. CONCLUSION: Cbz-NPs may be considered as a viable opportunity for anticancer drug delivery. PMID- 27225453 TI - Filler reinforcement in cross-linked elastomer nanocomposites: insights from fully atomistic molecular dynamics simulation. AB - Using a fully atomistic model, we perform large-scale molecular dynamics simulations of sulfur-cured polybutadiene (PB) and nanosilica-filled PB composites. A well-integrated network without sol fraction is built dynamically by cross-linking the coarse-grained precursor chains in the presence of embedded silica nanoparticles. Initial configurations for subsequent atomistic simulations are obtained by reverse mapping of the well-equilibrated coarse-grained systems. Based on the concept of "maximally inflated knot" introduced by Grosberg et al., we show that the networks simulated in this study behave as mechanically isotropic systems. Analysis of the network topology in terms of graph theory reveals that mechanically inactive tree-like structures are the dominant structural components of the weakly cross-linked elastomer, while cycles are mainly responsible for the transmission of mechanical forces through the network. We demonstrate that quantities such as the system density, thermal expansion coefficient, glass transition temperature and initial Young's modulus can be predicted in qualitative and sometimes even in quantitative agreement with experiments. The nano-filled system demonstrates a notable increase in the glass transition temperature and an approximately two-fold increase in the nearly equilibrium value of elastic modulus relative to the unfilled elastomer even at relatively small amounts of filler particles. We also examine the structural rearrangement of the nanocomposite subjected to tensile deformation. Under high strain-rate loading, the formation of structural defects (microcavities) within the polymer bulk is observed. The nucleation and growth of cavities in the post yielding strain hardening regime mainly take place at the elastomer/nanoparticle interfaces. As a result, the cavities are concentrated just near the embedded nanoparticles. Therefore, while the silica nanofiller increases the elastic modulus of the elastomer, it also creates a more defective structure of higher energy in comparison with the unfilled network. PMID- 27225452 TI - Various shades of red-a systematic analysis of qualitative estimation of ALA derived fluorescence in neurosurgery. AB - 5-Aminolevulinic acid (5-ALA)-fluorescence-guided resection is well established in many neuro-oncologic centers. Different classifications of 5-ALA-induced fluorescence have been reported. The aim of the systematic analysis was to evaluate the frequency of graduations, definitions, and designations of 5-ALA induced fluorescence qualities. A systematic database search of PubMed was performed to identify studies reporting (1) on 5-ALA fluorescence-guided either spinal or cranial surgery, (2) on qualitative estimation and/or categorization of 5-ALA-induced fluorescence, (3) in English, and (4) were published as peer reviewed original studies. Totally, 93 studies were identified. Different classification systems of 5-ALA-induced fluorescence were found. Over 60 % of the included studies used a dichotomized categorization of 5-ALA-induced fluorescence and 27.5 % of studies distinguished two different intensities of 5-ALA fluorescent tissue in addition to non-fluorescing tissue. More than 50 % of studies explicitly defined criteria for categorization of 5-ALA-induced fluorescence. The major limitation of the present analysis might be that it mainly comprises data from retrospective, uncontrolled, non-randomized trials. However, a precise definition of each 5-ALA-induced fluorescence quality is essential. Although dichotomized classification is the most common and simple graduation system, it may not be suitable for every clinical or scientific task. A three-level 5-ALA-induced fluorescence classification with precise definition of each fluorescence quality and their correlation with histological features would be more useful and reproducible in these cases. PMID- 27225454 TI - Genetic control of protein content and sedimentation volume in European winter wheat cultivars. AB - KEY MESSAGE: Breeding of bread wheat in the last decades has maintained a high baking quality despite the intensive selection for grain yield. The quality trait sedimentation volume but not protein content is mainly controlled by the Glu - A1, Glu - B1, Glu - D1, Gli - B1 , and Pinb - D1 loci which are differentially used in varieties from different European origins. Protein content and sedimentation volume are two important quality traits in wheat breeding. In this study, we used a panel of 407 European winter wheat cultivars to dissect the genetic architecture of both traits and to assess the potential of genomics assisted breeding. All lines were phenotyped in multi-location field trials, genotyped by a genotyping-by-sequencing approach, and assessed for the alleles at the Glu-A1, Glu-B1, Glu-D1, Gli-B1, and Pinb-D1 candidate loci. Our analyses revealed no effect of the candidate loci on protein content, but a strong effect on sedimentation volume, with Glu-B1 and Gli-B1 explaining 24.6 and 19.5 % of the genotypic variance, respectively. The genome-wide scan identified three quantitative trait loci (QTL) for protein content which jointly explained only 18.5 % of the genotypic variance. In contrast, four QTL were detected for sedimentation volume most likely identifying the Glu-B1 and Gli-B1 candidate loci and explaining approximately 60 % of the genotypic variance. We observed differences for both traits between countries of origin of the cultivars, accompanied by corresponding geographic differences in QTL allele frequencies. Furthermore, a genome-wide prediction approach resulted in a higher predictive ability for both traits as compared to marker-assisted selection based on the identified QTL. Taken together, our results illustrate a different genetic architecture of the two quality traits and show the potential of their genomics assisted improvement. PMID- 27225455 TI - Torsten Almen (1931-2016): the father of non-ionic iodine contrast media. AB - The Swedish radiologist Torsten Almen is the first clinical radiologist ever to have made a fundamental contribution to intravascular contrast medium design, the development of non-ionic contrast media. He became emotionally triggered by the patients' severe pain each time he injected the ionic "high-osmolar" contrast media when performing peripheral arteriographies in the early 1960s. One day he got a flash of genius that combined the observation of pain, a pathophysiological theory and how to eliminate it with suitable contrast media chemistry. After self studies in chemistry he developed the concept of iodine contrast media not dissociating into ions in solution to reduce their osmolality and even reach plasma isotonicity. He offered several pharmaceutical companies his concept of mono- and polymeric non-ionic agents but without response, since it was considered against the chemical laws of that time. Contrast media constructed as salts and dissociating into ions in solution was regarded an absolute necessity to achieve high enough water solubility and concentration for diagnostic purposes. Finally a small Norwegian company, Nyegaard & Co., took up his idea 1968 and together they developed the essentially painless "low-osmolar" monomeric non-ionic metrizamide (Amipaque) released in 1974 and iohexol (Omipaque) in 1982 followed by the "iso-osmolar" dimeric non-ionic iodixanol (Visipaque) released in 1993. This has implied a profound paradigm shift with regard to reduction of both hypertonic and chemotoxic side effects, which have been a prerequisite for the today's widespread use of contrast medium-enhanced CT and advanced endovascular interventional techniques even in fragile patients. PMID- 27225456 TI - Advances in novel influenza vaccines: a patent review. AB - The threat of a major human influenza pandemic such as the avian H5N1 or the 2009 new H1N1 has emphasized the need for effective prevention strategies to combat these pathogens. Although egg based influenza vaccines have been well established for a long time, it remains an ongoing public health need to develop alternative production methods that ensures improved safety, efficacy, and ease of administration compared with conventional influenza vaccines. This article is intended to cover some of the recent advances and related patents on the development of influenza vaccines including live attenuated, cell based, genomic and synthetic peptide vaccines. PMID- 27225457 TI - Calculibacillus koreensis gen. nov., sp. nov., an anaerobic Fe(III)-reducing bacterium isolated from sediment of mine tailings. AB - A strictly anaerobic bacterium, strain B5(T), was isolated from sediment of an abandoned coal mine in Taebaek, Republic of Korea. Cells of strain B5(T) were non spore-forming, straight, Gram-positive rods. The optimum pH and temperature for growth were pH 7.0 and 30 degrees C, respectively, while the strain was able to grow within pH and temperature ranges of 5.5-7.5 and 25-45 degrees C, respectively. Growth of strain B5(T) was observed at NaCl concentrations of 0 to 6.0% (w/v) with an optimum at 3.0-4.0% (w/v). The polar lipids consisted of phosphatidylethanolamine, phosphatidylglycerol, an unknown phospholipid and three unknown polar lipids. Strain B5(T) grew anaerobically by reducing nitrate, nitrite, ferric-citrate, ferric-nitrilotriacetate, elemental sulfur, thiosulfate, and anthraquinone-2-sulfonate in the presence of proteinaceous compounds, organic acids, and carbohydrates as electron donors. The isolate was not able to grow by fermentation. Strain B5(T) did not grow under aerobic or microaerobic conditions. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain B5(T) is most closely related to the genus Tepidibacillus (T. fermentans STGH(T); 96.3%) and Vulcanibacillus (V. modesticaldus BR(T); 94.6%). The genomic DNA G+C content (36.9 mol%) of strain B5(T) was higher than those of T. fermentans STGH(T) (34.8 mol%) and V. modesticaldus BR(T) (34.5 mol%). Based on its phenotypic, chemotaxonomic, and phylogenetic properties, we describe a new species of a novel genus Calculibacillus, represented by strain B5(T) (=KCTC 15397(T) =JCM 19989(T)), for which we propose the name Calculibacillus koreensis gen. nov., sp. nov. PMID- 27225458 TI - Dankookia rubra gen. nov., sp. nov., an alphaproteobacterium isolated from sediment of a shallow stream. AB - WS-10(T)-a Gram-negative, non-motile, and aerobic bacterial strain-was isolated from the sediment of a shallow stream in Korea. The optimum ranges of temperature and pH for growth were 20-40 degrees C (optimum 28 degrees C) and pH 6.0-8.0 (optimum pH 7.0), respectively. The DNA G+C content of strain WS-10(T) was 72.7 mol%. The major fatty acids (>5%) were summed feature 8 (C18:1 omega7c), summed feature 3 (C16:1 omega7c and/or C16:1 omega6c), C16:0, and C18:1 2-OH. The major polar lipids consisted of phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, and unidentified aminolipids. Q-10 was the predominant respiratory quinone. The highest similarities in the 16S rRNA gene sequence were shown with Paracraurococcus ruber (95.3%), Belnapia soli (95.3%), B. moabensis (95.1%), and B. rosea (95.0%). A phylogenetic analysis based on 16S rRNA gene sequence comparisons showed that strain WS-10T formed a distinct line within a clade containing the genera Paracraurococcus, Craurococcus, and Belnapia in the family Acetobacteraceae. On the basis of polyphasic evidence, strain WS-10(T) represents a novel species of a new genus in the family Acetobacteraceae, for which the name Dankookia rubra gen. nov., sp. nov. is proposed. The type strain of the type species is WS-10(T) (= KACC 18533(T) = JCM 30602(T)). PMID- 27225460 TI - Identification of D-amino acid dehydrogenase as an upstream regulator of the autoinduction of a putative acyltransferase in Corynebacterium glutamicum. AB - Expression of a putative acyltransferase encoded by NCgl- 0350 of Corynebacterium glutamicum is induced by cell-free culture fluids obtained from stationary-phase growth of both C. glutamicum and Pseudomonas aeruginosa, providing evidence for interspecies communication. Here, we further confirmed that such communication occurs by showing that acyltransferase expression is induced by culture fluid obtained from diverse Gram-negative and -positive bacterial strains, including Escherichia coli, Salmonella Typhimurium, Bacillus subtilis, Staphylococcus aureus, Mycobacterium sp. strain JC1, and Mycobacterium smegmatis. A homologous acyltransferase encoded by PA5238 of P. aeruginosa was also induced by fluids obtained from P. aeruginosa as well as other bacterial strains, as observed for NCgl0350 of C. glutamicum. Because C. glutamicum is difficult to study using molecular approaches, the homologous gene PA5238 of P. aeruginosa was used to identify PA5309 as an upstream regulator of expression. A homologous D-amino acid dehydrogenase encoded by NCgl- 2909 of C. glutamicum was cloned based on amino acid similarity to PA5309, and its role in the regulation of NCgl0350 expression was confirmed. Moreover, NCgl2909 played positive roles in growth of C. glutamicum. Thus, we identified a D-amino acid dehydrogenase as an upstream regulator of the autoinduction of a putative acyltransferase in C. glutamicum. PMID- 27225459 TI - PprM is necessary for up-regulation of katE1, encoding the major catalase of Deinococcus radiodurans, under unstressed culture conditions. AB - Deinococcus radiodurans is a poly-extremophilic organism, capable of tolerating a wide variety of different stresses, such as gamma/ultraviolet radiation, desiccation, and oxidative stress. PprM, a cold shock protein homolog, is involved in the radiation resistance of D. radiodurans, but its role in the oxidative stress response has not been investigated. In this study, we investigated the effect of pprM mutation on catalase gene expression. pprM disruption decreased the mRNA and protein levels of KatE1, which is the major catalase in D. radiodurans, under normal culture conditions. A pprM mutant strain (pprM MT) exhibited decreased catalase activity, and its resistance to hydrogen peroxide (H2O2) decreased accordingly compared with that of the wild-type strain. We confirmed that RecG helicase negatively regulates katE1 under normal culture conditions. Among katE1 transcriptional regulators, the positive regulator drRRA was not altered in pprM (-), while the negative regulators perR, dtxR, and recG were activated more than 2.5-fold in pprM MT. These findings suggest that PprM is necessary for KatE1 production under normal culture conditions by down-regulation of katE1 negative regulators. PMID- 27225461 TI - Purification, crystallization, and preliminary X-ray crystallographic analysis of the Group III chaperonin from Carboxydothermus hydrogenoformans. AB - Chaperonins (CPNs) are megadalton sized ATP-dependent nanomachines that facilitate protein folding through complex cycles of complex allosteric articulation. They consist of two back-to-back stacked multisubunit rings. CPNs are usually classified into Group I and Group II. Here, we report the crystallization of both the AMPPNP (an ATP analogue) and ADP bound forms of a novel CPN, classified as belonging to a third Group, recently discovered in the extreme thermophile Carboxydothermus hydrogenoformans. Crystals of the two forms were grown by the vapor batch crystallization method at 295 K. Crystals of the Ch CPN/AMPPNP complex diffracted to 3.0 A resolution and belonged to the space group P422, with unit-cell parameters a = b = 186.166, c = 160.742 A. Assuming the presence of four molecules in the asymmetric unit, the solvent content was estimated to be about 60.02%. Crystals of the Ch-CPN/ADP complex diffracted to 4.0 A resolution and belonged to the space group P4212, with unit-cell parameters a = b = 209.780, c = 169.813A. Assuming the presence of four molecules in the asymmetric unit, the solvent content was estimated to be about 70.19%. PMID- 27225462 TI - Characteristics of the community-genotype sequence type 72 methicillin-resistant Staphylococcus aureus isolates that underlie their persistence in hospitals. AB - Panton-Valentine leukocidin-negative methicillin-resistant Staphylococcus aureus (MRSA) clone ST72, known as a major community-associated MRSA in Korea, has emerged as an important pathogen in hospitals. To understand bacterial properties that underlie transformation of this clone into a nosocomial pathogen, we compared characteristics of the community-genotype ST72 MRSA isolates with those of ST5 and ST239 MRSA, which have been predominant nosocomial MRSA clones in Korea. Several genes associated with adhesion and virulence were absent or rarely found in ST72 isolates. Many ST72 isolates (70.1%) belonged to agr group I, but the agr group of other ST72 isolates could not be determined. As indicated by d hemolysin production, ST72 isolates expressed fully functional agr, whereas agr dysfunction was observed in ST5 and ST239 isolates. In the biofilm formation assay, no upregulation of biofilm-forming activity of ST72 MRSA was detected. However, ST72 isolates demonstrated persistence under hypotonic and desiccating conditions (survival rates 72.3% and 33.9%, respectively), which was similar to characteristics of ST5 or ST239 isolates. ST72- MRSA isolates showed low virulence, but properties of their functional agr system could facilitate their spread in hospitals. In conclusion, tolerance to stressful environments, e.g., hypotonic and dry conditions, may also contribute to survival of the community associated MRSA clones in healthcare facilities. PMID- 27225463 TI - Roles of human apolipoprotein E in the infectivity and replication of hepatitis C virus genotype 2a. AB - Hepatitis C virus (HCV) infection is associated with lipoproteins, and apolipoprotein E (apoE) plays an essential role in infectious HCV particles. Although the role of apoE in HCV infection is well known, its role in the replication of HCV remains unclear. The aims of this study were to determine the role of apoE in the RNA replication of major HCV genotypes 1b and 2a, and to determine whether this role is HCVgenotype-dependent using HCV genotype 1b replicon cells and HCV genotype 2a producing (HP) cells. HCV infection was blocked in Huh7.5 cells treated with low-density lipoproteins, very low-density lipoproteins, or apoE3. An apoE3-specific monoclonal antibody also efficiently neutralized HCV infectivity, and HCV infection was dramatically suppressed by the knockdown of apoE expression with an apoE-specific small interfering RNA, suggesting a requirement for apoE in infectious HCV particles. HCV RNA replication was not affected in HP cells treated with each apoE isoform or transfected with apoE-specific siRNAs. However, the knockdown of apoE expression suppressed RNA replication of HCV genotype 1b. The siRNA-mediated knockdown of apoE, apoA1, and apoB expression also suppressed the RNA replication of HCV genotype 1b, but not that of HCV genotype 2a. Taken together, these findings indicate that apoE plays an important role in HCV genotype 2a infection and in HCV genotype 1b RNA replication, but not in the replication of HCV genotype 2a. These results provide important information for the future development of HCV genotypespecific anti-HCV agents. PMID- 27225464 TI - Psychometric properties of the Seville quality of life questionnaire in Mexican patients with psychosis. AB - BACKGROUND: The Seville Quality of Life Questionnaire (CSCV) was designed to assess quality of life in patients with schizophrenia taking into account those facets particularly important in this disorder. The study aimed at applying the CSCV to a sample of Mexican patients with psychosis in an effort further substantiates the psychometric properties of the CSCV. METHODS: This cross sectional study included 61 patients (56 % female) with psychosis. Item-scale and item-factor correlations were analyzed, as well as scale-factor correlations. Cronbach's Alpha and principal component analysis with varimax rotation were used to assess internal consistency and construct validity, respectively. RESULTS: Analyses of both, disfavorable and favorable dimensions, showed a stronger item scale than item-factor correlation, in most cases significant, though. Internal consistency was significant and adequate; higher for scales than for factors. For the disfavorable and the favorable scales 11 and 2 factors were obtained, respectively; explained variance was low. CONCLUSIONS: In this sample of Mexican patients it was replicated that the CSCV is a valid and reliable instrument to assess quality of life in people with psychosis; the use of scale scores is recommended. PMID- 27225465 TI - Aromatase inhibitors and anti-synthetase syndrome. AB - Adjuvant therapy in postmenopausal women with endocrine-responsive breast cancer (BC) is actually centered on the use of anti-aromatase inhibitors (AI). Several reports, however, are emerging in literature associating the use of this drugs to rheumatic disorders. This case report describes the first case of anti-synthetase syndrome diagnosis after treatment with anti-estrogen agents in a patient with pre-existing rheumatoid arthritis. PMID- 27225466 TI - A flexible cure rate model for spatially correlated survival data based on generalized extreme value distribution and Gaussian process priors. AB - Our present work proposes a new survival model in a Bayesian context to analyze right-censored survival data for populations with a surviving fraction, assuming that the log failure time follows a generalized extreme value distribution. Many applications require a more flexible modeling of covariate information than a simple linear or parametric form for all covariate effects. It is also necessary to include the spatial variation in the model, since it is sometimes unexplained by the covariates considered in the analysis. Therefore, the nonlinear covariate effects and the spatial effects are incorporated into the systematic component of our model. Gaussian processes (GPs) provide a natural framework for modeling potentially nonlinear relationship and have recently become extremely powerful in nonlinear regression. Our proposed model adopts a semiparametric Bayesian approach by imposing a GP prior on the nonlinear structure of continuous covariate. With the consideration of data availability and computational complexity, the conditionally autoregressive distribution is placed on the region specific frailties to handle spatial correlation. The flexibility and gains of our proposed model are illustrated through analyses of simulated data examples as well as a dataset involving a colon cancer clinical trial from the state of Iowa. PMID- 27225467 TI - Visual working memory capacity increases between ages 3 and 8 years, controlling for gains in attention, perception, and executive control. AB - Research in adults has aimed to characterize constraints on the capacity of Visual Working Memory (VWM), in part because of the system's broader impacts throughout cognition. However, less is known about how VWM develops in childhood. Existing work has reached conflicting conclusions as to whether VWM storage capacity increases after infancy, and if so, when and by how much. One challenge is that previous studies did not control for developmental changes in attention and executive processing, which also may undergo improvement. We investigated the development of VWM storage capacity in children from 3 to 8 years of age, and in adults, while controlling for developmental change in exogenous and endogenous attention and executive control. Our results reveal that, when controlling for improvements in these abilities, VWM storage capacity increases across development and approaches adult-like levels between ages 6 and 8 years. More generally, this work highlights the value of estimating working memory, attention, perception, and decision-making components together. PMID- 27225469 TI - Epithelial to Mesenchymal Transition in Clear Cell Renal Cell Carcinoma with Rhabdoid Features. AB - AIMS: The aims of this study were to investigate the association of renal cell carcinoma (RCC) displaying rhabdoid features and morphologically mesenchymal characteristics with epithelial to mesenchymal transition (EMT), and to clarify the expression of EMT markers. METHODS: We investigated the expression of EMT markers (E-cadherin, vimentin, Snail, Slug, ZEB1, ZEB2 and Twist1) using immunohistochemistry, Western blotting and real-time polymerase chain reaction in 18 cases of clear cell RCC (ccRCC) with rhabdoid features and 74 ccRCC cases with Fuhrman grade 1-3 (G1 to G3). RESULTS: In ccRCCs with rhabdoid features, low E cadherin and high vimentin expression were found. In G1 to G3 ccRCCs, low E cadherin expression and high expression of vimentin, ZEB1 and ZEB2 were found. There was no significant difference in the immunoexpression of E-cadherin and vimentin between the two ccRCC groups. CONCLUSIONS: The rhabdoid features may histologically and biologically be associated with EMT in ccRCC. There is a possibility that in G1 to G3 ccRCCs showing epithelial structures, other cell cell adhesion mechanisms apart from E-cadherin adhesion may continue to work, and that ccRCC with rhabdoid features may be caused by an inactivation or loss of these mechanisms. PMID- 27225468 TI - Saccade latency indexes exogenous and endogenous object-based attention. AB - Classic studies of object-based attention have utilized keypress responses as the main dependent measure. However, people typically make saccades to fixate important objects. Recent work has shown that attention may act differently when it is deployed covertly versus in advance of a saccade. We further investigated the link between saccades and attention by examining whether object-based effects can be observed for saccades. We adapted the classical double-rectangle cueing paradigm of Egly, Driver, and Rafal (1994), and measured both the first saccade latency and the keypress reaction time (RT) to a target that appeared at the end of one of the two rectangles. Our results showed that saccade latencies exhibited higher sensitivity than did RTs for detecting effects of attention. We also assessed the generality of the attention effects by testing three types of cues: hybrid (predictive and peripheral), exogenous (nonpredictive and peripheral), and endogenous (predictive and central). We found that both RTs and saccade latencies exhibited effects of both space-based and object-based attentional selection. However, saccade latencies showed a more robust attentional modulation than RTs. For the exogenous cues, we observed a spatial inhibition of return along with an object-based effect, implying that object-based attention is independent of space based attention. Overall, our results revealed an oculomotor correlate of object based attention, suggesting that, in addition to spatial priority, object-level priority also affects saccade planning. PMID- 27225470 TI - Biosynthesis, biotechnological production, and applications of glucosylglycerols. AB - Glucosylglycerols (GGs) are known as compatible solutes accumulated by some bacteria including cyanobacteria as well as higher plants for their adaptations to salt or desiccation stresses. Since being identified in Japanese sake, their physiological effects and potential applications on human health cares have been explored in the following 15 years. Several different synthesis methods have been successively developed for the production of GGs. However, the efficiency of GG synthesis, especially biological synthesis, is still low. With the recent advances in genome sequencing and synthetic biology tools, systematical screening of enzyme candidates and metabolic engineering approaches is necessary for improving GG synthesis efficiency. In this review, we will summarize GG structure information, protective effects on human skin and digestive system as well as industrial enzymes, together with their synthesis by chemical, enzymatic, and biological in vivo approaches in detail, and provide some prospects on improving GG production. PMID- 27225471 TI - Optimal secretion of alkali-tolerant xylanase in Bacillus subtilis by signal peptide screening. AB - Xylanases are industrially important enzymes for xylan digestion. We experimentally screened over 114 Sec and 24 Tat pathway signal peptides, with two different promoters, for optimal production of an alkaline active xylanase (XynBYG) from Bacillus pumilus BYG in a Bacillus subtilis host. Though both promoters yielded highly consistent secretion levels (0.97 Pearson correlation coefficient), the Sec pathway was found to be more efficient than the Tat pathway for XynBYG secretion. Furthermore, the optimal signal peptide (phoB) for XynBYG secretion was found to be different from the optimal peptides for cutinase and esterase reported in previous studies. A partial least squares regression analysis further identified several statistically important variables: helical properties, amino acid composition bias, and the discrimination score in Signal P. These variables explain the observed 23 % variance in the secretion yield of XynBYG by the different signal peptides. The results also suggest that the helical propensity of a signal peptide plays a significant role in the beta-rich xylanase, but not in the helix-rich cutinase, suggesting a coupling of the conformations between the signal peptide and its cargo protein for optimal secretion. PMID- 27225472 TI - Alternative fermentation pathway of cinnamic acid production via phenyllactic acid. AB - Cinnamic acid (CA) is the chemical basis for bulk production of flavoring reagents and chemical intermediates, and it can be fermented from biomass. Phenylalanine ammonia lyase (PAL) has been used exclusively in the bacterial fermentation of sugar biomass in which the fermentation intermediate phenylalanine is deaminated to CA. Here, we designed an alternative metabolic pathway for fermenting glucose to CA. An Escherichia coli strain that generates phenylalanine in this pathway also produces Wickerhamia fluorescens phenylpyruvate reductase and ferments glucose to D-phenyllactate (D-PhLA) (Fujita et al. Appl Microbiol Biotechnol 97: 8887-8894, 2013). Thereafter, phenyllactate dehydratase encoded by fldABCI genes in Clostridium sporogenes converts the resulting D-PhLA into CA. The phenyllactate dehydratase expressed by fldABCI in the D-PhLA-producing bacterium fermented glucose to CA, but D-PhLA fermentation and phenyllactate dehydration were aerobic and anaerobic processes, respectively, which disrupted high-yield CA fermentation in single batch cultures. We overcame this disruption by sequentially culturing the two strains under aerobic and anaerobic conditions. We optimized the incubation periods of the respective aeration steps to produce 1.7 g/L CA from glucose, which exceeded the yield from PAL-dependent glucose fermentation to CA 11-fold. This process is a novel, efficient alternative to conventional PAL-dependent CA production. PMID- 27225473 TI - Anaerobic methane oxidation coupled to nitrite reduction can be a potential methane sink in coastal environments. AB - In the current study, we investigated nitrite-dependent anaerobic methane oxidation (N-DAMO) as a potential methane sink in the Hangzhou Bay and the adjacent Zhoushan sea area. The potential activity of the N-DAMO process was primarily observed in Hangzhou Bay by means of (13)C-labeling experiments, whereas very low or no potential N-DAMO activity could be detected in the Zhoushan sea area. The measured potential N-DAMO rates ranged from 0.2 to 1.3 nmol (13)CO2 g(-1) (dry sediment) day(-1), and the N-DAMO potentially contributed 2.0-9.4 % to the total microbial methane oxidation in the examined sediments. This indicated that the N-DAMO process may be an alternative pathway in the coastal methane cycle. Phylogenetic analyses confirmed the presence of Candidatus Methylomirabilis oxyfera-like bacteria in all the examined sediments, while the group A members (the dominant bacteria responsible for N-DAMO) were found mainly in Hangzhou Bay. Quantitative PCR showed that the 16S rRNA gene abundance of Candidatus M. oxyfera-like bacteria varied from 5.4 * 10(6) to 5.0 * 10(7) copies g(-1) (dry sediment), with a higher abundance observed in Hangzhou Bay. In addition, the overlying water NO3 (-) concentration and salinity were identified as the most important factors influencing the abundance and potential activity of Candidatus M. oxyfera-like bacteria in the examined sediments. This study showed the evidence of N-DAMO in coastal environments and indicated the importance of N DAMO as a potential methane sink in coastal environments. PMID- 27225474 TI - Practical two-step synthesis of enantiopure styrene oxide through an optimized chemoenzymatic approach. AB - Enantiopure styrene oxide (SO) and its derivatives are important building blocks for chiral synthesis. In this study, we developed an attractive "1-pot, 2-step" chemoenzymatic approach for producing enantiopure SO with 100 % theoretical yield. This approach involved asymmetric reduction of alpha-chloroacetophenone by an alcohol dehydrogenase (ADH; step 1), followed by base-induced ring closure (epoxidation) of enantiopure 2-chloro-1-phenylethanol produced by the ADH (step 2). By-product formation during epoxidation was suppressed to <1 % by adding methyl tert-butyl ether (MTBE) as the second phase. Therefore, with this optimized approach, ADH from Lactobacillus kefir (LkDH) successfully produced 1 M (S)-SO, with 99 % analytical yield and 97.8 % enantiomeric excess (ee). In the preparation of (R)-SO, a semi-rational strategy of active pocket iterative saturation mutagenesis (ISM) was successfully used to inverse the enantioselectivity of LkDH (muDH2, F147L/Y190P/A202F/M206H/V196L/S96D/K97V), which produced the opposite enantiomer (R)-2-chloro-1-phenylethanol. Through the optimized chemoenzymatic approach, muDH2 was successfully used to prepare 1 M (R) SO, with 98.1 % ee and 99.0 % analytical yield. Our results indicated that this optimized chemoenzymatic approach could be used to produce both enantiomers of SO at concentrations as high as 120 g/L within 14 h, which is the highest concentration as far as we know. MuDH2 obtained through ISM also showed reversed enantioselectivity toward another 13 aromatic ketones, compared with wild-type (WT) LkDH. Furthermore, a molecular docking experiment demonstrated that muDH2 inverted the binding orientation of the substrate, which may be the reason for its inverse enantioselectivity. PMID- 27225475 TI - Improvement of isobutanol production in Saccharomyces cerevisiae by increasing mitochondrial import of pyruvate through mitochondrial pyruvate carrier. AB - Subcellular compartmentalization of the biosynthetic enzymes is one of the limiting factors for isobutanol production in Saccharomyces cerevisiae. Previously, it has been shown that mitochondrial compartmentalization of the biosynthetic pathway through re-locating cytosolic Ehrlich pathway enzymes into the mitochondria can increase isobutanol production. In this study, we improved mitochondrial isobutanol production by increasing mitochondrial pool of pyruvate, a key substrate for isobutanol production. Mitochondrial isobutanol biosynthetic pathway was introduced into bat1Deltaald6Deltalpd1Delta strain, where genes involved in competing pathways were deleted, and MPC1, MPC2, and MPC3 genes encoding the subunits of mitochondrial pyruvate carrier (MPC) hetero-oligomeric complex were overexpressed with different combinations. Overexpression of Mpc1 and Mpc3 forming high-affinity MPCOX was more effective in improving isobutanol production than overexpression of Mpc1 and Mpc2 forming low-affinity MPCFERM. The final engineered strain overexpressing MPCOX produced 330.9 mg/L isobutanol from 20 g/L glucose, exhibiting about 22-fold increase in production compared to wild type. PMID- 27225476 TI - Community composition and activity of anaerobic ammonium oxidation bacteria in the rhizosphere of salt-marsh grass Spartina alterniflora. AB - Anaerobic ammonium oxidation (anammox) as an important nitrogen removal pathway has been investigated in intertidal marshes. However, the rhizosphere-driven anammox process in these ecosystems is largely overlooked so far. In this study, the community dynamics and activities of anammox bacteria in the rhizosphere and non-rhizosphere sediments of salt-marsh grass Spartina alterniflora (a widely distributed plant in estuaries and intertidal ecosystems) were investigated using clone library analysis, quantitative PCR assay, and isotope-tracing technique. Phylogenetic analysis showed that anammox bacterial diversity was higher in the non-rhizosphere sediments (Scalindua and Kuenenia) compared with the rhizosphere zone (only Scalindua genus). Higher abundance of anammox bacteria was detected in the rhizosphere (6.46 * 10(6)-1.56 * 10(7) copies g(-1)), which was about 1.5 fold higher in comparison with that in the non-rhizosphere zone (4.22 * 10(6) 1.12 * 10(7) copies g(-1)). Nitrogen isotope-tracing experiments indicated that the anammox process in the rhizosphere contributed to 12-14 % N2 generation with rates of 0.43-1.58 nmol N g(-1) h(-1), while anammox activity in the non rhizosphere zone contributed to only 4-7 % N2 production with significantly lower activities (0.28-0.83 nmol N g(-1) h(-1)). Overall, we propose that the rhizosphere microenvironment in intertidal marshes might provide a favorable niche for anammox bacteria and thus plays an important role in nitrogen cycling. PMID- 27225477 TI - Donor human milk for Muslim infants in the UK. PMID- 27225478 TI - DUSP8 Regulates Cardiac Ventricular Remodeling by Altering ERK1/2 Signaling. AB - RATIONALE: Mitogen-activated protein kinase (MAPK) signaling regulates the growth response of the adult myocardium in response to increased cardiac workload or pathological insults. The dual-specificity phosphatases (DUSPs) are critical effectors, which dephosphorylate the MAPKs to control the basal tone, amplitude, and duration of MAPK signaling. OBJECTIVE: To examine DUSP8 as a regulator of MAPK signaling in the heart and its impact on ventricular and cardiac myocyte growth dynamics. METHODS AND RESULTS: Dusp8 gene-deleted mice and transgenic mice with inducible expression of DUSP8 in the heart were used here to investigate how this MAPK-phosphatase might regulate intracellular signaling and cardiac growth dynamics in vivo. Dusp8 gene-deleted mice were mildly hypercontractile at baseline with a cardiac phenotype of concentric ventricular remodeling, which protected them from progressing towards heart failure in 2 surgery-induced disease models. Cardiac-specific overexpression of DUSP8 produced spontaneous eccentric remodeling and ventricular dilation with heart failure. At the cellular level, adult cardiac myocytes from Dusp8 gene-deleted mice were thicker and shorter, whereas DUSP8 overexpression promoted cardiac myocyte lengthening with a loss of thickness. Mechanistically, activation of extracellular signal-regulated kinases 1/2 were selectively increased in Dusp8 gene-deleted hearts at baseline and following acute pathological stress stimulation, whereas p38 MAPK and c-Jun N terminal kinases were mostly unaffected. CONCLUSIONS: These results indicate that DUSP8 controls basal and acute stress-induced extracellular signal-regulated kinases 1/2 signaling in adult cardiac myocytes that then alters the length-width growth dynamics of individual cardiac myocytes, which further alters contractility, ventricular remodeling, and disease susceptibility. PMID- 27225479 TI - Functional Importance of a Proteoglycan Coreceptor in Pathologic Lymphangiogenesis. AB - RATIONALE: Lymphatic vessel growth is mediated by major prolymphangiogenic factors, such as vascular endothelial growth factor (VEGF-C) and VEGF-D, among other endothelial effectors. Heparan sulfate is a linear polysaccharide expressed on proteoglycan core proteins on cell membranes and matrix, playing roles in angiogenesis, although little is known about any function(s) in lymphatic remodeling in vivo. OBJECTIVE: To explore the genetic basis and mechanisms, whereby heparan sulfate proteoglycans mediate pathological lymphatic remodeling. METHODS AND RESULTS: Lymphatic endothelial deficiency in the major heparan sulfate biosynthetic enzyme N-deacetylase/N-sulfotransferase-1 (Ndst1; involved in glycan-chain sulfation) was associated with reduced lymphangiogenesis in pathological models, including spontaneous neoplasia. Mouse mutants demonstrated tumor-associated lymphatic vessels with apoptotic nuclei. Mutant lymphatic endothelia demonstrated impaired mitogen (Erk) and survival (Akt) pathway signaling and reduced VEGF-C-mediated protection from starvation-induced apoptosis. Lymphatic endothelial-specific Ndst1 deficiency (in Ndst1(f/f)Prox1(+/CreERT2) mice) was sufficient to inhibit VEGF-C-dependent lymphangiogenesis. Lymphatic heparan sulfate deficiency reduced phosphorylation of the major lymphatic growth receptor VEGF receptor-3 in response to multiple VEGF-C species. Syndecan-4 was the dominantly expressed heparan sulfate proteoglycan in mouse lymphatic endothelia, and pathological lymphangiogenesis was impaired in Sdc4((-/-)) mice. On the lymphatic cell surface, VEGF-C induced robust association between syndecan-4 and VEGF receptor-3, which was sensitive to glycan disruption. Moreover, VEGF receptor-3 mitogen and survival signaling was reduced in the setting of Ndst1 or Sdc4 deficiency. CONCLUSIONS: These findings demonstrate the genetic importance of heparan sulfate and the major lymphatic proteoglycan syndecan-4 in pathological lymphatic remodeling. This may introduce novel future strategies to alter pathological lymphatic-vascular remodeling. PMID- 27225480 TI - Factors influencing choice of care-seeking for acute fever comparing private chemical shops with health centres and hospitals in Ghana: a study using case control methodology. AB - BACKGROUND: Several public health interventions to improve management of patients with fever are largely focused on the public sector yet a high proportion of patients seek care outside the formal healthcare sector. Few studies have provided information on the determinants of utilization of the private sector as against formal public sector. Understanding the differences between those who attend public and private health institutions, and their pathway to care, has significant practical implications. The chemical shop is an important source of care for acute fever in Ghana. METHODS: Case-control methodology was used to identify factors associated with seeking care for fever in the Dangme West District, Ghana. People presenting to health centres, or hospital outpatients, with a history or current fever were compared to counterparts from the same community with fever visiting a chemical shop. RESULTS: Of 600 patients, 150 each, were recruited from the district hospital and two health centres, respectively, and 300 controls from 51 chemical shops. Overall, 103 (17.2 %) patients tested slide positive for malaria. Specifically, 13.7 % (41/300) of chemical shop patients, 30.7 % (46/150) health centre and 10.7 % (16/150) hospital patients were slide positive. While it was the first option for care for 92.7 % (278/300) chemical shop patients, 42.7 % (64/150) of health centre patients first sought care from a chemical shop. More health centre patients (61.3 %; 92/150) presented with fever after more than 3 days than chemical shop patients (27.7 %; 83/300) [AOR = 0.19; p < 0.001 CI 0.11-0.30]. Although the hospital was the first option for 83.3 % (125/150) of hospital patients, most (63.3 %; 95/150) patients arrived there over 3 days after their symptoms begun. Proximity was significantly associated with utilization of each source of care. Education, but not other socioeconomic or demographic factors were significantly associated with chemical shop use. CONCLUSIONS: The private drug retail sector is the first option for the majority of patients, including poorer patients, with fever in this setting. Most patients with fever arrive at chemical shops with less delay and fewer signs of severity than at public health facilities. Improving chemical shop skills is a good opportunity to diagnose, treat or refer people with fever early. PMID- 27225481 TI - Yin Yang 1 is associated with cancer stem cell transcription factors (SOX2, OCT4, BMI1) and clinical implication. AB - The transcription factor Yin Yang 1 (YY1) is frequently overexpressed in cancerous tissues compared to normal tissues and has regulatory roles in cell proliferation, cell viability, epithelial-mesenchymal transition, metastasis and drug/immune resistance. YY1 shares many properties with cancer stem cells (CSCs) that drive tumorigenesis, metastasis and drug resistance and are regulated by overexpression of certain transcription factors, including SOX2, OCT4 (POU5F1), BMI1 and NANOG. Based on these similarities, it was expected that YY1 expression would be associated with SOX2, OCT4, BMI1, and NANOG's expressions and activities. Data mining from the proteomic tissue-based datasets from the Human Protein Atlas were used for protein expression patterns of YY1 and the four CSC markers in 17 types of cancer, including both solid and hematological malignancies. A close association was revealed between the frequency of expressions of YY1 and SOX2 as well as SOX2 and OCT4 in all cancers analyzed. Two types of dynamics were identified based on the nature of their association, namely, inverse or direct, between YY1 and SOX2. These two dynamics define distinctive patterns of BMI1 and OCT4 expressions. The relationship between YY1 and SOX2 expressions as well as the expressions of BMI1 and OCT4 resulted in the classification of four groups of cancers with distinct molecular signatures: (1) Prostate, lung, cervical, endometrial, ovarian and glioma cancers (YY1(lo)SOX2(hi)BMI1(hi)OCT4(hi)) (2) Skin, testis and breast cancers (YY1(hi)SOX2(lo)BMI1(hi)OCT4(hi)) (3) Liver, stomach, renal, pancreatic and urothelial cancers (YY1(lo)SOX2(lo)BMI1(hi)OCT4(hi)) and (4) Colorectal cancer, lymphoma and melanoma (YY1(hi)SOX2(hi)BMI1(lo)OCT4(hi)). A regulatory loop is proposed consisting of the cross-talk between the NF-kB/PI3K/AKT pathways and the downstream inter-regulation of target gene products YY1, OCT4, SOX2 and BMI1. PMID- 27225483 TI - Reliability of 3D laser-based anthropometry and comparison with classical anthropometry. AB - Anthropometric quantities are widely used in epidemiologic research as possible confounders, risk factors, or outcomes. 3D laser-based body scans (BS) allow evaluation of dozens of quantities in short time with minimal physical contact between observers and probands. The aim of this study was to compare BS with classical manual anthropometric (CA) assessments with respect to feasibility, reliability, and validity. We performed a study on 108 individuals with multiple measurements of BS and CA to estimate intra- and inter-rater reliabilities for both. We suggested BS equivalents of CA measurements and determined validity of BS considering CA the gold standard. Throughout the study, the overall concordance correlation coefficient (OCCC) was chosen as indicator of agreement. BS was slightly more time consuming but better accepted than CA. For CA, OCCCs for intra- and inter-rater reliability were greater than 0.8 for all nine quantities studied. For BS, 9 of 154 quantities showed reliabilities below 0.7. BS proxies for CA measurements showed good agreement (minimum OCCC > 0.77) after offset correction. Thigh length showed higher reliability in BS while upper arm length showed higher reliability in CA. Except for these issues, reliabilities of CA measurements and their BS equivalents were comparable. PMID- 27225482 TI - The impact of patient co-morbidities on the regenerative capacity of cardiac explant-derived stem cells. AB - BACKGROUND: Although patient-sourced cardiac stem cells repair damaged myocardium, the extent to which medical co-morbidities influence cardiac-derived cell products is uncertain. Therefore, we investigated the influence of atherosclerotic risk factors on the regenerative performance of human cardiac explant-derived cells (EDCs). METHODS: In this study, the Long Term Stratification for survivors of acute coronary syndromes model was used to quantify the burden of cardiovascular risk factors within a group of patients with established atherosclerosis. EDCs were cultured from human atrial appendages and injected into immunodeficient mice 7 days post-left coronary ligation. Cytokine arrays and enzyme linked immunoassays were used to determine the release of cytokines by EDCs in vitro, and echocardiography was used to determine regenerative capabilities in vivo. RESULTS: EDCs sourced from patients with more cardiovascular risk factors demonstrated a negative correlation with production of pro-healing cytokines (such as stromal cell derived factor 1alpha) and exosomes which had negative effects on the promotion of angiogenesis and chemotaxis. Reductions in exosomes and pro-healing cytokines with accumulating medical co-morbidities were associated with increases in production of the pro inflammatory cytokine interleukin-6 (IL-6) by EDCs. Increased patient co morbidities were also correlated with significant attenuation in improvements of left ventricular ejection fraction. CONCLUSIONS: The regenerative performance of the earliest precursor cell population cultured from human explant tissue declines with accumulating medical co-morbidities. This effect is associated with diminished production of pro-cardiogenic cytokines and exosomes while IL-6 is markedly increased. Predictors of cardiac events demonstrated a lower capacity to support angiogenesis and repair injured myocardium in a mouse model of myocardial infarction. PMID- 27225484 TI - A zwitterionic gel electrolyte for efficient solid-state supercapacitors. AB - Gel electrolytes have attracted increasing attention for solid-state supercapacitors. An ideal gel electrolyte usually requires a combination of advantages of high ion migration rate, reasonable mechanical strength and robust water retention ability at the solid state for ensuring excellent work durability. Here we report a zwitterionic gel electrolyte that successfully brings the synergic advantages of robust water retention ability and ion migration channels, manifesting in superior electrochemical performance. When applying the zwitterionic gel electrolyte, our graphene-based solid-state supercapacitor reaches a volume capacitance of 300.8 F cm(-3) at 0.8 A cm(-3) with a rate capacity of only 14.9% capacitance loss as the current density increases from 0.8 to 20 A cm(-3), representing the best value among the previously reported graphene-based solid-state supercapacitors, to the best of our knowledge. We anticipate that zwitterionic gel electrolyte may be developed as a gel electrolyte in solid-state supercapacitors. PMID- 27225485 TI - Interrupted commissural band annuloplasty prevents mitral stenosis. AB - BACKGROUND: Mitral annuloplasty is an important component of the treatment of degenerative mitral valve disease. However, postoperative echocardiography reveals elevated mitral gradients in some patients. We developed a technique that we termed interrupted commissural band annuloplasty (iCBA), which does not shorten either the anterior or posterior annulus and is not associated with the development of a mitral gradient. We compared the echocardiographic characteristics of patients treated using this method versus Cosgrove ring (COS) placement, both at rest and during exercise. METHODS: ICBA features placement of three sutures in the commissures using two bands and shortens the commissural annular length by 60 %. We used this method to treat 63 patients and placed Cosgrove bands in 58. Of all patients, 48 who underwent iCBA and 34 with COSs passed the exercise echocardiographic test. RESULTS: The maximal transmitral pressures at rest in the iCBA and Cosgrove groups were 8.04 +/- 0.74 and 11.30 +/ 0.88 mmHg (P = 0.0029), respectively, and the mean transmitral pressures at rest were 2.46 +/- 0.74 and 3.61 +/- 0.32 mmHg (P = 0.0037), respectively. The maximal transmitral pressures during exercise were 11.79 +/- 0.97 and 18.37 +/- 1.16 mmHg (P < 0.0001), and the mean transmitral pressures during exercise were 4.95 +/- 0.45 and 7.76 +/- 0.53 mmHg (P < 0.0001). CONCLUSIONS: ICBA prevents postoperative mitral stenosis both at rest and importantly during exercise. PMID- 27225486 TI - Mechanical properties of the everolimus-eluting bioresorbable vascular scaffold compared to the metallic everolimus-eluting stent. AB - BACKGROUND: Everolimus-eluting bioresorbable vascular scaffolds (BVS) represent an innovative treatment option for coronary artery disease. Clinical and angiographic results seem promising, however, data on its immediate procedural performance are still scarce. The aim of our study was to assess the mechanical properties of BVS by Optical Coherence Tomography (OCT) in clinical routine. METHODS: Post-implantation OCT images of 40 BVS were retrospectively compared to those of 40 metallic everolimus-eluting stents (EES). Post-procedural device related morphological features were assessed. This included incidences of gross underexpansion and the stent eccentricity index (SEI, minimum/maximum diameter) as a measure for focal radial strength. RESULTS: Patients receiving BVS were younger than those with EES (54.0 +/- 11.2 years versus 61.7 +/- 11.4 years, p = 0.012), the remaining baseline, vessel and lesion characteristics were comparable between groups. Lesion pre-dilatation was more frequently performed and inflation time was longer in the BVS than in the EES group (n = 34 versus n = 23, p = 0.006 and 44.2 +/- 12.8 versus 25.6 +/- 8.4 seconds, p < 0.001, respectively). There were no significant differences in maximal inflation pressures and post dilatation frequencies with non-compliant balloons between groups. Whereas gross device underexpansion was not significantly different, SEI was significantly lower in the BVS group (n = 12 (30 %) versus n = 14 (35 %), p = 0.812 and 0.69 +/ 0.08 versus 0.76 +/- 0.09, p < 0.001, respectively). There was no difference in major adverse cardiac event-rate at six months. CONCLUSION: Our data show that focal radial expansion was significantly reduced in BVS compared to EES in a clinical routine setting using no routine post-dilatation protocol. Whether these findings have impact on scaffold mid-term results as well as on clinical outcome has to be investigated in larger, randomized trials. PMID- 27225487 TI - The Role of Decision Models in Health Care Policy: A Case Study. AB - BACKGROUND: In 2009, the Centers for Medicare and Medicaid Services (CMS) underwent a National Coverage Determination on computed tomography colonography (CTC) to screen for colorectal cancer. The Cancer Intervention & Surveillance Network developed decision models to inform this decision. The purpose of our study was to investigate the role of models in this decision. METHODS: We performed a descriptive case study. We conducted semistructured telephone interviews with members of the CMS coverage and analysis group (CAG) and Medicare Coverage and Analysis Advisory Committee (MEDCAC) panelists. Informed by previously published literature, we developed a coding scheme to analyze interview transcripts, MEDCAC meeting transcripts, and the final CMS decision memo. RESULTS: Four members of the CAG and 8 MEDCAC panelists were interviewed. The total number of codes across all study documents was 772. We found evidence that decision makers believed in the adequacy of models to inform decision making. In interview transcripts, the code Models Are Adequate to Inform was more frequent than the code Models Are Inadequate to Inform (47 times v. 5). Discussion of model conceptualization dominated the MEDCAC meeting (Model Conceptualization assigned 113 times) and was frequently discussed during interviews (Model Conceptualization assigned 84 times). We also found evidence that the models helped to focus the policy discussion. Across study documents, the codes Focus on Cost, Focus on Clinical-Health Impact, and Focus on Inadequacy of Evidence Base were assigned 99, 98, and 97 times, respectively. CONCLUSIONS: Decision makers involved in the CTC decision believed in the adequacy of models to inform coverage decisions. The model played a role in focusing the CTC coverage policy discussion. PMID- 27225489 TI - Health-related quality of life in children with surgery for CHD: a study from the Swedish National Registry for Congenital Heart Disease. AB - BACKGROUND: As survival of children with CHD needing surgery has improved significantly, the need for follow-up in terms of health-related quality of life has become increasingly important. In this study, we sought to describe health related quality of life in children with CHD in relation to cardiac surgery. METHODS: A retrospective Swedish National Registry for Congenital Heart Disease survey measured using DISABKIDS chronic generic measure-short version included 337 children (age 9-17 years; 39% girls). The majority (n=319, 95%) of children had a biventricular heart, whereas the remaining had a univentricular heart. Cardiac surgery was performed in 197 (58%) children. Health-related quality of life was expressed as total score (100 highest) and given as medians and 10-90th percentiles. RESULTS: The overall total score was 95 (88-100). Children with a biventricular heart who had undergone three or more surgeries (n=31; 9%) had the lowest total score of 81 (61-97; p<0.001). Children with two or more surgeries and those with univentricular heart were classified in NYHA II more frequently than children with one or no cardiac surgery (p=0.005 and <0.001, respectively). Children with three or more surgeries and those with univentricular heart needed more help at school (p<0.001). Compared with children with other chronic diseases, children with CHD had a high total score except for children with three or more surgeries who had comparable total scores with children with other chronic diseases. CONCLUSION: Children with three or more cardiac surgeries and those with a univentricular heart appear to have lower health-related quality of life, cognitive ability, and NYHA classification. PMID- 27225490 TI - Association of atopic diseases and parvovirus B19 with acute lymphoblastic leukemia in childhood and adolescence in the northeast of Brazil. AB - BACKGROUND: Several factors related to the immune system, such as a history of allergies and virus infections, may be associated with acute lymphoblastic leukemia (ALL). The purpose of this study was to analyze whether the presence of atopic diseases and previous infection with parvovirus B19 and Epstein-Barr virus (EBV) are associated with the development of ALL. METHODS: This case-control study was performed in two tertiary hospitals located in northeastern Brazil. The study population included 60 patients who were diagnosed with non-T-cell ALL using myelogram and immunophenotyping and 120 patients in the control group. Atopy was evaluated via a parent questionnaire and medical records. Total immunoglobulin (Ig)E and IgG levels of parvovirus B19 and EBV were measured in the serum. Logistic regression was performed to assess the association between variables and odds of ALL. RESULTS: We identified a significant inverse association between rhinitis, urticaria and elevated IgE serum levels with ALL. A history of parvovirus B19 infection showed a significant association with this type of cancer [OR (95 % CI) 2.00 (1.94-4.26); P = 0.050]. In logistic regression, the presence of atopy was a protective factor [OR (95 % CI) 0.57 (0.38-0.83); P = 0.004], and the presence of IgG for parvovirus B19 was an important risk factor for ALL [OR (95 % CI) 2.20 (1.02-4.76); P = 0.043]. CONCLUSIONS: These results suggest that atopic diseases and elevated total IgE levels are associated with a potential protective effect on the development of ALL. Previous infection with parvovirus B19 contributed to ALL susceptibility. PMID- 27225492 TI - Is neutrophil-to-lymphocyte ratio valid to predict organ involvement in Henoch Schonlein purpura? PMID- 27225491 TI - GAS1 is present in the cerebrospinal fluid and is expressed in the choroid plexus of the adult rat. AB - Growth arrest specific 1 (GAS1) is a GPI-anchored protein that inhibits proliferation when overexpressed in tumors but during development it promotes proliferation and survival of different organs and tissues. This dual ability is caused by its capacity to interact both by inhibiting the signaling induced by the glial cell line-derived neurotrophic factor and by facilitating the activity of the sonic hedgehog pathway. GAS1 is expressed as membrane bound in different organs and as a secreted form by glomerular mesangial cells. In the developing central nervous system, GAS1 is found in neural progenitors; however, it continues to be expressed in the adult brain. Here, we demonstrate that soluble GAS1 is present in the cerebrospinal fluid (CSF) and it is expressed in the choroid plexus (CP) of the adult rat, the main producer of CSF. Additionally, we confirm the presence of GAS1 in blood plasma and liver of the adult rat, the principal source of blood plasma proteins. The pattern of expression of GAS1 is perivascular in both the CP and the liver. In vitro studies show that the fibroblast cell line NIH/3T3 expresses one form of GAS1 and releases two soluble forms into the supernatant. Briefly, in the present work, we show the presence of GAS1 in adult rat body fluids focusing in the CSF and the CP, and suggest that secreted GAS1 exists as two different isoforms. PMID- 27225493 TI - Downregulation of Insulin-Like Growth Factor-1 via Nitric Oxide Production in a Hypergalactosemic Model of Neonate Skin Fibroblast Cultures. AB - BACKGROUND: Galactosemia is a severe metabolic disorder known to cause hepatosplenomegaly, jaundice and cataracts in neonates, and many patients develop later complications such as mental retardation, disorders of motor function or speech, and hypergonadotrophic hypogonadism. The pathogenetic mechanisms of classical galactosemia are unclear; however, nitric oxide (NO) has been suggested to play a role. OBJECTIVES: Insulin-like growth factor-1 (IGF-1) is important for the growth and development of children, and the aim of this study was to examine the association of NO production with IGF-1 gene expression under galactosemic conditions. METHODS: Serum levels of IGF-1 and nitrite were measured in 15 galactosemia patients and 15 age- and gender-matched healthy controls. Fibroblast cultures established from postcircumcision foreskin of 3- to 8-day-old healthy neonates were treated for 72 h with 0-10 mM of galactose or 0-5 mM of galactose-1 phosphate (Gal-1-P) in the presence or absence of NO synthase inhibitor (L-NAME), and inducible NO synthase (iNOS) protein was measured using Western blot analysis. RT-PCR was performed to assess the IGF-1 gene expression. RESULTS: Galactosemia patients were observed to have significantly (p < 0.01) elevated serum nitrites and markedly decreased levels (p < 0.01) of serum IGF-1 as compared to healthy controls. The cotreatment of neonate skin fibroblast cultures with galactose and Gal-1-P significantly (p < 0.01) increased cellular levels of NO and iNOS protein expression, and decreased (p < 0.01) IGF-1 mRNA levels. Treatment with L-NAME, a NOS inhibitor, significantly (p < 0.05) alleviated a galactose/Gal-1-P-induced decrease in IGF-1 mRNA levels. CONCLUSION: These results suggest that NO mediates the downregulation of IGF-1 by Gal-1 P/galactose, thereby providing a new molecular mechanism and possible therapeutic insight for galactosemia-related complications. PMID- 27225494 TI - Hydrodynamic Radii of Ranibizumab, Aflibercept and Bevacizumab Measured by Time Resolved Phosphorescence Anisotropy. AB - PURPOSE: To measure the hydrodynamic radii of intravitreal anti-VEGF drugs ranibizumab, aflibercept and bevacizumab with MUs time-resolved phosphorescence anisotropy. METHODS: Ruthenium-based dye Ru(bpy)2(mcbpy - O - Su - ester)(PF6)2, whose lifetime of several hundred nanoseconds is comparable to the rotational correlation time of these drugs in buffer, was used as a label. The hydrodynamic radii were calculated from the rotational correlation times of the Ru(bpy)2(mcbpy - O - Su - ester)(PF6)2-labelled drugs obtained with time-resolved phosphorescence anisotropy measurements in buffer/glycerol solutions of varying viscosity. RESULTS: The measured radii of 2.76+/-0.04 nm for ranibizumab, 3.70+/ 0.03 nm for aflibercept and 4.58+/-0.01 nm for bevacizumab agree with calculations based on molecular weight and other experimental measurements. CONCLUSIONS: Time-resolved phosphorescence anisotropy is a relatively simple and straightforward method that allows experimental measurement of the hydrodynamic radius of individual proteins, and is superior to theoretical calculations which cannot give the required accuracy for a particular protein. PMID- 27225497 TI - Role of the Kynurenine Metabolism Pathway in Inflammation-Induced Depression: Preclinical Approaches. AB - Physically ill patients with chronic inflammation often present with symptoms of depression. Our understanding of the pathophysiology of inflammation-associated depression has benefited from preclinical studies on the mechanisms of sickness and clinical studies on the symptoms of sickness and depression that develop in patients treated with immunotherapy. Sickness behavior develops when the immune system is activated by pathogen- or damage-associated molecular patterns. It is a normal biological response to infection and cell injury. It helps the organism to mobilize its immune and metabolic defenses to fight the danger. Depression emerges on the background of sickness when the inflammatory response is too intense and long lasting or the resolution process is deficient. The transition from sickness to depression is mediated by activation of the kynurenine metabolism pathway that leads to the formation of neurotoxic kynurenine metabolites including quinolinic acid, an agonist of N-methyl-D-aspartate receptors. The neuroimmune processes and molecular factors that have been identified in the studies of inflammation-associated depression represent potential new targets for the development of innovative therapies for the treatment of major depressive disorders. PMID- 27225498 TI - Discriminative Stimulus Properties of Opioid Ligands: Progress and Future Directions. AB - Opioid receptors (MOP-r, KOP-r, DOP-r, as well as NOP-r) and their endogenous neuropeptide agonist systems are involved in diverse neurobiological and behavioral functions, in health and disease. These functions include pain and analgesia, addictions, and psychiatric diseases (e.g., depression-, anxiety-like, and stress-related disorders). Drug discrimination assays have been used to characterize the behavioral pharmacology of ligands with affinity at MOP-r, KOP r, or DOP-r (and to a lesser extent NOP-r). Therefore, drug discrimination studies with opioid ligands have an important continuing role in translational investigations of diseases that are affected by these neurobiological targets and their pharmacotherapy. PMID- 27225495 TI - Biopharmaceutical Evaluation of Novel Cyclosporine A Nano-matrix Particles for Inhalation. AB - PURPOSE: This study was undertaken to evaluate the biopharmaceutical properties of cyclosporine A (CsA)-loaded nano-matrix particles for inhalation. METHODS: Nano-matrix particles of CsA with mannitol (nCsAm) were prepared by a flash nano precipitation technique employing a multi-inlet vortex mixer and evaluated in terms of physicochemical properties, anti-inflammatory effect in the rat model of airway inflammation, pharmacokinetic behavior, and distributions of CsA to side effect-related organs after intratracheal administration. RESULTS: In nCsAm, spherical nano-particles of CsA were covered with mannitol and the mean particle size was 1.3 MUm. The in vitro Next Generation Impactor analysis demonstrated fine inhalation performance with a fine particle fraction value of 65.8%. Intratracheal nCsAm (100 MUg-CsA/rat) significantly attenuated the recruitment of inflammatory cells into the airway in the rat model of airway inflammation, followed by suppression of the inflammatory biomarkers. After intratracheal nCsAm at a pharmacologically effective dose (100 MUg-CsA/rat), there was a 42-47-fold decrease in the distribution of CsA to side-effect-related organs such as the kidney and liver compared with oral CsA at a toxic dose (10 mg-CsA/kg), potentially leading to avoidance of systemic side-effects of CsA. CONCLUSION: Upon these findings, nCsAm prepared with the flash nano-precipitation technique could be a novel dosage form of CsA for inhalation therapy of airway inflammation with a better safety margin. PMID- 27225496 TI - Targeting Nanomedicines to Prostate Cancer: Evaluation of Specificity of Ligands to Two Different Receptors In Vivo. AB - PURPOSE: This manuscript utilised in vivo multispectral imaging to demonstrate the efficacy of two different nanomedicine formulations for targeting prostate cancer. METHODS: Pegylated hyperbranched polymers were labelled with fluorescent markers and targeting ligands against two different prostate cancer markers; prostate specific membrane antigen (PSMA) and the protein kinase, EphrinA2 receptor (EphA2). The PSMA targeted nanomedicine utilised a small molecule glutamate urea inhibitor of the protein, while the EphA2 targeted nanomedicine was conjugated to a single-chain variable fragment based on the antibody 4B3 that has shown high affinity to the receptor. RESULTS: Hyperbranched polymers were synthesised bearing the different targeting ligands. In the case of the EphA2 targeting nanomedicine, significant in vitro uptake was observed in PC3 prostate cancer cells that overexpress the receptor, while low uptake was observed in LNCaP cells (that have minimal expression of this receptor). Conversely, the PSMA targeted nanomedicine showed high uptake in LNCaP cells, with only minor uptake in the PC3 cells. In a dual-tumour xenograft mouse model, the nanomedicines showed high uptake in tumours in which the receptor was overexpressed, with only minimal non-specific accumulation in the low-expression tumours. CONCLUSIONS: This work highlighted the importance of clearly defining the target of interest in next-generation nanomedicines, and suggests that dual-targeting in such nanomedicines may be a means to achieve greater efficacy. PMID- 27225499 TI - The Role of Dopamine in Inflammation-Associated Depression: Mechanisms and Therapeutic Implications. AB - Studies investigating the impact of a variety of inflammatory stimuli on the brain and behavior have consistently reported evidence that inflammatory cytokines affect the basal ganglia and dopamine to mediate depressive symptoms related to motivation and motor activity. Findings have included inflammation associated reductions in ventral striatal responses to hedonic reward, decreased dopamine and dopamine metabolites in cerebrospinal fluid, and decreased availability of striatal dopamine, all of which correlate with symptoms of anhedonia, fatigue, and psychomotor retardation. Similar relationships between alterations in dopamine-relevant corticostriatal reward circuitry and symptoms of anhedonia and psychomotor slowing have also been observed in patients with major depression who exhibit increased peripheral cytokines and other inflammatory markers, such as C-reactive protein. Of note, these inflammation-associated depressive symptoms are often difficult to treat in patients with medical illnesses or major depression. Furthermore, a wealth of literature suggests that inflammation can decrease dopamine synthesis, packaging, and release, thus sabotaging or circumventing the efficacy of standard antidepressant treatments. Herein, the mechanisms by which inflammation and cytokines affect dopamine neurotransmission are discussed, which may provide novel insights into treatment of inflammation-related behavioral symptoms that contribute to an inflammatory malaise. PMID- 27225500 TI - Design and management of public health outreach using interoperable mobile multimedia: an analysis of a national winter weather preparedness campaign. AB - BACKGROUND: The Office of Public Health Preparedness and Response (OPHPR) in the Centers for Disease Control and Prevention conducts outreach for public preparedness for natural and manmade incidents. In 2011, OPHPR conducted a nationwide mobile public health (m-Health) campaign that pushed brief videos on preparing for severe winter weather onto cell phones, with the objective of evaluating the interoperability of multimedia m-Health outreach with diverse cell phones (including handsets without Internet capability), carriers, and user preferences. METHODS: Existing OPHPR outreach material on winter weather preparedness was converted into mobile-ready multimedia using mobile marketing best practices to improve audiovisual quality and relevance. Middleware complying with opt-in requirements was developed to push nine bi-weekly multimedia broadcasts onto subscribers' cell phones, and OPHPR promoted the campaign on its web site and to subscribers on its govdelivery.com notification platform. Multimedia, text, and voice messaging activity to/from the middleware was logged and analyzed. RESULTS: Adapting existing media into mobile video was straightforward using open source and commercial software, including web pages, PDF documents, and public service announcements. The middleware successfully delivered all outreach videos to all participants (a total of 504 videos) regardless of the participant's device. 54 % of videos were viewed on cell phones, 32 % on computers, and 14 % were retrieved by search engine web crawlers. 21 % of participating cell phones did not have Internet access, yet still received and displayed all videos. The time from media push to media viewing on cell phones was half that of push to viewing on computers. CONCLUSIONS: Video delivered through multimedia messaging can be as interoperable as text messages, while providing much richer information. This may be the only multimedia mechanism available to outreach campaigns targeting vulnerable populations impacted by the digital divide. Anti-spam laws preserve the integrity of mobile messaging, but complicate campaign promotion. Person-to-person messages may boost enrollment. PMID- 27225502 TI - Vowel Height Allophony and Dorsal Place Contrasts in Cochabamba Quechua. AB - This paper reports on the results of two studies investigating the role of allophony in cueing phonemic contrasts. In Cochabamba Quechua, the uvularvelar place distinction is often cued by additional differences in the height of the surrounding vowels. An acoustic study documents the lowering effect of a preceding tautomorphemic or a following heteromorphemic uvular on the high vowels /i u/. A discrimination study finds that vowel height is a significant cue to the velar-uvular place contrast. These findings support a view of contrasts as collections of distinguishing properties, as opposed to oppositions in a single distinctive feature. PMID- 27225501 TI - Endogenous attention modulates early selective attention in psychopathy: An ERP investigation. AB - Psychopathic individuals are prone to act on urges without adequate consideration of future consequences or the rights of other individuals. One interpretation of this behavior is that it reflects abnormal selective attention (i.e., a failure to process information that is incongruent with their primary focus of attention; Hiatt, Schmitt, & Newman, Neuropsychology, 18, 50-59, 2004). Unfortunately, it is unclear whether this selective attention abnormality reflects top-down endogenous influences, such as the strength or specificity of attention focus (i.e., top down set) apart from other, more exogenous (bottom-up), effects on attention. To explore this question, we used an early visual event-related potential (N2pc) in combination with a modified visual search task designed to assess the effect of early endogenous (i.e., top-down) attention on the processing of set-congruent information. The task was administered to a sample of 70 incarcerated adult males, who were assigned to high, intermediate, and low psychopathy groups using Hare's Psychopathy Checklist-Revised (Hare, 2003). Based on the assumption that their failure to process set-incongruent information reflects the exaggerated effects of endogenous attention, we predicted that participants with high psychopathy scores would show an exaggerated N2pc response to set-congruent information. The results supported the hypothesis and provide novel electrophysiological evidence that psychopathy is associated with exaggerated endogenous attention effects during early stages of processing. Further research is needed to examine the implications of this finding for the well-established failure of psychopathic individuals to process set-incongruent information and inhibit inappropriate responses. PMID- 27225503 TI - Enhancements in hepatobiliary imaging: the spectrum of gadolinium-ethoxybenzyl diethylenetriaminepentaacetic acid usages in hepatobiliary magnetic resonance imaging. AB - Gadolinium-ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA) is a unique hepatocyte-specific contrast agent approved for clinical use in the United States in 2008. Gd-EOB-DTPA-enhanced MR has shown to improve detection and characterization of hepatic lesions. Gd-EOB-DTPA is now being routinely used in daily clinical practice worldwide. Therefore, it is important for radiologists to be familiar with the potential uses and pitfalls of Gd-EOB-DTPA, which extends beyond the assessment of focal hepatic lesions. The purpose of this article is to review the various usages of Gd-EOB-DTPA in hepatobiliary MR imaging. PMID- 27225504 TI - The Influence of Treatment Motivation on Outcomes of Social Skills Training for Juvenile Delinquents. AB - This study examined the influence of treatment motivation on posttreatment effectiveness of an outpatient, individual social skills training for juvenile delinquents imposed as a penal sanction. Propensity score matching was used to match a control group of juveniles receiving treatment as usual ( n = 108 of total N = 354) to a treatment group of juveniles receiving Tools4U, a social skills training with a parental component ( N = 115). Treatment motivation was examined as a moderator and predictor of treatment effects on impulsivity, social perspective-taking, social problem-solving, lack of critical reasoning, developmental task-related skills, and parenting skills. Treatment effects were mostly consistent across juveniles with different levels of treatment motivation. Only one moderating effect was found on active tackling (i.e., actively addressing problems), and predictive effects were found on seeking social support, cognitive empathy, hostile intent attribution, and self-centeredness. Implications for further research are discussed. PMID- 27225505 TI - Computational Design of Iron Diphosphine Complexes with Pendant Amines for Hydrogenation of CO2 to Methanol: A Mimic of [NiFe] Hydrogenase. AB - Inspired by the active-site structure of the [NiFe] hydrogenase, we have computationally designed the iron complex [P(tBu) 2 N(tBu) 2 )Fe(CN)2 CO] by using an experimentally ready-made diphosphine ligand with pendant amines for the hydrogenation of CO2 to methanol. Density functional theory calculations indicate that the rate-determining step in the whole catalytic reaction is the direct hydride transfer from the Fe center to the carbon atom in the formic acid with a total free energy barrier of 28.4 kcal mol(-1) in aqueous solution. Such a barrier indicates that the designed iron complex is a promising low-cost catalyst for the formation of methanol from CO2 and H2 under mild conditions. The key role of the diphosphine ligand with pendent amine groups in the reaction is the assistance of the cleavage of H2 by forming a Fe-H(delta-) ???H(delta+) -N dihydrogen bond in a fashion of frustrated Lewis pairs. PMID- 27225506 TI - Re: Clinical significance of prospectively assigned gleason tertiary pattern 4 in contemporary Gleason score 3 + 3 = 6 prostate cancer. PMID- 27225507 TI - Utility of up-front transoral robotic surgery in tailoring adjuvant therapy. AB - BACKGROUND: The purpose of this study was to describe how the up-front transoral robotic surgery (TORS) approach could be used to individually tailor adjuvant therapy based on surgical pathology. METHODS: Between January 2009 and December 2013, 76 patients received TORS for oropharyngeal squamous cell carcinoma (OPSCC). Clinical predictors of adjuvant therapy were analyzed and comparisons were made between recommended treatment guidelines for up-front surgery versus definitive nonsurgical approaches. RESULTS: Advanced N classification, human papillomavirus (HPV)-positive tumor, extracapsular spread (ECS; 26 of 76), perineural invasion (PNI; 14 of 76), and positive margins (7 of 76) were significant predictors of adjuvant chemoradiotherapy (CRT) (p < .05). Up-front TORS deintensified adjuvant therapy; 76% of stage I/II and 46% of stage III/IV patients avoided CRT. Conversely, pathologic staging resulted in 33% of patients who would have received radiotherapy (RT) alone based on clinical staging, to be intensified to receive adjuvant CRT. CONCLUSION: The TORS approach deintensifies adjuvant therapy and provides valuable pathologic information to intensify treatment in select patients. TORS may be less effective in deintensification of adjuvant therapy in patients with clinically advanced N classification disease. (c) 2016 Wiley Periodicals, Inc. Head Neck 38:1201-1207, 2016. PMID- 27225508 TI - Effects of Dietary Exposure to Sulfamethazine on the Hematological Parameters and Hepatic Oxidative Stress Biomarkers in Nile Tilapia (Oreochromis niloticus). AB - Sulfamethazine (SMZ) is one of the most commonly used sulfonamide compounds in fish farming, and its physiological effects on fish are unknown. SMZ was administered to juvenile Nile tilapia (Oreochromis niloticus) at a dose level of 422 mg kg(-1) body weight, for a period of 11 days, via medicated feed. Fish were divided into two groups, the control group (CG) and the group fed with SMZ in feed. The administration of SMZ did not alter the erythrograms and leukograms of the Nile tilapia. The SMZ-fed group showed the same hepatic lipid peroxidation (LPO) concentration as the CG. Nonetheless, the oral administration of SMZ raised the hepatic catalase (CAT) and glutathione S-transferase (GST) activities, the increase probably being sufficient to prevent hepatic LPO production. The oral administration of SMZ affects the hepatic GST and CAT activities of Nile tilapia. PMID- 27225509 TI - Drying and Storage Methods Affect Cyfluthrin Concentrations in Exposed Plant Samples. AB - Standard procedures do not exist for drying and storage of plant samples prior to chemical analyses. Since immediate analysis is not always possible, current research examined which plant drying and storage method yielded the highest cyfluthrin recovery rates compared to traditional mechanical freeze-drying methods. Fifteen mesocosms were planted with rice. Cyfluthrin (5 mg L(-1)) was amended into the water column of individual mesocosms. 48 h later, plant material in the water column was collected from each mesocosm. Control (mechanical freeze drying) recovery was significantly greater (p < 0.001) than all 14 combinations of drying and storage. Significant differences also existed between all 14 different combinations. Greatest cyfluthrin recoveries in non-control plants were from the freezer-greenhouse-freezer drying and storage method. Results offer evidence for the efficient plant drying and storage methods prior to cyfluthrin analysis. Future studies should perform comparable analyses on various pesticide classes to determine possible relationships. PMID- 27225510 TI - Enantioselective intermolecular cross Rauhut-Currier reactions of activated alkenes with acrolein. AB - The enantioselective intermolecular cross Rauhut-Currier reaction of acrolein with active olefins has been a long-standing challenge because of the competitive MBH reaction and polymerization. Herein a highly enantioselective intermolecular cross Rauhut-Currier reaction of acrolein with 3-acyl acrylates and 2-ene-1,4 diones, which is enabled by newly designed Peng-Phos catalysts. This method is scalable and highly enantioselective (up to 96% ee). Several transformations of the R-C products are carried out to showcase the synthetic utility. PMID- 27225511 TI - Primary tracheoesophageal puncture and cricopharyngeal myotomy in stapler assisted total laryngectomy. AB - OBJECTIVE: To evaluate the utility of the hybrid tracheoesophageal puncture procedure in stapler-assisted laryngectomy. METHODS: Patients who underwent total laryngectomy at a single institution from 2009 to 2015 were reviewed. The interventions assessed were surgical creation of a tracheoesophageal puncture and placement of a voice prosthesis. The outcomes measured included voicing ability and valve failure. RESULTS: Thirty-nine patients underwent total laryngectomy or pharyngolaryngectomy. Of these, nine underwent stapler-assisted laryngectomy; seven of the nine patients underwent concurrent stapler-assisted laryngectomy, cricopharyngeal myotomy and a hybrid tracheoesophageal puncture procedure. These seven patients were the focus of this review. Successful voicing and oral alimentation was achieved in all patients. Mean time to phonation was 30 days (range, 7-77 days) and mean time to first valve change was 90 days (range, 35-117 days). CONCLUSION: Primary tracheoesophageal puncture with concurrent voice prosthesis placement and cricopharyngeal myotomy is easily performed with stapler assisted laryngectomy. The hybrid tracheoesophageal puncture procedure is a simple method that enables a single operator to achieve primary tracheoesophageal puncture and valve placement; in addition, it facilitates concurrent cricopharyngeal myotomy. PMID- 27225512 TI - International Corner News : VII Iberoamerican Congress of Nuclear Cardiology and Cardiac Imaging. PMID- 27225514 TI - Development and validation of a phase analysis tool to measure interventricular mechanical dyssynchrony from gated SPECT MPI. AB - OBJECTIVES: The purpose of this study is to develop a right-ventricular (RV) phase analysis tool which when coupled with our left ventricular (LV) phase analysis tool can provide measurement of the interventricular mechanical dyssynchrony from gated SPECT myocardial perfusion imaging (MPI), and validate the tool by electrocardiography (ECG). METHODS: For each patient, short-axis LV and RV SPECT MPI images were input into an automatic sampling algorithm to generate the 3D maximal count circumferential profiles for both LV and RV in each cardiac frame. Subsequently, the samples of LV and RV were separately used by our phase analysis tool based on the first-harmonic Fourier approximation to calculate the contraction onset for each sample. The difference between contraction onsets of the middle LV free wall and middle LV septal wall represented the LV contraction delay; the difference between contraction onsets of the middle RV free wall and middle RV septal wall represented the RV contraction delay. The difference between the LV and RV contraction delays represented the interventricular contraction delay, which was compared with the interventricular conduction delay classified by ECG to validate the concordance of interventricular mechanical and electrical dyssynchrony. Sixty-one bundle branch block (BBB) patients with ischemic-dilated cardiomyopathy (26, 42.6%) or non-ischemic-dilated cardiomyopathy (35, 57.4%), who underwent 12-lead surface ECG and gated resting Tc-99m sestamibi SPECT, were retrospectively analyzed in this study. RESULTS: In the 30 patients with left bundle branch block (LBBB) by ECG, there were 27 patients whose LV contracted later than the RV according to SPECT; and in the 31 patients with right bundle branch block (RBBB) by ECG, there were 26 patients whose LV contracted earlier than the RV according to SPECT. In total, an agreement rate of 86.9% (53 of 61) was achieved between SPECT and ECG. The Kappa agreement rate was 73.8% (95% confidence interval 0.57-0.91). CONCLUSION: The preliminary results showed promise for the measurement of interventricular mechanical dyssynchrony in BBB patients with dilated cardiomyopathy using our phase analysis tool. PMID- 27225513 TI - Comprehensive review on cardio-oncology: Role of multimodality imaging. AB - Cancer and cardiovascular disease are the two leading causes of mortality worldwide. Evolving oncologic therapy, including the use of newer targeted agents, has led to an improvement in survival from childhood- and adult-onset cancers. Consequently, there has been a growing realization of cardiotoxic complications related to cancer therapy, with some complications manifesting over months to decades after completion of cancer treatment. This paper reviews cancer therapeutics-related cardiovascular toxicity and its manifestations, multimodality imaging techniques for surveillance and detection of this complication, and the current state of knowledge in this emerging field. PMID- 27225515 TI - Optimizing gated myocardial perfusion imaging processing for phase analysis. PMID- 27225516 TI - Optimization of a simultaneous dual-isotope 201Tl/123I-MIBG myocardial SPECT imaging protocol with a CZT camera for trigger zone assessment after myocardial infarction for routine clinical settings: Are delayed acquisition and scatter correction necessary? AB - BACKGROUND: Dual-isotope 201Tl/123I-MIBG SPECT can assess trigger zones (dysfunctions in the autonomic nervous system located in areas of viable myocardium) that are substrate for ventricular arrhythmias after STEMI. This study evaluated the necessity of delayed acquisition and scatter correction for dual-isotope 201Tl/123I-MIBG SPECT studies with a CZT camera to identify trigger zones after revascularization in patients with STEMI in routine clinical settings. METHODS: Sixty-nine patients were prospectively enrolled after revascularization to undergo 201Tl/123I-MIBG SPECT using a CZT camera (Discovery NM 530c, GE). The first acquisition was a single thallium study (before MIBG administration); the second and the third were early and late dual-isotope studies. We compared the scatter-uncorrected and scatter-corrected (TEW method) thallium studies with the results of magnetic resonance imaging or transthoracic echography (reference standard) to diagnose myocardial necrosis. RESULTS: Summed rest scores (SRS) were significantly higher in the delayed MIBG studies than the early MIBG studies. SRS and necrosis surface were significantly higher in the delayed thallium studies with scatter correction than without scatter correction, leading to less trigger zone diagnosis for the scatter-corrected studies. Compared with the scatter-uncorrected studies, the late thallium scatter corrected studies provided the best diagnostic values for myocardial necrosis assessment. CONCLUSIONS: Delayed acquisitions and scatter-corrected dual-isotope 201Tl/123I-MIBG SPECT acquisitions provide an improved evaluation of trigger zones in routine clinical settings after revascularization for STEMI. PMID- 27225517 TI - 18-kDa translocator protein ligand 18F-FEMPA: Biodistribution and uptake into atherosclerotic plaques in mice. AB - BACKGROUND: Radioligands of 18-kDa translocator protein (TSPO) expressed on activated macrophages are a potential approach for imaging of inflammation in atherosclerosis. We evaluated a novel TSPO-targeted tracer 18F-FEMPA for the detection of atherosclerotic plaque inflammation in mice. METHODS AND RESULTS: The distribution kinetics of 18F-FEMPA was evaluated by in vivo PET/CT imaging. 18F-FEMPA uptake was compared in atherosclerotic (LDLR-/-ApoB100/100, n = 10) and healthy mice (C57BL/6 N, n = 7) ex vivo at twenty minutes post-injection. Biodistribution was analyzed from harvested tissue samples, and aortas were sectioned for autoradiography. Aortas of LDLR-/-ApoB100/100 mice showed large, macrophage-rich atherosclerotic plaques. In vivo, 18F-FEMPA showed rapid blood clearance but no difference in aortic uptake between atherosclerotic and healthy mice. In the mice studied ex vivo at 20 minutes post-injection, quantification of radioactivity in the whole aorta showed 1.3-fold higher 18F-FEMPA accumulation in atherosclerotic than healthy mice (P = .028). Autoradiography showed higher tracer uptake in plaque areas with high macrophage content as compared with areas of no macrophages (count densities 190 +/- 54 vs 40 +/- 13 PSL/mm2, P < .001), but the uptake in the plaques was not higher than in the normal vessel wall (230 +/- 78 PSL/mm2). In vitro blocking showed specific accumulation in mouse and human atherosclerotic plaques. Immunohistochemistry confirmed co-localization of TSPO and macrophages. CONCLUSIONS: 18F-FEMPA shows rapid blood clearance and uptake in the mouse aorta. Uptake in atherosclerotic plaques correlated with the amount of macrophages, but did not exceed that in the normal vessel wall. PMID- 27225518 TI - Early subclinical inflammation correlates with outcomes in positive crossmatch kidney allografts. AB - The aim of this study was to investigate correlations between early subclinical findings (10- and 90-day histology and gene expression data) and late outcomes (transplant glomerulopathy and graft loss) in positive crossmatch kidney transplants (+XMKTx). We compared 34 +XMKTx (19 receiving eculizumab and 15 receiving standard of care without eculizumab) to 13 -XMKTx (between August 2001 and August 2011). At 10 days, light microscopy identified subclinical inflammation in only 18% of +XMKTx, while intragraft gene expression identified inflammation in 79% (gene sets for activated macrophages, dendritic cells, NK cells or T cells). Inflammation persisted at 90 days and was associated with the development of transplant glomerulopathy by 2 years and graft loss. In contrast, endothelial cell (EC) changes present at 90 days by either electron microscopy or gene expression were not associated with transplant glomerulopathy or graft loss in this cohort. Eculizumab treatment did not appear to alter inflammation or EC changes. Therefore, intragraft inflammation might be an appropriate surrogate marker of progression and also a target of therapy to prevent chronic antibody mediated rejection. PMID- 27225519 TI - Social media and digital technology use among Indigenous young people in Australia: a literature review. AB - INTRODUCTION: The use of social media and digital technologies has grown rapidly in Australia and around the world, including among Indigenous young people who face social disadvantage. Given the potential to use social media for communication, providing information and as part of creating and responding to social change, this paper explores published literature to understand how Indigenous Australian youth use digital technologies and social media, and its positive and negative impacts. METHODS: Online literature searches were conducted in three databases: PubMed, Google Scholar and Informit in August 2014; with further searches of additional relevant databases (Engineering Village; Communication & mass media complete; Computers & applied sciences complete; Web of Science) undertaken in May 2015. In addition, relevant literature was gathered using citation snowballing so that additional peer-reviewed and grey literature was included. Articles were deemed relevant if they discussed social media and/or digital technologies and Indigenous Australians. After reading and reviewing all relevant articles, a thematic analysis was used to identify overall themes and identify specific examples. RESULTS: A total of 22 papers were included in the review. Several major themes were identified about how and why Indigenous young people use social media: identity, power and control, cultural compatibility and community and family connections. Examples of marketing for health and health promotion approaches that utilize social media and digital technologies were identified. Negative uses of social media such as cyber bullying, cyber racism and the exchange of sexually explicit content between minors are common with limited approaches to dealing with this at the community level. DISCUSSION: Strong cultural identity and community and family connections, which can be enhanced through social media, are linked to improved educational and health outcomes. The confidence that Indigenous young people demonstrate when approaching the use of social media invites its further use, including in arenas where this group may not usually participate, such as in research. CONCLUSIONS: Future research could examine ways to minimise the misuse of social media while maximising its positive potential in the lives of Indigenous young people. Future research should also focus on the positive application of social media and showing evidence in health promotion interventions in order to reduce health inequities between Indigenous and non-Indigenous young people. PMID- 27225520 TI - Obstetric outcomes of isolated oligohydramnios during early-term, full-term and late-term periods and determination of optimal timing of delivery. AB - AIM: Our aim was to evaluate the obstetric outcomes of isolated oligohydramnios during the early-term, full-term, and late-term periods, and to determine the optimal timing of delivery. METHODS: A retrospective study was performed at a tertiary center. Isolated oligohydramnios cases were divided into early-term, full-term, and late-term groups. Evaluated outcomes were fetal birthweight, 5-min Apgar score < 7, meconium-stained amniotic fluid, neonatal intensive care unit admission, transient tachypnea of newborn (TTN), requirement of ventilator, newborn jaundice, mode of delivery, induction of labor, and undiagnosed small-for gestational-age fetus before delivery. Composite outcome was defined as perinatal outcomes taken together (neonatal intensive care unit admission, TTN, requirement of ventilator, and newborn jaundice). RESULTS: The study period included 1213 cases of term isolated oligohydramnios. Within this cohort there were 347 early term, 781 full-term and 85 late-term patients. The cesarean rate and the rate of newborn jaundice were higher in early-term cases (37.8% and 3.5%, respectively) than in full-term cases (30.1% and 0.9%, respectively). Meconium-stained amniotic fluid was higher in late-term than full-term cases. Timing of delivery did not affect occurrence of TTN, 5-min Apgar score < 7, ventilator requirement, or composite outcome. In total, 15-17% of isolated oligohydramnios cases involved undetected small-for-gestational-age fetuses. CONCLUSION: As this study was not a randomized controlled trial, a decisive conclusion may not be possible. However, until well-designed controlled studies are conducted, expectant management may be appropriate up to the full-term period and induction of labor may be appropriate management when the full-term period is reached. PMID- 27225521 TI - An all-glass 12 MUm ultra-thin and flexible micro-fluidic chip fabricated by femtosecond laser processing. AB - This study investigated and established a method, using femtosecond laser processing, to fabricate a 100%-glass-based 12 MUm ultra-thin and flexible micro fluidic chip. First we investigated the suitable pulse energy of the laser to fabricate ultra-thin glass sheets and then we fabricated a prototype glass micro fluidic chip. Two 1 mm-in-diameter orifices for facilitating alignment in the bonding step and one channel with a width of 20 MUm and a length of 25 mm were fabricated in a 4 MUm thickness ultra-thin glass sheet using the femtosecond laser; this forms layer 2 in the completed device. Next, the glass sheet with the channel was sandwiched between another glass sheet having an inlet hole and an outlet hole (layer 1) and a base glass sheet (layer 3); the three sheets were bonded to each other, resulting in a flexible, 100%-glass micro-fluidic chip with a thickness of approximately 12 MUm and a weight of 3.6 mg. The basic function of the glass micro-fluidic chip was confirmed by flowing 1 and 2 MUm in-diameter bead particles through the channel. The fabrication method clearly scales down the thickness limitation of flexible glass devices and offers a possible element technology for fabricating ultra-thin glass devices that can be applied to convection-enhanced delivery, implantable medical devices, wearable devices, and high-resolution imaging of small biological objects such as bacteria and proteins in the channel. PMID- 27225523 TI - Geometric Approximation: A New Computational Approach To Characterize Protein Dynamics from NMR Adiabatic Relaxation Dispersion Experiments. AB - A new computational strategy is reported that provides a fast approximation of numerical solutions of differential equations in general. The method is demonstrated with the analysis of NMR adiabatic relaxation dispersion experiments to reveal biomolecular dynamics. When an analytical solution to the theoretical equations describing a physical process is not available, the new approach can significantly accelerate the computational speed of the conventional numerical integration up to 10(5) times. NMR adiabatic relaxation dispersion experiments enhanced with optimized proton-decoupled pulse sequences, although extremely powerful, have previously been refractory to quantitative analysis. Both simulations and experimental validation demonstrate detectable "slow" (microsecond to millisecond) conformational exchange rates from 10(2) to 10(5) s( 1). This greatly expanded time-scale range enables the characterization of a wide array of conformational fluctuations for individual residues, which correlate with biomolecular function and were previously inaccessible. Moreover, the new computational method can be potentially generalized for analysis of new types of relaxation dispersion experiments to characterize the various dynamics of biomolecular systems. PMID- 27225522 TI - Properties of internalization factors contributing to the uptake of extracellular DNA into tumor-initiating stem cells of mouse Krebs-2 cell line. AB - BACKGROUND: Previously, we demonstrated that poorly differentiated cells of various origins, including tumor-initiating stem cells present in the ascites form of mouse cancer cell line Krebs-2, are capable of naturally internalizing both linear double-stranded DNA and circular plasmid DNA. METHODS: The method of co-incubating Krebs-2 cells with extracellular plasmid DNA (pUC19) or TAMRA-5' dUTP-labeled polymerase chain reaction (PCR) product was used. It was found that internalized plasmid DNA isolated from Krebs-2 can be transformed into competent Escherichia coli cells. Thus, the internalization processes taking place in the Krebs-2 cell subpopulation have been analyzed and compared, as assayed by E. coli colony formation assay (plasmid DNA) and cytofluorescence (TAMRA-DNA). RESULTS: We showed that extracellular DNA both in the form of plasmid DNA and a PCR product is internalized by the same subpopulation of Krebs-2 cells. We found that the saturation threshold for Krebs-2 ascites cells is 0.5 MUg DNA/10(6) cells. Supercoiled plasmid DNA, human high-molecular weight DNA, and 500 bp PCR fragments are internalized into the Krebs-2 tumor-initiating stem cells via distinct, non-competing internalization pathways. Under our experimental conditions, each cell may harbor 340-2600 copies of intact plasmid material, or up to 3.097 +/- 0.044*10(6) plasmid copies (intact or not), as detected by quantitative PCR. CONCLUSION: The internalization dynamics of extracellular DNA, copy number of the plasmids taken up by the cells, and competition between different types of double-stranded DNA upon internalization into tumor-initiating stem cells of mouse ascites Krebs-2 have been comprehensively analyzed. Investigation of the extracellular DNA internalization into tumor-initiating stem cells is an important part of understanding their properties and possible destruction mechanisms. For example, a TAMRA-labeled DNA probe may serve as an instrument to develop a target for the therapy of cancer, aiming at elimination of tumor stem cells, as well as developing a straightforward test system for the quantification of poorly differentiated cells, including tumor-initiating stem cells, in the bulk tumor sample (biopsy or surgery specimen). PMID- 27225524 TI - Association between oral health habits and dental caries among children in Pyongyang, Democratic People's Republic of Korea. AB - AIM: To evaluate the self-reported oral health habits and their association with the occurrence of dental caries among children in Pyongyang, Democratic People's Republic of Korea (DPRK), after 6 years of activities under the auspices of the Children's Oral Health Promotion Programme (COHPP). METHODS: The data were collected in September 2013 in two of the most central districts of Pyongyang City, DPRK. The sample consisted of 492 children aged 10 and 13 years who had participated in the COHPP for 6 years. The children filled in a self-completed, structured questionnaire on oral health habits and were examined clinically by a dentist. The differences in mean (SD) number of decayed primary (dt) and permanent teeth (DT) and their sum (dt + DT) subdivided according to genders, age groups, districts and self-reported oral health habits were evaluated using Mann Whitney U-test. The associations between self-reported oral health habits and the occurrence of dental caries were evaluated with chi-square test and logistic regression analyses. RESULTS: The school-aged children commonly reported healthy oral hygiene habits but sweet snacks were commonly used. The occurrence of dental caries associated statistically significantly with the frequency of sweet snacking (p=0.011) but not with the frequency of tooth brushing (p=0.725) or the use of water for thirst instead of sugary beverages (p=0.189). CONCLUSION: A more effective promotion of healthy dietary habits with innovative approaches and close collaboration with different social actors will be needed in future. PMID- 27225525 TI - Quantifying Variability of Manual Annotation in Cryo-Electron Tomograms. AB - Although acknowledged to be variable and subjective, manual annotation of cryo electron tomography data is commonly used to answer structural questions and to create a "ground truth" for evaluation of automated segmentation algorithms. Validation of such annotation is lacking, but is critical for understanding the reproducibility of manual annotations. Here, we used voxel-based similarity scores for a variety of specimens, ranging in complexity and segmented by several annotators, to quantify the variation among their annotations. In addition, we have identified procedures for merging annotations to reduce variability, thereby increasing the reliability of manual annotation. Based on our analyses, we find that it is necessary to combine multiple manual annotations to increase the confidence level for answering structural questions. We also make recommendations to guide algorithm development for automated annotation of features of interest. PMID- 27225526 TI - Neuron-Like Networks Between Ribosomal Proteins Within the Ribosome. AB - From brain to the World Wide Web, information-processing networks share common scale invariant properties. Here, we reveal the existence of neural-like networks at a molecular scale within the ribosome. We show that with their extensions, ribosomal proteins form complex assortative interaction networks through which they communicate through tiny interfaces. The analysis of the crystal structures of 50S eubacterial particles reveals that most of these interfaces involve key phylogenetically conserved residues. The systematic observation of interactions between basic and aromatic amino acids at the interfaces and along the extension provides new structural insights that may contribute to decipher the molecular mechanisms of signal transmission within or between the ribosomal proteins. Similar to neurons interacting through "molecular synapses", ribosomal proteins form a network that suggest an analogy with a simple molecular brain in which the "sensory-proteins" innervate the functional ribosomal sites, while the "inter proteins" interconnect them into circuits suitable to process the information flow that circulates during protein synthesis. It is likely that these circuits have evolved to coordinate both the complex macromolecular motions and the binding of the multiple factors during translation. This opens new perspectives on nanoscale information transfer and processing. PMID- 27225527 TI - Neurocognitive function in patients with head and neck cancer undergoing primary or adjuvant chemoradiation treatment. AB - PURPOSE: Cancer and cancer therapy-related neurocognitive changes negatively affect quality of life, yet few studies have examined neurocognitive changes in patients with head and neck cancer. The purpose of this study was to evaluate neurocognitive performance in patients with head and neck cancer at baseline before starting treatment and 3 months after treatment completion to assess treatment-associated changes in performance. METHODS: Patients with head and neck cancer who were to receive primary or adjuvant chemoradiation (N = 55) underwent neuropsychological testing before and 3 months posttreatment. Changes in neurocognitive performance were assessed using a practice effect adjusted Reliable Change Index. RESULTS: At baseline, 38 % of patients exhibited global neurocognitive impairment. Posttreatment, 21.8 % demonstrated declines in neurocognitive performance in at least one domain. Declines in domain-specific performance ranged from 1.8 to 12.7 % with the greatest decline in language, specifically verb retrieval. Domain-specific improvements ranged from 0 to 7.3 %. CONCLUSIONS: Patients had a high prevalence of baseline neurocognitive impairment. While neurocognitive performance posttreatment remained unchanged in the majority, almost 13 % suffered declines in language. Small percentages of patients exhibited improvements in their performance. Long-term effects and risk factors for neurocognitive decline in this population should be studied on a larger scale. PMID- 27225528 TI - Financial burden of colorectal cancer treatment among patients and their families in a middle-income country. AB - BACKGROUND: In Malaysia, the healthcare system consists of a government-run universal healthcare system and a co-existing private healthcare system. However, with high and ever rising healthcare spending on cancer management, cancer patients and their families are likely to become vulnerable to a healthcare related financial burden. Moreover, they may have to reduce their working hours and lose income. To better understand this issue, this study aims to assess the financial burden of colorectal cancer patients and their families in the first year following diagnosis. METHODS: Data on patient costs were collected prospectively in the first year following diagnosis by using a self-administered questionnaire and telephone interviews at three time points for all four stages of colorectal cancer. The patient cost data consisted of direct out-of-pocket payments for medical-related expenses such as hospital stays, tests and treatment and for non-medical items such as travel and food associated with hospital visits. In addition, indirect cost data related to the loss of productivity of the patient and caregiver(s) was assessed. The patient's perceived level of financial difficulty and types of coping strategy were also explored. RESULT: The total 1-year patient cost (both direct and indirect) increased with the stage of colorectal cancer: RM 6544.5 (USD 2045.1) for stage I, RM 7790.1 (USD 2434.4) for stage II, RM 8799.1 (USD 2749.7) for stage III and RM 8638.2 (USD 2699.4) for stage IV. The majority of patients perceived paying for their healthcare as somewhat difficult. The most frequently used financial coping strategy was a combination of current income and savings. CONCLUSION: Despite the high subsidisation in public hospitals, the management of colorectal cancer imposes a substantial financial burden on patients and their families. Moreover, the majority of patients and their families perceive healthcare payments as difficult. Therefore, it is recommended that policy- and decision-makers should further consider some financial protection strategies and support for cancer treatment because cancer is a very costly and chronic disease. PMID- 27225529 TI - Effect of Electron Transporting Layer on Bismuth-Based Lead-Free Perovskite (CH3NH3)3 Bi2I9 for Photovoltaic Applications. AB - Methylammonium iodo bismuthate ((CH3NH3)3Bi2I9) (MBI) perovskite is a promising alternative to rapidly progressing hybrid organic-inorganic lead perovskites because of its better stability and low toxicity compared to lead-based perovskites. Solution-processed perovskite fabricated by single-step spin-coating and subsequent heating produced polycrystalline films of hybrid perovskite (CH3NH3)3Bi2I9), whose morphology was influenced drastically by the nature of substrates. The optical measurements showed a strong absorption band around 500 nm. The devices made on anatase TiO2 mesoporous layer showed good performance with current density over 0.8 mA cm(-2) while the devices on brookite TiO2 layer and planar (free of porous layer) was inefficient. However, all the MBI devices were stable to ambient conditions for more than 10 weeks. PMID- 27225530 TI - Interaction of water with (silico)aluminophosphate zeotypes: a comparative investigation using dispersion-corrected DFT. AB - Porous aluminophosphates (AlPOs) and silicoaluminophosphates (SAPOs) with zeolite like structures have received considerable attention as potential adsorbents for heat transformation applications using water adsorption/desorption cycles. Since a detailed experimental characterisation of the water adsorption properties has only been performed for some of these materials, such as AlPO-18 (AEI topology) and SAPO-34 (CHA topology), more systematic insights regarding the influence of the pore topology and (for SAPOs) the arrangement of the framework protons on the affinity towards water are lacking. To study the relationships between structure and properties in more detail, the interaction of water with six structurally different AlPOs (with AEI, AFX, CHA, ERI, GIS, RHO topologies) and their SAPO analogues was investigated using dispersion-corrected density-functional theory (DFT-D) calculations. Different possible locations of silicon atoms and charge balancing protons were considered for the SAPO systems. The calculations for SAPOs at low water loadings (one H2O molecule per framework proton) revealed that the interaction energies exhibit a considerable variation, ranging from -75 to 100 kJ mol(-1) (per water molecule). The differences in interaction energy were rationalised with the different structural environment of the framework protons at which the water molecules are adsorbed. At high water uptakes (near saturation), interaction energies in the range of -65 kJ mol(-1) were obtained for all AlPOs, and there was no evidence for a marked influence of pore size and/or topology on the interaction strength. The interaction of water with SAPOs was found to be approximately 5 kJ mol(-1) stronger than for AlPOs due to an increased contribution of electrostatic interactions. An analysis of the structural changes upon water adsorption revealed striking differences between the distinct topologies, with the materials with GIS and RHO topologies being distorted much more drastically than the systems based on double six-ring (d6r) units. Moreover, the direct coordination of water molecules to framework aluminium atoms occurs more frequently in these materials, an observation that points towards a reduced structural stability upon hydration. PMID- 27225531 TI - Improved intra-array and interarray normalization of peptide microarray phosphorylation for phosphorylome and kinome profiling by rational selection of relevant spots. AB - Massive parallel analysis using array technology has become the mainstay for analysis of genomes and transcriptomes. Analogously, the predominance of phosphorylation as a regulator of cellular metabolism has fostered the development of peptide arrays of kinase consensus substrates that allow the charting of cellular phosphorylation events (often called kinome profiling). However, whereas the bioinformatical framework for expression array analysis is well-developed, no advanced analysis tools are yet available for kinome profiling. Especially intra-array and interarray normalization of peptide array phosphorylation remain problematic, due to the absence of "housekeeping" kinases and the obvious fallacy of the assumption that different experimental conditions should exhibit equal amounts of kinase activity. Here we describe the development of analysis tools that reliably quantify phosphorylation of peptide arrays and that allow normalization of the signals obtained. We provide a method for intraslide gradient correction and spot quality control. We describe a novel interarray normalization procedure, named repetitive signal enhancement, RSE, which provides a mathematical approach to limit the false negative results occuring with the use of other normalization procedures. Using in silico and biological experiments we show that employing such protocols yields superior insight into cellular physiology as compared to classical analysis tools for kinome profiling. PMID- 27225532 TI - Low-dose irradiation promotes Rad51 expression by down-regulating miR-193b-3p in hepatocytes. AB - Current evidence indicates that there is a relationship between microRNA (miRNA) mediated gene silencing and low-dose irradiation (LDIR) responses. Here, alterations of miRNA expression in response to LDIR exposure in male BALB/c mice and three different types of hepatocytes were investigated. The miRNome of the LDIR-exposed mouse spleens (0.01 Gy, 6.5 mGy/h) was analyzed, and the expression of miRNA and mRNA was validated by qRT-PCR. Western blotting, chromatin immunoprecipitation (ChIP), and luciferase assays were also performed to evaluate the interaction between miRNAs and their target genes and to gain insight into the regulation of miRNA expression. The expression of miRNA-193b-3p was down regulated in the mouse spleen and liver and in various hepatocytes (NCTC, Hepa, and HepG2 cell lines) in response to LDIR. The down-regulation of miR-193b-3p expression was caused by histone deacetylation on the miR-193b-3p promoter in the HepG2 cells irradiated with 0.01 Gy. However, the alteration of histone deacetylation and miR-193b-3p and Rad51 expression in response to LDIR was restored by pretreatment with N-acetyl-cyctein. In conclusion, we provide evidence that miRNA responses to LDIR include the modulation of cellular stress responses and repair mechanisms. PMID- 27225534 TI - Optimization of the beta LACTA test for the detection of extended-spectrum-beta lactamase-producing bacteria directly in urine samples. AB - The beta LACTATM test (BLT) is a chromogenic test detecting resistance to third generation cephalosporins on bacterial colonies. Some studies have shown that this test can be used directly in urine samples. The aim of this study was to determine the optimal conditions of use of this test in order to detect the ESBL producing bacteria directly in urine samples. During a 4-months period, a total of 365 consecutive urine samples were tested with the BLT using the recommendation of the manufacturer. We isolated 56 ESBL-producing bacteria and 17 AmpC-overproducing bacteria. ESBL- and/or AmpC beta-lactamase-producing bacteria isolates were systematically characterized by disc diffusion antibiotic susceptibility testing interpreted according to the guidelines of EUCAST. The sensitivity and the specificity for 3GC-resistance detection, regardless the mechanism of resistance, were, respectively, 60.3% and 100%, whereas for ESBL detection, it was, respectively, 75.4% and 99.7%. We applied then modification of the initial protocol considering urines with a bacteriuria >1000/MUL, a reading time at 30 min and considering any change of the initial colour as positive. The overall sensitivity was 81% and the sensitivity for ESBL-detection raised to 95.7%. PMID- 27225533 TI - Secondary visual cortex is critical to the expression of surprise-induced enhancements in cue associability in rats. AB - Considerable evidence indicates that reinforcement prediction error, the difference between the obtained and expected reinforcer values, modulates attention to potential cues for reinforcement. The surprising delivery or omission of a reinforcer enhances the associability of the stimuli that were present when the error was induced, so that they more readily enter into new associations in the future. Previous research from our laboratory identified brain circuit elements critical to the enhancement of stimulus associability by omission of an expected event and to the subsequent expression of that altered associability in more rapid learning. A key finding was that the rat posterior parietal cortex was essential during the encoding, consolidation and retrieval of associability memories that were altered by the surprising omission of an expected event in a serial prediction task. Here, we found that the function of adjacent secondary visual cortex was critical only to the expression of altered cue associability in that same task. This specialization of function is discussed in the context of broader cortical and subcortical networks for modulation of attention in associative learning, as well as recent anatomical investigations that suggest that the rodent posterior parietal cortex overlaps with and may subsume secondary visual cortex. PMID- 27225535 TI - Diagnostic workup for postmenopausal bleeding: a randomised controlled trial. AB - OBJECTIVE: To evaluate the effectiveness of hysteroscopy for the detection and treatment of endometrial polyps versus expectant management in women with postmenopausal bleeding (PMB), a thickened endometrium and benign endometrial sampling. DESIGN: Multicentre, randomised controlled trial. SETTING: Three academic hospitals and nine non-academic teaching hospitals in the Netherlands. POPULATION: Women with PMB, an endometrial thickness >4 mm and benign result from endometrial sampling. METHODS: Women were randomised to either further diagnostic workup by hysteroscopy (preceded by saline infusion sonography) or expectant management. MAIN OUTCOMES: The primary outcome measure was recurrence of PMB within a year after randomisation. Secondary outcome measures were time to recurrent bleeding and recurrent bleeding after more than 1 year. In the hysteroscopy group, the presence of polyps and the results of their histology were registered. RESULTS: Between January 2010 and October 2013, 200 women were randomised; 98 to hysteroscopy and 102 to expectant management. Within 1 year a total of 15 women (15.3%) in the hysteroscopy group experienced recurrent bleeding, versus 18 (18.0%) in the expectant management group (relative risk 0.85 (95% CI 0.46-1.59). In the hysteroscopy group, 50/98 (51%) polyps were diagnosed of which 6/98 (6%) showed evidence of endometrial (pre)malignancy; final pathology results after hysterectomy showed three women with hyperplasia with atypia and three women with endometrial cancer. CONCLUSION: In women with PMB, a thickened endometrium and benign endometrial sampling, operative hysteroscopy does not reduce recurrent bleeding. Hysteroscopy detected focal endometrial (pre)malignancy in 6% of women who had benign endometrial sampling. This finding indicates that in these women, further diagnostic workup is warranted to detect focal (pre)malignancies, missed by blind endometrial sampling. TWEETABLE ABSTRACT: In women with PMB, hysteroscopy does not reduce recurrent bleeding but is warranted to detect focal malignancy. PMID- 27225536 TI - Similar temperature responses suggest future climate warming will not alter partitioning between denitrification and anammox in temperate marine sediments. AB - Removal of biologically available nitrogen (N) by the microbially mediated processes denitrification and anaerobic ammonium oxidation (anammox) affects ecosystem N availability. Although few studies have examined temperature responses of denitrification and anammox, previous work suggests that denitrification could become more important than anammox in response to climate warming. To test this hypothesis, we determined whether temperature responses of denitrification and anammox differed in shelf and estuarine sediments from coastal Rhode Island over a seasonal cycle. The influence of temperature and organic C availability was further assessed in a 12-week laboratory microcosm experiment. Temperature responses, as characterized by thermal optima (Topt ) and apparent activation energy (Ea ), were determined by measuring potential rates of denitrification and anammox at 31 discrete temperatures ranging from 3 to 59 degrees C. With a few exceptions, Topt and Ea of denitrification and anammox did not differ in Rhode Island sediments over the seasonal cycle. In microcosm sediments, Ea was somewhat lower for anammox compared to denitrification across all treatments. However, Topt did not differ between processes, and neither Ea nor Topt changed with warming or carbon addition. Thus, the two processes behaved similarly in terms of temperature responses, and these responses were not influenced by warming. This led us to reject the hypothesis that anammox is more cold-adapted than denitrification in our study system. Overall, our study suggests that temperature responses of both processes can be accurately modeled for temperate regions in the future using a single set of parameters, which are likely not to change over the next century as a result of predicted climate warming. We further conclude that climate warming will not directly alter the partitioning of N flow through anammox and denitrification. PMID- 27225537 TI - High-resolution, hybrid optical trapping methods, and their application to nucleic acid processing proteins. AB - Optical tweezers have become a powerful tool to investigate nucleic-acid processing proteins at the single-molecule level. Recent advances in this technique have now enabled measurements resolving the smallest units of molecular motion, on the scale of a single base pair of DNA. In parallel, new instrumentation combining optical traps with other functionalities have been developed, incorporating mechanical manipulation along orthogonal directions or fluorescence imaging capabilities. Here, we review these technical advances, their capabilities, and limitations, focusing on benchmark studies of protein nucleic acid interactions they have enabled. We highlight recent work that combines several of these advances together and its application to nucleic-acid processing enzymes. Finally, we discuss future prospects for these exciting developments. (c) 2016 Wiley Periodicals, Inc. Biopolymers 105: 704-714, 2016. PMID- 27225538 TI - Direct Access to beta-Fluorinated Aldehydes by Nitrite-Modified Wacker Oxidation. AB - An aldehyde-selective Wacker-type oxidation of allylic fluorides proceeds with a nitrite catalyst. The method represents a direct route to prepare beta fluorinated aldehydes. Allylic fluorides bearing a variety of functional groups are transformed in high yield and very high regioselectivity. Additionally, the unpurified aldehyde products serve as versatile intermediates, thus enabling access to a diverse array of fluorinated building blocks. Preliminary mechanistic investigations suggest that inductive effects have a strong influence on the rate and regioselectivity of the oxidation. PMID- 27225539 TI - Synthetic Sensors for Reactive Oxygen Species Detection and Quantification: A Critical Review of Current Methods. AB - SIGNIFICANCE: Redox reactions play important roles in both physiological and pathological processes, highlighting the importance of quantifying and localizing intracellular redox-active components. Most research has focused on direct investigation of reactive oxygen species (ROS). Intensity-based fluorescent methods are very sensitive and easy to use, but they lack specificity and can produce artifacts. In this article, we focus on synthetic sensors, describing experimental pitfalls associated with their use. We also present alternative methods for the detection of free radicals. RECENT ADVANCES: New approaches have been developed to overcome the main artifact of intensity-based methods: spurious changes in fluorescence intensity caused by oxidation. These new approaches are based on analytical measurements of the oxidized sensors or techniques that are not susceptible to oxidation, such as electron spin resonance and fluorescence lifetime-based methods. Regardless of the approach, the need for detection of ROS on the subcellular level, especially in the mitochondria, has motivated the development of new probes. CRITICAL ISSUES: Flow cytometry systems and confocal microscopes are now available to the majority of biologists, and commercially available probes are, therefore, more widely used. The fact that these new applications are cited in thousands of publications makes these sensors even more attractive. FUTURE DIRECTIONS: The field of ROS detection by synthetic sensors continues to expand, bringing needed additional research to the development of robust techniques that are applicable both in vitro and in vivo. Antioxid. Redox Signal. 25, 520-533. PMID- 27225540 TI - Environmental Fate of Chiral Herbicide Fenoxaprop-ethyl in Water-Sediment Microcosms. AB - The environmental fate of the herbicide fenoxaprop-ethyl (FE) in water, sediment and water-sediment microcosm was studied and degradation products fenoxaprop (FA), ethyl-2-(4-hydroxyphenoxy)propanoate (EHPP), 2-(4-hydroxyphenoxy)propanoic acid (HPPA) and 6-chloro-2,3-dihydrobenzoxazol-2-one (CDHB) were monitored. FE, FA, EHPP and HPPA were chiral and the environmental behavior was investigated on an enantiomeric level. In water, sediment and water-sediment microcosms, fenoxaprop-ethyl degraded very fast with half-lives less than 1 day and it was found the herbicidally inactive S-enantiomer degraded faster. Fenoxaprop was the main primary degradation product which was quickly formed and the further degradation was relatively slow with half-lives of 6.4-12.4 days, and the S enantiomer degraded faster too. EHPP, HPPA and CDHB could be found and S-EHPP and S-HPPA were degraded preferentially. The effects of microorganism and water content were investigated and it was found that the enantioselectivity was attributed to microorganisms. In sediment, the main degradation pathway of fenoxaprop-ethyl was hydrolysis and the degradation rate of fenoxaprop-ethyl increased with water content. The degradation products and enantioselectivity should be considered for the impact of fenoxaprop-ethyl on the aquatic system. PMID- 27225541 TI - Systematic review of surgical treatment of pyoderma gangrenosum with negative pressure wound therapy or skin grafting. PMID- 27225542 TI - Combination of Radiotherapy and Targeted Agents in Brain Metastasis: An Update. AB - OPINION STATEMENT: The combination of radiation therapy and targeted agents (molecular inhibitors or immunotherapy) represents an opportunity to improve the outcomes of patients with brain metastases. The combination of whole-brain radiation therapy (WBRT) with targeted agents takes advantage of radiosensitization, while the combination with stereotactic radiosurgery (SRS) may allow one to substitute an effective systemic agent for adjuvant WBRT, the historical standard of care. This strategy may in turn allow the promotion of secondary prevention paradigms with possibly less cognitive toxicity. At present, the combination of targeted therapy with SRS rather than with WBRT is the more viable option although both avenues will likely have a role in the future management of brain metastases. Patients should be encouraged to enter clinical trials since the off-study use of these combinations will delay the advancement of the field. Caution is advised in the combination of radiation and targeted agents as unexpected toxicities can occur. Clinicians should avail themselves of clinical trials in order to offer patients these promising options and to move the field forward. In the absence of a clinical trial, we recommend the combination of SRS with targeted agents and deferred WBRT. Small, asymptomatic brain metastases may be best managed with single-modality targeted agents with deferred radiation therapy, preferably on a clinical trial. Advances in targeted therapies combined with radiation therapy will most likely improve local control and hopefully the quality of life and survival of patients with brain metastasis. PMID- 27225543 TI - Fabry Disease: Recognition, Diagnosis, and Treatment of Neurological Features. AB - OPINION STATEMENT: Fabry disease is an X-linked, lysosomal storage disorder caused by a mutation in the GLA gene leading to a deficiency in alpha galactosidase A enzyme (alpha-Gal A) activity, which in turn results in accumulation of globotriaosylceramide in the vascular endothelium and smooth muscle cells of different organs, including kidney and heart, finally leading to impairment or failure of organ function. The central and peripheral nervous systems are also affected leading to neurological manifestations such as cerebrovascular diseases, small fiber neuropathy (SFN), and dysautonomic disorders that may be the presenting clinical features in a proportion of patients. This review offers a complete update of all neurological aspects of Fabry disease and therapeutic options. The rarity of disease, as well as the incomplete knowledge regarding natural history, pathogenic mechanisms, and the uncertain efficacy of available therapies, make imperative the acquisition of standardized data on natural disease course. These data are fundamental for the development of new treatments better able to access the central nervous system, to bypass the neutralizing antibodies and to improve the heart and kidney function. PMID- 27225544 TI - European Patient Summary Guideline: Focus on Greece. AB - The European Patient Summary (PS) guideline specifies a minimal dataset of essential and important information for unplanned or emergency care initially defined in the epSOS project with aim to improve patients' safety and quality of Care. The eHealth Network of European Union (EU) Member State (MS) representatives established under Article 14 of the EU directive 2011/24 on patient rights to cross-border healthcare adopted PS guideline in November 2013 and since then the guideline has been part of MS strategic eHealth implementation plans, standardization efforts, and concrete regional, national, European and international projects. This paper reviews implementation efforts for the implementation of an operational patient summary service in Greece drawing on challenges and lessons learned for sustainable standards-based large scale eHealth deployment in Europe and abroad, as well as the reuse of best practices from international standards and integration profiles. PMID- 27225545 TI - Stream 1. mHealth/Devices/Applications/Biosensors. PMID- 27225546 TI - Adoption Space and the Idea-to-Market Process of Health Technologies. AB - Although Europe 'produces' excellent science, it has not been equally successful in translating scientific results into commercially successful companies in spite of European and national efforts invested in supporting the translation process. The Idea-to-Market process is highly complex due to the large number of actors and stakeholders. ITECH was launched to propose recommendations which would accelerate the Idea-to-Market process of health technologies leading to improvements in the competitiveness of the European health technology industry in the global markets. The project went through the following steps: defining the Idea-to-Market process model; collection and analysis of funding opportunities; identification of 12 gaps and barriers in the Idea-to-Market process; a detailed analysis of these supported by interviews; a prioritization process to select the most important issues; construction of roadmaps for the prioritized issues; and finally generating recommendations and associated action plans. Seven issues were classified as in need of actions. Three of these are part of the ongoing Medical Device Directive Reform (MDR), namely health technology assessment, post-market surveillance and regulatory process, and therefore not within the scope of ITECH. Recommendations were made for eHealth taxonomy; Education and training; Clinical trials and Adoption space and Human Factors Engineering (HFE). PMID- 27225547 TI - Multi-parametric prediction for cardiovascular risk assessment. AB - The employment of personal health systems (pHealth) is a valuable concept in the management of chronic diseases, particularly in the context of cardiovascular diseases. By means of a continuous monitoring of the patient it is possible to seamless access multiple sources of data, including physiological signals, providing professionals with a global and reliable view of the patient's status. In practice, it is possible the prompt diagnosis of events, the early prediction of critical events and the implementation of personalized therapies. Furthermore, the information collected during long periods creates new opportunities in the diagnosis of a disease, in its evolution, and in the prediction of possible complications. The focus of this work is the research and implementation of multi parametric algorithms for data analysis in pHealth context, including data mining techniques as well as physiological signal modelling and processing. In particular, fusion strategies for cardiovascular status evaluation (namely cardiovascular risk assessment and cardiac function estimation) and multi parametric prediction algorithms for the early detection of cardiovascular events (such as hypertension, syncope and heart failure decompensation) will be addressed. PMID- 27225548 TI - Wavelet-based signal analysis for heart failure hospitalization prediction. AB - Heart failure (HF) is commonly a chronic condition associated with frequent hospital admissions. Early knowledge about a possible deterioration of this condition would enable early treatment for the prevention of adverse events and related hospital admissions. In this paper we present a computational method for predictive information extraction from daily physiological signals, which can be obtained by a telemonitoring system with wearable sensors. It is based on wavelet analysis of temporal signal patterns. Experiments with data from patients enrolled in a telemonitoring protocol show that the proposed method is capable of predicting HF hospitalization events one day before they happen, even in the case of low compliance to the protocol. These results indicate a promising perspective towards a monitoring system that would provide improved life quality for HF patients. PMID- 27225549 TI - Walking Intensity Estimation with a Portable Pedobarography System. AB - The aim of this pilot study was to investigate the possibility to find a correlation between the output from a portable pedobarography system and the walking intensity expressed as walking speed. The system uses shoe insoles with force sensing resistors and wireless transmission of the data via Bluetooth. The force-time integral, at the toe-off phase of the step, for the force sensors in the forward part of the right foot was used to measure impulse data for 10 subjects performing walks in three different walking speeds. This data was then corrected by multiplication with the step frequency. This pilot study indicates that the portable pedobarography system output shows a linear relationship with the walking intensity expressed as walking speed on an individual level. PMID- 27225550 TI - Classification of knee arthropathy with accelerometer-based vibroarthrography. AB - One of the most common knee joint disorders is known as osteoarthritis which results from the progressive degeneration of cartilage and subchondral bone over time, affecting essentially elderly adults. Current evaluation techniques are either complex, expensive, invasive or simply fails into detection of small and progressive changes that occur within the knee. Vibroarthrography appeared as a new solution where the mechanical vibratory signals arising from the knee are recorded recurring only to an accelerometer and posteriorly analyzed enabling the differentiation between a healthy and an arthritic joint. In this study, a vibration-based classification system was created using a dataset with 92 healthy and 120 arthritic segments of knee joint signals collected from 19 healthy and 20 arthritic volunteers, evaluated with k-nearest neighbors and support vector machine classifiers. The best classification was obtained using the k-nearest neighbors classifier with only 6 time-frequency features with an overall accuracy of 89.8% and with a precision, recall and f-measure of 88.3%, 92.4% and 90.1%, respectively. Preliminary results showed that vibroarthrography can be a promising, non-invasive and low cost tool that could be used for screening purposes. Despite this encouraging results, several upgrades in the data collection process and analysis can be further implemented. PMID- 27225551 TI - PATHway: Decision Support in Exercise Programmes for Cardiac Rehabilitation. AB - Rehabilitation is important for patients with cardiovascular diseases (CVD) to improve health outcomes and quality of life. However, adherence to current exercise programmes in cardiac rehabilitation is limited. We present the design and development of a Decision Support System (DSS) for telerehabilitation, aiming to enhance exercise programmes for CVD patients through ensuring their safety, personalising the programme according to their needs and performance, and motivating them toward meeting their physical activity goals. The DSS processes data originated from a Microsoft Kinect camera, a blood pressure monitor, a heart rate sensor and questionnaires, in order to generate a highly individualised exercise programme and improve patient adherence. Initial results within the EU funded PATHway project show the potential of our approach. PMID- 27225552 TI - Non-Contact Heart Rate Monitoring Using Lab Color Space. AB - Research progressing during the last decade focuses more on non-contact based systems to monitor Heart Rate (HR) which are simple, low-cost and comfortable to use. Most of the non-contact based systems are using RGB videos which is suitable for lab environment. However, it needs to progress considerably before they can be applied in real life applications. As luminance (light) has significance contribution on RGB videos HR monitoring using RGB videos are not efficient enough in real life applications in outdoor environment. This paper presents a HR monitoring method using Lab color facial video captured by a webcam of a laptop computer. Lab color space is device independent and HR can be extracted through facial skin color variation caused by blood circulation considering variable environmental light. Here, three different signal processing methods i.e., Fast Fourier Transform (FFT), Independent Component Analysis (ICA) and Principal Component Analysis (PCA) have been applied on the color channels in video recordings and blood volume pulse (BVP) has been extracted from the facial regions. In this study, HR is subsequently quantified and compare with a reference measurement. The result shows that high degrees of accuracy have been achieved compared to the reference measurements. Thus, this technology has significant potential for advancing personal health care, telemedicine and many real life applications such as driver monitoring. PMID- 27225553 TI - Automated innovative diagnostic, data management and communication tool, for improving malaria vector control in endemic settings. AB - Malaria is a life-threatening disease that caused more than 400,000 deaths in sub Saharan Africa in 2015. Mass prevention of the disease is best achieved by vector control which heavily relies on the use of insecticides. Monitoring mosquito vector populations is an integral component of control programs and a prerequisite for effective interventions. Several individual methods are used for this task; however, there are obstacles to their uptake, as well as challenges in organizing, interpreting and communicating vector population data. The Horizon 2020 project "DMC-MALVEC" consortium will develop a fully integrated and automated multiplex vector-diagnostic platform (LabDisk) for characterizing mosquito populations in terms of species composition, Plasmodium infections and biochemical insecticide resistance markers. The LabDisk will be interfaced with a Disease Data Management System (DDMS), a custom made data management software which will collate and manage data from routine entomological monitoring activities providing information in a timely fashion based on user needs and in a standardized way. The ResistanceSim, a serious game, a modern ICT platform that uses interactive ways of communicating guidelines and exemplifying good practices of optimal use of interventions in the health sector will also be a key element. The use of the tool will teach operational end users the value of quality data (relevant, timely and accurate) to make informed decisions. The integrated system (LabDisk, DDMS & ResistanceSim) will be evaluated in four malaria endemic countries, representative of the vector control challenges in sub-Saharan Africa, (Cameroon, Ivory Coast, Ethiopia and Zambia), highly representative of malaria settings with different levels of endemicity and vector control challenges, to support informed decision-making in vector control and disease management. PMID- 27225554 TI - Chair/bedside diagnosis of oral and respiratory tract infections, and identification of antibiotic resistances for personalised monitoring and treatment. AB - Global healthcare systems are struggling with the enormous burden associated with infectious diseases, as well as the incessant rise of antimicrobial resistance. In order to adequately address these issues, there is an urgent need for rapid and accurate infectious disease diagnostics. The H2020 project DIAGORAS aims at diagnosing oral and respiratory tract infections using a fully integrated, automated and user-friendly platform for physicians' offices, schools, elderly care units, community settings, etc. Oral diseases (periodontitis, dental caries) will be detected via multiplexed, quantitative analysis of salivary markers (bacterial DNA and host response proteins) for early prevention and personalised monitoring. Respiratory Tract Infections will be diagnosed by means of DNA/RNA differentiation so as to identify their bacterial or viral nature. Together with antibiotic resistance screening on the same platform, a more efficient treatment management is expected at the point-of-care. At the heart of DIAGORAS lies a centrifugal microfluidic platform (LabDisk and associated processing device) integrating all components and assays for a fully automated analysis. The project involves an interface with a clinical algorithm for the comprehensive presentation of results to end-users, thereby increasing the platform's clinical utility. DIAGORAS' performance will be validated at clinical settings and compared with gold standards. PMID- 27225555 TI - Micro-Nano-Bio Diagnostic System for Food Pathogen Detection Revolutionizes Food Safety Management & Protects Consumers Health. AB - The development of integrated, fast and affordable platforms for pathogen detection is an emerging area where a multidisciplinary approach is necessary for designing microsystems employing miniaturized devices; these new technologies promise a significant advancement of the current state of analytical testing leading to improved healthcare. In this work, the development of a lab-on-chip microsystem platform for the genetic analysis of Salmonella in milk samples is presented. The heart of the platform is an acoustic detection biochip, integrated with a microfluidic module. This detection platform is combined with a micro processor, which, alongside with magnetic beads technology and a DNA micro amplification module, are responsible for performing sample pre-treatment, bacteria lysis, nucleic acid purification and amplification. Automated, multiscale manipulation of fluids in complex microchannel networks is combined with novel sensing principles developed by some of the partners. This system is expected to have a significant impact in food-pathogen detection by providing for the first time an integrated detection test for Salmonella screening in a very short time. Finally, thanks to the low cost and compact technologies involved, the proposed set-up is expected to provide a competitive analytical platform for direct application in field settings. PMID- 27225556 TI - Personalized Clinical Diagnosis in Data Bases for Treatment Support in Phthisiology. AB - The decision-making is a key event in the clinical practice. The program products with clinical decision support models in electronic data-base as well as with fixed decision moments of the real clinical practice and treatment results are very actual instruments for improving phthisiological practice and may be useful in the severe cases caused by the resistant strains of Mycobacterium tuberculosis. The methodology for gathering and structuring of useful information (critical clinical signals for decisions) is described. Additional coding of clinical diagnosis characteristics was implemented for numeric reflection of the personal situations. The created methodology for systematization and coding Clinical Events allowed to improve the clinical decision models for better clinical results. PMID- 27225557 TI - Design and development of an impedimetric-based system for the remote monitoring of home-based dialysis patients. AB - A key clinical challenge is to determine the desired 'dry weight' of a patient in order to terminate the dialysis procedure at the optimal moment and thus avoid the effects of over- and under-hydration. It has been found that the effects of haemodialysis on patients can be conveniently monitored using whole-body bioimpedance measurements. The identified need of assessing the hydrational status of patients undergoing haemodialysis at home gave rise to the present Dialydom (DIALYse a DOMicile) project. The aim of the project is to develop a convenient miniaturised impedance monitoring device for localised measurements (on the calf) in order to estimate an impedimetric hydrational index of the home based patient, and to transmit this and other parameters to a remote clinical site. Many challenges must be overcome to develop a robust and valid home-based device. Some of these are presented in the paper. PMID- 27225558 TI - Smartphone-based Continuous Blood Pressure Measurement Using Pulse Transit Time. AB - The increasing availability of low cost and easy to use personalized medical monitoring devices has opened the door for new and innovative methods of health monitoring to emerge. Cuff-less and continuous methods of measuring blood pressure are particularly attractive as blood pressure is one of the most important measurements of long term cardiovascular health. Current methods of noninvasive blood pressure measurement are based on inflation and deflation of a cuff with some effects on arteries where blood pressure is being measured. This inflation can also cause patient discomfort and alter the measurement results. In this work, a mobile application was developed to collate the PhotoPlethysmoGramm (PPG) waveform provided by a pulse oximeter and the electrocardiogram (ECG) for calculating the pulse transit time. This information is then indirectly related to the user's systolic blood pressure. The developed application successfully connects to the PPG and ECG monitoring devices using Bluetooth wireless connection and stores the data onto an online server. The pulse transit time is estimated in real time and the user's systolic blood pressure can be estimated after the system has been calibrated. The synchronization between the two devices was found to pose a challenge to this method of continuous blood pressure monitoring. However, the implemented continuous blood pressure monitoring system effectively serves as a proof of concept. This combined with the massive benefits that an accurate and robust continuous blood pressure monitoring system would provide indicates that it is certainly worthwhile to further develop this system. PMID- 27225559 TI - Laser Induced Forward Transfer: a study on the enhancement of sensitivity for multianalyte sensing. AB - In this article novel approaches for the improvement of the recorded signal coupled with the feasibility of multiple analyte detection, irrespective of the biosensor platform are being presented. The techniques that have been developed address commonly encountered issues that have traditionally hindered the commercialization of biosensors, such as cost, reproducibility and sensitivity and most importantly multianalyte detection. The fluorescence-based detection of copper is being described as an example of the use of Laser Induced Forward Transfer technique (LIFT) for the immobilization of biomolecules with high spatial resolution, in addition to a technique that involves the displacement of a short complementary strand to the immobilized probe molecule for the quantification of analyte binding and the enhancement of the recorded signal. PMID- 27225560 TI - Preliminary Evaluation of a Web-Oriented Assessment Tool for Emotion Recognition. AB - Perceiving and identifying emotions on facial expressions is one of the basic abilities that compose emotional intelligence, and is crucial for normal social functions. It is well documented that facial expression conveys information about felt emotion, and that expressive behavior can activate or regulate the emotion required by a given situation. Instruments measuring emotion perception based on facial expression have been found in literature either as stand-alone scales or as part of other tests. The proposed tool expands existing instruments to combine online availability while affording assessment of emotion recognition on a continuum of intensity. It was founded on Ekman's Facial Action Units, with two Virtual Characters (male and female) portraying five basic emotions Anger, Disgust, Fear, Joy, Sadness, plus Neutral expression. The user can navigate on the custom-made pentagon and choose the emotion and intensity level (1-5) through a single click. The preliminary evaluation of the tool on thirty normal subjects provided threshold data that can later be used as benchmarks to assess emotion perception sensitivity in psychiatric disorders such as depression and schizophrenia characterized by emotional dysfunction. PMID- 27225561 TI - Health and training monitoring system based on wearable sensors. AB - ITEA2 project CareWare approach efficiently perform wearable sensor data processing and data fusion in order to visualize the holistic view of user's health and training status personalized, intuitively and trustworthy way and give feedback for user about individualized intensity and time of exercising control. PMID- 27225562 TI - Creating an IOT That Notifies Concerned People for the Falls of Geriatric Patients. AB - A fall is a multifactorial phenomenon which cause an increase in both mortality and injury rates. The cause of a fall is mostly related to loss in reflexes especially in older ages. A number of large prospective studies shows that elderly patients have significant fractures and injuries even sometimes in some cases a fall can be concluded with deaths. However, in case of fall, if the situation is noticed and aided quickly, the life quality can be increased significantly in older people. With implementation of preventive strategies or premonitory devices, this devastating problem can be solved. The IOT project is a prototype with two versions which are needled and attached versions and accomplishes basic functions such as information about falls and send it through the internet. By this way, the falls are transmitted to concerned people or patient's relatives with position information. PMID- 27225563 TI - A computational platform for continuous seizure anticipation, monitoring and clinical evaluation. AB - The development of platforms that are able to continuously monitor and handle epileptic seizures in a non invasive manner is of great importance as they would improve the quality of life of drug resistant epileptic patients. In this work, a device and a computational platform is presented for acquiring low noise electroencephalographic signals, for the detection/prediction of epileptic seizures and the storage of ictal activity in an electronic personal health record. In order to develop this platform, a systematic clinical protocol was established including a number of drug resistant children from the University Hospital of Heraklion. Dry electrodes with innovative micro-spike design were proposed in order to increase the signal to noise ratio of the recorded EEG signals. A wearable low cost platform and its corresponding wireless communication protocol was developed focus on minimizing the interference with the patient's body. A computational subsystem with advanced algorithms provides detection/anticipation of upcoming seizure activity and aims to protect the patient from an accident due to a seizure or to improve his/her social life. Finally, the seizure activity information is stored in an electronic health record for further clinical evaluation. PMID- 27225564 TI - Stream 2. Smart Personal Health Systems/Deep Learning/Interoperability/Precision Medicine. PMID- 27225565 TI - Integrated Care and Connected Health Approaches Leveraging Personalised Health through Big Data Analytics. AB - Integrated care and connected health are two fast evolving concepts that have the potential to leverage personalised health. From the one side, the restructuring of care models and implementation of new systems and integrated care programs providing coaching and advanced intervention possibilities, enable medical decision support and personalized healthcare services. From the other side, the connected health ecosystem builds the means to follow and support citizens via personal health systems in their everyday activities and, thus, give rise to an unprecedented wealth of data. These approaches are leading to the deluge of complex data, as well as in new types of interactions with and among users of the healthcare ecosystem. The main challenges refer to the data layer, the information layer, and the output of information processing and analytics. In all the above mentioned layers, the primary concern is the quality both in data and information, thus, increasing the need for filtering mechanisms. Especially in the data layer, the big biodata management and analytics ecosystem is evolving, telemonitoring is a step forward for data quality leverage, with numerous challenges still left to address, partly due to the large number of micro-nano sensors and technologies available today, as well as the heterogeneity in the users' background and data sources. This leads to new R&D pathways as it concerns biomedical information processing and management, as well as to the design of new intelligent decision support systems (DSS) and interventions for patients. In this paper, we illustrate these issues through exemplar research targeting chronic patients, illustrating the current status and trends in PHS within the integrated care and connected care world. PMID- 27225566 TI - Designing smart analytical data services for a personal health framework. AB - Information in the healthcare domain and in particular personal health record information is heterogeneous by nature. Clinical, lifestyle, environmental data and personal preferences are stored and managed within such platforms. As a result, significant information from such diverse data is difficult to be delivered, especially to non-IT users like patients, physicians or managers. Another issue related to the management and analysis is the volume, which increases more and more making the need for efficient data visualization and analysis methods mandatory. The objective of this work is to present the architectural design for seamless integration and intelligent analysis of distributed and heterogeneous clinical information in the PHR context, as a result of a requirements elicitation process in iManageCancer project. This systemic approach aims to assist health-care professionals to orient themselves in the disperse information space and enhance their decision-making capabilities, to encourage patients to have an active role by managing their health information and interacting with health-care professionals. PMID- 27225567 TI - Psycho-emotional tools for better treatment adherence and therapeutic outcomes for cancer patients. AB - Personalized medicine should target not only the genetic and clinical aspects of the individual patients but also the different cognitive, psychological, family and social factors involved in various clinical choices. To this direction, in this paper, we present instruments to assess the psycho-emotional status of cancer patients and to evaluate the resilience in their family constructing in such a way an augmented patient profile. Using this profile, 1) information provision can be tailored according to patients characteristics; 2) areas of functioning can be monitored both by the patient and by the clinicians, providing suggestions and alerts; 3) personalized decision aids can be develop to increase patient's participation in the consultation process with their physicians and improve their satisfaction and involvement in the decision-making process. Our preliminary evaluation shows promising results and the potential benefits of the tools. PMID- 27225568 TI - A Sensor-Enabled Smartphone Application to Collect Eating Behavior Data for Population Screening. AB - The worldwide extent of obesity and eating disorders (ED) today highlights the necessity for efficient treatment, but also early prevention of eating-related diseases. A promising category of therapeutic and preventive interventions comes from the domain of behavioral informatics (BI), whose purpose is to monitor and modify harmful behaviors - unhealthy eating in the particular case - with the help of information and communication technologies. Smartphones have already shown great promise in delivering such BI interventions in the field of obesity and ED. In fact, plenty of smartphone applications aiming to monitor and support the change of eating behavior with the help of built-in or external sensors have been proposed in the scientific literature. However, to the best of our knowledge, no smartphone application up to date has been designed to collect eating behavior data for the purpose of population screening against obesity or ED. In this work we describe a novel, sensor-enabled smartphone application that captures in-meal behavioral data from multiple subjects in a brief data collection process, with the end goal of recording, in detail, the user's eating style throughout a cooked meal. These data can later be employed for assessing the subjects' risk for obesity or ED. The proposed application has undergone preliminary evaluation with respect to its usability and technical soundness, yielding promising results. PMID- 27225569 TI - Adapting Guidelines for Google Glass: the Case of Pediatric CPR. AB - Early recognition and management of patients at risk and more aggressive implementation of evidence-based resuscitation guidelines play a role to the reduction of patients' mortality. If, in paediatric emergency department, the proper adherence to the paediatric cardiac arrest guidelines is critical to increase the chance of survival, this adherence is unfortunately often suboptimal. Connected glasses, such as the Google Glass, offer an interesting support to provide guidelines at the point of care. However, existing guidelines format is not adapted to be used directly on the small screen of connected glasses. Their transformation to be displayed on the Google Glass is not a simple task. Problems such as the navigation and the formalization of the guidelines must be solved. In this article, we present the transformation process of the paediatric cardiac arrest algorithm from its paper version to its implementation on the Google Glass. PMID- 27225570 TI - Mediating the Cognitive Walkthrough with Patient Groups to achieve Personalized Health in Chronic Disease Self-Management System Evaluation. AB - The cognitive walkthrough (CW) is a task-based, expert inspection usability evaluation method involving benefits such as cost effectiveness and efficiency. A drawback of the method is that it doesn't involve the user perspective from real users but instead is based on experts' predictions about the usability of the system and how users interact. In this paper, we propose a way of involving the user in an expert evaluation method by modifying the CW with patient groups as mediators. This along with other modifications include a dual domain session facilitator, specific patient groups and three different phases: 1) a preparation phase where suitable tasks are developed by a panel of experts and patients, validated through the content validity index 2) a patient user evaluation phase including an individual and collaborative process part 3) an analysis and coding phase where all data is digitalized and synthesized making use of Qualitative Data Analysis Software (QDAS) to determine usability deficiencies. We predict that this way of evaluating will utilize the benefits of the expert methods, also providing a way of including the patient user of these self-management systems. Results from this prospective study should provide evidence of the usefulness of this method modification. PMID- 27225571 TI - Towards a Cross-domain Infrastructure to Support Electronic Identification and Capability Lookup for Cross-border ePrescription/Patient Summary Services. AB - Seamless patient identification, as well as locating capabilities of remote services, are considered to be key enablers for large scale deployment of facilities to support the delivery of cross-border healthcare. This work highlights challenges investigated within the context of the Electronic Simple European Networked Services (e-SENS) large scale pilot (LSP) project, aiming to assist the deployment of cross-border, digital, public services through generic, re-usable technical components or Building Blocks (BBs). Through the case for the cross-border ePrescription/Patient Summary (eP/PS) service the paper demonstrates how experience coming from other domains, in regard to electronic identification (eID) and capability lookup, can be utilized in trying to raise technology readiness levels in disease diagnosis and treatment. The need for consolidating the existing outcomes of non-health specific BBs is examined, together with related issues that need to be resolved, for improving technical certainty and making it easier for citizens who travel to use innovative eHealth services, and potentially share personal health records (PHRs) with other providers abroad, in a regulated manner. PMID- 27225572 TI - HeartDrive: A Broader Concept of Interoperability to Implement Care Processes for Heart Failure. AB - This paper originates from the HeartDrive project, a platform of services for a more effective, efficient and integrated management of heart failure and comorbidities. HeartDrive establishes a cooperative approach based on the concepts of continuity of care and extreme, patient oriented, customization of diagnostic, therapeutic and follow-up procedures. Definition and development of evidence based processes, migration from parceled and episode based healthcare provisioning to a workflow oriented model and increased awareness and responsibility of citizens towards their own health and wellness are key objectives of HeartDrive. In two scenarios for rehabilitation and home monitoring we show how the results are achieved by providing a solution that highlights a broader concept of cooperation that goes beyond technical interoperability towards semantic interoperability explicitly sharing process definitions, decision support strategies and information semantics. PMID- 27225573 TI - Towards mHealth Assessment Guidelines for interoperability: HL7 FHIR. AB - The number of health-related mobile apps (mHealth apps) has increased dramatically over the last three years. Health professionals have started recommending apps to their patients, while healthcare systems, advocacy groups, and professional societies review or commission apps of relevance to their members. Still the issues surrounding mHealth apps are strongly debated as policy makers and legislators seek to strike the right balance between a voluntary code of conduct and regulation that can offer eHealth consumers the guidance and support they need. This paper reviews the EU policy landscape surrounding mobile health focusing on issues identified in the Green paper and follow-up activities. Then, it moves on to discuss HL7 FHIR, the mHealth WG, and relevant standardization projects and reflect on the implications for large scale eHealth deployment in Europe. PMID- 27225574 TI - Exploring Barriers and Opportunities for Adoption of Web Portals in Russia. Example of a Tuberculosis Portal. AB - The aim was to study the opinions of tuberculosis patients and doctors and identify perceived opportunities and barriers to using a Web portal to optimize its use. The perceptions of 30 tuberculosis patients and 18 doctors (10 general practitioners and 8 TB specialists) from Tomsk, Russia were collected through semi-structured interviews. The responses were analyzed for content using principles of the grounded theory and thematic analysis, in order to gain insight into the participants' beliefs and attitudes towards adopting tuberculosis web portal to increase the efficiency of the treatment and rehabilitation process. PMID- 27225575 TI - Prediction of Outcome after Traumatic Brain Injury: Comparison of Disease State Index and IMPACT Calculator. AB - Traumatic brain injury (TBI) is a major cause of death and disability, especially in young adults. A reliable prediction of outcome after TBI is of great importance in clinical practice and research. We aimed to compare performance of the well-established IMPACT calculator and an alternative method, Disease State Index (DSI), in the prediction of six-month outcome after TBI. Performance of the models was evaluated using 2036 patients with moderate or severe TBI from the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) database. Prediction performance of both models was similar. The models with more variables provided better performance than the simpler models. This study showed that the DSI is a valid tool with efficient visualizations that can help clinicians with their decision making process in clinical practice. PMID- 27225576 TI - Return to Work After Lumbar Microdiscectomy - Personalizing Approach Through Predictive Modeling. AB - Lumbar disc herniation (LDH) is the most common disease among working population requiring surgical intervention. This study aims to predict the return to work after operative treatment of LDH based on the observational study including 153 patients. The classification problem was approached using decision trees (DT), support vector machines (SVM) and multilayer perception (MLP) combined with RELIEF algorithm for feature selection. MLP provided best recall of 0.86 for the class of patients not returning to work, which combined with the selected features enables early identification and personalized targeted interventions towards subjects at risk of prolonged disability. The predictive modeling indicated at the most decisive risk factors in prolongation of work absence: psychosocial factors, mobility of the spine and structural changes of facet joints and professional factors including standing, sitting and microclimate. PMID- 27225577 TI - Implementation of a Clinical Decision Support System for Interpretation of Laboratory Tests for Patients. AB - The paper presents the results of the development and implementation of an expert system that automatically generates doctors' letters based on the results of laboratory tests. Medical knowledge is expressed using a first order predicate based language. The system was implemented and evaluated in the Helix laboratory service. PMID- 27225578 TI - Implementation of a Web Portal for Diabetes Patients Using Open Source Data Visualization Libraries. AB - To provide a better doctor-patient communication and to better involve patients into a diagnostic and treatment process we implemented a web portal for diabetes patients using open source libraries to present medical data. The medical data was "archetyped" according to the ISO 13606 standard. Visualization properties were defined using visual medical concepts (VMC) in XML format. JQuery libraries were used to build static and dynamic diagrams. To implement user requirements' based interfaces we conducted interviews with doctors and patient focus groups. To test the usability of the portal we conducted usability testing interviews from January to February 2015. PMID- 27225579 TI - Estimating normal and abnormal activities using smartphones. AB - The main objective of this study is to propose a computational pipeline for the recognition of normal and abnormal activities based on smartphone accelerometer data. Methods and techniques that have been previously evaluated are further evolved and applied for the recognition of a large set of separate activities as well as a sequence of activities simulating a common scenario of daily living as a more realistic approach. For these purposes, the MobiAct dataset which encompass a set of normal activities of daily living (ADLs) and abnormal activities (falls) was used. The results show a classification accuracy of 99% for the recognition of separate ADLs, while a reduction of 5% is observed for the recognition of the scenarios. PMID- 27225580 TI - Personalized USB Biosensor Module for Effective ECG Monitoring. AB - The burden of chronic disease and associated disability present a major threat to financial sustainability of healthcare delivery systems. The need for cost effective early diagnosis and disease prevention is evident driving the development of personalized home health solutions. The proposed solution presents an easy to use ECG monitoring system. The core hardware component is a biosensor dongle with sensing probes at one end, and micro USB interface at the other end, offering reliable and unobtrusive sensing, preprocessing and storage. An additional component is a smart phone, providing both the biosensor's power supply and an intuitive user application for the real-time data reading. The system usage is simplified, with innovative solutions offering plug and play functionality avoiding additional driver installation. Personalized needs could be met with different sensor combinations enabling adequate monitoring in chronic disease, during physical activity and in the rehabilitation process. PMID- 27225584 TI - Dispersive Non-Geminate Recombination in an Amorphous Polymer:Fullerene Blend. AB - Recombination of free charge is a key process limiting the performance of solar cells. For low mobility materials, such as organic semiconductors, the kinetics of non-geminate recombination (NGR) is strongly linked to the motion of charges. As these materials possess significant disorder, thermalization of photogenerated carriers in the inhomogeneously broadened density of state distribution is an unavoidable process. Despite its general importance, knowledge about the kinetics of NGR in complete organic solar cells is rather limited. We employ time delayed collection field (TDCF) experiments to study the recombination of photogenerated charge in the high-performance polymer:fullerene blend PCDTBT:PCBM. NGR in the bulk of this amorphous blend is shown to be highly dispersive, with a continuous reduction of the recombination coefficient throughout the entire time scale, until all charge carriers have either been extracted or recombined. Rapid, contact-mediated recombination is identified as an additional loss channel, which, if not properly taken into account, would erroneously suggest a pronounced field dependence of charge generation. These findings are in stark contrast to the results of TDCF experiments on photovoltaic devices made from ordered blends, such as P3HT:PCBM, where non-dispersive recombination was proven to dominate the charge carrier dynamics under application relevant conditions. PMID- 27225585 TI - Shear stress regulates endothelial cell function through SRB1-eNOS signaling pathway. AB - AIM: The aim of this study was to explore whether transmembrane flow shear stress could regulate eNOS expression and mediate endothelial cell function via SR-B1 signaling transduction. METHODS: Parallel-plate flow chamber was used to impose laminar shear stress and evaluate the effect of shear stress upon human umbilical vein endothelial cells (HUVECs). The expression of SR-B1 and eNOS at both RNA and protein levels was detected under different dynamic conditions. RNA interference and gene transfection were performed to overexpress and knock down the SRB1 to confirm the role of SR-B1-eNOS signaling pathway. RESULTS: The expression levels of SR-B1 and eNOS were downregulated when HUVECs were treated with 4.2 dyne/cm(2) shear stress compared with those of the control group. However, the expression of SR-B1 and eNOS was upregulated as HUVECs exposed to 8.4 and 15 dyne/cm(2) shear stress. When exposed to 8.4 dyne/cm(2) , SR-B1 and eNOS expression was significantly higher compared with those of the other groups. When SR-B1 was knocked down through RNAi technique, the expression of eNOS was significantly downregulated than those of the other groups. While overexpression of SR-B1 could upregulate eNOS significantly. CONCLUSION: Shear stress regulates endothelial cell function through SR-B1-eNOS signaling pathway. SR-B1 may play a pivotal role in the process of anti-atherosclerosis. PMID- 27225587 TI - Inhibition of phagocytic activity of ARPE-19 cells by free radical mediated oxidative stress. AB - Oxidative stress is a main factor responsible for key changes leading to the onset of age-related macular degeneration (ARMD) that occur in the retinal pigment epithelium (RPE), which is involved in phagocytosis of photoreceptor outer segments (POS). In this study, hydrogen peroxide (H2O2), H2O2 and iron ions (Fe) or rose Bengal (RB) in the presence of NADH and Fe were used to model free radical mediated oxidative stress to test if free radicals and singlet oxygen have different efficiency to inhibit phagocytosis of ARPE-19 cells. Free radical mediated oxidative stress was confirmed by HPLC-EC(Hg) measurements of cholesterol hydroperoxides in treated cells. Electron paramagnetic resonance (EPR) spin trapping was employed to detect superoxide anion. Cell survival was analyzed by the MTT assay. Specific phagocytosis of fluorescein-5-isothiocyanate labeled POS and non-specific phagocytosis of fluorescent beads were measured by flow cytometry. HPLC analysis of cells photosensitized with RB in the presence of NADH and Fe indicated substantial increase in formation of free radical-dependent 7alpha/7beta-hydroperoxides. EPR spin trapping confirmed the photogeneration of superoxide anion in samples enriched with RB, NADH and Fe. For all three protocols sub-lethal oxidative stress induced significant inhibition of the specific phagocytosis of POS. In contrast, non-specific phagocytosis was inhibited only by H2O2 or H2O2 and Fe treatment. Inhibition of phagocytosis was transient and recoverable by 24 h. These results suggest that free radicals may exert similar to singlet oxygen efficiency in inhibiting phagocytosis of RPE cells, and that the effect depends on the location where initial reactive species are formed. PMID- 27225586 TI - Dynamic spatial patterns of leaf traits affect total respiration on the crown scale. AB - Temporal and spatial variations of leaf traits caused conflicting conclusions and great estimating errors of total carbon budget on crown scales. However, there is no effective method to quantitatively describe and study heterogeneous patterns of crowns yet. In this study, dynamic spatial patterns of typical ecological factors on crown scales were investigated during two sky conditions, and CEZs (crown ecological zones) method was developed for spatial crown zoning, within which leaf traits were statistically unchanged. The influencing factors on hourly and spatial variations of leaf dark respiration (Rd) were analysed, and total crown respiration (Rt) was estimated based on patterns of CEZs. The results showed that dynamic spatial patterns of air temperature and light intensity changed significantly by CEZs in special periods and positions, but not continuously. The contributions of influencing factors on variations of Rd changed with crown depth and sky conditions, and total contributions of leaf structural and chemical traits were higher during sunny days than ecological factors, but lower during cloudy days. The estimated errors of Rt may be obviously reduced with CEZs. These results provided some references for scaling from leaves to crown, and technical foundations for expanding lab-control experiments to open field ones. PMID- 27225588 TI - Canine Adipose-Derived Stem Cells: Purinergic Characterization and Neurogenic Potential for Therapeutic Applications. AB - The presented results evidence that canine adipose-derived stem cells (ADSCs) represent the premature population of stem cells with great biological potential and properties. ADCS are easy to obtain and culture, able to differentiate into the neurogenic lineage as well as it is easy to control their proliferation rate with nucleotides and nucleosides or analogues. We report that in vitro cultured canine ADSCs response to adenosine- and ATP-mediated stimulation. Differences in canine ADSCs and human mesenchymal stem cells in ecto-nucleotidase activity have been observed. The ecto-nucleotidase activity changes during ADSCs in vitro transdifferentiation into neurogenic lineage are fast and simple to analyze. Therefore, the simple analysis of ecto-enzymes activity allows for verification of the stem cells quality: their stemness or initiation of the differentiation process. The biological potential of the cells isolated from canine fat, as well as the good quality control of this cell culture, make them a promising tool for both experimental and therapeutic usage. J. Cell. Biochem. 118: 58-65, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27225589 TI - Integrated approach to testing and assessment for predicting rodent genotoxic carcinogenicity. AB - We investigated the performance of an integrated approach to testing and assessment (IATA), designed to cover different genotoxic mechanisms causing cancer and to replicate measured carcinogenicity data included in a new consolidated database. Genotoxic carcinogenicity was predicted based on positive results from at least two genotoxicity tests: one in vitro and one in vivo (which were associated with mutagenicity categories according to the Globally Harmonized System classification). Substances belonging to double positives mutagenicity categories were assigned to be genotoxic carcinogens. In turn, substances that were positive only in a single mutagenicity test were assigned to be mutagens. Chemicals not classified by the selected genotoxicity endpoints were assigned to be negative genotoxic carcinogens and subsequently evaluated for their capability to elicit non-genotoxic carcinogenicity. However, non-genotoxic carcinogenicity mechanisms were not currently included in the developed IATA. The IATA is docked to the OECD Toolbox and uses measured data for different genotoxicity endpoints when available. Alternatively, the system automatically provides predictions by SAR genotoxicity models using the OASIS Tissue Metabolism Simulator platform. When the developed IATA was tested against the consolidated database, its performance was found to be high, with sensitivity of 74% and specificity of 83%, when measured carcinogenicity data were used along with predictions falling within the models' applicability domains. Performance of the IATA would be slightly changed to a sensitivity of 80% and specificity of 72% when the evaluation by non-genotoxic carcinogenicity mechanisms was taken into account. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27225590 TI - Epigenetic inactivation of the CpG demethylase TET1 as a DNA methylation feedback loop in human cancers. AB - Promoter CpG methylation is a fundamental regulatory process of gene expression. TET proteins are active CpG demethylases converting 5-methylcytosine to 5 hydroxymethylcytosine, with loss of 5 hmC as an epigenetic hallmark of cancers, indicating critical roles of TET proteins in epigenetic tumorigenesis. Through analysis of tumor methylomes, we discovered TET1 as a methylated target, and further confirmed its frequent downregulation/methylation in cell lines and primary tumors of multiple carcinomas and lymphomas, including nasopharyngeal, esophageal, gastric, colorectal, renal, breast and cervical carcinomas, as well as non-Hodgkin, Hodgkin and nasal natural killer/T-cell lymphomas, although all three TET family genes are ubiquitously expressed in normal tissues. Ectopic expression of TET1 catalytic domain suppressed colony formation and induced apoptosis of tumor cells of multiple tissue types, supporting its role as a broad bona fide tumor suppressor. Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9. As only infrequent mutations of TET1 have been reported, compared to TET2, epigenetic silencing therefore appears to be the dominant mechanism for TET1 inactivation in cancers, which also forms a feedback loop of CpG methylation during tumorigenesis. PMID- 27225591 TI - Gene and MicroRNA Expression Are Predictive of Tumor Response in Rectal Adenocarcinoma Patients Treated With Preoperative Chemoradiotherapy. AB - Preoperative chemoradiotherapy (pCRT) followed by surgery is the standard treatment for locally advanced rectal cancer (LARC). However, tumor response to pCRT is not uniform, and there are no effective predictive methods. This study investigated whether specific gene and miRNA expression are associated with tumor response to pCRT. Tissue biopsies were obtained from patients before pCRT and resection. Gene and miRNA expression were analyzed using a one-color microarray technique that compares signatures between responders (R) and non-responders (NR), as measured based on tumor regression grade. Two groups composed of 38 "exploration cohort" and 21 "validation cohort" LARC patients were considered for a total of 32 NR and 27 R patients. In the first cohort, using SAM Two Class analysis, 256 genes and 29 miRNAs that were differentially expressed between the NR and R patients were identified. The anti-correlation analysis showed that the same 8 miRNA interacted with different networks of transcripts. The miR-630 appeared only with the NR patients and was anti-correlated with a single transcript: RAB5B. After PAM, the following eight transcripts were strong predictors of tumor response: TMEM188, ITGA2, NRG, TRAM1, BCL2L13, MYO1B, KLF7, and GTSE1. Using this gene set, an unsupervised cluster analysis was applied to the validation cohort and correctly assigned the patients to the NR or R group with 85.7% accuracy, 90% sensitivity, and 82% specificity. All three parameters reached 100% when both cohorts were considered together. In conclusion, gene and miRNA expression profiles may be helpful for predicting response to pCRT in LARC patients. J. Cell. Physiol. 232: 426-435, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27225593 TI - Erratum: Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression. PMID- 27225594 TI - Bariatric/metabolic surgery for diabetes: Incorporating a powerful treatment into standard care. PMID- 27225592 TI - CRISPR/Cas9-Mediated Immunity to Geminiviruses: Differential Interference and Evasion. AB - The CRISPR/Cas9 system has recently been used to confer molecular immunity against several eukaryotic viruses, including plant DNA geminiviruses. Here, we provide a detailed analysis of the efficiencies of targeting different coding and non-coding sequences in the genomes of multiple geminiviruses. Moreover, we analyze the ability of geminiviruses to evade the CRISPR/Cas9 machinery. Our results demonstrate that the CRISPR/Cas9 machinery can efficiently target coding and non-coding sequences and interfere with various geminiviruses. Furthermore, targeting the coding sequences of different geminiviruses resulted in the generation of viral variants capable of replication and systemic movement. By contrast, targeting the noncoding intergenic region sequences of geminiviruses resulted in interference, but with inefficient recovery of mutated viral variants, which thus limited the generation of variants capable of replication and movement. Taken together, our results indicate that targeting noncoding, intergenic sequences provides viral interference activity and significantly limits the generation of viral variants capable of replication and systemic infection, which is essential for developing durable resistance strategies for long-term virus control. PMID- 27225595 TI - How common is hypoglycemia after gastric bypass? PMID- 27225596 TI - Randomized clinical trial of portion-controlled prepackaged foods to promote weight loss. AB - OBJECTIVE: Providing portion-controlled prepackaged foods in a behavioral counseling intervention may promote more weight and fat loss than a standard self selected diet. METHODS: The primary aim was to test whether providing portion controlled prepackaged lunch and dinner entrees within a behavioral weight loss intervention promotes greater weight loss at 12 weeks compared to self-selected foods in adults with overweight/obesity. Other aims were to examine effects on biological factors, fitness, and meal satisfaction. One-half of those assigned to prepackaged entrees were provided items with a higher protein level (>25% energy) as an exploratory aim. RESULTS: Participants (N = 183) had a baseline weight of 95.9 (15.6) kg (mean [SD]) and BMI of 33.2 (3.5) kg/m(2) . Weight data at 12 weeks were available for 180 subjects. Weight loss for regular entree, higher protein entree, and control groups was 8.6 (3.9)%, 7.8 (5.1)%, and 6.0 (4.4)%, respectively (P < 0.05, intervention vs. control). Intervention participants lost more body fat than controls (5.7 [3.4] vs. 4.4 [3.3] kg, P < 0.05). CONCLUSIONS: A meal plan incorporating portion-controlled prepackaged entrees promotes greater weight and fat loss than a standard self-selected diet, with comparable meal satisfaction. Initial weight loss predicts long-term weight loss so these results are relevant to likelihood of longer term success. PMID- 27225597 TI - Risk of post-gastric bypass surgery hypoglycemia in nondiabetic individuals: A single center experience. AB - OBJECTIVE: The epidemiology of post-gastric bypass surgery hypoglycemia (PGBH) is incompletely understood. This study aimed to evaluate the risk of PGBH among nondiabetic patients and associated factors. METHODS: A cohort study of nondiabetic patients who underwent Roux-en-Y gastric bypass (RYGB) was conducted. PGBH was defined by any postoperative record of glucose < 60 mg/dL, diagnosis of hypoglycemia, or any medication use for treatment of PGBH. Kaplan-Meier analysis was used to describe PGBH occurrence, log-rank tests, and Cox regression to examine associated factors. RESULTS: Of the 1,206 eligible patients, 86% were female with mean age of 43.7 years, mean preoperative BMI of 48.7 kg/m(2) , and a mean follow-up of 4.8 years. The cumulative incidence of hypoglycemia at 1 and 5 years post-RYGB was 2.7% and 13.3%, respectively. Incidence of PGBH was identified in 158 patients and was associated with lower preoperative BMI (P = 0.048), lower preoperative HbA1c (P = 0.012), and higher 6-month percent of excess body weight loss (%EWL) (P = 0.001). A lower preoperative HbA1c (HR = 1.73, P = 0.0034) and higher 6-month %EWL (HR = 1.96, P = 0.0074) remained independently correlated with increased risk for PGBH in multi-regression analysis. CONCLUSIONS: The 5-year incidence of PGBH among nondiabetic individuals was 13.3% and was associated with a lower preoperative HbA1c and greater weight loss at 6 months following surgery. PMID- 27225598 TI - Tablet computers to support outpatient pulmonary rehabilitation in patients with COPD. AB - BACKGROUND: A minicomputer (tablet) with instructions and a training diary has the potential of facilitating adherence to pulmonary rehabilitation (PR). OBJECTIVE: To evaluate the effect of adding a tablet to a classic outpatient PR programme for COPD patients. METHODS: A total of 115 patients participated in a 7 to 10-week outpatient PR programme in groups of 10-12 individuals. Half of the groups were assigned to PR plus a tablet (tablet group) and the other groups were assigned to PR only (controls). Primary effect parameters were endurance shuttle walk time (ESWT) and disease-specific health status (COPD Assessment Test=CAT). RESULTS: The change in ESWT was significantly better in the control group (mean 167 sec) compared with the tablet group (mean 51 sec) (p<0.01), whereas the change in CAT score did not differ significantly between the two groups (-0.6 vs. -2.3) (p=0.17). CONCLUSIONS: Compared with usual PR, no significant improvements were seen in the group equipped with the tablet after 7-10 weeks of rehabilitation. Future studies should focus on long-term effects. PMID- 27225599 TI - Piezoelectric Control of the Exciton Wave Function in Colloidal CdSe/CdS Nanocrystals. AB - Using multiband k.p calculations, we show that strain-engineered piezoelectricity is a powerful tool to modulate the electron-hole spatial separation in a wide class of wurtzite CdSe/CdS nanocrystals. The inherent anisotropy of the hexagonal crystal structure leads to anisotropic strain and, consequently, to a pronounced piezoelectric field along the c axis, which can be amplified or quenched through a proper design of the core-shell structure. The use of large cores and thick shells promotes a gradual departure from quantum confined nanocrystals to a regime dominated by piezoelectric confinement. This allows excitons to evolve from the usual type-I and quasi-type-II behavior to a type-II behavior in dot-in dots, dot-in-rods, rod-in-rods, and dot-in-plates. Piezoelectric fields explain experimental observations for giant-shell nanocrystals, whose time-resolved photoluminescence reveals long exciton lifetimes for large cores, contrary to the expectations of standard quantum confinement models. They also explain the large differences in exciton lifetimes reported for different classes of CdSe/CdS nanocrystals. PMID- 27225600 TI - Toll-like receptor 4 signaling has a critical role in Porphyromonas gingivalis accelerated neointimal formation after arterial injury in mice. AB - Recently, we reported that a periodontopathic pathogen, Porphyromonas gingivalis (P. gingivalis), infection induced neointimal hyperplasia with enhanced expression of monocyte chemoattractant protein (MCP)-1 after arterial injury in wild-type mice. Toll-like receptor (TLR) 4 is known to be a key receptor for virulence factors of P. gingivalis. The aim of this study is to assess the hypothesis that TLR4 has a critical role in periodontopathic bacteria-induced neointimal formation after an arterial injury. Wild-type and TLR4-deficient mice were used in this study. The femoral arteries were injured, and P. gingivalis or vehicle was injected subcutaneously once per week. Fourteen days after arterial injury, murine femoral arteries were obtained for histopathological and immunohistochemical analyses. The anti-P. gingivalis IgG levels in P. gingivalis infected groups were significantly increased compared with the anti-P. gingivalis IgG levels of the corresponding non-infected groups in both wild-type and TLR4 deficient mice. TLR4 deficiency negated P. gingivalis-induced neointimal formation compared with that observed in wild-type mice and reduced the number of MCP-1 positive cells in the neointimal area. We conclude that P. gingivalis infection may promote neointimal formation after an arterial injury through TLR4 signaling. PMID- 27225601 TI - Cardiac remodeling after reduction of high-flow arteriovenous fistulas in end stage renal disease. AB - In patients with end-stage renal disease, excessive blood flow through an arteriovenous fistula (AVF) may lead to volume overload-induced cardiac remodeling and heart failure. It is unclear which patients with hyperfunctional AVF may benefit from AVF reduction or ligation. The indication for the procedure is often based on AVF flow. Because cardiac remodeling is driven by increased venous return, which is equivalent to cardiac output, we hypothesized that an elevated cardiac index (CI) might better identify subjects with reverse remodeling after AVF reduction. Thirty patients (age 52+/-12 years, 73% male) with AVF flow ?1.5 l min(-1) underwent comprehensive echocardiographic evaluations before and after AVF reduction. At baseline, 16 patients had a normal CI (2.5-3.8 l min(-1) m(-2)) and 14 had a high CI (4.0-6.0 l min(-1) m(-2)). A left ventricular end-diastolic diameter decrease after operation was predicted by elevated baseline CI (P<0.01), but not elevated AVF flow (P=0.07). There was a significant decrease in CI, left ventricular mass, left atrial and right ventricular diameter and pulmonary systolic pressure in the high CI group but not in the normal CI group. After AVF reduction, systemic vascular resistance decreased in the normal CI group, whereas it did not change in the high CI group. In conclusion, reduction of high-flow AVF leads to reverse cardiac remodeling but only in patients with elevated CI. The variability of the response of systemic vascular resistance to AVF flow may explain this observation. Increased CI but not increased AVF flow may better determine candidates for AVF reduction. PMID- 27225602 TI - Efficacy of treadmill exercises on arterial blood oxygenation, oxygen consumption and walking distance in healthy elderly people: a controlled trial. AB - BACKGROUND: Regular physical exercise and healthy lifestyle can improve aerobic power of the elderly, although lung capacity gradually deteriorates with age. The aims of the study are: a) to evaluate the therapeutic effect of a treadmill exercise program on arterial blood oxygenation (SaO2), maximum oxygen consumption (VO2max) and maximum walking distance (MWD) in healthy elderly people; b) to examine the outcome of the program at a supervised short-term and at an unsupervised long-term. METHODS: A prospective, not-randomized controlled intervention trial (NRCT) was conducted. Eighty participants were allocated into two homogeneous groups (training group, TG, n = 40; control group, CG, n = 40). Each group consisted of 20 men and 20 women. Pre-intervention measures of SaO2, VO2max and MWD were taken of each participant 1-week before the training program to establish the baseline. Also, during the training program, the participants were followed up at the 12, 30 and 48th week. The exercise program consisted of walking on a treadmill with fixed 0 % grade of inclination 3 times weekly for 48 weeks; the first 12 weeks were supervised and the remaining 36 weeks of the program were unsupervised. Participants in the control group were encouraged to walk twice a week during 45 min, and received standard recommendations for proper health. RESULTS: Related to the baseline, the SaO2, VO2max, and MWD is greater in the intervention group at the 12(th) (p <.001), 30(th) (p <.001) and 48(th) week (p <.001). Compared with the control group, there was also a significant improvement of SaO2, VO2max, and MWD valuesin the intervention group (p <.001) at the 12(th) (p <.001), 30(th) (p <.001) and 48(th) week (p <.001). Supervised intervention shows greater improvement of SaO2, VO2max, and MWD values than in the unsupervised one. CONCLUSION: These results show that performing moderate exercise, specifically walking 3 days a week, is highly recommended for healthy older people, improving aerobic power. TRIAL REGISTRATION: Current Controlled Trials ISRCTN12621097 . PMID- 27225603 TI - Interleukin-37 expression and its potential role in oral leukoplakia and oral squamous cell carcinoma. AB - Interleukin 37 (IL-37) has been reported to play a significant role in innate immune response and to be involved in several kinds of cancers. However, the investigation of association between IL-37 and oral mucosa carcinogenesis hasn't been clearly established. The aim of the study was to assess IL-37 expression and explore its role in oral mucosa carcinogenesis. The expression of IL-37 increased from normal control (NC) to Oral leukoplakia (OLK) and oral squamous cell carcinoma (OSCC). Moreover, statistically highly significant difference was present between scores of OLK with and without mild/moderate dysplasia (P < 0.001). In addition, IL-37 expression was lower in OSCC with lymph node metastasis than those without metastasis (P < 0.01). What's more, overexpression of IL-37 in RAW264.7 cells remarkably reduced the pseudopodia, vacuolization and the expression of IL-6, TNF-alpha, and IL-1beta. Finally, we found IL-37 and its receptor IL-18Ralpha but not its binding partner IL-18BP have similar tissue location and expression trend in different stages of oral mucosa carcinogenesis. Overall, IL-37 can be used as a biomarker for early oral tumorigenesis and for malignant transformation risk assessment of premalignant lesions. PMID- 27225604 TI - Design and synthesis of N-benzoyl amino acid derivatives as DNA methylation inhibitors. AB - The inhibition of human DNA Methyl Transferases (DNMT) is a novel promising approach to address the epigenetic dysregulation of gene expression in different diseases. Inspired by the validated virtual screening hit NSC137546, a series of N-benzoyl amino acid analogues was synthesized and obtained compounds were assessed for their ability to inhibit DNMT-dependent DNA methylation in vitro. The biological screening allowed the definition of a set of preliminary structure activity relationships and the identification of compounds promising for further development. Among the synthesized compounds, L-glutamic acid derivatives 22, 23, and 24 showed the highest ability to prevent DNA methylation in a total cell lysate. Compound 22 inhibited DNMT1 and DNMT3A activity in a concentration dependent manner in the micromolar range. In addition, compound 22 proved to be stable in human serum and it was thus selected as a starting point for further biological studies. PMID- 27225606 TI - Ultrasound guided chronic pain interventions (Part I). AB - Recently, ultrasonography (US) is an indispensible imaging technique in regional anesthesia practice. With the guidance of US, various invasive interventions in chronic pain pathologies of the musculoskeletal system, peripheral and neuroaxial pathologies has become possible. The management includes diagnostic blocks as weel as radiofrequency ablation and institution of neurolythic agents. During these algologic interventions we are able to see the target tissue, the dispersion of the drug and all nearby vascular structures. Besides these the US also protects the team from ionic radiation that one encounters when using flouroscopy or computed tomography. Latest publications in this field show that applicability of US in chronic pain syndromes is rapidly expanding with a good future. The additional equipment (echogenic needles, 3-D US etc.) will also expand its applications in algology practice. This review highlights different applications of US in chronic pain conditions. PMID- 27225605 TI - Neonatal management and outcomes of prenatally diagnosed CHDs. AB - OBJECTIVES: The aim of this study was to determine the probability of intervention at birth after prenatal diagnosis of CHD. METHODS: A 10-year retrospective study including all foetuses with a prenatally diagnosed CHD and those delivered in a tertiary-care cardiac centre between January, 2002 and December, 2011 was carried out. Patients were classified into eight groups according to the anticipated risk of neonatal intervention. RESULTS: The need for urgent intervention and/or PGE1 infusion within the first 48 hours of life was 47% (n=507/1080): 72% (n=248) for CHD at risk for a Rashkind procedure, 77% (n=72) for CHD with ductal-dependent pulmonary flow, 13% (n=22) for CHD with potentially ductal-dependent pulmonary flow, 94% (n=62) for CHD with ductal dependent systemic flow, 29% (n=88) for CHD with potentially ductal-dependant systemic flow, 50% (n=4) for total anomalous pulmonary venous connection, and 17% (n=1) for CHD with atrio-ventricular block. In all, 34% of the patients received PGE1 infusion and 21.4% underwent urgent catheter-based or surgical interventions; 10% of patients without anticipated risk (n=10) underwent an early intervention; 6.7% (n=73) of the patients died; and 55% (n=589) had an intervention before discharge from hospital. CONCLUSION: Half of the neonates with foetal CHD benefited from an urgent intervention or PGE1 infusion at birth. We recommend scheduled delivery and in utero transfer for transposition of the great arteries, double-outlet right ventricle with sub-pulmonary ventricular septal defect, total anomalous pulmonary venous connection, CHD with atrio ventricular block with heart rate <50, all ductal-dependant lesions, and CHD with potentially ductal-dependant systemic flow. PMID- 27225608 TI - Musculoskeletal system pain and related factors in mothers of children with cerebral palsy. AB - OBJECTIVES: The aim of the present study was to identify prevalence of musculoskeletal system diseases and related factors among mothers of children with cerebral palsy. METHODS: Eighty-five mothers of children with cerebral palsy were included as the treatment group, and 42 mothers of healthy children were included as the control group. Sociodemographic characteristics of all subjects were recorded. Musculoskeletal system pain was evaluated by the standardized Nordic Musculoskeletal Questionnaire, and level of depression was evaluated according to Beck's Depression Scale. RESULTS: Musculoskeletal system pain and depression scores of the treatment group were significantly higher than those of the control group. Most frequently reported by mothers in the treatment group was low back pain (44.7%). In multiple regression analysis, number of children, age, and functional level of the child with cerebral palsy, as well as depression level of the mother were identified as independent risk factors for musculoskeletal system pain. CONCLUSION: Mothers of children with cerebral palsy are at higher risk for musculoskeletal system pain and depression. Prevalence of musculoskeletal system pain in these mothers, especially those with older children who have lower functional statuses, should be kept in mind. PMID- 27225607 TI - [Comparison of two different antiseptics on contamination of epidural catheter tip]. AB - OBJECTIVES: The aim of the present study was to compare preventive effects of 10% povidone-iodine, and combination of 2-propanol and benzalkonium chloride skin antiseptics on contamination of epidural catheter tip. METHODS: Included were 160 patients aged 18-65 years with American Society of Anesthesiologists (ASA) physical status classifications of I-II. Patients were randomized. Povidone iodine was administered to group P (n=80) prior to insertion of antibiotic prophylaxis catheter; 2-propanol and benzalkonium chloride was administered to group B. Swabs obtained before and after administration of antiseptics were sent for culture. Antiseptics were applied to skin prior to catheter removal, as well as 48 hours after insertion. In sterile conditions, 2-3 cm pieces of catheter tips were sent to laboratory. Preoperative and postoperative complete blood count, body temperature, and signs of postoperative localized skin infection were recorded. RESULTS: Leukocyte, neutrophil, and lymphocyte counts were all within normal ranges in preoperative and postoperative. Swab cultures obtained following use of antiseptics were positive in 6 group P patients; coagulase-negative Staphylococcus was found in 5 patients, E. coli in 1, and were negative in group B. Difference between groups was statistically significant (p=0.013). Epidural catheter tip cultures were negative. CONCLUSION: Combination of 2-propanol and benzalkonium chloride was determined to be more effective in reducing skin flora around epidural catheter insertion site. PMID- 27225609 TI - [Levels of pain and self-efficacy of individuals with osteoarthritis]. AB - OBJECTIVES: This descriptive study was conducted to determine pain and self efficacy levels of individuals with osteoarthritis. METHODS: 83 patients, who were hospitalized in and admitted to physical therapy or rehabilitation outpatient clinic and had a primary diagnosis of osteoarthritis, were included in the study. The data of the study were collected by using patient information form, visual analog scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and arthritis self-efficacy scale. Pearson correlation analysis, t-test, and one-way analysis of variance were used to assess the data. A p value less than 0.05 was considered as statistically significant. RESULTS: The most frequent complaints of 78.5% of the individuals with osteoarthritis were pain and limitation of movement. The pain experienced by 69.9% affected their daily life activities so much. VAS mean score of the participants was 5.7+/-2.3, their WOMAC mean score was 56.3+/-14.8, and their self-efficacy score was 103.7+/-29.5. Self-efficacy levels of those, who were men, had a higher educational level, were not housewives, were independent in daily life activities and did not have an additional chronic disease, were higher compared to the other groups (p<0.05). In this study, a negative correlation between self-efficacy scores and VAS and WOMAC scores and a positive correlation between VAS and WOMAC scores were found (p<0.05). CONCLUSION: It was determined that self-efficacy of the individuals with osteoarthritis was moderate and gender, educational level, status of independence, pain, and functional level affected self-efficacy. PMID- 27225610 TI - [Comparison of thoracic epidural and paravertebral analgesia for postoperative pain control after thoracotomy]. AB - OBJECTIVES: In the present randomized, controlled, and blinded study, the effects of thoracic paravertebral analgesia were compared to those of epidural analgesia on postoperative pain, hemodynamics, and respiration rate following thoracotomy. METHODS: Patients scheduled for elective open-lung surgery were included. One hour prior to surgery, thoracic epidural catheters were used in 18 patients (ED group), and ultrasound-guided paravertebral catheters were used in 17 patients (PV group). Standard general anesthesia was administered to all. Following anesthesia, postoperative analgesia of levobupivacaine 0.1% and morphine 0.1 mg mL-1 was administered via catheter. Patient-controlled analgesia (PCA) regime with tramadol was initiated, and amounts of local anesthetics and tramadol demanded and delivered within the first 24 hours were recorded. Visual analog scale (VAS) pain score, sedation score, side effects, and vital signs (blood pressure, heart rate, and respiratory rate) were assessed by an observer blinded to patient data at 1, 2, 3, 4, 6, 12, and 24 hours. RESULTS: Differences in PCA bolus demands and deliveries were not statistically significant between the PV group (26.8+/-1.3 and 33.1+/-4.5) and the ED group (25.1+/-3.5 and 32.5+/-4.3). Neither were differences in VAS scores statistically significant (p=0.3). Rates of sedation among the PV group were lower than those of the ED group at 1 hour (p=0.001). Five patients in the ED (%28) group experienced hypotension (p=0.02). CONCLUSION: Paravertebral block with levobupivacaine 0.1% and morphine 0.1 mg mL 1 may be an alternative form of pain relief following thoracotomy. PMID- 27225611 TI - [Ultrasound-guided obturator block experience from past year at Kocaeli University Hospital]. AB - OBJECTIVES: Obturator nerve block is recommended to prevent obturator nerve reflex during transurethral resection. However, alternate techniques have been developed. The aim of the present study was to examine outcomes of interadductor approach. METHODS: After obtaining approval from the ethics committee, files of patients who underwent transurethral resection surgery between October 2013 and October 2014 were reviewed. RESULTS: A total of 137 transurethral resection patients were identified, in 69 (2 women, 67 men) of whom a combination of spinal anesthesia and obturator nerve block was used. Obturator nerve blocks were ultrasound-guided with interadductor approach. Nerve block was unsuccessful in 2 cases due to obturator nerve reflex. Surgeries were performed without complication. CONCLUSION: Obturator nerve block is an effective method of preventing obturator nerve reflex. Combination of obturator nerve block and spinal anesthesia seems to be a safe method of anesthesia in transurethral surgery. Ultrasound guidance improves success rates and provides additional advantages for patient safety. PMID- 27225612 TI - Ultrasound guided continuous paravertebral block in a patient with coronary heart disease and sleep apnea syndrome. AB - The case of a 77-year-old patient with severe coronary heart disease who underwent radical mastectomy with axillary lymph node dissection by ultrasound guided continuous paravertebral block (CPVB) is described in the present report. Radical mastectomy with axillary dissection is a surgical procedure that necessitates endotracheal intubation and is usually performed under general anesthesia, which carries heightened risk for patients with coronary heart disease (CHD) and sleep apnea syndrome (SAS). Ultrasound-guided CPVB is a simple and safe alternative technique that allows for the use of anesthesia and postoperative analgesia with minimal side effects. PMID- 27225613 TI - Sciatic neuropathy developed after injection during curettage. AB - Intramuscular injections are likely the most common cause of sciatic nerve injury in developing countries. Less common causes include piriformis syndrome, primary tumors of the sciatic nerve, metastatic tumors invading or compressing the nerve, endometriosis, vascular malformations, and prolonged immobilization or positioning. While the most reliable diagnostic and prognostic methods include nerve conduction studies and electromyography, magnetic resonance imaging has been suggested as an alternative method of determining type of lesion, establishing location, and investigating level of nerve involvement. A case of sciatic neuropathy that developed after intramuscular injection, with patient in prolonged lithotomy position and under sedation, is described. PMID- 27225614 TI - [Subcutaneous stimulation as additional therapy to spinal cord stimulation in a post-laminectomy syndrome patient]. AB - Spinal cord stimulation as treatment of chronic low back pain via neuromodulation has been frequently performed in recent years. The dorsal column is stimulated by an electrode placed at the epidural region. In the case presently described, subcutaneous lead was implanted in a patient with failed back syndrome after spinal cord stimulation was inadequate to treat back and gluteal pain. A 65-year old male had undergone surgery to treat lumbar disc herniation, after which he received physical therapy and multiple steroid injections due to unrelieved pain. He was admitted to the pain clinic with pain radiating to right gluteal muscle and leg. Spinal cord stimulation was performed and, as pain was not relieved, subcutaneous lead was applied to the right cluneal nerve distribution. Following treatment, the patient scored 1-2 on visual analog scale. Pain had been reduced by over 80%. Octad electrode was placed between T8 and T10 vertebrae after Tuohy needle was introduced to intervertebral area between L1 and L2. Paresthesia occurred in the right extremity. Boundaries were determined by area of right gluteal region in which paresthesia did not occur. Octad electrode was placed subcutaneously after vertical line was drawn from center point. Paresthesia occurred throughout the region. Pulse wave was 390-450 msec; frequency was 10-30 Hz. Subcutaneous electrode replacement is effective additional therapy when pain is not relieved by spinal cord stimulation. PMID- 27225615 TI - [A case of palmoplantar dysesthesia syndrome caused by capecitabine]. AB - Palmoplantar dysesthesia is a dermatologic toxic reaction caused by chemotherapeutics. Also known as hand-foot syndrome, it is not life-threatening, but does decrease quality of life. Dysesthesia, erythema, edema, and desquamation on palmoplantar region are observed clinically. Palmoplantar dysesthesia syndrome may be caused by chemotherapeutics including cytarabine, doxorubicin, capecitabine, epirubicin, docetaxel, vinorelbine, and 5-fluorouracil. The case of a 62-year-old woman who presented with diffuse erythema on palmoplantar area after use of capecitabine for metastatic breast carcinoma is described in the present report. Palmoplantar dysesthesia syndrome caused by capecitabine may affect patient compliance. PMID- 27225616 TI - Anesthetic and surgical management of patient with risk of anaphylaxis: patient safety and performance of alternative axillary brachial plexus block. PMID- 27225617 TI - The Effect of Treatment of Vitamin D Deficiency on the Level of P-Selectin and hs CRP in Patients With Thromboembolism: A Pilot Randomized Clinical Trial. AB - Despite the known role of vitamin D deficiency in development of thrombosis, no studies have evaluated the impact of treating of vitamin D deficiency on the markers of thrombosis. A pilot randomized clinical trial was done on 40 vitamin D deficient patients with deep vein thrombosis (DVT) or pulmonary embolism (PE). The intervention group received an oral dose of 50,000 IU vitamin D3 every week for 8 weeks, followed by 1 pearl every 2 weeks for 4 weeks (a total of 3 months), while the control group did not receive vitamin D. Then, P-selectin and hs-CRP were measured at baseline and 1 and 3 months after the intervention. There was no significant decrease in hs-CRP in either group after 1 month (P = .955) or after 3 months (P = .525). Likewise, there was no significant decrease in P-selectin between the 2 groups after 1 month (P = .921) or 3 months (P = .795). The results indicated that treatment of vitamin D deficiency had no significant effect on hs CRP or P-selectin after 3 months among DVT/PE patients. However, treatment of vitamin D deficiency in these patients resulted in the control of the international normalized ratio (INR) with the lower doses of warfarin. This observation is the first clinical report of enhancement of the anticoagulant effect of warfarin by the supplementing of vitamin D. Larger trials are needed to clearly show the effect of treating of vitamin D deficiency on thrombosis. PMID- 27225618 TI - [Formula: see text]Working memory and attention in pediatric brain tumor patients treated with and without radiation therapy. AB - Children are at risk for cognitive difficulties following the diagnosis and treatment of a brain tumor. Longitudinal studies have consistently demonstrated declines on measures of intellectual functioning, and recently it has been proposed that specific neurocognitive processes underlie these changes, including working memory, processing speed, and attention. However, a fine-grained examination of the affected neurocognitive processes is required to inform intervention efforts. Radiation therapy (RT) impacts white matter integrity, likely affecting those cognitive processes supported by distributed neural networks. This study examined working memory and attention in children during the early delayed stages of recovery following surgical resection and RT. The participants included 27 children diagnosed with pediatric brain tumor, treated with (n = 12) or without (n = 15) RT, who completed experimental and standardized measures of working memory and attention (n-back and digit span tasks). Children treated with radiation performed less well than those who did not receive radiation on the n-back measure, though performance at the 0-back level was considerably poorer than would be expected for both groups, perhaps suggesting difficulties with more basic processes such as vigilance. Along these lines, marginal differences were noted on digit span forward. The findings are discussed with respect to models of attention and working memory, and the interplay between the two. PMID- 27225619 TI - Statistical model for collisions and recollisions of inertial particles in mixing flows. AB - Finding a quantitative description of the rate of collisions between small particles suspended in mixing flows is a long-standing problem. Here we investigate the validity of a parameterisation of the collision rate for identical particles subject to Stokes force, based on results for relative velocities of heavy particles that were recently obtained within a statistical model for the dynamics of turbulent aerosols. This model represents the turbulent velocity fluctuations by Gaussian random functions. We find that the parameterisation gives quantitatively good results in the limit where the "ghost particle approximation" applies. The collision rate is a sum of two contributions due to "caustics" and to "clustering". Within the statistical model we compare the relative importance of these two collision mechanisms. The caustic formation rate is high when the particle inertia becomes large, and we find that caustics dominate the collision rate as soon as they form frequently. We compare the magnitude of the caustic contribution to the collision rate to the formation rate of caustics. PMID- 27225620 TI - Maximal aerobic power and anaerobic capacity in cycling across the age spectrum in male master athletes. AB - PURPOSE: We analyzed the best performance times of master cycling athletes in the 200-3000 m track competitions to estimate the decay of maximal aerobic power (MAP) and anaerobic capacity (AnS) with aging. METHODS: In various decades of age (30-80 years), MAP and AnS were estimated using an iterative procedure as the values that minimize the difference between: (1) the metabolic power ([Formula: see text]) necessary to cover a given distance (d) in the time t and; (2) the maximal metabolic power ([Formula: see text]) maintained at a constant level throughout the competition. RESULTS: MAP started decreasing at 45 years of age. Thereafter, it showed an average percent rate of decrease of about 16 % for decade, as previously shown in other classes of master athletes. In addition, AnS seemed to decay by about 11 % every 10 years from the second part of the fifth decade. CONCLUSIONS: The decay of MAP occurred in spite of the active lifestyle of the subjects and it may be attributed to the progressive impairment of maximal O2 delivery and/or of peripheral O2 utilization. The loss of AnS might derive from the progressive loss of muscle mass occurring after the fifth decade of life, to the progressive qualitative deterioration of the anaerobic energy yielding pathways or to the lower capacity of MN recruitment during maximal efforts. The proposed approach may be applied to other types of human locomotion of whom the relationship between performance t and [Formula: see text] is known. PMID- 27225621 TI - Outcome and CT differentiation of gallbladder neuroendocrine tumours from adenocarcinomas. AB - OBJECTIVES: To retrospectively investigate clinical outcome and differential CT features of gallbladder (GB) neuroendocrine tumours (NETs) from adenocarcinomas (ADCs). MATERIALS AND METHODS: Nineteen patients with poorly-differentiated (PD) NETs and 19 patients with PD ADCs were enrolled. Clinical outcome was compared by the Kaplan-Meier method. We assessed qualitative and quantitative CT features to identify significant differential CT features of PD NETs from ADCs using univariate and multivariate analyses. Receiver operating characteristic (ROC) analysis was used for quantitative CT features. RESULTS: PD NETs showed poorer prognosis with significantly shorter median survival days than ADCs (363 vs. 590 days, P = 0.03). On univariate analysis, NETs more frequently manifested as GB replacing type and showed well-defined margins accompanied with intact overlying mucosa. On multivariate analysis, well-defined margin was the sole significant CT differentiator (odds ratio = 27.817, P = 0.045). Maximum size of hepatic and lymph node (LN) metastases was significantly larger in NETs (11.0 cm and 4.62 cm) than ADCs (2.40 cm and 2.41 cm). Areas under ROC curves for tumour-to-mucosa ratio, maximum size of hepatic and LN metastasis were 0.772, 0.932 and 0.919, respectively (P < 0.05). CONCLUSION: GB PD NETs show poorer prognosis than ADCs. Well-defined margin, larger hepatic and LN metastases are useful CT differentiators of GB NETs from ADCs. KEY POINTS: * A well-defined margin is a useful CT differentiator of GB NETs from ADCs. * Hepatic and LN metastases are significantly larger in NETs than in ADCs. * Primary tumour and hepatic metastasis of NETs are more hyperattenuated than ADCs. PMID- 27225622 TI - EEG Source Reconstruction in Male Nonsmokers after Nicotine Administration during the Resting State. AB - Modern psychopharmacological research in humans focuses on how specific psychoactive molecules modulate oscillatory brain activity. We present state-of the-art EEG methods applied in a resting-state drug study. Thirty healthy male nonsmokers were randomly allocated either to a nicotine group (14 subjects, 7 mg transdermal nicotine) or a placebo group (16 subjects). EEG activity was recorded in eyes-open (EO) and eyes-closed (EC) conditions before and after drug administration. A source reconstruction (minimum norm algorithm) analysis was conducted within a frequency range of 8.5-18.4 Hz subdivided into three different frequency bands. During EO, nicotine reduced the power of oscillatory activity in the 12.5- to 18.4-Hz frequency band in the left middle frontal gyrus. In contrast, in the EC condition, nicotine reduced the power in the 8.5- to 10.4-Hz frequency band in the superior frontal gyri and in the 10.5- to 12.4-Hz and 12.5- to 18.4-Hz frequency bands in the supplementary motor areas. In summary, nicotine reduced the power of the 12.5- to 18.4-Hz band in the left middle frontal gyrus during EO, and it reduced power from 8.5 to 18.4 Hz in a brain area spanning from the superior frontal gyri to the supplementary motor areas during EC. In conclusion, the results suggest that nicotine counteracts the phenomenon of anteriorization of alpha activity, hence potentially increasing the level of vigilance. PMID- 27225623 TI - Mechanisms controlling human head stabilization during random rotational perturbations in the horizontal plane revisited. AB - This study repeats the experimental protocol for investigation of head stabilization in healthy humans, described by Keshner and Peterson (1995) but with a modification of the analysis. Head movements were considered with respect to the room instead of relative to the trunk. The aim was to investigate the approximate contribution of reflex and voluntary control across perturbing frequencies and conditions with modulation of visual information and mental attention and discuss the resulting outcome while comparing methods. Seventeen healthy individuals were asked to keep the head steady in space while subjected to pseudorandom rotational perturbations in the horizontal plane, firmly seated on an actuated chair. Both methods confirmed the results for gain in previous studies showing fair ability to keep the head steady in space below 1 Hz with vision. Compensation deteriorated when vision was removed and worsened further with addition of a mental task. Between 1 and 2 Hz, unity gain occurred between head and trunk movements, whereas above 2 Hz the head moved more than the trunk. For phase angles, the original method demonstrated a phase split occurring from ~1 Hz, a purely mathematical artifact that caused subjects with virtually identical movements to appear as significantly different. This artifact was eliminated by analyzing the head-room relative to trunk-room rather than head trunk relative to trunk-room angles, thus preventing potentially erroneous interpretations of the results. PMID- 27225624 TI - The effects of hibernation and forced disuse (neurectomy) on bone properties in arctic ground squirrels. AB - Bone loss is a well-known medical consequence of disuse such as in long-term space flight. Immobilization in many animals mimics the effects of space flight on bone mineral density. Decreases in metabolism are also thought to contribute to a loss of skeletal mass. Hibernating mammals provide a natural model of disuse and metabolic suppression. Hibernating ground squirrels have been shown to maintain bone strength despite long periods of disuse and decreased metabolism during torpor. This study examined if the lack of bone loss during torpor was a result of the decrease in metabolic rate during torpor or an evolutionary change in these animals affording protection against disuse. We delineated changes in bone density during natural disuse (torpor) and forced disuse (sciatic neurectomy) in the hind limbs of the arctic ground squirrel (AGS) over an entire year. We hypothesized that the animals would be resistant to bone loss due to immobilization and disuse during the winter hibernation season when metabolism is depressed but not the summer active season. This hypothesis was not supported. The animals maintained bone density (dual-energy X-ray absorptiometry) and most bone structural and mechanical properties in both seasons. This was observed in both natural and forced disuse, regardless of the known metabolic rate increase during the summer. However, trabecular bone volume fraction (microcomputed tomography) in the distal femur was lower in neurectomized AGS at the study endpoint. These results demonstrate a need to better understand the relationship between skeletal load (use) and bone density that may lead to therapeutics or strategies to maintain bone density in disuse conditions. PMID- 27225625 TI - A physiologically based hypothesis for learning proprioception and in approximating inverse kinematics. AB - A long-standing problem in muscle control is the "curse of dimensionality". In part, this problem relates to the fact that coordinated movement is only achieved through the simultaneous contraction and extension of multitude muscles to specific lengths. Couched in robotics terms, the problem includes the determination of forward and inverse kinematics. Of the many neurophysiological discoveries in cortex is the existence of position gradients. Geometrically, position gradients are described by planes in Euclidean space whereby neuronal activity increases as the hand approaches locations that lie in a plane. This work demonstrates that position gradients, when coupled with known physiology in the spinal cord, allows for a way to approximate proprioception (forward kinematics) and to specify muscle lengths for goal-directed postures (inverse kinematics). Moreover, position gradients provide a means to learn and adjust kinematics as animals learn to move and grow. This hypothesis is demonstrated using computer simulation of a human arm. Finally, experimental predictions are described that might confirm or falsify the hypothesis. PMID- 27225626 TI - Dexamethasone and insulin activate serum and glucocorticoid-inducible kinase 1 (SGK1) via different molecular mechanisms in cortical collecting duct cells. AB - Serum and glucocorticoid-inducible kinase 1 (SGK1) is a protein kinase that contributes to the hormonal control of renal Na(+) retention by regulating the abundance of epithelial Na(+) channels (ENaC) at the apical surface of the principal cells of the cortical collecting duct (CCD). Although glucocorticoids and insulin stimulate Na(+) transport by activating SGK1, the responses follow different time courses suggesting that these hormones act by different mechanisms. We therefore explored the signaling pathways that allow dexamethasone and insulin to stimulate Na(+) transport in mouse CCD cells (mpkCCDcl4). Dexamethasone evoked a progressive augmentation of electrogenic Na(+) transport that became apparent after ~45 min latency and was associated with increases in SGK1 activity and abundance and with increased expression of SGK1 mRNA Although the catalytic activity of SGK1 is maintained by phosphatidylinositol-OH-3-kinase (PI3K), dexamethasone had no effect upon PI3K activity. Insulin also stimulated Na(+) transport but this response occurred with no discernible latency. Moreover, although insulin also activated SGK1, it had no effect upon SGK1 protein or mRNA abundance. Insulin did, however, evoke a clear increase in cellular PI3K activity. Our data are consistent with earlier work, which shows that glucocorticoids regulate Na(+) retention by inducing sgk1 gene expression, and also establish that this occurs independently of increased PI3K activity. Insulin, on the other hand, stimulates Na(+) transport via a mechanism independent of sgk1 gene expression that involves PI3K activation. Although both hormones act via SGK1, our data show that they activate this kinase by distinct physiological mechanisms. PMID- 27225627 TI - Fuel for the work required: a practical approach to amalgamating train-low paradigms for endurance athletes. AB - Using an amalgamation of previously studied "train-low" paradigms, we tested the effects of reduced carbohydrate (CHO) but high leucine availability on cell signaling responses associated with exercise-induced regulation of mitochondrial biogenesis and muscle protein synthesis (MPS). In a repeated-measures crossover design, 11 males completed an exhaustive cycling protocol with high CHO availability before, during, and after exercise (HIGH) or alternatively, low CHO but high protein (leucine enriched) availability (LOW + LEU). Muscle glycogen was different (P < 0.05) pre-exercise (HIGH: 583 +/- 158, LOW + LEU: 271 +/- 85 mmol kg(-1) dw) but decreased (P < 0.05) to comparable levels at exhaustion (~100 mmol kg(-1) dw). Despite differences (P < 0.05) in exercise capacity (HIGH: 158 +/- 29, LOW + LEU: 100 +/- 17 min), exercise induced (P < 0.05) comparable AMPKalpha2 (3-4-fold) activity, PGC-1alpha (13-fold), p53 (2-fold), Tfam (1.5-fold), SIRT1 (1.5-fold), Atrogin 1 (2-fold), and MuRF1 (5-fold) gene expression at 3 h post exercise. Exhaustive exercise suppressed p70S6K activity to comparable levels immediately post-exercise (~20 fmol min(-1) mg(-1)). Despite elevated leucine availability post-exercise, p70S6K activity remained suppressed (P < 0.05) 3 h post-exercise in LOW + LEU (28 +/- 14 fmol min(-1) mg(-1)), whereas muscle glycogen resynthesis (40 mmol kg(-1) dw h(-1)) was associated with elevated (P < 0.05) p70S6K activity in HIGH (53 +/- 30 fmol min(-1) mg(-1)). We conclude: (1) CHO restriction before and during exercise induces "work-efficient" mitochondrial related cell signaling but; (2) post-exercise CHO and energy restriction maintains p70S6K activity at basal levels despite feeding leucine-enriched protein. Our data support the practical concept of "fuelling for the work required" as a potential strategy for which to amalgamate train-low paradigms into periodized training programs. PMID- 27225628 TI - Effect of adrenergic agonists on coronary blood flow: a laboratory study in healthy volunteers. AB - Myocardial oxygen supply and demand mismatch is fundamental to the pathophysiology of ischemia and infarction. The sympathetic nervous system, through alpha-adrenergic receptors and beta-adrenergic receptors, influences both myocardial oxygen supply and demand. In animal models, mechanistic studies have established that adrenergic receptors contribute to coronary vascular tone. The purpose of this laboratory study was to noninvasively quantify coronary responses to adrenergic receptor stimulation in humans. Fourteen healthy volunteers (11 men and 3 women) performed isometric handgrip exercise to fatigue followed by intravenous infusion of isoproterenol. A subset of individuals also received infusions of phenylephrine (n = 6), terbutaline (n = 10), and epinephrine (n = 4); all dosages were based on fat-free mass and were infused slowly to achieve steady-state. The left anterior descending coronary artery was visualized using Doppler echocardiography. Beat-by-beat heart rate (HR), blood pressure (BP), peak diastolic coronary velocity (CBVpeak), and coronary velocity time integral were calculated. Data are presented as M +/- SD Isometric handgrip elicited significant increases in BP, HR, and CBVpeak (from 23.3 +/- 5.3 to 34.5 +/- 9.9 cm/sec). Isoproterenol raised HR and CBVpeak (from 22.6 +/- 4.8 to 43.9 +/- 12.4 cm/sec). Terbutaline and epinephrine evoked coronary hyperemia whereas phenylephrine did not significantly alter CBVpeak. Different indices of coronary hyperemia (changes in CBVpeak and velocity time integral) were significantly correlated (R = 0.803). The current data indicate that coronary hyperemia occurs in healthy humans in response to isometric handgrip exercise and low-dose, steady state infusions of isoproterenol, terbutaline, and epinephrine. The contribution of beta1 versus beta2 receptors to coronary hyperemia remains to be determined. In this echocardiographic study, we demonstrate that coronary blood flow increases when beta-adrenergic receptors are stimulated (i.e., during exercise and different intravenous infusions). Our infusion paradigms and beat-by-beat imaging methodologies can be used in future studies to evaluate age-, sex-, and disease- differences in adrenergic control of coronary blood flow. PMID- 27225629 TI - Postoperative fluid retention after heart surgery is accompanied by a strongly positive sodium balance and a negative potassium balance. AB - The conventional model on the distribution of electrolyte infusions states that water will distribute proportionally over both the intracellular (ICV) and extracellular (ECV) volumes, while potassium homes to the ICV and sodium to the ECV Therefore, total body potassium is the most accurate measure of ICV and thus potassium balances can be used to quantify changes in ICV In cardiothoracic patients admitted to the ICU we performed complementary balance studies to measure changes in ICV and ECV In 39 patients, fluid, sodium, potassium, and electrolyte-free water (EFW) balances were determined to detect changes in ICV and ECV Cumulatively over 4 days, these patients received a mean +/- SE infusion of 14.0 +/- 0.6 L containing 1465 +/- 79 mmol sodium, 196 +/- 11 mmol potassium and 2.1 +/- 0.1 L EFW This resulted in strongly positive fluid (4.0 +/- 0.6 L) and sodium (814 +/- 75 mmol) balances but in negative potassium (-101 +/- 14 mmol) and EFW (-1.1 +/- 0.2 L) balances. We subsequently compared potassium balances (528 patients) and fluid balances (117 patients) between patients who were assigned to either a 4.0 or 4.5 mmol/L blood potassium target. Although fluid balances were similar in both groups, the additionally administered potassium (76 +/- 23 mmol) in the higher target group was fully excreted by the kidneys (70 +/- 23 mmol). These findings indicate that even in the context of rapid and profound volume expansion neither water nor potassium moves into the ICV. PMID- 27225630 TI - Ionic mechanisms maintaining action potential conduction velocity at high firing frequencies in an unmyelinated axon. AB - The descending contralateral movement detector (DCMD) is a high-performance interneuron in locusts with an axon capable of transmitting action potentials (AP) at more than 500 Hz. We investigated biophysical mechanisms for fidelity of high-frequency transmission in this axon. We measured conduction velocities (CVs) at room temperature during exposure to 10 mmol/L cadmium, a calcium current antagonist, and found significant reduction in CV with reduction at frequencies >200 Hz of ~10%. Higher temperatures induced greater CV reductions during exposure to cadmium across all frequencies of ~20-30%. Intracellular recordings during 15 min of exposure to cadmium or nickel, also a calcium current antagonist, revealed an increase in the magnitude of the afterhyperpolarization potential (AHP) and the time to recover to baseline after the AHP (Medians for Control: -19.8%; Nickel: 167.2%; Cadmium: 387.2%), that could be due to a T-type calcium current. However, the removal of extracellular calcium did not mimic divalent cation exposure suggesting calcium currents are not the cause of the AHP increase. Computational modeling showed that the effects of the divalent cations could be modeled with a persistent sodium current which could be blocked by high concentrations of divalent cations. Persistent sodium current shortened the AHP duration in our models and increased CV for high-frequency APs. We suggest that faithful, high-frequency axonal conduction in the DCMD is enabled by a mechanism that shortens the AHP duration like a persistent or resurgent sodium current. PMID- 27225631 TI - A Meta-Analysis of the Impact of Universal and Indicated Preventive Technology Delivered Interventions for Higher Education Students. AB - The uses of technology-delivered mental health treatment options, such as interventions delivered via computer, smart phone, or other communication or information devices, as opposed to primarily face-to-face interventions, are proliferating. However, the literature is unclear about their effectiveness as preventive interventions for higher education students, a population for whom technology-delivered interventions (TDIs) might be particularly fitting and beneficial. This meta-analytic review examines technological mental health prevention programs targeting higher education students either without any presenting problems (universal prevention) or with mild to moderate subclinical problems (indicated prevention). A systematic literature search identified 22 universal and 26 indicated controlled interventions, both published and unpublished, involving 4763 college, graduate, or professional students. As hypothesized, the overall mean effect sizes (ESs) for both universal (0.19) and indicated interventions (0.37) were statistically significant and differed significantly from each other favoring indicated interventions. Skill-training interventions, both universal (0.21) and indicated (0.31), were significant, whereas non-skill-training interventions were only significant among indicated (0.25) programs. For indicated interventions, better outcomes were obtained in those cases in which participants had access to support during the course of the intervention, either in person or through technology (e.g., email, online contact). The positive findings for both universal and indicated prevention are qualified by limitations of the current literature. To improve experimental rigor, future research should provide detailed information on the level of achieved implementation, describe participant characteristics and intervention content, explore the impact of potential moderators and mechanisms of success, collect post-intervention and follow-up data regardless of intervention completion, and use analysis strategies that allow for inclusion of cases with partially missing data. PMID- 27225632 TI - An assessment study of CVD related risk factors in a tribal population of India. AB - BACKGROUND: Non communicable diseases (NCDs) have become a major concern for global health. Cardiovascular diseases (CVDs) contribute 48 % towards the deaths due to NCDs in India. Though studies have been conducted in urban and rural areas, data related to tribal communities is limited. The present study aims to examine various CVD related risk factors including hypertension, elevated fasting blood glucose, obesity and metabolic syndrome among a tribal population. METHODS: The present study was an observational, cross- sectional study conducted on Rang Bhotias, a tribal population of India. The participants were adults of age between 20 and 60 years. Prior to blood sample collection, interview schedule was administered which included relevant information like age, lifestyle, socio economic status, education and occupation In addition to this, various anthropometric and physiological measurements were taken. Logistic regression was used to examine the association of the various health disorders related to CVDs with age, gender and behavioural factors (smoking, alcohol consumption and physical activity). RESULTS: A total of 288 participants were surveyed for the study including 104 males and 184 females. High BMI (56.6 %), hypertension (43.4 %), metabolic syndrome (39.2 %) and abdominal obesity (33.7 %) were the most prevalent CVD risk factors observed in the population. The multivariate logistic regression analysis, conducted to examine the contribution of risk factors including behavioural risk factors on the studied abnormalities, revealed age to be a significant risk factor for all the abnormalities except elevated fasting blood glucose. Gender and physical inactivity contributed significantly towards development of hypertension. Physical inactivity was also found to be associated with high BMI levels. CONCLUSION: In the present study, hypertension, high BMI levels, MS and abdominal obesity have been found to be high among the studied population. The status of the population with respect to these abnormalities implicates susceptibility of the community towards various common disorders. The prevention and treatment intervention programs should be implemented taking into consideration age and gender. PMID- 27225634 TI - alpha,beta-Double Electrophilic Addition of Allene-1,3-Dicarboxylic Esters for the Construction of Polysubstituted Furans by KI/tert-Butyl Hydroperoxide (TBHP) Promoted Oxidative Annulation. AB - An unprecedented KI/tert-butyl hydroperoxide promoted tandem Michael addition/oxidative annulation of allene-1,3-dicarboxylic esters and 1,3 dicarbonyl compounds has been developed. This procedure provides a new, facile, and transition-metal-free synthetic approach to afford polysubstituted furans in moderate to excellent yields (up to 93 %). This method first establishes a alpha,beta-double electrophilic reaction mode of allene-1,3-dicarboxylic esters to form 1,3-dicarbonyl compounds. PMID- 27225633 TI - Distinguishing Fear Versus Distress Symptomatology in Pediatric OCD. AB - Prior research has identified OCD subtypes or "clusters" of symptoms that differentially relate to clinical features of the disorder. Given the high comorbidity between OCD and anxiety, OCD symptom clusters may more broadly associate with fear and/or distress internalizing constructs. This study examines fear and distress dimensions, including physical concerns (fear), separation anxiety (fear), perfectionism (distress), and anxious coping (distress), as predictors of previously empirically-derived OCD symptom clusters in a sample of 215 youth diagnosed with primary OCD (ages 7-17, mean age = 12.25). Self-reported separation fears predicted membership in Cluster 1 (aggressive, sexual, religious, somatic obsessions, and checking compulsions) while somatic/autonomic fears predicted membership in Cluster 2 (symmetry obsessions and ordering, counting, repeating compulsions). Results highlight the diversity of pediatric OCD symptoms and their differential association with fear, suggesting the need to carefully assess both OCD and global fear constructs that might be directly targeted in treatment. PMID- 27225635 TI - Implicitly learned suppression of irrelevant spatial locations. AB - How do we ignore a salient, irrelevant stimulus whose location is predictable? A variety of studies using instructional manipulations have shown that participants possess the capacity to exert location-based suppression. However, for the visual search challenges we face in daily life, we are not often provided explicit instructions and are unlikely to consciously deliberate on what our best strategy might be. Instead, we might rely on our past experience-in the form of implicit learning-to exert strategic control. In this paper, we tested whether implicit learning could drive spatial suppression. In Experiment 1, participants searched displays in which one location contained a target, while another contained a salient distractor. An arrow cue pointed to the target location with 70 % validity. Also, unbeknownst to the participants, the same arrow cue predicted the distractor location with 70 % validity. Results showed facilitated RTs to the predicted target location, confirming target enhancement. Critically, distractor interference was reduced at the predicted distractor location, revealing that participants used spatial suppression. Further, we found that participants had no explicit knowledge of the cue-distractor contingencies, confirming that the learning was implicit. In Experiment 2, to seek further evidence for suppression, we modified the task to include occasional masked probes following the arrow cue; we found worse probe identification accuracy at the predicted distractor location than control locations, providing converging evidence that observers spatially suppressed the predicted distractor locations. These results reveal an ecologically desirable mechanism of suppression, which functions without the need for conscious knowledge or externally guided instructions. PMID- 27225636 TI - Predictive remapping gives rise to environmental inhibition of return. AB - Neurons in various brain regions predictively respond to stimuli that will be brought to their receptive fields by an impending eye movement. This neural mechanism, known as predictive remapping, has been suggested to underlie spatial constancy. Inhibition of return (IOR) is a bias against recently attended locations. The present study examined whether predictive remapping is a mechanism underlying IOR effects observed in environmental coordinates. The participant made saccades to a peripheral location after an IOR effect had been elicited by an onset cue and discriminated a target presented around the time of saccade onset. Immediately before the required saccade, IOR emerged at the retinal locus that would be brought to the cued location. A second task in which the participant maintained fixation during the entire trial ruled out the possibility that this IOR effect was simply the spillover of IOR from the cued location. These findings, for the first time, provide direct behavioral evidence that predictive remapping is a mechanism underlying environmental IOR. PMID- 27225637 TI - Implications of High Rates of Metastatic Prostate Cancer in BRCA2 Mutation Carriers. AB - BACKGROUND: Patients with germline BRCA2 gene mutations (BRCA2mut) have more aggressive prostate cancer. Analysis of all reported germline BRCA2mut prostate cancer cases allows better understanding of the clinicopathologic features and survival outcomes of these men. METHODS: A systematic review was performed with the MEDLINE database to capture articles evaluating clinicopathologic characteristics of men with BRCA2mut associated prostate cancer. Inclusion criteria were at least five subjects, confirmation of BRCA2mut status, and data for at least 2 clinical parameters of disease. Meta-analysis was performed on outcomes data. Chi-squared tests were used to compare disease features among men undergoing formal versus ad hoc screening, as well as an age of diagnosis less than versus greater than 65 years. Rates of metastatic disease among BRCA2mut cases were compared to rates among non-carrier control subjects and the general population using the SEER database. RESULTS: Twelve out of 289 studies met our inclusion criteria, representing 261 BRCA2mut men. Among carriers, the median age at diagnosis was 62 years and median PSA was 15 ng/dl with 95% of men having a PSA>3. Over 40% of BRCA2mut patients had T3/T4 disease and over 25% were metastatic at presentation. Survival was worse in BRCA2mut men with prostate cancer when compared to non-BRCA2mut subjects. BRCA2mut carriers had significantly higher rates of metastatic disease (18%) versus non-carrier controls (8%) and the SEER population (4%). CONCLUSIONS: BRCA2mut carriers are more likely to have poor risk of prostate cancer at presentation and exhibit worse oncologic outcomes relative to non-carriers, including a fourfold increase in metastatic disease. Younger men and those undergoing formal screening present with less advanced disease which supports a need for earlier identification and screening protocols. Additionally, this population may benefit from alternative therapeutic paradigms. Prostate 76:1135-1145, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27225639 TI - The Phonetics of Head and Body Movement in the Realization of American Sign Language Signs. AB - BACKGROUND/AIMS: Because the primary articulators for sign languages are the hands, sign phonology and phonetics have focused mainly on them and treated other articulators as passive targets. However, there is abundant research on the role of nonmanual articulators in sign language grammar and prosody. The current study examines how hand and head/body movements are coordinated to realize phonetic targets. METHODS: Kinematic data were collected from 5 deaf American Sign Language (ASL) signers to allow the analysis of movements of the hands, head and body during signing. In particular, we examine how the chin, forehead and torso move during the production of ASL signs at those three phonological locations. RESULTS: Our findings suggest that for signs with a lexical movement toward the head, the forehead and chin move to facilitate convergence with the hand. By comparison, the torso does not move to facilitate convergence with the hand for signs located at the torso. CONCLUSION: These results imply that the nonmanual articulators serve a phonetic as well as a grammatical or prosodic role in sign languages. Future models of sign phonetics and phonology should take into consideration the movements of the nonmanual articulators in the realization of signs. PMID- 27225638 TI - Expanding the spectrum of ALK-rearranged renal cell carcinomas in children: Identification of a novel HOOK1-ALK fusion transcript. PMID- 27225640 TI - Writing and erasing hidden optical information on covalently modified cellulose paper. AB - An unprecedented strategy for preparing photoresponsive cellulose paper enabling the storage of short-lived optical data by covalent photopatterning is disclosed. An ab initio design hinting that the covalent grafting of coumarins on the paper could yield valuable photoresponsive units was first performed. Second, light sensitive paper that can be reversibly altered upon irradiation at a specific wavelength was prepared by covalent surface functionalization with coumarins. Third, the validity of this strategy is demonstrated using the photolithography of several gripping patterns such as a dynamic QR code. PMID- 27225641 TI - Myeloid-derived suppressor cells as intruders and targets: clinical implications in cancer therapy. AB - Chronic inflammation, typical of various diseases including cancer, is a "silent bomb within the body," leading to complications that are only evident in most cases upon their appearance, when disease is already deteriorated. Chronic inflammation is associated with accumulation of myeloid-derived suppressor cells (MDSCs), which lead to immunosuppression. MDSCs have numerous harmful effects as they support tumor initiation, tumor growth and spreading, which in turn, perpetuate the inflammatory and suppressive conditions, thus preventing anticancer responses. As the concept of the immune system combating many types of tumors was revived in recent years, immunotherapy has dramatically changed the view of cancer treatment, and numerous novel therapies have been developed and approved by the FDA. However, cumulative clinical data point at very limited success rates. It is most likely that the developing chronic inflammation and MDSC-induced immunosuppression interfere with responses to such treatments and hence are major obstacles in achieving higher response rates to immune-based therapies. Moreover, chemotherapies were shown to have adverse immunoregulatory effects, enhancing or decreasing MDSC levels and activity, thus affecting treatment success. Therefore, therapeutic manipulations of chronic inflammation and MDSCs during cancer development are likely to enhance efficacy of immune- and chemo-based treatments, switching chronic pro-cancer inflammatory environments to an anticancerous milieu. Based on the functional relevance of immune networking in tumors, it is critical to merge monitoring immune system biomarkers into the traditional patient's categorization and treatment regimens. This will provide new tools for clinical practice, allowing appropriate management of cancer patients toward a better-personalized medicine. PMID- 27225642 TI - Circadian regulation of lipid metabolism. AB - The circadian system temporally coordinates daily rhythms in feeding behaviour and energy metabolism. The objective of the present paper is to review the mechanisms that underlie circadian regulation of lipid metabolic pathways. Circadian rhythms in behaviour and physiology are generated by master clock neurons in the suprachiasmatic nucleus (SCN). The SCN and its efferent targets in the hypothalamus integrate light and feeding signals to entrain behavioural rhythms as well as clock cells located in peripheral tissues, including the liver, adipose tissue and muscle. Circadian rhythms in gene expression are regulated at the cellular level by a molecular clock comprising a core set of clock genes/proteins. In peripheral tissues, hundreds of genes involved in lipid biosynthesis and fatty acid oxidation are rhythmically activated and repressed by clock proteins, hence providing a direct mechanism for circadian regulation of lipids. Disruption of clock gene function results in abnormal metabolic phenotypes and impaired lipid absorption, demonstrating that the circadian system is essential for normal energy metabolism. The composition and timing of meals influence diurnal regulation of metabolic pathways, with food intake during the usual rest phase associated with dysregulation of lipid metabolism. Recent studies using metabolomics and lipidomics platforms have shown that hundreds of lipid species are circadian-regulated in human plasma, including but not limited to fatty acids, TAG, glycerophospholipids, sterol lipids and sphingolipids. In future work, these lipid profiling approaches can be used to understand better the interaction between diet, mealtimes and circadian rhythms on lipid metabolism and risk for obesity and metabolic diseases. PMID- 27225643 TI - Genome Wide Analysis of Chlamydia pneumoniae for Candidate Vaccine Development. AB - BACKGROUND: Chlamydia pneumoniae (C. pneumoniae) is a pathogen associated with respiratory tract infection of humans and its viable presence in atherosclerotic plaques is also assumed to play significant function in cardiac diseases. Unavailability of effective antimicrobial drugs has implicated the urgent need of some more disease associated vaccines that may provide relief efficiently. Thus, present study has been undertaken to analyse the whole proteome of C. pneumoniae in order to propose bacterial proteins as candidate vaccine for CAD by taking the aid of 'Reverse Vaccinology'. METHODS: Whole proteome of C. pneumoniae was downloaded and redundancy was removed by CD-HIT web server. Similarity search between proteins of C. pneumoniae and Homo sapiens was performed by BLASTP to avoid human similar proteins. Virulent proteins were selected by VirulentPred web server. Sub cellular localization of identified proteins was investigated by LocTree3 and pSORTb servers. Surface accessibility area (SAA) and antigenic epitopes prediction has been undertaken by prediction of protease specificity (POPS) and Ellipro, NetMHCpan 3.0 servers respectively. Functional significance of identified proteins was predicted through 3D model construction followed by the ligand binding site, active site and domain characterization. RESULTS: Three reference proteins RVOM1, RVOM2, RVEC1 were predicted with the crucial role in C. pneumoniae that may be capable of inducing B cell and T cell response. CONCLUSION: Detailed analysis of these proteins indicated that they may be utilized as the vaccine candidates during the chlamydial infection in near future. PMID- 27225645 TI - Correction: Protocol for a randomised controlled trial of standard wound management versus negative pressure wound therapy in the treatment of adult patients with an open fracture of the lower limb: UK Wound management of Open Lower Limb Fractures (UK WOLFF). PMID- 27225644 TI - Magnetoencapsulated human islets xenotransplanted into swine: a comparison of different transplantation sites. AB - BACKGROUND: The fate of magnetically labeled, barium-gelled alginate/protamine sulfate/alginate microcapsules (APSA magnetocapsules) following xenotransplantation was assessed by magnetic resonance imaging (MRI) and histopathology. METHODS: Magnetocapsules with and without human islets were transplanted into five different clinically accessible sites: portal vein, subcutaneous tissue, skeletal muscle, the liver and the kidney subcapsular space. The surface of APSA magnetocapsules was modified using clinical-grade heparin to mitigate an instant blood-mediated inflammatory reaction. RESULTS: The accuracy of site-specific delivery was confirmed using a clinical 1.5T MRI setup, where the magnetocapsules appeared as distinct hypointense entities after transplantation. As proven by the Lee-White blood coagulation test, heparin treated APSA magnetocapsules did not induce blood clotting for more than 48 h in vitro. Heparinized magnetocapsules induced innate and adaptive immune responses in vivo regardless of the transplantation sites. CONCLUSION: We have demonstrated the feasibility of using a clinical 1.5T MRI to non-invasively detect the accuracy of APSA magnetocapsule injection into various clinically accessible transplantation sites. Among the investigated transplantation sites, the liver and kidney subcapsular space were found to be the least immuno-responsive toward xenografted magneto-encapsulated human islets. PMID- 27225647 TI - Correction. PMID- 27225646 TI - Trends in vital signs and routine biomarkers in patients with sepsis during resuscitation in the emergency department: a prospective observational pilot study. AB - OBJECTIVES: Sepsis lacks a reliable and readily available measure of disease activity. Thereby, it remains unclear how to monitor response to treatment. Research on numerous (new) biomarkers associated with sepsis provided disappointing results and little is known about changes in vital signs during sepsis resuscitation. We hypothesised that trends in vital signs together with routine biomarker levels during resuscitation might provide information about the response to treatment at a very early stage of sepsis in the emergency department (ED). We therefore explore trends in vital signs and routine biomarker levels during sepsis resuscitation in the ED. DESIGN: Prospective observational pilot study. SETTING: ED of a tertiary care teaching hospital. PARTICIPANTS: 99 Adult non-trauma patients with suspected infection and 2 or more systemic inflammatory response syndrome criteria admitted to the ED. PRIMARY AND SECONDARY OUTCOME MEASURES: Vital signs and biomarker levels at admittance (T0) and after 3 h in the ED (T1). RESULTS: In total, data of 99 patients were analysed. Of these patients, 63 presented with sepsis, 30 with severe sepsis and 6 with septic shock. All vital signs decreased, except for peripheral oxygen saturation which increased. Almost all routine biomarker levels decreased during resuscitation, except for C reactive protein, bands, potassium, troponin T and direct bilirubin which remained stable. Sodium, chloride and N-terminal prohormone of brain natriuretic peptide increased slightly. CONCLUSIONS: Vital signs and biomarker levels showed descending trends during resuscitation, except for parameters directly affected by treatment modalities. Despite these trends, most patients improved clinically. Trends in vital signs and routine biomarkers might be helpful in predicting clinical course and response to treatment in patients with sepsis during early resuscitation. PMID- 27225648 TI - Reactions and coping strategies in lay rescuers who have provided CPR to out-of hospital cardiac arrest victims: a qualitative study. AB - OBJECTIVE: Cardiopulmonary resuscitation (CPR) provided by community citizens is of paramount importance for out-of-hospital cardiac arrest (OHCA) victims' survival. Fortunately, CPR rates by community citizens seem to be rising. However, the experience of providing CPR is rarely investigated. The aim of this study was to explore reactions and coping strategies in lay rescuers who have provided CPR to OHCA victims. METHODS, PARTICIPANTS: This is a qualitative study of 20 lay rescuers who have provided CPR to 18 OHCA victims. We used a semistructured interview guide focusing on their experiences after providing CPR. SETTING: The study was conducted in the Stavanger region of Norway, an area with very high bystander CPR rates. RESULTS: Three themes emerged from the interview analysis: concern, uncertainty and coping strategies. Providing CPR had been emotionally challenging for all lay rescuers and, for some, had consequences in terms of family and work life. Several lay rescuers experienced persistent mental recurrences of the OHCA incident and had concerns about the outcome for the cardiac arrest victim. Unknown or fatal outcomes often caused feelings of guilt and were particularly difficult to handle. Several reported the need to be acknowledged for their CPR attempts. Health-educated lay rescuers seemed to be less affected than others. A common coping strategy was confiding in close relations, preferably the health educated. However, some required professional help to cope with the OHCA incident. CONCLUSIONS: Lay rescuers experience emotional and social challenges, and some struggle to cope in life after providing CPR in OHCA incidents. Experiencing a positive patient outcome and being a health-educated lay rescuer seem to mitigate concerns. Common coping strategies are attempts to reduce uncertainty towards patient outcome and own CPR quality. Further studies are needed to determine whether an organised professional follow-up can mitigate the concerns and uncertainty of lay rescuers. PMID- 27225649 TI - Development of a brief assessment and algorithm for ascertaining dementia in low income and middle-income countries: the 10/66 short dementia diagnostic schedule. AB - OBJECTIVES: To develop and evaluate a short version of the 10/66 dementia diagnostic schedule for use in low-income and middle-income countries. DESIGN: Split-half analysis for algorithm development and testing; cross-evaluation of short-schedule and standard-schedule algorithms in 12 community surveys. SETTINGS: (1) The 10/66 pilot sample data set of people aged 60 years and over in 25 international centres each recruiting the following samples: (a) dementia; (b) depression, no dementia; (c) no dementia, high education and (d) no dementia, low education. (2) Cross-sectional surveys of people aged 65 years or more from 12 urban and rural sites in 8 countries (Cuba, Dominican Republic, Peru, Mexico, Venezuela, India, China and Puerto Rico). PARTICIPANTS: In the 10/66 pilot samples, the algorithm for the short schedule was developed in 1218 participants and tested in 1211 randomly selected participants; it was evaluated against the algorithm for the standard 10/66 schedule in 16 536 survey participants. OUTCOME MEASURES: The short diagnostic schedule was derived from the Community Screening Instrument for Dementia, the CERAD 10-word list recall task and the Euro-D depression screen; it was evaluated against clinically assigned groups in the pilot data and against the standard schedule (using the Geriatric Mental State (GMS) rather than Euro-D) in the surveys. RESULTS: In the pilot test sample, the short-schedule algorithm ascertained dementia with 94.2% sensitivity. Specificities were 80.2% in depression, 96.6% in the high-education group and 92.7% in the low-education group. In survey samples, it coincided with standard algorithm dementia classifications with over 95% accuracy in most sites. Estimated dementia prevalences in the survey samples were not consistently higher or lower using the short compared to standard schedule. CONCLUSIONS: For epidemiological studies of dementia in low-income and middle-income settings where the GMS interview (and/or interviewer training required) is not feasible, the short 10/66 schedule and algorithm provide an alternative with acceptable levels of performance. PMID- 27225650 TI - Examining the pathways for young people with drug and alcohol dependence: a mixed method design to examine the role of a treatment programme. AB - INTRODUCTION: Young people with drug and alcohol problems are likely to have poorer health and other psychosocial outcomes than other young people. Residential treatment programmes have been shown to lead to improved health and related outcomes for young people in the short term. There is very little robust research showing longer term outcomes or benefits of such programmes. This paper describes an innovative protocol to examine the longer term outcomes and experiences of young people referred to a residential life management and treatment programme in Australia designed to address alcohol and drug issues in a holistic manner. METHODS AND ANALYSIS: This is a mixed-methods study that will retrospectively and prospectively examine young people's pathways into and out of a residential life management programme. The study involves 3 components: (1) retrospective data linkage of programme data to health and criminal justice administrative data sets, (2) prospective cohort (using existing programme baseline data and a follow-up survey) and (3) qualitative in-depth interviews with a subsample of the prospective cohort. The study will compare findings among young people who are referred and (a) stay 30 days or more in the programme (including those who go on to continuing care and those who do not); (b) start, but stay fewer than 30 days in the programme; (c) are assessed, but do not start the programme. ETHICS AND DISSEMINATION: Ethics approval has been sought from several ethics committees including a university ethics committee, state health departments and an Aboriginal-specific ethics committee. The results of the study will be published in peer-reviewed journals, presented at research conferences, disseminated via a report for the general public and through Facebook communications. The study will inform the field more broadly about the value of different methods in evaluating programmes and examining the pathways and trajectories of vulnerable young people. PMID- 27225651 TI - Elder mistreatment in a community dwelling population: the Malaysian Elder Mistreatment Project (MAESTRO) cohort study protocol. AB - INTRODUCTION: Despite being now recognised as a global health concern, there is still an inadequate amount of research into elder mistreatment, especially in low and middle-income regions. The purpose of this paper is to report on the design and methodology of a population-based cohort study on elder mistreatment among the older Malaysian population. The study aims at gathering data and evidence to estimate the prevalence and incidence of elder mistreatment, identify its individual, familial and social determinants, and quantify its health consequences. METHODS AND ANALYSIS: This is a community-based prospective cohort study using randomly selected households from the national census. A multistage sampling method was employed to obtain a total of 2496 older adults living in the rural Kuala Pilah district. The study is divided into two phases: cross-sectional study (baseline), and a longitudinal follow-up study at the third and fifth years. Elder mistreatment was measured using instrument derived from the previous literature and modified Conflict Tactic Scales. Outcomes of elder mistreatment include mortality, physical function, mental health, quality of life and health utilisation. Logistic regression models are used to examine the relationship between risk factors and abuse estimates. Cox proportional hazard regression will be used to estimate risk of mortality associated with abuse. Associated annual rate of hospitalisation and health visit frequency, and reporting of abuse, will be estimated using Poisson regression. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethics Committee of the University of Malaya Medical Center (MEC Ref 902.2) and the Malaysian National Medical Research Register (NMRR 12-1444-11726). Written consent was obtained from all respondents prior to baseline assessment and subsequent follow-up. Findings will be disseminated to local stakeholders via forums with community leaders, and health and social welfare departments, and published in appropriate scientific journals and presented at conferences. PMID- 27225653 TI - Treatment goal setting for complex patients: protocol for a scoping review. AB - INTRODUCTION: An increasing number of people are living longer with multiple health and social care needs, and may rely heavily on health system resources. When dealing with multiple conditions, patients, caregivers and healthcare providers (HCPs) often experience high treatment burden due to unclear care trajectories, a myriad of treatment decisions and few guidelines on how to manage care needs. By understanding patient and caregiver priorities, and setting treatment goals, HCPs may help improve patient outcomes and experiences. This study aims to examine the extent and nature of the literature on treatment goal setting in complex patients, identify gaps in evidence and areas for further inquiry and guide a research programme to develop definitions, measures and recommendations for treatment goal setting. METHODS AND ANALYSIS: This study protocol outlines a scoping review of the peer reviewed and the grey literature, using established scoping review methodology. Literature will be identified using a multidatabase and grey literature search strategy developed by two librarians. Papers and reports on the topic of goal setting that address complexity or complex patients will be included. Results of the search will be screened independently by two reviewers and included studies will be abstracted and charted in duplicate. ETHICS AND DISSEMINATION: Ethics approval is not required for this scoping review. Working with the knowledge users on the team, we will prepare educational materials and presentations to disseminate study findings to HCPs, caregivers and patients, and at relevant national and international conferences. Results will also be published in a peer-reviewed journal. PMID- 27225654 TI - Follicular Dendritic Cell Sarcoma of Appendix Presenting as Acute Appendicitis: An Exceptionally Rare Case Report. AB - Follicular dendritic cell sarcoma (FDCS) is a rare neoplasm that originates from dendritic cells of lymphoid follicles and shows low to intermediate malignant potential. It most commonly arises from lymph nodes, but may originate from a variety of extranodal sites. FDCS of appendix is exceptionally rare, and only a single case has been reported. Herein, we describe the clincopathological features of a case of FDCS originating from appendix with emphasis on being able to recognize this rare neoplasm in the context of the differential diagnosis of more common intraabdominal spindle cell tumors. PMID- 27225652 TI - Efficacy of an internet-based self-help intervention to reduce co-occurring alcohol misuse and depression symptoms in adults: study protocol of a three-arm randomised controlled trial. AB - INTRODUCTION: In the general population, alcohol use disorder and depression more often occur together than any other combination of a mental illness with a substance use disorder. It is important to have a cost-effective intervention that is able to reach at-risk individuals in the early stages of developing alcohol use disorders and depression disorders. METHODS AND ANALYSIS: This paper presents the protocol for a 3-arm multicentre randomised controlled trial (RCT) to test the efficacy and cost-effectiveness of the combined internet-based self help intervention Take Care of You (TCOY) to reduce alcohol misuse and depression symptoms in comparison with a waiting list control group and a comparable intervention focusing on problematic alcohol use only. The active interventions consist of modules designed to reduce alcohol use, based on the principles of motivational interviewing and methods of cognitive behavioural therapy, together with additional modules in the combined study arm to reduce symptoms of depression. Data will be collected at baseline, as well as at 3 and 6 months postrandomisation. The primary outcome is the quantity of alcohol used in the past 7 days. A number of secondary outcome measures will be studied. These include the Centre of Epidemiologic Studies of Depression Scale (CES-D) and a combined measure with the criteria of values below the cut-off for severe alcohol use disorder and for CES-D. Data analysis will follow the intention-to-treat principle using (generalised) linear mixed models. In order to investigate the interventions' cost-utility and cost-effectiveness, a full economic evaluation will be performed. ETHICS AND DISSEMINATION: This RCT will be executed in compliance with the Helsinki Declaration and has been approved by 2 local Ethics Committees. Results will be reported at conferences and in peer-reviewed publications. Participant-friendly summaries of trial findings will be published on the TCOY websites. TRIAL REGISTRATION NUMBER: ISRCTN10323951. PMID- 27225655 TI - Length-dependent Ca2+ activation in skeletal muscle fibers from mammalians. AB - We tested the hypotheses that 1) a decrease in activation of skeletal muscles at short sarcomere lengths (SLs) is caused by an inhibition of Ca(2+) release from the sarcoplasmic reticulum (SR), and 2) the decrease in Ca(2+) would be caused by an inhibition of action potential conduction from the periphery to the core of the fibers. Intact, single fibers dissected from the flexor digitorum brevis from mice were activated at different SLs, and intracellular Ca(2+) was imaged with confocal microscopy. Force decreased at SLs shorter than 2.1 MUm, while Ca(2+) concentration decreased at SLs below 1.9 MUm. The concentration of Ca(2+) at short SL was lower at the core than at the peripheries of the fiber. When the external concentration of Na(+) was decreased in the experimental media, impairing action potential conduction, Ca(2+) gradients were observed in all SLs. When caffeine was used in the experimental media, the gradients of Ca(2+) were abolished. We concluded that there is an inhibition of Ca(2+) release from the sarcoplasmic reticulum (SR) at short SLs, which results from a decreased conduction of action potential from the periphery to the core of the fibers. PMID- 27225656 TI - It's all about talking: two-way communication between proteasomal and lysosomal degradation pathways via ubiquitin. AB - Selective degradation of proteins requires a fine-tuned coordination of the two major proteolytic pathways, the ubiquitin-proteasome system (UPS) and autophagy. Substrate selection and proteolytic activity are defined by a plethora of regulatory cofactors influencing each other. Both proteolytic pathways are initiated by ubiquitylation to mark substrate proteins for degradation, although the size and/or topology of the modification are different. In this context E3 ubiquitin ligases, ensuring the covalent attachment of activated ubiquitin to the substrate, are of special importance. The regulation of E3 ligase activity, competition between different E3 ligases for binding E2 conjugation enzymes and substrates, as well as their interplay with deubiquitylating enzymes (DUBs) represent key events in the cross talk between the UPS and autophagy. The coordination between both degradation routes is further influenced by heat shock factors and ubiquitin-binding proteins (UBPs) such as p97, p62, or optineurin. Mutations in enzymes and ubiquitin-binding proteins or a general decline of both proteolytic systems during aging result in accumulation of damaged and aggregated proteins. Thus further mechanistic understanding of how UPS and autophagy communicate might allow therapeutic intervention especially against age-related diseases. PMID- 27225658 TI - AJP-Cell Physiology begins a theme series on the control of the proteostasis network in health and diseases. PMID- 27225657 TI - Fluid transport by the cornea endothelium is dependent on buffering lactic acid efflux. AB - Maintenance of corneal hydration is dependent on the active transport properties of the corneal endothelium. We tested the hypothesis that lactic acid efflux, facilitated by buffering, is a component of the endothelial fluid pump. Rabbit corneas were perfused with bicarbonate-rich (BR) or bicarbonate-free (BF) Ringer of varying buffering power, while corneal thickness was measured. Perfusate was collected and analyzed for lactate efflux. In BF with no added HEPES, the maximal corneal swelling rate was 30.0 +/- 4.1 MUm/h compared with 5.2 +/- 0.9 MUm/h in BR. Corneal swelling decreased directly with [HEPES], such that with 60 mM HEPES corneas swelled at 7.5 +/- 1.6 MUm/h. Perfusate [lactate] increased directly with [HEPES]. Similarly, reducing the [HCO3 (-)] increased corneal swelling and decreased lactate efflux. Corneal swelling was inversely related to Ringer buffering power (beta), whereas lactate efflux was directly related to beta. Ouabain (100 MUM) produced maximal swelling and reduction in lactate efflux, whereas carbonic anhydrase inhibition and an monocarboxylic acid transporter 1 inhibitor produced intermediate swelling and decreases in lactate efflux. Conversely, 10 MUM adenosine reduced the swelling rate to 4.2 +/- 0.8 MUm/h and increased lactate efflux by 25%. We found a strong inverse relation between corneal swelling and lactate efflux (r = 0.98, P < 0.0001). Introducing lactate in the Ringer transiently increased corneal thickness, reaching a steady state (0 +/- 0.6 MUm/h) within 90 min. We conclude that corneal endothelial function does not have an absolute requirement for bicarbonate; rather it requires a perfusing solution with high buffering power. This facilitates lactic acid efflux, which is directly linked to water efflux, indicating that lactate flux is a component of the corneal endothelial pump. PMID- 27225660 TI - Live-born diploid fetus complicated with partial molar pregnancy presenting with pre-eclampsia, maternal anemia, and seemingly huge placenta: A rare case of confined placental mosaicism and literature review. AB - A partial molar pregnancy almost always ends in miscarriage due to a triploid fetus. We describe a rare case of a singleton, partial molar pregnancy with a seemingly huge placenta, which continued to delivery of a live-born diploid baby. A 27-year-old primigravida suffered from severe pre-eclampsia and progressive anemia. The uterus was enormously enlarged for the gestational age. A cesarean section was performed because of deterioration of maternal status at 25 weeks' gestation, when more than 3000 mL blood spouted concurrently with the delivery of the placenta. The histological examination showed congestion in the decidua, which indicated disturbance of maternal venous return from the intervillous space. The chromosome complement of the placenta and the neonate were 69,XXX and 46,XX, respectively. We also reviewed all published cases of a singleton, partial molar pregnancy. A literature search yielded 18 cases of a singleton, diploid fetus with partial molar pregnancy. The mean gestational age at delivery was 24.5 +/- 6.2 weeks, and fetuses survived outside the uterus in only four cases (22.2%). Intriguingly, previous reports numbered 10 cases with diploid placenta as well as five cases with no karyotyping of the placenta, indicating that they may have included a complete mole in a twin pregnancy or placental mesenchymal dysplasia. In conclusion, this was the first case of placentomegaly that presented manifestations of excessive abdominal distension and maternal severe anemia, and the second case of a singleton, partial molar pregnancy confirmed by chromosome analysis resulting in a diploid living baby. PMID- 27225659 TI - [Congenital malformations of the growing spine : When should treatment be conservative and when should it be surgical?]. AB - Congenital malformations of the spine are caused by genetic and teratogenic factors. By means of asymmetrical longitudinal growth of the spine they can lead to deformity, most commonly to scoliosis. The malformations can be classified as failure of formation, failure of segmentation and mixed-type malformations. The extent of the deformity and its progression are determined by the remaining growth potential and the location and type of malformation. Up to one third of such deformities are associated with some sort of cardiac or urogenital malformation. The treatment concept is typically determined on an individual basis. Mild deformities often remain undetected. Conservative treatment using a brace has no substantial effect on the primary curve but might be helpful in the treatment of long sweeping, flexible, secondary curves. If rapid progression is documented or expected, surgical intervention as early as possible is warranted to prevent secondary structural changes. The surgical treatment should be focused on and limited to the site of malformation. The aim of surgery is the correction of the deformity at the site of asymmetrical growth. This can be achieved either by resection of a hemivertebra or by performing a vertebral column resection or other type of osteotomy. If notable compensatory, secondary curves are present, these can be corrected with growing rod constructs. The aim of all types of treatment is the correction of existing deformity or the prevention of its progression, in order to ensure balanced growth of the healthy regions of the spine. The present paper discusses the conservative and surgical treatment modalities available to achieve these aims. PMID- 27225661 TI - Asymmetric axonal edge guidance: a new paradigm for building oriented neuronal networks. AB - We present a novel kind of directional axon guides for brain-on-a-chip applications. Contrarily to previous works, the directionality in our design is created by rerouting axons growing in the unwanted direction back to their original compartment while leaving the other growth direction unaffected. This design yields state-of-the-art levels of directionality without the disadvantages of previously reported technologies. PMID- 27225662 TI - Editorial: Behavioral Medicine in the Asia Pacific. PMID- 27225663 TI - Contrasting "back home" and "here": how Northeast African migrant women perceive and experience health during pregnancy and postpartum in Canada. AB - BACKGROUND: International migration and the number of migrant women who experience pregnancy and childbirth in receiving countries have significantly increased in the last two decades. Migrant women often have unmet social and economic needs during pregnancy, and are more likely to have problems unaddressed by health care systems. In this qualitative study, we explored migrant women's perceptions and experiences of health during pregnancy and postpartum, while participating in a perinatal program offered through a community-based organization. Additionally, we examined sociocultural factors that might have shaped women's health upon migration to the Canadian city of Edmonton, Alberta. METHODS: A community-based participatory research approach was used to engage migrant women connected to a community-based perinatal program in Edmonton. A focused ethnography was conducted with four Northeast African communities (Eritrean, Ethiopian, Oromo and Somali), and involved 10 focus groups with women (n = 8, per group) and direct observations of weekly perinatal program activities. Data generation and analysis occurred concurrently, and all generated data were analyzed using qualitative content analysis to inductively derive codes and categories. RESULTS: Women expressed their perceptions and experiences of health during pregnancy and postpartum by contrasting their countries of origin with Canada, respectively identified as "back home" and "here". Differences in social support and the physical environment (both natural and built) between "back home" and "here" were commonly described as factors that shaped their opportunities to eat healthy, be physically active and emotionally well before and after having a baby "here". Overall, women described that in Canada they lacked the social and environmental factors perceived as key enablers of healthy pregnancies and postpartum. CONCLUSION: A complex network of factors seem to influence Northeast African women's health during pregnancy and postpartum upon migration to Canada. It is of the utmost importance to provide these women with the immediate sociocultural and environmental factors they need to successfully thrive during pregnancy and postpartum, especially while establishing social and support networks "here". PMID- 27225665 TI - Potential Anti-inflammatory Effects of Artemisia gorgonum on Rat Liver Injury Induced by CCl4 - ERRATUM. PMID- 27225664 TI - Cucurbitacin E Potently Modulates the Activity of Encephalitogenic Cells. AB - Cucurbitacin E (CucE) is a highly oxidized steroid consisting of a tetracyclic triterpene. It is a member of a Cucurbitacin family of biomolecules that are predominantly found in Cucurbitaceae plants. CucE has already been identified as a potent anti-inflammatory compound. Here, its effects on CD4(+) T helper (Th) cells and macrophages, as the major encephalitogenic cells in the autoimmunity of the central nervous system, were investigated. Production of major pathogenic Th cell cytokines: interferon-gamma and interleukin-17 were inhibited under the influence of CucE. The effects of CucE on CD4(+) T cells were mediated through the modulation of aryl hydrocarbon receptor, STAT3, NFkappaB, p38 MAPK, and miR 146 signaling. Further, production of nitric oxide and reactive oxygen species, as well as phagocytic ability, were inhibited in macrophages treated with CucE. These results imply that CucE possesses powerful antiencephalitogenic activity. PMID- 27225666 TI - Smaller grafts do not imply early recurrence in recipients transplanted for hepatocellular carcinoma: A Chinese experience. AB - Liver graft size has long been a critical issue in adult-to-adult living donor liver transplantation (LDLT). We analyzed China Liver Transplant Registry data (January 2007-December 2009), identifying 295 patients who underwent LDLT for hepatocellular carcinoma (HCC). The recipients were divided into two groups: A, graft-to-recipient body weight ratio (GRWR) <= 0.8% (n = 56); B, GRWR > 0.8% (n = 239). We evaluated donor, recipient, and operative factors and analyzed survival outcome and the risk factors affecting overall and recurrence survival. As a result, the overall survival rates of group B were significantly higher than that of group A (p = 0.009); the corresponding tumor-free survival rates did not differ significantly (p = 0.133). The overall survival rates among the 151 recipients who met the Hangzhou criteria did not differ significantly (p = 0.953), nor did the corresponding tumor-free survival rates (p = 0.893). Multivariate analysis determined that GRWR was a significant risk factor for poor survival but not for early recurrence. In conclusion, small grafts may predict poorer survival outcome but do not indicate earlier HCC recurrence in recipients transplanted for HCC, and survival outcome with smaller grafts is merely acceptable in selected recipients. PMID- 27225667 TI - Photopatterned Polydiacetylene Images Using a DNA Bio-Photomask. AB - We describe a novel strategy to fabricate a well-defined polydiacetylene (PDA) supramolecular pattern on polyvinylidene fluoride (PVDF) membrane utilizing a DNA bio-photomask. By focusing on that, the absorption spectrum of DNA molecules having a lambdamax at 260 nm overlaps with the wavelength at which the photopolymerization of the diacetylene monomer occurs, DNA molecules are used to define specific patterns on PVDF membranes coated with diacetylene lipids by shielding the applied 254 nm UV light and consequently preventing the photopolymerization of the lipids. As a result, the DNA-covered regions retain the original white color on the membrane while the regions uncovered by DNA molecules undergo the color change to blue through the photopolymerization by 254 nm UV irradiation. On the basis of the selective illumination through a DNA photomask, we precisely manufacture specific patterns using a microarray spotting method and also demonstrate the capability of this strategy to achieve a novel colorimetric DNA sensor without any complicated process. PMID- 27225668 TI - Efficacy and safety of regenerative cell therapy for pulmonary arterial hypertension in animal models: a preclinical systematic review protocol. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease (15 cases per million) that is characterized by widespread loss of the pulmonary microcirculation and elevated pulmonary vascular resistance leading to pathological right ventricular remodeling and ultimately right heart failure. Regenerative cell therapies (i.e., therapies involving cells with stem or progenitor-like properties) could potentially restore the effective lung microcirculation and provide a curative therapy for PAH. Preclinical evidence suggests that regenerative cell therapy using endothelial progenitor cells or mesenchymal stem cells may be beneficial in the treatment of PAH. These findings have led to the completion of a small number of human clinical trials, albeit with modest effect compared to animal studies. The objective of this systematic review is to compare the efficacy and safety of regenerative cell therapies in preclinical models of PAH as well as assess study quality to inform future clinical studies. METHODS: We will include preclinical studies of PAH in which a regenerative cell type was administered and outcomes compared to a disease control. The primary outcome will be pulmonary hemodynamics as assessed by measurement of right ventricular systolic pressure and/or mean pulmonary arterial pressure. Secondary outcomes will include mortality, survival, right ventricular remodeling, pulmonary vascular resistance, cardiac output, cardiac index, pulmonary acceleration time, tricuspid annular systolic excursion, and right ventricular wall thickness. Electronic searches of MEDLINE and EMBASE databases will be constructed and reviewed by the Peer Review of Electronic Search Strategies (PRESS) process. Search results will be screened independently in duplicate. Data from eligible studies will be extracted, pooled, and analyzed using random effects models. Risk of bias will be assessed using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk of bias tool, and individual study reporting will be assessed according to an itemized checklist based on the Animal Research: Reporting of In vivo Experiments (ARRIVE) guidelines. DISCUSSION: This systematic review will examine the efficacy and safety of regenerative cell therapy in preclinical models of PAH. As well, the literature will be assessed for study quality and risk of bias. The results will guide the design of future clinical trials and preclinical animal studies. SYSTEMATIC REVIEW REGISTRATION: CAMARADES ( http://www.dcn.ed.ac.uk/camarades/SyRF/Protocols.htm ). PMID- 27225669 TI - Tip enhanced Raman spectroscopy imaging of opaque samples in organic liquid. AB - Implementation of Tip Enhanced Raman Spectroscopy in liquid is still a challenge. We demonstrate herein its feasibility in an upright illumination/collection configuration. Through a thin layer of organic solvent covering the sample, laser focussing on the tip is possible, enabling TERS imaging in liquid. PMID- 27225670 TI - Black Phosphorus Nanosheets: Synthesis, Characterization and Applications. AB - Black phosphorus (BP) is an emerging two-dimensional (2D) material with a natural bandgap, which has unique anisotropy and extraordinary physical properties. Due to its puckered structure, BP exhibits strong in-plane anisotropy unlike other layered materials. The bandgap tunability of BP enables a wide range of ultrafast electronics and high frequency optoelectronic applications ranging from telecommunications to thermal imaging covering the nearly entire electromagnetic spectrum, whereas no other 2D material has this functionality. Here, recent advances in the synthesis, fabrication, anisotropic physical properties, and BP based devices including field effect transistors (FETs) and photodetectors, are discussed. Recent passivation approaches to address the degradation of BP, which is one of the main challenges to bring this material into real world applications, are also introduced. Finally, a comment is made on the recent developments in other emerging applications, future outlook and challenges ahead in BP research. PMID- 27225671 TI - Erratum to: Incidence and outcome of cardiac injury in patients with severe head trauma. PMID- 27225673 TI - The coevolution of recognition and social behavior. AB - Recognition of behavioral types can facilitate the evolution of cooperation by enabling altruistic behavior to be directed at other cooperators and withheld from defectors. While much is known about the tendency for recognition to promote cooperation, relatively little is known about whether such a capacity can coevolve with the social behavior it supports. Here we use evolutionary game theory and multi-population dynamics to model the coevolution of social behavior and recognition. We show that conditional harming behavior enables the evolution and stability of social recognition, whereas conditional helping leads to a deterioration of recognition ability. Expanding the model to include a complex game where both helping and harming interactions are possible, we find that conditional harming behavior can stabilize recognition, and thereby lead to the evolution of conditional helping. Our model identifies a novel hypothesis for the evolution of cooperation: conditional harm may have coevolved with recognition first, thereby helping to establish the mechanisms necessary for the evolution of cooperation. PMID- 27225672 TI - Solution structure and binding specificity of the p63 DNA binding domain. AB - p63 is a close homologue of p53 and, together with p73, is grouped into the p53 family of transcription factors. p63 is known to be involved in the induction of controlled apoptosis important for differentiation processes, germ line integrity and development. Despite its high homology to p53, especially within the DNA binding domain (DBD), p63-DBD does not show cooperative DNA binding properties and is significantly more stable against thermal and chemical denaturation. Here, we determined the solution structure of p63-DBD and show that it is markedly less dynamic than p53-DBD. In addition, we also investigate the effect of a double salt bridge present in p53-DBD, but not in p63-DBD on the cooperative binding behavior and specificity to various DNA sites. Restoration of the salt bridges in p63-DBD by mutagenesis leads to enhanced binding affinity to p53-specific, but not p63-specific response elements. Furthermore, we show that p63-DBD is capable of binding to anti-apoptotic BclxL via its DNA binding interface, a feature that has only been shown for p53 so far. These data suggest that all p53 family members - despite alterations in the specificity and binding affinity - are capable of activating pro-apoptotic pathways in a tissue specific manner. PMID- 27225674 TI - Underweight and pregnancy. PMID- 27225675 TI - Integrated multidisciplinary clinics should be the gold standard in managing progressive MS - NO. PMID- 27225676 TI - Integrated multidisciplinary clinics should be the gold standard in managing progressive MS - Commentary. PMID- 27225677 TI - Integrated multidisciplinary clinics should be the gold standard in managing progressive MS - YES. PMID- 27225678 TI - Overtreatment of displaced midshaft clavicle fractures. AB - Background and purpose - The best treatment for displaced clavicle fractures has been debated for decades. Operative treatment has become more common. However, several randomized trials comparing non-operative and operative treatment have not shown any compelling evidence in favor of surgery. We identified the preferred treatment of displaced midshaft clavicle fractures at public hospitals in 3 countries in Scandinavia. Patients and methods - A purpose-made multiple choice questionnaire in English was sent to all public hospitals in Denmark, Sweden, and Finland. This was addressed to the orthopedic surgeon responsible for treatment of clavicle fractures, and completed questionnaires were obtained from 85 of 118 hospitals. Results - In the 3 countries, 69 of the 85 hospitals that responded would treat displaced clavicle fractures operatively. Clear criteria for treatment allocation were used at 58 of the hospitals, with the remaining 27 using individual assessment in collaboration with the patient. Precontoured locking plates were mostly used, placed either superiorly (64/85) or anteriorly (10/85). Interpretation - Displaced midshaft clavicle fractures are mainly treated operatively in Sweden, Denmark, and Finland. This treatment is not supported by compelling evidence. PMID- 27225679 TI - Health and social predictors of applications to public housing: a population based analysis. AB - BACKGROUND: Residents of public housing are often in poor health. However, it is unclear whether poor health precedes residency in public housing. We compared the health of people who applied to public housing to people who did not apply and had similar socioeconomic characteristics. METHODS: Population-based administrative databases from Manitoba, Canada, containing health, housing and income assistance information were used to identify a cohort of individuals who applied to public housing and a matched cohort from the general population. Conditional logistic regression was used to test the association between a public housing application and health status and health service use, after controlling for income. RESULTS: There were 10 324 individuals in each of the public housing applicant and matched cohorts; the majority were women, young, urban residents, and received income assistance. A higher per cent of the public housing cohort had physician-diagnosed physical and mental health conditions compared to the matched cohort. Physical health, mental health and health service use were significantly associated with applying to public housing, after controlling for individual and area-level income. CONCLUSIONS: Applicants to public housing were in poorer health compared to people of the same income level who did not apply to public housing. These health issues may affect the long-term stability of their tenancy if appropriate services and supports are not provided. Additionally, preventing ill health, better management of mental health and additional supports may reduce the need for public housing, which, in turn, would alleviate the pressure on governments to provide this form of housing. PMID- 27225680 TI - Effects on cigarette consumption of a work-family supportive organisational intervention: 6-month results from the work, family and health network study. AB - BACKGROUND: Observational studies have linked work-family issues with cigarette consumption. This study examined the 6-month effects on cigarette consumption of a work-family supportive organisational intervention among nursing home workers. METHODS: Group randomised controlled trial where 30 nursing homes across New England states were randomly assigned to either usual practice or to a 4-month intervention aimed at reducing work-family conflict via increased schedule control and family supportive supervisory behaviours (FSSB). Cigarette consumption was based on self-reported number of cigarettes per week, measured at the individual level. RESULTS: A total of 1524 direct-care workers were enrolled in the trial. Cigarette consumption was prevalent in 30% of the sample, consuming an average of 77 cigarettes/week. Smokers at intervention sites reduced cigarette consumption by 7.12 cigarettes, while no reduction was observed among smokers at usual practice sites (b=-7.12, 95% CI -13.83 to -0.40, p<0.05) (d=-0.15). The majority of smokers were US-born White nursing assistants, and among this subgroup, the reduction in cigarette consumption was stronger (b=-12.77, 95% CI 22.31 to -3.22, p<0.05) (d=-0.27). Although the intervention prevented a decline in FSSB (d=0.08), effects on cigarette consumption were not mediated by FSSB. CONCLUSIONS: Cigarette consumption was reduced among smokers at organisations where a work-family supportive intervention was implemented. This effect, however, was not explained by specific targets of the intervention, but other psychosocial pathways related to the work-family interface. TRIAL REGISTRATION NUMBER: NCT02050204; results. PMID- 27225681 TI - Housing conditions and limitations in physical function among older adults. AB - INTRODUCTION: Housing conditions are an important social determinant of health. However, to the best of our knowledge, no previous study has systematically assessed the association between housing conditions and physical function limitations in older adults; moreover, whether this association is independent of the socioeconomic status achieved earlier in life is still uncertain. METHODS: Cross-sectional analysis conducted among 2012 non-institutionalised individuals aged >=60 years, who participated in the Seniors-ENRICA cohort. Participants reported the following poor housing conditions: living in a walk-up building, lacking heating, or feeling cold frequently. We assessed lower extremity performance with the Short Physical Performance Battery (SPPB), mobility or agility limitations with standardised questions, frailty according to the Fried criteria, and disability in instrumental activities of daily living (IADL) with the Lawton and Brody questionnaire. RESULTS: In analyses adjusting for demographic, behavioural and comorbidity variables, when compared with those living in homes without poor housing conditions, those with >=2 poor conditions showed worse scores in the SPPB (beta -1.06; 95% CI -1.46 to -0.65) and a higher frequency of agility limitation (OR 1.62; 95% CI 1.00 to 2.61) and frailty (OR 8.78; 95% CI 3.00 to 25.60). These associations held after adjustment for educational and occupational levels. Living in a walk-up building was associated with a higher frequency of frailty, while lacking heating was linked to lower scores in the 3 SPPB tests, as well as with an increased frequency of frailty and 4 of its components (exhaustion, slow walking speed, low physical activity and weakness). Feeling cold was linked to increased exhaustion. No association was found between housing conditions and IADL disability. CONCLUSIONS: Poor housing conditions, particularly living in a walk-up building and lacking heating, are independently associated with limitations in physical function in older adults. This entails serious inequalities in functional status, which should be firmly addressed. PMID- 27225682 TI - School and seasonality in youth suicide: evidence from Japan. AB - BACKGROUND: Seasonality in youth suicide has been speculated to be associated with the school calendar, as it tends to increase at the beginning of the academic year or after a long break, but robust empirical evidence remains scarce. METHODS: We examined the nationwide death records in the Vital Statistics of Japan to investigate the seasonal patterns of suicide among youth. Our data set included 108 968 suicides by individuals who died at 6-26 years of age between 1974 and 2014 in Japan. The daily frequencies of death were plotted against the Japanese school calendar, which has little regional and temporal variations. We also estimated a Poisson regression model to uncover the cyclical patterns of suicide deaths. RESULTS: We found that the frequencies of suicide by middle school students (ages 12-15 years) and high school students (ages 15-18 years) sharply increased around the dates when a school session began in April and September. These tended to be low during school breaks. The results of regression analysis suggested middle school students were more than twice as likely to die by suicide when the summer break ended and the second semester began, compared with the baseline week in July. Similarly, the frequency of suicide for high school students also increased by ~40% at the end of the summer break. Importantly, no such pattern was found for those aged 18-26 years. CONCLUSIONS: Our findings strongly indicate that the cyclical pattern of youth suicide is closely related to the school calendar. PMID- 27225683 TI - Nonautonomous Roles of MAB-5/Hox and the Secreted Basement Membrane Molecule SPON 1/F-Spondin in Caenorhabditis elegans Neuronal Migration. AB - Nervous system development and circuit formation requires neurons to migrate from their birthplaces to specific destinations.Migrating neurons detect extracellular cues that provide guidance information. In Caenorhabditis elegans, the Q right (QR) and Q left (QL) neuroblast descendants migrate long distances in opposite directions. The Hox gene lin-39 cell autonomously promotes anterior QR descendant migration, and mab-5/Hox cell autonomously promotes posterior QL descendant migration. Here we describe a nonautonomous role of mab-5 in regulating both QR and QL descendant migrations, a role masked by redundancy with lin-39 A third Hox gene, egl-5/Abdominal-B, also likely nonautonomously regulates Q descendant migrations. In the lin-39 mab-5 egl-5 triple mutant, little if any QR and QL descendant migration occurs. In addition to well-described roles of lin-39 and mab-5 in the Q descendants, our results suggest that lin-39, mab-5, and egl-5 might also pattern the posterior region of the animal for Q descendant migration. Previous studies showed that the spon-1 gene might be a target of MAB-5 in Q descendant migration. spon-1 encodes a secreted basement membrane molecule similar to vertebrate F-spondin. Here we show that spon-1 acts nonautonomously to control Q descendant migration, and might function as a permissive rather than instructive signal for cell migration. We find that increased levels of MAB-5 in body wall muscle (BWM) can drive the spon-1 promoter adjacent to the Q cells, and loss of spon-1 suppresses mab-5 gain of function. Thus, MAB-5 might nonautonomously control Q descendant migrations by patterning the posterior region of the animal to which Q cells respond. spon-1 expression from BWMs might be part of the posterior patterning necessary for directed Q descendant migration. PMID- 27225684 TI - Biotechnology and Bioengineering: Volume 113, Number 7, July 2016. PMID- 27225685 TI - Evaluation technology of lignocellulosic nanofibrils using quartz crystal microbalance. PMID- 27225686 TI - New methods for testing biomaterial implants. PMID- 27225688 TI - Boosting cyanobacterial H2 production through metabolic engineering. PMID- 27225687 TI - Let the robot work for you! PMID- 27225691 TI - Maternal Embryonic Leucine Zipper Kinase (MELK) as a Novel Mediator and Biomarker of Radioresistance in Human Breast Cancer. AB - PURPOSE: While effective targeted therapies exist for estrogen receptor-positive and HER2-positive breast cancer, no such effective therapies exist for triple negative breast cancer (TNBC); thus, it is clear that additional targets for radiosensitization and treatment are critically needed. EXPERIMENTAL DESIGN: Expression microarrays, qRT-PCR, and Western blotting were used to assess MELK RNA and protein expression levels. Clonogenic survival assays were used to quantitate the radiosensitivity of cell lines at baseline and after MELK inhibition. The effect of MELK knockdown on DNA damage repair kinetics was determined using gammaH2AX staining. The in vivo effect of MELK knockdown on radiosensitivity was performed using mouse xenograft models. Kaplan-Meier analysis was used to estimate local control and survival information, and a Cox proportional hazards model was constructed to identify potential factors impacting local recurrence-free survival. RESULTS: MELK expression is significantly elevated in breast cancer tissues compared with normal tissue as well as in TNBC compared with non-TNBC. MELK RNA and protein expression is significantly correlated with radioresistance in breast cancer cell lines. Inhibition of MELK (genetically and pharmacologically) induces radiation sensitivity in vitro and significantly delayed tumor growth in vivo in multiple models. Kaplan-Meier survival and multivariable analyses identify increasing MELK expression as being the strongest predictor of radioresistance and increased local recurrence in multiple independent datasets. CONCLUSIONS: Here, we identify MELK as a potential biomarker of radioresistance and target for radiosensitization in TNBC. Our results support the rationale for developing clinical strategies to inhibit MELK as a novel target in TNBC. Clin Cancer Res; 22(23); 5864-75. (c)2016 AACR. PMID- 27225690 TI - The Role of Oxidative Stress and Hypoxia in Pancreatic Beta-Cell Dysfunction in Diabetes Mellitus. AB - SIGNIFICANCE: Metabolic syndrome is a frequent precursor of type 2 diabetes mellitus (T2D), a disease that currently affects ~8% of the adult population worldwide. Pancreatic beta-cell dysfunction and loss are central to the disease process, although understanding of the underlying molecular mechanisms is still fragmentary. Recent Advances: Oversupply of nutrients, including glucose and fatty acids, and the subsequent overstimulation of beta cells, are believed to be an important contributor to insulin secretory failure in T2D. Hypoxia has also recently been implicated in beta-cell damage. Accumulating evidence points to a role for oxidative stress in both processes. Although the production of reactive oxygen species (ROS) results from enhanced mitochondrial respiration during stimulation with glucose and other fuels, the expression of antioxidant defense genes is unusually low (or disallowed) in beta cells. CRITICAL ISSUES: Not all subjects with metabolic syndrome and hyperglycemia go on to develop full-blown diabetes, implying an important role in disease risk for gene-environment interactions. Possession of common risk alleles at the SLC30A8 locus, encoding the beta-cell granule zinc transporter ZnT8, may affect cytosolic Zn2+ concentrations and thus susceptibility to hypoxia and oxidative stress. FUTURE DIRECTIONS: Loss of normal beta-cell function, rather than total mass, is increasingly considered to be the major driver for impaired insulin secretion in diabetes. Better understanding of the role of oxidative changes, its modulation by genes involved in disease risk, and effects on beta-cell identity may facilitate the development of new therapeutic strategies to this disease. Antioxid. Redox Signal. 26, 501-518. PMID- 27225692 TI - A Cancer Research UK First Time in Human Phase I Trial of IMA950 (Novel Multipeptide Therapeutic Vaccine) in Patients with Newly Diagnosed Glioblastoma. AB - PURPOSE: To perform a two-cohort, phase I safety and immunogenicity study of IMA950 in addition to standard chemoradiotherapy and adjuvant temozolomide in patients with newly diagnosed glioblastoma. IMA950 is a novel glioblastoma specific therapeutic vaccine containing 11 tumor-associated peptides (TUMAP), identified on human leukocyte antigen (HLA) surface receptors in primary human glioblastoma tissue. EXPERIMENTAL DESIGN: Patients were HLA-A*02-positive and had undergone tumor resection. Vaccination comprised 11 intradermal injections with IMA950 plus granulocyte macrophage colony-stimulating factor (GM-CSF) over a 24 week period, beginning 7 to 14 days prior to initiation of chemoradiotherapy (Cohort 1) or 7 days after chemoradiotherapy (Cohort 2). Safety was assessed according to NCI CTCAE Version 4.0 and TUMAP-specific T-cell immune responses determined. Secondary observations included progression-free survival (PFS), pretreatment regulatory T cell (Treg) levels, and the effect of steroids on T cell responses. RESULTS: Forty-five patients were recruited. Related adverse events included minor injection site reactions, rash, pruritus, fatigue, neutropenia and single cases of allergic reaction, anemia and anaphylaxis. Two patients experienced grade 3 dose-limiting toxicity of fatigue and anaphylaxis. Of 40 evaluable patients, 36 were TUMAP responders and 20 were multi-TUMAP responders, with no important differences between cohorts. No effect of pretreatment Treg levels on IMA950 immunogenicity was observed, and steroids did not affect TUMAP responses. PFS rates were 74% at 6 months and 31% at 9 months. CONCLUSIONS: IMA950 plus GM-CSF was well-tolerated with the primary immunogenicity endpoint of observing multi-TUMAP responses in at least 30% of patients exceeded. Further development of IMA950 is encouraged. Clin Cancer Res; 22(19); 4776-85. (c)2016 AACRSee related commentary by Lowenstein and Castro, p. 4760. PMID- 27225694 TI - EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non-Small Cell Lung Cancer: A Retrospective Analysis. AB - PURPOSE: PD-1 inhibitors are established agents in the management of non-small cell lung cancer (NSCLC); however, only a subset of patients derives clinical benefit. To determine the activity of PD-1/PD-L1 inhibitors within clinically relevant molecular subgroups, we retrospectively evaluated response patterns among EGFR-mutant, anaplastic lymphoma kinase (ALK)-positive, and EGFR wild type/ALK-negative patients. EXPERIMENTAL DESIGN: We identified 58 patients treated with PD-1/PD-L1 inhibitors. Objective response rates (ORR) were assessed using RECIST v1.1. PD-L1 expression and CD8(+) tumor-infiltrating lymphocytes (TIL) were evaluated by IHC. RESULTS: Objective responses were observed in 1 of 28 (3.6%) EGFR-mutant or ALK-positive patients versus 7 of 30 (23.3%) EGFR wild type and ALK-negative/unknown patients (P = 0.053). The ORR among never- or light (<=10 pack years) smokers was 4.2% versus 20.6% among heavy smokers (P = 0.123). In an independent cohort of advanced EGFR-mutant (N = 68) and ALK-positive (N = 27) patients, PD-L1 expression was observed in 24%/16%/11% and 63%/47%/26% of pre tyrosine kinase inhibitor (TKI) biopsies using cutoffs of >=1%, >=5%, and >=50% tumor cell staining, respectively. Among EGFR-mutant patients with paired, pre- and post-TKI-resistant biopsies (N = 57), PD-L1 expression levels changed after resistance in 16 (28%) patients. Concurrent PD-L1 expression (>=5%) and high levels of CD8(+) TILs (grade >=2) were observed in only 1 pretreatment (2.1%) and 5 resistant (11.6%) EGFR-mutant specimens and was not observed in any ALK positive, pre- or post-TKI specimens. CONCLUSIONS: NSCLCs harboring EGFR mutations or ALK rearrangements are associated with low ORRs to PD-1/PD-L1 inhibitors. Low rates of concurrent PD-L1 expression and CD8(+) TILs within the tumor microenvironment may underlie these clinical observations. Clin Cancer Res; 22(18); 4585-93. (c)2016 AACRSee related commentary by Gettinger and Politi, p. 4539. PMID- 27225695 TI - Co-existence of histopathological features is characteristic in drug reaction with eosinophilia and systemic symptoms and correlates with high grades of cutaneous abnormalities. AB - BACKGROUND: Only few studies had investigated the histopathological presentations of drug reaction with eosinophilia with systemic symptoms (DRESS). The results of these studies were diverse and not conclusive. A characteristic histopathological feature is still lacking. OBJECTIVE: We tempted to identify characteristic histopathological features in DRESS and to correlate them with clinical presentations. METHODS: We retrospectively collected data from patients treated from 1998 through 2015. Available skin specimens from probable or definite cases according to the RegiSCAR criteria were analysed for histopathological patterns, which were then compared with the patients' clinical presentations. Chi-squared test was used for comparisons, while Bonferroni correction was applied if multiple comparison tests were encountered. RESULTS: Fifty-six patients with an average age of 52 years were identified, including 22 definite cases. The single most common histopathological pattern was interface dermatitis (75%). The co existence of two or more patterns in a skin specimen was common (62.5%). In such cases, the co-existence of three patterns (the eczematous pattern, the interface dermatitis pattern and the vascular damage pattern) was most frequently encountered. It exhibited a significantly higher likelihood of being definite cases (P = 0.004) and was significantly associated with high grades of cutaneous abnormalities (P < 0.001). It showed a trend towards having higher grades of haematological abnormalities in patients with co-existence of three patterns (P = 0.04). In addition, patients with the co-existence of three patterns tended to have a higher rate of reactivation of human herpesvirus-6 than those with other patterns but not statistically significant (P = 0.052). CONCLUSION: The co existence of three histopathological patterns in a skin specimen is characteristic in DRESS and shows a significant association with clinical severity. PMID- 27225693 TI - Therapeutic Benefit of Selective Inhibition of p110alpha PI3-Kinase in Pancreatic Neuroendocrine Tumors. AB - PURPOSE: Mutations in the PI3K pathway occur in 16% of patients with pancreatic neuroendocrine tumors (PanNETs), which suggests that these tumors are an exciting setting for PI3K/AKT/mTOR pharmacologic intervention. Everolimus, an mTOR inhibitor, is being used to treat patients with advanced PanNETs. However, resistance to mTOR-targeted therapy is emerging partially due to the loss of mTOR dependent feedback inhibition of AKT. In contrast, the response to PI3K inhibitors in PanNETs is unknown. EXPERIMENTAL DESIGN: In the current study, we assessed the frequency of PI3K pathway activation in human PanNETs and in RIP1 Tag2 mice, a preclinical tumor model of PanNETs, and we investigated the therapeutic efficacy of inhibiting PI3K in RIP1-Tag2 mice using a combination of pan (GDC-0941) and p110alpha-selective (GDC-0326) inhibitors and isoform-specific PI3K kinase-dead-mutant mice. RESULTS: Human and mouse PanNETs showed enhanced pAKT, pPRAS40, and pS6 positivity compared with normal tissue. Although treatment of RIP1-Tag2 mice with GDC-0941 led to reduced tumor growth with no impact on tumor vessels, the selective inactivation of the p110alpha PI3K isoform, either genetically or pharmacologically, reduced tumor growth as well as vascular area. Furthermore, GDC-0326 reduced the incidence of liver and lymph node metastasis compared with vehicle-treated mice. We also demonstrated that tumor and stromal cells are implicated in the antitumor activity of GDC-0326 in RIP1-Tag2 tumors. CONCLUSIONS: Our data provide a rationale for p110alpha-selective intervention in PanNETs and unravel a new function of this kinase in cancer biology through its role in promoting metastasis. Clin Cancer Res; 22(23); 5805-17. (c)2016 AACR. PMID- 27225696 TI - Cannabis and tolerance: acute drug impairment as a function of cannabis use history. AB - Cannabis use history as predictor of neurocognitive response to cannabis intoxication remains subject to scientific and policy debates. The present study assessed the influence of cannabis on neurocognition in cannabis users whose cannabis use history ranged from infrequent to daily use. Drug users (N = 122) received acute doses of cannabis (300 MUg/kg THC), cocaine HCl (300 mg) and placebo. Cocaine served as active control for demonstrating neurocognitive test sensitivity. Executive function, impulse control, attention, psychomotor function and subjective intoxication were significantly worse after cannabis administration relative to placebo. Cocaine improved psychomotor function and attention, impaired impulse control and increased feelings of intoxication. Acute effects of cannabis and cocaine on neurocognitive performance were similar across cannabis users irrespective of their cannabis use history. Absence of tolerance implies that that frequent cannabis use and intoxication can be expected to interfere with neurocognitive performance in many daily environments such as school, work or traffic. PMID- 27225697 TI - Factors Associated With Ulcer Healing and Quality of Life in Patients With Diabetic Foot Ulcer. AB - A prospective nonrandomized cohort study on consecutive diabetic patients with foot ulcer was undertaken to assess the factors associated with the healing process or limb salvage and evaluate the impact of their treatment on their quality of life. Quality of life was evaluated using Diabetic Foot Ulcer Scale Short Form (DFS-SF) questionnaire before and after treatment. A total of 103 diabetic patients with ulcer (mean age 69.7 +/- 9.6 years, 77% male) were treated and followed up for 12 months. Ulcer healing, minor amputation, and major amputation rates were 41%, 41%, and 18%, respectively, while the mortality rate was 18%. Ulcer healing was associated with University of Texas wound grade 1 and the Study of Infections in Diabetic feet comparing Efficacy, Safety and Tolerability of Ertapenem versus Piperacillin/Tazobactam trial's diabetic foot infection wound score. Limb loss was associated with nonpalpable popliteal artery, longer in-hospital stay, and delay until referral. Quality of life was improved in all domains of DFS-SF ( P < .0001) throughout the cohort of our patients regardless of their outcome, and no outcome (healing, minor amputation, or major amputation) was superior to other. Significant improvement was observed in all domains of hygiene self-management after consultation during the follow-up period. PMID- 27225698 TI - Current Debates on the Treatment of Carotid Stenosis in Both Symptomatic and Asymptomatic Patients: A Reappraisal. PMID- 27225699 TI - Transcranial Doppler Emboli Identifies Asymptomatic Carotid Patients at High Stroke Risk: Why This Technique Should be Used More Widely. AB - With modern intensive medical therapy, the annual risk of ipsilateral stroke in asymptomatic carotid stenosis (ACS) is now ~0.5%. Therefore, even the relative low risks reported from the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) trial do not justify routine intervention in most (90%) of the patients with ACS. It is therefore necessary to identify the ~10% to15% of patients with ACS who have a stroke risk high enough to justify intervention. Transcranial Doppler (TCD) embolus detection has been shown in 2 prospective studies (one with 468 patients and the other with 467 patients) to identify patients at high risk and distinguish them from those who would be better served by medical therapy. There is no valid reason why carotid intervention should be carried out in ACS without first identifying that the patient's risk of stroke is higher than the risk of intervention. The best validated way to do this is by TCD embolus detection, and the cost of TCD equipment and training is approximately the same as the cost of 2 carotid stenting procedures in the United States. This procedure should be used more widely. PMID- 27225700 TI - Pulse Wave Velocity in Kawasaki Disease. AB - Kawasaki disease (KD) is an acute childhood febrile disease of unknown etiology. It exhibits not only coronary artery aneurysms in some cases but also systemic vasculitis. Whether KD is associated with accelerated atherosclerosis remains debatable. The measurement of pulse wave velocity (PWV) is useful as a simple, noninvasive measurement of arterial stiffness, an atherosclerotic manifestation. We herein present a systematic review of clinical studies that focused on PWV in patients with KD. A PubMed-based search identified 8 eligible studies published until June 2015. The PWV of patients with KD, regardless of antecedent coronary artery lesions, was high relative to controls, even though their blood pressure appeared to be similar. Although definitive conclusions cannot be made with the limited information, patients with KD may be at risk of systemic atherosclerosis in association with arterial stiffness. Further research, including longitudinal and outcome studies, is needed to determine the clinical significance of a potential increase in PWV in patients with KD. PMID- 27225701 TI - Serum Endothelial Cell-Specific Molecule 1 (Endocan) Levels in Patients With Acute Myocardial Infarction and Its Clinical Significance. AB - Endothelial dysfunction is involved in the process of acute myocardial infarction (AMI), that is, the endothelial cell-specific molecule 1 (ESM-1; endocan) is a novel endothelial dysfunction marker. However, the relationship between patients with AMI and serum ESM-1 levels is not very clear. Patients with AMI (n = 216) and a control group (n = 60) without AMI were included in the study. High sensitivity C-reactive protein (hsCRP) was measured, and the severity of AMI was assessed by a modified Gensini stenosis scoring system. Serum ESM-1 levels were significantly higher in the AMI group ( P < .05). High-sensitivity C-reactive protein levels were also significantly higher in the AMI group ( P < .05). In patients with AMI, serum ESM-1 levels were not significantly correlated with hsCRP levels. There was no significant correlation between serum ESM-1 level and Gensini score. Our findings suggest that serum ESM-1 levels may be a novel biomarker of endothelial dysfunction in patients with AMI. PMID- 27225702 TI - CORR Insights((r)): Low Frequency of Early Complications With Dual-mobility Acetabular Cups in Cementless Primary THA. PMID- 27225703 TI - CORR Insights((r)): Dual-mobility or Constrained Liners Are More Effective Than Preoperative Bariatric Surgery in Prevention of THA Dislocation. PMID- 27225704 TI - CORR Insights(r): Hypotensive Epidural Anesthesia Reduces Blood Loss in Pelvic and Sacral Bone Tumor Resections. PMID- 27225705 TI - Oxidation of flavonoids by hypochlorous acid: reaction kinetics and antioxidant activity studies. AB - Flavonoids, plant polyphenols, ubiquitous components of human diet, are excellent antioxidants. Hypochlorous acid (HOCl), produced by activated neutrophils, is highly reactive chlorinating and oxidizing species. It has been reported earlier that flavonoids are chlorinated by HOCl. Here we show that flavonoids from flavonol subclass are also oxidized by HOCl, but only if the latter is in a large molar excess (>= 10). The kinetics of this reaction was studied by stopped-flow spectrophotometry, at different pH. We found that flavonols were oxidized by HOCl with the rate constants of the order of 10(4)-10(5) M(-1) s(-1) at pH 7.5. Antioxidant activity of HOCl-modified flavonoids was measured by 2,2'-azinobis-(3 ethylbenzothiazoline-6-sulfonic acid) (ABTS) method. Slightly higher antioxidant activity, compared to parent compounds, was observed for flavonols after their reaction with equimolar or moderate excess of HOCl whereas flavonols treated with high molar excess of HOCl exhibited decrease in antioxidant activity. The mechanism of flavonoid reaction with HOCl at physiological pH is proposed, and biological consequences of this reaction are discussed. PMID- 27225707 TI - Communication of genetic-based risk of disease to influence behavior change. PMID- 27225708 TI - Enhancing synchronization stability in a multi-area power grid. AB - Maintaining a synchronous state of generators is of central importance to the normal operation of power grids, in which many networks are generally interconnected. In order to understand the condition under which the stability can be optimized, it is important to relate network stability with feedback control strategies as well as network structure. Here, we present a stability analysis on a multi-area power grid by relating it with several control strategies and topological design of network structure. We clarify the minimal feedback gain in the self-feedback control, and build the optimal communication network for the local and global control strategies. Finally, we consider relationship between the interconnection pattern and the synchronization stability; by optimizing the network interlinks, the obtained network shows better synchronization stability than the original network does, in particular, at a high power demand. Our analysis shows that interlinks between spatially distant nodes will improve the synchronization stability. The results seem unfeasible to be implemented in real systems but provide a potential guide for the design of stable power systems. PMID- 27225706 TI - In Vivo Probe of Lipid II-Interacting Proteins. AB - beta-Lactams represent one of the most important classes of antibiotics discovered to date. These agents block Lipid II processing and cell wall biosynthesis through inactivation of penicillin-binding proteins (PBPs). PBPs enzymatically load cell wall building blocks from Lipid II carrier molecules onto the growing cell wall scaffold during growth and division. Lipid II, a bottleneck in cell wall biosynthesis, is the target of some of the most potent antibiotics in clinical use. Despite the immense therapeutic value of this biosynthetic pathway, the PBP-Lipid II association has not been established in live cells. To determine this key interaction, we designed an unnatural d-amino acid dipeptide that is metabolically incorporated into Lipid II molecules. By hijacking the peptidoglycan biosynthetic machinery, photoaffinity probes were installed in combination with click partners within Lipid II, thereby allowing, for the first time, demonstration of PBP interactions in vivo with Lipid II. PMID- 27225709 TI - P-wave Variability and Atrial Fibrillation. AB - The analysis of P-wave template has been widely used to extract indices of Atrial Fibrillation (AF) risk stratification. The aim of this paper was to assess the potential of the analysis of the P-wave variability over time in patients suffering from atrial fibrillation. P-wave features extracted from P-wave template together with novel indices of P-wave variability have been estimated in a population of patients suffering from persistent AF and compared to those extracted from control subjects. We quantify the P-wave variability over time using three algorithms and we extracted three novel indices: one based on the cross-correlation coefficients among the P-waves (Cross-Correlation Index, CCI), one associated to variation in amplitude of the P-waves (Amplitude Dispersion Index, ADI), one sensible to the phase shift among P-waves (Warping Index, WI). The control group resulted to be characterized by shorter P-wave duration and by a less amount of fragmentation and variability, respect to AF patients. The parameter CCI shows the highest sensitivity (97.3%) and a good specificity (95%). PMID- 27225710 TI - Are medical students interested in sexual health education? A nationwide survey. AB - The majority of medical students and medical healthcare providers do not feel comfortable when addressing sexual problems. It was suggested that more courses in sexual health are needed at medical schools to overcome this shortcoming. To assess medical students' interest in and attitude about sexual health education at medical schools in Germany, a 13-item online questionnaire was developed. The link to the questionnaire was distributed at all medical schools in Germany. In total, 3264 medical students (69.9% female) from all 37 medical schools in Germany participated. Students from all universities indicated that contents related to sexual health are taught at their university. The majority (n=1809; 62.1%) answered that courses in sexual health should be mandatory. The types of educational experiences that were viewed as most appropriate were lectures (n=2281, 78.3%) and seminars without patient contact (n=1414, 48.5%). Students were most interested in child sexual abuse and sexually transmitted infections. It should be ensured that all medical students have acquired basic knowledge in diagnosing and treating frequent sexual problems at the end of their medical studies. Suggestions are made about how to improve current efforts of sexual health education at medical schools. PMID- 27225711 TI - Efficacy of vacuum erectile devices (VEDs) after radical prostatectomy: the initial Irish experience of a dedicated VED clinic. AB - Controversy exists regarding optimal penile rehabilitation program following radical prostatectomy (RP). Vacuum erectile devices (VEDs) have become an important component of penile rehabilitation protocols. The aim of this study was to assess the efficacy and patient satisfaction of a dedicated VED clinic. A voluntary telephone questionnaire was performed of all patients who attended a VED clinic to date in two university teaching hospitals. Patient demographics, histopathological characteristics and functional status (International Index of Erectile Function (IIEF) scores) were obtained from a retrospective review of a prospectively maintained database. Sixty-five men attended the dedicated VED clinic in the two university teaching hospitals. Forty-men (76.3%) men purchased a VED following the dedicated clinic. There was significant differences noted between the mean preoperative and the 3-month postoperative IIEF scores (22.08+/ 3.16 vs 11.3+/-3.08, P=0.0001) and between the 3-month postoperative IIEF score and the post-VED use IIEF score (11.3+/-3.08 vs 16.74+/-2.62, P=0.0001). Despite VED use, there was a significant reduction in erectile function from presurgery status (22.08+/-3.16 vs 16.74+/-2.62, P=0.0001). All patients reported that the dedicated VED was helpful and would recommend it to other patients. Our study demonstrates that, despite a reduction in erectile function after RP, successful erections are attainable with a VED. There is potential and need for the development of a standard penile rehabilitation program and treatment of ED after RP internationally. PMID- 27225712 TI - Chronic heart failure and mortality in patients with community-acquired Staphylococcus aureus bacteremia: a population-based cohort study. AB - BACKGROUND: Patients with chronic heart failure (CHF) may experience higher mortality of Staphylococcus aureus bacteremia (SAB) than patients without CHF due to insufficient cardiovascular responses during systemic infection. We investigated 90-day mortality in SAB patients with and without CHF. METHODS: Using population-based medical databases, we conducted a cohort study of all adult patients with community-acquired SAB (CA-SAB) in Northern Denmark, 2000 2011. Ninety-day mortality after SAB for patients with and without CHF was estimated by the Kaplan-Meier method. Based on Cox regression analysis, we computed hazard ratios as estimates of mortality rate ratios (MRRs) overall and stratified by CHF-related conditions (e.g., cardiomyopathy and valvular heart disease), CHF severity (defined by daily dosage of loop-diuretics), and CHF duration while adjusting for potential confounders. RESULTS: Among 2638 SAB patients, 390 (14.8 %) had a history of CHF. Ninety-day mortality was 45 % in patients with CHF and 30 % in patients without CHF, which yielded an adjusted MRR (aMRR) of 1.24 (95 % CI, 1.04-1.48). Compared to patients without CHF, the excess risk of death was most pronounced among patients with valvular heart disease (aMRR = 1.73 (95 % CI, 1.26-2.38)), patients with daily loop-diuretic dosages of 81-159 mg/day (aMRR = 1.55 (95 % CI, 1.11-2.14)) and >=160 mg/day (aMRR = 1.62 (95 % CI, 1.21-2.18)), and among patients with <3 years of CHF duration (aMRR = 1.43 (95 % CI, 1.14-1.78)). CONCLUSION: CA-SAB patients with CHF experienced increased 90-day mortality compared to patients without CHF. PMID- 27225713 TI - Effect of age on acute toxicity of cadmium, copper, nickel, and zinc in individual-metal exposures to Daphnia magna neonates. AB - In previous studies, variability was high among replicate acute cadmium (Cd) Daphnia magna lethality tests (e.g., >10-fold range of median effect concentrations [EC50s]), less among zinc (Zn) tests, and relatively low for copper (Cu) and nickel (Ni) tests. Although the US Environmental Protection Agency's (USEPA's) protocol includes starting toxicity tests with neonates less than 24 h old, the authors hypothesized that age-related differences in sensitivity to metals might occur even within that relatively narrow age range. Daphnia magna neonates were collected during 3 age windows (0-4 h, 10-14 h, and 20-24 h old) and immediately exposed to each of the 4 metals for 48 h using the standard USEPA protocol. In repeated sets of tests during different weeks, the Cd EC50 of the youngest neonates was approximately 10-fold greater than the EC50 of the oldest neonates (i.e., Cd was less toxic to the youngest neonates) and the EC50 of neonates aged 10 h to 14 h was intermediate. Age-related differences were negligible in Cu, Ni, and Zn tests. Therefore, variability in toxicity of Cd may partly be caused by temporal variability in neonate age at the start of toxicity tests. Decreasing the age range of D. magna used in toxicity tests could help to improve the accuracy and precision of toxicity models, particularly for metal mixtures. Environ Toxicol Chem 2017;36:113-119. (c) 2016 SETAC. PMID- 27225714 TI - Resveratrol promotes differentiation of mouse embryonic stem cells to cardiomyocytes. AB - AIM: Embryonic stem cells (ESCs) are capable to differentiate into cardiomyocytes, with the potential to treat cardiovascular diseases. However, directed differentiation is still a challenge faced by scientists. As a natural substance in grapes, resveratrol (RV) is important for cardiovascular protection. The studies of RV and its effects on ESC differentiation have potential clinical applications. METHODS: Using mouse embryonic stem cells (mESCs), we investigated the effects of different concentrations of RV (5, 10, 20, 50, and 100 MUmol/L) exposure on mESCs viability, expression levels of cardiac marker genes in embryoid bodies (EBs) derived from mESCs, expression levels of maturity indicative cardiac markers in cardiomyocytes derived from mESCs, and the beating properties of EBs. RESULTS: About 10 MUmol/L of RV showed no toxicity on cell viability and was the optimal concentration to promote mESC differentiation, induce mESC differentiation to cardiomyocytes, and gain the beating properties of EBs. CONCLUSION: RV can successfully direct the differentiation of mESCs into cardiomyocytes, shedding light on its future applications to treat cardiovascular diseases. PMID- 27225715 TI - Cytotoxic and inflammatory responses of TiO2 nanoparticles on human peripheral blood mononuclear cells. AB - Titanium dioxide nanoparticles (TiO2 -NPs) have been widely used in many applications. Owing to their nanoscale size, interactions between cells and NPs have been expansively investigated. With the health concerns raised regarding the adverse effects of these interactions, closer examination of whether TiO2 -NPs can induce toxicity towards human cells is greatly needed. Therefore, in this study, we investigated the cytotoxicity of TiO2 -NPs towards human blood cells (peripheral blood mononuclear cells [PBMCs]) in serum-free medium, for which there is little information regarding the cytotoxic effects of TiO2 -NPs. Our results provide evidence that PBMCs treated with TiO2 -NPs (at concentrations >=25 MUg ml(-1) ) for 24 h significantly reduced cell viability and significantly increased production of toxic mediators such as reactive oxygen species and inflammatory response cytokines such as interleukin-6 and tumor necrosis factor alpha (P < 0.05). Cell apoptosis induction also occurred at these concentrations. Significant expressions of cyclooxygenase-2 and interleukin-1beta were also observed in PBMCs treated with TiO2 -NPs at concentrations >=125 MUg ml(-1) . Our data presented here clearly indicate that the concentration of TiO2 -NPs (at size ~26.4 +/- 1.2 nm) applied to human blood cells has a strong impact on cytotoxic induction. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27225716 TI - The Role of Scoring Systems and Urine Dipstick in Prediction of Rhabdomyolysis induced Acute Kidney Injury: a Systematic Review. AB - INTRODUCTION: During the past decade, using serum biomarkers and clinical decision rules for early prediction of rhabdomyolysis-induced acute kidney injury (AKI) has received much attention from researchers. This study aimed to broadly review the value of scoring systems and urine dipstick in prediction of rhabdomyolysis-induced AKI. MATERIALS AND METHODS: The study was designed based on the guidelines of the Meta-analysis of Observational Studies in Epidemiology statement. Search was done in electronic databases of MEDLINE, EMBASE, Cochrane Library, Scopus, and Google Scholar by 2 independent reviewers. Studies evaluating AKI risk factors in rhabdomyolysis patients with the aim of developing a scoring model as well as those assessing the role of urine dipstick in these patients were included. RESULTS: Of the 5997 articles found, 143 were potentially relevant studies. After studying their full texts, 6 articles were entered into the systematic review. Two studies had developed or validated scoring systems of the "rule of thumb," and the AKI index, and the Mangled Extremity Severity Score. Four studies were on the predictive value of urine dipstick in risk prediction of rhabdomyolysis-induced AKI, with favorable results. CONCLUSIONS: The findings of this systematic review showed that based on the available resources, using the prediction rules and urine dipstick could be considered as valuable screening tools for detection of patients at risk for AKI following rhabdomyolysis. Yet, the external validity of the mentioned tools should be assessed before their general application in routine practice. PMID- 27225717 TI - Mutational Spectrum of the MEFV Gene in AA Amyloidosis Associated With Familial Mediterranean Fever. AB - INTRODUCTION: Familial Mediterranean fever (FMF) is a recessively inherited disease which is characterized by recurrent episodic fever, abdominal pain, and polyserositis. It is caused by mutations in the MEFV gene, encoding the pyrin protein. The most important complication of FMF is secondary (AA) amyloidosis that leads to kidney failure. This study aimed to identify the frequency and distribution of MEFV mutations in Turkish patients with FMF-associated AA amyloidosis. MATERIALS AND METHODS: A total of 57 patients with FMF-associated AA amyloidosis and 60 healthy controls were included in this study. We analyzed the MEFV gene for E148Q, M694V, M680I, and V726A mutations and R202Q variant by polymerase chain reaction and restriction fragment length polymorphism methods. Results. The male-female ratio was 0.72. The mean age of the patients was 29.8 +/ 12.8 years. Among the patients, the rate of the MEFV mutations was found to be 77.2%. The most frequently observed genotype was homozygous M694V mutation, which was present in 17 patients (29.8%, P < .001), followed by compound heterozygous M680I/M694V (14.3%, P = .01). The R202Q allele frequencies were significantly different between patients and control group (P = .02; odds ratio, 0.53; 95% confidence interval, 0.30 to 0.94). CONCLUSIONS: In this study, mutation analysis of MEFV gene confirmed that the most frequent mutation was homozygous M694V genotype. R202Q may be important in patients with FMF-associated AA amyloidosis. Thus, it is suggested that investigation of R202Q should be considered as a genetic test for Turkish FMF patients. PMID- 27225718 TI - Expression of T Helper 17 and Regulatory T Cell Cytokines and Molecules in Glomerulonephritis Class IV Systemic Lupus Erythematosus. AB - INTRODUCTION: Lupus nephritis is a serious organ involvement with unknown etiology, and glomerulonephritis class IV is one of the most severe forms of the disease which correlates with poor prognosis and death. Immunological abnormalities are implicated in the expression of lupus nephritis. In this study, we examined some T helper 17 and regulatory T-related cytokines and molecules in systemic lupus erythematosus patients with glomerulonephritis class IV. MATERIALS AND METHODS: The study group comprised of 20 glomerulonephritis class IV SLE patients and 20 sex- and age-matched SLE patients without kidney involvement as control group. Blood samples was collected from each participant, lymphocytes were isolated, and RNA was extracted from lymphocytes. Then cDNA was synthesized using reverse transcription enzyme, and finally using specific primers and probes, the expression levels of forkhead box P3 (Foxp3), transforming growth factor (TGF)-beta, interferon (IFN)-gamma, interleukin (IL)-6, and IL-17 genes were analyzed by real-time polymerase chain reaction based on the TaqMan method. RESULTS: The expression levels of IL-6, IL-17, IFN-gamma, and Foxp3 genes were significantly higher in SLE patients with glomerulonephritis class IV than those with non-nephritis SLE. However, the expression of TGF-beta was not significantly different between the SLE patients with and without glomerulonephritis class IV involvement. CONCLUSIONS: According to our results, it seems that in class IV glomerulonephritis patients, increased Foxp3-producing regulatory T cells has an imperfect capacity to control the pathogenic IL-17- and IFN-gamma-producing cells. PMID- 27225719 TI - Dietary Acid-Base Load and Risk of Chronic Kidney Disease in Adults: Tehran Lipid and Glucose Study. AB - INTRODUCTION: The objective was to examine whether dietary acid load was associated with chronic kidney disease (CKD) in adults. MATERIALS AND METHODS: The cross-sectional analyses included 4564 participants, aged 20 years and older, who participated in the 4th phase of the Tehran Lipid and Glucose Study and had complete dietary and serum creatinine data. Dietary data were obtained from using a 147-item food-frequency questionnaire. Dietary acid load was calculated as the potential renal acid load (PRAL). Anthropometrics, blood pressure, and fasting plasma glucose, and lipids were measured. Chronic kidney disease was defined as an estimated glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2 calculated using the Modification of Diet in Renal Disease equation. Risk of CKD was obtained in quartiles of PRAL with logistic recreation. RESULTS: The mean dietary PRAL of the participants was -22.0 mEq/d. After adjustment for age, sex, and body mass index, the odds ratio for CKD in the highest compared to the lowest quartile of PRAL was 1.38 (95% confidence interval [CI], 1.02 to 1.83). After additional adjustment for energy intake and smoking, the odds ratio for CKD in the 4th quartile of PRAL compared to the 1st was 1.42 (95% CI, 1.06 to 1.91). In the final model, after additional adjustment for dietary intake of total fat, carbohydrate, dietary fiber, fructose, sodium, diabetes mellitus, and hypertension, the risk of CKD in the highest dietary PRAL category, compared to the lowest, increased by 42%. CONCLUSIONS: After adjusting for possible confounding factors, we found that higher PRAL (more acidic diet) was associated with higher prevalent CKD in Iranian adults. PMID- 27225720 TI - Association of Serum Uric Acid With Cardiometabolic Risk Factors and Metabolic Syndrome in Iranian Adolescents: the CASPIAN-III Study. AB - INTRODUCTION: There is controversial evidence on association of serum acid uric (SUA) with cardiometabolic risk factors and metabolic syndrome in adults. This study aimed to investigate the associations of SUA levels, components of metabolic syndrome, and other cardiometabolic risk factors, in a nationally representative sample of Iranian adolescents. MATERIALS AND METHODS: This study included 132 participants who met the criteria of metabolic syndrome and 235 participants without metabolic syndrome. The participants were grouped according to the tertiles of SUA. Metabolic syndrome was defined according to the Adult Treatment Panel III criteria modified for children and adolescents. The relationship between SUA and cardiometabolic risk factors and metabolic syndrome was assessed by multivariable logistic regression analysis. RESULTS: The mean age of the participants was 15.21 +/- 2.35 years, with no significant difference between the boys and the girls. The participants whose SUA was categorized in the 2nd tertile and those falling into the 3rd tertile had significantly higher systolic blood pressure (P < .001) as compared with the lower tertile(s). A similar trend was documented for the overall high blood pressure. Metabolic syndrome was associated with the 2nd and 3rd tertiles of SUA as compared to the lower tertile(s), in the adjusted model (P < .001), with the risk increasing by at least 2 times. CONCLUSIONS: Our study showed that those adolescents with metabolic syndrome had higher SUA levels. Its association with some components of metabolic syndrome supports that SUA might be an additional component of metabolic syndrome even during adolescence. PMID- 27225721 TI - Protective Effect of Nigella Sativa on Renal Reperfusion Injury in Rat. AB - INTRODUCTION: This study was designed to investigate the effect of Nigella sativa (NS), in reperfusion-induced renal injury in rats. MATERIALS AND METHODS: A total of 24 male Sprague-Dawley rats were divided into 3 groups of controls and rats that underwent ischemia-reperfusion with and without pretreatment with NS. A rat model of renal reperfusion injury was induced by 45-minute occlusion of the bilateral renal pedicles and 24-hour reperfusion. In the NS group, a single dose NS (400 mg/kg orally) was administered by gastric gavage. RESULTS: Renal reperfusion caused severe histopathological injury such as tubular damage, atrophy dilatation, loss of brush border, and hydropic epithelial cell degenerations. Treatment with NS significantly attenuated the severity of reperfusion injury and significantly lowered tubulointerstitial damage score as compared with the reperfusion group. When kidney sections were stained with anti proliferating-cell nuclear antigen antibody, nuclear factor kappaB p65 antibody, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, there was a clear increase in the number of positive cells in the reperfusion group in the renal cortical tissues. However, there was a significant reduction in the number of stain-positive cells in kidney tissue from the NS group. Treatment of renal reperfusion injury with NS decreased the elevated tissue malondialdehyde levels and increased the reduced activities of the enzymatic antioxidants glutathione peroxidase and catalase. CONCLUSIONS: Pretreatment with NS has a protective effect against renal damage induced by renal reperfusion. This protective effect is possibly due to its ability to inhibit reperfusion-induced renal damage, apoptosis, and cell proliferation. PMID- 27225722 TI - Effects of Oral L-Carnitine Supplementation on Leptin and Adiponectin Levels and Body Weight of Hemodialysis Patients: a Randomized Clinical Trial. AB - INTRODUCTION: Carnitine supplementation may improve the general health and quality of life of hemodialysis patients by improving adipokines levels. The aim of the study was to investigate the effects of L-carnitine supplementation on leptin levels, adiponectin levels, and body weight of hemodialysis patients. MATERIALS AND METHODS: Fifty hemodialysis patients were randomly divided into the carnitine group, who received oral L-carnitine, 1 g/L for 3 months, and the control group. Anthropometric measurements and serum levels of adipokines were measured at baseline and at the end of the intervention. RESULTS: Forty-two participants completed the study. Serum leptin concentrations decreased after 12 weeks of the intervention in both groups, but these changes were not significant. The mean change of leptin concentration were, -1.7 +/- 19.0 ug/mL and -7.1 +/- 20.0 ug/mL in the carnitine group and the control group, respectively (P = .39). The mean adiponectin levels at baseline and after the intervention were 8.6 +/- 11.19 ug/mL and 9.8 +/- 4.1 ug/mL in the carnitine group (P = .67) and 5.0 +/- 2.5 ug/mL and 11.2 +/- 5.4 ug/mL in the control group, respectively (P < .001). Serum adiponectin levels increased significantly in the control group only. The decrease in body mass index was not significant. CONCLUSIONS: This study showed that a daily supplementation of 1000 mg oral syrup of L-carnitine for 12 weeks did not affect leptin and adiponectin levels or the body weight or body mass index of hemodialysis patients. PMID- 27225723 TI - Efficacy of Combined Plasmapheresis and Intravenous Immunoglobulin Therapy in Kidney Transplant Patients With Chronic Antibody-mediated Rejection. AB - INTRODUCTION: Antibody-mediated rejections (AMRs) are critical clinical issues encountered in short- and long-term follow-up of kidney transplant patients. Whereas plasmapheresis is a mainstay treatment option in acute AMR cases, there is a paucity of data regarding its efficacy in management of chronic AMR. This report describes our experience addressing this issue. MATERIALS AND METHODS: We retrospectively investigated the data of 7 kidney transplant patients diagnosed with chronic AMR who were on 5 sessions of plasmapheresis (1 to 2 volume exchanges with fresh frozen plasma) on alternate days and 200 mg/kg of intravenous immunoglobulin after each session of plasmapheresis. RESULTS: At 6 months after the initiation of treatment, 6 patients experienced partially improved kidney function. One patient had no response and her kidney function progressively deteriorated. CONCLUSIONS: Our preliminary results are encouraging for the combination of plasmapheresis and intravenous immunoglobulin as an adjunctive therapy for kidney transplant patients suffering from chronic AMR. PMID- 27225724 TI - Effects of Genetic Polymorphism in CYP3A4 and CYP3A5 Genes on Tacrolimus Dose Among Kidney Transplant Recipients. AB - INTRODUCTION: This study aimed to evaluate the effects of single nucleotide polymorphisms CYP3A4*1B and CYP3A5*3 on tacrolimus dose requirement among kidney transplant recipients. MATERIALS AND METHODS: Blood levels of tacrolimus were measured using microparticle enzyme immunoassay. Genotyping analysis utilized specific polymerase chain reaction-restriction fragment length polymorphism methods for 137 kidney transplant recipients. RESULTS: The median tacrolimus dose was significantly lower in the CYP3A4*1/*1 carriers (0.06 mg/kg/d; range, 0.007 mg/kg/d to 0.17 mg/kg/d) as compared to the CYP3A4*1B/*1B carriers (0.1 mg/kg/d; range, 0.03 mg/kg/d to 0.22 mg/kg/d; P = .001). Patients with at least 1 CYP3A5*1 wild-type allele required higher median doses of tacrolimus (median, 0.08 mg/kg/d; range, 0.03 mg/kg/d to 0.22 mg/kg/d) as compared to the CYP3A5*3 carriers (median, 0.05 mg/kg/d; range, 0.007 mg/kg/d to 0.17 mg/kg/d; P = .002). CONCLUSIONS: This study showed that tacrolimus dose requirement is lower in Jordanian kidney transplant recipients compared to other populations. Moreover, we found a correlation between genetic variations in CYP3A4 and CYP3A5 enzymes and tacrolimus blood levels among our kidney transplant recipients. PMID- 27225725 TI - Acquired Perforating Dermatosis Associated With End-stage Diabetic Kidney Failure in a Hemodialysis Patient. AB - Acquired perforating dermatosis (APD) is an uncommon skin disorder seen in majority among patients with chronic kidney disease and also in those with diabetes mellitus. We present the clinicopathological features of APD in a 65 year-old patient with diabetes mellitus and end-stage kidney disease on hemodialysis and review the recent advances in the management of APD, as well as the mechanisms of transepidermal elimination of perforating dermatoses. PMID- 27225726 TI - Towards a biofunctionalized vascular prosthesis: immune cell trapping via a growth factor receptor. AB - To improve the clinical performance of vascular prostheses, which is inacceptably low for implants with small diameters (< 6 mm), biofunctionalization of synthetic implants by endothelialization has become a major, although still unreached, aim. In order to be able to recruit native endothelial progenitor cells (EPCs) to luminal implant surfaces from the blood stream, we generated monoclonal antibodies against the EPC-specific vascular endothelial growth factor receptor 2 (VEGFR-2). Employing the very efficient genetic immunization strategy, > 10 000 hybridoma clones were generated. Screening with various deletion mutants of VEGFR 2, 49 highly-specific monoclonal antibodies (mAbs) covering all seven Ig domains of VEGFR-2 were selected. mAb 9H10 was characterized in detail. Once immobilized on synthetic surfaces, mAb 9H10 allowed, within min, nearly 100-fold enrichment of VEGFR-2-expressing cells under continuous flow conditions. Cell trapping was cell-type specific and essentially not affected by competing VEGFR-2-negative cells. To exclude that the antibody would adversely modify receptor responses, four different in vitro assays were employed. Cell proliferation, angiogenic tube formation, acetylated low-density lipoprotein uptake and VEGFR-2 phosphorylation remained unaffected, suggesting that the antibody did not interfere with the receptor functioning of human umbilical vascular endothelial cells. The molecular and cellular characteristics make the selected monoclonal antibody a very promising tool for the biofunctionalization of vascular implants. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27225727 TI - Pin1, the Master Orchestrator of Bone Cell Differentiation. AB - Pin1 is an enzyme that specifically recognizes the peptide bond between phosphorylated serine or threonine (pS/pT-P) and proline. This recognition causes a conformational change of its substrate, which further regulates downstream signaling. Pin1-/- mice show developmental bone defects and reduced mineralization. Pin1 targets RUNX2 (Runt-Related Transcription Factor 2), SMAD1/5, and beta-catenin in the FGF, BMP, and WNT pathways, respectively. Pin1 has multiple roles in the crosstalk between different anabolic bone signaling pathways. For example, it controls different aspects of osteoblastogenesis and increases the transcriptional activity of Runx2, both directly and indirectly. Pin1 also influences osteoclastogenesis at different stages by targeting PU.1 (Purine-rich nucleic acid binding protein 1), C-FOS, and DC-STAMP. The phenotype of Pin1-/- mice has led to the recent identification of multiple roles of Pin1 in different molecular pathways in bone cells. These roles suggest that Pin1 can be utilized as an efficient drug target in congenital and acquired bone diseases. J. Cell. Physiol. 232: 2339-2347, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27225728 TI - Proteomic Analysis of Mouse Oocytes Identifies PRMT7 as a Reprogramming Factor that Replaces SOX2 in the Induction of Pluripotent Stem Cells. AB - The reprogramming process that leads to induced pluripotent stem cells (iPSCs) may benefit from adding oocyte factors to Yamanaka's reprogramming cocktail (OCT4, SOX2, KLF4, with or without MYC; OSK(M)). We previously searched for such facilitators of reprogramming (the reprogrammome) by applying label-free LC-MS/MS analysis to mouse oocytes, producing a catalog of 28 candidates that are (i) able to robustly access the cell nucleus and (ii) shared between mature mouse oocytes and pluripotent embryonic stem cells. In the present study, we hypothesized that our 28 reprogrammome candidates would also be (iii) abundant in mature oocytes, (iv) depleted after the oocyte-to-embryo transition, and (v) able to potentiate or replace the OSKM factors. Using LC-MS/MS and isotopic labeling methods, we found that the abundance profiles of the 28 proteins were below those of known oocyte-specific and housekeeping proteins. Of the 28 proteins, only arginine methyltransferase 7 (PRMT7) changed substantially during mouse embryogenesis and promoted the conversion of mouse fibroblasts into iPSCs. Specifically, PRMT7 replaced SOX2 in a factor-substitution assay, yielding iPSCs. These findings exemplify how proteomics can be used to prioritize the functional analysis of reprogrammome candidates. The LC-MS/MS data are available via ProteomeXchange with identifier PXD003093. PMID- 27225729 TI - Consumption of dairy yogurt with the polysaccharide rhamnogalacturonan from the peel of the Korean citrus hallabong enhances immune function and attenuates the inflammatory response. AB - The aim of this study was to investigate the impact of consuming dairy yogurt supplemented with rhamnogalacturonan (RG), a polysaccharide from the peel of the Korean citrus hallabong, on natural killer (NK) cell activity and circulating cytokine levels. A randomized, double-blind, placebo-controlled study was conducted on 120 nondiabetic and nonobese subjects. Over an eight-week period, the test group consumed one pack (150 mL) of dairy yogurt containing 50 mg of probiotics and 100 mg of hallabong peel polysaccharide (60% RG) each day, whereas the placebo group consumed the same product without the hallabong peel supplement. NK cell activity (%) was measured based on the ratios of the effector cells (E; peripheral blood mononuclear cells, PBMCs) from each participant relative to the target cells (T; K562 cells) at E : T ratios of 10 : 1, 5 : 1, 2.5 : 1, or 1.25 : 1. NK cell activities under all assay conditions and interleukin (IL)-12 and interferon (IFN)-gamma levels were significantly increased in the test group at eight weeks compared to the baseline values, whereas the placebo group showed a significant increase only in NK cell activity at E : T = 1.25 : 1. The test group had significantly greater increases in the changes in serum NK cell activity at the E : T ratios of 10 : 1, 5 : 1, and 2.5 : 1 and in the increases in IL-12 and IFN-gamma levels than were observed in the placebo group, after adjusting for baseline values. After eight weeks of treatment, significant reductions were found in IL-6 and IL-1beta levels in both the placebo and test groups. The daily consumption of dairy yogurt supplemented with RG, a polysaccharide from the peel of the Korean citrus hallabong, enhanced NK cell function and attenuated pro-inflammatory cytokine levels (ClinicalTrials.gov: NCT02535663). PMID- 27225730 TI - Levoatriocardinal vein in D-transposition of the great arteries. AB - The levoatriocardinal vein is the embryological remnant of the connection between the pulmonary and systemic venous systems. It is a rare lesion that usually occurs in the presence of left-sided obstruction, developing as a pathway for decompression of the pulmonary veins. We report the first case of a levoatriocardinal vein in a patient with D-transposition of the great arteries. PMID- 27225732 TI - Sequential Right and Left Ventricular Assessment in Posttetralogy of Fallot Patients with Significant Pulmonary Regurgitation. AB - BACKGROUND: The natural history of right ventricular (RV) and left ventricular (LV) size and function among adults with tetralogy of Fallot (TOF) repair and hemodynamically significant pulmonary regurgitation (PR) is not known. The main aim of this study was to determine changes in RV and LV size and function over time in an adult population with TOF repair and hemodynamically significant pulmonary regurgitation. METHODS: Forty patients with repaired TOF and hemodynamically significant PR were included. These patients were identified on the basis of having more than one CMR between January 2008 and 2015. Patients with a prosthetic pulmonary valve or any cardiac intervention between CMR studies were excluded. Rate of progression (ROP) of RV dilation was determined for both indexed right ventricular end-systolic volume (RVESVi) and indexed right ventricular end-diastolic volume (RVEDVi), and calculated as the difference between the last and first volumes divided by the number of years between CMR#1 and CMR#2. Subjects were also divided into two groups based on the distribution of the ROP of RV dilation: Group I-rapid ROP (>50th percentile) and Group II slower ROP (<=50th percentile). RESULTS: The interval between CMR#1 and CMR#2 was 3.9 +/- 1.7 years (range 1-8 years). We did find a significant change in RVEDVi and RVESVi over this time period, although the magnitude of change was small. Nine patients (23%) had a reduction in right ventricular ejection fraction (RVEF) by greater than 5%, 13 patients (33%) had an increase in RVEDVi by greater than 10 mL/m2 and seven patients (18%) had an increase in RVESVi by greater than 10 mL/m2 . Median ROP for RVEDVi was 1.8 (range -10.4 to 21.8) mL/(m2 year); RVESVi 1.1 (range -5.8 to 24.5) mL/(m2 year) and RVEF -0.5 (range -8 to 4)%/year. Patients with a rapid ROP had significantly larger RV volumes at the time of CMR#1 and lower RVEF as compared to the slow ROP group. There was no overall significant change in LVEDVi, LVESVi, or LVEF over this time period. CONCLUSIONS: We have demonstrated, in a small population of patients with hemodynamically significant PR, that there is a small increase in RV volumes and decrease in RVEF over a mean 4-year period. We believe it to be reasonable practice to perform CMR at least every 4 years in asymptomatic patients with repaired TOF and hemodynamically significant PR. We found that LV volumes and function remained stable during the study period, suggesting that significant progressive LV changes are less likely to occur over a shorter time period. Our results inform a safe standardized approach to monitoring adults with hemodynamically significant PR post TOF repair and assist in planning allocation of this expensive and limited resource. PMID- 27225731 TI - SALM5 trans-synaptically interacts with LAR-RPTPs in a splicing-dependent manner to regulate synapse development. AB - Synaptogenic adhesion molecules play critical roles in synapse formation. SALM5/Lrfn5, a SALM/Lrfn family adhesion molecule implicated in autism spectrum disorders (ASDs) and schizophrenia, induces presynaptic differentiation in contacting axons, but its presynaptic ligand remains unknown. We found that SALM5 interacts with the Ig domains of LAR family receptor protein tyrosine phosphatases (LAR-RPTPs; LAR, PTPdelta, and PTPsigma). These interactions are strongly inhibited by the splice insert B in the Ig domain region of LAR-RPTPs, and mediate SALM5-dependent presynaptic differentiation in contacting axons. In addition, SALM5 regulates AMPA receptor-mediated synaptic transmission through mechanisms involving the interaction of postsynaptic SALM5 with presynaptic LAR RPTPs. These results suggest that postsynaptic SALM5 promotes synapse development by trans-synaptically interacting with presynaptic LAR-RPTPs and is important for the regulation of excitatory synaptic strength. PMID- 27225734 TI - Ultrasound guided chronic pain interventions (Part II). AB - Henceforth, ultrasonography (US) is an indispensible imaging technique in regional anesthesia practice. With the guidance of US, various invasive interventions in chronic pain pathologies of the musculoskeletal system, peripheral and neuroaxial pathologies has become possible. The management includes diagnostic blocks as weel as radiofrequency ablation and institution of neurolythic agents. During these algologic interventions we are able to see the target tissue, the dispersion of the drug and all nearby vascular structures. Besides these the US also protects the team from ionic radiation that one encounters when using flouroscopy of computed tomography. Latest publication in this field show that applicability of US in chronic pain syndromes is rapidly expanding with a good future. The additional equipment (echogenic needles, 3-D US etc.) will also expands its applications in algology practice. This review highlights different applications of US in chronic pain conditions. PMID- 27225735 TI - Preventive effect of dexketoprofen on postoperative pain. AB - OBJECTIVES: Preventive analgesia has been defined as reduction in noxious stimuli during preoperative, intraoperative, and postoperative periods. The aim of the present study was to prevent central sensitization by administering ketamine infusion throughout the surgical procedure. In addition, possible preventive effects of dexketoprofen when administered before and after incision were evaluated. METHODS: Fifty patients were included. Group I was administered 50 mg intravenous dexketoprofen prior to surgical incision, and Group II received the same amount 10 minutes after the incision had been made. Following induction of general anesthesia, all patients received a bolus of 0.50 mg/kg ketamine in 0.07 mg/kg/h intravenous infusion. RESULTS: When postoperative visual analog scale values were compared, values for Group I after 1 and 4 hours were significantly lower than those of Group II. In addition, morphine consumption at 4, 8, 12, and 24 hours was significantly lower in Group I. CONCLUSION: Combined with the prevention of central sensitization with ketamine, administration of dexketoprofen prior to incision led to a lower rate of morphine consumption and more effective analgesia than post-incision administration. PMID- 27225733 TI - Human iPSC-derived osteoblasts and osteoclasts together promote bone regeneration in 3D biomaterials. AB - Bone substitutes can be designed to replicate physiological structure and function by creating a microenvironment that supports crosstalk between bone and immune cells found in the native tissue, specifically osteoblasts and osteoclasts. Human induced pluripotent stem cells (hiPSC) represent a powerful tool for bone regeneration because they are a source of patient-specific cells that can differentiate into all specialized cell types residing in bone. We show that osteoblasts and osteoclasts can be differentiated from hiPSC-mesenchymal stem cells and macrophages when co-cultured on hydroxyapatite-coated poly(lactic co-glycolic acid)/poly(L-lactic acid) (HA-PLGA/PLLA) scaffolds. Both cell types seeded on the PLGA/PLLA especially with 5% w/v HA recapitulated the tissue remodeling process of human bone via coupling signals coordinating osteoblast and osteoclast activity and finely tuned expression of inflammatory molecules, resulting in accelerated in vitro bone formation. Following subcutaneous implantation in rodents, co-cultured hiPSC-MSC/-macrophage on such scaffolds showed mature bone-like tissue formation. These findings suggest the importance of coupling matrix remodeling through osteoblastic matrix deposition and osteoclastic tissue resorption and immunomodulation for tissue development. PMID- 27225736 TI - Comparison of education and balneotherapy efficacy in patients with fibromyalgia syndrome: A randomized, controlled clinical study. AB - OBJECTIVES: Fibromyalgia is a disease characterized by chronic, widespread pain. Pharmacological and non-pharmacological treatment methods are used. The aim of the present study was to determine the effect of balneotherapy on treatment of fibromyalgia syndrome, compared with education alone. METHODS: A total of 66 patients diagnosed with fibromyalgia syndrome were randomly separated into balneotherapy and control groups. Patients in both groups were informed about fibromyalgia syndrome. In addition, the balneotherapy group received 21 sessions of spa treatment with 34.8 degrees C thermomineral water, attending the spa 5 days a week. Patients were evaluated by visual analogue scale, tender point count, fibromyalgia impact questioning, and modified fatigue impact scale at initiation of treatment on the 15th day, 1st month, 3rd month, and 6th month. Evaluations were performed by the same doctor. RESULTS: Statistically significant improvement was detected in all parameters, compared to starting evaluation, in both groups. Most improved results among all parameters were observed in the balneotherapy group on the first 3-month follow-up. In addition, all parameters beyond tender point count and modified fatigue impact were improved on 6-month follow-up. CONCLUSION: It was concluded that addition of balneotherapy to patient education has both short- and long-term beneficial effects on female patients with fibromyalgia. PMID- 27225737 TI - Short-term efficacy of joint and soft tissue injections for musculoskeletal pain: An interventional cohort study. AB - OBJECTIVES: Musculoskeletal injections (MIs) are frequently used in conservative treatment-resistant cases. Joint or soft tissue (ST) corticosteroid (CS) or local anesthetic (LA) injections can be used to relieve musculoskeletal pain. Assessed in the present study was the short-term efficacy of MIs for pain relief, as was the relative efficacy of injections in various joint and ST sites. METHODS: An interventional prospective cohort design was employed in the present study. Joint or ST injections for musculoskeletal pathologies were performed in patients over 18 years of age who were resistant to conservative treatment methods. Pain during rest and activity were evaluated using visual analog scale (VAS) by different clinicians prior to treatment and 3 weeks after. At the end of the study, efficacy at 7 injection sites (myofascial trigger points, shoulder, knee, lateral epicondyle, plantar fascia, lumbar, and coccyx regions) was analyzed. RESULTS: Injections were administered to 225 of the 250 patients included. A total of 128 patients, of whom 94 were female, completed the study. Resting VAS values before and after treatment were 4.35+/-1.49 and 1.63+/-1.74, respectively. Activity VAS values before and after treatment were 8.41+/-1.33 and 4.04+/-2.37, respectively. Changes in resting and activity VAS values were significant (p<0.005). Significant reductions in pain were observed at all injection sites following treatment. CONCLUSION: Significant improvement in pain scores was observed 3 weeks after injections among all injection sites. LA or CS injections can be used safely and efficiently for pain relief over short time periods. PMID- 27225738 TI - [Validity and reliability study of sedation diagnosis method comfort scale]. AB - OBJECTIVES: The aim of the present methodological descriptive study was to test the validity and reliability of the COMFORT scale. METHODS: The study was conducted at a pediatric critical care unit at a university hospital between February 2009 and June 2010. Study sample included 84 pediatric patients (n=37) receiving mechanical ventilation. Data were collected via child information form, COMFORT scale, and visual analog scale (VAS). Having been assured of the language and context validity of the scale, researchers conducted reliability tests (Cronbach's alpha coefficient, item analysis), inter- and intra-observer reliability tests, and correlation analyses based on the data obtained during their own observations. RESULTS: Cronbach's alpha coefficient was 0.77. Results of the item analysis indicated that item-total correlations were satisfactorily high. Significance of inter-observer agreement was analyzed for each item, and it was found that weighted kappa values varied between 0.703 and 0.888. Convergent validity tests demonstrated a positive strong correlation between COMFORT scale scores of the primary researcher and the assistant researchers (r= 0.961, p<0.000), and between the scores of the COMFORT scale and the VAS (r= 0.775, p<0.000; r=0.786, p<0.000). CONCLUSION: It was concluded that the COMFORT scale was a valid and reliable method of measuring sedation levels of children receiving mechanical ventilation and being sedated in a pediatric critical care unit. PMID- 27225739 TI - Effects of peroperative intravenous paracetamol and lornoxicam for lumbar disc surgery on postoperative pain and opioid consumption: A randomized, prospective, placebo-controlled study. AB - OBJECTIVES: The aim of the present randomized, placebo-controlled study was to compare postoperative analgesic effects of peroperative paracetamol and lornoxicam administration. METHODS: Sixty adult patients with American Society of Anesthesiologists (ASA) risk classification I-II, who would undergo single-level lumbar discectomy under general anesthesia, were enrolled. Patients were administered either 1000 mg paracetamol (Group P), 8 mg lornoxicam (Group L), or saline (Group C) prior to induction of anesthesia (n=20 for all groups). All patients were administered the same anesthesia induction and maintainance. Postoperative analgesia was maintained with the same analgesic drug in each group. Rescue analgesia was supplied with intravenous meperidine delivered by a patient-controlled analgesia device. Numeric rating score (NRS) results, first analgesic demand time, and cumulative meperidine consumption were recorded postoperatively. Primary outcome was NRS at first postoperative hour. Secondary outcome was measure of opioid consumption during first 24 postoperative hours. RESULTS: At first postoperative hour, NRS of Group L [4 (0-8)] was lower than NRSs of Groups P and C [6(0-7); 6(0-9), respectively; p<0.016]. Time to first analgesic demand of Group L was longer, compared with those of the other groups (p<0.016). Cumulative postoperative meperidine consumption in Group L was less than those of Groups P and C at 2-, 12-, and 24-hour time intervals (p<0.016), while Groups P and C had similar findings for the same time intervals. CONCLUSION: Preoperative lornoxicam administration decreased early postoperative pain scores more effectively than paracetamol. PMID- 27225740 TI - Two cases of primary stabbing headache. AB - Primary stabbing headache is an excruciating and relatively rare type of headache that typically lasts for only a few seconds. Pain is predominantly felt in the distribution of the first division of the trigeminal nerve and can be experienced as single stabs or as a series of stabs, either per day or every few days. Primary stabbing headache has been well-defined for decades and must be kept in mind during diagnosis. Exclusion of other possible causes is necessary in order to establish diagnosis. Indomethacin has classically been considered the first treatment option, but therapeutic failure occurs in up to 35% of cases. Recent studies have suggested that cyclooxygenase-2 inhibitors, gabapentin, nifedipine, paracetamol, and melatonin are also effective treatments. PMID- 27225742 TI - [Application of spinal anesthesia in a pediatric patient with Duchenne's muscular dystrophy]. AB - Duchenne's muscular dystrophy (DMD) is a neuromuscular disease with a progressive course. It is the most common and most severe muscular dystrophic disorder for which the application of anesthesia is critical, due to muscle weakness, and cardiac and pulmonary involvement. Successful application of spinal anesthesia in a 2-year-old boy with DMD undergoing bilateral inguinal hernia repair is described in the present report. It is proposed that spinal anesthesia is an effective alternative to general anesthesia in certain pediatric patients, including those with DMD, for whom general anesthesia poses increased risk. PMID- 27225741 TI - [A case of painful legs and moving toes syndrome treated with gabapentin]. AB - A 58-year-old woman was evaluated following complaints of pain in both lower extremities and brief involuntary movements in her toes, which had begun 2 years prior. No signs were present beyond a curling, flexion/extension, abduction/adduction movement in the toes of both lower extremities, voluntarily stoppable during neurologic examination. During investigation into etiology, lumbar vertebrae MRI revealed a posterior annular protrusion causing partial compression of the dural sac and neural elements by the L3-4 and L4-5 discs. Semirhythmic repetitious movements were detected on electromyography performed on right extensor digitorum brevis (EDB) muscle with 200 mV and 1 Hz frequency. Patient was put on a gradually increased dose of gabapentin, starting at 1200 mg/day. A brief regression in pain and involuntary movements in feet and toes was observed. GABAergic agents are very effective treatment of painful legs and moving toes syndrome. The present clinically and electrophysiologically diagnosed case was considered worth reporting, as painful legs and moving toes syndrome is a very rare condition. PMID- 27225743 TI - [Cluster-like headache due to metformin therapy]. PMID- 27225744 TI - [A case of drug-resistant chronic cluster headache who response pregabalin]. PMID- 27225745 TI - Transverse-electric plasmonic modes of cylindrical graphene-based waveguide at near-infrared and visible frequencies. AB - Transverse-electric (TE) surface plasmons (SPs) are very unusual for plasmonics phenomenon. Graphene proposes a unique possibility to observe these plasmons. Due to transverse motion of carriers, TE SPs speed is usually close to bulk light one. In this work we discuss conditions of TE SPs propagation in cylindrical graphene-based waveguides. We found that the negativity of graphene conductivity's imaginary part is not a sufficient condition. The structure supports TE SPs when the core radius of waveguide is larger than the critical value Rcr. Critical radius depends on the light frequency and the difference of permittivities inside and outside the waveguide. Minimum value of Rcr is comparable with the wavelength of volume wave and corresponds to interband carriers transition in graphene. We predict that use of multilayer graphene will lead to decrease of critical radius. TE SPs speed may differ more significantly from bulk light one in case of epsilon-near-zero core and shell of the waveguide. Results may open the door for practical applications of TE SPs in optics, including telecommunications. PMID- 27225746 TI - Nitrogen stable isotopes reveal age-dependent dietary shift in the Japanese scallop Mizuhopecten yessoensis. AB - Ontogenetic niche shifts in diet are a consequence of changes in body size or resource partitioning between age classes. To better resolve the feeding patterns of the Japanese scallop Mizuhopecten yessoensis, we examined the relative importance of age and size in the diet of this species using stable isotope ratios of carbon (delta13C) and nitrogen (delta15N) from 2006 to 2009. Contribution of food sources was quantified using an isotope mixing model by comparing the muscle tissue isotope ratios to those of suspended particulate organic matter (SPOM) and their zooplankton prey (e.g. micro- and meso zooplankton). Unlike the delta13C values, which remained constant with age and size, muscle delta15N values were more positively correlated with age accounting for 69 % of variations than size with only 46 %. Increasing 15N values with age suggested that shifts in diet from SPOM to micro- and meso-zooplankton occurred during ontogeny in M. yessoensis. Results of the isotope mixing model indicated that SPOM contribution to scallop's diet decreased from 68 to 8 % while those of zooplankton increased from 15 to 50 % with increasing age. This study concludes that age-related dietary shift explains the enrichment of 15N, as a result of predation on zooplankton by M. yessoensis. PMID- 27225747 TI - Decreased Morphine Clearance in Neonates With Hypoxic Ischemic Encephalopathy Receiving Hypothermia. AB - Morphine is commonly used in neonates with hypothermic ischemic encephalopathy (HIE) during therapeutic hypothermia to provide comfort and analgesia. However, pharmacokinetic data to support morphine dosing in this vulnerable population are lacking. A prospective, 2-center clinical pharmacokinetic study of morphine was conducted in 20 neonates (birthweight, 1.82-5.3 kg) with HIE receiving hypothermia. Morphine dosing was per standard of care at each center. Morphine and glucuronide metabolites (morphine-3-glucuronide and morphine-6-gluronide) were measured via a validated dried blood spot liquid chromatography-tandem mass spectrometry assay. From the available concentration data (n = 106 for morphine; n = 106 for each metabolite), a population pharmacokinetic model was developed using nonlinear mixed-effects modeling. The clearance of morphine and glucuronide metabolites was best predicted by birthweight allometrically scaled using an exponent of 1.23. In addition, the clearance of each glucuronide metabolite was influenced by serum creatinine. No other significant predictors of clearance or volume of distribution were found. For a 3.5-kg neonate, morphine clearance was 0.77 L/h (CV, 48%), and the steady-state volume of distribution was 8.0 L (CV, 49%). Compared with previous studies in full-term newborns without HIE, morphine clearance was markedly lower. Dosing strategies customized for this vulnerable population will be needed. Applying the final population pharmacokinetic model, repeated Monte Carlo simulations (n = 1000 per simulation) were performed to evaluate various morphine dosing strategies that optimized achievement of morphine concentrations between 10 and 40 ng/mL. An optimized morphine loading dose of 50 MUg/kg followed by a continuous infusion of 5 MUg/kg/h was predicted across birthweights. PMID- 27225748 TI - Comment on "efficacy and safety of skeletonized mesh implants for advanced pelvic organ prolapse: 12 month follow up". PMID- 27225749 TI - Immunohistochemical Expression and Serum Levels of CD44 as Prognostic Indicators in Patients with Non-Small Cell Lung Cancer. AB - BACKGROUND/OBJECTIVES: CD44 is often expressed in various types of tumor cells and involved in a number of biological behaviors of malignancy. The present study focused on the clinical significance of the expression of CD44st and CD44v6 in non-small cell lung cancer (NSCLC). METHODS: The cohort consisted of 261 consecutive patients who had undergone complete resection of NSCLC. CD44 expression was evaluated in surgical specimens by immunohistochemical staining. Serum CD44 levels were determined using a sandwich ELISA (enzyme-linked immunosorbent assay). RESULTS: In the immunohistochemical analysis, significant correlations were observed between CD44 expression and clinicopathological factors such as the T factor, N factor, pathological stage, and histological type. The 5-year survival rates according to CD44v6 expression were 65.8 and 80.6% in the higher and lower expression groups, respectively (p = 0.0053). According to ELISA, the group with higher expression of serum CD44v6 also showed a significantly more unfavorable prognosis than the lower expression group (p = 0.014). According to multivariate analysis using these significant variables, serum CD44v6 level was found to be an independent prognostic factor (p = 0.048). CONCLUSIONS: CD44v6 overexpression and higher serum CD44v6 levels were found to be significantly unfavorable prognostic factors. PMID- 27225750 TI - Outcomes of thoracoscopic esophagectomy in prone position with laparoscopic gastric mobilization for esophageal cancer. AB - PURPOSE: The aim of this study was to evaluate the short- and long-term outcomes of thoracoscopic esophagectomy performed in the prone position (TSE-PP) followed by laparoscopic gastric mobilization (LGM) compared with open thoracotomy and LGM, for esophageal cancers. METHODS: We reviewed the records of 105 consecutive patients who underwent esophagectomy with LGM for esophageal cancer at Kochi Medical School. Among the study patients, 60 patients underwent TSE-PP, while 45 underwent open thoracotomy (OPEN group). The perioperative outcomes of the two groups were compared. RESULTS: Compared to the OPEN group, the TSE-PP group had lower blood loss (TSE-PP, 150 mL; OPEN, 430 mL; P < 0.001), longer operative time (TSE-PP, 609 min; OPEN, 570 min; P = 0.012), more lymph nodes dissected around the left recurrent laryngeal nerve (TSE-PP, 6; OPEN, 2; P < 0.001), and a shorter length of hospital stay (TSE-PP, 16.5 days; OPEN, 35 days; P < 0.001). The incidence of postoperative complications was similar in the two groups. Though the recurrence rate and overall survival were not significantly different in the two groups, the TSE-PP group had better overall survival rates than the OPEN group (P = 0.122). CONCLUSIONS: Patients who underwent TSE-PP with LGM for esophageal cancers recovered earlier after surgery compared to those who underwent open thoracotomy with LGM. PMID- 27225751 TI - The distribution pattern of ERalpha expression, ESR1 genetic variation and expression of growth factor receptors: association with breast cancer prognosis in Russian patients treated with adjuvant tamoxifen. AB - Identification of additional biomarkers associated with ER genomic and nongenomic pathways could be very useful to distinguish patients who will benefit from tamoxifen treatment. The aim of this study was to analyze the prognostic significance of the distribution pattern of ERalpha expression, ESR1 gene single nucleotide polymorphisms and expression levels of growth factor receptors in Russian hormone receptor-positive breast cancer patients treated with adjuvant tamoxifen. Formalin-fixed paraffin-embedded tumor tissue samples from 97 patients were examined for the distribution pattern of ERalpha expression, as well as for EGFR and TGF-betaR1 expression by immunohistochemistry. Genotypes for ESR1 +30T>C (rs2077647) and ESR1 2014G>A (rs2228480) were analyzed using a TaqMan assay. Progression-free survival (PFS) was used as an endpoint for the survival analyses. We found that patients with the heterogeneous distribution of ERalpha expression had poor prognosis on tamoxifen treatment (P = 0.021). We identified a high EGFR expression in patients who developed distant metastasis or recurrence during tamoxifen treatment (a tamoxifen-resistant group-TR) in contrast to the distant metastasis-free patients (a tamoxifen-sensitive group-TS) (80.0 vs. 41.9 %, respectively, P = 0.009). Carriers of the ESR12014A mutant allele were more prevalent among the TR patients compared to the TS patients (26.3 vs. 8.0 %, respectively, P = 0.009). EGFR expression and the distribution pattern of ERalpha expression were associated with the response to tamoxifen by both univariate and multivariate logistic regression analyses. The presence of these markers either alone or in combination was correlated with the worse PFS for all patients. Analysis of the distribution pattern of ERalpha expression and the EGFR status in tumor tissue may be valuable for patient selection for tamoxifen adjuvant therapy. PMID- 27225752 TI - Climatic conditions, twining and frequency of milking as factors affecting the risk of fetal losses in high-yielding Holstein cows in a hot environment. AB - An epidemiological study of risk factors for fetal losses was carried out on 62,403 high-yielding Holstein cows in 29 large highly technified dairy herds in northern Mexico (25 degrees N; 23.5 degrees C mean annual temperature). Multivariate multiple-group response model indicated that fetal losses between 43 and 260 days of pregnancy were 23 %. Heat-stressed cows at conception (temperature-humidity index, THI >82) were 14 times more likely (P < 0.01) to present fetal losses than not heat-stressed cows (27 vs. 18 %). Heat-stressed cows at 60 days of pregnancy (THI >82) were 4.5 times more likely (P < 0.01) to present fetal losses than cows suffering heat stress in early gestation (29.1 vs. 17.7 %). The proportion of cows experiencing fetal loss was lower for multiparous than primiparous cows (odds ratio; OR = 0.7). Cows with twin pregnancies had significantly increased chances of losing their fetuses than cows with a single fetus (33.6 vs. 20.7 %; P < 0.01). Cows with three milkings per day were 30 % more likely (P < 0.01) to lose their fetuses than cows milked twice daily. Cows calving in winter and spring had significantly increased chances of losing their fetuses than cows calving in summer and fall (30-35 vs. 4-5 %; P < 0.01). It was concluded that, in this particular environment, heat stress exert a great influence on fetal losses in high producing Holstein cows. PMID- 27225753 TI - A Metabolic Gene Cluster in the Wheat W1 and the Barley Cer-cqu Loci Determines beta-Diketone Biosynthesis and Glaucousness. AB - The glaucous appearance of wheat (Triticum aestivum) and barley (Hordeum vulgare) plants, that is the light bluish-gray look of flag leaf, stem, and spike surfaces, results from deposition of cuticular beta-diketone wax on their surfaces; this phenotype is associated with high yield, especially under drought conditions. Despite extensive genetic and biochemical characterization, the molecular genetic basis underlying the biosynthesis of beta-diketones remains unclear. Here, we discovered that the wheat W1 locus contains a metabolic gene cluster mediating beta-diketone biosynthesis. The cluster comprises genes encoding proteins of several families including type-III polyketide synthases, hydrolases, and cytochrome P450s related to known fatty acid hydroxylases. The cluster region was identified in both genetic and physical maps of glaucous and glossy tetraploid wheat, demonstrating entirely different haplotypes in these accessions. Complementary evidence obtained through gene silencing in planta and heterologous expression in bacteria supports a model for a beta-diketone biosynthesis pathway involving members of these three protein families. Mutations in homologous genes were identified in the barley eceriferum mutants defective in beta-diketone biosynthesis, demonstrating a gene cluster also in the beta diketone biosynthesis Cer-cqu locus in barley. Hence, our findings open new opportunities to breed major cereal crops for surface features that impact yield and stress response. PMID- 27225756 TI - An 8-Month Systems Toxicology Inhalation/Cessation Study in Apoe-/- Mice to Investigate Cardiovascular and Respiratory Exposure Effects of a Candidate Modified Risk Tobacco Product, THS 2.2, Compared With Conventional Cigarettes. PMID- 27225754 TI - Brain metastases as site of first and isolated recurrence of breast cancer: the role of systemic therapy after local treatment. AB - The role of systemic treatment was assessed after local therapy for breast cancer patients who developed central nervous system (CNS) metastases as a first and isolated recurrence. Subjects were 128 breast cancer patients with brain metastases as the first and isolated site of recurrence that were selected from 673 consecutive breast cancer patients with brain metastases treated at the same institution. Median survival from brain metastases in patients with and without systemic treatment after local therapy was respectively 15 and 4 months (p < 0.001). In patients with a Karnofsky Performance Status >=70 and those <70, survival was respectively 16 and 5.5 months (p < 0.001). The median survival from brain metastasis in patients with solitary brain metastasis, with and without systemic treatment after local therapy, was respectively 22 and 7 months (p = 0.003). Cox multivariate analysis demonstrated that good performance status, solitary brain metastasis and systemic therapy undertaken after local treatment were factors which prolonged survival. However patient survival was adversely affected by those having leptomeningeal metastasis associated with brain parenchymal lesions. Systemic therapy, undertaken after local treatment improved survival in those patients with breast cancer and brain metastases as the site of first and isolated recurrence. Further study is required in order to fully establish the role of systemic treatment for this patient group. PMID- 27225757 TI - Further Insight into the Brain's Rich-Club Architecture. PMID- 27225758 TI - Dissecting the Role of P/Q-Type Calcium Channels in Corticothalamic Circuit Dysfunction and Absence Epilepsy. PMID- 27225759 TI - AChRs Are Essential for the Targeting of Rapsyn to the Postsynaptic Membrane of NMJs in Living Mice. AB - Rapsyn, a 43 kDa scaffold protein, is required for the clustering of acetylcholine receptors (AChRs) at synaptic sites between mammalian motor neurons and muscle cells. However, the mechanism by which rapsyn is inserted and retained at postsynaptic sites at the neuromuscular junction (NMJ) in vivo remains largely unknown. We found that neither the N-terminal myristoylation nor the cysteine rich RING H2 domain of rapsyn is required for its stable association with the postsynaptic membrane of NMJs. When N-myristoylation-defective rapsyn-EGFP mutant (G2A) and RING-H2 domain truncated rapsyn-EGFP were electroporated into sternomastoid muscles, a strong rapsyn fluorescent signal was observed selectively at synapses, similar to WT rapsyn-EGFP. The targeting of rapsyn-EGFP (WT and mutants) is independent of synaptic activity because they were inserted at denervated NMJs. However, when the coiled-coil domain (the AChR-binding domain of rapsyn) is deleted, rapsyn fails to associate with AChRs at NMJs of living mice. In cultured myoblasts (in which AChRs are absent), myristoylated WT rapsyn mostly localizes to lysosomes and is not associated with the plasma membrane. However, in the presence of AChR subunits, rapsyn molecules were targeted to the cell surface and formed aggregates with AChRs. The targeting of AChRs to the cell membrane, in contrast, does not require rapsyn because expressed AChRs are visible on the cell membranes of rapsyn-deficient myoblasts. These results provide evidence for an active role of AChRs in the targeting of rapsyn to the NMJ in vivo SIGNIFICANCE STATEMENT: Rapsyn is required for the clustering of acetylcholine receptors (AChRs) at postsynaptic sites. However, the mechanism by which rapsyn is targeted to synaptic sites at the vertebrate neuromuscular junction remains unclear. In this study, we showed that the coiled-coil domain of rapsyn is required for its targeting to the cell surface via its interaction with AChRs. In contrast, the targeting of AChRs to the cell membrane does not require rapsyn. These results indicate that AChRs play a critical role in the insertion and/or association of rapsyn with the plasma membrane of synaptic sites. PMID- 27225760 TI - Loss of Homeostasis in the Direct Pathway in a Mouse Model of Asymptomatic Parkinson's Disease. AB - The characteristic slowness of movement in Parkinson's disease relates to an imbalance in the activity of striatal medium spiny neurons (MSNs) of the direct (dMSNs) and indirect (iMSNs) pathways. However, it is still unclear whether this imbalance emerges during the asymptomatic phase of the disease or if it correlates with symptom severity. Here, we have used in vivo juxtacellular recordings and transgenic mice showing MSN-type-specific expression of fluorescent proteins to examine striatal imbalance after lesioning dopaminergic neurons of the substantia nigra. Multivariate clustering analysis of behavioral data discriminated 2 groups of dopamine-lesioned mice: asymptomatic (42 +/- 7% dopaminergic neuron loss) and symptomatic (85 +/- 5% cell loss). Contrary to the view that both pathways have similar gain in control conditions, dMSNs respond more intensely than iMSNs to cortical inputs in control animals. Importantly, asymptomatic mice show significant functional disconnection of dMSNs from motor cortex without changes in iMSN connectivity. Moreover, not only the gain but also the timing of the pathways is altered in symptomatic parkinsonism, where iMSNs fire significantly more and earlier than dMSNs. Therefore, cortical drive to dMSNs decreases after partial nigrostriatal lesions producing no behavioral impairment, but additional alterations in the gain and timing of iMSNs characterize symptomatic rodent parkinsonism. SIGNIFICANCE STATEMENT: Prevailing models of Parkinson's disease state that motor symptoms arise from an imbalance in the activity of medium spiny neurons (MSNs) from the direct (dMSNs) and indirect (iMSNs) pathways. Therefore, it is hypothesized that symptom severity and the magnitude of this imbalanced activity are correlated. Using a mouse model of Parkinson's disease, we found that behaviorally undetectable nigrostriatal lesions induced a significant disconnection of dMSNs from the motor cortex. In contrast, iMSNs show an increased connectivity with the motor cortex, but only after a severe dopaminergic lesion associated with an evident parkinsonian syndrome. Overall, our data suggest that the lack of symptoms after a partial dopaminergic lesion is not due to compensatory mechanisms maintaining the activity of both striatal pathways balanced. PMID- 27225761 TI - Catecholamine-Mediated Increases in Gain Enhance the Precision of Cortical Representations. AB - Neurophysiological evidence suggests that neuromodulators, such as norepinephrine and dopamine, increase neural gain in target brain areas. Computational models and prominent theoretical frameworks indicate that this should enhance the precision of neural representations, but direct empirical evidence for this hypothesis is lacking. In two functional MRI studies, we examine the effect of baseline catecholamine levels (as indexed by pupil diameter and manipulated pharmacologically) on the precision of object representations in the human ventral temporal cortex using angular dispersion, a powerful, multivariate metric of representational similarity (precision). We first report the results of computational model simulations indicating that increasing catecholaminergic gain should reduce the angular dispersion, and thus increase the precision, of object representations from the same category, as well as reduce the angular dispersion of object representations from distinct categories when distinct-category representations overlap. In Study 1 (N = 24), we show that angular dispersion covaries with pupil diameter, an index of baseline catecholamine levels. In Study 2 (N = 24), we manipulate catecholamine levels and neural gain using the norepinephrine transporter blocker atomoxetine and demonstrate consistent, causal effects on angular dispersion and brain-wide functional connectivity. Despite the use of very different methods of examining the effect of baseline catecholamine levels, our results show a striking convergence and demonstrate that catecholamines increase the precision of neural representations. SIGNIFICANCE STATEMENT: Norepinephrine and dopamine are among the most widely distributed and ubiquitous neuromodulators in the mammalian brain and have a profound and pervasive impact on cognition. Baseline catecholamine levels tend to increase with increasing task engagement in tasks involving perceptual decisions, yet there is currently no direct evidence of the specific impact of these increases in catecholamine levels on perceptual encoding. Our results fill this void by showing that catecholamines enhance the precision of encoding cortical object representations, and by suggesting that this effect is mediated by increases in neural gain, thus offering a mechanistic account of our key finding. PMID- 27225762 TI - Optogenetic Visualization of Presynaptic Tonic Inhibition of Cerebellar Parallel Fibers. AB - Tonic inhibition was imaged in cerebellar granule cells of transgenic mice expressing the optogenetic chloride indicator, Clomeleon. Blockade of GABAA receptors substantially reduced chloride concentration in granule cells due to block of tonic inhibition. This indicates that tonic inhibition is a significant contributor to the resting chloride concentration of these cells. Tonic inhibition was observed not only in granule cell bodies, but also in their axons, the parallel fibers (PFs). This presynaptic tonic inhibition could be observed in slices both at room and physiological temperatures, as well as in vivo, and has many of the same properties as tonic inhibition measured in granule cell bodies. GABA application revealed that PFs possess at least two types of GABAA receptor: one high-affinity receptor that is activated by ambient GABA and causes a chloride influx that mediates tonic inhibition, and a second with a low affinity for GABA that causes a chloride efflux that excites PFs. Presynaptic tonic inhibition regulates glutamate release from PFs because GABAA receptor blockade enhanced both the frequency of spontaneous EPSCs and the amplitude of evoked EPSCs at the PF-Purkinje cell synapse. We conclude that tonic inhibition of PFs could play an important role in regulating information flow though cerebellar synaptic circuits. Such cross talk between phasic and tonic signaling could be a general mechanism for fine tuning of synaptic circuits. SIGNIFICANCE STATEMENT: This paper demonstrates that an unconventional form of signaling, known as tonic inhibition, is found in presynaptic terminals and affects conventional synaptic communication. Our results establish the basic characteristics and mechanisms of presynaptic tonic inhibition and show that it occurs in vivo as well as in isolated brain tissue. PMID- 27225763 TI - Synapse Formation in Monosynaptic Sensory-Motor Connections Is Regulated by Presynaptic Rho GTPase Cdc42. AB - Spinal reflex circuit development requires the precise regulation of axon trajectories, synaptic specificity, and synapse formation. Of these three crucial steps, the molecular mechanisms underlying synapse formation between group Ia proprioceptive sensory neurons and motor neurons is the least understood. Here, we show that the Rho GTPase Cdc42 controls synapse formation in monosynaptic sensory-motor connections in presynaptic, but not postsynaptic, neurons. In mice lacking Cdc42 in presynaptic sensory neurons, proprioceptive sensory axons appropriately reach the ventral spinal cord, but significantly fewer synapses are formed with motor neurons compared with wild-type mice. Concordantly, electrophysiological analyses show diminished EPSP amplitudes in monosynaptic sensory-motor circuits in these mutants. Temporally targeted deletion of Cdc42 in sensory neurons after sensory-motor circuit establishment reveals that Cdc42 does not affect synaptic transmission. Furthermore, addition of the synaptic organizers, neuroligins, induces presynaptic differentiation of wild-type, but not Cdc42-deficient, proprioceptive sensory neurons in vitro Together, our findings demonstrate that Cdc42 in presynaptic neurons is required for synapse formation in monosynaptic sensory-motor circuits. SIGNIFICANCE STATEMENT: Group Ia proprioceptive sensory neurons form direct synapses with motor neurons, but the molecular mechanisms underlying synapse formation in these monosynaptic sensory-motor connections are unknown. We show that deleting Cdc42 in sensory neurons does not affect proprioceptive sensory axon targeting because axons reach the ventral spinal cord appropriately, but these neurons form significantly fewer presynaptic terminals on motor neurons. Electrophysiological analysis further shows that EPSPs are decreased in these mice. Finally, we demonstrate that Cdc42 is involved in neuroligin-dependent presynaptic differentiation of proprioceptive sensory neurons in vitro These data suggest that Cdc42 in presynaptic sensory neurons is essential for proper synapse formation in the development of monosynaptic sensory-motor circuits. PMID- 27225764 TI - Similarity in Neuronal Firing Regimes across Mammalian Species. AB - The architectonic subdivisions of the brain are believed to be functional modules, each processing parts of global functions. Previously, we showed that neurons in different regions operate in different firing regimes in monkeys. It is possible that firing regimes reflect differences in underlying information processing, and consequently the firing regimes in homologous regions across animal species might be similar. We analyzed neuronal spike trains recorded from behaving mice, rats, cats, and monkeys. The firing regularity differed systematically, with differences across regions in one species being greater than the differences in similar areas across species. Neuronal firing was consistently most regular in motor areas, nearly random in visual and prefrontal/medial prefrontal cortical areas, and bursting in the hippocampus in all animals examined. This suggests that firing regularity (or irregularity) plays a key role in neural computation in each functional subdivision, depending on the types of information being carried. SIGNIFICANCE STATEMENT: By analyzing neuronal spike trains recorded from mice, rats, cats, and monkeys, we found that different brain regions have intrinsically different firing regimes that are more similar in homologous areas across species than across areas in one species. Because different regions in the brain are specialized for different functions, the present finding suggests that the different activity regimes of neurons are important for supporting different functions, so that appropriate neuronal codes can be used for different modalities. PMID- 27225765 TI - Nucleus Accumbens AMPA Receptors Are Necessary for Morphine-Withdrawal-Induced Negative-Affective States in Rats. AB - Dependence is a hallmark feature of opiate addiction and is defined by the emergence of somatic and affective withdrawal signs. The nucleus accumbens (NAc) integrates dopaminergic and glutamatergic inputs to mediate rewarding and aversive properties of opiates. Evidence suggests that AMPA glutamate-receptor dependent synaptic plasticity within the NAc underlies aspects of addiction. However, the degree to which NAc AMPA receptors (AMPARs) contribute to somatic and affective signs of opiate withdrawal is not fully understood. Here, we show that microinjection of the AMPAR antagonist NBQX into the NAc shell of morphine dependent rats prevented naloxone-induced conditioned place aversions and decreases in sensitivity to brain stimulation reward, but had no effect on somatic withdrawal signs. Using a protein cross-linking approach, we found that the surface/intracellular ratio of NAc GluA1, but not GluA2, increased with morphine treatment, suggesting postsynaptic insertion of GluA2-lacking AMPARs. Consistent with this, 1-naphthylacetyl spermine trihydrochloride (NASPM), an antagonist of GluA2-lacking AMPARs, attenuated naloxone-induced decreases in sensitivity to brain stimulation reward. Naloxone decreased the surface/intracellular ratio and synaptosomal membrane levels of NAc GluA1 in morphine-dependent rats, suggesting a compensatory removal of AMPARs from synaptic zones. Together, these findings indicate that chronic morphine increases synaptic availability of GluA1-containing AMPARs in the NAc, which is necessary for triggering negative-affective states in response to naloxone. This is broadly consistent with the hypothesis that activation of NAc neurons produces acute aversive states and raises the possibility that inhibiting AMPA transmission selectively in the NAc may have therapeutic value in the treatment of addiction. SIGNIFICANCE STATEMENT: Morphine dependence and withdrawal result in profound negative-affective states that play a major role in the maintenance of addiction. However, the underlying neurobiological mechanisms are not fully understood. We use a rat model of morphine dependence to show that GluA1 subunits of AMPA glutamate receptors in the nucleus accumbens (NAc), a brain region critical for modulating affective states, are necessary for aversive effects of morphine withdrawal. Using biochemical methods in NAc tissue, we show that morphine dependence increases cell surface expression of GluA1, suggesting that neurons in this area are primed for increased AMPA receptor activation upon withdrawal. This work is important because it suggests that targeting AMPA receptor trafficking and activation could provide novel targets for addiction treatment. PMID- 27225766 TI - Multivariate Patterns in the Human Object-Processing Pathway Reveal a Shift from Retinotopic to Shape Curvature Representations in Lateral Occipital Areas, LO-1 and LO-2. AB - Representations in early visual areas are organized on the basis of retinotopy, but this organizational principle appears to lose prominence in the extrastriate cortex. Nevertheless, an extrastriate region, such as the shape-selective lateral occipital cortex (LO), must still base its activation on the responses from earlier retinotopic visual areas, implying that a transition from retinotopic to "functional" organizations should exist. We hypothesized that such a transition may lie in LO-1 or LO-2, two visual areas lying between retinotopically defined V3d and functionally defined LO. Using a rapid event-related fMRI paradigm, we measured neural similarity in 12 human participants between pairs of stimuli differing along dimensions of shape exemplar and shape complexity within both retinotopically and functionally defined visual areas. These neural similarity measures were then compared with low-level and more abstract (curvature-based) measures of stimulus similarity. We found that low-level, but not abstract, stimulus measures predicted V1-V3 responses, whereas the converse was true for LO, a double dissociation. Critically, abstract stimulus measures were most predictive of responses within LO-2, akin to LO, whereas both low-level and abstract measures were predictive for responses within LO-1, perhaps indicating a transitional point between those two organizational principles. Similar transitions to abstract representations were not observed in the more ventral stream passing through V4 and VO-1/2. The transition we observed in LO-1 and LO-2 demonstrates that a more "abstracted" representation, typically considered the preserve of "category-selective" extrastriate cortex, can nevertheless emerge in retinotopic regions. SIGNIFICANCE STATEMENT: Visual areas are typically identified either through retinotopy (e.g., V1-V3) or from functional selectivity [e.g., shape-selective lateral occipital complex (LOC)]. We combined these approaches to explore the nature of shape representations through the visual hierarchy. Two different representations emerged: the first reflected low-level shape properties (dependent on the spatial layout of the shape outline), whereas the second captured more abstract curvature-related shape features. Critically, early visual cortex represented low-level information but this diminished in the extrastriate cortex (LO-1/LO-2/LOC), in which the abstract representation emerged. Therefore, this work further elucidates the nature of shape representations in the LOC, provides insight into how those representations emerge from early retinotopic cortex, and crucially demonstrates that retinotopically tuned regions (LO-1/LO-2) are not necessarily constrained to retinotopic representations. PMID- 27225767 TI - Sox11 Balances Dendritic Morphogenesis with Neuronal Migration in the Developing Cerebral Cortex. AB - The coordinated mechanisms balancing promotion and suppression of dendritic morphogenesis are crucial for the development of the cerebral cortex. Although previous studies have revealed important transcription factors that promote dendritic morphogenesis during development, those that suppress dendritic morphogenesis are still largely unknown. Here we found that the expression levels of the transcription factor Sox11 decreased dramatically during dendritic morphogenesis. Our loss- and gain-of-function studies using postnatal electroporation and in utero electroporation indicate that Sox11 is necessary and sufficient for inhibiting dendritic morphogenesis of excitatory neurons in the mouse cerebral cortex during development. Interestingly, we found that precocious suppression of Sox11 expression caused precocious branching of neurites and a neuronal migration defect. We also found that the end of radial migration induced the reduction of Sox11 expression. These findings indicate that suppression of dendritic morphogenesis by Sox11 during radial migration is crucial for the formation of the cerebral cortex. SIGNIFICANCE STATEMENT: Because dendritic morphology has profound impacts on neuronal information processing, the mechanisms underlying dendritic morphogenesis during development are of great interest. Our loss- and gain-of-function studies indicate that Sox11 is necessary and sufficient for inhibiting dendritic morphogenesis of excitatory neurons in the mouse cerebral cortex during development. Interestingly, we found that precocious suppression of Sox11 expression caused a neuronal migration defect. These findings indicate that suppression of dendritic morphogenesis by Sox11 during radial migration is crucial for the formation of the cerebral cortex. PMID- 27225768 TI - Tau Accumulation, Altered Phosphorylation, and Missorting Promote Neurodegeneration in Glaucoma. AB - Glaucoma, the leading cause of irreversible blindness worldwide, is characterized by the selective death of retinal ganglion cells (RGCs). Ocular hypertension is the most significant known risk factor for developing the disease, but the mechanism by which elevated pressure damages RGCs is currently unknown. The axonal-enriched microtubule-associated protein tau is a key mediator of neurotoxicity in Alzheimer's disease and other tauopathies. Using a well characterized in vivo rat glaucoma model, we show an age-related increase in endogenous retinal tau that was markedly exacerbated by ocular hypertension. Early alterations in tau phosphorylation, characterized by epitope-dependent hyperphosphorylation and hypophosphorylation, correlated with the appearance of tau oligomers in glaucomatous retinas. Our data demonstrate the mislocalization of tau in the somatodendritic compartment of RGCs subjected to high intraocular pressure. In contrast, tau was depleted from RGC axons in the optic nerve of glaucomatous eyes. Importantly, intraocular administration of short interfering RNA against tau effectively reduced retinal tau accumulation and promoted robust survival of RGC somas and axons, supporting a critical role for tau alterations in ocular hypertension-induced neuronal damage. Our study reveals that glaucoma displays signature pathological features of tauopathies, including tau accumulation, altered phosphorylation, and missorting; and identifies tau as a novel target to counter RGC neurodegeneration in glaucoma and prevalent optic neuropathies. SIGNIFICANCE STATEMENT: In this study, we investigated the role of tau in retinal ganglion cell (RGC) damage in glaucoma. We demonstrate that high intraocular pressure leads to a rapid increase in endogenous retinal tau with altered phosphorylation profile and the formation of tau oligomers. Tau accumulation was primarily observed in RGC dendrites, while tau in RGC axons within the optic nerve was depleted. Attenuation of endogenous retinal tau using a targeted siRNA led to striking protection of RGC somas and axons from hypertension-induced damage. Our study identifies novel and substantial alterations of endogenous tau protein in glaucoma, including abnormal subcellular distribution, an altered phosphorylation profile, and neurotoxicity. PMID- 27225769 TI - Irregular Firing and High-Conductance States in Spinal Motoneurons during Scratching and Swimming. AB - Intense synaptic transmission during scratch network activity increases conductance and induces irregular firing in spinal motoneurons. It is not known whether this high-conductance state is a select feature for scratching or a property that goes with spinal motor network activity in general. Here we compare conductance and firing patterns in spinal motoneurons during network activity for scratching and swimming in an ex vivo carapace-spinal cord preparation from adult turtles (Trachemys scripta elegans). The pattern and relative engagement of motoneurons are distinctly different in scratching and swimming. Nevertheless, we found increased synaptic fluctuations in membrane potential, irregular firing, and increased conductance in spinal motoneurons during scratch and swim network activity. Our finding indicates that intense synaptic activation of motoneurons is a general feature of spinal motor network activity. SIGNIFICANCE STATEMENT: Neurons embedded in active neural networks can enter high-conductance states with irregular firing. This was previously shown for spinal motoneurons during scratching. Because scratching is highly specialized rhythmic behavior, it is not known whether high-conductance states and irregular firing are a peculiarity for motoneurons during scratching. Here, using intracellular recordings from motoneurons in an ex vivo carapace-spinal cord preparation from adult turtles, we demonstrate that irregular firing and high-conductance states are present not only during scratching but also during swimming. Our findings suggest that irregular firing and high-conductance states could be a general feature for motor behaviors. PMID- 27225770 TI - Pharmacological Amelioration of Cone Survival and Vision in a Mouse Model for Leber Congenital Amaurosis. AB - RPE65, an abundant membrane-associate protein in the retinal pigment epithelium (RPE), is a key retinoid isomerase of the visual cycle necessary for generating 11-cis-retinal that functions not only as a molecular switch for activating cone and rod visual pigments in response to light stimulation, but also as a chaperone for normal trafficking of cone opsins to the outer segments. Many mutations in RPE65 are associated with Leber congenital amaurosis (LCA). A R91W substitution, the most frequent LCA-associated mutation, results in a severe decrease in protein level and enzymatic activity of RPE65, causing cone opsin mislocalization and early cone degeneration in the mutation knock-in mouse model of LCA. Here we show that R91W RPE65 undergoes ubiquitination-dependent proteasomal degradation in the knock-in mouse RPE due to misfolding. The 26S proteasome non-ATPase regulatory subunit 13 mediated degradation specifically of misfolded R91W RPE65. The mutation disrupted membrane-association and colocalization of RPE65 with lecithin:retinol acyltransferase (LRAT) that provides the hydrophobic substrate for RPE65. Systemic administration of sodium 4-phenylbutyrate (PBA), a chemical chaperone, increased protein stability, enzymatic activity, membrane-association, and colocalization of R91W RPE65 with LRAT. This rescue effect increased synthesis of 11-cis-retinal and 9-cis-retinal, a functional iso-chromophore of the visual pigments, led to alleviation of S-opsin mislocalization and cone degeneration in the knock-in mice. Importantly, PBA-treatment also improved cone mediated vision in the mutant mice. These results indicate that PBA, a U.S. Food and Drug Administration-approved safe oral medication, may provide a noninvasive therapeutic intervention that delays daylight vision loss in patients with RPE65 mutations. SIGNIFICANCE STATEMENT: LCA is a severe early onset retinal dystrophy. Recent clinical trials of gene therapy have implicated the need of an alternative or combination therapy to improve cone survival and function in patients with LCA caused by RPE65 mutations. Using a mouse model carrying the most frequent LCA associated mutation (R91W), we found that the mutant RPE65 underwent ubiquitination-dependent proteasomal degradation due to misfolding. Treatment of the mice with a chemical chaperone partially corrected stability, enzymatic activity, and subcellular localization of R91W RPE65, which was also accompanied by improvement of cone survival and vision. These findings identify an in vivo molecular pathogenic mechanism for R91W mutation and provide a feasible pharmacological approach that can delay vision loss in patients with RPE65 mutations. PMID- 27225771 TI - Shank Modulates Postsynaptic Wnt Signaling to Regulate Synaptic Development. AB - Prosap/Shank scaffolding proteins regulate the formation, organization, and plasticity of excitatory synapses. Mutations in SHANK family genes are implicated in autism spectrum disorder and other neuropsychiatric conditions. However, the molecular mechanisms underlying Shank function are not fully understood, and no study to date has examined the consequences of complete loss of all Shank proteins in vivo Here we characterize the single Drosophila Prosap/Shank family homolog. Shank is enriched at the postsynaptic membrane of glutamatergic neuromuscular junctions and controls multiple parameters of synapse biology in a dose-dependent manner. Both loss and overexpression of Shank result in defects in synaptic bouton number and maturation. We find that Shank regulates a noncanonical Wnt signaling pathway in the postsynaptic cell by modulating the internalization of the Wnt receptor Fz2. This study identifies Shank as a key component of synaptic Wnt signaling, defining a novel mechanism for how Shank contributes to synapse maturation during neuronal development. SIGNIFICANCE STATEMENT: Haploinsufficiency for SHANK3 is one of the most prevalent monogenic causes of autism spectrum disorder, making it imperative to understand how the Shank family regulates neurodevelopment and synapse function. We created the first animal model lacking all Shank proteins and used the Drosophila neuromuscular junction, a model glutamatergic synapse, to characterize the role of Shank at synapses. We identified a novel function of Shank in synapse maturation via regulation of Wnt signaling in the postsynaptic cell. PMID- 27225772 TI - Neogenin Promotes BMP2 Activation of YAP and Smad1 and Enhances Astrocytic Differentiation in Developing Mouse Neocortex. AB - Neogenin, a DCC (deleted in colorectal cancer) family receptor, is highly expressed in neural stem cells (NSCs). However, its function in NSCs remains to be explored. Here we provide in vitro and in vivo evidence for neogenin's function in NSCs to promote neocortical astrogliogenesis, but not self-renewal or neural differentiation. Mechanistically, neogenin in neocortical NSCs was required for BMP2 activation of YAP (yes associated protein). The active/nuclear YAP stabilized phospho-Smad1/5/8 and was necessary for BMP2 induction of astrocytic differentiation. Deletion of yap in mouse neocortical NSCs caused a similar deficit in neocortical astrogliogenesis as that in neogenin mutant mice. Expression of YAP in neogenin mutant NSCs diminished the astrocytic differentiation deficit in response to BMP2. Together, these results reveal an unrecognized function of neogenin in increasing neocortical astrogliogenesis, and identify a pathway of BMP2-neogenin-YAP-Smad1 for astrocytic differentiation in developing mouse neocortex. SIGNIFICANCE STATEMENT: Astrocytes, a major type of glial cells in the brain, play important roles in modulating synaptic transmission and information processing, and maintaining CNS homeostasis. The abnormal astrocytic differentiation during development contributes to dysfunctions of synaptic plasticity and neuropsychological disorders. Here we provide evidence for neogenin's function in regulation of the neocortical astrocyte differentiation during mouse brain development. We also provide evidence for the necessity of neogenin in BMP2/Smad1-induced astrocyte differentiation through YAP. Thus, our findings identify an unrecognized function of neogenin in mouse neocortical astrocyte differentiation, and suggest a signaling pathway, BMP2-neogenin-YAP-Smad1, underlying astrogliogenesis in developing mouse neocortex. PMID- 27225773 TI - Encoding of Touch Intensity But Not Pleasantness in Human Primary Somatosensory Cortex. AB - Growing interest in affective touch has delineated a neural network that bypasses primary somatosensory cortex (S1). Several recent studies, however, have cast doubt on the segregation of touch discrimination and affect, suggesting that S1 also encodes affective qualities. We used functional magnetic resonance imaging (fMRI) and repetitive transcranial magnetic stimulation (rTMS) to examine the role of S1 in processing touch intensity and pleasantness. Twenty-six healthy human adults rated brushing on the hand during fMRI. Intensity ratings significantly predicted activation in S1, whereas pleasantness ratings predicted activation only in the anterior cingulate cortex. Nineteen subjects also received inhibitory rTMS over right hemisphere S1 and the vertex (control). After S1 rTMS, but not after vertex rTMS, sensory discrimination was reduced and subjects with reduced sensory discrimination rated touch as more intense. In contrast, rTMS did not alter ratings of touch pleasantness. Our findings support divergent neural processing of touch intensity and pleasantness, with affective touch encoded outside of S1. SIGNIFICANCE STATEMENT: Growing interest in affective touch has identified a neural network that bypasses primary somatosensory cortex (S1). Several recent studies, however, cast doubt on the separation of touch discrimination and affect. We used functional magnetic resonance imaging and repetitive transcranial magnetic stimulation to demonstrate the representation of touch discrimination and intensity in S1, but the representation of pleasantness in the anterior cingulate cortex, not S1. Our findings support divergent neural processing of touch intensity and pleasantness, with affective touch encoded outside of S1. Our study contributes to growing delineation of the affective touch system, a crucial step in understanding its dysregulation in numerous clinical conditions such as autism, eating disorders, depression, and chronic pain. PMID- 27225774 TI - Retinal Circuitry Balances Contrast Tuning of Excitation and Inhibition to Enable Reliable Computation of Direction Selectivity. AB - Feedforward (FF) inhibition is a common motif in many neural networks. Typically, excitatory inputs drive both principal neurons and interneurons; the interneurons then inhibit the principal neurons, thereby regulating the strength and timing of the FF signal. The interneurons introduce a likely nonlinear processing step that could distort the excitation/inhibition (E/I) ratio in the principal neuron, potentially degrading the reliability of computation in the circuit. In the retina, FF inhibition is an essential feature of the circuitry underlying direction selectivity (DS): glutamatergic bipolar cells (BCs) provide excitatory input to direction-selective ganglion cells (DSGCs) and GABAergic starburst amacrine cells (SACs), and the SACs then provide FF inhibition onto DSGCs. Robust DS computation requires a consistent synaptic E/I ratio in the DSGC in various visual conditions. Here, we show in mouse retina that the E/I ratio is maintained in DSGCs over a wide stimulus contrast range due to compensatory mechanisms in the diverse population of presynaptic BCs. BC inputs to SACs exhibit higher contrast sensitivity, so that the subsequent nonlinear transformation in SACs reduces the contrast sensitivity of FF inhibition to match the sensitivity of direct excitatory inputs onto DSGCs. Measurements of light-evoked responses from individual BC synaptic terminals suggest that the distinct sensitivity of BC inputs reflects different contrast sensitivity between BC subtypes. Numerical simulations suggest that this network arrangement is crucial for reliable DS computation. SIGNIFICANCE STATEMENT: Properly balanced excitation and inhibition are essential for many neuronal computations across brain regions. Feedforward inhibition circuitry, in which a common excitatory source drives both the principal cell and an interneuron, is a typical mechanism by which neural networks maintain this balance. Feedforward circuits may become imbalanced at low stimulation levels, however, if the excitatory drive is too weak to overcome the activation threshold in the interneuron. Here we reveal how excitation and inhibition remain balanced in direction selective ganglion cells in the mouse retina over a wide visual stimulus range. PMID- 27225775 TI - Optogenetic Interrogation of Functional Synapse Formation by Corticospinal Tract Axons in the Injured Spinal Cord. AB - To restore function after injury to the CNS, axons must be stimulated to extend into denervated territory and, critically, must form functional synapses with appropriate targets. We showed previously that forced overexpression of the transcription factor Sox11 increases axon growth by corticospinal tract (CST) neurons after spinal injury. However, behavioral outcomes were not improved, raising the question of whether the newly sprouted axons are able to form functional synapses. Here we developed an optogenetic strategy, paired with single-unit extracellular recordings, to assess the ability of Sox11-stimulated CST axons to functionally integrate in the circuitry of the cervical spinal cord. Initial time course experiments established the expression and function of virally expressed Channelrhodopsin (ChR2) in CST cell bodies and in axon terminals in cervical spinal cord. Pyramidotomies were performed in adult mice to deprive the left side of the spinal cord of CST input, and the right CST was treated with adeno-associated virus (AAV)-Sox11 or AAV-EBFP control, along with AAV-ChR2. As expected, Sox11 treatment caused robust midline crossing of CST axons into previously denervated left spinal cord. Clear postsynaptic responses resulted from optogenetic activation of CST terminals, demonstrating the ability of Sox11-stimulated axons to form functional synapses. Mapping of the distribution of CST-evoked spinal activity revealed overall similarity between intact and newly innervated spinal tissue. These data demonstrate the formation of functional synapses by Sox11-stimulated CST axons without significant behavioral benefit, suggesting that new synapses may be mistargeted or otherwise impaired in the ability to coordinate functional output. SIGNIFICANCE STATEMENT: As continued progress is made in promoting the regeneration of CNS axons, questions of synaptic integration are increasingly prominent. Demonstrating direct synaptic integration by regenerated axons and distinguishing its function from indirect relay circuits and target field plasticity have presented technical challenges. Here we force the overexpression of Sox11 to stimulate the growth of corticospinal tract axons in the cervical spinal cord and then use specific optogenetic activation to assess their ability to directly drive postsynaptic activity in spinal cord neurons. By confirming successful synaptic integration, these data illustrate a novel optogenetic-based strategy to monitor and optimize functional reconnection by newly sprouted axons in the injured CNS. PMID- 27225777 TI - The Korean Prevocalic Palatal Glide: A Comparison with the Russian Glide and Palatalization. AB - Phonetic studies of the Korean prevocalic glides have often suggested that they are shorter in duration than those of languages like English, and lack a prolonged steady state. In addition, the formant frequencies of the Korean labiovelar glide are reported to be greatly influenced by the following vowel. In this study the Korean prevocalic palatal glide is investigated vis-a-vis the two phonologically similar configurations of another language - the glide /j/ and the secondary palatalization of Russian, with regard to the inherent duration of the glide component, F2 trajectory, vowel-to-glide coarticulation and glide-to-vowel coarticulation. It is revealed that the Korean palatal glide is closer to the Russian palatalization in duration and F2 trajectory, indicating a lack of steady state, and to the Russian segmental glide in the vowel-to-glide coarticulation degree. When the glide-to-vowel coarticulation is considered, the Korean palatal glide is distinguished from both Russian categories. The results suggest that both the Korean palatal glide and the Russian palatalization involve significant articulatory overlap, the former with the vowel and the latter with the consonant. Phonological implications of such a difference in coarticulation pattern are discussed, as well as the comparison between the Korean labiovelar and palatal glides. PMID- 27225776 TI - Rescue of Glaucomatous Neurodegeneration by Differentially Modulating Neuronal Endoplasmic Reticulum Stress Molecules. AB - Axon injury is an early event in neurodegenerative diseases that often leads to retrograde neuronal cell death and progressive permanent loss of vital neuronal functions. The connection of these two obviously sequential degenerative events, however, is elusive. Deciphering the upstream signals that trigger the neurodegeneration cascades in both neuronal soma and axon would be a key step toward developing the effective neuroprotectants that are greatly needed in the clinic. We showed previously that optic nerve injury-induced neuronal endoplasmic reticulum (ER) stress plays an important role in retinal ganglion cell (RGC) death. Using two in vivo mouse models of optic neuropathies (traumatic optic nerve injury and glaucoma) and adeno-associated virus-mediated RGC-specific gene targeting, we now show that differential manipulation of unfolded protein response pathways in opposite directions-inhibition of eukaryotic translation initiation factor 2alpha-C/EBP homologous protein and activation of X-box binding protein 1-promotes both RGC axons and somata survival and preserves visual function. Our results indicate that axon injury-induced neuronal ER stress plays an important role in both axon degeneration and neuron soma death. Neuronal ER stress is therefore a promising therapeutic target for glaucoma and potentially other types of neurodegeneration. SIGNIFICANCE STATEMENT: Neuron soma and axon degeneration have distinct molecular mechanisms although they are clearly connected after axon injury. We previously demonstrated that axon injury induces neuronal endoplasmic reticulum (ER) stress and that manipulation of ER stress molecules synergistically promotes neuron cell body survival. Here we investigated the possibility that ER stress also plays a role in axon degeneration and whether ER stress modulation preserves neuronal function in neurodegenerative diseases. Our results suggest that neuronal ER stress is a general mechanism of degeneration for both neuronal cell body and axon, and that therapeutic targeting of ER stress produces significant functional recovery. PMID- 27225778 TI - Infant exposure to Chinese famine increased the risk of hypertension in adulthood: results from the China Health and Retirement Longitudinal Study. AB - BACKGROUND: Early-life developmental adaptations in response to severe malnutrition may play a crucial role in susceptibility to hypertension. This study aimed to explore the associations between exposure to the Chinese famine (1959-1961) at fetal, infant and preschool stages during fetal life or childhood and the risk of hypertension in adulthood. METHODS: We used the data of 1,966 adults born between 1956 and 1964 in selected families from the China Health and Retirement Longitudinal Study (CHARLS) national survey. RESULTS: Prevalence of hypertension among adults in non-exposed, fetal-exposed, infant-exposed, and preschool-exposed cohorts was 18.9, 20.7, 28.7, and 23.4 %, respectively. In severely affected famine areas, only infant-exposed cohort had a significant increased risk of hypertension compared with non-exposed cohort (OR 2.12; 95 % CI 1.19, 3.79; P = 0.011), and the significance remained after adjusted gender, smoking, and drinking (OR 2.11; 95 % CI 1.18, 3.77; P = 0.012). After stratification by BMI and economic status, the risk of hypertension was higher for subjects with BMI >= 24 kg/m(2)(OR 2.09; 95 % CI 1.09, 4.01; P = 0.026) or high economic status(OR 2.26; 95 % CI 1.19, 4.31; P = 0.013) than those with BMI < 24 kg/m(2)(OR 1.65; 95 % CI 0.71, 3.83; P = 0.246) or low economic status (OR 2.18; 95 % CI 1.14, 4.18; P = 0.019) in infant-exposed cohort of severely affected famine areas. However, there was no consistent association observed in less severely affected area or other exposed cohorts in severely affected areas. CONCLUSIONS: Infanthood exposed to famine might increase the risk of hypertension in adulthood, and a postnatal 'rich' nutrient environment further increased the risk. PMID- 27225779 TI - Key priorities in the prevention and control of healthcare-associated infection: a survey of European and other international infection prevention experts. AB - PURPOSE: Prevention and control of healthcare-associated infection (HCAI) are important within and beyond Europe. However, it is unclear which areas are considered important by HCAI prevention and control professionals. This study assesses the priorities in the prevention and control of HCAI as judged by experts in the field. METHODS: A survey was conducted by the European Society of Clinical Microbiology and Infectious Diseases focussing on seven topics using SurveyMonkey(r). Through a newsletter distributed by email, about 5000 individuals were targeted throughout the world in February and March 2013. Participants were asked to rate the importance of particular topics from one (low importance) to ten (extraordinary importance), and there was no restriction on giving equal importance to more than one topic. RESULTS: A total of 589 experts from 86 countries participated including 462 from Europe (response rate: 11.8 %). Physicians accounted for 60 % of participants, and 57 % had ten or more years' experience in this area. Microbial epidemiology/resistance achieved the highest priority scoring with 8.9, followed by surveillance 8.2, and decolonisation/disinfection/antiseptics with 7.9. Under epidemiology/resistance, highly resistant Gram-negative bacilli scored highest (9.0-9.2). The provision of computerised healthcare information systems for the early detection of outbreaks was accorded the top priority under surveillance. The prevention of surgical site and central line infections ranked highest under the category of specific HCAI and HCAI in certain settings. Differences between regions are described. CONCLUSION: These findings reflect the concerns of experts in HCAI prevention and control. The results from this survey should inform national and international agencies on future action and research priorities. PMID- 27225780 TI - Reduction of Biological Sludge Production Applying an Alternating Oxic/anoxic Process in Water Line. AB - Alternating oxic/anoxic process, applied for the main objective of the improvement of nitrogen performances, was studied in terms of secondary effect of biomass reduction. The process was carried out in one real water resource recovery facility and the data were compared with the previous conventional period when a conventional process was adopted. The main mechanism of the process for the sludge minimization is recognized in the metabolic uncoupling. In fact, an increase of the specific oxygen uptake rate in the biological reactor was recorded stimulated by the change of the oxidation reduction potential environment. Moreover, the heterotrophic growth yield was measured equal to 0.385 kgVSS/kgCOD. The global percentage of reduction was tested with the mass balance of solids. The process is able to decrease the observed sludge yield up to 20%. The specific energy consumption was evaluated. PMID- 27225781 TI - Benzotriazole Enrichment in Snowmelt Discharge Emanating from Engineered Snow Storage Facilities. AB - Snowpacks in urban environments can retain a high load of anthropogenic contaminants that, upon melting, can deliver concentrated contaminant pulses into the aquatic environment. In climates with an extended period of snowfall accumulation, such as in Anchorage, Alaska, contaminant amplification within meltwater may affect aquatic ecosystem health. A spatiotemporal study of benzotriazoles on snow, meltwater and soils was performed in association with three urban snow disposal facilities. Benzotriazole elution from engineered snow disposal sites behaved similarly to inorganic salt and dissolved organic carbon (DOC) during the initial melt period, with maximum concentrations between 2.23 7.39 MUg/L; similar enrichment was observed in creeks. Assays of disposal site soils revealed the presence of tolytriazole. Furthermore, using fluorescence spectroscopy and PARAFAC analysis, a modeled component representative of benzotriazoles was identified, a possible indicator of anthropogenic input rather than a unique indicator for benzotriazole compounds. PMID- 27225782 TI - Potential of Brass to Remove Inorganic Hg(II) from Aqueous Solution through Amalgamation. AB - Brass shavings (CuZn45) were tested for their efficiency to remove Hg(II) from contaminated groundwater through amalgamation. The study was focused on long-term retention efficiency, the understanding of the amalgamation process and kinetics, and influences of filter surface alteration. Column tests were performed with brass filters (thickness 3 to 9 cm) flushed with 1000 MUg/L Hg solution for 8 hours under different flow rates (300 to 600 mL/h). Brass filters consistently removed >98% of Hg from solution independent of filter thickness and flow rate. In a long-term experiment (filter thickness 2 cm), Hg retention decreased from 96 to 92% within 2000 hours. Batch and column experiments for studying kinetics of Hg removal indicate ~100% Hg removal from solution within only 2 hours. Solid phase mercury thermo-desorption analysis revealed that Hg(0) diffusion into the brass surface controls kinetics of mercury retention. Brass surface alteration could be observed, but did not influence Hg retention. PMID- 27225783 TI - Biosorption of Ni(II) by Fig Male: Optimization and Modeling Using a Full Factorial Design. AB - The fig male (FM) is successfully used as biosorbent for Ni(2+) removal. The maximum removal efficiency (96.6%) is obtained at pH ~ 5 for a concentration of 1.70 mmol L(-1) and catalyst dose of 5 g L(-1) in less than 10 minutes. The Ni(2+) uptake follows a pseudo-second-order kinetic, the rate constants increase with increasing temperature, and an activation energy of 55.48 kJ mol(-1) is found. The thermodynamic parameters indicate a spontaneous endothermic bisorption. The isotherm data are fitted by the Langmuir and Dubinin-Radushkevich models. The former indicates a maximum Ni(2+) uptake of 0.459 mmol g(-1), which is higher than that of most biosorbents investigated to date. The FTIR spectra reveal the biosorption mechanism between Ni(2+) and FM functional groups. An empirical modeling is performed by using a 2(3) full factorial design, and a regression equation for Ni(2+) biosorption is determined. The biosorbent mass and pH are the most significant parameters affecting the Ni(2+) biosorption. PMID- 27225784 TI - Thermodynamic Equilibrium Calculations on Cd Transformation during Sewage Sludge Incineration. AB - Thermodynamic equilibrium calculations were performed to reveal the distribution of cadmium during the sewage sludge incineration process. During sludge incineration in the presence of major minerals, such as SiO2, Al2O3 and CaO, the strongest effect was exerted by SiO2 on the Cd transformation compared with the effect of others. The stable solid product of CdSiO3 was formed easily with the reaction between Cd and SiO2, which can restrain the emissions of gaseous Cd pollutants. CdCl2 was formed more easily in the presence of chloride during incineration, thus, the volatilization of Cd was advanced by increasing chlorine content. At low temperatures, the volatilization of Cd was restrained due to the formation of the refractory solid metal sulfate. At high temperatures, the speciation of Cd was not affected by the presence of sulfur, but sulfur could affect the formation temperature of gaseous metals. PMID- 27225785 TI - Characterization of Washoff Behavior of In-Sewer Deposits in Combined Sewer Systems. AB - In-sewer deposits in combined sewer systems (CSSs) are closely related with the behavior of first foul flush and combined sewer overflows. The artificial flushing experiment separating the washoff of in-sewer deposits from the inflow of surface pollutants was carried out to simulate first foul flush in a CSS. The washoff behaviors of each pollutant including chemical pollutants, bacterial indicators, and enteric viruses were intensively investigated. By using several morphological analyses, some of which were suggested through this study, the characteristics of first foul flush were examined. As a result, the washoff behaviors of each pollutant were characterized according to their (i) event load ratios (ELRs), (ii) time-series concentration and load curves, (iii) concentration vs. flow rate curves, and (iv) dimensionless runoff concentrations (DRCs). The first foul flush patterns of each parameter were categorized into 3 typical groups: the strong-, partial-, and no first foul flush group. The order of these groups signifies their different physicochemical properties of in-sewer deposits in CSSs, their strength of first foul flush phenomena, and the washoff priority as well. PMID- 27225786 TI - Impact of Diabetes Mellitus. PMID- 27225787 TI - Syk Inhibition in Ischemic Stroke. PMID- 27225788 TI - How Does Protein Disulfide Isomerase Get Into a Thrombus? PMID- 27225789 TI - The Canadian guidelines for the withdrawal of life-sustaining treatment: the role of evidence. PMID- 27225790 TI - Neither guidelines nor symptom-targeted opioids are harmful when withdrawing life sustaining measures. PMID- 27225791 TI - Empowering districts to target priorities for improving child health service in Uganda using change management and rapid assessment methods. AB - BACKGROUND: Local health system managers in low- and middle-income countries have the responsibility to set health priorities and allocate resources accordingly. Although tools exist to aid this process, they are not widely applied for various reasons including non-availability, poor knowledge of the tools, and poor adaptability into the local context. In Uganda, delivery of basic services is devolved to the District Local Governments through the District Health Teams (DHTs). The Community and District Empowerment for Scale-up (CODES) project aims to provide a set of management tools that aid contextualised priority setting, fund allocation, and problem-solving in a systematic way to improve effective coverage and quality of child survival interventions. DESIGN: Although the various tools have previously been used at the national level, the project aims to combine them in an integral way for implementation at the district level. These tools include Lot Quality Assurance Sampling (LQAS) surveys to generate local evidence, Bottleneck analysis and Causal analysis as analytical tools, Continuous Quality Improvement, and Community Dialogues based on Citizen Report Cards and U reports. The tools enable identification of gaps, prioritisation of possible solutions, and allocation of resources accordingly. This paper presents some of the tools used by the project in five districts in Uganda during the proof-of-concept phase of the project. RESULTS: All five districts were trained and participated in LQAS surveys and readily adopted the tools for priority setting and resource allocation. All districts developed health operational work plans, which were based on the evidence and each of the districts implemented more than three of the priority activities which were included in their work plans. CONCLUSIONS: In the five districts, the CODES project demonstrated that DHTs can adopt and integrate these tools in the planning process by systematically identifying gaps and setting priority interventions for child survival. PMID- 27225792 TI - Chronic disease, risk factors and disability in adults aged 50 and above living with and without HIV: findings from the Wellbeing of Older People Study in Uganda. AB - BACKGROUND: Data on the prevalence of chronic conditions, their risk factors, and their associations with disability in older people living with and without HIV are scarce in sub-Saharan Africa. OBJECTIVES: In older people living with and without HIV in sub-Saharan Africa: 1) to describe the prevalence of chronic conditions and their risk factors and 2) to draw attention to associations between chronic conditions and disability. METHODS: Cross-sectional individual level survey data from people aged 50 years and over living with and without HIV were analyzed from three study sites in Uganda. Diagnoses of chronic conditions were made through self-report, and disability was determined using the WHO Disability Assessment Schedule (WHODAS). We used ordered logistic regression and calculated predicted probabilities to show differences in the prevalence of multiple chronic conditions across HIV status, age groups, and locality. We used linear regression to determine associations between chronic conditions and the WHODAS. RESULTS: In total, 471 participants were surveyed; about half the respondents were living with HIV. The prevalence of chronic obstructive pulmonary disease and eye problems (except for those aged 60-69 years) was higher in the HIV-positive participants and increased with age. The prevalence of diabetes and angina was higher in HIV-negative participants. The odds of having one or more compared with no chronic conditions were higher in women (OR 1.6, 95% CI 1.1-2.3) and in those aged 70 years and above (OR 2.1, 95% CI 1.2-3.6). Sleep problems (coefficient 14.2, 95% CI 7.3-21.0) and depression (coefficient 9.4, 95% CI 1.2 17.0) were strongly associated with higher disability scores. CONCLUSION: Chronic conditions are common in older adults and affect their functioning. Many of these conditions are not currently addressed by health services in Uganda. There is a need to revise health care policy and practice in Uganda to consider the health needs of older people, particularly as the numbers of people living into older age with HIV and other chronic conditions are increasing. PMID- 27225793 TI - Air pollution modelling for birth cohorts: a time-space regression model. AB - BACKGROUND: To investigate air pollution effects during pregnancy or in the first weeks of life, models are needed that capture both the spatial and temporal variability of air pollution exposures. METHODS: We developed a time-space exposure model for ambient NO2 concentrations in Bern, Switzerland. We used NO2 data from passive monitoring conducted between 1998 and 2009: 101 rural sites (24,499 biweekly measurements) and 45 urban sites (4350 monthly measurements). We evaluated spatial predictors (land use; roads; traffic; population; annual NO2 from a dispersion model) and temporal predictors (meteorological conditions; NO2 from continuous monitoring station). Separate rural and urban models were developed by multivariable regression techniques. We performed ten-fold internal cross-validation, and an external validation using 57 NO2 passive measurements obtained at study participant's homes. RESULTS: Traffic related explanatory variables and fixed site NO2 measurements were the most relevant predictors in both models. The coefficient of determination (R(2)) for the log transformed models were 0.63 (rural) and 0.54 (urban); cross-validation R(2)s were unchanged indicating robust coefficient estimates. External validation showed R(2)s of 0.54 (rural) and 0.67 (urban). CONCLUSIONS: This approach is suitable for air pollution exposure prediction in epidemiologic research with time-vulnerable health effects such as those occurring during pregnancy or in the first weeks of life. PMID- 27225794 TI - Dissociated functional connectivity profiles for motor and attention deficits in acute right-hemisphere stroke. AB - Strokes often cause multiple behavioural deficits that are correlated at the population level. Here, we show that motor and attention deficits are selectively associated with abnormal patterns of resting state functional connectivity in the dorsal attention and motor networks. We measured attention and motor deficits in 44 right hemisphere-damaged patients with a first-time stroke at 1-2 weeks post onset. The motor battery included tests that evaluated deficits in both upper and lower extremities. The attention battery assessed both spatial and non-spatial attention deficits. Summary measures for motor and attention deficits were identified through principal component analyses on the raw behavioural scores. Functional connectivity in structurally normal cortex was estimated based on the temporal correlation of blood oxygenation level-dependent signals measured at rest with functional magnetic resonance imaging. Any correlation between motor and attention deficits and between functional connectivity in the dorsal attention network and motor networks that might spuriously affect the relationship between each deficit and functional connectivity was statistically removed. We report a double dissociation between abnormal functional connectivity patterns and attention and motor deficits, respectively. Attention deficits were significantly more correlated with abnormal interhemispheric functional connectivity within the dorsal attention network than motor networks, while motor deficits were significantly more correlated with abnormal interhemispheric functional connectivity patterns within the motor networks than dorsal attention network. These findings indicate that functional connectivity patterns in structurally normal cortex following a stroke link abnormal physiology in brain networks to the corresponding behavioural deficits. PMID- 27225795 TI - Monoscopic photogrammetry to obtain 3D models by a mobile device: a method for making facial prostheses. AB - PURPOSE: The aim of this study is to present the development of a new technique to obtain 3D models using photogrammetry by a mobile device and free software, as a method for making digital facial impressions of patients with maxillofacial defects for the final purpose of 3D printing of facial prostheses. METHODS: With the use of a mobile device, free software and a photo capture protocol, 2D captures of the anatomy of a patient with a facial defect were transformed into a 3D model. The resultant digital models were evaluated for visual and technical integrity. The technical process and resultant models were described and analyzed for technical and clinical usability. RESULTS: Generating 3D models to make digital face impressions was possible by the use of photogrammetry with photos taken by a mobile device. The facial anatomy of the patient was reproduced by a *.3dp and a *.stl file with no major irregularities. 3D printing was possible. CONCLUSIONS: An alternative method for capturing facial anatomy is possible using a mobile device for the purpose of obtaining and designing 3D models for facial rehabilitation. Further studies must be realized to compare 3D modeling among different techniques and systems. CLINICAL IMPLICATION: Free software and low cost equipment could be a feasible solution to obtain 3D models for making digital face impressions for maxillofacial prostheses, improving access for clinical centers that do not have high cost technology considered as a prior acquisition. PMID- 27225797 TI - Angiographic management of pseudoaneurysms of gastroduodenal artery following endoscopic sphincterotomy. AB - Gastrointestinal bleeding follows endoscopic sphincterotomy in 1 % to 10 % of patients. We report two cases of bleeding from pseudoaneurysms of the gastroduodenal artery occurring as a complication of endoscopic sphincterotomy. PMID- 27225796 TI - The machinery underlying malaria parasite virulence is conserved between rodent and human malaria parasites. AB - Sequestration of red blood cells infected with the human malaria parasite Plasmodium falciparum in organs such as the brain is considered important for pathogenicity. A similar phenomenon has been observed in mouse models of malaria, using the rodent parasite Plasmodium berghei, but it is unclear whether the P. falciparum proteins known to be involved in this process are conserved in the rodent parasite. Here we identify the P. berghei orthologues of two such key factors of P. falciparum, SBP1 and MAHRP1. Red blood cells infected with P. berghei parasites lacking SBP1 or MAHRP1a fail to bind the endothelial receptor CD36 and show reduced sequestration and virulence in mice. Complementation of the mutant P. berghei parasites with the respective P. falciparum SBP1 and MAHRP1 orthologues restores sequestration and virulence. These findings reveal evolutionary conservation of the machinery underlying sequestration of divergent malaria parasites and support the notion that the P. berghei rodent model is an adequate tool for research on malaria virulence. PMID- 27225798 TI - Prevalence, severity, and impact on quality of life of restless leg syndrome in patients with liver cirrhosis in India. AB - BACKGROUND AND AIM: Restless leg syndrome (RLS) has recently been shown to be increased in patients with liver cirrhosis (LC). We prospectively studied the prevalence and severity of RLS, and the effect of its presence on the quality of life (QoL) in Indian patients with LC. METHODS: Adult patients with stable LC (n = 121; 98 male; median age 47 [range 18-68] years; Child-Pugh class A/B/C 59/39/23), were prospectively enrolled along with a group of healthy, adult controls (n = 121; 84 male; median age 42 [19-70] years). Patients with recent (<4 weeks) worsening were excluded. The subjects underwent an initial screening for RLS, followed by a re-evaluation to confirm the diagnosis, using the International RLS Diagnostic Criteria, and assessment of its severity. All participants underwent QoL assessment. RESULTS: RLS was commoner in LC patients (8/121; 6.6 %) than in controls (1/121; p < 0.05; odds ratio = 8.5 [1.1-69.0]). Presence of RLS showed no association with specific gender (male 7/98, female 1/23), Child-Pugh class (A 5/59, B 1/39 and C 2/23) or cause of liver disease (alcohol 3/32, hepatitis B 1/18, hepatitis C 3/28, and cryptogenic 1/25). RLS severity was moderate (5), severe (2), or very severe (1). Though QoL scores were lower in patients with LC than in controls, those in patients with and without RLS were similar. CONCLUSION: RLS was commoner in patients with LC than in controls, but did not correlate with liver disease severity and did not adversely influence QoL in LC. PMID- 27225800 TI - Angiostrongylus cantonensis: a review of its distribution, molecular biology and clinical significance as a human pathogen. AB - Angiostrongylus cantonensis is a metastrongyloid nematode found widely in the Asia-Pacific region, and the aetiological agent of angiostrongyliasis; a disease characterized by eosinophilic meningitis. Rattus rats are definitive hosts of A. cantonensis, while intermediate hosts include terrestrial and aquatic molluscs. Humans are dead-end hosts that usually become infected upon ingestion of infected molluscs. A presumptive diagnosis is often made based on clinical features, a history of mollusc consumption, eosinophilic pleocytosis in cerebral spinal fluid, and advanced imaging such as computed tomography. Serological tests are available for angiostrongyliasis, though many tests are still under development. While there is no treatment consensus, therapy often includes a combination of anthelmintics and corticosteroids. Angiostrongyliasis is relatively rare, but is often associated with morbidity and sometimes mortality. Recent reports suggest the parasites' range is increasing, leading to fatalities in regions previously considered Angiostrongylus-free, and sometimes, delayed diagnosis in newly invaded regions. Increased awareness of angiostrongyliasis would facilitate rapid diagnosis and improved clinical outcomes. This paper summarizes knowledge on the parasites' life cycle, clinical aspects and epidemiology. The molecular biology of Angiostrongylus spp. is also discussed. Attention is paid to the significance of angiostrongyliasis in Australia, given the recent severe cases reported from the Sydney region. PMID- 27225799 TI - Arsenicosis, possibly from contaminated groundwater, associated with noncirrhotic intrahepatic portal hypertension. AB - BACKGROUND AND AIMS: Idiopathic noncirrhotic intrahepatic portal hypertension (NCIPH), a chronic microangiopathy of the liver caused by arsenicosis from use of contaminated groundwater, was reported from Asia. This study aimed to see, if in the twenty-first century, arsenicosis was present in NCIPH patients at our hospital and, if present, to look for groundwater contamination by arsenic in their residential locality. METHODS: Twenty-seven liver biopsy proven NCIPH patients, 25 portal hypertensive controls with hepatitis B or C related cirrhosis and 25 healthy controls, matched for residential locality, were studied. Eighty four percent to 96 % of study subjects belonged to middle or lower socioeconomic category. Arsenicosis was looked for by estimation of arsenic levels in finger/toe nails and by skin examination. Arsenic levels in nails and in ground water (in NCIPH patients with arsenicosis) was estimated by mass spectrometry. RESULTS: Nail arsenic levels were raised in five (10 %) portal hypertensive study subjects [two NCIPH patients (both had skin arsenicosis) and three portal hypertensive controls]. All of these five patients were residents of West Bengal or Bangladesh. Skin arsenicosis was noted in three NCIPH patients (11 %) compared to none of disease/healthy controls. Ground water from residential locality of one NCIPH patient with arsenicosis (from Bangladesh) showed extremely high level of arsenic (79.5 MUg/L). CONCLUSIONS: Arsenicosis and microangiopathy of liver, possibly caused by environmental contamination continues in parts of Asia. Further studies are needed to understand the mechanisms of such 'poverty-linked thrombophilia'. PMID- 27225801 TI - A fuzzy logic controller based approach to model the switching mechanism of the mammalian central carbon metabolic pathway in normal and cancer cells. AB - Dynamics of large nonlinear complex systems, like metabolic networks, depend on several parameters. A metabolic pathway may switch to another pathway in accordance with the current state of parameters in both normal and cancer cells. Here, most of the parameter values are unknown to us. A fuzzy logic controller (FLC) has been developed here for the purpose of modeling metabolic networks by approximating the reasons for the behaviour of a system and applying expert knowledge to track switching between metabolic pathways. The simulation results can track the switching between glycolysis and gluconeogenesis, as well as glycolysis and pentose phosphate pathways (PPP) in normal cells. Unlike normal cells, pyruvate kinase (M2 isoform) (PKM2) switches alternatively between its two oligomeric forms, i.e. an active tetramer and a relatively low activity dimer, in cancer cells. Besides, there is a coordination among PKM2 switching and enzymes catalyzing PPP. These phenomena help cancer cells to maintain their high energy demand and macromolecular synthesis. However, the reduction of initial adenosine triphosphate (ATP) to a very low concentration, decreasing initial glucose uptake, destroying coordination between glycolysis and PPP, and replacement of PKM2 by its relatively inactive oligomeric form (dimer) or inhibition of the translation of PKM2 may destabilize the mutated control mechanism of the mammalian central carbon metabolic (CCM) pathway in cancer cells. The performance of the model is compared appropriately with some existing ones. PMID- 27225802 TI - Serological evidence of acute rubella infection among under-fives in Mwanza: a threat to increasing rates of congenital rubella syndrome in Tanzania. AB - BACKGROUND: Control of rubella infection is essential for preventing congenital rubella syndrome (CRS) and one of the important steps is to define a target population for vaccination. Therefore this study was done to determine serological evidence of acute rubella infection among under-fives in order to anticipate the magnitude of rubella virus transmission in Tanzania. METHODS: A cross-sectional study involving children aged between 1 and 59 months was conducted between September and October 2014 before national rubella vaccination campaigns commenced. Rubella IgM antibodies were detected using commercial indirect enzyme-linked immunosorbent assay (ELISA). Data were analyzed using STATA version 11. RESULTS: A total of230 under-fives were enrolled, their median age was 14 (Interquartile range (IQR) 7-26) months. The overall seroprevalence of rubella IgM antibodies was 10.9 % (25/230) with two confirmed cases of CRS. Two sample Wilcoxon rank-sum test showed that the median age of rubella IgM seropositive children was significantly higher than that of IgM seronegative children (39 IQR: 18-51months vs. 14 IQR: 7-24 months, P < 0.001). On multivariate logistic regression analysis increase in age (OR: 1.07, 95 % CI; 1.03-1.1, P < 0.001) and residing in rural areas (OR: 8.07, 95 % CI; 1.43-45.6, P = 0.018) were independently found to predict acute rubella infection among under fives. CONCLUSION: Our findings indicate that rubella virus is prevalent in our setting posing a risk of transmitting to childbearing aged women hence increasing the risk of CRS. Increasing prevalence of acute infection with age in under-fives indicates the protective role of maternal antibodies among infants. The sustained vaccination programme of under-fives as effective measure to control CRS should be emphasized in developing countries. PMID- 27225804 TI - Clinical and prognostic utility of cardiovascular magnetic resonance imaging in myeloma patients with suspected cardiac amyloidosis. AB - OBJECTIVES: AL amyloidosis affects up to 30% of patients with multiple myeloma (MM), and cardiac involvement is associated with worse outcomes. Traditional screening modalities including EKG, echocardiography and biomarkers have limited value. The aim of this study was to evaluate the clinical and prognostic value of late gadolinium enhancement (LGE) by cardiovascular magnetic resonance (CMR) imaging in patients with plasma cell dyscrasias and suspected cardiac amyloidosis (CA). METHODS: A total of 251 consecutive patients with plasma cell dyscrasias who underwent CMR were enrolled in this study. Primary endpoint was all cause mortality. Clinical, ECG, echocardiographic, biomarker and CMR predictors of mortality were analyzed. RESULTS: Mean age of population was 63 +/- 10 years, 36% females and 19% African Americans. During a median follow-up duration of 28 months (IQR 5-56), there were 97 deaths (39%). Patients who died were more likely to have diabetes (28% vs. 14%; P = 0.03), CAD (28% vs. 16%; P = 0.04) and CKD (33% vs. 21%; P = 0.04). With endomyocardial biopsy as the gold standard (42 (17%) patients), amyloid pattern on CMR (LGE+) had sensitivity and negative predictive values of 100%; specificity and positive predictive values of 80 and 81% with an AUC 0.9 for CA. History of CAD (HR 1.64, 95% CI 1.01-2.6; P = 0.04), brain natriuretic peptide (HR 1.0003 95% CI 1.0001-1.0006; P = 0.004) and LGE + (HR 1.72, 95% CI 1.05-2.8; P = 0.02) were independent predictors of mortality. LGE+ possessed incremental prognostic value over clinical, laboratory and echocardiographic variables for mortality prediction. CONCLUSIONS: CMR is a clinically useful tool for diagnosis and prognostication in myeloma patients with suspected CA. PMID- 27225803 TI - Generation of a C57BL/6 MYC-Driven Mouse Model and Cell Line of Prostate Cancer. AB - INTRODUCTION: Transgenic mouse modeling is a favorable tool to reflect human prostate tumorigenesis and interactions between prostate cancer and the microenvironment. The use of GEMMs and derived cell lines represent powerful tools to study prostate cancer initiation and progression with an associated tumor microenvironment. Notably, such models provide the capacity for rapid preclinical therapy studies including immune therapies for prostate cancer treatment. METHODS: Backcrossing FVB Hi-MYC mice with C57BL/6N mice, we established a Hi-MYC transgenic mouse model on a C57BL/6 background (B6MYC). In addition, using a conditional reprogramming method, a novel C57BL/6 MYC driven prostate adenocarcinoma cell line was generated. RESULTS: Our results demonstrate that disease progression is significantly delayed in B6MYC when compared to their FVB counterparts. Current data also indicates infiltrating immune cells are present in pre-cancer lesions, prostate intraepithelial neoplasia (PIN). Further, immunophenotyping of this immune infiltrate demonstrates the predominant population as myeloid-derived suppressor cells (MDSC). Also, we successfully generated a B6MYC-CaP cell line, and determined that this new PCa cell line express markers of luminal epithelial lineage. DISCUSSION: This novel model of PCa provides a new platform to understand the cross talk between MYC driven prostate cancer and the microenvironment. Importantly, these models will be an ideal tool to support the clinical development of immunotherapy as well as other novel therapeutic strategies for prostate cancer treatment. Prostate 76:1192 1202, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27225805 TI - Multiple congenital arteriovenous fistulas draining into the right internal mammary vein with a large internal mammary varicose vein. PMID- 27225806 TI - Anomalous venous drainage: a rare case of cyanosis. PMID- 27225808 TI - A case of lifelong myocardial ischaemia. PMID- 27225807 TI - Deceleration time of left ventricular outflow tract flow as a simple surrogate marker for central haemodynamics at rest and as well as during exercise. AB - Background: The shape and duration of left ventricular outflow tract (LVOT) flow has not been applied to assess the central haemodynamics, although LVOT flow is confronted with afterload of arterial system during systole. The aim of this study was to evaluate whether the LVOT flow parameters are related with central systolic blood pressure (BP) and arterial compliance at rest and as well as during exercise. Methods: We studied 258 subjects (175 females, age 61 +/- 11 years) with normal left ventricular (LV) systolic function who underwent supine bicycle stress echocardiography and arterial tonometry simultaneously at rest and at peak exercise. Deceleration time (DT) of LVOT flow and RR interval were measured and deceleration time corrected for heart rate (DTc) was calculated. Peripheral and central haemodynamic parameters including systolic and diastolic BP, and augmentation index at a heart rate of 75 (AIx@75) were assessed using radial artery tonometry. Carotid femoral pulse wave velocity (PWV) was measured. ResultResults: Deceleration time corrected for heart rate was independently associated with central systolic BP and AIx@75 at rest (P < 0.001 and 0.006). Similarly, it also showed significant independent correlations with central systolic BP and AIx@75 during peak exercise (P = 0.006 and P = 0.021). In addition, DTc which measured both at rest and at peak exercise demonstrated significant positive correlations with PWV, suggesting association of prolonged DTc with arterial stiffening (P = 0.023 and P = 0.005). Conclusion: Prolongation of LVOT flow DTc represents raised central systolic BP and increased arterial stiffness not only at rest but also during exercise. Therefore, central aortic pressures and arterial stiffness influence the DT of LVOT flow at rest as well as during exercise in individuals with normal LV systolic function. PMID- 27225809 TI - Anomalous origin of pulmonary artery from aorta complicated by pulmonary thrombosis: diagnosed using echocardiography. PMID- 27225810 TI - A window to a bleeding heart. PMID- 27225811 TI - Cardiac calcified amorphous 'tumour': the CAT is on a broken line. PMID- 27225812 TI - Spontaneous thrombosis of the ductus arteriosus in a newborn, complicated by thrombus migration and massive pulmonary embolism. PMID- 27225813 TI - Echocardiographic and angiographic assessment of paravalvular regurgitation after TAVI: optimizing inter-technique reproducibility. AB - AIMS: Aortic regurgitation (AR) after transcatheter aortic valve implantation (TAVI) is often first diagnosed by angiography and then confirmed and followed-up by transthoracic echocardiography (TTE). Consistency between both methods is important for follow-up. We sought to determine inter-technique reproducibility of the assessment of paravalvular AR after TAVI. METHODS AND RESULTS: The study included 165 patients treated with a self-expanding bioprosthesis and had angiography and TTE performed at a median interval of 4 days. TTE parameters of AR severity included VARC score (the average AR grade determined by the echocardiographic VARC-II criteria), pressure half time (PHT), regurgitation jet features in long-axis views (LAX score) and colour Doppler (CD) score (=paravalvular AR jet circumferential extent (%) + LAX score). Using receiver operating characteristics curves, the cut-points that best defined an angiographic >mild AR were identified.On TTE, AR was paravalvular in all cases, multi-jet in 28%, and predominantly (64%) detected in the commissural region between the right and left coronary sinuses. Using VARC-II criteria (combining at least two), TTE agreed with angiographic classification in 53% of cases (k = 0.14). Greater than mild AR could better be defined by one of the following combinations of criteria: (i) LAX score >4.25 and VARC-II score >1.33; (ii) CD score >11.5 and PHT <400 ms. The combination of the CD score with PHT gave the best sum of sensitivity, specificity, positive, and negative predictive values. CONCLUSIONS: Agreement between angiography and TTE (using the VARC-II criteria) in the grading of post-TAVI AR is modest, and this might have contributed to the inconsistency of data on the rate and fate of paravalvular AR. Inter-technique reproducibility can be improved using a combination of CD and hemodynamic parameters. PMID- 27225814 TI - Compressive giant right atrial diverticulum. PMID- 27225815 TI - Utilization of electroanatomical mapping in the diagnosis of cardiac amyloidosis. PMID- 27225817 TI - Effect of transarterial embolization for post-partum hemorrhage on subsequent pregnancy. AB - Although pregnancy after transarterial embolization (TAE) has occasionally been reported, gelatin sponge was used as the embolic agent in most of these cases. Reports on the effect of TAE with permanent embolic agents such as N-butyl cyanoacrylate or coil on subsequent pregnancies are rare. We describe placenta accreta associated with difficult hemostasis in two patients who became pregnant after TAE with permanent embolic agents. In pregnancy after TAE with permanent embolic agents, placenta accreta occurs frequently and well-developed collateral vessels are highly likely, resulting in difficult hemostasis. Although the acceptability of pregnancy after TAE with permanent embolic agents is controversial, patients should be informed that pregnancy is extremely high risk. PMID- 27225816 TI - Coronary atherosclerotic plaque burden and composition by CT angiography in Caucasian and South Asian patients with stable chest pain. AB - Aims: South Asian (SA) patients are known to have an increased incidence of acute cardiovascular events compared with Caucasians. The aim of this observational study was to compare the prevalence of coronary stenoses, the amount and composition of coronary atherosclerosis in a cohort of Caucasian and SA patients with stable chest pain, in non-acute settings. Methods and Results: The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. In 963 consecutive Caucasian and SA patients undergoing coronary computed tomography angiography, atherosclerotic plaques were quantified using a semi automated algorithm. The vessel per cent diameter and area stenosis were measured. Plaque composition was examined from the measurement of calcified, non calcified, and total plaque burden. There were 420 Caucasian (238 males) and 543 SA (297 males) patients. Caucasian patients were older than SA patients (54.39 +/ 11.65 vs. 49.83 +/- 11.03 years) and had lower prevalence of diabetes (13.13 vs. 32.41%) and hyperlipidaemia (56.90 vs. 68.51%) (all P-values <0.001). After adjusting for differences in cardiovascular risk factors, there were no differences in per cent diameter and area stenosis, and no difference in the proportions of patients with one-, two-, or three-vessel disease. There was no difference in total plaque burden; however, the per cent non-calcified plaque composition was lower in Caucasians compared with SA (80.95 vs. 90.42%; P-value <0.001). Conclusion: This study conducted in non-acute settings showed an ethnic difference in composition of coronary atherosclerotic plaque with lower non calcified composition in Caucasian patients compared with SA patients, which was independent of age, diabetes, hyperlipidaemia, and the other available cardiovascular risk factors. PMID- 27225818 TI - Coarser wool is not a necessary consequence of sheep aging: allometric relationship between fibre diameter and fleece-free liveweight of Saxon Merino sheep. AB - The mean fibre diameter (MFD) of wool is the primary determinant of price, processing performance and textile quality. This study determines the primary influences on MFD as Saxon Merino sheep age, by allometrically relating MFD to fleece-free liveweight (FFLwt). In total, 79 sheep were grazed in combinations of three stocking rates and two grazing systems (GS: sheep only; mixed with Angora goats) and studied over 3 years. Measurements were made over 14 consecutive periods (Segments), including segments of FFLwt gain or FFLwt loss. Using shearing and liveweight records and dye-bands on wool, the FFLwt and average daily gain (ADG) of each sheep were determined for each segment. The mean and range in key measurements were as follows: FFLwt, 40.1 (23.1 to 64.1) kg; MFD, 18.8 (12.7 to 25.8) MUm. A random coefficient restricted maximum likelihood (REML) regression mixed model was developed to relate the logarithm of MFD to the logarithm of FFLwt and other effects. The model can be written in the form of ${?rm MFD}?,{?equals}?,?rkappa ?left( {{?rm GS,}?,{?rm A}{?rm ,}?,{?rm Segment}{?rm .Plot,}?,{?rm Segment,}?,{?rm ADG}} ?right){?times}{?rm FFLwt}^{{?left( {?ralpha ?left( {{?rm GS}} ?right){?plus}?rbeta ?left(?rm A ?right){?plus}?rgamma ?left( {{?rm Segment}{?rm .Plot}} ?right)} ?right)}} $ , where $?ralpha ?left( {{?rm GS}} ?right)?,{?equals}?,?;?left?{ {?matrix{?!?! {0.32?left( {{?rm SE}?,{?equals}?,{?rm 0}{?rm .038}} ?right)?,{?rm when}?,{?rm sheep}?,{?rm are}?,{?rm grazed}?,{?rm alone}} ?hfill ?cr ?!?!?!?!{0.49?left( {{?rm SE}?,{?equals}?,{?rm 0}{?rm .049}} ?right)?,{?rm when}?,{?rm sheep}?,{?rm are}?,{?rm mixed}?,{?rm with}?,{?rm goats}} ?hfill ?cr } } ?right.$ beta(A) is a random animal effect, gamma(Segment.Plot) a random effect associated with Segment.plot combinations, and kappa a constant that depends on GS, random animal effects, random Segment.plot combination effects, Segment and ADG. Thus, MFD was allometrically related to the cube root of FFLwt over seasons and years for sheep, but to the square root of FFLwt for sheep grazed with goats. The result for sheep grazed alone accords with a primary response being that the allocation of nutrients towards the cross-sectional growth of wool follicles is proportional to the changes in the skin surface area arising from changes in the size of the sheep. The proportionality constant varied systematically with ADG, and in sheep only grazing, was about 5 when sheep lost 100 g/day and about 6 when sheep gained 100 g/day. The proportionality constant did not systematically change with chronological age. The variation in the allometric coefficient between individual sheep indicates that some sheep were more sensitive to changes in FFLwt than other sheep. Key practical implications include the following: (a) the reporting of systematic increases in MFD with age is likely to be a consequence of allowing sheep to increase in size during shearing intervals as they age; (b) comparisons of MFD between sheep are more likely to have a biological basis when standardised to a common FFLwt and not just to a common age; PMID- 27225820 TI - Charged versus Neutral Hydrogen-Bonded Complexes: Is There a Difference in the Nature of the Hydrogen Bonds? AB - A theoretical study on some carboxylic acid dimers formed by positively or negatively charged molecules has been carried out by using DFT methods. The resulting dimers possess either a charge of +2 or -2. In addition, the corresponding neutral complexes have also been considered. The electron density distribution described by the atoms in molecules and the natural bond orbital methods, as well as the electric field maps of the systems, have been analyzed and compared without finding significant differences between the neutral and ionic complexes. The interaction energy along the dissociation path of the charged dimers shows both a local minimum and a local maximum, defining a stability region between them. When this energetic profile is recalculated by removing the repulsion between the charged groups, it resembles to those of the neutral molecules. Hence, the characteristics of the charged dimers are similar to those of the neutral ones: the addition of a repulsion term for the charged groups permits to retrieve the energetic profiles dependence with the distance in the charged system. The interacting quantum atom (IQA) method has been used to calculate the interaction energy terms, including the classic Coulombic term between the whole molecules and the corresponding of the carboxylic acid groups. The IQA results show repulsive electrostatic interactions when the whole molecules are considered in the ionic complexes, but attractive ones between the carboxylic groups in both neutral and ionic complexes. PMID- 27225819 TI - BRCA1-2 diagnostic workflow from next-generation sequencing technologies to variant identification and final report. AB - The BRCA1-BRCA2 genes predispose to hereditary breast and ovarian cancer, and the germline and mutational status of these genes defines a target population that can benefit from PARP inhibitor treatments. To respond to the increasing number of BRCA1-BRCA2 tests, it is necessary to shift to high-throughput technologies that are reliable and less time consuming. Different methodological platforms are dedicated to this purpose with different approaches and algorithms for analysis. Our aim was to set up a cost-effective and low time-consuming BRCA1-BRCA2 mutation detection workflow using the Ion Torrent PGM technology. A retrospective cohort of 40 patients with familial breast/ovarian cancer previously tested by Sanger sequencing and a prospective cohort of 72 patients (validation set) were analyzed. The validation set included 64 patients affected by familial breast/ovarian cancer and eight sporadic ovarian cancer cases, who are potential candidates for PARPi treatments. A complete and standardized workflow easily usable and suitable in a certified laboratory has been proved and validated. This includes all steps from library preparation to the final report. The use of next generation sequencing will be of benefit for patients enrolled in the genetic counseling process and, moreover, will enhance the process of selecting patients eligible for personalized treatments. (c) 2016 Wiley Periodicals, Inc. PMID- 27225821 TI - Label-free nonlinear optical microscopy detects early markers for osteogenic differentiation of human stem cells. AB - Tissue engineering by stem cell differentiation is a novel treatment option for bone regeneration. Most approaches for the detection of osteogenic differentiation are invasive or destructive and not compatible with live cell analysis. Here, non-destructive and label-free approaches of Raman spectroscopy, coherent anti-Stokes Raman scattering (CARS) and second harmonic generation (SHG) microscopy were used to detect and image osteogenic differentiation of human neural crest-derived inferior turbinate stem cells (ITSCs). Combined CARS and SHG microscopy was able to detect markers of osteogenesis within 14 days after osteogenic induction. This process increased during continued differentiation. Furthermore, Raman spectroscopy showed significant increases of the PO4(3-) symmetric stretch vibrations at 959 cm(-1) assigned to calcium hydroxyapatite between days 14 and 21. Additionally, CARS microscopy was able to image calcium hydroxyapatite deposits within 14 days following osteogenic induction, which was confirmed by Alizarin Red-Staining and RT- PCR. Taken together, the multimodal label-free analysis methods Raman spectroscopy, CARS and SHG microscopy can monitor osteogenic differentiation of adult human stem cells into osteoblasts with high sensitivity and spatial resolution in three dimensions. Our findings suggest a great potential of these optical detection methods for clinical applications including in vivo observation of bone tissue-implant-interfaces or disease diagnosis. PMID- 27225822 TI - Optimum anesthesia for reliable urethral pressure profilometry in female dogs and goats. AB - OBJECTIVES: To investigate the effects of propofol and isoflurane on urethral pressure profilometry of female dogs and goats, and to identify the method of anesthesia that least influences urethral pressure profilometry and to assess its reproducibility. METHODS: The effects of premedication with midazolam, propofol sedation and isoflurane anesthesia were assessed in five female dogs. The effects of propofol and isoflurane were compared in seven goats, whereas in another group of 19 goats, the state of deep propofol sedation was compared with the state of recovery from propofol sedation. The coefficient of reproducibility and within subject coefficient of variation were calculated to evaluate test-retest reproducibility. RESULTS: In conscious female dogs, maximal urethral closure pressure and functional area were significantly higher than under propofol or isoflurane (P = 0.04), but not different from the recovery state. In six of seven goats, maximal urethral closure pressure and functional area were higher when measured under propofol sedation than under isoflurane (median maximal urethral closure pressure, 69 vs 47 cmH2 O; P = 0.03). Maximal urethral closure pressure was lower under propofol than during recovery from propofol in 17 of 19 goats (median maximal urethral closure pressure, 54 vs 66 cmH2 O; P < 0.001). The test retest coefficient of reproducibility for goats was 28 cmH2 O, and the within subject coefficient of variation was 16%. CONCLUSIONS: In dogs, urethral pressure profilometry should be measured in conscious animals whenever possible. In goats, urethral pressure profilometry is least affected during recovery from propofol sedation, and it shows acceptable reproducibility under this condition. PMID- 27225823 TI - Disruption of Fibers from the Tau Model AcPHF6 by Naturally Occurring Aurones and Synthetic Analogues. AB - The formation of tau aggregates is strongly linked to the neurodegenerative process in tauopathies such as Alzheimer's disease (AD). Yet only a few molecules have shown to efficiently prevent the in vitro formation of those aggregates, and the identification of such molecules is still an ongoing interest in a therapeutic context. Herein, we report the in vitro evaluation of a series of aurones against the fibrillation of the tau-derived hexapeptide AcPHF6 model. Using thioflavin T-based fluorescence assays, circular dichroism and atomic force microscopy, we showed that aurones are capable of efficiently interacting with the tau-derived hexapeptide. Importantly, this work reveals a significant activity observed for polyhydroxylated aurones. In particular, aurone 23 displayed an almost complete inhibition of fibers formation as shown by AFM at a peptide/inhibitor 1:1 ratio. It is similar to that observed for myricetin, a polyphenolic compound, well-known to prevent the in vitro elongation of tau fibers. Moreover, a tetrahydroxylated isomer, compound 24, was shown as a chemical probe of fibers rather than an inhibitor. Consequently, these results highlight aurones as a new promising scaffold to interfere with tau aggregation for both treatment and diagnosis of AD. PMID- 27225824 TI - Hypoxia-responsive nanocarriers for cancer imaging and therapy: recent approaches and future perspectives. AB - Hypoxia, a condition in which the tissue is deprived of adequate oxygen supply, is a salient feature of various intractable diseases, including rheumatoid arthritis, ischemic stroke, and solid tumors. In particular, hypoxic regions in tumors are often associated with invasiveness, metastasis, and resistance to radiotherapy and chemotherapy. Given its unique role in tumor progression, hypoxia has been considered to be a primary target for the diagnosis and treatment of cancer. Owing to their sizes and tailorable physicochemical characteristics, nanocarriers are an emerging class of materials that are increasingly utilized in biomedical applications. Particularly, stimuli responsive nanocarriers, which release their payloads specifically at the tumor microenvironment, are materials of interest. Owing to the aberrant vascular properties of tumors, the transportation of anticancer drugs to hypoxic regions is challenging because they are distant from blood vessels. In addition, hypoxia upregulates various genes involved in drug resistance such as P-glycoprotein. To surmount the issues associated with hypoxia, nanocarriers that can release imaging agents or anticancer drugs in hypoxic regions must be developed. This review focuses on recently developed hypoxia-responsive conjugates or nanocarriers and their potential applications in cancer imaging and therapy. Low oxygen levels bring forth conformational changes in hypoxia-responsive nanocarriers through the cleavage or reduction of hypoxia-responsive functional groups. A greater understanding of these changes will help to design more efficient nanocarriers to address the challenges encountered with hypoxia in conventional chemotherapy. PMID- 27225825 TI - Comparison of archaeal and bacterial communities in two sponge species and seawater from an Indonesian coral reef environment. AB - Most existing coral reef studies have focused on a single biotope and a single domain (Archaea or Bacteria). Few coral reef studies have explored the archaeal and bacterial community simultaneously. In this study, we compare the diversity and composition of archaeal and bacterial communities in seawater and two closely related sponge species (Stylissa carteri and Stylissa massa) in the Berau reef system, Indonesia. A 16S rRNA gene barcoded pyrosequencing approach was used to test to what extent seawater, S. carteri and S. massa host compositionally distinct communities of Archaea and Bacteria. Proteobacteria dominated the bacterial communities of all three studied biotopes whereas Euryarchaeota was the most abundant archaeal phylum in seawater and Crenarchaeota the most abundant archaeal phylum in both Stylissa species. Biotopes explained 56% and 53% of the variation in archaeal and bacterial composition respectively and there was significant congruence between the composition of archaeal and bacterial communities. These results suggest that the processes that drive bacterial composition within the studied biotopes may be fundamentally similar to those that drive archaeal composition. PMID- 27225827 TI - Self-Sensitized Carbon Nitride Microspheres for Long-Lasting Visible-Light-Driven Hydrogen Generation. AB - A new type of metal-free photocatalyst is reported having a microsphere core of oxygen-containing carbon nitride and self-sensitized surfaces by covalently linked polymeric triazine dyes. These self-sensitized carbon nitride microspheres exhibit high visible-light activities in photocatalytic H2 generation with excellent stability for more than 100 h reaction. Comparing to the traditional g C3 N4 with activities terminated at 450 nm, the polymeric triazine dyes on the carbon nitride microsphere surface allow for effective wide-range visible-light harvesting and extend the H2 generation activities up to 600 nm. It is believed that this new type of highly stable self-sensitized metal-free structure opens a new direction of future development of low-cost photocatalysts for efficient and long-term solar fuels production. PMID- 27225828 TI - A tool for the consensual analysis of decision-making scenarios. AB - The authors believe there is a need for novel ways of enhancing professional judgment and discretion in the contemporary healthcare environment. The objective is to provide a framework to guide a discursive analysis of an ongoing clinical scenario by a small group of healthcare professionals (4-12) to achieve consensual understanding in the decision-making necessary to resolve specific healthcare inadequacies and promote organisational learning. REPVAD is an acronym for the framework's five decision-making dimensions of reasoning, evidence, procedures, values, attitudes and defences. The design is set out in terms of well-defined definitions of the dimensions, a rationale for using REPVAD, and explications of dimensions one at a time. Furthermore, the REPVAD process of application to a scenario is set out, and a didactic scenario is given to show how REPVAD works together with a sample case. A discussion is fleshed out in four real life student cases, and a conclusion indicates strengths and weaknesses and the possibility of further development and transferability. In terms of findings, the model has been tried, tested and refined over a number of years in the development of advanced practitioners at university healthcare faculties in two European countries. Consent was obtained from the four participating students. PMID- 27225826 TI - Multisignal control of expression of the LHCX protein family in the marine diatom Phaeodactylum tricornutum. AB - Diatoms are phytoplanktonic organisms that grow successfully in the ocean where light conditions are highly variable. Studies of the molecular mechanisms of light acclimation in the marine diatom Phaeodactylum tricornutum show that carotenoid de-epoxidation enzymes and LHCX1, a member of the light-harvesting protein family, both contribute to dissipate excess light energy through non photochemical quenching (NPQ). In this study, we investigate the role of the other members of the LHCX family in diatom stress responses. Our analysis of available genomic data shows that the presence of multiple LHCX genes is a conserved feature of diatom species living in different ecological niches. Moreover, an analysis of the levels of four P. tricornutum LHCX transcripts in relation to protein expression and photosynthetic activity indicates that LHCXs are differentially regulated under different light intensities and nutrient starvation, mostly modulating NPQ capacity. We conclude that multiple abiotic stress signals converge to regulate the LHCX content of cells, providing a way to fine-tune light harvesting and photoprotection. Moreover, our data indicate that the expansion of the LHCX gene family reflects functional diversification of its members which could benefit cells responding to highly variable ocean environments. PMID- 27225829 TI - Blue-shifted emission and enhanced quantum efficiency viapi-bridge elongation in carbazole-carborane dyads. AB - Carbazole-carborane linear dyads and di(carbazole)-carborane V-shaped dyads with phenyleneethynylene-based bridges have been synthesized. The V-shaped dyads display the expected red-shifts in the location of their UV-Vis absorption maxima on bridge-lengthening, but show unusual blue-shifts in charge-transfer (CT) emission on the same pi-system lengthening. These blue-shifts can be attributed to the 2n + 3 electron count within the carborane cluster in the excited state. The linear dyads luminesce via a combination of local excited (LE) and CT emission, with a red-shift in LE emission and a blue-shift in CT emission accompanying pi-bridge elongation. A quantum efficiency as high as 86% in the solution state is achieved from the hybrid LE/CT emission. Time-dependent density functional theory (TD-DFT) calculations at the excited state of these compounds have clarified the photoluminescence blue-shift and suggested a typical cluster C C bond elongation in the V-shaped dyads. Calculations on the elongated linear dyads have suggested that the electron density is localized at the phenyleneethynylene-containing bridge. PMID- 27225831 TI - A case of epidermolytic ichthyosis showing a very mild phenotype due to a novel tail extension mutation in KRT10. PMID- 27225832 TI - The Effects of Mipomersen on Inhibiting Hepatic VLDL Apolipoprotein B100 Synthesis and Propensity for Hepatic Steatosis. PMID- 27225830 TI - NLRP3 Deficiency Reduces Macrophage Interleukin-10 Production and Enhances the Susceptibility to Doxorubicin-induced Cardiotoxicity. AB - NLRP3 inflammasomes recognize non-microbial danger signals and induce release of proinflammatory cytokine interleukin (IL)-1beta, leading to sterile inflammation in cardiovascular disease. Because sterile inflammation is involved in doxorubicin (Dox)-induced cardiotoxicity, we investigated the role of NLRP3 inflammasomes in Dox-induced cardiotoxicity. Cardiac dysfunction and injury were induced by low-dose Dox (15 mg/kg) administration in NLRP3-deficient (NLRP3(-/-)) mice but not in wild-type (WT) and IL-1beta(-/-) mice, indicating that NLRP3 deficiency enhanced the susceptibility to Dox-induced cardiotoxicity independent of IL-1beta. Although the hearts of WT and NLRP3(-/-) mice showed no significant difference in inflammatory cell infiltration, macrophages were the predominant inflammatory cells in the hearts, and cardiac IL-10 production was decreased in Dox-treated NLRP3(-/-) mice. Bone marrow transplantation experiments showed that bone marrow-derived cells contributed to the exacerbation of Dox-induced cardiotoxicity in NLRP3(-/-) mice. In vitro experiments revealed that NLRP3 deficiency decreased IL-10 production in macrophages. Furthermore, adeno associated virus-mediated IL-10 overexpression restored the exacerbation of cardiotoxicity in the NLRP3(-/-) mice. These results demonstrated that NLRP3 regulates macrophage IL-10 production and contributes to the pathophysiology of Dox-induced cardiotoxicity, which is independent of IL-1beta. Our findings identify a novel role of NLRP3 and provided new insights into the mechanisms underlying Dox-induced cardiotoxicity. PMID- 27225833 TI - Discovery of Potent Succinate-Ubiquinone Oxidoreductase Inhibitors via Pharmacophore-linked Fragment Virtual Screening Approach. AB - Succinate-ubiquinone oxidoreductase (SQR) is an attractive target for fungicide discovery. Herein, we report the discovery of novel SQR inhibitors using a pharmacophore-linked fragment virtual screening approach, a new drug design method developed in our laboratory. Among newly designed compounds, compound 9s was identified as the most potent inhibitor with a Ki value of 34 nM against porcine SQR, displaying approximately 10-fold higher potency than that of the commercial control penthiopyrad. Further inhibitory kinetics studies revealed that compound 9s is a noncompetitive inhibitor with respect to the substrate cytochrome c and DCIP. Interestingly, compounds 8a, 9h, 9j, and 9k exhibited good in vivo preventive effects against Rhizoctonia solani. The results obtained from molecular modeling showed that the orientation of the R(2) group had a significant effect on binding with the protein. PMID- 27225836 TI - Transfusion-transmitted bacterial infection: a 2-year survey. PMID- 27225834 TI - Changing motor perception by sensorimotor conflicts and body ownership. AB - Experimentally induced sensorimotor conflicts can result in a loss of the feeling of control over a movement (sense of agency). These findings are typically interpreted in terms of a forward model in which the predicted sensory consequences of the movement are compared with the observed sensory consequences. In the present study we investigated whether a mismatch between movements and their observed sensory consequences does not only result in a reduced feeling of agency, but may affect motor perception as well. Visual feedback of participants' finger movements was manipulated using virtual reality to be anatomically congruent or incongruent to the performed movement. Participants made a motor perception judgment (i.e. which finger did you move?) or a visual perceptual judgment (i.e. which finger did you see moving?). Subjective measures of agency and body ownership were also collected. Seeing movements that were visually incongruent to the performed movement resulted in a lower accuracy for motor perception judgments, but not visual perceptual judgments. This effect was modified by rotating the virtual hand (Exp.2), but not by passively induced movements (Exp.3). Hence, sensorimotor conflicts can modulate the perception of one's motor actions, causing viewed "alien actions" to be felt as one's own. PMID- 27225837 TI - Determination of ibuprofen enantiomers in human plasma by HPLC-MS/MS: validation and application in neonates. AB - AIM: An adaptive method to determine ibuprofen enantiomers with limited volume of plasma required is necessary for investigating PK of ibuprofen in neonates. RESULTS: Enantiomer separation was achieved on a Lux cellulose 3 column with mobile phase consisting of methanol water (85:15, v/v) and formic acid (0.0075%) at isocratic rate of 0.2 ml/min. Calibration curve is linear for each enantiomer at the range of 0.1-60 MUg/ml. Validation was conducted and results met requirements regarding to intra- and inter-run precision, accuracy and recovery. No matrix effect or interference was observed from neonatal plasma or comedications. Only 20 MUl of plasma was requested in this study. CONCLUSION: This assay was specific and reliable to quantify ibuprofen enantiomers in neonate plasma. PMID- 27225838 TI - Investigation of the antifungal activity of carvacrol against strains of Cryptococcus neoformans. AB - BACKGROUND: Cryptococcus neoformans is the etiologic agent of opportunistic systemic fungal infection cryptococcosis, which affects individuals with compromised immune systems. Thus, natural products research has become important, since monoterpenes such as carvacrol, a promising molecule in the search antifungal agents, have shown significant biological activity. OBJECTIVE: The study aimed to investigate the antifungal activity and mode of action of carvacrol against strains of C. neoformans. METHODS: The minimum inhibitory concentration (MIC) was determined by microdilution method. Minimum fungicidal concentration (MFC) was performed by seeding technique on solid media. Studying the mode of action was performed using broth microdilution. RESULTS: The MIC ranged from 25 to 81 MUg/mL and the MFC ranged from 25 to 102 MUg/mL. Carvacrol bonded to exogenous ergosterol and cholesterol. DISCUSSION: The results suggest that carvacrol has antifungal activity against C. neoformans and its mode of action is related to fungal membrane instability. CONCLUSIONS: The phytoconstituent carvacrol may eventually become a drug; however, further studies are needed to elucidate its mechanism. PMID- 27225839 TI - Do asthma medications cause birth defects? PMID- 27225840 TI - External Validation of the Hestia Criteria for Identifying Acute Pulmonary Embolism Patients at Low Risk of Early Mortality. AB - INTRODUCTION: There are limited studies evaluating the ability of the Hestia criteria to accurately identify patients with acute pulmonary embolism (PE) at low risk of early mortality. We sought to externally validate the Hestia criteria for predicting in-hospital and 30-day post-PE mortality. METHODS: We retrospectively identified consecutive, adult, objectively confirmed PE patients presenting to the emergency department at our institution from November 21, 2010, to January 31, 2014. We ascertained the total number of Hestia criteria met for each patient, calculated the proportion of patients categorized as low risk (ie, no Hestia criteria met), and determined the accuracy of the Hestia criteria for predicting in-hospital and 30-day all-cause mortality. Mortality was determined through Social Security Death Index searches. RESULTS: A total of 577 patients with PE were included, of which 19 (3.3%) and 35 (6.6%) died in hospital or within 30 days of presentation. Both in-hospital and 30-day case fatality rates rose as the number of Hestia criteria increased. One-hundred forty nine (25.8%) patients were classified as low risk for early mortality, and none of these patients died within 30 days (negative predictive values of 100%). The Hestia criteria had excellent sensitivity (100%, 95% confidence interval [CI] = 79.1% 100% and 100%, 95% CI = 87.7%-100%) for predicting in-hospital and 30-day mortality but low specificity (<27.5% for both). The c-statistics for in-hospital and 30-day mortality were 83.5%, 95% CI = 77.1%-89.9% and 78.5%, 95% CI = 71.9% 85.1%. The predictive accuracy of the Hestia criteria remained acceptable in patients >80 years of age, with active cancer or chronic cardiopulmonary disease. CONCLUSION: The Hestia criteria have an acceptable predictive accuracy to identify patients with PE at low risk for in-hospital or 30-day mortality. PMID- 27225841 TI - Metformin Protects Cells from Mutant Huntingtin Toxicity Through Activation of AMPK and Modulation of Mitochondrial Dynamics. AB - Huntington's disease (HD) is a devastating neurodegenerative disease caused by the pathological elongation of the CAG repeats in the huntingtin gene. Caloric restriction (CR) has been the most reproducible environmental intervention to improve health and prolong life span. We have demonstrated that CR delayed onset and slowed disease progression in a mouse model of HD. Metformin, an antidiabetic drug, mimics CR by acting on cell metabolism at multiple levels. Long-term administration of metformin improved health and life span in mice. In this study, we showed that metformin rescued cells from mutant huntingtin (HTT)-induced toxicity, as indicated by reduced lactate dehydrogenase (LDH) release from cells and preserved ATP levels in cells expressing mutant HTT. Further mechanistic study indicated that metformin activated AMP-activated protein kinase (AMPK) and that inhibition of AMPK activation reduced its protective effects on mutant HTT toxicity, suggesting that AMPK mediates the protection of metformin in HD cells. Furthermore, metformin treatment prevented mitochondrial membrane depolarization and excess fission and modulated the disturbed mitochondrial dynamics in HD cells. We confirmed that metformin crossed the blood-brain barrier after oral administration and activated AMPK in the mouse brain. Our results urge further evaluation of the clinical potential for use of metformin in HD treatment. PMID- 27225842 TI - Soil Water Balance and Water Use Efficiency of Dryland Wheat in Different Precipitation Years in Response to Green Manure Approach. AB - Winter wheat (Triticum aestivum L.) monoculture is conventionally cultivated followed by two to three months of summer fallow in the Loess Plateau. To develop a sustainable cropping system, we conducted a six-year field experiment to investigate the effect of leguminous green manure (LGM) instead of bare fallow on the yield and water use efficiency (WUE) of winter wheat and the soil water balance (SWB) in different precipitation years in a semi-arid region of northwest China. Results confirmed that planting LGM crop consumes soil water in the fallow season can bring varied effects to the subsequent wheat. The effect is positive or neutral when the annual precipitation is adequate, so that there is no significant reduction in the soil water supplied to wheat. If this is not the case, the effect is negative. On average, the LGM crop increased wheat yield and WUE by 13% and 28%, respectively, and had considerable potential for maintaining the SWB (0-200 cm) compared with fallow management. In conclusion, cultivation of the LGM crop is a better option than fallow to improve the productivity and WUE of the next crop and maintain the soil water balance in the normal and wet years in the Loess Plateau. PMID- 27225843 TI - Chromatin dynamics during DNA replication. AB - Chromatin is composed of DNA and histones, which provide a unified platform for regulating DNA-related processes, mostly through their post-translational modification. During DNA replication, histone arrangement is perturbed, first to allow progression of DNA polymerase and then during repackaging of the replicated DNA. To study how DNA replication influences the pattern of histone modification, we followed the cell-cycle dynamics of 10 histone marks in budding yeast. We find that histones deposited on newly replicated DNA are modified at different rates: While some marks appear immediately upon replication (e.g., H4K16ac, H3K4me1), others increase with transcription-dependent delays (e.g., H3K4me3, H3K36me3). Notably, H3K9ac was deposited as a wave preceding the replication fork by ~5-6 kb. This replication-guided H3K9ac was fully dependent on the acetyltransferase Rtt109, while expression-guided H3K9ac was deposited by Gcn5. Further, topoisomerase depletion intensified H3K9ac in front of the replication fork and in sites where RNA polymerase II was trapped, suggesting supercoiling stresses trigger H3K9 acetylation. Our results assign complementary roles for DNA replication and gene expression in defining the pattern of histone modification. PMID- 27225845 TI - Hb Grifton [alpha87(F8)His->Pro; HBA1: C.263A > C (or HBA2)] Causes Abnormal Pulse Oximetry Measurements. AB - An asymptomatic toddler and his mother consistently demonstrated low transcutaneous pulse oximetry (SpO2) measurements, discordant with normal arterial blood gas analyses while breathing room air. Previous evaluations by medical teams were unable to identify an etiology of their perceived hypoxia. Further investigation revealed that the boy carried an abnormal variant, Hb Grifton or alpha87(F8)His->Pro; HBA1: c.263A > C (or HBA2), discovered on newborn screening, which was not suspected as the underlying cause of his abnormal pulse oximetry readings until an inpatient admission to our hospital for asymptomatic "hypoxia," where he was found to share these same characteristics with his mother. We showed that a difference in light absorption between the oxygenated Hb Grifton variant and oxygenated Hb A resulted in erroneous pulse oximetry values. This phenomenon has previously been reported in a handful of other variant Hbs. Astute clinical suspicion, in conjunction with laboratory testing leading to correct diagnoses of variant Hbs, may prevent expensive work-ups and unnecessary medical treatments for asymptomatic patients falsely presumed to be hypoxemic based on low pulse oximetry measurements. PMID- 27225844 TI - Genome-wide analysis of chromatin packing in Arabidopsis thaliana at single-gene resolution. AB - The three-dimensional packing of the genome plays an important role in regulating gene expression. We have used Hi-C, a genome-wide chromatin conformation capture (3C) method, to analyze Arabidopsis thaliana chromosomes dissected into subkilobase segments, which is required for gene-level resolution in this species with a gene-dense genome. We found that the repressive H3K27me3 histone mark is overrepresented in the promoter regions of genes that are in conformational linkage over long distances. In line with the globally dispersed distribution of RNA polymerase II in A. thaliana nuclear space, actively transcribed genes do not show a strong tendency to associate with each other. In general, there are often contacts between 5' and 3' ends of genes, forming local chromatin loops. Such self-loop structures of genes are more likely to occur in more highly expressed genes, although they can also be found in silent genes. Silent genes with local chromatin loops are highly enriched for the histone variant H3.3 at their 5' and 3' ends but depleted of repressive marks such as heterochromatic histone modifications and DNA methylation in flanking regions. Our results suggest that, different from animals, a major theme of genome folding in A. thaliana is the formation of structural units that correspond to gene bodies. PMID- 27225846 TI - Predicting patient survival after deceased donor kidney transplantation using flexible parametric modelling. AB - BACKGROUND: The influence of donor and recipient factors on outcomes following kidney transplantation is commonly analysed using Cox regression models, but this approach is not useful for predicting long-term survival beyond observed data. We demonstrate the application of a flexible parametric approach to fit a model that can be extrapolated for the purpose of predicting mean patient survival. The primary motivation for this analysis is to develop a predictive model to estimate post-transplant survival based on individual patient characteristics to inform the design of alternative approaches to allocating deceased donor kidneys to those on the transplant waiting list in the United Kingdom. METHODS: We analysed data from over 12,000 recipients of deceased donor kidney or combined kidney and pancreas transplants between 2003 and 2012. We fitted a flexible parametric model incorporating restricted cubic splines to characterise the baseline hazard function and explored a range of covariates including recipient, donor and transplant-related factors. RESULTS: Multivariable analysis showed the risk of death increased with recipient and donor age, diabetic nephropathy as the recipient's primary renal diagnosis and donor hypertension. The risk of death was lower in female recipients, patients with polycystic kidney disease and recipients of pre-emptive transplants. The final model was used to extrapolate survival curves in order to calculate mean survival times for patients with specific characteristics. CONCLUSION: The use of flexible parametric modelling techniques allowed us to address some of the limitations of both the Cox regression approach and of standard parametric models when the goal is to predict long-term survival. PMID- 27225848 TI - Novel HPS6 mutations identified by whole-exome sequencing in two Japanese sisters with suspected ocular albinism. AB - Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism, platelet dysfunction and ceroid deposition. We report suspected ocular albinism in two Japanese sisters, caused by mutations in the HPS6 (Hermansky-Pudlak syndrome 6) gene. Trio-based whole-exome sequencing (WES) identified novel compound heterozygous mutations in HPS6 (c.1898delC: mother origin and c.2038C>T: father origin) in the two sisters. To date, 10 associated mutations have been detected in HPS6. Although we detected no general manifestations, including platelet dysfunction, in the sisters, even in long-term follow-up, we established a diagnosis of HPS type 6 based on the HPS6 mutations and absence of dense bodies in the platelets, indicating that WES can identify cases of HPS type 6. To the best of our knowledge, this is the first report of HPS6 mutations in Japanese patients. PMID- 27225847 TI - Additive composite ABCG2, SLC2A9 and SLC22A12 scores of high-risk alleles with alcohol use modulate gout risk. AB - The aim of the present study was to evaluate the contribution of urate transporter genes and alcohol use to the risk of gout/tophi. Eight variants of ABCG2, SLC2A9, SLC22A12, SLC22A11 and SLC17A3 were genotyped in male individuals in a case-control study with 157 gout (33% tophi), 106 asymptomatic hyperuricaemia and 295 control subjects from Taiwan. The multilocus profiles of the genetic risk scores for urate gene variants were used to evaluate the risk of asymptomatic hyperuricaemia, gout and tophi. ABCG2 Q141K (T), SLC2A9 rs1014290 (A) and SLC22A12 rs475688 (C) under an additive model and alcohol use independently predicted the risk of gout (respective odds ratio for each factor=2.48, 2.03, 1.95 and 2.48). The additive composite Q141K, rs1014290 and rs475688 scores of high-risk alleles were associated with gout risk (P<0.0001). We observed the supramultiplicative interaction effect of genetic urate scores and alcohol use on gout and tophi risk (P for interaction=0.0452, 0.0033). The synergistic effect of genetic urate score 5-6 and alcohol use indicates that these combined factors correlate with gout and tophi occurrence. PMID- 27225849 TI - Expanding the mutation spectrum in 130 probands with ARPKD: identification of 62 novel PKHD1 mutations by sanger sequencing and MLPA analysis. AB - Autosomal recessive polycystic kidney disease (ARPKD) is a rare severe genetic disorder arising in the perinatal period, although a late-onset presentation of the disease has been described. Pulmonary hypoplasia is the major cause of morbidity and mortality in the newborn period. ARPKD is caused by mutations in the PKHD1 (polycystic kidney and hepatic disease 1) gene that is among the largest human genes. To achieve a molecular diagnosis of the disease, a large series of Italian affected subjects were recruited. Exhaustive mutation analysis of PKHD1 gene was carried out by Sanger sequencing and multiple ligation probe amplification (MLPA) technique in 110 individuals. A total of 173 mutations resulting in a detection rate of 78.6% were identified. Additional 20 unrelated patients, in whom it was not possible to analyze the whole coding sequence, have been included in this study. Taking into account the total number (n=130) of this cohort of patients, 107 different types of mutations have been detected in 193 mutated alleles. Out of 107 mutations, 62 were novel: 11 nonsense, 6 frameshift, 7 splice site mutations, 2 in-frame deletions and 2 multiexon deletion detected by MLPA. Thirty-four were missense variants. In conclusion, our report expands the spectrum of PKHD1 mutations and confirms the heterogeneity of this disorder. The population under study represents the largest Italian ARPKD cohort reported to date. The estimated costs and the time invested for molecular screening of genes with large size and allelic heterogeneity such as PKHD1 demand the use of next-generation sequencing (NGS) technologies for a faster and cheaper screening of the affected subjects. PMID- 27225850 TI - De novo MEIS2 mutation causes syndromic developmental delay with persistent gastro-esophageal reflux. AB - MEIS2 aberrations are considered to be the cause of intellectual disability, cleft palate and cardiac septal defect, as MEIS2 copy number variation is often observed with these phenotypes. To our knowledge, only one nucleotide-level change-specifically, an in-frame MEIS2 deletion-has so far been reported. Here, we report a female patient with a de novo nonsense mutation (c.611C>G, p.Ser204*) in MEIS2. She showed severe intellectual disability, moderate motor/verbal developmental delay, cleft palate, cardiac septal defect, hypermetropia, severe feeding difficulties with gastro-esophageal reflux and constipation. By reviewing this patient and previous patients with MEIS2 point mutations, we found that feeding difficulty with gastro-esophageal reflux appears to be one of the core clinical features of MEIS2 haploinsufficiency, in addition to intellectual disability, cleft palate and cardiac septal defect. PMID- 27225851 TI - Fabry disease in patients with hypertrophic cardiomyopathy: a practical approach to diagnosis. AB - This study aimed to develop a new set of screening criteria that is easily applicable and highly sensitive for the detection of patients at high risk of Fabry disease (FD) among hypertrophic cardiomyopathy (HCM) patients. We prospectively studied 273 consecutive unrelated patients who were referred to HCM clinic for unknown left ventricular hypertrophy. Among the 273 patients, we selected 65 high-risk patients who fulfilled at least one of our newly proposed screening criteria. All 273 patients were assayed for plasma alpha-galactosidase A (alpha-GAL A) activity. The new screening criteria were: (1) atypical HCM, (2) history or presence of documented arrhythmia, (3) short PR interval defined as <120 ms on electrocardiogram, and (4) symptoms of autonomic dysfunction. From this screening study, three unrelated patients (4.6%; 2 females and 1 male) were newly diagnosed with FD using alpha-GAL A activity and mutation analysis of the GLA gene. Using the screening method based on the newly proposed criteria, the prevalence of FD in our HCM population was 4.6% if at least one criterion was met and 18.8% if ?3 criteria were met. Therefore, our proposed criteria are easily applicable and highly sensitive for classifying patients at high risk of FD from HCM patients. PMID- 27225852 TI - MicroRNAs and liver disease. AB - The biological roles of microRNAs (miRNAs) have been extensively studied. miRNA122 represents more than half of the miRNAs expressed in the liver and has various physiological and pathological functions, which include enhancing hepatitis virus replication, regulating lipid metabolism and suppressing hepatocellular carcinoma. miRNAs, whether globally or individually, have been linked with hepatocarcinogenesis. Furthermore, some miRNAs have been shown to be involved in the pathogenesis of nonalcoholic steatohepatitis. Using nucleotide based strategies, these miRNAs may be developed as potential therapeutic targets. Because changes in miRNA expression can be measured in sera, they may be used as non-invasive biomarkers if they correctly reflect the pathological state of the liver. In this review, we show the biological roles of representative miRNAs in liver disease and discuss the current issues that remain to be clarified for future clinical applications. PMID- 27225853 TI - Safety and Tolerability of Stribild in the Southeast United States. AB - PURPOSE: The purpose of this study is to assess postmarketing safety and tolerability of Stribild (elvitegravir [EVG]/cobicistat [COBI]/tenofovir disoproxil fumarate [TDF]/emtricitabine [FTC]). METHODS: A retrospective, pharmacoepidemiologic study in 2 outpatient HIV clinics in the Southeast United States was conducted among adults receiving EVG/COBI/TDF/FTC. We evaluated incidence and treatment-related adverse events, including change in serum creatinine (SCr). RESULTS: Patients were primarily treatment experienced (n = 173, 60%), African American (n = 210, 73%), and males (n = 187, 65%). One hundred ninety-five (68%) patients had any increase in SCr, and 65 (23%) had an increase of >=0.3 mg/dL. Mean SCr change from baseline to peak was 0.2 mg/dL. Being treatment experienced (odds ratio [OR] = 2.21, 95% confidence interval [CI]: 1.12 4.38) was associated with SCr >=0.3 mg/dL, while body mass index >=30 kg/m(2) (OR = 0.41, 95% CI: 0.18-0.93) was protective. Twenty (7%) patients discontinued therapy, 3 due to acute kidney injury. CONCLUSION: Our results demonstrate limited adverse events and low discontinuation rates associated with EVG/COBI/TDF/FTC. PMID- 27225855 TI - Teaching by (bad) example: what a confused attempt to "advance" EBM reveals about its underlying problems: commentary on Jenicek, M. (2015). Do we need another discipline in medicine? From epidemiology and evidence-based medicine to cognitive medicine and medical thinking. Journal of evaluation in clinical practice, 21:1028-1034. AB - Professor Jenicek's paper is confused in that his proposal to 'integrate' what he means by 'evidence-based scientific theory and cognitive approaches to medical thinking' actually embodies a contradiction. But, although confused, he succeeds in teaching us more about the EBM debate than those who seem keen to forge ahead without addressing the underlying epistemological problems that Jenicek brings to our attention. Fundamental questions about the relationship between evidence, knowledge and reason still require resolution if we are to see a genuine advance in this debate. PMID- 27225854 TI - Antiretroviral Therapy in Children Less Than 24 Months of Age at Pediatric HIV Centers in Tanzania: 12-Month Clinical Outcomes and Survival. AB - BACKGROUND: Without antiretroviral therapy (ART), approximately one-half of HIV infected infants will die by two years. In 2010, the World Health Organization (WHO) recommended that all HIV-infected infants < 24 months be initiated on ART regardless of their clinical/immunologic status. However, there remains little published data detailing cohorts of infants on ART in Sub-Saharan Africa. This study describes baseline characteristics and 12 month outcomes of a cohort of HIV infected children < 24 months of age at pediatric HIV centers in Mwanza and Mbeya, Tanzania. MATERIALS AND METHODS: Retrospective chart review. INCLUSION CRITERIA: children < 24 months of age, initiated on ART at Baylor Children s Foundation Tanzania clinics, between March-December 2011. RESULTS: Baseline: Ninety-three children were initiated on ART at a median age of 13.4 months. Sixty seven percent had severe immunosuppression and 31.5% had severe malnutrition. OUTCOME: Seventy-three patients were still in care at 12 month follow-up, there were four (4.3%) deaths, five (5.4%) patients transferred, and 11 (11.8%) loss to follow-up. Average CD4% was 32.7 (p < 0.001). Ninety percent of patients were WHO treatment stage I (p < 0.001). Eighty-six percent had normal nutritional status (p < 0.001). CONCLUSION: Our cohort of HIV infected children < 24 months initiated on ART did well clinically at 12 month outcomes despite being severely immunocompromised and malnourished at baseline. Nevirapine based regimens had good 12 month clinical outcomes, regardless of maternal exposure. Loss to follow up rate was high for our cohort, demonstrating the need to develop strong mechanisms to counteract this. PMID- 27225856 TI - Importance of Flow Cytometry in the Cytopathologic Evaluation of Lymphoid Lesions Involving the Kidney. AB - BACKGROUND: Cytomorphology alone is often insufficient for the diagnosis and subclassification of lymphomas, so flow cytometry (FC) may be used as an adjuvant test. METHODS: Renal fine-needle aspirations (FNAs) performed from January 1993 to August 2014 were reviewed for FC data or a diagnosis of lymphoma. RESULTS: A total of 586 renal FNAs were collected. Thirty-three cases (5.1%) had FC analysis. Lymphoma was diagnosed 35 times (6%), and FC was performed in 21 (60%) cases. Both cytomorphology and FC were consistent with lymphoma in 20 cases. Cytomorphology alone was diagnostic of lymphoma in 15 cases. In 28 cases, biopsy from the kidney or another site was diagnostic of lymphoma. One subsequent biopsy revealed that a kidney FNA, which showed no definitive morphologic or FC evidence of lymphoma, likely represented necrotic diffuse large B-cell lymphoma. CONCLUSION: FC is a useful adjuvant diagnostic test for renal FNAs, particularly for subclassification and confirmation of the diagnosis when there is insufficient material for immunohistochemistry. FC should be interpreted with caution when a sample is limited or when there is suspicion of Hodgkin lymphoma, and further work-up is warranted when cytomorphology suggests lymphoma but FC is negative. PMID- 27225857 TI - Heat generation and light scattering of green fluorescent protein-like pigments in coral tissue. AB - Green fluorescent protein (GFP)-like pigments have been proposed to have beneficial effects on coral photobiology. Here, we investigated the relationships between green fluorescence, coral heating and tissue optics for the massive coral Dipsastraea sp. (previously Favia sp.). We used microsensors to measure tissue scalar irradiance and temperature along with hyperspectral imaging and combined imaging of variable chlorophyll fluorescence and green fluorescence. Green fluorescence correlated positively with coral heating and scalar irradiance enhancement at the tissue surface. Coral tissue heating saturated for maximal levels of green fluorescence. The action spectrum of coral surface heating revealed that heating was highest under red (peaking at 680 nm) irradiance. Scalar irradiance enhancement in coral tissue was highest when illuminated with blue light, but up to 62% (for the case of highest green fluorescence) of this photon enhancement was due to green fluorescence emission. We suggest that GFP like pigments scatter the incident radiation, which enhances light absorption and heating of the coral. However, heating saturates, because intense light scattering reduces the vertical penetration depth through the tissue eventually leading to reduced light absorption at high fluorescent pigment density. We conclude that fluorescent pigments can have a central role in modulating coral light absorption and heating. PMID- 27225858 TI - Time-varying effects of aromatic oil constituents on the survival of aquatic species: Deviations between model estimates and observations. AB - There is a need to study the time course of toxic chemical effects on organisms because there might be a time lag between the onset of chemical exposure and the corresponding adverse effects. For aquatic organisms, crude oil and oil constituents originating from either natural seeps or human activities can be relevant case studies. In the present study the authors tested a generic toxicokinetic model to quantify the time-varying effects of various oil constituents on the survival of aquatic organisms. The model is based on key parameters applicable to an array of species and compounds with baseline toxicity reflected by a generic, internal toxicity threshold or critical body burden (CBB). They compared model estimates with experimental data on the effects of 8 aromatic oil constituents on the survival of aquatic species including crustaceans and fish. The average model uncertainty, expressed as the root mean square error, was 0.25 (minimum-maximum, 0.04-0.67) on a scale between 0 and 1. The estimated survival was generally lower than the measured survival right after the onset of oil constituent exposure. In contrast, the model underestimated the maximum mortality for crustaceans and fish observed in the laboratory. Thus, the model based on the CBB concept failed to adequately predict the lethal effects of the oil constituents on crustaceans and fish. Possible explanations for the deviations between model estimates and observations may include incorrect assumptions regarding a constant lethal body burden, the absence of biotransformation products, and the steady state of aromatic hydrocarbon concentrations in organisms. Clearly, a more complex model approach than the generic model used in the present study is needed to predict toxicity dynamics of narcotic chemicals. Environ Toxicol Chem 2017;36:128-136. (c) 2016 SETAC. PMID- 27225859 TI - Anticholinergic premedication-induced fever in paediatric ambulatory ketamine anaesthesia. AB - OBJECTIVE: A randomized, double-blind, prospective study to evaluate the effect of anticholinergic drugs on thermoregulation in paediatric patients undergoing ambulatory anaesthesia with ketamine. METHODS: Patients were randomized to receive either 0.005 mg/kg glycopyrrolate or the equivalent volume of normal saline (placebo) at 30 min before ketamine anaesthesia. Body temperature was measured tympanically at baseline and at 0, 30, 60 and 90 min postoperatively. The quantity of saliva prodiced during surgery and incidence of fever were recorded. RESULTS: Body temperature was significantly higher in the glycopyrrolate group (n = 42) than the placebo group (n = 42) at 30, 60 and 90 min after surgery, and higher than baseline at 0, 30, 60 and 90 min after surgery. In the placebo group, body temperature was significantly higher than baseline at 0 and 30 min after surgery. Saliva secretion was significantly lower in the glycopyrrolate group than the placebo group. CONCLUSION: Routine premedication with adjunctive anticholinergics should not be considered in paediatric patients receiving ketamine sedation due to the increased risk of fever.Trial registration number, Clinicaltrials.gov: NCT02430272. PMID- 27225860 TI - Results of prosthetic rehabilitation on managing transtibial vascular amputation with silicone liner after wound closure. AB - OBJECTIVE: To investigate the effect of a standardized silicone liner programme on the duration of prosthetic rehabilitation in patients who underwent transtibial amputation as a result of peripheral arterial disease. METHODS: This retrospective study enrolled patients who underwent transtibial amputation followed by one of two stump management programmes at the same rehabilitation centre over a period of 14 years. The study compared the duration of rehabilitation following a standardized silicone liner programme compared with that following a conventional soft dressing programme. RESULTS: This study included 16 patients who underwent the silicone liner programme and 11 patients who underwent the soft dressing programme. There were no significant differences between the two groups in age, sex, interval between amputation and admission to the rehabilitation centre and stump length. The duration required for the completion of the rehabilitation programme was significantly shorter for the silicone liner programme compared with the soft dressing programme (mean +/- SD: 77.3 days +/- 13.4 versus 125.4 days +/- 66.4 days, respectively). CONCLUSION: A standardized silicone liner programme reduced the duration of rehabilitation and could be a valuable replacement for soft dressing-based stump management. PMID- 27225861 TI - Diagnostic value of elevated serum miRNA-143 levels in sepsis. AB - OBJECTIVE: To evaluate serum micro RNA-143 (miR-143) levels in patients with sepsis or non-infectious systemic inflammatory response syndrome (SIRS), and investigate its possible diagnostic or prognostic value. METHODS: Serum was obtained from patients with sepsis or SIRS and healthy control subjects. Relative miR-143 expression was determined using quantitative real time polymerase chain reaction. The diagnostic and prognostic value of serum miR-143 was evaluated. RESULTS: Serum miR-143 levels were significantly higher in patients with sepsis (n = 103) than patients with SIRS (n = 95) and healthy controls (n = 40). There were significant positive correlations between serum miR-143 level and SOFA and APACHE II scores in patients with sepsis (r = 0.794 and r = 0.825, respectively). Serum miR-143 had a sensitivity of 78.6% and specificity of 91.6% for distinguishing between sepsis and SIRS. There was no association between serum miR-143 and 28-day survival in patients with sepsis. CONCLUSION: Serum miR-143 is elevated in patients with sepsis, and may be a useful biomarker for distinguishing between sepsis and SIRS. PMID- 27225862 TI - Assessment of serum chemerin, vaspin and omentin-1 levels in patients with polycystic ovary syndrome. AB - OBJECTIVE: To determine serum chemerin, vaspin and omentin-1 in overweight and normal weight patients with polycystic ovary syndrome (PCOS) and investigate the possible relationship between these adipokines and metabolic syndrome. METHODS: This cross sectional study enrolled women with PCOS and healthy women. Serum chemerin, vaspin and omentin-1 were assessed by enzyme-linked immunosorbent assay methods. RESULTS: Forty patients with PCOS and 30 healthy controls were included in the study. In the PCOS group, 18 women were overweight (body mass index [BMI] = 25.0-29.9 kg/m(2)) and 22 had normal weight (BMI = 18.5-24.9 kg/m(2)). Chemerin, total cholesterol, dehydroepiandrosterone sulphate and free androgen index (FAI) were significantly higher; and high-density lipoprotein cholesterol and sex hormone binding globulin were significantly lower in overweight PCOS patients compared with normal weight PCOS patients. A positive correlation was found between chemerin and BMI, triglyceride, insulin, homeostatic model assessment of insulin resistance and FAI in the PCOS group. There was no difference in serum chemerin, vaspin and omentin-1 between PCOS patients and healthy controls. CONCLUSION: Circulating chemerin was increased in overweight compared with normal weight PCOS patients. The most predictive variables for circulating chemerin in PCOS patients were BMI, FAI and age. PMID- 27225864 TI - Involvement of autophagy in T cell biology. AB - Autophagy is an essential cellular pathway that sequesters various cytoplasmic components, including accumulated proteins, damaged organelles or invading microorganisms and delivers them to lysosomes for degradation. The function of autophagy has been reported in various tissues and systems, including its role in the regulation of cellular immunity. Autophagy plays a fundamental role at various stages of T cell maturation. It regulates the thymocyte selection and the generation of T cell repertoire by presenting intracellular antigens to MHC class molecules. Autophagy is crucial for metabolic regulation of T cells, and therefore supports cell survival and homeostasis, particularly in activated mature T cells. Furthermore, deletion of specific autophagy-related genes induces several immunological alterations including differentiation of activated T cells into regulatory, memory or natural killer T cells. In this review, we emphasize the impact of autophagy on T cell development, activation and differentiation, which is pivotal for the adaptive immune system. PMID- 27225863 TI - Epidural blood patch for spontaneous intracranial hypotension with chronic subdural haematoma: A case report and literature review. AB - Spinal leakage of cerebrospinal fluid (CSF) is considered to be the primary cause of spontaneous intracranial hypotension (SIH). Subdural haematoma (SDH) is a serious complication of SIH. This current report presents a case of bilateral SDH with SIH that was treated with epidural blood patching (EBP). A 43-year-old male complained of experiencing orthostatic headaches for 2 months without neurological signs. The patient worsened in a local hospital and was transferred to the Sir Run Run Hospital. Brain computed tomography showed bilateral SDH with a midline shift. The patient underwent emergency trephination in the left frontal temporal region. Postoperative magnetic resonance myelography showed a CSF leak originating at the T11-L2 level. As a consequence of clinical deterioration of the patient, EBP was subsequently performed at the T12-L1 level. The headache was rapidly relieved and later the SDH was completely absorbed. This case report and literature review aims to remind clinicians that SIH can cause SDH and that EBP is a viable treatment option. PMID- 27225865 TI - Phosphoramidate Ligation of Oligonucleotides in Nanoscale Structures. AB - The folding of long DNA strands into designed nanostructures has evolved into an art. Being based on linear chains only, the resulting nanostructures cannot readily be transformed into covalently linked frameworks. Covalently linking strands in the context of folded DNA structures requires a robust method that avoids sterically demanding reagents or enzymes. Here we report chemical ligation of the 3'-amino termini of oligonucleotides and 5'-phosphorylated partner strands in templated reactions that produce phosphoramidate linkages. These reactions produce inter-nucleotide linkages that are isoelectronic and largely isosteric to phosphodiesters. Ligations were performed at three levels of complexity, including the extension of branched DNA hybrids and the ligation of six scaffold strands in a small origami. PMID- 27225866 TI - Chronic Prostatitis/Chronic Pelvic Pain Syndrome is associated with Irritable Bowel Syndrome: A Population-based Study. AB - This study aimed to examine this association by comparing the risk of prior irritable bowel syndrome (IBS) between patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and matched controls in Taiwan. Data were retrieved from the Longitudinal Health Insurance Database 2005. This study included 4870 cases with CP/CPPS and 4870 age-matched controls. Conditional logistic regressions were conducted to examine associations of CP/CPPS with previously diagnosed IBS. We found that a total of 753 (7.7%) of the 9740 sampled patients had IBS prior to the index date; IBS was found in 497 (10.2%) cases and in 256 (5.3%) controls. Conditional logistic regression revealed a higher odds ratio (OR) of prior IBS (OR 2.05, 95% CI = 1.75-2.40) for cases than controls. Furthermore, after adjusting for the patients' monthly income, geographical location, urbanization level, and hypertension and coronary heart disease, the conditional logistic regression analysis indicated that cases were more likely than controls to have prior IBS (OR = 1.96, 95% CI = 1.67-2.29). Furthermore, we found that CP/CPPS was consistently and significantly associated with prior IBS regardless of age group. We concluded that the diagnosis of CP/CPPS was associated with previously diagnosed IBS. Urologists should be aware of the association between CP/CPPS and IBS when treating patients. PMID- 27225867 TI - Lower Blood Pressure-Induced Renal Hypoperfusion Promotes Cisplatin-Induced Nephrotoxicity. AB - BACKGROUND AND AIMS: Cisplatin-induced nephrotoxicity primarily occurs in the proximal tubules, and tubular injuries reduce glomerular filtration rates. Lower blood pressure causes renal hypoperfusion, which promotes ischemic acute kidney injury (AKI). Our study examined the relationship between lower blood pressure induced renal hypoperfusion and cisplatin-induced nephrotoxicity. METHODS: The relationship between cisplatin use and hypoalbuminemia is not clear. This study consisted of Japanese patients who received cisplatin as the first-line chemotherapy at Fujita Health University Hospital from April 2006 to December 2012. Hypoalbuminemia was defined as serum albumin levels <=3.5 mg/dl. RESULTS: Patients who experienced lower blood pressure during chemotherapy were included in the lower blood pressure group (n = 229), and those who did not were included in the normal blood pressure group (n = 743). Total cisplatin dose in the normal blood pressure and lower blood pressure groups was 58.9 +/- 23.8 and 55.0 +/- 20.4 mg/m2, respectively. The rate of severe nephrotoxicity was higher and overall survival was shorter in the lower blood pressure group than in the normal blood pressure group. In a multivariable analysis, lower blood pressure significantly correlated with hypoalbuminemia. CONCLUSIONS: To prevent ischemic AKI, nutrition and cachexia controlling are important parts of cancer treatment. PMID- 27225868 TI - JUMPg: An Integrative Proteogenomics Pipeline Identifying Unannotated Proteins in Human Brain and Cancer Cells. AB - Proteogenomics is an emerging approach to improve gene annotation and interpretation of proteomics data. Here we present JUMPg, an integrative proteogenomics pipeline including customized database construction, tag-based database search, peptide-spectrum match filtering, and data visualization. JUMPg creates multiple databases of DNA polymorphisms, mutations, splice junctions, partially trypticity, as well as protein fragments translated from the whole transcriptome in all six frames upon RNA-seq de novo assembly. We use a multistage strategy to search these databases sequentially, in which the performance is optimized by re-searching only unmatched high-quality spectra and reusing amino acid tags generated by the JUMP search engine. The identified peptides/proteins are displayed with gene loci using the UCSC genome browser. Then, the JUMPg program is applied to process a label-free mass spectrometry data set of Alzheimer's disease postmortem brain, uncovering 496 new peptides of amino acid substitutions, alternative splicing, frame shift, and "non-coding gene" translation. The novel protein PNMA6BL specifically expressed in the brain is highlighted. We also tested JUMPg to analyze a stable-isotope labeled data set of multiple myeloma cells, revealing 991 sample-specific peptides that include protein sequences in the immunoglobulin light chain variable region. Thus, the JUMPg program is an effective proteogenomics tool for multiomics data integration. PMID- 27225870 TI - Combination of Rapamycin and Resveratrol for Treatment of Bladder Cancer. AB - Loss of TSC1 function, a crucial negative regulator of mTOR signaling, is a common alteration in bladder cancer. Mutations in other members of the PI3K pathway, leading to mTOR activation, are also found in bladder cancer. This provides rationale for targeting mTOR for treatment of bladder cancer characterized by TSC1 mutations and/or mTOR activation. In this study, we asked whether combination treatment with rapamycin and resveratrol could be effective in concurrently inhibiting mTOR and PI3K signaling and inducing cell death in bladder cancer cells. In combination with rapamycin, resveratrol was able to block rapamycin-induced Akt activation, while maintaining mTOR pathway inhibition. In addition, combination treatment with rapamycin and resveratrol induced cell death specifically in TSC1-/- MEF cells, and not in wild-type MEFs. Similarly, resveratrol alone or in combination with rapamycin induced cell death in human bladder cancer cell lines. These data indicate that administration of resveratrol together with rapamycin may be a promising therapeutic option for treatment of bladder cancer. J. Cell. Physiol. 232: 436-446, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27225871 TI - Three-dimensional echo-planar cine imaging of cerebral blood supply using arterial spin labeling. AB - OBJECTIVE: Echo-planar imaging (EPI) with CYlindrical Center-out spatiaL Encoding (EPICYCLE) is introduced as a novel hybrid three-dimensional (3D) EPI technique. Its suitability for the tracking of a short bolus created by pseudo-continuous arterial spin labeling (pCASL) through the cerebral vasculature is demonstrated. MATERIALS AND METHODS: EPICYCLE acquires two-dimensional planes of k-space along center-out trajectories. These "spokes" are rotated from shot to shot about a common axis to encode a k-space cylinder. To track a bolus of labeled blood, the same subset of evenly distributed spokes is acquired in a cine fashion after a short period of pCASL. This process is repeated for all subsets to fill the whole 3D k-space of each time frame. RESULTS: The passage of short pCASL boluses through the vasculature of a 3D imaging slab was successfully imaged using EPICYCLE. By choosing suitable sequence parameters, the impact of slab excitation on the bolus shape could be minimized. Parametric maps of signal amplitude, transit time, and bolus width reflected typical features of blood transport in large vessels. CONCLUSION: The EPICYCLE technique was successfully applied to track a short bolus of labeled arterial blood during its passage through the cerebral vasculature. PMID- 27225869 TI - Impaired Gut-Liver-Brain Axis in Patients with Cirrhosis. AB - Cirrhosis is associated with brain dysfunction known as hepatic encephalopathy (HE). The mechanisms behind HE are unclear although hyperammonemia and systemic inflammation through gut dysbiosis have been proposed. We aimed to define the individual contribution of specific gut bacterial taxa towards astrocytic and neuronal changes in brain function using multi-modal MRI in patients with cirrhosis. 187 subjects (40 controls, 147 cirrhotic; 87 with HE) underwent systemic inflammatory assessment, cognitive testing, stool microbiota analysis and brain MRI analysis. MR spectroscopy (MRS) changes of increased Glutamate/glutamine, reduced myo-inositol and choline are hyperammonemia associated astrocytic changes, while diffusion tensor imaging (DTI) demonstrates changes in neuronal integrity and edema. Linkages between cognition, MRI parameters and gut microbiota were compared between groups. We found that HE patients had a significantly worse cognitive performance, systemic inflammation, dysbiosis and hyperammonemia compared to controls and cirrhotics without HE. Specific microbial families (autochthonous taxa negatively and Enterobacteriaceae positively) correlated with MR spectroscopy and hyperammonemia-associated astrocytic changes. On the other hand Porphyromonadaceae, were only correlated with neuronal changes on DTI without linkages with ammonia. We conclude that specific gut microbial taxa are related to neuronal and astrocytic consequences of cirrhosis-associated brain dysfunction. PMID- 27225872 TI - Dynamic comparison of pharyngeal stability during sleep in patients with obstructive sleep apnea syndrome treated with maxillomandibular advancement. AB - PURPOSE: To compare the dynamic differences occurring in the pharynx during sleep after maxillomandibular advancement (MMA) surgery for the treatment of patients with obstructive sleep apnea syndrome. METHODS: This was a prospective, cross sectional study conducted on 20 patients (15 men and 5 women) with a polysomnography diagnosis of obstructive sleep apnea (OSA) submitted to surgical treatment with MMA. All patients were submitted to magnetic resonance (MR) during propofol-induced sleep before and 6 months after surgery. Thirty linear measurements (30 sections) were obtained over time in the retrolingual (RL) region to compare their variability before and after MMA. RESULTS: The mean linear anteroposterior increase of the pharynx during induced sleep after MMA was 66 % in the RL region (P < 0.01). The coefficient of variation of the linear measurements was 117.5 % before surgery, being reduced to 51 % after surgery. CONCLUSIONS: MMA promoted an important increase of the pharynx during induced sleep and a more significant change in the variability of its lumen. With a lower variation in the diameter of the organ during the respiratory movements, there is greater airway stability and a consequent maintenance of the pharyngeal lumen that reduces or even prevents pharyngeal collapse. PMID- 27225874 TI - Scaling of photosynthesis and constitutive and induced volatile emissions with severity of leaf infection by rust fungus (Melampsora larici-populina) in Populus balsamifera var. suaveolens. AB - Fungal infections result in decreases in photosynthesis, induction of stress and signaling volatile emissions and reductions in constitutive volatile emissions, but the way different physiological processes scale with the severity of infection is poorly known. We studied the effects of infection by the obligate biotrophic fungal pathogen Melampsora larici-populina Kleb., the causal agent of poplar leaf rust disease, on photosynthetic characteristics, and constitutive isoprene and induced volatile emissions in leaves of Populus balsamifera var. suaveolens (Fisch.) Loudon. exhibiting different degrees of damage. The degree of fungal damage, quantified by the total area of chlorotic and necrotic leaf areas, varied between 0 (noninfected control) and ~60%. The rates of all physiological processes scaled quantitatively with the degree of visual damage, but the scaling with damage severity was weaker for photosynthetic characteristics than for constitutive and induced volatile release. Over the whole range of damage severity, the net assimilation rate per area (AA) decreased 1.5-fold, dry mass per unit area 2.4-fold and constitutive isoprene emissions 5-fold, while stomatal conductance increased 1.9-fold and dark respiration rate 1.6-fold. The emissions of key stress and signaling volatiles (methanol, green leaf volatiles, monoterpenes, sesquiterpenes and methyl salicylate) were in most cases nondetectable in noninfested leaves, and increased strongly with increasing the spread of infection. The moderate reduction in AA resulted from the loss of photosynthetically active biomass, but the reduction in constitutive isoprene emissions and the increase in induced volatile emissions primarily reflected changes in the activities of corresponding biochemical pathways. Although all physiological alterations in fungal-infected leaves occurred in a stress severity dependent manner, modifications in primary and secondary metabolic pathways scaled differently due to contrasting operational mechanisms. PMID- 27225873 TI - A phase II trial of the BCL-2 homolog domain 3 mimetic AT-101 in combination with docetaxel for recurrent, locally advanced, or metastatic head and neck cancer. AB - BACKGROUND: AT-101 is a BCL-2 Homolog domain 3 mimetic previously demonstrated to have tumoricidal effects in advanced solid organ malignancies. Given the evidence of activity in xenograft models, treatment with AT-101 in combination with docetaxel is a therapeutic doublet of interest in metastatic head and neck squamous cell carcinoma. PATIENTS AND METHODS: Patients included in this trial had unresectable, recurrent, or distantly metastatic head and neck squamous cell carcinoma (R/M HNSCC) not amenable to curative radiation or surgery. This was an open label randomized, phase II trial in which patients were administered AT-101 in addition to docetaxel. The three treatment arms were docetaxel, docetaxel plus pulse dose AT-101, and docetaxel plus metronomic dose AT-101. The primary endpoint of this trial was overall response rate. RESULTS: Thirty-five patients were registered and 32 were evaluable for treatment response. Doublet therapy with AT-101 and docetaxel was well tolerated with only 2 patients discontinuing therapy due to treatment related toxicities. The overall response rate was 11 % (4 partial responses) with a clinical benefit rate of 74 %. Median progression free survival was 4.3 months (range: 0.7-13.7) and overall survival was 5.5 months (range: 0.4-24). No significant differences were noted between dosing strategies. CONCLUSION: Although met with a favorable toxicity profile, the addition of AT-101 to docetaxel in R/M HNSCC does not appear to demonstrate evidence of efficacy. PMID- 27225875 TI - Use of Propofol in Combination with Remifentanil for Plastic and Reconstructive Surgery. PMID- 27225876 TI - The Effect of Patient Positioning on Amount of Intraoperative Bleeding in Rhinoplasty: A Randomized Controlled Trial. AB - BACKGROUND: There is a rich blood flow to the mucosa in the nasal region. In rhinoplasty, surgical procedures are performed in a narrow and confined space. So bleeding during surgery reduces visibility which can complicate the procedure. This study investigated the effects of the patient position on amount of intraoperative bleeding during surgical procedures. PATIENTS AND METHODS: This randomized controlled trial was conducted on 71 patients who underwent elective rhinoplasty. The patients were operated on in three groups. Group 1 consisted of 23 patients who were operated on in the supine position; Group 2 included 28 patients who were operated on using a 15 degrees angle reverse Trendelenburg position; Group 3 consisted of 20 patients who were operated on at a 20 degrees angle reverse Trendelenburg position. RESULTS: There were statistically significant differences between the groups in regard to surgeon satisfaction and the amount of intraoperative bleeding. The amount of intraoperative bleeding in Group 1 was significantly higher than those of Groups 2 and 3, and surgeon satisfaction was lower. CONCLUSIONS: Reverse Trendelenburg position reduces intraoperative bleeding in rhinoplasty patients while facilitating the procedure compared to the supine position. Surgery at a 15 degrees angle reverse Trendelenburg position provides the optimum working conditions by both significantly reducing intraoperative bleeding and allowing for comfortable conditions for the surgeon. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 27225877 TI - Freed Lower Lateral Cartilages with Intact Lateral Attachments: A Versatile Approach in Tip Plasty. AB - BACKGROUND: Tip plasty is an important procedure that contributes much to obtaining an aesthetically pleasant nose. To increase precision during the tip plasty procedure, control over the lower lateral cartilages should be maximized. This can be accomplished by extending the exposure of the cartilage framework. We present our "Freed Lower Lateral Cartilages With Intact Lateral Attachments" approach through which inferior lateral cartilages are being dissected free from their attachments, while only their lateral bases (lateral crural parts) are left intact. PATIENTS AND METHOD: A total of 1752 consecutive patients operated on with this approach were included. All patients were cosmetic rhinoplasty patients operated on between the years 1999 and 2014. During tip plasty, the lower lateral cartilages of all patients were totally dissected from all their attachments, while the lateral bases were left intact. The suture and graft techniques for the tip plasty procedure were then applied to reconfigure the tip region. RESULTS: The approach was used successfully in 1752 patients in a 15-year period. The mean age of patients was 33.5 years. The complication rate was 6.4 % and the revision rate was 4.7 % for the patients. Only 1.2 % of patients needed a revision surgery for tip and/or alar region. None of these patients needed further revision. The aesthetic and functional outcomes revealed high satisfaction rates. CONCLUSION: The "Freed Lower Lateral Cartilages With Intact Lateral Attachments" approach in tip plasty facilitates manipulation of the tip region while maintaining precise control to provide definition in terms of symmetry and three-dimensional configuration. Furthermore, it constitutes an autologous and practical platform on which nondestructive techniques can be performed in a combined and synergistic fashion. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 27225878 TI - Parent-Reported Executive Dysfunction in Children and Adolescents with Chiari Malformation Type 1. AB - BACKGROUND: Children with Chiari malformation type 1 (CM1) have increasingly presented to neurosurgery clinics. Limited research relating to the cognitive dysfunction experienced by this population has been completed. In adults, inhibition problems and executive dysfunction have been documented. METHODS: Seventy-seven parental reports of children with CM1 were included in the study. Parents completed questions on a scale rating daily executive functioning as well as reporting on common neurological symptoms. RESULTS: The sample consisted of 41 males and 36 females with a mean age of 133.57 +/- 42.18 months. Thirty-eight subjects had had decompression surgery. The most common neurological symptoms included: headache (69%), a history of pain (31%) and gait disturbance (20%). One third of the sample demonstrated overall executive functioning impairment, with working memory elevations being most prevalent (44%). Depression, gender, age and decompression surgery were not related to executive dysfunction. CONCLUSIONS: The parental report of executive dysfunction in children with CM1 was higher than the standardized healthy sample. Metacognitive problems, especially working memory and initiation problems were most prevalent. A quick parental rating scale identifying children with executive dysfunction may be beneficial for neurosurgeons and assist with referrals for a more comprehensive neuropsychological assessment. PMID- 27225879 TI - Tafluprost Ophthalmic Solution 0.0015 %: A Review in Glaucoma and Ocular Hypertension. AB - Tafluprost ophthalmic solution 0.0015 % preserved with benzalkonium chloride (BAK) 0.001 % is available in several Asian countries, including Japan. In pivotal trials, BAK-preserved tafluprost ophthalmic solution 0.0015 % lowered intraocular pressure (IOP) more effectively than placebo in Asian patients with normal-tension glaucoma and was at least as effective as latanoprost ophthalmic solution 0.005 % in Asian patients with primary open-angle glaucoma or ocular hypertension. In other prospective studies in Asian patients with glaucoma or ocular hypertension, tafluprost ophthalmic solution 0.0015 % was at least as effective as latanoprost ophthalmic solution 0.005 % or travoprost ophthalmic solution 0.004 % in terms of IOP lowering, and was considered easier to use and/or store. The efficacy of tafluprost ophthalmic solution 0.0015 % was maintained in the longer term. Tafluprost ophthalmic solution 0.0015 % was generally well tolerated. In conclusion, BAK-preserved tafluprost ophthalmic solution 0.0015 % remains a useful option for the treatment of Asian patients with glaucoma and ocular hypertension. PMID- 27225880 TI - Variation in PPP3CC Genotype Is Associated with Long-Term Recovery after Severe Brain Injury. AB - After experimental traumatic brain injury (TBI), calcineurin is upregulated; blocking calcineurin is associated with improved outcomes. In humans, variation in the calcineurin A-gamma gene (PPP3CC) has been associated with neuropsychiatric disorders, though any role in TBI recovery remains unknown. This study examines associations between PPP3CC genotype and mortality, as well as gross functional status assessed at admission using the Glasgow Coma Scale (GCS) and at 3, 6, and 12 months after severe TBI using the Glasgow Outcome Score (GOS). The following tagging single nucleotide polymorphisms (tSNPs) in PPP3CC were genotyped: rs2443504, rs2461491, rs2469749, and rs10108011. The rs2443504 AA genotype was univariately associated with GCS (p = 0.022), GOS at 3, 6, and 12 months (p = 0.002, p = 0.034, and p = 0.004, respectively), and mortality (p = 0.007). In multivariate analysis controlling for age, sex, and GCS, the AA genotype of rs2443504 was associated with GOS at 3 (p = 0.02), and 12 months (p = 0.01), with a trend toward significance at 6 months (p = 0.05); the AA genotype also was associated with mortality in the multivariate model (p = 0.04). Further work is warranted to better understand the role of calcineurin, as well as the genes encoding it and their relevance to outcomes after brain injury. PMID- 27225881 TI - Experimental Demonstration of a Hybrid-Quantum-Emitter Producing Individual Entangled Photon Pairs in the Telecom Band. AB - Quantum emitters generating individual entangled photon pairs (IEPP) have significant fundamental advantages over schemes that suffer from multiple photon emission, or schemes that require post-selection techniques or the use of photon number discriminating detectors. Quantum dots embedded within nanowires (QD-NWs) represent one of the most promising candidate for quantum emitters that provide a high collection efficiency of photons. However, a quantum emitter that generates IEPP in the telecom band is still an issue demanding a prompt solution. Here, we demonstrate in principle that IEPPs in the telecom band can be created by combining a single QD-NW and a nonlinear crystal waveguide. The QD-NW system serves as the single photon source, and the emitted visible single photons are split into IEPPs at approximately 1.55 MUm through the process of spontaneous parametric down conversion (SPDC) in a periodically poled lithium niobate (PPLN) waveguide. The compatibility of the QD-PPLN interface is the determinant factor in constructing this novel hybrid-quantum-emitter (HQE). Benefiting from the desirable optical properties of QD-NWs and the extremely high nonlinear conversion efficiency of PPLN waveguides, we successfully generate IEPPs in the telecom band with the polarization degree of freedom. The entanglement of the generated photon pairs is confirmed by the entanglement witness. Our experiment paves the way to producing HQEs inheriting the advantages of multiple systems. PMID- 27225883 TI - Surveying Breast Cancer's Genomic Landscape. AB - An in-depth analysis has produced the most comprehensive portrait to date of the myriad genomic alterations involved in breast cancer. In sequencing the whole genomes of 560 breast cancers and combining this information with published data from another 772 breast tumors, the research team uncovered several new genes and mutational signatures that potentially influence this disease. PMID- 27225882 TI - Spatial decision on allocating automated external defibrillators (AED) in communities by multi-criterion two-step floating catchment area (MC2SFCA). AB - BACKGROUND: The occurrence of out-of-hospital cardiac arrest (OHCA) is a critical life-threatening event which frequently warrants early defibrillation with an automated external defibrillator (AED). The optimization of allocating a limited number of AEDs in various types of communities is challenging. We aimed to propose a two-stage modeling framework including spatial accessibility evaluation and priority ranking to identify the highest gaps between demand and supply for allocating AEDs. METHODS: In this study, a total of 6135 OHCA patients were defined as demand, and the existing 476 publicly available AEDs locations and 51 emergency medical service (EMS) stations were defined as supply. To identify the demand for AEDs, Bayesian spatial analysis with the integrated nested Laplace approximation (INLA) method is applied to estimate the composite spatial risks from multiple factors. The population density, proportion of elderly people, and land use classifications are identified as risk factors. Then, the multi criterion two-step floating catchment area (MC2SFCA) method is used to measure spatial accessibility of AEDs between the spatial risks and the supply of AEDs. Priority ranking is utilized for prioritizing deployment of AEDs among communities because of limited resources. RESULTS: Among 6135 OHCA patients, 56.85 % were older than 65 years old, and 79.04 % were in a residential area. The spatial distribution of OHCA incidents was found to be concentrated in the metropolitan area of Kaohsiung City, Taiwan. According to the posterior mean estimated by INLA, the spatial effects including population density and proportion of elderly people, and land use classifications are positively associated with the OHCA incidence. Utilizing the MC2SFCA for spatial accessibility, we found that supply of AEDs is less than demand in most areas, especially in rural areas. Under limited resources, we identify priority places for deploying AEDs based on transportation time to the nearest hospital and population size of the communities. CONCLUSION: The proposed method will be beneficial for optimizing resource allocation while considering multiple local risks. The optimized deployment of AEDs can broaden EMS coverage and minimize the problems of the disparity in urban areas and the deficiency in rural areas. PMID- 27225884 TI - A Cross-Cultural Comparison of Symptom Reporting and Symptom Clusters in Heart Failure. AB - An understanding of symptoms in heart failure (HF) among different cultural groups has become increasingly important. The purpose of this study was to compare symptom reporting and symptom clusters in HF patients between a Western (the United States) and an Eastern Asian sample (China and Taiwan). A secondary analysis of a cross-sectional observational study was conducted. The data were obtained from a matched HF patient sample from the United States and China/Taiwan ( N = 240 in each). Eight selective items related to HF symptoms from the Minnesota Living with Heart Failure Questionnaire were analyzed. Compared with the U.S. sample, HF patients from China/Taiwan reported a lower level of symptom distress. Analysis of two different regional groups did not result in the same number of clusters using latent class approach: the United States (four classes) and China/Taiwan (three classes). The study demonstrated that symptom reporting and identification of symptom clusters might be influenced by cultural factors. PMID- 27225885 TI - Experiences and Attitudes of Nurses Regarding Complementary Health Approaches Used by Themselves and Their Patients. AB - Nurses' attitudes and experiences may affect the level of patient exposure to complementary health approaches (CHA), both now and in the future. The purpose of this study was to describe nurses' experience of CHA and their personal and professional attitudes to the use of CHA. The sample consisted of 220 nurses working at a university hospital in Antalya, Turkey. Data were collected using a questionnaire developed by the researchers. Nurses had a positive attitude toward CHA and reported mixed experiences of CHA for allergies, pain, and stress. This study may contribute to increased awareness of the potentially important role of nurses in delivery of CHAs. Hospital nurses should receive more training on CHA. Nurses should discuss the potential benefits and risks of CHA with patients. PMID- 27225886 TI - Terapeutic Potential of Microencapsulated Sertoli Cells in Huntington Disease. AB - INTRODUCTION: Immune dysfunction, promoted by pro-inflammatory cytokines, plays a pivotal role in neurodegeneration associated with Huntington's disease. AIMS: The aim of this study was to investigate the emerging immunoregulatory and antiinflammatory properties of Sertoli cells in Huntington's disease. METHODS: The experimental R6/2 mouse model of Huntington's disease was treated by a single intraperitoneal injection of microencapsulated prepubertal porcine Sertoli cells and lifespan, motor performance and striatal inflammatory pattern have been evaluated. RESULTS: The results of this study demonstrated that a single intraperitoneal injection of microencapsulated prepubertal porcine Sertoli cells uniquely improved performances and extended the life expectancy of R6/2 Huntington's disease mice, by immune dysfunction modulation in brain. CONCLUSIONS: This study highlights the immunomodulatory and trophic role of Sertoli cells that could be of help in the treatment of neurodegenerative disorders. PMID- 27225887 TI - Toxic effects of chemical dispersant Corexit 9500 on water flea Daphnia magna. AB - In 2010, approximately 2.1 million gallons of chemical dispersants, mainly Corexit 9500, were applied in the Gulf of Mexico to prevent the oil slick from reaching shorelines and to accelerate biodegradation of oil during the Deepwater Horizon oil spill. Recent studies have revealed toxic effects of Corexit 9500 on marine microzooplankton that play important roles in food chains in marine ecosystems. However, there is still little known about the toxic effects of Corexit 9500 on freshwater zooplankton, even though oil spills do occur in freshwater and chemical dispersants may be used in response to these spills. The cladoceran crustacean, water flea Daphnia magna, is a well-established model species for various toxicological tests, including detection of juvenile hormone like activity in test compounds. In this study, we conducted laboratory experiments to investigate the acute and chronic toxicity of Corexit 9500 using D. magna. The acute toxicity test was conducted according to OECD TG202 and the 48 h EC50 was 1.31 ppm (CIs 0.99-1.64 ppm). The reproductive chronic toxicity test was performed following OECD TG211 ANNEX 7 and 21 days LOEC and NOEC values were 4.0 and 2.0 ppm, respectively. These results indicate that Corexit 9500 has toxic effects on daphnids, particularly during the neonatal developmental stage, which is consistent with marine zooplankton results, whereas juvenile hormone like activity was not identified. Therefore, our findings of the adverse effects of Corexit 9500 on daphnids suggest that application of this type of chemical dispersant may have catastrophic impacts on freshwater ecosystems by disrupting the key food chain network. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27225888 TI - Swedish healthcare providers' perceptions of preconception expanded carrier screening (ECS)-a qualitative study. AB - Reproductive autonomy, medicalization, and discrimination against disabled and parental responsibility are the main ongoing ethical debates concerning reproductive genetic screening. To examine Swedish healthcare professionals' views on preconception expanded carrier screening (ECS), a qualitative study involving academic and clinical institutions in Sweden was conducted in September 2014 to February 2015. Eleven healthcare professionals including clinicians, geneticists, a midwife, and a genetic counselor were interviewed in depth using a semi-structured interview guide. The questionnaire was constructed after reviewing the main literature and meetings with relevant healthcare providers. The interviews were recorded, transcribed verbatim, and content analyzed for categories and subcategories. Participants nurtured many ethical and non-ethical concerns regarding preconception ECS. Among the ethical concerns were the potential for discrimination, medicalization, concerns with prioritization of healthcare resources, and effects on reproductive freedom. The effects of implementation of preconception ECS, its stakeholders, regulations, and motivation are some of non-ethical concerns. These concerns, if not addressed, may affect the uptake and usage of carrier screening within Swedish healthcare system. As this is a qualitative study with a small non-random sample size, the findings cannot be generalized. The participants had little to no working experience with expanded screening panels. Moreover, the interviews were conducted in English, a second language for the participants, which might have limited the expression of their views. However, the authors claim that the findings may be pertinent to similar settings in other Scandinavian countries. PMID- 27225889 TI - Effects of different femoral tunnel positions on tension changes in anterolateral ligament reconstruction. AB - PURPOSE: Several kinds of anterolateral ligament (ALL) reconstructions to augment intra-articular anterior cruciate ligament reconstruction to better control anterolateral rotational instability (ALRI) have been reported. However, the optimal femoral attachment site for ALL reconstruction is still unclear. The purpose of this study was to investigate the effects of different femoral attachment sites on the tension changes through knee motions in different situations in order to determine a recommended femoral attachment site for ALL reconstruction. METHODS: Six fresh-frozen cadaveric knees were included. ALL reconstructions were performed with three different femoral attachment sites (F1: 2 mm anterior and 2 mm distal to the lateral epicondyle, F2: 4 mm posterior and 8 mm proximal to the lateral epicondyle and F3: position for the lateral extra articular tenodesis). The graft tension changes were measured by a graft tensioning system during knee flexion-extension and manual maximum internal/external tibial rotation in the following situations: (1) intact, (2) ALL cut, (3) ALL and ACL cut and (4) ALL cut and ACL reconstructed. Effects of the different femoral attachment sites, the route superficial or deep to the LCL, and the situations of (1) to (4) were calculated via repeated-measures analysis of variance. RESULTS: The tension of F1 was higher in flexion and lower in extension, whereas the tension of F2 and F3 was higher in extension and lower in flexion. F2 showed the smallest tension change. Situations of (1) to (4) did not affect tension changes. The graft tension became higher with internal rotation and lower with external rotation regardless of femoral attachment sites or situations. CONCLUSION: With F2-4 mm posterior and 8 mm proximal to the lateral epicondyle-the reconstructed ALL had the least tension change with only a slight increase in tension as the knee extended. This result indicates that F2 is recommended for ALL reconstruction to better control ALRI, which will help determine the optimal femoral tunnel position for ALL reconstruction. PMID- 27225890 TI - Superior femoral component alignment can be achieved with Oxford microplasty instrumentation after minimally invasive unicompartmental knee arthroplasty. AB - PURPOSE: Oxford microplasty (MP) instrumentation has been developed to facilitate the reproducible and consistent performance of minimally invasive unicompartmental knee arthroplasty (MI-UKA) operation. The aim of this study was to compare the clinical and radiographic results of two groups of patients implanted using either a conventional instrumentation technique or an MP technique. METHODS: A prospective cohort study of 108 knees in 108 patients who underwent an MI-UKA procedure using either conventionally instrumented UKA (CI UKA) (52 knees of 52 patients) or MP-assisted UKA (MP-UKA) (56 knees of 56 patients). The clinical assessment included the Oxford Knee Score (OKS), the Knee Society Score (KSS), a visual analogue scale (VAS) for pain, and range of motion (ROM). Complications were also recorded. RESULTS: No significant differences were observed between the two groups regarding OKS, KSS, VAS, and ROM. There were also no significant differences in terms of mechanical limb alignment and tibia implant alignment. However, the MP-UKA group showed significantly more accurate positioning of the femoral component than the CI-UKA group. Additionally, the MP UKA group had more femoral prostheses implanted in the "satisfactory" range and fewer "outliers" than the CI-UKA group. No significant difference in complications was noted between the two groups. CONCLUSION: This study suggested that compared with CI-UKA, MP-UKA provides significant improvements in increasing the accuracy of sagittal and coronal implantation of the femoral component and in reducing the numbers of outliers for femoral prosthetic alignment. It is advocated that the MP system should be considered when MI-UKA is performed. LEVEL OF EVIDENCE: Therapeutic study, Level IV. PMID- 27225891 TI - Femoral footprint of the popliteus tendon may be at the risk of damage during total knee arthroplasty. AB - PURPOSE: The present study focused on the prevalence of incidental excision of the femoral footprint of the popliteus tendon during total knee arthroplasty and its associated risk factors. METHODS: A total of 275 knee arthroplasties were performed for 226 patients with varus knee osteoarthritis. The status of the femoral footprint of the popliteus tendon was intraoperatively evaluated and classified into three groups (preserved, partially excised, and completely excised), and the prevalence of the excision was identified. Femoral component size, the thickness of the resected distal femoral condyle, and preoperative patient demographic data were compared for the three groups. Ordinal logistic regression analysis was performed to reveal risk factors associated with the excision. RESULTS: The femoral footprint of the popliteus tendon was preserved in 132 knees (48.0 %), partially excised in 94 knees (34.2 %) and completely excised in 49 knees (17.8 %). The ordinal logistic regression analysis revealed thicker resection of the distal femoral condyle (p < 0.0001) and shorter body height (p = 0.0266) to be the independent risk factors for the excision. CONCLUSIONS: The incidental partial or complete excision of the femoral footprint of the popliteus tendon was identified in approximately half of the evaluated knees. Thicker resection of the distal femoral condyle and shorter body height were the most significant risk factors for the excision. LEVEL OF EVIDENCE: Case-control study, Level III. PMID- 27225892 TI - Breast cancer and social environment: getting by with a little help from our friends. AB - Social environment is a well-recognized determinant in health and wellbeing. Among breast cancer patients, inadequate social support is associated with a substantial increase in cancer-related mortality. A common explanation is that socially isolated individuals fare worse due to reduced instrumental support (i.e., assistance meeting the demands of treatment). However, the ability to replicate the detrimental effects of social isolation on mammary tumor growth in rodents strongly suggests an alternative explanation; i.e., socially isolated individuals have a physiological milieu that promotes tumor growth. This review summarizes the clinical and basic science literature supporting social influences on breast cancer, and provides a conceptual physiological framework for these effects. We propose that social environment contributes to the vast individual differences in prognosis among breast cancer survivors because social environment is capable of altering basic physiological processes, which in turn can modulate tumor growth. Appreciation of the role of social environment in breast cancer progression could promote the identification of patients at increased risk for poor outcomes. In addition, characterization of the underlying physiological mechanisms could lead to targeted disruption of detrimental pathways that promote tumor progression in socially isolated individuals, or exploitation of protective pathways activated through social engagement as novel therapeutic complements to contemporary treatments. PMID- 27225893 TI - The Role of PKR as a Potential Target for Treating Cardiovascular Diseases. AB - Cardiovascular diseases are the leading cause of death globally with limited treatment options. Despite improved pharmacological therapy, scientific understandings on the root mechanisms of cardiovascular diseases are still not fully understood. It is well known that inflammation plays a key role in the pathogenesis of cardiovascular diseases and controlling this inflammatory pathway may inhibit the progression of this chronic disease. Protein Kinase R (PKR), a serine threonine kinase is activated during various pathological conditions. Activation of PKR can induce apoptosis, inflammation and oxidative stress. Since PKR has multidimensional roles, thus PKR is an attractive target for treating cardiovascular and metabolic disorders. The goal of this review is to discuss potential role of PKR in cardiovascular diseases, pathways activated by it and association between pathways activated. PMID- 27225894 TI - Synergistic Inhibitory Effect of Rosuvastatin and Angiotensin II Type 2 Receptor Agonist on Vascular Remodeling. AB - We investigated the possibility that coadministration of rosuvastatin and compound 21 (C21), a selective angiotensin II type 2 (AT2) receptor agonist, could exert synergistic preventive effects on vascular injury. Vascular injury was induced by polyethylene cuff placement on the femoral artery in 9-week-old male C57BL/6J mice. Mice were treated with rosuvastatin and/or with C21 after cuff placement. Neointima formation was determined 14 days after the operation and cell proliferation, and superoxide anion production and expression of inflammatory cytokines were examined 7 days after cuff placement. Neointima formation was significantly attenuated by the treatment of rosuvastatin (5 mg kg( 1) day(-1)) or C21 (10 MUg kg(-1) day(-1)), associated with the decreases in proliferating cell nuclear antigen (PCNA) labeling index, oxidative stress, and the expression of inflammatory markers. Treatment with a noneffective dose of rosuvastatin (0.5 mg kg(-1) day(-1)) plus a low dose of C21 (1 MUg kg(-1) day( 1)) inhibited the PCNA labeling index, superoxide anion production, mRNA expressions of NAD(P)H subunits, and mRNA and protein expressions of inflammatory markers associated with marked inhibition of neointima formation. Angiotensin II type 1 (AT1) receptor mRNA expression did not differ the groups. By contrast, AT2 receptor mRNA expression was increased by administration of C21 at the dose of 10 MUg kg(-1) day(-1) but not by C21 at the dose of 1 MUg kg(-1) day(-1) or rosuvastatin. The combination of rosuvastatin and AT2 receptor agonist exerted synergistic preventive effects on vascular remodeling associated with the decreases in cell proliferation, oxidative stress, and inflammatory reaction. That could be a powerful approach to vascular disease prevention. PMID- 27225896 TI - Transcatheter Patent Ductus Arteriosus Occlusion in Small Infants. AB - BACKGROUND: Transcatheter patent ductus arteriosus (PDA) occlusion is feasible in small infants and may improve lung function in symptomatic patients. We aimed to describe transcatheter PDA closure in small infants including predictors of technical success and rate of complication and to identify factors associated with improved respiratory status after closure. METHODS: All patients in the NICU at our center who were referred for transcatheter PDA occlusion between 1/2010 and 11/2014 were retrospectively identified. Relevant details were extracted. Additionally, a modification of the respiratory severity score (RSS) (FiO2 * mean airway pressure) was used to characterize degree of pulmonary support before and at intervals after catheterization. RESULTS: Twenty patients were identified with median age of 96 days (13-247) and weight of 3.1 kg (1.7-4.7). The PDA was type F morphology in 14 (70%) patients. The PDA was successfully occluded in 16 (80%) patients. Ratio of minimum PDA diameter/length was >0.5 in all unsuccessful attempts and <0.4 in all successful cases (P = .01). Of the 16 cases of occlusion, Amplatzer Vascular Plug II was used in 15 (94%). No deaths or pulse loss occurred. Five (25%) patients required blood transfusion and transfusion was associated with lower hemoglobin (P = .049), lower weight (P = .008), and lower aortic pressure (P = .04). Excluding 1 patient with significant congenital heart disease, the RSS improved at 3 days in 9 (60%) patients and at 7 days in 12 (80%) compared with preintervention value. Patient factors were not associated with improved RSS at 3 or 7 days. CONCLUSIONS: In our cohort of symptomatic infants, transcatheter PDA occlusion was successful in most and a ratio of minimum PDA diameter/length of <0.4 was predictive of technical success. Using a surrogate for pulmonary support, the majority of patients were on less support 7 days after closure. PMID- 27225895 TI - Differential Regulation of Gene Expression by Cholesterol Biosynthesis Inhibitors That Reduce (Pravastatin) or Enhance (Squalestatin 1) Nonsterol Isoprenoid Levels in Primary Cultured Mouse and Rat Hepatocytes. AB - Squalene synthase inhibitors (SSIs), such as squalestatin 1 (SQ1), reduce cholesterol biosynthesis but cause the accumulation of isoprenoids derived from farnesyl pyrophosphate (FPP), which can modulate the activity of nuclear receptors, including the constitutive androstane receptor (CAR), farnesoid X receptor, and peroxisome proliferator-activated receptors (PPARs). In comparison, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (e.g., pravastatin) inhibit production of both cholesterol and nonsterol isoprenoids. To characterize the effects of isoprenoids on hepatocellular physiology, microarrays were used to compare orthologous gene expression from primary cultured mouse and rat hepatocytes that were treated with either SQ1 or pravastatin. Compared with controls, 47 orthologs were affected by both inhibitors, 90 were affected only by SQ1, and 51 were unique to pravastatin treatment (P < 0.05, >=1.5-fold change). When the effects of SQ1 and pravastatin were compared directly, 162 orthologs were found to be differentially coregulated between the two treatments. Genes involved in cholesterol and unsaturated fatty acid biosynthesis were up-regulated by both inhibitors, consistent with cholesterol depletion; however, the extent of induction was greater in rat than in mouse hepatocytes. SQ1 induced several orthologs associated with microsomal, peroxisomal, and mitochondrial fatty acid oxidation and repressed orthologs involved in cell cycle regulation. By comparison, pravastatin repressed the expression of orthologs involved in retinol and xenobiotic metabolism. Several of the metabolic genes altered by isoprenoids were inducible by a PPARalpha agonist, whereas cytochrome P450 isoform 2B was inducible by activators of CAR. Our findings indicate that SSIs uniquely influence cellular lipid metabolism and cell cycle regulation, probably due to FPP catabolism through the farnesol pathway. PMID- 27225897 TI - Left ventricular end-diastolic dimension as a predictive factor of outcomes in children with acute myocarditis. AB - In this study, we sought predictors of mortality in children with acute myocarditis and of incomplete recovery in the survivor group. We classified our patients into three groups according to their outcomes at last follow-up: full recovery was classified as group I, incomplete recovery was classified as group II, and death was classified as group III. In total, 55 patients were enrolled in the study: 33 patients in group I, 11 patients in group II, and 11 patients in group III. The initial left ventricular fractional shortening - left ventricular fractional shortening - was significantly lower in group III (p=0.001), and the left ventricular end-diastolic dimension z score was higher in groups II and III compared with group I (p=0.000). A multivariate analysis showed that the left ventricular end-diastolic dimension z score (odds ratio (OR), 1.251; 95% confidence interval (CI), 1.004-1.559), extracorporeal membrane oxygenation (OR, 9.842; 95% CI, 1.044-92.764), and epinephrine infusion (OR, 18.552; 95% CI, 1.759 195.705) were significant predictors of mortality. The left ventricular end diastolic dimension z score was the only factor that predicted incomplete recovery in the survivor group (OR, 1.360; 95% CI, 1.066-1.734; p=0.013). The receiver operating characteristic curve of the left ventricular end-diastolic dimension z score at admission showed a cut-off level of 3.01 for predicting mortality (95% CI, 0.714-0.948). In conclusion, a high left ventricular end diastolic dimension z score on admission was a significant predictor of worse outcomes, both regarding mortality and incomplete recovery. PMID- 27225898 TI - Content and quality of websites supporting self-management of chronic breathlessness in advanced illness: a systematic review. AB - Chronic breathlessness is a common, burdensome and distressing symptom in many advanced chronic illnesses. Self-management strategies are essential to optimise treatment, daily functioning and emotional coping. People with chronic illness commonly search the internet for advice on self-management. A review was undertaken in June 2015 to describe the content and quality of online advice on breathlessness self-management, to highlight under-served areas and to identify any unsafe content. Google was searched from Sydney, Australia, using the five most common search terms for breathlessness identified by Google Trends. We also hand-searched the websites of national associations. Websites were included if they were freely available in English and provided practical advice on self management. Website quality was assessed using the American Medical Association Benchmarks. Readability was assessed using the Flesch-Kincaid grades, with grade 8 considered the maximum acceptable for enabling access. Ninety-one web pages from 44 websites met the inclusion criteria, including 14 national association websites not returned by Google searches. Most websites were generated in the USA (n=28, 64%) and focused on breathing techniques (n=38, 86%) and chronic obstructive pulmonary disease (n=27, 61%). No websites were found to offer unsafe advice. Adherence to quality benchmarks ranged from 9% for disclosure to 77% for currency. Fifteen (54%) of 28 written websites required grade ?9 reading level. Future development should focus on advice and tools to support goal setting, problem solving and monitoring of breathlessness. National associations are encouraged to improve website visibility and comply with standards for quality and readability. PMID- 27225899 TI - Lack of GLYCOLATE OXIDASE1, but Not GLYCOLATE OXIDASE2, Attenuates the Photorespiratory Phenotype of CATALASE2-Deficient Arabidopsis. AB - The genes coding for the core metabolic enzymes of the photorespiratory pathway that allows plants with C3-type photosynthesis to survive in an oxygen-rich atmosphere, have been largely discovered in genetic screens aimed to isolate mutants that are unviable under ambient air. As an exception, glycolate oxidase (GOX) mutants with a photorespiratory phenotype have not been described yet in C3 species. Using Arabidopsis (Arabidopsis thaliana) mutants lacking the peroxisomal CATALASE2 (cat2-2) that display stunted growth and cell death lesions under ambient air, we isolated a second-site loss-of-function mutation in GLYCOLATE OXIDASE1 (GOX1) that attenuated the photorespiratory phenotype of cat2-2 Interestingly, knocking out the nearly identical GOX2 in the cat2-2 background did not affect the photorespiratory phenotype, indicating that GOX1 and GOX2 play distinct metabolic roles. We further investigated their individual functions in single gox1-1 and gox2-1 mutants and revealed that their phenotypes can be modulated by environmental conditions that increase the metabolic flux through the photorespiratory pathway. High light negatively affected the photosynthetic performance and growth of both gox1-1 and gox2-1 mutants, but the negative consequences of severe photorespiration were more pronounced in the absence of GOX1, which was accompanied with lesser ability to process glycolate. Taken together, our results point toward divergent functions of the two photorespiratory GOX isoforms in Arabidopsis and contribute to a better understanding of the photorespiratory pathway. PMID- 27225900 TI - Foxtail Mosaic Virus-Induced Gene Silencing in Monocot Plants. AB - Virus-induced gene silencing (VIGS) is a powerful technique to study gene function in plants. However, very few VIGS vectors are available for monocot plants. Here we report that Foxtail mosaic virus (FoMV) can be engineered as an effective VIGS system to induce efficient silencing of endogenous genes in monocot plants including barley (Hordeum vulgare L.), wheat (Triticum aestivum) and foxtail millet (Setaria italica). This is evidenced by FoMV-based silencing of phytoene desaturase (PDS) and magnesium chelatase in barley, of PDS and Cloroplastos alterados1 in foxtail millet and wheat, and of an additional gene IspH in foxtail millet. Silencing of these genes resulted in photobleached or chlorosis phenotypes in barley, wheat, and foxtail millet. Furthermore, our FoMV based gene silencing is the first VIGS system reported for foxtail millet, an important C4 model plant. It may provide an efficient toolbox for high-throughput functional genomics in economically important monocot crops. PMID- 27225901 TI - Sagittal malalignment has a significant association with postoperative leg pain in adult spinal deformity patients. AB - PURPOSE: To evaluate the association between spinopelvic sagittal parameters and leg pain in patients with adult spinal deformity (ASD) after adjusting for demographic and surgical variables. METHODS: A multicenter prospective ASD database (European Spine Study Group) was retrospectively reviewed. The characteristics (age, sex, body mass index, comorbidity, history of spine surgery, and radiographical coronal and sagittal parameters) of patients with preoperative and 6-month postoperative leg pain (PostLP; numerical rating scale score >=5) were analyzed using univariate and multivariate analyses. RESULTS: In this study, 204 patients (164 women and 40 men; mean age 53.1 years) were included. Fifty-three percent of the patients had preoperative leg pain (PreLP). The patients with PreLP had significantly worse sagittal parameters and less coronal Cobb angle than those with less leg pain; however, this association disappeared after adjustment for covariates. The PreLP of the ASD patients was successfully treated surgically in most cases; however, 24 % of the patients still had unexpected residual leg pain. Postoperative sagittal malalignment (sagittal vertical axis >=40 mm, T1 sagittal tilt >=0 degrees , pelvic tilt >=30 degrees ) was a significant risk factor of PostLP even after adjusting for covariates. CONCLUSIONS: Leg pain in patients with ASD was significantly associated with sagittal malalignment especially after surgical treatments. As these patients lose flexibility in the fused spinal segment, they can only depend on the remaining compensatory mechanisms below the pelvis (e.g., the hips and knees) to maintain a balanced posture. This may lead to a predisposition of these patients to postoperative leg symptoms related to spinal sagittal malalignment. PMID- 27225902 TI - Clinical, physical, and radiographic analyses of lumbar degenerative kyphosis and spondylolisthesis among community-based cohort. AB - PURPOSE: To investigate longitudinal radiographic changes, and physical characteristics of lumbar degenerative kyphosis (LDK) and spondylolisthesis (DS). METHODS: Two-hundred eighty nine community-based female subjects were recruited from population register and studied longitudinally for a mean 12.3 years. Upright entire spine radiographs were used to evaluate spinopelvic parameters, including lumbar lordosis (LL), pelvic incidence (PI), and vertebral slip (% slip). Physical measurements included lumbar range of motion (ROM), isometric trunk muscle strength, and photometric gait posture using change in trunk inclination angle (dTIA). RESULTS: Subjects' mean age (standard deviation: SD) was 56.9 (10.0) years at baseline and 68.5 (9.2) years at the final follow-up. Among 202 subjects who could perform instructed physical measurements, DS, defined as more than 5 % slip, was found in 50 subjects (24.8 %), and LDK, defined as LL of less than 1SD of mean value (<24.4 degrees ), was found in 24 subjects (11.9 %). DS subjects showed a significant weakness in trunk flexor strength (normal 282.5 +/- 73.0 N vs. DS 245.5 +/- 75.5 N, p = 0.0219), and LDK subjects showed significant differences in: trunk extensor strength (normal 493.4 +/- 172.8 N vs. LDK 386.3 +/- 167.6 N, p = 0.0066), ROM, and dTIA (normal 3.5 degrees +/- 2.7 degrees vs. LDK 7.6 degrees +/- 4.8 degrees , p < 0.0001). PI was significantly larger in DS and smaller in LDK than normal subjects (normal 53.8 degrees +/- 9.9 degrees vs. DS 58.2 degrees +/- 10.6 degrees , p = 0.0111; normal vs. LDK 48.4 degrees +/- 9.2 degrees , p = 0.0191). CONCLUSIONS: Current study showed that DS was associated with reduced trunk flexor strength, which might increase pelvic anteversion, and LDK was associated with reduced extensor strength, ROM, and ambulatory kyphosis. Physical characteristics should be evaluated for the successful management of adult spinal deformity. PMID- 27225903 TI - Radiocarbon dating of prehistoric phytoliths: a preliminary study of archaeological sites in China. AB - Phytoliths can occlude some organic carbon during their deposition in plants. This carbon fraction is recognised as an ideal dating material because of its high resistance to decomposition and post-deposition contamination at the time of phytolith formation. However, the reliability of phytolith radiocarbon dating has recently been questioned. The development of a new extraction protocol for phytoliths, with paired dating between phytoliths and other materials from the same sediment, may provide further evidence for the reliability of phytolith dating. We present an improved method for extracting phytoliths from soils. We compared the dating of phytoliths and other materials (e.g., charcoal and plant seeds) recovered at the same depth from seven pits at six archaeological sites in China. The estimated ages of the phytoliths and other materials were generally consistent, except for one outlier. We attribute this inconsistency to the post depositional processes of phytoliths in soil, rather than to the uptake of old carbon from the soil. Our results clearly show the potential for phytolith carbon dating at archaeological sites in the absence of other dating materials. PMID- 27225904 TI - Voltage-Gated Proton Channel in Human Glioblastoma Multiforme Cells. AB - Solid tumors tend to have a more glycolytic metabolism leading to an accumulation of acidic metabolites in their cytosol, and consequently, their intracellular pH (pHi) turns critically lower if the cells do not handle the acid excess. Recently, it was proposed that the voltage gated proton channels (HV1) can regulate the pHi in several cancers. Here we report the functional expression of voltage gated proton channels in a human glioblastoma multiforme (GBM) cell line, the most common and lethal brain tumor. T98G cells presented an outward, slow activating voltage-dependent proton current, which was also DeltapH-dependent and inhibited by ZnCl2, characterizing it as being conducted by HV1 channels. Furthermore, blocking HV1 channels with ZnCl2 significantly reduced the pHi, cell survival, and migration, indicating an important role for HV1 for tumor proliferation and progression in GBM. Overall, our results suggest that HV1 channels can be a new therapeutic target for GBM. PMID- 27225906 TI - STAT3 inhibition prevents lung inflammation, remodeling, and accumulation of Th2 and Th17 cells in a murine asthma model. AB - BACKGROUND: STAT3 drives development of Th17 cells and cytokine production by Th2 and Th17 cells, which contribute to asthma. Alternative asthma treatments are needed, especially for the Th17 phenotype. We sought to determine whether C188-9, a small-molecule STAT3 inhibitor, can block Th2 and Th17 cell expansion and cytokine production to prevent house dust mite (HDM)-induced airway inflammation and remodeling. METHODS: Three groups of C57BL/6 mice were treated intranasally (IN) and intraperitoneally (IP) daily for 3 weeks with the following: (i) vehicle 1 IN and vehicle 2 IP, (ii) HDM IN and vehicle 2 IP, or (iii) HDM IN and C188-9 IP. Sections of lung were stained with Alcian Blue/PAS and examined microscopically. Total (t) STAT3, STAT3 phosphorylated on Y705 (pSTAT3), IL-17, IL-13, IL-5, and IL-4 levels were measured in lung protein extracts and serum using Luminex beads. Frequencies of Th2-type and Th17-type lymphocytes were assessed in lungs and bronchoalveolar lavage fluid (BALF) by multiparametric flow cytometry. RESULTS: HDM inhalation markedly increased airway goblet cell numbers and thickness of the epithelium and subepithelial smooth muscle layer, which was accompanied in the whole lung by increased pSTAT3, IL-4, IL-5, IL-13, and IL-17, and % CD4+ T cells that produce IL-5, IL-13, and IL-17. HDM inhalation also increased serum IL-4 and IL-17 levels and increased BALF % CD4+ T cells that produce IL-5 and IL-13. Remarkably, treatment with C188-9 normalized each endpoint. CONCLUSION: HDM-induced airway inflammation, remodeling, and Th2/Th17 type cell accumulation involve STAT3 activation that can be prevented by C188-9 treatment. PMID- 27225905 TI - Neuronal differentiation in the developing human spinal ganglia. AB - The spatiotemporal developmental pattern of the neural crest cells differentiation toward the first appearance of the neuronal subtypes was investigated in developing human spinal ganglia (SG) between the fifth and tenth developmental week using immunohistochemistry and immunofluorescence methods. First neurofilament-200- (NF200, likely myelinated mechanoreceptors) and isolectin-B4-positive neurons (likely unmyelinated nociceptors) appeared already in the 5/6th developmental week and their number subsequently increased during the progression of development. Proportion of NF200-positive cells was higher in the ventral parts of the SG than in the dorsal parts, particularly during the 5/6th and 9/10th developmental weeks (Mann-Whitney, P = 0.040 and P = 0.003). NF200 and IB4 colocalized during the whole investigated period. calcitonin gene related peptide (CGRP; nociceptive responses), vanilloid receptor-1 (VR1; polymodal nociceptors), and calretinin (calcium signaling) cell immunoreactivity first appeared in the sixth week and eighth week, respectively, especially in the dorsal parts of the SG. VR1 and CGRP colocalized with NF00 during the whole investigated period. Our results indicate the high potential of early differentiated neuronal cells, which slightly decreased with the progression of SG differentiation. On the contrary, the number of neuronal subtypes displayed increasing differentiation at later developmental stage. The great diversity of phenotypic expression found in the SG neurons is the result of a wide variety of influences, occurring at different stages of development in a large potential repertory of these neurons. Understanding the pathway of neural differentiation in the human, SG could be important for the studies dealing with the process of regeneration of damaged spinal nerves or during the repair of pathological changes within the affected ganglia. Anat Rec, 299:1060-1072, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27225907 TI - [A plebiscite for medicine? Vaccines and democracy]. PMID- 27225908 TI - [Study of membrane receptors by atomic force microscopy]. PMID- 27225909 TI - [Calpains: a double edge sword]. PMID- 27225910 TI - [The Ro60 autoantigen, a mainstay in inflammation regulation]. PMID- 27225911 TI - [Anti-Mullerian hormone: an ovarian hormone exerting hypothalamic feedback?]. PMID- 27225912 TI - [Simultaneous recording of neuronal and vascular dynamics in mobile animals]. PMID- 27225913 TI - [Single cell next generation sequencing and characterization of new cell types]. PMID- 27225914 TI - [Proteinase 3: a new danger signal and a double agent in vasculitis]. PMID- 27225915 TI - [The neural estrogen receptor beta, a new player in female pubertal maturation]. PMID- 27225916 TI - [Hepatitis B virus and chromatin remodeling: HBx counteracts SETDB1/HP1/H3K9me3 transcriptional silencing]. PMID- 27225917 TI - [Heart failure from mitochondrial origin: a matter of diet?]. PMID- 27225918 TI - [Alteration of intestinal permeability: the missing link between gut microbiota modifications and inflammation in obesity?]. AB - The increasing incidence of obesity and associated metabolic complications is a worldwide public health issue. The role of the gut in the pathophysiology of obesity, with an important part for microbiota, is becoming obvious. In rodent models of diet-induced obesity, the modifications of gut microbiota are associated with an alteration of the intestinal permeability increasing the passage of food or bacterial antigens, which contribute to low-grade inflammation and insulin resistance. In human obesity, intestinal permeability modification, and its role in the crosstalk between gut microbiota changes and inflammation at systemic and tissular levels, are still poorly documented. Hence, further characterization of the triggering mechanisms of such inflammatory responses in obese subjects could enable the development of personalized intervention strategies that will help to reduce the risk of obesity-associated diseases. PMID- 27225919 TI - [Cardiac pathologies and aging: lessons from a tiny heart]. AB - The high level of conservation of the cardiogenic gene regulatory network as well as of the cellular and physiological characteristics of the cardiomyocytes between fly and human, makes the small heart of this invertebrate the simplest and most flexible genetic system to dissect the fundamental molecular mechanisms that are brought into play during the development, the establishment and the maintenance of the cardiac function. The recent improvements in techniques of measurements of cardiac function made it possible to validate Drosophila as a model of cardiomyopathies and arrhythmias of genetic and metabolic origin or dependent of ageing. The heart of the fly thus represents a model of choice to identify genes and their interactions implicated in cardiac pathologies. PMID- 27225920 TI - [The comeback of mitochondria in Drosophila apoptosis]. AB - The role of the mitochondrion in mammalian cell apoptosis has been established since the mid-1990s. However, the importance of this organelle in non-mammalian apoptosis has long been regarded as minor, notably because of the absence of a crucial role for cytochrome c in caspase activation. Recent results indicate that the control of caspase activation and apoptosis in Drosophila cell death occurs at the mitochondrial level. Numerous proteins that appear key for Drosophila apoptosis regulation constitutively or transiently bind to mitochondria. They participate in the cell death process at different levels such as degradation of an IAP caspase inhibitor, production of mitochondrial reactive oxygen species or stimulation of the mitochondrial fission machinery. The aim of this review is to take stock of these events that might have their counterpart in humans. PMID- 27225921 TI - [Mechanisms of caffeine-induced diuresis]. AB - Caffeine is an alkaloid which belongs to the family of methylxanthines and is present in beverages, food and drugs. Caffeine competitively antagonizes the adenosine receptors (AR), which are G protein-coupled receptors largely distributed throughout the body, including brain, heart, vessels and kidneys. Caffeine consumption has a well-known diuretic effect. The homeostasis of salt and water involves different segments of the nephron, in which adenosine plays complex roles depending on the differential expression of AR. Hence, caffeine increases glomerular filtration rate by opposing the vasoconstriction of renal afferent arteriole mediated by adenosine via type 1 AR during the tubuloglomerular feedback. Caffeine also inhibits Na(+) reabsorption at the level of renal proximal tubules. In addition, caffeine perturbs the hepatorenal reflex via sensory nerves in Mall's intrahepatic spaces. Here, we review the physiology of caffeine-induced natriuresis and diuresis, as well as the putative pathological implications. PMID- 27225922 TI - [AMPK, regulator of sperm energy and functions]. AB - The 5'-AMP-activated protein kinase, AMPK, is a key protein kinase in the metabolism of the cell that regulates many metabolic pathways. The involvement of cell metabolism in sperm ability to fertilize is well established, but only a few studies have focused on the role of AMPK in the control of male fertility. This article summarizes the known role of AMPK in this area. AMPK is involved in the regulation of sperm quality by its action on the proliferation of Sertoli cells. AMPK also directly controls the quality of sperm by its involvement in the regulation of motility and acrosome reaction. It is also involved in the management of lipid peroxidation and gametes antioxidant enzymes. Thus, AMPK appears as a key signaling protein for sperm and male fertility control. PMID- 27225923 TI - [A new pragmatic megaclassification of life]. PMID- 27225924 TI - [Eco-epidemiology: towards epidemiology of complexity]. AB - In order to solve public health problems posed by the epidemiology of risk factors centered on the individual and neglecting the causal processes linking the risk factors with the health outcomes, Mervyn Susser proposed a multilevel epidemiology called eco-epidemiology, addressing the interdependence of individuals and their connection with molecular, individual, societal, environmental levels of organization participating in the causal disease processes. The aim of this epidemiology is to integrate more than a level of organization in design, analysis and interpretation of health problems. After presenting the main criticisms of risk-factor epidemiology focused on the individual, we will try to show how eco-epidemiology and its development could help to understand the need for a broader and integrative epidemiology, in which studies designed to identify risk factors would be balanced by studies designed to answer other questions equally vital to public health. PMID- 27225925 TI - [Evaluating the epidemic risk from incomplete data]. PMID- 27225926 TI - [Foundlings and human experiment in the first step of the vaccination in France]. PMID- 27225927 TI - [A woman doctor in Algeria. The diary of Dorothee Chellier (1895-1899)]. PMID- 27225928 TI - [23andMe and motion sickness]. AB - A Genome Wide Association Study on propensity to motion sickness published by 23andMe gives interesting results, shows validity for self-reported phenotypic information and underlines the value of the model developed by the company for customer participation in genetic studies. PMID- 27225929 TI - [Dominique Labie (1920-2016)]. PMID- 27225930 TI - Mechanism and Selectivity of Ru(II) - and Rh(III) -Catalyzed Oxidative Spiroannulation of Naphthols and Phenols with Alkynes through a C-H Activation/Dearomatization Strategy. AB - The ruthenium- and rhodium-catalyzed oxidative spiroannulation of naphthols and phenols with alkynes was investigated by means of density functional theory calculations. The results show that the reaction undergoes O-H deprotonation/C(sp(2) )-H bond cleavage through a concerted metalation deprotonation mechanism/migratory insertion of the alkyne into the M-C bond to deliver the eight-membered metallacycle. However, the dearomatization through the originally proposed enol-keto tautomerization/C-C reductive elimination was calculated to be kinetically inaccessible. Alternatively, an unusual metallacyclopropene, generated from the isomerization of the eight-membered metallacycle through rotation of the C-C double bond, was identified as a key intermediate to account for the experimental results. The subsequent C-C coupling between the carbene carbon atom and the carbon atom of the 2-naphthol/phenol ring was calculated to be relatively facile, leading to the formation of the unexpected dearomatized products. The calculations reproduce quite well the experimentally observed formal [5+2] cycloaddition in the rhodium-catalyzed oxidative annulation of 2-vinylphenols with alkynes. The calculations show that compared with the case of 2-alkenylphenols, the presence of conjugation effects and less steric repulsion between the phenol ring and the vinyl moiety make the competing reductive oxyl migration become dominant, which enables the selectivity switch from the spiroannulation to the formal [5+2] cycloaddition. PMID- 27225931 TI - [MEK clarification: What is the task of the anesthesiologist?]. PMID- 27225932 TI - SIRT7 promotes genome integrity and modulates non-homologous end joining DNA repair. AB - Sirtuins, a family of protein deacetylases, promote cellular homeostasis by mediating communication between cells and environment. The enzymatic activity of the mammalian sirtuin SIRT7 targets acetylated lysine in the N-terminal tail of histone H3 (H3K18Ac), thus modulating chromatin structure and transcriptional competency. SIRT7 deletion is associated with reduced lifespan in mice through unknown mechanisms. Here, we show that SirT7-knockout mice suffer from partial embryonic lethality and a progeroid-like phenotype. Consistently, SIRT7-deficient cells display increased replication stress and impaired DNA repair. SIRT7 is recruited in a PARP1-dependent manner to sites of DNA damage, where it modulates H3K18Ac levels. H3K18Ac in turn affects recruitment of the damage response factor 53BP1 to DNA double-strand breaks (DSBs), thereby influencing the efficiency of non-homologous end joining (NHEJ). These results reveal a direct role for SIRT7 in DSB repair and establish a functional link between SIRT7-mediated H3K18 deacetylation and the maintenance of genome integrity. PMID- 27225934 TI - Movement of a Hybrid Zone Between Lineages of the Australian Glass Shrimp (Paratya australiensis). AB - In 1993, a population of freshwater glass shrimp (Paratya australiensis) was translocated from Kilcoy Creek to Branch Creek in the Conondale Range, Queensland. Subsequent genetic analysis revealed that the translocated and resident shrimp belonged to different mitochondrial DNA (mtDNA) lineages that were capable of hybridizing. Monitoring of the pools along Branch Creek up until 2002 suggested that the translocated lineage had an advantage in upstream pools and the resident lineage dominated downstream. Differential temperature tolerance and hybridization barriers such as hybrid inviability and mate selection were factors proposed to explain hybrid zone structure. The major objective of this study was to combine nuclear and mtDNA markers to identify the structure of the hybrid zone in 2013 and identify any changes that had occurred since 2002. Specifically, we used genetic data to test for evidence of hybrid zone movement and used the inbreeding coefficient (F IS) to investigate whether mating was random in the contact zone where hybridization barriers could be present. The results revealed that the hybrid zone center has shifted 510 m downstream since 2002. Increased rainfall in the region since 2010 could have facilitated this. Secondly, mating appears significantly nonrandom in the pools where both lineages occur, supporting the existence of partial hybridization barriers. This study reveals a complex and dynamic hybrid zone and exemplifies why multiple temporal studies are necessary to understand hybrid zone structure. PMID- 27225936 TI - The unique functional role of the C-HS hydrogen bond in the substrate specificity and enzyme catalysis of type 1 methionine aminopeptidase. AB - It is intriguing how nature attains recognition specificity between molecular interfaces where there is no apparent scope for classical hydrogen bonding or polar interactions. Methionine aminopeptidase (MetAP) is one such enzyme where this fascinating conundrum is at play. In this study, we demonstrate that a unique C-HS hydrogen bond exists between the enzyme methionine aminopeptidase (MetAP) and its N-terminal-methionine polypeptide substrate, which allows specific interaction between apparent apolar interfaces, imposing a strict substrate recognition specificity and efficient catalysis, a feature replicated in Type I MetAPs across all kingdoms of life. We evidence this evolutionarily conserved C-HS hydrogen bond through enzyme assays on wild-type and mutant MetAP proteins from Mycobacterium tuberculosis that show a drastic difference in catalytic efficiency. The X-ray crystallographic structure of the methionine bound protein revealed a conserved water bridge and short contacts involving the Met side-chain, a feature also observed in MetAPs from other organisms. Thermal shift assays showed a remarkable 3.3 degrees C increase in melting temperature for methionine bound protein compared to its norleucine homolog, where C-HS interaction is absent. The presence of C-HS hydrogen bonding was also corroborated by nuclear magnetic resonance spectroscopy through a change in chemical shift. Computational chemistry studies revealed the unique role of the electrostatic environment in facilitating the C-HS interaction. The significance of this atypical hydrogen bond is underscored by the fact that the function of MetAP is essential for any living cell. PMID- 27225935 TI - Retention of Ancestral Genetic Variation Across Life-Stages of an Endangered, Long-Lived Iteroparous Fish. AB - As with many endangered, long-lived iteroparous fishes, survival of razorback sucker depends on a management strategy that circumvents recruitment failure that results from predation by non-native fishes. In Lake Mohave, AZ-NV, management of razorback sucker centers on capture of larvae spawned in the lake, rearing them in off-channel habitats, and subsequent release ("repatriation") to the lake when adults are sufficiently large to resist predation. The effects of this strategy on genetic diversity, however, remained uncertain. After correction for differences in sample size among groups, metrics of mitochondrial DNA (mtDNA; number of haplotypes, N H , and haplotype diversity, H D ) and microsatellite (number of alleles, N A , and expected heterozygosity, H E ) diversity did not differ significantly between annual samples of repatriated adults and larval year classes or among pooled samples of repatriated adults, larvae, and wild fish. These findings indicate that the current management program thus far maintained historical genetic variation of razorback sucker in the lake. Because effective population size, N e , is closely tied to the small census population size (N c = ~1500-3000) of razorback sucker in Lake Mohave, this population will remain at risk from genetic, as well as demographic risk of extinction unless N c is increased substantially. PMID- 27225933 TI - Structural evidence for Nap1-dependent H2A-H2B deposition and nucleosome assembly. AB - Nap1 is a histone chaperone involved in the nuclear import of H2A-H2B and nucleosome assembly. Here, we report the crystal structure of Nap1 bound to H2A H2B together with in vitro and in vivo functional studies that elucidate the principles underlying Nap1-mediated H2A-H2B chaperoning and nucleosome assembly. A Nap1 dimer provides an acidic binding surface and asymmetrically engages a single H2A-H2B heterodimer. Oligomerization of the Nap1-H2A-H2B complex results in burial of surfaces required for deposition of H2A-H2B into nucleosomes. Chromatin immunoprecipitation-exonuclease (ChIP-exo) analysis shows that Nap1 is required for H2A-H2B deposition across the genome. Mutants that interfere with Nap1 oligomerization exhibit severe nucleosome assembly defects showing that oligomerization is essential for the chaperone function. These findings establish the molecular basis for Nap1-mediated H2A-H2B deposition and nucleosome assembly. PMID- 27225937 TI - Synthesis, structure and geometrically frustrated magnetism of the layered oxide stannide compounds Fe(Fe3-xMnx)Si2Sn7O16. AB - Fe4Si2Sn7O16 has a unique crystal structure that contains alternating layers of Fe(2+) ions octahedrally coordinated by O (oxide layer) and Sn (stannide layer), bridged by SiO4 tetrahedra. The formula can be written as FeFe3Si2Sn7O16 to emphasise the distinction between the layers. Here, we report the changes in structure and properties as iron is selectively replaced by manganese in the oxide layer. Solid-state synthesis was used to produce polycrystalline samples of Fe(Fe3-xMnx)Si2Sn7O16 for x<= 2.55, the structures of which were characterised using high-resolution synchrotron X-ray and neutron powder diffraction. Single crystal samples were also grown at x = 0.35, 0.95, 2.60 and characterised by single crystal X-ray diffraction. We show that manganese is doped exclusively into the oxide layer, and that this layer contains exclusively magnetically active high-spin M(2+) transition metal cations; while the stannide layer only accommodates non-magnetic low-spin Fe(2+). All samples show clear evidence of geometrically frustrated magnetism, which we associate with the fact that the topology of the high-spin M(2+) ions in the oxide layer describes a perfect kagome lattice. Despite this frustration, the x = 0 and x = 2.55 samples undergo long-range antiferromagnetic ordering transitions at 3.0 K and 2.5 K, respectively. PMID- 27225939 TI - A pilot trial of FLOT neoadjuvant chemotherapy for resectable esophagogastric junction adenocarcinoma. AB - Docetaxel is active in esophagogastric junction (EGJ) adenocarcinoma, and DCF (docetaxel/cisplatin/5-fluorouracil) has shown good results in the neoadjuvant setting. Its high rate of grade 3-4 mucosal toxicity (stomatitis and diarrhea) has limited its widespread adoption. A more recent docetaxel-based triplet, FLOT (5-fluorouracil, oxaliplatin and docetaxel) may be better tolerated. We conducted a pilot study of FLOT chemotherapy in EGJ adenocarcinoma patients and dysphagia to prospectively assess the rate of grade 3-4 mucosal toxicity and of pathological complete response (pCR) rate. Dysphagia and quality of life were measured with validated questionnaires. Ten patients were enrolled. Grade 3-4 mucosal toxicity rate was 0 %; pCR rate was 11 %; and near-complete pathological response rate 11 %. Dysphagia improvement or resolution was seen in 90 % of patients, and quality of life was stable before and after chemotherapy. FLOT is a safe and active neoadjuvant chemotherapy option for EGJ adenocarcinoma and should be compared to other standard regimens in randomized trials. PMID- 27225938 TI - K-Ras mutation detection in liquid biopsy and tumor tissue as prognostic biomarker in patients with pancreatic cancer: a systematic review with meta analysis. AB - K-Ras gene mutations have been found in most pancreatic cancers; however, conflicting data on the prognostic value of K-Ras mutations in pancreatic cancer have been published. We conducted a meta-analysis to assess its prognostic significance. Literature searches of PubMed, EMBASE, Cochrane Library, Web of Science and Google Scholar were performed through December 2015 to identify publications exploring the association of K-Ras mutation with overall survival. Forty eligible studies involving 3427 patients with pancreatic cancer were included in the present meta-analysis. Our analysis showed a hazard ratio (HR) of negative association with survival of 1.61 [95 % confidence interval (CI) 1.36 1.90; p < 0.01] in K-Ras mutant pancreatic cancer patients. In subgroup analyses, K-Ras mutations detected in tumor tissues and in liquid biopsies had HRs of 1.37 (95 % CI 1.20-1.57; p < 0.01) and 3.16 (95 % CI 2.1-4.71; p < 0.01), respectively. In addition, the HR was higher when K-Ras mutations were detected in fresh frozen samples (HR = 2.01, 95 % CI 1.28-3.16, p = 0.002) than in formalin-fixed, paraffin-embedded (FFPE) samples (HR = 1.29, 95 % CI 1.12-1.49, p < 0.01). Though K-Ras alterations are more frequent among non-East Asian individuals than East Asian individuals, there were no significant differences in HRs of survival between the two ethnic subgroups. In conclusion, this meta analysis suggests that K-Ras mutations are associated with a worse overall survival in pancreatic cancer patients, especially when mutations are detected in liquid biopsies or fresh frozen tumor tissue samples. PMID- 27225940 TI - Potential role of heat-shock protein 70 and interleukin-15 in the pathogenesis of threatened spontaneous abortions. AB - PROBLEM: The role of HSP70 and both its constitutive (Hsc) and inducible (Hsp) forms in the pathogenesis of threatened spontaneous abortions was investigated. METHOD OF STUDY: Immunohistology and/or immunofluorescence was used to analyze paraffin-embedded tissue sections, and reverse transcriptase-quantitative polymerase chain reaction and flow cytometry were used for analyses of decidual mononuclear cells (DMCs) and confocal microscopy for the detection of perforin, granulysin, and lysosome-associated membrane protein-1 (LAMP-1) in decidual lymphocytes (DLs). RESULTS: The percentage of single Hsp70(+) , Hsc70(+) , and IL 15(+) cells and mRNA levels of HSP70, CD91, and TLR4 were lower in the decidua basalis in cases of threatened miscarriages compared to that in cases of normal pregnancy. In a suspension of normal DMCs, IL-15 significantly decreased the HSP70 members and TLR4 in dendritic cells, T cells, and NK cells while increasing CD91 in NK cells alone. CONCLUSION: Downregulation of Hsc70, Hsp70, and IL-15 expression at gene and/or protein levels might support the retention of fertilization products in cases of missed abortion and blighted ovum. PMID- 27225941 TI - Clarifying dementia risk factors: treading in murky waters. AB - In light of the growing burden of dementia, continued research into risk factors and potential contributors to disease development is essential. Clearly established risk factors can not only inform our understanding of disease pathophysiology and treatments but also identify potential preventive strategies. While age and the ApoE4 allele have consistently been shown to increase risk of developing dementia (Kukull et al., 2002), other risk factors have been less studied or have had inconsistent findings. The study by Booker and colleagues (Booker et al., 2016) re-examines proposed late-life medical risk factors for incident dementia in a large population-based case-control study. This important contribution is best interpreted in the context of existing research. PMID- 27225942 TI - Interactions of warming and exposure affect susceptibility to parasite infection in a temperate fish species. AB - Predicting how elevated temperatures from climate change alter host-parasite interactions requires understandings of how warming affects host susceptibility and parasite virulence. Here, the effect of elevated water temperature and parasite exposure level was tested on parasite prevalence, abundance and burden, and on fish growth, using Pomphorhynchus laevis and its fish host Squalius cephalus. At 60 days post-exposure, prevalence was higher at the elevated temperature (22 degrees C) than ambient temperature (18 degrees C), with infections achieved at considerably lower levels of exposure. Whilst parasite number was significantly higher in infected fish at 22 degrees C, both mean parasite weight and parasite burden was significantly higher at 18 degrees C. There were, however, no significant relationships between fish growth rate and temperature, parasite exposure, and the infection parameters. Thus, whilst elevated temperature significantly influenced parasite infection rates, it also impacted parasite development rates, suggesting warming could have complex implications for parasite dynamics and host resistance. PMID- 27225943 TI - A pH-responsive DNA nanomachine-controlled catalytic assembly of gold nanoparticles. AB - The toehold-mediated DNA-strand-displacement reaction has unique programmable properties for driving the catalytic assembly of gold nanoparticles (AuNPs). Herein, we introduced a pH-responsive triplex structure into the DNA-strand displacement-based catalytic assembly system of DNA-AuNPs to add an additional controlling factor, namely the pH. In this catalytic system, the aggregation rate of AuNPs could be regulated by both internal factors (concentrations of substrate, target, etc.) and an external control (pH gradient). This strategy can be used to construct pH-induced DNA logic gates and sophisticated DNA networks as well as to image instantaneous pH changes in living cells. PMID- 27225944 TI - Graphene-Analogues Boron Nitride Nanosheets Confining Ionic Liquids: A High Performance Quasi-Liquid Solid Electrolyte. AB - Solid electrolytes are one of the most promising electrolyte systems for safe lithium batteries, but the low ionic conductivity of these electrolytes seriously hinders the development of efficient lithium batteries. Here, a novel class of graphene-analogues boron nitride (g-BN) nanosheets confining an ultrahigh concentration of ionic liquids (ILs) in an interlayer and out-of-layer chamber to give rise to a quasi-liquid solid electrolyte (QLSE) is reported. The electron insulated g-BN nanosheet host with a large specific surface area can confine ILs as much as 10 times of the host's weight to afford high ionic conductivity (3.85 * 10(-3) S cm(-1) at 25 degrees C, even 2.32 * 10(-4) S cm(-1) at -20 degrees C), which is close to that of the corresponding bulk IL electrolytes. The high ionic conductivity of QLSE is attributed to the enormous absorption for ILs and the confining effect of g-BN to form the ordered lithium ion transport channels in an interlayer and out-of-layer of g-BN. Furthermore, the electrolyte displays outstanding electrochemical properties and battery performance. In principle, this work enables a wider tunability, further opening up a new field for the fabrication of the next-generation QLSE based on layered nanomaterials in energy conversion devices. PMID- 27225945 TI - Gene by environmental interactions affecting oxidative phosphorylation and thermal sensitivity. AB - The oxidative phosphorylation (OxPhos) pathway is responsible for most aerobic ATP production and is the only metabolic pathway with proteins encoded by both nuclear and mitochondrial genomes. In studies examining mitonuclear interactions among distant populations within a species or across species, the interactions between these two genomes can affect metabolism, growth, and fitness, depending on the environment. However, there is little data on whether these interactions impact natural populations within a single species. In an admixed Fundulus heteroclitus population with northern and southern mitochondrial haplotypes, there are significant differences in allele frequencies associated with mitochondrial haplotype. In this study, we investigate how mitochondrial haplotype and any associated nuclear differences affect six OxPhos parameters within a population. The data demonstrate significant OxPhos functional differences between the two mitochondrial genotypes. These differences are most apparent when individuals are acclimated to high temperatures with the southern mitochondrial genotype having a large acute response and the northern mitochondrial genotype having little, if any acute response. Furthermore, acute temperature effects and the relative contribution of Complex I and II depend on acclimation temperature: when individuals are acclimated to 12 degrees C, the relative contribution of Complex I increases with higher acute temperatures, whereas at 28 degrees C acclimation, the relative contribution of Complex I is unaffected by acute temperature change. These data demonstrate a complex gene by environmental interaction affecting the OxPhos pathway. PMID- 27225946 TI - Long-lasting bradypnea induced by repeated social defeat. AB - Repeated social defeat in the rat induces long-lasting cardiovascular changes associated with anxiety. In this study, we investigated the effects of repeated social defeat on breathing. Respiratory rate was extracted from the respiratory sinus arrhythmia (RSA) peak frequency of the ECG in rats subjected to social defeat for 4 consecutive days. Respiratory rate was recorded under anesthesia 6 days (D+10) or 26 days (D+30) after social defeat. At D+10, defeated (D) rats spent less time in the open arms of the elevated plus maze test, had heavier adrenal glands, and displayed bradypnea, unlike nondefeated animals. At D+30, all signs of anxiety had disappeared. However, one-half of the rats still displayed bradypnea (DL rats, for low respiratory rate indicated by a lower RSA frequency), whereas those with higher respiratory rate (DH rats) had recovered. Acute blockade of the dorsomedial hypothalamus (DMH) or nucleus tractus solitarii (NTS) 5-HT3 receptors reversed bradypnea in all D rats at D+10 and in DL rats at D+30. Respiratory rate was also recorded in conscious animals implanted with radiotelemetric ECG probes. DH rats recovered between D+10 and D+18, whereas DL rats remained bradypneic until D+30. In conclusion, social stress induces sustained chronic bradypnea mediated by DMH neurons and NTS 5-HT3 receptors. These changes are associated with an anxiety-like state that persists until D+10, followed by recovery. However, bradypnea may persist in one-half of the population up until D+30, despite apparent recovery of the anxiety-like state. PMID- 27225947 TI - Glycine enhances muscle protein mass associated with maintaining Akt-mTOR-FOXO1 signaling and suppressing TLR4 and NOD2 signaling in piglets challenged with LPS. AB - Pro-inflammatory cytokines play a critical role in the pathophysiology of muscle atrophy. We hypothesized that glycine exerted an anti-inflammatory effect and alleviated lipopolysaccharide (LPS)-induced muscle atrophy in piglets. Pigs were assigned to four treatments including the following: 1) nonchallenged control, 2) LPS-challenged control, 3) LPS+1.0% glycine, and 4) LPS+2.0% glycine. After receiving the control, 1.0 or 2.0% glycine-supplemented diets, piglets were treated with either saline or LPS. At 4 h after treatment with saline or LPS, blood and muscle samples were harvested. We found that 1.0 or 2.0% glycine increased protein/DNA ratio, protein content, and RNA/DNA ratio in gastrocnemius or longissimus dorsi (LD) muscles. Glycine also resulted in decreased mRNA expression of muscle atrophy F-box (MAFbx) and muscle RING finger 1 (MuRF1) in gastrocnemius muscle. In addition, glycine restored the phosphorylation of Akt, mammalian target of rapamycin (mTOR), eukaryotic initiation factor 4E binding protein 1 (4E-BP1), and Forkhead Box O 1 (FOXO1) in gastrocnemius or LD muscles. Furthermore, glycine resulted in decreased plasma tumor necrosis factor-alpha (TNF-alpha) concentration and muscle TNF-alpha mRNA abundance. Moreover, glycine resulted in decreased mRNA expresson of Toll-like receptor 4 (TLR4), nucleotide binding oligomerization domain protein 2 (NOD2), and their respective downstream molecules in gastrocnemius or LD muscles. These results indicate glycine enhances muscle protein mass under an inflammatory condition. The beneficial roles of glycine on the muscle are closely associated with maintaining Akt-mTOR-FOXO1 signaling and suppressing the activation of TLR4 and/or NOD2 signaling pathways. PMID- 27225948 TI - Multiscale entropy analysis of heart rate variability in heart failure, hypertensive, and sinoaortic-denervated rats: classical and refined approaches. AB - The analysis of heart rate variability (HRV) by nonlinear methods has been gaining increasing interest due to their ability to quantify the complexity of cardiovascular regulation. In this study, multiscale entropy (MSE) and refined MSE (RMSE) were applied to track the complexity of HRV as a function of time scale in three pathological conscious animal models: rats with heart failure (HF), spontaneously hypertensive rats (SHR), and rats with sinoaortic denervation (SAD). Results showed that HF did not change HRV complexity, although there was a tendency to decrease the entropy in HF animals. On the other hand, SHR group was characterized by reduced complexity at long time scales, whereas SAD animals exhibited a smaller short- and long-term irregularity. We propose that short time scales (1 to 4), accounting for fast oscillations, are more related to vagal and respiratory control, whereas long time scales (5 to 20), accounting for slow oscillations, are more related to sympathetic control. The increased sympathetic modulation is probably the main reason for the lower entropy observed at high scales for both SHR and SAD groups, acting as a negative factor for the cardiovascular complexity. This study highlights the contribution of the multiscale complexity analysis of HRV for understanding the physiological mechanisms involved in cardiovascular regulation. PMID- 27225949 TI - Cerebral blood flow regulation in women across menstrual phase: differential contribution of cyclooxygenase to basal, hypoxic, and hypercapnic vascular tone. AB - In healthy young women, basal cerebral blood flow (CBF) and cerebrovascular reactivity may change across the menstrual cycle, but mechanisms remain untested. When compared with the early follicular phase of the menstrual cycle, we hypothesized women in late follicular phase would exhibit: 1) greater basal CBF, 2) greater hypercapnic increases in CBF, 3) greater hypoxic increases in CBF, and 4) increased cyclooxygenase (COX) signaling. We measured middle cerebral artery velocity (MCAv, transcranial Doppler ultrasound) in 11 healthy women (23 +/- 1 yr) during rest, hypoxia, and hypercapnia. Subjects completed four visits: two during the early follicular (~day 3) and two during the late follicular (~day 14) phases of the menstrual cycle, with and without COX inhibition (oral indomethacin). Isocapnic hypoxia elicited an SPO2 = 90% and SPO2 = 80% for 5 min each. Separately, hypercapnia increased end-tidal CO2 10 mmHg above baseline. Cerebral vascular conductance index (CVCi = MCAv/MABP.100, where MABP is mean arterial blood pressure) was calculated and a positive change reflected vasodilation (DeltaCVCi). Basal CVCi was greater in the late follicular phase (P < 0.001). Indomethacin decreased basal CVCi (~37%) and abolished the phase difference (P < 0.001). Hypoxic DeltaCVCi was similar between phases and unaffected by indomethacin. Hypercapnic DeltaCVCi was similar between phases, and indomethacin decreased hypercapnic DeltaCVCi (~68%; P < 0.001) similarly between phases. In summary, while neither hypercapnic nor hypoxic vasodilation is altered by menstrual phase, increased basal CBF in the late follicular phase is fully explained by a greater contribution of COX. These data provide new mechanistic insight into anterior CBF regulation across menstrual phases and contribute to our understanding of CBF regulation in women. PMID- 27225950 TI - elPBN neurons regulate rVLM activity through elPBN-rVLM projections during activation of cardiac sympathetic afferent nerves. AB - The external lateral parabrachial nucleus (elPBN) within the pons and rostral ventrolateral medulla (rVLM) contributes to central processing of excitatory cardiovascular reflexes during stimulation of cardiac sympathetic afferent nerves (CSAN). However, the importance of elPBN cardiovascular neurons in regulation of rVLM activity during CSAN activation remains unclear. We hypothesized that CSAN stimulation excites the elPBN cardiovascular neurons and, in turn, increases rVLM activity through elPBN-rVLM projections. Compared with controls, in rats subjected to microinjection of retrograde tracer into the rVLM, the numbers of elPBN neurons double-labeled with c-Fos (an immediate early gene) and the tracer were increased after CSAN stimulation (P < 0.05). The majority of these elPBN neurons contain vesicular glutamate transporter 3. In cats, epicardial bradykinin and electrical stimulation of CSAN increased the activity of elPBN cardiovascular neurons, which was attenuated (n = 6, P < 0.05) after blockade of glutamate receptors with iontophoresis of kynurenic acid (Kyn, 25 mM). In separate cats, microinjection of Kyn (1.25 nmol/50 nl) into the elPBN reduced rVLM activity evoked by both bradykinin and electrical stimulation (n = 5, P < 0.05). Excitation of the elPBN with microinjection of dl-homocysteic acid (2 nmol/50 nl) significantly increased basal and CSAN-evoked rVLM activity. However, the enhanced rVLM activity induced by dl-homocysteic acid injected into the elPBN was reversed following iontophoresis of Kyn into the rVLM (n = 7, P < 0.05). These data suggest that cardiac sympathetic afferent stimulation activates cardiovascular neurons in the elPBN and rVLM sequentially through a monosynaptic (glutamatergic) excitatory elPBN-rVLM pathway. PMID- 27225951 TI - Coordinate mobilization and burning of lipid stores. Focus on "Protein kinase A induces UCP1 expression in specific adipose depots to increase energy expenditure and improve metabolic health". PMID- 27225952 TI - Seasonal changes in brown adipose tissue mitochondria in a mammalian hibernator: from gene expression to function. AB - Brown adipose tissue (BAT) is a thermogenic organ that is vital for hibernation in mammals. Throughout the hibernation season, BAT mitochondrial uncoupling protein 1 (UCP1) enables rapid rewarming from hypothermic torpor to periodic interbout arousals (IBAs), as energy is dissipated as heat. However, BAT's unique ability to rewarm the body via nonshivering thermogenesis is not necessary outside the hibernation season, suggesting a potential seasonal change in the regulation of BAT function. Here, we examined the BAT mitochondrial proteome and mitochondrial bioenergetics in the thirteen-lined ground squirrel (Ictidomys tridecemlineatus) across four time points: spring, fall, torpor, and IBA. Relative mitochondrial content of BAT was estimated by measuring BAT pad mass, UCP1 protein content, and mitochondrial DNA (mtDNA) copy number. BAT mtDNA content was significantly lower in spring compared with torpor and IBA (P < 0.05). UCP1 mRNA and protein levels were highest during torpor and IBA. Respiration rates of isolated BAT mitochondria were interrogated at each complex of the electron transport chain. Respiration at complex II was significantly higher in torpor and IBA compared with spring (P < 0.05), suggesting an enhancement in mitochondrial respiratory capacity during hibernation. Additionally, proteomic iTRAQ labeling identified 778 BAT mitochondrial proteins. Proteins required for mitochondrial lipid translocation and beta-oxidation were upregulated during torpor and IBA and downregulated in spring. These data imply that BAT bioenergetics and mitochondrial content are not static across the year, despite the year-round presence of UCP1. PMID- 27225955 TI - Programmed pH-Driven Reversible Association and Dissociation of Interconnected Circular DNA Dimer Nanostructures. AB - The switchable pH-driven reversible assembly and dissociation of interlocked circular DNA dimers is presented. The circular DNA dimers are interconnected by pH-responsive nucleic acid bridges. In one configuration, the two-ring nanostructure is separated at pH = 5.0 to individual rings by reconfiguring the interlocking bridges into C-G.C(+) triplex units, and the two-ring assembly is reformed at pH = 7.0. In the second configuration, the dimer of circular DNAs is bridged at pH = 7.0 by the T-A.T triplex bridging units that are separated at pH = 10.0, leading to the dissociation of the dimer to single circular DNA nanostructures. The two circular DNA units are also interconnected by two pH responsive locks. The pH-programmed opening of the locks at pH = 5.0 or pH = 10.0 yields two isomeric dimer structures composed of two circular DNAs. The switchable reconfigured states of the circular DNA nanostructures are followed by time-dependent fluorescence changes of fluorophore/quencher labeled systems and by complementary gel electrophoresis experiments. The dimer circular DNA structures are further implemented as scaffolds for the assembly of Au nanoparticle dimers exhibiting controlled spatial separation. PMID- 27225954 TI - Possible role for brain prostanoid pathways in the development of angiotensin II salt hypertension in rats. AB - Prostanoids generated by the cyclooxygenase (COX) pathway appear to contribute to the neurogenic hypertension (HTN) in rats. The first goal of this study was to establish the time frame during which prostanoids participate in ANG II-salt HTN. We induced HTN using ANG II (150 ng.kg(-1).min(-1) sc) infusion for 14 days in rats on a high-salt (2% NaCl) diet. When ketoprofen pretreatment was combined with treatment during the first 7 days of ANG II infusion, development of HTN and increased neurogenic pressor activity (indexed by the depressor response to ganglion blockade) were significantly attenuated for the entire ANG II infusion period. This suggests that prostanoid generation caused by administration of ANG II and salt leads to an increase in neurogenic pressor activity and blood pressure (BP) via a mechanism that persists without the need for continuing prostanoid input. The second goal of this study was to determine whether prostanoid products specifically in the brain contribute to HTN development. Expression of prostanoid pathway genes was measured in brain regions known to affect neurogenic BP regulation. ANG II-treated rats exhibited changes in gene expression of phospholipase A2 (upregulated in organum vasculosum of the lamina terminalis, paraventricular nucleus, nucleus of the solitary tract, and middle cerebral artery) and lipocalin-type prostaglandin D synthase (upregulated in the organum vasculosum of the lamina terminalis). On the basis of our results, we propose that activation of the brain prostanoid synthesis pathway both upstream and downstream from COX at early stages plays an important role in the development of the neurogenic component of ANG II-salt HTN. PMID- 27225953 TI - Skeletal myofiber VEGF regulates contraction-induced perfusion and exercise capacity but not muscle capillarity in adult mice. AB - A single bout of exhaustive exercise signals expression of vascular endothelial growth factor (VEGF) in the exercising muscle. Previous studies have reported that mice with life-long deletion of skeletal myofiber VEGF have fewer capillaries and a severe reduction in endurance exercise. However, in adult mice, VEGF gene deletion conditionally targeted to skeletal myofibers limits exercise capacity without evidence of capillary regression. To explain this, we hypothesized that adult skeletal myofiber VEGF acutely regulates skeletal muscle perfusion during muscle contraction. A tamoxifen-inducible skeletal myofiber specific VEGF gene deletion mouse (skmVEGF-/-) was used to reduce skeletal muscle VEGF protein by 90% in adult mice. Three weeks after inducing deletion of the skeletal myofiber VEGF gene, skmVEGF-/- mice exhibited diminished maximum running speed (-10%, P < 0.05) and endurance capacity (-47%; P < 0.05), which did not persist after 8 wk. In skmVEGF-/- mice, gastrocnemius complex time to fatigue measured in situ was 71% lower than control mice. Contraction-induced perfusion measured by optical imaging during a period of electrically stimulated muscle contraction was 85% lower in skmVEGF-/- than control mice. No evidence of capillary rarefication was detected in the soleus, gastrocnemius, and extensor digitorum longus (EDL) up to 8 wk after tamoxifen-induced VEGF ablation, and contractility and fatigue resistance of the soleus measured ex vivo were also unchanged. The force-frequency of the EDL showed a small right shift, but fatigue resistance did not differ between EDL from control and skmVEGF-/- mice. These data suggest myofiber VEGF is required for regulating perfusion during periods of contraction and may in this manner affect endurance capacity. PMID- 27225957 TI - Frontal fibrosing alopecia with facial papules - three cases. PMID- 27225956 TI - EB1 regulates attachment of Ska1 with microtubules by forming extended structures on the microtubule lattice. AB - Kinetochore couples chromosome movement to dynamic microtubules, a process that is fundamental to mitosis in all eukaryotes but poorly understood. In vertebrates, spindle-kinetochore-associated (Ska1-3) protein complex plays an important role in this process. However, the proteins that stabilize Ska-mediated kinetochore-microtubule attachment remain unknown. Here we show that microtubule plus-end tracking protein EB1 facilitates Ska localization on microtubules in vertebrate cells. EB1 depletion results in a significant reduction of Ska1 recruitment onto microtubules and defects in mitotic chromosome alignment, which is also reflected in computational modelling. Biochemical experiments reveal that EB1 interacts with Ska1, facilitates Ska1-microtubule attachment and together stabilizes microtubules. Structural studies reveal that EB1 either with Ska1 or Ska complex forms extended structures on microtubule lattice. Results indicate that EB1 promotes Ska association with K-fibres and facilitates kinetochore microtubule attachment. They also implicate that in vertebrates, chromosome coupling to dynamic microtubules could be mediated through EB1-Ska extended structures. PMID- 27225959 TI - Treatment of hypoxemic respiratory failure in neonates: past, present and future. PMID- 27225958 TI - Effect of positive end-expiratory pressure on blood loss during retropubic and robot-assisted laparoscopic radical prostatectomy. AB - OBJECTIVES: To study the effect of end-expiratory pressure used during anesthesia on blood loss during radical prostatectomy. METHODS: We evaluated 247 patients who underwent either radical retropubic prostatectomy or robot-assisted laparoscopic prostatectomy at a single institution from 2008 to 2013 by one of four surgeons. Patient characteristics were compared using t-tests, rank sum or chi(2) -tests as appropriate. The association between positive end-expiratory pressure and estimated blood loss was tested using linear regression. RESULTS: Patients were classified into high (>=4 cmH2 O) and low (<=1 cmH2 O) positive-end expiratory pressure groups. Estimated blood loss in radical retropubic prostatectomy was higher in the high positive end-expiratory pressure group (1000 mL vs 800 mL, P = 0.042). Estimated blood loss in robot-assisted laparoscopic prostatectomy was lower in the high positive end-expiratory pressure group (150 mL vs 250 mL, P = 0.015). After adjusting for other factors known to influence blood loss, a 5-cmH2 O increase in positive end-expiratory pressure was associated with a 34.9% increase in estimated blood loss (P = 0.030) for radical retropubic prostatectomy, and a 33.0% decrease for robot-assisted laparoscopic prostatectomy (P = 0.038). CONCLUSIONS: In radical retropubic prostatectomy, high positive end-expiratory pressure was associated with higher estimated blood loss, and the benefits of positive end-expiratory pressure should be weighed against the risk of increased estimated blood loss. In robot-assisted laparoscopic prostatectomy, high positive end-expiratory pressure was associated with lower estimated blood loss, and might have more than just pulmonary benefits. PMID- 27225960 TI - Considerations in the management of hypoxemic respiratory failure and persistent pulmonary hypertension in term and late preterm neonates. AB - Recent advances in our understanding of neonatal pulmonary circulation and the underlying pathophysiology of hypoxemic respiratory failure (HRF)/persistent pulmonary hypertension of the newborn (PPHN) have resulted in more effective management strategies. Results from animal studies demonstrate that low alveolar oxygen tension (PAO2) causes hypoxic pulmonary vasoconstriction, whereas an increase in oxygen tension to normoxic levels (preductal arterial partial pressure of oxygen (PaO2) between 60 and 80 mm Hg and/or preductal peripheral capillary oxygen saturation between 90% and 97%) results in effective pulmonary vasodilation. Hyperoxia (preductal PaO2 >80 mm Hg) does not cause further pulmonary vasodilation, and oxygen toxicity may occur when high concentrations of inspired oxygen are used. It is therefore important to avoid both hypoxemia and hyperoxemia in the management of PPHN. In addition to oxygen supplementation, therapeutic strategies used to manage HRF/PPHN in term and late preterm neonates may include lung recruitment with optimal mean airway pressure and surfactant, inhaled and intravenous vasodilators and 'inodilators'. Clinical evidence suggests that administration of surfactant or inhaled nitric oxide (iNO) therapy at a lower acuity of illness can decrease the risk of extracorporeal membrane oxygenation/death, progression of HRF and duration of hospital stay. Milrinone may be beneficial as an inodilator and may have specific benefits following prolonged exposure to iNO plus oxygen owing to inhibition of phosphodiesterase (PDE)-3A. Additionally, sildenafil, and, in selected cases, hydrocortisone may be appropriate options after hyperoxia and oxidative stress owing to their effects on PDE-5 activity and expression. Continued investigation into these and other interventions is needed to optimize treatment and improve outcomes. PMID- 27225961 TI - Management of hypoxemic respiratory failure and pulmonary hypertension in preterm infants. AB - While diagnoses of hypoxemic respiratory failure (HRF) and pulmonary hypertension (PH) in preterm infants may be based on criteria similar to those in term infants, management approaches often differ. In preterm infants, HRF can be classified as 'early' or 'late' based on an arbitrary threshold of 28 postnatal days. Among preterm infants with late HRF, the pulmonary vascular abnormalities associated with bronchopulmonary dysplasia (BPD) represent a therapeutic challenge for clinicians. Surfactant, inhaled nitric oxide (iNO), sildenafil, prostacyclin and endothelin receptor blockers have been used to manage infants with both early and late HRF. However, evidence is lacking for most therapies currently in use. Chronic oral sildenafil therapy for BPD-associated PH has demonstrated some preliminary efficacy. A favorable response to iNO has been documented in some preterm infants with early PH following premature prolonged rupture of membranes and oligohydramnios. Management is complicated by a lack of clear demarcation between interventions designed to manage respiratory distress syndrome, prevent BPD and treat HRF. Heterogeneity in clinical phenotype, pathobiology and genomic underpinnings of BPD pose challenges for evidence-based management recommendations. Greater insight into the spectrum of disease phenotypes represented by BPD can optimize existing therapies and promote development of new treatments. In addition, better understanding of an individual's phenotype, genotype and biomarkers may suggest targeted personalized interventions. Initiatives such as the Prematurity and Respiratory Outcomes Program provide a framework to address these challenges using genetic, environmental, physiological and clinical data as well as large repositories of patient samples. PMID- 27225962 TI - Management of pulmonary hypertension in infants with congenital diaphragmatic hernia. AB - In infants with congenital diaphragmatic hernia (CDH), a posterolateral diaphragmatic defect results in herniation of abdominal contents into the chest and compression of the intrathoracic structures. In the most severe cases, hypoplasia of the ipsilateral and contralateral lungs, severe pulmonary hypertension (PH) and left ventricular (LV) hypoplasia/dysfunction all contribute to increased mortality. The management of PH in CDH is complicated by structural and functional changes in the heart, pulmonary vasculature, airways and lung parenchyma; consequently, determining optimal management strategies is challenging. Treatment of PH in patients with CDH changes as the underlying pathophysiology evolves in the days and weeks after birth. During the early transition, the use of pulmonary vasodilators is limited by LV structural and functional abnormalities, and pulmonary vasodilators such as inhaled nitric oxide (iNO) may have a limited role (for example, stabilization for extracorporeal membrane oxygenation (ECMO), treatment of marked preductal desaturation and treatment of PH as LV performance improves). In contrast, subacute treatment of PH in CDH with iNO has an important role in recurrent or persistent PH and potentially improves survival. Chronic PH and vascular abnormalities may persist into childhood in patients with CDH, contributing to late mortality. It is unclear how pulmonary vasodilator therapies, such as iNO, sildenafil and bosentan, will modulate late outcomes in CDH with late/chronic PH. PMID- 27225963 TI - The fetal circulation, pathophysiology of hypoxemic respiratory failure and pulmonary hypertension in neonates, and the role of oxygen therapy. AB - Neonatal hypoxemic respiratory failure (HRF), a deficiency of oxygenation associated with insufficient ventilation, can occur due to a variety of etiologies. HRF can result when pulmonary vascular resistance (PVR) fails to decrease at birth, leading to persistent pulmonary hypertension of newborn (PPHN), or as a result of various lung disorders including congenital abnormalities such as diaphragmatic hernia, and disorders of transition such as respiratory distress syndrome, transient tachypnea of newborn and perinatal asphyxia. PVR changes throughout fetal life, evident by the dynamic changes in pulmonary blood flow at different gestational ages. Pulmonary vascular transition at birth requires an interplay between multiple vasoactive mediators such as nitric oxide, which can be potentially inactivated by superoxide anions. Superoxide anions have a key role in the pathophysiology of HRF. Oxygen (O2) therapy, used in newborns long before our knowledge of the complex nature of HRF and PPHN, has continued to evolve. Over time has come the discovery that too much O2 can be toxic. Recommendations on the optimal inspired O2 levels to initiate resuscitation in term newborns have ranged from 100% (pre 1998) to the currently recommended use of room air (21%). Questions remain about the most effective levels, particularly in preterm and low birth weight newborns. Attaining the appropriate balance between hypoxemia and hyperoxemia, and targeting treatments to the pathophysiology of HRF in each individual newborn are critical factors in the development of improved therapies to optimize outcomes. PMID- 27225965 TI - Antenatal care visits during pregnancy and their effect on maternal and fetal outcomes in pre-eclamptic patients. AB - AIM: The frequency of antenatal care visits during pregnancy was examined to determine their effect on maternal and fetal outcomes in patients with pre eclampsia. METHODS: This study included 150 pregnant women with pre-eclampsia who attended the Outpatient Clinic of the Obstetrics and Gynecology Department, Ismailia General Hospital. The women were interviewed and their antenatal care visits recorded. Blood pressure control, cardiotocography, ultrasonographic and Doppler evaluations and the administration of methyldopa were recorded. We calculated the distribution of women who attended an adequate versus an inadequate number of antenatal care visits, examined the characteristics of the groups using significance tests, computed the risk of poor maternal and fetal outcomes and created regression analysis models. We also calculated the incidence rate of poor maternal and fetal outcomes, odds ratios and 95% confidence intervals. RESULTS: Women who attended an inadequate number of antenatal care visits had a significantly higher risk of post-partum hemorrhage, eclampsia, and intensive care unit admission compared with women who attended an adequate number of visits. Women who attended an inadequate number of visits had a 12-fold risk of a poor maternal outcome, a 53-fold risk of a poor fetal outcome and a significantly higher risk of neonatal mortality in comparison to women who attended an adequate number of antenatal visits. CONCLUSIONS: The frequency of antenatal care visits during pregnancy has a significant effect on maternal and fetal outcomes in patients with pre-eclampsia. PMID- 27225964 TI - Challenges, priorities and novel therapies for hypoxemic respiratory failure and pulmonary hypertension in the neonate. AB - Future priorities for the management of hypoxemic respiratory failure (HRF) and pulmonary hypertension include primary prevention of neonatal lung diseases, 'precision medicine' and translating promising clinical and preclinical research into novel therapies. Promising areas of investigation include noninvasive ventilation strategies, emerging pulmonary vasodilators (for example, cinaciguat, intravenous bosentan, rho-kinase inhibitors, peroxisome proliferator-activated receptor-gamma agonists) and hemodynamic support (arginine vasopressin). Research challenges include the optimal timing for primary prevention interventions and development of validated biomarkers that predict later disease or serve as surrogates for long-term respiratory outcomes. Differentiating respiratory disease endotypes using biomarkers and experimental therapies tailored to the underlying pathobiology are central to the concept of 'precision medicine' (that is, prevention and treatment strategies that take individual variability into account). The ideal biomarker should be expressed early in the neonatal course to offer an opportunity for effective and targeted interventions to modify outcomes. The feasibility of this approach will depend on the identification and validation of accurate, rapid and affordable point-of-care biomarker tests. Trials targeting patient-specific pathobiology may involve less risk than traditional randomized controlled trials that enroll all at-risk neonates. Such approaches would reduce trial costs, potentially with fewer negative trials and improved health outcomes. Initiatives such as the Prematurity and Respiratory Outcomes Program, supported by the National Heart, Lung, and Blood Institute, provide a framework to develop refined outcome measures and early biomarkers that will enhance our understanding of novel, mechanistic therapeutic targets that can be tested in clinical trials in neonates with HRF. PMID- 27225966 TI - Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa. AB - Increasing prevalence and severity of multi-drug-resistant (MDR) bacterial infections has necessitated novel antibacterial strategies. Ideally, new approaches would target bacterial pathogens while exerting selection for reduced pathogenesis when these bacteria inevitably evolve resistance to therapeutic intervention. As an example of such a management strategy, we isolated a lytic bacteriophage, OMKO1, (family Myoviridae) of Pseudomonas aeruginosa that utilizes the outer membrane porin M (OprM) of the multidrug efflux systems MexAB and MexXY as a receptor-binding site. Results show that phage selection produces an evolutionary trade-off in MDR P. aeruginosa, whereby the evolution of bacterial resistance to phage attack changes the efflux pump mechanism, causing increased sensitivity to drugs from several antibiotic classes. Although modern phage therapy is still in its infancy, we conclude that phages, such as OMKO1, represent a new approach to phage therapy where bacteriophages exert selection for MDR bacteria to become increasingly sensitive to traditional antibiotics. This approach, using phages as targeted antibacterials, could extend the lifetime of our current antibiotics and potentially reduce the incidence of antibiotic resistant infections. PMID- 27225968 TI - An LC-MRM method for measuring intestinal triglyceride assembly using an oral stable isotope-labeled fat challenge. AB - AIM: A traditional oral fatty acid challenge assesses absorption of triacylglycerol (TG) into the periphery through the intestines, but cannot distinguish the composition or source of fatty acid in the TG. Stable isotope labeled tracers combined with LC-MRM can be used to identify and distinguish TG synthesized with dietary and stored fatty acids. RESULTS: Concentrations of three abundant TGs (52:2, 54:3 and 54:4) were monitored for incorporation of one or two (2)H11-oleate molecules per TG. This method was subjected to routine assay validation and meets typical requirements for an assay to be used to support clinical studies. CONCLUSION: Calculations for the fractional appearance rate of TG in plasma are presented along with the intracellular enterocyte precursor pool for 12 study participants. PMID- 27225967 TI - Stigmergy co-ordinates multicellular collective behaviours during Myxococcus xanthus surface migration. AB - Surface translocation by the soil bacterium Myxococcus xanthus is a complex multicellular phenomenon that entails two motility systems. However, the mechanisms by which the activities of individual cells are coordinated to manifest this collective behaviour are currently unclear. Here we have developed a novel assay that enables detailed microscopic examination of M. xanthus motility at the interstitial interface between solidified nutrient medium and a glass coverslip. Under these conditions, M. xanthus motility is characterised by extensive micro-morphological patterning that is considerably more elaborate than occurs at an air-surface interface. We have found that during motility on solidified nutrient medium, M. xanthus forges an interconnected furrow network that is lined with an extracellular matrix comprised of exopolysaccharides, extracellular lipids, membrane vesicles and an unidentified slime. Our observations have revealed that M. xanthus motility on solidified nutrient medium is a stigmergic phenomenon in which multi-cellular collective behaviours are co ordinated through trail-following that is guided by physical furrows and extracellular matrix materials. PMID- 27225969 TI - Ochronosis-like condition in a cat. AB - BACKGROUND: Endogenous ochronosis is caused by a defect in the enzyme homogentisate 1,2-dioxygenase (HGD), which results in abnormal pigment deposition in the skin and urine abnormalities. Ochronosis previously has not been described histologically or ultrastructurally in a domestic animal species. HYPOTHESIS/OBJECTIVES: To describe the clinical, histopathological and ultrastructural findings in a case of aberrant pigmentation in a cat with features that resemble ochronosis. ANIMAL: A 5-year-old, spayed female Domestic short hair cat presented with multiple black cutaneous plaques on the face and progressive lethargy. The cat's urine turned brown when exposed to air. The familial history of the cat was unknown. METHODS: Clinical examination; histopathology, electron microscopy and mass/energy dispersive X-ray spectroscopy of tissues. RESULTS: Septic peritonitis and additional pigment in the spleen, intestine and lymph node were found at postmortem examination. The pigment was determined to be an organic compound and had a similar histological appearance, staining properties, ultrastructure and composition to ochronotic pigment. No mutations were found in exons 3, 6, 8 and 13 of the HGD gene in the cat. CONCLUSIONS AND CLINICAL IMPORTANCE: To the best of the authors' knowledge, this is the first report of a condition resembling ochronosis in a domestic animal species that has been evaluated with histopathology and advanced imaging techniques. It provides an additional differential in cases of aberrant pigmentation in cats. PMID- 27225970 TI - Evaluation of in vitro antioxidant, anticancer and in vivo antitumour activity of Termitomyces clypeatus MTCC 5091. AB - CONTEXT: Termitomyces clypeatus (Lyophyllaceae) is a filamentous edible mushroom, having ethnomedicinal uses. However, information about the antioxidant, anticancer and antitumour properties of this mushroom remains to be elucidated. OBJECTIVE: The study examines the in vitro antioxidant, anticancer and in vivo antitumour activity of T. clypeatus. MATERIALS AND METHODS: Antioxidant activity was evaluated with seven in vitro assays. Cytotoxicity of T. clypeatus was tested against a panel of cancer cells lines including U373MG, MDA-MB-468, HepG2, HL-60, A549, U937, OAW-42 and Y-79 using MTT assay. The antitumour activity of aqueous extract was evaluated against Ehrlich ascites carcinoma (EAC) tumour model in Swiss albino mice. RESULTS: HPLC analysis of aqueous extract revealed the presence of sugar entities. Termitomyces clypeatus showed excellent in vitro antioxidant activity. Termitomyces clypeatus was found cytotoxic against all cancer cells, among which it showed higher activity against U937 (IC50 25 +/- 1.02 MUg/mL). Treatment of EAC-bearing mice with varied doses of aqueous extract significantly (p < 0.01) reduced tumour volume, viable tumour cell count and improved haemoglobin content, RBC count, mean survival time, tumour inhibition and % increase life span. The enhanced antioxidant status in treated animals was evident from the decline in the levels of lipid peroxidation, increased levels of glutathione, catalase and superoxide dismutase. DISCUSSION: The analyzed data indicate that the aqueous extract of T. clypeatus exhibits significant antitumour activity, which might be due to the antioxidant effects on EAC bearing hosts. CONCLUSION: Termitomyces clypeatus possesses anticancer activity, valuable for application in food and drug products. PMID- 27225971 TI - Laparoscopic ventral mesh rectopexy vs Delorme's operation in management of complete rectal prolapse: a prospective randomized study. AB - AIM: Various surgical operations have been devised for the treatment of rectal prolapse, yet no ideal procedure has been described. The present study aims to compare the clinical and functional outcome of laparoscopic ventral mesh rectopexy (LVMR) and Delorme's operation for complete rectal prolapse. METHOD: Fifty patients with complete rectal prolapse were enrolled in this study. Patients were randomly selected to undergo either LVMR or Delorme's procedure after clinical, manometric and radiological evaluation. Patient characteristics, operative data, postoperative complications, recurrence of rectal prolapse and continence state were evaluated. Patients were followed for a mean duration of 18 months. RESULTS: Thirty-one (62%) patients were women and 19 (38%) patients were men with a mean age of 39.7 +/- 6.9 years. Patients were allocated into two equal groups: LVMR group and Delorme's group. Thirty-three (66%) complained of faecal incontinence preoperatively. Patients were followed for 18 months. There was no major postoperative complication or treatment death. Improvement in continence was reported in 80.9% of patients (83.3% in group 1 vs 71.4% in group 2). Recurrent prolapse was observed in 16% of patients in group 2 and 8% in group 1 (P = 0.66). The operation time was significantly greater in group 1 and the length of stay greater in group 2. There was no difference in the fall of constipation score between the groups. CONCLUSION: There was no statistically significant difference in the incidence of recurrence of complete rectal prolapse or postoperative improvement of symptoms between the two groups. Hospital stay was longer after Delorme's procedure but the operation time was shorter. Neither procedure proved definite superiority regarding the clinical and functional outcome at 18 months of follow-up. PMID- 27225972 TI - Teenage pregnancy: the impact of maternal adolescent childbearing and older sister's teenage pregnancy on a younger sister. AB - BACKGROUND: Risk factors for teenage pregnancy are linked to many factors, including a family history of teenage pregnancy. This research examines whether a mother's teenage childbearing or an older sister's teenage pregnancy more strongly predicts teenage pregnancy. METHODS: This study used linkable administrative databases housed at the Manitoba Centre for Health Policy (MCHP). The original cohort consisted of 17,115 women born in Manitoba between April 1, 1979 and March 31, 1994, who stayed in the province until at least their 20(th) birthday, had at least one older sister, and had no missing values on key variables. Propensity score matching (1:2) was used to create balanced cohorts for two conditional logistic regression models; one examining the impact of an older sister's teenage pregnancy and the other analyzing the effect of the mother's teenage childbearing. RESULTS: The adjusted odds of becoming pregnant between ages 14 and 19 for teens with at least one older sister having a teenage pregnancy were 3.38 (99 % CI 2.77-4.13) times higher than for women whose older sister(s) did not have a teenage pregnancy. Teenage daughters of mothers who had their first child before age 20 had 1.57 (99 % CI 1.30-1.89) times higher odds of pregnancy than those whose mothers had their first child after age 19. Educational achievement was adjusted for in a sub-population examining the odds of pregnancy between ages 16 and 19. After this adjustment, the odds of teenage pregnancy for teens with at least one older sister who had a teenage pregnancy were reduced to 2.48 (99 % CI 2.01-3.06) and the odds of pregnancy for teen daughters of teenage mothers were reduced to 1.39 (99 % CI 1.15-1.68). CONCLUSION: Although both were significant, the relationship between an older sister's teenage pregnancy and a younger sister's teenage pregnancy is much stronger than that between a mother's teenage childbearing and a younger daughter's teenage pregnancy. This study contributes to understanding of the broader topic "who is influential about what" within the family. PMID- 27225973 TI - Successful Aging in the Context of the Disablement Process: Working and Volunteering as Moderators on the Association Between Chronic Conditions and Subsequent Functional Limitations. AB - Objectives : This study evaluated the successful aging model by assessing the impact of two forms of productive engagement-working and volunteering-as potential interventions in the process of disablement. Method : The Health and Retirement Study was used to (a) estimate two-stage selection equations of (i) currently working part time and full time and (ii) currently volunteering less than 100 hours and volunteering 100 hours or more per year (net of chronic health problems) and (b) assess whether, net of selection, working, and volunteering moderate the association between chronic conditions and subsequent functional limitations. Results : Chronic conditions were associated with elevated levels of subsequent functional limitations, whereas both working and volunteering were associated with lower levels of subsequent functional limitations. Moreover, workers and volunteers of less than 100 hours per year experienced a reduction in the association of chronic conditions on subsequent functional limitations. Discussion : This research highlights the role of productive engagement as a key element in successful aging. Not only do work and volunteering have direct associations with health outcomes themselves, but they also act as potential interventions in the process of disablement by attenuating the way in which chronic conditions are translated into subsequent functional limitations. This suggests that (a) future research should apply successful aging models to health processes as well as health outcomes and (b) policy makers should support social institutions that foster late-life productive engagement. PMID- 27225974 TI - The antimicrobial peptide aureocin A53 as an alternative agent for biopreservation of dairy products. AB - AIMS: The aim of this study was to investigate the potential of aureocin A53, a staphylococcal antimicrobial peptide, for improving food safety. METHODS AND RESULTS: The antimicrobial activity of aureocin A53 against strains of Listeria monocytogenes isolated from food was tested and the bacteriocin proved to be bactericidal and bacteriolytic against the listerial strains. Aureocin A53 was neither toxic to eukaryotic cell lines nor haemolytic against sheep erythrocytes. It also exhibited a remarkable stability during storage at different temperatures and sensitivity to both simulated gastric juice and bile salts. When the antibacterial activity of aureocin A53 (256 AU ml(-1) ) was tested in skimmed milk artificially inoculated with a L. monocytogenes strain (1.0 * 10(4) CFU ml( 1) ) isolated from food, during storage at 4 degrees C, the bacteriocin reduced the viable counts by 7.7-log10 units up to 7 days of incubation, when compared with the controls not treated with the bacteriocin. CONCLUSIONS: Aureocin A53 exhibited several features considered important for biopreservation and remained fully active in a food matrix. SIGNIFICANCE AND IMPACT OF THE STUDY: Taken together, the results confirmed that aureocin A53 has potential to be used as a food preservative, representing an alternative to the use of nisin in biopreservation of dairy products. PMID- 27225975 TI - Deriving in vivo biotransformation rate constants and metabolite parent concentration factor/stable metabolite factor from bioaccumulation and bioconcentration experiments: An illustration with worm accumulation data. AB - Growing concern for the biological fate of organic contaminants and their metabolites and the urge to connect in vitro and in vivo toxicokinetics have prompted researchers to characterize the biotransformation behavior of organic contaminants in biota. The whole body biotransformation rate constant (kM ) is currently determined by the difference approach, which has significant methodological limitations. A new approach for determining kM from the kinetic observations of the parent contaminant and its intermediate metabolites is proposed. In this method, kM can be determined by fitting kinetic data of the parent contaminant and the metabolites to analytical equations that depict the bioaccumulation kinetics. The application of the proposed method is illustrated using worm bioaccumulation-biotransformation data collected from the literature. Furthermore, a metabolite parent concentration factor (MPCF) is also proposed to characterize the persistence of the metabolite in biota. Because both the proposed kM method and MPCF build on the existing theoretical framework for bioaccumulation, they can be readily incorporated into standard experimental bioaccumulation protocols or risk assessment procedures or frameworks. Possible limitations, implications, and future directions are elaborated. Environ Toxicol Chem 2016;35:2903-2909. (c) 2016 SETAC. PMID- 27225976 TI - Relative to Typical Antipsychotic Drugs, Aripiprazole Is a Safer Alternative for Alleviating Behavioral Disturbances After Experimental Brain Trauma. AB - BACKGROUND: Antipsychotic drugs (APDs) are used to manage traumatic brain injury (TBI)-induced behavioral disturbances, such as agitation and aggression. However, APDs exhibiting D2 receptor antagonism impede cognitive recovery after experimental TBI. Hence, empirical evaluation of APDs with different mechanistic actions is warranted. Aripiprazole (ARIP) is a D2 and 5-hydroxytryptamine1A (5 HT1A) receptor agonist; pharmacotherapies with these properties enhance cognition after TBI. OBJECTIVE: To test the hypothesis that ARIP would increase behavioral performance and decrease histopathology after TBI. METHODS: Adult male rats were subjected to either a controlled cortical impact (CCI) or sham injury and then randomly assigned to ARIP (0.1 or 1.0 mg/kg) or VEH (1.0 mL/kg, saline vehicle) groups. Treatments began 24 hours after surgery and were administered once daily for 19 days. Motor (beam-balance/beam-walk) and cognitive (Morris water maze) performance was assessed on postoperative days 1 to 5 and 14 to 19, respectively, followed by quantification of hippocampal CA1,3 neuron survival and cortical lesion volume. RESULTS: Beam-balance was significantly improved in the CCI + ARIP (1.0 mg/kg) group versus CCI + ARIP (0.1 mg/kg) and CCI + VEH (P < .05). Spatial learning and memory retention were significantly improved in the CCI + ARIP (0.1 mg/kg) group versus the CCI + ARIP (1.0 mg/kg) and CCI + VEH groups (P < .05). Both doses of ARIP reduced lesion size and CA3 cell loss versus VEH (P < .05). Importantly, neither dose of ARIP impeded functional recovery as previously reported with other APDs. CONCLUSION: These findings support the hypothesis and endorse ARIP as a safer APD for alleviating behavioral disturbances after TBI. PMID- 27225979 TI - Patterns on serpentine shapes elicit visual attention in marmosets (Callithrix jacchus). AB - Given the prevalence of threatening snakes in the evolutionary history, and modern-day environments of human and nonhuman primates, sensory, and perceptual abilities that allow for quick detection of, and appropriate response to snakes are likely to have evolved. Many studies have demonstrated that primates recognize snakes faster than other stimuli, and it is suggested that the unique serpentine shape is responsible for its quick detection. However, there are many nonthreatening serpentine shapes in the environment (e.g., vines) that are not threatening; therefore, other cues must be used to distinguish threatening from benign serpentine objects. In two experiments, we systematically evaluated how common marmosets (Callithrix jacchus) visually attend to specific snake-like features. In the first experiment, we examined if skin pattern is a cue that elicits increased visual inspection of serpentine shapes by measuring the amount of time the marmosets looked into a blind before, during, and after presentation of clay models with and without patterns. The marmosets spent the most time looking at the objects, both serpentine and triangle, that were etched with scales, suggesting that something may be uniquely salient about scales in evoking attention. In contrast, they showed relatively little interest in the unpatterned serpentine and control (a triangle) stimuli. In experiment 2, we replicated and extended the results of experiment 1 by adding additional stimulus conditions. We found that patterns on a serpentine shape generated more inspection than those same patterns on a triangle shape. We were unable to confirm that a scaled pattern is unique in its ability to elicit visual interest; the scaled models elicited similar looking times as line and star patterns. Our data provide a foundation for future research to examine how snakes are detected and identified by primates. Am. J. Primatol. 78:928-936, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27225977 TI - Upper-Limb Recovery After Stroke: A Randomized Controlled Trial Comparing EMG Triggered, Cyclic, and Sensory Electrical Stimulation. AB - BACKGROUND AND PURPOSE: This study compared the effect of cyclic neuromuscular electrical stimulation (NMES), electromyographically (EMG)-triggered NMES, and sensory stimulation on motor impairment and activity limitations in patients with upper-limb hemiplegia. METHODS: This was a multicenter, single-blind, multiarm parallel-group study of nonhospitalized hemiplegic stroke survivors within 6 months of stroke. A total of 122 individuals were randomized to receive either cyclic NMES, EMG-triggered NMES, or sensory stimulation twice every weekday in 40 minute sessions, over an 8 week-period. Patients were followed for 6 months after treatment concluded. RESULTS: There were significant increases in the Fugl-Meyer Assessment [F(1, 111) = 92.6, P < .001], FMA Wrist and Hand [F(1, 111) = 66.7, P < .001], and modified Arm Motor Ability Test [mAMAT; time effect: F(1, 111) = 91.0, P < .001] for all 3 groups. There was no significant difference in the improvement among groups in the FMA [F(2, 384) = 0.2, P = .83], FMA Wrist and Hand [F(2, 384) = 0.4, P = .70], or the mAMAT [F(2, 379) = 1.2, P = .31]. CONCLUSIONS: All groups exhibited significant improvement of impairment and functional limitation with electrical stimulation therapy applied within 6 months of stroke. Improvements were likely a result of spontaneous recovery. There was no difference based on the type of electrical stimulation that was administered. PMID- 27225980 TI - Co-operative working in aged care: The Cooperative for Healthy Ageing Research and Teaching Project. AB - OBJECTIVE: The objective of this study was to describe the partnership mechanisms that supported teaching and research in aged care, in one of the 16 funded projects under the auspices of the Teaching and Research in Aged Care Service project. Located in ACT and southern NSW, the Co-operative for Healthy Ageing Research and Teaching (CHART) was comprised of eleven partners from the residential care sector, higher education, and hospital and non-government sectors. METHODS: A descriptive study of the project engagement and partnership processes and outcomes using documentation review and stakeholder interviews. The overarching goal of the CHART project was to facilitate the development of aged care service models that combine teaching, learning and research. This study describes (i) the processes and investment required to enable care providers to partner in teaching and research activities; and (ii) the structure and practices required to build workforce capacity and create career pathways in the sector. RESULTS: Maintaining consistency of engagement and collaboration required significant, and often invisible, investment in partnership arrangements. Overall, the partnerships were often person, rather than organisation, dependent. New student placements were introduced, but support for continued nursing placements remained variable. Local practice innovation was advanced when partnership investment was aligned at strategic and operational levels. CONCLUSION: Continuous, and often invisible, investment in maintaining operational partnerships is critical to sustained change. Partnering in a private aged care service environment to achieve sector-wide changes was challenging, but the investment can result in innovation and service improvement. PMID- 27225981 TI - Interventions for female pattern hair loss. AB - BACKGROUND: Female pattern hair loss (FPHL), or androgenic alopecia, is the most common type of hair loss affecting women. It is characterised by progressive shortening of the duration of the growth phase of the hair with successive hair cycles, and progressive follicular miniaturisation with conversion of terminal to vellus hair follicles (terminal hairs are thicker and longer, while vellus hairs are soft, fine, and short). The frontal hair line may or may not be preserved. Hair loss can have a serious psychological impact on women. OBJECTIVES: To determine the efficacy and safety of the available options for the treatment of female pattern hair loss in women. SEARCH METHODS: We updated our searches of the following databases to July 2015: the Cochrane Skin Group Specialised Register, CENTRAL in the Cochrane Library (2015, Issue 6), MEDLINE (from 1946), EMBASE (from 1974), PsycINFO (from 1872), AMED (from 1985), LILACS (from 1982), PubMed (from 1947), and Web of Science (from 1945). We also searched five trial registries and checked the reference lists of included and excluded studies. SELECTION CRITERIA: We included randomised controlled trials that assessed the efficacy of interventions for FPHL in women. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality, extracted data and carried out analyses. MAIN RESULTS: We included 47 trials, with 5290 participants, of which 25 trials were new to this update. Only five trials were at 'low risk of bias', 26 were at 'unclear risk', and 16 were at 'high risk of bias'.The included trials evaluated a wide range of interventions, and 17 studies evaluated minoxidil. Pooled data from six studies indicated that a greater proportion of participants (157/593) treated with minoxidil (2% and one study with 1%) reported a moderate to marked increase in their hair regrowth when compared with placebo (77/555) (risk ratio (RR) = 1.93, 95% confidence interval (CI) 1.51 to 2.47; moderate quality evidence). These results were confirmed by the investigator rated assessments in seven studies with 1181 participants (RR 2.35, 95% CI 1.68 to 3.28; moderate quality evidence). Only one study reported on quality of life (QoL) (260 participants), albeit inadequately (low quality evidence). There was an important increase of 13.18 in total hair count per cm2 in the minoxidil group compared to the placebo group (95% CI 10.92 to 15.44; low quality evidence) in eight studies (1242 participants). There were 40/407 adverse events in the twice daily minoxidil 2% group versus 28/320 in the placebo group (RR 1.24, 95% CI 0.82 to 1.87; low quality evidence). There was also no statistically significant difference in adverse events between any of the individual concentrations against placebo.Four studies (1006 participants) evaluated minoxidil 2% versus 5%. In one study, 25/57 participants in the minoxidil 2% group experienced moderate to greatly increased hair regrowth versus 22/56 in the 5% group (RR 1.12, 95% CI 0.72 to 1.73). In another study, 209 participants experienced no difference based on a visual analogue scale (P = 0.062; low quality evidence). The assessments of the investigators based on three studies (586 participants) were in agreement with these findings (moderate quality evidence). One study assessed QoL (209 participants) and reported limited data (low quality evidence). Four trials (1006 participants) did not show a difference in number of adverse events between the two concentrations (RR 1.02, 95% CI 0.91 to 1.20; low quality evidence). Both concentrations did not show a difference in increase in total hair count at end of study in three trials with 631 participants (mean difference (MD) -2.12, 95% CI -5.47 to 1.23; low quality evidence).Three studies investigated finasteride 1 mg compared to placebo. In the finasteride group 30/67 participants experienced improvement compared to 33/70 in the placebo group (RR 0.95, 95% CI 0.66 to 1.37; low quality evidence). This was consistent with the investigators' assessments (RR 0.77, 95% CI 0.31 to 1.90; low quality evidence). QoL was not assessed. Only one study addressed adverse events (137 participants) (RR 1.03, 95% CI 0.45 to 2.34; low quality evidence). In two studies (219 participants) there was no clinically meaningful difference in change of hair count, whilst one study (12 participants) favoured finasteride (low quality evidence).Two studies (141 participants) evaluated low-level laser comb therapy compared to a sham device. According to the participants, the low-level laser comb was not more effective than the sham device (RR 1.54, 95% CI 0.96 to 2.49; and RR 1.18, 95% CI 0.74 to 1.89; moderate quality evidence). However, there was a difference in favour of low-level laser comb for change from baseline in hair count (MD 17.40, 95% CI 9.74 to 25.06; and MD 17.60, 95% CI 11.97 to 23.23; low quality evidence). These studies did not assess QoL and did not report adverse events per treatment arm and only in a generic way (low quality evidence). Low-level laser therapy against sham comparisons in two separate studies also showed an increase in total hair count but with limited further data.Single studies addressed the other comparisons and provided limited evidence of either the efficacy or safety of these interventions, or were unlikely to be examined in future trials. AUTHORS' CONCLUSIONS: Although there was a predominance of included studies at unclear to high risk of bias, there was evidence to support the efficacy and safety of topical minoxidil in the treatment of FPHL (mainly moderate to low quality evidence). Furthermore, there was no difference in effect between the minoxidil 2% and 5% with the quality of evidence rated moderate to low for most outcomes. Finasteride was no more effective than placebo (low quality evidence). There were inconsistent results in the studies that evaluated laser devices (moderate to low quality evidence), but there was an improvement in total hair count measured from baseline.Further randomised controlled trials of other widely-used treatments, such as spironolactone, finasteride (different dosages), dutasteride, cyproterone acetate, and laser-based therapy are needed. PMID- 27225982 TI - Absence of gliosis in a teleost model of spinal cord regeneration. AB - Among the cellular processes that follow injury to the central nervous system, glial scar formation is thought to be one of the major factors that prevent regeneration. In regeneration-competent organisms, glial scar formation has been a matter of controversy. We addressed this issue by examining the glial population after spinal cord injury in a model of regeneration competency, the knifefish Apteronotus leptorhynchus. Analysis of spinal cord sections immunostained against the glial markers glial fibrillary acidic protein, vimentin, or chondroitin sulfate proteoglycan failed to produce any evidence for the formation of a glial scar in the area of the lesion at post-injury survival times ranging from 5 to 185 days. This result was independent of the lesion paradigm applied-amputation of the caudal part of the spinal cord or hemisection lesioning-and similar after examination of transverse and longitudinal sections. We hypothesize that the well-developed network of radial glia in both the intact and the injured spinal cord provides a support system for regeneration of tissue lost to injury. This glial network is likely also involved in the generation of new cells, as indicated by the large subset of glial fibrillary acidic protein labeled glia that express the stem cell marker Sox2. PMID- 27225983 TI - The Role of Catalase C262T Gene Polymorphism in the Susceptibility and Survival of Cancers. AB - Catalase (CAT), one antioxidant enzyme, may provide resistance against many diseases. Many previous studies reported predictive and prognostic values of CAT C262T polymorphism in cancers, with divergent results. This study aimed to summarize the overall relationships between CAT C262T polymorphism and cancer risk or survival. A total of 27 eligible publications were included in susceptibility analysis, while 8 publications contained survival outcomes. The results revealed significant relationship between CAT C262T polymorphism and cancer risk(TT + CT vs CC: OR = 1.05, 95%CI = 1.00-1.10, P = 0.036), subgroup analyses indicated the CAT C262T polymorphism was significantly correlated with an increased risk for prostate cancer (TT vs CC + CT: OR = 1.43, 95%CI = 1.20 1.70, P < 0.001) and increased risk among Caucasians (TT vs CC + CT: OR = 1.19, 95%CI = 1.09-1.31, P < 0.001), while no associations between the polymorphism and Asian or mixed population were established. In the survival analysis, no interactions were identified between this polymorphism and cancer survival (TT + CT vs CC: HR = 1.37, 95%CI = 0.70-2.70, P = 0.36). In conclusion, the CAT C262T polymorphismmay be a candidate markerfor cancer risk with type-specific and population-specific effects but not a fine prognostic factor for cancer survival. PMID- 27225985 TI - Special challenges in the conservation of fishes and aquatic environments of South America. AB - In South America, the conservation of natural resources, particularly in relation to water and aquatic fauna, is an often-discussed issue. Unfortunately, there is still a large gap between thoughts and action. Scientists from different countries of the continent have however, produced a significant body of literature that should finally become the basis of emerging managerial models. PMID- 27225984 TI - Alpha-ketoglutarate promotes skeletal muscle hypertrophy and protein synthesis through Akt/mTOR signaling pathways. AB - Skeletal muscle weight loss is accompanied by small fiber size and low protein content. Alpha-ketoglutarate (AKG) participates in protein and nitrogen metabolism. The effect of AKG on skeletal muscle hypertrophy has not yet been tested, and its underlying mechanism is yet to be determined. In this study, we demonstrated that AKG (2%) increased the gastrocnemius muscle weight and fiber diameter in mice. Our in vitro study also confirmed that AKG dose increased protein synthesis in C2C12 myotubes, which could be effectively blocked by the antagonists of Akt and mTOR. The effects of AKG on skeletal muscle protein synthesis were independent of glutamate, its metabolite. We tested the expression of GPR91 and GPR99. The result demonstrated that C2C12 cells expressed GPR91, which could be upregulated by AKG. GPR91 knockdown abolished the effect of AKG on protein synthesis but failed to inhibit protein degradation. These findings demonstrated that AKG promoted skeletal muscle hypertrophy via Akt/mTOR signaling pathway. In addition, GPR91 might be partially attributed to AKG-induced skeletal muscle protein synthesis. PMID- 27225986 TI - Effects of resuscitation with polymerized porcine hemoglobin (pPolyHb) on hemodynamic stability and oxygen delivery in a rat model of hemorrhagic shock. AB - The objective of this study was to evaluate the effects of polymerized porcine hemoglobin (pPolyHb) on hemodynamic stability and oxygen delivery in a rat model of hemorrhagic shock. Rats underwent controlled hemorrhage, resulting in the loss of 65% of their blood volume in 90 minutes. The results showed that pPolyHb was superior to hetastarch and saline, and similar to whole blood, in restoring hemodynamic stability and reversing anaerobic metabolism caused by hemorrhage. Furthermore, pPolyHb improved oxygen supply and increased blood oxygen content. These data suggest that pPolyHb can be effective in improving tissue perfusion under conditions of severe hemorrhagic shock. PMID- 27225987 TI - Pattern Genes Suggest Functional Connectivity of Organs. AB - Human organ, as the basic structural and functional unit in human body, is made of a large community of different cell types that organically bound together. Each organ usually exerts highly specified physiological function; while several related organs work smartly together to perform complicated body functions. In this study, we present a computational effort to understand the roles of genes in building functional connection between organs. More specifically, we mined multiple transcriptome datasets sampled from 36 human organs and tissues, and quantitatively identified 3,149 genes whose expressions showed consensus modularly patterns: specific to one organ/tissue, selectively expressed in several functionally related tissues and ubiquitously expressed. These pattern genes imply intrinsic connections between organs. According to the expression abundance of the 766 selective genes, we consistently cluster the 36 human organs/tissues into seven functional groups: adipose &gland, brain, muscle, immune, metabolism, mucoid and nerve conduction. The organs and tissues in each group either work together to form organ systems or coordinate to perform particular body functions. The particular roles of specific genes and selective genes suggest that they could not only be used to mechanistically explore organ functions, but also be designed for selective biomarkers and therapeutic targets. PMID- 27225989 TI - Does Renal Artery Stenting Prevent Clinical Events? PMID- 27225990 TI - Evaluation of Systemic Inflammatory Response Biomarkers in Patients Receiving Chemotherapy for Unresectable and Recurrent Advanced Gastric Cancer. AB - BACKGROUND: The present study sought to evaluate an inflammation-based prognostic score (Glasgow prognostic score, GPS) and the neutrophil to lymphocyte ratio (NLR) as prognostic factors in patients receiving chemotherapy for advanced gastric cancer. METHODS: The study enrolled 224 patients who received chemotherapy for advanced gastric cancer at the Kochi Medical School from 2007 to 2014. Clinicopathological information and systemic inflammatory response data were obtained to investigate associations between baseline cancer-related prognostic variables and survival outcomes. RESULTS: The median survival time was significantly higher for patients with intestinal-type compared to diffuse-type histology (p = 0.039), a GPS 0 score compared to GPS 1 or 2 score (p = 0.004), and lower compared to higher NLR 4 (p = 0.002). Multivariate survival analysis identified high NLR 4 (HR 1.651; 95% CI 1.187-2.297; p = 0.003) and diffuse-type histology (HR 1.645; 95% CI 1.025-2.639; p = 0.039) as significant independent predictors associated with worse prognosis in the studied group of cancer patients. CONCLUSIONS: NLR and histological type are independent prognostic factors for patients receiving chemotherapy for unresectable and recurrent gastric cancer. PMID- 27225988 TI - Effects of Stenting for Atherosclerotic Renal Artery Stenosis on eGFR and Predictors of Clinical Events in the CORAL Trial. AB - BACKGROUND AND OBJECTIVES: Atherosclerotic renal artery stenosis may cause kidney function loss, but effects of stenting on eGFR and clinical events associated with CKD are uncertain. Our study objectives were to determine effects of stenting on eGFR and predictors of clinical events. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Participants (n=931) in the Cardiovascular Outcomes in Renal Artery Stenosis Trial (from May of 2005 to September of 2012) had >60% atherosclerotic renal artery stenosis and systolic hypertension on two or more antihypertensive drugs and/or stage >=3 CKD. The intervention was stenting versus no stenting on a background of risk factor management: renin-angiotensin system inhibition, statin, antiplatelet therapy, and smoking cessation education. The effect of stenting on eGFR by the serum creatinine-cystatin C Chronic Kidney Disease Epidemiology Collaboration equation was the prespecified analysis of kidney function. Predictors of eGFR and CKD outcomes (>=30% eGFR loss, ESRD, and death) and cardiovascular disease outcomes (stroke, myocardial infarction, heart failure, and death) controlling for eGFR and albuminuria were also determined. RESULTS: eGFR was 59+/-24 ml/min per 1.73 m(2) (mean+/-SD) at baseline. Over 3 years, eGFR change, assessed by generalized estimating equations, was -1.5+/-7.0 ml/min per 1.73 m(2) per year in the stent group versus -2.3+/-6.3 ml/min per 1.73 m(2) per year in the medical therapy only group (P=0.18). eGFR predictors (multiple variable generalized estimating equations) were age, albuminuria, systolic BP, and diabetes (inverse associations) as well as men, total cholesterol, and HDL cholesterol (positive associations). CKD outcomes events occurred in 19% (175 of 931), and predictors (Cox proportional hazards models) included albuminuria (positive association), systolic BP (positive association), and HDL cholesterol (inverse association). Cardiovascular disease outcomes events occurred in 22% (207 of 931), and predictors included age, albuminuria, total cholesterol, prior cardiovascular disease, and bilateral atherosclerotic renal artery stenosis (positive associations). CONCLUSIONS: Stenting did not influence eGFR in participants with atherosclerotic renal artery stenosis receiving renin angiotensin system inhibition-based therapy. Predictors of clinical events were traditional risk factors for CKD and cardiovascular disease. PMID- 27225991 TI - Creation of localized spins in graphene by ring-opening of epoxy derived hydroxyl. AB - Creation of high-density localized spins in the basal plane of graphene sheet by introduction of sp(3)-type defects is considered to be a potential route for the realization of high-magnetization graphene. Theoretical and experimental studies confirmed that hydroxyl can be an effective sp(3)-type candidate for inducing robust magnetic moment. However, the artificial generation of hydroxyl groups for creating high-density spins on the basal plane of graphene sheet is very scarce. Here we demonstrate that high-content hydroxyl groups can be generated on the basal plane of graphene oxide (GO) sheet by ring opening of epoxy groups. We show that by introduction of 10.74 at.% hydroxyl groups, the density of localized spins of GO can be significantly increased from 0.4 to 5.17 MUB/1000 C. Thus, this study provided an effective method to obtain graphene with high-density localized spins. PMID- 27225992 TI - Strength and Persistence of Energy-Based Vessel Seals Rely on Tissue Water and Glycosaminoglycan Content. AB - Vessel ligation using energy-based surgical devices is steadily replacing conventional closure methods during minimally invasive and open procedures. In exploring the molecular nature of thermally-induced tissue bonds, novel applications for surgical resection and repair may be revealed. This work presents an analysis of the influence of unbound water and hydrophilic glycosaminoglycans on the formation and resilience of vascular seals via: (a) changes in pre-fusion tissue hydration, (b) the enzymatic digestion of glycosaminoglycans (GAGs) prior to fusion and (c) the rehydration of vascular seals following fusion. An 11% increase in pre-fusion unbound water led to an 84% rise in vascular seal strength. The digestion of GAGs prior to fusion led to increases of up to 82% in seal strength, while the rehydration of native and GAG digested vascular seals decreased strengths by 41 and 44%, respectively. The effects of increased unbound water content prior to fusion combined with the effects of seal rehydration after fusion suggest that the heat-induced displacement of tissue water is a major contributor to tissue adhesion during energy-based vessel sealing. The effects of pre-fusion GAG-digestion on seal integrity indicate that GAGs are inhibitory to the bond formation process during thermal ligation. GAG digestion may allow for increased water transport and protein interaction during the fusion process, leading to the formation of stronger bonds. These findings provide insight into the physiochemical nature of the fusion bond, its potential for optimization in vascular closure and its application to novel strategies for vascular resection and repair. PMID- 27225993 TI - Semi-automatic Method for Ca2+ Imaging Data Analysis of Maturing Human Embryonic Stem Cells-Derived Retinal Pigment Epithelium. AB - Ca2+ is a second messenger controlling vital cellular processes, including cell maturation. Changes in Ca2+ signaling during maturation of human embryonic stem cell-derived retinal pigment epithelial cells (hESC-RPE) have not been assessed previously. The aim of this study was to investigate maturation-dependent changes in transient intracellular Ca2+ ([Ca2+] i ) increases in hESC-RPE. For this, we developed image analysis tools to evaluate cell-specific Ca2+ signals from the entire field of view. Spontaneous and mechanically induced transient [Ca2+] i increases (STIs and MITIs) were analyzed in hESC-RPEs cultured for 9 or 28 days, altogether from more than 80,000 cells. Both cultures showed STIs: the longer culture time resulted in twofold increase of amount of cells with STIs. Mechanical stimulation induced intercellular Ca2+ waves in cells from both time points, but longer culture time reduced Ca2+ wave spreading. Depletion of intracellular Ca2+ stores decreased cell fraction with STIs and MITIs at both time points, and absence of extracellular Ca2+ had similar effect on cells with STIs. To conclude, hESC-RPE cells undergo significant Ca2+ signaling re arrangements during a short maturation period increasing cell fraction with STIs, while decreasing coordinated cell response to mechanical stimulation. This knowledge and proposed analysis tools can be used for assessment of hESC-RPE maturation in vitro. PMID- 27225994 TI - Effects of nitrogen supply on Pseudo-nitzschia calliantha and Pseudo-nitzschia cf. seriata: field and laboratory experiments. AB - The effects of inorganic and organic nitrogen supply on the growth and domoic acid (DA) production of Pseudo-nitzschia cf. seriata and Pseudo-nitzschia calliantha from Bizerte Lagoon (SW Mediterranean Sea) were studied during field and laboratory experiments. Nitrogen enrichments (40 uM NO3 (-); 10 uM NH4 (+); 20 uM CH4N2O) and a control, with no added N, were carried out in separate carboys with seawater collected from Bizerte Lagoon. In the field experiments, all N-enrichments resulted in significant increases in chlorophyll a concentration, and maintained exponential growth until the end of the experiment. The initial diatom community was dominated by a bloom of P. cf. seriata (9.3 * 10(5) cells l(-1)). After 6 days of incubation, the abundance of P. cf. seriata was greatest in the urea addition (1.52 * 10(6) cells l(-1)), compared to the ammonium treatment (0.47 * 10(6) cells l(-1)), nitrate treatment (0.70 * 10(6) cells l(-1)) and control (0.36 * 10(6) cells l(-1)). The specific growth rates, calculated from increases in chlorophyll a and cell abundance, were statistically different across all treatments, with the highest in the urea and nitrate additions. Similar results were obtained from the laboratory experiments. These were carried out with P. calliantha isolated from Bizerte Lagoon and grown in f/2 medium enriched with 40 uM nitrate, 10 uM ammonium and 20 uM urea. The exponential growth rate was significantly faster for the cells cultured with urea (1.50 d(-1)) compared to the nitrate (0.90 d(-1)) and ammonium (0.80 d(-1)) treatments and the control (0.40 d(-1)). Analysis of DA, performed at the beginning and the end of the both experiments in all treatments, revealed very low concentrations (below the limit of quantification, 0.02- 1.310(-7) pg cell( 1), respectively).The field and laboratory experiments demonstrate that P.cf. seriata and P. calliantha are able to grow efficiently on the three forms of N, but with a preference for urea. PMID- 27225996 TI - Global Estimation of Surgical Procedures Needed for Forcibly Displaced Persons. AB - INTRODUCTION: Sixty million people were displaced from their homes due to conflict, persecution, or human rights violations at the end of 2014. This vulnerable population bears a disproportionate burden of disease, much of which is surgically treatable. We sought to estimate the surgical needs for forcibly displaced persons globally to inform humanitarian assistance initiatives. METHODS: Data regarding forcibly displaced persons, including refugees, internally displaced persons (IDPs), and asylum seekers were extracted from United Nations databases. Using the minimum proposed surgical rate of 4669 procedures per 100,000 persons annually, global, regional, and country-specific estimates were calculated. The prevalence of pregnancy and obstetric complications were used to estimate obstetric surgical needs. RESULTS: At least 2.78 million surgical procedures (IQR 2.58-3.15 million) were needed for 59.5 million displaced persons. Of these, 1.06 million procedures were required in North Africa and the Middle East, representing an increase of 50 % from current unmet surgical need in the region. Host countries with the highest surgical burden for the displaced included Syria (388,000 procedures), Colombia (282,000 procedures), and Iraq (187,000). Between 4 and 10 % of required procedures were obstetric surgical procedures. Children aged <18 years made up 52 % of the displaced, portending a substantial demand for pediatric surgical care. CONCLUSION: Approximately three million procedures annually are required to meet the surgical needs of refugees, IDPs, and asylum seekers. Most displaced persons are hosted in countries with inadequate surgical care capacity. These figures should be considered when planning humanitarian assistance and targeted surgical capacity improvements. PMID- 27225995 TI - Structural characterization of CYP144A1 - a cytochrome P450 enzyme expressed from alternative transcripts in Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis (Mtb) causes the disease tuberculosis (TB). The virulent Mtb H37Rv strain encodes 20 cytochrome P450 (CYP) enzymes, many of which are implicated in Mtb survival and pathogenicity in the human host. Bioinformatics analysis revealed that CYP144A1 is retained exclusively within the Mycobacterium genus, particularly in species causing human and animal disease. Transcriptomic annotation revealed two possible CYP144A1 start codons, leading to expression of (i) a "full-length" 434 amino acid version (CYP144A1-FLV) and (ii) a "truncated" 404 amino acid version (CYP144A1-TRV). Computational analysis predicted that the extended N-terminal region of CYP144A1-FLV is largely unstructured. CYP144A1 FLV and TRV forms were purified in heme-bound states. Mass spectrometry confirmed production of intact, His6-tagged forms of CYP144A1-FLV and -TRV, with EPR demonstrating cysteine thiolate coordination of heme iron in both cases. Hydrodynamic analysis indicated that both CYP144A1 forms are monomeric. CYP144A1-TRV was crystallized and the first structure of a CYP144 family P450 protein determined. CYP144A1-TRV has an open structure primed for substrate binding, with a large active site cavity. Our data provide the first evidence that Mtb produces two different forms of CYP144A1 from alternative transcripts, with CYP144A1-TRV generated from a leaderless transcript lacking a 5'-untranslated region and Shine-Dalgarno ribosome binding site. PMID- 27225997 TI - Evaluation of Cytochrome P450 3A4-Mediated Drug-Drug Interaction Potential for Cobimetinib Using Physiologically Based Pharmacokinetic Modeling and Simulation. AB - BACKGROUND AND OBJECTIVES: Cobimetinib is eliminated mainly through cytochrome P450 (CYP) 3A4-mediated hepatic metabolism in humans. A clinical drug-drug interaction (DDI) study with the potent CYP3A4 inhibitor itraconazole resulted in an approximately sevenfold increase in cobimetinib exposure. The DDI risk for cobimetinib with other CYP3A4 inhibitors and inducers needs to be assessed in order to provide dosing instructions. METHODS: A physiologically based pharmacokinetic (PBPK) model was developed for cobimetinib using in vitro data. It was then optimized and verified using clinical pharmacokinetic data and itraconazole-cobimetinib DDI data. The contribution of CYP3A4 to the clearance of cobimetinib in humans was confirmed using sensitivity analysis in a retrospective simulation of itraconazole-cobimetinib DDI data. The verified PBPK model was then used to predict the effect of other CYP3A4 inhibitors and inducers on cobimetinib pharmacokinetics. RESULTS: The PBPK model described cobimetinib pharmacokinetic profiles after both intravenous and oral administration of cobimetinib well and accurately simulated the itraconazole-cobimetinib DDI. Sensitivity analysis suggested that CYP3A4 contributes ~78 % of the total clearance of cobimetinib. The PBPK model predicted no change in cobimetinib exposure (area under the plasma concentration-time curve, AUC) with the weak CYP3A inhibitor fluvoxamine and a three to fourfold increase with the moderate CYP3A inhibitors, erythromycin and diltiazem. Similarly, cobimetinib exposure in the presence of strong (rifampicin) and moderate (efavirenz) CYP3A inducers was predicted to decrease by 83 and 72 %, respectively. CONCLUSION: This study demonstrates the value of using PBPK simulation to assess the clinical DDI risk inorder to provide dosing instructions with other CYP3A4 perpetrators. PMID- 27225998 TI - Focal Dystonia in Hemiplegic Upper Limb: Favorable Effect of Cervical Microsurgical DREZotomy Involving the Ventral Horn - A Report of 3 Patients. AB - BACKGROUND: Focal dystonia in hemiplegic upper limbs is poorly responsive to medications or classical neurosurgical treatments. Only repeated botulinum toxin injections show efficacy, but in most severe cases effects are transient. OBJECTIVES: Cervical DREZ lesioning, which has proven efficacious in hyperspasticity when done deeply (3-5 mm) in the dorsal horn, may have favorable effects on the dystonic component when performed down to, and including, the base of the ventral horn (5-6 mm in depth). METHODS: Three patients underwent deep cervical microsurgical DREZotomy (MDT) for focal dystonia in the upper limb. RESULTS: Hypertonia was reduced, and sustained dystonic postures were suppressed. Residual motor function (hidden behind hypertonia) came to the surface. CONCLUSIONS: Cervical MDT may be a useful armamentarium for treating refractory focal dystonia in the upper limb. PMID- 27225999 TI - Facing death in the intensive care unit. A phenomenological study of nurses' experiences. AB - BACKGROUND: Nurses may experience considerable emotional burden due to patient death, in part as they are generally the professionals who have the most contact with patients. OBJECTIVE: To describe the lived experience of Spanish nurses working in intensive care units regarding how they face the death of their patients. METHODS: A qualitative phenomenological study was performed. A purposeful sample was used. The data collection strategies used included in-depth unstructured and semi-structured interviews, field notes and personal documents. Afterwards, data were analyzed using the Giorgi proposal. RESULTS: 22 nurses participated, with a mean age of 40.8 years and a mean work experience of 13.8 years. Three themes were identified: 1) dealing with expectations of recovery, 2) accepting the age of death, and 3) experiencing emotional attachment. CONCLUSIONS: Nurses in intensive care units report a great emotional burden derived from patients death, Support programs for nurses should be organised within these units. PMID- 27226000 TI - Complementary Characteristics of Correlation Patterns in Morphometric Correlation Networks of Cortical Thickness, Surface Area, and Gray Matter Volume. AB - Morphometric correlation networks of cortical thickness, surface area, and gray matter volume have statistically different structural topology. However, there is no report directly describing their correlation patterns in view of interregional covariance. Here, we examined the characteristics of the correlation patterns in three morphometric networks of cortical thickness, surface area, and gray matter volume using a Venn diagram concept across 314 normal subjects. We found that over 60% of all nonoverlapping correlation patterns emerged with divergent unique patterns, while there were 10% of all common edges in ipsilateral and homotopic regions among the three morphometric correlation networks. It was also found that the network parameters of the three networks were different. Our findings showed that correlation patterns of the network itself can provide complementary information when compared with network properties. We demonstrate that morphometric correlation networks of distinct structural phenotypes have different correlation patterns and different network properties. This finding implies that the topology of each morphometric correlation network may reflect different aspects of each morphometric descriptor. PMID- 27226001 TI - Deconstructing the molecular architecture of olfactory areas using proteomics. AB - The anatomy of the olfactory system is highly complex, comprising a system of olfactory receptors, pathways for the transmission of olfactory information, and structures for the recognition, discrimination, and memorization of odors. During the last years, proteomics has emerged as a large-scale comprehensive approach to characterize and quantify specific olfactory-related proteomes in different biological conditions such as olfactory learning, neurodegeneration, and ageing between others. The current work reviews recent applications of proteomics to olfaction with particular focus on quantitative proteome profiling studies performed on olfactory areas from laboratory animal models as well as proteomic characterizations performed on specific brain structures and fluids involved in human smell. Finally, we will also discuss the potential application of proteomics to study global proteome dynamics and posttranslationally modified proteomes in order to unravel cell-signaling networks that occur from peripheral structures to olfactory cortical areas during odor processing. PMID- 27226002 TI - Medullary infarction causing coexistent SUNCT and trigeminal neuralgia. AB - Background Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) or with autonomic symptoms (SUNA) are grouped together within the trigeminal autonomic cephalalgias (TACs). However, the SUNCT and SUNA phenotype and management overlap with those of trigeminal neuralgia (TN). Additionally, a broad variety of cerebral pathologies are reportedly able to trigger either TN- or SUNCT-like pain, and emerging structural neuroimaging findings suggest the possible role of neurovascular conflict with the trigeminal nerve in SUNCT, further supporting aetiological and pathophysiological overlaps among SUNCT, SUNA and TN. Case report We present the first case of coexisting chronic SUNCT- and TN-like phenotypes caused by haemorrhagic infarct of the dorsolateral medulla. Discussion In light of our case, a perturbation of the dorsolateral medullary circuits may constitute an important pathophysiological component, supporting a unifying nosological hypothesis that considers SUNCT, SUNA and TN clinical variants of the same disorder. PMID- 27226003 TI - Recurrent coma and fever in familial hemiplegic migraine type 2. A prospective 15 year follow-up of a large family with a novel ATP1A2 mutation. AB - Background Familial hemiplegic migraine (FHM) is a rare monogenic migraine subtype characterised by attacks associated with transient motor weakness. Clinical information is mainly based on reports of small families with only short follow-up. Here, we document a prospective 15-year follow-up of an extended family with FHM type 2. Patients and methods After diagnosing FHM in a patient with severe attacks associated with coma and fever, we identified eight more family members with FHM and one with possible FHM. All family members were prospectively followed for 15 years. In total 13 clinically affected and 21 clinically non-affected family members were genetically tested and repeatedly investigated. Results A novel p.Arg348Pro ATP1A2 mutation was found in 14 family members: 12 with clinical FHM, one with psychomotor retardation and possible FHM, and one without FHM features. In 9/12 (75%) family members with genetically confirmed FHM, attacks were severe, long-lasting, and often associated with impaired consciousness and fever. Such attacks were frequently misdiagnosed and treated as viral meningitis or stroke. Epilepsy was reported in three family members with FHM and in the one with psychomotor retardation and possible FHM. Ataxia was not observed. Conclusion FHM should be considered in patients with recurrent coma and fever. PMID- 27226004 TI - Symptomatic trigeminal neuralgia and nocturnal thunderclap headache resulting from a carotid paraganglioma. PMID- 27226005 TI - Lithium limits trimethyltin-induced cytotoxicity and proinflammatory response in microglia without affecting the concurrent autophagy impairment. AB - Trimethyltin (TMT) is a highly toxic molecule present as an environmental contaminant causing neurodegeneration particularly of the limbic system both in humans and in rodents. We recently described the occurrence of impairment in the late stages of autophagy in TMT-intoxicated astrocytes. Here we show that similarly to astrocytes also in microglia, TMT induces the precocious block of autophagy indicated by the accumulation of the autophagosome marker, microtubule associated protein light chain 3. Consistent with autophagy impairment we observe in TMT-treated microglia the accumulation of p62/SQSTM1, a protein specifically degraded through this pathway. Lithium has been proved effective in limiting neurodegenerations and, in particular, in ameliorating symptoms of TMT intoxication in rodents. In our in vitro model, lithium displays a pro-survival and anti-inflammatory action reducing both cell death and the proinflammatory response of TMT-treated microglia. In particular, lithium exerts these activities without reducing TMT-induced accumulation of light chain 3 protein. In fact, the autophagic block imposed by TMT is unaffected by lithium administration. These results are of interest as defects in the execution of autophagy are frequently observed in neurodegenerative diseases and lithium is considered a promising therapeutic agent for these pathologies. Thus, it is relevant that this cation can still maintain its pro-survival and anti-inflammatory role in conditions of autophagy block. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27226006 TI - Integrated whole-heart computational workflow for inverse potential mapping and personalized simulations. AB - BACKGROUND: Integration of whole-heart activation simulations and inverse potential mapping (IPM) could benefit the guidance and planning of electrophysiological procedures. Routine clinical application requires a fast and adaptable workflow. These requirements limit clinical translation of existing simulation models. This study proposes a comprehensive finite element model (FEM) based whole-heart computational workflow suitable for IPM and simulations. METHODS: Three volunteers and eight patients with premature ventricular contractions underwent body surface potential (BSP) acquisition followed by a cardiac MRI (CMR) scan. The cardiac volumes were segmented from the CMR images using custom written software. The feasibility to integrate tissue characteristics was assessed by generating meshes with virtual edema and scar. Isochronal activation maps were constructed by identifying the fastest route through the cardiac volume using the Moller-Trumbore and Floyd-Warshall algorithms. IPM's were reconstructed from the BSP's. RESULTS: Whole-heart computational meshes were generated within seconds. The first point of atrial activation on IPM was located near the crista terminalis of the superior vena cave into the right atrium. The IPM demonstrated the ventricular epicardial breakthrough at the attachment of the moderator band with the right ventricular free wall. Simulations of sinus rhythm were successfully performed. The conduction through the virtual edema and scar meshes demonstrated delayed activation or a complete conductional block respectively. CONCLUSION: The proposed FEM based whole-heart computational workflow offers an integrated platform for cardiac electrical assessment using simulations and IPM. This workflow can incorporate patient-specific electrical parameters, perform whole heart cardiac activation simulations and accurately reconstruct cardiac activation sequences from BSP's. PMID- 27226007 TI - Impact of stent platform on longitudinal stent deformation: an in vivo frequency domain optical coherence tomography study. AB - Recently, longitudinal coronary stent deformation has been highlighted as a possible cause of drug-eluting stent failure. Although bench tests and in vivo studies have demonstrated difference in longitudinal stent strength among the stents with different platforms, its clinical impact is still unknown. Furthermore, it is unknown if modified stent platform favorably affect the incidence of stent deformation. The aim of this study was to investigate the longitudinal deformation of the everolimus-eluting stents (EES) with different stent platforms by using frequency domain optical coherence tomography (FD-OCT). Seventy-eight lesions treated with EES (Xience Prime: n = 26, Promus element: n = 29, Promus premier: n = 23) were studied. After successful stent implantation, FD OCT was performed and stent length was measured using three-dimensional reconstruction of the images in vivo. Percent longitudinal stent shortening (%SS) was defined as the in vivo stent length divided by nominal stent length. Longitudinal stent deformation was defined as %SS > 10 %. Patients' and procedural characteristics were similar among 3 EESs. There was no difference in mean %SS between Xience Prime, Promus Element and Promus Premier (1.0 +/- 5.8, 2.9 +/- 6.7 and 0.8 +/- 3.7 %, p = 0.322). Incidence of the longitudinal stent deformation was significantly higher in Promus Element than the other stents (0, 13.8 and 0 %, p = 0.028). Incidence of longitudinal stent deformation was different between EESs with different stent platforms. Stent material, stent design and/or stent delivery balloon may affect longitudinal stent deformation. PMID- 27226010 TI - Disease epidemics: lessons for resilience in an increasingly connected world. PMID- 27226009 TI - Transcriptomic analysis of the process of biofilm formation in Rhizobium etli CFN42. AB - Organisms belonging to the genus Rhizobium colonize leguminous plant roots and establish a mutually beneficial symbiosis. Biofilms are structured ecosystems in which microbes are embedded in a matrix of extracellular polymeric substances, and their development is a multistep process. The biofilm formation processes of R. etli CFN42 were analyzed at an early (24-h incubation) and mature stage (72 h), comparing cells in the biofilm with cells remaining in the planktonic stage. A genome-wide microarray analysis identified 498 differentially regulated genes, implying that expression of ~8.3 % of the total R. etli gene content was altered during biofilm formation. In biofilms-attached cells, genes encoding proteins with diverse functions were overexpressed including genes involved in membrane synthesis, transport and chemotaxis, repression of flagellin synthesis, as well as surface components (particularly exopolysaccharides and lipopolysaccharides), in combination with the presence of activators or stimulators of N-acyl homoserine lactone synthesis This suggests that R. etli is able to sense surrounding environmental conditions and accordingly regulate the transition from planktonic and biofilm growth. In contrast, planktonic cells differentially expressed genes associated with transport, motility (flagellar and twitching) and inhibition of exopolysaccharide synthesis. To our knowledge, this is the first report of nodulation and nitrogen assimilation-related genes being involved in biofilm formation in R. etli. These results contribute to the understanding of the physiological changes involved in biofilm formation by bacteria. PMID- 27226008 TI - Elevated ventricular wall stress disrupts cardiomyocyte t-tubule structure and calcium homeostasis. AB - AIMS: Invaginations of the cellular membrane called t-tubules are essential for maintaining efficient excitation-contraction coupling in ventricular cardiomyocytes. Disruption of t-tubule structure during heart failure has been linked to dyssynchronous, slowed Ca(2+) release and reduced power of the heartbeat. The underlying mechanism is, however, unknown. We presently investigated whether elevated ventricular wall stress triggers remodelling of t tubule structure and function. METHODS AND RESULTS: MRI and blood pressure measurements were employed to examine regional wall stress across the left ventricle of sham-operated and failing, post-infarction rat hearts. In failing hearts, elevated left ventricular diastolic pressure and ventricular dilation resulted in markedly increased wall stress, particularly in the thin-walled region proximal to the infarct. High wall stress in this proximal zone was associated with reduced expression of the dyadic anchor junctophilin-2 and disrupted cardiomyocyte t-tubular structure. Indeed, local wall stress measurements predicted t-tubule density across sham and failing hearts. Elevated wall stress and disrupted cardiomyocyte structure in the proximal zone were also associated with desynchronized Ca(2+) release in cardiomyocytes and markedly reduced local contractility in vivo. A causative role of wall stress in promoting t-tubule remodelling was established by applying stretch to papillary muscles ex vivo under culture conditions. Loads comparable to wall stress levels observed in vivo in the proximal zone reduced expression of junctophilin-2 and promoted t tubule loss. CONCLUSION: Elevated wall stress reduces junctophilin-2 expression and disrupts t-tubule integrity, Ca(2+) release, and contractile function. These findings provide new insight into the role of wall stress in promoting heart failure progression. PMID- 27226011 TI - Influence of Grape Maturity on Complex Carbohydrate Composition of Red Sparkling Wines. AB - This paper studied how grape maturity affected complex carbohydrate composition during red sparkling wine making and wine aging. Grape ripening stage (premature and mature grapes) showed a significant impact on the content, composition, and evolution of polysaccharides and oligosaccharides of sparkling wines. Polysaccharides rich in arabinose and galactose, mannoproteins, rhamnogalacturonans II, and oligosaccharides in base wines increased with maturity. For both maturity stages, polysaccharides rich in arabinose and galactose, and the glucuronic acid glycosyl residue of the oligosaccharides were the major carbohydrates detected in all vinification stages. The total glycosyl content of oligosaccharides decreased during the whole period of aging on yeast lees. The reduction of polysaccharides rich in arabinose and galactose and rhamnogalacturonans type II during the aging was more pronounced in mature samples. To our knowledge, this is the first report of the polysaccharide and oligosaccharide composition of red sparkling wines. PMID- 27226012 TI - The Sexual Stratification Hypothesis: Is the Decision to Arrest Influenced by the Victim/Suspect Racial/Ethnic Dyad? AB - The sexual stratification hypothesis suggests that criminal justice responses to sexual victimization will differ depending on the victim/suspect racial/ethnic dyad. Previous research examining the sexual stratification hypothesis has primarily focused on court processes, and the small body of literature examining arrest decisions is dated. There remains substantial opportunity for testing the sexual stratification hypothesis at response stages apart from the court level (i.e., arrest). Using quantitative data on 655 sexual assault complaints that were reported to the Los Angeles County Sherriff's Department (LASD) and the Los Angeles Police Department (LAPD) in 2008, this study examines the effect of the victim/suspect racial/ethnic dyad on the decision to arrest. Findings suggest that police consider the victim/suspect racial/ethnic dyad when making arrest decisions. In addition, victim characteristics, strength of evidence indicators, and measures of case factors predict the police decision to make an arrest. PMID- 27226013 TI - Masculine Discrepancy Stress, Emotion-Regulation Difficulties, and Intimate Partner Violence. AB - Research suggests that masculine socialization processes contribute to the perpetration of intimate partner violence (IPV) by men. Although this research has traditionally focused on men who strongly adhere to traditional gender norms, men who negatively evaluate themselves as falling short of these norms (a construct termed masculine discrepancy stress) have proven to be at increased risk of IPV perpetration. Likewise, men experiencing problems with emotion regulation, a multidimensional construct reflecting difficulties in effectively experiencing and responding to emotional states, are also at risk of IPV perpetration. In the present research, we tested the hypothesis that the link between discrepancy stress and IPV perpetration is mediated via difficulties in emotion regulation. Three hundred fifty-seven men completed online surveys assessing their experience of discrepancy stress, emotion-regulation difficulties, and history of IPV perpetration. Results indicated that discrepancy stressed men's use of physical IPV was fully mediated by emotion-regulation difficulties. In addition, emotion-regulation difficulties partially mediated the association between discrepancy stress and sexual IPV. Findings are discussed in terms of the potential utility of emotion-focused interventions for modifying men's experience and expression of discrepancy stress and reducing perpetration of IPV. PMID- 27226014 TI - Attachment Anxiety as a Risk Factor for Subsequent Intimate Partner Violence Victimization: A 6-Month Prospective Study Among College Women. AB - Recent research suggests that individuals with attachment difficulties are at increased risk for experiencing intimate partner violence (IPV) victimization. However, most studies conducted on this topic have been cross-sectional, leaving it unclear whether attachment difficulties actually precede this type of violence. The current 6-month prospective study examined the relation between adult attachment and subsequent IPV victimization in a sample of 133 college women. At Time 1, participants completed the Experiences in Close Relationships (ECR) questionnaire to assess the two underlying orthogonal dimensions of adult attachment (anxiety and avoidance) and the Traumatic Life Events Questionnaire (TLEQ) to assess prior exposure to interpersonal traumatic events. At follow-up, participants completed a modified version of the Revised Conflict Tactics Scale (CTS-2) to assess IPV victimization. Results indicated that attachment anxiety was associated with an increased risk for experiencing physical assault during the 6-month follow-up period, even after statistically adjusting for prior interpersonal trauma. In contrast, attachment avoidance was unrelated to subsequent IPV victimization. PMID- 27226015 TI - Fear of Crime: The Influence of General Fear, Risk, and Time Perspective. AB - Prior research on fear of crime has focused less on psychological causes than on sociological and demographic factors. This study, however, introduces time perspective (TP) as an important psychological variable in the understanding of fear of crime. Specifically, the article assesses the relationship between TP as a stable personality factor and the mediation of risk and general fear on fear of crime levels. Data were collected using the survey method from a sample of 375 respondents utilizing the following scales: Zimbardo Time Perspective Inventory (ZTPI) consisting of five TP subscales, Ferraro's perceived risk of victimization and fear of crime scales, and a general (non-crime) fear scale measuring pragmatic and abstract fear. Path analysis shows no significant direct relationships between the five TP subscales and fear of crime. However, indirect effects are observed for Past Negative TP and Present Fatalistic TP, with general fear (pragmatic and abstract) and risk of victimization mediating the relationship, and pragmatic fear having the greatest significant effect size. Results are discussed in the context of risk and general fear sensitivity and construal level theory. We conclude with recommendations for future research. PMID- 27226016 TI - Effects of subchronic extremely low-frequency electromagnetic field exposure on biochemical parameters in rats. AB - The objective of the present study was to systematically determine the effects of 50 Hertz (Hz) magnetic fields (MFs) on biochemical parameters in rats. Sixty-four adult (5 weeks old, 140-165 g) male Sprague-Dawley rats were randomly divided into four groups: sham, 20 uTesla (uT), 100 uT, and 500 uT 50 Hz MF ( n = 16 in each group). The rats in the MF groups were exposed for 2 h daily for up to 4 weeks. Under these experimental conditions, body weight, organ coefficients, biochemical parameters (blood lipids, myocardial enzymes, liver function, and renal function) were measured. We found that 50 Hz MFs had no significant effects on growth or on the majority of blood biochemical parameters, with the exception of creatinine and cholesterol. However, the changes in creatinine and cholesterol were relatively small and unlikely to be clinically relevant. PMID- 27226017 TI - On the long-term effects of methyl isocyanate on cell-mediated immunity in Bhopal gas-exposed long-term survivors and their offspring. AB - Methyl isocyanate (MIC) is a toxic industrial chemical that is documented as a potent respiratory toxicant. We investigated cell-mediated immunity (CMI) in the MIC-exposed long-term survivors and their offspring born after the Bhopal gas leak tragedy in 1984. Several earlier reports show inconsistency in the assessment of immunological effects of MIC on the human population. In these studies, important factors including lifestyle attributes were overlooked. We incorporated these factors also in our study of the basic cell-mediated immune function in the Bhopal MIC-affected population. Twenty-seven years after exposure, we assessed the circulating T-lymphocyte frequency using E-Rosette assay. A total of 46 MIC-exposed healthy long-term survivors and their offspring were studied vis-a-vis parallel gender-age group-matched unexposed controls from Bhopal and various other regions of India. The influence of several lifestyle variabilities (smoking, alcohol intake, and tobacco chewing) on T-lymphocyte frequency was also taken into consideration. Our observations suggest that Erythrocyte-Rosette-forming cell (E-RFC) distribution frequency is largely insignificant in the MIC-affected population as compared to controls ( p > 0.05). In the MIC-affected tobacco chewers, there was a trend of suppression in CMI (relative decrease = 10.3%) as compared to nonchewers. Overall, our results show negligible long-term effect of MIC on CMI measured in terms of E-RFC frequency. These observations are not in agreement with earlier findings that immunosuppressive effects of MIC exposure persist in the T-cells of the affected population. However, atypical lymphocytes were frequently observed as E-RFC in the exposed females when compared to all other subgroups. Hematopoietic disorders (atypical lymphocytosis) in the MIC-affected population along with previous reports on the cytogenetic and humoral immune system linking cancer risk and chronic obstructive pulmonary disease (COPD) are important. PMID- 27226018 TI - Omental flap after pelvic exenteration for pelvic cancer. AB - Pelvic infection is a significant clinical problem after pelvic exenteration. The clinical benefit of an omental flap in reducing the incidence of such infections is unknown. The aim of this study was to evaluate whether an omental flap after pelvic exenteration reduces the incidence of pelvic infection and the length of postoperative hospital stay. In this study, we demonstrate a safe, effective, simple method for reducing the incidence of pelvic infection using an omental flap. We performed pelvic exenteration for tumors that were suspected to have extensive invasion to the bladder, prostate, or uterus. The omentum was dissected from the transverse colon and greater curvature of the stomach. The flap was based on the right gastroepiploic vessels and tunneled in the retrocolic plane, through the mesentery of the transverse colon and ileocecum, to the defect. Twenty-seven patients were analyzed retrospectively. Ten patients received omental flaps, and 17 patients underwent pelvic exenteration without an omental flap. The incidence of pelvic infection was significantly reduced in the patients with omental flaps. PMID- 27226019 TI - Port-site metastasis after laparoscopic surgery for gastrointestinal cancer. AB - Although the incidence of port-site metastasis after laparoscopic surgery for colorectal cancer has markedly decreased since laparoscopic colectomy was first reported in 1991, it still has not reached zero. In colorectal cancer, the safety of laparoscopic surgery, including the low incidence of port-site metastasis, has been proven in large, randomized trials. In gastric cancer, reports of port-site metastasis are extremely rare, but we should await the results of ongoing trials. This brief review summarizes the current knowledge regarding port-site metastasis after laparoscopic surgery for colorectal and gastric cancer. PMID- 27226020 TI - Changes in fat-soluble vitamin levels after gastrectomy for gastric cancer. AB - Several authors have reported the relationship between gastric cancer risk and vitamins. However, there are few reports on fat-soluble vitamins after gastrectomy for gastric cancer. Fat malabsorption and suppression of food intake after gastrectomy for gastric cancer have been previously documented. Because of fat malabsorption and suppression of food intake, a potential deficiency in fat soluble vitamins, such as vitamins A, D, E, and K, has been readily suggested. In about 20 % of patients, the serum vitamin E levels were decreased. Indeed, vitamin E deficiency is a common complication after gastrectomy. Continuous vitamin E deficiency could develop from neurological symptoms, i.e., peripheral neuropathy, limb or truncal ataxia. The total cholesterol level is associated with the vitamin E levels. However, the serum vitamin A levels were decreased in only 1.8 % of patients. In total gastrectomy cases, the serum vitamin A level may readily decrease. In contrast, 1,25(OH)2 vitamin D deficiency, which is the most active vitamin D metabolite, is rare. Additionally, vitamin K deficiency after gastrectomy has not been reported thus far. Evidence that serum fat-soluble vitamin levels may decrease after gastrectomy for gastric cancer has not been established yet. Future research must explore fat-soluble vitamin deficiency after gastrectomy. PMID- 27226022 TI - [Food allergen regulations in the EU]. AB - With the implementation of EU regulation 1169/2011 in December 2014, labelling of allergenic ingredients has been extended to non-prepacked foods. The member states of the European Union were authorised to lay down national rules for the labelling of allergenic ingredients in non-prepacked foods. In Germany, this was accomplished through the introduction of the Vorlaufige Lebensmittelinformations Erganzungsverordnung (VorlLMIEV). Regulation 1169/2011 also changed the way allergenic ingredients are to be labelled on prepacked foods.This article provides an overview over the current regulations regarding the labelling of food allergens on prepacked and non-prepacked foods in the EU and Germany. PMID- 27226021 TI - Evaluation of Amount of Blood in Dry Blood Spots: Ring-Disk Electrode Conductometry. AB - A fixed area punch in dried blood spot (DBS) analysis is assumed to contain a fixed amount of blood, but the amount actually depends on a number of factors. The presently preferred approach is to normalize the measurement with respect to the sodium level, measured by atomic spectrometry. Instead of sodium levels, we propose electrical conductivity of the extract as an equivalent nondestructive measure. A dip-type small diameter ring-disk electrode (RDE) is ideal for very small volumes. However, the conductance (G) measured by an RDE depends on the depth (D) of the liquid below the probe. There is no established way of computing the specific conductance (sigma) of the solution from G. Using a COMSOL Multiphysics model, we were able to obtain excellent agreement between the measured and the model predicted conductance as a function of D. Using simulations over a large range of dimensions, we provide a spreadsheet-based calculator where the RDE dimensions are the input parameters and the procedure determines the 99% of the infinite depth conductance (G99) and the depth D99 at which this is reached. For typical small diameter probes (outer electrode diameter ~ <2 mm), D99 is small enough for dip-type measurements in extract volumes of ~100 MUL. We demonstrate the use of such probes with DBS extracts. In a small group of 12 volunteers (age 20-66), the specific conductance of 100 MUL aqueous extracts of 2 MUL of spotted blood showed a variance of 17.9%. For a given subject, methanol extracts of DBS spots nominally containing 8 and 4 MUL of blood differed by a factor of 1.8-1.9 in the chromatographically determined values of sulfate and chloride (a minor and major constituent, respectively). The values normalized with respect to the conductance of the extracts differed by ~1%. For serum associated analytes, normalization of the analyte value by the extract conductance can thus greatly reduce errors from variations in the spotted blood volume/unit area. PMID- 27226023 TI - Assisted conception and the risk of CHD: a case-control study. AB - Epidemiological studies suggest a higher prevalence of congenital malformations in children conceived through assisted reproductive technologies. There are a few studies that address CHD specifically and most have examined data from registries. We examined the relationship between CHD and assisted conception using data collected in a specialist paediatric cardiac service in the United Kingdom. Between April, 2010 and July, 2011, the parents of children attending paediatric cardiology clinics at the Royal Brompton Hospital, London, were invited to complete a questionnaire that enquired about the nature of their child's conception, the route for their original referral, and a number of potential confounding exposures. "Cases" were defined as children diagnosed with one or more carefully defined CHDs and "controls" as those with normal hearts. Of 894 new attendees with complete data, half of them were cases (n=410, 45.9%). The overall prevalence of assisted conception was 5.4% (n=44). Logistic regression analysis demonstrated a non-significant increase in the crude odds for the use of assisted reproduction (odds ratio 1.21, 95% confidence interval 0.66-2.22) in this group. After adjustment for gestation, parity, year of birth, and maternal age, the odds ratio reduced (odds ratio 0.95, 95% confidence interval 0.48-1.88). Increased rates of assisted conception were observed in a number of CHD subgroups, although no significant differences were found. These findings do not suggest an overall association between CHD and assisted reproduction in this population. PMID- 27226024 TI - Prevalence of Sleep Disorders in Thai Children. AB - OBJECTIVE: To evaluate the prevalence of sleep disorders in Thai children who underwent polysomnography at a single institution. METHODS: A retrospective analysis of pediatric polysomnographic studies was performed from January 2011 through December 2014. RESULTS: One hundred sixty-six studies were conducted; 142, 7, and 17 were diagnostic, split-night, and positive airway pressure (PAP) titration studies, respectively. In total, 136 diagnostic/split-night studies were performed to diagnose sleep disorders with presentation of snoring (92.6 %), heavy breathing (0.7 %), witnessed apnea (14.7 %), excessive daytime sleepiness (10.3 %), hyperactivity (2.2 %), restless sleep (11.0 %), enuresis/nocturia (5.9 %), abnormal behavior (4.4 %) and poor weight gain (0.7 %). Eleven diagnostic studies and one split-night study were performed to follow-up obstructive sleep apnea (OSA) after adenoidectomy and/or tonsillectomy. One diagnostic study was conducted to follow-up OSA after postmandibular distraction. OSA was the most common diagnosis with a prevalence of 92.7 %; 40.4 % of patients were diagnosed with severe OSA. The prevalence of sleep-related hypoventilation was 15.4 %. The second most common diagnosis was periodic limb movement disorder with a prevalence of 20.6 %. Seventeen PAP titration studies were performed. Four CPAP titration studies were conducted for OSA treatment. Twelve bi-level (BiPAP) titration studies were performed in eight children with hypoventilation. One BiPAP/average volume-assured pressure support titration was conducted in a patient with congenital central hypoventilation syndrome (CCHS). CONCLUSIONS: The prevalence of sleep disorders in Thai children who underwent polysomnography at a tertiary-care hospital is very high. The factors that contribute are the limited availability and high costs of polysomnography in Thailand. This information will encourage pediatricians to look for sleep disorders in children. PMID- 27226025 TI - TH17 Cells in STAT3 Related Hyper-IgE Syndrome. AB - OBJECTIVES: To assess the utility of T helper17 (TH17) cell enumeration vis-a-vis National Institutes of Health (NIH) scoring in Hyper IgE syndrome (HIES). METHODS: Clinical phenotypes of Hyper IgE syndrome patients with and without STAT3 mutation were analysed and correlated with absolute eosinophil count, serum IgE levels and TH17 cell numbers in 19 patients with clinically suspected HIES and compared with healthy controls (n = 20). RESULTS: The difference in serum IgE between patients with and without STAT3 mutation and healthy controls was statistically significant (p < 0.05). Six patients had NIH score > 40; of which 4 were positive for STAT3 pathogenic variants, whereas two patients in the group with no identifiable STAT3 pathogenic variant had NIH score > 40. NIH score had sensitivity of 80 % and specificity of 87.5 % to detect cases with STAT3 pathogenic variants. TH17 cells were markedly low in all cases with STAT3 pathogenic variants. Among patients without STAT3 pathogenic variants, none had low TH17 cell numbers. CONCLUSIONS: Low TH17 cell numbers together with NIH scores can be a better indicator for presence of STAT3 mutations. PMID- 27226026 TI - Dynamic enhancement patterns of intrahepatic cholangiocarcinoma in cirrhosis on contrast-enhanced computed tomography: risk of misdiagnosis as hepatocellular carcinoma. AB - This study aimed to assess the features of intrahepatic cholangiocarcinoma (ICC) at computerized tomography (CT) and verify the risk of misdiagnosis of ICC as hepatocellular carcinoma (HCC) in cirrhosis. CT appearances of 98 histologically confirmed ICC nodules from 84 cirrhotic patients were retrospectively reviewed, taking into consideration the pattern and dynamic contrast uptake during the arterial, portal venous and delayed phases. During the arterial phase, 53 nodules (54.1%) showed peripheral rim-like enhancement, 35 (35.7%) hyperenhancement, 9 (9.2%) hypoenhancement and 1 (1.0%) isoenhancement. The ICC nodules showed heterogeneous dynamic contrast patterns, being progressive enhancement in 35 nodules (35.7%), stable enhancement in 28 nodules (28.6%), wash-in and wash-out pattern in 15 nodules (15.3%) and all other enhancement patterns in 20 nodules (20.4%). There were no significant differences in the dynamic vascular patterns of ICC according to nodule size (p > 0.05). ICC in cirrhosis has varied enhancement patterns at contrast-enhanced multiphase multidetector CT. Though the majority of ICC did not display typical radiological hallmarks of HCC, if dynamic CT scan was used as the sole modality for the non-invasive diagnosis of nodules in cirrhosis, the risk of misdiagnosis of ICC for HCC is not negligible. PMID- 27226027 TI - Endoplasmic reticulum stress enhances fibrosis through IRE1alpha-mediated degradation of miR-150 and XBP-1 splicing. AB - ER stress results in activation of the unfolded protein response and has been implicated in the development of fibrotic diseases. In this study, we show that inhibition of the ER stress-induced IRE1alpha signaling pathway, using the inhibitor 4MU8C, blocks TGFbeta-induced activation of myofibroblasts in vitro, reduces liver and skin fibrosis in vivo, and reverts the fibrotic phenotype of activated myofibroblasts isolated from patients with systemic sclerosis. By using IRE1alpha(-/-) fibroblasts and expression of IRE1alpha-mutant proteins lacking endoribonuclease activity, we confirmed that IRE1alpha plays an important role during myofibroblast activation. IRE1alpha was shown to cleave miR-150 and thereby to release the suppressive effect that miR-150 exerted on alphaSMA expression through c-Myb. Inhibition of IRE1alpha was also demonstrated to block ER expansion through an XBP-1-dependent pathway. Taken together, our results suggest that ER stress could be an important and conserved mechanism in the pathogenesis of fibrosis and that components of the ER stress pathway may be therapeutically relevant for treating patients with fibrotic diseases. PMID- 27226030 TI - Thiazoyl phosphines. Design, reactivity, and complexation. AB - In spite of the numerous possible applications of thiazoles as ligands for catalysis and as active molecules in medicinal chemistry, only a few studies have dealt with their versatile chemistry. Several selective modifications of the structure of these derivatives and mainly of thiazoyl phosphines are detailed, thus illustrating the great possibilities to tailor at will their structures and therefore their properties. The formation of Ru and Au complexes is reported. Six of these new thiazoyl phosphines were characterized by X-ray crystallography as well as two of their gold complexes. PMID- 27226029 TI - The efficacy of amoxicillin sodium against streptococcosis in cultured olive flounder Paralichthys olivaceus and its pharmacokinetics. AB - The efficacy of amoxicillin sodium for controlling field and experimental Streptococcus iniae and S. parauberis infections in olive flounder (Paralichthys olivaceus) was evaluated after a single intramuscular administration. Furthermore, the minimal inhibitory concentrations (MIC) against 21 Streptococcus strains were determined. In addition, the pharmacokinetics and residue depletion in olive flounder were investigated. Single intramuscular doses of amoxicillin sodium at 20, 40, 80, and 160 mg/kg b.w. fish significantly reduced cumulative mortality rates to 18.8-31.3% (P < 0.05) for S. iniae and to 5.0-15.0% (P < 0.01) for S. parauberis, whereas the S. iniae- and S. parauberis-infected positive control groups showed cumulative mortality rates of 68.8% and 60.0%, respectively. In a S. parauberis outbreak, amoxicillin sodium reduced the cumulative mortality rate to 7.5% and 4.8% at 20 and 40 mg/kg b.w. fish, respectively, whereas that of the untreated control group was 35.2%. Peak plasma concentrations (Cmax ) following a single intramuscular dose of 40 and 80 mg/kg b.w. fish were 62.64 (Tmax , 1.59 h) and 87.61 (Tmax , 3.02 h) MUg/mL, respectively, with large AUC0-t /MIC and Cmax /MIC ratios, and sufficient T > MIC (time for maintaining plasma drug concentration greater than MICs) for S. iniae and S. parauberis. The estimated withdrawal period of amoxicillin sodium from muscle of olive flounder was about 8 days at 40 mg/kg b.w. fish (at 22 +/- 1 degrees C). These results demonstrated a single intramuscular administration of amoxicillin sodium to be effective against streptococcosis in olive flounder. PMID- 27226028 TI - The time-of-day of myocardial infarction onset affects healing through oscillations in cardiac neutrophil recruitment. AB - Myocardial infarction (MI) is the leading cause of death in Western countries. Epidemiological studies show acute MI to be more prevalent in the morning and to be associated with a poorer outcome in terms of mortality and recovery. The mechanisms behind this association are not fully understood. Here, we report that circadian oscillations of neutrophil recruitment to the heart determine infarct size, healing, and cardiac function after MI Preferential cardiac neutrophil recruitment during the active phase (Zeitgeber time, ZT13) was paralleled by enhanced myeloid progenitor production, increased circulating numbers of CXCR2(hi) neutrophils as well as upregulated cardiac adhesion molecule and chemokine expression. MI at ZT13 resulted in significantly higher cardiac neutrophil infiltration compared to ZT5, which was inhibited by CXCR2 antagonism or neutrophil-specific CXCR2 knockout. Limiting exaggerated neutrophilic inflammation at this time point significantly reduced the infarct size and improved cardiac function. PMID- 27226031 TI - Total Syntheses of Isowondonins Based on a Biosynthetic Pathway. AB - The first total syntheses of (-)-isowondonin A and (-)-isowondonin B, which are unusual imidazole marine alkaloids, has been accomplished through the development of methods for the selective formation of styryl sulfate group and regioselective alkylation of the imidazole. Application of the Noyori asymmetric hydrogenation of ketones allows the asymmetric synthesis. These results in conjunction with ECD calculations led to the determination of the absolute configuration of isowondonins. PMID- 27226032 TI - Sedimentitalea todarodis sp. nov., isolated from the intestinal tract of a Japanese flying squid. AB - A novel Gram-stain-negative, motile, aerobic and rod-shaped alphaproteobacterium, designated strain KHS03T, was isolated from the intestinal tract of a Japanese flying squid, Todarodes pacificus, which was collected from the East Sea, Korea. The new isolate shared 97.4 % 16S rRNA gene sequence similarity with Sedimentitalea nanhaiensis NH52FT. The isolate grew optimally at 25 degrees C and pH 7 in the presence of 1-2 % (w/v) NaCl, and had an absolute requirement of sodium ions for growth. The major cellular fatty acid was C18 : 1omega7c. The primary isoprenoid quinone was ubiquinone-10. Polar lipids comprised diphosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, an unidentified aminolipid and two unidentified lipids. Genotypic analyses indicated that the whole genomic DNA of the isolate had a G+C content of 59.9 mol%. DNA-DNA hybridization showed that the isolate shared 17.1+/ 2.3 % (reciprocal 17.0+/-1.9 %) genomic relatedness with the closest related type strain, S. nanhaiensis NH52FT. Strain KHS03T is thus suggested to represent a novel species of the genus Sedimentitalea, for which the name Sedimentitalea todarodis sp. nov. is proposed. The type strain is KHS03T (=KCTC 42412T=JCM 31160T). PMID- 27226033 TI - Clinical Phenotypes of Fontan Failure: Implications for Management. AB - Fontan failure has been variably and inconsistently described in the literature, leading to challenges in comparing studies and evaluating treatments. Development of a conceptual framework to describe clinical phenotypes will aid in consistent terminology in the literature. In the heart failure literature, several key concepts have been described-"heart failure" is a clinical syndrome of various etiologies, with phenotype-specific response to therapies. As the congenital heart disease community struggles to grapple with "Fontan failure," these concepts come to light. Fontan failure in the context of four clinical phenotypes, including evaluation, potential management strategies, and future directions is discussed. PMID- 27226034 TI - An Easily Accessible Self-Healing Transparent Film Based on a 2D Supramolecular Network of Hydrogen-Bonding Interactions between Polymeric Chains. AB - Self-healing polymers hold great promise for the future, enhancing in particular the longevity of polymeric materials. We describe a self-healing covalent polymer, presenting an extensive array of hydrogen-bonding sites based on the combination of urea, urethane, and bis-acyl-hydrazine units. Solvent-cast thin films prepared by polycondensation of a commercially available dihydrazide and a diisocyanate prepolymer exhibited excellent room temperature autonomous healing with almost full recovery of mechanical properties when two parts of a cut film were overlapped and gently pressed together. This autonomous healing upon damage may be attributed to the supramolecular dynamics of multiple lateral inter-chain hydrogen-bonding interactions between the polymer chains. The solid-state structure of a model compound incorporating the same structural backbone corroborates the existence of an extensive two-dimensional supramolecular hydrogen-bonding network. PMID- 27226035 TI - Intracellular Delivery: Diamond-Nanoneedle-Array-Facilitated Intracellular Delivery and the Potential Influence on Cell Physiology (Adv. Healthcare Mater. 10/2016). AB - G. Zhu, W. Zhang, X. Chen, and co-workers show on page 1157 that diamond needle arrays can efficiently deliver biomolecules into living cells. The study paves the way to a wide application of the nanonneedle treatment by systematically investigating the influence of the treatment on metabolic signal pathways. PMID- 27226038 TI - Cancer Immunotherapy: Comprehensive Mechanism Analysis of Mesoporous-Silica Nanoparticle-Induced Cancer Immunotherapy (Adv. Healthcare Mater. 10/2016). AB - A plain mesoporous silica (MS) nanoparticle without any immunomodulatory molecules enhances anti-cancer immunity in vivo. On page 1169, X.P. Wang, N. M. Tsuji, A. Ito and co-workers show that a plain MS nanoparticle promotes both Th1 and Th2 immune responses, and enhances the effector memory of CD4(+) and CD8(+) T cell populations in the three most important immune organs (bone marrow, lymph node and spleen) of mice. PMID- 27226037 TI - Pigmented Silk Nanofibrous Composite for Skeletal Muscle Tissue Engineering. AB - Skeletal muscle tissue engineering (SMTE) employs designed biomaterial scaffolds for promoting myogenic differentiation of myoblasts to functional myotubes. Oxidative stress plays a significant role in the biocompatibility of biomaterials as well as in the fate of myoblasts during myogenesis and is also associated with pathological conditions such as myotonic dystrophy. The inherent electrical excitability of muscle cells inspired the use of electroactive scaffolds for SMTE. Conducting polymers attracted the attention of researchers for their use in muscle tissue engineering. However, poor biocompatibility, biodegradability and development of oxidative stress associated immunogenic response limits the extensive use of synthetic conducting polymers for SMTE. In order to address the limitations of synthetic polymers, intrinsically electroactive and antioxidant silk fibroin/melanin composite films and electrospun fiber mats were fabricated and evaluated as scaffolds for promoting myogenesis in vitro. Melanin incorporation modulated the thermal stability, electrical conductivity of scaffolds, fiber alignment in electrospun mats and imparted good antioxidant properties to the scaffolds. The composite electrospun scaffolds promoted myoblast assembly and differentiation into uniformly aligned high aspect ratio myotubes. The results highlight the significance of scaffold topography along with conductivity in promoting myogenesis and the potential application of silk nanofibrous composite as electoractive platform for SMTE. PMID- 27226040 TI - Hyperglycemia induced structural and functional changes in human serum albumin of diabetic patients: a physico-chemical study. AB - Structural and functional changes in albumin are of particular interest as numerous studies in vivo have reported a strong involvement of glycated-HSA in the development and progression of chronic diabetic complications. Non-enzymatic addition of glucose molecules to a protein induces structural changes in it. These changes depend on the degree of glycation. In this study, conformational changes in glycated-HSA and its antioxidant capacity were evaluated. HSA was purified from diabetic patients with/without CKD and healthy subjects. Glycation induced an increase in the molecular mass of HSA as determined by mass spectroscopy. Further secondary and tertiary structural changes were observed by UV, circular dichroism (CD) spectroscopy, Fourier transform infrared spectroscopy (FTIR), tryptophan and 1-anilinonaphthalene-8-sulfonic acid (ANS) fluorescence. The mean alpha-helix content was found to be 59.46% for normal HSA and it was reduced down to 45.63% in HSA isolated from diabetic patients without CKD and to 37.48% in CKD-HSA. FTIR analysis showed Amide I and Amide II band shifting in HSA of diabetic patients without and with CKD. These findings indicate the secondary structure changes in glycated HSA. The tertiary structure is also affected by in vivo glycation as confirmed by intrinsic fluorescence and ANS fluorescence results. Consequently, these structural changes associated with glycation provoked a reduction in the free thiol group and a strong increment of protein carbonyl contents and the fructosamine level in glycated HSA. Antioxidant activity was evaluated by a RBC hemolysis test. The result indicates that the free radical scavenging capacities of HSA were decreased in diabetic patients with or without CKD. Our study revealed that structural and functional features of glycated HSA, isolated from diabetic patients with and without CKD were significantly different from the HSA isolated from non-diabetic subjects. Moreover these changes were more prominent in HSA isolated from diabetic patients with CKD. These findings suggest that active sites of HSA may not be available under extensive glycation, leading to the impairment of its important functions. Thus glycated HSA may be involved in the pathogenesis of diabetes and its complications such as chronic kidney disease. PMID- 27226042 TI - Metal-organic framework UiO-67-coated fiber for the solid-phase microextraction of nitrobenzene compounds from water. AB - A sol-gel coating technique was applied for the preparation of a solid-phase microextraction fiber by coating the metal-organic framework UiO-67 onto a stainless-steel wire. The prepared fiber was explored for the headspace solid phase microextraction of five nitrobenzene compounds from water samples before gas chromatography with mass spectrometric detection. The effects of the extraction temperature, extraction time, sample solution volume, salt addition, and desorption conditions on the extraction efficiency were optimized. Under the optimal conditions, the linearity was observed in the range of 0.015-12.0 MUg/L for the compounds in water samples, with the correlation coefficients (r) of 0.9945-0.9987. The limits of detection of the method were 5.0-10.0 ng/L, and the recoveries of the analytes from spiked water samples for the method were in the range of 74.0-102.0%. The precision for the measurements, expressed as the relative standard deviation, was less than 11.9%. PMID- 27226043 TI - New Innovative Technologies Changing Cytology. 19th International Congress of Cytology. Yokohama, Japan, May 29-June 1, 2016: Abstracts. PMID- 27226044 TI - Control of the mechanical strength of a bipyridine-based polymeric gel from linear nanofibre to helix with a chiral dopant. AB - A mixture of building blocks 1 and 2 having hydrazine moieties and aldehyde moieties, respectively, formed a gel by a hydrazone reaction in the absence and presence of cyclohexane diamines as chiral dopants and Fe(2+). In particular, the mechanical strength of the helical gel prepared from 1 and 2 in the presence of a chiral dopant and Fe(2+) was ca. 10-fold stronger as compared to that of the gel prepared from the building blocks 1 and 2 without a chiral dopant and Fe(2+). The improved mechanical strength was attributed to the formation of a helix. The results indicate that the mechanical strength of gels obtained by hydrazone reaction could be controlled by a chiral dopant and Fe(2+). PMID- 27226045 TI - Pragmatic inferences in context: learning to interpret contrastive prosody. AB - Can preschoolers make pragmatic inferences based on the intonation of an utterance? Previous work has found that young children appear to ignore intonational meanings and come to understand contrastive intonation contours only after age six. We show that four-year-olds succeed in interpreting an English utterance, such as "It LOOKS like a zebra", to derive a conversational implicature, namely [but it isn't one], as long as they can access a semantically stronger alternative, in this case "It's a zebra". We propose that children arrive at the implicature by comparing such contextually provided alternatives. Contextually leveraged inferences generalize across speakers and contexts, and thus drive the acquisition of intonational meanings. Our findings show that four year-olds and adults are able to bootstrap their interpretation of the contrast marking intonation by taking into account alternative utterances produced in the same context. PMID- 27226046 TI - CuO Nanoparticle Interaction with Arabidopsis thaliana: Toxicity, Parent-Progeny Transfer, and Gene Expression. AB - CuO nanoparticles (NPs) (20, 50 mg L(-1)) inhibited seedling growth of different Arabidopsis thaliana ecotypes (Col-0, Bay-0, and Ws-2), as well as the germination of their pollens and harvested seeds. For most of growth parameters (e.g., biomass, relative growth rate, root morphology change), Col-0 was the more sensitive ecotype to CuO NPs compared to Bay-0 and Ws-2. Equivalent Cu(2+) ions and CuO bulk particles had no effect on Arabidopsis growth. After CuO NPs (50 mg L(-1)) exposure, Cu was detected in the roots, leaves, flowers and harvested seeds of Arabidopsis, and its contents were significantly higher than that in CuO bulk particles (50 mg L(-1)) and Cu(2+) ions (0.15 mg L(-1)) treatments. Based on X-ray absorption near-edge spectroscopy analysis (XANES), Cu in the harvested seeds was confirmed as being mainly in the form of CuO (88.8%), which is the first observation on the presence of CuO NPs in the plant progeny. Moreover, after CuO NPs exposure, two differentially expressed genes (C-1 and C-3) that regulated root growth and reactive oxygen species generation were identified, which correlated well with the physiological root inhibition and oxidative stress data. This current study provides direct evidence for the negative effects of CuO NPs on Arabidopsis, including accumulation and parent-progeny transfer of the particles, which may have significant implications with regard to the risk of NPs to food safety and security. PMID- 27226047 TI - Primer Part 1-The building blocks of epilepsy genetics. AB - This is the first of a two-part primer on the genetics of the epilepsies within the Genetic Literacy Series of the Genetics Commission of the International League Against Epilepsy. In Part 1, we cover the foundations of epilepsy genetics including genetic epidemiology and the range of genetic variants that can affect the risk for developing epilepsy. We discuss various epidemiologic study designs that have been applied to the genetics of the epilepsies including population studies, which provide compelling evidence for a strong genetic contribution in many epilepsies. We discuss genetic risk factors varying in size, frequency, inheritance pattern, effect size, and phenotypic specificity, and provide examples of how genetic risk factors within the various categories increase the risk for epilepsy. We end by highlighting trends in epilepsy genetics including the increasing use of massive parallel sequencing technologies. PMID- 27226048 TI - Skin sample preparation by collagenase digestion for diclofenac quantification using LC-MS/MS after topical application. AB - BACKGROUND: Skin is the target site to evaluate the pharmacokinetic parameters of topical applications. Sample preparation is one of the influential steps in the bioanalysis of drugs in the skin. Evaluation of dermatopharmacokinetics at preclinical stage is challenging due to lack of proper sample preparation method. There is a need for an efficient sample preparation procedure for quantification of drugs in the skin using LC-MS/MS. RESULTS: The skin samples treated with collagenase followed by homogenization using a bead beater represents a best-fit method resulting in uniform homogenate for reproducible results. CONCLUSION: A new approach involving enzymatic treatment and mechanical homogenization techniques were evaluated for efficient sample preparation of skin samples in the bioanalysis. PMID- 27226049 TI - Quantization Effects on Complex Networks. AB - Weights of edges in many complex networks we constructed are quantized values of the real weights. To what extent does the quantization affect the properties of a network? In this work, quantization effects on network properties are investigated based on the spectrum of the corresponding Laplacian. In contrast to the intuition that larger quantization level always implies a better approximation of the quantized network to the original one, we find a ubiquitous periodic jumping phenomenon with peak-value decreasing in a power-law relationship in all the real-world weighted networks that we investigated. We supply theoretical analysis on the critical quantization level and the power laws. PMID- 27226050 TI - Bullous erythema ab igne with cutaneous reactive angiomatosis. PMID- 27226052 TI - Residents'corner March-April 2016. Editorial: What's new this month? PMID- 27226051 TI - A female case of Fox-Fordyce disease. PMID- 27226053 TI - Dermpath & Clinic: Zosteriform Lichen aureus. PMID- 27226054 TI - Seriously saRComa! The different faces of angiosarcoma. PMID- 27226056 TI - Erratum. PMID- 27226055 TI - sQuiz your knowledge: multiple erythematous-violaceous plaques and nodules in a patient with acute myeloid leukaemia. PMID- 27226057 TI - Case with pyoderma gangrenosum abruptly emerging around the wound of cesarean section for placenta previa with placenta accrete. AB - A 39-year-old woman underwent emergency cesarean section (CS) due to placenta previa totalis with massive bleeding. Two major problems emerged in this patient after CS was carried out. One was partial retention of the placenta due to placenta accreta. Another major and more serious problem was pyoderma gangrenosum (PG) widely appearing at the skin of the abdomen around the CS wound. Conservative treatment was performed for the retained placenta, and it had completely disappeared by 76 days after the CS. The diagnosis of PG was promptly made in consultation with a plastic surgeon and a dermatologist when a wide ulcer emerged around the CS wound, and high-dose prednisolone was administered as treatment. At 90 days following the CS, near-complete epithelialization was achieved. This extremely rare case reflects the importance of rapid diagnosis and treatment of PG. PMID- 27226058 TI - Glucocorticoid receptor isoforms direct distinct mitochondrial programs to regulate ATP production. AB - The glucocorticoid receptor (GR), a nuclear receptor and major drug target, has a highly conserved minor splice variant, GRgamma, which differs by a single arginine within the DNA binding domain. GRgamma, which comprises 10% of all GR transcripts, is constitutively expressed and tightly conserved through mammalian evolution, suggesting an important non-redundant role. However, to date no specific role for GRgamma has been reported. We discovered significant differences in subcellular localisation, and nuclear-cytoplasmic shuttling in response to ligand. In addition the GRgamma transcriptome and protein interactome was distinct, and with a gene ontology signal for mitochondrial regulation which was confirmed using Seahorse technology. We propose that evolutionary conservation of the single additional arginine in GRgamma is driven by a distinct, non-redundant functional profile, including regulation of mitochondrial function. PMID- 27226059 TI - MOLECULAR CHARACTERIZATION OF AUTOPHAGY-RELATED GENE 5 FROM Spodoptera exigua AND EXPRESSION ANALYSIS UNDER VARIOUS STRESS CONDITIONS. AB - Autophagy is not only involved in development, but also has been proved to attend immune response against invading pathogens. Autophagy protein 5 (ATG5) is an important autophagic protein, which plays a crucial role in autophagosome elongation. Although ATG5 has been well studied in mammal, yeast, and Drosophila, little is known about ATG5 in lepidopteran insects. We cloned putative SeAtg5 gene from Spodoptera exigua larvae by the rapid amplification of cDNA ends method, and its characteristics and the influences of multiple exogenous factors on its expression levels were then investigated. The results showed that the putative S. exigua SeATG5 protein is highly homologous to other insect ATG5 proteins, which has a conserved Pfm domain and multiple phosphorylation sites. Next, fluorescence microscope observation showed that mCherry-SeATG5 was distributed in both nucleus and cytoplasm of Spodoptera litura Sl-HP cells and partially co-localized with BmATG6-GFP, but it almost has no significant co localization with GFP-HaATG8. Then, the Western blot analysis demonstrated that GFP-SeATG5 conjugated with ATG12. Moreover, real-time PCR revealed that its expression levels significantly increased at the initiation of pupation and the stage of adult. In addition, the expression levels of SeAtg5 can be enhanced by the starvation, UV radiation, and infection of baculovirus and bacterium. However, the expression levels of SeAtg5 decreased at 24 h post treatments in all these treatments except in starvation. These results suggested that SeATG5 might be involved in response of S. exigua under various stress conditions. PMID- 27226060 TI - Revisiting the metastatic potential of childhood pineal parenchymal tumor of intermediate differentiation: a case report. PMID- 27226062 TI - Editorial Comment to Penile erection induces angiogenic, survival, and antifibrotic signals: Molecular events associated with penile erection induced by cavernous nerve stimulation in mice. PMID- 27226061 TI - Traumatic atlanto-occipital dislocation: do children and adolescents have better or worse outcomes than adults? A narrative review. AB - BACKGROUND: Traumatic atlanto-occipital dislocation is an uncommon, severely unstable pathology, which can lead to detrimental or even fatal neurological impairment. Specifically, children have consistently been reported to be more susceptible to this type of injury because of their disproportionately larger head, ligament laxity, and injury mechanisms. However, to date, rates of missed injury and outcomes including neurologic recovery of pediatric and adult populations following this insult have not been comparatively evaluated. METHODS: Standard search engines were used to investigate outcomes of traumatic atlanto occipital dislocation in children and adolescents compared to adults. CONCLUSIONS: Based on case reports and small series from the literature, it seems that children and adolescents tend to have a better likelihood of survival with the possibility of long-term neurological complications. Comparatively, adults who suffer traumatic atlanto-occipital dislocation either succumb to their injuries or survive with very little if any neurological complications. PMID- 27226063 TI - Prevalence of polyoma BK virus infection among living-donor renal transplant recipients. AB - BACKGROUND: Polyomavirus nephropathy (PVN) mainly caused by BK polyomavirus (BKPyV) remains the most common productive viral infection of the kidney in immunosuppressed patients. The diagnosis of PVN is based on the detection of BK viruria and BK viremia in conjunction with histological findings in the graft biopsy. METHODS: Our study was aimed to estimate the prevalence of productive BKPyV infection among renal transplant patients within the first year post transplant and identify those at risk of developing PVN. Our cross-sectional study was conducted on 134 kidney transplant patients. Evidence of BKPyV replication was assessed by viral quantification of blood and urine samples of studied patients using a quantitative real-time polymerase chain reaction (Q PCR)PCR), detection of decoy cells in urine cytology smears, histological examination of graft biopsies from Q-PCR BKPyV-positive patients, and immunohistochemical staining by simian virus 40 (SV40) antibody. RESULTS: Significant BKPyV infection was prevalent in 8% (n = 11) of our patients, with a peak of BKPyV infection about 8 months post transplant. BKPyV viral load by Q-PCR assay in these patients varied from 1350 to 20,000,000 (1.35 * 10(3) to 2 * 10(7) ) copies/mL for urine samples and 935 to 18,920 (9.35 * 10(2) to 1.89 * 10(4) ) copies/mL for blood samples. All the 11 patients were positive for decoy cells but only 3 developed PVN based on histology and positive SV40 staining. BKPyV infection was more prevalent in older patients. All patients responded to reduction in their immunosuppressive regimens, apart from 2 patients who required replacement of calcineurin inhibitors-based regimen with mammalian target of ramapycin inhibitors with an overall good response. CONCLUSION: Protocol screening programs based on detection of viral replication by viruria, viremia, and decoy cells in urine are necessary to shed light on patients with high virus replication and hence increased risk of developing PVN, and to allow early diagnosis and intervention. PMID- 27226064 TI - Morphological effects of porous poly-d,l-lactic acid/hydroxyapatite scaffolds produced by supercritical CO2 foaming on their mechanical performance. AB - A novel supercritical CO2 foaming technique was used to fabricate scaffolds of controllable morphology and mechanical properties, with the potential to tailor the scaffolds to specific tissue engineering applications. Biodegradable scaffolds are widely used as temporary supportive structures for bone regeneration. The scaffolds must provide a sufficient mechanical support while allowing cell attachment and growth as well as metabolic activities. In this study, supercritical CO2 foaming was used to prepare fully interconnected porous scaffolds of poly-d,l-lactic acid and poly-d,l-lactic acid/hydroxyapatite. The morphological, mechanical and cell behaviours of the scaffolds were measured to examine the effect of hydroxyapatite on these properties. These scaffolds showed an average porosity in the range of 86%-95%, an average pore diameter of 229-347 um and an average pore interconnection of 103-207 um. The measured porosity, pore diameter, and interconnection size are suitable for cancellous bone regeneration. Compressive strength and modulus of up to 36.03 +/- 5.90 and 37.97 +/- 6.84 MPa were measured for the produced porous scaffolds of various compositions. The mechanical properties presented an improvement with the addition of hydroxyapatite to the structure. The relationship between morphological and mechanical properties was investigated. The matrices with different compositions were seeded with bone cells, and all the matrices showed a high cell viability and biocompatibility. The number of cells attached on the matrices slightly increased with the addition of hydroxyapatite indicating that hydroxyapatite improves the biocompatibility and proliferation of the scaffolds. The produced poly-d,l-lactic acid/hydroxyapatite scaffolds in this study showed a potential to be used as bone graft substitutes. PMID- 27226065 TI - De Ritis ratio (aspartate transaminase/alanine transaminase ratio) as a significant prognostic factor after surgical treatment in patients with clear cell localized renal cell carcinoma: a propensity score-matched study. AB - OBJECTIVE: To evaluate the associations of preoperative De Ritis ratio (aspartate transaminase [AST]/alanine transaminase [ALT]) with postoperative clinical outcomes after surgical treatment of localized RCC. MATERIALS AND METHODS: We retrospectively reviewed data from 2 965 patients surgically treated for non metastatic RCC. Propensity scores for high AST/ALT ratio were calculated and 430 patients with a high AST/ALT ratio were matched to 1 117 patients with a low AST/ALT ratio. The association between AST/ALT ratio and postoperative outcomes was tested. Multivariate Cox analyses were performed to identify the independent predictors of progression-free (PFS), overall (OS) and cancer-specific survival (CSS). RESULTS: According to the receiver-operating curve of AST/ALT for cancer specific mortality, we stratified the patients into two groups using a threshold of 1.5. Before matching, patients with a high AST/ALT ratio had worse PFS, OS and CSS (all P < 0.001). In the propensity score-matched cohort with 1 547 patients, patients with a high AST/ALT ratio had inferior PFS, OS and CSS outcomes (all P < 0.001). Multivariate analysis showed that a high AST/ALT ratio was an independent predictor of disease progression (hazard ratio [HR] 1.372, 95% CI 1.003-1.882; P = 0.048), overall mortality (HR 1.559, 95% CI 1.069-2.272; P = 0.021), and cancer specific mortality (HR 1.974, 95% CI 1.250-3.118; P = 0.004). In a subgroup analysis according to tumour histology, high AST/ALT had a significant association with postoperative survival in clear-cell renal cell carcinoma (RCC), but not in non-clear-cell RCC. CONCLUSION: An elevated AST/ALT ratio was significantly associated with worse postoperative survival in patients surgically treated for localized clear-cell RCC. Further prospective studies are needed to understand the prognostic value of preoperative AST/ALT ratio. PMID- 27226066 TI - Unraveling Unprecedented Charge Carrier Mobility through Structure Property Relationship of Four Isomers of Didodecyl[1]benzothieno[3,2-b][1]benzothiophene. AB - The structural and electronic properties of four isomers of didodecyl[1] benzothieno[3,2-b][1]benzothiophene (C12-BTBT) have been investigated. Results show the strong impact of the molecular packing on charge carrier transport and electronic polarization properties. Field-induced time-resolved microwave conductivity measurements unravel an unprecedented high average interfacial mobility of 170 cm(2) V(-1) s(-1) for the 2,7-isomer, holding great promise for the field of organic electronics. PMID- 27226067 TI - Geographic origin influences the phenolic composition and antioxidant potential of wild Crataegus monogyna from Spain. AB - CONTEXT: Crataegus monogyna Jacq L. (Lind.) (Rosaceae) is used in folk medicine as a sedative, aerial parts being rich in polyphenols with antioxidant ability. OBJECTIVES: To study the variation in polyphenolic composition and antioxidant ability of spontaneous samples of C. monogyna in order to assess the relationship among these variables. MATERIALS AND METHODS: Aerial parts of C. monogyna were collected from nine different locations in central Spain and extracted with methanol after drying. Total polyphenols were determined by the Folin-Ciocalteu method using gallic acid (GA) as standard. Sixteen polyphenolic compounds (11 flavonoids and 5 phenolic acids) were identified and quantified by reversed-phase HPLC in one single analysis. The antioxidant ability was evaluated by the oxygen radical absorbance capacity (ORAC) and the free radical scavenging activity (DPPH) methods. Linear correlation analysis was used to explore the relationships between the studied variables. RESULTS: Total polyphenol content ranged between 117.729 +/- 0.011 and 204.286 +/- 0.015 mg GAE/g extract, depending on the geographic origin. No relationship was found between total polyphenols and antioxidant ability by the ORAC or DPPH methods. Chromatographic analysis yielded lower amounts of polyphenols (23.3-143.26 mg/kg), as only flavonoids and phenolic acids were quantified. All the samples exhibited antioxidant activity between 1.32 +/- 0.08 and 2.76 +/- 0.007 MUmol Trolox equivalents/mg and IC50 from 0.82 +/- 0.10 to 3.76 +/- 0.67 MUg/mL. CONCLUSION: A statistically significant relationship between flavonoids and phenolic acids content and the antioxidant potential obtained by the ORAC method for C. monogyna samples was proven. PMID- 27226068 TI - Graphical approaches using a Bonferroni mixture of weighted Simes tests. AB - Graphical approaches to multiple testing procedures are very flexible and easy to communicate with non-statisticians. The availability of the R package gMCP further propelled the application of graphical approaches in randomized clinical trials. Bretz et al. (Biometrical Journal 2011; 53:894-913) introduced a class of nonparametric testing procedures based on a Bonferroni mixture of weighted Simes tests for intersection hypotheses. Such approaches are extremely useful when the conditions for the Simes test are known to hold for hypotheses within certain subsets but may not hold for hypotheses across subsets. We describe the calculation of adjusted p-values for such approaches, which is currently not available in the gMCP package. We also optimize the generation of the weights for each intersection hypothesis in the closure of a graph-based multiple testing procedure, which can dramatically reduce the computing time for simulation-based power calculations. We show the validity of the Simes test for comparing several treatments with a control, performing noninferiority and superiority tests, or testing the treatment effect in an overall and a subpopulation for the normal, binary, count, and time-to-event data. The proposed method is illustrated using an example for designing a confirmatory clinical trial. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27226069 TI - Routine invasive strategies versus selective invasive strategies for unstable angina and non-ST elevation myocardial infarction in the stent era. AB - BACKGROUND: People with unstable angina and non-ST elevation myocardial infarction (UA/NSTEMI) are managed with a combination of medical therapy, invasive angiography and revascularisation. Specifically, two approaches have evolved: either a 'routine invasive' strategy whereby all patients undergo coronary angiography shortly after admission and, if indicated, coronary revascularisation; or a 'selective invasive' (also referred to as 'conservative') strategy in which medical therapy alone is used initially, with a selection of patients for angiography based upon evidence of persistent myocardial ischaemia. Uncertainty exists as to which strategy provides the best outcomes for these patients. This Cochrane review is an update of a Cochrane review originally published in 2006, to provide a robust comparison of these two strategies in the early management of patients with UA/NSTEMI. OBJECTIVES: To determine the benefits and harms associated with the following.1. A routine invasive versus a conservative or 'selective invasive' strategy for the management of UA/NSTEMI in the stent era.2. A routine invasive strategy with and without glycoprotein IIb/IIIa receptor antagonists versus a conservative strategy for the management of UA/NSTEMI in the stent era. SEARCH METHODS: We searched the following databases and additional resources up to 25 August 2015: the Cochrane Central Register of Controlled Trials (CENTRAL) on the Cochrane Library, MEDLINE and EMBASE, with no language restrictions. SELECTION CRITERIA: We included prospective randomised controlled trials (RCTs) that compared invasive with conservative or 'selective invasive' strategies in participants with acute UA/NSTEMI. DATA COLLECTION AND ANALYSIS: Two review authors screened the records and extracted data in duplicate. Using intention-to-treat analysis with random effects models, we calculated summary estimates of the risk ratio (RR) with 95% confidence intervals (CIs) for the primary endpoints of all-cause death, fatal and non-fatal myocardial infarction (MI), combined all-cause death or non-fatal MI, refractory angina and re-hospitalisation. We performed further analysis of included studies based on whether glycoprotein IIb/IIIa receptor antagonists were used routinely. We assessed the heterogeneity of included trials using Pearson chi2 (Chi2 test) and variance (I2 statistic) analysis. Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, we assessed the quality of the evidence and the GRADE profiler (GRADEPRO) was used to import data from Review Manager 5.3 (Review Manager) to create Summary of findings (SoF) tables. MAIN RESULTS: Eight RCTs with a total of 8915 participants (4545 invasive strategies, 4370 conservative strategies) were eligible for inclusion. We included three new studies and 1099 additional participants in this review update. In the all-study analysis, evidence did not show appreciable risk reductions in all-cause mortality (RR 0.87, 95% CI 0.64 to 1.18; eight studies, 8915 participants; low quality evidence) and death or non-fatal MI (RR 0.93, 95% CI 0.71 to 1.2; seven studies, 7715 participants; low quality evidence) with invasive strategies compared to conservative (selective invasive) strategies at six to 12 months follow-up. There was appreciable risk reduction in MI (RR 0.79, 95% CI 0.63 to 1.00; eight studies, 8915 participants; moderate quality evidence), refractory angina (RR 0.64, 95% CI 0.52 to 0.79; five studies, 8287 participants; moderate quality evidence) and re-hospitalisation (RR 0.77, 95% CI 0.63 to 0.94; six studies, 6921 participants; moderate quality evidence) with routine invasive strategies compared to conservative (selective invasive) strategies also at six to 12 months follow-up.Evidence also showed increased risks in bleeding (RR 1.73, 95% CI 1.30 to 2.31; six studies, 7584 participants; moderate quality evidence) and procedure-related MI (RR 1.87, 95% CI 1.47 to 2.37; five studies, 6380 participants; moderate quality evidence) with routine invasive strategies compared to conservative (selective invasive) strategies.The low quality evidence were as a result of serious risk of bias and imprecision in the estimate of effect while moderate quality evidence was only due to serious risk of bias. AUTHORS' CONCLUSIONS: In the all-study analysis, the evidence failed to show appreciable benefit with routine invasive strategies for unstable angina and non-ST elevation MI compared to conservative strategies in all-cause mortality and death or non-fatal MI at six to 12 months. There was evidence of risk reduction in MI, refractory angina and re-hospitalisation with routine invasive strategies compared to conservative (selective invasive) strategies at six to 12 months follow-up. However, routine invasive strategies were associated with a relatively high risk (almost double the risk) of procedure-related MI, and increased risk of bleeding complications. This systematic analysis of published RCTs supports the conclusion that, in patients with UA/NSTEMI, a selectively invasive (conservative) strategy based on clinical risk for recurrent events is the preferred management strategy. PMID- 27226070 TI - Clinical Value and Practical Worth of Repeated Measurements of Vascular Biomarkers in End-Stage Renal Disease. PMID- 27226071 TI - Modification of Ni-Rich FCG NMC and NCA Cathodes by Atomic Layer Deposition: Preventing Surface Phase Transitions for High-Voltage Lithium-Ion Batteries. AB - The energy density of current lithium-ion batteries (LIBs) based on layered LiMO2 cathodes (M = Ni, Mn, Co: NMC; M = Ni, Co, Al: NCA) needs to be improved significantly in order to compete with internal combustion engines and allow for widespread implementation of electric vehicles (EVs). In this report, we show that atomic layer deposition (ALD) of titania (TiO2) and alumina (Al2O3) on Ni rich FCG NMC and NCA active material particles could substantially improve LIB performance and allow for increased upper cutoff voltage (UCV) during charging, which delivers significantly increased specific energy utilization. Our results show that Al2O3 coating improved the NMC cycling performance by 40% and the NCA cycling performance by 34% at 1 C/-1 C with respectively 4.35 V and 4.4 V UCV in 2 Ah pouch cells. High resolution TEM/SAED structural characterization revealed that Al2O3 coatings prevented surface-initiated layered-to-spinel phase transitions in coated materials which were prevalent in uncoated materials. EIS confirmed that Al2O3-coated materials had significantly lower increase in the charge transfer component of impedance during cycling. The ability to mitigate degradation mechanisms for Ni-rich NMC and NCA illustrated in this report provides insight into a method to enable the performance of high-voltage LIBs. PMID- 27226072 TI - Dynamic heterogeneity and non-Gaussian statistics for acetylcholine receptors on live cell membrane. AB - The Brownian motion of molecules at thermal equilibrium usually has a finite correlation time and will eventually be randomized after a long delay time, so that their displacement follows the Gaussian statistics. This is true even when the molecules have experienced a complex environment with a finite correlation time. Here, we report that the lateral motion of the acetylcholine receptors on live muscle cell membranes does not follow the Gaussian statistics for normal Brownian diffusion. From a careful analysis of a large volume of the protein trajectories obtained over a wide range of sampling rates and long durations, we find that the normalized histogram of the protein displacements shows an exponential tail, which is robust and universal for cells under different conditions. The experiment indicates that the observed non-Gaussian statistics and dynamic heterogeneity are inherently linked to the slow-active remodelling of the underlying cortical actin network. PMID- 27226074 TI - Improving oral health for older people in the home care setting: An exploratory implementation study. AB - AIM: To explore how home care providers can support older people to maintain good oral health through implementing a model called Better Oral Health in Home Care (BOHHC). METHODS: A mixed method, pre- to post-implementation design was used. The Promoting Action on Research Implementation in Health Services framework informed the model's implementation process. RESULTS: High levels of dental need were identified at pre-implementation. Older people self-reported significant oral health improvements following the introduction of tailored home care strategies by care workers, who in turn reported a better understanding and knowledge of the importance of oral care for older people. CONCLUSION: The BOHHC Model provided an evidence-based approach for community-based prevention and early detection of oral health problems. Improving oral health for older people in the home care setting has significant practice and policy implications which require ongoing intersectoral facilitation involving aged care, vocational health education and dental sectors. PMID- 27226075 TI - Dr. Marcus Brewster: A Tribute to a Leader within the Pharmaceutical Sciences. PMID- 27226073 TI - Prenatal ketamine exposure causes abnormal development of prefrontal cortex in rat. AB - Ketamine is commonly used for anesthesia and as a recreational drug. In pregnant users, a potential neurotoxicity in offspring has been noted. Our previous work demonstrated that ketamine exposure of pregnant rats induces affective disorders and cognitive impairments in offspring. As the prefrontal cortex (PFC) is critically involved in emotional and cognitive processes, here we studied whether maternal ketamine exposure influences the development of the PFC in offspring. Pregnant rats on gestational day 14 were treated with ketamine at a sedative dose for 2 hrs, and pups were studied at postnatal day 0 (P0) or P30. We found that maternal ketamine exposure resulted in cell apoptosis and neuronal loss in fetal brain. Upon ketamine exposure in utero, PFC neurons at P30 showed more dendritic branching, while cultured neurons from P0 PFC extended shorter neurites than controls. In addition, maternal ketamine exposure postponed the switch of NR2B/2A expression, and perturbed pre- and postsynaptic protein expression in the PFC. These data suggest that prenatal ketamine exposure impairs neuronal development of the PFC, which may be associated with abnormal behavior in offsprings. PMID- 27226076 TI - Cops2 promotes pluripotency maintenance by Stabilizing Nanog Protein and Repressing Transcription. AB - The COP9 signalosome has been implicated in pluripotency maintenance of human embryonic stem cells. Yet, the mechanism for the COP9 signalosome to regulate pluripotency remains elusive. Through knocking down individual COP9 subunits, we demonstrate that Cops2, but not the whole COP9 signalosome, is essential for pluripotency maintenance in mouse embryonic stem cells. Down-regulation of Cops2 leads to reduced expression of pluripotency genes, slower proliferation rate, G2/M cell cycle arrest, and compromised embryoid differentiation of embryonic stem cells. Cops2 also facilitates somatic cell reprogramming. We further show that Cops2 binds to Nanog protein and prevent the degradation of Nanog by proteasome. Moreover, Cops2 functions as transcriptional corepressor to facilitate pluripotency maintenance. Altogether, our data reveal the essential role and novel mechanisms of Cops2 in pluripotency maintenance. PMID- 27226077 TI - Generation of Equine-Induced Pluripotent Stem Cells and Analysis of Their Therapeutic Potential for Muscle Injuries. AB - Horse health has become a major concern with the expansion of horse-related industries and sports; the importance of healthy muscles for horse performance and daily activities is undisputed. Here we generated equine-induced pluripotent stem cells (E-iPSCs) by reprogramming equine adipose-derived stem cells (E-ADSCs) into iPSCs using a polycistronic lentiviral vector encoding four transcription factors (i.e., Oct4, Sox2, Klf4, and c-Myc) and then examined their pluripotent characteristics. Subsequently, established E-iPSCs were transplanted into muscle injured Rag/ mdx mice. The histopathology results showed that E-iPSC-transplanted mice exhibited enhanced muscle regeneration compared to controls. In addition, E iPSC-derived myofibers were observed in the injured muscles. In conclusion, we show that E-iPSCs could be successfully generated from equine ADSCs and transplanted into injured muscles and that E-iPSCs have the capacity to induce regeneration of injured muscles. PMID- 27226078 TI - Quantitative trait locus analysis of body shape divergence in nine-spined sticklebacks based on high-density SNP-panel. AB - Heritable phenotypic differences between populations, caused by the selective effects of distinct environmental conditions, are of commonplace occurrence in nature. However, the actual genomic targets of this kind of selection are still poorly understood. We conducted a quantitative trait locus (QTL) mapping study to identify genomic regions responsible for morphometric differentiation between genetically and phenotypically divergent marine and freshwater nine-spined stickleback (Pungitius pungitius) populations. Using a dense panel of SNP-markers obtained by restriction site associated DNA sequencing of an F2 recombinant cross, we found 22 QTL that explained 3.5-12.9% of phenotypic variance in the traits under investigation. We detected one fairly large-effect (PVE = 9.6%) QTL for caudal peduncle length-a trait with a well-established adaptive function showing clear differentiation among marine and freshwater populations. We also identified two large-effect QTL for lateral plate numbers, which are different from the lateral plate QTL reported in earlier studies of this and related species. Hence, apart from identifying several large-effect QTL in shape traits showing adaptive differentiation in response to different environmental conditions, the results suggest intra- and interspecific heterogeneity in the genomic basis of lateral plate number variation. PMID- 27226080 TI - The hidden impact of a healthy-worker effect on the results of the Diesel Exhaust in Miners Study. PMID- 27226079 TI - Association between seasonal factors and multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic inflammatory disease that affects the central nervous system. MS is causing progressive and relapsing neurological disability, due to demyelination and axonal damage. The etiopathogenesis of MS is poorly understood. A number of environmental factors have been previously suggested, including: month of birth, vitamin D levels, smoking and viral infections. Previous studies assessing seasonal variation of relapses in multiple sclerosis have had conflicting results. The aim of this review is to assess the association between seasonal factors and MS, in terms of disease onset, relapses and activity. PMID- 27226081 TI - Comparison of Cystatin C and NGAL in Early Diagnosis of Acute Kidney Injury After Heart Transplantation. AB - BACKGROUND Acute kidney injury (AKI) is a risk factor for adverse hospital outcomes in recipients of a heart transplantation (HTx). Timely recognition of AKI is crucial for the initiation of proper treatment. We hypothesized that serum or urine biomarkers can predict AKI. MATERIAL AND METHODS In this prospective study we evaluated 117 consecutive patients after HTx. AKI was defined as an increase of the serum creatinine level by >=50% or a worsening of the renal function requiring renal replacement therapy during the first post-HTx week. We serially sampled serum cystatin C (S-cystatin C) as a marker of glomerular filtration and urinary neutrophil gelatinase-associated lipocalin (U-NGAL) as a marker of tubular damage. RESULTS A cohort of 30 patients (25.6%) fulfilled the criteria of AKI. S-cystatin C allowed the earliest separation between the AKI and non-AKI groups, with a significant difference present as soon as 3 h after surgery and it persisted on days 7, 10, and 30. The increase in S-cystatin C preceded the serum creatinine elevation by 4 days. In a multivariate analysis, S cystatin C >1.6 mg/L at 3 h after HTx predicted AKI with OR 4.3 (95% CI: 1.6 11.5). U-NGAL was significantly higher at day 3 in the AKI group (p=0.003) and elevated S-cystatin C (>=2.54 mg/L on day 7) could predict 1-year mortality in these HTx recipients. CONCLUSIONS Our study showed that the measurement of S cystatin C at 3 h after surgery may help to identify patients with high risk for renal complications. A persistent elevation of S-cystatin C also predicts 1-year mortality. PMID- 27226082 TI - Vertically encoded tetragonal hydrogel microparticles for multiplexed detection of miRNAs associated with Alzheimer's disease. AB - Encoded hydrogel particles have attracted attention in diagnostics as these particles can be used for high-performance multiplexed assays. Here, we present encoded tetragonal hydrogel microparticles for multiplexed detection of miRNAs that are strongly related to Alzheimer's disease (AD). The particles are comprised of vertically distinct code and probe regions, and incorporated with quantum dots (QDs) in the code regions. By virtue of the particle geometry, the particles can be synthesized at a high production rate in vertically stacked micro-flows using hydrodynamic focusing lithography. To detect multiple AD miRNAs, various code labels to identify the loaded probes are designed by changing wavelengths of QDs, increasing the number of code layers and adjusting the thickness of code layers. The probe regions are incorporated with complementary sequences of target miRNAs, and optimized for accurate and timely detection of AD-miRNAs. For proof of concept, we demonstrate the multiplexed capability of the particles by performing a 3-plexed assay of AD-miRNAs. PMID- 27226083 TI - Corporate profile: Sangamo BioSciences, Inc. AB - Sangamo BioSciences, Inc., (CA, USA) is the pioneer and leader in the next phase of molecular medicine; genome editing. The company's proprietary platform is based on a human DNA-binding motif, the zinc finger DNA-binding protein (ZFP). Sangamo engineers ZFPs to bind to virtually any DNA sequence with exquisite specificity, making the platform uniquely suitable for therapeutic applications. Zinc finger nucleases can be designed to enable therapeutic genome editing, to knockout a gene or add a DNA sequence to an investigator-chosen site in the genome. The company is focused on developing novel ZFP Therapeutics((r)) as potentially curative therapies for genetic and infectious diseases, including hemophilia, lysosomal storage disorders, hemoglobinopathies and HIV/AIDS. Sangamo is the only company with human clinical trials of this novel technology. PMID- 27226085 TI - Protein translation occurs in platelet concentrates despite riboflavin/UV light pathogen inactivation treatment. AB - PURPOSE: Pathogen inactivation technologies (PITs) were introduced into blood banking to further improve the safety of blood products. However, the UV light used in PITs to terminate pathogen growth might alter the functionality of the cells in the blood product as well as the protein profile of the blood components. This study employed proteomic approaches to assess changes in the platelet proteome and translatome. EXPERIMENTAL DESIGN: Apheresis-derived platelet concentrates treated with riboflavin/UV light or untreated controls were analyzed throughout blood bank storage by quantitative proteomics using iTRAQ and puromycin-associated nascent chain (PUNCH) proteomics. RESULTS: Quantitative proteomic analysis identified 408 individual proteins including 26 unique proteins that changed in the treated arm during storage. Proteomic results were confirmed using immunoblot analyses and results suggested a translational control of the protein expression profile. PUNCH proteomic analysis of day 7 samples from illuminated units identified 52 unique platelet proteins that incorporated puromycin, including proteins involved in the cytoskeleton, metabolism, and signaling. CONCLUSION AND CLINICAL RELEVANCE: This study demonstrates for the first time that platelets can synthesize proteins despite the riboflavin and UV treatment and suggests that platelets may possess a mechanism to protect their mRNA from damage by the PI treatment. PMID- 27226084 TI - Controlled Release of Collagen-Binding SDF-1alpha Improves Cardiac Function after Myocardial Infarction by Recruiting Endogenous Stem Cells. AB - Stromal cell-derived factor-1alpha (SDF-1alpha) is a well-characterized chemokine that mobilizes stem cells homing to the ischemic heart, which is beneficial for cardiac regeneration. However, clinically administered native SDF-1alpha diffuses quickly, thus decreasing its local concentration, and results in side effects. Thus, a controlled release system for SDF-1alpha is required to produce an effective local concentration in the ischemic heart. In this study, we developed a recombinant chemokine, consisting of SDF-1alpha and a collagen-binding domain, which retains both the SDF-1alpha and collagen-binding activity (CBD-SDF-1alpha). In an in vitro assay, CBD-SDF-1alpha could specifically bind to a collagen gel and achieve sustained release. An intramyocardial injection of CBD-SDF-1alpha after acute myocardial infarction demonstrated that the protein was largely tethered in the ischemic area and that controlled release had been achieved. Furthermore, CBD-SDF-1alpha enhanced the recruitment of c-kit positive (c-kit(+)) stem cells, increased capillary density and improved cardiac function, whereas NAT-SDF-1alpha had no such beneficial effects. Our findings demonstrate that CBD SDF-1alpha can specifically bind to collagen and achieve controlled release both in vitro and in vivo. Local delivery of this protein could mobilize endogenous stem cells homing to the ischemic heart and improve cardiac function after myocardial infarction. PMID- 27226086 TI - Erratum to: Predictors of return to work following motor vehicle related orthopaedic trauma. PMID- 27226087 TI - Emotional health, support, and self-efficacy in young adults with a history of language impairment. AB - Children and adolescents with language impairment (LI) are at risk of emotional health difficulties. However, less is known about whether these difficulties continue into adulthood for this group, or about the potential role of environmental resources (e.g., social support) or internal resources (e.g., self efficacy). This study investigates emotional health in 81 adults with a history of developmental LI (aged 24) compared with 87 age-matched peers (AMPs) using Beck Inventories. Social support and self-efficacy measures were examined as predictors. The results were fourfold: (1) adults with LI had higher levels of emotional health problems; (2) whilst the availability of social support was similar across groups, people with LI received more help from others compared to peers; (3) social support was not significantly related to emotional health in those with LI - in contrast, for AMPs, uptake of support indicated poorer emotional health; (4) self-efficacy was the strongest predictor of emotional health in both groups and fully mediated the relationship between language and emotional health (no moderation by group). This cross-sectional study has implications for concurrent factors that might affect emotional health outcomes for children and young people with and without LI. PMID- 27226090 TI - Type I IFNs Regulate Inflammation, Vasculopathy, and Fibrosis in Chronic Cutaneous Graft-versus-Host Disease. AB - Type I IFNs play a critical role in the immune response to viral infection and may also drive autoimmunity through modulation of monocyte maturation and promotion of autoreactive lymphocyte survival. Recent demonstrations of type I IFN gene signatures in autoimmune diseases, including scleroderma, led us to investigate the pathological role of IFNs in a preclinical model of sclerodermatous graft-versus-host disease. Using a neutralizing Ab against the type I IFN receptor IFNAR1, we observed a marked reduction in dermal inflammation, vasculopathy, and fibrosis compared with that seen in the presence of intact IFNAR1 signaling. The ameliorative effects of IFNAR1 blockade were restricted to the skin and were highly associated with inhibition of chronic vascular injury responses and not due to the inhibition of the T or B cell alloresponse. Inhibition of IFNAR1 normalized the overexpression of IFN-inducible genes in graft-versus-host disease skin and markedly reduced dermal IFN-alpha levels. Depletion of plasmacytoid dendritic cells, a major cellular source of type I IFNs, did not reduce the severity of fibrosis or type I IFN gene signature in the skin. Taken together, these studies demonstrate an important role for type I IFN in skin fibrosis, and they provide a rationale for IFNAR1 inhibition in scleroderma. PMID- 27226091 TI - Enhanced Expression of Bruton's Tyrosine Kinase in B Cells Drives Systemic Autoimmunity by Disrupting T Cell Homeostasis. AB - Upon BCR stimulation, naive B cells increase protein levels of the key downstream signaling molecule Bruton's tyrosine kinase (BTK). Transgenic CD19-hBtk mice with B cell-specific BTK overexpression show spontaneous germinal center formation, anti-nuclear autoantibodies, and systemic autoimmunity resembling lupus and Sjogren syndrome. However, it remains unknown how T cells are engaged in this pathology. In this study, we found that CD19-hBtk B cells were high in IL-6 and IL-10 and disrupted T cell homeostasis in vivo. CD19-hBtk B cells promoted IFN gamma production by T cells and expression of the immune-checkpoint protein ICOS on T cells and induced follicular Th cell differentiation. Crosses with CD40L deficient mice revealed that increased IL-6 production and autoimmune pathology in CD19-hBtk mice was dependent on B-T cell interaction, whereas IL-10 production and IgM autoantibody formation were CD40L independent. Surprisingly, in Btk overexpressing mice, naive B cells manifested increased CD86 expression, which was dependent on CD40L, suggesting that T cells interact with B cells in a very early stage of immune pathology. These findings indicate that increased BTK mediated signaling in B cells involves a positive-feedback loop that establishes T cell-propagated autoimmune pathology, making BTK an attractive therapeutic target in autoimmune disease. PMID- 27226092 TI - Characterization of the Inflammasome in Human Kupffer Cells in Response to Synthetic Agonists and Pathogens. AB - The liver is the largest gland in the human body and functions as an innate immune organ. Liver macrophages called Kupffer cells (KC) constitute the largest group of macrophages in the human body. Innate immune responses involving KC represent the first line of defense against pathogens in the liver. Human monocyte-derived macrophages have been used to characterize inflammasome responses that lead to the release of the proinflammatory cytokines IL-1beta and IL-18, but it has not yet been determined whether human KC contain functional inflammasomes. We show, to our knowledge for the first time, that KC express genes and proteins that make up several different inflammasome complexes. Moreover, activation of KC in response to the absent in melanoma 2 (AIM2) inflammasome led to the production of IL-1beta and IL-18, which activated IL-8 transcription and hepatic NK cell activity, respectively. Other inflammasome responses were also activated in response to selected bacteria and viruses. However, hepatitis B virus inhibited the AIM2 inflammasome by reducing the mRNA stability of IFN regulatory factor 7, which regulated AIM2 transcription. These data demonstrate the production of IL-1beta and IL-18 in KC, suggesting that KC contain functional inflammasomes that could be important players in the innate immune response following certain infections of the liver. We think our findings could potentially aid therapeutic approaches against chronic liver diseases that activate the inflammasome. PMID- 27226088 TI - Inhaled Antibiotics for Gram-Negative Respiratory Infections. AB - Gram-negative organisms comprise a large portion of the pathogens responsible for lower respiratory tract infections, especially those that are nosocomially acquired, and the rate of antibiotic resistance among these organisms continues to rise. Systemically administered antibiotics used to treat these infections often have poor penetration into the lung parenchyma and narrow therapeutic windows between efficacy and toxicity. The use of inhaled antibiotics allows for maximization of target site concentrations and optimization of pharmacokinetic/pharmacodynamic indices while minimizing systemic exposure and toxicity. This review is a comprehensive discussion of formulation and drug delivery aspects, in vitro and microbiological considerations, pharmacokinetics, and clinical outcomes with inhaled antibiotics as they apply to disease states other than cystic fibrosis. In reviewing the literature surrounding the use of inhaled antibiotics, we also highlight the complexities related to this route of administration and the shortcomings in the available evidence. The lack of novel anti-Gram-negative antibiotics in the developmental pipeline will encourage the innovative use of our existing agents, and the inhaled route is one that deserves to be further studied and adopted in the clinical arena. PMID- 27226093 TI - Human Lymphoid Tissues Harbor a Distinct CD69+CXCR6+ NK Cell Population. AB - Knowledge of human NK cells is based primarily on conventional CD56(bright) and CD56(dim) NK cells from blood. However, most cellular immune interactions occur in lymphoid organs. Based on the coexpression of CD69 and CXCR6, we identified a third major NK cell subset in lymphoid tissues. This population represents 30-60% of NK cells in marrow, spleen, and lymph node but is absent from blood. CD69(+)CXCR6(+) lymphoid tissue NK cells have an intermediate expression of CD56 and high expression of NKp46 and ICAM-1. In contrast to circulating NK cells, they have a bimodal expression of the activating receptor DNAX accessory molecule 1. CD69(+)CXCR6(+) NK cells do not express the early markers c-kit and IL 7Ralpha, nor killer cell Ig-like receptors or other late-differentiation markers. After cytokine stimulation, CD69(+)CXCR6(+) NK cells produce IFN-gamma at levels comparable to CD56(dim) NK cells. They constitutively express perforin but require preactivation to express granzyme B and exert cytotoxicity. After hematopoietic stem cell transplantation, CD69(+)CXCR6(+) lymphoid tissue NK cells do not exhibit the hyperexpansion observed for both conventional NK cell populations. CD69(+)CXCR6(+) NK cells constitute a separate NK cell population with a distinct phenotype and function. The identification of this NK cell population in lymphoid tissues provides tools to further evaluate the cellular interactions and role of NK cells in human immunity. PMID- 27226094 TI - CysLT1 Receptor Is Protective against Oxidative Stress in a Model of Irritant Induced Asthma. AB - The bronchoconstrictive and proinflammatory properties of cysteinyl leukotrienes (cysLTs) in allergic asthma mediate their effects predominantly through the cysLT1 receptor (cysLT1R). However, the role of cysLTs and cysLT1R in innate immune-triggered asthma is largely unexplored. We explored the synthesis of cysLTs and cysLT1R as determinants of airway responses in an oxidative stress induced model of irritant asthma. Wild-type (WT) mice exposed to 100 ppm Cl2 for 5 min had airway neutrophilia, increased cysLT production, and pulmonary expression of cysLT-related biosynthetic genes. CysLT1R-deficient (CysLTr1(-/-)) mice that were exposed to Cl2 demonstrated airway hyperresponsiveness to inhaled methacholine significantly greater than in WT BALB/c mice. Compared to WT mice, airway neutrophilia and keratinocyte chemoattractant production levels were higher in CysLTr1(-/-) mice and airway hyperresponsiveness was ameliorated using a granulocyte depletion Ab. CysLTr1(-/-) mice also demonstrated prolonged bronchial epithelial cell apoptosis following Cl2 WT mice showed increased antioxidant and NF erythroid 2-related factor 2 (Nrf2) gene expression, Nrf2 nuclear translocation in bronchial epithelial cells, and increased reduced glutathione/oxidized glutathione following Cl2 exposure whereas CysLTr1(-/-) mice did not. Furthermore, CysLTr1(-/-) mice demonstrated increased pulmonary E cadherin expression and soluble E-cadherin shedding compared with WT mice. Loss of a functional cysLT1R results in aberrant antioxidant response and increased susceptibility to oxidative injury, apparently via a cysLT1R-dependent impairment of Nrf2 function. PMID- 27226095 TI - Prevalence of psychosocial morbidity in children with type 1 diabetes mellitus: a survey from Northern India. AB - BACKGROUND: Children with type 1 diabetes mellitus (T1DM) are on intensive treatment regimen with the stress of maintaining normal sugars which may predispose them to psychological problems. The study aimed to assess the prevalence of psychosocial problems and to study their correlates in children with T1DM in India. METHODS: The study was conducted on 97 T1DM children (59 boys and 38 girls) between 4 and 15 years of age with at least 6 months of illness. Psychosocial problems were assessed using childhood psychopathological measurement schedule (CPMS) questionnaire. Information regarding glucose control and various demographic factors was recorded. Factors significantly associated with psychosocial problems were further analysed using multiple linear regression. RESULTS: Mean age of patients was 9.6 years. The prevalence of psychosocial problems was found to be 20%. Most common problems were conduct disorders (24.5%), special symptoms (24%), physical illness (23%), anxiety (10%) and depression (7%). Depression had the strongest correlation (r=0.316 and p=0.002) with glycosylated haemoglobin (HbA1c), followed by behavioural problems/low intelligence (r=0.236 and p=0.02). CPMS score had a strong positive correlation with number of hyperglycaemic episodes, number of hospitalisations in last 6 months and HbA1c value. HbA1c over last 6 months and total number of hospitalisations were significant independent predictors in determining psychosocial problems. CONCLUSIONS: Psychosocial problems were seen in 20% children with T1DM from India. Poor glycaemic control and increased number of hospitalisations are significantly associated with increased psychosocial problems in T1DM. PMID- 27226096 TI - A fatal outcome of complicated severe diabetic ketoacidosis in a 11-year-old girl. AB - Diabetic ketoacidosis (DKA) is a complex metabolic state characterized by hyperglycemia, metabolic acidosis and ketonuria. Cerebral edema is the most common rare complication of DKA in children. The objective of the study was to emphasize the importance of careful evaluation and monitoring for signs and symptoms of cerebral edema in all children undergoing treatment for DKA. We present a case of 11-year-old girl with a history of diabetes mellitus type I (T1DM) who presented with severe DKA complicated by hypovolemic shock, cerebral edema and hematemesis. Considering the fact that complications of DKA are rare and require a high index of clinical suspicion, early recognition and treatment are crucial for avoiding permanent damage. PMID- 27226097 TI - Idiopathic postprandial hyperinsulinaemic hypoglycaemia. AB - BACKGROUND: Idiopathic postprandial hyperinsulinaemic hypoglycaemia (PPHH) has rarely been reported in the paediatric age. The objective of this study was to describe the clinical characteristics, diagnosis and management in a group of children with PPHH. METHODS: Six children (three females) with a mean follow-up of 3.5+/-3.0 years at a single tertiary paediatric hospital. All had 24-h blood glucose monitoring, diagnostic fast and prolonged oral glucose tolerance test (OGTT). Follow-up included: 24-h blood glucose monitoring or continuous glucose monitoring system, prolonged OGTT and/or mixed meal (MM) test. RESULTS: Age at diagnosis ranged from 5.4 to 15.7 years and auxology parameters were within normal range in all subjects. All the children had a normal fasting tolerance for age. Prolonged OGTT demonstrated symptomatic hypoglycaemia after 120 min in all the patients with simultaneous detectable serum insulin concentration. Acarbose was tried in three patients, having a positive effect on glycaemic and symptom control, but due to side effects, only two patients continued acarbose in the long run. Diazoxide proved to be beneficial in one patient. The rest of the patients were managed with frequent feeds but despite this, prolonged OGTT/MM demonstrated on-going PPHH. CONCLUSIONS: Prolonged OGTT is necessary to diagnose PPHH in children. Acarbose is beneficial in children with PPHH, although not well tolerated. Patients managed exclusively on frequent feeds demonstrated persistent hypoglycaemia on OGTT. The underlying cause of the PPHH in these patients remains unknown. PMID- 27226098 TI - Comparative phytochemical profiling of Clerodendrum infortunatum with some selected medicinal plants predominant in the Sub-Himalayan region of West Bengal. AB - BACKGROUND: The aim of the present study was to quantify the phytochemicals of Clerodendrum infortunatum root and correlate on the basis of phytochemicals present with other medicinal plants belonging to different families. METHODS: Various standard biochemical and spectrophotometric methods were employed to study the phytochemical status of the root of C. infortunatum. All the analysis was performed in multiple sets. Various statistical methods like principal component analysis, dendogram, Euclidean distance and correlation study were done to compare the phytochemical profile of C. infortunatum with different selected medicinal plants belonging to different families. RESULTS: Results indicated the presence of various phytochemicals like phenol, alkaloid, flavonoid, tannin, thiamine, riboflavin, etc. Among the estimated phytochemicals, phenol had the highest quantity (65.59+/-1.26 mg/g) followed by lipid (27.51+/-0.23 mg/g) and tannin (16.40+/-0.07 mg/100 g). The phytochemical contents of C. infortunatum are much higher than those of the other reference plants. CONCLUSIONS: It may be concluded from the present study that the root of C. infortunatum contains very high amount of phytochemicals which are chiefly responsible for various medicinal properties. Therefore, the presence of the bioactive compounds in high quantity may lead to the potent medicinal value of C. infortunatum root. PMID- 27226089 TI - Prions: Beyond a Single Protein. AB - Since the term protein was first coined in 1838 and protein was discovered to be the essential component of fibrin and albumin, all cellular proteins were presumed to play beneficial roles in plants and mammals. However, in 1967, Griffith proposed that proteins could be infectious pathogens and postulated their involvement in scrapie, a universally fatal transmissible spongiform encephalopathy in goats and sheep. Nevertheless, this novel hypothesis had not been evidenced until 1982, when Prusiner and coworkers purified infectious particles from scrapie-infected hamster brains and demonstrated that they consisted of a specific protein that he called a "prion." Unprecedentedly, the infectious prion pathogen is actually derived from its endogenous cellular form in the central nervous system. Unlike other infectious agents, such as bacteria, viruses, and fungi, prions do not contain genetic materials such as DNA or RNA. The unique traits and genetic information of prions are believed to be encoded within the conformational structure and posttranslational modifications of the proteins. Remarkably, prion-like behavior has been recently observed in other cellular proteins-not only in pathogenic roles but also serving physiological functions. The significance of these fascinating developments in prion biology is far beyond the scope of a single cellular protein and its related disease. PMID- 27226099 TI - Analgesic properties of aqueous leaf extract of Haematostaphis barteri: involvement of ATP-sensitive potassium channels, adrenergic, opioidergic, muscarinic, adenosinergic and serotoninergic pathways. AB - BACKGROUND: Pain is the most common cause of patients seeking medical advice as a result of its association with different pathologies. This study evaluated the antinociceptive property of Haematostaphis barteri as well as the possible mechanism(s) associated with its antinociceptive property. METHODS: Mice were administered H. barteri (30-300 mg kg-1; p.o.), followed by intraplantar injection of 10 MUL of 5% formalin into the hind paws. The pain score was determined for 1 h in the formalin test. The possible nociceptive pathways involved in the antinociceptive action of H. barteri were determined by pre treating mice with theophylline (5 mg kg-1, a non-selective adenosine receptor antagonist), naloxone (2 mg kg-1, a non-selective opioid receptor antagonist), glibenclamide (8 mg kg-1; an ATP-sensitive K+ channel inhibitor), and atropine (3 mg kg-1; non-selective muscarinic antagonist). RESULTS: H. barteri (30-300 mg kg 1) significantly and dose dependently precluded both first and second phases of nociception. Pre-treatment with naloxone had no effect on the analgesic activities of H. barteri in the first phase. Again, pre-treatment with atropine and glibenclamide did not significantly reverse the neurogenic antinociception of the extract in phase 1. However, theophylline reversed the analgesic effect of the extract in the first phase. In phase 2, theophylline had no effect on the analgesic activities of the extract. Naloxone, atropine, and glibenclamide significantly blocked the antinociception of H. barteri in the inflammatory phase of the formalin test. CONCLUSIONS: H. barteri possesses antinociceptive property mediated via the opioidergic, adrenergic, muscarinic, ATP-sensitive K+ channels, and adenosinergic nociceptive pathways. PMID- 27226100 TI - Effect of protocatechuic acid on lipid profile and DNA damage in D-galactosamine induced hepatotoxic rats. AB - BACKGROUND: Our aim in this study is to investigate the effect of protocatechuic acid (PCA) on lipid profile and DNA damage in D-galactosamine (D-GalN)-induced hepatotoxic rats. METHODS: Hepatotoxicity was induced by a single intraperitoneal dose of D-GalN in male Wistar rats. The activities of hepatic markers and levels of kidney function markers were determined. The plasma and tissue lipid levels were estimated. DNA damage was determined by COMET assay. Histopathological examination was also performed using portions of the liver and kidney tissues. RESULTS: D-GalN-induced hepatotoxic rats showed increased in the activities of hepatic marker enzymes such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (GGT) in serum. The levels of kidney function markers such as urea, uric acid, and creatinine increased in serum. Levels of lipid profile such as total cholesterol (TC), triglycerides (TG), free fatty acid (FFA), and phospholipids (PLs) in the plasma and tissues (liver and kidney) were significantly increased in D-GalN-induced rats. In plasma, levels of very low density lipoprotein cholesterol (VLDL-C) and low-density lipoprotein cholesterol (LDL-C) significantly increased, whereas high-density lipoprotein cholesterol (HDL-C) level decreased in D-GalN-induced rats. Furthermore, D-GalN-induced rats showed increased percentage of tail DNA and tail length and decreased percentage of head DNA. Oral administration of PCA (100 mg/ kg BW) for 20 days improved these levels when compared to D-GalN-induced rats. These biochemical changes were reflected on the attenuation and the structural alteration of the liver and kidney integrity. CONCLUSIONS: The results of the study suggest that PCA has a potent hepatoprotective activity that may be linked to its antihyperlipidemic effect. PMID- 27226101 TI - The evolving world of ubiquitin: transformed polyubiquitin chains. AB - The regulation of diverse cellular events by proteins that have undergone post translational modification with ubiquitin is well documented. Ubiquitin can be polymerized and eight types of polyubiquitin chain contribute to the complexity and specificity of the ubiquitin signal. Unexpectedly, recent studies have shown that ubiquitin itself undergoes post-translational modification by acetylation and phosphorylation; moreover, amyloid-like fibrils comprised of polyubiquitin chains have been discovered. Thus, ubiquitin is not only conjugated to substrate proteins, but also modified and transformed itself. Here, we review these novel forms of ubiquitin signal, with a focus on fibril formation of polyubiquitin chains and its underlying biological relevance. PMID- 27226102 TI - Finding causative genes from high-dimensional data: an appraisal of statistical and machine learning approaches. AB - Modern biological experiments often involve high-dimensional data with thousands or more variables. A challenging problem is to identify the key variables that are related to a specific disease. Confounding this task is the vast number of statistical methods available for variable selection. For this reason, we set out to develop a framework to investigate the variable selection capability of statistical methods that are commonly applied to analyze high-dimensional biological datasets. Specifically, we designed six simulated cancers (based on benchmark colon and prostate cancer data) where we know precisely which genes cause a dataset to be classified as cancerous or normal - we call these causative genes. We found that not one statistical method tested could identify all the causative genes for all of the simulated cancers, even though increasing the sample size does improve the variable selection capabilities in most cases. Furthermore, certain statistical tools can classify our simulated data with a low error rate, yet the variables being used for classification are not necessarily the causative genes. PMID- 27226103 TI - Lack of genomic diversity in the SLC47A1 gene within the indigenous Xhosa population. AB - BACKGROUND: Multidrug and toxin extrusion 1 (MATE1) is an organic cation/H+ exchanger, localized in the apical membrane of proximal renal tubules, which mediates the cellular elimination of organic cations into the renal lumen. These organic cations include clinically important drugs such as metformin, oxaliplatin and cimetidine. Moreover, genetic polymorphisms of SLC47A1, the pharmacogenetically relevant gene encoding human MATE1, have been implicated in reduced transport or accumulation to cytotoxic levels of these drugs in vitro. However, little or no information is available on the minor allele frequency distribution of known SLC47A1 coding SNPs in the sub-Saharan African populations. METHODS: Thus, the aim of this study was to determine the baseline minor allele frequency distribution of 20 known coding SNPs in the SLC47A1 gene of 148 Xhosa individuals residing in Cape Town, South Africa. RESULTS: This study did not identify any of these known SLC47A1 coding SNPs in the Xhosa individuals who participated in this study. CONCLUSIONS: It is anticipated that whole genome or exome sequencing may reveal novel SNPs in the Xhosa and other sub-Saharan African populations, which may have been missed with the current genotyping strategy. PMID- 27226104 TI - Noncoding RNAs in human cancer: one step forward in diagnosis and treatment. PMID- 27226105 TI - Hibiscus sabdariffa (Roselle) Extracts and Wine: Phytochemical Profile, Physicochemical Properties, and Carbohydrase Inhibition. AB - Three varieties of Hibiscus sabdariffa were analyzed for their phytochemical content and inhibitory potential on carbohydrate-digesting enzymes as a basis for selecting a variety for wine production. The dark red variety was chosen as it was highest in phenolic content and an aqueous extract partially inhibited alpha glucosidase (maltase), with delphinidin 3-O-sambubioside, cyanidin 3-O sambubioside, and 3-O-caffeoylquinic acid accounting for 65% of this activity. None of the varieties significantly inhibited alpha-amylase. Regarding Hibiscus sabdariffa wine, the effect of fermentation temperature (20 and 30 degrees C) on the physicochemical, phytochemical, and aroma composition was monitored over 40 days. The main change in phytochemical composition observed was the hydrolysis of 3-O-caffeolquinic acid and the concomitant increase of caffeic acid irrespective of fermentation temperature. Wine fermented at 20 degrees C was slightly more active for alpha-glucosidase inhibition with more fruity aromas (ethyl octanoate), but there were more flowery notes (2-phenylethanol) at 30 degrees C. PMID- 27226106 TI - Activation of purinergic receptors (P2) in the renal medulla promotes endothelin dependent natriuresis in male rats. AB - Renal endothelin-1 (ET-1) and purinergic signaling systems regulate Na(+) reabsorption in the renal medulla. A link between the renal ET-1 and purinergic systems was demonstrated in vitro, however, the in vivo interaction between these systems has not been defined. To test whether renal medullary activation of purinergic (P2) receptors promotes ET-dependent natriuresis, we determined the effect of increased medullary NaCl loading on Na(+) excretion and inner medullary ET-1 mRNA expression in anesthetized adult male Sprague-Dawley rats in the presence and absence of purinergic receptor antagonism. Isosmotic saline (NaCl; 284 mosmol/kgH2O) was infused into the medullary interstitium (500 MUl/h) during a 30-min baseline urine collection period, followed by isosmotic or hyperosmotic saline (1,800 mosmol/kgH2O) for two further 30-min urine collection periods. Na(+) excretion was significantly increased during intramedullary infusion of hyperosmotic saline. Compared with isosmotic saline, hyperosmotic saline infused into the renal medulla caused significant increases in inner medullary ET-1 mRNA expression. Renal intramedullary infusion of the P2 receptor antagonist suramin inhibited the increase in Na(+) excretion and inner medullary ET-1 mRNA expression induced by NaCl loading in the renal medulla. Activation of medullary P2Y2/4 receptors by infusion of UTP increased urinary Na(+) excretion. Combined ETA and ETB receptor blockade abolished the natriuretic response to intramedullary infusion of UTP. These data demonstrate that activation of medullary P2 receptors promotes ET-dependent natriuresis in male rats, suggesting that the renal ET-1 and purinergic signaling systems interact to efficiently facilitate excretion of a NaCl load. PMID- 27226108 TI - ASK1: a new therapeutic target for kidney disease. AB - Stress-induced activation of p38 MAPK and JNK signaling is a feature of both acute and chronic kidney disease and is associated with disease progression. Inhibitors of p38 MAPK or JNK activation provide protection against inflammation and fibrosis in animal models of kidney disease; however, clinical trials of p38 MAPK and JNK inhibitors in other diseases (rheumatoid arthritis and pulmonary fibrosis) have been disappointing. Apoptosis signal-regulating kinase 1 (ASK1) acts as an upstream regulator for the activation of p38 MAPK and JNK in kidney disease. Mice lacking the Ask1 gene are healthy with normal homeostatic functions and are protected from acute kidney injury induced by ischemia-reperfusion and from renal interstitial fibrosis induced by ureteric obstruction. Recent studies have shown that a selective ASK1 inhibitor substantially reduced renal p38 MAPK activation and halted the progression of nephropathy in diabetic mice, and this has led to a current clinical trial of an ASK1 inhibitor in patients with stage 3 or 4 diabetic kidney disease. This review explores the rationale for targeting ASK1 in kidney disease and the therapeutic potential of ASK1 inhibitors based on current experimental evidence. PMID- 27226107 TI - The role of Nedd4-1 WW domains in binding and regulating human organic anion transporter 1. AB - Human organic anion transporter 1 (hOAT1), expressed at the basolateral membrane of kidney proximal tubule cells, mediates the active renal secretion of a diverse array of clinically important drugs, including anti-human immunodeficiency virus therapeutics, antitumor drugs, antibiotics, antihypertensives, and anti inflammatories. We have previously demonstrated that posttranslational modification of hOAT1 by ubiquitination is an important mechanism for the regulation of this transporter. The present study aimed at identifying the ubiquitin ligase for hOAT1 and its mechanism of action. We showed that overexpression of neural precursor cell expressed, developmentally downregulated (Nedd)4-1, an E3 ubiquitin ligase, enhanced hOAT1 ubiquitination, decreased hOAT1 expression at the cell surface, and inhibited hOAT1 transport activity. In contrast, overexpression of the ubiquitin ligase-dead mutant Nedd4-1/C867S was without effects on hOAT1. Furthermore, knockdown of endogenously expressed Nedd4 1 by Nedd4-1-specific small interfering RNA reduced hOAT1 ubiquitination. Immunoprecipitation experiments in cultured cells and rat kidney slices and immunofluorescence experiments in rat kidney slices showed that there was a physical interaction between OAT1 and Nedd4-1. Nedd4-1 contains four protein protein interacting WW domains. When these WW domains were inactivated by mutating two amino acid residues in each of the four WW domains (Mut-WW1: V210W/H212G, Mut-WW2: V367W/H369G, Mut-WW3: I440W/H442G, and Mut-WW4: I492W/H494G, respectively), only Mut-WW2 and Mut-WW3 significantly lost their ability to bind and to ubiquitinate hOAT1. As a result, Mut-WW2 and Mut-WW3 were unable to suppress hOAT1-mediated transport as effectively as wild-type Nedd4-1. In conclusion, this is the first demonstration that Nedd4-1 regulates hOAT1 ubiquitination, expression, and transport activity through its WW2 and WW3 domains. PMID- 27226109 TI - The podocyte and the proteoglycan. PMID- 27226111 TI - Single coronary artery with a pre-pulmonic dual left anterior descending artery and a retro-aortic left circumflex artery. AB - We present two cases of an unusual coronary artery anomaly, namely, a single coronary artery with retro-aortic course of the left circumflex artery and pre pulmonic course of the left anterior descending artery, and one of which showed a dual left anterior descending artery as well - a combination that has not yet been reported in the literature. PMID- 27226110 TI - Specific endothelial heparin-binding EGF-like growth factor deletion ameliorates renal injury induced by chronic angiotensin II infusion. AB - Transactivation of EGF receptor (EGFR) by angiotensin II (Ang II) plays important roles in the initiation and progression of chronic kidney diseases. Studies suggest that heparin-binding EGF-like factor (HB-EGF) may be a critical mediator in this process, but its role in vivo has not been investigated. In the current study, we found that in response to Ang II infusion, kidneys from endothelial HB EGF deletion mice had significantly reduced EGFR activation compared with controls. Meanwhile, deletion of endothelial HB-EGF expression decreased Ang II infusion related renal injury, as demonstrated by 1) less albuminuria; 2) less glomerulosclerosis; 3) preserved endothelial integrity and decreased podocyte injury, as shown by greater glomerular tuft area and WT1-positive cells, and fewer apoptotic cells measured by cleaved caspase 3 staining; 4) reduced inflammation in the perivascular area and interstitium measured by F4/80 and CD3 immunostaining; and 5) reduced renal fibrosis. In conclusion, our results suggest that shedding of HB-EGF from endothelium plays an important role in Ang II induced renal injury by linking Ang II-AT1R with EGFR transactivation. Inhibition of HB-EGF shedding could be a potential therapeutic strategy for chronic kidney disease. PMID- 27226112 TI - Probiotics as an Adjuvant Therapy in Major Depressive Disorder. AB - BACKGROUND: Major depressive disorder is a common, debilitating psychiatric disorder, which originates from the interaction of susceptibility genes and noxious environmental events, in particular stressful events. It has been shown that dysregulation of hypothalamus-pituitary-adrenal (HPA) axis, imbalance between anti- and pro-inflammatory cytokines, depletion of neurotransmitters (serotonin, norepinephrine and/or dopamine) in the central nervous system, altered glutamatergic and GABAergic transmission have an important role in the pathogenesis of depression. Due to numerous diverse biological events included in the pathophysiology of depression a large number of antidepressant drugs exerting distinct pharmacological effects have been developed. Nevertheless, clinical needs are still not solved. RESULTS: Relatively new research strategies advanced the understanding of psychiatric illness and their connections with disturbances in gastrointestinal tract. The existence of bidirectional communication between the brain and the gut has been proven, and an increasing body of evidence supports the hypothesis that cognitive and emotional processes are influenced through the brain-gut axis. On the other hand, microbiome may influence brain function and even behavior giving to the specific microorganisms a psychobiotic potential. CONCLUSIONS: In this review we discuss the possibilities of classical antidepressant drug treatment being supported with the psychobiotics/probiotic bacteria in patients suffering from major depressive disorder. PMID- 27226114 TI - Defibrillation Testing Strategies of Pediatric and Adult Congenital Electrophysiologists during ICD Implantation. AB - BACKGROUND: Recently, there has been an increasing number of internal medicine trained electrophysiologists who choose not to test for acute defibrillation efficacy during implantable cardioverter defibrillator (ICD) implantation. It is not known whether this same trend is seen in pediatric electrophysiologists, who care primarily for patients with congenital heart disease or primary electrical problems. METHODS: Through a 14-question survey created on Survey Monkey, we asked the members of the Pediatric and Adult Congenital Electrophysiology Society (PACES) for their approach to ICD implantation. In particular, respondents were asked for their individual practice preferences on testing for acute defibrillation efficacy, including methods used for testing. RESULTS: There were 108 survey respondents. Thirty-nine percent test acute defibrillation efficacy at all implants, while 46% test in most patients, barring any clinical concerns. Another 14% routinely test during initial ICD system implants but not during generator changes with existing leads. Less than 1% of respondents do not routinely test acute defibrillation efficacy. CONCLUSIONS: The practice preferences of pediatric electrophysiologists in evaluating for acute defibrillation efficacy during ICD implants are in contrast to the recent trend in their internal medicine-trained counterparts. More studies are needed to determine if practice changes should be considered in the pediatric and adult congenital patient population. PMID- 27226115 TI - [Differential diagnosis of panniculitides]. AB - Panniculitides are diseases of the subcutaneous tissue with heterogeneous etiology. They may develop consequent to infections, as a reaction to drugs, after thermal injury, as part of autoimmune diseases, in metabolic disorders or due to infectious organisms. The clinical presentation with subcutaneous nodules is often nonspecific. Moreover, the differentiation from vasculitides of medium sized vessels can be clinically challenging. Microscopic examination of biopsy specimens is of high importance in the differential diagnosis of panniculitides. Histopathologically, panniculitides can be classified according to the predominantly infiltrated area in septal and lobular panniculitides and they can be separated from vasculitides of medium-sized vessels. Diagnostic difficulties arise from inadequate biopsy specimens and from lack of clinicopathological correlation. This article summarizes diagnostic criteria of frequent and clinically important panniculitides. PMID- 27226116 TI - [Malignant melanoma]. PMID- 27226113 TI - Renal Nitric Oxide Deficiency and Chronic Kidney Disease in Young Sheep Born with a Solitary Functioning Kidney. AB - Previously, we demonstrated that renal hemodynamic responses to nitric oxide (NO) inhibition were attenuated in aged, hypertensive sheep born with a solitary functioning kidney (SFK). NO is an important regulator of renal function, particularly, in the postnatal period. We hypothesized that the onset of renal dysfunction and hypertension in individuals with a SFK is associated with NO deficiency early in life. In this study, renal and cardiovascular responses to L NAME infusion (N(w)-nitro-L-arginine methyl ester) were examined in 6-month old lambs born with a SFK, induced by fetal unilateral nephrectomy (uni-x). Renal responses to L-NAME were attenuated in uni-x sheep with the fall in glomerular filtration rate (GFR) and urinary sodium excretion (UNaV) being less in the uni-x compared to sham lambs (%DeltaGFR; -41 +/- 3 vs -54 +/- 4: P = 0.03, %DeltaUNaV; 48 +/- 5 vs -76 +/- 3, P = 0.0008). 24 hour-basal urinary nitrate and nitrite (NOx) excretion was less in the uni-x animals compared to the sham (NOx excretion MUM/min/kg; sham: 57 +/- 7; uni-x: 38 +/- 4, P = 0.02). L-NAME treatment reduced urinary NOx to undetectable levels in both groups. A reduction in NO bioavailability in early life may contribute to the initiation of glomerular and tubular dysfunction that promotes development and progression of hypertension in offspring with a congenital nephron deficit, including those with a SFK. PMID- 27226117 TI - Topoisomerase IIalpha poisoning and DNA double-strand breaking by chiral ruthenium(ii) complexes containing 2-furanyl-imidazo[4,5-f][1,10]phenanthroline derivatives. AB - Four chiral Ru(ii) complexes bearing furan ligands, Delta/Lambda [Ru(bpy)2(pocl)](2+) () and Delta/Lambda-[Ru(bpy)2(poi)](2+) () (bpy = 2,2' bipyridine, pocl = 2-(5-chlorofuran-2-yl)imidazo[4,5-f][1,10]phenanthroline, poi = 2-(5-5-iodofuran-2-yl)imidazo[4,5-f][1,10]phenanthroline), were synthesized and characterized. These Ru(ii) complexes showed antitumor activities against HeLa, A549, HepG2, HL-60 and K562 tumor cell lines, especially the HL-60 tumor cell line. Moreover, was more active than other complexes accounting for the different cellular uptakes. In addition, could accumulate in the nucleus of HL-60 cells, suggesting that nucleic acids were the cellular target of . Topoisomerase inhibition tests in vitro and in living cells confirmed that the four complexes acted as efficient topoisomerase IIalpha poisons, DNA double-strand breaks had also been observed from neutral single cell gel electrophoresis (comet assay). inhibited the growth of HL-60 cells through the induction of apoptotic cell death, as evidenced by the Alexa Fluor(r) 488 annexin V staining assays. The results demonstrated that acted as a topoisomerase IIalpha poison and caused DNA double-strand damage that could lead to apoptosis. PMID- 27226118 TI - A Multiplex Electrochemical Biosensor for Bloodstream Infection Diagnosis. AB - Accurate and timely detection of bacterial pathogens will improve the clinical management of infections. Herein, we demonstrate an electrochemical biosensor that directly detects bacteria in human blood samples, resulting in the rapid diagnosis of a bloodstream infection. The multiplex biosensor detects the species specific sequences of the 16S ribosomal RNA of bacteria for pathogen identification in physiological samples without preamplification. The analytical performance characteristics of the biosensor, including the limit of detection and probe cross-reactivity, are evaluated systematically. The feasibility of the biosensor for a diagnosis of a bloodstream infection is demonstrated by identifying bacterial clinical isolates spiked in whole blood and blood culture samples that were tested positive for bacteria. The electrochemical biosensor correctly identifies all the species in the samples with 100% concordance to microbiological analysis. PMID- 27226119 TI - Visible Light Driven Photocascade Catalysis: Ru(bpy)3(PF6)2/TBHP-Mediated Synthesis of Fused beta-Carbolines in Batch and Flow Microreactors. AB - 1,2,3,4-Tetrahydro-beta-carbolines were coupled with alpha-keto vinyl azides through an unprecedented visible light-Ru(bpy)3(PF6)2/TBHP mediated photocascade strategy that involves photosensitization, photoredox catalysis and [3 + 2] cycloaddition reaction. The scope and scale-up feasibility of the photocascade strategy was demonstrated by synthesizing 18 different fused beta-carbolines in moderate to good yields using batch and continuous flow microreactor. This operationally simple synthetic protocol allows the formation of one C-C and two C N new bonds in the overall transformation. PMID- 27226120 TI - A Review of Whole-Exome Sequencing Efforts Toward Hereditary Breast Cancer Susceptibility Gene Discovery. AB - Inherited genetic risk factors contribute toward breast cancer (BC) onset. BC risk variants can be divided into three categories of penetrance (high, moderate, and low) that reflect the probability of developing the disease. Traditional BC susceptibility gene discovery approaches that searched for high- and moderate risk variants in familial BC cases have had limited success; to date, these risk variants explain only ~30% of familial BC cases. Next-generation sequencing technologies can be used to search for novel high and moderate BC risk variants, and this manuscript reviews 12 familial BC whole-exome sequencing efforts. Study design, filtering strategies, and segregation and validation analyses are discussed. Overall, only a modest number of novel BC risk genes were identified, and 90% and 97% of the exome-sequenced families and cases, respectively, had no BC risk variants reported. It is important to learn from these studies and consider alternate strategies in order to make further advances. The discovery of new BC susceptibility genes is critical for improved risk assessment and to provide insight toward disease mechanisms for the development of more effective therapies. PMID- 27226121 TI - Thickening of inner retinal layers in the parafovea after bariatric surgery in patients with type 2 diabetes. AB - PURPOSE: Bariatric surgery dramatically improves the metabolic profile in patients with type 2 diabetes (T2D). We have previously reported a thickening of the retina after bariatric surgery and aimed to investigate these subclinical changes in retinal thickness and vessel calibres in more detail. METHODS: We examined 51 patients with T2D 2 weeks before and 1, 3, 6 and 12 months after bariatric surgery. Retinal thickness was measured with optical coherence tomography and automated segmentation in the fovea, parafovea and perifovea in each retinal layer. Retinal vessels were semiautomatically measured in a zone 0.5 1 disc diameters from the optic disc. RESULTS: The total macula thickened with a peak after 6 months in both univariate (2.7 +/- 0.4 MUm, p < 0.001) and multivariate analysis (2.2 +/- 0.7 MUm, p = 0.001). The thickening was most prominent in the parafoveal ring 1-3 mm from the centre and in the retinal nerve fibre layer and outer nuclear layer. A fall in HbA1c (p = 0.01) and longer duration of diabetes (p = 0.01) were associated with more thickening. The central retinal artery equivalent widened 22.1 MUm (+/-8.9, p = 0.01) in the multivariate analysis 12 months postoperatively. A reduction in blood pressure was associated with less widening of the arterioles (p = 0.01). CONCLUSION: Patients with T2D had thickening of the retina after gastric bypass surgery with a peak 6 months postoperatively. The thickening was most pronounced in the retinal nerve fibre layer and the outer nuclear layer of the parafovea. In multivariate analysis, the central retinal artery equivalent increased at 12 months. PMID- 27226122 TI - Multiple and Highly Selective Alkyne-Isonitrile C-C and C-N Couplings at Group 4 Metallocenes. AB - Reactions of the group 4 metallocene alkyne complexes [Cp'2 M(eta(2) -Me3 SiC2 SiMe3 )] [Cp'2 =rac-(ebthi)=rac-1,2-ethylene-1,1'-bis(eta(5) -tetrahydroindenyl): M=Ti, Zr, Hf; Cp'2 =Cp*2 (Cp*=eta(5) -pentamethylcyclopentadienyl): M=Zr] with 2,6-dimethylphenyl isocyanide (2-xylyl isonitrile, XyNC) were investigated. Depending on the metal, the Cp' ligand, and/or the stoichiometry, as well as the reaction temperature and time, different products were obtained. The products included simple end-on coordination compounds of XyNC in addition to those of the coupling of Me3 SiC2 SiMe3 with two, three, or four isonitriles to form enimine complexes, aza-metallacycloallenes, and fused heterocyclic systems, respectively. One example of the latter tricyclic compounds was subject to demetalation by using HCl. Molecular structures of the heterometallacycles were determined by X ray crystallography. The interconversion of the products was investigated by (1) H NMR spectroscopy. PMID- 27226124 TI - Streptococcuspantholopis sp. nov., isolated from faeces of the Tibetan antelope (Pantholops hodgsonii). AB - Two bacterial strains were isolated from faecal samples of Tibetan antelopes. The isolates were Gram-stain-positive, catalase-negative, coccus-shaped organisms that were tentatively identified as representing a novel streptococcal species based on their morphological features, biochemical test results and phylogenomic findings. Comparative 16S rRNA gene sequencing studies confirmed that the organisms were members of the genus Streptococcus, but they did not correspond to any recognized species of the genus. The nearest phylogenetic relative of the unknown coccus was Streptococcus ursoris NUM 1615T (93.4 % 16S rRNA gene sequence similarity). Analysis of groEL and rpoB gene sequences of the novel isolates showed interspecies divergence of 27.0 and 22.2 %, respectively, from the type strain of its closest 16S rRNA gene phylogenetic relative, S. ursoris. The complete genome of strain TA 26T has been sequenced. Digital DNA-DNA hybridization studies between strain TA 26T and other species of the genus Streptococcus deposited in the GenBank database showed less than 70 % DNA-DNA relatedness, supporting a novel species status of the strain. On the basis of their genotypic and phenotypic differences from recognized Streptococcus species, the two isolates represent a novel species of the genus Streptococcus, for which the nameStreptococcus pantholopis sp. nov. (type strain TA 26T=CGMCC 1.15667T=DSM 102135T) is proposed. PMID- 27226123 TI - Mcp3 is a novel mitochondrial outer membrane protein that follows a unique IMP dependent biogenesis pathway. AB - Mitochondria are separated from the remainder of the eukaryotic cell by the mitochondrial outer membrane (MOM). The MOM plays an important role in different transport processes like lipid trafficking and protein import. In yeast, the ER mitochondria encounter structure (ERMES) has a central, but poorly defined role in both activities. To understand the functions of the ERMES, we searched for suppressors of the deficiency of one of its components, Mdm10, and identified a novel mitochondrial protein that we named Mdm10 complementing protein 3 (Mcp3). Mcp3 partially rescues a variety of ERMES-related phenotypes. We further demonstrate that Mcp3 is an integral protein of the MOM that follows a unique import pathway. It is recognized initially by the import receptor Tom70 and then crosses the MOM via the translocase of the outer membrane. Mcp3 is next relayed to the TIM23 translocase at the inner membrane, gets processed by the inner membrane peptidase (IMP) and finally integrates into the MOM. Hence, Mcp3 follows a novel biogenesis route where a MOM protein is processed by a peptidase of the inner membrane. PMID- 27226126 TI - Carotid sheath 'intubation' during an emergency surgical cricothyroidotomy. PMID- 27226125 TI - Maturity-related Variability of the Thymus in Cynomolgus Monkeys (Macaca fascicularis). AB - Terminal body weights (TBWs), thymus weight parameters, and thymus morphology were retrospectively evaluated in 453 cynomolgus monkeys assigned to control groups on nonclinical toxicity studies. Morphology of bone, ovary, and testis/epididymis were used to determine maturity status of individual animals. There was no correlation between TBW and thymus weight (absolute and/or relative to TBW or brain weight). Thymus weight parameters and grades of decreased lymphocytes in the thymus were highly variable in immature animals compared to mature animals. There was also high (up to 11-fold) variability of thymus weight parameters within a given control group on the same study (generally 3 or 4 animals per sex). Several parameters evaluated had more pronounced age-related changes in males when compared to females. Our results demonstrate the inherent variability of thymus weight parameters and morphologic observations for cynomolgus monkeys on toxicology studies. Changes in thymus parameters in cynomolgus monkeys are unreliable indicators of immunomodulation or immunotoxicity in the absence of other relevant findings. Therefore, the thymus parameters commonly evaluated in preclinical safety assessments should not be the primary data set used to determine the presence of a direct test article-related effect on the immune system. PMID- 27226127 TI - Naphthalene ball poisoning: a rare cause of acquired methaemoglobinaemia. AB - A 15-year-old boy presented to emergency services with accidental naphthalene ball ingestion. Following consumption he developed methaemoglobinaemia, massive intravascular haemolysis and acute kidney injury. He had no history suggestive of congenital haemoglobin M disease. Development of severe methaemoglobinaemia and intravascular haemolysis is quite unusual after consumption of a single ball of naphthalene. The patient was managed with ascorbic acid and intravenous N-acetyl cysteine. He also required haemodialysis for acute kidney injury that developed secondary to pigment nephropathy. PMID- 27226128 TI - Postintubation airway obstruction caused by a retrotracheal haematoma. PMID- 27226129 TI - Anti-CCR4 Monoclonal Antibody Mogamulizumab Followed by the GDP (Gemcitabine, Dexamethasone and Cisplatin) Regimen in Primary Refractory Angioimmunoblastic T Cell Lymphoma. AB - There are few effective options for salvage therapy in elderly patients with relapsed or refractory angioimmunoblastic T-cell lymphoma (AITL). The anti-CCR4 antibody mogamulizumab works via antibody-dependent cytotoxic activity, reduces regulatory T cells, and evokes antitumor immunity in cancer patients. We report a 78-year-old patient with refractory AITL receiving a new immunochemotherapy consisting of sequential mogamulizumab administration followed by the GDP (gemcitabine, dexamethasone and cisplatin) regimen. A favorable consolidative effect of the GDP regimen could be observed in the patient who had partial remission after administration of mogamulizumab monotherapy. The regimen showed an acceptable toxicity profile without serious autoimmunity and an expected treatment response for the elderly patient with primary refractory AITL. This clinical case is the first report of salvage chemotherapy including mogamulizumab for primary refractory AITL described in the literature. PMID- 27226130 TI - Discharge Against Medical Advice in Traumatic Brain Injury: Follow-Up and Readmission Rate. AB - BACKGROUND: Patients who leave hospital against medical advice (AMA) may be at risk of adverse health outcomes, medical complications, and readmission. In this study, we examined the characteristics of patients who left AMA after traumatic brain injury (TBI), their rates of follow-up visits, and readmission. METHODS: We retrospectively studied 106 consecutive patients who left the tertiary trauma center AMA (1.8% of all admitted patients with a TBI). Preinjury health and social issues, mechanism of injury, computed tomography findings, and injury markers were collected. They were correlated to compliance with follow-up visits and unplanned emergency room (ER) visits and readmission rates. RESULTS: The most prevalent premorbid health or social-related issues were alcohol abuse (33%) and assault as a mechanism of trauma (33%). Only 15 (14.2%) subjects came to follow up visit for their TBI. Sixteen (15.1%) of the 106 subjects had multiple readmissions and/or ER visits related to substance abuse. Seven (6.6%) had multiple readmissions or ER visits with psychiatric reasons. Those patients with multiple readmissions and ER visits showed in higher proportion preexisting neurological condition (p=0.027), homelessness (p=0.012), previous neurosurgery (p=0.014), preexisting encephalomalacia (p=0.011), and had a higher ISS score (p=0.014) than those who were not readmitted multiple times. CONCLUSIONS: The significantly increased risks of multiple follow-up visits and readmission among TBI patients who leave hospital AMA are related to a premorbid vulnerability and psychosocial issues. Clinicians should target AMA TBI patients with premorbid vulnerability for discharge transition interventions. PMID- 27226131 TI - Controversies and problems of volume control and hypertension in haemodialysis. AB - Extracellular volume overload and hypertension are important contributors to the high risk of cardiovascular mortality in patients undergoing haemodialysis. Hypertension is present in more than 90% of patients at the initiation of haemodialysis and persists in more than two-thirds, despite use of several antihypertensive medications. High blood pressure is a risk factor for the development of left ventricular hypertrophy, heart failure, and mortality, although there are controversies with some study findings showing poor survival with low-but not high-blood pressure. The most frequent cause of hypertension in patients undergoing haemodialysis is volume overload, which is associated with poor cardiovascular outcomes itself independent of blood pressure. Although antihypertensive medications might not be successful to control blood pressure, extracellular volume reduction by persistent ultrafiltration and dietary salt restriction can produce favourable results with good blood pressure control. More frequent or longer haemodialysis can facilitate volume and blood pressure control. However, successful volume and blood pressure control is also possible in patients undergoing conventional haemodialysis. PMID- 27226132 TI - Factors affecting outcomes in patients reaching end-stage kidney disease worldwide: differences in access to renal replacement therapy, modality use, and haemodialysis practices. AB - More than 2 million people worldwide are being treated for end-stage kidney disease (ESKD). This Series paper provides an overview of incidence, modality use (in-centre haemodialysis, home dialysis, or transplantation), and mortality for patients with ESKD based on national registry data. We also present data from an international cohort study to highlight differences in haemodialysis practices that affect survival and the experience of patients who rely on this therapy, which is both life-sustaining and profoundly disruptive to their quality of life. Data illustrate disparities in access to renal replacement therapy of any kind and in the use of transplantation or home dialysis, both of which are widely considered preferable to in-centre haemodialysis for many patients with ESKD in settings where infrastructure permits. For most patients with ESKD worldwide who are treated with in-centre haemodialysis, overall survival is poor, but longer in some Asian countries than elsewhere in the world, and longer in Europe than in the USA, although this gap has reduced. Commendable haemodialysis practice includes exceptionally high use of surgical vascular access in Japan and in some European countries, and the use of longer or more frequent dialysis sessions in some countries, allowing for more effective volume management. Mortality is especially high soon after ESKD onset, and improved preparation for ESKD is needed including alignment of decision making with the wishes of patients and families. PMID- 27226133 TI - The heart and vascular system in dialysis. AB - The heart and the vascular tree undergo major structural and functional changes when kidney function declines and renal replacement therapy is required. The many cardiovascular risk factors and adaptive changes the heart undergoes include left ventricular hypertrophy and dilatation with concomitant systolic and diastolic dysfunction. Myocardial fibrosis is the consequence of impaired angio-adaptation, reduced capillary angiogenesis, myocyte-capillary mismatch, and myocardial micro arteriopathy. The vascular tree can be affected by both atherosclerosis and arteriosclerosis with both lipid rich plaques and abundant media calcification. Development of cardiac and vascular disease is rapid, especially in young patients, and the phenotype resembles all aspects of an accelerated ageing process and latent cardiac failure. The major cause of left ventricular hypertrophy and failure and the most common problem directly affecting myocardial function is fluid overload and, usually, hypertension. In situations of stress, such as intradialytic hypotension and hypoxaemia, the hearts of these patients are more vulnerable to developing cardiac arrest, especially when such episodes occur frequently. As a result, cardiac and vascular mortality are several times higher in dialysis patients than in the general population. Trials investigating one pharmacological intervention (eg, statins) have shown limitations. Pragmatic designs for large trials on cardio-active interventions are mandatory for adequate cardioprotective renal replacement therapy. PMID- 27226134 TI - Legal and regulatory framework for health worker retention in Mozambique: Public health law research to strengthen health systems and services. AB - Realizing the fundamental contribution of human resources to public health, the World Health Organization (WHO) issued policy recommendations for health worker retention. We reviewed Mozambique's laws and regulations and assessed the extent to which this legal and regulatory framework governing public sector health workers aligns with the WHO health worker retention recommendations. We provide guidance for future analysis of non-binding policies that may fill gaps identified in our review. We also indicate how to link legal analysis to the cycle by which research informs policy, policy informs practice, and practice leads to improvements in health systems and population health. Finally, we demonstrate the relevance of understanding and analyzing the impact of domestic laws on global health. Future research should assess implementation of health worker allowances and any associations with increased hiring, more equitable distribution, and improved retention - all are essential to public health in Mozambique.Journal of Public Health Policy advance online publication, 26 May 2016; doi:10.1057/jphp.2016.22. PMID- 27226135 TI - Characterising the safety of clomiphene citrate in male patients through prostate specific antigen, haematocrit, and testosterone levels. AB - OBJECTIVE: To determine the safety profile of clomiphene citrate (CC) in men being treated for hypogonadism or infertility by measuring prostate-specific antigen (PSA), haematocrit (Hct), and testosterone levels. PATIENTS AND METHODS: We identified patients presenting to our institution who were placed on CC, 50 mg every day or every other day, for male infertility and/or symptomatic hypoandrogenism between September 2013 and April 2016. Patients with documented exogenous testosterone, human chorionic gonadotrophin, or anastrozole use within 2 weeks of baseline evaluations were excluded. Our primary outcomes were the effects of CC on PSA, Hct, and total testosterone levels evaluated at the 3, 6, 9, or 12 months of follow-up. Outcomes were averaged within patients across visits and summarised by mean, median, range, standard deviation (SD) and the 95% confidence interval (CI) for the mean. RESULTS: A total of 77 patients had recorded PSA, Hct, and/or testosterone values. The mean (SD, range) age and body mass index was 34 (6, 22-51) years and 31 (6, 22-52) kg/m2 , respectively. The mean (SD) follow-up was 358 (29) days. Within this group, CC concentration was changed in 24 patients (31%) and was discontinued in 24 patients (31%). The median (range) duration of CC therapy before discontinuation was 127 (44-161) days. The use of CC significantly raised both mean total and bioavailable testosterone levels by 200 ng/dL and 126 ng/dL, respectively (P < 0.001). This increase in testosterone had significant clinical effects with improvements in Androgen Deficiency in Aging Male questionnaire scores (P < 0.01) but not Sexual Health Inventory for Men scores. CC had no effect on mean PSA (1 ng/dL, 95% CI 0.8-1.1) or Hct (49%, 95% CI 41-53) levels, which were within normal ranges. CONCLUSIONS: As more men are placed on CC for infertility or hypogonadism, characterising the safety effect profile becomes important. Our study found that CC significantly increased testosterone levels without changing PSA or Hct values. Because the biochemical response to CC can vary, we suggest scheduling laboratory evaluation at regular intervals; however, ordering routine assessment of PSA and Hct may not be necessary. PMID- 27226138 TI - Cluster size and composition dependent water deprotonation by free manganese oxide clusters. AB - In the quest for cheap and earth abundant but highly effective and energy efficient water splitting catalysts, manganese oxide represents one of the materials of choice. In the framework of a new hierarchical modeling strategy we employ free non-ligated manganese oxide clusters MnxOx+y(+) (x = 2-5, y = -1, 0, 1, 2) as simplified molecular models to probe the interaction of water with nano scale manganese oxide materials. Infrared multiple-photon dissociation (IR-MPD) spectroscopy in conjunction with first-principles spin density functional theory calculations is applied to study several series of MnxOx+y(H2O)n(+) complexes and reveal that the reaction of water with MnxOx+y(+) leads to the deprotonation of the water molecules via hydroxylation of the cluster oxo-bridges. This process is independent of the formal Mn oxidation state and occurs already for the first adsorbed water molecule and it proceeds until all oxo-bridges are hydroxylated. Additional water molecules are bound intact and favorably form H3O2 units with the hydroxylated oxo-bridges. Water adsorption and deprotonation is also found to induce structural transformations of the cluster core, including dimensionality crossover. Furthermore, the IR-MPD measurements reveal that clusters with one oxygen atom in excess MnxOx+1(+) contain a terminal O atom while clusters with two oxygen atoms in excess MnxOx+2(+) contain an intact O2 molecule which, however, dissociates upon adsorption of a minimum number of water molecules. These basic concepts could aid the future design of artificial water-splitting molecular catalysts. PMID- 27226136 TI - Once daily administration of the SGLT2 inhibitor, empagliflozin, attenuates markers of renal fibrosis without improving albuminuria in diabetic db/db mice. AB - Blood glucose control is the primary strategy to prevent complications in diabetes. At the onset of kidney disease, therapies that inhibit components of the renin angiotensin system (RAS) are also indicated, but these approaches are not wholly effective. Here, we show that once daily administration of the novel glucose lowering agent, empagliflozin, an SGLT2 inhibitor which targets the kidney to block glucose reabsorption, has the potential to improve kidney disease in type 2 diabetes. In male db/db mice, a 10-week treatment with empagliflozin attenuated the diabetes-induced upregulation of profibrotic gene markers, fibronectin and transforming-growth-factor-beta. Other molecular (collagen IV and connective tissue growth factor) and histological (tubulointerstitial total collagen and glomerular collagen IV accumulation) benefits were seen upon dual therapy with metformin. Albuminuria, urinary markers of tubule damage (kidney injury molecule-1, KIM-1 and neutrophil gelatinase-associated lipocalin, NGAL), kidney growth, and glomerulosclerosis, however, were not improved with empagliflozin or metformin, and plasma and intra-renal renin activity was enhanced with empagliflozin. In this model, blood glucose lowering with empagliflozin attenuated some molecular and histological markers of fibrosis but, as per treatment with metformin, did not provide complete renoprotection. Further research to refine the treatment regimen in type 2 diabetes and nephropathy is warranted. PMID- 27226137 TI - The Magea gene cluster regulates male germ cell apoptosis without affecting the fertility in mice. AB - While apoptosis is essential for male germ cell development, improper activation of apoptosis in the testis can affect spermatogenesis and cause reproduction defects. Members of the MAGE-A (melanoma antigen family A) gene family are frequently clustered in mammalian genomes and are exclusively expressed in the testes of normal animals but abnormally activated in a wide variety of cancers. We investigated the potential roles of these genes in spermatogenesis by generating a mouse model with a 210-kb genomic deletion encompassing six members of the Magea gene cluster (Magea1, Magea2, Magea3, Magea5, Magea6 and Magea8). Male mice carrying the deletion displayed smaller testes from 2 months old with a marked increase in apoptotic germ cells in the first wave of spermatogenesis. Furthermore, we found that Magea genes prevented stress-induced spermatogenic apoptosis after N-ethyl-N-nitrosourea (ENU) treatment during the adult stage. Mechanistically, deletion of the Magea gene cluster resulted in a dramatic increase in apoptotic germ cells, predominantly spermatocytes, with activation of p53 and induction of Bax in the testes. These observations demonstrate that the Magea genes are crucial in maintaining normal testicular size and protecting germ cells from excessive apoptosis under genotoxic stress. PMID- 27226139 TI - Pre-pregnancy body mass index, height and physical activity are associated with rate of gestational weight gain among Malaysian mothers. AB - AIM: Both inadequate and excessive weight gain during pregnancy can have immediate and long-term health risks for women and infants. This study investigated rate of gestational weight gain (GWG) and its associated factors in Malaysian pregnant women. METHODS: This cross-sectional study was conducted at maternal and child health clinics in Selangor and Negeri Sembilan between November 2010 and April 2012. A pre-tested questionnaire was used to obtain sociodemographic, obstetric, dietary intake and physical activity information. Current weight and height were measured using standard procedures. GWG rate was calculated as the average weekly weight gain in that particular trimester of pregnancy and further categorized according to the Institute of Medicine (IOM) recommendations. RESULTS: Mean GWG rate for all pre-pregnancy BMI categories in the second and third trimesters was higher than the IOM recommendations. Overweight women (adjusted OR, 4.26; 95%CI: 1.92-9.44) and women <153 cm tall (adjusted OR, 1.96; 95%CI: 1.21-3.18) tend to have inadequate GWG rate. Women with high pre-pregnancy body mass index (BMI; >=25.0 kg/m(2) ; overweight: adjusted OR, 3.88; 95%CI: 2.12-7.09; obese: adjusted OR, 2.34; 95%CI: 1.28-4.29) and low physical activity (adjusted OR, 1.74; 95%CI: 0.77-3.97) were two threefold more likely to have excessive GWG. CONCLUSION: Both inadequate and excessive GWG can have detrimental effects on the health of mothers and infants. Pre-pregnancy BMI, height and physical activity should be emphasized in prenatal care to ensure that women have adequate GWG rate. PMID- 27226140 TI - Systemic talc granulomatosis secondary to drug abuse. PMID- 27226141 TI - A review of disease progression models of Parkinson's disease and applications in clinical trials. AB - Quantitative disease progression models for neurodegenerative disorders are gaining recognition as important tools for drug development and evaluation. In Parkinson's disease (PD), several models have described longitudinal changes in the Unified Parkinson's Disease Rating Scale (UPDRS), one of the most utilized outcome measures for PD trials assessing disease progression. We conducted a literature review to examine the methods and applications of quantitative disease progression modeling for PD using a combination of key words including "Parkinson disease," "progression," and "model." For this review, we focused on models of PD progression quantifying changes in the total UPDRS scores against time. Four different models reporting equations and parameters have been published using linear and nonlinear functions. The reasons for constructing disease progression models of PD thus far have been to quantify disease trajectories of PD patients in active and inactive treatment arms of clinical trials, to quantify and discern symptomatic and disease-modifying treatment effects, and to demonstrate how model based methods may be used to design clinical trials. The historical lack of efficiency of PD clinical trials begs for model-based simulations in planning for studies that result in more informative conclusions, particularly around disease modification. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27226143 TI - Efficient All-Vacuum Deposited Perovskite Solar Cells by Controlling Reagent Partial Pressure in High Vacuum. AB - All-vacuum-deposited perovskite solar cells produced by controlling reagent partial pressure in high vacuum with newly developed multi-layer electron and hole transporting structures show outstanding power conversion efficiency of 17.6% and smooth, pinhole-free, micrometer-sized perovskite crystal grains. PMID- 27226142 TI - Negative regulation of bacterial killing and inflammation by two novel CD16 ligands. AB - Sepsis, a leading cause of death worldwide, involves exacerbated proinflammatory responses and inefficient bacterial clearance. Phagocytic cells play a crucial part in the prevention of sepsis by clearing bacteria through host innate receptors. Here, we used a phage display library to identify two peptides in Escherichia coli that interact with host innate receptors. One of these peptides, encoded by the wzxE gene of E. coli K-12, was involved in the transbilayer movement of a trisaccharide-lipid intermediate in the assembly of enterobacterial common antigen. Peptide-receptor interactions induced CD16-mediated inhibitory immunoreceptor tyrosine-based activating motif signaling, blocking the production of ROS and bacterial killing. This CD16-mediated inhibitory signaling was abrogated in a WzxE(-/-) mutant of E. coli K-12, restoring the production of ROS and bacterial killing. Taken together, the two novel CD16 ligands identified negatively regulate bacterial killing and inflammation. Our findings may contribute toward the development of new immunotherapies for E. coli-mediated infectious diseases and inflammation. PMID- 27226144 TI - Reinforcement and a cline in mating behaviour evolve in response to secondary contact and hybridization in shield-back katydids (Orthoptera: Tettigoniidae). AB - In a dispersal-limited species that has evolved reproductive character displacement at a contact zone, a cline in mating behaviour may result if gene flow diffuses alleles out of the contact zone into allopatric populations. Prior work has found such a clinal pattern in the shield-back katydid Aglaothorax morsei, in which the male calling songs in a sympatric population have a displaced, short interpulse interval that increases in length with increasing distance from the contact zone. In this study, molecular phylogenetic and female preference data show that (1) sympatric populations result from secondary contact, (2) hybridization in sympatry has resulted in unidirectional mitochondrial introgression and (3) female preferences are consistent with reproductive character displacement and could generate a cline in mating behaviour. These data together suggest a history of reinforcement, generally considered rare in acoustically communicating insects; thus, Aglaothorax represents an important example of a rarely documented evolutionary process. PMID- 27226145 TI - Anti-photoageing and anti-melanogenesis activities of chrysin. AB - CONTEXT: Melanin plays an important role in preventing skin photoageing by blocking ultraviolet B (UVB). However, East Asian women prefer light and fair skin, therefore they want to keep their skin from photoageing and at the same time reduce the melanin in their skin. Chrysin is a kind of natural flavonoid with luxurious biological activities, which has a very promising effect on achieving this goal. OBJECTIVE: To elucidate the effects and mechanisms of chrysin on photoageing and melanogenesis. MATERIALS AND METHODS: Human dermal fibroblasts (HDF) and B16 murine melanoma cells were incubated with chrysin (0-25 MUM) for 48 h. Anti-photoageing activity was examined in HDF by assessment of synthesis/degradation of collagen I, antioxidative and antisenescent activities through ELISA and colorimetric method. Anti-melanogenesis activity was tested by assessment of melanin, tyrosinase (TYR), melanogenic proteins inhibition activities in B16 cells using colorimetric and ELISA method. RESULTS: Chrysin increased collagen I secretion (50-121.54% at 6.25-25 MUM) and chrysin showed anti-photoageing activity by decreasing the degradation of collagen I, repairing oxidation damage and reducing the rate of HDF senescence. Furthermore, chrysin exhibited inhibitory activities with 3.00-20.35% reduction of melanin content at 6.25-25 MUM, and inhibited melanin synthesis through the inhibition of TYR activity and the suppression of melanogenic proteins (TYR, TYR-related protein 1/2 and microphthalmia-associated transcription factor) expressions. DISCUSSION AND CONCLUSION: Chrysin may have potential for developing a functional cosmetic agent because of its anti-photoageing and anti-melanogenesis activities. PMID- 27226146 TI - eHealth Literacy: In the Quest of the Contributing Factors. AB - BACKGROUND: Understanding the factors that influence eHealth in a country is particularly important for health policy decision makers and the health care market, as it provides critical information to develop targeted and tailored interventions for relevant patient-consumer segments, and further suggests appropriate strategies for training the health illiterate part of the population. OBJECTIVE: The objective of the study is to assess the eHealth literacy level of Greek citizens, using the eHealth Literacy Scale (eHEALS), and further explore the factors that shape it and are associated with it. METHODS: This empirical study relies on a unique sample of 1064 citizens in Greece in the year 2013. The participants were requested to answer various questions about their ability to solve health-related issues using the Internet, and to provide information about their demographic characteristics and life-style habits. Ordered logit models were used to describe a certain citizen's likelihood of being eHealth literate. RESULTS: The demographic factors show that the probability of an individual being eHealth literate decreases by 23% (P=.001) when the individual ages and increases by 53% (P<.001) when he or she acquires higher level of education. Among the life style variables, physical exercise appears to be strongly and positively associated with the level of eHealth literacy (P=.001). Additionally, other types of technology literacies, such as computer literacy and information literacy, further enhance the eHealth performance of citizens and have the greatest impact among all factors. CONCLUSIONS: The factors influencing eHealth literacy are complex and interdependent. However, the Internet is a disruptive factor in the relationship between health provider and health consumer. Further research is needed to examine how several factors associate with eHealth literacy, since, the latter is not only related to health care outcomes but also can be a tool for disseminating social inequalities. PMID- 27226147 TI - Model selection versus model averaging in dose finding studies. AB - A key objective of Phase II dose finding studies in clinical drug development is to adequately characterize the dose response relationship of a new drug. An important decision is then on the choice of a suitable dose response function to support dose selection for the subsequent Phase III studies. In this paper, we compare different approaches for model selection and model averaging using mathematical properties as well as simulations. We review and illustrate asymptotic properties of model selection criteria and investigate their behavior when changing the sample size but keeping the effect size constant. In a simulation study, we investigate how the various approaches perform in realistically chosen settings. Finally, the different methods are illustrated with a recently conducted Phase II dose finding study in patients with chronic obstructive pulmonary disease. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27226148 TI - Change in Pulse Wave Velocity and Short-Term Development of Cardiovascular Events in the Hemodialysis Population. AB - The association between single measurements of carotid-femoral pulse wave velocity (cfPWV) and cardiovascular (CV) events is driven by late events beyond 12 months of follow-up. This prospective study compares single measurements of cfPWV vs the 2-year delta cfPWV and the association with short-term development of CV events in hemodialysis patients. cfPWV was performed at t=0 and t=1 two years later, and patients were followed-up for development of CV events through 12 months (n=66). In Cox regression models adjusted for CV risk factors, history of CV events and delta cfPWV remained associated with the development of CV events (hazard ratio for prior CV events=8.9, P=.03; hazard ratio for delta cfPWV=1.14; P=.002). When delta cfPWV was substituted for single cfPWV measurement, none of the single measures were associated with new CV events. The change in cfPWV, but not single measurements of cfPWV, was associated with the development of CV events through 12 months. PMID- 27226151 TI - Barriers and perceptions regarding code status discussion with families of critically ill patients in a tertiary care hospital of a developing country: A cross-sectional study. AB - BACKGROUND: In Asian societies including Pakistan, a complex background of illiteracy, different familial dynamics, lack of patient's autonomy, religious beliefs, and financial constraints give new dimensions to code status discussion. Barriers faced by physicians during code status discussion in these societies are largely unknown. AIM: To determine the barriers and perceptions in discussion of code status by physicians. DESIGN: Questionnaire-based cross-sectional study. SETTING AND PARTICIPANTS: This study was conducted in the Department of Medicine of The Aga Khan University Hospital, Karachi, Pakistan. A total of 134 physicians who had discussed at least five code statuses in their lifetime were included. RESULTS: A total of 77 (57.4%) physicians responded. Family-related barriers were found to be the most common barriers. They include family denial (74.0%), level of education of family (66.2%), and conflict between individual family members (66.2%). Regarding personal barriers, lack of knowledge regarding prognosis (44.1%), personal discomfort in discussing death (29.8%), and fear of legal consequences (28.5%) were the top most barriers. In hospital-related barriers, time constraint (57.1%), lack of hospital administration support (48.0%), and suboptimal nursing care after do not resuscitate (48.0%) were the most frequent. There were significant differences among opinions of trainees when compared to those of attending physicians. CONCLUSION: Family-related barriers are the most frequent roadblocks in the end-of-life care discussions for physicians in Pakistan. Strengthening communication skills of physicians and family education are the potential strategies to improve end-of-life care. Large multi-center studies are needed to better understand the barriers of code status discussion in developing countries. PMID- 27226150 TI - Ivacaftor in cystic fibrosis adults: Czech experience with six years of follow up. AB - AIMS: Ivacaftor is a revolutionary treatment option for cystic fibrosis (CF) patients with G551D and other gating mutations. The aim of this study was to evaluate the clinical status of patients on ivacaftor who were followed for up to 6 years together with an evaluation of ivacaftor therapy in one patient with an initial FEV1 less than 40% of predicted value. METHODS: Data on development of clinical status and sinopulmonary-related therapies were obtained from patient health records during ivacaftor treatment lasting for up to six years and were compared with an equivalent period before ivacaftor administration. RESULTS: Five CF adults with a median age 28.6 years (range 21.4-35.6 years) with median FEV1 45% pred. (range 16-85% pred.) were included in the study. Four subjects were also participants in the STRIVE and PERSIST studies. Altogether, twenty-four patient-years of ivacaftor treatment were analyzed. The median FEV1 decline per year decreased from -4.5 to -0.9% pred. (P = 0.043). Reduction in number of days on antibiotic treatment and hospital stays was 21% (P < 0.001) and 75% (P = 0.003), respectively. Improvement and stabilization of lung function was observed for up to six years of treatment. In a patient with severe airway obstruction, an increase in the FEV1 value (30.4% from baseline) was documented during the first twelve months of treatment. CONCLUSION: Ivacaftor therapy resulted in improved and stabilized lung function in up to six years of treatment with a reduction in number of days on antibiotic treatment and hospital stays. Its efficiency was also displayed in a patient with severe airway obstruction. PMID- 27226149 TI - Up-regulated extracellular matrix components and inflammatory chemokines may impair the regeneration of cholestatic liver. AB - Although the healthy liver is known to have high regenerative potential, poor liver regeneration under pathological conditions remains a substantial problem. We investigated the key molecules that impair the regeneration of cholestatic liver. C57BL/6 mice were randomly subjected to partial hepatectomy and bile duct ligation (PH+BDL group, n = 16), partial hepatectomy only (PH group, n = 16), or sham operation (Sham group, n = 16). The liver sizes and histological findings were similar in the PH and sham groups 14 days after operation. However, compared with those in the sham group, the livers in mice in the PH+BDL group had a smaller size, a lower cell proliferative activity, and more fibrotic tissue 14 days after the operation, suggesting the insufficient regeneration of the cholestatic liver. Pathway-focused array analysis showed that many genes were up- or down-regulated over 1.5-fold in both PH+BDL and PH groups at 1, 3, 7, and 14 days after treatment. Interestingly, more genes that were functionally related to the extracellular matrix and inflammatory chemokines were found in the PH+BDL group than in the PH group at 7 and 14 days after treatment. Our data suggest that up-regulated extracellular matrix components and inflammatory chemokines may impair the regeneration of cholestatic liver. PMID- 27226152 TI - Preparation and applications of monolithic structures containing metal-organic frameworks. AB - Metal-organic frameworks are a new category of advanced porous materials with large surface areas and porosities, uniform pore sizes, tunable surface chemistry, and structural diversity. In combination with monoliths, they allow the fine tuning of desired interactions required in a variety of applications. This review article summarizes results of recent studies focused on synthetic strategies enabling incorporation of metal-organic frameworks in monolithic structures. A diverse array of applications including chromatographic separation, solid-phase microextraction, sample enrichment, heterogeneous catalysis, and enzymatic catalysis are also described. PMID- 27226153 TI - Heart rate reduction in coronary artery disease and heart failure. AB - Elevated heart rate is known to induce myocardial ischaemia in patients with coronary artery disease (CAD), and heart rate reduction is a recognized strategy to prevent ischaemic episodes. In addition, clinical evidence shows that slowing the heart rate reduces the symptoms of angina by improving microcirculation and coronary flow. Elevated heart rate is an established risk factor for cardiovascular events in patients with CAD and in those with chronic heart failure (HF). Accordingly, reducing heart rate improves prognosis in patients with HF, as demonstrated in SHIFT. By contrast, data from SIGNIFY indicate that heart rate is not a modifiable risk factor in patients with CAD who do not also have HF. Heart rate is also an important determinant of cardiac arrhythmias; low heart rate can be associated with atrial fibrillation, and high heart rate after exercise can be associated with sudden cardiac death. In this Review, we critically assess these clinical findings, and propose hypotheses for the variable effect of heart rate reduction in cardiovascular disease. PMID- 27226155 TI - Stem cells: The cancer's gone, but did chemotherapy damage your heart? PMID- 27226154 TI - Imaging of coronary atherosclerosis - evolution towards new treatment strategies. AB - Coronary atherosclerosis and the precipitation of acute myocardial infarction are highly complex processes, which makes accurate risk prediction challenging. Rapid developments in invasive and noninvasive imaging technologies now provide us with detailed, exquisite images of the coronary vasculature that allow direct investigation of a wide range of these processes. These modalities include sophisticated assessments of luminal stenoses and myocardial perfusion, complemented by novel measures of the atherosclerotic plaque burden, adverse plaque characteristics, and disease activity. Together, they can provide comprehensive, individualized assessments of coronary atherosclerosis as it occurs in patients. Not only can this information provide important pathological insights, but it can also potentially be used to guide personalized treatment decisions. In this Review, we describe the latest advances in both established and emerging imaging techniques, focusing on the strengths and weakness of each approach. Moreover, we discuss how these technological advances might be translated from attractive images into novel imaging strategies and definite improvements in clinical risk prediction and patient outcomes. This process will not be easy, and the many potential barriers and difficulties are also reviewed. PMID- 27226157 TI - Vagus Nerve Stimulation Exerts the Neuroprotective Effects in Obese-Insulin Resistant Rats, Leading to the Improvement of Cognitive Function. AB - Vagus nerve stimulation (VNS) therapy was shown to improve peripheral insulin sensitivity. However, the effects of chronic VNS therapy on brain insulin sensitivity, dendritic spine density, brain mitochondrial function, apoptosis and cognition in obese-insulin resistant subjects have never been investigated. Male Wistar rats (n = 24) were fed with either a normal diet (n = 8) or a HFD (n = 16) for 12 weeks. At week 13, HFD-fed rats were divided into 2 groups (n = 8/group). Each group was received either sham therapy or VNS therapy for an additional 12 weeks. At the end of treatment, cognitive function, metabolic parameters, brain insulin sensitivity, brain mitochondrial function, brain apoptosis, and dendritic spines were determined in each rat. The HFD-fed with Sham therapy developed brain insulin resistance, brain oxidative stress, brain inflammation, and brain apoptosis, resulting in the cognitive decline. The VNS group showed an improvement in peripheral and brain insulin sensitivity. VNS treatment attenuated brain mitochondrial dysfunction and cell apoptosis. In addition, VNS therapy increased dendritic spine density and improved cognitive function. These findings suggest that VNS attenuates cognitive decline in obese-insulin resistant rats by attenuating brain mitochondrial dysfunction, improving brain insulin sensitivity, decreasing cell apoptosis, and increasing dendritic spine density. PMID- 27226156 TI - Hsf1 and Hsp90 orchestrate temperature-dependent global transcriptional remodelling and chromatin architecture in Candida albicans. AB - Fever is a universal response to infection, and opportunistic pathogens such as Candida albicans have evolved complex circuitry to sense and respond to heat. Here we harness RNA-seq and ChIP-seq to discover that the heat shock transcription factor, Hsf1, binds distinct motifs in nucleosome-depleted promoter regions to regulate heat shock genes and genes involved in virulence in C. albicans. Consequently, heat shock increases C. albicans host cell adhesion, damage and virulence. Hsf1 activation depends upon the molecular chaperone Hsp90 under basal and heat shock conditions, but the effects are opposite and in part controlled at the level of Hsf1 expression and DNA binding. Finally, we demonstrate that Hsp90 regulates global transcription programs by modulating nucleosome levels at promoters of stress-responsive genes. Thus, we describe a mechanism by which C. albicans responds to temperature via Hsf1 and Hsp90 to orchestrate gene expression and chromatin architecture, thereby enabling thermal adaptation and virulence. PMID- 27226158 TI - Is multivisceral resection in locally advanced gastrointestinal stromal tumours an acceptable strategy? AB - BACKGROUND: Gastrointestinal stromal tumours (GISTs) represent the most common mesenchymal tumour of the gastrointestinal tract. Although the efficacy of targeted therapy cannot be over-emphasized, surgery remains the only curative primary treatment for patients with localized disease. The median size of GIST at diagnosis is approximately 5-7 cm; however, it is not uncommon for tumours to be as large as 30-40 cm and involving multiple viscera. METHODS: Data were retrospectively collected from patients with GISTs treated at the Singapore General Hospital and the National Cancer Centre Singapore over a 15-year period. Standard resection of GIST without any additional organ removal was termed as a single organ resection (SOR). If the tumour was adjacent to another organ, necessitating the removal of more than one organ, the procedure was defined as a multivisceral resection (MVR). We aim to evaluate the role of MVR in the management of large GISTs. RESULTS: A total of 187 patients underwent curative surgery for GIST between January 2000 and January 2014. Of the 187 patients, 40 (21%) underwent MVR whereas 147 (79%) had SOR. Patients in the MVR group had significantly larger tumour sizes (P < 0.001) yet R0 and R1 resection was achieved in all patients, and no intra-peritoneal rupture was reported. On comparison of MVR versus SOR groups, there was no significant difference in in hospital morbidity and mortality. CONCLUSION: MVR may be required to achieve negative margins in patients with large GISTs, and can be performed with acceptable morbidity and mortality. PMID- 27226159 TI - Nonalcoholic Fatty Liver Disease is Associated with Increased Carotid Intima Media Thickness in Type 1 Diabetic Patients. AB - A growing body of evidence suggests that NAFLD is associated with an increased risk of incident CVD events both in patients without diabetes and in those with type 2 diabetes (T2DM). However, no published data are available regarding the association between NAFLD and C-IMT in T1DM. A total of 722 patients (371 men) with T1DM were included in this cross-sectional study. The main outcome measures were detection of NAFLD, C-IMT and classical risk factors. The mean age of the subjects was 46.2 years, and 51.1% were male. The prevalence of NAFLD was 15.9%. NAFLD patients had a markedly greater C-IMT (0.81 +/- 0.25 vs. 0.69 +/- 0.18 mm; p < 0.001) and frequency of carotid plaque (28.9% vs. 16.9%; p < 0.05) than those without fatty liver. Moreover, the differences in C-IMT remained after adjusting for potential confounders. A stepwise linear regression analysis revealed that age (standardized beta, 0.326; p < 0.001), NAFLD (standardized beta, 0.151, p < 0.001), and hsCRP (standardized beta, 0.115, p = 0.008) were independently associated with C-IMT in all subjects. Our data show NAFLD is associated with elevated C-IMT in T1DM independent of conventional cardiovascular disease risk factors. PMID- 27226160 TI - Oncologic reconstruction of the hand and upper extremity: Maximizing functional outcomes. AB - Upper extremity malignancies have the potential to create significant functional impairment, and as such represent an opportunity for collaborative reconstruction to minimize potential morbidity. Given the increased complexity and array of potential reconstruction solutions, functional limb preservation is overwhelmingly and increasingly successful in appropriately selected patients. The purpose of this review is to familiarize the reader with the general functional considerations of the upper extremity, review major reconstructive options, and present a general algorithm for reconstruction and maintenance of function. J. Surg. Oncol. 2016;113:946-954. (c) 2016 Wiley Periodicals, Inc. PMID- 27226161 TI - State-of-the-art reconstruction of midface and facial deformities. AB - Oncologic resection involving the midface results in potentially disfiguring and challenging defects for the reconstructive surgeon. As with any defect, restoration of form and function is critical, but is particularly difficult in the midface, which is paramount to a patient's physical appearance and identify, as well as the patient's ability to breath, speak, see, and eat. Here, we present an algorithmic approach for optimizing outcomes in midfacial reconstruction utilizing the state-of-the-art reconstructive techniques. J. Surg. Oncol. 2016;113:962-970. (c) 2016 Wiley Periodicals, Inc. PMID- 27226162 TI - Anomalous domain periodicity observed in ferroelectric PbTiO3 nanodots having 180 degrees stripe domains. AB - Nanometer-scale ferroelectric dots and tubes have received a great deal of attention owing to their potential applications to nonvolatile memories and multi functional devices. As for the size effect of 180 degrees stripe domains in ferroelectric thin films, there have been numerous reports on the thickness dependent domain periodicity. All these studies have revealed that the domain periodicity (w) of 180 degrees stripe domains scales with the film thickness (d) according to the classical Landau-Lifshitz-Kittel (LLK) scaling law (w ? d(1/2)) down to the thickness of ~2 nm. In the case of PbTiO3 nanodots, however, we obtained a striking correlation that for the thickness less than a certain critical value, dc (~35 nm), the domain width even increases with decreasing thickness of the nanodot, which surprisingly indicates a negative value in the LLK scaling-law exponent. On the basis of theoretical considerations of dc, we attributed this anomalous domain periodicity to the finite lateral-size effect of a ferroelectric nanodot with an additional effect possibly coming from the existence of a thin non-ferroelectric surface layer. PMID- 27226163 TI - Accumulation of Deleterious Mutations Near Sexually Antagonistic Genes. AB - Mutation generates a steady supply of genetic variation that, while occasionally useful for adaptation, is more often deleterious for fitness. Recent research has emphasized that the fitness effects of mutations often differ between the sexes, leading to important evolutionary consequences for the maintenance of genetic variation and long-term population viability. Some forms of sex-specific selection-i.e., stronger purifying selection in males than females-can help purge a population's load of female-harming mutations and promote population growth. Other scenarios-e.g., sexually antagonistic selection, in which mutations that harm females are beneficial for males-inflate genetic loads and potentially dampen population viability. Evolutionary processes of sexual antagonism and purifying selection are likely to impact the evolutionary dynamics of different loci within a genome, yet theory has mostly ignored the potential for interactions between such loci to jointly shape the evolutionary genetic basis of female and male fitness variation. Here, we show that sexually antagonistic selection at a locus tends to elevate the frequencies of deleterious alleles at tightly linked loci that evolve under purifying selection. Moreover, haplotypes that segregate for different sexually antagonistic alleles accumulate different types of deleterious mutations. Haplotypes that carry female-benefit sexually antagonistic alleles preferentially accumulate mutations that are primarily male harming, whereas male-benefit haplotypes accumulate mutations that are primarily female harming. The theory predicts that sexually antagonistic selection should shape the genomic organization of genetic variation that differentially impacts female and male fitness, and contribute to sexual dimorphism in the genetic basis of fitness variation. PMID- 27226165 TI - Genetic Mapping of Millions of SNPs in Safflower (Carthamus tinctorius L.) via Whole-Genome Resequencing. AB - Accurate assembly of complete genomes is facilitated by very high density genetic maps. We performed low-coverage, whole-genome shotgun sequencing on 96 F6 recombinant inbred lines (RILs) of a cross between safflower (Carthamus tinctorius L.) and its wild progenitor (C. palaestinus Eig). We also produced a draft genome assembly of C. tinctorius covering 866 million bp (~two-thirds) of the expected 1.35 Gbp genome after sequencing a single, short insert library to ~21 * depth. Sequence reads from the RILs were mapped to this genome assembly to facilitate SNP identification, and the resulting polymorphisms were used to construct a genetic map. The resulting map included 2,008,196 genetically located SNPs in 1178 unique positions. A total of 57,270 scaffolds, each containing five or more mapped SNPs, were anchored to the map. This resulted in the assignment of sequence covering 14% of the expected genome length to a genetic position. Comparison of this safflower map to genetic maps of sunflower and lettuce revealed numerous chromosomal rearrangements, and the resulting patterns were consistent with a whole-genome duplication event in the lineage leading to sunflower. This sequence-based genetic map provides a powerful tool for the assembly of a low-cost draft genome of safflower, and the same general approach is expected to work for other species. PMID- 27226164 TI - A Genetic Mosaic Screen Reveals Ecdysone-Responsive Genes Regulating Drosophila Oogenesis. AB - Multiple aspects of Drosophila oogenesis, including germline stem cell activity, germ cell differentiation, and follicle survival, are regulated by the steroid hormone ecdysone. While the transcriptional targets of ecdysone signaling during development have been studied extensively, targets in the ovary remain largely unknown. Early studies of salivary gland polytene chromosomes led to a model in which ecdysone stimulates a hierarchical transcriptional cascade, wherein a core group of ecdysone-sensitive transcription factors induce tissue-specific responses by activating secondary branches of transcriptional targets. More recently, genome-wide approaches have identified hundreds of putative ecdysone responsive targets. Determining whether these putative targets represent bona fide targets in vivo, however, requires that they be tested via traditional mutant analysis in a cell-type specific fashion. To investigate the molecular mechanisms whereby ecdysone signaling regulates oogenesis, we used genetic mosaic analysis to screen putative ecdysone-responsive genes for novel roles in the control of the earliest steps of oogenesis. We identified a cohort of genes required for stem cell maintenance, stem and progenitor cell proliferation, and follicle encapsulation, growth, and survival. These genes encode transcription factors, chromatin modulators, and factors required for RNA transport, stability, and ribosome biogenesis, suggesting that ecdysone might control a wide range of molecular processes during oogenesis. Our results suggest that, although ecdysone target genes are known to have cell type-specific roles, many ecdysone response genes that control larval or pupal cell types at developmental transitions are used reiteratively in the adult ovary. These results provide novel insights into the molecular mechanisms by which ecdysone signaling controls oogenesis, laying new ground for future studies. PMID- 27226166 TI - Detecting Recombination Hotspots from Patterns of Linkage Disequilibrium. AB - With recent advances in DNA sequencing technologies, it has become increasingly easy to use whole-genome sequencing of unrelated individuals to assay patterns of linkage disequilibrium (LD) across the genome. One type of analysis that is commonly performed is to estimate local recombination rates and identify recombination hotspots from patterns of LD. One method for detecting recombination hotspots, LDhot, has been used in a handful of species to further our understanding of the basic biology of recombination. For the most part, the effectiveness of this method (e.g., power and false positive rate) is unknown. In this study, we run extensive simulations to compare the effectiveness of three different implementations of LDhot. We find large differences in the power and false positive rates of these different approaches, as well as a strong sensitivity to the window size used (with smaller window sizes leading to more accurate estimation of hotspot locations). We also compared our LDhot simulation results with comparable simulation results obtained from a Bayesian maximum likelihood approach for identifying hotspots. Surprisingly, we found that the latter computationally intensive approach had substantially lower power over the parameter values considered in our simulations. PMID- 27226167 TI - flyDIVaS: A Comparative Genomics Resource for Drosophila Divergence and Selection. AB - With arguably the best finished and expertly annotated genome assembly, Drosophila melanogaster is a formidable genetics model to study all aspects of biology. Nearly a decade ago, the 12 Drosophila genomes project expanded D. melanogaster's breadth as a comparative model through the community-development of an unprecedented genus- and genome-wide comparative resource. However, since its inception, these datasets for evolutionary inference and biological discovery have become increasingly outdated, outmoded, and inaccessible. Here, we provide an updated and upgradable comparative genomics resource of Drosophila divergence and selection, flyDIVaS, based on the latest genomic assemblies, curated FlyBase annotations, and recent OrthoDB orthology calls. flyDIVaS is an online database containing D. melanogaster-centric orthologous gene sets, CDS and protein alignments, divergence statistics (% gaps, dN, dS, dN/dS), and codon-based tests of positive Darwinian selection. Out of 13,920 protein-coding D. melanogaster genes, ~80% have one aligned ortholog in the closely related species, D. simulans, and ~50% have 1-1 12-way alignments in the original 12 sequenced species that span over 80 million yr of divergence. Genes and their orthologs can be chosen from four different taxonomic datasets differing in phylogenetic depth and coverage density, and visualized via interactive alignments and phylogenetic trees. Users can also batch download entire comparative datasets. A functional survey finds conserved mitotic and neural genes, highly diverged immune and reproduction-related genes, more conspicuous signals of divergence across tissue specific genes, and an enrichment of positive selection among highly diverged genes. flyDIVaS will be regularly updated and can be freely accessed at www.flydivas.info We encourage researchers to regularly use this resource as a tool for biological inference and discovery, and in their classrooms to help train the next generation of biologists to creatively use such genomic big data resources in an integrative manner. PMID- 27226168 TI - Genetic Architecture of Resistance to Stripe Rust in a Global Winter Wheat Germplasm Collection. AB - Virulence shifts in populations of Puccinia striiformis f. sp. tritici (Pst), the causal pathogen of wheat stripe rust, are a major challenge to resistance breeding. The majority of known resistance genes are already ineffective against current races of Pst, necessitating the identification and introgression of new sources of resistance. Germplasm core collections that reflect the range of genetic and phenotypic diversity of crop species are ideal platforms for examining the genetic architecture of complex traits such as resistance to stripe rust. We report the results of genetic characterization and genome-wide association analysis (GWAS) for resistance to stripe rust in a core subset of 1175 accessions in the National Small Grains Collection (NSGC) winter wheat germplasm collection, based on genotyping with the wheat 9K single nucleotide polymorphism (SNP) iSelect assay and phenotyping of seedling and adult plants under natural disease epidemics in four environments. High correlations among the field data translated into high heritability values within and across locations. Population structure was evident when accessions were grouped by stripe rust reaction. GWAS identified 127 resistance loci that were effective across at least two environments, including 20 with significant genome-wide adjusted P-values. Based on relative map positions of previously reported genes and QTL, five of the QTL with significant genome-wide adjusted P-values in this study represent potentially new loci. This study provides an overview of the diversity of Pst resistance in the NSGC winter wheat germplasm core collection, which can be exploited for diversification of stripe rust resistance in breeding programs. PMID- 27226169 TI - Genetic Regulation of Transcriptional Variation in Natural Arabidopsis thaliana Accessions. AB - An increased knowledge of the genetic regulation of expression in Arabidopsis thaliana is likely to provide important insights about the basis of the plant's extensive phenotypic variation. Here, we reanalyzed two publicly available datasets with genome-wide data on genetic and transcript variation in large collections of natural A. thaliana accessions. Transcripts from more than half of all genes were detected in the leaves of all accessions, and from nearly all annotated genes in at least one accession. Thousands of genes had high transcript levels in some accessions, but no transcripts at all in others, and this pattern was correlated with the genome-wide genotype. In total, 2669 eQTL were mapped in the largest population, and 717 of them were replicated in the other population. A total of 646 cis-eQTL-regulated genes that lacked detectable transcripts in some accessions was found, and for 159 of these we identified one, or several, common structural variants in the populations that were shown to be likely contributors to the lack of detectable RNA transcripts for these genes. This study thus provides new insights into the overall genetic regulation of global gene expression diversity in the leaf of natural A. thaliana accessions. Further, it also shows that strong cis-acting polymorphisms, many of which are likely to be structural variations, make important contributions to the transcriptional variation in the worldwide A. thaliana population. PMID- 27226171 TI - Author response: use of bioartificial dermal regeneration template for skin restoration in combat casualty injuries. AB - Response to: Leclere FM & Casoli V. Use of bioartificial dermal regeneration template for skin restoration in combat casualty injuries. Regen. Med. 11(4), 359 360 (2016). PMID- 27226172 TI - Persistent organic pollutants in Baltic herring (Clupea harengus)-an aspect of gender. AB - Persistent organic pollutants (POPs) are monitored regularly in water, sediment, and biota in the Baltic Sea. Lipophilic substances are measured in remarkable concentrations especially in the fatty parts of fish, such as herring (Clupea harengus). However, less lipophilic POPs, e.g. perfluorinated compounds (PFCs), can also be detected. For the first time to our knowledge, this study provides a broad range of contaminant concentrations simultaneously measured in filet, liver, and gonads of both sexes of Baltic herring. We analysed organochlorines, polybrominated diphenyl ethers (PBDEs), and PFCs in mature autumn-spawning individuals and found distinct organ pollutant pattern for all POPs in both sexes. POP concentrations found in the gonads of both sexes indicate that not only females but also males tend to reduce contaminants via reproduction. However, sex-dependent differences could be identified for hexachlorobenzene, PBDEs, and were most remarkable for PFCs. This transfer of contaminants to the gonads in both male and female herring is being underestimated, as it may directly affect the general reproduction success as well as the healthy development of the next generation. Hence, the accumulation of contaminants in the gonads should be considered one possible threat to a healthy wildlife as its achievement is stated by the Baltic Sea Action Plan. Inclusion of a periodic monitoring of POP concentrations in gonads of fish may be an important bioeffect measure to assess the environmental status of biota in the Baltic Sea. PMID- 27226173 TI - Heavy metals from non-exhaust vehicle emissions in urban and motorway road dusts. AB - The main sources of non-exhaust vehicular emissions that contribute to road dust are tire, brake and clutch wear, road surface wear, and other vehicle and road component degradation. This study is an attempt to identify and investigate heavy metals in urban and motorway road dusts as well as in dust from brake linings and tires. Road dust was collected from sections of the A-4 motorway in Poland, which is part of European route E40, and from urban roads in Katowice, Poland. Dust from a relatively unpolluted mountain road was collected and examined as a control sample. Selected metals Cd, Cr, Cu, Ni, Pb, Zn, Fe, Se, Sr, Ba, Ti, and Pd were analyzed using inductively coupled plasma-mass spectrometry, inductively coupled plasma (ICP)-optical emission spectroscopy, and atomic absorption spectroscopy on a range of size-fractionated road dust and brake lining dust (<20, 20-56, 56-90, 90-250, and >250 MUm). The compositions of brake lining and tire dust were also investigated using scanning electron microscopy-energy dispersive spectroscopy. To estimate the degree of potential environmental risk of non-exhaust emissions, comparison with the geochemical background and the calculations of geo-accumulation indices were performed. The finest fractions of urban and motorway dusts were significantly contaminated with all of the investigated metals, especially with Ti, Cu, and Cr, which are well-recognized key tracers of non-exhaust brake wear. Urban dust was, however, more contaminated than motorway dust. It was therefore concluded that brake lining and tire wear strongly contributed to the contamination of road dust. PMID- 27226174 TI - Differential gene expression in the duodenum, jejunum and ileum among crossbred beef steers with divergent gain and feed intake phenotypes. AB - Small intestine mass and cellularity were previously associated with cattle feed efficiency. The small intestine is responsible for the digestion of nutrients and absorption of fatty acids, amino acids and carbohydrates, and it contributes to the overall feed efficiency of cattle. The objective of this study was to evaluate transcriptome differences among the small intestine from cattle with divergent gain and feed intake. Animals most divergent from the bivariate mean in each of the four phenotypic Cartesian quadrants for gain * intake were selected, and the transcriptomes of duodenum, jejunum and ileum were evaluated. Gene expression analyses were performed comparing high gain vs. low gain animals, high intake vs. low intake animals and each of the phenotypic quadrants to all other groups. Genes differentially expressed within the high gain-low intake and low gain-high intake groups of animals included those involved in immune function and inflammation in all small intestine sections. The high gain-high intake group differed from the high gain-low intake group by immune response genes in all sections of the small intestine. In all sections of small intestine, animals with low gain-low intake displayed greater abundance of heat-shock genes compared to other groups. Several over-represented pathways were identified. These include the antigen-processing/presentation pathway in high gain animals and PPAR signaling, starch/sucrose metabolism, retinol metabolism and melatonin degradation pathways in the high intake animals. Genes with functions in immune response, inflammation, stress response, influenza pathogenesis and melatonin degradation pathways may have a relationship with gain and intake in beef steers. PMID- 27226170 TI - Recent advances in thromboresistant and antimicrobial polymers for biomedical applications: just say yes to nitric oxide (NO). AB - Biomedical devices are essential for patient diagnosis and treatment; however, when blood comes in contact with foreign surfaces or homeostasis is disrupted, complications including thrombus formation and bacterial infections can interrupt device functionality, causing false readings and/or shorten device lifetime. Here, we review some of the current approaches for developing antithrombotic and antibacterial materials for biomedical applications. Special emphasis is given to materials that release or generate low levels of nitric oxide (NO). Nitric oxide is an endogenous gas molecule that can inhibit platelet activation as well as bacterial proliferation and adhesion. Various NO delivery vehicles have been developed to improve NO's therapeutic potential. In this review, we provide a summary of the NO releasing and NO generating polymeric materials developed to date, with a focus on the chemistry of different NO donors, the polymer preparation processes, and in vitro and in vivo applications of the two most promising types of NO donors studied thus far, N-diazeniumdiolates (NONOates) and S-nitrosothiols (RSNOs). PMID- 27226175 TI - Dependence of Excited-State Properties of a Low-Bandgap Photovoltaic Copolymer on Side-Chain Substitution and Solvent. AB - The excited-state properties and chain conformations of a new low-bandgap copolymer based on benzo[1,2-b:4,5-b']dithiophene (BDT) and thieno[3,4 b]thiophene with meta-alkoxyphenyl-substituted side chains in solution were investigated comprehensively. Time-resolved spectroscopy suggested that the excited-state properties were sensitive to the conformations of the copolymer in solution. In addition, excited-state dynamics analyses revealed the photogeneration of triplet excited states by intersystem crossing (ISC) at a rate constant of ~0.4*10(9) s(-1) as a result of direct meta-alkoxyphenyl connection to the donor unit BDT irrespective to the macromolecular conformations. According to El-Sayed's rule, the fast ISC herein is correlated with the change of orbital types between singlet and triplet excited states as also shown by quantum chemical calculations. Our studies may shed light on the structure-property relationships of photovoltaic materials. PMID- 27226177 TI - Involvement of P2 receptors in regulation of glomerular permeability to albumin by extracellular nucleotides of intra-/extra-glomerular origins. AB - Plasma filtration through glomerular filtration barrier (GFB) is a key process to maintain fluid and electrolyte homeostasis. GFB consisting of endothelial cells, podocytes and basement membrane restricts passage of albumin but is permeable for smaller plasma molecules. Various biological agents, such as extracellular nucleotides influence activity of cells, which in turn affects permeability of GFB. Nucleotides are released from cells outside and within the glomeruli that activate the purinoceptors - P2Rs classified into ATP-gated non-selective ion channels, P2X receptors (P2XRs), and G-protein-coupled metabotropic P2Y receptors (P2YRs). P2Rs are expressed on cellular components of GFB. P2Rs activation triggers intracellular calcium concentration and calcium-dependent metabolism with subsequent affect on glomerular permeability to albumin. Purinergic dependent glomerular cell activation also affects the biophysical properties of acelluar glomerular basement membrane (GMB). Finally, P2Rs stimulation may lead to increased proteins excretion in urine. The involvement of P2Rs in increased GFB permeability to albumin may be expected under pathophysiological conditions characterized by increased albumin excretion in urine. PMID- 27226176 TI - Optimization of CRISPR/Cas9 genome editing to modify abiotic stress responses in plants. AB - Genome editing using the CRISPR/Cas9 system can be used to modify plant genomes, however, improvements in specificity and applicability are still needed in order for the editing technique to be useful in various plant species. Here, using genome editing mediated by a truncated gRNA (tru-gRNA)/Cas9 combination, we generated new alleles for OST2, a proton pump in Arabidopsis, with no off-target effects. By following expression of Cas9 and the tru-gRNAs, newly generated mutations in CRIPSR/Cas9 transgenic plants were detected with high average mutation rates of up to 32.8% and no off-target effects using constitutive promoter. Reducing nuclear localization signals in Cas9 decreased the mutation rate. In contrast, tru-gRNA Cas9 cassettes driven by meristematic- and reproductive-tissue-specific promoters increased the heritable mutation rate in Arabidopsis, showing that high expression in the germ line can produce bi-allelic mutations. Finally, the new mutant alleles obtained for OST2 exhibited altered stomatal closing in response to environmental conditions. These results suggest further applications in molecular breeding to improve plant function using optimized plant CRISPR/Cas9 systems. PMID- 27226178 TI - Aquaglyceroporins in the kidney: present state of knowledge and prospects. AB - Aquaporins belong to a family of small, transmembrane proteins that form channels selectively permeable for water. Some of them known as aquaglyceroporins also enable transportation of other small molecules such as glycerol, urea or ammonia. To date, 13 isoforms of aquaporins has been discovered in mammals (AQP0 - AQP12), 9 of which is localized in different parts of the renal tubular epithelium. In recent years, particular interest has been paid to aquaporins selectively permeable only to water molecules, determination of their localization and expression allowed to define the role of these proteins in renal excretion of water and their importance in the development of diseases. Alas, thus far the role in the physiological processes of the aquaglyceroporins localized in the kidneys has not been fully determined. This review summarizes our current knowledge on additional transport functions of renal AQPs (AQP3, AQP6, AQP7 and AQP8). On the basis of the information gathered and the opinions by many authors, it has been found that aquaglyceroporins are most probably the key element in the renal regulation of nitrogen balance and maintenance of the correct pH of body fluids. Elucidating additional transport functions of AQPs in the kidney will improve our understanding of the renal function in heath and diseases. The presented in this article prospect on renal aquaglyceroporin hopefully will stimulate future research in both basic and clinical fields. PMID- 27226179 TI - The exercise-induced myokine irisin does not show an association with depressiveness, anxiety and perceived stress in obese women. AB - Irisin has recently been proposed to act as a myokine secreted from skeletal muscle following exercise and to exert several health-beneficial effects, although its role is far from being established. In contrast to the growing body of literature on the biological regulation and function of irisin, there is no evidence on potential associations with mental functions. Since physical activity has been reported to have favorable impact on mental functions, we investigated the association of irisin with depressiveness, perceived stress, and anxiety as well as eating disorder symptoms in obese women. We included 98 female obese inpatients (age: mean +/- S.D. 43.9 +/- 12.5 years; body mass index 49.2 +/- 8.3 kg/m(2)) covering a broad spectrum of psychopathology. Depressiveness (PHQ-9), perceived stress (PSQ-20), anxiety (GAD-7), and eating disorder symptoms (EDI-2) were assessed psychometrically. Plasma irisin obtained at the same time was determined by ELISA. Irisin did not correlate with depressiveness (r = -0.03, P = 0.80), anxiety (r = 0.14, P = 0.17) and perceived stress (r = -0.14, P = 0.18) as well as eating disorder symptoms in general (r = -0.09, P = 0.39). No correlation of irisin was observed with any subscales of the PSQ-20 and EDI-2 (after Bonferroni correction). In conclusion, irisin is not associated with depressiveness, anxiety and perceived stress in female obese patients. These results do not support the assumption of irisin being involved in psychoendocrine pathways of the regulation of depression or other mental functions such as anxiety and perceived stress. PMID- 27226180 TI - High dietary fructose does not exacerbate the detrimental consequences of high fat diet on basilar artery function. AB - The objective of the study was to determine the effects of a high fat (HF) diet alone or with high fructose (HF/F) on functional and structural changes in the basilar arteries and cardiovascular health parameters in rats. Male Sprague Dawley rats were fed either a HF (30%) or HF/F (30/40%) diet for 12 weeks. The basilar artery was cannulated in a pressurized system (90 cm H2O) and vascular responses to KCl (30 - 120 mM), endothelin (10(-11) - 10(-7) M), acetylcholine (ACh) (10(-10) - 10(-4) M), diethylamine (DEA)-NONO-ate (10(-10) - 10(-4) M), and papaverine (10(-10) - 10(-4) M) were evaluated. Rats were also monitored for food intake, body weight, blood lipids, blood pressure, and heart rate. At death, asymmetrical dimethyl arginine level (ADMA) and leptin were assayed in serum. Although there was no significant difference in weight gain and food intake, HF and HF/F diets increased body fat composition and decreased the lean mass. HF/F diet accelerated the development of dyslipidemia. Although resting blood pressure remained unchanged, stress caused a significant elevation in blood pressure and a modest increase in heart rate in HF fed rats. Both HF and HF/F diet resulted in decreased response to endothelium-dependent and -independent relaxation, whereas increased basilar artery wall thickness was observed only in HF group. Serum leptin levels positively correlated with wall thickness. Moreover serum ADMA was increased and eNOS immunofluorescence was significantly decreased with both diets. These data suggest that the presence of high fructose in a HF diet does not exacerbate the detrimental consequences of a HF diet on basilar artery function. PMID- 27226181 TI - Assessment of incretins in oral glucose and lipid tolerance tests may be indicative in the diagnosis of metabolic syndrome aggravation. AB - Incretins stimulated by oral meals are claimed to be protective for the pancreatic beta cells, to increase insulin secretion, to inhibit glucagon release, slow gastric emptying (glucagon-like peptide-1) and suppress appetite. Recently it has however been suggested that glucagon-like peptide-1 (GLP-1) is putative early biomarker of metabolic consequences of the obesity associated proinflammatory state. The study was aimed to compare the release of incretins and some of early markers of inflammation at the fasting and postprandial period induced by functional oral glucose as well as lipid load in healthy controls and patients with metabolic syndrome (MS) to see if functional tests may be helpful in searching for the inflammatory status of patients. Fifty patients with MS and 20 healthy volunteers (C) participated in this study. The 3-hour oral glucose (OGTT) and the 8-hour oral lipid (OLTT) tolerance tests were performed. At fasting leptin and adiponectin, as well as every 30 minutes of OGTT and every 2 hours of OLTT blood concentration of GLP-1, glucose-dependent insulinotropic polypeptide (GIP), glucose, insulin, triglycerides, free fatty acids, glutathione peroxidase, interleukin-6, sE-selectin, monocyte chemoattractant protein-1 (MCP1) and visfatin were measured. At fasting and during both OGTT and OLTT the level of incretins did not differ between the MS and the C group. Both glucose and lipids reach food activated incretins secretion. Glucose was the main GLP-1 release activator, while the lipid load activated evidently GIP secretion. A significantly larger AUC-GIP after the lipid-rich meal over the carbohydrate meal was observed, while statistically bigger value of AUC-GLP-1 was noticed in OGTT than in OLTT (P < 0.001) within each of the investigated groups. In patients with the highest fasting plasma GIP concentration (3(rd) tertile), IL-6, MCP-1, sE selectin and visfatin blood levels were increased and correlated with glutathione peroxydase, leptin/adiponectin ratio, higher visfatin and interleukin-6 levels. The fat containing meals stimulate the long-lasting release of incretins, mainly GIP, parallel to the increase of the markers of low grade inflammation associating obesity in metabolic syndrome. The possibility of use of the postprandial (OLTT) GIP release measurement for the low grade inflammation progress in MS patients is suggested. PMID- 27226182 TI - Short-term antidiabetic treatment with insulin or metformin has a similar impact on the components of metabolic syndrome in women with gestational diabetes mellitus requiring antidiabetic agents: results of a prospective, randomised study. AB - Gestational diabetes mellitus (GDM) is associated with an increased prevalence of fetal and maternal complications primarily caused by maternal hyperglycemia, which results in abnormal fetal growth. Diet modification is a common first step in the treatment of GDM, followed by antidiabetic pharmacotherapy if this approach fails. Insulin therapy is generally accepted; however, oral hypoglycemic agents have been used in this population. In this prospective, randomised study, we compared maternal metabolic status after treatment with insulin or metformin. Pregnant women (gestational age: >= 20 weeks) with GDM requiring medical hypoglycemic treatment were randomly allocated to the Metformin (n = 35) or Insulin (n = 43) Groups. Maternal metabolic status - assessed by glycated hemoglobin (HBA1c) level, glycemic profile, insulin concentration, Homeostatic Model Assessment - Insulin Resistance index, and lipids - was recorded at booking and throughout pregnancy. The characteristics of the study group were: maternal age 33.5 +/- 5.9 years, gestational age at baseline 28.5 +/- 3.5 weeks, prepregnancy body mass index (BMI) 32.2 +/- 3.5 kg/m(2), HbA1c at baseline 5.6 +/ 0.6%, and average daily glycemia 5.9 +/- 0.6 mmol/dl. Fasting glycemia at term was significantly lower in the Insulin Group but there were no significant differences in mean daily glycemia, HbA1c and BMI at term between the groups. Longitudinally, there was a small but significant increase in BMI and a significant increase in high-density lipoprotein-cholesterol in the Insulin Group and a significant increase in the atherogenic index of plasma (AIP) and a trend towards higher triglycerides in the Metformin Group. Both fasting and average daily glycemia were significantly reduced following treatment in both groups. No such change was evident for HbA1c. In a relative risk analysis, metformin treatment was associated with an insignificant elevated risk of HbA1c, triglycerides and lipid indices falling within the highest quartile at term. The risk of gestational weight gain and total cholesterol falling within the highest quartile at term was insignificantly reduced in the Metformin Group. In conclusion, short-term antidiabetic treatment with insulin or metformin has a similar impact on markers of metabolic syndrome in women with GDM requiring antidiabetic treatment. Secondly, treatment with metformin is associated with increased triglyceride levels and higher AIP in the third trimester in pregnant women with GDM. PMID- 27226183 TI - Effect of melatonin supplementation on plasma lipid hydroperoxides, homocysteine concentration and chronic fatigue syndrome in multiple sclerosis patients treated with interferons-beta and mitoxantrone. AB - Multiple sclerosis (MS) prevalence is higher in geographic regions with less sunlight exposure. Melatonin participates in the effects of sunlight in healthy individuals and could play a role in MS pathophysiology. Melatonin crosses the blood-brain barrier and exerts antioxidative, immunomodulatory, and anti inflammatory effects. Chronic fatigue syndrome concerns 80 - 90% MS patients. The pathophysiology of chronic fatigue syndrome is unknown, however activation of immune, inflammatory, oxidative and nitrosative stress mechanisms and plasma lipid peroxide elevation was reported. Homocysteine increases plasma lipid hydroperoxides levels. The aim was to determine the effect of melatonin supplementation on chronic fatigue syndrome in MS patients and evaluate plasma lipid hydroxyperoxides (LHP) and homocysteine concentrations as a potential biochemical fatigue biomarkers. Into a case-control prospective study 102 MS patients divided according receiving immunomodifying MS treatment into groups: RRMS-pretreated, RRMS-INF-beta, SP/PPMS-mitoxantrone, RRMS-relapse were enrolled. Patients were supplemented with melatonin over 90 days. Plasma LHP, homocysteine concentration, brain MRI and fatigue score were examined. Results show that LHP concentrations were significantly higher in all studied MS groups vs. CONTROLS: In all MS patient groups melatonin application resulted in significant decrease in plasma LHP concentrations. Plasma homocysteine concentration was similar in healthy people, RRMS-pretreated, RRMS-INF-beta and SP/PP-MS-mitoxantrone groups. However, in the RRMS-relapse group plasma levels of homocysteine were significantly higher compared to the RRMS-pretreated group. There were no significant differences in plasma homocysteine concentration in the studied groups before and after melatonin application. The fatigue score was significantly lower in RRMS pretreated group compared to RRMS-INF-beta and SP/PP MS-mitoxantrone treated patients. Plasma lipid hydroxyperoxides could be potential biochemical chronic fatigue syndrome biomarker in MS patients and homocysteine could be a potential marker of acute phase of MS. Melatonin exerts beneficial effects in MS patients based on its' proved antioxidative properties. PMID- 27226184 TI - Preventive effects of procyanidin A2 on glucose homeostasis, pancreatic and duodenal homebox 1, and glucose transporter 2 gene expression disturbance induced by bisphenol A in male mice. AB - Procyanidins (PCs) as oligomeric compounds with antidiabetic properties formed from catechin and epicatechin molecules. Bisphenol A(BPA) is a common chemical material use in food and beverage packaging. The aim of this study was to explore the protective effects of procyanidin A2 (PCA2) against glucose homeostasis disturbance and gene expression of pancreatic and duodenal homebox 1 (Pdx1) as well as glucose transporter 2 (Glut2) induced by BPA in male mice. First tested these five concentrations of PCA2 (3 - 300 MUM) alone and in combination with BPA(100 MUg/L), on insulin secretion from isolated islets at in vitro condition. Next, examined the influence of BPA and PCA2 on islet apoptosis using flowcytometry. At in vivo condition, the BPA (100 MUg/kg) and PCA2 (10 MUmol/kg) administered for 20 days then, blood glucose and insulin, Pdx1 and, Glut2 genes expression, and oxidative stress markers examined. The results indicated that PCA2 strongly prevents islet cells apoptosis induced by BPA and, co administration of PCA2 and BPA modified hyperglycemia. BPA reduced Pdx1 and Glut2 mRNA expression and antioxidant level in pancreas tissue, whereas PCA2 prevented from these effects. The findings from these studies suggest that use of PCA2 rich plants have preventive effects on hyperglycemia, and type 2 diabetes. PMID- 27226185 TI - Glyprolines exert protective and repair-promoting effects in the rat stomach: potential role of the cytokine GRO/CINC-1. AB - Glyprolines have been reported to exert protective effects in the stomach. In this study, we examined the potential effects of intranasal administration of Pro Gly-Pro (PGP) and N-acetyl-Pro-Gly-Pro (AcPGP) on experimental gastric ulcer formation and healing. We also studied gastric release of the cytokine GRO/CINC 1, and its potential role in ulcer development and healing. Gastric ulcers were induced in rats by applying acetic acid to the serosa of the stomach. PGP and AcPGP were then administered at a dose of 3.7 MUmol/kg once daily on either days 1 - 3 (ulcer formation) or days 4 - 6 (ulcer healing). Measurement of ulcer area and histological examination of gastric tissue were carried out on days 4 and 7 after application of acetic acid. In vitro studies involved addition of the glyprolines to cultured rat gastric epithelial cells with or without lipopolysaccharide. Reverse transcription PCR, real-time PCR and ELISA were used for cytokine analysis. PGP and AcPGP significantly reduced ulcer areas on the 4(th) day and accelerated the healing on the 7(th) day compared with the control. After acetic acid-induced ulceration, the expression of GRO/CINC-1 mRNA in gastric tissue was increased 9-fold versus the sham-operated group. Treatment with PGP or AcPGP both significantly suppressed the expression of GRO/CINC-1 mRNA in gastric tissue. However, the glyprolines did not alter LPS-induced mRNA expression or release of GRO/CINC-1 from cultured rat gastric epithelial cells, even though those cells were harvested from rats subjected to the ulcer-induction procedure. The results of this study show that intranasal administration of PGP and AcPGP significantly increased resistance against acetic acid-induced ulceration and accelerated healing in the rats. These effects may be due, at least in part, to their ability to reduce the acetic acid-induced GRO/CINC-1 expression and production in gastric tissue. PMID- 27226186 TI - Role of curcumin in protection of gastric mucosa against stress-induced gastric mucosal damage. Involvement of hypoacidity, vasoactive mediators and sensory neuropeptides. AB - The antioxidizing properties of curcumin, a highly pleiotropic substance used for centuries in traditional medicine has been confirmed by numerous experimental and clinical studies. Curcumin exhibits anti-inflammatory, antiproliferative and anti angiogenic actions inhibiting the development and progression of tumors but the efficacy of this compound to influence gastric acid secretion n in the stomach and to affect the gastric mucosal damage induced by non-topical ulcerogenes such as stress has been little studied. We determined the effect of curcumin on basal and pentagastrin- or histamine-stimulated gastric secretion, in rats with surgically implemented gastric fistulas and we assessed the contribution of gastric secretion, endogenous prostaglandin (PG), endogenous nitric oxide (NO), as well as sensory afferent nerves in the mechanisms underlying the potential gastroprotective effects of curcumin against stress-induced gastric mucosal lesions. Rats exposed to water immersion and restraint stress (WRS) for 3.5 h were pretreated either with: 1) vehicle (saline); 2) curcumin (2.5 - 100 mg/kg i.g.) or 3) curcumin (50 mg/kg i.g.) combined with or without indomethacin (5 mg/kg i.p.), SC-560 (5 mg/kg i.g.) or rofecoxib (10 mg/kg i.g.); 4) curcumin (50 mg/kg i.g.) co-administered with (L-NNA (20 mg/kg i.p.) with or without L arginine (200 mg/kg i.g.), a substrate for NO-synthase; 5) curcumin (50 mg/kg i.g.) administered in rats with intact or capsaicin-induced functional ablation of sensory nerve fibers, and 6) curcumin (50 mg/kg i.g.) administered with capsazepine (5 mg/kg i.g.), the antagonist of vanilloid TRPV1 receptor. The number of gastric lesions was determined by planimetry, the gastric blood flow (GBF) was assessed by H2-gas clearance technique, the plasma gastrin concentrations were measured using the radioimmunoassay (RIA) and the expression of mRNA for tumor necrosis factor-alpha (TNF-alpha), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in gastric mucosa was evaluated by reverse transcription polymerase chain reaction (RT-PCR). Curcumin dose dependently reduced the WRS-induced gastric lesions, the dose inhibiting these lesions by 50% being about 50 mg/kg. These effects of curcumin were accompanied by an increase in GBF and the reduction in basal and histamine- or pentagastrin stimulated gastric acid secretion. The protective and hyperemic activities of curcumin (50 mg/kg i.g.) against WRS lesions were significantly attenuated (P < 0.05) in rats pretreated with rofecoxib and SC-560 and completely reversed (P < 0.01) by indomethacin. L-NNA significantly reduced (P < 0.05) the decrease in WRS induced lesions and the accompanying rise in GBF caused by curcumin and these effects were restored by concurrent treatment with L-arginine (200 mg/kg i.g.). The curcumin-induced decrease in the number of WRS-induced gastric lesions and accompanying increase in the GBF were significantly attenuated (P < 0.05) in capsaicin-denervated rats and in those pretreated with capsazepine. These effects of curcumin in rats with capsaicin denervation were restored by concomitant treatment with exogenous calcitonin gene related pepetide (CGRP) combined with curcumin and subsequently exposed to WRS. The expression of mRNA for TNF-alpha, COX-2 and iNOS was significantly increased (P < 0.05) in vehicle-pretreated control rats exposed to WRS and significantly attenuated (P < 0.05) by curcumin administered in graded dosages. We conclude that curcumin exerts gastroprotective and hyperemic activities against experimental stress-induced gastric lesions by mechanism involving endogenous prostaglandins, NO, the neuropeptides such as CGRP released from capsaicin-sensitive afferent nerves and the activation of vanilloid TRPV1 receptors located on these sensory nerve terminals. PMID- 27226188 TI - Effects of body temperature on post-anoxic oxidative stress from the perspective of postnatal physiological adaptive processes in rats. AB - It is well known that decrease in body temperature provides protection to newborns subjected to anoxia/ischemia. We hypothesized that the normal body temperature of 33 degrees C in neonatal rats (4 degrees C below normal body temperature in adults) is in fact a preadaptation to protect CNS from anoxia and further reductions as well as elevations in temperature may be counterproductive. Our experiments aimed to examine the effect of changes in body temperature on oxidative stress development in newborn rats exposed to anoxia. Two-day-old Wistar rats were divided into 4 temperature groups: i. hypothermic at body temperature of 31 degrees C, ii. maintaining physiological neonatal body temperature of 33 degrees C, iii. forced to maintain hyperthermic temperature of 37 degrees C, and i.v. forced to maintain hyperthermic temperature of 39 degrees C. The temperature was controlled starting 15 minutes before and afterword during 10 minutes of anoxia as well as for 2 hours post-anoxia. Cerebral concentrations of lipid peroxidation products malondialdehyde (MDA) and conjugated dienes (CD) and the activities of antioxidant enzymes had been determined post mortem: immediately after anoxia was finished and 3, 7, and 14 days later. There were no post-anoxic changes in the concentration of MDA, CD and in antioxidant enzymes activity in newborn rats kept at their physiological body temperature of 33 degrees C. In contrast, perinatal anoxia at body temperature elevated to 37 degrees C or 39 degrees C as well as under hypothermic conditions (31 degrees C) intensified post-anoxic oxidative stress and depleted the antioxidant pool. Overall, these findings suggest that elevated body temperature (hyperthermia or fever), as well as exceeding cooling beyond the physiological level of body temperature of newborn rats, may extend perinatal anoxia-induced brain lesions. Our findings provide new insights into the role of body temperature in anoxic insult in vivo. PMID- 27226187 TI - Inflammation increases oxidative DNA damage repair and stimulates preneoplastic changes in colons of newborn rats. AB - Oxidative DNA damage may be a risk factor for development of various pathologies, including malignancy. We studied inflammation triggered modulation of repair activity in the intestines of three weeks old rats injected i.p. with E.coli or S. typhimurium lipopolysaccharides (LPS) at doses of 1, 5 or 10 mg/kg. Subsequent formation in these animals of colonic preneoplastic lesions, aberrant crypt foci (ACF) was also investigated. Five days after LPS administration no differences were observed in repair rate of 1,N(6)-ethenoadenine (epsilonA), 3,N(4) ethenocytosine (epsilonC) and 8-oxoguanine (8-oxoG) in intestines of these rats, as measured by the nicking assay. However a significant increase in all three repair activities was found within one and two months after S. typhimurium LPS treatment. E. coli LPS significantly increased only the 8-oxoG repair. S. typhimurium LPS stimulated mRNA transcription of pro-inflammatory proteins, lipooxygenase-12 and cyclooxygenase-2, as well as some DNA repair enzymes like AP endonuclease (Ape1) and epsilonC-glycosylase (Tdg). mRNA level of DNA glycosylases excising epsilonA (MPG) and 8-oxoG (OGG1) was also increased by LPS treatment, but only at the highest dose. Transcription of all enzymes increased for up to 30 days after LPS, and subsequently decreased to the level observed before treatment, with the exception of APE1, which remained elevated even two months after LPS administration. Thus, the repair efficiency of epsilonA, epsilonC and 8-oxoG depends on the availability of APE1, which increases OGG1 and TDG turnover on damaged DNA, and presumably stimulates MPG. One and two months after administration of E. coli or S. typhimurium LPS, the number of aberrant crypt foci in rat colons increased in a dose and time dependent manner. Thus, inflammation stimulates the repair capacity for epsilonA, epsilonC and 8-oxoG, but simultaneously triggers the appearance of preneoplastic changes in the colons. This may be due to increased oxidative stress and imbalance in DNA repair. PMID- 27226189 TI - Elimination of extracellular dopamine in the medial prefrontal cortex of conscious mice analysed using selective enzyme and uptake inhibitors. AB - We have shown in a previous study that in the medial prefrontal cortex (mPFC) of Comt knockout animals, uptake1 followed by oxidation accounts for approximately 50% and uptake2 followed by O-methylation for the remaining 50% of dopamine clearance. However, compensatory mechanisms in genetically modified animals may have affected the result. Therefore, in the present study, we gave a high dose (30 mg/kg) of tolcapone in combination with pargyline and reboxetine to C57BL/6J mice to see whether the earlier findings could be confirmed. The three drugs were also given together. We used intracerebral microdialysis to determine the levels of extracellular dopamine and its metabolites in the mPFC. In addition, we analyzed dopamine, 3,4-dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA) contents in cortical and striatal synaptosomes to estimate the amount of releasable dopamine and dopamine turnover. In the prefrontal cortex of male C57BL/6J mice, the combination of two drugs (pargyline + tolcapone or reboxetine + tolcapone) generally elevated extracellular dopamine levels more than any single drug. Similar responses, although much weaker, were observed in female mice. Unexpectedly, triple treatment with pargyline, reboxetine and tolcapone did not increase dopamine outflow in the mPFC in either sex, and the treatment actually diminished dopamine outflow in the dorsal striatum. This seems to indicate that such an extensive treatment induces a fast and effective shut-down of dopamine release both in the mPFC and striatum to protect the brain from excess dopaminergic stimulation. The observed decrease in extracellular dopamine levels was not due to the depletion of releasable dopamine because abundant amounts of dopamine were present in synaptosomes. These results imply that the relative proportion of COMT-induced dopamine clearance may be somewhat lower than earlier estimated. PMID- 27226190 TI - Modulatory effects of steroid hormones, oxytocin, arachidonic acid, forskolin and cyclic AMP on the expression of aquaporin 1 and aquaporin 5 in the porcine uterus during placentation. AB - Aquaporins (AQPs) are proteins forming trans-membrane channels responsible for water transport. AQP1 and AQP5 are present in structures of the female reproductive system. In the uterus, these AQPs are involved in water movement between the intraluminal, interstitial and capillary compartments and their uterine expression is essential throughout the pregnancy, including its early stages. Thus, the study aimed to assess the influence of P4 (progesterone), E2 (estradiol), OT (oxytocin), AA (arachidonic acid), cAMP and FSK (forskolin) on the AQP1 and AQP5 mRNA and protein expression in the uterine tissue of gilts on Days 30 - 32 of gestation (the placentation period), following short (3 h) and long (24 h) incubations. Steroid hormones influenced the expression of AQP1 and AQP5; E2 up-regulated, but P4 down-regulated mRNAs of these AQPs, whereas the protein level of studied AQPs was increased by both steroids. OT treatment decreased AQP1 (after 24 h), but increased AQP5 (after 3 h) mRNA expression. Treatment with AA significantly reduced the AQP1 expression at the mRNA level, but stimulated at the protein level. The expression of AQP5 mRNA and protein was stimulated by AA. FSK markedly decreased AQP1 mRNA, but increased of AQP5 after 3 h incubation. In turn, cAMP stimulated and inhibited transcription of AQP5 after 3- and 24-h incubations, respectively. Immunohistochemical analysis confirmed the uterine localization of AQP1 in the apical and basal membranes of endothelial cells and AQP5 in the apical membranes of epithelial cells under control condition. Treatments with P4, E2, AA, cAMP or FSK have caused additional appearance of AQP5 labeling in the basolateral membranes of epithelial cells. These results suggest a participation of steroid hormones (P4 and E2), AA derivatives and cAMP in controlling the expression of AQP1 and AQP5 as well as the distribution of AQP5 in the uterine tissue of pregnant gilts during placentation (Days 30 - 32 of gestation). PMID- 27226192 TI - Characterization of the Aldehydes and Their Transformations Induced by UV Irradiation and Air Exposure of White Guanxi Honey Pummelo (Citrus Grandis (L.) Osbeck) Essential Oil. AB - Aldehydes are key aroma contributors of citrus essential oils. White Guanxi honey pummelo essential oil (WPEO) was investigated in its aldehyde constituents and their transformations induced by UV irradiation and air exposure by GC-MS, GC-O, and sensory evaluation. Nine aldehydes, i.e., octanal, nonanal, citronellal, decanal, trans-citral, cis-citral, perilla aldehyde, dodecanal, and dodecenal, were detected in WPEO. After treatment, the content of citronellal increased, but the concentrations of other aldehydes decreased. The aliphatic aldehydes were transformed to organic acids. Citral was transformed to neric acid, geranic acid, and cyclocitral. Aldehyde transformation caused a remarkable decrease in the minty, herbaceous, and lemon notes of WPEO. In fresh WPEO, beta-myrcene, d limonene, octanal, decanal, cis-citral, trans-citral, and dodecenal had the highest odor dilution folds. After the treatment, the dilution folds of decanal, cis-citral, trans-citral, and dodecenal decreased dramatically. This result provides information for the production and storage of aldehyde-containing products. PMID- 27226191 TI - Chemokine RANTES is increased at early stages of coronary artery disease. AB - Cardiovascular diseases, and in particular coronary artery disease (CAD), are the leading causes of death in Europe and represent around 50% of overall mortality. Numerous cardiovascular markers have been proposed in relation to cardiovascular risk prediction, in relation to cardiac and vascular and cerebral events. Chemokines which regulate immune cell vascular chemotaxis, including CCL5/RANTES are points of great interest. We hypothesized that chemokine RANTES level measured in peripheral blood may be associated with severity of atherosclerosis in patients with stable angina undergoing coronary angiography. RANTES and interleukin 18 (IL-18) levels were measured by ELISA. Classical and novel cardiovascular risk factors like brachial flow mediated dilation and intima-media thickness were analyzed in the context of chemokine levels and severity of atherosclerosis. Study included 62 consecutive patients with coronary atherosclerosis demonstrated by coronary angiography, (mean age 59.3 years (S.D. = 7.4)), divided into two groups: group I with lower severity of atherosclerosis, (n = 45) and group 2 with severe CAD (n = 17) based on coronary angiography. Groups were well balanced for classic risk factors for atherosclerosis. Mean RANTES level were significantly higher in patients in group I (67.9 ng/ml, S.E.M. = 3.97) than in group II (50.5 ng/ml, S.E.M. = 7.49; P = 0.03). In contrast, IL 18 levels were similar in both groups (255 pg/ml in group I and 315 pg/ml, S.E.M. = 40.91 in group I, P = 0.12), as well as hsCRP concentration (3.45 S.E.M. = 2.66 ng/ml and 4.69 ng/ml S.E.M.= 1.64 ng/ml respectively; P = 0.47). Flow-mediated dilatation (FMD) values have been significantly lower in group II than in group I (6.31; S.E.M. = 0.61; vs 4.41; S.E.M. = 0,56, respectively, P = 0.026), while nitroglycerine-mediated dilatation (NMD) did not differ, indicating more pronounced endothelial dysfunction. No significant correlations between chemokine RANTES levels and intima-media thickness (IMT), FMD measurements have been found in the total population studied. Chemokine RANTES level could become a useful marker of severity of coronary artery disease. Its lower levels were observed in patients with more diffuse disease. Elevated level of chemokine RANTES in patients with stable angina pectoris may evaluate patients to high risk group in plaque formation at early stages of atherosclerosis. PMID- 27226193 TI - The value of right ventricular longitudinal strain in the evaluation of adult patients with repaired tetralogy of Fallot: a new tool for a contemporary challenge. AB - OBJECTIVE: The role of right ventricular longitudinal strain for assessing patients with repaired tetralogy of Fallot is not fully understood. In this study, we aimed to evaluate its relation with other structural and functional parameters in these patients. METHODS: Patients followed-up in a grown-up CHD unit, assessed by transthoracic echocardiography, cardiac MRI, and treadmill exercise testing, were retrospectively evaluated. Right ventricular size and function and pulmonary regurgitation severity were assessed by echocardiography and MRI. Right ventricular longitudinal strain was evaluated in the four-chamber view using the standard semiautomatic method. RESULTS: In total, 42 patients were included (61% male, 32+/-8 years). The mean right ventricular longitudinal strain was -16.2+/-3.7%, and the right ventricular ejection fraction, measured by MRI, was 42.9+/-7.2%. Longitudinal strain showed linear correlation with tricuspid annular systolic excursion (r=-0.40) and right ventricular ejection fraction (r= 0.45) (all p<0.05), which in turn showed linear correlation with right ventricular fractional area change (r=0.50), pulmonary regurgitation colour length (r=0.35), right ventricular end-systolic volume (r=-0.60), and left ventricular ejection fraction (r=0.36) (all p<0.05). Longitudinal strain (beta= 0.72, 95% confidence interval -1.41, -0.15) and left ventricular ejection fraction (beta=0.39, 95% confidence interval 0.11, 0.67) were independently associated with right ventricular ejection fraction. The best threshold of longitudinal strain for predicting a right ventricular ejection fraction of <40% was -17.0%. CONCLUSIONS: Right ventricular longitudinal strain is a powerful method for evaluating patients with tetralogy of Fallot. It correlated with echocardiographic right ventricular function parameters and was independently associated with right ventricular ejection fraction derived by MRI. PMID- 27226194 TI - Percolation Phase Transition of Surface Air Temperature Networks under Attacks of El Nino/La Nina. AB - In this study, sea surface air temperature over the Pacific is constructed as a network, and the influences of sea surface temperature anomaly in the tropical central eastern Pacific (El Nino/La Nina) are regarded as a kind of natural attack on the network. The results show that El Nino/La Nina leads an abrupt percolation phase transition on the climate networks from stable to unstable or metastable phase state, corresponding to the fact that the climate condition changes from normal to abnormal significantly during El Nino/La Nina. By simulating three different forms of attacks on an idealized network, including Most connected Attack (MA), Localized Attack (LA) and Random Attack (RA), we found that both MA and LA lead to stepwise phase transitions, while RA leads to a second-order phase transition. It is found that most attacks due to El Nino/La Nina are close to the combination of MA and LA, and a percolation critical threshold Pc can be estimated to determine whether the percolation phase transition happens. Therefore, the findings in this study may renew our understandings of the influence of El Nino/La Nina on climate, and further help us in better predicting the subsequent events triggered by El Nino/La Nina. PMID- 27226195 TI - Membrane Interacting Peptides: A Review. AB - Membrane interacting peptides of natural or synthetic origins serve a variety of biological purposes. They have been extensively studied for their involvement in immunity, diseases, and for their potential as medical therapeutics and research tools. In this review membrane interacting peptides are categorized into four groups according to their function: antimicrobial peptides, cell-penetrating peptides, channel forming peptides and amyloid peptides. A historical overview of the development, their functional mechanisms, and recent advances are presented for each of the groups. Considerable research is still devoted to this field of study and in this report a representative sample of the latest studies is presented. A set of common features among peptide groups emerges as the understanding of their action mechanisms increase. The possibility of a membrane centric general model for peptide-membrane interaction is also discussed. This review seeks to provide a unifying view of the field and promote the interaction between research groups working on peptides that have so far been studied as belonging to completely different fields. PMID- 27226196 TI - The Role of Klotho Protein in Chronic Kidney Disease: Studies in Animals and Humans. AB - The identification of Klotho gene was a major discovery as the gene encodes a protein regulating multiple functions. A defect in Klotho gene expression in mice results in a phenotype of premature aging including shortened life span, growth retardation, hypogonadism, skin and muscle atrophies, vascular calcification, cognition impairment, motor neuron degeneration and others. This phenotype is associated with phosphate balance disorders and underlines the major function of Klotho in mineral metabolism. As another 2 related paralogs were discovered (beta Klotho, which is involved in bile acid and energy metabolism, and gamma-Klotho, with a yet to be defined function), this led to the revised naming of Klotho as alpha-Klotho. Two forms of alpha-Klotho protein have been reported: a membrane bound and a soluble one. Membrane Klotho forms a complex with fibroblast growth factor (FGF) receptors and functions as an obligate co-receptor for the FGF-23 phosphatonin in distal tubules. The soluble form of Klotho seems to function as a humoral factor and regulates glycoproteins on the cell surface including ion channels and growth factors. There is data suggesting that soluble Klotho exerts phosphaturic effects independently of FGF-23. Circulating soluble Klotho is produced either by proteolytic cleavage of the extracellular domain of the transmembrane form by two membrane-anchored proteases (ADAM10 and ADAM17) or by alternative mRNA splicing. In animal models Klotho has been shown to exert pleiotropic actions, including cytoprotection, anti-oxidation, anti-apoptosis, protection of vasculature, promotion of angiogenesis and vascularization, inhibition of fibrogenesis and preservation of stem cells. The exact diagnostic and therapeutic role of Klotho in humans is not fully known yet. The article presents the role of Klotho in physiology and different stages of chronic kidney disease (CKD). PMID- 27226197 TI - The Signal Pathway of Antibiotic Alternatives on Intestinal Microbiota and Immune Function. AB - Antibiotics are one of the most important discoveries in the 20th century and have been widely used for treating animal diseases in the 21st century. However, antibiotic resistance among bacterial pathogens and widespread concerns regarding their use in animals has received great attention all over the world. Great attention has focused on scientific breakthroughs of the alternatives to antibiotics. Various materials such as enzymes, prebiotics, probiotics, minerals, antimicrobial peptides, acidifiers, plants and plant extracts have been tested as possible antibiotics alternatives. Owing to their effects on intestinal microbiota and immune function, research efforts have been conducted on the application of these feed supplements. This review highlights promising research results about the alternatives to antibiotics in animal husbandry that are expected to beneficially limit the adverse effects of antibiotics and ensure the safety of animal-derived foods and the environment. PMID- 27226198 TI - Insulin and Lispro Insulin: What is Common and Different in their Behavior? AB - There are different insulin analogues with various pharmacokinetic characteristics, such as, rapid-acting, long-acting, or intermediate-acting analogues. Since insulin tends to form amyloid aggregates, it is of particular interest to measure characteristic times of formation of amyloid aggregates and compare those to action times for insulin and its analogues. For the study we have chosen one of the insulin analogues - insulin Lispro, which is a fast acting insulin analog. It is usually thought of amyloid aggregation as a nucleation dependent process. We have estimated the size of the primary nucleus to be one monomer and the size of the secondary nucleus to be around zero in both insulin and Lispro insulin aggregation processes. The main structural element of insulin and Lispro insulin amyloid fibrils is a rounded ring oligomer of about 6-7 nm in diameter, about 2-3 nm in height and about 2 nm in diameter of the hole. Fibrils of several MUm in length are produced due to interaction of such oligomers. The packing of ring oligomers in fibrils differs because of the difference in their orderliness. Though the initial stages of fibril formation (monomer, oligomer) are similar, the further process depends on the unique sequence of each peptide. Namely the sequence affects the final morphology of mature amyloids. These observations allow us to conclude that formation of fibrils by short peptides occurs via and by means of oligomer ring structures. Such an important issue as the nature of polymorphism of insulin amyloid fibrils has been settled by us. The role of early oligomeric aggregates in such processes as nucleation and aggregation of amyloid fibrils has been examined. PMID- 27226199 TI - Marine Depsipeptides as Promising Pharmacotherapeutic Agents. AB - Depsipeptides are a group of biologically active peptides that have at least one of the amide bonds replaced by an ester bond. These peptides sometimes present additional chemical modifications, including unusual amino acid residues in their structures. Depsipeptides are known to exhibit a large array of bioactivities, such as anticancer, antiproliferative, antimicrobial, antiviral and antiplasmodial properties. They are commonly found in marine organisms: bacteria, tunicates, mollusks, sponges, and others. Herein, we summarize the latest insights about marine depsipeptides, their mechanisms of action and potential as therapeutic agents. PMID- 27226200 TI - Continuous Cardiac Monitoring around Atrial Fibrillation Ablation: Insights on Clinical Classifications and End Points. AB - BACKGROUND: Atrial fibrillation (AF) is an arrhythmia that can be difficult to identify and classify with short-term monitoring. However, current standard of practice requires only short-term monitoring to determine AF classifications and identify symptom-arrhythmia correlations prior to AF ablation procedures. Insertable cardiac monitors (ICMs) offer continuous arrhythmia monitoring, which could lead to a more accurate measurement of AF burden than standard of practice. METHODS: This analysis focused on 121 patients enrolled in the LINQ Usability Study indicated for an AF ablation. Patients were followed for up to 1 year after ICM insertion. Clinical AF classifications were made by physicians prior to ICM implantation based on available clinical information. Device-detected AF burden and maximum daily burden were collected from device interrogations and remote transmissions. Device AF classifications were determined by categorizing the AF burden based on guidelines. RESULTS: Agreement between clinical and device AF classifications preablation was poor (48.3%, N = 58). The strongest agreement was in the paroxysmal AF group but still was only 61.8%. Furthermore, device-detected preablation AF burden led to the decision to defer AF ablation procedures in 16 (13.2%) patients. The median AF burden in patients with >=6 months follow-up postablation (n = 71) was reduced from 7.8% (interquartile range [IQR]: 0-32.1%) to 0% (IQR: 0-0.7%). CONCLUSIONS: ICM monitoring to determine AF burden pre- and post-AF ablation may have clinical utility for management of ablation candidates through more accurate AF classification and guiding treatment decisions. PMID- 27226201 TI - Photoluminescence, energy transfer and tunable color of Ce(3+), Tb(3+) and Eu(2+) activated oxynitride phosphors with high brightness. AB - New tuneable light-emitting Ca3Al8Si4O17N4:Ce(3+)/Tb(3+)/Eu(2+) oxynitride phosphors with high brightness have been prepared. When doped with trivalent cerium or divalent europium they present blue luminescence under UV excitation. The energy transfer from Ce(3+) to Tb(3+) and Ce(3+) to Eu(2+) ions is deduced from the spectral overlap between Ce(3+) emission and Tb(3+)/Eu(2+) excitation spectra. The energy-transfer efficiencies and corresponding mechanisms are discussed in detail, and the mechanisms of energy transfer from the Ce(3+) to Tb(3+) and Ce(3+) to Eu(2+) ions are demonstrated to be a dipole-quadrupole and dipole-dipole mechanism, respectively, by the Inokuti-Hirayama model. The International Commission on Illumination value of color tuneable emission as well as luminescence quantum yield (23.8-80.6%) can be tuned by controlling the content of Ce(3+), Tb(3+) and Eu(2+). All results suggest that they are suitable for UV light-emitting diode excitation. PMID- 27226202 TI - [Treatment of nasolacrimal duct obstruction from the otorhinolaryngologist's perspective]. AB - BACKGROUND: Epiphora is the classic symptom of nasolacrimal duct obstruction, particularly among elderly people. Dacryocystorhinostomy (DCR) via external (Toti) and endonasal (West) approaches are well-established surgical treatments. OBJECTIVE: The aim of the present article is to describe the etiology and diagnostics of nasolacrimal duct obstruction. Furthermore, treatment modalities are discussed according to the current literature, with particular consideration of the otorhinolaryngologist's perspective. MATERIALS AND METHODS: A search of the current literature focused on the past 5 years was performed in PubMed. RESULTS: Several retrospective and prospective randomized studies describe the external and endonasal DCR approaches as safe surgical procedures, with high success rates of around 90 %. The endoscope is standardly used for visualization during the endonasal approach. Powered instruments such as diamond drills enable generation of a large rhinostomy, even in very hard bone. The application of silicone stents does not confer a significant additional advantage in terms of postoperative success rates. CONCLUSION: DCR is a safe surgical procedure with high success rates. It can be strongly recommended for patients suffering from intra- or post-saccular nasolacrimal duct obstruction. Furthermore, the external and endonasal approaches (according to Toti and West, respectively) are comparable techniques. The use of silicone stents is indicated only in special cases. PMID- 27226203 TI - [Medical and psychological aspects of the treatment of connatal dacryostenosis : Parental evaluation of their own and their child's stress]. AB - BACKGROUND: Lacrimal probing and syringing for connatal dacryostenosis can be performed under local (LA) and general anesthesia (GA). In cases of invasive medical procedures, pain and anxiety can be distressing for children and their parents. MATERIALS AND METHODS: Using questionnaires (n = 65), parents were asked to evaluate their own stress and that of their child during lacrimal probing and syringing. Analyzing different subgroups, the impact of the kind of anesthesia (LA vs. GA), trust in medical treatment, therapeutic success, prior experiences with GA, parental educational level, age of parents and children, number of children, and time between the intervention and the interview on the stress was examined. Stress level was evaluated on a scale from 1 (no stress) to 10 (maximal stress). RESULTS: Mean children's age was 8.5 +/- 7.42 months. Mean age of the parents was 30.8 +/- 6.17 years. Treating children under LA, parents reported moderate to severe stress levels for themselves (mean, M = 7.15) and for their children (M = 7.82). Children's stress levels were significantly higher when the treatment was performed under LA (n = 47; M = 7.34) in comparison to GA (n = 18; M = 6.06; p < 0.05). Parents having two or more children reported significantly lower stress levels than those with only one child. Furthermore, prior experiences with GA led to significantly higher parental stress levels when their children were treated under GA. Other factors did not show any impact on parent's and children's stress levels. CONCLUSIONS: Parents might have been influenced by hearing the children's reaction (e. g., crying) during the intervention under LA. Nevertheless, parents had a higher acceptance of this type of intervention (LA) in comparison to GA. This effect was even stronger among parents with prior experience of GA. PMID- 27226205 TI - Directional moisture transfer through a wild silkworm cocoon wall. AB - A silkworm cocoon is a porous biological structure with multiple protective functions. In the current work, the authors have used both experimental and numerical methods to reveal the unique moisture transfer characteristics through a wild Antheraea pernyi silkworm cocoon wall, in comparison with the long domesticated Bombyx mori silkworm cocoon walls. The water vapor transmission and water vapor permeability (WVP) properties show that the A. pernyi cocoons exhibit directional moisture transfer behavior, with easier moisture transfer from inside out than outside in [e.g., the average WVP is 0.057 g/(h m bar) from inside out and is 0.034 g/(h m bar) from outside in]. Numerical analysis shows that the cubic mineral crystals in the outer section of the A. pernyi cocoon wall create a rough surface that facilitates air turbulence and promotes disturbance amplitude of the flow field, leading to lengthened water vapor transfer path and increased tortuosity of the moist air. It also indicates the vortex of water vapor can be generated in the outer section of cocoon wall, which increases the diffusion distance of water vapor and enhances the turbulence kinetic energy and turbulence eddy dissipation, signifying higher moisture resistance in the outer section. The difference in moisture resistance of the multiple A. pernyi cocoon layers is largely responsible for the unique directional moisture transfer behavior of this wild silkworm cocoon. These findings may inspire a biomimicry approach to develop novel lightweight moisture management materials and structures. PMID- 27226204 TI - Hepatitis B and C serologic profiles of Canadian organ donors and recipients: retrospective 10-year review at a single center. AB - BACKGROUND: Hepatitis C virus (HBV) and hepatitis C virus (HCV) are important causes of hepatitis and can be transmitted from organ donor to recipient. This study aimed to determine HBV and HCV serologic profiles of a population of Canadian solid organ transplant (SOT) donors and recipients, including prevalence of recipient HBV immunity. METHODS: Data on age, gender, organ transplanted, and pre-transplant HBV and HCV serology for SOT donors and recipients at a Canadian hospital from 2001 to 2011 were obtained from a transplant database. RESULTS: There were 2455 recipients (2205 adults, 250 children), and 1559 donors. Over 50% of adult and 44% of pediatric recipients were HBV non-immune pre-transplant. Pediatric recipients were more likely to have HBV vaccine immunity than were adult recipients (48.8% vs. 28.9%, P < 0.001). Prevalence of HBV vaccine immunity was highest in renal recipients (48.3% in adult, 63.2% in pediatric recipients). Recipient HBV vaccine immunity increased from 5.8% in 2001 to 44.5% in 2011 (P < 0.001). Of 134 adult recipients with prior HBV infection, 59 (44%) were co infected with HCV. Only 0.6% of adult non-liver recipients had acute or chronic HBV infection and 3.2% were anti-HCV positive. Only 2 donors had acute or chronic HBV infection, 29 had prior HBV infection, 9 were isolated hepatitis B core antibody positive, and 15 were anti-HCV positive. CONCLUSIONS: The prevalence of HBV vaccine immunity in SOT candidates is low, but increased from 2001 to 2011. Opportunities for quality improvement in pre-transplant HBV immunization exist. HCV co-infection is common in recipients with prior HBV infection. Prevalence of HCV infection in non-liver transplant recipients is low. PMID- 27226207 TI - Evaluation of the methods to identify patients who may benefit from PARP inhibitor use. AB - The effectiveness of poly (ADP-ribose) polymerase inhibitors (PARPi) in treating cancers associated with BRCA1/2 mutations hinges upon the concept of synthetic lethality and exemplifies the principles of precision medicine. Currently, most clinical trials are recruiting patients based on pathological subtypes or have included BRCA mutation analysis (germ line and/or somatic) as part of the selection criteria. Mounting evidence, however, suggests that these drugs may also be efficacious in tumors with defects in other genes involved in the homologous recombination repair pathway. Advances in molecular profiling techniques together with increased research efforts have led to a better understanding of the molecular aberrations underlying this BRCA-like phenotype and helped broaden the concept of BRCAness. Hence, it is likely that the list of predictive biomarkers for PARPi therapy will increase in future. There is currently no gold standard method of testing for PARPi response and no universal guidelines are in place on how to incorporate biomarker testing into routine clinical diagnostics. In this review, we explore the concept of BRCAness and highlight the different methods that have been used to identify patients who may benefit from the use of these anticancer agents. The identification of predictive biomarkers is crucial in improving patient selection and expanding the clinical applications of PARPi therapy. PMID- 27226206 TI - Ebola Virus Disease in Pregnancy: Clinical, Histopathologic, and Immunohistochemical Findings. AB - Here we describe clinicopathologic features of Ebola virus disease in pregnancy. One woman infected with Sudan virus in Gulu, Uganda, in 2000 had a stillbirth and survived, and another woman infected with Bundibugyo virus had a live birth with maternal and infant death in Isiro, the Democratic Republic of the Congo in 2012. Ebolavirus antigen was seen in the syncytiotrophoblast and placental maternal mononuclear cells by immunohistochemical analysis, and no antigen was seen in fetal placental stromal cells or fetal organs. In the Gulu case, ebolavirus antigen localized to malarial parasite pigment-laden macrophages. These data suggest that trophoblast infection may be a mechanism of transplacental ebolavirus transmission. PMID- 27226208 TI - Enhanced Physical Activity Improves Selected Outcomes in Children With ADHD: Systematic Review. AB - This review examines associations between physical activity (PA) and cognitive, behavioral, and physiological outcomes in children with attention deficit/hyperactivity disorder (ADHD). We reviewed studies on participants <=18 years old, published in English between January 1998 and December 2014, in PubMed, CINAHL, PsycINFO, and Cochrane Reviews. Twenty-six studies were grouped into two categories: those that did and did not account for effects of ADHD medications. The first category showed lower levels of PA and improved cognitive and behavioral outcomes in youth whose ADHD was treated with medications. The second category showed a positive association between PA levels and cognitive and behavioral outcomes in youth whose ADHD was not treated with medications. For both categories of studies, results were inconclusive regarding physiological outcomes. Randomized controlled trials are needed to better clarify the relationship between PA and outcomes in youth with ADHD, and particularly to understand the impact of ADHD medications on that relationship. PMID- 27226209 TI - Application of Heart Rate Variability in Diagnosis and Prognosis of Individuals with Diabetes Mellitus: Systematic Review. AB - BACKGROUND: The use of heart rate variability as a tool capable of discriminating individuals with diabetes mellitus is still little explored, as its use has been limited to comparing those with and without the disease. Thus, the purpose of this study was to verify the use of heart rate variability as a tool for diagnostic and prognostic evaluation in person with diabetes and to identify whether there are cutoff points generated from the use of this tool in these individuals. METHODS: A search was conducted in the electronic databases MEDLINE, Cochrane Library, Web of Science, EMBASE, and LILACS starting from the oldest records until January 2015, by means of descriptors related to the target condition, evaluated tool, and evaluation method. All the studies were evaluated for methodological quality using the QUADAS-2 instrument. RESULTS: Eight studies were selected. In general, the studies showed that the heart rate variability is useful to discriminate cardiac autonomic neuropathy in person with diabetes, and the sample entropy, SD1/SD2 indices, SDANN, HF, and slope of TFC have better discriminatory power to detect autonomic dysfunction, with sensitivity and specificity values ranging from 72% to 100% and 71% to 97%, respectively. CONCLUSION: Although there are methodological differences in indices used, in general, this tool demonstrated good sensitivity and specificity and can be used as an additional and/or complementary tool to the conventional autonomic tests, in order to obtain safer and more effective diagnostic, collaborating for better risk stratification conditions of these patients. PMID- 27226210 TI - Longibacter salinarum gen. nov., sp. nov., isolated from a marine solar saltern. AB - A bacterial strain, designated WDS2C18T, was isolated from a marine solar saltern from the coast of Weihai, Shandong Province, China. Cells of strain WDS2C18T were long rod-shaped, red, and approximately 6.0-12.0 um in length and 0.3-0.4 um in width. The strain was Gram-stain-negative, facultatively anaerobic, heterotrophic, catalase-positive and oxidase-negative. Optimal growth was observed at 40 degrees C, at pH 7.5-8.0 with 8-12 % (w/v) NaCl. Nitrate was not reduced. Glycerol, sucrose, starch and d-mannitol stimulated growth, but not glucose, d-fructose, d-galactose, d-lactose, maltose, d-mannose, d-xylose, d ribose, d-arabinose, l-rhamnose or cellobiose. The G+C content of the genomic DNA was 58.1 mol% (HPLC). The sole methyl naphthoquinone was MK-7 and the predominant cellular fatty acids (>10 %) were iso-C15 : 0 2-OH/C16 : 1omega7c, iso-C17 : 1omega9c, iso-C15 : 0 and iso-C17 : 0. The predominant polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, glycolipid, three unidentified phospholipids and two unidentified lipids. Phylogenetic analysis, based on 16S rRNA gene sequences, demonstrated that strain WDS2C18T was affiliated with the family Rhodothermaceae. The closest related neighbours were species of the genera Salisaeta andLongimonas; strain WDS2C18T shared highest 16S rRNA gene sequence similarities with Salisaeta longa DSM 21114T (91.7 %) and Longimonas halophila SYD6T (90.8 %) and less than 90.0 % to other species of the family Rhodothermaceae. On the basis of these phenotypic and phylogenetic data, strain WDS2C18T should be classified as representing a novel species of a new genus within the family Rhodothermaceae, for which the name Longibacter salinarum gen. nov., sp. nov. is proposed. The type strain of Longibacter salinarum is WDS2C18T (=MCCC 1H00132T=KCTC 52045T). PMID- 27226211 TI - First principles investigation of helium physisorption on an alpha-Al2O3(0001) surface. AB - The interaction of helium with an alpha-Al2O3(0001) surface was studied by density functional theory (DFT), with consideration of the effects of He coverage, surface defects, He-coadsorption and van der Waals interaction, respectively. Adsorption energies of helium atoms are very small as expected for a physisorbed state, varying from -20 to -5 meV, which is attributed to the small overlap between Al 3sp, O 2sp and He 1s states. A correlation is obtained for the adsorption energies and the He to nearest-neighbor Al atom distances on a clean (0001) surface. The He atom prefers to bound atop the Al site of the fourth atomic layer (Al4 hollow site), and the favorable site around an O-vacancy is atop the site of the O vacancy with less stability. The competition between O-He attraction and Al-He repulsion makes the He stable sites. As He-coverage on the surface increases, He atoms tend to form clusters, and coadsorption configuration is not solely determined by the most stable site but also by the He-He distance. The two co-adsorbed He atoms absorb on hollow sites Al4 and Al3, with a He-He distance of 2.767 A. The OBS dispersion corrected DFT energies are 2.2-4.4 times larger than the non-corrected DFT values and He-surface distances are smaller. Finally, implications on H/He interaction within alpha-Al2O3 as a tritium permeation barrier are discussed. PMID- 27226212 TI - Breastfeeding, Dental Biofilm Acidogenicity, and Early Childhood Caries. AB - AIM: This study evaluated the acidogenicity of human milk by the dental biofilms of children with and without early childhood caries (ECC). METHOD: Biofilms of 16 children (7 with ECC; 9 caries free) were exposed to human milk or 10% sucrose solution in the crossover design, and the biofilm pH was determined. RESULTS: Breastfeeding did not provoke a decrease in biofilm pH, irrespective of the children's caries status, whereas sucrose decreased the pH for both groups. In addition, higher x0394;pH5min (pH variation occurring at 5 min) was observed in the biofilms of ECC children (p < 0.05). The results suggest that breastfeeding may not contribute to ECC. PMID- 27226213 TI - Computational methods for image reconstruction. AB - Reconstructing images from indirect measurements is a central problem in many applications, including the subject of this special issue, quantitative susceptibility mapping (QSM). The process of image reconstruction typically requires solving an inverse problem that is ill-posed and large-scale and thus challenging to solve. Although the research field of inverse problems is thriving and very active with diverse applications, in this part of the special issue we will focus on recent advances in inverse problems that are specific to deconvolution problems, the class of problems to which QSM belongs. We will describe analytic tools that can be used to investigate underlying ill-posedness and apply them to the QSM reconstruction problem and the related extensively studied image deblurring problem. We will discuss state-of-the-art computational tools and methods for image reconstruction, including regularization approaches and regularization parameter selection methods. We finish by outlining some of the current trends and future challenges. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27226214 TI - Persistent vitreoretinal adhesion in eyes with peripheral exudative haemorrhagic chorioretinopathy. PMID- 27226215 TI - Paired boxed gene 1 expression: A single potential biomarker for differentiating endometrial lesions associated with favorable outcomes in patients with endometrial carcinoma. AB - AIM: Paired boxed gene 1 (PAX1) has previously been reported to be a methylation silenced gene in cases of cervical and ovarian cancers. We evaluated the expression of PAX1 in normal endometrium, endometrial hyperplasia and endometrial carcinoma (EC), and investigated the prognostic value of PAX1 expression in patients with EC. METHODS: We conducted a hospital-based retrospective review of PAX1 distribution immunohistochemically in 201 samples of endometrium from biopsy or hysterectomy. PAX1 immunoreactivity was classified into low and high score groups based upon the extent and intensity of staining. RESULTS: There was intense intranuclear staining for PAX1 in premalignant endometrial lesions. A high PAX1 score was observed in a high percentage of samples of normal endometrium (93.3%), in endometrial hyperplasia without atypia (97.2%) and in endometrial atypical hyperplasia (87.5%), but this level was found in only one third of the EC samples (30.1%). The PAX1 protein score was significantly higher in samples of premalignant endometrial lesions compared with those of EC (P < 0.001). Importantly, a higher PAX1 score in EC cases was correlated with good overall survival, with a hazard ratio of 0.22 for death (95% confidence interval, 0.05-0.96). CONCLUSIONS: PAX1 protein expression is a potential histopathology biomarker for the differential diagnosis of malignant and premalignant endometrial lesions. PAX1 is also a potential prognostic marker in cases of EC. PMID- 27226216 TI - Proactive Risk Assessment for Ebola-Infected Patients: A Systematic Approach to Identifying and Minimizing Risk to Healthcare Personnel. AB - Performing patient care while wearing high-level personal protective equipment presents risks to healthcare providers. Our failure mode effects analysis identified 81 overall risks associated with providing hygienic care and linen change to a patient with continuous watery stool. Implementation of checklists and scheduled pauses could potentially mitigate 76.5% of all risks. Infect Control Hosp Epidemiol 2016;37:867-871. PMID- 27226217 TI - Pulmonary computed tomography findings in patients with chronic aspiration detected by videofluoroscopic swallowing study. AB - OBJECTIVE: To demonstrate CT findings in patients with chronic aspiration compared with a control group without aspiration, as detected by the videofluoroscopic swallowing study (VFSS). METHODS: This retrospective, observational study included patients with and without diagnoses of aspiration confirmed by VFSS, who underwent CT examination of the lungs between 2010 and 2014. Two radiologists blinded to the presence of aspiration reviewed the images to detect the presence of any abnormality. Consensus was reached with a third radiologist. CT pulmonary findings (bronchial thickening, bronchiolectasis, centrilobular nodules, ground-glass opacities, atelectasis, consolidation and air trapping) were compared between the groups using the chi(2) test, with a significance level of 0.05. RESULTS: A total of 56 patients (28 patients with diagnoses of aspiration; 52% male, mean age 65 +/- 15 years) were included in the study. Patients with aspiration were more likely to than those in the control group to demonstrate atelectasis, centrilobular nodules, bronchiolectasis, consolidation and ground-glass opacities (all p < 0.05), with a significant predilection for the lower lobes (p < 0.001). Bronchial wall thickening and air trapping did not differ between groups. CONCLUSION: Atelectasis, centrilobular nodules, bronchiolectasis, consolidation and ground-glass opacities occurred more frequently in patients with aspiration than in those without aspiration, with a pronounced tendency for distribution in the lower lobes. ADVANCES IN KNOWLEDGE: CT findings of aspiration are very important, as pulmonary symptoms may be the first manifestation of this disorder. Knowledge of these findings is essential to enable the early diagnosis of aspiration disorders and prevent lung damage. PMID- 27226218 TI - Imaging features of chondromyxoid fibroma: report of 15 cases and literature review. AB - OBJECTIVE: Chondromyxoid fibroma (CMF) is a rare benign bony tumour. Our objectives are three-fold: first, comparing MRI, conventional radiography (CR) and CT characteristics of CMF; second, providing a literature review; and third, summarizing the role of imaging landmarks in the differential diagnosis with other bony lesions. METHODS: 15 patients with histopathologically proven CMF were retrospectively included. MR images were reviewed for typical findings and compared with imaging features on CR and CT. RESULTS: All lesions were isointense on T1 weighted images with a low intensity rim in nine cases corresponding to the perilesional sclerosis on CR and CT. Internal trabeculations were more prominent on CR than on CT due to corrugation and scalloping at the tumour's edge. CT was superior to CR in analysing the expansion of the lesion, cortical breakthrough and internal mineralization. T2 short tau inversion recovery or T2 weighted fat saturation images showed an intermediate to hyperintense signal in all lesions, mostly heterogeneous. Some lesions contained small internal cysts, and one lesion demonstrated a low signal intensity centrally, corresponding to internal mineralization on CT. Intense contrast enhancement was present in all lesions. Minimal bone and soft tissue oedema were seen in, respectively, six and three patients. CONCLUSION: The diagnosis of CMF is difficult because of overlap of characteristics with other bony lesions. Our comparative study puts forward advantages and limitations of different imaging modalities in the diagnosis of CMF. ADVANCES IN KNOWLEDGE: For the first time, imaging features of CMF are analysed and compared on CR, CT and MRI. PMID- 27226219 TI - Local staging and assessment of colon cancer with 1.5-T magnetic resonance imaging. AB - OBJECTIVE: The aim of this study was to assess the accuracy of 1.5-T MRI in the pre-operative local T and N staging of colon cancer and identification of extramural vascular invasion (EMVI). METHODS: Between 2010 and 2012, 60 patients with adenocarcinoma of the colon were prospectively recruited at 2 centres. 55 patients were included for final analysis. Patients received pre-operative 1.5-T MRI with high-resolution T2 weighted, gadolinium-enhanced T1 weighted and diffusion-weighted images. These were blindly assessed by two expert radiologists. Accuracy of the T-stage, N-stage and EMVI assessment was evaluated using post-operative histology as the gold standard. RESULTS: Results are reported for two readers. Identification of T3 disease demonstrated an accuracy of 71% and 51%, sensitivity of 74% and 42% and specificity of 74% and 83%. Identification of N1 disease demonstrated an accuracy of 57% for both readers, sensitivity of 26% and 35% and specificity of 81% and 74%. Identification of EMVI demonstrated an accuracy of 74% and 69%, sensitivity 63% and 26% and specificity 80% and 91%. CONCLUSION: 1.5-T MRI achieved a moderate accuracy in the local evaluation of colon cancer, but cannot be recommended to replace CT on the basis of this study. ADVANCES IN KNOWLEDGE: This study confirms that MRI is a viable alternative to CT for the local assessment of colon cancer, but this study does not reproduce the very high accuracy reported in the only other study to assess the accuracy of MRI in colon cancer staging. PMID- 27226220 TI - Motor subtype in Parkinson's disease: Different disorders or different stages of disease? PMID- 27226221 TI - Preparation and Characterization of Newly Discovered Fibrous Aggregates of Single Walled Carbon Nanohorns. AB - Fibrous aggregates composed of radially assembled graphene-based single-walled nanotubules are prepared, named here as fibrous aggregates of single-walled carbon nanohorns (fib-CNHs), whose structure resembles that of chenille stems. The newly discovered fib-CNHs are 30-100 nm in diameter and 1-10 MUm in length. The fib-CNHs show high dispersibility and conductivity. The fib-CNHs increase the advantages of nanocarbons in various fields. PMID- 27226222 TI - Liver test abnormalities in patients admitted for severe psoriasis: prevalence and associated risk factors. AB - BACKGROUND: Few epidemiologic data are available regarding biologic liver abnormalities during psoriasis flares. OBJECTIVES: The aim of this study was to assess the prevalence of biological liver test abnormalities (LTA) in a psoriasis population and the risk factors associated with LTA. METHODS: A retrospective cross-sectional study in four hospital dermatology tertiary care centres included patients admitted for severe psoriasis flare between 1st January 2010 and 31st December 2011. During the same period, a control population was selected comprising patients admitted for contact and/or atopic eczema. Data were collected on hospital records and biology software. LTA was defined as serum AST and/or ALT and/or ALP concentration above the upper normal limit (UNL) and/or GGT concentration above 2 UNL. Prevalence of LTA with 95% confidence intervals (95% CI) was compared between the psoriatic and control populations. Factors associated with LTA at P < 0.05 were considered for the final multivariate logistic regression model. RESULTS: Two hundred and forty psoriasis patients and 96 eczema control patients were included. One hundred and fifty-five(64.6%) of the psoriasis patients were male, aged 55 years on average (+/-17.6); 192 (80.0%) had plaque-type psoriasis (PV) and 52 (21.6%) had localized (n = 32) or generalized (n = 20) pustular psoriasis (PP). Prevalence of LTA was 36% (95% CI, 30-42) in the psoriatic population, significantly higher than in controls (17%, 95% CI 9.5-25). Risk factors independently associated with LTA comprised PV (OR 3.79; 95% CI 1.48-9.65), PP (OR 3.80; 95% CI 1.40-10.25) and previously diagnosed liver disease (underlying hepatic steatosis, viral hepatitis or excessive alcohol consumption) (OR 3.88; 95% CI 2.02-7.45). No association was found with systemic antipsoriatic drug therapies. CONCLUSION: In severe psoriasis, liver impacting comorbidities and/or specific psoriatic inflammation, the latter mostly in PP cases, more than drug-related liver toxicity, appears to predominantly account for LTA. Clinicians should be aware of this, to avoid unjustified withdrawal of useful systemic drugs. PMID- 27226224 TI - Swimming and twitching motility are essential for attachment and virulence of Pantoea ananatis in onion seedlings. AB - Pantoea ananatis is a widespread phytopathogen with a broad host range. Despite its ability to infect economically important crops, such as maize, rice and onion, relatively little is known about how this bacterium infects and colonizes host tissue or spreads within and between hosts. To study the role of motility in pathogenicity, we analysed both swimming and twitching motility in P. ananatis LMG 20103. Genetic recombineering was used to construct four mutants affected in motility. Two flagellar mutants were disrupted in the flgK and motA genes, required for flagellar assembly and flagellar rotation, respectively. Similarly, two twitching motility mutants were generated, impaired in the structure (pilA) and functioning (pilT) of the type IV pili. The role of swimming and twitching motility during the infection cycle of P. ananatis in onion seedlings was determined by comparing the mutant- and wild-type strains using several in vitro and in planta assays. From the results obtained, it was evident that flagella aid P. ananatis in locating and attaching to onion leaf surfaces, as well as in pathogenicity, whereas twitching motility is instrumental in the spread of the bacteria on the surface once attachment has occurred. Both swimming and twitching motility contribute towards the ability of P. ananatis to cause disease in onions. PMID- 27226225 TI - Voluntary Attentional Orienting in Schoolchildren: How Visual Orienting Skills Change During Primary School. AB - Voluntary attentional orienting is the foundation of the capacity to highlight relevant stimuli and suppress competing distractions. It plays a role in the scholastic skills. This study investigated the changes in the orienting skills in 630 schoolchildren (age range: 5.7-10.2 years old), who attended the first (N = 205, M = 6.1, SD = 0.4), third (212 children, M = 8.2, SD = 0.6), and fifth grade (213 children, M = 10, SD = 0.4) of four primary schools in Italy. Simple attentional orienting, choice attentional orienting on written stimuli, double attentional orienting (auditory and visual), and re-orienting were investigated. The tasks required pressing a key in response to some target stimuli. The stimuli were digits, images of objects, written words, letters, geometric forms, and auditory verbal stimuli. Results showed that attentional orienting improved with age. The children's performances depended on the type of stimuli and activities required for the task. The accuracy of re-orienting with written verbal stimuli did not improve during primary school. With increasing age, children became faster but not more able to focus on written verbal stimuli when shifting of attention was required. PMID- 27226227 TI - Laparoscopic-assisted anterior resection in Kartagener's syndrome. PMID- 27226226 TI - Downregulation of B-cell lymphoma/leukemia-2 by overexpressed microRNA 34a enhanced titanium dioxide nanoparticle-induced autophagy in BEAS-2B cells. AB - Titanium dioxide (TiO2) nanoparticles (TNPs) are manufactured worldwide for a wide range of applications and the toxic effect of TNPs on biological systems is gaining attention. Autophagy is recognized as an emerging toxicity mechanism triggered by nanomaterials. MicroRNA 34a (miR34a) acts as a tumor suppressor gene by targeting many oncogenes, but how it affects autophagy induced by TNPs is not completely understood. Here, we observed the activation of TNP-induced autophagy through monodansylcadaverine staining and LC3-I/LC3-II conversion. Meanwhile, the transmission electron microscope ultrastructural analysis showed typical morphological characteristics in autophagy process. We detected the expression of miR34a and B-cell lymphoma/leukemia-2 (Bcl-2). In addition, the underlying mechanism of TNP-induced autophagy was performed using overexpression of miR34a by lentivirus vector transfection. Results showed that TNPs induced autophagy generation evidently. Typical morphological changes in the process of autophagy were observed by the transmission electron microscope ultrastructural analysis and LC3-I/LC3-II conversion increased significantly in TNP-treated cells. Meanwhile, TNPs induced the downregulation of miR34a and increased the expression of Bcl-2. Furthermore, overexpressed miR34a decreased the expression of Bcl-2 both in messenger RNA and protein level, following which the level of autophagy and cell death rate increased after the transfected cells were incubated with TNPs for 24 hours. These findings provide the first evidence that overexpressed miR34a enhanced TNP-induced autophagy and cell death through targeted downregulation of Bcl-2 in BEAS-2B cells. PMID- 27226228 TI - Discovery and small RNA profile of Pecan mosaic-associated virus, a novel potyvirus of pecan trees. AB - A novel potyvirus was discovered in pecan (Carya illinoensis) showing leaf mosaic symptom through the use of deep sequencing of small RNAs. The complete genome of this virus was determined to comprise of 9,310 nucleotides (nt), and shared 24.0% to 58.9% nucleotide similarities with that of other Potyviridae viruses. The genome was deduced to encode a single open reading frame (polyprotein) on the plus strand. Phylogenetic analysis based on the whole genome sequence and coat protein amino acid sequence showed that this virus is most closely related to Lettuce mosaic virus. Using electron microscopy, the typical Potyvirus filamentous particles were identified in infected pecan leaves with mosaic symptoms. Our results clearly show that this virus is a new member of the genus Potyvirus in the family Potyviridae. The virus is tentatively named Pecan mosaic associated virus (PMaV). Additionally, profiling of the PMaV-derived small RNA (PMaV-sRNA) showed that the most abundant PMaV-sRNAs were 21-nt in length. There are several hotspots for small RNA production along the PMaV genome; two 21-nt PMaV-sRNAs starting at 811 nt and 610 nt of the minus-strand genome were highly repeated. PMID- 27226229 TI - Spontaneous ripple formation in phosphorene: electronic properties and possible applications. AB - According to the Mermin-Wagner theorem and theory of elasticity, long-range order in two-dimensional (2D) crystals will be inevitably destroyed due to a thermal fluctuation. Thus, a 2D lattice prefers a corrugation meaning that a 2D crystal is easy to present a ripple. In this work, we, via employing ab initio molecular dynamics (AIMD) simulations, for the first time evidenced that the inherent dynamics of phosphorene would lead to a spontaneous formation of ripples at room temperature. The height of a ripple closely associates with the temperature and the width. Via density functional theory (DFT) calculations, we further demonstrated that the emergence of ripples would remarkably reduce the bandgap of phosphorene. Via the construction of the unique phosphorene structure, we finally found that such a rippled structure is expected to be used in the light-emitting field. These results give us further knowledge of phosphorene, which goes beyond the current scope of phosphorene limited to the flat lattice. PMID- 27226230 TI - MALDI-MSI for the analysis of a 3D tissue-engineered psoriatic skin model. AB - MALDI-MS Imaging is a novel label-free technique that can be used to visualize the changes in multiple mass responses following treatment. Following treatment with proinflammatory cytokine interleukin-22 (IL-22), the epidermal differentiation of Labskin, a living skin equivalent (LSE), successfully modeled psoriasis in vitro. Masson's trichrome staining enabled visualization and quantification of epidermal differentiation between the untreated and IL-22 treated psoriatic LSEs. Matrix-assisted laser desorption ionization mass spectrometry imaging was used to observe the spatial location of the psoriatic therapy drug acetretin following 48 h treatments within both psoriatic and normal LSEs. After 24 h, the drug was primarily located in the epidermal regions of both the psoriatic and nonpsoriatic LSE models whereas after 48 h it was detectible in the dermis. PMID- 27226231 TI - Validation of a method for noninvasive prenatal testing for fetal aneuploidies risk and considerations for its introduction in the Public Health System. AB - OBJECTIVE: The aim of this study was to validate noninvasive prenatal testing (NIPT) for fetal aneuploidies by whole-genome massively parallel sequencing (MPS). METHODS: MPS was performed on cell-free DNA (cfDNA) isolated from maternal plasma in two groups: a first set of 186 euploid samples and a second set of 195 samples enriched of aneuploid cases (n = 69); digital PCR for fetal fraction (FF) assessment was performed on 178/381 samples. Cases with <10 * 106 reads (n = 54) were excluded for downstream data analysis. Follow-up data (invasive testing results or neonatal information) were available for all samples. Performances in terms of specificity/sensitivity and Z-score distributions were evaluated. RESULTS: All positive samples for trisomy 21 (T21) (n = 43), trisomy 18 (T18) (n = 6) and trisomy 13 (T13) (n = 7) were correctly identified (sensitivity: 99.9%); 5 false positive results were reported: 3 for T21 (specificity = 98.9%) and 2 for T13 (specificity = 99.4%). Besides FF, total cfDNA concentration seems another important parameter for MPS, since it influences the number of reads. CONCLUSIONS: The overall test accuracy allowed us introducing NIPT for T21, T18 and T13 as a clinical service for pregnant women after 10 + 4 weeks of gestation. Sex chromosome aneuploidy assessment needs further validation due to the limited number of aneuploid cases in this study. PMID- 27226232 TI - Bioinformatics-Driven New Immune Target Discovery in Disease. AB - Biomolecular network analysis has been widely applied in the discovery of cancer driver genes and molecular mechanism anatomization of many diseases on the genetic level. However, the application of such approach in the potential antigen discovery of autoimmune diseases remains largely unexplored. Here, we describe a previously uncharacterized region, with disease-associated autoantigens, to build antigen networks with three bioinformatics tools, namely NetworkAnalyst, GeneMANIA and ToppGene. First, we identified histone H2AX as an antigen of systemic lupus erythematosus by comparing highly ranked genes from all the built network-derived gene lists, and then a new potential biomarker for Behcet's disease, heat shock protein HSP 90-alpha (HSP90AA1), was further screened out. Moreover, 130 confirmed patients were enrolled and a corresponding enzyme-linked immunosorbent assay, mass spectrum analysis and immunoprecipitation were performed to further confirm the bioinformatics results with real-world clinical samples in succession. Our findings demonstrate that the combination of multiple molecular network approaches is a promising tool to discover new immune targets in diseases. PMID- 27226233 TI - Strongly Modulated Friction of a Film-Terminated Ridge-Channel Structure. AB - Natural contacting surfaces have remarkable surface mechanical properties, which has led to the development of bioinspired surface structures using rubbery materials with strongly enhanced adhesion and static friction. However, sliding friction of structured rubbery surfaces is almost always significantly lower than that of a flat control, often due to significant loss of contact. Here we show that a film-terminated ridge-channel structure can strongly enhance sliding friction. We show that with properly chosen materials and geometrical parameters the near surface structure undergoes mechanical instabilities along with complex folding and sliding of internal interfaces, which is responsible for the enhancement of sliding friction. Because this structure shows no enhancement of adhesion under normal indentation by a sphere, it breaks the connection between energy loss during normal and shear loading. This makes it potentially interesting in many applications, for instance in tires, where one wishes to minimize rolling resistance (normal loading) while maximizing sliding friction (shear loading). PMID- 27226234 TI - Tuberous sclerosis complex. AB - Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organ systems and is caused by loss-of-function mutations in one of two genes: TSC1 or TSC2. The disorder can affect both adults and children. First described in depth by Bourneville in 1880, it is now estimated that nearly 2 million people are affected by the disease worldwide. The clinical features of TSC are distinctive and can vary widely between individuals, even within one family. Major features of the disease include tumours of the brain, skin, heart, lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders, which can include autism spectrum disorder and cognitive disability. TSC1 (also known as hamartin) and TSC2 (also known as tuberin) form the TSC protein complex that acts as an inhibitor of the mechanistic target of rapamycin (mTOR) signalling pathway, which in turn plays a pivotal part in regulating cell growth, proliferation, autophagy and protein and lipid synthesis. Remarkable progress in basic and translational research, in addition to several randomized controlled trials worldwide, has led to regulatory approval of the use of mTOR inhibitors for the treatment of renal angiomyolipomas, brain subependymal giant cell astrocytomas and pulmonary lymphangioleiomyomatosis, but further research is needed to establish full indications of therapeutic treatment. In this Primer, we review the state-of-the-art knowledge in the TSC field, including the molecular and cellular basis of the disease, medical management, major knowledge gaps and ongoing research towards a cure. PMID- 27226235 TI - Integrative Behavioral Couple Therapy: Theoretical Background, Empirical Research, and Dissemination. AB - Integrative Behavioral Couple Therapy (IBCT), developed by Drs. Andrew Christensen and Neil Jacobson, builds off the tradition of behavioral couple therapy by including acceptance strategies as key components of treatment. Results from a large randomized clinical trial of IBCT indicate that it yields large and significant gains in relationship satisfaction. Furthermore, these benefits have been shown to persist for at least 5 years after treatment for the average couple. Not only does IBCT positively impact relationship constructs such as satisfaction and communication, but the benefits of therapy extend to individual, co-parenting, and child functioning. Moreover, IBCT has been shown to operate through the putative mechanisms of improvements in emotional acceptance, behavior change, and communication. IBCT was chosen for nationwide training and dissemination through the Veteran Affairs Medical Centers. Furthermore, the principles of IBCT have been translated into a web-based intervention for distressed couples, OurRelationship.com. IBCT is continuing to evolve and grow as research and technologies allow for continued evaluation and dissemination of this well-supported theoretical model. PMID- 27226236 TI - Impact of Different Promoters on Episomal Vectors Harbouring Characteristic Motifs of Matrix Attachment Regions. AB - We previously demonstrated that the characteristic sequence of matrix attachment regions (MARs) allows transgenes to be maintained episomally in CHO cells. In the present study, six commonly used promoters from human cytomegalovirus major immediate-early (CMV), simian vacuolating virus 40 (SV40), Rous sarcoma virus, Homo sapiens ubiquitin C, phosphoglycerate kinase, and beta-globin, respectively, were evaluated to determine their effects on transgene expression and stability in CHO cells stably transfected via the episomal vector harbouring characteristic MAR motifs. The CHO cells were transfected with vectors and then screened using G418, after which the stably transfected cells were split into two and further cultured either in the presence or absence of G418. Of the six promoters, the CMV promoter yielded the highest transgene expression levels and the highest transfection efficiency, whereas the SV40 promoter maintained transgene expression more stably during long-term culture than the other promoters did. The CMV and SV40 promoter-containing vectors were furthermore episomally maintained and conferred sustained eGFP expression in the cells even under nonselective conditions. On the basis of these findings, we conclude that the CMV promoter performs best in terms of yielding both high expression levels and high levels of stability using this episomal vector system. PMID- 27226237 TI - "Aroeira" (Myracrodruon urundeuva) methanol extract: the relationship between chemical compounds and cellular effects. AB - CONTEXT: "Aroeira" [Myracrodruon urundeuva Allemao (Anacardiaceae)] is a tree whose leaves have been studied for therapeutic purposes in medicine and dentistry. OBJECTIVE: The study chemically identifies the leaf extract of aroeira and determines its effect on human gingival fibroblasts. MATERIALS AND METHODS: An 80% methanol leave extract was obtained by maceration and chemically identified through flow-injection analysis-electrospray ionization-ion trap tandem mass spectrometry (FIA-ESI-IT-MSn). Cytotoxicity of the aroeira's methanol extract was evaluated in lineage of fibroblasts. Adherent cells were treated with different concentrations of aroeira's methanol extract in the medium: 0.1, 1, 10, 100 and 1000 MUg/mL. Control cells were cultivated in the medium only. Analyses were done at 24, 48, 72 and 96 h of culture by neutral red assay; and at 24, 48 and 96 h by crystal violet assay. RESULTS: FIA-ESI-IT-MS analysis determined the presence of compounds, for the first time in the species: quercetin-O-glucuronide and quercetin-O-deoxyhexose-O-glucose in the extract. On one hand, neutral red and crystal violet assay showed a reduction (to 50% up until 100%) of cellular viability of groups of 100 and 1000 MUg/mL compared with control at 96 h (p < 0.05). On the other hand, lower concentrations (0.1; 1 and 10 MUg/mL) of the extract were similar to that of the control at 96 h (p < 0.05), in general. CONCLUSIONS: In view of the results, we can conclude that the extract of aroeira presents tannins and flavonoids. Furthermore, the extract is capable of modulating the viability of human gingival fibroblasts according to its concentration. PMID- 27226238 TI - kappa-Opioid Receptor Stimulation Improves Endothelial Function via Akt stimulated NO Production in Hyperlipidemic Rats. AB - This study was designed to investigate the effect of U50,488H (a selective kappa opioid receptor agonist) on endothelial function impaired by hyperlipidemia and to determine the role of Akt-stimulated NO production in it. Hyperlipidemic model was established by feeding rats with a high-fat diet for 14 weeks. U50,488H and nor-BNI (a selective kappa-opioid receptor antagonist) were administered intraperitoneally. In vitro, the involvement of the PI3K/Akt/eNOS pathway in the effect of U50,488H was studied using cultured endothelial cells subjected to artificial hyperlipidemia. Serum total cholesterol and low-density lipoprotein cholesterol concentrations dramatically increased after high-fat diet feeding. Administration of U50,488H significantly alleviated endothelial ultrastructural destruction and endothelium-dependent vasorelaxation impairment caused by hyperlipidemia. U50,488H also increased Akt/eNOS phosphorylation and serum/medium NO level both in vivo and in vitro. U50,488H increased eNOS activity and suppressed iNOS activity in vivo. The effects of U50,488H were abolished in vitro by siRNAs targeting kappa-opioid receptor and Akt or PI3K/Akt/eNOS inhibitors. All effects of U50,488H were blocked by nor-BNI. These results demonstrate that kappa-opioid receptor stimulation normalizes endothelial ultrastructure and function under hyperlipidemic condition. Its mechanism is related to the preservation of eNOS phosphorylation through activation of the PI3K/Akt signaling pathway and downregulation of iNOS expression/activity. PMID- 27226239 TI - Design, synthesis and biological activity of 1H-indene-2-carboxamides as multi targeted anti-Alzheimer agents. AB - The aim of this study was to design new molecules and evaluate their anticholinesterase and amyloid beta (Abeta1-42) inhibition activities as multifunctional drug candidates for the treatment of Alzheimer's disease (AD). A series of 5,6-dimethoxy-1H-indene-2-carboxamides (1-22) was synthesized; cholinesterase inhibitory activities of the compounds were measured according to Ellman's colorimetric assay, while the thioflavin T assay was used for measuring the inhibition of Abeta1-42 aggregation. The results revealed that most compounds showed higher inhibitory activity against BuChE than AChE. Compounds 20 and 21 were found to be the most potent BuChE inhibitors with respective IC50 values of 1.08 and 1.09 MUM. Compounds 16, 20, 21 and 22 exhibited remarkable inhibition of Abeta1-42 aggregation. Kinetic analysis showed that the most potent BuChE inhibitor (20) acted as a noncompetitive inhibitor. Docking studies suggested that inhibitor 20 displayed many potential hydrogen-bondings with the PAS of BuChE. These results suggest that compound 20 may be an especially promising multifunctional drug for the prevention and treatment of AD. PMID- 27226240 TI - Efficient antitumor effect of co-drug-loaded nanoparticles with gelatin hydrogel by local implantation. AB - Tetrandrine (Tet) could enhance the antitumor effect of Paclitaxel (Ptx) by increasing intracellular Reactive Oxygen Species (ROS) levels, which leads to the possibility of co-delivery of both drugs for synergistic antitumor effect. In the current study, we reported an efficient, local therapeutic strategy employing effective Tet and Ptx delivery with a nanoparticle-loaded gelatin system. Tet- and Ptx co-loaded mPEG-PCL nanoparticles (P/T-NPs) were encapsulated into the physically cross-linked gelatin hydrogel and then implanted on the tumor site for continuous drug release. The drug-loaded gelatin hydrogel underwent a phase change when the temperature slowly increased. In vitro study showed that Tet/Ptx loaded PEG-b-PCL nanoparticles encapsulated within a gelatin hydrogel (P/T-NPs Gelatin) inhibited the growth and invasive ability of BGC-823 cells more effectively than the combination of free drugs or P/T-NPs. In vivo study validated the therapeutic potential of P/T-NPs-Gelatin. P/T-NPs-Gelatin significantly inhibited the activation of p-Akt and the downstream anti-apoptotic Bcl-2 protein and also inducing the activation of pro-apoptotic Bax protein. Moreover, the molecular-modulating effect of P/T-NPs-Gelatin on related proteins varied slightly under the influence of NAC, which was supported by the observations of the tumor volumes and weights. Based on these findings, local implantation of P/T-NPs-Gelatin may be a promising therapeutic strategy for the treatment of gastric cancer. PMID- 27226241 TI - Readability Analysis of the Package Leaflets for Biological Medicines Available on the Internet Between 2007 and 2013: An Analytical Longitudinal Study. AB - BACKGROUND: The package leaflet included in the packaging of all medicinal products plays an important role in the transmission of medicine-related information to patients. Therefore, in 2009, the European Commission published readability guidelines to try to ensure that the information contained in the package leaflet is understood by patients. OBJECTIVE: The main objective of this study was to calculate and compare the readability levels and length (number of words) of the package leaflets for biological medicines in 2007, 2010, and 2013. METHODS: The sample of this study included 36 biological medicine package leaflets that were downloaded from the European Medicines Agency website in three different years: 2007, 2010, and 2013. The readability of the selected package leaflets was obtained using the following readability formulas: SMOG grade, Flesch-Kincaid grade level, and Szigriszt's perspicuity index. The length (number of words) of the package leaflets was also measured. Afterwards, the relationship between these quantitative variables (three readability indexes and length) and categorical (or qualitative) variables were analyzed. The categorical variables were the year when the package leaflet was downloaded, the package leaflet section, type of medicine, year of authorization of biological medicine, and marketing authorization holder. RESULTS: The readability values of all the package leaflets exceeded the sixth-grade reading level, which is the recommended value for health-related written materials. No statistically significant differences were found between the three years of study in the readability indexes, although differences were observed in the case of the length (P=.002), which increased over the study period. When the relationship between readability indexes and length and the other variables was analyzed, statistically significant differences were found between package leaflet sections (P<.001) and between the groups of medicine only with regard to the length over the three studied years (P=.002 in 2007, P=.007 in 2010, P=.009 in 2013). Linear correlation was observed between the readability indexes (SMOG grade and Flesch Kincaid grade level: r(2)=.92; SMOG grade and Szigriszt's perspicuity index: r(2)=.81; Flesch-Kincaid grade level and Szigriszt's perspicuity index: r(2)=.95), but not between the readability indexes and the length (length and SMOG grade: r(2)=.05; length and Flesch-Kincaid grade level: r(2)=.03; length and Szigriszt's perspicuity index: r(2)=.02). CONCLUSIONS: There was no improvement in the readability of the package leaflets studied between 2007 and 2013 despite the European Commission's 2009 guideline on the readability of package leaflets. The results obtained from the different readability formulas coincided from a qualitative point of view. Efforts to improve the readability of package leaflets for biological medicines are required to promote the understandability and accessibility of this online health information by patients and thereby contribute to the appropriate use of medicines and medicine safety. PMID- 27226242 TI - Effect of short-term room temperature storage on the microbial community in infant fecal samples. AB - Sample storage conditions are important for unbiased analysis of microbial communities in metagenomic studies. Specifically, for infant gut microbiota studies, stool specimens are often exposed to room temperature (RT) conditions prior to analysis. This could lead to variations in structural and quantitative assessment of bacterial communities. To estimate such effects of RT storage, we collected feces from 29 healthy infants (0-3 months) and partitioned each sample into 5 portions to be stored for different lengths of time at RT before freezing at -80 degrees C. Alpha diversity did not differ between samples with storage time from 0 to 2 hours. The UniFrac distances and microbial composition analysis showed significant differences by testing among individuals, but not by testing between different time points at RT. Changes in the relative abundance of some specific (less common, minor) taxa were still found during storage at room temperature. Our results support previous studies in children and adults, and provided useful information for accurate characterization of infant gut microbiomes. In particular, our study furnished a solid foundation and justification for using fecal samples exposed to RT for less than 2 hours for comparative analyses between various medical conditions. PMID- 27226243 TI - A lateral signalling pathway coordinates shape volatility during cell migration. AB - Cell migration is fundamental for both physiological and pathological processes. Migrating cells usually display high dynamics in morphology, which is orchestrated by an integrative array of signalling pathways. Here we identify a novel pathway, we term lateral signalling, comprised of the planar cell polarity (PCP) protein Pk1 and the RhoGAPs, Arhgap21/23. We show that the Pk1-Arhgap21/23 complex inhibits RhoA, is localized on the non-protrusive lateral membrane cortex and its disruption leads to the disorganization of the actomyosin network and altered focal adhesion dynamics. Pk1-mediated lateral signalling confines protrusive activity and is regulated by Smurf2, an E3 ubiquitin ligase in the PCP pathway. Furthermore, we demonstrate that dynamic interplay between lateral and protrusive signalling generates cyclical fluctuations in cell shape that we quantify here as shape volatility, which strongly correlates with migration speed. These studies uncover a previously unrecognized lateral signalling pathway that coordinates shape volatility during productive cell migration. PMID- 27226244 TI - Compost biofortification with diazotrophic and P-solubilizing bacteria improves maturation process and P availability. AB - BACKGROUND: Phosphorus-containing fertilizers play an important role in tropical agriculture owing to the well documented shortage of plant-available P in soils. Traditional P fertilizer production is based on chemical processing of insoluble rock phosphate (RP), which includes an acid treatment at high temperature. Processing the RP increases fertilizer costs, making it unavailable for undercapitalized and typically family-based farmers. Biotechnological methods have been proposed as an alternative to increase phosphate availability in RP. In this study, Burkholderia silvatlantica and Herbaspirillum seropedicae were co inoculated into an RP-enriched compost with the aim of determining the effects of this technology on the levels of phosphatase activities and release of plant available P. RESULTS: Inoculation of both microorganisms resulted in higher organic matter decomposition and higher humic acid formation in composting. Herbaspirillum seropedicae was the most promising microorganism for the production of acid and alkaline phosphatase enzymes. Both microorganisms presented potential to increase the supply of P from poorly soluble sources owing to increased levels of water-soluble P and citric acid P. CONCLUSION: Burkholderia silvatlantica and H. seropedicae in RP-enriched compost may represent an important biotechnological tool to reduce the overall time required for composting and increase the supply of P from poorly soluble sources. (c) 2016 Society of Chemical Industry. PMID- 27226246 TI - Re: "The Johns Hopkins Bloomberg School of Public Health: A Brief History of a Century of Epidemiologic Discovery". PMID- 27226245 TI - Effect of Fluorine Substitution on the Charge Carrier Dynamics of Benzothiadiazole-Based Solar Cell Materials. AB - The femtosecond transient absorption (TA) characterization of a new benzothiadiazole (BT)-based donor-acceptor conjugated copolymer, poly[(2,6 dithieno[3,2-b:2',3'-d]thiophene)-alt-(4,7-di(4-octyldodecylthiopen-2-yl)-2,1,3 benzo[c][1,2,5]thiadiazole (PBT), as well as its fluorinated derivatives, PFBT and PDFBT, is carried out. Additionally, bulk heterojunction (BHJ) films consisting of the copolymers and [6,6]-phenyl-C71 -butylic acid methyl ester (PC70 BM) are examined using TA spectroscopy. Both the singlet excited state dynamics in the copolymers and the charge transfer state dynamics in the BHJs are investigated in terms of fluorination dependency; the fluorinated copolymers exhibit less singlet exciton recombination rate than the fluorine-free copolymer, and the BHJs including the fluorinated copolymers display slower monomolecular recombination than the fluorine-free analogue. Furthermore, the excitation intensity-dependent TA dynamics of the copolymers and BHJs is investigated, revealing that, when sufficiently high excitation intensity is used to induce annihilation processes, the fluorinated copolymers and BHJs incorporating the fluorinated copolymers show more rapid TA decay ascribable to morphological enhancement. These TA spectroscopic findings are found to correlate with the device characteristics with respect to fluorinated content in the polymer solar cells. In particular, both the short-circuit current density and fill factor of BHJ solar cells correspond closely with the fast decay parameters of the BHJ films under high excitation intensity. PMID- 27226247 TI - Re: "The Natural History of Human Polyomaviruses and Herpesviruses in Early Life The Rhea Birth Cohort in Greece". PMID- 27226248 TI - Aggio et al. Respond to "Lessons for Research on Cognitive Aging". PMID- 27226249 TI - Context-Specific Associations of Physical Activity and Sedentary Behavior With Cognition in Children. AB - In the present study, we investigated how overall and specific domains of physical activity and sedentary behavior at the age of 7 years were associated with cognition at the age of 11 years in 8,462 children from the Millennium Cohort Study. Data were collected from 2001 to 2013. Participation in domains of physical activity and sedentary behavior at 7 years of age were reported. Activity levels were also measured objectively. Cognition was assessed using the British Ability Scales. General linear models were used to assess longitudinal associations of physical activity and sedentary behavior, measured both objectively and via self-report, with cognition. Analyses were adjusted for prespecified covariates. Sports/physical activity club attendance (B = 0.6, 95% confidence interval (CI): 0.2, 1.1), doing homework (B = 0.5, 95% CI: 0.0, 0.9), and objectively measured sedentary time (B = 0.8, 95% CI: 0.1, 1.4) at age 7 years were positively associated with cognition at age 11 years in final the models. Television viewing was negatively associated with cognition (B = -1.7, 95% CI: -2.4, -1.0), although the association was attenuated to the null after adjustments for baseline cognition. Objectively measured light physical activity was inversely associated with cognition (B = -0.7, 95% CI: -1.3, -0.1). Moderate to-vigorous physical activity was also inversely associated with cognition in girls only (B = -1.1, 95% CI: -2.0, -0.3). Associations of physical activity and sedentary behavior with cognition appear to be context-specific in young people. PMID- 27226250 TI - Invited Commentary: Lessons for Research on Cognitive Aging From a Study of Children. AB - As the population ages, the burden of disease from cognitive decline and dementing illness is rising. In the absence of treatments to reverse cognitive decline, prevention is a public health priority. Physical fitness and physical activity have emerged as prevention targets based on evidence of "neuroprotective" benefits in observational studies. However, observational studies linking active lifestyle with successful cognitive aging might be subject to bias from "neuroselection," in which adults with better cognitive functioning are more likely to engage in healthy behaviors and avoid unhealthy ones. In their analysis of longitudinal data on several thousand children from the United Kingdom's Millennium Cohort Study, Aggio et al. (Am J Epidemiol. 2016;183(12):1075-1082) revealed that this pattern of neuroselection is already apparent in childhood. However, they also report data that suggest there are cognitive benefits to engaging in certain types of active behaviors over and above this selection. Their findings argue for greater attention to confounding by neuroselection in research on cognitive aging, and they suggest the possibility that early interventions to promote certain health behaviors may instill a virtuous cycle with benefits that accumulate across the lifespan. PMID- 27226252 TI - The role of curvature in Diels-Alder functionalization of carbon-based materials. AB - We have estimated theoretically the impact of curvature on the free energies of activation and reaction associated with Diels-Alder reactions on carbon-based materials. Significant reduction is observed for both energy values with increasing curvature for core-functionalization, while the opposite trend prevails for edge-functionalization, as further supported by SEM/fluorescence measurements. PMID- 27226253 TI - Specific Stabilization of c-MYC and c-KIT G-Quadruplex DNA Structures by Indolylmethyleneindanone Scaffolds. AB - Stabilization of G-quadruplex DNA structures by small molecules has emerged as a promising strategy for the development of anticancer drugs. Since G-quadruplex structures can adopt various topologies, attaining specific stabilization of a G quadruplex topology to halt a particular biological process is daunting. To achieve this, we have designed and synthesized simple structural scaffolds based on an indolylmethyleneindanone pharmacophore, which can specifically stabilize the parallel topology of promoter quadruplex DNAs (c-MYC, c-KIT1, and c-KIT2), when compared to various topologies of telomeric and duplex DNAs. The lead ligands (InEt2 and InPr2) are water-soluble and meet a number of desirable criteria for a small molecule drug. Highly specific induction and stabilization of the c-MYC and c-KIT quadruplex DNAs (DeltaT1/2 up to 24 degrees C) over telomeric and duplex DNAs (DeltaT1/2 ~ 3.2 degrees C) by these ligands were further validated by isothermal titration calorimetry and electrospray ionization mass spectrometry experiments (Ka ~ 10(5) to 10(6) M(-1)). Low IC50 (~2 MUM) values were emerged for these ligands from a Taq DNA polymerase stop assay with the c-MYC quadruplex forming template, whereas the telomeric DNA template showed IC50 values >120 MUM. Molecular modeling and dynamics studies demonstrated the 5' and 3'-end stacking modes for these ligands. Overall, these results demonstrate that among the >1000 quadruplex stabilizing ligands reported so far, the indolylmethyleneindanone scaffolds stand out in terms of target specificity and structural simplicity and therefore offer a new paradigm in topology specific G quadruplex targeting for potential therapeutic and diagnostic applications. PMID- 27226251 TI - The NEU1-selective sialidase inhibitor, C9-butyl-amide-DANA, blocks sialidase activity and NEU1-mediated bioactivities in human lung in vitro and murine lung in vivo. AB - Neuraminidase-1 (NEU1) is the predominant sialidase expressed in human airway epithelia and lung microvascular endothelia where it mediates multiple biological processes. We tested whether the NEU1-selective sialidase inhibitor, C9-butyl amide-2-deoxy-2,3-dehydro-N-acetylneuraminic acid (C9-BA-DANA), inhibits one or more established NEU1-mediated bioactivities in human lung cells. We established the IC50 values of C9-BA-DANA for total sialidase activity in human airway epithelia, lung microvascular endothelia and lung fibroblasts to be 3.74 uM, 13.0 uM and 4.82 uM, respectively. In human airway epithelia, C9-BA-DANA dose dependently inhibited flagellin-induced, NEU1-mediated mucin-1 ectodomain desialylation, adhesiveness for Pseudomonas aeruginosa and shedding. In lung microvascular endothelia, C9-BA-DANA reversed NEU1-driven restraint of cell migration into a wound and disruption of capillary-like tube formation. NEU1 and its chaperone/transport protein, protective protein/cathepsin A (PPCA), were differentially expressed in these same cells. Normalized NEU1 protein expression correlated with total sialidase activity whereas PPCA expression did not. In contrast to eukaryotic sialidases, C9-BA-DANA exerted far less inhibitory activity for three selected bacterial neuraminidases (IC50 > 800 uM). Structural modeling of the four human sialidases and three bacterial neuraminidases revealed a loop between the seventh and eighth strands of the beta-propeller fold, that in NEU1, was substantially shorter than that seen in the six other enzymes. Predicted steric hindrance between this loop and C9-BA-DANA could explain its selectivity for NEU1. Finally, pretreatment of mice with C9-BA-DANA completely protected against flagellin-induced increases in lung sialidase activity. Our combined data indicate that C9-BA-DANA inhibits endogenous and ectopically expressed sialidase activity and established NEU1-mediated bioactivities in human airway epithelia, lung microvascular endothelia, and fibroblasts in vitro and murine lungs in vivo. PMID- 27226255 TI - Characterization of Platinum and Iridium Oxyhydrate Surface Layers from Platinum and Iridium Foils. AB - Platinum and iridium polycrystalline foils were oxidized electrochemically through anodization to create thin platinum and iridium hydrous oxide layers, which were analyzed through laboratory photoelectron spectroscopy during heating and time series (temperature-programmed spectroscopy). The films contain oxygen in the form of bound oxides, water, and hydroxides and were investigated by depth profiling with high-energy photoelectron spectroscopy. The Pt films are unstable and begin to degrade immediately after removal from the electrolyte to form core shell structures with a metallic inner core and a hydrous oxide outer shell almost devoid of Pt. However, evidence was found for metastable intermediate states of degradation; therefore, it may be possible to manufacture PtOx phases with increased stability. Heating the film to even 100 degrees C causes accelerated degradation, which shows that stoichiometric oxides such as PtO2 or PtO are not the active species in the electrolyte. The Ir films exhibit increased stability and higher surface Ir content, and gentle heating at low temperatures leads to a decrease in defect density. Although both layers are based on noble metals, their surface structures are markedly different. The complexity of such hydrous oxide systems is discussed in detail with the goal of identifying the film composition more precisely. PMID- 27226254 TI - Allele-specific expression of mutated in colorectal cancer (MCC) gene and alternative susceptibility to colorectal cancer in schizophrenia. AB - Evidence has indicated that the incidence of colorectal cancer (CRC) among schizophrenia is lower than normal. To explore this potential protective effect, we employed an innovative strategy combining association study with allele specific expression (ASE) analysis in MCC gene. We first genotyped four polymorphisms within MCC in 312 CRC patients, 270 schizophrenia patients and 270 controls. Using the MassArray technique, we performed ASE measurements in a second sample series consisting of 50 sporadic CRC patients, 50 schizophrenia patients and 52 controls. Rs2227947 showed significant differences between schizophrenia cases and controls, and haplotype analysis reported some significant discrepancies among these three subject groups. ASE values of rs2227948 and rs2227947 presented consistently differences between CRC (or schizophrenia) patients and controls. Of the three groups, highest frequencies of ASE in MCC were concordantly found in CRC group, whereas lowest frequencies of ASE were observed in schizophrenia group. Similar trends were confirmed in both haplotype frequencies and ASE frequencies (i.e. CRC > control > schizophrenia). We provide a first indication that MCC might confer alterative genetic susceptibility to CRC in individuals with schizophrenia promising to shed more light on the relationship between schizophrenia and cancer progression. PMID- 27226256 TI - Could nitric oxide be a mediator of action of oxytocin on myocardial injury in rats? (Biochemical, histological and immunohistochemical study). AB - Oxytocin (OT) was revisited recently as a hormone of cardiovascular system with several new functions in cardiovascular regulation. But less is known about its role in acute myocardial injury (MI). The aim of our study was to investigate the possible protective effect of OT on the biochemical, histological and immunohistochemical changes of MI induced by isoprenaline (ISO) in adult male albino rats and studying the possible role of nitric oxide (NO) in its action. Forty male albino rats were divided into 5 groups: control rats (Group I), acute MI rats (Group II), rats pretreated with OT prior to induction of MI (Group III), rats injected with a combination of OT and atosiban (ATO, OT receptor antagonist) prior to induction of MI (Group IV). In Group V, a combination of OT and nitric oxide synthase inhibitor (L-NAME) were injected to the rats prior to induction of MI. The heart wall in all groups were taken and processed for histological, immunohistochemical, morphometrical and biochemical studies. We concluded that OT has antioxidant, anti-inflammatory and anti-apoptotic effects on MI and its effects is mediated through NO. PMID- 27226257 TI - Fathers of people with intellectual disability: A review of the literature. AB - The aim of this article is to review the literature related to fathers of people who have an intellectual disability (ID). Electronic databases and citation tracking were used to collate data using key terms such as fathers, adults with an ID, learning disability, mental handicap and developmental disability. Relevant articles were analysed and compared for commonality and difference. Eight themes emerged from the literature: response to diagnosis, varied response to ID, concern for the future, work, roles and relationships, impact of fathers upon child development, fathers and service providers, fathers' needs and coping strategies. This review of the literature presents areas of similarity and divergence and highlights the lack of information that relates specifically to fathers of adults. There are clear messages to service providers to support the inclusion of fathers and the need for further research in this area is indicated. PMID- 27226258 TI - Service providers' perceptions of and responses to bullying of individuals with disabilities. AB - A sample of 124 service providers (e.g. mental health professionals, educators, administrators) completed a survey about bullying of individuals with disabilities and the use and perceived effectiveness of resources and strategies to address bullying. Providing support and performing an action in response to bullying were reported to be used more often and were perceived as more effective than education and minimizing/ignoring. Service providers who reported that the individuals they worked with experienced cyberbullying more frequently were more likely to take action and use education. Those who attributed victimization to social differences were more likely to provide support. PMID- 27226259 TI - Supporting mentors working with students with intellectual disabilities in higher education. AB - Project Panther LIFE is an inclusive postsecondary transition program for students with intellectual disabilities providing university access and participation with the primary goal of employment at program completion. Students in the program receive support from their academic mentors and peer coaches during the academic year. This study examines the skills and activities mentors use during their weekly sessions with students with intellectual disabilities and identifies areas in which mentors may require further support or training. Data analysis revealed major themes related to inclusion, self-determination, and adaptive behavior skills. Upon review of the data, we suggest that mentors need ongoing support from transition programs especially in areas related to encouraging self-advocacy and supporting time management. PMID- 27226260 TI - Exploring the literature on music participation and social connectedness for young people with intellectual disability: A critical interpretive synthesis. AB - BACKGROUND: This article explores the literature on social connectedness and music for young people with disability. It then critically examines the level of congruence between the reported literature to date and current rights-based disability studies discourse. METHOD: A critical interpretive synthesis was used to examine 27 articles referencing the use of music for social connectedness. Areas of focus in the review are the nature of connections being fostered in music programs, the use of voice and collaboration. RESULTS: The majority of music programs reported on closed groups. Outdated 'expert' models of working persist. The use of participants' voice in the literature is growing, although there is a lack of collaboration and negative reporting. CONCLUSION: A shift in thinking heralds greater collaboration with participants, although this could be broadened to include decisions on research agendas, planning and evaluation. There is also need for active fostering of broader socio-musical pathways. PMID- 27226261 TI - Ablating the Imperceptible: A Novel Application of Para-Hisian Pacing. AB - In some elderly patients with atrial fibrillation, especially in combination with heart failure, a rate control strategy may be preferred. When pharmacological therapy is ineffective or not tolerated, it is reasonable to perform atrioventricular (AV) node ablation with ventricular pacing. We describe a case in which this approach was necessary for management. However, the presence of periprocedural, drug-induced AV block just before ablation provided a unique and challenging circumstance. We discuss the steps taken to ensure a successful procedure. PMID- 27226263 TI - Diagnostic shift in patients diagnosed with schizoaffective disorder: a systematic review and meta-analysis of rediagnosis studies. AB - OBJECTIVES: The diagnosis of schizoaffective disorder (SAD) is well established in clinical practice but is heavily disputed on theoretical grounds. We analyzed the extent and direction of diagnostic shift in SAD patients. METHODS: We searched Medline, Embase, and PsycINFO systematically for all studies documenting two diagnostic assessments at different points in time (rediagnosis studies) and used meta-analytic methods to quantify diagnostic shift. Multiple prespecified and post-hoc subgroup analyses (e.g., rater blinding) and meta-regressions (e.g., year of publication) were carried out. RESULTS: We included 31 studies out of 4,415 articles screened: 27 studies on the shift from and 23 studies on the shift to SAD (median time span was two years). A total of 36% of patients with a diagnosis of SAD at first assessment switch, many to schizophrenia (19%), 14% to affective disorders, and 6% to other disorders. Among patients diagnosed with SAD at second assessment, 55% had received a different diagnosis at first assessment, a large portion of whom had been initially diagnosed with affective disorder (24%), schizophrenia (18%), and other disorders (12%). CONCLUSIONS: Diagnostic shift in SAD patients is substantial. Psychiatrists need to reassess the diagnosis during the course of the illness and to adjust treatment. Slightly more diagnoses of SAD are changed to schizophrenia than to affective disorders, and among patients rediagnosed with SAD, fewer have been diagnosed with schizophrenia than with affective disorders. Thus, at the diagnostic level, there seems to be a slight trend toward schizophrenia during the course of functional psychoses. PMID- 27226262 TI - Blue-blocking glasses as additive treatment for mania: a randomized placebo controlled trial. AB - OBJECTIVES: The discovery of the blue lightsensitive retinal photoreceptor responsible for signaling daytime to the brain suggested that light to the circadian system could be inhibited by using blue-blocking orange tinted glasses. Blue-blocking (BB) glasses are a potential treatment option for bipolar mania. We examined the effectiveness of BB glasses in hospitalized patients with bipolar disorder in a manic state. METHODS: In a single-blinded, randomized, placebo controlled trial (RCT), eligible patients (with bipolar mania; age 18-70 years) were recruited from five clinics in Norway. Patients were assigned to BB glasses or placebo (clear glasses) from 6 p.m. to 8 a.m. for 7 days, in addition to treatment as usual. Symptoms were assessed daily by use of the Young Mania Rating Scale (YMRS). Motor activity was assessed by actigraphy, and compared to data from a healthy control group. Wearing glasses for one evening/night qualified for inclusion in the intention-to-treat analysis. RESULTS: From February 2012 to February 2015, 32 patients were enrolled. Eight patients dropped out and one was excluded, resulting in 12 patients in the BB group and 11 patients in the placebo group. The mean decline in YMRS score was 14.1 [95% confidence interval (CI): 9.7 18.5] in the BB group, and 1.7 (95% CI: -4.0 to 7.4) in the placebo group, yielding an effect size of 1.86 (Cohen's d). In the BB group, one patient reported headache and two patients experienced easily reversible depressive symptoms. CONCLUSIONS: This RCT shows that BB glasses are effective and feasible as add-on treatment for bipolar mania. PMID- 27226265 TI - Sex differences in mortality among patients admitted with affective disorders in North Norway: a 33-year prospective register study. AB - OBJECTIVE: Previous studies from North Norway showed significantly increased mortality in patients with schizophrenia and personality disorder. The aim of the present study was to investigate total and cause-specific mortality in inpatients with affective disorder in a 33-year follow-up cohort, with a specific focus on sex differences. METHODS: Based on a hospital case register covering all admissions to psychiatric hospital in the two northernmost counties in Norway from 1980 to 2012, 790 men and 866 women with major depressive disorder and 331 men and 514 women with bipolar disorder were included. The cohort was linked to the Norwegian Cause of Death Registry. The relative mortality in men compared to women was tested using Cox regression with attained age as the time variable. The standardized mortality ratio (SMR) of the patients when compared to the general population in Norway was calculated. RESULTS: Patients with affective disorders had twice the mortality of the general Norwegian population [SMR = 2.1, 95% confidence interval (CI): 1.9-2.3]. For major depressive disorder, the SMR for total mortality was higher among men (2.6, 95% CI: 2.2-3.0) than women (1.8, 95% CI: 1.5-2.1). For bipolar disorder, no difference was seen between men and women. The SMR for suicide among women showed an increasing trend throughout the period 1980-1990: 20.0 (95% CI: 10.4-38.4); 1991-2001: 27.0 (95% CI: 15.7-46.2); 2002 2012: 40.4 (95% CI: 23.0-71.2). CONCLUSIONS: The substantially increased mortality in patients with affective disorders in Norway has been persistent over a period of 33 years, despite extensive reforms in psychiatric health care. Indications of increasing SMR for suicide in women call for further research. PMID- 27226266 TI - [Skin and soft tissue infections (SSTIs)]. AB - Skin and Soft Tissue Infections (SSTIs) encompass a wide spectrum of inflammatory diseases of the skin, subcutis, fascia and muscles. Recent national trends indicate increasing rates of patients treated for these diagnoses at outpatient surgical department, but also of patients hospitalized with severe forms of SSTIs. Up to 90% fatality rates are reported in the literature for the most severe forms, resulting from underestimation of initial symptoms and therefore delayed onset of radical therapy only the phase of septic shock. The paper provides an interdisciplinary review of essential principles of the diagnosis and therapy of SSTIs, reflecting present knowledge supported by evidence-based medicine. KEY WORDS: skin and soft tissue infections - SSTIs - necrotizing fasciitis - diagnosis - therapy. PMID- 27226267 TI - [Kidney donors after circulatory death (DCD) - single centre experience]. AB - INTRODUCTION: Kidney procurement from donors after circulatory death (DCD) is an important part of worldwide transplantation programmes. The first kidney transplantation from DCD was successfully performed in the Czech Republic in 2002. METHOD: Forty four kidneys from DCD were procured in the Transplant Centre of Pilsen between 2002 and 2015. We used the technique of "in situ" procurement with the double balloon triple lumen catheter and 510 minutes of the no-touch interval. The method of pulsatile hypothermic perfusion was used to test the viability of the kidneys. Twenty eight recipients with mean age 51.1 (2673) years were transplanted. Sixteen (57.1%) kidneys were from the 2nd, 8 (28.6%) from the 3rd and 4 (14.3%) from the 4th category according to the Maastricht criteria. RESULTS: 30-day mortality and morbidity rates were 0 and 10.7% i. e.14.3% respectively (N=4). Primary non-function was presented in 2 (7.1%), and delayed graft function in 5 (17.9%) cases. One, five and ten years of recipient and graft survival rates were 100%, 86.4% and 76.7%; and 92.9%, 69.6% and 61.9%, respectively. The long-term results are fully comparable with kidneys transplanted from donors after brain death. CONCLUSION: DCD are an important source for kidney transplantation. Kidney transplantation from DCD is a logistically, economically and personally demanding method with very good long term results. KEY WORDS: donors after circulatory death - kidney transplantation results. PMID- 27226264 TI - Hypothyroidism risk compared among nine common bipolar disorder therapies in a large US cohort. AB - OBJECTIVES: Thyroid abnormalities in patients with bipolar disorder (BD) have been linked to lithium treatment for decades, yet other drugs have been less well studied. Our objective was to compare hypothyroidism risk for lithium versus the anticonvulsants and second-generation antipsychotics commonly prescribed for BD. METHODS: Administrative claims data on 24,574 patients with BD were analyzed with competing risk survival analysis. Inclusion criteria were (i) one year of no prior hypothyroid diagnosis nor BD drug treatment, (ii) followed by at least one thyroid test during BD monotherapy on lithium carbonate, mood-stabilizing anticonvulsants (lamotrigine, valproate, oxcarbazepine, or carbamazepine) or antipsychotics (aripiprazole, olanzapine, risperidone, or quetiapine). The outcome was cumulative incidence of hypothyroidism per drug, in the presence of the competing risk of ending monotherapy, adjusted for age, sex, physician visits, and thyroid tests. RESULTS: Adjusting for covariates, the four-year cumulative risk of hypothyroidism for lithium (8.8%) was 1.39-fold that of the lowest risk therapy, oxcarbazepine (6.3%). Lithium was non-statistically significantly different from quetiapine. While lithium conferred a higher risk when compared to all other treatments combined as a group, hypothyroidism risk error bars overlapped for all drugs. Treatment (p = 3.86e-3), age (p = 6.91e-10), sex (p = 3.93e-7), and thyroid testing (p = 2.79e-87) affected risk. Patients taking lithium were tested for hypothyroidism 2.26-3.05 times more frequently than those on other treatments. CONCLUSIONS: Thyroid abnormalities occur frequently in patients with BD regardless of treatment. Therefore, patients should be regularly tested for clinical or subclinical thyroid abnormalities on all therapies and treated as indicated to prevent adverse effects of hormone imbalances on mood. PMID- 27226268 TI - [Current status regarding surgical treatment of pancreatic cancer in the Czech Republic]. AB - INTRODUCTION: The aim is to map the current situation in the surgical treatment of pancreatic cancer in the Czech Republic. This information has been obtained from surgical treatment providers using a simple questionnaire and by identifying the so called high volume centres. The information has been collected in the interest of organizing and planning research projects in the field of pancreatic cancer treatment. METHOD: We addressed centres known to provide surgical treatment of pancreatic cancer. A simple questionnaire formulated one question about the total number of pancreatic resections, also separately for the diagnoses PDAC - C25, in the last two years (2014 and 2015). Other questions focused on the use of diagnostic methods, neoadjuvant therapy, preoperative assessment of risks, the possibility of rapid intraoperative histopathology examination, Leeds protocol, monitoring of morbidity and mortality including long term results, and the method of postoperative follow-up and treatment. UZIS (Institute of Health Information and Statistics of the Czech Republic) was addressed with a request to analyze the frequency of reported total numbers for DPE, LPE, TPE and to do the same with respect to diagnosis C 25 for the last two years, available for the entire Czech Republic (2013, 2014). RESULTS: Altogether 19 institutions were identified by the preceding audit, which reported more than 10 pancreatic resections annually; these institutions were addressed with the questionnaire. Sixteen institutions responded to the questions, 13 of them completely. CONCLUSION: The majority of potentially radical surgeries for PDAC in the Czech Republic are carried out at 6 institutions. All of the institutions that participated in the survey collect data about morbidity and mortality and monitor their results. KEY WORDS: pancreas cancer outcomes surgery. PMID- 27226269 TI - [Predictive and prognostic factors of gastric cancer]. AB - INTRODUCTION: Gastric cancer is a frequent malignant disease with poor prognosis. Most patients undergo only palliative treatment. Chemotherapy is another alternative but its effect differs in individual patients. METHOD: This is retrospective study. We enrolled 54 patients (N=54) according to the inclusion criteria. We performed quantification of gene expression of selected genes and some microRNA from tumour tissue, which was used for the diagnosis. Statistical analysis of the data was performed. RESULTS: We demonstrated a predictive value of gene expression of thynidylate synthase in tumour tissue for a therapeutic effect of chemotherapy based on 5-Fluorouracil or Capecitabine. At the same time, we demonstrated a predictive value of miR181, miR150, mir192 and miR342 microRNA levels from the tumour tissue. In addition, we succeeded to demonstrate a predictive value of miR221, miR224, miR520 and miR375 microRNA levels for a therapeutic effect of chemotherapy based on platinum derivates. CONCLUSION: Thanks to the use of efficient therapy predictors, we can distinguish those patients who will profit from chemotherapy from patients where an effect cannot be expected. Thanks to personified oncology therapy the quality of life of some patients can be improved while reducing the costs of the therapy by avoiding inefficient chemotherapy. Only an early diagnosis of gastric cancer can reverse the adverse prognosis of patients with this disease. KEY WORDS: gastric cancer - microRNA - prognostic markers - predictive markers. PMID- 27226270 TI - [Pedal bypass using venous allograft]. AB - INTRODUCTION: Pedal or distal crural bypass surgery for limb salvage is a method with very good long-term results. For patients in whom a suitable autologous venous graft is not available, the use of a venous allograft is an alternative procedure. CASE REPORT: A 68 years old man with ischaemic disease of lower extremities and gangrene of the left foot was admitted to our Centre in August 2014. He underwent percutaneous transluminal angioplasty of crural arteries of his left lower extremity. This, however, failed to improve peripheral circulation. The patient was then indicated for pedal or distal crural vascular reconstruction. Since no suitable autologous vein was available, distal bypass surgery using a donor graft remained the only option for limb salvage. Amputation of the toes on the left foot due to gangrene was necessary. Subsequently, femoro pedal bypass to the left common plantar artery was performed using a great saphenous vein allograft. The post-operative course was without complications, the pedal bypass was patent and toe amputation was with good healing. The patient remained in follow-up care. CONCLUSION: A good outcome of vascular reconstruction with an allograft depends on the availability of a suitable allograft and good patient compliance with post-operative care. In the case presented here, the pedal bypass grafting by means of an allograft helped to save the patients limb. KEY WORDS: pedal bypass venous allograft limb salvage. PMID- 27226271 TI - [Bouveret syndrome: a case report and literature review]. AB - Bouveret syndrome is a gastric outlet obstruction caused by impaction of a gallstone that passes through a cholecystoduodenal or cholecystogastric fistula. It is a rare disease, most common in elderly women with multiple comorbidities and high surgical risk. The diagnosis can be made either radiologically or endoscopically. Endoscopic extraction is the preferred therapeutic option. Surgical intervention is indicated when endoscopic methods fail. We describe a case of Bouveret syndrome in a 79 years old woman. The report is followed by a review of literature on the diagnostics and treatment of this rare syndrome. KEY WORDS: gallstones bilioenteric fistula gallstone ileus duodenal obstruction Bouveret syndrome. PMID- 27226272 TI - [Splenosis as a rare cause of abdominal pain]. AB - INTRODUCTION: Splenosis is the autotransplantation of splenic tissue in atypical locations in the abdomen, chest or other parts of the body. CASE REPORT: Authors present a case of splenosis in a 35 years old woman hospitalized with abdominal pain, who underwent splenectomy for traumatic rupture with splenic tissue implantation in the omentum 19 years ago. Surgical revision was indicated for intensive pain. Histopathology confirmed the diagnosis of splenosis in the excised tissue. CONCLUSION: Despite the abandonment of splenic tissue autotransplantation after splenectomy, surgeons may still encounter the diagnosis of splenosis in patients after traumatic splenic rupture. Any incidental finding of splenosis during an operation for another indication should be sent for histopathology examination. KEY WORDS: splenosis, splenectomy abdominal pain scintigraphy. PMID- 27226273 TI - Design strategy of surface decoration for efficient delivery of nanoparticles by computer simulation. AB - Understanding the role of surface decoration of nanoparticles in protein adsorption and cellular uptake is of great importance in biomedicine. Here, by using dissipative particle dynamics simulations, we take two typical coating polymers (i.e., hydrophilic and zwitterionic polymers) as an example, and systematically investigate their effect on cellular delivery of hydrophobic and charged nanoparticles (in the presence of serum protein). Our results show that though two types of polymers are charge-neutral and can both reduce the protein adsorption, there exist some differences between their ability of protein resistance, especially in the case of positively charged nanoparticles. Besides, it is found that the coating polymers may also greatly decrease the cellular uptake efficiency of nanoparticles. Nevertheless, and importantly, since the zwitterionic polymers may become positively charged under low pH environments, the nanoparticle can attach onto cell membrane more firmly than that coated with hydrophilic polymers, which can further enhance the active targeting of nanoparticles. Finally, we also provide the design maps for surface decoration to achieve efficient cellular delivery. These results can help better understand how to keep the balance between protein resistance and cell targeting, which may give some useful guidelines on optimal design of future nanomaterials in drug delivery. PMID- 27226274 TI - Unveiling the Differences of Secretome of Human Bone Marrow Mesenchymal Stem Cells, Adipose Tissue-Derived Stem Cells, and Human Umbilical Cord Perivascular Cells: A Proteomic Analysis. AB - The use of human mesenchymal stem cells (hMSCs) has emerged as a possible therapeutic strategy for CNS-related conditions. Research in the last decade strongly suggests that MSC-mediated benefits are closely related with their secretome. Studies published in recent years have shown that the secretome of hMSCs isolated from different tissue sources may present significant variation. With this in mind, the present work performed a comparative proteomic-based analysis through mass spectrometry on the secretome of hMSCs derived from bone marrow (BMSCs), adipose tissue (ASCs), and human umbilical cord perivascular cells (HUCPVCs). The results revealed that BMSCs, ASCs, and HUCPVCs differed in their secretion of neurotrophic, neurogenic, axon guidance, axon growth, and neurodifferentiative proteins, as well as proteins with neuroprotective actions against oxidative stress, apoptosis, and excitotoxicity, which have been shown to be involved in several CNS disorder/injury processes. Although important changes were observed within the secretome of the cell populations that were analyzed, all cell populations shared the capability of secreting important neuroregulatory molecules. The difference in their secretion pattern may indicate that their secretome is specific to a condition of the CNS. Nevertheless, the confirmation that the secretome of MSCs isolated from different tissue sources is rich in neuroregulatory molecules represents an important asset not only for the development of future neuroregenerative strategies but also for their use as a therapeutic option for human clinical trials. PMID- 27226275 TI - Compounds Containing Azole Scaffolds as Cyclooxygenase Inhibitors: A Review. AB - There has been considerable interest in azole-containing compounds as promising antiinflammatory agents. Designed compounds with five-membered nitrogen containing nuclei have demonstrated good anti-inflammatory activity, indicating their potential for the treatment of this highly irritating condition. Pyrazoles, have attracted much more attention than other azoles, however, reports on other azoles demonstrated that they were as effective as pyrazoles. This review describes the different classes of azoles designed as cyclooxygenase inhibitors and the effect of different structural modifications on their activity. PMID- 27226276 TI - Long-term selection for litter size in swine results in shifts in allelic frequency in regions involved in reproductive processes. AB - High-density genotype data were analyzed in three lines of swine that express substantial variation in sow fertility to uncover regions of the genome potentially influenced during selection for litter size traits. The experimental lines examined include the Nebraska Index Line (NIL), which has been subjected to long-term selection for litter size; a control line derived from the same population that founded NIL; and a commercial Duroc * Hampshire (D * H) population, in which no selection for litter size was practiced. Regions of the genome potentially affected by selection for litter size traits in NIL were determined by multiple lines of evidence, including altered allelic frequency compared to the other lines, loss of heterozygosity and relative extended haplotype homozygosity. Additionally, a genome-wide association study for litter size traits was conducted in a population based on NIL and commercial maternal line genetics. Several genomic regions identified as putative signatures of selection overlapped with QTL for litter size traits. One of these regions, located on SSC2 (13-14 Mb), includes the candidate gene P2X3R, which plays a role in implantation and sustained release of hormones associated with reproductive processes. Sequencing identified synonymous SNPs in P2X3R that are fixed in NIL but polymorphic with nearly equal frequencies in the D * H line, indicating a potential role of P2X3R in sow fertility. These results suggest that data derived from these lines can help to uncover and understand a portion of the genetic variance associated with fertility traits in swine. PMID- 27226277 TI - Low temperature synthesis of silicon quantum dots with plasma chemistry control in dual frequency non-thermal plasmas. AB - The advanced materials process by non-thermal plasmas with a high plasma density allows the synthesis of small-to-big sized Si quantum dots by combining low temperature deposition with superior crystalline quality in the background of an amorphous hydrogenated silicon nitride matrix. Here, we make quantum dot thin films in a reactive mixture of ammonia/silane/hydrogen utilizing dual-frequency capacitively coupled plasmas with high atomic hydrogen and nitrogen radical densities. Systematic data analysis using different film and plasma characterization tools reveals that the quantum dots with different sizes exhibit size dependent film properties, which are sensitively dependent on plasma characteristics. These films exhibit intense photoluminescence in the visible range with violet to orange colors and with narrow to broad widths (~0.3-0.9 eV). The observed luminescence behavior can come from the quantum confinement effect, quasi-direct band-to-band recombination, and variation of atomic hydrogen and nitrogen radicals in the film growth network. The high luminescence yields in the visible range of the spectrum and size-tunable low-temperature synthesis with plasma and radical control make these quantum dot films good candidates for light emitting applications. PMID- 27226278 TI - Serological Monitoring Is Key To Sustain Progress of the Maternal and Neonatal Tetanus Elimination Initiative. AB - In this issue of Clinical and Vaccine Immunology, Scobie and colleagues (H. M. Scobie et al., Clin Vaccine Immunol 23:546-554, 2016, http://dx.doi.org/10.1128/CVI.00052-16) report a nationwide serosurvey of tetanus immunity in >2,000 Cambodian women of child-bearing age to monitor progress toward maternal and neonatal tetanus elimination. This commentary discusses vaccines as interventions for disease control, elimination, and eradication and emphasizes the importance of the tools needed to monitor the effectiveness of initiatives that deliver the vaccines programmatically. PMID- 27226280 TI - Inhibitory Antibodies Targeting Emerging Viruses: Advancements and Mechanisms. AB - From Ebola virus outbreaks in Western Africa to the introduction of chikungunya and Zika viruses in the Americas, new and neglected viruses continue to emerge and spread around the world. Due to a lack of existing vaccines or specific therapeutics, little other than supportive care and attempts to interrupt transmission can be provided during initial outbreaks. This has prompted a shift in vaccine design and development to identify novel epitopes and mechanisms of protection that may offer a broader range of protection against groups or whole families of viruses. Receptor-binding domains and other motifs within viral envelope proteins represent one excellent opportunity to target communal epitopes shared by related viruses. Similarly, for viruses where envelope participates in driving viral egress from infected cells, shared epitopes need to be identified to guide the development of broadly protective antibodies and vaccines. Here, we discuss recent advances in our understanding of broadly protective humoral responses for emerging viruses. PMID- 27226279 TI - Immunogenicity and Protective Efficacy against Enterotoxigenic Escherichia coli Colonization following Intradermal, Sublingual, or Oral Vaccination with EtpA Adhesin. AB - Enterotoxigenic Escherichia coli (ETEC) strains are a common cause of diarrhea. Extraordinary antigenic diversity has prompted a search for conserved antigens to complement canonical approaches to ETEC vaccine development. EtpA, an immunogenic extracellular ETEC adhesin relatively conserved in the ETEC pathovar, has previously been shown to be a protective antigen following intranasal immunization. These studies were undertaken to explore alternative routes of EtpA vaccination that would permit use of a double mutant (R192G L211A) heat-labile toxin (dmLT) adjuvant. Here, oral vaccination with EtpA adjuvanted with dmLT afforded significant protection against small intestinal colonization, and the degree of protection correlated with fecal IgG, IgA, or total fecal antibody responses to EtpA. Sublingual vaccination yielded compartmentalized mucosal immune responses with significant increases in anti-EtpA fecal IgG and IgA, and mice vaccinated via this route were also protected against colonization. In contrast, while intradermal (i.d.) vaccination achieved high levels of both serum and fecal antibodies against both EtpA and dmLT, mice vaccinated via the i.d. route were not protected against subsequent colonization and the avidity of serum IgG and IgA EtpA-specific antibodies was significantly lower after i.d. immunization compared to other routes. Finally, we demonstrate that antiserum from vaccinated mice significantly impairs binding of LT to cognate GM1 receptors and shows near complete neutralization of toxin delivery by ETEC in vitro Collectively, these data provide further evidence that EtpA could complement future vaccine strategies but also suggest that additional effort will be required to optimize its use as a protective immunogen. PMID- 27226283 TI - Mono- and diiodo-1,2,3-triazoles and their mono nitro derivatives. AB - 4-Iodo-1H-1,2,3-triazole (2) and 4,5-diiodo-1H-1,2,3-triazole (3) were synthesized using an efficient and viable synthetic route. The N-alkylation of 3 resulted in the formation of two tautomers. The N-alkyl-diiodo-triazoles were nitrated with 100% nitric acid to form monoiodo-mononitro-triazoles. The structures of 2-methyl-4,5-diiodo-1,2,3-triazole (5), 1-ethyl-4,5-diiodo-1,2,3 triazole (6), 1-methyl-4-nitro-5-iodo-1,2,3-triazole (8) and 1-ethyl-4-nitro-5 iodo-1,2,3-triazole (10) were confirmed by X-ray crystal analysis. All of the new triazoles were fully characterized via NMR, and infrared spectra, and elemental analyses as well as by their thermal and sensitivity properties. Decomposition products calculated using Cheetah 7 software show that these iodo-nitro triazoles liberate iodine. PMID- 27226281 TI - Induction of Unconventional T Cells by a Mutant Mycobacterium bovis BCG Strain Formulated in Cationic Liposomes Correlates with Protection against Mycobacterium tuberculosis Infections of Immunocompromised Mice. AB - Earlier studies aimed at defining protective immunity induced by Mycobacterium bovis BCG immunization have largely focused on the induction of antituberculosis CD4(+) and CD8(+) T cell responses. Here we describe a vaccine consisting of a BCGDeltammaA4 deletion mutant formulated in dimethyl dioctadecyl-ammonium bromide (DDA) with d-(+)-trehalose 6,6'-dibehenate (TDB) (DDA/TDB) adjuvant (A4/Adj) that protected TCRdelta(-/-) mice depleted of CD4(+), CD8(+), and NK1.1(+) T cells against an aerosol challenge with M. tuberculosis These mice were significantly protected relative to mice immunized with a nonadjuvanted BCGDeltammaA4 (BCG-A4) mutant and nonvaccinated controls at 2 months and 9 months postvaccination. In the absence of all T cells following treatment with anti-Thy1.2 antibody, the immunized mice lost the ability to control the infection. These results indicate that an unconventional T cell population was mediating protection in the absence of CD4(+), CD8(+), NK1.1(+), and TCRgammadelta T cells and could exhibit memory. Focusing on CD4(-) CD8(-) double-negative (DN) T cells, we found that these cells accumulated in the lungs postchallenge significantly more in A4/Adj-immunized mice and induced significantly greater frequencies of pulmonary gamma interferon (IFN-gamma)-producing cells than were seen in the nonvaccinated or nonadjuvanted BCG control groups. Moreover, pulmonary DN T cells from the A4/Adj group exhibited significantly higher IFN-gamma integrated median fluorescence intensity (iMFI) values than were seen in the control groups. We also showed that enriched DN T cells from mice immunized with A4/Adj could control mycobacterial growth in vitro significantly better than naive whole-spleen cells. These results suggest that formulating BCG in DDA/TDB adjuvant confers superior protection in immunocompromised mice and likely involves the induction of long-lived memory DN T cells. PMID- 27226282 TI - Differences in iron and manganese concentration may confound the measurement of myelin from R1 and R2 relaxation rates in studies of dysmyelination. AB - A model of dysmyelination, the Long Evans Shaker (les) rat, was used to study the contribution of myelin to MR tissue properties in white matter. A large region of white matter was identified in the deep cerebellum and was used for measurements of the MR relaxation rate constants, R1 = 1/T1 and R2 = 1/T2 , at 7 T. In this study, R1 of the les deep cerebellar white matter was found to be 0.55 +/- 0.08 s (-1) and R2 was found to be 15 +/- 1 s(-1) , revealing significantly lower R1 and R2 in les white matter relative to wild-type (wt: R1 = 0.69 +/- 0.05 s(-1) and R2 = 18 +/- 1 s(-1) ). These deviated from the expected DeltaR1 and DeltaR2 values, given a complete lack of myelin in the les white matter, derived from the literature using values of myelin relaxivity, and we suspect that metals could play a significant role. The absolute concentrations of the paramagnetic transition metals iron (Fe) and manganese (Mn) were measured by a micro synchrotron radiation X-ray fluorescence (MUSRXRF) technique, with significantly greater Fe and Mn in les white matter than in wt (in units of MUg [metal]/g [wet weight tissue]: les: Fe concentration,19 +/- 1; Mn concentration, 0.71 +/- 0.04; wt: Fe concentration,10 +/- 1; Mn concentration, 0.47 +/- 0.04). These changes in Fe and Mn could explain the deviations in R1 and R2 from the expected values in white matter. Although it was found that the influence of myelin still dominates R1 and R2 in wt rats, there were non-negligible changes in the contribution of the metals to relaxation. Although there are already problems with the estimation of myelin from R1 and R2 changes in disease models with pathology that also affects the relaxation rate constants, this study points to a specific pitfall in the estimation of changes in myelin in diseases or models with disrupted concentrations of paramagnetic transition metals. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27226284 TI - Cost-Effectiveness Analysis of Safety-Engineered Devices. AB - OBJECTIVE To estimate the cost-effectiveness of safety-engineered devices (SEDs) relative to non-SEDs for winged steel needles, intravenous catheter stylets, suture needles, and insulin pen needles. DESIGN Decision analysis modeling. PARTICIPANTS Hypothetical cohort of healthcare workers who utilized needle devices. METHODS We developed a decision-analytic model to estimate and compare the life-cycle costs and benefits for SED and non-SED needle devices. For this cost-effectiveness analysis, we quantified the total direct medical cost per needlestick injury, number of needlestick injuries avoided, and incremental cost effectiveness ratio. Sensitivity analyses were performed to examine the robustness of the base-case analysis. RESULTS In the base-case analysis, we calculated the incremental cost-effectiveness ratios of SED winged steel needles, intravenous catheter stylets, suture needles, and insulin pen needles to be $2,633, $13,943, $1,792, and $1,269 per needlestick injury avoided, respectively. Sensitivity analyses showed that the calculated incremental cost-effectiveness ratio values for using SEDs did not fall below zero even after adjusting the values of each parameter. CONCLUSION The use of SED needle devices would not produce cost savings for hospitals. Government intervention may be needed to systematically protect healthcare workers in Japan from the risk of bloodborne pathogen infections. Infect Control Hosp Epidemiol 2016;37:1012-1021. PMID- 27226285 TI - Difference in post-termination of pregnancy contraception practice among Australia, New Zealand and Japan. PMID- 27226286 TI - Echinicola rosea sp. nov., a marine bacterium isolated from surface seawater. AB - A novel Gram-stain-negative, rod-shaped, gliding, halotolerant, aerobic, light pink-pigmented bacterium, strain JL3085T, was isolated from surface water of the South China Sea (16 degrees 49' 4" N 112 degrees 20' 24" E; temperature: 28.3 degrees C, salinity: 34.5%). The major respiratory quinone was menaquinone 7 (MK 7). The polar lipids of strain JL3085T comprised phosphatidylethanolamine, four unidentified phospholipids and three unidentified lipids. The major fatty acids were iso-C15 : 0, summed feature 3 (comprising iso-C15 : 0 2-OH and/or C16 : 1omega7c), iso-C17 : 0 3-OH, iso-C17 : 1omega9c, C17 : 1omega6c, anteiso-C15 : 0 and C16 : 1omega5c. The DNA G+C content of strain JL3085T was 43.8 mol%. 16S rRNA gene sequence analysis indicated that strain JL3085T was affiliated with the genus Echinicola, a member of the phylum Bacteroidetes, and was related most closely to Echinicola vietnamensis KMM 6221T (96.8 % similarity). DNA-DNA relatedness between strain JL3085T and E. vietnamensis KMM 6221T was 27.5 %. Based on the evidence presented here, strain JL3085T is regarded as representing a novel species of the genus Echinicola, for which the name Echinicola rosea sp. nov. is proposed. The type strain is JL3085T (=NBRC 111782T=CGMCC 1.15407T). PMID- 27226288 TI - You Can't Make a Silk Purse Out of a Sow's Ear: Time to Start Again with MCI Triage. AB - Horne S , Nutbeam T . You can't make a silk purse out of a sow's ear: time to start again with MCI triage. Prehosp Disaster Med. 2016;31(4):459-460. PMID- 27226287 TI - Sergey Sukhanov, a Russian Physician in Professor Arthur Van Gehuchten's Lab - Based on Original 19th Century Documents. AB - In 1898, Russian physician Sergey Alexeevich Sukhanov (1867-1915) spent a 3-month traineeship in Professor Arthur Van Gehuchten's anatomy laboratory in Louvain (Belgium). A folder containing 17 handwritten documents in Russian was recently discovered in the archives of the Museum of the History of Medicine, First Moscow State Medical University. The letters give a lively account of Sukhanov's everyday observations, experiences and opinions while he was in Van Gehuchten's lab. We took a selection of these notes and put them into medical and historical context. PMID- 27226289 TI - Xanthomonas citri ssp. citri requires the outer membrane porin OprB for maximal virulence and biofilm formation. AB - Xanthomonas citri ssp. citri (Xcc) causes canker disease in citrus, and biofilm formation is critical for the disease cycle. OprB (Outer membrane protein B) has been shown previously to be more abundant in Xcc biofilms compared with the planktonic state. In this work, we showed that the loss of OprB in an oprB mutant abolishes bacterial biofilm formation and adherence to the host, and also compromises virulence and efficient epiphytic survival of the bacteria. Moreover, the oprB mutant is impaired in bacterial stress resistance. OprB belongs to a family of carbohydrate transport proteins, and the uptake of glucose is decreased in the mutant strain, indicating that OprB transports glucose. Loss of OprB leads to increased production of xanthan exopolysaccharide, and the carbohydrate intermediates of xanthan biosynthesis are also elevated in the mutant. The xanthan produced by the mutant has a higher viscosity and, unlike wild-type xanthan, completely lacks pyruvylation. Overall, these results suggest that Xcc reprogrammes its carbon metabolism when it senses a shortage of glucose input. The participation of OprB in the process of biofilm formation and virulence, as well as in metabolic changes to redirect the carbon flux, is discussed. Our results demonstrate the importance of environmental nutrient supply and glucose uptake via OprB for Xcc virulence. PMID- 27226290 TI - Reply to Einarsson: The computational power of parallel network exploration with many bioagents. PMID- 27226291 TI - New biological device not faster than regular computer. PMID- 27226292 TI - Reply to Alberti: Are in vitro folding experiments relevant in vivo? PMID- 27226293 TI - Native, sequential protein folding via anchored N and C protein termini. PMID- 27226295 TI - Back to the roots and routes of dromedary domestication. PMID- 27226294 TI - nArgBP2 regulates excitatory synapse formation by controlling dendritic spine morphology. AB - Neural Abelson-related gene-binding protein 2 (nArgBP2) was originally identified as a protein that directly interacts with synapse-associated protein 90/postsynaptic density protein 95-associated protein 3 (SAPAP3), a postsynaptic scaffolding protein critical for the assembly of glutamatergic synapses. Although genetic deletion of nArgBP2 in mice leads to manic/bipolar-like behaviors resembling many aspects of symptoms in patients with bipolar disorder, the actual function of nArgBP2 at the synapse is completely unknown. Here, we found that the knockdown (KD) of nArgBP2 by specific small hairpin RNAs (shRNAs) resulted in a dramatic change in dendritic spine morphology. Reintroducing shRNA-resistant nArgBP2 reversed these defects. In particular, nArgBP2 KD impaired spine-synapse formation such that excitatory synapses terminated mostly at dendritic shafts instead of spine heads in spiny neurons, although inhibitory synapse formation was not affected. nArgBP2 KD further caused a marked increase of actin cytoskeleton dynamics in spines, which was associated with increased Wiskott Aldrich syndrome protein-family verprolin homologous protein 1 (WAVE1)/p21 activated kinase (PAK) phosphorylation and reduced activity of cofilin. These effects of nArgBP2 KD in spines were rescued by inhibiting PAK or activating cofilin combined with sequestration of WAVE. Together, our results suggest that nArgBP2 functions to regulate spine morphogenesis and subsequent spine-synapse formation at glutamatergic synapses. They also raise the possibility that the aberrant regulation of synaptic actin filaments caused by reduced nArgBP2 expression may contribute to the manifestation of the synaptic dysfunction observed in manic/bipolar disorder. PMID- 27226296 TI - Transcriptional regulator Bhlhe40 works as a cofactor of T-bet in the regulation of IFN-gamma production in iNKT cells. AB - Invariant natural killer T (iNKT) cells are a subset of innate-like T cells that act as important mediators of immune responses. In particular, iNKT cells have the ability to immediately produce large amounts of IFN-gamma upon activation and thus initiate immune responses in various pathological conditions. However, molecular mechanisms that control IFN-gamma production in iNKT cells are not fully understood. Here, we report that basic helix-loop-helix transcription factor family, member e40 (Bhlhe40), is an important regulator for IFN-gamma production in iNKT cells. Bhlhe40 is highly expressed in stage 3 thymic iNKT cells and iNKT1 subsets, and the level of Bhlhe40 mRNA expression is correlated with Ifng mRNA expression in the resting state. Although Bhlhe40-deficient mice show normal iNKT cell development, Bhlhe40-deficient iNKT cells show significant impairment of IFN-gamma production and antitumor effects. Bhlhe40 alone shows no significant effects on Ifng promoter activities but contributes to enhance T-box transcription factor Tbx21 (T-bet)-mediated Ifng promoter activation. Chromatin immunoprecipitation analysis revealed that Bhlhe40 accumulates in the T-box region of the Ifng locus and contributes to histone H3-lysine 9 acetylation of the Ifng locus, which is impaired without T-bet conditions. These results indicate that Bhlhe40 works as a cofactor of T-bet for enhancing IFN-gamma production in iNKT cells. PMID- 27226297 TI - Antifreeze proteins govern the precipitation of trehalose in a freezing-avoiding insect at low temperature. AB - The remarkable adaptive strategies of insects to extreme environments are linked to the biochemical compounds in their body fluids. Trehalose, a versatile sugar molecule, can accumulate to high levels in freeze-tolerant and freeze-avoiding insects, functioning as a cryoprotectant and a supercooling agent. Antifreeze proteins (AFPs), known to protect organisms from freezing by lowering the freezing temperature and deferring the growth of ice, are present at high levels in some freeze-avoiding insects in winter, and yet, paradoxically are found in some freeze-tolerant insects. Here, we report a previously unidentified role for AFPs in effectively inhibiting trehalose precipitation in the hemolymph (or blood) of overwintering beetle larvae. We determine the trehalose level (29.6 +/- 0.6 mg/mL) in the larval hemolymph of a beetle, Dendroides canadensis, and demonstrate that the hemolymph AFPs are crucial for inhibiting trehalose crystallization, whereas the presence of trehalose also enhances the antifreeze activity of AFPs. To dissect the molecular mechanism, we examine the molecular recognition between AFP and trehalose crystal interfaces using molecular dynamics simulations. The theory corroborates the experiments and shows preferential strong binding of the AFP to the fast growing surfaces of the sugar crystal. This newly uncovered role for AFPs may help explain the long-speculated role of AFPs in freeze-tolerant species. We propose that the presence of high levels of molecules important for survival but prone to precipitation in poikilotherms (their body temperature can vary considerably) needs a companion mechanism to prevent the precipitation and here present, to our knowledge, the first example. Such a combination of trehalose and AFPs also provides a novel approach for cold protection and for trehalose crystallization inhibition in industrial applications. PMID- 27226298 TI - Unique lipid anchor attaches Vi antigen capsule to the surface of Salmonella enterica serovar Typhi. AB - Polysaccharide capsules are surface structures that are critical for the virulence of many Gram-negative pathogenic bacteria. Salmonella enterica serovar Typhi is the etiological agent of typhoid fever. It produces a capsular polysaccharide known as "Vi antigen," which is composed of nonstoichiometrically O-acetylated alpha-1,4-linked N-acetylgalactosaminuronic acid residues. This glycan is a component of currently available vaccines. The genetic locus for Vi antigen production is also present in soil bacteria belonging to the genus Achromobacter Vi antigen assembly follows a widespread general strategy with a characteristic glycan export step involving an ATP-binding cassette transporter. However, Vi antigen producers lack the enzymes that build the conserved terminal glycolipid characterizing other capsules using this method. Achromobacter species possess a Vi antigen-specific depolymerase enzyme missing in S enterica Typhi, and we exploited this enzyme to isolate acylated Vi antigen termini. Mass spectrometry analysis revealed a reducing terminal N-acetylhexosamine residue modified with two beta-hydroxyl acyl chains. This terminal structure resembles one half of lipid A, the hydrophobic portion of bacterial lipopolysaccharides. The VexE protein encoded in the Vi antigen biosynthesis locus shares similarity with LpxL, an acyltransferase from lipid A biosynthesis. In the absence of VexE, Vi antigen is produced, but its physical properties are altered, its export is impaired, and a Vi capsule structure is not assembled on the cell surface. The structure of the lipidated terminus dictates a unique assembly mechanism and has potential implications in pathogenesis and vaccine production. PMID- 27226299 TI - VEX1 controls the allelic exclusion required for antigenic variation in trypanosomes. AB - Allelic exclusion underpins antigenic variation and immune evasion in African trypanosomes. These bloodstream parasites use RNA polymerase-I (pol-I) to transcribe just one telomeric variant surface glycoprotein (VSG) gene at a time, producing superabundant and switchable VSG coats. We identified trypanosome VSG exclusion-1 (VEX1) using a genetic screen for defects in telomere-exclusive expression. VEX1 was sequestered by the active VSG and silencing of other VSGs failed when VEX1 was either ectopically expressed or depleted, indicating positive and negative regulation, respectively. Positive regulation affected VSGs and nontelomeric pol-I-transcribed genes, whereas negative regulation primarily affected VSGs. Negative regulation by VEX1 also affected telomeric pol-I transcribed reporter constructs, but only when they contained blocks of sequence sharing homology with a pol-I-transcribed locus. We conclude that restricted positive regulation due to VEX1 sequestration, combined with VEX1-dependent, possibly homology-dependent silencing, drives a "winner-takes-all" mechanism of allelic exclusion. PMID- 27226301 TI - Uncovering variation in the patterns of aging. PMID- 27226300 TI - Coxiella burnetii effector CvpB modulates phosphoinositide metabolism for optimal vacuole development. AB - The Q fever bacterium Coxiella burnetii replicates inside host cells within a large Coxiella-containing vacuole (CCV) whose biogenesis relies on the Dot/Icm dependent secretion of bacterial effectors. Several membrane trafficking pathways contribute membranes, proteins, and lipids for CCV biogenesis. These include the endocytic and autophagy pathways, which are characterized by phosphatidylinositol 3-phosphate [PI(3)P]-positive membranes. Here we show that the C. burnetii secreted effector Coxiella vacuolar protein B (CvpB) binds PI(3)P and phosphatidylserine (PS) on CCVs and early endosomal compartments and perturbs the activity of the phosphatidylinositol 5-kinase PIKfyve to manipulate PI(3)P metabolism. CvpB association to early endosome triggers vacuolation and clustering, leading to the channeling of large PI(3)P-positive membranes to CCVs for vacuole expansion. At CCVs, CvpB binding to early endosome- and autophagy derived PI(3)P and the concomitant inhibition of PIKfyve favor the association of the autophagosomal machinery to CCVs for optimal homotypic fusion of the Coxiella containing compartments. The importance of manipulating PI(3)P metabolism is highlighted by mutations in cvpB resulting in a multivacuolar phenotype, rescuable by gene complementation, indicative of a defect in CCV biogenesis. Using the insect model Galleria mellonella, we demonstrate the in vivo relevance of defective CCV biogenesis by highlighting an attenuated virulence phenotype associated with cvpB mutations. PMID- 27226302 TI - Multiensemble Markov models of molecular thermodynamics and kinetics. AB - We introduce the general transition-based reweighting analysis method (TRAM), a statistically optimal approach to integrate both unbiased and biased molecular dynamics simulations, such as umbrella sampling or replica exchange. TRAM estimates a multiensemble Markov model (MEMM) with full thermodynamic and kinetic information at all ensembles. The approach combines the benefits of Markov state models-clustering of high-dimensional spaces and modeling of complex many-state systems-with those of the multistate Bennett acceptance ratio of exploiting biased or high-temperature ensembles to accelerate rare-event sampling. TRAM does not depend on any rate model in addition to the widely used Markov state model approximation, but uses only fundamental relations such as detailed balance and binless reweighting of configurations between ensembles. Previous methods, including the multistate Bennett acceptance ratio, discrete TRAM, and Markov state models are special cases and can be derived from the TRAM equations. TRAM is demonstrated by efficiently computing MEMMs in cases where other estimators break down, including the full thermodynamics and rare-event kinetics from high dimensional simulation data of an all-atom protein-ligand binding model. PMID- 27226303 TI - New paradigm to assess brain cell morphology by diffusion-weighted MR spectroscopy in vivo. AB - The brain is one of the most complex organs, and tools are lacking to assess its cellular morphology in vivo. Here we combine original diffusion-weighted magnetic resonance (MR) spectroscopy acquisition and novel modeling strategies to explore the possibility of quantifying brain cell morphology noninvasively. First, the diffusion of cell-specific metabolites is measured at ultra-long diffusion times in the rodent and primate brain in vivo to observe how cell long-range morphology constrains metabolite diffusion. Massive simulations of particles diffusing in synthetic cells parameterized by morphometric statistics are then iterated to fit experimental data. This method yields synthetic cells (tentatively neurons and astrocytes) that exhibit striking qualitative and quantitative similarities with histology (e.g., using Sholl analysis). With our approach, we measure major interspecies difference regarding astrocytes, whereas dendritic organization appears better conserved throughout species. This work suggests that the time dependence of metabolite diffusion coefficient allows distinguishing and quantitatively characterizing brain cell morphologies noninvasively. PMID- 27226304 TI - Stretching out the early steps in hearing. PMID- 27226305 TI - Monkey neurophysiology to clinical neuroscience and back again. PMID- 27226306 TI - CYP450-derived oxylipins mediate inflammatory resolution. AB - Resolution of inflammation has emerged as an active process in immunobiology, with cells of the mononuclear phagocyte system being critical in mediating efferocytosis and wound debridement and bridging the gap between innate and adaptive immunity. Here we investigated the roles of cytochrome P450 (CYP) derived epoxy-oxylipins in a well-characterized model of sterile resolving peritonitis in the mouse. Epoxy-oxylipins were produced in a biphasic manner during the peaks of acute (4 h) and resolution phases (24-48 h) of the response. The epoxygenase inhibitor SKF525A (epoxI) given at 24 h selectively inhibited arachidonic acid- and linoleic acid-derived CYP450-epoxy-oxlipins and resulted in a dramatic influx in monocytes. The epoxI-recruited monocytes were strongly GR1(+), Ly6c(hi), CCR2(hi), CCL2(hi), and CX3CR1(lo) In addition, expression of F4/80 and the recruitment of T cells, B cells, and dendritic cells were suppressed. sEH (Ephx2)(-/-) mice, which have elevated epoxy-oxylipins, demonstrated opposing effects to epoxI-treated mice: reduced Ly6c(hi) monocytes and elevated F4/80(hi) macrophages and B, T, and dendritic cells. Ly6c(hi) and Ly6c(lo) monocytes, resident macrophages, and recruited dendritic cells all showed a dramatic change in their resolution signature following in vivo epoxI treatment. Markers of macrophage differentiation CD11b, MerTK, and CD103 were reduced, and monocyte-derived macrophages and resident macrophages ex vivo showed greatly impaired phagocytosis of zymosan and efferocytosis of apoptotic thymocytes following epoxI treatment. These findings demonstrate that epoxy oxylipins have a critical role in monocyte lineage recruitment and activity to promote inflammatory resolution and represent a previously unidentified internal regulatory system governing the establishment of adaptive immunity. PMID- 27226309 TI - Networks of highly branched stigmarian rootlets developed on the first giant trees. AB - Lycophyte trees, up to 50 m in height, were the tallest in the Carboniferous coal swamp forests. The similarity in their shoot and root morphology led to the hypothesis that their rooting (stigmarian) systems were modified leafy shoot systems, distinct from the roots of all other plants. Each consists of a branching main axis covered on all sides by lateral structures in a phyllotactic arrangement; unbranched microphylls developed from shoot axes, and largely unbranched stigmarian rootlets developed from rhizomorphs axes. Here, we reexamined the morphology of extinct stigmarian systems preserved as compression fossils and in coal balls from the Carboniferous period. Contrary to the long standing view of stigmarian systems, where shoot-like rhizomorph axes developed largely unbranched, root-hairless rootlets, here we report that stigmarian rootlets were highly branched, developed at a density of ~25,600 terminal rootlets per meter of rhizomorph, and were covered in root hairs. Furthermore, we show that this architecture is conserved among their only extant relatives, herbaceous plants in the Isoetes genus. Therefore, despite the difference in stature and the time that has elapsed, we conclude that both extant and extinct rhizomorphic lycopsids have the same rootlet system architecture. PMID- 27226307 TI - Growth hormone is permissive for neoplastic colon growth. AB - Growth hormone (GH) excess in acromegaly is associated with increased precancerous colon polyps and soft tissue adenomas, whereas short-stature humans harboring an inactivating GH receptor mutation do not develop cancer. We show that locally expressed colon GH is abundant in conditions predisposing to colon cancer and in colon adenocarcinoma-associated stromal fibroblasts. Administration of a GH receptor (GHR) blocker in acromegaly patients induced colon p53 and adenomatous polyposis coli (APC), reversing progrowth GH signals. p53 was also induced in skin fibroblasts derived from short-statured humans with mutant GHR. GH-deficient prophet of pituitary-specific positive transcription factor 1 (Prop1)(-/-) mice exhibited induced colon p53 levels, and cross-breeding them with Apc(min+/-) mice that normally develop intestinal and colon tumors resulted in GH-deficient double mutants with markedly decreased tumor number and size. We also demonstrate that GH suppresses p53 and reduces apoptosis in human colon cell lines as well as in induced human pluripotent stem cell-derived intestinal organoids, and confirm in vivo that GH suppresses colon mucosal p53/p21. GH excess leads to decreased colon cell phosphatase and tensin homolog deleted on chromosome 10 (PTEN), increased cell survival with down-regulated APC, nuclear beta-catenin accumulation, and increased epithelial-mesenchymal transition factors and colon cell motility. We propose that GH is a molecular component of the "field change" milieu permissive for neoplastic colon growth. PMID- 27226308 TI - Chloroplast FBPase and SBPase are thioredoxin-linked enzymes with similar architecture but different evolutionary histories. AB - The Calvin-Benson cycle of carbon dioxide fixation in chloroplasts is controlled by light-dependent redox reactions that target specific enzymes. Of the regulatory members of the cycle, our knowledge of sedoheptulose-1,7 bisphosphatase (SBPase) is particularly scanty, despite growing evidence for its importance and link to plant productivity. To help fill this gap, we have purified, crystallized, and characterized the recombinant form of the enzyme together with the better studied fructose-1,6-bisphosphatase (FBPase), in both cases from the moss Physcomitrella patens (Pp). Overall, the moss enzymes resembled their counterparts from seed plants, including oligomeric organization PpSBPase is a dimer, and PpFBPase is a tetramer. The two phosphatases showed striking structural homology to each other, differing primarily in their solvent exposed surface areas in a manner accounting for their specificity for seven carbon (sedoheptulose) and six-carbon (fructose) sugar bisphosphate substrates. The two enzymes had a similar redox potential for their regulatory redox-active disulfides (-310 mV for PpSBPase vs. -290 mV for PpFBPase), requirement for Mg(2+) and thioredoxin (TRX) specificity (TRX f > TRX m). Previously known to differ in the position and sequence of their regulatory cysteines, the enzymes unexpectedly showed unique evolutionary histories. The FBPase gene originated in bacteria in conjunction with the endosymbiotic event giving rise to mitochondria, whereas SBPase arose from an archaeal gene resident in the eukaryotic host. These findings raise the question of how enzymes with such different evolutionary origins achieved structural similarity and adapted to control by the same light dependent photosynthetic mechanism-namely ferredoxin, ferredoxin-thioredoxin reductase, and thioredoxin. PMID- 27226310 TI - Conserved Anti-Mullerian Hormone: Anti-Mullerian Hormone Type-2 Receptor Specific Interaction and Intracellular Signaling in Teleosts. AB - In higher vertebrates, anti-Mullerian hormone (AMH) is required for Mullerian duct regression in fetal males. AMH is also produced during postnatal life in both sexes regulating steroidogenesis and early stages of folliculogenesis. Teleosts lack Mullerian ducts, but Amh has been identified in several species including European sea bass. However, information on Amh type-2 receptor (Amhr2), the specific receptor for Amh binding, is restricted to a couple of fish species. Here, we report on cloning sea bass amhr2, the production of a recombinant sea bass Amh, and the functional analysis of this ligand-receptor couple. Phylogenetic analysis revealed that sea bass amhr2 segregates with Amhr2 from other vertebrates. This piscine receptor is capable of activating Smad proteins. Antibodies raised against sea bass Amh were used to study native and recombinant Amh, revealing proteins in the range of 66-70 kDa corresponding to the full length Amh. Once proteolytically treated, recombinant sea bass Amh generates a 12 kDa C-terminal mature protein, suggesting that contrary to what has been described for other fish Amh proteins, this protein is processed in a similar way as mammalian AMH. The mature sea bass Amh is a biologically active protein able to bind sea bass Amhr2 and, surprisingly, also human AMHR2. In prepubertal sea bass testes, Amh was detected by immunohistochemistry mostly in Sertoli cells surrounding early germ-cell generations. During spermatogenesis, a weaker staining signal could be observed in Sertoli cells surrounding spermatocytes. PMID- 27226311 TI - Protein Inhibitor of Activated STAT3 (PIAS3) Is Down-Regulated in Eutopic Endometrium of Women with Endometriosis. AB - Endometriosis is a major cause of chronic pelvic pain and infertility. Activation of STAT3 appears central to the inflammatory phenotype of eutopic endometrium in women with endometriosis. However, the molecular mechanism by which this occurs remains unknown. Our objective is to determine how STAT3 activity is regulated in endometriosis. Protein inhibitor of activated STAT3 (PIAS3) is a negative regulator of STAT3 activity. We examined the levels of PIAS3 in endometrium from women with and without endometriosis using Western blot analysis and immunohistochemistry. Levels of PIAS3 are significantly lower, in contrast with phosphorylation of STAT3, in women with endometriosis compared to women without endometriosis. Furthermore, induction of endometriosis in the baboon showed a significant reduction of PIAS3 expression during the progression of the disease. Interferon-gamma (INFgamma) reduces PIAS3 protein levels and increases phospho STAT3 levels through CXCL10 in endometrial cells, Ishikawa, and 12Z cells. These results suggest that attenuation of PIAS3 causes aberrant activation of STAT3 in endometriosis, leading to inflammatory changes that may impair fertility or cause pain. PMID- 27226312 TI - Polyamine-Mediated Effects of Prolactin Dictate Emergence from Mink Obligate Embryonic Diapause. AB - Embryonic diapause is an evolutionary strategy to ensure that offspring are born when maternal and environmental conditions are optimal for survival. In many species of carnivores, obligate embryonic diapause occurs in every gestation. Reciprocal embryo transplant studies indicate that embryo arrest during diapause is conferred by uterine conditions and is due to a lack of specific factors necessary for continued development. In previous studies, global gene expression analysis revealed reduced uterine expression during diapause of a cluster of genes in the mink that regulate the abundance of polyamines, including ornithine decarboxylase 1 (ODC1). In addition, in vivo inhibition of the conversion of ornithine to the polyamine, putrescine, induced a reversible arrest in mink embryonic development and an arrest in trophoblast cell proliferation in vitro. Previous studies have implicated prolactin as the principal endocrine signal to terminate diapause. In this study, uterine expression of both the progesterone and estrogen receptors remained low at reactivation whilst the prolactin receptor was expressed at all times. Treatment of mink uterine epithelial cells with varying doses of prolactin indicated that this hormone induces ODC1 expression in the uterus via pSTAT1 and mTOR, thereby regulating uterine polyamine levels. In addition, we performed global gene expression analysis on mink embryos to further explore dynamic changes during diapause and found 94 genes upregulated at reactivation from diapause. Three polyamine-related genes, including ODC1, were also upregulated at reactivation from diapause. To establish whether polyamines mitigate escape from embryonic diapause, we collected mink embryos in diapause and incubated them in vitro with putrescine. Increase in embryo volume, the first indication of emergence from diapause, was observed within the first 5 days of culture in all viable embryos treated with putrescine, and the duration of embryo survival was increased threefold. Concomitant increases were also observed in both the total number of cells and the proportion of dividing cells in putrescine treated embryos whilst control embryos remained in the diapause state. In further studies, inhibition of polyamine synthesis abrogated proliferation in cells derived from the inner cell mass of the mink embryo, while putrescine induced dose-dependent increases in cell division. We conclude that supplementation of embryos in diapause with putrescine results in their escape from developmental dormancy. These results provide strong evidence that obligate diapause in vivo is caused by the paucity of polyamines necessary for activation of the embryo after prolactin-induced termination of diapause. PMID- 27226313 TI - Coxsackievirus and Adenovirus Receptor, a Tight Junction Protein, in Peri Implantation Mouse Embryos. AB - To understand the role of Coxsackievirus and adenovirus receptor (CAR), a tight junction (TJ) protein, in peri-implantation embryos, developmental expression of CAR and its role in paracellular permeability were examined in mouse embryos. Splice variants for transmembrane CAR, Car1, Car2, and Car3 mRNA, were expressed from 2-cell, morula, and blastocyst stages onward, respectively, whereas mRNA for soluble CAR was expressed in MII oocytes and 4-cell stage onward. On Western blot, ~46 kDa CAR proteins were detected in blastocysts. During the 4-cell embryos to morula stage, CAR was gradually concentrated at the contacts between blastomeres. In blastocysts, CAR was expressed at the cell contacts within the inner cell mass as well as in the trophectoderm (TE) where CAR was found together with ZO1 at the apical contacts, suggesting that CAR builds up apical TJs in TE and mediates cell adhesion in TE and inner cell mass. In blastocysts, CAR blocking antibodies under Ca(2+) switching increased the dextran permeability and decreased the volume of blastocoel and H19 and Cdx2 mRNA, suggesting the pivotal role of CAR in the blastocyst development and paracellular permeability barrier in TE. CAR was expressed in TE of implanting embryos as well as endometrial epithelium, suggesting the involvement of CAR in the interaction between implanting embryos and endometrium. At 5-6 days postcoitum, CAR was expressed together with ZO1 in the primitive endoderm, visceral endoderm, and epiblasts facing the pro-amniotic cavity, suggesting that CAR TJs contribute to the separation of epiblast from the blastocoel and development of the pro-amniotic cavity within epiblasts. PMID- 27226315 TI - Erratum. PMID- 27226317 TI - Flow-dependent myosin recruitment during Drosophila cellularization requires zygotic dunk activity. AB - Actomyosin contractility underlies force generation in morphogenesis ranging from cytokinesis to epithelial extension or invagination. In Drosophila, the cleavage of the syncytial blastoderm is initiated by an actomyosin network at the base of membrane furrows that invaginate from the surface of the embryo. It remains unclear how this network forms and how it affects tissue mechanics. Here, we show that during Drosophila cleavage, myosin recruitment to the cleavage furrows proceeds in temporally distinct phases of tension-driven cortical flow and direct recruitment, regulated by different zygotic genes. We identify the gene dunk, which we show is transiently transcribed when cellularization starts and functions to maintain cortical myosin during the flow phase. The subsequent direct myosin recruitment, however, is Dunk-independent but requires Slam. The Slam-dependent direct recruitment of myosin is sufficient to drive cleavage in the dunk mutant, and the subsequent development of the mutant is normal. In the dunk mutant, cortical myosin loss triggers misdirected flow and disrupts the hexagonal packing of the ingressing furrows. Computer simulation coupled with laser ablation suggests that Dunk-dependent maintenance of cortical myosin enables mechanical tension build-up, thereby providing a mechanism to guide myosin flow and define the hexagonal symmetry of the furrows. PMID- 27226316 TI - A system for studying mechanisms of neuromuscular junction development and maintenance. AB - The neuromuscular junction (NMJ), a cellular synapse between a motor neuron and a skeletal muscle fiber, enables the translation of chemical cues into physical activity. The development of this special structure has been subject to numerous investigations, but its complexity renders in vivo studies particularly difficult to perform. In vitro modeling of the neuromuscular junction represents a powerful tool to delineate fully the fine tuning of events that lead to subcellular specialization at the pre-synaptic and post-synaptic sites. Here, we describe a novel heterologous co-culture in vitro method using rat spinal cord explants with dorsal root ganglia and murine primary myoblasts to study neuromuscular junctions. This system allows the formation and long-term survival of highly differentiated myofibers, motor neurons, supporting glial cells and functional neuromuscular junctions with post-synaptic specialization. Therefore, fundamental aspects of NMJ formation and maintenance can be studied using the described system, which can be adapted to model multiple NMJ-associated disorders. PMID- 27226318 TI - miR-219 regulates neural progenitors by dampening apical Par protein-dependent Hedgehog signaling. AB - The transition of dividing neuroepithelial progenitors to differentiated neurons and glia is essential for the formation of a functional nervous system. Sonic hedgehog (Shh) is a mitogen for spinal cord progenitors, but how cells become insensitive to the proliferative effects of Shh is not well understood. Because Shh reception occurs at primary cilia, which are positioned within the apical membrane of neuroepithelial progenitors, we hypothesized that loss of apical characteristics reduces the Shh signaling response, causing cell cycle exit and differentiation. We tested this hypothesis using genetic and pharmacological manipulation, gene expression analysis and time-lapse imaging of zebrafish embryos. Blocking the function of miR-219, a microRNA that downregulates apical Par polarity proteins and promotes progenitor differentiation, elevated Shh signaling. Inhibition of Shh signaling reversed the effects of miR-219 depletion and forced expression of Shh phenocopied miR-219 deficiency. Time-lapse imaging revealed that knockdown of miR-219 function accelerates the growth of primary cilia, revealing a possible mechanistic link between miR-219-mediated regulation of apical Par proteins and Shh signaling. Thus, miR-219 appears to decrease progenitor cell sensitivity to Shh signaling, thereby driving these cells towards differentiation. PMID- 27226319 TI - Golgb1 regulates protein glycosylation and is crucial for mammalian palate development. AB - Cleft palate is a common major birth defect for which currently known causes account for less than 30% of pathology in humans. In this study, we carried out mutagenesis screening in mice to identify new regulators of palatogenesis. Through genetic linkage mapping and whole-exome sequencing, we identified a loss of-function mutation in the Golgb1 gene that co-segregated with cleft palate in a new mutant mouse line. Golgb1 is a ubiquitously expressed large coiled-coil protein, also known as giantin, that is localized at the Golgi membrane. Using CRISPR/Cas9-mediated genome editing, we generated and analyzed developmental defects in mice carrying additional Golgb1 loss-of-function mutations, which supported a crucial requirement for Golgb1 in palate development. Through maxillary explant culture assays, we demonstrate that the Golgb1 mutant embryos have intrinsic defects in palatal shelf elevation. Just prior to the developmental stage of palatal shelf elevation in wild-type littermates, Golgb1 mutant embryos exhibit increased cell density, reduced hyaluronan accumulation and impaired protein glycosylation in the palatal mesenchyme. Together, these results demonstrate that, although it is a ubiquitously expressed Golgi associated protein, Golgb1 has specific functions in protein glycosylation and tissue morphogenesis. PMID- 27226320 TI - SOX2 is sequentially required for progenitor proliferation and lineage specification in the developing pituitary. AB - Sox2 mutations are associated with pituitary hormone deficiencies and the protein is required for pituitary progenitor proliferation, but its function has not been well characterized in this context. SOX2 is known to activate expression of Six6, encoding a homeodomain transcription factor, in the ventral diencephalon. Here, we find that the same relationship likely exists in the pituitary. Moreover, because Six6 deletion is associated with a similar phenotype as described here for loss of Sox2, Six6 appears to be an essential downstream target of SOX2 in the gland. We also uncover a second role for SOX2. Whereas cell differentiation is reduced in Sox2 mutants, some endocrine cells are generated, such as POMC positive cells in the intermediate lobe. However, loss of SOX2 here results in complete downregulation of the melanotroph pioneer factor PAX7, and subsequently a switch of identity from melanotrophs to ectopic corticotrophs. Rescuing proliferation by ablating the cell cycle negative regulator p27 (also known as Cdkn1b) in Sox2 mutants does not restore melanotroph emergence. Therefore, SOX2 has two independent roles during pituitary morphogenesis; firstly, promotion of progenitor proliferation, and subsequently, acquisition of melanotroph identity. PMID- 27226321 TI - Adenomatous polyposis coli regulates radial axonal sorting and myelination in the PNS. AB - The tumor suppressor protein adenomatous polyposis coli (APC) is multifunctional it participates in the canonical Wnt/beta-catenin signal transduction pathway as well as modulating cytoskeleton function. Although APC is expressed by Schwann cells, the role that it plays in these cells and in the myelination of the peripheral nervous system (PNS) is unknown. Therefore, we used the Cre-lox approach to generate a mouse model in which APC expression is specifically eliminated from Schwann cells. These mice display hindlimb weakness and impaired axonal conduction in sciatic nerves. Detailed morphological analyses revealed that APC loss delays radial axonal sorting and PNS myelination. Furthermore, APC loss delays Schwann cell differentiation in vivo, which correlates with persistent activation of the Wnt signaling pathway and results in perturbed extension of Schwann cell processes and disrupted lamellipodia formation. In addition, APC-deficient Schwann cells display a transient diminution of proliferative capacity. Our data indicate that APC is required by Schwann cells for their timely differentiation to mature, myelinating cells and plays a crucial role in radial axonal sorting and PNS myelination. PMID- 27226322 TI - The insulator protein BEAF-32 is required for Hippo pathway activity in the terminal differentiation of neuronal subtypes. AB - The Hippo pathway is crucial for not only normal growth and apoptosis but also cell fate specification during development. What controls Hippo pathway activity during cell fate specification is incompletely understood. In this article, we identify the insulator protein BEAF-32 as a regulator of Hippo pathway activity in Drosophila photoreceptor differentiation. Though morphologically uniform, the fly eye is composed of two subtypes of R8 photoreceptor neurons defined by expression of light-detecting Rhodopsin proteins. In one R8 subtype, active Hippo signaling induces Rhodopsin 6 (Rh6) and represses Rhodopsin 5 (Rh5), whereas in the other subtype, inactive Hippo signaling induces Rh5 and represses Rh6. The activity state of the Hippo pathway in R8 cells is determined by the expression of warts, a core pathway kinase, which interacts with the growth regulator melted in a double-negative feedback loop. We show that BEAF-32 is required for expression of warts and repression of melted Furthermore, BEAF-32 plays a second role downstream of Warts to induce Rh6 and prevent Rh5 fate. BEAF-32 is dispensable for Warts feedback, indicating that BEAF-32 differentially regulates warts and Rhodopsins. Loss of BEAF-32 does not noticeably impair the functions of the Hippo pathway in eye growth regulation. Our study identifies a context specific regulator of Hippo pathway activity in post-mitotic neuronal fate, and reveals a developmentally specific role for a broadly expressed insulator protein. PMID- 27226323 TI - A biological timer in the fat body comprising Blimp-1, betaFtz-f1 and Shade regulates pupation timing in Drosophila melanogaster. AB - During the development of multicellular organisms, many events occur with precise timing. In Drosophila melanogaster, pupation occurs about 12 h after puparium formation and its timing is believed to be determined by the release of a steroid hormone, ecdysone (E), from the prothoracic gland. Here, we demonstrate that the ecdysone-20-monooxygenase Shade determines pupation timing by converting E to 20 hydroxyecdysone (20E) in the fat body, which is the organ that senses nutritional status. The timing of shade expression is determined by its transcriptional activator betaFtz-f1. The betaftz-f1 gene is activated after a decline in the expression of its transcriptional repressor Blimp-1, which is temporally expressed around puparium formation in response to a high titer of 20E. The expression level and stability of Blimp-1 is critical for the precise timing of pupation. Thus, we propose that Blimp-1 molecules function like sand in an hourglass in this precise developmental timer system. Furthermore, our data suggest that a biological advantage results from both the use of a transcriptional repressor for time determination and the association of developmental timing with nutritional status of the organism. PMID- 27226324 TI - Coordinated control of Notch/Delta signalling and cell cycle progression drives lateral inhibition-mediated tissue patterning. AB - Coordinating cell differentiation with cell growth and division is crucial for the successful development, homeostasis and regeneration of multicellular tissues. Here, we use bristle patterning in the fly notum as a model system to explore the regulatory and functional coupling of cell cycle progression and cell fate decision-making. The pattern of bristles and intervening epithelial cells (ECs) becomes established through Notch-mediated lateral inhibition during G2 phase of the cell cycle, as neighbouring cells physically interact with each other via lateral contacts and/or basal protrusions. Since Notch signalling controls cell division timing downstream of Cdc25, ECs in lateral contact with a Delta-expressing cell experience higher levels of Notch signalling and divide first, followed by more distant neighbours, and lastly Delta-expressing cells. Conversely, mitotic entry and cell division makes ECs refractory to lateral inhibition signalling, fixing their fate. Using a combination of experiments and computational modelling, we show that this reciprocal relationship between Notch signalling and cell cycle progression acts like a developmental clock, providing a delimited window of time during which cells decide their fate, ensuring efficient and orderly bristle patterning. PMID- 27226325 TI - Pbx1 is required for adult subventricular zone neurogenesis. AB - TALE-homeodomain proteins function as components of heteromeric complexes that contain one member each of the PBC and MEIS/PREP subclasses. We recently showed that MEIS2 cooperates with the neurogenic transcription factor PAX6 in the control of adult subventricular zone (SVZ) neurogenesis in rodents. Expression of the PBC protein PBX1 in the SVZ has been reported, but its functional role(s) has not been investigated. Using a genetic loss-of-function mouse model, we now show that Pbx1 is an early regulator of SVZ neurogenesis. Targeted deletion of Pbx1 by retroviral transduction of Cre recombinase into Pbx2-deficient SVZ stem and progenitor cells carrying floxed alleles of Pbx1 significantly reduced the production of neurons and increased the generation of oligodendrocytes. Loss of Pbx1 expression in neuronally committed neuroblasts in the rostral migratory stream in a Pbx2 null background, by contrast, severely compromised cell survival. By chromatin immunoprecipitation from endogenous tissues or isolated cells, we further detected PBX1 binding to known regulatory regions of the neuron specific genes Dcx and Th days or even weeks before the respective genes are expressed during the normal program of SVZ neurogenesis, suggesting that PBX1 might act as a priming factor to mark these genes for subsequent activation. Collectively, our results establish that PBX1 regulates adult neural cell fate determination in a manner beyond that of its heterodimerization partner MEIS2. PMID- 27226327 TI - Cardiovascular safety of metformin and sulfonylureas in patients with different cardiac risk profiles. AB - OBJECTIVES/BACKGROUND: Based on previous experiences, the Food and Drug Administration and the European Medicines Agency recommend that clinical trials for novel antidiabetic drugs are powered to detect increased cardiovascular risk. In this context, data concerning licensed drugs such as metformin and sulfonylureas are conflicting. The influence of baseline cardiovascular risk on any treatment effect appears obvious but has not been formally proven. We therefore evaluated association of metformin and sulfonylureas with cardiovascular events in patients with different cardiovascular risk profiles indicated by N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) levels. METHODS: 2024 patients with diabetes mellitus were included in this observational study. The primary endpoint was defined as a combination of cardiovascular events and death. Association of metformin and sulfonylureas was assessed using Cox regression models. Possible differences of these associations in patients with different NT-proBNP levels were studied by stratifying and through interaction analysis. RESULTS: During a median follow-up of 60 months, the primary endpoint occurred in 522 (26%) of patients. The median age was 63 years. A Cox regression analysis was adjusted for site of treatment, concomitant medication, age, gender, body mass index, glycated haemoglobin, duration of diabetes, glomerular filtration rate, cholesterol, and history of smoking and cardiac disease. Metformin was associated with a decreased risk in the cohort with elevated NT-proBNP >=300 pg/mL (HR 0.70, p=0.014) and a similar association was found for the interaction between metformin and NT-proBNP (p=0.001). There was neither an association for sulfonylureas nor a significant interaction between sulfonylureas and NT-proBNP. CONCLUSIONS: Metformin is associated with beneficial cardiovascular outcomes in patients with diabetes only when (sub)clinical cardiovascular risk defined by NT-proBNP levels is present. PMID- 27226328 TI - VAVD vacuum may cause bubble transgression in membrane oxygenators. AB - BACKGROUND: Vacuum-assisted venous drainage (VAVD) is widely used to enhance venous blood return from patients undergoing cardiopulmonary bypass (CPB). This vacuum can accidentally reach the oxygenator of the heart-lung machine and draw gas bubbles into the blood. This is known as bubble transgression (BT) and may cause air emboli in the arterial blood line. In order to avoid BT and minimize the risk of patient injury, knowledge of oxygenator tolerance to vacuum load is critical. Thus, the main aim of this thesis was to investigate how much vacuum a membrane oxygenator can withstand before BT appears. METHODS: We investigated four different adult oxygenators: Quadrox-i, Affinity Fusion, Capiox RX25 and Inspire 6M. They were tested in an in vitro setup where VAVD vacuum was allowed to reach the oxygenator through a non-occlusive roller pump. An ultrasonic clinical bubble counter, Gampt BCC 200, was used to count bubbles on the arterial line when the arterial pump was restarted. RESULTS: We observed a significant increase in bubble count for two of the oxygenators, caused by -30 mmHg of VAVD vacuum in the blood reservoir (Affinity Fusion and Inspire 6M). Massive air ingress was shown in two of the oxygenators, caused by -30 mmHg of VAVD vacuum in the reservoir (Capiox RX25) and -40 mmHg of VAVD vacuum in the reservoir (Affinity Fusion). CONCLUSION: VAVD vacuum may cause bubble transgression in an oxygenator. This was shown for all the oxygenators in this test. VAVD vacuum may cause visible massive air ingress in an oxygenator. This was shown for two of the oxygenators in this test (Capiox RX25 and Affinity Fusion). An alarm triggering on negative pressure in the oxygenator or a pressure relief valve might improve safety when using VAVD. PMID- 27226326 TI - The tyrosine kinase FER is responsible for the capacitation-associated increase in tyrosine phosphorylation in murine sperm. AB - Sperm capacitation is required for fertilization. At the molecular level, this process is associated with fast activation of protein kinase A. Downstream of this event, capacitating conditions lead to an increase in tyrosine phosphorylation. The identity of the tyrosine kinase(s) mediating this process has not been conclusively demonstrated. Recent experiments using stallion and human sperm have suggested a role for PYK2 based on the use of small molecule inhibitors directed against this kinase. However, crucially, loss-of-function experiments have not been reported. Here, we used both pharmacological inhibitors and genetically modified mice models to investigate the identity of the tyrosine kinase(s) mediating the increase in tyrosine phosphorylation in mouse sperm. Similar to stallion and human, PF431396 blocks the capacitation-associated increase in tyrosine phosphorylation. Yet, sperm from Pyk2(-/-) mice displayed a normal increase in tyrosine phosphorylation, implying that PYK2 is not responsible for this phosphorylation process. Here, we show that PF431396 can also inhibit FER, a tyrosine kinase known to be present in sperm. Sperm from mice targeted with a kinase-inactivating mutation in Fer failed to undergo capacitation-associated increases in tyrosine phosphorylation. Although these mice are fertile, their sperm displayed a reduced ability to fertilize metaphase II-arrested eggs in vitro. PMID- 27226329 TI - The Origin of Anti-Markovnikov Regioselectivity in Alkene Hydroamination Reactions Catalyzed by [Rh(DPEphos)](.). AB - The development of regioselective anti-Markovnikov alkene's hydroamination is a long-standing goal in catalysis. The [Rh(COD)(DPEphos)](+) complex is the most general and regioselective group 9 catalyst for such a process. The reaction mechanism for intermolecular hydroamination of alkenes catalyzed by [Rh(DPEphos)](+) complex is analyzed by means of DFT calculations. Hydroamination (alkene vs. amine activation routes) as well as oxidative amination pathways are analyzed. According to the computational results the operating mechanism can be generally described by alkene coordination, amine nucleophilic addition, proton transfer through the metal center and reductive elimination steps. The mechanism for the formation of the oxidative amination side product goes via a beta elimination after the nucleophilic addition and metal center protonation steps. The origin of the regioselectivity for the addition process (Markovnikov vs. anti Markovnikov additions) is shown to be not charge but orbitally driven. Remarkably, eta(2) to eta(1) slippage degree on the alkene coordination mode is directly related to the regioselective outcome. PMID- 27226330 TI - Reliability and Validity of a Material Resources Scale and Its Association With Depression Among Young Men Who Have Sex With Men: The P18 Cohort Study. AB - Socioeconomic status (SES) is a fundamental cause of ill health, but an understudied determinant of health for gay, bisexual, and other men who have sex with men (MSM). Surprisingly, few studies have examined the relations between poverty and depression among young MSM. The aims of this study were to determine the reliability and validity of an 18-item Family Resource Scale (FRS) as a measure of SES among YMSM and examine the relations between SES and depression, while taking into account factors associated with resilience or risk for poor mental health. Reliability of the SES scale was determined with Cronbach's alpha. Validity was assessed with factor analysis and bivariable comparisons with other SES measures. Multiple logistic regression was used to determine the relations between depressive symptomology (via the Beck Depression Inventory-II), SES, and gay-related psychosocial variables. In this racially/ethnically diverse sample (mean age = 21.8 years, 37.3% Hispanic/Latino, 30.5% White, 14.9% Black, and 17.0% other race/ethnicity), 70.8% reported incomes <= $10,000 and the mean FRS score was 4.1 ( SD = 0.9, range 0-5). The FRS demonstrated reliability (alpha = .91) and criterion and construct validity. The Beck Depression Inventory-II rated 17.6% with depressive symptomology. Higher FRS scores were associated with a lower odds of depression (adjusted odds ratio = 0.58; 95% confidence interval = 0.46-0.74) in logistic regression models controlling for gay community affinity and internalized homophobia. This diverse sample of YMSM in New York City reported substantial financial hardship and those who were more gay-identified had fewer material resources. Fewer material resources and internalized homophobia were both associated with higher odds of depression. PMID- 27226331 TI - Self-Assembled Colloidal Particle Clusters from In Situ Pickering-Like Emulsion Polymerization via Single Electron Transfer Mechanism. AB - A simple route is reported to synthesize colloidal particle clusters (CPCs) from self-assembly of in situ poly(vinylidene fluoride)/poly(styrene-co-tert-butyl acrylate) [PVDF/P(St-co-tBA)] Janus particles through one-pot seeded emulsion single electron transfer radical polymerization. In the in situ Pickering-like emulsion polymerization, the tBA/St/PVDF feed ratio and polymerization temperature are important for the formation of well-defined CPCs. When the tBA/St/PVDF feed ratio is 0.75 g/2.5 g/0.5 g and the reaction temperature is 35 degrees C, relatively uniform raspberry-like CPCs are obtained. The hydrophobicity of the P(St-co-tBA) domains and the affinity of PVDF to the aqueous environment are considered to be the driving force for the self-assembly of the in situ formed PVDF/P(St-co-tBA) Janus particles. The resultant raspberry like CPCs with PVDF particles protruding outward may be promising for superhydrophobic smart coatings. PMID- 27226332 TI - Pig epidemic diarrhoea virus S gene variant with a large deletion non-lethal to colostrum-deprived newborn piglets. AB - We previously identified a third porcine epidemic diarrhoea virus (PEDV) S variant with a large deletion of 582 nucleotides in the 5' terminal region of the S gene, in addition to the North American type and the S INDELs type. To investigate the pathogenicity of this variant, TTR-2/JPN/2014, we performed experimental infection using colostrum-deprived piglets and compared the results with those from the North American type PEDV, OKN-1/JPN/2013. Fifteen newborn piglets were divided into two groups of 7-8 piglets each and inoculated orally with one of PEDV isolates maintained at the eighth passage in Vero cell culture. Although all PEDV-inoculated piglets showed acute watery diarrhoea, lethality clearly differed between both PEDV-inoculated groups. Moreover, there were differences in virus distribution and lesions on the intestines between the two PEDV-inoculated groups. Therefore, our data suggest that the OKN-1/JPN/2013 PEDV isolate is virulent, whereas the TTR-2/JPN/2014 PEDV isolate is avirulent. PMID- 27226333 TI - Tuberous sclerosis complex. PMID- 27226334 TI - Valorization of antioxidants extracted from olive mill wastewater. AB - Antioxidants are highly important gradients used to preserve cosmetic products and reduce the effect of oxidative stress on the skin. The present work explores the possibility of using phenolic compounds of olive mill wastewater (OMW) as effective alternatives to the commercial antioxidants used in cosmetic formulations deemed by their allergic and carcinogenic effects. Esterification of tyrosol and hydroxytyrosol extracted from OMW with various fatty acids was conducted using Novozyme 435 lipase as a biocatalyst. Upon synthesis, butyrate, caprate, laurate, and palmitate tyrosyl and hydroxytyrosyl esters were isolated and evaluated for their antioxidant and antibacterial activities. Results showed that laurate derivatives are the most efficient in preventing lipid oxidation and inhibiting growth of pathogenic strains. In the prospective of industrial use, laurate tyrosyl and hydroxytyrosyl derivatives were incorporated in a formulation of moisturizer to substitute the commercial antioxidant butylated hydroxyltoluene. Oleuropein, extracted from olive leaves powder, was also tested as an antiaging ingredient in cosmetic formulations. The evaluation of physicochemical, microbiological, and sensorial properties of the new cosmetic products indicated that oleuropein and lipophilic derivatives do not affect the properties of the standard formulation. Oleuropein and lipophilic derivatives can be added as active ingredients to stabilize cosmetic preparations. PMID- 27226336 TI - Spectral Analysis of Electrocardiograms in Patients with Inducible Atrial Fibrillation after Catheter Ablation Predicts Sinus Rhythm Maintenance. AB - BACKGROUND: We aimed to develop a novel predictive marker for atrial fibrillation (AF) recurrence in patients with inducible AF after catheter ablation, based on power spectral analysis of baseline and postablation electrocardiograms. METHODS: Twenty-five patients who had undergone their first AF ablation procedure (pulmonary vein isolation and ganglionated plexi ablation) and had inducible AF after ablation were included. A 30-second interval of AF was chosen for each patient before and after ablation, and a periodogram of the atrial activity was computed. A ratio of the power in the dominant frequency to the power in the remainder of the periodogram (DFR) was calculated. RESULTS: Eight (32%) patients had recurrent AF at 1 year. The clinical and echocardiographic characteristics of patients with and without recurrence were similar (P > 0.05). After ablation, there was organization of atrial activity, evidenced by an increase in the DFR (0.28 +/- 0.22 vs 0.53 +/- 0.29; P = 0.001). The percent change in DFR before and after ablation (median [interquartile range]) was significantly higher in patients without AF recurrence (120% [30% to 344%] vs 3% [-27% to 66%]; P = 0.01). Receiver operating curve (ROC) analysis demonstrated that a less than 16% increase in DFR postablation was able to predict recurrence of AF (area under ROC curve = 0.82; P = 0.03) with 75% sensitivity and 94% specificity. CONCLUSION: AF ablation leads to variable organization of atrial activity. Organization of atrial activity after AF ablation is associated with lower 1-year recurrence rates and may be used intraprocedurally after as a novel end point for AF ablation. Larger prospective studies are warranted. PMID- 27226335 TI - Objective and specific tracking of anhedonia via event-related potentials in individuals with cocaine use disorders. AB - BACKGROUND: Hyposensitivity to non-drug reward, behaviorally manifested as anhedonia, is a hallmark of chronic substance use. Anhedonia is a transdiagnostic symptom underpinned by neurobiochemical disturbances in the reward circuit, yet an objective measure to assess anhedonia severity still eludes the field. We hypothesized that the Reward Positivity (RewP) component of the event-related potentials (ERPs) will specifically track anhedonia as the RewP is attributed to the same brain regions that are also implicated in anhedonia. METHODS: Forty-six individuals with cocaine use disorders (iCUD) performed a gambling task predicting whether they would win or lose money on each trial, while ERP data was acquired. RewP in response to predicted win trials was extracted from the ERPs using the principal component analysis. State anhedonia and depression severity were assessed using the Cocaine Selective Severity Assessment (CSSA). RESULTS: Although RewP amplitude correlated with both anhedonia and depression, only the RewP-anhedonia correlation survived a correction for depression severity. Further, a hierarchical multiple regression analysis revealed that anhedonia explained a significant amount of variance in the RewP amplitude, and this variance was significantly greater than that explained by demographics, severity and recency of drug use and even depression. CONCLUSIONS: These results show that RewP amplitude in response to rewarded trials tracks state anhedonia severity in iCUD. We argue that this association is perhaps driven by the activity in the dopaminergic mesocorticolimbic reward pathway that may underlie anhedonia symptomology as well as modulate RewP amplitude. PMID- 27226337 TI - Intestinal APCs of the endogenous nanomineral pathway fail to express PD-L1 in Crohn's disease. AB - Crohn's disease is a chronic inflammatory condition most commonly affecting the ileum and colon. The aetiology of Crohn's disease is complex and may include defects in peptidoglycan recognition, and/or failures in the establishment of intestinal tolerance. We have recently described a novel constitutive endogenous delivery system for the translocation of nanomineral-antigen-peptidoglycan (NAP) conjugates to antigen presenting cells (APCs) in intestinal lymphoid patches. In mice NAP conjugate delivery to APCs results in high surface expression of the immuno-modulatory molecule programmed death receptor ligand 1 (PD-L1). Here we report that NAP conjugate positive APCs in human ileal tissues from individuals with ulcerative colitis and intestinal carcinomas, also have high expression of PD-L1. However, NAP-conjugate positive APCs in intestinal tissue from patients with Crohn's disease show selective failure in PD-L1 expression. Therefore, in Crohn's disease intestinal antigen taken up by lymphoid patch APCs will be presented without PD-L1 induced tolerogenic signalling, perhaps initiating disease. PMID- 27226338 TI - Cost-effectiveness analysis of different systolic blood pressure targets for people with a history of stroke or transient ischaemic attack: Economic analysis of the PAST-BP study. AB - BACKGROUND: The PAST-BP trial found that using a lower systolic blood pressure target (<130 mmHg or lower versus <140 mmHg) in a primary care population with prevalent cerebrovascular disease was associated with a small additional reduction in blood pressure (2.9 mmHg). OBJECTIVES: To determine the cost effectiveness of an intensive systolic blood pressure target (<130 mmHg or lower) compared with a standard target (<140 mmHg) in people with a history of stroke or transient ischaemic attack on general practice stroke/transient ischaemic attack registers in England. METHODS: A Markov model with a one-year time cycle and a 30 year time horizon was used to estimate the cost per quality-adjusted life year of an intensive target versus a standard target. Individual patient level data were used from the PAST-BP trial with regard to change in blood pressure and numbers of primary care consultations over a 12-month period. Published sources were used to estimate life expectancy and risks of cardiovascular events and their associated costs and utilities. RESULTS: In the base-case results, aiming for an intensive blood pressure target was dominant, with the incremental lifetime costs being L169 lower per patient than for the standard blood pressure target with a 0.08 quality-adjusted life year gain. This was robust to sensitivity analyses, unless intensive blood pressure lowering reduced quality of life by 2% or more. CONCLUSION: Aiming for a systolic blood pressure target of <130 mmHg or lower is cost effective in people who have had a stroke/transient ischaemic attack in the community, but it is difficult to separate out the impact of the lower target from the impact of more active management of blood pressure. PMID- 27226339 TI - Inhibiting miR-21 attenuates experimental hepatic fibrosis by suppressing both the ERK1 pathway in HSC and hepatocyte EMT. AB - MicroRNA-21 (miR-21) has emerged as a critical regulatory molecule and an important serum marker in hepatic fibrogenesis. The aim of the present study was to investigate the role of inhibiting miR-21 on hepatic fibrosis treatment. Serum miR-21 levels in 60 healthy individuals and 180 patients with different stages of liver cirrhosis were examined, miR-21 levels in normal or cirrhotic human liver tissues (n=10 each) were also detected. An adenoviral vector (Ad-TuD-21) carrying the sponging ToughDecoy (TuD)-RNA sequence against miR-21 was constructed to reduce miR-21 expression efficiently in vitro and in vivo Histological and immunohistological examinations were performed to evaluate the inhibitory effects and mechanism of Ad-TuD-21 delivery into carbon tetrachloride (CCl4) induced hepatic fibrosis rats by targeting extracellular signal-regulated kinase 1 (ERK1) signalling in hepatic stellate cells (HSC) and hepatocyte epithelial-mesenchymal transition (EMT). Our results revealed that enhanced miR-21 levels in cirrhotic patients were related to the severity and activity of liver cirrhosis. Ad-TuD-21 administered to liver fibrosis rats could remarkably suppress profibrotic gene expression, cause histological improvements in liver and attenuate hepatic fibrosis significantly. More importantly, after Ad-TuD-21 treatment, inhibition of both the ERK1 signalling pathway in HSC and hepatocyte EMT was confirmed, which paralleled the enhancement of miR-21 target genes-sprouty2 (SPRY2) and hepatocyte nuclear factor 4alpha (HNF4alpha)-expression in vivo These data demonstrated that miR-21 is a key regulator to promote hepatic fibrogenesis, and sponging miR-21 expression may present a novel potentially therapeutic option for hepatic fibrosis. PMID- 27226340 TI - Benevolent Sexism, Attitudes Toward Motherhood, and Reproductive Rights: A Multi Study Longitudinal Examination of Abortion Attitudes. AB - Although Benevolent Sexism (BS)-an ideology that highly reveres women who conform to traditional gender roles-is cloaked in a superficially positive tone, being placed upon a pedestal is inherently restrictive. Accordingly, because the paternalistic beliefs associated with BS are based on the idealization of traditional gender roles (which include motherhood), BS should predict people's attitudes toward women's reproductive rights. Using data from a nationwide longitudinal panel study (N = 12,299), Study 1 showed that BS (but not Hostile Sexism) had cross-lagged effects on opposition to both elective and traumatic abortion. Study 2 (N = 309) extended these findings by showing that the relationship between BS and support for abortion was fully mediated by attitudes toward motherhood. These results highlight the pernicious nature of BS by demonstrating that the idealization of women-and motherhood, in particular-comes at a substantial cost (namely, the restriction of women's reproductive rights). PMID- 27226341 TI - Laser and light therapies for the treatment of nail psoriasis. AB - Psoriatic involvement of the nail is notoriously refractory to conventional therapy. Nail psoriasis has a high incidence amongst patients with psoriasis. It remains a significant cosmetic problem and thus, has a significant impact on quality of life. More recently, light and laser therapies have emerged as modalities for treatment of nail psoriasis. In this study, the efficacies of light and laser therapies are systematically reviewed. Light therapies involve ultraviolet light (with or without photosensitizers) or intense pulsed light. Alternatively, laser therapy in nail psoriasis is primarily administered using a 595-nm pulsed dye laser. These modalities have demonstrated significant improvement in psoriatic nail lesions, and even complete resolution in some cases. Both laser and light modalities have also been tested in combination with other systemic or topical therapeutics, with variable improvement in efficacy. Both laser and light therapies are generally well tolerated. Side-effects of light therapies include hyperpigmentation, itching and erythema; whereas, side effects of laser therapy are more frequent and include pain, purpura/petechiae and hyperpigmentation. Patterns of response to therapy were also seen based on presenting characteristics of the nail lesions: subungual hyperkeratosis and onycholysis appeared to be the most responsive to therapy, while nail pitting was the most resistant. Light or laser therapies have the potential to be an efficient and cost-effective in-office based treatment for nail psoriasis. However, more large-scale clinical trials are needed to assess their efficacy, particularly in combination with other therapeutic modalities. PMID- 27226343 TI - The effect of host plants on genotype variability in fitness and honeydew composition of Aphis fabae. AB - Aphid species can be polyphagous, feeding on multiple host plants across genera. As host plant species can have large variation in their phloem composition, this can affect aphid fitness and honeydew composition. Previous research showed significant intraspecific genotype variation in the composition of the honeydew carbohydrates of the black bean aphid Aphis fabae, with the ant attractant trisaccharide melezitose showing especially large variation across different genotypes. In this study, we test if variation in melezitose and carbohydrate composition of aphid honeydew could be linked to the adaptation of specific aphid genotypes to particular host plants. To this end, 4 high and 5 low melezitose secreting genotypes of the black bean aphid Aphis fabae were reared on 4 common host plants: broad bean, goosefoot, beet, and poppy. The carbohydrate composition, and in particular melezitose secretion, showed important aphid genotype and host plant interactions, with some genotypes being high melezitose secreting on 1 host plant but not on another. However, the interaction effects were not paralleled in the fitness measurements, even though there were significant differences in the average fitness across the different host plants. On the whole, this study demonstrates that aphid honeydew composition is influenced by complex herbivore-plant interactions. We discuss the relevance of these findings in the context of ant-aphid mutualisms and adaptive specialization in aphids. PMID- 27226342 TI - Prediction error, ketamine and psychosis: An updated model. AB - In 2007, we proposed an explanation of delusion formation as aberrant prediction error-driven associative learning. Further, we argued that the NMDA receptor antagonist ketamine provided a good model for this process. Subsequently, we validated the model in patients with psychosis, relating aberrant prediction error signals to delusion severity. During the ensuing period, we have developed these ideas, drawing on the simple principle that brains build a model of the world and refine it by minimising prediction errors, as well as using it to guide perceptual inferences. While previously we focused on the prediction error signal per se, an updated view takes into account its precision, as well as the precision of prior expectations. With this expanded perspective, we see several possible routes to psychotic symptoms - which may explain the heterogeneity of psychotic illness, as well as the fact that other drugs, with different pharmacological actions, can produce psychotomimetic effects. In this article, we review the basic principles of this model and highlight specific ways in which prediction errors can be perturbed, in particular considering the reliability and uncertainty of predictions. The expanded model explains hallucinations as perturbations of the uncertainty mediated balance between expectation and prediction error. Here, expectations dominate and create perceptions by suppressing or ignoring actual inputs. Negative symptoms may arise due to poor reliability of predictions in service of action. By mapping from biology to belief and perception, the account proffers new explanations of psychosis. However, challenges remain. We attempt to address some of these concerns and suggest future directions, incorporating other symptoms into the model, building towards better understanding of psychosis. PMID- 27226344 TI - Review article: acute severe ulcerative colitis - evidence-based consensus statements. AB - BACKGROUND: Acute severe ulcerative colitis (ASUC) is a potentially life threatening complication of ulcerative colitis. AIM: To develop consensus statements based on a systematic review of the literature of the management of ASUC to improve patient outcome. METHODS: Following a literature review, the Delphi method was used to develop the consensus statements. A steering committee, based in Australia, generated the statements of interest. Three rounds of anonymous voting were carried out to achieve the final results. Acceptance of statements was pre-determined by >=80% votes in 'complete agreement' or 'agreement with minor reservation'. RESULTS: Key recommendations include that patients with ASUC should be: hospitalised, undergo unprepared flexible sigmoidoscopy to assess severity and to exclude cytomegalovirus colitis, and be provided with venous thromboembolism prophylaxis and intravenous hydrocortisone 100 mg three or four times daily with close monitoring by a multidisciplinary team. Rescue therapy such as infliximab or ciclosporin should be started if insufficient response by day 3, and colectomy considered if no response to 7 days of rescue therapy or earlier if deterioration. With such an approach, it is expected that colectomy rate during admission will be below 30% and mortality less than 1% in specialist centres. CONCLUSION: These evidenced-based consensus statements on acute severe ulcerative colitis, developed by a multidisciplinary group, provide up-to-date best practice recommendations that improve and harmonise management as well as provide auditable quality assessments. PMID- 27226345 TI - Delivery of macromolecules into the endothelium of whole ex vivo human cornea by femtosecond laser-activated carbon nanoparticles. AB - BACKGROUND: The targeted delivery of drugs or genes into corneal endothelial cells (ECs) during eye banking could help improve graft quality and quantity. Physical methods raising less safety concerns than viral ones, we previously adapted, for in vitro ECs, a recent innovative technique of drug delivery based on the activation of carbon nanoparticles (CNPs) by a femtosecond laser (fsL). The aim of the present pilot study was to adapt this method to enable molecule delivery into the intact endothelium of ex vivo human corneas. METHODS: ECs from 40 organ-cultured corneas were perforated by photoacoustic reaction induced by irradiation of CNPs by a fsL. This enabled intracellular delivery of Alexa Fluor 488 dextran, a 4000 Da fluorescent macromolecule. The influence of increasing laser fluences (15, 20, 30 and 40 mJ/cm(2)) and of protective additives (ROCK inhibitor and poloxamer 407) on delivery and mortality rates was quantified using ImageJ. RESULTS: No dextran was delivered with a fluence lower than 20 mJ/cm(2). Dextran was delivered into 3% (range 0%-7%) of cells at 20 mJ/cm(2), 7% (range 2% 12%) at 30 mJ/cm(2) and reaching a median 13% (range 3%-24%) for 40 mJ/cm(2), showing that dextran uptake by ECs increased significantly with fluence. Induced mortality varied from 0% to 53% irrespective of fluence, but likely to be related with the endothelial status (EC density and morphometry, donor age, storage duration and presence of Descemet's folds). ROCK inhibitor slightly increased uptake efficiency, unlike poloxamer. However, none of them decreased the mortality induced by laser. CONCLUSIONS: This study shows that a macromolecule can be delivered specifically into ECs of a whole organ-cultured human cornea, using fsL-activated CNPs. The delivery rate was relatively high for a non-viral method. Further optimisation is required to understand and reduce variability in cell mortality. PMID- 27226346 TI - High incidence of dry eye in young children with allergic conjunctivitis in Southwest China. AB - PURPOSE: To identify the prevalence of dry eye in pediatric population with allergic conjunctivitis in Southwest China. METHODS: A single-centre, prospective, case-control study conducted between May 2015 and December 2015 included 40 children, 3-6 years of age, with seasonal allergic conjunctivitis (SAC) or perennial allergic conjunctivitis (PAC) and 40 age- and gender-matched children undergoing medical healthy examination without history of allergy or dry eye as a control. A dry eye score system (DESS) was administered to both groups. Slit-lamp examinations including tear film break-up time (TFBUT) and fluorescent corneal staining (FCS) were performed. Correlation analyses were performed to evaluate associations between measures of dry eye and signs and symptoms of AC. RESULTS: The prevalence of dry eye was 97.5% (78/80 eyes) in cases and 27.50% (22/80 eyes) in controls. Mean DESS score was 4.75 +/- 2.22 in the case group and 0.80 +/- 1.22 in the control group (p < 0.001). Symptoms of dry eye in the case group were mild (<6). Mean tear film break-up time was 6.54 +/- 1.48 seconds in the case group and 10.04 +/- 1.79 seconds in the control group (p < 0.001). Mean FCS scores were 0.79 +/- 1.34 and 0.21 +/- 0.57, respectively (p = 0.001). The DESS score and TFBUT were both associated with the duration of allergic conjunctivitis. CONCLUSION: The incidence of dry eye assessed by TFBUT was higher in young children with SAC and PAC than in controls. However, subjective symptoms of dry eye (DESS) were inconsistent with objective signs, indicating that close attention should be paid to the evaluation and treatment of dry eye in pediatric population with AC. PMID- 27226348 TI - Clonality, virulence and the occurrence of genes encoding antibiotic resistance among Staphylococcus warneri isolates from bloodstream infections. AB - Coagulase-negative Staphylococcuswarneri is an opportunistic pathogen capable of causing several infections, especially in patients with indwelling medical devices. We evaluated the virulence-associated properties of 23 clinical isolates recovered from blood specimens. In addition, the carriage of biofilm-associated genes, as well as antibiotic-resistant genes, was identified. S. warneri isolates appeared to be clonally unrelated and revealed a high degree of genetic diversity. All isolates revealed adhesion to epithelial cells, and 43.5 % of strains invaded the cells. Moreover, 52 % of isolates formed biofilm in vitro. PCR analysis demonstrated the presence of the ica operon, in two of the 12 biofilm-positive isolates. This indicated that biofilm formation, in this species, is not restricted to strains harbouring icaADBC genes, encoding polysaccharide intercellular adhesion. Analysis by confocal laser scanning microscopy revealed that biofilm-forming strains formed a three-dimensional structure, composed of mainly living cells. All strains revealed cell-contact cytotoxicity that was strongly associated with biofilm formation. Moreover, cell free supernatants, of 95 % of the isolates, expressed a cytotoxic activity which caused the destruction of HeLa cells. S. warneri capable of forming biofilm carried significantly more genes encoding resistance to beta-lactams, aminoglicosides and macrolide-lincosamide streptogramin B antibiotics than biofilm-negative isolates. We have shown that tigecycline/rifampicin is effective against bacteria growing as a biofilm. The biofilm inhibitory concentration range of tigecycline/rifampicin was <=1 ug ml-1. Results indicated that S. warneri have the ability to adhere, form biofilm, invade and destroy epithelial cells, which could be important mechanisms contributing to the development of diseases. PMID- 27226347 TI - The Evx1/Evx1as gene locus regulates anterior-posterior patterning during gastrulation. AB - Thousands of sense-antisense mRNA-lncRNA gene pairs occur in the mammalian genome. While there is usually little doubt about the function of the coding transcript, the function of the lncRNA partner is mostly untested. Here we examine the function of the homeotic Evx1-Evx1as gene locus. Expression is tightly co-regulated in posterior mesoderm of mouse embryos and in embryoid bodies. Expression of both genes is enhanced by BMP4 and WNT3A, and reduced by Activin. We generated a suite of deletions in the locus by CRISPR-Cas9 editing. We show EVX1 is a critical downstream effector of BMP4 and WNT3A with respect to patterning of posterior mesoderm. The lncRNA, Evx1as arises from alternative promoters and is difficult to fully abrogate by gene editing or siRNA approaches. Nevertheless, we were able to generate a large 2.6 kb deletion encompassing the shared promoter with Evx1 and multiple additional exons of Evx1as. This led to an identical dorsal-ventral patterning defect to that generated by micro-deletion in the DNA-binding domain of EVX1. Thus, Evx1as has no function independent of EVX1, and is therefore unlikely to act in trans. We predict many antisense lncRNAs have no specific trans function, possibly only regulating the linked coding genes in cis. PMID- 27226350 TI - Highly specific targeted mutagenesis in plants using Staphylococcus aureus Cas9. AB - The CRISPR/Cas9 system is an efficient and convenient tool for genome editing in plants. Cas9 nuclease derived from Streptococcus pyogenes (Sp) is commonly used in this system. Recently, Staphylococcus aureus Cas9 (SaCas9)-mediated genome editing was reported in human cells and Arabidopsis. Because SaCas9 (1053 a.a.) is smaller than SpCas9 (1368 a.a.), SaCas9 could have substantial advantages for delivering and expressing Cas9 protein, especially using virus vectors. Since the protospacer adjacent motif (PAM) sequence of SaCas9 (5'-NNGRRT-3') differs from that of SpCas9 (5'-NGG-3'), the use of this alternative Cas9 nuclease could expand the selectivity at potential cleavage target sites of the CRISPR/Cas9 system. Here we show that SaCas9 can mutagenize target sequences in tobacco and rice with efficiencies similar to those of SpCas9. We also analyzed the base preference for 'T' at the 6th position of the SaCas9 PAM. Targeted mutagenesis efficiencies in target sequences with non-canonical PAMs (5'-NNGRRV-3') were much lower than those with a canonical PAM (5'-NNGRRT-3'). The length of target sequence recognized by SaCas9 is one or two nucleotides longer than that recognized by SpCas9. Taken together, our results demonstrate that SaCas9 has higher sequence recognition capacity than SpCas9 and is useful for reducing off target mutations in crop. PMID- 27226349 TI - Vaginal Dysbiosis from an Evolutionary Perspective. AB - Evolutionary approaches are powerful tools for understanding human disorders. The composition of vaginal microbiome is important for reproductive success and has not yet been characterized in the contexts of social structure and vaginal pathology in non-human primates (NHPs). We investigated vaginal size, vulvovaginal pathology and the presence of the main human subtypes of Lactobacillus spp./ BV-related species in the vaginal microflora of baboons (Papio spp.). We performed morphometric measurements of external and internal genitalia (group I, n = 47), analyzed pathology records of animals from 1999-2015 (group II, n = 64 from a total of 12,776), and evaluated vaginal swabs using polymerase chain reaction (PCR) (group III, n = 14). A total of 68 lesions were identified in 64 baboons. Lactobacillus iners, Gardnerella vaginalis, Atopobium vaginae, Megasphaera I, and Megasphaera II were not detected. L. jensenii, L. crispatus, and L. gasseri were detected in 2/14 (14.2%), 1/14 (7.1%), and 1/14 (7.1%) samples, respectively. BVAB2 was detected in 5/14 (35.7%) samples. The differences in the vaginal milieu between NHP and humans might be the factor associated with human-specific pattern of placental development and should be taken in consideration in NHP models of human pharmacology and microbiology. PMID- 27226351 TI - Metabolic Disposition of Osimertinib in Rats, Dogs, and Humans: Insights into a Drug Designed to Bind Covalently to a Cysteine Residue of Epidermal Growth Factor Receptor. AB - Preclinical and clinical studies were conducted to determine the metabolism and pharmacokinetics of osimertinib and key metabolites AZ5104 and AZ7550. Osimertinib was designed to covalently bind to epidermal growth factor receptors, allowing it to achieve nanomolar cellular potency (Finlay et al., 2014). Covalent binding was observed in incubations of radiolabeled osimertinib with human and rat hepatocytes, human and rat plasma, and human serum albumin. Osimertinib, AZ5104, and AZ7550 were predominantly metabolized by CYP3A. Seven metabolites were detected in human hepatocytes, also observed in rat or dog hepatocytes at similar or higher levels. After oral administration of radiolabeled osimertinib to rats, drug-related material was widely distributed, with the highest radioactivity concentrations measured at 6 hours postdose in most tissues; radioactivity was detectable in 42% of tissues 60 days postdose. Concentrations of [(14)C]-radioactivity in blood were lower than in most tissues. After the administration of a single oral dose of 20 mg of radiolabeled osimertinib to healthy male volunteers, ~19% of the dose was recovered by 3 days postdose. At 84 days postdose, mean total radioactivity recovery was 14.2% and 67.8% of the dose in urine and feces. The most abundant metabolite identified in feces was AZ5104 (~6% of dose). Osimertinib accounted for ~1% of total radioactivity in the plasma of non-small cell lung cancer patients after 22 days of 80-mg osimertinib once daily treatment; the most abundant circulatory metabolites were AZ7550 and AZ5104 (<10% of total osimertinib-related material). Osimertinib is extensively distributed and metabolized in humans and is eliminated primarily via the fecal route. PMID- 27226353 TI - Nitrates for the Management of Acute Heart Failure Syndromes, A Systematic Review. AB - Intravenous nitrates are widely used in the management of acute heart failure syndrome (AHFS) yet with lack of robust evidence to support their use. We therefore sought to analyze all randomized studies that evaluated the effects of nitrates on clinical outcomes in patients with AHFS. In total, 15 relevant trials comparing nitrates and alternative interventions in 1824 patients were identified. All but 3 were conducted before 1998. No trials demonstrated a beneficial effect on mortality, apart from 1 trial reporting a reduction in mortality, which was related to the time of treatment. Retrospective review suggests that there is a lack of data to draw any firm conclusions concerning the use of nitrates in patients with AHFS. More studies are needed to evaluate the safety and efficacy of these agents in the modern era of guideline-directed use of heart failure therapy. PMID- 27226352 TI - Application of Static Models to Predict Midazolam Clinical Interactions in the Presence of Single or Multiple Hepatitis C Virus Drugs. AB - Asunaprevir (ASV), daclatasvir (DCV), and beclabuvir (BCV) are three drugs developed for the treatment of chronic hepatitis C virus infection. Here, we evaluated the CYP3A4 induction potential of each drug, as well as BCV-M1 (the major metabolite of BCV), in human hepatocytes by measuring CYP3A4 mRNA alteration. The induction responses were quantified as induction fold (mRNA fold change) and induction increase (mRNA fold increase), and then fitted with four nonlinear regression algorithms. Reversible inhibition and time-dependent inhibition (TDI) on CYP3A4 activity were determined to predict net drug-drug interactions (DDIs). All four compounds were CYP3A4 inducers and inhibitors, with ASV demonstrating TDI. The curve-fitting results demonstrated that fold increase is a better assessment to determine kinetic parameters for compounds inducing weak responses. By summing the contribution of each inducer, the basic static model was able to correctly predict the potential for a clinically meaningful induction signal for single or multiple perpetrators, but with over prediction of the magnitude. With the same approach, the mechanistic static model improved the prediction accuracy of DCV and BCV when including both induction and inhibition effects, but incorrectly predicted the net DDI effects for ASV alone or triple combinations. The predictions of ASV or the triple combination could be improved by only including the induction and reversible inhibition but not the ASV CYP3A4 TDI component. Those results demonstrated that static models can be applied as a tool to help project the DDI risk of multiple perpetrators using in vitro data. PMID- 27226354 TI - High efficiency all-polymer tandem solar cells. AB - In this work, we have reported for the first time an efficient all-polymer tandem cell using identical sub-cells based on P2F-DO:N2200. A high power conversion efficiency (PCE) of 6.70% was achieved, which is among the highest efficiencies for all polymer solar cells and 43% larger than the PCE of single junction cell. The largely improved device performance can be mainly attributed to the enhanced absorption of tandem cell. Meanwhile, the carrier collection in device remains efficient by optimizing the recombination layer and sub-cell film thickness. Thus tandem structure can become an easy approach to effectively boost the performance of current all polymer solar cells. PMID- 27226356 TI - Overexpression of NDUFA4L2 is associated with poor prognosis in patients with colorectal cancer. AB - BACKGROUND: NDUFA4L2 (NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like 2, also called NADH-ubiquinone oxidoreductase MLRQ subunit homologue) was clearly enriched in the mitochondrial fraction under hypoxic conditions, and immunofluorescence showed a clear colocalization of NDUFA4L2 and cytochrome c in some tumour cells. However, little study has investigated its prognostic value in colorectal cancer (CRC). METHODS: In our study, mRNA-NDUFA4L2 and protein expression were analysed in 150 cases of CRC and adjacent normal tissues using immunohistochemistry, semi-quantitative reverse transcriptase-polymerase chain reaction. The correlation between NDUFA4L2 expression and clinicopathological factors was evaluated by the Chi-square test. Overall survival of patients was analysed by the Kaplan-Meier method. RESULTS: NDUFA4L2 overexpression was observed in 84% (126/150) of CRC tissues, but only in 24.7% (37/150) of adjacent normal tissues (P < 0.05). Semi-quantitative reverse transcriptase-polymerase chain reaction showed average mRNA expression levels to be 23.34 +/- 1.356 and 4.34 +/- 1.132 for CRC tissue and adjacent normal tissue (P < 0.05). Statistical analysis showed a significant correlation of NDUFA4L2 expression with histological grade, Dukes' stages, lymph node metastasis and liver metastasis. More importantly, multivariate analysis indicated that overexpression of NDUFA4L2 was an independent prognostic factor for CRC patients (P = 0.002). NDUFA4L2 negative patients had a higher tumour-free/overall survival rate than patients with high NDUFA4L2 expression (P = 0.001 and 0.002, respectively). CONCLUSIONS: Our data suggest that NDUFA4L2 overexpression is associated with tumour progression and a poor prognosis in CRC patients. PMID- 27226357 TI - An electronically instrumented internal fixator for the assessment of bone healing. AB - OBJECTIVES: The monitoring of fracture healing is a complex process. Typically, successive radiographs are performed and an emerging calcification of the fracture area is evaluated. The aim of this study was to investigate whether different bone healing patterns can be distinguished using a telemetric instrumented femoral internal plate fixator. MATERIALS AND METHODS: An electronic telemetric system was developed to assess bone healing mechanically. The system consists of a telemetry module which is applied to an internal locking plate fixator, an external reader device, a sensor for measuring externally applied load and a laptop computer with processing software. By correlation between externally applied load and load measured in the implant, the elasticity of the osteosynthesis is calculated. The elasticity decreases with ongoing consolidation of a fracture or nonunion and is an appropriate parameter for the course of bone healing. At our centre, clinical application has been performed in 56 patients suffering nonunion or fracture of the femur. RESULTS: A total of 39 cases of clinical application were reviewed for this study. In total, four different types of healing curves were observed: fast healing; slow healing; plateau followed by healing; and non-healing. CONCLUSION: The electronically instrumented internal fixator proved to be valuable for the assessment of bone healing in difficult healing situations. Cost-effective manufacturing is possible because the used electronic components are derived from large-scale production. The incorporation of microelectronics into orthopaedic implants will be an important innovation in future clinical care.Cite this article: B. Kienast, B. Kowald, K. Seide, M. Aljudaibi, M. Faschingbauer, C. Juergens, J. Gille. An electronically instrumented internal fixator for the assessment of bone healing. Bone Joint Res 2016;5:191-197. DOI: 10.1302/2046-3758.55.2000611. PMID- 27226355 TI - BDNF rescues BAF53b-dependent synaptic plasticity and cocaine-associated memory in the nucleus accumbens. AB - Recent evidence implicates epigenetic mechanisms in drug-associated memory processes. However, a possible role for one major epigenetic mechanism, nucleosome remodelling, in drug-associated memories remains largely unexplored. Here we examine mice with genetic manipulations targeting a neuron-specific nucleosome remodelling complex subunit, BAF53b. These mice display deficits in cocaine-associated memory that are more severe in BAF53b transgenic mice compared with BAF53b heterozygous mice. Similar to the memory deficits, theta-induced long term potentiation (theta-LTP) in the nucleus accumbens (NAc) is significantly impaired in slices taken from BAF53b transgenic mice but not heterozygous mice. Further experiments indicate that theta-LTP in the NAc is dependent on TrkB receptor activation, and that BDNF rescues theta-LTP and cocaine-associated memory deficits in BAF53b transgenic mice. Together, these results suggest a role for BAF53b in NAc neuronal function required for cocaine-associated memories, and also that BDNF/TrkB activation in the NAc may overcome memory and plasticity deficits linked to BAF53b mutations. PMID- 27226358 TI - Tamoxifen Dose Escalation in Patients With Diminished CYP2D6 Activity Normalizes Endoxifen Concentrations Without Increasing Toxicity. AB - BACKGROUND: Polymorphic CYP2D6 is primarily responsible for metabolic activation of tamoxifen to endoxifen. We previously reported that by increasing the daily tamoxifen dose to 40 mg/day in CYP2D6 intermediate metabolizer (IM), but not poor metabolizer (PM), patients achieve endoxifen concentrations similar to those of extensive metabolizer patients on 20 mg/day. We expanded enrollment to assess the safety of CYP2D6 genotype-guided dose escalation and investigate concentration differences between races. METHODS: PM and IM breast cancer patients currently receiving tamoxifen at 20 mg/day were enrolled for genotype-guided escalation to 40 mg/day. Endoxifen was measured at baseline and after 4 months. Quality-of-life data were collected using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and Breast Cancer Prevention Trial Menopausal Symptom Scale at baseline and after 4 months. RESULTS: In 353 newly enrolled patients, genotype-guided dose escalation eliminated baseline concentration differences in IM (p = .08), but not PM (p = .009), patients. Endoxifen concentrations were similar in black and white patients overall (p = .63) and within CYP2D6 phenotype groups (p > .05). In the quality-of-life analysis of 480 patients, dose escalation did not meaningfully diminish quality of life; in fact, improvements were seen in several measures including the FACT Breast Cancer subscale (p = .004) and limitations in range of motion (p < .0001) in IM patients. CONCLUSION: Differences in endoxifen concentration during treatment can be eliminated by doubling the tamoxifen dose in IM patients, without an appreciable effect on quality of life. Validation of the association between endoxifen concentration and efficacy or prospective demonstration of improved efficacy is necessary to warrant clinical uptake of this personalized treatment strategy. IMPLICATIONS FOR PRACTICE: This secondary analysis of a prospective CYP2D6 genotype-guided tamoxifen dose escalation study confirms that escalation to 40 mg/day in patients with low-activity CYP2D6 phenotypes (poor or intermediate metabolizers) increases endoxifen concentrations without any obvious increases in treatment-related toxicity. It remains unknown whether endoxifen concentration is a useful predictor of tamoxifen efficacy, and thus, there is no current role in clinical practice for CYP2D6 genotype-guided tamoxifen dose adjustment. If future studies confirm the importance of endoxifen concentrations for tamoxifen efficacy and report a target concentration, this study provides guidance for a dose-adjustment approach that could maximize efficacy while maintaining patient quality of life. PMID- 27226359 TI - The Role of Capecitabine/Temozolomide in Metastatic Neuroendocrine Tumors. AB - BACKGROUND: Neuroendocrine tumors (NETs) are commonly treated with multimodality therapy. The combination of capecitabine and temozolomide (CAPTEM) has been suggested as a treatment option for patients with metastatic NETs. We present our experience with CAPTEM. METHODS: Data on NET patients who were placed on CAPTEM and received at least one cycle were obtained from a Velos eResearch database. Response rate was calculated by RECIST 1.1. Overall survival and progression-free survival (PFS) were calculated by the Kaplan-Meier survival method. RESULTS: A total of 29 patients (17 male and 12 female) were included. Median age at CAPTEM initiation was 58 years (range: 26-77). Primary tumors included 9 small bowel (31%), 15 pancreas (52%), 3 lung (10%), and 2 rectum (7%). Median number of CAPTEM cycles was 8 (range: 1-55). Partial response occurred in 5 patients (5 of 29, 17%); 14 patients (14 of 29, 48%) had stable disease, and 10 patients (10 of 29, 34%) had progressive disease. A total of 3 (20%) and 5 (33%) pancreatic NETs experienced partial response and stable disease, respectively. A total of 2 (14%) and 9 (64%) nonpancreatic NETs experienced partial response and stable disease, respectively. Partial response was noted in 1 patient (13%) and stable disease in 5 patients (63%) with Ki-67 values of less than 2%. In patients with Ki-67 values of 2%-20%, partial response was noted in 3 (19%) and stable disease in 8 (50%). Partial response and stable disease were noted in 1 patient each (20%) with Ki-67 values greater than 20%. Median PFS was 12 months. Adverse reactions caused dose reductions in 24% of patients. CONCLUSION: Although adverse reactions were experienced, most patients tolerated this regimen. CAPTEM should be considered as a reasonable treatment option for metastatic NET patients. IMPLICATIONS FOR PRACTICE: The role of chemotherapy in neuroendocrine tumors has evolved in recent years. The results of this study suggest that the combination of capecitabine and temozolomide provides an adequate treatment option and may prolong survival in patients with a wide variety of metastatic neuroendocrine tumors. Although prospective data are needed, this research adds to the abundance of retrospective experience with this combination that appears to show that capecitabine and temozolomide could potentially be an option for patients with advanced neuroendocrine tumors who have progressed on standard treatment. PMID- 27226360 TI - Value: The Next Frontier in Cancer Care. PMID- 27226361 TI - Vermicompost and farmyard manure improves food quality, antioxidant and antibacterial potential of Cajanus cajan (L. Mill sp.) leaves. AB - BACKGROUND: Pigeon pea (Cajanus cajan) leaves are a good source of nutrition and health benefitting phenolic compounds. However, its importance has not yet been effectively addressed. Recently, a 2-year field experiment was attempted in an alluvial soil to understand the role of various organic and inorganic fertilisers and their combinations not only on soil quality, but also on production of foremost phenolic compounds and imparting antioxidant and antibacterial properties in C. cajan under vermicompost treatments. RESULTS: Notable enhancements in crude protein, soluble carbohydrate, ash content and total flavonoid content were recorded in Cajanus leaves under vermicompost treatments. We detected a significant rise in carlinoside content in C. cajan leaves, which is known to reduce bilirubin concentration in hepatitis affected human blood. Farmyard manure treatments resulted in a high crude fibre content coupled with a substantially high concentration of total phenols, and chlorophyll. In addition, incorporation of vermicompost with or without inorganic fertiliser in the soil had a significant impact on antioxidant and antibacterial properties of C. cajan leaves. Above and beyond, farmyard manure and vermicompost positively influenced the physico-chemical health of the soil. CONCLUSION: The present nutrient management scheme based on organic input not only induced a higher yield of C. cajan endowed with improved antioxidant and antibacterial properties, but also enhanced the production of various phenolic compounds. (c) 2016 Society of Chemical Industry. PMID- 27226362 TI - Tumor budding is an independent risk factor for lymph node metastasis in cutaneous squamous cell carcinoma: a single center retrospective study. AB - BACKGROUND: Although tumor budding is acknowledged as a risk factor for lymph node metastasis in certain types of carcinoma, it is not well investigated in cutaneous squamous cell carcinomas (SCCs). In this study, we analyzed the correlation between tumor budding and nodal metastasis in cutaneous SCC. METHODS: Histopathologic specimens of 15 metastasizing and 144 non-metastasizing cutaneous SCC were retrospectively reviewed. Cut-off point for tumor budding was determined at five or more foci of an isolated cancer cell or a cluster comprising <5 cells /1.23 mm(2) in the invasive front of the tumor under hematoxylin and eosin sections. RESULTS: Tumor budding was positive in 93.3% of metastasizing cutaneous SCC and 25.7% of non-metastasizing cutaneous SCC, respectively (p < 0.0001). In multivariate analysis, tumor budding was an independent risk factor for nodal metastasis among the other risk factors (tumor size, tumor thickness, Clark level and poor differentiation) (p = 0.0021). In combination with tumor thickness >4 mm, tumor budding became a better marker for predicting nodal metastasis (sensitivity 93.3%, specificity 84.7%). CONCLUSIONS: In our cohort, tumor budding was an independent risk factor for nodal metastasis. Our data suggests the promising role of tumor budding in risk evaluation of cutaneous SCC. PMID- 27226363 TI - Gel it away: a simple cost-effective technique to make procedures on the hair bearing areas easy. PMID- 27226364 TI - Visualization and Sequencing of Membrane Remodeling Leading to Influenza Virus Fusion. AB - Protein-mediated membrane fusion is an essential step in many fundamental biological events, including enveloped virus infection. The nature of protein and membrane intermediates and the sequence of membrane remodeling during these essential processes remain poorly understood. Here we used cryo-electron tomography (cryo-ET) to image the interplay between influenza virus and vesicles with a range of lipid compositions. By following the population kinetics of membrane fusion intermediates imaged by cryo-ET, we found that membrane remodeling commenced with the hemagglutinin fusion protein spikes grappling onto the target membrane, followed by localized target membrane dimpling as local clusters of hemagglutinin started to undergo conformational refolding. The local dimples then transitioned to extended, tightly apposed contact zones where the two proximal membrane leaflets were in most cases indistinguishable from each other, suggesting significant dehydration and possible intermingling of the lipid head groups. Increasing the content of fusion-enhancing cholesterol or bis monoacylglycerophosphate in the target membrane led to an increase in extended contact zone formation. Interestingly, hemifused intermediates were found to be extremely rare in the influenza virus fusion system studied here, most likely reflecting the instability of this state and its rapid conversion to postfusion complexes, which increased in population over time. By tracking the populations of fusion complexes over time, the architecture and sequence of membrane reorganization leading to efficient enveloped virus fusion were thus resolved. IMPORTANCE: Enveloped viruses employ specialized surface proteins to mediate fusion of cellular and viral membranes that results in the formation of pores through which the viral genetic material is delivered to the cell. For influenza virus, the trimeric hemagglutinin (HA) glycoprotein spike mediates host cell attachment and membrane fusion. While structures of a subset of conformations and parts of the fusion machinery have been characterized, the nature and sequence of membrane deformations during fusion have largely eluded characterization. Building upon studies that focused on early stages of HA-mediated membrane remodeling, here cryo-electron tomography (cryo-ET) was used to image the three dimensional organization of intact influenza virions at different stages of fusion with liposomes, leading all the way to completion of the fusion reaction. By monitoring the evolution of fusion intermediate populations over the course of acid-induced fusion, we identified the progression of membrane reorganization that leads to efficient fusion by an enveloped virus. PMID- 27226366 TI - HIV-1-Specific Chimeric Antigen Receptors Based on Broadly Neutralizing Antibodies. AB - Although the use of chimeric antigen receptors (CARs) based on single-chain antibodies for gene immunotherapy of cancers is increasing due to promising recent results, the earliest CAR therapeutic trials were done for HIV-1 infection in the late 1990s. This approach utilized a CAR based on human CD4 as a binding domain and was abandoned for a lack of efficacy. The growing number of HIV-1 broadly neutralizing antibodies (BNAbs) offers the opportunity to generate novel CARs that may be more active and revisit this modality for HIV-1 immunotherapy. We used sequences from seven well-defined BNAbs varying in binding sites and generated single-chain-antibody-based CARs. These CARs included 10E8, 3BNC117, PG9, PGT126, PGT128, VRC01, and X5. Each novel CAR exhibited conformationally relevant expression on the surface of transduced cells, mediated specific proliferation and killing in response to HIV-1-infected cells, and conferred potent antiviral activity (reduction of viral replication in log10 units) to transduced CD8(+) T lymphocytes. The antiviral activity of these CARs was reproducible but varied according to the strain of virus. These findings indicated that BNAbs are excellent candidates for developing novel CARs to consider for the immunotherapeutic treatment of HIV-1. IMPORTANCE: While chimeric antigen receptors (CARs) using single-chain antibodies as binding domains are growing in popularity for gene immunotherapy of cancers, the earliest human trials of CARs were done for HIV-1 infection. However, those trials failed, and the approach was abandoned for HIV-1. The only tested CAR against HIV-1 was based on the use of CD4 as the binding domain. The growing availability of HIV-1 broadly neutralizing antibodies (BNAbs) affords the opportunity to revisit gene immunotherapy for HIV-1 using novel CARs based on single-chain antibodies. Here we construct and test a panel of seven novel CARs based on diverse BNAb types and show that all these CARs are functional against HIV-1. PMID- 27226365 TI - A Role of Influenza Virus Exposure History in Determining Pandemic Susceptibility and CD8+ T Cell Responses. AB - Novel influenza viruses often cause differential infection patterns across different age groups, an effect that is defined as heterogeneous demographic susceptibility. This occurred during the A/H2N2 pandemic, when children experienced higher influenza attack rates than adults. Since the recognition of conserved epitopes across influenza subtypes by CD8(+) cytotoxic T lymphocytes (CTLs) limit influenza disease, we hypothesized that conservation of CTL antigenic peptides (Ag-p) in viruses circulating before the pH2N2-1957 may have resulted in differential CTL immunity. We compared viruses isolated in the years preceding the pandemic (1941 to 1957) to which children and adults were exposed to viruses circulating decades earlier (1918 to 1940), which could infect adults only. Consistent with phylogenetic models, influenza viruses circulating from 1941 to 1957, which infected children, shared with pH2N2 the majority (~89%) of the CTL peptides within the most immunogenic nucleoprotein, matrix 1, and polymerase basic 1, thus providing evidence for minimal pH2N2 CTL escape in children. Our study, however, identified potential CTL immune evasion from pH2N2 irrespective of age, within HLA-A*03:01(+) individuals for PB1471-L473V/N476I variants and HLA-B*15:01(+) population for NP404-414-V408I mutant. Further experiments using the murine model of B-cell-deficient mice showed that multiple influenza infections resulted in superior protection from influenza-induced morbidity, coinciding with accumulation of tissue-resident memory CD8(+) T cells in the lung. Our study suggests that protection against H2N2-1957 pandemic influenza was most likely linked to the number of influenza virus infections prior to the pandemic challenge rather than differential preexisting CTL immunity. Thus, the regimen of a CTL-based vaccine/vaccine-component may benefit from periodic boosting to achieve fully protective, asymptomatic influenza infection. IMPORTANCE: Due to a lack of cross-reactive neutralizing antibodies, children are particularly susceptible to influenza infections caused by novel viral strains. Preexisting T cell immunity directed at conserved viral regions, however, can provide protection against influenza viruses, promote rapid recovery and better clinical outcomes. When we asked whether high susceptibility of children (compared to adults) to the pandemic H2N2 influenza strain was associated with immune evasion from T-cell immunity, we found high conservation within T-cell antigenic regions in pandemic H2N2. However, the number of influenza infections prior to the challenge was linked to protective, asymptomatic infections and establishment of tissue-resident memory T cells. Our study supports development of vaccines that prime and boost T cells to elicit cross-strain protective T cells, especially tissue-resident memory T cells, for lifelong immunity against distinct influenza viruses. PMID- 27226367 TI - Notwithstanding Circumstantial Alibis, Cytotoxic T Cells Can Be Major Killers of HIV-1-Infected Cells. AB - Several experiments suggest that in the chronic phase of human immunodeficiency virus type 1 (HIV-1) infection, CD8(+) cytotoxic T lymphocytes (CTL) contribute very little to the death of productively infected cells. First, the expected life span of productively infected cells is fairly long, i.e., about 1 day. Second, this life span is hardly affected by the depletion of CD8(+) T cells. Third, the rate at which mutants escaping a CTL response take over the viral population tends to be slow. Our main result is that all these observations are perfectly compatible with killing rates that are much faster than one per day once we invoke the fact that infected cells proceed through an eclipse phase of about 1 day before they start producing virus. Assuming that the major protective effect of CTL is cytolytic, we demonstrate that mathematical models with an eclipse phase account for the data when the killing is fast and when it varies over the life cycle of infected cells. Considering the steady state corresponding to the chronic phase of the infection, we find that the rate of immune escape and the rate at which the viral load increases following CD8(+) T cell depletion should reflect the viral replication rate, rho. A meta-analysis of previous data shows that viral replication rates during chronic infection vary between 0.5 <= rho <= 1 day(-1) Balancing such fast viral replication requires killing rates that are several times larger than rho, implying that most productively infected cells would die by cytolytic effects. IMPORTANCE: Most current data suggest that cytotoxic T cells (CTL) mediate their control of human immunodeficiency virus type 1 (HIV-1) infection by nonlytic mechanisms; i.e., the data suggest that CTL hardly kill. This interpretation of these data has been based upon the general mathematical model for HIV infection. Because this model ignores the eclipse phase between the infection of a target cell and the start of viral production by that cell, we reanalyze the same data sets with novel models that do account for the eclipse phase. We find that the data are perfectly consistent with lytic control by CTL and predict that most productively infected cells are killed by CTL. Because the killing rate should balance the viral replication rate, we estimate both parameters from a large set of published experiments in which CD8(+) T cells were depleted in simian immunodeficiency virus (SIV)-infected monkeys. This confirms that the killing rate can be much faster than is currently appreciated. PMID- 27226368 TI - Effects of MF59 Adjuvant on Induction of Isotype-Switched IgG Antibodies and Protection after Immunization with T-Dependent Influenza Virus Vaccine in the Absence of CD4+ T Cells. AB - CD4(+) T cells play a central role in orchestrating adaptive immunity. To better understand the roles of CD4(+) T cells in the effects of adjuvants, we investigated the efficacy of a T-dependent influenza virus split vaccine with MF59 or alum in CD4 knockout (CD4KO) and wild-type (WT) mice. CD4(+) T cells were required for the induction of IgG antibody responses to the split vaccine and the effects of alum adjuvant. In contrast, MF59 was found to be highly effective in raising isotype-switched IgG antibodies to a T-dependent influenza virus split vaccine in CD4KO mice or CD4-depleted WT mice equivalent to those in intact WT mice, thus overcoming the deficiency of CD4(+) T cells in helping B cells and inducing immunity against influenza virus. Vaccination with the MF59-adjuvanted influenza virus vaccine was able to induce protective CD8(+) T cells and long lived antibody-secreting cells in CD4KO mice. The effects of MF59 adjuvant in CD4KO mice might be associated with uric acid, inflammatory cytokines, and the recruitment of multiple immune cells at the injection site, but their cellularity and phenotypes were different from those in WT mice. These findings suggest a new paradigm of CD4-independent adjuvant mechanisms, providing the rationales to improve vaccine efficacy in infants, the elderly, immunocompromised patients, as well as healthy adults. IMPORTANCE: MF59-adjuvanted influenza vaccines were licensed for human vaccination, but the detailed mechanisms are not fully elucidated. CD4(+) T cells are required to induce antibody isotype switching and long-term memory responses. In contrast, we discovered that MF59 was highly effective in inducing isotype-switched IgG antibodies and long-term protective immune responses to a T-dependent influenza vaccine independent of CD4(+) T cells. These findings are highly significant for the following reasons: (i) MF59 can overcome a defect of CD4(+) T cells in inducing protective immunity to vaccination with a T-dependent influenza virus vaccine; (ii) a CD4-independent pathway can be an alternative mechanism for certain adjuvants such as MF59; and (iii) this study has significant implications for improving vaccine efficacies in young children, the elderly, and immunocompromised populations. PMID- 27226369 TI - Generating Bona Fide Mammalian Prions with Internal Deletions. AB - Mammalian prions are PrP proteins with altered structures causing transmissible fatal neurodegenerative diseases. They are self-perpetuating through formation of beta-sheet-rich assemblies that seed conformational change of cellular PrP. Pathological PrP usually forms an insoluble protease-resistant core exhibiting beta-sheet structures but no more alpha-helical content, loosing the three alpha helices contained in the correctly folded PrP. The lack of a high-resolution prion structure makes it difficult to understand the dynamics of conversion and to identify elements of the protein involved in this process. To determine whether completeness of residues within the protease-resistant domain is required for prions, we performed serial deletions in the helix H2 C terminus of ovine PrP, since this region has previously shown some tolerance to sequence changes without preventing prion replication. Deletions of either four or five residues essentially preserved the overall PrP structure and mutant PrP expressed in RK13 cells were efficiently converted into bona fide prions upon challenge by three different prion strains. Remarkably, deletions in PrP facilitated the replication of two strains that otherwise do not replicate in this cellular context. Prions with internal deletion were self-propagating and de novo infectious for naive homologous and wild-type PrP-expressing cells. Moreover, they caused transmissible spongiform encephalopathies in mice, with similar biochemical signatures and neuropathologies other than the original strains. Prion convertibility and transfer of strain-specific information are thus preserved despite shortening of an alpha-helix in PrP and removal of residues within prions. These findings provide new insights into sequence/structure/infectivity relationship for prions. IMPORTANCE: Prions are misfolded PrP proteins that convert the normal protein into a replicate of their own abnormal form. They are responsible for invariably fatal neurodegenerative disorders. Other aggregation prone proteins appear to have a prion-like mode of expansion in brains, such as in Alzheimer's or Parkinson's diseases. To date, the resolution of prion structure remains elusive. Thus, to genetically define the landscape of regions critical for prion conversion, we tested the effect of short deletions. We found that, surprisingly, removal of a portion of PrP, the C terminus of alpha-helix H2, did not hamper prion formation but generated infectious agents with an internal deletion that showed characteristics essentially similar to those of original infecting strains. Thus, we demonstrate that completeness of the residues inside prions is not necessary for maintaining infectivity and the main strain-specific information, while reporting one of the few if not the only bona fide prions with an internal deletion. PMID- 27226370 TI - Targeted Mutagenesis of Guinea Pig Cytomegalovirus Using CRISPR/Cas9-Mediated Gene Editing. AB - The cytomegaloviruses (CMVs) are among the most genetically complex mammalian viruses, with viral genomes that often exceed 230 kbp. Manipulation of cytomegalovirus genomes is largely performed using infectious bacterial artificial chromosomes (BACs), which necessitates the maintenance of the viral genome in Escherichia coli and successful reconstitution of virus from permissive cells after transfection of the BAC. Here we describe an alternative strategy for the mutagenesis of guinea pig cytomegalovirus that utilizes clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) mediated genome editing to introduce targeted mutations to the viral genome. Transient transfection and drug selection were used to restrict lytic replication of guinea pig cytomegalovirus to cells that express Cas9 and virus-specific guide RNA. The result was highly efficient editing of the viral genome that introduced targeted insertion or deletion mutations to nonessential viral genes. Cotransfection of multiple virus-specific guide RNAs or a homology repair template was used for targeted, markerless deletions of viral sequence or to introduce exogenous sequence by homology-driven repair. As CRISPR/Cas9 mutagenesis occurs directly in infected cells, this methodology avoids selective pressures that may occur during propagation of the viral genome in bacteria and may facilitate genetic manipulation of low-passage or clinical CMV isolates. IMPORTANCE: The cytomegalovirus genome is complex, and viral adaptations to cell culture have complicated the study of infection in vivo Recombineering of viral bacterial artificial chromosomes enabled the study of recombinant cytomegaloviruses. Here we report the development of an alternative approach using CRISPR/Cas9-based mutagenesis in guinea pig cytomegalovirus, a small-animal model of congenital cytomegalovirus disease. CRISPR/Cas9 mutagenesis can introduce the same types of mutations to the viral genome as bacterial artificial chromosome recombineering but does so directly in virus-infected cells. CRISPR/Cas9 mutagenesis is not dependent on a bacterial intermediate, and defined viral mutants can be recovered after a limited number of viral genome replications, minimizing the risk of spontaneous mutation. PMID- 27226371 TI - MAVS Expressed by Hematopoietic Cells Is Critical for Control of West Nile Virus Infection and Pathogenesis. AB - West Nile virus (WNV) is the most important cause of epidemic encephalitis in North America. Innate immune responses, which are critical for control of WNV infection, are initiated by signaling through pathogen recognition receptors, RIG I and MDA5, and their downstream adaptor molecule, MAVS. Here, we show that a deficiency of MAVS in hematopoietic cells resulted in increased mortality and delayed WNV clearance from the brain. In Mavs(-/-) mice, a dysregulated immune response was detected, characterized by a massive influx of macrophages and virus specific T cells into the infected brain. These T cells were polyfunctional and lysed peptide-pulsed target cells in vitro However, virus-specific T cells in the brains of infected Mavs(-/-) mice exhibited lower functional avidity than those in wild-type animals, and even virus-specific memory T cells generated by prior immunization could not protect Mavs(-/-) mice from WNV-induced lethal disease. Concomitant with ineffective virus clearance, macrophage numbers were increased in the Mavs(-/-) brain, and both macrophages and microglia exhibited an activated phenotype. Microarray analyses of leukocytes in the infected Mavs(-/-) brain showed a preferential expression of genes associated with activation and inflammation. Together, these results demonstrate a critical role for MAVS in hematopoietic cells in augmenting the kinetics of WNV clearance and thereby preventing a dysregulated and pathogenic immune response. IMPORTANCE: West Nile virus (WNV) is the most important cause of mosquito-transmitted encephalitis in the United States. The innate immune response is known to be critical for protection in infected mice. Here, we show that expression of MAVS, a key adaptor molecule in the RIG-I-like receptor RNA-sensing pathway, in hematopoietic cells is critical for protection from lethal WNV infection. In the absence of MAVS, there is a massive infiltration of myeloid cells and virus-specific T cells into the brain and overexuberant production of proinflammatory cytokines. These results demonstrate the important role that MAVS expression in hematopoietic cells has in regulating the inflammatory response in the WNV-infected brain. PMID- 27226372 TI - Viral Evasion and Manipulation of Host RNA Quality Control Pathways. AB - Viruses have evolved diverse strategies to maximize the functional and coding capacities of their genetic material. Individual viral RNAs are often used as substrates for both replication and translation and can contain multiple, sometimes overlapping open reading frames. Further, viral RNAs engage in a wide variety of interactions with both host and viral proteins to modify the activities of important cellular factors and direct their own trafficking, packaging, localization, stability, and translation. However, adaptations increasing the information density of small viral genomes can have unintended consequences. In particular, viral RNAs have developed features that mark them as potential targets of host RNA quality control pathways. This minireview focuses on ways in which viral RNAs run afoul of the cellular mRNA quality control and decay machinery, as well as on strategies developed by viruses to circumvent or exploit cellular mRNA surveillance. PMID- 27226373 TI - Glutathione Depletion Is Linked with Th2 Polarization in Mice with a Retrovirus Induced Immunodeficiency Syndrome, Murine AIDS: Role of Proglutathione Molecules as Immunotherapeutics. AB - Injection of the LP-BM5 murine leukemia virus into mice causes murine AIDS, a disease characterized by many dysfunctions of immunocompetent cells. To establish whether the disease is characterized by glutathione imbalance, reduced glutathione (GSH) and cysteine were quantified in different organs. A marked redox imbalance, consisting of GSH and/or cysteine depletion, was found in the lymphoid organs, such as the spleen and lymph nodes. Moreover, a significant decrease in cysteine and GSH levels in the pancreas and brain, respectively, was measured at 5 weeks postinfection. The Th2 immune response was predominant at all times investigated, as revealed by the expression of Th1/Th2 cytokines. Furthermore, investigation of the activation status of peritoneal macrophages showed that the expression of genetic markers of alternative activation, namely, Fizz1, Ym1, and Arginase1, was induced. Conversely, expression of inducible nitric oxide synthase, a marker of classical activation of macrophages, was detected only when Th1 cytokines were expressed at high levels. In vitro studies revealed that during the very early phases of infection, GSH depletion and the downregulation of interleukin-12 (IL-12) p40 mRNA were correlated with the dose of LP-BM5 used to infect the macrophages. Treatment of LP-BM5-infected mice with N-(N-acetyl-l-cysteinyl)-S-acetylcysteamine (I-152), an N-acetyl-cysteine supplier, restored GSH/cysteine levels in the organs, reduced the expression of alternatively activated macrophage markers, and increased the level of gamma interferon production, while it decreased the levels of Th2 cytokines, such as IL 4 and IL-5. Our findings thus establish a link between GSH deficiency and Th1/Th2 disequilibrium in LP-BM5 infection and indicate that I-152 can be used to restore the GSH level and a balanced Th1/Th2 response in infected mice. IMPORTANCE: The first report of an association between Th2 polarization and alteration of the redox state in LP-BM5 infection is presented. Moreover, it provides evidence that LP-BM5 infection causes a decrease in the thiol content of peritoneal macrophages, which can influence IL-12 production. The restoration of GSH levels by GSH-replenishing molecules can represent a new therapeutic avenue to fight this retroviral infection, as it reestablishes the Th1/Th2 balance. Immunotherapy based on the use of pro-GSH molecules would permit LP-BM5 infection and probably all those viral infections characterized by GSH deficiency and a Th1/Th2 imbalance to be more effectively combated. PMID- 27226374 TI - Human Cytomegalovirus pUL93 Links Nucleocapsid Maturation and Nuclear Egress. AB - Human cytomegalovirus (HCMV) pUL93 and pUL77 are both essential for virus growth, but their functions in the virus life cycle remain mostly unresolved. Homologs of pUL93 and pUL77 in herpes simplex virus 1 (HSV-1) and pseudorabies virus (PRV) are known to interact to form a complex at capsid vertices known as the capsid vertex-specific component (CVSC), which likely stabilizes nucleocapsids during virus maturation and also aids in nuclear egress. In herpesviruses, nucleocapsids assemble and partially mature in nuclear replication compartments and then travel to the inner nuclear membrane (INM) for nuclear egress. The factors governing the recruitment of nucleocapsids to the INM are not known. Kinetic analysis of pUL93 demonstrates that this protein is expressed late during infection and localizes primarily to the nucleus of infected cells. pUL93 associates with both virions and capsids and interacts with the components of the nuclear egress complex (NEC), namely, pUL50, pUL53, and pUL97, during infection. Also, multiple regions in pUL93 can independently interact with pUL77, which has been shown to help retain viral DNA during capsid assembly. These studies, combined with our earlier report of an essential role of pUL93 in viral DNA packaging, indicate that pUL93 serves as an important link between nucleocapsid maturation and nuclear egress. IMPORTANCE: HCMV causes life-threatening disease and disability in immunocompromised patients and congenitally infected newborns. In this study, we investigated the functions of HCMV essential tegument protein pUL93 and determined that it interacts with the components of the nuclear egress complex, namely, pUL50, pUL53, and pUL97. We also found that pUL93 specifically interacts with pUL77, which helps retain viral DNA during capsid assembly. Together, our data point toward an important role of pUL93 in linking virus maturation to nuclear egress. In addition to expanding our knowledge of the process of HCMV maturation, information from these studies will also be utilized to develop new antiviral therapies. PMID- 27226375 TI - A Genome-Wide RNA Interference Screen Identifies a Role for Wnt/beta-Catenin Signaling during Rift Valley Fever Virus Infection. AB - Rift Valley fever virus (RVFV) is an arbovirus within the Bunyaviridae family capable of causing serious morbidity and mortality in humans and livestock. To identify host factors involved in bunyavirus replication, we employed genome-wide RNA interference (RNAi) screening and identified 381 genes whose knockdown reduced infection. The Wnt pathway was the most represented pathway when gene hits were functionally clustered. With further investigation, we found that RVFV infection activated Wnt signaling, was enhanced when Wnt signaling was preactivated, was reduced with knockdown of beta-catenin, and was blocked using Wnt signaling inhibitors. Similar results were found using distantly related bunyaviruses La Crosse virus and California encephalitis virus, suggesting a conserved role for Wnt signaling in bunyaviral infection. We propose a model where bunyaviruses activate Wnt-responsive genes to regulate optimal cell cycle conditions needed to promote efficient viral replication. The findings in this study should aid in the design of efficacious host-directed antiviral therapeutics. IMPORTANCE: RVFV is a mosquito-borne bunyavirus that is endemic to Africa but has demonstrated a capacity for emergence in new territories (e.g., the Arabian Peninsula). As a zoonotic pathogen that primarily affects livestock, RVFV can also cause lethal hemorrhagic fever and encephalitis in humans. Currently, there are no treatments or fully licensed vaccines for this virus. Using high-throughput RNAi screening, we identified canonical Wnt signaling as an important host pathway regulating RVFV infection. The beneficial role of Wnt signaling was observed for RVFV, along with other disparate bunyaviruses, indicating a conserved bunyaviral replication mechanism involving Wnt signaling. These studies supplement our knowledge of the fundamental mechanisms of bunyavirus infection and provide new avenues for countermeasure development against pathogenic bunyaviruses. PMID- 27226376 TI - Tegument Protein ORF45 Plays an Essential Role in Virion Morphogenesis of Murine Gammaherpesvirus 68. AB - Tegument proteins play critical roles in herpesvirus morphogenesis. ORF45 is a conserved tegument protein of gammaherpesviruses; however, its role in virion morphogenesis is largely unknown. In this work, we determined the ultrastructural localization of murine gammaherpesvirus 68 (MHV-68) ORF45 and found that this protein was incorporated into virions around the site of host-derived vesicles. Notably, the absence of ORF45 inhibited nucleocapsid egress and blocked cytoplasmic virion maturation, demonstrating that ORF45 is essential for MHV-68 virion morphogenesis. PMID- 27226377 TI - Critical Role of the PA-X C-Terminal Domain of Influenza A Virus in Its Subcellular Localization and Shutoff Activity. AB - PA-X is a recently identified influenza virus protein that is composed of the PA N-terminal 191 amino acids and unique C-terminal 41 or 61 residues. We and others showed that PA-X has a strong ability to suppress host protein synthesis via host mRNA decay, which is mediated by endonuclease activity in its N-terminal domain (B. W. Jagger, H. M. Wise, J. C. Kash, K. A. Walters, N. M. Wills, Y. L. Xiao, R. L. Dunfee, L. M. Schwartzman, A. Ozinsky, G. L. Bell, R. M. Dalton, A. Lo, S. Efstathiou, J. F. Atkins, A. E. Firth, J. K. Taubenberger, and P. Digard, 2012, Science 337:199-204, http://dx.doi.org/10.1126/science.1222213, and E. A. Desmet, K. A. Bussey, R. Stone, and T. Takimoto, 2013, J Virol 87:3108-3118, http://dx.doi.org/10.1128/JVI.02826-12). However, the mechanism of host mRNA degradation, especially where and how PA-X targets mRNAs, has not been analyzed. In this study, we determined the localization of PA-X and the role of the C terminal unique region in shutoff activity. Quantitative subcellular localization analysis revealed that PA-X was located equally in both cytoplasm and nucleus. By characterizing a series of PA-X C-terminal deletion mutants, we found that the first 9 amino acids were sufficient for nuclear localization, but an additional 6 residues were required to induce the maximum shutoff activity observed with intact PA-X. Importantly, forced nuclear localization of the PA-X C-terminal deletion mutant enhanced shutoff activity, highlighting the ability of nuclear PA X to degrade host mRNAs more efficiently. However, PA-X also inhibited luciferase expression from transfected mRNAs synthesized in vitro, suggesting that PA-X also degrades mRNAs in the cytoplasm. Among the basic amino acids in the PA-X C terminal region, 3 residues, 195K, 198K, and 199R, were identified as key residues for inducing host shutoff and nuclear localization. Overall, our data indicate a critical role for the 15 residues in the PA-X C-terminal domain in degrading mRNAs in both the cytoplasm and nucleus. IMPORTANCE: Influenza A viruses express PA-X proteins to suppress global host gene expression, including host antiviral genes, to allow efficient viral replication in infected cells. However, little is known about how PA-X induces host shutoff. In this study, we showed that PA-X localized equally in both the cytoplasm and nucleus of the cells, but the nuclear localization of PA-X mediated by its C-terminal region has a significant impact on shutoff activity. Three basic residues at the C-terminal region play a critical role in nuclear localization, but additional basic residues were required for maximum shutoff activity. Our findings indicate that PA-X targets and degrades mRNAs in both the nucleus and cytoplasm, and that the first 15 residues of the PA-X unique C-terminal region play a critical role in shutoff activity. PMID- 27226378 TI - Deep Sequencing of the HIV-1 env Gene Reveals Discrete X4 Lineages and Linkage Disequilibrium between X4 and R5 Viruses in the V1/V2 and V3 Variable Regions. AB - HIV-1 requires the CD4 receptor and a coreceptor (CCR5 [R5 phenotype] or CXCR4 [X4 phenotype]) to enter cells. Coreceptor tropism can be assessed by either phenotypic or genotypic analysis, the latter using bioinformatics algorithms to predict tropism based on the env V3 sequence. We used the Primer ID sequencing strategy with the MiSeq sequencing platform to reveal the structure of viral populations in the V1/V2 and C2/V3 regions of the HIV-1 env gene in 30 late-stage and 6 early-stage subjects. We also used endpoint dilution PCR followed by cloning of env genes to create pseudotyped virus to explore the link between genotypic predictions and phenotypic assessment of coreceptor usage. We found out that the most stringently sequence-based calls of X4 variants (Geno2Pheno false positive rate [FPR] of <=2%) formed distinct lineages within the viral population, and these were detected in 24 of 30 late-stage samples (80%), which was significantly higher than what has been seen previously by using other approaches. Non-X4 lineages were not skewed toward lower FPR scores in X4 containing populations. Phenotypic assays showed that variants with an intermediate FPR (2 to 20%) could be either X4/dual-tropic or R5 variants, although the X4 variants made up only about 25% of the lineages with an FPR of <10%, and these variants carried a distinctive sequence change. Phylogenetic analysis of both the V1/V2 and C2/V3 regions showed evidence of recombination within but very little recombination between the X4 and R5 lineages, suggesting that these populations are genetically isolated. IMPORTANCE: Primer ID sequencing provides a novel approach to study genetic structures of viral populations. X4 variants may be more prevalent than previously reported when assessed by using next-generation sequencing (NGS) and with a greater depth of sampling than single genome amplification (SGA). Phylogenetic analysis to identify lineages of sequences with intermediate FPR values may provide additional information for accurately predicting X4 variants by using V3 sequences. Limited recombination occurs between X4 and R5 lineages, suggesting that X4 and R5 variants are genetically isolated and may be replicating in different cell types or that X4/R5 recombinants have reduced fitness. PMID- 27226379 TI - Release of Infectious Hepatitis C Virus from Huh7 Cells Occurs via a trans-Golgi Network-to-Endosome Pathway Independent of Very-Low-Density Lipoprotein Secretion. AB - The release of infectious hepatitis C virus (HCV) particles from infected cells remains poorly characterized. We previously demonstrated that virus release is dependent on the endosomal sorting complex required for transport (ESCRT). Here, we show a critical role of trans-Golgi network (TGN)-endosome trafficking during the assembly, but principally the secretion, of infectious virus. This was demonstrated by both small interfering RNA (siRNA)-mediated silencing of TGN associated adaptor proteins and a panel of dominant negative (DN) Rab GTPases involved in TGN-endosome trafficking steps. Importantly, interfering with factors critical for HCV release did not have a concomitant effect on secretion of triglycerides, ApoB, or ApoE, indicating that particles are likely released from Huh7 cells via pathways distinct from that of very-low-density lipoprotein (VLDL). Finally, we show that HCV NS2 perturbs TGN architecture, redistributing TGN membranes to closely associate with HCV core protein residing on lipid droplets. These findings support the notion that HCV hijacks TGN-endosome trafficking to facilitate particle assembly and release. Moreover, although essential for assembly and infectivity, the trafficking of mature virions is seemingly independent of host lipoproteins. IMPORTANCE: The mechanisms by which infectious hepatitis C virus particles are assembled and released from the cell are poorly understood. We show that the virus subverts host cell trafficking pathways to effect the release of virus particles and disrupts the structure of the Golgi apparatus, a key cellular organelle involved in secretion. In addition, we demonstrate that the mechanisms used by the virus to exit the cell are distinct from those used by the cell to release lipoproteins, suggesting that the virus effects a unique modification to cellular trafficking pathways. PMID- 27226380 TI - Linguistic Validation of an Interactive Communication Tool to Help French Speaking Children Express Their Cancer Symptoms. AB - Sisom is an interactive tool designed to help children communicate their cancer symptoms. Important design issues relevant to other cancer populations remain unexplored. This single-site, descriptive, qualitative study was conducted to linguistically validate Sisom with a group of French-speaking children with cancer, their parents, and health care professionals. The linguistic validation process included 6 steps: (1) forward translation, (2) backward translation, (3) patient testing, (4) production of a Sisom French version, (5) patient testing this version, and (6) production of the final Sisom French prototype. Five health care professionals and 10 children and their parents participated in the study. Health care professionals oversaw the translation process providing clinically meaningful suggestions. Two rounds of patient testing, which included parental participation, resulted in the following themes: (1) comprehension, (2) suggestions for improving the translations, (3) usability, (4) parental engagement, and (5) overall impression. Overall, Sisom was well received by participants who were forthcoming with input and suggestions for improving the French translations. Our proposed methodology may be replicated for the linguistic validation of other e-health tools. PMID- 27226381 TI - Synthesis and determination of absolute configuration of a non-peptidic alphavbeta6 integrin antagonist for the treatment of idiopathic pulmonary fibrosis. AB - A diastereoselective synthesis of (S)-3-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl) 4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1 yl)butanoic acid (1), a potential therapeutic agent for the treatment of Idiopathic Pulmonary Fibrosis, which is currently undergoing Phase I clinical trials is reported. The key steps in the synthesis involved alkylation of 2 methylnaphthyridine with (R)-N-Boc-3-(iodomethyl)-pyrrolidine, and an asymmetric Rh-catalysed addition of an arylboronic acid to a 4-(N-pyrrolidinyl)crotonate ester. The overall yield of the seven linear step synthesis was 8% and the product was obtained in >99.5% ee proceeding with 80% de. The absolute configuration of 1 was established by an alternative asymmetric synthesis involving alkylation of an arylacetic acid using Evans oxazolidinone chemistry, acylation using the resulting 2-arylsuccinic acid, and reduction. The absolute configuration of the benzylic asymmetric centre was established as (S). PMID- 27226382 TI - Estimating peak oxygen uptake based on postexercise measurements in swimming. AB - To assess the validity of postexercise measurements in estimating peak oxygen uptake (VO2peak) in swimming, we compared oxygen uptake (VO2) measurements during supramaximal exercise with various commonly adopted methods, including a recently developed heart rate - VO2 modelling procedure. Thirty-one elite swimmers performed a 200-m maximal swim where VO2 was measured breath-by-breath using a portable gas analyzer connected to a respiratory snorkel, 1 min before, during, and 3 min postexercise. VO2peak(-20-0) was the average of the last 20 s of effort. The following postexercise measures were compared: (i) first 20-s average (VO2peak(0-20)); (ii) linear backward extrapolation (BE) of the first 20 s (BE(20)), 30 s, and 3 * 20-, 4 * 20-, and 3 or 4 * 20-s averages; (iii) semilogarithmic BE at 20 s (LOG(20)) and at the other same time intervals as in linear BE; and (iv) predicted VO2peak using mathematical modelling (pVO2(0-20)]. Repeated-measures ANOVA and post-hoc Bonferroni tests compared VO2peak (criterion) and each estimated value. Pearson's coefficient of determination (r(2)) was used to assess correlation. Exercise VO2peak(-20-0) (mean +/- SD 3531 +/- 738 mL.min(-1)) was not different (p > 0.30) from pVO2(0-20) (3571 +/- 735 mL.min(-1)), BE(20) (3617 +/- 708 mL.min(-1)), or LOG(20) (3627 +/- 746 mL.min( 1)). pVO2(0-20) was very strongly correlated with exercise VO2peak (r(2) = 0.962; p < 0.001), and showed a low standard error of the estimate (146 mL.min(-1), 4.1%) and the lowest mean difference (40 mL.min(-1); 1.1%). We confirm that the new modelling procedure based on postexercise VO2 and heart rate measurements is a valid and accurate procedure for estimating VO2peak in swimmers and avoids the estimation bias produced by other methods. PMID- 27226383 TI - A ciliate memorizes the geometry of a swimming arena. AB - Previous studies on adaptive behaviour in single-celled organisms have given hints to the origin of their memorizing capacity. Here we report evidence that a protozoan ciliate Tetrahymena has the capacity to learn the shape and size of its swimming space. Cells confined in a small water droplet for a short period were found to recapitulate circular swimming trajectories upon release. The diameter of the circular trajectories and their duration reflected the size of the droplet and the period of confinement. We suggest a possible mechanism for this adaptive behaviour based on a Ca(2+) channel. In our model, repeated collisions with the walls of a confining droplet result in a slow rise in intracellular calcium that leads to a long-term increase in the reversal frequency of the ciliary beat. PMID- 27226384 TI - Correction to 'Contaminant adhesion (aerial/ground biofouling) on the skin of a gecko'. PMID- 27226385 TI - The impact of the revolution in hepatitis C treatment on hepatocellular carcinoma. AB - Hepatitis C infection represents a global health problem affecting ~200 million chronically infected patients worldwide. Owing to the development of a fibrogenic and inflammatory micromilieu in the liver, hepatitis C virus (HCV)-infected patients are at a high risk of developing fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The advent of direct-acting antiviral agents (DAAs), however, has spurred a revolution in the treatment of HCV patients with sustained viral response (SVR) rates exceeding 90% in real-life settings. Recent clinical trials suggest that these novel treatments will not only alter the epidemiology of HCV infection but also the incidence of HCV-induced complications including hepatic decompensation, liver transplantation and hepatocarcinogenesis. Here, we summarize data from clinical trials carried out in HCV patients with compensated and decompensated cirrhosis and analyze the impact of viral clearance on HCC development and treatment. Finally, we review and discuss current and future treatment options of HCV patients with HCC in pre- and post-transplantation settings. PMID- 27226386 TI - A photoredox catalyzed radical-radical coupling reaction: facile access to multi substituted nitrogen heterocycles. AB - Visible light induced photoredox catalysis is an efficient method for radical activation. Herein, we report the photoredox catalysis involving an intramolecular radical-radical coupling reaction that proceeds through a biradical intermediate. This protocol represents a new synthetic route to construct multi-substituted N-heterocycles. Four, five and six-membered N heterocyclic structures with a quaternary carbon center are accessible under mild conditions. PMID- 27226387 TI - Biochemical and Cellular Characterization and Inhibitor Discovery of Pseudomonas aeruginosa 15-Lipoxygenase. AB - Pseudomonas aeruginosa is an opportunistic pathogen that can cause nosocomial and chronic infections in immunocompromised patients. P. aeruginosa secretes a lipoxygenase, LoxA, but the biological role of this enzyme is currently unknown. LoxA is poorly similar in sequence to both soybean LOX-1 (s15-LOX-1) and human 15 LOX-1 (37 and 39%, respectively) yet has kinetics comparably fast versus those of s15-LOX-1 (at pH 6.5, Kcat = 181 +/- 6 s(-1) and Kcat/KM = 16 +/- 2 MUM(-1) s( 1)). LoxA is capable of efficiently catalyzing the peroxidation of a broad range of free fatty acid (FA) substrates (e.g., AA and LA) with high positional specificity, indicating a 15-LOX. Its mechanism includes hydrogen atom abstraction [a kinetic isotope effect (KIE) of >30], yet LoxA is a poor catalyst against phosphoester FAs, suggesting that LoxA is not involved in membrane decomposition. LoxA also does not react with 5- or 15-HETEs, indicating poor involvement in lipoxin production. A LOX high-throughput screen of the LOPAC library yielded a variety of low-micromolar inhibitors; however, none selectively targeted LoxA over the human LOX isozymes. With respect to cellular activity, the level of LoxA expression is increased when P. aeruginosa undergoes the transition to a biofilm mode of growth, but LoxA is not required for biofilm growth on abiotic surfaces. However, LoxA does appear to be required for biofilm growth in association with the host airway epithelium, suggesting a role for LoxA in mediating bacterium-host interactions during colonization. PMID- 27226388 TI - Indications for Insulin Pump Therapy in Type 1 Diabetes and Associations With Glycemic Control. AB - BACKGROUND: Real-world data regarding indications for use of insulin pump remain sparse. We investigated characteristics among individuals with type 1 diabetes (T1D) in relation to indication for use of insulin pump (CSII). Comparison was made with T1D subjects using multiple daily injections (MDI). METHODS: We included all individuals with T1D who had at least 1 registration in the National Diabetes Register during 2014-2015. Among 46 874 individuals, we excluded 2350 due to missing data. We examined 35 725 on MDI and 8799 on CSII regarding characteristics in relation to insulin delivery method, as well as association between insulin delivery and glycemic control (HbA1c) and presence of albuminuria. RESULTS: Unadjusted mean (SD) HbA1c was 63.84 (15.07) mmol/mol (7.99 [1.38]%) and 63.75 (13.19) mmol/mol (7.99 [1.21]%) in the MDI and CSII group, respectively. MDI and CSII users were on average 48.8 and 41.5 years old, respectively. MDI users were on average 26 years old and CSII users 17 years old at the time of diabetes diagnosis. Overall, a higher proportion of CSII users were females (53.5%). As compared with MDI, use of CSII was associated with up to 7.84 mmol/mol (0.72%) lower HbA1c in a multivariable adjusted model. Use of CSII was, however, not associated with risk of having albuminuria. CONCLUSIONS: CSII was used more frequently in younger individuals, early-onset diabetes, and problematic glycemic control. The use of CSII was associated with lower HbA1c among CSII users except from those who started CSII due to high HbA1c. PMID- 27226389 TI - 2016 Consensus statement on return to sport from the First World Congress in Sports Physical Therapy, Bern. AB - Deciding when to return to sport after injury is complex and multifactorial-an exercise in risk management. Return to sport decisions are made every day by clinicians, athletes and coaches, ideally in a collaborative way. The purpose of this consensus statement was to present and synthesise current evidence to make recommendations for return to sport decision-making, clinical practice and future research directions related to returning athletes to sport. A half day meeting was held in Bern, Switzerland, after the First World Congress in Sports Physical Therapy. 17 expert clinicians participated. 4 main sections were initially agreed upon, then participants elected to join 1 of the 4 groups-each group focused on 1 section of the consensus statement. Participants in each group discussed and summarised the key issues for their section before the 17-member group met again for discussion to reach consensus on the content of the 4 sections. Return to sport is not a decision taken in isolation at the end of the recovery and rehabilitation process. Instead, return to sport should be viewed as a continuum, paralleled with recovery and rehabilitation. Biopsychosocial models may help the clinician make sense of individual factors that may influence the athlete's return to sport, and the Strategic Assessment of Risk and Risk Tolerance framework may help decision-makers synthesise information to make an optimal return to sport decision. Research evidence to support return to sport decisions in clinical practice is scarce. Future research should focus on a standardised approach to defining, measuring and reporting return to sport outcomes, and identifying valuable prognostic factors for returning to sport. PMID- 27226391 TI - A Legal Framework to Support Development and Assessment of Digital Health Services. AB - BACKGROUND: Digital health services empower people to track, manage, and improve their own health and quality of life while delivering a more personalized and precise health care, at a lower cost and with higher efficiency and availability. Essential for the use of digital health services is that the treatment of any personal data is compatible with the Patient Data Act, Personal Data Act, and other applicable privacy laws. OBJECTIVE: The aim of this study was to develop a framework for legal challenges to support designers in development and assessment of digital health services. METHODS: A purposive sampling, together with snowball recruitment, was used to identify stakeholders and information sources for organizing, extending, and prioritizing the different concepts, actors, and regulations in relation to digital health and health-promoting digital systems. The data were collected through structured interviewing and iteration, and 3 different cases were used for face validation of the framework. RESULTS: A framework for assessing the legal challenges in developing digital health services (Legal Challenges in Digital Health [LCDH] Framework) was created and consists of 6 key questions to be used to evaluate a digital health service according to current legislation. CONCLUSIONS: Structured discussion about legal challenges in relation to health-promoting digital services can be enabled by a constructive framework to investigate, assess, and verify the digital service according to current legislation. The LCDH Framework developed in this study proposes such a framework and can be used in prospective evaluation of the relationship of a potential health-promoting digital service with the existing laws and regulations. PMID- 27226390 TI - First-in-class small molecule potentiators of cancer virotherapy. AB - The use of engineered viral strains such as gene therapy vectors and oncolytic viruses (OV) to selectively destroy cancer cells is poised to make a major impact in the clinic and revolutionize cancer therapy. In particular, several studies have shown that OV therapy is safe and well tolerated in humans and can infect a broad range of cancers. Yet in clinical studies OV therapy has highly variable response rates. The heterogeneous nature of tumors is widely accepted to be a major obstacle for OV therapeutics and highlights a need for strategies to improve viral replication efficacy. Here, we describe the development of a new class of small molecules for selectively enhancing OV replication in cancer tissue. Medicinal chemistry studies led to the identification of compounds that enhance multiple OVs and gene therapy vectors. Lead compounds increase OV growth up to 2000-fold in vitro and demonstrate remarkable selectivity for cancer cells over normal tissue ex vivo and in vivo. These small molecules also demonstrate enhanced stability with reduced electrophilicity and are highly tolerated in animals. This pharmacoviral approach expands the scope of OVs to include resistant tumors, further potentiating this transformative therapy. It is easily foreseeable that this approach can be applied to therapeutically enhance other attenuated viral vectors. PMID- 27226392 TI - A Preclinical Study of an Implanted Device in the Pulmonary Veins, Intended for the Treatment of Atrial Fibrillation in an Ovine Model. AB - BACKGROUND: Atrial fibrillation is the most frequent arrhythmia in adults of which the interventional cure is hampered by high recurrence rates. Recurrence after ablation is due to an incomplete isolation of the pulmonary veins. A new ablation technique was performed, in the antra of ovine pulmonary veins, by device implantation, which was heated through a wireless heat-generating system. METHODS AND RESULTS: Implants were placed transatrially in the pulmonary veins of sheep. Using a wireless heating system, the energy was afterward transferred through wires to the implanted device according to a defined protocol. The position of the implant and the applied lesions were macroscopically evaluated. Samples of the ablated tissue of the atrio-pulmonary vein junction were histologically and immunohistochemically examined. CONCLUSIONS: Six ablation procedures in four sheep were successfully performed without adverse cardiac reactions. Implantation of the device and the wireless heat generation was feasible. Sufficient heat was produced at the level of the antra of the pulmonary veins to create ablation lesions, which were histologically and immunohistochemically confirmed. PMID- 27226393 TI - Supramolecular Gels by Design: Towards the Development of Topical Gels for Self Delivery Application. AB - Following a supramolecular synthon approach, simple salt formation has been employed to gain access to a series of supramolecular gelators derived from the well-known non-steroidal anti-inflammatory drug (NSAID) ibuprofen. A well-studied gel-inducing supramolecular synthon, namely primary ammonium monocarboxylate (PAM), has been exploited to generate a series of PAM salts by reacting ibuprofen with various primary amines. Remarkably, all of the salts (S1-S7) thus synthesized proved to be good to moderate gelators of various polar and nonpolar solvents. Single-crystal and powder X-ray diffraction studies established the existence of the PAM synthons in the gel network, confirming the efficacy of the supramolecular synthon approach employed. Most importantly, the majority of the salts (S2, S3, S6, and S7) were capable of gelling methyl salicylate (MS), an important ingredient found in many commercial topical gels. In vitro experiments (MTT and PGE2 assays) revealed that all of the salts (except S3 and S7) were biocompatible (up to 0.5 mm concentration), and the most suited one, S6, displayed anti-inflammatory ability as good as that of the parent drug ibuprofen. A topical gel of S6 with methyl salicylate and menthol was found to be suitable for delivering the gelator drug in a self-delivery fashion in treating skin inflammation in mice. Histological studies, including immunohistology, were performed to further probe the role of the gelator drug S6 in treating inflammation. Cell imaging studies supported cellular uptake of the gelator drug in such biomedical application. PMID- 27226394 TI - The configuration of the vitreomacular interface determines the pattern of pseudophakic cystoid macular oedema. PMID- 27226395 TI - Chemistry and Biology in the Biosynthesis and Action of Thyroid Hormones. AB - Thyroid hormones (THs) are secreted by the thyroid gland. They control lipid, carbohydrate, and protein metabolism, heart rate, neural development, as well as cardiovascular, renal, and brain functions. The thyroid gland mainly produces l thyroxine (T4) as a prohormone, and 5'-deiodination of T4 by iodothyronine deiodinases generates the nuclear receptor binding hormone T3. In this Review, we discuss the basic aspects of the chemistry and biology as well as recent advances in the biosynthesis of THs in the thyroid gland, plasma transport, and internalization of THs in their target organs, in addition to the deiodination and various other enzyme-mediated metabolic pathways of THs. We also discuss thyroid hormone receptors and their mechanism of action to regulate gene expression, as well as various thyroid-related disorders and the available treatments. PMID- 27226396 TI - Synthesis of 2-Butanol by Selective Hydrogenolysis of 1,4-Anhydroerythritol over Molybdenum Oxide-Modified Rhodium-Supported Silica. AB - Rh-MoOx /SiO2 (Mo/Rh=0.13) is an effective catalyst for the hydrogenolysis of 1,4 anhydroerythritol (1,4-AHERY) and provides 2-BuOH in high yield of 51 %. This is the first report of the production of 2-BuOH from 1,4-AHERY by hydrogenolysis. 1,4-AHERY was more suitable as a starting material than erythritol because the 2 BuOH yield from erythritol was low (34 %). Based on the kinetics and comparison of reactivities of the related compounds using Rh-MoOx /SiO2 and Rh/SiO2 catalysts, the modification of Rh/SiO2 with MoOx leads to the high activity and high selectivity to 2-BuOH because of the generation of reactive hydride species and the strong adsorption of 1,4-AHERY on MoOx species. The reaction proceeds by main two routes, (I) the combination of single C-O hydrogenolysis with the desorption of intermediates, a usual route in hydrogenolysis, and (II) multiple C O hydrogenolysis without the desorption of intermediates from the active site, and the reaction mechanism for Route (II) is proposed. PMID- 27226397 TI - Photoinduced Synthesis of Dual-Emissive Tetraphenylethene-Based Dendrimers with Tunable Aggregates and Solution States Emissions. AB - Photoactive materials are actively researched, piloting breakthroughs that have enriched fundamental understanding of science, and have led to real applications. Tetraphenylethene, a photoactive molecule that is of interest from fundamental and applied perspectives, features photochemical properties that are not exploited in the design of photoactive, dual-emissive materials. Here, tetraphenylethene-based, dual-emissive dendrimers are constructed via a synthetic approach that involves a photochemical reaction that exploits the photochemistry of tetraphenylethene. These dendrimers are emissive in solution and in the aggregate state with tunable dual emissions at 368 and 469 nm. The photochemical reaction also tunes the size of the aggregates, increasing the size after UV irradiation. The reported synthetic strategy is a direct and facile approach to accessing dual-emissive macromolecules, especially tetraphenylethene-based systems for real applications. PMID- 27226398 TI - Surgical treatment of pulmonary artery aneurysm: an institutional experience and literature review. AB - OBJECTIVES: The occurrence of pulmonary artery aneurysm (PAA) is extremely rare in the clinical setting. Careful treatment should be considered because of the possibility of fatal complications including rupture, dissection, pulmonary embolism and heart failure. Our goal is to contribute a better understanding of this disease and its treatment. METHODS: Information on patients diagnosed with PAA was retrieved from the institute's database. The detailed data including aetiology, clinical presentation, diagnostic methods, operation methods and long term outcomes of the surgical cases were outlined and analysed. RESULTS: In total, 21 patients were diagnosed with PAA in Peking Union Medical College Hospital from 1980 to 2015, among whom 5 patients received surgical treatment, including 2 patients with giant PAAs. The complete remission rate of surgical cases was 80%, and the average postoperative hospital stay was 8.5 +/- 1.29 days. One postoperative death occurred due to distributive shock. CONCLUSIONS: PAAs must be seriously classified by aetiology to be treated appropriately. Patients with giant-size PAAs, and those with pulmonary hypertension, anatomical anomalies, and rapid growth and compression of neighbouring critical structures, are proper candidates for surgery. Surgical options include aneurysm repair and replacement with allogeneic/synthetic grafts, depending on the situation. Additionally, the correction of associated abnormalities should be performed simultaneously during surgery. Surgical outcomes are effective, and long-term prognoses are satisfactory. PMID- 27226399 TI - Is video-assisted thoracoscopic surgery talc pleurodesis superior to talc pleurodesis via tube thoracostomy in patients with secondary spontaneous pneumothorax? AB - A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was [in patients with secondary spontaneous pneumothorax (SSP)] is [video-assisted thoracoscopic surgery talc pleurodesis] superior to [talc pleurodesis through tube thoracostomy] in terms of [absence of recurrence and procedure morbidity]? Seventy-three papers were found using the reported search. In looking through our search strategy, we selected studies comparing both procedures and studies performing either procedures and stating their outcome, morbidity mortality and rate of recurrence. Hence, six studies and one society guideline represented the best evidence to answer the clinical question. The authors, journal, date, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Only one study compared both techniques and showed a higher length of hospital stay (14.2 vs 10.6 days; P = 0.033), higher rate of recurrence (30 vs 4.5%; P = 0.016) and higher mortality (5 vs 0%; P = 0.280) with tube thoracostomy talc pleurodesis in comparison with video-assisted thoracoscopic surgery (VATS) talc pleurodesis. Two studies looked at talc pleurodesis via tube thoracostomy (TT) alone for patients with secondary spontaneous pneumothorax (SSP). Talc pleurodesis was associated with an immediate success rate of 78.1 and 78.6%, with a short-term recurrence rate of 21.9 and 21.4%. No mortality was recorded in any study, but 1 patient (1.6%) in one study suffered from respiratory distress. No long follow-up periods were available in both studies; hence, there is no recording of long-term recurrence. Three studies looked at VATS talc pleurodesis alone in SSP patients. The procedure was associated with higher immediate success rates (90-100%) than TT pleurodesis alone with lower recurrence rates (0-10%). Average hospital stay was in the range of 3-4.7 days. Follow-up periods were 18, 22.7 and 24 months with recurrence rate ranging from 0 to 15%. No study was associated with major postoperative morbidity or in-hospital mortality. In conclusion, while there is only one study directly comparing both VATS and tube thoracostomy talc pleurodesis, the best evidence suggests that VATS talc pleurodesis for patients with secondary spontaneous pneumothorax should be considered the treatment of choice as it is associated with a higher immediate success rate, lower recurrence rate and a lower mortality than talc pleurodesis via tube thoracostomy. PMID- 27226400 TI - Functional and postoperative outcomes after preoperative exercise training in patients with lung cancer: a systematic review and meta-analysis. AB - Lung cancer is the leading cause of cancer-related death worldwide. For early stages of the disease, lung resection surgery remains the best treatment with curative intent, but significant morbidity is associated, especially among patients with poor pulmonary function and cardiorespiratory fitness. In those cases, the implementation of a preoperative exercise-based intervention could optimize patient's functional status before surgery and improve postoperative outcomes and enhance recovery. The aim of this systematic review is to provide the current body of knowledge regarding the effectiveness of a preoperative exercise-based intervention on postoperative and functional outcomes in patients with lung cancer submitted to lung resection surgery. A systematic review of the literature using CINAHL, EMBASE, MEDLINE, Pubmed, PEDro and SCOPUS was undertaken in September 2015 yielding a total of 1656 references. Two independent reviewers performed the assessment of the potentially eligible records against the inclusion criteria and finally, 21 articles were included in the review. Articles were included if they examined the effects of an exercise-based intervention on at least one of the selected outcomes: pulmonary function, (functional) exercise capacity, health-related quality of life (HRQoL) and postoperative outcomes (length of stay and postoperative complications). Fourteen studies were further selected for a meta-analysis to quantify the mean effect of the intervention and generate 95% confidence intervals (CIs) using the Cochrane Review Manager 5.0.25. For two of the outcomes included (exercise capacity and HRQoL), studies showed large heterogeneity and thus, a meta-analysis was considered inappropriate. Pulmonary function (forced vital capacity and forced expiratory volume in 1 s) was significantly enhanced after the intervention [standardized mean difference (SMD) = 0.38; 95% CI 0.14, 0.63 and SMD = 0.27, 95% CI 0.11, 0.42, respectively]. In comparison with the patients in the control groups, patients in the experimental groups spent less days in the hospital (mean difference = -4.83, 95% CI -5.9, -3.76) and had a significantly reduced risk for developing postoperative complications (risk ratios = 0.45; 95% CI 0.28, 0.74). In conclusion, preoperative exercise-based training improves pulmonary function before surgery and reduces in-hospital length of stay and postoperative complications after lung resection surgery for lung cancer. PMID- 27226401 TI - Early and late recurrence after intentional limited resection for cT1aN0M0, non small cell lung cancer: from a multi-institutional, retrospective analysis in Japan. AB - OBJECTIVES: In 2015, we reported the outcomes of patients undergoing intentional limited resection (ILR) for non-small-cell lung cancer (NSCLC) from a retrospective, multi-institutional large database in Japan. Here, we analyse the clinicopathological characteristics of the patients extracted from this database with late recurrence and compare them with those with early recurrence. METHODS: Of 1538 patients in the database with cT1aN0M0 NSCLC, 92 (6%) had recurrence. In this study, early recurrence was defined as recurrence within 5 years and late recurrence as recurrence beyond 5 years after surgery. We compared the clinicopathological characteristics and post-recurrence survival (PRS) between patients with early and late recurrence. RESULTS: Of the 92 patients with recurrence, 21 (23%) had late recurrence. Compared with the early recurrence group, there were significantly more adenocarcinomas and local recurrences in the late recurrence group (P = 0.04 for both). The 3- and 5-year PRS rates were 53 and 24%, respectively, and the median PRS period was 38 months. There were no significant differences in the PRS curves between patients with early and late recurrence (P = 0.12). Only 3 patients (0.2%) had recurrence more than 10 years after ILR. Of the 21 late-recurrence patients, 17 (81%) had tumours with a consolidation/tumour ratio (CTR) >0.25. CONCLUSIONS: Late recurrence occurred in 21 (23%) of 92 patients with recurrence after ILR for cT1aN0M0 NSCLC. Late recurrence was more likely to involve adenocarcinoma and local recurrence. It is thus considered reasonable to follow patients with a CTR >0.25 for 10 years after ILR. PMID- 27226402 TI - Functional and anatomical characterization of brown adipose tissue in heart failure with blood oxygen level dependent magnetic resonance. AB - Recent studies have suggested that brown adipose tissue (BAT) plays an important role in obesity, insulin resistance and heart failure. The characterization of BAT in vivo, however, has been challenging. No technique to comprehensively image BAT anatomy and function has been described. Moreover, the impact on BAT of the neuroendocrine activation seen in heart failure has only recently begun to be evaluated in vivo. The aim of this study was to use MRI to characterize the impact of heart failure on the morphology and function of BAT. Mice subjected to permanent ligation of the left coronary artery were imaged with MRI 6 weeks later. T2 weighted MRI of BAT volume and blood oxygen level dependent MRI of BAT function were performed. T2 * maps of BAT were obtained at multiple time points before and after administration of the beta3 adrenergic agonist CL 316 243 (CL). Blood flow to BAT was studied after CL injection using the flow alternating inversion recovery (FAIR) approach. Excised BAT tissue was analyzed for lipid droplet content and for uncoupling protein 1 (UCP1) mRNA expression. BAT volume was significantly lower in heart failure (51 +/- 1 mm(3) versus 65 +/- 3 mm(3) ; p < 0.05), and characterized by a reduction in lipid globules and a fourfold increase in UCP1 mRNA (p < 0.05). CL injection increased BAT T2 * in healthy animals but not in mice with heart failure (24 +/- 4% versus 6 +/- 2%; p < 0.01), consistent with an increase in flow in control BAT. This was confirmed by a significant difference in the FAIR response in BAT in control and heart failure mice. Heart failure results in the chronic activation of BAT, decreased BAT lipid stores and decreased BAT volume, and it is associated with a marked decrease in ability to respond to acute physiological stimuli. This may have important implications for substrate utilization and overall metabolic homeostasis in heart failure. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27226404 TI - Intraguild predation and competitive displacement between Nesidiocoris tenuis and Dicyphus maroccanus, two biological control agents in tomato pests. AB - Dicyphus maroccanus Wagner and Nesidiocoris tenuis Reuter (Hemiptera: Miridae) are 2 biological control agents in tomatoes. Through the crop seasons, a natural shift in the occurrence of both mirids in favor of N. tenuis has been observed at the end of the cropping cycle in eastern Spain. To better optimize their conservation, the reasons for the observed change, such as intraguild interactions (IGP) or the influence of environmental conditions, are worth elucidating. To do this, we first studied the IGP of adult females on heterospecific nymphs in the laboratory. We next studied exploitative competition between adults and nymphs of each species when feeding on Ephestia kueniella Zeller (Lepidoptera: Pyralidae) eggs in the laboratory. Finally, to analyze the competitive displacement between both mirids, we conducted a semifield experiment in which both predators were released together. All experiments were conducted at 2 temperature regimes (20 and 25 degrees C). Adult-to-nymph intraguild interactions occurred only at 25 oC at very low levels, showing that N. tenuis attacked and consumed a greater proportion of heterospecific nymphs. Nesidiocoris tenuis was a better competitor than D. maroccanus when feeding on the shared prey in the presence of its heterospecific nymph at 25 oC. In semifield conditions, N. tenuis showed a competitive advantage over D. maroccanus at both temperatures. We conclude that there is not direct interference between both species, however, N. tenuis has a greater ability to outcompete, since it is best adapted to higher temperatures and it is able to remove food sources for D. maroccanus. PMID- 27226403 TI - Stage-specific Proteomes from Onchocerca ochengi, Sister Species of the Human River Blindness Parasite, Uncover Adaptations to a Nodular Lifestyle. AB - Despite 40 years of control efforts, onchocerciasis (river blindness) remains one of the most important neglected tropical diseases, with 17 million people affected. The etiological agent, Onchocerca volvulus, is a filarial nematode with a complex lifecycle involving several distinct stages in the definitive host and blackfly vector. The challenges of obtaining sufficient material have prevented high-throughput studies and the development of novel strategies for disease control and diagnosis. Here, we utilize the closest relative of O. volvulus, the bovine parasite Onchocerca ochengi, to compare stage-specific proteomes and host parasite interactions within the secretome. We identified a total of 4260 unique O. ochengi proteins from adult males and females, infective larvae, intrauterine microfilariae, and fluid from intradermal nodules. In addition, 135 proteins were detected from the obligate Wolbachia symbiont. Observed protein families that were enriched in all whole body extracts relative to the complete search database included immunoglobulin-domain proteins, whereas redox and detoxification enzymes and proteins involved in intracellular transport displayed stage-specific overrepresentation. Unexpectedly, the larval stages exhibited enrichment for several mitochondrial-related protein families, including members of peptidase family M16 and proteins which mediate mitochondrial fission and fusion. Quantification of proteins across the lifecycle using the Hi-3 approach supported these qualitative analyses. In nodule fluid, we identified 94 O. ochengi secreted proteins, including homologs of transforming growth factor-beta and a second member of a novel 6-ShK toxin domain family, which was originally described from a model filarial nematode (Litomosoides sigmodontis). Strikingly, the 498 bovine proteins identified in nodule fluid were strongly dominated by antimicrobial proteins, especially cathelicidins. This first high-throughput analysis of an Onchocerca spp. proteome across the lifecycle highlights its profound complexity and emphasizes the extremely close relationship between O. ochengi and O. volvulus The insights presented here provide new candidates for vaccine development, drug targeting and diagnostic biomarkers. PMID- 27226406 TI - The rising cost of hospital care for children with gastroparesis: 2004-2013. AB - BACKGROUND: The cost of hospital care for adults with gastroparesis (GP) is increasing. Our objective was to evaluate the cost of hospital care for children with GP. METHODS: Using the Pediatric Health Information System, we selected hospitalizations with a diagnosis of GP (ICD-9 536.3), dyspepsia and other specified disorders of function of stomach (DYS, 536.8) and unspecified functional disorder of stomach (UFD, 536.9) from 2004 to 2013. We recorded dates of hospitalization, demographics, costs, and length of stay (LOS). KEY RESULTS: From 2004 to 2013, 4015 patients were admitted for GP (54.2% female, median age 8 years). Total cost of hospitalization for GP increased 5.8 fold from $6 185 390 to $35 654 075 (p = 0.0001). Cost per hospitalization did not change. Cost of initial hospitalization was highest in patients 0-5 years and lowest in patients 16-21 years (p < 0.0001). Number of hospitalizations each year for GP increased from 252 to 1310 (p < 0.0001) and unique patients hospitalized increased from 174 to 723 (p < 0.0001). Number of hospitalizations and unique patients for DYS/UFD also increased (p < 0.0001). LOS for GP did not change with time. Females and younger GP patients had more repeat hospitalizations (p < 0.0001, p < 0.0001). CONCLUSIONS & INFERENCES: The financial burden of hospitalization for pediatric GP has increased dramatically from 2004 to 2013, driven by a rise in number of hospitalizations and unique patients hospitalized each year. Cost and LOS per hospitalization remain stable. Unlike in adults, hospitalizations for DYS/UFD have also increased, suggesting that the increase in hospitalizations for GP is not secondary to changing diagnostic practices. PMID- 27226405 TI - Automated Axon Counting in Rodent Optic Nerve Sections with AxonJ. AB - We have developed a publicly available tool, AxonJ, which quantifies the axons in optic nerve sections of rodents stained with paraphenylenediamine (PPD). In this study, we compare AxonJ's performance to human experts on 100x and 40x images of optic nerve sections obtained from multiple strains of mice, including mice with defects relevant to glaucoma. AxonJ produced reliable axon counts with high sensitivity of 0.959 and high precision of 0.907, high repeatability of 0.95 when compared to a gold-standard of manual assessments and high correlation of 0.882 to the glaucoma damage staging of a previously published dataset. AxonJ allows analyses that are quantitative, consistent, fully-automated, parameter-free, and rapid on whole optic nerve sections at 40x. As a freely available ImageJ plugin that requires no highly specialized equipment to utilize, AxonJ represents a powerful new community resource augmenting studies of the optic nerve using mice. PMID- 27226408 TI - Mindful Mates: A Pilot Study of the Relational Effects of Mindfulness-Based Stress Reduction on Participants and Their Partners. AB - Very little is currently known about how increases in dispositional mindfulness through mindfulness training affect the quality of participants' romantic relationships, and no previous studies have examined how increases in specific facets of mindfulness differentially contribute to relationship health. Additionally, even less is known about how an individual's development of mindfulness skills affects the relationship satisfaction of his or her romantic partner. Thus, the purpose of this pilot study was to examine associations between changes in facets of mindfulness and relationship satisfaction among participants enrolled in a Mindfulness-Based Stress Reduction (MBSR) course and their nonenrolled romantic partners. Twenty MBSR participants and their nonenrolled partners (n = 40) completed measures of mindfulness and relationship satisfaction pre- and post-enrolled partners' completion of an MBSR course. Results indicated that enrolled participants significantly improved on all facets of mindfulness and relationship satisfaction, while nonenrolled partners did not significantly increase on any facet of mindfulness or relationship satisfaction. Moreover, enrolled participants' increases in Acting with Awareness were positively associated with increases in their own and their nonenrolled partners' relationship satisfaction, whereas increases in enrolled participants' Nonreactivity were positively associated with increases in their nonenrolled partners' (but not their own) relationship satisfaction. These results suggest that increasing levels of mindfulness (particularly specific aspects of mindfulness) may have positive effects on couples' relationship satisfaction and highlight mindfulness training as a promising tool for education and intervention efforts aimed at promoting relational health. PMID- 27226407 TI - The efficacy and safety of either infliximab or adalimumab in 362 patients with anti-TNF-alpha naive Crohn's disease. AB - BACKGROUND: TNFalpha antagonists, including infliximab (IFX) and adalimumab (ADA), have revolutionised treatment for Crohn's disease. Studies comparing efficacy in patients with Crohn's disease naive to TNFalpha antagonists are lacking. METHODS: Consecutive TNFalpha antagonist-naive patients with luminal or perianal Crohn's disease from four tertiary centres in Austria were assessed prospectively for induction and maintenance efficacy, and safety, of either IFX or ADA. RESULTS: In a total of 362 patients, 251 (69.3%) started IFX and 111 (30.7%) started ADA. At baseline, the median Harvey-Bradshaw Index (HBI) score was 8 (range 5-29) and 8 (5-36), and the median C-reactive protein (CRP) was 1.07 (interquartile range (IQR) 1.36) mg/dL and 1.16 (IQR 1.23) mg/dL for IFX and ADA, respectively. At week 12, there was no difference between IFX and ADA among patients with luminal Crohn's disease in clinical remission (IFX 128/204; 62.7% vs. ADA 68/107; 63.6%, P = 0.47), clinical response (IFX 154/204; 75.5% vs. ADA 82/107; 76.6%, P = 0.82) and steroid-free remission (IFX 110/204; 53.9% vs. ADA 61/107; 57%, P = 0.60). At 12 months, there were similar numbers of patients treated with IFX and ADA who maintained clinical remission (IFX 77/154; 50.4% vs. ADA 47/82; 57.3%, P = 0.48) and steroid-free remission (IFX 68/154; 44.3% vs. ADA 44/82; 53.7%, P = 0.16). Baseline CRP >0.7 mg/dL (OR 0.24; 95% CI 0.07-0.77, P = 0.01) was the only predictor of clinical remission at 12 months in patients who did not have escalation of anti-TNFalpha therapy. CONCLUSION: IFX and ADA appear comparable in clinical outcomes for patients with Crohn's disease who are naive to TNFalpha antagonists. PMID- 27226409 TI - A successful case of an anaplastic meningioma treated with chemotherapy for soft tissue sarcomas. AB - Malignant meningioma has a bad prognosis. Surgery and radiotherapy are the most effective therapeutic options, without an established role for chemotherapy. We report a case of 2-year-old male child with diagnosis of postoperative relapse of a malignant meningioma. Considering the rapid progression, the young age and the lack of effective therapeutic alternatives, the patient underwent multidisciplinary anticancer treatment with a protocol made for soft tissue sarcomas (EpSSG NRSSTS 2005 protocol), with positive outcome. This case represents a successful management of an anaplastic meningioma with a multimodal treatment, including chemotherapy, in a pediatric patient. PMID- 27226411 TI - Novel dipeptidyl hydroxamic acids that inhibit human and bacterial dipeptidyl peptidase III. AB - Human dipeptidyl peptidase III (hDPP III), a zinc-metallopeptidase of the family M49, is an activator of the Keap1-Nrf2 cytoprotective pathway involved in defense against oxidative stress. Pathophysiological roles of DPP III have not been elucidated yet, partly due to the lack of specific inhibitors. We showed that substrate analog H-Tyr-Phe-NHOH is a strong competitive inhibitor of hDPP III, while H-Tyr-Gly-NHOH expresses much weaker inhibition. To investigate the effects of amino acid substitutions in inhibitor P1 position, we synthesized three new dipeptidyl hydroxamates and examined their influence on the activity of hDPP III and DPP III from the human gut symbiont Bacteroides thetaiotaomicron. The extent of inhibition of hDPP III, but not of bacterial enzyme, was dependent on the amino acid in P1. H-Phe-Phe-NHOH is recognized as one of the strongest inhibitors of hDPP III (Ki = 0.028 MUM), and H-Phe-Leu-NHOH discriminated between human and bacterial ortholog of the M49 family. PMID- 27226410 TI - Thyroid Hormone Receptor beta Agonist Induces beta-Catenin-Dependent Hepatocyte Proliferation in Mice: Implications in Hepatic Regeneration. AB - Triiodothyronine (T3) induces hepatocyte proliferation in rodents. Recent work has shown molecular mechanism for T3's mitogenic effect to be through activation of beta-catenin signaling. Since systemic side effects of T3 may preclude its clinical use, and hepatocytes mostly express T3 hormone receptor beta (TRbeta), we investigated if selective TRbeta agonists like GC-1 may also have beta-catenin dependent hepatocyte mitogenic effects. Here we studied the effect of GC-1 and T3 in conditional knockouts of various Wnt pathway components. We also assessed any regenerative advantage of T3 or GC-1 when given prior to partial hepatectomy in mice. Mice administered GC-1 showed increased pSer675-beta-catenin, cyclin D1, BrdU incorporation, and PCNA. No abnormalities in liver function tests were noted. GC-1-injected liver-specific beta-catenin knockouts (beta-catenin LKO) showed decreased proliferation when compared to wild-type littermates. To address if Wnt signaling was required for T3- or GC-1-mediated hepatocyte proliferation, we used LRP5-6-LKO, which lacks the two redundant Wnt coreceptors. Surprisingly, decreased hepatocyte proliferation was also evident in LRP5-6-LKO in response to T3 and GC-1, despite increased pSer675-beta-catenin. Further, increased levels of active beta-catenin (hypophosphorylated at Ser33, Ser37, and Thr41) were evident after T3 and GC-1 treatment. Finally, mice pretreated with T3 or GC-1 for 7 days followed by partial hepatectomy showed a significant increase in hepatocyte proliferation both at the time (T0) and 24 h after surgery. In conclusion, like T3, TRbeta-selective agonists induce hepatocyte proliferation through beta catenin activation via both PKA- and Wnt-dependent mechanisms and confer a regenerative advantage following surgical resection. Hence, these agents may be useful regenerative therapies in liver transplantation or other surgical settings. PMID- 27226412 TI - Integrin-specific hydrogels functionalized with VEGF for vascularization and bone regeneration of critical-size bone defects. PMID- 27226413 TI - Solubilized liver extracellular matrix maintains primary rat hepatocyte phenotype in-vitro. PMID- 27226414 TI - Macrofossil evidence for a rapid and severe Cretaceous-Paleogene mass extinction in Antarctica. AB - Debate continues about the nature of the Cretaceous-Paleogene (K-Pg) mass extinction event. An abrupt crisis triggered by a bolide impact contrasts with ideas of a more gradual extinction involving flood volcanism or climatic changes. Evidence from high latitudes has also been used to suggest that the severity of the extinction decreased from low latitudes towards the poles. Here we present a record of the K-Pg extinction based on extensive assemblages of marine macrofossils (primarily new data from benthic molluscs) from a highly expanded Cretaceous-Paleogene succession: the Lopez de Bertodano Formation of Seymour Island, Antarctica. We show that the extinction was rapid and severe in Antarctica, with no significant biotic decline during the latest Cretaceous, contrary to previous studies. These data are consistent with a catastrophic driver for the extinction, such as bolide impact, rather than a significant contribution from Deccan Traps volcanism during the late Maastrichtian. PMID- 27226415 TI - The control of hyperglycemia by a novel trypsin resistant oral insulin preparation in alloxan induced type I diabetic mice. AB - A trypsin resistant oral insulin preparation was made by incubating insulin for 2 h at 23 degrees C with previously boiled cow milk at 100 degrees C that was coagulated with 0.6 M acetic acid. The precipitate was resuspended in the same volume of milk. The immunoblot analysis of the suspended proteins treated with 200 ng of trypsin/ml for 3 h demonstrated that the 80.1% of the insulin in the suspension survived the proteolytic degradation compared to 0% of the hormone survived in the control. The feeding of 0.4 ml (0.08 unit of insulin) of the resuspended proteins followed by 0.2 ml of the same protein to alloxan induced diabetic mice maximally decreased the blood glucose level from 508 +/- 10 mg/dl to 130 +/- 10 mg/dl in 7 h with simultaneous increase of the basal plasma concentration of insulin from 3 +/- 1.1 MUunits/ml to 18 +/- 1.5 MUunits/ml. In control experiment the absence of insulin in the identical milk suspension produced no hypoglycemic effect suggesting milk was not responsible for the hypoglycemic effect of milk-insulin complex. Coming out of insulin-casein complex from the intestinal gut to the circulation was spontaneous and facilitated diffusion transportation which was found from Gibbs free energy reaction. PMID- 27226416 TI - Critical Role of the Disintegrin Metalloprotease ADAM-like Decysin-1 [ADAMDEC1] for Intestinal Immunity and Inflammation. AB - BACKGROUND AND AIMS: ADAM [A Disintegrin And Metalloproteinase] is a family of peptidase proteins which have diverse roles in tissue homeostasis and immunity. Here, we study ADAM-like DECysin-1 [ADAMDEC1] a unique member of the ADAM family. ADAMDEC1 expression is restricted to the macrophage/dendritic cell populations of the gastrointestinal tract and secondary lymphoid tissue. The biological function of ADAMDEC1 is unknown but it has been hypothesised to play a role in immunity. The identification of reduced ADAMDEC1 expression in Crohn's disease patients has provided evidence of a potential role in bowel inflammation. METHODS: Adamdec1-/- mice were exposed to dextran sodium sulphate or infected orally with Citrobacter rodentium or Salmonella typhimurium. The clinical response was monitored. RESULTS: The loss of Adamdec1 rendered mice more susceptible to the induction of bacterial and chemical induced colitis, as evidenced by increased neutrophil infiltration, greater IL-6 and IL-1beta secretion, more weight loss and increased mortality. In the absence of Adamdec1, greater numbers of Citrobacter rodentium were found in the spleen, suggestive of a breakdown in mucosal immunity which resulted in bacteraemia. CONCLUSION: In summary, ADAMDEC1 protects the bowel from chemical and bacterial insults, failure of which may predispose to Crohn's disease. PMID- 27226417 TI - Histological Outcomes and Predictive Value of Faecal Markers in Moderately to Severely Active Ulcerative Colitis Patients Receiving Infliximab. AB - BACKGROUND AND AIMS: Histological healing has emerged as a promising therapeutic goal in ulcerative colitis. This is especially important in the context of biological therapies. The objectives of the present study were to investigate the ability of infliximab to induce histological remission in ulcerative colitis [UC] patients and to explore the utility of faecal calprotectin and lactoferrin in predicting histological activity. METHODS: Multi-centre, single-cohort, open label, 52-week trial including moderately to severely biological-naive UC patients receiving intravenous infliximab [5mg/kg]. The primary outcome was the proportion of patients with histological remission [Geboes index <= 3.0] after 8 weeks of treatment, scored by two independent pathologists. RESULTS: Twenty patients were included. The rate of histological remission increased from 5% at baseline to 15% and 35% at Week 8 and Week 52, respectively. At Week 8, 40% of patients were in clinical remission [Mayo <= 2] and 45% achieved mucosal healing [Mayo endoscopy subscore 0-1]. At Week 52, 25% of patients had clinical, endoscopic and histological remission. Faecal calprotectin and lactoferrin showed the highest correlation with histological activity at Week 8 (area under the curve [AUC] 94%, p = 0.017; and 96%, p = 0.013, respectively) and both markers revealed an excellent positive predictive value for this outcome at this time point [100%, p = 0.017; and 94%, p = 0.013, respectively]. CONCLUSIONS: Infliximab was able to induce histological remission. There was a good agreement between histology and faecal biomarkers. Faecal calprotectin and lactoferrin were good predictors of histological remission. Our data support inclusion of histology as a treatment target complementary to endoscopy in clinical trials when evaluating therapeutic response in UC. PMID- 27226418 TI - Perceptions of the Feasibility and Practicalities of Text Messaging-Based Infectious Disease Surveillance: A Questionnaire Survey. AB - BACKGROUND: In Vietnam, infectious disease surveillance data are collected via a paper-based system through four government tiers leading to a large delay. Meanwhile, mobile phones are abundant and very popular in the country, and known to be a useful tool in health care worldwide. Therefore, there is a great potential for the development of a timely disease surveillance system through the use of mobile phone short message service (SMS) text messages. OBJECTIVE: This study aims to explore insights about the feasibility and practicalities of the utilization of SMS text messaging-based interventions in disease-reporting systems by identifying potential challenges and barriers in the text messaging process and looking at lessons learned. METHODS: An SMS text messaging-based disease tracking system was set up in Vietnam with patient reports texted by clinic staff. Two 6-month trials utilizing this disease tracking system were designed and implemented in two northern provinces of Vietnam to report two infectious diseases: diarrhea and influenza-like illness. A structured self reported questionnaire was developed to measure the feasibility and practicalities of the system from the participants. On the completion of the second trial in 2013, participating health staff from 40 commune health centers in the two pilot provinces were asked to complete the survey (N=80). RESULTS: Most participants were female (61%, 49/80) and nearly half (44%, 35/80) were heads of a commune health center. Approximately two-thirds (63%, 50/80) of participants retained the basic structure of the SMS text message report and there was a strong influence (OR 28.2, 95% CI 5.3-151.2) of those people on the time they spent texting the information. The majority (88%, 70/80) felt the information conveyed in the SMS text message report was not difficult to understand. Most (86%, 69/80) believed that they could report all 28 infectious diseases asked for by the Ministry of Health by using SMS text messaging. CONCLUSIONS: From a health center staff perspective, a disease-reporting system utilizing text messaging technology is easy to use and has great potential to be implemented and expanded nationwide. The survey showed positive perceptions and feedback from the participants and contributed to a promising practical solution to improve the surveillance system of infectious disease in Vietnam. PMID- 27226419 TI - Ophthalmologic involvement in Leigh syndrome. PMID- 27226420 TI - Clinical pharmacokinetics of panobinostat, a novel histone deacetylase (HDAC) inhibitor: review and perspectives. AB - 1. Panobinostat is a recently approved histone deacetylase (HDAC) inhibitor. 2. The pharmacokinetic data of panobinostat in patients with hematologic malignancies and advanced solid tumors have been collated and reviewed from the various published clinical studies for over a decade. Further perspectives and anticipated challenges in the clinical therapy with panobinostat are discussed in the review. 3. Regardless of intravenous or oral dosing, panobinostat showed a high degree of inter-patient variability in the pharmacokinetics. After oral administration, most of the administered dose is extensively metabolized and the metabolites are either fecally or renally excreted with trace amount of intact panobinostat. Both cytochrome p450 (CYP) 3A4 and non-CYP mechanisms govern the clearance of panobinostat. CYP3A4-related drug-drug interactions with panobinostat have been documented with ketoconazole (inhibitor) and dexamethasone (inducer). 4. In summary, the clinical pharmacokinetic data of panobinostat, a promising HDAC inhibitor, obtained from various clinical studies do not appear to limit the utility of panobinostat in the clinic. PMID- 27226421 TI - Utility of maximum perfusion intensity as an ultrasonographic marker of intraneural blood flow. AB - : We quantified intraneural blood flow (INBF) using perfusion measurement software (PixelFlux), and compared it with the qualitative method of counting blood vessels (vessel score) in a cohort of carpal tunnel syndrome (CTS) patients. METHODS: Forty-seven patients (67 wrists) with a clinical and electrophysiological diagnosis of CTS, and 20 healthy controls (40 wrists) were enrolled. Median nerve ultrasound (US) was performed at the carpal tunnel inlet to measure the cross-sectional area (CSA) and vessel score. Power Doppler sonograms from nerves with detectable INBF were processed with PixelFlux to obtain the maximum perfusion intensity (MPI). RESULTS: Forty-nine percent of CTS patients had detectable INBF compared with none in the control group (P < 0.0001). MPI correlated significantly with vessel score (r = 0.945, P < 0.0001), CSA (r = 0.613, P < 0.0001), and electrophysiological severity (r = 0.440, P < 0.0001). MPI had higher intra- or interobserver reliability compared with vessel score (0.95 vs. 0.47). CONCLUSION: MPI is a better method for quantification of INBF. Muscle Nerve, 2016 Muscle Nerve 55: 77-83, 2017. PMID- 27226422 TI - Bacteriological study in perianal abscess is not useful and not cost-effective. AB - BACKGROUND: The detection of gut organisms in perianal abscesses has been postulated to suggest an underlying communication with the anal canal. However, recent studies appear to contradict this observation. The aim of this study is to determine the value of bacteriological studies in perianal abscesses. METHODS: A retrospective study of all patients who have had a surgical drainage of their perianal abscesses with concomitant microbiological examination from January 2010 to December 2012 was performed. Patients with known underlying anal fistula, Crohn's disease or previous perianal operations were excluded. RESULTS: A total of 164 patients, median age of 42.0 years (range 8-87) comprising of 78.7% males formed the study group. Gut organisms were cultured in 143 (87.2%) samples while 12 (7.3%) demonstrated skin organisms and nine did not yield any bacterial growth (5.5%). Twenty-nine (17.7%) patients developed anal fistula and 34 (20.7%) patients had a recurrence of the perianal abscess. The median follow-up period was 1450 (14-2391) days. There was no significant association between the presence of gut organism and development of fistulas (odds ratio = 0.48; 95% confidence interval = 0.17-1.37) or recurrence of perianal abscess (odds ratio = 1.66; 95% confidence interval = 0.46-6.01). CONCLUSION: Bacteriological culture in perianal abscess is not useful for predicting the development of anal fistula or abscess recurrence. Hence, there is no need to perform this investigation on a routine basis. PMID- 27226423 TI - Asymptomatic subjects with airway obstruction have significant impairment at exercise. AB - BACKGROUND: The relevance of screening for airway obstruction in subjects not complaining of COPD symptoms may depend on the definition of airway obstruction. Response to exercise in asymptomatic subjects with persistent airway obstruction as defined by a postbronchodilator FEV1/FVC <5th centile lower limit of normal (LLN) remains unknown. METHODS: Dyspnoea (Borg scale), exercise tolerance and ventilatory constraints on tidal volume expansion were assessed in 20 consecutive asymptomatic subjects with persistent mild airway obstruction detected by screening (postbronchodilator FEV1/FVC z-score: -2.14+/-0.29; FEV1 z-score: 1.02+/-0.64) undergoing incremental cycle cardiopulmonary exercise testing, compared with 20 healthy controls with normal spirometry matched for age, sex, body mass index and smoking history (FEV1/FVC z-score: -0.13+/-0.57; FEV1 z score: 0.32+/-0.67) and with 20 symptomatic patients with COPD matched for the same characteristics (FEV1/FVC z-score: -2.36+/-0.51; FEV1 z-score: -1.02+/ 0.48). RESULTS: Asymptomatic subjects with airway obstruction had higher dyspnoea ratings than controls during incremental exercise. Asymptomatic subjects with airway obstruction had also peak oxygen consumption and peak power output that were lower than controls, and similar to those observed in patients with COPD. Although less frequent than in COPD, dynamic hyperinflation was more frequent in asymptomatic subjects with airway obstruction than in controls (85%, 50% and 10%, respectively; p=0.01 in asymptomatic subjects vs controls and p=0.04 vs COPD). CONCLUSIONS: Although they did not present with chronic activity-related dyspnoea, subjects with a postbronchodilator FEV1/FVC=14 weeks; beta = -.22, p = .004), number of experimental patients (beta = -.10, p = .002), and global methodological quality score (beta = -.08, p = .04). Our findings suggest that the efficacy of theory-based interventions to promote PA could be overestimated consequently due to methodological weaknesses of RCTs and that interventions shorter than 14 weeks could maximize the increase of PA behavior. PMID- 27226433 TI - Complex karyotypes and KRAS and POT1 mutations impact outcome in CLL after chlorambucil-based chemotherapy or chemoimmunotherapy. AB - Genetic instability is a feature of chronic lymphocytic leukemia (CLL) with adverse prognosis. We hypothesized that chromosomal translocations or complex karyotypes and distinct somatic mutations may impact outcome after first-line chemoimmunotherapy of CLL patients. We performed metaphase karyotyping and next generation sequencing (NGS) of 85 genes in pretreatment blood samples obtained from 161 patients registered for CLL11, a 3-arm phase 3 trial comparing frontline chlorambucil (Clb) vs Clb plus rituximab (Clb-R) or Clb plus obinutuzumab in CLL patients with significant comorbidity. Chromosomal aberrations as assessed by karyotyping were observed in 68.8% of 154 patients, 31.2% carried translocations, and 19.5% showed complex karyotypes. NGS revealed 198 missense/nonsense mutations and 76 small indels in 76.4% of patients. The most frequently mutated genes were NOTCH1, SF3B1, ATM, TP53, BIRC3, POT1, XPO1, and KRAS Sole chemotherapy, treatment with Clb-R, or genetic lesions in TP53 (9.9% of patients) and KRAS (6.2% of patients) were significantly associated with nonresponse to study therapy. In multivariate models, complex karyotypes and POT1 mutations (8.1% of patients) represented significant prognostic factors for an unfavorable survival, independently of IGHV mutation status, Binet stage, and serum beta-2 microglobuline. Patients with the copresence of complex karyotypes and deletions/mutations involving TP53 demonstrated a particularly short survival. In summary, this is the first prospective, controlled study in CLL patients that shows a role of complex karyotype aberrations as an independent prognostic factor for survival after front-line therapy. Moreover, the study identifies mutations in KRAS and POT1 as novel determinants of outcome after chemoimmunotherapy using chlorambucil and anti-CD20 treatment. PMID- 27226434 TI - Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM 010): a phase 3b study in refractory multiple myeloma. AB - Patients with relapsed and/or refractory multiple myeloma (RRMM) have poor prognosis. The STRATUS study assessed safety and efficacy of pomalidomide plus low-dose dexamethasone in the largest cohort to date of patients with RRMM. Patients who failed treatment with bortezomib and lenalidomide and had adequate prior alkylator therapy were eligible. Pomalidomide 4 mg was given on days 1-21 of 28-day cycles with low-dose dexamethasone 40 mg (20 mg for patients aged >75 years) on days 1, 8, 15, and 22 until progressive disease or unacceptable toxicity. Safety was the primary end point; secondary end points included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Among 682 patients enrolled, median age was 66 years, and median time since diagnosis was 5.3 years. Median number of prior regimens was 5. Most patients were refractory to both lenalidomide and bortezomib (80.2%). Median follow-up was 16.8 months; median duration of treatment was 4.9 months. Most frequent grade 3/4 treatment-emergent adverse events were hematologic (neutropenia [49.7%], anemia [33.0%], and thrombocytopenia [24.1%]). Most common grade 3/4 nonhematologic toxicities were pneumonia (10.9%) and fatigue (5.9%). Grade 3/4 venous thromboembolism and peripheral neuropathy were rare (1.6% each). The ORR was 32.6%, and the median DOR was 7.4 months. Median PFS and OS were 4.6 months and 11.9 months, respectively. We present the largest trial to date evaluating pomalidomide plus low-dose dexamethasone in patients with RRMM, further confirming that this regimen offers clinically meaningful benefit and is generally well tolerated. www.Clinicaltrials.gov identifier NCT01712789. PMID- 27226435 TI - IL-4 rescues surface IgM expression in chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) cells express poor levels of surface immunoglobulin (sIg), and many are minimally activated or anergic in response to B-cell receptor (BCR) crosslinking in vitro. Paradoxically, CLL cells in patients are highly activated through BCR signaling and expand in proliferation centers, suggesting that the function of sIg signaling is rescued. Here, we find that, compared with normal naive B cells, CLL cells express a low level of total CD79b protein but normal levels of CD79a and IgM protein. Association of both CD79a and CD79b to IgM is markedly reduced. We further find that interleukin-4 (IL-4) markedly rescues CD79b and sIgM protein in CLL samples. These changes significantly enhance signaling in response to BCR crosslinking. Furthermore, we find that these changes are more pronounced in immunoglobulin heavy chain variable (IGHV)-unmutated CLL cells than IGHV-mutated CLL cells. The results described herein reveal that reduced sIgM is due to low expression of total CD79b protein in CLL cells. IL-4 substantially restores CD79b protein expression, sIgM expression, and BCR signaling. PMID- 27226436 TI - Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies. AB - Long-lived, self-renewing, multipotent T memory stem cells (TSCM) can trigger profound and sustained tumor regression but their rareness poses a major hurdle to their clinical application. Presently, clinically compliant procedures to generate relevant numbers of this T-cell population are undefined. Here, we provide a strategy for deriving large numbers of clinical-grade tumor-redirected TSCM starting from naive precursors. CD8(+)CD62L(+)CD45RA(+) naive T cells enriched by streptamer-based serial-positive selection were activated by CD3/CD28 engagement in the presence of interleukin-7 (IL-7), IL-21, and the glycogen synthase-3beta inhibitor TWS119, and genetically engineered to express a CD19 specific chimeric antigen receptor (CD19-CAR). These conditions enabled the generation of CD19-CAR-modified CD8(+) TSCM that were phenotypically, functionally, and transcriptomically equivalent to their naturally occurring counterpart. Compared with CD8(+) T cells generated with clinical protocols currently under investigation, CD19-CAR-modified CD8(+) TSCM exhibited enhanced metabolic fitness and mediated robust, long-lasting antitumor responses against systemic acute lymphoblastic leukemia xenografts. This clinical-grade platform provides the basis for a phase 1 trial evaluating the activity of CD19-CAR modified CD8(+) TSCM in patients with B-cell malignancies refractory to prior allogeneic hematopoietic stem cell transplantation. PMID- 27226438 TI - Sex Differences in White Matter Microstructure in the Human Brain Predominantly Reflect Differences in Sex Hormone Exposure. AB - Sex differences have been described regarding several aspects of human brain morphology; however, the exact biological mechanisms underlying these differences remain unclear in humans. Women with the complete androgen insensitivity syndrome (CAIS), who lack androgen action in the presence of a 46,XY karyotype, offer the unique opportunity to study isolated effects of sex hormones and sex chromosomes on human neural sexual differentiation. In the present study, we used diffusion tensor imaging to investigate white matter (WM) microstructure in 46,XY women with CAIS (n = 20), 46,XY comparison men (n = 30), and 46,XX comparison women (n = 30). Widespread sex differences in fractional anisotropy (FA), with higher FA in comparison men than in comparison women, were observed. Women with CAIS showed female-typical FA throughout extended WM regions, predominantly due to female typical radial diffusivity. These findings indicate a predominant role of sex hormones in the sexual differentiation of WM microstructure, although sex chromosome genes and/or masculinizing androgen effects not mediated by the androgen receptor might also play a role. PMID- 27226437 TI - Guidelines for the Diagnosis and Treatment of Chronic Functional Constipation in Korea, 2015 Revised Edition. AB - The Korean Society of Neurogastroenterology and Motility first published guidelines for chronic constipation in 2005 and was updated in 2011. Although the guidelines were updated using evidence-based process, they lacked multidisciplinary participation and did not include a diagnostic approach for chronic constipation. This article includes guidelines for diagnosis and treatment of chronic constipation to realistically fit the situation in Korea and to be applicable to clinical practice. The guideline development was based upon the adaptation method because research evidence was limited in Korea, and an organized multidisciplinary group carried out systematical literature review and series of evidence-based evaluations. Six guidelines were selected using the Appraisal of Guidelines for Research & Evaluation (AGREE) II process. A total 37 recommendations were adopted, including 4 concerning the definition and risk factors of chronic constipation, 8 regarding diagnoses, and 25 regarding treatments. The guidelines are intended to help primary physicians and general health professionals in clinical practice in Korea, to provide the principles of medical treatment to medical students, residents, and other healthcare professionals, and to help patients for choosing medical services based on the information. These guidelines will be updated and revised periodically to reflect new diagnostic and therapeutic methods. PMID- 27226440 TI - Repeated Structural Imaging Reveals Nonlinear Progression of Experience-Dependent Volume Changes in Human Motor Cortex. AB - Evidence for experience-dependent structural brain change in adult humans is accumulating. However, its time course is not well understood, as intervention studies typically consist of only 2 imaging sessions (before vs. after training). We acquired up to 18 structural magnetic resonance images over a 7-week period while 15 right-handed participants practiced left-hand writing and drawing. After 4 weeks, we observed increases in gray matter of both left and right primary motor cortices relative to a control group; 3 weeks later, these differences were no longer reliable. Time-series analyses revealed that gray matter in the primary motor cortices expanded during the first 4 weeks and then partially renormalized, in particular in the right hemisphere, despite continued practice and increasing task proficiency. Similar patterns of expansion followed by partial renormalization are also found in synaptogenesis, cortical map plasticity, and maturation, and may qualify as a general principle of structural plasticity. Research on human brain plasticity needs to encompass more than 2 measurement occasions to capture expansion and potential renormalization processes over time. PMID- 27226441 TI - Dual Cortical Plasticity After Spinal Cord Injury. AB - During cortical development, plasticity reflects the dynamic equilibrium between increasing and decreasing functional connectivity subserved by synaptic sprouting and pruning. After adult cortical deafferentation, plasticity seems to be dominated by increased functional connectivity, leading to the classical expansive reorganization from the intact to the deafferented cortex. In contrast, here we show a striking "decrease" in the fast cortical responses to high intensity forepaw stimulation 1-3 months after complete thoracic spinal cord transection, as evident in both local field potentials and intracellular in vivo recordings. Importantly, this decrease in fast cortical responses co-exists with an "increase" in cortical activation over slower post-stimulus timescales, as measured by an increased forepaw-to-hindpaw propagation of stimulus-triggered cortical up-states, as well as by the enhanced slow sustained depolarization evoked by high-frequency forepaw stimuli in the deafferented hindpaw cortex. This coincidence of diminished fast cortical responses and enhanced slow cortical activation offers a dual perspective of adult cortical plasticity after spinal cord injury. PMID- 27226439 TI - Reconfiguration of Intrinsic Functional Coupling Patterns Following Circumscribed Network Lesions. AB - Communication between cortical regions is necessary for optimal cognitive processing. Functional relationships between cortical regions can be inferred through measurements of temporal synchrony in spontaneous activity patterns. These relationships can be further elaborated by surveying effects of cortical lesions upon inter-regional connectivity. Lesions to cortical hubs and heteromodal association regions are expected to induce distributed connectivity changes and higher-order cognitive deficits, yet their functional consequences remain relatively unexplored. Here, we used resting-state fMRI to investigate intrinsic functional connectivity (FC) and graph theoretical metrics in 12 patients with circumscribed lesions of the medial prefrontal cortex (mPFC) portion of the Default Network (DN), and compared these metrics with those observed in healthy matched comparison participants and a sample of 1139 healthy individuals. Despite significant mPFC destruction, patients did not demonstrate weakened intrinsic FC among undamaged DN nodes. Instead, network-specific changes were manifested as weaker negative correlations between the DN and attentional and somatomotor networks. These findings conflict with the DN being a homogenous system functionally anchored at mPFC. Rather, they implicate a role for mPFC in mediating cross-network functional interactions. More broadly, our data suggest that lesions to association cortical hubs might induce clinical deficits by disrupting communication between interacting large-scale systems. PMID- 27226442 TI - The Dorsoventral Patterning of Human Forebrain Follows an Activation/Transformation Model. AB - The anteroposterior patterning of the central nervous system follows an activation/transformation model, which proposes that a prospective telencephalic fate will be activated by default during the neural induction stage, while this anterior fate could be transformed posteriorly according to caudalization morphogens. Although both extrinsic signals and intrinsic transcription factors have been implicated in dorsoventral (DV) specification of vertebrate telencephalon, the DV patterning model remains elusive. This is especially true in human considering its evolutionary trait and uniqueness of gene regulatory networks during neural induction. Here, we point to a model that human forebrain DV patterning also follows an activation/transformation paradigm. Human neuroectoderm (NE) will activate a forebrain dorsal fate automatically and this default anterior dorsal fate does not depend on Wnts activation or Pax6 expression. Forced expression of Pax6 in human NE hinders its ventralization even under sonic hedgehog (Shh) treatment, suggesting that the ventral fate is repressed by dorsal genes. Genetic manipulation of Nkx2.1, a key gene for forebrain ventral progenitors, shows that Nkx2.1 is neither necessary nor sufficient for Shh-driven ventralization. We thus propose that Shh represses dorsal genes of human NE and subsequently transforms the primitively activated dorsal fate ventrally in a repression release manner. PMID- 27226443 TI - Functional Changes in the Language Network in Response to Increased Amyloid beta Deposition in Cognitively Intact Older Adults. PMID- 27226445 TI - The Role of Working Memory in the Probabilistic Inference of Future Sensory Events. AB - The ability to represent the emerging regularity of sensory information from the external environment has been thought to allow one to probabilistically infer future sensory occurrences and thus optimize behavior. However, the underlying neural implementation of this process is still not comprehensively understood. Through a convergence of behavioral and neurophysiological evidence, we establish that the probabilistic inference of future events is critically linked to people's ability to maintain the recent past in working memory. Magnetoencephalography recordings demonstrated that when visual stimuli occurring over an extended time series had a greater statistical regularity, individuals with higher working-memory capacity (WMC) displayed enhanced slow-wave neural oscillations in the theta frequency band (4-8 Hz.) prior to, but not during stimulus appearance. This prestimulus neural activity was specifically linked to contexts where information could be anticipated and influenced the preferential sensory processing for this visual information after its appearance. A separate behavioral study demonstrated that this process intrinsically emerges during continuous perception and underpins a realistic advantage for efficient behavioral responses. In this way, WMC optimizes the anticipation of higher level semantic concepts expected to occur in the near future. PMID- 27226444 TI - Stress Degrades Prefrontal Cortex Neuronal Coding of Goal-Directed Behavior. AB - Stress, pervasive in modern society, impairs prefrontal cortex (PFC)-dependent cognitive processes, an action implicated in multiple psychopathologies and estimated to contribute to nearly half of all work place accidents. However, the neurophysiological bases for stress-related impairment of PFC-dependent function remain poorly understood. The current studies examined the effects of stress on PFC neural coding during a working memory task in rats. Stress suppressed responses of medial PFC (mPFC) neurons strongly tuned to a diversity of task events, including delay and outcome (reward, error). Stress-related impairment of task-related neuronal activity included multidimensional coding by PFC neurons, an action that significantly predicted cognitive impairment. Importantly, the effects of stress on PFC neuronal signaling were highly conditional on tuning strength: stress increased task-related activity in the larger population of PFC neurons weakly tuned to task events. Combined, stress elicits a profound collapse of task representations across the broader population of PFC neurons. PMID- 27226446 TI - Cortical Thickness of Functionally Defined Visual Areas in Schizophrenia and Bipolar Disorder. AB - Patients with schizophrenia show specific abnormalities in visual perception, and patients with bipolar disorder may have related perceptual deficits. During tasks that highlight perceptual dysfunction, patients with schizophrenia show abnormal activity in visual brain areas, including the lateral occipital complex (LOC) and early retinotopic cortex. It is unclear whether the anatomical structure of those visual areas is atypical in schizophrenia and bipolar disorder. In members of those two patient groups and healthy controls, we localized LOC and early retinotopic cortex individually for each participant using functional magnetic resonance imaging (MRI), then measured the thickness of those regions of interest using structural MRI scans. In both regions, patients with schizophrenia had the thinnest cortex, controls had the thickest cortex, and bipolar patients had intermediate cortical thickness. A control region, motor cortex, did not show this pattern of group differences. The thickness of each visual region of interest was significantly correlated with performance on a visual object masking task, but only in schizophrenia patients. These findings suggest an anatomical substrate for visual processing abnormalities that have been found with both neural and behavioral measures in schizophrenia and other severe mental illnesses. PMID- 27226447 TI - Respiratory and autonomic dysfunction in congenital central hypoventilation syndrome. AB - The developmental lineage of the PHOX2B-expressing neurons in the retrotrapezoid nucleus (RTN) has been extensively studied. These cells are thought to function as central respiratory chemoreceptors, i.e., the mechanism by which brain Pco2 regulates breathing. The molecular and cellular basis of central respiratory chemoreception is based on the detection of CO2 via intrinsic proton receptors (TASK-2, GPR4) as well as synaptic input from peripheral chemoreceptors and other brain regions. Murine models of congenital central hypoventilation syndrome designed with PHOX2B mutations have suggested RTN neuron agenesis. In this review, we examine, through human and experimental animal models, how a restricted number of neurons that express the transcription factor PHOX2B play a crucial role in the control of breathing and autonomic regulation. PMID- 27226449 TI - Differences in chloride gradients allow for three distinct types of synaptic modulation by endocannabinoids. AB - Endocannabinoids can elicit persistent depression of excitatory and inhibitory synapses, reducing or enhancing (disinhibiting) neural circuit output, respectively. In this study, we examined whether differences in Cl(-) gradients can regulate which synapses undergo endocannabinoid-mediated synaptic depression vs. disinhibition using the well-characterized central nervous system (CNS) of the medicinal leech, Hirudo verbana Exogenous application of endocannabinoids or capsaicin elicits potentiation of pressure (P) cell synapses and depression of both polymodal (Npoly) and mechanical (Nmech) nociceptive synapses. In P synapses, blocking Cl(-) export prevented endocannabinoid-mediated potentiation, consistent with a disinhibition process that has been indicated by previous experiments. In Nmech neurons, which are depolarized by GABA due to an elevated Cl(-) equilibrium potentials (ECl), endocannabinoid-mediated depression was prevented by blocking Cl(-) import, indicating that this decrease in synaptic signaling was due to depression of excitatory GABAergic input (disexcitation). Npoly neurons are also depolarized by GABA, but endocannabinoids elicit depression in these synapses directly and were only weakly affected by disruption of Cl(-) import. Consequently, the primary role of elevated ECl may be to protect Npoly synapses from disinhibition. All forms of endocannabinoid-mediated plasticity required activation of transient potential receptor vanilloid (TRPV) channels. Endocannabinoid/TRPV-dependent synaptic plasticity could also be elicited by distinct patterns of afferent stimulation with low-frequency stimulation (LFS) eliciting endocannabinoid-mediated depression of Npoly synapses and high-frequency stimulus (HFS) eliciting endocannabinoid-mediated potentiation of P synapses and depression of Nmech synapses. These findings demonstrate a critical role of differences in Cl(-) gradients between neurons in determining the sign, potentiation vs. depression, of synaptic modulation under normal physiological conditions. PMID- 27226448 TI - Heat pulse excitability of vestibular hair cells and afferent neurons. AB - In the present study we combined electrophysiology with optical heat pulse stimuli to examine thermodynamics of membrane electrical excitability in mammalian vestibular hair cells and afferent neurons. We recorded whole cell currents in mammalian type II vestibular hair cells using an excised preparation (mouse) and action potentials (APs) in afferent neurons in vivo (chinchilla) in response to optical heat pulses applied to the crista (DeltaT ~ 0.25 degrees C per pulse). Afferent spike trains evoked by heat pulse stimuli were diverse and included asynchronous inhibition, asynchronous excitation, and/or phase-locked APs synchronized to each infrared heat pulse. Thermal responses of membrane currents responsible for APs in ganglion neurons were strictly excitatory, with Q10 ~ 2. In contrast, hair cells responded with a mix of excitatory and inhibitory currents. Excitatory hair cell membrane currents included a thermoelectric capacitive current proportional to the rate of temperature rise (dT/dt) and an inward conduction current driven by DeltaT An iberiotoxin sensitive inhibitory conduction current was also evoked by DeltaT, rising in <3 ms and decaying with a time constant of ~24 ms. The inhibitory component dominated whole cell currents in 50% of hair cells at -68 mV and in 67% of hair cells at -60 mV. Responses were quantified and described on the basis of first principles of thermodynamics. Results identify key molecular targets underlying heat pulse excitability in vestibular sensory organs and provide quantitative methods for rational application of optical heat pulses to examine protein biophysics and manipulate cellular excitability. PMID- 27226450 TI - A combined TMS-EEG study of short-latency afferent inhibition in the motor and dorsolateral prefrontal cortex. AB - Combined transcranial magnetic stimulation and electroencephalography (TMS-EEG) enables noninvasive neurophysiological investigation of the human cortex. A TMS paradigm of short-latency afferent inhibition (SAI) is characterized by attenuation of the motor-evoked potential (MEP) and modulation of N100 of the TMS evoked potential (TEP) when TMS is delivered to motor cortex (M1) following median nerve stimulation. SAI is a marker of cholinergic activity in the motor cortex; however, the SAI has not been tested from the prefrontal cortex. We aimed to explore the effect of SAI in dorsolateral prefrontal cortex (DLPFC). SAI was examined in 12 healthy subjects with median nerve stimulation and TMS delivered to M1 and DLPFC at interstimulus intervals (ISIs) relative to the individual N20 latency. SAI in M1 was tested at the optimal ISI of N20 + 2 ms. SAI in DLPFC was investigated at a range of ISI from N20 + 2 to N20 + 20 ms to explore its temporal profile. For SAI in M1, the attenuation of MEP amplitude was correlated with an increase of TEP N100 from the left central area. A similar spatiotemporal neural signature of SAI in DLPFC was observed with a marked increase of N100 amplitude. SAI in DLPFC was maximal at ISI N20 + 4 ms at the left frontal area. These findings establish the neural signature of SAI in DLPFC. Future studies could explore whether DLPFC-SAI is neurophysiological marker of cholinergic dysfunction in cognitive disorders. PMID- 27226451 TI - Short-latency afferent inhibition determined by the sensory afferent volley. AB - Short-latency afferent inhibition (SAI) is characterized by the suppression of the transcranial magnetic stimulation motor evoked potential (MEP) by the cortical arrival of a somatosensory afferent volley. It remains unknown whether the magnitude of SAI reflects changes in the sensory afferent volley, similar to that observed for somatosensory evoked potentials (SEPs). The present study investigated stimulus-response relationships between sensory nerve action potentials (SNAPs), SAI, and SEPs and their interrelatedness. Experiment 1 (n = 23, age 23 +/- 1.5 yr) investigated the stimulus-response profile for SEPs and SAI in the flexor carpi radialis muscle after stimulation of the mixed median nerve at the wrist using ~25%, 50%, 75%, and 100% of the maximum SNAP and at 1.2* and 2.4* motor threshold (the latter equated to 100% of the maximum SNAP). Experiment 2 (n = 20, age 23.1 +/- 2 yr) probed SEPs and SAI stimulus-response relationships after stimulation of the cutaneous digital nerve at ~25%, 50%, 75%, and 100% of the maximum SNAP recorded at the elbow. Results indicate that, for both nerve types, SAI magnitude is dependent on the volume of the sensory afferent volley and ceases to increase once all afferent fibers within the nerve are recruited. Furthermore, for both nerve types, the magnitudes of SAI and SEPs are related such that an increase in excitation within somatosensory cortex is associated with an increase in the magnitude of afferent-induced MEP inhibition. PMID- 27226452 TI - Does gravity influence the visual line bisection task? AB - The visual line bisection task (LBT) is sensitive to perceptual biases of visuospatial attention, showing slight leftward (for horizontal lines) and upward (for vertical lines) errors in healthy subjects. It may be solved in an egocentric or allocentric reference frame, and there is no obvious need for graviceptive input. However, for other visual line adjustments, such as the subjective visual vertical, otolith input is integrated. We hypothesized that graviceptive input is incorporated when performing the LBT and predicted reduced accuracy and precision when roll-tilted. Twenty healthy right-handed subjects repetitively bisected Earth-horizontal and body-horizontal lines in darkness. Recordings were obtained before, during, and after roll-tilt (+/-45 degrees , +/ 90 degrees ) for 5 min each. Additionally, bisections of Earth-vertical and oblique lines were obtained in 17 subjects. When roll-tilted +/-90 degrees ear down, bisections of Earth-horizontal (i.e., body-vertical) lines were shifted toward the direction of the head (P < 0.001). However, after correction for vertical line-bisection errors when upright, shifts disappeared. Bisecting body horizontal lines while roll-tilted did not cause any shifts. The precision of Earth-horizontal line bisections decreased (P <= 0.006) when roll-tilted, while no such changes were observed for body-horizontal lines. Regardless of the trial condition and paradigm, the scanning direction of the bisecting cursor (leftward vs. rightward) significantly (P <= 0.021) affected line bisections. Our findings reject our hypothesis and suggest that gravity does not modulate the LBT. Roll tilt-dependent shifts are instead explained by the headward bias when bisecting lines oriented along a body-vertical axis. Increased variability when roll-tilted likely reflects larger variability when bisecting body-vertical than body horizontal lines. PMID- 27226453 TI - Synaptic integration of transplanted interneuron progenitor cells into native cortical networks. AB - Interneuron-based cell transplantation is a powerful method to modify network function in a variety of neurological disorders, including epilepsy. Whether new interneurons integrate into native neural networks in a subtype-specific manner is not well understood, and the therapeutic mechanisms underlying interneuron based cell therapy, including the role of synaptic inhibition, are debated. In this study, we tested subtype-specific integration of transplanted interneurons using acute cortical brain slices and visualized patch-clamp recordings to measure excitatory synaptic inputs, intrinsic properties, and inhibitory synaptic outputs. Fluorescently labeled progenitor cells from the embryonic medial ganglionic eminence (MGE) were used for transplantation. At 5 wk after transplantation, MGE-derived parvalbumin-positive (PV+) interneurons received excitatory synaptic inputs, exhibited mature interneuron firing properties, and made functional synaptic inhibitory connections to native pyramidal cells that were comparable to those of native PV+ interneurons. These findings demonstrate that MGE-derived PV+ interneurons functionally integrate into subtype-appropriate physiological niches within host networks following transplantation. PMID- 27226454 TI - Neural and neurochemical basis of reinforcement-guided decision making. AB - Decision making is an adaptive behavior that takes into account several internal and external input variables and leads to the choice of a course of action over other available and often competing alternatives. While it has been studied in diverse fields ranging from mathematics, economics, ecology, and ethology to psychology and neuroscience, recent cross talk among perspectives from different fields has yielded novel descriptions of decision processes. Reinforcement-guided decision making models are based on economic and reinforcement learning theories, and their focus is on the maximization of acquired benefit over a defined period of time. Studies based on reinforcement-guided decision making have implicated a large network of neural circuits across the brain. This network includes a wide range of cortical (e.g., orbitofrontal cortex and anterior cingulate cortex) and subcortical (e.g., nucleus accumbens and subthalamic nucleus) brain areas and uses several neurotransmitter systems (e.g., dopaminergic and serotonergic systems) to communicate and process decision-related information. This review discusses distinct as well as overlapping contributions of these networks and neurotransmitter systems to the processing of decision making. We end the review by touching on neural circuitry and neuromodulatory regulation of exploratory decision making. PMID- 27226455 TI - Preferential distribution of nociceptive input to motoneurons with muscle units in the cranial portion of the upper trapezius muscle. AB - Pain is associated with changes in the neural drive to muscles. For the upper trapezius muscle, surface electromyography (EMG) recordings have indicated that acute noxious stimulation in either the cranial or the caudal region of the muscle leads to a relative decrease in muscle activity in the cranial region. It is, however, not known if this adaption reflects different recruitment thresholds of the upper trapezius motor units in the cranial and caudal region or a nonuniform nociceptive input to the motor units of both regions. This study investigated these potential mechanisms by direct motor unit identification. Motor unit activity was investigated with high-density surface EMG signals recorded from the upper trapezius muscle of 12 healthy volunteers during baseline, control (intramuscular injection of isotonic saline), and painful (hypertonic saline) conditions. The EMG was decomposed into individual motor unit spike trains. Motor unit discharge rates decreased significantly from control to pain conditions by 4.0 +/- 3.6 pulses/s (pps) in the cranial region but not in the caudal region (1.4 +/- 2.8 pps; not significant). These changes were compatible with variations in the synaptic input to the motoneurons of the two regions. These adjustments were observed, irrespective of the location of noxious stimulation. These results strongly indicate that the nociceptive synaptic input is distributed in a nonuniform way across regions of the upper trapezius muscle. PMID- 27226456 TI - Bariatric surgery should be an option for treating type 2 diabetes, societies say. PMID- 27226458 TI - Three new treatments for diabetes recommended by NICE. PMID- 27226457 TI - Organizational-Level Strategies With or Without an Activity Tracker to Reduce Office Workers' Sitting Time: Rationale and Study Design of a Pilot Cluster Randomized Trial. AB - BACKGROUND: The office workplace is a key setting in which to address excessive sitting time and inadequate physical activity. One major influence on workplace sitting is the organizational environment. However, the impact of organizational level strategies on individual level activity change is unknown. Further, the emergence of sophisticated, consumer-targeted wearable activity trackers that facilitate real-time self-monitoring of activity, may be a useful adjunct to support organizational-level strategies, but to date have received little evaluation in this workplace setting. OBJECTIVE: The aim of this study is to evaluate the feasibility, acceptability, and effectiveness of organizational level strategies with or without an activity tracker on sitting, standing, and stepping in office workers in the short (3 months, primary aim) and long-term (12 months, secondary aim). METHODS: This study is a pilot, cluster-randomized trial (with work teams as the unit of clustering) of two interventions in office workers: organizational-level support strategies (eg, visible management support, emails) or organizational-level strategies plus the use of a waist-worn activity tracker (the LUMOback) that enables self-monitoring of sitting, standing, and stepping time and enables users to set sitting and posture alerts. The key intervention message is to 'Stand Up, Sit Less, and Move More.' Intervention elements will be implemented from within the organization by the Head of Workplace Wellbeing. Participants will be recruited via email and enrolled face to-face. Assessments will occur at baseline, 3, and 12 months. Time spent sitting, sitting in prolonged (>=30 minute) bouts, standing, and stepping during work hours and across the day will be measured with activPAL3 activity monitors (7 days, 24 hours/day protocol), with total sitting time and sitting time during work hours the primary outcomes. Web-based questionnaires, LUMOback recorded data, telephone interviews, and focus groups will measure the feasibility and acceptability of both interventions and potential predictors of behavior change. RESULTS: Baseline and follow-up data collection has finished. Results are expected in 2016. CONCLUSIONS: This pilot, cluster-randomized trial will evaluate the feasibility, acceptability, and effectiveness of two interventions targeting reductions in sitting and increases in standing and stepping in office workers. Few studies have evaluated these intervention strategies and this study has the potential to contribute both short and long-term findings. PMID- 27226459 TI - Screening for prostate cancer: time to put all the data on the table. PMID- 27226460 TI - Development and Validation of an LC-MS-MS Method for Determination of Simvastatin and Simvastatin Acid in Human Plasma: Application to a Pharmacokinetic Study. AB - A liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous determination of simvastatin (SV) and simvastatin acid (SVA) in human plasma. To improve assay sensitivity and achieve simultaneous analysis, SVA monitored in (-)ESI (electrospray ionization) mode within the first 4.5 min and SV thereafter in (+)ESI mode. The separation of all compounds was achieved in about 6.2 min using a C18 reverse-phase fused-core((r)) column (Ascentis((r)) Express C18) and a mobile phase, which was composed of 2.00 +/- 0.05 mM ammonium acetate buffer titrated to pH 3.8 with glacial acetic acid acetonitrile (25:75, v/v), in isocratic mode at a flow rate of 0.500 mL/min. Additionally, a solid-phase extraction step was performed to reduce any ion suppression and/or enhancement effects. The developed method was linear in the concentration range of 0.100-74.626 ng/mL for SV, and 0.100-48.971 ng/mL for SVA, with correlation coefficient greater than 0.99 for both analytes. The method has shown tremendous reproducibility, with intra- and inter-day precision <7.6%, and intra- and interday accuracy within +/-10.9% of nominal values, for the both analytes. The method was successfully applied to characterize the pharmacokinetic profiles of SV and SVA following an oral administration of 40 mg SV tablet to healthy human volunteers. PMID- 27226461 TI - A Fast and Reliable UPLC-PAD Fingerprint Analysis of Chimonanthus salicifolius Combined with Chemometrics Methods. AB - A novel fingerprinting approach was developed by means of ultra-high-performance liquid chromatography with photodiode array detector (UPLC-PAD) for the quality control of Chimonanthus salicifolius (C. salicifolius). All UPLC analyses were carried out on a Waters Acquity BEH Phenyl column (2.1 * 50 mm, 1.7 MUm particle size) at 48 degrees C, with a gradient mobile phase composed of 0.1% aqueous phosphoric acid and acetonitrile at a flow rate of 0.2 mL/min. The method validation results demonstrated the developed method possessing desirable precision [<0.88% relative standard deviation (RSD)], reproducibility (<1.87% RSD), stability (<1.42% RSD) and allowing fingerprint analysis in one chromatographic run within 21 min. The quality assessment was achieved by using chemometrics methods including similarity analysis, hierarchical clustering analysis and principal component analysis. The developed method can be used for further quality control of C. salicifolius. PMID- 27226462 TI - Development of Novel RP-HPLC Method for Separation and Estimation of Critical Geometric Isomer and Other Related Impurities of Tafluprost Drug Substance and Identification of Major Degradation Compounds by Using LC-MS. AB - A novel, simple, sensitive and stability-indicating reverse-phase high performance liquid chromatography (RP-HPLC) method was developed and validated for the quantitative determination of the geometric isomer (Trans) and other related substances in the active pharmaceutical ingredient (API) of Tafluprost (TFL), with their determination by an assay. A chromatographic separation of TFL and its impurities was achieved with a C18 analytical column, using gradient elution with mobile phase A consisting of a mixture of water, methanol and orthophosphoric acid (900:100:1, v/v) and mobile phase B consisting of a mixture of acetonitrile and water (900:100, v/v). The instrumental settings included a flow rate of 1.0 mL/min for related substances and 1.2 mL/min for the assay, a column temperature of 50 degrees C and a detector wavelength of 210 nm, using a photodiode array detector. TFL was exposed to thermal, photolytic, hydrolytic and oxidative stress conditions and the stressed samples were analyzed by the proposed method. Peak homogeneity data of TFL were obtained by using a photodiode array detector in the stressed sample chromatograms, which demonstrated the specificity of the method for estimation in the presence of degradants. The developed method was validated for parameters such as precision, accuracy, linearity, limit of detection, limit of quantification, ruggedness and robustness as per ICH guidelines. PMID- 27226463 TI - QbD-Driven Development and Validation of a HPLC Method for Estimation of Tamoxifen Citrate with Improved Performance. AB - The current studies entail Quality by Design (QbD)-enabled development of a simple, rapid, sensitive and cost-effective high-performance liquid chromatographic method for estimation of tamoxifen citrate (TMx). The factor screening studies were performed using a 7-factor 8-run Taguchi design. Systematic optimization was performed employing Box-Behnken design by selecting the mobile phase ratio, buffer pH and oven temperature as the critical method parameters (CMPs) identified from screening studies, thus evaluating the critical analytical attributes (CAAs), namely, peak area, retention time, theoretical plates and peak tailing as the parameters of method robustness. The optimal chromatographic separation was achieved using acetonitrile and phosphate buffer (pH 3.5) 52:48 v/v as the mobile phase with a flow rate 0.7 mL/min, an oven temperature 40 degrees C and UV detection at 256 nm. The method was validated as per the ICH recommended conditions, which revealed high degree of linearity, accuracy, precision, sensitivity and robustness over the existing liquid chromatographic methods of the drug. Also the method was applied for the estimation of TMx in nanostructured formulations, which indicated no significant change in the retention time. In a nutshell, the studies demonstrated successful development of the HPLC method of TMx with improved understanding of the relationship among the influential variables for enhancing the method performance. PMID- 27226464 TI - Biomass smoke as a risk factor for chronic obstructive pulmonary disease: effects on innate immunity. AB - Chronic obstructive pulmonary disease (COPD), a major cause of mortality and morbidity worldwide, is considered an archetypical disease of innate immunity, where inhaled particles and gases trigger an inflammatory response, favoring tissue proliferation in small airways and tissue destruction in lung parenchyma, in addition to the recruitment of immune cells to these compartments. Although cigarette smoking is still considered the main risk factor for developing COPD, the trend of proposing biomass smoke (BS) exposure as a principal risk factor is gaining importance, as around 3 billion people worldwide are exposed to this pollutant daily. A considerable amount of evidence has shown the potential of BS as an enhancer of lung inflammation. However, an impairment of some innate immune responses after BS exposure has also been described. Regarding the mechanisms by which biomass smoke alters the innate immune responses, three main classes of cell surface receptors-the TLRs, the scavenger receptors and the transient receptor potential channels-have shown the ability to transduce signals initiated after BS exposure. This article is an updated and comprehensive review of the immunomodulatory effects described after the interaction of BS components with these receptors. PMID- 27226465 TI - Impact of Actinobacillus pleuropneumoniae biofilm mode of growth on the lipid A structures and stimulation of immune cells. AB - Actinobacillus pleuropneumoniae (APP), the etiologic agent of porcine pleuropneumonia, forms biofilms on biotic and abiotic surfaces. APP biofilms confers resistance to antibiotics. To our knowledge, no studies have examined the role of APP biofilm in immune evasion and infection persistence. This study was undertaken to (i) investigate biofilm-associated LPS modifications occurring during the switch to biofilm mode of growth; and (ii) characterize pro inflammatory cytokines expression in porcine pulmonary alveolar macrophages (PAMs) and proliferation in porcine PBMCs challenged with planktonic or biofilm APP cells. Extracted lipid A samples from biofilm and planktonic cultures were analyzed by HPLC high-resolution, accurate mass spectrometry. Biofilm cells displayed significant changes in lipid A profiles when compared with their planktonic counterparts. Furthermore, in vitro experiments were conducted to examine the inflammatory response of PAMs exposed to UV-inactivated APP grown in biofilm or in suspension. Relative mRNA expression of pro-inflammatory genes IL1, IL6, IL8 and MCP1 decreased in PAMs when exposed to biofilm cells compared to planktonic cells. Additionally, the biofilm state reduced PBMCs proliferation. Taken together, APP biofilm cells show a weaker ability to stimulate innate immune cells, which could be due, in part, to lipid A structure modifications. PMID- 27226466 TI - Immune response and gut microbial community structure in bumblebees after microbiota transplants. AB - Microbial communities are a key component of host health. As the microbiota is initially 'foreign' to a host, the host's immune system should respond to its acquisition. Such variation in the response should relate not only to host genetic background, but also to differences in the beneficial properties of the microbiota. However, little is known about such interactions. Here, we investigate the gut microbiota of the bumblebee, Bombus terrestris, which has a protective function against the bee's natural trypanosome gut parasite, Crithidia bombi We transplanted 'resistant' and 'susceptible' microbiota into 'resistant' and 'susceptible' host backgrounds, and studied the activity of the host immune system. We found that bees from different resistance backgrounds receiving a microbiota differed in aspects of their immune response. At the same time, the elicited immune response also depended on the received microbiota's resistance phenotype. Furthermore, the microbial community composition differed between microbiota resistance phenotypes (resistant versus susceptible). Our results underline the complex feedback between the host's ability to potentially exert selection on the establishment of a microbial community and the influence of the microbial community on the host immune response in turn. PMID- 27226467 TI - Australian spiny mountain crayfish and their temnocephalan ectosymbionts: an ancient association on the edge of coextinction? AB - Australian spiny mountain crayfish (Euastacus, Parastacidae) and their ecotosymbiotic temnocephalan flatworms (Temnocephalida, Platyhelminthes) may have co-occurred and interacted through deep time, during a period of major environmental change. Therefore, reconstructing the history of their association is of evolutionary, ecological, and conservation significance. Here, time calibrated Bayesian phylogenies of Euastacus species and their temnocephalans (Temnohaswellia and Temnosewellia) indicate near-synchronous diversifications from the Cretaceous. Statistically significant cophylogeny correlations between associated clades suggest linked evolutionary histories. However, there is a stronger signal of codivergence and greater host specificity in Temnosewellia, which co-occurs with Euastacus across its range. Phylogeography and analyses of evolutionary distinctiveness (ED) suggest that regional differences in the impact of climate warming and drying had major effects both on crayfish and associated temnocephalans. In particular, Euastacus and Temnosewellia show strong latitudinal gradients in ED and, conversely, in geographical range size, with the most distinctive, northern lineages facing the greatest risk of extinction. Therefore, environmental change has, in some cases, strengthened ecological and evolutionary associations, leaving host-specific temnocephalans vulnerable to coextinction with endangered hosts. Consequently, the extinction of all Euastacus species currently endangered (75%) predicts coextinction of approximately 60% of the studied temnocephalans, with greatest loss of the most evolutionarily distinctive lineages. PMID- 27226468 TI - Rhythmic modulation of visual contrast discrimination triggered by action. AB - Recent evidence suggests that ongoing brain oscillations may be instrumental in binding and integrating multisensory signals. In this experiment, we investigated the temporal dynamics of visual-motor integration processes. We show that action modulates sensitivity to visual contrast discrimination in a rhythmic fashion at frequencies of about 5 Hz (in the theta range), for up to 1 s after execution of action. To understand the origin of the oscillations, we measured oscillations in contrast sensitivity at different levels of luminance, which is known to affect the endogenous brain rhythms, boosting the power of alpha-frequencies. We found that the frequency of oscillation in sensitivity increased at low luminance, probably reflecting the shift in mean endogenous brain rhythm towards higher frequencies. Importantly, both at high and at low luminance, contrast discrimination showed a rhythmic motor-induced suppression effect, with the suppression occurring earlier at low luminance. We suggest that oscillations play a key role in sensory-motor integration, and that the motor-induced suppression may reflect the first manifestation of a rhythmic oscillation. PMID- 27226469 TI - Social life and sanitary risks: evolutionary and current ecological conditions determine waste management in leaf-cutting ants. AB - Adequate waste management is vital for the success of social life, because waste accumulation increases sanitary risks in dense societies. We explored why different leaf-cutting ants (LCA) species locate their waste in internal nest chambers or external piles, including ecological context and accounting for phylogenetic relations. We propose that waste location depends on whether the environmental conditions enhance or reduce the risk of infection. We obtained the geographical range, habitat and refuse location of LCA from published literature, and experimentally determined whether pathogens on ant waste survived to the high soil temperatures typical of xeric habitats. The habitat of the LCA determined waste location after phylogenetic correction: species with external waste piles mainly occur in xeric environments, whereas those with internal waste chambers mainly inhabit more humid habitats. The ancestral reconstruction suggests that dumping waste externally is less derived than digging waste nest chambers. Empirical results showed that high soil surface temperatures reduce pathogen prevalence from LCA waste. We proposed that LCA living in environments unfavourable for pathogens (i.e. xeric habitats) avoid digging costs by dumping the refuse above ground. Conversely, in environments suitable for pathogens, LCA species prevent the spread of diseases by storing waste underground, presumably, a behaviour that contributed to the colonization of humid habitats. These results highlight the adaptation of organisms to the hygienic challenges of social living, and illustrate how sanitary behaviours can result from a combination of evolutionary history and current environmental conditions. PMID- 27226470 TI - Spatial and temporal genetic structure at the fourth trophic level in a fragmented landscape. AB - A fragmented habitat becomes increasingly fragmented for species at higher trophic levels, such as parasitoids. To persist, these species are expected to possess life-history traits, such as high dispersal, that facilitate their ability to use resources that become scarce in fragmented landscapes. If a specialized parasitoid disperses widely to take advantage of a sparse host, then the parasitoid population should have lower genetic structure than the host. We investigated the temporal and spatial genetic structure of a hyperparasitoid (fourth trophic level) in a fragmented landscape over 50 * 70 km, using microsatellite markers, and compared it with the known structures of its host parasitoid, and the butterfly host which lives as a classic metapopulation. We found that population genetic structure decreases with increasing trophic level. The hyperparasitoid has fewer genetic clusters (K = 4), than its host parasitoid (K = 15), which in turn is less structured than the host butterfly (K = 27). The genetic structure of the hyperparasitoid also shows temporal variation, with genetic differentiation increasing due to reduction of the population size, which reduces the effective population size. Overall, our study confirms the idea that specialized species must be dispersive to use a fragmented host resource, but that this adaptation has limits. PMID- 27226471 TI - Correction to: Climate change surpasses land-use change in the contracting range boundary of a winter-adapted mammal. PMID- 27226472 TI - Reef fishes can recognize bleached habitat during settlement: sea anemone bleaching alters anemonefish host selection. AB - Understanding how bleaching impacts the settlement of symbiotic habitat specialists and whether there is flexibility in settlement choices with regard to habitat quality is essential given our changing climate. We used five anemonefishes (Amphiprion clarkii, Amphiprion latezonatus, Amphiprion ocellaris, Amphiprion percula and Premnas biaculeatus) and three host sea anemones (Entacmaea quadricolor, Heteractis crispa and Heteractis magnifica) in paired choice flume experiments to determine whether habitat naive juveniles have the olfactory capabilities to distinguish between unbleached and bleached hosts, and how this may affect settlement decisions. All anemonefishes were able to distinguish between bleached and unbleached hosts, and responded only to chemical cues from species-specific host anemones irrespective of health status, indicating a lack of flexibility in host use. While bleached hosts were selected as habitat, this occurred only when unbleached options were unavailable, with the exception of A. latezonatus, which showed strong preferences for H. crispa regardless of health. This study highlights the potential deleterious indirect impacts of declining habitat quality during larval settlement in habitat specialists, which could be important in the field, given that bleaching events are becoming increasingly common. PMID- 27226473 TI - Reproductive dynamics shapes genomotype composition in an allopolyploid complex. AB - Hybrid complexes are composed of organisms with multiple combinations of parental genomes (genomotypes) that interconnect through nets of crosses. Although several such complexes are well established without speciation or extinction, mechanisms shaping their dynamics remain poorly understood. In this study, we quantified the reproductive success of the allopolyploid Iberian fish Squalius alburnoides in experimental free-access and directional crosses involving the most common genomotypes. Specifically, we analysed the paternity of the offspring produced when females had free access to male genomotypes and quantified variations in egg allocation, fertilization rate, and offspring survival among crosses involving each male genomotype. The composition of the offspring produced from free-access crosses varied significantly from that expected from random mating, suggesting that offspring production and viability are not independent of parental male genomotype. Moreover, directional crosses producing the genomotype most commonly found in wild populations appeared to be the most successful, with females laying more eggs, and fertilization rate and offspring survival being the highest. These results suggest that reproductive dynamics plays a relevant role in structuring the genomotype composition of populations and opens a path to future research on the ecology and evolutionary biology of allopolyploids and their multiplicity of possible evolutionary pathways. PMID- 27226474 TI - Superior discrimination for hue than for saturation and an explanation in terms of correlated neural noise. AB - The precision of human colour discrimination depends on the region of colour space in which measurements are made and on the direction in which the compared colours-the discriminanda-differ. Working in a MacLeod-Boynton chromaticity diagram scaled so that thresholds at the white point were equal for the two axes, we made measurements at reference points lying on lines that passed at 45 degrees or -45 degrees through the white point. At a given reference chromaticity, we measured thresholds either for saturation (i.e. for discriminanda lying radially along the line passing through the white point) or for hue (i.e. for discriminanda lying on a tangent of a circle passing through the reference point and centred on the white point). The discriminanda always straddled the reference point in chromaticity. The attraction of this arrangement is that the two thresholds can be expressed in common units. All that differs between saturation and hue measurements is the phase with which the short-wave signal is combined with the long-/middle-wave signal. Except for chromaticities very close to the white point, saturation thresholds were systematically higher than hue thresholds. We offer a possible explanation in terms of correlated neural noise. PMID- 27226475 TI - Treating cattle with antibiotics affects greenhouse gas emissions, and microbiota in dung and dung beetles. AB - Antibiotics are routinely used to improve livestock health and growth. However, this practice may have unintended environmental impacts mediated by interactions among the wide range of micro- and macroorganisms found in agroecosystems. For example, antibiotics may alter microbial emissions of greenhouse gases by affecting livestock gut microbiota. Furthermore, antibiotics may affect the microbiota of non-target animals that rely on dung, such as dung beetles, and the ecosystem services they provide. To examine these interactions, we treated cattle with a commonly used broad-spectrum antibiotic and assessed downstream effects on microbiota in dung and dung beetles, greenhouse gas fluxes from dung, and beetle size, survival and reproduction. We found that antibiotic treatment restructured microbiota in dung beetles, which harboured a microbial community distinct from those in the dung they were consuming. The antibiotic effect on beetle microbiota was not associated with smaller size or lower numbers. Unexpectedly, antibiotic treatment raised methane fluxes from dung, possibly by altering the interactions between methanogenic archaea and bacteria in rumen and dung environments. Our findings that antibiotics restructure dung beetle microbiota and modify greenhouse gas emissions from dung indicate that antibiotic treatment may have unintended, cascading ecological effects that extend beyond the target animal. PMID- 27226476 TI - Metabolic rate covaries with fitness and the pace of the life history in the field. AB - Metabolic rate reflects the 'pace of life' in every organism. Metabolic rate is related to an organism's capacity for essential maintenance, growth and reproduction-all of which interact to affect fitness. Although thousands of measurements of metabolic rate have been made, the microevolutionary forces that shape metabolic rate remain poorly resolved. The relationship between metabolic rate and components of fitness are often inconsistent, possibly because these fitness components incompletely map to actual fitness and often negatively covary with each other. Here we measure metabolic rate across ontogeny and monitor its effects on actual fitness (lifetime reproductive output) for a marine bryozoan in the field. We also measure key components of fitness throughout the entire life history including growth rate, longevity and age at the onset of reproduction. We found that correlational selection favours individuals with higher metabolic rates in one stage and lower metabolic rates in the other-individuals with similar metabolic rates in each developmental stage displayed the lowest fitness. Furthermore, individuals with the lowest metabolic rates lived for longer and reproduced more, but they also grew more slowly and took longer to reproduce initially. That metabolic rate is related to the pace of the life history in nature has long been suggested by macroevolutionary patterns but this study reveals the microevolutionary processes that probably generated these patterns. PMID- 27226477 TI - Reproducibility of Uniform Spheroid Formation in 384-Well Plates: The Effect of Medium Evaporation. AB - Spheroid cultures of cancer cells reproduce the spatial dimension-induced in vivo tumor traits more effectively than the conventional two-dimensional cell cultures. With growing interest in spheroids for high-throughput screening (HTS) assays, there is an increasing demand for cost-effective miniaturization of reproducible spheroids in microtiter plates (MPs). However, well-to-well variability in spheroid size, shape, and growth is a frequently encountered problem with almost every culture method that has prevented the transfer of spheroids to the HTS platform. This variability partly arises due to increased susceptibility of MPs to edge effects and evaporation-induced changes in the growth of spheroids. In this study, we examined the effect of evaporation on the reproducibility of spheroids of tumor and nontumor cell lines in 384-well plates, and show that culture conditions that prevent evaporation-induced medium loss result in the formation of uniform spheroids across the plate. Additionally, we also present a few technical improvements to increase the scalability of the liquid-overlay spheroid culturing technique in MPs, together with a simple software routine for the quantification of spheroid size. We believe that these cost-effective improvements will aid in further improvement of spheroid cultures for HTS drug discovery. PMID- 27226478 TI - Specific functional pathologies of Cx43 mutations associated with oculodentodigital dysplasia. AB - Oculodentodigital dysplasia (ODDD) is a rare genetic disease that affects the development of multiple organs in the human body. More than 70 mutations in the gap junction connexin43 (Cx43) gene, GJA1, are associated with ODDD, most of which are inherited in an autosomal dominant manner. Many patients exhibit similar clinical presentations. However, there is high intrafamilial and interfamilial phenotypic variability. To better understand this variability, we established primary human dermal fibroblast cultures from several ODDD patients and unaffected controls. In the present study, we characterized three fibroblast lines expressing heterozygous p.L7V, p.G138R, and p.G143S Cx43 variants. All ODDD fibroblasts exhibited slower growth, reduced migration, and defective cell polarization, traits common to all ODDD fibroblasts studied so far. However, we found striking differences in overall expression levels, with p.L7V down regulated at the mRNA and protein level. Although all of the Cx43 variants could traffic to the cell surface, there were stark differences in gap junction plaque formation, gap junctional intercellular communication, Cx43 phosphorylation, and hemichannel activity among Cx43 variants, as well as subtle differences in myofibroblast differentiation. Together these findings enabled us to discover mutation-specific pathologies that may help to predict future clinical outcomes. PMID- 27226479 TI - Specific requirements of nonbilayer phospholipids in mitochondrial respiratory chain function and formation. AB - Mitochondrial membrane phospholipid composition affects mitochondrial function by influencing the assembly of the mitochondrial respiratory chain (MRC) complexes into supercomplexes. For example, the loss of cardiolipin (CL), a signature non bilayer-forming phospholipid of mitochondria, results in disruption of MRC supercomplexes. However, the functions of the most abundant mitochondrial phospholipids, bilayer-forming phosphatidylcholine (PC) and non-bilayer-forming phosphatidylethanolamine (PE), are not clearly defined. Using yeast mutants of PE and PC biosynthetic pathways, we show a specific requirement for mitochondrial PE in MRC complex III and IV activities but not for their formation, whereas loss of PC does not affect MRC function or formation. Unlike CL, mitochondrial PE or PC is not required for MRC supercomplex formation, emphasizing the specific requirement of CL in supercomplex assembly. Of interest, PE biosynthesized in the endoplasmic reticulum (ER) can functionally substitute for the lack of mitochondrial PE biosynthesis, suggesting the existence of PE transport pathway from ER to mitochondria. To understand the mechanism of PE transport, we disrupted ER-mitochondrial contact sites formed by the ERMES complex and found that, although not essential for PE transport, ERMES facilitates the efficient rescue of mitochondrial PE deficiency. Our work highlights specific roles of non bilayer-forming phospholipids in MRC function and formation. PMID- 27226480 TI - Iterative sorting of apical and basolateral cargo in Madin-Darby canine kidney cells. AB - For several decades, the trans-Golgi network (TGN) was considered the most distal stop and hence the ultimate protein-sorting station for distinct apical and basolateral transport carriers that reach their respective surface domains in the direct trafficking pathway. However, recent reports of apical and basolateral cargoes traversing post-Golgi compartments accessible to endocytic ligands before their arrival at the cell surface and the post-TGN breakup of large pleomorphic membrane fragments that exit the Golgi region toward the surface raised the possibility that compartments distal to the TGN mediate or contribute to biosynthetic sorting. Here we describe the development of a novel assay that quantitatively distinguishes different cargo pairs by their degree of colocalization at the TGN and by the evolution of colocalization during their TGN to-surface transport. Keys to the high resolution of our approach are 1) conversion of perinuclear organelle clustering into a two-dimensional microsomal spread and 2) identification of TGN and post-TGN cargo without the need for a TGN marker that universally cosegregates with all cargo. Using our assay, we provide the first evidence that apical NTRp75 and basolateral VSVG in Madin-Darby canine kidney cells still undergo progressive sorting after they exit the TGN toward the cell surface. PMID- 27226481 TI - Dual control by Cdk1 phosphorylation of the budding yeast APC/C ubiquitin ligase activator Cdh1. AB - The antagonism between cyclin-dependent kinases (Cdks) and the ubiquitin ligase APC/C-Cdh1 is central to eukaryotic cell cycle control. APC/C-Cdh1 targets cyclin B and other regulatory proteins for degradation, whereas Cdks disable APC/C-Cdh1 through phosphorylation of the Cdh1 activator protein at multiple sites. Budding yeast Cdh1 carries nine Cdk phosphorylation sites in its N-terminal regulatory domain, most or all of which contribute to inhibition. However, the precise role of individual sites has remained unclear. Here, we report that the Cdk phosphorylation sites of yeast Cdh1 are organized into autonomous subgroups and act through separate mechanisms. Cdk sites 1-3 had no direct effect on the APC/C binding of Cdh1 but inactivated a bipartite nuclear localization sequence (NLS) and thereby controlled the partitioning of Cdh1 between cytoplasm and nucleus. In contrast, Cdk sites 4-9 did not influence the cell cycle-regulated localization of Cdh1 but prevented its binding to the APC/C. Cdk sites 4-9 reside near two recently identified APC/C interaction motifs in a pattern conserved with the human Cdh1 orthologue. Thus a Cdk-inhibited NLS goes along with Cdk-inhibited APC/C binding sites in yeast Cdh1 to relay the negative control by Cdk1 phosphorylation of the ubiquitin ligase APC/C-Cdh1. PMID- 27226482 TI - Long-term dynamics of multisite phosphorylation. AB - Multisite phosphorylation cycles are ubiquitous in cell regulation systems and are studied at multiple levels of complexity, from molecules to organisms, with the ultimate goal of establishing predictive understanding of the effects of genetic and pharmacological perturbations of protein phosphorylation in vivo. Achieving this goal is essentially impossible without mathematical models, which provide a systematic framework for exploring dynamic interactions of multiple network components. Most of the models studied to date do not discriminate between the distinct partially phosphorylated forms and focus on two limiting reaction regimes, distributive and processive, which differ in the number of enzyme-substrate binding events needed for complete phosphorylation or dephosphorylation. Here we use a minimal model of extracellular signal-related kinase regulation to explore the dynamics of a reaction network that includes all essential phosphorylation forms and arbitrary levels of reaction processivity. In addition to bistability, which has been studied extensively in distributive mechanisms, this network can generate periodic oscillations. Both bistability and oscillations can be realized at high levels of reaction processivity. Our work provides a general framework for systematic analysis of dynamics in multisite phosphorylation systems. PMID- 27226483 TI - Membrane dynamics during cellular wound repair. AB - Cells rapidly reseal after damage, but how they do so is unknown. It has been hypothesized that resealing occurs due to formation of a patch derived from rapid fusion of intracellular compartments at the wound site. However, patching has never been directly visualized. Here we study membrane dynamics in wounded Xenopus laevis oocytes at high spatiotemporal resolution. Consistent with the patch hypothesis, we find that damage triggers rampant fusion of intracellular compartments, generating a barrier that limits influx of extracellular dextrans. Patch formation is accompanied by compound exocytosis, local accumulation and aggregation of vesicles, and rupture of compartments facing the external environment. Subcellular patterning is evident as annexin A1, dysferlin, diacylglycerol, active Rho, and active Cdc42 are recruited to compartments confined to different regions around the wound. We also find that a ring of elevated intracellular calcium overlaps the region where membrane dynamics are most evident and persists for several minutes. The results provide the first direct visualization of membrane patching during membrane repair, reveal novel features of the repair process, and show that a remarkable degree of spatial patterning accompanies damage-induced membrane dynamics. PMID- 27226484 TI - Comparative Plasmodium gene overexpression reveals distinct perturbation of sporozoite transmission by profilin. AB - Plasmodium relies on actin-based motility to migrate from the site of infection and invade target cells. Using a substrate-dependent gliding locomotion, sporozoites are able to move at fast speed (1-3 MUm/s). This motility relies on a minimal set of actin regulatory proteins and occurs in the absence of detectable filamentous actin (F-actin). Here we report an overexpression strategy to investigate whether perturbations of F-actin steady-state levels affect gliding locomotion and host invasion. We selected two vital Plasmodium berghei G-actin binding proteins, C-CAP and profilin, in combination with three stage-specific promoters and mapped the phenotypes afforded by overexpression in all three extracellular motile stages. We show that in merozoites and ookinetes, additional expression does not impair life cycle progression. In marked contrast, overexpression of C-CAP and profilin in sporozoites impairs circular gliding motility and salivary gland invasion. The propensity for productive motility correlates with actin accumulation at the parasite tip, as revealed by combinations of an actin-stabilizing drug and transgenic parasites. Strong expression of profilin, but not C-CAP, resulted in complete life cycle arrest. Comparative overexpression is an alternative experimental genetic strategy to study essential genes and reveals effects of regulatory imbalances that are not uncovered from deletion-mutant phenotyping. PMID- 27226485 TI - Polo kinase Cdc5 associates with centromeres to facilitate the removal of centromeric cohesin during mitosis. AB - Sister chromatid cohesion is essential for tension-sensing mechanisms that monitor bipolar attachment of replicated chromatids in metaphase. Cohesion is mediated by the association of cohesins along the length of sister chromatid arms. In contrast, centromeric cohesin generates intrastrand cohesion and sister centromeres, while highly cohesin enriched, are separated by >800 nm at metaphase in yeast. Removal of cohesin is necessary for sister chromatid separation during anaphase, and this is regulated by evolutionarily conserved polo-like kinase (Cdc5 in yeast, Plk1 in humans). Here we address how high levels of cohesins at centromeric chromatin are removed. Cdc5 associates with centromeric chromatin and cohesin-associated regions. Maximum enrichment of Cdc5 in centromeric chromatin occurs during the metaphase-to-anaphase transition and coincides with the removal of chromosome-associated cohesin. Cdc5 interacts with cohesin in vivo, and cohesin is required for association of Cdc5 at centromeric chromatin. Cohesin removal from centromeric chromatin requires Cdc5 but removal at distal chromosomal arm sites does not. Our results define a novel role for Cdc5 in regulating removal of centromeric cohesins and faithful chromosome segregation. PMID- 27226486 TI - Conditional knockout of polarity complex (atypical) PKCiota reveals an anti inflammatory function mediated by NF-kappaB. AB - The conserved proteins of the polarity complex made up of atypical PKC (aPKC, isoforms iota and zeta), Par6, and Par3 determine asymmetry in several cell types, from Caenorhabditis elegans oocytes to vertebrate epithelia and neurons. We previously showed that aPKC is down-regulated in intestinal epithelia under inflammatory stimulation. Further, expression of constitutively active PKCiota decreases NF-kappaB activity in an epithelial cell line, the opposite of the effect reported in other cells. Here we tested the hypothesis that aPKC has a dual function in epithelia, inhibiting the NF-kappaB pathway in addition to having a role in apicobasal polarity. We achieved full aPKC down-regulation in small intestine villi and colon surface epithelium using a conditional epithelium specific knockout mouse. The results show that aPKC is dispensable for polarity after cell differentiation, except for known targets, including ROCK and ezrin, claudin-4 expression, and barrier permeability. The aPKC defect resulted in increased NF-kappaB activity, which could be rescued by IKK and ROCK inhibitors. It also increased expression of proinflammatory cytokines. In contrast, expression of anti-inflammatory IL-10 decreased. We conclude that epithelial aPKC acts upstream of multiple mechanisms that participate in the inflammatory response in the intestine, including, but not restricted to, NF-kappaB. PMID- 27226487 TI - Higher-order oligomerization of Spc110p drives gamma-tubulin ring complex assembly. AB - The microtubule (MT) cytoskeleton plays important roles in many cellular processes. In vivo, MT nucleation is controlled by the gamma-tubulin ring complex (gammaTuRC), a 2.1-MDa complex composed of gamma-tubulin small complex (gammaTuSC) subunits. The mechanisms underlying the assembly of gammaTuRC are largely unknown. In yeast, the conserved protein Spc110p both stimulates the assembly of the gammaTuRC and anchors the gammaTuRC to the spindle pole body. Using a quantitative in vitro FRET assay, we show that gammaTuRC assembly is critically dependent on the oligomerization state of Spc110p, with higher-order oligomers dramatically enhancing the stability of assembled gammaTuRCs. Our in vitro findings were confirmed with a novel in vivo gammaTuSC recruitment assay. We conclude that precise spatial control over MT nucleation is achieved by coupling localization and higher-order oligomerization of the receptor for gammaTuRC. PMID- 27226488 TI - New particle formation in the free troposphere: A question of chemistry and timing. AB - New particle formation (NPF) is the source of over half of the atmosphere's cloud condensation nuclei, thus influencing cloud properties and Earth's energy balance. Unlike in the planetary boundary layer, few observations of NPF in the free troposphere exist. We provide observational evidence that at high altitudes, NPF occurs mainly through condensation of highly oxygenated molecules (HOMs), in addition to taking place through sulfuric acid-ammonia nucleation. Neutral nucleation is more than 10 times faster than ion-induced nucleation, and growth rates are size-dependent. NPF is restricted to a time window of 1 to 2 days after contact of the air masses with the planetary boundary layer; this is related to the time needed for oxidation of organic compounds to form HOMs. These findings require improved NPF parameterization in atmospheric models. PMID- 27226489 TI - Macrophage-Mediated Trogocytosis Leads to Death of Antibody-Opsonized Tumor Cells. AB - Understanding the complex behavior of effector cells such as monocytes or macrophages in regulating cancerous growth is of central importance for cancer immunotherapy. Earlier studies using CD20-specific antibodies have demonstrated that the Fcgamma receptor (FcgammaR)-mediated transfer of the targeted receptors from tumor cells to these effector cells through trogocytosis can enable escape from antibody therapy, leading to the viewpoint that this process is protumorigenic. In the current study, we demonstrate that persistent trogocytic attack results in the killing of HER2-overexpressing breast cancer cells. Further, antibody engineering to increase FcgammaR interactions enhances this tumoricidal activity. These studies extend the complex repertoire of activities of macrophages to trogocytic-mediated cell death of HER2-overexpressing target cells and have implications for the development of effective antibody-based therapies. Mol Cancer Ther; 15(8); 1879-89. (c)2016 AACR. PMID- 27226491 TI - An in vitro study on the genotoxic effect of substituted furans in cells transfected with human metabolizing enzymes: 2,5-dimethylfuran and furfuryl alcohol. AB - 2,5-Dimethylfuran (DMF) and furfuryl alcohol (FFA) are two substituted furans that are formed during the processing of foods and have also been used as food flavorings. DMF and FFA are proposed to be bioactivated by human sulfotransferases (SULTs) which are not expressed in conventional cell lines used for genotoxicity testing. Therefore, in addition to the standard V79 cell line, we used a transfected V79 derived cell line co-expressing human cytochrome P450 (CYP) 2E1 and human SULT1A1 to assess the genotoxicity of DMF and FFA. The alkaline single cell gel electrophoresis (SCGE) assay was used to detect DNA damage in the form of single strand breaks and alkali-labile sites after exposure to DMF (0.5h; 0.5, 1, 1.5 or 2mM) or FFA (3h; 1, 3, 6 or 15mM). DMF induced DNA damage in V79 cells in a concentration-dependent manner irrespective of the expression of human CYP2E1 and SULT1A1. Almost no increase in the level of DNA damage was detected after exposure to FFA, except for a weak effect at the highest concentration in the transfected cell line. The results suggest that DNA damage in V79 cells from exposure to DMF detected by the alkaline SCGE assay is independent of human CYP2E1 and SULT1A1, and the genotoxic effect of FFA, as assessed by SCGE, is minimal in V79 cells. PMID- 27226490 TI - Developmental origins of inflammatory and immune diseases. AB - Epidemiological and experimental animal studies show that suboptimal environments in fetal and neonatal life exert a profound influence on physiological function and risk of diseases in adult life. The concepts of the 'developmental programming' and Developmental Origins of Health and Diseases (DOHaD) have become well accepted and have been applied across almost all fields of medicine. Adverse intrauterine environments may have programming effects on the crucial functions of the immune system during critical periods of fetal development, which can permanently alter the immune function of offspring. Immune dysfunction may in turn lead offspring to be susceptible to inflammatory and immune diseases in adulthood. These facts suggest that inflammatory and immune disorders might have developmental origins. In recent years, inflammatory and immune disorders have become a growing health problem worldwide. However, there is no systematic report in the literature on the developmental origins of inflammatory and immune diseases and the potential mechanisms involved. Here, we review the impacts of adverse intrauterine environments on the immune function in offspring. This review shows the results from human and different animal species and highlights the underlying mechanisms, including damaged development of cells in the thymus, helper T cell 1/helper T cell 2 balance disturbance, abnormal epigenetic modification, effects of maternal glucocorticoid overexposure on fetal lymphocytes and effects of the fetal hypothalamic-pituitary-adrenal axis on the immune system. Although the phenomena have already been clearly implicated in epidemiologic and experimental studies, new studies investigating the mechanisms of these effects may provide new avenues for exploiting these pathways for disease prevention. PMID- 27226492 TI - BAP18 coactivates androgen receptor action and promotes prostate cancer progression. AB - BPTF associated protein of 18 kDa (BAP18) has been reported as a component of MLL1-WDR5 complex. However, BAP18 is an uncharacterized protein. The detailed biological functions of BAP18 and underlying mechanisms have not been defined. Androgen receptor (AR), a member of transcription factor, plays an essential role in prostate cancer (PCa) and castration-resistant prostate cancer (CRPC) progression. Here, we demonstrate that BAP18 is identified as a coactivator of AR in Drosophilar experimental system and mammalian cells. BAP18 facilitates the recruitment of MLL1 subcomplex and AR to androgen-response element (ARE) of AR target genes, subsequently increasing histone H3K4 trimethylation and H4K16 acetylation. Knockdown of BAP18 attenuates cell growth and proliferation of PCa cells. Moreover, BAP18 depletion results in inhibition of xenograft tumor growth in mice even under androgen-depletion conditions. In addition, our data show that BAP18 expression in clinical PCa samples is higher than that in benign prostatic hyperplasia (BPH). Our data suggest that BAP18 as an epigenetic modifier regulates AR-induced transactivation and the function of BAP18 might be targeted in human PCa to promote tumor growth and progression to castration-resistance. PMID- 27226494 TI - EZH2 is required for mouse oocyte meiotic maturation by interacting with and stabilizing spindle assembly checkpoint protein BubRI. AB - Enhancer of zeste homolog 2 (EZH2) trimethylates histone H3 Lys 27 and plays key roles in a variety of biological processes. Stability of spindle assembly checkpoint protein BubR1 is essential for mitosis in somatic cells and for meiosis in oocytes. However, the role of EZH2 in oocyte meiotic maturation was unknown. Here, we presented a mechanism underlying EZH2 control of BubR1 stability in the meiosis of mouse oocytes. We identified a methyltransferase activity-independent function of EZH2 by demonstrating that EZH2 regulates spindle assembly and the polar body I extrusion. EZH2 was increased with the oocyte progression from GVBD to MII, while EZH2 was concentrated on the chromosomes. Interestingly, inhibition of EZH2 methyltranferase activity by DZNep or GSK343 did not affect oocyte meiotic maturation. However, depletion of EZH2 by morpholino led to chromosome misalignment and abnormal spindle assembly. Furthermore, ectopic expression of EZH2 led to oocyte meiotic maturation arrested at the MI stage followed by chromosome misalignment and aneuploidy. Mechanistically, EZH2 directly interacted with and stabilized BubR1, an effect driving EZH2 into the concert of meiosis regulation. Collectively, we provided a paradigm that EZH2 is required for mouse oocyte meiotic maturation. PMID- 27226493 TI - The stringent factor RelA adopts an open conformation on the ribosome to stimulate ppGpp synthesis. AB - Under stress conditions, such as nutrient starvation, deacylated tRNAs bound within the ribosomal A-site are recognized by the stringent factor RelA, which converts ATP and GTP/GDP to (p)ppGpp. The signaling molecules (p)ppGpp globally rewire the cellular transcriptional program and general metabolism, leading to stress adaptation. Despite the additional importance of the stringent response for regulation of bacterial virulence, antibiotic resistance and persistence, structural insight into how the ribosome and deacylated-tRNA stimulate RelA mediated (p)ppGpp has been lacking. Here, we present a cryo-EM structure of RelA in complex with the Escherichia coli 70S ribosome with an average resolution of 3.7 A and local resolution of 4 to >10 A for RelA. The structure reveals that RelA adopts a unique 'open' conformation, where the C-terminal domain (CTD) is intertwined around an A/T-like tRNA within the intersubunit cavity of the ribosome and the N-terminal domain (NTD) extends into the solvent. We propose that the open conformation of RelA on the ribosome relieves the autoinhibitory effect of the CTD on the NTD, thus leading to stimulation of (p)ppGpp synthesis by RelA. PMID- 27226495 TI - An unusual cause of superior vena cava syndrome after pacemaker implantation. PMID- 27226496 TI - Typical atrial flutter with muscular type tricuspid atresia. PMID- 27226498 TI - The NCCN 21st Annual Conference: Discussing Key Issues and Updated NCCN Guidelines. PMID- 27226499 TI - NCCN Evidence Blocks. AB - NCCN has developed a series of Evidence Blocks: graphics that provide ratings for each recommended treatment regimen in terms of efficacy, toxicity, quality and consistency of the supporting data, and affordability. The NCCN Evidence Blocks are currently available in 10 tumor types within the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). At a glance, patients and providers can understand how a given treatment was assessed by the NCCN Guidelines Panel and get a sense of how a given treatment may match individual needs and preferences. Robert W. Carlson, MD, CEO of NCCN, described the reasoning behind this new feature and how the tool is used, and Eric Jonasch, MD, Professor of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center, and Vice Chair of the NCCN Kidney Cancer Panel, described its applicability in the management of metastatic renal cell carcinoma. PMID- 27226497 TI - Perioperative management of antithrombotic treatment during implantation or revision of cardiac implantable electronic devices: the European Snapshot Survey on Procedural Routines for Electronic Device Implantation (ESS-PREDI). AB - The European Snapshot Survey on Procedural Routines for Electronic Device Implantation (ESS-PREDI) was a prospective European survey of consecutive adults who had undergone implantation/surgical revision of a cardiac implantable electronic device (CIED) on chronic antithrombotic therapy (enrolment March-June 2015). The aim of the survey was to investigate perioperative treatment with oral anticoagulants and antiplatelets in CIED implantation or surgical revision and to determine the incidence of complications, including clinically significant pocket haematomas. Information on antithrombotic therapy before and after surgery and bleeding and thromboembolic complications occurring after the intervention was collected at first follow-up. The study population comprised 723 patients (66.7% men, 76.9% aged >=66 years). Antithrombotic treatment was continued during surgery in 489 (67.6%) patients; 6 (0.8%) had their treatment definitively stopped; 46 (6.4%) were switched to another antithrombotic therapy. Heparin bridging was used in 55 out of 154 (35.8%) patients when interrupting vitamin K antagonist (VKA) treatment. Non-vitamin K oral anticoagulant (NOAC) treatment was interrupted in 88.7% of patients, with heparin bridging in 25.6%, but accounted for only 25.3% of the oral anticoagulants used. A total of 108 complications were observed in 98 patients. No intracranial haemorrhage or embolic events were observed. Chronic NOAC treatment before surgery was associated with lower rates of minor pocket haematoma (1.4%; P= 0.042) vs. dual antiplatelet therapy (13.0%), VKA (11.4%), VKA + antiplatelet (9.2%), or NOAC + antiplatelet (7.7%). Similar results were observed for bleeding complications (P= 0.028). Perioperative management of patients undergoing CIED implantation/surgical revision while on chronic antithrombotic therapy varies, with evidence of a disparity between guideline recommendations and practice patterns in Europe. Haemorrhagic complications were significantly less frequent in patients treated with NOACs. Despite this, the incidence of severe pocket haematomas was low. PMID- 27226500 TI - The Role of Biosimilars. AB - As biologics go off-patent, the field of oncology is grappling with incorporating biosimilars. These are highly similar (but not generic versions of) biologic agents, and they are approved based on showing "near fingerprint identity" in structure and potency. Their introduction is expected to increase competition and lower treatment costs. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Myeloid Growth Factors has incorporated the first biosimilar approved in the United States, filgrastim-sndz, into its recommendations. At the NCCN 21st Annual Conference, Andrew D. Zelenetz, MD, PhD, provided an overview of biosimilars, describing the process of their development and approval; Pamela S. Becker, MD, PhD, discussed the NCCN Guidelines recommendations for the use of filgrastim-sndz and of tbo-filgrastim, which was approved in the United States as a true biologic agent. The use of tbo-filgrastim can be somewhat confusing, as it does not have the same indications as the other growth factors. PMID- 27226501 TI - NCCN Roundtable: Palliative Care: Providing Comfort From a Patient and Provider Perspective. AB - The words "palliative care" can be threatening for many patients, particularly for those who do not understand what they mean. In fact, according to a survey by the American Cancer Society, about 70% of adults in the United States are not at all knowledgeable about palliative care and how to get it. Often confused with hospice care, palliative care is a rapidly evolving and relatively new specialty focusing on a wide range of issues faced by patients with cancer both during and after treatment. At the NCCN 21st Annual Conference, a distinguished panel assembled to discuss palliative care through the eyes of patients and providers alike. The panel explored some of the barriers to integrating palliative care as well as strategies for overcoming these obstacles to ensure that patients have the opportunity to benefit from the valuable yet often unheralded services provided by palliative care specialists. PMID- 27226502 TI - Major Changes in Systemic Therapy for Advanced Melanoma. AB - Over the past 5 years, a host of new agents have radically changed the therapeutic landscape in advanced melanoma; gone are the days when the only active agents were interferon and dacarbazine. Nearly 25 years ago, few patients with stage IV melanoma reached 2-year survival; today, these survival curves have risen substantially. At the NCCN 21st Annual Conference, John A. Thompson, MD, discussed updates with longer duration of patient follow-up for immune checkpoint therapies. He also reviewed some of the newer approvals in advanced melanoma, including the combination of ipilimumab and nivolumab, high-dose ipilimumab, the oncolytic virus therapy talimogene laherparepvec, and the molecularly targeted combination of the BRAF and MEK inhibitors vemurafenib and cobimetinib. PMID- 27226503 TI - NCCN Guidelines Update: Breast Cancer. AB - The updates to management of early invasive breast cancer in 2016 are minor but have important treatment implications for patients. The NCCN Guidelines Panel for Breast Cancer has added endocrine therapy to its recommendations for the neoadjuvant treatment of patients with ER-rich tumors. For women who are premenopausal at diagnosis, the NCCN Guidelines suggest tamoxifen for 5 years, with or without ovarian suppression, or an aromatase inhibitor for 5 years combined with ovarian suppression or ablation. For HER2-positive patients, neoadjuvant pertuzumab is acceptable, and in advanced estrogen receptor-positive disease, palbociclib can be given with endocrine therapy. Hypofractionation is now the preferred approach for whole-breast irradiation after breast-conserving therapy. Regional nodal irradiation should be strongly considered for women with 1 to 3 positive lymph nodes and is indicated for those with 4 or more positive nodes. PMID- 27226504 TI - Strategies for the Management of Early-Stage Breast Cancer in Older Women. AB - Older patients with breast cancer (aged >=65 years) are often undertreated with both locoregional and systemic therapies and have been shown to have higher breast cancer-specific mortality. These patients are also excluded from most clinical trials; therefore, treatment recommendations are extrapolated from younger populations. The data that do exist, however, show that older patients usually tolerate and respond well to conventional treatments. When selecting treatments for breast cancer, age should not be the chief consideration; comorbidities and functional status are also important, as is life expectancy. For patients with an estimated survival of less than 5 years, aggressive treatment may be discouraged; however, if the estimated survival is 5 years or more, treatment according to recurrence risk is recommended. In the curative setting, undertreatment should be avoided. PMID- 27226506 TI - New NCCN Guidelines for Vulvar Cancer. AB - For the first time, NCCN Guidelines are available for vulvar cancer, a rare gynecologic cancer. Early-stage cancers can be managed by surgery and observation, and many of these patients can be cured. Lymph node status drives treatment and correlates with survival. Positive groinal nodes require additional therapy, including radiation plus chemotherapy, depending on stage. Sentinel lymph node biopsy is recommended in selected patients. PMID- 27226505 TI - Controversies in Breast Cancer Screening Strategies. AB - A panel discussion on controversies in breast cancer screening held recently at the NCCN 21st Annual Conference included only a few controversies. Representatives of the U.S. Preventive Services Task Force, American Cancer Society, and NCCN disagreed primarily on 2 main areas: when to start screening (ages 40, 45, or 50 years) and frequency of screening (annual vs biennial). Panelists from these organizations presented the rationales for their respective recommendations. PMID- 27226507 TI - Multigene Testing in Localized Prostate Cancer. AB - Currently, there are several commercially available multigene tests for risk stratification in prostate cancer. These tests have been validated retrospectively; however, prospective studies are needed to fully establish their clinical roles. In some cases, molecular studies may add value, and updated NCCN Guidelines recommend "consideration" of molecular tests under certain circumstances, such as to help ascertain the likelihood of death from conservative management, of biochemical progression after radical prostatectomy or external-beam therapy, and of developing metastasis after radical prostatectomy or salvage radiotherapy. PMID- 27226508 TI - Evolving Use of Androgen Deprivation Therapy in Prostate Cancer Management. AB - Since its introduction more than 70 years ago, the use of androgen deprivation therapy (ADT) for prostate cancer has evolved to become part of a multimodal management approach. In this presentation from the NCCN 21st Annual Conference, James L. Mohler, MD, reviewed data that inform these strategies and gave his bottom-line recommendations on issues such as ADT plus radiotherapy, continuous versus intermittent ADT, ADT for positive nodes, and ADT plus docetaxel. He suggested that ADT plus radiation therapy should be used in patients at high risk, intermittent ADT is more appropriate for most patients than continuous ADT, and docetaxel should be given with ADT for high-volume metastatic disease. PMID- 27226509 TI - Metastatic Colorectal Cancer: Lessons Learned, Future Possibilities. AB - Survival of patients with metastatic colorectal cancer has dramatically improved over the past 20 years, primarily because physicians have become adept at using the many regimens approved for this patient population. Future advances may come from understanding molecular subtypes, finding and treating new actionable mutations, and harnessing the immune system. PMID- 27226510 TI - Management of Advanced-Phase Chronic Myelogenous Leukemia. AB - Chronic myelogenous leukemia represents the poster child of successful precision medicine in cancer, with amazing survival results achieved with targeted tyrosine kinase inhibitors (TKIs) in many patients with chronic-phase disease. Unfortunately, however, this good news has not extended to patients in blast crisis, for whom survival has not clearly been improved with TKIs. During his presentation at the NCCN 21st Annual Conference, Jerald P. Radich, MD, briefly explored the biology behind advanced-stage disease and several of the molecular findings in disease progression. He also reviewed some of the therapeutic options in advanced disease, emphasizing that transplantation, although fraught with some difficulties, offers the best long-term prognosis for patients in blast crisis. PMID- 27226511 TI - Management of EGFR Mutation-Positive Non-Small Cell Lung Cancer. AB - For appropriate treatment selection, the updated NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) recommend broad molecular profiling for all patients with nonsquamous disease. Three different tyrosine kinase inhibitors (TKIs) are recommended as first-line treatment of EGFR mutation-positive NSCLC: gefitinib, erlotinib, and afatinib. Most patients whose disease responds will still experience progression, and the type of disease progression drives management. Systemic progression requires switching TKI treatment, whereas patients with oligoprogression and central nervous system progression may have their new lesions treated but continue on their TKI. A new third-generation TKI has been approved and others are currently under development, and new combinations of these drugs with a VEGFR inhibitor offer promise to improve outcomes. PMID- 27226512 TI - NCCN Guidelines Update for Multiple Myeloma. AB - The updated NCCN Guidelines for Multiple Myeloma feature several changes in the diagnosis and management of this disease. Criteria for treatment initiation have been broadened, new staging has been recommended, and new classes of agents and combinations are included as recommended treatment. Monoclonal antibodies are among the expanded therapeutic choices, along with a histone deacetylase inhibitor and third-generation proteosome inhibitor, and there is excitement about exploring new immune-based approaches. PMID- 27226513 TI - Role of Imaging in Diagnosing and Staging Pancreatic Cancer. AB - Imaging is a key component of diagnosis and staging of pancreatic cancer. CT, MRI, and endoscopic ultrasound are the most used and approved imaging modalities. The updated NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pancreatic Adenocarcinoma feature a recently published Pancreatic Ductal Adenocarcinoma Radiology Reporting Template endorsed by the Society of Abdominal Radiology and the American Pancreatic Association. The goal of the template is to standardize the reporting of the imaging findings and to improve communication among the various team members treating patients with pancreatic cancer, to ensure appropriate patient management. PMID- 27226514 TI - Central Nervous System: Notable Developments in the Management of Primary and Recurrent Gliomas. AB - Over the past 30 years, the incidence of primary brain tumors has been increasing. Primary brain tumors are a heterogeneous group of central nervous system cancers with a wide range of outcomes and therapeutic strategies. As a result, prognostic features and molecular markers play a critical role in selecting treatment options for patients with brain tumors. At the NCCN 21st Annual Conference, Louis Burt Nabors, MD, reviewed the most appropriate adjuvant therapy for 3 types of brain tumors-primary low-grade gliomas, anaplastic oligodendrogliomas, and malignant gliomas-and shared supportive clinical trial data and NCCN recommendations. PMID- 27226515 TI - Sexual Function in Cancer Survivors: Updates to the NCCN Guidelines for Survivorship. AB - By the year 2024, predictions estimate that there will be approximately 19 million cancer survivors in the United States, many of whom will experience the physical and/or psychosocial long-term effects of cancer and its treatment. Although sexual dysfunction is common among these individuals, causing increased distress and negatively impacting quality of life, this critical part of survivorship care is often underrecognized and undertreated. At the NCCN 21st Annual Conference, Drs. Melisko and Narus reviewed the sexual function recommendations in the NCCN Guidelines for Survivorship, offering practical strategies for assessing and managing both female and male sexual dysfunction. PMID- 27226516 TI - Understanding and Utilizing Patient Preferences in Cancer Treatment Decisions. AB - Shared decision-making is a complex endeavor that should take into account the patient's personal preferences regarding treatment options. To truly empower patients to be partners in decision-making, especially in situations in which their preferences are important, physicians must learn to communicate better and to distinguish between what is "medical fact" versus a "value judgement." Knowing what are, when to ask, and how to ask the right questions will help physicians be effective in guiding patients toward the right treatments. PMID- 27226517 TI - Cancer Pain Management: Strategies for Safe and Effective Opioid Prescribing. AB - Although controversial in recent years, the use of opioid analgesics is a fundamental component of the management of patients with malignant pain. Decisions about whether to initiate opioid therapy require comprehensive patient assessment and a great deal of compassion, with an eye toward achieving a safety balance among patients, prescribers, and the community. At the NCCN 21st Annual Conference, Judith Paice, PhD, RN, reviewed the basics of pain assessment, the dangers of undertreatment and overtreatment, goals of pain management, and practical strategies for navigating through the continuum of pain and substance abuse. PMID- 27226518 TI - Commentary on 'The effect of depot medroxyprogesterone acetate on postnatal depression: a randomised clinical trial'. PMID- 27226519 TI - Comparison of Eligibility Criteria Between Protocols, Registries, and Publications of Cancer Clinical Trials. AB - Trial registration and public accessibility of appended or published protocols of phase III randomized clinical trials (RCTs) allow comparison of reported research with essential aspects of trial design. We determined how eligibility criteria of participants specified in protocols were described in trial registries and articles of 255 cancer RCTs published in leading journals. The mean proportion of matching eligibility criteria between protocols and publications per trial (the primary endpoint) was 44.0% (95% confidence interval [CI] = 40.8% to 47.3%). Almost all discrepancies in eligibility criteria (96.7%, 95% CI = 96.1% to 97.3%) suggested to readers of articles that a broader study population was included. The mean proportion of matching eligibility criteria between protocols and registries was 72.9% (95% CI = 68.2% to 77.7%, the secondary endpoint). We conclude that there are substantial differences in eligibility criteria between trial protocols, registries and articles. Inaccurate reporting of eligibility criteria may prevent appropriate assessment of the applicability of trial results. PMID- 27226522 TI - In Memoriam: F. Stephen Vogel, MD. PMID- 27226520 TI - Monocyte exosomes induce adhesion molecules and cytokines via activation of NF kappaB in endothelial cells. AB - HIV-infected individuals have activated monocytes with an IFNalpha phenotype and elevated levels of circulating LPS. These individuals also have a risk of premature cardiovascular disease. The effect of activated monocyte exosomes (Exos) on endothelial cells is unknown. To determine whether Exos from immune activated monocytes could alter endothelial cell expression and contribute to monocyte/macrophage transmigration and adhesion, we isolated Exos from monocytes stimulated with IFNalpha, LPS, or both (I/L). We show that monocyte Exos contain different inflammatory microRNA cargo depending on stimulation. When LPS Exos or I/L Exos were added to HUVECs, we found a significant increase in adhesion molecule ICAM-1, chemokine ligand (CCL)-2, and cytokine IL-6 mRNAs and proteins compared with cells treated with IFNalpha Exos or Exos derived from unstimulated monocytes. Inhibition of transcription factor NF-kappaB, a common inflammatory cytokine pathway, prevented induction of CCL2, IL6, and ICAM1 Inhibition of TLR4 resulted in differential blockage of the targets. Our results demonstrate for the first time that primary human monocyte Exos enter endothelial cells and cause dysfunction via the TLR4 and NF-kappaB pathways, which may contribute to heart disease in HIV infection and other diseases involving chronic immune activation. Tang, N., Sun, B., Gupta, A., Rempel, H., Pulliam, L. Monocyte exosomes induce adhesion molecules and cytokines via activation of NF-kappaB in endothelial cells. PMID- 27226523 TI - Additional proposals to reduce comorbidity in patients with chronic inflammatory rheumatic diseases: comment on 'Points to consider for reporting, screening for and preventing selected comorbidities in chronic inflammatory rheumatic diseases in daily practice: a EULAR initiative' by Baillet et al. PMID- 27226524 TI - Issues with anti-Gr1 antibody-mediated myeloid-derived suppressor cell depletion. PMID- 27226525 TI - Interventions for paediatric surgery patients with comorbid autism spectrum disorder: a systematic literature review. AB - AIMS: To survey perioperative management practices for paediatric patients diagnosed with autism spectrum disorder (ASD). METHODS: A systematic review was carried out of empirical studies and case reports published in peer-reviewed journals of current best practices and behavioural interventions for paediatric patients with ASD who had undergone surgery. RESULTS: The final sample included 11 articles published between 1997 and 2016 that met broad inclusion criteria of surveying perioperative interventions for the ASD population. There is broad endorsement across the scant publications on this topic of the following practices: increased attention to individual patient needs, rehearsal and other desensitisation efforts, departure from a sole focus on sedation or restraint of the combative or uncooperative patient and engaging caregivers in tuning perioperative management to individual needs. CONCLUSIONS: This review supports the need for an individualised structure and approach to the perioperative care of these unique patients. PMID- 27226526 TI - Informed consent for paediatric clinical trials in Europe. AB - OBJECTIVE: Paediatric clinical trials are often conducted as multinational trials. Informed consent or assent is part of the ethics committee approval for clinical trials. The consent requirements vary between countries due to national laws and regulations, which are not harmonised in Europe. These discrepancies can present challenges for paediatric clinical trials. The aim of this study was to assemble these consent and assent requirements across the European Economic Area. The collated national requirements have not been publicly available before, despite a real need for this data. METHODS: National consent and assent requirements for paediatric clinical trials were analysed and collated for 25 European Union Member States and 2 European Free Trade Association countries until the end of 2014. The data were retrieved from existing databases and through communication with the competent authorities and selected ethics committees. Results from a literature search for international or national guidelines, declarations and conventions and academic societies' publications served as comparison material. RESULTS: Consent and assent requirements are heterogeneous across these countries. We compiled our findings in 'The Informed Consent and Assent Tool Kit', a table including 27 national consent and assent requirements listed by individual country. CONCLUSIONS: Wide variation in paediatric consents and assents presents challenges for multinational paediatric trials in Europe. The toolkit is available for all those involved in paediatric clinical trials and ethics committees, providing a new platform for proactive feedback on informed consent requirements, and may finally lead to a needed harmonisation process, including uniform standards accepted across Europe. PMID- 27226527 TI - Human Mitochondrial Transcription Initiation Complexes Have Similar Topology on the Light and Heavy Strand Promoters. AB - Transcription is a highly regulated process in all domains of life. In human mitochondria, transcription of the circular genome involves only two promoters, called light strand promoter (LSP) and heavy strand promoter (HSP), located in the opposite DNA strands. Initiation of transcription occurs upon sequential assembly of an initiation complex that includes mitochondrial RNA polymerase (mtRNAP) and the initiation factors mitochondrial transcription factor A (TFAM) and TFB2M. It has been recently suggested that the transcription initiation factor TFAM binds to HSP and LSP in opposite directions, implying that the mechanisms of transcription initiation are drastically dissimilar at these promoters. In contrast, we found that binding of TFAM to HSP and the subsequent recruitment of mtRNAP results in a pre-initiation complex that is remarkably similar in topology and properties to that formed at the LSP promoter. Our data suggest that assembly of the pre-initiation complexes on LSP and HSP brings these transcription units in close proximity, providing an opportunity for regulatory proteins to simultaneously control transcription initiation in both mtDNA strands. PMID- 27226528 TI - Diabetes Impairs Wnt3 Protein-induced Neurogenesis in Olfactory Bulbs via Glutamate Transporter 1 Inhibition. AB - Diabetes is associated with impaired cognitive function. Streptozotocin (STZ) induced diabetic rats exhibit a loss of neurogenesis and deficits in behavioral tasks involving spatial learning and memory; thus, impaired adult hippocampal neurogenesis may contribute to diabetes-associated cognitive deficits. Recent studies have demonstrated that adult neurogenesis generally occurs in the dentate gyrus of the hippocampus, the subventricular zone, and the olfactory bulbs (OB) and is defective in patients with diabetes. We hypothesized that OB neurogenesis and associated behaviors would be affected in diabetes. In this study, we show that inhibition of Wnt3-induced neurogenesis in the OB causes several behavioral deficits in STZ-induced diabetic rats, including impaired odor discrimination, cognitive dysfunction, and increased anxiety. Notably, the sodium- and chloride dependent GABA transporters and excitatory amino acid transporters that localize to GABAergic and glutamatergic terminals decreased in the OB of diabetic rats. Moreover, GAT1 inhibitor administration also hindered Wnt3-induced neurogenesis in vitro Collectively, these data suggest that STZ-induced diabetes adversely affects OB neurogenesis via GABA and glutamate transporter systems, leading to functional impairments in olfactory performance. PMID- 27226529 TI - High Throughput Combinatorial Formatting of PcrV Nanobodies for Efficient Potency Improvement. AB - Improving potencies through concomitant blockage of multiple epitopes and avid binding by fusing multiple (different) monovalent Nanobody building blocks via linker sequences into one multivalent polypeptide chain is an elegant alternative to affinity maturation. We explored a large and random formatting library of bivalent (combinations of two identical) and biparatopic (combinations of two different) Nanobodies for functional blockade of Pseudomonas aeruginosa PcrV. PcrV is an essential part of the P. aeruginosa type III secretion system (T3SS), and its oligomeric nature allows for multiple complex binding and blocking options. The library screening yielded a large number of promising biparatopic lead candidates, revealing significant (and non-trivial) preferences in terms of Nanobody building block and epitope bin combinations and orientations. Excellent potencies were confirmed upon further characterization in two different P. aeruginosa T3SS-mediated cytotoxicity assays. Three biparatopic Nanobodies were evaluated in a lethal mouse P. aeruginosa challenge pneumonia model, conferring 100% survival upon prophylactic administration and reducing lung P. aeruginosa burden by up to 2 logs. At very low doses, they protected the mice from P. aeruginosa infection-related changes in lung histology, myeloperoxidase production, and lung weight. Importantly, the most potent Nanobody still conferred protection after therapeutic administration up to 24 h post-infection. The concept of screening such formatting libraries for potency improvement is applicable to other targets and biological therapeutic platforms. PMID- 27226530 TI - MicroRNA-214 Reduces Insulin-like Growth Factor-1 (IGF-1) Receptor Expression and Downstream mTORC1 Signaling in Renal Carcinoma Cells. AB - Elevated IGF-1/insulin-like growth factor-1 receptor (IGF-1R) autocrine/paracrine signaling in patients with renal cell carcinoma is associated with poor prognosis of the disease independent of their von Hippel-Lindau (VHL) status. Increased expression of IGF-1R in renal cancer cells correlates with their potency of tumor development and progression. The mechanism by which expression of IGF-1R is increased in renal carcinoma is not known. We report that VHL-deficient and VHL positive renal cancer cells possess significantly decreased levels of mature, pre , and pri-miR-214 than normal proximal tubular epithelial cells. We identified an miR-214 recognition element in the 3'UTR of IGF-1R mRNA and confirmed its responsiveness to miR-214. Overexpression of miR-214 decreased the IGF-1R protein levels, resulting in the inhibition of Akt kinase activity in both types of renal cancer cells. IGF-1 provoked phosphorylation and inactivation of PRAS40 in an Akt dependent manner, leading to the activation of mTORC1 signal transduction to increase phosphorylation of S6 kinase and 4EBP-1. Phosphorylation-deficient mutants of PRAS40 and 4EBP-1 significantly inhibited IGF-1R-driven proliferation of renal cancer cells. Expression of miR-214 suppressed IGF-1R-induced phosphorylation of PRAS40, S6 kinase, and 4EBP-1, indicating inhibition of mTORC1 activity. Finally, miR-214 significantly blocked IGF-1R-forced renal cancer cell proliferation, which was reversed by expression of 3'UTR-less IGF-1R and constitutively active mTORC1. Together, our results identify a reciprocal regulation of IGF-1R levels and miR-214 expression in renal cancer cells independent of VHL status. Our data provide evidence for a novel mechanism for IGF-1R-driven renal cancer cell proliferation involving miR-214 and mTORC1. PMID- 27226531 TI - Natural Product Anacardic Acid from Cashew Nut Shells Stimulates Neutrophil Extracellular Trap Production and Bactericidal Activity. AB - Emerging antibiotic resistance among pathogenic bacteria is an issue of great clinical importance, and new approaches to therapy are urgently needed. Anacardic acid, the primary active component of cashew nut shell extract, is a natural product used in the treatment of a variety of medical conditions, including infectious abscesses. Here, we investigate the effects of this natural product on the function of human neutrophils. We find that anacardic acid stimulates the production of reactive oxygen species and neutrophil extracellular traps, two mechanisms utilized by neutrophils to kill invading bacteria. Molecular modeling and pharmacological inhibitor studies suggest anacardic acid stimulation of neutrophils occurs in a PI3K-dependent manner through activation of surface expressed G protein-coupled sphingosine-1-phosphate receptors. Neutrophil extracellular traps produced in response to anacardic acid are bactericidal and complement select direct antimicrobial activities of the compound. PMID- 27226532 TI - Genetic Ablation of Calcium-independent Phospholipase A2gamma Induces Glomerular Injury in Mice. AB - Glomerular visceral epithelial cells (podocytes) play a critical role in the maintenance of glomerular permselectivity. Podocyte injury, manifesting as proteinuria, is the cause of many glomerular diseases. We reported previously that calcium-independent phospholipase A2gamma (iPLA2gamma) is cytoprotective against complement-mediated glomerular epithelial cell injury. Studies in iPLA2gamma KO mice have demonstrated an important role for iPLA2gamma in mitochondrial lipid turnover, membrane structure, and metabolism. The aim of the present study was to employ iPLA2gamma KO mice to better understand the role of iPLA2gamma in normal glomerular and podocyte function as well as in glomerular injury. We show that deletion of iPLA2gamma did not cause detectable albuminuria; however, it resulted in mitochondrial structural abnormalities and enhanced autophagy in podocytes as well as loss of podocytes in aging KO mice. Moreover, after induction of anti-glomerular basement membrane nephritis in young mice, iPLA2gamma KO mice exhibited significantly increased levels of albuminuria, podocyte injury, and loss of podocytes compared with wild type. Thus, iPLA2gamma has a protective functional role in the normal glomerulus and in glomerulonephritis. Understanding the role of iPLA2gamma in glomerular pathophysiology provides opportunities for the development of novel therapeutic approaches to glomerular injury and proteinuria. PMID- 27226533 TI - Autocrine Signaling Underlies Fast Repetitive Plasma Membrane Translocation of Conventional and Novel Protein Kinase C Isoforms in beta Cells. AB - PKC signaling has been implicated in the regulation of many cell functions, including metabolism, cell death, proliferation, and secretion. Activation of conventional and novel PKC isoforms is associated with their Ca(2+)- and/or diacylglycerol (DAG)-dependent translocation to the plasma membrane. In beta cells, exocytosis of insulin granules evokes brief (<10 s) local DAG elevations ("spiking") at the plasma membrane because of autocrine activation of P2Y1 purinoceptors by ATP co-released with insulin. Using total internal reflection microscopy, fluorescent protein-tagged PKCs, and signaling biosensors, we investigated whether DAG spiking causes membrane recruitment of PKCs and whether different classes of PKCs show characteristic responses. Glucose stimulation of MIN6 cells triggered DAG spiking with concomitant repetitive translocation of the novel isoforms PKCdelta, PKCepsilon, and PKCeta. The conventional PKCalpha, PKCbetaI, and PKCbetaII isoforms showed a more complex pattern with both rapid and slow translocation. K(+) depolarization-induced PKCepsilon translocation entirely mirrored DAG spiking, whereas PKCbetaI translocation showed a sustained component, reflecting the subplasma membrane Ca(2+) concentration ([Ca(2+)]pm), with additional effect during DAG spikes. Interference with DAG spiking by purinoceptor inhibition prevented intermittent translocation of PKCs and reduced insulin secretion but did not affect [Ca(2+)]pm elevation or sustained PKCbetaI translocation. The muscarinic agonist carbachol induced pronounced transient PKCbetaI translocation and sustained recruitment of PKCepsilon. When rise of [Ca(2+)]pm was prevented, the carbachol-induced DAG and PKCepsilon responses were somewhat reduced, but PKCbetaI translocation was completely abolished. We conclude that exocytosis-induced DAG spikes efficiently recruit both conventional and novel PKCs to the beta cell plasma membrane. PKC signaling is thus implicated in autocrine regulation of beta cell function. PMID- 27226534 TI - MicroRNA-223 Promotes Type I Interferon Production in Antiviral Innate Immunity by Targeting Forkhead Box Protein O3 (FOXO3). AB - Effective recognition of viral infection and subsequent triggering of antiviral innate immune responses are essential for the host antiviral defense, which is tightly regulated by multiple regulators, including microRNAs. Previous reports have shown that some microRNAs are induced during virus infection and participate in the regulation of the innate antiviral response. However, whether the type I IFN response is regulated by miR-223 is still unknown. Here, we reported that vesicular stomatitis virus (VSV) infection induced significant up-regulation of miR-223 in murine macrophages. We observed that miR-223 overexpression up regulated type I IFN expression levels in VSV-infected macrophages. We also demonstrated that miR-223 directly targets FOXO3 to regulate the type I IFN production. Furthermore, type I IFN, which is triggered by VSV infection, is responsible for the up-regulation of miR-223, thus forming a positive regulatory loop for type I IFN production. Our results uncovered a novel mechanism of miR 223-mediated regulation of type I IFN production in the antiviral innate immunity for the first time. PMID- 27226535 TI - The Spring alpha-Helix Coordinates Multiple Modes of HCV (Hepatitis C Virus) NS3 Helicase Action. AB - Genomic DNA replication requires helicases to processively unwind duplexes. Although helicases encoded by positive-strand RNA viruses are necessary for RNA genome replication, their functions are not well understood. We determined structures of the hepatitis C virus helicase (NS3h) in complex with the transition state ATP mimic ADP.AlF4 (-) and compared them with the previous nucleic acid-associated ternary complexes. The results suggested that nucleic acid binding promotes a structural change of the spring helix at the transition state, optimizing the interaction network centered on the nucleophilic water. Analysis of ATP hydrolysis with and without conformational restraints on the spring helix further supported the importance of its action for both nucleic acid stimulated and basal catalysis. We further found that an F238P substitution, predicted to destabilize the helix, diminished viral RNA replication without significantly affecting ATP-dependent duplex unwinding. The stability of the secondary structure, thus, seems critical for additional functions of NS3h. Taken together, the results suggest that the spring helix may be central to the coordination of multiple modes of NS3h action. Further characterization centered on this element may help understand the molecular details of how the viral helicase facilitates RNA replication. This new structural information may also aid efforts to develop specific inhibitors targeting this essential viral enzyme. PMID- 27226536 TI - Dynamic Heterogeneity of Brachyury in Mouse Epiblast Stem Cells Mediates Distinct Response to Extrinsic Bone Morphogenetic Protein (BMP) Signaling. AB - Mouse pluripotent cells, such as embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs), provide excellent in vitro systems to study imperative pre- and postimplantation events of in vivo mammalian development. It is known that mouse ESCs are dynamic heterogeneous populations. However, it remains largely unclear whether and how EpiSCs possess heterogeneity and plasticity similar to that of ESCs. Here, we show that EpiSCs are discriminated by the expression of a specific marker T (Brachyury) into two populations. The T-positive (T(+)) and the T negative (T(-)) populations can be interconverted within the same culture condition. In addition, the two populations display distinct responses to bone morphogenetic protein (BMP) signaling and different developmental potentials. The T(-) EpiSCs are preferentially differentiated into ectoderm lineages, whereas T(+) EpiSCs have a biased potential for mesendoderm fates. Mechanistic studies reveal that T(+) EpiSCs have an earlier and faster response to BMP4 stimulation than T(-) EpiSCs. Id1 mediates the commitment of T(-) EpiSCs to epidermal lineage during BMP4 treatment. On the other hand, Snail modulates the conversion of T(+) EpiSCs to mesendoderm fates with the presence of BMP4. Furthermore, T expression is essential for epithelial-mesenchymal transition during EpiSCs differentiation. Our findings suggest that the dynamic heterogeneity of the T(+)/T(-) subpopulation primes EpiSCs toward particular cell lineages, providing important insights into the dynamic development of the early mouse embryo. PMID- 27226537 TI - Role of Conserved Disulfide Bridges and Aromatic Residues in Extracellular Loop 2 of Chemokine Receptor CCR8 for Chemokine and Small Molecule Binding. AB - Chemokine receptors play important roles in the immune system and are linked to several human diseases. The initial contact of chemokines with their receptors depends on highly specified extracellular receptor features. Here we investigate the importance of conserved extracellular disulfide bridges and aromatic residues in extracellular loop 2 (ECL-2) for ligand binding and activation in the chemokine receptor CCR8. We used inositol 1,4,5-trisphosphate accumulation and radioligand binding experiments to determine the impact of receptor mutagenesis on both chemokine and small molecule agonist and antagonist binding and action in CCR8. We find that the seven-transmembrane (TM) receptor conserved disulfide bridge (7TM bridge) linking transmembrane helix III (TMIII) and ECL-2 is crucial for chemokine and small molecule action, whereas the chemokine receptor conserved disulfide bridge between the N terminus and TMVII is needed only for chemokines. Furthermore, we find that two distinct aromatic residues in ECL-2, Tyr(184) (Cys + 1) and Tyr(187) (Cys + 4), are crucial for binding of the CC chemokines CCL1 (agonist) and MC148 (antagonist), respectively, but not for small molecule binding. Finally, using in silico modeling, we predict an aromatic cluster of interaction partners for Tyr(187) in TMIV (Phe(171)) and TMV (Trp(194)). We show in vitro that these residues are crucial for the binding and action of MC148, thus supporting their participation in an aromatic cluster with Tyr(187) This aromatic cluster appears to be present in a large number of CC chemokine receptors and thereby could play a more general role to be exploited in future drug development targeting these receptors. PMID- 27226538 TI - A Plasma Membrane Association Module in Yeast Amino Acid Transporters. AB - Amino acid permeases (AAPs) in the plasma membrane (PM) of Saccharomyces cerevisiae are responsible for the uptake of amino acids and involved in regulation of their cellular levels. Here, we report on a strong and complex module for PM association found in the C-terminal tail of AAPs. Using in silico analyses and mutational studies we found that the C-terminal sequences of Gap1, Bap2, Hip1, Tat1, Tat2, Mmp1, Sam3, Agp1, and Gnp1 are about 50 residues long, associate with the PM, and have features that discriminate them from the termini of organellar amino acid transporters. We show that this sequence (named PMasseq) contains an amphipathic alpha-helix and the FWC signature, which is palmitoylated by palmitoyltransferase Pfa4. Variations of PMasseq, found in different AAPs, lead to different mobilities and localization patterns, whereas the disruption of the sequence has an adverse effect on cell viability. We propose that PMasseq modulates the function and localization of AAPs along the PM. PMasseq is one of the most complex protein signals for plasma membrane association across species and can be used as a delivery vehicle for the PM. PMID- 27226539 TI - Tail-anchored Protein Insertion in Mammals: FUNCTION AND RECIPROCAL INTERACTIONS OF THE TWO SUBUNITS OF THE TRC40 RECEPTOR. AB - The GET (guided entry of tail-anchored proteins)/TRC (transmembrane recognition complex) pathway for tail-anchored protein targeting to the endoplasmic reticulum (ER) has been characterized in detail in yeast and is thought to function similarly in mammals, where the orthologue of the central ATPase, Get3, is known as TRC40 or Asna1. Get3/TRC40 function requires an ER receptor, which in yeast consists of the Get1/Get2 heterotetramer and in mammals of the WRB protein (tryptophan-rich basic protein), homologous to yeast Get1, in combination with CAML (calcium-modulating cyclophilin ligand), which is not homologous to Get2. To better characterize the mammalian receptor, we investigated the role of endogenous WRB and CAML in tail-anchored protein insertion as well as their association, concentration, and stoichiometry in rat liver microsomes and cultured cells. Functional proteoliposomes, reconstituted from a microsomal detergent extract, lost their activity when made with an extract depleted of TRC40-associated proteins or of CAML itself, whereas in vitro synthesized CAML and WRB together were sufficient to confer insertion competence to liposomes. CAML was found to be in ~5-fold excess over WRB, and alteration of this ratio did not inhibit insertion. Depletion of each subunit affected the levels of the other one; in the case of CAML silencing, this effect was attributable to destabilization of the WRB transcript and not of WRB protein itself. These results reveal unanticipated complexity in the mutual regulation of the TRC40 receptor subunits and raise the question as to the role of the excess CAML in the mammalian ER. PMID- 27226540 TI - Effect of Hypertriglyceridemia on Beta Cell Mass and Function in ApoC3 Transgenic Mice. AB - Hypertriglyceridemia results from increased production and decreased clearance of triglyceride-rich very low-density lipoproteins, a pathological condition that accounts for heightened risk of ischemic vascular diseases in obesity and type 2 diabetes. Despite its intimate association with insulin resistance, whether hypertriglyceridemia constitutes an independent risk for beta cell dysfunction in diabetes is unknown. Answering this fundamental question is stymied by the fact that hypertriglyceridemia is intertwined with hyperglycemia and insulin resistance in obese and diabetic subjects. To circumvent this limitation, we took advantage of apolipoprotein C3 (ApoC3)-transgenic mice, a model with genetic predisposition to hypertriglyceridemia. We showed that ApoC3-transgenic mice, as opposed to age/sex-matched wild-type littermates, develop hypertriglyceridemia with concomitant elevations in plasma cholesterol and non-esterified fatty acid levels. Anti-insulin and anti-glucagon dual immunohistochemistry in combination with morphometric analysis revealed that ApoC3-transgenic and wild-type littermates had similar beta cell and alpha cell masses as well as islet size and architecture. These effects correlated with similar amplitudes of glucose stimulated insulin secretion and similar degrees of postprandial glucose excursion in ApoC3-transgenic versus wild-type littermates. Oil Red O histology did not visualize lipid infiltration into islets, correlating with the lack of ectopic triglyceride and cholesterol depositions in the pancreata of ApoC3 transgenic versus wild-type littermates. ApoC3-transgenic mice, despite persistent hypertriglyceridemia, maintained euglycemia under both fed and fasting conditions without manifestation of insulin resistance and fasting hyperinsulinemia. Thus, hypertriglyceridemia per se is not an independent risk factor for beta cell dysfunction in ApoC3 transgenic mice. PMID- 27226541 TI - Energetic Mechanism of Cytochrome c-Cytochrome c Oxidase Electron Transfer Complex Formation under Turnover Conditions Revealed by Mutational Effects and Docking Simulation. AB - Based on the mutational effects on the steady-state kinetics of the electron transfer reaction and our NMR analysis of the interaction site (Sakamoto, K., Kamiya, M., Imai, M., Shinzawa-Itoh, K., Uchida, T., Kawano, K., Yoshikawa, S., and Ishimori, K. (2011) Proc. Natl. Acad. Sci. U.S.A. 108, 12271-12276), we determined the structure of the electron transfer complex between cytochrome c (Cyt c) and cytochrome c oxidase (CcO) under turnover conditions and energetically characterized the interactions essential for complex formation. The complex structures predicted by the protein docking simulation were computationally selected and validated by the experimental kinetic data for mutant Cyt c in the electron transfer reaction to CcO. The interaction analysis using the selected Cyt c-CcO complex structure revealed the electrostatic and hydrophobic contributions of each amino acid residue to the free energy required for complex formation. Several charged residues showed large unfavorable (desolvation) electrostatic interactions that were almost cancelled out by large favorable (Columbic) electrostatic interactions but resulted in the destabilization of the complex. The residual destabilizing free energy is compensated by the van der Waals interactions mediated by hydrophobic amino acid residues to give the stabilized complex. Thus, hydrophobic interactions are the primary factors that promote complex formation between Cyt c and CcO under turnover conditions, whereas the change in the electrostatic destabilization free energy provides the variance of the binding free energy in the mutants. The distribution of favorable and unfavorable electrostatic interactions in the interaction site determines the orientation of the binding of Cyt c on CcO. PMID- 27226542 TI - Complement Membrane Attack and Tumorigenesis: A SYSTEMS BIOLOGY APPROACH. AB - Tumor development driven by inflammation is now an established phenomenon, but the role that complement plays remains uncertain. Recent evidence has suggested that various components of the complement (C) cascade may influence tumor development in disparate ways; however, little attention has been paid to that of the membrane attack complex (MAC). This is despite abundant evidence documenting the effects of this complex on cell behavior, including cell activation, protection from/induction of apoptosis, release of inflammatory cytokines, growth factors, and ECM components and regulators, and the triggering of the NLRP3 inflammasome. Here we present a novel approach to this issue by using global gene expression studies in conjunction with a systems biology analysis. Using network analysis of MAC-responsive expression changes, we demonstrate a cluster of co regulated genes known to have impact in the extracellular space and on the supporting stroma and with well characterized tumor-promoting roles. Network analysis highlighted the central role for EGF receptor activation in mediating the observed responses to MAC exposure. Overall, the study sheds light on the mechanisms by which sublytic MAC causes tumor cell responses and exposes a gene expression signature that implicates MAC as a driver of tumor progression. These findings have implications for understanding of the roles of complement and the MAC in tumor development and progression, which in turn will inform future therapeutic strategies in cancer. PMID- 27226543 TI - Structural and Functional Investigations of the Effector Protein LpiR1 from Legionella pneumophila. AB - Legionella pneumophila is a causative agent of a severe pneumonia, known as Legionnaires' disease. Legionella pathogenicity is mediated by specific virulence factors, called bacterial effectors, which are injected into the invaded host cell by the bacterial type IV secretion system. Bacterial effectors are involved in complex interactions with the components of the host cell immune and signaling pathways, which eventually lead to bacterial survival and replication inside the mammalian cell. Structural and functional studies of bacterial effectors are, therefore, crucial for elucidating the mechanisms of Legionella virulence. Here we describe the crystal structure of the LpiR1 (Lpg0634) effector protein and investigate the effects of its overexpression in mammalian cells. LpiR1 is an alpha-helical protein that consists of two similar domains aligned in an antiparallel fashion. The hydrophilic cleft between the domains might serve as a binding site for a potential host cell interaction partner. LpiR1 binds the phosphate group at a conserved site and is stabilized by Mn(2+), Ca(2+), or Mg(2+) ions. When overexpressed in mammalian cells, a GFP-LpiR1 fusion protein is localized in the cytoplasm. Intracellular signaling antibody array analysis revealed small changes in the phosphorylation state of several components of the Akt signaling pathway in HEK293T cells overexpressing LpiR1. PMID- 27226544 TI - Exon Skipping in the RET Gene Encodes Novel Isoforms That Differentially Regulate RET Protein Signal Transduction. AB - Rearranged during transfection (RET), a receptor tyrosine kinase that is activated by the glial cell line-derived neurotrophic factor family ligands (GFLs), plays a crucial role in the development and function of the nervous system and additionally is required for kidney development and spermatogenesis. RET encodes a transmembrane receptor that is 20 exons long and produces two known protein isoforms differing in C-terminal amino acid composition, referred to as RET9 and RET51. Studies of human pheochromocytomas identified two additional novel transcripts involving the skipping of exon 3 or exons 3, 4, and 5 and are referred to as RET(Delta) (E3) and RET(Delta) (E345), respectively. Here we report the presence of Ret(Delta) (E3) and Ret(Delta) (E345) in zebrafish, mice, and rats and show that these transcripts are dynamically expressed throughout development of the CNS, peripheral nervous system, and kidneys. We further explore the biochemical properties of these isoforms, demonstrating that, like full-length RET, RET(DeltaE3) and RET(DeltaE345) are trafficked to the cell surface, interact with all four GFRalpha co-receptors, and have the ability to heterodimerize with full-length RET. Signaling experiments indicate that RET(DeltaE3) is phosphorylated in a similar manner to full-length RET. RET(DeltaE345), in contrast, displays higher baseline autophosphorylation, specifically on the catalytic tyrosine, Tyr(905), and also on one of the most important signaling residues, Tyr(1062) These data provide the first evidence for a physiologic role of these isoforms in RET pathway function. PMID- 27226545 TI - Characterization of the Regulation of CD46 RNA Alternative Splicing. AB - Here we present a detailed analysis of the alternative splicing regulation of human CD46, which generates different isoforms with distinct functions. CD46 is a ubiquitous membrane protein that protects host cells from complement and plays other roles in immunity, autophagy, and cell adhesion. CD46 deficiency causes an autoimmune disorder, and this protein is also involved in pathogen infection and cancer. Before this study, the mechanisms of CD46 alternative splicing remained unexplored even though dysregulation of this process has been associated with autoimmune diseases. We proved that the 5' splice sites of CD46 cassette exons 7 and 8 encoding extracellular domains are defined by noncanonical mechanisms of base pairing to U1 small nuclear RNA. Next we characterized the regulation of CD46 cassette exon 13, whose inclusion or skipping generates different cytoplasmic tails with distinct functions. Using splicing minigenes, we identified multiple exonic and intronic splicing enhancers and silencers that regulate exon 13 inclusion via trans-acting splicing factors like PTBP1 and TIAL1. Interestingly, a common splicing activator such as SRSF1 appears to repress CD46 exon 13 inclusion. We also report that expression of CD46 mRNA isoforms is further regulated by non-sense-mediated mRNA decay and transcription speed. Finally, we successfully manipulated CD46 exon 13 inclusion using antisense oligonucleotides, opening up opportunities for functional studies of the isoforms as well as for therapeutics for autoimmune diseases. This study provides insight into CD46 alternative splicing regulation with implications for its function in the immune system and for genetic disease. PMID- 27226546 TI - Lysosomal Dysfunction Caused by Cellular Accumulation of Silica Nanoparticles. AB - Nanoparticles (NPs) are widely used as components of drugs or cosmetics and hold great promise for biomedicine, yet their effects on cell physiology remain poorly understood. Here we demonstrate that clathrin-independent dynamin 2-mediated caveolar uptake of surface-functionalized silica nanoparticles (SiNPs) impairs cell viability due to lysosomal dysfunction. We show that internalized SiNPs accumulate in lysosomes resulting in inhibition of autophagy-mediated protein turnover and impaired degradation of internalized epidermal growth factor, whereas endosomal recycling proceeds unperturbed. This phenotype is caused by perturbed delivery of cargo via autophagosomes and late endosomes to SiNP-filled cathepsin B/L-containing lysosomes rather than elevated lysosomal pH or altered mTOR activity. Given the importance of autophagy and lysosomal protein degradation for cellular proteostasis and clearance of aggregated proteins, these results raise the question of beneficial use of NPs in biomedicine and beyond. PMID- 27226547 TI - Integrin alphavbeta1 Modulation Affects Subtype B Avian Metapneumovirus Fusion Protein-mediated Cell-Cell Fusion and Virus Infection. AB - Avian metapneumovirus (aMPV) fusion (F) protein mediates virus-cell membrane fusion to initiate viral infection, which requires F protein binding to its receptor(s) on the host cell surface. However, the receptor(s) for aMPV F protein is still not identified. All known subtype B aMPV (aMPV/B) F proteins contain a conserved Arg-Asp-Asp (RDD) motif, suggesting that the aMPV/B F protein may mediate membrane fusion via the binding of RDD to integrin. When blocked with integrin-specific peptides, aMPV/B F protein fusogenicity and viral replication were significantly reduced. Specifically we identified integrin alphav and/or beta1-mediated F protein fusogenicity and viral replication using antibody blocking, small interfering RNAs (siRNAs) knockdown, and overexpression. Additionally, overexpression of integrin alphav and beta1 in aMPV/B non permissive cells conferred aMPV/B F protein binding and aMPV/B infection. When RDD was altered to RAE (Arg-Ala-Glu), aMPV/B F protein binding and fusogenic activity were profoundly impaired. These results suggest that integrin alphavbeta1 is a functional receptor for aMPV/B F protein-mediated membrane fusion and virus infection, which will provide new insights on the fusogenic mechanism and pathogenesis of aMPV. PMID- 27226549 TI - Identification and Characterization of Heptaprenylglyceryl Phosphate Processing Enzymes in Bacillus subtilis. AB - In Archaea, ether lipids play an essential role as the main building blocks of the cellular membrane. Recently, ether lipids have also been discovered in the domain of Bacteria, and the key enzymes that catalyze their synthesis, glycerol-1 phosphate dehydrogenase and heptaprenylglyceryl phosphate synthase, have been described. In Bacillales, heptaprenylglyceryl phosphate does not become linked to a second polyprenyl moiety like ether lipids in Archaea but is dephosphorylated and acetylated. Here, we report on the enzymes that catalyze these reactions. We enriched the phosphatase activity from a B. subtilis cell extract and suppose that dephosphorylation is catalyzed by the phosphatase PhoB or by any other phosphatase in an unspecific manner. By screening a B. subtilis knock-out library for deficiency in acetylation, the yvoF gene product was identified to be the acetyltransferase. The acetyl-CoA-dependent enzyme YvoF is a close relative of maltose O-acetyltransferase (MAT). Its catalytic properties were analyzed and compared with MAT. YvoF and MAT partially overlap in substrate and product range in vitro, but MAT is not able to complement the yvoF knock-out in vivo. PMID- 27226548 TI - Opposing Effects of Cyclooxygenase-2 (COX-2) on Estrogen Receptor beta (ERbeta) Response to 5alpha-Reductase Inhibition in Prostate Epithelial Cells. AB - Current pharmacotherapies for symptomatic benign prostatic hyperplasia (BPH), an androgen receptor-driven, inflammatory disorder affecting elderly men, include 5alpha-reductase (5AR) inhibitors (i.e. dutasteride and finasteride) to block the conversion of testosterone to the more potent androgen receptor ligand dihydrotestosterone. Because dihydrotestosterone is the precursor for estrogen receptor beta (ERbeta) ligands, 5AR inhibitors could potentially limit ERbeta activation, which maintains prostate tissue homeostasis. We have uncovered signaling pathways in BPH-derived prostate epithelial cells (BPH-1) that are impacted by 5AR inhibition. The induction of apoptosis and repression of the cell adhesion protein E-cadherin by the 5AR inhibitor dutasteride requires both ERbeta and TGFbeta. Dutasteride also induces cyclooxygenase type 2 (COX-2), which functions in a negative feedback loop in TGFbeta and ERbeta signaling pathways as evidenced by the potentiation of apoptosis induced by dutasteride or finasteride upon pharmacological inhibition or shRNA-mediated ablation of COX-2. Concurrently, COX-2 positively impacts ERbeta action through its effect on the expression of a number of steroidogenic enzymes in the ERbeta ligand metabolic pathway. Therefore, effective combination pharmacotherapies, which have included non-steroidal anti-inflammatory drugs, must take into account biochemical pathways affected by 5AR inhibition and opposing effects of COX-2 on the tissue protective action of ERbeta. PMID- 27226550 TI - Biochemical Characterization of the Human Mitochondrial Replicative Twinkle Helicase: SUBSTRATE SPECIFICITY, DNA BRANCH MIGRATION, AND ABILITY TO OVERCOME BLOCKADES TO DNA UNWINDING. AB - Mutations in the c10orf2 gene encoding the human mitochondrial DNA replicative helicase Twinkle are linked to several rare genetic diseases characterized by mitochondrial defects. In this study, we have examined the catalytic activity of Twinkle helicase on model replication fork and DNA repair structures. Although Twinkle behaves as a traditional 5' to 3' helicase on conventional forked duplex substrates, the enzyme efficiently dissociates D-loop DNA substrates irrespective of whether it possesses a 5' or 3' single-stranded tailed invading strand. In contrast, we report for the first time that Twinkle branch-migrates an open-ended mobile three-stranded DNA structure with a strong 5' to 3' directionality preference. To determine how well Twinkle handles potential roadblocks to mtDNA replication, we tested the ability of the helicase to unwind substrates with site specific oxidative DNA lesions or bound by the mitochondrial transcription factor A. Twinkle helicase is inhibited by DNA damage in a unique manner that is dependent on the type of oxidative lesion and the strand in which it resides. Novel single molecule FRET binding and unwinding assays show an interaction of the excluded strand with Twinkle as well as events corresponding to stepwise unwinding and annealing. TFAM inhibits Twinkle unwinding, suggesting other replisome proteins may be required for efficient removal. These studies shed new insight on the catalytic functions of Twinkle on the key DNA structures it would encounter during replication or possibly repair of the mitochondrial genome and how well it tolerates potential roadblocks to DNA unwinding. PMID- 27226552 TI - Protein Kinase CK2alpha Maintains Extracellular Signal-regulated Kinase (ERK) Activity in a CK2alpha Kinase-independent Manner to Promote Resistance to Inhibitors of RAF and MEK but Not ERK in BRAF Mutant Melanoma. AB - The protein kinase casein kinase 2 (CK2) is a pleiotropic and constitutively active kinase that plays crucial roles in cellular proliferation and survival. Overexpression of CK2, particularly the alpha catalytic subunit (CK2alpha, CSNK2A1), has been implicated in a wide variety of cancers and is associated with poorer survival and resistance to both conventional and targeted anticancer therapies. Here, we found that CK2alpha protein is elevated in melanoma cell lines compared with normal human melanocytes. We then tested the involvement of CK2alpha in drug resistance to Food and Drug Administration-approved single agent targeted therapies for melanoma. In BRAF mutant melanoma cells, ectopic CK2alpha decreased sensitivity to vemurafenib (BRAF inhibitor), dabrafenib (BRAF inhibitor), and trametinib (MEK inhibitor) by a mechanism distinct from that of mutant NRAS. Conversely, knockdown of CK2alpha sensitized cells to inhibitor treatment. CK2alpha-mediated RAF-MEK kinase inhibitor resistance was tightly linked to its maintenance of ERK phosphorylation. We found that CK2alpha post translationally regulates the ERK-specific phosphatase dual specificity phosphatase 6 (DUSP6) in a kinase dependent-manner, decreasing its abundance. However, we unexpectedly showed, by using a kinase-inactive mutant of CK2alpha, that RAF-MEK inhibitor resistance did not rely on CK2alpha kinase catalytic function, and both wild-type and kinase-inactive CK2alpha maintained ERK phosphorylation upon inhibition of BRAF or MEK. That both wild-type and kinase inactive CK2alpha bound equally well to the RAF-MEK-ERK scaffold kinase suppressor of Ras 1 (KSR1) suggested that CK2alpha increases KSR facilitation of ERK phosphorylation. Accordingly, CK2alpha did not cause resistance to direct inhibition of ERK by the ERK1/2-selective inhibitor SCH772984. Our findings support a kinase-independent scaffolding function of CK2alpha that promotes resistance to RAF- and MEK-targeted therapies. PMID- 27226551 TI - Developmentally Regulated RNA-binding Protein 1 (Drb1)/RNA-binding Motif Protein 45 (RBM45), a Nuclear-Cytoplasmic Trafficking Protein, Forms TAR DNA-binding Protein 43 (TDP-43)-mediated Cytoplasmic Aggregates. AB - Cytoplasmic protein aggregates are one of the pathological hallmarks of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Several RNA-binding proteins have been identified as components of inclusion bodies. Developmentally regulated RNA binding protein 1 (Drb1)/RNA-binding motif protein 45 is an RNA-binding protein that was recently described as a component in ALS- and FTLD-related inclusion bodies. However, the molecular mechanism underlying cytoplasmic Drb1 aggregation remains unclear. Here, using an in vitro cellular model, we demonstrated that Drb1 co-localizes with cytoplasmic aggregates mediated by TAR DNA-binding protein 43, a major component of ALS and FTLD-related inclusion bodies. We also defined the domains involved in the subcellular localization of Drb1 to clarify the role of Drb1 in the formation of cytoplasmic aggregates in ALS and FTLD. Drb1 predominantly localized in the nucleus via a classical nuclear localization signal in its carboxyl terminus and is a shuttling protein between the nucleus and cytoplasm. Furthermore, we identify a double leucine motif serving as a nuclear export signal. The Drb1 mutant, presenting mutations in both nuclear localization signal and nuclear export signal, is prone to aggregate in the cytoplasm. The mutant Drb1-induced cytoplasmic aggregates not only recruit TAR DNA-binding protein 43 but also decrease the mitochondrial membrane potential. Taken together, these results indicate that perturbation of Drb1 nuclear cytoplasmic trafficking induces toxic cytoplasmic aggregates, suggesting that mislocalization of Drb1 is involved in the cause of cytotoxicity in neuronal cells. PMID- 27226553 TI - Charged Amino Acid-rich Leucine Zipper-1 (Crlz-1) as a Target of Wnt Signaling Pathway Controls Pre-B Cell Proliferation by Affecting Runx/CBFbeta-targeted VpreB and lambda5 Genes. AB - The proliferation of pre-B cells is known to further increase the clonal diversity of B cells at the stage of pre-B cells by allowing the same rearranged heavy chains to combine with differently rearranged light chains in a subsequent developmental stage. Crlz-1 (charged amino acid-rich leucine zipper-1) was found to control this proliferation of pre-B cells by working as a Wnt (wingless related mouse mammary tumor virus integration site) target gene in these cells. Mechanistically, Crlz-1 protein functioned by mobilizing cytoplasmic CBFbeta (core binding factor beta) into the nucleus to allow Runx (runt-related transcription factor)/CBFbeta heterodimerization. Runx/CBFbeta then turned on its target genes such as EBF (early B cell factor), VpreB, and lambda5 and thereby pre-B cell receptor signaling, leading to the expression of cyclins D2 and D3 Actually, the proliferative function of Crlz-1 was demonstrated by not only Crlz 1 or beta-catenin knockdown but also Crlz-1 overexpression. Furthermore, the mechanistic view that the proliferative function of Crlz-1 is caused by relaying Wnt/beta-catenin to pre-B cell receptor signaling pathways through the regulation of Runx/CBFbeta heterodimerization was also verified by employing niclosamide, XAV939, and LiCl as Wnt inhibitors and activator, respectively. PMID- 27226554 TI - The Interaction between Cancer Stem Cell Marker CD133 and Src Protein Promotes Focal Adhesion Kinase (FAK) Phosphorylation and Cell Migration. AB - CD133, a widely known cancer stem cell marker, has been proved to promote tumor metastasis. However, the mechanism by which CD133 regulates metastasis remains largely unknown. Here, we report that CD133 knockdown inhibits cancer cell migration, and CD133 overexpression promotes cell migration. CD133 expression is beneficial to activate the Src-focal adhesion kinase (FAK) signaling pathway. Further studies show that CD133 could interact with Src, and the region between amino acids 845 and 857 in the CD133 C-terminal domain is indispensable for its interaction with Src. The interaction activates Src to phosphorylate its substrate FAK and to promote cell migration. Likewise, a Src binding-deficient CD133 mutant loses the abilities to increase Src and FAK phosphorylation and to promote cell migration. Inhibition of Src activity by PP2, a known Src activity inhibitor, could block the activation of FAK phosphorylation and cell migration induced by CD133. In summary, our data suggest that activation of FAK by the interaction between CD133 and Src promotes cell migration, providing clues to understand the migratory mechanism of CD133(+) tumor cells. PMID- 27226555 TI - S100A1 Protein Does Not Compete with Calmodulin for Ryanodine Receptor Binding but Structurally Alters the Ryanodine Receptor.Calmodulin Complex. AB - S100A1 has been suggested as a therapeutic agent to enhance myocyte Ca(2+) cycling in heart failure, but its molecular mode of action is poorly understood. Using FRET, we tested the hypothesis that S100A1 directly competes with calmodulin (CaM) for binding to intact, functional ryanodine receptors type I (RyR1) and II (RyR2) from skeletal and cardiac muscle, respectively. Our FRET readout provides an index of acceptor-labeled CaM binding near donor-labeled FKBP (FK506-binding protein 12.6) on the cytoplasmic domain of RyR in isolated sarcoplasmic reticulum vesicles. S100A1 (0.01-400 MUm) partially inhibited FRET (i.e. CaM binding), with Ki > 10 MUm, for both RyR1 and RyR2. The high [S100A1] required for partial effects on FRET indicates a lack of competition by S100A1 on CaM/RyR binding under normal physiological conditions. High-resolution analysis of time-resolved FRET detects two structural states of RyR-bound CaM, which respond to [Ca(2+)] and are isoform-specific. The distribution of these structural states was perturbed only by high micromolar [S100A1], which promoted a shift of bound CaM to a lower FRET orientation (without altering the amount of CaM bound to RyR). Thus, high micromolar S100A1 does alter the CaM/RyR interaction, without involving competition. Nevertheless, submicromolar S100A1 can alter RyR function, an effect that is influenced by both [Ca(2+)] and [CaM]. We conclude that CaM and S100A1 can concurrently bind to and functionally modulate RyR1 and RyR2, but this does not involve direct competition at the RyR CaM binding site. PMID- 27226556 TI - Biochemical Classification of Disease-associated Mutants of RAS-like Protein Expressed in Many Tissues (RIT1). AB - RAS-like protein expressed in many tissues 1 (RIT1) is a disease-associated RAS subfamily small guanosine triphosphatase (GTPase). Recent studies revealed that germ-line and somatic RIT1 mutations can cause Noonan syndrome (NS), and drive proliferation of lung adenocarcinomas, respectively, akin to RAS mutations in these diseases. However, the locations of these RIT1 mutations differ significantly from those found in RAS, and do not affect the three mutational "hot spots" of RAS. Moreover, few studies have characterized the GTPase cycle of RIT1 and its disease-associated mutants. Here we developed a real-time NMR-based GTPase assay for RIT1 and investigated the effect of disease-associated mutations on GTPase cycle. RIT1 exhibits an intrinsic GTP hydrolysis rate similar to that of H-RAS, but its intrinsic nucleotide exchange rate is ~4-fold faster, likely as a result of divergent residues near the nucleotide binding site. All of the disease-associated mutations investigated increased the GTP-loaded, activated state of RIT1 in vitro, but they could be classified into two groups with different intrinsic GTPase properties. The S35T, A57G, and Y89H mutants exhibited more rapid nucleotide exchange, whereas F82V and T83P impaired GTP hydrolysis. A RAS-binding domain pulldown assay indicated that RIT1 A57G and Y89H were highly activated in HEK293T cells, whereas T83P and F82V exhibited more modest activation. All five mutations are associated with NS, whereas two (A57G and F82V) have also been identified in urinary tract cancers and myeloid malignancies. Characterization of the effects on the GTPase cycle of RIT1 disease associated mutations should enable better understanding of their role in disease processes. PMID- 27226557 TI - RNA Polymerase II Trigger Loop Mobility: INDIRECT EFFECTS OF Rpb9. AB - Rpb9 is a conserved RNA polymerase II (pol II) subunit, the absence of which confers alterations to pol II enzymatic properties and transcription fidelity. It has been suggested previously that Rpb9 affects mobility of the trigger loop (TL), a structural element of Rpb1 that moves in and out of the active site with each elongation cycle. However, a biochemical mechanism for this effect has not been defined. We find that the mushroom toxin alpha-amanitin, which inhibits TL mobility, suppresses the effect of Rpb9 on NTP misincorporation, consistent with a role for Rpb9 in this process. Furthermore, we have identified missense alleles of RPB9 in yeast that suppress the severe growth defect caused by rpb1-G730D, a substitution within Rpb1 alpha-helix 21 (alpha21). These alleles suggest a model in which Rpb9 indirectly affects TL mobility by anchoring the position of alpha21, with which the TL directly interacts during opening and closing. Amino acid substitutions in Rpb9 or Rpb1 that disrupt proposed anchoring interactions resulted in phenotypes shared by rpb9Delta strains, including increased elongation rate in vitro Combinations of rpb9Delta with the fast rpb1 alleles that we identified did not result in significantly faster in vitro misincorporation rates than those resulting from rpb9Delta alone, and this epistasis is consistent with the idea that defects caused by the rpb1 alleles are related mechanistically to the defects caused by rpb9Delta. We conclude that Rpb9 supports intra-pol II interactions that modulate TL function and thus pol II enzymatic properties. PMID- 27226558 TI - Cellular Casein Kinase 2 and Protein Phosphatase 2A Modulate Replication Site Assembly of Bluetongue Virus. AB - A number of cytoplasmic replicating viruses produce cytoplasmic inclusion bodies or protein aggregates; however, a hallmark of viruses of the Reoviridae family is that they utilize these sites for purposes of replication and capsid assembly, functioning as viral assembly factories. Here we have used bluetongue virus (BTV) as a model system for this broad family of important viruses to understand the mechanisms regulating inclusion body assembly. Newly synthesized viral proteins interact with sequestered viral RNA molecules prior to capsid assembly and double stranded RNA synthesis within viral inclusion bodies (VIBs). VIBs are predominantly comprised of a BTV-encoded non-structural protein 2 (NS2). Previous in vitro studies indicated that casein kinase 2 (CK2) mediated the phosphorylation of NS2, which regulated the propensity of NS2 to form larger aggregates. Using targeted pharmacological reagents, specific mutation in the viral genome by reverse genetics and confocal microscopy, here we demonstrate that CK2 activity is important for BTV replication. Furthermore, we show that a novel host cell factor, protein phosphatase 2A, is involved in NS2 dephosphorylation and that, together with CK2, it regulates VIB morphology and virus replication. Thus, these two host enzymes influence the dynamic nature of VIB assembly/disassembly, and these concerted activities may be relevant to the assembly and the release of these cores from VIBs. PMID- 27226559 TI - Neutralization of RANTES and Eotaxin Prevents the Loss of Dopaminergic Neurons in a Mouse Model of Parkinson Disease. AB - Parkinson disease (PD) is second only to Alzheimer disease as the most common human neurodegenerative disorder. Despite intense investigation, no interdictive therapy is available for PD. Recent studies indicate that both innate and adaptive immune processes are active in PD. Accordingly, we found a rapid increase in RANTES (regulated on activation normal T cell expressed and secreted) and eotaxin, chemokines that are involved in T cell trafficking, in vivo in the substantia nigra pars compacta and the serum of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-intoxicated mice. RANTES and eotaxin were also up regulated in the substantia nigra pars compacta of post-mortem PD brains as compared with age-matched controls. Therefore, we investigated whether neutralization of RANTES and eotaxin could protect against nigrostriatal degeneration in MPTP-intoxicated mice. Interestingly, after peripheral administration, functional blocking antibodies against RANTES and eotaxin reduced the infiltration of CD4(+) and CD8(+) T cells into the nigra, attenuated nigral expression of proinflammatory molecules, and suppressed nigral activation of glial cells. These findings paralleled dopaminergic neuronal protection, normalized striatal neurotransmitters, and improved motor functions in MPTP intoxicated mice. Therefore, we conclude that attenuation of the chemokine dependent adaptive immune response may be of therapeutic benefit for PD patients. PMID- 27226560 TI - Synaptogyrin-2 Promotes Replication of a Novel Tick-borne Bunyavirus through Interacting with Viral Nonstructural Protein NSs. AB - Synaptogyrin-2 is a non-neuronal member of the synaptogyrin family involved in synaptic vesicle biogenesis and trafficking. Little is known about the function of synaptogyrin-2. Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease characterized by high fever, thrombocytopenia, and leukocytopenia with high mortality, caused by a novel tick-borne phlebovirus in the family Bunyaviridae. Our previous studies have shown that the viral nonstructural protein NSs forms inclusion bodies (IBs) that are involved in viral immune evasion, as well as viral RNA replication. In this study, we sought to elucidate the mechanism by which NSs formed the IBs, a lipid droplet-based structure confirmed by NSs co-localization with perilipin A and adipose differentiation-related protein (ADRP). Through a high throughput screening, we identified synaptogyrin-2 to be highly up-regulated in response to SFTS bunyavirus (SFTSV) infection and to be a promoter of viral replication. We demonstrated that synaptogyrin-2 interacted with NSs and was translocated into the IBs, which were reconstructed from lipid droplets into large structures in infection. Viral RNA replication decreased, and infectious virus titers were lowered significantly when synaptogyrin-2 was silenced in specific shRNA expressing cells, which correlated with the reduced number of the large IBs restructured from regular lipid droplets. We hypothesize that synaptogyrin-2 is essential to promoting the formation of the IBs to become virus factories for viral RNA replication through its interaction with NSs. These findings unveil the function of synaptogyrin-2 as an enhancer in viral infection. PMID- 27226561 TI - Kruppel-like Factor 3 (KLF3/BKLF) Is Required for Widespread Repression of the Inflammatory Modulator Galectin-3 (Lgals3). AB - The Lgals3 gene encodes a multifunctional beta-galactoside-binding protein, galectin-3. Galectin-3 has been implicated in a broad range of biological processes from chemotaxis and inflammation to fibrosis and apoptosis. The role of galectin-3 as a modulator of inflammation has been studied intensively, and recent evidence suggests that it may serve as a protective factor in obesity and other metabolic disorders. Despite considerable interest in galectin-3, little is known about its physiological regulation at the transcriptional level. Here, using knockout mice, chromatin immunoprecipitations, and cellular and molecular analyses, we show that the zinc finger transcription factor Kruppel-like factor 3 (KLF3) directly represses galectin-3 transcription. We find that galectin-3 is broadly up-regulated in KLF3-deficient mouse tissues, that KLF3 occupies regulatory regions of the Lgals3 gene, and that KLF3 directly binds its cognate elements (CACCC boxes) in the galectin-3 promoter and represses its activation in cellular assays. We also provide mechanistic insights into the regulation of Lgals3, demonstrating that C-terminal binding protein (CtBP) is required to drive optimal KLF3-mediated silencing. These findings help to enhance our understanding of how expression of the inflammatory modulator galectin-3 is controlled, opening up avenues for potential therapeutic interventions in the future. PMID- 27226562 TI - Systems-wide Experimental and Modeling Analysis of Insulin Signaling through Forkhead Box Protein O1 (FOXO1) in Human Adipocytes, Normally and in Type 2 Diabetes. AB - Insulin resistance is a major aspect of type 2 diabetes (T2D), which results from impaired insulin signaling in target cells. Signaling to regulate forkhead box protein O1 (FOXO1) may be the most important mechanism for insulin to control transcription. Despite this, little is known about how insulin regulates FOXO1 and how FOXO1 may contribute to insulin resistance in adipocytes, which are the most critical cell type in the development of insulin resistance. We report a detailed mechanistic analysis of insulin control of FOXO1 in human adipocytes obtained from non-diabetic subjects and from patients with T2D. We show that FOXO1 is mainly phosphorylated through mTORC2-mediated phosphorylation of protein kinase B at Ser(473) and that this mechanism is unperturbed in T2D. We also demonstrate a cross-talk from the MAPK branch of insulin signaling to stimulate phosphorylation of FOXO1. The cellular abundance and consequently activity of FOXO1 are halved in T2D. Interestingly, inhibition of mTORC1 with rapamycin reduces the abundance of FOXO1 to the levels in T2D. This suggests that the reduction of the concentration of FOXO1 is a consequence of attenuation of mTORC1, which defines much of the diabetic state in human adipocytes. We integrate insulin control of FOXO1 in a network-wide mathematical model of insulin signaling dynamics based on compatible data from human adipocytes. The diabetic state is network-wide explained by attenuation of an mTORC1-to-insulin receptor substrate-1 (IRS1) feedback and reduced abundances of insulin receptor, GLUT4, AS160, ribosomal protein S6, and FOXO1. The model demonstrates that attenuation of the mTORC1-to-IRS1 feedback is a major mechanism of insulin resistance in the diabetic state. PMID- 27226563 TI - Overexpression of miR-223 Tips the Balance of Pro- and Anti-hypertrophic Signaling Cascades toward Physiologic Cardiac Hypertrophy. AB - MicroRNAs (miRNAs) have been extensively examined in pathological cardiac hypertrophy. However, few studies focused on profiling the miRNA alterations in physiological hypertrophic hearts. In this study we generated a transgenic mouse model with cardiac-specific overexpression of miR-223. Our results showed that elevation of miR-223 caused physiological cardiac hypertrophy with enhanced cardiac function but no fibrosis. Using the next generation RNA sequencing, we observed that most of dys-regulated genes (e.g. Atf3/5, Egr1/3, Sfrp2, Itgb1, Ndrg4, Akip1, Postn, Rxfp1, and Egln3) in miR-223-transgenic hearts were associated with cell growth, but they were not directly targeted by miR-223. Interestingly, these dys-regulated genes are known to regulate the Akt signaling pathway. We further identified that miR-223 directly interacted with 3'-UTRs of FBXW7 and Acvr2a, two negative regulators of the Akt signaling. However, we also validated that miR-223 directly inhibited the expression of IGF-1R and beta1 integrin, two positive regulators of the Akt signaling. Lastly, Western blotting did reveal that Akt was activated in miR-223-overexpressing hearts. Adenovirus mediated overexpression of miR-223 in neonatal rat cardiomyocytes induced cell hypertrophy, which was blocked by the addition of MK2206, a specific inhibitor of Akt Taken together, these data represent the first piece of work showing that miR 223 tips the balance of promotion and inactivation of Akt signaling cascades toward activation of Akt, a key regulator of physiological cardiac hypertrophy. Thus, our study suggests that the ultimate phenotype outcome of a miRNA may be decided by the secondary net effects of the whole target network rather than by several primary direct targets in an organ/tissue. PMID- 27226564 TI - Rab5 Isoforms Specifically Regulate Different Modes of Endocytosis in Leishmania. AB - Differential functions of Rab5 isoforms in endocytosis are not well characterized. Here, we cloned, expressed, and characterized Rab5a and Rab5b from Leishmania and found that both of them are localized in the early endosome. To understand the role of LdRab5 isoforms in different modes of endocytosis in Leishmania, we generated transgenic parasites overexpressing LdRab5a, LdRab5b, or their dominant-positive (LdRab5a:Q93L and LdRab5b:Q80L) or dominant-negative mutants (LdRab5a:N146I and LdRab5b:N133I). Using LdRab5a or its mutants overexpressing parasites, we found that LdRab5a specifically regulates the fluid phase endocytosis of horseradish peroxidase and also specifically induced the transport of dextran-Texas Red to the lysosomes. In contrast, cells overexpressing LdRab5b or its mutants showed that LdRab5b explicitly controls receptor-mediated endocytosis of hemoglobin, and overexpression of LdRab5b:WT enhanced the transport of internalized Hb to the lysosomes in comparison with control cells. To unequivocally demonstrate the role of Rab5 isoforms in endocytosis in Leishmania, we tried to generate null-mutants of LdRab5a and LdRab5b parasites, but both were lethal indicating their essential functions in parasites. Therefore, we used heterozygous LdRab5a(+/-) and LdRab5b(+/-) cells. LdRab5a(+/-) Leishmania showed 50% inhibition of HRP uptake, but hemoglobin endocytosis was uninterrupted. In contrast, about 50% inhibition of Hb endocytosis was observed in LdRab5b(+/-) cells without any significant effect on HRP uptake. Finally, we tried to identify putative LdRab5a and LdRab5b effectors. We found that LdRab5b interacts with clathrin heavy chain and hemoglobin receptor. However, LdRab5a failed to interact with the clathrin heavy chain, and interaction with hemoglobin receptor was significantly less. Thus, our results showed that LdRab5a and LdRab5b differentially regulate fluid phase and receptor mediated endocytosis in Leishmania. PMID- 27226565 TI - The alpha-Arrestin ARRDC3 Regulates the Endosomal Residence Time and Intracellular Signaling of the beta2-Adrenergic Receptor. AB - Arrestin domain-containing protein 3 (ARRDC3) is a member of the mammalian alpha arrestin family, which is predicted to share similar tertiary structure with visual-/beta-arrestins and also contains C-terminal PPXY motifs that mediate interaction with E3 ubiquitin ligases. Recently, ARRDC3 has been proposed to play a role in regulating the trafficking of G protein-coupled receptors, although mechanistic insight into this process is lacking. Here, we focused on characterizing the role of ARRDC3 in regulating the trafficking of the beta2 adrenergic receptor (beta2AR). We find that ARRDC3 primarily localizes to EEA1 positive early endosomes and directly interacts with the beta2AR in a ligand independent manner. Although ARRDC3 has no effect on beta2AR endocytosis or degradation, it negatively regulates beta2AR entry into SNX27-occupied endosomal tubules. This results in delayed recycling of the receptor and a concomitant increase in beta2AR-dependent endosomal signaling. Thus, ARRDC3 functions as a switch to modulate the endosomal residence time and subsequent intracellular signaling of the beta2AR. PMID- 27226566 TI - Rifampin Resistance Mutations Are Associated with Broad Chemical Remodeling of Mycobacterium tuberculosis. AB - Global control of tuberculosis has become increasingly complicated with the emergence of multidrug-resistant strains of Mycobacterium tuberculosis First-line treatments are anchored by two antibiotics, rifampin and isoniazid. Most rifampin resistance occurs through the acquisition of missense mutations in the rifampin resistance-determining region, an 81-base pair region encoding the rifampin binding site on the beta subunit of RNA polymerase (rpoB). Although these mutations confer a survival advantage in the presence of rifampin, they may alter the normal process of transcription, thereby imposing significant fitness costs. Because the downstream biochemical consequences of the rpoB mutations are unknown, we used an organism-wide screen to identify the number and types of lipids changed after rpoB mutation. A new mass spectrometry-based profiling platform systematically compared ~10,000 cell wall lipids in a panel of rifampin resistant mutants within two genetically distinct strains, CDC1551and W-Beijing. This unbiased lipidomic survey detected quantitative alterations (>2-fold, p < 0.05) in more than 100 lipids in each mutant. By focusing on molecular events that change among most mutants and in both genetic backgrounds, we found that rifampin resistance mutations lead to altered concentrations of mycobactin siderophores and acylated sulfoglycolipids. These findings validate a new organism-wide lipidomic analysis platform for drug-resistant mycobacteria and provide direct evidence for characteristic remodeling of cell wall lipids in rifampin-resistant strains of M. tuberculosis The specific links between rifampin resistance and named lipid factors provide diagnostic and therapeutic targets that may be exploited to address the problem of drug resistance. PMID- 27226567 TI - Xyloside-primed Chondroitin Sulfate/Dermatan Sulfate from Breast Carcinoma Cells with a Defined Disaccharide Composition Has Cytotoxic Effects in Vitro. AB - We previously reported that the xyloside 2-(6-hydroxynaphthyl) beta-d xylopyranoside (XylNapOH), in contrast to 2-naphthyl beta-d-xylopyranoside (XylNap), specifically reduces tumor growth both in vitro and in vivo Although there are indications that this could be mediated by the xyloside-primed glycosaminoglycans (GAGs) and that these differ in composition depending on xyloside and cell type, detailed knowledge regarding a structure-function relationship is lacking. In this study we isolated XylNapOH- and XylNap-primed GAGs from a breast carcinoma cell line, HCC70, and a breast fibroblast cell line, CCD-1095Sk, and demonstrated that both XylNapOH- and XylNap-primed chondroitin sulfate/dermatan sulfate GAGs derived from HCC70 cells had a cytotoxic effect on HCC70 cells and CCD-1095Sk cells. The cytotoxic effect appeared to be mediated by induction of apoptosis and was inhibited in a concentration-dependent manner by the XylNap-primed heparan sulfate GAGs. In contrast, neither the chondroitin sulfate/dermatan sulfate nor the heparan sulfate derived from CCD-1095Sk cells primed on XylNapOH or XylNap had any effect on the growth of HCC70 cells or CCD 105Sk cells. These observations were related to the disaccharide composition of the XylNapOH- and XylNap-primed GAGs, which differed between the two cell lines but was similar when the GAGs were derived from the same cell line. To our knowledge this is the first report on cytotoxic effects mediated by chondroitin sulfate/dermatan sulfate. PMID- 27226568 TI - Regulation of Vacuolar H+-ATPase (V-ATPase) Reassembly by Glycolysis Flow in 6 Phosphofructo-1-kinase (PFK-1)-deficient Yeast Cells. AB - Yeast 6-phosphofructo-1-kinase (PFK-1) has two subunits, Pfk1p and Pfk2p. Deletion of Pfk2p alters glucose-dependent V-ATPase reassembly and vacuolar acidification (Chan, C. Y., and Parra, K. J. (2014) Yeast phosphofructokinase-1 subunit Pfk2p is necessary for pH homeostasis and glucose-dependent vacuolar ATPase reassembly. J. Biol. Chem. 289, 19448-19457). This study capitalized on the mechanisms suppressing vacuolar H(+)-ATPase (V-ATPase) in pfk2Delta to gain new knowledge of the mechanisms underlying glucose-dependent V-ATPase regulation. Because V-ATPase is fully assembled in pfk2Delta, and glycolysis partially suppressed at steady state, we manipulated glycolysis and assessed its direct involvement on V-ATPase function. At steady state, the ratio of proton transport to ATP hydrolysis increased 24% after increasing the glucose concentration from 2% to 4% to enhance the glycolysis flow in pfk2Delta. Tighter coupling restored vacuolar pH when glucose was abundant and glycolysis operated below capacity. After readdition of glucose to glucose-deprived cells, glucose-dependent V1Vo reassembly was proportional to the glycolysis flow. Readdition of 2% glucose to pfk2Delta cells, which restored 62% of ethanol concentration, led to equivalent 60% V1Vo reassembly levels. Steady-state level of assembly (100% reassembly) was reached at 4% glucose when glycolysis reached a threshold in pfk2Delta (>=40% the wild-type flow). At 4% glucose, the level of Pfk1p co-immunoprecipitated with V ATPase decreased 58% in pfk2Delta, suggesting that Pfk1p binding to V-ATPase may be inhibitory in the mutant. We concluded that V-ATPase activity at steady state and V-ATPase reassembly after readdition of glucose to glucose-deprived cells are controlled by the glycolysis flow. We propose a new mechanism by which glucose regulates V-ATPase catalytic activity that occurs at steady state without changing V1Vo assembly. PMID- 27226569 TI - Macrophage Migration Inhibitory Factor-CXCR4 Receptor Interactions: EVIDENCE FOR PARTIAL ALLOSTERIC AGONISM IN COMPARISON WITH CXCL12 CHEMOKINE. AB - An emerging number of non-chemokine mediators are found to bind to classical chemokine receptors and to elicit critical biological responses. Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that exhibits chemokine-like activities through non-cognate interactions with the chemokine receptors CXCR2 and CXCR4, in addition to activating the type II receptor CD74. Activation of the MIF-CXCR2 and -CXCR4 axes promotes leukocyte recruitment, mediating the exacerbating role of MIF in atherosclerosis and contributing to the wealth of other MIF biological activities. Although the structural basis of the MIF-CXCR2 interaction has been well studied and was found to engage a pseudo-ELR and an N-like loop motif, nothing is known about the regions of CXCR4 and MIF that are involved in binding to each other. Using a genetic strain of Saccharomyces cerevisiae that expresses a functional CXCR4 receptor, site specific mutagenesis, hybrid CXCR3/CXCR4 receptors, pharmacological reagents, peptide array analysis, chemotaxis, fluorescence spectroscopy, and circular dichroism, we provide novel molecular information about the structural elements that govern the interaction between MIF and CXCR4. The data identify similarities with classical chemokine-receptor interactions but also provide evidence for a partial allosteric agonist compared with CXCL12 that is possible due to the two binding sites of CXCR4. PMID- 27226570 TI - New Insight into the Catalytic Mechanism of Bacterial MraY from Enzyme Kinetics and Docking Studies. AB - Phospho-MurNAc-pentapeptide translocase (MraY) catalyzes the synthesis of Lipid I, a bacterial peptidoglycan precursor. As such, MraY is essential for bacterial survival and therefore is an ideal target for developing novel antibiotics. However, the understanding of its catalytic mechanism, despite the recently determined crystal structure, remains limited. In the present study, the kinetic properties of Bacillus subtilis MraY (BsMraY) were investigated by fluorescence enhancement using dansylated UDP-MurNAc-pentapeptide and heptaprenyl phosphate (C35-P, short-chain homolog of undecaprenyl phosphate, the endogenous substrate of MraY) as second substrate. Varying the concentrations of both of these substrates and fitting the kinetics data to two-substrate models showed that the concomitant binding of both UDP-MurNAc-pentapeptide-DNS and C35-P to the enzyme is required before the release of the two products, Lipid I and UMP. We built a model of BsMraY and performed docking studies with the substrate C35-P to further deepen our understanding of how MraY accommodates this lipid substrate. Based on these modeling studies, a novel catalytic role was put forward for a fully conserved histidine residue in MraY (His-289 in BsMraY), which has been experimentally confirmed to be essential for MraY activity. Using the current model of BsMraY, we propose that a small conformational change is necessary to relocate the His-289 residue, such that the translocase reaction can proceed via a nucleophilic attack of the phosphate moiety of C35-P on bound UDP-MurNAc pentapeptide. PMID- 27226571 TI - Interferon beta (IFN-beta) Production during the Double-stranded RNA (dsRNA) Response in Hepatocytes Involves Coordinated and Feedforward Signaling through Toll-like Receptor 3 (TLR3), RNA-dependent Protein Kinase (PKR), Inducible Nitric Oxide Synthase (iNOS), and Src Protein. AB - The sensing of double-stranded RNA (dsRNA) in the liver is important for antiviral defenses but can also contribute to sterile inflammation during liver injury. Hepatocytes are often the target of viral infection and are easily injured by inflammatory insults. Here we sought to establish the pathways involved in the production of type I interferons (IFN-I) in response to extracellular poly(I:C), a dsRNA mimetic, in hepatocytes. This was of interest because hepatocytes are long-lived and, unlike most immune cells that readily die after activation with dsRNA, are not viewed as cells with robust antimicrobial capacity. We found that poly(I:C) leads to rapid up-regulation of inducible nitric oxide synthase (iNOS), double-stranded RNA-dependent protein kinase (PKR), and Src. The production of IFN-beta was dependent on iNOS, PKR, and Src and partially dependent on TLR3/Trif. iNOS and Src up-regulation was partially dependent on TLR3/Trif but entirely dependent on PKR. The phosphorylation of TLR3 on tyrosine 759 was shown to increase in parallel to IFN-beta production in an iNOS- and Src-dependent manner, and Src was found to directly interact with TLR3 in the endosomal compartment of poly(I:C)-treated cells. Furthermore, we identified a robust NO/cGMP/PKG-dependent feedforward pathway for the amplification of iNOS expression. These data identify iNOS/NO as an integral component of IFN-beta production in response to dsRNA in hepatocytes in a pathway that involves the coordinated activities of TLR3/Trif and PKR. PMID- 27226573 TI - Different Soluble Forms of the Interleukin-6 Family Signal Transducer gp130 Fine tune the Blockade of Interleukin-6 Trans-signaling. AB - Soluble forms of the IL-6 receptor (sIL-6R) bind to the cytokine IL-6 with similar affinity as the membrane-bound IL-6R. IL-6.sIL-6R complexes initiate IL-6 trans-signaling via activation of the ubiquitously expressed membrane-bound beta receptor glycoprotein 130 (gp130). Inhibition of IL-6 trans-signaling has been shown to be favorable in numerous inflammatory diseases. Furthermore, different soluble forms of gp130 (sgp130) exist that, together with the sIL-6R, are thought to form a buffer for IL-6 in the blood. However, a functional role for the different sgp130 forms has not been described to date. Here we demonstrate that the metalloproteases ADAM10 and ADAM17 can produce sgp130 by ectodomain shedding of gp130, even though this mechanism only accounts for a minor proportion of sgp130 in the circulation. We further show that full-length sgp130 and the shorter forms sgp130-rheumatoid arthritis-associated peptide (RAPS) and sgp130 E10 are differentially expressed in a cell type- specific manner. Remarkably, full-length sgp130 is expressed by monocytes, but this expression is completely lost during differentiation into macrophages in vitro Using genetically engineered murine pre-B cells that secrete different forms of sgp130, we found that these secreted sgp130 proteins are able to prevent trans-signaling-driven cell proliferation of the secreting cells, whereas conditioned supernatant from these cells failed to block IL-6 trans-signaling in other cells. Thus, our data suggest that the different sgp130 forms are released from cells into their immediate surroundings and appear to form cell-associated gradients to modulate their own susceptibility for IL-6 trans-signaling. PMID- 27226572 TI - Comprehensive Analysis of Mouse Bitter Taste Receptors Reveals Different Molecular Receptive Ranges for Orthologous Receptors in Mice and Humans. AB - One key to animal survival is the detection and avoidance of potentially harmful compounds by their bitter taste. Variable numbers of taste 2 receptor genes expressed in the gustatory end organs enable bony vertebrates (Euteleostomi) to recognize numerous bitter chemicals. It is believed that the receptive ranges of bitter taste receptor repertoires match the profiles of bitter chemicals that the species encounter in their diets. Human and mouse genomes contain pairs of orthologous bitter receptor genes that have been conserved throughout evolution. Moreover, expansions in both lineages generated species-specific sets of bitter taste receptor genes. It is assumed that the orthologous bitter taste receptor genes mediate the recognition of bitter toxins relevant for both species, whereas the lineage-specific receptors enable the detection of substances differently encountered by mice and humans. By challenging 34 mouse bitter taste receptors with 128 prototypical bitter substances in a heterologous expression system, we identified cognate compounds for 21 receptors, 19 of which were previously orphan receptors. We have demonstrated that mouse taste 2 receptors, like their human counterparts, vary greatly in their breadth of tuning, ranging from very broadly to extremely narrowly tuned receptors. However, when compared with humans, mice possess fewer broadly tuned receptors and an elevated number of narrowly tuned receptors, supporting the idea that a large receptor repertoire is the basis for the evolution of specialized receptors. Moreover, we have demonstrated that sequence-orthologous bitter taste receptors have distinct agonist profiles. Species-specific gene expansions have enabled further diversification of bitter substance recognition spectra. PMID- 27226574 TI - Gallic Acid Is an Antagonist of Semen Amyloid Fibrils That Enhance HIV-1 Infection. AB - Recent in vitro studies have demonstrated that amyloid fibrils found in semen from healthy and HIV-infected men, as well as semen itself, can markedly enhance HIV infection rates. Semen fibrils are made up of multiple naturally occurring peptide fragments derived from semen. The best characterized of these fibrils are SEVI (semen-derived enhancer of viral infection), made up of residues 248-286 of prostatic acidic phosphatase, and the SEM1 fibrils, made up of residues 86-107 of semenogelin 1. A small molecule screen for antagonists of semen fibrils identified four compounds that lowered semen-mediated enhancement of HIV-1 infectivity. One of the four, gallic acid, was previously reported to antagonize other amyloids and to exert anti-inflammatory effects. To better understand the mechanism by which gallic acid modifies the properties of semen amyloids, we performed biophysical measurements (atomic force microscopy, electron microscopy, confocal microscopy, thioflavin T and Congo Red fluorescence assays, zeta potential measurements) and quantitative assays on the effects of gallic acid on semen-mediated enhancement of HIV infection and inflammation. Our results demonstrate that gallic acid binds to both SEVI and SEM1 fibrils and modifies their surface electrostatics to render them less cationic. In addition, gallic acid decreased semen-mediated enhancement of HIV infection but did not decrease the inflammatory response induced by semen. Together, these observations identify gallic acid as a non-polyanionic compound that inhibits semen-mediated enhancement of HIV infection and suggest the potential utility of incorporating gallic acid into a multicomponent microbicide targeting both the HIV virus and host components that promote viral infection. PMID- 27226575 TI - Protein Kinase Mitogen-activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4) Promotes Obesity-induced Hyperinsulinemia. AB - Previous studies revealed a paradox whereby mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) acted as a negative regulator of insulin sensitivity in chronically obese mice, yet systemic deletion of Map4k4 did not improve glucose tolerance. Here, we report markedly reduced glucose-responsive plasma insulin and C-peptide levels in whole body Map4k4-depleted mice (M4K4 iKO) as well as an impaired first phase of insulin secretion from islets derived from M4K4 iKO mice ex vivo After long-term high fat diet (HFD), M4K4 iKO mice pancreata also displayed reduced beta cell mass, fewer proliferating beta cells and reduced islet-specific gene mRNA expression compared with controls, although insulin content was normal. Interestingly, the reduced plasma insulin in M4K4 iKO mice exposed to chronic (16 weeks) HFD was not observed in response to acute HFD challenge or short term treatment with the insulin receptor antagonist S961. Furthermore, the improved insulin sensitivity in obese M4K4 iKO mice was abrogated by high exogenous insulin over the course of a euglycemic clamp study, indicating that hypoinsulinemia promotes insulin sensitivity in chronically obese M4K4 iKO mice. These results demonstrate that protein kinase Map4k4 drives obesity-induced hyperinsulinemia and insulin resistance in part by promoting insulin secretion from beta cells in mice. PMID- 27226576 TI - Cathepsin B Activity Initiates Apoptosis via Digestive Protease Activation in Pancreatic Acinar Cells and Experimental Pancreatitis. AB - Pancreatitis is associated with premature activation of digestive proteases in the pancreas. The lysosomal hydrolase cathepsin B (CTSB) is a known activator of trypsinogen, and its deletion reduces disease severity in experimental pancreatitis. Here we studied the activation mechanism and subcellular compartment in which CTSB regulates protease activation and cellular injury. Cholecystokinin (CCK) increased the activity of CTSB, cathepsin L, trypsin, chymotrypsin, and caspase 3 in vivo and in vitro and induced redistribution of CTSB to a secretory vesicle-enriched fraction. Neither CTSB protein nor activity redistributed to the cytosol, where the CTSB inhibitors cystatin-B/C were abundantly present. Deletion of CTSB reduced and deletion of cathepsin L increased intracellular trypsin activation. CTSB deletion also abolished CCK induced caspase 3 activation, apoptosis-inducing factor, as well as X-linked inhibitor of apoptosis protein degradation, but these depended on trypsinogen activation via CTSB. Raising the vesicular pH, but not trypsin inhibition, reduced CTSB activity. Trypsin inhibition did not affect apoptosis in hepatocytes. Deletion of CTSB affected apoptotic but not necrotic acinar cell death. In summary, CTSB in pancreatitis undergoes activation in a secretory, vesicular, and acidic compartment where it activates trypsinogen. Its deletion or inhibition regulates acinar cell apoptosis but not necrosis in two models of pancreatitis. Caspase 3-mediated apoptosis depends on intravesicular trypsinogen activation induced by CTSB, not CTSB activity directly, and this mechanism is pancreas-specific. PMID- 27226578 TI - Combinatorial Histone Readout by the Dual Plant Homeodomain (PHD) Fingers of Rco1 Mediates Rpd3S Chromatin Recruitment and the Maintenance of Transcriptional Fidelity. AB - The plant homeodomain (PHD) finger is found in many chromatin-associated proteins and functions to recruit effector proteins to chromatin through its ability to bind both methylated and unmethylated histone residues. Here, we show that the dual PHD fingers of Rco1, a member of the Rpd3S histone deacetylase complex recruited to transcribing genes, operate in a combinatorial manner in targeting the Rpd3S complex to histone H3 in chromatin. Although mutations in either the first or second PHD finger allow for Rpd3S complex formation, the assembled complexes from these mutants cannot recognize nucleosomes or function to maintain chromatin structure and prevent cryptic transcriptional initiation from within transcribed regions. Taken together, our findings establish a critical role of combinatorial readout in maintaining chromatin organization and in enforcing the transcriptional fidelity of genes. PMID- 27226577 TI - Reciprocal Regulation of the Cardiac Epigenome by Chromatin Structural Proteins Hmgb and Ctcf: IMPLICATIONS FOR TRANSCRIPTIONAL REGULATION. AB - Transcriptome remodeling in heart disease occurs through the coordinated actions of transcription factors, histone modifications, and other chromatin features at pathology-associated genes. The extent to which genome-wide chromatin reorganization also contributes to the resultant changes in gene expression remains unknown. We examined the roles of two chromatin structural proteins, Ctcf (CCCTC-binding factor) and Hmgb2 (high mobility group protein B2), in regulating pathologic transcription and chromatin remodeling. Our data demonstrate a reciprocal relationship between Hmgb2 and Ctcf in controlling aspects of chromatin structure and gene expression. Both proteins regulate each others' expression as well as transcription in cardiac myocytes; however, only Hmgb2 does so in a manner that involves global reprogramming of chromatin accessibility. We demonstrate that the actions of Hmgb2 on local chromatin accessibility are conserved across genomic loci, whereas the effects on transcription are loci dependent and emerge in concert with histone modification and other chromatin features. Finally, although both proteins share gene targets, Hmgb2 and Ctcf, neither binds these genes simultaneously nor do they physically colocalize in myocyte nuclei. Our study uncovers a previously unknown relationship between these two ubiquitous chromatin proteins and provides a mechanistic explanation for how Hmgb2 regulates gene expression and cellular phenotype. Furthermore, we provide direct evidence for structural remodeling of chromatin on a genome-wide scale in the setting of cardiac disease. PMID- 27226579 TI - Histamine Regulates Actin Cytoskeleton in Human Toll-like Receptor 4-activated Monocyte-derived Dendritic Cells Tuning CD4+ T Lymphocyte Response. AB - Histamine, a major mediator in allergic diseases, differentially regulates the polarizing ability of dendritic cells after Toll-like receptor (TLR) stimulation, by not completely explained mechanisms. In this study we investigated the effects of histamine on innate immune reaction during the response of human monocyte derived DCs (mDCs) to different TLR stimuli: LPS, specific for TLR4, and Pam3Cys, specific for heterodimer molecule TLR1/TLR2. We investigated actin remodeling induced by histamine together with mDCs phenotype, cytokine production, and the stimulatory and polarizing ability of Th0. By confocal microscopy and RT-PCR expression of Rac1/CdC42 Rho GTPases, responsible for actin remodeling, we show that histamine selectively modifies actin cytoskeleton organization induced by TLR4, but not TLR2 and this correlates with increased IL4 production and decreased IFNgamma by primed T cells. We also demonstrate that histamine-induced cytoskeleton organization is at least in part mediated by down-regulation of small Rho GTPase CdC42 and the protein target PAK1, but not by down-regulation of Rac1. The presence and relative expression of histamine receptors HR1-4 and TLRs were determined as well. Independently of actin remodeling, histamine down regulates IL12p70 and CXCL10 production in mDCs after TLR2 and TLR4 stimulation. We also observed a trend of IL10 up-regulation that, despite previous reports, did not reach statistical significance. PMID- 27226580 TI - Purinergic A2b Receptor Activation by Extracellular Cues Affects Positioning of the Centrosome and Nucleus and Causes Reduced Cell Migration. AB - The tight, relative positioning of the nucleus and centrosome in mammalian cells is important for the regulation of cell migration. Under pathophysiological conditions, the purinergic A2b receptor can regulate cell motility, but the underlying mechanism remains unknown. Expression of A2b, normally low, is increased in tissues experiencing adverse physiological conditions, including hypoxia and inflammation. ATP is released from such cells. We investigated whether extracellular cues can regulate centrosome-nucleus positioning and cell migration. We discovered that hypoxia as well as extracellular ATP cause a reversible increase in the distance between the centrosome and nucleus and reduced cell motility. We uncovered the underlying pathway: both treatments act through the A2b receptor and specifically activate the Epac1/RapGef3 pathway. We show that cells lacking A2b do not respond in this manner to hypoxia or ATP but transfection of A2b restores this response, that Epac1 is critically involved, and that Rap1B is important for the relative positioning of the centrosome and nucleus. Our results represent, to our knowledge, the first report demonstrating that pathophysiological conditions can impact the distance between the centrosome and nucleus. Furthermore, we identify the A2b receptor as a central player in this process. PMID- 27226581 TI - Conformational Selection and Submillisecond Dynamics of the Ligand-binding Domain of the N-Methyl-d-aspartate Receptor. AB - The N-methyl-d-aspartate (NMDA) receptors are heteromeric non-selective cation channels that require the binding of glycine and glutamate for gating. Based on crystal structures, the mechanism of partial agonism at the glycine-binding site is thought to be mediated by a shift in the conformational equilibrium between an open clamshell and a closed clamshell-like structure of the bilobed ligand binding domain (LBD). Using single-molecule Forster resonance energy transfer (smFRET) and multiparameter fluorescence detection, which allows us to study the conformational states and dynamics in the submillisecond time scale, we show that there are at least three conformational states explored by the LBD: the low FRET, medium FRET, and high FRET states. The distance of the medium and low FRET states corresponds to what has been observed in crystallography structures. We show that the high FRET state, which would represent a more closed clamshell conformation than that observed in the crystal structure, is most likely the state initiating activation, as evidenced by the fact that the fraction of the protein in this state correlates well with the extent of activation. Furthermore, full agonist bound LBDs show faster dynamic motions between the medium and high FRET states, whereas they show slower dynamics when bound to weaker agonists or to antagonists. PMID- 27226582 TI - How Phosphorylation and ATPase Activity Regulate Anion Flux though the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). AB - The cystic fibrosis transmembrane conductance regulator (CFTR, ABCC7), mutations of which cause cystic fibrosis, belongs to the ATP-binding cassette (ABC) transporter family and works as a channel for small anions, such as chloride and bicarbonate. Anion channel activity is known to depend on phosphorylation by cAMP dependent protein kinase A (PKA) and CFTR-ATPase activity. Whereas anion channel activity has been extensively investigated, phosphorylation and CFTR-ATPase activity are still poorly understood. Here, we show that the two processes can be measured in a label-free and non-invasive manner in real time in live cells, stably transfected with CFTR. This study reveals three key findings. (i) The major contribution (>=90%) to the total CFTR-related ATP hydrolysis rate is due to phosphorylation by PKA and the minor contribution (<=10%) to CFTR-ATPase activity. (ii) The mutant CFTR-E1371S that is still conductive, but defective in ATP hydrolysis, is not phosphorylated, suggesting that phosphorylation requires a functional nucleotide binding domain and occurs in the post-hydrolysis transition state. (iii) CFTR-ATPase activity is inversely related to CFTR anion flux. The present data are consistent with a model in which CFTR is in a closed conformation with two ATPs bound. The open conformation is induced by ATP hydrolysis and corresponds to the post-hydrolysis transition state that is stabilized by phosphorylation and binding of chloride channel potentiators. PMID- 27226583 TI - Binding of Plasmodium falciparum Merozoite Surface Proteins DBLMSP and DBLMSP2 to Human Immunoglobulin M Is Conserved among Broadly Diverged Sequence Variants. AB - Diversity at pathogen genetic loci can be driven by host adaptive immune selection pressure and may reveal proteins important for parasite biology. Population-based genome sequencing of Plasmodium falciparum, the parasite responsible for the most severe form of malaria, has highlighted two related polymorphic genes called dblmsp and dblmsp2, which encode Duffy binding-like (DBL) domain-containing proteins located on the merozoite surface but whose function remains unknown. Using recombinant proteins and transgenic parasites, we show that DBLMSP and DBLMSP2 directly and avidly bind human IgM via their DBL domains. We used whole genome sequence data from over 400 African and Asian P. falciparum isolates to show that dblmsp and dblmsp2 exhibit extreme protein polymorphism in their DBL domain, with multiple variants of two major allelic classes present in every population tested. Despite this variability, the IgM binding function was retained across diverse sequence representatives. Although this interaction did not seem to have an effect on the ability of the parasite to invade red blood cells, binding of DBLMSP and DBLMSP2 to IgM inhibited the overall immunoreactivity of these proteins to IgG from patients who had been exposed to the parasite. This suggests that IgM binding might mask these proteins from the host humoral immune system. PMID- 27226584 TI - Tranilast Blocks the Interaction between the Protein S100A11 and Receptor for Advanced Glycation End Products (RAGE) V Domain and Inhibits Cell Proliferation. AB - The human S100 calcium-binding protein A11 (S100A11) is a member of the S100 protein family. Once S100A11 proteins bind to calcium ions at EF-hand motifs, S100A11 changes its conformation, promoting interaction with target proteins. The receptor for advanced glycation end products (RAGE) consists of three extracellular domains, including the V domain, C1 domain, and C2 domain. In this case, the V domain is the target for mutant S100A11 (mS100A11) binding. RAGE binds to the ligands, resulting in cell proliferation, cell growth, and several signal transduction cascades. We used NMR and fluorescence spectroscopy to demonstrate the interactions between mS100A11and RAGE V domain. The tranilast molecule is a drug used for treating allergic disorders. We discovered that the RAGE V domain and tranilast would interact with mS100A11 by using (1)H-(15)N HSQC NMR titrations. According to the results, we obtained two binary complex models from the HADDOCK program, S100A11-RAGE V domain and S100A11-tranilast, respectively. We overlapped two binary complex models with the same orientation of S100A11 homodimer and demonstrated that tranilast would block the binding site between S100A11 and the RAGE V domain. We further utilized a water-soluble tetrazolium-1 assay to confirm this result. We think that the results will be potentially useful in the development of new anti-cancer drugs. PMID- 27226585 TI - Organization into Higher Ordered Ring Structures Counteracts Membrane Binding of IM30, a Protein Associated with Inner Membranes in Chloroplasts and Cyanobacteria. AB - The IM30 (inner membrane-associated protein of 30 kDa), also known as the Vipp1 (vesicle-inducing protein in plastids 1), has a crucial role in thylakoid membrane biogenesis and maintenance. Recent results suggest that the protein binds peripherally to membranes containing negatively charged lipids. However, although IM30 monomers interact and assemble into large oligomeric ring complexes with different numbers of monomers, it is still an open question whether ring formation is crucial for membrane interaction. Here we show that binding of IM30 rings to negatively charged phosphatidylglycerol membrane surfaces results in a higher ordered membrane state, both in the head group and in the inner core region of the lipid bilayer. Furthermore, by using gold nanorods covered with phosphatidylglycerol layers and single particle spectroscopy, we show that not only IM30 rings but also lower oligomeric IM30 structures interact with membranes, although with higher affinity. Thus, ring formation is not crucial for, and even counteracts, membrane interaction of IM30. PMID- 27226586 TI - Ajuba Phosphorylation by CDK1 Promotes Cell Proliferation and Tumorigenesis. AB - Recent studies identified the adaptor protein Ajuba as a positive regulator of Yes-associated protein (YAP) oncogenic activity through inhibiting large tumor suppressor (Lats1/2) core kinases of the Hippo pathway, a signaling pathway that plays important roles in cancer. In this study, we define a novel mechanism for phospho-regulation of Ajuba in mitosis and its biological significance in cancer. We found that Ajuba is phosphorylated in vitro and in vivo by cyclin-dependent kinase 1 (CDK1) at Ser(119) and Ser(175) during the G2/M phase of the cell cycle. Mitotic phosphorylation of Ajuba controls the expression of multiple cell cycle regulators; however, it does not affect Hippo signaling activity, nor does it induce epithelial-mesenchymal transition. We further showed that mitotic phosphorylation of Ajuba is sufficient to promote cell proliferation and anchorage-independent growth in vitro and tumorigenesis in vivo Collectively, our discoveries reveal a previously unrecognized mechanism for Ajuba regulation in mitosis and its role in tumorigenesis. PMID- 27226587 TI - Reprogramming Nurse-like Cells with Interferon gamma to Interrupt Chronic Lymphocytic Leukemia Cell Survival. AB - Nurse-like cells (NLCs) play a central role in chronic lymphocytic leukemia (CLL) because they promote the survival and proliferation of CLL cells. NLCs are derived from the monocyte lineage and are driven toward their phenotype via contact-dependent and -independent signals from CLL cells. Because of the central role of NLCs in promoting disease, new strategies to eliminate or reprogram them are needed. Successful reprogramming may be of extra benefit because NLCs express Fcgamma receptors (FcgammaRs) and thus could act as effector cells within the context of antibody therapy. IFNgamma is known to promote the polarization of macrophages toward an M1-like state that is no longer tumor-supportive. In an effort to reprogram the phenotype of NLCs, we found that IFNgamma up-regulated the M1-related markers CD86 and HLA-DR as well as FcgammaRIa. This corresponded to enhanced FcgammaR-mediated cytokine production as well as rituximab-mediated phagocytosis of CLL cells. In addition, IFNgamma down-regulated the expression of CD31, resulting in withdrawal of the survival advantage on CLL cells. These results suggest that IFNgamma can re-educate NLCs and shift them toward an effector-like state and that therapies promoting local IFNgamma production may be effective adjuvants for antibody therapy in CLL. PMID- 27226588 TI - The Nuclear Zinc Finger Protein Zfat Maintains FoxO1 Protein Levels in Peripheral T Cells by Regulating the Activities of Autophagy and the Akt Signaling Pathway. AB - Forkhead box O1 (FoxO1) is a key molecule for the development and functions of peripheral T cells. However, the precise mechanisms regulating FoxO1 expression in peripheral T cells remain elusive. We previously reported that Zfat(f/f) CD4Cre mice showed a marked decline in FoxO1 protein levels in peripheral T cells, partially through proteasomal degradation. Here we have identified the precise mechanisms, apart from proteasome-mediated degradation, of the decreased FoxO1 levels in Zfat-deficient T cells. First, we confirmed that tamoxifen inducible deletion of Zfat in Zfat(f/f)-CreERT2 mice coincidently decreases FoxO1 protein levels in peripheral T cells, indicating that Zfat is essential for maintaining FoxO1 levels in these cells. Although the proteasome-specific inhibitors lactacystin and epoxomicin only moderately increase FoxO1 protein levels, the inhibitors of lysosomal proteolysis bafilomycin A1 and chloroquine restore the decreased FoxO1 levels in Zfat-deficient T cells to levels comparable with those in control cells. Furthermore, Zfat-deficient T cells show increased numbers of autophagosomes and decreased levels of p62 protein, together indicating that Zfat deficiency promotes lysosomal FoxO1 degradation through autophagy. In addition, Zfat deficiency increases the phosphorylation levels of Thr-308 and Ser-473 of Akt and the relative amounts of cytoplasmic to nuclear FoxO1 protein levels, indicating that Zfat deficiency causes Akt activation, leading to nuclear exclusion of FoxO1. Our findings have demonstrated a novel role of Zfat in maintaining FoxO1 protein levels in peripheral T cells by regulating the activities of autophagy and the Akt signaling pathway. PMID- 27226589 TI - Gene Repression in Haloarchaea Using the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-Cas I-B System. AB - The clustered regularly interspaced short palindromic repeats (CRISPR)-Cas system is used by bacteria and archaea to fend off foreign genetic elements. Since its discovery it has been developed into numerous applications like genome editing and regulation of transcription in eukaryotes and bacteria. For archaea currently no tools for transcriptional repression exist. Because molecular biology analyses in archaea become more and more widespread such a tool is vital for investigating the biological function of essential genes in archaea. Here we use the model archaeon Haloferax volcanii to demonstrate that its endogenous CRISPR-Cas system I-B can be harnessed to repress gene expression in archaea. Deletion of cas3 and cas6b genes results in efficient repression of transcription. crRNAs targeting the promoter region reduced transcript levels down to 8%. crRNAs targeting the reading frame have only slight impact on transcription. crRNAs that target the coding strand repress expression only down to 88%, whereas crRNAs targeting the template strand repress expression down to 8%. Repression of an essential gene results in reduction of transcription levels down to 22%. Targeting efficiencies can be enhanced by expressing a catalytically inactive Cas3 mutant. Genes can be targeted on plasmids or on the chromosome, they can be monocistronic or part of a polycistronic operon. PMID- 27226590 TI - Topology and Structure/Function Correlation of Ring- and Gate-forming Domains in the Dynamic Secretin Complex of Thermus thermophilus. AB - Secretins are versatile outer membrane pores used by many bacteria to secrete proteins, toxins, or filamentous phages; extrude type IV pili (T4P); or take up DNA. Extrusion of T4P and natural transformation of DNA in the thermophilic bacterium Thermus thermophilus requires a unique secretin complex comprising six stacked rings, a membrane-embedded cone structure, and two gates that open and close a central channel. To investigate the role of distinct domains in ring and gate formation, we examined a set of deletion derivatives by cryomicroscopy techniques. Here we report that maintaining the N0 ring in the deletion derivatives led to stable PilQ complexes. Analyses of the variants unraveled that an N-terminal domain comprising a unique betabetabetaalphabeta fold is essential for the formation of gate 2. Furthermore, we identified four betaalphabetabetaalpha domains essential for the formation of the N2 to N5 rings. Mutant studies revealed that deletion of individual ring domains significantly reduces piliation. The N1, N2, N4, and N5 deletion mutants were significantly impaired in T4P-mediated twitching motility, whereas the motility of the N3 mutant was comparable with that of wild-type cells. This indicates that the deletion of the N3 ring leads to increased pilus dynamics, thereby compensating for the reduced number of pili of the N3 mutant. All mutants exhibit a wild-type natural transformation phenotype, leading to the conclusion that DNA uptake is independent of functional T4P. PMID- 27226591 TI - Truncated Glucagon-like Peptide-1 and Exendin-4 alpha-Conotoxin pl14a Peptide Chimeras Maintain Potency and alpha-Helicity and Reveal Interactions Vital for cAMP Signaling in Vitro. AB - Glucagon-like peptide-1 (GLP-1) signaling through the glucagon-like peptide 1 receptor (GLP-1R) is a key regulator of normal glucose metabolism, and exogenous GLP-1R agonist therapy is a promising avenue for the treatment of type 2 diabetes mellitus. To date, the development of therapeutic GLP-1R agonists has focused on producing drugs with an extended serum half-life. This has been achieved by engineering synthetic analogs of GLP-1 or the more stable exogenous GLP-1R agonist exendin-4 (Ex-4). These synthetic peptide hormones share the overall structure of GLP-1 and Ex-4, with a C-terminal helical segment and a flexible N terminal tail. Although numerous studies have investigated the molecular determinants underpinning GLP-1 and Ex-4 binding and signaling through the GLP 1R, these have primarily focused on the length and composition of the N-terminal tail or on how to modulate the helicity of the full-length peptides. Here, we investigate the effect of C-terminal truncation in GLP-1 and Ex-4 on the cAMP pathway. To ensure helical C-terminal regions in the truncated peptides, we produced a series of chimeric peptides combining the N-terminal portion of GLP-1 or Ex-4 and the C-terminal segment of the helix-promoting peptide alpha-conotoxin pl14a. The helicity and structures of the chimeric peptides were confirmed using circular dichroism and NMR, respectively. We found no direct correlation between the fractional helicity and potency in signaling via the cAMP pathway. Rather, the most important feature for efficient receptor binding and signaling was the C terminal helical segment (residues 22-27) directing the binding of Phe(22) into a hydrophobic pocket on the GLP-1R. PMID- 27226592 TI - The Endocytic Fate of the Transferrin Receptor Is Regulated by c-Abl Kinase. AB - Clathrin-mediated endocytosis of transferrin (Tf) and its cognate receptor (TfR1) is a central pathway supporting the uptake of trophic iron. It has generally been assumed that this is a constitutive process. However, we have reported that the non-receptor tyrosine kinase, Src, is activated by Tf to facilitate the internalization of the Tf-TfR1 ligand-receptor complex. As an extension of these findings, we have tested whether subsequent trafficking steps might be regulated by additional kinase-dependent cascades, and we observed a significant endocytic block by inhibiting c-Abl kinase by a variety of methods. Importantly, Tf internalization was reduced significantly in all of these cell models and could be restored by re-expression of WT c-Abl. Surprisingly, this attenuated Tf-TfR1 endocytosis was due to a substantial drop in both the surface and total cellular receptor levels. Additional studies with the LDL receptor showed a similar effect. Surprisingly, immunofluorescence microscopy of imatinib-treated cells revealed a marked colocalization of internalized TfR1 with late endosomes/lysosomes, whereas attenuating the lysosome function with several inhibitors reduced this receptor loss. Importantly, inhibition of c-Abl resulted in a striking redistribution of the chaperone Hsc70 from a diffuse cytosolic localization to an association with the TfR1 at the late endosome-lysosome. Pharmacological inhibition of Hsc70 ATPase activity in cultured cells by the drug VER155008 prevents this chaperone-receptor interaction, resulting in an accumulation of the TfR1 in the early endosome. Thus, inhibition of c-Abl minimizes receptor recycling pathways and results in chaperone-dependent trafficking of the TfR1 to the lysosome for degradation. These findings implicate a novel role for c-Abl and Hsc70 as an unexpected regulator of Hsc70-mediated transport of trophic receptor cargo between the early and late endosomal compartments. PMID- 27226593 TI - Substrate-selective Inhibition of Cyclooxygeanse-2 by Fenamic Acid Derivatives Is Dependent on Peroxide Tone. AB - Cyclooxygenase-2 (COX-2) catalyzes the oxygenation of arachidonic acid (AA) and endocannabinoid substrates, placing the enzyme at a unique junction between the eicosanoid and endocannabinoid signaling pathways. COX-2 is a sequence homodimer, but the enzyme displays half-of-site reactivity, such that only one monomer of the dimer is active at a given time. Certain rapid reversible, competitive nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to inhibit COX-2 in a substrate-selective manner, with the binding of inhibitor to a single monomer sufficient to inhibit the oxygenation of endocannabinoids but not arachidonic acid. The underlying mechanism responsible for substrate-selective inhibition has remained elusive. We utilized structural and biophysical methods to evaluate flufenamic acid, meclofenamic acid, mefenamic acid, and tolfenamic acid for their ability to act as substrate-selective inhibitors. Crystal structures of each drug in complex with human COX-2 revealed that the inhibitor binds within the cyclooxygenase channel in an inverted orientation, with the carboxylate group interacting with Tyr-385 and Ser-530 at the top of the channel. Tryptophan fluorescence quenching, continuous-wave electron spin resonance, and UV-visible spectroscopy demonstrate that flufenamic acid, mefenamic acid, and tolfenamic acid are substrate-selective inhibitors that bind rapidly to COX-2, quench tyrosyl radicals, and reduce higher oxidation states of the heme moiety. Substrate-selective inhibition was attenuated by the addition of the lipid peroxide 15-hydroperoxyeicosatertaenoic acid. Collectively, these studies implicate peroxide tone as an important mechanistic component of substrate selective inhibition by flufenamic acid, mefenamic acid, and tolfenamic acid. PMID- 27226594 TI - Preferential Phosphorylation on Old Histones during Early Mitosis in Human Cells. AB - How histone post-translational modifications (PTMs) are inherited through the cell cycle remains poorly understood. Canonical histones are made in the S phase of the cell cycle. Combining mass spectrometry-based technologies and stable isotope labeling by amino acids in cell culture, we question the distribution of multiple histone PTMs on old versus new histones in synchronized human cells. We show that histone PTMs can be grouped into three categories according to their distributions. Most lysine mono-methylation and acetylation PTMs are either symmetrically distributed on old and new histones or are enriched on new histones. In contrast, most di- and tri-methylation PTMs are enriched on old histones, suggesting that the inheritance of different PTMs is regulated distinctly. Intriguingly, old and new histones are distinct in their phosphorylation status during early mitosis in the following three human cell types: HeLa, 293T, and human foreskin fibroblast cells. The mitotic hallmark H3S10ph is predominantly associated with old H3 at early mitosis and becomes symmetric with the progression of mitosis. This same distribution was observed with other mitotic phosphorylation marks, including H3T3/T6ph, H3.1/2S28ph, and H1.4S26ph but not S28/S31ph on the H3 variant H3.3. Although H3S10ph often associates with the neighboring Lys-9 di- or tri-methylations, they are not required for the asymmetric distribution of Ser-10 phosphorylation on the same H3 tail. Inhibition of the kinase Aurora B does not change the distribution despite significant reduction of H3S10ph levels. However, K9me2 abundance on the new H3 is significantly reduced after Aurora B inhibition, suggesting a cross-talk between H3S10ph and H3K9me2. PMID- 27226595 TI - An EF-hand-containing Protein in Trypanosoma brucei Regulates Cytokinesis Initiation by Maintaining the Stability of the Cytokinesis Initiation Factor CIF1. AB - Trypanosoma brucei undergoes cytokinesis uni-directionally from the anterior tip of the new flagellum attachment zone (FAZ) toward the posterior end of the cell. We recently delineated a novel signaling pathway composed of polo-like kinase, cytokinesis initiation factor 1 (CIF1), and aurora B kinase that acts in concert at the new FAZ tip to regulate cytokinesis initiation. To identify new cytokinesis regulators, we carried out proximity-dependent biotin identification and identified many CIF1 binding partners and near neighbors. Here we report a novel CIF1-binding protein, named CIF2, and its mechanistic role in cytokinesis initiation. CIF2 interacts with CIF1 in vivo and co-localizes with CIF1 at the new FAZ tip during early cell cycle stages. RNAi of CIF2 inhibited the normal, anterior-to-posterior cytokinesis but activated an alternative, posterior-to anterior cytokinesis. CIF2 depletion destabilized CIF1 and disrupted the localization of polo-like kinase and aurora B kinase to the new FAZ tip, thus revealing the mechanistic role of CIF2 in cytokinesis initiation. Surprisingly, overexpression of CIF2 also inhibited the normal, anterior-to-posterior cytokinesis and triggered the alternative, posterior-to-anterior cytokinesis, suggesting a tight control of CIF2 protein abundance. These results identified a new regulator in the cytokinesis regulatory pathway and reiterated that a backup cytokinesis pathway is activated by inhibiting the normal cytokinesis pathway. PMID- 27226596 TI - Endoplasmic Reticulum-associated Degradation of Pca1p, a Polytopic Protein, via Interaction with the Proteasome at the Membrane. AB - Endoplasmic reticulum-associated degradation (ERAD) plays a critical role in the destruction of terminally misfolded proteins at the secretory pathway. The system also regulates expression levels of several proteins such as Pca1p, a cadmium exporter in yeast. To gain better insight into the mechanisms underlying ERAD of Pca1p and other polytopic proteins by the proteasome in the cytosol, our study determined the roles for the molecular factors of ERAD in dislodging Pca1p from the endoplasmic reticulum (ER). Inactivation of the 20S proteasome leads to accumulation of ubiquitinated Pca1p in the ER membrane, suggesting a role for the proteasome in extraction of Pca1p from the ER. Pca1p formed a complex with the proteasome at the membrane in a Doa10p E3 ligase-dependent manner. Cdc48p is required for recruiting the proteasome to Pca1p. Although the Ufd2p E4 ubiquitin chain extension enzyme is involved in efficient degradation of Pca1p, Ufd2p deficient cells did not affect the formation of a complex between Pca1p and the proteasome. Two other polytopic membrane proteins undergoing ERAD, Ste6*p and Hmg2p, also displayed the same outcomes observed for Pca1p. However, poly ubiquitinated Cpy1*p, a luminal ERAD substrate, was detected in the cytosol independent of proteolytic activities of the proteasome. These results indicate that extraction and degradation of polytopic membrane proteins at the ER is a coupled event. This mechanism would relieve the cost of exposed hydrophobic domains in the cytosol during ERAD. PMID- 27226598 TI - Tmc1 Is a Dynamically Regulated Effector of the Rpn4 Proteotoxic Stress Response. AB - The ubiquitin-proteasome system represents the major pathway of selective intracellular protein degradation in eukaryotes. Misfolded proteins represent an important class of substrates for this pathway, and the failure to destroy misfolded proteins is associated with a number of human diseases. The transcription factor Rpn4 mediates a key proteotoxic stress response whose best known function is to control proteasome abundance by a homeostatic feedback mechanism. Here we identify the uncharacterized zinc finger protein Tmc1 as a dynamically regulated stress-responsive protein. Rpn4 induces TMC1 transcription in response to misfolded proteins. However, this response is counteracted by rapid proteasome-dependent degradation of Tmc1, which serves to normalize Tmc1 protein levels after induction. Precise control of Tmc1 levels is needed in vivo to survive multiple stressors related to proteostasis. Thus, Tmc1 represents a novel effector and substrate of the Rpn4 proteotoxic stress response. PMID- 27226597 TI - Insights into Lysine Deacetylation of Natively Folded Substrate Proteins by Sirtuins. AB - Sirtuins are NAD(+)-dependent lysine deacylases, regulating a variety of cellular processes. The nuclear Sirt1, the cytosolic Sirt2, and the mitochondrial Sirt3 are robust deacetylases, whereas the other sirtuins have preferences for longer acyl chains. Most previous studies investigated sirtuin-catalyzed deacylation on peptide substrates only. We used the genetic code expansion concept to produce natively folded, site-specific, and lysine-acetylated Sirt1-3 substrate proteins, namely Ras-related nuclear, p53, PEPCK1, superoxide dismutase, cyclophilin D, and Hsp10, and analyzed the deacetylation reaction. Some acetylated proteins such as Ras-related nuclear, p53, and Hsp10 were robustly deacetylated by Sirt1-3. However, other reported sirtuin substrate proteins such as cyclophilin D, superoxide dismutase, and PEPCK1 were not deacetylated. Using a structural and functional approach, we describe the ability of Sirt1-3 to deacetylate two adjacent acetylated lysine residues. The dynamics of this process have implications for the lifetime of acetyl modifications on di-lysine acetylation sites and thus constitute a new mechanism for the regulation of proteins by acetylation. Our studies support that, besides the primary sequence context, the protein structure is a major determinant of sirtuin substrate specificity. PMID- 27226599 TI - Crystal Structures of the Human Doublecortin C- and N-terminal Domains in Complex with Specific Antibodies. AB - Doublecortin is a microtubule-associated protein produced during neurogenesis. The protein stabilizes microtubules and stimulates their polymerization, which allows migration of immature neurons to their designated location in the brain. Mutations in the gene that impair doublecortin function and cause severe brain formation disorders are located on a tandem repeat of two doublecortin domains. The molecular mechanism of action of doublecortin is only incompletely understood. Anti-doublecortin antibodies, such as the rabbit polyclonal Abcam 18732, are widely used as neurogenesis markers. Here, we report the generation and characterization of antibodies that bind to single doublecortin domains. The antibodies were used as tools to obtain structures of both domains. Four independent crystal structures of the N-terminal domain reveal several distinct open and closed conformations of the peptide linking N- and C-terminal domains, which can be related to doublecortin function. An NMR assignment and a crystal structure in complex with a camelid antibody fragment show that the doublecortin C-terminal domain adopts the same well defined ubiquitin-like fold as the N terminal domain, despite its reported aggregation and molten globule-like properties. The antibodies' unique domain specificity also renders them ideal research tools to better understand the role of individual domains in doublecortin function. A single chain camelid antibody fragment specific for the C-terminal doublecortin domain affected microtubule binding, whereas a monoclonal mouse antibody specific for the N-terminal domain did not. Together with steric considerations, this suggests that the microtubule-interacting doublecortin domain observed in cryo-electron micrographs is the C-terminal domain rather than the N-terminal one. PMID- 27226601 TI - Toward Understanding the Molecular Bases of Stretch Activation: A STRUCTURAL COMPARISON OF THE TWO TROPONIN C ISOFORMS OF LETHOCERUS. AB - Muscles are usually activated by calcium binding to the calcium sensory protein troponin-C, which is one of the three components of the troponin complex. However, in cardiac and insect flight muscle activation is also produced by mechanical stress. Little is known about the molecular bases of this calcium independent activation. In Lethocerus, a giant water bug often used as a model system because of its large muscle fibers, there are two troponin-C isoforms, called F1 and F2, that have distinct roles in activating the muscle. It has been suggested that this can be explained either by differences in structural features or by differences in the interactions with other proteins. Here we have compared the structural and dynamic properties of the two proteins and shown how they differ. We have also mapped the interactions of the F2 isoform with peptides spanning the sequence of its natural partner, troponin-I. Our data have allowed us to build a model of the troponin complex and may eventually help in understanding the specialized function of the F1 and F2 isoforms and the molecular mechanism of stretch activation. PMID- 27226600 TI - Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors. AB - G protein-coupled receptors (GPCRs) from the secretin-like (class B) family are key players in hormonal homeostasis and are important drug targets for the treatment of metabolic disorders and neuronal diseases. They consist of a large N terminal extracellular domain (ECD) and a transmembrane domain (TMD) with the GPCR signature of seven transmembrane helices. Class B GPCRs are activated by peptide hormones with their C termini bound to the receptor ECD and their N termini bound to the TMD. It is thought that the ECD functions as an affinity trap to bind and localize the hormone to the receptor. This in turn would allow the hormone N terminus to insert into the TMD and induce conformational changes of the TMD to activate downstream signaling. In contrast to this prevailing model, we demonstrate that human class B GPCRs vary widely in their requirement of the ECD for activation. In one group, represented by corticotrophin-releasing factor receptor 1 (CRF1R), parathyroid hormone receptor (PTH1R), and pituitary adenylate cyclase activating polypeptide type 1 receptor (PAC1R), the ECD requirement for high affinity hormone binding can be bypassed by induced proximity and mass action effects, whereas in the other group, represented by glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), the ECD is required for signaling even when the hormone is covalently linked to the TMD. Furthermore, the activation of GLP-1R by small molecules that interact with the intracellular side of the receptor is dependent on the presence of its ECD, suggesting a direct role of the ECD in GLP-1R activation. PMID- 27226602 TI - Activation of Peroxisome Proliferator-activated Receptor gamma (PPARgamma) and CD36 Protein Expression: THE DUAL PATHOPHYSIOLOGICAL ROLES OF PROGESTERONE. AB - Progesterone or its analog, one of components of hormone replacement therapy, may attenuate the cardioprotective effects of estrogen. However, the underlying mechanisms have not been fully elucidated. Expression of CD36, a receptor for oxidized LDL (oxLDL) that enhances macrophage/foam cell formation, is activated by the transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma). CD36 also functions as a fatty acid transporter to influence fatty acid metabolism and the pathophysiological status of several diseases. In this study, we determined that progesterone induced macrophage CD36 expression, which is related to progesterone receptor (PR) activity. Progesterone enhanced cellular oxLDL uptake in a CD36-dependent manner. Mechanistically, progesterone increased PPARgamma expression and PPARgamma promoter activity in a PR-dependent manner and the binding of PR with the progesterone response element in the PPARgamma promoter. Specific deletion of macrophage PPARgamma (MphiPPARgamma KO) expression in mice abolished progesterone-induced macrophage CD36 expression and cellular oxLDL accumulation. We also determined that, associated with gestation and increased serum progesterone levels, CD36 and PPARgamma expression in mouse adipose tissue, skeletal muscle, and peritoneal macrophages were substantially activated. Taken together, our study demonstrates that progesterone can play dual pathophysiological roles by activating PPARgamma expression, in which progesterone increases macrophage CD36 expression and oxLDL accumulation, a negative effect on atherosclerosis, and enhances the PPARgamma-CD36 pathway in adipose tissue and skeletal muscle, a protective effect on pregnancy. PMID- 27226603 TI - Multiple Quality Control Pathways Limit Non-protein Amino Acid Use by Yeast Cytoplasmic Phenylalanyl-tRNA Synthetase. AB - Non-protein amino acids, particularly isomers of the proteinogenic amino acids, present a threat to proteome integrity if they are mistakenly inserted into proteins. Quality control during aminoacyl-tRNA synthesis reduces non-protein amino acid incorporation by both substrate discrimination and proofreading. For example phenylalanyl-tRNA synthetase (PheRS) proofreads the non-protein hydroxylated phenylalanine derivative m-Tyr after its attachment to tRNA(Phe) We now show in Saccharomyces cerevisiae that PheRS misacylation of tRNA(Phe) with the more abundant Phe oxidation product o-Tyr is limited by kinetic discrimination against o-Tyr-AMP in the transfer step followed by o-Tyr-AMP release from the synthetic active site. This selective rejection of a non-protein aminoacyl-adenylate is in addition to known kinetic discrimination against certain non-cognates in the activation step as well as catalytic hydrolysis of mispaired aminoacyl-tRNA(Phe) species. We also report an unexpected resistance to cytotoxicity by a S. cerevisiae mutant with ablated post-transfer editing activity when supplemented with o-Tyr, cognate Phe, or Ala, the latter of which is not a substrate for activation by this enzyme. Our phenotypic, metabolomic, and kinetic analyses indicate at least three modes of discrimination against non protein amino acids by S. cerevisiae PheRS and support a non-canonical role for SccytoPheRS post-transfer editing in response to amino acid stress. PMID- 27226604 TI - Mechanistic Target of Rapamycin (mTOR) Inhibition Synergizes with Reduced Internal Ribosome Entry Site (IRES)-mediated Translation of Cyclin D1 and c-MYC mRNAs to Treat Glioblastoma. AB - Our previous work has demonstrated an intrinsic mRNA-specific protein synthesis salvage pathway operative in glioblastoma (GBM) tumor cells that is resistant to mechanistic target of rapamycin (mTOR) inhibitors. The activation of this internal ribosome entry site (IRES)-dependent mRNA translation initiation pathway results in continued translation of critical transcripts involved in cell cycle progression in the face of global eIF-4E-mediated translation inhibition. Recently we identified compound 11 (C11), a small molecule capable of inhibiting c-MYC IRES translation as a consequence of blocking the interaction of a requisite c-MYC IRES trans-acting factor, heterogeneous nuclear ribonucleoprotein A1, with its IRES. Here we demonstrate that C11 also blocks cyclin D1 IRES dependent initiation and demonstrates synergistic anti-GBM properties when combined with the mechanistic target of rapamycin kinase inhibitor PP242. The structure-activity relationship of C11 was investigated and resulted in the identification of IRES-J007, which displayed improved IRES-dependent initiation blockade and synergistic anti-GBM effects with PP242. Mechanistic studies with C11 and IRES-J007 revealed binding of the inhibitors within the UP1 fragment of heterogeneous nuclear ribonucleoprotein A1, and docking analysis suggested a small pocket within close proximity to RRM2 as the potential binding site. We further demonstrate that co-therapy with IRES-J007 and PP242 significantly reduces tumor growth of GBM xenografts in mice and that combined inhibitor treatments markedly reduce the mRNA translational state of cyclin D1 and c-MYC transcripts in these tumors. These data support the combined use of IRES-J007 and PP242 to achieve synergistic antitumor responses in GBM. PMID- 27226605 TI - Dysferlin Binds SNAREs (Soluble N-Ethylmaleimide-sensitive Factor (NSF) Attachment Protein Receptors) and Stimulates Membrane Fusion in a Calcium sensitive Manner. AB - Resealing of tears in the sarcolemma of myofibers is a necessary step in the repair of muscle tissue. Recent work suggests a critical role for dysferlin in the membrane repair process and that mutations in dysferlin are responsible for limb girdle muscular dystrophy 2B and Miyoshi myopathy. Beyond membrane repair, dysferlin has been linked to SNARE-mediated exocytotic events including cytokine release and acid sphingomyelinase secretion. However, it is unclear whether dysferlin regulates SNARE-mediated membrane fusion. In this study we demonstrate a direct interaction between dysferlin and the SNARE proteins syntaxin 4 and SNAP 23. In addition, analysis of FRET and in vitro reconstituted lipid mixing assays indicate that dysferlin accelerates syntaxin 4/SNAP-23 heterodimer formation and SNARE-mediated lipid mixing in a calcium-sensitive manner. These results support a function for dysferlin as a calcium-sensing SNARE effector for membrane fusion events. PMID- 27226606 TI - Structural Insights into an Oxalate-producing Serine Hydrolase with an Unusual Oxyanion Hole and Additional Lyase Activity. AB - In Burkholderia species, the production of oxalate, an acidic molecule, is a key event for bacterial growth in the stationary phase. Oxalate plays a central role in maintaining environmental pH, which counteracts inevitable population collapsing alkaline toxicity in amino acid-based culture medium. In the phytopathogen Burkholderia glumae, two enzymes are responsible for oxalate production. First, the enzyme oxalate biosynthetic component A (ObcA) catalyzes the formation of a tetrahedral C6-CoA adduct from the substrates acetyl-CoA and oxaloacetate. Then the ObcB enzyme liberates three products from the C6-CoA adduct: oxalate, acetoacetate, and CoA. Interestingly, these two stepwise reactions are catalyzed by a single bifunctional enzyme, Obc1, from Burkholderia thailandensis and Burkholderia pseudomallei Obc1 has an ObcA-like N-terminal domain and shows ObcB activity in its C-terminal domain despite no sequence homology with ObcB. We report the crystal structure of Obc1 in its apo and glycerol-bound form at 2.5 A and 2.8 A resolution, respectively. The Obc1 N terminal domain is essentially identical both in structure and function to that of ObcA. Its C-terminal domain has an alpha/beta hydrolase fold that has a catalytic triad for oxalate production and a novel oxyanion hole distinct from the canonical HGGG motif in other alpha/beta hydrolases. Functional analyses through mutagenesis studies suggested that His-934 is an additional catalytic acid/base for its lyase activity and liberates two additional products, acetoacetate and CoA. These results provide structural and functional insights into bacterial oxalogenesis and an example of divergent evolution of the alpha/beta hydrolase fold, which has both hydrolase and lyase activity. PMID- 27226607 TI - The Activity of Menkes Disease Protein ATP7A Is Essential for Redox Balance in Mitochondria. AB - Copper-transporting ATPase ATP7A is essential for mammalian copper homeostasis. Loss of ATP7A activity is associated with fatal Menkes disease and various other pathologies. In cells, ATP7A inactivation disrupts copper transport from the cytosol into the secretory pathway. Using fibroblasts from Menkes disease patients and mouse 3T3-L1 cells with a CRISPR/Cas9-inactivated ATP7A, we demonstrate that ATP7A dysfunction is also damaging to mitochondrial redox balance. In these cells, copper accumulates in nuclei, cytosol, and mitochondria, causing distinct changes in their redox environment. Quantitative imaging of live cells using GRX1-roGFP2 and HyPer sensors reveals highest glutathione oxidation and elevation of H2O2 in mitochondria, whereas the redox environment of nuclei and the cytosol is much less affected. Decreasing the H2O2 levels in mitochondria with MitoQ does not prevent glutathione oxidation; i.e. elevated copper and not H2O2 is a primary cause of glutathione oxidation. Redox misbalance does not significantly affect mitochondrion morphology or the activity of respiratory complex IV but markedly increases cell sensitivity to even mild glutathione depletion, resulting in loss of cell viability. Thus, ATP7A activity protects mitochondria from excessive copper entry, which is deleterious to redox buffers. Mitochondrial redox misbalance could significantly contribute to pathologies associated with ATP7A inactivation in tissues with paradoxical accumulation of copper (i.e. renal epithelia). PMID- 27226608 TI - Conserved Sequence Preferences Contribute to Substrate Recognition by the Proteasome. AB - The proteasome has pronounced preferences for the amino acid sequence of its substrates at the site where it initiates degradation. Here, we report that modulating these sequences can tune the steady-state abundance of proteins over 2 orders of magnitude in cells. This is the same dynamic range as seen for inducing ubiquitination through a classic N-end rule degron. The stability and abundance of His3 constructs dictated by the initiation site affect survival of yeast cells and show that variation in proteasomal initiation can affect fitness. The proteasome's sequence preferences are linked directly to the affinity of the initiation sites to their receptor on the proteasome and are conserved between Saccharomyces cerevisiae, Schizosaccharomyces pombe, and human cells. These findings establish that the sequence composition of unstructured initiation sites influences protein abundance in vivo in an evolutionarily conserved manner and can affect phenotype and fitness. PMID- 27226609 TI - Direct Comparison of Manganese Detoxification/Efflux Proteins and Molecular Characterization of ZnT10 Protein as a Manganese Transporter. AB - Manganese homeostasis involves coordinated regulation of specific proteins involved in manganese influx and efflux. However, the proteins that are involved in detoxification/efflux have not been completely resolved nor has the basis by which they select their metal substrate. Here, we compared six proteins, which were reported to be involved in manganese detoxification/efflux, by evaluating their ability to reduce manganese toxicity in chicken DT40 cells, finding that human ZnT10 (hZnT10) was the most significant contributor. A domain swapping and substitution analysis between hZnT10 and the zinc-specific transporter hZnT1 showed that residue Asn(43), which corresponds to the His residue constituting the potential intramembranous zinc coordination site in other ZnT transporters, is necessary to impart hZnT10's unique manganese mobilization activity; residues Cys(52) and Leu(242) in transmembrane domains II and V play a subtler role in controlling the metal specificity of hZnT10. Interestingly, the His -> Asn reversion mutant in hZnT1 conferred manganese transport activity and loss of zinc transport activity. These results provide important information about manganese detoxification/efflux mechanisms in vertebrate cells as well as the molecular characterization of hZnT10 as a manganese transporter. PMID- 27226610 TI - Investigating the Mechanism by Which Gain-of-function Mutations to the alpha1 Glycine Receptor Cause Hyperekplexia. AB - Hyperekplexia is a rare human neuromotor disorder caused by mutations that impair the efficacy of glycinergic inhibitory neurotransmission. Loss-of-function mutations in the GLRA1 or GLRB genes, which encode the alpha1 and beta glycine receptor (GlyR) subunits, are the major cause. Paradoxically, gain-of-function GLRA1 mutations also cause hyperekplexia, although the mechanism is unknown. Here we identify two new gain-of-function mutations (I43F and W170S) and characterize these along with known gain-of-function mutations (Q226E, V280M, and R414H) to identify how they cause hyperekplexia. Using artificial synapses, we show that all mutations prolong the decay of inhibitory postsynaptic currents (IPSCs) and induce spontaneous GlyR activation. As these effects may deplete the chloride electrochemical gradient, hyperekplexia could potentially result from reduced glycinergic inhibitory efficacy. However, we consider this unlikely as the depleted chloride gradient should also lead to pain sensitization and to a hyperekplexia phenotype that correlates with mutation severity, neither of which is observed in patients with GLRA1 hyperekplexia mutations. We also rule out small increases in IPSC decay times (as caused by W170S and R414H) as a possible mechanism given that the clinically important drug, tropisetron, significantly increases glycinergic IPSC decay times without causing motor side effects. A recent study on cultured spinal neurons concluded that an elevated intracellular chloride concentration late during development ablates alpha1beta glycinergic synapses but spares GABAergic synapses. As this mechanism satisfies all our considerations, we propose it is primarily responsible for the hyperekplexia phenotype. PMID- 27226611 TI - Identification and Functional Characterization of a Novel OprD-like Chitin Uptake Channel in Non-chitinolytic Bacteria. AB - Chitoporin from the chitinolytic marine Vibrio has been characterized as a trimeric OmpC-like channel responsible for effective chitin uptake. In this study we describe the identification and characterization of a novel OprD-like chitoporin (so-called EcChiP) from Escherichia coli The gene was identified, cloned, and functionally expressed in the Omp-deficient E. coli BL21 (Omp8) Rosetta strain. On size exclusion chromatography, EcChiP had an apparent native molecular mass of 50 kDa, as predicted by amino acid sequencing and mass analysis, confirming that the protein is a monomer. Black lipid membrane reconstitution demonstrated that EcChiP could readily form stable, monomeric channels in artificial phospholipid membranes, with an average single channel conductance of 0.55 +/- 0.01 nanosiemens and a slight preference for cations. Single EcChiP channels showed strong specificity, interacting with long chain chitooligosaccharides but not with maltooligosaccharides. Liposome swelling assays indicated the bulk permeation of neutral monosaccharides and showed the size exclusion limit of EcChiP to be ~200-300 Da for small permeants that pass through by general diffusion while allowing long chain chitooligosaccharides to pass through by a facilitated diffusion process. Taking E. coli as a model, we offer the first evidence that non-chitinolytic bacteria can activate a quiescent ChiP gene to express a functional chitoporin, enabling them to take up chitooligosaccharides for metabolism as an immediate source of energy. PMID- 27226612 TI - Molecular Features of Phosphatase and Tensin Homolog (PTEN) Regulation by C terminal Phosphorylation. AB - PTEN is a tumor suppressor that functions to negatively regulate the PI3K/AKT pathway as the lipid phosphatase for phosphatidylinositol 3,4,5-triphosphate. Phosphorylation of a cluster of Ser/Thr residues (amino acids 380-385) on the C terminal tail serves to alter the conformational state of PTEN from an open active state to a closed inhibited state, resulting in a reduction of plasma membrane localization and inhibition of enzyme activity. The relative contribution of each phosphorylation site to PTEN autoinhibition and the structural basis for the conformational closure is still unclear. To further the structural understanding of PTEN regulation by C-terminal tail phosphorylation, we used protein semisynthesis to insert stoichiometric and site-specific phospho Ser/Thr(s) in the C-terminal tail of PTEN. Additionally, we employed photo-cross linking to map the intramolecular PTEN interactions of the phospho-tail. Systematic evaluation of the PTEN C-tail phospho-cluster showed autoinhibition, and conformational closure was influenced by the aggregate effect of multiple phospho-sites rather than dominated by a single phosphorylation site. Moreover, photo-cross-linking suggested a direct interaction between the PTEN C-tail and a segment in the N-terminal region of the catalytic domain. Mutagenesis experiments provided additional insights into how the PTEN phospho-tail interacts with both the C2 and catalytic domains. PMID- 27226613 TI - Pathogenic Mutations in the Valosin-containing Protein/p97(VCP) N-domain Inhibit the SUMOylation of VCP and Lead to Impaired Stress Response. AB - Valosin-containing protein/p97(VCP) is a hexameric ATPase vital to protein degradation during endoplasmic reticulum stress. It regulates diverse cellular functions including autophagy, chromatin remodeling, and DNA repair. In addition, mutations in VCP cause inclusion body myopathy, Paget disease of the bone, and frontotemporal dementia (IBMPFD), as well as amyotrophic lateral sclerosis. Nevertheless, how the VCP activities were regulated and how the pathogenic mutations affect the function of VCP during stress are not unclear. Here we show that the small ubiquitin-like modifier (SUMO)-ylation of VCP is a normal stress response inhibited by the disease-causing mutations in the N-domain. Under oxidative and endoplasmic reticulum stress conditions, the SUMOylation of VCP facilitates the distribution of VCP to stress granules and nucleus, and promotes the VCP hexamer assembly. In contrast, pathogenic mutations in the VCP N-domain lead to reduced SUMOylation and weakened VCP hexamer formation upon stress. Defective SUMOylation of VCP also causes altered co-factor binding and attenuated endoplasmic reticulum-associated protein degradation. Furthermore, SUMO-defective VCP fails to protect against stress-induced toxicity in Drosophila Therefore, our results have revealed SUMOylation as a molecular signaling switch to regulate the distribution and functions of VCP during stress response, and suggest that deficiency in VCP SUMOylation caused by pathogenic mutations will render cells vulnerable to stress insults. PMID- 27226614 TI - Sulfur Denitrosylation by an Engineered Trx-like DsbG Enzyme Identifies Nucleophilic Cysteine Hydrogen Bonds as Key Functional Determinant. AB - Exposure of bacteria to NO results in the nitrosylation of cysteine thiols in proteins and low molecular weight thiols such as GSH. The cells possess enzymatic systems that catalyze the denitrosylation of these modified sulfurs. An important player in these systems is thioredoxin (Trx), a ubiquitous, cytoplasmic oxidoreductase that can denitrosylate proteins in vivo and S-nitrosoglutathione (GSNO) in vitro However, a periplasmic or extracellular denitrosylase has not been identified, raising the question of how extracytoplasmic proteins are repaired after nitrosative damage. In this study, we tested whether DsbG and DsbC, two Trx family proteins that function in reducing pathways in the Escherichia coli periplasm, also possess denitrosylating activity. Both DsbG and DsbC are poorly reactive toward GSNO. Moreover, DsbG is unable to denitrosylate its specific substrate protein, YbiS. Remarkably, by borrowing the CGPC active site of E. coli Trx-1 in combination with a T200M point mutation, we transformed DsbG into an enzyme highly reactive toward GSNO and YbiS. The pKa of the nucleophilic cysteine, as well as the redox and thermodynamic properties of the engineered DsbG are dramatically changed and become similar to those of E. coli Trx-1. X-ray structural insights suggest that this results from a loss of two direct hydrogen bonds to the nucleophilic cysteine sulfur in the DsbG mutant. Our results highlight the plasticity of the Trx structural fold and reveal that the subtle change of the number of hydrogen bonds in the active site of Trx-like proteins is the key factor that thermodynamically controls reactivity toward nitrosylated compounds. PMID- 27226615 TI - Crystal Structures of the SpoIID Lytic Transglycosylases Essential for Bacterial Sporulation. AB - Bacterial spores are the most resistant form of life known on Earth and represent a serious problem for (i) bioterrorism attack, (ii) horizontal transmission of microbial pathogens in the community, and (iii) persistence in patients and in a nosocomial environment. Stage II sporulation protein D (SpoIID) is a lytic transglycosylase (LT) essential for sporulation. The LT superfamily is a potential drug target because it is active in essential bacterial processes involving the peptidoglycan, which is unique to bacteria. However, the absence of structural information for the sporulation-specific LT enzymes has hindered mechanistic understanding of SpoIID. Here, we report the first crystal structures with and without ligands of the SpoIID family from two community relevant spore forming pathogens, Bacillus anthracis and Clostridium difficile. The structures allow us to visualize the overall architecture, characterize the substrate recognition model, identify critical residues, and provide the structural basis for catalysis by this new family of enzymes. PMID- 27226616 TI - A Common Signal Patch Drives AP-1 Protein-dependent Golgi Export of Inwardly Rectifying Potassium Channels. AB - Nearly all members of the inwardly rectifying potassium (Kir) channel family share a cytoplasmic domain structure that serves as an unusual AP-1 clathrin adaptor-dependent Golgi export signal in one Kir channel, Kir2.1 (KCNJ2), raising the question whether Kir channels share a common Golgi export mechanism. Here we explore this idea, focusing on two structurally and functionally divergent Kir family members, Kir2.3 (KCNJ4) and Kir4.1/5.1 (KCNJ10/16), which have ~50% amino identity. We found that Golgi export of both channels is blocked upon siRNA mediated knockdown of the AP-1 gamma subunit, as predicted for the common AP-1 dependent trafficking process. A comprehensive mutagenic analysis, guided by homology mapping in atomic resolution models of Kir2.1, Kir2.3, and Kir4.1/5.1, identified a common structure that serves as a recognition site for AP-1 binding and governs Golgi export. Larger than realized from previous studies with Kir2.1, the signal is created by a patch of residues distributed at the confluence of cytoplasmic N and C termini. The signal involves a stretch of hydrophobic residues from the C-terminal region that form a hydrophobic cleft, an adjacent cluster of basic residues within the N terminus, and a potential network of salt bridges that join the N- and C-terminal poles together. Because patch formation and AP-1 binding are dependent on proper folding of the cytoplasmic domains, the signal provides a common quality control mechanism at the Golgi for Kir channels. These findings identify a new proteostatic mechanism that couples protein folding of channels to forward trafficking in the secretory pathway. PMID- 27226617 TI - Structural Insights into the Polyphyletic Origins of Glycyl tRNA Synthetases. AB - Glycyl tRNA synthetase (GlyRS) provides a unique case among class II aminoacyl tRNA synthetases, with two clearly widespread types of enzymes: a dimeric (alpha2) species present in some bacteria, archaea, and eukaryotes; and a heterotetrameric form (alpha2beta2) present in most bacteria. Although the differences between both types of GlyRS at the anticodon binding domain level are evident, the extent and implications of the variations in the catalytic domain have not been described, and it is unclear whether the mechanism of amino acid recognition is also dissimilar. Here, we show that the alpha-subunit of the alpha2beta2 GlyRS from the bacterium Aquifex aeolicus is able to perform the first step of the aminoacylation reaction, which involves the activation of the amino acid with ATP. The crystal structure of the alpha-subunit in the complex with an analog of glycyl adenylate at 2.8 A resolution presents a conformational arrangement that properly positions the cognate amino acid. This work shows that glycine is recognized by a subset of different residues in the two types of GlyRS. A structural and sequence analysis of class II catalytic domains shows that bacterial GlyRS is closely related to alanyl tRNA synthetase, which led us to define a new subclassification of these ancient enzymes and to propose an evolutionary path of alpha2beta2 GlyRS, convergent with alpha2 GlyRS and divergent from AlaRS, thus providing a possible explanation for the puzzling existence of two proteins sharing the same fold and function but not a common ancestor. PMID- 27226618 TI - Central Leptin and Tumor Necrosis Factor-alpha (TNFalpha) in Diurnal Control of Blood Pressure and Hypertension. AB - Leptin and TNFalpha can individually work in the brain to affect blood pressure; however, it remains unknown whether these two cytokines might have an interactive role in this process and, if so, how. In this work, we found that leptin stimulation led to TNFalpha production under both in vitro and in vivo conditions, and diurnal fluctuation of leptin concentrations in the cerebrospinal fluid predicted the circadian changes of TNFalpha gene expression in the hypothalamus. Signaling analysis showed that leptin stimulation led to a rapid and strong STAT3 activation followed by a second-phase moderate STAT3 activation, which was selectively abolished by anti-inflammatory chemical PS1145 or TNFalpha antagonist WP9QY. Physiological study in normal mice revealed that diurnal rise of blood pressure was abrogated following central administration of PS1145 or a leptin receptor antagonist. Central TNFalpha pretreatment was found to potentiate the effect of leptin in elevating blood pressure in normal mice. In pathophysiology, dietary obesity mimicked TNFalpha pretreatment in promoting leptin-induced blood pressure rise, and this effect was blocked by central treatment with either PS1145 or WP9QY. Hence, central leptin employs TNFalpha to mediate the diurnal blood pressure elevation in physiology while enhancement of this mechanism can contribute to hypertension development. PMID- 27226619 TI - The Human 343delT HSPB5 Chaperone Associated with Early-onset Skeletal Myopathy Causes Defects in Protein Solubility. AB - Mutations of HSPB5 (also known as CRYAB or alphaB-crystallin), a bona fide heat shock protein and molecular chaperone encoded by the HSPB5 (crystallin, alpha B) gene, are linked to multisystem disorders featuring variable combinations of cataracts, cardiomyopathy, and skeletal myopathy. This study aimed to investigate the pathological mechanisms involved in an early-onset myofibrillar myopathy manifesting in a child harboring a homozygous recessive mutation in HSPB5, 343delT. To study HSPB5 343delT protein dynamics, we utilize model cell culture systems including induced pluripotent stem cells derived from the 343delT patient (343delT/343delT) along with isogenic, heterozygous, gene-corrected control cells (WT KI/343delT) and BHK21 cells, a cell line lacking endogenous HSPB5 expression. 343delT/343delT and WT KI/343delT-induced pluripotent stem cell-derived skeletal myotubes and cardiomyocytes did not express detectable levels of 343delT protein, contributable to the extreme insolubility of the mutant protein. Overexpression of HSPB5 343delT resulted in insoluble mutant protein aggregates and induction of a cellular stress response. Co-expression of 343delT with WT prevented visible aggregation of 343delT and improved its solubility. Additionally, in vitro refolding of 343delT in the presence of WT rescued its solubility. We demonstrate an interaction between WT and 343delT both in vitro and within cells. These data support a loss-of-function model for the myopathy observed in the patient because the insoluble mutant would be unavailable to perform normal functions of HSPB5, although additional gain-of-function effects of the mutant protein cannot be excluded. Additionally, our data highlight the solubilization of 343delT by WT, concordant with the recessive inheritance of the disease and absence of symptoms in carrier individuals. PMID- 27226620 TI - Independent Biological and Biochemical Functions for Individual Structural Domains of Drosophila Linker Histone H1. AB - Linker histone H1 is among the most abundant components of chromatin. H1 has profound effects on chromosome architecture. H1 also helps to tether DNA- and histone-modifying enzymes to chromatin. Metazoan linker histones have a conserved tripartite structure comprising N-terminal, globular, and long, unstructured C terminal domains. Here we utilize truncated Drosophila H1 polypeptides in vitro and H1 mutant transgenes in vivo to interrogate the roles of these domains in multiple biochemical and biological activities of H1. We demonstrate that the globular domain and the proximal part of the C-terminal domain are essential for H1 deposition into chromosomes and for the stability of H1-chromatin binding. The two domains are also essential for fly viability and the establishment of a normal polytene chromosome structure. Additionally, through interaction with the heterochromatin-specific histone H3 Lys-9 methyltransferase Su(var)3-9, the H1 C terminal domain makes important contributions to formation and H3K9 methylation of heterochromatin as well as silencing of transposons in heterochromatin. Surprisingly, the N-terminal domain does not appear to be required for any of these functions. However, it is involved in the formation of a single chromocenter in polytene chromosomes. In summary, we have discovered that linker histone H1, similar to core histones, exerts its multiple biological functions through independent, biochemically separable activities of its individual structural domains. PMID- 27226621 TI - Proinsulin Shares a Motif with Interleukin-1alpha (IL-1alpha) and Induces Inflammatory Cytokine via Interleukin-1 Receptor 1. AB - Although it has been established that diabetes increases susceptibility to infections, the role of insulin (INS) in the immune response is unknown. Here, we investigated the immunological function of INS. Proinsulin dimer (pINSd) was a potent immune stimulus that induced inflammatory cytokines, but mature INS was unable to induce an immune response. An affinity-purified rabbit polyclonal antibody raised against mature IL-1alpha recognized IL-1alpha and pINS but failed to detect mature INS and IL-1beta. Analysis of the pINS sequence revealed the existence of an INS/IL-1alpha motif in the C-peptide of pINS. Surprisingly, the INS/IL-1alpha motif was recognized by monoclonal antibody raised against IL 1alpha. Deleting the INS/IL-1alpha motif in pINSd and IL-1alpha changed their activities. To investigate the pINSd receptor, the reconstitution of IL-1 receptor 1 (IL-1R1) in Wish cells restored pINSd activity that was reversed by an IL-1R antagonist. These data suggested that pINSd needs IL-1R1 for inflammatory cytokine induction. Mouse embryo fibroblast cells of IL-1R1-deficient mice further confirmed that pINSd promotes immune responses through IL-1R1. PMID- 27226622 TI - Substrate Recognition by the Cdh1 Destruction Box Receptor Is a General Requirement for APC/CCdh1-mediated Proteolysis. AB - The anaphase-promoting complex, or cyclosome (APC/C), is a ubiquitin ligase that selectively targets proteins for degradation in mitosis and the G1 phase and is an important component of the eukaryotic cell cycle control system. How the APC/C specifically recognizes its substrates is not fully understood. Although well characterized degron motifs such as the destruction box (D-box) and KEN-box are commonly found in APC/C substrates, many substrates apparently lack these motifs. A variety of alternative APC/C degrons have been reported, suggesting either that multiple modes of substrate recognition are possible or that our definitions of degron structure are incomplete. We used an in vivo yeast assay to compare the G1 degradation rate of 15 known substrates of the APC/C co-activator Cdh1 under normal conditions and conditions that impair binding of D-box, KEN-box, and the recently identified ABBA motif degrons to Cdh1. The D-box receptor was required for efficient proteolysis of all Cdh1 substrates, despite the absence of canonical D-boxes in many. In contrast, the KEN-box receptor was only required for normal proteolysis of a subset of substrates and the ABBA motif receptor for a single substrate in our system. Our results suggest that binding to the D-box receptor may be a shared requirement for recognition and processing of all Cdh1 substrates. PMID- 27226623 TI - Calcium-Oxidant Signaling Network Regulates AMP-activated Protein Kinase (AMPK) Activation upon Matrix Deprivation. AB - The AMP-activated protein kinase (AMPK) has recently been implicated in anoikis resistance. However, the molecular mechanisms that activate AMPK upon matrix detachment remain unexplored. In this study, we show that AMPK activation is a rapid and sustained phenomenon upon matrix deprivation, whereas re-attachment to the matrix leads to its dephosphorylation and inactivation. Because matrix detachment leads to loss of integrin signaling, we investigated whether integrin signaling negatively regulates AMPK activation. However, modulation of focal adhesion kinase or Src, the major downstream components of integrin signaling, failed to cause a corresponding change in AMPK signaling. Further investigations revealed that the upstream AMPK kinases liver kinase B1 (LKB1) and Ca(2+)/calmodulin-dependent protein kinase kinase beta (CaMKKbeta) contribute to AMPK activation upon detachment. In LKB1-deficient cells, we found AMPK activation to be predominantly dependent on CaMKKbeta. We observed no change in ATP levels under detached conditions at early time points suggesting that rapid AMPK activation upon detachment was not triggered by energy stress. We demonstrate that matrix deprivation leads to a spike in intracellular calcium as well as oxidant signaling, and both these intracellular messengers contribute to rapid AMPK activation upon detachment. We further show that endoplasmic reticulum calcium release-induced store-operated calcium entry contributes to intracellular calcium increase, leading to reactive oxygen species production, and AMPK activation. We additionally show that the LKB1/CaMKK-AMPK axis and intracellular calcium levels play a critical role in anchorage-independent cancer sphere formation. Thus, the Ca(2+)/reactive oxygen species-triggered LKB1/CaMKK-AMPK signaling cascade may provide a quick, adaptable switch to promote survival of metastasizing cancer cells. PMID- 27226624 TI - A Native Threonine Coordinates Ordered Water to Tune Light-Oxygen-Voltage (LOV) Domain Photocycle Kinetics and Osmotic Stress Signaling in Trichoderma reesei ENVOY. AB - Light-oxygen-voltage (LOV) domain-containing proteins function as small light activated modules capable of imparting blue light control of biological processes. Their small modular nature has made them model proteins for allosteric signal transduction and optogenetic devices. Despite intense research, key aspects of their signal transduction mechanisms and photochemistry remain poorly understood. In particular, ordered water has been identified as a possible key mediator of photocycle kinetics, despite the lack of ordered water in the LOV active site. Herein, we use recent crystal structures of a fungal LOV protein ENVOY to interrogate the role of Thr(101) in recruiting water to the flavin active site where it can function as an intrinsic base to accelerate photocycle kinetics. Kinetic and molecular dynamic simulations confirm a role in solvent recruitment to the active site and identify structural changes that correlate with solvent recruitment. In vivo analysis of T101I indicates a direct role of the Thr(101) position in mediating adaptation to osmotic stress, thereby verifying biological relevance of ordered water in LOV signaling. The combined studies identify position 101 as a mediator of both allostery and photocycle catalysis that can impact organism physiology. PMID- 27226625 TI - Elmo2 Is a Regulator of Insulin-dependent Glut4 Membrane Translocation. AB - Elmo2, a member of the Elmo protein family, has been implicated in the regulation of Rac1 and Akt activation. Recently, we found that Elmo2 specifically interacts with ClipR-59. Because Akt and Rac1 have been implicated in insulin dependent Glut4 membrane translocation, we hypothesize here that Elmo2 may play a role in insulin-dependent Glut4 membrane translocation. Accordingly, we found that overexpression of Elmo2 enhanced, whereas its knockdown suppressed, insulin dependent Glut4 membrane translocation in both 3T3-L1 adipocytes and L6 skeletal muscle cells. We also examined whether Elmo2 contributes to the insulin-mediated activation of Rac1 and Akt. We found that Elmo2 is required for insulin-induced Rac1 GTP loading, but not AKT activation, in L6 cells induced by insulin. Instead, Elmo2 is required to promote the insulin-induced membrane association of Akt. Together, our studies demonstrate that Elmo2 is a new regulator of insulin dependent Glut4 membrane translocation through modulating Rac1 activity and Akt membrane compartmentalization. PMID- 27226627 TI - Structural and Kinetic Analysis of Miscoding Opposite the DNA Adduct 1,N6 Ethenodeoxyadenosine by Human Translesion DNA Polymerase eta. AB - 1,N(6)-Ethenodeoxyadenosine (1,N(6)-epsilondA) is the major etheno lesion formed in the reaction of DNA with epoxides substituted with good leaving groups (e.g. vinyl chloride epoxide). This lesion is also formed endogenously in DNA from lipid oxidation. Recombinant human DNA polymerase eta (hpol eta) can replicate oligonucleotide templates containing 1,N(6)-epsilondA. In steady-state kinetic analysis, hpol eta preferred to incorporate dATP and dGTP, compared with dTTP. Mass spectral analysis of incorporation products also showed preferred purine (A, G) incorporation and extensive -1 frameshifts, suggesting pairing of the inserted purine and slippage before further replication. Five x-ray crystal structures of hpol eta ternary complexes were determined, three at the insertion and two at the extension stage. Two insertion complexes revealed incoming non-hydrolyzable dATP or dGTP analogs not pairing with but instead in a staggered configuration relative to 1,N(6)-epsilondA in the anti conformation, thus opposite the 5'-T in the template, explaining the proclivity for frameshift misincorporation. In another insertion complex, dTTP was positioned opposite 1,N(6)-epsilondA, and the adduct base was in the syn conformation, with formation of two hydrogen bonds. At the extension stage, with either an incorporated dA or dT opposite 1,N(6) epsilondA and 2'-deoxythymidine-5'-[(alpha,beta)-imido]triphosphate opposite the 5'-A, the 3'-terminal nucleoside of the primer was disordered, consistent with the tendency not to incorporate dTTP opposite 1,N(6)-epsilondA. Collectively, the results show a preference for purine pairing opposite 1,N(6)-epsilondA and for -1 frameshifts. PMID- 27226626 TI - Characterization of C-terminal Splice Variants of Cav1.4 Ca2+ Channels in Human Retina. AB - Voltage-gated Ca(2+) channels (Cav) undergo extensive alternative splicing that greatly enhances their functional diversity in excitable cells. Here, we characterized novel splice variants of the cytoplasmic C-terminal domain of Cav1.4 Ca(2+) channels that regulate neurotransmitter release in photoreceptors in the retina. These variants lack a portion of exon 45 and/or the entire exon 47 (Cav1.4Deltaex p45, Cav1.4Deltaex 47, Cav1.4Deltaex p45,47) and are expressed in the retina of primates but not mice. Although the electrophysiological properties of Cav1.4Deltaex p45 are similar to those of full-length channels (Cav1.4FL), skipping of exon 47 dramatically alters Cav1.4 function. Deletion of exon 47 removes part of a C-terminal automodulatory domain (CTM) previously shown to suppress Ca(2+)-dependent inactivation (CDI) and to cause a positive shift in the voltage dependence of channel activation. Exon 47 is crucial for these effects of the CTM because variants lacking this exon show intense CDI and activate at more hyperpolarized voltages than Cav1.4FL The robust CDI of Cav1.4Deltaex 47 is suppressed by CaBP4, a regulator of Cav1.4 channels in photoreceptors. Although CaBP4 enhances activation of Cav1.4FL, Cav1.4Deltaex 47 shows similar voltage dependent activation in the presence and absence of CaBP4. We conclude that exon 47 encodes structural determinants that regulate CDI and voltage-dependent activation of Cav1.4, and is necessary for modulation of channel activation by CaBP4. PMID- 27226628 TI - A Camelid-derived Antibody Fragment Targeting the Active Site of a Serine Protease Balances between Inhibitor and Substrate Behavior. AB - A peptide segment that binds the active site of a serine protease in a substrate like manner may behave like an inhibitor or a substrate. However, there is sparse information on which factors determine the behavior a particular peptide segment will exhibit. Here, we describe the first x-ray crystal structure of a nanobody in complex with a serine protease. The nanobody displays a new type of interaction between an antibody and a serine protease as it inserts its complementary determining region-H3 loop into the active site of the protease in a substrate-like manner. The unique binding mechanism causes the nanobody to behave as a strong inhibitor as well as a poor substrate. Intriguingly, its substrate behavior is incomplete, as 30-40% of the nanobody remained intact and inhibitory after prolonged incubation with the protease. Biochemical analysis reveals that an intra-loop interaction network within the complementary determining region-H3 of the nanobody balances its inhibitor versus substrate behavior. Collectively, our results unveil molecular factors, which may be a general mechanism to determine the substrate versus inhibitor behavior of other protease inhibitors. PMID- 27226630 TI - Unraveling Growth Factor Signaling and Cell Cycle Progression in Individual Fibroblasts. AB - Cultured cells require the actions of growth factors to enter the cell cycle, but how individual members of a population respond to the same stimulus remains unknown. Here we have employed continuous monitoring by live cell imaging in a dual-reporter cell model to investigate the regulation of short-term growth factor signaling (protein kinase B (PKB/Akt) activity) and longer-term progression through the cell cycle (cyclin-dependent kinase 2 activity). In the total population, insulin-like growth factor-I (IGF-I)-enhanced cell cycle entry by >5-fold compared with serum-free medium (from 13.5 to 78%), but at the single cell level we observed a broad distribution in the timing of G1 exit (4-24 h, mean ~12 h) that did not vary with either the amount or duration of IGF-I treatment. Cells that failed to re-enter the cell cycle exhibited similar responses to IGF-I in terms of integrated Akt activity and migration distance compared with those that did. We made similar observations with EGF, PDGF-AA, and PDGF-BB. As potential thresholds of growth factor-mediated cell cycle progression appeared to be heterogeneous within the population, the longer-term proliferative outcomes of individual cells to growth factor stimulation could not be predicted based solely on acute Akt signaling responses, no matter how robust these might be. Thus, although we could define a relationship at the population level between growth factor-induced Akt signaling dynamics and cell cycle progression, we could not predict the fate of individual cells. PMID- 27226629 TI - The Coronary Artery Disease-associated Coding Variant in Zinc Finger C3HC-type Containing 1 (ZC3HC1) Affects Cell Cycle Regulation. AB - Genome-wide association studies have to date identified multiple coronary artery disease (CAD)-associated loci; however, for most of these loci the mechanism by which they affect CAD risk is unclear. The CAD-associated locus 7q32.2 is unusual in that the lead variant, rs11556924, is not in strong linkage disequilibrium with any other variant and introduces a coding change in ZC3HC1, which encodes NIPA. In this study, we show that rs11556924 polymorphism is associated with lower regulatory phosphorylation of NIPA in the risk variant, resulting in NIPA with higher activity. Using a genome-editing approach we show that this causes an effective decrease in cyclin-B1 stability in the nucleus, thereby slowing its nuclear accumulation. By perturbing the rate of nuclear cyclin-B1 accumulation, rs11556924 alters the regulation of mitotic progression resulting in an extended mitosis. This study shows that the CAD-associated coding polymorphism in ZC3HC1 alters the dynamics of cell-cycle regulation by NIPA. PMID- 27226631 TI - Functional Characterization of the Odorant Receptor 51E2 in Human Melanocytes. AB - Olfactory receptors, which belong to the family of G-protein-coupled receptors, are found to be ectopically expressed in non-sensory tissues mediating a variety of cellular functions. In this study we detected the olfactory receptor OR51E2 at the transcript and the protein level in human epidermal melanocytes. Stimulation of primary melanocytes with the OR51E2 ligand beta-ionone significantly inhibited melanocyte proliferation. Our results further showed that beta-ionone stimulates melanogenesis and dendritogenesis. Using RNA silencing and receptor antagonists, we demonstrated that OR51E2 activation elevated cytosolic Ca(2+) and cAMP, which could mediate the observed increase in melanin synthesis. Co-immunocytochemical stainings using a specific OR51E2 antibody revealed subcellular localization of the receptor in early endosomes associated with EEA-1 (early endosome antigen 1). Plasma membrane preparations showed that OR51E2 protein is present at the melanocyte cell surface. Our findings thus suggest that activation of olfactory receptor signaling by external compounds can influence melanocyte homeostasis. PMID- 27226632 TI - Dual Roles of Group IID Phospholipase A2 in Inflammation and Cancer. AB - Phospholipase A2 enzymes have long been implicated in the promotion of inflammation by mobilizing pro-inflammatory lipid mediators, yet recent evidence suggests that they also contribute to anti-inflammatory or pro-resolving programs. Group IID-secreted phospholipase A2 (sPLA2-IID) is abundantly expressed in dendritic cells in lymphoid tissues and resolves the Th1 immune response by controlling the steady-state levels of anti-inflammatory lipids such as docosahexaenoic acid and its metabolites. Here, we show that psoriasis and contact dermatitis were exacerbated in Pla2g2d-null mice, whereas they were ameliorated in Pla2g2d-overexpressing transgenic mice, relative to littermate wild-type mice. These phenotypes were associated with concomitant alterations in the tissue levels of omega3 polyunsaturated fatty acid (PUFA) metabolites, which had the capacity to reduce the expression of pro-inflammatory and Th1/Th17-type cytokines in dendritic cells or lymph node cells. In the context of cancer, however, Pla2g2d deficiency resulted in marked attenuation of skin carcinogenesis, likely because of the augmented anti-tumor immunity. Altogether, these results underscore a general role of sPLA2-IID as an immunosuppressive sPLA2 that allows the microenvironmental lipid balance toward an anti inflammatory state, exerting beneficial or detrimental impact depending upon distinct pathophysiological contexts in inflammation and cancer. PMID- 27226633 TI - Expression and Function of Group IIE Phospholipase A2 in Mouse Skin. AB - Recent studies using knock-out mice for various secreted phospholipase A2 (sPLA2) isoforms have revealed their non-redundant roles in diverse biological events. In the skin, group IIF sPLA2 (sPLA2-IIF), an "epidermal sPLA2" expressed in the suprabasal keratinocytes, plays a fundamental role in epidermal-hyperplasic diseases such as psoriasis and skin cancer. In this study, we found that group IIE sPLA2 (sPLA2-IIE) was expressed abundantly in hair follicles and to a lesser extent in basal epidermal keratinocytes in mouse skin. Mice lacking sPLA2-IIE exhibited skin abnormalities distinct from those in mice lacking sPLA2-IIF, with perturbation of hair follicle ultrastructure, modest changes in the steady-state expression of a subset of skin genes, and no changes in the features of psoriasis or contact dermatitis. Lipidomics analysis revealed that sPLA2-IIE and -IIF were coupled with distinct lipid pathways in the skin. Overall, two skin sPLA2s, hair follicular sPLA2-IIE and epidermal sPLA2-IIF, play non-redundant roles in distinct compartments of mouse skin, underscoring the functional diversity of multiple sPLA2s in the coordinated regulation of skin homeostasis and diseases. PMID- 27226634 TI - NDUFAF5 Hydroxylates NDUFS7 at an Early Stage in the Assembly of Human Complex I. AB - Complex I (NADH ubiquinone oxidoreductase) in mammalian mitochondria is an L shaped assembly of 45 proteins. One arm lies in the inner membrane, and the other extends about 100 A into the matrix of the organelle. The extrinsic arm contains binding sites for NADH, the primary electron acceptor FMN, and seven iron-sulfur clusters that form a pathway for electrons linking FMN to the terminal electron acceptor, ubiquinone, which is bound in a tunnel in the region of the junction between the arms. The membrane arm contains four antiporter-like domains, energetically coupled to the quinone site and involved in pumping protons from the matrix into the intermembrane space contributing to the proton motive force. Seven of the subunits, forming the core of the membrane arm, are translated from mitochondrial genes, and the remaining subunits, the products of nuclear genes, are imported from the cytosol. Their assembly is coordinated by at least thirteen extrinsic assembly factor proteins that are not part of the fully assembled complex. They assist in insertion of co-factors and in building up the complex from smaller sub-assemblies. One such factor, NDUFAF5, belongs to the family of seven-beta-strand S-adenosylmethionine-dependent methyltransferases. However, similar to another family member, RdmB, it catalyzes the introduction of a hydroxyl group, in the case of NDUFAF5, into Arg-73 in the NDUFS7 subunit of human complex I. This modification occurs early in the pathway of assembly of complex I, before the formation of the juncture between peripheral and membrane arms. PMID- 27226636 TI - Structural and Functional Characterization of Programmed Ribosomal Frameshift Signals in West Nile Virus Strains Reveals High Structural Plasticity Among cis Acting RNA Elements. AB - West Nile virus (WNV) is a prototypical emerging virus for which no effective therapeutics currently exist. WNV uses programmed -1 ribosomal frameshifting (-1 PRF) to synthesize the NS1' protein, a C terminally extended version of its non structural protein 1, the expression of which enhances neuro-invasiveness and viral RNA abundance. Here, the NS1' frameshift signals derived from four WNV strains were investigated to better understand -1 PRF in this quasispecies. Sequences previously predicted to promote -1 PRF strongly promote this activity, but frameshifting was significantly more efficient upon inclusion of additional 3' sequence information. The observation of different rates of -1 PRF, and by inference differences in the expression of NS1', may account for the greater degrees of pathogenesis associated with specific WNV strains. Chemical modification and mutational analyses of the longer and shorter forms of the -1 PRF signals suggests dynamic structural rearrangements between tandem stem-loop and mRNA pseudoknot structures in two of the strains. A model is suggested in which this is employed as a molecular switch to fine tune the relative expression of structural to non-structural proteins during different phases of the viral replication cycle. PMID- 27226635 TI - The Modifier of Transcription 1 (Mot1) ATPase and Spt16 Histone Chaperone Co regulate Transcription through Preinitiation Complex Assembly and Nucleosome Organization. AB - Modifier of transcription 1 (Mot1) is a conserved and essential Swi2/Snf2 ATPase that can remove TATA-binding protein (TBP) from DNA using ATP hydrolysis and in so doing exerts global effects on transcription. Spt16 is also essential and functions globally in transcriptional regulation as a component of the facilitates chromatin transcription (FACT) histone chaperone complex. Here we demonstrate that Mot1 and Spt16 regulate a largely overlapping set of genes in Saccharomyces cerevisiae. As expected, Mot1 was found to control TBP levels at co regulated promoters. In contrast, Spt16 did not affect TBP recruitment. On a global scale, Spt16 was required for Mot1 promoter localization, and Mot1 also affected Spt16 localization to genes. Interestingly, we found that Mot1 has an unanticipated role in establishing or maintaining the occupancy and positioning of nucleosomes at the 5' ends of genes. Spt16 has a broad role in regulating chromatin organization in gene bodies, including those nucleosomes affected by Mot1. These results suggest that the large scale overlap in Mot1 and Spt16 function arises from a combination of both their unique and shared functions in transcription complex assembly and chromatin structure regulation. PMID- 27226637 TI - alpha-Synuclein Fibrils Exhibit Gain of Toxic Function, Promoting Tau Aggregation and Inhibiting Microtubule Assembly. AB - alpha-Synuclein is the major component of Lewy bodies and Lewy neurites in Parkinson disease and dementia with Lewy bodies and of glial cytoplasmic inclusions in multiple system atrophy. It has been suggested that alpha-synuclein fibrils or intermediate protofibrils in the process of fibril formation may have a toxic effect on neuronal cells. In this study, we investigated the ability of soluble monomeric alpha-synuclein to promote microtubule assembly and the effects of conformational changes of alpha-synuclein on Tau-promoted microtubule assembly. In marked contrast to previous findings, monomeric alpha-synuclein had no effect on microtubule polymerization. However, both alpha-synuclein fibrils and protofibrils inhibited Tau-promoted microtubule assembly. The inhibitory effect of alpha-synuclein fibrils was greater than that of the protofibrils. Dot blot overlay assay and spin-down techniques revealed that alpha-synuclein fibrils bind to Tau and inhibit microtubule assembly by depleting the Tau available for microtubule polymerization. Using various deletion mutants of alpha-synuclein and Tau, the acidic C-terminal region of alpha-synuclein and the basic central region of Tau were identified as regions involved in the binding. Furthermore, introduction of alpha-synuclein fibrils into cultured cells overexpressing Tau protein induced Tau aggregation. These results raise the possibility that alpha synuclein fibrils interact with Tau, inhibit its function to stabilize microtubules, and also promote Tau aggregation, leading to dysfunction of neuronal cells. PMID- 27226638 TI - Attenuation of PKR-like ER Kinase (PERK) Signaling Selectively Controls Endoplasmic Reticulum Stress-induced Inflammation Without Compromising Immunological Responses. AB - Inflammation and endoplasmic reticulum (ER) stress are associated with many neurological diseases. ER stress is brought on by the accumulation of misfolded proteins in the ER, which leads to activation of the unfolded protein response (UPR), a conserved pathway that transmits signals to restore homeostasis or eliminate the irreparably damaged cell. We provide evidence that inhibition or genetic haploinsufficiency of protein kinase R-like endoplasmic reticulum kinase (PERK) can selectively control inflammation brought on by ER stress without impinging on UPR-dependent survival and adaptive responses or normal immune responses. Using astrocytes lacking one or both alleles of PERK or the PERK inhibitor GSK2606414, we demonstrate that PERK haploinsufficiency or partial inhibition led to reduced ER stress-induced inflammation (IL-6, CCL2, and CCL20 expression) without compromising prosurvival responses. In contrast, complete loss of PERK blocked canonical PERK-dependent UPR genes and promoted apoptosis. Reversal of eIF2alpha-mediated translational repression using ISRIB potently suppressed PERK-dependent inflammatory gene expression, indicating that the selective modulation of inflammatory gene expression by PERK inhibition may be linked to attenuation of eIF2alpha phosphorylation and reveals a previously unknown link between translational repression and transcription of inflammatory genes. Additionally, ER-stressed astrocytes can drive an inflammatory M1-like phenotype in microglia, and this can be attenuated with inhibition of PERK. Importantly, targeting PERK neither disrupted normal cytokine signaling in astrocytes or microglia nor impaired macrophage phagocytosis or T cell polarization. Collectively, this work suggests that targeting PERK may provide a means for selective immunoregulation in the context of ER stress without disrupting normal immune function. PMID- 27226639 TI - Hepatic Aryl Hydrocarbon Receptor Attenuates Fibroblast Growth Factor 21 Expression. AB - The Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in many physiological processes. Several studies indicate that AHR is also involved in energy homeostasis. Fibroblast growth factor 21 (FGF21) is an important regulator of the fasting and feeding responses. When administered to various genetic and diet-induced mouse models of obesity, FGF21 can attenuate obesity-associated morbidities. Here, we explore the role of AHR in hepatic Fgf21 expression through the use of a conditional, hepatocyte-targeted AHR knock-out mouse model (Cre(Alb)Ahr(Fx/Fx)). Compared with the congenic parental strain (Ahr(Fx/Fx)), non-fasted Cre(Alb)Ahr(Fx/Fx) mice exhibit a 4-fold increase in hepatic Fgf21 expression, as well as elevated expression of the FGF21-target gene Igfbp1 Furthermore, in vivo agonist activation of AHR reduces hepatic Fgf21 expression during a fast. The Fgf21 promoter contains several putative dioxin response elements (DREs). Using EMSA, we demonstrate that the AHR-ARNT heterodimer binds to a specific DRE that overlaps binding sequences for peroxisome proliferator-activated receptor alpha (PPARalpha), carbohydrate response element-binding protein (ChREBP), and cAMP response element-binding protein, hepatocyte specific (CREBH). In addition, we reveal that agonist activated AHR impairs PPARalpha-, ChREBP-, and CREBH-mediated promoter activity in Hepa-1 cells. Accordingly, agonist treatment in Hepa-1 cells ablates potent ER stress-driven Fgf21 expression, and pre-treatment with AHR antagonist blocks this effect. Finally, we show that pre-treatment of primary human hepatocytes with AHR agonist diminishes PPARalpha-, glucose-, and ER stress-driven induction of FGF21 expression, indicating the effect is not mouse-specific. Together, our data show that AHR contributes to hepatic energy homeostasis, partly through the regulation of FGF21 expression and signaling. PMID- 27226641 TI - Solving the Riddle of the Role of Sphingolipids in Cell Signaling. PMID- 27226640 TI - Activation of Epidermal Growth Factor Receptor/p38/Hypoxia-inducible Factor 1alpha Is Pivotal for Angiogenesis and Tumorigenesis of Malignantly Transformed Cells Induced by Hexavalent Chromium. AB - Hexavalent chromium (Cr(VI))-containing compounds are well established environmental carcinogens. Most mechanistic investigations of Cr(VI)-induced carcinogenesis focus on oxidative stress and various cellular responses, leading to malignant cell transformation or the first stage of metal-induced carcinogenesis. The development of malignantly transformed cells into tumors that require angiogenesis is the second stage. This study focuses on the second stage, in particular, the role of EGF receptor (EGFR) signaling in angiogenesis and tumorigenesis of Cr(VI)-transformed cells. Our preliminary studies have shown that EGFR is constitutively activated in Cr(VI)-transformed cells, in lung tissue from Cr(VI)-exposed animals, and in lung tumor tissue from a non-smoking worker occupationally exposed to Cr(VI) for 19 years. Using in vitro and in vivo models, the present study has investigated the role of EGFR in angiogenesis of Cr(VI) transformed cells. The results show that Cr(VI)-transformed cells are angiogenic. Hypoxia-inducible factor-1alpha, pro-angiogenic protein matrix metalloproteinase 1, and VEGF are all highly expressed in Cr(VI)-transformed cells, in lung tissue from animals exposed to Cr(VI), and in lung tumor tissue from a non-smoking worker occupationally exposed to Cr(VI) for 19 years. p38 MAPK is also activated in Cr(VI)-transformed cells and in human lung tumor tissue. Inhibition of EGFR reduces p38 MAPK, resulting in decreased expression of hypoxia-inducible factor 1alpha, metalloproteinase 1, and VEGF, leading to suppressions of angiogenesis and tumorigenesis. Overall, the present study has demonstrated that EGFR plays an important role in angiogenesis and tumorigenesis of Cr(VI)-transformed cells. PMID- 27226642 TI - beta-Catenin N- and C-terminal tails modulate the coordinated binding of adherens junction proteins to beta-catenin. PMID- 27226643 TI - Regulation of beta-catenin structure and activity by tyrosine phosphorylation. PMID- 27226644 TI - Presenilin-1 interacts with plakoglobin and enhances plakoglobin-Tcf-4 association. IMPLICATIONS FOR THE REGULATION OF beta-CATENIN/Tcf-4-DEPENDENT TRANSCRIPTION. PMID- 27226645 TI - Sphingosine kinases are not required for inflammatory responses in macrophages. PMID- 27226646 TI - Stathmin is a highly sensitive and specific biomarker for vulvar high-grade squamous intraepithelial lesions. AB - AIMS: Differentiating between human papilloma virus-dependent vulvar low-grade and high-grade squamous intraepithelial lesions (LSILs and HSILs) remains difficult in selected cases. Stathmin, a protein involved in cell cycle progression, might be a useful additional marker for this differentiation. The aim of this study was to investigate the additional diagnostic value of stathmin expression in vulvar intraepithelial neoplastic (VIN) lesions. METHODS: Immunohistochemical analysis was used to evaluate stathmin, P16 and Ki67 expression in 91 samples, including LSILs (n=16), HSILs (n=50), differentiated VIN (dVIN; n=10), lichen sclerosis (LS; n=10) and normal vulvar tissue (n=5). RESULTS: Stathmin was expressed in more than one-third of the epithelium in all HSILs and in 20% of LSILs. P16 and Ki67 were expressed in more than one-third of the epithelium in 94% of HSILs and in 13% and 40% of LSILs, respectively. Stathmin was expressed in more than one-third of the epithelium in 10% of the dVIN and in none of the LS or normal lesions. P16 and Ki67 expression was not present in more than one-third of the epithelium in any of these lesions. The sensitivity of stathmin for differentiating between LSILs and HSILs was 100% compared with a sensitivity of 94% for both p16 and Ki67. The specificity of stathmin, p16 and Ki67 was 80%, 87% and 60%, respectively. CONCLUSIONS: Stathmin is a highly sensitive and specific biomarker for the diagnosis of vulvar HSIL. In addition to the more commonly used immunohistochemical markers p16 and Ki67, stathmin can be a useful diagnostic tool for identifying HSILs, especially in cases in which differentiating between LSIL and HSIL is difficult. PMID- 27226647 TI - The p-Value You Can't Buy. AB - There is growing frustration with the concept of the p-value. Besides having an ambiguous interpretation, the p-value can be made as small as desired by increasing the sample size, n. The p-value is outdated and does not make sense with big data: Everything becomes statistically significant. The root of the problem with the p-value is in the mean comparison. We argue that statistical uncertainty should be measured on the individual, not the group, level. Consequently, standard deviation (SD), not standard error (SE), error bars should be used to graphically present the data on two groups. We introduce a new measure based on the discrimination of individuals/objects from two groups, and call it the D-value. The D-value can be viewed as the n-of-1 p-value because it is computed in the same way as p while letting n equal 1. We show how the D-value is related to discrimination probability and the area above the receiver operating characteristic (ROC) curve. The D-value has a clear interpretation as the proportion of patients who get worse after the treatment, and as such facilitates to weigh up the likelihood of events under different scenarios. [Received January 2015. Revised June 2015.]. PMID- 27226648 TI - Determination of Carboxypeptidase Activity in Clinical Pathogens by Gas Chromatography-Mass Spectrometry. AB - A novel method for the determination of benzoic acid has been employed to identify carboxypeptidase activities in clinically relevant pathogens. Benzoic acid was determined after chemical derivatization by gas chromatography-mass spectrometry (GC-MS). N-Benzoyl amino acid substrates were evaluated for the detection of carboxypeptidase activities in a number of clinical pathogens. Upon enzymatic hydrolysis of these substrates, benzoic acid was produced which was detected by extraction from the liquid culture supernatant, derivatization as the trimethylsilyl ester, with subsequent analysis by GC-MS. Enzymatic hydrolysis of N-benzoyl glycine was observed for S. agalactiae, M. morganii, and A. baumannii. In addition, P. fluorescens was found to hydrolyze N-benzoyl-L-glutamic acid. Although the method provides an alternative approach for determining carboxypeptidase activity, ultimately it would not be a suitable method in a clinical setting. However, the method is well-suited for identifying carboxypeptidase activities that have not been previously described or to corroborate a carboxypeptidase assay with the ninhydrin reagent. PMID- 27226649 TI - Periodical capacity setting methods for make-to-order multi-machine production systems. AB - The paper presents different periodical capacity setting methods for make-to order, multi-machine production systems with stochastic customer required lead times and stochastic processing times to improve service level and tardiness. These methods are developed as decision support when capacity flexibility exists, such as, a certain range of possible working hours a week for example. The methods differ in the amount of information used whereby all are based on the cumulated capacity demand at each machine. In a simulation study the methods' impact on service level and tardiness is compared to a constant provided capacity for a single and a multi-machine setting. It is shown that the tested capacity setting methods can lead to an increase in service level and a decrease in average tardiness in comparison to a constant provided capacity. The methods using information on processing time and customer required lead time distribution perform best. The results found in this paper can help practitioners to make efficient use of their flexible capacity. PMID- 27226650 TI - Reward magnitude effects on temporal discrimination. AB - Changes in reward magnitude or value have been reported to produce effects on timing behavior, which have been attributed to changes in the speed of an internal pacemaker in some instances and to attentional factors in other cases. The present experiments therefore aimed to clarify the effects of reward magnitude on timing processes. In Experiment 1, rats were trained to discriminate a short (2 s) vs. a long (8 s) signal followed by testing with intermediate durations. Then, the reward on short or long trials was increased from 1 to 4 pellets in separate groups. Experiment 2 measured the effect of different reward magnitudes associated with the short vs. long signals throughout training. Finally, Experiment 3 controlled for satiety effects during the reward magnitude manipulation phase. A general flattening of the psychophysical function was evident in all three experiments, suggesting that unequal reward magnitudes may disrupt attention to duration. PMID- 27226651 TI - A thermodynamic study of the cadmium-neodymium system. AB - ABSTRACT: Cd vapor pressures were determined over Cd-Nd samples by an isopiestic method. The measurements were carried out in the temperature range from about 690 to 1200 K and over a composition range between 48 and 92 at % Cd. From the vapor pressures, thermodynamic activities of Cd were derived for all samples at their respective sample temperatures, and partial molar enthalpies of Cd were obtained from the temperature dependence of the activities. With these partial molar enthalpies, the Cd activities were converted to a common temperature of 873 K. By means of a Gibbs-Duhem integration Nd activities and integral Gibbs energies were calculated, using a literature value of DeltafG for the phase Cd6Nd as integration constant. A minimum of DeltafG ~ -38 kJ g-atom-1 at 873 K was obtained for the phase CdNd, a value that compares well with other CdRE compounds. GRAPHICAL ABSTRACT: PMID- 27226652 TI - Synthesis, spectroscopic and crystallographic analysis of the Zn-complex of a di(beta,beta'-sulfoleno)pyrrin: model for Zn-complexes of bilirubin and of phylloxanthobilins. AB - ABSTRACT: A high yield preparation, spectroscopic and crystallographic investigation of the crystalline Zn-complex of a di(beta,beta'-sulfoleno)pyrrin are reported here. In the brightly green fluorescent Zn-complex of the hardly luminescent di(beta,beta'-sulfoleno)pyrrin, the metal ion is bound by two di(beta,beta'-sulfoleno)pyrrin ligands, as revealed first by its mass spectra. The crystal structure of this Zn-complex of the di(beta,beta'-sulfoleno)pyrrin confirmed a regular 2:1 composition of the bidentate di(beta,beta' sulfoleno)pyrrin ligand and the metal ion. The latter was coordinated in a distorted tetrahedral fashion, as found in other dipyrrin Zn-complexes. The here studied Zn-complex of a designed di(beta,beta'-sulfoleno)pyrrin ligand provides insights into the coordination properties of the proposed (2:1)- and (2:2) complexes of phylloxanthobilin and bilirubin, respectively, which are two abundant natural bilin-type tetrapyrroles. GRAPHICAL ABSTRACT: PMID- 27226653 TI - Viscosity of liquid Co-Sn alloys: thermodynamic evaluation and experiment. AB - Shear viscosity measurements were performed for liquid Co-Sn alloys over a wide temperature range above the respective liquidus temperatures. A high temperature oscillating-cup viscometer was used. It was found experimentally that viscosity as a function of temperature obeys an Arrhenius law. The data were compared with calculated values, obtained from different thermodynamic approaches. A good agreement was found between experimental results and calculated ones by the Budai Benko-Kaptay model. PMID- 27226654 TI - Food choices and peer relationships: Examining 'a taste for necessity' in a network context. AB - The knowledge of how our taste preferences in food are shaped by our social lives has largely developed without attention to the roles played by relationships with other people. While the well-known sociological work of Pierre Bourdieu highlights the relationship of economic, cultural, and social capital with food consumption, very little scholarship concerned with food has given explicit empirical attention to social network connectivity as a form of social capital. To bridge this gap, this investigation utilizes data from a prospective cohort study of health in which both the food choices of several thousand individuals and their social ties with peers are examined. Comparing the relative social connectedness of individuals and their common food choices provides a new perspective on taste formation and maintenance and provides new evidence of how interpersonal mechanisms play a role in food choice and taste preferences. PMID- 27226655 TI - The Paradox of Success at a No-Excuses School. AB - No recent reform has had so profound an effect as no-excuses schools in increasing the achievement of low-income, black and Hispanic students. In the past decade, no-excuses schools-whose practices include extended instructional time, data-driven instruction, ongoing professional development, and a highly structured disciplinary system-have emerged as one of the most influential urban school-reform models. Yet almost no research has been conducted on the everyday experiences of students and teachers inside these schools. Drawing from 18 months of ethnographic fieldwork inside one no-excuses school and interviews with 92 school administrators, teachers, and students, I argue that even in a school promoting social mobility, teachers still reinforce class-based skills and behaviors. Because of these schools' emphasis on order as a prerequisite to raising test scores, teachers stress behaviors that undermine success for middle class children. As a consequence, these schools develop worker-learners-children who monitor themselves, hold back their opinions, and defer to authority-rather than lifelong learners. I discuss the implications of these findings for market based educational reform, inequality, and research on noncognitive skills. PMID- 27226656 TI - On the Direct Decomposition of Nilpotent Expanded Groups. AB - We decompose certain nilpotent expanded groups into a direct product such that the additive group of each factor is either a p-group or torsion-free. PMID- 27226657 TI - Where do we go in terms of safety and quality of obstetric care in Colombia? PMID- 27226658 TI - A cross sectional study of leptospirosis and fetal death in Yucatan, Mexico. AB - INTRODUCTION: Leptospirosis is a zoonotic disease affecting mainly to low income human population. Acute leptospiral infection during pregnancy has been associated with spontaneous abortion and fetal death during the first trimester and the abortion may occur as consequence of systemic failure. OBJECTIVE: To estimate the frequency of Leptospira interrogans infection in women with spontaneous abortion in the state of Yucatan, Mexico. METHODS: A cross sectional study on women with spontaneous abortion was conducted. Serum samples were tested for Leptospirosis by the microaglutination test, to estimate the frequency of the infecting serovar. The indirect ELISA IgM was used to detect recent infection by L. interrogans. DNA was extracted from paraffin-embedded tissue of placenta for PCR detection of L. interrogans. RESULTS: Overall frequency of infection with L. interrogans in the 81 women with abortion was 13.6%. Five of the 12 serovars evaluated were found and included. Two of the 11 women with abortion and positive to microaglutination test were also positive to the ELISA IgM test. None samples were positive for PCR Leptospira diagnosis. CONCLUSION: two women could be associated with spontaneous abortion due to leptospirosis, because they showed antibodies against L. interrogans in the microaglutination test and ELISA IgM assays. Differences between regions were found with respect to the prevalences of lesptospirosis. PMID- 27226659 TI - Relationship between super antigenicity, antimicrobial resistance and origin of Staphylococcus aureus isolated. AB - INTRODUCTION: Staphylococcus aureus is a pathogen that causes food poisoning as well as hospital and community acquired infections. OBJECTIVE: Establish the profile of superantigen genes among hospital isolates in relation to clinical specimen type, susceptibility to antibiotics and hospital or community acquisition. METHODS: Eighty one isolates obtained from patients at Colombian hospital, were classified by antimicrobial susceptibility, specimen type and hospital or community acquired . The PCR uniplex and multiplex was used for detection of 22 superantigen genes (18 enterotoxins, tsst-1 and three exfoliative toxins). RESULTS: Ninety five point one percent of isolates harbored one or more of the genes with an average of 5.6 genes. Prevalence of individual genes was variable and the most prevalent was seg (51.9%). Thirty nine genotypes were obtained, and the genotype gimnou (complete egc cluster) was the most prevalent alone (16.0%) and in association with other genes (13.6%). The correlation between presence of superantigens and clinical specimen or antimicrobial susceptibility showed no significant difference. But there was significant difference between presence of superantigens and the origin of the isolates, hospital or community acquired (p= 0.049). CONCLUSIONS: The results show the variability of the superantigen genes profile in hospital isolates and shows no conclusive relationship with the clinical sample type and antimicrobial susceptibility, but there was correlation with community and hospital isolates. The analysis of the interplay between virulence, epidemic and antibiotic resistance of bacterial populations is needed to predict the future of infectious diseases. PMID- 27226660 TI - Do we really ponder about necessity of intravenous hydration in acute bronchiolitis? AB - OBJECTIVE: The goal was to establish the role of intravenous hydration therapy on mild bronchiolitis. METHODS: This was a retrospective case control study. Infants between 1 month and 2 years of age admitted to our general pediatrics ward between June 2012 and June 2013 with a diagnosis of uncomplicated acute bronchiolitis were enrolled to the study. Hospital medical files were reviewed to get information about children personal history, symptoms of the disease, disease severity scores and their management. Patients were classified into 4 groups according to the management; nebulized short-acting beta2-agonist (salbutamol) +hydration; nebulized short-acting beta2-agonist (salbutamol); hydration and neither bronchodilator nor hydration. We examined length of stay in the hospital as an outcome measure. RESULTS: A total of 94 infants were studied. There was no significant difference between groups in terms of length of stay in hospital. CONCLUSIONS: IV hydration is not effective on length of stay in hospital in mild acute bronchiolitis patients. PMID- 27226661 TI - Self-reported vaccination in the elderly: SABE Bogota study, Colombia. AB - OBJECTIVES: To determine the frequency of vaccination in older adults within the city of Bogota and to estimate the association with sociodemographic and health factors. METHODS: This is a secondary data analysis from the SABE-Bogota Study, a cross-sectional population-based study that included a total of 2,000 persons aged 60 years. Weighted percentages for self-reported vaccination [influenza, pneumococcal, tetanus] were determined. The association between vaccination and covariates was evaluate by logistic regression models. RESULTS: A total of 73.0% of respondents received influenza, 57.8% pneumococcal and 47.6% tetanus vaccine. Factors independently associated with vaccination included: 1- age (65-74 years had higher odds of receiving vaccinations, compared to 60-64 years); 2- socioeconomic status (SES) (higher SES had lower odds of having influenza and pneumococcal vaccines, compared to those with lower SES); 3- health insurance (those with contributive or subsidized health insurance had higher odds (between 3 and 5 times higher) of having vaccinations, compared to those with no insurance); 4- older adults with better functional status (greater Lawton scores) had increased odds for all vaccinations; 5- older adults with higher comorbidity had increased odds for influenza and pneumococcal vaccinations. CONCLUSION: Vaccination campaigns should be strengthened to increase vaccination coverage, especially in the group more reticent to vaccination or vulnerable to reach it such as the disabled elder. PMID- 27226663 TI - Palliative care team visits. Qualitative study through participant observation. AB - OBJECTIVES: To describe the clinical encounters that occur when a palliative care team provides patient care and the features that influence these encounters and indicate whether they are favorable or unfavorable depending on the expectations and feelings of the various participants. METHODS: A qualitative case study conducted via participant observation. A total of 12 observations of the meetings of palliative care teams with patients and families in different settings (home, hospital and consultation room) were performed. The visits were follow-up or first visits, either scheduled or on demand. Content analysis of the observation was performed. RESULTS: The analysis showed the normal follow-up activity of the palliative care unit that was focused on controlling symptoms, sharing information and providing advice on therapeutic regimens and care. The environment appeared to condition the patients' expressions and the type of patient relationship. Favorable clinical encounter conditions included kindness and gratitude. Unfavorable conditions were deterioration caused by approaching death, unrealistic family objectives and limited resources. CONCLUSION: Home visits from basic palliative care teams play an important role in patient and family well-being. The visits seem to focus on controlling symptoms and are conditioned by available resources. PMID- 27226662 TI - Alcohol use disorders and psychiatric diseases in Colombia. AB - BACKGROUND: An accurate understanding of co-occurrence and comorbidity of alcohol use disorders (AUD) in Colombia is crucial for public health. OBJECTIVE: A secondary analysis was conducted, using a 2003/2004 government's population database to determine the lifetime associations between AUD and other mental and addictive disorders in people of Colombia aged 18-65 years. METHODS: Several statistical analysis were performed: testing prevalence difference in mental disorders by whether the individual had an AUD; a stratified analysis by gender and logistic regression analyses accounting for differences in demographic, socio economic, behavioral and self-reported health status variables. RESULTS: People with AUD comprised 9% of the population, of which 88% were males and on average 37 years old. They were more likely to be males, be working, and be current smokers; and less likely to be at home or retired. The population with AUD had greater chance to comply with criteria for all disorders but minor depressive disorder, post-traumatic stress disorder, nicotine dependence, and oppositional defiant disorder. CONCLUSION: This study demonstrates a high prevalence of mental disorders in the adult population with AUD in Colombia. The findings highlight the importance of comorbidity as a sign of disease severity and impact on public health and supports the need for training of more professionals and developing appropriate interventions and services. PMID- 27226664 TI - Objective evaluation of surgical competency for minimally invasive surgery with a collection of simple tests. AB - OBJECTIVE: This study aims at determining if a collection of 16 motor tests on a physical simulator can objectively discriminate and evaluate practitioners' competency level, i.e. novice, resident, and expert. METHODS: An experimental design with three study groups (novice, resident, and expert) was developed to test the evaluation power of each of the 16 simple tests. An ANOVA and a Student Newman-Keuls (SNK) test were used to analyze results of each test to determine which of them can discriminate participants' competency level. RESULTS: Four of the 16 tests used discriminated all of the three competency levels and 15 discriminated at least two of the three groups (alpha= 0.05). Moreover, other two tests differentiate beginners' level from intermediate, and other seven tests differentiate intermediate level from expert. CONCLUSION: The competency level of a practitioner of minimally invasive surgery can be evaluated by a specific collection of basic tests in a physical surgical simulator. Reduction of the number of tests needed to discriminate the competency level of surgeons can be the aim of future research. PMID- 27226665 TI - Clinical outcomes of kidney transplants on patients with end-stage renal disease secondary to lupus nephritis, polycystic kidney disease and diabetic nephropathy. AB - BACKGROUND: Patients with lupus nephritis could progress to end-stage renal disease (10-22%); hence, kidney transplants should be considered as the treatment of choice for these patients. OBJECTIVE: To evaluate the clinical outcomes after kidney transplants in patients with chronic kidney diseases secondary to lupus nephritis, polycystic kidney disease and diabetes nephropathy at Pablo Tobon Uribe Hospital. METHODS: A descriptive and retrospective study performed at one kidney transplant center between 2005 and 2013. RESULTS: A total of 136 patients, 27 with lupus nephritis (19.9%), 31 with polycystic kidney disease (22.8%) and 78 with diabetes nephropathy (57.4%), were included in the study. The graft survivals after one, three and five years were 96.3%, 82.5% and 82.5% for lupus nephritis; 90%, 86% and 76.5% for polycystic kidney disease and 91.7%, 80.3% and 67.9% for diabetes nephropathy, respectively, with no significant differences (p= 0.488); the rate of lupus nephritis recurrence was 0.94%/person-year. The etiology of lupus vs diabetes vs polycystic disease was not a risk factor for a decreased time of graft survival (Hazard ratio: 1.43; 95% CI: 0.52-3.93). CONCLUSION: Kidney transplant patients with end stage renal disease secondary to lupus nephritis has similar graft and patient survival success rates to patients with other kidney diseases. The complication rate and risk of recurrence for lupus nephritis are low. Kidney transplants should be considered as the treatment of choice for patients with end stage renal disease secondary to lupus nephritis. PMID- 27226666 TI - Small clonal B-cell population in the bone marrow as a possible tool in the diagnosis of occult primary parotid lymphoma. AB - CASE DESCRIPTION: An 82-years old Hispanic woman with a past medical history significant for pulmonary thromboembolism on oral anticoagulation, rheumatoid arthritis, and hypertension developed a new onset thrombocytopenia. CLINICAL FINDINGS: Small clonal B-cells populations (SCBP) also known as monoclonal B-cell lymphocytosis was found as part of the workup for an idiopathic thrombocytopenia and lead ultimately to the diagnosis of parotid primary follicular lymphoma coexisting with Warthin tumor involving the bone marrow in a small extent and oncocytic papilloma located in the maxillary sinus. TREATMENT AND OUTCOME: Patient was treated with Rituximab monotherapy with improvement on her platelet count. CLINICAL RELEVANCE: Although it is unclear the role of this clonal cells, they may work as a possible diagnostic tool for occult lymphomas. Further prospective studies are needed to confirm this possible association. PMID- 27226667 TI - Evocation to the Dr. Carlos J. Finlay Barres on the centennial of his death. AB - About the editorial of the Professor Guillermo Llanos: "Carlos J. Finlay: the forgotten Pasteur of America", a hundred years after his death and through a documental review, a summary of the life and work of this great man of science was conducted. Finlay was a notable figure of the American medicine, he conceived a new infection way able to explain the propagation of the yellow fever, and added the possibility of their scientific confirmation by an experimental method. For all the above-mentioned Finlay was recognized as the humanity's benefactor. PMID- 27226668 TI - Preeclampsia prevention. PMID- 27226669 TI - Calcium and linoleic acid supplements in the prevention of preeclampsia. PMID- 27226670 TI - Conceptual, epidemiological and methodological design aspects for the study of pre-eclampsia. PMID- 27226671 TI - Authors Response: Preeclampsia prevention: a case-control study nested in a cohort. PMID- 27226672 TI - Predictors of Abstinence Self-Efficacy: Examining the role of HIV-risk Sexual Behavior. AB - Abstinence self-efficacy, or the confidence in ones' beliefs in one's ability to effectively engage in behaviors to maintain substance use abstinence, is a crucial recovery resource. However, little research has been conducted on what predicts increases in this recovery resource. Understanding predictors of abstinence self-efficacy could help social service practitioners in creating effective treatment plans/interventions while extending what is presently known in this small body of research. Predictors of abstinence self-efficacy were analyzed among a sample of ex-offenders (224 men and 46 women) who were completing inpatient treatment for substance use disorders. Hierarchical linear regression was conducted to examine changes in participants' abstinence self efficacy in relation to factors directly related (HIV-risk drug use behaviors, substance use, 12-step meeting attendance) and indirectly related (HIV-risk sexual behaviors, incarceration histories) to substance use. HIV-risk sexual behaviors and substance use predicted significant decreases in abstinence self efficacy whereas 12-step meeting attendance predicted significant increases. However, incarceration histories and HIV-risk drug use behaviors were not significant predictors of abstinence self-efficacy. Findings suggest HIV-risk sexual behavior should be considered when assessing relapse prevention for persons with substance use disorders, and that researchers should examine behaviors that are not directly related to substance use when investigating recovery resources. PMID- 27226673 TI - A Functional Approach to Deconvolve Dynamic Neuroimaging Data. AB - Positron emission tomography (PET) is an imaging technique which can be used to investigate chemical changes in human biological processes such as cancer development or neurochemical reactions. Most dynamic PET scans are currently analyzed based on the assumption that linear first-order kinetics can be used to adequately describe the system under observation. However, there has recently been strong evidence that this is not the case. To provide an analysis of PET data which is free from this compartmental assumption, we propose a nonparametric deconvolution and analysis model for dynamic PET data based on functional principal component analysis. This yields flexibility in the possible deconvolved functions while still performing well when a linear compartmental model setup is the true data generating mechanism. As the deconvolution needs to be performed on only a relative small number of basis functions rather than voxel by voxel in the entire three-dimensional volume, the methodology is both robust to typical brain imaging noise levels while also being computationally efficient. The new methodology is investigated through simulations in both one-dimensional functions and 2D images and also applied to a neuroimaging study whose goal is the quantification of opioid receptor concentration in the brain. PMID- 27226674 TI - Statistical Inference in Hidden Markov Models Using k-Segment Constraints. AB - Hidden Markov models (HMMs) are one of the most widely used statistical methods for analyzing sequence data. However, the reporting of output from HMMs has largely been restricted to the presentation of the most-probable (MAP) hidden state sequence, found via the Viterbi algorithm, or the sequence of most probable marginals using the forward-backward algorithm. In this article, we expand the amount of information we could obtain from the posterior distribution of an HMM by introducing linear-time dynamic programming recursions that, conditional on a user-specified constraint in the number of segments, allow us to (i) find MAP sequences, (ii) compute posterior probabilities, and (iii) simulate sample paths. We collectively call these recursions k-segment algorithms and illustrate their utility using simulated and real examples. We also highlight the prospective and retrospective use of k-segment constraints for fitting HMMs or exploring existing model fits. Supplementary materials for this article are available online. PMID- 27226675 TI - Analysis of physical demands during bulk bag closing and sealing. AB - Several tools are sold and recommended for closing and sealing flexible intermediate bulk containers (bulk bags) which are used to transport product that has been mined and processed. However, there is limited information on the risks, physical demands, or the benefits of using one tool over another. The purpose of this study was to evaluate the physical demands involved with two closing methods and several sealing tools in order to provide recommendations for selecting tools to reduce exposure to risk factors for work-related musculoskeletal disorders. In this study, twelve participants completed bag closing and sealing tasks using two different closing methods and eight sealing tools on two types of bulk bags. Physical demands and performance were evaluated using muscle activity, perceived exertion, subjective ratings of use, and time. Results indicate that using the "flowering" method to close bags required on average 32% less muscle activity, 30% less perceived exertion, 42% less time, and was preferred by participants compared to using the "snaking" method. For sealing, there was no single method significantly better across all measures; however, using a pneumatic cable tie gun consistently had the lowest muscle activity and perceived exertion ratings. The pneumatic cable tie gun did require approximately 33% more time to seal the bag compared to methods without a tool, but the amount of time to seal the bag was comparable to using other tools. Further, sealing a spout bulk bag required on average 13% less muscle activity, 18% less perceived exertion, 35% less time, and was preferred by participants compared to sealing a duffle bulk bag. The current results suggest that closing the spout bag using the flowering method and sealing the bag using the pneumatic cable tie gun that is installed with a tool balancer is ergonomically advantageous. Our findings can help organizations select methods and tools that pose the lowest physical demands when closing and sealing bulk bags. PMID- 27226676 TI - Lead shielding efficiency from the gamma background measurements in the salt cavern of the Polkowice-Sieroszowice copper mine. AB - The studies of lead shielding efficiency from the gamma background measurements were performed in the salt cavern of the copper mine - a site considered for an underground laboratory. Within the energy range of 50-2700 keV, the measured gamma-ray count rates normalized to the mass of the high-purity detectors germanium crystal are 5.93 and 6.32 s-1kg-1 for the used low-background and portable spectrometers, respectively. The gamma-ray flux of 0.124 (2) cm-2s-1 connected with the natural radioisotopes was observed by the portable HPGe, including 0.026 (1) cm-2s-1 contribution of radon decay products, whereas the photon flux at the spectrum continuum was 0.18 (5) cm-2s-1. PMID- 27226677 TI - Factors contributing to the perpetration of workplace incivility: the importance of organizational aspects and experiencing incivility from others. AB - In recent years a growing amount of research has been conducted in the area of workplace incivility. Whereas many studies have focused on the victims and the consequences of incivility, little attention has been paid to the perpetrators and antecedents of workplace incivility. This study aims to identify possible antecedents of workplace incivility, by investigating organizational aspects as well as the possibility that being the target of incivility from co-workers and supervisors could induce incivility. A total of 512 employees (378 women and 133 men) in the school sector in a Swedish municipality completed an online questionnaire. Overall, the results of structural equation modelling analyses showed that organizational variables were related to the perpetration of incivility. A direct relationship was found between being uncivil and organizational change, job insecurity, low social support from co-workers and high job demands. However, the strongest relationship was found between experienced incivility from co-workers and instigated incivility. This could be reflecting a climate or culture of incivility in the organization, and carry implications for future practice in interventions against workplace incivility. The results indicate the importance of focusing on the perspective of the instigator to gain knowledge about the process of workplace incivility. PMID- 27226678 TI - Stuck in a job: being "locked-in" or at risk of becoming locked-in at the workplace and well-being over time. AB - In this study, being "locked-in" at the workplace is conceptualized as being in a non-preferred workplace while at the same time perceiving low employability. The aim of the study was to investigate how being locked-in or at risk of becoming locked-in (being in a non-preferred workplace yet currently satisfied, combined with perceiving low employability) relates to well-being (subjective health and depressive symptoms). The hypotheses were tested in a Swedish longitudinal sample (T1 in 2010 and T2 in 2012) of permanent employees (N = 3491). The results showed that stability with regard to locked-in-related status (being non-locked-in, at risk of becoming locked-in, or locked-in at both T1 and T2) was related to significant and stable differences in well-being. The non-locked-in status was associated with better well-being than being at risk of becoming locked-in. Moreover, those at risk of becoming locked-in showed better well-being than those with stable locked-in status. Changes towards non-locked-in were accompanied by significant improvements in well-being, and changes towards locked-in were associated with impairments in well-being. The relationships that were found could not be attributed to differences in demographic variables and occupational preference. The findings indicate that being locked-in is detrimental to well being. This has implications for preventative interventions. PMID- 27226679 TI - The role of fine needle aspiration cytology and core biopsy in the diagnosis of palpable breast masses. AB - BACKGROUND: The modern approach to palpable breast masses is to get cytopathologic diagnosis before definitive surgery. We aimed to compare fine needle aspiration cytology (FNAC) with core biopsy in histopathologic diagnosis of palpable breast masses. MATERIALS AND METHODS: Data were collected on 123 women who have suspicious palpable breast masses from 2007 to 2010. RESULTS: Of the 123 patients, core biopsies were performed on 64 patients (Group 1) and FNAC on 59 patients (Group 2). Malignancy was confirmed in 25 out of 32 clinically suspicious patients in Group 1 (78.1%), and 20 out of 21 participants in Group 2 (95.2%). Among the clinically suspicious patients, 81.8% of 33 patients in Group 1, and 90.3% of 31 patients in Group 2 were identified malignancy. Sensitivity was 100% for core biopsy and 95% for FNAC. Specificity was 100% in both procedures. False negativity rate in FNAC were 5%. CONCLUSION: Sensitivity and specificity showed that in the case of true histopathologic classification, core biopsy is superior to FNAC. Nevertheless, FNAC's role as a fast, simple and cheap diagnosis cannot be ignored. It is an effective diagnostic tool in most patients, in comparison to the correct and specific typing of core biopsies in benign lesions which protect patients from the open biopsy. PMID- 27226680 TI - Comparison of treatment of unstable intertrochanteric fracture with different arthroplasty methods. AB - BACKGROUND: Intertrochanteric femur fractures are elderly is very common and can be treated by different fixation methods such as internal fixation and arthroplasty. In our study, we investigated the correlation between the hemiarthroplasty treatment method and functional results. MATERIALS AND METHODS: The study consists of 121 patients with intertrochanteric fractures and these patients are divided into three groups. Eighty-five were male and 36 were female. Group I was uncemented bipolar hemiarthroplasty patients, Group II was cemented bipolar hemiarthroplasty and Group III was cemented calcar preserving bipolar hemiarthroplasty. Mean follow-up period was 16 months. Harris hip score was used to evaluate functional outcome of the patients. RESULTS: There were no significant differences between three groups when comparing the mortality rate in the 1(st) month and 1(st) year but all time mortality was proportionally lower in Group I comparing to the two other groups. There were no significant differences between three groups when comparing the functional results in 1(st) month and 1(st) year. CONCLUSION: In our study, uncemented bipolar hemiarthroplasty is a preferable treatment over the two other arthroplasty treatment model (cemented bipolar and calcar preserving) regarding to the mortality rate since there is no significant difference between. This conclusion needs further studies with greater number of patients. PMID- 27226681 TI - Prevalence of metabolic syndrome among HIV-infected patients in Ghana: A cross sectional study. AB - BACKGROUND: Prevalence of metabolic syndrome (MetS) in HIV-infected patients is very limited in the Ghanaian setting and may vary across the globe by the different study populations and criteria used. AIM: We investigated the prevalence of MetS among HIV-infected patients receiving highly active antiretroviral therapy (HAART) at the St. Dominic Hospital, Akwatia, Ghana. PATIENTS AND METHODS: This cross-sectional study recruited 433 HIV-infected patients (294 on HAART and 139 HAART-naive) from the period of February 2013 to December 2013. Information on the demographic, clinical, anthropometric characteristics were obtained and lipid profile for each patient was assessed. MetS was assessed based on the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III), World Health Organization (WHO) and International Diabetes Federation (IDF) criteria. RESULTS: The prevalence of MetS was 24.5% according to WHO criteria, 48.3% by NCEP-ATP III criteria, and 42.3% by IDF criteria. In general, participants on HAART were significantly associated with higher prevalence of MetS compared to those without HAART (P < 0.05) irrespective of the criteria used. Prevalence of clustering components of MetS was significantly higher among those on HAART when risk scores of 2 and above were used compared with those not on HAART (P < 0.05). CONCLUSION: HAART recipient developed MetS as indicated by dyslipidemia, high blood pressure, and abnormal body fat. It is incumbent on health giver to incorporate MetS assessment as a part of treatment and management plan in patients receiving HAART. PMID- 27226682 TI - Quality of life of patients surgically treated for ameloblastoma. AB - BACKGROUND: The surgical management of ameloblastoma can have a profound functional and psychological effect on a patient's quality of life (QoL). The aim of this study was to compare the pre- and post-operative QoL outcomes of patients requiring surgical treatment for ameloblastoma. PATIENTS AND METHODS: A total number of 30 patients were identified as fulfilling the criteria for this study. They included 18 males and 12 females, aged between 14 and 47 years with a mean of 27.3 years (standard deviation 10.2). Each patient completed a modified version of the University of Washington QoL questionnaire version 4, a day to surgery and postoperatively on the 7(th) day, 3 months, and 6 months. RESULTS: Following surgical treatment of patients for ameloblastoma, the QoL decreased immediately after surgery. It then gradually improved over time and exceeded the preoperative value at 6 months postoperatively. When analyzed with respect to location, posteriorly placed tumors had the best postoperative QoL outcome. Patients expressed concern more about their appearance preoperatively while postoperative concerns were mostly focused on their ability to chew. CONCLUSION: Significant improvement occurred in QoL scores following surgical management of ameloblastoma. The small sample size utilized in this study limits a definitive conclusion. A larger multicenter study is therefore recommended. PMID- 27226683 TI - Pedometer-determined physical activity profile of healthcare professionals in a Nigerian tertiary hospital. AB - BACKGROUND: Healthcare professionals (HCPs) are perceived as statutory advocates for healthy living and promotion of healthy behaviors such as regular participation in physical activity (PA). This study assessed and compared pedometer-determined PA of different urban HCPs in a Nigerian tertiary hospital. MATERIALS AND METHODS: A cross-sectional study involving 180 HCPs from a tertiary hospital in Lagos, Nigeria. PA was measured by daily walking steps using a pedometer. RESULTS: The mean step count obtained was 7,396.94 +/- 2,714.63 steps/day. Only 20% of the HCPs met a minimum PA of 10,000 steps/day. About one third (34.4%) of the HCPs were low active and less than a quarter (23.9%) were somewhat active. Further, less than half (43.9%) of the HCPs were found to have PA levels >=7,500 steps/day. Overall, nurses had the highest step counts (7,980 steps/day) followed by physiotherapists (7,332 steps/day), while pharmacists had the lowest step counts (6,201 steps/day). There was however no significant difference in the mean step counts of the various cadres of the HCPs (P > 0.05). Step counts of HCPs were found to significantly negatively correlate with their age (r = -0.53; P < 0.001), body mass index (r = -0.39; P < 0.001), and body fat percentage (r = -0.42; P < 0.001). CONCLUSION: PA profile of the HCPs was mostly characterized by a low active PA level and less than a quarter met the recommended minimum of 10,000 steps/day. PMID- 27226684 TI - Effect of preserved and preservative-free timolol eye drops on tear film stability in healthy Africans. AB - BACKGROUND: Preserved versus nonpreserved formulations for ophthalmic use have been well described in the literature although not specifically in the African population where beta blockers are frequently used as the first-line therapy due to economic and availability issues. This study sought to determine the effect of preserved and preservative-free Timolol eye drops on tear film stability in healthy black Africans. MATERIALS AND METHODS: Sixty healthy nondry eye subjects aged 19-25 years were randomly assigned into four groups (n = 15) and differently treated with eye drops of phosphate buffered saline (PBS), preservative-free timolol (PFT), benzalkonium chloride (BAK) only, and BAK-preserved timolol (BPT). Noninvasive tear break-up time (NITBUT) was measured using the keratometer at baseline and 30, 60, and 90 min after drop application. RESULTS: No significant decline in NITBUT was observed following treatment with PFT and PBS. However, BAK treatment showed a positive time-dependent significant decline in NITBUT (P < 0.001) while a significant decline in the BPT-treated group was only found at 90 min (-3.52 s; P < 0.001). In comparison to the PFT-treated group, treatment with BAK and BPT showed significantly lower NITBUT (P < 0.001). CONCLUSION: BPT is associated with a significant decline in tear film stability in black Africans. This finding has implications in the management of glaucoma in patients with high risk of dry eyes in this population. PMID- 27226685 TI - Diverticular disease at colonoscopy in Lagos State, Nigeria. AB - BACKGROUND: The upsurge in the reported cases of diverticular disease (DD) has led to a re-appraisal of the earlier held views that it was a rare entity in Nigeria. The advent of colonoscopy has contributed in no small way to this change. We sought to determine the clinical characteristics, indications for colonoscopy, and intra-procedural findings among these patients. MATERIALS AND METHODS: A retrospective cross-sectional study was carried out on the colonoscopy records from four private endoscopy units based in Lagos State, Nigeria. The records were drawn from a 5-year period (August 2010 to July 2015). The endoscopy logs and reports were reviewed, and the bio data, indications, and colonoscopy findings were gleaned. RESULTS: A total of 265 colonoscopies were carried out in the stated period. Of these, 28 (10.6%) had DD. Of the patients with DD, 5 (17.9%) were females while 23 (82.1%) were males. Their ages ranged from 46 to 94 years (mean = 68.2 +/- 11 years). Fifteen patients had been referred for the procedure on account of hematochezia alone (15 = 53.6%). Other reasons for referral included abdominal pain alone (2 = 7%), hematochezia plus abdominal pain (5 = 17.9%), and change in bowel habits (3 = 10.8%). Ten (35%) patients had pan colonic involvement. Regional disease involved the right side alone in only one case (3.5%) while the other combinations of sites are as follows; 6 (21.4%) in the sigmoid colon alone, 2 (7%) in the descending colon alone, 5 (17.9%) in the sigmoid-descending colon, 4 (14.3%) in the sigmoid-descending-transverse colon, thus the sigmoid colon was involved in 25 (89.3%) cases. Five cases (17.9%) had endoscopic features suggestive of diverticulitis. CONCLUSIONS: DD should no longer be regarded as a rare problem in the Nigerian patient. The study findings support the notion of higher prevalence among the elderly, in males, and of sigmoid colon involvement. PMID- 27226686 TI - Evaluation of oxidant-antioxidant balance and total antioxidant capacity of serum in children with urinary tract infection. AB - BACKGROUND: Urinary tract infection (UTI) is the most common bacterial infections in children. This studyaimed to investigate the oxidative and antioxidate status of plasma in patients with UTI and to compare them with those of the controls. METHODS: This case-control study of 50-75 children in the given order was performed in 2013 at the Pediatric Clinic of infections in Zahedan Hospital of Ali Ibn Abi Talib. The antioxidative status of plasma were evaluated by measuring the total antioxidant capacity (TAC) The oxidative status of samples was assessed by measuring the total peroxide and the oxidative stress index (OSI) levels. The means of the parameters were compared and the relationship among them was determined. Data were analyzed using SPSS 20 (IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp). Student's t-test and Mann-Whitney U-test were applied in various situations of our questions; 95% confidence interval was considered for the level of significance. RESULTS: The results showed that total oxidant serum status in UTI patients was higher compared to controls when total antioxidant serum was lower. The balance of oxidant-antioxidant serum was in favor of oxidant serum and this term was confirmed by OSI. CONCLUSION: Our results showed that the plasma levels of TAC in patients with UTI were decreased compared to controls, and oxidant-antioxidant balance and OSI caused increased OS in patients. PMID- 27226687 TI - Association between serum uric acid, urinary albumin excretion, and glycated hemoglobin in Type 2 diabetic patient. AB - BACKGROUND: Diabetes mellitus (DM) is a chronic disease characterized by insulin deficiency or peripheral resistance resulting in hyperglycemia. Poor glycemic control leads to diabetic complications. Hyperuricemia has been reported with increased risk of renal insufficiency. The aim of this study was to evaluate the relationship between serum uric acid concentration, degree of urinary albumin excretion (UAE) and glycated hemoglobin (HbA1c) in Type 2 DM (T2DM) patients. MATERIALS AND METHODS: Serum uric acid concentrations, urine microalbumin, and HbA1c were measured in fifty T2DM patients. We then evaluated relationship between uric acid concentrations, degree of UAE and glycemic control as well as other confounding variables. RESULTS: Serum uric acid concentration correlated positively with UAE (r = 0.323, P < 0.05), age (r = 0.337, P < 0.05), age at onset (r = 0.341, P < 0.05), and duration of DM (r = 0.312, P < 0.05). Multiple regression analysis demonstrated that serum uric acid concentration (beta = 0.293, P < 0.0001), duration of DM (beta = 0.261, P < 0.0001), HbA1c (beta = 0.173, P < 0.005), and systolic blood pressure (beta = 0.268, P < 0.005) were independent determinants of UAE. CONCLUSIONS: Serum uric acid concentration is associated with microalbuminuria and HbA1c in T2DM patients. PMID- 27226688 TI - Comparative study of Clinical Assessment of Nutritional status score and proportionality indices in the assessment of fetal malnutrition in term newborns. AB - BACKGROUND: Fetal malnutrition (FM) which describes the underweight/wasting seen in newborns is a significant contributor to perinatal morbidity and mortality and requires proper documentation. The objective of this study was to assess the nutritional status of term newborns at birth using Clinical Assessment of Nutritional (CAN) status score and four other anthropometric indices and to compare the efficiency of CAN score and the anthropometric indices in identifying FM in term newborns. MATERIALS AND METHODS: The study was conducted on live singleton babies delivered >=37-42 completed weeks of gestation at the inborn unit of Lagos University Teaching Hospital without major congenital abnormalities or severe perinatal illness. Birth weights and lengths were recorded at birth. Ponderal index (PI), body mass index (BMI), and mid-arm/head circumference (MAC/HC) ratio were calculated and the values were compared with standard curves. The CAN score consisted of inspection and estimation of loss of subcutaneous tissues and muscles. FM was defined as CAN score <25. Data were analyzed using the Statistical Package for Social Sciences statistics software version 17.0. RESULTS: Two hundred and eighty-two newborns were analyzed. FM was identified in 14.5%, 10.3%, 13.1%, and 2.8% of newborns using CAN score, PI, BMI, and MAC/HC ratio, respectively. Out of the FM babies identified by CAN score, PI, MAC/HC, and BMI identified 19.5%, 12.3%, and 53.7% of them as FM also. BMI was the most sensitive anthropometric index for detecting FM. CONCLUSION: CAN score is a simple clinical tool for identifying FM and when used in conjunction with BMI will enhance FM detection. PMID- 27226689 TI - Treatment of complex nonunion of the shaft of the tibia using Ilizarov technique and its functional outcome. AB - BACKGROUND: A complex nonunion of the shaft of the tibia is a major cause of morbidity and mortality in patients with lower extremity injuries. AIMS: The aim of this study was to evaluate the outcome of the functional and radiological outcome of complex nonunion shaft of tibia, treated by radical debridement, Ilizarov ring fixator with compression and distraction osteogenesis. METHODS: From 2005 to 2010, sixty cases of complex nonunion shaft of tibia were included in our study. All infected nonunions were managed by radical debridement, fixed with Ilizarov ring fixator, monofocal/bifocal compression, and distraction osteogenesis. The average duration of follow-up is 36 months (26-50 months). The functional evaluation was done by using Association for the Study and Application of Methods of Ilizarov (ASAMI) scoring system and bone union with serial radiographs. RESULTS: All patients had a successful union. The mean time for union was 7 months (5-9 months). The mean time of fixator removal is 12 months (8 14 months). Every patient had pin tract infections which were successfully treated with oral antibiotics. Four patients had an equinus deformity, one patient had insignificant limb shortening (1.5 cm), and three patients had soft tissue dystrophy. Using the ASAMI scoring system, we obtained 45 excellent, 10 good, 3 fair, and 2 poor functional results. CONCLUSIONS: The Ilizarov technique for complex nonunions has a high rate of success in achieving union and eradicating infection, bone loss, and malalignment. Radical debridement is the key step to control bone infection. PMID- 27226690 TI - Tuberculous lymphadenopathy: Experience from the referral center of Northern India. AB - BACKGROUND: Lymphadenopathy is the common form of extrapulmonary tuberculosis (TB) in the developing country like India. The aim of the study was to assess the clinical and the pathological features of tuberculous peripheral lymphadenopathy along with the effect of the antitubercular drugs on its clinical course. MATERIALS AND METHODS: A prospective study was carried out in the department of pulmonary medicine from July 2013 to June 2014. Clinico-demographical and pathological characteristics of the patients of tuberculous lymphadenopathy were studied. RESULTS: Two and four cases, 84 (41.2%) male and 120 (58.8%) females were diagnosed as the cases of tuberculous lymphadenopathy. Mean age of the patients were 28.45 +/- 12.83. Palpable mass (100%) was the most common presenting feature. Cervical lymphadenopathy (92.6%) was the most common presentation of peripheral tuberculous lymphadenopathy. Most common cytological pattern seen was epithelioid granuloma with caseous necrosis (32.84%) followed by epithelioid granuloma without caseous necrosis on fine needle aspiration cytology (FNAC). Directly observed treatment short course (DOTS) for TB was effective in treating tuberculous lymphadenopathy. CONCLUSION: Tuberculous lymphadenopathy affects female more often than males. FNAC is the effective mean in diagnosing tuberculous lymphadenopathy. DOTS is the effective mean for treating tuberculous lymphadenopathy. PMID- 27226691 TI - Periprosthetic joint infection treated via bone cement and without the removal of hardware. AB - Periprosthetic joint infection (PJI) is a challenging complication with a frequency of 0.5-3%. The patient's age, recurrent surgeries, and comorbid systemic diseases increase the risk of infection. Although the current approach in the treatment of PJI is a two-stage revision; sometimes, removing all the implants can lead to more serious complications. PJI's complications are increase in the time of surgery, loss of blood volume, and increase in the amount of bone loss. Infected soft tissue and dead bone tissue debridement must be made in all cases. One of our cases had bone defects due to recurrent hip arthroplasty revisions. Our case that was given PJI treatment by covering the well-fixed components with bone cement and removing only the mobile parts was discussed in line with the literature. PMID- 27226692 TI - Pericentric inversion of chromosome 9 causing infertility and subsequent successful in vitro fertilization. AB - One of the most common and benign variants of normal human karyotype is pericentric inversion of chromosome 9 (inv[9][p11q13]). Despite being categorized as a normal variant, there are several reports of its association with various disease conditions. Here, we report a 27 year old female, who presented to us with primary infertility. The woman was diagnosed with inv (9)(p11q13) which was acknowledged as the reason for her otherwise unexplained infertility. The couple thereupon underwent in vitro fertilization using donor oocyte resulting in live birth. The clinical significance of this minor chromosomal rearrangement, need for genetic counseling, and subsequent reproductive guidance is highlighted in this report. PMID- 27226693 TI - Teacher-student relationship at university: an important yet under-researched field. AB - This article reviews the extant research on the relationship between students and teachers in higher education across three main areas: the quality of this relationship, its consequences and its antecedents. The weaknesses and gaps in prior research are highlighted and the importance of addressing the multi dimensional and context-bound nature of teacher-student relationships is proposed. A possible agenda for future research is outlined. PMID- 27226694 TI - The practical paradox of technology: The influence of communication technology use on employee burnout and engagement. AB - Technological advancements in the workplace frequently have produced contradictory effects by facilitating accessibility and efficiency while increasing interruptions and unpredictability. We combine insights from organizational paradoxes and the job demands-resources model to construct a framework identifying positive and negative mechanisms in the relationship between communication technology use (CTU) and employee well-being, operationalized as work engagement and burnout. In this study of Dutch workers, we demonstrate that CTU increases well-being through positive pathways (accessibility and efficiency) and decreases well-being through negative pathways (interruptions and unpredictability). We highlight the importance of (1) investigating CTU resources and demands simultaneously to grasp the relationship between CTU and employee well-being, and (2) considering CTU's downsides to successfully implement new communication technologies and flexible work designs. PMID- 27226695 TI - Twelve-Minute Daily Yoga Regimen Reverses Osteoporotic Bone Loss. AB - OBJECTIVE: Assess the effectiveness of selected yoga postures in raising bone mineral density (BMD). METHODS: Ten-year study of 741 Internet-recruited volunteers comparing preyoga BMD changes with postyoga BMD changes. OUTCOME MEASURES: Dual-energy x-ray absorptiometric scans. Optional radiographs of hips and spine and bone quality study (7 Tesla). RESULTS: Bone mineral density improved in spine, hips, and femur of the 227 moderately and fully compliant patients. Monthly gain in BMD was significant in spine (0.0029 g/cm2, P = .005) and femur (0.00022 g/cm2, P = .053), but in 1 cohort, although mean gain in hip BMD was 50%, large individual differences raised the confidence interval and the gain was not significant for total hip (0.000357 g/cm2). No yoga-related serious injuries were imaged or reported. Bone quality appeared qualitatively improved in yoga practitioners. CONCLUSION: Yoga appears to raise BMD in the spine and the femur safely. PMID- 27226696 TI - When Change Causes Stress: Effects of Self-construal and Change Consequences. AB - PURPOSE: Organizational change can be a major stress factor for employees. We investigate if stress responses can be explained by the extent to which there is a match between employee self-construal (in personal or collective terms) and change consequences (i.e., does the change particularly have consequences for the individual or for the group). We further investigate if the interactive effect of self-construal and change consequences on stress will be mediated by feelings of uncertainty. DESIGN/METHODOLOGY/APPROACH: Data were obtained in three studies. Study 1, a laboratory study, focused on physiological stress. Study 2, a business scenario, focused on anticipated stress. Study 3, a cross-sectional survey, focused on perceived stress. Studies 2 and 3 also included measures of uncertainty in order to test its mediating qualities. FINDINGS: Change is more likely to lead to stress when the change has consequences for matters that are central to employees' sense of self, and particularly so when the personal self is salient. This effect is mediated by feelings of uncertainty. IMPLICATIONS: Understanding why some people experience stress during change, while others do so to a lesser extent, may be essential for improving change management practices. It may help to prevent change processes being unnecessarily stressful for employees. ORIGINALITY/VALUE: This is one of the first studies to show that different kinds of change may be leading to uncertainty or stress, depending on employees' level of self-construal. The multi-method approach boosts the confidence in our findings. PMID- 27226697 TI - Why Do Situational Interviews Predict Performance? Is it Saying How You Would Behave or Knowing How You Should Behave? AB - PURPOSE: The present study examined two theoretical explanations for why situational interviews predict work-related performance, namely (a) that they are measures of interviewees' behavioral intentions or (b) that they are measures of interviewees' ability to correctly decipher situational demands. DESIGN/METHODOLOGY/APPROACH: We tested these explanations with 101 students, who participated in a 2-day selection simulation. FINDINGS: In line with the first explanation, there was considerable similarity between what participants said they would do and their actual behavior in corresponding work-related situations. However, the underlying postulated mechanism was not supported by the data. In line with the second explanation, participants' ability to correctly decipher situational demands was related to performance in both the interview and work related situations. Furthermore, the relationship between the interview and performance in the work-related situations was partially explained by this ability to decipher situational demands. IMPLICATIONS: Assessing interviewees' ability to identify criteria might be of additional value for making selection decisions, particularly for jobs where it is essential to assess situational demands. ORIGINALITY/VALUE: The present study made an effort to open the 'black box' of situational interview validity by examining two explanations for their validity. The results provided only moderate support for the first explanation. However, the second explanation was fully supported by these results. PMID- 27226698 TI - Eating Together at the Firehouse: How Workplace Commensality Relates to the Performance of Firefighters. AB - Cooperative activities among coworkers can provide valuable group-level benefits; however, previous research has often focused on artificial activities that require extraordinary efforts away from the worksite. We investigate organizational benefits that firms might obtain through various supports for coworkers to engage in commensality (i.e., eating together). We conducted field research within firehouses in a large city to explore the role that interacting over food might have for work-group performance. Using a mix of qualitative and quantitative methods, our field research shows a significant positive association between commensality and work-group performance. Our findings establish a basis for research and practice that focuses on ways that firms can enhance team performance by leveraging the mundane and powerful activity of eating. PMID- 27226699 TI - Influence of silicate on enrichment of highly productive microalgae from a mixed culture. AB - Microalgae have the potential to supply a biobased society with essential feedstocks like sugar and lipids. Besides being productive, strains used for this purpose should grow fast, be resistant to predators, and have good harvestability properties. Diatoms, a class of siliceous algae, have these and other preferred characteristics. In this paper, we describe the enrichment of microalgae in sequencing batch reactors with and without supply of silicate. Both reactors were operated with a light-dark cycle. To maximize storage compound production, carbon fixation and nitrogen uptake were uncoupled by limiting the availability of nitrate to the dark phase. After ten cycles, a stable culture was established in both reactors. The diatom Nitzschia sp. dominated the silicate-rich reactor, and the green algae Chlamydomonas sp. dominated the silicate-depleted reactor. Over the remaining 27 cycles of the experiment, the microalgal community structure did not change, indicating a highly stable system. Although the dominant microalga was highly dependent on the presence of silicate, the performance of both microalgal enrichments was similar. Polymers of glucose were stored during the nitrogen-limited light period. On organic matter dry weight basis, the sugar content of the biomass increased during the light period from 17 +/- 4 to 53 +/- 4 % for the silicate-limited culture, and from 14 +/- 4 to 43 +/- 4 % (w w-1) for the silicate excess culture. These results show that storage compound production can be achieved under various conditions, as long as a selective environment is maintained. PMID- 27226700 TI - A new flagellated dispersion stage in Paraphysoderma sedebokerense, a pathogen of Haematococcus pluvialis. AB - The blastocladialean fungus Paraphysoderma sedebokerense Boussiba, Zarka and James is a devastating pathogen of the commercially valuable green microalga Haematococcus pluvialis, a natural source of the carotenoid pigment astaxanthin. First identified in commercial Haematococcus cultivation facilities, P. sedebokerense is hypothesised to have a complex life cycle that switches between a vegetative and a resting phase depending on favourable or unfavourable growth conditions. Rather unusually for blastocladialean fungi, P. sedebokerense was described as lacking flagellated zoospores and only propagating via aplanosporic amoeboid cells. However, during repeated microscopic observation of P. sedebokerense cultivated in optimal conditions, we detected fast-swimming, transiently uniflagellated zoospores which rapidly transform into infectious amoeboid swarmers, the existence of which suggests a closer than previously thought relatedness of P. sedebokerense to its sister genera Physoderma and Urophlyctis. Additionally, we found some morphological and physiological differences between amoeboid swarmers and discuss hypotheses about their significance. These amoeboid and flagellated propagules are key to the dissemination of P. sedebokerense and are probably also the life stages most vulnerable to adverse environmental conditions. They are therefore a prime target for the development of disease management protocols in industrial cultivation facilities, a goal which requires a detailed understanding of their physiology. PMID- 27226701 TI - Do home-based exercise interventions improve outcomes for frail older people? Findings from a systematic review. AB - BACKGROUND: Frailty is common in older age, and is associated with important adverse health outcomes including increased risk of disability and long-term care admission. OBJECTIVES: To evaluate whether home-based exercise interventions improve outcomes for frail older people. DATA SOURCES: We searched systematically for randomised controlled trials (RCTs) and cluster RCTs, with literature searching to February 2010. STUDY SELECTION: All trials that evaluated home-based exercise interventions for frail older people were eligible. Primary outcomes were mobility, quality of life and daily living activities. Secondary outcomes included long-term care admission and hospitalisation. RESULTS: Six RCTs involving 987 participants met the inclusion criteria. Four trials were considered of high quality. One high quality trial reported improved disability in those with moderate but not severe frailty. Meta-analysis of long-term care admission rates identified a trend towards reduced risk. Inconsistent effects on other primary and secondary outcomes were reported in the other studies. CONCLUSIONS: There is preliminary evidence that home-based exercise interventions may improve disability in older people with moderate, but not severe, frailty. There is considerable uncertainty regarding effects on important outcomes including quality of life and long-term care admission. Home-based exercises are a potentially simple, safe and widely applicable intervention to prevent dependency decline for frail older people. PMID- 27226702 TI - Diagnostics for Respondent-driven Sampling. AB - Respondent-driven sampling (RDS) is a widely used method for sampling from hard to-reach human populations, especially populations at higher risk for HIV. Data are collected through peer-referral over social networks. RDS has proven practical for data collection in many difficult settings and is widely used. Inference from RDS data requires many strong assumptions because the sampling design is partially beyond the control of the researcher and partially unobserved. We introduce diagnostic tools for most of these assumptions and apply them in 12 high risk populations. These diagnostics empower researchers to better understand their data and encourage future statistical research on RDS. PMID- 27226703 TI - Impact of Mindfulness Training on Physiological Measures of Stress and Objective Measures of Attention Control in a Military Helicopter Unit. AB - Objective: This study sought to determine if mindfulness training (MT) has a measurable impact on stress and attentional control as measured by objective physiological and psychological means. Background: Periods of persistent, intensive work demands are known to compromise recovery and attentional capacity. The effects of 4-month MT on salivary cortisol and performance on 2 computer based cognitive tasks were tested on a military helicopter unit exposed to a prolonged period of high workload. Methods: MT participants were compared to a wait list control group on levels of saliva cortisol and performance on a go-no go test and a test of stimulus-driven attentional capture. Participants also reported mental demands on the go-no go test, time of wakeup, sleep duration, quality of sleep, outcome expectancies, physical activity level, self-perceived mindfulness, and symptoms of depression and anxiety. Results: The results from a mixed between-within analysis revealed that the MT participants compared to the control group had a larger pre to post increase in high- and low-cortisol slopes, and decrease in perceived mental demand imposed by the go-no go test. Conclusion: MT alleviates some of the physiological stress response and the subjective mental demands of challenging tasks in a military helicopter unit during a period of high workload. PMID- 27226704 TI - Postneurosurgical Central Nervous System Infection Due to Enterococcus faecalis Successfully Treated With Intraventricular Vancomycin. AB - Infections from Enterococcus faecalis and Enterococcus faecium are uncommon in the post-neurosurgical intervention setting., [1, 2, 3, 4] Intraventricular antibiotics are recommended when standard intravenous therapy fails. [5] Here we present a case of post-neurosurgical ventriculitis, meningitis, and cerebritis in an oncology patient caused by refractory Enterococcus faecalis successfully treated with intraventricular vancomycin. PMID- 27226705 TI - Coevolution of RAC Small GTPases and their Regulators GEF Proteins. AB - RAC proteins are small GTPases involved in important cellular processes in eukaryotes, and their deregulation may contribute to cancer. Activation of RAC proteins is regulated by DOCK and DBL protein families of guanine nucleotide exchange factors (GEFs). Although DOCK and DBL proteins act as GEFs on RAC proteins, DOCK and DBL family members are evolutionarily unrelated. To understand how DBL and DOCK families perform the same function on RAC proteins despite their unrelated primary structure, phylogenetic analyses of the RAC, DBL, and DOCK families were implemented, and interaction patterns that may suggest a coevolutionary process were searched. Interestingly, while RAC and DOCK proteins are very well conserved in humans and among eukaryotes, DBL proteins are highly divergent. Moreover, correlation analyses of the phylogenetic distances of RAC and GEF proteins and covariation analyses between residues in the interacting domains showed significant coevolution rates for both RAC-DOCK and RAC-DBL interactions. PMID- 27226706 TI - Bioinformatic Studies to Predict MicroRNAs with the Potential of Uncoupling RECK Expression from Epithelial-Mesenchymal Transition in Cancer Cells. AB - RECK is downregulated in many tumors, and forced RECK expression in tumor cells often results in suppression of malignant phenotypes. Recent findings suggest that RECK is upregulated after epithelial-mesenchymal transition (EMT) in normal epithelium-derived cells but not in cancer cells. Since several microRNAs (miRs) are known to target RECK mRNA, we hypothesized that certain miR(s) may be involved in this suppression of RECK upregulation after EMT in cancer cells. To test this hypothesis, we used three approaches: (1) text mining to find miRs relevant to EMT in cancer cells, (2) predicting miR targets using four algorithms, and (3) comparing miR-seq data and RECK mRNA data using a novel non parametric method. These approaches identified the miR-183-96-182 cluster as a strong candidate. We also looked for transcription factors and signaling molecules that may promote cancer EMT, miR-183-96-182 upregulation, and RECK downregulation. Here we describe our methods, findings, and a testable hypothesis on how RECK expression could be regulated in cancer cells after EMT. PMID- 27226707 TI - Prediction of the Risk for Essential Hypertension among Carriers of C825T Genetic Polymorphism of G Protein beta3 (GNB3) Gene. AB - BACKGROUND: The guanine nucleotide-binding protein beta polypeptide 3 (GNB3) 825T allele encodes a product that enhances the activation of heterotrimeric G proteins, which is associated with the occurrence of the splice variant Gbeta3 s that could play a role in vascular reactivity and hyperproliferation of smooth muscle cells, that makes such proteins attractive candidate gene products for susceptibility to essential hypertension (EH). OBJECTIVE: To predict the risk for EH in individuals with C825T genetic polymorphism of G protein beta3 gene. METHODS: The study consisted of 222 normotensive individuals and 216 hypertensive patients. Individuals were genotyped for C825T genetic polymorphism of G protein beta3 gene rs5443 by using restriction fragment length polymorphism. RESULTS: Frequencies of C and T alleles were 58.1% and 41.9%, respectively, in the control group compared with 47.7% and 52.3%, respectively, in the hypertensive group. The carriers of rs5443 (T) allele exhibited a significant greater risk for EH compared with the carriers of rs5443 (C) allele (odds ratio = 1.5, 95% confidence interval = 1.2-2.0). CONCLUSION: T allele is a risk factor for EH in the Egyptian population, which may be used as a prognostic and a therapeutic target of prophylaxis. PMID- 27226708 TI - Effectiveness, durability, and safety of darunavir/ritonavir in HIV-1-infected patients in routine clinical practice in Italy: a postauthorization noninterventional study. AB - Current antiretroviral (ARV) therapy for the treatment of human immunodeficiency virus (HIV-1)-infected patients provides long-term control of viral load (VL). Darunavir (DRV) is a nonpeptidomimetic protease inhibitor approved for use with a ritonavir booster (DRV/r). This study evaluated the effectiveness of DRV/r in combination with other ARV agents in routine clinical practice in Italy. In this descriptive observational study, data on utilization of DRV/r, under the conditions described in the marketing authorization, were collected from June 2009 to December 2012. Effectiveness (VL <50 copies/mL), tolerability, and durability in four patient groups (two DRV/r-experienced, one ARV-experienced DRV/r-naive, and one ARV-naive) were analyzed. Secondary objectives included immunological response, safety, and persistence/discontinuation rates. In total, 875 of 883 enrolled patients were included in the analysis: of these, 662 (75.7%) completed the follow-up until the end of 2012 and 213 (24.3%) withdrew from the study earlier. Initial DRV dose was 600 mg twice daily (67.1%) or 800 mg once daily (32.9%). Only 16 patients (1.8%) withdrew from the study due to virological failure. Virological response proportions were higher in patients virologically suppressed at study entry versus patients with baseline VL >=50 copies/mL in each ARV-experienced group, while there was no consistent difference across study groups and baseline VL strata according to baseline CD4(+) cell count. CD4(+) cell count increased from study entry to last study visit in all the four groups. DRV/r was well tolerated, with few discontinuations due to study-emergent nonfatal adverse events (3.0% overall, including 2.1% drug-related) or deaths (3.0% overall, all non-drug-related); 35.3% of patients reported >=1 adverse events. These observational data show that DRV/r was effective and well tolerated in the whole patient population described here. The DRV/r-containing regimen provided viral suppression in a high percentage of patients in all groups, with low rates of discontinuation due to virological failure. PMID- 27226710 TI - The effect of knowledge and expectations on adherence to and persistence with antidepressants. AB - PURPOSE: Adherence to and persistence with antidepressants are often suboptimal. However, little is known about how patient knowledge and outcome expectations may influence antidepressant adherence and persistence. METHOD: Individuals who had been prescribed their first antidepressant to treat depression in the preceding 6 months were recruited to an online survey via Facebook. Knowledge, education received, and initial outcome expectations were analyzed for associations with persistence and adherence. RESULTS: Two hundred and twenty surveys were analyzed. A total of 117 participants had taken their antidepressant for at least 3 months; another 25 had never started or stopped after <3 months without consulting their doctor. Differences in expectations and various educational messages among persistent and nonpersistent participants were identified. Having received the instruction "don't stop it without checking with your doctor" was a significant independent predictor of persistence (odds ratio [OR] =5.9, 95% confidence interval [CI] =1.4-24.5). At the time of the survey, 82.7% of participants were taking an antidepressant and 77.9% were adherent. Significant independent predictors of adherence were a greater age (OR =1.1, 95% CI =1.0-1.2), knowledge (OR =1.6, 95% CI =1.1-2.3), being informed of common side effects (OR =5.5, 95% CI =1.1-29.0), and having discussed ways to solve problems (OR =3.9, 95% CI =1.1 14.5). CONCLUSION: Improving outcome expectations and particular educational messages may increase adherence and persistence. Greater knowledge may enhance adherence. Further investigation is warranted to determine whether a focus on these simple educational messages will improve outcomes in patients who commence an antidepressant. PMID- 27226709 TI - Pharmacoinformatic and molecular docking studies reveal potential novel antidepressants against neurodegenerative disorders by targeting HSPB8. AB - Charcot-Marie-Tooth (CMT) disease is an inherited peripheral neuromuscular disorder characterized by length-dependent and progressive degeneration of peripheral nerves, leading to muscular weakness. Research has shown that mutated HSPB8 may be responsible for depression, neurodegenerative disorders, and improper functioning of peripheral nerves, resulting in neuromuscular disorders like CMT. In the current work, a hybrid approach of virtual screening and molecular docking studies was followed by homology modeling and pharmacophore identification. Detailed screening analyses were carried out by 2-D similarity search against prescribed antidepressant drugs with physicochemical properties. LigandScout was employed to ascertain novel molecules and pharmacophore properties. In this study, we report three novel compounds that showed maximum binding affinity with HSPB8. Docking analysis elucidated that Met37, Ser57, Ser58, Trp60, Thr63, Thr114, Lys115, Asp116, Gly117, Val152, Val154, Leu186, Asp189, Ser190, Gln191, and Glu192 are critical residues for ligand-receptor interactions. Our analyses suggested paroxetine as a potent compound for targeting HSPB8. Selected compounds have more effective energy scores than the selected drug analogs. Additionally, site-directed mutagenesis could be significant for further analysis of the binding pocket. The novel findings based on an in silico approach may be momentous for potent drug design against depression and CMT. PMID- 27226711 TI - Quantitative computed tomography measurements of emphysema for diagnosing asthma chronic obstructive pulmonary disease overlap syndrome. AB - BACKGROUND: The diagnostic criteria of asthma-COPD overlap syndrome (ACOS) are controversial. Emphysema is characteristic of COPD and usually does not exist in typical asthma patients. Emphysema in patients with asthma suggests the coexistence of COPD. Quantitative computed tomography (CT) allows repeated evaluation of emphysema noninvasively. We investigated the value of quantitative CT measurements of emphysema in the diagnosis of ACOS. METHODS: This study included 404 participants; 151 asthma patients, 125 COPD patients, and 128 normal control subjects. All the participants underwent pulmonary function tests and a high-resolution CT scan. Emphysema measurements were taken with an Airway Inspector software. The asthma patients were divided into high and low emphysema index (EI) groups based on the percentage of low attenuation areas less than -950 Hounsfield units. The characteristics of asthma patients with high EI were compared with those having low EI or COPD. RESULTS: The normal value of percentage of low attenuation areas less than -950 Hounsfield units in Chinese aged >40 years was 2.79%+/-2.37%. COPD patients indicated more severe emphysema and more upper-zone-predominant distribution of emphysema than asthma patients or controls. Thirty-two (21.2%) of the 151 asthma patients had high EI. Compared with asthma patients with low EI, those with high EI were significantly older, more likely to be male, had more pack-years of smoking, had more upper-zone predominant distribution of emphysema, and had greater airflow limitation. There were no significant differences in sex ratios, pack-years of smoking, airflow limitation, or emphysema distribution between asthma patients with high EI and COPD patients. A greater number of acute exacerbations were seen in asthma patients with high EI compared with those with low EI or COPD. CONCLUSION: Asthma patients with high EI fulfill the features of ACOS, as described in the Global Initiative for Asthma and Global Initiative for Chronic Obstructive Lung Disease guidelines. Quantitative CT measurements of emphysema may help in diagnosing ACOS. PMID- 27226712 TI - Preparation of catechin extracts and nanoemulsions from green tea leaf waste and their inhibition effect on prostate cancer cell PC-3. AB - Green tea is one of the most commonly consumed natural health beverages in Taiwan's market, with the major functional component catechin being shown to possess several biological activities such as antioxidation, anticancer, and prevention of cardiovascular disease. The objectives of this study were to develop a high-performance liquid chromatography-mass spectrometry method to determine the variety and content of catechins in green tea leaf waste, a by product obtained during processing of tea beverage. In addition, catechin nanoemulsion was prepared to study its inhibition effect on prostate cancer cell PC-3. Results showed that a total of eight catechin standards were separated within 25 minutes by using a Gemini C18 column and a gradient mobile phase of 0.1% formic acid (A) and acetonitrile (B) with flow rate at 1 mL/min, column temperature at 30 degrees C, and detection wavelength at 280 nm. Among various extraction solvents, 50% ethanol generated the highest yield of total catechins from tea leaf waste, of which five catechins were identified and quantified. The catechin nanoemulsion was composed of catechin extract, lecithin, Tween 80, and deionized water in an appropriate proportion, with the mean particle size being 11.45 nm, encapsulation efficiency 88.1%, and zeta potential -66.3 mV. A high stability of catechin nanoemulsion was shown over a storage period of 120 days at 4 degrees C. Both catechin extract and nanoemulsion could inhibit growth of PC-3 tumor cells, with the half maximal inhibitory concentration being 15.4 MUg/mL and 8.5 MUg/mL, respectively. The PC-3 cell cycle was arrested at S phase through elevation of P27 expression and decline of cyclin A, cyclin B, cyclin-dependent kinase 2, and cyclin-dependent kinase 1 expression. In addition, both catechin extract and nanoemulsion could induce apoptosis of PC-3 cells through decrease in B-cell lymphoma 2 (bcl-2) expression and increase in cytochrome c expression for activation of caspase-3, caspase-8, and caspase-9. Taken together, both caspase dependent and caspase-independent pathways may be involved in apoptosis of PC-3 cells. PMID- 27226714 TI - Synergistic inhibition of colon cancer cell growth with nanoemulsion-loaded paclitaxel and PI3K/mTOR dual inhibitor BEZ235 through apoptosis. AB - Colon cancer is the third most common cancer in the world, with drug resistance and metastasis being the major challenges to effective treatments. To overcome this, combination therapy with different chemotherapeutics is a common practice. In this study, we demonstrated that paclitaxel (PTX) together with BEZ235 exhibited a synergetic inhibition effect on colon cancer cell growth. Furthermore, nanoemulsion (NE)-loaded PTX and BEZ235 were more effective than the free drug, and a combination treatment of both NE drugs increased the efficiency of the treatments. BEZ235 pretreatment before adding PTX sensitized the cancer cells further, suggesting a synergistic inhibition effect through the phosphatidylinositol-3-kinases/protein kinase B/mammalian target of rapamycin pathway. The 50% inhibitory concentrations for BEZ235 were 127.1 nM and 145.0 nM and for PTX 9.7 nM and 9.5 nM for HCT-116 and HT-29 cells, respectively. When loaded with NE the 50% inhibitory concentrations for BEZ235 decreased to 52.6 nM and 55.6 nM and for PTX to 1.9 nM and 2.3 nM for HCT-116 and HT-29 cells, respectively. Combination treatment with 10 nM NE-BEZ235 and 0.6 nM and 1.78 nM NE-PTX could kill 50% of HCT-116 and HT-29, respectively. The cell death caused by the treatment was through apoptotic cell death, which coincided with decreased expression of anti-apoptotic protein B-cell lymphoma 2. Our data indicate that the combination therapy of PTX with the phosphatidylinositol-3-kinases/protein kinase B/mammalian target of rapamycin dual inhibitor BEZ235 using NE delivery may hold promise for a more effective approach for colon cancer treatment. PMID- 27226715 TI - Guanfacine extended release for children and adolescents with attention deficit/hyperactivity disorder: efficacy following prior methylphenidate treatment. AB - Guanfacine extended release (GXR) and atomoxetine (ATX) are nonstimulant treatments for attention-deficit/hyperactivity disorder (ADHD). As nonstimulant treatments are often used after stimulants in ADHD, GXR was assessed relative to prior stimulant treatment in a randomized controlled trial (RCT), in which ATX was included as a reference arm, and in the open-label phase of a randomized withdrawal study (RWS). Participants were 6-17 years old with ADHD Rating Scale version IV (ADHD-RS-IV) scores >=32 and Clinical Global Impressions - Severity scores >=4. RCT participants received dose-optimized GXR (1-7 mg/day), ATX (10 100 mg/day), or placebo for 10-13 weeks. RWS participants received dose-optimized GXR (1-7 mg/day) for 13 weeks. Participants' last stimulant medication prior to enrolment, and reasons for stopping this medication, were collected at baseline. Change from baseline ADHD-RS-IV score and the proportion of responders were assessed by prior stimulant exposure. Of 163 RCT and 296 RWS participants who had previously received stimulant treatment, 142 and 224, respectively, had received methylphenidate (MPH); due to the low number of participants and the heterogeneity of non-MPH treatments, we only report data for prior MPH treatment. The most frequent reasons for stopping MPH were lack of effectiveness or side effects. Placebo-adjusted ADHD-RS-IV changes from baseline were significant in participants receiving GXR (prior MPH, -9.8, P<0.001, effect size [ES] 0.85; stimulant-naive, -7.6, P<0.001, ES 0.65). In ATX-treated participants, significant placebo-adjusted differences were seen in stimulant-naive (-5.0, P=0.022, ES 0.43) but not prior MPH-treated (-1.8, P>0.05, ES 0.15) participants. More participants met responder criteria with GXR versus placebo, regardless of prior treatment. GXR response was unaffected by prior stimulant treatment; ATX produced improvement only in stimulant-naive participants relative to placebo. These findings may be relevant to clinical decision-making regarding sequencing of ADHD treatments. PMID- 27226713 TI - Synthesis, toxicity, biocompatibility, and biomedical applications of graphene and graphene-related materials. AB - Graphene is a two-dimensional atomic crystal, and since its development it has been applied in many novel ways in both research and industry. Graphene possesses unique properties, and it has been used in many applications including sensors, batteries, fuel cells, supercapacitors, transistors, components of high-strength machinery, and display screens in mobile devices. In the past decade, the biomedical applications of graphene have attracted much interest. Graphene has been reported to have antibacterial, antiplatelet, and anticancer activities. Several salient features of graphene make it a potential candidate for biological and biomedical applications. The synthesis, toxicity, biocompatibility, and biomedical applications of graphene are fundamental issues that require thorough investigation in any kind of applications related to human welfare. Therefore, this review addresses the various methods available for the synthesis of graphene, with special reference to biological synthesis, and highlights the biological applications of graphene with a focus on cancer therapy, drug delivery, bio-imaging, and tissue engineering, together with a brief discussion of the challenges and future perspectives of graphene. We hope to provide a comprehensive review of the latest progress in research on graphene, from synthesis to applications. PMID- 27226716 TI - Cognitive deficits in patients with obsessive-compulsive disorder - electroencephalography correlates. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) is associated with cognitive dysfunction. Although there are several studies focused on the neurobiology of OCD, little is known about the biological correlates of the cognitive deficit linked to this disorder. The aim of our study was to examine the association between cognitive impairment and current source density markers in patients with OCD. METHODS: Resting-state eyes-closed electroencephalography (EEG) data were recorded in 20 patients with OCD and 15 healthy controls who were involved in the study. Cortical EEG sources were estimated by standardized low-resolution electromagnetic tomography in seven frequency bands: delta (1.5-6 Hz), theta (6.5 8 Hz), alpha-1 (8.5-10 Hz), alpha-2 (10.5-12 Hz), beta-1 (12.5-18 Hz), beta-2 (18.5-21 Hz), and beta-3 (21.5-30 Hz). Cognitive performance was measured by the Trail-Making Test (versions A and B), Stroop CW Test, and D2 Test. RESULTS: Frontal delta and theta EEG sources showed significantly higher activity in the whole group of patients with OCD (N=20) than in control subjects (N=15). Subsequent analysis revealed that this excess of low-frequency activity was present only in the subgroup of eleven patients with cognitive impairment (based on the performance in the Trail-Making Test - A). The subgroup of patients with normal cognitive functions (N=9) did not differ in cortical EEG sources from healthy controls. CONCLUSION: The present results suggest that frontal low frequency cortical sources of resting-state EEG rhythms can distinguish groups of cognitively impaired and cognitively intact patients with OCD. Based on our results, future studies should consider whether the present methodological approach provides clinically useful information for the revelation of cognitive impairment in patients with OCD. PMID- 27226717 TI - Possible sertraline-induced extrapyramidal adverse effects in an adolescent. AB - Sertraline has been considered to be a relatively safe selective serotonin reuptake inhibitor for adolescents for a long time. We report herein a case of a 16-year-old Chinese boy with depression who experienced extrapyramidal-like effects, for example, facial spasm, upper limb dystonia, akathisia, and other disturbed behaviors, while being treated with sertraline 200 mg per day. His movement symptoms were significantly alleviated after the discontinuation of sertraline and the administration of scopolamine. This finding indicates that albeit infrequent, sertraline may cause severe extrapyramidal symptoms in adolescent patients, suggesting that clinicians should be alert to the neurological side effects of sertraline in young patients. PMID- 27226719 TI - Quality of Life in Patients with Substance Use Disorders Admitted to Detoxification Compared with Those Admitted to Hospitals for Medical Disorders: Follow-Up Results. AB - Quality of life (QoL) in patients admitted to a general hospital was compared with those admitted to a detoxification unit for the treatment of substance use disorder (SUD). This study combines data from two separate data collections: a cross-sectional study in a general hospital unit (somatic sample, N = 519) and a follow-up study in a detoxification unit (SUD sample, N = 140). A total of 659 patients recruited during 2008-2013 were included in this study. All patients completed a generic QoL questionnaire at inclusion, and the SUD sample also completed it at the six-month follow-up. SUD patients experienced comparably low physical QoL and had significantly lower psychological, social, and existential QoL domain scores when compared with the somatic sample. Mental distress and having a SUD were the major factors explaining variations in QoL, with both influencing QoL negatively. In the SUD sample, QoL improved moderately at the six month follow-up with less improvement for the domain relationship to a partner. To facilitate the recovery of SUD patients, clinicians must view their patients' situation holistically and invest efforts into the different life domains affected by poor QoL. PMID- 27226718 TI - Triglyceride-rich lipoproteins as a causal factor for cardiovascular disease. AB - Approximately 25% of US adults are estimated to have hypertriglyceridemia (triglyceride [TG] level >=150 mg/dL [>=1.7 mmol/L]). Elevated TG levels are associated with increased cardiovascular disease (CVD) risk, and severe hypertriglyceridemia (TG levels >=500 mg/dL [>=5.6 mmol/L]) is a well-established risk factor for acute pancreatitis. Plasma TG levels correspond to the sum of the TG content in TG-rich lipoproteins (TRLs; ie, very low-density lipoproteins plus chylomicrons) and their remnants. There remains some uncertainty regarding the direct causal role of TRLs in the progression of atherosclerosis and CVD, with cardiovascular outcome studies of TG-lowering agents, to date, having produced inconsistent results. Although low-density lipoprotein cholesterol (LDL-C) remains the primary treatment target to reduce CVD risk, a number of large-scale epidemiological studies have shown that elevated TG levels are independently associated with increased incidence of cardiovascular events, even in patients treated effectively with statins. Genetic studies have further clarified the causal association between TRLs and CVD. Variants in several key genes involved in TRL metabolism are strongly associated with CVD risk, with the strength of a variant's effect on TG levels correlating with the magnitude of the variant's effect on CVD. TRLs are thought to contribute to the progression of atherosclerosis and CVD via a number of direct and indirect mechanisms. They directly contribute to intimal cholesterol deposition and are also involved in the activation and enhancement of several proinflammatory, proapoptotic, and procoagulant pathways. Evidence suggests that non-high-density lipoprotein cholesterol, the sum of the total cholesterol carried by atherogenic lipoproteins (including LDL, TRL, and TRL remnants), provides a better indication of CVD risk than LDL-C, particularly in patients with hypertriglyceridemia. This article aims to provide an overview of the available epidemiological, clinical, and genetic evidence relating to the atherogenicity of TRLs and their role in the progression of CVD. PMID- 27226720 TI - A Retrospective Study Evaluating the Impact of Preoperative Breast MRI on Surgical Decision-Making in Young Patients (<=50 Years) with Invasive Breast Cancer. AB - INTRODUCTION: Breast magnetic resonance imaging (MRI) is considered a more sensitive diagnostic test for detecting invasive breast cancer than mammography or breast ultrasound. Breast MRI may be particularly useful in younger premenopausal women with higher density breast tissue for differentiating between dense fibroglandular breast tissue and breast malignancies. The main objective of this study was to determine the impact of preoperative breast MRI on surgical decision-making in young women with breast cancer. METHODS: A retrospective review of patients with newly diagnosed invasive breast cancer and age of <=50 years was performed. All patients underwent physical examination, preoperative mammogram, breast ultrasound, and bilateral breast MRI. Two breast cancer surgeons reviewed the preoperative mammogram report, breast ultrasound report, and physical examination summary and were asked if they would recommend a lumpectomy, a quandrantectomy, or a mastectomy. A few weeks later, the two surgeons were shown the same information with the breast MRI report and were asked what type of surgery they would now recommend. In each case, MRI was classified by two adjudicators as having affected the surgical outcome in a positive, negative, or neutral fashion. A positive impact was defined as the situation where breast MRI detected additional disease that was not found on physical examination, mammogram, or breast ultrasound and led to an appropriate change in surgical management. A negative impact was defined as the situation where breast MRI led the surgeon to recommend more extensive surgery, with less extensive disease actually found at pathology. No impact was defined as the situation where MRI findings did not alter surgical recommendations or outcomes. RESULTS: Of 37 patients whose charts were reviewed, five patients were deemed to be ineligible due to having received neoadjuvant chemotherapy, having previous breast implants, or having had their tumor fully excised during biopsy. In total, 32 patients met the inclusion criteria of this study and were appropriate for analysis. The median age of our study patient population was 42 years. The pathologic diagnosis was invasive ductal carcinoma in 91% (29/32) of patients and invasive lobular carcinoma in 9% (3/32) of patients. For surgeon A, clinical management was altered in 21/32 (66%) patients, and for surgeon B, management was altered in 13/32 (41%) patients. The most common change in surgical decision making after breast MRI was from breast-conserving surgery to a mastectomy. Mastectomy rates were similar between both surgeons after breast MRI. After reviewing the pathology results and comparing them with the breast MRI results, it was determined that breast MRI led to a positive outcome in 13/32 (41%) patients. Breast MRI led to no change in surgical management in 15/32 (47%) patients and resulted in a negative change in surgical management in 4/32 (13%) patients. Bilateral breast MRI detected a contralateral breast cancer in 2/32 (6%) patients. CONCLUSIONS: Preoperative breast MRI alters surgical management in a significant proportion of younger women diagnosed with breast cancer. Prospective studies are needed to confirm these findings and to help determine if this change in surgical decision-making will result in improved local control. PMID- 27226721 TI - Opportunities to maximize value with integrated palliative care. AB - Palliative care involves aggressively addressing and treating psychosocial, spiritual, religious, and family concerns, as well as considering the overall psychosocial structures supporting a patient. The concept of integrated palliative care removes the either/or decision a patient needs to make: they need not decide if they want either aggressive chemotherapy from their oncologist or symptom-guided palliative care but rather they can be comanaged by several clinicians, including a palliative care clinician, to maximize the benefit to them. One common misconception about palliative care, and supportive care in general, is that it amounts to "doing nothing" or "giving up" on aggressive treatments for patients. Rather, palliative care involves very aggressive care, targeted at patient symptoms, quality-of-life, psychosocial needs, family needs, and others. Integrating palliative care into the care plan for individuals with advanced diseases does not necessarily imply that a patient must forego other treatment options, including those aimed at a cure, prolonging of life, or palliation. Implementing interventions to understand patient preferences and to ensure those preferences are addressed, including preferences related to palliative and supportive care, is vital in improving the patient-centeredness and value of surgical care. Given our aging population and the disproportionate cost of end-of-life care, this holds great hope in bending the cost curve of health care spending, ensuring patient-centeredness, and improving quality and value of care. Level 1 evidence supports this model, and it has been achieved in several settings; the next necessary step is to disseminate such models more broadly. PMID- 27226722 TI - Effects of Various Kynurenine Metabolites on Respiratory Parameters of Rat Brain, Liver and Heart Mitochondria. AB - Previously, we demonstrated that the endogenous glutamate receptor antagonist kynurenic acid dose-dependently and significantly affected rat heart mitochondria. Now we have investigated the effects of L-tryptophan, L-kynurenine, 3-hydroxykynurenine and kynurenic, anthranilic, 3-hydroxyanthranilic, xanthurenic and quinolinic acids on respiratory parameters (ie, state 2, state 3), respiratory control index (RC) and ADP/oxygen ratio in brain, liver and heart mitochondria of adult rats. Mitochondria were incubated with glutamate/malate (5 mM) or succinate (10 mM) and in the presence of L-tryptophan metabolites (1 mM) or in the absence, as control. Kynurenic and anthranilic acids significantly reduced RC values of heart mitochondria in the presence of glutamate/malate. Xanthurenic acid significantly reduced RC values of brain mitochondria in the presence of glutamate/malate. Furthermore, 3-hydroxykynurenine and 3 hydroxyanthranilic acid decreased RC values of brain, liver and heart mitochondria using glutamate/malate. In the presence of succinate, 3 hydroxykynurenine and 3-hydroxyanthranilic acid affected RC values of brain mitochondria, whereas in liver and heart mitochondria only 3-hydroxykynurenine lowered RC values significantly. Furthermore, lowered ADP/oxygen ratios were observed in brain mitochondria in the presence of succinate with 3 hydroxykynurenine and 3-hydroxyanthranilic acid, and to a lesser extent with glutamate/malate. In addition, 3-hydroxyanthranilic acid significantly lowered the ADP/oxygen ratio in heart mitochondria exposed to glutamate/malate, while in the liver mitochondria only a mild reduction was found. Tests of the influence of L-tryptophan and its metabolites on complex I in liver mitochondria showed that only 3-hydroxykynurenine, 3-hydroxyanthranilic acid and L-kynurenine led to a significant acceleration of NADH-driven complex I activities. The data indicate that L-tryptophan metabolites had different effects on brain, liver and heart mitochondria. Alterations of L-tryptophan metabolism might have an impact on the bioenergetic activities of brain, liver and/or heart mitochondria and might be involved in the development of clinical symptoms such as cardiomyopathy, hepatopathy and dementia. PMID- 27226724 TI - Upregulation of nucleostemin in colorectal cancer and its effects on cell malignancy [Retraction]. AB - [This retracts the article on p. 1805 in vol. 8, PMID: 26229488.]. PMID- 27226723 TI - Tissue microRNA-21 expression predicted recurrence and poor survival in patients with colorectal cancer - a meta-analysis. AB - OBJECTIVE: MicroRNA-21 (miR-21) has been shown to play an important role in cancer prognosis. We performed a meta-analysis to evaluate the prognostic effect of miR-21 from tissues and serum on survival of the patients with colorectal cancer (CRC). METHODS: Relevant studies were identified by searching PubMed, Embase, and Cochrane Library. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) of total and subgroup analyses, for overall survival (OS) and disease-free survival (DFS), were calculated to investigate the association between miR-21 expression and CRC prognosis. RESULTS: Our analysis included eleven studies (3,669 subjects). In addition, four studies explored the association between miR-21 and DFS, and ten studies focused on the prognostic value of miR-21 for OS. Our results indicated that increased miR-21 expression of tissues predicted both poor DFS and OS in patients with CRC (DFS: HR =1.59, 95% CI =1.20-2.10; OS: HR =1.53, 95% CI =1.23-1.90). Consistent results were observed among colon cancer and quantitative real-time polymerase chain reaction subgroups. CONCLUSION: Meta-analysis indicated that miR-21 predicted recurrence and poor survival in patients with CRC. miR-21 may be more suitable to predict cancer prognosis in colon cancer patients. PMID- 27226725 TI - Oncolytic viruses as immunotherapy: progress and remaining challenges. AB - Oncolytic viruses (OVs) comprise an emerging cancer therapeutic modality whose activity involves both direct tumor cell lysis and the induction of immunogenic cell death (ICD). Cellular proteins released from the OV-lysed tumor cells, known as damage-associated molecular patterns and tumor-associated antigens, activate dendritic cells and elicit adaptive antitumor immunity. Interaction with the innate immune system and the development of long-lasting immune memory also contribute to OV-induced cell death. The degree to which the ICD component contributes to the clinical efficacy of OV therapy is still unclear. Modulation of a range of immune interactions may be beneficial or detrimental in nature and the interactions depend on the specific tumor, the site and extent of the disease, the immunosuppressive tumor microenvironment, the OV platform, the dose, time, and delivery conditions, as well as individual patient responses. To enhance the contribution of ICD, OVs have been engineered to express immunostimulatory genes and strategies have been developed to combine OV therapy with chemo- and immune-based therapeutic regimens. However, these approaches carry the risk that they may also be tolerogenic depending on their levels and the presence of other cytokines, their direct antiviral effects, and the timing and conditions of their expression. The contribution of autophagy to adaptive immunity, the ability of the OVs to kill cancer stem cells, and the patient's baseline immune status are additional considerations. This review focuses on the complex and as yet poorly understood balancing act that dictates the outcome of OV therapy. We summarize current understanding of the OVs' function in eliciting antitumor immunity and its relationship to therapeutic efficacy. Also discussed are the criteria involved in restraining antiviral immune responses and minimizing pathology while promoting antitumor immunity to override immune tolerance. PMID- 27226726 TI - miR-125b inhibited epithelial-mesenchymal transition of triple-negative breast cancer by targeting MAP2K7. AB - MicroRNAs (miRNAs) play important roles in diverse biological processes and are emerging as key regulators of tumorigenesis and tumor progression. Among the differentially expressed miRNAs in breast cancer, miR-125b was revealed to be deregulated and associated with poor prognosis and chemoresistance in triple negative breast cancer (TNBC), but the mechanism is still unknown. In our study, we showed downregulated expression of miR-125b in TNBC tissues and decreased migration and invasion in miR-125b-expressing Hs578T cells. MAP2K7 was then detected to be a novel target of miR-125b, and downregulation of MAP2K7 by miR 125b was similar to transient knockdown of MAP2K7 which hindered epithelial mesenchymal transition (EMT) of Hs578T cells. Upregulation of MAP2K7 in miR-125b overexpressing Hs578T cells partly rescued the migration and invasion suppression of miR-125b. Furthermore, MAP2K7 was overexpressed in TNBC samples compared with normal tissues and negatively correlated with miR-125b expression. In light of these findings, miR-125b emerged as a tumor suppressor in TNBC by targeting MAP2K7 to inhibit EMT. PMID- 27226727 TI - Prognostic significance of PD-L1 expression in patients with gastric cancer in East Asia: a meta-analysis. AB - The overexpression of programmed cell death-ligand 1(PD-L1) has been observed in gastric cancer (GC). However, whether the expression of PD-L1 in tumor cells or blood serum is associated with the prognosis of patients with GC remains unclear. Therefore, we performed a meta-analysis to evaluate the prognostic significance of PD-L1 expression in GC. Electronic databases were searched systematically. Studies that met the inclusion criteria were included in the meta-analysis. Data concerning the hazard ratio (HR) for overall survival and disease-free survival with a 95% confidence interval (CI) according to the expression status of PD-L1 evaluated by immunohistochemistry or enzyme-linked immunosorbent assay were extracted. The data were analyzed using a random effects model. Subgroup analyses were proposed. Our results showed that eight studies with 950 patients met the inclusion criteria and were included in the meta-analysis. The pooled HR for overall survival indicated that patients with PD-L1-positive expression had significantly shorter survival time compared with the PD-L1-negative group (HR 1.60, 95% CI 1.09-2.36, P=0.012). The pooled HR for disease-free survival demonstrated that the difference between the two groups was not statistically significant (HR 1.02, 95% CI 0.32-3.20, P=0.98). In conclusion, our results indicate that the evaluation of PD-L1 overexpression in GC tissue or blood serum may be useful in the future as a novel prognostic factor. PMID- 27226728 TI - Emerging treatment options for myelofibrosis: focus on pacritinib. AB - Myelofibrosis (MF) is a myeloid malignancy associated with a heavy symptomatic burden that decreases quality of life and presents a risk for leukemic transformation. While there are limited curative treatments, the recent discovery of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway dysregulation has led to many clinical investigations for new treatment approaches. This review provides practical knowledge on the disease state, an overview of treatment options, and specifically focuses on the efficacy and safety of pacritinib in the management of MF. Pacritinib is a novel selective inhibitor of JAK2 and FMS-related tyrosine kinase 3 (FLT3) currently in Phase III trials for the treatment of MF. Thus far, studies have demonstrated clinical efficacy in reducing splenomegaly and constitutional symptoms. Common adverse events were gastrointestinal in nature, while hematologic toxicity was limited. However, it was announced that all ongoing clinical trials on pacritinib have been placed on hold by the US Food and Drug Administration in February 2016, due to concerns for increased intracranial hemorrhage and cardiac events. With comprehensive risk-benefit analysis of clinical trial data, the utility of pacritinib in the management of MF may be more clearly defined. PMID- 27226729 TI - Serum microRNA-199a/b-3p as a predictive biomarker for treatment response in patients with hepatocellular carcinoma undergoing transarterial chemoembolization. AB - OBJECTIVE: The aim of this study was to investigate whether the level of serum microRNA-199a/b-3p (miR-199a/b-3p) can serve as a predictor of treatment response to transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). METHODS: Serum miR-199a/b-3p expression level was measured in 132 patients with HCC before TACE (t1) and 3-5 days after TACE (t2). Additionally, 126 patients of these 132 patients had levels measured 4 weeks after TACE (t3) and 3-5 days after second TACE (t4). Serum miR-199a/b-3p expression levels were compared with those of 50 healthy controls. Correlations between miR-199a/b-3p expression levels and clinicopathologic factors and tumor responsiveness were analyzed. The modified Response Evaluation Criteria in Solid Tumors assessment was conducted at t3. RESULTS: A lower mean baseline miR-199a/b 3p expression level was observed in patients with HCC compared with healthy controls (0.68+/-0.81 vs 2.50+/-2.16, P<0.001). A negative correlation between baseline miR-199a/b-3p expression levels and tumor size (P<0.001) was observed. The nonresponder group had significantly lower miR-199a/b-3p expression levels than the responder group at t1 (0.77+/-1.09 vs 1.96+/-1.32, P<0.001). In addition, the decrease in miR-199a/b-3p at t2 was greater in the responder group than in the nonresponder group (P=0.011). A higher proportion of the responder group achieved a >25% decrease in serum miR-199a/b-3p expression levels compared with the nonresponder group (64% vs 39%). CONCLUSION: Serum miR-199a/b-3p may represent a novel biomarker for predicting efficacy of TACE in patients with HCC. PMID- 27226730 TI - Shorter telomere length of T-cells in peripheral blood of patients with lung cancer. AB - PURPOSE: Telomere shortening occurs in tumor tissues and peripheral blood lymphocytes of many common human malignancies, including lung cancer, but its variation in T-cells has never been investigated. Thus, the aim of this study was to assess telomere length in T-cells and its correlation with the clinical characteristics of patients with lung cancer. PATIENTS AND METHODS: A total of 40 patients with lung cancer but without prior cancer history and 25 healthy individuals were selected. T-cells were isolated and their telomere lengths were measured using quantitative real-time polymerase chain reaction methods. RESULTS: Telomere length in T-cells was significantly shorter in patients with lung cancer than in controls (P<0.001). Shorter telomere length was significantly associated with increased clinical stage (P=0.008) and distant metastasis (P=0.028). Naive T cells from patients with lung cancer had significantly decreased telomere length when compared with those from controls (P=0.012). CONCLUSION: The shortened telomere length in T-cells occurred in naive T-cells and might be related to lung cancer progression. PMID- 27226731 TI - Dabrafenib: a new opportunity for the treatment of BRAF V600-positive melanoma. AB - Prior to 2011, the 1-year survival rates for patients suffering from advanced or metastatic melanoma was as low as 33%, with a median overall survival of about 9 months. Several chemotherapeutic regimens have been applied, either as monochemotherapy or as polychemotherapy, overall not resulting in an improvement of progression-free or overall survival. Novel insights into the epidemiology and biology of melanoma allowed the development of newer therapies. The discovery of mutations in BRAF, a part of the mitogen-activated protein kinase, allowed the development of two BRAF inhibitors, vemurafenib and dabrafenib, which significantly improved the outcome of metastatic melanoma treatment. This article reviews the mechanism of action, efficacy, and safety profile of dabrafenib. An in-depth knowledge of this medication will encourage clinicians to select the appropriate therapeutic strategy for each patient, as well as to prevent or adequately manage side effects, optimizing, thus, the drug's applicability. PMID- 27226732 TI - miR-17-92a-1 cluster host gene (MIR17HG) evaluation and response to neoadjuvant chemoradiotherapy in rectal cancer. AB - Neoadjuvant chemoradiotherapy (NCRT) followed by surgery is the gold standard for the treatment of patients with locally advanced rectal cancer (LARC). However, response is variable, and no predictive markers have been validated. The amplification of 13q31-34 seemed to distinguish between nonresponders and responders to NCRT. The miR-17-92a-1 cluster host gene (MIR17HG), which is involved in the development, progression, and aggressiveness of colorectal cancer, and the ABCC4 gene, an ATP-binding cassette transporter, are located at this region. Moreover, the transcription factor c-Myc is closely related to MIR17HG. The aim of this study was to examine the role of MIR17HG, ABCC4, and CMYC gene copy numbers (CNs) in determining response to NCRT. We analyzed DNA CN of pretherapy biopsies from 108 LARC patients and the expression of microRNA (miR)-17, miR-18a, miR-19a, miR-19b-1, miR-20a, and miR-92a-1 in 34 biopsies. MIR17HG, CMYC, and ABCC4 gene CNs were frequently altered in pretreatment tumors, amplification being the most frequent alteration. With regard to response to therapy, 41% of responders showed MIR17HG deletion, while MIR17HG amplification was observed in 41% of nonresponders. With regard to pathological T stage (ypT), a higher percentage of ypT3-4 than ypT0-2 tumors showed MIR17HG amplification. Finally, a higher, albeit nonsignificant, variability in the expression of MIR17HG cluster members was detected in nonresponders compared to responders. No association was observed between clinical pathological parameters and ABCC4 or CMYC CN. Our data did not highlight a significant association between MIR17HG, CMYC, and ABCC4 gene CNs and response to NCRT in LARC. However, MIR17HG gene amplification would seem to be related to a lack of response. Evaluation of the expression of MIR17HG cluster members is warranted in a larger case series, together with functional studies, to evaluate the potential of this gene as a new predictive marker. PMID- 27226733 TI - A double-blind randomized controlled trial comparing dexamethasone and clonidine as adjuvants to a ropivacaine sciatic popliteal block for foot surgery. AB - BACKGROUND AND AIMS: A popliteal block is effective in managing postoperative pain for foot surgery, but since the duration of analgesia is limited following a single-shot popliteal fossa block technique, methods to prolong effective postoperative analgesia are mandatory. The aim of this study was to assess the effect of adjuvants to ropivacaine on the duration of sensory and motor block. METHODS: In this double-blind randomized placebo-controlled study, we evaluated the analgesic effect of clonidine or dexamethasone (DXM) when added to ropivacaine for hallux valgus surgery. After obtaining institutional ethics research board approval and written informed consent, a total of 72 patients were randomly allocated. Fifty-seven of these patients were statistically analyzed. All patients received an ultrasound-guided single-shot popliteal fossa block with 30 mL of ropivacaine 0.75%, supplemented with saline, clonidine 100 ug, or DXM 5 mg. The primary end point was time to first pain sensation. Secondary end points were time to complete sensory and motor block regression. RESULTS: Compared to saline, duration to first pain sensation was prolonged by 9 hours (mean +/- standard deviation: 31+/-9 hours) (42%) in the DXM group (P=0.024) and by 6 hours (28+/-10 hours) (27%) in the clonidine group (P=0.024). Compared to saline, DXM prolonged both complete sensory and motor blockade by 12 hours (25+/-7 hours) (46%) and 13 hours (36+/-6 hours) (55%), respectively, while clonidine prolonged complete sensory and motor blockade by 7 hours (30+/-7 hours) (27%) and 2 hours (22+/-5 hours) (10%), respectively. DXM prolonged sensory block regression time by 6 hours (21+/-7 hours) (41%) and clonidine by 2 hours (17+/-6 hours) (13%) compared to the control group (P=0.006). Similarly, DXM prolonged motor block regression by 7 hours (25+/-7 hours) (46%) and clonidine by 4 hours (21+/-4 hours) (19%) (P<0.0001). CONCLUSION: Addition of DXM and clonidine to ropivacaine significantly prolonged the duration of postoperative sensory and motor block. PMID- 27226734 TI - The effect of implementing a new guideline and operative pro forma on the detection and management of third- and fourth-degree perineal tears. AB - BACKGROUND: Obstetric anal sphincter injury (OASI) is a serious complication of vaginal births, resulting in possible long-term consequences such as incontinence and pain. Adequate detection and management of these injuries is vital in minimizing the impact they have on women. AIM: To assess the rates of detection, management, and outcomes of OASI before and after the implementation of a new clinical practice guideline and operative pro forma. MATERIALS AND METHODS: A 12 month audit of the incidence, management, and outcomes of OASI was conducted in 2009. An operative pro forma and practice guideline were implemented in 2010 followed by a further audit undertaken between 2010 and 2012. Statistical analysis was performed to determine any significant change in practice. RESULTS: The distribution of risk factors for OASI including primiparity, birthweight, and type of vaginal delivery was similar between the two audited groups. After implementation of the pro forma, the reported incidence of OASI increased from 1.62% to 3.1% (P=0.004). Significant changes in management included an increase in the use of recommended suture material (48% vs 80%, P=0.002), postoperative antibiotics (78% vs 99%, P=0.001), postoperative catheterization (52% vs 90%, P<0.001), and inpatient physiotherapy consultations (44% vs 97%, P=<0.001). An increase was seen in women attending their 6-week follow-up appointment (33% vs 54% P=0.058); however, this was just below the level of statistical significance. CONCLUSION: The introduction of the new pro forma and guideline resulted in an increase in the reported incidence of OASI, improved management, and follow-up of patients. PMID- 27226735 TI - Clinical use and applications of histone deacetylase inhibitors in multiple myeloma. AB - The incorporation of various novel therapies has resulted in a significant survival benefit in newly diagnosed and relapsed patients with multiple myeloma (MM) over the past decade. Despite these advances, resistance to therapy leads to eventual relapse and fatal outcomes in the vast majority of patients. Hence, there is an unmet need for new safe and efficacious therapies for continued improvement in outcomes. Given the role of epigenetic aberrations in the pathogenesis and progression of MM and the success of histone deacetylase inhibitors (HDACi) in other malignancies, many HDACi have been tried in MM. Various preclinical studies helped us to understand the antimyeloma activity of different HDACi in MM as a single agent or in combination with conventional, novel, and immune therapies. The early clinical trials of HDACi depicted only modest single-agent activity, but recent studies have revealed encouraging clinical response rates in combination with other antimyeloma agents, especially proteasome inhibitors. This led to the approval of the combination of panobinostat and bortezomib for the treatment of relapsed/refractory MM patients with two prior lines of treatment by the US Food and Drug Administration. However, it remains yet to be defined how we can incorporate HDACi in the current therapeutic paradigms for MM that will help to achieve longer disease control and significant survival benefits. In addition, isoform-selective and/or class selective HDAC inhibition to reduce unfavorable side effects needs further evaluation. PMID- 27226736 TI - Impact of Concanavalin-A-Mediated Cytoskeleton Disruption on Low-Density Lipoprotein Receptor-Related Protein-1 Internalization and Cell Surface Expression in Glioblastomas. AB - The low-density lipoprotein receptor-related protein 1 (LRP-1) is a multiligand endocytic receptor, which plays a pivotal role in controlling cytoskeleton dynamics during cancer cell migration. Its rapid endocytosis further allows efficient clearance of extracellular ligands. Concanavalin-A (ConA) is a lectin used to trigger in vitro physiological cellular processes, including cytokines secretion, nitric oxide production, and T-lymphocytes activation. Given that ConA exerts part of its effects through cytoskeleton remodeling, we questioned whether it affected LRP-1 expression, intracellular trafficking, and cell surface function in grade IV U87 glioblastoma cells. Using flow cytometry and confocal microscopy, we found that loss of the cell surface 600-kDa mature form of LRP-1 occurs upon ConA treatment. Consequently, internalization of the physiological alpha2-macroglobulin and the synthetic angiopep-2 ligands of LRP-1 was also decreased. Silencing of known mediators of ConA, such as the membrane type-1 matrix metalloproteinase, and the Toll-like receptors (TLR)-2 and TLR-6 was unable to rescue ConA-mediated LRP-1 expression decrease, implying that the loss of LRP-1 was independent of cell surface relayed signaling. The ConA-mediated reduction in LRP-1 expression was emulated by the actin cytoskeleton-disrupting agent cytochalasin-D, but not by the microtubule inhibitor nocodazole, and required both lysosomal- and ubiquitin-proteasome system-mediated degradation. Our study implies that actin cytoskeleton integrity is required for proper LRP-1 cell surface functions and that impaired trafficking leads to specialized compartmentation and degradation. Our data also strengthen the biomarker role of cell surface LRP-1 functions in the vectorized transport of therapeutic angiopep bioconjugates into brain cancer cells. PMID- 27226737 TI - Targeted Radionuclide Therapy: Practical Applications and Future Prospects. AB - In recent years, there has been a proliferation in the development of targeted radionuclide cancer therapy. It is now possible to use baseline clinical and imaging assessments to determine the most effective therapy and to tailor this therapy during the course of treatment based on radiation dosimetry and tumor response. Although this personalized approach to medicine has the advantage of maximizing therapeutic effect while limiting toxicity, it can be challenging to implement and expensive. Further, in order to use targeted radionuclide therapy effectively, there is a need for multidisciplinary awareness, education, and collaboration across the scientific, industrial, and medical communities. Even more important, there is a growing understanding that combining radiopharmaceuticals with conventional treatment such as chemotherapy and external beam radiotherapy may limit patient morbidity while improving survival. Developments in radiopharmaceuticals as biomarkers capable of predicting therapeutic response and targeting disease are playing a central role in medical research. Adoption of a practical approach to manufacturing and delivering radiopharmaceuticals, assessing patient eligibility, optimizing post-therapy follow-up, and addressing reimbursement issues will be essential for their success. PMID- 27226738 TI - Multiple Air Embolism During Coronary Angiography: How Do We Deal With It? AB - Coronary air embolism remains a serious complication of cardiac catheterization despite careful prevention. The complications of coronary air embolism range from clinically insignificant events to acute coronary syndrome, cardiogenic shock, and death. We report here a case of multiple air emboli in both left coronary arteries, complicated by cardiogenic shock and ventricular fibrillation in a 49 year-old male patient undergoing elective percutaneous coronary intervention. The patient recovered after supportive measures, including oxygen, intravenous dopamine infusion, and cardiac compression, and repeated forceful injection of heparinized saline successfully resolved the air emboli. He then eventually underwent successful percutaneous coronary intervention in the left anterior descending artery without any residual stenosis. PMID- 27226739 TI - Clinical and Biochemical Characteristics of Diabetes Ketoacidosis in a Tertiary Hospital in Riyadh. AB - Diabetes is the fifth leading cause of death worldwide. Diabetic ketoacidosis (DKA) is a life-threatening acute complication of diabetes. The aim of this study is to investigate the clinical and biochemical characteristics of DKA among 400 patients admitted to hospital, most of whom had type 1 diabetes (n = 372; 93%). Vomiting (n = 319; 79.8%), nausea (n = 282; 70.5%), and abdominal pain (n = 303; 75.8%) were the presenting symptoms most commonly experienced by the patients. Tachycardia was the most common clinical sign noted in the patients on admission (n = 243; 61.8%). The predominant precipitating cause of DKA was noncompliance to an insulin regimen (n = 215; 54.2%). Recurrent DKA admissions in type 1 diabetes patients was higher than those with type 2 diabetes (n = 232 versus n = 9, respectively; P = 0.002). Recurrent DKA admissions in female patients were higher than in male patients (n = 167 versus n = 74, respectively; P = 0.002). Continued diabetic education (given to n = 384; 94%) and counseling on the importance of adhering to the recommended medical regime, addressing the social and cultural barriers that precipitate DKA, as well as the provision of timely medical attention may greatly reduce DKA episodes and their associated complications. PMID- 27226740 TI - Obstetric, Sociodemographic, and Psychosocial Problems of Postpartum Adolescents of Huambo, Angola. AB - This study aims to establish a profile of teenage pregnancy (<20 years) at a hospital in Huambo, Angola. Subjects were categorized into two age groups, 10-16 and 17-19 years. We interviewed 381 mothers in the postpartum maternity ward of the Central Hospital of Huambo. Statistical analysis then followed two stages, a descriptive analysis of the study population and analysis through a bivariate 2 * 2 table, using a chi-squared test to evaluate the hypothesis of homogeneity of proportions with a significance level of 5%. Comparing the two groups revealed a more frequent occurrence of problems among mothers under 17 years of age, including a higher frequency of involvement with unemployed parents, more often not living with parents, and fewer prenatal consultations. PMID- 27226741 TI - Activity in Pregnancy for Patients with a History of Preterm Birth. AB - Preterm birth remains a leading cause of neonatal morbidity and mortality throughout the world. Numerous risk factors for preterm birth have been identified, including non-Hispanic black race, a variety of social and behavioral factors, infections, and history of a prior preterm delivery. Of these, a history of prior spontaneous preterm birth is one of the strongest risk factors. Traditionally, women with a history of preterm birth or those deemed at high risk for preterm delivery have been placed on bed rest or a reduced activity regimen during their pregnancy. However, there is little evidence to support this recommendation. Recent research has suggested that regular physical activity and exercise during pregnancy is safe and does not increase the risk of preterm delivery. Therefore, physicians should encourage women with a history of preterm birth to exercise throughout pregnancy according to guidelines published by the American College of Obstetricians and Gynecologists as long as they are receiving regular prenatal care and their current health status permits exercise. However, there are no randomized controlled trials evaluating exercise prescription in women with a history of preterm birth, hence additional research is needed in this area. PMID- 27226743 TI - Studies in Hawaiian Diptera III: New Distributional Records for Canacidae and a New Endemic Species of Procanace. AB - The distributions of Hawaiian Canacidae, comprising nearly 800 individual collection events, are reviewed and a total of four new island records are reported. These include Canaceoides angulatus from Kahoolawae and Procanace bifurcata from Molokai and Maui, and Procanace constricta from Oahu. A new species from Kauai, Procanace hardyi O'Grady and Pak, is described. This species is closely related to P. constricta from Oahu, Maui, Molokai and Hawaii and shares a similar constriction of the abdomen between tergites four and five but differs in the configuration of the seventh abdominal tergite. Detailed distribution maps for all species are included. PMID- 27226742 TI - Recent perspectives on the anticancer properties of aqueous extracts of Nigerian Vernonia amygdalina. AB - Innovative developments are necessary for treating and defeating cancer, an oftentimes deadly group of diseases characterized by the uncontrolled growth and spread of abnormal cells. Breast cancer (BC) is the second leading cause of cancer-related deaths of women in the USA, and prostate cancer (PC) is the second leading cause of cancer-related deaths of American men. Although some efficacious BC drugs are pharmaceutically marketed, they affect the quality of life for some patients because they are toxic in that their usages have been accompanied by side effects such as stroke, thrombosis, slow heart rate, seizure, increased blood pressure, nausea, emesis, and more. Therefore, there is an urgent need for the discovery of molecular markers for early detection of this disease and discovery of targets for the development of novel, less toxic therapeutics. A botanical plant Vernonia amygdalina has been widely used in Nigerian and other Central and West African cultures for centuries as an herbal medicine. Mounting evidence suggests that treatment with low concentrations of aqueous leaf extracts of the edible Nigerian V. amygdalina plant (Niger-VA) arrests the proliferative activities and induces apoptosis in estrogen receptor-positive, estrogen receptor negative, and triple-negative human breast cancerous cells and in androgen independent human PC-3. Also, in athymic mice, Niger-VA potentiates increased efficacies and optimizes treatment outcomes when given as a cotreatment with conventional chemotherapy drugs. Evidence of its noticeable cytostatic activities ranging from changes in DNA synthesis to growth inhibition, mechanisms of inducing apoptosis in different cancer cell lines, and in vivo antitumorigenic activities and chemopreventive efficacy reinforce the idea that Niger-VA deserves increased attention for further development as a phytoceutical, anticancer drug entity. Hence, the present review article highlights impactful published literature on the anticancer effects of Niger-VA in multiple cancerous cell lines and in a nude mouse model, supporting its potential usefulness as a natural product, chemotherapeutic medicine for treatment of both BC and PC. PMID- 27226744 TI - Macro-invertebrate Biodiversity of a Coastal Prairie with Vernal Pool Habitat. AB - BACKGROUND: The California Coastal Prairie has the highest biodiversity of North America's grasslands, but also has the highest percentage of urbanization. The most urbanized part of the California Coastal Prairie is its southernmost area, in Los Angeles County. This southernmost region, known as the Los Angeles Coastal Prairie, was historically dotted with vernal pools, and has a unique biodiverse composition. More than 99.5% of its estimated original 95 km(2) (23,475 acres), as well as almost all its vernal pool complexes, have been lost to urbanization. The Madrona Marsh Preserve, in Torrance, California, safeguards approximately 18 hectares (44 acres) of Los Angeles Coastal Prairie and includes a complex of vernal pools. Its aquatic biodiversity had been studied, predominantly to genus level, but its terrestrial macro-invertebrates were virtually unknown, aside from butterfly, dragonfly, and damselfly observations. NEW INFORMATION: In order to better understand the biodiversity at the Madrona Marsh Preserve, a minimally invasive macro-invertebrate inventory was conducted. The results of this inventory, with 689 invertebrate organisms recorded, covering eight phyla, 13 classes, 39 orders, and 222 families, are presented in this document. PMID- 27226745 TI - Two new species of Erythromelana Townsend, 1919 (Diptera: Tachinidae) from Area de Conservacion Guanacaste in northwestern Costa Rica. AB - BACKGROUND: We describe two new species in the genus Erythromelana Townsend, 1919 from Area de Conservacion Guanacaste (ACG) in northwestern Costa Rica. Both species were reared from wild-caughtcaterpillars of Eois spp. (Lepidoptera: Geometridae). We provide a concise description of each species using morphology, life history, molecular data, and photographic documentation. NEW INFORMATION: Erythromelana jimmychevezi Fleming & Wood sp. nov. Erythromelana glenriverai Fleming & Wood sp. nov. PMID- 27226746 TI - Flies from L.A., The Sequel: A further twelve new species of Megaselia (Diptera: Phoridae) from the BioSCAN Project in Los Angeles (California, USA). AB - BACKGROUND: Presented are continued results from the BioSCAN Project, an urban biodiversity study sampling primarily from private backyards in Los Angeles, California (USA). Presented are continued results from the BioSCAN Project, an urban biodiversity study sampling primarily from private backyards in Los Angeles, California (USA). NEW INFORMATION: Twelve new species of Megaselia (Diptera: Phoridae) are described: M. baileyae, M. friedrichae, M. gonzalezorum, M. joanneae, M. losangelensis, M. phyllissunae, M. pongsaiae, M. shatesae, M. stoakesi, M. studentorum, M. voluntariorum, M. wongae. PMID- 27226747 TI - Rediscovery and redescription of Centrodora damoni (Girault) (Hymenoptera: Aphelinidae) from Australia, an egg parasitoid of Gonipterus spp (Coleoptera: Curculionidae), after nearly a century. AB - BACKGROUND: Centrodora is a relatively common and widespread genus of morphologically diverse species, and is the most polyphagous genus known within the Aphelinidae, attacking eggs of insects in addition to pupae of Diptera and Hymenoptera, and nymphs of Hemiptera (Polaszek 1991). There are currently about 60 valid species in the genus, but given its morphological and biological diversity, some elevation of species-groups and subgenera to genus-level might be useful in future. Centrodora is represented in Australia by twelve species (Noyes 2015). NEW INFORMATION: Centrodora damoni (Girault) is redescribed and diagnosed from recently collected specimens reared from the eucalyptus weevil Gonipterus sp. near scutellatus Gyllenhal (Coleoptera: Curculionidae) from Tasmania, Australia. A lectotype is designated from a syntype specimen. PMID- 27226748 TI - A new species of Phosocephala Townsend, 1908 (Diptera: Tachinidae) from Area de Conservacion Guanacaste in northwestern Costa Rica. AB - BACKGROUND: We describe a new species of Phosocephala Townsend, and provide a new collection record, and description of the previously unknown male, of Phosocephala metallica Townsend, from Area de Conservacion Guanacaste (ACG), northwestern Costa Rica. All ACG specimens were reared from wild-caught Lepidoptera larvae (Lepidoptera: Erebidae, Nolidae). We provide a concise description of both species using morphology, life history, molecular data, and photographic documentation. The new species is authored and described by Fleming and Wood. NEW INFORMATION: Phosocephala alexanderi sp. n. PMID- 27226749 TI - Checklist of British and Irish Hymenoptera - Trigonaloidea. AB - BACKGROUND: The British and Irish checklist of Trigonaloidea comprises a single species, Pseudogonalos hahnii(Spinola), which is the only species in Europe. NEW INFORMATION: Country-level distribution and nomenclature of Pseudogonalos hahniiare updated. PMID- 27226750 TI - Checklist of British and Irish Hymenoptera - Proctotrupoidea. AB - BACKGROUND: A revised checklist of the British and Irish Heloridae and Proctotrupidae (Proctotrupoidea) substantially updates the previous comprehensive checklist, dating from 1978. Country level data (i.e. occurrence in England, Scotland, Wales, Ireland and the Isle of Man) is reported where known. NEW INFORMATION: A total of three Heloridae and 39 Proctotrupidae (including only certainly recorded species) represents a 27% increase in the British list since 1978. Most species are still poorly known and there has been a dearth of taxonomic and faunistic work on the British and Irish fauna. PMID- 27226751 TI - A key to the East Palaearctic and Oriental species of the genus Rhysipolis Foerster, and the first host records of Rhysipolis longicaudatus Belokobylskij (Hymenoptera: Braconidae: Rhysipolinae). AB - BACKGROUND: A key to the East Palaearctic and northern Oriental species of Rhysipolis Foerster, 1862 (Hymenoptera: Braconidae: Rhysipolinae) is presented. Rhysipolis longicaudatus Belokobylskij, 1994 (stat. nov.) is redescribed, the first host records are given and it is reported new for China. NEW INFORMATION: Rhysipolis longicaudatus was reared from Taleporia sp. (Lepidoptera: Psychidae) in Inner Mongolia Autonomous Region and from Bazaria turensis Ragonot (Lepidoptera: Pyralidae) in Qinghai Province. PMID- 27226752 TI - Survey of the ants (Hymenoptera: Formicidae) of the Greek Thrace. PMID- 27226753 TI - Capturing biodiversity: linking a cyanobacteria culture collection to the "scratchpads" virtual research environment enhances biodiversity knowledge. AB - BACKGROUND: Currently, cyanobacterial diversity is examined using a polyphasic approach by assessing morphological and molecular data (Komarek 2015). However, the comparison of morphological and genetic data is sometimes hindered by the lack of cultures of several cyanobacterial morphospecies and inadequate morphological data of sequenced strains (Rajaniemi et al. 2005). Furthermore, in order to evaluate the phenotypic plasticity within defined taxa, the variability observed in cultures has to be compared to the range in natural variation (Komarek and Mares 2012). Thus, new tools are needed to aggregate, link and process data in a meaningful way, in order to properly study and understand cyanodiversity. NEW INFORMATION: An online database on cyanobacteria has been created, namely the Cyanobacteria culture collection (CCC) (http://cyanobacteria.myspecies.info/) using as case studies cyanobacterial strains isolated from lakes of Greece, which are part of the AUTH culture collection (School of Biology, Aristotle University of Thessaloniki). The database hosts, for the first time, information and data such as morphology/morphometry, biogeography, phylogeny, microphotographs, distribution maps, toxicology and biochemical traits of the strains. All this data are structured managed, and presented online and are publicly accessible with a recently developed tool, namely "Scratchpads", a taxon-centric virtual research environment allowing browsing the taxonomic classification and retrieving various kinds of relevant information for each taxon. PMID- 27226754 TI - New records of Gerromorpha and Nepomorpha (Insecta: Hemiptera: Heteroptera) from South America. AB - BACKGROUND: Aquatic and semiaquatic Heteroptera occur on all continents except Antarctica and occupy a wide variety of habitats, including lentic and lotic water bodies, perennial or temporary. In the Neotropical Region, there is a lack of knowledge concerning the geographical distribution of most represented species, which can only be solved by the collection of specimens in under-studied areas and publication of new records and lists of species. NEW INFORMATION: New records are presented for eleven species of Gerromorpha and ten Nepomorpha, including first records from Venezuela (Brachymetra lata, Limnogonus hyalinus, Rhagovelia evidis, Tenagobia peruana, Limnocoris burmeisteri, L. fittkaui fittkaui, Placomerus micans, and Martarega gonostyla), the Venezuelan State of Bolivar (Cylindrostethus palmaris, R. elegans, R. tenuipes, and Ambrysus stali), the Brazilian State of Bahia (Martarega bentoi), Peru (Euvelia lata), and the Peruvian Region of Arequipa (Microvelia pulchella). PMID- 27226755 TI - First report of the genus Phytodietus Gravenhorst, 1829 (Hymenoptera: Ichneumonidae: Tryphoninae) from Thailand. AB - BACKGROUND: The genus Phytodietus Gravenhorst, 1829 is a species rich group of ichneumonid parasitoid wasps. It is represented in all zoogeographical regions, but knowledge of Phytodietus species in the Oriental region is patchy and restricted to some countries. NEW INFORMATION: Here the genus Phytodietus is recorded from Thailand for the first time based on three species. Diagnosis and illustrations of P. longicauda (Uchida, 1931), P. pitambari Kaur et Jonathan, 1979 and P. spinipes (Cameron, 1905) are given. Furthermore, known distributional and biological data of the species are summarised and an identification key to the species is provided. PMID- 27226756 TI - Description of a new species of Acrostichus Rahm 1928 (Nematoda: Diplogastridae) from India with a note on its position and relationship with the congeners. AB - BACKGROUND: The clade Diplogastridae Micoletzky 1922 largely represents the bacterivorous or predatory nematodes that very often demonstrate phoretic, necromenic or parasitic associations with insects (Sudhaus and Furst von Lieven 2003). That is the reason, much of the diversity of the family remains undocumented because of their absence from routine soil samples. Due to their variable habitats and niches, these nematodes show ample variation in their stomal armature, feeding behavior and life cycle patterns. NEW INFORMATION: The paper describes and illustrates a new diplogastrid species of genus Acrostichus Rahm 1928 that appears to be the link between the genera Diplogastrellus Paramonov et al. 1952a and Acrostichus. Acrostichus medius n. sp. is characterised by hermaphroditic females and males having faintly striated longitudinal ridges, demarcated lateral fields, amalgamated lips, six adradial cheilostomal plates, moderately-built dorsal tooth, relatively smaller posterior genital branch; large oval uterine pouch and males with robust, heavily cuticularised spicules, each with hood-like capitulum, deeply forked distal end with fine extensions and a ventral attenuated arm; gubernaculum 2/3 of spicule length and rudiments of bursa confined to posterior four pairs of genital papillae. The biogeographical distribution of Acrostichus has been mapped and the relationship between congeners has been analysed cladistically and discussed. PMID- 27226757 TI - Checklist of British and Irish Hymenoptera - aculeates (Apoidea, Chrysidoidea and Vespoidea). AB - BACKGROUND: The checklist of British and Irish aculeate Hymenoptera (Apoidea, Chrysidoidea and Vespoidea) is revised. Species distribution is summarised for all species at the level of country (England, Scotland, Wales, Ireland and Isle of Man). NEW INFORMATION: The 601 native species represent an increase of 25 on the 1978 checklist, comprising mostly new discoveries. This increase is nearly balanced by the 23 species now presumed to be extinct in Britain and Ireland. PMID- 27226758 TI - First record of Phanuropsis laniger Johnson in Brazil and first record of Phanuropsis semiflaviventris Girault in Amazonas (Hymenoptera: Platygastridae) with notes of their hosts, stink-bugs of cupuacu. AB - BACKGROUND: We report the first record and collection of Phanuropsis laniger Johnson, 1987, for Brazil since its original description. In addition we expand the distribution of Phanuropsis semiflaviventris Girault, 1916, for Amazonas, Brazil and present an updated list of records for both species with the occurrence of P. semiflaviventris in egg of stink-bugs on cupuacu (Theobroma grandiflorum). NEW INFORMATION: First record of Phanuropsis laniger Johnson, 1987, for Brazil. We also expanded the distribution of Phanuropsis semiflaviventris Girault, 1916, for the state of Amazonas, Brazil. PMID- 27226759 TI - Checklist of British and Irish Hymenoptera - Braconidae. AB - BACKGROUND: The checklist of British and Irish Braconidae is revised, based in large part on the collections of the National Museums of Scotland, Edinburgh, and the Natural History Museum, London. Distribution records are provided at the country level together with extensive synonymy and bibliography. NEW INFORMATION: Of the 1,338 species regarded as valid, presumed native and certainly identified, 83 are here recorded for the first time from the British Isles. One new synonym is established (Dyscritus suffolciensis Morley, 1933 = Syntretus splendidus (Marshall, 1887) syn. nov.). PMID- 27226760 TI - The Shiny Cowbird, Molothrus bonariensis (Gmelin, 1789) (Aves: Icteridae), at 2,800 m asl in Quito, Ecuador. AB - BACKGROUND: The Shiny Cowbird, Molothrus bonariensis Gmelin, 1789, is a brood parasite of hundreds of small-bodied birds that is native to South American lowlands. Within the last 100 years this species has been expanding its range throughout the Caribbean, towards North America, but has rarely been seen above 2,000 m asl. NEW INFORMATION: Here, we present records of Shiny Cowbirds in Quito, a city located 2,800 m above sea level that harbors a bird community typical of the Andean valleys. We found two juvenile individuals parasitizing two different pairs of Rufous-collared Sparrow (Zonotrichia capensis Muller, 1776). This report constitutes an altitudinal range expansion of reproductive populations of ca. 500m, which may have beenprompted by anthropogenic disturbance. PMID- 27226761 TI - Checklist of Serengeti Ecosystem Grasses. AB - We present the first taxonomic checklist of the Poaceae species of the Serengeti, Tanzania. A review of the literature and herbarium specimens recorded 200 species of grasses, in line with similar studies in other parts of East Africa. The checklist is supported by a total of 939 herbarium collections. Full georeferenced collection data is made available alongside a summary checklist in pdf format. More than a quarter of the species are known from a single collection highlighting the need for further research, especially concerning the rare species and their distribution. PMID- 27226762 TI - Are you afraid of the dark? Notes on the psychology of belief in histories of science and the occult. AB - The popular view of the inherent conflict between science and the occult has been rendered obsolete by recent advances in the history of science. Yet, these historiographical revisions have gone unnoticed in the public understanding of science and public education at large. Particularly, reconstructions of the formation of modern psychology and its links to psychical research can show that the standard view of the latter as motivated by metaphysical bias fails to stand up to scrutiny. After highlighting certain basic methodological maxims shared by psychotherapists and historians, I will try to counterbalance simplistic claims of a 'need to believe' as a precondition of scientific open-mindedness regarding the occurrence of parapsychological phenomena by discussing instances revealing a presumably widespread 'will to disbelieve' in the occult. I shall argue that generalized psychological explanations are only helpful in our understanding of history if we apply them in a symmetrical manner. PMID- 27226763 TI - Editorial Current Fungal Genomics. PMID- 27226764 TI - Perspectives in Genomics The Future of Fungi in 'omics, era. PMID- 27226765 TI - Recent Progress on Systems and Synthetic Biology Approaches to Engineer Fungi As Microbial Cell Factories. AB - Filamentous fungi are remarkable organisms naturally specialized in deconstructing plant biomass and this feature has a tremendous potential for biofuel production from renewable sources. The past decades have been marked by a remarkable progress in the genetic engineering of fungi to generate industry compatible strains needed for some biotech applications. In this sense, progress in this field has been marked by the utilization of high-throughput techniques to gain deep understanding of the molecular machinery controlling the physiology of these organisms, starting thus the Systems Biology era of fungi. Additionally, genetic engineering has been extensively applied to modify wellcharacterized promoters in order to construct new expression systems with enhanced performance under the conditions of interest. In this review, we discuss some aspects related to significant progress in the understating and engineering of fungi for biotechnological applications, with special focus on the construction of synthetic promoters and circuits in organisms relevant for industry. Different engineering approaches are shown, and their potential and limitations for the construction of complex synthetic circuits in these organisms are examined. Finally, we discuss the impact of engineered promoter architecture in the single cell behavior of the system, an often-neglected relationship with a tremendous impact in the final performance of the process of interest. We expect to provide here some new directions to drive future research directed to the construction of high-performance, engineered fungal strains working as microbial cell factories. PMID- 27226766 TI - Heat Shock Proteins in Dermatophytes: Current Advances and Perspectives. AB - Heat shock proteins (HSPs) are proteins whose transcription responds rapidly to temperature shifts. They constitute a family of molecular chaperones, involved in the proper folding and stabilisation of proteins under physiological and adverse conditions. HSPs also assist in the protection and recovery of cells exposed to a variety of stressful conditions, including heat. The role of HSPs extends beyond chaperoning proteins, as they also participate in diverse cellular functions, such as the assembly of macromolecular complexes, protein transport and sorting, dissociation of denatured protein aggregates, cell cycle control, and programmed cell death. They are also important antigens from a variety of pathogens, are able to stimulate innate immune cells, and are implicated in acquired immunity. In fungi, HSPs have been implicated in virulence, dimorphic transition, and drug resistance. Some HSPs are potential targets for therapeutic strategies. In this review, we discuss the current understanding of HSPs in dermatophytes, which are a group of keratinophilic fungi responsible for superficial mycoses in humans and animals. Computational analyses were performed to characterise the group of proteins in these dermatophytes, as well as to assess their conservation and to identify DNA-binding domains (5'-nGAAn-3') in the promoter regions of the hsp genes. In addition, the quantification of the transcript levels of few genes in a pacC background helped in the development of an extended model for the regulation of the expression of the hsp genes, which supports the participation of the pH responsive transcriptional regulator PacC in this process. PMID- 27226767 TI - Influence of N-glycans on Expression of Cell Wall Remodeling Related Genes in Paracoccidioides brasiliensis Yeast Cells. AB - Paracoccidioidomycosis is the most prevalent systemic mycosis in Latin America. It is caused by the temperature-dependent dimorphic fungus Paracoccidioides brasiliensis. The P. brasiliensis cell wall is a dynamic outer structure, composed of a network of glycoproteins and polysaccharides, such as chitin, glucan and N-glycosylated proteins. These glycoproteins can interact with the host to affect infection rates, and are known to perform other functions. We inhibited N-linked glycosylation using tunicamycin (TM), and then evaluated the expression of P. brasiliensis genes related to cell wall remodeling. Our results suggest that cell wall synthesis related genes, such as beta-1,3 glucanosyltransferase (PbGEL3), 1,3-beta-D-glucan synthase (PbFKS1), and alpha 1,4-amylase (PbAMY), as well as cell wall degrading related genes, such as N acetyl-beta-D-glucosaminidase (PbNAG1), alpha-1,3-glucanase (PbAGN), and beta-1,3 glucanase (PbBGN1 and PbBGN2), have their expression increased by the N glycosylation inhibition, as detected by qRT-PCR. The observed increases in gene expression levels reveal possible compensatory mechanisms for diminished enzyme activity due to the lack of glycosylation caused by TM. PMID- 27226768 TI - Trichoderma reesei CRE1-mediated Carbon Catabolite Repression in Re-sponse to Sophorose Through RNA Sequencing Analysis. AB - Carbon catabolite repression (CCR) mediated by CRE1 in Trichoderma reesei emerged as a mechanism by which the fungus could adapt to new environments. In the presence of readily available carbon sources such as glucose, the fungus activates this mechanism and inhibits the production of cellulolytic complex enzymes to avoid unnecessary energy expenditure. CCR has been well described for the growth of T. reesei in cellulose and glucose, however, little is known about this process when the carbon source is sophorose, one of the most potent inducers of cellulase production. Thus, we performed high-throughput RNA sequencing to better understand CCR during cellulase formation in the presence of sophorose, by comparing the mutant ?cre1 with its parental strain, QM9414. Of the 9129 genes present in the genome of T. reesei, 184 were upregulated and 344 downregulated in the mutant strain ?cre1 compared to QM9414. Genes belonging to the CAZy database, and those encoding transcription factors and transporters are among the gene classes that were repressed by CRE1 in the presence of sophorose; most were possible indirectly regulated by CRE1. We also observed that CRE1 activity is carbon-dependent. A recent study from our group showed that in cellulose, CRE1 repress different groups of genes when compared to sophorose. CCR differences between these carbon sources may be due to the release of cellodextrins in the cellulose polymer, resulting in different targets of CRE1 in both carbon sources. These results contribute to a better understanding of CRE1-mediated CCR in T. reesei when glucose comes from a potent inducer of cellulase production such as sophorose, which could prove useful in improving cellulase production by the biotechnology sector. PMID- 27226769 TI - Molecular Diversity of Seed-borne Fusarium Species Associated with Maize in India. AB - A total of 106 maize seed samples were collected from different agro-climatic regions of India. Sixty-two Fusarium isolates were recovered, 90% of which were identified as Fusarium verticillioides based on morphological and molecular characters. Use of the tef-1alpha gene corrected/refined the morphological species identifications of 11 isolates, and confirmed those of the remaining isolates. Genetic diversity among the Fusarium isolates involved multilocus fingerprinting profiles by Inter Simple Sequence Repeats (ISSR) UPGMA and tef 1alpha gene phenetic analyses; for which, we observed no significant differences among the isolates based on geographic origin or fumonisin production; most of the subdivision related to species. Genotyping was performed on the F. verticillioides isolates, using 12 primer sets from the fumonisin pathway, to elucidate the molec-ular basis of fumonisin production or non-production. One fumonisin-negative isolate, UOMMF-16, was unable to amplify nine of the 12 fumonisin cluster genes tested. We also used the CD-ELISA method to confirm fumonisin production for our 62 Fusarium isolates. Only 15 isolates were found to be fumonisin-negative. Interestingly, genotypic characterization re-vealed six isolates with various gene deletion patterns that also tested positive for the production of fumonisins via CD-ELISA. Our findings confirm the importance of molecular studies for species delimitation, and for observing genetic and phenotypic diversity, among the Fusaria. PMID- 27226770 TI - The Relation Between Promoter Chromatin Status, Xyr1 and Cellulase Ex-pression in Trichoderma reesei. AB - The ascomycete Trichoderma reesei is used for the production of plant cell wall degrading enzymes in industrial scale. The interplay of the transactivator Xyr1 and the repressor Cre1 mainly regulates the expression of these enzymes. During induc-ing conditions, such as in the presence of sophorose, the transcription of the two major cellulase-encoding genes, cbh1 and cbh2, is activated as well as the expression of xyr1. In the presence of D-glucose carbon catabolite repression mediated by Cre1 takes place and the expression of Xyr1 and the plant cell wall degrading enzymes is down-regulated. In this study we compare the chromatin status of xyr1, cbh1, and cbh2 promoters in the wild-type strain and the Cre1 deficient strain Rut-C30. Chromatin rearrangement occurs in the xyr1 promoter during induction on sophorose. Chromatin opening and protein-DNA interactions in the xyr1 promoter were detected especially in a region located 0.9 kb upstream the translation start co-don, which bears several putative Cre1-binding sites and a CCAAT-box. Moreover, the xyr1 promoter is overall more acces-sible in a cre1 truncated background, no matter which carbon source is present. This makes the xyr1 regulatory sequence a good target for promoter engineering aiming at the enhancement of cellulase production. PMID- 27226771 TI - Prevalence of the Lyme Disease Spirochete, Borrelia burgdorferi, in Blacklegged Ticks, Ixodes scapularis at Hamilton-Wentworth, Ontario. AB - Lyme disease has emerged as a major health concern in Canada, where the etiological agent, Borrelia burgdorferi sensu lato (s.l.), a spirochetal bacterium, is typically spread by the bite of certain ticks. This study explores the presence of B. burgdorferi s.l. in blacklegged ticks, Ixodes scapularis, collected at Dundas, Ontario (a locality within the region of Hamilton Wentworth). Using passive surveillance, veterinarians and pet groomers were asked to collect blacklegged ticks from dogs and cats with no history of travel. Additionally, I. scapularis specimens were submitted from local residents and collected by flagging. Overall, 12 (41%) of 29 blacklegged ticks were infected with B. burgdorferi s.l. Using polymerase chain reaction (PCR) and DNA sequencing, two borrelial amplicons were characterized as B. burgdorferi sensu stricto (s.s.), a genospecies pathogenic to humans and certain domestic animals. Notably, three different vertebrate hosts each had two engorged I. scapularis females removed on the same day and, likewise, one cat had three repeat occurrences of this tick species. These multiple infestations suggest that a population of I. scapularis may be established in this area. The local public health unit has been underreporting the presence of B. burgdorferi s.l.-infected I. scapularis in the area encompassing Dundas. Our findings raise concerns about the need to erect tick warning signs in parkland areas. Veterinarians, medical professionals, public health officials, and the general public must be vigilant that Lyme disease-carrying blacklegged ticks pose a public health risk in the Dundas area and the surrounding Hamilton-Wentworth region. PMID- 27226772 TI - Genetic Polymorphisms of Transcription Factor NRF2 and of its Host Gene Sulfiredoxin (SRXN1) are Associated with Cerebrovascular Disease in a Finnish Cohort, the TAMRISK Study. AB - Oxidative stress is involved in the pathophysiology of many cardiovascular disorders, such as hypertension and atherosclerosis. NRF2 is the primary transcriptional regulator of several antioxidant genes, including that of sulfiredoxin (SRXN1). The association of genotypes of NRF2 and SRXN1 with cardiovascular conditions was studied in a Finnish cohort of 336 subjects with diagnosed hypertension and 480 normotensive controls from the Tampere adult population cardiovascular risk study (TAMRISK). Samples were genotyped for four SNPs (rs1962142, rs2706110, rs6721961 and rs6706649) in the NRF2 gene region and four SNPs (rs6053666, rs6116929, rs2008022, rs6085283) in the SRXN1 gene region using Competitive Allele Specific PCR (KASP) technique. Cardiovascular diseases were followed up from 2005 to 2014 using the Finnish National Hospital Discharge Registry (HILMO). Four out of eight studied polymorphisms: rs6721961, rs1962142, rs2706110 of NRF2, and rs6053666 of SRXN1 were associated with cerebrovascular disease. NRF2 polymorphism rs6721961 showed association with hypertension. NRF2 and SRXN1 polymorphisms, previously thought to be associated with human disease, appear to be associated particularly with cerebrovascular disease. PMID- 27226773 TI - Secretion of N- and O-linked Glycoproteins from 4T1 Murine Mammary Carcinoma Cells. AB - Breast cancer is one of the most common cancers that affect women globally and accounts for ~23% of all cancers diagnosed in women. Breast cancer is also one of the leading causes of death primarily due to late stage diagnoses and a lack of effective treatments. Therefore, discovering protein expression biomarkers is mandatory for early detection and thus, critical for successful therapy. Two dimensional electrophoresis (2D-E) coupled with lectin-based analysis followed by mass spectrometry were applied to identify potential biomarkers in the secretions of a murine mammary carcinoma cell line. Comparisons of the protein profiles of the murine 4T1 mammary carcinoma cell line and a normal murine MM3MG mammary cell line indicated that cadherin-1 (CDH), collagenase 3 (MMP-13), Viral envelope protein G7e (VEP), Gag protein (GAG) and Hypothetical protein LOC433182 (LOC) were uniquely expressed by the 4T1 cells, and pigment epithelium-derived factor (PEDF) was exclusively secreted by the MM3MG cells. Further analysis by a lectin based study revealed that aberrant O-glycosylated CDH, N-glycosylated MMP-13 and LOC were present in the 4T1 medium. These differentially expressed N- and O linked glycoprotein candidates, which were identified by combining lectin-based analysis with 2D-E, could serve as potential diagnostic and prognostic markers for breast cancer. PMID- 27226774 TI - Screening for Fabry Disease by Urinary Globotriaosylceramide Isoforms Measurement in Patients with Left Ventricular Hypertrophy. AB - BACKGROUND: Left ventricular hypertrophy (LVH) is a frequent echocardiographic feature in Fabry disease (FD) and in severe cases may be confused with hypertrophic cardiomyopathy (HCM) of other origin. The prevalence of FD in patients primarily diagnosed with HCM varies considerably in screening and case finding studies, respectively. In a significant proportion of patients, presenting with only mild or moderate LVH and unspecific clinical signs FD may remain undiagnosed. Urinary Gb3 isoforms have been shown to detect FD in both, women and men. We examined whether this non-invasive method would help to identify new FD cases in a non-selected cohort of patients with various degree of LVH. METHODS AND RESULTS: Consecutive patients older than 18 years with a diastolic interventricular septal wall thickness of >=12mm determined by echocardiography were included. Referral diagnosis was documented and spot urine was collected. Gb3 was measured by mass spectroscopy. Subjects with an elevated Gb3-24:18 ratio were clinically examined for signs of FD, alpha-galactosidase-A activity in leukocytes was determined and GLA-mutation-analysis was performed. We examined 2596 patients. In 99 subjects urinary Gb3 isoforms excretion were elevated. In these patients no new cases of FD were identified by extended FD assessment. In two of three patients formerly diagnosed with FD Gb3-24:18 ratio was elevated and would have led to further diagnostic evaluation. CONCLUSION: Measurement of urinary Gb3 isoforms in a non-selected cohort with LVH was unable to identify new cases of FD. False positive results may be prevented by more restricted inclusion criteria and may improve diagnostic accuracy of this method. PMID- 27226775 TI - The Influence of Acute Hyperglycemia in an Animal Model of Lacunar Stroke That Is Induced by Artificial Particle Embolization. AB - Animal and clinical studies have revealed that hyperglycemia during ischemic stroke increases the stroke's severity and the infarct size in clinical and animal studies. However, no conclusive evidence demonstrates that acute hyperglycemia worsens post-stroke outcomes and increases infarct size in lacunar stroke. In this study, we developed a rat model of lacunar stroke that was induced via the injection of artificial embolic particles during full consciousness. We then used this model to compare the acute influence of hyperglycemia in lacunar stroke and diffuse infarction, by evaluating neurologic behavior and the rate, size, and location of the infarction. The time course of the neurologic deficits was clearly recorded from immediately after induction to 24 h post-stroke in both types of stroke. We found that acute hyperglycemia aggravated the neurologic deficit in diffuse infarction at 24 h after stroke, and also aggravated the cerebral infarct. Furthermore, the infarct volumes of the basal ganglion, thalamus, hippocampus, and cerebellum but not the cortex were positively correlated with serum glucose levels. In contrast, acute hyperglycemia reduced the infarct volume and neurologic symptoms in lacunar stroke within 4 min after stroke induction, and this effect persisted for up to 24 h post-stroke. In conclusion, acute hyperglycemia aggravated the neurologic outcomes in diffuse infarction, although it significantly reduced the size of the cerebral infarct and improved the neurologic deficits in lacunar stroke. PMID- 27226776 TI - Autophagy Has a Beneficial Role in Relieving Cigarette Smoke-Induced Apoptotic Death in Human Gingival Fibroblasts. AB - The deleterious role of cigarette smoke has long been documented in various human diseases including periodontal complications. In this report, we examined this adverse effect of cigarette smoke on human gingival fibroblasts (HGFs) which are critical not only in maintaining gingival tissue architecture but also in mediating immune responses. As well documented in other cell types, we also observed that cigarette smoke promoted cellular reactive oxygen species in HGFs. And we found that this cigarette smoke-induced oxidative stress reduced HGF viability through inducing apoptosis. Our results indicated that an increased Bax/Bcl-xL ratio and resulting caspase activation underlie the apoptotic death in HGFs exposed to cigarette smoke. Furthermore, we detected that cigarette smoke also triggered autophagy, an integrated cellular stress response. Interesting, a pharmacological suppression of the cigarette smoke-induced autophagy led to a further reduction in HGF viability while a pharmacological promotion of autophagy increased the viability of HGFs with cigarette smoke exposures. These findings suggest a protective role for autophagy in HGFs stressed with cigarette smoke, highlighting that modulation of autophagy can be a novel therapeutic target in periodontal complications with cigarette smoke. PMID- 27226777 TI - EphB4/ephrinB2 Contributes to Imatinib Resistance in Chronic Myeloid Leukemia Involved in Cytoskeletal Proteins. AB - INTRODUCTION: The mechanism of EphB4/ephrinB2 in the resistance of chronic myelogenous leukemia to imatinib keeps unknown. METHODS: The imatinib resistant chronic myelogenous leukemia cell line-K562-R, was established. EphB4 receptor expression was detected in patients and resistant cells. Cell migration and drug sensitivity were tested in the EphB4 knockdown cells and mouse models. RESULTS: The EphB4 receptor was over-expressed in blast crisis patients compared to chronic phase patients. The level of EphB4 receptor expression was associated with a complete cytogenetic response within 12 months. Enhanced expression of the EphB4 receptor was detected in the K562-R cells. EphB4 knockdown inhibited cell migration ability and restored sensitivity to imatinib in vitro and in vivo. Restored sensitivity to imatinib was observed in K562-R cells, along with increased levels of phospho-EphB4 and decreased phosphorylation levels of RhoA, Rac1, and Cdc42. CONCLUSION: Our study illustrates that aberrant activation of EphB4/ephrinB2 may mediate chronic myeloid leukemia resistance involved in cytoskeletal proteins. PMID- 27226779 TI - OCT4 Remodels the Phenotype and Promotes Angiogenesis of HUVECs by Changing the Gene Expression Profile. AB - It has been shown that forced expression of four mouse stem cell factors (OCT4, Sox2, Klf4, and c-Myc) changed the phenotype of rat endothelial cells to vascular progenitor cells. The present study aimed to explore whether the expression of OCT4 alone might change the phenotype of human umbilical vein endothelial cells (HUVECs) to endothelial progenitor cells and, if so, to examine the possible mechanism involved. A Matrigel-based in vitro angiogenesis assay was used to evaluate the angiogenesis of the cells; the gene expression profile was analyzed by an oligonucleotide probe-based gene array chip and validated by RT-QPCR. The cellular functions of the mRNAs altered by OCT4 were analyzed with Gene Ontology. We found that induced ectopic expression of mouse OCT4 in HUVECs significantly enhanced angiogenesis of the cells, broadly changed the gene expression profile and particularly increased the expression of CD133, CD34, and VEGFR2 (KDR) which are characteristic marker molecules for endothelial progenitor cells (EPCs). Furthermore by analyzing the cellular functions that were targeted by the mRNAs altered by OCT4 we found that stem cell maintenance and cell differentiation were among the top functional response targeted by up-regulated and down-regulated mRNAs upon forced expression of OCT4. These results support the argument that OCT4 remodels the phenotype of HUVECs from endothelial cells to EPCs by up regulating the genes responsible for stem cell maintenance and down-regulating the genes for cell differentiation. PMID- 27226778 TI - An Association Map on the Effect of Flavonoids on the Signaling Pathways in Colorectal Cancer. AB - Colorectal cancer (CRC) is the third most common type of cancer in the world, causing thousands of deaths annually. Although chemotherapy is known to be an effective treatment to combat colon cancer, it produces severe side effects. Natural products, on the other hand, appear to generate fewer side effects than do chemotherapeutic drugs. Flavonoids are polyphenolic compounds found in various fruits and vegetables known to possess antioxidant activities, and the literature shows that several of these flavonoids have anti-CRC propertiesFlavonoids are classified into five main subclasses: flavonols, flavanones, flavones, flavan-3 ols, and flavanonols. Of these subclasses, the flavanonols have a minimum effect against CRC, whereas the flavones play an important role. The main targets for the inhibitory effect of flavonoids on CRC signaling pathways are caspase; nuclear factor kappa B; mitogen-activated protein kinase/p38; matrix metalloproteinase (MMP)-2, MMP-7, and MMP-9; p53; beta-catenin; cyclin-dependent kinase (CDK)2 and CDK4; and cyclins A, B, D, and E. In this review article, we summarize the in vitro and in vivo studies that have been performed since 2000 on the anti-CRC properties of flavonoids. We also describe the signaling pathways affected by flavonoids that have been found to be involved in CRC. Some flavonoids have the potential to be an effective alternative to chemotherapeutic drugs in the treatment of colon cancer; well-controlled clinical studies should, however, be conducted to support this proposal. PMID- 27226781 TI - Empowerment model for nurse leaders' participation in health policy development: an east African perspective. AB - BACKGROUND: Nurses comprise the largest portion of the health care workforce in most countries; they interact closely with patients and communities, they work throughout the day and within all sectors of health care. Their breath of practice gives them a broad understanding of requirements of the health care system, of how factors in the environment affect the health outcomes of clients and communities. Nurses' involvement in health policy development ensures that health services are: safe, effective, available and inexpensive. METHODS: A Delphi survey was utilized and included the following criteria: expert panelists, three iterative rounds, qualitative and quantitative analysis, and building consensus. The overall aim of the study was to develop "An Empowerment Model for Nurse Leaders' participation in Health Policy Development". The study included purposively selected sample of national nurse leaders from the three East African countries of Kenya, Tanzania and Uganda. The study was conducted in three iterative rounds. Data collection tools were questionnaires. Data analysis was done by examining the data for the most commonly occurring concepts in the first round and descriptive statistics in the second and third rounds. RESULTS: The findings of the study support the development of the "Empowerment Model for Nurse Leaders' Participation in Health Policy Development". Further the study identified that there was a significant gap in and barriers to participation in health policy activity and that an opportunity seems to exist to enable and develop nurse leaders' role and involvement in this respect. There was consensus on factors considered to be facilitators and barriers to nurse leaders' involvement in health policy development. Furthermore, consensus was achieved on essential leadership attributes that enhance nurse leaders' participation in health policy development. The model was validated a small sample of the nurse leaders' who participated in the study. CONCLUSION: The model provides a framework with an aim of facilitating involvement in health policy activity. Nurses need to be strategic in ensuring that they place themselves and others on the forefront of the policy development arena. The empowerment model suggests proactive and strategic involvement of nurses and nurse leaders in health policy development activities. PMID- 27226780 TI - Glycated Albumin Predicts Long-term Survival in Patients Undergoing Hemodialysis. AB - BACKGROUND: In patients with advanced renal dysfunction undergoing maintenance hemodialysis, glycated albumin (GA) levels may be more representative of blood glucose levels than hemoglobin A1C levels. The aim of this study was to determine the predictive power of GA levels on long-term survival in hemodialysis patients. METHODS: A total of 176 patients with a mean age of 68.2 years were enrolled. The median duration of follow-up was 51.0 months. Receiver-operating characteristic curve analysis was utilized to determine the optimal cutoff value. We examined the cumulative survival rate by Kaplan-Meier estimates and the influence of known survival factors with the multivariate Cox proportional-hazard regression model. RESULTS: In the whole patient group, cumulative survival in the low GA group was better than in the high GA group (p=0.030), with more prominence in those aged <70 years (p=0.029). In subgroup analysis, both diabetic (DM) and non-DM patients with low GA had a better cumulative survival compared with those with high GA. The risk of mortality increased by 3.0% for each 1% increase in serum GA level in all patients undergoing hemodialysis. CONCLUSIONS: In addition to serving as a glycemic control marker, GA levels may be useful for evaluating the risk of death in both DM and non-DM patients on hemodialysis. PMID- 27226782 TI - Field Survey Measures of Olfaction: The Olfactory Function Field Exam (OFFE). AB - Population-based field research on human olfaction has been limited by a lack of feasible assessment tools. Previous olfactory survey research has measured only odor identification, with no research being done on odor detection (i.e., a person's sensitivity to detect a particular odor). Laboratory studies suggest that deficits in both aspects of olfactory function may be related to physical health, mental health and cognition, social function, including overall quality of life, and even mortality. However, field studies are needed to validate and extend these findings in large representative samples. Here we describe the olfactory function field exam, an instrument that can be deployed in field environments by lay interviewers to evaluate both odor identification and odor detection rapidly, practically, and accurately. Use of this new survey tool in future field-based population health studies will elucidate the impact of olfactory function on a myriad of health and social conditions. PMID- 27226783 TI - Tobacco Cessation Interventions for Underserved Women. AB - Despite high rates of smoking among some subgroups of women, there is a lack of tailored interventions to address smoking cessation among women. We identify components of a women-centered approach to tobacco cessation by analyzing 3 bodies of literature: sex and gender influences in tobacco use and addiction; evidence-based tobacco cessation guidelines; and best practices in delivery of women-centered care. Programming for underserved women should be tailored, build confidence and increase motivation, integrate social justice issues and address inequities, and be holistic and comprehensive. Addressing the complexity of women's smoking and tailoring appropriately could help address smoking among subpopulations of women. PMID- 27226784 TI - Rapid Screening of Antimicrobial Synthetic Peptides. AB - Increasing resistance to conventional antibiotics among microorganisms is one of the leading problems of medicine nowadays. Antimicrobial peptides are compounds exhibiting both antibacterial and antifungal activities. However, it is difficult to predict whether a designed new compound would exhibit any biological activity. Moreover, purification of the peptides is one of the most time-consuming and expensive steps of the synthesis that sometimes leads to unnecessary loss of solvents and reagents. In our study we have developed a thin-layer chromatography (TLC) direct bioautography technique for rapid determination of antimicrobial activity of peptides without the necessity of high-performance liquid chromatography purification. In this assay, crude peptides were applied and separated on a TLC plate. Then, pre-prepared plates were dipped into microbial suspension and incubated under optimum conditions for bacteria and fungi as well. The activity of the tested compounds was visualized by spraying the TLC plates with a cell viability reagent, resazurin (7-hydroxy-3H-phenoxazin-3-one 10 oxide). Effectiveness of this assay was compared with minimal inhibitory concentration results obtained by broth microdilution assay. Interestingly, so far such a screening method has not been applied for this group of compounds. PMID- 27226785 TI - Exabundanti cautela: From the tragedy of inadvertent sarcoma morcellation to inappropriate myoma screening. PMID- 27226786 TI - Office Hysteroscopy. An operative gold standard technique and an important contribution to Patient Safety. AB - According to World Health Organization (WHO), about 1 out of 10 hospitalized patients suffers an adverse event, in developed countries, being an adverse event an injury related to medical management, in contrast to complications of disease. These events cause both unnecessary suffering and huge cost to health systems. This issue is so important that WHO has defined it as a global health problem and in 2004 launched the World Alliance for Patient Safety, with the aim to coordinate, disseminate and accelerate improvements in Patient Safety. Office Hysteroscopy (OH), as an independent technique of the hospital circuit, has the ideal conditions to be qualified as the gold standard technique for the surgical treatment of intracavitary uterine pathology. It does not require the use of an operating room, hospital admission and general or locoregional anaesthesia. The appropriate surgical techniques, allied to pain control, allow OH to resolve much more than 90 % of the surgical needs of the intracavitary uterine pathology, thus being an important contribution for Patient Safety. PMID- 27226787 TI - Laparoscopic versus robotic-assisted sacrocolpopexy for pelvic organ prolapse: a systematic review. AB - The use of robot-assisted surgery (RAS) has gained popularity in the field of gynaecology, including pelvic floor surgery. To assess the benefits of RAS, we conducted a systematic review of randomized controlled trials comparing laparoscopic and robotic-assisted sacrocolpopexy. The Cochrane Library (1970 January 2015), MEDLINE (1966 to January 2015), and EMBASE (1974 to January 2015) were searched, as well as ClinicalTrials.gov and the International Clinical Trials Registry Platform. We identified two randomized trials (n = 78) comparing laparoscopic with robotic sacrocolpopexy. The Paraiso 2011 study showed that laparoscopic was faster than robotic sacrocolpopexy (199 +/- 46 vs. 265 +/- 50 min; p < .001), yet in the ACCESS trial, no difference was present (225 +/- 62.3 vs. 246.5 +/- 51.3 min; p = .110). Costs for using the robot were significantly higher in both studies, however, in the ACCESS trial, only when purchase and maintenance of the robot was included (LSC US$11,573 +/- 3191 vs. RASC US$19,616 +/- 3135; p < .001). In the Paraiso study, RASC was more expensive even without considering those costs (LSC US$ 14,342 +/- 2941 vs. RASC 16,278 +/- 3326; p = 0.008). Pain was reportedly higher after RASC, although at different time points after the operation. There were no differences in anatomical outcomes, pelvic floor function, and quality of life. The experience with RASC was tenfold lower than that with LSC in both studies. The heterogeneity between the two studies precluded a meta-analysis. Based on small randomized studies, with surgeons less experienced in RAS than in laparoscopic surgery, robotic surgery significantly increases the cost of a laparoscopic sacrocolpopexy. RASC would be more sustainable if its costs would be lower. Though RASC may have other benefits, such as reduction of the learning curve and increased ergonomics or dexterity, these remain to be demonstrated. PMID- 27226788 TI - Innate Immune System for Diagnostics and Therapy: Progress in Fundamental Knowledge and Clinical Application. PMID- 27226790 TI - Platelet Interaction with Innate Immune Cells. AB - Beyond their traditional role in haemostasis and thrombosis, platelets are increasingly recognised as immune modulatory cells. Activated platelets and platelet-derived microparticles can bind to leukocytes, which stimulates mutual activation and results in rapid, local release of platelet-derived cytokines. Thereby platelets modulate leukocyte effector functions and contribute to inflammatory and immune responses to injury or infection. Platelets enhance leukocyte extravasation, differentiation and cytokine release. Platelet neutrophil interactions boost oxidative burst, neutrophil extracellular trap formation and phagocytosis and play an important role in host defence. Platelet interactions with monocytes propagate their differentiation into macrophages, modulate cytokine release and attenuate macrophage functions. Depending on the underlying pathology, platelets can enhance or diminish leukocyte cytokine production, indicating that platelet-leukocyte interactions represent a fine balanced system to restrict excessive inflammation during infection. In atherosclerosis, platelet interaction with neutrophils, monocytes and dendritic cells accelerates key steps of atherogenesis by promoting leukocyte extravasation and foam cell formation. Platelet-leukocyte interactions at sites of atherosclerotic lesions destabilise atherosclerotic plaques and promote plaque rupture. Leukocytes in turn also modulate platelet function and production, which either results in enhanced platelet destruction or increased platelet production. This review aims to summarise the key effects of platelet-leukocyte interactions in inflammation, infection and atherosclerosis. PMID- 27226789 TI - Perspectives for Monocyte/Macrophage-Based Diagnostics of Chronic Inflammation. AB - Low-grade chronic inflammation underlies the development of the most dangerous cardiometabolic disorders including type 2 diabetes and its vascular complications. In contrast to acute inflammation induced by bacteria and viruses, chronic inflammation can be driven by abnormal reaction to endogenous factors, including Th2 cytokines, metabolic factors like advanced glycation end products (AGEs), modified lipoproteins, or hyperglycemia. The key innate immune cells that recognize these factors in blood circulation are monocytes. Inflammatory programming of monocytes which migrate into tissues can, in turn, result into generation of tissue macrophages with pathological functions. Therefore, determination of the molecular and functional phenotype of circulating monocytes is a very promising diagnostic tool for the identification of hidden inflammation, which can precede the development of the pathology. Here we propose a new test system for the identification of inflammatory programming of monocytes: surface biomarkers and ex vivo functional system. We summarize the current knowledge about surface biomarkers for monocyte subsets, including CD16, CCR2, CX3CR1, CD64, stabilin-1 and CD36, and their association with inflammatory human disorders. Furthermore, we present the design of an ex vivo monocyte-based test system with minimal set of parameters as a potential diagnostic tool for the identification of personalized inflammatory responses. PMID- 27226791 TI - Natural Killer Cells for Therapy of Leukemia. AB - Clinical application of natural killer (NK) cells against leukemia is an area of intense investigation. In human leukocyte antigen-mismatched allogeneic hematopoietic stem cell transplantations (HSCT), alloreactive NK cells exert powerful anti-leukemic activity in preventing relapse in the absence of graft versus-host disease, particularly in acute myeloid leukemia patients. Adoptive transfer of donor NK cells post-HSCT or in non-transplant scenarios may be superior to the currently widely used unmanipulated donor lymphocyte infusion. This concept could be further improved through transfusion of activated NK cells. Significant progress has been made in good manufacturing practice (GMP)-compliant large-scale production of stimulated effectors. However, inherent limitations remain. These include differing yields and compositions of the end-product due to donor variability and inefficient means for cryopreservation. Moreover, the impact of the various novel activation strategies on NK cell biology and in vivo behavior are barely understood. In contrast, reproduction of the third-party NK 92 drug from a cryostored GMP-compliant master cell bank is straightforward and efficient. Safety for the application of this highly cytotoxic cell line was demonstrated in first clinical trials. This novel 'off-the-shelf' product could become a treatment option for a broad patient population. For specific tumor targeting chimeric-antigen-receptor-engineered NK-92 cells have been designed. PMID- 27226792 TI - A Player and Coordinator: The Versatile Roles of Eosinophils in the Immune System. AB - Eosinophils have traditionally been associated with allergic diseases and parasite infection. Research advances in the recent decades have brought evolutionary changes in our understanding of eosinophil biology and its roles in immunity. It is currently recognized that eosinophils play multiple roles in both innate and adaptive immunity. As effector cells in innate immunity, eosinophils exert a pro-inflammatory and destructive role in the Th2 immune response associated with allergic inflammation or parasite infection. Eosinophils can also be recruited by danger signals released by pathogen infections or tissue injury, inducing host defense against parasitic, fungal, bacterial or viral infection or promoting tissue repair and remodeling. Eosinophils also serve as nonprofessional antigen-presenting cells in response to allergen challenge or helminth infection, and, meanwhile, are known to function as a versatile coordinator that actively regulates or interacts with various immune cells including T lymphocytes and dendritic cells. More roles of eosinophils implicated in immunity have been proposed including in immune homeostasis, allograft rejection, and anti-tumor immunity. Eosinophil interactions with structural cells are also implicated in the mechanisms in allergic inflammation and in Helicobacter pylori gastritis. These multifaceted roles of eosinophils as both players and coordinators in immune system are discussed in this review. PMID- 27226793 TI - Toll-Like Receptor 7-Targeted Therapy in Respiratory Disease. AB - Allergic asthma and allergic rhinitis are inflammatory diseases of the respiratory tract characterized by an excessive type-2 T helper cell (Th2) immune response. Toll-like receptor 7 (TLR7) is a single-stranded viral RNA receptor expressed in the airway that initiates a Th1 immune response and has garnered interest as a novel therapeutic target for treatment of allergic airway diseases. In animal models, synthetic TLR7 agonists reduce airway hyperreactivity, eosinophilic inflammation, and airway remodeling while decreasing Th2-associated cytokines. Furthermore, activation of TLR7 rapidly relaxes airway smooth muscle via production of nitric oxide. Thus, TLR7 has dual bronchodilator and anti inflammatory effects. Two TLR7 ligands with promising pharmacologic profiles have entered clinical trials for the treatment of allergic rhinitis. Moreover, TLR7 agonists are potential antiviral therapies against respiratory viruses. TLR7 agonists enhance influenza vaccine efficacy and also reduce viral titers when given during an active airway infection. In this review, we examine the current data supporting TLR7 as a therapeutic target in allergic airway diseases. PMID- 27226795 TI - A Rare Case of Transfusion Transmission of Hepatitis A Virus to Two Patients with Haematological Disease. AB - BACKGROUND: This paper describes the transmission of hepatitis A virus (HAV) to two blood recipients from a healthy donor that later presented to the blood bank with jaundice. METHODS: The RNA of HAV was detected by qualitative nested reverse transcription polymerase chain reaction (nested RT-PCR) and quantified by real time RT-PCR. HAV RNA samples were genotyped by direct sequencing of PCR products. A sequence from a fragment of 168 bp from the VP1/2A HAV region was used to construct a phylogenetic tree. CASE REPORT: A 31-year-old male donor accepted for donation of a whole blood unit returned to the blood bank with clinical jaundice 20 days after donation. His serological and NAT tests were negative for HBV and HCV. Serological tests for HAV IgM and IgG were negative on donation sample but positive on follow-up sample, confirming donor's HAV acute infection. Both recipients of red blood cells (R1) and platelet concentrate (R2) from the same implicated donation were HAV IgM-negative and IgG-positive. Qualitative PCR was positive on samples from all three individuals and phylogenetic analysis of viruses proved HAV transmission to the two recipients of blood products. HAV viral load on donor follow-up sample and the platelet recipient was 1.3 and 1.5 * 10(3) IU/ml, respectively. The RBC recipient, also infected by HCV, was undergoing bone marrow transplantation and died from fulminant hepatitis, 26 days after the implicated HAV transfusion. CONCLUSION: The blood donor, a garbage collector, spontaneously returned to the blood bank when developing jaundice. This highlights the importance of donor education to immediately report to blood banks of any signs and symptoms related to infectious disease developed after blood donation. The fact that one immunocompromised patient with HCV infection died from fulminant hepatitis after receiving a HAV-contaminated platelet transfusion underpins the importance of a HAV vaccination program for these group of patients. PMID- 27226796 TI - Safety and Efficacy of Adding Ribavirin to Interferon or Peginterferon in Treatment of Hepatitis C Infection in Patients With Thalassemia: A Systematic Review on Randomized Controlled Trials. AB - CONTEXT: Hepatitis C virus (HCV) infection is a major cause of liver-morbidity and mortality among patients with thalassemia. Peginterferon plus ribavirin is currently the recommended therapy for hepatitis C infection in patients do not have thalassemia, but using ribavirin in patients with thalassemia is restricted due to its hemolytic effect. To evaluate the efficacy and safety of adding ribavirin to peginterferon or interferon, authors performed a systematic review on the available literatures. EVIDENCE ACQUISITION: Trials were identified through electronic database, manual searches of journals and bibliographies and approaching authors of trials. Randomized trials that enrolled patients with a diagnosis of thalassemia and chronic hepatitis C infection treated with interferon or peginterferon with or without ribavirin were included. Two investigators independently evaluated the trials for inclusion criteria, risk of bias and data extraction. The primary outcomes were sustained virological response (SVR), liver-related morbidity, mortality and adverse events. The odds ratios from each trial were calculated individually and in the subgroup analysis of trials. Data were analyzed with fixed-effect model. RESULTS: Three randomized clinical trials with 92 patients were included. All three trials had unclear risk of bias. Compared with peginterferon monotherapy, adding ribavirin to peginterferon had significant beneficial effect on sustained virological response (OR = 3.44, 95% CI: 1.18 - 10.06). There was no significant difference between combination therapy and monotherapy in the end of treatment achievement response. Other than about 30% increase in blood transfusion due to anemia that returned to normal level 2 - 3 months after treatment, there was no significant increase in side effects followed by adding ribavirin to pegylated interferon (Peg-IFN). Data were insufficient to determine the impact of genotype, viral load and age on the response to treatment. CONCLUSIONS: Compared with monotherapy, adding ribavirin to treatment is more effective in removing hepatitis C virus from the bloodstream in patients with thalassemia, it is also more effective in reducing the relapse rate after treatment. Except the increase in blood transfusion, there was no significant increase in side effects followed by adding ribavirin. PMID- 27226797 TI - The Prevalence of Hepatitis B Virus Among Municipal Solid Waste Workers: Necessity for Immunization of At-Risk Groups. AB - BACKGROUND: Hepatitis B virus (HBV) is likely to be more prevalent in certain populations and occupational groups, such as municipal solid waste workers (MSWWs). OBJECTIVES: The current study aimed to estimate the prevalence of HBV and its risk factors among MSWWs compared to other municipal employees not exposed to waste. PATIENTS AND METHODS: The current cross-sectional study included 654 municipal employees in Zahedan (south-eastern Iran). A sample of blood was taken from each participant and tested for HBsAg through the enzyme linked immunosorbent assay (ELISA). Demographic and other data on high risk behaviors were also collected through in-depth interviews. Data were analyzed using chi-square test and multiple regression analysis by STATA. RESULTS: The overall prevalence of HBV among municipal employees was 3.06% (95% CI: 1.70 - 4.30); however, it varied among the different employee subgroups as follows: 6.20% (95% CI: 2.70 - 9.70) in MSWWs, 3.3% (95% CI: 0.08 - 5.80) in drivers and 1% among staff who were not exposed to waste. Multiple regression analysis showed that exposure to waste [OR = 9.36; 95% CI = 2.01 - 43.7], lack of vaccination against HBV [OR = 3.83; 95% CI = 1.86 - 25.2], jaundice [OR = 6.91; 95% CI = 1.51 - 31.5], history of endoscopy [OR = 2.86; 95% CI = 1.08 - 7.62], and high risk behaviors [OR = 4.80; 95% CI = 1.96 - 27.2] were independently associated with HBV. CONCLUSIONS: Greater encouragement for immunization against HBV as well as better education on HBV transmission routes and work safety precautions should be implemented to reduce the prevalence of HBV in MSWWs. PMID- 27226794 TI - Until Death Do Us Part: Necrosis and Oxidation Promote the Tumor Microenvironment. AB - Tumor proliferation is concomitant with autophagy, limited apoptosis, and resultant necrosis. Necrosis is associated with the release of damage-associated molecular pattern molecules (DAMPs), which act as 'danger signals', recruiting inflammatory cells, inducing immune responses, and promoting wound healing. Most of the current treatment strategies for cancer (chemotherapy, radiation therapy, hormonal therapy) promote DAMP release following therapy-induced tumor death by necroptosis and necrosis. Myeloid cells (monocytes, dendritic cells (DCs), and granulocytes), as well as mesenchymal stromal cells (MSCs) belong to the early immigrants in response to unscheduled cell death, initiating and modulating the subsequent inflammatory response. Responding to DAMPs, MSCs, and DCs promote an immunosuppressive milieu, while eosinophils induce oxidative conditions limiting the biologic activity of DAMPs over time and distance. Regulatory T cells are strongly affected by pattern recognition receptor signaling in the tumor microenvironment and limit immune reactivity coordinately with myeloid-derived suppressor cells. Means to 'aerobically' oxidize DAMPs provide a novel strategy for limiting tumor progression. The present article summarizes our current understanding of the impact of necrosis on the tumor microenvironment and the influence of oxidative conditions found within this setting. PMID- 27226798 TI - Hepatitis E Virus Circulation in Italy: Phylogenetic and Evolutionary Analysis. AB - BACKGROUND: Hepatitis E virus (HEV), a major cause of acute viral hepatitis in developing countries, has been classified into four main genotypes and a number of subtypes. New genotypes have been recently identified in various mammals, including HEV genotype 3, which has a worldwide distribution. It is widespread among pigs in developed countries. OBJECTIVES: This study investigated the genetic diversity of HEV among humans and swine in Italy. The date of origin and the demographic history of the HEV were also estimated. MATERIALS AND METHODS: A total of 327 HEV sequences of swine and humans from Italy were downloaded from the national centre for biotechnology information. Three different data sets were constructed. The first and the second data set were used to confirm the genotype of the sequences analyzed. The third data set was used to estimate the mean evolutionary rate and to determine the time-scaled phylogeny and demographic history. RESULTS: The Bayesian maximum clade credibility tree and the time of the most common recent ancestor estimates showed that the root of the tree dated back to the year 1907 (95% HPD: 1811 - 1975). Two main clades were found, divided into two subclades. Skyline plot analysis, performed separately for human and swine sequences, demonstrated the presence of a bottleneck only in the skyline plot from the swine sequences. Selective pressure analysis revealed only negatively selected sites. CONCLUSIONS: This study provides support for the hypothesis that humans are probably infected after contact with swine sources. The findings emphasize the importance of checking the country of origin of swine and of improving sanitary control measures from the veterinary standpoint to prevent the spread of HEV infection in Italy. PMID- 27226799 TI - The Association of Pre-S/S Gene Mutations and Hepatitis B Virus Vertical Transmission. AB - BACKGROUND: HBV Pre-S/S gene mutations can occur before or after implementation of combined vaccination program. HBV Prs-S/S gene mutation is a risk factor of vaccination failure and frequently causes HBV vertical transfection. OBJECTIVES: To assess the association of hepatitis B virus (HBV) S gene mutations with vertical transmission. PATIENTS AND METHODS: In this prospective nested case control study, a total of 60 pregnant women with positive serum HBsAg and HBV DNA >= 10(7) IU/mL were divided into a case group (15 cases with vaccination failure) and a control group (45 cases with vaccination success) according to whether their infants tested positive for HBV infection. Mothers and their children in the case group were further sub-divided into groups including mothers, newborns and infant (the same newborns at age of seven months). The pre-S/S gene mutations were detected by PCR and sequenced and its association with vertical transmission of HBV was analyzed. RESULTS: HBV genotype B was the dominant genotype in the both groups' mothers. Each mother-child pair in case group had the same HBV genotype. There were no significant differences in mutation frequencies of HBV Pre-S/S gene between case and control groups' mothers (Fragment 1 (M): 2 vs. 4, P > 0.05; Fragment 2 (M): 10 vs. 10, P > 0.05), or among the mothers, newborns and infants in the case group (Fragment 1 (M): 2, 2, and 3, respectively, P > 0.05; Fragment 2 (M): 10, 10 and 10 respectively, P > 0.05). Mutation site analysis of the both groups' mothers demonstrated 108 different mutation sites in the HBV pre S/S gene, with 105 silent mutations and 5 missense mutations including ntA826G, ntC531T, ntT667C, ntC512T and ntC546A. Among 15 mother-newborn-infant pairs with successful PCR and sequence in case group, 7 (41.17%) mother-newborn pairs, 9 (60.00%) mother-infant pairs and 3 (20.00%) infant-newborn pairs had different mutation sites. CONCLUSIONS: HBV in children due to vaccination failure was resulted from vertical transmission. HBV Pre-S/S gene mutations were prevalent and could occur before or after vaccination. Therefore, simply analyzing mutation frequency of HBV gene was not of value. To advance blocking HBV vertical transmission, future studies should focus on specific mutation sites, potentially associated with vaccination failure. PMID- 27226801 TI - Factors Affecting Exercise Test Performance in Patients After Liver Transplantation. AB - BACKGROUND: Cardiovascular diseases are a leading cause of morbidity and mortality in solid organ transplant recipients. In addition, low physical activity is a risk factor for cardiac and cerebrovascular complications. OBJECTIVES: This study examined potential relationships between physical activity, health-related quality of life (HRQoL), risk factors for cardiovascular disease, and an exercise test in liver-graft recipients. PATIENTS AND METHODS: A total of 107 participants (62 men/45 women) who had received a liver transplantation (LT) at least 6 months previously were evaluated. Physical activity was assessed using three different questionnaires, while HRQoL was assessed using the medical outcomes study short form (SF)-36 questionnaire, and health behaviors were evaluated using the health behavior inventory (HBI). The exercise test was performed in a standard manner. RESULTS: Seven participants (6.5%) had a positive exercise test, and these individuals were older than those who had a negative exercise test (P = 0.04). A significant association between a negative exercise test and a higher level of physical activity was shown by the Seven-day physical activity recall questionnaire. In addition, HRQoL was improved in various domains of the SF-36 in participants who had a negative exercise test. No correlations between physical activity, the exercise test and healthy behaviors, as assessed via the HBI were observed. CONCLUSIONS: Exercise test performance was affected by lower quality of life and lower physical activity after LT. With the exception of hypertension, well known factors that affect the risk of coronary artery disease had no effect on the exercise test results. PMID- 27226800 TI - The Correlation Between Interferon Lambda 3 Gene Polymorphisms and Susceptibility to Hepatitis B Virus Infection. AB - BACKGROUND: Cytokines are proteins that mediate innate and adaptive immunity responses. It is hypothesized that interferon lambda 3 (IFNL3) levels can influence the outcome of chronic hepatitis B virus (HBV) infection. Polymorphisms in IFN genes have been associated with response to infection. OBJECTIVES: This study was carried-out to investigate the association of IFNL3 gene polymorphisms (rs12979860 and rs8099917) with HBV susceptibility, in chronic HBV-infected patients. PATIENTS AND METHODS: In this case-control study, we determined IFNL3 single nucleotide polymorphisms (SNPs) (rs12979860 and rs8099917) in 221 individuals, with chronic HBV infection, and 200 healthy individuals, who were voluntary blood donors, with negative test for HBV. Alleles and genotypes analyses were performed by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. RESULTS: The frequencies of the rs12979860 and rs8099917 genotypes were not significantly different between the HBV-infected and the control groups (CC:CT:TT of 30.3%:48.0%:21.7% vs. 33.0%:49.0%:18.0%, P > 0.05, and GG:GT:TT of 5.8%:39.4%:54.8% vs. 5.0%:41.0%:54.0%, P > 0.05, respectively). Also, the frequencies of the alleles were not significantly different between both groups (C:T of 54.3%:45.7% vs. 57.5%:42.5%, P > 0.05, and G:T of 25.6%:74.4% vs. 25.5%:74.5%, P > 0.05, respectively) and the chronic HBV infection. There were no significant differences between patients, with at least one rs12979860C and or rs8099917T alleles compared to the healthy controls (rs12979860: CT + CC:TT, OR = 1.26, 95%CI = 0.78 - 2.04, P = 0.341 and rs8099917: GT + TT:GG, OR = 1.03, 95%CI = 0.70 - 1.51, P = 0.877, respectively). CONCLUSIONS: Our study showed no correlation between rs12979860 and rs8099917 SNPs and chronic HBV infection. Further studies, with larger sample sizes and different ethnicities, are necessary to validate our findings. PMID- 27226802 TI - Characterization of Occult Hepatitis B Infection Among Injecting Drug Users in Tehran, Iran. AB - BACKGROUND: Hepatitis B virus (HBV) infection is a major health problem worldwide. OBJECTIVES: The aim of this study was to investigate the frequency of occult hepatitis B infection (OBI) and its associated risk factors, together with the molecular characterization of the virus in injecting drug users of Tehran. PATIENTS AND METHODS: The study consisted of 229 injecting drug users. Serum samples were collected and tested for the presence of hepatitis B core antibody (HBcAb) and hepatitis B surface antigen (HBsAg) by an enzyme-linked immunosorbent assay (ELISA). HBV B virus DNA was extracted from the serum samples, and a fragment of the S gene was amplified using the nested polymerase chain reaction. The genotype, subgenotypes, subtype, and S gene mutation of HBV were determined by direct sequencing. A phylogenetic tree was constructed using the neighbor joining method. RESULTS: Sixty-four (28%) participants were HBcAb positive, 59 cases were HBcAb positive and HBsAg negative, and 5 cases were HBsAg positive. Hepatitis B DNA was found in three HBsAg-positive cases. Thirteen of 59 (22%) individuals were hepatitis B DNA positive. The phylogenetic tree of hepatitis B DNA showed the existence of genotype D. The only significant correlation was between sharing a syringe and OBI. CONCLUSIONS: In comparison with the rate of HBcAb positivity reported in other Iranian studies, the rate was higher in the present study. There were a few variations, genotypes, and subtypes among the infected injecting drug users. Further investigations are needed to unravel the molecular characterization of OBI. PMID- 27226803 TI - Relative Importance of Hepatitis B and C Viruses in Hepatocellular Carcinoma in EMRO Countries and the Middle East: A Systematic Review. AB - CONTEXT: Hepatocellular carcinoma (HCC) is the second most common cancer-related death worldwide. Although many factors including dietary aflatoxin B1 (AFB1) and alcoholic and non-alcoholic fatty liver diseases can lead to HCC, globally most HCC cases are due to hepatitis B virus (HBV) and hepatitis C virus (HCV). Considering the importance of these viral factors in most HCC cases and relative lack of literature from eastern Mediterranean region office of world health organization (EMRO) countries and the Middle East, we decided to perform this systematic review to find distribution of viral etiology of HCC in these regions. EVIDENCE ACQUISITION: In this systemic review, we included all studies from 1 January 1989 to 1 September 2015 with at least 20 samples that measured HBV surface antigen (HBsAg) and antibodies to HCV (anti-HCV). The authors searched MEDLINE, Embase, Popline, Web of Science and WHO indexed databases. We searched the following MeSH terms; hepatocellular carcinoma, hepatitis B virus and hepatitis C virus or hepacvirus. Only studies using second- and third-generation HCV assays were included. Only articles studying HCC patients from EMRO countries and the Middle East were analyzed. Duplicate results that reported the same cases more than once were found and omitted. Studies in English and Farsi were reviewed. If the study was eligible, we recorded the following data; the first author, publication year and journal, study population and number and percentage of patients with different serologic statuses. RESULTS: We found 44 studies from 12 countries in EMRO and the Middle East. HCC cases from Iran, Lebanon, Turkey and Yemen were mainly due to HBV, while those of North African nations (Egypt, Tunisia, Morocco, Algeria and Somalia) in addition to Saudi Arabia and Pakistan were mostly HCV related. Sudan showed a high seronegativity and HBV infection in its HCC cases. Unfortunately, some countries from EMRO and the Middle East did not have eligible studies. CONCLUSIONS: HBV and HCV are important culprits of HCC in EMRO countries and the Middle East and different nations need different strategies to tackle them accordingly. Countries with high rates of HBV such as Turkey should continue their HBV vaccination and also increase sanitation. Nations with high HCV rates such as Egypt should maintain their blood product monitoring in addition to increased sanitation, especially regarding injection drug users (IDU). PMID- 27226805 TI - Hepatitis Monthly, an International Journal in the Field of Hepatology. PMID- 27226804 TI - The HBsAg Prevalence Among Blood Donors From Eastern Mediterranean and Middle Eastern Countries: A Systematic Review and Meta-Analysis. AB - CONTEXT: The world health organization (WHO) recommends that all blood donations should be screened for evidence of infections, such as hepatitis B. The present study aimed to determine the prevalence of hepatitis B surface antigen (HBsAg) in blood donors at the eastern Mediterranean region office (EMRO) of the WHO and middle eastern countries. EVIDENCE ACQUISITION: A meta-analysis was carried out based on the results of an electronic literature search of PubMed, Ovid, Scopus, and Google Scholar for articles published from January 1, 2000, to August 31, 2015. In accordance with a significant homogeneity test and a large value of I2, the random effects model was used to aggregate data from the studies and produce the pooled estimates using the "Metan" command. RESULTS: We included 66 eligible studies. The pooled prevalence of HBsAg in blood donors of both EMRO and middle eastern (E and M) countries was 2.03% (95% confidence interval [CI]: 1.79 - 2.26). In addition, the prevalence rates in the EMRO countries was 1.99% (95% CI: 1.84 - 2.14) and 1.62% in the Middle Eastern countries (95% CI: 1.36 - 1.88). The prevalence among blood donors with more than one study was 1.58% in Egypt, 0.58% in Iran, 0.67% in Iraq, 2.84% in Pakistan, 3.02% in Saudi Arabia, 1.68% in Turkey, and 5.05% in Yemen. CONCLUSIONS: Based on the WHO classification of hepatitis B virus (HBV) prevalence, the prevalence of HBsAg in blood donors from E and M countries reached an intermediate level. However, there were low prevalence levels in some E and M countries. PMID- 27226806 TI - Are People More Inclined to Vote at 16 than at 18? Evidence for the First-Time Voting Boost Among 16- to 25-Year-Olds in Austria. AB - Potential consequences of lowering voting age to 16 have been discussed in recent scientific and public debates. This article examines turnout of young voters aged 16 to 17 in Austria, the first European country that lowered the general voting age to 16. For this purpose we use unique data taken from electoral lists of two recent Austrian regional elections. The results support the idea that the so called "first-time voting boost" is even stronger among the youngest voters as turnout was (a) higher compared to 18- to 20-year-old first-time voters and (b) not substantially lower than the average turnout rate. We conclude that our findings are encouraging for the idea of lowering voting age as a means to establish higher turnout rates in the future. PMID- 27226807 TI - Development and Characterization of a High Sensitivity Segmented Fast Neutron Spectrometer (FaNS-2). AB - We present the development of a segmented fast neutron spectrometer (FaNS-2) based upon plastic scintillator and 3He proportional counters. It was designed to measure both the flux and spectrum of fast neutrons in the energy range of few MeV to 1 GeV. FaNS-2 utilizes capture-gated spectroscopy to identify neutron events and reject backgrounds. Neutrons deposit energy in the plastic scintillator before capturing on a 3He nucleus in the proportional counters. Segmentation improves neutron energy reconstruction while the large volume of scintillator increases sensitivity to low neutron fluxes. A main goal of its design is to study comparatively low neutron fluxes, such as cosmogenic neutrons at the Earth's surface, in an underground environment, or from low-activity neutron sources. In this paper, we present details of its design and construction as well as its characterization with a calibrated 252Cf source and monoenergetic neutron fields of 2.5 MeV and 14 MeV. Detected monoenergetic neutron spectra are unfolded using a Singular Value Decomposition method, demonstrating a 5% energy resolution at 14 MeV. Finally, we discuss plans for measuring the surface and underground cosmogenic neutron spectra with FaNS-2. PMID- 27226808 TI - Giving social support to outside family may be a desirable buffer against depressive symptoms in community-dwelling older adults: Japan gerontological evaluation study. AB - BACKGROUND: Depression is the leading cause of impaired quality of life and burden upon societies. Social supports can buffer against depressive symptoms effectively. The aim of this study is to determine the type of social support to have a positive relationship with depressive symptoms in healthy population. METHODS: 11,869 male and 12,763 female residents within the age range of 65-100 were analyzed cross-sectionally with regard to depressive symptoms (evaluated by the Japanese version of the 15-item Geriatric Depression Scale), social supports (four dimensions: giving or receiving, emotional or instrumental), and covariates utilizing data collected by the Japan Gerontological Evaluation Study. Analyzed participants were GDS scores <= 10 and independence in ADL, who could give and receive supports well. Multiple linear models were applied for the analysis. RESULTS: All supports between husband and wife were significantly associated with lower depressive degrees. In comparison with the differences between receiving and giving supports in predictive effects on depressive degrees, giving social supports to outside family, emotional or instrumental, were associated with fewer depressive symptoms. CONCLUSIONS: There is a possibility that not only supports between husband and wife but giving social supports to outside family accounts for psychological benefits against depression, in addition to supports between husband and wife. PMID- 27226809 TI - The association between duration of untreated psychosis in first psychotic episode patients and help seeking behaviors in Jogjakarta, Indonesia. AB - Help seeking is predictor of prognosis in the first episode of psychotic disorders. Caregivers play a key role in deciding from whom to seek help. In Indonesia, caregivers often seek help from alternative healers first and health professionals later, which is believed to result in delayed psychiatric treatment and risk for poor prognosis. This study measured the duration of untreated psychosis (DUP) in a sample of 100 persons being treated for a first episode of psychosis in Yogyakarta, Indonesia. We attempted to measure and determine associations among caregivers' explanatory models, help seeking behaviors and DUP in this sample. The data were then statistically analyzed. The DUP for this population was very short. Most caregivers were parents or spouses (72 and 12%, respectively) and at the time of being interviewed described medical explanatory models for the psychotic symptoms (60%). A majority described having visited traditional/alternative healers prior to their visit to health professionals (67%). Despite this, the DUP was not significantly different for these two groups. Thus, first resort to traditional/alternative healers did not predict prolonged DUP. Further study with a larger sample is needed to better understand the relationship between care seeking, use of alternative healers and DUP in Indonesia. PMID- 27226810 TI - The chicken erythrocyte epigenome. AB - BACKGROUND: Transcriptional regulation is impacted by multiple layers of genome organization. A general feature of transcriptionally active chromatin is sensitivity to DNase I and association with acetylated histones. However, very few of these active DNase I-sensitive domains, such as the chicken erythrocyte beta-globin domain, have been identified and characterized. In chicken polychromatic erythrocytes, dynamically acetylated histones associated with DNase I-sensitive, transcriptionally active chromatin prevent histone H1/H5-induced insolubility at physiological ionic strength. RESULTS: Here, we identified and mapped out all the transcriptionally active chromosomal domains in the chicken polychromatic erythrocyte genome by combining a powerful chromatin fractionation method with next-generation DNA and RNA sequencing. Two classes of transcribed chromatin organizations were identified on the basis of the extent of solubility at physiological ionic strength. Highly transcribed genes were present in multigenic salt-soluble chromatin domains ranging in length from 30 to over 150 kb. We identified over 100 highly expressed genes that were organized in broad dynamically highly acetylated, salt-soluble chromatin domains. Highly expressed genes were associated with H3K4me3 and H3K27ac and produced discernible antisense transcripts. The moderately- and low-expressing genes had highly acetylated, salt soluble chromatin regions confined to the 5' end of the gene. CONCLUSIONS: Our data provide a genome-wide profile of chromatin signatures in relation to expression levels in chicken polychromatic erythrocytes. PMID- 27226811 TI - Combining art and science in healthcare. PMID- 27226813 TI - Characterization of the near-field and convectional transport behavior of micro and nanoparticles in nanoscale plasmonic optical lattices. AB - Here, we report the characterization of the transport of micro- and nanospheres in a simple two-dimensional square nanoscale plasmonic optical lattice. The optical potential was created by exciting plasmon resonance by way of illuminating an array of gold nanodiscs with a loosely focused Gaussian beam. This optical potential produced both in-lattice particle transport behavior, which was due to near-field optical gradient forces, and high-velocity (~MUm/s) out-of-lattice particle transport. As a comparison, the natural convection velocity field from a delocalized temperature profile produced by the photothermal heating of the nanoplasmonic array was computed in numerical simulations. This work elucidates the role of photothermal effects on micro- and nanoparticle transport in plasmonic optical lattices. PMID- 27226814 TI - A Qualitative Phenomenological Exploration of Teachers' Experience With Nutrition Education. AB - Background: Nutrition education delivered by classroom teachers has become a popular intervention designed to combat childhood obesity. However, few qualitative studies have explored nutrition education with teachers Purpose: The purpose of this study was to explore how elementary teachers describe their experience with nutrition education. Methods: A qualitative phenomenological approach was used. Semistructured interviews, observations, and document analysis were conducted with 10 teachers who delivered nutrition education in their classrooms. Inductive coding was used to determine invariant constituents, reduce constituents to categories, and cluster categories into themes. Reliability and validity were accomplished through intercoder agreement, audio recording, triangulation, bracketing, and member checking. Results: Results identified 5 core themes related to roles teachers play in nutrition education, the importance placed upon nutrition, motivation for supplementary activities, barriers, and a triadic relationship between students, teachers, and curriculum. Discussion: Findings reveal interactions within the nutrition education experience in which teachers balance barriers with their value of nutrition education and motivation to help students make healthy choices. Translation to Health Education Practice: Health educators should work with classroom teachers at the program design, implementation, and evaluation stages of curriculum development to better address needs and facilitate the delivery of high-quality nutrition education for students. PMID- 27226812 TI - Sirtuin functions and modulation: from chemistry to the clinic. AB - Sirtuins are NAD(+)-dependent histone deacetylases regulating important metabolic pathways in prokaryotes and eukaryotes and are involved in many biological processes such as cell survival, senescence, proliferation, apoptosis, DNA repair, cell metabolism, and caloric restriction. The seven members of this family of enzymes are considered potential targets for the treatment of human pathologies including neurodegenerative diseases, cardiovascular diseases, and cancer. Furthermore, recent interest focusing on sirtuin modulators as epigenetic players in the regulation of fundamental biological pathways has prompted increased efforts to discover new small molecules able to modify sirtuin activity. Here, we review the role, mechanism of action, and biological function of the seven sirtuins, as well as their inhibitors and activators. PMID- 27226816 TI - Evidence based review of type 2 diabetes prevention and management in low and middle income countries. AB - AIM: To identify the newest approaches to type 2 diabetes (T2DM) prevention and control in the developing world context. METHODS: We conducted a systematic review of published studies of diabetes prevention and control programs in low and middle-income countries, as defined by the World Bank. We searched PubMed using Medical Subject Headings terms. Studies needed to satisfy four criteria: (1) Must be experimental; (2) Must include patients with T2DM or focusing on prevention of T2DM; (3) Must have a lifestyle intervention component; (4) Must be written in English; and (5) Must have measurable outcomes related to diabetes. RESULTS: A total of 66 studies from 20 developing countries were gathered with publication dates through September 2014. India contributed the largest number of trials (11/66). Of the total 66 studies reviewed, all but 3 studies reported evidence of favorable outcomes in the prevention and control of type 2 diabetes. The overwhelming majority of studies reported on diabetes management (56/66), and among these more than half were structured lifestyle education programs. The evidence suggests that lifestyle education led by allied health professionals (nurses, pharmacists) were as effective as those led by physicians or a team of clinicians. The remaining diabetes management interventions focused on diet or exercise, but the evidence to recommend one approach over another was weak. CONCLUSION: Large experimental diabetes prevention/control studies of dietary and exercise interventions are lacking particularly those that consider quality rather than quantity of carbohydrates and alternative exercise. PMID- 27226817 TI - Mutual relations between sleep deprivation, sleep stealers and risk behaviours in adolescents. AB - OBJECTIVES: The aim is to evaluate the mutual influences between sleep duration/sleep deprivation (SD) and the sleep stealers/adolescent risk behaviours. METHODS: The national survey is a component of the Health Behaviour in School-Aged Children (HBSC) study, it is based on a school-based self completed questionnaire; 3476 students were randomly selected from 139 randomly chosen Portuguese schools using as an unit the class, 53.8% were girls; 45.9% attended the 8th grade and 54.1% the 10th grade; the mean age was 14.9 years. The measured variables were: 1) gender and age; 2) sociodemographics; 3) sleep duration during the week and during weekends and computed SD; 4) screen time (computer use during the week and during the week end (PC use); watching TV and mobile phone use; 5) earlier sexual behaviour; 6) violent behaviours: fights, use of weapons; 7) use of tobacco, alcohol and drugs. The statistical analysis included Pearson chi-square tests and logistic regression. RESULTS: Excessive use of mobile phone, of computer use during weekdays, and internet facilities; substance use; violence and earlier sexual relations had significantly higher prevalence in sleep deprived adolescents. By logistic regression only using PC during weekdays, tobacco, drugs and weapons were associated to SD, while SD was associated to PC use during weekdays, tobacco use and drugs' use. Computer uses tend to be associated among themselves. Mobile phone is associated with computer practices and with alcohol and tobacco use. Tobacco is associated with most risk behaviours. Alcohol use is associated with other substance use, computer use and violent behaviours. Violence behaviours, earlier sex and drugs use tend to be associated among themselves. CONCLUSIONS: Sleep stealers use and risk behaviours are more prevalent in sleep deprived adolescents, but, in spite of significant individual associations, models of risk behaviours are still lacking. PMID- 27226815 TI - Insulin-secreting beta cells require a post-genomic concept. AB - Pancreatic insulin-secreting beta cells are essential in maintaining normal glucose homeostasis accomplished by highly specialized transcription of insulin gene, of which occupies up to 40% their transcriptome. Deficiency of these cells causes diabetes mellitus, a global public health problem. Although tremendous endeavors have been made to generate insulin-secreting cells from human pluripotent stem cells (i.e., primitive cells capable of giving rise to all cell types in the body), a regenerative therapy to diabetes has not yet been established. Furthermore, the nomenclature of beta cells has become inconsistent, confusing and controversial due to the lack of standardized positive controls of developmental stage-matched in vivo cells. In order to minimize this negative impact and facilitate critical research in this field, a post-genomic concept of pancreatic beta cells might be helpful. In this review article, we will briefly describe how beta cells were discovered and islet lineage is developed that may help understand the cause of nomenclatural controversy, suggest a post-genomic definition and finally provide a conclusive remark on future research of this pivotal cell. PMID- 27226818 TI - Altered clot microstructure detected in obstructive sleep apnoea hypopnoea syndrome. AB - Abnormal clot microstructure plays a pivotal role in the pathophysiology of thromboembolic diseases. Assessing the viscoelastic properties of clot microstructure using novel parameters, Time to Gel Point (T GP ), Fractal Dimension (d f ) and clot elasticity (G' GP ) could explain the increased cardiovascular and thromboembolic events in patients with Obstructive Sleep Apnoea Hypopnea Syndrome (OSAHS). We wanted to compare T GP , d f , and G' GP and their diurnal variation in OSAHS and symptomatic comparators. thirty six patients attending a sleep disturbed breathing clinic with symptoms of OSAHS were recruited. T GP , d f and G' GP were measured alongside standard coagulation screening, thrombin generation assays, and platelet aggregometry at 16:00 h and immediately after an in-patient sleep study at 07:30 h. OSAHS group had significantly lower afternoon d f than comparators (1.705+/-0.033 vs. 1.731+/ 0.031, p<0.05). d f showed diurnal variation and only in the OSAHS group, being significantly lower in the afternoon than morning (p<0.05). Diurnal changes in d f correlated with 4% DR, even after controlling for BMI (r=0.37, p=0.02). The lower d f in the afternoon in OSAHS suggests a partial compensatory change that may make up for other pro-clotting abnormalities/hypertension during the night. The change to the thrombotic tendency in the afternoon is biggest in severe OSAHS. d f Shows promise as a new microstructural indicator for abnormal haemostasis in OSAHS. PMID- 27226819 TI - Extreme late chronotypes and social jetlag challenged by Antarctic conditions in a population of university students from Uruguay. AB - In humans, a person's chronotype depends on environmental cues and on individual characteristics, with late chronotypes prevailing in youth. Social jetlag (SJL), the misalignment between an individual's biological clock and social time, is higher in late chronotypes. Strong SJL is expected in Uruguayan university students with morning class schedules and very late entertainment activities. Sleep disorders have been reported in Antarctic inhabitants, that might be a response to the extreme environment or to the strictness of Antarctic life. We evaluated, for the first time in Uruguay, the chronotypes and SJL of 17 undergraduate students of the First Uruguayan Summer School on Antarctic Research, using Munich Chronotype Questionnaire (MCTQ) and sleep logs (SL) recorded during 3 phases: pre-Antarctic, Antarctic, and post-Antarctic. The midsleep point of free days corrected for sleep debt on work days (MSFsc,) was used as proxy of individuals' chronotype, whose values (around 6 a.m.) are the latest ever reported. We found a SJL of around 2 h in average, which correlated positively with MSFsc, confirming that late chronotypes generate a higher sleep debt during weekdays. Midsleep point and sleep duration significantly decreased between pre-Antarctic and Antarctic phases, and sleep duration rebounded to significant higher values in the post-Antarctic phase. Waking time, but not sleep onset time, significantly varied among phases. This evidence suggests that sleep schedules more likely depended on the social agenda than on the environmental light-dark shifts. High motivation of students towards Antarctic activities likely induced a subjective perception of welfare non-dependent on sleep duration. PMID- 27226820 TI - Immunomodulation by classical conditioning in NZB/W (F1) mice: Lifespan and diurnal variation. AB - Systemic Lupus Eritematosus (SLE) is a systemic inflammatory disease often treated with the agent cyclophosphamide (CY), known by provoking important adverse reactions to the organism. Ader and Cohen have demonstrated an alternative way of administrating this agent based on pavlovian conditioning, in order to reduce the aggression caused by CY. Considering the influence of the temporal organization on learning and memory processes, the purpose of this study was to understand the temporal aspects involved in the conditioned immunomodulation. In a search for circadian modulation, we selected NZB/W (F1) female mice, a strain that spontaneously develop SLE. Divided into two major groups, the animals were submitted, in different phases of day, to a classical conditioning immunomodulation protocol, consisting in weekly parings of saccharin solution and CY injections. The success of the paradigm was evaluated by comparing lifespan among the groups. Simultaneously, it was monitored the water intake behavior, in order to correlate the stability of two rhythmic parameters, amplitude and spectral power density of the 24-h rhythm, with the progression of SLE. Our results indicate that mice could benefit from the conditioning task performed either in the light phase or in the dark phase of the LD cycle, as expressed by an increased lifespan. Concerning the rhythmic parameters, there was evidence of association between the rhythmic stability and the evolution of SLE, demonstrated by the maintenance of healthy levels of amplitude and spectral potency of the 24-h rhythm in animals exposed to the conditioning paradigm. PMID- 27226822 TI - Coupling the Multizone Airflow and Contaminant Transport Software CONTAM with EnergyPlus Using Co-Simulation. AB - Building modelers need simulation tools capable of simultaneously considering building energy use, airflow and indoor air quality (IAQ) to design and evaluate the ability of buildings and their systems to meet today's demanding energy efficiency and IAQ performance requirements. CONTAM is a widely-used multizone building airflow and contaminant transport simulation tool that requires indoor temperatures as input values. EnergyPlus is a prominent whole-building energy simulation program capable of performing heat transfer calculations that require interzone and infiltration airflows as input values. On their own, each tool is limited in its ability to account for thermal processes upon which building airflow may be significantly dependent and vice versa. This paper describes the initial phase of coupling of CONTAM with EnergyPlus to capture the interdependencies between airflow and heat transfer using co-simulation that allows for sharing of data between independently executing simulation tools. The coupling is accomplished based on the Functional Mock-up Interface (FMI) for Co simulation specification that provides for integration between independently developed tools. A three-zone combined heat transfer/airflow analytical BESTEST case was simulated to verify the co-simulation is functioning as expected, and an investigation of a two-zone, natural ventilation case designed to challenge the coupled thermal/airflow solution methods was performed. PMID- 27226823 TI - NGR-tagged nano-gold: A new CD13-selective carrier for cytokine delivery to tumors. AB - Colloidal gold (Au), a well-tolerated nanomaterial, is currently exploited for several applications in nanomedicine. We show that gold nanoparticles tagged with a novel tumor-homing peptide containing Asn-Gly-Arg (NGR), a ligand of CD13 expressed by the tumor neovasculature, can be exploited as carriers for cytokine delivery to tumors. Biochemical and functional studies showed that the NGR molecular scaffold/linker used for gold functionalization is critical for CD13 recognition. Using fibrosarcoma-bearing mice, NGR-tagged nanodrugs could deliver extremely low, yet pharmacologically active doses of tumor necrosis factor (TNF), an anticancer cytokine, to tumors with no evidence of toxicity. Mechanistic studies confirmed that CD13 targeting was a primary mechanism of drug delivery and excluded a major role of integrin targeting consequent to NGR deamidation, a degradation reaction that generates the isoAsp-Gly-Arg (isoDGR) integrin ligand. NGR-tagged gold nanoparticles can be used, in principle, as a novel platform for single- or multi-cytokine delivery to tumor endothelial cells for cancer therapy. PMID- 27226821 TI - REM sleep deprivation promotes a dopaminergic influence in the striatal MT2 anxiolytic-like effects. AB - The aim of this study was to investigate the possible anxiolytic-like effects of striatal MT2 activation, and its counteraction induced by the selective blockade of this receptor. Furthermore, we analyzed this condition under the paradigm of rapid eye movement (REM) sleep deprivation (REMSD) and the animal model of Parkinson's disease (PD) induced by rotenone. Male Wistar rats were infused with intranigral rotenone (12 MUg/MUL), and 7 days later were subjected to 24 h of REMSD. Afterwards the rats underwent striatal micro-infusions of selective melatonin MT2 receptor agonist, 8-M-PDOT (10 MUg/MUL) or selective melatonin MT2 receptor antagonist, 4-P-PDOT (5 MUg/MUL) or vehicle. Subsequently, the animals were tested in the open-field (OP) and elevated plus maze (EPM) tests. Results indicated that the activation of MT2 receptors produced anxiolytic-like effects. In opposite, the MT2 blockade did not show an anxiogenic-like effect. Besides, REMSD induced anxiolytic-like effects similar to 8-M-PDOT. MT2 activation generated a prevalent locomotor increase compared to MT2 blockade in the context of REMSD. Together, these results suggest a striatal MT2 modulation associated to the REMSD-induced dopaminergic supersensitivity causing a possible dopaminergic influence in the MT2 anxiolytic-like effects in the intranigral rotenone model of PD. PMID- 27226824 TI - Delay and restricted access of new molecules in Turkey compared to the United States and European Union. AB - OBJECTIVE: This study compares the performances of new-molecule (NM) launches in Turkey with those in the European Union and United States for the years 2007 2013. METHODS: The Thomson Reuters Newport Horizon for Innovators Database is used to identify NMs with a launch date after January 1, 2007, worldwide and marketing authorization approval after January 1, 2007, in the European Union. The launch dates for the European Union, the United States, and Turkey were retrieved from the same database. Data for Turkey were confirmed via IMS and RxMedia. RESULTS: Out of 183 records identified that are launched in the European Union, the United States, or both, 44 of the NMs are launched in Turkey (24%). CONCLUSION: The results of this study show that 24% of the NMs that are launched in either the European Union or United States were able to be launched in Turkey with a mean delay of 821 days (2.25 years). PMID- 27226825 TI - New drug regulations in France: what are the impacts on market access? Part 1 - Overview of new drug regulations in France. AB - Access to the French drug market is being impacted by an ongoing dramatic shift in practice as well as by two laws that came into force in December 2011. This new environment has been described and analyzed in two separate articles. The first article aims to describe the recent changes in access to the French drug market. The severity of the condition being treated, which used to be the main determinant of the drug's reimbursement level in France, has now been replaced with the drugs' efficacy criterion. Moreover, the effect size required for acknowledging drug innovation has substantially increased. Perceived evidence might also be more important than actual evidence. Comparative evidence and real world data are considered critical conditions for marketing authorization. Cost effectiveness studies will now be part of the market access requirements for all drugs in order to satisfy the selection criteria for medico-economic assessment. PMID- 27226826 TI - Drug reformulations and repositioning in pharmaceutical industry and its impact on market access: reassessment of nomenclature. AB - BACKGROUND: Medicinal products that have been developed and approved for one disease may be the object of additional clinical development in other disease areas or of additional pharmaceutical development for new and different formulations. The newly developed products can be named as repositioned or reformulated products, respectively. Market access of repositioned or reformulated products in Europe and the United States is an interesting object of study as it may provide clarity about which parameters are assessed and considered to bring added value, other than the molecule itself. As such, we aim to evaluate if the added value of repositioned or reformulated medicinal products can be systematically described, quantified, and predicted. As a first step toward investigating the impact of market access on drug research and development trends for repositioned and reformulated products, it is necessary to have consistency in the designations for the case studies evaluated in this project. In an attempt to achieve that consistency, the current study aims to propose harmonized definitions for the repositioning and reformulation strategies and to propose a taxonomy for the medicinal products derived thereof. METHODS: A systematic literature review was conducted to collect information on existing cases of repositioning or reformulation. A search strategy was developed by defining the search objectives, targeted data sources, search keywords, and inclusion/exclusion criteria for the retrieved documents. RESULTS: A total of 505 publications were retrieved through a search of the main data sources. The screenings and the ad hoc search led to a total of 56 publications to be used for the case study data extraction. In total, 87 repositioning and/or reformulation cases were found described in the literature, 23 of which presented different definitions and/or classifications by different authors. CONCLUSION: Given the disparity and inconsistency of terminologies and classifications in the literature, a harmonized nomenclature for drug repositioning, reformulation, and combination cases will allow for a robust analysis of the added value and market access conditions attributed for each strategy and case type as assessed by regulators and payors in Europe and the United States. After evaluation of the existing terminologies and given the absence of clear and consistent definitions for drug reformulation and repositioning in the literature, we propose a global terminology and taxonomy in order to cover all of the previously unclear definitions and classifications for repositioned and reformulated products. PMID- 27226827 TI - The Market Access Society launches a new journal. PMID- 27226828 TI - Benefits of probabilistic sensitivity analysis - a review of NICE decisions. AB - OBJECTIVE: Since 2004, the National Institute of Health and Clinical Excellence (NICE) has required manufacturers to conduct a probabilistic sensitivity analysis (PSA) in their technology appraisals. The objective of this review is to assess the cost-effectiveness of different technology appraisals and compare them with the actual decision made by the NICE based on PSA. METHODS: The search term 'probabilistic sensitivity analysis' was used on the NICE home page (25 January 2012). The appraisals identified in the search were assessed and subjected to further review, if a probability of being cost-effective was provided, regardless of the threshold indicated. If several probabilities were provided, the number provided by the evidence review group was used. If several scenarios were presented, the base case scenario was chosen. Finally, the probabilities of being cost-effective were compared with the actual decision made, which could result in two outcomes: recommended or not recommended. RESULTS: A total of 31 assessments were included for the final review. The results were plotted on a graph to illustrate whether there was a relationship between the PSA outcomes and the final recommendation. The assessments were ranked according to their probability of being cost-effective. CONCLUSION: A higher probability of a technology being cost-effective was correlated with more positive decision-making. There appeared to be a clear threshold at which technologies with a 40% certainty of being cost effective tended to be recommended, whereas those below the threshold were not recommended. The reports suggested that the incremental cost-effectiveness ratios (ICER) estimate was not a robust driver of decision-making. A NICE applicant should pay increased attention to the PSA in addition to the ICER estimate. PMID- 27226829 TI - New drug regulations in France: what are the impacts on market access? Part 2 - impacts on market access and impacts for the pharmaceutical industry. AB - Access to the French drug market is being impacted by an ongoing dramatic shift in practice as well as by two laws that came into force in December 2011. This new environment has been described and analyzed in two separate articles. This second article analyzes how this new environment will actually impact the access to French drug market. French drug market access will be increasingly driven by comparative-effectiveness and cost-effectiveness data, and an increased role of postmarketing studies in the years to come. This access is evolving in a more complex environment for stakeholders due to the uncertainties surrounding these changes and it will be more complex and difficult for the pharmaceutical industry to address. The main issue faced by the pharmaceutical companies will be to minimize uncertainty at the time of a drug's launch to narrow the decision window. This is a major change of paradigm for the pharmaceutical business, in which pre- and postlaunch risks are directed toward the pharmaceutical industry. PMID- 27226830 TI - Pharmaceutical expenditure forecast model to support health policy decision making. AB - BACKGROUND AND OBJECTIVE: With constant incentives for healthcare payers to contain their pharmaceutical budgets, modelling policy decision impact became critical. The objective of this project was to test the impact of various policy decisions on pharmaceutical budget (developed for the European Commission for the project 'European Union (EU) Pharmaceutical expenditure forecast' - http://ec.europa.eu/health/healthcare/key_documents/index_en.htm). METHODS: A model was built to assess policy scenarios' impact on the pharmaceutical budgets of seven member states of the EU, namely France, Germany, Greece, Hungary, Poland, Portugal, and the United Kingdom. The following scenarios were tested: expanding the UK policies to EU, changing time to market access, modifying generic price and penetration, shifting the distribution chain of biosimilars (retail/hospital). RESULTS: Applying the UK policy resulted in dramatic savings for Germany (10 times the base case forecast) and substantial additional savings for France and Portugal (2 and 4 times the base case forecast, respectively). Delaying time to market was found be to a very powerful tool to reduce pharmaceutical expenditure. Applying the EU transparency directive (6-month process for pricing and reimbursement) increased pharmaceutical expenditure for all countries (from 1.1 to 4 times the base case forecast), except in Germany (additional savings). Decreasing the price of generics and boosting the penetration rate, as well as shifting distribution of biosimilars through hospital chain were also key methods to reduce pharmaceutical expenditure. Change in the level of reimbursement rate to 100% in all countries led to an important increase in the pharmaceutical budget. CONCLUSIONS: Forecasting pharmaceutical expenditure is a critical exercise to inform policy decision makers. The most important leverages identified by the model on pharmaceutical budget were driven by generic and biosimilar prices, penetration rate, and distribution. Reducing, even slightly, the prices of generics had a major impact on savings. However, very aggressive pricing of generic and biosimilar products might make this market unattractive and can be counterproductive. Worth noting, delaying time to access innovative products was also identified as an effective leverage to increase savings but might not be a desirable policy for breakthrough products. Increasing patient financial contributions, either directly or indirectly via their private insurances, is a more likely scenario rather than expanding the national pharmaceutical expenditure coverage. PMID- 27226831 TI - Challenges in generating costs and utilisation rates associated with castration resistant prostate cancer. AB - BACKGROUND: Prostate cancer (PCa), the most commonly diagnosed cancer among men in the United States and Europe, is an escalating resource allocation issue across healthcare systems in the Western world. The impact of skeletal-related events, associated with castration-resistant prostate cancer (CRPC), is considerable with many new therapies being sought to treat these events in a cost effective manner. AIMS: The aim of this paper is to provide insight into the level of constraints associated with devising cost frameworks for economic analysis of CRPC in the Irish healthcare setting. METHODS: An informal questionnaire was devised to obtain estimates of utilisation to populate a decision tree model; existing parameters from the literature were also employed. Cost parameters included Irish reference costs, and a costs literature review was undertaken; a healthcare payer perspective was adopted. Pharmacy dosages used for modelling costs were calculated for an average 75 kg male. RESULTS: The estimated average cost of care associated with adverse events in CRPC was ?23,264. Approximately 40% of the costs of CRPC are attributed to skeletal-related events; therefore, reducing the number of skeletal-related events could significantly reduce the cost of care. In attempting to generate accurate and reliable cost parameters, this study highlights the challenges of conducting economic analysis in the Irish healthcare setting. CONCLUSION: This study presents leading treatments and associated costs for CRPC patients in the Republic of Ireland (RoI), which are expected to steadily increase with demographic shifts. Further research is warranted in this area due to the limitations encountered in the study. PMID- 27226832 TI - Health technology assessment in middle-income countries: recommendations for a balanced assessment system. AB - Because of significant differences in institutional contexts, health technology assessment (HTA) systems that are in place in core pharmaceutical markets may not be suitable, fully or in part, for middle-income countries (MICs) and for other noncore markets. Particular challenges may arise when systems based on the economic evaluation paradigm are conceptualized and implemented in MICs, sometimes with an insufficient level of awareness of the local institutional factors that influence pricing and reimbursement decision making. Focusing on pharmaceuticals, this article investigates possible development directions for HTA systems in MICs and noncore markets bearing similar institutional characteristics, and it provides recommendations for a balanced assessment system (BAS). For this, the main paradigms of HTA have also been reviewed briefly and factors influencing HTA and pricing and reimbursement decisions in MICs and in similar noncore countries have been summarized. The proposed BAS framework takes into account available resources and capabilities and is supposed to facilitate access to new pharmaceuticals while ensuring the transparency of decision-making processes and the stability of the pharmaceutical budget. PMID- 27226833 TI - Drug repurposing in pharmaceutical industry and its impact on market access: market access implications. AB - BACKGROUND: Drug repurposing is a group of development strategies employed in order to overcome some of the hurdles innate to drug research and development. Drug repurposing includes drug repositioning, reformulation and combination. OBJECTIVE: This study aimed to identify the determinants of successful market access outcome for drug repurposing in the United States of America (USA) and in Europe. METHODS: The case studies of repurposing strategies were identified through a systematic review of the literature. Price information and reimbursement conditions for all the case studies were collected mainly through access of public datasources. A list of attributes that could be associated with market access outcome (price level and reimbursement conditions) was developed, discussed, and validated by an external expert group. Detailed information for all attributes was researched and collected for each case study. Bivariate regression models were conducted to identify factors associated with price change for all repurposing cases. A similar analysis was performed for reformulation and repositioning cases, in the USA and in Europe, separately. A significance level of 5% was used for all analyses. RESULTS: A total of 144 repurposing case studies were included in the statistical analysis for evaluation of mean price change. Combination cases (the combination of two or more individual drug components) were excluded from the statistical analysis due to the low number of cases retrieved. The main attributes associated with a significant price increase for overall repurposing cases were 'change in administration setting to hospital' (374%, p<0.0001), 'addressing unmet needs' (69%, p<0.05), 'reformulations belonging to Group 3'-that is, change in administration route (117%, p<0.001), and being a repurposed product with the 'same brand name' as the original product (65%, p<0.05). CONCLUSION: We found that the ability of the repurposed product to address unmet needs, a reformulation where the target product had a different administration route than the source product, and having a similar brand name for repurposed and original products, were variables that impacted a positive price change for repurposed drugs overall. Our research results also suggested that orphan designation could have a positive impact for repositioning in the USA, in particular. Although a change of administration from ambulatory to hospital setting seemed to be significantly correlated with a price increase for the target product, only one case was retrieved for this parameter; as such, it was not possible to infer a firm correlation between this parameter and a change in price. PMID- 27226834 TI - Pharmaceutical market access in emerging markets: concepts, components, and future. AB - This article intends to consolidate the concepts of pharmaceutical market access and highlight its growing importance in emerging markets. Market access has gained considerable attention worldwide as countries try to contain their escalating healthcare expenditures amidst the global economic slowdown. This has resulted in governments adopting stricter measures for new product approval. Thus, pharmaceutical companies are finding it increasingly difficult to successfully address the specific challenges posed by various government and regulatory agencies and stakeholders. There is an increasing need to establish market access functions, especially in emerging markets, where the complex, dynamic healthcare landscape confounds product approval and uptake. Moreover, emerging markets are the engines of growth today, and, thus, performing in these markets is critical for the majority of pharmaceutical companies. To address the challenges posed by regulatory agencies and diverse stakeholders, a customized market access strategy is the need of the hour. A market access framework with specific tools and tactics will help companies to plan, implement, and monitor stakeholder engagement activities. PMID- 27226835 TI - And if the discovery of new drugs for the treatment of brain diseases depends on Asian countries? AB - At the present time, developed countries are making a huge financial effort to support neuroscience research programs, particularly in the fields of advanced research and treatment of brain diseases and mental disorders. A part of this financial support is devoted to drug discovery programs. The purpose of this communication is to focus on the different parameters (economic, social, and scientific) allowing for the prominent belief that the discovery of new efficient drugs to treat brain disease to an increasing extent is likely to emanate from the Asian countries. A special focus on drug research and discovery in France reveals that, due to the current social context, the lack of small pharmaceutical ventures, the Mediator drug scandal, and the economic situation, the potential for discovering and developing new drugs is dramatically declining. PMID- 27226836 TI - The value of quantitative patient preferences in regulatory benefit-risk assessment. AB - Quantitative patient preferences are a method to involve patients in regulatory benefit-risk assessment. Assuming preferences can be elicited, there might be multiple advantages to their use. Legal, methodological and procedural issues do however imply that preferences are currently at most part of the solution on how to best involve patients in regulatory decision making. Progress is recently made on these issues. PMID- 27226837 TI - EU pharmaceutical expenditure forecast. AB - BACKGROUND AND OBJECTIVES: With constant incentives for healthcare payers to contain their pharmaceutical budgets, forecasting has become critically important. Some countries have, for instance, developed pharmaceutical horizon scanning units. The objective of this project was to build a model to assess the net effect of the entrance of new patented medicinal products versus medicinal products going off-patent, with a defined forecast horizon, on selected European Union (EU) Member States' pharmaceutical budgets. This model took into account population ageing, as well as current and future country-specific pricing, reimbursement, and market access policies (the project was performed for the European Commission; see http://ec.europa.eu/health/healthcare/key_documents/index_en.htm). METHOD: In order to have a representative heterogeneity of EU Member States, the following countries were selected for the analysis: France, Germany, Greece, Hungary, Poland, Portugal, and the United Kingdom. A forecasting period of 5 years (2012 2016) was chosen to assess the net pharmaceutical budget impact. A model for generics and biosimilars was developed for each country. The model estimated a separate and combined effect of the direct and indirect impacts of the patent cliff. A second model, estimating the sales development and the risk of development failure, was developed for new drugs. New drugs were reviewed individually to assess their clinical potential and translate it into commercial potential. The forecast was carried out according to three perspectives (healthcare public payer, society, and manufacturer), and several types of distribution chains (retail, hospital, and combined retail and hospital). Probabilistic and deterministic sensitivity analyses were carried out. RESULTS: According to the model, all countries experienced drug budget reductions except Poland (+?41 million). Savings were expected to be the highest in the United Kingdom (-?9,367 million), France (-?5,589 million), and, far behind them, Germany (-?831 million), Greece (-?808 million), Portugal (-?243 million), and Hungary (-?84 million). The main source of savings came from the cardiovascular, central nervous system, and respiratory areas and from biosimilar entries. Oncology, immunology, and inflammation, in contrast, lead to additional expenditure. The model was particularly sensitive to the time to market of branded products, generic prices, generic penetration, and the distribution of biosimilars. CONCLUSIONS: The results of this forecast suggested a decrease in pharmaceutical expenditure in the studied period. The model was sensitive to pharmaceutical policy decisions. PMID- 27226838 TI - Economic impact of new active substance status on EU payers' budgets: example of dimethyl fumarate (Tecfidera((r))) for multiple sclerosis. AB - BACKGROUND: Recently, collaboration between regulators and payers was set up and was mainly focused on evidence generation along product clinical development. However, neither the regulatory path nor the new active substance status (NASs) was considered. Granting NASs will provide the product with 8 years of data protection and 2 years of market exclusivity during which no generic could enter the market. OBJECTIVE: To review the economic impact (for payers) of NASs granted by the European Medicines Agency (EMA) for dimethyl fumarate (DMF), developed by Biogen and approved for multiple sclerosis (MS) as Tecfidera((r)) on 3 February 2014. METHOD: We reviewed the available DMF-containing products and identified their indication and price through relevant databases and official Web sites. The economic impact of Tecfidera((r)) on payers' budgets was calculated assuming NASs was or was not granted. The forecast was identified in Datamonitor. RESULTS: Results identified four products already containing DMF as the main or unique active substance. This would have potentially prevented Tecfidera((r)) from being granted NASs. The EMA Committee for Medicinal Products for Human Use (CHMP) denied Tecfidera((r)) NASs and, following a company appeal, reversed its position opening as polemic. The impact of that decision has been evaluated at ?7 to ?10 billion over a 10-year period. CONCLUSION: NASs is a critical decision because it does have a major budget impact for payers, and it prevents generic competition. Current European Union (EU) regulations on that topic are unclear and open up too many interpretations thus distorting fair trade and affecting payers' bills. Greater clarity and more stringent rules are required to prevent mistrust of this EMA decision. PMID- 27226839 TI - Drug reformulations and repositioning in the pharmaceutical industry and their impact on market access: regulatory implications. AB - BACKGROUND: Repurposing has become a mainstream strategy in drug development, but it faces multiple challenges, amongst them the increasing and ever changing regulatory framework. This is the second study of a series of three-part publication project with the ultimate goal of understanding the market access rationale and conditions attributed to drug repurposing in the United States and in Europe. The aim of the current study to evaluate the regulatory path associated with each type of repurposing strategy according to the previously proposed nomenclature in the first article of this series. METHODS: From the cases identified, a selection process retrieved a total of 141 case studies in all countries, harmonized for data availability and common approval in the United States and in Europe. Regulatory information for each original and repurposed drug product was extracted, and several related regulatory attributes were also extracted such as, designation change and filing before or after patent expiry, among others. Descriptive analyses were conducted to determine trends and to investigate potential associations between the different regulatory paths and attributes of interest, for reformulation and repositioning cases separately. RESULTS: Within the studied European countries, most of the applications for reformulated products were filed through national applications. In contrast, for repositioned products, the centralized procedure was the most frequent regulatory pathway. Most of the repurposing cases were approved before patent expiry, and those cases have followed more complex regulatory pathways in the United States and in Europe. For new molecular entities filed in the United States, a similar number of cases were developed by serendipity and by a hypothesis-driven approach. However, for the new indication's regulatory pathway in the United States, most of the cases were developed through a hypothesis-driven approach. CONCLUSION: The regulations in the United States and in Europe for drug repositionings and reformulations allowed confirming that repositioning strategies were usually filed under a more complex regulatory process than reformulations. Also, it seems that parameters such as patent expiry and type of repositioning approach or reformulation affect the regulatory pathways chosen for each case. PMID- 27226840 TI - Are payers treating orphan drugs differently? AB - BACKGROUND: Some orphan drugs can cost hundreds of thousands of dollars annually per patient. As a result, payer sensitivity to the cost of orphan drugs is rising, particularly in light of increased numbers of new launches in recent years. In this article, we examine payer coverage in the United States, England and Wales, and the Netherlands of outpatient orphan drugs approved between 1983 and 2012, as well as the 11 most expensive orphan drugs. METHODS: We collected data from drug regulatory agencies as well as payers and drug evaluation authorities. RESULTS: We found that orphan drugs have more coverage restrictions than non-orphan drugs in all three jurisdictions. From an economic perspective, the fact that a drug is an orphan product or has a high per-unit price per se should not imply a special kind of evaluation by payers, or necessarily the imposition of more coverage restrictions. CONCLUSION: Payers should consider the same set of decision criteria that they do with respect to non-orphan drugs: disease severity, availability of treatment alternatives, level of unmet medical need, and cost-effectiveness, criteria that justifiably may be taken into account and traded off against one another in prescribing and reimbursement decisions for orphan drugs. PMID- 27226841 TI - Pricing and reimbursement of novel oncology drugs in Sweden. PMID- 27226842 TI - Is the gap between micro- and macroeconomic assessments in health care well understood? The case of vaccination and potential remedies. AB - Vaccination is an established intervention that reduces the burden and prevents the spread of infectious diseases. Investing in vaccination is known to offer a wide range of economic and intangible benefits that can potentiate gains for the individual and for society. The discipline of economics provides us with microeconomic and macroeconomic methods for evaluating the economic gains attributed to health status changes. However, the observed gap between micro and macro estimates attributed to health presents challenges to our understanding of health-related productivity changes and, consequently, economic benefits. The gap suggests that the manner in which health-related productive output is quantified in microeconomic models might not adequately reflect the broader economic benefit. We propose that there is a transitional domain that links the micro- and macroeconomic improvement attributed to health status changes. Currently available economic evaluation methods typically omit these consequences, however; they may be adjusted to integrate these transitional consequences. In practical terms, this may give rise to multipliers to apply toward indirect costs to account for the broader macroeconomic benefits linked to changes in health status. In addition, it is possible to consider that different medical conditions and health care interventions may pose different multiplying effects, suggesting that the manner in which resources are allocated within health services gives rise to variation in the amount of the micro-macro gap. An interesting way to move forward in integrating the micro- and macro-level assessment might be by integrating computable general equilibrium (CGE) models as part of the evaluation framework, as was recently performed for pandemic flu and malaria vaccination. PMID- 27226843 TI - Novel methodology for pharmaceutical expenditure forecast. AB - BACKGROUND AND OBJECTIVE: The value appreciation of new drugs across countries today features a disruption that is making the historical data that are used for forecasting pharmaceutical expenditure poorly reliable. Forecasting methods rarely addressed uncertainty. The objective of this project was to propose a methodology to perform pharmaceutical expenditure forecasting that integrates expected policy changes and uncertainty (developed for the European Commission as the 'EU Pharmaceutical expenditure forecast'; see http://ec.europa.eu/health/healthcare/key_documents/index_en.htm). METHODS: 1) Identification of all pharmaceuticals going off-patent and new branded medicinal products over a 5-year forecasting period in seven European Union (EU) Member States. 2) Development of a model to estimate direct and indirect impacts (based on health policies and clinical experts) on savings of generics and biosimilars. Inputs were originator sales value, patent expiry date, time to launch after marketing authorization, price discount, penetration rate, time to peak sales, and impact on brand price. 3) Development of a model for new drugs, which estimated sales progression in a competitive environment. Clinical expected benefits as well as commercial potential were assessed for each product by clinical experts. Inputs were development phase, marketing authorization dates, orphan condition, market size, and competitors. 4) Separate analysis of the budget impact of products going off-patent and new drugs according to several perspectives, distribution chains, and outcomes. 5) Addressing uncertainty surrounding estimations via deterministic and probabilistic sensitivity analysis. RESULTS: This methodology has proven to be effective by 1) identifying the main parameters impacting the variations in pharmaceutical expenditure forecasting across countries: generics discounts and penetration, brand price after patent loss, reimbursement rate, the penetration of biosimilars and discount price, distribution chains, and the time to reach peak sales for new drugs; 2) estimating the statistical distribution of the budget impact; and 3) testing different pricing and reimbursement policy decisions on health expenditures. CONCLUSIONS: This methodology was independent of historical data and appeared to be highly flexible and adapted to test robustness and provide probabilistic analysis to support policy decision making. PMID- 27226844 TI - Health economic value of an innovation: delimiting the scope and framework of future market entry agreements. AB - BACKGROUND AND OBJECTIVES: The objective of our paper is to offer a new, payer friendly taxonomy of market entry agreements (MEAs) that aims to twin contracts with their methodological designs in an effort to clarify the distinction between contracts that are based on performance and those that are based on demonstrated effect. METHODS: Our analysis proceeds in two stages: First, we delimit the scope and framework of pay for performance (P4P) and pay for demonstrated effect (P4E) agreements. Second, we distinguish the methodological designs supporting the implementation of each of these contracts. RESULTS: We elucidate why P4P contracts prevent the payer from funding the true effectiveness of an innovation by expanding on their limitations. These include: 1) the normative nature of comparisons, 2) the impossibility of true effect imputability for each individual, and 3) the use of intermediary outcome measures. We then explore three main criticisms that payers must take into account when reasoning in terms of performance rather than in terms of the product effectiveness. CONCLUSION: The potential effect that performance-based reimbursements may have on dissociating the components of the cost-effectiveness ratio constitutes an obstacle to a true health economic reasoning. PMID- 27226845 TI - Feasibility and attractiveness of indication value-based pricing in key EU countries. AB - Indication value-based pricing (IBP) has been proposed in the United States as a tool to capture the differential value of drugs across indications or patient groups and is in the early phases of implementation. In Europe, no major country has experimented with IBP or is seriously discussing its use. We assessed how the reimbursement and pricing environment allows for IBP in seven European countries, evaluating both incentives and hurdles. In price setting countries such as France and Germany, the Health Technology Assessment and pricing process already accounts for differences of value across indications. In countries where differential value drives coverage decisions such as the United Kingdom and Sweden, IBP is likely to be used, at least partially, but not in the short-term. Italy is already achieving some form of differential value through managed entry agreements, whereas in Spain the electronic prescription system provides the infrastructure necessary for IBP but other hurdles exist. PMID- 27226846 TI - Preface : Invited Issue Editor, Professor Joon-Ki Kang, and the Topic, Craniosynostosis. PMID- 27226847 TI - Genetic Syndromes Associated with Craniosynostosis. AB - Craniosynostosis is defined as the premature fusion of one or more of the cranial sutures. It leads not only to secondary distortion of skull shape but to various complications including neurologic, ophthalmic and respiratory dysfunction. Craniosynostosis is very heterogeneous in terms of its causes, presentation, and management. Both environmental factors and genetic factors are associated with development of craniosynostosis. Nonsyndromic craniosynostosis accounts for more than 70% of all cases. Syndromic craniosynostosis with a certain genetic cause is more likely to involve multiple sutures or bilateral coronal sutures. FGFR2, FGFR3, FGFR1, TWIST1 and EFNB1 genes are major causative genes of genetic syndromes associated with craniosynostosis. Although most of syndromic craniosynostosis show autosomal dominant inheritance, approximately half of patients are de novo cases. Apert syndrome, Pfeiffer syndrome, Crouzon syndrome, and Antley-Bixler syndrome are related to mutations in FGFR family (especially in FGFR2), and mutations in FGFRs can be overlapped between different syndromes. Saethre-Chotzen syndrome, Muenke syndrome, and craniofrontonasal syndrome are representative disorders showing isolated coronal suture involvement. Compared to the other types of craniosynostosis, single gene mutations can be more frequently detected, in one-third of coronal synostosis patients. Molecular diagnosis can be helpful to provide adequate genetic counseling and guidance for patients with syndromic craniosynostosis. PMID- 27226848 TI - Development and Growth of the Normal Cranial Vault : An Embryologic Review. AB - Understanding the development of a skull deformity requires an understanding of the normal morphogenesis of the cranium. Craniosynostosis is the premature, pathologic ossification of one or more cranial sutures leading to skull deformities. A review of the English medical literature using textbooks and standard search engines was performed to gather information about the prenatal development and growth of the cranial vault of the neurocranium. A process of morphogenic sequencing begins during prenatal development and growth, continues postnatally, and contributes to the basis for the differential manner of growth of cranial vault bones. This improved knowledge might facilitate comprehension of the pathophysiology of craniosynostosis. PMID- 27226849 TI - Craniosynostosis in Growing Children : Pathophysiological Changes and Neurosurgical Problems. AB - Craniosynostosis is defined as the premature fusion of one or more cranial sutures resulting in skull deformity. Characteristically, this disorder can cause diverse neurosurgical problems, as well as abnormal skull shape. Intracranial hypertension, hydrocephalus, Chiari malformation and neuropsychological dysfunction are the major neurosurgical concerns in children with craniosynostosis. In this review article, we investigate pathophysiology, characteristics and proper neurosurgical management of these neurosurgical issues, respectively. PMID- 27226851 TI - Update of Diagnostic Evaluation of Craniosynostosis with a Focus on Pediatric Systematic Evaluation and Genetic Studies. AB - Most craniosynostoses are sporadic, but may have an underlying genetic basis. Secondary and syndromic craniosynostosis accompanies various systemic diseases or associated anomalies. Early detection of an associated disease may facilitate the interdisciplinary management of patients and improve outcomes. For that reason, systematic evaluation of craniosynostosis is mandatory. The authors reviewed systematic evaluation of craniosynostosis with an emphasis on genetic analysis. PMID- 27226850 TI - Physiological Changes and Clinical Implications of Syndromic Craniosynostosis. AB - Syndromic craniosynostosis has severe cranial stenosis and deformity, combined with hypoplastic maxillary bone and other developmental skeletal lesions. Among these various lesions, upper air way obstruction by hypoplastic maxillary bone could be the first life-threatening condition after birth. Aggressive cranial vault expansion for severely deformed cranial vaults due to multiple synostoses is necessary even in infancy, to normalize the intracranial pressure. Fronto orbital advancement (FOA) is recommended for patients with hypoplastic anterior part of cranium induced by bicoronal and/or metopic synostoses, and posterior cranial vault expansion is recommended for those with flattening of the posterior part of the cranium by lambdoid synostosis. Although sufficient spontaneous reshaping of the cranium can be expected by expansive cranioplasty, keeping the cranial bone flap expanded sufficiently is often difficult when the initial expansion is performed during infancy. So far distraction osteogenesis (DO) is the only method to make it possible and to provide low rates of re-expansion of the cranial vault. DO is quite beneficial for both FOA and posterior cranial vault expansion, compared with the conventional methods. Associated hydrocephalus and chronic tonsillar herniation due to lambdoid synostosis can be surgically treatable. Abnormal venous drainages from the intracranial space and air way obstruction should be always considered at any surgical procedures. Neurosurgeons have to know well about the managements not only of the deformed cranial vault and the associated brain lesions but also of other multiple skeletal lesions associated with syndromic craniosynostosis, to improve treatment outcome. PMID- 27226852 TI - Craniosynostosis : Updates in Radiologic Diagnosis. AB - The purpose of this article is to review imaging findings and to discuss the optimal imaging methods for craniosynostosis. The discussion of imaging findings are focused on ultrasonography, plain radiography, magnetic resonance imaging and computed tomography with 3-dimensional reconstruction. We suggest a strategy for imaging work-up for the diagnosis, treatment planning and follow-up to minimize or avoid ionized radiation exposure to children by reviewing the current literature. PMID- 27226853 TI - Minimally Invasive Suturectomy and Postoperative Helmet Therapy : Advantages and Limitations. AB - Various operative techniques are available for the treatment of craniosynostosis. The patient's age at presentation is one of the most important factors in the determination of the surgical modality. Minimally invasive suturectomy and postoperative helmet therapy may be performed for relatively young infants, whose age is younger than 6 months. It relies upon the potential for rapid brain growth in this age group. Its minimal invasiveness is also advantageous. In this article, we review the advantages and limitations of minimally invasive suturectomy followed by helmet therapy for the treatment of craniosynostosis. PMID- 27226854 TI - Distraction Osteogenesis Update: Introduction of Multidirectional Cranial Distraction Osteogenesis. AB - In this review, we discuss in detail our current procedure for treating craniosynostosis using multidirectional cranial distraction osteogenesis (MCDO). The MCDO method allows all phenotypes of skull deformity to be reshaped by distraction osteogenesis, except in patients who are 5 months of age or younger and patients with posterior cranial vault problems. We report the results of clinical data of 36 children with craniosynostosis who underwent MCDO between 2005 and 2014 in our institute. This method has the following benefits, such as a high flexibility of reshaping, shorter treatment period and less invasive secondary intervention. We also discuss the other distraction osteogenesis techniques that are used to treat craniosynostosis and compare them with MCDO. The preferred procedure for correction of craniosynostosis may depend on the patient's age, the extent of deformity, and the extent of correction achievable by surgery. We can arrange the combinations of various methods according to the advantage and disadvantage of each technique. PMID- 27226855 TI - Neurodevelopmental Problems in Non-Syndromic Craniosynostosis. AB - Craniosynostosis is the premature fusion of calvarial sutures, resulting in deformed craniofacial appearance. Hence, for a long time, it has been considered an aesthetic disorder. Fused sutures restrict growth adjacent to the suture, but compensatory skull growth occurs to accommodate the growing brain. The primary goal for the management of this craniofacial deformity has been to release the constricted skull and reform the distorted shape of the skull vault. However, the intellectual and behavioral prognosis of affected children has also been taken into consideration since the beginning of the modern era of surgical management of craniosynostosis. A growing body of literature indicates that extensive surgery, such as the whole-vault cranioplasty approach, would result in better outcomes. In addition, the age at treatment is becoming a major concern for optimal outcome in terms of cosmetic results as well as neurodevelopment. This review will discuss major concerns regarding neurodevelopmental issues and related factors. PMID- 27226856 TI - Current and Future Perspectives in Craniosynostosis. AB - Craniosynostosis has a varied clinical spectrum, ranging from isolated single suture involvement to multi-sutural fusions. Greater understanding of the pathogenesis of craniosynostosis has led to the development of practical treatment protocols. Three stages of growth have determined the approach to managing craniosynostosis : the early period, up to 12 months; the intermediate period, from 1 to 10 years; and the late period, beginning at 10 years. This review discusses current surgical management and future perspectives in craniosynostosis. PMID- 27226857 TI - Effects of a Temperature-Sensitive, Anti-Adhesive Agent on the Reduction of Adhesion in a Rabbit Laminectomy Model. AB - OBJECTIVE: A common cause of failure in laminectomy surgery is when epidural, peridural, or perineural adhesion occurs postoperatively. The purpose of this study is to examine the efficacy of a temperature-sensitive, anti-adhesive agent (TSAA agent), Guardix-SG(r), as a mechanical barrier for the prevention or reduction of peridural scar adhesion in a rabbit laminectomy model. METHODS: Twenty-six mature rabbits were used for this study. Each rabbit underwent two separate laminectomies at lumbar vertebrae L3 and L6, left empty (the control group) and applied 2 mL of the TSAA agent (the experimental group), respectively. Invasive scar formation or inflammation after laminectomy was quantitatively evaluated by measuring the thickness of the dura, the distance from the surface of dura to the scar tissues, the number of inflammatory cells in the scar tissues at the laminectomy site, and the concentration of collagen in histological sections. RESULTS: At 6 weeks postsurgery, the dura was significantly thinner and the distance from the surface of dura to the scar tissues was greater in the experimental group than in the control group (p=0.04 and p=0.01). The number of inflammatory cells was not significantly different in the two groups (p=0.08), although the mean number of inflammatory cells was relatively lower in the experimental group than in the control group. CONCLUSION: The current study suggests that the TSAA agent, Guardix-SG(r), could be useful as an interpositional physical barrier after laminectomy for the prevention or reduction of adhesion. PMID- 27226858 TI - Sildenafil Ameliorates Advanced Glycation End Products-Induced Mitochondrial Dysfunction in HT-22 Hippocampal Neuronal Cells. AB - OBJECTIVE: Accumulation of advanced glycation end-products (AGE) and mitochondrial glycation is importantly implicated in the pathological changes of the brain associated with diabetic complications, Alzheimer disease, and aging. The present study was undertaken to determine whether sildenafil, a type 5 phosphodiesterase type (PDE-5) inhibitor, has beneficial effect on neuronal cells challenged with AGE-induced oxidative stress to preserve their mitochondrial functional integrity. METHODS: HT-22 hippocampal neuronal cells were exposed to AGE and changes in the mitochondrial functional parameters were determined. Pretreatment of cells with sildenafil effectively ameliorated these AGE-induced deterioration of mitochondrial functional integrity. RESULTS: AGE-treated cells lost their mitochondrial functional integrity which was estimated by their MTT reduction ability and intracellular ATP concentration. These cells exhibited stimulated generation of reactive oxygen species (ROS), disruption of mitochondrial membrane potential, induction of mitochondrial permeability transition, and release of the cytochrome C, activation of the caspase-3 accompanied by apoptosis. Western blot analyses and qRT-PCR demonstrated that sildenafil increased the expression level of the heme oxygenase-1 (HO-1). CoPP and bilirubin, an inducer of HO-1 and a metabolic product of HO-1, respectively, provided a similar protective effects. On the contrary, the HO-1 inhibitor ZnPP IX blocked the effect of sildenafil. Transfection with HO-1 siRNA significantly reduced the protective effect of sildenafil on the loss of MTT reduction ability and MPT induction in AGE-treated cells. CONCLUSION: Taken together, our results suggested that sildenafil provides beneficial effect to protect the HT-22 hippocampal neuronal cells against AGE-induced deterioration of mitochondrial integrity, and upregulation of HO-1 is involved in the underlying mechanism. PMID- 27226859 TI - Aneurysmal Neck Clipping as the Primary Treatment Option for Both Ruptured and Unruptured Middle Cerebral Artery Aneurysms. AB - OBJECTIVE: Although middle cerebral artery (MCA) aneurysms are less amenable to coil embolization, an increasing number of studies support favorable endovascular treatment for them. The purpose of this study is to compare the outcomes of two different treatments (surgery versus coiling) and evaluate the benefits of surgical clipping for MCA aneurysms. METHODS: Here we retrospectively analyzed the outcomes of 178 ruptured and unruptured MCA aneurysms treated in patients between September 2008 and April 2012. Parameters assessing treatment outcomes include degree of aneurysm occlusion, presence of regrowth, clinical status, and complications. RESULTS: Among 178 MCA aneurysms, 153 were treated surgically. After a mean follow-up of 12 months, the surgery group showed a clinically significant complete occlusion rate (98%) compared with the coiling group (56%) (p<0.001). Follow-up radiologic evaluation showed a higher regrowth rate (four of 16 cases) in the coiling group than in the surgery group (one of 49 cases) (p=0.003). There was no statistically significant difference in favorable clinical outcome rate between the two groups. The procedure-related permanent morbidity and mortality rates were 2% (three of 153 cases) in the surgery group and 0% (0 of 25 cases) in the coiling group. CONCLUSION: Compared to endovascular treatment, surgical neck clipping for both ruptured and unruptured MCA aneurysms results in a significantly higher complete obliteration rate and less regrowth. Therefore, even in this endovascular era, we still recommend surgical clipping as the primary treatment option for MCA aneurysms rather than coil embolization. PMID- 27226860 TI - Do Trunk Muscles Affect the Lumbar Interbody Fusion Rate?: Correlation of Trunk Muscle Cross Sectional Area and Fusion Rates after Posterior Lumbar Interbody Fusion Using Stand-Alone Cage. AB - OBJECTIVE: Although trunk muscles in the lumbar spine preserve spinal stability and motility, little is known about the relationship between trunk muscles and spinal fusion rate. The aim of the present study is to evaluate the correlation between trunk muscles cross sectional area (MCSA) and fusion rate after posterior lumbar interbody fusion (PLIF) using stand-alone cages. METHODS: A total of 89 adult patients with degenerative lumbar disease who were performed PLIF using stand-alone cages at L4-5 were included in this study. The cross-sectional area of the psoas major (PS), erector spinae (ES), and multifidus (MF) muscles were quantitatively evaluated by preoperative lumbar magnetic resonance imaging at the L3-4, L4-5, and L5-S1 segments, and bone union was evaluated by dynamic lumbar X rays. RESULTS: Of the 89 patients, 68 had bone union and 21 did not. The MCSAs at all segments in both groups were significantly different (p<0.05) for the PS muscle, those at L3-4 and L4-5 segments between groups were significantly different (p=0.048, 0.021) for the ES and MF muscles. In the multivariate analysis, differences in the PS MCSA at the L4-5 and L5-S1 segments remained significant (p=0.048, 0.043 and odds ratio=1.098, 1.169). In comparison analysis between male and female patients, most MCSAs of male patients were larger than female's. Fusion rates of male patients (80.7%) were higher than female's (68.8%), too. CONCLUSION: For PLIF surgery, PS muscle function appears to be an important factor for bone union and preventing back muscle injury is essential for better fusion rate. PMID- 27226861 TI - A Morphometric Study of the Obturator Nerve around the Obturator Foramen. AB - OBJECTIVE: Obturator neuropathy is a rare condition. Many neurosurgeons are unfamiliar with the obturator nerve anatomy. The purpose of this study was to define obturator nerve landmarks around the obturator foramen. METHODS: Fourteen cadavers were studied bilaterally to measure the distances from the nerve root to relevant anatomical landmarks near the obturator nerve, including the anterior superior iliac spine (ASIS), the pubic tubercle, the inguinal ligament, the femoral artery, and the adductor longus. RESULTS: The obturator nerve exits the obturator foramen and travels infero-medially between the adductors longus and brevis. The median distances from the obturator nerve exit zone (ONEZ) to the ASIS and pubic tubercle were 114 mm and 30 mm, respectively. The median horizontal and vertical distances between the pubic tubercle and the ONEZ were 17 mm and 27 mm, respectively. The shortest median distance from the ONEZ to the inguinal ligament was 19 mm. The median inguinal ligament lengths from the ASIS and the median pubic tubercle to the shortest point were 103 mm and 24 mm, respectively. The median obturator nerve lengths between the ONEZ and the adductor longus and femoral artery were 41 mm and 28 mm, respectively. CONCLUSION: The obturator nerve exits the foramen 17 mm and 27 mm on the horizontal and sagittal planes, respectively, from the pubic tubercle below the pectineus muscle. The shallowest area is approximately one-fifth medially from the inguinal ligament. This study will help improve the accuracy of obturator nerve surgeries to better establish therapeutic plans and decrease complications. PMID- 27226862 TI - The Prevalence of Undiagnosed Presurgical Cognitive Impairment and Its Postsurgical Clinical Impact in Older Patients Undergoing Lumbar Spine Surgery. AB - OBJECTIVE: Because elderly patients are undergoing more surgeries, the importance of postoperative cognitive impairment (CI) evaluations is rising, especially for spine surgery, which is related to subjective pain. We investigated the prevalence of undiagnosed CI among elderly patients who underwent spine surgery and the impact of CI on postoperative outcomes. METHODS: The preoperative cognitive statuses of 129 patients over 65 who underwent lumbar spine surgery from 2012 to 2014 were determined with the Mini-Mental State Examination, and patients with scores under 24 were diagnosed with CI. The patients were then divided into a CI group (n=49) and non-cognitive impairment (NCI) group (n=80). RESULTS: Among the 129 patients, 49 (38.0%) were diagnosed with CI, and 9 (7.0%) had severe CI. The age of the CI group (72.88+/-6.20 years) was significantly greater than that of the NCI group (69.96+/-4.53 years). In contrast, the postoperative visual analog scale scores and performance statuses did not differ significantly. However, postoperative delirium was more frequent and the hospital stay length was longer in the CI group compared with the NCI group (p<0.05). CONCLUSION: A high prevalence of undiagnosed CI was discovered among elderly patients undergoing spine surgery. The existence of CI was associated with higher rates of postoperative delirium and prolonged hospital stays, which affected clinical outcomes. Thus, CI assessments should be included in preoperative evaluations of elderly patients prior to spine surgery. PMID- 27226863 TI - Sagittal Pelvic Radius in Low-Grade Isthmic Lumbar Spondylolisthesis of Chinese Population. AB - OBJECTIVE: To investigate the variation of pelvic radius and related parameters in low-grade isthmic lumbar spondylolisthesis. METHODS: Seventy-four patients with isthmic lumbar spondylolisthesis and 47 controls were included in this study. There were 17 males and 57 females between 30 and 66 years of age, including 30 with grade I slippages and 44 grade II slippages; diseased levels included 34 cases on L4 and 40 cases on L5. Thoracic kyphosis (TK), the pelvic radius (PR), the pelvic angle (PA), pelvic morphology (PR-S1), and total lumbopelvic lordosis (PR-T12) were assessed from radiographs. RESULTS: Statistically significant differences were found for the PA, PR-T12, and PR-S1 (24.5+/-6.6 degrees , 83.7+/-9.8 degrees , and 25.4+/-11.2 degrees , respectively) of the patients with spondylolisthesis and the healthy volunteers (13.7+/-7.8 degrees , 92.9+/-9.2 degrees , and 40.7+/-8.9 degrees , respectively). The TK/PR-T12 ratios were between 0.15 and 0.75. However, there were no differences in all the parameters between the L4 and L5 spondylolysis subgroups (p>0.05). The TK and PR-S1 of grade II were less than grade I, but the PA was greater. The PR-T12 of female patients were less than male patients, but the PA was greater (p<0.05). CONCLUSION: Pelvic morphology differed in patients with low-grade isthmic lumbar spondylolisthesis compared to controls. Gender and the grade of slippage impacted the sagittal configuration of the pelvis, but the segment of the vertebral slip did not. Overall, the spine of those with spondylolisthesis remains able to maintain sagittal balance despite abnormal pelvic morphology. PMID- 27226864 TI - Infantile Dural Arteriovenous Fistula of the Transverse Sinus Presenting with Ocular Symptoms, Case Reports and Review of Literature. AB - Dural arteriovenous fistula (DAVF) of the transverse sinus with ophthalmic manifestations in young children are rare. We reviewed two cases of direct AVF of the transverse sinus with ocular manifestations managed at our institution. The first, a 2.5 years old male child presented with left exophthalmos. Angiography revealed AVF between the occipital artery and the transverse sinus. The second, a 2 years old female child, complained of left exophthalmos. Imaging studies showed bilateral direct AVFs of the transverse sinus with bilateral dysmaturation of the sigmoid sinus. Transarterial embolization was done in both cases. Clinical and radiological follow up revealed complete cure.This report suggests that DAVF of the transverse sinus supplied by the external carotid branches can present with ophthalmic manifestations especially if there is distal venous stenosis or obliteration involving sigmoid sinus. Transarterial embolization using coils and liquid embolic agents could be safe and feasible to obliterate the fistula. PMID- 27226865 TI - Adult Intracranial Gliofibroma : A Case Report and Review of the Literature. AB - Gliofibroma is an extremely rare biphasic tumor with an astrocytic and benign mesenchymal component, which commonly occurs within the first two decades of life. The exact biological behavior of the tumor is not fully understood. Therefore, it is not listed as a distinct entity in the current World Health Organization classification of central nervous system tumors. Here, we describe a rare case of gliofibroma, which was located on the medial temporal lobe in a 61 year-old woman. Preoperatively, we misdiagnosed it as a meningioma because it was a well-demarcated and well-enhanced extra-axial mass with calcification and bony destruction. On the histopathological and immunohistochemical examination, the tumor consisted of a mixture of glial tissue and mesenchymal tissue and it was finally diagnosed as a gliofibroma. To our knowledge, this case of intracranial gliofibroma is in the oldest patient ever reported. PMID- 27226866 TI - Injury of the Arcuate Fasciculus in the Nondominant Hemisphere by Subfalcine Herniation in Patients with Intracerebral Hemorrhage : Two Case Reports and Literature Review. AB - Using diffusion tensor tractography (DTT), we demonstrated injury of the arcuate fasciculus (AF) in the nondominant hemisphere in two patients who showed subfalcine herniation after intracerebral hemorrhage (ICH) in the dominant hemisphere. Two patients (patient 1 and patient 2) with ICH and six age-matched control patients who have ICH on the left corona radiata and basal ganglia without subfalcine herniation were recruited for this study. DTT was performed at one month after onset in patient 1 and patient 2. AFs of both hemispheres in both patients were disrupted between Wernicke's and Broca's areas. The fractional anisotropy value and tract numbers of the right AFs in both patients were found to be more than two standard deviations lower than those of control patients. In contrast, the apparent diffusion coefficient value was more than two standard deviations higher than those of control patients. Using the configuration and parameters of DTT, we confirmed injury of the AF in the nondominant hemisphere in two patients with subfalcine herniation following ICH in the dominant hemisphere. Therefore, DTT would be a useful tool for detection of underlying injury of the AF in the nondominant hemisphere in patients with subfalcine herniation. PMID- 27226867 TI - Posttraumatic Intracranial Tuberculous Subdural Empyema in a Patient with Skull Fracture. AB - Intracranial tuberculous subdural empyema (ITSE) is extremely rare. To our knowledge, only four cases of microbiologically confirmed ITSE have been reported in the English literature to date. Most cases have arisen in patients with pulmonary tuberculosis regardless of trauma. A 46-year-old man presented to the emergency department after a fall. On arrival, he complained of pain in his head, face, chest and left arm. He was alert and oriented. An initial neurological examination was normal. Radiologic evaluation revealed multiple fractures of his skull, ribs, left scapula and radius. Though he had suffered extensive skull fractures of his cranium, maxilla, zygoma and orbital wall, the sustained cerebral contusion and hemorrhage were mild. Eighteen days later, he suddenly experienced a general tonic-clonic seizure. Radiologic evaluation revealed a subdural empyema in the left occipital area that was not present on admission. We performed a craniotomy, and the empyema was completely removed. Microbiological examination identified Mycobacterium tuberculosis (M. tuberculosis). After eighteen months of anti-tuberculous treatment, the empyema disappeared completely. This case demonstrates that tuberculosis can induce empyema in patients with skull fractures. Thus, we recommend that M. tuberculosis should be considered as the probable pathogen in cases with posttraumatic empyema. PMID- 27226868 TI - Rapid Visual Deterioration Caused by Posterior Fossa Arachnoid Cyst. AB - Posterior fossa is a site next to the middle fossa where arachnoid cyst frequently occurs. Generally, most arachnoid cysts are asymptomatic and are found incidentally in most cases. Although arachnoid cysts are benign and asymptomatic lesions, patients with posterior fossa arachnoid cysts often complain of headaches, gait disturbance, and ataxia due to the local mass effects on the cerebellum. We observed a patient with a posterior fossa arachnoid cyst who had visual symptoms and a headache, but did not have gait disturbance and ataxia. We recommended an emergency operation for decompression, but the patient refused for personal reasons. After 7 days, the patient revisited our hospital in a state of near-blindness. We suspected that the arachnoid cyst induced the hydrocephalus and thereby the enlarged third ventricle directly compressed optic nerves. Compressed optic nerves were rapidly aggravated during the critical seven days; consequently, the patient's vision was damaged despite the operation. Considering the results of our case, it is important to keep in mind that the aggravation of symptoms cannot be predicted; therefore, symptomatic arachnoid cysts should be treated without undue delay. PMID- 27226869 TI - Quadriplegia Following Epileptic Seizure : Things to Keep in Mind. AB - People with epilepsy are believed to be at a higher risk of incurring accidental injury than people who do not have seizures. The incidence of injury, either due to seizure or accident as a consequent of seizure is also high and varies from 0.03% to 3%. The most common injuries are head contusions, lacerations, burns and fractures. In this article, we present a case of quadriplegia after a generalized epileptic seizure. PMID- 27226870 TI - Device for Catheter Placement of External Ventricular Drain. AB - To introduce a new device for catheter placement of an external ventricular drain (EVD) of cerebrospinal fluid (CSF). This device was composed of three portions, T shaped main body, rectangular pillar having a central hole to insert a catheter and an arm pointing the tragus. The main body has a role to direct a ventricular catheter toward the right or left inner canthus and has a shallow longitudinal opening to connect the rectangular pillar. The arm pointing the tragus is controlled by back and forth movement and turn of the pillar attached to the main body. Between April 2012 and December 2014, 57 emergency EVDs were performed in 52 patients using this device in the operating room. Catheter tip located in the frontal horn in 52 (91.2%), 3rd ventricle in 2 (3.5%) and in the wall of the frontal horn of the lateral ventricle in 3 EVDs (5.2%). Small hemorrhage along to catheter tract occurred in 1 EVD. CSF was well drained through the all EVD catheters. The accuracy of the catheter position and direction using this device were 91% and 100%, respectively. This device for EVD guides to provide an accurate position of catheter tip safely and easily. PMID- 27226871 TI - Essentials of Neurosurgical Procedures and Operations Published by Korean Neurosurgical Society. PMID- 27226872 TI - Hepatitis E Virus Infection Among Chronic Hemodialysis. PMID- 27226873 TI - Distribution of tsst-1 and mecA Genes in Staphylococcus aureus Isolated From Clinical Specimens. AB - BACKGROUND: Staphylococcus aureus is a harmful pathogen known to express numerous virulence factors and cause severe infections. High levels of methicillin resistant Staphylococcus aureus (MRSA) strains are one of the important healthcare problems because of the inefficient treatment of these infections. OBJECTIVES: The purpose of the current study is to evaluate the incidence of the toxic shock syndrome toxin (tsst-1) gene and its association with the prevalence of the mecA gene and drug resistance. MATERIALS AND METHODS: The presence of the tsst-1 and mecA genes was investigated by polymerase chain reaction (PCR) among S. aureus isolated from 197 clinical samples. In addition, resistance tests to 12 antibiotics were carried out by the disc diffusion method. RESULTS: Among the 197 isolates, 134 (68%) contained the tsst-1 genes and 172 (87.3%) contained the mecA genes. The prevalence of both genes was higher among male cases and samples purified from wounds and blood. We found no significant correlation between the presences of the two mentioned genes within isolates. The highest resistance we observed among our samples was to penicillin. None of isolates was resistant to vancomycin or linezolid. A significant correlation was observed between the presence of the mecA gene and resistance to oxacillin, gentamicin, kanamycin, erythromycin, tetracycline, cotrimoxazole, clindamycin, cephazolin and the multi drug resistant property, which is resistance to more than three antibiotics (P < 0.05). CONCLUSIONS: Our outcomes showed elevated incidences of tsst-1 positive and MRSA strains with higher rates of antibiotic resistance. The conflict between our findings and other records may be due to differences in geographic regions. PMID- 27226874 TI - Prevalence of Extended-Spectrum Beta-Lactamase-Producing Klebsiella pneumoniae Isolates in Nosocomial and Community-Acquired Urinary Tract Infections. AB - BACKGROUND: Klebsiella pneumoniae is a family member of Enterobacteriaceae. Isolates of K. pneumoniae produce enzymes that cause decomposition of third generation cephalosporins. These enzymes are known as extended-spectrum beta lactamase (ESBL). Resistance of K. pneumoniae to beta-lactamase antibiotics is commonly mediated by beta-lactamase genes. OBJECTIVES: The aim of this study was to identify the ESBL produced by K. pneumoniae isolates that cause community acquired and nosocomial urinary tract infections within a one-year period (2013 to 2014) in Kashani and Hajar university hospitals of Shahrekord, Iran. PATIENTS AND METHODS: From 2013 to 2014, 150 strains of K. pneumoniae isolate from two different populations with nosocomial and community-acquired infections were collected. The strains were then investigated by double disk synergism and multiplex polymerase chain reaction (PCR). RESULTS: The study population of 150 patients with nosocomial and community-acquired infections were divided to two groups of 75 each. We found that 48 of the K. pneumoniae isolates in the patients with nosocomial infection and 39 isolates in those with community-acquired infections produced ESBL. The prevalence of TEM1, SHV1 and VEB1 in ESBL-producing isolates in nosocomial patients was 24%, 29.3% and 10.6%, and in community acquired patients, 17.3%, 22.7% and 8%, respectively. CONCLUSIONS: The prevalence of ESBL-producing K. pneumoniae isolate is of great concern; therefore, continuous investigation seems essential to monitor ESBL-producing bacteria in patients with nosocomial and community-acquired infections. PMID- 27226875 TI - Enhancing the Anti-Enterococci Activity of Different Antibiotics by Combining With Metal Oxide Nanoparticles. AB - BACKGROUND: Enterococci have emerged as more virulent and multidrug-resistant in community and hospital settings. The emergence of vancomycin resistant enterococci (VRE) in hospitals has posed a serious threat to public health. The widespread use of antibiotics to treat VRE infections has resulted in the development of resistant forms of these organisms. OBJECTIVES: Present study deals with the efficacy of antibiotic-nanoparticle combination against clinical isolates of VRE. This study has effectively evaluated the anti-enterococcal activity of metallic nanoparticles and their combination with antibiotics with the aim to search for new biocidal combinations. MATERIALS AND METHODS: Initially, the isolates were identified by various biochemical tests and also by PCR, targeting ddl, vanA and vanB genes. Antibiotic susceptibility testing was carried out by disc diffusion method. Minimum inhibitory concentration (MIC) of both antibiotics and metal nanoparticles against VRE was done using broth dilution method. On the basis of MICs, a combination of both antibiotics and nanoparticles was used by physical mixing of antibiotics and different concentrations of nanoparticles. RESULTS: The MIC of metal nanoparticles were found in the range of 0.31 - 30 mM. The combination of both antibiotics and nanoparticles has effectively reduced the MICs of ciprofloxacin from 16 - 256 MUg/mL to 2 - 16 MUg/mL, erythromycin 1024 - 2048 MUg/mL to 128 - 512 MUg/mL, methicillin 32 - 256 MUg/mL to 8 - 64 MUg/mL and vancomycin 2 - 512 MUg/mL to 0.5 - 64 MUg/mL. CONCLUSIONS: Among the nanoparticles, ZnO was found as a potent metallic nanoparticle which effectively reduced the MIC upon combination with the antibiotics. The combination exhibited enhanced bactericidal activity against multidrug resistant clinical strains of VRE with dose dependency. Further extensive study on this aspect can prove their beneficial clinical use against resistant pathogens to combat increasing resistance to antibiotics. PMID- 27226876 TI - Optimized Expression, Purification of Herpes B Virus gD Protein in Escherichia coli, and Production of Its Monoclonal Antibodies. AB - BACKGROUND: Herpes B virus (BV) is a zoonotic disease caused by double-stranded enveloped DNA virus with cercopithecidae as its natural host. The mortality rate of infected people could be up to 70% with fatal encephalitis and encephalomyelitis. Up to now, there are no effective treatments for BV infection. Among the various proteins encoded by monkey B virus, gD, a conserved structural protein, harbors important application value for serological diagnosis of frequent variations of the monkey B virus. OBJECTIVES: This study aimed to expressed the gD protein of BV in Escherichia coli by a recombinant vector, and prepare specific monoclonal antibodies against gD of BV to pave the way for effective and quick diagnosis reagent research. MATERIALS AND METHODS: The gD gene of BV was optimized by OptimWiz to improve codon usage bias and synthesis, and the recombinant plasmid, pET32a/gD, was constructed and expressed in E. coli Rosetta (DE3). The expressed fusion protein, His-gD, was purified and the BALB/c mice were immunized by this protein. Spleen cells from the immunized mice and SP2/0 myeloma cells were fused together, and the monoclonal cell strains were obtained by indirect enzyme-linked immunosorbent assay (ELISA) screening, followed by preparation of monoclonal antibody ascetic fluid. RESULTS: The optimized gD protein was highly expressed in E. coli and successfully purified. Five monoclonal antibodies (mAbs) against BV were obtained and named as 4E3, 3F8, 3E7, 1H3 and 4B6, and with ascetic fluid titers of 2 * 10(6), 2 * 10(5), 2 * 10(5), 2 * 10(3) and 2 * 10(2), respectively. The 1H3 and 4E3 belonged to the IgG2b subclass, while 3E7, 3F8 and 4B6 belonged to the IgG1 subclass. CONCLUSIONS: The cell lines obtained in this work secreted potent, stable and specific anti-BV mAbs, which were suitable for the development of herpes B virus diagnosis reagents. PMID- 27226877 TI - Detection of Human Metapneumovirus and Respiratory Syncytial Virus by Real-Time Polymerase Chain Reaction Among Hospitalized Young Children in Iran. AB - BACKGROUND: Acute respiratory infection plays an important role in hospitalization of children in developing countries; detection of viral causes in such infections is very important. The respiratory syncytial virus (RSV) is the most common etiological agent of viral lower respiratory tract infection in children, and human metapneumovirus (hMPV) is associated with both upper and lower respiratory tract infections among infants and children. OBJECTIVES: This study evaluated the frequency and seasonal prevalence of hMPV and RSV in hospitalized children under the age of five, who were admitted to Aliasghar children's hospital of Iran University of Medical Sciences from March 2010 until March 2013. PATIENTS AND METHODS: Nasopharyngeal or throat swabs from 158 hospitalized children with fever and respiratory distress were evaluated for RSV and hMPV RNA by the real-time polymerase chain reaction (PCR) method. RESULTS: Among the 158 children evaluated in this study, 49 individuals (31.1%) had RSV infection while nine individuals (5.7%) had hMPV infection. Five (55.5%) of the hMPV-infected children were male while four (44.5%) were female and 27 (55.2%) of the RSV-infected patients were females and 22 (44.8%) were males. The RSV infections were detected in mainly < one year old children and hMPV infections were detected mainly in > one year old children. Both RSV and hMPV infections had occurred mainly during winter and spring seasons. CONCLUSIONS: Respiratory syncytial virus was the major cause of acute respiratory infection in children under one-year of age while human metapneumovirus had a low prevalence in this group. The seasonal occurrence of both viruses was the same. PMID- 27226878 TI - Construction and Immunogenicity Analysis of Hepatitis C Virus (HCV) Truncated Non Structural Protein 3 (NS3) Plasmid Vaccine. AB - BACKGROUND: To develop hepatitis C virus (HCV) vaccine, induction of potent humoral and T cell response against immunogenic targets with conserved region should be achieved. T cell response against NS3 is often associated with complete clearance of the virus. OBJECTIVES: Herein, we expressed the truncated form of NS3 in a mammalian cell line and evaluated immune responses of NS3 DNA vaccine in BALB/c. MATERIALS AND METHODS: The partial length of NS3 gene, which encodes immunogenic epitopes (1095 - 1379 aa), was amplified by reverse transcription polymerase chain reaction (RT-PCR) on RNA obtained from a patient with HCV, inserted into pcDNA3.1 plasmid using XhoI/HindIII sites, and finally evaluated by restriction analysis and sequencing. After transfection of the recombinant plasmid into HEK293T cells, the NS3 protein expression was confirmed by western blotting. Mice were immunized intra-dermally close to the base of the mice tail with four doses in two-weeks intervals and the immune responses were assessed using total and subtypes of IgG antibody assay, cell proliferation and cytokine assay. RESULTS: The pcDNA3.1 plasmid harboring the coding sequence of NS3 (pc NS3) was constructed and confirmed with the expected size. Proper expression of the recombinant protein in transfected HEK 293T cells was confirmed using western blotting. The immunization results indicated that pc-NS3 induced significant levels of total antibody, IgG2a subclass antibody, Interferon (IFN)-gamma, Interleukin (IL)-4 and proliferation assay compared to the control group (P < 0.05). CONCLUSIONS: The pc-NS3 possesses the capacity to express NS3 in the mammalian cell line and demonstrated strong immunogenicity in a murine model. Our primary results demonstrated that the immunogenic truncated region of NS3 could be used as a potential vaccine candidate against hepatitis C. PMID- 27226879 TI - The High Prevalence of the Varicella Zoster Virus in Patients With Relapsing Remitting Multiple Sclerosis: A Case-Control Study in the North of Iran. AB - BACKGROUND: Multiple sclerosis (MS) is the most common neurological autoimmune disease, characterized by multifocal areas of inflammatory demyelination within the central nervous system. It has been hypothesized that the stimulation of the immune system by viral infections is the leading cause of MS among susceptible individuals. OBJECTIVES: The aim of this study was to investigate the prevalence of the varicella zoster virus (VZV) in patients with relapsing-remitting multiple sclerosis. PATIENTS AND METHODS: Plasma and peripheral blood mononuclear cells (PBMCs) collected from MS patients (n = 82) and controls (n = 89) were screened for the presence of anti-VZV antibodies and VZV DNA by the ELISA and PCR methods. DNA was extracted from all samples, and VZV infection was examined by the PCR technique. Statistical analysis was used to investigate the frequency of the virus in MS patients and a healthy control group. RESULTS: Of all the MS patients, 78 (95.1%) and 21 (25.6%) were positive for anti-VZV and VZV DNA, respectively. Statistical analysis of the PCR results showed a significant correlation between the abundance of VZV and MS disease (P < 0.001). However, there was no significant correlation between the abundance of anti-VZV antibodies and MS disease by the ELISA method. CONCLUSIONS: These results support the hypothesis that VZV may contribute to MS in establishing a systemic infection process and inducing an immune response. PMID- 27226880 TI - The effects of pomegranate extract on normal adult rat kidney: A stereological study. AB - Pomegranate (Punica granatum L.) has been used widely in the traditional medicine of various civilizations for more than 5000 years. The pomegranate tree has several parts; each part has useful medicinal effects. Previous studies have demonstrated the antibacterial, antioxidant, and anti-inflammatory properties of pomegranate. The aim of the present study was to determine whether administration of pomegranate extract could result in morphometric changes in the kidneys of rats. Eighteen male rats (180-200 g) were divided into three groups that received either: G1, distilled water; G2, 250 mg kg(-1) pomegranate extract; and G3, 500 mg kg(-1) pomegranate extract via oral gavages daily for eight weeks. At the end of eight weeks, the rats were euthanized and their kidneys were removed and processed for morphometric analyses. In rats received pomegranate extract, the kidney weight, kidney weight/body weight ratio, cortex v/lume and glomerular volume were increased (p < 0.05), while, medulla volume and the number of glomeruli per kidney did not change. No pathological lesions were observed in the kidney. Therefore, pomegranate hydro-alcoholic extract at doses of 250 and 500 (mg kg(-1)) increased the volume of some parts of the kidney; however, it did not cause any pathological changes in the kidney. PMID- 27226881 TI - Inhibitory effect of Zataria multiflora Boiss. essential oil, alone and in combination with monolaurin, on Listeria monocytogenes. AB - Listeria monocytogenes is one of the major causes of infections in developing countries. In this study, chemical composition and anti-listerial effect of the essential oil of Zataria multiflora Boiss. alone and in combination with monolaurin were evaluated at different pH values (5, 6, and 7) and temperatures (5 C and 30 C). Chemical composition of Zataria multiflora Boiss. essential oil was evaluated by gas chromatography-mass spectrometry (GC-MS) analysis. Minimum inhibitory concentration (MIC) of the essential oil and monolaurin were determined using microbroth dilution method and the interactions of essential oil and monolaurin were determined by the evaluation of fractional inhibitory concentrations (FIC) index. Carvacrol (63.20%) and thymol (15.10%) were found as the main components of the essential oil. The MIC values of the oil and monolaurin at pH 7 and 30 C were measured as 312.50 ug mL(-1) and 125.00 ug mL( 1), respectively. Combination of monolaurin and Z. multiflora essential oil were found to act synergistically (FIC index < 0.5) against L. monocytogenes under different pH and temperature conditions. Decrease in the pH and temperature values have increased the anti-listerial activity of monolaurin and the essential oil. The lowest MIC value of monolaurin and essential oil was observed at pH 5 and 5 C. According to our results, the oil alone or in combination with monolaurin at low pH and temperature conditions showed a promising inhibitory effect on L. monocytogenes. PMID- 27226882 TI - Effects of propolis, royal jelly, honey and bee pollen on growth performance and immune system of Japanese quails. AB - Effect of ethanolic extract of propolis, royal jelly, honey and bee pollen in comparison with virginiamycin (as growth promoter antibiotic) as regards the performance and immune system of Japanese quail were assessed. We used 256 mixed sex quail chicks in a completely randomized design by eight treatments, including control, ethanolic extract of propolis 1000 (PE1) and 5000 (PE2) mg kg(-1), pollen powder 1000 (PO1) and 5000 (PO2) mg kg(-1), royal jelly 100 mg kg(-1) (RJ), honey 22 g L(-1) of drinking water (H) and virginiamycin 150 mg kg(-1) (V), and four replicates of eight birds in each replication for 42 days. There was significant differences for weight gain (WG), feed intakes (FI) and feed conversion ratio (FCR) between experimental groups. In addition, WG in V treatment (18.82%), H and PO2 treatments (16.87%) and RJ treatment (12.00%) were significantly higher than to control group (p < 0.01). Significantly higher values of FCR were recorded in control group while group PE2 exhibited a significant decrease for 1 to 42 day (p < 0.05). The results of effect of bee products on antibodies titer showed an increase in the Newcastle disease (ND) titer when compared with control and virginiamycin groups (p < 0.01). There was significant difference in antibody production against avian influenza (AI) and sheep red blood cells (p < 0.01). Significant differences were observed in heterophils to lymphocytes ratio among PE1, PE2, PO1 and PO2 with V and control groups (p < 0.01). PMID- 27226883 TI - Evaluation of tendon healing using fibroblast like synoviocytes in rabbits: A biomechanical study. AB - Tendon never restores the complete biological and mechanical properties after healing. Several techniques are available for tissue-engineered biological augmentation for tendon healing like stem cells. Recently, synovium has been investigated as a source of cells for tissue engineering. In the present study, we investigated potentials of fibroblast like synoviocytes (FLSs) in tendon healing. Sixteen rabbits were divided randomly into control and treatment groups. One rabbit was used as a donor of synovial membrane (synovium). The injury model was unilateral complete transection through the middle one third of deep digital flexor tendon (DDFT). Subsequently, the tendon stumps were sutured with 3/0 nylon. In treatment group, 0.1 mL phosphate-buffered saline (PBS) solution containing 1 * 10(6) nucleated cells of FLSs was injected intratendinously at both tendon stumps just next to incision line. In control group, 0.1 mL PBS without FLSs was used for intratendinous injection. Model animals were euthanized at eight weeks, DDFTs were harvested and prepared for biomechanical study. Results of study showed that, there was no significant differences in biomechanical parameters values between FLSs treated and control groups. In conclusion, intratendinous injection of FLSs did not improve biomechanical properties during eight weeks in rabbit. PMID- 27226884 TI - Peroxisome proliferator-activated receptors (PPARalpha, PPARgamma and PPARbeta/delta) gene expression profile on ram spermatozoa and their relation to the sperm motility. AB - Peroxisome proliferator-activated receptors (PPARs) are a member of nuclear receptors superfamily, which mainly regulate the expression of target genes involved in lipid and energy metabolism. These receptors are divided to three isotypes: PPARalpha, PPARgamma and PPARbeta/delta. Each isotype has a distinct tissue distribution relating to the distinct functions. In this study, the mRNA abundance for PPARalpha, PPARgamma and PPARbeta/delta was evaluated and compared with high and low motile ram spermatozoa. Semen samples from 6 adult rams were fractionated on a two layer discontinuous Percoll gradient to high and low motile sperm and quantitative parameters of sperm motility were determined by CASA. Total RNA was extracted and the mRNA abundance for each gene was measured by relative quantification technique with Real time PCR. The levels of three isotypes of PPAR transcripts were significantly higher in high motile semen samples using quantitative RT-PCR. Some of sperm motility indices were also significantly correlated with PPARalpha and PPARgamma relative expression. This study revealed the novel association of PPAR gene isotypes with sperm motility. Data from our study suggested PPARs are one of the possible factors that can be studied in male infertility. PMID- 27226885 TI - Measure of energy related biochemical metabolites changes during peri-partum period in Makouei breed sheep. AB - Makouei sheep is one of the famous breeds in Iran which is reared in Azerbaijan province for their meat, milk and wool. Fifty clinically healthy Makouei ewes were selected to study the variations in energy-related blood metabolites during peri-partum period. Blood was collected from Jugular vein from each sheep on day 7 before the expected lambing time, day of parturition and also day 7 postpartum to determine total protein, albumin, urea, cholesterol, glucose, triglyceride, beta-hydroxybutyrate (BHB) and non- esterified fatty acid (NEFA) levels. Serum total protein and albumin concentrations were gradually decreased during pre partum period and reached the lowest level after parturition (p > 0.05). Blood urea concentration was significantly decreased to the lowest level at parturition (p < 0.05). Serum cholesterol and triglycerides were gradually decreased and reached low levels after lambing (p < 0.05). Serum glucose concentrations were significantly lower at pre-partum period than post-partum (p < 0.05). The serum NEFA and BHB concentrations were higher before lambing and thereafter decreased (p < 0.05). Current findings regarding the blood parameters may expand our knowledge for the diagnosis and prognosis of reproductive and metabolic diseases in Makouei sheep during these phases. PMID- 27226886 TI - Developmental study of rectum in broiler chicken: A stereological and morphometrical study. AB - The objective of this study was to investigate development of the weight and the morphological development of the rectum in broiler chickens. Twenty broiler chickens (Ross 308) were used in this experiment and they were 12, 20, 35 and 44 days of age. Samples from the rectum of chicks were sectioned in an unbiased manner and examined quantitatively using stereology. In addition, the weight of both body (BW) and rectum and also rectum weight as a proportion of BW, height and width of the villi and thickness of rectum wall were measured. The results revealed that the body and rectum weight were increased with age. The greatest rectum weight as a proportion of BW was observed on day 20. An increase in height and width of the villi during the study period were obtained. The increase was more significant on days 35 and 44 than on days 12 and 20 (p < 0.05). There were significant difference in thickness of tunica mucosa, submucosa and muscular layer of the rectum on day 20 compared to day 35 (p < 0.05). The increase in the volume density of the wall, tunica mucosa and tunica muscular was greater on day 20 than on day 35. However, significant differences were observed in volume density of this layers between days 35 and 44 compared to days 12 and 20 (p < 0.05). PMID- 27226887 TI - Effects of histidine and vitamin C on isoproterenol-induced acute myocardial infarction in rats. AB - In the present study, we investigated the effects of histidine and vitamin C (alone or in combination) treatments against isoproterenol (a beta-adrenergic receptor agonist)-induced acute myocardial infarction in rats. We used propranolol (a beta-adrenergic receptor blocker) to compare the results. Rats were given intraperitoneal injections of histidine (40 mg kg(-1)) and vitamin C (40 mg kg(-1)) alone and combined daily for 21 days. Propranolol (10 mg kg(-1)) was orally administered daily for 10 days (from day 11 to day 21). Myocardial infarction was induced by subcutaneous injections of 150 mg kg(-1) of isoproterenol at an interval of 24 hr on days 20 and 21. Blood and tissue samples were taken for histopathological and biochemical evaluations following electrocardiography recording on day 21. Isoproterenol elevated ST segment, increased heart weight, heart rate, serum activities of aspartate transaminase, lactate dehydrogenase, creatine kinase-MB and heart tissue content of malondialdehyde, and decreased R wave amplitude and superoxide dismutase and catalase activities of heart tissue. Necrosis, edema and inflammatory cells infiltration were observed in myocardial tissue sections. Our results indicated that histidine and vitamin C alone, and especially in combination prevent isoproterenol-induced cardiotoxicity and have similar protective effects with propranolol. Cardioprotective effects of histidine and vitamin C may be associated with their ability to reduce free radical-induced toxic effects. PMID- 27226888 TI - A study of visceral leishmaniasis in owned dogs with dermal lesions in Mashhad area, Khorasan Razavi province. AB - Dog is the main reservoir host of visceral leishmaniasis in Iran. The present study was carried out to investigate visceral leishmaniasis in owned dogs with dermal lesions in Mashhad, Khorasan Razavi province. Thirty- nine owned dogs with dermal lesions were selected. During study, four of dogs were euthanized. The dermal smears, blood and tissue samples were collected and examined using parasitological, serological and molecular methods. A total of 39 examined dogs, leishman bodies were microscopically detected in 33.30% (13/39) of dermal smears. The sera samples were tested by indirect immunofluorescent antibody test (IFAT). Antibody against Leishmania infantum was detected in 26.00% (10/39) dogs. According to semi-nested PCR, DNA of Leishmania infantum was detected in 2.50% (1/39) of blood samples and in 75.00 % (3/4) of different tissues of euthanized dogs. BLAST analysis of the sequenced samples indicated a 99.00% similarity with kDNA of Leishmania infantum. Based on the results, it is concluded that visceral leishmaniasis due to L. infantum is distributed among household dogs of this area and it needs more surveillance to control the disease by public health and veterinary authorities. PMID- 27226889 TI - Protective effect of ethyl pyruvate on mice sperm parameters in phenylhydrazine induced hemolytic anemia. AB - The aim of the present study was to assess the protective effect of ethyl pyruvate (EP) on sperm quality parameters, testosterone level and malondialdehyde (MDA) in phenylhydrazine (PHZ) treated mice. For this purpose, 32 NMRI mice with the age range of 8 to 10 weeks, weight average 26.0 +/- 2.0 g, were randomly divided into four equal groups. The control group (1) received normal saline (0. 1 mL per day) by intraperitoneal injection (IP). Group 2 (PHZ group) was treated with initial dose of PHZ (8 mg 100 g(-1), IP) followed by 6 mg 100 g(-1) , IP every 48 hr. Group 3, (Group PHZ+EP) received PHZ (according to the previous prescription) with EP (40 mg kg(-1), daily, IP). Ethyl pyruvate group (4) received only EP (40 mg kg(-1), daily, IP). Treatment period was 35 days. After euthanasia, sperms from caudal region of epididymis were collected and the total mean sperm count, sperm viability, motility and morphology were determined. Testis tissue MDA and serum testosterone levels of all experimental groups were also evaluated. A considerable reduction in mean percentage of number, natural morphology of sperm, sperm motility and viability and serum testosterone concentration besides DNA injury increment among mice treating with PHZ in comparison with control group were observed. However, in PHZ+EP group the above mentioned parameters were improved. This study showed that PHZ caused induction of toxicity on sperm parameters and reduction of testosterone as well as the increment of MDA level and EP as an antioxidant could reduce destructive effects of PHZ on sperm parameters, testosterone level and lipid peroxidation. PMID- 27226890 TI - Molecular identification and phylogenic analysis of Bartonella henselae isolated from Iranian cats based on gltA gene. AB - One of the most important species of the Bartonella genus is B. henselae that causes a zoonotic infection, cat scratch disease (CSD). The main source of the bacteria is cat and the carrier is Ctenocephalides felis flea. One hundred and forty nail and saliva samples were collected from 70 domestic cats. Positive samples for B. henselae were characterized by polymerase chain reaction (PCR) and sequencing. Sequences of gltA gene were trimmed using BioEdit software and then compared with the sequences of the same gene from B. henselae isolated from cats and humans in GenBank database. Phylogenic tree was constructed using CLC Sequence Viewer software and unweighted pair group method with arithmetic mean (UPGMA) method. Molecular assessments showed that five samples out of 70 nail samples (7.14%) and one sample out of 70 saliva samples (1.42%) were genetically positive for B. henselae. At least an 87.00% similarity was seen between the gene sequences from the current study and the reference sequences from the GenBank database. Phylogenic analysis has shown that strains isolated in this study were grouped in a different haplo group, compared to other strains. Among the Asian countries, the prevalence of the bacteria in Iran was close to that in Japan and Turkey. In conclusion, findings of this study showed the prevalence of B. henselae in Iranian cats which is important due to its public health issues, especially for the immunocompromised pet owners. PMID- 27226891 TI - Parasitic infection in various stages life of cultured Acipenser persicus. AB - The present study was conducted to evaluate the status of the parasite fauna in Acipenser persicus at different development stages, in order to find prevention protocols for parasitic diseases in this valuable species. For this purpose, sampling from each sex breeder, 10 egg samples, 5-day-old larvae (n = 20), 20-day old larvae (n = 80) and fingerling of A. persicus (n = 60) released in earthen ponds were done. After the bioassay and preparing wet mount from the internal and external organs, identification was done according to the keys. According to the results, no fauna parasites were isolated from egg samples and 5-day-old larvae; but Trichodina spp. was isolated from 20-day-old larvae. Also, the same protozoan was isolated from fingerling released in earthen ponds, the mean intensity, prevalence and range of contamination by fingerling were higher with compared to 20-day-old larvae. Trichodina sp. and Diplostomum spathaceum were isolated from skin and eyes of females, respectively. However, Trichodina sp. and Ichthyophthirius multifiliis were isolated from skin of male breeders. In this study, no parasites were isolated from internal organs of larves and fingerling but four intestinal parasites included: Cucullanus sphaerocephlaus, Anisakis sp., Skyrjabinopsilus semiarmatus, and Lepto-rhynchoides plagicephalu were isolated from internal organs of breeder. Based on a wide range of parasitic infection observed in various life stages of A. persicus, it seems necessary to consider hygienic and management measures. PMID- 27226892 TI - Large B-cell lymphoma in a dog: A cyto-histopathological evaluation and Immunophenotyping according to WHO classification for canine lymphomas. AB - In the present study, we described cyto-histopathological features and immunophenotyping of the large B-cell lymphoma in an 8-year-old mixed breed dog with applying the World Health Organization (WHO) system of classification of canine lymphomas. In fine-needle aspiration (FNA), lymph nodes were involved by neoplastic cells of intermediate to large size with deep blue cytoplasm; consist of centroblasts, immunoblast and medium-sized cells. Histopathologically, the follicles and sinuses of lymph nodes were replaced by sheets of numerous immunoblasts (less than 90.0% of total cells) and centroblasts. Numerous mitotic figures were also observed. Immunohistochemical analysis presented that the neoplastic cells express B-cell phenotype CD20 and CD79a, but do not stain for T phenotype CD3. On the basis of cytology, histopathology and immunohistochemical findings, the present tumor was diagnosed as diffuse large B-cell lymphoma, high grade centroblastic type (DLBCL-CB) according to WHO histological classification. Applying this classification system for diagnosis of canine lymphomas is very useful and has a high accuracy and consistency. However, further co-operative studies between clinicians and pathologists should be performed, in order to improve the effectiveness of this classification. PMID- 27226893 TI - Patent ductus arteriosus in a lamb: A case report. AB - Patent ductus arteriosus (PDA) is a persistent patency of a vessel normally present in the fetus that connects the pulmonary arterial system to the aorta. The ductus arteriosus fails to close at birth when breathing commences and placental blood circulation is removed. Closure of the ductus arteriosus arises in response to decline pulmonary vascular resistance and increased systemic vascular resistance. This report describes a case of PDA in a two-month-old male lamb with clinical signs of machinery murmur, tachycardia, increase respiratory rate, weakness and ill thrift. Echocardiographic examination and necropsy finding confirmed PDA. PMID- 27226894 TI - Tobacco Use and its Relationship with Health Complaints Among Employees of Kermanshah Province, Iran. AB - BACKGROUND: Identifying the pattern of tobacco use and its related factors in employees is crucial. This study aimed to investigate the pattern of tobacco use and its related factors in employees of Kermanshah Province, Iran. METHODS: In 2012, 7129 employees were investigated in a cross-sectional study using the census method. Data on tobacco use and on several chronic diseases obtained using a standardized questionnaire on noncommunicable diseases risk factors of the World Health Organization through face-to-face interviews. Statistical analysis was performed based on the Chi-square test and multivariate logistic regression. RESULTS: In general, the prevalence of tobacco use, smoking cigarettes, and smoking waterpipe was 9.9%, 8.9%, and 1.2% among the employees, respectively. Tobacco use was significantly higher in the age group over 40 (14.0%), in male gender (13.3%), in married individuals (10.8%) and in those with diploma and lower degree (16.4%), (P < 0.001). At the individual level, the odds ratio of tobacco use was 1.5 (95% confidence interval [CI]: 1.2-1.8) in hypertensive, 1.8 (95% CI: 1.2-2.6) in diabetic employees and 1.7 (95% CI: 1.3-2.3) in those with heart diseases, compared to healthy individuals. After adjusting for age, gender, marital status and educational level, there was not any significant relationship between tobacco use and health complaints and only the demographic variables remained significant. CONCLUSIONS: Preventive public health policies are mandatory especially in younger ages and male employees to promote their knowledge on disadvantages of tobacco use. PMID- 27226896 TI - Acid-base balance, serum electrolytes and need for non-invasive ventilation in patients with hypercapnic acute exacerbation of chronic obstructive pulmonary disease admitted to an internal medicine ward. AB - BACKGROUND: Hypoventilation produces or worsens respiratory acidosis in patients with hypercapnia due to acute exacerbations of chronic obstructive pulmonary disease (AECOPD). In these patients acid-base and hydroelectrolite balance are closely related. Aim of the present study was to evaluate acid-base and hydroelectrolite alterations in these subjects and the effect of non-invasive ventilation and pharmacological treatment. METHODS: We retrospectively analysed 110 patients consecutively admitted to the Internal Medicine ward of Cava de' Tirreni Hospital for acute exacerbation of hypercapnic chronic obstructive pulmonary disease. On admission all patients received oxygen with a Venturi mask to maintain arterial oxygen saturation at least >90 %, and received appropriate pharmacological treatment. Non-Invasive Ventilation (NIV) was started when, despite optimal therapy, patients had severe dyspnea, increased work of breathing and respiratory acidosis. Based on Arterial Blood Gas (ABG) data, we divided the 110 patients in 3 groups: A = 51 patients with compensated respiratory acidosis; B = 36 patients with respiratory acidosis + metabolic alkalosis; and C = 23 patients with respiratory acidosis + metabolic acidosis. 55 patients received only conventional therapy and 55 had conventional therapy plus NIV. RESULTS: The use of NIV support was lower in the patients belonging to group B than in those belonging to group A and C (25 %, vs 47 % and 96 % respectively; p < 0.01). A statistically significant association was found between pCO2 values and serum chloride concentrations both in the entire cohort and in the three separate groups. CONCLUSIONS: Our study shows that in hypercapnic respiratory acidosis due to AECOPD, differently from previous studies, the metabolic alkalosis is not a negative prognostic factor neither determines greater NIV support need, whereas the metabolic acidosis in addition to respiratory acidosis is an unfavourable element, since it determines an increased need of NIV and invasive mechanical ventilation support. PMID- 27226895 TI - Asymmetry of fusiform structure in autism spectrum disorder: trajectory and association with symptom severity. AB - BACKGROUND: While asymmetry in the fusiform gyrus (FFG) has been reported in functional and structural studies in typically developing controls (TDC), few studies have examined FFG asymmetry in autism spectrum disorder (ASD) subjects and those studies are limited by small sample sizes, and confounded by cognitive ability or handedness. No previous work has examined FFG surface area or cortical thickness asymmetry in ASD; nor do we understand the trajectory of FFG asymmetry over time. Finally, it is not known how FFG structural asymmetry relates to ASD symptom severity. METHODS: In this study, we examined FFG volume, surface area, and cortical thickness asymmetry, as well as their cross-sectional trajectories in a large sample of right-handed males aged 7 to 25 years with 128 ASD and 127 TDC subjects using general linear models. In addition, we examined the relationship between FFG asymmetry and ASD severity using the Autism Diagnostic Observation Schedule (ADOS) and Gotham autism severity scores. RESULTS: Findings revealed that while group differences were evident with mean leftward asymmetry in ASD and mean near symmetry in TDC volume and surface area, asymmetry for both groups existed on a spectrum encompassing leftward and rightward asymmetry. In ASD subjects, volume asymmetry was negatively associated with ADOS and autism severity score symptom measures, with a subset of rightward asymmetric patients being most severely affected. We also observed differential trajectory of surface area asymmetry: ASD subjects exhibited a change from leftward asymmetry toward symmetry from age 7 to 25, whereas TDCs exhibited the reverse trend with a change from near symmetry toward leftward symmetry over the observed age range. CONCLUSIONS: Abnormalities in FFG structural asymmetry are related to symptom severity in ASD and show differential developmental trajectory compared to TDC. This study is the first to note these findings. These results may have important implications for understanding the role of FFG asymmetry in ASD. PMID- 27226897 TI - A novel technique for detoxification of phenol from wastewater: Nanoparticle Assisted Nano Filtration (NANF). AB - BACKGROUND: Phenol is one of the most versatile and important organic compound. It is also a growing concern as water pollutants due to its high persistence and toxicity. Removal of Phenol from wastewaters was investigated using a novel nanoparticle adsorption and nanofiltration technique named as Nanoparticle Assisted Nano Filtration (NANF). METHODS: The nanoparticle used for NANF study were silver nanoparticles and synthesized to three distinct average particle sizes of 10 nm, 40 nm and 70 nm. The effect of nanoparticle size, their concentrations and their tri and diparticle combinations upon phenol removal were studied. RESULTS: Total surface areas (TSA) for various particle size and concentrations have been calculated and the highest was 4710 * 10(12 )nm(2 )for 10 nm particles and 180 ppm concentration while the lowest was for 2461 * 10(11) for 70 nm and 60 ppm concentrations. Tri and diparticle studies showed more phenol removal % than that of their individual particles, particularly for using small particles on large membrane pore size and large particles at low concentrations. These results have also been confirmed with COD and toxicity removal studies. CONCLUSIONS: The combination of nanoparticles adsorption and nanofiltration results in high phenol removal and mineralization, leading to the conclusion that NANF has very high potential for treating toxic chemical wastewaters. PMID- 27226898 TI - Effect of feeding mixed microbial culture fortified with trace minerals on ruminal fermentation, nutrient digestibility, nitrogen and trace mineral balance in Sheep. AB - BACKGROUND: The aim of the present study was to determine the effects of feeding trace mineralsfortified mixed microbial culture (TMC) on ruminal fermentation, nutrient digestibility, blood electrolyte status, nitrogen balance, and trace mineral balance in sheep. METHODS: Mixed microbes [0.6 % (v/w) of Enterobacter sp., Bacillus sp., Lactobacillus sp., and Saccharomyces sp.] were cultured with 99 % feedstuffs and 0.4 % trace minerals including zinc and copper for ensiling. Six sheep (a mean body weight of 46.5 +/- 1.2 kg) were fed two diets: a control diet (concentrate mix and rye straw) and an experimental diet (a control diet + 3.1 % TMC). RESULTS: TMC feeding did not induce negative effects on ruminal fermentation, nutrient digestibility, blood electrolytes, and nitrogen balance in sheep. Feeding with TMC increased the intake of trace minerals (p < 0.05) and did not affect absorption of trace minerals in the whole digestive tract. Feeding with TMC increased fecal excretion and absorbable intake, and retention of zinc and copper (p < 0.05) by 71 % and 77 %, respectively. CONCLUSION: Feeding with TMC resulted in higher zinc and copper bioavailability and retention without any adverse effects on sheep performance. PMID- 27226900 TI - Endocytosis and serpentine filopodia drive blebbishield-mediated resurrection of apoptotic cancer stem cells. AB - The blebbishield emergency program helps to resurrect apoptotic cancer stem cells (CSCs) themselves. Understanding the mechanisms behind this program is essential to block resurrection of CSCs during cancer therapy. Here we demonstrate that endocytosis drives serpentine filopodia to construct blebbishields from apoptotic bodies and that a VEGF-VEGFR2-endocytosis-p70S6K axis governs subsequent transformation. Disengagement of RalGDS from E-cadherin initiates endocytosis of RalGDS and its novel interaction partners cdc42, VEGFR2, cleaved beta-catenin, and PKC-zeta as well as its known interaction partner K-Ras. We also report novel interactions of p45S6K (cleaved p70S6K) and PKM-zeta with PAK-1 filopodia-forming machinery specifically in blebbishields. Thus, a RalGDS-endocytosis-filopodia VEGFR2-K-Ras-p70S6K axis drives the blebbishield emergency program, and therapeutic targeting of this axis might prevent resurrection of CSCs during cancer therapy. PMID- 27226899 TI - Antifibrotic therapies to control cardiac fibrosis. AB - Cardiac fibrosis occurs naturally after myocardial infarction. While the initially formed fibrotic tissue prevents the infarcted heart tissue from rupture, the progression of cardiac fibrosis continuously expands the size of fibrotic tissue and causes cardiac function decrease. Cardiac fibrosis eventually evolves the infarcted hearts into heart failure. Inhibiting cardiac fibrosis from progressing is critical to prevent heart failure. However, there is no efficient therapeutic approach currently available. Myofibroblasts are primarily responsible for cardiac fibrosis. They are formed by cardiac fibroblast differentiation, fibrocyte differentiation, epithelial to mesenchymal transdifferentiation, and endothelial to mesenchymal transition, driven by cytokines such as transforming growth factor beta (TGF-beta), angiotensin II and platelet-derived growth factor (PDGF). The approaches that inhibit myofibroblast formation have been demonstrated to prevent cardiac fibrosis, including systemic delivery of antifibrotic drugs, localized delivery of biomaterials, localized delivery of biomaterials and antifibrotic drugs, and localized delivery of cells using biomaterials. This review addresses current progresses in cardiac fibrosis therapies. PMID- 27226902 TI - Learning Disabilities: Opportunities and challenges in Oman. PMID- 27226901 TI - Cdk2 phosphorylation of Bcl-xL after stress converts it to a pro-apoptotic protein mimicking Bax/Bak. AB - Apoptosis is a regulated form of cell death that proceeds by defined biochemical pathways. Most apoptosis is controlled by interactions between pro-survival and pro-apoptotic Bcl-2 family proteins in which death is often the consequence of permeabilization of the mitochondrial outer membrane. Many drugs affect this equilibrium to favor apoptosis but this process is not completely understood. We show that the chemotherapeutic drug cisplatin initiates an apoptotic pathway by phosphorylation of a pro-survival Bcl-2 family member, Bcl-xL, by cyclin dependent kinase 2. The phosphorylation occurred at a previously unreported site and its biologic significance was demonstrated by a phosphomimetic modification of Bcl-xL that was able to induce apoptosis without addition of cisplatin. The mechanism of cell death induction was similar to that initiated by pro-apoptotic Bcl-2 family proteins, that is, phosphorylated Bcl-xL translocated to the mitochondrial membrane, and formed pores in the membrane. This initiated cytochrome c release and caspase activation that resulted in cell death. PMID- 27226903 TI - Mechanisms of Diabetes-Induced Liver Damage: The role of oxidative stress and inflammation. AB - Diabetes mellitus is a non-communicable disease that occurs in both developed and developing countries. This metabolic disease affects all systems in the body, including the liver. Hyperglycaemia, mainly caused by insulin resistance, affects the metabolism of lipids, carbohydrates and proteins and can lead to non alcoholic fatty liver disease, which can further progress to non-alcoholic steatohepatitis, cirrhosis and, finally, hepatocellular carcinomas. The underlying mechanism of diabetes that contributes to liver damage is the combination of increased oxidative stress and an aberrant inflammatory response; this activates the transcription of pro-apoptotic genes and damages hepatocytes. Significant involvement of pro-inflammatory cytokines-including interleukin (IL) 1beta, IL-6 and tumour necrosis factor-alpha-exacerbates the accumulation of oxidative damage products in the liver, such as malondialdehyde, fluorescent pigments and conjugated dienes. This review summarises the biochemical, histological and macromolecular changes that contribute to oxidative liver damage among diabetic individuals. PMID- 27226904 TI - Sclerosing Encapsulating Peritonitis: Review. AB - Sclerosing encapsulating peritonitis (SEP) is a rare chronic inflammatory condition of the peritoneum with an unknown aetiology. Also known as abdominal cocoon, the condition occurs when loops of the bowel are encased within the peritoneal cavity by a membrane, leading to intestinal obstruction. Due to its rarity and non-specific clinical features, it is often misdiagnosed. The condition presents with recurrent episodes of small bowel obstruction and can be idiopathic or secondary; the latter is associated with predisposing factors such as peritoneal dialysis or abdominal tuberculosis. In the early stages, patients can be managed conservatively; however, surgical intervention is necessary for those with advanced stage intestinal obstruction. A literature review revealed 118 cases of SEP; the mean age of these patients was 39 years and 68.0% were male. The predominant presentation was abdominal pain (72.0%), distension (44.9%) or a mass (30.5%). Almost all of the patients underwent surgical excision (99.2%) without postoperative complications (88.1%). PMID- 27226905 TI - Topical, Biological and Clinical Challenges in the Management of Patients with Acne Vulgaris. AB - Acne vulgaris is one of the most common chronic inflammatory skin disorders among adolescents and young adults. It is associated with substantial morbidity and, rarely, with mortality. The exact worldwide incidence and prevalence are currently unknown. Current challenges involve improving understanding of the underlying pathophysiology of acne vulgaris and developing a practical treatment consensus. Expert panel discussions were held in 2013 and 2014 among a group of scientists and clinicians from the Omani and United Arab Emirate Dermatology Societies to ascertain the current optimal management of acne vulgaris, identify clinically relevant end-points and construct suitable methodology for future clinical trial designs. This article reviews the discussions of these sessions and recent literature on this topic. PMID- 27226906 TI - Shining a Light on Task-Shifting Policy: Exploring opportunities for adaptability in non-communicable disease management programmes in Uganda. AB - In terms of disease burden, many low- and middle-income countries are currently experiencing a transition from infectious to chronic diseases. In Uganda, non communicable diseases (NCDs) have increased significantly in recent years; this challenge is compounded by the healthcare worker shortage and the underfunded health system administration. Addressing the growing prevalence of NCDs requires evidence-based policies and strategies to reduce morbidity and mortality rates; however, the integration and evaluation of new policies and processes pose many challenges. Task-shifting is the process whereby specific tasks are transferred to health workers with less training and fewer qualifications. Successful implementation of a task-shifting policy requires appropriate skill training, clearly defined roles, adequate evaluation, an enhanced training capacity and sufficient health worker incentives. This article focuses on task-shifting policy as a potentially effective strategy to address the growing burden of NCDs on the Ugandan healthcare system. PMID- 27226907 TI - Screening for Anti-Cancer Compounds in Marine Organisms in Oman. AB - OBJECTIVES: Marine organisms are a rich source of bioactive molecules with potential applications in medicine, biotechnology and industry; however, few bioactive compounds have been isolated from organisms inhabiting the Arabian Gulf and the Gulf of Oman. This study aimed to isolate and screen the anti-cancer activity of compounds and extracts from 40 natural products of marine organisms collected from the Gulf of Oman. METHODS: This study was carried out between January 2012 and December 2014 at the Sultan Qaboos University, Muscat, Oman. Fungi, bacteria, sponges, algae, soft corals, tunicates, bryozoans, mangrove tree samples and sea cucumbers were collected from seawater at Marina Bandar Al-Rowdha and Bandar Al-Khayran in Oman. Bacteria and fungi were isolated using a marine broth and organisms were extracted with methanol and ethyl acetate. Compounds were identified from spectroscopic data. The anti-cancer activity of the compounds and extracts was tested in a Michigan Cancer Foundation (MCF)-7 cell line breast adenocarcinoma model. RESULTS: Eight pure compounds and 32 extracts were investigated. Of these, 22.5% showed strong or medium anti-cancer activity, with malformin A, kuanoniamine D, hymenialdisine and gallic acid showing the greatest activity, as well as the soft coral Sarcophyton sp. extract. Treatment of MCF-7 cells at different concentrations of Sarcophyton sp. extracts indicated the induction of concentration-dependent cell death. Ultrastructural analysis highlighted the presence of nuclear fragmentation, membrane protrusion, blebbing and chromatic segregation at the nuclear membrane, which are typical characteristics of cell death by apoptosis induction. CONCLUSION: Some Omani marine organisms showed high anti-cancer potential. The efficacy, specificity and molecular mechanisms of anti-cancer compounds from Omani marine organisms on various cancer models should be investigated in future in vitro and in vivo studies. PMID- 27226908 TI - Healthcare-Associated Methicillin-Resistant Staphylococcus aureus: Clinical characteristics and antibiotic resistance profile with emphasis on macrolide lincosamide-streptogramin B resistance. AB - OBJECTIVES: Healthcare-associated methicillin-resistant Staphylococcus aureus (MRSA) is a common pathogen worldwide and its multidrug resistance is a major concern. This study aimed to determine the clinical characteristics and antibiotic susceptibility profile of healthcare-associated MRSA with emphasis on resistance to macrolide-lincosamide-streptogramin B (MLSB) phenotypes and vancomycin. METHODS: This cross-sectional study was carried out between February 2014 and February 2015 across four tertiary care hospitals in Mangalore, South India. Healthcare-associated infections among 291 inpatients at these hospitals were identified according to the Centers for Disease Control and Prevention guidelines. Clinical specimens were collected based on infection type. S. aureus and MRSA isolates were identified and antibiotic susceptibility tests performed using the Kirby-Bauer disk diffusion method. The minimum inhibitory concentration of vancomycin was determined using the Agar dilution method and inducible clindamycin resistance was detected with a double-disk diffusion test (D-test). RESULTS: Out of 291 healthcare-associated S. aureus cases, 88 were MRSA (30.2%). Of these, 54.6% were skin and soft tissue infections. All of the isolates were susceptible to teicoplanin and linezolid. Four MRSA isolates exhibited intermediate resistance to vancomycin (4.6%). Of the MRSA strains, 10 (11.4%) were constitutive MLSB phenotypes, 31 (35.2%) were inducible MLSB phenotypes and 14 (15.9%) were macrolide-streptogramin B phenotypes. CONCLUSION: Healthcare associated MRSA multidrug resistance was alarmingly high. In routine antibiotic susceptibility testing, a D-test should always be performed if an isolate is resistant to erythromycin but susceptible to clindamycin. Determination of the minimum inhibitory concentration of vancomycin is necessary when treating patients with MRSA infections. PMID- 27226909 TI - Effect of Khat (Catha edulis) Use on the Bioavailability, Plasma Levels and Antimalarial Activity of Chloroquine. AB - OBJECTIVES: This study aimed to evaluate the effect of khat (Catha edulis) on chloroquine (CQ) bioavailability in healthy Yemeni adults and its effect on CQ plasma levels and parasite clearance among malaria patients. METHODS: This study took place between January and April 2007 in Bajil and Sana'a, Yemen. Two CQ doses (600 mg each) were given to 15 healthy males on separate occasions; the first dose was followed by a khat-chewing session (phase one) while controls abstained from khat-chewing for the second (phase two). Additionally, 103 patients with Plasmodium falciparum-induced malaria, including both regular khat chewers (n = 57) and non-khat chewers (n = 46), were treated with CQ (25 mg/kg) over three days. Pharmacokinetic parameters were analysed among both controls and malaria patients. Parasite clearance was also investigated for the latter group. RESULTS: The mean area under the concentration-time curve (AUC) was 2,108.9 versus 2,797.4 ng/hour/mL, mean peak plasma concentration (Cmax) was 415.6 versus 508.7 ng/mL and mean time to reach Cmax was 3.8 versus 3.6 hours for controls in phase one versus phase two, respectively; both AUC and Cmax levels were significantly reduced by khat-chewing (P <0.050). For khat- versus non-khat chewing malaria patients, mean plasma CQ concentrations were 266.4 ng/mL versus 427.5 ng/mL (P <0.001). Furthermore, CQ was effective in 71.7% and 75.4% of non khat and khat-chewing malaria patients, respectively (P = 0.823). CONCLUSION: Khat-chewing was found to significantly reduce plasma CQ levels among healthy volunteers and malaria patients. While receiving CQ treatment, patients should be advised not to chew khat. PMID- 27226910 TI - Knowledge of Coronary Heart Disease Risk Factors among a Community Sample in Oman: Pilot study. AB - OBJECTIVES: The aim of this study was to assess the knowledge of Omani adults regarding conventional coronary heart disease (CHD) risk factors and to identify demographic variables associated with these knowledge levels. METHODS: This descriptive cross-sectional pilot study was carried out among a convenience sample of 130 adults attending a health awareness fair held in a local shopping mall in Muscat, Oman, in November 2012. A modified version of the Heart Disease Facts Questionnaire in both English and Arabic was used to assess knowledge of CHD risk factors. Scores were calculated by summing the correct answers for each item (range: 0-21). Inadequate knowledge was indicated by a mean score of <70%. Descriptive and multivariate logistic regression analyses were performed to establish the participants' knowledge levels and identify associated demographic variables. RESULTS: A total of 114 subjects participated in the study (response rate: 87.7%). Of these, 69 participants (60.5%) had inadequate mean CHD knowledge scores. Knowledge of CHD risk factors was significantly associated with body mass index (odds ratio [OR] = 0.739; P = 0.023), marital status (OR = 0.057; P = 0.036) and education level (OR = 9.243; P = 0.006). CONCLUSION: Low knowledge levels of CHD risk factors were observed among the studied community sample in Oman; this is likely to limit the participants' ability to engage in preventative practices. These findings support the need for education programmes to enhance awareness of risk factors and prevention of CHD in Oman. PMID- 27226911 TI - Spousal Concordance of Diabetes Mellitus among Women in Ajman, United Arab Emirates. AB - OBJECTIVES: Spousal concordance is defined as similar behaviours and associated health statuses between spouses. This study aimed to identify the concordance of diabetes mellitus (DM) and related variables among genetically unrelated couples in Ajman, United Arab Emirates (UAE). METHODS: This cross-sectional study included 270 married women attending either the Mushairef Health Center or the Gulf Medical College Hospital in Ajman between May and November 2012. A validated questionnaire was designed to determine sociodemographic characteristics and a history or family history of DM, hypertension, coronary artery disease or dyslipidaemia among the women and their husbands. The weight, height, body mass index, waist circumference, fasting blood sugar and glycated haemoglobin (HbA1c) levels of all women were measured. RESULTS: Of the women, 39.3% of those with diabetic husbands and 39.9% of those with non-diabetic husbands were diabetic themselves (P >0.050). The prevalence of DM spousal concordance was 17.8%. A history of hypertension, coronary artery disease and dyslipidaemia was significantly more frequent among women whose husbands had a history of the same conditions (P = 0.001, 0.040 and 0.002, respectively). Spousal concordance of abnormal glycaemia among non-diabetic women with diabetic husbands was significant (P = 0.001). Having a diabetic husband (P = 0.006) and being obese (P = 0.009) were the only significant predictors of hyperglycaemia among non diabetic women after controlling for confounding factors. CONCLUSION: There was significant concordance of abnormal glycaemia among non-diabetic women with diabetic husbands. The spouses of diabetic patients may therefore be a target population for regular hyperglycaemia and DM screening. PMID- 27226912 TI - Understanding Preclerkship Medical Students' Poor Performance in Prescription Writing. AB - OBJECTIVES: This study aimed to explore reasons for poor performance in prescription writing stations of the objective structured practical examination (OSPE) and absenteeism in prescription writing sessions among preclerkship medical students at the Arabian Gulf University (AGU) in Manama, Bahrain. METHODS: This descriptive study was carried out between September 2014 and June 2015 among 157 preclerkship medical students at AGU. Data were collected using focus group discussions and a questionnaire with closed- and open-ended items. RESULTS: All 157 students participated in the study (response rate: 100.0%). The most frequently cited reasons for poor performance in OSPE stations were an inability to select the correct drugs (79.6%), treatment duration (69.4%), drug quantity (69.4%) and drug formulation (68.2%). Additionally, students reported inadequate time for completing the stations (68.8%). During focus group discussions, students reported other reasons for poor performance, including examination stress and the difficulty of the stations. Absenteeism was attributed to the length of each session (55.4%), lack of interest (50.3%), reliance on peers for information (48.4%) and optional attendance policies (47.1%). Repetitive material, large group sessions, unmet student expectations and the proximity of the sessions to summative examinations were also indicated to contribute to absenteeism according to open-ended responses or focus group discussions. CONCLUSION: This study suggests that AGU medical students perform poorly in prescription writing OSPE stations because of inadequate clinical pharmacology knowledge. Participation in prescription writing sessions needs to be enhanced by addressing the concerns identified in this study. Strategies to improve attendance and performance should take into account the learner-teacher relationship. PMID- 27226913 TI - Paediatric Blunt Torso Trauma: Injury mechanisms, patterns and outcomes among children requiring hospitalisation at the Sultan Qaboos University Hospital, Oman. AB - OBJECTIVES: Trauma is the greatest cause of morbidity and mortality in paediatric/adolescent populations worldwide. This study aimed to describe trauma mechanisms, patterns and outcomes among children with blunt torso trauma admitted to the Sultan Qaboos University Hospital (SQUH) in Muscat, Oman. METHODS: This retrospective single-centre study involved all children <=12 years old with blunt torso trauma admitted for paediatric surgical care at SQUH between January 2009 and December 2013. Medical records were analysed to collect demographic and clinical data. RESULTS: A total of 70 children were admitted with blunt torso trauma during the study period, including 39 (55.7%) male patients. The mean age was 5.19 +/- 2.66 years. Of the cohort, 35 children (50.0%) received their injuries after having been hit by cars as pedestrians, while 19 (27.1%) were injured by falls, 12 (17.1%) during car accidents as passengers and four (5.7%) by falling heavy objects. According to computed tomography scans, thoracic injuries were most common (65.7%), followed by abdominal injuries (42.9%). The most commonly involved solid organs were the liver (15.7%) and spleen (11.4%). The majority of the patients were managed conservatively (92.9%) with a good outcome (74.3%). The mortality rate was 7.1%. Most deaths were due to multisystem involvement. CONCLUSION: Among children with blunt torso trauma admitted to SQUH, the main mechanism of injury was motor vehicle accidents. As a result, parental education and enforcement of infant car seat/child seat belt laws are recommended. Conservative management was the most successful approach. PMID- 27226914 TI - Depression, Anxiety and Stress among Saudi Arabian Dermatology Patients: Cross sectional study. AB - OBJECTIVES: This study aimed to determine the prevalence of depression, anxiety and stress among Saudi Arabian dermatology patients and to assess associations with sociodemographic and clinical characteristics. METHODS: This cross-sectional study was conducted among 300 consecutive dermatology patients visiting King Abdulaziz Medical City in Riyadh, Saudi Arabia, in August 2015. The Arabic version of the Depression, Anxiety and Stress Scale was used to screen for symptoms of depression, anxiety and stress. Quality of life (QOL) was assessed using the Dermatology Life Quality Index. RESULTS: A total of 254 dermatology patients participated in the study (response rate: 84.7%). The prevalence of depression, anxiety and stress was 12.6%, 22.1% and 7.5%, respectively. The presence of at least one of these negative emotional states was noted among 24.4% of the cohort (95% confidence interval: 19.3-30.2%). Depression was significantly higher among subjects who lacked family support (26.5% versus 10.7%; P = 0.006) while anxiety was less common among patients who engaged in physical exercise (14.5% versus 29.4%; P = 0.005). According to the multivariate logistic regression analysis, poor QOL and a lack of family support were significant predictors of a negative emotional state. CONCLUSION: Almost a quarter of the studied Saudi Arabian dermatology patients were found to suffer from at least one negative emotional state. A lack of family support and poor QOL were the primary factors associated with a negative emotional state. Interventional studies are needed to examine the effects of social and family support on psychological conditions among Saudi Arabian dermatology patients. PMID- 27226915 TI - Patients' Perceptions Towards the Participation of Medical Students in their Care. AB - OBJECTIVES: Patient interaction is a vital part of healthcare training. This study aimed to investigate patients' perceptions of the participation of medical students in their care. METHODS: This descriptive cross-sectional study was conducted between October 2014 and March 2015 among 430 patients admitted to the medical and surgical wards at the King Abdulaziz Medical City, Riyadh, Saudi Arabia. An Arabic questionnaire was designed to assess the demographic characteristics of the patients and their perceptions of students' participation in their medical care. RESULTS: A total of 416 patients completed the survey (response rate: 97%). Overall, 407 patients (98%) acknowledged the educational benefit of involving medical students in their care. A total of 368 patients (88%) had no objection to a medical student being involved in their care. Of these, 98% were willing to be asked about their medical history by medical students, 89% would permit physical examinations by medical students and 39% preferred that the gender of the medical student match their own. Education level (P <0.003), a positive prior experience with a medical student (P <0.001) and perception of the medical students' attitudes (P <0.001) had a significant effect on patients' acceptance of medical students participating in their care. CONCLUSION: In general, the patients had a positive perception of medical students, with most patients acknowledging the educational benefit of student participation in patient care. As patients' perceptions of students' professionalism, confidence and respect for privacy were significantly related to acceptance of care, education on these aspects should be a priority in medical curricula. PMID- 27226916 TI - Unusual Indolent Course of a Chronic Active Epstein-Barr Virus-Associated Natural Killer Cell Lymphoproliferative Disorder. AB - Natural killer (NK) cell lymphoproliferative disorders are uncommon and the Epstein-Barr virus (EBV) plays an important aetiological role in their pathogenesis. We report a 20-year-old male with a chronic active EBV infection associated with a NK cell lymphoproliferative disorder which had an unusual indolent course. He presented to the Sultan Qaboos University Hospital in Muscat, Oman, in December 2011 with a history of intermittent fever and coughing. Examinations revealed generalised lymphadenopathy, hepatosplenomegaly, leukocytosis, transaminitis, diffuse bilateral lung infiltrates and bone marrow lymphocyte involvement. A polymerase chain reaction (PCR) test revealed a high EBV viral load in the peripheral blood cells. The patient received a course of piperacillin-tazobactam for Klebsiella pneumoniae, but no active treatment for the lymphoproliferative disorder. However, his lymphocyte count, serum lactate dehydrogenase and liver enzymes dropped spontaneously. In addition, EBV PCR copies fluctuated and then decreased significantly. He remained clinically asymptomatic over the following four years. PMID- 27226917 TI - The Difficult Diagnosis of Ischaemic Papillary Muscle Rupture: Case report from an urban emergency department. AB - We present a rare case of severe ischaemic papillary muscle rupture in a 67-year old male patient who was admitted to the Emergency Department of the University Hospital Bern, Switzerland, in November 2013 with acute chest pain. On admission, the patient's blood pressure was 60/40 mm/Hg, his pulse was 110 beats per minute and his respiratory rate was 20 breaths per minute. An electrocardiogram was normal and focused assessment with sonography in trauma was negative. Transthoracic echocardiography showed possible thickening of the mitral valve leaflet with no indications of severe mitral insufficiency or wall motion abnormalities. Triple-rule-out computed tomography angiography revealed no pulmonary emboli or aortic dissection, although coronary atherosclerosis was present. Finally, severe insufficiency of the mitral valve with rupture of the papillary muscle, likely due to ischaemia, was observed via transoesophageal echocardiography. The patient underwent a successful surgical intervention and was discharged 10 days later in stable condition. PMID- 27226918 TI - Acute Anteroseptal Myocardial Infarction after a Negative Exercise Stress Test. AB - A myocardial infarction is a rare complication which can occur after an exercise stress test. We report a 48-year-old male who was referred to the Mildura Cardiology Practice, Victoria, Australia, in August 2014 with left-sided chest pain. He underwent an exercise stress test which was negative for myocardial ischaemia. However, the patient presented to the Emergency Department of the Mildura Base Hospital 30 minutes after the test with severe retrosternal chest pain. An acute anteroseptal ST segment elevation myocardial infarction was observed on electrocardiography. After thrombolysis, he was transferred to a tertiary hospital where coronary angiography subsequently revealed significant left anterior descending coronary artery stenosis. Thrombus aspiration and a balloon angioplasty were performed. The patient was discharged three days after the surgical procedure in good health. PMID- 27226919 TI - Single-Incision Multi-Port Appendectomy for a Patient with Situs Inversus Totalis: First case report. AB - Situs inversus totalis (SIT) is a rare autosomal recessive condition involving the complete lateral transposition of the organs. When individuals with this condition suffer from appendicitis, associated pain and symptoms are usually present on the left side, resulting in diagnostic difficulties. Moreover, the laparoscopic removal of the left-sided appendix may pose practical problems during surgery. Removal of an inflamed appendix is generally performed using a multiple-port laparoscopy. We report a 22-year-old male who presented to the Lifeline Institute of Minimal Access Surgery in Chennai, India, in April 2015 with pain in the left iliac fossa. Chest X-rays and ultrasonography confirmed SIT with an acutely inflamed appendix on the left side. The patient underwent a single-incision multi-port laparoscopic appendectomy with a successful outcome. To the best of the authors' knowledge, this is the first report in the literature of a single-incision multi-port appendectomy in a patient with SIT. PMID- 27226920 TI - Aspergillus flavus-Induced Brain Abscess in an Immunocompetent Child: Case report. AB - Intracranial aspergillosis is an extremely rare manifestation of invasive aspergillosis in immunocompetent children and is associated with high morbidity and mortality. We report a 12-year-old immunocompetent male child who was referred to the King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia, in May 2010 after a sudden-onset headache and loss of consciousness. Brain imaging revealed a large right space-occupying occipital lesion and the patient underwent a craniotomy and resection. Histopathology of the lesion revealed necrotising granulomatous fungal encephalitis with many hyphae engulfed by multinucleated giant histiocytes. Two days later, a computed tomography scan showed debulking of the fungal mass and the patient was discharged on oral voriconazole. However, imaging at a six-week follow-up showed progression of the abnormality. A residual or persistent fungal brain lesion was suspected. Further neurosurgical resection of the lesion was performed and cultures showed growth of Aspergillus flavus. The patient was treated successfully with antifungal therapy over the following two years. PMID- 27226921 TI - Right Ventricular Thrombus and Cerebral Artery Aneurysm in a Patient with Behcet's Disease. AB - We report a 35-year-old woman referred to the Imam Ali Hospital, Kermanshah, Iran, in July 2014 for evaluation of postoperative dyspnoea after neurosurgery performed seven days previously for a ruptured cerebral artery aneurysm. She was known to have Behcet's disease with a history of recurrent oral and genital aphthous ulcers and uveitis. At referral, her symptoms included vertigo, dysarthria, palpitations and chest pain. Transthoracic echocardiography (TTE) revealed a large thrombus in her right ventricle outflow tract and open-heart surgery was performed eight days after the previous surgery to remove the clot. The postoperative period was complicated by transient acute renal failure, which resolved spontaneously. The patient was discharged 13 days after the cardiac surgery on warfarin, prednisolone, azathioprine and cyclophosphamide. Cyclophosphamide and azathioprine were discontinued after three months as the symptoms had completely resolved; however, prednisolone was continued due to recurrent uveitis. A 10-month follow-up TTE scan revealed no thrombus recurrence and treatment with warfarin and prednisolone was continued. PMID- 27226922 TI - Congenital Giant Left Atrium with Severe Mitral Valve Regurgitation. PMID- 27226923 TI - Molluscum Contagiosum Over Tattooed Skin. PMID- 27226924 TI - Dirt-Like Hyperpigmented Plaques on the Neck and Linea Alba of a 12-Year-Old Girl. PMID- 27226925 TI - Tracheolaryngeal Adenoid Cystic Carcinoma: The tumour that almost took her breath away. PMID- 27226926 TI - Effectiveness of Interventions, Programs and Strategies for Gender-based Violence Prevention in Refugee Populations: An Integrative Review. AB - BACKGROUND: Gender based violence (GBV) remains one of the most serious threats to the health and safety of women and girls worldwide. The problem is even more pronounced in refugee populations where women and girls are at increased risk of violence. In 2015, UNHCR reported the highest number of forcibly displaced people in recorded history. Despite growing need, there have been few rigorous evaluations of interventions aimed at primary GBV prevention and no systematic reviews of GBV prevention efforts specifically focused on refugee populations; reviews to date have primarily examined prevention of conflict related sexual violence, with very limited focus on other forms of GBV such as intimate partner violence Methods: This study reviewed the scientific literature addressing strategies for primary prevention of GBV and their effectiveness among refugee populations over the past ten years (2006 to 2015). Narrative content analysis methods were used to extract findings related to prevention activities/programs recommended by the global humanitarian community, such as sociocultural norms change, rebuilding family and community support structures, improving accountability systems, designing effective services and facilities, working with formal and traditional legal systems, monitoring and documenting GBV, and/or engaging men and boys in GBV prevention and response. RESULTS: Study findings indicate that a range of GBV prevention activities recommended by the global humanitarian community are currently being applied in a variety of settings. However, there remains a limited body of evidence on the effectiveness of GBV prevention programs, interventions, and strategies, especially among refugee populations. CONCLUSION: Commonly agreed upon standards or guidelines for evaluation of GBV prevention programming, and publication of evaluations conducted using these guidelines, could assist humanitarian stakeholders to build and disseminate an evidence base of effective GBV prevention interventions, programs and strategies. Evaluation of GBV prevention efforts, especially among refugee populations, must be given higher priority to justify continuation or revision of recommended GBV activities/programs being implemented in diverse humanitarian settings. PMID- 27226927 TI - Multivariate Conditional Outlier Detection and Its Clinical Application. AB - This paper overviews and discusses our recent work on a multivariate conditional outlier detection framework for clinical applications. PMID- 27226928 TI - The biological challenge of myalgic encephalomyelitis/chronic fatigue syndrome: a solvable problem. PMID- 27226929 TI - Spatial and Spectral Characterization of Human Retinal Pigment Epithelium Fluorophore Families by Ex Vivo Hyperspectral Autofluorescence Imaging. AB - PURPOSE: Discovery of candidate spectra for abundant fluorophore families in human retinal pigment epithelium (RPE) by ex vivo hyperspectral imaging. METHODS: Hyperspectral autofluorescence emission images were captured between 420 and 720 nm (10-nm intervals), at two excitation bands (436-460, 480-510 nm), from three locations (fovea, perifovea, near-periphery) in 20 normal RPE/Bruch's membrane (BrM) flatmounts. Mathematical factorization extracted a BrM spectrum (S0) and abundant lipofuscin/melanolipofuscin (LF/ML) spectra of RPE origin (S1, S2, S3) from each tissue. RESULTS: Smooth spectra S1 to S3, with perinuclear localization consistent with LF/ML at all three retinal locations and both excitations in 14 eyes (84 datasets), were included in the analysis. The mean peak emissions of S0, S1, and S2 at lambdaex 436 nm were, respectively, 495 +/- 14, 535 +/- 17, and 576 +/- 20 nm. S3 was generally trimodal, with peaks at either 580, 620, or 650 nm (peak mode, 650 nm). At lambdaex 480 nm, S0, S1, and S2 were red-shifted to 526 +/- 9, 553 +/- 10, and 588 +/- 23 nm, and S3 was again trimodal (peak mode, 620 nm). S1 often split into two spectra, S1A and S1B. S3 strongly colocalized with melanin. There were no significant differences across age, sex, or retinal location. CONCLUSIONS: There appear to be at least three families of abundant RPE fluorophores that are ubiquitous across age, retinal location, and sex in this sample of healthy eyes. Further molecular characterization by imaging mass spectrometry and localization via super-resolution microscopy should elucidate normal and abnormal RPE physiology involving fluorophores. TRANSLATIONAL RELEVANCE: Our results help establish hyperspectral autofluorescence imaging of the human retinal pigment epithelium as a useful tool for investigating retinal health and disease. PMID- 27226930 TI - Reliability of a Manual Procedure for Marking the EZ Endpoint Location in Patients with Retinitis Pigmentosa. AB - PURPOSE: We developed and evaluated a training procedure for marking the endpoints of the ellipsoid zone (EZ), also known as the inner segment/outer segment (IS/OS) border, on frequency domain optical coherence tomography (fdOCT) scans from patients with retinitis pigmentosa (RP). METHODS: A manual for marking EZ endpoints was developed and used to train 2 inexperienced graders. After training, an experienced grader and the 2 trained graders marked the endpoints on fdOCT horizontal line scans through the macula from 45 patients with RP. They marked the endpoints on these same scans again 1 month later. RESULTS: Intragrader agreement was excellent. The intraclass correlation coefficient (ICC) was 0.99, the average difference of endpoint locations (19.6 MUm) was close to 0 MUm, and the 95% limits were between -284 and 323 MUm, approximately +/-1.1 degrees . Intergrader agreement also was excellent. The ICC values were 0.98 (time 1) and 0.97 (time 2), the average difference among graders was close to zero, and the 95% limits of these differences was less than 350 MUm, approximately 1.2 degrees , for both test times. CONCLUSIONS: While automated algorithms are becoming increasingly accurate, EZ endpoints still have to be verified manually and corrected when necessary. With training, the inter- and intragrader agreement of manually marked endpoints is excellent. TRANSLATIONAL RELEVANCE: For clinical studies, the EZ endpoints can be marked by hand if a training procedure, including a manual, is used. The endpoint confidence intervals, well under +/-2.0 degrees , are considerably smaller than the 6 degrees spacing for the typically used static visual field. PMID- 27226931 TI - Polyethylene Glycol-Based Synthetic Hydrogel Sealant for Closing Vitrectomy Wounds: An In Vivo and Histological Study. AB - PURPOSE: We conducted an in vivo study using Dutch pigmented rabbit eyes to test the usefulness of polyethylene glycol (PEG) sealant for the closure of sutureless sclerotomies in microincisional vitrectomy surgery (MIVS). METHODS: Three-port, 23-gauge vitrectomy was performed on rabbit eyes. After air leakage was confirmed by the application of 0.625% povidone-iodine at the sclerotomy site, PEG sealant was subconjunctivally injected using a 27-gauge needle through conjunctival incisions to cover the sclerotomy wounds, following which it was polymerized by the application of xenon light for 60 seconds. Ophthalmological examinations and intraocular pressure measurements were conducted the day before and 1, 3, 5, and 7 days after surgery. The eyes were enucleated for histological evaluation 7 days after surgery. RESULTS: PEG sealant was rapidly polymerized by the application of xenon light after subconjunctival injection, and it firmly sealed the sclerotomies without air leakage, as confirmed by povidone-iodine dropping, in all cases. Conjunctival and scleral wounds closed with PEG sealant were successfully attached and remained intact till the end of the follow-up period. There was no sign of postoperative hypotony or infection in any eye, and no adverse effects of PEG sealant were found. In histological examination, linear scar formation and eosinophilic staining of collagen fibers were observed at the sclerotomy sites, while the sclerotomy tunnels appeared tightly closed. CONCLUSIONS: PEG sealant can be useful for the closure of sutureless 23-gauge vitrectomy incisions in rabbits. TRANSLATIONAL RELEVANCE: The PEG sealant may become an effective option for closing vitrectomy incisions including pediatric cases. PMID- 27226932 TI - Diagnosis of Normal and Abnormal Color Vision with Cone-Specific VEPs. AB - PURPOSE: Normal color vision depends on normal long wavelength (L), middle wavelength (M), and short wavelength sensitive (S) cones. Hereditary "red-green" color vision deficiency (CVD) is due to a shift in peak sensitivity or lack of L or M cones. Hereditary S cone CVD is rare but can be acquired as an early sign of disease. Current tests detect CVD but few diagnose type or severity, critical for linking performance to real-world demands. The anomaloscope and newer subjective tests quantify CVD but are not applicable to infants or cognitively impaired patients. Our purpose was to develop an objective test of CVD with sensitivity and specificity comparable to current tests. METHODS: A calibrated visual-evoked potential (VEP) display and Food and Drug Administration-approved system was used to record L, M, and S cone-specific pattern-onset VEPs from 18 color vision normals (CVNs) and 13 hereditary CVDs. VEP amplitudes and latencies were compared between groups to establish VEP sensitivity and specificity. RESULTS: Cone VEPs show 100% sensitivity for diagnosis of CVD and 94% specificity for confirming CVN. L cone (protan) CVDs showed a significant increase in L cone latency (53.1 msec, P < 0.003) and decreased amplitude (10.8 uV, P < 0.0000005) but normal M and S cone VEPs (P > 0.31). M cone (deutan) CVDs showed a significant increase in M cone latency (31.0 msec, P < 0.000004) and decreased amplitude (8.4 uV, P < 0.006) but normal L and S cone VEPs (P > 0.29). CONCLUSIONS: Cone-specific VEPs offer a rapid, objective test to diagnose hereditary CVD and show potential for detecting acquired CVD in various diseases. TRANSLATIONAL RELEVANCE: This paper describes the efficacy of cone-specific color VEPs for quantification of normal and abnormal color vision. The rapid, objective nature of this approach makes it suitable for detecting color sensitivity loss in infants and the cognitively impaired. PMID- 27226933 TI - Morselized Amniotic Membrane Tissue for Refractory Corneal Epithelial Defects in Cicatricial Ocular Surface Diseases. AB - PURPOSE: To evaluate the clinical efficacy of morselized amniotic membrane and umbilical cord tissue (MAU) in treating refractory corneal epithelial defect in ocular cicatricial diseases. METHODS: Retrospective review of four patients with ocular cicatricial diseases treated with topical MAU for corneal epithelial defects refractory to conventional treatments including topical lubricants, autologous serum, bandage contact lens, and tarsorraphy. Their symptoms, corneal staining, conjunctival inflammation, and visual acuity were compared before and after treatment. RESULTS: After topical application of MAU twice daily, two patients demonstrated rapid corneal epithelialization with prompt visual acuity improvement at the first day. All patients showed corneal epithelialization in 7.3 +/- 2.6 days accompanied by a significant relief of symptoms, reduction of ocular surface inflammation, and improvement of visual acuity. CONCLUSION: This pilot study suggests topical MAU can be developed into a novel treatment for treating refractory corneal epithelial defects. TRANSLATIONAL RELEVANCE: Topical MAU can be an effective novel treatment for refractory corneal epithelial defects. PMID- 27226934 TI - Poring over two-pore channel pore mutants. AB - Two-pore channels are members of the voltage-gated ion channel superfamily. They localise to the endolysosomal system and are likely targets for the Ca2+ mobilising messenger NAADP. In this brief review, we relate mutagenesis of the TPC pore to a recently published homology model and discuss how pore mutants are informing us of TPC function. Molecular physiology of these ubiquitous proteins is thus emerging. PMID- 27226935 TI - Asymptomatic Evolution and Regression of Temporal Lobe Necrosis After Adjuvant Radiation for Skin Cancer: A Case Report and Review of Literature. AB - Temporal Lobe Necrosis (TLN) is not an expected complication of adjuvant radiation therapy (RT) for skin cancers and has become uncommon otherwise in daily practice due to improved RT planning and modern delivery techniques. TLN is a great mimic and can be mistaken for disease recurrence, metastasis to the brain, or high grade primary brain tumor. This case report demonstrates the importance of diagnosing the entity, its natural evolution, and dosimetric correlation with published constraints. It emphasizes the importance of thorough clinical examination on follow-up and review of previous radiation plan when encountered with challenging differentials. We also provide a review of clinical presentations, imaging modalities, and management options for patients with suspected TLN. PMID- 27226936 TI - Surgical Cavity Constriction and Local Progression Between Resection and Adjuvant Radiosurgery for Brain Metastases. AB - Stereotactic radiosurgery (SRS) to a surgical cavity after brain metastasis resection is a promising treatment for improving local control. The optimal timing of adjuvant SRS, however, has yet to be determined. Changes in resection cavity volume and local progression in the interval between surgery and SRS are likely important factors in deciding when to proceed with adjuvant SRS. We conducted a retrospective review of patients with a brain metastasis treated with surgical resection followed by SRS to the resection cavity. Post-operative and pre-radiosurgery magnetic resonance imaging (MRI) was reviewed for evidence of cavity volume changes, amount of edema, and local tumor progression. Resection cavity volume and edema volume were measured using volumetric analysis. We identified 21 consecutive patients with a brain metastasis treated with surgical resection and radiosurgery to the resection cavity. Mean age was 57 yrs. The most common site of metastasis was the frontal lobe (38%), and the most common primary neoplasms were lung adenocarcinoma and melanoma (24% each). The mean postoperative resection cavity volume was 7.8 cm(3) and shrank to a mean of 4.5 cm(3) at the time of repeat imaging for radiosurgical planning (median 41 days after initial post-operative MRI), resulting in a mean reduction in cavity volume of 43%. Patients who underwent pre-SRS imaging within 1 month of their initial post-operative MRI had a mean volume reduction of 13% compared to 61% in those whose pre-SRS imaging was >=1 month (p=0.0003). Post-resection edema volume was not related to volume reduction (p=0.59). During the interval between MRIs, 52% of patients showed evidence of tumor progression within the resection cavity wall. There was no significant difference in local recurrence if the interval between resection and radiosurgery was <1 month (n=8) versus >=1 month (n=13, p=0.46). These data suggest that the surgical cavity after brain metastasis resection constricts over time with greater constriction seen in patients whose pre-SRS imaging is >=1 month after initial post-operative imaging. Given that there was no difference in local recurrence rate, the data suggest there is benefit in waiting in order to treat a smaller resection cavity. PMID- 27226937 TI - Medical Students' Attitudes Toward Non-Adherent Patients Before and After a Simulated Patient-Role Activity and Small-Group Discussion: Revisited. AB - Introduction This study seeks to explore whether the documented decline in medical student empathy can be prevented or slowed using simulated patient-role activities and small-group discussions about the patient experience of living with a chronic illness. Methods First-year students (M1, n = 118) at the University of Central Florida College of Medicine (UCFCOM) participated in a simulated patient-role activity resembling the experience of a patient with Type 2 diabetes mellitus. The activity included taking daily "medication," participating in moderate exercise, and maintaining a low carbohydrate diet. At the end of the simulated patient-role activity, students took part in a small group discussion about their experiences. Students completed the Jefferson Scale of Physician Empathy: Student Version (JSPE:S) before and after the activity. Additionally, fourth-year students (M4) at UCFCOM completed the JSPE:S to serve as the control, as this class completed the curriculum without any simulated patient-role activities. Results A total of 86 responses out of 118 possible M1 participants (73% response rate) were received. Of these, 62 surveys were completed and were therefore used for statistical analysis. A dependent sample t test revealed no statistically significant increase on pre-activity (M = 111.15, SD = 8.56) and post-activity (M = 111.38, SD = 9.12) empathy scores (p = .78). A positive correlation was revealed to exist between pre- and post-activity empathy scores (r = 0.72, p < 0.001). Empathy comparisons for the full sample M1 post activity results (n = 62) and the M4 results (n = 16, M = 106.56, SD = 10.61) revealed no statistically significant difference (p = .11). Discussion Although previous authors have shown that patient role-playing activities, such as those performed in this study, should maintain and/or increase empathy in medical students, our findings suggest that on a short-term scale, empathy levels were not affected by the activity. PMID- 27226938 TI - Peroneus Tertius Tendon Tear: A Rare Cause of Lateral Ankle Pain. AB - The peroneus tertius (PT) muscle is a variably present muscle, uncommonly found in humans. Injury to the PT tendon is rare with virtually no cases reported in the literature. As a consequence of the rarity of this injury, there is little clinical information regarding injury or rupture of the PT muscle and tendon. We present a case of injury involving this rare anatomical variant. Magnetic resonance (MR) imaging demonstrates a short segment longitudinal split tear adjacent to the tendinous insertion of the peroneus tertius muscle. Knowledge of this rare anatomic variant and the potential for associated pathology is critical in the management of the patient. Directing the orthopedic surgeon, or podiatrist, to this finding is critical for directing intervention. PMID- 27226940 TI - Chronic Lymphedema of the Lower Limb: A Rare Cause of Dislocation of Total Hip Arthroplasty. AB - Total hip arthroplasty (THA) in a patient with chronic lymphedema of both lower limbs is rarely reported in the literature. Chronic lymphedema is a challenging condition associated with various complications especially in a patient with THA. However, dislocation of the total hip prosthesis due to acute exacerbation of lower limb swelling in the postoperative period is an extremely rare complication. The cause that led to the dislocation of the prosthesis is intricate and difficult to assess, as this has not been discussed in the literature yet. We believe that the excessive weight of the limb due to chronic lymphedema had a deleterious effect on the biomechanics of total hip prosthesis, thereby increasing the tendency for dislocation. This case illustrates that chronic lymphedema of the lower limb should be dealt with aggressively using various modalities like intermittent pneumatic compression pumps and compression stockings after THA in such patients. PMID- 27226939 TI - Tracheal Diverticulum Following Paratracheal Hypofractionated Radiotherapy in the Setting of Prior and Subsequent Bevacizumab. AB - We present the case of a 63-year-old woman with limited metastatic colorectal cancer to the lungs and liver treated with FOLFIRI-bevacizumab, followed by consolidative hypofractionated radiotherapy to right paratracheal metastatic lymphadenopathy. We treated the right paratracheal site with 60 Gy in 15 fractions (70 Gy equivalent dose in 2 Gy fractions). The patient tolerated the treatment well, and six months later started a five-month course of FOLFIRI bevacizumab for new metastatic disease. She presented to our clinic six months after completing this, complaining of productive cough with scant hemoptysis, and was found to have localized tracheal wall breakdown and diverticulum in the region of prior high-dose radiation therapy, threatening to progress to catastrophic tracheovascular fistula. This was successfully repaired surgically after a lack of response to conservative measures. We urge caution in treating patients with vascular endothelial growth factor (VEGF) inhibitors in the setting of hypofractionated radiotherapy involving the mucosa of tubular organs, even when these treatments are separated by months. Though data is limited as to the impact of sequence, this may be particularly an issue when VEGF inhibitors follow prior radiotherapy. PMID- 27226941 TI - Quality of Prostate Cancer Treatment Information on Cancer Center Websites. AB - INTRODUCTION: Cancer center websites are trusted sources of internet information about treatment options for prostate cancer. The quality of information on these websites is unknown. The objective of this study was to evaluate the quality of information on cancer center websites addressing prostate cancer treatment options, outcomes, and toxicity. MATERIALS AND METHODS: We evaluated the websites of all National Cancer Institute-designated cancer centers to determine if sufficient information was provided to address eleven decision-specific knowledge questions from the validated Early Prostate Cancer Treatment Decision Quality Instrument. We recorded the number of questions addressed, the number of clicks to reach the prostate cancer-specific webpage, evaluation time, and Spanish and mobile accessibility. Correlation between evaluation time and questions addressed were calculated using the Pearson coefficient. RESULTS: Sixty-three websites were reviewed. Eighty percent had a prostate cancer-specific webpage reached in a median of three clicks. The average evaluation time was 6.5 minutes. Information was available in Spanish on 24% of sites and 59% were mobile friendly. Websites provided sufficient information to address, on average, 19% of questions. No website addressed all questions. Evaluation time correlated with the number of questions addressed (R(2) = 0.42, p < 0.001). CONCLUSIONS: Cancer center websites provide insufficient information for men with localized prostate cancer due to a lack of information about and direct comparison of specific treatment outcomes and toxicities. Information is also less accessible in Spanish and on mobile devices. These data can be used to improve the quality and accessibility of prostate cancer treatment information on cancer center websites. PMID- 27226942 TI - Technique for Robotic Stereotactic Irradiation of Choroidal Melanoma. AB - Radiotherapy has a long history in the organ-sparing management of choroidal melanoma. Joining plaque radiotherapy and proton irradiation, stereotactic robotic photon irradiation is a new tool in the radiation oncologist's armamentarium for ocular tumors. The non-coplanar fields with steep dose gradients are well suited to spare uninvolved retina, anterior chamber, and the optic nerve. In our practice, it is the preferred treatment for melanomas that are non-amenable to standard plaque brachytherapy. Since late 2010, we have treated more than 40 patients with our robotic linear accelerator. This case based technical note outlines the technique used at the University of Montreal, Montreal, Canada. PMID- 27226943 TI - Primary Malignant Melanoma of Renal Pelvis with Extensive Clear Cell Change. AB - Our presentation illustrates a rare case of primary renal pelvis malignant melanoma in a 35-year-old man. The diagnosis of malignant melanoma was based on immunophenotype and the detection of intracellular melanin pigment. The renal origin was proven by the presence of scattered melanocytes within the urothelium of the pelvis. The tumor exhibited extensive clear cell change that closely mimics clear cell renal cell carcinoma. The patient's clinical history did not disclose any signs of previous melanocytic skin or mucosa lesions. Differential diagnosis includes tumors capable of synthesizing melanin or expressing melanocytic markers. PMID- 27226944 TI - Prognostic Value of MR Imaging Texture Analysis in Brain Non-Small Cell Lung Cancer Oligo-Metastases Undergoing Stereotactic Irradiation. AB - BACKGROUND : Stereotactic irradiation is widely used in brain oligo-metastases treatment. The aim of this study is to evaluate the prognostic value of magnetic resonance imaging (MRI) texture analysis (TA) of brain metastases (BM) of non small cell lung cancer (NSCLC). MATERIALS AND METHODS : This study included thirty-eight consecutive patients undergoing stereotactic irradiation, that is, stereotactic fractionated radiotherapy (SRT) or radiosurgery (SRS), from January 2011 to December 2014 for 1-2 brain BM from NSCLC. Whole-brain radiotherapy (WBRT) was not delivered. The diagnostic MRI DICOM (Digital Imaging and Communications in Medicine) images were collected and analyzed with a homemade ImageJ macro, and typical TA parameters (mean, standard deviation, skewness, kurtosis, entropy, and uniformity) were evaluated for: brain progression-free survival; modality of brain metastatic progression (local progression or/and new metastases); and overall survival, after SRT/SRS. RESULTS: After SRT/SRS 14 patients (36.8%) experienced recurrence in the brain, with a recurrence in the irradiated site (five patients, 13.2%), new metastases (11 patients, 28.9%), local recurrence and new metastases (two patients, 5.25%). Nineteen patients (50%) died of tumor progression or other causes. Entropy and uniformity were significantly associated with local progression, whereas kurtosis was significantly associated with both local progression and new brain metastases. CONCLUSIONS : These results appear promising, since the knowledge of factors correlated with the modality of brain progression after stereotactic irradiation of brain oligo-metastatic foci of NSCLC might help in driving the best treatment in these patients (association of SRT/SRS with WBRT? Increase of SRT/SRS dose?). Our preliminary data needs confirmation in large patient series. PMID- 27226945 TI - Acute Presentation of Lumbar Spinal Schwannoma Due to Torsion: A Case Report. AB - Although schwannomas are common spinal tumors with insidious presentations, acute neurological deterioration is an extremely rare manifestation that can occur in the setting of tumor torsion and infarction. The present case reports an unusual presentation of a spinal schwannoma that underwent torsion and infarction. A 65 year-old male presented initially with acute radicular pain progressing to cauda equina syndrome and confusion. MRI of the lumbar spine revealed an intradural extramedullary lesion at the level of L1/L2 measuring 1.1x0.9 cm. Intraoperatively, a reddish mass was seen caudally twisted around itself. Gross total resection was achieved with a final diagnosis of schwannoma with areas of infarction. At his six week follow up clinical visit, the patient was asymptomatic and his neurological exam was normal. The neurosurgeon should be aware of such atypical radiographic and clinical presentation amongst the spectrum of clinical manifestation of these nerve sheath tumors. PMID- 27226946 TI - Exploring barriers to and enablers of adequate healthcare for Indigenous Australian prisoners with cancer: a scoping review drawing on evidence from Australia, Canada and the United States. AB - BACKGROUND: International frameworks supported by national principles in Australia stipulate that prisoners should be provided with health services equivalent to those provided in the general community. However, a number of barriers unique to the prison system may hinder the provision of equitable healthcare for this population. In Australia, Indigenous people carry a greater burden of cancer mortality, which the Cancer Data and Aboriginal Disparities (CanDAD) project is seeking to address. During the course of recruiting participants to the CanDAD study, Indigenous Australian prisoners with cancer emerged as an important, under-researched but difficult to access sub-group. METHODS: This scoping review sought to identify barriers and facilitators of access to adequate and equitable healthcare for Indigenous Australian prisoners with cancer in Australia. This review demonstrated a lack of research and, as such, the scoping review was extended to prisoners with cancer in Australia, New Zealand, the United States and Canada. This approach was taken in order to summarise the existing body of evidence regarding the barriers and facilitators of access to adequate and equitable healthcare for those who are incarcerated and suffering from cancer, and highlight areas that may require further investigation. RESULTS: Eight studies or commentaries were found to meet the inclusion criteria. This limited set of findings pointed to a range of possible barriers faced by prisoners with cancer, including a tension between the prisons' concern with security versus the need for timely access to medical care. CONCLUSION: Findings identified here offer potential starting points for research and policy development. Further research is needed to better elucidate how barriers to adequate cancer care for prisoners may be identified and overcome, in Australia and internationally. Furthermore, given Indigenous Australians' over burden of cancer mortality and over-representation in the prison system, further research is needed to identify whether there are a unique set of barriers for this group. PMID- 27226948 TI - Mobile Interventions Targeting Risky Drinking Among University Students: A Review. AB - Mobile interventions based on text messages, automated telephone programs (interactive voice response (IVR)), and smartphone apps offer a new approach targeting hazardous alcohol use in university students. This review covers seven recent studies involving college or university students that evaluated intervention efficacy in comparison to controls: four using text messages, one using IVR, and two smartphone apps. Only the study evaluating IVR reported positive results for the primary outcome. Two of the text message studies reported positive results on secondary outcomes, while the other two reported no differences in comparison to control groups. For smartphone apps, one study reported positive results on secondary outcomes, while the other showed no differences in comparison to controls for a web-based app and negative results for a native app. Further development of mobile interventions is needed for this at-risk population, both in terms of intervention content and use of robust research designs. PMID- 27226947 TI - Pharmacotherapy of Co-Occurring Schizophrenia and Substance Use Disorders. AB - Substance use disorders, common in patients with schizophrenia, can lead to poor outcomes. Here we review the literature on the use of antipsychotics in patients with co-occurring schizophrenia and substance use disorder as well as evidence for the use of adjunctive pharmacological treatments targeting substance use in these patients. We also discuss a neurobiological formulation suggesting that the cooccurrence of these disorders may be related to a dysfunction in the dopamine mediated brain reward circuitry. Typical antipsychotics do not appear to decrease substance use in this population. Randomized, controlled trials provide some support for use of the atypical antipsychotic clozapine for co-occurring cannabis use disorder, naltrexone and disulfiram for alcohol use disorder, and also nicotine replacement therapy, sustained-release bupropion and varenicline for tobacco use disorder. Nonetheless, data regarding treatment in patients with these co-occurring disorders are still limited, and many studies reported to date have been either underpowered or did not include a control condition. Further research is needed to evaluate optimal pharmacotherapeutic strategies for this population. PMID- 27226949 TI - Ambrosia artemisiifolia (ragweed) in Germany - current presence, allergological relevance and containment procedures. AB - Ambrosia artemisiifolia (ragweed) is a neophyte in Europe and Germany, which originated from the United States of America. In the USA the rate of sensitization against ragweed equals that of grass pollen, and without containment the rate of allergic sensitizations against ragweed pollen will clearly increase. Currently, the most frequent sensitizations in Germany are against grass pollen, followed by sensitizations against house dust mite and birch pollen. Ragweed pollen evokes symptoms at about 10 pollen/m3, grass pollen at about 15 pollen/m3. These concentrations of ragweed pollen are only reached on limited occasions in Germany. Ragweed cross-reacts with mugwort (Artemisia vulgaris) and a correct diagnosis is only feasible with the ragweed specific allergen Amb a 1. Due to cross reactivity with mugwort, new sensitizations against ragweed pollen are not needed to evoke allergic symptoms. The neophyte encounters an already mugwort-sensitized population, extends the pollen season and may provoke new sensitizations. Ragweed sensitizations are characterized by an increased tendency to also affect the lower airways, which is less with mugwort sensitizations. Thus containment of ragweed is needed. Ragweed seeds are imported or spread by contaminated bird feed, the transport of ragweed contaminated soil (also in tyre treads) and agricultural products from infested areas. States bordering on ragweed positive areas, like Brandenburg and Bavaria, are especially at risk and invasion is already underway. Ragweed seeds survive up to 40 years in soil, and so extended timescales for eradication and observations are needed. Germany is, compared to other countries like France (Rhone-Valley), Italy (Po-Valley), Ukraine and Hungary, limited in respect to ragweed infestation. Conditions in Germany are therefore favourable for the containment of ragweed. Switzerland implemented legislation against birdseed contamination by ragweed early during the plants expansion, and obligatory ragweed registration- and eradication showed that ragweed containment is possible. Without counter measures ragweed expansion in Germany will take place, resulting in more allergic disease. Considering the increasing number of allergic individuals, even without ragweed invasion, containment of the neophyte should be actively persued. Unfortunately, time is running out. PMID- 27226950 TI - Evidence vs. efficacy in allergen-specific immunotherapy: Considerations using the example of tradable products in Germany. AB - The recently published S2k-guideline on (allergen-) specific immunotherapy (AIT) provides an excellent overview of the evidence on allergen preparations available for AIT in Germany based on the published efficacy studies. Publications based on the guideline are currently being used by the German associations of statutory health insurance physicians and German health insurance funds to open a discussion on the reimbursement status of allergen preparations. In our view, calling the reimbursement status of perscribable and tradable AIT preparations into question on the basis of an assessment of the current body of evidence in the guideline is to be rigidly opposed. In Germany the Paul Ehrlich Institute (PEI) is the only authority empowered to decide on the marketability of AIT preparations, and decisions on the reimbursement status of AIT products need to be based on cost-benefit analyses and not solely on an evaluation of the evidence. The present article aims to examine the relationship between the evidence, efficacy, tradability, and reimbursability of AIT preparations. PMID- 27226951 TI - Clinical spectrum of alpha-Gal syndrome: from immediate-type to delayed immediate type reactions to mammalian innards and meat. AB - The term alpha-Gal syndrome describes a novel IgE-mediated immediate-type allergy to the disaccharide galactose-alpha-1,3-galactose (alpha-Gal). Its classification as a syndrome is proposed on the basis of its clinical relevance in three different fields of allergy: food, drugs, and tick bites. The main focus of the present article is on alpha-Gal as an eliciting allergen in food allergy. It was recently shown that immediate-type allergies to pork kidney and other mammalian innards belong to the spectrum of alpha-Gal syndrome. These allergic reactions manifest as classic immediate-type allergies with a typical latency of under 1 h. The phenomenon of a delayed-onset immediate-type allergy with a latency of 3-6 h following ingestion of mammalian meat is considered pathognomonic for alpha-Gal syndrome. This clinically distinct type of presentation can be explained using the concept of food-dependent exercise-induced anaphylaxis (FDEIA). However, clinical observations and challenge testing in this constellation reveal that individual sensitivity in alpha-Gal patients is highly variable and which broadens our basic understanding of alpha-Gal syndrome. PMID- 27226952 TI - Tracking control of piezoelectric actuator using adaptive model. AB - Piezoelectric actuators (PEAs) have been widely used in micro- and nanopositioning applications due to their fine resolution, rapid responses, and large actuating forces. However, a major deficiency of PEAs is that their accuracy is seriously limited by hysteresis. This paper presents adaptive model predictive control technique for reducing hysteresis in PEAs based on autoregressive exogenous model. Experimental results show the effectiveness of the proposed method. PMID- 27226953 TI - Recent Advances in Development and Application of Physiologically-Based Pharmacokinetic (PBPK) Models: a Transition from Academic Curiosity to Regulatory Acceptance. AB - There is a renewed surge of interest in applications of physiologically-based pharmacokinetic (PBPK) models by the pharmaceutical industry and regulatory agencies. Developing PBPK models within a systems pharmacology context allows separation of the parameters pertaining to the animal or human body (the system) from that of the drug and the study design which is essential to develop generic drug-independent models used to extrapolate PK/PD properties in various healthy and patient populations. This has expanded the classical paradigm to a 'predict learn-confirm-apply' concept. Recently, a number of drug labels are informed by simulation results generated using PBPK models. These cases show that either the simulations are used in lieu of conducting clinical studies or have informed the drug label that otherwise would have been silent in some specific situations. It will not be surprising to see applications of these models in implementing precision dosing at the point of care in the near future. PMID- 27226954 TI - Emerging roles of FGF signaling in hepatocellular carcinoma. PMID- 27226956 TI - Comments on human eurytremiasis in Brazil. AB - Eurytremiasis is an important parasitic disease of cattle that was recently suggested to be a neglected and emerging human disease in Brazil. Based on a misinterpretation of the life cycle of the parasite, it was suggested that a great number of people could be infected with this fluke in the country. In the present letter, aspects of the life cycle of Eurytrema spp. are revisited and clarified. The mechanism of transmission previously reported for the few accidental human cases involved the ingestion of raw or undercooked insects (grasshoppers and crickets) harboring the infective metacercariae. In reality, the zoonotic potential of Eurytrema species is extremely low, and human eurytremiasis is not, and probably never will be, a zoonotic disease in countries where entomophagy is not a common food habit. PMID- 27226957 TI - Reader's Forum. PMID- 27226958 TI - Evaluation of digital dental models obtained from dental cone-beam computed tomography scan of alginate impressions. AB - OBJECTIVE: To investigate the dimensional accuracy of digital dental models obtained from the dental cone-beam computed tomography (CBCT) scan of alginate impressions according to the time elapse when the impressions are stored under ambient conditions. METHODS: Alginate impressions were obtained from 20 adults using 3 different alginate materials, 2 traditional alginate materials (Alginoplast and Cavex Impressional) and 1 extended-pour alginate material (Cavex ColorChange). The impressions were stored under ambient conditions, and scanned by CBCT immediately after the impressions were taken, and then at 1 hour intervals for 6 hours. After reconstructing three-dimensional digital dental models, the models were measured and the data were analyzed to determine dimensional changes according to the elapsed time. The changes within the measurement error were regarded as clinically acceptable in this study. RESULTS: All measurements showed a decreasing tendency with an increase in the elapsed time after the impressions. Although the extended-pour alginate exhibited a less decreasing tendency than the other 2 materials, there were no statistically significant differences between the materials. Changes above the measurement error occurred between the time points of 3 and 4 hours after the impressions. CONCLUSIONS: The results of this study indicate that digital dental models can be obtained simply from a CBCT scan of alginate impressions without sending them to a remote laboratory. However, when the impressions are not stored under special conditions, they should be scanned immediately, or at least within 2 to 3 hours after the impressions are taken. PMID- 27226959 TI - Five-year investigation of a large orthodontic patient population at a dental hospital in South Korea. AB - OBJECTIVE: The purpose of this study was to investigate the characteristics of orthodontic patients at Yonsei Dental Hospital from 2008 to 2012. METHODS: We evaluated Angle's classification from molar relationships, classification of skeletal malocclusion from the A point-nasion-B point angle, facial asymmetry, and temporomandibular joint disorders (TMDs) from the records of 7,476 patients who received an orthodontic diagnosis. The orthognathic surgery rate, extraction rate, and extraction sites were determined from the records of 4,861 treated patients. RESULTS: The patient number increased until 2010 and gradually decreased thereafter. Most patients were aged 19-39 years, with a gradual increase in patients aged >= 40 years. Angle's Class I, Class II divisions 1 and 2, and Class III malocclusions were observed in 27.7%, 25.6%, 10.6%, and 36.1% patients, respectively, with a gradual decrease in the frequency of Class I malocclusion. The proportion of patients with skeletal Class I, Class II, and Class III malocclusions was 34.3%, 34.3%, and 31.4%, respectively, while the prevalence of facial asymmetry and TMDs was 11.0% and 24.9%, respectively. The orthognathic surgery rate was 18.5%, with 70% surgical patients exhibiting skeletal Class III malocclusion. The overall extraction rate among nonsurgical patients was 35.4%, and the maxillary and mandibular first premolars were the most commonly extracted teeth. CONCLUSIONS: The most noticeable changes over time included a decrease in the patient number after 2010, an increase in the average patient age, and a decrease in the frequency of Angle's Class I malocclusion. Our results suggest that periodic characterization is necessary to meet the changing demands of orthodontic patients. PMID- 27226955 TI - MicroRNA-regulated viral vectors for gene therapy. AB - Safe and effective gene therapy approaches require targeted tissue-specific transfer of a therapeutic transgene. Besides traditional approaches, such as transcriptional and transductional targeting, microRNA-dependent post transcriptional suppression of transgene expression has been emerging as powerful new technology to increase the specificity of vector-mediated transgene expression. MicroRNAs are small non-coding RNAs and often expressed in a tissue-, lineage-, activation- or differentiation-specific pattern. They typically regulate gene expression by binding to imperfectly complementary sequences in the 3' untranslated region (UTR) of the mRNA. To control exogenous transgene expression, tandem repeats of artificial microRNA target sites are usually incorporated into the 3' UTR of the transgene expression cassette, leading to subsequent degradation of transgene mRNA in cells expressing the corresponding microRNA. This targeting strategy, first shown for lentiviral vectors in antigen presenting cells, has now been used for tissue-specific expression of vector encoded therapeutic transgenes, to reduce immune response against the transgene, to control virus tropism for oncolytic virotherapy, to increase safety of live attenuated virus vaccines and to identify and select cell subsets for pluripotent stem cell therapies, respectively. This review provides an introduction into the technical mechanism underlying microRNA-regulation, highlights new developments in this field and gives an overview of applications of microRNA-regulated viral vectors for cardiac, suicide gene cancer and hematopoietic stem cell therapy, as well as for treatment of neurological and eye diseases. PMID- 27226960 TI - Preparation and antimicrobial assay of ceramic brackets coated with TiO2 thin films. AB - OBJECTIVE: Different methods have been utilized to prevent enamel demineralization and other complications during orthodontic treatment. However, none of these methods can offer long-lasting and effective prevention of orthodontic complications or interventions after complications occur. Considering the photocatalytic effect of TiO2 on organic compounds, we hoped to synthesize a novel bracket with a TiO2 thin film to develop a photocatalytic antimicrobial effect. METHODS: The sol-gel dip coating method was used to prepare TiO2 thin films on ceramic bracket surfaces. Twenty groups of samples were composed according to the experimental parameters. Crystalline structure and surface morphology were characterized by X-ray diffraction and scanning electron microscopy, respectively; film thickness was examined with a surface ellipsometer. The photocatalytic properties under ultraviolet (UV) light irradiation were analyzed by evaluating the degradation ratio of methylene blue (MB) at a certain time. Antibacterial activities of selected thin films were also tested against Lactobacillus acidophilus and Candida albicans. RESULTS: Films with 5 coating layers annealed at 700C showed the greatest photocatalytic activity in terms of MB decomposition under UV light irradiation. TiO2 thin films with 5 coating layers annealed at 700C exhibited the greatest antimicrobial activity under UV-A light irradiation. CONCLUSIONS: These results provide promising guidance in prevention of demineralization by increasing antimicrobial activities of film coated brackets. PMID- 27226961 TI - Effect of labiolingual inclination of a maxillary central incisor and surrounding alveolar bone loss on periodontal stress: A finite element analysis. AB - OBJECTIVE: The aim of this study was to investigate whether labial tooth inclination and alveolar bone loss affect the moment per unit of force (Mt/F) in controlled tipping and consequent stresses on the periodontal ligament (PDL). METHODS: Three-dimensional models (n = 20) of maxillary central incisors were created with different labial inclinations (5 degrees , 10 degrees , 15 degrees , and 20 degrees ) and different amounts of alveolar bone loss (0, 2, 4, and 6 mm). The Mt/F necessary for controlled tipping (Mt/Fcont) and the principal stresses on the PDL were calculated for each model separately in a finite element analysis. RESULTS: As labial inclination increased, Mt/Fcont and the length of the moment arm decreased. In contrast, increased alveolar bone loss caused increases in Mt/Fcont and the length of the moment arm. When Mt/F was near Mt/Fcont, increases in Mt/F caused compressive stresses to move from a predominantly labial apical region to a palatal apical position, and tensile stresses in the labial area moved from a cervical position to a mid-root position. Although controlled tipping was applied to the incisors, increases in alveolar bone loss and labial tooth inclination caused increases in maximum compressive and tensile stresses at the root apices. CONCLUSIONS: Increases in alveolar bone loss and labial tooth inclination caused increases in stresses that might cause root resorption at the root apex, despite the application of controlled tipping to the incisors. PMID- 27226962 TI - Assessment of anterior-posterior jaw relationships in Korean adults using the nasion true vertical plane in cone-beam computed tomography images. AB - OBJECTIVE: The aims of this study were to investigate a simple method for assessing anterior-posterior jaw relationships via cone-beam computed tomography (CBCT) images taken in the natural head position (NHP) relative to the nasion true vertical plane (NTVP), and measure normative data in Korean adults with normal profiles. METHODS: Subjects were selected from patients presenting for third molar extraction and evaluated as having normal profiles by three examiners. The CBCT images of 80 subjects (39 males, 41 females) were taken in the NHP according to Solow and Tallgren's method. Linear measurements of the A point, B-point, and Pog were calculated relative to the NTVP. Student's t-test was used to assess sexual differences in these measurements. RESULTS: The mean linear measurements of the A-point, B-point, and Pog relative to the NTVP were 0.18 mm (standard deviation [SD], 4.77 mm), -4.00 mm (SD, 6.62 mm), and -2.49 mm (SD, 7.14 mm) respectively in Korean males, and 1.48 mm (SD, 4.21 mm), -4.07 mm (SD, 6.70 mm) and -2.91 mm (SD, 7.25 mm) in Korean females respectively. There were no statistically significant differences between Korean males and females (p < 0.05). CONCLUSIONS: Three-dimensional CBCT analysis using the NTVP is a simple and reliable method for assessing anterior-posterior skeletal relationships. PMID- 27226963 TI - New prediction equations for the estimation of maxillary mandibular canine and premolar widths from mandibular incisors and mandibular first permanent molar widths: A digital model study. AB - OBJECTIVE: The primary aim of the study was to generate new prediction equations for the estimation of maxillary and mandibular canine and premolar widths based on mandibular incisors and first permanent molar widths. METHODS: A total of 2,340 calculations (768 based on the sum of mandibular incisor and first permanent molar widths, and 1,572 based on the maxillary and mandibular canine and premolar widths) were performed, and a digital stereomicroscope was used to derive the the digital models and measurements. Mesiodistal widths of maxillary and mandibular teeth were measured via scanned digital models. RESULTS: There was a strong positive correlation between the estimation of maxillary (r = 0.85994, r(2) = 0.7395) and mandibular (r = 0.8708, r(2) = 0.7582) canine and premolar widths. The intraclass correlation coefficients were statistically significant, and the coefficients were in the strong correlation range, with an average of 0.9. Linear regression analysis was used to establish prediction equations. Prediction equations were developed to estimate maxillary arches based on Y = 15.746 + 0.602 * sum of mandibular incisors and mandibular first permanent molar widths (sum of mandibular incisors [SMI] + molars), Y = 18.224 + 0.540 * (SMI + molars), and Y = 16.186 + 0.586 * (SMI + molars) for both genders, and to estimate mandibular arches the parameters used were Y = 16.391 + 0.564 * (SMI + molars), Y = 14.444 + 0.609 * (SMI + molars), and Y = 19.915 + 0.481 * (SMI + molars). CONCLUSIONS: These formulas will be helpful for orthodontic diagnosis and clinical treatment planning during the mixed dentition stage. PMID- 27226964 TI - Do customized orthodontic appliances and vibration devices provide more efficient treatment than conventional methods? AB - The incorporation of technological advances in the field of clinical orthodontics to increase treatment efficiency has led to the development of customized appliances (Insignia(r)), archwires (Suresmile(r)), and the production of devices to enhance tooth movement (Acceledent(r)). This review presents a comprehensive study of the literature concerning these products, and analyzes the available evidence of their efficiency. To date, one pilot study has evaluated the efficiency of the Insignia(r) system, three retrospective studies have assessed the efficiency of the Suresmile(r) system, and a few Acceledent(r) reports have described its effect on treatment time. Critical appraisal of the reviewed papers revealed that the efficiency of the Insignia(r) system cannot be confirmed based on the available evidence, while the use of Suresmile(r) can reduce overall treatment time in simple cases. The acceleration of tooth movement by Acceledent(r) devices has not yet been confirmed. PMID- 27226966 TI - Surgical correction of septal deviation after Le Fort I osteotomy. AB - BACKGROUND: The Le Fort I osteotomy is one of the most widely used and useful procedure to correct the dentofacial deformities of the midface. The changes of the maxilla position affect to overlying soft tissue including the nasal structure. Postoperative nasal septum deviation is a rare and unpredicted outcome after the surgery. There are only a few reports reporting the management of this complication. CASE PRESENTATION: In our department, three cases of the postoperative nasal septum deviation after the Le Fort I osteotomy had been experienced. Via limited intraoral circumvestibular incision, anterior maxilla, the nasal floor, and the anterior aspect of the septum were exposed. The cartilaginous part of the nasal septum was resected and repositioned to the midline and the anterior nasal spine was recontoured. Alar cinch suture performed again to prevent the sides of nostrils from flaring outwards. After the procedure, nasal septum deviation was corrected and the esthetic outcomes were favorable. CONCLUSION: Careful extubation, intraoperative management of nasal septum, and meticulous examination of pre-existing nasal septum deviation is important to avoid postoperative nasal septum deviation. If it existed after the maxillary osteotomy, septum repositioning technique of the current report can successfully correct the postoperative septal deviation. PMID- 27226965 TI - Long-term follow-up of early cleft maxillary distraction. AB - BACKGROUND: Most of cleft lip and palate patients have the esthetic and functional problems of midfacial deficiencies due to innate developmental tendency and scar tissues from repeated operations. In these cases, maxillary protraction is required for the harmonious facial esthetics and functional occlusion. CASE PRESENTATION: A 7-year old boy had been diagnosed as severe maxillary constriction due to unilateral complete cleft lip and palate. The author tried to correct the secondary deformity by early distraction osteogenesis with the aim of avoiding marked psychological impact from peers of elementary school. From 1999 to 2006, repeated treatments, which consisted of Le Fort I osteotomy and face mask distraction, and complementary maxillary protraction using miniplates were performed including orthodontics. But, final facial profile was not satisfactory, which needs compromising surgery. CONCLUSIONS: The result of this study suggests that if early distraction treatment is performed before facial skeletal growth is completed, an orthognathic surgery or additional distraction may be needed later. Maxillofacial plastic and reconstructive surgeons should notify this point when they plan early distraction treatment for cleft maxillary deformity. PMID- 27226967 TI - Screening for developmental delay among children aged 1-4 years: a systematic review. AB - BACKGROUND: Existing guidelines on screening children less than 5 years of age for developmental delay vary. In this systematic review, we synthesized the literature on the effectiveness and harms of screening for developmental delay in asymptomatic children aged 1-4 years. METHODS: We searched MEDLINE, Embase and PsychINFO for relevant articles published to June 16, 2015. We identified studies that included children aged 1-4 years who were not at high risk of developmental delay, screened in a primary care setting. Randomized trials and controlled cohort studies were considered for benefits (cognitive, academic and functional outcomes); no restrictions on study design were imposed for the review of harms. RESULTS: Two studies were included. One used the Ages and Stages Questionnaire II for screening and reported significantly more referrals to early intervention in the intervention groups than in the control group (relative risk [RR] 1.95, 95% confidence interval [CI] 1.49-2.54, in the intervention group with office support and RR 1.71, 95% CI 1.30-2.25, in the intervention group without office support). The time to referral was 70% shorter in the intervention group with office support (rate ratio 0.30, 95% CI 0.19-0.48) and 64% shorter in the intervention group without office support (rate ratio 0.36, 95% CI 0.23-0.59), compared with the control group. The other study used the VroegTijdige Onderkenning Ontwikkelingsstoornissen Language Screening instrument to screen children aged 15 months at enrolment for language delay. It reported no differences between groups in academic performance outcomes at age 8 years. INTERPRETATION: The evidence on screening for developmental delay in asymptomatic children aged 1-4 years is inconclusive. Further research with longer-term outcomes is needed to inform decisions about screening and screening intervals. PMID- 27226968 TI - Diverse Renal Phenotypes Observed in a Single Family with a Genetic Mutation in Paired Box Protein 2. AB - A common renal phenotype of paired box protein 2 (PAX2) mutations is renal coloboma syndrome. We report a single family with diverse renal phenotypes associated with PAX2 mutation. The proband presented steroid-resistant focal segmental glomerulosclerosis with optic coloboma, whereas his two sons showed severe renal hypoplasia with end-stage renal disease, with or without optic coloboma. In all three cases, a heterozygous PAX2 genetic mutation was identified (exon 2; NM_003987.3:c.76dupG, p.Val26Glyfs*28). Based on histopathological findings of the proband, we hypothesized that autophagic dysfunction was associated with the pathophysiology of the focal segmental glomerulosclerosis with PAX2 mutation. Detailed funduscopic examination - including the optic disc - might be useful for the diagnosis of renal anomalies associated with PAX2 mutation. PMID- 27226969 TI - Protracted Clinical Course of Postinfectious Glomerulonephritis in a Previously Healthy Child. AB - Acute postinfectious glomerulonephritis (PIGN) affects children typically after upper respiratory tract or skin infections with streptococci but can complicate the course of other infections. In children, it is generally a self-limiting disease with excellent prognosis. This paper reports a previously healthy 4-year old boy who experienced a protracted course of PIGN with persisting episodes of gross haematuria, proteinuria, decreased complement C3c levels but normal P creatinine levels. Due to the protracted course and the nephrotic-range proteinuria, a renal biopsy was performed 6 months after the initial presentation and the overall pathology was consistent with acute endocapillary glomerulonephritis. PMID- 27226970 TI - Can you handle this? The impact of object affordances on how co-speech gestures are produced. AB - Hand gestures are tightly coupled with speech and with action. Hence, recent accounts have emphasised the idea that simulations of spatio-motoric imagery underlie the production of co-speech gestures. In this study, we suggest that action simulations directly influence the iconic strategies used by speakers to translate aspects of their mental representations into gesture. Using a classic referential paradigm, we investigate how speakers respond gesturally to the affordances of objects, by comparing the effects of describing objects that afford action performance (such as tools) and those that do not, on gesture production. Our results suggest that affordances play a key role in determining the amount of representational (but not non-representational) gestures produced by speakers, and the techniques chosen to depict such objects. To our knowledge, this is the first study to systematically show a connection between object characteristics and representation techniques in spontaneous gesture production during the depiction of static referents. PMID- 27226971 TI - Rapid, scalable, and low-cost purification of recombinant adeno-associated virus produced by baculovirus expression vector system. AB - Recombinant adeno-associated viruses (rAAV) are largely used for gene transfer in research, preclinical developments, and clinical trials. Their broad in vivo biodistribution and long-term efficacy in postmitotic tissues make them good candidates for numerous gene transfer applications. Upstream processes able to produce large amounts of rAAV were developed, particularly those using baculovirus expression vector system. In parallel, downstream processes present a large panel of purification methods, often including multiple and time consuming steps. Here, we show that simple tangential flow filtration, coupled with an optimized iodixanol-based isopycnic density gradient, is sufficient to purify several liters of crude lysate produced by baculovirus expression vector system in only one working day, leading to high titers and good purity of rAAV products. Moreover, we show that the viral vectors retain their in vitro and in vivo functionalities. Our results demonstrate that simple, rapid, and relatively low cost methods can easily be implemented for obtaining a high-quality grade of gene therapy products based on rAAV technology. PMID- 27226972 TI - Bioluminescence imaging in live cells and animals. AB - The use of bioluminescent reporters in neuroscience research continues to grow at a rapid pace as their applications and unique advantages over conventional fluorescent reporters become more appreciated. Here, we describe practical methods and principles for detecting and imaging bioluminescence from live cells and animals. We systematically tested various components of our conventional fluorescence microscope to optimize it for long-term bioluminescence imaging. High-resolution bioluminescence images from live neurons were obtained with our microscope setup, which could be continuously captured for several hours with no signs of phototoxicity. Bioluminescence from the mouse brain was also imaged noninvasively through the intact skull with a conventional luminescence imager. These methods demonstrate how bioluminescence can be routinely detected and measured from live cells and animals in a cost-effective way with common reagents and equipment. PMID- 27226973 TI - Clinical application of near-infrared spectroscopy in patients with traumatic brain injury: a review of the progress of the field. AB - Near-infrared spectroscopy (NIRS) is a technique by which the interaction between light in the near-infrared spectrum and matter can be quantitatively measured to provide information about the particular chromophore. Study into the clinical application of NIRS for traumatic brain injury (TBI) began in the 1990s with early reports of the ability to detect intracranial hematomas using NIRS. We highlight the advances in clinical applications of NIRS over the past two decades as they relate to TBI. We discuss recent studies evaluating NIRS techniques for intracranial hematoma detection, followed by the clinical application of NIRS in intracranial pressure and brain oxygenation measurement, and conclude with a summary of potential future uses of NIRS in TBI patient management. PMID- 27226974 TI - Correction of motion artifacts and serial correlations for real-time functional near-infrared spectroscopy. AB - Functional near-infrared spectroscopy (fNIRS) is a relatively low-cost, portable, noninvasive neuroimaging technique for measuring task-evoked hemodynamic changes in the brain. Because fNIRS can be applied to a wide range of populations, such as children or infants, and under a variety of study conditions, including those involving physical movement, gait, or balance, fNIRS data are often confounded by motion artifacts. Furthermore, the high sampling rate of fNIRS leads to high temporal autocorrelation due to systemic physiology. These two factors can reduce the sensitivity and specificity of detecting hemodynamic changes. In a previous work, we showed that these factors could be mitigated by autoregressive-based prewhitening followed by the application of an iterative reweighted least squares algorithm offline. This current work extends these same ideas to real-time analysis of brain signals by modifying the linear Kalman filter, resulting in an algorithm for online estimation that is robust to systemic physiology and motion artifacts. We evaluated the performance of the proposed method via simulations of evoked hemodynamics that were added to experimental resting-state data, which provided realistic fNIRS noise. Last, we applied the method post hoc to data from a standing balance task. Overall, the new method showed good agreement with the analogous offline algorithm, in which both methods outperformed ordinary least squares methods. PMID- 27226975 TI - Single-particle tracking uncovers dynamics of glutamate-induced retrograde transport of NF-kappaB p65 in living neurons. AB - Retrograde transport of NF-kappaB from the synapse to the nucleus in neurons is mediated by the dynein/dynactin motor complex and can be triggered by synaptic activation. The caliber of axons is highly variable ranging down to 100 nm, aggravating the investigation of transport processes in neurites of living neurons using conventional light microscopy. We quantified for the first time the transport of the NF-kappaB subunit p65 using high-density single-particle tracking in combination with photoactivatable fluorescent proteins in living mouse hippocampal neurons. We detected an increase of the mean diffusion coefficient ([Formula: see text]) in neurites from [Formula: see text] to [Formula: see text] after stimulation with glutamate. We further observed that the relative amount of retrogradely transported p65 molecules is increased after stimulation. Glutamate treatment resulted in an increase of the mean retrograde velocity from [Formula: see text] to [Formula: see text], whereas a velocity increase from [Formula: see text] to [Formula: see text] was observed for anterogradely transported p65. This study demonstrates for the first time that glutamate stimulation leads to an increased mobility of single NF-kappaB p65 molecules in neurites of living hippocampal neurons. PMID- 27226976 TI - Fat-water MRI of a diet-induced obesity mouse model at 15.2T. AB - Quantitative fat-water MRI (FWMRI) methods provide valuable information about the distribution, volume, and composition of adipose tissue (AT). Ultra high field FWMRI of animal models may have the potential to provide insights into the progression of obesity and its comorbidities. Here, we present quantitative FWMRI with all known confounder corrections on a 15.2T preclinical scanner for noninvasive in vivo monitoring of an established diet-induced obesity mouse model. Male C57BL/6J mice were placed on a low-fat (LFD) or a high-fat diet (HFD). Three-dimensional (3-D) multiple gradient echo MRI at 15.2T was performed at baseline, 4, 8, 12, and 16 weeks after diet onset. A 3-D fat-water separation algorithm and additional processing were used to generate proton-density fat fraction (PDFF), local magnetic field offset, and [Formula: see text] maps. We examined these parameters in perirenal AT ROIs from LFD and HFD mice. The data suggest that PDFF, local field offset, and [Formula: see text] have different time course behaviors between LFD and HFD mice over 16 weeks. This work suggests FWMRI at 15.2T may be a useful tool for longitudinal studies of adiposity due to the advantages of ultra high field although further investigation is needed to understand the observed time course behavior. PMID- 27226977 TI - Invasive ductal breast carcinoma detector that is robust to image magnification in whole digital slides. AB - Invasive ductal breast carcinomas (IDBCs) are the most frequent and aggressive subtypes of breast cancer, affecting a large number of Canadian women every year. Part of the diagnostic process includes grading the cancerous tissue at the microscopic level according to the Nottingham modification of the Scarff-Bloom Richardson system. Although reliable, there exists a growing interest in automating the grading process, which will provide consistent care for all patients. This paper presents a solution for automatically detecting regions expressing IDBC in images of microscopic tissue, or whole digital slides. This represents the first stage in a larger solution designed to automatically grade IDBC. The detector first tessellated whole digital slides, and image features were extracted, such as color information, local binary patterns, and histograms of oriented gradients. These were presented to a random forest classifier, which was trained and tested using a database of 66 cases diagnosed with IDBC. When properly tuned, the detector balanced accuracy, F1 score, and Dice's similarity coefficient were 88.7%, 79.5%, and 0.69, respectively. Overall, the results seemed strong enough to integrate our detector into a larger solution equipped with components that analyze the cancerous tissue at higher magnification, automatically producing the histopathological grade. PMID- 27226978 TI - Ultrafast electron diffraction optimized for studying structural dynamics in thin films and monolayers. AB - A compact electron source specifically designed for time-resolved diffraction studies of free-standing thin films and monolayers is presented here. The sensitivity to thin samples is achieved by extending the established technique of ultrafast electron diffraction to the "medium" energy regime (1-10 kV). An extremely compact design, in combination with low bunch charges, allows for high quality diffraction in a lensless geometry. The measured and simulated characteristics of the experimental system reveal sub-picosecond temporal resolution, while demonstrating the ability to produce high quality diffraction patterns from atomically thin samples. PMID- 27226979 TI - Comment on "Structural dynamics of cisplatin binding to histidine in a protein" [Struct. Dyn. 1, 034701 (2014)]. PMID- 27226980 TI - Ultrafast electronic and vibrational dynamics in brominated aluminum corroles: Energy relaxation and triplet formation. AB - We combined femtosecond (fs) VIS pump-IR probe spectroscopy with fs VIS pump supercontinuum probe spectroscopy to characterize the photoreaction of the hexacoordinated Al(tpfc-Br8)(py)2 in a comprehensive way. Upon fs excitation at ~400 nm in the Soret band, the excitation energy relaxes with a time constant of (250 +/- 80) fs to the S2 and S1 electronic excited states. This is evident from the rise time of the stimulated emission signal in the visible spectral range. On the same time scale, narrowing of broad infrared signals in the C=C stretching region around 1500 cm(-1) is observed. Energy redistribution processes are visible in the vibrational and electronic dynamics with time constants between ~2 ps and ~20 ps. Triplet formation is detected with a time constant of (95 +/- 3) ps. This is tracked by the complete loss of stimulated emission. Electronic transition of the emerging triplet absorption band overlaps considerably with the singlet excited state absorption. In contrast, two well separated vibrational marker bands for triplet formation were identified at 1477 cm(-1) and at 1508 cm( 1). These marker bands allow a precise identification of triplet dynamics in corrole systems. PMID- 27226981 TI - High prevalence of side population in human cancer cell lines. AB - Cancer cell lines are essential platforms for performing cancer research on human cells. We here demonstrate that, across tumor entities, human cancer cell lines harbor minority populations of putative stem-like cells, molecularly defined by dye extrusion resulting in the side population phenotype. These findings establish a heterogeneous nature of human cancer cell lines and argue for their stem cell origin. This should be considered when interpreting research involving these model systems. PMID- 27226982 TI - High and low dose radiation effects on mammary adenocarcinoma cells - an epigenetic connection. AB - The successful treatment of cancer, including breast cancer, depends largely on radiation therapy and proper diagnostics. The effect of ionizing radiation on cells and tissues depends on the radiation dose and energy level, but there is insufficient evidence concerning how tumor cells respond to the low and high doses of radiation that are often used in medical diagnostic and treatment modalities. The purpose of this study was to investigate radiation-induced gene expression changes in the MCF-7 breast adenocarcinoma cell line. Using microarray technology tools, we were able to screen the differential gene expressions profiles between various radiation doses applied to MCF-7 cells. Here, we report the substantial alteration in the expression level of genes after high-dose treatment. In contrast, no dramatic gene expression alterations were noticed after the application of low and medium doses of radiation. In response to a high radiation dose, MCF-7 cells exhibited down-regulation of biological pathways such as cell cycle, DNA replication, and DNA repair and activation of the p53 pathway. Similar dose-dependent responses were seen on the epigenetic level, which was tested by a microRNA expression analysis. MicroRNA analysis showed dose-dependent radiation-induced microRNA expression alterations that were associated with cell cycle arrest and cell death. An increased rate of apoptosis was determined by an Annexin V assay. The results of this study showed that high doses of radiation affect gene expression genetically and epigenetically, leading to alterations in cell cycle, DNA replication, and apoptosis. PMID- 27226983 TI - Breast tumor response to ultrasound mediated excitation of microbubbles and radiation therapy in vivo. AB - Acoustically stimulated microbubbles have been demonstrated to perturb endothelial cells of the vasculature resulting in biological effects. In the present study, vascular and tumor response to ultrasound-stimulated microbubble and radiation treatment was investigated in vivo to identify effects on the blood vessel endothelium. Mice bearing breast cancer tumors (MDA-MB-231) were exposed to ultrasound after intravenous injection of microbubbles at different concentrations, and radiation at different doses (0, 2, and 8 Gy). Mice were sacrificed 12 and 24 hours after treatment for histopathological analysis. Tumor growth delay was assessed for up to 28 days after treatment. The results demonstrated additive antitumor and antivascular effects when ultrasound stimulated microbubbles were combined with radiation. Results indicated tumor cell apoptosis, vascular leakage, a decrease in tumor vasculature, a delay in tumor growth and an overall tumor disruption. When coupled with radiation, ultrasound-stimulated microbubbles elicited synergistic anti-tumor and antivascular effects by acting as a radioenhancing agent in breast tumor blood vessels. The present study demonstrates ultrasound driven microbubbles as a novel form of targeted antiangiogenic therapy in a breast cancer xenograft model that can potentiate additive effects to radiation in vivo. PMID- 27226984 TI - High-frequency ultrasound analysis of post-mitotic arrest cell death. AB - Non-invasive monitoring of cancer cell death would permit rapid feedback on treatment response. One technique showing such promise is quantitative ultrasound. High-frequency ultrasound spectral radiofrequency analysis was used to study cell death in breast cancer cell samples. Quantitative ultrasound parameters, including attenuation, spectral slope, spectral 0-MHz-intercept, midband fit, and fitted parameters displayed significant changes with paclitaxel induced cell death, corresponding to observations of morphological changes seen in histology and electron microscopy. In particular, a decrease in spectral slope from 0.24+/-0.07 dB/MHz to 0.04+/-0.09 dB/MHz occurred over 24 hours of treatment time and was identified as an ultrasound parameter capable of differentiating post-mitotic arrest cell death from classical apoptosis. The formation of condensed chromatin aggregates of 1 micron or greater in size increased the number of intracellular scatterers, consistent with a hypothesis that nuclear material is a primary source of ultrasound scattering in dying cells. It was demonstrated that the midband fit quantitatively correlated to cell death index, with a Pearson R-squared value of 0.99 at p<0.01. These results suggest that high frequency ultrasound can not only qualitatively assess the degree of cancer cell death, but may be used to quantify the efficacy of chemotherapeutic treatments. PMID- 27226986 TI - Erratum: Replication stress in MLL-rearrangements. AB - [This corrects the article on p. 938 in vol. 2, PMID: 26909360.]. PMID- 27226985 TI - Quantitative ultrasound imaging of therapy response in bladder cancer in vivo. AB - BACKGROUND AND AIMS: Quantitative ultrasound (QUS) was investigated to monitor bladder cancer treatment response in vivo and to evaluate tumor cell death from combined treatments using ultrasound-stimulated microbubbles and radiation therapy. METHODS: Tumor-bearing mice (n=45), with bladder cancer xenografts (HT- 1376) were exposed to 9 treatment conditions consisting of variable concentrations of ultrasound-stimulated Definity microbubbles [nil, low (1%), high (3%)], combined with single fractionated doses of radiation (0 Gy, 2 Gy, 8 Gy). High frequency (25 MHz) ultrasound was used to collect the raw radiofrequency (RF) data of the backscatter signal from tumors prior to, and 24 hours after treatment in order to obtain QUS parameters. The calculated QUS spectral parameters included the mid-band fit (MBF), and 0-MHz intercept (SI) using a linear regression analysis of the normalized power spectrum. RESULTS AND CONCLUSIONS: There were maximal increases in QUS parameters following treatments with high concentration microbubbles combined with 8 Gy radiation: (DeltaMBF = +6.41 +/- 1.40 (+/-SD) dBr and SI= + 7.01 +/- 1.20 (+/-SD) dBr. Histological data revealed increased cell death, and a reduction in nuclear size with treatments, which was mirrored by changes in quantitative ultrasound parameters. QUS demonstrated markers to detect treatment effects in bladder tumors in vivo. PMID- 27226987 TI - Food shortage can drive body temperature regulation in wild heterothermic vertebrates. AB - Food availability is expected to trigger hibernation and torpor (ie heterothermy) use. Yet, laboratory experiments under controlled conditions dominate, and this hypothesis remains largely untested under natural conditions. Further experimental manipulations of food availability must therefore be conducted in the wild, accounting for other covarying environmental stressors. PMID- 27226988 TI - Non-invasive monitoring of brain temperature by near-infrared spectroscopy. AB - Optical techniques are promising methods for measuring tissue temperature noninvasively due to the transparency of tissue to near infrared-light and the temperature dependent light-absorbing properties of endogenous absorbers, particularly water. Besides being noninvasive, the instruments are compact and portable, permitting bedside monitoring. PMID- 27226989 TI - Tree-hugging behavior beats the heat. AB - Animals can exploit spatial and temporal variation in microclimates to avoid stressful conditions, behavior that is likely to become increasingly important in a warming world. Recent research shows that during hot weather cool tree trunk surfaces can provide an important heat-loss avenue for arboreal mammals and other tree-dwelling animals. PMID- 27226990 TI - Ultra-sensitive thermometer based on a compact optical resonator. AB - This article demonstrates a thermometer based on millimeter-scale crystalline disk optical-resonator. By measuring the relative speed difference between 2 colors of light that travel inside the disk, the temperature changes of the disk was measured with a precision of 30 billionths of a degree. PMID- 27226991 TI - How hibernation and hypothermia help to improve anticoagulant control. AB - Winter is coming. Some animals successfully cope with the hostility of this season by hibernating. But how do hibernators survive the procoagulant state of months of immobility at very low body temperatures, with strongly decreased blood flow and increased blood viscosity? Changing the coagulation system seems crucial for preventing thromboembolic complications. PMID- 27226992 TI - The human thermoneutral and thermal comfort zones: Thermal comfort in your own skin blood flow. AB - Human thermoregulation is achieved via autonomic and behavioral responses. Autonomic responses involve 2 synchronous 'components'. One counteracts large thermal perturbations, eliciting robust heat loss or gain (i.e., sweating or shivering). The other fends off smaller insults, relying solely on changes in sensible heat exchange (i.e., skin blood flow). This sensible component occurs within the thermoneutral zone [i.e., the ambient temperature range in which temperature regulation is achieved only by sensible heat transfer, without regulatory increases in metabolic heat production (e.g., shivering) or evaporative heat loss (e.g., sweating)].(1) The combination of behavior and sensible heat exchange permits a range of conditions that are deemed thermally comfortable, which is defined as the thermal comfort zone.(1) Notably, we spend the majority of our lives within the thermoneutral and thermal comfort zones. It is only when we are unable to stay within these zones that deleterious health and safety outcomes can occur (i.e., hypo- or hyperthermia). Oddly, although the thermoneutral zone and thermal preference (a concept similar to the thermal comfort zone) has been extensively studied in non-human animals, our understanding of human thermoregulation within the thermoneutral and thermal comfort zones remains rather crude. PMID- 27226993 TI - A paradoxical role for alarin in the nervous control of energy homeostasis and thermoregulation: orexigenic but hypermetabolic. AB - Alarin is a lately discovered member of the galanin family of peptides. Although it has orexigenic effects in the brain, alarin induces thermoregulatory responses, which promote an increase of core temperature in rats. With some delay intracerebroventricular injections of alarin causes a 15% rise in metabolic rate at an ambient temperature of 25 degrees C and a pronounced fall in tail skin temperature, i.e. peripheral vasoconstriction, at 28 degrees C. PMID- 27226995 TI - 30 years hids-Travels between bedside and bench. AB - In this paper I describe more than 30 years of investigations of the autoinflammatory syndrome hyper-IgD syndrome (HIDS). In the first paper after the recognition of the syndrome published in 1984, we described the characteristics of this periodic fever syndrome. The hypotheses regarding the pathogenesis of the fever and the acute phase response in these patients prompted us to study interleukin-1 (IL-1), the cytokine formerly described as endogenous pyrogen and lymphocyte activating factor. Although we were unable to find elevated concentrations of IL-1 in the circulation, we discovered that white blood cells spontaneously produced elevated amounts of IL-1b. A major next discovery was the identification of the gene defect by us and others in 1999: quite unexpectedly the mevalonate kinase, an enzyme in the cholesterol synthesis pathway was found to be mutated. We were able to describe a founder effect and a phenotypic continuum with the classical mevalonate aciduria in the years to follow. A major step forward was the finding that recombinant interleukin-1 receptor antagonist (anakinra) was an effective treatment for the majority of patients. Thus, research over a period of three decades after the first recognition of the syndrome, has yielded much insight into the pathogenesis as well as an effective therapy for HIDS. PMID- 27226994 TI - Links between thermoregulation and aging in endotherms and ectotherms. AB - While the link between thermoregulation and aging is generally accepted, much further research, reflection, and debate is required to elucidate the physiological and molecular pathways that generate the observed thermal-induced changes in lifespan. Our aim in this review is to present, discuss, and scrutinize the thermoregulatory mechanisms that are implicated in the aging process in endotherms and ectotherms. Our analysis demonstrates that low body temperature benefits lifespan in both endothermic and ectothermic organisms. Research in endotherms has delved deeper into the physiological and molecular mechanisms linking body temperature and longevity. While research in ectotherms has been steadily increasing during the past decades, further mechanistic work is required in order to fully elucidate the underlying phenomena. What is abundantly clear is that both endotherms and ectotherms have a specific temperature zone at which they function optimally. This zone is defended through both physiological and behavioral means and plays a major role on organismal senescence. That low body temperature may be beneficial for lifespan is contrary to conventional medical theory where reduced body temperature is usually considered as a sign of underlying pathology. Regardless, this phenomenon has been targeted by scientists with the expectation that advancements may compress morbidity, as well as lower disease and mortality risk. The available evidence suggests that lowered body temperature may prolong life span, yet finding the key to temperature regulation remains the problem. While we are still far from a complete understanding of the mechanisms linking body temperature and longevity, we are getting closer. PMID- 27226997 TI - A Valentine's Day bouquet for Temperature readers: pleasing with prizes, searching for the right words, and keeping things mysterious. AB - This editorial tells its readers that the journal Temperature awards its first prizes for best papers to Boris Kingma and Assaf Yacobi. It also discusses the use of several thermoregulation-related terms and expressions, including "cold temperature," "thermoneutral temperature," and "warm-sensitive" and offers, arguably, better alternatives. The editorial also contains a new puzzle: how can color affect temperature perception? PMID- 27226996 TI - The history of fever, leukocytic pyrogen and interleukin-1. AB - There has been great progress in the 30 y since the reporting in 1984 of the cDNA for interleukin1 (IL1) beta in the human and IL1alpha in the mouse. However, the history of IL1 begins in the early 1940s with investigations into the nature of an endogenous fever-producing protein released rabbit peritoneal neutrophils. Most researchers in immunology today are unaware that the field of cytokines, particularly the field of inflammatory cytokines. Toll-like receptors and innate immunity traces back to studies on fever. Researchers in infectious diseases wanted to know about an endogenous protein that caused fever, independent of infection. The endogenous fever-producing protein was called by various names: granulocyte, endogenous or leukocytic pyrogen. It is a fascinating and sometimes controversial story for biology and medicine and for the treatment of inflammatory diseases. Few imagined that this fever-producing protein would play such a major role in nearly every cell and in most diseases. This paper reviews the true background and milestones of interleukin1 from the purification of leukocytic pyrogen to the first cDNA of IL1beta and the validation of cytokine biology from ill-defined factors to its present day importance. PMID- 27226998 TI - Thermal physiology in a changing thermal world. AB - This editorial focuses on articles submitted to the Temperature call "Thermal Physiology in a Changing Thermal World." It highlights an array of topics related to thermoregulatory and metabolic functions in adverse environments, and the complexity and adaptability of the systems to changing climatic conditions, at various levels of body organization. PMID- 27226999 TI - Temperature in the spotlight of drug abuse research. AB - This editorial summarizes Temperature's special issue entitled "Temperature and Toxicology with a Focus on Drugs of Abuse" (2014, volume 1, issue 3), dedicated to the multiple recent discoveries related to the thermoregulatory effects of xenobiotics. Several basic and clinical studies on xenobiotic-induced hyperthermia are reported that propose novel mechanisms and treatments. PMID- 27227000 TI - Behind the Mpemba paradox. AB - Mpemba paradox results from hydrogen-bond anomalous relaxation. Heating stretches the O:H nonbond and shortens the H-O bond via Coulomb coupling; cooling reverses this process to emit heat at a rate depending on its initial storage. Skin ultra low mass density raises the thermal diffusivity and favors outward heat flow from the liquid. PMID- 27227001 TI - Hypoxic turtles keep their cool. AB - Several species of freshwater turtles spend the winter submerged in ice-covered lakes in a state of severe metabolic depression. It has been proposed that the hibernating turtles are comatose and entirely unresponsive, which raises the question of how they detect the arrival of spring and whether they respond to sensory information during hibernation. Using evoked potential studies in cold hypoxic turtles exposed to light and vibration, we show that hibernating turtles maintain neural responsiveness to light stimuli during prolonged hypoxia, while responsiveness to vibration is lost. This reveals a state of differential neural shutdown, in different sensory systems in the cold hypoxic turtle brain. In behavioral studies we show that turtles held for 14 days in hibernation increase locomotor activity in response to light or elevated temperatures, but not to vibration or increased oxygen. We conclude that hibernating freshwater turtles are not comatose, but remain vigilant during overwintering in cold hypoxia. PMID- 27227002 TI - A new approach for comparing thermoregulatory responses of subjects with different body sizes. AB - The time-dependent assessment of human thermoregulatory responses during exercise, such as changes in core temperature and sweating, are commonplace in research laboratories worldwide. Moreover, researchers wishing to identify potential impairments in these responses due to factors such as obesity, age, disease and injury, must typically adopt a between-group experimental design. PMID- 27227003 TI - Can targeting glutamate receptors with long-term heat acclimation improve outcomes following hypoxic injury? AB - Long-term heat acclimation appears to improve tolerance to hypoxic insults in various tissues, including brain, providing a promising avenue to improve functional outcomes following cerebrovascular events. Glutamate discharge is implicated in dysfunction following hypoxic stress and thus, targeting glutamate receptors with heat acclimation could improve cognitive outcomes following hypoxic injury. PMID- 27227004 TI - A glance at "PPTR 2014" - the 5th International Symposium on the Physiology and Pharmacology of Temperature Regulation. PMID- 27227005 TI - Paradox of temperature decreasing without unique explanation. PMID- 27227006 TI - Which is the correct answer to the Mpemba puzzle? PMID- 27227007 TI - Functions of Prdm16 in thermogenic fat cells. AB - The PR-domain containing 16 (Prdm16) protein is a powerful inducer of the thermogenic phenotype in fat cells. In both developmental (brown) and induced (beige) thermogenic adipose tissue, Prdm16 has a critical role in maintaining proper tissue structure and function. It has roles throughout the course of differentiation, beginning with lineage determination activity in precursor cells, and continuing with coactivator functions that enable and maintain thermogenic gene expression. These abilities are primarily mediated by interactions with other adipogenic factors, suggesting that Prdm16 acts to coordinate the overall brown adipose phenotype. Mouse models have confirmed that thermogenic adipose depends upon Prdm16, and that this type of fat tissue provides substantial metabolic protection against the harmful effects of a high fat/high energy diet. Activation of Prdm16, therefore, holds promise for stimulating thermogenesis in fat cells to reduce human obesity and its complications. PMID- 27227008 TI - Human skin wetness perception: psychophysical and neurophysiological bases. AB - The ability to perceive thermal changes in the surrounding environment is critical for survival. However, sensing temperature is not the only factor among the cutaneous sensations to contribute to thermoregulatory responses in humans. Sensing skin wetness (i.e. hygrosensation) is also critical both for behavioral and autonomic adaptations. Although much has been done to define the biophysical role of skin wetness in contributing to thermal homeostasis, little is known on the neurophysiological mechanisms underpinning the ability to sense skin wetness. Humans are not provided with skin humidity receptors (i.e., hygroreceptors) and psychophysical studies have identified potential sensory cues (i.e. thermal and mechanosensory) which could contribute to sensing wetness. Recently, a neurophysiological model of human wetness sensitivity has been developed. In helping clarifying the peripheral and central neural mechanisms involved in sensing skin wetness, this model has provided evidence for the existence of a specific human hygrosensation strategy, which is underpinned by perceptual learning via sensory experience. Remarkably, this strategy seems to be shared by other hygroreceptor-lacking animals. However, questions remain on whether these sensory mechanisms are underpinned by specific neuromolecular pathways in humans. Although the first study on human wetness perception dates back to more than 100 years, it is surprising that the neurophysiological bases of such an important sensory feature have only recently started to be unveiled. Hence, to provide an overview of the current knowledge on human hygrosensation, along with potential directions for future research, this review will examine the psychophysical and neurophysiological bases of human skin wetness perception. PMID- 27227010 TI - Effect of the sympathetic nervous system co-transmitters ATP and norepinephrine on thermoregulatory response to cooling. AB - The existence of co-transmitters of the sympathetic nervous system norepinephrine (NE) and ATP implies variations in the neuromodulator mechanisms of physiological processes. The role of ATP, as a transmitter of the peripheral part of sympathetic nervous system in the formation of thermoregulatory response is not clear. Whether ATP modulates any parameters of thermoregulatory response to cold; if yes, whether co-transmitters of sympathetic nervous system ATP and NE differently modulate thermoregulatory response and on which parameters of cold defense response the influence of ATP is more pronounced. Experiments were carried out on rats. ATP (10(-6)), NE (10(-3)), and their mixture introduced iontophoretically into skin. Their effects on thermoregulatory parameters (temperature parameters, total oxygen consumption, carbon dioxide release, muscle activity, respiratory coefficient) were studied in thermoneutral conditions (without cold load) and under the cooling. In thermoneutral conditions both ATP and NE enhance total metabolism through increase in metabolic rate of lipids, NE effect being more expressed. It was shown that ATP and NE influence predominantly on the different components of the metabolic response to cold. ATP affects to the greatest extent on cold muscular thermogenesis by increasing shivering almost twofold and lowering its initiation temperature thresholds, whereas NE mainly promotes increase in non-shivering thermogenesis. When introducing the mixture of these biological substances the effect of NE is more expressed and the ATP effect is weakened. The obtained results allow to suggest that in vivo the NE effects can be more expressed when the sympathetic nervous system is stimulated by cold. Thus, NE and ATP being co-transmitters and predominantly acting on the different processes of cold thermogenesis (ATP on shivering and NE on non-shivering) may organize the certain sequence of cold defense responses. PMID- 27227009 TI - Responses of the hands and feet to cold exposure. AB - An initial response to whole-body or local exposure of the extremities to cold is a strong vasoconstriction, leading to a rapid decrease in hand and foot temperature. This impairs tactile sensitivity, manual dexterity, and muscle contractile characteristics while increasing pain and sympathetic drive, decreasing gross motor function, occupational performance, and survival. A paradoxical and cyclical vasodilatation often occurs in the fingers, toes, and face, and this has been termed the hunting response or cold-induced vasodilatation (CIVD). Despite being described almost a century ago, the mechanisms of CIVD are still disputed; research in this area has remained largely descriptive in nature. Recent research into CIVD has brought increased standardization of methodology along with new knowledge about the impact of mediating factors such as hypoxia and physical fitness. Increasing mechanistic analysis of CIVD has also emerged along with improved modeling and prediction of CIVD responses. The present review will survey work conducted during this century on CIVD, its potential mechanisms and modeling, and also the broader context of manual function in cold conditions. PMID- 27227011 TI - The onset of daily torpor is regulated by the same low body mass in lean mice and in mice with diet-induced obesity. AB - Effects of reducing body mass on body core temperature and locomotor activity of mice originally kept on conventional rodent diet (Group-1) were compared to those made obese by feeding them a high-fat diet (Group-2), both groups being kept at a cool ambient temperature. Based on earlier experience, threshold torpor core temperature of 31 degrees was chosen as the endpoint to decreasing body mass. It was hypothesized that the onset of this hypothermia develops in obese mice only when their body mass approaches a similar low body mass as in lean mice. Mice in Group-1 maintained nocturnal core temperature but developed marked daytime hypothermia of 30-31 degrees C with their body mass approaching 20 g by this time. Mice in Group-2 could maintain normal circadian temperature rhythm for 3 weeks before similar daytime hypothermia started to develop while their body mass dropped also to about 20 g. Mice belonging to Group-1 or Group-2 could regain original body mass after re-feeding with the original diet within 2 days or 5 weeks, respectively. In the course of the development of daily torpor, nighttime normothermia was accompanied by progressive increases in locomotor activity in both groups of mice. It is concluded that in mice a marked fall of daytime body core temperature is only induced when a similar low critical body mass is reached, irrespective of the initial body mass. In other words, in both groups of mice the nutritional state determines the threshold for the thermoregulatory change during torpor. PMID- 27227012 TI - Spicy science: David Julius and the discovery of temperature-sensitive TRP channels. AB - This invited biographical review covers the career of Dr. David Julius and his discovery of thermosensitive TRP channels. Dr. Julius is currently the Morris Herzstein Chair in Molecular Biology and Medicine and Professor and Chair of Physiology at the University of California, San Francisco Medical School. He is a member of the National Academy of Sciences and has received many distinguished awards for his landmark discoveries of the molecular basis of pain and thermosensation. PMID- 27227013 TI - Protecting western redcedar from deer browsing-with a passing reference to TRP channels. AB - This editorial is about tree farming. It proposes to test in an experiment whether co-planting (in the same hole) western redcedar (WRC, Thuja plicata) with Sitka spruce (Picea sitchensis) protects WRC seedlings from wildlife browsing. This sustainable protection method is an alternative to the traditional use of mechanical devices and big-game repellents. Many repellents contain transient receptor potential (TRP) agonists, such as capsaicin, a TRP vanilloid-1 agonist. This editorial also delivers a puzzle: while herbivores avoid capsaicin, why do people living in hot climates consume large quantities of it (in chili peppers)? PMID- 27227014 TI - Feeling hot, feeling cold: TRP channels-a great story unfolds. AB - This editorial is about the roles that TRP channels play in heat and cold sensation and body temperature regulation. These roles may be exploited for therapeutic purposes (indeed, drugs targeting TRPV1, TRPA1 and TRPM8 channels are currently undergoing clinical trials for indications that range from pain through chronic cough and overactive bladder to cancer) or, conversely, may limit drug development (for example, several TRPV1 antagonists were withdrawn from clinical trials due to the hyperthermic reaction that they caused). In the future, modulation of thermosensitive TRP channels may ultimately find application in the treatment not only of pain, but also itch, stroke, asthma, and metabolic disorders. Of the multitude of targets involved in temperature sensation and body temperature regulation, why TRP channels? And why now? PMID- 27227015 TI - The foundation of sensory pharmacology: Nicholas (Miklos) Jancso and the Szeged contribution. AB - Capsaicin became an indispensable tool in pain research after the discovery of its unique pharmacological actions by Nicholas (Miklos) Jancso Jr. in the late 1940s. This "History Article" introduces his achievements leading to the foundation of "sensory pharmacology" and subsequent research in that field at the University of Szeged, Hungary. PMID- 27227016 TI - The evolutionary divergence of TRPA1 channel: heat-sensitive, cold-sensitive and temperature-insensitive. AB - The Transient Receptor Potential Ankyrin 1 ion channel is heat-sensitive in invertebrate and ancestral vertebrates, cold-sensitive in rodents, and temperature-insensitive in primates. This remarkable divergence in temperature sensitivity is in contrast to its role in sensing electrophilic compounds, which is conserved during animal evolution. PMID- 27227017 TI - Modulating the surface expression of cold receptors. AB - Temperature sensing is essential in every organism in order to adapt and survive. However, the mechanisms by which temperature is perceived and detected remain unclear. Recent findings on thermally-activated ion channels have shed light on the puzzle and unravel molecular entities for temperature detection and transduction in mammals. PMID- 27227018 TI - A TRiP to the plasma membrane. AB - TRP ion channels are ubiquitously present in the mammalian body and take part in numerous key physiological functions, including temperature sensing, taste perception, osmo-regulation, cardiac function, renal function, development, and glucose homeostasis. The mechanisms whereby TRP channels are transported to the plasma membrane, where most of them exert their physiological actions, remains a poorly understood aspect of TRP channel biology. PMID- 27227019 TI - To not be hot when TRPV1 is not. AB - Induction of hyperthermia emerged as a major side effect impeding the development of antagonists of the transient receptor potential vanilloid-1 (TRPV1) nociceptor. New ligands are now exploiting the complicated pharmacology of TRPV1 to avoid hyperthermia while insights continue to grow regarding the mechanistic basis for the action of TRPV1 ligands on thermoregulation. PMID- 27227020 TI - Future approaches to therapeutic hypothermia: a symposium report. PMID- 27227021 TI - TRP channels and temperature in airway disease-clinical significance. AB - Temperatures above and below what is generally regarded as "comfortable" for the human being have long been known to induce various airway symptoms, especially in combination with exercise in cold climate with temperatures below 0 degrees C, which is naturally since exercise is followed by enhanced ventilation and thus greater amounts of inhaled cold air. The aim was to highlight the knowledge we have today on symptoms from the airways (here also including the eyes) arisen from various temperatures; the mechanisms, the pathophysiology and their clinical significance. The most common eye and airway conditions related to temperature changes are dry eye disease, rhinitis, laryngeal dysfunction, asthma, chronic obstructive pulmonary disease and chronic cough. Transient receptor potential (TRP) ion channels are probably involved in all temperature induced airway symptoms but via different pathways, which are now beginning to be mapped out. In asthma, the most persuasive hypothesis today is that cold-induced asthmatic bronchoconstriction is induced by dehydration of the airway mucosa, from which it follows that provocations with osmotic stimuli like hypertonic saline and mannitol can be used as a surrogate for exercise provocation as well as dry air inhalation. In chronic unexplained cough there seems to be a direct influence of cold air on the TRP ion channels followed by coughing and increased cough sensitivity to inhaled capsaicin. Revelations in the last decades of the ability of several airway TRP ion channels to sense and react to ambient air temperature have opened new windows for the understanding of the pathogenesis in a diversity of airway reactions appearing in many common respiratory diseases. PMID- 27227022 TI - TRP ion channels in thermosensation, thermoregulation and metabolism. AB - In humans, the TRP superfamily of cation channels includes 27 related molecules that respond to a remarkable variety of chemical and physical stimuli. While physiological roles for many TRP channels remain unknown, over the past years several have been shown to function as molecular sensors in organisms ranging from yeast to humans. In particular, TRP channels are now known to constitute important components of sensory systems, where they participate in the detection or transduction of osmotic, mechanical, thermal, or chemosensory stimuli. We here summarize our current understanding of the role individual members of this versatile receptor family play in thermosensation and thermoregulation, and also touch upon their immerging role in metabolic control. PMID- 27227023 TI - Biophysical analysis of thermosensitive TRP channels with a special focus on the cold receptor TRPM8. AB - Mammals maintain homeostatic control of their body temperature. Therefore, these organisms are expected to have adaptations that confer the ability to detect and react to both self and ambient temperature. Temperature-activated ion channels have been discovered to be the primary molecular determinants of thermosensation. The most representative group of these determinants constitutes members of the transient receptor potential superfamily, TRP, which are activated by either low or high temperatures covering the whole range of physiologically relevant temperatures. This review makes a critical assessment of existing analytical methods of temperature-activated TRP channel mechanisms using the cold-activated TRPM8 channel as a paradigm. PMID- 27227024 TI - TRPM3 in temperature sensing and beyond. AB - TRPM3, also known as melastatin 2 (MLSN2), LTRPC3 (long TRPC3) and KIAA1616, is a member of the TRPM subfamily of transient receptor potential (TRP) ion channels. The channel was originally identified as a volume-regulated ion channel that can be activated upon reduction of the extracellular osmolality. Later, the channel was proposed to be involved in the modulation of insulin release in pancreatic islets. However, new evidence has uncovered a role of TRPM3 as a thermosensitive nociceptor channel implicated in the detection of noxious heat. The channel is functionally expressed in a subset of neurons of the somatosensory system and can be activated by heat. The purpose of the present review is to summarize existing knowledge of the expression, biophysics and pharmacology of TRPM3 and to serve as a guide for future studies aimed at improving the understanding of the mechanism of thermosensation and proposed physiological functions of TRPM3. PMID- 27227025 TI - Species-specific temperature sensitivity of TRPA1. AB - Transient receptor potential ankyrin 1 (TRPA1) is a polymodal ion channel sensitive to temperature and chemical stimuli. The importance of temperature and aversive chemical detection for survival has driven the evolutionary diversity of TRPA1 sensitivity. This diversity can be observed in the various roles of TRPA1 in different species, where it is proposed to act as a temperature-insensitive chemosensor, a heat transducer, a noxious cold transducer, or a detector of low intensity heat for prey localization. Exploring the variation of TRPA1 functions among species provides evolutionary insight into molecular mechanisms that fine tune thermal and chemical sensitivity, and offers an opportunity to address basic principles of temperature gating in ion channels. A decade of research has yielded a number of hypotheses describing physiological roles of TRPA1, modulators of its activity, and biophysical principles of gating. This review surveys the diversity of TRPA1 adaptations across evolutionary taxa and explores possible mechanisms of TRPA1 activation. PMID- 27227026 TI - Thermotaxis, circadian rhythms, and TRP channels in Drosophila. AB - The fruit fly Drosophila melanogaster is a poikilothermic organism that must detect and respond to both fine and coarse changes in environmental temperature in order maintain optimal body temperature, synchronize behavior to daily temperature fluctuations, and to avoid potentially injurious environmental hazards. Members of the Transient Receptor Potential (TRP) family of cation channels are well known for their activation by changes in temperature and their essential roles in sensory transduction in both invertebrates and vertebrates. The Drosophila genome encodes 13 TRP channels, and several of these have key sensory transduction and modulatory functions in allowing larval and adult flies to make fine temperature discriminations to attain optimal body temperature, detect and avoid large environmental temperature fluctuations, and make rapid escape responses to acutely noxious stimuli. Drosophila use multiple, redundant signaling pathways and neural circuits to execute these behaviors in response to both increases and decreases in temperature of varying magnitudes and time scales. A plethora of powerful molecular and genetic tools and the fly's simple, well-characterized nervous system have given Drosophila neurobiologists a powerful platform to study the cellular and molecular mechanisms of TRP channel function and how these mechanisms are conserved in vertebrates, as well as how these channels function within sensorimotor circuits to generate both simple and complex thermosensory behaviors. PMID- 27227027 TI - Induction of therapeutic hypothermia by pharmacological modulation of temperature sensitive TRP channels: theoretical framework and practical considerations. AB - Therapeutic hypothermia has emerged as a remarkably effective method of neuroprotection from ischemia and is being increasingly used in clinics. Accordingly, it is also a subject of considerable attention from a basic scientific research perspective. One of the fundamental problems, with which current studies are concerned, is the optimal method of inducing hypothermia. This review seeks to provide a broad theoretical framework for approaching this problem, and to discuss how a novel promising strategy of pharmacological modulation of the thermosensitive ion channels fits into this framework. Various physical, anatomical, physiological and molecular aspects of thermoregulation, which provide the foundation for this text, have been comprehensively reviewed and will not be discussed exhaustively here. Instead, the first part of the current review, which may be helpful for a broader readership outside of thermoregulation research, will build on this existing knowledge to outline possible opportunities and research directions aimed at controlling body temperature. The second part, aimed at a more specialist audience, will highlight the conceptual advantages and practical limitations of novel molecular agents targeting thermosensitive Transient Receptor Potential (TRP) channels in achieving this goal. Two particularly promising members of this channel family, namely TRP melastatin 8 (TRPM8) and TRP vanilloid 1 (TRPV1), will be discussed in greater detail. PMID- 27227031 TI - Osamu Hayaishi-from the discovery of oxygenases in soil microorganisms to unraveling the enigma of sleep in mammals. PMID- 27227030 TI - TRPV1 ligands with hyperthermic, hypothermic and no temperature effects in rats. AB - Transient receptor potential vanilloid 1 (TRPV1) is a multifunctional ion channel playing important roles in a numerous biological processes including the regulation of body temperature. Within distinct and tight chemical space of chromanyl ureas TRPV1 ligands were identified that exhibit distinctive pharmacology and a spectrum of thermoregulatory effects ranging from hypothermia to hyperthermia. The ability to manipulate these effects by subtle structural modifications of chromanyl ureas may serve as a productive approach in TRPV1 drug discovery programs addressing either side effect or desired target profiles of the compounds. Because chromanyl ureas in the TRPV1 context are generally antagonists, we verified observed partial agonist effects of a subset of compounds within that chemotype by comparing the in vitro profile of Compound 3 with known partial agonist 5'-I-RTX. PMID- 27227028 TI - The involvement of TRPV1 in emesis and anti-emesis. AB - Diverse transmitter systems (e.g. acetylcholine, dopamine, endocannabinoids, endorphins, glutamate, histamine, 5-hydroxytryptamine, substance P) have been implicated in the pathways by which nausea and vomiting are induced and are targets for anti-emetic drugs (e.g. 5-hydroxytryptamine3 and tachykinin NK1 antagonists). The involvement of TRPV1 in emesis was discovered in the early 1990s and may have been overlooked previously as TRPV1 pharmacology was studied in rodents (mice, rats) lacking an emetic reflex. Acute subcutaneous administration of resiniferatoxin in the ferret, dog and Suncus murinus revealed that it had "broad-spectrum" anti-emetic effects against stimuli acting via both central (vestibular system, area postrema) and peripheral (abdominal vagal afferents) inputs. One of several hypotheses discussed here is that the anti emetic effect is due to acute depletion of substance P (or another peptide) at a critical site (e.g. nucleus tractus solitarius) in the central emetic pathway. Studies in Suncus murinus revealed a potential for a long lasting (one month) effect against the chemotherapeutic agent cisplatin. Subsequent studies using telemetry in the conscious ferret compared the anti-emetic, hypothermic and hypertensive effects of resiniferatoxin (pungent) and olvanil (non-pungent) and showed that the anti-emetic effect was present (but reduced) with olvanil which although inducing hypothermia it did not have the marked hypertensive effects of resiniferatoxin. The review concludes by discussing general insights into emetic pathways and their pharmacology revealed by these relatively overlooked studies with TRPV1 activators (pungent an non-pungent; high and low lipophilicity) and antagonists and the potential clinical utility of agents targeted at the TRPV1 system. PMID- 27227032 TI - Introduction to the special issue of the journal Temperature on Japanese thermal physiology. AB - This editorial introduces the special issue of the journal Temperature on thermal physiology in Japan and acknowledges significant contributions of Japanese scientists to the development of thermal biology and physiology. This special issue contains articles on the history of Japanese thermal physiology and physiologists, invited reviews, research papers, and other contributions. It shows clearly that thermophysiology is a vibrant discipline in today's Japan. PMID- 27227029 TI - Effect of capsaicin on thermoregulation: an update with new aspects. AB - Capsaicin, a selective activator of the chemo- and heat-sensitive transient receptor potential (TRP) V1 cation channel, has characteristic feature of causing long-term functional and structural impairment of neural elements supplied by TRPV1/capsaicin receptor. In mammals, systemic application of capsaicin induces complex heat-loss response characteristic for each species and avoidance of warm environment. Capsaicin activates cutaneous warm receptors and polymodal nociceptors but has no effect on cold receptors or mechanoreceptors. In this review, thermoregulatory features of capsaicin-pretreated rodents and TRPV1 mediated neural elements with innocuous heat sensitivity are summarized. Recent data support a novel hypothesis for the role of visceral warmth sensors in monitoring core body temperature. Furthermore, strong evidence suggests that central presynaptic nerve terminals of TRPV1-expressing cutaneous, thoracic and abdominal visceral receptors are activated by innocuous warmth stimuli and capsaicin. These responses are absent in TRPV1 knockout mice. Thermoregulatory disturbance induced by systemic capsaicin pretreatment lasts for months and is characterized by a normal body temperature at cool environment up to a total dose of 150 mg/kg s.c. Upward differential shift of set points for activation vasodilation, other heat-loss effectors and thermopreference develops. Avoidance of warm ambient temperature (35 degrees C, 40 degrees C) is severely impaired but thermopreference at cool ambient temperatures (Tas) are not altered. TRPV1 knockout or knockdown and genetically altered TRPV1, TRPV2 and TRPM8 knockout mice have normal core temperature in thermoneutral or cool environments, but the combined mutant mice have impaired regulation in warm or cold (4 degrees C) environments. Several lines of evidence support that in the preoptic area warmth sensitive neurons are activated and desensitized by capsaicin, but morphological evidence for it is controversial. It is suggested that these neurons have also integrator function. Fever is enhanced in capsaicin-desensitized rats and the inhibition observed after pretreatment with low i.p. doses does not support in the light of their warmth sensitivity the concept that abdominal TRPV1-expressing nerve terminals serve as nonthermal chemosensors for reference signals in thermoregulation. PMID- 27227033 TI - History of thermal and environmental physiology in Japan: the heritage of Yas Kuno. AB - Dr. Yas Kuno was a pioneer in the field of sweat gland physiology. He trained many research scientists who formed the first generation of thermal physiologists. In turn, these investigators recruited qualified investigators, forming the second and third generations of thermal physiologists. At present, the third and fourth generations of investigators are actively engaged in research, expanding their interests to neurophysiology, chronobiology and exercise physiology. PMID- 27227034 TI - Eckhart Simon, a German physiologist's connections with physiology in Japan. AB - Eckhart Simon's research in the fields of Thermal and Regulatory Physiology is distinguished by exemplary relations with Thermal Physiology in Japan. The essay outlines the fields in which he has cooperated with Japanese physiologists. A list of joint publications documents their contributions to Eckhart Simon's and his department's scientific achievements. PMID- 27227035 TI - Thermoregulation and menstrual cycle. PMID- 27227036 TI - The importance of systematic approaches in the study of emesis. AB - Nausea and vomiting are among the most basic of human experiences and unfortunately accompany a wide variety of clinical treatments as side effects. Despite decades of research, the neural mechanisms of nausea and vomiting (emesis) remain elusive. TRPV1 represents a possibly overlooked and understudied pharmacological target with anti-emetic potential. PMID- 27227037 TI - Psychogenic fever, functional fever, or psychogenic hyperthermia? AB - Psychogenic fever reflects a phenomenon where core body temperature is high (up to 41 degrees C) or low-grade high (37-38 degrees C) during either acute or chronic stress. Underlying mechanisms are distinct from infection-induced fever and involve the central and sympathetic nervous systems. Psychogenic fever appears a complex psychological, physiological and endocrinological phenomenon. PMID- 27227038 TI - The ins and outs of prostaglandin E2 in fever. PMID- 27227039 TI - Shaping our understanding of endothermic thermoregulation. PMID- 27227040 TI - Thermosensors or not, this is the question. PMID- 27227041 TI - The thermostat concept - significant for mechanical temperature control systems, but irrelevant to mammalian thermoregulatory networks. PMID- 27227042 TI - Thermal information from the skin: the signal processing and the role in behavioral thermoregulation. PMID- 27227043 TI - Letter on Kobayashi's view of cutaneous thermoreceptors and their role in thermoregulation. PMID- 27227044 TI - Temperature receptors in cutaneous nerve endings are not thermostat molecules that induce thermoregulatory behaviors against thermal load. PMID- 27227045 TI - What feels warmer? A red skin versus a red object. PMID- 27227046 TI - Thermosensors or thermostats: new arguments. PMID- 27227047 TI - Impact of hand and object colors on object temperature perception. PMID- 27227048 TI - Temperature receptors in cutaneous nerve endings are thermostat molecules that induce thermoregulatory behaviors against thermal load. AB - When skin temperature falls below a set-point, mammals experience "cold in the skin" and exhibit heat-seeking behaviors for error correction. Physiological thermostats should perform the behavioral thermoregulation, and it is important to identify the thermostats. A classical model of the sensory system states that thermoreceptors (e.g., thermoTRPs) in skin nerve endings are sensors that transform temperature into the firing rate codes that are sent to the brain, where the codes are decoded as "cold" by a labeled line theory. However, the view that the temperature code is transformed into "cold" (not temperature) is conflicting. Another model states that a thermostat exists in the brain based on the view that a skin thermo-receptor is a sensor. However, because animals have no knowledge of the principle of temperature measurement, the brain is unable to measure skin temperature with a thermometer calibrated based on a code table of each sensor in the skin. Thus, these old models cannot identify the thermostats. We have proposed a new model in which temperature receptors in a nerve ending are molecules of the thermostats. When skin temperature falls below a set-point, these molecules as a whole induce impulses as command signals sent to the brain, where these impulses activate their target neurons for "cold" and heat-seeking behaviors for error correction. Our study challenges the famous models that sensory receptor is a sensor and the brain is a code processor. PMID- 27227049 TI - Neural circuit for psychological stress-induced hyperthermia. AB - Psychological stress-induced hyperthermia (PSH) is a basic physiological stress response to increase physical performances to defend homeostasis and life from stressors, such as natural enemies. However, excessive and long-lasting stressors can lead to chronic hyperthermia, particularly recognized in humans as a psychosomatic symptom called "psychogenic fever." The sympathetic and neuroendocrine responses that can contribute to PSH include brown adipose tissue (BAT) thermogenesis, cutaneous vasoconstriction, tachycardia and glucocorticoid secretion. Research on the central circuits underlying these stress responses has recently revealed several fundamental circuit mechanisms including hypothalamomedullary pathways driving the sympathetic stress responses. Psychological stress activates a monosynaptic glutamatergic excitatory neurotransmission from the dorsomedial hypothalamus (DMH) to sympathetic premotor neurons in the rostral medullary raphe region (rMR) to drive BAT thermogenesis and tachycardia, leading to the development of PSH. This glutamatergic neurotransmission could be potentiated by orexin neurons in the lateral hypothalamus through their projections to the rMR. Psychological stress also activates another monosynaptic pathway from the DMH to the paraventricular hypothalamic nucleus to stimulate the hypothalamo-pituitary-adrenal axis for the secretion of glucocorticoids. PSH is independent from the prostaglandin-mediated trigger mechanism for inflammation-induced fever, and several forebrain regions are considered to provide stress-driven inputs to the DMH to activate the sympathetic- and neuroendocrine-driving neurons. The circuit mechanism of PSH based on animal experiments would be relevant to understandings of the etiology of psychogenic fever in humans. This review describes the current understandings of the central circuit mechanism of PSH with recent important progress in research. PMID- 27227050 TI - Involvement of neurogenesis in the hypothalamic area in establishing long-term heat acclimation in rats. AB - This review summarizes earlier studies of long-term heat acclimation (LHA) in rats. Since thermoregulatory changes of LHA are stable and sustained, persisting functional and morphological changes are expected to occur in the thermoregulatory centers. Heat exposure increases the number of newborn cells in the ependymal layer of the third ventricle. With time, these newborn cells migrate into the hypothalamic parenchyma and differentiate to immature or mature neurons, some of which integrate into hypothalamic neuralne tworks. The generation of new functional neurons in the hypothalamus may be an important mechanism of LHA. PMID- 27227051 TI - Psychogenic fever: how psychological stress affects body temperature in the clinical population. AB - Psychogenic fever is a stress-related, psychosomatic disease especially seen in young women. Some patients develop extremely high core body temperature (Tc) (up to 41 degrees C) when they are exposed to emotional events, whereas others show persistent low-grade high Tc (37-38 degrees C) during situations of chronic stress. The mechanism for psychogenic fever is not yet fully understood. However, clinical case reports demonstrate that psychogenic fever is not attenuated by antipyretic drugs, but by psychotropic drugs that display anxiolytic and sedative properties, or by resolving patients' difficulties via natural means or psychotherapy. Animal studies have demonstrated that psychological stress increases Tc via mechanisms distinct from infectious fever (which requires proinflammatory mediators) and that the sympathetic nervous system, particularly beta3-adrenoceptor-mediated non-shivering thermogenesis in brown adipose tissue, plays an important role in the development of psychological stress-induced hyperthermia. Acute psychological stress induces a transient, monophasic increase in Tc. In contrast, repeated stress induces anticipatory hyperthermia, reduces diurnal changes in Tc, or slightly increases Tc throughout the day. Chronically stressed animals also display an enhanced hyperthermic response to a novel stress, while past fearful experiences induce conditioned hyperthermia to the fear context. The high Tc that psychogenic fever patients develop may be a complex of these diverse kinds of hyperthermic responses. PMID- 27227052 TI - Thermoregulation under pressure: a role for orexin neurons. AB - In the past, studies on stress responses and sleep/wake regulation were performed separately. The discovery of orexin (hypocretin) in 1998, however, dramatically changed the course of research and new findings regarding its role in these complex processes provided a better insight into their interactions and intricacies. Orexin-containing neuronal activity has been found to be minimal during sleep. It increases during the waking period and further increases during the active waking period, which includes stress responses and exploratory behaviors. Autonomic regulation of the body, which includes body temperature, blood flow, and ventilation, is also activated along with the change in vigilance states. Our recent findings suggest that orexin neurons act as a conductor of orchestration for vigilance states, behaviors, and autonomic functions. Body temperature regulation by orexin neurons seems to be mediated by one of its cotransmitters while cardiovascular and respiratory regulation are mediated by orexin itself. PMID- 27227053 TI - Control of cutaneous blood flow by central nervous system. AB - Hairless skin acts as a heat exchanger between body and environment, and thus greatly contributes to body temperature regulation by changing blood flow to the skin (cutaneous) vascular bed during physiological responses such as cold- or warm-defense and fever. Cutaneous blood flow is also affected by alerting state; we 'go pale with fright'. The rabbit ear pinna and the rat tail have hairless skin, and thus provide animal models for investigating central pathway regulating blood flow to cutaneous vascular beds. Cutaneous blood flow is controlled by the centrally regulated sympathetic nervous system. Sympathetic premotor neurons in the medullary raphe in the lower brain stem are labeled at early stage after injection of trans-synaptic viral tracer into skin wall of the rat tail. Inactivation of these neurons abolishes cutaneous vasomotor changes evoked as part of thermoregulatory, febrile or psychological responses, indicating that the medullary raphe is a common final pathway to cutaneous sympathetic outflow, receiving neural inputs from upstream nuclei such as the preoptic area, hypothalamic nuclei and the midbrain. Summarizing evidences from rats and rabbits studies in the last 2 decades, we will review our current understanding of the central pathways mediating cutaneous vasomotor control. PMID- 27227054 TI - How genetically engineered systems are helping to define, and in some cases redefine, the neurobiological basis of sleep and wake. AB - The advent of genetically engineered systems, including transgenic animals and recombinant viral vectors, has facilitated a more detailed understanding of the molecular and cellular substrates regulating brain function. In this review we highlight some of the most recent molecular biology and genetic technologies in the experimental "systems neurosciences," many of which are rapidly becoming a methodological standard, and focus in particular on those tools and techniques that permit the reversible and cell-type specific manipulation of neurons in behaving animals. These newer techniques encompass a wide range of approaches including conditional deletion of genes based on Cre/loxP technology, gene silencing using RNA interference, cell-type specific mapping or ablation and reversible manipulation (silencing and activation) of neurons in vivo. Combining these approaches with viral vector delivery systems, in particular adeno associated viruses (AAV), has extended, in some instances greatly, the utility of these tools. For example, the spatially- and/or temporally-restricted transduction of specific neuronal cell populations is now routinely achieved using the combination of Cre-driver mice and stereotaxic-based delivery of AAV expressing Cre-dependent cassettes. We predict that the experimental application of these tools, including creative combinatorial approaches and the development of even newer reagents, will prove necessary for a complete understanding of the neuronal circuits subserving most neurobiological functions, including the regulation of sleep and wake. PMID- 27227055 TI - beta-amyloid infusion into lateral ventricle alters behavioral thermoregulation and attenuates acquired heat tolerance in rats. AB - We investigated behavioral thermoregulatory function and acquired heat tolerance of beta-amyloid (Abeta)-infused rats. Male Wistar rats were anesthetized and implanted in the intraperitoneal cavity with a temperature transmitter. Abeta peptide (4.9-5.5 nmol) was dissolved in a solvent of 35% acetonitrile and 0.1% trifluoroacetic acid (pH 2.0). The solvent was used as the vehicle. An osmotic pump contained 234 +/- 13.9 MUl of Abeta solution was subcutaneously implanted in the back and was cannulated into the left cerebral ventricle. Moreover, 0.5 ug of AlCl3 was injected into the right cerebral ventricle with a micro syringe pump (Abeta-infused rats). The solvent-infused rats were used as control rats (CN rats). After 2 weeks, rats were placed in a thermal gradient and their intra abdominal temperature (T ab ) and their ambient temperatures (T a ) selected (T s ) were measured for 3 consecutive days. In an additional study, rats were kept at a T a of 32 degrees C for 4 weeks to attain heat acclimation. Then, rats were subjected to a heat tolerance test, i.e. they were exposed to a T a of 36 degrees C for 160 min. Although there were clear day-night variations of T s and T ab in CN rats, patterns were significantly abolished in Abeta-infused rats. Moreover, heat tolerance obtained by heat acclimation was attenuated in Abeta-infused rats. These results suggest that Abeta-infusion in the lateral ventricle modifies behavioral thermoregulation and lowers an ability to acclimate to heat in rats. PMID- 27227057 TI - The cock, the Academy, and the best scientific journal in the world. AB - The reader is invited to travel to Ancient Greece, contemporary Brazil, and other places in a fantasy search for the best scientific journal. This whimsical search does not rely on the impact factor, the most popular tool used in real life for finding good journals. Instead, it takes advantage of the so-called authority factor, a recently proposed alternative to the impact factor. The authority factor of a particular journal is the mean h-index (Hirsch's index) of the most suitable group of this journal's editors. Having no connection to any major function of scientific journals, and also being arbitrary (which group of editors to select?), this factor is poorly suited for any technical analysis, but it seems to work well for "small-talk" editorials and self-promotion by complacent editors. Interestingly, the highest authority factor we could find belongs to the journal Temperature. This claim, however, should not be taken too seriously. PMID- 27227056 TI - Prostaglandin transporter in the rat brain: its localization and induction by lipopolysaccharide. AB - Prostaglandin E2 (PGE2) is produced in the brain during infectious/inflammatory diseases, and it mediates acute-phase responses including fever. In the recovery phase of such diseases, PGE2 disappears from the brain through yet unidentified mechanisms. Rat prostaglandin transporter (PGT), which facilitates transmembrane transport of PGE2, might be involved in the clearance of PGE2 from the brain. Here, we examined the cellular localization of PGT mRNA and its protein in the brains of untreated rats and those injected intraperitoneally with a pyrogen lipopolysaccharide (LPS) or saline. PGT mRNA was weakly expressed in the arachnoid membrane of untreated rats and saline-injected ones, but was induced in blood vessels of the subarachnoidal space and choroid plexus and in arachnoid membrane at 5 h and 12 h after LPS injection. In the same type of cells, PGT-like immunoreactivity was found in the cytosol and cell membrane even under nonstimulated conditions, and its level was also elevated after LPS injection. PGT-positive cells in blood vessels were identified as endothelial cells. In most cases, PGT was not colocalized with cyclooxygenase-2, a marker of prostaglandin producing cells. The PGE2 level in the cerebrospinal fluid reached its peak at 3 h after LPS, and then dropped over 50% by 5 h, which time point coincides with the maximum PGT mRNA expression and enhanced level of PGT protein. These results suggest that PGT is involved in the clearance of PGE2 from the brain during the recovery phase of LPS-induced acute-phase responses. PMID- 27227058 TI - Physical performance and environmental conditions: 2014 World Soccer Cup and 2016 Summer Olympics in Brazil. AB - This editorial is for the special issue "Temperature sciences in Brazil" of the journal Temperature. It focuses on the physical performance and environmental conditions during the 2014 World Cup and the coming 2016 Summer Olympics. It emphasizes that a hot and humid environment imposes a great challenge to the human thermoregulation system, can lead to performance decrements, and increases the risk of developing hyperthermia. Adequate hydration, acclimatization, and body cooling strategies are effective interventions to minimize the risks associated with exercise in the heat. PMID- 27227059 TI - Thermal biology in Brazil: a summary of a 100-year legacy. PMID- 27227060 TI - Reduced oxygen utilization in septic shock: disorder or adaptation? AB - A fall in oxygen utilization during septic or endotoxic shock is thought to reflect circulatory hypoxia or mitochondrial dysfunction, but these pathology oriented hypotheses do not explain all clinical observations. Here we discuss an alternative hypothesis of how oxygen utilization could fall as the result of a physiological thermometabolic adaptation. PMID- 27227061 TI - PAF is a potent pyrogen and cryogen in rodents, but it does not mediate thermoregulatory responses to bacterial endotoxin. AB - Concordance between lipopolysaccharide and platelet activating factor - mediated events have suggested that the latter likely mediates all effects induced by the former. In this issue of Temperature, Steiner and Romanovsky challenge this notion, showing that while platelet activating factor is a potent pyrogenic mediator, the thermoregulatory responses to lipopolysaccharide are instead induced by prostaglandins. PMID- 27227062 TI - Thermal windows and heat exchange. PMID- 27227063 TI - The pathophysiology of heat exposure. PMID- 27227064 TI - Thermogenesis in ectothermic vertebrates. PMID- 27227065 TI - "Science without Borders" program and Brazilian-Hungarian collaboration in thermoregulation. PMID- 27227067 TI - Regulation of brown adipose tissue recruitment, metabolism and thermogenic function by peroxisome proliferator-activated receptor gamma. AB - Brown adipose tissue contributes importantly to homeothermy and energy balance in rodents due its ability under demand to produce heat through a process denominated nonshivering thermogenesis. Such thermogenic ability of brown adipocytes relies on the activity of mitochondrial uncoupling protein 1 that, when properly activated, dissipates energy from oxidative metabolism as heat. Brown adipose tissue sympathetic innervation through norepinephrine release not only induces brown adipocyte lipolysis and thermogenesis, but also acts as the major determinant of tissue mass, cellularity and mitochondrial content. Several pieces of evidence gathered over the years indicate that, in addition to tissue sympathetic innervation, the nuclear receptor peroxisome proliferator-activated receptor gamma plays an important role in regulating the development, metabolism and thermogenic function of brown adipose tissue. Herein we review the main evidence supporting such key role of peroxisome proliferator-activated receptor gamma to brown fat biology and discuss the future directions of this important area of research. PMID- 27227066 TI - Thermoregulatory responses in exercising rats: methodological aspects and relevance to human physiology. AB - Rats are used worldwide in experiments that aim to investigate the physiological responses induced by a physical exercise session. Changes in body temperature regulation, which may affect both the performance and the health of exercising rats, are evident among these physiological responses. Despite the universal use of rats in biomedical research involving exercise, investigators often overlook important methodological issues that hamper the accurate measurement of clear thermoregulatory responses. Moreover, much debate exists regarding whether the outcome of rat experiments can be extrapolated to human physiology, including thermal physiology. Herein, we described the impact of different exercise intensities, durations and protocols and environmental conditions on running induced thermoregulatory changes. We focused on treadmill running because this type of exercise allows for precise control of the exercise intensity and the measurement of autonomic thermoeffectors associated with heat production and loss. Some methodological issues regarding rat experiments, such as the sites for body temperature measurements and the time of day at which experiments are performed, were also discussed. In addition, we analyzed the influence of a high body surface area-to-mass ratio and limited evaporative cooling on the exercise induced thermoregulatory responses of running rats and then compared these responses in rats to those observed in humans. Collectively, the data presented in this review represent a reference source for investigators interested in studying exercise thermoregulation in rats. In addition, the present data indicate that the thermoregulatory responses of exercising rats can be extrapolated, with some important limitations, to human thermal physiology. PMID- 27227068 TI - Current understanding on the neurophysiology of behavioral thermoregulation. AB - Temperature influence on the physiology and biochemistry of living organisms has long been recognized, which propels research in the field of thermoregulation. With the cloning and characterization of the transient receptor potential (TRP) ion channels as the principal temperature sensors of the mammalian somatosensory neurons, the understanding, at a molecular level, of thermosensory and thermoregulatory mechanisms became promising. Because thermal environment can be extremely hostile (temperature range on earth's surface is from ~ -69 degrees C to 58 degrees C), living organisms developed an array of thermoregulatory strategies to guarantee survival, which include both autonomic mechanisms, which aim at increasing or decreasing heat exchange between body, and ambient and behavioral strategies. The knowledge regarding neural mechanisms involved in autonomic thermoregulatory strategies has progressed immensely compared to the knowledge on behavioral thermoregulation. This review aims at collecting the up to-date knowledge on the neural basis for behavioral thermoregulation in mammals in order to point out perspectives and deployment of this research field. PMID- 27227069 TI - Temperature and toxic Tau in Alzheimer's disease: new insights. AB - Alzheimer's disease (AD), the most common dementia in the elderly, is characterized by cognitive impairment and severe autonomic symptoms such as disturbance in core body temperature (Tc), which may be predictors or early events in AD onset. Inclusions of phosphorylated Tau (p-Tau) are a hallmark of AD and other neurodegenerative disorders called "Tauopathies." Animal and human studies show that anesthesia augments p-Tau levels through reduction of Tc, with implications for AD. Additionally, hypothermia impairs memory and cognitive function. The molecular networks related to Tc that are associated with AD remain poorly characterized. Under physiological conditions, Tau binds microtubules, promoting their assembly and stability. The dynamically regulated Tau-microtubule interaction plays an important role in structural remodeling of the cytoskeleton, having important functions in neuronal plasticity and memory in the hippocampus. Hypothermia-induced increases in p-Tau levels are significant, with an 80% increase for each degree Celsius below normothermic conditions. Although the effects of temperature on Tau phosphorylation are evident, its effects on p-Tau degradation remain poorly understoodWe review information concerning the mechanisms of Tau regulation of neuron plasticity via its effects on microtubule dynamics, with focus on pathways regulating the abundance of phosphorylated Tau species. We highlight the effects of temperature on molecular mechanisms influencing the development of Tau-related diseases. Specifically, we argue that cold might preferentially affects central nervous system structures that are highly reliant upon plasticity, such as the hippocampus, and that the effect of cold on Tau phosphorylation may constitute a pathology-initiating trigger leading to neurodegeneration. PMID- 27227070 TI - Insights into the role of heat shock protein 72 to whole-body heat acclimation in humans. AB - Heat acclimation results in systemic and cellular adaptions that reduce the negative effect of heat and, consequently, the risk of heat illness. Although the classical changes observed with heat acclimation lead to increased tolerance to exercise in the heat by reducing heat storage (reflected in reduced core and skin temperatures) and increasing whole-body capacity for heat dissipation (greater plasma volume, sweat output, and skin blood flow), it appears that heat acclimation also induces changes at the cellular level that might increase tolerance of the whole organism to a higher core temperature for the development of fatigue. Thermotolerance is a process that involves increased resilience to an otherwise lethal heat stress that follows a sublethal exposure to heat. Thermotolerance is believed to be the result of increased content of heat shock proteins (Hsp), specially a member of the 70 kDa family, Hsp72 kDa. In humans, we and others have reported that heat acclimation increases intracellular Hsp72 levels. This increase in intracellular Hsp72 could improve whole-body organism thermotolerance by maintaining intestinal epithelial tight junction barriers, by increasing resistance to gut-associated endotoxin translocation, or by reducing the inflammatory response. In this review, we will initially provide an overview of the physiological adaptations induced by heat acclimation and emphasize the main cellular changes that occur with heat acclimation associated with intracellular accumulation of Hsp72. Finally, we will present an argument for a role of whole-body heat acclimation in augmenting cellular thermotolerance, which may protect vital organs from deleterious effects of heat stress in humans. PMID- 27227072 TI - TRP channels: a missing bond in the entrainment mechanism of peripheral clocks throughout evolution. AB - Circadian rhythm may be understood as a temporal organization that works to orchestrate physiological processes and behavior in a period of approximately 24 h. Because such temporal organization has evolved in the presence of predictable environmental clues, such as day length, tides, seasons, and temperature, the organism has confronted the natural selection in highly precise intervals of opportunities and risks, generating temporal programs and resetting mechanisms, which are well conserved among different taxa of animals. The present review brings some evidence of how these programs may have co-evolved in systems able to deal with 2 or more environmental clues, and how they similarly function in different group of animals, stressing how important temperature and light were to establish the temporal organizations. For example, melanopsin and rhodopsin, photopigments present respectively in circadian and visual photoreceptors, are required for temperature discrimination in Drosophila melanogaster. These pigments may signal light and temperature via activation of cationic membrane channel, named transient-receptor potential channel (TRP). In fact, TRPs have been suggested to function as thermal sensor for various groups of animals. Another example is the clock machinery at the molecular level. A set of very-well conserved proteins, known as clock proteins, function as transcription factors in positive and negative auto-regulatory loops generating circadian changes of their expression, and of clock-controlled genes. Similar molecular machinery is present in organisms as diverse as cyanobacteria (Synechococcus), fungi (Neurospora), insects (Drosophila), and vertebrates including humans. PMID- 27227073 TI - Platelet-activating factor is a potent pyrogen and cryogen, but it does not mediate lipopolysaccharide fever or hypothermia. AB - We examined whether platelet-activating factor (PAF) and its receptor mediate lipopolysaccharide (LPS)-induced fever and hypothermia in rats. Two highly potent, structurally distinct antagonists of the PAF receptor, CV6209 and WEB2086, were used. At a neutral ambient temperature (Ta) of 30oC, administration of LPS at a low (10 MUg/kg, i.v.) or high (1,000 MUg/kg, i.v.) dose resulted in fever. The response to the high dose was turned into hypothermia at a subneutral Ta of 22oC. Neither LPS-induced fever nor hypothermia was affected by pretreatment with CV6209 (5 mg/kg, i.v.) or WEB2086 (5 mg/kg, i.v.). However, both PAF antagonists were efficacious in blocking the thermoregulatory response caused by PAF (334 pmol/kg/min, 1 h, i.v.), regardless of whether the response was a fever (at 30oC) or hypothermia (at 22oC). Additional experiments showed that the thermoregulatory responses to LPS and PAF are also distinct in terms of their mediation by prostaglandins. Neither PAF fever nor PAF hypothermia was affected by pretreatment with the cyclooxygenase-2 inhibitor SC236 (5 mg/kg, i.p.), which is known to abrogate LPS fever. The responses to PAF were also unaffected by pretreatment with the cyclooxygenase-1 inhibitor SC560 (5 mg/kg, i.p.), which is known to attenuate LPS hypothermia. In conclusion, PAF infusion at a picomolar dose causes fever at thermoneutrality but hypothermia in a subthermoneutral environment, both responses being dependent on the PAF receptor and independent of prostaglandins. However, the PAF receptor does not mediate LPS induced fever or hypothermia, thus challenging the dogma that PAF is an upstream mediator of responses to LPS. PMID- 27227075 TI - Thermal biology of the toad Rhinella schneideri in a seminatural environment in southeastern Brazil. AB - The toad, Rhinella schneideri, is a large-bodied anuran amphibian with a broad distribution over South America. R. schneideri is known to be active at night during the warm/rainy months and goes into estivation during the dry/cold months; however, there is no data on the range of body temperatures (Tb) experienced by this toad in the field, and how environmental factors, thermoregulatory behaviors or activity influence them. By using implantable temperature dataloggers, we provide an examination of Tb variation during an entire year under a seminatural setting (emulating its natural habitat) monitored with thermosensors. We also used data on preferred Tb, allowing us to express the effectiveness of thermoregulation quantitatively. Paralleling its cycle of activity, R. schneideri exhibited differences in its daily and seasonal profile of Tb variation. During the active season, toads spent daytime hours in shelters and, therefore, did not explore microhabitats with higher thermal quality, such as open areas in the sun. At nighttime, the thermal suitability of microhabitats shifted as exposed microhabitats experienced greater temperature drops than the more insulated shelter. As toads became active at night, they were driven to the more exposed areas and, as a result, thermoregulatory effectiveness decreased. Our results, therefore, indicate that, during the active season, a compromise between thermoregulation and nocturnal activity may be at play. During the estivation period, R. schneideri spent the entire day cycle inside the shelter. As toads did not engage in nocturnal activity in those areas with low thermal quality, the overall effectiveness of thermoregulation was, indeed, elevated. In conclusion, we showed that daily and seasonal variation in Tb of an anuran species is highly associated with their respective pattern of activity and may involve important physiological and ecological compromises. PMID- 27227076 TI - Feeling cold is contagious. PMID- 27227077 TI - Ambient temperature modulates yawning. PMID- 27227071 TI - Central mediators involved in the febrile response: effects of antipyretic drugs. AB - Fever is a complex signal of inflammatory and infectious diseases. It is generally initiated when peripherally produced endogenous pyrogens reach areas that surround the hypothalamus. These peripheral endogenous pyrogens are cytokines that are produced by leukocytes and other cells, the most known of which are interleukin-1beta, tumor necrosis factor-alpha, and interleukin-6. Because of the capacity of these molecules to induce their own synthesis and the synthesis of other cytokines, they can also be synthesized in the central nervous system. However, these pyrogens are not the final mediators of the febrile response. These cytokines can induce the synthesis of cyclooxygenase-2, which produces prostaglandins. These prostanoids alter hypothalamic temperature control, leading to an increase in heat production, the conservation of heat, and ultimately fever. The effect of antipyretics is based on blocking prostaglandin synthesis. In this review, we discuss recent data on the importance of prostaglandins in the febrile response, and we show that some endogenous mediators can still induce the febrile response even when known antipyretics reduce the levels of prostaglandins in the central nervous system. These studies suggest that centrally produced mediators other than prostaglandins participate in the genesis of fever. Among the most studied central mediators of fever are corticotropin-releasing factor, endothelins, chemokines, endogenous opioids, and substance P, which are discussed herein. Additionally, recent evidence suggests that these different pathways of fever induction may be activated during different pathological conditions. PMID- 27227078 TI - Hot genes and hot tropics. PMID- 27227074 TI - Ondansetron and promethazine have differential effects on hypothermic responses to lithium chloride administration and to provocative motion in rats. AB - We recently reported that provocative motion (rotation in a home cage) causes hypothermic responses in rats, similar to the hypothermic responses associated with motion sickness in humans. Many stimuli inducing emesis in species with an emetic reflex also provoke hypothermia in the rat, therefore we hypothesized that a fall in body temperature may reflect a "nausea-like" state in these animals. As rats do not possess an emetic reflex, we employed a pharmacological approach to test this hypothesis. In humans, motion- and chemically-induced nausea have differential sensitivity to anti-emetics. We thus tested whether the hypothermia induced in rats by provocative motion (rotation at 0.7 Hz) and by the emetic LiCl (63 mg/kg i.p.) have a similar differential pharmacological sensitivity. Both provocations caused a comparable robust fall in core body temperature (-1.9 +/- 0.3 degrees C and -2.0 +/- 0.2 degrees C for chemical and motion provocations, respectively). LiCl(-)induced hypothermia was completely prevented by ondansetron (2mg/kg, i.p., a 5-HT3 receptor antagonist that reduces cancer chemotherapy induced nausea and vomiting), but was insensitive to promethazine (10 mg/kg, i.p., a predominantly histamine-H1 and muscarinic receptor antagonist that is commonly used to treat motion sickness). Conversely, motion-induced hypothermia was unaffected by ondansetron but promethazine reduced the rate of temperature decline from 0.20 +/- 0.02 to 0.11 +/- 0.03 degrees C/min (P < 0.05) with a trend to decrease the magnitude. We conclude that this differential pharmacological sensitivity of the hypothermic responses of vestibular vs. chemical etiology in rats mirrors the observations in other pre-clinical models and humans, and thus supports the idea that a "nausea-like" state in rodents is associated with disturbances in thermoregulation. PMID- 27227079 TI - Why do people living in hot climates like their food spicy? PMID- 27227080 TI - The experienced temperature sensitivity and regulation survey. AB - Individuals differ in thermosensitivity, thermoregulation, and zones of thermoneutrality and thermal comfort. Whereas temperature sensing and effectuating processes occur in part unconsciously and autonomic, awareness of temperature and thermal preferences can affect thermoregulatory behavior as well. Quantification of trait-like individual differences of thermal preferences and experienced temperature sensitivity and regulation is therefore relevant to obtain a complete understanding of human thermophysiology. Whereas several scales have been developed to assess instantaneous appreciation of heat and cold exposure, a comprehensive scale dedicated to assess subjectively experienced autonomic or behavioral thermoregulatory activity has been lacking so far. We constructed a survey that specifically approaches these domains from a trait-like perspective, sampled 240 volunteers across a wide age range, and analyzed the emergent component structure. Participants were asked to report their thermal experiences, captured in 102 questions, on a 7-point bi-directional Likert scale. In a second set of 32 questions, participants were asked to indicate the relative strength of experiences across different body locations. Principal component analyses extracted 21 meaningful dimensions, which were sensitive to sex differences and age-related changes. The questions were also assessed in a matched sample of 240 people with probable insomnia to evaluate the sensitivity of these dimensions to detect group differences in a case-control design. The dimensions showed marked mean differences between cases and controls. The survey thus has discriminatory value. It can freely be used by anyone interested in studying individual or group differences in thermosensitivity and thermoregulation. PMID- 27227081 TI - Arterio-venous anastomoses in the human skin and their role in temperature control. AB - Arterio-venous anastomoses (AVAs) are direct connections between small arteries and small veins. In humans they are numerous in the glabrous skin of the hands and feet. The AVAs are short vessel segments with a large inner diameter and a very thick muscular wall. They are densely innervated by adrenergic axons. When they are open, they provide a low-resistance connection between arteries and veins, shunting blood directly into the venous plexuses of the limbs. The AVAs play an important role in temperature regulation in humans in their thermoneutral zone, which for a naked resting human is about 26 degrees C to 36 degrees C, but lower when active and clothed. From the temperature control center in the hypothalamus, bursts of nerve impulses are sent simultaneously to all AVAs. The AVAs are all closed near the lower end and all open near the upper end of the thermoneutral zone. The small veins in the skin of the arms and legs are also contracted near the lower end of the thermoneutral zone and relax to a wider cross section as the ambient temperature rises. At the cold end of the thermoneutral range, the blood returns to the heart through the deep veins and cools the arterial blood through a countercurrent mechanism. As the ambient temperature rises, more blood is returned through the superficial venous plexuses and veins and heats the skin surface of the full length of the 4 limbs. This skin surface is responsible for a large part of the loss of heat from the body toward the upper end of the thermoneutral zone. PMID- 27227082 TI - Urinary thrombomodulin and catecholamine levels are interrelated in healthy volunteers immersed in cold and warm water. AB - Severe hypothermia has been shown to influence the levels of catecholamines and thrombomodulin, an endothelial protein essentially involved in the regulation of haemostasis and inflammation. A link between thrombomodulin and catecholamines during cold exposure has also been previously suggested. The aim of this study was to assess the influence of short-term cold exposure without hypothermia on catecholamines and the circulating and urinary thrombomodulin levels. Seven healthy male subjects were immersed in cold water (+10 degrees C) for 10 minutes followed by a 20-minute immersion in +28 degrees C water. Warm water immersion was performed separately for each subject (+30 degrees C for 30 minutes). Thrombomodulin and catecholamine concentrations were measured from pre- and post immersion (up to 23 hours) samples. In urine, the thrombomodulin level correlated strongly with adrenaline (rho = 0.806) and noradrenaline (rho = 0.760) levels. There were no significant differences in thrombomodulin levels between immersion temperatures. Post-immersion urinary thrombomodulin levels were significantly lower than the pre-immersion level at both immersion temperatures. Median concentrations of plasma noradrenaline and urinary adrenaline were higher after exposure to +10 degrees C than to +30 degrees C. Thus, further evidence of the association between thrombomodulin and catecholamines was gained in a physiologically relevant setting in humans. Additionally, it is evident that a short-term cold exposure was not able to elicit changes in the thrombomodulin levels in a follow-up period of up to 23 hours. These findings provide further understanding of the physiological responses to cold during immersion, and of the potential influence of stress on haemostatic and inflammatory responses. PMID- 27227083 TI - High intensity interval training in the heat enhances exercise-induced lipid peroxidation, but prevents protein oxidation in physically active men. AB - Aim. The purpose of this study was to determine the response of circulating markers of lipid and protein oxidation following an incremental test to exhaustion before and after 4 weeks of high-intensity interval training performed in the heat. Methods. To address this question, 16 physically active men (age = 23 +/- 2 years; body mass = 73 +/- 12 kg; height = 173 +/- 6 cm; % body fat = 12.5 +/- 6 %; body mass index = 24 +/- 4 kg/m(2)) were allocated into 2 groups: control group (n = 8) performing high-intensity interval training at 22 degrees C, 55% relative humidity and heat group (n = 8) training under 35 degrees C, 55% relative humidity. Both groups performed high-intensity interval training 3 times per week for 4 consecutive weeks, accumulating a total of 12 training sessions. Before and after the completion of 4 weeks of high-intensity interval training, participants performed an incremental cycling test until exhaustion under temperate environment (22 degrees C, 55% relative humidity) where blood samples were collected after the test for determination of exercise-induced changes in oxidative damage biomarkers (thiobarbituric acid reactive species and protein carbonyls). Results. When high-intensity interval training was performed under control conditions, there was an increase in protein carbonyls (p < 0.05) following the incremental test to exhaustion with no changes in thiobarbituric acid reactive species. Conversely, high-intensity interval training performed in high environmental temperature enhanced the incremental exercise-induced increases in thiobarbituric acid reactive species (p < 0.05) with no changes in protein carbonyls. Conclusion. In conclusion, 4 weeks of high-intensity interval training performed in the heat enhances exercise-induced lipid peroxidation, but prevents protein oxidation following a maximal incremental exercise in healthy active men. PMID- 27227084 TI - The effect of 10 days of heat acclimation on exercise performance in acute hypobaric hypoxia (4350 m). AB - To examine the effect ("cross-tolerance") of heat acclimation (HA) on exercise performance upon exposure to acute hypobaric hypoxia (4350 m). Eight male cyclists residing at 1600 m performed tests of maximal aerobic capacity (VO2max) at 1600 m and 4350 m, a 16 km time-trial at 4350 m, and a heat tolerance test at 1600 m before and after 10 d HA at 40 degrees C, 20% RH. Resting blood samples were obtained pre-and post- HA to estimate changes in plasma volume (DeltaPV). Successful HA was indicated by significantly lower exercise heart rate and rectal temperature on day 10 vs. day 1 of HA and during the heat tolerance tests. Heat acclimation caused a 1.9% DeltaPV, however VO2max was not significantly different at 1600 m or 4350 m. Time-trial cycling performance improved 28 sec after HA (p = 0.07), suggesting a possible benefit for exercise performance at acute altitude and that cross-tolerance between these variables may exist in humans. These findings do not clearly support the use of HA to improve exercise capacity and performance upon acute hypobaric hypoxia, however they do indicate that HA is not detrimental to either exercise capacity or performance. PMID- 27227085 TI - A personal recollection: 60 years in thermoregulation. PMID- 27227086 TI - Award-winning papers published in Temperature in 2014. PMID- 27227087 TI - Brazil: What country is this? PMID- 27227088 TI - Taking thermal physiology to where the wild things are. PMID- 27227089 TI - Prostaglandin E2 that triggers fever is synthesized through an endocannabinoid- dependent pathway. PMID- 27227090 TI - HSP72 Up-regulation with heat acclimation. PMID- 27227091 TI - Tim Bartness, Ph.D. (1953-2015). PMID- 27227092 TI - Preference for hot pepper: A complex interplay of personal, cultural, and pharmacological effects. PMID- 27227093 TI - Hot stuff - do people living in hot climates like their food spicy hot or not? PMID- 27227094 TI - Seeking the tropical heat - a matter of microbes? PMID- 27227095 TI - It remains a mystery why people living in hot climates consume spicier food. PMID- 27227096 TI - Why do people living in hot climates like their food spicy? PMID- 27227097 TI - Some like it hot (ever more so in the tropics): A puzzle with no solution. PMID- 27227098 TI - Pungency: A reason for the sluggish expansion of hot spicy foods from the tropics. PMID- 27227099 TI - Comprehensive thermal preference phenotyping in mice using a novel automated circular gradient assay. AB - Currently available behavioral assays to quantify normal cold sensitivity, cold hypersensitivity and cold hyperalgesia in mice have betimes created conflicting results in the literature. Some only capture a limited spectrum of thermal experiences, others are prone to experimenter bias or are not sensitive enough to detect the contribution of ion channels to cold sensing because in mice smaller alterations in cold nociception do not manifest as frank behavioral changes. To overcome current limitations we have designed a novel device that is automated, provides a high degree of freedom, i.e. thermal choice, and eliminates experimenter bias. The device represents a thermal gradient assay designed as a circular running track. It allows discerning exploratory behavior from thermal selection behavior and provides increased accuracy by providing measured values in duplicate and by removing edge artifacts. Our custom-designed automated offline analysis by a blob detection algorithm is devoid of movement artifacts, removes light reflection artifacts and provides an internal quality control parameter which we validated. The assay delivers discrete information on a large range of parameters extracted from the occupancy of thermally defined zones such as preference temperature and skew of the distribution. We demonstrate that the assay allows increasingly accurate phenotyping of thermal sensitivity in transgenic mice by disclosing yet unrecognized details on the phenotypes of TRPM8 , TRPA1- and TRPM8/A1-deficient mice. PMID- 27227100 TI - Human whole body cold adaptation. AB - Reviews on whole body human cold adaptation generally do not distinguish between population studies and dedicated acclimation studies, leading to confusing results. Population studies show that indigenous black Africans have reduced shivering thermogenesis in the cold and poor cold induced vasodilation in fingers and toes compared to Caucasians and Inuit. About 40,000 y after humans left Africa, natives in cold terrestrial areas seems to have developed not only behavioral adaptations, but also physiological adaptations to cold. Dedicated studies show that repeated whole body exposure of individual volunteers, mainly Caucasians, to severe cold results in reduced cold sensation but no major physiological changes. Repeated cold water immersion seems to slightly reduce metabolic heat production, while repeated exposure to milder cold conditions shows some increase in metabolic heat production, in particular non-shivering thermogenesis. In conclusion, human cold adaptation in the form of increased metabolism and insulation seems to have occurred during recent evolution in populations, but cannot be developed during a lifetime in cold conditions as encountered in temperate and arctic regions. Therefore, we mainly depend on our behavioral skills to live in and survive the cold. PMID- 27227103 TI - Mapping international practice patterns in EUS-guided tissue sampling: outcome of a global survey. AB - BACKGROUND AND STUDY AIMS: Although Endoscopic Ultrasound (EUS)-guided tissue sampling is widely used, the optimal sampling strategy remains subject of debate. We evaluated practice patterns within the international endosonographic community. PATIENTS AND METHODS: An online questionnaire was sent to 400 endosonographers from the United States, Europe, and Asia. RESULTS: A total of 186 (47 %) endosonographers participated: United States 54 (29 %), Europe 85 (46 %), and Asia 47 (25 %). European (75 %) and Asian (84 %) respondents routinely check coagulation status, whereas US respondents only check on indication (64 %, P = 0.007). While propofol sedation is standard in the United States (83 %), conscious sedation is still widely used in Europe (52 %) and Asia (84 %, P < 0.001). Overall, the 22-gauge needle is most commonly used (52 %). For fine needle aspiration (FNA) of solid pancreatic lesions, 22-gauge (45 %) and 25-gauge (49 %) needles are used equally. For fine-needle biopsy (FNB) of solid masses, the 25-gauge device is less favored than the 22-gauge FNA device (49 % versus 21 %). The 19-gauge needle is generally used for FNB of submucosal masses (62 %). Rapid on-site pathological evaluation (ROSE) is utilized more often by US (98 %) than by European and Asian respondents (51 %, P < 0.001). Cytolyt (52 %), formalin (15 %) and alcohol (15 %) are used for FNA specimen preservation in the United States and Europe, while saline (27 %) and alcohol (38 %) are widely used in Asia (P < 0.001). CONCLUSIONS: EUS-guided tissue sampling practices vary substantially within the international endosonographic community and differ considerably from recommendations expressed in guidelines. Because the clinical relevance of these variations is largely unknown, the outcome of this survey suggests a need for further studies. PMID- 27227102 TI - Characteristics of hyperthermia-induced hyperventilation in humans. AB - In humans, hyperthermia leads to activation of a set of thermoregulatory responses that includes cutaneous vasodilation and sweating. Hyperthermia also increases ventilation in humans, as is observed in panting dogs, but the physiological significance and characteristics of the hyperventilatory response in humans remain unclear. The relative contribution of respiratory heat loss to total heat loss in a hot environment in humans is small, and this hyperventilation causes a concomitant reduction in arterial CO2 pressure (hypocapnia), which can cause cerebral hypoperfusion. Consequently, hyperventilation in humans may not contribute to the maintenance of physiological homeostasis (i.e., thermoregulation). To gain some insight into the physiological significance of hyperthermia-induced hyperventilation in humans, in this review, we discuss 1) the mechanisms underlying hyperthermia-induced hyperventilation, 2) the factors modulating this response, and 3) the physiological consequences of the response. PMID- 27227101 TI - Body temperature regulation in diabetes. AB - The effects of type 1 and type 2 diabetes on the body's physiological response to thermal stress is a relatively new topic in research. Diabetes tends to place individuals at greater risk for heat-related illness during heat waves and physical activity due to an impaired capacity to dissipate heat. Specifically, individuals with diabetes have been reported to have lower skin blood flow and sweating responses during heat exposure and this can have important consequences on cardiovascular regulation and glycemic control. Those who are particularly vulnerable include individuals with poor glycemic control and who are affected by diabetes-related complications. On the other hand, good glycemic control and maintenance of aerobic fitness can often delay the diabetes-related complications and possibly the impairments in heat loss. Despite this, it is alarming to note the lack of information regarding diabetes and heat stress given the vulnerability of this population. In contrast, few studies have examined the effects of cold exposure on individuals with diabetes with the exception of its therapeutic potential, particularly for type 2 diabetes. This review summarizes the current state of knowledge regarding the impact of diabetes on heat and cold exposure with respect to the core temperature regulation, cardiovascular adjustments and glycemic control while also considering the beneficial effects of maintaining aerobic fitness. PMID- 27227105 TI - Endoscopic ultrasound fine-needle aspiration vs. fine-needle biopsy: tissue is always the issue. PMID- 27227104 TI - A randomized controlled cross-over trial and cost analysis comparing endoscopic ultrasound fine needle aspiration and fine needle biopsy. AB - BACKGROUND AND STUDY AIMS: Techniques to optimize endoscopic ultrasound-guided tissue acquisition (EUS-TA) in a variety of lesion types have not yet been established. The primary aim of this study was to compare the diagnostic yield (DY) of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) to endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) for pancreatic and non pancreatic masses. PATIENTS AND METHODS: Consecutive patients referred for EUS-TA underwent randomization to EUS-FNA or EUS-FNB at four tertiary-care medical centers. A maximum of three passes were allowed for the initial method of EUS-TA and patients were crossed over to the other arm based on on-site specimen adequacy. RESULTS: A total of 140 patients were enrolled. The overall DY was significantly higher with specimens obtained by EUS-FNB compared to EUS-FNA (90.0 % vs. 67.1 %, P = 0.002). While there was no difference in the DY between the two groups for pancreatic masses (FNB: 91.7 % vs. FNA: 78.4 %, P = 0.19), the DY of EUS-FNB was higher than the EUS-FNA for non-pancreatic lesions (88.2 % vs. 54.5 %, P = 0.006). Specimen adequacy was higher for EUS-FNB compared to EUS-FNA for all lesions (P = 0.006). There was a significant rescue effect of crossover from failed FNA to FNB in 27 out of 28 cases (96.5 %, P = 0.0003). Decision analysis showed that the strategy of EUS-FNB was cost saving compared to EUS-FNA over a wide range of cost and outcome probabilities. CONCLUSIONS: RESULTS of this RCT and decision analysis demonstrate superior DY and specimen adequacy for solid mass lesions sampled by EUS-FNB. PMID- 27227106 TI - Usefulness of virtual chromoendoscopy in the evaluation of subtle small bowel ulcerative lesions by endoscopists with no experience in videocapsule. AB - BACKGROUND AND STUDY AIMS: In videocapsule endoscopy examination (VCE), subtle variations in mucosal hue or pattern such as those seen in ulcerations can be difficult to detect, depending on the experience of the reader. Our aim was to test whether virtual chromoendoscopy (VC) techniques, designed to enhance the contrast between the lesion and the normal mucosa, could improve the characterization of ulcerative mucosal lesions. PATIENTS AND METHODS: Fifteen trainees or young gastroenterologists with no experience in VCE were randomly assigned to evaluate 250 true ulcerative and 100 false ulcerative, difficult-to interpret small bowel lesions, initially as white light images (WLI) and then, in a second round, with the addition of one VC setting or again as WLI, labeling them as real lesions or artifacts. RESULTS: On the overall image evaluation, an improvement in lesion characterization was observed by adding any chromoendoscopy setting, especially Blue mode and FICE 1, with increases in accuracy of 13 % [95 %CI 0.8, 25.3] and 7.1 % [95 %CI - 17.0, 31.3], respectively. However, when only false ulcerative images were considered, with the same presets (Blue mode and FICE 1), there was a loss in accuracy of 10.7 % [95 %CI - 10.9, 32.3] and 7.3 % [95 %CI - 1.3, 16.0], respectively. The interobserver agreement was poor for both readings. CONCLUSIONS: VC helps beginner VCE readers correctly categorize difficult-to-interpret small bowel mucosal ulcerative lesions. However, false lesions tend to be misinterpreted as true ulcerative with the same presets. Therefore care is advised in using VC especially under poor bowel preparation. PMID- 27227107 TI - Correlation of the location of superficial Barrett's esophageal adenocarcinoma (s BEA) with the direction of gastroesophageal reflux. AB - BACKGROUND: Superficial Barrett's esophageal adenocarcinoma (s-BEA) in Barrett's esophagus frequently occurs in the right wall of the esophagus. Our aim was to examine the correlation between the location of s-BEA and the direction of acid and non-acid reflux in patients with Barrett's esophagus. PATIENTS AND METHODS: We performed 24-h pH monitoring in 33 s-BEA patients using a pH catheter with eight sensors. One sensor was located at the 6 o'clock position in the lower esophagus and sensors 1 - 8 were arranged counterclockwise at the same level. The catheter was positioned at the same level as the s-BEA. We measured the maximal total duration of acid (MTD-A) and non-acid (MTD-NA) reflux. When the direction of MTD-A and MTD-NA coincided with the location of the s-BEA, the case was defined as coincidental and we calculated the rate of coincidence, and the probability of the rate of coincidence was estimated with 95 % confidence intervals (95 %CI). RESULTS: Among the 33 cases of s-BEA examined, the rate of coincidence of both MTD-A and MTD-NA was 24/33 (72.7 %) (95 %CI 0.54 - 0.87). The rate of coincidence of either MTD-A or MTD-NA was 30/33 (90.9 %) (95 %CI 0.76 - 0.98). CONCLUSIONS: Our study revealed that the location of s-BEA mostly corresponds to the direction of MTD-A or MTD-NA. Accurate observation of the distribution of acid or non-acid reflux by pH monitoring would aid early detection of s-BEA by endoscopy. PMID- 27227108 TI - Safety and short-term outcomes of endoscopic submucosal dissection for early gastric cancer in elderly patients. AB - BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) has become widely accepted as a minimally invasive treatment for early gastric cancer (EGC), and opportunities to use ESD to treat EGC in elderly patients are increasing. The objective of this study was to elucidate the safety and efficacy of ESD in elderly patients. PATIENTS AND METHODS: Between April 2006 and March 2013, a total of 892 patients with EGC were prospectively recruited to undergo ESD according to definite inclusion criteria. The short-term outcomes and incidence of complications in 345 of these patients who were 75 years of age or older (elderly group) were compared with the short-term outcomes and incidence of complications in the remaining 547 patients (non-elderly group). Factors associated with the occurrence of pneumonia and delirium were also investigated. RESULTS: The R0 resection rate did not differ between the two groups (96.2 % in the elderly group vs. 96.7 % in the non-elderly group; P = 0.65). The incidence of pneumonia (7.5 % vs. 1.8 %; P < 0.01) and incidence of delirium (10.1 % vs. 1.1 %; P < 0.01) were significantly higher in the elderly group. The incidence of post-ESD bleeding and incidence of perforation were similar in the two groups. No emergency surgery was required, but one patient in the non-elderly group died of aspiration pneumonia. On multivariate analysis, age 75 years or older, cerebrovascular disease, chronic obstructive pulmonary disease, delirium, and remnant stomach or gastric tube were independent risk factors for pneumonia, and age 75 years or older, diabetes, dementia, and pneumonia were independent risk factors for delirium. CONCLUSION: ESD for EGC was feasible for elderly patients in good condition. However, pneumonia and delirium may develop more frequently after ESD in elderly patients with co-morbidities. PMID- 27227109 TI - Gastroscopy-related adverse cardiac events and bleeding complications among patients treated with coronary stents and dual antiplatelet therapy. AB - BACKGROUND AND STUDY AIMS: Dual antiplatelet therapy (DAPT) is recommended following percutaneous coronary intervention (PCI) with drug-eluting stent (DES). DAPT is a risk factor for gastrointestinal bleeding. We aimed to quantify (1) the rate of gastroscopy within 12 months after PCI, (2) the rate of adverse cardiac events and gastroscopy-related bleeding complications within 30 days of gastroscopy, and (3) the association between antiplatelet therapy and these events. PATIENTS AND METHODS: Patients receiving gastroscopy within 12 months of PCI were identified and two nested case-control analyses were performed within the PCI cohort by linking Danish medical registries. Cases were patients with adverse cardiac events (cardiac death, myocardial infarction, or stent thrombosis) or hemostatic intervention. In both studies, controls were patients with gastroscopy including biopsy without adverse cardiac events and hemostatic intervention, respectively. Medical records were reviewed to obtain information on exposure to DAPT. RESULTS: We identified 22 654 PCI patients of whom 1497 patients (6.6 %) underwent gastroscopy. Twenty-two patients (1.5 %) suffered an adverse cardiac event, 93 patients (6.2 %) received hemostatic intervention during or within 30 days of the index gastroscopy. Interrupting DAPT was associated with a 3.46 times higher risk of adverse cardiac events (95 %CI 0.49 - 24.7). Discontinuation of one antiplatelet agent did not increase the risk (OR 0.65, 95 %CI 0.17 - 2.47). No hemostatic interventions were caused by endoscopic complications. CONCLUSION: Gastroscopy can be safely performed in PCI patients treated with DES and single antiplatelet therapy while interruption of DAPT may be associated with an increased risk of adverse cardiac events. PMID- 27227110 TI - Colonoscopy without sedation: Patient factors alone are less likely to influence its uptake. AB - BACKGROUND AND STUDY AIMS: Conscious sedation during colonoscopy minimizes discomfort, improves polyp detection rates, and reduces technical failure, but carries medication-related risks and requires dedicated and costly recovery services. Sedation-free procedures may offer a safer alternative. We aimed to compare this group with those receiving sedation to determine differences in patient characteristics, cecal intubation rates, polyp detection rates, discomfort levels and safety in patients for whom anesthesia is high risk. PATIENTS AND METHODS: Prospectively collected data from all colonoscopies performed over a 1-year period at three district general hospitals were analyzed. Conscious sedation was offered to all patients and outcomes in those who refused were compared with outcomes in those who received sedation. RESULTS: One hundred ninety-four of 1694 (11 %) colonoscopies were performed without sedation (61 % male, P < 0.001) but rates varied between hospitals. Of these, 55 % were American Society of Anesthesiologists (ASA) grade 3 or more and 5 % experienced moderate discomfort, compared to 40 % (P < 0.0001) and 10 % (P = 0.023) respectively of those receiving sedation. They were more likely to have indications of rectal bleeding or frequency of stool and less likely to have anaemia or macroscopic inflammation at colonoscopy. Complications, completion. and polyp detection rates were similar in both groups. CONCLUSIONS: Colonoscopy without sedation can be completed successfully in select patients without compromising comfort or polyp detection rates and is safe in those for whom anesthesia is high risk. It is therefore a safe alternative for clinicians concerned about sedation, but the findings suggest that hospital, rather than patient factors, may prevent its uptake. PMID- 27227111 TI - Pain and sedation during colonoscopy - a never ending story. PMID- 27227112 TI - High definition i-SCAN endoscopy with water immersion technique accurately reflects histological severity of celiac disease. AB - BACKGROUND AND AIMS: Severe villous atrophy can be revealed with conventional white light endoscopy (WLE), however, milder grades or patchy villous atrophy are more difficult to detect. Novel endoscopic techniques such as high definition i SCAN endoscopy with the water immersion technique (i-SCAN-HDWI) may provide the ability to visualize duodenal villi more accurately. We aimed to determine the performance of i-SCAN-HDWI in evaluating the severity of histological damage in the duodenum of patients with celiac disease. PATIENTS AND METHODS: A retrospective cohort study was performed in a single tertiary academic endoscopic center. We studied 58 patients (46 women; median age 36.5 years, range 18 - 72 years) with positive anti-TTG IgA antibody. The villous pattern of the second part of the duodenum was assessed by WLE and i-SCAN-HDWI. The endoscopic grades in both techniques were correlated using Marsh histologic grades by Spearman correlation coefficient. The diagnostic accuracy of i-SCAN-HDWI for detection of patchy or complete atrophy of the villi was evaluated. RESULTS: A significant correlation was demonstrated between endoscopic grade using i-SCAN-HDWI and Marsh histologic grade (r = 0.732; P < 0.00001). The correlation between WLE grade and Marsh histologic grade was inferior to i-SCAN-HDWI (r = 0.31; P = 0.01). The sensitivity of i-SCAN-HDWI was 96 % (95 %CI: 85 - 99 %) and the specificity was 63 % (95 %CI: 26 - 90 %) in diagnosing abnormal biopsy consistent with celiac disease. CONCLUSION: i-SCAN-HDWI endoscopy can reflect the histological severity of celiac disease more accurately than conventional WLE alone. This novel endoscopic imaging can improve the diagnostic yield of duodenal biopsies in celiac patients, especially for those with a patchy distribution of villous damage. PMID- 27227113 TI - Endoscopic evaluation of celiac disease. PMID- 27227114 TI - Endoscopic ablation is a cost-effective cancer preventative therapy in patients with Barrett's esophagus who have elevated genomic instability. AB - BACKGROUND: The surveillance of patients with nondysplastic Barrett's esophagus (NDBE) has a high cost and is of limited effectiveness in preventing esophageal adenocarcinoma (EAC). Ablation for NDBE remains expensive and controversial. Biomarkers of genomic instability have shown promise in identifying patients with NDBE at high risk for progression to EAC. Here, we evaluate the cost effectiveness of using such biomarkers to stratify patients with NDBE by risk for EAC and, subsequently, the cost-effectiveness of ablative therapy. METHODS: A Markov decision tree was used to evaluate four strategies in a hypothetical cohort of 50-year old patients with NDBE over their lifetime: strategy I, natural history without surveillance; strategy II, surveillance per current guidelines; strategy III, ablation for all patients; strategy IV, risk stratification with use of a biomarker panel to assess genomic instability (i. e., mutational load [ML]). Patients with no ML underwent minimal surveillance, patients with low ML underwent standard surveillance, and patients with high ML underwent ablation. The incremental cost-effectiveness ratio (ICER) and incremental net health benefit (INHB) were assessed. RESULTS: Strategy IV provided the best values for quality-adjusted life years (QALYs), ICER, and INHB in comparison with strategies II and III. RESULTS were robust in sensitivity analysis. In a Monte Carlo analysis, the relative risk for the development of cancer in the patients managed with strategy IV was decreased. Critical determinants of strategy IV cost effectiveness were the complete response rate, cost of ablation, and surveillance interval in patients with no ML. CONCLUSION: The use of ML to stratify patients with NDBE by risk was the most cost-effective strategy for preventive EAC treatment. Targeting ablation toward patients with high ML presents an opportunity for a paradigm shift in the management of NDBE. PMID- 27227115 TI - Barium impaction therapy with balloon occlusion for deep colonic diverticular bleeding: a three-case series. AB - BACKGROUND AND AIMS: In hemostasis for colonic diverticular bleeding, the incidence of recurrent bleeding is higher in deep colonic diverticulum than in shallow. We aimed to improve and evaluate barium impaction therapy using an enteroscopic overtube with balloon. PATIENTS AND METHOD: We performed barium impaction therapy in three patients with a diagnosis of deep colonic diverticular bleeding. The tip of the overtube was inserted to reach the cecum using the conventional method. After deflating the colon, the enteroscope was removed. The balloon in the tube was inflated, followed by barium filling via the tube. Sufficient pressure was applied by ensuring no regurgitation into the small intestine side. The entire colon was continuously filled with barium in stages. RESULTS: Post-treatment bleeding was controllable without adverse events in all three patients. CONCLUSION: This novel barium impaction therapy using an enteroscopic overtube with balloon was effectively performed without adverse events. PMID- 27227116 TI - Clinical analysis of moderate-to-deep-sedation by nonmedical sedation practitioners in 597 patients undergoing gastrointestinal endoscopy: a retrospective study. AB - BACKGROUND AND STUDY AIM: The purpose of this study was to evaluate whether moderate-to-deep sedation with propofol and alfentanil can be administered safely by nonmedical sedation practitioners, and the outcomes of this practice in the Netherlands. We retrospectively analyzed the occurrence of sedation-related complications in patients undergoing gastrointestinal endoscopic procedures. PATIENTS AND METHODS: In this study, 597 adult patients consecutively underwent upper gastrointestinal endoscopic procedures. The health status of the patients was screened according to a standardized protocol, and the patients were sedated by trained nonmedical sedation practitioners. Their vital signs were continuously monitored and recorded. All patients received oxygen, and the depth of sedation was continuously assessed and recorded. Mild and severe complications were recorded and analyzed. RESULTS: All patients recovered uneventfully, and no mortality occurred. Overall, of the 597 sedated patients, 85 had mild and 4 had severe complications. Hypoxemia and upper airway obstruction, which were easily managed by trained nonmedical sedation practitioners, were the most common events. Hypotension was rare. No signs or symptoms suggestive of aspiration were reported. CONCLUSION: Moderate-to-deep sedation has been and continues to be a risky medical procedure. Serious complications of propofol/opioid-based sedation, especially respiratory and cardiovascular adverse events, may occur. These complications need to be recognized rapidly and appropriately managed. Our study shows that well-trained nonmedical sedation practitioners can be entrusted to take responsibility for the safe administration of moderate-to-deep sedation. PMID- 27227117 TI - The Polyp Manager: a new tool for optimal polyp documentation during colonoscopy. A pilot study. AB - BACKGROUND AND STUDY AIMS: Conventional reporting of polyps is often incomplete. We tested the Polyp Manager (PM), a new software application permitting the endoscopist to document polyps in real time during colonoscopy. We studied completeness of polyp descriptions, user-friendliness and the potential time benefit. PATIENTS AND METHODS: In two Dutch hospitals colonoscopies were performed with PM (as a touchscreen endoscopist-operated device or nurse-operated desktop application). Completeness of polyp descriptions was compared to a historical group with conventional reporting (CRH). Prospectively, we compared user-friendliness (VAS-scores) and time benefit of the endoscopist-operated PM to conventional reporting (CR) in one hospital. Duration of colonoscopy and time needed to report polyps and provide a pathology request were measured. Provided that using PM does not prolong colonoscopy, the sum of the latter two was considered as a potential time-benefit if the PM were fully integrated into a digital reporting system. RESULTS: A total of 144 regular colonoscopies were included in the study. Both groups were comparable with regard to patient characteristics, duration of colonoscopy and number of polyps. Using the PM did reduce incomplete documentation of the following items in CRH-reports: location (96 % vs 82 %, P = 0.01), size (95 % vs 89 %, P = 0.03), aspect (71 % vs 36 %, P < 0.001) and completeness of removal (61 % vs 37 %, P < 0.001). In the prospective study 23 PM-colonoscopies where compared to 28 CR-colonoscopies. VAS scores were significantly higher in the endoscopist-operated PM group. Time to report was 01:27 +/- 01:43 minutes (median + interquartile range) in the entire group (PM as CR), reflecting potential time benefit per colonoscopy. CONCLUSIONS: The PM is a user-friendly tool that seems to improve completeness of polyp reporting. Once integrated with digital reporting systems, it is probably time saving as well. PMID- 27227118 TI - Learning curve for peroral endoscopic myotomy. AB - BACKGROUND AND STUDY AIMS: Although peroral endoscopic myotomy (POEM) is being performed more frequently, the learning curve for gastroenterologists performing the procedure has not been well studied. The aims of this study were to define the learning curve for POEM and determine which preoperative and intraoperative factors predict the time that will be taken to complete the procedure and its different steps. PATIENTS AND METHODS: Consecutive patients who underwent POEM performed by a single expert gastroenterologist for the treatment of achalasia or spastic esophageal disorders were included. The POEM procedure was divided into four steps: mucosal entry, submucosal tunneling, myotomy, and closure. Nonlinear regression was used to determine the POEM learning plateau and calculate the learning rate. RESULTS: A total of 60 consecutive patients underwent POEM in an endoscopy suite. The median length of procedure (LOP) was 88 minutes (range 36 - 210), and the mean (+/- standard deviation [SD]) LOP per centimeter of myotomy was 9 +/- 5 minutes. The total operative time decreased significantly as experience increased (P < 0.001), with a "learning plateau" at 102 minutes and a "learning rate" of 13 cases. The mucosal entry, tunneling, and closure times decreased significantly with experience (P < 0.001). The myotomy time showed no significant decrease with experience (P = 0.35). When the mean (+/- SD) total procedure times for the learning phase and the corresponding comparator groups were compared, a statistically significant difference was observed between procedures 11 - 15 and procedures 16 - 20 (15.5 +/- 2.4 min/cm and 10.1 +/- 2.7 min/cm, P = 0.01) but not thereafter. A higher case number was significantly associated with a decreased LOP (P < 0.001). CONCLUSION: In this single-center retrospective study, the minimum threshold number of cases required for an expert interventional endoscopist performing POEM to reach a plateau approached 13. PMID- 27227119 TI - Seven cases of upper gastrointestinal bleeding after cold biopsy. AB - BACKGROUND AND STUDY AIMS: Routine biopsy of the upper gastrointestinal tract is performed with increasing frequency. It is generally considered to be safe without significant complication. However, gastrointestinal bleeding as a result of cold biopsy is a known complication. We report seven cases of upper gastrointestinal bleeding after cold biopsy and discuss clinical data, risks factors, severity and management of this event. We suggest that physicians must be more cautious with this rare but potentially severe complication. PMID- 27227120 TI - Cross-sectional small intestinal surveillance of maintenance hemodialysis patients using video capsule endoscopy: SCHEMA study. AB - BACKGROUND AND STUDY AIMS: Small intestinal pathology in hemodialysis (HD) patients has been studied in only a small number of retrospective case series. One method for noninvasively surveying small intestinal disorders is video capsule endoscopy (VCE). The primary aim of this study was to investigate the prevalence of small intestinal abnormalities among asymptomatic maintenance HD outpatients using VCE. The secondary aim was to assess the clinical impact of these abnormalities. PATIENTS AND METHODS: This study consisted of two phases. In phase I, a cross-sectional study, a cohort of patients who received maintenance HD three times weekly at an outpatient hemodialysis clinic were studied using VCE. Phase II was a prospective cohort study with follow up for 1 year after VCE. RESULTS: Fifty-six patients were enrolled in this study, and two were excluded from analysis due to capsule retention in the stomach. The prevalence of small bowel abnormalities in HD patients was 64.8 % (35/54) (95 % confidential interval 52.1 % - 77.6 %). Of 54 patients, 21 (38.9 %) had mucosal lesions, 10 (18.5 %) had vascular lesions, and 4 (7.4 %) had both lesion types. During the 1-year follow-up period, events occurred in four patients. A small bowel-associated event was observed in one patient, who underwent laparoscopy-assisted small intestinal partial resection 3 months after diagnosis by VCE. All patients in whom events were seen had small bowel abnormalities; no events were observed in the VCE-negative group. CONCLUSIONS: Although asymptomatic maintenance HD patients had a high prevalence of small bowel abnormalities (64.8 %), they did not have a high incidence of small bowel-associated events during the 1-year follow-up. PMID- 27227121 TI - Change in gastric emptying eight weeks after endoscopic submucosal dissection in patients with early gastric cancer. AB - BACKGROUND: Gastric emptying after endoscopic submucosal dissection (ESD) for early gastric cancer is not clear. The aim of this study was to evaluate changes in gastric emptying from before ESD to 8 weeks after ESD. METHODS: In total, 54 patients with early gastric cancer were enrolled in this study. A breath test with carbon 13 ((13)C) was conducted before ESD and at 1 and 8 weeks after ESD. The Tlag and T1/2 values were analyzed at each time point. The primary outcomes were the changes in the Tlag and T1/2 values from before ESD to 1 and 8 weeks after ESD. The secondary outcomes were the factors associated with the changes in the Tlag and T1/2 values. RESULTS: Gastric emptying was delayed at 1 and 8 weeks after ESD compared with before ESD (Tlag P = 0.002, P < 0.001; T1/2 P = 0.005, P = 0.001, respectively). The changes in the Tlag and T1/2 values from before ESD to 1 week after ESD were greater for proximal stomach lesions than for distal stomach lesions (P = 0.028, P < 0.001). Proximal stomach lesions were identified as the significant factor that influenced changes in the Tlag and T1/2 values from before ESD to 1 week after ESD in the multivariate analyses (Tlag P = 0.003, T1/2 P = 0.005). CONCLUSIONS: ESD induced delayed gastric emptying until 8 weeks after ESD. Proximal stomach lesions were also associated with decreased emptying 1 week after ESD. PMID- 27227122 TI - Is alcohol required for effective pancreatic cyst ablation? The prospective randomized CHARM trial pilot study. AB - BACKGROUND AND STUDY AIMS: In this study, we aim to determine the safety and feasibility of an alcohol-free approach to pancreatic cyst ablation using a chemotherapeutic ablation cocktail. PATIENTS AND METHODS: In this prospective, randomized, double-blinded pilot study, 10 patients with known mucinous type pancreatic cysts underwent endoscopic ultrasound (EUS)-guided fine needle aspiration and then lavage with either 80 % ethanol or normal saline. Both groups were then treated with a cocktail of paclitaxel and gemcitabine. Primary outcomes were reduction in cyst volume and rates of complications. RESULTS: At 6 months, patients randomized to the alcohol arm had an 89 % average volume reduction, with a 91 % reduction noted in the alcohol-free arm. Complete ablation was achieved in 67 % of patients in the alcohol-free arm at both 6 and 12 months, whereas the alcohol group recorded complete ablation rates of 50 % and 75 % at 6 and 12 months, respectively. One patient in the alcohol arm developed acute pancreatitis (20 %) with no adverse events in the alcohol-free arm. CONCLUSIONS: This study revealed similar ablation rates between the alcohol ablation group and the alcohol-free arm and demonstrates the safety and feasibility of an alcohol-free ablation protocol. This pilot study suggests that alcohol may not be required for effective cyst ablation. PMID- 27227123 TI - First Description of Oral Cryptococcus neoformans Causing Osteomyelitis of the Mandible, Manubrium and Third Rib with Associated Soft Tissue Abscesses in an Immunocompetent Host. AB - The majority of disseminated cryptococcal infections occur in patients with acquired immunodeficiency syndrome (AIDS), with only 11-14% of cases occurring in patients without AIDS. Most non-AIDS related cases (75%) occur in patients with another immune deficiency. Here, we present the first case of mucocutaneous cryptococcal disease in an immunocompetent host, review the epidemiology of risk factors associated with disseminated cryptococcal disease, and describe a rational workup for a possible acquired immunodeficiency. While rare, 25% of non AIDS related cryptococcal disease will occur in individuals without an identifiable immunodeficiency and should prompt a work up for cell-mediated immunodeficiency and monitored for closely for progression of other opportunistic infections. PMID- 27227124 TI - Stories From the Field: The Use of Information and Communication Technologies to Address the Health Needs of Underserved Populations in Latin America and the Caribbean. AB - BACKGROUND: As their availability grew exponentially in the last 20 years, the use of information and communication technologies (ICT) in health has been widely espoused, with many emphasizing their potential to decrease health inequities. Nonetheless, there is scarce availability of information regarding ICT as tools to further equity in health, specifically in Latin American and Caribbean settings. OBJECTIVE: Our aim was to identify initiatives that used ICT to address the health needs of underserved populations in Latin America and Caribbean. Among these projects, explore the rationale behind the selection of ICT as a key component, probe perceptions regarding contributions to health equity, and describe the challenges faced during implementation. METHODS: We conducted an exploratory qualitative study. Interviews were completed via Skype or face-to face meetings using a semistructured interview guide. Following participant consent, interviews were audio recorded and verbatim transcriptions were developed. All transcriptions were coded using ATLASti7 software. The text was analyzed for patterns, shared themes, and diverging opinions. Emerging findings were reviewed by all interviewers and shared with participants for feedback. RESULTS: We interviewed representatives from eight organizations in six Latin American and Caribbean countries that prominently employed ICT in health communication, advocacy, or surveillance projects. ICT expanded project's geographic coverage, increased their reach into marginalized or hard-to-reach groups, and allowed real-time data collection. Perceptions of contributions to health equity resided mainly in the provision of health information and linkage to health services to members of groups experiencing greater morbidity because of poverty, remote place of residence, lack of relevant public programs, and/or stigma and discrimination, and in more timely responses by authorities to the health needs of these groups as a result of the increased availability of strategic information on morbidity and its social determinants. Most projects faced initial resistance to implementation because of lack of precedents. Their financial and technical sustainability was threatened by reliance on external funding and weak transitional structures amidst key staff changes. Projects often experienced challenges in establishing meaningful communication with target audience members, mainly because of divergent motivations behind ICT use between projects and its target audience and the lack of access or familiarity with ICT among the most underserved members of such audiences. CONCLUSIONS: ICT can benefit projects focusing on the health needs of underserved populations by expanding the breadth and depth of target audience coverage and improving data management. Most projects tended to be small, short-term pilot interventions with limited engagement with the formal health sector and did not include health equity as an explicit component. Collaborative projects with government institutions, particularly those with health surveillance objectives, seemed to be the most optimistic about long-term sustainability. PMID- 27227125 TI - The Digital Distribution of Public Health News Surrounding the Human Papillomavirus Vaccination: A Longitudinal Infodemiology Study. AB - BACKGROUND: New media changes the dissemination of public health information and misinformation. During a guest appearance on the Today Show, US Representative Michele Bachmann claimed that human papillomavirus (HPV) vaccines could cause "mental retardation". OBJECTIVE: The purpose of this study is to explore how new media influences the type of public health information users access, as well as the impact to these platforms after a major controversy. Specifically, this study aims to examine the similarities and differences in the dissemination of news articles related to the HPV vaccination between Google News and Twitter, as well as how the content of news changed after Michele Bachmann's controversial comment. METHODS: This study used a purposive sampling to draw the first 100 news articles that appeared on Google News and the first 100 articles that appeared on Twitter from August 1-October 31, 2011. Article tone, source, topics, concerns, references, publication date, and interactive features were coded. The intercoder reliability had a total agreement of .90. RESULTS: Results indicate that 44.0% of the articles (88/200) about the HPV vaccination had a positive tone, 32.5% (65/200) maintained a neutral tone, while 23.5% (47/200) presented a negative tone. Protection against diseases 82.0% (164/200), vaccine eligibility for females 75.5% (151/200), and side effects 59.0% (118/200) were the top three topics covered by these articles. Google News and Twitter articles significantly differed in article tone, source, topics, concerns covered, types of sources referenced in the article, and uses of interactive features. Most notably, topic focus changed from public health information towards political conversation after Bachmann's comment. Before the comment, the HPV vaccine news talked more often about vaccine dosing (P<.001), duration (P=.005), vaccine eligibility for females (P=.03), and protection against diseases (P=.04) than did the later pieces. After the controversy, the news topic shifted towards politics (P=.01) and talked more about HPV vaccine eligibility for males (P=.01). CONCLUSIONS: This longitudinal infodemiology study suggests that new media influences public health communication, knowledge transaction, and poses potential problems in the amount of misinformation disseminated during public health campaigns. In addition, the study calls for more research to adopt an infodemiology approach to explore relationships between online information supply and public health decisions. PMID- 27227126 TI - The Annual American Men's Internet Survey of Behaviors of Men Who Have Sex With Men in the United States: Protocol and Key Indicators Report 2013. AB - BACKGROUND: Men who have sex with men (MSM) are disproportionately affected by human immunodeficiency virus (HIV) and there is evidence that this population is participating in increasingly risky sexual behavior. These changes are occurring in the context of new modes of online social interaction-many MSM now report first meeting their sex partners on the Internet. Better monitoring of key behavioral indicators among MSM requires the use of surveillance strategies that capitalize on these new modes of interaction. Therefore, we developed an annual cross-sectional behavioral survey of MSM in the United States, the American Men's Internet Survey (AMIS). OBJECTIVE: The purpose of this paper was to provide a description of AMIS methods. In addition we report on the first cycle of data collection (December 2013 through May 2014; AMIS-2013) on the same key indicators used for national HIV behavioral surveillance. METHODS: AMIS-2013 recruited MSM from a variety of websites using banner advertisements or email blasts. Adult men currently residing in the United States were eligible to participate if they had ever had sex with a man. We examined demographic and recruitment characteristics using multivariable regression modeling (P<.05) stratified by the participants' self-reported HIV status. RESULTS: In the AMIS-2013 round, 79,635 persons landed on the study page and 14,899 were eligible, resulting in 10,377 completed surveys from MSM representing every US state. Participants were mainly white, 40 years or older, living in the US South, living in urban areas, and recruited from a general social networking website. Self-reported HIV prevalence was 10.73% (n=1113). Compared to HIV-negative/unknown status participants, HIV-positive participants were more likely to have had anal sex without a condom with any male partner in the past 12 months (72.24% versus 61.24%, respectively; P<.001) and more likely to have had anal sex without a condom with their last male sex partner who was discordant/unknown HIV status (42.95% versus 13.62%, respectively; P<.001). Illicit substance use in the past 12 months was more likely to be reported by HIV-positive participants than HIV-negative/unknown status participants (39.17% versus 26.85%, respectively; P<.001). The vast majority of HIV-negative/unknown status participants (84.05%) had been previously HIV tested, but less than half (44.20%) had been tested in the past 12 months. Participants 18-24 years of age were more likely than those 40 years or older to have had anal sex without a condom with a discordant/unknown HIV status partner, were more likely to report substance use, and were less likely to have been HIV tested. Compared to general social networking, those from a geospatial social networking website were more likely to have reported all risk behaviors but were more likely to have been HIV tested. CONCLUSIONS: The first round of AMIS generated useful behavioral measures from more than 10,000 MSM Internet users. Preliminary findings identified some subgroups of MSM Internet users that are at potentially higher risk of HIV acquisition/transmission. AMIS will provide an ongoing data source for examining trends in sexual risk behavior of MSM. This will help to plan and monitor the impact of programs to improve this population's health. PMID- 27227127 TI - Geosocial-Networking App Usage Patterns of Gay, Bisexual, and Other Men Who Have Sex With Men: Survey Among Users of Grindr, A Mobile Dating App. AB - BACKGROUND: Geosocial-networking apps like Grindr have been used increasingly among men who have sex with men (MSM) to meet anonymous partners. These mobile dating apps employ global positioning system technology to facilitate connections with other users based on their current location. These new technologies have generated quicker and easier modes for men who have sex with men to meet potential partners based on attraction and physical proximity. OBJECTIVE: The aim of this study is to describe geosocial-networking app use and recent sexual behaviors of MSM in the Atlanta metropolitan statistical area. METHODS: Our sample was recruited from Grindr, the most commonly used of these mobile apps among MSM, using broadcast advertising. Advertisements were displayed over the course of a 72-hour period and participants were directed to a Web-based survey. RESULTS: In total, 604 men clicked through the advertisement, and 92 users completed the survey. One-third (38.0%) of the men reported using these mobile apps to meet new sexual partners, and one-fifth (18.5%) used them to "kill time" when bored. Men reporting currently being in a relationship were less likely to report using these mobile apps to meet other MSM to date or to find a boyfriend or romantic partner, but more likely to report using these mobile apps to meet other MSM to have sex, X (2) 24=12.1, P=.016. Respondents had current accounts on 3.11 mobile apps (SD 1.84) on average, with Grindr being the most common (100%), followed by Scruff (52.5%), and Jack'd (45.7%). Most men were most active in the late night (40.2%), and on weekdays (64.1%). Each day, on average, men reported opening these mobile apps 8.38 times (SD 8.10) and spent 1.31 hours (SD 1.15) on these mobile apps. The age respondents began using these mobile apps was associated with the age at their first instance of insertive anal sex (r80=.527, P<.001) and receptive anal sex (r76=.527, P<.001). CONCLUSIONS: These findings suggest that MSM use multiple mobile apps and spend significant time on them. For these reasons, HIV prevention interventions could be delivered on these mobile apps. PMID- 27227128 TI - The Effect of Commuting Patterns on HIV Care Attendance Among Men Who Have Sex With Men (MSM) in Atlanta, Georgia. AB - BACKGROUND: Travel-related barriers to human immunodeficiency virus (HIV) care, such as commute time and mode of transportation, have been reported in the United States. OBJECTIVE: The objective of the study was to investigate the association between public transportation use and HIV care attendance among a convenience sample of Atlanta-based, HIV-positive men who have sex with men (MSM), evaluate differences across regions of residence, and estimate the relationship between travel distance and time by mode of transportation taken to attend appointments. METHODS: We used Poisson regression to estimate the association between use of public transportation to attend HIV-related medical visits and frequency of care attendance over the previous 12 months. The relationship between travel distance and commute time was estimated using linear regression. Kriging was used to interpolate commute time to visually examine geographic differences in commuting patterns in relation to access to public transportation and population-based estimates of household vehicle ownership. RESULTS: Using public transportation was associated with lower rates of HIV care attendance compared to using private transportation, but only in south Atlanta (south: aRR: 0.75, 95% CI 0.56, 1.0, north: aRR: 0.90, 95% CI 0.71, 1.1). Participants living in south Atlanta were more likely to have longer commute times associated with attending HIV visits, have greater access to public transportation, and may live in areas with low vehicle ownership. A majority of attended HIV providers were located in north and central Atlanta, despite there being participants living all across the city. Estimated commute times per mile traveled were three times as high among public transit users compared to private transportation users. CONCLUSIONS: Improving local public transit and implementing use of mobile clinics could help address travel-related barriers to HIV care. PMID- 27227129 TI - Electronic Cigarette Marketing Online: a Multi-Site, Multi-Product Comparison. AB - BACKGROUND: Electronic cigarette awareness and use has been increasing rapidly. E cigarette brands have utilized social networking sites to promote their products, as the growth of the e-cigarette industry has paralleled that of Web 2.0. These online platforms are cost-effective and have unique technological features and user demographics that can be attractive for selective marketing. The popularity of multiple sites also poses a risk of exposure to social networks where e cigarette brands might not have a presence. OBJECTIVE: To examine the marketing strategies of leading e-cigarette brands on multiple social networking sites, and to identify how affordances of the digital media are used to their advantage. Secondary analyses include determining if any brands are benefitting from site demographics, and exploring cross-site diffusion of marketing content through multi-site users. METHODS: We collected data from two e-cigarette brands from four social networking sites over approximately 2.5 years. Content analysis is used to search for themes, population targeting, marketing strategies, and cross site spread of messages. RESULTS: Twitter appeared to be the most frequently used social networking site for interacting directly with product users. Facebook supported informational broadcasts, such as announcements regarding political legislation. E-cigarette brands also differed in their approaches to their users, from informal conversations to direct product marketing. CONCLUSIONS: E-cigarette makers use different strategies to market their product and engage their users. There was no evidence of direct targeting of vulnerable populations, but the affordances of the different sites are exploited to best broadcast context specific messages. We developed a viable method to study cross-site diffusion, although additional refinement is needed to account for how different types of digital media are used. PMID- 27227130 TI - Texting-Based Reporting of Adverse Drug Reactions to Ensure Patient Safety: A Feasibility Study. AB - BACKGROUND: Paper-based adverse drug reaction (ADR) reporting has been in practice for more than 6 decades. Health professionals remain the primary source of reports, while the value of patients' reporting is yet unclear. With the increasing popularity of using electronic gadgets in health, it is expected that the electronic transmission of reports will become the norm within a few years. OBJECTIVE: The aims of this study are to investigate whether short messaging service or texting can provide an alternative or supplemental method for ADR reporting given the increasing role of mobile phones in health care monitoring; to determine the usefulness of texting in addition to paper-based reporting of ADRs by resident physicians; and to describe the barriers to ADR reporting and estimate the cost for setting up and maintaining a texting-computer reporting system. METHODS: This was a pre-post cross-sectional study that measured the number of ADRs texted by 51 resident physicians for 12 months from the Department of Obstetrics and Gynecology and the Department of Adult Medicine of a tertiary government hospital in Manila, Philippines, with 1350-bed capacity. Reports were captured by a texting-computer reporting system. Prior to its implementation, key informant interview and focus group discussion were conducted. Baseline information and practice on the existing paper-based reporting system were culled from the records of the hospital's Pharmacy and Therapeutics Committee. A postintervention survey questionnaire was administered at the end of 12 months. RESULTS: Only 3 ADRs were texted by 51 resident physicians in 12 months (reporting rate 3/51 or 6%). By contrast, 240 ADRs from the paper-based reporting system from 848 resident physicians of the study hospital were collected and tabulated (reporting rate 240/848 or 28.3%). Texting ADRs was not efficient because of power interruption, competition with the existing paper-based reporting system, and unforeseen expiration of prepaid text loads/credits. The 3 ADRs texted were a report of vivid dreams and nightmares, a report of disturbing dreams and memory lapses, both of which were due to montelukast use, and a report of hepatitis from an isoniazid/rifampicin fixed-dose combination. Nineteen of 51 resident physicians (37%) registered in the reporting system responded to the postintervention survey. The most common reasons for not reporting ADRs were no adverse reaction identified 11/19 (58%) and restrictive reporting syntax 4/19 (21%). All doctors preferred a free form of reporting. The direct cost of the texting-based reporting system was calculated to be US $5581.40 and the indirect cost was US $9989.40. The total cost for texting-based ADR reporting system for 12 months was US $15,570.79. CONCLUSIONS: Reporting of ADRs via texting could be lower compared with an existing ADR paper-based system. Problems of Internet connectivity, reporting syntax, and expiration and reliability of text loads/credits should be addressed while implementing a text-based ADR reporting system in a developing country. PMID- 27227132 TI - A Comparison of Self-Reported and Objective Physical Activity Measures in Young Australian Women. AB - BACKGROUND: The evidence for beneficial effects of recommended levels of physical activity is overwhelming. However, 70% of Australians fail to meet these levels. In particular, physical activity participation by women falls sharply between ages 16 to 25 years. Further information about physical activity measures in young women is needed. Self-administered questionnaires are often used to measure physical activity given their ease of application, but known limitations, including recall bias, compromise the accuracy of data. Alternatives such as objective measures are commonly used to overcome this problem, but are more costly and time consuming. OBJECTIVE: To compare the output between the Modified Active Australia Survey (MAAS), the International Physical Activity Questionnaire (IPAQ), and an objective physical activity measure-the SenseWear Armband (SWA)-to evaluate the test-retest reliability of the MAAS and to determine the acceptability of the SWA among young women. METHODS: Young women from Victoria, Australia, aged 18 to 25 years who had participated in previous studies via Facebook advertising were recruited. Participants completed the two physical activity questionnaires online, immediately before and after wearing the armband for 7 consecutive days. Data from the SWA was blocked into 10-minute activity times. Follow-up IPAQ, MAAS, and SWA data were analyzed by comparing the total continuous and categorical activity scores, while concurrent validity of IPAQ and MAAS were analyzed by comparing follow-up scores. Test-retest reliability of MAAS was analyzed by comparing MAAS total physical activity scores at baseline and follow-up. Participants provided feedback in the follow-up questionnaire about their experience of wearing the armband to determine acceptability of the SWA. Data analyses included graphical (ie, Bland-Altman plot, scatterplot) and analytical (ie, canonical correlation, kappa statistic) methods to determine agreement between MAAS, IPAQ, and SWA data. RESULTS: A total of 58 participants returned complete data. Comparisons between the MAAS and IPAQ questionnaires (n=52) showed moderate agreement for both categorical (kappa=.48, P<.001) and continuous data (r=.69, P<.001). Overall, the IPAQ tended to give higher scores. No significant correlation was observed between SWA and IPAQ or MAAS continuous data, for both minute-by-minute and blocked SWA data. The SWA tended to record lower scores than the questionnaires, suggesting participants tended to overreport their amount of physical activity. The test-retest analysis of MAAS showed moderate agreement for continuous outcomes (r=.44, P=.001). However, poor agreement was seen for categorical outcomes. The acceptability of the SWA to participants was high. CONCLUSIONS: Moderate agreement between the MAAS and IPAQ and moderate reliability of the MAAS indicates that the MAAS may be a suitable alternative to the IPAQ to assess total physical activity in young women, due to its shorter length and consequently lower participant burden. The SWA, and likely other monitoring devices, have the advantage over questionnaires of avoiding overreporting of self-reported physical activity, while being highly acceptable to participants. PMID- 27227131 TI - Patient-Reported Outcomes and Total Health Care Expenditure in Prediction of Patient Satisfaction: Results From a National Study. AB - BACKGROUND: Health care quality is often linked to patient satisfaction. Yet, there is a lack of national studies examining the relationship between patient satisfaction, patient-reported outcomes, and medical expenditure. OBJECTIVE: The aim of this study is to examine the contribution of physical health, mental health, general health, and total health care expenditures to patient satisfaction using a longitudinal, nationally representative sample. METHODS: Using data from the 2010-2011 Medical Expenditure Panel Survey, analyses were conducted to predict patient satisfaction from patient-reported outcomes and total health care expenditures. The study sample consisted of adult participants (N=10,157), with sampling weights representative of 233.26 million people in the United States. RESULTS: The results indicated that patient-reported outcomes and total health care expenditure were associated with patient satisfaction such that higher physical and mental function, higher general health status, and higher total health care expenditure were associated with higher patient satisfaction. CONCLUSIONS: We found that patient-reported outcomes and total health care expenditure had a significant relationship with patient satisfaction. As more emphasis is placed on health care value and quality, this area of research will become increasingly needed and critical questions should be asked about what we value in health care and whether we can find a balance between patient satisfaction, outcomes, and expenditures. Future research should apply big data analytics to investigate whether there is a differential effect of patient reported outcomes and medical expenditures on patient satisfaction across different medical specialties. PMID- 27227133 TI - The US National Tuberculosis Surveillance System: A Descriptive Assessment of the Completeness and Consistency of Data Reported from 2008 to 2012. AB - BACKGROUND: In 2009, the Tuberculosis (TB) Information Management System transitioned into the National TB Surveillance System to allow use of 4 different types of electronic reporting schemes: state-built, commercial, and 2 schemes developed by the Centers for Disease Control and Prevention. Simultaneously, the reporting form was revised to include additional data fields. OBJECTIVE: Describe data completeness for the years 2008-2012 and determine the impact of surveillance changes. METHODS: Data were categorized into subgroups and assessed for completeness (eg, the percentage of patients dead at diagnosis who had a date of death reported) and consistency (eg, the percentage of patients alive at diagnosis who erroneously had a date of death reported). Reporting jurisdictions were grouped to examine differences by reporting scheme. RESULTS: Each year less than 1% of reported cases had missing information for country of origin, race, or ethnicity. Patients reported as dead at diagnosis had death date (a new data field) missing for 3.6% in 2009 and 4.4% in 2012. From 2010 to 2012, 313 cases (1%) reported as alive at diagnosis had a death date and all of these were reported through state-built or commercial systems. The completeness of reporting for guardian country of birth for pediatric patients (a new data field) ranged from 84% in 2009 to 88.2% in 2011. CONCLUSIONS: Despite major changes, completeness has remained high for most data elements in TB surveillance. However, some data fields introduced in 2009 remain incomplete; continued training is needed to improve national TB surveillance data. PMID- 27227134 TI - An Integrated Service Delivery Model to Identify Persons Living with HIV and to Provide Linkage to HIV Treatment and Care in Prioritized Neighborhoods: A Geotargeted, Program Outcome Study. AB - BACKGROUND: Recent studies have demonstrated that high human immunodeficiency virus (HIV) prevalence (2.1%) rates exist in "high-risk areas" of US cities that are comparable to rates in developing nations. Community-based interventions (CBIs) have demonstrated potential for improving HIV testing in these areas, thereby facilitating early entry and engagement in the HIV continuum of care. By encouraging neighborhood-based community participation through an organized community coalition, Project LINK sought to demonstrate the potential of the CBI concept to improve widespread HIV testing and referral in an area characterized by high poverty and HIV prevalence with few existing HIV-related services. OBJECTIVE: This study examines the influence of Project LINK to improve linkage to-care and HIV engagement among residents of its target neighborhoods. METHODS: Using a venue-based sampling strategy, survey participants were selected from among all adult participants aged 18 years or more at Project LINK community events (n=547). We explored multilevel factors influencing continuum-of-care outcomes (linkage to HIV testing and CBI network referral) through combined geospatial-survey analyses utilizing hierarchical linear model methodologies and random-intercept models that adjusted for baseline effect differences among zip codes. The study specifically examined participant CBI utilization and engagement in relation to individual and psychosocial factors, as well as neighborhood characteristics including the availability of HIV testing services, and the extent of local prevention, education, and clinical support services. RESULTS: Study participants indicated strong mean intention to test for HIV using CBI agencies (mean 8.66 on 10-point scale [SD 2.51]) and to facilitate referrals to the program (mean 8.81 on 10-point scale [SD 1.86]). Individual-level effects were consistent across simple multiple regression and random-effects models, as well as multilevel models. Participants with lower income expressed greater intentions to obtain HIV tests through LINK (P<.01 across models). HIV testing and CBI referral intention were associated with neighborhood-level factors, including reduced availability of support services (testing P<.001), greater proportion of black/African Americans (testing and referral P<.001), and reduced socioeconomic capital (testing P=.017 and referral P<.001). Across models, participants expressing positive attitudes toward the CBI exhibited greater likelihood of engaging in routine HIV testing (P<.01) and referring others to HIV care (P<.01). Transgender individuals indicated greater intent to refer others to the CBI (P<.05). These outcomes were broadly influenced by distal community-level factors including availability of neighborhood HIV support organizations, population composition socioeconomic status, and high HIV prevalence. CONCLUSIONS: Project LINK demonstrated its potential as a geotargeted CBI by evidencing greater individual intention to engage in HIV testing, care, and personal referrals to its coalition partner organizations. This study highlights important socioecological effects of US-based CBIs to improve HIV testing and initiate acceptable mechanisms for prompt referral to care among a vulnerable population. PMID- 27227135 TI - Machine Translation of Public Health Materials From English to Chinese: A Feasibility Study. AB - BACKGROUND: Chinese is the second most common language spoken by limited English proficiency individuals in the United States, yet there are few public health materials available in Chinese. Previous studies have indicated that use of machine translation plus postediting by bilingual translators generated quality translations in a lower time and at a lower cost than human translations. OBJECTIVE: The purpose of this study was to investigate the feasibility of using machine translation (MT) tools (eg, Google Translate) followed by human postediting (PE) to produce quality Chinese translations of public health materials. METHODS: From state and national public health websites, we collected 60 health promotion documents that had been translated from English to Chinese through human translation. The English version of the documents were then translated to Chinese using Google Translate. The MTs were analyzed for translation errors. A subset of the MT documents was postedited by native Chinese speakers with health backgrounds. Postediting time was measured. Postedited versions were then blindly compared against human translations by bilingual native Chinese quality raters. RESULTS: The most common machine translation errors were errors of word sense (40%) and word order (22%). Posteditors corrected the MTs at a rate of approximately 41 characters per minute. Raters, blinded to the source of translation, consistently selected the human translation over the MT+PE. Initial investigation to determine the reasons for the lower quality of MT+PE indicate that poor MT quality, lack of posteditor expertise, and insufficient posteditor instructions can be barriers to producing quality Chinese translations. CONCLUSIONS: Our results revealed problems with using MT tools plus human postediting for translating public health materials from English to Chinese. Additional work is needed to improve MT and to carefully design postediting processes before the MT+PE approach can be used routinely in public health practice for a variety of language pairs. PMID- 27227136 TI - Building a Mobile HIV Prevention App for Men Who Have Sex With Men: An Iterative and Community-Driven Process. AB - BACKGROUND: Gay, bisexual, and other men who have sex with men (MSM) account for a disproportionate burden of new HIV infections in the United States. Mobile technology presents an opportunity for innovative interventions for HIV prevention. Some HIV prevention apps currently exist; however, it is challenging to encourage users to download these apps and use them regularly. An iterative research process that centers on the community's needs and preferences may increase the uptake, adherence, and ultimate effectiveness of mobile apps for HIV prevention. OBJECTIVE: The aim of this paper is to provide a case study to illustrate how an iterative community approach to a mobile HIV prevention app can lead to changes in app content to appropriately address the needs and the desires of the target community. METHODS: In this three-phase study, we conducted focus group discussions (FGDs) with MSM and HIV testing counselors in Atlanta, Seattle, and US rural regions to learn preferences for building a mobile HIV prevention app. We used data from these groups to build a beta version of the app and theater tested it in additional FGDs. A thematic data analysis examined how this approach addressed preferences and concerns expressed by the participants. RESULTS: There was an increased willingness to use the app during theater testing than during the first phase of FGDs. Many concerns that were identified in phase one (eg, disagreements about reminders for HIV testing, concerns about app privacy) were considered in building the beta version. Participants perceived these features as strengths during theater testing. However, some disagreements were still present, especially regarding the tone and language of the app. CONCLUSIONS: These findings highlight the benefits of using an interactive and community-driven process to collect data on app preferences when building a mobile HIV prevention app. Through this process, we learned how to be inclusive of the larger MSM population without marginalizing some app users. Though some issues in phase one were able to be addressed, disagreements still occurred in theater testing. If the app is going to address a large and diverse risk group, we cannot include niche functionality that may offend some of the target population. PMID- 27227137 TI - Tracking Hookah Bars in New York: Utilizing Yelp as a Powerful Public Health Tool. AB - BACKGROUND: While cigarette use has seen a steady decline in recent years, hookah (water pipe) use has rapidly increased in popularity. While anecdotal reports have noted a rise in hookah bars, methodological difficulties have prevented researchers from drawing definitive conclusions about the number of hookah bars in any given location. There is no publicly available database that has been shown to reliably provide this information. It is now possible to analyze Internet trends as a measure of population behavior and health-related phenomena. OBJECTIVE: The objective of the study was to investigate whether Yelp can be used to accurately identify the number of hookah bars in New York State, assess the distribution and characteristics of hookah bars, and monitor temporal trends in their presence. METHODS: Data were obtained from Yelp that captures a variety of parameters for every business listed in their database as of October 28, 2014, that was tagged as a "hookah bar" and operating in New York State. Two algebraic models were created: one estimated the date of opening of a hookah bar based on the first Yelp review received and the other estimated whether the bar was open or closed based on the date of the most recent Yelp review. These findings were then compared with empirical data obtained by Internet searches. RESULTS: From 2014 onward, the date of the first Yelp review predicts the opening date of new hookah bars to within 1 month. Yelp data allow the estimate of such venues and demonstrate that new bars are not randomly distributed, but instead are clustered near colleges and in specific racial/ethnic neighborhoods. New York has seen substantially more new hookah bars in 2012-2014 compared with the number that existed prior to 2009. CONCLUSIONS: Yelp is a powerful public health tool that allows for the investigation of various trends and characteristics of hookah bars. New York is experiencing tremendous growth in hookah bars, a worrying phenomenon that necessitates further investigation. PMID- 27227138 TI - Implementation of a Multimodal Mobile System for Point-of-Sale Surveillance: Lessons Learned From Case Studies in Washington, DC, and New York City. AB - BACKGROUND: In tobacco control and other fields, point-of-sale surveillance of the retail environment is critical for understanding industry marketing of products and informing public health practice. Innovations in mobile technology can improve existing, paper-based surveillance methods, yet few studies describe in detail how to operationalize the use of technology in public health surveillance. OBJECTIVE: The aims of this paper are to share implementation strategies and lessons learned from 2 tobacco, point-of-sale surveillance projects to inform and prepare public health researchers and practitioners to implement new mobile technologies in retail point-of-sale surveillance systems. METHODS: From 2011 to 2013, 2 point-of-sale surveillance pilot projects were conducted in Washington, DC, and New York, New York, to capture information about the tobacco retail environment and test the feasibility of a multimodal mobile data collection system, which included capabilities for audio or video recording data, electronic photographs, electronic location data, and a centralized back end server and dashboard. We established a preimplementation field testing process for both projects, which involved a series of rapid and iterative tests to inform decisions and establish protocols around key components of the project. RESULTS: Important components of field testing included choosing a mobile phone that met project criteria, establishing an efficient workflow and accessible user interfaces for each component of the system, training and providing technical support to fieldworkers, and developing processes to integrate data from multiple sources into back-end systems that can be utilized in real-time. CONCLUSIONS: A well-planned implementation process is critical for successful use and performance of multimodal mobile surveillance systems. Guidelines for implementation include (1) the need to establish and allow time for an iterative testing framework for resolving technical and logistical challenges; (2) developing a streamlined workflow and user-friendly interfaces for data collection; (3) allowing for ongoing communication, feedback, and technology related skill-building among all staff; and (4) supporting infrastructure for back-end data systems. Although mobile technologies are evolving rapidly, lessons learned from these case studies are essential for ensuring that the many benefits of new mobile systems for rapid point-of-sale surveillance are fully realized. PMID- 27227139 TI - Agenda Setting for Health Promotion: Exploring an Adapted Model for the Social Media Era. AB - BACKGROUND: The foundation of best practice in health promotion is a robust theoretical base that informs design, implementation, and evaluation of interventions that promote the public's health. This study provides a novel contribution to health promotion through the adaptation of the agenda-setting approach in response to the contribution of social media. This exploration and proposed adaptation is derived from a study that examined the effectiveness of Twitter in influencing agenda setting among users in relation to road traffic accidents in Saudi Arabia. OBJECTIVE: The proposed adaptations to the agenda setting model to be explored reflect two levels of engagement: agenda setting within the social media sphere and the position of social media within classic agenda setting. This exploratory research aims to assess the veracity of the proposed adaptations on the basis of the hypotheses developed to test these two levels of engagement. METHODS: To validate the hypotheses, we collected and analyzed data from two primary sources: Twitter activities and Saudi national newspapers. Keyword mentions served as indicators of agenda promotion; for Twitter, interactions were used to measure the process of agenda setting within the platform. The Twitter final dataset comprised 59,046 tweets and 38,066 users who contributed by tweeting, replying, or retweeting. Variables were collected for each tweet and user. In addition, 518 keyword mentions were recorded from six popular Saudi national newspapers. RESULTS: The results showed significant ratification of the study hypotheses at both levels of engagement that framed the proposed adaptions. The results indicate that social media facilitates the contribution of individuals in influencing agendas (individual users accounted for 76.29%, 67.79%, and 96.16% of retweet impressions, total impressions, and amplification multipliers, respectively), a component missing from traditional constructions of agenda-setting models. The influence of organizations on agenda setting is also highlighted (in the data of user interactions, organizational accounts registered 17% and 14.74% as source and target of interactions, respectively). In addition, 13 striking similarities showed the relationship between newspapers and Twitter on the mentions trends line. CONCLUSIONS: The effective use of social media platforms in health promotion intervention programs requires new strategies that consider the limitations of traditional communication channels. Conducting research is vital to establishing a strong basis for modifying, designing, and developing new health promotion strategies and approaches. PMID- 27227140 TI - Direct-to-Patient Research: Piloting a New Approach to Understanding Drug Safety During Pregnancy. AB - BACKGROUND: Little is known about the effects of human fetal exposure when a new drug is authorized unless it was specifically developed for use in pregnancy. Since many factors may contribute to adverse fetal effects, having comprehensive information about in utero exposures will enhance our ability to make correct determinations about causality. OBJECTIVE: The objective of the study was to assess the extent to which women, recruited without the intervention of health care professionals (HCPs), will provide information, suitable for research purposes, via the Internet or by phone on some potential risk factors in pregnancy. METHODS: To pilot direct-to-patient research for pharmacovigilance, we conducted a prospective, noninterventional study of medication use and lifestyle factors as part of the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) Consortium. Consenting women who self-identified as pregnant and residing in the United Kingdom (UK), Denmark (DK), The Netherlands, or Poland were recruited and could then choose to provide data every 2 or 4 weeks via the Internet or a telephonic interactive voice response system (IVRS). Self-reported drug use was compared with pharmacy register data in DK and with electronic health records in the UK. RESULTS: Recruited women were on average older and more highly educated than the general population. Most respondents chose a frequency of every 4 weeks (56.99%, 1177/2065). Only 29.83% (464/1555) of women with due dates occurring during the study provided information on pregnancy outcome. For those responding by Internet, over 90.00% (1915/2065) reported using >1 pregnancy-related medication, 83.34% (1721/2065) reported using >1 other medicine, and 23.53% (486/2065) reported only over-the-counter medications, not counting herbals and dietary supplements. Some respondents (7.16%, 148/2065) reported that they chose not to take a prescribed medication (mostly medicines for pain or inflammation, and for depression) and 1.30% (27/2065) reported using medicines that had been prescribed to a friend or family member (oxycodone, paracetamol, and medications for acid related problems). Relatively few respondents reported using fish oil (4.60%, 95/2065), other dietary supplements (1.88%, 39/2065), herbal products (7.07%, 146/2065), or homeopathic products (1.16%, 24/2065). Most medications for chronic conditions that were listed in the Danish prescription registry were also self reported (83.3%, 145/174 agreement), with larger discrepancies for medications indicated for short-term use (54.0%, 153/283 agreement) and pregnancy-related medications (66.1%, 78/118). CONCLUSIONS: Self-reported information on medication use as well as other potential teratogenic factors can be collected via the Internet, although recruitment costs are not insubstantial and maintaining follow up is challenging. Direct data collection from consumers adds detail, but clinical input may be needed to fully understand patients' medical histories and capture birth outcomes. PMID- 27227141 TI - Identifying Adverse Effects of HIV Drug Treatment and Associated Sentiments Using Twitter. AB - BACKGROUND: Social media platforms are increasingly seen as a source of data on a wide range of health issues. Twitter is of particular interest for public health surveillance because of its public nature. However, the very public nature of social media platforms such as Twitter may act as a barrier to public health surveillance, as people may be reluctant to publicly disclose information about their health. This is of particular concern in the context of diseases that are associated with a certain degree of stigma, such as HIV/AIDS. OBJECTIVE: The objective of the study is to assess whether adverse effects of HIV drug treatment and associated sentiments can be determined using publicly available data from social media. METHODS: We describe a combined approach of machine learning and crowdsourced human assessment to identify adverse effects of HIV drug treatment solely on individual reports posted publicly on Twitter. Starting from a large dataset of 40 million tweets collected over three years, we identify a very small subset (1642; 0.004%) of individual reports describing personal experiences with HIV drug treatment. RESULTS: Despite the small size of the extracted final dataset, the summary representation of adverse effects attributed to specific drugs, or drug combinations, accurately captures well-recognized toxicities. In addition, the data allowed us to discriminate across specific drug compounds, to identify preferred drugs over time, and to capture novel events such as the availability of preexposure prophylaxis. CONCLUSIONS: The effect of limited data sharing due to the public nature of the data can be partially offset by the large number of people sharing data in the first place, an observation that may play a key role in digital epidemiology in general. PMID- 27227142 TI - The Tobacco Pack Surveillance System: A Protocol for Assessing Health Warning Compliance, Design Features, and Appeals of Tobacco Packs Sold in Low- and Middle Income Countries. AB - BACKGROUND: Tobacco remains the world's leading preventable cause of death, with the majority of tobacco-caused deaths occurring in low- and middle-income countries. The first global health treaty, the Framework Convention on Tobacco Control (FCTC), outlines a set of policy initiatives that have been demonstrated as effective in reducing tobacco use. Article 11 of the FCTC focuses on using the tobacco package to communicate tobacco-caused harms; it also seeks to restrict the delivery of misleading information about the product on the pack. OBJECTIVE: The objective of this study was to establish a surveillance system for tobacco packs in the 14 low- and middle-income countries with the greatest number of smokers. The Tobacco Pack Surveillance System (TPackSS) monitors whether required health warnings on tobacco packages are being implemented as intended, and identifies pack designs and appeals that might violate or detract from the communication of harm-related information and undermine the impact of a country's tobacco packaging laws. The protocol outlined is intended to be applicable or adaptable for surveillance efforts in other countries. METHODS: Tobacco packs were collected in 14 countries during 2013. The intention was, to the extent possible, to construct a census of "unique" pack presentations available for purchase in each country. The TPackSS team partnered with in-country field staff to implement a standardized protocol for acquiring packs from 36 diverse neighborhoods across three cities in each country. At the time of purchase, data on price and place of acquisition of each pack was recorded. The field staff, according to a standardized protocol, then photographed packs before they were shipped to the United States for coding and archiving. RESULTS: Each pack was coded for compliance with the country-specific health warning label laws, as well as for key design features of the pack and appeals of the branding elements. The coding protocols were developed based upon prior research, expert opinion, and communication theories. Each pack was coded by two independent coders, with consistency of personnel across the project. We routinely measured intercoder reliability, and only retained variables for which a good level of reliability was achieved. Variables where reliability was too low were not included in final analyses, and any inconsistencies in coding were resolved on a daily basis. CONCLUSIONS: Across the 14 countries, the TPackSS team collected 3307 tobacco packs. We have established a publicly accessible, Internet archive of these packs that is intended for use by the tobacco control policy advocacy and research community. PMID- 27227143 TI - A Qualitative Examination of Respondent-Driven Sampling (RDS) Peer Referral Challenges Among Young Transwomen in the San Francisco Bay Area. AB - BACKGROUND: Efforts have focused on developing innovative recruitment strategies to engage the most marginalized of populations in public health research. Respondent-driven sampling (RDS) has been found to be an effective sampling strategy for hard-to-reach, hidden populations. Though studies have documented RDS peer referral as challenging, literature contextualizing these challenges is scant and rarely do they discuss the role of Internet technologies. OBJECTIVE: The objective of the study was to explore reasons for peer referral challenges in a human immunodeficiency virus (HIV) risk and resilience study among a hidden population of youth, specifically, young transwomen. These findings amplify the unique opportunities Internet technologies bring to public health research and methodology. METHODS: We conducted focused, semistructured, qualitative interviews with 16 young transwomen to investigate the reasons why youth did or did not refer peers to an RDS study for transwomen ages 16-24 in the San Francisco Bay Area. Qualitative interview data were coded and analyzed using grounded theory. RESULTS: Participants discussed specific barriers and facilitators related to four factors that include study design, study implementation, community characteristics, and individual characteristics, which contributed to RDS peer referral challenges. CONCLUSIONS: Our grounded theory analysis identifies important considerations for future RDS studies with hidden youth populations. Exploring research participants' experiences is integral in strengthening future epidemiologic research efforts that plan to use RDS to sample and estimate the hidden epidemics among at-risk youth and transgender women. Additionally, Internet technologies and Web-based adaptations offer solutions to traditional RDS peer referral challenges, having the potential to increase accessibility and use among hidden youth populations. PMID- 27227144 TI - The Measles Vaccination Narrative in Twitter: A Quantitative Analysis. AB - BACKGROUND: The emergence of social media is providing an alternative avenue for information exchange and opinion formation on health-related issues. Collective discourse in such media leads to the formation of a complex narrative, conveying public views and perceptions. OBJECTIVE: This paper presents a study of Twitter narrative regarding vaccination in the aftermath of the 2015 measles outbreak, both in terms of its cyber and physical characteristics. We aimed to contribute to the analysis of the data, as well as presenting a quantitative interdisciplinary approach to analyze such open-source data in the context of health narratives. METHODS: We collected 669,136 tweets referring to vaccination from February 1 to March 9, 2015. These tweets were analyzed to identify key terms, connections among such terms, retweet patterns, the structure of the narrative, and connections to the geographical space. RESULTS: The data analysis captures the anatomy of the themes and relations that make up the discussion about vaccination in Twitter. The results highlight the higher impact of stories contributed by news organizations compared to direct tweets by health organizations in communicating health-related information. They also capture the structure of the antivaccination narrative and its terms of reference. Analysis also revealed the relationship between community engagement in Twitter and state policies regarding child vaccination. Residents of Vermont and Oregon, the two states with the highest rates of non-medical exemption from school-entry vaccines nationwide, are leading the social media discussion in terms of participation. CONCLUSIONS: The interdisciplinary study of health-related debates in social media across the cyber-physical debate nexus leads to a greater understanding of public concerns, views, and responses to health-related issues. Further coalescing such capabilities shows promise towards advancing health communication, thus supporting the design of more effective strategies that take into account the complex and evolving public views of health issues. PMID- 27227145 TI - The Importance of Computer Science for Public Health Training: An Opportunity and Call to Action. AB - A century ago, the Welch-Rose Report established a public health education system in the United States. Since then, the system has evolved to address emerging health needs and integrate new technologies. Today, personalized health technologies generate large amounts of data. Emerging computer science techniques, such as machine learning, present an opportunity to extract insights from these data that could help identify high-risk individuals and tailor health interventions and recommendations. As these technologies play a larger role in health promotion, collaboration between the public health and technology communities will become the norm. Offering public health trainees coursework in computer science alongside traditional public health disciplines will facilitate this evolution, improving public health's capacity to harness these technologies to improve population health. PMID- 27227146 TI - Development of the Health Atlas of Jalisco: A New Web-Based Service for the Ministry of Health and the Community in Mexico. AB - BACKGROUND: Maps have been widely used to provide a visual representation of information of a geographic area. Health atlases are collections of maps related to conditions, infrastructure or services provided. Various countries have put resources towards producing health atlases that support health decision makers to enhance their services to the communities. Latin America, as well as Spain, have produced several atlases of importance such as the interactive mortality atlas of Andalucia, which is very similar to the one that is presented in this paper. In Mexico, the National Institute of Public Health produced the only health atlas found that is of relevance. It was published online in 2003 and is currently still active. OBJECTIVE: The objective of this work is to describe the methods used to develop the Health Atlas of Jalisco (HAJ), and show its characteristics and how it interactively works with the user as a Web-based service. METHODS: This work has an ecological design in which the analysis units are the 125 municipalities (counties) of the state of Jalisco, Mexico. We created and published online a geographic health atlas displaying a system based on input from official health database of the Health Ministry of Jalisco (HMJ), and some databases from the National Institute of Statistics and Geography (NISGI). The atlas displays 256 different variables as health-direct or health-related indicators. Instant Atlas software was used to generate the online application. The atlas was developed using these procedures: (1) datasheet processing and base maps generation, (2) software arrangements, and (3) website creation. RESULTS: The HAJ is a Web-based service that allows users to interact with health and general data, regions, and categories according to their information needs and generates thematic maps (eg, the total population of the state or of a single municipality grouped by age or sex). The atlas is capable of displaying more than 32,000 different maps by combining categories, indicators, municipalities, and regions. Users can select the entire province, one or several municipalities, and the indicator they require. The atlas then generates and displays the requested map. CONCLUSIONS: This atlas is a Web-based service that interactively allows users to review health indicators such as structure, supplies, processes, and the impact on public health and related sectors in Jalisco, Mexico. One of the main interests is to reduce the number of information requests that the Ministry of Health receives every week from the general public, media reporters, and other government sectors. The atlas will support transparency, information diffusion, health decision-making, and the formulation of new public policies. Furthermore, the research team intends to promote research and education in public health. PMID- 27227147 TI - Use of Electronic Health Records and Geographic Information Systems in Public Health Surveillance of Type 2 Diabetes: A Feasibility Study. AB - BACKGROUND: Data routinely collected in electronic health records (EHRs) offer a unique opportunity to monitor chronic health conditions in real-time. Geographic information systems (GIS) may be an important complement in the analysis of those data. OBJECTIVE: The aim of this study was to explore the feasibility of using primary care EHRs and GIS for population care management and public health surveillance of chronic conditions, in Portugal. Specifically, type 2 diabetes was chosen as a case study, and we aimed to map its prevalence and the presence of comorbidities, as well as to identify possible populations at risk for cardiovascular complications. METHODS: Cross-sectional study using individual level data from 514 primary care centers, collected from three different types of EHRs. Data were obtained on adult patients with type 2 diabetes (identified by the International Classification of Primary Care [ICPC-2] code, T90, in the problems list). GISs were used for mapping the prevalence of diabetes and comorbidities (hypertension, dyslipidemia, and obesity) by parish, in the region of Lisbon and Tagus Valley. Descriptive statistics and multivariate logistic regression were used for data analysis. RESULTS: We identified 205,068 individuals with the diagnosis of type 2 diabetes, corresponding to a prevalence of 5.6% (205,068/3,659,868) in the study population. The mean age of these patients was 67.5 years, and hypertension was present in 71% (144,938/205,068) of all individuals. There was considerable variation in diagnosed comorbidities across parishes. Diabetes patients with concomitant hypertension or dyslipidemia showed higher odds of having been diagnosed with cardiovascular complications, when adjusting for age and gender (hypertension odds ratio [OR] 2.16, confidence interval [CI] 2.10-2.22; dyslipidemia OR 1.57, CI 1.54-1.60). CONCLUSIONS: Individual-level data from EHRs may play an important role in chronic disease surveillance, namely through the use of GIS. Promoting the quality and comprehensiveness of data, namely through patient involvement in their medical records, is crucial to enhance the feasibility and usefulness of this approach. PMID- 27227148 TI - An International Study of the Ability and Cost-Effectiveness of Advertising Methods to Facilitate Study Participant Self-Enrolment Into a Pilot Pharmacovigilance Study During Early Pregnancy. AB - BACKGROUND: Knowledge of the fetal effects of maternal medication use in pregnancy is often inadequate and current pregnancy pharmacovigilance (PV) surveillance methods have important limitations. Patient self-reporting may be able to mitigate some of these limitations, providing an adequately sized study sample can be recruited. OBJECTIVE: To compare the ability and cost-effectiveness of several direct-to-participant advertising methods for the recruitment of pregnant participants into a study of self-reported gestational exposures and pregnancy outcomes. METHODS: The Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) pregnancy study is a non interventional, prospective pilot study of self-reported medication use and obstetric outcomes provided by a cohort of pregnant women that was conducted in Denmark, the Netherlands, Poland, and the United Kingdom. Direct-to-participant advertisements were provided via websites, emails, leaflets, television, and social media platforms. RESULTS: Over a 70-week recruitment period direct-to participant advertisements engaged 43,234 individuals with the study website or telephone system; 4.78% (2065/43,234) of which were successfully enrolled and provided study data. Of these 90.4% (1867/2065) were recruited via paid advertising methods, 23.0% (475/2065) of whom were in the first trimester of pregnancy. The overall costs per active recruited participant were lowest for email (?23.24) and website (?24.41) advertisements and highest for leaflet (?83.14) and television (?100.89). Website adverts were substantially superior in their ability to recruit participants during their first trimester of pregnancy (317/668, 47.5%) in comparison with other advertising methods (P<.001). However, we identified international variations in both the cost-effectiveness of the various advertisement methods used and in their ability to recruit participants in early pregnancy. CONCLUSIONS: Recruitment of a pregnant cohort using direct-to participant advertisement methods is feasible, but the total costs incurred are not insubstantial. Future research is needed to identify advertising strategies capable of recruiting large numbers of demographically representative pregnant women, preferentially in early pregnancy. PMID- 27227149 TI - Estimating the Population Sizes of Men Who Have Sex With Men in US States and Counties Using Data From the American Community Survey. AB - BACKGROUND: In the United States, male-to-male sexual transmission accounts for the greatest number of new human immunodeficiency virus (HIV) diagnoses and a substantial number of sexually transmitted infections (STI) annually. However, the prevalence and annual incidence of HIV and other STIs among men who have sex with men (MSM) cannot be estimated in local contexts because demographic data on sexual behavior, particularly same-sex behavior, are not routinely collected by large-scale surveys that allow analysis at state, county, or finer levels, such as the US decennial census or the American Community Survey (ACS). Therefore, techniques for indirectly estimating population sizes of MSM are necessary to supply denominators for rates at various geographic levels. OBJECTIVE: Our objectives were to indirectly estimate MSM population sizes at the county level to incorporate recent data estimates and to aggregate county-level estimates to states and core-based statistical areas (CBSAs). METHODS: We used data from the ACS to calculate a weight for each county in the United States based on its relative proportion of households that were headed by a male who lived with a male partner, compared with the overall proportion among counties at the same level of urbanicity (ie, large central metropolitan county, large fringe metropolitan county, medium/small metropolitan county, or nonmetropolitan county). We then used this weight to adjust the urbanicity-stratified percentage of adult men who had sex with a man in the past year, according to estimates derived from the National Health and Nutrition Examination Survey (NHANES), for each county. We multiplied the weighted percentages by the number of adult men in each county to estimate its number of MSM, summing county-level estimates to create state- and CBSA-level estimates. Finally, we scaled our estimated MSM population sizes to a meta-analytic estimate of the percentage of US MSM in the past 5 years (3.9%). RESULTS: We found that the percentage of MSM among adult men ranged from 1.5% (Wyoming) to 6.0% (Rhode Island) among states. Over one-quarter of MSM in the United States resided in 1 of 13 counties. Among counties with over 300,000 residents, the five highest county-level percentages of MSM were San Francisco County, California at 18.5% (66,586/359,566); New York County, New York at 13.8% (87,556/635,847); Denver County, Colorado at 10.5% (25,465/243,002); Multnomah County, Oregon at 9.9% (28,949/292,450); and Suffolk County, Massachusetts at 9.1% (26,338/289,634). Although California (n=792,750) and Los Angeles County (n=251,521) had the largest MSM populations of states and counties, respectively, the New York City-Newark-Jersey City CBSA had the most MSM of all CBSAs (n=397,399). CONCLUSIONS: We used a new method to generate small area estimates of MSM populations, incorporating prior work, recent data, and urbanicity-specific parameters. We also used an imputation approach to estimate MSM in rural areas, where same-sex sexual behavior may be underreported. Our approach yielded estimates of MSM population sizes within states, counties, and metropolitan areas in the United States, which provide denominators for calculation of HIV and STI prevalence and incidence at those geographic levels. PMID- 27227150 TI - Why do Patients Forget to Take Immunosuppression Medications and Miss Appointments: Can a Mobile Phone App Help? AB - BACKGROUND: Kidney transplant recipients must adhere to their immunosuppressive medication regimen. However, non-adherence remains a major problem. OBJECTIVE: The aim of this paper is to determine how kidney transplant recipients remember to take their medications, and assess their perception and beliefs about adherence to immunosuppressive medications and barriers to medication adherence. In addition, we aim to assess perception and beliefs about willingness to use a hypothetical, mobile phone app to improve adherence. METHODS: We conducted a qualitative study that included an average of three home or workplace visits of kidney transplant recipients (N=16) from a single urban transplant center. RESULTS: The qualitative study revealed that transplant recipients understood the importance of taking their immunosuppressive medications and this motivated them to take their medications. The visits showed that most participants have incorporated medication use into their daily lives and that any minor deviation from daily routines could result in non-adherence. Participants also reported other barriers to adherence. All participants were interested in using an app to remind them to take their medication; however, they reported potential barriers to using the app. CONCLUSIONS: Although kidney transplant recipients understood the importance of medication adherence, there were significant barriers to maintaining adherence. Participants also reported interest in using a mobile phone app. PMID- 27227151 TI - Leveraging Big Data to Improve Health Awareness Campaigns: A Novel Evaluation of the Great American Smokeout. AB - BACKGROUND: Awareness campaigns are ubiquitous, but little is known about their potential effectiveness because traditional evaluations are often unfeasible. For 40 years, the "Great American Smokeout" (GASO) has encouraged media coverage and popular engagement with smoking cessation on the third Thursday of November as the nation's longest running awareness campaign. OBJECTIVE: We proposed a novel evaluation framework for assessing awareness campaigns using the GASO as a case study by observing cessation-related news reports and Twitter postings, and cessation-related help seeking via Google, Wikipedia, and government-sponsored quitlines. METHODS: Time trends (2009-2014) were analyzed using a quasi experimental design to isolate spikes during the GASO by comparing observed outcomes on the GASO day with the simulated counterfactual had the GASO not occurred. RESULTS: Cessation-related news typically increased by 61% (95% CI 35 87) and tweets by 13% (95% CI -21 to 48) during the GASO compared with what was expected had the GASO not occurred. Cessation-related Google searches increased by 25% (95% CI 10-40), Wikipedia page visits by 22% (95% CI -26 to 67), and quitline calls by 42% (95% CI 19-64). Cessation-related news media positively coincided with cessation tweets, Internet searches, and Wikipedia visits; for example, a 50% increase in news for any year predicted a 28% (95% CI -2 to 59) increase in tweets for the same year. Increases on the day of the GASO rivaled about two-thirds of a typical New Year's Day-the day that is assumed to see the greatest increases in cessation-related activity. In practical terms, there were about 61,000 more instances of help seeking on Google, Wikipedia, or quitlines on GASO each year than would normally be expected. CONCLUSIONS: These findings provide actionable intelligence to improve the GASO and model how to rapidly, cost-effectively, and efficiently evaluate hundreds of awareness campaigns, nearly all for the first time. PMID- 27227152 TI - Leveraging Social Media to Promote Public Health Knowledge: Example of Cancer Awareness via Twitter. AB - BACKGROUND: As social media becomes increasingly popular online venues for engaging in communication about public health issues, it is important to understand how users promote knowledge and awareness about specific topics. OBJECTIVE: The aim of this study is to examine the frequency of discussion and differences by race and ethnicity of cancer-related topics among unique users via Twitter. METHODS: Tweets were collected from April 1, 2014 through January 21, 2015 using the Twitter public streaming Application Programming Interface (API) to collect 1% of public tweets. Twitter users were classified into racial and ethnic groups using a new text mining approach applied to English-only tweets. Each ethnic group was then analyzed for frequency in cancer-related terms within user timelines, investigated for changes over time and across groups, and measured for statistical significance. RESULTS: Observable usage patterns of the terms "cancer", "breast cancer", "prostate cancer", and "lung cancer" between Caucasian and African American groups were evident across the study period. We observed some variation in the frequency of term usage during months known to be labeled as cancer awareness months, particularly September, October, and November. Interestingly, we found that of the terms studied, "colorectal cancer" received the least Twitter attention. CONCLUSIONS: The findings of the study provide evidence that social media can serve as a very powerful and important tool in implementing and disseminating critical prevention, screening, and treatment messages to the community in real-time. The study also introduced and tested a new methodology of identifying race and ethnicity among users of the social media. Study findings highlight the potential benefits of social media as a tool in reducing racial and ethnic disparities. PMID- 27227153 TI - Exploring the Feasibility and Potential of Virtual Panels for Soliciting Feedback on Nutrition Education Materials: A Proof-of-Concept Study. AB - BACKGROUND: A changing and cluttered information landscape has put pressure on health organizations to produce consumer information materials that are not only factual but high quality and engaging to audiences. User-centered design methods can be useful in obtaining feedback from consumers; however, they are labor intensive and slow, which is not responsive to the fast-paced communication landscape influenced by social media. EatRight Ontario (ERO), a provincial nutrition and health support program of Dietitians of Canada, develops evidence based resources for consumers and sought to increase user-centered design activities by exploring whether the standard approach to feedback could be replicated online. While online feedback has been used in marketing research, few examples are available in health promotion and public health to guide programming and policy. OBJECTIVE: This study compared a traditional in-person approach for recruitment and feedback using paper surveys with an Internet-based approach using Facebook as a recruitment tool and collecting user feedback via the Web. The purpose of the proof-of-concept study was to explore the feasibility of the approach and compare an online versus traditional approach in terms of recruitment issues and response. METHODS: An exploratory, two-group comparative trial was conducted using a convenience and purposive sampling. Participants reviewed a handout on healthy eating and then completed an 18-item survey with both forced-choice items and open-ended responses. One group viewed a hard-copy prototype and completed a paper survey and the other viewed a PDF prototype via Web links and completed a Web survey. The total days required to fulfill the sample for each group were used as the primary method of efficiency calculation. RESULTS: In total, 44 participants (22 per condition) completed the study, consisting of 42 women and 2 men over the age of 18. Few significant differences were detected between the groups. Statistically significant (P<=.05) differences were detected on four attitudinal variables related to the document reviewed and include perceived length of the document, perceived attractiveness, likelihood of contacting ERO for food and nutrition questions in the future, and likelihood of recommending ERO to a friend. In all cases, the responses were more favorable to the document or ERO with the online group. All other variables showed no difference between them. A content review of the qualitative feedback found relative consistency in word use and number of words used, indicating relative parity in the amount of data generated between conditions. The online condition achieved its sampling target in 9 days, while the in-person method took 79 days to achieve the target. CONCLUSIONS: An online process of recruitment through Facebook and solicitation of online feedback is a feasible model that yields comparable response levels to in-person methods for user feedback. The online approach appears to be a faster and less resource-intensive approach than traditional in-person methods for feedback generation. PMID- 27227154 TI - Medical Institutions and Twitter: A Novel Tool for Public Communication in Japan. AB - BACKGROUND: Twitter is a free social networking and microblogging service on the Internet. Medical professionals and patients have started to use Twitter in medicine. Twitter use by medical institutions can interactively and efficiently provide public health information and education for laypeople. OBJECTIVE: This study examined Twitter usage by medical institutions. METHODS: We reviewed all Japanese user accounts in which the names of medical institutions were described in the user's Twitter profile. We then classified medical institutions' tweets by content. RESULTS: We extracted 168 accounts for medical institutions with >=500 followers. The medical specialties of those accounts were dentistry and oral surgery (n=73), dermatology (n=12), cosmetic surgery (n=10), internal medicine (n=10), ophthalmology (n=6), obstetrics and gynecology (n=5), plastic surgery (n=2), and others (n=50). Of these, 21 accounts tweeted medical knowledge and 45 accounts tweeted guidance about medical practice and consultation hours, including advertisements. In the dentistry and oral surgery accounts, individual behavior or thinking was the most frequent (22/71, 31%) content. On the other hand, consultation including advertisements was the most frequent (14/23, 61%) in cosmetic surgery, plastic surgery, and dermatology. CONCLUSIONS: Some medical specialties used Twitter for disseminating medical knowledge or guidance including advertisements. This indicates that Twitter potentially can be used for various purposes by different medical specialties. PMID- 27227155 TI - Mobile Technology for Empowering Health Workers in Underserved Communities: New Approaches to Facilitate the Elimination of Neglected Tropical Diseases. AB - BACKGROUND: As global mobile phone penetration increases, direct health information communication from hard-to-reach communities is becoming commonplace. Mobile health (mHealth) tools that enable disease control programs to benefit from this information, while simultaneously empowering community members to take control of their own health, are vital to the goal of universal health care. OBJECTIVE: Our aim was to highlight the development of the Liverpool mHealth Suite (LMS), which has been designed to address this need and improve health services for neglected tropical diseases being targeted for global elimination, such as lymphatic filariasis. METHODS: The LMS has two main communication approaches-short message service and mobile phone apps-to facilitate real-time mass drug administration (MDA) coverage, reporting patient numbers, managing stock levels of treatment supplies, and exchanging health information to improve the quality of care of those affected. RESULTS: The LMS includes the MeasureSMS MDA tool to improve drug supplies and MDA coverage rates in real-time (currently being trialed in urban Tanzania); the MeasureSMS-Morbidity tool to map morbidity, including lymphedema and hydrocele cases (initially piloted in rural Malawi and Ghana, then extended to Ethiopia, and scaled up to large urban areas in Bangladesh and Tanzania); the LyMSS-lymphedema management supply system app to improve distribution of treatments (trialed for 6 months in Malawi with positive impacts on health workers and patients); and the HealthFront app to improve education and training (in development with field trials planned). CONCLUSIONS: The current success and scale-up of the LMS by many community health workers in rural and urban settings across Africa and Asia highlights the value of this simple and practical suite of tools that empowers local health care workers to contribute to local, national, and global elimination of disease. PMID- 27227156 TI - Effectiveness of Implementation of Electronic Malaria Information System as the National Malaria Surveillance System in Thailand. AB - BACKGROUND: In moving toward malaria elimination, one strategy is to implement an active surveillance system for effective case management. Thailand has developed and implemented the electronic Malaria Information System (eMIS) capturing individualized electronic records of suspected or confirmed malaria cases. OBJECTIVE: The main purpose of this study was to determine how well the eMIS improves the quality of Thailand's malaria surveillance system. In particular, the focus of the study was to evaluate the effectiveness of the eMIS in terms of the system users' perception and the system outcomes (ie, quality of data) regarding the management of malaria patients. METHODS: A mixed-methods technique was used with the framework based on system effectiveness attributes: data quality, timeliness, simplicity, acceptability, flexibility, stability, and usefulness. Three methods were utilized: data records review, survey of system users, and in-depth interviews with key stakeholders. From the two highest endemic provinces, paper forms matching electronic records of 4455 noninfected and 784 malaria-infected cases were reviewed. Web-based anonymous questionnaires were distributed to all 129 eMIS data entry staff throughout Thailand, and semistructured interviews were conducted with 12 management-level officers. RESULTS: The eMIS is well accepted by system users at both management and operational levels. The data quality has enabled malaria personnel to perform more effective prevention and control activities. There is evidence of practices resulting in inconsistencies and logical errors in data reporting. Critical data elements were mostly completed, except for a few related to certain dates and area classifications. Timeliness in reporting a case to the system was acceptable with a delay of 3-4 days. The evaluation of quantitative and qualitative data confirmed that the eMIS has high levels of simplicity, acceptability, stability, and flexibility. CONCLUSIONS: Overall, the system implemented has achieved its objective. The results of the study suggested that the eMIS helps improve the quality of Thailand's malaria surveillance system. As the national malaria surveillance system, the eMIS's functionalities have provided the malaria staff working at the point of care with close-to-real-time case management data quality, covering case detection, case investigation, drug compliance, and follow up visits. Such features has led to an improvement in the quality of the malaria control program; the government officials now have quicker access to both individual and aggregated data to promptly react to possible outbreak. The eMIS thus plays one of the key roles in moving toward the national goal of malaria elimination by the next decade. PMID- 27227157 TI - Improving HIV Surveillance Data for Public Health Action in Washington, DC: A Novel Multiorganizational Data-Sharing Method. AB - BACKGROUND: The National HIV/AIDS Strategy calls for active surveillance programs for human immunodeficiency virus (HIV) to more accurately measure access to and retention in care across the HIV care continuum for persons living with HIV within their jurisdictions and to identify persons who may need public health services. However, traditional public health surveillance methods face substantial technological and privacy-related barriers to data sharing. OBJECTIVE: This study developed a novel data-sharing approach to improve the timeliness and quality of HIV surveillance data in three jurisdictions where persons may often travel across the borders of the District of Columbia, Maryland, and Virginia. METHODS: A deterministic algorithm of approximately 1000 lines was developed, including a person-matching system with Enhanced HIV/AIDS Reporting System (eHARS) variables. Person matching was defined in categories (from strongest to weakest): exact, very high, high, medium high, medium, medium low, low, and very low. The algorithm was verified using conventional component testing methods, manual code inspection, and comprehensive output file examination. Results were validated by jurisdictions using internal review processes. RESULTS: Of 161,343 uploaded eHARS records from District of Columbia (N=49,326), Maryland (N=66,200), and Virginia (N=45,817), a total of 21,472 persons were matched across jurisdictions over various strengths in a matching process totaling 21 minutes and 58 seconds in the privacy device, leaving 139,871 uniquely identified with only one jurisdiction. No records matched as medium low or low. Over 80% of the matches were identified as either exact or very high matches. Three separate validation methods were conducted for this study, and they all found >=90% accuracy between records matched by this novel method and traditional matching methods. CONCLUSIONS: This study illustrated a novel data sharing approach that may facilitate timelier and better quality HIV surveillance data for public health action by reducing the effort needed for traditional person-matching reviews without compromising matching accuracy. Future analyses will examine the generalizability of these findings to other applications. PMID- 27227158 TI - Intragroup Stigma Among Men Who Have Sex with Men: Data Extraction from Craigslist Ads in 11 Cities in the United States. AB - BACKGROUND: Gay, bisexual, and other men who have sex with men (MSM) regularly experience homophobic discrimination and stigma. While previous research has examined homophobic and HIV-related intergroup stigma originating from non-MSM directed at MSM, less is known about intragroup stigma originating from within MSM communities. While some research has examined intragroup stigma, this research has focused mostly on HIV-related stigma. Intragroup stigma may have a unique influence on sexual risk-taking behaviors as it occurs between sexual partners. Online sexual networking venues provide a unique opportunity to examine this type of stigma. OBJECTIVE: The purpose of this study is to examine the presence and patterns of various types of intragroup stigma represented in Men Seeking Men Craigslist sex ads. METHODS: Data were collected from ads on Craigslist sites from 11 of the 12 US metropolitan statistical areas with the highest HIV/AIDS prevalence. Two categories of data were collected: self-reported characteristics of the authors and reported biases in the ads. Chi-square tests were used to examine patterns of biases across cities and author characteristics. RESULTS: Biases were rarely reported in the ads. The most commonly reported biases were against men who were not "disease and drug free (DDF)," representing stigma against men living with HIV or a sexually transmitted infection. Patterns in bias reporting occurred across cities and author characteristics. There were no variations based on race, but ageism (mostly against older men) varied based on the ad author's age and self-reported DDF status; bias against feminine gender expression varied based on self-reported sexual orientation; bias against "fat" men varied by self-reported DDF status; bias against "ugly" men varied by a self report of being good-looking; and bias against people who do not have a DDF status varied based on self-reported HIV status and self-reported DDF status. CONCLUSIONS: Despite an overall low reporting of biases in ads, these findings suggest that there is a need to address intragroup stigma within MSM communities. The representation of biases and intragroup stigma on Craigslist may result from internalized stigma among MSM while also perpetuating further internalization of stigma for men who read the sex ads. Understanding patterns in the perpetuation of intragroup stigma can help to better target messages aimed at making cultural and behavioral shifts in the perpetration of intragroup stigma within MSM communities. PMID- 27227159 TI - Promoting a Hand Hygiene Program Using Social Media: An Observational Study. AB - BACKGROUND: Hand hygiene is an important component in infection control to protect patient safety and reduce health care-associated infection. OBJECTIVE: Our aim was to evaluate the efficacy of different social media on the promotion of a hand hygiene (HH) program. METHODS: The observational study was conducted from May 5 to December 31, 2014, at a 2600-bed tertiary care hospital. A 3-minute video of an HH campaign in 8 languages was posted to YouTube. The Chinese version was promoted through three platforms: the hospital website, the hospital group email, and the Facebook site of a well-known Internet illustrator. The video traffic was analyzed via Google Analytics. HH compliance was measured in November 2013 and 2014. RESULTS: There were 5252 views of the video, mainly of the Chinese language version (3509/5252, 66.81%). The NTUH website had 24,000 subscribers, and 151 of them viewed the video (connection rate was 151/24,000, 0.63%). There were 9967 users of the hospital email group and the connection rate was 0.91% (91/9967). The connection rate was 6.17% (807/13,080) from Facebook, significantly higher than the other 2 venues (both P<.001). HH compliance sustained from 83.7% (473/565) in 2013 to 86.7% (589/679) in 2014 (P=.13) among all HCWs. CONCLUSIONS: Facebook had the highest connection rate in the HH video campaign. The use of novel social media such as Facebook should be considered for future programs that promote hand hygiene and other healthy behaviors. PMID- 27227160 TI - Considerations for Public Health Organizations Attempting to Implement a Social Media Presence: A Qualitative Study. AB - BACKGROUND: In the past decade, social media has become an integral part of our everyday lives, but research on how this tool is used by public health workers and organizations is still developing. Budget cuts and staff reduction in county departments have required employees to take on more responsibilities. These reductions have caused a reduction in the time for training or collaborating with others in the field. To make up for the loss, many employees are seeking collaboration through social media sites but are unable to do so because state departments block these Internet sites. OBJECTIVE: This study sought to highlight the key considerations and decision-making process for a public health organization deciding whether to implement a social media presence for their organization. METHODS: Using 3 structured interviews, 15 stakeholders were questioned on their personal experience with social media, experience within the context of public health, and their thoughts on implementation for their center. Interviews were coded using constant comparative qualitative methods. RESULTS: The following themes emerged from the interviews: (1) personal experience with technology and social networking sites, (2) use of social networking sites in public health, (3) use of social networking sites in work environments, (4) social networking sites access, (5) ways the Rural South Public Health Training Center could use social networking sites, and (6) perceived outcomes of social networking site usage for the Rural South Public Health Training Center (positive and negative). CONCLUSIONS: The collective voice of the center showed a positive perceived perception of social media implementation, with the benefits outweighing the risks. Despite the benefits, there is a cautious skepticism of the importance of social networking site use. PMID- 27227161 TI - Factors Associated With Condom Breakage During Anal Intercourse: A Cross Sectional Study of Men Who Have Sex With Men Recruited in an Online Survey. AB - BACKGROUND: Within the United States, HIV affects men who have sex with men (MSM) disproportionally compared to the general population. In 2011, MSM represented nearly two-thirds of all new HIV infections while representing less than 2% of the US male population. Condoms continue to be the foundation of many HIV prevention programs; however, the failure rate of condoms during anal intercourse among MSM is estimated to be 0.5% to 8%, and condom breakages leave those affected at high risk for HIV transmission. OBJECTIVE: Estimate the frequency of condom breakage and associated demographic and behavioral factors during last act of anal intercourse using data from a national online HIV prevention survey of MSM. METHODS: From March 19 to April 16, 2009, data were collected on 9005 MSM through an online survey of US MSM recruited through a social networking site. Using multivariable logistic regression and controlling for several demographic and sexual risk behaviors, we estimated odds ratios of the association between condom breakage and several risk factors. RESULTS: In the study, 8063 participants reported having at least one male sexual partner in the last 12 months. The median age of participants was 21 years (range 18-65). More than two thirds (68.2%, 5498/8063) reported anal intercourse during last sex and 16.90% (927/5498) reported using a condom during last anal intercourse act. Condom breakage was reported by 4.4% (28/635) participants who engaged in receptive anal intercourse and 3.5% (16/459) participants who engaged in insertive anal intercourse, with an overall failure rate of 4.0% (95% CI 3.2%-6.0%). Age (adjusted odds ratio [aOR] per 5 years: 0.53 (95% CI 0.30-0.94), number of male sex partners (aOR per 5 sex partners: 1.03 (95% CI 1.00-1.08), and being high or buzzed during sex with a casual sex partner (aOR: 3.14, 95% CI 1.02-9.60) were associated with condom breakage. CONCLUSIONS: Our results indicate condom breakage is an important problem for MSM that may be more common for younger men, for men with more partners, and during sex with casual partners after alcohol consumption or drug use. A better understanding of why condom breakage occurs more often in these groups is needed to improve educational efforts. Further, during this time of expanded interest in new condom designs, consideration should be given to how condom design might minimize breakage during anal sex. PMID- 27227163 TI - Understanding Digital Technology Access and Use Among New York State Residents to Enhance Dissemination of Health Information. AB - BACKGROUND: Many state and local health departments, as well as community organizations, have been using new technologies to disseminate health information to targeted populations. Yet little data exist that show access and use patterns, as well as preferences for receiving health information, at the state level. OBJECTIVE: This study was designed to obtain information about media and technology use, and health information seeking patterns, from a sample of New York State (NYS) residents. METHODS: A cross-sectional telephone survey (with mobile phones and landlines) was developed to assess media and technology access, use patterns, and preferences for receiving health information among a sample of 1350 residents in NYS. The survey used random digit dialing methodology. A weighted analysis was conducted utilizing Stata/SE software. RESULTS: Data suggest that NYS residents have a high level of computer and Internet use; 82% have at least one working computer at home, and 85% use the Internet at least sometimes. Mobile phone use is also high; 90% indicated having a mobile phone, and of those 63% have a smartphone. When asked about preferences for receiving health information from an organization, many people preferred websites (49%); preferences for other sources varied by demographic characteristics. CONCLUSIONS: Findings suggest that the Internet and other technologies are viable ways to reach NYS residents, but agencies and organizations should still consider using traditional methods of communication in some cases, and determine appropriate channels based on the population of interest. PMID- 27227162 TI - Gordie Howe's "Miraculous Treatment": Case Study of Twitter Users' Reactions to a Sport Celebrity's Stem Cell Treatment. AB - BACKGROUND: Former Detroit Red Wing Gordie Howe received stem cell (SC) treatment in Mexico in December 2014 for a stroke he suffered in October 2014. The news about his positive response to the SC treatment prompted discussion on social networks like Twitter. OBJECTIVE: This study aims to provide information about discussions that took place on Twitter regarding Howe's SC treatment and SC treatment in general. In particular, this study examines whether tweets portrayed a positive or negative attitude towards Howe's SC treatment, whether or not tweets mention that the treatment is unproven, and whether the tweets mention risks associated with the SC treatment. METHODS: This is an infodemiology study, harnessing big data published on the Internet for public health research and analysis of public engagement. A corpus of 2783 tweets about Howe's SC treatment was compiled using a program that collected English-language tweets from December 19, 2014 at 00:00 to February 7, 2015 at 00:00. A content analysis of the corpus was conducted using a coding framework developed through a two-stage process. RESULTS: 78.87% (2195/2783) of tweets mentioned improvements to Howe's health. Only one tweet explicitly mentioned that Howe's SC treatment was unproven, and 3 tweets warned that direct-to-consumer SC treatments lacked scientific evidence. In addition, 10.31% (287/2783) of tweets mentioned challenges with SC treatment that have been raised by scientists and researchers, and 3.70% (103/2783) of tweets either defined Howe as a "stem cell tourist" or claimed that his treatment was part of "stem cell tourism". In general, 71.79% (1998/2783) of tweets portrayed a positive attitude towards Howe's SC treatment. CONCLUSIONS: Our study found the responses to Howe's treatment on Twitter to be overwhelmingly positive. There was far less attention paid to the lack of scientific evidence regarding the efficacy of the treatment. Unbalanced and uncritical discussion on Twitter regarding SC treatments is another example of inaccurate representations of SC treatments that may create unrealistic expectations that will facilitate the market for unproven stem cell therapies. PMID- 27227164 TI - Bedaquiline and Pyrazinamide Treatment Responses Are Affected by Pulmonary Lesion Heterogeneity in Mycobacterium tuberculosis Infected C3HeB/FeJ Mice. AB - BALB/c and Swiss mice are routinely used to validate the effectiveness of tuberculosis drug regimens, although these mouse strains fail to develop human like pulmonary granulomas exhibiting caseous necrosis. Microenvironmental conditions within human granulomas may negatively impact drug efficacy, and this may not be reflected in non-necrotizing lesions found within conventional mouse models. The C3HeB/FeJ mouse model has been increasingly utilized as it develops hypoxic, caseous necrotic granulomas which may more closely mimic the pathophysiological conditions found within human pulmonary granulomas. Here, we examined the treatment response of BALB/c and C3HeB/FeJ mice to bedaquiline (BDQ) and pyrazinamide (PZA) administered singly and in combination. BALB/c mice consistently displayed a highly uniform treatment response to both drugs, while C3HeB/FeJ mice displayed a bimodal response composed of responsive and less responsive mice. Plasma pharmacokinetic analysis of dissected lesions from BALB/c and C3HeB/FeJ mice revealed that PZA penetrated lesion types from both mouse strains with similar efficiency. However, the pH of the necrotic caseum of C3HeB/FeJ granulomas was determined to be 7.5, which is in the range where PZA is essentially ineffective under standard laboratory in vitro growth conditions. BDQ preferentially accumulated within the highly cellular regions in the lungs of both mouse strains, although it was present at reduced but still biologically relevant concentrations within the central caseum when dosed at 25 mg/kg. The differential treatment response which resulted from the heterogeneous pulmonary pathology in the C3HeB/FeJ mouse model revealed several factors which may impact treatment efficacy, and could be further evaluated in clinical trials. PMID- 27227165 TI - White matter involvement in a family with a novel PDGFB mutation. AB - Primary familial brain calcification (PFBC) (formerly idiopathic basal ganglia calcification; Fahr disease) is an autosomal dominant cerebral microvascular calcifying disorder with variable clinical and imaging features.(1) Four causative genes have been identified: SLC20A2,(2) PDGFRB,(3) PDGFB,(4) and XPR1.(5). PMID- 27227166 TI - Differences in PTSD Symptomatology Among Latinos with Childhood and Adult Trauma: The Moderating Effect of Acculturation. AB - The development of PTSD has been shown to be dependent on a variety of factors, including ethnicity, whether the trauma was experienced as a child or adult, and acculturation. Using 104 Latinos who had completed treatment for substance abuse disorder(s), this study compared PTSD symptomatology for individuals reporting their worst traumatic event (WTE) in childhood versus adulthood. The moderating effect of acculturation was also examined. Although many studies have reported on the pernicious effects of childhood trauma, very few have provided direct comparisons of child and adult trauma in terms of PTSD symptoms. Results indicated that those reporting their WTE in childhood had greater PTSD symptomatology than those reporting in adulthood. Acculturation moderated the relationship between timing of the trauma and PTSD symptoms. Specifically, those who reported their WTE in childhood and had the lower levels of acculturation reported the higher number of PTSD symptoms. Implications and future directions are discussed. PMID- 27227167 TI - Radioactive Nanomaterials for Multimodality Imaging. AB - Nuclear imaging techniques, including primarily positron emission tomography (PET) and single-photon emission computed tomography (SPECT), can provide quantitative information for a biological event in vivo with ultra-high sensitivity, however, the comparatively low spatial resolution is their major limitation in clinical application. By convergence of nuclear imaging with other imaging modalities like computed tomography (CT), magnetic resonance imaging (MRI) and optical imaging, the hybrid imaging platforms can overcome the limitations from each individual imaging technique. Possessing versatile chemical linking ability and good cargo-loading capacity, radioactive nanomaterials can serve as ideal imaging contrast agents. In this review, we provide a brief overview about current state-of-the-art applications of radioactive nanomaterials in the circumstances of multimodality imaging. We present strategies for incorporation of radioisotope(s) into nanomaterials along with applications of radioactive nanomaterials in multimodal imaging. Advantages and limitations of radioactive nanomaterials for multimodal imaging applications are discussed. Finally, a future perspective of possible radioactive nanomaterial utilization is presented for improving diagnosis and patient management in a variety of diseases. PMID- 27227169 TI - Mindfulness Based Stress Reduction for Academic Evaluation Anxiety: A Naturalistic Longitudinal Study. AB - Mindfulness based stress reduction (MBSR) for academic evaluation anxiety and self-confidence in 70 help-seeking bachelor's and master's students was examined. A repeated measures analysis of covariance on the 46 students who completed pretreatment and posttreatment measures (median age = 24 years, 83% women) showed that evaluation anxiety and self-confidence improved. A growth curve analysis with all 70 original participants showed reductions in both cognitive and emotional components of evaluation anxiety, and that reduction continued postintervention. Although more research is needed, this study indicates that MBSR may reduce evaluation anxiety. PMID- 27227170 TI - Stress Domain Effects in French Phonology and Phonological Development. AB - In this paper, we discuss two distinct data sets. The first relates to the so called allophonic process of closed-syllable laxing in Quebec French, which targets final (stressed) vowels even though these vowels are arguably syllabified in open syllables in lexical representations. The second is found in the forms produced by a first language learner of European French, who displays an asymmetry in her production of CVC versus CVCV target (adult) forms. The former display full preservation (with concomitant manner harmony) of both consonants. The latter undergoes deletion of the initial syllable if the consonants are not manner-harmonic in the input. We argue that both patterns can be explained through a phonological process of prosodic strengthening targeting the head of the prosodic domain which, in the contexts described above, yields the incorporation of final consonants into the coda of the stressed syllable. PMID- 27227168 TI - Non-invasive differentiation of benign renal tumors from clear cell renal cell carcinomas using clinically translatable hyperpolarized 13C pyruvate magnetic resonance. AB - Localized renal tumors are increasingly detected incidentally at imaging. Conventional imaging cannot reliably differentiate the 20% of these tumors that are benign from malignant renal cell carcinomas (RCCs), leading to unnecessary surgical resection and resulting morbidity associated with surgery. Here, we investigated hyperpolarized 13C pyruvate metabolism in live patient-derived renal tumor tissue slices using a novel magnetic resonance (MR) -compatible bioreactor platform. We demonstrated for the first time that clear cell RCCs (ccRCCs), which account for 70-80% of all RCCs, have increased lactate production as well as rapid lactate efflux compared to benign renal tumors. This difference is attributed to increased lactate dehydrogenase A and monocarboxylate transporter 4 expression in ccRCCs. This distinctive metabolic phenotype can be used to differentiate RCCs from benign renal tumors using clinically translatable hyperpolarized 13C pyruvate MR. PMID- 27227171 TI - Crizotinib: heart failure. PMID- 27227172 TI - SSRI antidepressants: extrapyramidal reactions. PMID- 27227173 TI - Gliptins: disabling joint pain. PMID- 27227174 TI - Mirabegron: hypertension, stroke. PMID- 27227175 TI - Midwest Nursing Research Society News. PMID- 27227176 TI - Foreword. PMID- 27227177 TI - Foreword. PMID- 27227178 TI - MRI as a tool for non-invasive vascular profiling: a pilot study in patients with aortic coarctation. AB - AIM: While the overall concept of aortic coarctation has changed from one of simple obstruction to one that includes significant vascular dysfunction, this has not yet been translated into the diagnostic and treatment process. To close this gap, we sought to demonstrate the usefulness of an additional non-invasive vascular profile. METHOD: During a pilot study in eight coarctation patients, aortic area compliance, aortic distensibility, time phase shift and blood flow (distribution) were calculated from cine-MRI and 2D-/4D-velocity-encoded MRI sequences. RESULTS: Compared to healthy individuals, a significantly lower aortic compliance and reduced flow to the descending aorta were found in patients with coarctation. DISCUSSION: These differences underline the potential usefulness of a combined vascular profile in coarctation patients. CONCLUSION: It was successfully shown that functional vascular profiling of the aorta is feasible to be acquired non-invasively in a clinical setting and can provide additional diagnostic information. These can be the key input parameters for computational fluid dynamics-modeling. PMID- 27227179 TI - Reports Highlight Importance of Residency Training in Underserved Areas. PMID- 27227180 TI - ONC Maps Out Plan to Improve Health IT. PMID- 27227181 TI - AAFP Urges CMS to Revise ACO Proposal. PMID- 27227182 TI - Report Details Savings Achieved by PCMHs. PMID- 27227184 TI - AAMC Predicts Significant Primary Care Physician Shortage by 2025. PMID- 27227183 TI - IOM Recommends Renaming, Redefining Chronic Fatigue Syndrome. PMID- 27227185 TI - Primary Care, Family Medicine Shine in 2015 Osteopathic Match. PMID- 27227186 TI - Preface. PMID- 27227269 TI - Acute intoxication of four individuals following use of the synthetic cannabinoid MAB-CHMINACA. AB - CONTEXT: The largest group of new psychoactive substances (NPS) are synthetic cannabinoids (SC). Those that become controlled are immediately replaced by new uncontrolled substances. The recent resurgence of the NPS market in Poland resulted in a further amendment to the Drug Addiction Counteraction Act. This resulted in significant changes in the composition of "legal high" preparations, and consequently a large outbreak of intoxications with SC was reported in Poland at the beginning of July 2015. CASE DETAILS: This paper describes the circumstances of intoxication and toxicological findings in an acute intoxication of four individuals with MAB-CHMINACA. They each smoked tobacco mixed with powder from the package with the description "AM-2201". The adverse effects observed in the individuals included vomiting, seizures, limb twisting, muscle tremors, aggression, agitation, slurred speech, blood pressure spikes, wheezing, respiratory failure and losses of consciousness. Blood samples were analysed using liquid chromatography with mass spectrometry. Results from analysis performed on the blood samples showed the presence of MAB-CHMINACA, while AM-2201 was not found (LOD 0.09 ng/mL). The determined concentrations were 5.2, 1.3, 1.7 and 14.6 ng/mL, respectively. The analyses of the blood did not reveal any other substances (excluding medicines given in hospital). CONCLUSION: The presented cases show the health risks associated with MAB-CHMINACA use and confirm that "legal high" preparations do not always contain a substance represented on the package. PMID- 27227270 TI - A Copper-Nitroxide Adduct Exhibiting Separate Single Crystal-to-Single Crystal Polymerization-Depolymerization and Spin Crossover Transitions. AB - A complex cascade of solid-state processes initiated by variation of temperature was found for the heterospin complex [Cu(hfac)2L(Me/Et)] formed in the reaction of copper(II) hexafluoroacetylacetonate [Cu(hfac)2] with stable nitronyl nitroxide 2-(1-methyl-3-ethyl-1H-pyrazol-4-yl)-4,4,5,5-tetramethyl-4,5-dihydro-1H imidazole-3-oxide-1-oxyl (L(Me/Et)). The cooling of the compound below 260 K initiated a solid-state chemical reaction, which led to a depolymerization of chains and formation of a pair heterospin complex [Cu(hfac)2L(Me/Et)2][[Cu(hfac)2]3L(Me/Et)2]. Further decrease in temperature below 144 K led to a spin transition accompanied by a drastic decrease in the effective magnetic moment from 2.52 to 2.24 MUB. When the compound was heated, the order of effects was reversed: at first, the magnetic moment abruptly increased, and then the molecular fragments of the pair cluster united into polymer chains. Two hysteresis loops correspond to this cascade of temperature induced structural transformations on the experimental dependence MUeff(T): one at high (T? = 283 K and T? = 260 K) and the other at low (T? = 161 K, T? = 144 K) temperature. The spin transitions were also recorded for the [[Cu(hfac)2]3L(Bu/Et)2] and [[Cu(hfac)2]5L(Bu/Et)4] molecular complexes, which are models of the trinuclear fragment of the {[Cu(hfac)2]3L(Me/Et)2} pair cluster. PMID- 27227271 TI - One-Pot Amide Bond Formation from Aldehydes and Amines via a Photoorganocatalytic Activation of Aldehydes. AB - A mild, one-pot, and environmentally friendly synthesis of amides from aldehydes and amines is described. Initially, a photoorganocatalytic reaction of aldehydes with di-isopropyl azodicarboxylate leads to an intermediate carbonyl imide, which can react with a variety of amines to afford the desired amides. The initial visible light-mediated activation of a variety of monosubstituted or disubstituted aldehydes is usually fast, occurring in a few hours. Following the photocatalytic reaction, addition of the primary amine at room temperature or the secondary amine at elevated temperatures leads to the corresponding amide from moderate to excellent yields without epimerization. This methodology was applied in the synthesis of Moclobemide, a drug against depression and social anxiety. PMID- 27227272 TI - Serum Salusin-beta Levels Are Correlated with Slow Coronary Flow. AB - CONTEXT: Slow coronary flow (SCF) is a special coronary microvascular disorder associated with recurrent chest pain. The pathogenesis of SCF remain unclear. OBJECTIVES: We sought to assess whether serum salusin-beta levels are correlated with SCF. METHODS: We enrolled 76 patients with angiographically confirmed SCF and 108 age- and gender-matched controls. We measured serum salusin-beta levels by enzyme-linked immunosorbent assay and coronary flow rate was assessed using thrombolysis in myocardial infarction frame count (TFC). RESULTS: Serum salusin beta levels were elevated in SCF patients compared with controls (4.33 [range 3.52-5.87] nmol/L vs. 3.76 [range 2.98-4.67] nmol/L). Multivariate logistic regression analysis revealed that salusin-beta in serum was the independent predictor of SCF (odds ratio = 1.814). Serum salusin-beta levels were independently correlated with mean-TFC (r = 0.355, p = 0.002). CONCLUSIONS: Serum salusin-beta levels were independently associated with SCF. Therefore, our findings implicate a potential role of salusin-beta in the pathophysiology of SCF and provide insights on both risk stratification and modification in this patient population. PMID- 27227273 TI - Perceptions of sexual harassment by evidence quality, perceiver gender, feminism, and right wing authoritarianism: Debunking popular myths. AB - This study examined the critique in public discourse that sexual harassment (SH) victim advocates, particularly women and feminists, ignore the quality of evidence in a SH claim and are reluctant to find evidence of a false accusation. To balance the inquiry, the study also examined whether right wing authoritarians (RWAs) also ignore evidence quality and presume such claims are false accusations. Participants were 961 U.S. adults (51% female) who completed an online experiment in which they read either a gender harassment (GH) or unwanted sexual attention (USA) scenario of hostile work environment SH and rated the scenario on severity, perceived guilt of the accused, belief that the accused should receive negative job consequences, and likelihood that the claimant was making a false accusation. Scenarios varied by the strength of the evidence in support of the SH claim. Participants completed measures of identification with and support for feminism, RWA, and demographic variables. Results found that contrary to expectations, evidence had a stronger effect on women's, feminists', and feminism supporters' perceptions and to a lesser extent RWAs' perceptions of the scenarios. When evidence was weak, women and feminists, compared to others, were less supportive of the prosecution, but when evidence was strong they were more supportive of the prosecution than were others. These findings address criticisms that advocates for gender equity and victim's rights, particularly women and feminists, are unable to reach fair judgments of SH complaints. (PsycINFO Database Record PMID- 27227274 TI - Juror sensitivity to false confession risk factors: Dispositional vs. situational attributions for a confession. AB - Research on jurors' perceptions of confession evidence suggests that jurors may not be sensitive to factors that can influence the reliability of a confession. Jurors' decisions tend not to be influenced by situational pressures to confess, which suggests that jurors commit the correspondence bias when evaluating a confession. One method to potentially increase sensitivity and counteract the correspondence bias is by highlighting a motivation other than guilt for the defendant's confession. We conducted 3 experiments to evaluate jurors' sensitivity to false confession risk factors. Participants read a trial transcript that varied the presence of false confession risk factors within an interrogation. Some participants also read testimony that presented an alternative motivation for the confession (expert testimony, Experiments 1 and 3; defendant testimony, Experiment 2). Across 3 experiments, participants were generally able to distinguish between interrogation practices that can produce a false confession, regardless of the presence or absence of expert or defendant testimony. Experiment 3 explored whether participants' attributions for the confessor's motivation were affected by interrogative pressure and expert testimony, and whether these attributions affected verdicts. Participants' reluctance to convict when false confession risk factors were present was associated with situational, rather than dispositional, attributions regarding the defendant's motivation to confess. It is possible that increased knowledge is responsible for participants' improved sensitivity to false confession risk factors. (PsycINFO Database Record PMID- 27227275 TI - How old is old in allegations of age discrimination? The limitations of existing law. AB - Under Title VII, courts may give a mixed motive instruction allowing jurors to determine that defendants are liable for discrimination if an illegal factor (here: race, color, religion, sex, or national origin) contributed to an adverse decision. Recently, the Supreme Court held that to conclude that an employer discriminated against a worker because of age, the Age Discrimination in Employment Act, unlike Title VII of the Civil Rights Act of 1964, requires "but for" causality, necessitating jurors to find that age was the determinative factor in an employer's adverse decision regarding that worker. Using a national online sample (N = 392) and 2 study phases, 1 to measure stereotypes, and a second to present experimental manipulations, this study tested whether older worker stereotypes as measured through the lens of the Stereotype Content Model, instruction type (but for vs. mixed motive causality), and plaintiff age influenced mock juror verdicts in an age discrimination case. Decision modeling in Phase 2 with 3 levels of case orientation (i.e., proplaintiff, prodefendant, and neutral) showed that participants relied on multiple factors when making a decision, as opposed to just 1, suggesting that mock jurors favor a mixed model approach to discrimination verdict decisions. In line with previous research, instruction effects showed that mock jurors found in favor of plaintiffs under mixed motive instructions but not under "but for" instructions especially for older plaintiffs (64- and 74-year-old as opposed to 44- and 54-year-old plaintiffs). Most importantly, in accordance with the Stereotype Content Model theory, competence and warmth stereotypes moderated the instruction effects found for specific judgments. The results of this study show the importance of the type of legal causality required for age discrimination cases. (PsycINFO Database Record PMID- 27227276 TI - Blind sequential lineup administration reduces both false identifications and confidence in those false identifications. AB - One of the most recommended procedures proposed by eyewitness experts is the use of double-blind lineups, in which the administrator does not know the identity of the suspect in the lineup. But despite the near universality of this recommendation, there is surprisingly little empirical research to support the claim that nonblind administration inflates false identifications. What little research has been conducted has shown conflicting findings with regard to the conditions under which nonblind administration affects false identifications, as well as its effects on witness confidence. The current study attempts to elucidate this effect. Student-participants (n = 312) were randomly assigned to play the role of either a lineup administrator (who were either told the identity of the suspect in the lineup or not) or a mock crime witness. Following unbiased instructions, administrators presented either a target-present or target-absent sequential lineup to the witness while being surreptitiously videorecorded. Nonblind administration significantly inflated false, but not correct, identifications, and significantly inflated witness confidence in those false identifications. Video recordings indicated that nonblind administrators were significantly more likely than blind administrators to smile (a) while the witness was viewing a photograph of the suspect, and (b) after a suspect identification. Results provide stronger support for the use of blind lineup administration by broadening the conditions under which nonblind administration is shown to inflate false identifications. Possible reconciliations for conflicting findings in the literature are discussed. (PsycINFO Database Record PMID- 27227287 TI - Update on the birth weight standard and its diagnostic value in small for gestational age (SGA) infants in China. AB - OBJECTIVES: To identify the difference between the current newborn birth weight standard and the previous standard in China, and to evaluate the diagnostic value of newborn birth weight in small for gestational age (SGA) infants. METHODS: A retrospective analysis was conducted of 112 441 delivery cases in 2011, from 39 hospitals at different levels in 14 provinces and autonomous regions. Cases with incomplete data, gestational age <24 weeks, or severe fetal malformations or fetal death were excluded. Data were recorded and entered on hard paper copies and into an online database. SPSS 18.0 and SAS 9.2 statistical software were used for data analysis. RESULTS: This study included 109 004 valid cases with an average birth weight of 3226.02 +/- 525.82 g. Birth weight changed significantly from 1988 for all gestational ages. In preterm infants with gestational age <37 weeks, birth weight for each gestational week was lower than that in the birth weight standard from 15 cities in China in 1988 (p < 0.001). Full-term infants with gestational ages from 37 to 41+6 weeks showed significantly higher average birth weights compared with the previous birth weight standards (p < 0.001). The birth weight standard in this study exhibited better correlations than did the previous standard with regard to the diagnoses of adverse pregnancy outcomes, including SGA infants, stillbirth, neonatal asphyxia, neonatal death and neonatal complications; with RR values of 18.843 (9.656-36.774; 95% CI), 33.125 (14.576 75.275), 24.254 (10.630-56.256) and 2.492 (0.328-18.909), respectively. CONCLUSIONS: The current birth weight standard used in Chinese medical institutions was enacted in 1988. This is not suitable for today's socioeconomic and clinical requirements, and needs to be updated. Diagnosis of preterm infants with SGA based upon the updated demographic birth weight standard manifested higher accuracy and avoided unnecessary medical interventions. However, the updated demographic birth weight standards were no better diagnostically than the previous standard for full-term infants. Customized birth weight standards from larger sample sizes and multi-center studies will be necessary to determine the appropriate birth weight standards in developing countries. PMID- 27227288 TI - Topological variability and sex differences in fingerprint ridge density in a sample of the Sudanese population. AB - Fingerprints are important biometric variables that show manifold utilities in human biology, human morphology, anthropology, and genetics. Their role in forensics as a legally admissible tool of identification is well recognized and is based on their stability following full development, individualistic characteristics, easy classification of their patterns, and uniqueness. Nevertheless, fingerprint ridge density and its variability have not been previously studied in the Sudanese population. Hence, this study was conducted to analyze the topological variability in epidermal ridge density and to assess the possibility of its application in determining sex of Sudanese Arabs. The data used for this study were prints of all 10 fingers of 200 Sudanese Arab individuals (100 men and 100 women) aged between 18 and 28 years. Fingerprint ridge density was assessed for three different areas (radial, ulnar and proximal) for all 10 fingers of each subject. Significant variability was found between the areas (p < 0.01). Women showed significantly higher ridge density in the three areas for all and each fingers. Men and women showed similar patterns of densities with distal areas being denser than proximal ones. Side asymmetry was more evident in distal areas. Ridge density thresholds for discrimination of sexes were developed. Hence, fingerprints found in forensic examinations/crime scenes can be useful to determine sex of Sudanese individuals based on fingerprint ridge density; furthermore, ridge density can be considered a morphological trait for individual variation in forensic anthropology. PMID- 27227289 TI - Effects of h-BN addition on microstructures and mechanical properties of beta CaSiO3 bioceramics. AB - The main purpose of this study consists in investigating the effects of h-BN addition on the sinterability of beta-CaSiO3 (beta-CS) bioceramics. beta-CS bioceramics with different contents of h-BN were prepared at the sintering temperature ranging from 800 degrees C to 1100 degrees C. The results showed that h-BN can be successfully used as sintering additive by being oxidized to form low melting point B2O3 related glassy phase and enhanced the flexural strength by the formation of rod-like beta-CS grains. beta-CS bioceramics with 1wt% h-BN sintered at 1000 degrees C revealed flexural strength and fracture toughness of 182.2MPa and 2.4MPam(1/2) respectively, which were much higher than that of pure beta-CS bioceramics (30.2MPa, 0.53MPam(1/2)) fabricated in the same processing condition. PMID- 27227290 TI - Duration of Infusion Set Survival in Lipohypertrophy Versus Nonlipohypertrophied Tissue in Patients with Type 1 Diabetes. AB - BACKGROUND: Improved insulin infusion set survival and faster insulin action are important issues for pump users and for the development of an artificial pancreas. The current recommendation is to change infusion sets every 3 days. Our objectives were to determine the effect of lipohypertrophy (LH) on infusion set survival and continuous glucose monitoring glucose levels. RESEARCH DESIGN AND METHODS: In this multicenter crossover trial, we recruited 20 subjects (age 28.1 +/- 9.0 years) with type 1 diabetes (duration 17.5 +/- 8.8 years) and an area of lipohypertrophied tissue >3 cm. Subjects alternated weekly wearing a Teflon infusion set in an area of either LH or non-LH for 4 weeks. Sets were changed after (a) failure or (b) surviving 7 days of use. RESULTS: The least-squares mean duration of infusion set survival for sets that lasted <7 days in lipohypertrophied tissue was 4.31 days compared with 4.12 days in nonlipohypertrophied tissue (P = 0.71). The average duration of set survival for individual subjects ranged from 2.2 to 7.0 days. Infusion sets in lipohypertrophied tissue failed due to hyperglycemia in 35% of subjects compared with 23% in nonlipohypertrophied tissue (P = 0.22). Both lipohypertrophied and nonlipohypertrophied tissues displayed a general increase in mean daily glucose after the third day of infusion set wear, but daily mean glucose did not differ by tissue type (P > 0.38 on each day). CONCLUSION: LH did not significantly affect infusion set survival or mean glucose. Achieving optimal infusion set performance requires research into factors affecting set survival. Additionally, the recommendation for duration of set change may need to be individualized. PMID- 27227292 TI - Bordetella holmesii: Still Emerging and Elusive 20 Years On. AB - Since the first description of Bordetella holmesii in 1995, almost 100 publications have contributed to the increasing knowledge of this emerging bacterium. Although first reported to induce bacteremia mainly in immunocompromised patients, it has also been isolated in healthy persons and has shown the capacity to induce pertussis-like symptoms and other clinical entities, such as meningitis, arthritis, or endocarditis. Respiratory diseases are generally less severe than those induced by Bordetella pertussis. However, B. holmesii was found to have a higher capacity of invasiveness given the various infection sites in which it was isolated. The diagnosis is difficult, particularly as it is a slow-growing organism but also because respiratory infections are systematically misdiagnosed as B. pertussis. Treatment is delicate, as its susceptibility to macrolides (prescribed in respiratory infections) and ceftriaxone (used in invasive disease) is challenged. Regarding prevention, there is no consensus on prophylactic treatment following index cases and no vaccine is available. Epidemiological data are also sparse, with few prevalence studies available. In this chapter, we provide an overview of the current state of knowledge on B. holmesii. PMID- 27227291 TI - Mechanisms of Antibiotic Resistance. AB - Emergence of resistance among the most important bacterial pathogens is recognized as a major public health threat affecting humans worldwide. Multidrug resistant organisms have not only emerged in the hospital environment but are now often identified in community settings, suggesting that reservoirs of antibiotic resistant bacteria are present outside the hospital. The bacterial response to the antibiotic "attack" is the prime example of bacterial adaptation and the pinnacle of evolution. "Survival of the fittest" is a consequence of an immense genetic plasticity of bacterial pathogens that trigger specific responses that result in mutational adaptations, acquisition of genetic material, or alteration of gene expression producing resistance to virtually all antibiotics currently available in clinical practice. Therefore, understanding the biochemical and genetic basis of resistance is of paramount importance to design strategies to curtail the emergence and spread of resistance and to devise innovative therapeutic approaches against multidrug-resistant organisms. In this chapter, we will describe in detail the major mechanisms of antibiotic resistance encountered in clinical practice, providing specific examples in relevant bacterial pathogens. PMID- 27227293 TI - Measles in the United States since the Millennium: Perils and Progress in the Postelimination Era. AB - This article describes measles and measles vaccination, along with the challenges, successes, and progress in the postelimination era. PMID- 27227295 TI - Cronobacter spp. AB - The Cronobacter group of pathogens, associated with severe and potentially life threatening diseases, until recently were classified as a single species, Enterobacter sakazakii. The group was reclassified in 2007 into the genus Cronobacter as a member of the Enterobacteriaceae. This chapter outlines the history behind the epidemiology, analyzes how our understanding of these bacteria has evolved, and highlights the clinical significance the Cronobacter spp. have for neonatal and elderly patient populations and treatment of the associated infections. PMID- 27227296 TI - Novel Targets of Antimicrobial Therapies. AB - Antibiotics are undoubtedly a pillar of modern medicine; their discovery in 1929 revolutionized the fight against infectious disease, instigating a worldwide decline in infection-associated mortality. Throughout the 1930s, 1940s, and 1950s the golden age of antibiotic discovery was underway with numerous new classes of antibiotics identified and brought to market. By 1962 all of our currently known families of antibiotics had been discovered, and it was a widely held belief, that humanity had conquered infectious disease. Despite varying bacterial cellular targets, most antibiotics targeted exponentially multiplying bacteria by interfering with integral processes such as peptidoglycan synthesis or ribosomal activity. The very nature of this targeted approach has driven the emergence of antibiotic-resistant bacteria.Methods of antibiotic identification relied solely on scientific observation, and while chemical analogues such as amoxicillin, derived from penicillin, continued to be developed, they retained the same mechanisms of action and hence the same bacterial targets. This article describes and discusses some of the emerging novel targets for antimicrobial treatments, highlighting pivotal research on which our ability to continue to successfully treat bacterial infection relies. PMID- 27227297 TI - Iron Acquisition Strategies of Bacterial Pathogens. AB - Iron is an essential micronutrient for both microbes and humans alike. For well over half a century we have known that this element, in particular, plays a pivotal role in health and disease and, most especially, in shaping host-pathogen interactions. Intracellular iron concentrations serve as a critical signal in regulating the expression not only of high-affinity iron acquisition systems in bacteria, but also of toxins and other noted virulence factors produced by some major human pathogens. While we now are aware of many strategies that the host has devised to sequester iron from invading microbes, there are as many if not more sophisticated mechanisms by which successful pathogens overcome nutritional immunity imposed by the host. This review discusses some of the essential components of iron sequestration and scavenging mechanisms of the host, as well as representative Gram-negative and Gram-positive pathogens, and highlights recent advances in the field. Last, we address how the iron acquisition strategies of pathogenic bacteria may be exploited for the development of novel prophylactics or antimicrobials. PMID- 27227298 TI - Recent Advances and Understanding of Using Probiotic-Based Interventions to Restore Homeostasis of the Microbiome for the Prevention/Therapy of Bacterial Diseases. AB - The importance of the microbiome in health and disease has galvanized interest in using manipulations of the gastrointestinal ecosystem to prevent and/or combat gut bacterial infections and to restore mucosal homeostasis in patients with generalized microbial imbalances (i.e., dysbiosis), including the human inflammatory bowel diseases, Crohn's disease, and ulcerative colitis. Probiotics, prebiotics, or their combination use (i.e., synbiotics) are one mechanism for modifying the microbiota and exerting direct and indirect effects on the host immune responses and metabolomics profiles. These beneficial effects are transferred through various pathways, including the production of antimicrobial peptides, promoting the growth of beneficial microbes and enhancing immunomodulatory functions via various metabolites. While probiotic therapy has been used empirically for decades with mixed success, the recent advances in molecular and mass spectrophotometric techniques for the characterization of the complexity and diversity of the intestinal microbiome has aided in better understanding of host-microbe interactions. It is important to better understand the functional properties of the microbiome, because it is now clear that the microbiota secretes many metabolites that have a direct impact on host immune responses. This information will improve selection of the most appropriate probiotic strains that selectively target intestinal disease processes. PMID- 27227299 TI - The Spore Coat. AB - Spores of Clostridiales and Bacillales are encased in a complex series of concentric shells that provide protection, facilitate germination, and mediate interactions with the environment. Analysis of diverse spore-forming species by thin-section transmission electron microscopy reveals that the number and morphology of these encasing shells vary greatly. In some species, they appear to be composed of a small number of discrete layers. In other species, they can comprise multiple, morphologically complex layers. In addition, spore surfaces can possess elaborate appendages. For all their variability, there is a consistent architecture to the layers encasing the spore. A hallmark of all Clostridiales and Bacillales spores is the cortex, a layer made of peptidoglycan. In close association with the cortex, all species examined possess, at a minimum, a series of proteinaceous layers, called the coat. In some species, including Bacillus subtilis, only the coat is present. In other species, including Bacillus anthracis, an additional layer, called the exosporium, surrounds the coat. Our goals here are to review the present understanding of the structure, composition, assembly, and functions of the coat, primarily in the model organism B. subtilis, but also in the small but growing number of other spore-forming species where new data are showing that there is much to be learned beyond the relatively well developed basis of knowledge in B. subtilis. To help summarize this large field and define future directions for research, we will focus on key findings in recent years. PMID- 27227300 TI - Pathoadaptive Mutations in Uropathogenic Escherichia coli. AB - Uropathogenic Escherichia coli (UPEC) are opportunistic human pathogens that primarily circulate as part of commensal intestinal microbiota. Though they have the ability to survive and proliferate in various urinary tract compartments, the urinary tract is a transient, occasional habitat for UPEC. Because of this, most of the UPEC traits have originally evolved to serve in intestinal colonization and transmission. Some of these bacterial traits serve as virulence factors - they are critical to or assist in survival of UPEC as pathogens, and the structure and/or function may be specialized for the infection. Other traits could serve as anti-virulence factors - they represent liability in the urinary tract and are under selection to be lost or inactivated during the infection. Inactivation, variation, or other changes of the bacterial genes that increase the pathogen's fitness during the infection are called pathoadaptive mutations. This chapter describes examples of pathoadaptive mutations in UPEC and provides rationale for their further in-depth study. PMID- 27227301 TI - The Phagocyte, Metchnikoff, and the Foundation of Immunology. AB - Since the ability of some cells to engulf particulate material was observed before Metchnikoff, he did not "discover" phagocytosis, as is sometimes mentioned in textbooks. Rather, he assigned to particle internalization the role of defending the host against noxious stimuli, which represented a new function relative to the previously recognized task of intracellular digestion. With this proposal, Metchnikoff built the conceptual framework within which immunity could finally be seen as an active host function triggered by noxious stimuli. In this sense, Metchnikoff can be rightly regarded as the father of all immunological sciences and not only of innate immunity or myeloid cell biology. Moreover, the recognition properties of his phagocyte fit surprisingly well with recent discoveries and modern models of immune sensing. For example, rather than assigning to immune recognition exclusively the function of eliminating nonself components (as others did after him), Metchnikoff viewed phagocytes as homeostatic agents capable of monitoring the internal environment and promoting tissue remodeling, thereby continuously defining the identity of the organism. No doubt, Metchnikoff's life and creativity can provide, still today, a rich source of inspiration. PMID- 27227303 TI - Fungal Infections Associated with Contaminated Steroid Injections. AB - In mid-September 2012, the largest healthcare-associated outbreak in U.S. history began. Before it was over, 751 patients were reported with fungal meningitis, stroke, spinal or paraspinal infection, or peripheral osteoarticular infection, and 64 (8.5%) died. Most patients had undergone epidural injection, and a few osteoarticular injection, of methylprednisolone acetate that had been manufactured at the New England Compounding Center (NECC). The offending pathogen in most cases was Exserohilum rostratum, a brown-black soil organism that previously was a rare cause of human infection. Three lots of methylprednisolone were contaminated with mold at NECC; the mold from unopened bottles of methylprednisolone was identical by whole-genome sequencing to the mold that was isolated from ill patients. Early cases manifested as meningitis, some patients suffered posterior circulation strokes, and later cases were more likely to present with localized infection at the injection site, including epidural abscess or phlegmon, vertebral diskitis or osteomyelitis, and arachnoiditis with intradural involvement of nerve roots. Many patients with spinal or paraspinal infection required surgical intervention. Recommendations for treatment evolved over the first few weeks of the outbreak. Initially, combination therapy with liposomal amphotericin B and voriconazole was recommended for all patients; later, combination therapy was recommended only for those who were most ill, and voriconazole monotherapy was recommended for most patients. Among those patients who continued antifungal therapy for at least 6 months, outcomes for most appeared to be successful, although a few patients remain on therapy. PMID- 27227294 TI - Gram-Positive Uropathogens, Polymicrobial Urinary Tract Infection, and the Emerging Microbiota of the Urinary Tract. AB - Gram-positive bacteria are a common cause of urinary-tract infection (UTI), particularly among individuals who are elderly, pregnant, or who have other risk factors for UTI. Here we review the epidemiology, virulence mechanisms, and host response to the most frequently isolated Gram-positive uropathogens: Staphylococcus saprophyticus, Enterococcus faecalis, and Streptococcus agalactiae. We also review several emerging, rare, misclassified, and otherwise underreported Gram-positive pathogens of the urinary tract including Aerococcus, Corynebacterium, Actinobaculum, and Gardnerella. The literature strongly suggests that urologic diseases involving Gram-positive bacteria may be easily overlooked due to limited culture-based assays typically utilized for urine in hospital microbiology laboratories. Some UTIs are polymicrobial in nature, often involving one or more Gram-positive bacteria. We herein review the risk factors and recent evidence for mechanisms of bacterial synergy in experimental models of polymicrobial UTI. Recent experimental data has demonstrated that, despite being cleared quickly from the bladder, some Gram-positive bacteria can impact pathogenic outcomes of co-infecting organisms. When taken together, the available evidence argues that Gram-positive bacteria are important uropathogens in their own right, but that some can be easily overlooked because they are missed by routine diagnostic methods. Finally, a growing body of evidence demonstrates that a surprising variety of fastidious Gram-positive bacteria may either reside in or be regularly exposed to the urinary tract and further suggests that their presence is widespread among women, as well as men. Experimental studies in this area are needed; however, there is a growing appreciation that the composition of bacteria found in the bladder could be a potentially important determinant in urologic disease, including susceptibility to UTI. PMID- 27227305 TI - Innovative Solutions to Sticky Situations: Antiadhesive Strategies for Treating Bacterial Infections. AB - Bacterial adherence to host tissue is an essential process in pathogenesis, necessary for invasion and colonization and often required for the efficient delivery of toxins and other bacterial effectors. As existing treatment options for common bacterial infections dwindle, we find ourselves rapidly approaching a tipping point in our confrontation with antibiotic-resistant strains and in desperate need of new treatment options. Bacterial strains defective in adherence are typically avirulent and unable to cause infection in animal models. The importance of this initial binding event in the pathogenic cascade highlights its potential as a novel therapeutic target. This article seeks to highlight a variety of strategies being employed to treat and prevent infection by targeting the mechanisms of bacterial adhesion. Advancements in this area include the development of novel antivirulence therapies using small molecules, vaccines, and peptides to target a variety of bacterial infections. These therapies target bacterial adhesion through a number of mechanisms, including inhibition of pathogen receptor biogenesis, competition-based strategies with receptor and adhesin analogs, and the inhibition of binding through neutralizing antibodies. While this article is not an exhaustive description of every advancement in the field, we hope it will highlight several promising examples of the therapeutic potential of antiadhesive strategies. PMID- 27227306 TI - The Role of Punctuated Evolution in the Pathogenicity of Influenza Viruses. AB - Influenza is an acute respiratory disease caused by influenza viruses. Evolutionarily, all influenza viruses are zoonoses, arising in the animal reservoir and spilling over into the human population. Several times a century, one of these zoonotic events results in a new influenza virus lineage becoming established in humans and circulating for years or decades as an endemic strain. The worldwide pandemic that occurs shortly after the nascent virus becomes established can have a profound impact on morbidity and mortality. Because influenza viruses continually evolve and the illness they engender can vary considerably based on characteristics of the strain, the weather, other circulating or endemic pathogens, as well as the number of susceptible hosts, the impact of each season on human health is unpredictable. Over time, the general pattern is for pandemic strains to adapt and gradually take on characteristics of seasonal strains with lower virulence and a diminished synergism with bacterial pathogens. Study of this punctuated evolution yields a number of insights into the overall pathogenicity of influenza viruses. PMID- 27227304 TI - Chronic Bacterial Pathogens: Mechanisms of Persistence. AB - Many bacterial pathogens can cause acute infections that are cleared with the onset of adaptive immunity, but a subset of these pathogens can establish persistent, and sometimes lifelong, infections. While bacteria that cause chronic infections are phylogenetically diverse, they share common features in their interactions with the host that enable a protracted period of colonization. This article will compare the persistence strategies of two chronic pathogens from the Proteobacteria, Brucella abortus and Salmonella enterica serovar Typhi, to consider how these two pathogens, which are very different at the genomic level, can utilize common strategies to evade immune clearance to cause chronic intracellular infections of the mononuclear phagocyte system. PMID- 27227302 TI - Staying Alive: Vibrio cholerae's Cycle of Environmental Survival, Transmission, and Dissemination. AB - Infectious diseases kill nearly 9 million people annually. Bacterial pathogens are responsible for a large proportion of these diseases, and the bacterial agents of pneumonia, diarrhea, and tuberculosis are leading causes of death and disability worldwide. Increasingly, the crucial role of nonhost environments in the life cycle of bacterial pathogens is being recognized. Heightened scrutiny has been given to the biological processes impacting pathogen dissemination and survival in the natural environment, because these processes are essential for the transmission of pathogenic bacteria to new hosts. This chapter focuses on the model environmental pathogen Vibrio cholerae to describe recent advances in our understanding of how pathogens survive between hosts and to highlight the processes necessary to support the cycle of environmental survival, transmission, and dissemination. We describe the physiological and molecular responses of V. cholerae to changing environmental conditions, focusing on its survival in aquatic reservoirs between hosts and its entry into and exit from human hosts. PMID- 27227307 TI - The Role of Biotin in Bacterial Physiology and Virulence: a Novel Antibiotic Target for Mycobacterium tuberculosis. AB - Biotin is an essential cofactor for enzymes present in key metabolic pathways such as fatty acid biosynthesis, replenishment of the tricarboxylic acid cycle, and amino acid metabolism. Biotin is synthesized de novo in microorganisms, plants, and fungi, but this metabolic activity is absent in mammals, making biotin biosynthesis an attractive target for antibiotic discovery. In particular, biotin biosynthesis plays important metabolic roles as the sole source of biotin in all stages of the Mycobacterium tuberculosis life cycle due to the lack of a transporter for scavenging exogenous biotin. Biotin is intimately associated with lipid synthesis where the products form key components of the mycobacterial cell membrane that are critical for bacterial survival and pathogenesis. In this review we discuss the central role of biotin in bacterial physiology and highlight studies that demonstrate the importance of its biosynthesis for virulence. The structural biology of the known biotin synthetic enzymes is described alongside studies using structure-guided design, phenotypic screening, and fragment-based approaches to drug discovery as routes to new antituberculosis agents. PMID- 27227308 TI - Microbial Endocrinology in the Pathogenesis of Infectious Disease. AB - Microbial endocrinology represents the intersection of two seemingly disparate fields, microbiology and neurobiology, and is based on the shared presence of neurochemicals that are exactly the same in host as well as in the microorganism. The ability of microorganisms to not only respond to, but also produce, many of the same neurochemicals that are produced by the host, such as during periods of stress, has led to the introduction of this evolutionary-based mechanism which has a role in the pathogenesis of infectious disease. The consideration of microbial endocrinology-based mechanisms has demonstrated, for example, that the prevalent use of catecholamine-based synthetic drugs in the clinical setting contributes to the formation of biofilms in indwelling medical devices. Production of neurochemicals by microorganisms most often employs the same biosynthetic pathways as those utilized by the host, indicating that acquisition of host neurochemical-based signaling system in the host may have been acquired due to lateral gene transfer from microorganisms. That both host and microorganism produce and respond to the very same neurochemicals means that there is bidirectionality contained with the theoretical underpinnings of microbial endocrinology. This can be seen in the role of microbial endocrinology in the microbiota-gut-brain axis and its relevance to infectious disease. Such shared pathways argue for a role of microorganism-neurochemical interactions in infectious disease. PMID- 27227310 TI - The Versatile Type VI Secretion System. AB - Bacterial type VI secretion systems (T6SSs) function as contractile nanomachines to puncture target cells and deliver lethal effectors. In the 10 years since the discovery of the T6SS, much has been learned about the structure and function of this versatile protein secretion apparatus. Most of the conserved protein components that comprise the T6SS apparatus itself have been identified and ascribed specific functions. In addition, numerous effector proteins that are translocated by the T6SS have been identified and characterized. These protein effectors usually represent toxic cargoes that are delivered by the attacker cell to a target cell. Researchers in the field are beginning to better understand the lifestyle or physiology that dictates when bacteria normally express their T6SS. In this article, we consider what is known about the structure and regulation of the T6SS, the numerous classes of antibacterial effector T6SS substrates, and how the action of the T6SS relates to a given lifestyle or behavior in certain bacteria. PMID- 27227312 TI - Stress Responses, Adaptation, and Virulence of Bacterial Pathogens During Host Gastrointestinal Colonization. AB - Invading pathogens are exposed to a multitude of harmful conditions imposed by the host gastrointestinal tract and immune system. Bacterial defenses against these physical and chemical stresses are pivotal for successful host colonization and pathogenesis. Enteric pathogens, which are encountered due to the ingestion of or contact with contaminated foods or materials, are highly successful at surviving harsh conditions to colonize and cause the onset of host illness and disease. Pathogens such as Campylobacter, Helicobacter, Salmonella, Listeria, and virulent strains of Escherichia have evolved elaborate defense mechanisms to adapt to the diverse range of stresses present along the gastrointestinal tract. Furthermore, these pathogens contain a multitude of defenses to help survive and escape from immune cells such as neutrophils and macrophages. This chapter focuses on characterized bacterial defenses against pH, osmotic, oxidative, and nitrosative stresses with emphasis on both the direct and indirect mechanisms that contribute to the survival of each respective stress response. PMID- 27227311 TI - Metalloproteinases: a Functional Pathway for Myeloid Cells. AB - Myeloid cells have diverse roles in regulating immunity, inflammation, and extracellular matrix turnover. To accomplish these tasks, myeloid cells carry an arsenal of metalloproteinases, which include the matrix metalloproteinases and the adamalysins. These enzymes have diverse substrate repertoires, and are thus involved in mediating proteolytic cascades, cell migration, and cell signaling. Dysregulation of metalloproteinases contributes to pathogenic processes, including inflammation, fibrosis, and cancer. Metalloproteinases also have important nonproteolytic functions in controlling cytoskeletal dynamics during macrophage fusion and enhancing transcription to promote antiviral immunity. This review highlights the diverse contributions of metalloproteinases to myeloid cell functions. PMID- 27227313 TI - The Role of Bacterial Spores in Metal Cycling and Their Potential Application in Metal Contaminant Bioremediation. AB - Bacteria are one of the premier biological forces that, in combination with chemical and physical forces, drive metal availability in the environment. Bacterial spores, when found in the environment, are often considered to be dormant and metabolically inactive, in a resting state waiting for favorable conditions for them to germinate. However, this is a highly oversimplified view of spores in the environment. The surface of bacterial spores represents a potential site for chemical reactions to occur. Additionally, proteins in the outer layers (spore coats or exosporium) may also have more specific catalytic activity. As a consequence, bacterial spores can play a role in geochemical processes and may indeed find uses in various biotechnological applications. The aim of this review is to introduce the role of bacteria and bacterial spores in biogeochemical cycles and their potential use as toxic metal bioremediation agents. PMID- 27227314 TI - Structural and Functional Analysis of the Allosteric Inhibition of IRE1alpha with ATP-Competitive Ligands. AB - The accumulation of unfolded proteins under endoplasmic reticulum (ER) stress leads to the activation of the multidomain protein sensor IRE1alpha as part of the unfolded protein response (UPR). Clustering of IRE1alpha lumenal domains in the presence of unfolded proteins promotes kinase trans-autophosphorylation in the cytosol and subsequent RNase domain activation. Interestingly, there is an allosteric relationship between the kinase and RNase domains of IRE1alpha, which allows ATP-competitive inhibitors to modulate the activity of the RNase domain. Here, we use kinase inhibitors to study how ATP-binding site conformation affects the activity of the RNase domain of IRE1alpha. We find that diverse ATP competitive inhibitors of IRE1alpha promote dimerization and activation of RNase activity despite blocking kinase autophosphorylation. In contrast, a subset of ATP-competitive ligands, which we call KIRAs, allosterically inactivate the RNase domain through the kinase domain by stabilizing monomeric IRE1alpha. Further insight into how ATP-competitive inhibitors are able to divergently modulate the RNase domain through the kinase domain was gained by obtaining the first structure of apo human IRE1alpha in the RNase active back-to-back dimer conformation. Comparison of this structure with other existing structures of IRE1alpha and integration of our extensive structure activity relationship (SAR) data has led us to formulate a model to rationalize how ATP-binding site ligands are able to control the IRE1alpha oligomeric state and subsequent RNase domain activity. PMID- 27227315 TI - Impact of the Sensory Neurons on Melanoma Growth In Vivo. AB - Nerve endings are often identified within solid tumors, but their impact on the tumor growth and progression remains poorly understood. Emerging data suggests that the central nervous system may affect cancer development and spreading via the hypothalamic-pituitary-adrenal axis and autonomous nervous system. However, the role of the afferent sensory neurons in tumor growth is unclear, except some reports on perineural invasion in prostate and pancreatic cancer and cancer related pain syndrome. Here, we provide the results of primary testing of the concept that the interaction between melanoma cells and sensory neurons may induce the formation of tumor-supporting microenvironment via attraction of immune regulatory cells by the tumor-activated dorsal root ganglion (DRG) neurons. We report that despite DRG cells not directly up-regulating proliferation of melanoma cells in vitro, presence of DRG neurons allows tumors to grow significantly faster in vivo. This effect has been associated with increased production of chemokines by tumor-activated DRG neurons and attraction of myeloid-derived suppressor cells both in vitro and in vivo. These initial proof-of-concept results justify further investigations of the sensory (afferent) nervous system in the context of tumorigenesis and the local protumorigenic immunoenvironment. PMID- 27227309 TI - The Staphylococcal Biofilm: Adhesins, Regulation, and Host Response. AB - The staphylococci comprise a diverse genus of Gram-positive, nonmotile commensal organisms that inhabit the skin and mucous membranes of humans and other mammals. In general, staphylococci are benign members of the natural flora, but many species have the capacity to be opportunistic pathogens, mainly infecting individuals who have medical device implants or are otherwise immunocompromised. Staphylococcus aureus and Staphylococcus epidermidis are major sources of hospital-acquired infections and are the most common causes of surgical site infections and medical device-associated bloodstream infections. The ability of staphylococci to form biofilms in vivo makes them highly resistant to chemotherapeutics and leads to chronic diseases. These biofilm infections include osteomyelitis, endocarditis, medical device infections, and persistence in the cystic fibrosis lung. Here, we provide a comprehensive analysis of our current understanding of staphylococcal biofilm formation, with an emphasis on adhesins and regulation, while also addressing how staphylococcal biofilms interact with the immune system. On the whole, this review will provide a thorough picture of biofilm formation of the staphylococcus genus and how this mode of growth impacts the host. PMID- 27227316 TI - Phosphonic Acids for Interfacial Engineering of Transparent Conductive Oxides. AB - Transparent conducting oxides (TCOs), such as indium tin oxide and zinc oxide, play an important role as electrode materials in organic-semiconductor devices. The properties of the inorganic-organic interface-the offset between the TCO Fermi level and the relevant transport level, the extent to which the organic semiconductor can wet the oxide surface, and the influence of the surface on semiconductor morphology-significantly affect device performance. This review surveys the literature on TCO modification with phosphonic acids (PAs), which has increasingly been used to engineer these interfacial properties. The first part outlines the relevance of TCO surface modification to organic electronics, surveys methods for the synthesis of PAs, discusses the modes by which they can bind to TCO surfaces, and compares PAs to alternative organic surface modifiers. The next section discusses methods of PA monolayer deposition, the kinetics of monolayer formation, and structural evidence regarding molecular orientation on TCOs. The next sections discuss TCO work-function modification using PAs, tuning of TCO surface energy using PAs, and initiation of polymerizations from TCO tethered PAs. Finally, studies that examine the use of PA-modified TCOs in organic light-emitting diodes and organic photovoltaics are compared. PMID- 27227320 TI - Heteroarene-Directed Oxidative sp(2) C-H Bond Allylation with Aliphatic Alkenes Catalyzed by an (Electron-Deficient eta(5)-Cyclopentadienyl)rhodium(III) Complex. AB - It has been established that the oxidative sp(2) C-H bond allylation with aliphatic alkenes proceeds under mild conditions by using heteroarenes as directing groups and an (electron-deficient eta(5)-cyclopentadienyl)rhodium(III) complex, [Cp(E)RhCl2]2, as a precatalyst. In sharp contrast, the use of [Cp*RhCl2]2 instead of [Cp(E)RhCl2]2 led to a complex mixture of products under the same reaction conditions. PMID- 27227321 TI - Interactions between Fragmented Seagrass Canopies and the Local Hydrodynamics. AB - The systematic creation of gaps within canopies results in fragmentation and the architecture of fragmented canopies differs substantially from non-fragmented canopies. Canopy fragmentation leads to spatial heterogeneity in hydrodynamics and therefore heterogeneity in the sheltering of canopy communities. Identifying the level of instability due to canopy fragmentation is important for canopies in coastal areas impacted by human activities and indeed, climate change. The gap orientation relative to the wave direction is expected to play an important role in determining wave attenuation and sheltering. Initially we investigated the effect of a single transversal gap within a canopy (i.e. a gap oriented perpendicular to the wave direction) on hydrodynamics, which was compared to fully vegetated canopies (i.e. no gaps) and also to bare sediment. The wave velocity increased with gap width for the two canopy densities studied (2.5% and 10% solid plant fraction) reaching wave velocities found over bare sediments. The turbulent kinetic energy (TKE) within the gap also increased, but was more attenuated by the adjacent vegetation than the wave velocity. As expected, denser canopies produced a greater attenuation of both the wave velocity and the turbulent kinetic energy within an adjacent gap, compared to sparse canopies. Using non-dimensional analysis and our experimental data, a parameterization for predicting TKE in a canopy gap was formulated, as a function of easily measured variables. Based on the experimental results, a fragmented canopy model was then developed to determine the overall mixing level in such canopies. The model revealed that canopies with large gaps present more mixing than canopies with small gaps despite having the same total gap area in the canopy. Furthermore, for the same total gap area, dense fragmented canopies provide more shelter than sparse fragmented canopies. PMID- 27227322 TI - Isolation, Characterization, and Reactivity of Fe8Me12(-): Kochi's S = 1/2 Species in Iron-Catalyzed Cross-Couplings with MeMgBr and Ferric Salts. AB - Iron-catalyzed cross-couplings with simple ferric salts have been known since the 1970s, pioneered by Kochi for cross-coupling using alkylmagnesium nucleophiles including MeMgBr. While Kochi observed the formation of a S = 1/2 iron species in reactions of simple ferric salts with MeMgBr proposed to be an iron(I) species, the identity of this species has remained undefined for nearly 40 years. Herein, we report the isolation and characterization of [MgCl(THF)5][Fe8Me12], which combined with EPR and MCD studies is shown to be consistent with Kochi's S = 1/2 species. Reaction studies with beta-bromostyrene demonstrate that this species alone displays minimal reactivity but, when combined with additional MeMgBr, leads to rapid and selective formation of cross-coupled product. PMID- 27227323 TI - Management of Persistent or Recurrent Structural Neck Disease in Differentiated Thyroid Carcinoma: Point and Counterpoint. PMID- 27227324 TI - A Novel Affibody-Auristatin E Conjugate With a Potent and Selective Activity Against HER2+ Cell Lines. AB - Targeted therapy is a new type of cancer treatment that most often uses biologically active drugs attached to a monoclonal antibody. This so called antibody-drug conjugate strategy allows the use of highly toxic substances that target tumor cells specifically, leaving healthy tissues largely unaffected. Over the last few years, antibody-drug conjugates have become a powerful tool in cancer treatment. We developed and characterized a novel cytotoxic conjugate against HER2 tumors in which the antibody has been substituted with a much smaller molecule: the affibody. The conjugate is composed of the ZHER2:2891 affibody that recognizes HER2 and a highly potent cytotoxic drug auristatin E. The ZHER2:2891 molecule does not contain cysteine(s) in its amino acid sequence. We generated 3 variants of ZHER2:2891, each containing a single cysteine to allow conjugation through the maleimide group that is present in the cytotoxic component. In 2 variants, we introduced single S46C and D53C substitutions. In the third variant, a short Drug Conjugation Sequence (DCS) containing a single cysteine was introduced at the C-terminus of ZHER2:2891, resulting in ZHER2:2891 DCS. The latter variant exhibited a significantly higher conjugation yield, and therefore its cytotoxicity has been studied more thoroughly. The ZHER2:2891-DCS MMAE conjugate killed the HER2-overexpressing SK-BR-3 and MDA-MB-453 cells efficiently (IC50 values of 5.2 and 24.8 nM, respectively). The T-47-D and MDA-MB 231 cells that express normal levels of HER2 were significantly less sensitive to the conjugate (IC50 values of 135.6 and 161.5 nM, respectively). Overall, we have demonstrated for the first time that proteins other than antibodies/antibody fragments can be successfully combined with a linker-drug module, resulting in conjugates that eliminate cancer cells selectively. PMID- 27227326 TI - Discovery of 7-(Prolinol-N-yl)-2-phenylamino-thiazolo[5,4-d]pyrimidines as Novel Non-Nucleoside Partial Agonists for the A2A Adenosine Receptor: Prediction from Molecular Modeling. AB - We describe the identification of 7-(prolinol-N-yl)-2-phenylamino-thiazolo[5,4 d]pyrimidines as a novel chemotype of non-nucleoside partial agonists for the A2A adenosine receptor (A2AAR). Molecular-modeling indicated that the (S)-2 hydroxymethylene-pyrrolidine could mimic the interactions of agonists' ribose, suggesting that this class of compounds could have agonistic properties. This was confirmed by functional assays on the A2AAR, where their efficacy could be associated with the presence of the 2-hydroxymethylene moiety. Additionally, the best compound displays promising affinity, selectivity profile, and physicochemical properties. PMID- 27227325 TI - Immune-related Adverse Events of Dendritic Cell Vaccination Correlate With Immunologic and Clinical Outcome in Stage III and IV Melanoma Patients. AB - The purpose of this study was to determine the toxicity profile of dendritic cell (DC) vaccination in stage III and IV melanoma patients, and to evaluate whether there is a correlation between side effects and immunologic and clinical outcome. This is a retrospective analysis of 82 stage III and 137 stage IV melanoma patients, vaccinated with monocyte-derived or naturally circulating autologous DCs loaded with tumor-associated antigens gp100 and tyrosinase. Median follow-up time was 54.3 months in stage III patients and 12.9 months in stage IV patients. Treatment-related adverse events occurred in 84% of patients; grade 3 toxicity was present in 3% of patients. Most common adverse events were flu-like symptoms (67%) and injection site reactions (50%), and both correlated with the presence of tetramer-positive CD8 T cells (both P<0.001). In stage III melanoma patients experiencing flu-like symptoms, median overall survival (OS) was not reached versus 32.3 months in patients without flu-like symptoms (P=0.009); median OS in patients with an injection site reaction was not reached versus 53.7 months in patients without an injection site reaction (P<0.05). In stage IV melanoma patients (primary uveal and mucosal melanomas excluded), median OS in patients with or without flu-like symptoms was 13.1 versus 8.9 months, respectively (P=0.03); median OS in patients with an injection site reaction was 15.7 months versus 9.8 months in patients without an injection site reaction (P=0.003). In conclusion, DC vaccination is safe and tolerable and the occurrence of the immune related side effects, such as flu-like symptoms and injection site reactions, correlates with immunologic and clinical outcome. PMID- 27227327 TI - Photoacclimatory Responses of Zostera marina in the Intertidal and Subtidal Zones. AB - Photoacclimatory responses of the seagrass Zostera marina in the intertidal and subtidal zones were investigated by measuring chlorophyll a fluorescence parameters, photosynthetic pigments, leaf delta13C values, and shoot morphology in two bay systems. Intertidal plants had higher carotenoid concentrations than subtidal plants to avoid photodamage under excess light conditions during the day. The maximum relative electron transport rate (rETRmax) and minimum saturation irradiance (Ek) of the intertidal plants were higher than those of the subtidal plants, whereas photosynthetic efficiency (alpha) and maximum quantum yield (Fv/Fm) were higher in subtidal plants. The intertidal plants also had significantly greater Stern-Volmer non-photochemical quenching (NPQ) than that of the subtidal plants. These results suggest that the subtidal plants photoacclimated to use limited light more efficiently, and the intertidal plants exhibited photosynthetic responses to minimize photodamage at excess irradiance. The delta13C values of leaf tissues were more negative in the intertidal plants than those in the subtidal plants, suggesting that the intertidal plants used atmospheric or dissolved CO2 for photosynthesis during emersion. Effective quantum yield (DeltaF/Fm') in the intertidal plants decreased more slowly after emersion than that in the subtidal plants, indicating higher desiccation tolerance of the intertidal plants. The intertidal plants also recovered more rapidly from desiccation damage than the subtidal plants, suggesting photosynthetic adaptation to desiccation stress. The photosynthetic plasticity of Z. marina in response to variable environmental conditions most likely allows this species to occur in the intertidal and subtidal zones. PMID- 27227328 TI - Two UGT84 Family Glycosyltransferases Catalyze a Critical Reaction of Hydrolyzable Tannin Biosynthesis in Pomegranate (Punica granatum). AB - Hydrolyzable tannins (HTs) play important roles in plant herbivore deterrence and promotion of human health. A critical step in HT production is the formation of 1 O-galloyl-beta-D-glucopyranoside (beta-glucogallin, ester-linked gallic acid and glucose) by a UDP-glucosyltransferase (UGT) activity. We cloned and biochemically characterized four candidate UGTs from pomegranate (Punica granatum), of which only UGT84A23 and UGT84A24 exhibited beta-glucogallin forming activities in enzyme assays. Although overexpression and single RNAi knockdown pomegranate hairy root lines of UGT84A23 or UGT84A24 did not lead to obvious alterations in punicalagin (the prevalent HT in pomegranate) accumulation, double knockdown lines of the two UGTs resulted in largely reduced levels of punicalagins and bis hexahydroxydiphenyl glucose isomers. An unexpected accumulation of galloyl glucosides (ether-linked gallic acid and glucose) was also detected in the double knockdown lines, suggesting that gallic acid was utilized by an unidentified UGT activity for glucoside formation. Transient expression in Nicotiana benthamiana leaves and immunogold labeling in roots of pomegranate seedlings collectively indicated cytosolic localization of UGT84A23 and UGT84A24. Overall, functional characterization and localization of UGT84A23 and UGT84A24 open up opportunities for further understanding the regulatory control of HT metabolism in plants and its coordination with other biochemical pathways in the metabolic network. PMID- 27227330 TI - An Early Instance of Upper Palaeolithic Personal Ornamentation from China: The Freshwater Shell Bead from Shuidonggou 2. AB - We report the discovery and present a detailed analysis of a freshwater bivalve from Shuidonggou Locality 2, layer CL3. This layer is located c. 40 cm below layer CL2, which has yielded numerous ostrich eggshell beads. The shell is identified as the valve of a Corbicula fluminea. Data on the occurrence of this species in the Shuidonggou region during Marine Isotope Stage 3 and taphonomic analysis, conducted in the framework of this study, of a modern biocoenosis and thanatocoenosis suggest that the archeological specimen was collected at one of the numerous fossil or sub-fossil outcrops where valves of this species were available at the time of occupation of level CL3. Experimental grinding and microscopic analysis of modern shells of the same species indicate that the Shuidonggou shell was most probably ground on coarse sandstone to open a hole on its umbo, attach a thread, and use the valve as a personal ornament. Experimental engraving of freshwater shells and microscopic analysis identify an incision crossing the archaeological valve outer surface as possible deliberate engraving. Reappraisal of the site chronology in the light of available radiocarbon evidence suggests an age of at least 34-33 cal kyr BP for layer CL3. Such estimate makes the C. fluminea recovered from CL3 one of the earliest instances of personal ornamentation and the earliest example of a shell bead from China. PMID- 27227329 TI - Prevalence and Fate of Carbapenemase Genes in a Wastewater Treatment Plant in Northern China. AB - Carbapenemase-producing strains of bacteria, which were primarily found in the medical field, have increasingly been found in the environment, thus posing potential risks to public health. One possible way for carbapenemase genes to enter the environment is via wastewater. Therefore, the goal of this study was to determine the occurrence and fate of five high-risk carbapenemase genes in a wastewater treatment plant (WWTP) in northern China using real-time qPCR. Results showed that the blaKPC-2, blaGES-1, and blaIMP-1 genes prevailed throughout all processing stages (even in the chlorination disinfection unit) in the WWTP, whereas the blaVIM-2 and blaOXA-48 genes were not detected in all samples. Worryingly, considerable amounts of carbapenemase genes ((1.54 +/- 0.61) * 103 copies/mL to (2.14+/- 0.41) * 105 copies/mL) were detected in WWTP effluent samples, while the majority of the carbapenemase genes were transported to the dewatered sludge with concentrations from (6.51 +/- 0.14) * 109 copies/g to (6.18 +/- 0.63) * 1010 copies/g dry weight. Furthermore, a total of 97 KPC-2-producing strains, belonging to 8 bacterial genera, were isolated from the WWTP. Sequencing of 16S rRNA revealed that most of KPC-2 producing isolates were opportunistic pathogens, including Klebsiella spp. (10.3%), Enterococcus spp. (11.3%), Acinetobacter spp. (19.6%), Escherichia spp. (12.4%), Shigella spp. (17.5%), Stenotrophomonas spp. (10.3%) and Wautersiella spp. (9.3%). Moreover, blaKPC-2 genes were identified for the first time in Paenibacillus spp. isolates (an indigenous bacteria), indicating an increased risk of horizontal transfer between clinical pathogens and environmental bacteria. Indeed, a conjugation experiment demonstrated transfer of the blaKPC-2 gene to an E.coli J53 strain from a Klebsiella strain isolated from the WWTP. To our knowledge, this is the first study to obtain Paenibacillus spp. isolates carrying the carbapenemase gene and to quantify the abundance of carbapenemase genes in the environment. PMID- 27227331 TI - The Prediction of Key Cytoskeleton Components Involved in Glomerular Diseases Based on a Protein-Protein Interaction Network. AB - Maintenance of the physiological morphologies of different types of cells and tissues is essential for the normal functioning of each system in the human body. Dynamic variations in cell and tissue morphologies depend on accurate adjustments of the cytoskeletal system. The cytoskeletal system in the glomerulus plays a key role in the normal process of kidney filtration. To enhance the understanding of the possible roles of the cytoskeleton in glomerular diseases, we constructed the Glomerular Cytoskeleton Network (GCNet), which shows the protein-protein interaction network in the glomerulus, and identified several possible key cytoskeletal components involved in glomerular diseases. In this study, genes/proteins annotated to the cytoskeleton were detected by Gene Ontology analysis, and glomerulus-enriched genes were selected from nine available glomerular expression datasets. Then, the GCNet was generated by combining these two sets of information. To predict the possible key cytoskeleton components in glomerular diseases, we then examined the common regulation of the genes in GCNet in the context of five glomerular diseases based on their transcriptomic data. As a result, twenty-one cytoskeleton components as potential candidate were highlighted for consistently down- or up-regulating in all five glomerular diseases. And then, these candidates were examined in relation to existing known glomerular diseases and genes to determine their possible functions and interactions. In addition, the mRNA levels of these candidates were also validated in a puromycin aminonucleoside(PAN) induced rat nephropathy model and were also matched with existing Diabetic Nephropathy (DN) transcriptomic data. As a result, there are 15 of 21 candidates in PAN induced nephropathy model were consistent with our predication and also 12 of 21 candidates were matched with differentially expressed genes in the DN transcriptomic data. By providing a novel interaction network and prediction, GCNet contributes to improving the understanding of normal glomerular function and will be useful for detecting target cytoskeleton molecules of interest that may be involved in glomerular diseases in future studies. PMID- 27227332 TI - Characteristics of Foreign-Born Persons in the Swiss Hepatitis C Cohort Study: Implications for Screening Recommendations. AB - BACKGROUND: Switzerland recommends individuals who originate from high-prevalence countries to be screened for hepatitis C virus (HCV) infection. However, not all these persons are equally at risk. We thus aimed to describe the number and characteristics of persons with HCV infection born outside of Switzerland. METHODS: We compared characteristics of anti-HCV-positive individuals in the Swiss Hepatitis C Cohort Study (SCCS) and of HCV cases reported to the Federal Office of Public Health (FOPH), with those of the general population in Switzerland. Persons who inject drugs (PWID) and persons who do not inject drugs (non-PWID) were compared by age groups for different countries of origin (represented by >=1% of participants in the SCCS or FOPH). RESULTS: We included 4,199 persons from the SCCS and 26,610 cases from the FOPH. Both groups had similar characteristics. In both data sources non-PWID were more frequent in foreign-born than in Swiss-born persons (63% versus 34% in the SCCS). The only subgroup with a clearly higher proportion both in the SCCS and FOPH than in the general population were persons over 60 years from Italy and Spain, with a 3.7- and 2.8-fold increase in the SCCS. These persons were non-PWID (99%), less frequently HIV- and anti-HBc positive and more often female than PWID from Italy and Spain; cirrhosis at enrolment was frequent (31%). Their HCV genotypes were consistent with those observed in elderly non-PWID of their birth countries. In the FOPH a higher proportion than in the general population was also seen for cases from Georgia and Russia. CONCLUSION: The identification of subgroups in which HCV infection is particularly frequent might allow for better targeting HCV screening among foreign-born persons in Switzerland and elsewhere. PMID- 27227333 TI - Correction to: Weng Z, et al. Stem Cells Dev 2014 Jul 15;23:1704-1716. PMID- 27227334 TI - Bacterial and Archaeal Diversity in the Gastrointestinal Tract of the North American Beaver (Castor canadensis). AB - The North American Beaver (Castor canadensis) is the second largest living rodent and an iconic symbol of Canada. The beaver is a semi-aquatic browser whose diet consists of lignocellulose from a variety of plants. The beaver is a hindgut fermenter and has an enlarged ceacum that houses a complex microbiome. There have been few studies examining the microbial diversity in gastrointestinal tract of hindgut fermenting herbivores. To examine the bacterial and archaeal communities inhabiting the gastrointestinal tract of the beaver, the microbiome of the ceacum and feaces was examined using culture-independent methods. DNA from the microbial community of the ceacum and feaces of 4 adult beavers was extracted, and the16S rRNA gene was sequenced using either bacterial or archaeal specific primers. A total of 1447 and 1435 unique bacterial OTUs were sequenced from the ceacum and feaces, respectively. On average, the majority of OTUs within the ceacum were classified as Bacteroidetes (49.2%) and Firmicutes (47.6%). The feaces was also dominated by OTUs from Bacteroidetes (36.8%) and Firmicutes (58.9%). The composition of bacterial community was not significantly different among animals. The composition of the ceacal and feacal microbiome differed, but this difference is due to changes in the abundance of closely related OTUs, not because of major differences in the taxonomic composition of the communities. Within these communities, known degraders of lignocellulose were identified. In contrast, to the bacterial microbiome, the archaeal community was dominated by a single species of methanogen, Methanosphaera stadtmanae. The data presented here provide the first insight into the microbial community within the hindgut of the beaver. PMID- 27227335 TI - Correction: Temporal Patterns of Larval Fish Occurrence in a Large Subtropical River. AB - [This corrects the article DOI: 10.1371/journal.pone.0146441.]. PMID- 27227337 TI - Coverage-dependent geometries of nanowires on Ge(0 0 1)-Au surfaces: modification of trenches. AB - Despite intense research the microscopic atomic structure of Au-induced nanowires on Ge(0 0 1) substrates is still under discussion. We analyse a variety of structural models for Au-induced nanowires on the Ge(0 0 1) surface using first principles calculations. Here we focus on subridge modifications at higher Au coverages and study geometries based on the giant missing row model with Ge-Ge dimers in the grooves between the nanowires due to replacing them by Ge-Au heterodimers or Au-Au homodimers. Stable geometries are predicted for higher Au coverages, which however have only a minor influence on the electronic structure. The findings are interpreted that the Au coverage and the actual geometry may vary in the various experiments according to the preparation conditions. PMID- 27227338 TI - Facile one-pot synthesis of highly monodisperse nickel microspheres with raised nickel dots and their adsorption performance for heavy metal ions. AB - This report describes the facile solvothermal synthesis of highly monodispersed nickel microspheres with surfaces uniformly covered by nickel dots. Synthesis parameters including reaction times and reagent concentrations significantly influence the microspheric particle characteristics. The novelty of the synthetic method in this work is twofold: first, the controlled synthesis of Ni metallic microspheres using ethylene glycol as the precursor of a reductant and urea as the origin of OH(-) has never been reported. Second, there are few studies on the construction of Ni microspheres covered by uniform Ni dots using a one-step solvothermal method. Importantly, the as-prepared Ni microspheres show an improved ability to remove Cd(2+) ions even at high concentrations in water and a unique adsorption isotherm having an increasing adsorption capacity for Cd(2+) ions. The presence of Ni dots was considered to play an important role in the onset of the adsorption process. We believe that this work opens up new and possibly exciting opportunities in the field of adsorption of heavy metal ions. PMID- 27227336 TI - Molecular Analysis of Rising Fluoroquinolone Resistance in Belgian Non-Invasive Streptococcus pneumoniae Isolates (1995-2014). AB - We present the results of a longitudinal surveillance study (1995-2014) on fluoroquinolone resistance (FQ-R) among Belgian non-invasive Streptococcus pneumoniae isolates (n = 5,602). For many years, the switch to respiratory fluoroquinolones for the treatment of (a)typical pneumonia had no impact on FQ-R levels. However, since 2011 we observed a significant decrease in susceptibility towards ciprofloxacin, ofloxacin and levofloxacin with peaks of 9.0%, 6.6% and 3.1% resistant isolates, respectively. Resistance to moxifloxacin arised sporadically, and remained <1% throughout the entire study period. We observed classical topoisomerase mutations in gyrA (n = 25), parC (n = 46) and parE (n = 3) in varying combinations, arguing against clonal expansion of FQ-R. The impact of recombination with co-habiting commensal streptococci on FQ-R remains marginal (10.4%). Notably, we observed that a rare combination of DNA Gyrase mutations (GyrA_S81L/GyrB_P454S) suffices for high-level moxifloxacin resistance, contrasting current model. Interestingly, 85/422 pneumococcal strains display MICCIP values which were lowered by at least four dilutions by reserpine, pointing at involvement of efflux pumps in FQ-R. In contrast to susceptible strains, isolates resistant to ciprofloxacin significantly overexpressed the ABC pump PatAB in comparison to reference strain S. pneumoniae ATCC 49619, but this could only be linked to disruptive terminator mutations in a fraction of these. Conversely, no difference in expression of the Major Facilitator PmrA, unaffected by reserpine, was noted between susceptible and resistant S. pneumoniae strains. Finally, we observed that four isolates displayed intermediate to high-level ciprofloxacin resistance without any known molecular resistance mechanism. Focusing future molecular studies on these isolates, which are also commonly found in other studies, might greatly assist in the battle against rising pneumococcal drug resistance. PMID- 27227339 TI - Animal Models Are Valid to Uncover Disease Mechanisms. PMID- 27227340 TI - Two polyketide synthases are necessary for 4-hydroxy-5-methylcoumarin biosynthesis in Gerbera hybrida. AB - Gerbera (Gerbera hybrida) is an economically important ornamental species and a model plant of the Asteraceae family for flower development and secondary metabolism. Gerberin and parasorboside, two bitter tasting glucosidic lactones, are produced in high amounts in nearly all gerbera tissues. Gerbera and its close relatives also produce a rare coumarin, 4-hydroxy-5-methylcoumarin (HMC). Unlike most coumarins, 5-methylcoumarins have been suggested to be derived through the acetate-malonate pathway. All of these polyketide-derived glucosylated molecules are considered to have a role in defense against herbivores and phytopathogens in gerbera. Gerbera expresses three genes encoding 2-pyrone synthases (G2PS1-3). The enzymes are chalcone synthase-like polyketide synthases with altered starter substrate specificity. We have shown previously that G2PS1 is responsible for the synthesis of 4-hydroxy-6-methyl-2-pyrone (triacetolactone), a putative precursor of gerberin and parasorboside. Here we show that polyketide synthases G2PS2 and G2PS3 are necessary for the biosynthesis of HMC in gerbera, and that a reductase enzyme is likely required to complete the pathway to HMC. G2PS2 is expressed in the leaf blade and inflorescences of gerbera, while G2PS3 is strictly root specific. Heterologous expression of G2PS2 or G2PS3 in tobacco leads to the formation of 4,7-dihydroxy-5-methylcoumarin, apparently an unreduced precursor of HMC, while ectopic expression in gerbera leads to HMC formation in tissues where nontransgenic tissue does not express the genes and does not accumulate the compound. Using protein modelling and site-directed mutagenesis we identified the residues I203 and T344 in G2PS2 and G2PS3 to be critical for pentaketide synthase activity. PMID- 27227341 TI - Internal Lymphedema Correlates with Subjective and Objective Measures of Dysphagia in Head and Neck Cancer Patients. AB - BACKGROUND: Tumor/treatment-related internal lymphedema (IL) and/or external lymphedema (EL) are associated with functional deficits and increased symptom burden in head and neck cancer patients (HNCP). Previously, we noted association between EL/IL and patient-reported dysphagia using the Vanderbilt Head and Neck Symptom Survey (VHNSS) version 1.0. OBJECTIVE: To determine the relationship between IL/EL and subjective and objective measures of swallowing function. METHODS: Eighty-one HNCP completed: (1) VHNSS version 2.0, including 13 swallowing/nutrition-related questions grouped into three clusters: swallow solids (ss), swallow liquids (sl), and nutrition(nt); (2) physical assessment of EL using Foldi scale; (3) endoscopic assessment of IL using Patterson scale (n = 56); and (4) modified barium swallow study rated by dysphagia outcome and severity scale (DOSS) and in conjunction with a swallow evaluation by National Outcomes Measurement System (NOMS). Examinations were performed at varied time points to assess lymphedema spectrum, from baseline (n = 15, 18.1%) to 18 months post-therapy (n = 20, 24.1%). RESULTS: VHNSS swallow/nutrition items scores correlated with NOMS/DOSS ratings (p < 0.001). Highest correlation was with NOMS: ss (-0.73); sl (-0.61); nt (-0.56). VHNSS swallow/nutrition scores correlated with maximum grade of swelling for any single structure on Patterson scale: ss (0.43; p = 0.001); sl (0.38; p = 0.004); nt (0.41; p = 0.002). IL of aryepiglottic/pharyngoepiglottic folds, epiglottis, and pyriform sinus were most strongly correlated with VHNSS and NOMS ratings. NOMS/DOSS ratings correlated with EL (> = -0.34; p < 0.01). No meaningful correlations exist between VHNSS swallow/nutrition items and EL (< +/- 0.15, p > 0.20). CONCLUSIONS: IL correlated with subjective and objective measures of swallow dysfunction. Longitudinal analysis of trajectory and impact of IL/EL on dysphagia is ongoing. PMID- 27227342 TI - Racial and ethnic differences in patient navigation: Results from the Patient Navigation Research Program. AB - BACKGROUND: Patient navigation was developed to address barriers to timely care and reduce cancer disparities. The current study explored navigation and racial and ethnic differences in time to the diagnostic resolution of a cancer screening abnormality. METHODS: The authors conducted an analysis of the multisite Patient Navigation Research Program. Participants with an abnormal cancer screening test were allocated to either navigation or control. The unadjusted median time to resolution was calculated for each racial and ethnic group by navigation and control. Multivariable Cox proportional hazards models were fit, adjusting for sex, age, cancer abnormality type, and health insurance and stratifying by center of care. RESULTS: Among a sample of 7514 participants, 29% were non-Hispanic white, 43% were Hispanic, and 28% were black. In the control group, black individuals were found to have a longer median time to diagnostic resolution (108 days) compared with non-Hispanic white individuals (65 days) or Hispanic individuals (68 days) (P<.0001). In the navigated groups, black individuals had a reduction in the median time to diagnostic resolution (97 days) (P<.0001). In the multivariable models, among controls, black race was found to be associated with an increased delay to diagnostic resolution (hazard ratio, 0.77; 95% confidence interval, 0.69-0.84) compared with non-Hispanic white individuals, which was reduced in the navigated arm (hazard ratio, 0.85; 95% confidence interval, 0.77 0.94). CONCLUSIONS: Patient navigation appears to have the greatest impact among black patients, who had the greatest delays in care. Cancer 2016. (c) 2016 American Cancer Society. Cancer 2016;122:2715-2722. (c) 2016 American Cancer Society. PMID- 27227344 TI - Adolescent idiopathic scoliosis. PMID- 27227343 TI - New mouse model of skeletal muscle atrophy using spiral wire immobilization. AB - INTRODUCTION: Disuse-induced skeletal muscle atrophy is a serious concern; however, there is not an effective mouse model to elucidate the molecular mechanisms. We developed a noninvasive atrophy model in mice. METHODS: After the ankle joints of mice were bandaged into a bilateral plantar flexed position, either bilateral or unilateral hindlimbs were immobilized by wrapping in bonsai steel wire. RESULTS: After 3, 5, or 10 days of immobilization of the hip, knee, and ankle, the weight of the soleus and plantaris muscles decreased significantly in both bilateral and unilateral immobilization. MAFbx/atrogin-1 and MuRF1 mRNA was found to have significantly increased in both muscles, consistent with disuse induced atrophy. Notably, the procedure did not result in either edema or necrosis in the fixed hindlimbs. CONCLUSIONS: This method allows repeated, direct access to the immobilized muscle, making it a useful procedure for concurrent application and assessment of various therapeutic interventions. Muscle Nerve 54: 788-791, 2016. PMID- 27227345 TI - Genetics of systemic lupus erythematosus and Sjogren's syndrome: an update. AB - PURPOSE OF REVIEW: To describe the recent studies on the genetics of systemic lupus erythematosus (SLE) and Sjogren's syndrome. RECENT FINDINGS: We overview the most recent findings on the genetic susceptibility of the diseases and provide information on their genetic similarities and differences. SUMMARY: SLE and Sjogren's syndrome are two closely related systemic autoimmune diseases that share multiple clinical and molecular aspects, including a significant number of susceptibility genes. Several genome-wide association studies were recently published in different populations that provide a better picture of their molecular mechanisms. It is becoming clear that their genetic architecture is quite well established, but more information is required on expression quantitative trait loci, epigenetic genome-wide analyses, gene * gene interactions and the role of rare variants. PMID- 27227347 TI - Combined hepatocellular-cholangiocarcinoma in a patient with Abernethy malformation and tetralogy of Fallot: A case report. AB - Abernethy malformation is a rare congenital anomaly of the portal vein where the portal blood bypasses the liver. We report the first case of a patient with Abernethy malformation and tetralogy of Fallot associated with nodular regenerative hyperplasia and focal nodular hyperplasia (FNH), which finally evolved to a giant hepatocellular-cholangiocarcinoma (HCC-CC) of the liver, successfully resected. (Hepatology 2016;64:1800-1802). PMID- 27227346 TI - Update on cardiovascular disease in lupus. AB - PURPOSE OF REVIEW: Atherosclerotic cardiovascular disease confers significant morbidity and mortality in patients with systemic lupus erythematosus (SLE) and cannot be fully explained by traditional cardiovascular risk factors. Recent immunologic discoveries have outlined putative pathways in SLE that may also accelerate the development of atherosclerosis. RECENT FINDINGS: Aberrant innate and adaptive immune responses implicated in lupus pathogenesis may also contribute to the development of accelerated atherosclerosis in these patients. Defective apoptosis, abnormal lipoprotein function, autoantibodies, aberrant neutrophil responses, and a dysregulated type I interferon pathway likely contribute to endothelial dysfunction. SLE macrophages have an inflammatory phenotype that may drive progression of plaque. SUMMARY: Recent discoveries have placed increased emphasis on the immunology of atherosclerotic cardiovascular disease. Understanding the factors that drive the increased risk for cardiovascular disease in SLE patients may provide selective therapeutic targets for reducing inflammation and improving outcomes in atherosclerosis. PMID- 27227348 TI - Maillard Chemistry in Clouds and Aqueous Aerosol As a Source of Atmospheric Humic Like Substances. AB - The reported optical, physical, and chemical properties of aqueous Maillard reaction mixtures of small aldehydes (glyoxal, methylglyoxal, and glycolaldehyde) with ammonium sulfate and amines are compared with those of aqueous extracts of ambient aerosol (water-soluble organic carbon, WSOC) and the humic-like substances (HULIS) fraction of WSOC. Using a combination of new and previously published measurements, we examine fluorescence, X-ray absorbance, UV/vis, and IR spectra, complex refractive indices, (1)H and (13)C NMR spectra, thermograms, aerosol and electrospray ionization mass spectra, surface activity, and hygroscopicity. Atmospheric WSOC and HULIS encompass a range of properties, but in almost every case aqueous aldehyde-amine reaction mixtures are squarely within this range. Notable exceptions are the higher UV/visible absorbance wavelength dependence (Angstrom coefficients) observed for methylglyoxal reaction mixtures, the lack of surface activity of glyoxal reaction mixtures, and the higher N/C ratios of aldehyde-amine reaction products relative to atmospheric WSOC and HULIS extracts. The overall optical, physical, and chemical similarities are consistent with, but not demonstrative of, Maillard chemistry being a significant secondary source of atmospheric HULIS. However, the higher N/C ratios of aldehyde-amine reaction products limits the source strength to <=50% of atmospheric HULIS, assuming that other sources of HULIS incorporate only negligible quantities of nitrogen. PMID- 27227349 TI - Irritable bowel syndrome. PMID- 27227350 TI - Differentiated Expression Patterns and Phagocytic Activities of Type 1 and 2 Microglia. AB - PURPOSE: The purpose of this study was to elucidate the differentiated expression patterns and phagocytic activities of two subtypes of microglia. METHODS: A rat optic nerve crush model was used to identify the expression patterns of two subtypes of microglia. Primary microglia were isolated from rat mixed glial cultures. Subsequently, in vitro experiments evaluating the phagocytosis of axonal debris were performed to analyze responsiveness to immunologic modulators (lipopolysaccharide [LPS], interleukin [IL]-4 and interferon [IFN]-gamma), and we assessed the effects of LPS and IL-4 in the optic nerve crush model. The expression levels of IL-4-associated signaling molecules were analyzed in immunoblotting experiments. RESULTS: In the optic nerve crush model, increased numbers of microglia were found, and a minor and transient population was identified as type 1 microglia. The type 2 microglia phagocytosed more axonal debris than the type 1 microglia. The activities of both subtypes of microglia were enhanced by treatment with LPS and IFN-gamma. However, the phagocytic activity of the type 1 microglia, which showed activated STAT6 signal transduction, was significantly inhibited by stimulation with the anti inflammatory cytokine IL-4. LPS reduced the fragmentation of axons in crushed nerve fibers, whereas the axonal debris remained in IL-4-treated rats subjected to optic nerve crush. CONCLUSIONS: The present study revealed the time-dependent distribution of the two subpopulations of microglia in an optic nerve crush model and IL-4-dependent inhibition of the phagocytosis of axonal debris by type 1 but not type 2 microglia. PMID- 27227351 TI - Continuous Intraocular Pressure Monitoring During Nocturnal Sleep in Patients With Obstructive Sleep Apnea Syndrome. AB - PURPOSE: To evaluate intraocular pressure (IOP) changes during nocturnal sleep in patients with obstructive sleep apnea syndrome (OSAS) using a contact lens sensor (CLS). METHODS: This was a prospective cohort study. Seven OSAS patients who had no ocular diseases except mild cataract were enrolled. Each subject underwent CLS based continuous IOP monitoring on one eye simultaneously with overnight polysomnography. We classified the nocturnal IOP records into nonapnea IOP and apnea IOP, according to the duration of apnea events on polysomnography within each IOP measurement time of 30 seconds every 5 minutes. RESULTS: Differences between IOP levels during nonapnea and apnea phases were statistically analyzed. The mean apnea-hypopnea index, the total number of these events per hour of sleep, was 44.2 +/- 21.0, indicating the participants' severity of OSAS as moderate to severe. The mean range of IOP fluctuations during nocturnal sleep was 262.3 +/- 59.5 mV eq. All patients showed lower mean IOP levels during apnea events than during nonapnea phases, with statistically significant differences detected in four of the seven patients. On average, in all seven eyes, IOP values significantly decreased by 23.1 +/- 16.4 mV eq in association with apnea events. CONCLUSIONS: Obstructive apnea led to an immediate IOP decline during nocturnal sleep in patients with OSAS. Attention should be paid to IOP-independent etiology, such as episodic hypoxia, potentially linking OSAS and glaucoma. PMID- 27227352 TI - Quantification of Focal Outflow Enhancement Using Differential Canalograms. AB - PURPOSE: To quantify regional changes of conventional outflow caused by ab interno trabeculectomy (AIT). METHODS: Gonioscopic, plasma-mediated AIT was established in enucleated pig eyes. We developed a program to automatically quantify outflow changes (R, package eye-canalogram, github.com) using a fluorescent tracer reperfusion technique. Trabecular meshwork (TM) ablation was demonstrated with fluorescent spheres in six eyes before formal outflow quantification with two-dye reperfusion canalograms in six additional eyes. Eyes were perfused with a central, intracameral needle at 15 mm Hg. Canalograms and histology were correlated for each eye. RESULTS: The pig eye provided a model with high similarity to AIT in human patients. Histology indicated ablation of TM and unroofing of most Schlemm's canal segments. Spheres highlighted additional circumferential and radial outflow beyond the immediate area of ablation. Differential canalograms showed that AIT caused an increase of outflow of 17 +/- 5-fold inferonasally, 14 +/- 3-fold superonasally, and also an increase in the opposite quadrants with a 2 +/- 1-fold increase superotemporally, and 3 +/- 3 inferotemporally. Perilimbal specific flow image analysis showed an accelerated nasal filling with an additional perilimbal flow direction into adjacent quadrants. CONCLUSIONS: A quantitative, differential canalography technique was developed that allows us to quantify supraphysiological outflow enhancement by AIT. PMID- 27227353 TI - Risk factors of thrombosis in a single method of microsurgical head and neck reconstruction: A multi-institutional study of 773 reconstructions with a free jejunal graft after total pharyngolaryngoesophagectomy for hypopharyngeal cancer. AB - BACKGROUND: The risk factors for thrombus formation in anastomotic vessels in free-flap head and neck reconstruction have been previously reported. However, the evidence is inconsistent. METHODS: In total, 773 patients who underwent free jejunal graft reconstruction after pharyngolaryngoesophagectomy for hypopharyngeal cancer were enrolled at 12 institutions in Japan from 1995 to 2006. Both the resection area and the applied reconstruction method were constrained to overcome the limitations of previous studies. After the exclusion of recurrent cases, odds ratios (ORs) and 95% confidence intervals (CIs) for thrombosis were calculated in a multivariate logistic regression analysis. RESULTS: Postoperative anastomotic thrombosis developed in 23 patients (3.0%). In the multivariate analysis, the OR for thrombosis per 100-mL increase in blood loss was 1.24 (95% CI = 1.02-1.51), even after controlling for other risk factors. CONCLUSION: Our results show that the blood loss volume is an independent risk factor for thrombosis in free tissue grafts. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: 1708-1716, 2016. PMID- 27227354 TI - Three-month outcomes of ziv-aflibercept in the treatment of diabetic macular oedema. PMID- 27227355 TI - A facile one-step solution deposition via non-solvent/solvent mixture for efficient organometal halide perovskite light-emitting diodes. AB - Although organometal halide perovskite materials have shown great potential in light-emitting diodes, their performance is greatly restricted by the poor morphology of the perovskite layer. In this work, we demonstrate a facile one step solution method to improve the perovskite film morphology via a non solvent/solvent mixture. An efficient CH3NH3PbBr3-based light-emitting diode was prepared with a chlorobenzene/N,N-dimethylformamide mixed solvent. A high efficiency of 0.54 cd A(-1) is demonstrated, which is 22 times higher than that of a device fabricated by a traditional one-step solution process. Furthermore, the uniformity of the emission region and the device stability are strongly improved by this facile one-step solution process. Our work paves a new way for the morphological control of perovskite films for application in light-emitting diodes. PMID- 27227356 TI - Former smokers with non-small-cell lung cancers: a comprehensive investigation of clinicopathologic characteristics, oncogenic drivers, and prognosis. AB - The aim of this present investigation was to evaluate the clinicopathologic characteristics, oncogenic drivers, and prognosis of former smokers with non small-cell lung cancer (NSCLC), and to compare them with those of the current and never smokers. This investigation was a single-institution retrospective study of 2289 NSCLC patients, who were classified as former, current, or never smokers. A collection was made of the clinicopathological characteristics, spectra of well identified driver genes and survival rates. The survival rates were compared using log-rank test, and independent prognostic factors, identified using Cox regression analysis. Of 2289 NSCLC patients, 257 (11.2%) were former smokers; 868 (37.9%), current smokers; and 1164 (50.9%), never smokers. Compared with the current, the former were characterized by older age at diagnosis (64.3y vs. 59.9y; P < 0.001), earlier TNM stage (stage I, 47.9% vs. 39.5%; P = 0.017), fewer solid predominance in adenocarcinomas (16.2% vs. 29.5%; P = 0.005), and more EGFR mutation (33.2% vs. 20.7%; P < 0.001) but less KRAS mutation (6.7% vs. 11.9%, P = 0.041). No statistically significant survival differences were observed between the former and current. However, the light former smokers presented favorable overall survival when compared with the light current and heavy former or current (the light former vs. the heavy former, P = 0.028; the light former vs. the light current, P = 0.048; and the light former vs. the heavy current, P = 0.048). Our findings suggest that the former smokers with NSCLCs can have distinctive clinicopathologic characteristics, oncogenic drivers, and prognosis, and they, especially the light former, can benefit from smoking cessation. PMID- 27227357 TI - In vivo performance of an acellular disc-like angle ply structure (DAPS) for total disc replacement in a small animal model. AB - Total intervertebral disc replacement with a biologic engineered disc may be an alternative to spinal fusion for treating end-stage disc disease. In previous work, we developed disc-like angle ply structures (DAPS) that replicate the structure and function of the native disc and a rat tail model to evaluate DAPS in vivo. Here, we evaluated a strategy in which, after in vivo implantation, endogenous cells could colonize the acellular DAPS and form an extracellular matrix organized by the DAPS topographical template. To do so, acellular DAPS were implanted into the caudal spines of rats and evaluated over 12 weeks by mechanical testing, histology, and microcomputed tomography. An external fixation device was used to stabilize the implant site and various control groups were included to evaluate the effect of immobilization. There was robust tissue formation within the DAPS after implantation and compressive mechanical properties of the implant matched that of the native motion segment. Immobilization provided a stable site for fibrous tissue formation after either a discectomy or a DAPS implantation, but bony fusion eventually resulted, with segments showing intervertebral bridging after long-term implantation, a process that was accelerated by the implanted DAPS. Thus, while compressive mechanical properties were replicated after DAPS implantation, methods to actively prevent fusion must be developed. Future work will focus on limiting fusion by remobilizing the motion segment after a period of integration, delivering pro chondrogenic factors, and pre-seeding DAPS with cells prior to implantation. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:23-31, 2017. PMID- 27227359 TI - Indoor air pollution and the risk of orofacial clefts in a rural population in Shanxi province, China. AB - BACKGROUND: Shanxi Province is a region in China with a high incidence of orofacial clefts (OFCs). Our objective is to investigate the effect of maternal exposure to indoor air pollution (IAP) from coal combustion and tobacco smoke on the risk of an infant being born with orofacial clefts. METHODS: Data were derived from an ongoing population-based case-control study of major external structural birth defects in Shanxi Province. Subjects included 213 cases with OFCs and 1319 healthy babies born between November 2002 and December 2014 in four rural counties. Exposure information was collected by face-to-face interview with mothers within 1 week of delivery or pregnancy termination. The authors derived an exposure index by integrating a series of IAP-related characteristics concerning dwelling and lifestyle. RESULTS: Increased odds of OFC were associated with IAP exposure from heating (adjusted odds ratio [aOR] = 2.4; 95% confidence interval [CI], 1.2-4.5) and from smoking (aOR = 1.8; 95% CI: 1.3, 2.5), but not with exposure from cooking (aOR = 0.9; 95% CI, 0.6-1.4). Compared with women without IAP exposure, the aORs of OFC for children of women with exposure indices of 1, 2, 3 and >= 4 were 1.1 (95% CI, 0.6-1.8), 1.4 (95% CI, 0.8-2.4), 1.8 (95% CI, 1.0-3.2), and 3.4 (95% CI, 1.6-7.4), respectively, demonstrating a clear dose response trend (p < 0.001). CONCLUSION: Periconceptional exposure to IAP from coal combustion and tobacco smoking may increase the risk of OFCs in offsprings of women in Shanxi Province. Birth Defects Research (Part A) 106:708-715, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27227360 TI - HAM/TSP. PMID- 27227358 TI - Tumor-associated macrophages induce capillary morphogenesis of lymphatic endothelial cells derived from human gastric cancer. AB - Tumor lymphangiogenesis is a major prognostic indicator of gastric cancer. Tumor induced inflammation has been shown to attract tumor-associated macrophages that affect lymphangiogenesis. However, detailed mechanisms of macrophage-induced lymphangiogenesis have not been elucidated. Here, we evaluated the interaction between tumor-associated macrophages and lymphatic endothelial cells (LECs) derived from lymph nodes (LNs) of human gastric cancer. Lymphatic endothelial cells were directly or indirectly cocultured with macrophages from healthy human blood, with or without the supernatant of the gastric cancer cell line, OCUM-12. We analyzed the effect of cancer pretreated macrophages and of macrophages from metastatic LNs of gastric cancer on LECs. We observed morphological changes of LECs in coculture and assessed the gene expression of possible lymphangiogenic molecules of macrophages and LECs after contact coculture, and of cancer pretreated macrophages, by quantitative RT-PCR. Specimens of metastatic LN of gastric cancer were immunofluorescently stained. We found that tubulogenesis of LECs was observed only in the contact coculture model. OCUM-12 cells promoted macrophage-induced tubulogenesis of LECs. Relative gene expression of MMP and adhesion molecules was significantly upregulated in both capillary-forming LECs and cocultured macrophages. Cancer pretreated macrophages upregulated lymphangiogenic factors including inflammatory cytokines, MMPs, adhesion molecules, and vascular endothelial growth factor-C. Blocking of intercellular adhesion molecule-1 and macrophage activation suppressed tubulogenesis of LECs. Immunohistochemistry showed macrophages localized around lymphatic vessels. Our results suggested that interaction between LECs and macrophages may be an important initial step of tumor lymphangiogenesis developing LN metastasis. Understanding of its mechanisms could be useful for future therapeutics of gastric cancer. PMID- 27227362 TI - Facing up to stereotypes. PMID- 27227361 TI - Scalable Production of Molybdenum Disulfide Based Biosensors. AB - We demonstrate arrays of opioid biosensors based on chemical vapor deposition grown molybdenum disulfide (MoS2) field effect transistors (FETs) coupled to a computationally redesigned, water-soluble variant of the MU-opioid receptor (MOR). By transferring dense films of monolayer MoS2 crystals onto prefabricated electrode arrays, we obtain high-quality FETs with clean surfaces that allow for reproducible protein attachment. The fabrication yield of MoS2 FETs and biosensors exceeds 95%, with an average mobility of 2.0 cm(2) V(-1) s(-1) (36 cm(2) V(-1) s(-1)) at room temperature under ambient (in vacuo). An atomic length nickel-mediated linker chemistry enables target binding events that occur very close to the MoS2 surface to maximize sensitivity. The biosensor response calibration curve for a synthetic opioid peptide known to bind to the wild-type MOR indicates binding affinity that matches values determined using traditional techniques and a limit of detection ~3 nM (1.5 ng/mL). The combination of scalable array fabrication and rapid, precise binding readout enabled by the MoS2 transistor offers the prospect of a solid-state drug testing platform for rapid readout of the interactions between novel drugs and their intended protein targets. PMID- 27227363 TI - Old player, new partner: EGFRvIII and cytokine receptor signaling in glioblastoma. PMID- 27227364 TI - Olfactory bulb connectomics: a silver lining. PMID- 27227365 TI - What stays the same in orbitofrontal cortex. PMID- 27227367 TI - Corrigendum: Laterodorsal tegmentum interneuron subtypes oppositely regulate olfactory cue-induced innate fear. PMID- 27227368 TI - UNICON: A Powerful and Easy-to-Use Compound Library Converter. AB - The accurate handling of different chemical file formats and the consistent conversion between them play important roles for calculations in complex cheminformatics workflows. Working with different cheminformatic tools often makes the conversion between file formats a mandatory step. Such a conversion might become a difficult task in cases where the information content substantially differs. This paper describes UNICON, an easy-to-use software tool for this task. The functionality of UNICON ranges from file conversion between standard formats SDF, MOL2, SMILES, PDB, and PDBx/mmCIF via the generation of 2D structure coordinates and 3D structures to the enumeration of tautomeric forms, protonation states, and conformer ensembles. For this purpose, UNICON bundles the key elements of the previously described NAOMI library in a single, easy-to-use command line tool. PMID- 27227369 TI - Nanohole Structuring for Improved Performance of Hydrogenated Amorphous Silicon Photovoltaics. AB - While low hole mobilities limit the current collection and efficiency of hydrogenated amorphous silicon (a-Si:H) photovoltaic devices, attempts to improve mobility of the material directly have stagnated. Herein, we explore a method of utilizing nanostructuring of a-Si:H devices to allow for improved hole collection in thick absorber layers. This is achieved by etching an array of 150 nm diameter holes into intrinsic a-Si:H and then coating the structured material with p-type a-Si:H and a conformal zinc oxide transparent conducting layer. The inclusion of these nanoholes yields relative power conversion efficiency (PCE) increases of ~45%, from 7.2 to 10.4% PCE for small area devices. Comparisons of optical properties, time-of-flight mobility measurements, and internal quantum efficiency spectra indicate this efficiency is indeed likely occurring from an improved collection pathway provided by the nanostructuring of the devices. Finally, we estimate that through modest optimizations of the design and fabrication, PCEs of beyond 13% should be obtainable for similar devices. PMID- 27227366 TI - Pericytes of the neurovascular unit: key functions and signaling pathways. AB - Pericytes are vascular mural cells embedded in the basement membrane of blood microvessels. They extend their processes along capillaries, pre-capillary arterioles and post-capillary venules. CNS pericytes are uniquely positioned in the neurovascular unit between endothelial cells, astrocytes and neurons. They integrate, coordinate and process signals from their neighboring cells to generate diverse functional responses that are critical for CNS functions in health and disease, including regulation of the blood-brain barrier permeability, angiogenesis, clearance of toxic metabolites, capillary hemodynamic responses, neuroinflammation and stem cell activity. Here we examine the key signaling pathways between pericytes and their neighboring endothelial cells, astrocytes and neurons that control neurovascular functions. We also review the role of pericytes in CNS disorders including rare monogenic diseases and complex neurological disorders such as Alzheimer's disease and brain tumors. Finally, we discuss directions for future studies. PMID- 27227370 TI - Operative Start Time Does Not Affect Post-Operative Infection Risk. AB - BACKGROUND: Surgical care is delivered 24 h a day at most institutions. Alarmingly, some authors have found that certain operative start times are associated with greater morbidity and mortality rates. This effect has been noted in both the public and private sector. Although some of these differences may be related to process, they may also be caused by the human circadian rhythm and corresponding changes in host defenses. We hypothesized that the time of day of an operation would impact the frequency of certain post-operative outcomes significantly. METHODS: Cases at a single tertiary-care center reported to the American College of Surgeons National Surgical Quality Improvement Program over a 10-year period were identified. Operative start times were divided into six-hour blocks, with 6 am to noon serving as the reference. Standard univariable techniques were applied. Multivariable logistic regression with mixed effects modeling then was used to determine the relation between operative start times and infectious outcomes, controlling for surgeon clustering. Statistical significance was set at p < 0.01. RESULTS: A total of 21,985 cases were identified, of which 2,764 (12.6%) were emergency procedures. Overall, 9.7% (n = 2,142) of patients experienced some post-operative infectious complication. Seventy percent of these infections (n = 1,506) were surgical site infections. On univariable analysis considering all cases, nighttime and evening operations had higher rates of post-operative infections than those in performed during the day (9.1% from 6 am to noon; 9.7% from noon to 6 pm; 14.8% from 6 pm to midnight; and 14.4% from midnight to 6 am; p < 0.001). On multivariable analysis, operative start time was not associated with the risk of post-operative infection, even when emergency cases were considered independently. CONCLUSION: Our data suggest that operative start times have no correlation with post-operative infectious complications. Further work is required to identify the source of the time dependent outcome variability observed in previous studies. PMID- 27227371 TI - Total Synthesis and Stereochemical Assignment of Callyspongiolide. AB - Total synthesis of four callyspongiolide stereoisomers led to unambiguous assignment of relative and absolute stereochemistry of the natural product. Key features of the convergent, fully stereocontrolled route include the use of Krische allylation, Kiyooka Aldol reaction, Kocienski-Julia olefination, Still Gennari olefination, Yamaguchi macrocyclization, and Sonogashira coupling reaction. Biological evaluation of the synthesized compounds against an array of cancer cells revealed that the stereochemistry of the macrolactone core played an important role. PMID- 27227372 TI - Goldilocks Catalysts: Computational Insights into the Role of the 3,3' Substituents on the Selectivity of BINOL-Derived Phosphoric Acid Catalysts. AB - BINOL-derived phosphoric acids provide effective asymmetric catalysis for many organic reactions. Catalysts based on this scaffold show a large structural diversity, especially in the 3,3' substituents, and little is known about the molecular requirements for high selectivity. As a result, selection of the best catalyst for a particular transformation requires a trial and error screening process, as the size of the 3,3' substituents is not simply related to their efficacy: the right choice is neither too large nor too small. We have developed an approach to identify and quantify structural features on the catalyst that determine selectivity. We show that the application of quantitative steric parameters (a new measure, AREA(theta), and rotation barrier) to an imine hydrogenation reaction allows the identification of catalyst features necessary for efficient stereoinduction, validated by QM/MM hybrid calculations. PMID- 27227373 TI - Fatal Abusive Head Trauma Among Children Aged <5 Years - United States, 1999 2014. AB - In the United States, abusive head trauma (AHT) is one of the leading causes of maltreatment fatalities among infants and children, accounting for approximately one third of these deaths (1). Monitoring trends in AHT and evaluating prevention strategies have historically been difficult because of differences in AHT definitions used in research and surveillance. CDC's case definition for AHT and data from the National Vital Statistics System were used to examine the trends in fatal AHT during 1999-2014 using Joinpoint trend analysis software. During this period, AHT resulted in nearly 2,250 deaths among U.S. resident children aged <5 years. Whereas rates were relatively stable during 1999-2009, there was a statistically significant average annual decline of 13.0% in fatal AHT rates during 2009-2014. The fatal AHT rates in 2013 and 2014 (0.41 and 0.43 per 100,000 children aged <5 years, respectively) were the lowest in the 16-year study period. Although this decline in AHT deaths is encouraging, more can be done to prevent AHT, including family-based interventions and policies that create safe, stable, nurturing relationships and environments for children. PMID- 27227374 TI - Copper-Mediated [3 + 2] Oxidative Cyclization Reaction of N-Tosylhydrazones and beta-Ketoesters: Synthesis of 2,3,5-Trisubstituted Furans. AB - The first attempt at utilizing N-tosylhydrazones as two-carbon synthons has been successfully achieved, which underwent a copper-mediated [3 + 2] oxidative cyclization reaction to afford 2,3,5-trisubstituted furans in moderate to good yields. The features of this method include inexpensive metal catalyst, readily available substrates, high regioselectivity, and convenient operation. The studies provide important approaches for further exploration of the powerful and diverse reaction abilities of N-tosylhydrazones. PMID- 27227375 TI - Clinical characteristics of alpha-pyrrolidinovalerophenone (alpha-PVP) poisoning. AB - CONTEXT: alpha-Pyrrolidinovalerophenone (alpha-PVP) is a synthetic cathinone that has been abused in recent years. The clinical presentation of acute alpha-PVP poisoning has not been well characterized. OBJECTIVE: To elucidate the clinical features of acute alpha-PVP poisoning. MATERIALS AND METHODS: This retrospective case series included eight subjects that visited our hospital emergency department (ED) between March 2012 and November 2014 and had analytically confirmed blood alpha-PVP levels. Data related to subject demographics, clinical history, laboratory findings, blood drug levels, and outcome were collected. RESULTS: The median age of the eight study subjects was 27 (range; 21-63) years, and six were male. Drug preparations had been administered by rectal insertion (three subjects) or inhalation (five subjects). The time between drug exposure and presentation at the ED was 8.5 (1-24) h and blood alpha-PVP concentrations ranged from 1.0 to 52.5 ng/ml. Although psychiatric and neurological findings were reported before arrival at the ED in 5/8 and 7/8 subjects, respectively, these were only observed in 1/8 and 2/8 subjects, respectively, at the ED. Symptoms of high body temperature (3/8), tachycardia (5/8), hypertension (3/8), acid-base balance disorder (5/8), coagulopathy (4/6), blood creatinine phosphokinase >190 U/l (6/8), and a blood lactate level > 1.7 mmol/l (5/7) were observed. All subjects survived and were discharged. CONCLUSIONS: This retrospective case series showed that after acute exposure to alpha-PVP, transient neuropsychiatric findings were accompanied by more persistent sympathomimetic physical findings, disorders of acid-base balance and blood coagulation, high blood creatinine phosphokinase, and hyperlactacidemia. PMID- 27227376 TI - Ir(III)-Catalyzed Carbenoid Functionalization of Benzamides: Synthesis of N Methoxyisoquinolinediones and N-Methoxyisoquinolinones. AB - A mild and efficient Ir(III)-catalyzed C-H carbenoid functionalization strategy has been developed to access N-methoxyisoquinolinediones and N methoxyisoquinolinones. The reaction proceeds efficiently in high yield at room temperature over a broad range of substrates without requirement of any additional oxidants or a base. PMID- 27227377 TI - Advancing the Chemistry of CuWO4 for Photoelectrochemical Water Oxidation. AB - Photoelectrochemical (PEC) cells are an ongoing area of exploration that provide a means of converting solar energy into a storable chemical form (molecular bonds). In particular, using PEC cells to drive the water splitting reaction to obtain H2 could provide a clean and sustainable route to convert solar energy into chemical fuels. Since the discovery of catalytic water splitting on TiO2 photoelectrodes by Fujishima and Honda, significant efforts have been directed toward developing high efficiency metal oxides to use as photocatalysts for this reaction. Improving the efficiency of PEC cells requires developing chemically stable, and highly catalytic anodes for the oxygen-evolution reaction (OER). This water oxidation half reaction requires four protons and four electrons coupling in two bond making steps to form O2, which limits the rate. Our group has accelerated efforts in CuWO4 as a candidate for PEC OER chemistry. Its small band gap of 2.3 eV allows for using visible light to drive OER, and the reaction proceeds with a high degree of chemoselectivity, even in the presence of more kinetically accessible anions such as chloride, which is common to seawater. Furthermore, CuWO4 is a chemically robust material when subjected to the highly oxidizing conditions of PEC OER. The next steps for accelerating research using this (and other), ternary phase oxides, is to move beyond reporting the basic PEC measurements to understanding fundamental chemical reaction mechanisms operative during OER on semiconductor surfaces. In this Account, we outline the process for PEC OER on CuWO4 thin films with emphasis on the chemistry of this reaction, the reaction rate and selectivity (determined by controlled-potential coulometry and oxygen-detection experiments). We discuss key challenges with CuWO4 such as slow kinetics and the presence of an OER-mediating mid-gap state, probed by electrochemical impedance spectroscopy. We propose that this mid-gap state imparts the observed chemoselectivity of OER on CuWO4. We introduce insights into the chemical mechanism of PEC OER on CuWO4 using Tafel analysis of electrochemical polarization. We measure Tafel slopes of ~161 mV/dec, showing that PEC OER proceeds at a slower rate on CuWO4 than on common electrocatalysts for this reaction. Moreover, the observed photocurrent is independent of the borate buffer concentration, signaling that the buffer plays no role in the rate determining elementary step of the reaction. Finally, we explore some recent developments in doping this material with Co (a known electrocatalytically active metal) and in coupling it with a transparent manganese phosphate (MnPO) electrocatalyst. We find that introducing Co into the wolframite structure leads to detrimental recombination of photogenerated charge carriers. However, coupling CuWO4 with MnPO increases the photocurrent density. Despite some of these challenges, CuWO4 proves to be a robust, visible light absorbing photoanode that can oxidize water with a high degree of selectivity and is therefore worthy of further exploration. Even if new compositions emerge that show better reactivity, this material serves as an excellent proving ground for the common challenges in developing ternary-phase oxides and other compositionally complex materials. PMID- 27227378 TI - Climate Benefits of U.S. EPA Programs and Policies That Reduced Methane Emissions 1993-2013. AB - The United States (U.S.) Environmental Protection Agency (EPA) has established voluntary programs to reduce methane (CH4) emissions, and regulations that either directly reduce CH4 or provide co-benefits of reducing CH4 emissions while controlling for other air pollutants. These programs and regulations address four sectors that are among the largest domestic CH4 emissions sources: municipal solid waste landfills, oil and natural gas, coal mining, and agricultural manure management. Over the 1993-2013 time period, 127.9 Tg of CH4 emissions reductions were attributed to these programs, equal to about 18% of the counterfactual (or potential) domestic emissions over that time, with almost 70% of the abatement due to landfill sector regulations. Reductions attributed to the voluntary programs increased nearly continuously during the study period. We quantified how these reductions influenced atmospheric CH4 concentration and global temperature, finding a decrease in concentration of 28 ppb and an avoided temperature rise of 0.006 degrees C by 2013. Further, we monetized the climate and ozone-health impacts of the CH4 reductions, yielding an estimated benefit of $255 billion. These results indicate that EPA programs and policies have made a strong contribution to CH4 abatement, with climate and air quality benefits. PMID- 27227379 TI - A Ferromagnetic Salicylaldoximate/Azide Mn(II)2Mn(III)6 Cluster with an S = 17 Ground State and a Single-Molecule-Magnet Response. AB - One new Mn(II)2Mn(III)6 cluster exhibiting an S = 17 spin ground state and single molecule-magnet properties has been designed linking Mn(III)3-salicylaldoximate triangles and tetracoordinated Mn(II) cations by means of end-on azido bridges. The ferromagnetic coupling has been rationalized as a function of their structural parameters. PMID- 27227380 TI - Discovery of (S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl 1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (GDC-0994), an Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibitor in Early Clinical Development. AB - The extracellular signal-regulated kinases ERK1/2 represent an essential node within the RAS/RAF/MEK/ERK signaling cascade that is commonly activated by oncogenic mutations in BRAF or RAS or by upstream oncogenic signaling. While targeting upstream nodes with RAF and MEK inhibitors has proven effective clinically, resistance frequently develops through reactivation of the pathway. Simultaneous targeting of multiple nodes in the pathway, such as MEK and ERK, offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Described herein is the discovery and characterization of GDC-0994 (22), an orally bioavailable small molecule inhibitor selective for ERK kinase activity. PMID- 27227382 TI - Journey to Here. PMID- 27227381 TI - The Influence of Family History Risk Levels of Diabetes on Disease Prevalence in a High-Risk Diabetic Chinese Population. AB - BACKGROUND: Diabetes is associated with genetic susceptibility, and family history is a risk factor. The study investigated the association between different family history risk levels and the prevalence of diabetes in a multi high-risk cohort and evaluated the impact of family history of diabetes on insulin secretion and insulin sensitivity. MATERIALS AND METHODS: We analyzed data from 9754 adults who participated in the Shanghai High-Risk Diabetic Screen Project between 2002 and 2012. The association among three family history risk levels (mild, moderate, and high) with the prevalence of diabetes, insulin secretion, and insulin sensitivity was evaluated in the multi high-risk cohort. RESULTS: Overall, 69.6%, 24.8%, and 5.6% of participants were categorized as having mild, moderate, and high familial risk, respectively. The standardized prevalence was higher in the high family history risk group (43.1%) than in the moderate group (37.3%) and in the mild group (23.5%) (P < 0.001). The odds ratios (ORs) were significantly increased in the moderate group (OR 1.27, 95% confidence interval [CI] 1.15-1.40, P < 0.05) and in the high group (OR 1.69, 95% CI 1.41 2.02, P < 0.05). Among the 3245 normal glucose tolerance participants, insulin secretion significantly declined with increasing levels of family history risk, but there were no significant differences in insulin sensitivity among the three groups. CONCLUSION: The prevalence of diabetes was independently associated with an increasing family history risk level among multi high-risk Chinese populations. Subjects with moderate and high familial history of diabetes displayed a significant decrease in insulin secretion. PMID- 27227383 TI - Interactions of Pri-miRNA-34b/c and TP53 Polymorphisms on the Risk of Osteoporosis. AB - BACKGROUND: Osteoporosis (OP) is a common, multifactorial disorder. Here, we investigated the association between polymorphisms in pri-miR-34b/c (rs4938723) and TP53 (Arg72Pro) and the prevalence of OP. METHODS: A total of 681 individuals were assessed in a case-control study, including 310 patients with OP and 371 controls. Variants in pri-miR-34b/c and TP53 were identified using a polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The presence of the CC and CT/CC pri-miR-34b/c genotypes were associated with a significantly reduced risk of OP compared with the TT genotype (CC vs. TT: odds ratio [OR] = 0.32, 95% confidence intervals [CI] = 0.17-0.59; p < 0.001; CT/CC vs. TT: OR = 0.69, 95% CI = 0.51-0.93; p = 0.016). The CC genotype was also associated with a significantly reduced OP risk compared with the TT/CT genotypes (OR = 0.35, 95% CI = 0.19-0.64; p < 0.001). Furthermore, compared with the carriers of the Arg72Pro GG genotype, carriers of the CC genotype had a 2.21-fold increased OP risk (95% CI = 1.45-3.37; p < 0.001) and CG/CC genotypes carriers had a 1.96-fold increased OP risk (95% CI = 1.39-2.76; p < 0.001). CONCLUSIONS: The present findings indicate that pri-miR-34b/c rs4938723 and TP53 Arg72Pro polymorphisms may contribute to the risk of OP. PMID- 27227390 TI - Scanning tunneling spectroscopy study of the Dirac spectrum of germanene. AB - The temperature dependence of the density of states of germanene, synthesized on Ge/Pt crystals, has been investigated with scanning tunneling spectroscopy. After correction for thermal broadening, a virtually perfect V-shaped density of states, which is a hallmark of a two-dimensional Dirac system, has been found. In an attempt to directly measure the energy dispersion relation via quasiparticle interference we have recorded spatial maps of the differential conductivity near the edges and defects of germanene. Unfortunately, we did not find any sign of Friedel oscillations. The absence of these Friedel oscillations hints to the occurrence of Klein tunneling. PMID- 27227384 TI - Assessment of lung deposition and analysis of the effect of fluticasone/salmeterol hydrofluoroalkane (HFA) pressurized metered dose inhaler (pMDI) in stable persistent asthma patients using functional respiratory imaging. AB - BACKGROUND: Unambiguously for inhaled products, PK measures are best suited for ensuring that the total systemic exposure is equivalent for two products but cannot provide regional information about lung deposition and structural changes. Functional respiratory imaging (FRI) has been demonstrated to be sensitive for distinguishing small but imperative differences related to a single treatment. METHODS: In this study FRI is used in 16 asthmatic patients to assess equivalence in regional deposition for two products (fluticasone/salmeterol, test and reference) by directly measuring regional functional and structural changes within the lungs following its administration. RESULTS: No differences were observed between the lung deposition patterns and the effects on lung structure and function of two products, having the same formulation and manufactured by different organizations using FRI. CONCLUSIONS: Results using FRI complement PK assessments. The added value of this approach to the conventional clinical methods could be significant. PMID- 27227391 TI - Mycobacterium chelonae Scleral Abscess After Intravitreal Ranibizumab Injection. AB - PURPOSE: To report a case of Mycobacterium chelonae scleral abscess after an intravitreal injection of ranibizumab. METHODS: A 54-year-old female received an intravitreal ranibizumab injection for diabetic macular edema. Two weeks postinjection, a scleral abscess developed at the injection site. The patient was treated with incision and drainage of the abscess, subconjunctival injection of amikacin, topical clarithromycin and amikacin, and oral clarithromycin. RESULTS: After 4 weeks of treatment, the inflammation and infection resolved, and the patient returned to best-corrected preinjection visual acuity. CONCLUSIONS: Injection-site scleral abscesses are very rare and serious complications of intravitreal injections. Once the abscess is drained, it is possible to identify the organism and treat the infection with appropriate combination antibiotic therapy. PMID- 27227392 TI - Spectrum of Clinical Signs and Genetic Characterization of Gelatinous Drop-Like Corneal Dystrophy in a Colombian Family. AB - PURPOSE: To describe the clinical signs of gelatinous drop-like corneal dystrophy (GDLD) in a consanguineous Colombian family and determine the underlying genetic cause. METHODS: We performed ocular examination of available family members and bidirectionally Sanger sequenced the GDLD-associated gene, TACSTD2. In one individual, the presence of subepithelial amyloid was confirmed with biopsy. RESULTS: The parents were consanguineous and 5 of their 10 children had GDLD. Typical mulberry subepithelial deposits with subepithelial vascularization were present in 3 individuals; 2 individuals only had mild polymorphic anterior stromal opacity. We identified a homozygous TACSTD2 missense mutation, c.551A>G, p.(Tyr184Cys), in the affected family members. Both parents were heterozygous for the mutation, and unaffected siblings were either heterozygous or homozygous wild type for this allele. In the Colombian population, this mutation has a minor allele frequency of 0.53%. CONCLUSION: The clinical presentation of GDLD in this family was variable and does not solely support an age-dependent progression of the phenotype, suggesting that environmental or other genetic factors can modify phenotypic expression. The relatively high prevalence of this mutation in the Colombian population suggests that other individuals may have undiagnosed subclinical disease. PMID- 27227393 TI - Correlation of Sex and Myopia With Corneal Epithelial and Stromal Thicknesses. AB - PURPOSE: To measure the corneal epithelial thickness (CET) and stromal thickness (ST) in normal subjects, and to also evaluate their correlation with gender, age, and myopia severity. METHODS: A total of 162 normal subjects were enrolled; they were divided into 3 groups based on their refractive status: "low myopia" (-0.25 to -3.0 D), "moderate myopia" (-3.0 to -6.0 D), and "high myopia" (more than -6.0 D). The CET and total corneal thickness were obtained using optical coherence tomography, and the regional thicknesses and topographic variability were compared among the 3 myopia groups and between men and women. Furthermore, the correlation between the thickness measurements and gender, age, and refractive status was analyzed. RESULTS: The CET and ST of the central segment (2 mm in diameter) did not significantly differ between the 3 groups. In the paracentral and midperipheral zones (annuli 2-5 mm and 5-6 mm from the center), the CET in some areas, and the ST in most areas, differed significantly among the 3 groups. The CET values of men and women in the central segment were 54.6 +/- 3.5 MUm and 52.8 +/- 3.5 MUm, respectively (P = 0.003). Similar differences were observed in the paracentral and midperipheral zones. Multiple regression analysis suggested that the CET is related to gender, whereas the ST is associated with myopia severity. Age was not correlated with either the CET or ST. CONCLUSIONS: The CET is significantly greater in men than in women, and is not correlated with myopia severity, whereas the ST is inversely correlated with myopia severity, without significant gender difference. PMID- 27227394 TI - Anterior Segment Optical Coherence Tomography of Patients With Late-Onset Tunnel Fungal Infections With Endophthalmitis After Cataract Surgery. AB - PURPOSE: To report the use of anterior segment optical coherence tomography for characterization of late-onset tunnel fungal infections with endophthalmitis after cataract surgery. METHODS: Case reports. RESULTS: A 77-year-old female (case 1) and a 76-year-old male (case 2) who received cataract surgery 15 and 1 year before their initial visits, respectively, were treated with topical steroids based on a diagnosis of uveitis, because they showed growing white lesions on the upper iris and beneath the cataract scleral wound. Irrigation of the anterior chambers and removal of the white lesions were performed in each case, and microbiological tests were positive for fungi (case 1, a positive culture of Fusarium sp.; case 2, a filamentous fungus present in a direct smear) in the white lesions. Both cases were diagnosed as late-onset fungal endophthalmitis after cataract surgery and were treated with topical and systemic antifungal agents. However, the white lesions reappeared, and the inflammation in the anterior chambers worsened. Anterior segment optical coherence tomography showed the spread of the white lesions into the scleral incisions from cataract surgery. Deroofing of the tunnel and sclerocorneal patch grafts were performed in both cases to treat the fungal tunnel infections. After these treatments, inflammation of both corneas and anterior chambers subsided. CONCLUSIONS: Anterior segment optical coherence tomography can be used to identify late-onset fungal tunnel infections with endophthalmitis after cataract surgery. PMID- 27227395 TI - In Vivo Measurement of Human Corneal Impedance Value. AB - PURPOSE: To examine the validity of in vivo electrical corneal resistance (CR) measurements taken by a corneal resistance device (CRD). METHODS: Eighty-two eyes (mean age +/- SD, 50.1 +/- 23.3; range, 22-87 years: 50 eyes of 33 males and 32 eyes of 17 females) of patients who had undergone cataract surgery and volunteers at the Kanazawa Medical University Hospital were enrolled. The CR was compared among gender; age; side, that is, left versus right eye; healthy (fluorescein negative) versus epithelium-injured eyes (fluorescein-positive), corneal radius of curvature; corneal endothelial cell count; and corneal thickness. RESULTS: The mean +/- SD of the CR in the 82 eyes was 273.2 +/- 78.2 Omega. By age group, the mean +/- SD CR was 283.3 +/- 87.4 Omega (30 eyes) in the 20s, 275.0 +/- 50.0 Omega (4 eyes) in the 30s, 266.7 +/- 70.7 Omega (9 eyes) in the 40s, 257.1 +/- 53.5 Omega (7 eyes) in the 50s, 242.9 +/- 78.7 Omega (7 eyes) in the 60s, 266.7 +/- 84.0 Omega (18 eyes) in the 70s, and 300.0 +/- 81.6 Omega (7 eyes) in the 80s, with no significant difference among the groups. By gender, the mean +/- SD CR was 270.0 +/- 83.0 Omega (50 eyes) in males and 278.0 +/- 71.0 Omega (32 eyes) in females. By side, the CR values were 282.9 +/- 83.4 Omega (44 eyes) in the right eye, 265.9 +/- 71.3 Omega (41 eyes) in the left eye, with no significant difference among the groups. By status, the values were 280.0 +/- 70.0 Omega (44 eyes) in healthy eyes and 200.0 +/- 144.2 Omega (13 eyes) in injured eyes, with a significant between-group difference (P = 0.009). The mean +/- SD corneal thickness (0.56 +/- 0.03 mm) in 46 healthy eyes was slightly correlated with the CR. CONCLUSIONS: The CRD quantitatively measured the CR in healthy eyes. The CR did not differ significantly by age, gender, or left versus right eye. The significant difference in CR between the healthy and injured eyes showed that the measurements have validity. PMID- 27227396 TI - Hemorrhagic Descemet Membrane Detachment Following Syphilitic Interstitial Keratitis. AB - PURPOSE: Syphilitic interstitial keratitis is a stromal inflammatory disease with characteristic secondary vascularization. This case illustrates a late complication of hemorrhagic Descemet membrane detachment. METHODS: Case report. RESULTS: The patient presented with painless sudden visual loss and progressive shallowing of the anterior chamber caused by hemorrhagic Descemet membrane detachment. She had corneal neovascularization and a positive syphilis serology. Owing to the risk of pupil block glaucoma, the patient had surgical drainage of the blood via an ab externo approach. CONCLUSIONS: This case illustrates a previously unreported complication of syphilitic interstitial keratitis. The patient recovered good visual acuity and had residual pigment deposits in the pre Descemet interface. PMID- 27227398 TI - Successful Treatment of Conjunctival Lymphangiectasia With Subconjunctival Injection of Bevacizumab. AB - PURPOSE: To report a novel intervention for the treatment of conjunctival lymphangiectasia-subconjunctival injection of bevacizumab. METHODS: A 53-year-old white male presented with a 3-month history of right ocular discomfort and redness unresponsive to conventional topical treatment of lubricants and steroids. A clinical diagnosis of conjunctival lymphangiectasia was confirmed by biopsy. Bevacizumab (25 mg/mL) was injected subconjunctivally into the affected area. RESULTS: An improvement in the degree of conjunctival chemosis was evident at 5 days postinjection. At 1-month follow-up, symptoms had fully resolved. No recurrence had been observed at 3 years' follow-up. CONCLUSIONS: Subconjunctival bevacizumab injection may be an effective treatment for conjunctival lymphangiectasia. PMID- 27227397 TI - Influence of Omega 3 and 6 Fatty Acids on Human Meibomian Gland Epithelial Cells. AB - PURPOSE: Oral supplementation with omega 3 (omega-3) and/or 6 (omega-6) fatty acids (FAs) has been reported to alleviate the signs and symptoms of dry eye disease and to improve the expressibility and quality of meibum, in patients with meibomian gland dysfunction. We tested our hypothesis that these FA effects may reflect a direct FA action on human meibomian gland epithelial cells. METHODS: Immortalized human meibomian gland epithelial cells (IHMGECs) were cultured with omega-3, omega-6, or both FAs together for up to 7 days in the presence or absence of serum. After FA exposure, cells were analyzed for lipid expression, lysosome content, and proliferative ability. RESULTS: Our research shows that omega-3 and omega-6 stimulate the accumulation of small neutral lipid-containing vesicles, but not lysosomes, in IHMGECs. This vesicular effect was associated with a 2.4- to 3.7-fold increase in the cellular content of triglycerides after omega-3 and omega-6 treatment, respectively. The combination of both FAs together also enhanced triglyceride levels. Of interest, culture of IHMGECs with omega-3 and azithromycin, a known inducer of IHMGEC differentiation, led to a significantly greater amount of total neutral lipids, relative to that found with azithromycin alone. Cellular exposure to the FAs did not alter the expression of free or esterified cholesterol, or phospholipids. Further, these FAs, alone or together, prevented the proliferation of IHMGECs in serum-free, but not serum containing, media. CONCLUSIONS: Our findings support our hypothesis and demonstrate that omega-3 and omega-6 can act directly on IHMGECs to influence the quality and quantity of intracellular lipids. PMID- 27227399 TI - Late Stromal Rejection in Deep Anterior Lamellar Keratoplasty: A Case Series. AB - PURPOSE: To report a series of 4 cases (3 patients) with late stromal graft rejection 32 to 46 months after an uneventful deep anterior lamellar keratoplasty (DALK). METHODS: Three patients (4 eyes), who had undergone an uneventful DALK for keratoconus (3 eyes) and infectious keratitis (1 eye) 32 to 46 months previously presented with a history of ocular discomfort and redness, with reduced visual acuity in 3 eyes. In all cases, all sutures had been removed at least 18 months previously. On examination, there was superficial and in 2 eyes deep neovascularization. In 2 eyes, the vessels extended within the interface between the donor and host corneas. The stroma of the donor cornea adjacent to the areas of vascularization was edematous. A diagnosis of stromal graft rejection was made, and the patients were administered intensive topical corticosteroids. RESULTS: All eyes responded well to treatment, becoming more comfortable, with decreasing redness, reversal of corneal edema, and return of prerejection best corrected visual acuity with up to 18 months follow-up. The patients continued to receive tapering dosage of topical corticosteroid for 12 months. In 1 eye topical steroids were reintroduced at 13 months because of a further rejection episode. CONCLUSIONS: These cases of late stromal rejection after DALK provide clinical evidence that donor keratocytes may persist in such lamellar grafts for extended periods and that patients should be warned that rejection may occur years after surgery. PMID- 27227400 TI - Gatifloxacin 0.3% Versus Fortified Tobramycin-Cefazolin in Treating Nonperforated Bacterial Corneal Ulcers: Randomized, Controlled Trial. PMID- 27227401 TI - The Prevalence of Electroconvulsive Therapy Use Since 1973: A Meta-analysis. AB - OBJECTIVES: A formal meta-analysis of the use of electroconvulsive therapy (ECT) has never been conducted before in literature reviews or syntheses. Such a study would be hampered by heterogeneity and potential reporting biases. However, it would provide a single comparable measure to allow an analysis of statistical key dimensions such as trends across time and psychiatric resources available. It would also help planners and decision makers to set standards and benchmarks for national and regional guidelines for quality assurance and research in health services. METHODS: We surveyed different databases for relevant studies, limited from 1973 to October 2013. Data were extracted independently by 4 reviewers. The articles retrieved were peerreviewed studies (data-based studies or surveys) presenting ECT population rates (annual patient rates calculated from the general population) or number of patients receiving ECT during or after 1973 and attending a psychiatric establishment (either hospitals or approved ECT delivery centers for inpatients and outpatients in well-defined geographic areas). RESULTS: This meta-analysis includes a total of 18 studies from 12 countries. A composite event rate of 16.9/100,000 inhabitants emerged, characterized by high heterogeneity. Across the countries assessed, the prevalence of ECT was higher in older studies. CONCLUSIONS: By its prevalence, ECT remains rare to exceptional as a specialist treatment for mental disorders. Heterogeneity across regions or countries could best be explained by insufficient standardization of ECT procedures and practices. Linked health databases and audits could help strengthen the effectiveness of ECT in relation to primary outcomes such as suicide and help determine the gap in ECT provision, if any. PMID- 27227402 TI - Electroconvulsive Therapy Alone for Schizophrenia: A Meta-analysis of Randomized, Single-blind, Controlled Trials [RETRACTED]. AB - PURPOSE: Electroconvulsive therapy (ECT) is a common treatment in practice for schizophrenia in most developing countries. This is a meta-analysis of the efficacy and safety of ECT alone versus antipsychotic (AP) monotherapy for schizophrenia using randomized, single-blind, controlled trial (RCT) data. METHODS: Two assessors independently extracted data. Standardized and weighted mean difference (SMD/WMD), odds ratios (ORs) +/- 95% confidence intervals (CIs), and number needed to harm (NNH) were calculated by Review Manager Version 5.3 and the Comprehensive Meta-Analysis Version 2 software. RESULTS: Five RCTs (n = 365; age, 34.1 +/- 4.7 years; percentage of male, 52.8 +/- 9.5; range on the Jaded scale, 2-3) were identified and analyzed. Electroconvulsive therapy alone was superior to AP monotherapy with chlorpromazine, haloperidol, paliperidone, clozapine, and risperidone, respectively, regarding symptomatic improvement at last-observation end point (SMD, -0.84; P = 0.02; I = 89%). Improvement with ECT separated from AP as early as weeks 1 to 2 (SMD, -1.26; P = 0.01; I = 89%). Meta analysis of the end point memory quotient of the Wechsler Memory Scale-Revised, Chinese version, revealed that the ECT alone group had poorer memory performance than the AP group (WMD, -9.34; P < 0.00001; I = 0%), but the difference lost its significance within 2 weeks after ECT (WMD, 0.09 to -6.54; P = 0.11-0.97; I = 0%). Compared with AP monotherapy, ECT was associated with more memory impairment (OR, 14.11; P = 0.004; NNH, 6) but with less akathisia (OR, 0.06; P = 0.0009; NNH, 6), tremor (OR, 0.08; P = 0.02; NNH, 7), and tachycardia (OR, 0.06; P = 0.006; NNH, 5). There were no significant differences in other adverse events and all-cause discontinuation. CONCLUSIONS: Electroconvulsive therapy alone could be an effective and safe treatment option for schizophrenia, with transient memory impairment and headache being the major side effects. PMID- 27227403 TI - Risk of Care Home Placement following Acute Hospital Admission: Effects of a Pay for-Performance Scheme for Dementia. AB - INTRODUCTION: The Quality and Outcomes Framework, or QOF, rewards primary care doctors (GPs) in the UK for providing certain types of care. Since 2006, GPs have been paid to identify patients with dementia and to conduct an annual review of their mental and physical health. During the review, the GP also assesses the carer's support needs, including impact of caring, and ensures that services are co-ordinated across care settings. In principle, this type of care should reduce the risk of admission to long-term residential care directly from an acute hospital ward, a phenomenon considered to be indicative of poor quality care. However, this potential effect has not previously been tested. METHODS: Using English data from 2006/07 to 2010/11, we ran multilevel logit models to assess the impact of the QOF review on the risk of care home placement following emergency admission to acute hospital. Emergency admissions were defined for (a) people with a primary diagnosis of dementia and (b) people with dementia admitted for treatment of an ambulatory care sensitive condition. We adjusted for a wide range of potential confounding factors. RESULTS: Over the study period, 19% of individuals admitted to hospital with a primary diagnosis of dementia (N = 31,120) were discharged to a care home; of those admitted for an ambulatory care sensitive condition (N = 139,267), the corresponding figure was 14%. Risk factors for subsequent care home placement included older age, female gender, vascular dementia, incontinence, fall, hip fracture, and number of comorbidities. Better performance on the QOF review was associated with a lower risk of care home placement but only when the admission was for an ambulatory care sensitive condition. CONCLUSIONS: The QOF dementia review may help to reduce the risk of long-term care home placement following acute hospital admission. PMID- 27227404 TI - Strain Distribution in Root Surface Dentin of Maxillary Central Incisors during Lateral Compaction. AB - AIM: To precisely quantify the circumferential strains created along the radicular dentin of maxillary incisors during a simulated clinical procedure of lateral compaction. METHODS: Six miniature strain gauges were bonded on the roots of fourteen recently extracted maxillary central incisors that were subjected to root canal instrumentation. The strain gauges were bonded at three levels (apical, middle, and coronal) and four aspects (buccal, lingual, mesial, and distal) of the roots. Each tooth was embedded in a PVC cylinder containing polyvinyl-siloxane impression material. Root filling was then performed by simulating the clinical procedure of lateral compaction using nickel-titanium finger spreaders. The force applied to the spreader and the strains developing in the surface root dentin were continuously recorded at a frequency of 10 Hz. RESULTS: The highest strains that developed during lateral compaction were in the mesial and distal aspects at the apical level of the root. The magnitudes of the maximal mesial/distal strains at the apical as well as the mid-root levels were approximately 2.5-3 times higher than those at the buccal/lingual aspects (p = 0.041). The strains decreased significantly (p<0.04) from the apical through the mid-root levels to the coronal level, yielding gradients of 2.5- and 6-fold, respectively. The mesial and distal strains were consistently tensile and did not differ significantly; however, the buccal strains were generally 35-65% higher than the lingual strains (p = 0.078). Lateral compaction resulted in the gradual build-up of residual strains, resulting in generation of a 'stair-step' curve. These strains declined gradually and almost completely disappeared after 1000 sec. CONCLUSIONS: With proper mounting of several miniature strain gauges at various levels and aspects of the root, significant circumferential strains can be monitored under clinically relevant compaction forces. The residual strains at the end of lateral compaction are not stored in the dentin but decrease gradually to negligible levels. PMID- 27227405 TI - Predicting Ancestral Segmentation Phenotypes from Drosophila to Anopheles Using In Silico Evolution. AB - Molecular evolution is an established technique for inferring gene homology but regulatory DNA turns over so rapidly that inference of ancestral networks is often impossible. In silico evolution is used to compute the most parsimonious path in regulatory space for anterior-posterior patterning linking two Dipterian species. The expression pattern of gap genes has evolved between Drosophila (fly) and Anopheles (mosquito), yet one of their targets, eve, has remained invariant. Our model predicts that stripe 5 in fly disappears and a new posterior stripe is created in mosquito, thus eve stripe modules 3+7 and 4+6 in fly are homologous to 3+6 and 4+5 in mosquito. We can place Clogmia on this evolutionary pathway and it shares the mosquito homologies. To account for the evolution of the other pair rule genes in the posterior we have to assume that the ancestral Dipterian utilized a dynamic method to phase those genes in relation to eve. PMID- 27227406 TI - Multifaceted Intervention to Prevent Venous Thromboembolism in Patients Hospitalized for Acute Medical Illness: A Multicenter Cluster-Randomized Trial. AB - BACKGROUND: Misuse of thromboprophylaxis may increase preventable complications for hospitalized medical patients. OBJECTIVES: To assess the net clinical benefit of a multifaceted intervention in emergency wards (educational lectures, posters, pocket cards, computerized clinical decision support systems and, where feasible, electronic reminders) for the prevention of venous thromboembolism. PATIENTS/METHODS: Prospective cluster-randomized trial in 27 hospitals. After a pre-intervention period, centers were randomized as either intervention (n = 13) or control (n = 14). All patients over 40 years old, admitted to the emergency room, and hospitalized in a medical ward were included, totaling 1,402 (712 intervention and 690 control) and 15,351 (8,359 intervention and 6,992 control) in the pre-intervention and intervention periods, respectively. RESULTS: Symptomatic venous thromboembolism or major bleeding (primary outcome) occurred at 3 months in 3.1% and 3.2% of patients in the intervention and control groups, respectively (adjusted odds ratio: 1.02 [95% confidence interval: 0.78-1.34]). The rates of thromboembolism (1.9% vs. 1.9%), major bleedings (1.2% vs. 1.3%), and mortality (11.3% vs. 11.1%) did not differ between the groups. Between the pre-intervention and intervention periods, the proportion of patients who received prophylactic anticoagulant treatment more steeply increased in the intervention group (from 35.0% to 48.2%: +13.2%) than the control (40.7% to 44.1%: +3.4%), while the rate of adequate thromboprophylaxis remained stable in both groups (52.4% to 50.9%: -1.5%; 49.1% to 48.8%: -0.3%). CONCLUSIONS: Our intervention neither improved adequate prophylaxis nor reduced the rates of clinical events. New strategies are required to improve thromboembolism prevention for hospitalized medical patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01212393. PMID- 27227407 TI - Leukemia Inhibitory Factor Enhances Endogenous Cardiomyocyte Regeneration after Myocardial Infarction. AB - Cardiac stem cells or precursor cells regenerate cardiomyocytes; however, the mechanism underlying this effect remains unclear. We generated CreLacZ mice in which more than 99.9% of the cardiomyocytes in the left ventricular field were positive for 5-bromo-4-chloro-3-indolyl-beta-d-galactoside (X-gal) staining immediately after tamoxifen injection. Three months after myocardial infarction (MI), the MI mice had more X-gal-negative (newly generated) cells than the control mice (3.04 +/- 0.38/mm2, MI; 0.47 +/- 0.16/mm2, sham; p < 0.05). The cardiac side population (CSP) cell fraction contained label-retaining cells, which differentiated into X-gal-negative cardiomyocytes after MI. We injected a leukemia inhibitory factor (LIF)-expression construct at the time of MI and identified a significant functional improvement in the LIF-treated group. At 1 month after MI, in the MI border and scar area, the LIF-injected mice had 31.41 +/- 5.83 X-gal-negative cardiomyocytes/mm2, whereas the control mice had 12.34 +/ 2.56 X-gal-negative cardiomyocytes/mm2 (p < 0.05). Using 5-ethynyl-2' deoxyurinide (EdU) administration after MI, the percentages of EdU-positive CSP cells in the LIF-treated and control mice were 29.4 +/- 2.7% and 10.6 +/- 3.7%, respectively, which suggests that LIF influenced CSP proliferation. Moreover, LIF activated the Janus kinase (JAK)signal transducer and activator of transcription (STAT), mitogen-activated protein kinase/extracellular signal-regulated (MEK)extracellular signal-regulated kinase (ERK), and phosphatidylinositol 3 kinase (PI3K)-AKT pathways in CSPs in vivo and in vitro. The enhanced green fluorescent protein (EGFP)-bone marrow-chimeric CreLacZ mouse results indicated that LIF did not stimulate cardiogenesis via circulating bone marrow-derived cells during the 4 weeks following MI. Thus, LIF stimulates, in part, stem cell derived cardiomyocyte regeneration by activating cardiac stem or precursor cells. This approach may represent a novel therapeutic strategy for cardiogenesis. PMID- 27227408 TI - Exposure to Mycobacterium tuberculosis during Flexible Bronchoscopy in Patients with Unexpected Pulmonary Tuberculosis. AB - OBJECTIVE: Recent guidelines recommend the use by healthcare personnel of a fit tested N95 particulate respirator or higher-grade respiratory precaution in a patient undergoing bronchoscopy when pulmonary tuberculosis (PTB) is suspected. However, PTB may be unexpectedly diagnosed in this setting and therefore not evaluated, resulting in the unexpected exposure to Mycobacterium tuberculosis (MTB) of healthcare workers in the bronchoscopy suite. Here, we examined the incidence of unexpected exposure to MTB during flexible bronchoscopy and determined the exposure-related factors. METHODS: Between 2011 and 2013, a retrospective study was conducted to evaluate unexpected diagnoses of PTB in the bronchoscopy suite. During the study period, 1650 consecutive patients for whom previous CT scans were available and who underwent bronchoscopy for respiratory disease other than PTB were included. The results of bronchial washing, bronchoalveolar lavage, and post-bronchoscopic sputum were reviewed. RESULTS: PTB was unexpectedly diagnosed in 76 patients (4.6%). The presence of anthracofibrosis [odds ratio (OR), 3.878; 95% confidence interval (CI), 1.291 11.650; P = 0.016), bronchiectasis (OR, 1.974; 95% CI, 1.095-3.557; P = 0.024), or atelectasis (OR, 1.740; 95% CI, 1.010-2.903; P = 0.046) as seen on chest CT scan was independently associated with unexpected PTB. Patients with both anthracofibrosis and atelectasis were at much higher risk of unexpected PTB (OR, 4.606; 95% CI, 1.383-15.342; P = 0.013). CONCLUSIONS: The risk of MTB exposure by healthcare personnel in the bronchoscopy suite due to patients with undiagnosed PTB has been underestimated. Therefore, in geographic regions with an intermediate PTB prevalence, such as South Korea (97/100,000 persons per year), higher-grade respiratory precaution, such as a fit-tested N95 particulate respirator, should be considered to prevent occupational exposure to MTB during routine bronchoscopy, especially in patients with CT-confirmed anthracofibrosis, bronchiectasis, or atelectasis. PMID- 27227409 TI - Associations between Restrained Eating and the Size and Frequency of Overall Intake, Meal, Snack and Drink Occasions in the UK Adult National Diet and Nutrition Survey. AB - Obesity is a global public health priority. Restrained eating is related to obesity and total energy intake but associations with the eating patterns are unclear. We examined the associations of restrained eating with the size and frequency of intake occasions among 1213 British adult (19-64 y) participants in a cross-sectional analysis of the UK National Diet and Nutrition Survey 2000. The Dutch Eating Behaviour Questionnaire assessed restrained eating. Overall intake occasions were all energy consumed in a 60 min period. A food-based classification separated intake occasions into meals, snacks, or drinks from seven-day weighed food diaries. Average daily frequency and size (kcal) of overall intake, meal, snack and drink occasions were calculated and associations with restrained eating were modelled using multiple linear regression including under-reporting of energy intake, age, gender, BMI, emotional eating, external eating and physical activity as covariates. Restrained eating was very weakly positively correlated with overall intake (r = 0.08, p<0.05) and meal frequency (r = 0.10, p<0.05) but not snack or drink frequency (r = 0.02 and -0.02 respectively). Adjusted regressions showed a one-point change in restrained eating was associated with 0.07 (95% CI 0.03, 0.11) more meal occasions/day and 0.13 (95% CI 0.01, 0.25) extra overall intake occasions/day. Overall intake occasion size was weakly negatively correlated with restrained eating regardless of type (r = -0.16 to -0.20, all p<0.0001). Adjusted regressions showed each one point increase in restrained eating was associated with lower-energy meals (-15 kcal 95% CI -5.9, -24.2) and drinks (-4 kcal 95%CI -0.1, -8), but not snacks or overall intake occasions. Among a national sample of UK adults, greater restrained eating was associated with smaller and slightly more frequent eating, suggesting that restrained eaters restrict their energy intake by reducing meal/drink size rather than skipping snacks. PMID- 27227410 TI - Stability and Change in Genetic and Environmental Influences on Well-Being in Response to an Intervention. AB - Genetic and environmental influences on complex traits can change in response to developmental and environmental contexts. Here we explore the impact of a positive activity intervention on the genetic and environmental influences on well-being and mental health in a sample of 750 adolescent twins. Twins completed a 10-week online well-being intervention, consisting of kindness and gratitude tasks and matched control activities. The results showed significant improvements both in well-being and in internalizing symptoms in response to the intervention activities. We used multivariate twin analyses of repeated measures, tracking stability and change in genetic and environmental influences, to assess the impact of this environmental intervention on these variance components. The heritability of well-being remained high both before and after the intervention, and the same genetic effects were important at each stage, even as well-being increased. The overall magnitude of environmental influences was also stable across the intervention; however, different non-shared environmental influences emerged during the intervention. Our study highlights the value of exploring the innovations in non-shared environmental influences that could provide clues to the mechanisms behind improvements in well-being. The findings also emphasize that even traits strongly influenced by genetics, like well-being, are subject to change in response to environmental interventions. PMID- 27227411 TI - Lack of Significant Effects of Chlamydia trachomatis Infection on Cervical Adenocarcinoma Risk: Nested Case-Control Study. AB - BACKGROUND: A role of Chlamydia trachomatis in HPV-induced cervical carcinogenesis has been reported for cervical cancer but studies on cervical adenocarcinoma are limited. METHODS: A total of 1,553 cervical smears taken up to 26 years before diagnosis in a large population-based nested case-control study of cervical adenocarcinoma (AC, 132 cases with matched controls), and adenocarcinoma in situ (AIS, 159 cases with matched controls) were tested for C. trachomatis and HPV DNA by a type-specific PCR bead-based multiplex genotyping (TS-MPG) assay. RESULTS: Only 1.7% of samples were positive for C. trachomatis, with no significant differences between AC/AIS cases and controls. HPV-positivity was detected in 49.3% of C. trachomatis-negative and 65.4% C. trachomatis positive samples, respectively. CONCLUSIONS: A large prospective study did not find any risk for cervical adenocarcinoma and/or AIS conferred by C. trachomatis infection. IMPACT: C. trachomatis appears not to be involved in cervical adenocarcinomas. PMID- 27227412 TI - The Impact of Inventory Management on Stock-Outs of Essential Drugs in Sub Saharan Africa: Secondary Analysis of a Field Experiment in Zambia. AB - OBJECTIVE: To characterize the impact of widespread inventory management policies on stock-outs of essential drugs in Zambia's health clinics and develop related recommendations. METHODS: Daily clinic storeroom stock levels of artemether lumefantrine (AL) products in 2009-2010 were captured in 145 facilities through photography and manual transcription of paper forms, then used to determine historical stock-out levels and estimate demand patterns. Delivery lead-times and estimates of monthly facility accessibility were obtained through worker surveys. A simulation model was constructed and validated for predictive accuracy against historical stock-outs, then used to evaluate various changes potentially affecting product availability. FINDINGS: While almost no stock-outs of AL products were observed during Q4 2009 consistent with primary analysis, up to 30% of surveyed facilities stocked out of some AL product during Q1 2010 despite ample inventory being simultaneously available at the national warehouse. Simulation experiments closely reproduced these results and linked them to the use of average past monthly issues and failure to capture lead-time variability in current inventory control policies. Several inventory policy enhancements currently recommended by USAID | DELIVER were found to have limited impact on product availability. CONCLUSIONS: Inventory control policies widely recommended and used for distributing medicines in sub-Saharan Africa directly account for a substantial fraction of stock-outs observed in common situations involving demand seasonality and facility access interruptions. Developing central capabilities in peripheral demand forecasting and inventory control is critical. More rigorous independent peer-reviewed research on pharmaceutical supply chain management in low-income countries is needed. PMID- 27227413 TI - Real-Time Label-Free Embolus Detection Using In Vivo Photoacoustic Flow Cytometry. AB - Thromboembolic events are one of the world's leading causes of death among patients. Embolus or clot formations have several etiologies including paraneoplastic, post-surgery, cauterization, transplantation, or extracorporeal circuits. Despite its medical significance, little progress has been made in early embolus detection, screening and control. The aim of our study is to test the utility of the in vivo photoacoustic (PA) flow cytometry (PAFC) technique for non-invasive embolus detection in real-time. Using in vivo PAFC, emboli were non invasively monitored in the bloodstream of two different mouse models. The tumor free mouse model consisted of two groups, one in which the limbs were clamped to produce vessel stasis (7 procedures), and one where the mice underwent surgery (7 procedures). The melanoma-bearing mouse model also consisted of two groups, one in which the implanted tumor underwent compression (8 procedures), and one where a surgical excision of the implanted tumor was performed (8 procedures). We demonstrated that the PAFC can detect a single embolus, and has the ability to distinguish between erythrocyte-rich (red) and leukocyte/platelet-rich (white) emboli in small vessels. We show that, in tumor-bearing mice, the level of circulating emboli was increased compared to tumor-free mice (p = 0.0013). The number of circulating emboli temporarily increased in the tumor-free control mice during vessel stasis (p = 0.033) and after surgical excisions (signed-rank p = 0.031). Similar observations were noted during tumor compression (p = 0.013) and after tumor excisions (p = 0.012). For the first time, it was possible to detect unlabeled emboli in vivo non-invasively, and to confirm the presence of pigmented tumor cells within circulating emboli. The insight on embolus dynamics during cancer progression and medical procedures highlight the clinical potential of PAFC for early detection of cancer and surgery-induced emboli to prevent the fatal thromboembolic complications by well-timed therapy. PMID- 27227415 TI - On the difficulty of mending metacognitive illusions: A priori theories, fluency effects, and misattributions of the interleaving benefit. AB - Interleaving exemplars of to-be-learned categories-rather than blocking exemplars by category-typically enhances inductive learning. Learners, however, tend to believe the opposite, even after their own performance has benefited from interleaving. In Experiments 1 and 2, the authors examined the influence of 2 factors that they hypothesized contribute to the illusion that blocking enhances inductive learning: Namely, that (a) blocking creates a sense of fluent extraction during study of the features defining a given category, and (b) learners come to the experimental task with a pre-existing belief that blocking instruction by topic is superior to intermixing topics. In Experiments 3-5, the authors attempted to uproot learners' belief in the superiority of blocking through experience-based and theory-based debiasing techniques by (a) providing detailed theory-based information as to why blocking seems better, but is not, and (b) explicitly drawing attention to the link between study schedule and subsequent performance, both of which had only modest effects. Only when they disambiguated test performance on the 2 schedules by separating them (Experiment 6) did the combination of experience- and theory-based debiasing lead a majority of learners to appreciate interleaving. Overall, the results indicate that 3 influences combine to make altering learners' misconceptions difficult: the sense of fluency that can accompany nonoptimal modes of instruction; pre-existing beliefs learners bring to new tasks; and the willingness, even eagerness, to believe that 1 is unique as a learner-that what enhances others' learning differs from what enhances one's own learning. (PsycINFO Database Record PMID- 27227414 TI - X-Ray Solution Scattering Study of Four Escherichia coli Enzymes Involved in Stationary-Phase Metabolism. AB - The structural analyses of four metabolic enzymes that maintain and regulate the stationary growth phase of Escherichia coli have been performed primarily drawing on the results obtained from solution small angle X-ray scattering (SAXS) and other structural techniques. The proteins are (i) class I fructose-1,6 bisphosphate aldolase (FbaB); (ii) inorganic pyrophosphatase (PPase); (iii) 5 keto-4-deoxyuronate isomerase (KduI); and (iv) glutamate decarboxylase (GadA). The enzyme FbaB, that until now had an unknown structure, is predicted to fold into a TIM-barrel motif that form globular protomers which SAXS experiments show associate into decameric assemblies. In agreement with previously reported crystal structures, PPase forms hexamers in solution that are similar to the previously reported X-ray crystal structure. Both KduI and GadA that are responsible for carbohydrate (pectin) metabolism and acid stress responses, respectively, form polydisperse mixtures consisting of different oligomeric states. Overall the SAXS experiments yield additional insights into shape and organization of these metabolic enzymes and further demonstrate the utility of hybrid methods, i.e., solution SAXS combined with X-ray crystallography, bioinformatics and predictive 3D-structural modeling, as tools to enrich structural studies. The results highlight the structural complexity that the protein components of metabolic networks may adopt which cannot be fully captured using individual structural biology techniques. PMID- 27227416 TI - Near-Infrared Light-Triggered Switchable Nanoparticles for Targeted Chemo/Photothermal Cancer Therapy. AB - Accumulation of nanoparticles in solid tumors depends on their extravasation, but their efficacy is often compromised by intrinsic physiological heterogeneity in tumors. The conventional solutions to circumvent this problem are size control of nanoparticles or increasing the vascular permeability. The aim of this study is to investigate the combination effect of size variation of stimuli-responsive nanoparticles and improved vascular permeability triggered by near-infrared (NIR) light irradiation. Doxorubicin (DOX), a clinically proven drug for bladder cancer, was encapsulated in the nanocomposites with high loading content up to 45%. We show that NIR light-responsive size-switchable nanocarriers could considerably enhance the tumor-targeting of DOX in bladder tumor-bearing mice. Moreover, a combination of NIR-induced hyperthermia and DOX-mediated chemotherapy resulted in remarkable inhibition of tumor growth in mice. Histological results suggest that the change in morphology of tumor microvasculature may account for enhanced extravasation and accumulation of the nanodrugs upon NIR irradiation. Together, these data suggest that external stimuli-responsive drug delivery system offers a safe and effective means of targeted chemo/photothermal therapy. PMID- 27227417 TI - Correction to Multiple Src Homology 3 Binding to the Ubiquitin Ligase Itch Conserved Proline-Rich Region. PMID- 27227418 TI - Sodium in Store and Restaurant Food Environments - Guam, 2015. AB - Compared with the United States overall, Guam has higher mortality rates from cardiovascular disease and stroke (1). Excess sodium intake can increase blood pressure and risk for cardiovascular disease (2,3). To determine the availability and promotion of lower-sodium options in the nutrition environment, the Guam Department of Public Health and Social Services (DPHSS) conducted an assessment in September 2015 using previously validated tools adapted to include sodium measures. Stores (N = 114) and restaurants (N = 63) were randomly sampled by region (north, central, and south). Data from 100 stores and 62 restaurants were analyzed and weighted to account for the sampling design. Across the nine product types assessed, lower-sodium products were offered less frequently than regular sodium products (p<0.001) with <50% of stores offering lower-sodium canned vegetables, tuna, salad dressing, soy sauce, and hot dogs. Lower-sodium products were also less frequently offered in small stores than large (two or more cash registers) stores. Reduced-sodium soy sauce cost more than regular soy sauce (p<0.001) in stores offering both options in the same size bottle. Few restaurants engaged in promotion practices such as posting sodium information (3%) or identifying lower-sodium entrees (1%). Improving the availability and promotion of lower-sodium foods in stores and restaurants could help support healthier eating in Guam. PMID- 27227419 TI - Self-assembly of a unique 3d/4f heterometallic square prismatic box-like coordination cage. AB - We present the synthesis and characterization of a unique, slightly distorted square prismatic, box-like coordination cage of type [Cu6Dy8L8(MeOH)8(H2O)6](NO3)12.chisolvent obtained via the supramolecular assembly between a non-centrosymmetric Dy(iii) metalloligand and Cu(ii) nitrate. Magnetic susceptibility measurements indicate that the complex behaves as a single-molecule magnet. PMID- 27227420 TI - Simulation of 2D NMR Spectra of Carbohydrates Using GODESS Software. AB - Glycan Optimized Dual Empirical Spectrum Simulation (GODESS) is a web service, which has been recently shown to be one of the most accurate tools for simulation of (1)H and (13)C 1D NMR spectra of natural carbohydrates and their derivatives. The new version of GODESS supports visualization of the simulated (1)H and (13)C chemical shifts in the form of most 2D spin correlation spectra commonly used in carbohydrate research, such as (1)H-(1)H TOCSY, COSY/COSY-DQF/COSY-RCT, and (1)H (13)C edHSQC, HSQC-COSY, HSQC-TOCSY, and HMBC. Peaks in the simulated 2D spectra are color-coded and labeled according to the signal assignment and can be exported in JCAMP-DX format. Peak widths are estimated empirically from the structural features. GODESS is available free of charge via the Internet at the platform of the Carbohydrate Structure Database project ( http://csdb.glycoscience.ru ). PMID- 27227421 TI - Integrated Microalgae Analysis Photobioreactor for Rapid Strain Selection. AB - Algal photosynthesis is considered to be a sustainable, alternative, and renewable solution to generating green energy. For high-productivity algaculture in diverse local environments, a high-throughput screening method is needed to select algal strains from naturally available or genetically engineered strains. Herein, we present an integrated plasmonic photobioreactor for rapid, high throughput screening of microalgae. Our 3D nanoplasmonic optical cavity-based photobioreactor permits the amplification of a selective wavelength favorable to photosynthesis in the cavity. The hemispheric plasmonic cavity allows intercellular interaction to be promoted in the optically favorable milieu and also permits effective visual examination of algal growth. Using Chlamydomonas reinhardtii, we demonstrated a 2-fold enhanced growth rate and a 1.5-fold lipid production rate with no distinctive lag phase. By facilitating growth and biomass conversion rates, the integrated microalgae analysis platform will serve as rapid microalgae screening platforms for biofuel applications. PMID- 27227422 TI - Quantification of Phenolic Antioxidant Moieties in Dissolved Organic Matter by Flow-Injection Analysis with Electrochemical Detection. AB - Phenolic moieties in dissolved organic matter (DOM) play important roles as antioxidants in oxidation processes in natural and engineered systems. This work presents an automated and highly sensitive flow injection analysis (FIA) system coupled to both spectrophotometric and electrochemical detection to quantify electron-donating phenolic moieties in DOM by determining the number of electrons that these moieties transfer to an added chemical oxidant, the radical cation of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS(*+)). The FIA system was successfully validated using Trolox as a redox standard. Highest method sensitivity was attained when combining the FIA with chronoamperometric detection, resulting in limits of quantification of picomolar amounts of Trolox and nanogram amounts of DOM (corresponding to solutions with <1 mg carbon per liter). The analysis of DOM isolates showed a strong linear correlation between the number of electrons donated and their titrated phenol contents, supporting oxidation of phenols by ABTS(*+). The broad application spectrum of the FIA system to dilute natural DOM samples was illustrated by analyzing water samples collected from northern peatlands and by monitoring the oxidation of phenols in one peat sample upon incubation with a phenol oxidase. The superior analytical capability of the FIA system allows quantifying phenols and monitoring phenol dynamics in dilute DOM samples. PMID- 27227423 TI - Complication Rates in Delayed Reconstruction of the Head and Neck After Mohs Micrographic Surgery. AB - IMPORTANCE: Same-day Mohs reconstructive surgery is not always possible owing to patient factors, scheduling, and complexity of defect, but there is hesitancy in delaying closure of such defects. OBJECTIVE: To describe the frequency of and predictors of complications in patients undergoing delayed facial reconstruction after Mohs micrographic surgery (MMS). DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective, multi-institutional cohort study from February 1, 1989, to December 31, 2012. Data were pooled from 2 institutions: University of Washington Medical Center and Virginia Mason Medical Center. All patients who underwent MMS for facial carcinomas with delayed (non-same-day) reconstruction were included. We excluded those with incomplete medical records and no follow-up. The analysis was performed from June 2014 to March 2016. MAIN OUTCOMES AND MEASURES: Our main outcome measure was postoperative complication, classified as immediate (<=24 hours after surgery) or delayed (>24 hours after surgery). RESULTS: A total of 415 cases in 342 patients were identified. Reconstruction occurred from 1 to 11 days after excision, with 95.4% of repairs occurring within 2 days of MMS. The overall complication rate was 8.2%. The total delayed complication rate was 7.7% (32 of 415 cases). The overall infection rate was 2.4%. In terms of patient characteristics, reconstruction delayed more than 2 days, bone or cartilage exposure, and large defects were associated with complications. In terms of defect location and reconstruction type, complications were associated with composite defects (those that included >1 facial subunit) and use of interpolated flaps with cartilage grafting. We used these variables in a multivariable logistic regression model and found that composite location, use of interpolated flap with cartilage grafting, and reconstruction delayed more than 2 days were associated with postoperative complications. Among the variables in the model, composite location of defects, interpolated flap with cartilage grafting, and delayed reconstruction greater than 2 days were found to have a statistically significant association with a complication (OR, 3.48 [95% CI, 1.16-10.56]; OR, 4.93 [95% CI, 1.44-16.95]; OR, 4.26 [95% CI, 1.24-14.60], respectively). CONCLUSIONS AND RELEVANCE: To our knowledge, this is the largest study to report complication rates in delayed reconstruction of MMS defects in the head and neck, noting a rate that is similar to what has been reported in the literature. We noted a statistically significant increased risk of complications when reconstruction is performed for composite defects, if an interpolated flap with cartilage is performed, and if reconstruction is performed after more than 2 days. LEVEL OF EVIDENCE: 3. PMID- 27227424 TI - Biosimilar epoetin zeta: extrapolation of indications and real world utilization experience. AB - INTRODUCTION: There is an essential need for clinicians to understand the development and approval process of biosimilars. Extrapolation of efficacy and safety data from one indication to another may be considered by a comprehensive comparability program including safety, efficacy and immunogenicity, which detect potentially clinically relevant differences. AREAS COVERED: This article specifically discusses the approval of epoetin zeta (RetacritTM, Hospira, a Pfizer company) and the EMA reasoning for extrapolation of indications. Additionally, the results of the ongoing utilization surveillance program that was approved in 2007 and has analyzed over 120 million patient days of epoetin zeta treatment are presented. EXPERT OPINION: At the time of approval, uncertainty of safety and efficacy is much less for biosimilars than for new innovative products. Approval of indications based on extrapolation of data is based on sound and objective scientific criteria and a logical consequence of the biosimilar concept that has been successfully implemented in the European Union. Biosimilar epoetin has been used extensively in patients in Europe for nine years. Following a review of the known risks and ADR information received in almost 120 million patient-days' worth of experience, the risks associated with treatment with epoetin zeta remain similar to those of the reference product. PMID- 27227426 TI - Should we develop screens for multi-drug antibiotic tolerance? PMID- 27227427 TI - Hysteresis, Stability, and Ion Migration in Lead Halide Perovskite Photovoltaics. AB - Ion migration has been suspected as the origin of various irreproducible and unstable properties, most notably the hysteresis, of lead halide perovskite photovoltaic (PV) cells since the early stage of the research. Although many evidence of ionic movement have been presented both numerically and experimentally, a coherent and quantitative picture that accounts for the observed irreproducible phenomena is still lacking. At the same time, however, it has been noticed that in certain types of PV cells, the hysteresis is absent or at least within the measurement reproducibility. We have previously shown that the electronic properties of hysteresis-free cells are well represented in terms of the conventional inorganic semiconductors. The reproducibility of these measurements was confirmed typically within tens of minutes under the biasing field of -1 V to +1.5 V. In order to probe the effect of ionic motion in the hysteresis-free cells, we extended the time scale and the biasing rage in the electronic measurements, from which we conclude the following: (1) From various evidence, it appears that ion migration is inevitable. However, it does not cause detrimental effects to the PV operation. (2) We propose, based on the quantitative characterization, that the degradation is more likely due to the chemical change at the interfaces between the carrier selective layers and perovskite rather than the compositional change of the lead iodide perovskite bulk. Together, they give much hope in the use of the lead iodide perovskite in the use of actual application. PMID- 27227428 TI - Atrial fibrillation. PMID- 27227429 TI - A Community Based Study on the Mode of Transmission, Prevention and Treatment of Buruli Ulcers in Southwest Cameroon: Knowledge, Attitude and Practices. AB - BACKGROUND: Buruli ulcer (BU) is a neglected tropical disease affecting the skin, tissues and in some cases the bones, caused by the environmental pathogen Mycobacterium ulcerans (M. ulcerans). Its mode of transmission is still elusive. Delayed treatment may cause irreversible disabilities with consequent social and economic impacts on the victim. Socio-cultural beliefs, practices and attitudes in endemic communities have been shown to influence timely treatment causing disease management, prevention and control a great challenge. An assessment of these factors in endemic localities is important in designing successful intervention strategies. Considering this, we assessed the knowledge, attitude and practices regarding BU in three endemic localities in the South West region, Cameroon to highlight existing misconceptions that need to be addressed to enhance prompt treatment and facilitate effective prevention and control. METHODS AND FINDINGS: A cross-sectional study was executed in three BU endemic health districts. Using qualitative and quantitative approaches we surveyed 320 randomly selected household heads, interviewed BU patients and conducted three focus group discussions (FGDs) to obtain information on awareness, beliefs, treatment, and attitudes towards victims. The influence of socio-demographic factors on these variables was investigated. RESULTS: Respondents (84.4%) had a good knowledge of BU though only 65% considered it a health problem while 49.4% believed it is contagious. Socio-demographic factors significantly (P<0.05) influenced awareness of BU, knowledge and practice on treatment and attitudes towards victims. Although the majority of respondents stated the hospital as the place for appropriate treatment, FGDs and some BU victims preferred witchdoctors/herbalists and prayers, and considered the hospital as the last option. We documented beliefs about the disease which could delay treatment. CONCLUSION: Though we are reporting a high level of knowledge of BU, there exist fallacies about BU and negative attitudes towards victims in communities studied. Efforts towards disease eradication must first of all target these misconceptions. PMID- 27227430 TI - Optimizing spectral CT parameters for material classification tasks. AB - In this work, we propose a framework for optimizing spectral CT imaging parameters and hardware design with regard to material classification tasks. Compared with conventional CT, many more parameters must be considered when designing spectral CT systems and protocols. These choices will impact material classification performance in a non-obvious, task-dependent way with direct implications for radiation dose reduction. In light of this, we adapt Hotelling Observer formalisms typically applied to signal detection tasks to the spectral CT, material-classification problem. The result is a rapidly computable metric that makes it possible to sweep out many system configurations, generating parameter optimization curves (POC's) that can be used to select optimal settings. The proposed model avoids restrictive assumptions about the basis material decomposition (e.g. linearity) and incorporates signal uncertainty with a stochastic object model. This technique is demonstrated on dual-kVp and photon counting systems for two different, clinically motivated material classification tasks (kidney stone classification and plaque removal). We show that the POC's predicted with the proposed analytic model agree well with those derived from computationally intensive numerical simulation studies. PMID- 27227431 TI - Hydrotrifluoromethylation of Unactivated Alkenes and Alkynes Enabled by an Electron-Donor-Acceptor Complex of Togni's Reagent with a Tertiary Amine. AB - An electron-donor-acceptor (EDA) complex between Togni's reagent and a tertiary amine has been introduced. The existence of this EDA complex was supported by NMR titration experiments. The hydrotrifluoromethylation of unactivated aliphatic alkenes and alkynes enabled by this EDA complex has also been developed. This hydrotrifluoromethylation protocol is operationally simple and promoted by a tertiary amine. PMID- 27227432 TI - Computational insights into the origin of decrease/increase in potency of N-CDPCB analogues toward FTO. PMID- 27227434 TI - Clinicopathologic Correlation of Lens Epithelial Metaplasia and Late Intraocular Lens Dislocation After Repair of Retinal Detachment. AB - IMPORTANCE: In-the-bag intraocular lens dislocation is an uncommon but serious complication of cataract surgery in patients with previous repair of retinal detachment. The causative mechanism is currently unknown. We report histologic findings from a retrospective case series from 1993 to 2010 and suggest a possible mechanism to explain this association. OBSERVATIONS: Clinical characteristics of 8 patients presenting with in-the-bag intraocular lens dislocation after repair of retinal detachment were evaluated. Explanted capsular bags from 3 of these patients were compared with pathologic changes of crystalline lenses associated with retinal detachment. Histologic examination of the explanted capsular bags revealed a paucicellular membrane that covered the concertina-like folded surface of the lens capsule. The lens capsule was devoid of epithelial cell nuclei and showed excessive thickening with the presence of spindle-shaped cells, such as fibroblasts. Collagen fibers were noted in the extracellular matrix. CONCLUSIONS AND RELEVANCE: Previous studies of crystalline lens pathologic findings associated with retinal detachment have shown changes in the epithelium with migration and subsequent metaplasia of epithelial cells, resulting in excessive thickening of the anterior capsule with a layer of fibrous tissue. In this retrospective series, similar histologic findings were seen, suggesting that zonular dehiscence and lens dislocation may result from progressive capsular contraction secondary to retinal detachment-induced lens epithelial metaplasia. PMID- 27227433 TI - Virtual Experiments Enable Exploring and Challenging Explanatory Mechanisms of Immune-Mediated P450 Down-Regulation. AB - Hepatic cytochrome P450 levels are down-regulated during inflammatory disease states, which can cause changes in downstream drug metabolism and hepatotoxicity. Long-term, we seek sufficient new insight into P450-regulating mechanisms to correctly anticipate how an individual's P450 expressions will respond when health and/or therapeutic interventions change. To date, improving explanatory mechanistic insight relies on knowledge gleaned from in vitro, in vivo, and clinical experiments augmented by case reports. We are working to improve that reality by developing means to undertake scientifically useful virtual experiments. So doing requires translating an accepted theory of immune system influence on P450 regulation into a computational model, and then challenging the model via in silico experiments. We build upon two existing agent-based models-an in silico hepatocyte culture and an in silico liver-capable of exploring and challenging concrete mechanistic hypotheses. We instantiate an in silico version of this hypothesis: in response to lipopolysaccharide, Kupffer cells down regulate hepatic P450 levels via inflammatory cytokines, thus leading to a reduction in metabolic capacity. We achieve multiple in vitro and in vivo validation targets gathered from five wet-lab experiments, including a lipopolysaccharide-cytokine dose-response curve, time-course P450 down regulation, and changes in several different measures of drug clearance spanning three drugs: acetaminophen, antipyrine, and chlorzoxazone. Along the way to achieving validation targets, various aspects of each model are falsified and subsequently refined. This iterative process of falsification-refinement validation leads to biomimetic yet parsimonious mechanisms, which can provide explanatory insight into how, where, and when various features are generated. We argue that as models such as these are incrementally improved through multiple rounds of mechanistic falsification and validation, we will generate virtual systems that embody deeper credible, actionable, explanatory insight into immune system-drug metabolism interactions within individuals. PMID- 27227435 TI - Formation of 1,10-Phenanthroline-N,N'-dioxide under Mild Conditions: The Kinetics and Mechanism of the Oxidation of 1,10-Phenanthroline by Peroxomonosulfate Ion (Oxone). AB - This paper confirms the unexpected formation of 1,10-phenanthroline-N,N'-dioxide (phenO2) when 1,10-phenanthroline (phen) is oxidized by peroxomonosulfate ion (PMS) in a neutral aqueous solution. The kinetics of oxidation of phen by PMS features a complex pH dependence. In 1.00 M H2SO4, 1,10-phenanthroline-mono-N oxide (phenO) is the sole product of the reaction. The rate of the N-oxidation is highly dependent on pH with a maximum at pH ~6.7. The formation of phenO occurs via two parallel pathways: the rate constant of the oxidation of phen (k = 3.1 +/ 0.1 M(-1) s(-1)) is significantly larger than that of Hphen(+) [k = (4.1 +/- 0.3) * 10(-3) M(-1) s(-1)] because the two N atoms are open to oxidative attack in the deprotonated substrate while an internal hydrogen bond hinders the oxidation of the protonated form. With an excess of PMS, four consecutive oxidation steps were found in nearly neutral solutions. In the early stage of the reaction, the stepwise oxidation results in the formation of phenO, which is converted into phenO2 in the second step. The formation of phenO2 was confirmed by (1)H NMR and ESI-MS methods. The results presented here offer the possibility of designing an experimental protocol for preparing phenO2. PMID- 27227446 TI - Histoplasma capsulatum sinusitis: Possible way of revelation to the disseminated form of histoplasmosis in HIV patients: Case report and literature review. AB - INTRODUCTION: Histoplasma capsulatum is rarely found in nose and sinuses in immunocompetent and even in immunosupressed patients. A literature review revealed rare cases of H. capsulatum sinusitis and the case we describe in this paper is the first case of H. capsulatum sinusitis in Morocco. The purpose of our work is to present a rare case of H. capsulatum sinusitis and a literature review. CASE REPORT: A male patient, at his 39 presented to the emergency with suffered from nasal congestion and yellow postnasal rhinorrhea, occasional headaches and epistaxis for over than two months. He had human immunodeficiency virus (HIV) infection for 6 years with failing treatment adherence and he had an opportunistic infection and unconfirmed pulmonary tuberculosis treated 3 years ago. Computerized tomography from paranasal sinus revealed complete opacification of the ethmoid-maxillary sinuses in the right fossa, consistent with acute sinusitis. The cultures of the sinus aspirate, skin biopsy, were positive for H. capsulatum and the histology of the nasal mucosa and skin biopsy specimen of the rash evoking a sinusitis and cutaneous histoplasmosis. The patient was started a treatment with intravenous amphotericin B at a rate of 1 mg/kg/day with clear clinical and biological improvement. DISCUSSION: Cultures and histopathologic study confirm histoplasmosis. Itraconazole and amphotericin B are the first line drugs. CONCLUSION: Patients with progressive disseminated histoplasmosis and those with AIDS should be treated with amphotericin B, and the ENT should suspect of opportunistic agents in immunosupressed patients with sinusitis. PMID- 27227448 TI - Cataract. PMID- 27227447 TI - Electrocatalytic Reduction of CO2 by Group 6 M(CO)6 Species without "Non Innocent" Ligands. AB - To understand the electrocatalytic CO2 reduction of metal carbonyl complexes without "non-innocent" ligands, the electrochemical responses of group 6 M(CO)6 (M = Cr, Mo, or W) and group 7 M2(CO)10 (M = Mn or Re) complexes were examined under Ar and CO2 at a glassy carbon electrode. All of the complexes showed changes in their cyclic voltammograms under CO2. The group 6 hexacarbonyl species show a significant increase in current under CO2 during metal-based reduction, corresponding to catalytic reduction of CO2. Bulk electrolysis experiments with Mo(CO)6 showed that CO was the primary product. The group 7 dimers showed very little change during metal-based reduction, but return oxidation responses disappeared, indicative of a chemical reaction after exposure to CO2 without catalysis. Addition of H2O, a proton source, to the solutions under CO2 decreased the catalytic current of the group 6 carbonyls and had no effect on the responses of the group 7 carbonyls. The group 6 M(CO)6 species are notable in that that they are effective catalysts without the need for an added "non-innocent" ligand such as 2,2'-bipyridine. PMID- 27227449 TI - See One, Do One, Teach One, But Practice First. PMID- 27227450 TI - Alzheimer's Amyloid-beta Sequesters Caspase-3 in Vitro via Its C-Terminal Tail. AB - Amyloid-beta (Abeta), the main constituent in senile plaques found in the brain of patients with Alzheimer's disease (AD), is considered as a causative factor in AD pathogenesis. The clinical examination of the brains of patients with AD has demonstrated that caspase-3 colocalizes with senile plaques. Cellular studies have shown that Abeta can induce neuronal apoptosis via caspase-3 activation. Here, we performed biochemical and in silico studies to investigate possible direct effect of Abeta on caspase-3 to understand the molecular mechanism of the interaction between Abeta and caspase-3. We found that Abeta conformers can specifically and directly sequester caspase-3 activity in which freshly prepared Abeta42 is the most potent. The inhibition is noncompetitive, and the C-terminal region of Abeta plays an important role in sequestration. The binding of Abeta to caspase-3 was examined by cross-linking and proteolysis and by docking and all atom molecular dynamic simulations. Experimental and in silico results revealed that Abeta42 exhibits a higher binding affinity than Abeta40 and the hydrophobic C-terminal region plays a key role in the caspase-Abeta interaction. Overall, our study describes a novel mechanism demonstrating that Abeta sequesters caspase-3 activity via direct interaction and facilitates future therapeutic development in AD. PMID- 27227451 TI - Statin Intensity or Achieved LDL? Practice-based Evidence for the Evaluation of New Cholesterol Treatment Guidelines. AB - BACKGROUND: The recently updated American College of Cardiology/American Heart Association cholesterol treatment guidelines outline a paradigm shift in the approach to cardiovascular risk reduction. One major change included a recommendation that practitioners prescribe fixed dose statin regimens rather than focus on specific LDL targets. The goal of this study was to determine whether achieved LDL or statin intensity was more strongly associated with major adverse cardiac events (MACE) using practice-based data from electronic health records (EHR). METHODS: We analyzed the EHR data of more than 40,000 adult patients on statin therapy between 1995 and 2013. Demographic and clinical variables were extracted from coded data and unstructured clinical text. To account for treatment selection bias we performed propensity score stratification as well as 1:1 propensity score matched analyses. Conditional Cox proportional hazards modeling was used to identify variables associated with MACE. RESULTS: We identified 7,373 adults with complete data whose cholesterol appeared to be actively managed. In a stratified propensity score analysis of the entire cohort over 3.3 years of follow-up, achieved LDL was a significant predictor of MACE outcome (Hazard Ratio 1.1; 95% confidence interval, 1.05-1.2; P < 0.0004), while statin intensity was not. In a 1:1 propensity score matched analysis performed to more aggressively control for covariate balance between treatment groups, achieved LDL remained significantly associated with MACE (HR 1.3; 95% CI, 1.03 1.7; P = 0.03) while treatment intensity again was not a significant predictor. CONCLUSIONS: Using EHR data we found that on-treatment achieved LDL level was a significant predictor of MACE. Statin intensity alone was not associated with outcomes. These findings imply that despite recent guidelines, achieved LDL levels are clinically important and LDL titration strategies warrant further investigation in clinical trials. PMID- 27227452 TI - A Rose by Any Other Name: Plant Identification Knowledge & Socio-Demographics. AB - Concern has been expressed over societal losses of plant species identification skills. These losses have potential implications for engagement with conservation issues, gaining human wellbeing benefits from biodiversity (such as those resulting from nature-based recreational activities), and early warning of the spread of problematic species. However, understanding of the prevailing level of species identification skills, and of its key drivers, remains poor. Here, we explore socio-demographic factors influencing plant identification knowledge and ability to classify plants as native or non-native, employing a novel method of using real physical plants, rather than photographs or illustrations. We conducted face-to-face surveys at three different sites chosen to capture respondents with a range of socio-demographic circumstances, in Cornwall, UK. We found that survey participants correctly identified c.60% of common plant species, were significantly worse at naming non-native than native plants, and that less than 20% of people recognised Japanese knotweed Fallopia japonica, which is a widespread high profile invasive non-native in the study region. Success at naming plants was higher if participants were female, a member of at least one environmental, conservation or gardening organisation, in an older age group (than the base category of 18-29 years), or a resident (rather than visitor) of the study area. Understanding patterns of variation in plant identification knowledge can inform the development of education and engagement strategies, for example, by targeting sectors of society where knowledge is lowest. Furthermore, greater understanding of general levels of identification of problematic invasive non-native plants can guide awareness and education campaigns to mitigate their impacts. PMID- 27227453 TI - Prognostic and Clinicopathological Value of Programmed Death Ligand-1 in Breast Cancer: A Meta-Analysis. AB - Recently, the interest in programmed death ligand-1 (PD-L1) as a prognostic marker in several types of malignant tumors has increased. In the present meta analysis, we aimed to explore the prognostic and clinicopathological value of PD L1 in breast cancer. We searched Medline/PubMed, Web of Science, EMBASE, the Cochrane Library databases, and grey literature from inception until January 20, 2016. Studies concerning breast cancer that focused on PD-L1 expression and studies reporting survival data were included; two authors independently performed the data extraction. The pooled risk ratio (RR) and 95% confidence interval (CI) were assessed to determine the association between the clinicopathological parameters of patients and PD-L1 expression. Five studies involving 2061 patients were included in this meta-analysis. The results indicated that positive/higher PD-L1 expression was a negative predictor for breast cancer, with an RR of 1.64 (95% CI, 1.14-2.34) for the total mortality risk and an RR of 2.53 (95% CI, 1.78-3.59) for the mortality risk 10 years after surgery. Moreover, positive/higher PD-L1 expression was significantly associated with positive lymph node metastasis (RR, 1.33; 95% CI, 1.04-1.70), poor nuclear grade (RR, 1.24; 95% CI, 1.07-1.43), and negative estrogen receptor status (RR, 2.45; 95% CI, 1.31-4.60) in breast cancer patients. Our findings suggest that PD L1 can serve as a significant biomarker for poor prognosis and the adverse clinicopathologic features of breast cancer and could facilitate the better management of individual patients. PMID- 27227454 TI - Heterogeneity of Human Neutrophil CD177 Expression Results from CD177P1 Pseudogene Conversion. AB - Most humans harbor both CD177neg and CD177pos neutrophils but 1-10% of people are CD177null, placing them at risk for formation of anti-neutrophil antibodies that can cause transfusion-related acute lung injury and neonatal alloimmune neutropenia. By deep sequencing the CD177 locus, we catalogued CD177 single nucleotide variants and identified a novel stop codon in CD177null individuals arising from a single base substitution in exon 7. This is not a mutation in CD177 itself, rather the CD177null phenotype arises when exon 7 of CD177 is supplied entirely by the CD177 pseudogene (CD177P1), which appears to have resulted from allelic gene conversion. In CD177 expressing individuals the CD177 locus contains both CD177P1 and CD177 sequences. The proportion of CD177hi neutrophils in the blood is a heritable trait. Abundance of CD177hi neutrophils correlates with homozygosity for CD177 reference allele, while heterozygosity for ectopic CD177P1 gene conversion correlates with increased CD177neg neutrophils, in which both CD177P1 partially incorporated allele and paired intact CD177 allele are transcribed. Human neutrophil heterogeneity for CD177 expression arises by ectopic allelic conversion. Resolution of the genetic basis of CD177null phenotype identifies a method for screening for individuals at risk of CD177 isoimmunisation. PMID- 27227455 TI - Low Health System Performance, Indigenous Status and Antivenom Underdosage Correlate with Spider Envenoming Severity in the Remote Brazilian Amazon. AB - BACKGROUND: A better knowledge of the burden and risk factors associated with severity due to spider bites would lead to improved management with a reduction of sequelae usually seen for this neglected health problem, and would ensure proper use of antivenoms in remote localities in the Brazilian Amazon. The aim of this study was to analyze the profile of spider bites reported in the state of Amazonas in the Western Brazilian Amazon, and to investigate potential risk factors associated with severity of envenomation. METHODOLOGY/PRINCIPAL FINDINGS: We used a case-control study in order to identify factors associated with spider bite severity in the Western Brazilian Amazon from 2007 to 2014. Patients evolving to any severity criteria were considered cases and those with non-severe bites were included in the control group. All variables were retrieved from the official Brazilian reporting systems. Socioeconomical and environmental components were also included in a multivariable analysis in order to identify ecological determinants of incidence and severity. A total of 1,181 spider bites were recorded, resulting in an incidence of 4 cases per 100,000 person/year. Most of the spider bites occurred in males (65.8%). Bites mostly occurred in rural areas (59.5%). The most affected age group was between 16 and 45 years old (50.9%). A proportion of 39.7% of the bites were related to work activities. Antivenom was prescribed to 39% of the patients. Envenomings recorded from urban areas [Odds ratio (OR) = 0.40 (95%CI = 0.30-0.71; p<0.001)] and living in a municipality with a mean health system performance index (MHSPI >median [OR = 0.64 (95%CI = 0.39-0.75; p<0.001)] were independently associated with decreased risk of severity. Work related accidents [OR = 2.09 (95%CI = 1.49-2.94; p<0.001)], Indigenous status [OR = 2.15 (95%CI = 1.19-3.86; p = 0.011)] and living in a municipality located >300 km away from the state capital Manaus [OR = 1.90 (95%CI = 1.28-2.40; p<0.001)] were independently associated with a risk of severity. Living in a municipality located >300 km away from the state capital Manaus [OR = 1.53 (95%CI = 1.15-2.02; p = 0.003)] and living in a municipality with a MHSPI 300 km away from the state capital Manaus could be contributing factors to higher severity of spider envenomings in this area, as well as to antivenom underdosage. PMID- 27227456 TI - Elevated Levels of Protein Disulfide Isomerase and Binding Immunoglobulin Protein Implicated in Spinal Cord Injury Paraplegia Patients with Pressure Ulcers. AB - AIMS: To explore the associations between two endoplasmic reticulum (ER) stress proteins, protein disulfide isomerase (PDI), binding immunoglobulin protein (BIP), and the development and progression of pressure ulcers (PUs) in spinal cord injury (SCI) paraplegia patients. METHODS: ELISA kits were used to measure the levels of serum PDI and BIP in 67 SCI paraplegia patients with PUs and 61 SCI paraplegia patients without PUs. The associations between PDI and BIP, PU formation, PU staging, and pressure ulcer scale for healing (PUSH) score were analyzed. RESULTS: The patients in the PU group had higher levels of PDI and BIP than those in the non-PU group (both p < 0.05). Furthermore, the levels of PDI were positively correlated with those of BIP (r = 0.707, p < 0.0001). There were significant differences in the PDI and BIP levels among the different stages of PU (all p < 0.05). As the PU stages progressed, the levels of PDI and BIP first increased, then decreased, and finally peaked at stage III of the PUs. The PUSH scores significantly declined 7 days after debridement for the PU stage II (p < 0.01) but showed no significant difference between stages III and IV at 7 days after debridement (p > 0.05). The PUSH scores also decreased at 28 days after debridement for stages II, III, and IV (all p < 0.01). Higher PUSH scores indicated a longer time of debridement accompanied by a longer wound surface healing time (p < 0.05). CONCLUSION: ER stress proteins may be involved in the process of PU formation and healing; moreover, the levels of PDI and BIP were also associated with the severity of the PUs. Finally, we found that the PUSH scores can be used as a reference to evaluate PU severity and healing. PMID- 27227457 TI - Feasibility of Home-Based Computerized Working Memory Training With Children and Adolescents With Sickle Cell Disease. AB - BACKGROUND: Children with sickle cell disease (SCD) are at increased risk for neurocognitive deficits, yet the literature describing interventions to ameliorate these problems and promote academic achievement is limited. We evaluated the feasibility and preliminary efficacy of a home-based computerized working memory (WM) training intervention (Cogmed) in children with SCD. PROCEDURE: Youth with SCD between the age of 7 and 16 years completed an initial neuropsychological assessment; those with WM deficits were loaned an iPad on which they accessed Cogmed at home. Participants were instructed to work on Cogmed 5 days each week for 5 weeks (25 training sessions). We examined Cogmed usage characteristics and change on WM assessment scores following the intervention. RESULTS: Of the 21 participants (M age = 11.38, SD = 2.78; Mdn age = 10.00, interquartile range [IQR] = 5.00; 52% female) screened, 60% exhibited WM deficits (n = 12) and received the intervention and 50% (n = 6) completed Cogmed. The mean number of sessions completed was 15.83 (SD = 7.73; Mdn = 17.00, IQR = 16.00); females were more likely to complete Cogmed, chi(2) (1) = 6.00, P = 0.01. Participants who reported lower SCD-related pain impact completed more sessions (r = 0.71, P = 0.01). Children who completed Cogmed exhibited improvements in verbal WM, visuospatial short-term memory, and visuospatial WM. CONCLUSIONS: Initial findings suggest Cogmed is associated with WM improvement in youth with SCD; however, adherence was lower than expected. Home-based WM interventions may ameliorate SCD-related WM deficits but strategies are needed to address barriers to program completion. PMID- 27227458 TI - Nomogram prediction for survival of patients with oral cavity squamous cell carcinoma. AB - BACKGROUND: Nomograms are visual predictive tools that are widely used for estimating cancer prognosis. The purpose of this study was to develop a prognostic tool that will accurately predict overall survival (OS) in individual patients with oral cancer. METHODS: Medical records of 609 patients with cancer of the oral cavity were retrospectively analyzed. The stepdown method was used to select the statistically most influential predictors for inclusion in the final nomogram for predicting OS. RESULTS: The most influential predictors of mortality probability were age, comorbidities, clinical lymph node status, stage of disease, tumor thickness, differentiation, and perineural invasion. Nomogram was developed for prediction of 5-year OS. CONCLUSION: Nomogram has been widely used in a number of cancers, but its application in oral cancer prognostication has not been explored. In this study, we have developed a nomogram that can accurately estimate 5-year OS in patients with oral cavity cancer. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: 1826-1831, 2016. PMID- 27227459 TI - Anti-inflammatory Effect of Methyl Gallate on Experimental Arthritis: Inhibition of Neutrophil Recruitment, Production of Inflammatory Mediators, and Activation of Macrophages. AB - Methyl gallate (MG) is a prevalent phenolic acid in the plant kingdom, and its presence in herbal medicines might be related to its remarkable biological effects, such as its antioxidant, antitumor, and antimicrobial activities. Although some indirect evidence suggests anti-inflammatory activity for MG, there are no studies demonstrating this effect in animal models. Herein, we demonstrated that MG (0.7-70 mg/kg) inhibited zymosan-induced experimental arthritis in a dose-dependent manner. The oral administration of MG (7 mg/kg) attenuates arthritis induced by zymosan, affecting edema formation, leukocyte migration, and the production of inflammatory mediators (IL-1beta, IL-6, TNF alpha, CXCL-1, LTB4, and PGE2). Pretreatment with MG inhibited in vitro neutrophil chemotaxis elicited by CXCL-1, as well as the adhesion of these cells to TNF-alpha-primed endothelial cells. MG also impaired zymosan-stimulated macrophages by inhibiting IL-6 and NO production, COX-2 and iNOS expression, and intracellular calcium mobilization. Thus, MG is likely to present an anti inflammatory effect by targeting multiple cellular events such as the production of various inflammatory mediators, as well as leukocyte activation and migration. PMID- 27227460 TI - A Pilot Clinical Trial to Objectively Assess the Efficacy of Electroacupuncture on Gait in Patients with Parkinson's Disease Using Body Worn Sensors. AB - BACKGROUND: Gait disorder, a key contributor to fall and poor quality of life, represents a major therapeutic challenge in Parkinson's disease (PD). The efficacy of acupuncture for PD remains unclear, largely due to methodological flaws and lack of studies using objective outcome measures. OBJECTIVE: To objectively assess the efficacy of electroacupuncture (EA) for gait disorders using body-worn sensor technology in patients with PD. METHODS: In this randomized pilot study, both the patients and assessors were masked. Fifteen PD patients were randomly assigned to an experimental group (n = 10) or to a control group (n = 5). Outcomes were assessed at baseline and after completion of three weekly EA treatments. Measurements included gait analysis during single-task habitual walking (STHW), dual-task habitual walking (DTHW), single-task fast walking (STFW), dual-task fast walking (DTFW). In addition, Unified Parkinson's Disease Rating Scale (UPDRS), SF-12 health survey, short Falls Efficacy Scale International (FES-I), and visual analog scale (VAS) for pain were utilized. RESULTS: All gait parameters were improved in the experimental group in response to EA treatment. After adjustment by age and BMI, the improvement achieved statistical significant level for gait speed under STHW, STFW, and DTFW (9%-19%, p<0.05) as well as stride length during DTFW (9%, p = 0.037) and midswing speed during STFW (6%, p = 0.033). No significant changes were observed in the control group (p>0.110). The highest correlation between gait parameters and UPRDS scores at baseline was observed between gait speed during STFW and UPDRS II (r = -0.888, p = 0.004). The change in this gait parameter in response to active intervention was positively correlated with baseline UPDRS (r = 0.595, p = 0.057). Finally, comparison of responses to treatment between groups showed significant improvement, prominently in gait speed (effect size 0.32-1.16, p = 0.001). CONCLUSIONS: This study provides the objective proof of concept for potential benefits of non-pharmaceutical based EA therapy on enhancing gait in patients with PD. TRIAL REGISTRATION: ClinicalTrials.gov NCT02556164. PMID- 27227461 TI - Crystal Structure of the FERM-SH2 Module of Human Jak2. AB - Jak-family tyrosine kinases mediate signaling from diverse cytokine receptors. Binding of Jaks to their cognate receptors is mediated by their N-terminal region, which contains FERM and SH2 domains. Here we describe the crystal structure of the FERM-SH2 region of Jak2 at 3.0A resolution. The structure reveals that these domains and their flanking linker segments interact intimately to form an integrated structural module. The Jak2 FERM-SH2 structure closely resembles that recently described for Tyk2, another member of the Jak family. While the overall architecture and interdomain orientations are preserved between Jak2 and Tyk2, we identify residues in the putative receptor-binding groove that differ between the two and may contribute to the specificity of receptor recognition. Analysis of Jak mutations that are reported to disrupt receptor binding reveals that they lie in the hydrophobic core of the FERM domain, and are thus expected to compromise the structural integrity of the FERM-SH2 unit. Similarly, analysis of mutations in Jak3 that are associated with severe combined immunodeficiency suggests that they compromise Jak3 function by destabilizing the FERM-SH2 structure. PMID- 27227462 TI - Inhibition of the Arabidopsis bHLH transcription factor by monomerization through abscisic acid-induced phosphorylation. AB - We have demonstrated that the Arabidopsis basic helix-loop-helix (bHLH) transcription factor, ABA-responsive kinase substrate 1 (AKS1; also known as FLOWERING BHLH 3, FBH3), enhances K(+) channel expression in guard cells leading to stomatal opening. The expression is suppressed by ABA-induced phosphorylation of AKS1. Here we show that the phosphorylation results in the monomerization of AKS1 multimers and inhibits AKS1 binding to DNA. AKS1 forms homo-multimers which dissociate following phosphorylation. Replacement of a critical amino acid in the bHLH domain inhibited multimer formation and decreased the binding of AKS1 to DNA. The monomerization was elicited via phosphorylation at three serine residues, which is mediated by SNF1-related protein kinase 2.6 (SnRK2.6), in the vicinity of bHLH domain. Furthermore, ABA induced the phosphorylation-dependent release of AKS1 from DNA, thereby suppressing transcriptional activity in vivo. Our results document a mechanism that inhibits gene expression by phosphorylation of a bHLH transcription factor. PMID- 27227464 TI - "Diagnostic Algorithm for Patients With Suspected Giant Cell Arteritis" Useful, but No Substitute for Thorough Histopathology. PMID- 27227463 TI - Impaired Corpus Cavernosum Relaxation Is Accompanied by Increased Oxidative Stress and Up-Regulation of the Rho-Kinase Pathway in Diabetic (Db/Db) Mice. AB - Basal release of nitric oxide from endothelial cells modulates contractile activity in the corpus cavernosum via inhibition of the RhoA/Rho-kinase signaling pathway. We aimed to investigate nitric oxide bioavailability, oxidative stress and the Rho-kinase pathway in the relaxation of the corpus cavernosum of an obese and diabetic model of mice (db/db mice). We hypothesized that in db/db mice impaired relaxation induced by Rho-kinase inhibitor is accompanied by diminished NO bioavailability, increased oxidative stress and upregulation of the RhoA/Rho kinase signalling pathway. Cavernosal strips from male lean and non-diabetic db/+ and db/db mice were mounted in myographs and isometric force in response to Rho kinase inhibitor Y-27632 was recorded. Enzyme activity and protein expression of oxidative stress markers and key molecules of the RhoA/Rho-kinase pathway were analyzed. The Rho-kinase inhibitor Y-27632 concentration-dependently caused corpus cavernosum relaxation and inhibited cavernosal contractions. Nonetheless, a rightward shift in the curves obtained in corpus cavernosum of db/db mice was observed. Compared to db/+, this strain presented increased active RhoA, higher MYPT-1 phosphorylation stimulated by phenylephrine, and increased expression of ROKalpha and Rho-GEFs. Further, we observed normal expression of endothelial and neuronal NOS in corpus cavernosum of db/db mice. However, nitrate/nitrate (NOx) levels were diminished, suggesting decreased NO bioavailability. We measured the oxidant status and observed increased lipid peroxidation, with decreased SOD activity and expression. In conclusion, our data demonstrate that in db/db mice, upregulation of the RhoA/Rho-kinase signalling pathway was accompanied by decreased NO bioavailability and increased oxidative stress contributing to impaired relaxation of the corpus cavermosum of db/db mice. PMID- 27227465 TI - "Diagnostic Algorithm for Patients With Suspected Giant Cell Arteritis" Useful, but No Substitute for Thorough Histopathology: Response. PMID- 27227466 TI - Palinopsia: Side Effect of Topiramate and Acetazolamide. PMID- 27227467 TI - SCIDs and related disorders. PMID- 27227469 TI - Recurrent Nevi in a Skin Graft Following Excision of Giant Congenital Melanocytic Nevus. PMID- 27227468 TI - Discovery of Novel Orally Active Tetrahydro-Naphthyl-N-Acylhydrazones with In Vivo Anti-TNF-alpha Effect and Remarkable Anti-Inflammatory Properties. AB - LASSBio-1524 was designed as inhibitor of the IKK-beta (kappa beta kinase inhibitor) enzyme, which participates in the activation of the nuclear factor kappaB (NF-kappaB) canonical pathway, and its three N-acylhydrazone new analogues, LASSBio-1760, LASSBio-1763 and LASSBio-1764 are now being tested on their anti-inflammatory potential. The activity of these compounds was evaluated with the subcutaneous air pouch induced by carrageenan and by subsequent measurement of tumor necrosis factor-alpha (TNF-alpha), nitric oxide (NO) and reactive oxygen species (ROS). In the acute inflammation model, the oral pretreatment with doses from 0.3 to 30 mg/kg of N-acylhydrazone derivatives was able to significantly reduce leukocyte migration to the cavity. Pretreatment with LASSBio-1524 and its analogues also decreased NO, TNF-alpha and ROS biosynthesis an events closely involved with NF-kB pathway. The tetrahydronaphthyl-N acylhydrazone derivative LASSBio-1764 was the most promising compound from this series, surpassing even LASSBio-1524. Additionally, none of the compounds demonstrated myelotoxicity or cytotoxicity. Cell viability was assayed and these compounds demonstrated to be safe at different concentrations. Western blot analysis demonstrated that LASSBio-1524 and LASSBio-1760 inhibited NF-kappaB expression in RAW 264.7 cell lineage. Our data indicate that the tested compounds have anti-inflammatory activity, which may be related to inhibition of leukocyte migration, reducing the production of NO, TNF-alpha and ROS. LASSBio-1524 and LASSBio-1760, in addition to these features, also reduced p65 nuclear expression assessed by western blot in RAW 264.7 murine cells. PMID- 27227470 TI - Soft-Tissue Augmentation With Hyaluronic Acid Filler for Labia Majora and Mons Pubis. PMID- 27227471 TI - Invasive Squamous Cell Carcinoma: A Comparison of Tumors With or Without Horn Presentation Based on Age, Sex, Anatomic Site, Tumor Diameter, Depth of Invasion, and Grade of Differentiation in 1,666 Cases. AB - INTRODUCTION: Invasive squamous cell carcinoma (SCC) may present clinically with or without a horn. OBJECTIVE: To compare invasive SCC with or without horn presentation by anatomic site, tumor diameter, depth, and grade of differentiation. MATERIALS AND METHODS: The above characteristics of invasive SCC with or without horns were compared using a logistic regression model adjusted for potential confounders. RESULTS: There were 7.0% horns (n = 116) and 93.0% nonhorns (n = 1,550) in 1,666 cases. The median tumor diameter was 6 mm for horns, and 8 mm for nonhorn cases, p < .001. The median depth of invasion was 0.8 mm for horn cases and 1.3 mm for nonhorns, p < .001. Most cases were well differentiated SCC for both horns (n = 102, 87.9%) and nonhorns (n = 1,265, 81.6%) p = .07. Horn cases had a borderline significant shift to well differentiation with moderate differentiation in 11.2% of cases (n = 13) and poor differentiation in 0.9% (n = 1). CONCLUSION: Horns presented on invasive SCC with reduced tumor diameters and reduced invasion depths compared to nonhorns. Horns presenting on invasive SCC were usually well differentiated. However, moderate and even poor differentiation can occur within a horn base. PMID- 27227472 TI - Usefulness of a Self-Retaining Retraction System in Mohs Micrographic Surgery. PMID- 27227473 TI - Successful Treatment of a Red and Black Professional Tattoo in Skin Type VI With a Picosecond Dual-Wavelength, Neodymium-Doped Yttrium Aluminium Garnet Laser. PMID- 27227474 TI - Continuous Wave Potassium Titanyl Phosphate Laser Treatment is Safe and Effective for Xanthelasma Palpebrarum. AB - BACKGROUND: Although not an accepted standard treatment, the 532-nm continuous wave potassium titanyl phosphate (CW-KTP) laser might be a powerful device to treat xanthelasma palpebrarum (XP). OBJECTIVE: To determine the safety and efficacy of CW-KTP laser treatment for XP. MATERIALS AND METHODS: Between January 2013 and January 2015, 30 consecutive patients with XP were treated with a 532-nm CW-KTP laser (spot size: 0.9 mm, power: 5.0 W, fluence: 36-38 J/cm, pulse width: 46 milliseconds, frequency: 2.0 Hz, passes per session: 3). In a retrospective study design, safety and efficacy data were collected and analyzed. RESULTS: Overall, 29/30 (97%) of patients had an excellent cosmetical result. Downtime was 1 week with crusted lesions. Although slight hypopigmentation was common, only 1/30 (3%) patients had hypopigmentation that was more than expected. Recurrences (13/30; 43%) were frequent, so that yearly maintenance therapy was warranted. No major side effects were noticed. CONCLUSION: Continuous wave KTP laser therapy is safe and highly effective for XP, although regular follow-up treatments are often necessary to maintain the achieved cosmetic results. PMID- 27227475 TI - Alar Notching and Retraction. PMID- 27227476 TI - Repair of Two Adjacent Defects of the Lateral Nasal Tip and Ala. PMID- 27227477 TI - Psammoma Bodies in Cutaneous Squamous Cell Carcinoma. PMID- 27227478 TI - Reconstruction of a Large Full-Thickness Nasal Defect. PMID- 27227479 TI - Successful Treatment of Recalcitrant Plantar Warts With Bleomycin and Microneedling. PMID- 27227481 TI - RGTA in corneal wound healing after transepithelial laser ablation in a rabbit model: a randomized, blinded, placebo-controlled study. AB - PURPOSE: To evaluate the efficacy of the agent RGTA for epithelial, stromal and nerve regeneration after laser-induced corneal wounding in rabbits. METHODS: After excimer laser wounding of the anterior cornea in 25 New Zealand white rabbits, topical RGTA or placebo was applied in a randomized, masked manner. Fluorescein epithelial staining was performed on the first 5 postoperative days. In vivo confocal microscopy of corneal subbasal nerves and stroma was performed preoperatively and on week 2, 4, 8 and 16. At 16 weeks, corneas were stained for beta-III tubulin expression. RESULTS: Postoperatively, all epithelia had closed by at least 90% after the third postoperative day. No significant difference in epithelial wound size was found between RGTA and placebo-treated groups, and RGTA did not hinder fluorescein binding. After epithelial wound closure, corneas remained transparent to 16 weeks. By confocal microscopy, subclinical stromal haze was significantly deeper in placebo-treated eyes (mean depth 60 MUm) relative to RGTA group (52 MUm), p = 0.02. Regenerating beta-III tubulin-positive subbasal nerves were observed in all corneas, but partial masking by haze rendered quantitative analysis unreliable. CONCLUSIONS: RGTA restored stromal microarchitecture and reduced subclinical haze relative to placebo. The mild epithelial wound quickly healed regardless of treatment suggesting an optimal natural healing process in freshly wounded healthy corneas, and indicating that RGTA may be more suitable for healing of chronic or more aggressive wounds. Limitations of the rabbit model for nerve quantification in the presence of haze should also be recognized. PMID- 27227480 TI - Complexities in Isolation and Purification of Multiple Viruses from Mixed Viral Infections: Viral Interference, Persistence and Exclusion. AB - Successful purification of multiple viruses from mixed infections remains a challenge. In this study, we investigated peste des petits ruminants virus (PPRV) and foot-and-mouth disease virus (FMDV) mixed infection in goats. Rather than in a single cell type, cytopathic effect (CPE) of the virus was observed in cocultured Vero/BHK-21 cells at 6th blind passage (BP). PPRV, but not FMDV could be purified from the virus mixture by plaque assay. Viral RNA (mixture) transfection in BHK-21 cells produced FMDV but not PPRV virions, a strategy which we have successfully employed for the first time to eliminate the negative stranded RNA virus from the virus mixture. FMDV phenotypes, such as replication competent but noncytolytic, cytolytic but defective in plaque formation and, cytolytic but defective in both plaque formation and standard FMDV genome were observed respectively, at passage level BP8, BP15 and BP19 and hence complicated virus isolation in the cell culture system. Mixed infection was not found to induce any significant antigenic and genetic diversity in both PPRV and FMDV. Further, we for the first time demonstrated the viral interference between PPRV and FMDV. Prior transfection of PPRV RNA, but not Newcastle disease virus (NDV) and rotavirus RNA resulted in reduced FMDV replication in BHK-21 cells suggesting that the PPRV RNA-induced interference was specifically directed against FMDV. On long-term coinfection of some acute pathogenic viruses (all possible combinations of PPRV, FMDV, NDV and buffalopox virus) in Vero cells, in most cases, one of the coinfecting viruses was excluded at passage level 5 suggesting that the long-term coinfection may modify viral persistence. To the best of our knowledge, this is the first documented evidence describing a natural mixed infection of FMDV and PPRV. The study not only provides simple and reliable methodologies for isolation and purification of two epidemiologically and economically important groups of viruses, but could also help in establishing better guidelines for trading animals that could transmit further infections and epidemics in disease free nations. PMID- 27227482 TI - Synthesis and screening of triazolopyrimidine scaffold as multi-functional agents for Alzheimer's disease therapies. AB - In present study a series of triazolopyrimidine-quinoline and cyanopyridine quinoline hybrids were designed, synthesized and evaluated as acetylcholinesterase inhibitors (AChEIs). Molecular docking and scoring was utilized for the design of inhibitors. The molecules were synthesized via an easily accessible, convergent synthetic route. Three triazolopyrimidine based compounds showed nanomolar activity towards acetylcholinesterase. Among them, Ethyl 6-fluoro-4-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1 yl)quinoline-3-carboxylate (10d), strongly inhibited AChE with IC50 value of 42 nM. Furthermore compound 10d was identified as most promising compound with 12 fold selectivity against butyrylcholinesterase (BuChE). This compound displayed a composed multitargeted profile with promising inhibition of self-induced and AChE - induced Abeta aggregation and antioxidant activity. PMID- 27227484 TI - Plasmacytic posttransplant lymphoproliferative disorder with hyperviscosity syndrome in a child after liver transplant. PMID- 27227483 TI - Soluble and membrane-bound interleukin (IL)-15 Ralpha/IL-15 complexes mediate proliferation of high-avidity central memory CD8+ T cells for adoptive immunotherapy of cancer and infections. AB - The lack of persistence of infused T cells is a principal limitation of adoptive immunotherapy in man. Interleukin (IL)-15 can sustain memory T cell expansion when presented in complex with IL-15Ralpha (15Ralpha/15). We developed a novel in vitro system for generation of stable 15Ralpha/15 complexes. Immunologically quantifiable amounts of IL-15 were obtained when both IL-15Ralpha and IL-15 genes were co-transduced in NIH 3T3 fibroblast-based artificial antigen-presenting cells expressing human leucocyte antigen (HLA) A:0201, beta2 microglobulin, CD80, CD58 and CD54 [A2-artificial antigen presenting cell (AAPC)] and a murine pro-B cell line (Baf-3) (A2-AAPC15Ralpha/15 and Baf-315Ralpha/15 ). Transduction of cells with IL-15 alone resulted in only transient expression of IL-15, with minimal amounts of immunologically detectable IL-15. In comparison, cells transduced with IL-15Ralpha alone (A2-AAPCRalpha ) demonstrated stable expression of IL-15Ralpha; however, when loaded with soluble IL-15 (sIL-15), these cells sequestered 15Ralpha/15 intracellularly and also demonstrated minimal amounts of IL-15. Human T cells stimulated in vitro against a viral antigen (CMVpp65) in the presence of 15Ralpha/15 generated superior yields of high-avidity CMVpp65 epitope specific T cells [cytomegalovirus-cytotoxic T lymphocytes (CMV-CTLs)] responding to <= 10- 13 M peptide concentrations, and lysing targets cells at lower effector : target ratios (1 : 10 and 1 : 100), where sIL-15, sIL-2 or sIL-7 CMV-CTLs demonstrated minimal or no activity. Both soluble and surface presented 15Ralpha/15, but not sIL-15, sustained in-vitro expansion of CD62L+ and CCR7+ central memory phenotype CMV-CTLs (TCM ). 15Ralpha/15 complexes represent a potent adjuvant for augmenting the efficacy of adoptive immunotherapy. Such cell bound or soluble 15Ralpha/15 complexes could be developed for use in combination immunotherapy approaches. PMID- 27227485 TI - T1rho and T2 -based characterization of regional variations in intervertebral discs to detect early degenerative changes. AB - Lower back pain is one of the main contributors to morbidity and chronic disability in the United States. Despite the significance of the problem, it is still not well understood. There is a clear need for objective, non-invasive biomarkers to localize specific pain generators and identify early stage changes to enable reliable diagnosis and treatment. In this study we focus on intervertebral disc degeneration as a source of lower back pain. Quantitative imaging markers T1rho and T2 have been shown to be promising techniques for in vivo diagnosis of biochemical degeneration in discs due to their sensitivity to macromolecular changes in proteoglycan content and collagen integrity. We describe a semi-automated technique for quantifying T1rho and T2 relaxation time maps in the nucleus pulposus (NP) and the annulus fibrosus (AF) of the lumbar intervertebral discs. Compositional changes within the NP and AF associated with degeneration occur much earlier than the visually observable structural changes. The proposed technique rigorously quantifies these biochemical changes taking into account subtle regional variations to allow interpretation of early degenerative changes that are difficult to interpret with traditional MRI techniques and clinical subjective grading scores. T1rho and T2 relaxation times in the NP decrease with degenerative severity in the disc. Moreover, standard deviation and texture measurements of these values show sharper and more significant changes during early degeneration compared to later degenerative stages. Our results suggest that future prospective studies should include automated T1rho and T2 metrics as early biomarkers for disc degeneration-induced lower back pain. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1373-1381, 2016. PMID- 27227486 TI - Joint distraction in advanced haemophilic ankle arthropathy. PMID- 27227487 TI - Retest of a Principal Components Analysis of Two Household Environmental Risk Instruments. AB - Household Risk Perception (HRP) and Self-Efficacy in Environmental Risk Reduction (SEERR) instruments were developed for a public health nurse-delivered intervention designed to reduce home-based, environmental health risks among rural, low-income families. The purpose of this study was to test both instruments in a second low-income population that differed geographically and economically from the original sample. Participants (N = 199) were recruited from the Women, Infants, and Children (WIC) program. Paper and pencil surveys were collected at WIC sites by research-trained student nurses. Exploratory principal components analysis (PCA) was conducted, and comparisons were made to the original PCA for the purpose of data reduction. Instruments showed satisfactory Cronbach alpha values for all components. HRP components were reduced from five to four, which explained 70% of variance. The components were labeled sensed risks, unseen risks, severity of risks, and knowledge. In contrast to the original testing, environmental tobacco smoke (ETS) items was not a separate component of the HRP. The SEERR analysis demonstrated four components explaining 71% of variance, with similar patterns of items as in the first study, including a component on ETS, but some differences in item location. Although low-income populations constituted both samples, differences in demographics and risk exposures may have played a role in component and item locations. Findings provided justification for changing or reducing items, and for tailoring the instruments to population-level risks and behaviors. Although analytic refinement will continue, both instruments advance the measurement of environmental health risk perception and self-efficacy. (c) 2016 Wiley Periodicals, Inc. PMID- 27227488 TI - E3 Ubiquitin ligase RNF126 regulates the progression of tongue cancer. AB - This study aims to analyze the role of RNF126 in the oncogenesis of tongue cancer. The cell proliferation and viability of human tongue cancer cells, SCC25 and SCC9 cells, were determined by cell counting and MTT assay, respectively. The effect of RNF126 on regulating AKT signaling pathway was analyzed through western blotting. The transplantation tumor model of nude mice was used to evaluate the tumorigenecity of RNF126. Knockdown of RNF126 inhibited the proliferation and viability of SCC9 and SCC25 cells. Inhibition of RNF126 also decreased the activity of AKT1 as well as its downstream molecules. Furthermore, RNF126 regulated the tumor volume on mice model. These data suggested that RNF126 might be related to the progression of tongue cancer through regulating AKT signaling pathway. PMID- 27227489 TI - State Variation in Health Care Service Utilization: United States, 2014. AB - KEY FINDINGS: Data from the National Health Interview Survey, 2014 *The percentage of adults without a usual place of medical care ranged from 2.8% in Vermont to 26.7% in Nevada. *The percentage of adults who did not have a general doctor visit in the past 12 months ranged from 15.9% in Vermont to 48.1% in Montana. *The percentage of adults without a usual place of medical care was lower in states that expanded Medicaid compared with nonexpansion states. *The percentage of adults without a usual place of medical care or who did not see a general doctor in the past 12 months was lower in states with partnership marketplaces compared with Federally Facilitated Marketplace states. State-level differences in the percentage of uninsured Americans, along with other factors, may affect health care access and utilization (1-4). This report examines the prevalence of two health care utilization measures among adults aged 18-64 by state. Additionally, differences by Medicaid expansion status and state Health Insurance Marketplace type are examined. Estimates are based on the 2014 National Health Interview Survey, a nationally representative sample of the noninstitutionalized U.S. PMID- 27227493 TI - Age-related changes in the morphology and protein expression of the thymus of healthy yaks (Bos grunniens). AB - OBJECTIVE To evaluate age-related changes in the morphology and expression of cluster of differentiation 3 (CD3), S100 beta, and caspase-3 of the thymus of healthy yaks (Bos grunniens). ANIMALS 15 healthy male yaks of various ages from highland plateaus. PROCEDURES Yaks were allocated to 3 groups on the basis of age (newborn [1 to 7 days old; n = 5], juvenile [5 to 7 months old, 5], and adult [3 to 4 years old; 5]) and euthanized. The thymus was harvested from each yak within 10 minutes after euthanasia. Morphological characteristics were assessed by histologic examination and transmission electron microscopy. Expression of CD3, S100 beta, and caspase-3 mRNA and protein was measured by quantitative real-time PCR assay, Western blot analysis, and immunohistochemical staining. RESULTS As age increased, functional thymic tissue was replaced with adipose and connective tissues and the thymic capsule thickened. Expression of CD3 and S100 beta mRNA and protein decreased with age, whereas expression of caspase-3 mRNA and protein increased with age. Immunohistochemical staining revealed that CD3-positive thymocytes were located within both the thymic cortex and medulla, S100 beta positive thymic dendritic cells were located in the corticomedullary junction and medulla, and caspase-3-positive thymocytes were diffusely scattered throughout the cortex and medulla. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that age-related thymic changes in yaks that live on highland plateaus were similar to those observed in humans and other mammals. Thus, yaks might serve as a model to study thymic immune system adaptations to high elevations. PMID- 27227495 TI - Effects of regional limb perfusion volume on concentrations of amikacin sulfate in synovial and interstitial fluid samples from anesthetized horses. AB - OBJECTIVE To evaluate the effect of volume of IV regional limb perfusion (IVRLP) on amikacin concentrations in synovial and interstitial fluid of horses. ANIMALS 8 healthy adult horses. PROCEDURES Each forelimb was randomly assigned to receive IVRLP with 4 mL of amikacin sulfate solution (250 mg/mL) plus 56 mL (total volume, 60 mL) or 6 mL (total volume, 10 mL) of lactated Ringer solution. Horses were anesthetized, and baseline synovial and interstitial fluid samples were collected. A tourniquet was placed, and the assigned treatment was administered via the lateral palmar digital vein. Venous blood pressure in the distal portion of the limb was recorded. Additional synovial fluid samples were collected 30 minutes (just before tourniquet removal) and 24 hours after IVRLP began; additional interstitial fluid samples were collected 6 and 24 hours after IVRLP began. RESULTS 30 minutes after IVRLP began, mean amikacin concentration in synovial fluid was significantly greater for the large-volume (459 MUg/mL) versus small-volume (70 MUg/mL) treatment. Six hours after IVRLP, mean concentration in interstitial fluid was greater for the large-volume (723 MUg/mL) versus small volume (21 MUg/mL) treatment. Peak venous blood pressure after large-volume IVRLP was significantly higher than after small-volume IVRLP, with no difference between treatments in time required for pressure to return to baseline. CONCLUSIONS AND CLINICAL RELEVANCE Study findings suggested that large-volume IVRLP would deliver more amikacin to metacarpophalangeal joints of horses than would small-volume IVRLP, without a clinically relevant effect on local venous blood pressure, potentially increasing treatment efficacy. PMID- 27227494 TI - Effects of magnesium sulfate and propofol on the minimum alveolar concentration preventing motor movement in sevoflurane-anesthetized dogs. AB - OBJECTIVE To evaluate the effect of MgSO4, alone and in combination with propofol, on the minimum alveolar concentration preventing motor movement (MACNM) in sevoflurane-anesthetized dogs. ANIMALS 6 healthy purpose-bred adult male Beagles (least squares mean +/- SEM body weight, 12.0 +/- 1.1 kg). PROCEDURES Dogs were anesthetized 3 times at weekly intervals. The MACNM was measured 45 minutes after induction of anesthesia (baseline; MACNM-B) and was determined each time by use of a noxious electrical stimulus. Treatments were administered as a loading dose and constant rate infusion (CRI) as follows: treatment 1, MgSO4 loading dose of 45 mg/kg and CRI of 15 mg/kg/h; treatment 2, propofol loading dose of 4 mg/kg and CRI of 9 mg/kg/h; and treatment 3, MgSO4 and propofol combination (same doses used previously for each drug). A mixed-model ANOVA and Tukey-Kramer tests were used to determine effects of each treatment on the percentage decrease from MACNM-B. Data were reported as least squares mean +/- SEM values. RESULTS Decrease from MACNM-B was 3.4 +/- 3.1%, 48.3 +/- 3.1%, and 50.3 +/- 3.1%, for treatments 1, 2, and 3, respectively. The decrease for treatments 2 and 3 was significantly different from that for treatment 1; however, no significant difference existed between results for treatments 2 and 3. CONCLUSIONS AND CLINICAL RELEVANCE MgSO4 did not affect MACNM, nor did it potentiate the effects of propofol on MACNM. Administration of MgSO4 in this study appeared to provide no clinical advantage as an anesthetic adjuvant. PMID- 27227496 TI - Use of three-dimensional accelerometers to evaluate behavioral changes in cattle experimentally infected with bovine viral diarrhea virus. AB - OBJECTIVE To assess the use of 3-D accelerometers to evaluate behavioral changes in cattle experimentally infected with a low-virulent strain of bovine viral diarrhea virus (BVDV). ANIMALS 20 beef steers (mean weight, 238 kg). PROCEDURES Calves were allocated to a BVDV (n = 10) or control (10) group. On day 0, calves in the BVDV group were inoculated with a low-virulent strain of BVDV (4 * 10(6) TCID50, intranasally), and calves in the control group were sham inoculated with BVDV-free medium (4 mL; intranasally). An accelerometer was affixed to the right hind limb of each calf on day -7 to record activity (lying, walking, and standing) continuously until 35 days after inoculation. Baseline was defined as days -7 to -1. Blood samples were collected at predetermined times for CBC, serum biochemical analysis, virus isolation, and determination of anti-BVDV antibody titers. RESULTS All calves in the BVDV group developed viremia and anti-BVDV antibodies but developed only subclinical or mild disease. Calves in the control group did not develop viremia or anti-BVDV antibodies. Mean time allocated to each activity did not differ significantly between the BVDV and control groups on any day except day 8, when calves in the BVDV group spent less time standing than the calves in the control group. Following inoculation, calves in both groups tended to spend more time lying and less time walking and standing than they did during baseline. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that behavioral data obtained by accelerometers could not distinguish calves subclinically infected with BVDV from healthy control calves. However, subtle changes in the behavior of the BVDV-infected calves were detected and warrant further investigation. PMID- 27227497 TI - Ultrasonographic appearance of the major duodenal papilla in dogs without evidence of hepatobiliary, pancreatic, or gastrointestinal tract disease. AB - OBJECTIVE To determine the ultrasonographic appearance of the major duodenal papilla (MDP) in dogs without evidence of hepatobiliary, pancreatic, or gastrointestinal tract disease. ANIMALS 40 adult client-owned dogs examined because of conditions that did not include hepatobiliary, pancreatic, or gastrointestinal tract disease. PROCEDURES Ultrasonographic examination of the MDP was performed. Each MDP was measured in 3 planes. Intraobserver reliability of measurements was determined, and associations between MDP dimensions and characteristics of the dogs were investigated. Histologic examination of longitudinal sections of the MDP was performed for 1 dog to compare the ultrasonographic and histologic appearance. RESULTS The MDP appeared as a layered structure with a hyperechoic outer layer, hypoechoic middle layer, and hyperechoic inner layer that corresponded to the duodenal serosa, duodenal muscularis, and duodenal submucosa, respectively. Layers visible during ultrasonographic examinations were consistent with layers identified histologically. Intraobserver reliability was substantial for each plane of measurement. Mean +/- SD length, width, and height of the MDP were 15.2 +/- 3.5 mm, 6.3 +/- 1.6 mm, and 4.3 +/- 1.0 mm, respectively. An increase in body weight of dogs was significantly associated with increased values for all measurements. CONCLUSIONS AND CLINICAL RELEVANCE The ultrasonographic appearance and approximate dimensions of the MDP of dogs without evidence of hepatobiliary, pancreatic, or gastrointestinal tract disease were determined. Additional studies are needed to evaluate possible ultrasonographic lesions of the MDP in dogs with hepatobiliary, pancreatic, or intestinal diseases and to investigate clinical implications of these lesions with regard to diagnosis and prognosis. PMID- 27227498 TI - Effect of disrupted mitochondria as a source of damage-associated molecular patterns on the production of tumor necrosis factor alpha by splenocytes from dogs. AB - OBJECTIVE To evaluate the effects of damage-associated molecular patterns (DAMPs) derived from disrupted mitochondria on canine splenocytes and other immune cells. SAMPLES Liver, spleen, and bone marrow samples obtained from 8 cadavers of healthy research Beagles that had been euthanized for other purposes. PROCEDURES Mitochondria were obtained from canine hepatocytes, and mitochondrial DAMPs (containing approx 75% mitochondrial proteins) were prepared. Mitochondrial DAMPs and the nuclear cytokine high-mobility group box protein 1 were applied to splenocytes, bone marrow-differentiated dendritic cells, and a canine myelomonocytic cell (DH82) line for 6 or 24 hours. Cell culture supernatants from splenocytes, dendritic cells, and DH82 cells were assayed for tumor necrosis factor alpha with an ELISA. Expression of tumor necrosis factor alpha mRNA in splenocytes was evaluated with a quantitative real-time PCR assay. RESULTS In all cell populations evaluated, production of tumor necrosis factor alpha was consistently increased by mitochondrial DAMPs at 6 hours (as measured by an ELISA). In contrast, high-mobility group box protein 1 did not have any independent proinflammatory effects in this experimental system. CONCLUSIONS AND CLINICAL RELEVANCE The study revealed an in vitro inflammatory effect of mitochondrial DAMPs (containing approx 75% mitochondrial proteins) in canine cells and validated the use of an in vitro splenocyte model to assess DAMP induced inflammation in dogs. This experimental system may aid in understanding the contribution of DAMPs to sepsis and the systemic inflammatory response syndrome in humans. Further studies in dogs are needed to validate the biological importance of these findings and to evaluate the in vivo role of mitochondrial DAMPs in triggering and perpetuating systemic inflammatory states. PMID- 27227499 TI - 24-hour evaluation of dental plaque bacteria and halitosis after consumption of a single placebo or dental treat by dogs. AB - OBJECTIVE To determine whether consumption of a single dental treat with specific mechanical properties and active ingredients would provide a 24-hour effect on dental plaque bacteria and halitosis in dogs. ANIMALS 10 dogs of various breeds from a privately owned colony that had received routine dental scaling and polishing 4 weeks before the study began. PROCEDURES Dogs were randomly assigned to receive 1 placebo or dental treat first. A 4-week washout period was provided, and then dogs received the opposite treatment. Oral plaque and breath samples were collected before and 0.5, 3, 12, and 24 hours after treat consumption. Volatile sulfur compounds (VSCs) concentration was measured in breath samples. Total aerobic, total anaerobic, Porphyromonas gulae, Prevotella intermedia-like, Tannerella forsythia, and Fusobacterium nucleatum bacterial counts (measured via bacterial culture) and total live bacterial counts, total live and dead bacterial counts, and bacterial vitality (measured via quantitative real-time PCR assay) were assessed in plaque samples. RESULTS Compared with placebo treat consumption, dental treat consumption resulted in a significant decrease in breath VSCs concentration and all plaque bacterial counts, without an effect on bacterial vitality. Effects of the dental treat versus the placebo treat persisted for 12 hours for several bacterial counts and for 24 hours for breath VSCs concentration. CONCLUSIONS AND CLINICAL RELEVANCE Although clinical benefits should be investigated in larger scale, longer-term studies, results of this study suggested that feeding the evaluated dental treat may help to decrease oral bacterial growth in dogs for 12 hours and oral malodor for 24 hours. A feeding interval of 12 hours is therefore recommended. PMID- 27227500 TI - Changes in the dimension and volume of feline injection-site sarcomas following formalin fixation as determined by use of the ellipsoid volume formula and three dimensional computed tomography software. AB - OBJECTIVE To evaluate changes in the dimension and volume of feline injection site sarcomas (FISSs) before (in vivo) and after surgical excision and formalin fixation (ex vivo) as determined by measurements obtained from 2-D and 3-D CT images. SAMPLE 10 excised FISSs. PROCEDURES The maximum length, width, and depth of each FISS were measured on contrast-enhanced 2-D CT images of the tumor obtained in vivo and ex vivo. Those measurements were used to estimate tumor volume with the standard ellipsoid formula. Tumor volume was also calculated from 3-D CT images with software that used a volume-rendering algorithm. Student paired t tests were used for comparisons between the in vivo and ex vivo assessments. RESULTS Small decreases were detected in maximum tumor length, width, and depth between the in vivo and ex vivo assessments; however, tumor length was the only dimension that decreased significantly between the 2 assessments. Median tumor volume decreased significantly between the in vivo and ex vivo assessments regardless of the method used to estimate it. Tumor volume estimated by the ellipsoid formula was significantly lower than that estimated by the 3-D CT software at both assessments. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that shrinkage of FISSs following excision and formalin fixation was small and may be less than that of grossly normal tissue. Tumor volume estimated by the ellipsoid formula was consistently less than that estimated by 3-D CT software and should not be used when accuracy of tumor volume is of particular concern and advanced CT imaging is available. PMID- 27227501 TI - Comparison of the in vitro anticollagenase efficacy of homologous serum and plasma on degradation of corneas of cats, dogs, and horses. AB - OBJECTIVE To compare the anticollagenase efficacy of fresh feline, canine, and equine serum and plasma on in vitro corneal degradation. SAMPLE Grossly normal corneas from recently euthanized dogs, cats, and horses and fresh serum and plasma from healthy dogs, cats, and horses. PROCEDURES Serum and plasma were pooled by species and used for in vitro experiments. Corneas were collected and stored at -80 degrees C. Sections of cornea were dried, weighed, and incubated in saline (0.9% NaCl) solution with clostridial collagenase and homologous fresh serum or plasma. Corneal degradation was assessed as the percentage of corneal weight loss and hydroxyproline concentration, compared with results for positive and negative control samples. RESULTS Homologous fresh serum and plasma significantly reduced the percentage of corneal weight loss, compared with results for positive control samples. No significant difference was found in percentage of corneal weight loss between incubation with serum or plasma for feline, canine, and equine corneas. Canine serum and plasma significantly reduced hydroxyproline concentrations, whereas inclusion of feline and equine serum or plasma did not, compared with results for positive control samples. Hydroxyproline concentrations were moderately correlated with percentage of corneal weight loss for feline samples and weakly correlated for equine samples, but they were not correlated for canine samples. CONCLUSIONS AND CLINICAL RELEVANCE In this study, the anticollagenase efficacy of fresh feline, canine, and equine serum was not different from that of plasma. Plasma should be an acceptable substitute for serum in the topical treatment of keratomalacia. PMID- 27227502 TI - Pharmacokinetics and tissue elimination of flunixin in veal calves. AB - OBJECTIVE To describe plasma pharmacokinetic parameters and tissue elimination of flunixin in veal calves. ANIMALS 20 unweaned Holstein calves between 3 and 6 weeks old. PROCEDURES Each calf received flunixin (2.2 mg/kg, IV, q 24 h) for 3 days. Blood samples were collected from all calves before the first dose and at predetermined times after the first and last doses. Beginning 24 hours after injection of the last dose, 4 calves were euthanized each day for 5 days. Plasma and tissue samples were analyzed by ultraperformance liquid chromatography. Pharmacokinetic parameters were calculated by compartmental and noncompartmental methods. RESULTS Mean +/- SD plasma flunixin elimination half-life, residence time, and clearance were 1.32 +/- 0.94 hours, 12.54 +/- 10.96 hours, and 64.6 +/- 40.7 mL/h/kg, respectively. Mean hepatic and muscle flunixin concentrations decreased to below FDA-established tolerance limits (0.125 and 0.025 MUg/mL, respectively) for adult cattle by 3 and 2 days, respectively, after injection of the last dose of flunixin. Detectable flunixin concentrations were present in both the liver and muscle for at least 5 days after injection of the last dose. CONCLUSIONS AND CLINICAL RELEVANCE The labeled slaughter withdrawal interval for flunixin in adult cattle is 4 days. Because administration of flunixin to veal calves represents extralabel drug use, any detectable flunixin concentrations in edible tissues are considered a violation. Results indicated that a slaughter withdrawal interval of several weeks may be necessary to ensure that violative tissue residues of flunixin are not detected in veal calves treated with that drug. PMID- 27227503 TI - Pharmacokinetics of bupivacaine after intraperitoneal administration to cats undergoing ovariohysterectomy. AB - OBJECTIVE To evaluate pharmacokinetics of bupivacaine after IP administration to cats undergoing ovariohysterectomy. ANIMALS 8 healthy cats. PROCEDURES Anesthesia was induced with propofol and maintained with isoflurane. Buprenorphine (0.02 mg/kg, IV) and meloxicam (0.2 mg/kg, SC) were administered. A 20-gauge catheter was inserted into a jugular vein for blood sample collection. A ventral midline incision was made, and a solution of 0.5% bupivacaine (2 mg/kg) diluted with an equal volume of saline (0.9% NaCl) solution (final concentration, 0.25% bupivacaine) was injected into the peritoneal space over the right and left ovarian pedicles and caudal aspect of the uterus before ovariohysterectomy. Cats were monitored for signs of bupivacaine toxicosis. Venous blood samples (2 mL) were collected before (time 0) and 2, 5, 10, 15, 20, 30, 60, 120, and 240 minutes after bupivacaine administration. Plasma bupivacaine concentrations were determined with a liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were determined by data plotting followed by analysis with a noncompartmental model. RESULTS No signs of bupivacaine toxicosis were observed. Maximum bupivacaine plasma concentration was 1,030 +/- 497.5 ng/mL at a mean +/- SD value of 30 +/- 24 minutes after administration. Mean elimination half-life was 4.79 +/- 2.7 hours. Mean clearance indexed by bioavailability and volume of distribution indexed by bioavailability were 0.35 +/- 0.18 L*h/kg and 2.10 +/- 0.84 L/kg, respectively. CONCLUSIONS AND CLINICAL RELEVANCE Intraperitoneal administration of bupivacaine resulted in concentrations that did not cause observable toxicosis. Studies to investigate analgesic effects for this technique in cats are warranted. PMID- 27227504 TI - Comparative pharmacokinetics of ceftiofur hydrochloride and ceftiofur sodium after administration to water buffalo (Bubalus bubalis). AB - OBJECTIVE To evaluate pharmacokinetics and bioavailability after administration of ceftiofur hydrochloride and ceftiofur sodium to water buffalo (Bubalus bubalis). ANIMALS 5 healthy adult water buffalo (3 males and 2 nonlactating females). PROCEDURES All animals received a dose (2.2 mg/kg) of 3 ceftiofur products (2 commercially available suspensions of ceftiofur hydrochloride [CEF1 and CEF2, IM] and ceftiofur sodium [CEF3, IV]). Blood samples were collected for up to 196 hours. Concentrations of ceftiofur in plasma were determined by use of high-performance liquid chromatography, and pharmacokinetic parameters were calculated on the basis of noncompartmental methods. RESULTS Most of the pharmacokinetic parameters, except for bioavailability and the area under the concentration-time curve extrapolated to infinity, were significantly different between the 2 products administered IM. Mean +/- SD bioavailability of CEF1 and CEF2 was 89.57 +/- 32.84% and 86.28 +/- 11.49%, respectively, which indicated good absorption of both products. In addition, there was a longer drug residence time for CEF1 than for CEF2. Data analysis for CEF1 revealed a flip-flop phenomenon. CONCLUSIONS AND CLINICAL RELEVANCE In this study, there was good absorption of CEF1, and CEF1 had a longer drug residence time in vivo than did CEF2. On the basis of pharmacokinetic parameters and the in vitro antimicrobial susceptibility, a dosage regimen of 2.2 mg/kg administered at 48- and 36-hour intervals for CEF1 and CEF2, respectively, could be an appropriate choice for the treatment of buffalo with infectious diseases. PMID- 27227505 TI - Assessment of the attenuation of an intra-abdominal vein by use of a silicone polyacrylic acid gradual venous occlusion device in dogs and cats. AB - OBJECTIVE To evaluate the closure rate and completeness of closure for a silicone polyacrylic acid gradual venous occlusion device placed around an intra-abdominal vein to simulate gradual occlusion of an extrahepatic portosystemic shunt. ANIMALS 3 purpose-bred cats and 2 purpose-bred dogs. PROCEDURES The device was surgically placed around an external (cats) or internal (dogs) iliac vein. Computed tomographic angiography was performed at the time of surgery and 2, 4, and 6 weeks after surgery. Ultrasonographic examinations of blood flow through the vein within the device were performed at the time of surgery and at weekly intervals thereafter. Dogs were euthanized 6 weeks after surgery, and the external iliac veins were harvested for histologic examination. RESULTS The prototype gradual venous occlusion device was successfully placed in all animals, and all animals recovered without complications following the placement procedure. The vessel was completely occluded in 2 cats by 6 weeks after surgery, as determined on the basis of results of CT and ultrasonography; there was incomplete occlusion with a luminal diameter of 1.5 mm in the other cat by 6 weeks after surgery. The vessel was completely occluded in both dogs by 6 weeks after surgery. Histologic examination of the external iliac veins obtained from the dogs revealed minimal inflammation of the vessel wall and no thrombus formation. CONCLUSIONS AND CLINICAL RELEVANCE The prototype device induced gradual attenuation of an intra-abdominal vessel over a 6-week period. This device may provide another option for gradual occlusion of extrahepatic portosystemic shunts. PMID- 27227506 TI - Effects of successive tracheal resection and anastomosis on tracheal diameter and position of lobar bronchi in dogs. AB - OBJECTIVE To evaluate the effects of successive large-segment tracheal resection and anastomosis on tracheal diameter and position of lobar bronchi in dogs. ANIMALS 5 adult Beagles. PROCEDURES Right lateral radiographs were obtained for all dogs and used to measure tracheal length. Dogs were then euthanized, and successive segmental tracheal resections (intervals of 10% from 20% to 50% of the tracheal length), each of which was followed by anastomosis, were performed in each cadaver. Tracheobronchoscopy was performed before the first tracheal resection and after each of the anastomoses to evaluate tracheal diameter and changes in position of lobar bronchi. RESULTS Tracheal diameter was minimally affected by resections up to 50% of the tracheal length. Diameter of the trachea and position of bronchi were not affected by resection of 20% of the tracheal length. Changes in the position of various lobar bronchi were detected after resection of 30% of the tracheal length. CONCLUSIONS AND CLINCIAL RELEVANCE In this study, tracheal resections of 20% of the tracheal length were accommodated, possibly as a result of stretching of the annular ligament. Resections of >= 30% of the tracheal length altered the position of lobar bronchi. Clinical effects, if any, attributable to these changes in bronchial position remain to be elucidated. PMID- 27227507 TI - In Situ Mechanical Testing of Nanostructured Bijel Fibers. AB - Bijels are a class of soft materials with potential for application in diverse areas including healthcare, food, energy, and reaction engineering due to their unique structural, mechanical, and transport properties. To realize their potential, means to fabricate, characterize, and manipulate bijel mechanics are needed. We recently developed a method based on solvent transfer-induced phase separation (STRIPS) that enables continuous fabrication of hierarchically structured bijel fibers from a broad array of constituent fluids and nanoparticles using a microfluidic platform. Here, we introduce an in situ technique to characterize bijel fiber mechanics at initial and final stages of the formation process within a microfluidics device. By manipulation of the hydrodynamic stresses applied to the fiber, the fiber is placed under tension until it breaks into segments. Analysis of the stress field allows fracture strength to be inferred; fracture strengths can be as high as several thousand Pa, depending on nanoparticle content. These findings broaden the potential for the use of STRIPS bijels in applications with different mechanical demands. Moreover, our in situ mechanical characterization method could potentially enable determination of properties of other soft fibrous materials made of hydrogels, capillary suspensions, colloidal gels, or high internal phase emulsions. PMID- 27227508 TI - High-Content and Semi-Automated Quantification of Responses to Estrogenic Chemicals Using a Novel Translucent Transgenic Zebrafish. AB - Rapid embryogenesis, together with genetic similarities with mammals, and the desire to reduce mammalian testing, are major incentives for using the zebrafish model in chemical screening and testing. Transgenic zebrafish, engineered for identifying target gene expression through expression of fluorophores, have considerable potential for both high-content and high-throughput testing of chemicals for endocrine activity. Here we generated an estrogen responsive transgenic zebrafish model in a pigment-free "Casper" phenotype, facilitating identification of target tissues and quantification of these responses in whole intact fish. Using the ERE-GFP-Casper model we show chemical type and concentration dependence for green fluorescent protein (GFP) induction and both spatial and temporal responses for different environmental estrogens tested. We also developed a semiautomated (ArrayScan) imaging and image analysis system that we applied to quantify whole body fluorescence responses for a range of different estrogenic chemicals in the new transgenic zebrafish model. The zebrafish model developed provides a sensitive and highly integrative system for identifying estrogenic chemicals, their target tissues and effect concentrations for exposures in real time and across different life stages. It thus has application for chemical screening to better direct health effects analysis of environmental estrogens and for investigating the functional roles of estrogens in vertebrates. PMID- 27227509 TI - Spatiotemporally Resolved Tracking of Bacterial Responses to ROS-Mediated Damage at the Single-Cell Level with Quantitative Functional Microscopy. AB - Herein we report on the implementation of photofunctional microparticles in combination with optical tweezers for the investigation of bacterial responses to oxidative stress by means of quantitative functional microscopy. A combination of a strongly hydrophobic axially substituted Si(IV) phthalocyanine adsorbed onto silica microparticles was developed, and the structural and photophysical characterization was carried out. The microparticles are able to produce reactive oxygen species under the fluorescence microscope upon irradiation with red light, and the behavior of individual bacteria can be consequently investigated in situ and in real time at the single cell level. For this purpose, a methodology was introduced to monitor phototriggered changes with spatiotemporal resolution. The defined distance between the photoactive particles and individual bacteria can be fixed under the microscope before the photosensitization process is started, and the photoinduced damage can be monitored by tracing the time-dependent fluorescence turn-on of a suitable marker. The results showed a distance dependent photoinduced death time, defined as the onset of the incorporation of propidium iodide. Our methodology constitutes a new tool for the in vitro design and evaluation of photosensitizers for the treatment of cancer and infectious diseases with the aid of functional optical microscopy, as it enables a quantitative response evaluation of living systems toward oxidative stress. More generally, it provides a way to understand the response of an ensemble of living entities to reactive oxygen species by analyzing the behavior of a set of individual organisms. PMID- 27227510 TI - Raman microspectroscopy for probing the impact of a dietary antioxidant on human breast cancer cells. AB - Breast cancer is the second most common type of cancer worldwide and the most frequent among women, being the fifth cause of death from neoplastic disease. Since this is an oxidative-stress related neoplasia, it is largely preventable. A dietary isoflavone abundant in soybean - daidzein - is currently being investigated owing to its chemopreventive and/or chemotherapeutic properties towards the human MDA-MB-231 (metastatic, estrogen-unresponsive) and MCF-7 (estrogen-responsive) breast cancer cell lines. Biological assays for evaluation of antitumour and anti-invasive activities were combined with state-of-the-art vibrational microspectroscopy techniques. At 50 and 100 MUM concentrations and 48 h incubation time, daidzein was found to induce a marked decrease in cell viability (ca. 50%) for MDA-MB-231 and MCF-7 cells (respectively ca. 50% and 42%) and 40% inhibition of cell migration. MicroRaman analysis of fixed cells upon exposure to this isoflavone unveiled its metabolic impact on both cell lines. Multivariate data analysis (unsupervised PCA) led to a clear discrimination between the control and DAID-exposed cells, with distinctive effects on their biochemical profile, particularly regarding DNA, lipids and protein components, in a cell-dependent way. This is the first reported study on the impact of dietary antioxidants on cancer cells by microRaman techniques. PMID- 27227511 TI - Synergistic Allosteric Mechanism of Fructose-1,6-bisphosphate and Serine for Pyruvate Kinase M2 via Dynamics Fluctuation Network Analysis. AB - Pyruvate kinase M2 (PKM2) plays a key role in tumor metabolism and regulates the rate-limiting final step of glycolysis. In tumor cells, there are two allosteric effectors for PKM2: fructose-1,6-bisphosphate (FBP) and serine. However, the relationship between FBP and serine for allosteric regulation of PKM2 is unknown. Here we constructed residue/residue fluctuation correlation network based on all atom molecular dynamics simulations to reveal the regulation mechanism. The results suggest that the correlation network in bound PKM2 is distinctly different from that in the free state, FBP/PKM2, or Ser/PKM2. The community network analysis indicates that the information can freely transfer from the allosteric sites of FBP and serine to the substrate site in bound PKM2, while there exists a bottleneck for information transfer in the network of the free state. Furthermore, the binding free energy between the substrate and PKM2 for bound PKM2 is significantly lower than either of FBP/PKM2 or Ser/PKM2. Thus, a hypothesis of "synergistic allosteric mechanism" is proposed for the allosteric regulation of FBP and serine. This hypothesis was further confirmed by the perturbational and mutational analyses of community networks and binding free energies. Finally, two possible synergistic allosteric pathways of FBP-K433-T459 R461-A109-V71-R73-MG2-OXL and Ser-I47-C49-R73-MG2-OXL were identified based on the shortest path algorithm and were confirmed by the network perturbation analysis. Interestingly, no similar pathways could be found in the free state. The process targeting on the allosteric pathways can better regulate the glycolysis of PKM2 and significantly inhibit the progression of tumor. PMID- 27227512 TI - Mechanism of the Reaction of Human Manganese Superoxide Dismutase with Peroxynitrite: Nitration of Critical Tyrosine 34. AB - Human Mn-containing superoxide dismutase (hMnSOD) is a mitochondrial enzyme that metabolizes superoxide radical (O2(*-)). O2(*-) reacts at diffusional rates with nitric oxide to yield a potent nitrating species, peroxynitrite anion (ONOO(-)). MnSOD is nitrated and inactivated in vivo, with active site Tyr34 as the key oxidatively modified residue. We previously reported a k of ~1.0 * 10(5) M(-1) s( 1) for the reaction of hMnSOD with ONOO(-) by direct stopped-flow spectroscopy and the critical role of Mn in the nitration process. In this study, we further established the mechanism of the reaction of hMnSOD with ONOO(-), including the necessary re-examination of the second-order rate constant by an independent method and the delineation of the microscopic steps that lead to the regio specific nitration of Tyr34. The redetermination of k was performed by competition kinetics utilizing coumarin boronic acid, which reacts with ONOO(-) at a rate of ~1 * 10(6) M(-1) s(-1) to yield the fluorescence product, 7 hydroxycoumarin. Time-resolved fluorescence studies in the presence of increasing concentrations of hMnSOD provided a k of ~1.0 * 10(5) M(-1) s(-1), fully consistent with the direct method. Proteomic analysis indicated that ONOO(-), but not other nitrating agents, mediates the selective modification of active site Tyr34. Hybrid quantum-classical (quantum mechanics/molecular mechanics) simulations supported a series of steps that involve the initial reaction of ONOO(-) with Mn(III) to yield Mn(IV) and intermediates that ultimately culminate in 3-nitroTyr34. The data reported herein provide a kinetic and mechanistic basis for rationalizing how MnSOD constitutes an intramitochondrial target for ONOO(-) and the microscopic events, with atomic level resolution, that lead to selective and efficient nitration of critical Tyr34. PMID- 27227513 TI - Nasal Septal Anatomy in Skeletally Mature Patients With Cleft Lip and Palate. AB - IMPORTANCE: Septal deviation commonly occurs in patients with cleft lip and palate (CLP); however, the contribution of the cartilaginous and bony septum to airway obstruction in skeletally mature patients is poorly understood. OBJECTIVES: To describe the internal nasal airway anatomy of skeletally mature patients with CLP and to determine the contributors to airway obstruction. DESIGN, SETTING, AND PARTICIPANTS: This single-center retrospective review included patients undergoing cone-beam computed tomography (CBCT) from November 1, 2011, to July 6, 2015, at the cleft lip and palate division of a major academic tertiary referral center. Patients met inclusion criteria for the study if they were at least 15 years old at the time of CBCT, and images were used only if they were obtained before Le Fort I osteotomy and/or formal septorhinoplasty. Twenty-four skeletally mature patients with CLP and 16 age-matched control individuals were identified for the study. MAIN OUTCOMES AND MEASURES: Septal deviation and airway stenosis were measured in the following 3 coronal sections: at the cartilaginous septum (anterior nasal spine), bony septum (posterior nasal spine), and midpoint between the anterior and posterior nasal spine. The perpendicular plate of the ethmoid bone and vomer displacement were measured as angles from the vertical plane at the coronal section of maximal septal deviation. The site of maximal septal deviation was identified. RESULTS: Among the 40 study participants, 26 were male. The mean (SD) age was 21 (5) and 23 (6) years for patients with CLP and controls, respectively. Septal deviation in patients with CLP was significantly worse than that of controls at the anterior nasal spine (2.1 [0.5] vs 0.8 [0.2] mm; P < .05) and posterior nasal spine (2.9 [0.5] vs 1.0 [0.3] mm; P < .01) and most severe at the midpoint (mean [SD], 4.4 [0.6] vs 2.1 [0.3] mm; P < .01). The point of maximal septal deviation occurred in the bony posterior half of the nasal airway in 27 of 40 patients (68%). The CLP bony angular deviation from the vertical plane was significant in the CLP group compared with the control group (perpendicular plate of the ethmoid bone, 14 degrees [2 degrees ] vs 8 degrees [1 degrees ]; vomer, 34 degrees [5 degrees ] vs 13 degrees [2 degrees ]; P < .05 for both), and vomer deviation was significantly associated with anterior nasal airway stenosis (r = -0.61; P < .01). CONCLUSIONS AND RELEVANCE: Skeletally mature patients with CLP have significant septal deviation involving bone and cartilage. Resection of the bony and cartilaginous septum should be considered at the time of definitive cleft rhinoplasty. LEVEL OF EVIDENCE: NA. PMID- 27227514 TI - Protein chemical synthesis by alpha-ketoacid-hydroxylamine ligation. AB - Total chemical synthesis of proteins allows researchers to custom design proteins without the complex molecular biology that is required to insert non-natural amino acids or the biocontamination that arises from methods relying on overexpression in cells. We describe a detailed procedure for the chemical synthesis of proteins with the alpha-ketoacid-hydroxylamine (KAHA ligation), using (S)-5-oxaproline (Opr) as a key building block. This protocol comprises two main parts: (i) the synthesis of peptide fragments by standard fluorenylmethoxycarbonyl (Fmoc) chemistry and (ii) the KAHA ligation between fragments containing Opr and a C-terminal peptide alpha-ketoacid. This procedure provides an alternative to native chemical ligation (NCL) that could be valuable for the synthesis of proteins, particularly targets that do not contain cysteine residues. The ligation conditions-acidic DMSO/H2O or N-methyl-2-pyrrolidinone (NMP)/H2O-are ideally suited for solubilizing peptide segments, including many hydrophobic examples. The utility and efficiency of the protocol is demonstrated by the total chemical synthesis of the mature betatrophin (also called ANGPTL8), a 177-residue protein that contains no cysteine residues. With this protocol, the total synthesis of the betatrophin protein has been achieved in around 35 working days on a multimilligram scale. PMID- 27227516 TI - Hepatocellular carcinoma. PMID- 27227515 TI - Protein induced by vitamin K absence or antagonist-II (PIVKA-II) specifically increased in Italian hepatocellular carcinoma patients. AB - OBJECTIVE: As a marker for Hepatocellular Carcinoma (HCC), Protein Induced by Vitamin K Absence II (PIVKA-II) seems to be superior to alpha fetoprotein (AFP). To better characterize the role of PIVKA-II, both AFP and PIVKA-II have been measured in Italian patients with diagnosis of HCC compared with patients affected by non-oncological liver pathologies. MATERIALS AND METHODS: Sixty serum samples from patients with HCC, 60 samples from patients with benign liver disease and 60 samples obtained from healthy blood donors were included in the study. PIVKA-II and AFP were measured by LUMIPULSE((r)) G1200 (Fujirebio-Europe, Belgium). We considered as PIVKA-II cutoff 70 mAU/ml (mean +3SD) of the values observed in healthy subjects. RESULTS: The evaluation of PIVKA-II showed a positivity of 70% in patients with HCC and 5% in patients with benign diseases (p < 0.0001) whereas high levels of AFP were observed in 55% of HCC patients and in 47% of patients with benign diseases. The combined Receiver Operating Characteristic (ROC) analysis of the two analytes revealed a higher sensitivity (75%) compared to those observed for the individual biomarkers. In conclusion, we demonstrate that as a marker for HCC, PIVKA-II is more specific for HCC and less prone to elevation during chronic liver diseases. CONCLUSIONS: The combination of the two biomarkers, evaluated by the ROC analysis, improved the specificity compared to a single marker. These data suggest that the combined analysis of the two markers could be a useful tool in clinical practice. PMID- 27227517 TI - MR-guided dynamic PET reconstruction with the kernel method and spectral temporal basis functions. AB - Recent advances in dynamic positron emission tomography (PET) reconstruction have demonstrated that it is possible to achieve markedly improved end-point kinetic parameter maps by incorporating a temporal model of the radiotracer directly into the reconstruction algorithm. In this work we have developed a highly constrained, fully dynamic PET reconstruction algorithm incorporating both spectral analysis temporal basis functions and spatial basis functions derived from the kernel method applied to a co-registered T1-weighted magnetic resonance (MR) image. The dynamic PET image is modelled as a linear combination of spatial and temporal basis functions, and a maximum likelihood estimate for the coefficients can be found using the expectation-maximization (EM) algorithm. Following reconstruction, kinetic fitting using any temporal model of interest can be applied. Based on a BrainWeb T1-weighted MR phantom, we performed a realistic dynamic [(18)F]FDG simulation study with two noise levels, and investigated the quantitative performance of the proposed reconstruction algorithm, comparing it with reconstructions incorporating either spectral analysis temporal basis functions alone or kernel spatial basis functions alone, as well as with conventional frame-independent reconstruction. Compared to the other reconstruction algorithms, the proposed algorithm achieved superior performance, offering a decrease in spatially averaged pixel-level root-mean square-error on post-reconstruction kinetic parametric maps in the grey/white matter, as well as in the tumours when they were present on the co-registered MR image. When the tumours were not visible in the MR image, reconstruction with the proposed algorithm performed similarly to reconstruction with spectral temporal basis functions and was superior to both conventional frame-independent reconstruction and frame-independent reconstruction with kernel spatial basis functions. Furthermore, we demonstrate that a joint spectral/kernel model can also be used for effective post-reconstruction denoising, through the use of an EM-like image-space algorithm. Finally, we applied the proposed algorithm to reconstruction of real high-resolution dynamic [(11)C]SCH23390 data, showing promising results. PMID- 27227518 TI - Divergent Synthesis of Quinazolin-4(3H)-ones and Tryptanthrins Enabled by a tert Butyl Hydroperoxide/K3PO4-Promoted Oxidative Cyclization of Isatins at Room Temperature. AB - A synergetic tert-butyl hydroperoxide/K3PO4-promoted oxidative cyclization has been developed for the facile synthesis of various functionalized quinazolin 4(3H)-ones from commercially available isatins and amidine hydrochlorides at room temperature. The synthetic utility of this strategy was illustrated by the convenient synthesis of tryptanthrin derivatives via a self-dimerization of isatins under the same conditions. PMID- 27227520 TI - Correction Re: Tissue Engineering, Part B, 2015;21(1):157-165. PMID- 27227519 TI - The Clinical Characteristics and Predictors of Refractory Mycoplasma pneumoniae Pneumonia in Children. AB - OBJECTIVE: To analyze the clinical characteristics of refracory Mycoplasma pneumoniae pneumonia (RMPP), and explore the related factors predicting RMPP. METHODS: Retrospective analysis was performed on 634 children with Mycoplasma pneumoniae pneumonia (MPP) hospitalized in our hospital between January 1, 2011 and December 31, 2014. The clinical features, laboratory data, radiological findings between the RMPP group and the general Mycoplasma pneumoniae pneumonia (GMPP) group were compared and the predictive values of related factors were analyzed. RESULTS: The median age of the RMPP patients (n = 145) was much older than that of the GMPP patients (n = 489) (P<0.01). We also found more severe presentations, higher incidence of extra-pulmonary complications and more serious radiological findings in RMPP group, which needed oxygen more often, longer antibiotics administration and intensive care (P<0.05). Meanwhile, the levels of C-reactive protein (CRP), lactic dehydrogenase (LDH), immunoglobulin A (IgM), interleukin (IL)-6, IL-10, interferon gamma (IFN-gamma) and the percentage of neutrophils, CD8+ in RMPP group were significantly higher than those in GMPP group (P<0.05); while the levels of prealbumin (PAB) were lower than that in GMPP group (P<0.01). In ROC curve analysis, the percentage of neutrophil, CRP, LDH, PAB, IL-6, IL-10 and IFN-gamma were useful for differentiating patients with RMPP from those with GMPP. Multiple logistic regression analysis showed that the CRP>=16.5mg/L, LDH >=417IU/L and IL-6 >=14.75pg/ml were significant predictors regarding to RMPP. CONCLUSIONS: CRP>=16.5mg/L, LDH >=417IU/L and IL-6 >=14.75pg/ml might be the significant predictors of RMPP in children, which can aid in early recognition of RMPP. PMID- 27227521 TI - The Madrid Affective Database for Spanish (MADS): Ratings of Dominance, Familiarity, Subjective Age of Acquisition and Sensory Experience. AB - The current study presents ratings by 540 Spanish native speakers for dominance, familiarity, subjective age of acquisition (AoA), and sensory experience (SER) for the 875 Spanish words included in the Madrid Affective Database for Spanish (MADS). The norms can be downloaded as supplementary materials for this manuscript from https://figshare.com/s/8e7b445b729527262c88 These ratings may be of potential relevance to researches who are interested in characterizing the interplay between language and emotion. Additionally, with the aim of investigating how the affective features interact with the lexicosemantic properties of words, we performed correlational analyses between norms for familiarity, subjective AoA and SER, and scores for those affective variables which are currently included in the MADs. A distinct pattern of significant correlations with affective features was found for different lexicosemantic variables. These results show that familiarity, subjective AoA and SERs may have independent effects on the processing of emotional words. They also suggest that these psycholinguistic variables should be fully considered when formulating theoretical approaches to the processing of affective language. PMID- 27227522 TI - Proptosis in a Healthy Young Woman. PMID- 27227523 TI - Use of Cooking Fuels and Cataract in a Population-Based Study: The India Eye Disease Study. AB - BACKGROUND: Biomass cooking fuels are commonly used in Indian households, especially by the poorest socioeconomic groups. Cataract is highly prevalent in India and the major cause of vision loss. The evidence on biomass fuels and cataract is limited. OBJECTIVES: To examine the association of biomass cooking fuels with cataract and type of cataract. METHODS: We conducted a population based study in north and south India using randomly sampled clusters to identify people >= 60 years old. Participants were interviewed and asked about cooking fuel use, socioeconomic and lifestyle factors and attended hospital for digital lens imaging (graded using the Lens Opacity Classification System III), anthropometry, and blood collection. Years of use of biomass fuels were estimated and transformed to a standardized normal distribution. RESULTS: Of the 7,518 people sampled, 94% were interviewed and 83% of these attended the hospital. Sex modified the association between years of biomass fuel use and cataract; the adjusted odds ratio (OR) for a 1-SD increase in years of biomass fuel use and nuclear cataract was 1.04 (95% CI: 0.88, 1.23) for men and 1.28 (95% CI: 1.10, 1.48) for women, p interaction = 0.07. Kerosene use was low (10%). Among women, kerosene use was associated with nuclear (OR = 1.76, 95% CI: 1.04, 2.97) and posterior subcapsular cataract (OR = 1.71, 95% CI: 1.10, 2.64). There was no association among men. CONCLUSIONS: Our results provide robust evidence for the association of biomass fuels with cataract for women but not for men. Our finding for kerosene and cataract among women is novel and requires confirmation in other studies. Citation: Ravilla TD, Gupta S, Ravindran RD, Vashist P, Krishnan T, Maraini G, Chakravarthy U, Fletcher AE. 2016. Use of cooking fuels and cataract in a population-based study: the India Eye Disease Study. Environ Health Perspect 124:1857-1862; http://dx.doi.org/10.1289/EHP193. PMID- 27227534 TI - When To Let Go-Diradical Intermediates from Zwitterionic Transition State Structures? AB - Several Brummond-Chen thermal intramolecular (2 + 2)-cycloaddition reactions were examined using density functional theory calculations. The results of these calculations indicate that it is possible for these reactions to involve diradical intermediates that form directly from zwitterionic transition state structures. The likelihood of this scenario was shown to be sensitive to both the nature of substituents and solvent polarity. PMID- 27227533 TI - The Impact of Racism on the Sexual and Reproductive Health of African American Women. AB - African American women are disproportionately affected by multiple sexual and reproductive health conditions compared with women of other races/ethnicities. Research suggests that social determinants of health, including poverty, unemployment, and limited education, contribute to health disparities. However, racism is a probable underlying determinant of these social conditions. This article uses a socioecological model to describe racism and its impact on African American women's sexual and reproductive health. Although similar models have been used for specific infectious and chronic diseases, they have not described how the historical underpinnings of racism affect current sexual and reproductive health outcomes among African American women. We propose a socioecological model that demonstrates how social determinants grounded in racism affect individual behaviors and interpersonal relationships, which may contribute to sexual and reproductive health outcomes. This model provides a perspective to understand how these unique contextual experiences are intertwined with the daily lived experiences of African American women and how they are potentially linked to poor sexual and reproductive health outcomes. The model also presents an opportunity to increase dialog and research among public health practitioners and encourages them to consider the role of these contextual experiences and supportive data when developing prevention interventions. Considerations address the provision of opportunities to promote health equity by reducing the effects of racism and improving African American women's sexual and reproductive health. PMID- 27227535 TI - Frequency of Teriparatide Administration Affects the Histological Pattern of Bone Formation in Young Adult Male Mice. AB - Evidence supports that daily and once-weekly administration of teriparatide, human (h)PTH(1-34), enhance bone mass in osteoporotic patients. However, it is uncertain whether different frequencies of hPTH(1-34) administration would induce bone formation similarly in terms of quantity and quality. To investigate that issue, mice were subjected to different frequencies of PTH administration, and their bones were histologically examined. Frequencies of administration were 1 time/2 days, 1 time a day, and 2 and 4 times a day. Mice were allocated to either to control or to 3 different dosing regimens: 80 MUg/kg of hPTH(1-34) per injection (80 MUg/kg per dose), 80 MUg/kg of hPTH(1-34) per day (80 MUg/kg . d), or 20 MUg/kg of hPTH(1-34) per day (20 MUg/kg . d). With the regimens of 80 MUg/kg per dose and 80 MUg/kg . d, high-frequency hPTH(1-34) administration increased metaphyseal trabecular number. However, 4 doses per day induced the formation of thin trabeculae, whereas the daily PTH regimen resulted in thicker trabeculae. A similar pattern was observed with the lower daily hPTH(1-34) dose (20 MUg/kg . d): more frequent PTH administration led to the formation of thin trabeculae, showing a thick preosteoblastic cell layer, several osteoclasts, and scalloped cement lines that indicated accelerated bone remodeling. On the other hand, low-frequency PTH administration induced new bone with mature osteoblasts lying on mildly convex surfaces representative of arrest lines, which suggests minimodeling-based bone formation. Thus, high-frequency PTH administration seems to increase bone mass rapidly by forming thin trabeculae through accelerated bone remodeling. Alternatively, low-frequency PTH administration leads to the formation of thicker trabeculae through bone remodeling and minimodeling. PMID- 27227536 TI - The Inflammatory Phenotype in Failed Metal-On-Metal Hip Arthroplasty Correlates with Blood Metal Concentrations. AB - INTRODUCTION: Hip arthroplasty is the standard treatment of a painful hip destruction. The use of modern metal-on-metal (MOM) bearing surfaces gained popularity in total hip arthroplasties during the last decade. Recently, worrisome failures due to adverse reaction to metal debris (ARMD), including pseudotumor response, have been widely reported. However, the pathogenesis of this reaction remains poorly understood. The aim of the present study was to investigate the ARMD response by flow cytometry approach. METHODS: Sixteen patients with a failed Articular Surface Replacement (ASR) hip prosthesis were included in the study. Samples of pseudotumor tissues collected during revision surgery were degraded by enzyme digestion and cells were typed by flow cytometry. Whole blood chromium and cobalt concentrations were analyzed with mass spectrometry before revision surgery. RESULTS: Flow cytometry analysis showed that the peri-implant pseudotumor tissue expressed two principal phenotypes, namely macrophage-dominated and T-lymphocyte-dominated response; the average portions being 54% (macrophages) and 25% (T-lymphocytes) in macrophage-dominated inflammation and 20% (macrophages) and 54% (T-lymphocytes) in T-lymphocyte dominated response. The percentages of B-lymphocytes and granulocytes were lower in both phenotypes. Interestingly, the levels of blood chromium and cobalt were significantly higher in patients with macrophage-dominated response. CONCLUSIONS: The results suggest that the adverse tissue reactions induced by MOM wear particles contain heterogeneous pathogeneses and that the metal levels are an important factor in the determination of the inflammatory phenotype. The present results support the hypothesis that higher metal levels cause cytotoxicity and tissue injury and macrophages are recruited to clear the necrotic debris. On the other hand, the adverse response developed in association with lower metal levels is T-lymphocyte-dominated and is likely to reflect hypersensitivity reaction. PMID- 27227537 TI - "I Use Weed for My ADHD": A Qualitative Analysis of Online Forum Discussions on Cannabis Use and ADHD. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a risk factor for problematic cannabis use. However, clinical and anecdotal evidence suggest an increasingly popular perception that cannabis is therapeutic for ADHD, including via online resources. Given that the Internet is increasingly utilized as a source of healthcare information and may influence perceptions, we conducted a qualitative analysis of online forum discussions, also referred to as threads, on the effects of cannabis on ADHD to systematically characterize the content patients and caregivers may encounter about ADHD and cannabis. METHODS: A total of 268 separate forum threads were identified. Twenty percent (20%) were randomly selected, which yielded 55 separate forum threads (mean number of individual posts per forum thread = 17.53) scored by three raters (Cohen's kappa = 0.74). A final sample of 401 posts in these forum threads received at least one endorsement on predetermined topics following qualitative coding procedures. RESULTS: Twenty-five (25%) percent of individual posts indicated that cannabis is therapeutic for ADHD, as opposed to 8% that it is harmful, 5% that it is both therapeutic and harmful, and 2% that it has no effect on ADHD. This pattern was generally consistent when the year of each post was considered. The greater endorsement of therapeutic versus harmful effects of cannabis did not generalize to mood, other (non-ADHD) psychiatric conditions, or overall domains of daily life. Additional themes emerged (e.g., cannabis being considered sanctioned by healthcare providers). CONCLUSIONS: Despite that there are no clinical recommendations or systematic research supporting the beneficial effects of cannabis use for ADHD, online discussions indicate that cannabis is considered therapeutic for ADHD-this is the first study to identify such a trend. This type of online information could shape ADHD patient and caregiver perceptions, and influence cannabis use and clinical care. PMID- 27227538 TI - Detangling the Effects of Environmental Filtering and Dispersal Limitation on Aggregated Distributions of Tree and Shrub Species: Life Stage Matters. AB - The pervasive pattern of aggregated tree distributions in natural communities is commonly explained by the joint effect of two clustering processes: environmental filtering and dispersal limitation, yet little consensus remains on the relative importance of the two clustering processes on tree aggregations. Different life stages of examined species were thought to be one possible explanation of this disagreement, because the effect of environmental filtering and dispersal limitation are expected to increase and decrease with tree life stages, respectively. However, few studies have explicitly tested these expectations. In this study, we evaluated these expectations by three different methods (species habitat association test based on Poisson Clustering model and spatial point pattern analyses based on Heterogeneous Poisson model and the jointly modeling approach) using 36 species in a 20-ha subtropical forest plot. Our results showed that the percentage of species with significant habitat association increased with life stages, and there were fewer species affected by dispersal limitation in later life stages compared with those in earlier stages. Percentage of variance explained by the environmental filtering and dispersal limitation also increases and decreases with life stages. These results provided a promising alternative explanation on the existing mixed results about the relative importance of the two clustering processes. These findings also highlighted the importance of plant life stages for fully understanding species distributions and species coexistence. PMID- 27227539 TI - The Contribution of GWAS Loci in Familial Dyslipidemias. AB - Familial combined hyperlipidemia (FCH) is a complex and common familial dyslipidemia characterized by elevated total cholesterol and/or triglyceride levels with over five-fold risk of coronary heart disease. The genetic architecture and contribution of rare Mendelian and common variants to FCH susceptibility is unknown. In 53 Finnish FCH families, we genotyped and imputed nine million variants in 715 family members with DNA available. We studied the enrichment of variants previously implicated with monogenic dyslipidemias and/or lipid levels in the general population by comparing allele frequencies between the FCH families and population samples. We also constructed weighted polygenic scores using 212 lipid-associated SNPs and estimated the relative contributions of Mendelian variants and polygenic scores to the risk of FCH in the families. We identified, across the whole allele frequency spectrum, an enrichment of variants known to elevate, and a deficiency of variants known to lower LDL-C and/or TG levels among both probands and affected FCH individuals. The score based on TG associated SNPs was particularly high among affected individuals compared to non affected family members. Out of 234 affected FCH individuals across the families, seven (3%) carried Mendelian variants and 83 (35%) showed high accumulation of either known LDL-C or TG elevating variants by having either polygenic score over the 90th percentile in the population. The positive predictive value of high score was much higher for affected FCH individuals than for similar sporadic cases in the population. FCH is highly polygenic, supporting the hypothesis that variants across the whole allele frequency spectrum contribute to this complex familial trait. Polygenic SNP panels improve identification of individuals affected with FCH, but their clinical utility remains to be defined. PMID- 27227540 TI - Serum Fatty Acids Are Correlated with Inflammatory Cytokines in Ulcerative Colitis. AB - BACKGROUND AND AIMS: Ulcerative colitis (UC) is associated with increased dietary intake of fat and n-6 polyunsaturated fatty acids (PUFA). Modification of fat metabolism may alter inflammation and disease severity. Our aim was to assess differences in dietary and serum fatty acid levels between control and UC subjects and associations with disease activity and inflammatory cytokines. METHODS: Dietary histories, serum, and colonic tissue samples were prospectively collected from 137 UC subjects and 38 controls. Both histologic injury and the Mayo Disease Activity Index were assessed. Serum and tissue cytokines were measured by Luminex assay. Serum fatty acids were obtained by gas chromatography. RESULTS: UC subjects had increased total fat and oleic acid (OA) intake, but decreased arachidonic acid (AA) intake vs controls. In serum, there was less percent saturated fatty acid (SFA) and AA, with higher monounsaturated fatty acids (MUFA), linoleic acid, OA, eicosapentaenoic acid (EPA), and docosapentaenoic acid (DPA) in UC. Tissue cytokine levels were directly correlated with SFA and inversely correlated with PUFA, EPA, and DPA in UC subjects, but not controls. 5-aminosalicylic acid therapy blunted these associations. CONCLUSIONS: In summary, we found differences in serum fatty acids in UC subjects that correlated with pro-inflammatory tissue cytokines. We propose that fatty acids may affect cytokine production and thus be immunomodulatory in UC. PMID- 27227541 TI - Roughness gradients on zirconia for rapid screening of cell-surface interactions: Fabrication, characterization and application. AB - Roughness is one of the key parameters for successful osseointegration of dental implants. The understanding of how roughness affects cell response is thus crucial to improve implant performance. Surface gradients, which allow rapid and systematic investigations of cell-surface interactions, have the potential to facilitate this task. In this study, a novel method aiming to produce roughness gradients at the surface of zirconia using hydrofluoric acid etching was implemented. The topography was exhaustively characterized at the microscale and nanoscale by white light interferometry and atomic force microscopy, including the analysis of amplitude, spatial, hybrid, functional, and fractal parameters. A rapid screening of the influence of roughness on human mesenchymal stem cell morphology was conducted and potential correlations between roughness parameters and cell morphology were investigated. The roughness gradient induced significant changes in cell area (p < 0.001), aspect ratio (p = 0.01), and solidity (p = 0.026). Nanoroughness parameters were linearly correlated to cell solidity (p < 0.005), while microroughness parameters appeared nonlinearly correlated to cell area, highlighting the importance of multiscale optimization of implant topography to induce the desired cell response. The gradient method proposed here drastically reduces the efforts and resources necessary to study cell-surface interactions and provides results directly transferable to industry. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2502-2514, 2016. PMID- 27227542 TI - Susceptibility-Weighted Imaging of Glioma: Update on Current Imaging Status and Future Directions. AB - Susceptibility-weighted imaging (SWI) provides invaluable insight into glioma pathophysiology and internal tumoral architecture. The physical contribution of intratumoral susceptibility signal (ITSS) may correspond to intralesional hemorrhage, calcification, or tumoral neovascularity. In this review, we present emerging evidence of ITSS for assessment of intratumoral calcification, grading of glioma, and factors influencing the pattern of ITSS in glioblastoma. SWI phase imaging assists in identification of intratumoral calcification that aids in narrowing the differential diagnosis. Development of intratumoral calcification posttreatment of glioma serves as an imaging marker of positive therapy response. Grading of tumors with ITSS using information attributed to microhemorrhage and neovascularity in SWI correlates with MR perfusion parameters and histologic grading of glioma and enriches preoperative prognosis. Quantitative susceptibility mapping may provide a means to discriminate subtle calcifications and hemorrhage in tumor imaging. Recent data suggest ITSS patterns in glioblastoma vary depending on tumoral volume and sublocation and correlate with degree of intratumoral necrosis and neovascularity. Increasingly, there is a recognized role of obtaining contrast-enhanced SWI (CE-SWI) for assessment of tumoral margin in high-grade glioma. Significant higher concentration of gadolinium accumulates at the border of the tumoral invasion zone as seen on the SWI sequence; this results from contrast-induced phase shift that clearly delineates the tumor margin. Lastly, absence of ITSS may aid in differentiation between high-grade glioma and primary CNS lymphoma, which typically shows absence of ITSS. We conclude that SWI and CE-SWI are indispensable tools for diagnosis, preoperative grading, posttherapy surveillance, and assessment of glioma. PMID- 27227543 TI - Evaluation of a Mathematical Model of Rat Body Weight Regulation in Application to Caloric Restriction and Drug Treatment Studies. AB - The purpose of this work is to develop a mathematical model of energy balance and body weight regulation that can predict species-specific response to common pre clinical interventions. To this end, we evaluate the ability of a previously published mathematical model of mouse metabolism to describe changes in body weight and body composition in rats in response to two short-term interventions. First, we adapt the model to describe body weight and composition changes in Sprague-Dawley rats by fitting to data previously collected from a 26-day caloric restriction study. The calibrated model is subsequently used to describe changes in rat body weight and composition in a 23-day cannabinoid receptor 1 antagonist (CB1Ra) study. While the model describes body weight data well, it fails to replicate body composition changes with CB1Ra treatment. Evaluation of a key model assumption about deposition of fat and fat-free masses shows a limitation of the model in short-term studies due to the constraint placed on the relative change in body composition components. We demonstrate that the model can be modified to overcome this limitation, and propose additional measurements to further test the proposed model predictions. These findings illustrate how mathematical models can be used to support drug discovery and development by identifying key knowledge gaps and aiding in the design of additional experiments to further our understanding of disease-relevant and species-specific physiology. PMID- 27227545 TI - Colorectal cancer. PMID- 27227546 TI - Methyl Protodioscin, a Steroidal Saponin, Inhibits Neointima Formation in Vitro and in Vivo. AB - Restenosis (or neointimal hyperplasia) remains a clinical limitation of percutaneous coronary angioplasty. Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are known to be involved in the development of restenosis. The present study aimed to investigate the ability and molecular mechanisms of methyl protodioscin (1), a steroidal saponin isolated from the root of Dioscorea nipponica, to inhibit neointimal formation. Our study demonstrated that 1 markedly inhibited the growth and migration of VSMCs (A7r5 cells). A cytometric analysis suggested that 1 induced growth inhibition by arresting VSMCs at the G1 phase of the cell cycle. A rat carotid artery balloon injury model indicated that neointima formation of the balloon-injured vessel was markedly reduced after extravascular administration of 1. Compound 1 decreased the expression levels of ADAM15 (a disintegrin and metalloprotease 15) and its downstream signaling pathways in the VSMCs. Moreover, the expressions and activities of matrix metalloproteinases (MMP-2 and MMP-9) were also suppressed by 1 in a concentration-dependent manner. Additionally, the molecular mechanisms appear to be mediated, in part, through the downregulation of ADAM15, FAK, ERK, and PI3K/Akt. PMID- 27227547 TI - Vitiligo. PMID- 27227544 TI - Hemoporfin Photodynamic Therapy for Port-Wine Stain: A Randomized Controlled Trial. AB - BACKGROUND AND OBJECTIVES: Photodynamic therapy (PDT) has shown potentially beneficial results in treating port-wine stain, but its benefit-risk profile remains undefined. This study aimed to evaluate the efficacy and safety of PDT conducted with hemoporfin and a 532 nm continuous wave laser to treat port-wine stain clinically. PATIENTS AND METHODS: This randomized clinical trial was conducted in eight hospitals in China. Participants were adolescent and adult patients (age range: 14-65 years old) with port-wine stain. During stage 1 (day 1 to week 8) all patients were randomized at a 3:1 ratio to treatment (532 nm laser irradiation (96-120 J/cm2) with hemoporfin (5mg/kg; PDT-hemoporfin, n = 330)) or placebo groups (irradiation with placebo (PDT-placebo, n = 110)); during stage 2 (week 8 to 16) patients in both groups were offered treatment. Clinician evaluators, who were blind to the study, classified each case on the following four-level scale according to assessment of before and after standardized pictures of the lesion area: no improvement: <20%; some improvement: 20-59%; great improvement: 60-89%; or nearly completely resolved: >=90%. The primary efficacy endpoint was proportion of patients achieving at least some improvement at week 8. The secondary efficacy endpoints were proportion of patients achieving nearly completely resolved or at least great improvement at week 8, proportion of patients achieving early completely resolved, at least great improvement, or at least some improvement at week 16, and the corresponding satisfaction of the investigators and the patients (designated as 'excellent', 'good', 'moderate', or 'ineffective') at weeks 8 and 16. RESULTS: Compared to the PDT-placebo group, the PDT-hemoporfin group showed a significantly higher proportion of patients that achieved at least some improvement (89.7% [n = 295; 95% CI, 85.9%-92.5%] vs. 24.5% [n = 27; 95% CI, 17.4%-33.3%]) at week 8 (P < 0.0001) and higher improvements for all secondary efficacy endpoints. Treatment reactions occurred in 99.5% (n = 731; 95% CI, 98.7%-99.8%) of the PDT-hemoporfin treatments (n = 735). Hyperpigmentation occurred in 22.9 per 100 patient-treatments (n = 168; 95% CI, 20.0-26.0) in the PDT-hemoporfin treated patients. CONCLUSIONS: Hemoporfin mediated PDT is an effective and safe treatment option for adolescent and adult patients with port-wine stain. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-TRC-08000213. PMID- 27227549 TI - Synthetic strategies for plant signalling studies: molecular toolbox and orthogonal platforms. AB - Plants deploy a wide array of signalling networks integrating environmental cues with growth, defence and developmental responses. The high level of complexity, redundancy and connection between several pathways hampers a comprehensive understanding of involved functional and regulatory mechanisms. The implementation of synthetic biology approaches is revolutionizing experimental biology in prokaryotes, yeasts and animal systems and can likewise contribute to a new era in plant biology. This review gives an overview on synthetic biology approaches for the development and implementation of synthetic molecular tools and techniques to interrogate, understand and control signalling events in plants, ranging from strategies for the targeted manipulation of plant genomes up to the spatiotemporally resolved control of gene expression using optogenetic approaches. We also describe strategies based on the partial reconstruction of signalling pathways in orthogonal platforms, like yeast, animal and in vitro systems. This allows a targeted analysis of individual signalling hubs devoid of interconnectivity with endogenous interacting components. Implementation of the interdisciplinary synthetic biology tools and strategies is not exempt of challenges and hardships but simultaneously most rewarding in terms of the advances in basic and applied research. As witnessed in other areas, these original theoretical-experimental avenues will lead to a breakthrough in the ability to study and comprehend plant signalling networks. PMID- 27227548 TI - Inhibition of Spinal Oxidative Stress by Bergamot Polyphenolic Fraction Attenuates the Development of Morphine Induced Tolerance and Hyperalgesia in Mice. AB - Citrus Bergamia Risso, commonly known as Bergamot, is a fruit whose Essential Oil and Bergamot Polyphenolic Fraction have numerous medicinal properties. It is also an excellent antioxidant and in this study, for the first time, its potential effect on morphine induced tolerance in mice has been investigated. Our studies revealed that development of antinociceptive tolerance to repeated doses of morphine in mice is consistently associated with increased formation of superoxide, malondialdehyde and tyrosine-nitrated proteins in the dorsal horn of the spinal cord such as the enzyme glutamine synthase. Nitration of this protein is intimately linked to inactivation of its biological function and resulting increase of glutamate levels in the spinal cord. Administration of Bergamot Polyphenolic Fraction (5-50 mg/kg) attenuated tolerance development. This effect was accompanied by reduction of superoxide and malondialdehyde production, prevention of GS nitration, re-establishment of its activity and of glutamate levels. Our studies confirmed the main role of free radicals during the cascade of events induced by prolonged morphine treatment and the co-administration of natural derivatives antioxidant such as Bergamot Polyphenolic Fraction can be an important therapeutic approach to restore opioids analgesic efficacy. PMID- 27227550 TI - Impact of disruptions on anaesthetic workflow during anaesthesia induction and patient positioning: A prospective study. AB - BACKGROUND: Work disruption in operating rooms hinders flow of patients and increases chances of error. Previous studies have largely considered the types of disruption occurring in operating rooms, but have not analysed systematically the objective impact of disruption. OBJECTIVE: The objective was to evaluate the impact of disruption on time efficiency in preoperative anaesthetic work in the operating room and to link disruption to failures in co-ordination of care. DESIGN: Prospective, cross-sectional and observational study. SETTING: Disruptions were evaluated in operating rooms of five hospitals across three countries: Australia (one community hospital, one teaching hospital); Thailand (two community hospitals); China (one teaching hospital). PARTICIPANTS: The preoperative phase of anaesthesia induction/patient positioning of 64 surgical patients across specialities was prospectively evaluated (Australia = 33; Thailand = 12; China = 10). Further, interviews were carried out with 16 consultant anaesthetists and surgeons and 13 senior operating room nurses involved in the care of these patients. MAIN OUTCOME MEASURES: Disruptions were identified by trained observers in real time during the preoperative phase; four types of care co-ordination problems were identified from the interviews with senior anaesthetists, surgeons and nurses, and linked to the disruptions. Descriptive analyses of time efficiency were performed. RESULTS: Complete data were available from 55 cases. Good inter-observer agreement was obtained across measurements (range 74 to 92%). An average of three disruptions per case during the preoperative phase, were observed (range 2 to 9). 'Disruption types': disruptive staff activities were associated with most timewasting (median = 1 min per case, range 0 min 0 s to 4 min 45 s per case). 'Care co-ordination problems': co-ordination lapses within the operating room team, and between them and the preoperative team were associated with most timewasting (median = 1 min per case, range 0 min 0 s to 5 min 0 s per case). CONCLUSION: The study quantifies time inefficiencies affecting anaesthetic work during the preoperative phase. Work disruption wastes time and is preventable. PMID- 27227551 TI - Reply to: association of preoperative cardiovascular drugs with short-term mortality after coronary artery bypass grafting. PMID- 27227552 TI - Modulation of Recombinant Human alpha1 Glycine Receptors by Mono- and Disaccharides: A Kinetic Study. AB - Glycine receptors (GlyRs) mediate fast synaptic inhibition in spinal cord, brainstem, and higher brain centers. Recently, glucose was identified as a positive modulator of GlyR-mediated currents. Here, we investigated extent and kinetics of the positive modulation of recombinant human alpha1 glycine receptors by different mono- and disaccharides and sorbitol using patch-clamp recording techniques. Glucose and fructose augmented glycine-mediated whole-cell currents with an EC50 of 6-7 mM. At concentrations > 10 mM, the maximum of current enhancement was reached within ~30 min. Kinetics of GlyR modulation resemble those of protein glycation. On-rates were <0.5 h for saturating concentrations of monosaccharides and ~1.5 h for disaccharides. Off-rates were considerably slower (>24 h). Galactose, the C4-epimer of glucose, and the sugar alcohol sorbitol had no effect on GlyR currents. Recent cryoelectron microscopy structures were used to identify a potential binding site for saccharides near the ivermectin binding pocket with lysine 143 as possible attachment site. The GlyR mutant alpha1(K143A) was not potentiated by glucose, suggesting an involvement of this residue in glycine receptor modulation by saccharides. PMID- 27227553 TI - Structural, Magnetic, and Optical Properties of A3V4(PO4)6 (A = Mg, Mn, Fe, Co, Ni). AB - Combined synchrotron and neutron powder diffraction indicates that A3V4(PO4)6 (A = Mg, Mn, Fe, Co, Ni) compounds crystallize with triclinic P1 symmetry. Lattice parameters expand as expected with successive increases in the ionic radius of the A(2+) ion. Cation disorder on the octahedral sites increases as the ionic radii of A(2+) ion decreases. Direct-current magnetic susceptibility measurements indicate that all compounds with magnetic A(2+) ions order anti-ferromagnetically with transition temperatures ranging from 12 to 15 K. Effective magnetic moments for A3V4(PO4)6 (A = Mg, Mn, Fe, Co, Ni) are 5.16, 11.04, 10.08, 9.76, and 7.96 MUB per formula unit, respectively, in line with calculated values for high-spin transition metal ions. With the exception of Co3V4(PO4)6 the ultraviolet-visible spectra are dominated by d-d transitions of the V(3+) ions. The striking emerald green color of Co3V4(PO4)6 arises from the combined effects of d-d transitions involving both V(3+) and Co(2+). PMID- 27227554 TI - Effect of ATM-111 (G>A) Polymorphism on Cancer Risk: A Meta-Analysis. AB - OBJECTIVE: To assess the relationship between the ataxia telangiectasia mutated (ATM) gene-111 (G>A) polymorphism and cancer risk. METHODS: The PubMed, EMBASE, Web of Science, and China National Knowledge Infrastructure databases were searched comprehensively. A total of 16 case-control studies with 12,273 cases and 13,046 controls were included in this meta-analysis; 12 of them were from the Chinese population. Five studies assessed smoking effects, including 3038 smokers and 1003 nonsmokers. Odds ratio (OR) was determined by using a genetic model-free approach. Heterogeneity was quantified by I(2) statistics. Publication bias was also evaluated. RESULTS: The recessive model (AA vs. AG + GG) was suggested as the most appropriate genetic model. After elimination of heterogeneity, it was found that the ATM-111 (G>A) AA genotype is significantly associated with increased susceptibility to overall cancer risk in a fixed effects model (OR = 1.09; 95% CI = 1.03-1.15; p < 0.01; I(2) < 0.01). In the subgroup analysis, the result of pooled analyses among the Chinese population revealed similar associations (OR = 1.12; 95% CI = 1.04-1.22; p < 0.01; I(2) < 0.01). As for specific cancer analysis, an increase was correlated with lung cancer risk (OR = 1.12; 95% CI = 1.01-1.24; p = 0.03) and breast cancer risk (OR = 1.08; 95% CI = 1.00-1.16; p = 0.05). In addition, a stronger association was found among nonsmokers (OR = 1.31; 95% CI = 1.13-1.52; p < 0.01). CONCLUSION: This meta analysis suggests that AA genotype of the ATM-111 gene (G>A) may be a risk factor for breast cancer and lung cancer, especially among nonsmokers, within the Chinese population. PMID- 27227555 TI - Rapid Classification and Identification of Microcystis aeruginosa Strains Using MALDI-TOF MS and Polygenetic Analysis. AB - Matrix-assisted laser desorption-ionization-time-of-flight mass spectrometry (MALDI-TOF MS) was used to establish a rapid, simple, and accurate method to differentiate among strains of Microcystis aeruginosa, one of the most prevalent types of bloom-forming cyanobacteria. M. aeruginosa NIES-843, for which a complete genome has been sequenced, was used to characterize ribosomal proteins as biomarkers and to optimize conditions for observing ribosomal proteins as major peaks in a given mass spectrum. Thirty-one of 52 ribosomal subunit proteins were detected and identified along the mass spectrum. Fifty-five strains of M. aeruginosa from different habitats were analyzed using MALDI-TOF MS; among these samples, different ribosomal protein types were observed. A polygenetic analysis was performed using an unweighted pair-group method with arithmetic means and different ribosomal protein types to classify the strains into five major clades. Two clades primarily contained toxic strains, and the other three clades contained exclusively non-toxic strains. This is the first study to differentiate cyanobacterial strains using MALDI-TOF MS. PMID- 27227556 TI - Self-tonometry as a complement in the investigation of glaucoma patients. AB - PURPOSE: To evaluate the reliability of intraocular pressure measured by patients with glaucoma themselves using a new hand-held tonometer and to observe whether the intraocular pressure (IOP) variations have the same pattern on different days while glaucoma treatment is constant. METHODS: Eighty-seven patients diagnosed with open-angle glaucoma or ocular hypertension were recruited to the study. Intraocular pressure measured using Goldmann applanation tonometry (GAT) was compared with IOP measured using tonometry at baseline and on the second visit. Patients measured their IOP at home using the hand-held tonometers. RESULTS: The mean difference between GAT and iCare(r) values varies from 0 to 1 mmHg. Seventy eight per cent of iCare(r) measurements were within 3 mmHg of the GAT measurements. Approximately 64% of the study eyes had higher IOP in the morning than in the afternoon/evening. Circadian patterns differed between consecutive days in 47% of the study eyes. There were IOP peaks outside office hours in up to 16% of the study eyes. CONCLUSION: Measurements made using rebound self-tonometry are accurate and could be used to complement the investigation of patients with glaucoma. Intraocular pressure curves provide valuable data usable when adapting glaucoma treatment. PMID- 27227557 TI - Mindreading Dysfunction in Avoidant Personality Disorder Compared With Other Personality Disorders. AB - The ability to reflect on one's own states of mind and those of others (metacognition or mindreading) is strongly implicated in personality disorders (PDs). Metacognition involves different abilities, and there is evidence that specific abilities can be selectively impaired in different PDs. The purposes of this study were to compare metacognitive competence in avoidant PD (AvPD) with that in other PDs and to investigate whether there is a specific profile for AvPD. Sixty-three patients with AvPD and 224 patients with other PDs were assessed using the Metacognitive Assessment Interview. AvPD patients showed difficulties with two metacognitive functions: monitoring and decentration, even when the severity of psychopathology was controlled for. These results support the hypothesis of specific profiles of metacognitive dysfunction in different PDs and highlight a close link between impaired monitoring and decentration functions and the inhibited and withdrawn personality style typical of AvPD. PMID- 27227558 TI - The Revolving Door Phenomenon in an Italian Acute Psychiatric Ward: A 5-Year Retrospective Analysis of the Potential Risk Factors. AB - To highlight the revolving door (RD) phenomenon in an acute psychiatric ward, we retrospectively identified the patients hospitalized three or more times in a calendar year from 1/1/2009 to 31/12/2013 as RD patients (RDP). We collected sociodemographic and clinical variables of RDP and statistically analyzed the potential RD risk factors. We divided RDP into "high" and "extremely high" utilizers and evaluated the variables related to more frequent readmissions. RDP represented 5.68% of all patients and their hospitalizations (RDH) 25% of all admissions. The statistically significant risk factors for all RDH were "disability pension," "substance abuse/dependence," "mild/severe aggressiveness," and "psychiatric and social rehabilitative programs". The comparison between "high" and "extremely high" utilizers showed that "manic episodes" and "personality disorders," among the diagnoses, "familial relational conflicts" and "violence/suicidality", among the hospitalization reasons, were statistically significant risk factors for more frequent readmissions. RD phenomenon was greatly affected by severe clinical conditions with social disability. PMID- 27227560 TI - The influence of particle size distribution on dose conversion factors for radon progeny in the underground excavations of hard coal mine. AB - In Polish underground mines, hazards caused by enhanced natural radioactivity occur. The sources of radiation exposure are short-lived radon decay products, mine waters containing radium 226Ra and 228Ra and the radioactive sediments that can precipitate out of these waters. For miners, the greatest exposure is usually due to short-lived radon decay products. The risk assessment is based on the measurement of the total potential alpha energy concentration (PAEC) and the evaluation of the related dose by using the dose conversion factor as recommended by relevant legal requirements. This paper presents the results of measurements of particle size distributions of ambient aerosols in an underground hard coal mine, the assessment of the radioactive particle size distribution of the short lived radon decay products and the corresponding values of dose conversion factors. The measurements of the ambient airborne particle size distribution were performed in the range from a few nanometers to about 20 MUm. The study therefore included practically the whole class of respirable particles. The results showed that the high concentration of ultrafine and fine aerosols measured can significantly affect the value of the dose conversion factors, and consequently the corresponding committed effective dose, to which the miners can be exposed. PMID- 27227559 TI - Plasmacytoid dendritic cells and type 1 interferon promote peripheral expansion of forkhead box protein 3(+) regulatory T cells specific for the ubiquitous RNA binding nuclear antigen La/Sjogren's syndrome (SS)-B. AB - RNA-binding nuclear antigens are a major class of self-antigen to which immune tolerance is lost in rheumatic diseases. Serological tolerance to one such antigen, La/Sjogren's syndrome (SS)-B (La), is controlled by CD4(+) T cells. This study investigated peripheral tolerance to human La (hLa) by tracking the fate of hLa-specific CD4(+) T cells expressing the transgenic (Tg) 3B5.8 T cell receptor (TCR) after adoptive transfer into lymphocyte-replete recipient mice expressing hLa as a neo-self-antigen. After initial antigen-specific cell division, hLa specific donor CD4(+) T cells expressed forkhead box protein 3 (FoxP3). Donor cells retrieved from hLa Tg recipients displayed impaired proliferation and secreted interleukin (IL)-10 in vitro in response to antigenic stimulation. Transfer of highly purified FoxP3-negative donor cells demonstrated that accumulation of hLa-specific regulatory T cells (Treg ) was due primarily to expansion of small numbers of donor Treg . Depletion of recipient plasmacytoid dendritic cells (pDC), but not B cells, severely hampered the accumulation of FoxP3(+) donor Treg in hLa Tg recipients. Recipient pDC expressed tolerogenic markers and higher levels of co-stimulatory and co-inhibitory molecules than B cells. Adoptive transfer of hLa peptide-loaded pDC into mice lacking expression of hLa recapitulated the accumulation of hLa-specific Treg . Blockade of the type 1 interferon (IFN) receptor in hLa Tg recipients of hLa-specific T cells impaired FoxP3(+) donor T cell accumulation. Therefore, peripheral expansion of Treg specific for an RNA-binding nuclear antigen is mediated by antigen-presenting pDC in a type 1 IFN-dependent manner. These results reveal a regulatory function of pDC in controlling autoreactivity to RNA-binding nuclear antigens. PMID- 27227561 TI - Modelling Deposition and Erosion rates with RadioNuclides (MODERN) - Part 2: A comparison of different models to convert 239+240Pu inventories into soil redistribution rates at unploughed sites. AB - Sheet erosion is one of the major threats to alpine soils. To quantify its role and impact in the degradation processes of alpine grasslands, the application of Fallout Radionuclides (FRN) showed very promising results. The specific characteristics of plutonium 239 + 240 (239+240Pu), such as the homogeneous fallout distribution, the long half-life and the cost and time effective measurements make this tracer application for investigating soil degradation in Alpine grasslands more suitable than any other FRN (e.g. 137Cs). However, the conversion of 239+240Pu inventories into soil erosion rates remains a challenge. Currently available conversion models have been developed mainly for 137Cs with later adaptation to other FRN (e.g. Excess 210Pb, and 7Be), each model being defined for specific land use (ploughed and/or unploughed) and processes (erosion or deposition). As such, they may fail in describing correctly the distribution of Pu isotopes in the soil. A new conversion model, MODERN, with an adaptable algorithm to estimate erosion and deposition rates from any FRN inventory changes was recently proposed (Arata et al., 2016). In this complementary contribution, the authors compare the application of MODERN to other available conversion models. The results show a good agreement between soil redistribution rates obtained from MODERN and from the models currently used by the FRN scientific community (i.e. the Inventory Method). PMID- 27227562 TI - The rate of radon remediation in Ireland 2011-2015: Establishing a base line rate for Ireland's National Radon Control Strategy. AB - Radon is the greatest source of radiation exposure to the public. In Ireland, it is estimated that approximately 7% of the national housing stock have radon concentrations above the Reference Level of 200 Bq m-3. A radon test can be carried out to identify homes with radon levels above the Reference Level. However there is no health benefit associated with radon testing unless it leads to remediation. Surveys to establish the rate of remediation in Ireland, that is the proportion of householders who having found levels of radon above the Reference Level proceed to carry out remediation work have been carried out in 2011 and 2013. Reasons for not carrying out remediation work were also investigated. In 2015 the survey was repeated to establish the current rate of remediation and reasons for not remediating. This report presents the results of that survey. It also compiles the data from all three surveys to identify any trends over time. The rate of remediation is an important parameter in estimating the effectiveness of programmes aimed at reducing radon levels. Currently the rate of remediation is 22% and the main reasons householders gave for not remediating were not certain there is a serious risk and concern about the cost of the work. In Ireland, this figure of 22% will be now used as a baseline metric against which the effectiveness of its National Radon Control Strategy will be measured over time. PMID- 27227563 TI - Approximate total Fe content determined by Mossbauer spectrometry: Application to determine the correlation between gamma-ray-emitter activities and total content of Fe phases in soils of the Province of Buenos Aires, Argentina. AB - Pearson correlation coefficients between 40K, 226Ra and 232Th activities and the total Fe phase fractions yielded by Mossbauer spectroscopy have been calculated for soils of the Province of Buenos Aires, Argentina. Total fractions of Fe phases have been obtained from the relative fractions reported in previous works weighted by the Fe soil content and the recoilless-fraction of each Fe phase. An approximate method based on the relationship between the Mossbauer spectral absorption area (obtained from the 57Fe Mossbauer data) and the total Fe concentration (determined by colorimetric methods, after microwave assisted acid digestion of soil samples) has been used for the first time to determine the Fe concentration in soils with an accuracy of 15%. Protocol to extend the method for unknown samples is also discussed. The determined new coefficients differ from those reported previously. A significant and positive correlation between the total fraction of Fe2+ and the 40K activity values has been obtained. This result validates the hypothesis put forward in a previous work, i.e., that illite captures the 40K existing in the soil. In addition, with the new approximation, the Pearson correlation coefficients for the other natural radionuclides give values that indicate that the methodology reported here is appropriate to study the correlations between the activity values with the total fractions of Fe phases. PMID- 27227564 TI - Comparison of Photoselective Vaporization versus Holmium Laser Enucleation for Treatment of Benign Prostate Hyperplasia in a Small Prostate Volume. AB - OBJECTIVE: Photoselective vaporization of the prostate (PVP) using GreenLight and Holmium laser enucleation of the prostate (HoLEP) is an important surgical technique for management of benign prostate hyperplasia (BPH). We aimed to compare the effectiveness and safety of PVP using a 120 W GreenLight laser with HoLEP in a small prostate volume. METHODS: Patients who underwent PVP or HoLEP surgery for BPH at our institutions were reviewed from May 2009 to December 2014 in this retrospective study. Among them, patients with prostate volumes < 40 mL based on preoperative trans-rectal ultrasonography were included in this study. Peri-operative and post-operative parameters-such as International Prostate Symptom Score (IPSS), quality of life (QoL), maximum urinary flow rate (Qmax), post-void residual urine volume (PVR), and complications-were compared between the groups. RESULTS: PVP was performed in 176 patients and HoLEP in162 patients. Preoperative demographic data were similar in both groups, with the exception of PVR. Operative time and catheter duration did not show significant difference. Significant improvements compared to preoperative values were verified at the postoperative evaluation in both groups in terms of IPSS, QoL, Qmax, and PVR. Comparison of the postoperative parameters between the PVP and HoLEP groups demonstrated no significant difference, with the exception of IPSS voiding subscore at 1 month postoperatively (5.9 vs. 3.8, P< 0.001). There was no significant difference in postoperative complications between the two groups. CONCLUSION: Our data suggest that PVP and HoLEP are efficient and safe surgical treatment options for patients with small prostate volume. PMID- 27227566 TI - Two new double mutant alleles of the F7 gene and a literature review on alleles with two mutations in FVII deficiency. PMID- 27227565 TI - Association between subchondral bone structure and osteoarthritis histopathological grade. AB - Despite increasing evidence that subchondral bone contributes to osteoarthritis (OA) pathogenesis, little is known about local changes in bone structure compared to cartilage degeneration. This study linked structural adaptation of subchondral bone with histological OA grade. Twenty-five osteochondral samples of macroscopically different degeneration were prepared from tibiae of 14 patients. Samples were scanned with micro-computed tomography (MUCT) and both conventional structural parameters and novel 3D parameters based on local patterns were analyzed from the subchondral plate and trabecular bone. Subsequently, samples were processed for histology and evaluated for OARSI grade. Each bone parameter and OARSI grade was compared to assess structural adaptation of bone with OA severity. In addition, thicknesses of cartilage, calcified cartilage, and subchondral plate were analyzed from histological sections and compared with subchondral bone plate thickness from MUCT. With increasing OARSI grade, the subchondral plate became thicker along with decreased specific bone surface, while there was no change in tissue mineral density. Histological analysis showed that subchondral plate thickness from MUCT also includes calcified cartilage. Entropy of local patterns increased with OA severity, reflecting higher tissue heterogeneity. In the trabecular compartment, bone volume fraction and both trabecular thickness and number increased with OARSI grade while trabecular separation and structure model index decreased. Also, elevation of local patterns became longitudinal in the subchondral plate and axial transverse in trabecular bone with increasing OARSI grade. This study demonstrates the possibility of radiological assessment of OA severity by structural analysis of bone. (c) 2016 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. J Orthop Res 35:785-792, 2017. PMID- 27227567 TI - Colony-stimulating factor 1 should be considered when studying the miR-28-5p-IL 34-macrophage feedback loop in hepatocellular carcinoma. PMID- 27227568 TI - Effects of pulsed electromagnetic fields on peripheral blood circulation in people with diabetes: A randomized controlled trial. AB - Cutaneous blood flow provides nourishment that plays an essential role in maintaining skin health. We examined the effects of pulsed electromagnetic fields (PEMFs) on cutaneous circulation of dorsal feet. Twenty-two patients with diabetes mellitus (DM) and 21 healthy control subjects were randomly allocated to receive either PEMFs or sham PEMFs (0.5 mT, 12 Hz, 30 min). Blood flow velocity and diameter of the small vein were examined by using ultrasound biomicroscopy; also, microcirculation at skin over the base of the 1st metatarsal bone (Flux1) and distal 1st phalange (Flux2) was measured by laser Doppler flowmetry before and after intervention. Results indicated that PEMFs produced significantly greater changes in blood flow velocity of the smallest observable vein than did sham PEMFs (both P < 0.05) in both types of subjects. However, no significant difference was found in changes of vein diameter, nor in Flux1 and Flux2, between PEMFs and sham PEMFs groups in subjects with or without DM. We hypothesized that PEMFs would increase blood flow velocity of the smallest observable vein in people with or without DM. Bioelectromagnetics. 37:290-297, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27227570 TI - Access and Utilization of Selected Preventive Health Services Among Adolescents Aged 10-17. AB - KEY FINDINGS: Data from the National Health Interview Survey *The percentages of adolescents aged 10-17 who did not have a usual place for preventive care, did not receive a well-child checkup in the past 12 months, or did not have a dental visit in the past 12 months decreased from 2008 to 2014. *In 2014, 2% of adolescents aged 10-17 did not have a usual place for preventive care, 21% did not receive a well-child checkup, and 12% did not have a dental visit in the past 12 months. *In 2014, the percentages of adolescents not having a usual place for preventive care, not receiving a well-child checkup, and not having a dental visit were higher for those aged 16-17 compared with those in younger age groups. These percentages also varied by race and ethnicity, poverty status, and insurance status. PMID- 27227569 TI - Role of DUSP1/MKP1 in tumorigenesis, tumor progression and therapy. AB - Dual-specificity phosphatase-1 (DUSP1/MKP1), as a member of the threonine tyrosine dual-specificity phosphatase family, was first found in cultured murine cells. The molecular mechanisms of DUSP1-mediated extracellular signal-regulated protein kinases (ERKs) dephosphorylation have been subsequently identified by studies using gene knockout mice and gene silencing technology. As a protein phosphatase, DUSP1 also downregulates p38 MAPKs and JNKs signaling through directly dephosphorylating threonine and tyrosine. It has been detected that DUSP1 is involved in various functions, including proliferation, differentiation, and apoptosis in normal cells. In various human cancers, abnormal expression of DUSP1 was observed which was associated with prognosis of tumor patients. Further studies have revealed its role in tumorigenesis and tumor progression. Besides, DUSP1 has been found to play a role in tumor chemotherapy, immunotherapy, and biotherapy. In this review, we will focus on the function and mechanism of DUSP1 in tumor cells and tumor treatment. PMID- 27227571 TI - Cardiometabolic risk markers of normal weight and excess body weight in Brazilian adolescents. AB - Excess body weight leads to a variety of metabolic changes and increases the risk for cardiovascular diseases (CVD) in adulthood. The objective of this study was to investigate the presence of risk markers for CVD among Brazilian adolescents of normal weight and with excess body weight. The markers included blood pressure, C-reactive protein, homocysteine, tumor necrosis factor alpha, fibrinogen, fasting insulin and glucose, homeostasis model assessment of insulin resistance (HOMA-IR), leptin, total cholesterol, low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), and triglycerides. We calculated odds ratios (OR) using logistic regression and adjusted for potential confounders such as age, sex, physical activity, and socioeconomic background. Compared with normal weight subjects, overweight/obese adolescents were more likely to have higher systolic blood pressure (OR = 3.49, p < 0.001), fasting insulin (OR = 8.03, p < 0.001), HOMA-IR (OR = 8.03, p < 0.001), leptin (OR = 5.55, p < 0.001), and LDL-c (OR = 5.50, p < 0.001) and lower serum HDL-c concentrations (OR = 2.76, p = 0.004). After adjustment for confounders, the estimates did not change substantially, except for leptin for which the risk associated with overweight increased to 11.09 (95% CI: 4.05-30.35). In conclusion, excess body weight in adolescents exhibits strong associations with several markers that are established as causes of CVD in adults. This observation stresses the importance of primary prevention and of maintaining a healthy body weight throughout adolescence to reduce the global burden of CVD. PMID- 27227573 TI - Growth-Factor Nanocapsules That Enable Tunable Controlled Release for Bone Regeneration. AB - Growth factors are of great potential in regenerative medicine. However, their clinical applications are largely limited by the short in vivo half-lives and the narrow therapeutic window. Thus, a robust controlled release system remains an unmet medical need for growth-factor-based therapies. In this research, a nanoscale controlled release system (degradable protein nanocapsule) is established via in situ polymerization on growth factor. The release rate can be finely tuned by engineering the surface polymer composition. Improved therapeutic outcomes can be achieved with growth factor nanocapsules, as illustrated in spinal cord fusion mediated by bone morphogenetic protein-2 nanocapsules. PMID- 27227574 TI - Smarter Stormwater Systems. AB - Existing stormwater systems require significant investments to meet challenges imposed by climate change, rapid urbanization, and evolving regulations. There is an unprecedented opportunity to improve urban water quality by equipping stormwater systems with low-cost sensors and controllers. This will transform their operation from static to adaptive, permitting them to be instantly "redesigned" to respond to individual storms and evolving land uses. PMID- 27227575 TI - Property and Shape Modulation of Carbon Fibers Using Lasers. AB - An exciting challenge is to create unduloid-reinforcing fibers with tailored dimensions to produce synthetic composites with improved toughness and increased ductility. Continuous carbon fibers, the state-of-the-art reinforcement for structural composites, were modified via controlled laser irradiation to result in expanded outwardly tapered regions, as well as fibers with Q-tip (cotton-bud) end shapes. A pulsed laser treatment was used to introduce damage at the single carbon fiber level, creating expanded regions at predetermined points along the lengths of continuous carbon fibers, while maintaining much of their stiffness. The range of produced shapes was quantified and correlated to single fiber tensile properties. Mapped Raman spectroscopy was used to elucidate the local compositional and structural changes. Irradiation conditions were adjusted to create a swollen weakened region, such that fiber failure occurred in the laser treated region producing two fiber ends with outwardly tapered ends. Loading the tapered fibers allows for viscoelastic energy dissipation during fiber pull-out by enhanced friction as the fibers plough through a matrix. In these tapered fibers, diameters were locally increased up to 53%, forming outward taper angles of up to 1.8 degrees . The tensile strength and strain to failure of the modified fibers were significantly reduced, by 75% and 55%, respectively, ensuring localization of the break in the expanded region; however, the fiber stiffness was only reduced by 17%. Using harsher irradiation conditions, carbon fibers were completely cut, resulting in cotton-bud fiber end shapes. Single fiber pull-out tests performed using these fibers revealed a 6.75-fold increase in work of pull out compared to pristine carbon fibers. Controlled laser irradiation is a route to modify the shape of continuous carbon fibers along their lengths, as well as to cut them into controlled lengths leaving tapered or cotton-bud shapes. PMID- 27227576 TI - Notes from the Field: Outbreak of Serogroup B Meningococcal Disease at a University - California, 2016. AB - On January 31, 2016, the Santa Clara County Public Health Department (SCCPHD) was notified of a suspected case of meningococcal disease in a university undergraduate student. By February 2, two additional suspected cases had been reported in undergraduate students living on the same campus. The index patient (patient A) required intensive care, whereas patients B and C had milder illness; there were no deaths. All three patients were part of overlapping social networks and had attended the same events during the week before the onset of patient A's symptoms, but whether they had direct contact with one another could not be verified. Serogroup B Neisseria meningitidis was identified in cerebrospinal fluid and blood from patient A and in blood from patient B. Serogroup B has been responsible for all U.S. college outbreaks of meningococcal disease since 2011 (1). Laboratory results for patient C were inconclusive. PMID- 27227577 TI - High-throughput proteomics and the fight against pathogens. AB - Pathogens pose a major threat to human and animal welfare. Understanding the interspecies host-pathogen protein-protein interactions could lead to the development of novel strategies to combat infectious diseases through the rapid development of new therapeutics. The first step in understanding the host pathogen crosstalk is to identify interacting proteins in order to define crucial hot-spots in the host-pathogen interactome, such as the proposed pharmaceutical targets by means of high-throughput proteomic methodologies. In order to obtain holistic insight into the inter- and intra-species bimolecular interactions, apart from the proteomic approach, sophisticated in silico modeling is used to correlate the obtained large data sets with other omics data and clinical outcomes. Since the main focus in this area has been directed towards human medicine, it is time to extrapolate the existing expertise to a new emerging field: the 'systems veterinary medicine'. Therefore, this review addresses high throughput mass spectrometry-based technology for monitoring protein-protein interactions in vitro and in vivo and discusses pathogen cultivation, model host cells and available bioinformatic tools employed in vaccine development. PMID- 27227578 TI - Unintended pregnancy during the first year after breast cancer diagnosis. AB - OBJECTIVES: Young women experience high levels of anxiety and distress during cancer diagnosis and therapy, and it can be devastating to become pregnant in this vulnerable state. Pregnancy during cancer treatment is strongly discouraged, as radiotherapy and chemotherapy administered during the first trimester of pregnancy result in increased congenital malformations. METHODS: In this study, we analysed an unselected, consecutive cohort of young breast cancer (BC) patients with regard to unintended pregnancy during the first year after BC diagnosis. We analysed all patients who were <=40 years of age at initial BC diagnosis (n = 100, mean age at diagnosis: 35.9 years), according to data from the Basel Breast Cancer Database. The frequency of unintended pregnancy was assessed, and particular attention was given to patients' obstetric and reproductive history. RESULTS: Forty-two percent of the cohort (mean age 36.5 years) were identified as not at risk of unintended pregnancy during the first year after BC diagnosis. However, 58% of the cohort (mean age 35.6 years) were using an ineffective contraceptive method and thus were at risk of unintended pregnancy. The rate of unintended pregnancy was 3.5% in this group (two patients). Oncologists should be aware that the use of reliable contraception should be discussed before starting, and also during, adjuvant therapy. CONCLUSIONS: Oncologists should consider actively referring young BC patients to a gynaecologist to ensure proper contraceptive counselling. PMID- 27227579 TI - Sulfoluciferin is Biosynthesized by a Specialized Luciferin Sulfotransferase in Fireflies. AB - Firefly luciferin is a specialized metabolite restricted to fireflies (family Lampyridae) and other select families of beetles (order Coleoptera). Firefly luciferin undergoes luciferase-catalyzed oxidation to produce light, thereby enabling the luminous mating signals essential for reproductive success in most bioluminescent beetles. Although firefly luciferin and luciferase have become widely used biotechnological tools, questions remain regarding the physiology and biochemistry of firefly bioluminescence. Here we report sulfoluciferin to be an in vivo derivative of firefly luciferin in fireflies and report the cloning of luciferin sulfotransferase (LST) from the North American firefly Photinus pyralis. LST catalyzes the production of sulfoluciferin from firefly luciferin and the sulfo-donor PAPS. Sulfoluciferin is abundant in several surveyed firefly genera as well as in the bioluminescent elaterid beetle Pyrophorus luminosus at a low level. We propose that sulfoluciferin could serve as a luciferin storage molecule in fireflies and that LST may find use as a new tool to modulate existing biotechnological applications of the firefly bioluminescent system. PMID- 27227650 TI - Correction: Forecasting Seizures Using Bivariate Intracranial EEG Measures and SVM in Naturally Occurring Canine Epilepsy. AB - [This corrects the article DOI: 10.1371/journal.pone.0133900.]. PMID- 27227649 TI - Brain Microstructural Abnormalities Are Related to Physiological Alterations in End-Stage Renal Disease. AB - PURPOSE: To study whole-brain microstructural alterations in patients with end stage renal disease (ESRD) and examine the relationship between brain microstructure and physiological indictors in the disease. MATERIALS AND METHODS: Diffusion tensor imaging data were collected from 35 patients with ESRD (28 men, 18-61 years) and 40 age- and gender-matched healthy controls (HCs, 32 men, 22-58 years). A voxel-wise analysis was then used to identify microstructural alterations over the whole brain in the ESRD patients compared with the HCs. Multiple biochemical measures of renal metabolin, vascular risk factors, general cognitive ability and dialysis duration were correlated with microstructural integrity for the patients. RESULTS: Compared to the HCs, the ESRD patients exhibited disrupted microstructural integrity in not only white matter (WM) but also gray matter (GM) regions, as characterized by decreased fractional anisotropy (FA) and increased mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). Further correlation analyses revealed that the in MD, AD and RD values showed significantly positive correlations with the blood urea nitrogen in the left superior temporal gyrus and significantly negative correlations with the calcium levels in the left superior frontal gyrus (orbital part) in the patients. CONCLUSION: Our findings suggest that ESRD is associated with widespread diffusion abnormalities in both WM and GM regions in the brain, and microstructural integrity of several GM regions are related to biochemical alterations in the disease. PMID- 27227651 TI - A randomized controlled trial of a transdiagnostic Internet intervention for individuals with panic and phobias - One size fits all. AB - BACKGROUND AND OBJECTIVES: Many individuals with anxiety disorders do not receive professional treatment. Internet interventions have shown to be effective in the treatment of anxiety. The present randomized controlled trial was designed to examine the effectiveness of a short-term (4-week) Internet intervention in treating panic disorder, agoraphobia, social anxiety disorder, and specific phobias ('ConfID'). We addressed the questions of whether this transdiagnostic program would affect these disorders to varying degrees and whether there would be moderators of effectiveness. METHODS: Adults who were recruited in online forums for anxiety underwent an online baseline assessment (N = 179) and were randomized either to the intervention group (ConfID) or the control group (care as usual). Online post-assessment took place 4 weeks later. The primary outcome was assessed with the Beck Anxiety Inventory (BAI); the secondary outcomes targeted the disorder-specific symptoms, depression, and somatization. RESULTS: Participants in the intervention group showed a significantly stronger anxiety reduction compared to participants receiving care as usual (small-to-medium effect size between groups in intention-to-treat analysis). The treatment effect was similar for the different disorders and was moderated by participants' attitudes towards Internet interventions. Secondary outcomes yielded effect sizes in the medium range. LIMITATIONS: Moderate treatment adherence, lack of measures beyond online self-reports, and unavailability of long-term results. CONCLUSIONS: The study provides further evidence that transdiagnostic Internet interventions are promising in reducing the existing treatment gap in individuals with panic disorder and phobias. Results extend previous findings by showing that significant effects can also be reached by comprehensive short-term programs and that the effects might be moderated by participants' attitudes towards Internet interventions. PMID- 27227652 TI - Reactivity of nano-size zinc powder in the aqueous solution of [FeIII(edta)(H2O)]. AB - Nitrogen mono-oxide and sulfur dioxide can be removed by simultaneous absorption into aqueous mixed solutions of sulfite and [FeII(edta)]H2O)]2-, ferrous ion coordinated to an anion of ethylene-diaminetetraacetic acid (EDTA or edta). In the industrial system with coexisting oxygen in the gas phase, [FeII(edta)](H2O)]2- complex is oxidized to [FeIII(edta)](H2O)]- by molecular oxygen. Because the ferric complex has no capability for reaction with NO, the suppression of this undesired oxidation process is a very important technological problem to be overcome. In our preceding work, we discussed the reduction kinetics of ferric ion by metal powder on the basis of the kinetic data regarding the ferric ion reduction in aqueous solutions of [FeIII(edta)](H2O)]- containing aluminum, tin or zinc powders. Zinc powder of normal size was recognized as an effective reducing agent. In the present work, augmentation of reducing capability of zinc powder was examined more. The rate of reduction of nano-size zinc powder was found to be about 11 times higher than that of normal-size zinc one. PMID- 27227653 TI - ADHD. PMID- 27227656 TI - IgA nephropathy. PMID- 27227654 TI - Maternal and Fetal Outcomes After Therapy for Hodgkin or Non-Hodgkin Lymphoma Diagnosed During Pregnancy. AB - IMPORTANCE: The management of lymphoma diagnosed during pregnancy is controversial and has been guided largely by findings from case reports and small series. OBJECTIVE: To determine maternal and fetal outcomes of women diagnosed with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) during pregnancy. DESIGN, SETTING, AND PARTICIPANTS: This retrospective analysis studied a cohort of 39 pregnant women diagnosed with HL and NHL (31 HL and 8 NHL) at a single specialized cancer institution between January 1991 and December 2014. MAIN OUTCOMES AND MEASURES: We examined data on disease and treatment characteristics, as well as maternal and fetal complications and outcomes. The Kaplan-Meier method was used to compare progression free survival (PFS) and overall survival (OS) according to receipt of antenatal therapy and other clinical factors. Univariate and multivariate analyses were performed by using Cox proportional hazard regression models to identify potential associations between clinical and treatment factors and survival. RESULTS: The median (range) age of the 39 women in the patient cohort was 28 (19-38) years; 32 women (82%) had stage I or II disease at diagnosis, and 13 had bulky disease. Three women electively terminated the pregnancy to allow immediate systemic therapy; of the remaining 36 women, 24 received antenatal therapy (doxorubicin based combination chemotherapy in 20 of 24 patients), and 12 deferred therapy until after delivery. Four women experienced miscarriage, all of whom had received antenatal systemic therapy and 2 during the first trimester. Delivery occurred at a median (range) of 37 (32-42) weeks and was no different based on receipt of antenatal (median [range], 37 [33 42] weeks) vs postnatal (median [range], 37 [32-42] weeks) therapy (P = .21). No gross fetal malformations or anomalies were detected. At a median (range) follow up time of 67.9 (8.8-277.5) months since the diagnosis of lymphoma, 5-year rates of PFS and OS were 74.7% and 82.4%, respectively; these rates did not differ according to timing of therapy. On univariate analysis, bulky disease (>10 cm), extranodal nonbone marrow involvement, and poor performance status (Eastern Cooperative Oncology Group score, >=2) predicted increased risk of disease progression. On multivariate analysis, extranodal nonbone marrow disease and performance status remained significant for both PFS and OS. CONCLUSIONS AND RELEVANCE: Systemic therapy given for lymphoma after the first trimester of pregnancy is likely safe and results in acceptable maternal and fetal outcomes. PMID- 27227655 TI - Diastereoselective Synthesis of Structurally and Stereochemically Diversified 2 Oxa-7-azabicyclo[4.1.0]hept-3-enyl Carboxylates and Their Potential Application toward the Synthesis of Functionalized Pyranooxazolone and Pyrrole Derivatives through Skeletal Transformations. AB - An advanced protocol for the diastereoselective intramolecular aziridination reaction has been developed to synthesize 2-oxa-7-azabicyclo[4.1.0]hept-3-en-1-yl carboxylates from their corresponding 4-H-pyrans and spiropyrans analogues employing iodosylbenznene as the exclusive oxidant in the presence of carboxylic acid and triethylamine. High structural and stereochemical diversity of these pyran fused NH-azridine scaffolds makes them useful in evaluating their biological and pharmacological activities by SAR studies. Additionally, their potential synthetic application has been uncovered by efficient transformation into biologically relevant novel pyranooxazolone and pyrrole derivatives. PMID- 27227657 TI - Behavioral Risk Factor Surveillance System State-Added Questions: Leveraging an Existing Surveillance System to Improve Knowledge of Women's Reproductive Health. AB - As the prevalence of chronic conditions among women of reproductive age continues to rise, studies assessing the intersection of chronic disease and women's reproductive health status are increasingly needed. However, many data systems collect only limited information on women's reproductive health, thereby hampering the appraisal of risk and protective factors across the life span. One way to expand the study of women's health with minimal investment in time and resources is to integrate questions on reproductive health into existing surveillance systems. In 2013, previously validated questions on women's self reported reproductive history, use of contraception, and infertility were added to the Behavioral Risk Factor Surveillance System (BRFSS) by seven states (Connecticut, Kentucky, Massachusetts, Mississippi, Ohio, Texas, and Utah); all female respondents aged 18-50 years were included in the pool of respondents for these state-added questions. Of 8691 women who completed the questions, 13.2% reported ever experiencing infertility and 59.8% of those at risk for unintended pregnancy reported using contraception at last intercourse. The information garnered from the state-added reproductive health questions can be augmented with the BRFSS core questions on health-related risk behaviors, chronic conditions, and use of preventive services. Expanding existing data collection systems with supplemental questions on women's reproductive health can provide important information on risk factors and outcomes that may not be available from other sources. PMID- 27227658 TI - A case-control study on reduced HDL2b in patients with polycystic ovarian syndrome. AB - High-density lipoprotein (HDL) is an important factor associated with the increasing risk of future ischaemic heart disease. In this study, we analyzed serum HDL2b level in the patients with polycystic ovary syndrome (PCOS). Total of 60 female patients with PCOS was enrolled for assessment and another 60 non-PCOS females with matched age and weight were selected as control. A highly sensitive microfluidic chip was employed to analyze the serum HDL subfractions. Serum HDL2b and HDL2b/HDL ratio were decreased in PCOS group than those in the control group (p < 0.05). Pearson correlation analysis revealed that serum HDL2b level was negatively correlated with body mass index, waist circumference, waist-to-hip ratio, INS0, HOMA-IR, T, estradiol, triglyceride (TG) and low-density lipoprotein (LDL)-C; and the ratio of HDL2b/HDL was negatively correlated with T, TG and LDL C. Stepwise multiple regression analyses showed a reverse correlation for HDL2b and its ratio to HDL with hyperandrogenism. The results suggested that a reduction of serum HDL2b and its ratio to total serum HDL in PCOS patients by using the microfluidic chip method assessment. Hyperandrogenism was the main factor to affect HDL2b and its ratio to total HDL in PCOS patients, and it might increase the incidence of atherosclerosis as well as the risk of coronary heart disease. PMID- 27227659 TI - Palladium-Catalyzed Annulation of Internal Alkynes: Direct Access to pi Conjugated Ullazines. AB - A palladium-catalyzed cyclization reaction of 1-(2,6-dibromophenyl)-1H-pyrroles with alkynes has been developed to construct various pi-conjugated indolizino[6,5,4,3-ija]quinolones (ullazines) with a reactive functional group tolerance. As illustrative examples, three new ullazine-based sensitizers are synthesized, and the performance of these dyes is examined in DSSC devices, which demonstrates the potential of direct C-H functionalization in the construction of organic optoelectronic materials. PMID- 27227660 TI - Influence of Managed Care on the Variation in Rate and Timing of Cataract Surgery. PMID- 27227661 TI - Fast and accurate sensitivity analysis of IMPT treatment plans using Polynomial Chaos Expansion. AB - The highly conformal planned dose distribution achievable in intensity modulated proton therapy (IMPT) can severely be compromised by uncertainties in patient setup and proton range. While several robust optimization approaches have been presented to address this issue, appropriate methods to accurately estimate the robustness of treatment plans are still lacking. To fill this gap we present Polynomial Chaos Expansion (PCE) techniques which are easily applicable and create a meta-model of the dose engine by approximating the dose in every voxel with multidimensional polynomials. This Polynomial Chaos (PC) model can be built in an automated fashion relatively cheaply and subsequently it can be used to perform comprehensive robustness analysis. We adapted PC to provide among others the expected dose, the dose variance, accurate probability distribution of dose volume histogram (DVH) metrics (e.g. minimum tumor or maximum organ dose), exact bandwidths of DVHs, and to separate the effects of random and systematic errors. We present the outcome of our verification experiments based on 6 head-and-neck (HN) patients, and exemplify the usefulness of PCE by comparing a robust and a non-robust treatment plan for a selected HN case. The results suggest that PCE is highly valuable for both research and clinical applications. PMID- 27227671 TI - A Socio-Ecological Approach for Identifying and Contextualising Spatial Ecosystem Based Adaptation Priorities at the Sub-National Level. AB - Climate change adds an additional layer of complexity to existing sustainable development and biodiversity conservation challenges. The impacts of global climate change are felt locally, and thus local governance structures will increasingly be responsible for preparedness and local responses. Ecosystem-based adaptation (EbA) options are gaining prominence as relevant climate change solutions. Local government officials seldom have an appropriate understanding of the role of ecosystem functioning in sustainable development goals, or access to relevant climate information. Thus the use of ecosystems in helping people adapt to climate change is limited partially by the lack of information on where ecosystems have the highest potential to do so. To begin overcoming this barrier, Conservation South Africa in partnership with local government developed a socio ecological approach for identifying spatial EbA priorities at the sub-national level. Using GIS-based multi-criteria analysis and vegetation distribution models, the authors have spatially integrated relevant ecological and social information at a scale appropriate to inform local level political, administrative, and operational decision makers. This is the first systematic approach of which we are aware that highlights spatial priority areas for EbA implementation. Nodes of socio-ecological vulnerability are identified, and the inclusion of areas that provide ecosystem services and ecological resilience to future climate change is innovative. The purpose of this paper is to present and demonstrate a methodology for combining complex information into user-friendly spatial products for local level decision making on EbA. The authors focus on illustrating the kinds of products that can be generated from combining information in the suggested ways, and do not discuss the nuance of climate models nor present specific technical details of the model outputs here. Two representative case studies from rural South Africa demonstrate the replicability of this approach in rural and peri-urban areas of other developing and least developed countries around the world. PMID- 27227673 TI - Mechanoresponsiveness of human umbilical cord mesenchymal stem cells in in vitro chondrogenesis-A comparative study with growth factor induction. AB - Fetal-derived mesenchymal stem cells especially human umbilical cord matrix mesenchymal stem cells (hUCMSCs), with their ease of availability, pluripotency, and high expansion potential have emerged as an alternative solution for stem cell based cartilage therapies. An attempt to elucidate the effect of dynamic mechanical compression in modulating the chondrogenic differentiation of hUCMSCs is done in this study to add on to the knowledge of optimizing chondrogenic signals necessary for the effective differentiation of these stem cells and subsequent integration to the surrounding tissues. hUCMSCs were seeded in porous poly (vinyl alcohol)-poly (caprolactone) (PVA-PCL) scaffolds and cultured in chondrogenic medium with/without TGF-beta3 and were subjected to a dynamic compression of 10% strain, 1 Hz for 1/4 h for 7 days. The results on various analysis shows that the extent of dynamic compression is an important factor affecting cell viability. Mechanical stimulation in the form of dynamic compression stimulates expression of chondrogenic genes even in the absence of chondrogenic growth factors and also augments growth factor induced chondrogenic potential of hUCMSC. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2554-2566, 2016. PMID- 27227674 TI - Intravoxel incoherent motion MRI in differentiation between recurrent carcinoma and postchemoradiation fibrosis of the skull base in patients with nasopharyngeal carcinoma. AB - PURPOSE: To determine the capacity of intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) in differential diagnosis between recurrent carcinoma and postchemoradiation fibrosis of skull base in patients with nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: Eleven patients with recurrent NPC and 21 patients with postchemoradiation fibrosis in the skull base were enrolled. All the diagnoses were proved by endoscopic biopsy or imaging follow-up. IVIM MRI was performed to obtain quantitative parameters including D (pure diffusion), f (perfusion fraction), and D* (pseudodiffusion). D, f, and D* were compared between two groups; the diagnostic performances of D and f were evaluated using the receiver operating characteristic (ROC) analysis. RESULTS: D and f values were significantly lower in recurrent carcinoma than that in fibrosis (P < 0.001; P = 0.001). No significant difference was found in D* values between recurrent carcinoma and fibrosis (P = 0.229). ROC curve analysis showed that the area under the curve of D and f values were 0.996 and 0.838, respectively. Respective cutoff values with sensitivity, specificity, and accuracy were: D = 1.161 * 10-3 mm2 /s (sensitivity 100.0%, specificity 95.2%, accuracy 96.9%), f = 0.109 (sensitivity 81.8%, specificity 71.4%, accuracy 75.0%). CONCLUSION: Recurrent NPC and postchemoradiation fibrosis in the skull base have distinctive D and f values. IVIM MRI could be used to differentiate between recurrent carcinoma and postchemoradiation fibrosis in patients with NPC. J. Magn. Reson. Imaging 2016;44:1556-1564. PMID- 27227672 TI - Contribution of Cyclooxygenase End Products and Oxidative Stress to Intrahepatic Endothelial Dysfunction in Early Non-Alcoholic Fatty Liver Disease. AB - INTRODUCTION: Metabolic syndrome induces endothelial dysfunction, a surrogate marker of cardiovascular disease. In parallel, metabolic syndrome is frequently associated with non-alcoholic fatty liver disease (NAFLD), which may progress to cirrhosis. The aim of the present study was to evaluate intrahepatic endothelial dysfunction related to cyclooxygenase end products and oxidative stress as possible mechanisms involved in the pathophysiology of NAFLD. MATERIALS AND METHODS: Sprague-Dawley rats were fed standard diet (control-diet, CD) or high fat-diet (HFD) for 6 weeks. Metabolic syndrome was assessed by recording arterial pressure, lipids, glycemia and rat body weight. Splanchnic hemodynamics were measured, and endothelial dysfunction was evaluated using concentration-effect curves to acetylcholine. Response was assessed with either vehicle, L-NG Nitroarginine (L-NNA), indomethacin, tempol, or a thromboxane receptor antagonist, SQ 29548. We quantified inflammation, fibrosis, oxidative stress, nitric oxide (NO) bioavailability and thromboxane B2 levels. RESULTS: HFD rats exhibited metabolic syndrome together with the presence of NAFLD. Compared to control-diet livers, HFD livers showed increased hepatic vascular resistance unrelated to inflammation or fibrosis, but with decreased NO activity and increased oxidative stress. Endothelial dysfunction was observed in HFD livers compared with CD rats and improved after cyclooxygenase inhibition or tempol pre incubation. However, pre-incubation with SQ 29548 did not modify acetylcholine response. CONCLUSIONS: Our study provides evidence that endothelial dysfunction at an early stage of NAFLD is associated with reduced NO bioavailability together with increased cyclooxygenase end products and oxidative stress, which suggests that both pathways are involved in the pathophysiology and may be worth exploring as therapeutic targets to prevent progression of the disease. PMID- 27227675 TI - Study on Light Interception and Biomass Production of Different Cotton Cultivars. AB - Identifying the characteristics of light interception and utilization is of great significance for improving the potential photosynthetic activity of plants. The present research investigates the differences in absorbing and converting photosynthetically active radiation (PAR) among various cotton cultivars. Field experiments were conducted in 2012, 2013 and 2014 in Anyang, Henan, China. Ten cultivars with different maturity and plant architectures were planted at a density of 60,000 plants ha-1 in randomized blocks, with three replicates. The spatial distribution of light in canopy was measured and quantified with a geo statistical method, according to which the cumulative amount of intercepted radiation was calculated by Simpson 3/8 rules. Finally, light interception was analyzed in association with the biomass accumulation of different cultivars. The key results were: (1) late-maturing varieties with an incompact plant architecture captured more solar radiation throughout the whole growth period than middle varieties with columnar architecture and even more than early varieties with compact architecture, and they produced more biomass; (2) the highest PAR interception ratio and the maximum biomass accumulation rate occurred during the blossoming and boll-forming stage, when leaf area index (LAI) reached its peak; (3) the distribution within the canopy presented a significant spatial heterogeneity, and at late growing stage, the PAR was mainly intercepted by upper canopies in incompact-type plant communities, but was more homogeneous in columnar-type plants; however, the majority of radiation was transmitted through the canopy in compact-type colonies; (4) there was not a consistent variation relationship between the cumulative intercepted PAR (iPAR) and biomass among these cultivars over the three years of the study. Based on these results, we attempted to clarify the distinction in light spatial distribution within different canopies and the patterns of PAR interception in diverse cotton cultivars with different hereditary characters, thereby providing a significant basis for researchers to select cultivars with appropriate growth period and optimal plant architecture for improvement of light interception and utilization. PMID- 27227677 TI - pH Regulation of Electrogenic Sugar/H+ Symport in MFS Sugar Permeases. AB - Bacterial sugar symporters in the Major Facilitator Superfamily (MFS) use the H+ (and in a few cases Na+) electrochemical gradients to achieve active transport of sugar into the cell. Because a number of structures of MFS sugar symporters have been solved recently, molecular insight into the transport mechanism is possible from detailed functional analysis. We present here a comparative electrophysiological study of the lactose permease (LacY), the fucose permease (FucP) and the xylose permease (XylE), which reveals common mechanistic principles and differences. In all three symporters energetically downhill electrogenic sugar/H+ symport is observed. Comparison of the pH dependence of symport at symmetrical pH exhibits broad bell-shaped pH profiles extending over 3 to 6 pH units and a decrease at extremely alkaline pH >= 9.4 and at acidic to neutral pH = 4.6-7.5. The pH dependence can be described by an acidic to neutral apparent pK (pKapp) and an alkaline pKapp. Experimental evidence suggests that the alkaline pKapp is due to H+ depletion at the protonation site, while the acidic pKapp is due to inhibition of deprotonation. Since previous studies suggest that a single carboxyl group in LacY (Glu325) may be the only side chain directly involved in H+ translocation and a carboxyl side chain with similar properties has been identified in FucP (Asp46) and XylE (Asp27), the present results imply that the pK of this residue is switched during H+/sugar symport in all three symporters. PMID- 27227676 TI - Molecular Basis and Therapeutic Strategies to Rescue Factor IX Variants That Affect Splicing and Protein Function. AB - Mutations that result in amino acid changes can affect both pre-mRNA splicing and protein function. Understanding the combined effect is essential for correct diagnosis and for establishing the most appropriate therapeutic strategy at the molecular level. We have identified a series of disease-causing splicing mutations in coagulation factor IX (FIX) exon 5 that are completely recovered by a modified U1snRNP particle, through an SRSF2-dependent enhancement mechanism. We discovered that synonymous mutations and missense substitutions associated to a partial FIX secretion defect represent targets for this therapy as the resulting spliced-corrected proteins maintains normal FIX coagulant specific activity. Thus, splicing and protein alterations contribute to define at the molecular level the disease-causing effect of a number of exonic mutations in coagulation FIX exon 5. In addition, our results have a significant impact in the development of splicing-switching therapies in particular for mutations that affect both splicing and protein function where increasing the amount of a correctly spliced protein can circumvent the basic functional defects. PMID- 27227678 TI - Is Cesarean Delivery Preferable in Twin Pregnancies at >=36 Weeks Gestation? AB - BACKGROUND: The optimal mode of delivery in twin pregnancies remains controversial. A recent randomized trial did not find any benefit of planned cesarean vs. vaginal delivery at 32-38 weeks gestation, but the trial was not powered to detect a moderate effect. We aimed to evaluate the impact of cesarean delivery on perinatal mortality and severe neonatal morbidity in twin pregnancies at >=32 weeks through a large database exploration approach with the power to detect moderate risk differences. METHODS: In a retrospective birth cohort study using the U.S. matched multiple births, 1995-2000 (the available largest multiple birth dataset), we compared perinatal outcomes in twins (n = 181,810 pregnancies) delivered at 32-41 weeks gestation without congenital anomalies. The primary outcome was a composite of perinatal death and severe neonatal morbidity. Cox regression was used to estimate the adjusted hazard ratio (aHR) controlling for the propensity to cesarean delivery, fetal characteristics (sex, birth weight, birth weight discordance, same-sex twin or not) and twin-cluster level dependence. Prospective risks were calculated using the fetuses-at-risk denominators. RESULTS: The overall rates of the primary outcome were slightly lower in intended cesarean (6.20%) vs. vaginal (6.45%) deliveries. The aHRs of the primary outcome were in favor of vaginal delivery at 32 (aHR = 1.06, p = 0.03) or 33 (aHR = 1.22, p<0.001) weeks, neutral at 34-35 weeks, but in favor of cesarean delivery at 36 (aHR = 0.94, p = 0.004), 37, 38 and 39+ weeks (aHR: 0.72 to 0.78, all p<0.001). The lower risk of the primary outcome for cesarean vs. vaginal deliveries at 36+ weeks of gestation remained when the analyses were restricted to different-sex (dichorionic) twins (aHR = 0.84, 95% CI 0.80-0.88). CONCLUSION: Cesarean delivery may be beneficial for perinatal outcomes overall in twin pregnancies at >=36 weeks gestation. PMID- 27227679 TI - A Phase II Randomized Controlled Trial Comparing Safety, Procedure Time, and Cost of the PrePexTM Device to Forceps Guided Surgical Circumcision in Zimbabwe. AB - BACKGROUND: The World Health Organization (WHO) and the Joint United Nations Program on HIV/AIDS promote MC (male circumcision) as a key HIV prevention strategy where HIV prevalence and incidence are high and MC prevalence is low. In Zimbabwe, to achieve the 1.26 million circumcisions needed to be performed by 2015 to achieve optimal MC coverage, a new approach was needed. The primary objective of the current trial was to assess the performance (safety, procedure time, and cost) of the PrePex device compared to forceps-guided surgical circumcision. METHODS AND FINDINGS: This Phase II, randomized, open-label trial in Zimbabwe involved healthy, non-circumcised adult male volunteers who were randomly assigned to the PrePex device (n = 160) or surgical arm (n = 80). Three doctors and 4 nurses, all certified on both circumcision methods, performed the procedures. The PrePex device procedure involves a plastic ring with a rubber O ring that necrotizes the foreskin to facilitate easy and minimally invasive removal. Total procedure time was the primary endpoint. Adverse event (AE) data were also gathered for 90 days post-procedure. All 80 participants in the surgical arm and 158 participants in the PrePex arm achieved complete circumcision. The total procedure time for the PrePex device was approximately one-third of the total surgical procedure (4.8 minutes, Standard Deviation [SD]: 1.2 versus 14.6 minutes; SD: 4.2; p<0.00001). There were 2 AEs for 2 participants (rate of 1.3%, 95% Confidence Interval: 0.0025-4.53%), which were resolved with simple intervention. The AEs were device related, including 1 case of pain leading to device removal and 1 case of removal of the device. CONCLUSIONS: The trial supports previous studies' conclusions that the PrePex procedure is safe, quick, easy to apply, and effective in terms of procedure time as an alternative to traditional surgical circumcision. The PrePex device has great potential for use in overburdened health systems and in resource-limited settings and is recommended for use in rapid scale-up of adult MC in Zimbabwe. TRIAL REGISTRATION: ClinicalTrials.gov NCT01956370. PMID- 27227681 TI - Schizophrenia. PMID- 27227680 TI - Association of Anthropometric and Bioelectrical Impedance Analysis Measures of Adiposity with High Molecular Weight Adiponectin Concentration. AB - OBJECTIVE: To investigate the relationship between adiposity measures and plasma concentration of high molecular weight (HMW) adiponectin. METHODS: In a Chinese sample (n = 1081), we performed measurements of anthropometry and bioelectrical impedance analysis (BIA). We defined overweight and obesity as a body mass index between 24 and 27.4 kg/m2 and >= 27.5 kg/m2, respectively, and central obesity as a waist circumference >= 90 cm in men and >= 80 cm in women. Plasma HMW adiponectin concentration was measured by the ELISA method. RESULTS: Plasma HMW adiponectin concentration was significantly (P < 0.0001) higher in women (n = 677, 2.47 MUg/mL) than men (n = 404, 1.58 MUg/mL) and correlated with advancing age in men (r = 0.28) and women (r = 0.29). In adjusted analyses, it was lower in the presence of overweight (n = 159, 1.26 MUg/mL in men and n = 227, 2.15MUg/mL in women) and obesity (n = 60, 1.31 MUg/mL and n = 82, 2.10 MUg/mL, respectively) than normal weight subjects (n = 185, 2.07MUg/mL and n = 368, 2.94 MUg/mL, respectively) and in the presence of central obesity (n = 106, 1.28 MUg/mL and n = 331, 2.12 MUg/mL, respectively) than subjects with a normal waist circumference (n = 298, 1.74 MUg/mL and n = 346, 2.74 MUg/mL, respectively). In multiple regression analyses stratified for gender, adjusted for confounders and considered separately each of the adiposity measures, all adiposity measures were significantly (r -0.18 to -0.31, P < 0.001) associated with plasma HMW adiponectin concentration. However, in further stratified and adjusted regression analyses considered stepwise all adiposity measures, only waist-to-hip ratio was significantly (P < 0.05) associated with plasma HMW adiponectin concentration in men (r = -0.10) and women (r = -0.15). CONCLUSIONS: Anthropometric measures of obesity, such as waist-to-hip ratio, but not BIA measures, are independently associated with plasma adiponectin concentration. PMID- 27227683 TI - Brain arteriovenous malformations. PMID- 27227682 TI - Condensation of Macrocyclic Polyketides Produced by Penicillium sp. DRF2 with Mercaptopyruvate Represents a New Fungal Detoxification Pathway. AB - Application of a refined procedure of experimental design and chemometric analysis to improve the production of curvularin-related polyketides by a marine derived Penicillium sp. DRF2 resulted in the isolation and identification of cyclothiocurvularins 6-8 and cyclosulfoxicurvularins 10 and 11, novel curvularins condensed with a mercaptolactate residue. Two additional new curvularins, 3 and 4, are also reported. The structures of the sulfur-bearing curvularins were unambiguously established by analysis of spectroscopic data and by X-ray diffraction analysis. Analysis of stable isotope feeding experiments with [U (13)C3(15)N]-l-cysteine confirmed the presence of the 2-hydroxy-3 mercaptopropanoic acid residue in 6-8 and the oxidized sulfoxide in 10 and 11. Cyclothiocurvularins A (6) and B (7) are formed by spontaneous reaction between 10,11-dehydrocurvularin (2) and mercaptopyruvate (12) obtained by transamination of cysteine. High ratios of [U-(13)C3(15)N]-l-cysteine incorporation into cyclothiocurvularin B (7), the isolation of two diastereomers of cyclothiocurvularins, the lack of cytotoxicity of cyclothiocurvularin B (7) and its methyl ester (8), and the spontaneous formation of cyclothiocurvularins from 10,11-dehydrocurvularin and mercaptopyruvate provide evidence that the formation of cyclothiocurvularins may well correspond to a 10,11-dehydrocurvularin detoxification process by Penicillium sp. DRF2. PMID- 27227685 TI - A New Morphological Phylogeny of the Ophiuroidea (Echinodermata) Accords with Molecular Evidence and Renders Microfossils Accessible for Cladistics. AB - Ophiuroid systematics is currently in a state of upheaval, with recent molecular estimates fundamentally clashing with traditional, morphology-based classifications. Here, we attempt a long overdue recast of a morphological phylogeny estimate of the Ophiuroidea taking into account latest insights on microstructural features of the arm skeleton. Our final estimate is based on a total of 45 ingroup taxa, including 41 recent species covering the full range of extant ophiuroid higher taxon diversity and 4 fossil species known from exceptionally preserved material, and the Lower Carboniferous Aganaster gregarius as the outgroup. A total of 130 characters were scored directly on specimens. The tree resulting from the Bayesian inference analysis of the full data matrix is reasonably well resolved and well supported, and refutes all previous classifications, with most traditional families discredited as poly- or paraphyletic. In contrast, our tree agrees remarkably well with the latest molecular estimate, thus paving the way towards an integrated new classification of the Ophiuroidea. Among the characters which were qualitatively found to accord best with our tree topology, we selected a list of potential synapomorphies for future formal clade definitions. Furthermore, an analysis with 13 of the ingroup taxa reduced to the lateral arm plate characters produced a tree which was essentially similar to the full dataset tree. This suggests that dissociated lateral arm plates can be analysed in combination with fully known taxa and thus effectively unlocks the extensive record of fossil lateral arm plates for phylogenetic estimates. Finally, the age and position within our tree implies that the ophiuroid crown-group had started to diversify by the Early Triassic. PMID- 27227684 TI - Cytological Anal Squamous Intraepithelial Lesions Associated with Anal High-Risk Human Papillomavirus Infections among Men Who Have Sex with Men in Northern Thailand. AB - BACKGROUND: Anal cancer, one of human papillomavirus (HPV) related malignancies, has increased in recent decades, particularly among men who have sex with men (MSM) and HIV-infected (HIV+) persons. We aimed to explore the prevalence of anal squamous intraepithelial lesions (ASIL) using Papanicolau (Pap) screening among MSM in northern Thailand and its associated factors. METHODS: Two hundreds MSM aged >=18 years reporting receptive anal intercourse in the prior 6 months were recruited from July 2012 through January 2013. Medical history and behavioral data were collected by staff interview and computer-assisted self interview. Anal Pap smear, HPV genotyping, and HIV testing were performed. Two pathologists blinded to HPV and HIV status reported cytologic results by Bethesda classification. RESULTS: Mean age was 27.2 years (range 18-54). Overall, 86 (43.0%) had ASIL: 28 (14.2%) with atypical cells of undetermined significance (ASCUS), 1 (0.5%) with atypical squamous cells-cannot exclude high-grade squamous intraepithelial lesion (ASC-H), 56 (28.4%) with low-grade squamous intraepithelial lesion (LSIL), and 1 (0.5%) with high-grade squamous intraepithelial lesion (HSIL). ASIL was associated by univariate analysis (p <=0.05) with older age, gender identity other than bisexual (i.e., gay men and transgender women), rectal douching, anal symptoms, genital warts, HIV positivity, and high-risk-HPV infection. However, on multiple logistic regression ASIL was associated only with high-risk HPV type (p = 0.002) and HIV infection (p = 0.01). CONCLUSIONS: ASIL is quite common in high-risk MSM in northern Thailand and is associated with high-risk HPV types and HIV infection. Routine anal Pap screening should be considered, given the high frequency of ASIL, particularly in the HIV+. High resolution anoscopy (HRA), not done here, should be to confirm PAP smears whose sensitivity and specificity are quite variable. Timely HPV vaccination should be considered for this population. PMID- 27227686 TI - The NnCenH3 protein and centromeric DNA sequence profiles of Nelumbo nucifera Gaertn. (sacred lotus) reveal the DNA structures and dynamics of centromeres in basal eudicots. AB - Centromeres on eukaryotic chromosomes consist of large arrays of DNA repeats that undergo very rapid evolution. Nelumbo nucifera Gaertn. (sacred lotus) is a phylogenetic relict and an aquatic perennial basal eudicot. Studies concerning the centromeres of this basal eudicot species could provide ancient evolutionary perspectives. In this study, we characterized the centromeric marker protein NnCenH3 (sacred lotus centromere-specific histone H3 variant), and used a chromatin immunoprecipitation (ChIP)-based technique to recover the NnCenH3 nucleosome-associated sequences of sacred lotus. The properties of the centromere binding protein and DNA sequences revealed notable divergence between sacred lotus and other flowering plants, including the following factors: (i) an NnCenH3 alternative splicing variant comprising only a partial centromere-targeting domain, (ii) active genes with low transcription levels in the NnCenH3 nucleosomal regions, and (iii) the prevalence of the Ty1/copia class of long terminal repeat (LTR) retrotransposons in the centromeres of sacred lotus chromosomes. In addition, the dynamic natures of the centromeric region showed that some of the centromeric repeat DNA sequences originated from telomeric repeats, and a pair of centromeres on the dicentric chromosome 1 was inactive in the metaphase cells of sacred lotus. Our characterization of the properties of centromeric DNA structure within the sacred lotus genome describes a centromeric profile in ancient basal eudicots and might provide evidence of the origins and evolution of centromeres. Furthermore, the identification of centromeric DNA sequences is of great significance for the assembly of the sacred lotus genome. PMID- 27227687 TI - Adaptation of liver stiffness measurement depth in bariatric surgery candidates with suspected nonalcoholic fatty liver disease. AB - BACKGROUND AND AIMS: A thick layer of subcutaneous adipose tissue may lead to an overestimation of liver stiffness by transient elastography. The aim of this study was to assess whether liver stiffness measurement (LSM) was overestimated using an XL probe in patients with severe obesity and, if so, to reprocess the data to the adapted depth to obtain the appropriate LSM (LSMa). METHODS: A total of 152 obese patients prospectively underwent bariatric surgery and needle liver biopsy. Liver stiffness was measured by transient elastography 15 days before. To determine whether the LSM was overestimated, an expert operator retrospectively determined whether the skin-to-capsula distance was greater than 35 mm by analyzing the hyperechogenicity of ultrasound signals and the measured slope between 35 and 75 mm. In the case of an overestimation, a deeper measurement depth was selected to calculate the LSMa. RESULTS: There was an overestimation of the LSM obtained between 35 and 75 mm in 76 patients (50%). Among these patients, the LSMa was obtained between 40 and 75 mm in 49 patients and between 45 and 80 mm in 27 patients. Only the percentage of steatosis was independently and positively correlated with LSM overestimation. The areas under receiver operating characteristic of LSMa was 0.82+/-0.04 for predicting fibrosis stage F3. The Obuchowski measure was 0.85+/-0.02. CONCLUSION: The LSM was overestimated in severely obese patients obtained between 35 and 75 mm using an XL probe in 76 patients (50%), but LSM can be performed correctly in these patients after adapting the measurement depth to deeper beneath the patients' skin. PMID- 27227688 TI - High variation in treatment strategies for gastrointestinal angiodysplasias. AB - OBJECTIVE: Angiodysplasias (ADs) are the second leading cause of gastrointestinal bleeding in the elderly. The impact extends from no symptoms to chronic anaemia. Treatment guidelines are lacking. The aim of this study was to assess the current practice of gastrointestinal ADs and explore possible new research areas. On the basis of existing evidence, we would like to propose a treatment algorithm. METHODS: We administered a 19-item web-based survey to gastroenterologists in the Netherlands between February and April of 2015. RESULTS: A total of 111 (response rate 28%) gastroenterologists completed the survey (mean age=47 years; 24% women). The respondents identified Von Willebrand disease (17%), chronic kidney disease (21%) and aortic stenosis (77%) as risk factors for the development of ADs. Colonoscopy (54%) and esophagogastroduodenoscopy (43%) were the preferred first tools to screen for ADs. The favoured (77%) first treatment option is endoscopic argon plasma coagulation, whereas 20% start iron supplementation or blood transfusions. Treatment strategy is mostly (65%) based on the location of the ADs. Small bowel ADs are considered the most difficult to treat, because of the need for balloon enteroscopy. Of the gastroenterologists, 13% would treat ADs as a coincident finding during endoscopy. Medical therapy is mostly started in refractory ADs, and thalidomide (40%) is preferred over octreotide (19%). Thalidomide is more preferred by gastroenterologists working in a teaching hospital. CONCLUSION: Identification of risk factors and treatment of ADs vary widely between gastroenterologists in the Netherlands. Further research is needed to create an evidence-based guideline and thereby optimize the management of symptomatic ADs. PMID- 27227689 TI - Seventeen Novel Mutations in PCCA and PCCB Genes in Indian Propionic Acidemia Patients, and Their Outcomes. AB - AIMS: The goal of this study was to identify mutations in the propionyl-CoA carboxylase alpha subunit (PCCA) and propionyl-CoA carboxylase beta subunit (PCCB) genes, and to assess their effects on propionic academia (PA) patients. METHODOLOGY: Twenty-five Indian children with PA were enrolled in this study. Bidirectional Sanger sequencing was performed on both the coding and flanking regions of the PCCA and PCCB genes and the chromatograms were analyzed. Bioinformatic tools were used to classify novel variations into pathogenic or benign. RESULTS: The majority of the cases (19/25, 76%) were of the early-onset (<90 days of age) type and 5 were of the late-onset type. The majority of patients had mutations in the PCCA gene (18/25). A total of 26 mutations were noted: 20 in the PCCA gene and 6 in PCCB gene. Seventeen mutations were novel (14 in PCCA and 3 in PCCB). The SNP c.937C>T (p.Arg313Ter), was noted in 9/36 (25%) alleles in the PCCA gene. All of the children were symptomatic and only three survived who are doing well with no major disabilities. CONCLUSION: The spectrum of mutations in the PCCA and PCCB genes among Indians is distinct from other populations. The absence of a common mutation signifies the heterogeneity and admixture of various subpopulations. These findings also suggest that individuals of Indian origin may not benefit from the mutation-based "carrier screening panels" offered by many genetic laboratories. PMID- 27227690 TI - Evaluation of Water Exchange Kinetics on [Ln(AAZTAPh-NO2)(H2O)q](x) Complexes Using Proton Nuclear Magnetic Resonance. AB - Water exchange kinetics on [Ln(AAZTAPh-NO2)(H2O)q](-) (Ln = Gd(3+), Dy(3+), or Tm(3+)) were determined by (1)H nuclear magnetic resonance (NMR) measurements. The number of inner-sphere water molecules was found to change from two to one when going from Dy(3+) to Tm(3+). The calculated water exchange rate constants obtained by variable-temperature proton transverse relaxation rates are 3.9 * 10(6), 0.46 * 10(6), and 0.014 * 10(6) s(-1) at 298 K for Gd(3+), Dy(3+), and Tm(3+), respectively. Variable-pressure measurements were used to assess the water exchange mechanism. The results indicate an associative and dissociative interchange mechanism for Gd(3+) and Dy(3+) complexes with DeltaV(?) values of 1.4 and 1.9 cm(3) mol(-1), respectively. An associative activation mode (Ia or A mechanism) was obtained for the Tm(3+) complex (DeltaV(?) = -5.6 cm(3) mol(-1)). Moreover, [Dy(AAZTAPh-NO2)(H2O)2](-) with a very high transverse relaxivity value was found as a potential candidate for negative contrast agents for high-field imaging applications. PMID- 27227691 TI - Ultramicronized palmitoylethanolamide in spinal cord injury neuropathic pain: a randomized, double-blind, placebo-controlled trial. AB - Neuropathic pain and spasticity after spinal cord injury (SCI) represent significant problems. Palmitoylethanolamide (PEA), a fatty acid amide that is produced in many cells in the body, is thought to potentiate the action of endocannabinoids and to reduce pain and inflammation. This randomized, double blind, placebo-controlled, parallel multicenter study was performed to investigate the effect of ultramicronized PEA (PEA-um) as add-on therapy on neuropathic pain in individuals with SCI. A pain diary was completed and questionnaires were completed before and after the 12-week treatment with either placebo or PEA-um. The primary outcome measure was the change in mean neuropathic pain intensity from the 1-week baseline period to the last week of treatment measured on a numeric rating scale ranging from 0 to 10. The primary efficacy analysis was the intention to treat (baseline observation carried forward). Secondary outcomes included a per protocol analysis and effects on spasticity, evoked pain, sleep problems, anxiety, depression, and global impression of change. We randomized 73 individuals with neuropathic pain due to SCI, of which 5 had a major protocol violation, and thus 68 were included in the primary analysis. There was no difference in mean pain intensity between PEA-um and placebo treatment (P = 0.46, mean reductions in pain scores 0.4 (-0.1 to 0.9) vs 0.7 (0.2-1.2); difference of means 0.3 (-0.4 to 0.9)). There was also no effect of PEA-um as add-on therapy on spasticity, insomnia, or psychological functioning. PEA was not associated with more adverse effects than placebo. PMID- 27227692 TI - Cognitive behavioral therapy for chronic pain is effective, but for whom? AB - Moderator analyses are reported for posttreatment outcomes in a large, randomized, controlled effectiveness trial for chronic pain for hip and knee osteoarthritis (N = 256). Pain Coping Skills Training, a form of cognitive behavioral therapy, was compared to usual care. Treatment was delivered by nurse practitioners in patients' community doctors' offices. Consistent with meta analyses of pain cognitive behavioral therapy efficacy, treatment effects in this trial were significant for several primary and secondary outcomes, but tended to be small. This study was designed to examine differential response to treatment for patient subgroups to guide clinical decision-making for treatment. Based on existing literature, demographic (age, sex, race/ethnicity, and education) and clinical variables (disease severity, body mass index, patient treatment expectations, depression, and patient pain coping style) were specified a priori as potential moderators. Trial outcome variables (N = 15) included pain, fatigue, self-efficacy, quality of life, catastrophizing, and use of pain medication. Results yielded 5 significant moderators for outcomes at posttreatment: pain coping style, patient expectation for treatment response, radiographically assessed disease severity, age, and education. Thus, sex, race/ethnicity, body mass index, and depression at baseline were not associated with level of treatment response. In contrast, patients with interpersonal problems associated with pain coping did not benefit much from the treatment. Although most patients projected positive expectations for the treatment prior to randomization, only those with moderate to high expectations benefited. Patients with moderate to high osteoarthritis disease severity showed stronger treatment effects. Finally, the oldest and most educated patients showed strong treatment effects, while younger and less educated did not. PMID- 27227693 TI - Adolescent context of exposure to prescription opioids and substance use disorder symptoms at age 35: a national longitudinal study. AB - The objective of this study was to examine the association of context of prescription opioid exposure (ie, medical or nonmedical) in adolescence with the subsequent risk of nonmedical use of prescription opioids (NMUPO) and substance use disorder (SUD) symptoms at age 35. Multiple cohorts of nationally representative probability samples of U.S. high school seniors (n = 4072) were surveyed through self-administered questionnaires and followed longitudinally from adolescence (modal age 18, graduating classes 1976-1996) to age 35 (1993 2013). Main outcome measures were past-year NMUPO and SUD symptoms. The medical and NMUPO during adolescence was significantly associated with NMUPO at age 35. Relative to no prescription opioid exposure, medical use of prescription opioids without any history of NMUPO during adolescence was not associated with SUD symptoms at age 35. In contrast, compared with no prescription opioid exposure during adolescence, the adjusted odds ratios (AORs) associated with SUD symptoms at age 35 were greater among those with a history of both medical use of prescription opioids and NMUPO during adolescence, AOR = 1.49 (95% CI = 1.13 1.97); and among those who reported NMUPO only, AOR = 2.61 (95% CI = 1.88-3.61). The findings indicate medical use of prescription opioids without any history of NMUPO in adolescence is not associated with SUD symptoms at age 35, whereas any NMUPO in adolescence predicts SUD symptoms at age 35. Screening instruments and preventive intervention programs to reduce NMUPO and SUDs must account for the context associated with prescription opioid exposure during adolescence. PMID- 27227694 TI - Rapid identification of bacteria associated with Acute Oak Decline by high resolution melt analysis. AB - Two Gram-negative Enterobacteriaceae, Gibbsiella quercinecans and Brenneria goodwinii, are frequently isolated from oak suffering from Acute Oak Decline. These two species are difficult to identify based on colony morphology, carbohydrate utilization or 16S rRNA gene sequence, and identification using gyrB gene sequencing is time-consuming and laborious. A rapid identification technique, based on high-resolution melt analysis of the atpD gene, was designed to efficiently process numerous isolates from an increasing number of affected woodlands and parks. Principal component analysis of the resulting melt curves from strains of G. quercinecans, B. goodwinii and their close phylogenetic relatives allowed differentiation into distinct clusters based on species or subspecies identity. SIGNIFICANCE AND IMPACT OF THE STUDY: Acute Oak Decline is an increasing threat to Britain's native oak population. Two novel bacterial species both belonging to the family Enterobacteriaceae, Gibbsiella quercinecans and Brenneria goodwinii, are thought to play an important role in symptom development. Here, we describe a rapid identification technique using high resolution melt analysis of the atpD gene able to assign isolates to either G. quercinecans or B. goodwinii in a single assay, greatly reducing the time taken to identify if either or both of these species are present in symptomatic oak. PMID- 27227695 TI - Biomaterials for intervertebral disc regeneration: past performance and possible future strategies. AB - Intervertebral disc (IVD) degeneration is associated with most cases of cervical and lumbar spine pathologies, amongst which chronic low back pain has become the number one cause of loss of quality-adjusted life years. In search of alternatives to the current less than optimal and usually highly invasive treatments, regenerative strategies are being devised, none of which has reached clinical practice as yet. Strategies include the use of stem cells, gene therapy, growth factors and biomaterial carriers. Biomaterial carriers are an important component in musculoskeletal regenerative medicine techniques. Several biomaterials, both from natural and synthetic origin, have been used for regeneration of the IVD in vitro and in vivo. Aspects such as ease of use, mechanical properties, regenerative capacity, and their applicability as carriers for regenerative and anti-degenerative factors determine their suitability for IVD regeneration. The current review provides an overview of the biomaterials used with respect to these properties, including their drawbacks. In addition, as biomaterial application until now appears to have been based on a mix of mere availability and intuition, a more rational design is proposed for future use of biomaterials for IVD regeneration. Ideally, high-throughput screening is used to identify optimally effective materials, or alternatively medium content comparative studies should be carried out to determine an appropriate reference material for future studies on novel materials. PMID- 27227696 TI - Detached concern?: Emotional socialization in twenty-first century medical education. AB - Early works in medical sociology have been pivotal in the development of scholarly knowledge about emotions, emotional socialization, and empathy within medical training, medical education, and medical contexts. Yet despite major shifts in both medical education and in medicine writ-large, medical sociologists' focus on emotions has largely disappeared. In this paper, we argue that due to recent radical transformations in the medical arena, emotional socialization within medical education should be of renewed interest for sociologists. Developments in medical education such as increased diversity among enrollees, the rise of patient health movements, and curricular transformation have made this context a particularly interesting case for sociologists working on a variety of questions related to structural, organizational, and cultural change. We offer three areas of debate within studies in medical education that sociologists may be interested in studying: 1) gendered and racialized differences in the performance of clinical skills related to emotion, 2) differences in self-reported empathy among subspecialties, and 3) loss of empathy during the third year or clinical year of medical school. PMID- 27227697 TI - Desire for weight loss, weight-related social contact, and body mass outcomes. AB - OBJECTIVE: This study evaluated whether desiring to lose weight is associated with subsequent changes in social contact with individuals perceived to be thinner or heavier. METHODS: Longitudinal data were used to examine associations between desiring to lose weight at baseline and social contact with thinner and heavier individuals across a 1-year follow-up period (N = 9,335, 2013-2014 Gallup National Panel). How baseline social contact is linked to body mass outcomes among those desiring to lose weight (N = 7,134) was also examined. RESULTS: Over time, individuals desiring to lose weight interacted more frequently (+69 interactions/year, on average) and were more likely to possess social ties (tie probability +0.12) with heavier individuals while lessening their interactions ( 51 interactions/year) and decreasing their likelihood of ties (tie probability 0.048) with thinner individuals. On the other hand, increasing contacts and interactions with thinner individuals, and declining contacts and interactions with heavier individuals, were linked to actual weight loss. CONCLUSIONS: Using national longitudinal data, an important mismatch was demonstrated between the social contacts created by individuals desiring weight loss and the contextual factors possibly useful for weight loss. This may help to explain why weight loss is often unsuccessful. PMID- 27227698 TI - Steroidogenic Factor 1, Pit-1, and Adrenocorticotropic Hormone: A Rational Starting Place for the Immunohistochemical Characterization of Pituitary Adenoma. AB - CONTEXT: -Pituitary adenoma classification is complex, and diagnostic strategies vary greatly from laboratory to laboratory. No optimal diagnostic algorithm has been defined. OBJECTIVE: -To develop a panel of immunohistochemical (IHC) stains that provides the optimal combination of cost, accuracy, and ease of use. DESIGN: -We examined 136 pituitary adenomas with stains of steroidogenic factor 1 (SF-1), Pit-1, anterior pituitary hormones, cytokeratin CAM5.2, and alpha subunit of human chorionic gonadotropin. Immunohistochemical staining was scored using the Allred system. Adenomas were assigned to a gold standard class based on IHC results and available clinical and serologic information. Correlation and cluster analyses were used to develop an algorithm for parsimoniously classifying adenomas. RESULTS: -The algorithm entailed a 1- or 2-step process: (1) a screening step consisting of IHC stains for SF-1, Pit-1, and adrenocorticotropic hormone; and (2) when screening IHC pattern and clinical history were not clearly gonadotrophic (SF-1 positive only), corticotrophic (adrenocorticotropic hormone positive only), or IHC null cell (negative-screening IHC), we subsequently used IHC for prolactin, growth hormone, thyroid-stimulating hormone, and cytokeratin CAM5.2. CONCLUSIONS: -Comparison between diagnoses generated by our algorithm and the gold standard diagnoses showed excellent agreement. When compared with a commonly used panel using 6 IHC for anterior pituitary hormones plus IHC for a low-molecular-weight cytokeratin in certain tumors, our algorithm uses approximately one-third fewer IHC stains and detects gonadotroph adenomas with greater sensitivity. PMID- 27227699 TI - Defining adherence to prophylaxis in haemophilia. PMID- 27227700 TI - Role of miR-155 in the regulation of MMP-16 expression in intervertebral disc degeneration. AB - The molecular mechanisms of intervertebral disc degeneration (IDD) remain elusive. We found that miR-155 is down-regulated in degenerative nucleus pulposus (NP), and more severe degeneration is correlated with higher matrix metallopeptidase 16 (MMP-16) expression. MMP-16 also degraded matrix aggrecan. Here, we addressed the in vivo miR-155-mediated pathological impact on IDD using a classic puncture mouse model. Lentiviral upregulated-miR-155 or downregulated miR-155 was transduced into the discs of C57 mice, which was validated by real time polymerase chain reaction (real-time PCR) and in situ hybridization. Immunohistochemistry and western blotting revealed that up-regulation of miR-155 resulted in down-regulation of MMP-16 and an increase in aggrecan and collagen type II in mouse NP; whereas, down-regulation of miR-155 resulted in up regulation of MMP-16 and a decrease in aggrecan in mouse NP. Radiographic and histological analysis showed that the up-regulation of miR-155 attenuated IDD, while down-regulation of miR-155 resulted in the deterioration of IDD. These findings indicate that decreased miR-155 contributed to the up-regulation of MMP 16 in vivo, and MMP-16 further degraded aggrecan and collagen type II, leading to the dehydration and degeneration of discs. Our findings revealed a therapeutic role for miR-155 in IDD. (c) 2017 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 35:1323-1334, 2017. PMID- 27227702 TI - Measuring fluctuations in paranoia: Validity and psychometric properties of brief state versions of the Paranoia Checklist. AB - Research increasingly assesses momentary changes in paranoia in order to elucidate causal mechanisms. Observed or manipulated changes in postulated causal factors should result in fluctuations in state paranoid ideation. Previous studies often employed a state-adapted Paranoia Checklist (Freeman et al., 2005) to measure state paranoia. This study examined whether the Paranoia Checklist or subsets of its items are appropriate for this purpose. Thirteen studies (N=860) were subjected to meta-analyses of each Paranoia Checklist item. We selected items based on (1) whether they showed pre-to-post change in the expected direction and (2) whether this effect was larger in experimental vs. control conditions. All resulting item selections were cross-validated on a hold-out sample (n=1893). Finally, we explored how much variation in paranoia was captured by the state-adapted version in a brief ambulatory assessment study (N=32). A thirteen item State Paranoia Checklist as well as a five item and a three item Brief State Paranoia Checklist were extracted. Cross validation revealed better model fit and increased sensitivity to change. Multilevel analysis indicated 25 30% of the variance in the Brief State Paranoia Checklists to be due to intra individual daily fluctuations in paranoia. Our analyses produced reliable and valid revised scales. Increases in change sensitivity indicate that future assessment of state paranoia in experimental and ambulatory assessment studies can be optimized by using the revised scales. PMID- 27227701 TI - Inflammatory cytokines and nuclear factor-kappa B activation in adolescents with bipolar and major depressive disorders. AB - Adults with bipolar disorder (BD) and major depressive disorder (MDD) have higher circulating levels of proinflammatory cytokines than healthy controls. However, it is not known whether pediatric-onset patients with BD or MDD show increases in levels of inflammation or activation of nuclear factor kappa B (NF-kappaB), a key transcription factor in inflammatory signaling. Circulating levels of inflammatory cytokines, as well as spontaneous and stimulated levels of activated NF-kappaB in total peripheral blood mononuclear cells, monocytes and lymphocytes were measured in adolescents with BD (n=18), MDD (n=13), or no psychiatric history (n=20). Participants had a range of mood symptoms at time of testing. Adolescents with BD had significantly higher spontaneous levels of NF-kappaB in peripheral blood mononuclear cells, monocyte and lymphocyte populations, and higher plasma levels of IL-1beta than healthy controls. Following stimulation with recombinant human TNF-alpha, participants with BD and MDD both had greater increases in NF-kappaB in monocytes than controls. Further, greater stimulated increases of NF-kappaB in monocytes were associated with the current severity of depressive symptoms. The results are limited by the small sample and cross sectional design. Interventions that target early immunological dysregulation should be examined in relation to long-term outcomes in youth with bipolar and depressive disorders. CLINICAL TRIAL REGISTRATION INFORMATION: Early Intervention for Youth at Risk for Bipolar Disorder, https://clinicaltrials.gov/ct2/show/NCT01483391. PMID- 27227703 TI - Application of functional analysis methods to assess human-dog interactions. AB - Research on owner-dog relationships suggests that they have remarkable features, paralleling those of infant to parents. In this study, we investigated whether, after being separated, access to the owner would function as a reinforcer for domestic dog behavior. We then conducted a functional analysis to determine the specific functional reinforcer (e.g., owner access, attention). Our results demonstrate that owner access can function as a reinforcer. This has implications for understanding the owner-dog relationship and using owner access as a training tool. PMID- 27227705 TI - Source localization of S-cone and L/M-cone driven signals using silent substitution flash stimulation. AB - This study aimed to analyze the neuronal sources of the visual evoked potentials after flash stimulation of the S- and the L/M-cone driven channels of the visual system. For 11 volunteers a 64-channel electroencephalography (EEG) was recorded during selective excitation of both color opponent channels. Individual and grand average data were analyzed topographically. Source localization was carried out using a realistically shaped three compartment boundary element model (BEM) and a mirrored moving dipole model. We found two main components (N1, P1) in all subjects, as well as a third late component in most subjects. For these components significant latency differences (N1=33 ms, P1=22 ms; p<0.05) between both color opponent channels were found. The results showed no differences in the topography and no differences in dipole localization between both color channels. Talairach coordinates of grand averages indicated activation in area 18. Comparison of results of separately stimulated eyes revealed no differences. Our findings showed that neural processing occurs in the same areas of the visual cortex for stimuli with different spectral properties. The signals of S- and L/M cone driven channels are transmitted in distinct pathways to the cortex. Thus, the observed latency differences might be caused by different anatomical and functional properties of these pathways. PMID- 27227704 TI - Measured cardiorespiratory fitness and self-reported physical activity: associations with cancer risk and death in a long-term prospective cohort study. AB - Physical activity is inversely associated with risk of some cancers. The relation with cancer-specific death remains uncertain. Mainly, studies on relationships between physical activity and cancer are based on self-reported physical activity (SPA). Hereby, we examined whether measured cardiorespiratory fitness (CRF) is associated with cancer risk, mortality, and case fatality. We also describe relationships between SPA and these outcomes, and between CRF and SPA. A cohort of 1997 healthy Norwegian men, aged 40-59 years at inclusion in 1972-75, was followed throughout 2012. At baseline, CRF was objectively measured. SPA (leisure time and occupational) was obtained through a questionnaire. Relationships between CRF or SPA, and the outcomes were estimated using Cox regression, adjusted for age, body mass index (BMI), and smoking. Pearson correlation coefficients evaluated agreements between CRF and SPA. During follow-up, 758 men were diagnosed with cancer and 433 cancer deaths occurred. Analyses revealed lower cancer risk (Hazard ratio [HR] 0.85, 95% confidence intervals [CI]: 0.68 1.00), mortality (HR 0.68, 95% CI: 0.53-0.88), and case fatality (HR 0.74, 95% CI: 0.57-0.96), in men with high CRF compared to low CRF. Light leisure time SPA was associated with lower cancer risk (HR 0.70, 95% CI: 0.56-0.86) and mortality (HR 0.64 95% CI: 0.49-0.83), whereas strenuous occupational SPA was associated with higher risks (HR 1.42, 95% CI: 1.13-1.78 and HR 1.45, 95% CI: 1.09-1.93). Correlations between CRF and SPA were 0.351 (P < 0.001) and -0.106 (P < 0.001) for leisure time and occupational SPA, respectively. A high midlife CRF may be beneficial for cancer risk, cancer mortality, and case fatality. PMID- 27227706 TI - The face towards nature. PMID- 27227707 TI - The role of socioeconomic position as an effect-modifier of the association between outdoor air pollution and children's asthma exacerbations: an equity focused systematic review. AB - BACKGROUND: The role of socioeconomic position (SEP) as an effect modifier of the association between asthma exacerbations and outdoor air pollution remains unclear. OBJECTIVE: To identify and summarize the evidence regarding SEP as an effect modifier of the association between asthma exacerbations and outdoor air pollution in children. METHODS: We conducted searches in five electronic databases from January 1950 to June 2015 with no language restriction. Observational studies involving children, measuring any non-biological outdoor air pollutant exposure, resulting in any asthma-related health service use, and reporting measures of effect by individual or aggregated SEP measures were included. RESULTS: Ten studies met the inclusion criteria. Five studies reported on hospitalizations, three on emergency department visits, one on ambulatory visits, and one on repeat hospital visits. Six studies identified differential effects of the effect of air pollution on asthma outcomes by SEP with stronger effects for children with a low SEP level; however, the analysis of interaction between air pollutants and SEP was significant in one study of asthma hospitalizations only. The differential effect was reported using individual and aggregated SEP measures. CONCLUSION: This review reveals that there is weak evidence of SEP as an effect-modifier of the association between air pollution and children's asthma exacerbations. While stronger negative effects on asthma related hospitalizations occur for children living in a lower SEP, the sample size of some of the original studies limited the statistical assessment of the modification effect. PMID- 27227708 TI - The effect of centrifugation speed and time on pre-analytical platelet activation. AB - BACKGROUND: The results of laboratory analyses are affected by pre-analytical variables, and in particular can platelets be activated by shear handling stress and secrete granular substances. We therefore evaluated the effect of centrifugation speed and time on pre-analytical platelet activation. METHODS: Citrate- and EDTA-anticoagulated blood from healthy volunteers were centrifuged at 80-10,000 g for 5-15 min to prepare plasma and platelet-rich plasma. Pre analytical platelet activation was assessed by flow cytometric measurement of platelet P-selectin (CD62p) expression. Blood cell counts, mean platelet volume (MPV), immature platelet fraction (IPF), and platelet distribution width (PDW) were measured. Platelet aggregation in platelet-rich plasma induced by arachidonic acid (AA), ADP or thrombin receptor activator peptide-6 (TRAP) was tested by 96-well aggregometry. RESULTS: The median percentage of platelets expressing P-selectin in citrate- and EDTA-plasma centrifuged at 2000 g for 10 min were 43% [interquartile range (IQR), 38%-53%] and 56% (IQR, 31%-78%), respectively (p=0.82). Platelet-rich plasma prepared at 100-250 g for 10 min had significantly lower platelet P-selectin expression (11%-15%), p<0.001. Platelet count in plasma samples decreased with increasing speed but platelets were only completely removed if plasma was re-centrifuged. In platelet-rich plasma, increasing centrifugation speed significantly increased platelet yield but decreased contamination from other blood cells, platelet composition was altered as platelet parameters (MPV, IPF, and PDW) was lowered. Platelet aggregation was not affected by the centrifugation speed platelet-rich plasma was prepared. CONCLUSIONS: Proportional to centrifugation speed, platelets in plasma and platelet-rich plasma were activated with centrifugation speed, cell content and composition changed while platelet aggregation was unaltered. PMID- 27227709 TI - Evaluation of antiphospholipid antibody assays using latent class analysis to address the lack of a reference standard. AB - BACKGROUND: Method evaluation of new assays for the detection of antiphospholipid antibodies (aPL) such as anti-cardiolipin (aCL) or anti-beta2-glycoprotein I (abeta2-GPI) is challenging, as no internationally accepted reference material is available yet. Besides a lack of standardization, unacceptable inter-laboratory comparability of established tests is regularly observed. Owing to the absence of a commonly accepted reference standard, the evaluation of two research surface plasmon resonance (SPR) biosensor assays was performed using statistical methods from latent class analysis (LCA). METHODS: aCL and abeta2-GPI IgG and IgM were measured in sera from 63 antiphospholipid syndrome patients, fulfilling the Sydney criteria, and in 34 healthy controls with four commercial assays. LCA was performed on the results and sera were assigned to the antibody-positive or antibody-negative group. Sera were subsequently evaluated in the SPR assays for aCL and abeta2-GPI. Optimal cutoffs and diagnostic performances of the research systems were established employing the LCA-derived gold standard. RESULTS: With area under the curve results of 0.96 and 0.89 for the detection of aCL and abeta2 GPI, the research SPR assays discriminated well between antibody-positive and antibody-negative sera. Their sensitivities and specificities were comparable to the investigated commercial immunoassays. CONCLUSIONS: SPR assays are a suitable tool for the detection of aCL and abeta2-GPI with diagnostic performances not different from currently available commercial tests. LCA enabled the calculation of sensitivities and specificities for aPL assays in absence of a reference standard. PMID- 27227710 TI - Detection of the heterozygote of hemoglobin Constant Spring by alpha-thalassemia immunochromatographic strip test. PMID- 27227711 TI - Uncertainty in measurement and total error - are they so incompatible? AB - There appears to be a growing debate with regard to the use of "Westgard style" total error and "GUM style" uncertainty in measurement. Some may argue that the two approaches are irreconcilable. The recent appearance of an article "Quality goals at the crossroads: growing, going, or gone" on the well-regarded Westgard Internet site requires some comment. In particular, a number of assertions which relate to ISO 15189 and uncertainty in measurement appear misleading. An alternate view of the key issues raised by Westergard may serve to guide and enlighten others who may accept such statements at face value. PMID- 27227712 TI - Evidence that neuropeptide FF receptor type 1 is not the physiological unacylated ghrelin receptor. PMID- 27227713 TI - Hyperglycemic memory in metabolism and cancer. AB - Hyperglycemia is a hallmark of both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Recent evidence strongly suggests that prolonged exposure to hyperglycemia can epigenetically modify gene expression profiles in human cells and that this effect is sustained even after hyperglycemic control is therapeutically achieved; this phenomenon is called hyperglycemic memory. This metabolic memory effect contributes substantially to the pathology of various diabetic complications, such as diabetic retinopathy, hypertension, and diabetic nephropathy. Due to the metabolic memory in cells, diabetic patients suffer from various complications, even after hyperglycemia is controlled. With regard to this strong association between diabetes and cancer risk, cancer cells have emerged as key target cells of hyperglycemic memory in diabetic cancer patients. In this review, we will discuss the recent understandings of the molecular mechanisms underlying hyperglycemic memory in metabolism and cancer. PMID- 27227714 TI - Special Issue on Data-Adaptive Statistical Inference. PMID- 27227715 TI - Statistical Inference for Data Adaptive Target Parameters. AB - Consider one observes n i.i.d. copies of a random variable with a probability distribution that is known to be an element of a particular statistical model. In order to define our statistical target we partition the sample in V equal size sub-samples, and use this partitioning to define V splits in an estimation sample (one of the V subsamples) and corresponding complementary parameter-generating sample. For each of the V parameter-generating samples, we apply an algorithm that maps the sample to a statistical target parameter. We define our sample split data adaptive statistical target parameter as the average of these V-sample specific target parameters. We present an estimator (and corresponding central limit theorem) of this type of data adaptive target parameter. This general methodology for generating data adaptive target parameters is demonstrated with a number of practical examples that highlight new opportunities for statistical learning from data. This new framework provides a rigorous statistical methodology for both exploratory and confirmatory analysis within the same data. Given that more research is becoming "data-driven", the theory developed within this paper provides a new impetus for a greater involvement of statistical inference into problems that are being increasingly addressed by clever, yet ad hoc pattern finding methods. To suggest such potential, and to verify the predictions of the theory, extensive simulation studies, along with a data analysis based on adaptively determined intervention rules are shown and give insight into how to structure such an approach. The results show that the data adaptive target parameter approach provides a general framework and resulting methodology for data-driven science. PMID- 27227716 TI - Evaluations of the Optimal Discovery Procedure for Multiple Testing. AB - The Optimal Discovery Procedure (ODP) is a method for simultaneous hypothesis testing that attempts to gain power relative to more standard techniques by exploiting multivariate structure [1]. Specializing to the example of testing whether components of a Gaussian mean vector are zero, we compare the power of the ODP to a Bonferroni-style method and to the Benjamini-Hochberg method when the testing procedures aim to respectively control certain Type I error rate measures, such as the expected number of false positives or the false discovery rate. We show through theoretical results, numerical comparisons, and two microarray examples that when the rejection regions for the ODP test statistics are chosen such that the procedure is guaranteed to uniformly control a Type I error rate measure, the technique is generally less powerful than competing methods. We contrast and explain these results in light of previously proven optimality theory for the ODP. We also compare the ordering given by the ODP test statistics to the standard rankings based on sorting univariate p-values from smallest to largest. In the cases we considered the standard ordering was superior, and ODP rankings were adversely impacted by correlation. PMID- 27227717 TI - Model-Based Recursive Partitioning for Subgroup Analyses. AB - The identification of patient subgroups with differential treatment effects is the first step towards individualised treatments. A current draft guideline by the EMA discusses potentials and problems in subgroup analyses and formulated challenges to the development of appropriate statistical procedures for the data driven identification of patient subgroups. We introduce model-based recursive partitioning as a procedure for the automated detection of patient subgroups that are identifiable by predictive factors. The method starts with a model for the overall treatment effect as defined for the primary analysis in the study protocol and uses measures for detecting parameter instabilities in this treatment effect. The procedure produces a segmented model with differential treatment parameters corresponding to each patient subgroup. The subgroups are linked to predictive factors by means of a decision tree. The method is applied to the search for subgroups of patients suffering from amyotrophic lateral sclerosis that differ with respect to their Riluzole treatment effect, the only currently approved drug for this disease. PMID- 27227718 TI - The Orthogonally Partitioned EM Algorithm: Extending the EM Algorithm for Algorithmic Stability and Bias Correction Due to Imperfect Data. AB - We propose an extension of the EM algorithm that exploits the common assumption of unique parameterization, corrects for biases due to missing data and measurement error, converges for the specified model when standard implementation of the EM algorithm has a low probability of convergence, and reduces a potentially complex algorithm into a sequence of smaller, simpler, self-contained EM algorithms. We use the theory surrounding the EM algorithm to derive the theoretical results of our proposal, showing that an optimal solution over the parameter space is obtained. A simulation study is used to explore the finite sample properties of the proposed extension when there is missing data and measurement error. We observe that partitioning the EM algorithm into simpler steps may provide better bias reduction in the estimation of model parameters. The ability to breakdown a complicated problem in to a series of simpler, more accessible problems will permit a broader implementation of the EM algorithm, permit the use of software packages that now implement and/or automate the EM algorithm, and make the EM algorithm more accessible to a wider and more general audience. PMID- 27227719 TI - A Sequential Rejection Testing Method for High-Dimensional Regression with Correlated Variables. AB - We propose a general, modular method for significance testing of groups (or clusters) of variables in a high-dimensional linear model. In presence of high correlations among the covariables, due to serious problems of identifiability, it is indispensable to focus on detecting groups of variables rather than singletons. We propose an inference method which allows to build in hierarchical structures. It relies on repeated sample splitting and sequential rejection, and we prove that it asymptotically controls the familywise error rate. It can be implemented on any collection of clusters and leads to improved power in comparison to more standard non-sequential rejection methods. We complement the theoretical analysis with empirical results for simulated and real data. PMID- 27227720 TI - A Case Study of the Impact of Data-Adaptive Versus Model-Based Estimation of the Propensity Scores on Causal Inferences from Three Inverse Probability Weighting Estimators. AB - OBJECTIVE: Consistent estimation of causal effects with inverse probability weighting estimators is known to rely on consistent estimation of propensity scores. To alleviate the bias expected from incorrect model specification for these nuisance parameters in observational studies, data-adaptive estimation and in particular an ensemble learning approach known as Super Learning has been proposed as an alternative to the common practice of estimation based on arbitrary model specification. While the theoretical arguments against the use of the latter haphazard estimation strategy are evident, the extent to which data adaptive estimation can improve inferences in practice is not. Some practitioners may view bias concerns over arbitrary parametric assumptions as academic considerations that are inconsequential in practice. They may also be wary of data-adaptive estimation of the propensity scores for fear of greatly increasing estimation variability due to extreme weight values. With this report, we aim to contribute to the understanding of the potential practical consequences of the choice of estimation strategy for the propensity scores in real-world comparative effectiveness research. METHOD: We implement secondary analyses of Electronic Health Record data from a large cohort of type 2 diabetes patients to evaluate the effects of four adaptive treatment intensification strategies for glucose control (dynamic treatment regimens) on subsequent development or progression of urinary albumin excretion. Three Inverse Probability Weighting estimators are implemented using both model-based and data-adaptive estimation strategies for the propensity scores. Their practical performances for proper confounding and selection bias adjustment are compared and evaluated against results from previous randomized experiments. CONCLUSION: Results suggest both potential reduction in bias and increase in efficiency at the cost of an increase in computing time when using Super Learning to implement Inverse Probability Weighting estimators to draw causal inferences. PMID- 27227721 TI - AUC-Maximizing Ensembles through Metalearning. AB - Area Under the ROC Curve (AUC) is often used to measure the performance of an estimator in binary classification problems. An AUC-maximizing classifier can have significant advantages in cases where ranking correctness is valued or if the outcome is rare. In a Super Learner ensemble, maximization of the AUC can be achieved by the use of an AUC-maximining metalearning algorithm. We discuss an implementation of an AUC-maximization technique that is formulated as a nonlinear optimization problem. We also evaluate the effectiveness of a large number of different nonlinear optimization algorithms to maximize the cross-validated AUC of the ensemble fit. The results provide evidence that AUC-maximizing metalearners can, and often do, out-perform non-AUC-maximizing metalearning methods, with respect to ensemble AUC. The results also demonstrate that as the level of imbalance in the training data increases, the Super Learner ensemble outperforms the top base algorithm by a larger degree. PMID- 27227722 TI - Selection Bias When Using Instrumental Variable Methods to Compare Two Treatments But More Than Two Treatments Are Available. AB - Instrumental variable (IV) methods are widely used to adjust for the bias in estimating treatment effects caused by unmeasured confounders in observational studies. It is common that a comparison between two treatments is focused on and that only subjects receiving one of these two treatments are considered in the analysis even though more than two treatments are available. In this paper, we provide empirical and theoretical evidence that the IV methods may result in biased treatment effects if applied on a data set in which subjects are preselected based on their received treatments. We frame this as a selection bias problem and propose a procedure that identifies the treatment effect of interest as a function of a vector of sensitivity parameters. We also list assumptions under which analyzing the preselected data does not lead to a biased treatment effect estimate. The performance of the proposed method is examined using simulation studies. We applied our method on The Health Improvement Network (THIN) database to estimate the comparative effect of metformin and sulfonylureas on weight gain among diabetic patients. PMID- 27227723 TI - Doubly Robust and Efficient Estimation of Marginal Structural Models for the Hazard Function. AB - In social and health sciences, many research questions involve understanding the causal effect of a longitudinal treatment on mortality (or time-to-event outcomes in general). Often, treatment status may change in response to past covariates that are risk factors for mortality, and in turn, treatment status may also affect such subsequent covariates. In these situations, Marginal Structural Models (MSMs), introduced by Robins (1997. Marginal structural models Proceedings of the American Statistical Association. Section on Bayesian Statistical Science, 1-10), are well-established and widely used tools to account for time-varying confounding. In particular, a MSM can be used to specify the intervention specific counterfactual hazard function, i. e. the hazard for the outcome of a subject in an ideal experiment where he/she was assigned to follow a given intervention on their treatment variables. The parameters of this hazard MSM are traditionally estimated using the Inverse Probability Weighted estimation Robins (1999. Marginal structural models versus structural nested models as tools for causal inference. In: Statistical models in epidemiology: the environment and clinical trials. Springer-Verlag, 1999:95-134), Robins et al. (2000), (IPTW, van der Laan and Petersen (2007. Causal effect models for realistic individualized treatment and intention to treat rules. Int J Biostat 2007;3:Article 3), Robins et al. (2008. Estimaton and extrapolation of optimal treatment and testing strategies. Statistics in Medicine 2008;27(23):4678-721)). This estimator is easy to implement and admits Wald-type confidence intervals. However, its consistency hinges on the correct specification of the treatment allocation probabilities, and the estimates are generally sensitive to large treatment weights (especially in the presence of strong confounding), which are difficult to stabilize for dynamic treatment regimes. In this paper, we present a pooled targeted maximum likelihood estimator (TMLE, van der Laan and Rubin (2006. Targeted maximum likelihood learning. The International Journal of Biostatistics 2006;2:1-40)) for MSM for the hazard function under longitudinal dynamic treatment regimes. The proposed estimator is semiparametric efficient and doubly robust, offering bias reduction over the incumbent IPTW estimator when treatment probabilities may be misspecified. Moreover, the substitution principle rooted in the TMLE potentially mitigates the sensitivity to large treatment weights in IPTW. We compare the performance of the proposed estimator with the IPTW and a on-targeted substitution estimator in a simulation study. PMID- 27227724 TI - Data-Adaptive Bias-Reduced Doubly Robust Estimation. AB - Doubly robust estimators have now been proposed for a variety of target parameters in the causal inference and missing data literature. These consistently estimate the parameter of interest under a semiparametric model when one of two nuisance working models is correctly specified, regardless of which. The recently proposed bias-reduced doubly robust estimation procedure aims to partially retain this robustness in more realistic settings where both working models are misspecified. These so-called bias-reduced doubly robust estimators make use of special (finite-dimensional) nuisance parameter estimators that are designed to locally minimize the squared asymptotic bias of the doubly robust estimator in certain directions of these finite-dimensional nuisance parameters under misspecification of both parametric working models. In this article, we extend this idea to incorporate the use of data-adaptive estimators (infinite dimensional nuisance parameters), by exploiting the bias reduction estimation principle in the direction of only one nuisance parameter. We additionally provide an asymptotic linearity theorem which gives the influence function of the proposed doubly robust estimator under correct specification of a parametric nuisance working model for the missingness mechanism/propensity score but a possibly misspecified (finite- or infinite-dimensional) outcome working model. Simulation studies confirm the desirable finite-sample performance of the proposed estimators relative to a variety of other doubly robust estimators. PMID- 27227725 TI - Optimal Individualized Treatments in Resource-Limited Settings. AB - An individualized treatment rule (ITR) is a treatment rule which assigns treatments to individuals based on (a subset of) their measured covariates. An optimal ITR is the ITR which maximizes the population mean outcome. Previous works in this area have assumed that treatment is an unlimited resource so that the entire population can be treated if this strategy maximizes the population mean outcome. We consider optimal ITRs in settings where the treatment resource is limited so that there is a maximum proportion of the population which can be treated. We give a general closed-form expression for an optimal stochastic ITR in this resource-limited setting, and a closed-form expression for the optimal deterministic ITR under an additional assumption. We also present an estimator of the mean outcome under the optimal stochastic ITR in a large semiparametric model that at most places restrictions on the probability of treatment assignment given covariates. We give conditions under which our estimator is efficient among all regular and asymptotically linear estimators. All of our results are supported by simulations. PMID- 27227726 TI - Super-Learning of an Optimal Dynamic Treatment Rule. AB - We consider the estimation of an optimal dynamic two time-point treatment rule defined as the rule that maximizes the mean outcome under the dynamic treatment, where the candidate rules are restricted to depend only on a user-supplied subset of the baseline and intermediate covariates. This estimation problem is addressed in a statistical model for the data distribution that is nonparametric, beyond possible knowledge about the treatment and censoring mechanisms. We propose data adaptive estimators of this optimal dynamic regime which are defined by sequential loss-based learning under both the blip function and weighted classification frameworks. Rather than a priori selecting an estimation framework and algorithm, we propose combining estimators from both frameworks using a super learning based cross-validation selector that seeks to minimize an appropriate cross-validated risk. The resulting selector is guaranteed to asymptotically perform as well as the best convex combination of candidate algorithms in terms of loss-based dissimilarity under conditions. We offer simulation results to support our theoretical findings. PMID- 27227727 TI - Second-Order Inference for the Mean of a Variable Missing at Random. AB - We present a second-order estimator of the mean of a variable subject to missingness, under the missing at random assumption. The estimator improves upon existing methods by using an approximate second-order expansion of the parameter functional, in addition to the first-order expansion employed by standard doubly robust methods. This results in weaker assumptions about the convergence rates necessary to establish consistency, local efficiency, and asymptotic linearity. The general estimation strategy is developed under the targeted minimum loss based estimation (TMLE) framework. We present a simulation comparing the sensitivity of the first and second-order estimators to the convergence rate of the initial estimators of the outcome regression and missingness score. In our simulation, the second-order TMLE always had a coverage probability equal or closer to the nominal value 0.95, compared to its first-order counterpart. In the best-case scenario, the proposed second-order TMLE had a coverage probability of 0.86 when the first-order TMLE had a coverage probability of zero. We also present a novel first-order estimator inspired by a second-order expansion of the parameter functional. This estimator only requires one-dimensional smoothing, whereas implementation of the second-order TMLE generally requires kernel smoothing on the covariate space. The first-order estimator proposed is expected to have improved finite sample performance compared to existing first-order estimators. In the best-case scenario of our simulation study, the novel first order TMLE improved the coverage probability from 0 to 0.90. We provide an illustration of our methods using a publicly available dataset to determine the effect of an anticoagulant on health outcomes of patients undergoing percutaneous coronary intervention. We provide R code implementing the proposed estimator. PMID- 27227728 TI - One-Step Targeted Minimum Loss-based Estimation Based on Universal Least Favorable One-Dimensional Submodels. AB - Consider a study in which one observes n independent and identically distributed random variables whose probability distribution is known to be an element of a particular statistical model, and one is concerned with estimation of a particular real valued pathwise differentiable target parameter of this data probability distribution. The targeted maximum likelihood estimator (TMLE) is an asymptotically efficient substitution estimator obtained by constructing a so called least favorable parametric submodel through an initial estimator with score, at zero fluctuation of the initial estimator, that spans the efficient influence curve, and iteratively maximizing the corresponding parametric likelihood till no more updates occur, at which point the updated initial estimator solves the so called efficient influence curve equation. In this article we construct a one-dimensional universal least favorable submodel for which the TMLE only takes one step, and thereby requires minimal extra data fitting to achieve its goal of solving the efficient influence curve equation. We generalize these to universal least favorable submodels through the relevant part of the data distribution as required for targeted minimum loss-based estimation. Finally, remarkably, given a multidimensional target parameter, we develop a universal canonical one-dimensional submodel such that the one-step TMLE, only maximizing the log-likelihood over a univariate parameter, solves the multivariate efficient influence curve equation. This allows us to construct a one-step TMLE based on a one-dimensional parametric submodel through the initial estimator, that solves any multivariate desired set of estimating equations. PMID- 27227729 TI - Cerium(III) and Uranium(IV) Complexes of the 2-Fluorophenyl Trimethylsilyl Amide Ligand: C-F -> Ln/An Interactions that Modulate the Coordination Spheres of f Block Elements. AB - 2-fluorophenyl trimethylsilyl amide, N(SiMe3)(C6H4F)(-) was shown to engage in stronger C-F -> Ce(III) interactions than pentafluorophenyl trimethylsilyl amide, N(SiMe3)(C6F5)(-), through a comparative study of the Ce(III) model complexes Ce[N(SiMe3)(C6H4F)]3 (1-F1) and Ce[N(SiMe3)(C6F5)]3 (1-F5). The presence of multiple C-F -> U(IV) interactions led to complexes 2-X (X = Cl, C=CPh, OMe) with threefold geometries, featuring a trigonal pyramidal UN3Cl core in the solid state structures. Density functional theory calculations were applied to 2-Cl to investigate the strength of the C-F -> U(IV) interactions and the influence of such interactions on resulting geometries. PMID- 27227734 TI - Health of Non-Hispanic Asian Adults: United States, 2010-2014. AB - KEY FINDINGS: Data from the National Health Interview Survey, 2010-2014 *Non Hispanic Asian adults were less likely than all U.S. adults to be in fair or poor health, have multiple chronic conditions, have serious psychological distress in the past 30 days, or be limited in work or social participation. *Chinese adults reported better health on all five measures in this report compared with all U.S. adults. *Chinese adults (11.3%) were less likely than Filipino (22.3%), Asian Indian (16.9%), Japanese (16.8%), or Vietnamese (15.6%) adults to have multiple chronic conditions. *Chinese (1.8%) and Asian Indian (1.5%) adults were about one half as likely as Japanese adults (4.1%) to have a work limitation. *Chinese (2.4%), Japanese (2.2%), and Vietnamese (2.4%) adults were about one-half as likely as Korean adults (4.6%) to be limited in social participation. PMID- 27227735 TI - Adipocyte-specific overexpression of retinol-binding protein 4 causes hepatic steatosis in mice. AB - : There is considerable evidence that both retinoids and retinol-binding protein 4 (RBP4) contribute to the development of liver disease. To understand the basis for this, we generated and studied transgenic mice that express human RBP4 (hRBP4) specifically in adipocytes. When fed a chow diet, these mice show an elevation in adipose total RBP4 (mouse RBP4 + hRBP4) protein levels. However, no significant differences in plasma RBP4 or retinol levels or in hepatic or adipose retinoid (retinol, retinyl ester, and all-trans-retinoic acid) levels were observed. Strikingly, male adipocyte-specific hRBP4 mice fed a standard chow diet display significantly elevated hepatic triglyceride levels at 3-4 months of age compared to matched littermate controls. When mice were fed a high-fat diet, this hepatic phenotype, as well as other metabolic phenotypes (obesity and glucose intolerance), worsened. Because adipocyte-specific hRBP4 mice have increased tumor necrosis factor-alpha and leptin expression and crown-like structures in adipose tissue, our data are consistent with the notion that adipose tissue is experiencing RBP4-induced inflammation that stimulates increased lipolysis within adipocytes. Our data further establish that elevated hepatic triglyceride levels result from increased hepatic uptake of adipose-derived circulating free fatty acids. We obtained no evidence that elevated hepatic triglyceride levels arise from increased hepatic de novo lipogenesis, decreased hepatic free fatty acid oxidation, or decreased very-low-density lipoprotein secretion. CONCLUSION: Our investigations establish that RBP4 expressed in adipocytes induces hepatic steatosis arising from primary effects occurring in adipose tissue. (Hepatology 2016;64:1534-1546). PMID- 27227736 TI - Notes from the Field: Expanded Chemoprophylaxis Offered in Response to a Case of Meningococcal Meningitis in an Elementary School - Indiana, 2015. AB - On December 11, 2015, the Fort Wayne-Allen County (Indiana) Department of Health was notified by a local hospital laboratory of a suspected case of meningococcal meningitis based on Gram stain results of cerebrospinal fluid. The county health department interviewed close family members and friends of the patient to establish an infectious period, timeline of events, and possible exposures. Close medical and household contacts were offered chemoprophylaxis (1). This case was associated with an elementary school. The patient had intermittent, close, potentially face-to-face contact with many students, and was reported to have had a persistent, productive cough throughout the exposure period. In light of these unusual circumstances, and the fact that elementary school-aged children are not routinely vaccinated against meningococcal disease,* local and state health officials, with CDC support, decided to offer chemoprophylaxis to the patient's contacts. A total of 581 child and adult contacts were identified. PMID- 27227737 TI - Synthesis and characterization of extremely small gold nanoshells, and comparison of their photothermal conversion capacity with gold nanorods. AB - The current methods for preparing gold nanoshells (AuNSs) produce shells with a diameter of approximately 40 nm or larger, with a relatively large polydispersity. However, AuNSs with smaller diameters and more monodispersity are better suited for biomedical applications. In this work, we present a modified method for the preparation of AuNSs, based on the use of sacrificial silver nanoparticles (AgNPs). We customized the Lee-Meisel method to prepare small and monodisperse AgNPs that were used as sacrificial nanoparticles to prepare extremely small monodispersed AuNSs with an average diameter from 17 to 25 +/- 4 nm. We found that these AuNSs are faceted, and that the oxidized silver likely dissolves out of the nanoparticles through some of the facets on the AuNSs. This leads to a silver oxide plug on the surface of the AuNSs, which has not been reported before. The smaller AuNSs, prepared under the best conditions, absorb in the near infrared region (NIR) that is appropriate for applications, such as photothermal therapy or medical imaging. The AuNSs showed absorption peaks in the NIR similar to those of gold nanorods (AuNRs) but with better photothermal capacity. In addition, because of their negative charge, these AuNSs are more biocompatible than the positively charged AuNRs. The synthesis of small, monodisperse, stable and biocompatible nanoparticles, like the ones presented in this work, is of prime importance in biomedical applications. PMID- 27227738 TI - Single Walled Carbon Nanohorns as Catalytic Counter Electrodes for Co(III)/(II) Electron Mediators in Dye Sensitized Cells. AB - The electrochemical properties of both pristine single walled carbon nanohorns (SWCNHS) and their chemically oxidized form (ox-SWCNHS) spray coated onto fluorine doped SnO2 (FTO) were investigated in the framework of the fabrication of cobalt based transparent dye sensitized solar cells (DSSCs). These new nanocarbon substrates, evaluated in conjunction with the Co(bpy)3(2+/3+) (bpy = 2,2'-bipyridine) redox mediator, are endowed with excellent electrocatalytic properties, ease of fabrication, and very promising stability and display a great potential for replacing the best noble metal and conductive polymer catalytic materials in the building of semitransparent counter electrodes in new generation photoelectrochemical devices. PMID- 27227739 TI - Bleeding patterns of HIV-infected women using an etonogestrel-releasing contraceptive implant and efavirenz-based or lopinavir/ritonavir-based antiretroviral therapy. AB - OBJECTIVES: The use of progestogen-only contraceptives may cause a change in bleeding pattern, which is a common cause of discontinuation of these methods. Co administration with some antiretroviral therapies (ART) changes the bioavailability of the etonogestrel (ENG)-releasing contraceptive implant, possibly affecting the bleeding pattern. Bleeding patterns were evaluated in HIV positive users of the ENG implant co-administered with two common ART regimens. METHODS: Forty-five HIV-positive women who wished to use an ENG implant were included in this study: 15 had received zidovudine/lamivudine (AZT/3TC) + lopinavir/ritonavir (LPV/r) for >=3 months (LPV/r-based ART group), 15 had received AZT/3TC + efavirenz (EFV) for >=3 months (EFV-based ART group), and 15 had not received ART (non-ART group). Bleeding patterns were evaluated at 3 and 6 months after implant placement using a standard bleeding calendar. RESULTS: Amenorrhoea and infrequent bleeding rates were higher in the LPV/r-based ART group (50% and 36%, respectively) than in the other groups (non-ART group, 36% and 29%, respectively; EFV-based ART group, 7% and 14.5%, respectively; p = 0.01). The EFV-based ART group more frequently had regular bleeding (71.5%) compared with the other groups (LPV/r-based ART group, 7%; non-ART group, 21%; p = 0.01). The proportions of women with frequent and prolonged bleeding were similar (p > 0.05) in the three groups. CONCLUSIONS: The co-administration of EFV based or LPV/r-based ART with the ENG implant affected the expected bleeding patterns during use of the implant, although unfavourable bleeding (frequent and prolonged) was not associated with the medications under evaluation. PMID- 27227740 TI - The Structure of the Bimolecular Complex between Amphotericin B and Ergosterol in Membranes Is Stabilized by Face-to-Face van der Waals Interaction with Their Rigid Cyclic Cores. AB - Amphotericin B (AmB) is a polyene macrolide antibiotic isolated from Streptomyces nodosus. The antifungal activity of AmB can be attributed to the formation of an ion-channel assembly in the presence of ergosterol (Erg), in which there are two different AmB-Erg orientations, parallel and antiparallel, as reported previously. In this study, to elucidate the structures of those AmB-Erg complexes based on solid-state nuclear magnetic resonance, a (19)F-labeled AmB derivative was newly prepared by a hybrid synthesis that utilized degradation products from the drug. Using the 2-(trimethylsilyl)ethoxymethyl (SEM) group as the protecting group for the carboxylic acid moiety of AmB, the fully deprotected labeled AmB compounds were obtained successfully. Then, these labeled AmBs were subjected to (13)C{(19)F} rotational-echo double-resonance (REDOR) experiments in hydrated lipid bilayers. The results indicated the coexistence of parallel and antiparallel orientations for AmB and Erg pairing, at a ratio of 7:3. A total of six distances between AmB and Erg were successfully obtained. Geometry analysis using the distance constraints derived from the REDOR experiments provided the plausible AmB-Erg complex structure for both the parallel and antiparallel interactions. The flat macrolide of AmB and the tetracyclic core of Erg closely contacted in a face-to-face manner, thus maximizing the van der Waals interaction between the two molecules. This interaction can be attributed to the coexistence of both the parallel and antiparallel orientations. PMID- 27227744 TI - Letter To the Editor. PMID- 27227743 TI - Erratum. PMID- 27227745 TI - Dynamics of Colonization and Expression of Pathogenicity Related Genes in Fusarium oxysporum f.sp. ciceri during Chickpea Vascular Wilt Disease Progression. AB - Fusarium wilt caused by Fusarium oxysporum f.sp. ciceri (Foc) is a constant threat to chickpea productivity in several parts of the world. Understanding the molecular basis of chickpea-Foc interaction is necessary to improve chickpea resistance to Foc and thereby the productivity of chickpea. We transformed Foc race 2 using green fluorescent protein (GFP) gene and used it to characterize pathogen progression and colonization in wilt-susceptible (JG62) and wilt resistant (Digvijay) chickpea cultivars using confocal microscopy. We also employed quantitative PCR (qPCR) to estimate the pathogen load and progression across various tissues of both the chickpea cultivars during the course of the disease. Additionally, the expression of several candidate pathogen virulence genes was analyzed using quantitative reverse transcriptase PCR (qRT-PCR), which showed their characteristic expression in wilt-susceptible and resistant chickpea cultivars. Our results suggest that the pathogen colonizes the susceptible cultivar defeating its defense; however, albeit its entry in the resistant plant, further proliferation is severely restricted providing an evidence of efficient defense mechanism in the resistant chickpea cultivar. PMID- 27227747 TI - Friedel-Crafts Alkylation of Arenes with 2-Halogeno-2-CF3-styrenes under Superacidic Conditions. Access to Trifluoromethylated Ethanes and Ethenes. AB - The formation of the corresponding benzyl cations [ArHC(+)-CH(X)CF3] takes place under protonation of E-/Z-2-halogeno-2-CF3 styrenes [ArCH?C(X)CF3, X = F, Cl, Br] in superacids. The structures of these new electrophiles were studied by means of NMR and theoretical DFT calculations. According to these data, in the case of bromo derivatives, the formed cations, most probably, exist as cyclic bromonium ions; however, in the cases of chloro and fluoro derivatives, open forms are more preferable. Subsequent reaction of these benzyl cations with arenes proceeds as Friedel-Crafts alkylation to afford 1,1-diaryl-2-halo-3,3,3-trifluoropropanes [Ar(Ar')CH-CH(X)CF3] in high yields (up to 96%) as a mixture of two diastereomers. The prepared halogenopropanes were easily converted into the corresponding mixtures of E-/Z-trifluoromethylated diarylethenes [Ar(Ar')C?CCF3] (in yields up to 96%) by dehydrohalogenation with base (KOH or t-BuOK). The mechanism of elimination (E2 and Ecb) depends on the nature of the leaving group and reaction conditions. PMID- 27227746 TI - Amide Proton Transfer Imaging of Diffuse Gliomas: Effect of Saturation Pulse Length in Parallel Transmission-Based Technique. AB - In this study, we evaluated the dependence of saturation pulse length on APT imaging of diffuse gliomas using a parallel transmission-based technique. Twenty two patients with diffuse gliomas (9 low-grade gliomas, LGGs, and 13 high-grade gliomas, HGGs) were included in the study. APT imaging was conducted at 3T with a 2-channel parallel transmission scheme using three different saturation pulse lengths (0.5 s, 1.0 s, 2.0 s). The 2D fast spin-echo sequence was used for imaging. Z-spectrum was obtained at 25 frequency offsets from -6 to +6 ppm (step 0.5 ppm). A point-by-point B0 correction was performed with a B0 map. Magnetization transfer ratio (MTRasym) and DeltaMTRasym (contrast between tumor and normal white matter) at 3.5 ppm were compared among different saturation lengths. A significant increase in MTRasym (3.5 ppm) of HGG was found when the length of saturation pulse became longer (3.09 +/- 0.54% at 0.5 s, 3.83 +/- 0.67% at 1 s, 4.12 +/- 0.97% at 2 s), but MTRasym (3.5 ppm) was not different among the saturation lengths in LGG. DeltaMTRasym (3.5 ppm) increased with the length of saturation pulse in both LGG (0.48 +/- 0.56% at 0.5 s, 1.28 +/- 0.56% at 1 s, 1.88 +/- 0.56% at 2 s and HGG (1.72 +/- 0.54% at 0.5 s, 2.90 +/- 0.49% at 1 s, 3.83 +/- 0.88% at 2 s). In both LGG and HGG, APT-weighted contrast was enhanced with the use of longer saturation pulses. PMID- 27227748 TI - Comparison of Outcomes Between Patients Treated by Therapeutic Hypothermia for Cardiac Arrest Due to Cardiac or Respiratory Causes. AB - Outcome for patients experiencing out-hospital cardiac arrest (OHCA) due to respiratory causes is poor, even with treatment by therapeutic hypothermia (TH). The purpose of this study is to clarify difference in outcome and respiratory state during resuscitation between cases due to respiratory causes versus those due to cardiac causes, to establish alternative strategies for the patient. This study was conducted as a retrospective analysis of patients with post CA syndrome who underwent TH. Patients were divided into two groups according to cause of CA: cardiac (C group) or respiratory (R group). Utstein Style data, outcome, and arterial blood gas (ABG) findings after emergency room admission of the two groups were compared. Of 74 patients treated with TH during the 2-year study period, 49 were placed in the C group and 19 in the R group. The rates of ventricular fibrillation/pulseless ventricular tachycardia at initial rhythm were significantly higher in the C group than in the R group. The rate of favorable neurological outcome was significantly higher in the C group (15/49: 30.6%) than in the R group (1/19: 5.3%) 30 days after resuscitation. In the ABG findings, PaCO2 was significantly higher in the R group than in the C group. For patients experiencing OHCA from respiratory causes, TH was less effective and PaCO2 accumulated immediately after admission. From this, interpretation of the significance of PaCO2 in these patients at the early stage after return of spontaneous circulation should be seriously considered. PMID- 27227749 TI - Use of an electrochemically-induced proton-coupled electron transfer reaction to control dimerization in a ureidopyrimidone 4 H-bond array. AB - Cyclic voltammetric and spectroelectrochemical evidence is presented showing that the H-bonded dimer formed from a ureidopyrimidone derivative containing a phenylenediamine redox couple can be reversibly broken apart at mM concentrations in CH2Cl2 by an electrochemically induced proton-coupled electron transfer reaction. PMID- 27227750 TI - Fibromyalgia. PMID- 27227752 TI - Clostridium difficile infection. PMID- 27227753 TI - Additions to Funding/Support. PMID- 27227751 TI - Suicidal Ideation During the Postpartum Period. AB - OBJECTIVE: To examine the association between suicidal ideation (SI), 3 weeks, 3 months, and 6 months postpartum with demographic, psychosocial, clinical factors, and depressive/anxiety symptoms (measured 24-48 hours after delivery), among a cohort of postpartum women. METHODS: This study included 1,073 mothers who gave birth in a large tertiary New York City hospital (2009-2010). Later, self-report SI was assessed using the suicide measure from the Edinburgh Postnatal Depression Scale and from the Patient Health Questionnaire. RESULTS: Two percent of participants presented with SI during the first 6 months postpartum. In bivariate analyses, race/ethnicity, nativity, insurance, and language were significantly correlated with SI 3 weeks, 3 months, and 6 months postpartum. Screening positive for depression (p = 0.0245) and anxiety (0.0454), assessed 1-2 days postpartum, was significantly correlated with later SI in bivariate analyses, as were antepartum complications (p = 0.001), depressive history (0.001), and self efficacy (0.045). In adjusted models, antepartum complications (OR = 4.681, 95% CI = 1.99-10.99) and depressive history (OR-3.780, 95% CI = 1.514-9.441) were significantly associated with later postpartum SI. Heightened self-efficacy reduced the odds of later SI (p = 0.050). CONCLUSION: Findings suggest that SI among a relatively healthy group of new mothers occurs with some frequency. Mothers with a history of depression and antepartum complications may be at increased risk. PMID- 27227754 TI - Chronically Retained Intraocular Air. PMID- 27227755 TI - Laparoscopic and ultrasound assisted management of gallstone ileus after biliointestinal bypass Case report and a review of literature. AB - AIM: To report about an additional case of biliary ileus after bariatric surgery is reported and extensively reviewing the literature on this topic. MATERIAL OF STUDY: We reviewed the literature and found three cases of gallstone ileus (GI) that occurred after bariatric surgery. DISCUSSION: A 41 year old patient presented a GI eight years after a biliointestinal bypass (BIB) for morbid obesity. The patient complained of abdominal pain for two weeks. Computed tomography (CT) and abdominal ultrasound (US) allowed a preoperative diagnosis of GI and planning of surgical strategy. Surgical treatment was carried out through laparoscopic-assisted enterolithotomy alone procedure. This choice is supported discussing the related issues: morbidity, potential recurrence, eventual developing of gallbladder carcinoma. CONCLUSION: It is the first reported case of GI after BIB preoperatively diagnosed through CT scan and US, and treated with a laparoscopic assisted approach. Additional considerations concerning preoperative diagnosis, surgical strategy, technical details and follow-up can be usefully applied even in non post-bariatric biliary ileus. KEY WORDS: Biliointestinal bypass, Gallstone ileus, Laparoscopy, Ultrasonography. PMID- 27227756 TI - Neuroendocrine liver metastases: Value of apparent diffusion coefficient and enhancement ratios for characterization of histopathologic grade. AB - PURPOSE: To assess the value of apparent diffusion coefficient (ADC) measured with diffusion-weighted imaging (DWI) and enhancement ratios (ER) measured with contrast-enhanced T1-weighted imaging (CE-T1WI) for the characterization of histopathologic tumor grade of neuroendocrine tumor liver metastases (NETLM). MATERIALS AND METHODS: Twenty-two patients with pathology-proven NETLM and pretreatment 1.5 Tesla (T) and 3T MRI including DWI were included in this Institutional Review Board-approved retrospective study. ADC histogram parameters, including mean, minimum (min), skewness, and kurtosis as well as ER, were computed for all lesions. Tumor grading was based on the World Health Organization 2010 classification. Kruskal-Wallis and Mann-Whitney test were used to assess for differences in ADC and ER between different tumor grades. MRI parameters were correlated with pathologic findings using Spearman correlation test. Receiver operating characteristic analysis was performed to determine optimum thresholds for predicting tumor grade. RESULTS: Forty-eight NETLM (mean size 3.5 cm) were analyzed with the following grade distribution: G1 (n = 25), G2 (n = 16), and G3 (n = 7). ADC-mean (*10-3 mm2 /s) of G3 tumors (0.87 +/- 0.43) was significantly lower than that of G1 (1.47 +/- 0.63) and G2 (1.27 +/- 0.63; P = 0.042). A weak significant negative correlation was observed between ADC and tumor grade (ADC-mean: r = -0.33, P = 0.02; ADC-min: r = -0.37, P = 0.01) and Ki 67 (ADC-mean: r = -0.31, P = 0.03; ADC-min: r = -0.39, P = 0.007). AUROC, sensitivity and specificity of ADC-mean/ADC-min/ER (measured at the early arterial phase) for differentiation of G3 versus G1-G2 were 0.80/0.76/0.67, 100%/50%/70%, and 68.4%/84.2%/66.6%, respectively. CONCLUSION: ADC is a promising marker for characterization of histopathologic grade of NETLM. These results should be confirmed in a prospective study. J. Magn. Reson. Imaging 2016;44:1432 1441. PMID- 27227757 TI - Greek-origin royal jelly improves the lipid profile of postmenopausal women. AB - AIM: Menopause transition is associated with chronic conditions such as osteoporosis and cardiovascular disease. Concerns about the long-term safety of menopausal hormone therapy make alternative natural methods an appealing approach to management. The aim of this study was to examine the effect of royal jelly (RJ) on cardiovascular and bone turnover markers in clinically healthy postmenopausal women. METHODS: A total of 36 postmenopausal healthy women were studied in a prospective follow-up study. Participants received 150 mg of RJ daily for three months. Circulating cardiovascular risk markers [lipid profile, antithrombin-III (ATIII), Protein C, Protein S, Plasminogen Activator Inhibitor-1 (PAI-1)] and bone turnover parameters [Total calcium, phosphate (P), parathormone (PTH), total type-1 Procollagen N-terminal (P1NP), Osteocalcin and serum collagen type 1 cross-linked C-telopeptide (CTX)] were compared between the baseline and the three-month visit. RESULTS: The RJ used in this study was particularly rich in medium chain fatty acids, compounds with hypolipidemic properties, which comprised 63% of the dry weight fatty content. RJ treatment resulted in a significant increase in high density lipoprotein - cholesterol (HDL-C 60.2 mg/dL +/- 12.3 versus 64.7 mg/dL +/- 13.9, 7.7% increase, p = 0.0003), as well as in a significant decrease in low density lipoprotein - cholesterol (LDL-C, 143.9 +/- 37.5 versus 136.2 +/- 32, 4.1% decrease, p = 0.011) and in total cholesterol (224.4 +/- 38.6 to 216.1 +/- 36.5, 3.09% decrease, p = 0.018). No statistical significant changes were found in the remaining cardiovascular or the bone turnover parameters. CONCLUSIONS: The intake of RJ 150 mg for three months is associated with significant improvements of the lipid profile of postmenopausal women. RJ supplementation may offer an alternative method of controlling the menopause - associated dyslipidemia. PMID- 27227758 TI - Kinetically Blocked Stable 5,6:12,13-Dibenzozethrene: A Laterally pi-Extended Zethrene with Enhanced Diradical Character. AB - Although the ground-state and physical properties of zethrene and recently invented 1,2:8,9-dibenzozethrene have been well studied, the other dibenzozethrene isomer, i.e., 5,6:12,13-dibenzozethrene, remained unexplored. A short synthetic route to a kinetically blocked stable 5,6:12,13-dibenzozethrene derivative 5 is presented. The ground state is found to be open-shell singlet experimentally, and the theoretical y0 was enhanced to 0.414, which corroborates nicely with the experimental and theoretical singlet-triplet energy gap. PMID- 27227768 TI - Deferoxamine released from poly(lactic-co-glycolic acid) promotes healing of osteoporotic bone defect via enhanced angiogenesis and osteogenesis. AB - The regeneration capacity of osteoporotic bones is generally lower than that of normal bones. Current methods of osteoporotic bone defect treatment are not always satisfactory. Recent studies demonstrate that activation of the hypoxia inducible factor-1alpha (HIF-1alpha) pathway, by genetic methods or hypoxia mimicking agents, could accelerate bone regeneration. However, little is known as to whether modulating the HIF-1alpha pathway promotes osteoporotic defect healing. To address this problem in the present study, we first demonstrated that HIF-1alpha and vascular endothelial growth factor expression levels are lower in osteoporotic bones than in normal bones. Second, we loaded poly(Lactic-co glycolic acid) (PLGA) with the hypoxia-mimetic agent deferoxamine (DFO). DFO released from PLGA had no significant effect on the proliferation of mesenchymal stem cells (MSCs); however, DFO did enhance the osteogenic differentiation of MSCs. In addition, DFO upregulated the mRNA expression levels of angiogenic factors in MSCs. Endothelial tubule formation assays demonstrate that DFO promoted angiogenesis in human umbilical vein endothelial cells. Third, untreated PLGA scaffolds (PLGA group) or DFO-containing PLGA (PLGA + DFO group) were implanted into critically sized osteoporotic femur defects in ovariectomized rats. After treatment periods of 14 or 28 days, micro-CT, histological, CD31 immunohistochemical, and dynamic bone histomorphometric analyses showed that DFO dramatically stimulated bone formation and angiogenesis in a critically sized osteoporotic femur defect model. Our in vitro and in vivo results demonstrate that DFO may promote the healing of osteoporotic bone defects due to enhanced angiogenesis and osteogenesis. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2515-2527, 2016. PMID- 27227769 TI - The Long Noncoding RNA MALAT-1 Is Highly Expressed in Ovarian Cancer and Induces Cell Growth and Migration. AB - BACKGROUND: Metastasis associated in lung adenocarcinoma transcript-1 (MALAT-1) is overexpressed during cancer progression and promotes cell migration and invasion in many solid tumors. However, its role in ovarian cancer remains poorly understood. METHODS: Expressions of MALAT-1 were detected in 37 normal ovarian tissues and 45 ovarian cancer tissues by reverse transcription polymerase chain reaction (RT-PCR). Cell proliferation was observed by CCK-8 assay; Flow cytometry was used to measure cell cycle and apoptosis; Cell migration was detected by transwell migration and invasion assay. In order to evaluate the function of MALAT-1, shRNA combined with DNA microarray and Functional enrichment analysis were performed to determine the transcriptional effects of MALAT-1 silencing in OVCAR3 cells. RNA and protein expression were measured by qRT-PCR and Western blotting, respectively. RESULTS: We found that upregulation of MALAT-1 mRNA in ovarian cancer tissues and enhanced MALAT-1 expression was associated with FIGO stage. Knockdown of MALAT-1 expression in OVCAR3 cells inhibited cell proliferation, migration, and invasion, leading to G0/G1 cell cycle arrest and apoptosis. Overexpressed MALAT-1 expression in SKOV3 cells promoted cell proliferation, migration and invasion. Downregulation of MALAT-1 resulted in significant change of gene expression (at least 2-fold) in 449 genes, which regulate proliferation, cell cycle, and adhesion. As a consequence of MALAT-1 knockdown, MMP13 protein expression decreased, while the expression of MMP19 and ADAMTS1 was increased. CONCLUSIONS: The present study found that MALAT-1 is highly expressed in ovarian tumors. MALAT-1 promotes the growth and migration of ovarian cancer cells, suggesting that MALAT-1 may be an important contributor to ovarian cancer development. PMID- 27227770 TI - Correction: Circulating Inflammatory Mediators as Potential Prognostic Markers of Human Colorectal Cancer. AB - [This corrects the article DOI: 10.1371/journal.pone.0148186.]. PMID- 27227771 TI - The Usefulness of Assessing and Identifying Workers' Temperaments and Their Effects on Occupational Stress in the Workplace. AB - The relationship between temperaments and mental disorders has been reported in previous studies, but there has been little attention to temperaments in the occupational safety and health research. The aim of this study was to clarify the effects of temperaments on occupational stress among local government employees. The subjects were 145 Japanese daytime workers in local government. Temperaments were assessed by the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego-Auto questionnaire (TEMPS-A). Occupational stress was assessed using the Generic Job Stress Questionnaire (GJSQ). Hierarchical multiple linear regression analysis was used. Hyperthymic temperament predicted a higher level of job control, and a lower level of role ambiguity and job future ambiguity. Irritable temperament predicted a lower level of social support from supervisors and a higher level of role conflict, variance in workload and intragroup conflict. Anxious temperament predicted a lower level of social support from coworkers and a higher level of job future ambiguity. The sample size was small. Only Japanese local government employees were surveyed. Hyperthymic temperament played a protective role, and irritable, anxious temperament played a vulnerable role against one's own occupational stress and recognizing the roles they play in work life would lead to self-insight. Additionally, recognition of the temperaments and temperament-related stressors by one's supervisors or coworkers would facilitate provision of social support. PMID- 27227772 TI - Old World Cutaneous Leishmaniasis and Refugee Crises in the Middle East and North Africa. PMID- 27227773 TI - Effects of Soil Salinity on Sucrose Metabolism in Cotton Fiber. AB - Cotton (Gosspium hirsutum L.) is classified as a salt tolerant crop. However, its yield and fiber quality are negatively affected by soil salinity. Studies on the enzymatic differences in sucrose metabolism under different soil salinity levels are lacking. Therefore, field experiments, using two cotton cultivars, CCRI-79 (salt-tolerant) and Simian 3 (salt-sensitive), were conducted in 2013 and 2014 at three different salinity levels (1.15 dS m-1 [low soil salinity], 6.00 dS m-1 [medium soil salinity], and 11.46 dS m-1 [high soil salinity]). The objective was to elucidate the effects of soil salinity on sucrose content and the activity of key enzymes that are related to sucrose metabolism in cotton fiber. Results showed that as the soil salinity increased, cellulose content, sucrose content, and sucrose transformation rate declined; the decreases in cellulose content and sucrose transformation rate caused by the increase in soil salinity were more in Simian 3 than those in CCRI-79. With increase in soil salinity, activities of sucrose metabolism enzymes sucrose phophate synthase (SPS), acidic invertase, and alkaline invertase were decreased, whereas sucrose synthase (SuSy) activity increased. However, the changes displayed in the SuSy and SPS activities in response to increase in soil salinity were different and the differences were large between the two cotton cultivars. These results illustrated that suppressed cellulose synthesis and sucrose metabolism under high soil salinity were mainly due to the change in SPS, SuSy, and invertase activities, and the difference in cellulose synthesis and sucrose metabolism in fiber for the two cotton cultivars in response to soil salinity was determined mainly by both SuSy and SPS activities. PMID- 27227774 TI - Peptides in Bronchoalveolar Lavage in Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous disease with a significant public health burden. Currently there is no biomarker that identifies those at risk of developing COPD, progression of disease or disease phenotypes. We performed metabolomic profiling of bronchoalveolar lavage fluid (BALF) from COPD patients to determine if metabolites correlated with clinical measurements such as lung function, functional status and degree of emphysema. METHODS: Metabolomic components of BALF from 59 subjects with COPD and 20 healthy controls were separated by reversed-phase UPLC and analyzed by ESI-ToF mass spectrometry. We used univariate analysis and multiple regression models to investigate associations between metabolomic features and various clinical variables, such as lung function, functional status as measured by the St. George Respiratory Quotient Score and emphysema as measured by the CT density mask score. RESULTS: We identified over 3900 features by mass spectrometry, many consistent with peptides. Subjects with severe COPD had increased concentration of peptides compared to controls (p < 9.526e-05). The peptide concentration correlated with spirometry, specifically pulmonary function tests associated with airflow obstruction. There was no correlation with CT density, i.e. emphysema, or functional status. CONCLUSIONS: Metabolomic profiling of BALF in COPD patients demonstrated a significant increase in peptides compared to healthy controls that associated strongly to lung function, but not emphysema or functional status. PMID- 27227775 TI - Sampling Enrichment toward Target Structures Using Hybrid Molecular Dynamics Monte Carlo Simulations. AB - Sampling enrichment toward a target state, an analogue of the improvement of sampling efficiency (SE), is critical in both the refinement of protein structures and the generation of near-native structure ensembles for the exploration of structure-function relationships. We developed a hybrid molecular dynamics (MD)-Monte Carlo (MC) approach to enrich the sampling toward the target structures. In this approach, the higher SE is achieved by perturbing the conventional MD simulations with a MC structure-acceptance judgment, which is based on the coincidence degree of small angle x-ray scattering (SAXS) intensity profiles between the simulation structures and the target structure. We found that the hybrid simulations could significantly improve SE by making the top ranked models much closer to the target structures both in the secondary and tertiary structures. Specifically, for the 20 mono-residue peptides, when the initial structures had the root-mean-squared deviation (RMSD) from the target structure smaller than 7 A, the hybrid MD-MC simulations afforded, on average, 0.83 A and 1.73 A in RMSD closer to the target than the parallel MD simulations at 310K and 370K, respectively. Meanwhile, the average SE values are also increased by 13.2% and 15.7%. The enrichment of sampling becomes more significant when the target states are gradually detectable in the MD-MC simulations in comparison with the parallel MD simulations, and provide >200% improvement in SE. We also performed a test of the hybrid MD-MC approach in the real protein system, the results showed that the SE for 3 out of 5 real proteins are improved. Overall, this work presents an efficient way of utilizing solution SAXS to improve protein structure prediction and refinement, as well as the generation of near native structures for function annotation. PMID- 27227777 TI - 22q11.2 deletion syndrome. PMID- 27227776 TI - Glucocorticoids Enhance Muscle Proteolysis through a Myostatin-Dependent Pathway at the Early Stage. AB - Myostatin, a member of the TGF-beta superfamily of secreted proteins, is expressed primarily in skeletal muscle. It negatively regulates muscle mass and is associated with glucocorticoid-induced muscle atrophy. However, it remains unclear whether myostatin is involved in glucocorticoid-induced muscle protein turnover. The aim of the present study was to investigate the role of myostatin in protein metabolism during dexamethasone (DEX) treatment. Protein synthesis rates and the expression of the genes for myostatin, ubiquitin-proteasome atrogin 1, MuRF1, FoxO1/3a and mTOR/p70S6K were determined. The results show that DEX decreased (P<0.05) protein synthesis rates while increasing the abundance of myostatin. DEX increased (P<0.05) the level of phospho-FoxO1/3a (Thr 24/32) and the expression of MuRF1. In contrast, DEX treatment had no detectable effect on atrogin-1 protein levels (P>0.05). The phosphorylation levels of mTOR and p70S6K were decreased by DEX treatment (P<0.05). Follistatin treatment inhibited the DEX induced increase in myostatin (P<0.05) and the activation of phosphor-FoxO1/3a (Thr 24/32) (P< 0.05) and MuRF1 (P<0.05). Follistatin treatment had no influence on the protein synthesis rate or on the phosphorylation levels of mTOR (Ser 2448) and p70S6K (Thr 389) (P> 0.05). In conclusion, the present study suggests that the myostatin signalling pathway is associated with glucocorticoid-induced muscle protein catabolism at the beginning of exposure. Myostatin is not a main pathway associated with the suppression of muscle protein synthesis by glucocorticoids. PMID- 27227778 TI - pks63787, a Polyketide Synthase Gene Responsible for the Biosynthesis of Benzenoids in the Medicinal Mushroom Antrodia cinnamomea. AB - Antrodia cinnamomea, a unique resupinate basidiomycete endemic to Taiwan, has potent medicinal activities. The reddish basidiocarps and mycelia generally exhibit abundant metabolites and higher biological activity. To investigate the pigments of A. cinnamomea, polyketide synthase (PKS) genes were characterized based on its partially deciphered genome and the construction of a fosmid library. Furthermore, a gene disruption platform was established via protoplast transformation and homologous recombination. Of four putative polyketide synthase genes, pks63787 was selected and disrupted in the monokaryotic wild-type (wt) strain f101. Transformant Deltapks63787 was deficient in the synthesis of several aromatic metabolites, including five benzenoids and two benzoquinone derivatives. Based on these results, a biosynthetic pathway for benzenoid derivatives was proposed. The pks63787 deletion mutant not only displayed a reduced red phenotype compared to the wt strain but also displayed less 1,1-biphenyl-2-picrylhydrazyl free radical scavenging activity. This finding suggests that PKS63787 is responsible for the biosynthesis of pigments and metabolites related to the antioxidant activity of A. cinnamomea. The present study focuses on the functional characterization of the PKS gene, the fluctuations of its profile of secondary metabolites, and interpretation of the biosynthesis of benzenoids. PMID- 27227779 TI - A Systematic Review of the Modifying Effect of Anaesthetic Drugs on Metastasis in Animal Models for Cancer. AB - BACKGROUND: Distant metastasis or local recurrence after primary tumour resection remain a major clinical problem. The anaesthetic technique used during oncologic surgery is suggested to influence the metastatic process. While awaiting the results of ongoing randomised controlled trials (RCTs), we have analyzed the evidence regarding the influence of anaesthetic drugs on experimental tumour metastasis in animal studies. METHODS: PubMed and Embase were searched until April 21st, 2015. Studies were included in the systematic review when they 1) assessed the effect of an anaesthetic drug used in clinical practice on the number or incidence of metastasis in animal models with experimental cancer, 2) included an appropriate control group, and 3) presented unique data. RESULTS: 20 studies met the inclusion criteria (published between 1958-2010). Data on number of metastases could be retrieved from 17 studies. These studies described 41 independent comparisons, 33 of which could be included in the meta-analysis (MA). The incidence of metastases was studied in 3 unique papers. From these 3 papers, data on 7 independent comparisons could be extracted and included in the MA. Locally administered local anaesthetics appear to decrease the number of metastases (SMD -6.15 [-8.42; -3.88]), whereas general anaesthetics (RD: 0.136 [0.045, 0.226]), and more specifically volatile anaesthetics (SMD 0.54 [0.24; 0.84]), appear to increase the number and risk of metastases in animal models for cancer. CONCLUSIONS: Anaesthetics influence the number and incidence of metastases in experimental cancer models. Although more high quality experimental research is necessary, based on the currently available evidence from animal studies, there is no indication to suggest that locally administered local anaesthetics are harmful during surgery in cancer patients. Volatile anaesthetics, however, might increase metastasis in animal models and clinical trials investigating this possibly harmful effect should receive priority. The results of our systematic review in animal studies are broadly consistent with clinical reports that anaesthetic technique does seem to affect the tumour metastasis process. PMID- 27227781 TI - A study of ultrasonic physical modeling of isotropic media based on dynamic similitude. AB - For decades, seismic and ultrasonic physical modeling has been used to help the geophysicists to understand the phenomena related to the elastic wave propagation on isotropic and anisotropic media. Most of the published works related to physical modeling use physical similitudes between model and field (geological environment) only in the geometric and, sometimes, in the kinematics sense. The dynamic similitude is approximately or, most of the time, not obeyed due to the difficulty to reproduce, in laboratory, the forces and tensions excited inside the earth when elastic waves propagate. In this work, we use expressions for dynamic similitude related to the ratio between stiffness coefficients or Lame parameters. The resulting expression for dynamic similitude shows that this type of similitude has multiple solutions in the context of dynamic stress (non uniqueness problem). However, the regularization of this problem can be reached by controlling porosity and clay content. Ultrasonic measurements (elastic) as well as petrophysical measurements (density, porosity and clay content) in synthetic sandstone rocks show how difficult it is to reproduce experimentally the three physical similarities studied in this work. PMID- 27227782 TI - Non-small-cell lung cancer. PMID- 27227780 TI - Overweight and Obesity in School Children of a Hill State in North India: Is the Dichotomy Urban-Rural or Socio-Economic? Results from a Cross-Sectional Survey. AB - INTRODUCTION: Overweight and obesity are a public health problem in India not only in adults but also in children. The authors sought to estimate the prevalence of overweight and obesity in school-going children of 6-17 years of age and examine its demographic and dietary correlates in context of their urban rural status and socio-economic status. METHODS: In this cross-sectional survey height and weight were measured in 1266 school children in government and private schools of urban and rural areas. Dietary assessment was done using single day 24 hour dietary recall method. The data were analyzed using SPSS (IBM SPSS Statistics Version 19) and WHO AnthroPlus Software. Factorial ANOVA was used for testing interaction within and between subgroups for continuous variables and Chi square test was used for categorical variables. RESULTS: It was found that the overall prevalence of overweight was 15.6% of which 5.4% were obese, with maximum prevalence in boys attending urban private schools. The mean caloric intake in the study population with 24-hour dietary recall method was 1558.2 kilocalories (SD: 428 kilocalories). CONCLUSION: Overweight and obesity is a significant problem in school-going children. Higher socio-economic status continues to remain an important driver of this epidemic in the younger generation and affects demographic and dietary determinants of this problem. PMID- 27227785 TI - Chiral DHIP-Based Metal-Organic Frameworks for Enantioselective Recognition and Separation. AB - Two chiral porous 2,3-dihydroimidazo[1,2-a]pyridine (DHIP)-based metal-organic frameworks (MOFs) are assembled from an enantiopure dipyridyl-functionalized DHIP bridging ligand. The Zn-DHIP MOF shows a good enantioseparation performance toward aromatic sulfoxides, and the heterogeneous adsorbent can be readily recovered and reused without significant degradation of the separation performance. PMID- 27227783 TI - Late-life Cognitive Activity and Dementia: A Systematic Review and Bias Analysis. AB - BACKGROUND: Engaging in late-life cognitive activity is often proposed as a strategy to delay or prevent Alzheimer's disease (AD) and other dementias. However, it is unclear to what extent the available evidence supports a causal effect of cognitive activity in dementia prevention. METHODS: We systematically searched PubMed and EMBASE through June 2014 to identify peer-reviewed epidemiologic studies of cognitive activity and incidence of AD or all-cause dementia. Eligible articles analyzed data from cohort or nested case-control studies, explicitly defined cognitive activity, evaluated participants for AD or all-cause dementia using clearly defined criteria, and provided effect estimates adjusted for at least age and sex. We describe methodologic issues and biases relevant to interpretation of these studies, and quantify the degree of bias due to confounding and reverse causation required to nullify typically observed associations. RESULTS: We reviewed 12 studies involving 13,939 participants and 1,663 dementia cases, of which 565 were specifically evaluated as AD. Most studies found associations between late-life cognitive activity and lower AD and/or all-cause dementia incidence. Differences in cognitive activity operationalization across studies precluded meta-analysis of effect estimates. Our bias analysis indicated that the observed inverse associations are probably robust to unmeasured confounding, and likely only partially explained by reverse causation. CONCLUSION: Our systematic review and bias analyses provide support for the hypothesis that late-life cognitive activity offers some reduction in AD and all-cause dementia risk. However, more data are needed to confirm this relationship and on the optimal type, duration, intensity, and timing of that activity. PMID- 27227786 TI - Debunking the Myth of the Genetic Superman. PMID- 27227784 TI - Arabidopsis COGWHEEL1 links light perception and gibberellins with seed tolerance to deterioration. AB - Light is a major regulator of plant growth and development by antagonizing gibberellins (GA), and we provide evidence for a role of light perception and GA in seed coat formation and seed tolerance to deterioration. We have identified two activation-tagging mutants of Arabidopsis thaliana, cog1-2D and cdf4-1D, with improved seed tolerance to deterioration linked to increased expression of COG1/DOF1.5 and CDF4/DOF2.3, respectively. These encode two homologous DOF transcription factors, with COG1 most highly expressed in seeds. Improved tolerance to seed deterioration was reproduced in transgenic plants overexpressing these genes, and loss of function from RNA interference resulted in opposite phenotypes. Overexpressions of COG1 and CDF4 have been described to attenuate various light responses mediated by phytochromes. Accordingly, we found that phyA and phyB mutants exhibit increased seed tolerance to deterioration. The phenotype of tolerance to deterioration conferred by gain of function of COG1 and by loss of function of phytochromes is of maternal origin, is also observed under natural aging conditions and correlates with a seed coat with increased suberin and reduced permeability. In developing siliques of the cog1-2D mutant the expression of the GA biosynthetic gene GA3OX3 and levels of GA1 are higher than in the wild type. These results explain the antagonism between phytochromes and COG1 in terms of the inhibition and the activation, respectively, of GA action. PMID- 27227787 TI - The blood-tendon barrier: identification and characterisation of a novel tissue barrier in tendon blood vessels. AB - Tissue barriers function as "gate keepers" between different compartments (usually blood and tissue) and are formed by specialised membrane-associated proteins, localising to the apicolateral plasma membrane domain of epithelial and endothelial cells. By sealing the paracellular space, the free diffusion of solutes and molecules across epithelia and endothelia is impeded. Thereby, tissue barriers contribute to the establishment and maintenance of a distinct internal and external environment, which is crucial during organ development and allows maintenance of an organ-specific homeostatic milieu. So far, various epithelial and endothelial tissue barriers have been described, including the blood-brain barrier, the blood-retina barrier, the blood-testis barrier, the blood-placenta barrier, and the cerebrospinal fluid (CSF)-brain barrier, which are vital for physiological function and any disturbance of these barriers can result in severe organ damage or even death. Here, we describe the identification of a novel barrier, located in the vascular bed of tendons, which we term the blood-tendon barrier (BTB). By using immunohistochemistry, transmission electron microscopy, and tracer studies we demonstrate the presence of a functional endothelial barrier within tendons restricting the passage of large blood-borne molecules into the surrounding tendon tissue. We further provide in vitro evidence that the BTB potentially contributes to the creation of a distinct internal tissue environment impacting upon the proliferation and differentiation of tendon resident cells, effects which might be fundamental for the onset of tendon pathologies. PMID- 27227788 TI - Age-Related Differences in Maximal and Rapid Torque Characteristics of the Hip Extensors and Dynamic Postural Balance in Healthy, Young and Old Females. AB - Palmer, TB, Thiele, RM, and Thompson, BJ. Age-related differences in maximal and rapid torque characteristics of the hip extensors and dynamic postural balance in healthy, young and old females. J Strength Cond Res 31(2): 480-488, 2017-The purpose of this study was to examine age-related differences in maximal and rapid torque characteristics of the hip extensor muscles and dynamic postural balance in healthy, young and older females. Eleven younger (age, 26 +/- 8 years) and 11 older (age, 67 +/- 8 years) females performed 2 isometric maximal voluntary contractions (MVCs) of the hip extensor muscles. Absolute and relative peak torque (PT) and rate of torque development (RTD) at early (0-50 ms) and late (0 200 ms) phases of muscle contraction were examined during each MVC. Dynamic postural balance was assessed using a commercially designed balance testing device, which provides a measurement of dynamic stability based on the overall stability index (OSI). Results indicated that absolute PT and early (RTD50) and late (RTD200) RTD variables were lower (p = 0.009-0.050), and postural OSI was higher (p = 0.011) in the old compared with the younger females; however, no differences were observed for relative PT or RTD variables (p = 0.113-0.895). A significant relationship was also observed in the older (r = -0.601; p = 0.050) but not the younger (r = -0.132; p = 0.698) females between RTD50 and OSI. The lower absolute PT and RTD and higher OSI values for the old females may contribute to the increased functional limitations often observed in older adults. The significant relationship observed in the older females between OSI and RTD50 perhaps suggests that these age-related declines in explosive strength may be an important characteristic relevant to dynamic balance scores, especially in older populations. PMID- 27227789 TI - Modifiable Anthropometric Characteristics Are Associated With Unilateral and Bilateral Carry Performance. AB - Beck, B, Carstairs, GL, Billing, DC, Caldwell, JN, and Middleton, KJ. Modifiable anthropometric characteristics are associated with unilateral and bilateral carry performance. J Strength Cond Res 31(2): 489-494, 2017-A mismatch between physical ability and task requirements can increase the risk of on-the-job injury. Therefore, understanding key anthropometric characteristics associated with job performance is important in developing targeted training programs and selecting employees in physically demanding occupations. The aims of this study were to understand which anthropometric and demographic (age/sex) characteristics were associated with performance in a unilateral stretcher carry and bilateral jerry can and kettle bell carries. Sixty-seven enlisted Australian Army soldiers (46 men and 21 women) participated in this investigation. Body composition was quantified using dual-energy X-ray absorptiometry. Univariate and multivariable regression techniques were used to quantify correlations between anthropometric characteristics and carry performance. Median carry distance was 650 m (interquartile range [IQR] = 425-1,025 m) in the stretcher carry, 300 m (IQR = 215-445 m) in the jerry can carry, and 265 m (IQR = 200-400 m) in the kettle bell carry. Univariate analyses demonstrated that whole body, trunk, upper arm, forearm, and leg lean mass, as well as stature and body mass were associated with performance across the 3 carry tasks. Of these, leg lean mass was shown to be a key characteristic associated with carry performance. Subsequently, it is suggested that training programs focus on whole-body lean mass with specific emphasis on leg lean mass. Additionally, we demonstrated that age and sex were not significantly associated with carry performance when controlling for leg lean mass, indicating that modifiable factors can be targeted in training programs to improve job performance. PMID- 27227790 TI - Quantification of Accelerometer Derived Impacts Associated With Competitive Games in National Collegiate Athletic Association Division I College Football Players. AB - Wellman, AD, Coad, SC, Goulet, GC, and McLellan, CP. Quantification of accelerometer derived impacts associated with competitive games in National Collegiate Athletic Association division I college football players. J Strength Cond Res 31(2): 330-338, 2017-The aims of the present study were to (a) examine positional impact profiles of National Collegiate Athletic Association (NCAA) division I college football players using global positioning system (GPS) and integrated accelerometry (IA) technology and (b) determine if positional differences in impact profiles during competition exist within offensive and defensive teams. Thirty-three NCAA division I Football Bowl Subdivision players were monitored using GPS and IA (GPSports) during 12 regular season games throughout the 2014 season. Individual player data sets (n = 294) were divided into offensive and defensive teams, and positional subgroups. The intensity, number, and distribution of impact forces experienced by players during competition were recorded. Positional differences were found for the distribution of impacts within offensive and defensive teams. Wide receivers sustained more very light and light to moderate (5-6.5 G force) impacts than other position groups, whereas the running backs were involved in more severe (>10 G force) impacts than all offensive position groups, with the exception of the quarterbacks (p <= 0.05). The defensive back and linebacker groups were subject to more very light (5.0-6.0 G force) impacts, and the defensive tackle group sustained more heavy and very heavy (7.1-10 G force) impacts than other defensive positions (p <= 0.05). Data from the present study provide novel quantification of positional impact profiles related to the physical demands of college football games and highlight the need for position-specific monitoring and training in the preparation for the impact loads experienced during NCAA division I football competition. PMID- 27227791 TI - The Effects of a Single Whole-Body Cryotherapy Exposure on Physiological, Performance, and Perceptual Responses of Professional Academy Soccer Players After Repeated Sprint Exercise. AB - Russell, M, Birch, J, Love, T, Cook, CJ, Bracken, RM, Taylor, T, Swift, E, Cockburn, E, Finn, C, Cunningham, D, Wilson, L, and Kilduff, LP. The effects of a single whole-body cryotherapy exposure on physiological, performance, and perceptual responses of professional academy soccer players after repeated sprint exercise. J Strength Cond Res 31(2): 415-421, 2017-In professional youth soccer players, the physiological, performance, and perceptual effects of a single whole body cryotherapy (WBC) session performed shortly after repeated sprint exercise were investigated. In a randomized, counterbalanced, and crossover design, 14 habituated English Premier League academy soccer players performed 15 * 30 m sprints (each followed by a 10 m forced deceleration) on 2 occasions. Within 20 minutes of exercise cessation, players entered a WBC chamber (Cryo: 30 seconds at -60 degrees C, 120 seconds at -135 degrees C) or remained seated (Con) indoors in temperate conditions (~25 degrees C). Blood and saliva samples, peak power output (countermovement jump), and perceptual indices of recovery and soreness were assessed pre-exercise and immediately, 2-hour and 24-hour postexercise. When compared with Con, a greater testosterone response was observed at 2-hour (+32.5 +/- 32.3 pg.ml, +21%) and 24-hour (+50.4 +/- 48.9 pg.ml, +28%) postexercise (both P = 0.002) in Cryo (trial * treatment interaction: P = 0.001). No between-trial differences were observed for other salivary (cortisol and testosterone/cortisol ratio), blood (lactate and creatine kinase), performance (peak power output), or perceptual (recovery or soreness) markers (all trial * treatment interactions: P > 0.05); all of which were influenced by exercise (time effects: all P <= 0.05). A single session of WBC performed within 20 minutes of repeated sprint exercise elevated testosterone concentrations for 24 hours but did not affect any other performance, physiological, or perceptual measurements taken. Although unclear, WBC may be efficacious for professional soccer players during congested fixture periods. PMID- 27227792 TI - The Role of the Trunk Control in Athletic Performance of a Reactive Change-of Direction Task. AB - Edwards, S, Austin, AP, and Bird, SP. The role of the trunk control in athletic performance of a reactive change-of-direction task. J Strength Cond Res 31(1): 126-139, 2017-Agility is vital to success in team sport competition with the trunk argued to play a key role in sport performance. This study explored the role of trunk control during a reactive change-of-direction task (R-COD) and field-based measures of athletic performance. Twenty male players completed field based athletic performance assessments (modified Illinois agility test [mIAT], 3 repetition maximum back squat, and 5 countermovement jumps [CMJ]) and R-CODs, during which 3-dimensional ground reaction forces and kinematics were recorded. Trunk control was assessed as the sum of the trunk relative to the pelvis range of motion (ROM) in all 3 planes during the R-COD. Participants with the highest (HIGH, n = 7) and lowest (LOW, n = 7) trunk ROM values were grouped. The HIGH group achieved significantly shorter mIAT time duration, higher CMJ height, and lower knee flexion angles, greater trunk lateral flexion and rotation relative to pelvis, and greater angular momentum during the R-COD compared with the LOW group. Superior athletic performance was associated with decreased trunk control (high trunk ROM) during the R-COD. Although this study suggested that trunk control is a vital component of performance, it is unknown whether this trunk control is inherent or an effect of training history, nor does not support current optimal athletic performance recommendation of decreased trunk motion during R-COD. PMID- 27227793 TI - Effects of a Strength Training Session After an Exercise Inducing Muscle Damage on Recovery Kinetics. AB - Abaidia, A-E, Delecroix, B, Leduc, C, Lamblin, J, McCall, A, Baquet, G, and Dupont, G. Effects of a strength training session after an exercise inducing muscle damage on recovery kinetics. J Strength Cond Res 31(1): 115-125, 2017-The purpose of this study was to investigate the effects of an upper-limb strength training session the day after an exercise inducing muscle damage on recovery of performance. In a randomized crossover design, subjects performed the day after the exercise, on 2 separate occasions (passive vs. active recovery conditions) a single-leg exercise (dominant in one condition and nondominant in the other condition) consisting of 5 sets of 15 eccentric contractions of the knee flexors. Active recovery consisted of performing an upper-body strength training session the day after the exercise. Creatine kinase, hamstring strength, and muscle soreness were assessed immediately and 20, 24, and 48 hours after exercise induced muscle damage. The upper-body strength session, after muscle-damaging exercise accelerated the recovery of slow concentric force (effect size = 0.65; 90% confidence interval = -0.06 to 1.32), but did not affect the recovery kinetics for the other outcomes. The addition of an upper-body strength training session the day after muscle-damaging activity does not negatively affect the recovery kinetics. Upper-body strength training may be programmed the day after a competition. PMID- 27227794 TI - Individual Heart Rate Variability Responses to Preseason Training in High Level Female Soccer Players. AB - Flatt, AA, Esco, MR, and Nakamura, FY. Individual heart rate variability responses to preseason training in high level female soccer players. J Strength Cond Res 31(2): 531-538, 2017-The purpose of this study was to track changes in training load (TL) and recovery status indicators throughout a 2-week preseason and to interpret the meaning of these changes on an individual basis among 8 division-1 female soccer players. Weekly averages for heart rate variability (logarithm of the root mean square of successive R-R interval differences [lnRMSSD]), TL, and psychometrics were compared with effect sizes (ESs) and magnitude-based inferences. Relationships were determined with Pearson correlations. Group analysis showed a very likely moderate decrease for total TL (TTL) (TTL week 1 = 1,203 +/- 198, TTL week 2 = 977 +/- 288; proportion = 1/2/97, ES = -0.93) and a likely small increase in lnRMSSD (week 1 = 74.2 +/- 11.1, week 2 = 78.1 +/- 10.5; proportion = 81/14/5, ES = 0.35). Fatigue demonstrated a very likely small improvement (week 1 = 5.03 +/- 1.09, week 2 = 5.51 +/- 1.00; proportion = 95/4/1; ES = 0.45), whereas the other psychometrics did not substantially change. A very large correlation was found between changes in TL and lnRMSSD (r = -0.85), whereas large correlations were found between lnRMSSD and perceived fatigue (r = 0.56) and soreness (r = 0.54). Individual analysis suggests that 2 subjects may benefit from decreased TL, 2 subjects may benefit from increased TL, and 4 subjects may require no intervention based on their psychometric and lnRMSSD responses to the TL. Individual weekly changes in lnRMSSD varied among subjects and related strongly with individual changes in TL. Training intervention based on lnRMSSD and wellness responses may be useful for preventing the accumulation of fatigue in female soccer players. PMID- 27227795 TI - A Methodological Report: Adapting the 505 Change-of-Direction Speed Test Specific to American Football. AB - Lockie, RG, Jalilvand, F, Orjalo, AJ, Giuliano, DV, Moreno, MR, and Wright, GA. A methodological report: Adapting the 505 change-of-direction speed test specific to American football. J Strength Cond Res 31(2): 539-547, 2017-The 505 involves a 10-m sprint past a timing gate, followed by a 180 degrees change-of-direction (COD) performed over 5 m. This methodological report investigated an adapted 505 (A505) designed to be football-specific by changing the distances to 10 and 5 yd. Twenty-five high school football players (6 linemen [LM]; 8 quarterbacks, running backs, and linebackers [QB/RB/LB]; 11 receivers and defensive backs [R/DB]) completed the A505 and 40-yd sprint. The difference between A505 and 0 to 10-yd time determined the COD deficit for each leg. In a follow-up session, 10 subjects completed the A505 again and 10 subjects completed the 505. Reliability was analyzed by t-tests to determine between-session differences, typical error (TE), and coefficient of variation. Test usefulness was examined via TE and smallest worthwhile change (SWC) differences. Pearson's correlations calculated relationships between the A505 and 505, and A505 and COD deficit with the 40-yd sprint. A 1-way analysis of variance (p <= 0.05) derived between-position differences in the A505 and COD deficit. There were no between-session differences for the A505 (p = 0.45-0.76; intraclass correlation coefficient = 0.84-0.95; TE = 2.03-4.13%). Additionally, the A505 was capable of detecting moderate performance changes (SWC0.5 > TE). The A505 correlated with the 505 and 40-yard sprint (r = 0.58-0.92), suggesting the modified version assessed similar qualities. Receivers and defensive backs were faster than LM in the A505 for both legs, and right-leg COD deficit. Quarterbacks, running backs, and linebackers were faster than LM in the right-leg A505. The A505 is reliable, can detect moderate performance changes, and can discriminate between football position groups. PMID- 27227796 TI - Reduction of soy isoflavones by use of Escherichia coli whole-cell biocatalyst expressing isoflavone reductase under aerobic conditions. AB - Soy isoflavone metabolites are currently receiving much attention due to the stronger and wider bioactivities than that of isoflavones. Therefore, biosynthesis of isoflavone metabolites by isolated isoflavone biotransforming bacteria is important. However, the biosynthesis process must be under obligate anaerobic conditions due to the reduction reactions catalysed by isoflavone biotransforming bacteria. In this study, we cloned the daidzein and genistein reductase gene (dgr) from Slackia sp. AUH-JLC159. The recombinant Escherichia coli (E. coli) whole-cell was used for the first time as the biocatalyst for aerobic biosynthesis of dihydrodaidzein (DHD) and dihydrogenistein (DHG) from soy isoflavones daidzein and genistein. Our results indicated that the recombinant E. coli whole-cell was able to reduce daidzein and genistein to DHD and DHG under aerobic conditions, while the maximal concentration of the substrate daidzein or genistein that the E. coli whole-cell was able to convert efficiently was only 0.4 mmol l(-1) . Under the optimized conditions, the maximal concentration of daidzein or genistein that the E. coli whole-cell was able to convert efficiently was increased to 1.4 mmol l(-1) . Our results demonstrated that E. coli whole cell is an efficient biocatalyst for biosynthesis of isoflavone metabolites under aerobic conditions. SIGNIFICANCE AND IMPACT OF THE STUDY: Soy isoflavone metabolites, which are more biologically active than their precursor isoflavones, are currently receiving much more attention. However, the non-natural isoflavone metabolites are synthesized or biosynthesized under obligate anaerobic conditions. Here, we describe a new approach to the reduction of soy isoflavones daidzein and genistein under aerobic conditions by use of the recombinant Escherichia coli whole-cell expressing isoflavone reductase. Our study provides the first evidence that isoflavone metabolites, such as dihydrodaidzein and dihydrogenistein, are able to be produced efficiently under aerobic conditions. PMID- 27227797 TI - Mild cognitive impairment is prevalent in persons with severe obesity. AB - OBJECTIVE: This study examines the prevalence of mild cognitive impairment (MCI) in a sample of adults with severe obesity and whether undergoing bariatric surgery reduces the frequency of MCI. METHODS: A total of 171 participants with severe obesity (mean age = 43.07 +/- 11.21) completed computerized cognitive testing. A subset of participants underwent bariatric surgery as part of the Longitudinal Assessment of Bariatric Surgery project. MCI was operationalized using commonly used criteria to establish prevalence in the overall sample and to examine possible changes after bariatric surgery. RESULTS: More than half of the overall sample met criteria for MCI at baseline (53.8%), and MCI was prevalent even in young and middle-aged adults with severe obesity. Within the subset of participants who underwent bariatric surgery, the prevalence of MCI was reduced by 48.9% at 12-month follow-up (from 53.4% to 27.3%). CONCLUSIONS: Findings suggest that many individuals with severe obesity meet criteria for MCI and that prevalence rates decline after bariatric surgery. A better understanding of the mechanisms linking severe obesity to adverse neurological outcomes is much needed. PMID- 27227798 TI - Multimodal blood loss prevention approach including intra-articular tranexamic acid in primary total knee arthroplasty for patients with severe haemophilia A. PMID- 27227812 TI - Modulation of Proton-Coupled Electron Transfer through Molybdenum-Quinonoid Interactions. AB - An expanded series of pi-bound molybdenum-quinonoid complexes supported by pendant phosphines has been synthesized. These compounds formally span three protonation-oxidation states of the quinonoid fragment (catechol, semiquinone, quinone) and two different oxidation states of the metal (Mo(0), Mo(II)), notably demonstrating a total of two protons and four electrons accessible in the system. Previously, the reduced Mo(0)-catechol complex 1 and its reaction with dioxygen to yield the two-proton/two-electron oxidized Mo(0)-quinone compound 4 was explored, while, herein, the expansion of the series to include the two-electron oxidized Mo(II)-catechol complex 2, the one-proton/two-electron oxidized Mo semiquinone complex 3, and the two-proton/four-electron oxidized Mo(II)-quinone complexes 5 and 6 is reported. Transfer of multiple equivalents of protons and electrons from the Mo(0) and Mo(II) catechol complexes, 1 and 2, to H atom acceptor TEMPO suggests the presence of weak O-H bonds. Although thermochemical analyses are hindered by the irreversibility of the electrochemistry of the present compounds, the reactivity observed suggests weaker O-H bonds compared to the free catechol, indicating that proton-coupled electron transfer can be facilitated significantly by the pi-bound metal center. PMID- 27227811 TI - Self-gated cardiac cine imaging using phase information. AB - PURPOSE: To obtain multiphase cardiac cine images with high resolution, a novel self-gating method for both cardiac and respiratory motions is proposed. METHODS: The proposed method uses the phase of projection data obtained from a separate axial slice to measure cardiac and respiratory motion, after the acquisition of every k-space line in the image plane. Cardiac motion is estimated from the phase of the projection data passing through the aorta, which is amplified by superior inferior directional bipolar gradients, whereas respiratory motion is estimated from the phase of the left-right directional projection data of the abdomen. To verify the proposed self-gating method, a simulation and in vivo steady state free precession cardiac imaging were performed. RESULTS: The proposed method provides high resolution multiphase cardiac cine images. Using the proposed self gating method, the phase variation of the projection data offers information about cardiac and respiratory motions that is equivalent to external gating devices. CONCLUSION: The proposed method can capture time-resolved cardiac and respiratory motion from the phase information of the projection data. Because the projection data is obtained from a separate gating slice, the self-gating signals are not affected by imaging planes. Magn Reson Med 77:1216-1222, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27227813 TI - Stratifying prostate cancer patients by relative lymph node involvement: population- and modeling-based study. AB - It is estimated that about 10% of new prostate cancer (PCa) cases are lymph node positive (LN+). We have previously discussed the role of the inflection point (IP) of an inverse Gompertzian survival curve as a surrogate for disease incurability. In this study, we aimed to stratify curability of different patient cohorts with pathologically positive lymph nodes through modeling survival curves by different percentages of LN involvement (%LN+) postoperatively and calculating associated IPs. From the Surveillance, Epidemiology, and End Results (SEER) database, we selected LN+ PCa patients undergoing radical prostatectomy. Modeling of relative survival curves using inverse Gompertzian kinetics for increasing value of maximal %LN+ involvement allowed stratification of cohort into groups with <10%, 10-40%, and greater or equal to 40% of LN+ out of all LNs sampled. Data were retrieved for 5903 patients. For the entire cohort, relative survival was 96%, 87%, and 76% at 5, 10, and 15 years, respectively. For %LN +, <10% the IP was about 27 years postoperatively. Patients with 10-40% LN+ had an IP at about 10 years; for those with more than 40% LN+, the IP was 7 years. A 10-year relative survival decreases from 97% for <10% LN+ to 71% for more than 40% LN+. While better therapies for LN + PCa are badly needed, this patient cadre is not homogenous and should be stratified by %LN+ in future clinical trials. PMID- 27227814 TI - Evaluation of increasing antecedent specificity in goal statements on adherence to positive behavior-management strategies. AB - We evaluated the impact of antecedent specificity in goal statements on adherence to positive behavior-management strategies. Teaching staff were recruited from 2 different school settings where there were routine expectations to use behavior specific praise in the classroom, but adherence was poor. In a concurrent multiple baseline design, the use of behavior-specific praise by 4 participants was found to be unaffected by goal statements that increasingly specified the behavior to be used and the conditions under which the behavior should occur. However, adherence by 3 of the 4 participants did change when goal statements included teacher-specified frequencies with which the behavior should occur. Results were systematically replicated in a second study in which, in a concurrent multiple baseline design, 3 participants showed marked increases in adherence when goal statements specified the target behavior, the conditions under which it should occur, and the frequency with which it should occur. PMID- 27227816 TI - Tailoring Mixed-Halide, Wide-Gap Perovskites via Multistep Conversion Process. AB - Wide-band-gap mixed-halide CH3NH3PbI3-XBrX-based solar cells have been prepared by means of a sequential spin-coating process. The spin-rate for PbI2 as well as its repetitive deposition are important in determining the cross-sectional shape and surface morphology of perovskite, and, consequently, J-V performance. A perovskite solar cell converted from PbI2 with a dense bottom layer and porous top layer achieved higher device performance than those of analogue cells with a dense PbI2 top layer. This work demonstrates a facile way to control PbI2 film configuration and morphology simply by modification of spin-coating parameters without any additional chemical or thermal post-treatment. PMID- 27227817 TI - Physician Office Visits by Children for Well and Problem-focused Care: United States, 2012. AB - KEY FINDINGS: Data from the National Ambulatory Medical Care Survey, 2012 *Physician office visit rates for well care were lower for school-aged (those aged 6-11 years) children (31 per 100 population) and adolescents aged 12-17 years (29 per 100 population) than for younger children (349 and 74 per 100 population for children under age 1 year and 1-5 years, respectively). *Visit rates for well and problem-focused care were highest for general pediatricians (59 and 173 per 100 population) compared with other primary (7 and 25 per 100 population) and specialty care providers (1 and 24 per 100 population) across all age groups. *Among school-aged and adolescent children, a higher percentage of well-care visits had recommended height, weight, and blood pressure measurements recorded, compared with visits for problem-focused care. PMID- 27227818 TI - Coaxial carbon@boron nitride nanotube arrays with enhanced thermal stability and compressive mechanical properties. AB - Vertically aligned carbon nanotube (CNT) arrays have aroused considerable interest because of their remarkable mechanical properties. However, the mechanical behaviour of as-synthesized CNT arrays could vary drastically at a macro-scale depending on their morphologies, dimensions and array density, which are determined by the synthesis method. Here, we demonstrate a coaxial carbon@boron nitride nanotube (C@BNNT) array with enhanced compressive strength and shape recoverability. CNT arrays are grown using a commercially available thermal chemical vapor deposition (TCVD) technique and an outer BNNT with a wall thickness up to 1.37 nm is introduced by a post-growth TCVD treatment. Importantly, compared to the as-grown CNT arrays which deform almost plastically upon compression, the coaxial C@BNNT arrays exhibit an impressive ~4-fold increase in compressive strength with nearly full recovery after the first compression cycle at a 50% strain (76% recovery maintained after 10 cycles), as well as a significantly high and persistent energy dissipation ratio (~60% at a 50% strain after 100 cycles), attributed to the synergistic effect between the CNT and outer BNNT. Additionally, the as-prepared C@BNNT arrays show an improved structural stability in air at elevated temperatures, attributing to the outstanding thermal stability of the outer BNNT. This work provides new insights into tailoring the mechanical and thermal behaviours of arbitrary CNT arrays which enables a broader range of applications. PMID- 27227815 TI - Circulating let-7 levels in plasma and extracellular vesicles correlate with hepatic fibrosis progression in chronic hepatitis C. AB - The goal of this study was to determine whether an association exists between circulating microRNA (miRNA) levels and disease progression in chronic hepatitis C (CHC), whether plasma or extracellular vesicles (EVs) were optimal for miRNA measurement and their correlation with hepatic miRNA expression, and the mechanistic plausibility of this association. We studied 130 CHC patients prospectively followed over several decades. A comprehensive miRNA profile in plasma using microarray with 2578 probe sets showed 323 miRNAs differentially expressed between healthy individuals and CHC patients, but only six that distinguished patients with mild versus severe chronic hepatitis. Eventually, let 7a/7c/7d-5p and miR-122-5p were identified as candidate predictors of disease progression. Cross-sectional analyses at the time of initial liver biopsy showed that reduced levels of let-7a/7c/7d-5p (let-7s) in plasma were correlated with advanced histological hepatic fibrosis stage and other fibrotic markers, whereas miR-122-5p levels in plasma were positively correlated with inflammatory activity, but not fibrosis. Measuring let-7s levels in EVs was not superior to intact plasma for discriminating significant hepatic fibrosis. Longitudinal analyses in 60 patients with paired liver biopsies showed that let-7s levels in plasma markedly declined over time in parallel with fibrosis progression. However, circulating let-7s levels did not parallel those in the liver. CONCLUSION: Of all miRNAs screened, the let-7 family showed the best correlation with hepatic fibrosis in CHC. A single determination of let-7s levels in plasma did not have superior predictive value for significant hepatic fibrosis compared with that of fibrosis-4 index, but the rate of let-7s decline in paired longitudinal samples correlated well with fibrosis progression. Pathway analysis suggested that low levels of let-7 may influence hepatic fibrogenesis through activation of transforming growth factor beta signaling in hepatic stellate cells. (Hepatology 2016;64:732-745). PMID- 27227819 TI - Increased Biological Effective Dose of Radiation Correlates with Prolonged Survival of Patients with Limited-Stage Small Cell Lung Cancer: A Systematic Review. AB - OBJECTIVE: Thoracic radiotherapy (TRT) is a critical component of the treatment of limited-stage small cell lung cancer (LS-SCLC). However, the optimal radiation dose/fractionation remains elusive. This study reviewed current evidence and explored the dose-response relationship in patients with LS-SCLC who were treated with radiochemotherapy. MATERIALS AND METHODS: A quantitative analysis was performed through a systematic search of PubMed, Web of Science, and the Cochrane Library. The correlations between the biological effective dose (BED) and median overall survival (mOS), median progression-free survival (mPFS), 1-, 3-, and 5 year overall survival (OS) as well as local relapse (LR) were evaluated. RESULTS: In all, 2389 patients in 19 trials were included in this study. Among these 19 trials, seven were conducted in Europe, eight were conducted in Asia and four were conducted in the United States. The 19 trials that were included consisted of 29 arms with 24 concurrent and 5 sequential TRT arms. For all included studies, the results showed that a higher BED prolonged the mOS (R2 = 0.198, p<0.001) and the mPFS (R2 = 0.045, p<0.001). The results also showed that increased BED improved the 1-, 3-, and 5-year OS. A 10-Gy increment added a 6.3%, a 5.1% and a 3.7% benefit for the 1-, 3-, and 5-year OS, respectively. Additionally, BED was negatively correlated with LR (R2 = 0.09, p<0.001). A subgroup analysis of concurrent TRT showed that a high BED prolonged the mOS (p<0.001) and the mPFS (p<0.001), improved the 1-, 3-, and 5-year OS (p<0.001) and decreased the rate of LR (p<0.001). CONCLUSION: This study showed that an increased BED was associated with improved OS, PFS and decreased LR in patients with LS-SCLC who were treated with combined chemoradiotherapy, which indicates that the strategy of radiation dose escalation over a limited time frame is worth exploring in a prospective clinical trial. PMID- 27227820 TI - Role of Ca(2+) in the Stability and Function of TMEM16F and 16K. AB - There are 10 transmembrane protein (TMEM) 16-family proteins in humans and mice. Among them, TMEM16F acts as a Ca(2+)-dependent phospholipid scramblase at the plasma membrane. However, how Ca(2+) activates TMEM16F's phospholipid-scramblase activity has not been elucidated. Here we found that in the presence of Ca(2+), TMEM16K (whose function is unknown) directly binds Ca(2+) to form a stable complex that can be detected by blue-native polyacrylamide gel electrophoresis. In the absence of Ca(2+), TMEM16K and TMEM16F aggregated, suggesting that their structure is stabilized by Ca(2+). Comprehensive mutagenesis of acidic residues in TMEM16K's cytoplasmic and transmembrane regions identified five residues that are critical for binding Ca(2+). These residues were well conserved between TMEM16F and 16K, and point mutations of these residues in TMEM16F reduced its ability to support Ca(2+)-dependent phospholipid scrambling. Our results suggest that Ca(2+) binds TMEM16F directly and induces conformational changes that support its stability and function. PMID- 27227822 TI - Announcement: National High Blood Pressure Education Month - May 2016. AB - May is National High Blood Pressure Education Month. High blood pressure (hypertension) is a major contributor to heart disease and stroke, two leading causes of death in the United States.* High blood pressure affects one third of U.S. adults, or approximately 75 million persons, yet approximately 11 million of these persons are not aware they have hypertension, and approximately 18 million are not being treated (unpublished data) (1,2). PMID- 27227821 TI - Animal Models of Rheumatoid Arthritis (I): Pristane-Induced Arthritis in the Rat. AB - BACKGROUND: To facilitate the development of therapies for rheumatoid arthritis (RA), the Innovative Medicines Initiative BTCure has combined the experience from several laboratories worldwide to establish a series of protocols for different animal models of arthritis that reflect the pathogenesis of RA. Here, we describe chronic pristane-induced arthritis (PIA) model in DA rats, and provide detailed instructions to set up and evaluate the model and for reporting data. METHODS: We optimized dose of pristane and immunization procedures and determined the effect of age, gender, and housing conditions. We further assessed cage-effects, reproducibility, and frequency of chronic arthritis, disease markers, and efficacy of standard and novel therapies. RESULTS: Out of 271 rats, 99.6% developed arthritis after pristane-administration. Mean values for day of onset, day of maximum arthritis severity and maximum clinical scores were 11.8+/-2.0 days, 20.3+/-5.1 days and 34.2+/-11 points on a 60-point scale, respectively. The mean frequency of chronic arthritis was 86% but approached 100% in long-term experiments over 110 days. Pristane was arthritogenic even at 5 microliters dose but needed to be administrated intradermally to induce robust disease with minimal variation. The development of arthritis was age-dependent but independent of gender and whether the rats were housed in conventional or barrier facilities. PIA correlated well with weight loss and acute phase reactants, and was ameliorated by etanercept, dexamethasone, cyclosporine A and fingolimod treatment. CONCLUSIONS: PIA has high incidence and excellent reproducibility. The chronic relapsing-remitting disease and limited systemic manifestations make it more suitable than adjuvant arthritis for long-term studies of joint-inflammation and screening and validation of new therapeutics. PMID- 27227823 TI - Rates and Predictors of Obesity Among African American Sexual Minority Women. AB - PURPOSE: The purpose of this study is to examine rates of and risk factors for obesity in a community sample of African American sexual minority women (SMW). METHODS: Data were collected using self-administered paper-and-pencil survey questionnaires (n = 219). RESULTS: Participants were primarily middle aged (M = 40.1; standard deviation [SD] = 10.5 years), well educated (56.9% with a college education and above), insured (82.3%), and had a median income range from $30,000 to $39,999. The mean body mass index (BMI) of the sample was 31.6 (SD = 8.0). Based on BMI scores, over half of the participants were identified as obese (53.9%) and 25.6% were overweight. A number of comorbid illnesses were reported that could be exacerbated by excess weight, including arthritis (21.3%), adult onset diabetes (4.9%), back problems (23.2%), high cholesterol (15.3%), high blood pressure (19.2%), and heart disease (12%). Multiple risk factors for obesity were observed, including infrequent exercise (<3 times/week = 50.9%), low levels of fruit/vegetable consumption (<=1 serving daily = 39.9%), and frequent consumption of red meat (>=3 times/week = 21.2%). Psychosocial risk factors were also reported, including "eating in response to stress" (46.0%). Depression scores predicted eating in response to stress. One-third of the sample reported interest in weight management interventions. CONCLUSIONS: African American SMW report high rates of obesity, chronic health conditions exacerbated by weight, and health and dietary behaviors that increase risk for weight-related health disparities. These study findings have implications for additional research and intervention development. PMID- 27227825 TI - Pancreatic cancer. PMID- 27227824 TI - Quantifying metal-induced susceptibility artifacts of the instrumented spine at 1.5T using fast-spin echo and 3D-multispectral MRI. AB - PURPOSE: To evaluate magnetic resonance imaging (MRI) artifacts near metallic spinal instrumentation using both conventional metal artifact reduction sequences (MARS) and 3D multispectral imaging sequences (3D-MSI). MATERIALS AND METHODS: Both MARS and 3D-MSI images were acquired in 10 subjects with titanium spinal hardware on a 1.5T GE 450W scanner. Clinical computed tomography (CT) images were used to measure the volume of the implant using seed-based region growing. Using 30-40 landmarks, the MARS and 3D-MSI images were coregistered to the CT images. Three independent users manually segmented the artifact volume from both MR sequences. For five L-spine subjects, one user independently segmented the nerve root in both MARS and 3D-MSI images. RESULTS: For all 10 subjects, the measured artifact volume for the 3D-MSI images closely matched that of the CT implant volume (absolute error: 4.3 +/- 2.0 cm3 ). The MARS artifact volume was ~8-fold higher than that of the 3D-MSI images (30.7 +/- 20.2, P = 0.002). The average nerve root volume for the MARS images was 24 +/- 7.3% lower than the 3D-MSI images (P = 0.06). CONCLUSION: Compared to 3D-MSI images, the higher-resolution MARS images may help study features farther away from the implant surface. However, the MARS images retained substantial artifacts in the slice-dimension that result in a larger artifact volume. These artifacts have the potential to obscure physiologically relevant features, and can be mitigated with 3D-MSI sequences. Hence, MR study protocols may benefit with the inclusion both MARS and 3D-MSI sequences to accurately study pathology near the spine. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:51-58. PMID- 27227826 TI - The Rise of Disease Ecology and Its Implications for Parasitology- A Review. AB - : Many fields in the biological sciences have witnessed a shift away from organism- or taxon-focused research and teaching in favor of more conceptual and process-driven paradigms. The field of parasitology is no exception, despite the diversity of topics and taxa it encompasses. Concurrently, however, interest in disease ecology has increased dramatically, suggesting new opportunities that merit exploration, as well as the need for parasitology to promote its long history of ecological research to do so. Here we undertake a quantitative analysis of metrics relating to publications, research funding, career opportunities, and undergraduate teaching to comprehensively illustrate the rising prominence of disease ecology. While we distinguish generally between the fields of parasitology and disease ecology, we also emphasize the common interests and complementary approaches that enhanced integration could offer. To illustrate why enhanced integration between these 2 fields is increasingly critical, we highlight 2 successful areas in which parasitology and disease ecology have intersected (community assembly and scale, and the effects of natural enemies on life history traits). We conclude by identifying "frontier topics" that will benefit from greater cooperation and interaction between these currently relatively separate areas and the need for principal investigators to identify and communicate changes in their discipline to students and trainees, which will collectively result in many possible new benefits and prospects for current and future researchers. PMID- 27227827 TI - Location, Location, Location: Five Facts about Tissue Tropism and Pathogenesis. PMID- 27227828 TI - A Reversibly Sealed, Easy Access, Modular (SEAM) Microfluidic Architecture to Establish In Vitro Tissue Interfaces. AB - Microfluidic barrier tissue models have emerged as advanced in vitro tools to explore interactions with external stimuli such as drug candidates, pathogens, or toxins. However, the procedures required to establish and maintain these systems can be challenging to implement for end users, particularly those without significant in-house engineering expertise. Here we present a module-based approach that provides an easy-to-use workflow to establish, maintain, and analyze microscale tissue constructs. Our approach begins with a removable culture insert that is magnetically coupled, decoupled, and transferred between standalone, prefabricated microfluidic modules for simplified cell seeding, culture, and downstream analysis. The modular approach allows several options for perfusion including standard syringe pumps or integration with a self-contained gravity-fed module for simple cell maintenance. As proof of concept, we establish a culture of primary human microvascular endothelial cells (HMVEC) and report combined surface protein imaging and gene expression after controlled apical stimulation with the bacterial endotoxin lipopolysaccharide (LPS). We also demonstrate the feasibility of incorporating hydrated biomaterial interfaces into the microfluidic architecture by integrating an ultra-thin (< 1 MUm), self assembled hyaluronic acid/peptide amphiphile culture membrane with brain-specific Young's modulus (~ 1kPa). To highlight the importance of including biomimetic interfaces into microscale models we report multi-tiered readouts from primary rat cortical cells cultured on the self-assembled membrane and compare a panel of mRNA targets with primary brain tissue signatures. We anticipate that the modular approach and simplified operational workflows presented here will enable a wide range of research groups to incorporate microfluidic barrier tissue models into their work. PMID- 27227829 TI - Quantifying the Epidemiological Impact of Vector Control on Dengue. PMID- 27227831 TI - Meta-Analysis of Serum Insulin-Like Growth Factor 1 in Alzheimer's Disease. AB - Insulin-like growth factor 1 (IGF-1) serum levels have been reported to be altered in Alzheimer's disease patients, and it was suggested that the changes in IGF-1 serum level may play a role in disease pathology and progression. However, this notion remained controversial due to conflicting findings. We conducted a meta-analysis to determine the relationship between IGF-1 serum levels and Alzheimer's disease. We searched the databases PUBMED, Ovid SP, and Cochrane library for relevant studies. The primary data analyzed was serum IGF-1 from Alzheimer's disease subjects and controls. Pooled weighted mean difference using a random effects model was used to determine the relationship between serum levels and disease state. Nine studies were included in the meta-analysis compromising a total of 1639 subjects. The pooled weighted mean difference was 2.27ng/ml (95% CI: [-22.221, 17.66]) with a P value of 0.82. Thus our finding did not show clear relationship between low IGF-1 and Alzheimer's disease subjects. We did not find evidence of publication bias by analyzing a funnel plot as well as Egger's and Begg's tests. While eight out of the nine studies included in this meta-analysis detected a statistically significant increase or decrease in serum levels of IGF-1 in Alzheimer's disease subjects, the analysis as a whole did not show a significant trend in either direction. Thus, IGF-1 level is likely a critical personalized factor. A large database of clinical trials is required for better understanding the relationship between IGF-1 levels and Alzheimer's disease. PMID- 27227830 TI - Authentication of Herbal Supplements Using Next-Generation Sequencing. AB - BACKGROUND: DNA-based testing has been gaining acceptance as a tool for authentication of a wide range of food products; however, its applicability for testing of herbal supplements remains contentious. METHODS: We utilized Sanger and Next-Generation Sequencing (NGS) for taxonomic authentication of fifteen herbal supplements representing three different producers from five medicinal plants: Echinacea purpurea, Valeriana officinalis, Ginkgo biloba, Hypericum perforatum and Trigonella foenum-graecum. Experimental design included three modifications of DNA extraction, two lysate dilutions, Internal Amplification Control, and multiple negative controls to exclude background contamination. Ginkgo supplements were also analyzed using HPLC-MS for the presence of active medicinal components. RESULTS: All supplements yielded DNA from multiple species, rendering Sanger sequencing results for rbcL and ITS2 regions either uninterpretable or non-reproducible between the experimental replicates. Overall, DNA from the manufacturer-listed medicinal plants was successfully detected in seven out of eight dry herb form supplements; however, low or poor DNA recovery due to degradation was observed in most plant extracts (none detected by Sanger; three out of seven-by NGS). NGS also revealed a diverse community of fungi, known to be associated with live plant material and/or the fermentation process used in the production of plant extracts. HPLC-MS testing demonstrated that Ginkgo supplements with degraded DNA contained ten key medicinal components. CONCLUSION: Quality control of herbal supplements should utilize a synergetic approach targeting both DNA and bioactive components, especially for standardized extracts with degraded DNA. The NGS workflow developed in this study enables reliable detection of plant and fungal DNA and can be utilized by manufacturers for quality assurance of raw plant materials, contamination control during the production process, and the final product. Interpretation of results should involve an interdisciplinary approach taking into account the processes involved in production of herbal supplements, as well as biocomplexity of plant-plant and plant-fungal biological interactions. PMID- 27227832 TI - Exploring the Origin of Differential Binding Affinities of Human Tubulin Isotypes alphabetaII, alphabetaIII and alphabetaIV for DAMA-Colchicine Using Homology Modelling, Molecular Docking and Molecular Dynamics Simulations. AB - Tubulin isotypes are found to play an important role in regulating microtubule dynamics. The isotype composition is also thought to contribute in the development of drug resistance as tubulin isotypes show differential binding affinities for various anti-cancer agents. Tubulin isotypes alphabetaII, alphabetaIII and alphabetaIV show differential binding affinity for colchicine. However, the origin of differential binding affinity is not well understood at the molecular level. Here, we investigate the origin of differential binding affinity of a colchicine analogue N-deacetyl-N-(2-mercaptoacetyl)-colchicine (DAMA-colchicine) for human alphabetaII, alphabetaIII and alphabetaIV isotypes, employing sequence analysis, homology modeling, molecular docking, molecular dynamics simulation and MM-GBSA binding free energy calculations. The sequence analysis study shows that the residue compositions are different in the colchicine binding pocket of alphabetaII and alphabetaIII, whereas no such difference is present in alphabetaIV tubulin isotypes. Further, the molecular docking and molecular dynamics simulations results show that residue differences present at the colchicine binding pocket weaken the bonding interactions and the correct binding of DAMA-colchicine at the interface of alphabetaII and alphabetaIII tubulin isotypes. Post molecular dynamics simulation analysis suggests that these residue variations affect the structure and dynamics of alphabetaII and alphabetaIII tubulin isotypes, which in turn affect the binding of DAMA-colchicine. Further, the binding free-energy calculation shows that alphabetaIV tubulin isotype has the highest binding free-energy and alphabetaIII has the lowest binding free-energy for DAMA-colchicine. The order of binding free energy for DAMA-colchicine is alphabetaIV ? alphabetaII >> alphabetaIII. Thus, our computational approaches provide an insight into the effect of residue variations on differential binding of alphabetaII, alphabetaIII and alphabetaIV tubulin isotypes with DAMA-colchicine and may help to design new analogues with higher binding affinities for tubulin isotypes. PMID- 27227833 TI - New Cricetid Rodents from Strata near the Eocene-Oligocene Boundary in Erden Obo Section (Nei Mongol, China). AB - New cricetids (Eucricetodon wangae sp. nov., Eucricetodon sp. and Pappocricetodon siziwangqiensis sp. nov.) are reported from the lower and middle parts of the "Upper Red" beds of the Erden Obo section in Nei Mongol, China. Eucricetodon wangae is more primitive than other known species of the genus from lower Oligocene of Asia and Europe in having a single anterocone on M1, a single connection between the protocone and the paracone, the anterior metalophule connection in M1-2 and weaker anteroconid and ectomesolophid in lower molars. Pappocricetodon siziwangqiensis is more advanced than other species of the genus in permanently missing P4 and having posterior protolophule connection. These fossils suggest that the age of the "Upper Red" of the Erden Obo section is younger than the age of the Upper Eocene Houldjin and Caijiachong formations, but older than those containing the Shandgolian faunas; the "Upper Red" is most closely correlative to the Ergilian beds in age, and probably close to the Eocene/Oligocene boundary. Given the age estimate, Eucricetodon wangae provides the new evidence to support that cricetid dispersal from Asia to Europe occurred prior to the Eocene-Oligocene boundary. PMID- 27227834 TI - Error in Figure Legends. PMID- 27227836 TI - Editorial Comment: Therapeutic Hypothermia and Temperature Management. PMID- 27227835 TI - Different Effects of Metarhizium anisopliae Strains IMI330189 and IBC200614 on Enzymes Activities and Hemocytes of Locusta migratoria L. AB - BACKGROUND: Metarhizium is an important class of entomopathogenic fungi in the biocontrol of insects, but its virulence is affected by insect immunity. To clarify the mechanism in virulence of Metarhizium, we compared the immunological differences in Locusta migratoria L. when exposed to two strains of Metarhizium anisopliae (Ma). RESULTS: The virulence of Ma IMI330189 was significantly higher than that of Ma IBC200614 to locust, and IMI330189 overcame the hemocytes and began destroying the hemocytes of locust at 72 h after spray, while locust is immune to IBC200614. IMI330189 could overcome the humoral immunity of locust by inhibiting the activities of phenol oxidase (PO), esterases, multi-function oxidases (MFOs) and acetylcholinesterases in locust while increasing the activities of glutathione-S-transferases (GSTs), catalase and aryl-acylamidase (AA). However IBC200614 inhibit the activities of GSTs and AA in locust and increase the activities of MFOs, PO, superoxide dismutase, peroxidase and chitinase in locust. The changes of enzymes activities in period of infection showed that the time period between the 2nd and the 5th day after spray is critical in the pathogenic process. CONCLUSION: These results found the phenomenon that Ma initiatively broke host hemocytes, revealed the correlation between the virulence of Ma and the changes of enzymes activities in host induced by Ma, and clarified the critical period in the infection of Ma. So, these results should provide guidance for the construction of efficient biocontrol Ma strains. PMID- 27227838 TI - Biomimetic Collective Total Synthesis of Bioactive Carbazole Alkaloids Indizoline, Mafaicheenamine A, Claulamine A, Claulansine A, and the Proposed Claulamine E. AB - The common precursor 1-methoxy-2-prenyl-3-carbomethoxycarbazole was synthesized from dimethyl indolylmethylenesuccinate in four steps. Well-planned reductive and/or oxidative transformations and intramolecular cyclizations were performed on a pivotal common precursor to accomplish collective first total synthesis of titled natural products and proposed claulamine E. Burgess reagent induced formation of kinetically controlled product claulamine A, and intramolecular cyclizations to form bicyclic claulansine A were the key reactions. An alternatively attempted synthesis failed to provide the structural isomer of proposed claulamine E. PMID- 27227837 TI - Production of 3-Hydroxypropionic Acid via the Propionyl-CoA Pathway Using Recombinant Escherichia coli Strains. AB - Our study aimed to produce the commercially promising platform chemical 3 hydroxypropionic acid (3-HP) via the propionyl-CoA pathway in genetically engineered Escherichia coli. Recombinant E. coli Ec-P overexpressing propionyl CoA dehydrogenase (PACD, encoded by the pacd gene from Candida rugosa) under the T7 promoter produced 1.33 mM of 3-HP in a shake flask culture supplemented with 0.5% propionate. When propionate CoA-transferase (PCT, encoded by the pct gene from Megasphaera elsdenii) and 3-hydroxypropionyl-CoA dehydratase (HPCD, encoded by the hpcd gene from Chloroflexus aurantiacus) were expressed along with PACD, the 3-HP titer of the resulting E. coli Ec-PPH strain was improved by 6-fold. The effect of the cultivation conditions on the 3-HP yield from propionate in the Ec PPH strain was also investigated. When cultured at 30 degrees C with 1% glucose in addition to propionate, 3-HP production by Ec-PPH increased 2-fold and 12-fold compared to the cultivation at 37 degrees C (4.23 mM) or without glucose (0.68 mM). Deletion of the ygfH gene encoding propionyl-CoA: succinate CoA-transferase from Ec-PPH (resulting in the strain Ec-?Y-PPH) led to increase of 3-HP production in shake flask experiments (15.04 mM), whereas the strain Ec-?Y-PPH with deletion of the prpC gene (encoding methylcitrate synthase in the methylcitrate cycle) produced 17.76 mM of 3-HP. The strain Ec-?Y-?P-PPH with both ygfH and prpC genes deleted produced 24.14 mM of 3-HP, thus showing an 18-fold increase in the 3-HP titer in compare to the strain Ec-P. PMID- 27227839 TI - Polyamine derivatives: a revival of an old neglected scaffold to fight resistant Gram-negative bacteria? AB - Emergence of multidrug-resistant pathogens was responsible for microbial infections and inefficacy of numerous antimicrobial therapies has induced a need for the research of new classes of antibiotics. In this review, we will focus our interest toward the biological properties of polyamino antimicrobial agents. PMID- 27227840 TI - Welcoming Our Bright, Shiny New Colleagues. AB - We were all new nurses once. PMID- 27227841 TI - The Professional Introduction. AB - The key to establishing the relationship between nurse and patient. PMID- 27227842 TI - Hands-On Care. PMID- 27227843 TI - Consequences of 12-Hour Shifts. PMID- 27227844 TI - The Big Picture. PMID- 27227847 TI - Rates of Premature Death Rise in Rural Counties. AB - Smoking patterns, diet, and a lack of access to care may account for large health disparities. PMID- 27227849 TI - States Providing Inaccurate Clinical Information Before Abortion. AB - Misinformation is common, particularly regarding first-trimester fetal development. PMID- 27227850 TI - Early Ingestion of Peanuts May Be Effective in Reducing Peanut Allergies. AB - Protection apparently persists for one year, but important questions remain. PMID- 27227852 TI - HPV Vaccine Linked to Steep Reduction of Virus in Teen Girls. AB - Women in their early 20s also experienced a significant, though smaller, decrease. PMID- 27227855 TI - Evidence-Based Care Is Highly Valued but Underused by Many Nurse Executives. AB - Nursing executives create an evidence-based culture. PMID- 27227857 TI - Violence Against Nurses in the Workplace. AB - Consolidated approaches are needed from employers, victims, and the political system. PMID- 27227858 TI - Praxbind Available as Antidote to Bleeding from Pradaxa. PMID- 27227859 TI - New Adjunct Therapy for Partial-Onset Seizures. PMID- 27227860 TI - Improving Adherence to Drug Regimens. PMID- 27227864 TI - Securement and Dressing Devices for Central Venous Catheters. AB - Editor's note: This is a summary of a nursing care-related systematic review from the Cochrane Library. PMID- 27227865 TI - Nurses in the Civil Rights Movement. AB - Six brave, committed health care workers who joined the struggle for racial equality. PMID- 27227866 TI - Just Breathe: A Nurse's Tough Love Proves Crucial During One Mother's Labor. AB - Updated several times a week with posts by a wide variety of authors, AJN's blog Off the Charts allows us to provide more timely-and often more personal perspectives on professional, policy, and clinical issues. Best of the Blog will be a regular column to bring AJN readers recent posts that we think deserve a wider audience. To read more, please visit: www.ajnoffthecharts.com. PMID- 27227867 TI - Palliative Chemotherapy. AB - This article is the first in a series on palliative care developed in collaboration with the Hospice and Palliative Nurses Association (HPNA; http://hpna.advancingexpertcare.org). The HPNA aims to guide nurses in preventing and relieving suffering and in giving the best possible care to patients and families, regardless of the stage of disease or the need for other therapies. The HPNA offers education, certification, advocacy, leadership, and research. PMID- 27227868 TI - Improving Access to Human Milk in the NICU (and Beyond). AB - As part of its Raise the Voice campaign to showcase nurses who are key players in transforming health care, the American Academy of Nursing has identified nurses they call edge runners-"practical innovators who have led the way in bringing new thinking and new methods to a wide range of health care challenges." This is the sixth in AJN's series of profiles of these nursing innovators. Read and be proud of what nurses can accomplish. PMID- 27227869 TI - A New Nurse's First Days at the Bedside. AB - This column is designed to help new nurses in their first year at the bedside-a time of insecurity, growth, and constant challenges-and to offer advice as they learn what it means to be a nurse. This first article addresses new nurses' anxiety at the bedside and offers practical tips on how to prepare for your first day. PMID- 27227870 TI - A False-Positive Screening Mammogram Suggests Higher Breast Cancer Risk. PMID- 27227871 TI - Long-Term Aspirin Use May Reduce Cancer Risk. PMID- 27227872 TI - Wheelchair-Bound Patients Who Exercise Can Prevent Further Disability. PMID- 27227873 TI - The Incidence of Dementia is Decreasing. PMID- 27227874 TI - I'm Not a Nurse, but My Mother Was. AB - When crisis strikes close to home, who will fill the gap left by a mother's death? PMID- 27227875 TI - New insights in the selection and management of cancer patients applicants for ovarian tissue cryopreservation. AB - Ovarian tissue cryopreservation (OTC), representing a promising strategy to preserve ovarian function in cancer patients, is recommended to women younger than 35 years. This study aimed to identify endocrine and biometric parameters as additional selection criteria for OTC. One hundred and ninety-one cancer patients before chemoradiotherapy and OTC and 43 controls were investigated. Mean +/- SD, median, quartiles, 5th and 95th centiles and correlations of FSH, LH, estradiol, inhibin-B, anti-Mullerian hormone (AMH), ovarian volume and antral follicle count (AFC) were assessed. Most ovarian reserve parameters presented typical variations of ovulatory menstrual cycle, except AMH and AFC showing minimal fluctuations across the menstrual cycle. The 5th centiles of AMH (0.31and 0.4 ng/mL in controls and cancer patients, respectively) and AFC (five follicular structures in both groups) could be conjectured as minimum thresholds to include patients aged <35 years in OTC; below this threshold patients of any age should be excluded from OTC. Conversely, patients with AMH and AFC above the 25th centiles (1.2-1.6 ng/mL and 9-10 follicular structures in controls and cancer patients, respectively) might be inserted in OTC regardless of age. Baseline assessment of AMH and AFC might be considered as selection criteria, in addition to chronological age, to take decision of OTC in cancer patients. PMID- 27227877 TI - Acne vulgaris. PMID- 27227876 TI - The Effect of Subcutaneous Fat on Electrical Impedance Myography: Electrode Configuration and Multi-Frequency Analyses. AB - This study investigates the impact of the subcutaneous fat layer (SFL) thickness on localized electrical impedance myography (EIM), as well as the effects of different current electrodes, varying in distance and direction, on EIM output. Twenty-three healthy subjects underwent localized multi-frequency EIM on their biceps brachii muscles with a hand-held electrode array. The EIM measurements were recorded under three different configurations: wide (or outer) longitudinal configuration 6.8 cm, narrow (or inner) longitudinal configuration 4.5 cm, and narrow transverse configuration 4.5 cm. Ultrasound was applied to measure the SFL thickness. Coefficients of determination (R2) of three EIM variables (resistance, reactance, and phase) and SFL thickness were calculated. For the longitudinal configuration, the wide distance could reduce the effects of the subcutaneous fat when compared with the narrow distance, but a significant correlation still remained for all three EIM parameters. However, there was no significant correlation between SFL thickness and reactance in the transverse configuration (R2 = 0.0294, p = 0.434). Utilizing a ratio of 50kHz/100kHz phase was found to be able to help reduce the correlation with SFL thickness for all the three configurations. The findings indicate that the appropriate selection of the current electrode distance, direction and the multi-frequency phase ratio can reduce the impact of subcutaneous fat on EIM. These settings should be evaluated for future clinical studies using hand-held localized arrays to perform EIM. PMID- 27227878 TI - Silver-Mediated anti-Markovnikov and Markovnikov-Selective Hydrotrifluoromethylthiolation of Terminal Alkynes. AB - The first example of direct hydrotrifluoromethylthiolation of terminal alkynes in the presence of AgSCF3 and K2S2O8 was established for the synthesis of a variety of vinyl trifluoromethyl thioethers. The anti-Markovnikov and Markovnikov adducts were obtained in moderate to good yields via two different reaction systems. Studies to probe the mechanism of the anti-Markovnikov addition reactions including the radical trapping experiments, kinetic isotope effect experiments, and deuterated experiments for determination of H-sources were conducted. PMID- 27227879 TI - Suppression of USP18 Potentiates the Anti-HBV Activity of Interferon Alpha in HepG2.2.15 Cells via JAK/STAT Signaling. AB - Ubiquitin-specific protease 18 (USP18, also known as UBP43) has both interferon stimulated gene 15 (ISG15) dependent and ISG15-independent functions. By silencing the expression of USP18 in HepG2.2.15 cells, we studied the effect of USP18 on the anti-HBV activity of IFN-F and demonstrated that knockdown of USP18 significantly Inhibited the HBV expression and increased the expression of ISGs. Levels of hepatitis B virus surface antigen (HBsAg), hepatitis B virus e antigen (HBeAg), HBV DNA and intracellular hepatitis B virus core antigen (HBcAg) were dramatically decreased with or without treatment of indicated dose of IFN-F. Suppression of USP18 activated the JAK/STAT signaling pathway as shown by the increased and prolonged expression of phosphorylated signal transducer and activator of transcription 1 (p-STAT1) in combination with enhanced expression of several interferon stimulated genes (ISGs). Our results indicated that USP18 modulates the anti-HBV activity of IFN-F via activation of the JAK/STAT signaling pathway in Hepg2.2.15 cells. PMID- 27227880 TI - Quantitative Trait Loci for Yield and Yield-Related Traits in Spring Barley Populations Derived from Crosses between European and Syrian Cultivars. AB - In response to climatic changes, breeding programmes should be aimed at creating new cultivars with improved resistance to water scarcity. The objective of this study was to examine the yield potential of barley recombinant inbred lines (RILs) derived from three cross-combinations of European and Syrian spring cultivars, and to identify quantitative trait loci (QTLs) for yield-related traits in these populations. RILs were evaluated in field experiments over a period of three years (2011 to 2013) and genotyped with simple sequence repeat (SSR) and single nucleotide polymorphism (SNP) markers; a genetic map for each population was constructed and then one consensus map was developed. Biological interpretation of identified QTLs was achieved by reference to Ensembl Plants barley gene space. Twelve regions in the genomes of studied RILs were distinguished after QTL analysis. Most of the QTLs were identified on the 2H chromosome, which was the hotspot region in all three populations. Syrian parental cultivars contributed alleles decreasing traits' values at majority of QTLs for grain weight, grain number, spike length and time to heading, and numerous alleles increasing stem length. The phenomic and molecular approaches distinguished the lines with an acceptable grain yield potential combining desirable features or alleles from their parents, that is, early heading from the Syrian breeding line (Cam/B1/CI08887//CI05761) and short plant stature from the European semidwarf cultivar (Maresi). PMID- 27227881 TI - Potentially Reversible Effect of Niacin Therapy on Edema From Retinal Vein Occlusion. PMID- 27227882 TI - A Neuronal Culture System to Detect Prion Synaptotoxicity. AB - Synaptic pathology is an early feature of prion as well as other neurodegenerative diseases. Although the self-templating process by which prions propagate is well established, the mechanisms by which prions cause synaptotoxicity are poorly understood, due largely to the absence of experimentally tractable cell culture models. Here, we report that exposure of cultured hippocampal neurons to PrPSc, the infectious isoform of the prion protein, results in rapid retraction of dendritic spines. This effect is entirely dependent on expression of the cellular prion protein, PrPC, by target neurons, and on the presence of a nine-amino acid, polybasic region at the N-terminus of the PrPC molecule. Both protease-resistant and protease-sensitive forms of PrPSc cause dendritic loss. This system provides new insights into the mechanisms responsible for prion neurotoxicity, and it provides a platform for characterizing different pathogenic forms of PrPSc and testing potential therapeutic agents. PMID- 27227883 TI - Projected Impact of Dengue Vaccination in Yucatan, Mexico. AB - Dengue vaccines will soon provide a new tool for reducing dengue disease, but the effectiveness of widespread vaccination campaigns has not yet been determined. We developed an agent-based dengue model representing movement of and transmission dynamics among people and mosquitoes in Yucatan, Mexico, and simulated various vaccine scenarios to evaluate effectiveness under those conditions. This model includes detailed spatial representation of the Yucatan population, including the location and movement of 1.8 million people between 375,000 households and 100,000 workplaces and schools. Where possible, we designed the model to use data sources with international coverage, to simplify re-parameterization for other regions. The simulation and analysis integrate 35 years of mild and severe case data (including dengue serotype when available), results of a seroprevalence survey, satellite imagery, and climatological, census, and economic data. To fit model parameters that are not directly informed by available data, such as disease reporting rates and dengue transmission parameters, we developed a parameter estimation toolkit called AbcSmc, which we have made publicly available. After fitting the simulation model to dengue case data, we forecasted transmission and assessed the relative effectiveness of several vaccination strategies over a 20 year period. Vaccine efficacy is based on phase III trial results for the Sanofi-Pasteur vaccine, Dengvaxia. We consider routine vaccination of 2, 9, or 16 year-olds, with and without a one-time catch-up campaign to age 30. Because the durability of Dengvaxia is not yet established, we consider hypothetical vaccines that confer either durable or waning immunity, and we evaluate the use of booster doses to counter waning. We find that plausible vaccination scenarios with a durable vaccine reduce annual dengue incidence by as much as 80% within five years. However, if vaccine efficacy wanes after administration, we find that there can be years with larger epidemics than would occur without any vaccination, and that vaccine booster doses are necessary to prevent this outcome. PMID- 27227884 TI - Lack of Phenotypical and Morphological Evidences of Endothelial to Hematopoietic Transition in the Murine Embryonic Head during Hematopoietic Stem Cell Emergence. AB - During mouse ontogeny, hematopoietic cells arise from specialized endothelial cells, i.e., the hemogenic endothelium, and form clusters in the lumen of arterial vessels. Hemogenic endothelial cells have been observed in several embryonic tissues, such as the dorsal aorta, the placenta and the yolk sac. Recent work suggests that the mouse embryonic head also produces hematopoietic stem cells (HSCs)/progenitors. However, a histological basis for HSC generation in the head has not yet been determined because the hematopoietic clusters and hemogenic endothelium in the head region have not been well characterized. In this study, we used whole-mount immunostaining and 3D confocal reconstruction techniques to analyze both c-Kit+ hematopoietic clusters and Runx1+ hemogenic endothelium in the whole-head vasculature. The number of c-Kit+ hematopoietic cells was 20-fold less in the head arteries than in the dorsal aorta. In addition, apparent nascent hematopoietic cells, which are characterized by a "budding" structure and a Runx1+ hemogenic endothelium, were not observed in the head. These results suggest that head HSCs may not be or are rarely generated from the endothelium in the same manner as aortic HSCs. PMID- 27227886 TI - WITHDRAWN: Tongue scraping for treating halitosis. PMID- 27227885 TI - Extra Molting and Selection on Nymphal Growth in the Desert Locust. AB - In insects, extra-molting has been viewed as a compensatory mechanism for nymphal growth that contributes to optimize body weight for successful reproduction. However, little is known on the capacity of extra-molting to evolve in natural populations, which limits our understanding of how selection acts on nymphal growth. We used a multi-generational pedigree, individual monitoring and quantitative genetics models to investigate the evolution of extra-molting and its impact on nymphal growth in a solitarious population of the desert locust, Schistocerca gregaria. Growth compensation via extra-molting was observed for 46% of the females, whose adult weight exceeded by 4% that of other females, at a cost of a 22% longer development time. We found a null heritability for body weight threshold only, and the highest and a strongly female-biased heritability for extra molting. Our genetic estimates show that (1) directional selection can act on growth rate, development time and extra-molting to optimize body weight threshold, the target of stabilizing selection, (2) extra-molting can evolve in natural populations, and (3) a genetic conflict, due to sexually antagonistic selection on extra-molting, might prevent its fixation. Finally, we discuss how antagonistic selection between solitarious and gregarious environments and/or genetic correlations between growth and phase traits might also impact the evolution of extra-molting in locusts. PMID- 27227888 TI - Assessing Rotation-Invariant Feature Classification for Automated Wildebeest Population Counts. AB - Accurate and on-demand animal population counts are the holy grail for wildlife conservation organizations throughout the world because they enable fast and responsive adaptive management policies. While the collection of image data from camera traps, satellites, and manned or unmanned aircraft has advanced significantly, the detection and identification of animals within images remains a major bottleneck since counting is primarily conducted by dedicated enumerators or citizen scientists. Recent developments in the field of computer vision suggest a potential resolution to this issue through the use of rotation invariant object descriptors combined with machine learning algorithms. Here we implement an algorithm to detect and count wildebeest from aerial images collected in the Serengeti National Park in 2009 as part of the biennial wildebeest count. We find that the per image error rates are greater than, but comparable to, two separate human counts. For the total count, the algorithm is more accurate than both manual counts, suggesting that human counters have a tendency to systematically over or under count images. While the accuracy of the algorithm is not yet at an acceptable level for fully automatic counts, our results show this method is a promising avenue for further research and we highlight specific areas where future research should focus in order to develop fast and accurate enumeration of aerial count data. If combined with a bespoke image collection protocol, this approach may yield a fully automated wildebeest count in the near future. PMID- 27227887 TI - The Loss of Lam2 and Npr2-Npr3 Diminishes the Vacuolar Localization of Gtr1-Gtr2 and Disinhibits TORC1 Activity in Fission Yeast. AB - In mammalian cells, mTORC1 activity is regulated by Rag GTPases. It is thought that the Ragulator complex and the GATOR (GAP activity towards Rags) complex regulate RagA/B as its GDP/GTP exchange factor (GEF) and GTPase-activating protein (GAP), respectively. However, the functions of components in these complexes remain elusive. Using fission yeast as a model organism, here we found that the loss of Lam2 (SPBC1778.05c), a homolog of a Ragulator component LAMTOR2, as well as the loss of Gtr1 or Gtr2 phenocopies the loss of Npr2 or Npr3, homologs of GATOR components Nprl2 or Nprl3, respectively. These phenotypes were rescued by TORC1 inhibition using pharmacological or genetic means, and the loss of Lam2, Gtr1, Gtr2, Npr2 or Npr3 disinhibited TORC1 activity under nitrogen depletion, as measured by Rps6 phosphorylation. Consistently, overexpression of GDP-locked Gtr1S20L or GTP-locked Gtr2Q60L, which suppress TORC1 activity in budding yeast, rescued the growth defect of Deltagtr1 cells or Deltagtr2 cells, respectively, and the loss of Lam2, Npr2 or Npr3 similarly diminished the vacuolar localization and the protein levels of Gtr1 and Gtr2. Furthermore, Lam2 physically interacted with Npr2 and Gtr1. These findings suggest that Lam2 and Npr2-Npr3 function together as a tether for GDP-bound Gtr1 to the vacuolar membrane, thereby suppressing TORC1 activity for multiple cellular functions. PMID- 27227897 TI - Is the Colonisation of Staphylococcus aureus in Pets Associated with Their Close Contact with Owners? AB - In human beings and animals, staphylococci constitute part of the normal microbial population. Staphylococcus aureus could be classified as an opportunistic pathogen because the bacteria are noted in clinically healthy individuals, but when the immune system becomes compromised, they can also cause a wide range of infections. The objective of this study was to test the hypothesis that cats who are in close contact with their owners are at the greatest risk of being colonised with S. aureus. Two groups of cats were investigated: single, pet (domestic) cats that do not have outdoor access; and a local population of feral cats living in urban areas. The prevalence of S. aureus in domestic cats was 19.17%, while it's prevalence in the feral cat population was only 8.3%; which was statistically significant. Analysis of antibiotic resistance, at the genotypic as well as phenotypic level, showed that S. aureus isolates from pet cats were more likely to harbour antibiotic resistant determinants. The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in households was 10.21%, while in feral cats it was only 1.4%. In conclusion, this study has revealed a correlation between close contact with humans and a higher risk of the cats being colonised with S. aureus and harbouring the antibiotic resistant determinants. PMID- 27227898 TI - Characterization of Three Venom Peptides from the Spitting Spider Scytodes thoracica. AB - We present the solution-state NMR structures and preliminary functional characterizations of three venom peptides identified from the spitting spider Scytodes thoracica. Despite little sequence identity to other venom peptides, structural characterization reveals that these peptides contain an inhibitor cystine knot motif common to many venom peptides. These are the first structures for any peptide or protein from spiders of the Scytodidae family. Many venom peptides target neuronal ion channels or receptors. However, we have not been able to determine the target of these Scytodes peptides so we can only state with certainty the channels and receptors that they do not target. PMID- 27227899 TI - The effects of intertrial interval and instructional format on skill acquisition and maintenance for children with autism spectrum disorders. AB - We replicated and extended the study by Koegel, Dunlap, and Dyer (1980) by examining the effects of 3 intertrial-interval (ITI) durations on skill acquisition in 2 children with autism spectrum disorders. Specifically, we compared the effect of short (2 s), progressive (2 s to 20 s), and long (20 s) ITIs on participants' mastery of tacts or intraverbals presented in massed-trial and varied-trial instructional formats. We also measured (a) stereotypic and problem behavior during the ITI, (b) maintenance of skills, and (c) responding to novel adults and settings. Results showed that short ITIs in a varied-trial format produced the most efficient acquisition of skills; however, most ITI durations produced more efficient skill acquisition in a varied format compared to a massed format. The trial format and ITI duration associated with the lowest levels of stereotypic and problem behavior during the ITI and responding during maintenance and novel adult and setting probes differed across participants. PMID- 27227900 TI - Bombyx mori E26 transformation-specific 2 (BmEts2), an Ets family protein, represses Bombyx mori Rels (BmRels)-mediated promoter activation of antimicrobial peptide genes in the silkworm Bombyx mori. AB - E26 transformation-specific (Ets) family transcription factors are known to play roles in various biological phenomena, including immunity, in vertebrates. However, the mechanisms by which Ets proteins contribute to immunity in invertebrates remain poorly understood. In this study, we identified a cDNA encoding BmEts2, which is a putative orthologue of Drosophila Yan and human translocation-ets-leukemia/Ets-variant gene 6, from the silkworm Bombyx mori. Expression of the BmEts2 gene was significantly increased in the fat bodies of silkworm larvae in response to injection with Escherichia coli and Staphylococcus aureus. BmEts2 overexpression dramatically repressed B. mori Rels (BmRels) mediated promoter activation of antimicrobial peptide genes in silkworm cells. Conversely, gene knockdown of BmEts2 significantly enhanced BmRels activity. In addition, two kappaB sites located on the 5' upstream region of cecropin B1 were found to be involved in the repression of BmRels-mediated promoter activation. Protein-competition analysis further demonstrated that BmEts2 competitively inhibited binding of BmRels to kappaB sites. Overall, BmEts2 acts as a repressor of BmRels-mediated transactivation of antimicrobial protein genes by inhibiting the binding of BmRels to kappaB sites. PMID- 27227901 TI - Anorexia nervosa. PMID- 27227902 TI - Comparative study of two perfusion routes with different flow in decellularization to harvest an optimal pulmonary scaffold for recellularization. AB - Decellularization processes may variably distort or degrade extracellular matrix (ECM) structure. In this study, two perfusion routes (PR) were tested on SD rat lung samples. One decellularization protocol, PR1, was perfused through the pulmonary artery. The other decellularization protocol, PR2, was perfused through the trachea. Both decellularization protocols were used by the same detergent based (sodium dodecyl sulphate and Triton X-100) with different flow continuous perfusion. There was no visible difference in vessel architecture between PR1- and PR2-decellularized scaffold. However, the airway structure and alveoli architecture of pulmonary decellularized scaffolds generated through PR2 at a flow rate of 8 mL/min were destroyed partly when compared to that in native lung and PR1-decellularized scaffold. Ultramicroscopic assessment of scaffolds was similar in both protocols and showed filamentous ECM with preserved fiber disposition and structure. Histological analysis and immunostaining showed no detectable cells remaining in the pulmonary scaffolds compare with native lung. The DNA concentration was significantly reduced in the decellularized scaffolds compared to the native lungs. A549 cells reseeded onto decellularized pulmonary scaffolds were no significant difference between PR1 and PR2 in cell viability, p > 0.05. We conclude that under the same high flow velocity status, perfusion decellularization through the pulmonary artery may be an optimal pathway to obtain decellularized scaffolds for pulmonary regeneration. This article is protected by copyright. All rights reserved. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2567-2575, 2016. PMID- 27227903 TI - MR Imaging Biomarkers to Monitor Early Response to Hypoxia-Activated Prodrug TH 302 in Pancreatic Cancer Xenografts. AB - TH-302 is a hypoxia-activated prodrug known to activate selectively under the hypoxic conditions commonly found in solid tumors. It is currently being evaluated in clinical trials, including two trials in Pancreatic Ductal Adenocarcinomas (PDAC). The current study was undertaken to evaluate imaging biomarkers for prediction and response monitoring of TH-302 efficacy in xenograft models of PDAC. Dynamic contrast-enhanced (DCE) and diffusion weighted (DW) magnetic resonance imaging (MRI) were used to monitor acute effects on tumor vasculature and cellularity, respectively. Three human PDAC xenografts with known differential responses to TH-302 were imaged prior to, and at 24 h and 48 hours following a single dose of TH-302 or vehicle to determine if imaging changes presaged changes in tumor volumes. DW-MRI was performed at five b-values to generate apparent diffusion coefficient of water (ADC) maps. For DCE-MRI, a standard clinically available contrast reagent, Gd-DTPA, was used to determine blood flow into the tumor region of interest. TH-302 induced a dramatic decrease in the DCE transfer constant (Ktrans) within 48 hours after treatment in the sensitive tumors, Hs766t and Mia PaCa-2, whereas TH-302 had no effect on the perfusion behavior of resistant SU.86.86 tumors. Tumor cellularity, estimated from ADC, was significantly increased 24 and 48 hours after treatment in Hs766t, but was not observed in the Mia PaCa-2 and SU.86.86 groups. Notably, growth inhibition of Hs766t was observed immediately (day 3) following initiation of treatment, but was not observed in MiaPaCa-2 tumors until 8 days after initiation of treatment. Based on these preclinical findings, DCE-MRI measures of vascular perfusion dynamics and ADC measures of cell density are suggested as potential TH 302 response biomarkers in clinical trials. PMID- 27227904 TI - Stem/progenitor cells in liver regeneration. AB - In severely or chronically injured livers where the proliferative capacity of hepatocytes is compromised, putative stem/progenitor cells are supposed to be activated. These cells are generally characterized as biliary epithelial cell marker-positive cells that emerge ectopically in the parenchymal region of the liver, as determined by histopathological examination of various liver diseases in humans and animal models. Whereas the biliary system indeed harbors cells with stem/progenitor activity that can be defined ex vivo, genetic lineage tracing studies in mice have casted doubt on their exact contribution as the genuine stem/progenitor cell population that differentiates in situ into hepatocytes. Here, I briefly review recent advances in the characterization and certification of the stem/progenitor cells in the adult liver and discuss the ongoing and future challenges to further our understanding of the cellular basis of liver regeneration. (Hepatology 2016;64:663-668). PMID- 27227905 TI - Production cross-sections of radionuclides from alpha-induced reactions on natural copper up to 50MeV. AB - The excitation functions were measured for the (nat)Cu(alpha,x)(66,67)Ga,(65)Zn,(57,58,60)Co reactions in the energy range of 16.5 -50MeV. A conventional stacked-foil activation technique combined with HPGe gamma-ray spectrometry was employed to determine cross-sections. The measured cross-sections were critically compared with relevant previous experimental data and also with the evaluated data in the TENDL-2014 library. Present results confirmed some of the previous experimental data, whereas only a partial agreement was found with the evaluated data. The measured data are useful for reducing the existing discrepancies in the literature, to improve the nuclear reaction model codes, and to enrich the experimental database towards various applications. PMID- 27227906 TI - Medical expenditures in patients with high risk of diabetes: Effects of BMI, hypertension, and health-related quality of life. AB - OBJECTIVE: To evaluate the health-related quality of life (HRQOL) of patients with diabetes and persons at high risk of developing diabetes and the association between HRQOL scores and subsequent medical expenditures in these persons. METHODS: Data came from the Medical Expenditure Panel Survey. Body mass index (BMI) and hypertension were used to identify risk of diabetes. Burden was assessed by comparing SF-12 physical (PCS) and mental (MCS) summary scores in patients with diabetes and those at risk of having diabetes to the age- and gender-adjusted PCS and MCS of those with normal BMI and no hypertension. Associations between PCS and MCS and medical expenditures were modeled using a two-part model that controlled for clinical and demographic factors. Percent increase in expenditure associated with PCS and MCS differences was evaluated as the ratio of estimated expenditure, holding other factors fixed. RESULTS: Diabetes risk factors were associated with up to 9-point lower PCS and 3-point lower MCS score. Overall, 1-, 2-, 5-, and 10-point lower PCS scores were associated with 2.9%, 5.8%, 15.0%, and 31.8% higher expenditures, and lower MCS scores were associated with 1.3%, 2.6%, 6.5%, and 13.5% higher expenditures, respectively. CONCLUSIONS: The reported associations can help clinicians and researchers interpret the magnitude of HRQOL score differences. PMID- 27227907 TI - Variants of the CDH1 (E-Cadherin) Gene Associated with Oral Clefts in the Thai Population. AB - OBJECTIVE: The etiology of oral clefts in humans is genetically complex and mutations in multiple genes have been linked with clefting. CDH1 (E-cadherin) has been found to be involved in lip and palate development, and CDH1 mutations are associated with oral clefts in some populations. MATERIALS AND METHODS: To determine if there is an association between CDH1 and oral clefting in a Thai population, we sequenced the entire 6.5-kb coding region of the CDH1 gene in 80 oral cleft patients and compared the identified variants with those found in 138 unrelated Thai individuals who did not have oral clefts, as genotyped by exome sequencing. RESULTS: Among the oral cleft patients, four nonsynonymous single nucleotide variants (SNVs), c.1235T>C (p.V412A), c.1273G>A (p.V425I), c.1565C>T (p.T522I), and c.1888C>G (p.L630V), were identified. Only one nonsynonymous variant (c.1409C>T; p.T470I) was found among the 138 noncleft exomes. The frequency of nonsynonymous SNVs on the CDH1 gene in oral cleft patients (4/80) was significantly higher than that in the control group (1/138) (p = 0.042). CONCLUSION: We found that nonsynonymous variants of CDH1 were associated with oral clefts in the Thai population. PMID- 27227908 TI - Toll-Like Receptor 3 is Associated With the Risk of HCV Infection and HBV-Related Diseases. AB - There are inconsistent data on the association of risk of hepatitis virus infection and hepatitis virus-related diseases with the toll-like receptor 3 (TLR3) gene.Several common polymorphism sites were targeted to assess the risk of HBV infection, HCV infection, and HBV-related diseases.Meta-analysis combining data for 3547 cases and 2797 controls from 8 studies was performed in this study. Pooled ORs were calculated to measure the risk of hepatitis virus infection and hepatitis virus-related diseases. Fixed-effects pooled ORs were calculated using the Mantel-Haenszel method.The TLR3 gene was associated with a significantly increased risk of HBV-related diseases among 1355 patients and 1130 controls ([pooled OR, [95%CI]: 1.30, [1.15-1.48] for dominant; 1.77, [1.35-2.31] for recessive; 1.28 [1.16-1.41] for allele frequency). Subgroup analyses by a polymorphism site indicated an increased risk of HCV infection in relation to the TT/CT genotypes of rs3775291 (1.50 [1.11-2.01]), and a decreased risk ascribed to the T allele (0.20 [0.16-0.25]). We also noted an association between rs3775291 and significantly increased risk of HBV-related diseases (2.23 [1.55-3.21]). No significant inter-study heterogeneity or publication bias was detected in the analyses.These data suggest a likely effect on the risk to infect HCV and develop HBV-related diseases for the TLR3 gene. Large-scale studies with racially diverse populations are required to validate these findings. PMID- 27227909 TI - Experience of Intraoperative Cell Salvage in Surgical Correction of Spinal Deformity: A Retrospective Review of 124 Patients. AB - The effect of intraoperative cell salvage (ICS) in surgical correction of spinal deformity remained controversial. This study was to quantitatively demonstrate its effect. In all, 124 patients having ICS in surgical correction of spinal deformity were included. These patients would be divided into 3 groups. Group 1 blood loss less than 15 mL/kg; group 2-between 15 and 37.5 mL/kg; and group 3 more than 37.5 mL/kg. The mean blood loss was 37.2 mL/kg and patients received 872.2 mL salvaged blood on average. The prevalence of intraoperative transfusion of allogenic RBC was 62.9% and the amount averaged 3.4 U. In groups 1 to 3, the prevalence of intraoperative allogenic transfusion was 23.5%, 66.7%, and 100%, respectively. Logistic analysis showed blood loss minus autotransfusion was of significance in predicting intraoperative transfusion, whereas the blood loss or autotransfusion alone was not, implicating an important role of ICS in saving allogenic RBC. The maximum decrease of hemoglobin after operation occurred in the third day, and the magnitude was 45.7 g/L. No severe complications related to ICS were observed. In summary, ICS could decrease the amount of allogenic transfusion in surgical correction of spinal deformity. However, in terms of reducing prevalence of allogenic transfusion, it had a protective effect only in patients with small blood loss. PMID- 27227910 TI - Case Report of Contrast-Enhanced Ultrasound Features of Primary Hepatic Neuroendocrine Tumor: A CARE-Compliant Article. AB - Primary hepatic neuroendocrine tumors (PHNETs) are very rare and their clinical features and treatment outcomes are not well understood. It is difficult to reach a proper diagnosis before biopsy or resection. The aim of this study was to analyze the imaging features of PHNETs on contrast-enhanced ultrasound (CEUS). The clinical characteristics, CEUS findings, pathological features, treatment and prognosis of 6 patients with PHNET treated in our hospital were retrospectively analyzed.Most PHNETs occurred in middle-aged patients, and the most common clinical manifestation was right upper quadrant palpable mass and abdominal pain. Multiple small anechoic intralesional cavities occurred frequently in PHNET. Multilocular cystic with internal septation or monolocular with wall nodule could also be detected. On contrast-enhanced ultrasonography (CEUS), heterogeneous hyperenhancement in the arterial phase and wash-out hypoenhancement were observed in most patients, while computed tomography scanning yielded similar results. Diagnosis of PHNET was confirmed by immunohistochemical result and follow-up with the absence of extrahepatic primary sites. Five patients received surgical resection and 2 cases exhibited recurrence. Transcatheter arterial chemoembolization was performed in 1 patient with recurrence. Only 1 patient received conservative care. The median overall survival in 5 patients who underwent surgical treatment was 27 months (18-36 months). PHNET is a rare tumor, and its diagnosis is difficult. The CEUS features reported in this series may enrich the knowledge base for characterization of PHNET. PMID- 27227911 TI - A Rapid and Accurate Method to Evaluate Helicobacter pylori Infection, Clarithromycin Resistance, and CYP2C19 Genotypes Simultaneously From Gastric Juice. AB - Because Helicobacter pylori (H pylori) would cause carcinogenesis of the stomach, we need sufficient information for deciding on an appropriate strategy of eradication. Many factors affect the efficacy of eradication including antimicrobial resistance (especially clarithromycin resistance) and CYP2C19 polymorphism. This study was to survey the efficiency of gastric juice for detecting H pylori infection, clarithromycin resistance, and CYP2C19 polymorphism.The specimens of gastric juice were collected from all patients while receiving gastroscopy. DNA was extracted from gastric juice and then urease A and cag A were amplified by polymerase chain reaction (PCR) for detecting the existence of H pylori. By PCR-restriction fragment length polymorphism (PCR RFLP), the 23S rRNA of H pylori and CYP2C19 genotypes of host were examined respectively. During endoscopy examination, biopsy-based specimens were also collected for rapid urease test, culture, and histology. The blood samples were also collected for analysis of CYP2C19 genotypes. We compared the results of gastric juice tests with the results of traditional clinical tests.When compared with the results from traditional clinical tests, our results from gastric juice showed that the sensitivity (SEN), specificity (SPE), positive predictive value (PPV), negative predictive value (NPV), and accuracy to detect H pylori infection were 92.1% (105/114), 92.9% (143/154), 90.5% (105/116), 94.1% (143/152), and 92.5% (248/268), respectively. The SEN, SPE, PPV, and NPV to detect clarithromycin resistance were 97.3% (36/37), 91.5% (43/47), 90.0% (36/40), and 97.7% (43/44), respectively. By using PCR-RFLP, the consistency of human CYP2C19 gene polymorphism from blood samples and gastric juice was as high as 94.9% (149/157).The manipulated gastric juice is actually an effective diagnostic sample for evaluation of H pylori existence, clarithromycin resistance, and host CYP2C19 polymorphism. PMID- 27227912 TI - The Associations Between the Polymorphisms of Vitamin D Receptor and Coronary Artery Disease: A Systematic Review and Meta-Analysis. AB - Vitamin D receptor (VDR) polymorphisms were indicated to be associated with coronary artery disease (CAD); however, published studies reported inconsistent results.The aim of this meta-analysis is to reach a more accurate estimation of the relationship between VDR genetic polymorphisms and CAD risk.Eligible studies were retrieved by searching PubMed, Embase, VIP, Wanfang and China National Knowledge Infrastructure databases. Included and excluded criteria were formulated. The case group was patients with CAD, and the control group was healthy subjects. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate VDR polymorphisms associations with CAD risk. Heterogeneity was evaluated by Q statistic and I statistic.Seven studies of a total of 2306 CAD patients and 4151 control subjects met the inclusion criteria. The pooled results from Taq1 showed increased risk in allelic model (OR = 1.14, 95% CI = 1.02-1.28), dominant model (OR = 1.21, 95% CI = 1.02-1.43), heterozygote model (OR = 1.19, 95% CI = 1.00-1.1.42), and homozygote model (OR = 1.27, 95% CI = 1.01-1.61). Besides, Fok1 T > C showed decreased risk in allelic model (OR = 0.81, 95% CI = 0.65-1.00) and Fok1 A > G also showed decreased risk in allelic model (OR = 0.67, 95% CI = 0.45-1.00) and recessive model (OR = 0.55, 95% CI = 0.31-0.97). In Caucasian subgroup, Bsm1showed increased risk in allelic model (OR = 1.23, 95% CI = 1.02-1.47), heterozygote model (OR = 1.20, 95% CI = 1.00-1.44), and homozygote model (OR = 1.22, 95% CI = 1.02-1.45). In CAD patients with type 2 diabetes mellitus (T2DM), Apa1showed a decreased risk in heterozygote model (OR = 0.80, 95% CI = 0.66-0.98); however, increased risk in recessive model (OR = 5.00, 95% CI = 2.74-9.13) was discovered in CAD patients without T2DM.The Fok1 polymorphism may play a protective role in CAD, and the possible protective role in Apa1 CA genotype in CAD patients with T2DM needs further studies. The Taq1 polymorphism is found to be associated with a significant increase in CAD risk based on our analysis; moreover, increased risk in Apa1 polymorphism in CAD patients without T2DM and Bsm1 polymorphism in Caucasian group is also detected. PMID- 27227913 TI - Should Splenic Hilar Lymph Nodes be Dissected for Siewert Type II and III Esophagogastric Junction Carcinoma Based on Tumor Diameter?: A Retrospective Database Analysis. AB - The aim of the study is to identify the value of a spleen-preserving No. 10 lymphadenectomy (SPL) for Siewert type II/III adenocarcinoma of the esophagogastric junction (AEG).From January 2007 to June 2014, 694 patients undergoing radical total gastrectomy for Siewert type II/III AEG were analyzed. Oncologic outcomes were compared between SPL and no SPL (No. 10D+ and No. 10D-) groups.The incidence of No. 10 lymph node metastasis (LNM) was 12.3%. No significant differences in the incidence of No. 10 LNM were found between Siewert type II AEG with tumor diameters of <4 cm and >=4 cm (P = 0.071). However, Siewert type III AEG with a tumor diameter >=4 cm showed a significantly higher frequency of No. 10 LNM compared with a tumor diameter <4 cm (P < 0.001). The No. 10D+ group had superior 3-year overall survival (OS) and disease-free survival (DFS) rates compared with the No. 10D- group (P = 0.030 and P = 0.005, respectively). For patients with Siewert type II and type III AEG with a tumor diameter <4 cm, the 3-year OS and DFS rates were similar between the 2 groups. However, the No. 10D+ group had better 3-year OS (66.6% vs 51.1%, P = 0.019) and DFS (63.2% vs 45.9%, P = 0.007) rates for Siewert type III AEG with a tumor diameter >=4 cm. A multivariate Cox regression showed that SPL was an independent prognostic factor in Siewert type III AEG with a tumor diameter >=4 cm.SPL may improve the prognosis of Siewert type III AEG with a tumor diameter >=4 cm, whereas SPL may be omitted without decreasing survival in patients with Siewert type II or type III AEG with a tumor diameter <4 cm. PMID- 27227914 TI - The Clinical Characteristics of Metanephric Adenoma: A Case Report and Literature Review. AB - We describe the clinical presentation, diagnosis, treatment, and follow-up data of a 39-year-old woman with asymptomatic right kidney tumor, which was later histopathologically diagnosed as metanephric adenoma (MA). Macroscopically, the tumor had integrity tegument with homogeneous and gray cutting surface. Microscopically, the tumor cells were formed in adenoid or papillary pattern and contained psammoma bodies, without distinctive atypia. Immunohistochemistry results showed they were negative for creatine kinase 7, epithelial membrane antigen, and renal cell carcinoma, and positive for AE1/AE3, vimentin, and Wilms Tumor 1. Pathological diagnosis was MA. The 48 months' follow-up information was available without recurrence.According to this case and literature review, we figured that it is difficult to make a definite diagnosis of MA only by image examination. Nephron-sparing surgery is eligible to treat MA. Long-term active surveillance is necessary because of the uncertainty of the biological behavior and cellular origin of MA. PMID- 27227915 TI - An Online Atlas for Exploring Spatio-Temporal Patterns of Cancer Mortality (1972 2011) and Incidence (1995-2008) in Taiwan. AB - Public health mapping and Geographical Information Systems (GIS) are already being used to locate the geographical spread of diseases. This study describes the construction of an easy-to-use online atlas of cancer mortality (1972-2011) and incidence (1995-2008) in Taiwan.Two sets of color maps were made based on "age-adjusted mortality by rate" and "age-adjusted mortality by rank." AJAX (Asynchronous JavaScript and XML), JSON (JavaScript Object Notation), and SVG (Scaling Vector Graphic) were used to create the online atlas. Spatio-temporal patterns of cancer mortality and incidence in Taiwan over the period from 1972 to 2011 and from 1995 to 2008.The constructed online atlas contains information on cancer mortality and incidence (http://taiwancancermap.csmu-liawyp.tw/). The common GIS functions include zoom and pan and identity tools. Users can easily customize the maps to explore the spatio-temporal trends of cancer mortality and incidence using different devices (such as personal computers, mobile phone, or pad). This study suggests an easy- to-use, low-cost, and independent platform for exploring cancer incidence and mortality. It is expected to serve as a reference tool for cancer prevention and risk assessment.This online atlas is a cheap and fast tool that integrates various cancer maps. Therefore, it can serve as a powerful tool that allows users to examine and compare spatio-temporal patterns of various maps. Furthermore, it is an-easy-to use tool for updating data and assessing risk factors of cancer in Taiwan. PMID- 27227916 TI - Impact of Age and Myopia on the Rate of Visual Field Progression in Glaucoma Patients. AB - Myopia is rapidly increasing in young populations and patients with glaucoma associated with myopia are reported to be young aged in East Asia. These young patients have a longer life expectancy, which increases their risk of end-of-life visual disabilities. There is a need to understand the clinical course of myopic glaucoma patients, which may be important for the care of these myopic populations. In this study, we evaluated the relationship between the age at presentation and the rate of glaucoma progression in the visual field (VF) according to the presence of myopia. The study was conducted as a prospective observational study including 179 patients with open-angle glaucoma who had undergone at least 5 VF examinations with a follow-up of at least 5 years. The progression rate of the mean deviation (MD) and the pattern standard deviation (PSD) are expressed as change in decibels (dB) per year. The slopes of the MD and PSD were calculated by linear regression analyses. Factors related to the slope of VF MD changes were analyzed with correlation and regression analyses. The slope of the linear fit line plotted against age at presentation and the rate of change in the VF MD was -0.026 (P < 0.001) in the myopic group and -0.008 (P = 0.167) in the nonmyopic group; the relationship was more prominent in the myopic group than the nonmyopic group. In the myopic group, age (beta = -0.417; 95% confidence intervals (CI), -0.651 to -0.200; P = 0.050) and baseline untreated intraocular pressure (beta = -0.179; 95% CI, -0.331 to -0.028; P = 0.022) were significantly related to the rate of change in the MD, which was only the presence of disc hemorrhage (beta = -0.335; 95% CI, -0.568 to -0.018; P = 0.022) in the nonmyopic group. Age at presentation was significantly related to the rate of change in the VF in glaucomatous eyes with myopia compared to eyes without myopia. Older age was significantly related to the rate of change in the VF only in myopic glaucomatous eyes. PMID- 27227917 TI - A Successfully Treated Metastatic Choriocarcinoma Coexistent With Pregnancy: A Case Report of a 4-Year Follow-Up. AB - Gestational choriocarcinoma ended with a successful parturition is extremely rare, especially in cases where multiple metastases occurred.A 29-year-old Chinese primigravida was admitted with vaginal bleeding at 32 gestational week, and diagnosed with gestational choriocarcinoma with vaginal, pulmonary, and cerebral metastasis after pathological, and imaging examination. At 33 gestational week, a healthy infant was delivered by cesarean section. Although no evidence of choriocarcinoma or any other forms of gestational trophoblastic diseases was found in the placenta and uterine curettages, the patient was given 7 cycles of postpartum chemotherapy. Her serum beta-human chorionic gonadotropin level fell to the normal range, and the metastatic lesions reduced. The baby is still free from diseases, and the patient reports no clinical manifestation 4 years after the hospital discharge.Despite its rapid metastases and complications, gestational choriocarcinoma still can be successfully treated by postpartum chemotherapy with the least delay. PMID- 27227918 TI - Differences Between the "Chinese AMS Score" and the Lake Louise Score in the Diagnosis of Acute Mountain Sickness. AB - The Chinese AMS score (CAS) is used in clinical medicine and research to diagnosis acute mountain sickness (AMS). However, the Lake Louise Score (LLS) is the well-accepted standard for diagnosing AMS. The difference between the CAS and LLS questionnaires is that the CAS considers more nonspecific symptoms. The aim of the present study was to evaluate differences in AMS prevalence according to the LLS and CAS criteria. We surveyed 58 males who traveled from Chongqing (300 m) to Lhasa (3658 m) via the Qinghai-Tibet train. Cases of AMS were diagnosed using LLS and CAS questionnaires in a few railway stations at different evaluation areas along the road. We subsequently evaluated discrepancies in values related to the prevalence of AMS determined using the 2 types of questionnaires (CAS and LLS). The prevalence of CAS-diagnosed AMS indicated that the percentage of AMS cases among the 58 young men was 29.3% in Golmud, 60.3% in Tanggula, 63.8% in Lhasa, 22.4% on the first day after arrival in Lhasa, 27.6% on the second day, 24.1% on the third day, and 12.1% on the fourth day. The prevalence of LLS-diagnosed AMS in Golmud was 10.3%, 38% in Lhasa, and 6.9% on day 1, the prevalence in each station was lower than that as assessed by the CAS. Our experimental data indicate that AMS diagnoses ascertained using the CAS indicate a higher AMS prevalence than those ascertained using the LLS. Through statistical analysis, the CAS seems capable of effectively diagnosing AMS as validated by LLS (sensitivity 61.8%, specificity 92.7%). PMID- 27227919 TI - Incidence of Depression and Associated Factors in Patients With Type 2 Diabetes in Quebec, Canada: A Population-Based Cohort Study. AB - It has been reported that the risk of depression is higher among people with type 2 diabetes compared with a nondiabetic population. Among diabetic patients, depression has been associated with worse self-care behaviors, poor glycemic control, and an increased risk of diabetes complications. Identifying factors associated with the occurrence of depression may help physicians identify earlier diabetic patients at a high risk of developing depression, improve prevention, and accelerate proper treatment. To our knowledge, very few population-based studies have reported on the incidence of clinically diagnosed depression as a consequence of type 2 diabetes over a long follow-up period. The objective of this study was to estimate the incidence of clinically diagnosed depression among type 2 diabetic patients newly treated with oral antidiabetic drugs (ADs) and to identify factors associated with the occurrence of depression.Administrative claims data from the public health insurance plan were used to identify a cohort of new oral AD users aged >=18 years between 2000 and 2006. Patients were followed from oral AD treatment initiation until the diagnosis of depression, ineligibility for the public drug plan, death, or the end of the study, whichever came first. Incidence rates were determined using person-time analysis. Factors associated with depression were identified using multivariable Cox regression analysis.We identified 114,366 new oral AD users, of which 4808 had a diagnosis of depression. The overall incidence rate of depression was 9.47/1000 person years (PYs) (10.72/1000 PYs for women and 8.27/1000 PYs for men). The incidence of depression was higher during the year after oral AD treatment initiation. Independent factors associated with depression included having had mental disorders other than depression, hospitalization, a higher number of different drugs taken and of physicians visited during the year before oral AD initiation. Moreover, we observed a statistically significant age-by-socioeconomic status interaction.The incidence of diagnosed depression is higher during the first year after oral AD treatment initiation. Clinicians could pay particular attention to women, patients starting an AD at a young age, those with a low socioeconomic status, and especially those with a history of anxiety or dementia. PMID- 27227920 TI - Recommended Initial Antimicrobial Therapy for Emphysematous Pyelonephritis: 51 Cases and 14-Year-Experience of a Tertiary Referral Center. AB - The aim of this study was to investigate the profiles of pathogens and patterns of antibiotic resistance of emphysematous pyelonephritis (EPN), offering recommendations for initial antibiotic treatment.Between January, 2001, and November, 2014, demographic data, presenting clinical features, management strategies, and treatment outcomes of 51 patients with EPN were retrospectively reviewed, analyzing microbiological characteristics of causative pathogens and patterns of antibiotic resistance.Overall survival rate was 90.2% (46/51). Pathogens isolated most frequently were Escherichia coli (49.0%), Klebsiella pneumoniae (19.6%), and Proteus mirabilis (17.7%). Approximately 24% of E coli isolates and 22% K pneumoniae isolates were resistant to fluoroquinolones. Improper empiric antibiotic use (P = 0.02) and third-generation cephalosporin resistant pathogens (G3CRP) (P = 0.01) were significantly more common in cases of patient fatality. Prior hospitalization and antibiotic use within past year (P = 0.03), need for emergency hemodialysis (P = 0.03), and development of disseminated intravascular coagulation (DIC) (P = 0.03) were factors correlating significantly with microbial resistance to third-generation cephalosporins. The area under the receiver operating characteristic curve was 0.91. The cut-off point determined by the maximum Youden index for 2 of these 3 factors yielded a sensitivity of 0.8 and specificity of 0.93.Third-generation cephalosporins are recommended as initial treatment of EPN. In patients with histories of prior hospitalization and antibiotic use and in those needing emergency hemodialysis or developing DIC, carbapenem is the empiric antibiotic of choice. Patients presenting with 2 or more factors carry the highest risk of G3CRP involvement. Fluoroquinolone and gentamicin should be avoided. PMID- 27227921 TI - Cost-Effectiveness and Quality of Care of a Comprehensive ART Program in Malawi. AB - The aim of this study is to assess the cost-effectiveness of a holistic, comprehensive human immunodeficiency virus (HIV) treatment Program in Malawi.Comprehensive cost data for the year 2010 have been collected at 30 facilities from the public network of health centers providing antiretroviral treatment (ART) throughout the country; two of these facilities were operated by the Disease Relief through Excellent and Advanced Means (DREAM) program.The outcomes analysis was carried out over five years comparing two cohorts of patients on treatment: 1) 2387 patients who started ART in the two DREAM centers during 2008, 2) patients who started ART in Malawi in the same year under the Ministry of Health program.Assuming the 2010 cost as constant over the five years the cost-effective analysis was undertaken from a health sector and national perspective; a sensitivity analysis included two hypothesis of ART impact on patients' income.The total cost per patient per year (PPPY) was $314.5 for the DREAM protocol and $188.8 for the other Malawi ART sites, with 737 disability adjusted life years (DALY) saved among the DREAM program patients compared with the others. The Incremental Cost-Effectiveness Ratio was $1640 per DALY saved; it ranged between $896-1268 for national and health sector perspective respectively. The cost per DALY saved remained under $2154 that is the AFR-E-WHO regional gross domestic product per capita threshold for a program to be considered very cost effective.HIV/acquired immune deficiency syndrome comprehensive treatment program that joins ART with laboratory monitoring, treatment adherence reinforcing and Malnutrition control can be very cost-effective in the sub-Saharan African setting. PMID- 27227922 TI - Hybrid Surgery Versus Anterior Cervical Discectomy and Fusion in Multilevel Cervical Disc Diseases: A Meta-Analysis. AB - To investigate the outcomes and reliability of hybrid surgery (HS) versus anterior cervical discectomy and fusion (ACDF) for the treatment of multilevel cervical spondylosis and disc diseases.Hybrid surgery, combining cervical disc arthroplasty (CDA) with fusion, is a novel treatment to multilevel cervical degenerated disc disease in recent years. However, the effect and reliability of HS are still unclear compared with ACDF.To investigate the studies of HS versus ACDF in patients with multilevel cervical disease, electronic databases (Medline, Embase, Pubmed, Cochrane library, and Cochrane Central Register of Controlled Trials) were searched. Studies were included when they compared HS with ACDF and reported at least one of the following outcomes: functionality, neck pain, arm pain, cervical range of motion (ROM), quality of life, and incidence of complications. No language restrictions were used. Two authors independently assessed the methodological quality of included studies and extracted the relevant data.Seven clinical controlled trials were included in this study. Two trials were prospective and the other 5 were retrospective. The results of the meta-analysis indicated that HS achieved better recovery of NDI score (P = 0.038) and similar recovery of VAS score (P = 0.058) compared with ACDF at 2 years follow-up. Moreover, the total cervical ROM (C2-C7) after HS was preserved significantly more than the cervical ROM after ACDF (P = 0.000) at 2 years follow up. Notably, the compensatory increase of the ROM of superior and inferior adjacent segments was significant in ACDF groups at 2-year follow-up (P < 0.01), compared with HS.The results demonstrate that HS provides equivalent outcomes and functional recovery for cervical disc diseases, and significantly better preservation of cervical ROM compared with ACDF in 2-year follow-up. This suggests the HS is an effective alternative invention for the treatment of multilevel cervical spondylosis to preserve cervical ROM and reduce the risk of adjacent disc degeneration. Nonetheless, more well-designed studies with large groups of patients are required to provide further evidence for the benefit and reliability of HS for the treatment of cervical disk diseases. PMID- 27227923 TI - Erdheim-Chester Disease as a Mimic of IgG4-Related Disease: A Case Report and a Review of a Single-Center Cohort. AB - Immunoglobulin-G4 (IgG4)-related disease (IgG4RD) is a fibro-inflammatory disorder characterized by tissue-infiltrating IgG4 plasma cells, and, often, high serum IgG4. Several autoimmune, infectious, or proliferative conditions mimic IgG4RD. Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis, characterized by foamy histiocytic infiltration, fibrosis, and chronic inflammation. ECD and IgG4RD manifestations may overlap.A patient presented with huge fibrous retroperitoneal masses causing compression on neighboring structures; the case posed the challenge of the differential diagnosis between IgG4RD and ECD mainly because of a prominent serum and tissue IgG4 response.Retroperitoneal biopsy led to the diagnosis of ECD; the V600E BRAF mutation was found. Treatment with the BRAF inhibitor vemurafenib was started.Treatment failed to induce mass regression and the patient died after 3 months of therapy. Prompted by this case, we examined serum and tissue IgG4 in a series of 15 ECD patients evaluated at our center, and found that approximately one-fourth of the cases have increased IgG4 in the serum and often in the tissue.The differential diagnosis between IgG4RD and ECD can be challenging, as some ECD patients have prominent IgG4 responses. This suggests the possibility of common pathogenic mechanisms between ECD and IgG4RD. PMID- 27227924 TI - Body Temperature at the Emergency Department as a Predictor of Mortality in Patients With Bacterial Infection. AB - Hypothermia is a risk factor for death in intensive care unit (ICU) patients with severe sepsis and septic shock. In the present study, we investigated the association between body temperature (BT) on arrival at the emergency department (ED) and mortality in patients with bacterial infection.We conducted a retrospective cohort study in consecutive ED patients over 15 years of age with bacterial infection who were admitted to an urban teaching hospital in Japan between 2010 and 2012. The main outcome measure was 30-day in-hospital mortality. Each patient was assigned to 1 of 6 categories based on BT at ED admission. We conducted multivariable logistic regression analysis to adjust for predictors of death.A total of 913 patients were enrolled in the study. The BT categories were <36, 36 to 36.9, 37 to 37.9, 38 to 38.9, 39 to 39.9, and >=40 degrees C, with respective mortalities of 32.5%, 14.1%, 8.7%, 8.2%, 5.7%, and 5.3%. Multivariable analysis showed that the risk of death was significantly low in patients with BT 37 to 37.9 degrees C (adjusted odds ratio [AOR]: 0.2; 95% confidence interval [CI] 0.1-0.6, P = 0.003), 38-38.9 degrees C (AOR: 0.2; 95% CI 0.1-0.6, P = 0.002), 39-39.9 degrees C (AOR: 0.2; 95% CI 0.1-0.5, P = 0.001), and >=40 degrees C (AOR: 0.1; 95% CI 0.02-0.4, P = 0.001), compared with hypothermic patients (BT <36 degrees C).The higher BT on arrival at ED, the better the outcomes observed in patients with bacterial infection were. PMID- 27227925 TI - A Bayesian Approach to Identifying New Risk Factors for Dementia: A Nationwide Population-Based Study. AB - Dementia is one of the most disabling and burdensome health conditions worldwide. In this study, we identified new potential risk factors for dementia from nationwide longitudinal population-based data by using Bayesian statistics.We first tested the consistency of the results obtained using Bayesian statistics with those obtained using classical frequentist probability for 4 recognized risk factors for dementia, namely severe head injury, depression, diabetes mellitus, and vascular diseases. Then, we used Bayesian statistics to verify 2 new potential risk factors for dementia, namely hearing loss and senile cataract, determined from the Taiwan's National Health Insurance Research Database.We included a total of 6546 (6.0%) patients diagnosed with dementia. We observed older age, female sex, and lower income as independent risk factors for dementia. Moreover, we verified the 4 recognized risk factors for dementia in the older Taiwanese population; their odds ratios (ORs) ranged from 3.469 to 1.207. Furthermore, we observed that hearing loss (OR = 1.577) and senile cataract (OR = 1.549) were associated with an increased risk of dementia.We found that the results obtained using Bayesian statistics for assessing risk factors for dementia, such as head injury, depression, DM, and vascular diseases, were consistent with those obtained using classical frequentist probability. Moreover, hearing loss and senile cataract were found to be potential risk factors for dementia in the older Taiwanese population. Bayesian statistics could help clinicians explore other potential risk factors for dementia and for developing appropriate treatment strategies for these patients. PMID- 27227926 TI - Relaxin Level in Patients With Atrial Fibrillation and Association with Heart Failure Occurrence: A STROBE Compliant Article. AB - Atrial fibrillation (AF) is the most common arrhythmia requiring medical treatment and has been associated with enhanced atrial fibrosis and heart failure (HF). Relaxin (RLX), an antifibrosis and antiinflammatory peptide hormone, may be used to evaluate atrial fibrosis and is associated with HF occurrence in AF. We aimed to clarify the clinical significance of RLX level in patients with AF.We measured circulating levels of RLX and other fibrosis-related factors in 311 patients with sinus rhythm (SR; n = 116) or AF (n = 195). All discharged AF patients were followed up for the occurrence of HF for a mean of 6 months.Circulating levels of RLX were significantly different in patients with AF as compared with SR (P < 0.001), and in the subgroup analysis of AF. RLX level was correlated with left atrial diameter (LAD; R = 0.358, P < 0.001). Among followed up AF patients, on Kaplan-Meier curve analysis, patients with the third RLX tertile (T3) had a significantly higher HF rate than those with the 1st tertile (T1) (P = 0.002) and the cut-off value was 294.8 ng/L (area under the ROC curve [AUC] = 0.723). On multivariable analysis, HF occurrence with AF was associated with increased tertile of serum RLX level (odds ratio [OR] 2.659; confidence interval [95% CI] 1.434-4.930; P = 0.002).RLX is associated with fibrosis-related biomarkers and significantly elevated in AF. RLX was related to the HF occurrence in patients with AF. PMID- 27227927 TI - Pretransplant Hepatitis B Viral Infection Increases Risk of Death After Kidney Transplantation: A Multicenter Cohort Study in Korea. AB - Clinical outcomes in kidney transplant recipients (KTRs) with hepatitis B virus (HBV) have not been thoroughly evaluated. Here, we investigated recent posttransplant clinical outcomes of KTRs with HBV and compared them with KTRs with hepatitis C virus (HCV) and seronegative KTRs.Of 3855 KTRs from April 1999 to December 2011, we enrolled 3482 KTRs who had viral hepatitis serology data; the patients were followed up for 89.1 +/- 54.1 months. The numbers of recipients with HBV and HCV were 160 (4.6%) and 55 (1.6%), respectively. We analyzed the clinical outcomes, including overall mortality and graft failure, among patients who had undergone kidney transplantation.Patients with HBV showed poorer survival (P = 0.019; adjusted hazard ratio [HR] = 2.370; 95% confidence interval [CI]: 1.155-4.865) than KTRs without HBV. However, the graft survival of patients with chronic hepatitis B did not differ from that of patients without HBV. Hepatic complications were the primary causes of mortality of KTRs with HBV. Mortality significantly correlated with a higher grade of inflammation (P = 0.002) and with the use of lamivudine or adefovir antiviral treatment (P = 0.016). HBV-positive KTRs treated with the new-generation antiviral agent entecavir showed improved patient survival compared with KTRs receiving lamivudine (log-rank P = 0.050). HCV did not affect patient survival; however, it increased the incidence of graft failure (P = 0.010; adjusted HR = 2.899; 95% CI: 1.289-6.519). KTRs with HCV had an increased incidence of acute rejection (log-rank P = 0.005, crude HR = 2.144; 95% CI: 1.341-3.426; P = 0.001).KTRs with chronic hepatitis B may exhibit poor survival due to post-transplantation hepatic complications. Pretransplant histological liver evaluations and adequate antiviral management with potent nucleoside/nucleotide analogues are needed to improve the survival of KTRs with chronic hepatitis B even when liver function is within the normal range. PMID- 27227928 TI - Body Mass Index and Cancer Mortality Among Korean Older Middle-Aged Men: A Prospective Cohort Study. AB - The association of body mass index (BMI; kg/m) with overall and site-specific cancer mortality in Asians is not well understood. A total of 113,478 men from the Korean Veterans Health Study who returned a postal survey in 2004 were followed up until 2010. The adjusted hazard ratios (HRs) of cancer mortality were calculated using a Cox model. During 6.4 years of follow-up, 3478 men died from cancer. A reverse J-curve association with a nadir at 25.0 to 27.4 kg/m was observed. Below 25 kg/m, the HRs of death for each 5 kg/m decrease in BMI were 1.72 (95% confidence interval = 1.57-1.90) for overall cancer; 3.63 (2.57-5.12) for upper aerodigestive tract (UADT) cancers, including oral cavity and larynx [HR = 4.21 (2.18-8.12)] and esophagus [HR = 2.96 (1.82-4.81)] cancers; 1.52 (1.35 1.71) for non-UADT and non-lung cancers, including stomach [HR = 2.72 (2.13 3.48)] and large intestine [HR = 1.68 (1.20-2.36)] cancers; and 1.93 (1.59-2.34) for lung cancer. In the range of 25 to 47 kg/m, the HRs for each 5 kg/m increase in BMI were 1.27 (1.03-1.56) for overall cancer mortality and 1.57 (1.02-2.43) for lung cancer mortality. In individuals <25 kg/m, inverse associations with mortality from overall cancer and non-UADT and non-lung cancer were stronger in never-smokers than in current smokers. Both low and high BMI were strong predictors of mortality from overall and several site-specific cancers in Korean men. Further research is needed to evaluate whether interventions involving weight change (loss or gain) reduce the risk of cancer or improve the survival. PMID- 27227929 TI - No Significant Effect of ASAP1 Gene Variants on the Susceptibility to Tuberculosis in Chinese Population. AB - Recent studies have proposed that the ASAP1 gene participates in regulating the adaptive immune response to Mycobacterium tuberculosis infection. A GWAS study has reported that ASAP1 polymorphisms (rs4733781 and rs10956514) were associated with the risk of tuberculosis (TB) in Russians. But due to population heterogeneity, different races would have different causative polymorphisms, and the aim of this study was to investigate the association between single nucleotide polymorphisms (SNPs) of the ASAP1 gene and TB risk in Chinese population.A total of 7 SNPs in the ASAP1 gene were genotyped in 1115 Western Chinese Han and 914 Tibetan population using an improved multiplex ligation detection reaction (iMLDR) method. The associations of SNPs with TB risk and clinical phenotypes were determined based on the distributions of allelic frequencies and different genetic models. A meta-analysis was carried out to further assess the relationship between ASAP1 polymorphism and TB risk.Statistical comparisons of cases and controls after correction for multiple testing did not yield any significant associations with the risk of TB via analyses of a single locus, haplotype, and subgroup differences. Meta-analysis showed no evidence supporting association between rs10956514 and overall risk for TB. Subsequent analysis referring to the genotypes of SNPs in relationship to clinical phenotypes identified that rs4236749 was associated with different serum C-reactive protein levels, suggesting a role of this locus in influencing the inflammatory state of Western Chinese Han patients with TB.Our present data revealed that ASAP1 polymorphisms are unlikely to confer susceptibility to TB in the Western Chinese Han and Tibetan populations, which challenges the promising roles of the ASAP1 gene in the development of TB and highlights the importance of validating the association findings across ethnicities. PMID- 27227930 TI - Perioperative Standard Oral Nutrition Supplements Versus Immunonutrition in Patients Undergoing Colorectal Resection in an Enhanced Recovery (ERAS) Protocol: A Multicenter Randomized Clinical Trial (SONVI Study). AB - To compare immunonutrition versus standard high calorie nutrition in patients undergoing elective colorectal resection within an Enhanced Recovery After Surgery (ERAS) program.Despite progress in recent years in the surgical management of patients with colorectal cancer (ERAS programs), postoperative complications are frequent. Nutritional supplements enriched with immunonutrients have recently been introduced into clinical practice. However, the extent to which the combination of ERAS protocols and immunonutrition benefits patients undergoing colorectal cancer surgery is unknown.The SONVI study is a prospective, multicenter, randomized trial with 2 parallel treatment groups receiving either the study product (an immune-enhancing feed) or the control supplement (a hypercaloric hypernitrogenous supplement) for 7 days before colorectal resection and 5 days postoperatively.A total of 264 patients were randomized. At baseline, both groups were comparable in regards to age, sex, surgical risk, comorbidity, and analytical and nutritional parameters. The median length of the postoperative hospital stay was 5 days with no differences between the groups. A decrease in the total number of complications was observed in the immunonutrition group compared with the control group, primarily due to a significant decrease in infectious complications (23.8% vs. 10.7%, P = 0.0007). Of the infectious complications, wound infection differed significantly between the groups (16.4% vs. 5.7%, P = 0.0008). Other infectious complications were lower in the immunonutrition group but were not statistically significantly different.The implementation of ERAS protocols including immunonutrient-enriched supplements reduces the complications of patients undergoing colorectal resection.This study is registered with ClinicalTrial.gov: NCT02393976. PMID- 27227931 TI - Hypersplenism Associated With Late-Presenting Congenital Diaphragmatic Hernia: A Rare Combination. Case Report. AB - Congenital diaphragmatic hernia (CDH) is a rare developmental anomaly of the diaphragm that mainly presents mainly in newborns. Even less common is late-onset CDH associated with hypersplenism. We report a 10-year-old male who presented with coughing, blood-stained sputum, and fever. He was diagnosed with CDH complicating hypersplenism after computed tomography was done. The patient was treated by CDH repair and splenectomy, and remained asymptomatic at 6-month follow-up. Computed tomography can be an important diagnostic option in this rare combination of CDH and hypersplenism, and surgical intervention is strongly recommended. PMID- 27227932 TI - Expression of FOXO6 is Associated With Oxidative Stress Level and Predicts the Prognosis in Hepatocellular Cancer: A Comparative Study. AB - The aim of this study was to explore the association of Forkhead box O6 (FOXO6) expression with oxidative stress level and prognosis of hepatocellular cancer (HCC).The case group included tissues of HCC from 128 patients who were hospitalized in Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery of First Affiliated Hospital, School of Medicine, Zhejiang University. The control group included normal liver tissues from 74 patients. RT-PCR and Western blot were used to test expressions of FOXO6, heme oxygenase (HO)-1, glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT). Dihydroethidium (DHE) was dyed to observe reactive oxygen species (ROS) level. Immunohistochemistry was used to test FOXO6 expression. FOXO6 was silenced in HepG2 cells to detect cell proliferation and apoptosis. The expressions of ROS, HO-1, GPx, SOD, CAT, p27, and cyclin D1 were also detected to further explore the possible mechanism.The expressions of FOXO6, HO-1, GPx, SOD, and CAT in HCC tissue was significantly higher than those in normal and adjacent HCC tissues (P <0.05). The tumor size, TNM stage, Alpha-fetoprotein (AFP) level, the presence or absence of hepatitis B surface antigen (HbsAg), and differentiation degree were related to FOXO6 expression level (all P <0.05). COX analysis showed that high FOXO6 expression, male, positive HBsAg, advanced TNM staging, high expression of AFP, and low degree of differentiation were all risk factors for prognosis in HCC (P <0.05). Compared with the blank group (C group, without transfection) and the negative control (NC) group, the mRNA expressions of ROS, FOXO6, HO-1, SOD, GPx, and CAT were decreased (P <0.05). si-RNA group had significantly decreased proliferation speed during 24 to 72 hours (P <0.05), whereas si-FOXO6 group had remarkably increased G0/G1 staged cells and decreased S-staged cells (P <0.05). The si-FOXO6 group showed notably increased apoptosis rate (P <0.05) and p27 expressions as well as decreased cyclin D1 expressions (P <0.05).FOXO6 was highly expressed in HCC tissue and was related to oxidative stress levels. Furthermore, FOXO6 expression can be used as a biomarker for deterioration and prognosis of liver cancer, which may provide a novel treatment target for HCC therapy. PMID- 27227933 TI - Sodium Bicarbonate Prevents Contrast-Induced Nephropathy in Addition to Theophylline: A Randomized Controlled Trial. AB - In this study, we investigated whether hydration with sodium bicarbonate is superior to hydration with saline in addition to theophylline (both groups) in the prophylaxis of contrast-induced nephropathy (CIN). It was a prospective, randomized, double-blinded study in a university hospital on 2 general intensive care units (63% of investigations) and normal wards.After approval of the local ethics committee and informed consent 152 patients with screening serum creatinine >=1.1 mg/dL and/or at least 1 additional risk factor for CIN undergoing intravascular contrast media (CM) exposure were randomized to receive a total of 9 mL/kg bicarbonate 154 mmol/L (group B; n = 74) or saline 0.9% (group S; n = 78) hydration within 7 h in addition to intravenous application of 200 mg theophylline. Serum creatinine was determined immediately before, 24 and 48 h after CM exposure. As primary endpoint we investigated the incidence of CIN (increase of serum creatinine >=0.5 mg/dL and/or >=25% within 48 h of CM).Both groups were comparable regarding baseline characteristics. Incidence of CIN was significantly less frequent with bicarbonate compared to sodium hydration (1/74 [1.4%] vs 7/78 [9.0%]; P = 0.035). Time course of serum creatinine was more favorable in group B with decreases in serum creatinine after 24 h (-0.084 mg/dL [95% confidence interval: -0.035 to -0.133 mg/dL]; P = 0.008) and 48 h (-0.093 mg/dL (-0.025 to -0.161 mg/dL); P = 0.007) compared to baseline which were not observed in group S.In patients at increased risk of CIN receiving prophylactic theophylline, hydration with sodium bicarbonate reduces contrast-induced renal impairment compared to hydration with saline. PMID- 27227934 TI - IL-8 Alterations in HIV-1 Infected Children With Disease Progression. AB - Disease progression in HIV-1 infected children is faster than in adults. Less than 5% of the infected children maintain stable CD4 counts beyond 7 years of infection and are termed long-term nonprogressors (LTNPs). Delineating the host immune response in antiretroviral naive (ART) and treated HIV-1 infected children at different disease stages will help in understanding the immunopathogenesis of the disease.A total of 79 asymptomatic, perinatally HIV-1 infected children (50 ART naive and 29 ART treated) and 8 seronegative donors were recruited in this study. T- and B-cell activation PCR arrays were performed from the cDNA, using total RNA extracted from the peripheral blood mononuclear cells (PBMCs) of 14 HIV 1 infected children at different stages of the disease. The differentially expressed genes were identified. Quantitative RT-PCR was performed for the (interleukin-8) IL-8 gene and its transcriptional mediators, that is, SHP2, GRB2, and IL-8R (IL-8 receptor/CXCR1). Plasma levels of IL-8 were measured by flow cytometry.Gene array data revealed a higher expression of IL-8 in the ART naive HIV-1 infected progressors and in ART nonresponders than LTNPs and ART responders, respectively. Quantitative RT-PCR analysis demonstrated a significant higher expression of IL-8 (P < 0.001), its receptor CXCR1 (P = 0.03) and the upstream signaling molecule SHP2 (P = 0.04) in the progressors versus LTNPs. Plasma levels of IL-8 were significantly higher in progressors versus LTNPs (P < 0.001), and ART nonresponders versus ART responders (P < 0.001). A significant negative correlation of plasma levels of IL-8 with CD4 counts (cells/MUL) was observed in HIV-1 infected ART naive subjects (r = -0.488; P < 0.001), while the IL-8 levels positively correlated with viral load in the ART treated children (r = 0.5494; P < 0.001). ART naive progressors on follow up demonstrated a significant reduction in the mRNA expression (P = 0.05) and plasma levels of IL-8 (P = 0.05) post 6 months of ART initiation suggesting the beneficial role of ART therapy in reducing inflammation in infected children.Our data suggest that IL-8 may serve as a potential prognostic marker in adjunct with CD4 counts to monitor disease progression in the HIV-1 infected children and the efficacy of ART. PMID- 27227935 TI - Clinicopathological Features Associated With the Prognosis of Patients With Adrenal Cortical Carcinoma: Usefulness of the Ki-67 Index. AB - Adrenocortical carcinoma (ACC) is a rare tumor with a poor prognosis. Identification of clinicopathological features and molecular prognostic markers is important for the treatment of ACC. The aim of this study was to evaluate the clinical and histopathological features of ACC for prognostic prediction.This retrospective cohort study included 86 patients pathologically confirmed with ACC in a single center. Ki-67 index was evaluated by immunohistochemical staining of paraffin-embedded samples.The median age of the 86 (46 male and 40 female) patients with ACC was 49 years old (range 21-78), and the mean primary tumor size was 12.2 +/- 5.2 cm. ACCs were incidentally found in 29 patients (34%). Three patients (3%) had bilateral ACC, and 59 patients (69%) had distant metastasis (37 synchronous and 22 metachronous). Twenty-four patients (28%) had symptoms from hormone excess or mass effects, and 25 patients (29%) had nonspecific symptoms. The 5-year survival rate for ACC was 28%. Sixty patients underwent surgical treatment, including 37 patients with an R0 resection. Tumor size, Ki-67 index, stage, and resection status were independently associated with overall survival by multivariate analysis. In patients with R0 resection, recurrence was significantly associated with larger tumor size and functional tumor.Tumor size, Ki-67 index, stage, and resection status are important prognostic indicators of survival in ACC patients. PMID- 27227936 TI - Population-Based Prevalence of Intellectual Disability and Autism Spectrum Disorders in Western Australia: A Comparison With Previous Estimates. AB - To investigate the prevalence of intellectual disability (ID) and/or autism spectrum disorders (ASDs) in Western Australia (WA).A cohort of children born from 1983 to 2010 in WA with an ID and/or ASD were identified using the population-based IDEA (Intellectual Disability Exploring Answers) database, which ascertains cases through the Disability Services Commission (DSC) as well as education sources. Information on race, gender, mother's residence at birth and deaths was obtained through linkage to the Midwives Notification System and the Mortality Register. Diagnostic information on the cause of ID was obtained through review of medical records where available and children were classified as biomedical cause, ASD, or unknown cause.An overall prevalence of ID of 17.0/1000 livebirths (95% CI: 16.7, 17.4) showed an increase from the 10-year previous prevalence of 14.3/1000. The prevalence for mild or moderate ID was 15.0 (95% CI: 14.6, 15.3), severe ID was 1.2 (95% CI: 1.1, 1.3), and unknown level of ID was 0.9 (95% CI: 0.8, 1.0)/1000 livebirths. The prevalence for Aboriginal children was 39.0/1000 compared with 15.7/1000 for non-Aboriginal children, giving a prevalence ratio of 2.5 (95% CI: 2.4, 2.6). Prevalence of all ASD was 5.1/1000 of which 3.8/1000 had ASD and ID.The prevalence of ID has risen in WA over the last 10 years with most of this increase due to mild or moderate ID. Whilst the prevalence of ASD has also increased over this time this does not fully explain the observed increase. Aboriginal children are at a 2.5-fold risk of ID but are less likely to be accessing disability services. PMID- 27227937 TI - Evaluating the Minimal Specimens From Endoscopic Ultrasound-Guided Fine-Needle Aspiration in Pancreatic Masses. AB - Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has become one of the most useful diagnostic modalities for the diagnosis of pancreatic mass. The aim of this study was to investigate the role of analyzing the minimal specimens obtained by EUS-FNA for the diagnosis of solid masses of pancreas.This study consisted of retrospective and prospective analyses. The retrospective study was performed on 116 patients who underwent EUS-FNA of solid masses for cytological smear, histological analysis, and combined analysis including immunohistochemical (IHC) staining. In the prospective study, 79 patients were enrolled to evaluate the quality and accuracy of EUS-FNA histological analysis and feasibility of IHC staining.The final diagnoses of all patients included pancreatic cancer (n = 126), nonpancreatic cancer (n = 21), other neoplasm (n = 27), and benign lesions (n = 21). In our retrospective study, the combined analysis was more sensitive than cytological analysis alone (P < 0.01). The overall sensitivity of cytology, histology, and combined analysis was 69.8%, 67.2%, and 81.8%, respectively. In the prospective analysis, 64.2% of all punctures were helpful for determining the diagnosis and 40.7% provided sufficient tissue for IHC staining. Histological analysis was helpful for diagnosis in 74.7% of patients. IHC staining was necessary for a definite diagnosis in 11.4% of patients, especially in the cases of nonmalignant pancreatic mass.Histological analysis and IHC study of EUS-FNA specimens was useful for the accurate diagnosis of pancreatic and peripancreatic lesions. Combined analysis showed significantly higher sensitivity than cytology alone because IHC staining was helpful for a diagnosis in some patients. PMID- 27227938 TI - Death Due to Intra-aortic Migration of Kirschner Wire From the Clavicle: A Case Report and Review of the Literature. AB - Migration of orthopedic fixation wires into the ascending aorta though a rare occurrence can have devastating consequences. Therefore, prompt recognition, with immediate and cautious retrieval of the implant is paramount in averting these complications.We present a case of a 5-year-old boy with the intra-aortic migration of a K-wire used for the treatment of a right clavicle fracture. He was transferred to us with a history of syncope, chest pain, and shortness of breath 7 days after K-wire placement, which was performed at another hospital. On CT scan, the wire was found to be partially inside the ascending aorta, which was associated with massive hemopericardium and cardiac tamponade. The patient was taken up for emergency surgery for the removal K-wire and for the management of cardiac temponade. However, the patient developed cardiac arrest during the induction of intravenous anesthesia and endotracheal intubation. The K-wire was retrieved from the thorax via thoracotomy. However, the patient died 10 days after the surgery.As the migration of wires and pins during orthopedic surgery can cause potentially fatal complications, these should be used very cautiously, especially for percutaneous treatment of shoulder girdle fractures. The patients with such implants should be followed frequently, both clinically and radiographically. If migration occurs, the patient should be closely monitored for emergent complications and the K-wire should be extracted immediately. PMID- 27227939 TI - Associations of Health-Risk Behaviors and Health Cognition With Sexual Orientation Among Adolescents in School: Analysis of Pooled Data From Korean Nationwide Survey From 2008 to 2012. AB - Homosexual adolescents may face significant health disparities. We examined health-risk behaviors and health cognition related to homosexual behavior in a representative sample of adolescents.Data were obtained from 129,900 adolescents between 2008 and 2012 over 5 cycles of the Korean Youth Risk Behavior Survey, a national survey of students in grades 7 to 12. Various health-risk behaviors and aspects of health cognition were compared between homosexual and heterosexual adolescents and analyzed with multiple logistic regression models.Compared with heterosexual adolescents (n = 127,594), homosexual adolescents (n = 2306) were more likely to engage in various health-risk behaviors and to have poor health cognition. In multiple logistic regression analysis, not living with parents, alcohol experience (adjusted odds ratio, 1.50; 95% confidence interval, 1.26-1.78 for males and 1.66; 1.33-2.07 for females), smoking experience (1.80; 1.54-2.10 for males and 3.15; 2.61-3.79 for females), and drug experience (3.65; 2.81-4.80 for males and 3.23; 2.35-4.46 for females) were associated with homosexual behavior. Homosexual adolescents were more likely to use adult internet content (2.82; 2.27-3.50 for males and 7.42; 4.19-13.15 for females), and to be depressed (1.21; 1.03-1.43 for males and 1.32; 1.06-1.64 for females). In addition, suicide ideation (1.51; 1.26-1.81 for males and 1.47; 1.16-1.86 for females) and attempts (1.67; 1.37-2.05 for males and 1.65; 1.34-2.03 for females) were significantly more prevalent among homosexual adolescents.Homosexual adolescents report disparities in various aspects of health-risk behavior and health cognition, including use of multiple substances, adult internet content and inappropriate weight loss methods, suicide ideation and attempts, and depressive mood. These factors should be addressed relevantly to develop specific interventions regarding sexual minorities. PMID- 27227940 TI - Cardiac Autonomic Function in Patients With Ankylosing Spondylitis: A Case Control Study. AB - Ankylosing spondylitis (AS) is a chronic inflammatory disease involing spine and enthesis. The primary aim of this study is to investigate the autonomic nervous system (ANS) function and the association between ANS and the functional status or disease activity in AS.The study included 42 AS patients, all fulfilling the modified New York criteria. All the patients are totally symptom free for ANS involvement and had normal neurological findings. These AS patients and 230 healthy volunteers receive analysis of 5 minutes heart rate variability (HRV) in lying posture. In addition, disease activity and functional status of these AS patients are assessed by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), and Bath Ankylosing Spondylitis Global Score (BAS-G).Both groups were age and sex-matched. Although the HRV analysis indicates that the peaks of total power (TP, 0-0.5 Hz) and high-frequency power (HF, 0.15-0.40 Hz) are similar in both groups, the activities of low-frequency power (LF, 0.04-0.15 Hz), LF in normalized units (LF%), and the ratio of LF to HF (LF/HF) in AS patients are obviously lower than healthy controls. The erythrocyte sedimentation rate and C-reactive protein revealed negative relationship with HF. The AS patients without peripheral joint disease have higher LF, TP, variance, LF%, and HF than the patients with peripheral joint disease. The AS patients without uvetis have higher HF than the patients with uvetis. The total scores of BASDI, BASFI, and BAS-G do not show any association to HRV parameters.AS patients have significantly abnormal cardiac autonomic regulation. This is closely related with some inflammatory activities. Reduced autonomic function may be one of the factors of high cardiovascular risk in AS patients. PMID- 27227941 TI - The Retroperitoneal Laparoscopic Renal Capsulectomy for Spontaneous Renal Subcapsular Fluid Collection: A Case-Series Report and Literature Review. AB - Spontaneous renal subcapsular fluid collection may occur as a rare presentation of nephritic syndrome, and distension of the renal capsula and Gerota fascia due to massive fluid accumulation may cause pain. In addition, hypertension secondary to renal ischemia and activation of renin-angiotensin-aldosterone system may also occur. The objective of this study is to evaluate the surgical outcome of retroperitoneal laparoscopic renal capsulectomy for patients with this disease.We retrospectively analyzed the clinical data of 10 female patients with spontaneous renal subcapsular fluid collection, diagnosed with B ultrasound and enhanced computed tomography (CT) scan. Eight patients first underwent percutaneous renal subcapsular drainage, which seemed to be less effective, and then all patients underwent retroperitoneal laparoscopic renal capsulectomy. The volume of renal subcapsular fluid was documented, the fluid was examined by routine biochemical tests, and the excised renal capsules underwent pathological examination individually. The postoperative drainage time for each patient was documented, and follow-up was conducted 1, 3, 6, 12 months, and 2 years postoperatively.Retroperitoneal laparoscopic renal capsulectomy was successfully performed in all patients with no major complications. The average volume of renal subcapsular fluid was 436 milliliter (mL, 180-880 mL) in light yellow color, and the concentration of creatinine and urea nitrogen was quite similar to that of serum. The pathological findings revealed fibrous dysplasia of the renal capsule with chronic infiltration of inflammatory cells. The average drainage time was 11.5 days (5-30 days) postoperatively. All patients recovered 1 month after the operation and there were no recurrences with a mean follow-up period of 12 months (6-24 months).The reason for spontaneous renal subcapsular fluid collection is unknown, and the aim of treatment is mainly to alleviate symptoms. In our experience, retroperitoneal laparoscopic renal capsulectomy is an effective surgical treatment, especially for patients who were refractory to percutaneous renal subcapsular drainage, with no observed recurrence. PMID- 27227942 TI - Effectiveness of 18F-FDG-PET/CT vs Bone Scintigraphy in Treatment Response Assessment of Bone Metastases in Breast Cancer. AB - The aim of the study was to examine the effectiveness of fluorine-18 fluoro-2 deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) versus bone scintigraphy (BS) in treatment response assessment of bone metastases in breast cancer.The medical records of breast cancer patients with metastatic bone disease were reviewed retrospectively in our hospital from the period of January 2003 until April 2014. We included in our study patients evaluated by BS and/or 18F-FDG-PET/CT. Group 1 included patients who underwent pre- and post treatment BS. Group 2 included patients who underwent pre- and post-treatment 18F FDG-PET/CT scans. Group 3 included patients who underwent pretreatment BS and post-treatment both modalities. Functional and structural bone changes were monitored on pre- and post-treatment scans.Group 1 included 71 patients, average age of 49.5 y (range 28-73 y). Post-treatment results were as follows: 34% stable disease, 43% progressed disease, 19% improved disease, 3% resolved disease, and 2% relapsed disease. Group 2 included 32 patients, average age 53.2 y (ranges between 37 and 78 y). Post-treatment results were as follows: 3% stable disease, 15% progressed disease, 15% improved disease, 53% resolved disease, and 14% relapsed disease. After treatment, the total symptomatic/imaging concordance rate was 51% in BS and 83% in 18F-FDG-PET/CT. Structurally, most patients with newly diagnosed metastatic bone disease had predominantly osteolytic lesions, which became mixed or osteoblastic after treatment as noted on CT images of responders. Group 3 included 8 patients, average age 48.9 y (ranges 32-64 y). Five patients had stable disease according to BS. 18F-FDG-PET/CT was concordant in 3/5 patients and discordant in 2/5 patients. Three patients had progressed disease on BS with concordant findings on 18F-FDG-PET/CT.18F-FDG-PET/CT was found a powerful tool in treatment response assessment of bone metastases in breast cancer and consistent with clinical status of the patients as it reflects tumor activity. BS is insufficient for response assessment of bone metastases as it reflects osteoblastic reaction of the bone against metastatic disease which increases as the disease responds to treatment. PMID- 27227943 TI - Assessment of The Lymphatic System of the Genitalia Using Magnetic Resonance Lymphography Before and After Treatment of Male Genital Lymphedema. AB - Treatment for chronic male genital lymphedema (GL) is limited. No standard treatment or validated instrument to assess GL is available. The aim of this study was to explore whether magnetic resonance lymphography (MRL) could be used to assess GL, select proper treatment for patients, and monitor postoperative progress.This is a retrospective analysis of a prospectively acquired cohort of men with GL presenting for MRL over a 7-year period. Thirty-six of 47 eligible men were included. All men were offered preoperative and postoperative MRL and assigned a morphology and function classification. Men with mild, moderate, and severe nodal dysfunction underwent complex decongestive physiotherapy (CDP), lymphoveneous microsurgery, and surgical excision, respectively. The volume reductions in the genitalia of patients with mild and moderate nodal dysfunction were recorded and compared using Student t test.The abnormal superficial and deep lymphatic vessels in the lymphedematous genitalia were detected by MRL, and inguinal lymph node dysfunction was classified by MRL. Seven patients with mild dysfunction who underwent CDP showed a more significant mean volume reduction in the genitalia than did 9 patients with moderate dysfunction. Three patients with hyperplasia and moderate dysfunction who underwent microsurgical operations and 17 patients with hypoplasia and moderate or severe nodal dysfunction who underwent surgical excision had excellent cosmetic results with no lymphedema at the 3- to 5-year follow-up.MRL can be used to assess morphological and functional lymphatic abnormalities in GL, preoperatively select appropriate treatment, and postoperatively evaluate treatment outcomes. PMID- 27227944 TI - PD-1 rs2227982 Polymorphism Is Associated With the Decreased Risk of Breast Cancer in Northwest Chinese Women: A Hospital-Based Observational Study. AB - Programmed death-1 (PD-1) is crucial in cancer and is well characterized as a negative T-cell regulator that functions by delivering inhibitory signals. We aimed to evaluate the relationship between PD-1 polymorphisms (rs10204525, rs2227982, and rs7421861) and breast cancer risk.We selected 560 breast cancer patients and 583 age-, sex-, and ethnicity-matched healthy controls from Northwest China. The PD-1 polymorphisms were genotyped by using Sequenom MassARRAY. Associations were estimated with odds ratios (ORs) and 95% confidence intervals (95% CIs).For the rs10204525 and rs7421861 polymorphisms, no differences in breast cancer risk were found in any of the genetic models. For the rs2227982 polymorphism, the variant genotypes were significantly associated with decreased breast cancer risk (CT vs CC: OR = 0.68, 95% CI = 0.52-0.91; CT + TT vs CC: OR = 0.69, 95% CI = 0.53-0.90). In analyses stratified by age, the decreased risk was observed among the younger subjects (OR = 0.68, 95% CI = 0.47 0.97). We found that the decreased risk observed for the variant genotypes of rs2227982 was associated with the Her-2 status (CT vs CC: OR = 0.55, 95% CI = 0.37-0.84; CT + TT vs CC: OR = 0.56, 95% CI = 0.38-0.82). The haplotype analysis showed that the Ars10204525 Trs2227982 Crs7421861 haplotype was associated with a significantly decreased risk of breast cancer (OR = 0.50, 95% CI = 0.34-0.75).Our findings support an association between the PD-1 rs2227982 polymorphism and decreased breast cancer risk, especially in Her-2 positive breast cancer patients in the Chinese population. PMID- 27227945 TI - The Association Between Alcohol Consumption and Left Ventricular Ejection Fraction: An Observational Study on a General Population. AB - The results of previous studies on the relation between alcohol consumption and heart failure (HF) have been inconsistent. This study aimed to evaluate the association between alcohol consumption and left ventricular ejection fraction (LVEF) in a general population.A total of 10,824 adults were examined using a multistage cluster sampling method to select a representative sample of individuals who were at least 35-years old. The participants were asked to provide information about their alcohol consumption. Echocardiograms were obtained, and LVEF was calculated using modified Simpson's rule.Of the 10,824 participants included in the present study, 46.1% were males, and the mean participant age was 54 years; age ranged from 35 to 93 years. The overall prevalence of LVEF< 0.50 and LVEF < 0.40 in the studied population was 11.6% and 2.9%, respectively. The prevalence of LVEF < 0.5 and LVEF < 0.04 was higher in both the moderate and heavy drinker groups than in the nondrinker group (P <0.05). Multivariate logistic regression analyses corrected according to the different levels of alcohol consumption showed that moderate and heavy drinkers had an -1.3-fold and 1.2-fold higher risk of LVEF <0.5, respectively, than nondrinkers (OR: 1.381, 95% CI: 1.115-1.711, P = 0.003 for moderate drinkers; OR: 1.246, 95% CI: 1.064-1.460, P = 0.006 for heavy drinkers). Heavy drinkers had an ~1.5-fold higher risk of decreased LVEF < 0.4 than nondrinkers (OR: 1.482, 95% CI: 1.117-1.965, P = 0.006). Moderate drinkers did not show a risk of decreased LVEF < 0.4 that was significantly higher than that of nondrinkers (OR: 1.183, 95% CI: 0.774-1.808, P = 0.437).According to these results, we concluded that increased alcohol consumption was associated with decreased LVEF compared with no alcohol consumption in this general population. PMID- 27227946 TI - Primary Renal Rhabdomyosarcoma in an Adolescent With Tumor Thrombosis in the Inferior Vena Cava and Right Atrium: A Case Report and Review of the Literature. AB - Although the second peak of the age distribution of rhabdomyosarcoma (RMS) is at adolescence, renal RMS is extremely rare at this age group. This tumor is indistinguishable from other renal tumors based on clinical and imaging findings, and the diagnosis relies on histology and immunohistochemical staining. We report a unique case of adolescent renal RMS associated with tumor thrombus extending into the inferior vena cava (IVC) and right atrium.An 18-year-old female adolescent presented with shortness of breath and palpitations, associated with right flank discomfort, and hematuria. A pleomorphic-type renal RMS with Budd Chiari syndrome and arrhythmia induced by IVC and RA thrombosis was diagnosed. Despite complete tumor resection, the patient developed multiple lung metastases a month after surgery. Chemotherapy was recommended, but the patient declined. She died within a year of the initial operation.Adolescent renal RMS is rare and associated with poor outcome. Early aggressive multimodal therapy seems to be appropriate, in particular, in the presence of tumor thrombosis. PMID- 27227947 TI - Somatosensory Amplification, Anxiety, and Depression in Patients With Hepatitis B: Impact on Functionality. AB - In the present study, we aimed to determine the differences in body image along with anxiety and depression levels, and also to evaluate their impact on disability parameters in patients with hepatitis B.Our study comprised 77 patients with hepatitis B (n = 41, chronic active patients; n = 36, patients with inactive hepatitis B) and 53 healthy individuals (control group). Enrolled patients responded to several questionnaires, including a sociodemographic form, Sheehan Disability Scale (SDS), Hospital Anxiety and Depression Scale (HADS), and Somatosensory Amplification Scale.Patients with chronic active hepatitis B (CAHB) had higher levels of somatosensory perception than patients with inactive hepatitis B (IHB) and control group (P < 0.001, P = 0.001, respectively). Patients with CAHB had high scores on all the 3 domains of SDS (work/school, P < 0.001; social life, P < 0.001; and family life, P < 0.001). Also, patients with CAHB had a significantly higher HADS total score, HADS anxiety score, and HADS depression score than control group (P < 0.001, P < 0.001, P < 0.001, respectively). No significant difference was noted between patients with CAHB and patients with IHB with regard to HADS depression score; however, HADS anxiety and HADS total scores were significantly higher in the CAHB group (NS, P = 0.027, P = 0.035, respectively). Moreover, the IHB group exhibited higher scores for the work/school and social life domains of SDS than those of the control group (P = 0.008, P = 0.047).Although patients with CAHB may present with somatosensory amplification, anxiety, and depression, patients with IHB do not exhibit such symptoms. However, functionality is affected in both carrier and active patient groups. We believe that routine health checks of patients with hepatitis B should include psychiatric evaluation, psychiatric examination, and follow-up. PMID- 27227948 TI - Myasthenia Crisis Induced by Pegylated-Interferon in Patient With Chronic Hepatitis C: A Case Report. AB - Myasthenia gravis is occasionally associated with thymoma that needs surgical resection and may progress to severe respiratory failure. We experienced a rare case of myasthenia crisis during antiviral therapy for chronic hepatitis C, in whom mediastinal thymoma was discovered and successfully managed with surgical thymectomy and meticulous medical care.A 47-year-old-male patient complained of sudden diplopia 1 week after stopping 11-week administration of pegylated interferon and ribavirin for chronic hepatitis C. Ophthalmologic examinations revealed ptosis on the right eyelid and restricted right eye movement. Myasthenia gravis was confirmed by positive repetitive nerve stimulation test and positive serum antiacetylcholine receptor antibody test, and mediastinal thymoma was found on chest CT scan. The ocular myasthenia gravis progressed to respiratory failure even after discontinuing antiviral treatment but eventually recovered with thymectomy, anticholinesterase administration, steroid pulse therapy, and prolonged ventilator care. We describe the clinical features of this life threatening complication of interferon treatment along with previous myasthenia crisis cases by interferon for chronic hepatitis C.In patients with chronic hepatitis C who is going to receive interferon-based antiviral treatment, physicians need to keep in mind the potential life-threatening manifestations of myasthenia gravis before and during antiviral treatment especially when patients complain of muscular weakness and easy fatigability. PMID- 27227949 TI - Association Between Histone Methyltransferase hSETD1A and Prognosis in Patients With Triple-Negative Breast Cancer After Surgery: A Retrospective Study in the Chinese Female Population. AB - Breast cancer, the most common cancer in women, is a serious public health issue. Triple-negative breast cancer (TNBC), which lacks expression of the estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2, accounts for ~15% of breast cancer cases. Treatment of TNBC patients has proven difficult because of the lack of expression of hormone receptors. We conducted a retrospective study to investigate the prognostic impact of histone methyltransferase, hSETD1A, on overall survival in TNBC cases after surgery. In total, 159 TNBC cases were enrolled and clinicopathological characteristics were obtained from medical records. hSETD1A status of each subject was determined using immunohistochemistry. The chi-squared test was used to compare 5-year overall survival rates of all subjects according to clinical characteristics, and both univariate and multivariate analyses were conducted to calculate the hazard ratios and 95% confidence intervals. Advanced tumor-node-metastasis stage stage, larger tumor size, vascular invasion, metastasis in the initial diagnosis, and hSETD1A expression were correlated with worse outcome. Among all factors identified, metastasis in the initial diagnosis had the greatest impact on survival. The results indicated that hSETD1A positivity was correlated with shorter survival among TNBC cases, suggesting it may serve as a prognostic biomarker for patients with TNBC. PMID- 27227950 TI - Diagnostic Value of Serum IgG4 for IgG4-Related Disease: A PRISMA-compliant Systematic Review and Meta-analysis. AB - Many studies about serum IgG4 for the diagnosis of IgG4-related disease (IgG4-RD) have been reported. However, these studies had relatively small sample sizes and the diagnostic accuracy values varied much between them.The aim of this study was to perform a meta-analysis to evaluate the diagnostic value of serum IgG4 for IgG4-RD.We conducted a search of relevant articles using MEDLINE, EMBASE, Web of Science, SCOPUS, and Cochrane Library databases published before December 2015.Studies those assessed the diagnostic accuracy of serum IgG4 for IgG4-RD and those provided the cut-off value for serum IgG4 were included.Data were synthesized using the random-effect model. Statistical analysis was performed using STATA with the MIDAS module and Meta-DiSc 1.4 software.A total of 9 case control studies were analyzed, which included 1235 patients with IgG4-RD and 5696 overall controls. The pooled estimate, for a cut-off value ranged from 135 to 144 mg/dL, produced a sensitivity of 87.2% (95% CI, 85.2-89.0%) and a specificity of 82.6% (95% CI, 81.6-83.6%). The positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were 6.48 (95% CI, 3.98 10.57), 0.14 (95% CI, 0.09-0.21), and 45.15 (95% CI, 23.41-87.06), respectively. The area under the curve (AUC) of the summary receiver operating characteristic curve (SROC) was 0.94 (0.92-0.96). When a cut-off value of 2-fold the upper limit of normal was used (ranged from 270 to 280 mg/dL), the pooled sensitivity was 63% (95% CI, 60.0-66.0%), and the specificity was 94.8% (95% CI, 94.1-95.4%). The PLR, NLR, and DOR were 13.3 (95% CI, 7.39-24.0), 0.41 (95% CI, 0.29-0.58) and 33.42 (95% CI, 13.88-80.43), respectively. The AUC of the SROC was 0.92 (0.90 0.94).Only a relatively small number of studies were included, and significant heterogeneity was observed in this meta-analysis.Serum IgG4 is a modestly effective marker to diagnose IgG4-RD. Doubling the cut-off value for IgG4 could not improve the overall test characteristics. A high specificity inevitably accompanies with a significant sacrifice in sensitivity. PMID- 27227951 TI - Patients With Combined Membranous Nephropathy and Focal Segmental Glomerulosclerosis Have Comparable Clinical and Autoantibody Profiles With Primary Membranous Nephropathy: A Retrospective Observational Study. AB - Patients with combined membranous nephropathy (MN) and focal segmental glomerulosclerosis (FSGS) have been reported with different clinical significance. Investigations on the possible mechanisms of the combined glomerular lesions are necessary but scarce. Twenty patients with both MN and FSGS lesions were enrolled in the study. Sixty-five patients with primary MN and 56 patients with primary FSGS were used as disease controls. Clinical data on renal biopsy and during follow-up were collected. Circulating anti-phospholipase A2 receptor (PLA2R) antibody, glomerular PLA2R expression, IgG4 deposition, and soluble urokinase receptor (suPAR) levels were detected. We found that patients with combined lesions presented with older age, less proteinuria, higher albumin, and better renal function on biopsy. These were comparable to the patients with primary MN, but differed from the patients with primary FSGS. Patients with combined lesions showed higher stages of MN, no cellular variant on FSGS classification, and more common (100.0%) tubulointerstitial injury than both primary MN and primary FSGS patients. In the patients with combined lesions, 80.0% had circulating anti-PLA2R antibody and 68.4% had IgG4 predominant deposition in glomeruli, which were comparable to primary MN. The patients with combined lesions had significantly lower urinary suPAR concentrations, than the primary FSGS patients (315.6 +/- 151.0 vs 752.1 +/- 633.9 pg/MUmol; P = 0.002), but similar to the primary MN patients (267.9 +/- 147.5 pg/MUmol). We conclude that patients with combined MN and FSGS may share the same underlying pathogenesis with primary MN. The FSGS lesion might be secondary to primary MN. PMID- 27227952 TI - Clinical Results and Complications of Lower Limb Lengthening for Fibular Hemimelia: A Report of Eight Cases. AB - Fibular hemimelia is a rare but the most common congenital long bone deficiency, encompassing a broad range of anomalies from isolated fibular hypoplasia up to substantial femoral and tibial shortening with ankle deformity and foot deficiency. Most cases of fibular hemimelia manifest clinically significant leg length discrepancy (LLD) with time that requires adequate correction by bone lengthening for stable walking. Bone lengthening procedures, especially those for pathological bones, are sometimes associated with severe complications, such as delayed consolidation, fractures, and deformities of the lengthened bones, leading to prolonged healing time and residual LLD at skeletal maturity. The purpose of this study was to review our clinical results of lower limb lengthening for fibular hemimelia.This study included 8 Japanese patients who diagnosed with fibular hemimelia from physical and radiological findings characteristic of fibular hemimelia and underwent single or staged femoral and/or tibial lengthening during growth or after skeletal maturity. LLD, state of the lengthened callus, and bone alignment were evaluated with full-length radiographs of the lower limb. Previous interventions, associated congenital anomalies, regenerate fractures were recorded with reference to medical charts and confirmed on appropriate radiographs. Successful lengthening was defined as the healing index <50 days/cm without regenerate fractures.A significant difference was observed in age at surgery between successful and unsuccessful lengthening. The incidence of regenerate fractures was significantly correlated with callus maturity before frame removal. LLD was corrected within 11 mm, whereas mechanical axis deviated laterally.Particular attention should be paid to the status of callus maturation and the mechanical axis deviation during the treatment period in fibular hemimelia. PMID- 27227953 TI - Integration of Chinese Herbal Medicine Therapy Improves Survival of Patients With Chronic Lymphocytic Leukemia: A Nationwide Population-Based Cohort Study. AB - Utilization of Chinese Medicine (CM) is not uncommon in patients with chronic lymphocytic leukemia (CLL). However, the current knowledge of the usage and efficacy of CM among CLL patients is limited. The aim of this study was to determine the impact of integrative Chinese Herbal Medicine (CHM) on the disease course of CLL and ascertain the herbal products most commonly prescribed to patients with CLL.A Taiwanese nationwide population-based study involving the use of Western medicine and CM services provided by the National Health Insurance (NHI) was conducted.An NHI Research Database-based cohort study was performed; the timeframe of the study was January 2000 to December 2010. The end of the follow-up period was defined as December 31, 2011.A total of 808 patients were diagnosed with CLL in Taiwan within the defined study period. After randomly matching for age and sex and excluding patients younger than 18 years of age, data from 616 patients were analyzed.The 2 study groups both received standard of care treatment. In addition, 1 group also received CHM. Patients who were registered as receiving other forms of CM, such as acupuncture, were excluded.Hazard ratios of mortality were used to determine the influence of CHM and the therapeutic potential of herbal products.In total, 616 CLL patients were included in the analyses. We found that the HR associated with the adjunctive use of CHM was less than half when compared to the non-CHM group (0.43, 95% CI 0.33 0.55, P < 0.0001) and that treatment-naive patients who used CHM had the lowest HR. We also established that this association between reduction in HR and CHM was dose-dependent, and the longer CHM users received prescriptions, the lower the HR (P < 0.001).We supplied data from a relatively large population that spanned a significant amount of time. Our data suggests that the treatment of CLL with adjunctive CHM may have a substantial positive impact on mortality, especially for treatment-naive patients. Further research is needed to confirm whether there is a direct causal relationship between CHM and the outcomes displayed. PMID- 27227954 TI - Efficacy and Safety of Intensity-Modulated Radiotherapy Following Transarterial Chemoembolization in Patients With Unresectable Hepatocellular Carcinoma. AB - Three-dimensional conformal radiotherapy in combination with transarterial chemoembolization (TACE) has been beneficial in patients with unresectable hepatocellular carcinoma (HCC). There have been few clinical reports on the use of intensity-modulated radiotherapy (IMRT) in combination with TACE for these patients. The purpose of this study was to assess the efficacy and toxicity of IMRT following TACE in unresectable HCC.The medical records of consecutive patients with unresectable HCC, who underwent IMRT following TACE from January 2009 to June 2014, were retrospectively reviewed in order to assess the overall survival (OS), progression-free survival (PFS), tumor response, and treatment associated toxicity.A total of 64 lesions in 54 patients were included in the analysis. IMRT was delivered at a median dose of 50 Gy (range 44-70 Gy) at 1.8 to 2.0 Gy per fraction. The overall response rate was achieved in 64.8% of patients with complete response in 20.4% of patients at 3 months after completion of IMRT. The median OS was 20.2 months (95% CI = 8.6-31.9), and the actuarial 1-, 2-, and 3-year OS rates were 84.6%, 49.7%, and 36.7%, respectively. The median PFS was 10.5 months (95% CI = 7.3-13.7) and the 1-, 2-, and 3-year PFS rates were 44.2%, 23.4%, and 14.6%, respectively. The responders had a significantly higher OS rate than the nonresponders (3-year OS 48.0% vs 14.4%, P = 0.001). During and the first month following IMRT, 10 (18.5%) patients developed grade 3 hematological toxicity, and 3 (5.6%) developed grade 3 hepatic toxicity. No patient experienced grade 4 or 5 toxicity. Radiation-induced liver disease was not observed.Our findings suggest that IMRT following TACE could be a favorable treatment option for both its safety profile and clinical benefit in patients with unresectable HCC. PMID- 27227955 TI - Prognostic Model of Death and Distant Metastasis for Nasopharyngeal Carcinoma Patients Receiving 3DCRT/IMRT in Nonendemic Area of China. AB - Few studies were conducted to explore the prognostic factors for nonendemic nasopharyngeal carcinoma (NPC) in the era of 3-dimensional conformal radiation therapy (3DCRT)/intensity-modulated radiation therapy (IMRT). The aim of this study was to evaluate the potential prognostic factors for nonendemic NPC.Between January 2004 and December 2011, a total of 393 nonendemic NPC patients receiving 3DCRT/IMRT were reviewed according to the inclusion and exclusion criteria. The prognostic factors we analyzed included age, T stage, N stage, lymph node diameter, primary tumor volume, WHO histology types, and cranial nerve related symptoms. All patients were staged according to the 7th edition of the American Joint Committee on Cancer (AJCC) system. The factors found to be associated with the endpoints by univariate analyses were then entered into multivariate Cox proportional hazards regression analysis.The median follow-up time was 61.4 months (range: 4-130 months). The 5-year local recurrent-free survival (LRFS), nodal relapse-free survival (NRFS), distant metastasis free survival (DMFS), and disease-specific survival (DSS) for all patients were 89.3%, 96.4%, 73.5%, and 74.3%, respectively. Multivariate analysis indicated that N stage (N2-3), WHO pathologic type II, and primary tumor volume (>23 mL) were 3 independent prognostic factors for DSS and DMFS. According to the number of prognostic factors, patients were divided into 3 risk groups: low-risk group (patients without any risk factors); intermediate-risk group (patients with only 1 risk factor); and high-risk group (patients with more than 2 risk factors). The 5-year DSS for low, intermediate, and high-risk groups were 91.5%, 75.2%, and 49.3%, respectively (P < 0.001). The 5-year DMFS for low, intermediate, and high-risk groups were 89.4%, 77.9%, and 49.4%, respectively (P < 0.001).Advanced N stage (N2-3), larger tumor volume (>23 mL), and histological WHO type II are independently prognostic factors for nonendemic NPC patients in China. PMID- 27227956 TI - Depressive Symptoms, Patient Satisfaction, and Quality of Life Over Time in Automated and Continuous Ambulatory Peritoneal Dialysis Patients: A Prospective Multicenter Propensity-Matched Study. AB - Health-related quality of life (HRQOL) is an important clinical outcome for dialysis patients. However, relative superiority in HRQOL between automated peritoneal dialysis (APD) and continuous ambulatory peritoneal dialysis (CAPD) are not clearly known. We compared HRQOL over time between APD and CAPD patients and evaluated factors associated with HRQOL.All 260 incident patients initiating APD or CAPD at multiple centers throughout Korea were prospectively enrolled in this study between October 2010 and February 2013. HRQOL, depressive symptoms, and renal treatment satisfaction were assessed 1 and 12 months after the start of dialysis by the Kidney Disease Quality of Life Short Form 36 (KDQOL-36), the Beck Depression Inventory (BDI), and the Renal Treatment Satisfaction Questionnaire (RTSQ), respectively.Of 196 patients who completed all questionnaires and did not change the peritoneal dialysis (PD) modality during the 1-year follow-up period, 160 were matched. APD patients showed better baseline HRQOL than CAPD patients for the symptoms, patient satisfaction, pain, and social function domains. There were no differences in HRQOL between the 2 groups at 12 months, and CAPD patients had significantly greater improvements in symptoms (P = 0.02), the mental composite summary (P = 0.03), and health status domains (P = 0.03) than APD patients. There were similar improvements in depressive symptoms (P = 0.01) and patient satisfaction with treatment (P = 0.01) in CAPD and APD patients. Interestingly, depressive symptoms, not PD modality, was the most influential and consistent factor for HRQOL. Despite the spontaneous improvement of depressive symptoms, considerable PD patients still had depressive symptoms at the 1-year appointment.APD has no advantage over CAPD for HRQOL. Considering the substantial negative effect of depressive symptoms on HRQOL, it is important to evaluate PD patients for depression and to treat those with depression to improve their HRQOL. PMID- 27227957 TI - Ability of Serum C-Reactive Protein Concentrations to Predict Complications After Laparoscopy-Assisted Gastrectomy: A Prospective Cohort Study. AB - Inflammatory markers, including C-reactive protein (CRP) and white blood cell (WBC), are widely available in clinical practice. However, their predictive roles for infectious complications following laparoscopy-assisted gastrectomy (LAG) have not been investigated. Our aim was to investigate the diagnostic accuracy of CRP concentrations and WBC counts for early detection of infectious complications following LAG and to construct a nomogram for clinical decision-making.The clinical data of consecutive patients who underwent LAG with curative intent between December 2013 and March 2015 were prospectively collected. Postoperative complications were recorded according to the Clavien-Dindo classification. The diagnostic value of CRP concentrations and WBC counts was evaluated by area under the curve of receiver-operating characteristic curves. Optimal cutoff values were determined by Youden index. Univariate and multivariate logistic regression analyses were performed to identify risk factors for complications, after which a nomogram was constructed.Twenty-nine of 278 patients (10.4%) who successfully underwent LAG developed major complications (grade >=III). CRP concentration on postoperative day 3 (POD 3) and WBC count on POD 7 had the highest diagnostic accuracy for major complications with an area under the curve value of 0.86 (95% confidence interval [CI], 0.79-0.92] and 0.68 (95% CI, 0.56-0.79) respectively. An optimal cutoff value of 172.0 mg/L was identified for CRP, yielding a sensitivity of 0.79 (95% CI, 0.60-0.92) and specificity 0.74 (95% CI, 0.68-0.80). Multivariate analysis identified POD3 CRP concentrations >=172.0 mg/L, Eastern Cooperative Oncology Group Performance Status >=1, presence of preoperative comorbidity, and operation time >=240 min as risk factors for major complications after LAG.The optimal cut-off value of CRP on POD3 to predict complications following LAG was 172.0 mg/L and a CRP-based nomogram may contribute to early detection of complications after LAG. PMID- 27227958 TI - Surgical Intervention Improves Survival for Metastatic Non-Small Cell Lung Cancer Patients. AB - Surgical intervention for stage IV non-small cell lung cancer (NSCLC) is still controversial. This study sought to evaluate the clinical effects of surgical intervention on survival in patients with stage IV NSCLCs and to identify the cohort benefitting the most from surgery.A retrospective study from the Surveillance, Epidemiology, and End Results database was performed to compare the survival of stage IV NSCLC patients who had undergone surgery with those who did not undergo surgery. Overall survival (OS) was evaluated using the Kaplan-Meier method and the log-rank test. The Cox proportional hazards model was used for multivariate analysis.The total number of eligible patients was 43,538, including 16.8% in the M1a stage and 83.2% in the M1b stage. The percentages of patients with no surgery (NONE), only metastatic tumor resection (MTR), only primary tumor resection (PTR), and both primary and metastatic tumor resection (PMTR) were 89.0%, 6.7%, 3.5%, and 0.8%, respectively; the corresponding 5-year survival rates were 2.0%, 4.0%, 13.0%, and 20.0%, respectively (P < 0.001); and the corresponding OS rates were 11.1 months, 14.7 months, 29.4 months, and 34.9 months, respectively (P < 0.001). Notably, the pairwise comparisons of 5-year survival rate and OS among the subgroups were all statistically significant. The multivariate analysis showed that surgical intervention was correlated with longer survival in patients with stage IV NSCLC. The stratified analysis showed significant differences in the OS on strata of the M1a stage and strata of the M1b stage. In the M1a stage, patients with PTR had significantly better OS than those with NONE (P < 0.001) or MTR (P < 0.001) but showed no significant differences compared with those with PMTR (P = 0.174); patients with MTR did not have prolonged survival compared with patients with NONE (P = 0.185), and they also did not have prolonged survival compared with patients with PMTR (P = 0.052). In the M1b stage, pairwise comparisons of OS were all statistically significant among the subgroups (P < 0.001).Surgical intervention can prolong survival to different degrees according to the modalities of surgery in stage IV NSCLC. PMID- 27227959 TI - Spectrum of Opportunistic Infections and Risk Factors for In-Hospital Mortality of Admitted AIDS Patients in Shanghai. AB - To investigate the frequency and the spectrum of major opportunistic infections (OIs), evaluate the major clinical factors associated with each specific OI, and identify the risk factors for in-hospital death among HIV patients in East China.A retrospective cohort study was made including all the HIV-infected patients who were admitted for the first time to the Shanghai Public Health Clinical Center during June 1, 2013 to June 1, 2015. The demographic and clinical data were collected. Comparison of continuous variables was analyzed by one-way ANOVA and rank sum test. Person chi test and Fisher exact test were applied to analyze the categorical variables. A Cox proportional hazards regression model was used to determine the risk for the occurrence of in-hospital death.In total, 920 patients were enrolled with age of 41.59 +/- 13.36 years and 91% male. Median CD4 was 34 (IQR, 13-94) cells/MUL. Among these patients, 94.7% acquired OIs while the rest developed malignancies. Pneumocystis pneumonia and bacterial coinfection (42.1%) was found to be the most common OIs, followed by tuberculosis (31.4%), CMV (20.9%), Cryptococcosis (9.0%), and MAC infection (5.2%). Of the above 5 major OIs, CMV-infected patients had the lowest median CD4 cell count 22.50 (IQR, 7.50-82.00) while the patients with tuberculosis infection had the highest count 61.00 (IQR, 27.00-176.00). In-hospital death rate was 4.2 per 100 person-years among these patients. Of note, admitted patients with 2 types of OIs (2.20, 95% CI 1.39-3.48) and those patients who were 40-year old or older (1.75, 95% CI 1.10 2.78) had a higher risk of such death.Pneumocystis pneumonia and tuberculosis were still the leading causes for the admission of HIV-infected patients in East China, and these patients tended to have very low CD4 cell counts. It is believed that expanding the HIV screening test and pushing the infected ones get ART earlier is required for generating a more successful HIV management strategy. PMID- 27227960 TI - Comparison between Stromal Vascular Fraction and Adipose Mesenchymal Stem Cells in Remodeling Hypertrophic Scars. AB - Hypertrophic scars (HTS) are characterized by excessive amount of collagen deposition and principally occur following burn injuries or surgeries. In absence of effective treatments, the use of mesenchymal stem/stromal cells, which have been shown to attenuate fibrosis in various applications, seems of interest. The objectives of the present study were therefore to evaluate the effect of human adipose tissue-derived mesenchymal stem cells (hASC) on a pre-existing HTS in a humanized skin graft model in Nude mice and to compare the efficacy of hASCs versus stromal vascular fraction (SVF). We found that injection of SVF or hASCs resulted in an attenuation of HTS as noticed after clinical evaluation of skin thickness, which was associated with lower total collagen contents in the skins of treated mice and a reduced dermis thickness after histological analysis. Although both SVF and hASCs were able to significantly reduce the clinical and histological parameters of HTS, hASCs appeared to be more efficient than SVF. The therapeutic effect of hASCs was attributed to higher expression of TGFbeta3 and HGF, which are important anti-fibrotic mediators, and to higher levels of MMP-2 and MMP-2/TIMP-2 ratio, which reflect the remodelling activity responsible for fibrosis resorption. These results demonstrated the therapeutic potential of hASCs for clinical applications of hypertrophic scarring. PMID- 27227962 TI - Cystic fibrosis. PMID- 27227961 TI - Ice-Active Substances from the Infective Juveniles of the Freeze Tolerant Entomopathogenic Nematode, Steinernema feltiae. AB - Steinernema feltiae is a moderately freezing tolerant nematode, that can withstand intracellular ice formation. We investigated recrystallization inhibition, thermal hysteresis and ice nucleation activities in the infective juveniles of S. feltiae. Both the splat cooling assay and optical recrystallometry indicate the presence of ice active substances that inhibit recrystallization in the nematode extract. The substance is relatively heat stable and largely retains the recrystallization inhibition activity after heating. No thermal hysteresis activity was detected but the extract had a typical hexagonal crystal shape when grown from a single seed crystal and weak ice nucleation activity. An ice active substance is present in a low concentration, which may be involved in the freezing survival of this species by inhibiting ice recrystallization. PMID- 27227963 TI - Multi-responsive hybrid particles: thermo-, pH-, photo-, and magneto-responsive magnetic hydrogel cores with gold nanorod optical triggers. AB - The research strategy described in this manuscript harnesses the attractive properties of hydrogels, gold nanorods (Aurods), and magnetic nanoparticles (MNPs) by synthesizing one unique multi-responsive nanostructure. This novel hybrid structure consists of silica-coated magnetic particles encapsulated within a thermo-responsive P(NIPAM-co-AA) hydrogel network on which Aurods are assembled. Furthermore, this research demonstrates that these composite particles respond to several forms of external stimuli (temperature, pH, light, and/or applied magnetic field) owing to their specific architecture. Exposure of the hybrid particles to external stimuli led to a systematic and reversible variation in the hydrodynamic diameter (swelling-deswelling) and thus in the optical properties of the hybrid particles (red-shifting of the plasmon band). Such stimuli-responsive volume changes can be effectively exploited in drug-delivery applications. PMID- 27227964 TI - The artificial control of enhanced optical processes in fluorescent molecules on high-emittance metasurfaces. AB - Plasmon-enhanced optical processes in molecules have been extensively but individually explored for Raman scattering, fluorescence, and infrared light absorption. In contrast to recent progress in the interfacial control of hot electrons in plasmon-semiconductor hybrid systems, plasmon-molecule hybrid systems have remained to be a conventional scheme, mainly assuming electric-field enhancement. This was because it was difficult to control the plasmon-molecule interface in a well-controlled manner. We here experimentally substantiate an obvious change in artificially enhanced optical processes of fluorescence/Raman scattering in fluorescent molecules on high-emittance plasmo-photonic metasurfaces with/without a self-assembled monolayer of sub-nm thickness. These results indicate that the enhanced optical processes were successfully selected under artificial configurations without any additional chemical treatment that modifies the molecules themselves. Although Raman-scattering efficiency is generally weak in high-fluorescence-yield molecules, it was found that Raman scattering becomes prominent around the molecular fingerprint range on the metasurfaces, being enhanced by more than 2000 fold at the maximum for reference signals. In addition, the highly and uniformly enhancing metasurfaces are able to serve as two-way functional, reproducible, and wavelength-tunable platforms to detect molecules at very low densities, being distinct from other platforms reported so far. The change in the enhanced signals suggests that energy diagrams in fluorescent molecules are changed in the configuration that includes the metal molecule interface, meaning that plasmon-molecule hybrid systems are rich in the phenomena beyond the conventional scheme. PMID- 27227965 TI - Animal Magnetism: Metaphoric Cues Alter Perceptions of Romantic Partners and Relationships. AB - The psychological state of love is difficult to define, and we often rely on metaphors to communicate about this state and its constituent experiences. Commonly, these metaphors liken love to a physical force-it sweeps us off our feet, causes sparks to fly, and ignites flames of passion. Even the use of "attraction" to refer to romantic interest, commonplace in both popular and scholarly discourse, implies a force propelling two objects together. The present research examined the effects of exposing participants to a physical force (magnetism) on subsequent judgments of romantic outcomes. Across two studies, participants exposed to magnets reported greater levels of satisfaction, attraction, intimacy, and commitment. PMID- 27227966 TI - Protoilludane, Illudane, Illudalane, and Norilludane Sesquiterpenoids from Granulobasidium vellereum. AB - Two new and seven known sesquiterpene compounds were isolated from an agar plate culture of Granulobasidium vellereum, isolated from a log of Ulmus sp. The two new structures were elucidated with spectroscopic methods as an illudalane derivative, granulolactone (1), and a 15-norilludane, granulodione (9). The acaricidal and insecticidal activities of the isolated compounds were examined in vitro against two major horticultural pests, the two-spotted spider mite Tetranychus urticae and the glasshouse thrips Heliothrips haemorrhoidalis, respectively. PMID- 27227967 TI - Betel quid chewing alters functional connectivity in frontal and default networks: A resting-state fMRI study. AB - PURPOSE: To explore the acute effect of betel quid (BQ) use on functional network connectivity by comparing the global functional brain networks and their subsets before and immediately after BQ chewing. MATERIALS AND METHODS: Resting-state functional magnetic resonance imaging (fMRI) was performed in 27 healthy male participants before and just after chewing BQ on a 3.0T scanner with a gradient echo echo planar imaging sequence. Independent component analysis (ICA) was used to determine components that represent the brain's functional networks and their spatial aspects of functional connectivity. A paired t-test was used for exploring the connectivity differences in each network before and after BQ chewing. RESULTS: Sixteen networks were identified by ICA. Nine of them showed connectivity differences before and after BQ chewing (P < 0.05 false discovery rate corrected): (A) orbitofrontal, (B) left frontoparietal, (C) visual, (D) right frontoparietal, (E) anterior default mode, (F) medial frontal/anterior cingulate (G) frontotemporal, (H) occipital/parietal, (I) occipital/temporal/cerebellum. Moreover, networks A, B, C, D, G, H, and I showed increased connectivity, while networks E and F showed decreased connectivity in participants after BQ chewing compared to before chewing. CONCLUSION: The acute effects of BQ use appear to actively alter functional connectivity of frontal and default networks that are known to play a key role in addictive behavior. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:157-166. PMID- 27227968 TI - Complexation of [Gd(DTTA-Me)(H2O)2](-) by Fluoride and Its Consequences to Water Exchange. PMID- 27227969 TI - Identification and functional activity of a staphylocoagulase type XI variant originating from staphylococcal food poisoning isolates. AB - Staphylocoagulase, an extracellular protein secreted by Staphylococcus aureus, has been used as an epidemiological marker. At least 12 serotypes and 24 genotypes subdivided on the basis of nucleotide sequence have been reported to date. In this study, we identified a novel staphylocoagulase nucleotide sequence, coa310, from staphylococcal food poisoning isolates that had the ability to coagulate plasma, but could not be typed using the conventional method. The protein encoded by coa310 contained the six fundamental conserved domains of staphylocoagulase. The full-length nucleotide sequence of coa310 shared the highest similarity (77.5%) with that of staphylocoagulase-type (SCT) XIa. The sequence of the D1 region, which would be responsible for the determination of SCT, shared the highest similarity (91.8%) with that of SCT XIa. These results suggest that coa310 is a novel variant of SCT XI. Moreover, we demonstrated that coa310 encodes a functioning coagulase, by confirming the coagulating activity of the recombinant protein expressed from coa310. This is the first study to directly demonstrate that Coa310, a putative SCT XI, has coagulating activity. These findings may be useful for the improvement of the staphylocoagulase-typing method, including serotyping and genotyping. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study to identify a novel variant of staphylocoagulase type XI based on its nucleotide sequence and to demonstrate coagulating activity in the variant using a recombinant protein. Elucidation of the variety of staphylocoagulases will provide suggestions for further improvement of the staphylocoagulase-typing method and contribute to our understanding of the epidemiologic characterization of Staphylococcus aureus. PMID- 27227970 TI - Na+ Influx Induced by New Antimalarials Causes Rapid Alterations in the Cholesterol Content and Morphology of Plasmodium falciparum. AB - Among the several new antimalarials discovered over the past decade are at least three clinical candidate drugs, each with a distinct chemical structure, that disrupt Na+ homeostasis resulting in a rapid increase in intracellular Na+ concentration ([Na+]i) within the erythrocytic stages of Plasmodium falciparum. At present, events triggered by Na+ influx that result in parasite demise are not well-understood. Here we report effects of two such drugs, a pyrazoleamide and a spiroindolone, on intraerythrocytic P. falciparum. Within minutes following the exposure to these drugs, the trophozoite stage parasite, which normally contains little cholesterol, was made permeant by cholesterol-dependent detergents, suggesting it acquired a substantial amount of the lipid. Consistently, the merozoite surface protein 1 and 2 (MSP1 and MSP2), glycosylphosphotidylinositol (GPI)-anchored proteins normally uniformly distributed in the parasite plasma membrane, coalesced into clusters. These alterations were not observed following drug treatment of P. falciparum parasites adapted to grow in a low [Na+] growth medium. Both cholesterol acquisition and MSP1 coalescence were reversible upon the removal of the drugs, implicating an active process of cholesterol exclusion from trophozoites that we hypothesize is inhibited by high [Na+]i. Electron microscopy of drug-treated trophozoites revealed substantial morphological changes normally seen at the later schizont stage including the appearance of partial inner membrane complexes, dense organelles that resemble "rhoptries" and apparent nuclear division. Together these results suggest that [Na+]i disruptor drugs by altering levels of cholesterol in the parasite, dysregulate trophozoite to schizont development and cause parasite demise. PMID- 27227971 TI - Zika in the United States of America and a Fateful 1969 Decision. AB - The United States Gulf Coast's current risk to Zika transmitted by Aedes aegypti mosquitoes can be traced back to some important federal health policy decisions made during the 1960s. PMID- 27227972 TI - The Ethiopian Health Extension Program and Variation in Health Systems Performance: What Matters? AB - BACKGROUND: Primary health care services are fundamental to improving health and health equity, particularly in the context of low and middle-income settings where resources are scarce. During the past decade, Ethiopia undertook an ambitious investment in primary health care known as the Ethiopian Health Extension Program that recorded impressive gains in several health outcomes. Despite this progress, substantial disparities in health outcomes persist across the country. The objective of this study was to understand how variation in the implementation of the primary health care efforts may explain differences in key health outcomes. METHODS AND FINDINGS: We conducted a qualitative study of higher performing and lower-performing woredas using site visits and in-depth interviews undertaken in 7 woredas. We classified woredas as higher-performing or lower performing based on data on 5 indicators. We conducted a total of 94 open-ended interviews; 12-15 from each woreda. The data were analyzed using the constant comparative method of qualitative data analysis. Substantial contrasts were apparent between higher-performing and lower-performing woredas in use of data for problem solving and performance improvement; collaboration and respectful relationships among health extension workers, community members, and health center staff; and coordination between the woreda health office and higher-level regulatory and financing bodies at the zonal and regional levels. We found similarities in what was reported to motivate or demotivate health extension workers and other staff. Additionally, higher-performing and lower-performing woredas shared concerns about hospitals being isolated from health centers and health posts. Participants from both woredas also highlighted a mismatch between the urban health extension program design and the urban-dwelling communities' expectations for primary health care. CONCLUSIONS: Data-informed problem solving, respectful and supportive relationships with the community, and strong support from zonal and regional health bureaus contributed to woreda performance, suggesting avenues for achieving higher performance in primary health care. PMID- 27227973 TI - Psychophysical Evaluation of the Capability for Phantom Limb Movement in Forearm Amputees. AB - A phantom limb is the sensation that an amputated limb is still attached to the body and is moving together with other body parts. Phantom limb phenomenon is often described on the basis of the patient's subjective sense, for example as represented using a visual analog scale (VAS). The aim of this study was to propose a novel quantification method for behavioral aspect of phantom limb by psychophysics. Twelve unilateral forearm amputees were asked to perform phantom wrist motion with various motion frequencies (60, 80, 100, 120, 140, 160, 180, 200, 220, 240% of preferred speed). The attainment of phantom limb motion in each session was rated by the VAS ranging from 0 (hard) to 10 (easy). The relationship between the VAS and motion frequency was mathematically fitted by quadric function, and the value of shift and the degree of steepness were obtained as evaluation variables for the phantom limb movement. In order to test whether the proposed method can reasonably quantify the characteristics of phantom limb motion, we compared the variables among three different phantom limb movement conditions: (1) unilateral (phantom only), (2) bimanual, and (3) bimanual wrist movement with mirror reflection-induced visual feedback (MVF). While VAS rating showed a larger extent of inter- and intra-subject variability, the relationship of the VAS in response to motion frequency could be fitted by quadric curve, and the obtained parameters based on quadric function well characterize task dependent changes in phantom limb movement. The present results suggest the potential usefulness of psychophysical evaluation as a validate assessment tool of phantom limb condition. PMID- 27227974 TI - Risk of Diabetes in Older Adults with Co-Occurring Depressive Symptoms and Cardiometabolic Abnormalities: Prospective Analysis from the English Longitudinal Study of Ageing. AB - High depressive symptoms and cardiometabolic abnormalities are independently associated with an increased risk of diabetes. The purpose of this study was to assess the association of co-occurring depressive symptoms and cardiometabolic abnormalities on risk of diabetes in a representative sample of the English population aged 50 years and older. Data were from the English Longitudinal Study of Ageing. The sample comprised of 4454 participants without diabetes at baseline. High depressive symptoms were based on a score of 4 or more on the 8 item binary Centre for Epidemiologic Studies-Depression scale. Cardiometabolic abnormalities were defined as 3 or more cardiometabolic risk factors (hypertension, impaired glycemic control, systemic inflammation, low high-density lipoprotein cholesterol, high triglycerides, and central obesity). Cox proportional hazards regressions assessed the association between co-occurring depressive symptoms and cardiometabolic abnormalities with incidence of diabetes. Multiple imputation by chained equations was performed to account for missing data. Covariates included age, sex, education, income, smoking status, physical activity, alcohol consumption, and cardiovascular comorbidity. The follow-up period consisted of 106 months, during which 193 participants reported a diagnosis of diabetes. Diabetes incidence rates were compared across the following four groups: 1) no or low depressive symptoms and no cardiometabolic abnormalities (reference group, n = 2717); 2) high depressive symptoms only (n = 338); 3) cardiometabolic abnormalities only (n = 1180); and 4) high depressive symptoms and cardiometabolic abnormalities (n = 219). Compared to the reference group, the hazard ratio for diabetes was 1.29 (95% CI 0.63, 2.64) for those with high depressive symptoms only, 3.88 (95% CI 2.77, 5.44) for those with cardiometabolic abnormalities only, and 5.56 (95% CI 3.45, 8.94) for those with both high depressive symptoms and cardiometabolic abnormalities, after adjusting for socio-demographic, lifestyle and clinical variables. These findings suggest that those with high depressive symptoms and cardiometabolic abnormalities are at a particularly increased risk of type 2 diabetes. PMID- 27227975 TI - A Screening Tool for Assessing Alcohol Use Risk among Medically Vulnerable Youth. AB - BACKGROUND: In an effort to reduce barriers to screening for alcohol use in pediatric primary care, the National Institute on Alcoholism and Alcohol Abuse (NIAAA) developed a two-question Youth Alcohol Screening Tool derived from population-based survey data. It is unknown whether this screening tool, designed for use with general populations, accurately identifies risk among youth with chronic medical conditions (YCMC). This growing population, which comprises nearly one in four youth in the US, faces a unique constellation of drinking related risks. METHOD: To validate the NIAAA Youth Alcohol Screening Tool in a population of YCMC, we performed a cross-sectional validation study with a sample of 388 youth ages 9-18 years presenting for routine subspecialty care at a large children's hospital for type 1 diabetes, persistent asthma, cystic fibrosis, inflammatory bowel disease, or juvenile idiopathic arthritis. Participants self administered the NIAAA Youth Alcohol Screening Tool and the Diagnostic Interview Schedule for Children as a criterion standard measure of alcohol use disorders (AUD). Receiver operating curve analysis was used to determine cut points for identifying youth at moderate and highest risk for an AUD. RESULTS: Nearly one third of participants (n = 118; 30.4%) reported alcohol use in the past year; 86.4% (106) of past year drinkers did not endorse any AUD criteria, 6.8% (n = 8) of drinkers endorsed a single criterion, and 6.8% of drinkers met criteria for an AUD. Using the NIAAA tool, optimal cut points found to identify youth at moderate and highest risk for an AUD were >= 6 and >=12 drinking days in the past year, respectively. CONCLUSIONS: The NIAAA Youth Alcohol Screening Tool is highly efficient for detecting alcohol use and discriminating disordered use among YCMC. This brief screen appears feasible for use in specialty care to ascertain alcohol related risk that may impact adversely on health status and disease management. PMID- 27227976 TI - The Complete Mitochondrial Genome Sequence of Bactericera cockerelli and Comparison with Three Other Psylloidea Species. AB - Potato psyllid (Bactericera cockerelli) is an important pest of potato, tomato and pepper. Not only could a toxin secreted by nymphs results in serious phytotoxemia in some host plants, but also over the past few years B. cockerelli was shown to transmit "Candidatus Liberibacter solanacearum", the putative bacterial pathogen of potato zebra chip (ZC) disease, to potato and tomato. ZC has caused devastating losses to potato production in the western U.S., Mexico, and elsewhere. New knowledge of the genetic diversity of the B. cockerelli is needed to develop improved strategies to manage pest populations. Mitochondrial genome (mitogenome) sequencing provides important knowledge about insect evolution and diversity in and among populations. This report provides the first complete B. cockerelli mitogenome sequence as determined by next generation sequencing technology (Illumina MiSeq). The circular B. cockerelli mitogenome had a size of 15,220 bp with 13 protein-coding gene (PCGs), 2 ribosomal RNA genes (rRNAs), 22 transfer RNA genes (tRNAs), and a non-coding region of 975 bp. The overall gene order of the B. cockerelli mitogenome is identical to three other published Psylloidea mitogenomes: one species from the Triozidae, Paratrioza sinica; and two species from the Psyllidae, Cacopsylla coccinea and Pachypsylla venusta. This suggests all of these species share a common ancestral mitogenome. However, sequence analyses revealed differences between and among the insect families, in particular a unique region that can be folded into three stem-loop secondary structures present only within the B. cockerelli mitogenome. A phylogenetic tree based on the 13 PCGs matched an existing taxonomy scheme that was based on morphological characteristics. The available complete mitogenome sequence makes it accessible to all genes for future population diversity evaluation of B. cockerelli. PMID- 27227977 TI - Improved Durability of Electrocatalyst Based on Coating of Carbon Black with Polybenzimidazole and their Application in Polymer Electrolyte Fuel Cells. AB - Improvement of durability of the electrocatalyst has been the key issue to be solved for the practical application of polymer electrolyte membrane fuel cells. One of the promising strategies to improve the durability is to enhance the oxidation stability of the carbon-supporting materials. In this report, we describe in detail the mechanism of the stability improvement of carbon blacks (CBs; Vulcan and Ketjen) by coating with polybenzimidazole (PBI). Nitrogen adsorption experiments reveal that the PBI coating of CBs results in the capping of the gates of the CB-micropores by the PBI. Since the surface of the micropores inside the CBs are inherently highly oxidized, the capping of such pores effectively prevents the penetration of the electrolyte into the pore and works to avoid the further oxidation of interior of the micropore, which is proved by cyclic voltammogram measurements. Above mechanism agrees very well with the dramatic enhancement of the durability of the membrane electrode assembly fabricated using Pt on the PBI-coated CBs as an electrocatalyst compared to the conventional Pt/CB (PBI-non coated) catalyst. PMID- 27227978 TI - Lung-Derived Microscaffolds Facilitate Diabetes Reversal after Mouse and Human Intraperitoneal Islet Transplantation. AB - There is a need to develop three-dimensional structures that mimic the natural islet tissue microenvironment. Endocrine micro-pancreata (EMPs) made up of acellular organ-derived micro-scaffolds seeded with human islets have been shown to 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 three months in vitro. The aim of this study was to investigate the capacity of EMPs to restore euglycemia in vivo after transplantation of mouse or human islets in chemically diabetic mice. We proposed that the organ-derived EMPs would restore the extracellular components of the islet microenvironment, generating favorable conditions for islet function and survival. EMPs seeded with 500 mouse islets were implanted intraperitoneally into streptozotocin-induced diabetic mice and reverted diabetes in 67% of mice compared to 13% of controls (p = 0.018, n = 9 per group). Histological analysis of the explanted grafts 60 days post-transplantation stained positive for insulin and exhibited increased vascular density in a collagen-rich background. EMPs were also seeded with human islets and transplanted into the peritoneal cavity of immune-deficient diabetic mice at 250 islet equivalents (IEQ), 500 IEQ and 1000 IEQ. Escalating islet dose increased rates of normoglycemia (50% of the 500 IEQ group and 75% of the 1000 IEQ group, n = 3 per group). Human c-peptide levels were detected 90 days post-transplantation in a dose-response relationship. Herein, we report reversal of diabetes in mice by intraperitoneal transplantation of human islet seeded on EMPs with a human islet dose as low as 500 IEQ. PMID- 27227980 TI - MicroRNAs Involved in Acute Rejection and Tolerance in Murine Cardiac Allografts. AB - OBJECTIVES: Induction of immunologic tolerance is the ultimate goal of organ transplant. To investigate the involvement of microRNA in tolerance induction after organ transplant, murine cardiac allografts were performed and the expression of microRNA in the grafts was analyzed. MATERIALS AND METHODS: Cardiac allografts were performed using C57BL/10 (H2-Kb) to CBA/N (H2-Kk) fully mismatched combination with or without eicosapentaenoic acid for tolerance induction. Ten microRNA, mir-146a, 15b, 223, 23a, 27a, 34a, 451, 101a, 101b, 148a, discovered in hepatic grafts were examined by quantitative reverse transcription polymerase chain reaction using RNA from the cardiac allografts. RESULTS: The administration of eicosapentaenoic acid markedly prolonged the cardiac allograft survival (median survival time > 100 days) and decreased the pathological score. Quantitative reverse transcription polymerase chain reaction revealed that mir-223 was up-regulated in accordance with pathological deterioration as compared with the expression observed in the syngeneic grafts. In contrast, the other microRNA was down-regulated. Pearson product moment correlation analysis demonstrated that the expression patterns of mir-223 and mir 146a had high or moderate positive associations between the cardiac and haptic allografts in mice. CONCLUSIONS: The change in the microRNA expression in the allografts suggests that microRNA plays a role in the induction and/or maintenance of tolerance after allograft transplant. Our findings suggest that mir-223 may be associated with rejection while mir-146a, -15b, -23a, -27a, -34a, 451, -101a, -101b, -148a may be involved in tolerance. A superior grasp of the mechanism for rejection and tolerance observed in the murine heart allotransplant model may provide a better curative treatment strategy to mitigate allograft rejection. PMID- 27227979 TI - Membrane Insertion for the Detection of Lipopolysaccharides: Exploring the Dynamics of Amphiphile-in-Lipid Assays. AB - Shiga toxin-producing Escherichia coli is an important cause of foodborne illness, with cases attributable to beef, fresh produce and other sources. Many serotypes of the pathogen cause disease, and differentiating one serotype from another requires specific identification of the O antigen located on the lipopolysaccharide (LPS) molecule. The amphiphilic structure of LPS poses a challenge when using classical detection methods, which do not take into account its lipoglycan biochemistry. Typically, detection of LPS requires heat or chemical treatment of samples and relies on bioactivity assays for the conserved lipid A portion of the molecule. Our goal was to develop assays to facilitate the direct and discriminative detection of the entire LPS molecule and its O antigen in complex matrices using minimal sample processing. To perform serogroup identification of LPS, we used a method called membrane insertion on a waveguide biosensor, and tested three serogroups of LPS. The membrane insertion technique allows for the hydrophobic association of LPS with a lipid bilayer, where the exposed O antigen can be targeted for specific detection. Samples of beef lysate were spiked with LPS to perform O antigen specific detection of LPS from E. coli O157. To validate assay performance, we evaluated the biophysical interactions of LPS with lipid bilayers both in- and outside of a flow cell using fluorescence microscopy and fluorescently doped lipids. Our results indicate that membrane insertion allows for the qualitative and reliable identification of amphiphilic LPS in complex samples like beef homogenates. We also demonstrated that LPS induced hole formation does not occur under the conditions of the membrane insertion assays. Together, these findings describe for the first time the serogroup-specific detection of amphiphilic LPS in complex samples using a membrane insertion assay, and highlight the importance of LPS molecular conformations in detection architectures. PMID- 27227981 TI - The Effect of Combined Pulsed Wave Low-Level Laser Therapy and Human Bone Marrow Mesenchymal Stem Cell-Conditioned Medium on Open Skin Wound Healing in Diabetic Rats. AB - OBJECTIVE: The nobility of this scientific study was to investigate the combined effects of pulsed wave low-level laser therapy (PWLLLT) and human bone marrow mesenchymal stem cell-conditioned medium (hBM-MSC-CM) on the biomechanical parameters of wounds in an experimental model for diabetes mellitus (DM). BACKGROUND DATA: PWLLLT exhibited biostimulatory effects on wounds in diabetic animals. Secretomes can be administered into wounds by the use of BM-MSC-CM. MATERIALS AND METHODS: Type I DM was induced in rats by streptozotocin (STZ). Two wounds were made on proximal and distal parts in the dorsal region of each rat. Rats were divided into four groups. The first group was considered as the control group. The second group received hBM-MSC-CM. The third group received PWLLLT. The fourth group received hBM-MSC-CM+LASER. hBM-MSC-CM was administrated twice intraperitoneally. The proximal wounds in the third and fourth groups were treated with a pulsed laser by 890 nm wavelength, 80 Hz frequency, and 0.2 J/cm(2) energy densities. On the 15th day, a standard sample from each healing wound was submitted for biomechanical examination. The data were analyzed by analysis of variance test. RESULTS: PWLLLT and hBM-MSC-CM, alone or in combination, significantly increased biomechanical parameters within the healing wounds. However, PWLLLT was statistically more effective compared with the hBM MSC-CM. In the third and fourth groups, the numbers of wound closures were significantly enhanced in proximal part, contrary to the control ones. CONCLUSIONS: It was magnificently attained that PWLLLT significantly accelerated the wound healing process in the experimental model for STZ-induced type I DM rats. PMID- 27227982 TI - Shared Decision Making, Fast and Slow: Implications for Informed Consent, Resource Utilization, and Patient Satisfaction in Orthopaedic Surgery. AB - INTRODUCTION: Through shared decision making, the physician and patient exchange information to arrive at an agreement about the patient's preferred treatment. This process is predicated on the assumption that there is a single preferred treatment, and the goal of the dialog is to discover it. In contrast, psychology theory (ie, prospect theory) suggests that people can make decisions both analytically and intuitively through parallel decision-making processes, and depending on how the choice is framed, the two processes may not agree. Thus, patients may not have a single preferred treatment, but rather separate intuitive and analytic preferences. The research question addressed here is whether subjects might reveal different therapeutic preferences based on how a decision is framed. METHODS: Five clinical scenarios on the management of tibial plateau fractures were constructed. Healthy volunteers were asked to select among treatments offered. Four weeks later, the scenarios were presented again; the facts of the scenario were unchanged, but the description was altered to test the null hypothesis that minor changes in wording would not lead the subjects to change their decision about treatment. For example, incomplete improvement after surgery was described first as a gain from the preoperative state and then as a loss from the preinjury state. RESULTS: In all five cases, the variation predicted by psychology theory was detected. Respondents were affected by whether choices were framed as avoided losses versus potential gains; by emotional cues; by choices reported by others (ie, bandwagon effect); by the answers proposed to them in the question (ie, anchors); and by seemingly irrelevant options (ie, decoys). DISCUSSION: The influence of presentation on preferences can be highly significant in orthopaedic surgery. The presence of parallel decision-making processes implies that the standard methods of obtaining informed consent may require further refinement. Furthermore, if the way that information is portrayed makes surgery more or less appealing, the use of services may be subject to unwanted influence. If surgery were accepted preoperatively by the patient's intuitive process but evaluated after the fact by the analytic process (or vice versa), well-indicated and well-performed surgery may still fail to provide patient satisfaction. PMID- 27227983 TI - Complications After Surgical Management of Proximal Femoral Metastasis: A Retrospective Study of 417 Patients. AB - BACKGROUND: Proximal femoral fractures resulting from metastatic disease often require surgical management. Few studies have compared surgical techniques, and physicians' preferred strategies vary. This study compared revision and complication rates among surgical strategies. METHODS: The study consisted of a retrospective review of electronic medical records of 417 consecutive patients with proximal femoral metastasis or multiple myeloma who underwent intramedullary nailing (n = 302), endoprosthetic reconstruction (n = 70), and open reduction and internal fixation (n = 45) between 1999 and 2014 at two orthopaedic oncology centers. Primary outcome measures were revisions and 30-day systemic complications. Secondary outcome measures were total estimated blood loss, anesthesia time, duration of hospital admission, and 30-day survival. RESULTS: Revision rates did not differ between strategies (5.3% after intramedullary nailing, 11% after endoprosthetic reconstruction, and 13% after open reduction and internal fixation; P = 0.134). When reasons for revision were assessed separately, fixation failure was most common after open reduction and internal fixation (13% versus 3.0% after intramedullary nailing and none after endoprosthetic reconstruction; P < 0.001), whereas deep infection was most common after endoprosthetic reconstruction (8.6% versus 2.0% after intramedullary nailing and none after open reduction and internal fixation; P = 0.010). Overall systemic complication rates did not differ between strategies (8.3% after intramedullary nailing, 14% after endoprosthetic reconstruction, and 11% after open reduction and internal fixation; P = 0.268). CONCLUSION: Implant-specific complications and their timing should be considered in the choice of surgical strategy. Analysis of secondary outcomes and risk factors for systemic complications could aid in surgical decision making. LEVEL OF EVIDENCE: Therapeutic Level III. PMID- 27227984 TI - An Approach to Lumbar Revision Spine Surgery in Adults. AB - Along with the increase in lifestyle expectations in the aging population, a dramatic rise in surgical rates has been observed over the past 2 decades. Consequently, the rate of revision spine surgery is expected to increase. A systematic approach to treatment is required for the adult patient presenting with late or chronic complications after spinal surgery. Patient assessment includes elucidating current symptoms and knowledge of the previous surgery, performing a detailed assessment, and obtaining appropriate studies. Subsequently, differential diagnoses are formulated based on whether the pathology arises from the same levels or adjacent levels of the spine and whether it relates to the previous decompression or fusion. Finally, familiarity with different surgical approaches is imperative in treating the common pathologies encountered in this patient population. PMID- 27227985 TI - Intramedullary Fixation of Clavicle Fractures: Anatomy, Indications, Advantages, and Disadvantages. AB - Historically, management of displaced midshaft clavicle fractures has consisted of nonsurgical treatment. However, recent literature has supported surgical repair of displaced and shortened clavicle fractures. Several options exist for surgical fixation, including plate and intramedullary (IM) fixation. IM fixation has the potential advantages of a smaller incision and decreased dissection and soft-tissue exposure. For the last two decades, the use of Rockwood and Hagie pins represented the most popular form of IM fixation, but concerns exist regarding stability and complications. The use of alternative IM implants, such as Kirschner wires, titanium elastic nails, and cannulated screws, also has been described in limited case series. However, concerns persist regarding the complications associated with the use of these implants, including implant failure, migration, skin complications, and construct stability. Second generation IM implants have been developed to reduce the limitations of earlier IM devices. Although anatomic and clinical studies have supported IM fixation of midshaft clavicle fractures, further research is necessary to determine the optimal fixation method. PMID- 27227986 TI - Chronic Elbow Dislocation: Evaluation and Management. AB - Chronic elbow dislocation is defined as a dislocation that has remained unreduced for >2 weeks. The soft-tissue and skeletal changes that develop during this time usually prevent successful closed reduction. These changes include the development of extensive intra-articular fibrotic tissue, as well as contracture of the triceps, collateral ligaments, and elbow capsule. Ulnar nerve involvement and associated fractures may also be present. Because treatment of chronic elbow dislocation is challenging, a stepwise approach is used in the evaluation and management of this condition. No large series of data are available to guide treatment. Most patients are treated on the basis of the surgeon's anecdotal experience. Treatment typically involves open reduction, often with the use of hinged external fixators. The role of triceps lengthening or primary collateral ligament reconstruction remains a topic of debate. PMID- 27227987 TI - AAOS Research Symposium Updates and Consensus: Biologic Treatment of Orthopaedic Injuries. AB - Strategies that seek to enhance musculoskeletal tissue regeneration and repair by modulating the biologic microenvironment at the site of injury have considerable therapeutic potential. Current and emerging biologic approaches include the use of growth factors, platelet-rich plasma, stem cell therapy, and scaffolds. The American Academy of Orthopaedic Surgeons hosted a research symposium in November 2015 to review the current state-of-the-art biologic treatments of articular cartilage, muscle, tendon, and bone injuries and identify knowledge gaps related to these emerging treatments. This review outlines the findings of the symposium and summarizes the consensus reached on how best to advance research on biologic treatment of orthopaedic injuries. PMID- 27227988 TI - Validation and Recalibration of Two Multivariable Prognostic Models for Survival and Independence in Acute Stroke. AB - INTRODUCTION: Various prognostic models have been developed for acute stroke, including one based on age and five binary variables ('six simple variables' model; SSVMod) and one based on age plus scores on the National Institutes of Health Stroke Scale (NIHSSMod). The aims of this study were to externally validate and recalibrate these models, and to compare their predictive ability in relation to both survival and independence. METHODS: Data from a large clinical trial of oxygen therapy (n = 8003) were used to determine the discrimination and calibration of the models, using C-statistics, calibration plots, and Hosmer Lemeshow statistics. Methods of recalibration in the large and logistic recalibration were used to update the models. RESULTS: For discrimination, both models functioned better for survival (C-statistics between .802 and .837) than for independence (C-statistics between .725 and .735). Both models showed slight shortcomings with regard to calibration, over-predicting survival and under predicting independence; the NIHSSMod performed slightly better than the SSVMod. For the most part, there were only minor differences between ischaemic and haemorrhagic strokes. Logistic recalibration successfully updated the models for a clinical trial population. CONCLUSIONS: Both prognostic models performed well overall in a clinical trial population. The choice between them is probably better based on clinical and practical considerations than on statistical considerations. PMID- 27227989 TI - miR-135a Inhibits the Invasion of Cancer Cells via Suppression of ERRalpha. AB - MicroRNA-135a (miR-135a) down-modulates parameters of cancer progression and its expression is decreased in metastatic breast cancers (as compared to non metastatic tumors) as well as in prostate tumors relative to normal tissue. These expression and activity patterns are opposite to those of the Estrogen-Related Receptor alpha (ERRalpha), an orphan member of the nuclear receptor family. Indeed high expression of ERRalpha correlates with poor prognosis in breast and prostate cancers, and the receptor promotes various traits of cancer aggressiveness including cell invasion. Here we show that miR-135a down-regulates the expression of ERRalpha through specific sequences of its 3'UTR. As a consequence miR-135a also reduces the expression of downstream targets of ERRalpha. miR-135a also decreases cell invasive potential in an ERRalpha dependent manner. Our results suggest that the decreased expression of miR-135a in metastatic tumors leads to elevated ERRalpha expression, resulting in increased cell invasion capacities. PMID- 27227992 TI - A Mechanism for Fair Distribution of Resources without Payments. AB - We design a mechanism for Fair and Efficient Distribution of Resources (FEDoR) in the presence of strategic agents. We consider a multiple-instances, Bayesian setting, where in each round the preference of an agent over the set of resources is a private information. We assume that in each of r rounds n agents are competing for k non-identical indivisible goods, (n > k). In each round the strategic agents declare how much they value receiving any of the goods in the specific round. The agent declaring the highest valuation receives the good with the highest value, the agent with the second highest valuation receives the second highest valued good, etc. Hence we assume a decision function that assigns goods to agents based on their valuations. The novelty of the mechanism is that no payment scheme is required to achieve truthfulness in a setting with rational/strategic agents. The FEDoR mechanism takes advantage of the repeated nature of the framework, and through a statistical test is able to punish the misreporting agents and be fair, truthful, and socially efficient. FEDoR is fair in the sense that, in expectation over the course of the rounds, all agents will receive the same good the same amount of times. FEDoR is an eligible candidate for applications that require fair distribution of resources over time. For example, equal share of bandwidth for nodes through the same point of access. But further on, FEDoR can be applied in less trivial settings like sponsored search, where payment is necessary and can be given in the form of a flat participation fee. FEDoR can be a good candidate in a setting like that to solve the problem of starvation of publicity slots for some advertisers that have a difficult time determining their true valuations. To this extent we perform a comparison with traditional mechanisms applied to sponsored search, presenting the advantage of FEDoR. PMID- 27227990 TI - Prefrontal Cortex Activation and Young Driver Behaviour: A fNIRS Study. AB - Road traffic accidents consistently show a significant over-representation for young, novice and particularly male drivers. This research examines the prefrontal cortex activation of young drivers and the changes in activation associated with manipulations of mental workload and inhibitory control. It also considers the explanation that a lack of prefrontal cortex maturation is a contributing factor to the higher accident risk in this young driver population. The prefrontal cortex is associated with a number of factors including mental workload and inhibitory control, both of which are also related to road traffic accidents. This experiment used functional near infrared spectroscopy to measure prefrontal cortex activity during five simulated driving tasks: one following task and four overtaking tasks at varying traffic densities which aimed to dissociate workload and inhibitory control. Age, experience and gender were controlled for throughout the experiment. The results showed that younger drivers had reduced prefrontal cortex activity compared to older drivers. When both mental workload and inhibitory control increased prefrontal cortex activity also increased, however when inhibitory control alone increased there were no changes in activity. Along with an increase in activity during overtaking manoeuvres, these results suggest that prefrontal cortex activation is more indicative of workload in the current task. There were no differences in the number of overtakes completed by younger and older drivers but males overtook significantly more than females. We conclude that prefrontal cortex activity is associated with the mental workload required for overtaking. We additionally suggest that the reduced activation in younger drivers may be related to a lack of prefrontal maturation which could contribute to the increased crash risk seen in this population. PMID- 27227994 TI - Retinoblastoma. PMID- 27227993 TI - Analysis of the In Vivo Turnover of CD4+ T-Cell Subsets in Chronically SIV Infected Sooty Mangabeys. AB - Aberrant turnover of memory CD4+ T-cells is central to Acquired Immunodeficiency Syndrome (AIDS) progression. Understanding the relationship between the turnover of CD4+ subsets and immunological homeostasis during simian immunodeficiency virus (SIV) infection in natural hosts may provide insight into mechanisms of immune regulation that may serve as models for therapeutic intervention in Human Immunodeficiency Virus (HIV)-infected persons. Sooty mangabeys (SMs) have naturally evolved with SIV to avoid AIDS progression while maintaining healthy peripheral CD4+ T-cell counts and thus represent a model by which therapeutic interventions for AIDS progression might be elucidated. To assess the relationship between the turnover of CD4+ subsets and immunological homeostasis during SIV infection in non-progressive hosts, we treated 6 SIV-uninfected and 9 SIV-infected SMs with 2'-bromo-5'-deoxyuridine (BrdU) for 14 days and longitudinally assessed CD4+ T-cell subset turnover by polychromatic flow cytometry. We observed that, in SIV-infected SMs, turnover of CD4+ T-cell naive and central, transitional, and effector memory subsets is comparable to that in uninfected animals. Comparable turnover of CD4+ T-cell subsets irrespective of SIV-infection status likely contributes to the lack of aberrant immune activation and disease progression observed after infection in non-progressive hosts. PMID- 27227995 TI - Recruiting Dementia Caregivers Into Clinical Trials: Lessons Learnt From the Australian TRANSCENDENT Trial. AB - The burden on those caring for a person with dementia is substantial. Although quality research assists in addressing the needs of these caregivers, recruiting caregivers into clinical studies is often problematic. This investigation explores the difficulties and successes in recruiting dementia caregivers into community-based clinical research by reporting the findings of a mixed-method substudy of a multicenter randomized controlled trial involving 40 community dwelling dementia caregivers living in Adelaide, South Australia. Data for the substudy were derived from standardized trial monitoring documentation and structured telephone interviews. From a total of 16 distinct methods used across a 12-month recruitment campaign, the most cost-effective strategy was the distribution of flyers through a single study site. This approach generated the greatest number of enrollments of all methods used, achieving a 67% recruitment yield. The least cost-effective strategy, with a 0% recruitment yield, was the publication of a newspaper advertisement. Themes that emerged from the interviews pointed toward 5 key facilitators and 3 barriers to future trial recruitment. This study has generated new insights into the effective recruitment of dementia caregivers into clinical trials. We anticipate that these lessons learnt will assist in shaping the recruitment strategies of future studies of dementia caregivers. PMID- 27227996 TI - Diffusion Tensor Changes According to Age at Onset and Apolipoprotein E Genotype in Alzheimer Disease. AB - Age at onset is one of the most important factors that affects the clinical course in Alzheimer disease (AD), whereas other factors such as apolipoprotein E (apoE) genotype may also play a major role. In this study, we aimed to investigate the effect of age at onset and apoE genotype on white-matter changes in AD using diffusion tensor imaging. About 213 patients with AD and 66 normal individuals underwent diffusion tensor imaging, and apoE genotype was obtained in all AD patients and in 24 normal individuals. When multiple regression analysis was conducted, a younger age at onset was associated with lower fractional anisotropy in both deep-located long-range limbic and association fibers and superficial-located short-range association fibers in the frontal, the temporal, and the parietal lobes, and with a higher mean diffusivity in deep-located fibers and the bilateral medial thalamus. When analyzed separately in apoE e4 carriers and noncarriers, e4 carriers showed an association between a younger age at onset and lower fractional anisotropy, mainly in deep-located fibers, whereas noncarriers showed this association in both deep-located and superficial-located fibers. There was no difference in the spatial distribution between carriers and noncarriers in the association between the age at onset and mean diffusivity. Our results suggest that the topographical distribution of white-matter changes in AD is significantly affected by the interaction between age at onset and apoE genotype. PMID- 27227997 TI - Fragmentation, auto-modification and post ionisation proton bound dimer ion formation: the differential mobility spectrometry of low molecular weight alcohols. AB - Differential mobility spectrometry (DMS) is currently being used for environmental monitoring of space craft atmospheres and has been proposed for the rapid assessment of patients at accident and emergency receptions. Three studies investigated hitherto undescribed complexity in the DMS spectra of methanol, ethanol, propan-1-ol and butan-1-ol product ions formed from a (63)Ni ionisation source. 54 000 DMS spectra obtained over a concentration range of 0.01 mg m( 3)(g) to 1.80 g m(-3)(g) revealed the phenomenon of auto-modification of the product ions. This occurred when the neutral vapour concentration exceeded the level required to induce a neutral-ion collision during the low field portion of the dispersion field waveform. Further, post-ionisation cluster-ion formation or protonated monomer/proton bound dimer inter-conversion within the ion-filter was indicated by apparent shifts in the values of the protonated monomer compensation field maximum; indicative of post-ionisation conversion of the protonated monomer to a proton-bound dimer. APCI-DMS-quadrupole mass spectrometry studies enabled the ion dissociation products from dispersion-field heating to be monitored and product ion fragmentation relationships to be proposed. Methanol was not observed to dissociate, while propan-1-ol and butan-1-ol underwent dissociation reactions consistent with dehydration processes that led ultimately to the generation of what is tentatively assigned as a cyclo-C3H3(+) ion (m/z 39) and hydrated protons. Studies of the interaction of ion filter temperature with dispersion field heating of product ions isolated dissociation/fragmentation product ions that have not been previously described in DMS. The implications of these combined findings with regard to data sharing and data interpretation were highlighted. PMID- 27227998 TI - Relationship between Community Collectivization and Financial Vulnerability of Female Sex Workers in Southern India. AB - INTRODUCTION: Studies exploring the linkages between financial vulnerabilities and community collectivization of female sex workers (FSWs) are scarce in India despite having potential policy implications. To fill this gap in the literature, this study attempts to understand the financial vulnerabilities among FSWs and assess the relationship between community collectivization and financial vulnerabilities in southern India. DATA AND METHODS: Data were drawn from a cross sectional, behavioral tracking survey (BTS)-2014, conducted among FSWs (N = 2400) in Andhra Pradesh, a southern state of India under the Avahan-India AIDS initiative program. Adjusted odds ratios (AOR) and their 95% confidence intervals (CI) were estimated through multivariate logistic regression, to assess the independent relationships of the degree of community collectivization indicators with financial vulnerability indicators, adjusting for socio-demographic characteristics. RESULTS: Most FSWs (87%) reported having either one or more financial vulnerability and nearly one-fifth had a high financial vulnerability. The risk of facing financial vulnerability was significantly lower among FSWs with a high degree of perceived collective efficacy (15% vs 31%; AOR: 0.4; 95% CI: 0.3-0.5) and collective agency (4% vs 21%; AOR: 0.2; 95% CI: 0.1-0.3) as compared to their respective counterparts, after controlling for their individual socio-demographic characteristics. FSWs with a high degree of collective efficacy are also less likely to report different components of financial vulnerability (e.g. income, saving, expenditure, and debt). CONCLUSION: This study finding suggests that community-led interventions such as improving collectivization are promising strategies to address financial vulnerabilities and a path to a sustainable reduction of HIV risk. This study calls for further evidence-based research and measurement of the effects of community-led approaches in addressing the financial vulnerabilities of the key population at risk for HIV. PMID- 27227999 TI - Effect of Sunlight Exposure on Bone Mineral Density in Children with Severe Disability. AB - The aim of this study was to determine the efficacy of sunlight exposure for increasing bone mineral density (BMD) in children with severe disability. The subjects were five children with severe disability, aged 6 to 8 years. BMD was measured at baseline and after 3, 6, 9, and 12 months of starting sunlight exposure. All caregivers of patients were instructed to create opportunities to stay outdoors. Daily sunlight exposure time was defined as hours of staying outdoors. Mean hours of sunbathing per day were calculated at baseline and after 3, 6, 9, and 12 months of starting sunlight exposure. Sunlight exposure tended to be longer after starting than before starting in all patients, but the difference was not significant (p = 0.052). Along with the increase in sunlight exposure, BMD increased significantly after the start of sunlight exposure in all patients (p < 0.01). The serum values of total alkaline phosphatase and intact parathyroid hormone were significantly decreased and that of 25-hydroxyvitamin D was significantly increased 12 months after starting sunlight exposure. No patients had bone fractures after the start of sunlight exposure. These results suggest that sunlight exposure increased BMD, and that this may reduce the risk of bone fracture in children with disability. PMID- 27228000 TI - The Complexity Signature: Developing a Tool to Communicate Biopsychosocial Severity of Disease for Children with Chronic Neurological Complexity. AB - Aim For children with medical complexity, interdisciplinary treatment approaches are required to address the various aspects defined within the biopsychosocial model. Methods The present study identifies dimensions of the biopsychosocial model to generate a standardized visualized severity score for chronic neurological diseases in children. We demonstrate the score's applicability and usefulness in clinical practice among clinicians with and without pediatric board certification with the aid of illustrative patient cases. The results are compared by Spearman correlation coefficient. Results Nine dimensions were identified as the basis for the development of the score, which consists of five grades of severity for each of the selected neuropediatric subsections. All board certified pediatricians would recommend the application of the severity score in clinical routine. Furthermore, a good correlation was revealed between direct and indirect (severity score) assessment. Interpretation The severity score developed in this study takes into account biopsychosocial aspects of chronic diseases while being comprehensible and easily applicable in clinical routine-a biopsychosocial signature serving as an excellent, striking communication basis within the interdisciplinary team. However, upcoming studies including more patient cases are needed for further refinement. PMID- 27228001 TI - Clinical Impact of MALDI-TOF MS Identification and Rapid Susceptibility Testing on Adequate Antimicrobial Treatment in Sepsis with Positive Blood Cultures. AB - Shortening the turn-around time (TAT) of positive blood culture (BC) identification (ID) and susceptibility results is essential to optimize antimicrobial treatment in patients with sepsis. We aimed to evaluate the impact on antimicrobial prescription of a modified workflow of positive BCs providing ID and partial susceptibility results for Enterobacteriaceae (EB), Pseudomonas aeruginosa and Staphylococcus aureus on the day of BC positivity detection. This study was divided into a pre-intervention period (P0) with a standard BC workflow followed by 2 intervention periods (P1, P2) with an identical modified workflow. ID was performed with MALDI-TOF MS from blood, on early or on overnight subcultures. According to ID results, rapid phenotypic assays were realized to detect third generation cephalosporin resistant EB/P. aeruginosa or methicillin resistant S. aureus. Results were transmitted to the antimicrobial stewardship team for patient's treatment revision. Times to ID, to susceptibility results and to optimal antimicrobial treatment (OAT) were compared across the three study periods. Overall, 134, 112 and 154 positive BC episodes in P0, P1 and P2 respectively were included in the analysis. Mean time to ID (28.3 hours in P0) was reduced by 65.3% in P1 (10.2 hours) and 61.8% in P2 (10.8 hours). Mean time to complete susceptibility results was reduced by 27.5% in P1 and 27% in P2, with results obtained after 32.4 and 32.6 hours compared to 44.7 hours in P0. Rapid tests allowed partial susceptibility results to be obtained after a mean time of 11.8 hours in P1 and 11.7 hours in P2. Mean time to OAT was decreased to 21.6 hours in P1 and to 17.9 hours in P2 compared to 36.1 hours in P0. Reducing TAT of positive BC with MALDI-TOF MS ID and rapid susceptibility testing accelerated prescription of targeted antimicrobial treatment thereby potentially improving the patients' clinical outcome. PMID- 27228002 TI - Serum anti-Mullerian hormone levels after ovarian drilling for the second-line treatment of polycystic ovary syndrome: a pilot-randomized study comparing laparoscopy and transvaginal hydrolaparoscopy. AB - Aim of the study was to asses and compare serum anti-Mullerian harmone (AMH) levels after laparoscopic ovarian drilling (LOD) and transvaginal hydrolaparoscopy (THL) ovarian drilling in clomifene citrate (CC)-resistant polycystic ovary syndrome (PCOS) patients; secondary outcome was to evaluate postoperative pain to estimate the acceptability of procedures. A total of 246 patients with CC-resistant PCOS were randomized into two groups: 123 underwent LOD and 123 underwent THL ovarian drilling. AMH serum levels were evaluated before and after the procedure; moreover, women were asked to rate pain on a visual analog scale (VAS) from 0 (no pain, perfectly acceptable) to 10 (unbearable pain, completely unacceptable). In both groups, postoperative serum AMH levels were significantly reduced compared to preoperative levels (6.06 +/- 1.18 and 5.84 +/- 1.16 versus 5.00 +/- 1.29 and 4.83 +/- 1.10; p < 0.0001). Comparing postoperative serum AMH levels, no statistically significant difference was observed between the two surgical technique. After the procedure, mean pain VAS score was significantly higher for women who underwent LOD ovarian drilling in comparison to THL (3.26 +/- 1.1 versus 1.11 +/- 0.5; p < 0.0001). In conclusion, THL ovarian drilling is comparable to the LOD in terms of reduction in AMH, but it is preferred by patients in terms of acceptability. These results could support to use of THL ovarian drilling in the treatment of patients with CC resistant PCOS. PMID- 27228003 TI - A General Catalyst for Site-Selective C(sp(3))-H Bond Amination of Activated Secondary over Tertiary Alkyl C(sp(3))-H Bonds. AB - The discovery of transition metal complexes capable of promoting general, catalyst-controlled and selective carbon-hydrogen (C-H) bond amination of activated secondary C-H bonds over tertiary alkyl C(sp(3))-H bonds is challenging, as substrate control often dominates when reactive nitrene intermediates are involved. In this letter, we report the design of a new silver complex, [(Py5Me2)AgOTf]2, that displays general and good-to-excellent selectivity for nitrene insertion into propargylic, benzylic, and allylic C-H bonds over tertiary alkyl C(sp(3))-H bonds. PMID- 27228004 TI - Erectile dysfunction. PMID- 27228005 TI - Visual-motor integration, visual perception, and fine motor coordination in a population of children with high levels of Fetal Alcohol Spectrum Disorder. AB - BACKGROUND: Visual-motor integration (VMI) skills are essential for successful academic performance, but to date no studies have assessed these skills in a population-based cohort of Australian Aboriginal children who, like many children in other remote, disadvantaged communities, consistently underperform academically. Furthermore, many children in remote areas of Australia have prenatal alcohol exposure (PAE) and Fetal Alcohol Spectrum Disorder (FASD), which are often associated with VMI deficits. METHODS: VMI, visual perception, and fine motor coordination were assessed using The Beery-Buktenica Developmental Test of Visual-Motor Integration, including its associated subtests of Visual Perception and Fine Motor Coordination, in a cohort of predominantly Australian Aboriginal children (7.5-9.6 years, n=108) in remote Western Australia to explore whether PAE adversely affected test performance. Cohort results were reported, and comparisons made between children i) without PAE; ii) with PAE (no FASD); and iii) FASD. The prevalence of moderate (<=16th percentile) and severe (<=2nd percentile) impairment was established. RESULTS: Mean VMI scores were 'below average' (M=87.8+/-9.6), and visual perception scores were 'average' (M=97.6+/ 12.5), with no differences between groups. Few children had severe VMI impairment (1.9%), but moderate impairment rates were high (47.2%). Children with FASD had significantly lower fine motor coordination scores and higher moderate impairment rates (M=87.9+/-12.5; 66.7%) than children without PAE (M=95.1+/-10.7; 23.3%) and PAE (no FASD) (M=96.1+/-10.9; 15.4%). CONCLUSIONS: Aboriginal children living in remote Western Australia have poor VMI skills regardless of PAE or FASD. Children with FASD additionally had fine motor coordination problems. VMI and fine motor coordination should be assessed in children with PAE, and included in FASD diagnostic assessments. PMID- 27228006 TI - Parental coping with adolescent developmental disabilities in terms of stress, sense of coherence and hope within the Druze community of Israel. AB - BACKGROUND: Many studies have examined the coping resources of parents of children with disabilities but most have involved Western families and only a few refer to unique and traditional cultures. AIM: This study sought to compare Druze parents of adolescents with and without developmental disabilities (DD) in the context of Druze traditions and beliefs and whether they may lead to better coping by parents of a child with DD. The study used the measures of stress; sense of coherence (SOC) - an orientation towards the world which reflects an ongoing confidence that things fall into place in a logical and meaningful way; and hope. METHODS AND PROCEDURES: The sample group consisted of 99 Druze parents of adolescents with and without DD enrolled in regular and special schools in Israel. The parents were asked to complete four questionnaires on demography, stress, SOC (Sense of coherence) and hope. OUTCOMES AND RESULTS: The research findings indicate a higher sense of parental stress and a lower overall SOC, particularly meaningfulness, and hope among parents of adolescents with DD. There was no difference between the two groups of parents with respect to marital, economic and overall stress or in the other two components of SOC. CONCLUSIONS AND IMPLICATIONS: The results of the study partly contradict the assumption in the limited literature about Druze that they may cope better with life stressors as a result of their traditions and beliefs. The results also indicate the need for further research and culturally-based intervention programs. PMID- 27228007 TI - Ferromagnetic Polarization: The Quantum Picture of Switching On/Off Single Molecule Magnetism. AB - The mixed 3d-4f pentanuclear complex (Bu4N)[Mn(III)4Y(III)(shi)4(OAc)4(CH3OH)4].CH3OH.H2O (1) (H3shi = salicylhydroxamic acid) was synthesized by the direct reaction of Y(NO3)3.6H2O, Mn(OAc)2.4H2O, and H3shi. When an additional ligand, (NHBu3)3[W(CN)8].2H2O, was added, the mixed 3d-4f-5d hexanuclear complex (Et4N)5[Mn(III)4Y(III)(shi)4(OAc)4W(V)(CN)8](WO4)0.5 (2) was obtained. X-ray crystallographic analysis shows that the 3d-4f complex 1 represents a 12 metallacrown-4 (12-MC-4) structure, in which the metallacrown ring [Mn-N-O]4 connection captures one Y(III) ion with four bridging acetate anions, completing the eight-coordinated environment around Y(III) ion, while four methanol molecules each coordinate to the Mn(III) ions on the other side of the Y(III) ion. After octacyanotungstate is introduced, the [W(V)(CN)8] group substitutes for four methanol molecules of 1 to form complex 2. Magnetic studies indicate the overall antiferromagnetic coupling present within the MC ring of complex 1. However, interestingly, the dominant ferromagnetic coupling between Mn(III) ions was observed in complex 2. A susceptibility analysis shows that the natural spin alignments in 12-MC-4 metallacrowns are tuned from overall antiferromagnetic to dominant ferromagnetic fashions by magnetic coupling between Mn(III) ions and the W(V) ion. Complex 1 [Mn(III)4Y(III)] retains an S = 0 ground state, and complex 2 [Mn(III)4Y(III)W(V)] shows obvious single-molecule magnet (SMM) behavior with an ST = 11/2 ground state, respectively, before and after introduction of the octacyanotungstate group. The spin frustration geometrical structure constructed by four Mn(III) ions and one W(V) ion was considered as the key factor for switching on the SMM properties of the 12-MC-4 system. PMID- 27228008 TI - Association of MSX1 c.*6C > T Variant with Nonsyndromic Cleft Lip With or Without Cleft Palate in Turkish Patients. AB - OBJECTIVE: Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is among the most common birth defects, with a birth prevalence of 1/1000 in Caucasians. MSX1 (muscle segment homeobox gene 1) is a strong candidate gene for nsCL/P. The aim of this study was to investigate the association between MSX1 variants and nsCL/P in Turkish patients. PATIENTS AND METHODS: Our study included 80 patients with nsCL/P and 125 age-matched healthy individuals. Genomic DNA was isolated from peripheral blood leukocytes and exon 2 of the MSX1 gene was amplified using polymerase chain reaction (PCR). After PCR, we sequenced the products using an automated sequencer. RESULTS: We found the c.*6C > T variation in the MSX1 gene. This variant in the 3' untranslated region is located 6 bp downstream of the stop codon (TAG) in exon 2. Forty-eight individuals (60%) of 80 in the case group had the CT genotype. We revealed a statistically significant association between the MSX1 c.*6C > T variant and nsCL/P in Turkey (p = 0.01). CONCLUSION: Our identification of the c.*6C > T variant appears to be the first reported result associating variants of the MSX1 gene with nsCL/P patients. PMID- 27228009 TI - Needlescopic intragastric surgery facilitated by newly developed 2mm instruments. AB - BACKGROUND: Intragastric surgery is a percutaneous endoluminal surgery in the stomach aimed at resection of tumors located at the esophagogastric junction (EGJ). We developed needlescopic intragastric surgery performed via 2 mm, 2 mm, and 5 mm ports (PEIGS-225). MATERIAL AND METHODS: In cooperation with Niti-On Co., Ltd. we developed a series of 2 mm instruments including grasping forceps, a cannula, a laparoscope, an electrocautery, scissors, and a needle holder. OPERATIVE TECHNIQUE: Two 2 mm trocars and a 5 mm one are inserted into the gastric lumen percutaneously. Intragastric procedures are performed by the instruments brought through those three ports. The specimen is extracted via the esophageal-oral route. The defect in the gastroesophageal wall is closed by hand suture. After the intragastric procedure, the 5 mm stab wound on the gastric wall is closed by hand-suture, while the 2 mm wounds are left untreated. PATIENTS: Between March and August 2015 PEIGS-225 was performed in five patients. RESULTS: There was no operative conversion. The mean operation time was 96 minutes. There were no perioperative complications. Pathological findings indicated that the margin was negative in all cases. CONCLUSION: Needlescopic intragasric surgery performed via the smallest access (2 mm, 2 mm, 5 mm) is enabled by the 2 mm instruments developed by us. PMID- 27228010 TI - Gustatory receptors in Lepidoptera: chemosensation and beyond. AB - Lepidoptera is one of the most widespread insect orders and includes several agriculturally important insect species. Ecological success of the lepidopteran insects partly depends on their adaptive chemoreception tactics, which play an important role in the selection of hosts, egg-laying sites and mates. Members of the G-protein coupled receptor family, gustatory receptors (GRs), are an integral part of the Lepidoptera chemosensory machinery. They are expressed in chemosensory neurones and are known to detect different environmental stimuli. Here, we discuss various aspects of the lepidopteran GRs with an emphasis on their roles in different processes such as chemosensation, host selection and adaptation. Phylogenetic analyses have shown that the large diversity of GR genes may have been generated through gene duplication and positive selection events, which also show lineage- and tissue-specific expression. Moreover, lepidopteran GR proteins are diverse and demonstrate broad ligand selectivity for several molecules including sugars, deterrents, salts and CO2 . Binding of ligands to GRs generates multiple downstream changes at the cellular level, which are followed by changes in behaviour. GRs play a critical role in chemosensation and influence the insect's behaviour. Overall, insect GRs are potential targets in the design of effective insect control strategies. PMID- 27228011 TI - Follicular cell-derived thyroid cancer. PMID- 27228012 TI - Asthma. PMID- 27228014 TI - Using Balance Function to Screen for Vestibular Impairment in Children With Sensorineural Hearing Loss and Cochlear Implants. AB - OBJECTIVES: 1) To determine if bilateral vestibular dysfunction can be predicted by performance on standardized balance tasks in children with sensorineural hearing loss (SNHL) and cochlear implants (CI). 2) To provide clinical recommendations for screening for vestibular impairment in children with SNHL. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary care pediatric implant center. PATIENTS: Pediatric patients (4.8-18.6 years) with profound SNHL using CIs. INTERVENTIONS: Vestibular end-organ (horizontal canal and otoliths), and balance assessment. MAIN OUTCOME MEASURES: Comparison of balance skills, measured by the Bruininks Oseretsky Test of Motor Proficiency II (BOT-2), was performed between two groups of children with SNHL and CI: 1) total bilateral vestibular loss (TBVL) (n = 45), and 2) normal bilateral vestibular function (n = 20). Sensitivity, specificity, and suitability of each task as a screening tool for the detection of TBVL were assessed. RESULTS: Balance as measured by the BOT 2 balance subtest was significantly poorer in children with TBVL then those with normal vestibular function (p < 0.0001). "Eyes closed" tasks best identified children with TBVL having the highest sensitivity and specificity. One-foot standing eyes closed was found to have the best performance as a screening tool for TBVL using a timed cutoff of 4 seconds. CONCLUSION: A brief in-office screen of balance function using one of the BOT-2 balance subtest tasks, one-foot standing eyes closed, is able to identify children at risk of TBVL with excellent sensitivity and specificity and should be used to screen for TBVL in all children presenting with SNHL. PMID- 27228013 TI - Anaesthesia Management for Awake Craniotomy: Systematic Review and Meta-Analysis. AB - BACKGROUND: Awake craniotomy (AC) renders an expanded role in functional neurosurgery. Yet, evidence for optimal anaesthesia management remains limited. We aimed to summarise the latest clinical evidence of AC anaesthesia management and explore the relationship of AC failures on the used anaesthesia techniques. METHODS: Two authors performed independently a systematic search of English articles in PubMed and EMBASE database 1/2007-12/2015. Search included randomised controlled trials (RCTs), observational trials, and case reports (n>4 cases), which reported anaesthetic approach for AC and at least one of our pre-specified outcomes: intraoperative seizures, hypoxia, arterial hypertension, nausea and vomiting, neurological dysfunction, conversion into general anaesthesia and failure of AC. Random effects meta-analysis was used to estimate event rates for four outcomes. Relationship with anaesthesia technique was explored using logistic meta-regression, calculating the odds ratios (OR) and 95% confidence intervals [95%CI]. RESULTS: We have included forty-seven studies. Eighteen reported asleep-awake-asleep technique (SAS), twenty-seven monitored anaesthesia care (MAC), one reported both and one used the awake-awake-awake technique (AAA). Proportions of AC failures, intraoperative seizures, new neurological dysfunction and conversion into general anaesthesia (GA) were 2% [95%CI:1-3], 8% [95%CI:6 11], 17% [95%CI:12-23] and 2% [95%CI:2-3], respectively. Meta-regression of SAS and MAC technique did not reveal any relevant differences between outcomes explained by the technique, except for conversion into GA. Estimated OR comparing SAS to MAC for AC failures was 0.98 [95%CI:0.36-2.69], 1.01 [95%CI:0.52-1.88] for seizures, 1.66 [95%CI:1.35-3.70] for new neurological dysfunction and 2.17 [95%CI:1.22-3.85] for conversion into GA. The latter result has to be interpreted cautiously. It is based on one retrospective high-risk of bias study and significance was abolished in a sensitivity analysis of only prospectively conducted studies. CONCLUSION: SAS and MAC techniques were feasible and safe, whereas data for AAA technique are limited. Large RCTs are required to prove superiority of one anaesthetic regime for AC. PMID- 27228015 TI - Direction-reversing Nystagmus in Horizontal and Posterior Semicircular Canal Canalolithiasis. AB - OBJECTIVES: To investigate the incidence and characteristics of direction reversing nystagmus in patients with horizontal (HSCC) and posterior semicircular canal (PSCC) canalolithiasis, and evaluate the effect of direction-reversing nystagmus on the treatment outcome. STUDY DESIGN: A retrospective study. METHODS: Between March 2014 and September 2015, 63 and 92 consecutive patients with HSCC and PSCC canalolithiasis, respectively, were enrolled. Positional nystagmus characteristics were examined using video-nystagmography. RESULTS: In HSCC canalolithiasis, direction-reversing nystagmus was observed in 73% of patients (46 of 63), of which 19 cases were bilateral and 27 unilateral. In patients with bilateral reversal, maximal slow-phase velocity (mSPV) was significantly greater when the head turned to the lesioned side than to the healthy side in both the first and second phase. In all patients with unilateral reversal, direction reversing nystagmus always occurred in the side of stronger initial nystagmus in a supine roll test. The mean mSPV of first phase nystagmus was significantly greater on the side with reversal than without (p < 0.001). The duration of second-phase nystagmus exceeded 60 seconds in all patients with reversal. Although not statistically significant (p = 0.059), patients presenting with direction-reversing nystagmus required more repositioning maneuver sessions. In contrast to HSCC canalolithiasis, only 4% of patients (4 of 92) with PSCC canalolithiasis exhibited spontaneous reversal of initial nystagmus. CONCLUSION: The incidence of direction-reversing nystagmus was higher in HSCC canalolithiasis than in PSCC canalolithiasis, and second-phase (direction-reversing) nystagmus in HSCC canalolithiasis has a prolonged duration. Short-term adaptation of the vestibulo-ocular reflex may be responsible for the development of direction reversing nystagmus. PMID- 27228016 TI - The Effect of Simulated Mastoid Obliteration on the Mechanical Output of Electromagnetic Transducers. AB - BACKGROUND: The electromagnetic transducers of implantable middle ear hearing devices or direct acoustic cochlear implants (DACIs) are intended for implantation in an air-filled middle ear cavity. When implanted in an obliterated radical mastoid cavity, they would be surrounded by fatty tissue of unknown elastic properties, potentially attenuating the mechanical output. Here, the elastic properties of this tissue were determined experimentally and the vibrational output of commonly used electromagnetic transducers in an obliterated radical mastoid cavity was investigated in vitro using a newly developed method. METHODS: The Young's moduli of human fatty tissue samples (3-mm diameter), taken fresh from the abdomen or from the radical mastoid cavity during revision surgeries, were determined by indentation tests. Two phantom materials having Young's moduli similar to and higher than (worst case scenario) the tissue were identified. The displacement output of a DACI, a middle ear transducer (MET) and a floating mass transducer (FMT), was measured when embedded in the phantom materials in a model radical cavity and compared with the output of the nonembedded transducers. RESULTS: The here-determined Young's moduli of fresh human abdominal fatty tissue were comparable to the moduli of human breast fat tissue. When embedded in the phantom materials, the displacement output amplitude at 0.1 to 10 kHz of the DACI and MET was attenuated by maximally 5 dB. The attenuation of the output of the FMT was also minor at 0.5 to 10 kHz, but significantly reduced by up to 35 dB at lower frequencies. CONCLUSION: Using the method developed here, the Young's moduli of small soft tissue samples could be estimated and the effect of obliteration on the mechanical output of electromagnetic transducers was investigated in vitro. Our results demonstrate that the decrease in vibrational output of the DACI and MET in obliterated mastoid cavities is expected to be minor, having no major impact on clinical indication. Although no major attenuation of vibrational output of the FMT was found for frequencies >0.5 kHz, for implantations in patients the attenuation at frequencies <0.5 kHz may have to be taken into account. PMID- 27228017 TI - Surgical Anatomy of the Human Round Window Region: Implication for Cochlear Endoscopy Through the External Auditory Canal. AB - OBJECTIVE: To enable development of an endoscope for cellular-level optical imaging of the inner ear. STUDY DESIGN: A prospective study of 50 cadaveric human temporal bones to define detailed surgical anatomy of the round window (RW) region and the range of angles necessary to reach the RW membrane perpendicularly via the external ear canal. MAIN OUTCOME MEASURE: The transcanal angle to the RW membrane was surgically measured in 3D intact specimens, and correlated with the angle calculated from temporal bone computed tomography (CT) scans of the same specimens obtained before and after measurements in situ. RESULTS: Surgically measured transcanal angles to the RW membrane correlated well with the radiographically measured angles. The angles ranged from 110 to 127 degrees, with the median of 115 degrees and the middle 50% ranging from 109 to 119 degrees. Four temporal bones were excluded because of pathology. The opening of the RW niche was located posteriorly in six bones (13%), inferiorly in 18 bones (39%), and postero-inferiorly in 22 bones (48%). The angles were not statistically different among the three orientations of the RW niche. CONCLUSIONS: By correlating measurement from cadaveric human temporal bones and their CT scans, we defined key parameters necessary for designing an endoscope for intracochlear imaging using a minimally invasive approach through the external auditory canal. The excellent correlation between the measurement on the CT scan and the actual shape of the probe that was able to reach the RW through the ear canal enables selection of the probe using the CT data. PMID- 27228019 TI - "Self-Assessment of Hearing Disabilities in Cochlear Implant Users Using the SSQ and the Reduced SSQ5 Version. Otology & Neurotology 2013;34: 1622-9". PMID- 27228018 TI - Participant-generated Cochlear Implant Programs: Speech Recognition, Sound Quality, and Satisfaction. AB - OBJECTIVE: To determine whether patient-derived programming of one's cochlear implant (CI) stimulation levels may affect performance outcomes. BACKGROUND: Increases in patient population, device complexity, outcome expectations, and clinician responsibility have demonstrated the necessity for improved clinical efficiency. METHODS: Eighteen postlingually deafened adult CI recipients (mean = 53 years; range, 24-83 years) participated in a repeated-measures, within participant study designed to compare their baseline listening program to an experimental program they created. RESULTS: No significant group differences in aided sound-field thresholds, monosyllabic word recognition, speech understanding in quiet, speech understanding in noise, nor spectral modulation detection (SMD) were observed (p > 0.05). Four ears (17%) improved with the experimental program for speech presented at 45 dB SPL and two ears (9%) performed worse. Six ears (27.3%) improved significantly with the self-fit program at +10 dB signal-to noise ratio (SNR) and four ears (26.6%) improved in speech understanding at +5 dB SNR. No individual scored significantly worse when speech was presented in quiet at 60 dB SPL or in any of the noise conditions tested. All but one participant opted to keep at least one of the self-fitting programs at the completion of this study. Participants viewed the process of creating their program more favorably (t = 2.11, p = 0.012) and thought creating the program was easier than the traditional fitting methodology (t = 2.12, p = 0.003). Average time to create the self-fit program was 10 minutes, 10 seconds (mean = 9:22; range, 4:46-24:40). CONCLUSIONS: Allowing experienced adult CI recipients to set their own stimulation levels without clinical guidance is not detrimental to success. PMID- 27228020 TI - Long-term Follow-up Study of the Sandwich Cartilage Shoe Technique in Cases of Insecure Stapes Footplate. AB - OBJECTIVE: Analysis of the audiometric results after repair of a defective footplate with the sandwich cartilage shoe technique in a follow-up study. STUDY DESIGN: Retrospective analysis of audiometric data. SETTING: Hospital. PATIENTS: The cohort consisted of 12 patients, who underwent ossicular reconstruction after sandwich cartilage shoe technique in a case of insecure stapes footplate. The mean age was 42.7 years with an equal sex distribution. In every patient, cholesteatoma was the reason for surgery with 75% being revision cases. INTERVENTION: Sandwich cartilage shoe technique in case of insecure stapes footplate at the department of otorhinolaryngology, head and neck surgery at the University of Cologne over an 8-year period (2007-2015). MAIN OUTCOME MEASURE: The use of the "sandwich cartilage shoe technique" in case of a broken or unstable footplate allows a safe occlusion of the open vestibule. RESULTS: The statistical analysis revealed a significant improvement of the pure-tone average (p = 0.011) and air-bone gap (ABG) (p = 0.016) after total ossicular replacement prosthesis (TORP) implantation. The hearing was stable at 9 months of follow up. CONCLUSION: The sandwich cartilage shoe technique offers a safe and effective option as a two-stage procedure in treating patients with fractures of the stapes footplate in case of chronic otitis media. In view of the possible risk of deafness going along with a destruction of an inner ear window, our results can be considered substantial as all our patients will at least be able to regain "social hearing" as they all either achieved a hearing threshold is less than 30 dB or can be sufficiently supplied with a conventional hearing aid. PMID- 27228021 TI - Characteristics and Spontaneous Recovery of Tinnitus Related to Idiopathic Sudden Sensorineural Hearing Loss. AB - OBJECTIVE: To evaluate the characteristics and spontaneous recovery of tinnitus related to idiopathic sudden sensorineural hearing loss (ISSNHL). STUDY DESIGN: Retrospective analysis from two randomized placebo-controlled clinical trials for treatment of ISSNHL within 48 hours from onset (Study A), or of tinnitus related to ISSNHL within 3 months from onset (Study B). SETTING: Forty-eight European sites (academic tertiary referral centers, private ENT practices). PATIENTS: One hundred thirteen adult patients of which 65 with hearing loss >=30 dB (Study A) and 48 with persistent acute tinnitus (Study B) at baseline. INTERVENTIONS: Intratympanic (i.t.) injection of placebo gel in single dose or in triple dose during 3 consecutive days. MAIN OUTCOME MEASURES: Frequency of tinnitus, subjective tinnitus loudness, rates of complete tinnitus remission, and complete hearing recovery during 3 months follow-up. RESULTS: In acute ISSNHL, tinnitus loudness decreased rapidly in cases of mild-moderate hearing loss, and tinnitus had completely resolved in two-thirds of patients after 3 months. Hearing recovery preceded tinnitus resolution. When associated with severe-profound hearing loss, tinnitus improved significantly less. Complete hearing recovery and full tinnitus remission were both about three times more frequent in mild moderate hearing loss patients than in severe-profound cases. Improvement in tinnitus loudness over time can be approximated by a negative exponential function. CONCLUSIONS: Prognosis for ISSNHL-related tinnitus is relatively poor in case of severe-profound hearing loss and the longer it has persisted. Alleviation or management of tinnitus should be a key therapeutic objective especially in pronounced ISSNHL cases. PMID- 27228022 TI - WITHDRAWN: Mouthrinses for the treatment of halitosis. PMID- 27228023 TI - Clinical Connections. PMID- 27228025 TI - Wafer-Scale Microwire Transistor Array Fabricated via Evaporative Assembly. AB - One-dimensional (1D) nano/microwires have attracted significant attention as promising building blocks for various electronic and optical device applications. The integration of these elements into functional device networks with controlled alignment and density presents a significant challenge for practical device applications. Here, we demonstrated the fabrication of wafer-scale microwire field-effect transistor (FET) arrays based on well-aligned inorganic semiconductor microwires (indium-gallium-zinc-oxide (IGZO)) and organic polymeric insulator microwires fabricated via a simple and large-area evaporative assembly technique. This microwire fabrication method offers a facile approach to precisely manipulating the channel dimensions of the FETs. The resulting solution processed monolithic IGZO microwire FETs exhibited a maximum electron mobility of 1.02 cm(2) V(-1) s(-1) and an on/off current ratio of 1 * 10(6). The appropriate choice of the polymeric microwires used to define the channel lengths enabled fine control over the threshold voltages of the devices, which were employed to fabricate high-performance depletion-load inverters. Low-voltage-operated microwire FETs were successfully fabricated on a plastic substrate using a high capacitance ion gel gate dielectric. The microwire fabrication technique involving evaporative assembly provided a facile, effective, and reliable method for preparing flexible large-area electronics. PMID- 27228026 TI - Spatial and Temporal Trends in Insecticide Resistance among Malaria Vectors in Chad Highlight the Importance of Continual Monitoring. AB - BACKGROUND: A longitudinal Anopheles gambiae s.l. insecticide resistance monitoring programme was established in four sentinel sites in Chad 2008-2010. When this programme ended, only sporadic bioassays were performed in a small number of sites. METHODS: WHO diagnostic dose assays were used to measure the prevalence of insecticide resistance to 0.1% bendiocarb, 4% DDT, 0.05% deltamethrin, 1% fenitrothion, and 0.75% permethrin in the main malaria vectors at the beginning and end of the malaria transmission season for three years 2008 2010, with subsequent collections in 2011 and 2014. Species and molecular identification of An. gambiae M and S forms and kdr genotyping was performed using PCR-RLFP; circumsporozoite status was assessed using ELISA. RESULTS: Between 2008 and 2010, significant changes in insecticide resistance profiles to deltamethrin and permethrin were seen in 2 of the sites. No significant changes were seen in resistance to DDT in any site during the study period. Testing performed after the period of routine monitoring had ended showed dramatic increases to DDT and pyrethroid resistance in 3 sites. No resistance to organophosphate or carbamate insecticides was detected. An. arabiensis was the predominate member of the An. gambiae complex in all 4 sites; adult collections showed temporal variation in species composition in only 1 site. Kdr analysis identified both 1014F and 1014S alleles in An. gambiae S only. Circumsporozoite analysis showed the highest vector infection rates were present in Donia, a site with extensive use of agricultural insecticides. CONCLUSIONS: During the monitoring gap of four years, significant changes occurred in resistance prevalence in 3 of the 4 sites (p = <0.001), endangering the efficacy of currently implemented malaria control interventions. Significant changes in insecticide resistance profiles and a lack of kdr resistance alleles in adult populations highlight the urgent need for comprehensive entomological monitoring to be implemented and sustained in country. PMID- 27228027 TI - Functional Cooperativity between ABCG4 and ABCG1 Isoforms. AB - ABCG4 belongs to the ABCG subfamily, the members of which are half transporters composed of a single transmembrane and a single nucleotide-binding domain. ABCG proteins have a reverse domain topology as compared to other mammalian ABC transporters, and have to form functional dimers, since the catalytic sites for ATP binding and hydrolysis, as well as the transmembrane domains are composed of distinct parts of the monomers. Here we demonstrate that ABCG4 can form homodimers, but also heterodimers with its closest relative, ABCG1. Both the full length and the short isoforms of ABCG1 can dimerize with ABCG4, whereas the ABCG2 multidrug transporter is unable to form a heterodimer with ABCG4. We also show that contrary to that reported in some previous studies, ABCG4 is predominantly localized to the plasma membrane. While both ABCG1 and ABCG4 have been suggested to be involved in lipid transport or regulation, in accordance with our previous results regarding the long version of ABCG1, here we document that the expression of both the short isoform of ABCG1 as well as ABCG4 induce apoptosis in various cell types. This apoptotic effect, as a functional read-out, allowed us to demonstrate that the dimerization between these half transporters is not only a physical interaction but functional cooperativity. Given that ABCG4 is predominantly expressed in microglial-like cells and endothelial cells in the brain, our finding of ABCG4-induced apoptosis may implicate a new role for this protein in the clearance mechanisms within the central nervous system. PMID- 27228028 TI - Is a Knowledge of Surface Topology and Contact Angles Enough to Define the Drop Impact Outcome? AB - It is well known that a superhydrophobic surface may not be able to repel impacting droplets because of the so-called Cassie-to-Wenzel transition. It has been proven that a critical value of the receding contact angle (thetaR) exists for the complete rebound of water, recently experimentally measured to be 100 degrees for a large range of impact velocities. On the contrary, in the present work, no rebound was observed when low-surface-tension liquids such as hexadecane (sigma = 27.5 mN/m at 25 degrees C) are concerned, even for very low impact velocities and very high values of thetaR and low contact angle hysteresis. Therefore, the critical threshold of thetaR ~ 100 degrees does not sound acceptable for all liquids and for all hydrophobic surfaces. For the same Weber numbers, a Cassie-to-Wenzel state transition occurs after the impact as a result of the easier penetration of low-surface-tension fluids in the surface structure. Hence, a criterion for the drop rebound of low-surface-tension liquids must consider not only the contact angle values with surfaces but also their surface tension and viscosity. This suggests that, even if it is possible to produce surfaces with enhanced static repellence against oils and organics, generally the realization of synthetic materials with self-cleaning and antisticking abilities in dynamic phenomena, such as spray impact, remains an unsolved task. Moreover, it is demonstrated that the chemistry of the surface, the physicochemical interactions with the liquid drops, and the possible wettability gradient of the surface asperity also play important roles in determining the critical Weber number above which impalement occurs. Therefore, the classical numerical simulations of drop impact on dry surfaces are definitively not able to capture the final outcomes of the impact for all possible fluids if the surface topology and chemistry and/or the wettability gradient in the surface structure are not properly reflected. PMID- 27228030 TI - Health Insurance Continuity and Health Care Access and Utilization, 2014. AB - KEY FINDINGS: Data from the National Health Interview Survey *During 2014, 78.1% of adults aged 18-64 were insured at the time of interview and had been insured for more than a year. *About 6.4% of adults were insured at the time of interview but had a period of no insurance in the past year. *About 12.3% of adults were uninsured at the time of interview and had been uninsured for more than a year, and 3.2% were uninsured at the time of interview but had a period of insurance coverage in the past year. *Those insured at the time of interview and insured for more than a year were more likely than those with any period of no insurance to have a usual place of care, visited a health care provider, received a flu vaccine, and were less likely to have had an unmet medical need due to cost. PMID- 27228029 TI - Effects of Soil Salinity on Sucrose Metabolism in Cotton Leaves. AB - This study investigated sucrose metabolism of the youngest fully expanded main stem leaf (MSL) and the subtending leaf of cotton (Gossypium hirsutum L.) boll (LSCB) of salt-tolerant (CCRI-79) and salt-sensitive (Simian 3) cultivars and its relationship to boll weight under low, medium and high soil salinity stress in Dafeng, China, in 2013 and 2014. The results showed that with increased soil salinity, 1) both the chlorophyll content and net photosynthetic rate (Pn) decreased, while the internal CO2 concentration firstly declined, and then increased in the MSL and LSCB; 2) carbohydrate contents in the MSL reduced significantly, while sucrose and starch contents in the LSCB increased, as did the activities of sucrose phosphate synthase (SPS) and sucrose synthase (SuSy) in both the MSL and LSCB; 3) but invertase activity in both the MSL and LSCB did not change significantly. Our study also showed that the LSCB was more sensitive to soil salinity than was the MSL. Of the measured physiological indices, higher SPS activity, mainly controlled by sps3, may contribute to adaption of the LSCB to soil salinity stress because SPS is beneficial for efficiently sucrose synthesis, reduction of cellular osmotic potential and combined actions of Pn, and sucrose transformation rate and SPS may contribute to the reduction in boll weight under soil salinity stress. PMID- 27228031 TI - Differences in Psychosocial Predictors of Obesity Among LGBT Subgroups. AB - PURPOSE: The purpose of the current study was to examine the overall presence of and differences in rates of overweight/obesity among a large, nationally diverse sample of lesbian, gay, bisexual, transgender (LGBT)-identified individuals (i.e., cisgender lesbians, cisgender gay men, cisgender bisexual women, cisgender bisexual men, transgender women, and transgender men) and to identify specific psychosocial predictors of obesity within each of the six LGBT subgroups. METHODS: A total of 2702 LGBT-identified participants participated in the online study. Participants completed a series of demographic questions (including weight and height) and the Depression Anxiety Stress Scale 21. RESULTS: The percentage of participants who were overweight/obese did not differ significantly across LGBT subgroups, with 61.1% of the total sample being overweight/obese. However, the percentage of participants who self-reported body mass indexes in the obese range differed significantly across the six LGBT subgroups, with the highest prevalence in transgender men (46.0%). In addition, the predictors of obesity varied by subgroup, with age a significant predictor for cisgender lesbians, cisgender gay men, and cisgender bisexual women, relationship status for cisgender bisexual women, employment status for both cisgender gay men and cisgender bisexual women, education level for cisgender lesbians, and depression, anxiety, and stress for cisgender gay men. None of the examined psychosocial factors emerged as predictors of obesity for cisgender bisexual men, transgender women, or transgender men. CONCLUSION: These findings suggest that there are substantial variations in the presence and predictors of obesity across LGBT subgroups that support the need for culturally tailored healthy weight promotion efforts within the LGBT community. PMID- 27228033 TI - Influence of Managed Care on the Variation in Rate and Timing of Cataract Surgery Reply. PMID- 27228032 TI - Symbolic Play and Novel Noun Learning in Deaf and Hearing Children: Longitudinal Effects of Access to Sound on Early Precursors of Language. AB - In the largest, longitudinal study of young, deaf children before and three years after cochlear implantation, we compared symbolic play and novel noun learning to age-matched hearing peers. Participants were 180 children from six cochlear implant centers and 96 hearing children. Symbolic play was measured during five minutes of videotaped, structured solitary play. Play was coded as "symbolic" if the child used substitution (e.g., a wooden block as a bed). Novel noun learning was measured in 10 trials using a novel object and a distractor. Cochlear implant vs. normal hearing children were delayed in their use of symbolic play, however, those implanted before vs. after age two performed significantly better. Children with cochlear implants were also delayed in novel noun learning (median delay 1.54 years), with minimal evidence of catch-up growth. Quality of parent-child interactions was positively related to performance on the novel noun learning, but not symbolic play task. Early implantation was beneficial for both achievement of symbolic play and novel noun learning. Further, maternal sensitivity and linguistic stimulation by parents positively affected noun learning skills, although children with cochlear implants still lagged in comparison to hearing peers. PMID- 27228034 TI - No evidence of exposure to environmental estrogens in two feral fish species sampled from the Yarra River, Australia: A comparison with Northern Hemisphere studies. AB - Environmental estrogens originate from a variety of sources including sewage treatment plant (STP) effluents and adverse physiological effects (endocrine disruption) have been observed in several fish species sampled downstream of STP discharges. In this study we examined common carp (Cyprinus carpio) and roach (Rutilis rutilis) for signs of exposure to environmental estrogens in the iconic Yarra River, Melbourne, Australia. The Yarra River flows through the city of Melbourne and more than 2 million people live within the catchment. Two STPs discharge water into the Yarra River within the middle reaches, and the areas immediately downstream of these discharge locations were the focus of this study. Carp and roach were chosen as test species since both have been utilised extensively for endocrine disruption research throughout Europe, North America and Asia, and data from various international studies was used for comparison with the results of the present study. Neither species showed evidence of exposure to environmental estrogens, with no elevation of plasma vitellogenin levels in males and no incidence of intersex gonads. Most physiological endpoints in both species from this study were within ranges reported in carp and roach from reference sites in other studies, however some degenerative histological changes in both male and female gonads were observed. Surface water samples showed no estrogenic activity (measured by the yeast-estrogen screen, YES), but did display strong anti-estrogenic and weak androgenic activity (measured by the yeast-androgen screen, YAS). Whilst the results show no evidence of impacts from environmental estrogens in the Yarra River, the presence of both anti-estrogenic and androgenic activity in water samples, as well as some gonadal changes in carp is concerning and indicates that our focus needs to broaden, in order to look for biological impacts in resident fauna that might be due to environmental pollutants other than environmental estrogens. PMID- 27228037 TI - A good day. PMID- 27228035 TI - The Safety Behavior Assessment Form: Development and Validation. AB - OBJECTIVE: To develop and validate an easy to administer measure of safety behaviors called the Safety Behavior Assessment Form (SBAF). METHOD: We provide reliability and validity evidence from four studies. The first study used a cross sectional design with a sample consisting of both clinical (U.S. military Veterans; n = 42) and nonclinical participants (undergraduates; n = 198). Study 2 used a cross-sectional design with a sample of U.S. military Veterans (n = 215). Study 3 used a pre-post treatment design with a sample of U.S. military Veterans (n = 42). Study 4 used a 2-time-point longitudinal design with a sample of undergraduates (n = 77). RESULTS: The SBAF demonstrated strong levels of internal consistency and test-retest reliability in all four studies. The SBAF also demonstrated predictive and discriminant validity. In Study 3, the SBAF predicted anxious, but not depressive, treatment outcomes in a sample of Veterans. In Study 4, the SBAF predicted prospective changes in anxiety over a 2-week interval in a sample of undergraduates even after controlling for a competing measure of safety behaviors. CONCLUSION: Results of these four studies indicate that the SBAF is a reliable and valid measure of safety behaviors that can be used in both clinical and nonclinical settings. PMID- 27228038 TI - Acute calcium pyrophosphate deposition arthropathy. AB - Acute calcium pyrophosphate deposition (CPPD) arthropathy, also called pseudogout, is common, and becomes more prevalent as patients age. The presenting symptoms are similar to both gout and septic arthritis but may be treated differently. This article describes a typical patient presentation and management from an emergency medicine and orthopedic surgery standpoint. PMID- 27228039 TI - Botulinum toxin: A lift for chronic migraines. AB - Chronic migraines are a common condition among patients seen in primary care and management often is a challenge. Despite existing therapies to help manage this condition, many patients continue to experience undue stress and diminished quality of life secondary to pain. This article briefly reviews treatments for migraine and introduces the role of onabotulinumtoxin A (Botox A) in improving the management of chronic migraines. PMID- 27228041 TI - What is the role of concentrated insulin in diabetes management? AB - Two concentrated analog insulins, long-acting insulin glargine U-300 (Toujeo) and rapid-acting insulin lispro (Humalog U-200), were recently approved by the FDA. Providers must be aware of clinical differences in these new product formulations compared with their nonconcentrated formulations, so that they can select appropriate patients for these products and minimize drug errors. PMID- 27228042 TI - An incidental diagnosis of multiple pacemaker lead fractures. AB - Lead fractures are uncommon complications of pacemaker implantation. This article describes a patient with an incidental diagnosis of multiple atrial lead fractures many years after pacemaker implantation. PMID- 27228043 TI - An incorrect diagnosis and an unexpected cause of respiratory failure. AB - Thoracic aortic aneurysms often are asymptomatic or cause nonspecific symptoms such as cough, dyspnea, wheezing, or dysphagia. Acute onset of severe chest, neck, back, or abdominal pain may indicate an aortic rupture or dissection. Early identification and treatment, including optimized medical management and evaluation for surgical intervention, are necessary to improve patient outcomes. PMID- 27228044 TI - Caring for transgender patients. AB - Clinicians need a better understanding of transgender populations and a systematic approach to treating transgender patients medically and psychologically while managing any potential judgment or bias. This article explains key concepts, describes transgender patient health concerns, and discusses how to perform a comprehensive history. PMID- 27228045 TI - Does previous healthcare experience increase success in physician assistant training? AB - OBJECTIVE: Healthcare experience is used by many physician assistant (PA) programs to rank applicants. Despite a large healthcare literature base evaluating admissions factors, little information is available on the relationship of healthcare experience and educational outcomes. We aimed to test whether previous healthcare experience is associated with increased success during the clinical portion of the PA educational process. METHODS: Hours of direct healthcare experience reported on Central Application Service for Physician Assistants applications for 124 students in the classes of 2009 through 2013 were associated with a calculated average preceptor evaluation score for each student and with average standardized-patient examination scores for a subset of students. RESULTS: Average student age was 28.7 years and median healthcare experience was 2,257 hours (range 390-16,400). Previous healthcare experience was not significantly correlated with preceptor evaluations or standardized-patient examination scores. CONCLUSIONS: This 5-year single institution pilot study did not support the hypothesis that healthcare experience is associated with improved clinical year outcomes. PMID- 27228046 TI - Adhesive capsulitis. PMID- 27228047 TI - Riociguat for pulmonary hypertension. AB - Riociguat is newly approved by the FDA for treatment of patients with groups 1 or 4 pulmonary hypertension. Although several vasodilators are on the market for the treatment of pulmonary hypertension group 1, none have been shown to be invariably effective in the treatment of chronic thromboembolic pulmonary hypertension. PMID- 27228048 TI - What are these papules on the patient's nose? PMID- 27228049 TI - Anticipatory guidance: Not just for patients. PMID- 27228050 TI - Psychometric Properties of the Physical Activity Questionnaire for Older Children in Italy: Testing the Validity among a General and Clinical Pediatric Population. AB - The purpose of this research was to assess an Italian version of the Physical Activity Questionnaire for Older Children (PAQ-C-It). Three separate studies were conducted, whereby testing general psychometric properties, construct validity, concurrent validity and the factor structure of the PAQ-C-It among general and clinical pediatric population. Study 1 (n = 1170) examined the psychometric properties, internal consistency, factor structure (exploratory factor analysis, EFA) and construct validity with enjoyment perception during physical activity. Study 2 (n = 59) reported on reliability, construct validity with enjoyment and BMI, and on cross-sectional concurrent validity with objectively measured MVPA (tri-axial accelerometry) over the span of seven consecutive days. Study 3 (n = 58) examined the PAQ-C-It reliability, construct validity with BMI and VO2max as the objective measurement among a population of children with congenital heart defects (CHD). In study 2 and 3, the factor structure of the PAQ-C-It was then re examined with an EFA. The PAQ-C-It showed acceptable to good reliability (alpha .70 to .83). Results on construct validity showed moderate but significant association with enjoyment perception (r = .30 and .36), with BMI (r = -.30 and .79 for CHD simple form), and with the VO2max (r = .55 for CHD simple form). Significant concurrent validity with the objectively measured MVPA was reported (rho = .30, p < .05). Findings of the EFA suggested a two-factor structure for the PAQ-C-It, with items 2, 3, and 4 contributing little to the total score. This study supports the PAQ-C-It as an appropriate instrument to assess the MVPA levels of Italian children, including children with simple forms of CHD. Support is given to the possible instrument effectiveness on a large international perspective in order to level out data gathering across the globe. PMID- 27228051 TI - Telemedicine for a General Screening of Retinal Disease Using Nonmydriatic Fundus Cameras in Optometry Centers: Three-Year Results. AB - PURPOSE: Describe the first 3 years of highly specialized retinal screening through a web platform using a retinologists' network for image reading. METHODS: All patients who came to centers in the network and consented to fundus photography were included. Images were evaluated by ophthalmologists. We describe number of patients, age, visual acuity, retinal abnormalities, medical recommendations, and factors associated with abnormal retinographies. RESULTS: Fifty thousand three hundred eighty-four patients were included; mean age 52.3 years (range 3-99). Mean visual acuity 20/25. Of the total cohort, 75% had normal retinographies, 22% had abnormalities, 1% referred acute floaters, 1% referred acute symptoms with normal retinography, and 1% could not be assessed. Ophthalmological referral was recommended in 12,634 patients: 9% urgent visit, 11% preferential (2-3 weeks), and 80% an ordinary visit. Age-related maculopathy signs were the most common abnormalities (2,456 patients, 4.8%). Epiretinal membrane was the second (764 cases, 1.5%). Diabetic retinopathy was suspected in 543 patients (1%), and nevi in 358 patients (0.7%). Patients older than 50 years had significantly more retinal abnormalities (31.5%) than younger ones (11.1%) (p < 0.0001; odds ratio [OR] 2.47; confidence interval [CI] 2.37-2.57). Patients with almost one eye with a myopic defect greater than -5 spherical equivalent had a higher risk of presenting abnormalities (p < 0.001; OR 1.04; CI 1.03-1.05). CONCLUSIONS: A high rate of asymptomatic retinal abnormalities was detected in this general screening, justifying this practice. Many patients who visit optometrists in Spain are unaware that they would benefit from ophthalmological monitoring. The ophthalmic community should lead initiatives of the type presented to preserve and guarantee quality standards. PMID- 27228052 TI - Improvements in glycemic control after gastric bypass occur despite persistent adipose tissue inflammation. AB - OBJECTIVE: Type 2 diabetes commonly goes into remission following Roux-en-Y gastric bypass (RYGB). As the mechanisms remain incompletely understood, a reduction in adipose tissue inflammation may contribute to these metabolic improvements. Therefore, whether RYGB reduces adipose tissue inflammation compared with equivalent weight loss from an intensive lifestyle intervention was investigated. METHODS: Sixteen people with obesity and type 2 diabetes were randomized to RYGB or lifestyle intervention. Fasting blood and subcutaneous abdominal adipose tissue were obtained before and after the loss of ~7% of baseline weight. Adipose tissue inflammation was assessed by whole-tissue gene expression and flow cytometry-based quantification of tissue leukocytes. RESULTS: At 7% weight loss, insulin and metformin use were reduced among the RYGB but not the Lifestyle cohort, while fasting glucose and insulin declined in both. Adipose tissue inflammation increased modestly after RYGB and to a similar extent following nonsurgical weight loss. In both groups, the number of neutrophils increased severalfold (P < 0.001), mRNA levels of the proinflammatory cytokine interleukin-1beta increased (P = 0.037), and mRNA expression of the anti inflammatory and insulin-sensitizing adipokine adiponectin decreased (P = 0.010). CONCLUSIONS: A reduction in adipose tissue inflammation is not one of the acute weight loss-independent mechanisms through which RYGB exerts its antidiabetes effects. PMID- 27228054 TI - Usefulness of Tacrolimus without Basiliximab in Well-Matched Living-Donor Renal Transplant Recipients in Korea. AB - OBJECTIVES: Basiliximab is used alongside tacrolimus-based immunosuppression for routine induction therapy, even for well-matched living-donor renal transplant recipients. Because tacrolimus is a different drug from cyclosporine, this study examined the utility of tacrolimus-based immunosuppression without basiliximab for well-matched living-donor renal transplant recipients. MATERIALS AND METHODS: This prospective study evaluated 36 patients who underwent 1 to 3 human leukocyte antigens mismatched living-donor renal transplants without basiliximab induction therapy between April 2012 and March 2015 (group 1). All transplants were ABO compatible and T-flow negative and were followed until April 2015. Tacrolimus based triple therapy was used for maintenance immunosuppression. The control group comprised 72 age- and sex-matched patients who underwent 1 to 3 human leukocyte antigens mismatched living-donor renal transplants with basiliximab induction therapy during the same period (group 2). RESULTS: Two patients in group 1 and 12 patients in group 2 had infection,with cytomegalovirus infection and Pneumocystis pneumonia infection occurring only in group 2 and BK virus and urinary tract infection reported in both groups, with a similar incidence. One patient from group 2 had sepsis. Although the incidence of infection tended to be lower in group 1 than in group 2 (5.6% vs 16.7%), the overall incidence of infection was not significantly different (P=.135). In addition, there were no significant differences in incidence of acute rejection between groups 1 and 2 (2.8% vs 4.2%; P=.699). All patients showed stable renal function after treatment. CONCLUSIONS: Tacrolimus-based triple drug maintenance immunosuppression without basiliximab might be an optimal treatment choice for individuals undergoing well-matched living-donor renal transplant. PMID- 27228055 TI - Synthesis and Antimalarial Activity of Mallatojaponin C and Related Compounds. AB - The phloroglucinol mallotojaponin C (1) from Mallotus oppositifolius, which was previously shown by us to have both antiplasmodial and cytocidal activities against the malaria parasite Plasmodium falciparum, was synthesized in three steps from 2',4',6'-trihydroxyacetophenone, and various derivatives were synthesized in an attempt to improve the bioactivity of this class of compounds. Two derivatives, the simple prenylated phloroglucinols 12 and 13, were found to have comparable antiplasmodial activities to that of mallotojaponin C. PMID- 27228053 TI - Follicular Lymphoma Tregs Have a Distinct Transcription Profile Impacting Their Migration and Retention in the Malignant Lymph Node. AB - We have previously shown that regulatory T cells (Tregs) infiltrating follicular lymphoma lymph nodes are quantitatively and qualitatively different than those infiltrating normal and reactive nodes. To gain insight into how such Treg populations differ, we performed RNA sequence (RNAseq) analyses on flow sorted Tregs from all three sources. We identify several molecules that could contribute to the observed increased suppressive capacity of follicular lymphoma nodal tregs, including upregulation of CTLA-4, IL-10, and GITR, all confirmed by protein expression. In addition, we identify, and confirm functionally, a novel mechanism by which Tregs target to and accumulate within a human tumor microenvironment, through the down regulation of S1PR1, SELL (L-selectin) and CCR7, potentially resulting in greater lymph node retention. In addition we identify and confirm functionally the upregulation of the chemokine receptor CXCR5 as well as the secretion of the chemokines CXCL13 and IL-16 demonstrating the unique ability of the follicular derived Tregs to localize and accumulate within not only the malignant lymph node, but also localize and accumulate within the malignant B cell follicle itself. Such findings offer significant new insights into how follicular lymphoma nodal Tregs may contribute to the biology of follicular lymphoma and identify several novel therapeutic targets. PMID- 27228056 TI - Data-Driven Identification of Risk Factors of Patient Satisfaction at a Large Urban Academic Medical Center. AB - BACKGROUND: The Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey is the first publicly reported nationwide survey to evaluate and compare hospitals. Increasing patient satisfaction is an important goal as it aims to achieve a more effective and efficient healthcare delivery system. In this study, we develop and apply an integrative, data-driven approach to identify clinical risk factors that associate with patient satisfaction outcomes. METHODS: We included 1,771 unique adult patients who completed the HCAHPS survey and were discharged from the inpatient Medicine service from 2010 to 2012. We collected 266 clinical features including patient demographics, lab measurements, medications, disease categories, and procedures. We developed and applied a data driven approach to identify risk factors that associate with patient satisfaction outcomes. FINDINGS: We identify 102 significant risk factors associating with 18 surveyed questions. The most significantly recurrent clinical risk factors were: self-evaluation of health, education level, Asian, White, treatment in BMT oncology division, being prescribed a new medication. Patients who were prescribed pregabalin were less satisfied particularly in relation to communication with nurses and pain management. Explanation of medication usage was associated with communication with nurses (q = 0.001); however, explanation of medication side effects was associated with communication with doctors (q = 0.003). Overall hospital rating was associated with hospital environment, communication with doctors, and communication about medicines. However, patient likelihood to recommend hospital was associated with hospital environment, communication about medicines, pain management, and communication with nurse. CONCLUSIONS: Our study identified a number of putatively novel clinical risk factors for patient satisfaction that suggest new opportunities to better understand and manage patient satisfaction. Hospitals can use a data-driven approach to identify clinical risk factors for poor patient satisfaction to support development of specific interventions to improve patients' experience of care. PMID- 27228059 TI - Errata: Vol. 65, No. 19. AB - In the report, "Prevalence of Doctor-Diagnosed Arthritis at State and County Levels - United States, 2014," multiple errors occurred. PMID- 27228057 TI - BANK1 Regulates IgG Production in a Lupus Model by Controlling TLR7-Dependent STAT1 Activation. AB - The purpose of our study was to investigate the effects of the adaptor Bank1 in TLR7 signaling using the B6.Sle1.yaa mouse, a lupus model that develops disease through exacerbated TLR7 expression. Crosses of B6.Sle1.yaa with Bank1-/- mice maintained several B and myeloid cell phenotypes close to normal wild-type levels. Most striking was the reduction in total serum IgG antibodies, but not of IgM, and reduced serum levels of autoantibodies, IL-6, and BAFF. Bank1 deficiency did modify numbers of MZ B cells and total B cell numbers, as well as expression of CXCR4 by follicular helper T cells. Other T cell changes were not observed. Bank1 deficiency did not modify numbers of germinal center B cells or plasma cells or clinical disease outcomes. Purified B cells from Bank1 deficient mice had strongly reduced Ifnb, Ifna4, Irf7, Aicda and Stat1 gene expression following TLR7 agonist stimulation. Interestingly, phosphorylation of Tyr701, but not of Ser727 of STAT1, was impaired in splenic B cells from B6.Sle1.yaa.Bank1-/- mice, as was the nuclear translocation of IRF7 in response to TLR7 agonist stimulation. Further, Bank1 deficiency in B6.Sle1.yaa mice reduced the production of IgG2c after in vitro TLR7 agonist stimulation. Our results demonstrate that Bank1 controls TLR7-mediated type I interferon production. Combined with the control of the nuclear translocation of IRF7, the modulation of STAT1 transcription and phosphorylation, Bank1 contributes to IgG production during development of autoimmune disease. PMID- 27228058 TI - Marked Rise in the Prevalence of Asymptomatic Plasmodium falciparum Infection in Rural Gabon. AB - Control strategies implemented a decade ago led to a marked reduction in the prevalence of malaria in many countries. In Dienga, southeastern Gabon, the prevalence of microscopic P. falciparum infection was 7% in 2003, close to the pre-elimination threshold of 5%. The aim of this work was to determine the prevalence of P. falciparum infection in the same community a decade later. A cohort of 370 individuals aged from 3 to 85 years living in Dienga was investigated for P. falciparum infection; during six passages (P) in 15-month period. Demographic data were collected, along with behaviors and attitudes towards malaria. Plasmodium infection was diagnosed by microscopy (ME), followed by PCR to detect submicroscopic infection. The prevalence of P. falciparum infection in P1, P2, P3, P4, P5 and P6 was respectively 43.5% (25.1% ME+, 18.4% PCR+); 40.9% (27.0% ME+, 13.9% PCR+), 52.7% (26.1% ME+, 26.6% PCR+); 34.1% (14.1% ME+, 20% PCR+), 57.7% (25.4.% ME+, 32.3% PCR+); and 46.2% (21.4% ME+, 24.8% PCR+) with an overall average of 45.9% (95%CI [37.0-54.7], 23.2% ME+ and 22.7% PCR+). P4 and P5 prevalences were statically different throughout the six passages. Microscopic prevalence was significantly higher than that observed ten years ago (23% [n = 370] vs 7% [n = 323], p < 0.001). Asymptomatic infections were the most frequent (96%). Gametocytes were detected in levels ranging from 5.9% to 13.9%. Insecticide-treated nets, indoor residual insecticides, and self-medication were used by respectively 33.2% (95%CI [29.0-37.4]), 17.7% (95%CI [15.5-19.9]) and 12.1% (95%CI [10.6-13.6]) of the study population. A near-threefold increase in P. falciparum infection has been observed in a rural area of southeastern Gabon during a 10-year period. Most infections were asymptomatic, but these subjects likely represent a parasite reservoir. These findings call for urgent reinforcement of preventive measures. PMID- 27228067 TI - Manic Reaction in a Child Induced by Guanfacine-Extended Release. PMID- 27228068 TI - Incorporating Time-Dose-Response into Legionella Outbreak Models. AB - A novel method was used to incorporate in vivo host-pathogen dynamics into a new robust outbreak model for legionellosis. Dose-response and time-dose-response (TDR) models were generated for Legionella longbeachae exposure to mice via the intratracheal route using a maximum likelihood estimation approach. The best-fit TDR model was then incorporated into two L. pneumophila outbreak models: an outbreak that occurred at a spa in Japan, and one that occurred in a Melbourne aquarium. The best-fit TDR from the murine dosing study was the beta-Poisson with exponential-reciprocal dependency model, which had a minimized deviance of 32.9. This model was tested against other incubation distributions in the Japan outbreak, and performed consistently well, with reported deviances ranging from 32 to 35. In the case of the Melbourne outbreak, the exponential model with exponential dependency was tested against non-time-dependent distributions to explore the performance of the time-dependent model with the lowest number of parameters. This model reported low minimized deviances around 8 for the Weibull, gamma, and lognormal exposure distribution cases. This work shows that the incorporation of a time factor into outbreak distributions provides models with acceptable fits that can provide insight into the in vivo dynamics of the host pathogen system. PMID- 27228069 TI - Sodium content in products used to treat haemophilia. PMID- 27228071 TI - Error in Figures and Table. PMID- 27228070 TI - Pseudomonas aeruginosa: targeting cell-wall metabolism for new antibacterial discovery and development. AB - Pseudomonas aeruginosa is a leading cause of hospital-acquired infections and is resistant to most antibiotics. With therapeutic options against P. aeruginosa dwindling, and the lack of new antibiotics in advanced developmental stages, strategies for preserving the effectiveness of current antibiotics are urgently required. beta-Lactam antibiotics are important agents for treating P. aeruginosa infections, thus, adjuvants that potentiate the activity of these compounds are desirable for extending their lifespan while new antibiotics - or antibiotic classes - are discovered and developed. In this review, we discuss recent research that has identified exploitable targets of cell-wall metabolism for the design and development of compounds that hinder resistance and potentiate the activity of antipseudomonal beta-lactams. PMID- 27228072 TI - Nicotine-Mediated Regulation of Nicotinic Acetylcholine Receptors in Non-Small Cell Lung Adenocarcinoma by E2F1 and STAT1 Transcription Factors. AB - Cigarette smoking is the major risk factor for non-small cell lung cancer (NSCLC), which accounts for 80% of all lung cancers. Nicotine, the addictive component of tobacco smoke, can induce proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), angiogenesis, and survival in NSCLC cell lines, as well as growth and metastasis of NSCLC in mice. This nicotine-mediated tumor progression is facilitated through activation of nicotinic acetylcholine receptors (nAChRs), specifically the alpha7 subunit; however, how the alpha7 nAChR gene is regulated in lung adenocarcinoma is not fully clear. Here we demonstrate that the alpha7 nAChR gene promoter is differentially regulated by E2F and STAT transcription factors through a competitive interplay; E2F1 induces the promoter, while STAT transcription factors repress it by binding to an overlapping site at a region -294 through -463bp upstream of the transcription start site. Treatment of cells with nicotine induced the mRNA and protein levels of alpha7 nAChR; this could be abrogated by treatment with inhibitors targeting Src, PI3K, MEK, alpha7 nAChR, CDK4/6 or a disruptor of the Rb-Raf-1 interaction. Further, nicotine-mediated induction of alpha7 nAChR was reduced when E2F1 was depleted and in contrast elevated when STAT1 was depleted by siRNAs. Interestingly, extracts from e-cigarettes, which have recently emerged as healthier alternatives to traditional cigarette smoking, can also induce alpha7 nAChR expression in a manner similar to nicotine. These results suggest an autoregulatory feed-forward loop that induces the levels of alpha7 nAChR upon exposure to nicotine, which enhances the strength of the signal. It can be imagined that such an induction of alpha7 nAChR contributes to the tumor promoting functions of nicotine. PMID- 27228075 TI - Kinematic and behavioral analyses of protective stepping strategies and risk for falls among community living older adults. AB - BACKGROUND: Protective stepping evoked by externally applied lateral perturbations reveals balance deficits underlying falls. However, a lack of comprehensive information about the control of different stepping strategies in relation to the magnitude of perturbation limits understanding of balance control in relation to age and fall status. The aim of this study was to investigate different protective stepping strategies and their kinematic and behavioral control characteristics in response to different magnitudes of lateral waist pulls between older fallers and non-fallers. METHODS: Fifty-two community dwelling older adults (16 fallers) reacted naturally to maintain balance in response to five magnitudes of lateral waist-pulls. The balance tolerance limit (BTL, waist-pull magnitude where protective steps transitioned from single to multiple steps), first step control characteristics (stepping frequency and counts, spatial-temporal kinematic, and trunk position at landing) of four naturally selected protective step types were compared between fallers and non fallers at- and above-BTL. FINDINGS: Fallers took medial-steps most frequently while non-fallers most often took crossover-back-steps. Only non-fallers varied their step count and first step control parameters by step type at the instants of step initiation (onset time) and termination (trunk position), while both groups modulated step execution parameters (single stance duration and step length) by step type. Group differences were generally better demonstrated above BTL. INTERPRETATION: Fallers primarily used a biomechanically less effective medial-stepping strategy that may be partially explained by reduced somato sensation. Fallers did not modulate their step parameters by step type at first step initiation and termination, instances particularly vulnerable to instability, reflecting their limitations in balance control during protective stepping. PMID- 27228076 TI - Genetics of Bietti Crystalline Dystrophy. AB - Bietti crystalline dystrophy (BCD) is an inherited retinal degenerative disease characterized by crystalline deposits in the retina, followed by progressive atrophy of the retinal pigment epithelium (RPE), choriocapillaris, and photoreceptors. CYP4V2 has been identified as the causative gene for BCD. The CYP4V2 gene belongs to the cytochrome P450 superfamily and encodes for fatty acid omega-hydroxylase of both saturated and unsaturated fatty acids. The CYP4V2 protein is localized most abundantly within the endoplasmic reticulum in the RPE and is postulated to play a role in the physiological lipid recycling system between the RPE and photoreceptors to maintain visual function. Electroretinographic assessments have revealed progressive dysfunction of rod and cone photoreceptors in patients with BCD. Several genotypes have been associated with more severe phenotypes based on clinical and electrophysiological findings. With the advent of multimodal imaging with spectral domain optical coherence tomography, fundus autofluorescence, and adaptive optics scanning laser ophthalmoscopy, more precise delineation of BCD severity and progression is now possible, allowing for the potential future development of targets for gene therapy. PMID- 27228077 TI - Implementation of a High-Resolution Single-Nucleotide Polymorphism Array in Analyzing the Products of Conception. AB - AIMS: To demonstrate the value of a whole-genome high-resolution single nucleotide polymorphism (SNP) array for the elucidation of genetic causes underlying pregnancy loss. METHODS: The SNP array combined with SNPs and oligonucleotide probes was used to examine 60 samples of products of conception, including chorionic villi, fetal parts, and fetal blood. RESULTS: The SNP array yielded a 38.3% (23/60) abnormality rate. In addition to the most common aneuploidy, it detected 16.7% additional aberrations involving copy number variation, triploidy, loss of heterozygosity or low-level mosaicism. CONCLUSION: This whole-genome high-resolution SNP array not only provides copy number information but also identifies the heterozygosity status, which facilitates the discovery of the novel genetic alterations associated with pregnancy failure and improves the management of subsequent pregnancies. PMID- 27228078 TI - Adverse Perinatal Outcome in Subsequent Pregnancy after Stillbirth by Placental Vascular Disorders. AB - OBJECTIVE: To evaluate outcome in the pregnancy following a stillbirth (SB) by a placental vascular disorders. STUDY DESIGN: A prospective, observational, multicenter study was conducted in woman with a history of stillbirth (> 22 weeks) between 2005 and June 2013, in 3 Italian University Hospitals. Causes of SB were previously identified after extensive investigations. Pregnant women were enrolled within the first trimester. The main outcome was "adverse neonatal outcome", including perinatal death, fetal growth restriction, early preterm birth <33+6 weeks, hypoxic-ischemic encephalopathy, intracranial hemorrhage or respiratory distress. RESULTS: Out of 364 index pregnancies, 320 women (87.9%) had a subsequent pregnancy during the study period. Forty-seven had an early pregnancy loss. Out of 273 babies, 67 (24.5%) had an adverse perinatal outcome, including 1 SB and 1 early neonatal death (3.7/1000). Women who had a SB related to placental vascular disorders (39.6%), were at higher risk of an adverse neonatal outcome compared with women whose SB was unexplained or resulted from other causes (Adj. OR = 2.1, 95%CI: 1.2-3.8). Moreover, also obesity independently predicts an adverse perinatal outcome (Adj OR = 2.1, 95%CI: 1.1 4.3). CONCLUSION: When previous SB is related to placental vascular disorders there is a high risk for adverse neonatal outcomes in the subsequent pregnancy. Maternal obesity is an additional risk factor. PMID- 27228079 TI - Construction of Large-Volume Tissue Mimics with 3D Functional Vascular Networks. AB - We used indirect stereolithography (SL) to form inner-layered fluidic networks in a porous scaffold by introducing a hydrogel barrier on the luminal surface, then seeded the networks separately with human umbilical vein endothelial cells and human lung fibroblasts to form a tissue mimic containing vascular networks. The artificial vascular networks provided channels for oxygen transport, thus reducing the hypoxic volume and preventing cell death. The endothelium of the vascular networks significantly retarded the occlusion of channels during whole blood circulation. The tissue mimics have the potential to be used as an in vitro platform to examine the physiologic and pathologic phenomena through vascular architecture. PMID- 27228080 TI - Phylogenetic Diversity in the Macromolecular Composition of Microalgae. AB - The elemental stoichiometry of microalgae reflects their underlying macromolecular composition and influences competitive interactions among species and their role in the food web and biogeochemistry. Here we provide a new estimate of the macromolecular composition of microalgae using a hierarchical Bayesian analysis of data compiled from the literature. The median macromolecular composition of nutrient-sufficient exponentially growing microalgae is 32.2% protein, 17.3% lipid, 15.0% carbohydrate, 17.3% ash, 5.7% RNA, 1.1% chlorophyll-a and 1.0% DNA as percent dry weight. Our analysis identifies significant phylogenetic differences in macromolecular composition undetected by previous studies due to small sample sizes and the large inherent variability in macromolecular pools. The phylogenetic differences in macromolecular composition lead to variations in carbon-to-nitrogen ratios that are consistent with independent observations. These phylogenetic differences in macromolecular and elemental composition reflect adaptations in cellular architecture and biochemistry; specifically in the cell wall, the light harvesting apparatus, and storage pools. PMID- 27228082 TI - Decolorization of synthetic brilliant green carpet industry dye through fungal co culture technology. AB - Aim of the present study was to evaluate the efficiency of fungal co-culture for the decolorization of synthetic brilliant green carpet industry dye. For this purpose two lignocellulolytic fungi Pleurotus florida (PF) and Rhizoctonia solani (RS) were employed. The study includes determination of enzyme profiles (laccase and peroxidase), dye decolorization efficiency of co-culture and crude enzyme extracts. Both fungi produced laccase and Mn peroxidase and successfully decolorized solutions of different concentrations (2.0, 4.0, 6.0, & 8.0(w/v) of dye. The co-culture resulted highest 98.54% dye decolorization at 2% (w/v) of dye as compared to monocultures (82.12% with PF and 68.89% with RS) during 12 days of submerged fermentation. The lower levels of dyes were rapidly decolorized, while higher levels in slow order as 87.67% decolorization of 8% dye. The promising achievement of the study was remarkable decolorizing efficiency of co-culture over monocultures. The direct treatment of the mono and co-culture enzyme extracts to dye also influenced remarkable. The highest enzymatic decolorization was through combined (PF and RS) extracts, while lesser by monoculture extracts. Based on the observations and potentiality of co-culture technology; further it can be exploited for the bioremediation of areas contaminated with hazardous environmental pollutants including textile and other industry effluents. PMID- 27228081 TI - Upper Airway Resistance Syndrome Patients Have Worse Sleep Quality Compared to Mild Obstructive Sleep Apnea. AB - PURPOSE: To compare sleep quality and sustained attention of patients with Upper Airway Resistance Syndrome (UARS), mild Obstructive Sleep Apnea (OSA) and normal individuals. METHODS: UARS criteria were presence of excessive daytime sleepiness (Epworth Sleepiness Scale-ESS->= 10) and/or fatigue (Modified Fatigue Impact Scale-MFIS->= 38) associated to Apnea/hypopnea index (AHI) <= 5 and Respiratory Disturbance Index (RDI) > 5 events/hour of sleep or more than 30% of total sleep time with flow limitation. Mild OSA was considered if the presence of excessive daytime sleepiness (ESS >= 10) and/or fatigue (MFIS >= 38) associated to AHI >= 5 and <= 15 events/hour. "Control group" criteria were AHI < 5 events/hour and RDI <= 5 events/hour and ESS <= 9, without any sleep, clinical, neurological or psychiatric disorder. 115 individuals (34 UARS and 47 mild OSA patients and 34 individuals in "control group"), adjusted for age, gender, body mass index (BMI) and schooling years, performed sleep questionnaires and sustained attention evaluation. Psychomotor Vigilance Task (PVT) was performed five times (each two hours) from 8 a.m. to 4 p.m. RESULTS: UARS patients had worse sleep quality (Functional Outcomes of Sleep Questionnaire-FOSQ-and Pittsburgh Sleep Quality Index-PSQI: p < 0.05) and more fatigue than mild OSA patients (p = 0.003) and scored significantly higher in both Beck inventories than "control group" (p < 0.02). UARS patients had more lapses early in the morning (in time 1) compared to the results in the afternoon (time 5) than mild OSA (p = 0.02). Mild OSA patients had more lapses in times 2 than in time 5 compared to "control group" (p = 0.04). CONCLUSIONS: UARS patients have a worse sleep quality, more fatigue and a worse early morning sustained attention compared to mild OSA. These last had a worse sustained attention than controls. PMID- 27228083 TI - Polar Noncentrosymmetric ZnMoSb2O7 and Nonpolar Centrosymmetric CdMoSb4O10: d(10) Transition Metal Size Effect Influencing the Stoichiometry and the Centricity. AB - Two new quaternary molybdenum(VI) antimony(III) oxides, ZnMoSb2O7 and CdMoSb4O10, have been synthesized in phase-pure form. The title compounds consist of highly polarizable cations, i.e., d(0) (Mo(6+)) and d(10) (Zn(2+) or Cd(2+)), and lone pair cations (Sb(3+)). ZnMoSb2O7 exhibits a three-dimensional framework with ZnO4, MoO4, and SbO4 polyhedra in the polar space group P21, whereas CdMoSb4O10 exhibits one-dimensional tubule structures with CdO6, MoO4, and SbO3 polyhedra in the space group P21/m. Several synthetic efforts suggest that the the dissimilar radii of Zn(2+) and Cd(2+) that can accommodate polyhedra of Sb(3+) cations influence the stoichiometry as well as the centricity for the reported materials. Spectroscopic, thermal, and elemental analyses are reported along with dipole moment calculations. Nonlinear optical properties and their structural origin are examined for polar ZnMoSb2O7 as well. PMID- 27228084 TI - Plasma Soluble (Pro)renin Receptor Reflects Renal Damage. AB - BACKGROUND: (Pro)renin receptor [(P)RR], a specific receptor for renin and prorenin, was identified as a member of the renin-angiotensin system (RAS). (P)RR is cleaved by furin, and soluble (P)RR [s(P)RR] is secreted into the extracellular space. Previous reports have indicated that plasma s(P)RR levels show a significant positive relationship with urinary protein levels, which represent renal damage. However, it is not fully known whether plasma s(P)RR reflects renal damage. METHODS: We recruited 25 patients who were admitted to our hospital to undergo heminephrectomy. Plasma s(P)RR levels were examined from blood samples drawn before nephrectomy. The extent of renal damage was evaluated by the levels of tubulointerstitial fibrosis. Immunohistochemical analysis of intrarenal (P)RR and cell surface markers (cluster of differentiation [CD]3, CD19, and CD68) was performed on samples taken from the removed kidney. Moreover, double staining of (P)RR and cell surface markers was also performed. RESULTS: There were significant positive relationships between plasma s(P)RR and tubulointerstitial fibrosis in all the patients and those not receiving RAS blocker therapy. Significant positive relationships were found between plasma s(P)RR levels and the extent of tubulointerstitial fibrosis after adjustment for age, sex, body weight, blood pressure, and plasma angiotensin II, in all the patients and those not receiving RAS blockers. Moreover, (P)RR expression was elevated in infiltrated mononuclear cells but not connecting tubules or collecting ducts and vessels. Infiltrated cells positive for (P)RR consisted of CD3 and CD68 but not CD19. CONCLUSIONS: These data suggest that plasma s(P)RR levels may reflect (P)RR expression levels in infiltrated mononuclear cells, which can be a surrogate marker of renal damage. PMID- 27228085 TI - Effective healing of chronic rotator cuff injury using recombinant bone morphogenetic protein-2 coated dermal patch in vivo. AB - Biologic augmentation for rotator cuff repair is a challenging treatment in patients with chronic large, massive, and irreparable rotator cuff injuries. Particularly, the use of an extracellular matrix (ECM) patch such as dermal tissue offered improved biomechanical properties in previous studies. Cytokines induce cell chemotaxis, proliferation, matrix synthesis, and cell differentiation. Moreover, osteoinductive growth factors such as bone morphogenetic protein-2 (BMP-2) affect the formation of new bone and fibrocartilage in lesions. However, the effects of using a dermal patch in combination with BMP-2 have not been evaluated to date, although many researchers have recognized the importance thereof. In this study, rhBMP-2-coated dermal patch (1 cm * 2 cm) isolated from human cadaveric donor was inserted in a rabbit model of chronic rotator cuff injury for in vivo evaluation. Bone mineral density and biomechanical strength were tested and histological and histomorphometric analyses were performed. The results showed that insertion of an rhBMP-2-coated acellular dermal patch not only significantly ameliorated new bone formation, it also improved biomechanical properties such as ultimate tensile strength. Thus, the use of this combination may improve the chronic rotator cuff injury-healing rate and clinical outcomes after rotator cuff repair. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1840-1846, 2017. PMID- 27228086 TI - Correlations between the minimum and mean apparent diffusion coefficient values of hepatocellular carcinoma and tumor grade. AB - PURPOSE: To investigate the correlations between the minimum and mean apparent diffusion coefficient (ADC) values of hepatocellular carcinoma (HCC) and pathological grade. MATERIALS AND METHODS: Preoperative magnetic resonance imaging (MRI) images of 241 patients with HCC confirmed by pathology were retrospectively analyzed. All patients underwent preoperative diffusion-weighted imaging (DWI) on a 1.5T MRI scanner. The mean and minimum ADC values of the tumors were measured. The ADC values were compared in tumors with different grades and the correlations between ADC values and pathological grade were analyzed. Receiver operating characteristic (ROC) curves of ADC values were obtained and compared to distinguish poorly and nonpoorly differentiated HCCs. Interobserver agreements were assessed by intraclass correlation coefficient (ICC). RESULTS: The mean and minimum ADC values of poorly differentiated HCCs were lower than those of nonpoorly differentiated HCCs (P = 0.000, 0.000, respectively). The mean and minimum ADC values were negatively correlated with pathological grade (rs = -0.180 and -0.202, respectively) (P = 0.005, 0.002, respectively). For the differentiation between poorly and nonpoorly differentiated HCCs, the mean ADC value provided a sensitivity of 69.57% and a specificity of 73.39% with a cutoff value of 0.96 * 10-3 mm2 /s while the minimum ADC value showed a sensitivity of 78.26% and a specificity of 61.47% with a cutoff value of 0.90 * 10-3 mm2 /s. No significant difference existed between both ROC curves (P = 0.64). The ICC for the measurements of the mean and minimum ADC values was 0.92 (95% confidence interval [CI] 0.90-0.93) and 0.91 (95% CI 0.89-0.93), respectively. CONCLUSION: DWI of HCC could preoperatively provide quantitative parameters for predicting tumor histological grade. J. Magn. Reson. Imaging 2016;44:1442-1447. PMID- 27228087 TI - Serum Malondialdehyde Concentration and Glutathione Peroxidase Activity in a Longitudinal Study of Gestational Diabetes. AB - AIMS: The main goal of this study was to evaluate the presence of oxidative damage and to quantify its level in gestational diabetes. METHODS: Thirty-six healthy women and thirty-six women with gestational diabetes were studied in the three trimesters of pregnancy regarding their levels of oxidative stress markers. These women were diagnosed with diabetes in the second trimester of pregnancy. Blood glucose levels after 100g glucose tolerance test were higher than 190, 165 or 145 mg/dl, 1, 2 or 3 hours after glucose intake. RESULTS: The group of women with gestational diabetes had higher serum malondialdehyde levels, with significant differences between groups in the first and second trimester. The mean values of serum glutathione peroxidase activity in the diabetic women were significantly lower in the first trimester. In the group of women with gestational diabetes there was a negative linear correlation between serum malondialdehyde concentration and glutathione peroxidase activity in the second and third trimester. CONCLUSIONS: In this observational and longitudinal study in pregnant women, the alterations attributable to oxidative stress were present before the biochemical detection of the HbA1c increase. Usual recommendations once GD is detected (adequate metabolic control, as well as any other normally proposed to these patients) lowered the concentration of malondialdehyde at the end of pregnancy to the same levels of the healthy controls. Serum glutathione peroxidase activity in women with gestational diabetes increased during the gestational period. PMID- 27228088 TI - Accelerated high-bandwidth MR spectroscopic imaging using compressed sensing. AB - PURPOSE: To develop a compressed sensing (CS) acceleration method with a high spectral bandwidth exploiting the spatial-spectral sparsity of MR spectroscopic imaging (MRSI). METHODS: Accelerations were achieved using blip gradients during the readout to perform nonoverlapped and stochastically delayed random walks in kx -ky -t space, combined with block-Hankel matrix completion for efficient reconstruction. Both retrospective and prospective CS accelerations were applied to (13) C MRSI experiments, including in vivo rodent brain and liver studies with administrations of hyperpolarized [1-(13) C] pyruvate at 7.0 Tesla (T) and [2 (13) C] dihydroxyacetone at 3.0 T, respectively. RESULTS: In retrospective undersampling experiments using in vivo 7.0 T data, the proposed method preserved spectral, spatial, and dynamic fidelities with R(2) >= 0.96 and >= 0.87 for pyruvate and lactate signals, respectively, 750-Hz spectral separation, and up to 6.6-fold accelerations. In prospective in vivo experiments, with 3.8-fold acceleration, the proposed method exhibited excellent spatial localization of metabolites and peak recovery for pyruvate and lactate at 7.0 T as well as for dihydroxyacetone and its metabolic products with a 4.5-kHz spectral span (140 ppm at 3.0 T). CONCLUSIONS: This study demonstrated the feasibility of a new CS approach to accelerate high spectral bandwidth MRSI experiments. Magn Reson Med 76:369-379, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27228089 TI - Intestinal Perforation in Renal Transplant Recipients: A Single Center Experience of 2123 Recipients. AB - OBJECTIVES: Intestinal perforation remains a clinical challenge and potentially lethal complication in renal transplant recipients. Immunosuppression not only places the patient at risk for intestinal perforation but also masks classic clinical symptoms and signs of acute abdominal pain, leading to delayed diagnosis and proper treatment. The aim of our study is to present the experience of our center on the treatment of intestinal perforation in renal transplant recipients. MATERIALS AND METHODS: This study reported 11 patients (0.52%) with intestinal perforation among a group of 2123 patients who received renal transplants in the Transplantation Unit at Laikon General Hospital in Athens, Greece from 1983 to August 2015. RESULTS: One patient died from septic shock before any surgery, and 3 patients died during the early postoperative period, resulting in a morality rate of 36.3%. All patients who died had a functioning graft. From the patients who were discharged, the mean follow-up was 16 months (range, 4-32 months). CONCLUSIONS: Intestinal perforation after renal transplant is a major and potentially lethal complication. Clinical presentation is usually equivocal, and the transplant surgeon should be highly suspicious when treating a renal transplant recipient with acute abdominal pain, even in cases without other predisposing factors (diverticulitis, ischemic colitis, and so forth), so that this condition could be investigated and unmasked. PMID- 27228090 TI - LC-MS/MS determination and interaction of the main components from the traditional Chinese drug pair Danshen-Sanqi based on rat intestinal absorption. AB - The Chinese drug pair Danshen (Salvia miltiorrhiza)-Sanqi (Panax ginseng) has been widely used for centuries treating various cardiovascular disorders, among which salvianlic acid B (SAB), ginsenoside Rg1 (GRg1 ), ginsenoside Rb1 (GRb1 ) and notoginsenoside R1 (NGR1 ) were identified as the major components. The present study focused on the interaction between these components based on investigating their intestinal absorption using the Ussing chamber technique. The concentrations of SAB, GRg1 , GRb1 and NGR1 in the intestinal perfusate were determined by LC-MS/MS method, followed by Q (accumulative quantity) and Papp (apparent permeability). The results showed that all these four main components displayed very low permeabilities, which implied their poor absorption in the rat intestine. The intestinal absorption level of SAB displayed regioselectivity: duodenum < jejunum < ileum. However, there was no significant difference in the absorption of GRg1 and GRb1 in the different segments. The Q and Papp values of the four main components were obviously increased in jejunum when co administrating Danshen extract with Sanqi extract. In conclusion, compatibility of Danshen and Sanqi could remarkably improve the intestinal absorption level of the main components in the pair. To some extent, this might explain the nature of the compatibility mechanisms of composite formulae in TCMs. PMID- 27228091 TI - IgE Sensitization Profiles Differ between Adult Patients with Severe and Moderate Atopic Dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) is a complex chronic inflammatory disease where allergens can act as specific triggering factors. AIM: To characterize the specificities of IgE-reactivity in patients with AD to a broad panel of exogenous allergens including microbial and human antigens. METHODOLOGY: Adult patients with AD were grouped according to the SCORAD index, into severe (n = 53) and moderate AD (n = 126). As controls 43 patients were included with seborrhoeic eczema and 97 individuals without history of allergy or skin diseases. Specific IgE reactivity was assessed in plasma using Phadiatop(r), ImmunoCapTM, micro arrayed allergens, dot-blotted recombinant Malassezia sympodialis allergens, and immune-blotted microbial and human proteins. RESULTS: IgE reactivity was detected in 92% of patients with severe and 83% of patients with moderate AD. Sensitization to cat allergens occurred most frequently, followed by sensitization to birch pollen, grass pollen, and to the skin commensal yeast M. sympodialis. Patients with severe AD showed a significantly higher frequency of IgE reactivity to allergens like cat (rFel d 1) and house dust mite (rDer p 4 and 10), to Staphylococcus aureus, M. sympodialis, and to human antigens. In contrast, there were no significant differences in the frequencies of IgE reactivity to the grass pollen allergens rPhl p 1, 2, 5b, and 6 between the two AD groups. Furthermore the IgE reactivity profile of patients with severe AD was more spread towards several different allergen molecules as compared to patients with moderate AD. CONCLUSION: We have revealed a hitherto unknown difference regarding the molecular sensitization profile in patients with severe and moderate AD. Molecular profiling towards allergen components may provide a basis for future investigations aiming to explore the environmental, genetic and epigenetic factors which could be responsible for the different appearance and severity of disease phenotypes in AD. PMID- 27228094 TI - Insomnia disorder. PMID- 27228092 TI - Comparison of Effectiveness between Tension-Free Vaginal Tape (TVT) and Trans Obturator Tape (TOT) in Patients with Stress Urinary Incontinence and Intrinsic Sphincter Deficiency. AB - BACKGROUND: The aim of this study was to compare the two types of mid-urethral slings for stress urinary incontinence (SUI) with intrinsic sphincter deficiency (ISD). METHODS: This retrospective study included patients who underwent tension free vaginal tape (TVT) procedure or transobturator tape (TOT) procedure by a single surgeon for SUI with ISD, defined as Valsalva leak point pressure (VLPP) < 60 cmH2O in a urodynamic study. Cases of neurogenic bladder, previous SUI surgery, and concomitant cystocele repair were excluded. The primary outcome was treatment success at 12 months, defined by self-reported absence of symptoms, no leakage episodes recorded, and no retreatment. RESULTS: Among the 157 women who were included in the final analysis, 105 patients received TVT and 52 patients received TOT. Age, underlying diseases, Stamey grade, cystocele grade, and presence of urge incontinence were not significantly different between the two groups. Urodynamic parameters including maximal urethral closing pressure, detrusor overactivity, VLPP, urethral hypermobility (Q-tip >= 30 degrees ), were also comparable between the two groups. Success rate was significantly higher in the TVT group than in the TOT group (95.2% vs. 82.7%, p = 0.009). On multivariate analysis, only TOT surgery (OR = 3.922, 95%CI = 1.223-12.582, p = 0.022) was a risk factor for failure following surgical treatment. CONCLUSION: TVT is more effective than TOT in treatment of female SUI with ISD. PMID- 27228093 TI - Intestinal Microbiota Is Influenced by Gender and Body Mass Index. AB - Intestinal microbiota changes are associated with the development of obesity. However, studies in humans have generated conflicting results due to high inter individual heterogeneity in terms of diet, age, and hormonal factors, and the largely unexplored influence of gender. In this work, we aimed to identify differential gut microbiota signatures associated with obesity, as a function of gender and changes in body mass index (BMI). Differences in the bacterial community structure were analyzed by 16S sequencing in 39 men and 36 post menopausal women, who had similar dietary background, matched by age and stratified according to the BMI. We observed that the abundance of the Bacteroides genus was lower in men than in women (P<0.001, Q = 0.002) when BMI was > 33. In fact, the abundance of this genus decreased in men with an increase in BMI (P<0.001, Q<0.001). However, in women, it remained unchanged within the different ranges of BMI. We observed a higher presence of Veillonella (84.6% vs. 47.2%; X2 test P = 0.001, Q = 0.019) and Methanobrevibacter genera (84.6% vs. 47.2%; X2 test P = 0.002, Q = 0.026) in fecal samples in men compared to women. We also observed that the abundance of Bilophila was lower in men compared to women regardless of BMI (P = 0.002, Q = 0.041). Additionally, after correcting for age and sex, 66 bacterial taxa at the genus level were found to be associated with BMI and plasma lipids. Microbiota explained at P = 0.001, 31.17% variation in BMI, 29.04% in triglycerides, 33.70% in high-density lipoproteins, 46.86% in low-density lipoproteins, and 28.55% in total cholesterol. Our results suggest that gut microbiota may differ between men and women, and that these differences may be influenced by the grade of obesity. The divergence in gut microbiota observed between men and women might have a dominant role in the definition of gender differences in the prevalence of metabolic and intestinal inflammatory diseases. PMID- 27228095 TI - Covalency-Driven Dimerization of Plutonium(IV) in a Hydroxamate Complex. AB - The reaction of formohydroxamic acid [NH(OH)CHO, FHA] with Pu(III) should result in stabilization of the trivalent oxidation state. However, slow oxidation to Pu(IV) occurs, which leads to formation of the dimeric plutonium(IV) formohydroxamate complex Pu2(FHA)8. In addition to being reductants, hydroxamates are also strong pi-donor ligands. Here we show that formation of the Pu2(FHA)8 dimer occurs via covalency between the 5f orbitals on plutonium and the pi* orbitals of FHA(-) anions, which gives rise to a broad and intense ligand-to metal charge-transfer feature. Time-dependent density functional theory calculations corroborate this assignment. PMID- 27228096 TI - Psychological preparation and postoperative outcomes for adults undergoing surgery under general anaesthesia. AB - BACKGROUND: In a review and meta-analysis conducted in 1993, psychological preparation was found to be beneficial for a range of outcome variables including pain, behavioural recovery, length of stay and negative affect. Since this review, more detailed bibliographic searching has become possible, additional studies testing psychological preparation for surgery have been completed and hospital procedures have changed. The present review examines whether psychological preparation (procedural information, sensory information, cognitive intervention, relaxation, hypnosis and emotion-focused intervention) has impact on the outcomes of postoperative pain, behavioural recovery, length of stay and negative affect. OBJECTIVES: To review the effects of psychological preparation on postoperative outcomes in adults undergoing elective surgery under general anaesthetic. SEARCH METHODS: We searched the Cochrane Register of Controlled Trials (CENTRAL 2014, Issue 5), MEDLINE (OVID SP) (1950 to May 2014), EMBASE (OVID SP) (1982 to May 2014), PsycINFO (OVID SP) (1982 to May 2014), CINAHL (EBESCOhost) (1980 to May 2014), Dissertation Abstracts (to May 2014) and Web of Science (1946 to May 2014). We searched reference lists of relevant studies and contacted authors to identify unpublished studies. We reran the searches in July 2015 and placed the 38 studies of interest in the 'awaiting classification' section of this review. SELECTION CRITERIA: We included randomized controlled trials of adult participants (aged 16 or older) undergoing elective surgery under general anaesthesia. We excluded studies focusing on patient groups with clinically diagnosed psychological morbidity. We did not limit the search by language or publication status. We included studies testing a preoperative psychological intervention that included at least one of these seven techniques: procedural information; sensory information; behavioural instruction; cognitive intervention; relaxation techniques; hypnosis; emotion-focused intervention. We included studies that examined any one of our postoperative outcome measures (pain, behavioural recovery, length of stay, negative affect) within one month post-surgery. DATA COLLECTION AND ANALYSIS: One author checked titles and abstracts to exclude obviously irrelevant studies. We obtained full reports of apparently relevant studies; two authors fully screened these. Two authors independently extracted data and resolved discrepancies by discussion.Where possible we used random-effects meta-analyses to combine the results from individual studies. For length of stay we pooled mean differences. For pain and negative affect we used a standardized effect size (the standardized mean difference (SMD), or Hedges' g) to combine data from different outcome measures. If data were not available in a form suitable for meta-analysis we performed a narrative review. MAIN RESULTS: Searches identified 5116 unique papers; we retrieved 827 for full screening. In this review, we included 105 studies from 115 papers, in which 10,302 participants were randomized. Mainly as a result of updating the search in July 2015, 38 papers are awaiting classification. Sixty one of the 105 studies measured the outcome pain, 14 behavioural recovery, 58 length of stay and 49 negative affect. Participants underwent a wide range of surgical procedures, and a range of psychological components were used in interventions, frequently in combination. In the 105 studies, appropriate data were provided for the meta-analysis of 38 studies measuring the outcome postoperative pain (2713 participants), 36 for length of stay (3313 participants) and 31 for negative affect (2496 participants). We narratively reviewed the remaining studies (including the 14 studies with 1441 participants addressing behavioural recovery). When pooling the results for all types of intervention there was low quality evidence that psychological preparation techniques were associated with lower postoperative pain (SMD -0.20, 95% confidence interval (CI) -0.35 to -0.06), length of stay (mean difference -0.52 days, 95% CI -0.82 to 0.22) and negative affect (SMD -0.35, 95% CI -0.54 to -0.16) compared with controls. Results tended to be similar for all categories of intervention, although there was no evidence that behavioural instruction reduced the outcome pain. However, caution must be exercised when interpreting the results because of heterogeneity in the types of surgery, interventions and outcomes. Narratively reviewed evidence for the outcome behavioural recovery provided very low quality evidence that psychological preparation, in particular behavioural instruction, may have potential to improve behavioural recovery outcomes, but no clear conclusions could be reached.Generally, the evidence suffered from poor reporting, meaning that few studies could be classified as having low risk of bias. Overall,we rated the quality of evidence for each outcome as 'low' because of the high level of heterogeneity in meta-analysed studies and the unclear risk of bias. In addition, for the outcome behavioural recovery, too few studies used robust measures and reported suitable data for meta-analysis, so we rated the quality of evidence as 'very low'. AUTHORS' CONCLUSIONS: The evidence suggested that psychological preparation may be beneficial for the outcomes postoperative pain, behavioural recovery, negative affect and length of stay, and is unlikely to be harmful. However, at present, the strength of evidence is insufficient to reach firm conclusions on the role of psychological preparation for surgery. Further analyses are needed to explore the heterogeneity in the data, to identify more specifically when intervention techniques are of benefit. As the current evidence quality is low or very low, there is a need for well-conducted and clearly reported research. PMID- 27228097 TI - Statistical Determination of the Gating Windows for Respiratory-Gated Radiotherapy Using a Visible Guiding System. AB - Respiratory-gated radiation therapy (RGRT) is used to minimize the radiation dose to normal tissue in lung-cancer patients. Although determining the gating window in the respiratory phase of patients is important in RGRT, it is not easy. Our aim was to determine the optimal gating window when using a visible guiding system for RGRT. Between April and October 2014, the breathing signals of 23 lung cancer patients were recorded with a real-time position management (RPM) respiratory gating system (Varian, USA). We performed statistical analysis with breathing signals to find the optimal gating window for guided breathing in RGRT. When we compared breathing signals before and after the breathing training, 19 of the 23 patients showed statistically significant differences (p < 0.05). The standard deviation of the respiration signals after breathing training was lowest for phases of 30%-70%. The results showed that the optimal gating window in RGRT is 40% (30%-70%) with respect to repeatability for breathing after respiration training with the visible guiding system. RGRT was performed with the RPM system to confirm the usefulness of the visible guiding system. The RPM system and our visible guiding system improve the respiratory regularity, which in turn should improve the accuracy and efficiency of RGRT. PMID- 27228099 TI - Targeted Polymeric Nanoparticles for Brain Delivery of High Molecular Weight Molecules in Lysosomal Storage Disorders. AB - Lysosomal Storage Disorders (LSDs) are a group of metabolic syndromes, each one due to the deficit of one lysosomal enzyme. Many LSDs affect most of the organ systems and overall about 75% of the patients present neurological impairment. Enzyme Replacement Therapy, although determining some systemic clinical improvements, is ineffective on the CNS disease, due to enzymes' inability to cross the blood-brain barrier (BBB). With the aim to deliver the therapeutic enzymes across the BBB, we here assayed biodegradable and biocompatible PLGA nanoparticles (NPs) in two murine models for LSDs, Mucopolysaccharidosis type I and II (MPS I and MPS II). PLGA-NPs were modified with a 7-aminoacid glycopeptide (g7), yet demonstrated to be able to deliver low molecular weight (MW) molecules across the BBB in rodents. We specifically investigated, for the first time, the g7-NPs ability to transfer a model drug (FITC-albumin) with a high MW, comparable to the enzymes to be delivered for LSDs brain therapy. In vivo experiments, conducted on wild-type mice and knockout mouse models for MPS I and II, also included a whole series of control injections to obtain a broad preliminary view of the procedure efficiency. Results clearly showed efficient BBB crossing of albumin in all injected mice, underlying the ability of NPs to deliver high MW molecules to the brain. These results encourage successful experiments with enzyme-loaded g7-NPs to deliver sufficient amounts of the drug to the brain district on LSDs, where exerting a corrective effect on the pathological phenotype. PMID- 27228100 TI - ApoE epsilon4 Is Associated With Cognition, Brain Integrity, and Atrophy in HIV Over Age 60. AB - BACKGROUND: There are contradicting reports on the associations between Apolipoprotein E4 (ApoE epsilon4) and brain outcomes in HIV with some evidence that relationships may be greatest in older age groups. METHODS: We assessed cognition in 76 clinically stable HIV-infected participants over age 60 and genotyped ApoE. Sixty-one of these subjects underwent structural brain magnetic resonance imaging and diffusion tensor imaging. RESULTS: The median age of the participants was 64 years (range: 60-84) and the median estimated duration of HIV infection was 22 years. Apo epsilon4 carriers (n = 19) were similar to noncarriers (n = 57) in sex (95% vs. 96% male), and education (16.0 vs. 16.2 years) ApoE epsilon4 carriers demonstrated greater deficits in cognitive performance in the executive domain (P = 0.045) and had reduced fractional anisotropy and increased mean diffusivity throughout large white matter tracts within the brain compared with noncarriers. Tensor-based morphometry analyses revealed ventricular expansion and atrophy in the posterior corpus callosum, thalamus, and brainstem among HIV-infected ApoE epsilon4 carriers compared with epsilon4 noncarriers. CONCLUSIONS: In this sample of older HIV-infected individuals, having at least 1 ApoE epsilon4 allele was associated with decreased cognitive performance in the executive functioning domain, reduced brain white matter integrity, and brain atrophy. Brain atrophy was most prominent in the posterior corpus callosum, thalamus, and brainstem. This pattern of cognitive deficit, atrophy, and damage to white matter integrity was similar to that described in HIV, suggesting an exacerbation of HIV-related pathology; although emergence of other age-associated neurodegenerative disorders cannot be excluded. PMID- 27228101 TI - Type of Referral, Dialysis Start and Choice of Renal Replacement Therapy Modality in an International Integrated Care Setting. AB - INTRODUCTION: Integrated Care Settings (ICS) provide a holistic approach to the transition from chronic kidney disease into renal replacement therapy (RRT), offering at least both types of dialysis. OBJECTIVES: To analyze which factors determine type of referral, modality provision and dialysis start on final RRT in ICS clinics. METHODS: Retrospective analysis of 626 patients starting dialysis in 25 ICS clinics in Poland, Hungary and Romania during 2012. Scheduled initiation of dialysis with a permanent access was considered as planned RRT start. RESULTS: Modality information (80% of patients) and renal education (87%) were more frequent (p<0.001) in Planned (P) than in Non-Planned (NP) start. Median time from information to dialysis start was 2 months. 89% of patients started on hemodialysis, 49% were referred late to ICS (<3 months from referral to RRT) and 58% were NP start. Late referral, non-vascular renal etiology, worse clinical status, shorter time from information to RRT and less peritoneal dialysis (PD) were associated with NP start (p<0.05). In multivariate logistic regression analysis, P start (p<=0.05) was associated with early referral, eGFR >8.2 ml/min, >2 months between information and RRT initiation and with vascular etiology after adjustment for age and gender. "Optimal care," defined as ICS follow-up >12 months plus modality information and P start, occurred in 23%. CONCLUSIONS: Despite the high rate of late referrals, information and education were widely provided. However, NP start was high and related to late referral and may explain the low frequency of PD. PMID- 27228102 TI - Synthesis and Behavior of Cetyltrimethyl Ammonium Bromide Stabilized Zn1+xSnO3+x (0 <= x <=1) Nano-Crystallites. AB - We report synthesis of cetyltrimethyl ammonium bromide (CTAB) stabilized Zn1+xSnO3+x (0 <= x <=1) nano-crystallites by facile cost-effective wet chemistry route. The X-ray diffraction patterns of as-synthesized powders at the Zn/Sn ratio of 1 exhibited formation of ZnSn(OH)6. Increasing the Zn/Sn ratio further resulted in the precipitation of an additional phase corresponding to Zn(OH)2. The decomposition of these powders at 650 degrees C for 3h led to the formation of the orthorhombic phase of ZnSnO3 and tetragonal SnO2-type phase of Zn2SnO4 at the Zn/Sn ratio of 1 and 2, respectively, with the formation of their mixed phases at intermediate compositions, i.e., at Zn/Sn ratio of 1.25, 1.50 and 1.75, respectively. The lattice parameters of orthorhombic and tetragonal phases were a ~ 3.6203 A, b ~ 4.2646 A and c ~ 12.8291A (for ZnSnO3) and a = b ~ 5.0136 A and c ~ 3.3055A (for Zn2SnO4). The transmission electron micrographs revealed the formation of nano-crystallites with aspect ratio ~ 2; the length and thickness being 24, 13 nm (for ZnSnO3) and 47, 22 nm (for Zn2SnO4), respectively. The estimated direct bandgap values for the ZnSnO3 and Zn2SnO4 were found to be 4.21 eV and 4.12 eV, respectively. The ac conductivity values at room temperature (at 10 kHz) for the ZnSnO3 and Zn2SnO4 samples were 8.02 * 10-8 Omega-1 cm-1 and 6.77 * 10-8 Omega-1 cm-1, respectively. The relative permittivity was found to increase with increase in temperature, the room temperature values being 14.24 and 25.22 for the samples ZnSnO3 and Zn2SnO4, respectively. Both the samples, i.e., ZnSnO3 and Zn2SnO4, exhibited low values of loss tangent up to 300 K, the room temperature values being 0.89 and 0.72, respectively. A dye-sensitized solar cell has been fabricated using the optimized sample of zinc stannate photo-anode, i.e., Zn2SnO4. The cyclic voltammetry revealed oxidation and reduction around 0.40 V (current density ~ 11.1 mA/cm2) and 0.57 V (current density- 11.7 mA/cm2) for Zn2SnO4 photo-anode in presence of light. PMID- 27228103 TI - Civil alcohol policy in Muslim majority countries: need for global tools, expert support and local partnerships. PMID- 27228104 TI - Time lapse microscopy is useful for elective single-embryo transfer. AB - The aim of our study was to evaluate time lapse microscopy (TLM) as a selection tool for single-embryo transfer (SET) on day 5, blastocyst stage. An observational cohort study was conducted. Patients who had SET were compared to patients who had double embryo transfer (DET). A total of 108 patients were included in analysis, 83 had SET, and 25 underwent DET. Embryos were incubated and evaluated using TLM. The pregnancy rates were similar between the groups (42.2% in SET and 48.0% in DET). However, the multiple pregnancy rate was significantly higher in the DET group compared to the SET group (41.7% versus 2.9%, respectively; p < 0.001). This study concludes that SET with TLM do not decrease pregnancy rates compared to DET. However, transfers of two embryos increase the rate of multiple pregnancies. PMID- 27228105 TI - Does trust matter more in virtual teams? A meta-analysis of trust and team effectiveness considering virtuality and documentation as moderators. AB - Team trust has often been discussed both as requirement and as challenge for team effectiveness, particularly in virtual teams. However, primary studies on the relationship between trust and team effectiveness have provided mixed findings. The current review summarizes existing studies on team trust and team effectiveness based on meta-analytic methodology. In general, we assumed team trust to facilitate coordination and cooperation in teams, and therefore to be positively related with team effectiveness. Moreover, team virtuality and documentation of interactions were considered as moderators of this relationship because they should affect perceived risks during teamwork. While team virtuality should increase, documentation of interaction should decrease the relationship between team trust and team effectiveness. Findings from 52 studies with 54 independent samples (representing 12,615 individuals in 1,850 teams) confirmed our assumptions. In addition to the positive overall relationship between team trust and team effectiveness criteria (rho = .33), the relationship between team trust and team performance was stronger in virtual teams (rho = .33) as compared to face-to-face teams (rho = .22), and weaker when team interactions were documented (rho = .20) as compared to no such documentation (rho = .29). Thus, documenting team interactions seems to be a viable complement to trust-building activities, particularly in virtual teams. (PsycINFO Database Record PMID- 27228106 TI - Bioinspired Multifunctional Paper-Based rGO Composites for Solar-Driven Clean Water Generation. AB - Reusing polluted water through various decontamination techniques has appeared as one of the most practical approaches to address the global shortage of clean water. Rather than relying on single decontamination mechanism, herein we report the preparation and utilization of paper-based composites for multifunctional solar-driven clean water generation that is inspired by the multiple water purification approaches in biological systems. The reduced graphene oxide (rGO) sheets within such composites can efficiently remove organic contaminants through physical adsorption mechanism. Under solar irradiation, the floating rGO composites can instantly generate localized heating, which not only can directly generate clean water through distillation mechanism but also significantly enhance adsorption removal performance with the assistance of upward vapor flow. Such porous-structured paper-based composites allow for facile incorporation of photocatalysts to regenerate clean water out of contaminated water with combined adsorption, photodegradation, and interfacial heat-assisted distillation mechanisms. Within a homemade all-in-one water treatment device, the practical applicability of the composites for multifunctional clean water generation has been demonstrated. PMID- 27228107 TI - Chronic obstructive pulmonary disease. PMID- 27228108 TI - Drug-Induced Liver Failure Requiring Liver Transplant: Report and Review of the Role of Albendazole in Managing Echinococcal Infection. AB - Albendazole is often used as adjunctive therapy in the treatment of echinococcal infection to reduce cyst viability before and prevent recurrence after surgical treatment. In this report, we present a 38-year-old Iraqi woman with Echinococcus initiated on albendazole therapy who developed acute liver failure 6 weeks after treatment. Investigation for common viral and autoimmune causes of liver injury was unremarkable, and a liver biopsy revealed changes consistent with severe, drug-induced liver injury. Despite discontinuation of albendazole, liver function continued to deteriorate, prompting rescue with an orthotopic liver transplant. Often used perioperatively in the management of Echinococcus infection, albendazole can induce idiosyncratic severe liver injury, mandating close monitoring for hepatotoxicity. PMID- 27228109 TI - Isolation and Classification of Fungal Whitefly Entomopathogens from Soils of Qinghai-Tibet Plateau and Gansu Corridor in China. AB - Qinghai-Tibet Plateau and Gansu Corridor of China with distinct geographic and climatic conditions are remote and less disturbed by humans, in which are likely to find some new strains of fungal entomopathogens against B-biotype whiteflies that is a very important invading pest worldwide. In this research, nineteen strains among six species of entomogenous fungi were isolated from the soil samples collected from 32 locations in Qinghai-Tibet Plateau and Gansu Corridor. From the data of isolation rates, it was indicated that the good biodiversity of entomogenous fungi was found in the soil covered good vegetations. On the contrary, no strains were isolated from the desert areas. In addition, the dominant species, Isaria fumosorosea and Metarhizium anisopliae var. anisopliae in the Qinghai-Tibet Plateau are different from the strains of other places based on ITS genetic homology analysis. It was verified that the Qinghai-Tibet Plateau area was less disturbed by human, and the fungi in this place exchanged less compared with other regional species. All of these strains showed the pathogenicity against the B-biotype whitefly with the mortality of more than 30%. However, a few strains of Paecilomyces lilacinus, Lecanicillium psalliotae, Aspergillus ustus, I. fumosorosea and M. anisopliae var. anisopliae had better virulence with LC50s of 0.36-26.44*10(6) spores/mL on post-treatment day 6-7. Especially, the L. psalliotae strain LpTS01 was the greatest virulence with LC50 of 0.36*10(6)spores/mL and LT50 of 4.23d. Our research thus presents some new insights to discover new entomopathogenic fungal strains used for B-biotype whitefly biocontrol. PMID- 27228110 TI - Association Between Occlusion Therapy and Optotype Visual Acuity in Children Using Data From the Infant Aphakia Treatment Study: A Secondary Analysis of a Randomized Clinical Trial. AB - IMPORTANCE: Patching has been a mainstay in treating unilateral congenital cataract. However, its efficacy has not been rigorously assessed. OBJECTIVE: To examine the association between patching and visual acuity in a cohort of children treated for unilateral congenital cataract. DESIGN, SETTING, AND PARTICIPANTS: This study was a secondary analysis of a randomized clinical trial (Infant Aphakia Treatment Study) of infants born from August 1, 2004, through December 31, 2008, who were treated with 1 of 2 treatments for unilateral congenital cataract and followed up to 5 years of age. Data analysis was performed from March 1, 2013, to March 1, 2016. INTERVENTIONS: Cataract extraction and randomization to receipt of an intraocular lens vs being left aphakic for the first 5 years of life. MAIN OUTCOMES AND MEASURES: Caregivers reported patching in the previous 48 hours in quarterly semistructured telephone interviews. The mean number of hours of patching per day was calculated from surgery to the first birthday (n = 92) and between 12 and 48 months of age (n = 102). Monocular optotype acuity was assessed at 41/2 years of age by a traveling examiner using the Aphakia Treatment Study HOTV protocol. RESULTS: The Infant Aphakia Treatment Study enrolled 114 children; 57 were randomized to each treatment group. At 41/2 years of age, optotype visual acuity was assessed in 112 children. The current analyses exclude an additional 3 children (2 who had adverse events that limited visual potential and 1 who had Stickler syndrome), leaving 109 total children analyzed (59 female [54.1%] and 92 white [84.4%]). Caregivers reported patching their children a mean (SD) of 3.73 (1.47) hours per day in the first year of life and 3.43 (2.04) hours per day thereafter. An association between reported patching and treatment was not identified (mean difference in first year, -0.29 hours per day; 95% CI, -0.90 to 0.33 hours per day; mean difference between 12 and 48 months of age, -0.40 hours per day; 95% CI, -1.20 to 0.40 hours per day). Visual acuity was associated with reported hours of patching in the first year of life (r = -0.32; 95% CI, -0.49 to -0.13) and between 12 and 48 months of age (r = -0.36; 95% CI, -0.52 to -0.18). However, patching accounted for less than 15% of the variance in logMAR acuity at 41/2 years of age. CONCLUSIONS AND RELEVANCE: These results support the association of occlusion throughout the preschool years with improved visual acuity in infants treated for unilateral congenital cataract. However, similar visual outcomes were achieved with varying amounts of patching. These conclusions should be interpreted in the context of limitations related to generalizability from incomplete data collected in a clinical trial. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00212134. PMID- 27228111 TI - Fluorogenic Substrates for Visualizing Acidic Organelle Enzyme Activities. AB - Lysosomes are acidic cytoplasmic organelles that are present in all nucleated mammalian cells and are involved in a variety of cellular processes including repair of the plasma membrane, defense against pathogens, cholesterol homeostasis, bone remodeling, metabolism, apoptosis and cell signaling. Defects in lysosomal enzyme activity have been associated with a variety of neurological diseases including Parkinson's Disease, Lysosomal Storage Diseases, Alzheimer's disease and Huntington's disease. Fluorogenic lysosomal staining probes were synthesized for labeling lysosomes and other acidic organelles in a live-cell format and were shown to be capable of monitoring lysosomal metabolic activity. The new targeted substrates were prepared from fluorescent dyes having a low pKa value for optimum fluorescence at the lower physiological pH found in lysosomes. They were modified to contain targeting groups to direct their accumulation in lysosomes as well as enzyme-cleavable functions for monitoring specific enzyme activities using a live-cell staining format. Application to the staining of cells derived from blood and skin samples of patients with Metachromatic Leukodystrophy, Krabbe and Gaucher Diseases as well as healthy human fibroblast and leukocyte control cells exhibited localization to the lysosome when compared with known lysosomal stain LysoTracker(r) Red DND-99 as well as with anti-LAMP1 Antibody staining. When cell metabolism was inhibited with chloroquine, staining with an esterase substrate was reduced, demonstrating that the substrates can be used to measure cell metabolism. When applied to diseased cells, the intensity of staining was reflective of lysosomal enzyme levels found in diseased cells. Substrates specific to the enzyme deficiencies in Gaucher or Krabbe disease patient cell lines exhibited reduced staining compared to that in non-diseased cells. The new lysosome-targeted fluorogenic substrates should be useful for research, diagnostics and monitoring the effect of secondary therapeutic agents on lysosomal enzyme activity in drug development for the lysosomal storage disorders and allied diseases. PMID- 27228112 TI - Immigration Stress and Alcohol Use Severity Among Recently Immigrated Hispanic Adults: Examining Moderating Effects of Gender, Immigration Status, and Social Support. AB - OBJECTIVE: Identifying and understanding determinants of alcohol use behavior among Hispanic immigrants is an increasingly significant public health concern. Although prior research has examined associations of cultural stressors with alcohol use among Hispanics, few studies have tested these associations among recent adult immigrants. As such, this study aimed to examine (a) the association of immigration stress on alcohol use severity among recently immigrated Hispanic adults (<= 1 year in the United States) and (b) the moderating effects of gender, immigration status, and social support. METHOD: A hierarchical multiple regression and moderation analyses were conducted on a sample of 527 participants in South Florida. RESULTS: Results indicated that, after controlling for demographic variables, preimmigration drinking behavior, and dimensions of social support, the association of higher immigration stress with higher alcohol use severity was statistically significant. Moderation analyses indicated that immigration stress had a statistically significant association with alcohol use severity among men, but not women. Also, dimensions of social support consistently reduced the deleterious effect of immigration stress on alcohol use severity. CONCLUSION: This study adds to the scarce literature on cultural stressors and alcohol use among recent Hispanic immigrants. Findings suggest that it may be important to design gender-specific interventions and that increasing levels of social support may offset the effects of immigration stress on alcohol use. PMID- 27228114 TI - The Free Energy Landscape of GABA Binding to a Pentameric Ligand-Gated Ion Channel and Its Disruption by Mutations. AB - Pentameric ligand-gated ion channels (pLGICs) of the Cys-loop superfamily are important neuroreceptors that mediate fast synaptic transmission. They are activated by the binding of a neurotransmitter, but the details of this process are still not fully understood. As a prototypical pLGIC, here we choose the insect resistance to dieldrin (RDL) receptor involved in resistance to insecticides and investigate the binding of the neurotransmitter GABA to its extracellular domain at the atomistic level. We achieve this by means of MU-sec funnel-metadynamics simulations, which efficiently enhance the sampling of bound and unbound states by using a funnel-shaped restraining potential to limit the exploration in the solvent. We reveal the sequence of events in the binding process from the capture of GABA from the solvent to its pinning between the charged residues Arg111 and Glu204 in the binding pocket. We characterize the associated free energy landscapes in the wild-type RDL receptor and in two mutant forms, where the key residues Arg111 and Glu204 are mutated to Ala. Experimentally these mutations produce nonfunctional channels, which is reflected in the reduced ligand binding affinities due to the loss of essential interactions. We also analyze the dynamical behavior of the crucial loop C, whose opening allows the access of GABA to the binding site and closure locks the ligand into the protein. The RDL receptor shares structural and functional features with other pLGICs; hence, our work outlines a valuable protocol to study the binding of ligands to pLGICs beyond conventional docking and molecular dynamics techniques. PMID- 27228113 TI - Temporal Expression of Peripheral Blood Leukocyte Biomarkers in a Macaca fascicularis Infection Model of Tuberculosis; Comparison with Human Datasets and Analysis with Parametric/Non-parametric Tools for Improved Diagnostic Biomarker Identification. AB - A temporal study of gene expression in peripheral blood leukocytes (PBLs) from a Mycobacterium tuberculosis primary, pulmonary challenge model Macaca fascicularis has been conducted. PBL samples were taken prior to challenge and at one, two, four and six weeks post-challenge and labelled, purified RNAs hybridised to Operon Human Genome AROS V4.0 slides. Data analyses revealed a large number of differentially regulated gene entities, which exhibited temporal profiles of expression across the time course study. Further data refinements identified groups of key markers showing group-specific expression patterns, with a substantial reprogramming event evident at the four to six week interval. Selected statistically-significant gene entities from this study and other immune and apoptotic markers were validated using qPCR, which confirmed many of the results obtained using microarray hybridisation. These showed evidence of a step change in gene expression from an 'early' FOS-associated response, to a 'late' predominantly type I interferon-driven response, with coincident reduction of expression of other markers. Loss of T-cell-associate marker expression was observed in responsive animals, with concordant elevation of markers which may be associated with a myeloid suppressor cell phenotype e.g. CD163. The animals in the study were of different lineages and these Chinese and Mauritian cynomolgous macaque lines showed clear evidence of differing susceptibilities to Tuberculosis challenge. We determined a number of key differences in response profiles between the groups, particularly in expression of T-cell and apoptotic makers, amongst others. These have provided interesting insights into innate susceptibility related to different host 'phenotypes. Using a combination of parametric and non parametric artificial neural network analyses we have identified key genes and regulatory pathways which may be important in early and adaptive responses to TB. Using comparisons between data outputs of each analytical pipeline and comparisons with previously published Human TB datasets, we have delineated a subset of gene entities which may be of use for biomarker diagnostic test development. PMID- 27228115 TI - Vitamin D in Reproductive Health and Pregnancy. AB - Vitamin D has been primarily known for its role in maintaining calcium and phosphorus homeostasis and promoting healthy bone mineralization. Emerging evidence suggests that vitamin D may have a plethora of other functions including cardiometabolic and immunological effects and a role in modulating human reproductive processes. Despite this, vitamin D deficiency (VDD) remains highly prevalent worldwide due to the limited availability of foods that are naturally high or fortified with vitamin D, increased sun avoidance behaviors and use of sunscreen due to fear of skin cancer, and increased sedentary indoor lifestyles, especially among those of reproductive age. This review examines current and emerging evidence for the role of vitamin D in reproductive health including in fertility, conception, and pregnancy outcomes, and outlines areas for future research. We found that existing evidence is based primarily on animal models and in vitro studies with some recent support from observational studies in humans. While these studies indicate that VDD may be a risk factor for adverse fertility and pregnancy outcomes, there is insufficient evidence to establish causality. Future efforts to clarify the benefits of vitamin D in reproductive health may bring about practical, simple, and cost-effective means of improving fertility and pregnancy outcomes. PMID- 27228116 TI - Effects of Atomoxetine in Individuals with Attention-Deficit/Hyperactivity Disorder and Low-Functioning Autism Spectrum Disorder. AB - OBJECTIVES: This naturalistic, retrospective study investigated the effects of atomoxetine (ATX) on attention-deficit/hyperactivity disorder (ADHD) symptoms and autistic features in children with autism spectrum disorders (ASDs) and intellectual disability (ID). METHODS: Participants (n = 37, age range 6-17 years, mean: 10.16 +/- 3.60) were assessed at baseline, 4th and 12th weeks using Clinical Global Impressions (CGI) scales, DSM-IV-based ADHD-rating scale (ADHD RS), and amended Turkish version of Aberrant Behavior Checklist (ABC). The primary outcome measure was a treatment response defined by a CGI-improvement score of 1 or 2 together with a decrease of at least 25% in the parent-rated ADHD RS total score at the end of 12th week. RESULTS: Five patients (13.5%) stopped medication at 4 weeks due to ineffectivity (2) and intolerable side effects (increased motor activity and talkativeness [n = 1], irritability [n = 2], temper outbursts [n = 2], and increased blood pressure [n = 1]). Sixteen patients (43.2%) were judged to be responders according to primary outcome measure. Improvement rate on CGI scale was 48.8%. On ADHD-RS, there were significant reductions between baseline and 4th week and between baseline and 12th week in both hyperactivity and inattention, and between baseline and 12th week in impulsivity scores. Decrease was significant in hyperactivity and social withdrawal subscales of the parent-reported ABC. Responders based on primary outcome measure were not significantly different from nonresponders in terms of sociodemographic features or clinical parameters, including intellectual, language, autism symptom, and ADHD symptom levels. CONCLUSION: In this chart review, ATX appears to be safe and effective for social withdrawal and ADHD symptoms in children with ASD and ID. PMID- 27228117 TI - MYC cis-Elements in PsMPT Promoter Is Involved in Chilling Response of Paeonia suffruticosa. AB - The MPT transports Pi to synthesize ATP. PsMPT, a chilling-induced gene, was previously reported to promote energy metabolism during bud dormancy release in tree peony. In this study, the regulatory elements of PsMPT promoter involved in chilling response were further analyzed. The PsMPT transcript was detected in different tree peony tissues and was highly expressed in the flower organs, including petal, stigma and stamen. An 1174 bp of the PsMPT promoter was isolated by TAIL-PCR, and the PsMPT promoter::GUS transgenic Arabidopsis was generated and analyzed. GUS staining and qPCR showed that the promoter was active in mainly the flower stigma and stamen. Moreover, it was found that the promoter activity was enhanced by chilling, NaCl, GA, ACC and NAA, but inhibited by ABA, mannitol and PEG. In transgenic plants harboring 421 bp of the PsMPT promoter, the GUS gene expression and the activity were significantly increased by chilling treatment. When the fragment from -421 to -408 containing a MYC cis-element was deleted, the chilling response could not be observed. Further mutation analysis confirmed that the MYC element was one of the key motifs responding to chilling in the PsMPT promoter. The present study provides useful information for further investigation of the regulatory mechanism of PsMPT during the endo-dormancy release. PMID- 27228118 TI - An Individual Differences Approach to Temporal Integration and Order Reversals in the Attentional Blink Task. AB - BACKGROUND: The reduced ability to identify a second target when it is presented in close temporal succession of a first target is called the attentional blink (AB). Studies have shown large individual differences in AB task performance, where lower task performance has been associated with more reversed order reports of both targets if these were presented in direct succession. In order to study the suggestion that reversed order reports reflect loss of temporal information, in the current study, we investigated whether individuals with a larger AB have a higher tendency to temporally integrate both targets into one visual event by using an AB paradigm containing symbol target stimuli. METHODOLOGY/PRINCIPAL FINDINGS: Indeed, we found a positive relation between the tendency to temporally integrate information and individual AB magnitude. In contrast to earlier work, we found no relation between order reversals and individual AB magnitude. The occurrence of temporal integration was negatively related to the number of order reversals, indicating that individuals either integrated or separated and reversed information. CONCLUSION: We conclude that individuals with better AB task performance use a shorter time window to integrate information, and therefore have higher preservation of temporal information. Furthermore, order reversals observed in paradigms with alphanumeric targets indeed seem to at least partially reflect temporal integration of both targets. Given the negative relation between temporal integration and 'true' order reversals observed with the current symbolic target set, these two behavioral outcomes seem to be two sides of the same coin. PMID- 27228119 TI - Covariation Analysis of Serumal and Urinary Metabolites Suggests Aberrant Glycine and Fatty Acid Metabolism in Chronic Hepatitis B. AB - BACKGROUND: Chronic hepatitis b (CHB) is one of the most serious viral diseases threatening human health by putting patients at lifelong risk of cirrhosis and hepatocellular carcinoma (HCC). Although some proofs of altered metabolites in CHB were accumulated, its metabolic mechanism remains poorly understood. Analyzing covariations between metabolites may provide new hints toward underlying metabolic pathogenesis in CHB patients. METHODS: The present study collected paired urine and serum samples from the same subjects including 145 CHB and 23 healthy controls. A large-scale analysis of metabolites' covariation within and across biofluids was systematically done to explore the underlying biological evidences for reprogrammed metabolism in CHB. Randomization and relative ranking difference were introduced to reduce bias caused by different sample size. More importantly, functional indication was interpreted by mapping differentially changed covariations to known metabolic pathways. RESULTS: Our results suggested reprogrammed pathways related to glycine metabolism, fatty acids metabolism and TCA cycle in CHB patients. With further improvement, the covariation analysis combined with network association study would pave new alternative way to interpret functional clues in clinical multi-omics data. PMID- 27228120 TI - Worry Among Mexican American Caregivers of Community-Dwelling Elders. AB - This mixed methods, multi-site, National Institute of Nursing Research (NINR) funded, interdisciplinary, descriptive study aimed to identify expressions of worry in qualitative data obtained from caregiving Mexican American (MA) families assisting older adults. The purpose of this portion of the inquiry was to determine how worry is expressed, what happens to caregivers when they worry, and what adaptive strategies they used. We examined semi-structured interviews completed during six in-home visits with 116 caregivers. We identified 366 worry quotations from 639 primary documents in ATLAS.ti, entered them into matrices, and organized findings under thematic statements. Caregivers expressed cultural and contextual worries, worried about transitions and turning points in care, and identified adaptive strategies. Despite these strategies, worry persisted. Constant worry may be an allied, important aspect of caregiver burden. We need additional longitudinal research to better understand the experience of MA caregivers for older adults and to provide empirically supported interventions, programs, and services that reduce worry. PMID- 27228121 TI - Building and Validating Complex Models of Breast Cancer Risk. PMID- 27228122 TI - Longitudinal Analysis of the Intestinal Microbiota in Persistently Stunted Young Children in South India. AB - Stunting or reduced linear growth is very prevalent in low-income countries. Recent studies have demonstrated a causal relationship between alterations in the gut microbiome and moderate or severe acute malnutrition in children in these countries. However, there have been no primary longitudinal studies comparing the intestinal microbiota of persistently stunted children to that of non-stunted children in the same community. In this pilot study, we characterized gut microbial community composition and diversity of the fecal microbiota of 10 children with low birth weight and persistent stunting (cases) and 10 children with normal birth weight and no stunting (controls) from a birth cohort every 3 months up to 2 years of age in a slum community in south India. There was an increase in diversity indices (P <0.0001) with increasing age in all children. However, there were no differences in diversity indices or in the rates of their increase with increasing age between cases and controls. The percent relative abundance of the Bacteroidetes phylum was higher in stunted compared to control children at 12 months of age (P = 0.043). There was an increase in the relative abundance of this phylum with increasing age in all children (P = 0.0380) with no difference in the rate of increase between cases and controls. There was a decrease in the relative abundance of Proteobacteria (P = 0.0004) and Actinobacteria (P = 0.0489) with increasing age in cases. The microbiota of control children was enriched in probiotic species Bifidobacterium longum and Lactobacillus mucosae, whereas that of stunted children was enriched in inflammogenic taxa including those in the Desulfovibrio genus and Campylobacterales order. Larger, longitudinal studies on the compositional and functional maturation of the microbiome in children are needed. PMID- 27228123 TI - Bronchiolitis: Analysis of 10 consecutive epidemic seasons. AB - Bronchiolitis is the leading cause of hospitalization in infants under 12 months. Our aims were to analyze epidemiological characteristics of infants with bronchiolitis over 10 consecutive seasons and to evaluate whether there are any clinical differences between infants hospitalized for bronchiolitis during epidemic peak months and infants in non-peak months. We enrolled consecutive enrolled 723 previously healthy term infants hospitalized at the Paediatric Emergency Department, "Sapienza" University of Rome over the period 2004-2014. Fourteen respiratory viruses were detected from nasopharyngeal aspirates by molecular methods. Clinical and demographic data were extracted from clinical charts. Viruses were detected in 351 infants (48.5%): RSV in 234 (32.4%), RV in 44 (6.1%), hBoV in 11 (1.5%), hMPV in 12 (1.6%), co-infections in 39 (5.4%), and other viruses in 11 (1.5%). Analyzing the 10 epidemic seasons, we found higher incidence for bronchiolitis every 4 years with a peak during the months December January. Infants hospitalized during peak months had lower family history for asthma (P = 0.003), more smoking mothers during pregnancy (P = 0.036), were slightly higher breastfed (0.056), had lower number of blood eosinophils (P = 0.015) and had a higher clinical severity score (P = 0.017). RSV was detected mostly during peak months, while RV was equally distributed during the seasons. We found some variations in bronchiolitis incidence during epidemics, and discriminative characteristics in infants hospitalized for bronchiolitis during peak months and in non-peak months, that might reflect two different populations of children. Pediatr Pulmonol. 2016;51:1330-1335. (c) 2016 Wiley Periodicals, Inc. PMID- 27228124 TI - Genetic polymorphisms and the adequacy of brain stimulation: state of the art. AB - INTRODUCTION: Heterogeneity of therapeutic response to brain stimulation techniques has inspired scientists to uncover the secrets to success or failure of these projects. Genetic polymorphisms are one of the major causes of this heterogeneity. AREAS COVERED: More than twenty genetic variants within more than ten genes (e.g. BDNF, COMT, DRD2, TRPV1, 5-HT1A, 5-HHT, P2RX7, VEGF, TPH1, TPH2, ACE, APOE, GNB3, NET, NMDA receptors, and RGS4) have been investigated, among which the BDNF gene and its polymorphism, Val66Met, is the best documented variant. We review the genotypic combinations, which are reported to interact with the work of brain stimulation, of which the DRD2 C957T polymorphism is the most prominent type. Finally, implications of transcranial magnetic stimulation in deciphering the interaction between genetic background (e.g. SCN1A and 5-HTT) and drugs (e.g. carbamazepine and citalopram) at the cortical excitability level is explained. Expert commentary: Studies are ongoing to find missing factors responsible for heterogeneity of response to brain stimulation techniques. Further knowledge about genetic factors affecting the therapeutic response to brain stimulation techniques might provide helpful guidelines for choosing ideal candidates for treatment. PMID- 27228125 TI - Low-Level Laser Therapy (780 nm) on VEGF Modulation at Partially Injured Achilles Tendon. AB - OBJECTIVE: The aim of this study was to analyze the modulatory effects of near infrared (780 nm) low-level laser therapy (LLLT) on the presence of the vascular endothelial growth factor (VEGF) in the partially injured Achilles tendons of rats. BACKGROUND: LLLT stimulates the healing process for Achilles tendon injuries, although the extent of the modulatory effect of LLLT on the VEGF levels found in the injured tendons remains unclear. METHODS: Sixty-five male Wistar rats were distributed in the following seven groups: LASER 1, 3, and 7 (10 partially injured Achilles tendons in each group, which were treated with LLLT for 1, 3, and 7 days, respectively); Sham 1, 3, and 7 (same injury, with simulated LLLT); Control group containing the five remaining animals and in which no procedures were performed. LLLT was applied once a day for 10 sec, with a mean power of 70 mW and fluency of 17.5 J/cm(2). After euthanasia, all of the Achilles tendons were surgically removed and the VEGF levels were analyzed using immunohistochemistry. RESULTS: The VEGF levels remained close to normal (p > 0.05) when comparing the experimental groups (LASER and Sham: 1, 3, and 7) with the Control group. CONCLUSION: LLLT did not stimulate the expression of VEGF in the treated Achilles tendons. PMID- 27228126 TI - Genetic Characterization and Classification of Human and Animal Sapoviruses. AB - Sapoviruses (SaVs) are enteric caliciviruses that have been detected in multiple mammalian species, including humans, pigs, mink, dogs, sea lions, chimpanzees, and rats. They show a high level of diversity. A SaV genome commonly encodes seven nonstructural proteins (NSs), including the RNA polymerase protein NS7, and two structural proteins (VP1 and VP2). We classified human and animal SaVs into 15 genogroups (G) based on available VP1 sequences, including three newly characterized genomes from this study. We sequenced the full length genomes of one new genogroup V (GV), one GVII and one GVIII porcine SaV using long range RT PCR including newly designed forward primers located in the conserved motifs of the putative NS3, and also 5' RACE methods. We also determined the 5'- and 3' ends of sea lion GV SaV and canine GXIII SaV. Although the complete genomic sequences of GIX-GXII, and GXV SaVs are unavailable, common features of SaV genomes include: 1) "GTG" at the 5'-end of the genome, and a short (9~14 nt) 5' untranslated region; and 2) the first five amino acids (M [A/V] S [K/R] P) of the putative NS1 and the five amino acids (FEMEG) surrounding the putative cleavage site between NS7 and VP1 were conserved among the chimpanzee, two of five genogroups of pig (GV and GVIII), sea lion, canine, and human SaVs. In contrast, these two amino acid motifs were clearly different in three genogroups of porcine (GIII, GVI and GVII), and bat SaVs. Our results suggest that several animal SaVs have genetic similarities to human SaVs. However, the ability of SaVs to be transmitted between humans and animals is uncertain. PMID- 27228127 TI - Comprehensive RNA-Seq Analysis on the Regulation of Tomato Ripening by Exogenous Auxin. AB - Auxin has been shown to modulate the fruit ripening process. However, the molecular mechanisms underlying auxin regulation of fruit ripening are still not clear. Illumina RNA sequencing was performed on mature green cherry tomato fruit 1 and 7 days after auxin treatment, with untreated fruit as a control. The results showed that exogenous auxin maintained system 1 ethylene synthesis and delayed the onset of system 2 ethylene synthesis and the ripening process. At the molecular level, genes associated with stress resistance were significantly up regulated, but genes related to carotenoid metabolism, cell degradation and energy metabolism were strongly down-regulated by exogenous auxin. Furthermore, genes encoding DNA demethylases were inhibited by auxin, whereas genes encoding cytosine-5 DNA methyltransferases were induced, which contributed to the maintenance of high methylation levels in the nucleus and thus inhibited the ripening process. Additionally, exogenous auxin altered the expression patterns of ethylene and auxin signaling-related genes that were induced or repressed in the normal ripening process, suggesting significant crosstalk between these two hormones during tomato ripening. The present work is the first comprehensive transcriptome analysis of auxin-treated tomato fruit during ripening. Our results provide comprehensive insights into the effects of auxin on the tomato ripening process and the mechanism of crosstalk between auxin and ethylene. PMID- 27228129 TI - QuickStats: Age-Adjusted Prevalence*(,)(?) of Adults Aged >=18 Years with Hypertension(S) Who Are Aware They Have Hypertension,( ) by Sex and Race/Ethnicity - National Health and Nutrition Examination Survey, United States, 2011-2014. AB - For the period 2011-2014, 83.3% of adults aged >=18 years with hypertension were aware of their hypertension status. Overall, a smaller percentage of non-Hispanic Asian adults (74.0%) with hypertension were aware of their status compared with non-Hispanic white (83.9%), non-Hispanic black (85.9%), and Hispanic adults (80.5%) with hypertension. This pattern generally was found for both men and women, with the exception of non-Hispanic Asian men and Hispanic men, where the difference was not significant. A larger percentage of non-Hispanic black and Hispanic women were aware of their hypertension condition compared with non Hispanic black and Hispanic men, respectively. PMID- 27228128 TI - Squamous Metaplasia Is Increased in the Bronchial Epithelium of Smokers with Chronic Obstructive Pulmonary Disease. AB - AIMS: To quantify the extent of squamous metaplasia in bronchial biopsies and relate it to the presence of chronic obstructive pulmonary disease (COPD), a smoking-related pathology. METHODS: Bronchial biopsies (n = 15 in each group) from smokers with COPD GOLD stage1 and GOLD stage2, smokers without COPD and healthy non-smokers were stained immunohistochemically with a panel of antibodies that facilitated the identification of pseudostratified epithelium and distinction of squamous metaplasia and squamous epithelium from tangentially cut epithelium. The percentage length of each of these epithelial phenotypes was measured as a percent of total epithelial length using computerised image analysis. Sections were also stained for carcinoembryonic antigen and p53, early markers of carcinogenesis, and Ki67, and the percentage epithelial expression measured. RESULTS: The extent of squamous metaplasia was significantly increased in both COPD1 and COPD2 compared to healthy smokers and healthy non-smokers. The amount of fully differentiated squamous epithelium was also increased in COPD1 and COPD2 compared to healthy non-smokers, as was the expression of carcinoembryonic antigen. These features correlated with one other. CONCLUSION: In subjects with COPD there is a loss of pseudostratified epithelium accompanied by an increase in squamous metaplasia with transition into a fully squamous epithelium and expression of early markers of carcinogenesis. PMID- 27228130 TI - Disparate Strain Dependent Thermal Conductivity of Two-dimensional Penta Structures. AB - Two-dimensional (2D) carbon allotrope called penta-graphene was recently proposed from first-principles calculations and various similar penta-structures emerged. Despite significant effort having been dedicated to electronic structures and mechanical properties, little research has been focused on thermal transport in penta-structures. Motivated by this, we performed a comparative study of thermal transport properties of three representative pentagonal structures, namely penta graphene, penta-SiC2, and penta-SiN2, by solving the phonon Boltzmann transport equation with interatomic force constants extracted from first-principles calculations. Unexpectedly, the thermal conductivity of the three penta structures exhibits diverse strain dependence, despite their very similar geometry structures. While the thermal conductivity of penta-graphene exhibits standard monotonic reduction by stretching, penta-SiC2 possesses an unusual nonmonotonic up-and-down behavior. More interestingly, the thermal conductivity of penta-SiN2 has 1 order of magnitude enhancement due to the strain induced buckled to planar structure transition. The mechanism governing the diverse strain dependence is identified as the competition between the change of phonon group velocity and phonon lifetime of acoustic phonon modes with combined effect from the unique structure transition for penta-SiN2. The disparate thermal transport behavior is further correlated to the fundamentally different bonding nature in the atomic structures with solid evidence from the distribution of deformation charge density and more in-depth molecular orbital analysis. The reported giant and robust tunability of thermal conductivity may inspire intensive research on other derivatives of penta-structures as potential materials for emerging nanoelectronic devices. The fundamental physics understood from this study also solidifies the strategy to engineer thermal transport properties of broad 2D materials by simple mechanical strain. PMID- 27228131 TI - Genetic Analyses of the Internal Transcribed Spacer Sequences Suggest Introgression and Duplication in the Medicinal Mushroom Agaricus subrufescens. AB - The internal transcribed spacer (ITS) region of the nuclear ribosomal RNA gene cluster is widely used in fungal taxonomy and phylogeographic studies. The medicinal and edible mushroom Agaricus subrufescens has a worldwide distribution with a high level of polymorphism in the ITS region. A previous analysis suggested notable ITS sequence heterogeneity within the wild French isolate CA487. The objective of this study was to investigate the pattern and potential mechanism of ITS sequence heterogeneity within this strain. Using PCR, cloning, and sequencing, we identified three types of ITS sequences, A, B, and C with a balanced distribution, which differed from each other at 13 polymorphic positions. The phylogenetic comparisons with samples from different continents revealed that the type C sequence was similar to those found in Oceanian and Asian specimens of A. subrufescens while types A and B sequences were close to those found in the Americas or in Europe. We further investigated the inheritance of these three ITS sequence types by analyzing their distribution among single spore isolates from CA487. In this analysis, three co-dominant markers were used firstly to distinguish the homokaryotic offspring from the heterokaryotic offspring. The homokaryotic offspring were then analyzed for their ITS types. Our genetic analyses revealed that types A and B were two alleles segregating at one locus ITSI, while type C was not allelic with types A and B but was located at another unlinked locus ITSII. Furthermore, type C was present in only one of the two constitutive haploid nuclei (n) of the heterokaryotic (n+n) parent CA487. These data suggest that there was a relatively recent introduction of the type C sequence and a duplication of the ITS locus in this strain. Whether other genes were also transferred and duplicated and their impacts on genome structure and stability remain to be investigated. PMID- 27228132 TI - Interplay of innate and adaptive immunity in metal-induced hypersensitivity. AB - Metal-induced hypersensitivity is driven by T cell sensitization to metal ions. Recent advances in our understanding of the complex interactions between innate and adaptive immunity have expanded our knowledge of the pathogenesis of these diseases. Metals activate the innate immune system through direct binding to pathogen recognition receptors, activation of the inflammasome, or the induction of cellular death and release of alarmins. Certain metals can serve as adjuvants, promoting dendritic cell activation and migration as well as antigen presentation to metal-specific T cells. These T cells can recognize metals as haptens or as altered MHC-peptide complexes. The ability of metals to create these neoantigens emphasizes the similarity between metal-induced hypersensitivity and autoimmunity. PMID- 27228133 TI - Isolation and Short-Term Persistence of Ehrlichia ewingii in Cell Culture. AB - Ehrlichia ewingii is the causative agent of human and canine granulocytic ehrlichiosis. Since its discovery in 1970, little work has been done to characterize the pathogen or study the transmission dynamics due to the inability to grow the agent in vitro. The aim of this study was to assess the suitability of multiple cell lines and media formulations for propagation of E. ewingii in cell culture. In this study, we present an overview of attempts to isolate E. ewingii from the buffy coat of goats naturally infected by Amblyomma americanum ticks, as well as a methodology for maintaining the pathogen for up to 16 weeks in culture. The most promising results were seen with HL-60 cells differentiated by the addition of 1.5% DMSO to the media and supplemented with 8 mM l-glutamine. Cultures were passaged multiple times, and fluorescence and morulae were observed by indirect fluorescent antibody test and Diff-Quik staining. It is our hope that this information will provide a foundation for future attempts to propagate and maintain E. ewingii in cell culture. PMID- 27228135 TI - Calcific aortic stenosis. PMID- 27228134 TI - On the relationship between epidemiology and policy. PMID- 27228136 TI - Preparation of Antispermidine/Spermine-N1-Acetyltransferase Monoclonal Antibodies. AB - Spermidine/spermine N1-acetyltransferase (SSAT) is a catabolic regulator of polyamines, ubiquitous molecules essential for cell proliferation and differentiation. Anti-SSAT antibodies (monoclonal antibodies [mAbs]) of high titer were prepared by immunizing BALB/c mice with multifocal intradermal injections and by fusing high-titer antibody-producing spleen cells with myeloma cells of SP2/0 origin. Four mAbs were selected for further characterization as classes and subclasses. Antibodies were produced by these three clones with high affinities ranging from 10(9) to 10(11) M(-1). These clones were found to be of the immunoglobulin IgG1 subclass with kappa light chain. They could recognize SSAT as determined by Western blot and immunohistochemistry. The specificity of one clone, 4H6, was studied by using the small interfering RNA (siRNA) on SSAT. 4H6 was also compared with the commercial antibody. The produced mAbs will be a useful tool for further investigation of SSAT functions in organisms. PMID- 27228139 TI - The relationship between blood pressure variability and Pooled Cohort Risk Assessment Equations 10-year cardiovascular risk score. AB - BACKGROUND: Recent attention has focused on the clinical significance of blood pressure variability (BPV) in explaining the adverse cardiovascular consequences of hypertension. We therefore analyze the impact of 24 h BPV on the development of future cardiovascular disease determined by The Pooled Cohort Risk Assessment Equations 10-year risk calculator. MATERIALS AND METHODS: We analyzed 250 adult patients, ages 40-80 years old. The ambulatory blood pressure monitoring was recorded automatically. We defined the mean blood pressure values, SD, and coefficient of variation (CV) of blood pressure on the basis of the recorded 24 h ambulatory blood pressure monitoring values as an indicator for BPV.Patients were divided into two groups according to their Pooled Cohort Risk Assessment Equations 10-year risk profile (<7.5 and >=7.5%). RESULTS: Besides the mean systolic blood pressure (SBP), parameters showing the BPV such as SD and CV of mean blood pressures were also significantly higher in patients with an elevated 10-year risk score compared with others. Only CV of SBP and pulse pressure showed a clear association with the 10-year risk in multivariate logistic regression analysis. The results suggested that each 1% increase in CV of SBP could lead to a 1.258-fold increase in The Pooled Cohort Risk Assessment Equations 10-year risk score. CONCLUSION: In the present study, we found that independent of baseline SBP, increased CV of SBP within 24 h was associated with increased cardiovascular risk, as assessed by The Pooled Cohort Risk Assessment Equations 10-year risk calculator. PMID- 27228140 TI - Activation of the HPA axis and depression of feeding behavior induced by restraint stress are separately regulated by PACAPergic neurotransmission in the mouse. AB - We measured serum CORT elevation in wild-type and PACAP-deficient C57BL/6N male mice after acute (1 h) or prolonged (2-3 h) daily restraint stress for 7 d. The PACAP dependence of CORT elevation was compared to that of stress-induced hypophagia. Daily restraint induced unhabituated peak CORT elevation, and hypophagia/weight loss, of similar magnitude for 1, 2, and 3 h of daily restraint, in wild-type mice. Peak CORT elevation, and hypophagia, were both attenuated in PACAP-deficient mice for 2 and 3 h daily restraint. Hypophagia induced by 1-h daily restraint was also greatly reduced in PACAP-deficient mice, however CORT elevation, both peak and during recovery from stress, was unaffected. Thus, hypothalamic PACAPergic neurotransmission appears to affect CRH gene transcription and peptide production, but not CRH release, in response to psychogenic stress. A single exposure to restraint sufficed to trigger hypophagia over the following 24 h. PACAP deficiency attenuated HPA axis response (CORT elevation) to prolonged (3 h) but not acute (1 h) single-exposure restraint stress, while hypophagia induced by either a single 1 h or a single 3 h restraint were both abolished in PACAP-deficient mice. These results suggest that PACAP's actions to promote suppression of food intake following an episode of psychogenic stress is unrelated to the release of CRH into the portal circulation to activate the pituitary-adrenal axis. Furthermore, demonstration of suppressed food intake after a single 1-h restraint stress provides a convenient assay for investigating the location of the synapses and circuits mediating the effects of PACAP on the behavioral sequelae of psychogenic stress. PMID- 27228141 TI - Insulin released from titanium discs with insulin coatings-Kinetics and biological activity. AB - Local administration of insulin from a titanium surface has been demonstrated to increase bone formation in non-diabetic rats. The authors hypothesized that insulin was released from the titanium surface and with preserved biological activity after the release. Thus, in the present in vitro study, human recombinant insulin was immobilized onto titanium discs, and the insulin release kinetics was evaluated using Electro-chemiluminescence immunoassay. Neutral Red uptake assay and mineralization assay were used to evaluate the biological effects of the released insulin on human osteoblast-like MG-63 cells. The results confirmed that insulin was released from titanium surfaces during a six-week period. Etching the disc prior to insulin coating, thickening of the insulin coating and incubation of the discs in serum-enriched cell culture medium increased the release. However, longer storage time decreased the release of insulin. Furthermore, the released insulin had retained its biological activity, as demonstrated by the significant increase in cell number and a stimulated mineralization process, upon exposure to released insulin. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1847-1854, 2017. PMID- 27228142 TI - Understanding the Structure of Reversible Coordination Polymers Based on Europium in Electrostatic Assemblies Using Time-Resolved Luminescence. AB - In situ characterization of the structure of reversible coordination polymers remains a challenge because of their dynamic and concentration-responsive nature. It is especially difficult to determine these structures in their self-assemblies where their degree of polymerization responds to the local concentration. In this paper, we report on the structure of reversible lanthanide coordination polymers in electrostatic assemblies using time-resolved luminescence (TRL) measurement. The reversible coordinating system is composed of the bifunctional ligand 1,11 bis(2,6-dicarboxypyridin-4-yloxy)-3,6,9-trioxaundecane (L2EO4) and europium ion Eu(3+). Upon mixing with the positively charged diblock copolymer poly(2 vinylpyridine)-b-poly(ethylene oxide) (P2VP41-b-PEO205), electrostatic polyion micelles are formed and the negatively charged L2EO4-Eu coordination complex simultaneously transforms into coordination "polymers" in the micellar core. By virtue of the water-sensitive luminescence of Eu(3+), we are able to obtain the structural information of the L2EO4-Eu coordination polymers before and after the formation of polyion micelles. Upon analyzing the fluorescence decay curves of Eu(3+) before and after micellization, the fraction of Eu(3+) fully coordinated with L2EO4 is found to increase from 32 to 83%, which verifies the occurrence of chain extension of the L2EO4-Eu coordination polymers in the micellar core. Our work provides a qualitative picture for the structure change of reversible coordination polymers, which allows us to look into these "invisible" structures. PMID- 27228143 TI - Hunting, pet trade, and forest size effects on population viability of a critically endangered Neotropical primate, Sapajus xanthosternos (Wied-Neuwied, 1826). AB - The yellow-breasted capuchin monkey (Sapajus xanthosternos) is one of the seven Brazilian primates that are currently threatened with extinction. Although the species is known to be threatened by habitat loss, hunting, and illegal pet trade, few data exist on how these threats influence its long-term population persistence. We conducted population viability analyses (PVAs) to estimate minimum viable populations of S. xanthosternos under 10 threat scenarios (i.e., varying hunting pressure and varying number of infants captured for the pet trade) for five forest fragments with different estimated carrying capacities (K). We also estimated the minimum forest fragment size required to sustain viable populations living under the same 10 threat scenarios, based on critical numbers of K obtained in sensitivity tests, below which the population would be unviable. Our PVAs suggests that hunting has a higher impact on population viability in comparison to threats from the pet trade. Annual losses of adult and young females from hunting had the most detrimental effect on population persistence under all forest fragment sizes. Such hunting pressure is not sustainable for populations living in areas <=3,460 ha, since these areas may not support populations of >=84 individuals. The seven largest of the 13 protected areas currently harboring capuchins should be effective at maintaining viable populations in the long term even under the greatest threat scenarios we modeled. Other large forest patches, mainly in the western part of the species distribution, are recommended as priority areas for protection to increase the chances of capuchins' survival for the long term. In addition, forest fragments of <=782.8 ha cannot maintain viable populations, even when there are no threats from hunting or from captures for the pet trade. Increased law enforcement is necessary to prevent the hunting and capture of capuchins, especially within larger forest fragments. Am. J. Primatol. 78:950-960, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27228144 TI - Venous thrombosis. PMID- 27228145 TI - Airtraq Laryngoscope Versus the Conventional Macintosh Laryngoscope During Pediatric Intubation Performed by Nurses: A Randomized Crossover Manikin Study With Three Airway Scenarios. AB - OBJECTIVES: We hypothesized that the Airtraq laryngoscope (Airtraq LLC, Bonita Springs, Fla) is beneficial for intubation of pediatric manikins while performing cardiopulmonary resuscitation (CPR). In the present study, we evaluated the effectiveness of the Macintosh (MAC) laryngoscope (HEINE Optotechnik, Munich, Germany) and Airtraq in 3 simulated CPR scenarios. METHODS: A randomized crossover simulation trial was designed. Eighty-three nurses intubated the trachea of a PediaSIM CPR training manikin (FCAE HealthCare, Sarasota, Fla) using the MAC and Airtraq in a normal airway scenario, normal airway with chest compression scenario, and difficult airway with chest compression scenario. The participants were directed to perform a maximum of 3 attempts in each scenario. The success rate, time to intubation, Cormack & Lehane grade, dental compression, and the ease of intubation were measured. RESULTS: All participants performed successful intubation with the Airtraq in all 3 scenarios. In all scenarios, the success rate was significantly higher and the time to intubation was significantly shorter with the Airtraq than with the MAC. Glottic visualization using the Cormack-Lehane scale was also better when using Airtraq in all scenarios. CONCLUSIONS: In this manikin study, we found that the Airtraq can be used successfully for the intubation of pediatric manikins with normal and difficult airways by medical staff without previous experience in pediatric intubation. Moreover, intubation can be achieved without interrupting chest compression. The use of the Airtraq compared with the MAC led to faster time to intubation. Nevertheless, we recommend that the performance of the Airtraq and the MAC during CPR should be further evaluated in a clinical setting. PMID- 27228146 TI - Defining No Pain, Mild, Moderate, and Severe Pain Based on the Faces Pain Scale Revised and Color Analog Scale in Children With Acute Pain. AB - OBJECTIVES: The aims of this study were to define the Faces Pain Scale-Revised (FPS-R) and Color Analog Scale (CAS) scores associated with no pain, mild pain, moderate pain, and severe pain in children with acute pain, and to identify differences based on age, sex, and ethnicity. METHODS: We conducted a prospective observational study in 2 pediatric emergency departments of children aged 4 to 17 years with painful and nonpainful conditions. We assessed their pain intensity using the FPS-R, CAS, and qualitative measures. Pain score cut points that best differentiated adjacent categories of pain were identified using a receiver operating characteristic-based method. Cut points were compared within subgroups based on age, sex, and ethnicity. RESULTS: We enrolled 620 patients, of whom 314 had painful conditions. The mean age was 9.2 years; 315 (50.8%) were in the younger age group (aged 4-7 years); 291 (46.8%) were female; and 341 (55%) were Hispanic. The scores best representing categories of pain for the FPS-R were as follows: no pain, 0 and 2; mild pain, 4; moderate pain, 6; and severe pain, 8 and 10. For the CAS, these were 0 to 1, 1.25 to 2.75, 3 to 5.75, and 6 to 10, respectively. Children with no pain frequently reported nonzero pain scores. There was considerable overlap of scores associated with mild and moderate pain. There were no clinically meaningful differences of scores representing each category of pain based on age, ethnicity, and race. CONCLUSIONS: We defined pain scores for the FPS-R and CAS associated with categories of pain intensity in children with acute pain that are generalizable across subgroups based on patient characteristics. There were minor but potentially important differences in pain scores used to delineate categories of pain intensity compared to prior convention. PMID- 27228147 TI - Acute Hemorrhagic Edema of Infancy: Still a Challenge for the Pediatrician. AB - We report a case of acute hemorrhagic edema of infancy (AHEI) occurred in an 11 month-old male infant after upper respiratory tract infection. The onset was dramatic with petechiae, ecchymosis, and annular, nummular, or targetoid purpuric plaques on the extremities, face, and ears. Acute hemorrhagic edema of infancy is a benign form of leukocytoclastic vasculitis that typically affects children between 4 and 24 months of age. The etiology remains still unknown. The potential triggers of AHEI include preceding bacterial or viral infections, immunizations, and drugs. Although the clinical picture is fearful, in the majority of cases, it involves only cutaneous small vessels. Recognizing this as a distinct clinical entity allows to establish an appropriate prognosis for this rare benign disease in children.This report could be a helpful reminder, especially for emergency physicians, to discriminate AHEI from other more severe diseases, such as meningococcal sepsis. PMID- 27228148 TI - Acute Focal Bacterial Nephritis Associated With Central Nervous System Manifestations: A Report of 2 Cases and Review of the Literature. AB - Acute focal bacterial nephritis (AFBN) is a localized bacterial infection of the kidney presenting as an inflammatory mass without frank abscess formation. In children, most patients with AFBN present with nonspecific conditions, such as fever, vomiting, and abdominal pain. A small number of reported cases are accompanied by neurological symptoms, including meningeal irritation, unconsciousness, and seizures. We experienced 2 rare cases of AFBN associated with central nervous system lesions. The first case was a 3-year-old girl who had neurological symptoms, including unconsciousness and seizures, with AFBN associated with acute reversible encephalopathy. The second case was a 5-year-old girl who had neurological symptoms, including unconsciousness, with AFBN accompanied by clinically mild encephalitis/encephalopathy with a reversible splenial lesion. PMID- 27228150 TI - Tracing Road Network Bottleneck by Data Driven Approach. AB - Urban road congestions change both temporally and spatially. They are essentially caused by network bottlenecks. Therefore, understanding bottleneck dynamics is critical in the goal of reasonably allocating transportation resources. In general, a typical bottleneck experiences the stages of formation, propagation and dispersion. In order to understand the three stages of a bottle neck and how the bottleneck moves on a road network, traffic flow data can be used to reconstruct these dynamics. However, raw traffic flow data is usually flawed in many ways. For instance some portion of data may be missing due to the failure of data collection devices, or some random factors in the data make it hard to identify real bottlenecks. In this paper a "user voting method" is proposed to deal with such raw-data-related issues. In this method, road links are ranked according to the weighed sum of certain performance measures and the links that are ranked relatively high are regarded as recurrent bottlenecks in a network, and several bottlenecks form a bottleneck area. A series of bottleneck parameters can be defined based on the identified bottleneck areas, such as bottleneck coverage, bottleneck link length, etc. Identifying bottleneck areas and calculating the bottleneck parameters for each time interval can reflect the evolution of the bottlenecks and also help trace how the bottlenecks move. PMID- 27228149 TI - Threonine 89 Is an Important Residue of Profilin-1 That Is Phosphorylatable by Protein Kinase A. AB - OBJECTIVE: Dynamic regulation of actin cytoskeleton is at the heart of all actin based cellular events. In this study, we sought to identify novel post translational modifications of Profilin-1 (Pfn1), an important regulator of actin polymerization in cells. METHODOLOGY: We performed in vitro protein kinase assay followed by mass-spectrometry to identify Protein Kinase A (PKA) phosphorylation sites of Pfn1. By two-dimensional gel electrophoresis (2D-GE) analysis, we further examined the changes in the isoelectric profile of ectopically expressed Pfn1 in HEK-293 cells in response to forskolin (FSK), an activator of cAMP/PKA pathway. Finally, we combined molecular dynamics simulations (MDS), GST pull-down assay and F-actin analyses of mammalian cells expressing site-specific phosphomimetic variants of Pfn1 to predict the potential consequences of phosphorylation of Pfn1. RESULTS AND SIGNIFICANCE: We identified several PKA phosphorylation sites of Pfn1 including Threonine 89 (T89), a novel site. Consistent with PKA's ability to phosphorylate Pfn1 in vitro, FSK stimulation increased the pool of the most negatively charged form of Pfn1 in HEK-293 cells which can be attenuated by PKA inhibitor H89. MDS predicted that T89 phosphorylation destabilizes an intramolecular interaction of Pfn1, potentially increasing its affinity for actin. The T89D phosphomimetic mutation of Pfn1 elicits several changes that are hallmarks of proteins folded into alternative three-dimensional conformations including detergent insolubility, protein aggregation and accelerated proteolysis, suggesting that T89 is a structurally important residue of Pfn1. Expression of T89D-Pfn1 induces actin:T89D-Pfn1 co clusters and dramatically reduces overall actin polymerization in cells, indicating an actin-sequestering action of T89D-Pfn1. Finally, rendering T89 non phosphorylatable causes a positive charge shift in the isoelectric profile of Pfn1 in a 2D gel electrophoresis analysis of cell extracts, a finding that is consistent with phosphorylation of a certain pool of intracellular Pfn1 on the T89 residue. In summary, we propose that T89 phosphorylation could have major functional consequences on Pfn1. This study paves the way for further investigation of the potential role of Pfn1 phosphorylation in PKA-mediated regulation of actin-dependent biological processes. PMID- 27228151 TI - Simultaneous Orthotopic Liver Transplantation With Abdominal Aortic Aneurysm Repair: A Case Report. AB - The simultaneous occurrence of an abdominal aortic aneurysm and liver cirrhosis needing surgical treatment is extremely rare. There is still controversy regarding the timing of abdominal aortic aneurysm repair and liver transplantation and regarding optimal treatment of the aneurysm. Here, we describe a 70-year-old white male patient who presented with end-stage liver disease secondary to chronic hepatitis C with a solitary hepatocellular carcinoma measuring 5.5 cm in diameter in the right liver lobe. A pretransplant work-up resulted in discovery of a 6.7-cm abdominal aortic aneurysm. The decision was made to perform orthotopic liver transplantation with simultaneous aneurysm repair. The patient was initially explored through a median laparotomy. The liver transplant was performed first with the graft prepared on the back table using a standard procedure. The liver graft was transplanted using a "piggy-back" technique with end-to-side caval and end-to-end portal vein anastomosis. The arterial anastomosis was performed with an end-to-end anastomosis between the donor's proper hepatic artery and the recipient's common hepatic artery. The bile duct anastomosis was performed with an end-to-end anastomosis. A midline incision was extended to the pubis. After proximal and distal vascular control of the infrarenal aorta, resection of the abdominal aortic aneurysm was performed followed by reconstruction with an InterVascular 22-mm prosthesis using 3.0 Prolene in a running fashion. Eight days after surgery, the patient was discharged and remained well during the 2-year follow-up. Although rare, in a patient with end-stage liver disease and abdominal aortic aneurysm, a simultaneous liver transplantation and aneurysm repair procedure represents the safest treatment solution. PMID- 27228152 TI - LncRNApred: Classification of Long Non-Coding RNAs and Protein-Coding Transcripts by the Ensemble Algorithm with a New Hybrid Feature. AB - As a novel class of noncoding RNAs, long noncoding RNAs (lncRNAs) have been verified to be associated with various diseases. As large scale transcripts are generated every year, it is significant to accurately and quickly identify lncRNAs from thousands of assembled transcripts. To accurately discover new lncRNAs, we develop a classification tool of random forest (RF) named LncRNApred based on a new hybrid feature. This hybrid feature set includes three new proposed features, which are MaxORF, RMaxORF and SNR. LncRNApred is effective for classifying lncRNAs and protein coding transcripts accurately and quickly. Moreover,our RF model only requests the training using data on human coding and non-coding transcripts. Other species can also be predicted by using LncRNApred. The result shows that our method is more effective compared with the Coding Potential Calculate (CPC). The web server of LncRNApred is available for free at http://mm20132014.wicp.net:57203/LncRNApred/home.jsp. PMID- 27228153 TI - TissueMiner: A multiscale analysis toolkit to quantify how cellular processes create tissue dynamics. AB - Segmentation and tracking of cells in long-term time-lapse experiments has emerged as a powerful method to understand how tissue shape changes emerge from the complex choreography of constituent cells. However, methods to store and interrogate the large datasets produced by these experiments are not widely available. Furthermore, recently developed methods for relating tissue shape changes to cell dynamics have not yet been widely applied by biologists because of their technical complexity. We therefore developed a database format that stores cellular connectivity and geometry information of deforming epithelial tissues, and computational tools to interrogate it and perform multi-scale analysis of morphogenesis. We provide tutorials for this computational framework, called TissueMiner, and demonstrate its capabilities by comparing cell and tissue dynamics in vein and inter-vein subregions of the Drosophila pupal wing. These analyses reveal an unexpected role for convergent extension in shaping wing veins. PMID- 27228156 TI - Nonalcoholic fatty liver disease. PMID- 27228154 TI - Mapping replication dynamics in Trypanosoma brucei reveals a link with telomere transcription and antigenic variation. AB - Survival of Trypanosoma brucei depends upon switches in its protective Variant Surface Glycoprotein (VSG) coat by antigenic variation. VSG switching occurs by frequent homologous recombination, which is thought to require locus-specific initiation. Here, we show that a RecQ helicase, RECQ2, acts to repair DNA breaks, including in the telomeric site of VSG expression. Despite this, RECQ2 loss does not impair antigenic variation, but causes increased VSG switching by recombination, arguing against models for VSG switch initiation through direct generation of a DNA double strand break (DSB). Indeed, we show DSBs inefficiently direct recombination in the VSG expression site. By mapping genome replication dynamics, we reveal that the transcribed VSG expression site is the only telomeric site that is early replicating - a differential timing only seen in mammal-infective parasites. Specific association between VSG transcription and replication timing reveals a model for antigenic variation based on replication derived DNA fragility. PMID- 27228155 TI - Banking Umbilical Cord Blood (UCB) Stem Cells: Awareness, Attitude and Expectations of Potential Donors from One of the Largest Potential Repository (India). AB - BACKGROUND: The concept of Umbilical Cord blood (UCB) stem cells is emerging as a non-invasive, efficacious alternative source of hematopoietic stem cells to treat a variety of blood and bone marrow diseases, blood cancers, metabolic disorders and immune deficiencies. Aim of the present study was to determine the level of awareness about banking UCB among pregnant women in India. We also assessed patient perception for banking of UCB and explored the patient expectations of banking UCB in future. This is the first study to assess current attitudes, in a sample population of potential donors from one of the largest potential UCB repository (India). Obtaining this information may help optimize recruitment efforts and improve patient education. MATERIAL AND METHOD: Present explorative questionnaire based survey included 254 pregnant women in the final analysis. RESULTS: We established only 26.5% pregnant women in our study population knew what exactly is meant by UCB. A large proportion (55.1%) was undecided on whether they want to bank UCB or not. Women were more aware of the more advertised private cord blood banking compared to public banking. More than half of the pregnant women expected their obstetrician to inform them regarding UCB. One third of the women in our population had undue expectations from banking of the UCB. CONCLUSION: Obstetricians should play a more active role in explaining the patients regarding pros and cons of UCB banking. PMID- 27228157 TI - Determination of chloramphenicol in biological matrices by solid-phase membrane micro-tip extraction and capillary electrophoresis. AB - Solid-phase membrane micro-tip extraction (SPMMTE) and capillary electrophoresis (CE) methods were developed and validated for analysis of chloramphenicol in human plasma and urine samples. Iron composite nanoparticles were prepared using green technology. CE was carried out using a silica capillary (60 cm * 50 MUm i.d.), phosphate buffer (50 mm, 8.0 pH)-acetonitrile (95:5, v/v) as the background electrolyte, 10 kV voltage, 280 nm detection, 20 s injection time and 27 +/- 1 degrees C temperature. Frusemide was used as an internal standard. The values of migration time, electrophoretic mobility, electrophoretic velocity and theoretical plates of chloramphenicol were 12.254 min, 4.44 * 10, 7.41 * 10 and 11,227. The limits of detection and quantitation of chloramphenicol were 0.1 and 1.0 MUg/mL. Recovery of chloramphenicol in the standard solution was 95%. Solid phase membrane micro-tip extraction and capillary electrophoresis methods may be used to analyze chloramphenicol in human plasma and urine samples of any patient. PMID- 27228158 TI - Base Rates of Depressive Symptoms in Patients with Coronary Heart Disease: An Individual Symptom Analysis. AB - BACKGROUND: Major depression is common in coronary heart disease (CHD) but challenging to diagnose. Instead of focusing on the overall diagnosis of depression, base rates of depressive symptoms could facilitate screening and management of psychopathology in CHD. The present study investigates the frequency of individual depressive symptoms in CHD and their impact on cardiac and subjective health. METHODS: In total, 1337 in- and outpatients with CHD were screened for depressive symptoms with the Patient Health Questionnaire-9 (PHQ-9) at three different cardiac treatment sites. Tables stratified by age and gender were designed to illustrate base rates of depressive symptoms. Multiple regression analyses adjusted for sociodemographic and clinical data were conducted to test associations between individual depressive symptoms and quality of life as well impairment caused angina pectoris and dyspnea. RESULTS: During the last 14 days, more than half of patients reported a loss of energy (74.9%, 95% Confidence Interval (CI): 70.6-79.2), sleeping problems (69.4%, 95% CI: 64.9 74.0), loss of interest (55.7%, 95% CI: 50.8-60.7). In contrast, psychomotor change (25.6%, 95%CI: 21.3-30.0), feelings of failure (21.9%, 95%CI: 17.7-26.0), suicidal ideations (14.1%, 95%CI: 10.7-17.6) were less frequently reported. Depending on the outcome, only particular depressive symptoms were highly associated with low quality of life and impairment caused by angina pectoris and dyspnea. Loss of energy was the only depressive symptom that reliably predicted all three outcomes. CONCLUSIONS: Depressive symptoms in CHD are frequent but vary widely in terms of frequency. Findings underline the differential effects of individual depressive symptoms on cardiac health. Presented base rates of depressive symptoms offer clinicians a new way to judge the severity of individual depressive symptoms and to communicate individual PHQ-9 profiles with patients with respect to gender, age, cardiac symptoms and quality of life. PMID- 27228159 TI - Lovastatin Analogues from the Soil-Derived Fungus Aspergillus sclerotiorum PSU RSPG178. AB - Three new lovastatin analogues (1, 4, and 5) together with four known lovastatin derivatives, namely, lovastatin (2), alpha,beta-dehydrolovastatin (3), alpha,beta dehydrodihydromonacolin K (6), and alpha,beta-dehydro-4a,5-dihydromonacolin L (7), were isolated from the soil-derived fungus Aspergillus sclerotiorum PSU RSPG178. Their structures were established using spectroscopic evidence. Compound 5 exhibited the most potent activity against HMG-CoA reductase, with an IC50 value of 387 MUM. In addition, the present study indicated the direct interaction of compound 5 with HMG-CoA reductase. Compound 5 was considered to be noncytotoxic against noncancerous Vero cells, with an IC50 value of 40.0 MUM, whereas compound 2 displayed much stronger activity, with an IC50 value of 2.2 MUM. PMID- 27228160 TI - Chemical philanthropy: a path forward for antibiotic discovery? PMID- 27228161 TI - Genome-Wide Association Study for Traits Related to Plant and Grain Morphology, and Root Architecture in Temperate Rice Accessions. AB - BACKGROUND: In this study we carried out a genome-wide association analysis for plant and grain morphology and root architecture in a unique panel of temperate rice accessions adapted to European pedo-climatic conditions. This is the first study to assess the association of selected phenotypic traits to specific genomic regions in the narrow genetic pool of temperate japonica. A set of 391 rice accessions were GBS-genotyped yielding-after data editing-57000 polymorphic and informative SNPS, among which 54% were in genic regions. RESULTS: In total, 42 significant genotype-phenotype associations were detected: 21 for plant morphology traits, 11 for grain quality traits, 10 for root architecture traits. The FDR of detected associations ranged from 3 . 10-7 to 0.92 (median: 0.25). In most cases, the significant detected associations co-localised with QTLs and candidate genes controlling the phenotypic variation of single or multiple traits. The most significant associations were those for flag leaf width on chromosome 4 (FDR = 3 . 10-7) and for plant height on chromosome 6 (FDR = 0.011). CONCLUSIONS: We demonstrate the effectiveness and resolution of the developed platform for high-throughput phenotyping, genotyping and GWAS in detecting major QTLs for relevant traits in rice. We identified strong associations that may be used for selection in temperate irrigated rice breeding: e.g. associations for flag leaf width, plant height, root volume and length, grain length, grain width and their ratio. Our findings pave the way to successfully exploit the narrow genetic pool of European temperate rice and to pinpoint the most relevant genetic components contributing to the adaptability and high yield of this germplasm. The generated data could be of direct use in genomic-assisted breeding strategies. PMID- 27228162 TI - Is Fluorescence Valid to Monitor Removal of Protein Bound Uremic Solutes in Dialysis? AB - The aim of this study was to evaluate the contribution and removal dynamics of the main fluorophores during dialysis by analyzing the spent dialysate samples to prove the hypothesis whether the fluorescence of spent dialysate can be utilized for monitoring removal of any of the protein bound uremic solute. A high performance liquid chromatography system was used to separate and quantify fluorophoric solutes in the spent dialysate sampled at the start and the end of 99 dialysis sessions, including 57 hemodialysis and 42 hemodiafiltration treatments. Fluorescence was acquired at excitation 280 nm and emission 360 nm. The main fluorophores found in samples were identified as indole derivatives: tryptophan, indoxyl glucuronide, indoxyl sulfate, 5-hydroxy-indoleacetic acid, indoleacetyl glutamine, and indoleacetic acid. The highest contribution (35 +/- 11%) was found to arise from indoxyl sulfate. Strong correlation between contribution values at the start and end of dialysis (R2 = 0.90) indicated to the stable contribution during the course of the dialysis. The reduction ratio of indoxyl sulfate was very close to the decrease of the total fluorescence signal of the spent dialysate (49 +/- 14% vs 51 +/- 13% respectively, P = 0.30, N = 99) and there was strong correlation between these reduction ratio values (R2 = 0.86). On-line fluorescence measurements were carried out to illustrate the technological possibility for real-time dialysis fluorescence monitoring reflecting the removal of the main fluorophores from blood into spent dialysate. In summary, since a predominant part of the fluorescence signal at excitation 280 nm and emission 360 nm in the spent dialysate originates from protein bound derivatives of indoles, metabolites of tryptophan and indole, the fluorescence signal at this wavelength region has high potential to be utilized for monitoring the removal of slowly dialyzed uremic toxin indoxyl sulfate. PMID- 27228163 TI - CD14 Is a Co-Receptor for TLR4 in the S100A9-Induced Pro-Inflammatory Response in Monocytes. AB - The cytosolic Ca2+-binding S100A9 and S100A8 proteins form heterodimers that are primarily expressed in human neutrophils and monocytes. We have recently shown that S100A9 binds to TLR4 in vitro and induces TLR4-dependent NF-kappaB activation and a pro-inflammatory cytokine response in monocytes. In the present report we have further investigated the S100A9-mediated stimulation of TLR4 in monocytes. Using transmission immunoelectron microscopy, we detected focal binding of S100A9 to monocyte membrane subdomains containing the caveolin-1 protein and TLR4. Furthermore, the S100A9 protein was detected in early endosomes of the stimulated cells, indicating that the protein could be internalized by endocytosis. Although stimulation of monocytes with S100A9 was strictly TLR4 dependent, binding of S100A9 to the plasma membrane and endocytosis of S100A9 was still detectable and coincided with CD14 expression in TLR4-deficient cells. We therefore investigated whether CD14 would be involved in the TLR4-dependent stimulation and could show that the S100A9-induced cytokine response was inhibited both in CD14-deficient cells and in cells exposed to CD14 blocking antibodies. Further, S100A9 was not internalized into CD14-deficient cells suggesting a direct role of CD14 in endocytosis of S100A9. Finally, we could detect satiable binding of S100A9 to CD14 in surface plasmon resonance experiments. Taken together, these results indicate that CD14 is a co-receptor of TLR4 in the S100A9-induced cytokine response. PMID- 27228165 TI - Synthesis, Structure, Band Gap, and Near-Infrared Photosensitivity of a New Chalcogenide Crystal, (NH4)4Ag12Sn7Se22. AB - A new chalcogenide crystal, (NH4)4Ag12Sn7Se22 (FJSM-STS), has been solvothermally synthesized. The crystal structure, which is composed of arrays of [Sn3Se9]n(6n-) chains interconnecting [SnAg6Se10]n(10n-) and [Ag3Se4]n(5n-) layers, is unprecedented among the reported A/Ag/Sn/Q (A = cation; Q = S, Se, and Te) compounds. Optical absorption together with theoretical calculations of the band structure indicate a direct band gap of 1.21 eV for FJSM-STS, which is close to the ideal band gap to maximize the photoconversion efficiency proposed by Shockley and Queisser. The toxic-metal-free crystal of FJSM-STS exhibits obvious photosensitivity in the near-infrared range. The variates of power and temperature on the photosensitivity have been studied. PMID- 27228166 TI - Molecular MRI in the Earth's Magnetic Field Using Continuous Hyperpolarization of a Biomolecule in Water. AB - In this work, we illustrate a method to continuously hyperpolarize a biomolecule, nicotinamide, in water using parahydrogen and signal amplification by reversible exchange (SABRE). Building on the preparation procedure described recently by Truong et al. [ J. Phys. Chem. B , 2014 , 118 , 13882 - 13889 ], aqueous solutions of nicotinamide and an Ir-IMes catalyst were prepared for low-field NMR and MRI. The (1)H-polarization was continuously renewed and monitored by NMR experiments at 5.9 mT for more than 1000 s. The polarization achieved corresponds to that induced by a 46 T magnet (P = 1.6 * 10(-4)) or an enhancement of 10(4). The polarization persisted, although reduced, if cell culture medium (DPBS with Ca(2+) and Mg(2+)) or human cells (HL-60) were added, but was no longer observable after the addition of human blood. Using a portable MRI unit, fast (1)H-MRI was enabled by cycling the magnetic field between 5 mT and the Earth's field for hyperpolarization and imaging, respectively. A model describing the underlying spin physics was developed that revealed a polarization pattern depending on both contact time and magnetic field. Furthermore, the model predicts an opposite phase of the dihydrogen and substrate signal after one exchange, which is likely to result in the cancelation of some signal at low field. PMID- 27228164 TI - Proteomic Study of Entamoeba histolytica Trophozoites, Cysts, and Cyst-Like Structures. AB - The cyst stage of Entamoeba histolytica is a promising therapeutic target against human amoebiasis. Our research team previously reported the production in vitro of Cyst-Like Structures (CLS) sharing structural features with cysts, including rounded shape, size reduction, multinucleation, and the formation of a chitin wall coupled to the overexpression of glucosamine 6-phosphate isomerase, the rate limiting enzyme of the chitin synthesis pathway. A proteomic study of E. histolytica trophozoites, cysts, and in vitro-produced CLS is reported herein to determine the nature of CLS, widen our knowledge on the cyst stage, and identify possible proteins and pathways involved in the encystment process. Total protein extracts were obtained from E. histolytica trophozoites, CLS, and partially purified cysts recovered from the feces of amoebic human patients; extracts were trypsin-digested and analyzed by LC-MS/MS. In total, 1029 proteins were identified in trophozoites, 550 in CLS, and 411 in cysts, with 539, 299, and 84 proteins unique to each sample, respectively, and only 74 proteins shared by all three stages. About 70% of CLS proteins were shared with trophozoites, even though differences were observed in the relative protein abundance. While trophozoites showed a greater abundance of proteins associated to a metabolically active cell, CLS showed higher expression of proteins related to proteolysis, redox homeostasis, and stress response. In addition, the expression of genes encoding for the cyst wall proteins Jessie and Jacob was detected by RT-PCR and the Jacob protein identified by Western blotting and immunofluorescence in CLS. However, the proteomic profile of cysts as determined by LC-MS/MS was very dissimilar to that of trophozoites and CLS, with almost 40% of hypothetical proteins. Our global results suggest that CLS are more alike to trophozoites than to cysts, and they could be generated as a rapid survival response of trophozoites to a stressful condition, which allows the parasite to survive temporarily inside a chitin-like resistant cover containing Jacob protein. Our findings lead us to suggest that encystment and CLS formation could be distinct stress responses. In addition, we show that cysts express a high number of genes with unknown function, including four new, highly antigenic, possibly membrane located proteins that could be targets of therapeutic and diagnostic usefulness. PMID- 27228167 TI - Whole Exome Sequencing Analysis Identifies Mutations in LRP5 in Indian Families with Familial Exudative Vitreoretinopathy. AB - BACKGROUND: Familial exudative vitreoretinopathy (FEVR, OMIM 133780) is a severe inherited retinal disorder characterized by incomplete retinal vascular development and neovascularization. At least five genes have been reported to be associated with FEVR, including NDP, LRP5, FZD4, TSPAN12, and ZNF408. Recently reported data showed that mutations in the KIF11 gene can also lead to FEVR conditions. Previous studies suggested that known mutations only explain approximately 40-60% of FEVR cases in different populations. PURPOSE: To investigate the causative genetic mutations in four Indian families with FEVR. METHODS: Whole exome sequencing was carried out to analyze the genomic DNA samples from the four FEVR proband patients and Sanger sequencing was utilized to verify all identified polymorphisms. A luciferase assay was used to test the mutant protein activity. RESULTS: We identified four novel LRP5 missense mutations in these FEVR families: c.C1042T (p.R348W), c.G1141A (p.D381N), c.C1870T (p.R624W), and c.A4550G (p.Y1517C). The luciferase assay demonstrated that all four of these LRP5 mutations led to significant reduction of enzymatic activity with response to NORRIN, suggesting that they are pathogenic. CONCLUSION: Our findings expand the mutational spectrum of FEVR in the Indian population and provide some guidelines in clinical diagnosis. PMID- 27228168 TI - Dominant-Negative Effect of a Missense Variant in the TASK-2 (KCNK5) K+ Channel Associated with Balkan Endemic Nephropathy. AB - TASK-2, a member of the Two-Pore Domain (K2P) subfamily of K+ channels, is encoded by the KCNK5 gene. The channel is expressed primarily in renal epithelial tissues and a potentially deleterious missense variant in KCNK5 has recently been shown to be prevalent amongst patients predisposed to the development of Balkan Endemic Nephropathy (BEN), a chronic tubulointerstitial renal disease of unknown etiology. In this study we show that this variant (T108P) results in a complete loss of channel function and is associated with a major reduction in TASK-2 channel subunits at the cell surface. Furthermore, these mutant subunits have a suppressive or 'dominant-negative' effect on channel function when coexpressed with wild-type subunits. This missense variant is located at the extracellular surface of the M2 transmembrane helix and by using a combination of structural modelling and further functional analysis we also show that this highly-conserved threonine residue is critical for the correct function of other K2P channels. These results therefore provide further structural and functional insights into the possible pathophysiological effects of this missense variant in TASK-2. PMID- 27228169 TI - Data Fitting to Study Ablated Hard Dental Tissues by Nanosecond Laser Irradiation. AB - Laser ablation of dental hard tissues is one of the most important laser applications in dentistry. Many works have reported the interaction of laser radiations with tooth material to optimize laser parameters such as wavelength, energy density, etc. This work has focused on determining the relationship between energy density and ablation thresholds using pulsed, 5 nanosecond, neodymium-doped yttrium aluminum garnet; Nd:Y3Al5O12 (Nd:YAG) laser at 1064 nanometer. For enamel and dentin tissues, the ablations have been performed using laser-induced breakdown spectroscopy (LIBS) technique. The ablation thresholds and relationship between energy densities and peak areas of calcium lines, which appeared in LIBS, were determined using data fitting. Furthermore, the morphological changes were studied using Scanning Electron Microscope (SEM). Moreover, the chemical stability of the tooth material after ablation has been studied using Energy-Dispersive X-Ray Spectroscopy (EDX). The differences between carbon atomic % of non-irradiated and irradiated samples were tested using statistical t-test. Results revealed that the best fitting between energy densities and peak areas of calcium lines were exponential and linear for enamel and dentin, respectively. In addition, the ablation threshold of Nd:YAG lasers in enamel was higher than that of dentin. The morphology of the surrounded ablated region of enamel showed thermal damages. For enamel, the EDX quantitative analysis showed that the atomic % of carbon increased significantly when laser energy density increased. PMID- 27228170 TI - HeartWare Left Ventricular Assist Device Implantation Combined with Surgical Ventricular Reconstruction. AB - Left ventricular assist devices (LVADs) extend survival of patients with end stage heart failure as a bridge to transplant or for destination therapy. However, implant of these devices may be challenging, especially in cases of a left ventricular aneurysm involving the left ventricular apical wall. In this report, we describe a symptomatic patient with ischemic cardiomyopathy and a large left ventricular anterior aneurysm treated by reconstruction of the left ventricle and simultaneous implant of the HeartWare LVAD system (HVAD; HeartWare International, Inc., Framingham, MA, USA). PMID- 27228171 TI - Diabetic kidney disease. PMID- 27228172 TI - Contribution of Hydrogen Bonds to Paper Strength Properties. AB - The objective of this work was to investigate the influence of hydrogen bonds between fibres on static and dynamic strength properties of paper. A commercial bleached pinewood kraft pulp was soaked in water, refined in a PFI, and used to form paper webs in different solvents, such as water, methanol, ethanol, n propanol and n-butanol, to determine the effect of their dipole moment on static and dynamic strength properties of resulting paper sheets. Paper which was formed in water, being the solvent of the highest dipole moment among the tested ones, showed the highest breaking length and tear resistance. When paper webs were formed in n-butanol, which was the least polar among the solvents, these parameters were reduced by around 75%. These results provide evidence of the importance of water in paper web formation and strong impact of hydrogen bonds between fibres on strength properties of paper. PMID- 27228173 TI - An H2A Histone Isotype, H2ac, Associates with Telomere and Maintains Telomere Integrity. AB - Telomeres are capped at the ends of eukaryotic chromosomes and are composed of TTAGGG repeats bound to the shelterin complex. Here we report that a replication dependent histone H2A isotype, H2ac, was associated with telomeres in human cells and co-immunoprecipitates with telomere repeat factor 2 (TRF2) and protection of telomeres protein 1 (POT1), whereas other histone H2A isotypes and mutations of H2ac did not bind to telomeres or these two proteins. The amino terminal basic domain of TRF2 was necessary for the association with H2ac and for the recruitment of H2ac to telomeres. Depletion of H2ac led to loss of telomeric repeat sequences, the appearance of dysfunctional telomeres, and chromosomal instability, including chromosomal breaks and anaphase bridges, as well as accumulation of telomere-associated DNA damage factors in H2ac depleted cells. Additionally, knockdown of H2ac elicits an ATM-dependent DNA damage response at telomeres and depletion of XPF protects telomeres against H2ac-deficiency-induced G-strand overhangs loss and DNA damage response, and prevents chromosomal instability. These findings suggest that the H2A isotype, H2ac, plays an essential role in maintaining telomere functional integrity. PMID- 27228174 TI - Meniscal Allograft Transplantation Does Not Prevent or Delay Progression of Knee Osteoarthritis. AB - BACKGROUND: Meniscal tears are common knee injuries. Meniscal allograft transplantation (MAT) has been advocated to alleviate symptoms and delay osteoarthritis (OA) after meniscectomy. We investigated (1) the long-term outcome of MAT as a treatment of symptomatic meniscectomy, (2) most important factors affecting survivorship and (3) OA progression. METHODS: From 1989 till 2013, 329 MAT were performed in 313 patients. Clinical and radiographic results and MAT survival were evaluated retrospectively. Failure was defined as conversion to knee arthroplasty (KA) or total removal of the MAT. RESULTS: Mean age at surgery was 33 years (15-57); 60% were males. No-to-mild cartilage damage was found in 156 cases, moderate-to-severe damage in 130. Simultaneous procedures in 118 patients included cartilage procedures, osteotomy or ACL-reconstruction. At a mean follow-up of 6.8 years (0.2-24.3years), 5 patients were deceased and 48 lost (14.6%), 186 MAT were in situ (56.5%) whilst 90 (27.4%) had been removed, including 63 converted to a KA (19.2%). Cumulative allograft survivorship was 15.1% (95% CI:13.9-16.3) at 24.0 years. In patients <35 years at surgery, survival was significantly better (24.1%) compared to >=35 years (8.0%) (p = 0.017). In knees with no-to-mild cartilage damage more allografts survived (43.0%) compared to moderate-to-severe damage (6.6%) (p = 0.003). Simultaneous osteotomy significantly deteriorated survival (0% at 24.0 years) (p = 0.010). 61% of patients underwent at least one additional surgery (1-11) for clinical symptoms after MAT. Consecutive radiographs showed significant OA progression at a mean of 3.8 years (p<0.0001). Incremental Kellgren-Lawrence grade was +1,1 grade per 1000 days (2,7yrs). CONCLUSIONS: MAT did not delay or prevent tibiofemoral OA progression. 19.2% were converted to a knee prosthesis at a mean of 10.3 years. Patients younger than 35 with no-to-mild cartilage damage may benefit from MAT for relief of symptoms (survivorship 51.9% at 20.2 years), but patients and healthcare payers and providers should be aware of the high number of surgical re-interventions. PMID- 27228175 TI - Rapid Diagnosis of Lung Tumors, a Feasability Study Using Maldi-Tof Mass Spectrometry. AB - OBJECTIVE: Despite recent advances in imaging and core or endoscopic biopsies, a percentage of patients have a major lung resection without diagnosis. We aimed to assess the feasibility of a rapid tissue preparation/analysis to discriminate cancerous from non-cancerous lung tissue. METHODS: Fresh sample preparations were analyzed with the Microflex LTTM MALDI-TOF analyzer. Each main reference spectra (MSP) was consecutively included in a database. After definitive pathological diagnosis, each MSP was labeled as either cancerous or non-cancerous (normal, inflammatory, infectious nodules). A strategy was constructed based on the number of concordant responses of a mass spectrometry scoring algorithm. A 3-step evaluation included an internal and blind validation of a preliminary database (n = 182 reference spectra from the 100 first patients), followed by validation on a whole cohort database (n = 300 reference spectra from 159 patients). Diagnostic performance indicators were calculated. RESULTS: 127 cancerous and 173 non cancerous samples (144 peripheral biopsies and 29 inflammatory or infectious lesions) were processed within 30 minutes after biopsy sampling. At the most discriminatory level, the samples were correctly classified with a sensitivity, specificity and global accuracy of 92.1%, 97.1% and 95%, respectively. CONCLUSIONS: The feasibility of rapid MALDI-TOF analysis, coupled with a very simple lung preparation procedure, appears promising and should be tested in several surgical settings where rapid on-site evaluation of abnormal tissue is required. In the operating room, it appears promising in case of tumors with an uncertain preoperative diagnosis and should be tested as a complementary approach to frozen-biopsy analysis. PMID- 27228176 TI - WITHDRAWN: Immediate-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults. PMID- 27228177 TI - HIV-1 subtype B: Traces of a pandemic. AB - Human migration is a major process that shaped the origin and dissemination of HIV. Within HIV-1, subtype B (HIV-1B) is the most disseminated variant and it is assumed to be the causative agent in approximately 11% of all cases of HIV worldwide. Phylogenetic studies have revealed that HIV-1B emerged in Kinshasa (Africa) and was introduced into the Caribbean region via Haiti in or around 1966 by human migration. After localized dispersion, the virus was brought to the United States of America via homosexual/bisexual contact around 1969. Inside USA, the incidence of HIV-1B infection increased exponentially and it became established in the population, affecting not only homosexual individuals but also heterosexual individuals and injecting drug users. Soon after, the virus was disseminated and became established in other regions, including Europe, Asia, Latin America, and Australia. Recent studies suggest that, in addition to this pandemic clade, several lineages have emerged from Haiti and reached other Caribbean and Latin American countries via short-distance dissemination. Different subtype B genetic variants have also been detected in these epidemics. Four genetic variants have been described to date: subtype B', which mainly circulates in Thailand and other Asian countries; a specific variant mainly found in Trinidad and Tobago; the GPGS variant, which is primarily detected in Korea; and the GWGR variant, which is mainly detected in Brazil. This paper reviews the evolution of HIV-1B and its impact on the human population. PMID- 27228178 TI - A germline variant affects putative miRNA-binding sites at the F8 3'UTR and acts as a potential haemophilia A phenotype modifier in Southern Brazilian patients. PMID- 27228179 TI - Tunable photochemical properties of a covalently anchored and spatially confined organic polymer in a layered compound. AB - A covalently anchored and spatially confined organic polymer was formed in a layered compound with a surface-modified layer. The resultant anchored and confined polymer showed tunable photochemical properties with the incorporation of a variety of guest molecules originating from the specific incorporation states. The layer surface of an inorganic layered compound was modified by an organic molecule with vinyl groups. The precursor layered composite accommodated N-vinylcarbazole (VCz), a vinyl monomer, in the hydrophobic interlayer space. The introduction of VCz induced the simultaneous exfoliation of the layered structures and copolymerization with vinyl groups on the layer surface. The covalently anchored and spatially confined poly(N-vinylcarbazole) (PVCz) with tunable photochemical properties was formed in a layered structure. The present study shows the versatile potential of polymers with anchored and confined states in surface-functionalized layered composites. PMID- 27228180 TI - Stoichiometry and Affinity of Thioflavin T Binding to Sup35p Amyloid Fibrils. AB - In this work two modes of binding of the fluorescent probe thioflavin T to yeast prion protein Sup35p amyloid fibrils were revealed by absorption spectrometry of solutions prepared by equilibrium microdialysis. These binding modes exhibited significant differences in binding affinity and stoichiometry. Moreover, the absorption spectrum and the molar extinction coefficient of the dye bound in each mode were determined. The fluorescence quantum yield of the dye bound in each mode was determined via a spectrofluorimetric study of the same solutions in which the recorded fluorescence intensity was corrected for the primary inner filter effect. As previously predicted, the existence of one of the detected binding modes may be due to the incorporation of the dye into the grooves along the fiber axis perpendicular to the beta-sheets of the fibrils. It was assumed that the second type of binding with higher affinity may be due to the existence of ThT binding sites that are localized to areas where amyloid fibrils are clustered. PMID- 27228181 TI - MRI Based Localisation and Quantification of Abscesses following Experimental S. aureus Intravenous Challenge: Application to Vaccine Evaluation. AB - PURPOSE: To develop and validate a sensitive and specific method of abscess enumeration and quantification in a preclinical model of Staphylococcus aureus infection. METHODS: S. aureus infected murine kidneys were fixed in paraformaldehyde, impregnated with gadolinium, and embedded in agar blocks, which were subjected to 3D magnetic resonance microscopy on a 9.4T MRI scanner. Image analysis techniques were developed, which could identify and quantify abscesses. The result of this imaging was compared with histological examination. The impact of a S. aureus Sortase A vaccination regime was assessed using the technique. RESULTS: Up to 32 murine kidneys could be imaged in a single MRI run, yielding images with voxels of about 25 MUm3. S. aureus abscesses could be readily identified in blinded analyses of the kidneys after 3 days of infection, with low inter-observer variability. Comparison with histological sections shows a striking correlation between the two techniques: all presumptive abscesses identified by MRI were confirmed histologically, and histology identified no abscesses not evident on MRI. In view of this, simulations were performed assuming that both MRI reconstruction, and histology examining all sections of the tissue, were fully sensitive and specific at abscess detection. This simulation showed that MRI provided more sensitive and precise estimates of abscess numbers and volume than histology, unless at least 5 histological sections are taken through the long axis of the kidney. We used the MRI technique described to investigate the impact of a S. aureus Sortase A vaccine. CONCLUSION: Post mortem MRI scanning of large batches of fixed organs has application in the preclinical assessment of S. aureus vaccines. PMID- 27228182 TI - Older adults experience difficulty completing the lines and dots tasks of the Motor Assessment Scale. AB - BACKGROUND: The advanced hand activities item of the Motor Assessment Scale (Upper Limb items, UL-MAS) includes the 'lines' and 'dots' tasks, which require skilful pencil use. Prior Rasch analysis studies identify these two tasks as the most difficult to achieve for stroke survivors compared with the other advanced hand activities. Yet it is unknown if healthy, older adults can perform these two tasks. OBJECTIVES: To describe the performance of older adults' without stroke on the 'lines' and 'dots' tasks, relationship between age and task performance, and relationship between writing speed and performance on the 'lines' task. METHODS: Cross-sectional study design. A sample of healthy older Australians (n = 120) aged between 60 and 99 years completed the UL-MAS 'lines' and 'dots' tasks and wrote two sentences using pencil. RESULTS: Fifty-four participants (45%) failed the UL-MAS 'lines' task. Differences in line drawing performance across age groups were statistically significant (chi-square = 9.02, df = 3, p = .03). Eleven participants (9%) failed the 'dots' task, mostly from the 90 to 99 year age group. Participants who passed the 'lines' task wrote sentences faster than participants who failed (p<.001). CONCLUSION: Older adults may not pass the UL MAS 'lines' and 'dots' tasks due to age and individual skill level. PMID- 27228183 TI - Phospholipase A2 as a point of care alternative to serum amylase and pancreatic lipase. AB - Acute pancreatitis is a relatively common and potentially fatal condition, but the presenting symptoms are non-specific and diagnosis relies largely on the measurement of amylase activity by the hospital clinical laboratory. In this work we develop a point of care test for pancreatitis measuring concentration of secretory phospholipase A2 group IB (sPLA2-IB). Novel antibodies for sPLA2-IB were raised and used to design an ELISA and a lateral flow device (LFD) for the point of care measurement of sPLA2-IB concentration, which was compared to pancreatic amylase activity, lipase activity, and sPLA2-IB activity in 153 serum samples. 98 of these samples were obtained from the pathology unit of a major hospital and classified retrospectively according to presence or absence of pancreatitis, and the remaining 55 were obtained from commercial sources to serve as high lipase (n = 20), CA19-9 positive (n = 15), and healthy (n = 20) controls. sPLA2-IB concentration correlated well with the serum activity of both amylase and lipase, and performed at least as well as either markers in the differentiation of pancreatitis from controls. PMID- 27228184 TI - Effect of a combination of antiplatelet and antithrombotic pretreatment on myocardial perfusion in patients with an acute ST-segment elevation myocardial infarction undergoing a primary percutaneous coronary intervention. AB - INTRODUCTION: Primary percutaneous coronary intervention (PCI) is the preferred method of reperfusion in ST-segment elevation myocardial infarction patients. Adjunctive pharmacotherapy is, however, still under investigation. OBJECTIVE: To assess the effect of combined pharmacologic therapy on myocardial perfusion and infarct size in relation to time delays. MATERIALS AND METHODS: We studied 309 consecutive ST-segment elevation myocardial infarction patients admitted within 12 h from symptom onset with (a) chest pain persisting for more than 30 min, (b) ST-segment elevation more than 1 mm in at least two contiguous leads, and (c) pretreatment with 600 mg of clopidogrel, 300 mg of aspirin, and 5000 U of intravenous heparin. Group I (n=90) included patients transferred directly to cathlab (immediate transfer) and group II (n=219) included patients transferred by referring hospitals (staged transfer). The results of thrombolysis in myocardial infarction (TIMI) flow before and after PCI, ST-segment resolution (STSR), troponin T level, and myocardial blush grade were analyzed in relation to delay to intervention. RESULTS: The delay between pharmacologic pretreatment and angiography was two times longer in cases of staged transfer (80 vs. 47.5 min; P<0.0001). Despite the longer delay, higher rates of preangiography total STSR (26.4 vs. 15.5%; P=0.039) and initial TIMI flow 3 (20.1 vs. 11.1%; P=0.059) were observed in those patients. Differences in the rate of total STSR (70.3 vs. 66.7%; P=0.52), TIMI flow 3 (91.3 vs. 88.9%; P=0.33), and myocardial blush grade (60.7 vs. 63.3%; P=0.66) were no longer observed after PCI. Similarly, the peak troponin T level was also comparable (3.6 vs. 3.9 ng/ml; P=0.74). CONCLUSION: Pretreatment with a combination of antiplatelet and antithrombotic agents may improve myocardial perfusion and compromise longer delay to a mechanical intervention. PMID- 27228185 TI - Early neoatherosclerosis after bioresorbable vascular scaffold implantation: insights from optical coherence tomography. PMID- 27228186 TI - Novel oral anticoagulants in the management of coronary artery disease. AB - Despite advances in interventional and pharmacologic therapy, survivors of myocardial infarction remain at an increased risk of subsequent cardiovascular events. Initial pharmacological management includes both platelet inhibition and parenteral anticoagulation, whereas long-term pharmacological therapy relies on antiplatelet therapy for prevention of thrombotic complications. Biomarkers showing ongoing thrombin generation after acute coronary syndromes suggest that anticoagulants may provide additional benefit in reducing cardiovascular events. We review the pharmacokinetics of novel anticoagulants, clinical trial results, the role of monitoring, and future directions for the use of novel oral anticoagulants in the treatment of coronary artery disease. Clinical trials have shown that long-term use of oral anticoagulants decreases the risk of cardiovascular events, but they do so at a cost of an increased risk of bleeding. Future studies will need to identify optimal treatment combinations for selected patients and conditions that address both the appropriate combination of therapy and the appropriate dosage of each agent when used in combination. PMID- 27228189 TI - Curculigoside augments cell-mediated immune responses in metastatic tumor-bearing animals. AB - A positive modulation of immune system is necessary for preparing the body to fight against malignant tumor cells. In the present study, the stimulatory effect of Curculigoside on cell-mediated immune response against the metastasis of B16F10 melanoma cells was analyzed in C57BL/6 mice. Curculigoside is a phenolic glucoside present in the plant Curculigo orchioides Gaertn. (Family - Amaryllidaceae). Administration of Curculigoside enhanced the natural killer (NK) cell activity, antibody-dependent cell-mediated cytotoxicity and complement mediated cytotoxicity in metastatic tumor-bearing animals, when compared to the untreated control animals. The compound was also found to be effective in reducing the levels of proinflammatory cytokines such as TNF-alpha, IL-1beta, IL 6 and GM-CSF during metastasis. Besides these, levels of TH1 cytokines, such as IL-2 and IFN-gamma, were significantly enhanced (p < 0.001) by Curculigoside administration and thereby reduces the metastatic lung colony formation along with an increased lifespan of the experimental animals. These studies provide an evidence for the stimulation of cell-mediated immune responses by Curculigoside against B16F10-induced metastatic tumor progression in experimental animals. PMID- 27228187 TI - Contribution of Estrone Sulfate to Cell Proliferation in Aromatase Inhibitor (AI) -Resistant, Hormone Receptor-Positive Breast Cancer. AB - Aromatase inhibitors (AIs) effectively treat hormone receptor-positive postmenopausal breast cancer, but some patients do not respond to treatment or experience recurrence. Mechanisms of AI resistance include ligand-independent activation of the estrogen receptor (ER) and signaling via other growth factor receptors; however, these do not account for all forms of resistance. Here we present an alternative mechanism of AI resistance. We ectopically expressed aromatase in MCF-7 cells expressing green fluorescent protein as an index of ER activity. Aromatase-overexpressing MCF-7 cells were cultured in estrogen-depleted medium supplemented with testosterone and the AI, letrozole, to establish letrozole-resistant (LR) cell lines. Compared with parental cells, LR cells had higher mRNA levels of steroid sulfatase (STS), which converts estrone sulfate (E1S) to estrone, and the organic anion transporter peptides (OATPs), which mediate the uptake of E1S into cells. LR cells proliferated more in E1S supplemented medium than did parental cells, and LR proliferation was effectively inhibited by an STS inhibitor in combination with letrozole and by ER-targeting drugs. Analysis of ER-positive primary breast cancer tissues showed a significant correlation between the increases in the mRNA levels of STS and the OATPs in the LR cell lines, which supports the validity of this AI-resistant model. This is the first study to demonstrate the contribution of STS and OATPs in E1S metabolism to the proliferation of AI-resistant breast cancer cells. We suggest that E1S metabolism represents a new target in AI-resistant breast cancer treatment. PMID- 27228190 TI - Antiepileptic drug therapy and recommendations for withdrawal in patients with seizures and epilepsy due to neurocysticercosis. AB - INTRODUCTION: Neurocysticercosis (NCC) is a leading causes of secondary epilepsy worldwide. There is increasing evidence on the epileptogenic role of NCC, and the presence of edema, calcified scars, gliosis and hippocampal sclerosis support this phenomenon. AREAS COVERED: We summarized principles of antiepileptic drug (AED) therapy as well as risk factors associated with seizure recurrence after AED withdrawal in patients with NCC. Expert commentary: First-line AED monotherapy is effective as a standard approach to control seizures in most NCC patients. Risks and benefits of AED withdrawal have not been systematically studied, and this decision must be individualized. However, a seizure-free period of at least two years seem prudent before attempting withdrawal. Risk factors for seizure recurrence after AED withdrawal include a history of status epilepticus, poor seizure control during treatment, neuroimaging evidence of perilesional gliosis, hippocampal sclerosis and calcified lesions, as well as persistence of paroxysmal activity in the EEG. PMID- 27228191 TI - Factors related to curved femur in elderly Japanese women. AB - BACKGROUND: Multiple factors are involved in the development of atypical femoral fractures, and excessive curvature of the femur is thought to be one of them. However, the pathogenesis of femoral curvature is unknown. We evaluated the influence of factors related to bone metabolism and posture on the development of femoral curvature. METHODS: A total of 139 women participated in the present study. Curvatures were measured using antero-posterior and lateral radiography of the femur. We evaluated some bone and vitamin D metabolism markers in serum, the bone mineral density (BMD), lumbar spine alignment, and pelvic tilt. RESULTS: We divided the women into two groups, curved and non-curved groups, based on the average plus standard deviation as the cut-off between the groups. When univariate logistic regression analysis was performed to detect factors affecting femoral curvature, the following were identified as indices significantly affecting the curvature: age of the patients, serum concentrations of calcium, intact parathyroid hormone, pentosidine, homocysteine and 25-hydroxyvitamin D (25(OH)D), and BMD of the proximal femur (P < 0.05) both in the lateral and anterior curvatures. When we used multivariate analyses to assess these factors, only 25(OH)D and age (lateral and anterior standardized odds ratio: 0.776 and 0.385, and 2.312 and 4.472, respectively) affected the femoral curvature (P < 0.05). CONCLUSION: Femoral curvature is strongly influenced by age and serum vitamin D. PMID- 27228192 TI - Alkaline phosphatase activity in airway fluid obtained by tracheal wash from adult horses. AB - BACKGROUND: Collection of fluid from the lower respiratory tract (LRT) plays an important role in both the pathophysiological investigation and diagnosis of respiratory tract disease. Enzymes such as ALP are, among others, indicators of cell damage or death, type II pneumocyte proliferation, and neutrophil invasion, and have been useful as biomarkers of respiratory disease in other species. OBJECTIVES: The purpose of this study was to determine and compare tracheal wash (TW) ALP activity in healthy horses and horses with LRT inflammation (LRTI) determined by TW cytology profile. METHODS: Tracheal washes were collected from asymptomatic adult geldings to measure ALP activity. The horses were allocated to the healthy group or the group with LRT inflammation based on differential leukocyte counts of TW preparations. Horses with > 20% neutrophils and > 1% eosinophils were allocated to the LRTI group, the horses with < 20% neutrophils and < 1% eosinophils were the controls. RESULTS: Tracheal wash ALP activity, measured using a semiautomatic chemistry analyzer, was statistically significantly higher in 18 horses with LRTI (18.9 +/- 11.2 * 10(3) U/L) than in healthy horses (10.3 +/- 5.9 * 10(3) U/L) (P = .021). CONCLUSIONS: Determining tracheal wash ALP activity is a simple, inexpensive and safe technique that can be used to facilitate the early diagnosis of equine respiratory disease, since it is higher in asymptomatic adult horses with a TW cytology profile consistent with LRT inflammation than in healthy adult horses with a normal TW cytology profile. PMID- 27228194 TI - Tiny Turtles Purchased at Pet Stores are a Potential High Risk for Salmonella Human Infection in the Valencian Region, Eastern Spain. AB - Turtles may be considered unsafe pets, particularly in households with children. This study aimed to assess Salmonella carriage by turtles in pet stores and in private ownership to inform the public of the potential health risk, enabling informed choices around pet selection. During the period between September and October 2013, 24 pet stores and 96 private owners were sampled in the Valencian Region (Eastern Spain). Salmonella identification procedure was based on ISO 6579: 2002 recommendations (Annex D). Salmonella strains were serotyped in accordance with Kauffman-White-Le-Minor technique. The rate of isolation of Salmonella was very high from pet store samples (75.0% +/- 8.8%) and moderate for private owners (29.0% +/- 4.6%). Serotyping revealed 18 different serotypes among two Salmonella enterica subspecies: S. enterica subsp. enterica and S. enterica subsp. diarizonae. Most frequently isolated serotypes were Salmonella Typhimurium (39.5%, 17/43) and Salmonella Pomona (9.3%, 4/43). Serotypes identified have previously been reported in turtles, and child Salmonella infections associate with pet turtle exposure. The present study clearly demonstrates that turtles in pet stores, as well as in private owners, could be a direct or indirect source of a high risk of human Salmonella infections. In addition, pet stores should advise their customers of the potential risks associated with reptile ownership. PMID- 27228193 TI - Investigation and Treatment of Fusidic Acid Resistance Among Methicillin Resistant Staphylococcal Isolates from Egypt. AB - Methicillin resistance among staphylococci isolated from patients in northern Egypt has escalated alarmingly in the past decade. Data about the prevalence of fusidic acid (FA) resistance in Egyptian clinical isolates are limited. This work investigates the prevalence and mechanism of FA resistance among 81 methicillin resistant staphylococcal isolates from major hospitals of Alexandria, Egypt. Some combinations for treating infections due to resistant isolates were studied. Twenty-six isolates (32.1%) were FA resistant (minimum inhibitory concentrations [MICs] = 2-1,024 MUg/ml), and fusB and fusC genes coding for FA resistance were detected in 30.77% and 34.62% of the FA-resistant strains, respectively. One highly resistant isolate, S502 (MIC = 1,024 MUg/ml), possessed both genes. Plasmid curing resulted in fusB loss and MIC decrease by 16-64 folds. Conjugation caused acquisition of FA resistance among susceptible isolates. Serial passages in subinhibitory FA concentrations produced mutants with increased MIC by 4-32 folds. The combination of FA with rifampin, gentamicin, or ampicillin/sulbactam, in a subinhibitory concentration, was synergistic against the isolates, including serial passage mutants, decreasing number of survivors by an average of 2-4 logs. A relatively moderate rate of FA resistance was detected in Alexandria hospitals. Combination therapy with gentamicin, rifampin, or ampicillin/sulbactam is crucial to preserve the effectiveness of FA. PMID- 27228195 TI - Cerebral palsy. PMID- 27228197 TI - Spina bifida. PMID- 27228196 TI - Density Distribution of Pharyngeal Carriage of Meningococcus in Healthy Young Adults: New Approaches to Studying the Epidemiology of Colonization and Vaccine Indirect Effects. AB - BACKGROUND: Improved understanding of Neisseria meningitidis (Nm) carriage biology and better methods for detection and quantification would facilitate studies of potential impact of new vaccines on colonization and transmission in adolescents. METHODS: We performed plate cultures on 107 oropharyngeal swabs stored frozen in skim milk tryptone glucose glycerol (STGG) broth and previously positive for Nm. We compared quantitative polymerase chain reaction (qPCR) detection of Nm in 601 STGG-swabs with culture. Using qPCR (n = 87), a log-phase broth culture standard curve and semiquantitative plate cultures (n = 68), we measured density of carriage. We compared qPCR genogrouping of DNA extracts from STGG-swabs and from plate culture lawns (n = 110) with purified isolates (n = 80). RESULTS: Swab storage resulted in only 10% loss of culture sensitivity. Direct sodC qPCR Nm detection yielded more positives (87/601, 14.5%) than culture (80/601, 13.3%). Most samples (57/110) positive by culture were also positive by qPCR and vice versa, but discrepancies (single positives) were frequent among low density samples. sodC qPCR was positive in 79/80 isolates but in only 65 by ctrA qPCR. Density both by culture and qPCR varied across 4 orders of magnitude with the majority being low (<50 bacteria-gene copies/mL) and a minority being high (>1000). Genogrouping qPCRs yielded more positive results when performed on DNA extracts from lawn cultures. CONCLUSIONS: We provide the first description of the distribution of Nm carriage density. This could be important for understanding transmission dynamics and population-level effectiveness of adolescent vaccine programs. Storage of swabs frozen in STGG for batched laboratory analysis facilitates carriage studies and direct sodC qPCR for Nm combined with qPCR genogrouping of lawn culture extracts provides accurate, detailed description of colonization. PMID- 27228198 TI - Patient Factors, Donor Age, and Graft Storage Duration Affect Osteochondral Allograft Outcomes in Knees with or without Comorbidities. AB - Limited data exists defining preoperative variables that affect outcomes after osteochondral allograft transplantation (OAT) in the knee. In this retrospective study, we examined 75 patients who underwent OAT for large (>=2 cm2) grade IV cartilage defects in the femoral condyle. Patient variables evaluated included the following: smoking, workers compensation, body mass index (BMI), pre-injury activity level, number, and the type of co-morbidities in the operated knee, lesion location and number of grafts placed. OCA donor age and graft storage duration from procurement were also evaluated. Preoperative and postoperative visual analogue scale (VAS) pain scores were the primary outcome measure. Overall, 53 patients (71%) had successful outcomes, with 81% of patients without co-morbidities having successful outcomes. Active patients were significantly (p = 0.023) more likely to have a successful outcome than low activity patients. Patients with BMI <35 were 4 times more likely to have a successful outcome (p = 0.01). There were no significant differences based on donor age. Patients with transplanted grafts stored >28 days were significantly (p = 0.048) and 2.6 times more likely to have an unsuccessful outcome. This study provides new evidence for preoperative patient factors and graft variables that may influence the overall outcome after osteochondral transplantation in the knee. PMID- 27228200 TI - Physical activity of relatively high intensity in mid-pregnancy predicts lower glucose tolerance levels. AB - INTRODUCTION: Physical activity (PA) is recommended as part of therapy for patients with impaired glucose tolerance. Whether such recommendations are also justified for pregnant women is less well established. We investigated the association between PA and glucose tolerance in pregnancy. MATERIAL AND METHODS: A non-selective sample of 217 pregnant women was recruited at a routine 20 week ultrasound examination. Participants answered the International Physical Activity Questionnaire (IPAQ) about frequency, intensity and duration of daily physical activity in the past 7 days and underwent oral glucose tolerance testing (OGTT) between 24 and 28 weeks. A subset of 72 overweight/obese pregnant women wore a pedometer for 1 week with assessment of IPAQ score and pedometric correlations to this. RESULTS: Of the sample, 177 attended for OGTT; 51% were overweight or obese. The mean (SD) fasting glucose was 4.5 (0.4) mmol/L, and 12% had gestational diabetes mellitus. Only one-third engaged in vigorous PA. After adjustment for pre-pregnancy BMI, age and parity, those engaging in vigorous PA had significantly lower fasting glucose levels (by 0.15 mmol/L, 95% CI 0.03-0.27) compared with those not vigorously active. This decrease was similar in both normal and overweight/obese women. There were fewer cases of gestational diabetes (p = 0.03) among the vigorously active women (3/56; 5%) than among those who were not active (19/121; 16%). No association with glucose tolerance was observed for physical activity of moderate intensity. CONCLUSIONS: Only vigorous physical activity appears beneficial with respect to maternal glucose tolerance, both among normal, overweight and obese women. PMID- 27228199 TI - Interaction effects on cytochrome P450 both in vitro and in vivo studies by two major bioactive xanthones from Halenia elliptica D. Don. AB - The major components, 1-hydroxy-2,3,5-trimethoxy-xanthone (HM-1) and 1,5 dihydroxy-2,3-dimethoxy-xanthone (HM-5) isolated from Halenia elliptica D. Don (Gentianaceae), could cause vasodilatation in rat coronary artery with different mechanisms. In this work, high-performance liquid chromatography coupled to ion trap time-of-flight mass spectrometry (LCMS-IT-TOF) was used to clarify the metabolic pathways, and CYP450 isoform involvement of HM-1 and HM-5 were also studied in rat. At the same time, in vivo inhibition effects of HM-1 and ethyl acetate extracts from origin herb were studied. Three metabolites of HM-5 were found in rat liver microsomes (RLMs); demethylation and hydroxylation were the major phase I metabolic reactions for HM-5. Multiple CYP450s were involved in metabolism of HM-1 and HM-5. The inhibition study showed that HM-5 inhibited Cyp1a2, 2c6 and 2d2 in RLMs. HM-1 inhibited activities of Cyp1a2, Cyp2c6 and Cyp3a2. In vivo experiment demonstrated that both HM-1 and ethyl acetate extracts could inhibit Cyp3a2 in rats. In conclusion, the metabolism of xanthones from the origin herb involved multiple CYP450 isoforms; in vitro, metabolism of HM-5 was similar to that of its parent drug HM-1, but their inhibition effects upon CYP450s were different; in vivo, Cyp3a2 could be inhibited by HM-1 and ethyl acetate extracts. PMID- 27228201 TI - alpha-Cyclodextrin Interacts Close to Vinblastine Site of Tubulin and Delivers Curcumin Preferentially to the Tubulin Surface of Cancer Cell. AB - Tubulin is the key cytoskeleton component, which plays a crucial role in eukaryotic cell division. Many anticancer drugs have been developed targeting the tubulin surface. Recently, it has been shown that few polyhydroxy carbohydrates perturb tubulin polymerization. Cyclodextrin (CD), a polyhydroxy carbohydrate, has been extensively used as the delivery vehicle for delivery of hydrophobic drugs to the cancer cell. However, interaction of CD with intracellular components has not been addressed before. In this Article, we have shown for the first time that alpha-CD interacts with tubulin close to the vinblastine site using molecular docking and Forster resonance energy transfer (FRET) experiment. In addition, we have shown that alpha-CD binds with intracellular tubulin/microtubule. It delivers a high amount of curcumin onto the cancer cell, which causes severe disruption of intracellular microtubules. Finally, we have shown that the inclusion complex of alpha-CD and curcumin (CCC) preferentially enters into the human lung cancer cell (A549) as compared to the normal lung fibroblast cell (WI38), causes apoptotic death, activates tumor suppressor protein (p53) and cyclin-dependent kinase inhibitor 1 (p21), and inhibits 3D spheroid growth of cancer cell. PMID- 27228203 TI - A Cytoplasmic Form of Gaussia luciferase Provides a Highly Sensitive Test for Cytotoxicity. AB - The elimination of unfavorable chemicals from our environment and commercial products requires a sensitive and high-throughput in vitro assay system for drug induced hepatotoxicity. Some previous methods for evaluating hepatotoxicity measure the amounts of cytoplasmic enzymes secreted from damaged cells into the peripheral blood or culture medium. However, most of these enzymes are proteolytically digested in the extracellular milieu, dramatically reducing the sensitivity and reliability of such assays. Other methods measure the decrease in cell viability following exposure to a compound, but such endpoint assays are often confounded by proliferation of surviving cells that replace dead or damaged cells. In this study, with the goal of preventing false-negative diagnoses, we developed a sensitive luminometric cytotoxicity test using a stable form of luciferase. Specifically, we converted Gaussia luciferase (G-Luc) from an actively secreted form to a cytoplasmic form by adding an ER-retention signal composed of the four amino acids KDEL. The bioluminescent signal was >30-fold higher in transgenic HepG2 human hepatoblastoma cells expressing G-Luc+KDEL than in cells expressing wild-type G-Luc. Moreover, G-Luc+KDEL secreted from damaged cells was stable in culture medium after 24 hr at 37 degrees C. We evaluated the accuracy of our cytotoxicity test by subjecting identical samples obtained from chemically treated transgenic HepG2 cells to the G-Luc+KDEL assay and luminometric analyses based on secretion of endogenous adenylate kinase or cellular ATP level. Time-dependent accumulation of G-Luc+KDEL in the medium increased the sensitivity of our assay above those of existing tests. Our findings demonstrate that strong and stable luminescence of G-Luc+KDEL in human hepatocyte-like cells, which have high levels of metabolic activity, make it suitable for use in a high-throughput screening system for monitoring time dependent cytotoxicity in a limited number of cells. PMID- 27228202 TI - High rate of thiamine deficiency among inpatients with cancer referred for psychiatric consultation: results of a single site prevalence study. AB - OBJECTIVE: Thiamine deficiency (TD) is increasingly recognized in medically ill patients. The prevalence of TD among cancer patients is unknown. This study aims to characterize the prevalence of TD among inpatients with cancer. METHODS: Retrospective chart review of patients admitted to a large cancer center who were referred for psychiatric consultation and whose serum thiamine concentration was measured. Patients with alcohol use were excluded. RESULTS: Among 217 patients with various cancer types, TD was found in 55.3%. Risk factors included fluorouracil-based chemotherapy, significant weight loss, and undergoing active cancer treatment. Almost all patients were normal weight, overweight, or obese, and few had concomitant vitamin B12 or folate deficiency. A total of 17.5% were receiving multivitamin supplementation. Nearly half (49.8%) did not receive empiric treatment with thiamine and among those who did, treatment delay occurred in the majority of cases (59.6%). Measurement of serum thiamine concentration preceded psychiatric consultation in only 10.6% of cases. CONCLUSIONS: Our findings suggest that TD is highly prevalent among inpatients with cancer, even among normal and overweight individuals, in the absence of other vitamin deficiencies, and while receiving multivitamin supplements. Several potential risk factors were identified, including active cancer treatment. Evaluation of TD was most commonly not initiated by oncologists. Failure to treat and treatment delay were common. Given these findings, oncologists must be vigilant about detecting TD among inpatients with cancer. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27228204 TI - Nutrition factors predict earlier acquisition of motor and language milestones among young children in Haiti. AB - AIM: To examine the nutrition-related factors associated with motor and language development among young children living in a poor urban area of Haiti. METHODS: Children aged 6-11 months (n = 583) were enrolled and followed monthly for one year. World Health Organization motor developmental milestones and vowel and consonant counts were assessed. Longitudinal regression models were applied to assess the association of anthropometric, dietary intake, infectious disease morbidity and socio-economic and demographic factors on developmental outcomes. RESULTS: At baseline, 9.4% were stunted or length-for-age Z score < -2, and 30.2% were mild-to-moderately stunted or length-for-age Z score < -1. Stunting status was significantly associated with motor and phonetic language acquisition at each time point during infancy. Several nutrition factors significantly predicted earlier achievement of motor and language development outcomes in longitudinal models: child anthropometry; breastfeeding and complementary feeding frequencies; dietary diversity; egg and oil intake; and reduced infectious disease morbidities. Increases in the length-for-age Z score significantly predicted all motor and language outcomes and yielded the best fit models compared to other anthropometric indicators (p < 0.001). CONCLUSION: Child development interventions may be enhanced by incorporating nutrition strategies such as improved diet quality, breastfeeding promotion and diarrhoeal disease mitigation. PMID- 27228205 TI - GpDSR7, a Novel E3 Ubiquitin Ligase Gene in Grimmia pilifera Is Involved in Tolerance to Drought Stress in Arabidopsis. AB - The growth and development of plants under drought stress depends mainly on the expression levels of various genes and modification of proteins. To clarify the molecular mechanism of drought-tolerance of plants, suppression subtractive hybridisation cDNA libraries were screened to identify drought-stress-responsive unigenes in Grimmia pilifera, and a novel E3 ubiquitin ligase gene, GpDSR7, was identified among the 240 responsive unigenes. GpDSR7 expression was induced by various abiotic stresses, particularly by drought. GpDSR7 displayed E3 ubiquitin ligase activity in vitro and was exclusively localised on the ER membrane in Arabidopsis mesophyll protoplasts. GpDSR7-overexpressing transgenic Arabidopsis plants showed a high water content and survival ratio under drought stress. Moreover, the expression levels of some marker genes involved in drought stress were higher in the transgenic plants than in wild-type plants. These results suggest that GpDSR7, an E3 ubiquitin ligase, is involved in tolerance to drought stress at the protein modification level. PMID- 27228206 TI - Effect of Temporary Ovarian Suppression on Chemotherapy-Induced Amenorrhea, Pregnancy, and Outcome. PMID- 27228208 TI - Association Between Head Tilt and Asymmetric Epiblepharon. AB - IMPORTANCE: Epiblepharon is known to be bilateral and symmetric. However, asymmetric epiblepharon is frequently observed in patients with head tilt and, to date, this condition has not been investigated. OBJECTIVES: To evaluate the clinical features of epiblepharon in patients with head tilt and to analyze the association between the direction of head tilt and epiblepharon asymmetry. DESIGN, SETTING, AND PARTICIPANTS: The medical records of 1074 Korean children who received a diagnosis of epiblepharon between January 1, 2006, and October 31, 2013, at Seoul National University Bundang Hospital were retrospectively reviewed. The data collected included sex, age, extent and asymmetric presentation of epiblepharon, and direction and cause of head tilt. MAIN OUTCOMES AND MEASURES: The presence of epiblepharon asymmetry in patients with head tilt as well as the association between the direction of head tilt and the side having more severe epiblepharon. RESULTS: Of 1074 patients (536 boys; mean [SD] age, 5.4 [2.6] years) with epiblepharon, 38 individuals (3.5%) showed head tilt. The causes of head tilt were superior oblique palsy (18 patients [47.4%]), congenital muscular torticollis (10 [26.3%]), dissociated vertical deviation (3 [7.9%]), and unknown (7 [18.4%]). Asymmetric epiblepharon was more common in children with vs without head tilt (34 [89.5%] vs 80 [7.7%]; P < .001, Fisher exact test). Of the 34 patients with head tilt and asymmetric epiblepharon, the direction of head tilt was consistent with the side having more severe epiblepharon in 29 individuals (85.3%) and inconsistent in 5 individuals (14.7%) (P = .009). CONCLUSIONS AND RELEVANCE: These data suggest that, in patients with epiblepharon and head tilt, epiblepharon is most often asymmetric and is severe in the head tilted side. These results suggest that patients with asymmetric epiblepharon should be evaluated for head tilt. PMID- 27228207 TI - A Single-Dose, Single-Period Pharmacokinetic Assessment of an Extended-Release Orally Disintegrating Tablet of Methylphenidate in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder. AB - OBJECTIVE: To determine the pharmacokinetic (PK) profile of a proprietary formulation of methylphenidate (MPH) in children and adolescents with attention deficit/hyperactivity disorder (ADHD) in a phase 1 study. Methylphenidate extended-release orally disintegrating tablets (MPH XR-ODTs) combine two technologies in a single-tablet formulation-an extended-release profile that was designed for once-daily dosing in an ODT that does not require water or chewing for ingestion. METHODS: This was a single-dose, open-label, single-period, single treatment study, in which 32 children with ADHD who were receiving MPH in doses of 40 or 60 mg before beginning the study each received a 60-mg dose (2 * 30 mg) of MPH XR-ODT. The following plasma PK parameters of MPH were determined for participants grouped by age (6-7, 8-9, 10-12, and 13-17 years old): maximum concentration (Cmax), time to maximum concentration (Tmax), elimination half-life (T1/2), area under the curve from 0 hours to infinity (AUCinf), oral clearance (CL/F), and volume of distribution in the terminal phase (Vz/F). Safety and tolerability were also assessed. RESULTS: A total of 32 participants received the study drug. For all participants, plasma concentration-time profiles of MPH exhibited a broad peak after administration of MPH XR-ODT through ~8 hours, indicating extended release from the formulation, followed by an apparent first order elimination phase. As age increased, MPH exposure decreased and mean estimates of CL/F increased; however, weight-normalized CL/F values were comparable across age groups. Similarly, mean estimates of Vz/F increased with age, but weight-normalization decreased differences across age groups, with the exception of the youngest age group, which had higher values. All adverse events (AEs) were mild. CONCLUSION: This XR-ODT formulation of MPH demonstrated weight normalized clearance rates that were consistent across all age groups, a PK profile consistent with once-daily dosing, and an AE profile consistent with this class of medication in children and adolescents with ADHD. PMID- 27228210 TI - Type 2 diabetes mellitus. PMID- 27228209 TI - Phylogenetic and size constrains on cranial ontogenetic allometry of spiny rats (Echimyidae, Rodentia). AB - Analysis of ontogenetic development is crucial for understanding the emergence of phenotypic discrepancies between animal taxa. The study of allometric trajectories within a phylogenetic context is a feasible approach to assess the morphological change across different evolutionary lineages. Here, we report the disparity of multivariate ontogenetic allometry in the Echimyidae, a taxonomically diverse rodent family, as well as the effects of size on the evolution of skull ontogeny. The ontogenetic trajectories of 15 echimyid operational taxonomic unities (12 genera plus one genus with three species) belonging to all subfamilies and major clades, when plotted in allometric space, revealed strong and significant phylogenetic signals. Allometric trajectories were found to be constrained by phylogenetic ancestry, with changes approximately adjusting to a Brownian motion model of evolution. Moreover, the occupation of allometric space by echimyid taxa was significantly correlated with adult size rather than with shape, suggesting that the variation in adult size might result in critically intrinsic and structural constraints on allometric coefficients. These findings disagreed with the hypothesis that allometric disparities might be mainly adaptive with undetectable phylogenetic signals. PMID- 27228211 TI - Further understanding of the pathology of glioma: implications for the clinic. AB - INTRODUCTION: Glioma classification and grading has been historically based in morphologic appearance of tumor cells: astrocytomas, oligodendrogliomas, oligoastrocytomas and ependymomas. Recent molecular advances have transformed the field of neuro-oncology, as some molecular markers harbor diagnostic, prognostic and therapeutic implications. AREAS COVERED: In this paper we will review the major molecular changes associated with gliomas and their implications in diagnosis, prognosis, and opportunities in therapeutics. Expert commentary: Based on current understanding, adult diffuse infiltrating gliomas can be molecularly divided into three to five major subgroups with different clinical outcomes. Pediatric gliomas harbor mutations for H3F3A, ATRX and DAXX but not IDH. Circumscribed low-grade gliomas tend to have BRAF alterations. Clinical behavior of ependymomas correlates more with location than WHO grading. Posterior fossa ependymomas tend to behave worse than their cerebral or spinal cord counterparts. However, with the posterior fossa ependymomas, two distinct subtypes have emerged molecularly. PMID- 27228212 TI - Nano-ZnO leads to tubulin macrotube assembly and actin bundling, triggering cytoskeletal catastrophe and cell necrosis. AB - Zinc is a crucial element in biology that plays chief catalytic, structural and protein regulatory roles. Excess cytoplasmic zinc is toxic to cells so there are cell-entry and intracellular buffering mechanisms that control intracellular zinc availability. Tubulin and actin are two zinc-scavenging proteins that are essential components of the cellular cytoskeleton implicated in cell division, migration and cellular architecture maintenance. Here we demonstrate how exposure to different ZnO nanostructures, namely ZnO commercial nanoparticles and custom made ZnO nanowires, produce acute cytotoxic effects in human keratinocytes (HaCat) and epithelial cells (HeLa) triggering a dose-dependent cell retraction and collapse. We show how engulfed ZnO nanoparticles dissolve intracellularly, triggering actin filament bundling and structural changes in microtubules, transforming these highly dynamic 25 nm diameter polymers into rigid macrotubes of tubulin, severely affecting cell proliferation and survival. Our results demonstrate that nano-ZnO causes acute cytoskeletal collapse that triggers necrosis, followed by a late reactive oxygen species (ROS)-dependent apoptotic process. PMID- 27228213 TI - High Content Screening Analysis to Evaluate the Toxicological Effects of Harmful and Potentially Harmful Constituents (HPHC). AB - Cigarette smoke (CS) is a major risk factor for cardiovascular and lung diseases. Because CS is a complex aerosol containing more than 7,000 chemicals it is challenging to assess the contributions of individual constituents to its overall toxicity. Toxicological profiles of individual constituents as well as mixtures can be however established in vitro, by applying high through-put screening tools, which enable the profiling of Harmful and Potentially Harmful Constituents (HPHCs) of tobacco smoke, as defined by the U.S. Food and Drug Administration (FDA). For an initial assessment, an impedance-based instrument was used for a real-time, label-free assessment of the compound's toxicity. The instrument readout relies on cell adhesion, viability and morphology that all together provide an overview of the cell status. A dimensionless parameter, named cell index, is used for quantification. A set of different staining protocols was developed for a fluorescence imaging-based investigation and a HCS platform was used to gain more in-depth information on the kind of cytotoxicity elicited by each HPHC. Of the 15 constituents tested, only five were selected for HCS-based analysis as they registered a computable LD50 (< 20 mM). These included 1 aminonaphtalene, Arsenic (V), Chromium (VI), Crotonaldehyde and Phenol. Based on their effect in the HCS, 1-aminonaphtalene and Phenol could be identified to induce mitochondrial dysfunction, and, together with Chromium (VI) as genotoxic based on the increased histone H2AX phosphorylation. Crotonaldehyde was identified as an oxidative stress inducer and Arsenic as a stress kinase pathway activator. This study demonstrates that a combination of impedance-based and HCS technologies provides a robust tool for in vitro assessment of CS constituents. PMID- 27228214 TI - Quantitative Assessment of the Impact of Fluorine Substitution on P-Glycoprotein (P-gp) Mediated Efflux, Permeability, Lipophilicity, and Metabolic Stability. AB - Strategic replacement of one or more hydrogen atoms with fluorine atom(s) is a common tactic to improve potency at a given target and/or to modulate parameters such as metabolic stability and pKa. Molecular weight (MW) is a key parameter in design, and incorporation of fluorine is associated with a disproportionate increase in MW considering the van der Waals radius of fluorine versus hydrogen. Herein we examine a large compound data set to understand the effect of introducing fluorine on the risk of encountering P-glycoprotein mediated efflux (as measured by MDR efflux ratio), passive permeability, lipophilicity, and metabolic stability. Statistical modeling of the MDR ER data demonstrated that an increase in MW as a result of introducing fluorine atoms does not lead to higher risk of P-gp mediated efflux. Fluorine-corrected molecular weight (MWFC), where the molecular weight of fluorine has been subtracted, was found to be a more relevant descriptor. PMID- 27228215 TI - Trends in the Rare Earth Element Content of U.S.-Based Coal Combustion Fly Ashes. AB - Rare earth elements (REEs) are critical and strategic materials in the defense, energy, electronics, and automotive industries. The reclamation of REEs from coal combustion fly ash has been proposed as a way to supplement REE mining. However, the typical REE contents in coal fly ash, particularly in the United States, have not been comprehensively documented or compared among the major types of coal feedstocks that determine fly ash composition. The objective of this study was to characterize a broad selection of U.S. fly ashes of varied geological origin in order to rank their potential for REE recovery. The total and nitric acid extractable REE content for more than 100 ash samples were correlated with characteristics such as the major element content and coal basin to elucidate trends in REE enrichment. Average total REE content (defined as the sum of the lanthanides, yttrium, and scandium) for ashes derived from Appalachian sources was 591 mg kg(-1) and significantly greater than in ashes from Illinois and Powder River basin coals (403 and 337 mg kg(-1), respectively). The fraction of critical REEs (Nd, Eu, Tb, Dy, Y, and Er) in the fly ashes was 34-38% of the total and considerably higher than in conventional ores (typically less than 15%). Powder River Basin ashes had the highest extractable REE content, with 70% of the total REE recovered by heated nitric acid digestion. This is likely due to the higher calcium content of Powder River Basin ashes, which enhances their solubility in nitric acid. Sc, Nd, and Dy were the major contributors to the total REE value in fly ash, based on their contents and recent market prices. Overall, this study shows that coal fly ash production could provide a substantial domestic supply of REEs, but the feasibility of recovery depends on the development of extraction technologies that could be tailored to the major mineral content and origins of the feed coal for the ash. PMID- 27228216 TI - Using Mass Spectrometry to Quantify Rituximab and Perform Individualized Immunoglobulin Phenotyping in ANCA-Associated Vasculitis. AB - Therapeutic monoclonal immunoglobulins (mAbs) are used to treat patients with a wide range of disorders including autoimmune diseases. As pharmaceutical companies bring more fully humanized therapeutic mAb drugs to the healthcare market analytical platforms that perform therapeutic drug monitoring (TDM) without relying on mAb specific reagents will be needed. In this study we demonstrate that liquid-chromatography-mass spectrometry (LC-MS) can be used to perform TDM of mAbs in the same manner as smaller nonbiologic drugs. The assay uses commercially available reagents combined with heavy and light chain disulfide bond reduction followed by light chain analysis by microflow-LC electrospray ionization-quadrupole-time-of-flight mass spectrometry (ESI-Q-TOF MS). Quantification is performed using the peak areas from multiply charged mAb light chain ions using an in-house developed software package developed for TDM of mAbs. The data presented here demonstrate the ability of an LC-MS assay to quantify a therapeutic mAb in a large cohort of patients in a clinical trial. The ability to quantify any mAb in serum via the reduced light chain without the need for reagents specific for each mAb demonstrates the unique capabilities of LC-MS. This fact, coupled with the ability to phenotype a patient's polyclonal repertoire in the same analysis further shows the potential of this approach to mAb analysis. PMID- 27228218 TI - Effects of Subretinal Gene Transfer at Different Time Points in a Mouse Model of Retinal Degeneration. AB - Lysophosphatidylcholine acyltransferase 1 (LPCAT1) is necessary for photoreceptors to generate an important lipid component of their membranes. The absence of LPCAT1 results in early and rapid rod and cone degeneration. Retinal degeneration 11 (rd11) mice carry a mutation in the Lpcat1 gene, and are an excellent model of early-onset rapid retinal degeneration (RD). To date, no reports have documented gene therapy administration in the rd11 mouse model at different ages. In this study, the AAV8 (Y733F)-smCBA-Lpcat1 vector was subretinally injected at postnatal day (P) 10, 14, 18, or 22. Four months after injection, immunohistochemistry and analysis of retinal morphology showed that treatment at P10 rescued about 82% of the wild-type retinal thickness. However, the diffusion of the vector and the resulting rescue were limited to an area around the injection site that was only 31% of the total retinal area. Injection at P14 resulted in vector diffusion that covered approximately 84% of the retina, and we found that gene therapy was more effective against RD when exposure to light was limited before and after treatment. We observed long-term preservation of electroretinogram (ERG) responses, and preservation of retinal structure, indicating that early treatment followed by limited light exposure can improve gene therapy effectiveness for the eyes of rd11 mice. Importantly, delayed treatment still partially preserved M-cones, but not S-cones, and M-cones in the rd11 retina appeared to have a longer window of opportunity for effective preservation with gene therapy. These results provide important information regarding the effects of subretinal gene therapy in the mouse model of LPCAT1 deficiency. PMID- 27228219 TI - Correlating Cellulose Nanocrystal Particle Size and Surface Area. AB - Cellulose nanocrystals (CNCs) are negatively charged nanorods that present challenges for characterization of particle size distribution and surface area two of the common parameters for characterizing nanomaterials. CNC size distributions have been measured by two microscopy methods: atomic force microscopy (AFM) and transmission electron microscopy (TEM). The agreement between the two methods is good for length measurements, after taking into consideration tip-convolution effects for AFM. However, TEM widths are almost twice as large as AFM heights-an effect that we hypothesize is due to counting of a larger fraction of laterally associated CNCs in the TEM images. Overall, the difficulty of selecting individual particles for analysis and possible bias due to selection of a specific particle size during sample deposition are the main limitations associated with the microscopy measurements. The microscopy results were compared to Z-average data from dynamic light scattering, which is a useful method for routine analysis and for examining trends in size as a function of sample treatment. Measurements as a function of sonication energy were used to provide information on the presence of aggregates in the sample. Magic-angle spinning solid-state NMR was employed to estimate the surface area of CNCs based on the ratio of integrated spectral intensities of resonances stemming from C4 sites at the crystallite surfaces and from all C4 sites. Our approach was adapted from the application of solid-state NMR to characterize larger cellulose microfibers and appears to provide a useful estimate that overcomes the limitations of using the BET method for measuring surface areas of highly aggregated nanomaterials. The solid-state NMR results show that the lateral dimension of the CNCs is consistent with that of elementary cellulose crystallites. PMID- 27228220 TI - Enhanced Carbon Dioxide Capture from Landfill Gas Using Bifunctionalized Benzimidazole-Linked Polymers. AB - Tuning the binding affinity of small gases and their selective uptake by porous adsorbents are vital for effective CO2 removal from gas mixtures for environmental protection and fuel upgrading. In this study, an amine functionalized benzimidazole-linked polymer (BILP-6-NH2) was synthesized by a combination of pre- and postsynthetic modification techniques in two steps. Presynthetic incorporation of nitro groups resulted in stoichiometric functionalization (1 nitro/phenyl) in addition to noninvasive functionalization, where more than 80% of the surface area maintained compared to BILP-6. Experimental studies presented enhanced CO2 uptake and CO2/CH4 selectivity in BILP-6-NH2 compared to BILP-6, which are governed by the synergetic effect of benzimidazole and amine moieties. DFT calculations were used to understand the interaction modes of CO2 with BILP-6-NH2 and confirmed the efficacy of amine groups. Encouraged by the enhanced uptake and selectivity in BILP-6-NH2, we have evaluated its performance in landfill gas separation under vacuum swing adsorption (VSA) settings, which resulted in very promising working capacity and sorbent selection parameters outperforming most of the best solid adsorbent in the literature. PMID- 27228221 TI - Individual personality differences in Port Jackson sharks Heterodontus portusjacksoni. AB - This study examined interindividual personality differences between Port Jackson sharks Heterodontus portusjacksoni utilizing a standard boldness assay. Additionally, the correlation between differences in individual boldness and stress reactivity was examined, exploring indications of individual coping styles. Heterodontus portusjacksoni demonstrated highly repeatable individual differences in boldness and stress reactivity. Individual boldness scores were highly repeatable across four trials such that individuals that were the fastest to emerge in the first trial were also the fastest to emerge in subsequent trials. Additionally, individuals that were the most reactive to a handling stressor in the first trial were also the most reactive in a second trial. The strong link between boldness and stress response commonly found in teleosts was also evident in this study, providing evidence of proactive-reactive coping styles in H. portusjacksoni. These results demonstrate the presence of individual personality differences in sharks for the first time. Understanding how personality influences variation in elasmobranch behaviour such as prey choice, habitat use and activity levels is critical to better managing these top predators which play important ecological roles in marine ecosystems. PMID- 27228222 TI - Aryl-Decorated Ru(II) Polypyridyl-type Photosensitizer Approaching NIR Emission with Microsecond Excited State Lifetimes. AB - Bis-tridentate Ru(II) complexes based on the dqp scaffold (dqp is 2,6-di(quinolin 8-yl)pyridine) with multiple aryl substituents were explored to tailor the absorption and emission properties. A synthetic methodology was developed for the facile synthesis and purification of homo- and heteroleptic bis-tridentate Ru complexes. The effect of the aryl substituents in the para positions of the pyridine and quinoline subunits was detailed by X-ray crystallography, steady state and time-resolved spectroscopy, electrochemistry, and computational methods. The attachment of the aryl groups results in enhanced molar extinction coefficients with the largest effect in the pyridine position, whereas the quinoline substituent leads to red-shifted emission tailing into the NIR region (up to 800 nm). Notably, the excited state lifetimes remain in the microsecond time scale even in the presence of O2, whereas the emission quantum yields are slightly increased with respect to the parental complex [Ru(dqp)2](2+). The peripheral functional groups (Br, Me, OMe) have only a minor impact on the optical properties and are attractive to utilize such complexes as functional building blocks. PMID- 27228224 TI - A validated case definition for chronic rhinosinusitis in administrative data: a Canadian perspective. AB - BACKGROUND: Pharmacoepidemiological research using administrative databases has become increasingly popular for chronic rhinosinusitis (CRS); however, without a validated case definition the cohort evaluated may be inaccurate resulting in biased and incorrect outcomes. The objective of this study was to develop and validate a generalizable administrative database case definition for CRS using International Classification of Diseases, 9th edition (ICD-9)-coded claims. METHODS: A random sample of 100 patients with a guideline-based diagnosis of CRS and 100 control patients were selected and then linked to a Canadian physician claims database from March 31, 2010, to March 31, 2015. The proportion of CRS ICD 9-coded claims (473.x and 471.x) for each of these 200 patients were reviewed and the validity of 7 different ICD-9-based coding algorithms was evaluated. RESULTS: The CRS case definition of >=2 claims with a CRS ICD-9 code (471.x or 473.x) within 2 years of the reference case provides a balanced validity with a sensitivity of 77% and specificity of 79%. Applying this CRS case definition to the claims database produced a CRS cohort of 51,000 patients with characteristics that were consistent with published demographics and rates of comorbid asthma, allergic rhinitis, and depression. CONCLUSION: This study has validated several coding algorithms; based on the results a case definition of >=2 physician claims of CRS (ICD-9 of 471.x or 473.x) within 2 years provides an optimal level of validity. Future studies will need to validate this administrative case definition from different health system perspectives and using larger retrospective chart reviews from multiple providers. PMID- 27228223 TI - Association of Oseltamivir Activation with Gender and Carboxylesterase 1 Genetic Polymorphisms. AB - Oseltamivir, an inactive anti-influenza virus prodrug, is activated (hydrolysed) in vivo by carboxylesterase 1 (CES1) to its active metabolite oseltamivir carboxylate. CES1 functions are significantly associated with certain CES1 genetic variants and some non-genetic factors. The purpose of this study was to investigate the effect of gender and several CES1 genetic polymorphisms on oseltamivir activation using a large set of individual human liver samples. CES1 mediated oseltamivir hydrolysis and CES1 genotypes, including the G143E (rs71647871), rs2244613, rs8192935, the -816A>C (rs3785161) and the CES1P1/CES1P1VAR, were determined in 104 individual human livers. The results showed that hepatic CES1 protein expression in females was 17.3% higher than that in males (p = 0.039), while oseltamivir activation rate in the livers from female donors was 27.8% higher than that from males (p = 0.076). As for CES1 genetic polymorphisms, neither CES1 protein expression nor CES1 activity on oseltamivir activation was significantly associated with the rs2244613, rs8192935, -816A>C or CES1P1/CES1P1VAR genotypes. However, oseltamivir hydrolysis in the livers with the genotype 143G/E was approximately 40% of that with the 143G/G genotype (0.7 +/- 0.2 versus 1.8 +/- 1.1 nmole/mg protein/min, p = 0.005). In summary, the results suggest that hepatic oseltamivir activation appears to be more efficient in females than that in males, and the activation can be impaired by functional CES1 variants, such as the G143E. However, clinical implication of CES1 gender differences and pharmacogenetics in oseltamivir pharmacotherapy warrants further investigations. PMID- 27228225 TI - Association of Polymorphisms in IL1beta -511C>T, IL1RN 86 bp VNTR, and IL6 174G>C Genes with Clinical Dengue Signs and Symptoms in Brazilian Dengue Patients. AB - Dengue is an important infectious disease that has high morbidity and mortality rates in most tropical and subtropical areas of the world. The diversity of the clinical manifestations involved in the outcome of dengue virus infection is affected by the relationship between serotype/genotype of the virus, host immune status, host genetic background, and environmental factors. Polymorphisms in interleukin (IL) genes have been associated with risk of developing symptomatic dengue. This study aimed to determine the association of the single-nucleotide polymorphisms of IL1beta -511C>T, IL1RN 86 bp VNTR, and IL6 -174G>C genes with the clinical features of 198 individuals admitted to the Sao Jose Infectious Diseases Hospital with suspected dengue infection. Dengue was confirmed in 118 of the patients. The control group consisted of 80 other individuals who had symptoms similar to dengue, but negative for that. A higher frequency of increased hematocrit (p = 0.009), leukopenia (p = 0.000007), neutropenia (p = 0.0004), lymphocytosis (p = 0.00001), monocytosis (p = 0.004), atypical lymphocytes (p = 0.03), and thrombocytopenia (p = 0.0000009) was observed in the dengue patients. Among the polymorphisms studied, only IL1beta (-511C>T) was associated with dizziness, (p = 0.01), suggesting that IL1beta may be related to hypotensive episodes and increased vascular permeability. These results pointed out the importance of the IL1beta (-511C>T) polymorphism in the development of clinical symptoms of dengue symptomology. PMID- 27228226 TI - Translational and Rotational Diffusion of Two Differently Charged Solutes in Ethylammonium Nitrate-Methanol Mixture: Does the Nanostructure of the Amphiphiles Influence the Motion of the Solute? AB - In this Article, we have investigated the translational and rotational diffusion of two structurally similar but differently charged solutes (rhodamine 6G perchlorate and fluorescein sodium salt) in ethylammonium nitrate (EAN)-methanol (CH3OH) mixture to understand the effect of added ionic liquid on the motion of the solutes. EAN and CH3OH both are amphiphilic molecules and characterized by an extended hydrogen bonding network. Recently, Russina et al. found that a wide distribution of clusters exist in the CH3OH rich region (0.10 <= chiEAN <= 0.15) and EAN molecules preserve their bulk-sponge-like morphology (Russina, O.; Sferrazza, A.; Caminiti, R.; Triolo, A. J. Phys. Chem. Lett. 2014, 5, 1738-1742). The effect of this microheterogeneous mixture on the solute's motion shows some interesting results compared to other PIL (protic ionic liquid)-cosolvent mixtures. Analysis of the time-resolved anisotropy data with the aid of Stokes Einstein-Debye (SED) hydrodynamic theory predicts that the reorientation time of both of the solutes appears close to the stick hydrodynamic line in the methanol rich region. The hydrogen bond accepting solutes experience specific interaction with CH3OH, and with increasing concentration of EAN, the specific interaction between the solute and solvent molecules is decreased while the decrease is more prominent in the low mole fraction of EAN due to the large size of cluster formation. The temperature dependent anisotropy measurements show that the hydrogen bonding interaction between EAN and CH3OH is increased with increasing temperature. Moreover, fluorescence correlation spectroscopy (FCS) shows the dynamic heterogeneity of the mixture which is due to the segregation of the alkyl chain of the PIL. Formation of a large cluster at a low mole fraction of IL (0.10 <= chiEAN <= 0.15) can be proved by the insensitivity of the translational diffusion and rotational activation energy of the solutes to the concentration of EAN. Thus, the result of the work suggests that the addition of EAN to the CH3OH affects the specific interaction between solute and solvent and, as a consequence, the translational motion as well as the rotational motion of the solutes are modulated. PMID- 27228227 TI - Bioactive Sesquiterpenoid and Polyacetylene Glycosides from Atractylodes lancea. AB - Nine new sesquiterpenoids (1-9), five new polyacetylenes (10-14), and six known compounds were isolated from the rhizomes of Atractylodes lancea. These new chemical structures were established using NMR, MS, and ECD data. Notably, compounds 3-5, the aglycone of which possesses two stereogenic centers (C-5 and C 7), exhibited similar ECD spectra to compounds 1 and 2, the aglycone of which possesses one stereogenic center (C-7). Such a difference was supported by the experimental and calculated ECD data and single-crystallographic analyses of 3a. In addition, compound 3 inhibited lipopolysaccharide-induced NO production in BV2 cells with an IC50 value of 11.39 MUM (positive control curcumin, IC50 = 4.77 MUM); compound 4 showed better hepatoprotective activity against N-acetyl-p aminophenol-induced HepG2 cell injury than the positive drug (bicyclol) at a concentration of 10 MUM (p < 0.001). PMID- 27228228 TI - Childhood diabetes in Africa. AB - PURPOSE OF REVIEW: This review summarizes the current state of diabetes in African children. RECENT FINDINGS: Type 1 diabetes is the most common form of pediatric diabetes in Africa. Significant improvements have been achieved over the last 6 years, including the training of more than 60 pediatric endocrinologists who are now practicing in 14 African nations, greater training of other healthcare providers, increased availability of insulin through the efforts of philanthropic organizations and industry, modestly better availability of testing supplies, and the introduction of patient education materials in native languages. However, there is still a long way to go before the standard-of care available to children in resource-rich nations is available to children with diabetes in Africa. SUMMARY: Here, we review the known epidemiology, pathophysiology, complications, and treatment of diabetes in children in Africa. PMID- 27228229 TI - Clinical correlates of autonomic response during tilting test in hypertrophic cardiomyopathy. AB - AIMS: The aim is to investigate autonomic nervous system imbalance in hypertrophic cardiomyopathy (HCM) by combining echocardiographic morphological and functional parameters with the analysis of the autonomic responses to orthostatic stress. METHODS: A 10-min tilting test and a transthoracic echocardiogram focused on ventricular septal systolic (S wave) and diastolic function (isovolumic relaxation time) were performed. Low frequency on high frequency ratio (LF/HF) and RR variation (variation of beat to beat intervals) in response to passive orthostatism were used as measures of sympathetic reflex activation [delta LF/HF (D-LF/HF) and delta RR (DRR), respectively]. Brain natriuretic peptide was measured. RESULTS: A total of 50 HCM patients were categorized in two groups: D-LF/HF more than 0 (group 1, sympathetic response) and D-LF/HF 0 or less (group 2, parasympathetic response). Patients in group 2 had higher New York Heart Association class, a more frequent history of atrial fibrillation (38 versus 9% P = 0.04) or syncope (46 versus 12% P = 0.01) and an increased septal isovolumic relaxation time (122 versus 82 ms P = 0.02). The same categorization was made according to lowest quartile DRR (DRR at least 23 ms, group 1: sympathetic response; DRR less than 23 ms, group 2: parasympathetic response). In group 2, patients were older, with advanced New York Heart Association class and higher history of atrial fibrillation. CONCLUSIONS: Autonomic response to passive orthostatism in HCM appears correlated with specific functional features of the hypertrophic heart. Altered neural afferent traffic from the localized area of segmental hypertrophy resulted in autonomic changes with a blunted sympathetic response, and an inappropriate vagal activation, especially in patients with history of atrial fibrillation or syncope. PMID- 27228233 TI - Overcoming beta-lactam resistance in Gram-negative pathogens. PMID- 27228234 TI - XPG Gene Polymorphisms and the Risk of Gastric Cardia Adenocarcinoma. AB - BACKGROUND: Polymorphisms in DNA repair genes can alter an individual's DNA repair capability and contribute to the risk of various cancers. AIMS: This study was designed to evaluate the association of single-nucleotide polymorphisms (SNPs) in the XPG gene with the risk of gastric cardia adenocarcinoma (GCA) in a high-incidence population in northern China. METHODS: Two SNPs from 431 GCA patients and 432 healthy controls were genotyped using the polymerase chain reaction/ligase detection reaction (PCR-LDR) method. RESULTS: The rs751402 C/T SNP T allele and the T/T genotype were associated with an increased risk of GCA in younger individuals (<=61 years) (odds ratio [OR] = 1.33 and 1.77, 95% confidence interval [CI] = 1.00-1.76 and 1.12-3.30, respectively). The rs873601 G/A SNP was not associated with susceptibility to GCA. CONCLUSIONS: Our findings indicate that the rs751402 C/T SNP has potential as a predictive marker for the risk of GCA and that carriers of the T/T genotype should receive periodic upper gastrointestinal fiber tests to facilitate the early detection and early treatment of GCA. PMID- 27228230 TI - Patient-reported outcome measures in arthroplasty registries Report of the Patient-Reported Outcome Measures Working Group of the International Society of Arthroplasty Registries Part II. Recommendations for selection, administration, and analysis. AB - - The International Society of Arthroplasty Registries (ISAR) Patient-Reported Outcome Measures (PROMs) Working Group have evaluated and recommended best practices in the selection, administration, and interpretation of PROMs for hip and knee arthroplasty registries. The 2 generic PROMs in common use are the Short Form health surveys (SF-36 or SF-12) and EuroQol 5-dimension (EQ-5D). The Working Group recommends that registries should choose specific PROMs that have been appropriately developed with good measurement properties for arthroplasty patients. The Working Group recommend the use of a 1-item pain question ("During the past 4 weeks, how would you describe the pain you usually have in your [right/left] [hip/knee]?"; response: none, very mild, mild, moderate, or severe) and a single-item satisfaction outcome ("How satisfied are you with your [right/left] [hip/knee] replacement?"; response: very unsatisfied, dissatisfied, neutral, satisfied, or very satisfied). Survey logistics include patient instructions, paper- and electronic-based data collection, reminders for follow up, centralized as opposed to hospital-based follow-up, sample size, patient- or joint-specific evaluation, collection intervals, frequency of response, missing values, and factors in establishing a PROMs registry program. The Working Group recommends including age, sex, diagnosis at joint, general health status preoperatively, and joint pain and function score in case-mix adjustment models. Interpretation and statistical analysis should consider the absolute level of pain, function, and general health status as well as improvement, missing data, approaches to analysis and case-mix adjustment, minimal clinically important difference, and minimal detectable change. The Working Group recommends data collection immediately before and 1 year after surgery, a threshold of 60% for acceptable frequency of response, documentation of non-responders, and documentation of incomplete or missing data. PMID- 27228236 TI - Bacterial Lipopolysaccharide, Lipopolysaccharide-Binding Protein, and Other Inflammatory Markers in Obesity and After Bariatric Surgery. AB - Obesity is associated with altered gut microbiota and low-grade inflammation. A key factor in the inflammatory process is endotoxin lipopolysaccharide (LPS). Plasma LPS levels and sensory agent lipopolysaccharide-binding protein (LBP) are shown to be elevated in obesity. This elevation may be due to increased intestinal permeability and incorporation of a high-fat diet accompanied by overfeeding. Bariatric surgery has become a popular treatment option that results in stable weight loss and improvement of obesity-related conditions. Studies outlined in this review show reduced LPS and LBP levels after different bariatric procedures. LPS receptor CD14 and mRNA expression toll-like receptor 2 (TLR2) and toll-like receptor 4 (TLR4) were also shown to have reduced levels following surgery. Changes in LPS and LPS components after bariatric surgery are shown to be linked to the surgical technique of the procedure and restriction of caloric intake. Additionally, changes in the gut microbiota provide some insight to the reduction of inflammatory markers after surgery. The beneficial effects of bariatric surgery are not dependent on weight loss alone. The inflammatory pathway plays a key role in the improvement of metabolic complications following surgery that should be further examined. Additional research is needed to evaluate short- and long-term changes of LPS and LPS components after bariatric surgery, including how those assessments can be applied to clinical practice. PMID- 27228235 TI - Long-term follow-up of renal function assessing serum cystatin C in dogs with diabetes mellitus or hyperadrenocorticism. AB - BACKGROUND: Serum cystatin C (sCysC) is used as biomarker for glomerular filtration rate (GFR). The effects of diabetes mellitus (DM) on renal function in dogs are unclear. Some renal variables have been evaluated in dogs with hyperadrenocorticism (HAC), but not sCysC. OBJECTIVES: The purpose of this study was the validation of a particle-enhanced nephelometric immunoassay (PENIA) for measuring canine sCysC, and to assess renal function in dogs with DM or HAC. METHODS: A PENIA was analytically validated for canine sCysC by determining imprecision and linearity. In a longitudinal 6-month study, renal function of 14 DM dogs was assessed, using serum creatinine, GFR, urinary protein-to-creatinine (UPC) ratio, urinary markers, systolic blood pressure (SBP), and sCysC, and compared to 17 healthy dogs at baseline. Furthermore, sCysC was measured at initial presentation and during a 12-month follow-up in 22 HAC dogs. RESULTS: The sCysC intra- and inter-assay variation coefficients were < 8% and highly linear (r = .997). About 33% and 67% of DM dogs had persistent proteinuria and systemic hypertension, respectively, but there were no significant differences in GFR, UPC, and urinary markers over time, and compared with healthy dogs at initial presentation. Serum CysC decreased significantly (P < .05) over time within the DM group. It did not change significantly over time within the HAC group. CONCLUSIONS: A PENIA measured sCysC linearly and precisely. There were no clinically relevant renal alterations over time in dogs with DM, although persistent proteinuria was observed. In dogs with HAC, sCysC measurement was not useful, although significant GFR changes occurred over time. PMID- 27228242 TI - Acute rheumatic fever and rheumatic heart disease. PMID- 27228241 TI - The functional brain connectome of the child and autism spectrum disorders. AB - Brain connectomics is a relatively new field of research that maps the brain's large-scale structural and functional networks at rest. The connectome of the human brain develops progressively from early infancy to late adolescence, and this review describes the theory behind the concept and its applicability to studying the development and dynamics of brain networks through graph theoretical metrics. We also describe how the brain connectome concept could further our understanding of autism spectrum disorders (ASD) CONCLUSION: Further research into the functional child brain connectome concept could enhance our understanding of atypical brain connectivity patterns presumed to be linked to ASD. PMID- 27228243 TI - Clinical Practice Guidelines: Role of Implant Design and Systems in Management of the Edentulous Maxilla. AB - No abstract available. PMID- 27228244 TI - Guided Implant Surgery in the Edentulous Maxilla: A Systematic Review. AB - PURPOSE: This systematic review verified the usefulness/limitations of static surgical guides during implant surgery in the edentulous maxilla. The PICO question was: "Does the use of digitally generated surgical guides vs conventional techniques affect the following outcomes: surgical complications, implant complications, prosthesis complications, implant survival, prosthesis survival, economics, patient satisfaction, and maintenance intervention?" MATERIALS AND METHODS: The electronic searches retrieved 2,588 unique articles from which eventually 36 full-text articles were read for eligibility. Because no randomized controlled clinical trials could be found, the PICO question had to be reformulated, now only looking to the outcome of digitally generated surgical guides without comparison with conventional techniques. RESULTS: Although long term data are lacking, the outcome of implants placed with a static guide and of the prosthetic reconstruction seems similar to that expected from conventional techniques. The number of surgical complications with guided surgery is negligible. Guided flapless implant surgery offers slightly more comfort for the patient; however, the economic benefits are unclear. CONCLUSION: Implant therapy via static surgical guides in the maxilla is predictable, with slightly more comfort for the patient but with only minor economic advantages. PMID- 27228245 TI - Clinical Practice Guidelines: Role of Imaging to Guide Implant Placement in the Edentulous Maxilla. AB - No abstract available. PMID- 27228246 TI - Biologics and Cell Therapy Tissue Engineering Approaches for the Management of the Edentulous Maxilla: A Systematic Review. AB - PURPOSE: The aim of this systematic review was to evaluate current and emerging regenerative approaches for implant site development in the edentulous atrophic maxilla using tissue engineering and regenerative medicine (TERM) principles and to identify priorities for future research. MATERIALS AND METHODS: Two independent examiners conducted a comprehensive search using specific keywords to identify original clinical studies using TERM for implant site development in the edentulous atrophic maxilla including indications for alveolar ridge preservation, horizontal alveolar augmentation, maxillary sinus augmentation, and augmentation of severe vertical or combined defects. Endpoints included clinical, radiographic, histologic, and patient-centered outcomes. RESULTS: The initial search identified 3,061 articles. The final selection included 89 articles, of which 12 evaluated alveolar ridge preservation, 6 horizontal defects, 61 maxillary sinus augmentation, and 11 management of severe vertical or combined defects. A summary of the main findings relative to the effect of TERM-based approaches applied for implant site development in the atrophic maxillary segments is presented. Marked heterogeneity among included studies prevented meaningful quantitative analysis. The following relevant effects of TERM-based therapies for site development in the edentulous atrophic maxilla were observed: (1) recombinant human bone morphogenetic protein-2 in an absorbable collagen sponge carrier increased bone augmentation; (2) recombinant human platelet derived growth factor BB in combination with freeze-dried bone allograft or beta tricalcium phosphate accelerated bone formation through accelerated remodeling of carrier biomaterials; (3) autologous cell therapy enhanced clinical and radiographic outcomes; (4) autologous cell therapy in alveolar ridge preservation provided superior histomorphometric outcomes (vital bone formation) at 6 weeks; and (5) platelet-rich plasma formulations combined with autologous bone grafts for maxillary sinus augmentation increased radiographic density and accelerated bone mineralization at 6 months. CONCLUSION: Clinical success has been demonstrated with the application of different TERM modalities for implant site development in the edentulous atrophic maxilla. However, indications are narrow and further study is needed. Clinical trials assessing meaningful outcomes, involving larger populations, and with longer follow-up are warranted to discern the effectiveness of the achieved results compared with a valid control. PMID- 27228247 TI - Clinical Practice Guidelines: Role of Biologics to Assist in Ridge Development. AB - No abstract available. PMID- 27228248 TI - Maxillary Complete Denture Outcomes: A Systematic Review of Patient-Based Outcomes. AB - PURPOSE: The aim of this systematic review is to report on the current knowledge regarding patient satisfaction as a primary outcome for maxillary complete denture therapy. We asked, "For the maxillary edentulous patient treated using maxillary dentures, what are the patient-based outcomes regarding quality of life and treatment satisfaction." MATERIALS AND METHODS: An electronic search of publications up to March 2014 was established using four databases: PubMed, Web of Science, Scopus, and Embase. To meet the ultimate goal of establishing clinical guidelines based on available information, prospective comparative studies, cohort prospective studies, and retrospective studies on more than 10 subjects were included. The electronic search identified 4,530 articles that were evaluated at the title, abstract, and article level to include 31 articles of interest. The patient-based outcomes and satisfaction data included were examined and reported. RESULTS: The studies included 5,485 participants. Of these, 2,685 were identified as wearing maxillary complete dentures. Reported mean ages ranged from 59.7 to 73.6 years. A systematic review indicated that the provision of new maxillary complete dentures for edentulous patients results in improved self reported satisfaction and oral health-related quality of life. The included reports, while providing evidence that complete denture satisfaction of participants and new dentures improve self-reported outcomes, did not include variables that influence these positive outcomes. CONCLUSION: A broad range of evidence supports the use of complete dentures for rehabilitation of the edentulous maxilla. When considering treatment of the edentulous maxilla, the expectations of patients for esthetic and phonetic (social) rehabilitation are high and can be met using maxillary complete dentures as the mode of prosthetic rehabilitation. Patients dissatisfied with new complete dentures may be referred for dental implant therapies involving fixed or removable prostheses. PMID- 27228249 TI - Protocols for the Maxillary Implant Overdenture: A Systematic Review. AB - PURPOSE: To evaluate patient-related outcomes in restoring the edentulous maxilla with an implant overdenture. MATERIALS AND METHODS: A comprehensive systematic review of the literature was conducted. Publications reporting patient-based outcomes with concomitant data on implant and/or prosthetic success were selected using predetermined inclusion criteria that were agreed upon by the two reviewers. RESULTS: Twenty-three publications related to 20 study cohorts were identified to meet the inclusion criteria for maxillary implant overdentures: two randomized controlled trials (RCTs), 13 prospective case series including two crossover trials, and five retrospective studies. CONCLUSION: An implant overdenture offers a stabilized removable solution for the edentulous maxilla, which provides increased patient satisfaction and quality of life improvement. A palateless design supported by four to six implants with a wide anteroposterior span has been successfully applied in some investigations. A higher failure rate was experienced with machined implants, particularly with short implants (length < 10 mm). Although both splinted and solitary anchorage systems are advocated, maintenance is higher for solitary attachments and inflammation is increased beneath the bars. Long-term maintenance care is essential for all designs. Well designed RCTs with larger sample cohorts with longer follow-up periods are required to amplify patient- and clinician-based outcomes. PMID- 27228250 TI - Bone Augmentation of the Edentulous Maxilla for Implant Placement: A Systematic Review. AB - PURPOSE: Multiple bone augmentation techniques are available to allow implant placement in the atrophic maxilla. However, questions remain, regarding which methods are most predictable and have the best dental implant survival rate (SR) in grafted bone. The aim of this systematic review was to evaluate literature from the last 30 years to determine predictability of bone grafting of the edentulous maxilla for implant placement as well as for implant SR. MATERIALS AND METHODS: A systematic review was performed of studies conducted during the period 1980 to 2014, specifically focusing on the edentulous maxilla and bone grafting. Surgical techniques discussed in the publications included were guided bone regeneration (GBR), sinus augmentation, onlay bone grafting, nasal floor grafting, and Le Fort I interpositional grafting. All identified articles were evaluated and screened to meet strict inclusion criteria of at least 10 patients, complete maxillary edentulism, 1-year follow-up, and information regarding implant SR. A total of 974 articles were identified with electronic and manual searches. On further evaluation of the titles and abstracts, 44 articles were excluded. Full texts of the articles that met the inclusion criteria were reviewed, of which 40 articles were included in the systematic review. RESULTS: For onlay bone grafting, 16 studies were included and analyzed, and the weighted mean implant SR was 85.2%. For the GBR technique, two studies were included, with a reported SR ranging from 96.1% to 100%. For Le Fort I interpositional grafting, 11 studies were included, with a weighted mean SR of 89.6%. For the sinus augmentation technique, 12 studies were investigated and the weighted mean SR was 91.5%. For the combination technique, six studies were analyzed and the weighted mean SR was 93.6%. CONCLUSIONS: All five treatment modalities discussed-onlay bone grafting, GBR, Le Fort I interpositional grafting, maxillary sinus augmentation, and/or nasal floor inlay grafting or the combination approach-can be successfully used to augment edentulous maxillary ridge with high implant SRs. PMID- 27228251 TI - Maxillary Implant-Supported Fixed Prosthesis: A Survey of Reviews and Key Variables for Treatment Planning. AB - PURPOSE: This review was conducted to provide information to support the establishment of clinical guidelines for the treatment of maxillary edentulism using implant-supported fixed dental prostheses. MATERIALS AND METHODS: Initial efforts were directed toward a systematic review with a defined PICO question: "For maxillary edentulous patients with dental implants treated using a fixed prosthesis, what is the impact of prosthesis design on prosthesis survival and complications?" Following a title search of more than 3,000 titles identified by electronic search of PubMed, 180 articles were identified that addressed the clinical evaluation of maxillary dental implant prostheses. The broad methodologic heterogeneity and clinical variation among reports precluded this approach for a systematic review. The information was extracted using a standardized extraction table by two pairs of investigators, and the reported outcomes were then summarized according to reported outcomes for implant prostheses supported by four, six, or eight implants using unitary or segmented prostheses. RESULTS: This review indicated that high prosthetic survival is observed using all approaches. The advantages of using fewer implants and a unitary prosthesis are revealed in the surgical phases, and complications commonly involve the fracture or detachment of acrylic teeth and reduced access for proper oral hygiene and related biologic complications. Using six implants typically involved grafting of posterior regions with advantages of reduced cantilevers and redundancy of implant support. Reduced prosthesis survival in these cases was associated with poor implant distribution. Segmented prostheses supported by six or more implants offered greater prosthetic survival, perhaps due to posterior implant placement. Advantages of a segmented prosthesis included pragmatic issues of accommodating divergent implants, attaining passive fit, combining prosthetic materials, and relative simplicity of repair. CONCLUSION: The existing literature demonstrated that maxillary edentulism may be treated successfully using alternative approaches involving four, six, or more implants. The procedural diagnostics, treatment, and maintenance for these different approaches all require advanced knowledge and careful communication among the therapeutic team. The prosthetic therapeutic success requires maintenance, repair, and possible multiple replacements within the patient's lifetime. PMID- 27228252 TI - Clinical Practice Guidelines: Role of Prosthetic Management of the Edentulous Maxilla. AB - No abstract available. PMID- 27228253 TI - Clinical Practice Guidelines: Role of Bone Augmentation for Implant Placement in the Edentulous Maxilla. AB - No abstract available. PMID- 27228254 TI - A Systematic Review of the Role of Implant Design in the Rehabilitation of the Edentulous Maxilla. AB - PURPOSE: To identify and critically appraise scientific publications evaluating the possible effect of implant design on treatment outcomes in the rehabilitation of patients with a fully edentulous maxilla. MATERIALS AND METHODS: Scientific reports were sought in three electronic bibliographic databases, combined with searches for meeting abstracts, and in the grey literature. English, German, or Scandinavian scientific publications on prospective or retrospective longitudinal studies with effects of an implant design or feature on the treatment outcomes were eligible. Minimum requirement for inclusion was at least 10 study participants who were followed up for at least 2 years after implant loading. The PRISMA guidelines were followed for selecting data to extract from the individual studies. These were characteristics of the individual studies, risk of bias within individual studies, and the results of individual studies. Three editorial teams independently identified and extracted the data. RESULTS: The search resulted in 998 primary studies, of which 525 met the inclusion criteria and were read in full text. Of these, 105 studies were included in qualitative syntheses. Seventeen studies were designed with an objective to assess effects of implant design or feature on outcomes, 23 studies described tilted implants to enable placement of longer implants, 30 studies reported effects of implants placed in zygomatic bone with or without additional alveolar implants, and 9 studies reported effects of implants placed in pterygoid bone or other bony buttresses with or without additional alveolar implants. Sixteen articles reported bone augmentation with simultaneous or delayed implant placement in patients with a predominantly Cawood-Howell bone class V and VI maxilla. Ten papers reported effects of implant design on outcomes, despite the lack of an a priori stated objective to assess a particular implant design or feature. There is a lack of compelling data to state that one particular implant system or design feature stands out amidst others, when applied to restoring the fully edentulous maxilla with implant-retained prostheses. CONCLUSION: This systematic review failed to identify compelling evidence to conclude that any particular implant or feature affects the treatment outcome in patients with a fully edentulous maxilla. PMID- 27228255 TI - Academy of Osseointegration's Summit on Clinical Practice Guidelines for the Edentulous Maxilla: Overview, Process, and Outcomes-Changing the Face of Implant Dentistry. AB - PURPOSE: Starting in 2012, the Academy of Osseointegration initiated the planning process for an AO Summit to develop clinical practice guidelines (CPGs) for management of the edentulous maxilla. MATERIALS AND METHODS: A planning committee led by Professor Clark Stanford and Dr Ole Jensen created a work plan based on five domain areas to be addressed by the summit. The five domain areas were defined as: (1) role of grafting for ridge development for implant placement, (2) role of implant design and systems in management of the edentulous maxilla, (3) role of imaging to guide implant placement, (4) role of biologics to assist in ridge development, and (5) role of prosthetic management. RESULTS: The summit was held in August 2014, and the results are presented in this overview. All of the supporting systematic reviews and the detailed CPGs are presented in this special edition of JOMI. CONCLUSION: While the evidence was observed to be weak in regard to the literature for most of the systematic reviews, the summit strived to establish the current best evidence and practical CPGs that will assist clinicians in practice. PMID- 27228257 TI - The relevance of experiential avoidance in breast cancer distress: insights from a psychological group intervention. AB - BACKGROUND: Research on the implication of experiential avoidance in the aetiology and maintenance of diverse forms of psychopathology has grown considerably over the last 10 years. However, the potential contribution of experiential avoidance to cancer-related distress has received limited attention. Accordingly, the objective of this study was to examine the association between experiential avoidance, symptoms of anxiety and depression, and quality of life (QoL) during the course of a psychological group intervention for women with breast cancer. METHODS: Fifty-four women with breast cancer participated in a psychological group intervention designed to reduce distress and improve QoL. Participants completed measures of experiential avoidance, anxiety and depressive symptoms, and QoL upon the first and last sessions. RESULTS: A path analysis revealed that, after controlling for baseline measures, smaller reductions in experiential avoidance during the course of the intervention predicted smaller reductions in anxiety and depressive symptoms. Also, experiential avoidance had a negative indirect effect on QoL via depressive symptoms. CONCLUSIONS: Experiential avoidance may perpetuate the emotional problems commonly found in women with breast cancer and attenuate improvements associated with participation in psychological interventions. Implications for clinical practice in psycho oncology are discussed. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27228256 TI - Breast Cancer Risk From Modifiable and Nonmodifiable Risk Factors Among White Women in the United States. AB - Importance: An improved model for risk stratification can be useful for guiding public health strategies of breast cancer prevention. Objective: To evaluate combined risk stratification utility of common low penetrant single nucleotide polymorphisms (SNPs) and epidemiologic risk factors. Design, Setting, and Participants: Using a total of 17 171 cases and 19 862 controls sampled from the Breast and Prostate Cancer Cohort Consortium (BPC3) and 5879 women participating in the 2010 National Health Interview Survey, a model for predicting absolute risk of breast cancer was developed combining information on individual level data on epidemiologic risk factors and 24 genotyped SNPs from prospective cohort studies, published estimate of odds ratios for 68 additional SNPs, population incidence rate from the National Cancer Institute-Surveillance, Epidemiology, and End Results Program cancer registry and data on risk factor distribution from nationally representative health survey. The model is used to project the distribution of absolute risk for the population of white women in the United States after adjustment for competing cause of mortality. Exposures: Single nucleotide polymorphisms, family history, anthropometric factors, menstrual and/or reproductive factors, and lifestyle factors. Main Outcomes and Measures: Degree of stratification of absolute risk owing to nonmodifiable (SNPs, family history, height, and some components of menstrual and/or reproductive history) and modifiable factors (body mass index [BMI; calculated as weight in kilograms divided by height in meters squared], menopausal hormone therapy [MHT], alcohol, and smoking). Results: The average absolute risk for a 30-year-old white woman in the United States developing invasive breast cancer by age 80 years is 11.3%. A model that includes all risk factors provided a range of average absolute risk from 4.4% to 23.5% for women in the bottom and top deciles of the risk distribution, respectively. For women who were at the lowest and highest deciles of nonmodifiable risks, the 5th and 95th percentile range of the risk distribution associated with 4 modifiable factors was 2.9% to 5.0% and 15.5% to 25.0%, respectively. For women in the highest decile of risk owing to nonmodifiable factors, those who had low BMI, did not drink or smoke, and did not use MHT had risks comparable to an average woman in the general population. Conclusions and Relevance: This model for absolute risk of breast cancer including SNPs can provide stratification for the population of white women in the United States. The model can also identify subsets of the population at an elevated risk that would benefit most from risk-reduction strategies based on altering modifiable factors. The effectiveness of this model for individual risk communication needs further investigation. PMID- 27228258 TI - A Risk Prediction Model Based on Lymph-Node Metastasis in Poorly Differentiated Type Intramucosal Gastric Cancer. AB - BACKGROUND AND AIM: Endoscopic submucosal dissection (ESD) for undifferentiated type early gastric cancer is regarded as an investigational treatment. Few studies have tried to identify the risk factors that predict lymph-node metastasis (LNM) in intramucosal poorly differentiated adenocarcinomas (PDC). This study was designed to develop a risk scoring system (RSS) for predicting LNM in intramucosal PDC. METHODS: From January 2002 to July 2015, patients diagnosed with mucosa-confined PDC, among those who underwent curative gastrectomy with lymph node dissection were reviewed. A risk model based on independent predicting factors of LNM was developed, and its performance was internally validated using a split sample approach. RESULTS: Overall, LNM was observed in 5.2% (61) of 1169 patients. Four risk factors [Female sex, tumor size >= 3.2 cm, muscularis mucosa (M3) invasion, and lymphatic-vascular involvement] were significantly associated with LNM, which were incorporated into the RSS. The area under the receiver operating characteristic curve for predicting LNM after internal validation was 0.69 [95% confidence interval (CI), 0.59-0.79]. A total score of 2 points corresponded to the optimal RSS threshold with a discrimination of 0.75 (95% CI 0.69-0.81). The LNM rates were 1.6% for low risk (<2 points) and 8.9% for high risk (>=2 points) patients, with a negative predictive value of 98.6% (95% CI 0.98-1.00). CONCLUSIONS: A RSS could be useful in clinical practice to determine which patients with intramucosal PDC have low risk of LNM. PMID- 27228260 TI - Huntington disease. PMID- 27228259 TI - The lymphatic system: A new frontier in hepatology. PMID- 27228262 TI - Experimental Toxoplasmosis in Rats Induced Orally with Eleven Strains of Toxoplasma gondii of Seven Genotypes: Tissue Tropism, Tissue Cyst Size, Neural Lesions, Tissue Cyst Rupture without Reactivation, and Ocular Lesions. AB - BACKGROUND: The protozoan parasite Toxoplasma gondii is one of the most widely distributed and successful parasites. Toxoplasma gondii alters rodent behavior such that infected rodents reverse their fear of cat odor, and indeed are attracted rather than repelled by feline urine. The location of the parasite encysted in the brain may influence this behavior. However, most studies are based on the highly susceptible rodent, the mouse. METHODOLOGY/PRINCIPAL FINDINGS: Latent toxoplasmosis was induced in rats (10 rats per T. gondii strains) of the same age, strain, and sex, after oral inoculation with oocysts (natural route and natural stage of infection) of 11 T. gondii strains of seven genotypes. Rats were euthanized at two months post inoculation (p.i.) to investigate whether the parasite genotype affects the distribution, location, tissue cyst size, or lesions. Tissue cysts were enumerated in different regions of the brains, both in histological sections as well in saline homogenates. Tissue cysts were found in all regions of the brain. The tissue cyst density in different brain regions varied extensively between rats with many regions highly infected in some animals. Overall, the colliculus was most highly infected although there was a large amount of variability. The cerebral cortex, thalamus, and cerebellum had higher tissue cyst densities and two strains exhibited tropism for the colliculus and olfactory bulb. Histologically, lesions were confined to the brain and eyes. Tissue cyst rupture was frequent with no clear evidence for reactivation of tachyzoites. Ocular lesions were found in 23 (25%) of 92 rat eyes at two months p.i. The predominant lesion was focal inflammation in the retina. Tissue cysts were seen in the sclera of one and in the optic nerve of two rats. The choroid was not affected. Only tissue cysts, not active tachyzoite infections, were detected. Tissue cysts were seen in histological sections of tongue of 20 rats but not in myocardium and leg muscle. CONCLUSION/SIGNIFICANCE: This study reevaluated in depth the rat model of toxoplasmosis visualizing cyst rupture and clarified many aspects of the biology of the parasite useful for future investigations. PMID- 27228263 TI - Dynamic cerebral reorganization in the pathophysiology of schizophrenia: a MRI derived cortical thickness study. AB - BACKGROUND: A structural neuroanatomical change indicating a reduction in brain tissue is a notable feature of schizophrenia. Several pathophysiological processes such as aberrant cortical maturation, progressive tissue loss and compensatory tissue increase could contribute to the structural changes seen in schizophrenia. METHOD: We studied cortical thickness using surface-based morphometry in 98 clinically stable patients with schizophrenia and 83 controls. Using a pattern classification approach, we studied whether the features that discriminate patients from controls vary across the different stages of the illness. Using a covariance analysis, we also investigated if concurrent increases accompany decreases in cortical thickness. RESULTS: Very high levels of accuracy (96.3%), specificity (98.8%) and sensitivity (88%) were noted when classifying patients with <2 years of illness from controls. Within the patient group, reduced thickness was consistently accompanied by increased thickness in distributed brain regions. A pattern of cortical amelioration or normalization (i.e. reduced deviation from controls) was noted with increasing illness duration. While temporo-limbic and fronto-parietal regions showed reduced thickness, the occipital cortex showed increased thickness, especially in those with a long-standing illness. CONCLUSION: A compensatory remodelling process might contribute to the cortical thickness variations in different stages of schizophrenia. Subtle cerebral reorganization reflecting the inherent plasticity of brain may occur concomitantly with processes contributing to tissue reduction in adult patients with schizophrenia. PMID- 27228264 TI - A randomized clinical trial of a supportive versus a skill-based couple-focused group intervention for breast cancer patients. AB - OBJECTIVE: The aims of this study were to evaluate the efficacy of the 2 types of couple-focused group interventions on couples' psychological and relationship functioning, and to examine possible moderators for each intervention. METHOD: Three hundred and two women with early stage breast cancer who were recruited within 1 year of diagnosis and their spouses were randomly assigned to either an 8 session enhanced couple-focused group intervention (ECG) or a couples' support group (SG). Couples completed surveys at 4 time points: preintervention, 1 week postgroup, 6 months, and 1 year. RESULTS: Analyses indicated that anxiety, depressive symptoms, and cancer-specific distress declined and positive well being improved for couples enrolled in both ECG and SG. Thus, neither treatment was superior in terms of reduction of distress or improvements in positive well being. Moderator effects indicated that, among patients reporting higher levels of cancer-specific preintervention distress, anxiety, depression, and well-being over the 1-year postintervention time period were significantly lower among SG couples than ECG couples. When patient cancer-specific preintervention distress was low, these 3 outcomes were more positive in ECG relative to SG. A similar pattern with regard to anxiety was illustrated when the moderator effects for perceived partner unsupportive behavior was examined, and a similar pattern was seen for anxiety and well-being for preintervention marital satisfaction. CONCLUSIONS: A couple-focused supportive group therapy may be more effective for distressed patients, whereas a structured, skills-based couples' group therapy may be more effective for less distressed patients. (PsycINFO Database Record PMID- 27228265 TI - Does continuous positive airway pressure for extubation in congenital tracheoesophageal fistula increase the risk of anastomotic leak? A retrospective cohort study. AB - AIM: Immediate post-operative care of tracheoesophageal fistula (TEF) and oesophageal atresia (EA) requires mechanical ventilation. Early extubation is preferred, but subsequent respiratory distress may warrant re-intubation. Continuous positive airway pressure (CPAP) is a well-established modality to prevent extubation failures in preterm infants. However, it is not favoured in TEF/EA, because of the theoretical risk of oesophageal anastomotic leak (AL). The aim of this study was to find out if post-extubation CPAP is associated with increased risk of AL. METHODS: Retrospective cohort study (2007-2014). RESULTS: Fifty-one infants underwent primary repair in the newborn period. Median age at surgery was 24 h (interquartile range: 12, 24). In the post-extubation period, 10 received CPAP, whereas 41 did not. The median post-operative day at the commencement of CPAP was 2.5 days (interquartile range: 1, 6 days). Zero out of 10 in the CPAP group and 4/41 in the 'no CPAP' group developed AL on routine post operative contrast studies (P = 0.57). Zero out of 10 in the CPAP group and 1/41 in the 'no CPAP group' developed recurrence of TEF necessitating re-surgery (P = 1.00). The neonate with recurrent fistula also had coarctation of aorta and needed protracted hospitalisation of 6 months, mainly because of the recurrence of TEF. CONCLUSION: The use of CPAP in the immediate post-extubation period after corrective surgery for TEF/EA appears to be safe and may not be associated with increased risk of AL or recurrence of the fistula. Information from other centres, surveys and large databases is needed to define the benefits and risks of use of CPAP in these infants. PMID- 27228266 TI - Effects of orlistat vs. metformin on weight loss-related clinical variables in women with PCOS: systematic review and meta-analysis. AB - AIMS: The aim of this study was to assess the effects of orlistat on weight loss related clinical variables in overweight/obese women with polycystic ovary syndrome (PCOS) and to compare treatment with orlistat vs. metformin in this group. METHODS: We conducted a systematic review and meta-analysis of the evidence about the use of orlistat in women with PCOS. We searched the literature published until May 2015 in MEDLINE, Cochrane Central Register of Controlled Trials and LILACS. RESULTS: Of 3951 studies identified, nine were included in the systematic review (three prospective, non-randomised studies and six randomised control trials). Eight studies used the Rotterdam criteria and 1 used NIH criteria to diagnose PCOS. Data suggest that orlistat promotes a significant reduction in BMI/weight in overweight/obese PCOS women. Eight studies evaluated orlistat impact on testosterone. Seven reported an improvement in testosterone levels. Eight studies evaluated impact on insulin resistance, and five reported improvement. Finally, five studies evaluated impact on lipid profile, and four reported improvement. Three randomised control trials were included in the fixed effects model meta-analysis for a total of 121 women with PCOS. Orlistat and metformin had similar positive effects on BMI (-0.65%, 95% CI: -2.03 to 0.73), HOMA (-3.60%, 95% CI: -16.99 to 9.78), testosterone (-2.08%, 95% CI: -13.08 to 8.93) and insulin (-5.51%, 95% CI: -22.27 to 11.26). CONCLUSION(S): The present results suggest that orlistat leads to significant reduction in BMI/body weight in PCOS. In addition, the available evidence indicates that orlistat and metformin have similar effects in reducing BMI, HOMA, testosterone and insulin in overweight/obese PCOS women. This study was registered in PROSPERO under number CRD42014012877. PMID- 27228267 TI - Psychological Distress, Physical Symptoms, and the Role of Attachment Style in Acupuncture. AB - Context * Attachment research has contributed significantly to the understanding of the origins as well as the treatment of psychological and somatic distress; however, no study so far has explored the role of attachment in acupuncture. The effects on endogenous opioids of both acupuncture and intimate interpersonal bonding as well as clients' reliance on a practitioner's care may suggest that individual differences in attachment style could be linked to individual differences in responses to acupuncture. Objective * The study intended to investigate the role of attachment style in determining outcomes in acupuncture. Design * A pre- and postintervention, single group, quasiexperimental design was used. Setting * Treatment and data collection took place in an acupuncture clinic in London, England, United Kingdom. PARTICIPANTS: Eighty-two acupuncture clients with a mean age of 46 +/- 14.53 took part in the study. Participants suffered from a variety of somatic and psychological complaints. Intervention * Traditional Chinese acupuncture was administered to all participants in weekly sessions, with the mean number of sessions that participants received being 5 +/- 3.5. Outcome Measures * Psychological distress and somatic symptoms were measured using the General Heath Questionnaire (GHQ-12) and the Bradford Somatic Inventory (BSI), respectively. The Relationship Questionnaire (RQ) was used to assess attachment style, with the 4 styles being secure, dismissing, preoccupied, and fearful. Results * After treatment, both somatic and nonsomatic distress were reduced (P < .001), whereas pretreatment associations between attachment insecurity and symptom severity ceased to exist. The strength rather than the quality of the attachment style moderated the reduction in somatic distress, whereas the preoccupied style of attachment moderated the effects of medically unexplained symptoms on distress. Conclusions * Attachment style may have an impact on acupuncture outcomes by predisposing individuals to different patterns of opioid elicitation and a different manner of relating to the practitioner. PMID- 27228268 TI - Acupressure and Transcutaneous Electrical Acupoint Stimulation for Improving Uremic Pruritus: A Randomized, Controlled Trial. AB - Context * Uremic pruritus, a frequent and compromising symptom for patients with advanced or end-stage renal disease (ESRD), strongly reduces the patient's quality of life. Pruritus may be extremely difficult to control because therapeutic options are limited. Topical products are frequently used for easing pruritus, but their effects are generally temporary and marginal. Although acupressure and electrical-stimulation methods for the application of acupressure have been evaluated separately in terms of pruritus efficiency in different studies, the existence of any difference between the efficacies of the 2 methods has not been assessed yet. Objective * The study intended to test the effectiveness of acupressure and transcutaneous electrical acupoint stimulation (TEAS) on uremic pruritus in patients who were receiving the routine hemodialysis treatment. Design * The study was a randomized, controlled trial. Setting * The study took place in hemodialysis units located in hemodialysis centers in Turkey. Participants * Participants were patients in the hemodialysis units who were under hemodialysis treatment and had experienced uremic pruritus. Intervention * Participants were randomly assigned to the acupressure group (intervention group), the TEAS group (intervention group), or the control group. For the 2 intervention groups, the treatment was applied 3 */wk during the 4 wk of the study on the large intestine (LI-11) acupuncture points in the arm, for a total of 12 sessions. Outcome Measures * The study measured the severity of participants' pruritus using a patient information form and a visual analogue scale (VAS). The data were collected at baseline and posttreatment. Results * A total of 75 patients participated in the study. The results indicated that patients in the acupressure and TEAS groups had significant reductions from baseline to posttreatment in their levels of discomfort from uremic pruritus compared with patients in the control group. However, no differences existed between the acupressure and the TEAS patients in terms of outcome measures. Conclusions * The research team concluded that both acupressure and TEAS applied to hemodialysis patients was effective in reducing uremic pruritus. The study provided support for an alternative method for health care providers in managing hemodialysis patients with symptoms of uremic pruritus. PMID- 27228269 TI - Perforators, the Underlying Anatomy of Acupuncture Points. AB - Context * As a critical concept in acupuncture, acupuncture points, or acupoints for short, are currently believed to be 3-dimensional structures composed of skin, muscles, tendons, nerves, blood vessels, lymph nodes, and other special tissues. No known specific tissue or organ has been confirmed to be an acupoint. However, from a microsurgeon's point of view, a special vascular structure exists around each acupoint (ie, perforators or arterioles of 0.3-1.5 mm that pierce deeply through the fascia). Objective * The current research team investigated the theory that perforators are the anatomical basis of acupoints. Design * A reference list of acupoints and of perforators near the acupoints was proposed, and the distributions were analyzed. Using the World Health Organization (WHO) list, "Standard Acupuncture Point Locations in the Western Pacific Region," 2 experienced acupuncturists identified the needling depth and angle as well as verified the acupoint locations. Perforators with amplitudes of 1 cm or more were identified by 3 veteran microsurgeons. Setting * The study was carried out in an osteopathic research center at the 89th Hospital of the People's Liberation Army, in Weifang, Shandong, China. From October 2013 to October 2014, patients who required skin flap transplantation were enrolled for observation. Outcome Measures * To evaluate the theory, the current research team observed subcutaneous perforating points in flap donor sites and operative incision areas and compared those points with the acupoints located by acupuncturists. Results * The perforators and acupoints were found to be closely correlated. Several distribution patterns of acupoints and perforators have emerged and further confirmed the research team's theory. Conclusions * The hypothesis could facilitate theoretical understanding of the mechanism and essence of acupuncture. PMID- 27228270 TI - Acupuncture is Effective for Chronic Knee Pain: A Reanalysis of the Australian Acupuncture Trial. AB - Context * In the October 2014 issue of the Journal of the American Medical Association (JAMA), Hinman et al published the results of an Australian clinical trial on acupuncture in a paper entitled "Acupuncture for Chronic Knee Pain: A Randomized Clinical Trial" (JAMA report), in which they concluded that neither acupuncture nor laser acupuncture had any greater effects than sham laser acupuncture for pain or function for patients aged 50 y and older with moderate to-severe knee pain. That study has been criticized extensively by international scholars for its validity because serious methodological flaws existed throughout the study's design, implementation, and conclusions. Objective * The current study intended to re-examine the prior study's conclusions about the efficacy of acupuncture for chronic knee pain. Design * The current research team performed a reanalysis of relevant data from the JAMA report. Intervention * The original study included 4 groups: (1) an acupuncture group, which received needle acupuncture, inferred by the current authors to have been set up to be a positive control in the original study; (2) a laser acupuncture group, which received laser acupuncture; (3) a sham laser acupuncture group, which received sham laser acupuncture and acted as the negative controls for the laser acupuncture intervention; and (4) a control group, which received conventional care but no acupuncture or laser treatments. The study lasted 12 wk. Outcome Measures * The measures included evaluations in the following areas: (1) poststudy modifications an evaluation of the consistency of the JAMA report with the study's intentions as identified for a grant that was originally approved and funded by the Australian National Health and Medical Research Council (NHMRC) in 2009, as indicated in the study's trial registration, and as compared with the published protocols and to the study's originally stated objectives; (2) high heterogeneity an assessment of the heterogeneity among the 4 groups for the overall outcome related to pain; (3) ineffectiveness of laser acupuncture-an analysis of laser acupuncture's efficacy for chronic knee pain as stated in the JAMA report, using effect size (ES); (4) effectiveness of acupuncture-a reanalysis of acupuncture's efficacy for chronic knee pain in comparison with the original analysis in the JAMA report, using ES; and (5) acupuncture after data adjustment-a new analysis of acupuncture's efficacy for chronic knee pain using data from the original study that was discussed in the JAMA report, using ES, with an estimation after data adjustment and elimination of the dilution effect of the Zelen design. Results * Contrary to a general impression that acupuncture was the focus, laser acupuncture was the primary intervention tested in the actual study, "Laser Acupuncture in Patients With Chronic Knee Pain: A Randomized, Placebo Controlled Trial." The study discussed in the JAMA report was neither a truly randomized, controlled trial (RCT) for acupuncture nor was it an appropriately designed, randomized study in general. High heterogeneity was found among its groups in the evaluation of overall pain in patients. Both the ES of 0.60 that had been set by Hinman et al for the minimal clinically important difference (MCID) and the resulting interpretation of results in the JAMA report were not appropriate. Using the original study's criteria of efficacy, the reanalysis has confirmed that the laser acupuncture was not effective, whereas the acupuncture was found to be moderately effective for chronic knee pain (P < .05) for both overall pain and function at 12 wk, with an ES of 0.58, or after the adjustment of the data, with an ES of 0.67. Conclusions * The JAMA study was neither a conventional RCT nor an appropriately randomized trial, and its results are probably invalid. The ES of 0.60 for the MCID that was used in the JAMA study and the resulting explanation were not appropriate. Even with an ES of 0.60 for the MCID, acupuncture remained effective after data adjustment. Consequently, compared with conventional care, acupuncture treatment was found to be moderately effective for chronic knee pain in patients aged 50 y and older. PMID- 27228271 TI - Chinese Medicinal Herbs in the Treatment of Upper Airway Cough Syndrome: A Systematic Review of Randomized, Controlled Trials. AB - Context * Upper airway cough syndrome (UACS), previously called postnasal drip syndrome (PNDS), has been considered universally to be one of the most common causes of chronic cough. As an important part of complementary and alternative therapy, traditional Chinese medicine (TCM) has found an exact curative therapy for chronic cough through clinical practice for thousands of years. Objective * The aim of the current review was to investigate systematically the beneficial and adverse effects of Chinese medicinal herbs (CMH) in the treatment of UACS. Design * The research team performed searches in 11 main databases from respective inception to October 31, 2015, supplemented with manual retrieval of other data. Only randomized, controlled trials (RCTs) reporting on the effectiveness of CMH in patients with UACS were included. Descriptive and quantitative data on the studies' designs, population demographics, interventions, outcomes, and methodological quality were extracted and tabulated. Methodological quality was assessed using the Cochrane risk-of-bias system and the quality of the evidence was evaluated using the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) system. Participants * The reviewed studies included 1355 participants-720 in the CMH groups and 635 in the control groups-of both genders, from various professional and ethnic groups, and with a wide range of ages. They all had a duration of cough symptoms of longer than 8 wk and a clinical diagnosis of chronic cough induced by UACS that was supported by appropriate physical findings. Outcome Measures * The primary outcomes included (1) TCM recovery rate and (2) TCM cough symptom score. TCM's curative effect was calculated as the cumulative percentage of the symptom-score reduction (PSSR), estimated between baseline and postintervention. The cough symptom scores were graded according to the Chinese Criteria Guiding Principle of Clinical Research on New Drugs of TCM, with the scores being classified into 4 grades. Those scores ranged from 0-3 (ie, 0, 1, 2, 3, respectively), or 0-9 (ie, 0, 3, 6, 9, respectively), with the higher scores signifying a more frequent and severe cough. Results * A total of 16 studies that had been published in Chinese journals was ultimately identified for the review. The majority of methodological judgments demonstrated an unclear risk of bias. A meta-analysis was conducted using a random effects model due to the poor homogeneity of the studies. Compared with Western medicine (WM), patients in both the CMH groups and the integrated therapy groups showed (1) a higher TCM recovery rate; (2) better relief of primary symptoms, including cough and postnasal dripping; (3) a reduction in physical signs, including the cobblestone appearance of the oropharyngeal mucosa or mucus in the oropharynx; and (4) a lower risk of cough relapse. No severe adverse events occurred in either group. Conclusions * CMH may be a safe and effective alternative for the treatment of UACS. The study highlighted the paucity of reliable clinical evidence for CMH and the need for RCTs of higher quality in the future. PMID- 27228272 TI - Electromagnetic Field Devices and Their Effects on Nociception and Peripheral Inflammatory Pain Mechanisms. AB - Context * During cell-communication processes, endogenous and exogenous signaling affects normal and pathological developmental conditions. Exogenous influences, such as extra-low-frequency (ELF) electromagnetic fields (EMFs) have been shown to affect pain and inflammation by modulating G-protein coupling receptors (GPCRs), downregulating cyclooxygenase-2 (Cox-2) activity, and downregulating inflammatory modulators, such as tumor necrosis factor alpha (TNF-alpha) and interleukin 1 beta (IL-1beta) as well as the transcription factor nuclear factor kappa B (NF-kappaB). EMF devices could help clinicians who seek an alternative or complementary treatment for relief of patients chronic pain and disability. Objective * The research team intended to review the literature on the effects of EMFs on inflammatory pain mechanisms. Design * We used a literature search of articles published in PubMed using the following key words: low-frequency electromagnetic field therapy, inflammatory pain markers, cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), opioid receptors, G protein coupling receptors, and enzymes. Setting * The study took place at the Wake Forest School of Medicine in Winston-Salem, NC, USA. Results * The mechanistic pathway most often considered for the biological effects of EMF is the plasma membrane, across which the EMF signal induces a voltage change. Oscillating EMF exerts forces on free ions that are present on both sides of the plasma membrane and that move across the cell surface through transmembrane proteins. The ions create a forced intracellular vibration that is responsible for phenomena such as the influx of extracellular calcium (Ca2+) and the binding affinity of calmodulin (CaM), which is the primary transduction pathway to the secondary messengers, cAMP and cGMP, which have been found to influence inflammatory pain. Conclusions * An emerging body of evidence indicates the existence of a frequency-dependent interaction between the mechanical interventions of EMF and cell signaling along the peripheral inflammatory pain pathway. PMID- 27228274 TI - Christie Fleetwood, ND, RPh: The Essential Role of Pharmaceutical Knowledge in Naturopathic Practice. AB - No Abstract Available. PMID- 27228273 TI - Use of Strontium Chloride for the Treatment of Osteoporosis: A Case Report. AB - Context * Strontium ranelate is an approved prescription medication for the treatment of osteoporosis in Europe. In the United States, the only available forms of strontium are those that are nonprescription, dietary supplements. Some patients with osteoporosis use those products because they prefer an alternate treatment to conventional therapy. Currently, no controlled trials have been conducted on the effectiveness of the supplements for treating osteoporosis. Objective * The study intended to examine how one woman responded to the use of strontium chloride. Design * This was a retrospective case study. Setting * The woman in the case study was a patient in an academic urban women's health clinic in Minneapolis, MN, USA. Participant * The participant was a postmenopausal woman with a history of vertebral fracture. Intervention * The participant took 680 mg daily of strontium chloride for 2.5 y. Outcome Measures * The patient had begun receiving dual-energy X-ray absorptiometry (DXA) scans in 2004 and continued to receive follow-up scans every 2 y. After beginning strontium therapy in December 2011, she received DXA scans in March 2012 and May 2014. Results * During the study, the analysis of the patient's DXA scans showed a positive increase in the bone mineral density (BMD) of her vertebrae and her right hip and maintenance of her BMD in her left hip. Conclusions * Although the current case report does not provide enough evidence to conclude that US dietary supplements of strontium are effective in preventing fractures, it demonstrates a positive experience for one patient. PMID- 27228277 TI - Glioma. PMID- 27228275 TI - Risk Factors Associated With the Ophthalmoscopic Findings Identified in Infants With Presumed Zika Virus Congenital Infection. AB - IMPORTANCE: The Zika virus (ZIKV) might cause microcephaly and ophthalmoscopic findings in infants of mothers infected during pregnancy. OBJECTIVE: To assess and identify possible risk factors for ophthalmoscopic findings in infants born with microcephaly and a presumed clinical diagnosis of ZIKV intrauterine infection. DESIGN, SETTING, AND PARTICIPANTS: We conducted a cross-sectional study at the Altino Ventura Foundation in Recife, Brazil, that included 40 infants with microcephaly born in Pernambuco state, Brazil, between May and December 2015. Toxoplasmosis, rubella, cytomegalovirus, syphilis, and human immunodeficiency virus were ruled out in all of them. Testing of cerebrospinal fluid for ZIKV using IgM antibody-capture enzyme-linked immunosorbent assay was performed in 24 of 40 infants (60.0%). The infants and mothers underwent ocular examinations. The infants were divided into 2 groups, those with and without ophthalmoscopic alterations, for comparison. MAIN OUTCOMES AND MEASURES: Identification of risk factors for ophthalmoscopic findings in infants born with microcephaly and ZIKV intrauterine infection. RESULTS: Among the 40 infants, the mean (SD) age was 2.2 (1.2) months (range, 0.1-7.3 months). Of the 24 infants tested, 100% had positive results for ZIKV infection: 14 of 22 infants (63.6%) from the group with ophthalmoscopic findings and 10 of 18 infants (55.6%) from the group without ophthalmoscopic findings. The major symptoms reported in both groups were rash by 26 mothers (65.0%), fever by 9 mothers (22.5%), headache by 9 mothers (22.5%), and arthralgia by 8 mothers (20.0%). No mothers reported conjunctivitis or other ocular symptoms during pregnancy or presented signs of uveitis at the time of examination. Thirty-seven eyes (46.3%) of 22 infants (55.0%) had ophthalmoscopic alterations. Ten mothers (71.4%) of infants with ocular findings reported symptoms during the first trimester (frequency, 0.48; 95% CI, 0.02-0.67; P = .04). A difference was also observed between the groups of infants with and without ocular findings regarding the cephalic perimeter: mean (SD) of 28.8 (1.7) and 30.3 (1.5), respectively (frequency, -1.50; 95% CI, -2.56 to -0.51; P = .004). CONCLUSIONS AND RELEVANCE: Ocular involvement in infants with presumed ZIKV congenital infection were more often seen in infants with smaller cephalic diameter at birth and in infants whose mothers reported symptoms during the first trimester. PMID- 27228278 TI - Imaging of Brain Tumors with Copper-64 Chloride: Early Experience and Results. AB - OBJECTIVES: To conduct the first investigational study that is aimed at evaluating the ability of the simple salt (64)CuCl2 to diagnose cerebral tumors in patients affected by glioblastoma multiforme (GBM). METHODS: Nineteen patients with a documented history and radiologic evidence of brain tumors were enrolled in the study. Eighteen patients were diagnosed with GBM, and one patient was diagnosed with grade II astrocytoma. After initial cerebral magnetic resonance imaging (MRI), patients were administered with (64)CuCl2 (13 MBq/kg) and brain positron emission tomography (PET)/computed tomography (CT) imaging was performed at 1, 3, and 24 hours after administration. Standardized uptake values (SUVs) were calculated and used to figure out the pharmacokinetic profile of the tracer. Absorbed radiation doses were estimated using OLINDA/EXM. RESULTS: Copper-64 chloride clearly visualized brain cancerous lesions within 1 hour after injection, with stable retention of radioactivity at 3 and 24 hours. Excellent agreement was found between PET/CT and MRI. No uptake of the tracer was observed in low-grade astrocytoma. The agent cleared rapidly from the blood and was mostly excreted through the liver, without significant kidney washout. Analysis of time variation of SUVmax values showed persistent uptake in malignant tissues with a slight increase of radioactive concentration at 24 hours. CONCLUSIONS: Copper-64 chloride has favorable biological properties for brain imaging and warrants further investigation as a diagnostic tracer for GBM. PMID- 27228279 TI - Microencapsulation of Lactobacillus rhamnosus GG by Transglutaminase Cross-Linked Soy Protein Isolate to Improve Survival in Simulated Gastrointestinal Conditions and Yoghurt. AB - Microencapsulation is an effective way to improve the survival of probiotics in simulated gastrointestinal (GI) conditions and yoghurt. In this study, microencapsulation of Lactobacillus rhamnosus GG (LGG) was prepared by first cross-linking of soy protein isolate (SPI) using transglutaminase (TGase), followed by embedding the bacteria in cross-linked SPI, and then freeze-drying. The survival of microencapsulated LGG was evaluated in simulated GI conditions and yoghurt. The results showed that a high microencapsulation yield of 67.4% was obtained. The diameter of the microencapsulated LGG was in the range of 52.83 to 275.16 MUm. Water activity did not differ between free and microencapsulated LGG after freeze-drying. The survival of microencapsulated LGG under simulated gastric juice (pH 2.5 and 3.6), intestinal juice (0.3% and 2% bile salt) and storage at 4 degrees C were significantly higher than that of free cells. The survival of LGG in TGase cross-linked SPI microcapsules was also improved to 14.5 +/- 0.5% during storage in yoghurt. The microencapsulation of probiotics by TGase treated SPI can be a suitable alternative to polysaccharide gelation technologies. PMID- 27228282 TI - Kidney stones. PMID- 27228281 TI - Fabrication of Silica-Coated Hollow Carbon Nanospheres Encapsulating Fe3O4 Cluster for Magnetical and MR Imaging Guided NIR Light Triggering Hyperthermia and Ultrasound Imaging. AB - Iron oxide nanoparticles (IONPs)-carbon (C) hybrid zero-dimensional nanostructures normally can be categorized into core-shell and yolk-shell architectures. Although IONP-C is a promising theranostic nanoagent, the in vivo study has surprisingly been less described. In addition, little effort has strived toward the fabrication of yolk-shell compared to the core-shell structures. In this context, we synthesized a yolk-shell type of the silica coated hollow carbon nanospheres encapsulating IONPs cluster, which can be dispersed in aqueous solution for systemic studies in vivo, via the preparation involving the mixed micellization, polymerization/hollowing, sol-gel (hydration condensation), and pyrolysis processes. Through a surface modification of the polyethylenimine followed by the sol-gel process, the silica shell coating was able to escape from condensing and sintering courses resulting in aggregation, due to the annealing. Not limited to the well-known functionalities in magnetical targeting and magnetic resonance (MR) imaging for IONP-C hybrid structures, we expanded this yolk-shell NPs as a near-infrared (NIR) light-responsive echogenic nanoagent giving an enhanced ultrasound imaging. Overall, we fabricated the NIR sensitive yolk-shell IONP-C to activate ultrasound imaging and photothermal ablation under magnetically and MR imaging guided therapy. PMID- 27228280 TI - Deep brain stimulation for the treatment of uncommon tremor syndromes. AB - INTRODUCTION: Deep brain stimulation (DBS) has become a standard therapy for the treatment of select cases of medication refractory essential tremor and Parkinson's disease however the effectiveness and long-term outcomes of DBS in other uncommon and complex tremor syndromes has not been well established. Traditionally, the ventralis intermedius nucleus (VIM) of the thalamus has been considered the main target for medically intractable tremors; however alternative brain regions and improvements in stereotactic techniques and hardware may soon change the horizon for treatment of complex tremors. AREAS COVERED: In this article, we conducted a PubMed search using different combinations between the terms 'Uncommon tremors', 'Dystonic tremor', 'Holmes tremor' 'Midbrain tremor', 'Rubral tremor', 'Cerebellar tremor', 'outflow tremor', 'Multiple Sclerosis tremor', 'Post-traumatic tremor', 'Neuropathic tremor', and 'Deep Brain Stimulation/DBS'. Additionally, we examined and summarized the current state of evolving interventions for treatment of complex tremor syndromes. Expert commentary: Recently reported interventions for rare tremors include stimulation of the posterior subthalamic area, globus pallidus internus, ventralis oralis anterior/posterior thalamic subnuclei, and the use of dual lead stimulation in one or more of these targets. Treatment should be individualized and dictated by tremor phenomenology and associated clinical features. PMID- 27228284 TI - Understanding the Complexity of Porous Graphitic Carbon (PGC) Chromatography: Modulation of Mobile-Stationary Phase Interactions Overcomes Loss of Retention and Reduces Variability. AB - Porous graphitic carbon (PGC) is an important tool in a chromatographer's armory that retains polar compounds with mass spectrometry (MS)-compatible solvents. However, its applicability is severely limited by an unpredictable loss of retention, which can be attributed to contamination. The solutions offered fail to restore the original retention and our observations of retention time shifts of gemcitabine/metabolites on PGC are not consistent with contamination. The mobile phase affects the ionization state of analytes and the polarizable PGC surface that influences the strength of dispersive forces governing retention on the stationary phase. We hypothesized that failure to maintain the same PGC surface before and after running a gradient is a cause of the observed retention loss/variability on PGC. Herein, we optimize the choice of mobile phase solvent in a gradient program with three parts: a preparatory phase, which allows binding of analytes to column; an elution phase, which gives the required separation/peak shape; and a maintenance phase, to preserve the required retention capacity. Via liquid chromatography/tandem mass spectrometry (LC-MS/MS) analysis of gemcitabine and its metabolites extracted from tumor tissue, we demonstrate reproducible chromatography on three PGC columns of different ages. This approach simplifies use of the PGC to the same level as that of a C-18 column, removes the need for column regeneration, and minimizes run times, thus allowing PGC columns to be used to their full potential. PMID- 27228283 TI - A neural basis for the spatial suppression of visual motion perception. AB - In theory, sensory perception should be more accurate when more neurons contribute to the representation of a stimulus. However, psychophysical experiments that use larger stimuli to activate larger pools of neurons sometimes report impoverished perceptual performance. To determine the neural mechanisms underlying these paradoxical findings, we trained monkeys to discriminate the direction of motion of visual stimuli that varied in size across trials, while simultaneously recording from populations of motion-sensitive neurons in cortical area MT. We used the resulting data to constrain a computational model that explained the behavioral data as an interaction of three main mechanisms: noise correlations, which prevented stimulus information from growing with stimulus size; neural surround suppression, which decreased sensitivity for large stimuli; and a read-out strategy that emphasized neurons with receptive fields near the stimulus center. These results suggest that paradoxical percepts reflect tradeoffs between sensitivity and noise in neuronal populations. PMID- 27228285 TI - A circulating miRNA assay as a first-line test for prostate cancer screening. AB - BACKGROUND: Prostate cancer (PCa) screening currently relies on prostate-specific antigen (PSA) testing and digital rectal examination. However, recent large-scale studies have questioned the long-term efficacy of these tests, and biomarkers that accurately identify PCa are needed. METHODS: We analysed the levels of circulating microRNAs (miRNAs) in patients with elevated PSA who were diagnosed with either localised PCa (n=36) or benign prostatic hyperplasia (BPH, n=31) upon biopsy. Real-time RT-PCR with Taqman probes was used to measure plasma levels of miRNAs. To circumvent problems associated with circulating miRNA quantitation, we computed the expression ratios of upregulated and downregulated miRNAs. RESULTS: The miR-106a/miR-130b and miR-106a/miR-223 ratios were significantly different between the biopsy-positive and BPH groups (P<0.0001), and yielded statistical power values that were >0.99. Both miRNA ratios were highly sensitive and more specific than PSA in discriminating localised PCa from BPH. Receiver operating characteristic curve analysis revealed area under curve values of 0.81 (miR 106a/miR-130b) and 0.77 (miR-106a/miR-223). CONCLUSIONS: Testing for circulating miR-106a/miR-130b and miR-106a/miR-223 ratios may reduce the costs and morbidity of unnecessary biopsies and is feasible for large-scale screening, as it requires measuring only three miRNAs. PMID- 27228286 TI - Polygenic susceptibility to testicular cancer: implications for personalised health care. PMID- 27228288 TI - Progression of breast cancer following locoregional ipsilateral recurrence: importance of interval time. PMID- 27228287 TI - Effects of microsatellite instability on recurrence patterns and outcomes in colorectal cancers. AB - BACKGROUND: Among colorectal cancers (CRCs), high-frequency microsatellite instability (MSI-H) is associated with a better prognosis, compared with low frequency MSI or microsatellite stability (MSI-L/MSS). However, it is unclear whether MSI affects the prognosis of recurrent CRCs. METHODS: This study included 2940 patients with stage I-III CRC who underwent complete resection. The associations of MSI status with recurrence patterns, disease-free survival (DFS), overall survival from diagnosis to death (OS1), and overall survival from recurrence to death (OS2) were analysed. RESULTS: A total of 261 patients (8.9%) had MSI-H CRC. Patients with MSI-H CRC had better DFS, compared to patients with MSI-L/MSS CRC (hazard ratio (HR): 0.619, P<0.001). High-frequency microsatellite instability CRC was associated with more frequent local recurrence (30.0% vs 12.0%, P=0.032) or peritoneal metastasis (40.0% vs 12.3%, P=0.003), and less frequent lung (10.0% vs 42.5%, P=0.004) or liver metastases (15.0% vs 44.7%, P=0.01). Recurrent MSI-H CRC was associated with worse OS1 (HR: 1.363, P=0.035) and OS2 (HR: 2.667, P<0.001). An analysis of patients with colon cancer yielded similar results. CONCLUSIONS: Recurrence patterns differed between MSI-H CRC and MSI-L/MSS CRC, and recurrent MSI-H CRCs had a worse prognosis. PMID- 27228289 TI - Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer. PMID- 27228290 TI - Enthusiasm for cancer screening in Great Britain: a general population survey. PMID- 27228291 TI - Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas. PMID- 27228292 TI - Predicting microbiologically defined infection in febrile neutropenic episodes in children: global individual participant data multivariable meta-analysis. PMID- 27228293 TI - Lifestyle and reproductive risk factors associated with anal cancer in women aged over 50 years. PMID- 27228294 TI - Selective organ preservation with neo-adjuvant chemotherapy for the treatment of muscle invasive transitional cell carcinoma of the bladder. PMID- 27228295 TI - Epstein-Barr virus and carcinomas: rare association of the virus with gastric adenocarcinomas. PMID- 27228296 TI - Has the survival of patients with glioblastoma changed over the years? PMID- 27228297 TI - Decomposition of spontaneous fluctuations in tumour oxygenation using BOLD MRI and independent component analysis. PMID- 27228298 TI - Biological activity of the thyroid TRK-T3 oncogene requires signalling through Shc. PMID- 27228300 TI - Production and Release of Selenomethionine and Related Organic Selenium Species by Microorganisms in Natural and Industrial Waters. AB - Laboratory algal cultures exposed to selenate were shown to produce and release selenomethionine, selenomethionine oxide, and several other organic selenium metabolites. Released discrete organic selenium species accounted for 1.6-13.1% of the selenium remaining in the media after culture death, with 1.3-6.1% of the added selenate recovered as organic metabolites. Analysis of water from an industrially impacted river collected immediately after the death of massive annual algal blooms showed that no selenomethionine or selenomethionine oxide was present. However, other discrete organic selenium species, including a cyclic oxidation product of selenomethionine, were observed, indicating the previous presence of selenomethionine. Industrial biological treatment systems designed for remediation of selenium-contaminated waters were shown to increase both the concentration of organic selenium species in the effluent, relative to influent water, and the fraction of organic selenium to up to 8.7% of the total selenium in the effluent, from less than 1.1% in the influent. Production and emission of selenomethionine, selenomethionine oxide, and other discrete organic selenium species were observed. These findings are discussed in the context of potentially increased selenium bioavailability caused by microbial activity in aquatic environments and biological treatment systems, despite overall reductions in total selenium concentration. PMID- 27228299 TI - Risk factors of proteinuria in renal cell carcinoma patients treated with VEGF inhibitors: a secondary analysis of pooled clinical trial data. AB - BACKGROUND: Proteinuria is a common adverse effect of vascular endothelial growth factor targeted agents, particularly in metastatic renal cell carcinoma (mRCC). However, risk factors for proteinuria are poorly defined. METHODS: Data on 1392 mRCC patients using pazopanib or sunitinib were pooled from two Phase-III clinical trials. Risk factors and prognostic effect of on-therapy proteinuria were evaluated by Cox proportional hazards regression. RESULTS: Any-grade (1-4) and grade 3/4 proteinuria incidence were 15.0% and 3.7%, respectively. Asian ethnicity, diabetes, baseline systolic blood pressure (SBP), pre-existing grade 1 proteinuria and prior nephrectomy were significant independent predictors of either any-grade or grade 3/4 proteinuria. Proteinuria, particularly grade 3/4 (adjusted hazard ratio 0.53 (95% confidence interval 0.30-0.92)), was associated with improved overall survival. CONCLUSIONS: In mRCC patients using pazopanib or sunitinib, Asian ethnicity, diabetes, SBP, pre-existing proteinuria and prior nephrectomy were independent predictors of on-therapy proteinuria, which was associated with improved survival. PMID- 27228301 TI - Computational Estimate of the Photophysical Capabilities of Four Series of Organometallic Iron(II) Complexes. AB - In this study, we examine a large range of organometallic iron(II) complexes with the aim of computationally identifying the most promising ones in terms of photophysical properties. These complexes combine polypyridine, bis(phosphine), and carbon-bound ligands. Density functional theory has allowed us to establish a comparative Jablonski diagram displaying the lowest singlet, triplet, and quintet states. All of the proposed FeN5C or FeN3P2C complexes unfavorably possess a lowest triplet state of metal-centered (MC) nature. Among the FeN4C2 and FeN2P2C2 series, the carbene complexes display the least favorable excited-state distribution, also having a low-lying (3)MC state. Validating our design strategy, we are now able to propose seven iron(II) complexes displaying a lowest excited state of triplet metal-to-ligand charge-transfer nature. PMID- 27228302 TI - Does Notch play a tumor suppressor role across diverse squamous cell carcinomas? AB - The role of Notch pathway in tumorigenesis is highly variable. It can be tumor suppressive or pro-oncogenic, typically depending on the cellular context. Squamous cell carcinoma (SCC) is a cancer of the squamous cell, which can occur in diverse human tissues. SCCs are one of the most frequent human malignancies for which the pathologic mechanisms remain elusive. Recent genomic analysis of diverse SCCs identified marked levels of mutations in NOTCH1, implicating Notch signaling pathways in the pathogenesis of SCCs. In this review, evidences highlighting NOTCH's role in different types of SCCs are summarized. Moreover, based on accumulating structural information of the NOTCH receptor, the functional consequences of NOTCH1 gene mutations identified from diverse SCCs are analyzed, emphasizing loss of function of Notch in these cancers. Finally, we discuss the convergent view on an intriguing possibility that Notch may function as tumor suppressor in SCCs across different tissues. These mechanistic insights into Notch signaling pathways will help to guide the research of SCCs and development of therapeutic strategies for these cancers. PMID- 27228303 TI - The Role of the Mucosa in Normal and Abnormal Bladder Function. AB - The internal face of the detrusor smooth muscle wall of the urinary bladder is covered by a mucosa, separating muscle from the hostile environment of urine. However, the mucosa is more than a very low permeability structure and offers a sensory function that monitors the extent of bladder filling and composition of the urine. The mucosa may be considered as a single functional structure and comprises a tight epithelial layer under which is a basement membrane and lamina propria. The latter region itself is a complex of afferent nerves, blood vessels, interstitial cells and in some species including human beings a muscularis mucosae. Stress on the bladder wall through physical or chemical stressors elicits release of chemicals, such as ATP, acetylcholine, prostaglandins and nitric oxide that modulate the activity of either afferent nerves or the muscular components of the bladder wall. The release and responses are graded so that the mucosa forms a dynamic sensory structure, and there is evidence that the gain of this system is increased in pathologies such as overactive bladder and bladder pain syndrome. This system therefore potentially provides a number of drug targets against these conditions, once a number of fundamental questions are answered. These include how is mediator release regulated; what are the intermediate roles of interstitial cells that surround afferent nerves and blood vessels; and what is the mode of communication between urothelium and muscle - by diffusion of mediators or by cell-to-cell communication? PMID- 27228304 TI - Supramolecular Hydrophobic Aggregates in Hydrogels Partially Inhibit Ice Formation. AB - Prevention of ice crystallization is a challenging problem with implications in diverse applications, as well as examining the fundamental low temperature physics of water. Here, we demonstrate a simple route, inspired by water confinement in antifreeze proteins, to inhibit crystallization and provide high water mobility of highly supercooled water using supramolecular hydrogels of copolymers of dimethylacrylamide (DMA) and 2-(N-ethylperfluorooctane sulfonamido)ethyl acrylate (FOSA). These hydrogels can suppress or inhibit freezing of their water, depending on the copolymer composition. Dynamic and static neutron scattering indicate that hydrogels using the copolymer with 22 mol % FOSA partially inhibit ice formation. This behavior is attributed to confinement (<2 nm) of water between the hydrophobic FOSA nanodomains that prevents 45% of the water within the hydrogel from freezing even at 205 K. Very fast dynamics of the amorphous water are observed at 220 K with an effective local diffusivity decreased by only a factor of 2 from that observed at 295 K within the hydrogel using the copolymer with 22 mol % FOSA. The spacing between the hydrophobic nanodomains, tuned through the copolymer composition, appears to modulate the water that can crystallize. These fully hydrated hydrogels (at equilibrium with liquid water at 295 K) can enable a significant fraction of highly supercooled water to be stable down to at least 205 K. PMID- 27228305 TI - Geoelectrical monitoring of simulated subsurface leakage to support high-hazard nuclear decommissioning at the Sellafield Site, UK. AB - A full-scale field experiment applying 4D (3D time-lapse) cross-borehole Electrical Resistivity Tomography (ERT) to the monitoring of simulated subsurface leakage was undertaken at a legacy nuclear waste silo at the Sellafield Site, UK. The experiment constituted the first application of geoelectrical monitoring in support of decommissioning work at a UK nuclear licensed site. Images of resistivity changes occurring since a baseline date prior to the simulated leaks revealed likely preferential pathways of silo liquor simulant flow in the vadose zone and upper groundwater system. Geophysical evidence was found to be compatible with historic contamination detected in permeable facies in sediment cores retrieved from the ERT boreholes. Results indicate that laterally discontinuous till units forming localized hydraulic barriers substantially affect flow patterns and contaminant transport in the shallow subsurface at Sellafield. We conclude that only geophysical imaging of the kind presented here has the potential to provide the detailed spatial and temporal information at the (sub-)meter scale needed to reduce the uncertainty in models of subsurface processes at nuclear sites. PMID- 27228306 TI - Effects of solution chemistry on antimicrobial activities of silver nanoparticles against Gordonia sp. AB - Silver nanoparticles (NPs) are the largest and fastest growing category of nanotechnology-based medicines and consumer products. Silver can have great toxicity to some aquatic organisms and, as a biocidal agent, may also damage or alter the most abundant and vulnerable beneficial microorganisms in the environment, such as Gordonia sp. However, considering the complex chemical background of natural waters, silver NPs can have complicated interactions with background chemicals such as chloride, surfactants, and dissolved natural organic matters (NOM). The results of this study show that the average particle size and dispersivity of silver NPs and the surface characteristics play an important role in the toxicity of silver NPs. Aggregation was enhanced for silver NPs in 10mM NaNO3, but not much in 10mM NaCl due to reactions with chloride. However, the presence of 3mM sodium dodecyl sulfate (SDS) or 8mgC/L Suwannee River (SR) NOM appeared to reduce the aggregation of silver NPs. Regarding the bactericidal effect of silver NPs, solubility analysis suggests silver NPs inactivate Gordonia sp. differently from Ag(+) and/or a slow release of Ag(+) from silver NPs. When the silver NP concentration was raised from 7.3 to 29.2mg/L in DI water, the log inactivation rate of Gordonia sp. increased from 0.16+/-0.04 to 0.45+/-0.13. However, with 29.2mg/L silver NPs the log inactivation rate reached 1.40+/-0.26 in 3mM SDS. The presence of SRNOM mitigated the bactericidal efficacy of silver NPs due to surface coating/adsorption. On the other hand, 10mM NaCl reduced the log inactivation rate to 0.07+/-0.07 due to the formation of likely less toxic silver chloride species, such as AgCl, AgCl2(-), AgCl3(2-), and AgCl4(3-). PMID- 27228307 TI - Daphnane Diterpenes from Daphne genkwa Activate Nurr1 and Have a Neuroprotective Effect in an Animal Model of Parkinson's Disease. AB - Nurr1 is an orphan nuclear receptor that is essential for the differentiation and maintenance of dopaminergic neurons in the brain, and it is a therapeutic target for Parkinson's disease (PD). During the screening for Nurr1 activators from natural sources using cell-based assay systems, a methanol extract of the combined stems and roots of Daphne genkwa was found to activate the transcriptional function of Nurr1 at a concentration of 3 MUg/mL. The active components were isolated and identified as genkwanine N (1) and yuanhuacin (2). Both compounds 1 and 2 significantly enhanced the function of Nurr1 at 0.3 MUM. Nurr1-specific siRNA abolished the activity of 1 and 2, strongly suggesting that transcriptional activation by 1 and 2 occurred through the modulation of Nurr1 function. Additionally, treatment with 1 and 2 inhibited 6-hydroxydopamine (6 OHDA)-induced neuronal cell death and lipopolysaccharide (LPS)-induced neuroinflammation. Moreover, in a 6-OHDA-lesioned rat model of PD, intraperitoneal administration of 2 (0.5 mg/kg/day) for 2 weeks significantly improved behavioral deficits and reduced tyrosine hydroxylase (TH)-positive dopaminergic neuron death induced by 6-OHDA injection and had a beneficial effect on the inflammatory response in the brain. Accordingly, compounds 1 and 2, the first reported Nurr1 activators of natural origin, are potential lead compounds for the treatment of PD. PMID- 27228309 TI - Quantitative MRI to understand Alzheimer's disease pathophysiology. AB - PURPOSE OF REVIEW: The role of white matter damage in the progression of Alzheimer's disease and the associated cognitive symptoms is becoming increasingly clearer. This is partly because of the advent of diffusion tensor imaging, which, in combination with other quantitative MRI techniques, offers unique insights into the patholophysiology of Alzheimer's disease in vivo. The purpose of this review is to integrate the most recent imaging findings, with respect to understanding Alzheimer's disease pathophysiology, and identifying potential biomarkers with diagnostic and prognostic value. RECENT FINDINGS: Consistent with patterns of gray matter atrophy, white matter damage in Alzheimer's disease is localized within white matter tracts connecting the temporal lobe with the rest of the brain, including the cingulum, the uncinate fasciculus and the fornix. These abnormalities are often correlated with adjacent gray matter tissue loss, and with cognitive performance. The relationship between these findings and loss of functional connectivity supports the hypothesis of disconnection as a mechanism for the spread of Alzheimer's disease. SUMMARY: White matter abnormalities occur early in Alzheimer's disease, and might actively contribute to the progression of the disease. Functional and structural gray matter abnormalities parallel the white matter changes, and successful biomarkers are likely to be multiparametric. PMID- 27228308 TI - The burden of community-managed acute respiratory infections in the first 2-years of life. AB - BACKGROUND: Contemporary information on acute respiratory infections (ARIs) in children is based on hospital cohorts, primary healthcare presentations, and high risk birth cohort studies. We describe the burden and determinants of symptomatic episodes of ARIs in unselected healthy infants in the first 2-years of life. METHODS: One hundred and fifty-four infants from subtropical Brisbane, Australia participated in a longitudinal, community-based birth cohort study. A daily tick box diary captured pre-defined respiratory symptoms. Parents also completed a burden diary, recording family physician and hospital visits, and antibiotic use. RESULTS: Participants contributed 88,032 child-days (78.2% of expected), of which 17,316 (19.7%) days were symptomatic during 1,651 ARI episodes: incidence rate 0.56 ARIs per child-month (95%CI: 0.54, 0.59). Runny nose (14,220 days; 6.0-days median duration) and dry cough (6,880 days; 4.0-days median duration) were reported most frequently. Overall, 955 burden diaries recorded 455 family physician visits (1-8 visits per ARI) and 48 hospital presentations, including six hospital admissions. Antibiotics were prescribed on 209 occasions (21.9% of ARI episodes where burden diary submitted). Increasing age, non-summer seasons, and attendance at childcare were associated with an increased risk of ARI. CONCLUSIONS: ARIs are a common cause of morbidity in the first 2-years of life, with children experiencing 13 discrete ARI episodes and almost 5-months of respiratory symptoms. Most ARIs are managed in the community by parents and family physicians. Antibiotic prescribing remains common for ARIs in young children. Secular societal changes, including greater use of childcare in early childhood, may have maintained the high ARI incidence in this age-group. Pediatr Pulmonol. 2016;51:1336-1346. (c) 2016 Wiley Periodicals, Inc. PMID- 27228310 TI - Analysis of the Pressure and Temperature Dependence of the Complex-Forming Bimolecular Reaction CH3OCH3 + Fe(.). AB - The kinetics of the reaction CH3OCH3 + Fe(+) has been studied between 250 and 600 K in the buffer gas He at pressures between 0.4 and 1.6 Torr. Total rate constants and branching ratios for the formation of Fe(+)O(CH3)2 adducts and of Fe(+)OCH2 + CH4 products were determined. Quantum-chemical calculations provided the parameters required for an analysis in terms of statistical unimolecular rate theory. The analysis employed a recently developed simplified representation of the rates of complex-forming bimolecular reactions, separating association and chemical activation contributions. Satisfactory agreement between experimental results and kinetic modeling was obtained that allows for an extrapolation of the data over wide ranges of conditions. Possible reaction pathways with or without spin-inversion are discussed in relation to the kinetic modeling results. PMID- 27228311 TI - Pre- and Delayed Treatments With Ranolazine Ameliorate Ventricular Arrhythmias and Nav1.5 Downregulation in Ischemic/Reperfused Rat Hearts. AB - Enhanced late sodium current (late INa) and intracellular Nav1.5 redistribution contribute to ischemia/reperfusion (I/R)-induced arrhythmias. Ranolazine can reduce lethal arrhythmias by inhibiting late INa. However, little is known regarding its role in regulating the distribution of Nav1.5 during I/R. Therefore, we investigated the roles of ranolazine in post-I/R Nav1.5 expression and distribution in myocardium. Male Sprague Dawley rats were randomly assigned to 4 groups: sham, I/R, Ran Pre, and Ran Delay. Electrocardiogram and arterial pressure were recorded during the procedure. Nav1.5 mRNA and protein levels in peri-infarct cardiac tissue were determined by real-time polymerase chain reaction, Western blotting, and immunofluorescence. To further confirm the regulation of ranolazine on Nav1.5, GS967, another late INa inhibitor was used. Both pre- and delayed ranolazine treatments significantly reduced the incidence of severe ventricular arrhythmias, along with shortened corrected QT interval by 29.55% and QRS duration by 18.38% during I/R. The protein level of Nav1.5 decreased by 31.63% after I/R. Ranolazine and GS967 remained Nav1.5 protein expression and Nav1.5 redistribution on intercalated discs and lateral membranes, without affecting Nav1.5 mRNA level. In conclusion, upregulating Nav1.5 expression and redistribution on the intercalated discs and lateral membranes of cardiomyocytes may underlie the antiarrhythmic effects of ranolazine in I/R rats. PMID- 27228312 TI - Neighbourhood disadvantage and smoking: Examining the role of neighbourhood-level psychosocial characteristics. AB - PURPOSE: This study aims to determine if neighbourhood psychosocial characteristics contribute to inequalities in smoking among residents from neighbourhoods of differing socioeconomic disadvantage. METHODS: This cross sectional study includes 11,035 residents from 200 neighbourhoods in Brisbane, Australia in 2007. Self-reported measures were obtained for smoking and neighbourhood psychosocial characteristics (perceptions of incivilities, crime and safety, and social cohesion). Neighbourhood socioeconomic disadvantage was measured using a census-derived index. Data were analysed using multilevel logistic regression random intercept models. RESULTS: Smoking was associated with neighbourhood disadvantage; this relationship remained after adjustment for individual-level socioeconomic position. Area-level perceptions of crime and safety and social cohesion were not independently associated with smoking, and did not explain the higher prevalence of smoking in disadvantaged areas; however, perceptions of incivilities showed an independent effect. CONCLUSIONS: Some neighbourhood psychosocial characteristics seem to contribute to the higher rates of smoking in disadvantaged areas. PMID- 27228313 TI - Divergent evolution of cis-acting peroxisome proliferator-activated receptor elements that differentially control the tandemly duplicated fatty acid-binding protein genes, fabp1b.1 and fabp1b.2, in zebrafish. AB - Gene duplication is thought to facilitate increasing complexity in the evolution of life. The fate of most duplicated genes is nonfunctionalization: functional decay resulting from the accumulation of mutations. According to the duplication degeneration-complementation (DDC) model, duplicated genes are retained by subfunctionalization, where the functions of the ancestral gene are sub-divided between duplicate genes, or by neofunctionalization, where one of the duplicates acquires a new function. Here, we report the differential regulation of the zebrafish tandemly duplicated fatty acid-binding protein genes, fabp1b.1 and fabp1b.2, by peroxisome proliferator-activated receptors (PPAR). fabp1b.1 mRNA levels were induced in tissue explants of liver, but not intestine, by PPAR agonists. fabp1b.1 promoter activity was induced to a greater extent by rosiglitazone (PPARgamma-selective agonist) compared to WY 14,643 (PPARalpha selective agonist) in HEK293A cells. Mutation of a peroxisome proliferator response element (PPRE) at -1232 bp in the fabp1b.1 promoter reduced PPAR dependent activation. fabp1b.2 promoter activity was not affected by PPAR agonists. Differential regulation of the duplicated fabp1b promoters may be the result of PPRE loss in fabp1b.2 during a meiotic crossing-over event. Retention of PPAR inducibility in fabp1b.1 and not fabp1b.2 suggests unique regulation and function of the fabp1b duplicates. PMID- 27228316 TI - Patent foramen ovale. PMID- 27228314 TI - Peroxo and Superoxo Moieties Bound to Copper Ion: Electron-Transfer Equilibrium with a Small Reorganization Energy. AB - Oxygenation of [Cu2(UN-O(-))(DMF)](2+) (1), a structurally characterized dicopper Robin-Day class I mixed-valent Cu(II)Cu(I) complex, with UN-O(-) as a binucleating ligand and where dimethylformamide (DMF) binds to the Cu(II) ion, leads to a superoxo-dicopper(II) species [Cu(II)2(UN-O(-))(O2(*-))](2+) (2). The formation kinetics provide that kon = 9 * 10(-2) M(-1) s(-1) (-80 degrees C), DeltaH(?) = 31.1 kJ mol(-1) and DeltaS(?) = -99.4 J K(-1) mol(-1) (from -60 to 90 degrees C data). Complex 2 can be reversibly reduced to the peroxide species [Cu(II)2(UN-O(-))(O2(2-))](+) (3), using varying outer-sphere ferrocene or ferrocenium redox reagents. A Nernstian analysis could be performed by utilizing a monodiphenylamine substituted ferrocenium salt to oxidize 3, leading to an equilibrium mixture with Ket = 5.3 (-80 degrees C); a standard reduction potential for the superoxo-peroxo pair is calculated to be E degrees = +130 mV vs SCE. A literature survey shows that this value falls into the range of biologically relevant redox reagents, e.g., cytochrome c and an organic solvent solubilized ascorbate anion. Using mixed-isotope resonance Raman (rRaman) spectroscopic characterization, accompanied by DFT calculations, it is shown that the superoxo complex consists of a mixture of MU-1,2- (2(1,2)) and MU-1,1- (2(1,1)) isomers, which are in rapid equilibrium. The electron transfer process involves only the MU-1,2-superoxo complex [Cu(II)2(UN-O(-))(MU-1,2-O2(*-))](2+) (2(1,2)) and MU-1,2-peroxo structures [Cu(II)2(UN-O(-))(O2(2-))](+) (3) having a small bond reorganization energy of 0.4 eV (lambdain). A stopped-flow kinetic study results reveal an outer-sphere electron transfer process with a total reorganization energy (lambda) of 1.1 eV between 2(1,2) and 3 calculated in the context of Marcus theory. PMID- 27228317 TI - The protective effect of olfactory ensheathing cells on post-injury spiral ganglion cells. AB - CONCLUSIONS: Transplantation of OECs into the cochlea may protect and increase the survival of SGCs. OBJECTIVE: To investigate the protective effect of the transplantation of olfactory ensheathing cells (OECs) on injured spiral ganglion cells (SGCs) in rats. METHODS: OECs were transplanted into the cochlea in rats with SGCs that were injured by kanamycin sulfate (KM). An equal volume of D-Hanks was injected into the cochlea of control rats. Auditory brainstem responses (ABRs) were recorded from the rats in both groups to monitor changes in hearing thresholds. Immunofluorescence was employed to examine the density and morphology of SGCs to assess the ototoxic condition of the cochlea. RESULTS: There was no significant difference in the ABR threshold at each frequency between the control and experimental groups. Notably, in the experimental group, a number of Hoechst 3334-labeled nuclei were detected from the apex to the basal turn of the cochlea, demonstrating that the OECs were successfully transplanted and survived in the cochlea. In the experimental group, most of the SGCs were tightly arranged, and the nuclear membrane, chromatin, and nucleolus were all clear. The SGCs in the control group were loosely arranged, and only a few normal SGCs were observed in this group. PMID- 27228318 TI - BILATERAL COATS REACTION IN BANNAYAN-ZONANA SYNDROME: A SINGLE CASE REPORT. AB - PURPOSE: To report the clinical features of bilateral Coats reaction in a patient with Bannayan-Zonana syndrome. METHODS: The clinical course and retinal manifestations of a 21-year-old patient with Bannayan-Zonana syndrome and bilateral Coats reaction were studied. Retinal manifestations were documented with clinical examination, ultrawide-field color imaging, and ultrawide-field fluorescein angiography. RESULTS: Best-corrected visual acuities were 20/25 OD and 20/25 OS. Anterior segment examinations were normal bilaterally. The inferotemporal quadrant of the left retina demonstrated retinal telangiectasias, exudation, and a neurosensory retinal detachment extending to the mid-periphery. Fluorescein angiography demonstrated bilateral peripheral nonperfusion and vascular staining. An epiretinal membrane also involved the left macula. CONCLUSION: Bannayan-Zonana syndrome is an autosomal-dominant, hamartomatous disease characterized by a mutation spectrum that involves genes responsible for vascular development. Retinal vascular abnormalities and exudation can be a manifestation of this syndrome. PMID- 27228319 TI - A Tetra-Primer Amplification Refractory System Technique for the Cost-Effective and Novel Genotyping of Eight Single-Nucleotide Polymorphisms of the Catechol-O Methyltransferase Gene. AB - AIMS: Catechol-O-methyltransferase (COMT) is an enzyme involved in the degradation of catecholamine neurotransmitters. Due to its role in neurotransmitter flux, multiple COMT variants have been associated with the development of psychiatric disorders. Notably, select single-nucleotide polymorphisms (SNPs) of the COMT gene have been implicated in schizophrenia risk, severity, and treatment response. In recognition of the value of a streamlined genotyping method for COMT SNP detection, this study was designed to develop a simple and economical tetra-primer amplification refractory mutation system (T ARMS) assay for the concurrent detection of eight COMT SNPs: rs4680, rs737865, rs165599, rs2075507, rs4633, rs4818, rs6269, and rs165774. MATERIALS AND METHODS: T-ARMS is a genotyping method that uses polymerase chain reaction (PCR) to amplify a multiplex reaction consisting of two primer pairs. T-ARMS primers are customized to each SNP and designed to generate different-sized allele-specific amplicons. This assay was applied to a total of 39 genomic DNA samples. Genotypic designations across the panel of SNPs were subsequently validated by Sanger sequencing. RESULTS: T-ARMS reliably and unambiguously detected all three genotypes (homozygous wild type, heterozygous, and homozygous mutant) for each of the eight COMT SNPs. CONCLUSIONS: Compared to traditional low-throughput methods that require post-PCR modification or high-throughput technologies that require sophisticated equipment, T-ARMS is a cost-effective and efficient assay that can be easily adapted by any standard molecular diagnostics laboratory. This T-ARMS assay provides a practical and robust method for COMT SNP detection. PMID- 27228320 TI - BCOR-CCNB3-positive soft tissue sarcoma with round-cell and spindle-cell histology: a series of four cases highlighting the pitfall of mimicking poorly differentiated synovial sarcoma. AB - AIMS: BCOR-CCNB3 sarcoma is a genetically defined undifferentiated malignancy with Ewing sarcoma (ES)-like round cells, and preferentially affects the bones of male adolescents. Sarcomas harbouring BCOR-CCNB3 rarely arise from soft tissues; therefore, we aimed to report four cases to expand the clinicopathological spectrum. METHODS AND RESULTS: By reverse transcription polymerase chain reaction and confirmatory sequencing, we detected a BCOR-CCNB3 transcript in primary undifferentiated sarcomas of the deep musculature of four male patients, comprising two teenagers (aged 14 and 17 years) and two adults (aged 34 and 44 years). The tumours originated in the back (n = 2), pelvis (n = 1), and thigh (n = 1), and were 70-140 mm in size (mean, 107 mm). All tumours showed sheets of primitive round or ovoid cells with vesicular nuclei, active mitosis (28-41/10 high-power fields), variably prominent nucleoli, and geographical necrosis. This major component transformed into fascicles of elongated spindle cells with staghorn vessels and a myxoid reticular stroma, accounting for 10-50% of areas. All cases were positive for CD99, three were positive for TLE1, and one was positive for EMA, indicating poorly differentiated synovial sarcomas (PDSSs). Nuclear cyclin B3 reactivity was present in all cases, but not in molecularly confirmed atypical ESs and PDSSs. At the last follow-up (median, 13.5 months), one patient had died of lung metastasis, two were alive with tumours, and one was tumour-free. CONCLUSIONS: BCOR-CCNB3-positive sarcomas may primarily occur in soft tissues of adults and show PDSS-mimicking round-cell and spindle-cell histology with aggressive behaviour. Cyclin B3 is useful for selecting candidates for BCOR-CCNB3 molecular testing. PMID- 27228321 TI - Real-Space Mapping of Surface Trap States in CIGSe Nanocrystals Using 4D Electron Microscopy. AB - Surface trap states in copper indium gallium selenide semiconductor nanocrystals (NCs), which serve as undesirable channels for nonradiative carrier recombination, remain a great challenge impeding the development of solar and optoelectronics devices based on these NCs. In order to design efficient passivation techniques to minimize these trap states, a precise knowledge about the charge carrier dynamics on the NCs surface is essential. However, selective mapping of surface traps requires capabilities beyond the reach of conventional laser spectroscopy and static electron microscopy; it can only be accessed by using a one-of-a-kind, second-generation four-dimensional scanning ultrafast electron microscope (4D S-UEM) with subpicosecond temporal and nanometer spatial resolutions. Here, we precisely map the collective surface charge carrier dynamics of copper indium gallium selenide NCs as a function of the surface trap states before and after surface passivation in real space and time using S-UEM. The time-resolved snapshots clearly demonstrate that the density of the trap states is significantly reduced after zinc sulfide (ZnS) shelling. Furthermore, the removal of trap states and elongation of carrier lifetime are confirmed by the increased photocurrent of the self-biased photodetector fabricated using the shelled NCs. PMID- 27228324 TI - Higher Carotid Intima-Media Thickness in Subclinical Hypothyroidism Associated with the Metabolic Syndrome. AB - BACKGROUND: The subclinical hypothyroidism (SH) and the metabolic syndrome (MS) have been associated with increased risk of atherosclerosis and cardiovascular disease (CVD). The measurement of carotid intima-media thickness (IMT) is capable of detecting early signs of atherosclerotic disease. The goal of the study was to compare the carotid IMT of patients with SH with and without the MS. METHODS: Twenty-nine SH patients were subdivided into two groups: one with MS (SH + MS) and one without MS (SH - MS). The study also assessed a group of euthyroid patients (n = 31), also subdivided into two groups: one with MS (EU + MS) and one without MS (EU - MS). The clinical and laboratory data and the mean and maximum carotid IMT of the groups were compared. RESULTS: Maximum (P = 0.012) and mean (P = 0.025) IMT were higher in the SH + MS group than in the SH-MS group. Maximum IMT was higher in the SH + MS group than in the EU + MS group (P = 0.048). Maximum IMT was positively correlated with fasting glucose (FG; R = 0.621; P < 0.01) and body mass index (R = 0.258; P = 0.041) and negatively correlated with low-density lipoprotein cholesterol (LDL-C) (R = -0.297; P = 0.017). Mean IMT was positively correlated with FG (R = 0.580; P < 0.01), systolic blood pressure (R = 0.292; P = 0.02), and triglycerides (R = 0.250; P = 0.048) and negatively correlated with LDL-C (R = -0.288; P = 0.022). CONCLUSIONS: SH + MS patients have higher IMT than SH - MS or EU + MS patients, suggesting that SH may be one more CVD risk factor in patients with the MS. PMID- 27228326 TI - Systemic sclerosis. PMID- 27228325 TI - Clinicians in 25 countries prefer to use lower levels of oxygen to resuscitate preterm infants at birth. AB - AIM: This study determined current international clinical practice and opinions regarding initial fractional inspired oxygen (FiO2 ) and pulse oximetry (SpO2 ) targets for delivery room resuscitation of preterm infants of less than 29 weeks of gestation. METHODS: An online survey was disseminated to neonatal clinicians via established professional clinical networks using a web-based survey programme between March 9 and June 30, 2015. RESULTS: Of the 630 responses from 25 countries, 60% were from neonatologists. The majority (77%) would target SpO2 between the 10th to 50th percentiles values for full-term infants. The median starting FiO2 was 0.3, with Japan using the highest (0.4) and the UK using the lowest (0.21). New Zealand targeted the highest SpO2 percentiles (median 50%). Most respondents agreed or did not disagree that a trial was required that compared the higher FiO2 of 0.6 (83%), targeting the 50th SpO2 percentile (60%), and the lower FiO2 of 0.21 (80%), targeting the 10th SpO2 percentile (78%). Most (65%) would join this trial. Many considered that evidence was lacking and further research was needed. CONCLUSION: Clinicians currently favour lower SpO2 targets for preterm resuscitation, despite acknowledging the lack of evidence for benefit or harm, and 65% would join a clinical trial. PMID- 27228327 TI - Concerns underlying treatment preferences of advanced cancer patients with children. AB - BACKGROUND: Decision-making about advanced cancer treatment is complex and may be influenced by patients' family context, including the presence of children. We explored how parental values and concerns motivate patients' preferences about aggressiveness of advanced cancer treatment as well as preferences for palliative care and hospice services. METHODS: We conducted semi-structured interviews with 42 patients with advanced cancer who had at least one child under 18 years. We created and applied thematic codes. Descriptive analyses were used to report the number of participants who mentioned each code. RESULTS: The majority of participants (29/42) reported that having children influenced their preferences for advanced cancer care. For most parents, extending life to maximize the time they had left to parent their children was important in guiding treatment preferences. Others prioritized preserving their physical condition and parental functioning and remaining physically close to their children. Many parents discussed life extension and parental functioning preservation as competing priorities. Most of the sample expressed interest in palliative care services and hospice, but responses by several participants reflected concerns about dying at home and lack of clarity about the role of early palliative care. CONCLUSIONS: Parents in our sample expressed that maximizing time with their children and preserving parental functioning were important concerns underlying their preferences for advanced cancer care. Future research should assess the palliative and end-of-life care needs and preferences of parents with advanced cancer, which may differ from those of non-parents. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27228328 TI - Reply. PMID- 27228329 TI - Investigating Salmonella Eko from Various Sources in Nigeria by Whole Genome Sequencing to Identify the Source of Human Infections. AB - Twenty-six Salmonella enterica serovar Eko isolated from various sources in Nigeria were investigated by whole genome sequencing to identify the source of human infections. Diversity among the isolates was observed and camel and cattle were identified as the primary reservoirs and the most likely source of the human infections. PMID- 27228330 TI - Radiofrequency Ablation, MR Thermometry, and High-Spatial-Resolution MR Parametric Imaging with a Single, Minimally Invasive Device. AB - Purpose To develop and demonstrate in vitro and in vivo a single interventional magnetic resonance (MR)-active device that integrates the functions of precise identification of a tissue site with the delivery of radiofrequency (RF) energy for ablation, high-spatial-resolution thermal mapping to monitor thermal dose, and quantitative MR imaging relaxometry to document ablation-induced tissue changes for characterizing ablated tissue. Materials and Methods All animal studies were approved by the institutional animal care and use committee. A loopless MR imaging antenna composed of a tuned microcable either 0.8 or 2.2 mm in diameter with an extended central conductor was switched between a 3-T MR imaging unit and an RF power source to monitor and perform RF ablation in bovine muscle and human artery samples in vitro and in rabbits in vivo. High-spatial resolution (250-300-MUm) proton resonance frequency shift MR thermometry was interleaved with ablations. Quantitative spin-lattice (T1) and spin-spin (T2) relaxation time MR imaging mapping was performed before and after ablation. These maps were compared with findings from gross tissue examination of the region of ablated tissue after MR imaging. Results High-spatial-resolution MR imaging afforded temperature mapping in less than 8 seconds for monitoring ablation temperatures in excess of 85 degrees C delivered by the same device. This produced irreversible thermal injury and necrosis. Quantitative MR imaging relaxation time maps demonstrated up to a twofold variation in mean regional T1 and T2 after ablation versus before ablation. Conclusion A simple, integrated, minimally invasive interventional probe that provides image-guided therapy delivery, thermal mapping of dose, and detection of ablation-associated MR imaging parametric changes was developed and demonstrated. With this single device approach, coupling-related safety concerns associated with multiple conductor approaches were avoided. (c) RSNA, 2016 Online supplemental material is available for this article. PMID- 27228331 TI - Limited Hospital Variation in the Use and Yield of CT for Pulmonary Embolism in Patients Undergoing Total Hip or Total Knee Replacement Surgery. AB - Purpose To evaluate the variation among U.S. hospitals in overall use and yield of in-hospital computed tomographic (CT) pulmonary angiography (PA) in patients undergoing total hip replacement (THR) or total knee replacement (TKR) surgery. Materials and Methods Patients in the Premier Research Database who underwent elective TKR or THR between 2007 and 2011 were enrolled in this HIPAA-compliant, institutional review board-approved retrospective observational study. The informed consent requirement was waived. Hospitals were categorized into low, medium, and high tertiles of CT PA use to compare baseline patient- and hospital level characteristics and pulmonary embolism (PE) positivity rates. To further investigate between-hospital variation in CT PA use, a hierarchical logistic regression model that included hospital-specific random effects and fixed patient and hospital-level effects was used. The intraclass correlation coefficient (ICC) was used to measure the amount of variability in CT PA use attributable to between-hospital variation. Results The cohort included 205 198 patients discharged from 178 hospitals (median of 734.5 patients discharged per hospital; interquartile range, 316-1461 patients) with 3647 CT PA studies (1.8%). The crude frequency of CT PA scans among the hospitals ranged from 0% to 6.2% (median, 1.6%); more than 90% of the hospitals performed CT PA in less than 3% of their patients. The mean hospital-level PE positivity rate was 12.3% (median, 9.1%); there was no significant difference in PE positivity rate across low through high CT PA use tertiles (11.3%, 11.9%, 12.9%, P = .37). After adjustment for hospital- and patient-level factors, the remaining amount of interhospital variation was relatively low (ICC, 9.0%). Conclusion Limited interhospital variation in use and yield of in-hospital CT PA was observed among patients undergoing TKR or THR in the United States. (c) RSNA, 2016 Online supplemental material is available for this article. PMID- 27228332 TI - Prospective Assessment of Correlation between US Acoustic Radiation Force Impulse and MR Elastography in a Pediatric Population: Dispersion of US Shear-Wave Speed Measurement Matters. AB - Purpose To evaluate the correlation between ultrasonographic (US) point shear wave elastography (SWE) and magnetic resonance (MR) elastography liver shear-wave speed (SWS) measurements in a pediatric population and to determine if US data dispersion affects this relationship. Materials and Methods Institutional review board approval was obtained for this HIPAA-compliant investigation; informed consent and patient assent (as indicated) were obtained. Patients (age range, 0 21 years) undergoing clinical liver MR elastography between July 2014 and November 2015 were prospectively enrolled. Patients underwent two-dimensional gradient-recalled-echo 1.5-T MR elastography with point SWE performed immediately before or immediately after MR elastography. Spearman rank correlation coefficients were calculated to assess the relationship and agreement between point SWE and MR elastography SWS measurements. Uni- and multivariate logistic regression were performed to identify predictors of US data dispersion, with the best multivariate model selected based on Akaike information criterion. Results A total of 55 patients (24 female) were enrolled (mean age, 14.0 years +/- 3.9 (standard deviation) (range, 3.5-21.4 years). There was fair correlation between point SWE and MR elastography SWS values for all patients (rho = 0.33, P = .016). Correlation was substantial, however, when including only patients with minimal US data dispersion (n = 26, rho = 0.61, P = .001). Mean body mass index (BMI) was significantly lower in patients with minimal US data dispersion than in those with substantial US data dispersion (25.4 kg/m2 +/- 7.8 vs 32.3 kg/m2 +/- 8.3, P = .003). At univariate analysis, BMI (odds ratio, 1.12; 95% confidence interval [CI]: 1.03, 1.21; P = .006) and abdominal wall thickness (odds ratio, 2.50; 95% CI: 1.32, 4.74; P = .005) were significant predictors of US data dispersion. In the best multivariate model, BMI was the only significant predictor (odds ratio, 1.11; 95% CI: 1.03, 1.20; P = .009). Conclusion Point SWE and MR elastography liver SWS measurements correlate well in patients with a BMI of less than 30 kg/m2 and minimal US data dispersion; increasing US data dispersion is directly related to a higher BMI. (c) RSNA, 2016. PMID- 27228333 TI - The Potential Role of Patient Navigation in Low- and Middle-Income Countries for Patients With Cancer. PMID- 27228334 TI - Priming effects between spatial meaning of verbs and numbers are modulated by time intervals: Early interference and late facilitation. AB - In 2 recent studies it has been shown that processing high or low number primes (8, 9 vs. 1, 2) affect the processing of subsequent target words with an implicit spatial cue up or down (e.g., sky, to rise vs. floor, to fall) (Lachmair, Dudschig, de la Vega, & Kaup, 2014a; Lachmair, Dudschig, Ruiz Fernandez, & Kaup, 2014b). It has been argued that the interactions for number-noun and number-verb pairs are due to overlapping representations of numbers and words. If this is true, one should find similar interactions by using words as primes and numbers as targets (neuronal-overlap-of-meaning hypothesis). It has also been argued that the reversed interaction for number-verb pairs as shown in Lachmair et al. (2014b) might be due to a dynamic simulation of the associated motion (dynamic spatial-grounding hypothesis). This was tested by using 3 different time intervals for target presentation. The results show first that the neuronal overlap-of-meaning hypothesis was only supported for verb-number pairs (Experiment 1), not for noun-number pairs (Experiment 2). Second, the dynamic spatial-grounding hypothesis was supported by the results for verb-number pairs as expected. This suggests that neuronal representations of numbers and verbs share common spatial meaning attributes. Moreover, the results suggest that the meaning of verbs with implicit directional cue up or down is dynamically simulated according to the course of their movement. (PsycINFO Database Record PMID- 27228335 TI - Variation in paediatric clinical practice: A review of care in inpatient, outpatient and emergency department settings. PMID- 27228337 TI - One-dimensional metallic surface states of Pt-induced atomic nanowires on Ge(0 0 1). AB - Surface states of platinum-induced atomic nanowires on a germanium (0 0 1) surface, which shows a structural phase transition at 80 K, were studied by angle resolved photoelectron spectroscopy (ARPES). We observed four one-dimensional metallic surface states, among which, two bands were reported in our previous study (Yaji et al 2013 Phys. Rev. B 87 241413). One of the newly-found two bands is a quasi-one-dimensional state and is split into two due to the Rashba effect. Photoelectron intensity from one of the spin-polarized branches is reduced at a boundary of the surface Brillouin zone below the phase transition temperature. The reduction of the photoelectron intensity in the low temperature phase is interpreted as the interference of photoelectrons, not as the Peierls instability. We also discuss the low energy properties of the metallic surface states and their spin splitting using high-resolution ARPES with a vacuum ultraviolet laser. PMID- 27228336 TI - Phosphorus remobilization from rice flag leaves during grain filling: an RNA-seq study. AB - The physiology and molecular regulation of phosphorus (P) remobilization from vegetative tissues to grains during grain filling is poorly understood, despite the pivotal role it plays in the global P cycle. To test the hypothesis that a subset of genes involved in the P starvation response are involved in remobilization of P from flag leaves to developing grains, we conducted an RNA seq analysis of rice flag leaves during the preremobilization phase (6 DAA) and when the leaves were acting as a P source (15 DAA). Several genes that respond to phosphate starvation, including three purple acid phosphatases (OsPAP3, OsPAP9b and OsPAP10a), were significantly up-regulated at 15 DAA, consistent with a role in remobilization of P from flag leaves during grain filling. A number of genes that have not been implicated in the phosphate starvation response, OsPAP26, SPX MFS1 (a putative P transporter) and SPX-MFS2, also showed expression profiles consistent with involvement in P remobilization from senescing flag leaves. Metabolic pathway analysis using the KEGG system suggested plastid membrane lipid synthesis is a critical process during the P remobilization phase. In particular, the up-regulation of OsPLDz2 and OsSQD2 at 15 DAA suggested phospholipids were being degraded and replaced by other lipids to enable continued cellular function while liberating P for export to developing grains. Three genes associated with RNA degradation that have not previously been implicated in the P starvation response also showed expression profiles consistent with a role in P mobilization from senescing flag leaves. PMID- 27228338 TI - Challenges in Applying the Results of Clinical Trials to Clinical Practice. AB - The relevance of clinical trial results to clinical practice hinges on 2 critical questions: Will the results be replicated in one's practice, and Are the results clinically important? The answers to the following 5 questions may help one determine how relevant a study result is to clinical practice. First, have steps been taken to minimize bias (eg, masking, randomization)? Second, is the result likely due to the treatment (vs confounding factors)? Third, is the result unlikely to be due to chance? Fourth, is the study population representative of your patients? Fifth, is the totality of the evidence consistent across studies? To determine if a study result is likely to be clinically important, consider a 3 step approach. In step 1, decide, a priori, what a clinically meaningful difference between 2 treatments would be to define regions of beneficial, harmful, and trivial outcomes. In step 2, determine whether the CIs around the average outcome include the range of beneficial outcomes and lie outside the range of harmful outcomes. In step 3, determine the proportion of patients achieving a clinically meaningful benefit. If the CIs mostly include the range of beneficial outcomes and lie outside the range of clinically harmful outcomes and if a substantial proportion of patients achieve a clinically meaningful benefit, then the intervention is probably clinically important. Application of clinical trial results to clinical practice requires critical analysis of the extant literature as well as good clinical judgment. PMID- 27228341 TI - Axial spondyloarthritis. PMID- 27228340 TI - MicroRNA-1301-Mediated RanGAP1 Downregulation Induces BCR-ABL Nuclear Entrapment to Enhance Imatinib Efficacy in Chronic Myeloid Leukemia Cells. AB - Chronic myeloid leukemia (CML) is a myeloproliferative disease. Imatinib (IM), the first line treatment for CML, is excessively expensive and induces various side effects in CML patients. Therefore, it is essential to investigate a new strategy for improving CML therapy. Our immunoblot data revealed that RanGTPase activating protein 1 (RanGAP1) protein levels increased by approximately 30-fold in K562 cells compared with those in normal cells. RanGAP1 is one of the important components of RanGTPase system, which regulates the export of nuclear protein. However, whether RanGAP1 level variation influences BCR-ABL nuclear export is still unknown. In this report, using shRNA to downregulate RanGAP1 expression level augmented K562 cell apoptosis by approximately 40% after treatment with 250 nM IM. Immunofluorescence assay also indicated that three-fold of nuclear BCR-ABL was detected. These data suggest that BCR-ABL nuclear entrapment induced by RanGAP1 downregulation can be used to improve IM efficacy. Moreover, our qRT-PCR data indicated a trend of inverse correlation between the RanGAP1 and microRNA (miR)-1301 levels in CML patients. MiR-1301, targeting the RanGAP1 3' untranslated region, decreased by approximately 100-fold in K562 cells compared with that in normal cells. RanGAP1 downregulation by miR-1301 transfection impairs BCR-ABL nuclear export to increase approximately 60% of cell death after treatment of 250 nM IM. This result was almost the same as treatment with 1000 nM IM alone. Furthermore, immunofluorescence assay demonstrated that Tyr-99 of nuclear P73 was phosphorylated accompanied with nuclear entrapment of BCR-ABL after transfection with RanGAP1 shRNA or miR-1301 in IM-treated K562 cells. Altogether, we demonstrated that RanGAP1 downregulation can mediate BCR ABL nuclear entrapment to activate P73-dependent apoptosis pathway which is a novel strategy for improving current IM treatment for CML. PMID- 27228342 TI - Genetically Similar Isolates of Salmonella enterica Serotype Enteritidis Persistent in China for a Long-Term Period. AB - Salmonella enterica serotype Enteritidis (S. Enteritidis) is an important causative agent of nontyphoidal salmonellosis in human populations. In this study, we collected 72 S. Enteritidis strains from 2004 to 2014 in Ningbo, mid east China. Of the 72 strains, we identified a dominant clone of 58 strains recovered from patient's feces (n = 48), blood (n = 1), pleural effusion (n = 1), chickens (n = 3), and dessert cakes (n = 5) by pulsed-field gel electrophoresis (PFGE) and variable-number of tandem repeat analysis (MLVA). The profile arrangements of MLVA were SE1-SE2-SE3-SE5-SE6-SE8-SE9: 4-4-3-11-10-1-3. These dominant strains were susceptible to ampicillin, chloramphenicol, tetracycline, ciprofloxacin, gentamicin, cefotaxime and trimethoprim-sulfamethoxazole, and resistant to nalidixic acid. Additionally, all isolates harboured virulence genes invA, sipA, sopE, and spvB when tested by PCR. Our results reveal that genetically similar S. Enteritidis strains which accounted for several outbreaks as well as blood infection and pleural cavity infection are prevalent in China for a long-term period. This situation calls for further attention in the prevention and control of foodborne disease caused by Salmonella species. PMID- 27228343 TI - Fostering Disruptive Interdisciplinary Science. PMID- 27228344 TI - Principles of Systems Biology-No. 5. AB - If systems biology is about understanding how links between components yield emergent phenomena, this month's Cell Systems Call (Cell Systems 1, 307) contains a veritable bounty of examples, showcasing the breadth of the field from systems oceanography to molecular evolution to the influence of cellular niche microenvironments on stem cell development. PMID- 27228345 TI - Caenorhabditis elegans Gets Metabolic Network Models. AB - Two genome-scale network models for Caenorhabditis elegans offer a powerful new way to delineate context-dependent metabolic activity in the worm. PMID- 27228346 TI - Scaling-Up Signaling Pathway Analysis. AB - A new technique for simultaneously measuring the activities of many signaling pathways unravels interconnected signaling networks. PMID- 27228347 TI - Slider thickness promotes lubricity: from 2D islands to 3D clusters. AB - The sliding of three-dimensional clusters and two-dimensional islands adsorbed on crystal surfaces represents an important test case to understand friction. Even for the same material, monoatomic islands and thick clusters will not as a rule exhibit the same friction, but specific differences have not been explored. Through realistic molecular dynamics simulations of the static friction of gold on graphite, an experimentally relevant system, we uncover as a function of gold thickness a progressive drop of static friction from monolayer islands, that are easily pinned, towards clusters, that slide more readily. The main ingredient contributing to this thickness-induced lubricity appears to be the increased effective rigidity of the atomic contact, acting to reduce the cluster interdigitation with the substrate. A second element which plays a role is the lateral contact size, which can accommodate the solitons typical of the incommensurate interface only above a critical contact diameter, which is larger for monolayer islands than for thick clusters. The two effects concur to make clusters more lubric than islands, and large sizes more lubric than smaller ones. These conclusions are expected to be of broader applicability in diverse nanotribological systems, where the role played by static, and dynamic, friction is generally quite important. PMID- 27228348 TI - Drug vaping applied to cannabis: Is "Cannavaping" a therapeutic alternative to marijuana? AB - Therapeutic cannabis administration is increasingly used in Western countries due to its positive role in several pathologies. Dronabinol or tetrahydrocannabinol (THC) pills, ethanolic cannabis tinctures, oromucosal sprays or table vaporizing devices are available but other cannabinoids forms can be used. Inspired by the illegal practice of dabbing of butane hashish oil (BHO), cannabinoids from cannabis were extracted with butane gas, and the resulting concentrate (BHO) was atomized with specific vaporizing devices. The efficiency of "cannavaping," defined as the "vaping" of liquid refills for e-cigarettes enriched with cannabinoids, including BHO, was studied as an alternative route of administration for therapeutic cannabinoids. The results showed that illegal cannavaping would be subjected to marginal development due to the poor solubility of BHO in commercial liquid refills (especially those with high glycerin content). This prevents the manufacture of liquid refills with high BHO concentrations adopted by most recreational users of cannabis to feel the psychoactive effects more rapidly and extensively. Conversely, "therapeutic cannavaping" could be an efficient route for cannabinoids administration because less concentrated cannabinoids-enriched liquid refills are required. However, the electronic device marketed for therapeutic cannavaping should be carefully designed to minimize potential overheating and contaminant generation. PMID- 27228349 TI - The emerging role of Toll-like receptor 4 in myocardial inflammation. AB - Toll-like receptors (TLRs) are a family of pattern recognition receptors involved in cardiovascular diseases. Notably, numerous studies have demonstrated that TLR4 activates the expression of several of pro-inflammatory cytokine genes that play pivotal roles in myocardial inflammation, particularly myocarditis, myocardial infarction, ischemia-reperfusion injury, and heart failure. In addition, TLR4 is an emerging target for anti-inflammatory therapies. Given the significance of TLR4, it would be useful to summarize the current literature on the molecular mechanisms and roles of TLR4 in myocardial inflammation. Thus, in this review, we first introduce the basic knowledge of the TLR4 gene and describe the activation and signaling pathways of TLR4 in myocardial inflammation. Moreover, we highlight the recent progress of research on the involvement of TLR4 in myocardial inflammation. The information reviewed here may be useful to further experimental research and to increase the potential of TLR4 as a therapeutic target. PMID- 27228350 TI - Eicosapentaenoic acid attenuates dexamethasome-induced apoptosis by inducing adaptive autophagy via GPR120 in murine bone marrow-derived mesenchymal stem cells. AB - Long-term use of glucocorticoids is a widespread clinical problem, which currently has no effective solution other than discontinuing the use. Eicosapentaenoic acid (EPA), an omega-3 long chain polyunsaturated fatty acid (n 3 PUFA), which is largely contained in fish or fish oil, has been reported to promote cell viability and improve bone metabolism. However, little is known about the effects of EPA on dexamethasome (Dex)-induced cell apoptosis. In this study, we showed that EPA-induced autophagy of murine bone marrow-derived mesenchymal stem cells (mBMMSCs). Meanwhile, EPA, but not arachidonic acid (AA), markedly inhibited Dex-induced apoptosis and promoted the viability of mBMMSCs. We also observed that EPA-induced autophagy was modulated by GPR120, but not GPR40. Further experiments showed that the mechanism of EPA-induced autophagy associated with GPR120 modulation involved an increase in the active form of AMP activated protein kinase and a decrease in the activity of mammalian target of RAPA. The protective effect of EPA on Dex-induced apoptosis via GPR120-meditated induction of adaptive autophagy was supported by in vivo experiments. In summary, our findings may have important implications in developing future strategies to use EPA in the prevention and therapy of the side effects induced by long-term Dex-abuse. PMID- 27228352 TI - 'Mitochondrial energy imbalance and lipid peroxidation cause cell death in Friedreich's ataxia'. AB - Friedreich's ataxia (FRDA) is an inherited neurodegenerative disease. The mutation consists of a GAA repeat expansion within the FXN gene, which downregulates frataxin, leading to abnormal mitochondrial iron accumulation, which may in turn cause changes in mitochondrial function. Although, many studies of FRDA patients and mouse models have been conducted in the past two decades, the role of frataxin in mitochondrial pathophysiology remains elusive. Are the mitochondrial abnormalities only a side effect of the increased accumulation of reactive iron, generating oxidative stress? Or does the progressive lack of iron sulphur clusters (ISCs), induced by reduced frataxin, cause an inhibition of the electron transport chain complexes (CI, II and III) leading to reactive oxygen species escaping from oxidative phosphorylation reactions? To answer these crucial questions, we have characterised the mitochondrial pathophysiology of a group of disease-relevant and readily accessible neurons, cerebellar granule cells, from a validated FRDA mouse model. By using live cell imaging and biochemical techniques we were able to demonstrate that mitochondria are deregulated in neurons from the YG8R FRDA mouse model, causing a decrease in mitochondrial membrane potential (?Psim) due to an inhibition of Complex I, which is partially compensated by an overactivation of Complex II. This complex activity imbalance leads to ROS generation in both mitochondrial matrix and cytosol, which results in glutathione depletion and increased lipid peroxidation. Preventing this increase in lipid peroxidation, in neurons, protects against in cell death. This work describes the pathophysiological properties of the mitochondria in neurons from a FRDA mouse model and shows that lipid peroxidation could be an important target for novel therapeutic strategies in FRDA, which still lacks a cure. PMID- 27228351 TI - Long intergenic non-coding RNA APOC1P1-3 inhibits apoptosis by decreasing alpha tubulin acetylation in breast cancer. AB - Increasing evidence indicates that long non-coding RNAs (lncRNAs) act as important regulatory factors in tumor progression. However, their roles in breast cancer remain largely unknown. In present studies, we identified aberrantly expressed long intergenic non-coding RNA APOC1P1-3 (lincRNA-APOC1P1-3) in breast cancer by microarray, verified it by quantitative real-time PCR, and assessed methylation status in the promoter region by pyrosequencing. We also investigated the biological functions with plasmid transfection and siRNA silencing experiments, and further explored their mechanisms by RNA pull-down and RNA immunoprecipitation to identify binding proteins. We found that 224 lncRNAs were upregulated in breast cancer, whereas 324 were downregulated. The lincRNA-APOC1P1 3 was overexpressed in breast cancer, which was related to tumor size and hypomethylation in its promoter region. We also found that APOC1P1-3 could directly bind to tubulin to decrease alpha-tubulin acetylation, to inactivate caspase-3, and to inhibit apoptosis. This study demonstrates that overexpression of APOC1P1-3 can inhibit breast cancer apoptosis. PMID- 27228354 TI - Post-transplant lymphoproliferative disorders. PMID- 27228355 TI - Fractional Factorial Design of MALDI-TOF-MS Sample Preparations for the Optimized Detection of Phospholipids and Acylglycerols. AB - Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) has successfully been used for the analysis of high molecular weight compounds, such as proteins and nucleic acids. By contrast, analysis of low molecular weight compounds with this technique has been less successful due to interference from matrix peaks which have a similar mass to the target analyte(s). Recently, a variety of modified matrices and matrix additives have been used to overcome these limitations. An increased interest in lipid analysis arose from the feasibility of correlating these components with many diseases, e.g. atherosclerosis and metabolic dysfunctions. Lipids have a wide range of chemical properties making their analysis difficult with traditional methods. MALDI-TOF-MS shows excellent potential for sensitive and rapid analysis of lipids, and therefore this study focuses on computational-analytical optimization of the analysis of five lipids (4 phospholipids and 1 acylglycerol) in complex mixtures using MALDI-TOF-MS with fractional factorial design (FFD) and Pareto optimality. Five different experimental factors were investigated using FFD which reduced the number of experiments performed by identifying 720 key experiments from a total of 8064 possible analyses. Factors investigated included the following: matrices, matrix preparations, matrix additives, additive concentrations, and deposition methods. This led to a significant reduction in time and cost of sample analysis with near optimal conditions. We discovered that the key factors used to produce high quality spectra were the matrix and use of appropriate matrix additives. PMID- 27228356 TI - Controlling Coordination Geometries: Ru-Carbene Complexes with Tetra-NHC Ligands. AB - The synthesis of the first ruthenium(II) complexes bearing open-chain tetra-N heterocyclic carbene (tetra-NHC) ligands via in situ transmetalation is described. The ruthenium complexes show differing coordination geometries depending on the length of the alkyl linker. Replacement of the two cis acetonitrile ligands in the methylene bridged ruthenium complex by nucleophiles also influences the coordination geometry. Both structural motifs were evaluated in transfer hydrogenation (TH) of acetophenone, and in particular the sawhorse type coordinated system exhibits remarkable activity with turnover frequencies of more than 100 000 h(-1). PMID- 27228353 TI - Hearts deficient in both Mfn1 and Mfn2 are protected against acute myocardial infarction. AB - Mitochondria alter their shape by undergoing cycles of fusion and fission. Changes in mitochondrial morphology impact on the cellular response to stress, and their interactions with other organelles such as the sarcoplasmic reticulum (SR). Inhibiting mitochondrial fission can protect the heart against acute ischemia/reperfusion (I/R) injury. However, the role of the mitochondrial fusion proteins, Mfn1 and Mfn2, in the response of the adult heart to acute I/R injury is not clear, and is investigated in this study. To determine the effect of combined Mfn1/Mfn2 ablation on the susceptibility to acute myocardial I/R injury, cardiac-specific ablation of both Mfn1 and Mfn2 (DKO) was initiated in mice aged 4-6 weeks, leading to knockout of both these proteins in 8-10-week-old animals. This resulted in fragmented mitochondria (electron microscopy), decreased mitochondrial respiratory function (respirometry), and impaired myocardial contractile function (echocardiography). In DKO mice subjected to in vivo regional myocardial ischemia (30 min) followed by 24 h reperfusion, myocardial infarct size (IS, expressed as a % of the area-at-risk) was reduced by 46% compared with wild-type (WT) hearts. In addition, mitochondria from DKO animals had decreased MPTP opening susceptibility (assessed by Ca(2+)-induced mitochondrial swelling), compared with WT hearts. Mfn2 is a key mediator of mitochondrial/SR tethering, and accordingly, the loss of Mfn2 in DKO hearts reduced the number of interactions measured between these organelles (quantified by proximal ligation assay), attenuated mitochondrial calcium overload (Rhod2 confocal microscopy), and decreased reactive oxygen species production (DCF confocal microscopy) in response to acute I/R injury. No differences in isolated mitochondrial ROS emissions (Amplex Red) were detected in response to Ca(2+) and Antimycin A, further implicating disruption of mitochondria/SR tethering as the protective mechanism. In summary, despite apparent mitochondrial dysfunction, hearts deficient in both Mfn1 and Mfn2 are protected against acute myocardial infarction due to impaired mitochondria/SR tethering. PMID- 27228358 TI - Ear ossicle morphology of the Jurassic euharamiyidan Arboroharamiya and evolution of mammalian middle ear. AB - The middle ear bones of Mesozoic mammals are rarely preserved as fossils and the morphology of these ossicles in the earliest mammals remains poorly known. Here, we report the stapes and incus of the euharamiyidan Arboroharamiya from the lower Upper Jurassic (~160 Ma) of northern China, which represent the earliest known mammalian middle ear ossicles. Both bones are miniscule in relation to those in non-mammalian cynodonts. The skull length/stapedial footplate diameter ratio is estimated as 51.74 and the stapes length as the percentage of the skull length is 4%; both numbers fall into the stapes size ranges of mammals. The stapes is "rod like" and has a large stapedial foramen. It is unique among mammaliaforms in having a distinct posterior process that is interpreted as for insertion of the stapedius muscle and homologized to the ossified proximal (stapedial) end of the interhyal, on which the stapedius muscle attached. The incus differs from the quadrate of non-mammalian cynodonts such as morganucodontids in having small size and a slim short process. Along with lack of the postdentary trough and Meckelian groove on the medial surface of the dentary, the ossicles suggest development of the definitive mammalian middle ear (DMME) in Arboroharamiya. Among various higher-level phylogenetic hypotheses of mammals, the one we preferred places "haramiyidans" within Mammalia. Given this phylogeny, development of the DMME took place once in the allotherian clade containing euharamiyidans and multituberculates, probably independent to those of monotremes and therians. Thus, the DMME has evolved at least three times independently in mammals. Alternative hypothesis that placed "haramiyidans" outside of Mammalia would require independent acquisition of the DMME in multituberculates and euharamiyidans as well as parallel evolution of numerous derived similarities in the dentition, occlusion pattern, mandibles, cranium, and postcranium between the two groups and between "haramiyidans" and other mammals. J. Morphol. 279:441-457, 2018. (c) 2016 Wiley Periodicals, Inc. PMID- 27228357 TI - In Vitro Gene Silencing of the Fish Microsporidian Heterosporis saurida by RNA Interference. AB - Heterosporis saurida, a microsporidian parasite of lizardfish, Saurida undosquamis, causes severe economic losses in marine aquaculture. Among the novel approaches being explored for treatment of parasitic infections in aquaculture is small interfering RNA molecules. The aim of the present study was to investigate the efficiency of using siRNA to knock down expression of specific genes of H. saurida in vitro. For this purpose, siRNAs specific for ATP/ADP antiporter 1 and methionine aminopeptidase II genes were designed and tested using a previously developed in vitro cultivation model. Silencing of H. saurida target genes was assessed and the efficacy of using siRNA for inhibition of gene expression was measured by quantitative real-time polymerase chain reaction (PCR). Silencing of ATP/ADP antiporter 1 or methionine aminopeptidase II by siRNA reduced H. saurida infection levels in EK-1 cells 40% and 60%, respectively, as measured by qRT-PCR and spore counts. Combined siRNA treatment of both ATP/ADP antiporter 1 and methionine aminopeptidase II siRNAs was more effective against H. saurida infection as seen by the 16S rRNA level and spore counts. Our study concluded that siRNA could be used to advance development of novel approaches to inhibit H. saurida and provide an alternative approach to combat microsporidia. PMID- 27228359 TI - Science beyond boundary: are premature discoveries things of the past? AB - Mendel's name more than of any other draws our attention to the personal side in terms of success and failure in science. Mendel lived 19 years after presenting his research findings and died without receiving any recognition for his work. Are premature discoveries things of the past, you may ask? I review the material basis of science in terms of science boundary and field accessibility and analyze the possibility of premature discoveries in different fields of science such as, for example, physics and biology. I conclude that science has reached a stage where progress is being made mostly by pushing the boundary of the known from inside than by leaping across boundaries. As more researchers become engaged in science, and as more publications become open access, on-line, and interactive, the probability of an important discovery remaining buried and going unrecognized would become exceedingly small. Of course, as examples from physics show, a new theory or an important idea can always lie low, unrecognized until it becomes re discovered and popularized by other researchers. Thus, premature discoveries will become less likely but not forbidden. PMID- 27228360 TI - Cognitive Dysfunction in Children with Heart Disease: The Role of Anesthesia and Sedation. AB - As physicians and caregivers of children with congenital heart disease, we are aware of the increasing need for procedures requiring anesthesia. While these procedures may be ideal for medical and cardiac surgical management, the risks and benefits must be assessed carefully. There are well known risks of cardiovascular and respiratory complications from anesthesia and sedation and a potentially under-appreciated risk of neurocognitive dysfunction. Both animal and human studies support the detrimental effects of repeated anesthetic exposure on the developing brain. Although the studies in humans are less convincing of this risk, the Society of Pediatric Anesthesia jointly with SmartTots provided a consensus statement on the use of anesthetic and sedative drugs in infants and toddlers when speaking to families. (www.pedsanesthesia.org; http://smarttots.org/wp content/uploads/2015/10/ConsensusStatementV910.5.2015.pdf). An excerpt of the statement is "Concerns regarding the unknown risk of anesthetic exposure to your child's brain development must be weighed against the potential harm associated with cancelling or delaying a needed procedure. Each child's care must be evaluated individually based on age, type, and urgency of the procedure and other health factors. This review provides a summary of the current evidence regarding anesthesia-induced neurotoxicity and the developing brain and its implications for children with congenital heart disease. PMID- 27228361 TI - Probing the Reaction Mechanism of Aluminum/Poly(vinylidene fluoride) Composites. AB - Energetic thin films with high mass loadings of nanosized components have been recently fabricated using electrospray deposition. These films are composed of aluminum nanoparticles (nAl) homogeneously dispersed in an energetic fluoropolymer binder, poly(vinylidene fluoride) (PVDF). The nascent oxide shell of the nAl has been previously shown to undergo a preignition reaction (PIR) with fluoropolymers such as polytetrafluoroethylene (PTFE). This work examines the PIR between alumina and PVDF to further explain the reaction mechanism of the Al/PVDF system. Temperature jump (T-jump) ignition experiments in air, argon, and vacuum environments showed that the nAl is fluorinated by gas phase species due to a decrease in reactivity in a vacuum. Thermogravimetric analysis coupled with differential scanning calorimetry (TGA/DSC) was used to confirm the occurrence of a PIR, and gas phase products during the PIR and fluorination of nAl were investigated with temperature jump time-of-flight mass spectrometry (T-jump TOFMS). Results show a direct correlation between the amount of alumina in the PVDF film and the relative signal intensity of hydrogen fluoride release (HF). Although the PIR between alumina and PVDF plays an important role in the Al/PVDF reaction mechanism, burn speeds of Al/PVDF films containing additional pure alumina particles showed no burn speed enhancement. PMID- 27228362 TI - Multiple Noncovalent Bonding in Halogen Complexes with Oxygen Organics. I. Tertiary Amides. AB - The present work describes the structure and binding of adducts of N,N' diacetylpiperazine with halogens and interhalogens based on combination of different experimental methods and quantum chemical calculations. On the basis of conductometric and spectro-photometric experimental results, behavior of complexes in the acetonitrile solution was described. The iodine adduct with N,N' diacetylpiperazine fully degrades into components. Adducts of interhalogens I-X (X = Cl or Br) with N,N'-diacetylpiperazine in acetonitrile partially dissociate to anionic [X-I-X](-) and cationic species. In the solid state, molecules are connected via C?O...I, C-H...I, and Cl...Cl attractive interactions. N,N' diacetylpiperazine...dihalogen complex is stabilized by simultaneous C?O...I and C-H...I interactions. Such binding mode allows to explain the problems of the direct halogenation of acetyl-containing compounds with molecular halogens as reagents. We believe that the observed binding pattern can be used as prototypical for future design of halogeno complexes. PMID- 27228364 TI - AXIN2 Polymorphisms and Their Association with Colorectal Cancer in Mexican Patients. AB - AIM: The aim of this study was to investigate the association of the rs2240308 and rs1133683 polymorphisms in the AXIN2 gene with colorectal cancer (CRC) in Mexican patients. MATERIALS AND METHODS: Genomic DNAs from 201 CRC patients and 100 healthy blood donors were analyzed for AXIN2 gene polymorphisms by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. Statistical associations were calculated using the odds ratio (OR) test. RESULTS: The genotype distribution of the rs1133683 polymorphism C > T showed a statistical difference between the two study groups (p = 0.0019). Moreover, OR analyses demonstrated that individuals with either the C/T or T/T genotype have a decreased risk for CRC compared with individuals with the C/C genotype (OR = 0.47, 95% confidence interval [CI] = 0.25-0.86, p = 0.0134 and OR = 0.24, 95% CI = 0.10-0.57, p = 0.005, respectively). This association was also evident in a stratified analysis based on tumor-node-metastasis (TNM) stage. For the rs2240308 polymorphism C > T, the OR analysis showed a significantly increased risk for carriers of the T/T genotype (OR = 2.64, 95% CI = 1.12-6.24, p = 0.0236) and this association was also evident in the stratified analysis by TNM stage. CONCLUSION: Our results indicate the possibility that variations in the AXIN2 gene may play a significant role in promoting or preventing CRC development. PMID- 27228363 TI - Improved 6-year overall survival in AT/RT - results of the registry study Rhabdoid 2007. AB - Atypical teratoid rhabdoid tumors (AT/RT) are characterized by mutations and subsequent inactivation of SMARCB1 (INI1, hSNF5), a predilection for very young children and an unfavorable outcome. The European Registry for rhabdoid tumors (EU-RHAB) was established to generate a common European database and to establish a standardized treatment regimen as the basis for phase I/II trials. Thus, genetic analyses, neuropathologic and radiologic diagnoses, and a consensus treatment regimen were prospectively evaluated. From 2005 to 2009, 31 patients with AT/RT from four countries were recruited into the registry study Rhabdoid 2007 and treated with systemic and intraventricular chemotherapy. Eight patients received high-dose chemotherapy, 23 radiotherapy, and 17 maintenance therapy. Reference evaluations were performed in 64% (genetic analyses, FISH, MLPA, sequencing) up to 97% (neuropathology, INI1 stain). Germ-line mutations (GLM) were detected in 6/21 patients. Prolonged overall survival was associated with age above 3 years, radiotherapy and achievement of a complete remission. 6-year overall and event-free survival rates were 46% (+/-0.10) and 45% (+/-0.09), respectively. Serious adverse events and one treatment-related death due to insufficiency of a ventriculo peritoneal shunt (VP-shunt) and consecutive herniation were noted. Acquisition of standardized data including reference diagnosis and a standard treatment schedule improved data quality along with a survival benefit. Treatment was feasible with significant but manageable toxicity. Although our analysis is biased due to heterogeneous adherence to therapy, EU-RHAB provides the best available basis for phase I/II clinical trials. PMID- 27228365 TI - Novel assessments of systemic calcification propensity. AB - PURPOSE OF REVIEW: Blood is a biological fluid, which controls the precipitation of calcium and phosphate and transports mineral debris. This review presents and discusses the current concepts and novel assessment methods of systemic calcification propensity in blood. RECENT FINDINGS: Calcium and phosphate combine with calcification-inhibiting proteins, mainly fetuin-A, to form amorphous calcium phosphate-containing primary calciprotein particles (CPPs). These nanosized mineral-protein clusters undergo spontaneous transformation to secondary CPP, which contain crystalline calcium phosphate. Two recently developed methods assess complementary aspects of the calcification propensity of serum. The CPP-fetuin-A method determines the amount of sedimentable fetuin-A, whereas the T50-Test determines the transformation time point T50 from amorphous to crystalline CPPs in artificially supersaturated serum.Clinical studies in renal patients have already demonstrated close associations of the CPP-fetuin-A method with all-cause mortality, severity of coronary calcification and aortic stiffness, and of the T50-Test with cardiovascular and all-cause mortality, renal graft failure and aortic stiffening. SUMMARY: Systemic calcification propensity can be assessed by two novel methods providing complementary information about the status and performance of the humoral calcification-regulating system in serum. These tests may help guide better patient care in the future with the use of more individualized therapies. PMID- 27228367 TI - Menopause. PMID- 27228366 TI - To What Extent Can Full-Scale Wastewater Treatment Plant Effluent Influence the Occurrence of Silver-Based Nanoparticles in Surface Waters? AB - Silver-based nanoparticles (Ag-b-NPs) emitted by wastewater treatment plants (WWTPs) are considered to be widely present in the natural environment. However, there is much that is unknown about the effect of WWTP effluent on the occurrence of Ag-b-NPs in surface waters. On the basis of field analysis of representative WWTPs in Germany, we demonstrate that more than 96.4% of Ag-b-NPs from wastewater influent are removed through WWTPs, even though influent contains Ag-b-NP concentrations of tens to hundreds ng L(-1), resulting in effluent Ag-b-NP concentrations of 0.7-11.1 ng L(-1) over the seasons. The estimated flux of Ag-b NPs associated with WWTPs effluent discharge is ~33 kg y(-1) in Germany. WWTPs effluent increases Ag-b-NP levels of the River Isar to 2.0-8.6 ng L(-1), while remarkable decreases are observed at sites ~1.5 km downstream of each discharge point, and Ag-b-NP levels then keep stable (0.9-2.3 ng L(-1)) until the next discharge point, showing subtle differences in Ag-b-NP levels between the river and reference lakes without industrial sources and WWTPs effluent discharge. Our results demonstrate that WWTPs effluent can exert a clear influence on the occurrence of Ag-b-NPs in surface waters. PMID- 27228368 TI - Enhanced Inflammatory Transcriptome in the Granulosa Cells of Women With Polycystic Ovarian Syndrome. AB - CONTEXT: Polycystic ovarian syndrome (PCOS), the most common endocrine disorder of reproductive-aged women, is associated with systemic low-grade inflammation. OBJECTIVE: We propose that increased or altered intrafollicular inflammatory reactions also occur in periovulatory follicles of PCOS patients. DESIGN: Gene profiling and quantitative PCR (qPCR) analyses in granulosa-lutein cells (GCs) collected from PCOS and non-PCOS women undergoing in vitro fertilization were compared with serum and follicular fluid (FF) levels of cytokines and chemokines. SETTING: This was a university-based study. PATIENTS: Twenty-one PCOS and 45 control patients were recruited: demographic, hormone, body mass index, and pregnancy outcomes were abstracted from patient data files. INTERVENTIONS: GC cytokine/chemokine mRNAs were identified and analyzed by gene-chip microarrays/qPCR before and after culture with human chorionic gonadotropin, DHT, IL-6, or IL-8; serum/FF cytokine levels were also analyzed. MAIN OUTCOME MEASURES: Relative serum/FF cytokine levels and GC cytokine expression before and after culture were compared and related to body mass index. RESULTS: The following results were found: 1) PCOS GCs express elevated transcripts encoding cytokines, chemokines, and immune cell markers, 2) based on gene profiling and qPCR analyses, obese PCOS patients define a distinct PCOS disease subtype with the most dramatic increases in proinflammatory and immune-related factors, and 3) human chorionic gonadotropin and DHT increased cytokine production in cultured GCs, whereas cytokines augmented cytokine and vascular genes, indicating that hyperandrogenism/elevated LH and obesity in PCOS women augment intrafollicular cytokine production. CONCLUSIONS: Intrafollicular androgens and cytokines likely comprise a local regulatory loop that impacts GC expression of cytokines and chemokines and the presence of immune cells; this loop is further enhanced in the obese PCOS subtype. PMID- 27228370 TI - Sun Exposure Behavior, Seasonal Vitamin D Deficiency, and Relationship to Bone Health in Adolescents. AB - CONTEXT: Vitamin D is essential for bone health in adolescence, when there is rapid bone mineral content accrual. Because cutaneous sun exposure provides vitamin D, there is no recommended oral intake for UK adolescents. OBJECTIVE: Our objective was to assess seasonal vitamin D status and its contributors in white Caucasian adolescents and examine bone health in those found deficient. DESIGN: Prospective cohort study was undertaken. SETTING: Six schools in Greater Manchester, UK, were included. PARTICIPANTS: Participants were 131 adolescents between 12 and 15 years of age. INTERVENTION(S): Seasonal assessment of circulating 25-hydroxyvitamin D (25OHD), personal sun exposure, and dietary vitamin D. Adolescents deficient (25OHD <10 ng/ml/25 nmol/liter) in at least one season underwent dual-energy X-ray absorptiometry (lumbar spine, femoral neck), with bone mineral apparent density correction for size, and peripheral quantitative computed tomography (distal radius) for volumetric bone mineral density (BMD). MAIN OUTCOME MEASURE: Serum 25OHD and BMD measurements. RESULTS: Mean 25OHD was highest in September: 24.1 (SD, 6.9) ng/ml and lowest in January: 15.5 (5.9) ng/ml. Over the year, 16% were deficient in >= one season and 79% insufficient (25OHD <20 ng/ml/50 nmol/liter) including 28% in September. Dietary vitamin D was low year-round, whereas personal sun exposure was seasonal and predominantly across the school week. Holidays accounted for 17% variation in peak 25OHD (P < .001). Nineteen adolescents underwent bone assessment, which showed low femoral neck bone mineral apparent density vs matched reference data (P = .0002), three with Z less than or equal to -2.0 distal radius trabecular volumetric BMD. CONCLUSIONS: Sun exposure levels failed to provide adequate vitamin D, with approximately one-quarter of adolescents insufficient even at summer peak. Seasonal vitamin D deficiency was prevalent and those affected had low BMD. Recommendations on vitamin D acquisition are indicated in this age group. PMID- 27228369 TI - Baseline AMH Level Associated With Ovulation Following Ovulation Induction in Women With Polycystic Ovary Syndrome. AB - CONTEXT: Anti-Mullerian hormone (AMH) reduces aromatase activity and sensitivity of follicles to FSH stimulation. Therefore, elevated serum AMH may indicate a higher threshold for response to ovulation induction in women with polycystic ovary syndrome (PCOS). OBJECTIVE: This study sought to determine the association between AMH levels and ovulatory response to treatment among the women enrolled into the Pregnancy in PCOS II (PPCOS II) trial. DESIGN AND SETTING: This was a secondary analysis of data from a randomized clinical trial in academic health centers throughout the United States Participants: A total of 748 women age 18-40 years, with PCOS and measured AMH levels at baseline, were included in this study. MAIN OUTCOME MEASURES: Couples were followed for up to five treatment cycles to determine ovulation (midluteal serum progesterone > 5 ng/mL) and the dose required to achieve ovulation. RESULTS: A lower mean AMH and AMH per follicle was observed among women who ovulated compared with women who never achieved ovulation during the study (geometric mean AMH, 5.54 vs 7.35 ng/mL; P = .0001; geometric mean AMH per follicle, 0.14 vs 0.18; P = .01) after adjustment for age, body mass index, T, and insulin level. As AMH levels increased, the dose of ovulation induction medication needed to achieve ovulation also increased. No associations were observed between antral follicle count and ovulation. CONCLUSIONS: These results suggest that high serum AMH is associated with a reduced response to ovulation induction among women with PCOS. Women with higher AMH levels may require higher doses of medication to achieve ovulation. PMID- 27228371 TI - Accelerated longitudinal gray/white matter contrast decline in aging in lightly myelinated cortical regions. AB - Highly myelinated cortical regions seem to develop early and are more robust to age-related decline. By use of different magnetic resonance imaging (MRI) measures such as contrast between T1- and T2-weighted MRI scans (T1w/T2w) it is now possible to assess correlates of myelin content in vivo. Further, previous studies indicate that gray/white matter contrast (GWC) become blurred as individuals' age, apparently reflecting age-related changes in myelin structure. Here we address whether longitudinal changes in GWC are dependent on initial myelin content within tissue as defined by baseline T1w/T2w contrast, and hypothesize that lightly myelinated regions undergo more decline longitudinally. A sample of 207 healthy adult participants (range: 20-84 years) was scanned twice (interscan interval: 3.6 years). Results showed widespread longitudinal reductions of GWC throughout the cortical surface, especially in the frontal cortices, mainly driven by intensity decay in the white matter. Annual rate of GWC blurring showed acceleration with age in temporal and medial prefrontal regions. Moreover, the anatomical distribution of increased rate of GWC decline with advancing age was strongly related to baseline levels of intracortical myelin. This study provides a first evidence of accelerated regional GWC blurring with advancing age, relates GWC patterns to cortical myeloarchitectonics and supports the hypothesis of increased age-related vulnerability of lightly myelinated areas. Hum Brain Mapp 37:3669-3684, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27228372 TI - Maxillofacial Traumas in Farmers Caused by Farm Animals, Agricultural Vehicles, and Materials. AB - OBJECTIVE: It has been aimed at evaluating the relationship of maxillofacial fractures in farmers, which are caused due to traumas while working in farms, with trauma etiologies, maxillofacial fracture areas, age, sex, and seasonal variables. METHODS: Among the farmers who have come to our emergency service unit as a result of maxillofacial trauma between 2010 and 2012, 146 patients have been analyzed retrospectively. The patients' demographic findings, trauma etiologies, seasonal variables of trauma, and maxillofacial fracture area distribution have been analyzed. RESULTS: Patients' age varies between 12 and 80 and 87 of them are female (59.59%), while 59 are male (40.41%). The subjects' etiological distribution is as follows: 47.5% is traumas caused by cattle among the farm animals; 15.75% is traumas caused by the blows of agricultural tools; 12.33% is traumas caused by tractor accidents; 9.59% is traumas caused by falling from haystacks; 7.53% is traumas caused by falling from agricultural vehicles, and 6.85% is traumas caused by horse kicks. When trauma etiology, age, sex, seasonal distribution, and the maxillofacial fractures were analyzed, statistically significant results have been determined. CONCLUSIONS: Although the number of maxillofacial traumas is considerably high in farmers due to farm animals, agricultural devices, and agricultural tools, while these traumas can cause functional and aesthetically minor fractures on the face, they can cause important and serious fractures as well. While knowing the mechanism of etiological fractures and accidents in different study groups can be guiding in the speedy diagnosis and treatment of possible fractures, it can also be helpful in taking precautions against traumas in these groups as well. PMID- 27228373 TI - A Rare Cause of Hoarseness: Laryngeal Verruca Vulgaris. AB - Verruca vulgaris is a cutaneous disease manifested with a single or multiple, small painless lesions that may involve keratinized or nonkeratinized epithelium. It can be localized at skin or mucosa. It is a benign lesion; however, it is of importance to discriminate from verrucous carcinoma to plan treatment, especially in those with laryngeal localization. Total excision is adequate in the management of verruca vulgaris; thus, accurate differential diagnosis is essential to avoid unnecessary surgical interventions. Here, the authors presented a patient with verruca vulgaris which was totally excised by cold-blade surgical excision. PMID- 27228374 TI - A Thyroglossal Cyst With Double Duct Seen in an Adult Patient. AB - Thyroglossal duct cysts (TDCs) are one of the most common congenital cervical masses that develop in children. Double TDCs are reported in very few patients in the literature. However, the authors did not come across any thyroglossal cyst with double duct in the English literature. A 35-year female patient consulted to authors' clinic with complaints of a swelling localized on the left side of the neck and recurrent purulent discharge. A Sistrunk operation was planned and during the operation, 2 fistula tracts, both terminated in the hyoid bone, were exposed.Usually, only one fistulous tract opens onto the skin; however, in the authors' patient, the authors encountered TDC with double ducti. To authors' knowledge, no similar patients were reported in the literature. PMID- 27228375 TI - The Use of Neuronavigation as an Adjunct in Facial Reconstructive Surgery. AB - Neuronavigation, a ubiquitous tool used in neurosurgery, is rarely used in maxillofacial reconstructive surgery despite it offering many advantages without any disadvantage to the patient. The present report describes one patient with complex gun-shot wound facial injury and one patient with a rare malignant peripheral nerve sheath tumor involving the skull base, in which neuronavigation was used to improve the accuracy of bony reduction and minimize surgical invasiveness. Although neuronavigation is not necessary for all maxillofacial surgery, it can be a useful adjunct in complex maxillofacial reconstruction and maxillofacial tumor resection. PMID- 27228376 TI - Papillary Squamous Cell Carcinoma of the Cheek. AB - Papillary squamous cell carcinoma (PSCC) is a rare variant of squamous cell carcinoma. The predominant occurrence sites are larynx, oropharynx, and nasopharynx. Only a few patients have been reported in the oral cavity. Theoretically, it could be easily diagnosed based on pathological investigation, but due to its growth pattern, the most part of the mass is covered by benign squamous papilloma. There might be some misdiagnosis and therefore the surgical resection is not so radical. Herein, the authors report an unusual patient of PSCC. The whole process of diagnosis and treatment might provide some useful knowledge for future PSCC patients. PMID- 27228377 TI - Feeding in Oral Cancer Patients After Massive Ablative Surgery: Percutaneous Endoscopic Gastrostomy or Nasogastric Tube. AB - Feeding after ablative oral cancer surgery is a major concern in postoperative care phase. The aim of this study was to compare postoperative phase of healing in patients undergoing nasogastric tube insertion and percutaneous endoscopic gastrostomy. In this single randomized clinical trial, 40 patients were randomly allocated to 2 groups according to a randomized list: group one (20 patients) had nasogastric tube for 4 weeks and group two (20 patients) underwent percutaneous endoscopic gastrostomy for 4 weeks or more after the surgery. Occurrence of infection and wound dehiscence was assessed. Weight loss was defined as reduction in patients' weight at 4 weeks after the surgery compared with preoperation. Weight loss was 7.9 +/- 1.91 kg in group one and 5.3 +/- 1.38 kg in group two; the difference in this regard between the 2 groups was statistically significant (P = 0.001). In group one, 10 subjects had dehiscence versus 3 subjects in group two; this difference was significant (P = 0.04). Analysis of the data demonstrated a significant difference in postsurgical infection between the 2 groups (P = 0.044). It seems that gastrostomy may be an appropriate method for feeding in patients with extensive oral cancer. PMID- 27228378 TI - The Use of Foley Catheter for Treatment of Unstable Fracture Zygomatic Arch. AB - The isolated zygomatic arch fractures represent 21% of zygomatic-maxillary fractures and the falls is the main etiology. This type of fracture is easily reduced through several methods and the most used is the reduction through the surgical temporal approach of Gillies. The present patient illustrates the success treatment of a patient with isolated zygomatic arch fracture which a Foley catheter was used to stabilize the fracture reduction. PMID- 27228379 TI - Analysis of Facial Injuries Caused by Power Tools. AB - The number of injuries caused by power tools is steadily increasing as more domestic woodwork is undertaken and more power tools are used recreationally. The injuries caused by the different power tools as a consequence of accidents are an issue, because they can lead to substantial costs for patients and the national insurance system. The increase in hand surgery as a consequence of the use of power tools and its economic impact, and the characteristics of the hand injuries caused by power saws have been described. In recent years, the authors have noticed that, in addition to hand injuries, facial injuries caused by power tools commonly present to the emergency room. This study aimed to review the data in relation to facial injuries caused by power saws that were gathered from patients who visited the trauma center at our hospital over the last 4 years, and to analyze the incidence and epidemiology of the facial injuries caused by power saws. The authors found that facial injuries caused by power tools have risen continually. Facial injuries caused by power tools are accidental, and they cause permanent facial disfigurements and functional disabilities. Accidents are almost inevitable in particular workplaces; however, most facial injuries could be avoided by providing sufficient operator training and by tool operators wearing suitable protective devices. The evaluation of the epidemiology and patterns of facial injuries caused by power tools in this study should provide the information required to reduce the number of accidental injuries. PMID- 27228381 TI - Synthesis of Indole-Substituted Indanones via Palladium(II)-Catalyzed Tandem Reaction of ortho-Electron-Deficient Alkynyl-Substituted Aryl Aldehydes with Indoles. AB - A Pd(OAc)2-catalyzed cyclization reaction of ortho-electron-deficient alkynyl substituted aryl aldehydes with indoles was accomplished, providing an efficient and economical way to synthesize indole-substituted indanones. The electron withdrawing group attached to the alkyne and the nucleophilic indole play important roles in the formation of the indanone ring. PMID- 27228380 TI - Pressure injury prevention strategies in acute medical inpatients: an observational study. AB - BACKGROUND: Pressure injuries are a patient safety issue. Despite the suite of prevention strategies, sustained reductions in pressure injury prevalence rates have not been achieved. Generally, nurses are usually responsible for assessing patients' pressure injury risk, and then implementing appropriate prevention strategies. The study aim was to describe five planned and implemented pressure injury prevention strategies (risk assessment, management plan, support surface, repositioning, and education), and determine if a relationship existed between the planning and implementation of support surfaces and regular repositioning. METHOD: An observational study collecting data using chart audits and semi structured observations. Data were analysed using descriptive and inferential statistics. This study was set in four medical units across two Australian metropolitan hospitals. The sample comprised adult medical inpatients with reduced mobility. A subsample of participants assessed at pressure injury risk on admission was drawn from this sample. Participants were aged >=18 years, had a hospital length of stay of >=3 days prior to recruitment, provided an informed consent, and had reduced mobility. RESULTS: There was suboptimal planning and implementation of pressure injury prevention strategies for the sample and subsample. There was a significant relationship between planned and implemented support surfaces at both hospitals; however, no relationship existed between the planned and implemented of regular repositioning at either site. CONCLUSION: The planning and implementation of pressure injury strategies is haphazard. Patients received support surfaces; however, gaps exist in pressure injury risk assessment, management planning, regular repositioning, and patient education. PMID- 27228382 TI - Cardiopulmonary exercise performance is reduced in congenital diaphragmatic hernia survivors. AB - BACKGROUND: Congenital diaphragmatic hernia (CDH) is associated with lung hypoplasia. CDH survivors may have pulmonary morbidity that can decrease cardiopulmonary exercise. We aimed to examine whether cardiopulmonary exercise testing (CPET) results differ in CDH survivors versus healthy age-matched controls and whether CPET results among CDH survivors differ according to self reported daily activity. METHODS: In one medical center in Croatia, CDH survivors patients with surgically corrected CDH who were alive at age 5 years-were invited to participate in spirometry and CPET. Values were compared with those of controls matched 2:1 by age and sex for each CDH survivor aged 7 years or older. RESULTS: Among 27 CDH survivors aged 5-20 years, 13 (48%) had continued symptoms or spirometric evidence of pulmonary disease. Compared with controls (n = 44), survivors (n = 22) had lower peak oxygen consumption (VO2 mean [SD], 35.7 [6.9] vs. 45.3 [8.2] ml/kg per min; P < 0.001). At peak exercise, VO2/heart rate (P < 0.001), tidal volume (P = 0.005), and minute ventilation (P < 0.001) were lower in survivors, but the maximal respiratory rate was not different (P = 0.72). Among survivors, mean (SD) VO2peak (ml/kg per min) differed by self-reported activity level: athletic, 40.3 (5.0); normal, 35.8 (6.5); and sedentary, 32.1 (6.8) (by ANOVA, P = 0.10 across three groups and P = 0.04 athletic vs. sedentary). CONCLUSION: More than half of CDH survivors continue to have chronic pulmonary disease. CDH survivors had lower aerobic exercise capacity than controls. Self-reporting information on daily activities may identify CDH patients with low VO2max who may benefit from physical training. Pediatr Pulmonol. 2016;51:1320-1329. (c) 2016 Wiley Periodicals, Inc. PMID- 27228383 TI - Genetically Engineered Phage-Templated MnO2 Nanowires: Synthesis and Their Application in Electrochemical Glucose Biosensor Operated at Neutral pH Condition. AB - To conveniently obtain one-dimensional MnO2 nanowires (NWs) with controlled structure and unique properties for electron transfer, the genetically engineered M13 phages were used as templates for precise nucleation and growth of MnO2 crystals in filamentous phage scaffolds, via the spontaneous oxidation of Mn(2+) in alkaline solution. It was found that the morphology of NWs could be tailored by the surface charge of M13 mutants. MnO2 crystals were uniformly distributed on the surface of negatively charged tetraglutamate-fused phage (M13-E4), significantly different from irregular MnO2 agglomeration on the weakly negatively charged wild-type phage and positively charged tetraarginine-fused phage. The as-synthesized M13-E4@MnO2 NWs could catalyze the electro-oxidation of H2O2 at neutral pH. To demonstrate the superiority of the electrocatalytic activity in the solution containing plenty of chloride ions at neutral pH, both glucose oxidase and as-prepared MnO2 NWs were used for fabricating the glucose biosensor. The proposed biosensor showed a wide linear range (5 MUM to 2 mM glucose), a low limit of detection of 1.8 MUM glucose (S/N = 3), good interassay and intra-assay reproducibility and satisfactory storage stability. Due to the superiorities of synthesis and electrochemical performance, the as-prepared MnO2 NWs are promising for applications in electrocatalysis, electrochemical sensor, and supercapacitor. PMID- 27228384 TI - Developing energy efficient lignin biomass processing - towards understanding mediator behaviour in ionic liquids. AB - Environmental concerns have brought attention to the requirement for more efficient and renewable processes for chemicals production. Lignin is the second most abundant natural polymer, and might serve as a sustainable resource for manufacturing fuels and aromatic derivatives for the chemicals industry after being depolymerised. In this work, the mediator 2,2'-azino-bis(3 ethylbenthiazoline-6-sulfonic acid) diammonium salt (ABTS), commonly used with enzyme degradation systems, has been evaluated by means of cyclic voltammetry (CV) for enhancing the oxidation of the non-phenolic lignin model compound veratryl alcohol and three types of lignin (organosolv, Kraft and lignosulfonate) in the ionic liquid 1-ethyl-3-methylimidazolium ethyl sulfate, ([C2mim][C2SO4]). The presence of either veratryl alcohol or organosolv lignin increased the second oxidation peak of ABTS under select conditions, indicating the ABTS-mediated oxidation of these molecules at high potentials in [C2mim][C2SO4]. Furthermore, CV was applied as a quick and efficient way to explore the impact of water in the ABTS-mediated oxidation of both organosolv and lignosulfonate lignin. Higher catalytic efficiencies of ABTS were observed for lignosulfonate solutions either in sodium acetate buffer or when [C2mim][C2SO4] (15 v/v%) was present in the buffer solution, whilst there was no change found in the catalytic efficiency of ABTS in [C2mim][C2SO4]-lignosulfonate mixtures relative to ABTS alone. In contrast, organosolv showed an initial increase in oxidation, followed by a significant decrease on increasing the water content of a [C2mim][C2SO4] solution. PMID- 27228385 TI - A Simple, Rapid, and Highly Sensitive Electrochemical DNA Sensor for the Detection of alpha- and beta-Thalassemia in China. AB - BACKGROUND: Because of the life-consuming treatment and severe consequences associated with thalassemia, it is more effective to prevent than cure thalassemia. Rapid and sensitive detection is critical for controlling thalassemia. In this study, we developed a rapid and accurate test to genotype nondeletional alpha- and beta-thalassemia mutations by an electrochemical DNA sensor. METHODS: Screen-printed electrodes were used as electrochemical transducers for the sensor, in which the capture probe DNA was attached to the golden surface of the working electrode via an S-Au covalent bond, which is highly suitable for immobilizing the biological element. In addition, two types of ferrocene with varying redox potentials for modified signal probe DNA were adopted. The hybridization signal is detected by alternating current voltammetry when the capture probe and signal probe hybridize with the target DNA. RESULTS: With this technique, 12 types of nondeletional alpha- and beta-thalassemia mutations were detected, which constitute more than 90% of all the nondeletional types of thalassemia mutation determinants found in China, including the CD142 (TAA>CAA) Constand spring, CD125 (CTG>CCG) Quonsze, CD122 (CAC>CAG) Weastmead, 28 (A>G), Cap+1 (A>C), initiation codon (ATG>AGG), CD17 (AAG>TAG), CD26 (GAG>AAG), CD31(-C), CD41-42 (-CTTT), CD71-72 (+A), and IVS-II-654 (C>T) mutations. Concordance levels were 100% within the 20 blood samples of homozygous wild-type individuals and 238 blood samples of heterozygous mutant individuals. CONCLUSIONS: The electrochemical DNA sensor developed here can be applied for rapid genotyping of thalassemia or other clinical genotyping applications and is useful for early screening of thalassemia in high-risk groups by minimizing the time and investment cost. PMID- 27228386 TI - Severe drug-induced liver injury related to therapy with dimethyl fumarate. PMID- 27228387 TI - Outcomes of social class and classism in first- and continuing-generation college students. AB - The purpose of this study was to examine perceptions of classism that may explain links between social class, first-generation college student status, and academic and well-being outcomes. Specifically, with a sample of 1,225 college students from a public university, we examined social class and first-generation status as predictors of institutionalized, citational, and interpersonal classism and classism as a predictor of life satisfaction, academic satisfaction, and grade point average (GPA). Partially supporting hypotheses, social class and first generation status predicted institutionalized classism and interpersonal classism, and social class predicted citational classism. In turn, institutionalized classism and citational classism negatively predicted life satisfaction, and institutionalized classism negatively predicted academic satisfaction. Indirect effects were significant from social class to life satisfaction via institutionalized and citational classism, from social class to academic satisfaction via institutionalized classism, and from first-generation status to life satisfaction via institutionalized classism. Social class also had direct effects to life satisfaction, academic satisfaction, and GPA, and first generation status had direct effects to academic satisfaction and GPA. Implications for research and practice are discussed. (PsycINFO Database Record PMID- 27228388 TI - Assessment the long-term effects of septoplasty surgery on olfactory function. AB - OBJECTIVES: This research aimed to evaluate pre-operatively and post-operatively the olfactory function of patients who had undergone surgery in our clinic for chronic nasal blockage via the Connecticut Chemosensory Clinical Research Center (CCCRC) smell test. METHOD: Thirty-seven patients (24 females, 13 males) were enrolled in this study. All had undergone surgery in our clinic due to chronic nasal blockage (not for smell dysfunction), having been diagnosed with septal deviation in conjunction with concha bullosa and/or inferior turbinate hypertrophy. This is a prospective study without a control group. The mean age was 33.74 +/- 8.98 (range =19-54). All of the operations were performed under general anesthesia. CCCRC smell tests were performed on every patient before the operation and at post-operative 1st week, 6th week, 6th month, and 1st year. RESULTS: In this study, we found that septoplasty, in conjunction with middle concha surgery and/or inferior concha radiofrequency, did not affect the olfactory function negatively. CONCLUSION: Although nasal surgery has the potential to affect the smell function negatively, it was found that olfactory function was not affected after the surgery during a considerably long follow-up period. Moreover, an improvement in smell function was detected at post-operative 6th month and 1st year. PMID- 27228389 TI - Oxygen Incorporation and Release in Metastable Bixbyite V2O3 Nanocrystals. AB - A new, metastable polymorph of V2O3 with a bixbyite structure was recently stabilized in colloidal nanocrystal form. Here, we report the reversible incorporation of oxygen in this material, which can be controlled by varying temperature and oxygen partial pressure. Based on X-ray diffraction (XRD) and thermogravimetric analysis, we find that oxygen occupies interstitial sites in the bixbyite lattice. Two oxygen atoms per unit cell can be incorporated rapidly and with minimal changes to the structure while the addition of three or more oxygen atoms destabilizes the structure, resulting in a phase change that can be reversed upon oxygen removal. Density functional theory (DFT) supports the reversible occupation of interstitial sites in bixbyite by oxygen, and the 1.1 eV barrier to oxygen diffusion predicted by DFT matches the activation energy of the oxidation process derived from observations by in situ XRD. The observed rapid oxidation kinetics are thus facilitated by short diffusion paths through the bixbyite nanocrystals. Due to the exceptionally low temperatures of oxidation and reduction, this earth-abundant material is proposed for use in oxygen storage applications. PMID- 27228390 TI - Voice Change, Odynophagia, and Neck Pain Following a Sneeze. PMID- 27228391 TI - Magnetically-responsive silica-gold nanobowls for targeted delivery and SERS based sensing. AB - Composite colloidal structures with multi-functional properties have wide applications in targeted delivery of therapeutics and imaging contrast molecules and high-throughput molecular bio-sensing. We have constructed a multifunctional composite magnetic nanobowl using the bottom-up approach on an asymmetric silica/polystyrene Janus template consisting of a silica shell around a partially exposed polystyrene core. The nanobowl consists of a silica bowl and a gold exterior shell with iron oxide magnetic nanoparticles sandwiched between the silica and gold shells. The nanobowls were characterized by electron microscopy, atomic force microscopy, magnetometry, vis-NIR and FTIR spectroscopy. Magnetically vectored transport of these nanobowls was ascertained by time-lapsed imaging of their flow in fluid through a porous hydrogel under a defined magnetic field. These magnetically-responsive nanobowls show distinct surface enhanced Raman spectroscopy (SERS) imaging capability. The PEGylated magnetically responsive nanobowls show size-dependent cellular uptake in vitro. PMID- 27228392 TI - Prosodic expectations in silent reading: ERP evidence from rhyme scheme and semantic congruence in classic Chinese poems. AB - In an ERP study, classic Chinese poems with a well-known rhyme scheme were used to generate an expectation of a rhyme in the absence of an expectation for a specific character. Critical characters were either consistent or inconsistent with the expected rhyme scheme and semantically congruent or incongruent with the content of the poem. These stimuli allowed us to examine whether a top-down rhyme scheme expectation would affect relatively early components of the ERP associated with character-to-sound mapping (P200) and lexically-mediated semantic processing (N400). The ERP data revealed that rhyme scheme congruence, but not semantic congruence modulated the P200: rhyme-incongruent characters elicited a P200 effect across the head demonstrating that top-down expectations influence early phonological coding of the character before lexical-semantic processing. Rhyme scheme incongruence also produced a right-lateralized N400-like effect. Moreover, compared to semantically congruous poems, semantically incongruous poems produced a larger N400 response only when the character was consistent with the expected rhyme scheme. The results suggest that top-down prosodic expectations can modulate early phonological processing in visual word recognition, indicating that prosodic expectations might play an important role in silent reading. They also suggest that semantic processing is influenced by general knowledge of text genre. PMID- 27228393 TI - Diabetes recurrence after haemolytic uraemic syndrome outbreak in Adelaide. PMID- 27228394 TI - The Need to Expand Access to Hepatitis C Virus Drugs in the Indian Health Service. PMID- 27228395 TI - An atomic scale study of surface termination and digital alloy growth in InGaAs/AlAsSb multi-quantum wells. AB - An atomic scale study has been performed to understand the influence of the (As,Sb) shutter sequences during interface formation on the optical properties of InGaAs/AlAsSb quantum wells. Our cross-sectional scanning tunneling microscopy results show that the onset of the Sb profile is steep in the Sb-containing layers whereas an appreciable segregation of Sb in the subsequently grown Sb free layers is observed. The steep rise of the Sb profile is due to extra Sb that is supplied to the surface prior to the growth of the Sb-containing layers. No relation is found between the (As,Sb) termination conditions of the Sb-containing layers and the resulting Sb profiles in the capping layers. Correspondingly we see that the optical properties of these quantum wells are also nearly independent on the (As,Sb) shutter sequences at the interface. Digital alloy growth in comparison to conventional molecular beam epitaxy growth was also explored. X-ray results suggest that the structural properties of the quantum well structures grown by conventional molecular beam epitaxy techniques are slightly better than those formed by digital alloy growth. However photoluminescence studies indicate that the digital alloy samples give rise to a more intense and broader photoluminescence emission. Cross-sectional scanning tunneling microscopy measurements reveal that lateral composition modulations present in the digital alloys are responsible for the enhancement of the photoluminescence intensity and inhomogeneous broadening. PMID- 27228397 TI - On Tree-Based Phylogenetic Networks. AB - A large class of phylogenetic networks can be obtained from trees by the addition of horizontal edges between the tree edges. These networks are called tree-based networks. We present a simple necessary and sufficient condition for tree-based networks and prove that a universal tree-based network exists for any number of taxa that contains as its base every phylogenetic tree on the same set of taxa. This answers two problems posted by Francis and Steel recently. A byproduct is a computer program for generating random binary phylogenetic networks under the uniform distribution model. PMID- 27228398 TI - Varicella zoster virus infection. PMID- 27228399 TI - Quality Evaluation of Shelled and Unshelled Macadamia Nuts by Means of Near Infrared Spectroscopy (NIR). AB - The quality of shelled and unshelled macadamia nuts was assessed by means of Fourier transformed near-infrared (FT-NIR) spectroscopy. Shelled macadamia nuts were sorted as sound nuts; nuts infected by Ecdytolopha aurantiana and Leucopteara coffeella; and cracked nuts caused by germination. Unshelled nuts were sorted as intact nuts (<10% half nuts, 2014); half nuts (March, 2013; November, 2013); and crushed nuts (2014). Peroxide value (PV) and acidity index (AI) were determined according to AOAC. PCA-LDA shelled macadamia nuts classification resulted in 93.2% accurate classification. PLS PV prediction model resulted in a square error of prediction (SEP) of 3.45 meq/kg, and a prediction coefficient determination value (Rp (2) ) of 0.72. The AI PLS prediction model was better (SEP = 0.14%, Rp (2) = 0.80). Although adequate classification was possible (93.2%), shelled nuts must not contain live insects, therefore the classification accuracy was not satisfactory. FT-NIR spectroscopy can be successfully used to predict PV and AI in unshelled macadamia nuts, though. PMID- 27228400 TI - Climatic and environmental aspects of the Mongol withdrawal from Hungary in 1242 CE. AB - The Mongol invasion of Eastern Europe, and especially its sudden withdrawal from Hungary in 1242 CE, has generated much speculation and an array of controversial theories. None of them, however, considered multifaceted environmental drivers and the coupled analysis of historical reports and natural archives. Here we investigate annually resolved, absolutely dated and spatially explicit paleoclimatic evidence between 1230 and 1250 CE. Documentary sources and tree ring chronologies reveal warm and dry summers from 1238-1241, followed by cold and wet conditions in early-1242. Marshy terrain across the Hungarian plain most likely reduced pastureland and decreased mobility, as well as the military effectiveness of the Mongol cavalry, while despoliation and depopulation ostensibly contributed to widespread famine. These circumstances arguably contributed to the determination of the Mongols to abandon Hungary and return to Russia. While overcoming deterministic and reductionist arguments, our 'environmental hypothesis' demonstrates the importance of minor climatic fluctuations on major historical events. PMID- 27228401 TI - Muscle at Risk: The Multiple Impacts of Ammonia on Sarcopenia and Frailty in Cirrhosis. PMID- 27228402 TI - Liver Biopsy: The Reports of Its Demise Are Greatly Exaggerated. PMID- 27228403 TI - Body Composition Features Predict Overall Survival in Patients With Hepatocellular Carcinoma. AB - OBJECTIVES: Existing prognostic models for patients with hepatocellular carcinoma (HCC) have limitations. Analytic morphomics, a novel process to measure body composition using computational image-processing algorithms, may offer further prognostic information. The aim of this study was to develop and validate a prognostic model for HCC patients using body composition features and objective clinical information. METHODS: Using computed tomography scans from a cohort of HCC patients at the VA Ann Arbor Healthcare System between January 2006 and December 2013, we developed a prognostic model using analytic morphomics and routine clinical data based on multivariate Cox regression and regularization methods. We assessed model performance using C-statistics and validated predicted survival probabilities. We validated model performance in an external cohort of HCC patients from Parkland Hospital, a safety-net health system in Dallas County. RESULTS: The derivation cohort consisted of 204 HCC patients (20.1% Barcelona Clinic Liver Cancer classification (BCLC) 0/A), and the validation cohort had 225 patients (22.2% BCLC 0/A). The analytic morphomics model had good prognostic accuracy in the derivation cohort (C-statistic 0.80, 95% confidence interval (CI) 0.71-0.89) and external validation cohort (C-statistic 0.75, 95% CI 0.68-0.82). The accuracy of the analytic morphomics model was significantly higher than that of TNM and BCLC staging systems in derivation (P<0.001 for both) and validation (P<0.001 for both) cohorts. For calibration, mean absolute errors in predicted 1 year survival probabilities were 5.3% (90% quantile of 7.5%) and 7.6% (90% quantile of 12.5%) in the derivation and validation cohorts, respectively. CONCLUSION: Body composition features, combined with readily available clinical data, can provide valuable prognostic information for patients with newly diagnosed HCC. PMID- 27228404 TI - Effects of Rifaximin on Transit, Permeability, Fecal Microbiome, and Organic Acid Excretion in Irritable Bowel Syndrome. AB - OBJECTIVES: Rifaximin relieves irritable bowel syndrome (IBS) symptoms, bloating, abdominal pain, and loose or watery stools. Our objective was to investigate digestive functions in rifaximin-treated IBS patients. METHODS: In a randomized, double-blind, placebo-controlled, parallel-group study, we compared the effects of rifaximin, 550 mg t.i.d., and placebo for 14 days in nonconstipated IBS and no evidence of small intestinal bacterial overgrowth (SIBO). All subjects completed baseline and on-treatment evaluation of colonic transit by scintigraphy, mucosal permeability by lactulose-mannitol excretion, and fecal microbiome, bile acids, and short chain fatty acids measured on random stool sample. Overall comparison of primary response measures between treatment groups was assessed using intention-to-treat analysis of covariance (ANCOVA, with baseline value as covariate). RESULTS: There were no significant effects of treatment on bowel symptoms, small bowel or colonic permeability, or colonic transit at 24 h. Rifaximin was associated with acceleration of ascending colon emptying (14.9+/ 2.6 h placebo; 6.9+/-0.9 h rifaximin; P=0.033) and overall colonic transit at 48 h (geometric center 4.0+/-0.3 h placebo; 4.7+/-0.2 h rifaximin; P=0.046); however, rifaximin did not significantly alter total fecal bile acids per g of stool or proportion of individual bile acids or acetate, propionate, or butyrate in stool. Microbiome studies showed strong associations within subjects, modest associations with time across subjects, and a small but significant association of microbial richness with treatment arm (rifaximin vs. treatment). CONCLUSIONS: In nonconstipated IBS without documented SIBO, rifaximin treatment is associated with acceleration of colonic transit and changes in microbial richness; the mechanism for reported symptomatic benefit requires further investigation. PMID- 27228405 TI - Comparative Proteomic Analysis of Whole-Gut Lavage Fluid and Pancreatic Juice Reveals a Less Invasive Method of Sampling Pancreatic Secretions. AB - OBJECTIVES: There are currently no reliable, non-invasive screening tests for pancreatic ductal adenocarcinoma. The fluid secreted from the pancreatic ductal system ("pancreatic juice") has been well-studied as a potential source of cancer biomarkers. However, it is invasive to collect. We recently observed that the proteomic profile of intestinal effluent from the bowel in response to administration of an oral bowel preparation solution (also known as whole-gut lavage fluid, WGLF) contains large amounts of pancreas-derived proteins. We therefore hypothesized that the proteomic profile is similar to that of pancreatic juice. In this study, we compared the proteomic profiles of 77 patients undergoing routine colonoscopy with the profiles of 19 samples of pure pancreatic juice collected during surgery. METHODS: WGLF was collected from patients undergoing routine colonoscopy, and pancreatic juice was collected from patients undergoing pancreatic surgery. Protein was isolated from both samples using an optimized method and analyzed by LC-MS/MS. Identified proteins were compared between samples and groups to determine similarity of the two fluids. We then compared our results with literature reports of pancreatic juice-based studies to determine similarity. RESULTS: We found 104 proteins in our pancreatic juice samples, of which 90% were also found in our WGLF samples. The majority (67%) of the total proteins found in the WGLF were common to pancreatic juice, with intestine-specific proteins making up a smaller proportion. CONCLUSIONS: WGLF and pancreatic juice appear to have similar proteomic profiles. This supports the notion that WGLF is a non-invasive, surrogate bio-fluid for pancreatic juice. Further studies are required to further elucidate its role in the diagnosis of pancreatic cancer. PMID- 27228406 TI - Structures of Fluoranthene Reagent Anions Used in Electron Transfer Dissociation and Proton Transfer Reaction Tandem Mass Spectrometry. AB - Ion/ion reactions have in recent years seen widespread use in ion activation methods such as electron transfer dissociation (ETD) tandem mass spectrometry (MS/MS) as well as in charge manipulation of highly charged peptides/proteins and their fragments by proton transfer reaction (PTR). These techniques have, in combination, enabled top-down proteomics on limited-resolution benchtop mass spectrometry platforms such as quadrupole ion traps. Anions generated by chemical ionization of fluoranthene are often used for both ETD and PTR reactions; the radical anion of fluoranthene (m/z 202) for ETD and the closed-shell anion resulting from H atom attachment to the radical anion (m/z 203) for PTR. Here we use infrared ion spectroscopy in combination with density functional theory calculations to identify the structures of these reagent anions. We establish that the m/z 203 PTR reagent anion possesses a structure that deviates from what has been suggested previously and provides some insight into the reaction mechanism involved in PTR. PMID- 27228407 TI - Intriguing Physical and Chemical Properties of Phosphorus Corroles. AB - The fluorescence intensity of phosphorus corroles increases upon meso-aryl C-F/C H and P-OH/P-F substitutions, the latter affects corrole-centered redox processes more than C-H/C-F substitution on the corrole's skeleton, and the presence of F atoms allows for the first experimental insight into the electronic structures of oxidized corroles. Experimental and theoretical methodologies reveal that mono- but not bis-chlorosulfonation of the corrole skeleton is under kinetic control. Selective introduction of heavy atoms leads to complexes that are phosphorescent at room temperature. PMID- 27228408 TI - Acute myeloid leukaemia. PMID- 27228410 TI - A new dihydrofurocoumarin from the fruits of Pandanus tectorius Parkinson ex Du Roi. AB - From the fruit of Pandanus tectorius Parkinson ex Du Roi, one new dihydrofurocoumarin, named pandanusin A (1) and 15 known compounds, including one furanocoumarin (2), two coumarins (3, 4), four lignans (5-8), one neolignan (9), two flavonoids (10, 11), three phenolics (12-14), one monoglyceride (15) and one monosaccharide (16) were isolated by various chromatography methods. Among them, compounds (3-5) were obtained from the Pandanus genus for the first time and compounds (9-14, 16) were reported from this species for the first time. Their structures were elucidated by HR-ESI-MS, NMR 1D and 2D experiments and comparison with previous reported data. The alpha-glucosidase inhibitory activity of all compounds was measured. The isolated compounds (1-12, 14) showed better alpha glucosidase inhibitory activity (IC50 = 42.2, 36.5, 84.7, 73.2, 40.8, 26.7, 76.5, 33.8, 68.1, 14.4, 22.1, 81.5, 43.8 MUM, respectively) than the standard drug acarbose (IC50 = 214.5 MUM). PMID- 27228409 TI - The spectrum of structural and functional imaging abnormalities in temporal lobe epilepsy. AB - OBJECTIVE: Although most temporal lobe epilepsy (TLE) patients show marked hippocampal sclerosis (HS) upon pathological examination, 40% present with no significant cell loss but gliotic changes only. To evaluate effects of hippocampal pathology on brain structure and functional networks, we aimed at dissociating multimodal magnetic resonance imaging (MRI) characteristics in patients with HS (TLE-HS) and those with gliosis only (TLE-G). METHODS: In 20 TLE HS, 19 TLE-G, and 25 healthy controls, we carried out a novel MRI-based hippocampal subfield surface analysis that integrated volume, T2 signal intensity, and diffusion markers with seed-based hippocampal functional connectivity. RESULTS: Compared to controls, TLE-HS presented with marked ipsilateral atrophy, T2 hyperintensity, and mean diffusivity increases across all subfields, whereas TLE-G presented with dentate gyrus hypertrophy, focal increases in T2 intensity and mean diffusivity. Multivariate assessment confirmed a more marked ipsilateral load of anomalies across all subfields in TLE-HS, whereas anomalies in TLE-G were restricted to the subiculum. A between-cohort dissociation was independently suggested by resting-state functional connectivity analysis, revealing marked hippocampal decoupling from anterior and posterior default mode hubs in TLE-HS, whereas TLE-G did not differ from controls. Back projection connectivity analysis from cortical targets revealed consistently decreased network embedding across all subfields in TLE-HS, while changes in TLE G were limited to the subiculum. Hippocampal disconnectivity strongly correlated to T2 hyperintensity and marginally to atrophy. INTERPRETATION: Multimodal MRI reveals diverging structural and functional connectivity profiles across the TLE spectrum. Pathology-specific modulations of large-scale functional brain networks lend novel evidence for a close interplay of structural and functional disruptions in focal epilepsy. Ann Neurol 2016;80:142-153. PMID- 27228411 TI - Improvement of Survival Rate for Patients with Hepatocellular Carcinoma Using Transarterial Chemoembolization in Combination with Three-Dimensional Conformal Radiation Therapy: A Meta-Analysis. AB - BACKGROUND Transarterial chemoembolization (TACE) has been used alone or in combination with three-dimensional conformal radiation therapy (3DCRT) for treating hepatocellular carcinoma (HCC). The overall survival rate of HCC patients undergoing both treatments, however, has not been systematically studied. The aim of this meta-analysis-based study was to evaluate the overall efficacy of the combined therapy or monotherapy, thereby providing information for clinical treatment. MATERIAL AND METHODS We searched Google Scholar, PubMed, and Chinese National Knowledge Infrastructure (CNKI) for eligible studies, and a total of 17 case-control studies (including HCC patients treated by TACE plus 3DCRT or TACE alone) were included to perform the meta-analysis. Based on the available data, we assessed the improvements of 1-year, 2-year, and 3-year survival rate for the combination therapy of TACE and 3DCRT or TACE alone. Furthermore, the analysis was also stratified by the tumor response: complete response (CR), partial response (PR), no response (NR) and progressive disease (PD). Statistical analysis was performed using STATA 12 (Stata Statistical Software: Release 12). RESULTS The results show that HCC patients receiving combination therapy have significantly increased overall survival rate when compared to those receiving TACE alone (1-year survival rate: OR=1.95, 95% CI 1.54-2.47, p=7.3*10^-8; 2-year survival rate: OR=1.87, 95% CI 1.49-2.34, p=1.6*10^-7; 3-year survival rate: OR=2.00, 95% CI 1.52-2.64, p=1.8*10^-6). CONCLUSIONS Assessment of tumor response demonstrates that the combination therapy can efficiently increase the tumor response rate (CR+PR: OR=2.29, 95% CI 1.70-3.08, p=1.1*10^-7), with a lower rate of subsequent tumor development (PD: OR=0.25, 95% CI 0.15-0.40, p=5.5*10^-8). PMID- 27228413 TI - Critical Role of Redox Mediator in Suppressing Charging Instabilities of Lithium Oxygen Batteries. AB - Redox mediators have been widely applied to reduce the charge overpotentials of lithium-oxygen (Li-O2) batteries. Here, we reveal the critical role of redox mediator in suppressing the charging instability of Li-O2 batteries. Using high temporal resolution online electrochemical mass spectrometry, we show that charging with redox mediators (using lithium bromide as a model system) significantly reduces parasitic gas evolution and improves oxygen recovery efficiency. Using redox mediator transforms the charge reactions from electrochemical pathways to chemical pathways, which unexpectedly bypasses the formation of highly reactive intermediates upon electro-oxidation of lithium peroxide (Li2O2). Such transformation reduces self-amplifying degradation reactions of electrode and electrolyte in Li-O2 cells. We further show that the improved stability associated with the redox mediator is much more pronounced at higher charging rates, owing to fast charge-transfer kinetics of the redox mediator. Together, we show that employing redox mediator not only reduces the charge overpotential but also suppresses side reactions of Li-O2 cells with improved charging rate. Our work demonstrates that transforming electro-oxidation of Li2O2 to chemical oxidation of Li2O2 is a promising strategy to simultaneously mitigate charging side reactions and achieve low overpotential for the Li-O2 batteries. PMID- 27228412 TI - Improved Synthesis and In Vitro Evaluation of an Aptamer Ribosomal Toxin Conjugate. AB - Delivery of toxins, such as the ricin A chain, Pseudomonas exotoxin, and gelonin, using antibodies has had some success in inducing specific toxicity in cancer treatments. However, these antibody-toxin conjugates, called immunotoxins, can be bulky, difficult to express, and may induce an immune response upon in vivo administration. We previously reported delivery of a recombinant variant of gelonin (rGel) by the full-length prostate-specific membrane antigen (PSMA) binding aptamer, A9, to potentially circumvent some of these problems. Here, we report a streamlined approach to generating aptamer-rGel conjugates utilizing a chemically synthesized minimized form of the A9 aptamer. Unlike the full-length A9 aptamer, this minimized variant can be chemically synthesized with a 5' terminal thiol. This facilitates the large scale synthesis and generation of aptamer toxin conjugates linked by a reducible disulfide linkage. Using this approach, we generated aptamer-toxin conjugates and evaluated their binding specificity and toxicity. On PSMA(+) LNCaP prostate cancer cells, the A9.min-rGel conjugate demonstrated an IC50 of ~60 nM. Additionally, we performed a stability analysis of this conjugate in mouse serum where the conjugate displayed a t1/2 of ~4 h, paving the way for future in vivo experiments. PMID- 27228414 TI - Lactobacillus reuteri treatment and DSS colitis: new insight into the mechanism of protection. PMID- 27228416 TI - Scaling Laws and Critical Properties for fcc and hcp Metals. AB - The determination of the critical parameters of metals has remained particularly challenging both experimentally, because of the very large temperatures involved, and theoretically, because of the many-body interactions that take place in metals. Moreover, experiments have shown that these systems exhibit an unusually strong asymmetry of their binodal. Recent theoretical work has led to new similarity laws, based on the calculation of the Zeno line and of the underlying Boyle parameters, which provided results for the critical properties of atomic and molecular systems in excellent agreement with experiments. Using the recently developed expanded Wang-Landau (EWL) simulation method, we evaluate the grand canonical partition function, over a wide range of conditions, for 11 fcc and hcp metals (Ag, Al, Au, Be, Cu, Ir, Ni, Pb, Pd, Pt, and Rh), modeled with a many-body interaction potential. This allows us to calculate the binodal, Zeno line, and Boyle parameters and, in turn, obtain the critical properties for these systems. We also propose two scaling laws for the enthalpy and entropy of vaporization, and identify critical exponents of 0.4 and 1.22 for these two laws, respectively. PMID- 27228415 TI - Compliance with adjuvant capecitabine in patients with stage II and III colon cancer: comparison of administrative versus medical record data. AB - We aimed to examine the frequency of treatment delays as well as the reasons and appropriateness of such delays in early stage colon cancer patients receiving adjuvant capecitabine by comparing data from pharmacy dispensing versus medical records. Patients diagnosed with stage II or III colon cancer from 2008 to 2012 and who received at least two cycle of adjuvant capecitabine were reviewed for treatment delays. Data from pharmacy dispensing and patient medical records were compared. Multivariate regression models were constructed to identify predictors of treatment delays. A total of 697 patients were analyzed: median age was 70 years (IQR 30-89), 394 (57%) were men, 598 (86%) reported Eastern Cooperative Oncology Group 0/1, and 191 (27%) had stage II disease. In this study cohort, 396 (57%) patients experienced at least 1 treatment delay during their adjuvant treatment. Upon medical record review, half of treatment delays identified using pharmacy administrative data were actually attributable to side effects, of which over 90% were considered clinically appropriate for patients to withhold rather than to continue the drug. The most prevalent side effects were hand-foot syndrome and diarrhea which occurred in 176 (44%) and 67 (17%) patients, respectively. Multivariate analysis revealed a statistically significant association between stage and inappropriate treatment delays whereby patients with stage II disease were more likely to experience drug noncompliance (OR 1.79, 95% CI: 1.27-2.53, P < 0.001) than those with stage III disease. Compliance with adjuvant capecitabine was reasonable. Adherence ascertained from pharmacy administrative data differs significantly from that obtained from medical records. PMID- 27228417 TI - The universal 2012 definition of myocardial infarction compared to the 2007 definition. AB - OBJECTIVES: The third Universal 2012 definition of myocardial infarction (MI) has not been compared to the Universal 2007 definition with regard to the number of cases identified, classification and mortality. DESIGN: We examined potential MI events according to the two universal definitions in 1494 patients admitted to the University hospital during the 12 months. Patients were included either because of an MI discharge diagnosis (815 patients) or due to elevated troponin I levels without an MI discharge diagnosis (679 patients). RESULTS: Applying the Universal 2012 definition resulted in 760 of the 1494 patients suffering from MI, as compared to 769 according to the Universal 2007 definition. The lower number of MI events applying the 2012 definition was mainly explained by the stricter definition of Type 4a MI. The 760 MI events were classified as Type 1 (685), 2 (27), 3 (28), 4a (13), 4b (3) and 5 (4). CONCLUSIONS: The application of the third Universal 2012 definition of MI instead of the Universal 2007 definition resulted in a 1% reduction of the total number of MIs. For a practical clinical purpose, the reduction was confined to patients with Type 4a MI. The change of definition had no impact on all-cause mortality. PMID- 27228418 TI - Update on myopia. AB - PURPOSE OF REVIEW: Myopia is progressing at faster than predicted rates for reasons that are still unknown. The public health consequences worldwide, are also becoming a burden on healthcare costs. There have been numerous studies published attempting to determine the cause of myopia progression and methods of prevention. RECENT FINDINGS: The review examines recent articles that have tried to explain myopia progression and the increase in prevalence across the globe. Additionally, this review provides up-to-date research on current treatment options and their efficacy. SUMMARY: Although this topic has been an increased area of study recently, even more studies are needed to find a definitive treatment for the prevention of myopia. PMID- 27228419 TI - Refractive changes after strabismus surgery. AB - PURPOSE OF REVIEW: The purpose of this review is to report the impact of strabismus surgery on refractive error. RECENT FINDINGS: Vector analysis was recently employed to show that refractive changes often occur after strabismus surgery but are transient and regress over time. SUMMARY: Studies have shown that while transient changes in refractive error often occur, even statistically significant shifts are often not clinically important, and regress with long-term follow-up. PMID- 27228421 TI - New contenders and revisiting the familiar in an election year. PMID- 27228420 TI - Instrument-based pediatric vision screening. AB - PURPOSE OF REVIEW: The purpose is to review currently available instruments for vision screening in young children. RECENT FINDINGS: Instrumentation continues to evolve. Although the current generation of photoscreeners and autorefractors strive to identify amblyopia risk factors, newer technology aims to directly identify amblyopia in young children. Acceptance of instrument-based vision screening for this population has led to increased reimbursement for the procedure in primary care practices. SUMMARY: Instrument-based vision screening in the young child is an accepted method of screening for amblyopia. Innovations in instrumentation will continue to improve its implementation. PMID- 27228422 TI - Melanoma. PMID- 27228426 TI - Single-crystal and humidity-controlled powder diffraction study of the breathing effect in a metal-organic framework upon water adsorption/desorption. AB - Herein we report a study on water adsorption/desorption-triggered single-crystal to single-crystal transformations in a MOF, by single-crystal and humidity controlled powder X-ray diffraction and water-sorption measurements. We identified a gate-opening effect at a relative humidity of 85% upon water adsorption, and a gate-closure effect at a relative humidity of 55 to 77% upon water desorption. This reversible breathing effect between the "open" and the "closed" structures of the MOF involves the cleavage and formation of several coordination bonds. PMID- 27228427 TI - Diastereoselective Synthesis of 5-Heteroaryl-Substituted Prolines Useful for Controlling Peptide-Bond Geometry. AB - A versatile diastereoselective Friedel-Crafts alkylation reaction of heteroaryl systems with a cyclic enecarbamate for the preparation of 5-heteroaryl substituted proline analogues in good yields has been developed. These heterocyclic tethered cyclic amino acid building blocks constitute important structural motifs in many biologically active molecules. The impact of the substitution on proline cis/trans isomerization was explored by carrying out solution conformational studies by NMR on 5-furanyl-substituted proline containing peptides. Conformational analysis revealed that the peptide bond is constrained in an exclusively trans conformation. PMID- 27228428 TI - Accuracy of clinical swallowing evaluation for diagnosis of dysphagia in children with laryngomalacia or glossoptosis. AB - OBJECTIVE: To investigate the accuracy of clinical evaluation of swallowing in a sample of children with laryngomalacia or glossoptosis and describe the prevalence of dysphagia in each of these diseases, as well as characterize the swallow response to speech and language therapy interventions. STUDY DESIGN: Children aged 1 month to 11 years receiving care at the Department of Otolaryngology, Hospital de Clinicas de Porto Alegre, Brazil, were evaluated in a cross-sectional design. Evaluation of swallowing was performed at two time points by two blinded speech-language pathologists, one responsible for clinical evaluation and the other for videofluoroscopic study. The protocols employed were based on the instruments proposed by DeMatteo et al. (DeMatteo C, Matovich D, Hjartarson A. Comparison of clinical and videofluoroscopic evaluation of children with feeding and swallowing difficulties. Dev Med Child Neurol 2005;47:149-157.). RESULTS: The study sample consisted of 29 patients: 10 patients with laryngomalacia and 19 patients with glossoptosis. The sensitivity of clinical evaluation did not exceed 50% in any of the evaluations, but specificity reached 100% in some cases, using thickened liquids. The prevalence of dysphagia was 100%, and the use of thickened liquids significantly reduced tracheal aspiration. CONCLUSIONS: Dysphagia was highly prevalent in this sample. The sensitivity of clinical evaluation to detect laryngeal penetration and tracheal aspiration was low, as the majority of aspiration events were silent. The videofluoroscopic study is important in order to determine a safest method to feed the patient. Pediatr Pulmonol. 2017;52:41-47. (c) 2016 Wiley Periodicals, Inc. PMID- 27228429 TI - High energy supercapattery with an ionic liquid solution of LiClO4. AB - A supercapattery combining an ideally polarized capacitor-like electrode and a battery-like electrode is demonstrated theoretically and practically using an ionic liquid electrolyte containing 1-butyl-1-methylpyrrolidinium tri(pentafluoroethyl)trifluorophosphate (BMPyrrFAP), gamma-butyrolactone (gamma GBL) and LiClO4. The electrochemical deposition and dissolution of lithium metal on a platinum and glass carbon electrode were investigated in this ionic liquid solution. The CVs showed that the fresh electrochemically deposited lithium metal was stable in the electrolyte, which encouraged the investigation of this ionic liquid solution in a supercapattery with a lithium battery negative electrode. The active material counted specific energy of the supercapattery based on a lithium negative electrode and an activated carbon (Act-C) positive electrode could reach 230 W h kg(-1) under a galvanostatic charge-discharge current density of 1 mA cm(-2). The positive electrode material (Act-C) was also investigated by CV, AC impedance, SEM and BET. The non-uniform particle size and micropores dominated porous structure of the Act-C enabled its electric double layer capacitor (EDLC) behavior in the ionic liquid solution. The measured specific capacitance of the Act-C in this ionic liquid solution is higher than the same Act-C in aqueous solution, which indicates the Act-C can also perform well in the ionic liquid electrolyte. PMID- 27228430 TI - Reference values and associated factors for Japanese newborns' blood pressure and pulse rate: the babies' and their parents' longitudinal observation in Suzuki Memorial Hospital on intrauterine period (BOSHI) study. AB - OBJECTIVE: Currently, normative means and ranges of blood pressure (BP) and pulse rates in Japanese newborns are not available. The objective of the present study was to estimate BP, pulse rate, and their distribution among Japanese newborns. METHODS: Using oscillometric devices, arm or calf BP and pulse rate levels were obtained from 3148 infants born between 2007 and 2014, consecutively at Suzuki Memorial Hospital, Iwanuma, Japan. Of those, data from 2628 full-term, singleton newborns with BP measured on day 3 after birth were analyzed. RESULTS: Arm SBP/DBP and pulse rate in the reference group (n = 2628) were 70.5 +/- 7.4/44.3 +/- 6.7 mmHg and 117.3 +/- 16.6 bpm, respectively. The 5-95th percentiles were 58 83 mmHg for SBP, 35-57 mmHg for DBP, and 91-145 bpm for pulse rate. Similar values were obtained from calf measurements. In multiple regression analysis, birth weight and spontaneous cephalic delivery were positively and light/deep sleep was inversely associated with higher arm SBP/DBP (P <= 0.04), whereas sex, Apgar score, gestational age, and mother's age did not significantly affect BP levels (P >= 0.06). Male sex, gestational age, spontaneous cephalic delivery, and light/deep sleep were inversely associated with higher pulse rate (P <= 0.02). CONCLUSION: The present study is the first to show the distributions of Asian newborns' BP levels and pulse rate. The assessment of newborns' BP levels and pulse rate should consider birth weight, gestational age after birth, and actual condition at BP measurement. PMID- 27228431 TI - Head orientation should be considered in ultrasound studies on carotid artery distensibility. AB - INTRODUCTION: During ultrasound distensibility assessment of the carotid artery, the patient's head is usually rotated sideward and slightly upward to optimize visibility of the carotid segment. Head rotation may affect vessel length and thus the longitudinal strain of the arterial segment. Because the longitudinal and circumferential mechanical behaviour of an artery are intrinsically related, head rotation may influence circumferential mechanics and thereby measured distensibility. METHODS: In 12 apparently healthy volunteers (age 22 +/- 3 years, mean +/- SD, 6 men/6 women), we investigated whether head rotation led to a change in absolute and relative distension of the common carotid artery (CCA) by performing ultrasound examinations with the head in two orientations. Additionally, CCA length was measured in both orientations with MRI to assess whether indeed a change in length occurred because of head rotation. Rotation induced longitudinal strain was calculated from these lengths. RESULTS: We found a significant decrease of 0.054 mm (6.8%, P = 0.001) and 0.007 (5.6%, P = 0.019) in absolute and relative distension with head rotation, respectively. MRI measurements showed a significant rotation-induced longitudinal strain of 1.7 +/- 2.3% (P = 0.032). CONCLUSION: We conclude that consistent head rotation during a CCA ultrasound assessment causes a significant and clinically relevant bias in carotid artery distension measurements. The impact of unstandardized use of head rotation in studies with carotid distensibility as an outcome measure can therefore not be neglected; thus, standardization is highly recommendable. PMID- 27228432 TI - Renal denervation in treatment-resistant essential hypertension. A randomized, SHAM-controlled, double-blinded 24-h blood pressure-based trial. AB - BACKGROUND: Renal denervation (RDN), treating resistant hypertension, has, in open trial design, been shown to lower blood pressure (BP) dramatically, but this was primarily with respect to office BP. METHOD: We conducted a SHAM-controlled, double-blind, randomized, single-center trial to establish efficacy data based on 24-h ambulatory BP measurements (ABPM). Inclusion criteria were daytime systolic ABPM at least 145 mmHg following 1 month of stable medication and 2 weeks of compliance registration. All RDN procedures were carried out by an experienced operator using the unipolar Medtronic Flex catheter (Medtronic, Santa Rosa, California, USA). RESULTS: We randomized 69 patients with treatment-resistant hypertension to RDN (n = 36) or SHAM (n = 33). Groups were well balanced at baseline. Mean baseline daytime systolic ABPM was 159 +/- 12 mmHg (RDN) and 159 +/- 14 mmHg (SHAM). Groups had similar reductions in daytime systolic ABPM compared with baseline at 3 months [-6.2 +/- 18.8 mmHg (RDN) vs. -6.0 +/- 13.5 mmHg (SHAM)] and at 6 months [-6.1 +/- 18.9 mmHg (RDN) vs. -4.3 +/- 15.1 mmHg (SHAM)]. Mean usage of antihypertensive medication (daily defined doses) at 3 months was equal [6.8 +/- 2.7 (RDN) vs. 7.0 +/- 2.5 (SHAM)].RDN performed at a single center and by a high-volume operator reduced ABPM to the same level as SHAM treatment and thus confirms the result of the HTN3 trial. CONCLUSION: Further, clinical use of RDN for treatment of resistant hypertension should await positive results from double-blinded, SHAM-controlled trials with multipolar ablation catheters or novel denervation techniques. PMID- 27228433 TI - Visit-to-visit blood pressure variability and future functional decline in old age. AB - OBJECTIVE: Higher blood pressure variability (BPV), independent of mean blood pressure (BP), has been associated with adverse health outcomes. We investigated the association between visit-to-visit BPV and functional decline in older adults at high cardiovascular risk. METHODS: In PROspective Study of Pravastatin in the Elderly at Risk, 4745 participants with mean age of 75.2 years and high cardiovascular risk were followed for a mean of 3.2 years. BP was measured in every 3 months during the first 18 months. BPV was defined as the intraindividual SD of measurements across these visits. Functional status in basic and instrumental activities of daily living was measured using the Barthel (ADL) and Lawton (IADL) scales, first at 18 months and then during follow-up until 48 months. Functional decline was calculated over this period. RESULTS: BPV was not cross-sectionally associated with functional status at 18 months. Higher SBPV was associated with steeper functional decline, whereas DBPV was not. Each 10 mmHg higher SBPV was associated with a 0.064 (95% confidence interval 0.016-0.112, P = 0.009) annual decline in ADL score and with a 0.078 decline (95% confidence interval 0.020-0.136, P = 0.008) in IADL score. These associations were not modified by sex, hypertension or antihypertensives. These findings were independent of mean BP, cardiovascular risk factors and morbidities and cognition. CONCLUSION: Higher visit-to-visit SBPV but not DBPV was associated with steeper functional decline in older adults at high cardiovascular risk. Higher SBPV is a novel risk factor for functional decline. PMID- 27228434 TI - Effects of blood pressure lowering treatment in hypertension: 8. Outcome reductions vs. discontinuations because of adverse drug events - meta-analyses of randomized trials. AB - BACKGROUND: Previous meta-analyses of randomized controlled trials (RCTs) of blood pressure (BP)-lowering treatment provided overwhelming evidence that treatment markedly reduces risk of cardiovascular outcomes in hypertensive patients. However, adverse events associated with BP-lowering treatment have never been surveyed systematically. OBJECTIVES: Identifying among BP-lowering RCTs those reporting a common and meaningful index of treatment-attributed adverse events, and describing the burden of these adverse events accompanying the benefits of mortality and morbidity reduction induced by treatment. METHODS: The database consisted of the BP-lowering RCTs (active vs. placebo or less active treatment) we have described (70 RCTs, 255 970 participants, 1 091 964 patient years). A common index of relevant adverse events was identified as permanent treatment discontinuation attributed to treatment adverse events. Risk ratios and 95% confidence intervals, standardized to a SBP/DBP reduction of 10/5 mmHg, of seven fatal and nonfatal outcomes and of treatment discontinuations for adverse events were calculated (random-effects model). The relationships of outcome reductions and discontinuation excess to SBP and DBP reductions were investigated by meta-regressions. RESULTS: Forty-four RCTs provided data on treatment discontinuations for adverse events and six more on serious adverse events because of treatment (179 949 patients, 719 796 patient-years). In these 50 RCTs, a significant 24% reduction of major cardiovascular event risk was associated with a significant 89% increase in the risk of discontinuations (33 major cardiovascular effects prevented and 84 excess discontinuations/1000 patients for 5 years). Metaregression analysis indicated that both outcome reductions and treatment discontinuation excess were significantly related to the extent of SBP and DBP reduction, but absolute treatment discontinuation excess disproportionally increased with larger BP reductions than increase in outcome risk reduction. Furthermore, a standard SBP reduction was found associated with a constant relative reduction, but a smaller absolute reduction of cardiovascular events, and a greater relative excess of treatment discontinuations when the achieved SBP was below 130 mmHg rather than in higher ranges. CONCLUSION: The burden of adverse events associated with BP-lowering treatment should be considered not to deny patients the overwhelming benefits of BP lowering, but whenever the extent of the BP lowering or the BP target to be achieved are discussed. PMID- 27228435 TI - Early blood pressure lowering treatment in acute stroke. Ordinal analysis of vascular events in the Scandinavian Candesartan Acute Stroke Trial (SCAST). AB - OBJECTIVE: Early blood pressure-lowering treatment appears to be beneficial in patients with acute intracerebral haemorrhage and potentially in ischaemic stroke. We used a new method for analysis of vascular events in the Scandinavian Candesartan Acute Stroke Trial to see if the effect was dependent on the timing of treatment. METHODS: Scandinavian Candesartan Acute Stroke Trial was a randomized controlled and placebo-controlled trial of candesartan within 30 h of ischaemic or haemorrhagic stroke. Of 2029 patients, 231 (11.4%) had a vascular event (vascular death, nonfatal stroke or nonfatal myocardial infarction) during the first 6 months. The modified Rankin Scale (mRS) score following a vascular event was used to categorize vascular events in order of severity: no event (n = 1798), minor (mRS 0-2, n = 59), moderately severe (mRS 3-4, n = 57) and major event (mRS 5-6, n = 115). We used ordinal logistic regression for analysis and adjusted for predefined prognostic variables. RESULTS: Candesartan had no overall effect on vascular events (adjusted common odds ratio 1.11, 95% confidence interval 0.84-1.47, P = 0.48), and the effects were the same in ischaemic and haemorrhagic stroke. Among the patients treated within 6 h, the adjusted common odds ratio for vascular events was 0.37, 95% confidence interval 0.16-0.84, P = 0.02, and there was no heterogeneity of effect between ischaemic and haemorrhagic strokes. CONCLUSION: Ordinal analysis of vascular events showed no overall effect of candesartan in the subacute phase of stroke. The effect of treatment given within 6 h of stroke onset appears promising, and will be addressed in ongoing trials. Ordinal analysis of vascular events is feasible and can be used in future trials. PMID- 27228436 TI - Heterogeneous recurrence analysis of heartbeat dynamics for the identification of sleep apnea events. AB - Obstructive sleep apnea (OSA) is a common sleep disorder that affects 24% of adult men and 9% of adult women. It occurs due to the occlusion of the upper airway during sleep, thereby leading to a decrease of blood oxygen level that triggers arousals and sleep fragmentation. OSA significantly impacts the quality of sleep and it is known to be responsible for a number of health complications, such as high blood pressure and type 2 diabetes. Traditional diagnosis of OSA relies on polysomnography, which is expensive, time-consuming and inaccessible to the general population. Recent advancement of sensing provides an unprecedented opportunity for the screening of OSA events using single-channel electrocardiogram (ECG). However, existing approaches are limited in their ability to characterize nonlinear dynamics underlying ECG signals. As such, hidden patterns of OSA-altered cardiac electrical activity cannot be fully revealed and understood. This paper presents a new heterogeneous recurrence model to characterize the heart rate variability for the identification of OSA. A nonlinear state space is firstly reconstructed from a time series of RR intervals that are extracted from single-channel ECGs. Further, the state space is recursively partitioned into a hierarchical structure of local recurrence regions. A new fractal representation is designed to efficiently characterize state transitions among segmented sub-regions. Statistical measures are then developed to quantify heterogeneous recurrence patterns. In addition, we integrate classification models with heterogeneous recurrence features to differentiate healthy subjects from OSA patients. Experimental results show that the proposed approach captures heterogeneous recurrence patterns in the transformed space and provides an effective tool to detect OSA using one-lead ECG signals. PMID- 27228437 TI - Simplified strong ion difference approach to acid-base balance in healthy foals. AB - OBJECTIVE: To determine the strong ion difference (SIDa ) and total nonvolatile weak buffers (ATOT ) in healthy foals during the first year of life and to compare reference biochemistry laboratory with analyzers available during emergency hours. DESIGN: Prospective study performed over 2 years. SETTING: University teaching hospital. ANIMALS: Two hundred thirty-six healthy foals distributed in 6 groups: A (21 days-2 months), B (2-3 months), C (3-6 months), D (6-9 months), E (9-12 months), and 33 neonatal foals (< 21 days old). INTERVENTIONS: Blood samples were obtained to determine L-lactate, sodium, potassium, chloride, and total plasma protein concentrations. In neonatal foals, samples were analyzed using 4 different devices. Reference intervals of SIDa and ATOT for each of the analyzers under comparison were established using mean +/- 2 standard deviations. Age effect was evaluated using one-way ANOVA analysis. Linear regression in neonatal foals was employed to obtain a new equation to estimate ATOT from total plasma protein concentration. MEASUREMENTS AND MAIN RESULTS: A significant age effect was observed for ATOT and SIDa . In all foals younger than 6 months, ATOT values were lower than in older foals (P < 0.003). A clinically and statistically significant difference in SIDa was detected only in the neonatal period (P < 0.001). The equation to estimate ATOT from total plasma protein adjusted for neonatal foals is ATOT = 2.5 * total plasma protein concentration. CONCLUSIONS: Reference intervals of ATOT should be considered different from adults during the first 6 months of life in horses. Regarding SIDa , values should be considered different only during first 21 days of life. PMID- 27228447 TI - Stability and Aggregation Kinetics of Titania Nanomaterials under Environmentally Realistic Conditions. AB - Nanoparticle morphology is expected to play a significant role in the stability, aggregation behavior, and ultimate fate of engineered nanomaterials in natural aquatic environments. The aggregation kinetics of ellipsoidal and spherical titanium dioxide (TiO2) nanoparticles (NPs) under different surfactant loadings, pH values, and ionic strengths were investigated in this study. The stability results revealed that alteration of surface charge was the stability determining factor. Among five different surfactants investigated, sodium citrate and Suwannee river fulvic acid (SRFA) were the most effective stabilizers. It was observed that both types of NPs were more stable in monovalent salts (NaCl and NaNO3) as compared with divalent salts (Ca(NO3)2 and CaCl2). The aggregation of spherical TiO2 NPs demonstrated a strong dependency on the ionic strength regardless of the presence of mono or divalent salts; while the ellipsoids exhibited a lower dependency on the ionic strength but was more stable. This work acts as a benchmark study toward understanding the ultimate fate of stabilized NPs in natural environments that are rich in Ca(CO3)2, NaNO3, NaCl, and CaCl2 along with natural organic matters. PMID- 27228448 TI - Early visual deprivation severely compromises the auditory sense of space in congenitally blind children. AB - A recent study has shown that congenitally blind adults, who have never had visual experience, are impaired on an auditory spatial bisection task (Gori, Sandini, Martinoli, & Burr, 2014). In this study we investigated how thresholds for auditory spatial bisection and auditory discrimination develop with age in sighted and congenitally blind children (9 to 14 years old). Children performed 2 spatial tasks (minimum audible angle and space bisection) and 1 temporal task (temporal bisection). There was no impairment in the temporal task for blind children but, like adults, they showed severely compromised thresholds for spatial bisection. Interestingly, the blind children also showed lower precision in judging minimum audible angle. These results confirm the adult study and go on to suggest that even simpler auditory spatial tasks are compromised in children, and that this capacity recovers over time. (PsycINFO Database Record PMID- 27228449 TI - Training young children on sequential relations among numbers and spatial decomposition: Differential transfer to number line and mental transformation tasks. AB - Are there differential benefits of training sequential number knowledge versus spatial skills for children's numerical and spatial performance? Three- to five year-old children (N = 84) participated in 1 session of either sequential training (e.g., what comes before and after the number 5?) or non-numerical spatial training (i.e., decomposition of shapes). Children who received sequential training showed near transfer to a number ordering task and far transfer to a number line task. Furthermore, these children showed more improvement on the version of the number line task where a midpoint reference was presented (i.e., at 5) than on the version without a midpoint. Before the training, the midpoint reference did not enhance performance. In contrast, although children who received non-numerical spatial training showed near transfer to a 2-D mental transformation task, they did not show transfer to number ordering or number line tasks, even though spatial skills were correlated with performance on these tasks. These results support the view that knowledge of sequential relations among successive numbers is an important aspect of children's early numeracy knowledge in tasks that require ordinal understanding of numbers from 1 to 10 and support the educational importance of developing numerical activities that enhance children's understanding of these relations. (PsycINFO Database Record PMID- 27228450 TI - Who helps whom? Investigating the development of adolescent prosocial relationships. AB - We investigated adolescent prosocial relations by examining social networks based on the question "Who helps you (e.g., with homework, with repairing a flat [bicycle] tire, or when you are feeling down?)." The effects of individual characteristics (academic achievement, symptoms of depressive mood, and peer status) on receiving help and giving help were examined, and we investigated the contribution of (dis)similarity between adolescents to the development of prosocial relations. Gender, structural network characteristics, and friendship relations were taken into account. Data were derived from the Social Network Analysis of Risk behavior in Early adolescence (SNARE) study, and contained information on students in 40 secondary school classes across 3 waves (N = 840, M age = 13.4, 49.7% boys). Results from longitudinal social network analyses (RSiena) revealed tendencies toward reciprocation of help and exchange of help within helping groups. Furthermore, boys were less often mentioned as helpers, particularly by girls. Depressed adolescents were less often mentioned as helpers, especially by low-depressed peers. Moreover, lower academic achievers indicated that they received help from their higher achieving peers. Rejected adolescents received help more often, but they less often helped low-rejected peers. Last, low- and high-popular adolescents less often helped each other, and also high-popular adolescents less often helped each other. These findings show that (dis)similarity in these characteristics is an important driving factor underlying the emergence and development of prosocial relations in the peer context, and that prosocial behavior should be defined in terms of benefitting particular others. (PsycINFO Database Record PMID- 27228451 TI - The interplay of maternal sensitivity and gentle control when predicting children's subsequent academic functioning: Evidence of mediation by effortful control. AB - The goal of this work was to examine the complex interrelation of mothers' early gentle control and sensitivity in predicting children's effortful control (EC) and academic functioning. Maternal gentle control, maternal sensitivity, and children's EC were measured when children were 18, 30, and 42 months of age (T1, T2, and T3, respectively), and measures of children's academic functioning were combined across 72 and 84 months (T5/T6; Ns = 255, 222, 200, 162, and 143). Using structural equation modeling, results demonstrated that T1 maternal sensitivity moderated the relation between T1 maternal gentle control and T2 EC, and T3 EC predicted children's later academic functioning. There was evidence for moderated mediation, such that when maternal sensitivity was high, children's EC mediated the relation between T1 maternal gentle control and children's academic functioning, even after controlling for stability of the constructs. The relation between maternal gentle control and children's EC was not significant under conditions of low maternal sensitivity. Implications for parenting programs are offered and future research directions are discussed. (PsycINFO Database Record PMID- 27228452 TI - Maternal sensitivity and effortful control in early childhood as predictors of adolescents' adjustment: The mediating roles of peer group affiliation and social behaviors. AB - Longitudinal links between early childhood temperament, maternal sensitivity, and adolescents' adjustment have been proposed and found in several longitudinal studies, but the mechanisms of influence have not been explored. The authors examined the paths from maternal sensitivity and temperament in early childhood to adolescents' prosocial, aggressive, and delinquent behaviors via childhood social behaviors and peer group affiliation. Data at 54 months, Grade 3 (M age = 9.03, SD = .31), Grade 6 (M age = 11.95, SD = .34), and Grade 9 (M age = 15.57, SD = .78) from the NICHD SECCYD longitudinal investigation of 1,364 participants (52% boys) was analyzed. Overall, results yielded evidence that maternal sensitivity and child temperament at 54 months of age predicted prosocial, aggressive, and delinquent outcomes at age 15. Affiliation with peer groups (especially with prosocial peers) and social behaviors in childhood mediated the aforementioned paths for effortful control, but not for maternal sensitivity. Discussion focuses on the implications for understanding the long-term effects of early childhood predictors on behavioral outcomes in adolescence. (PsycINFO Database Record PMID- 27228453 TI - The end is (not) near: Aging, essentialism, and future time perspective. AB - Beliefs about aging influence how we interpret and respond to changes within and around us. Essentialist beliefs about aging are defined as views that link chronological age with inherent and immutable properties underlying aging-related changes. These beliefs may influence the experience of aging-related changes and shape people's outlook of the future. We hypothesized that people who endorse essentialist beliefs about aging report a more limited future time perspective. Two studies provided correlational (Study 1, N = 250; 18-77 years) and experimental (Study 2, N = 103; 20-77 years) evidence that essentialist beliefs about aging affect people's future time perspective. In addition, Study 2 and Study 3 (N = 174; 34-67 years) tested the underlying mechanism and provided evidence that perception of aging-related threat explains the effect of essentialist beliefs on a reduced future time perspective. These findings highlight the fundamental role of essentialist beliefs about aging for the perception of time horizons in the context of aging. (PsycINFO Database Record PMID- 27228455 TI - Ghrelin level negatively predicts quality of life in obese women. AB - A cross-sectional cohort study was conducted to investigate whether ghrelin level in obese women predicts the quality of life (QOL). A total of 307 subjects fulfilled the criteria: (1) age between 20 and 65 years old, (2) body mass index >=27 kg/m2 (3) waist circumference >=80 cm were enrolled in the study. All subjects were assigned to one of the plasma ghrelin level categories according to the quartiles. The median of age and BMI of the 307 obese women were 45 +/- 18 years and 29.9 +/- 4.1 kg/m2, respectively. The main outcome evaluated is the associations of plasma ghrelin level and QOL, which were evaluated using multiple linear regression analysis. Results of linear trend test show significant statistical difference in plasma lipoproteins (triglyceride, cholesterol, HDL cholestero and LDL-cholesterol = and levels of obesity-related hormone peptides, including leptin, adiponectin, insulin among quartiles of ghrelin. Multiple liner regression analysis of serum obesity-related hormone peptide level and QOL using stepwise method shows ghrelin concentration was the only predictor of QOL, including PCS-12 level (beta = -0.18, p = 0.001), MCS-12 level (beta = -0.14, p = 0.009), WHOQOL-BREF scores: physical (beta = -0.13, p = 0.03), psychological (beta = -0.16, p = 0.007), social (beta = -0.21, p = < 0.001), and environmental (beta = -0.22, p = <0.001), after adjusting other factors for obese female subjects. This study demonstrated that ghrelin concentration is strongly associated with QOL level among obese women. Hence, ghrelin concentration might be a valuable marker to be monitored in obese women. PMID- 27228457 TI - Obstructive sleep apnoea syndrome. PMID- 27228454 TI - Glial biomarkers in human central nervous system disease. AB - There is a growing understanding that aberrant GLIA function is an underlying factor in psychiatric and neurological disorders. As drug discovery efforts begin to focus on glia-related targets, a key gap in knowledge includes the availability of validated biomarkers to help determine which patients suffer from dysfunction of glial cells or who may best respond by targeting glia-related drug mechanisms. Biomarkers are biological variables with a significant relationship to parameters of disease states and can be used as surrogate markers of disease pathology, progression, and/or responses to drug treatment. For example, imaging studies of the CNS enable localization and characterization of anatomical lesions without the need to isolate tissue for biopsy. Many biomarkers of disease pathology in the CNS involve assays of glial cell function and/or response to injury. Each major glia subtype (oligodendroglia, astroglia and microglia) are connected to a number of important and useful biomarkers. Here, we describe current and emerging glial based biomarker approaches for acute CNS injury and the major categories of chronic nervous system dysfunction including neurodegenerative, neuropsychiatric, neoplastic, and autoimmune disorders of the CNS. These descriptions are highlighted in the context of how biomarkers are employed to better understand the role of glia in human CNS disease and in the development of novel therapeutic treatments. GLIA 2016;64:1755-1771. PMID- 27228458 TI - Can spectral-spatial image segmentation be used to discriminate experimental burn wounds? AB - Hyperspectral imaging (HSI) is a noncontact and noninvasive optical modality emerging the field of medical research. The goal of this study was to determine the ability of HSI and image segmentation to discriminate burn wounds in a preclinical porcine model. A heated brass rod was used to introduce burn wounds of graded severity in a pig model and a sequence of hyperspectral data was recorded up to 8-h postinjury. The hyperspectral images were processed by an unsupervised spectral-spatial segmentation algorithm. Segmentation was validated using results from histology. The proposed algorithm was compared to K-means segmentation and was found superior. The obtained segmentation maps revealed separated zones within the burn sites, indicating a variation in burn severity. The suggested image-processing scheme allowed mapping dynamic changes of spectral properties within the burn wounds over time. The results of this study indicate that unsupervised spectral-spatial segmentation applied on hyperspectral images can discriminate burn injuries of varying severity. PMID- 27228459 TI - Mucous Cytokine Levels in Chronic Rhinosinusitis-Associated Olfactory Loss. AB - IMPORTANCE: Olfactory loss is a frequent symptom of patients with chronic rhinosinusitis (CRS), but our understanding of how inflammatory cytokines affect olfaction is limited. OBJECTIVES: To examine whether inflammatory cytokines are present in the olfactory cleft and whether they correlate with objective olfaction. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study, patients with CRS underwent quantitative olfactory testing using the Sniffin Sticks test to calculate a composite threshold discrimination identification (TDI) score from October 21, 2013, to November 12, 2015. Nasal mucus was collected using a sponge placed in the olfactory cleft for 5 minutes, and Cytometric Bead Array was used to measure secreted immunomodulatory products. Correlations between TDI score and secreted mediators were then calculated. Data analysis was performed from October 15, 2015, to December 17, 2015. MAIN OUTCOMES AND MEASURES: Composite TDI scores and mean secreted mediator levels in mucus from the olfactory cleft. RESULTS: Thirty-four patients were enrolled (mean [SD] age, 57.3 [15.7] years; female, 21 [61.8%]; white, 26 [76.5]). The TDI scores were lower in patients with CRS with nasal polyps (CRSwNP) than in patients with CRS without nasal polyps (CRSsNP) (difference, 8.7; 95% CI, 2.5-15.0; P = .007). Interleukin (IL) 5 levels were inversely correlated with TDI scores in patients with CRSwNP and those with CRSsNP (mean [SE] beta estimate, -46.56 [15.11]; P = .005), whereas IL-6, IL-7, and vascular endothelial growth factor A were positively correlated with TDI scores only in the CRSwNP cohort. Subscale olfactory TDI scores followed similar correlations to composite TDI scores. CONCLUSIONS AND RELEVANCE: In this study, inflammatory cytokines were found in mucus collected from the olfactory cleft. Levels of IL-5, in addition to other cytokines, were associated with objective olfactory function. Further inquiry is needed to establish the source of mucous cytokines and establish whether they play a causal role in olfactory loss. PMID- 27228460 TI - RFX1 maintains testis cord integrity by regulating the expression of Itga6 in male mouse embryos. AB - Formation and maintenance of testis cords during embryogenesis are essential for establishing testicular structure and function in adults. At least five genes (Wt1, Dhh, Sox8/Sox9, and Dax1) appear to be required for the maintenance of testis cord integrity in mice. Here, we report that RFX1 is specifically expressed in fetal Sertoli cells. Mouse embryos conditionally deficient in Rfx1 (Rfx1(flox/flox) , Amh-Cre) possessed disrupted testis cords, as the basal lamina lining was fragmented or completely absent in some areas of the testes. Spermatogenesis was blocked, leading to complete infertility. Expression of integrin alpha-6 was significantly decreased in Rfx1-deficient testes compared to control testes; indeed, luciferase and chromatin immunoprecipitation assays indicated that RFX1 directly activates transcription of Itga6 (the gene coding for integrin alpha-6). Taken together, RFX1 transcriptionally targets Itga6 in Sertoli cells, thereby, helping maintain the integrity of the basal lamina during testis cord development. Mol. Reprod. Dev. 83: 606-614, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27228461 TI - Translation and protein expression of lncRNAs: Impact for liver disease and hepatocellular carcinoma. PMID- 27228462 TI - Correlation between morphology, electron band structure, and resistivity of Pb atomic chains on the Si(5 5 3)-Au surface. AB - Structural and electron transport properties of multiple Pb atomic chains fabricated on the Si(5 5 3)-Au surface are investigated using scanning tunneling spectroscopy, reflection high electron energy diffraction, angular resolved photoemission electron spectroscopy and in situ electrical resistance. The study shows that Pb atomic chains growth modulates the electron band structure of pristine Si(5 5 3)-Au surface and hence changes its sheet resistivity. Strong correlation between chains morphology, electron band structure and electron transport properties is found. To explain experimental findings a theoretical tight-binding model of multiple atomic chains interacting on effective substrate is proposed. PMID- 27228463 TI - Conservation of Terrestrial Vertebrates in a Global Hotspot of Karst Area in Southwestern China. AB - The karst area of southwest China (KASC) is the largest piece of karst landscape on the earth and a global biodiversity hot-spot with high concentrations of endemic species. Although a number of nature reserves (NRs) have been established across the region, the representativeness of biodiversity of the NR system is still unknown. Based on comprehensive literature and field surveys, and intensive consultations with zoologists and wildlife managers, we compiled distributions of 1,204 terrestrial vertebrate species and 271 NRs in KASC. We found Jinxiu, Mengla, Hekou, and Jinghong have the richest amphibian species; Jinxiu has the highest species richness of reptiles; Jinghong, Menghai, and Mengla have the largest numbers of avian species; whereas, Mengla, Longzhou, and Ningming have the greatest mammalian diversity in the region. Gap analysis among NR system, species richness pattern, and five biogeographic indicators found insufficient representation of the NR system on territorial vertebrate diversity. The conservation effectiveness in Guizhou Province was much lower than that in Guangxi and Yunnan Provinces. Under-representation and over-representation simultaneously occurred in many of the ecoregions, elevation classes, vegetation types, landcover categories, and human disturbance intensity gradients. For conservation of terrestrial vertebrates in KASC, several suggestions were presented in this study. PMID- 27228465 TI - Navigating highly homologous genes in a molecular diagnostic setting: a resource for clinical next-generation sequencing. AB - PURPOSE: Next-generation sequencing (NGS) is now routinely used to interrogate large sets of genes in a diagnostic setting. Regions of high sequence homology continue to be a major challenge for short-read technologies and can lead to false-positive and false-negative diagnostic errors. At the scale of whole-exome sequencing (WES), laboratories may be limited in their knowledge of genes and regions that pose technical hurdles due to high homology. We have created an exome-wide resource that catalogs highly homologous regions that is tailored toward diagnostic applications. METHODS: This resource was developed using a mappability-based approach tailored to current Sanger and NGS protocols. RESULTS: Gene-level and exon-level lists delineate regions that are difficult or impossible to analyze via standard NGS. These regions are ranked by degree of affectedness, annotated for medical relevance, and classified by the type of homology (within-gene, different functional gene, known pseudogene, uncharacterized noncoding region). Additionally, we provide a list of exons that cannot be analyzed by short-amplicon Sanger sequencing. CONCLUSION: This resource can help guide clinical test design, supplemental assay implementation, and results interpretation in the context of high homology.Genet Med 18 12, 1282 1289. PMID- 27228464 TI - Tracheal cartilaginous sleeves in children with syndromic craniosynostosis. AB - PURPOSE: Because a tracheal cartilaginous sleeve (TCS) confers a significant mortality risk that can be mitigated with appropriate intervention, we sought to describe the prevalence and associated genotypes in a large cohort of children with syndromic craniosynostosis. METHODS: Chart review of patients with syndromic craniosynostosis across two institutions. RESULTS: In a cohort of 86 patients with syndromic craniosynostosis, 31 required airway evaluation under anesthesia. TCS was found in 19, for an overall prevalence of 22%. FGFR2, TWIST1, and FGFR3 mutations were identified in children with TCS. All five children with a W290C mutation in FGFR2 had TCS, and most previously reported children with W290C had identification of TCS or early death. In contrast, TCS was not associated with other mutations at residue 290. CONCLUSION: There is an association between TCS and syndromic craniosynostosis, and it appears to be particularly high in individuals with the W290C mutation in FGFR2. Referral to a pediatric otolaryngologist and consideration of operative airway evaluation (i.e., bronchoscopy or rigid endoscopy) in all patients with syndromic craniosynostosis should be considered to evaluate for TCS. Results from genetic testing may help providers weigh the risks and benefits of early airway evaluation and intervention in children with higher-risk genotypes.Genet Med 19 1, 62-68. PMID- 27228466 TI - Rice (Oryza sativa japonica) Albumin Suppresses the Elevation of Blood Glucose and Plasma Insulin Levels after Oral Glucose Loading. AB - The suppressive effect of rice albumin (RA) of 16 kDa on elevation of blood glucose level after oral loading of starch or glucose and its possible mechanism were examined. RA suppressed the increase in blood glucose levels in both the oral starch tolerance test and the oral glucose tolerance test. The blood glucose concentrations 15 min after the oral administration of starch were 144 +/- 6 mg/dL for control group and 127 +/- 4 mg/dL for RA 200 mg/kg BW group, while those after the oral administration of glucose were 157 +/- 7 mg/dL for control group and 137 +/- 4 mg/dL for RA 200 mg/kg BW group. However, in the intraperitoneal glucose tolerance test, no significant differences in blood glucose level were observed between RA and the control groups, indicating that RA suppresses the glucose absorption from the small intestine. However, RA did not inhibit the activity of mammalian alpha-amylase. RA was hydrolyzed to an indigestible high-molecular-weight peptide (HMP) of 14 kDa and low-molecular weight peptides by pepsin and pancreatin. Furthermore, RA suppressed the glucose diffusion rate through a semipermeable membrane like dietary fibers in vitro. Therefore, the indigestible HMP may adsorb glucose and suppress its absorption from the small intestine. PMID- 27228468 TI - Respiratory function and symptoms in young preterm children in the contemporary era. AB - OBJECTIVE: To determine the relationships between respiratory symptoms, lung function, and neonatal events in young preterm children. METHODS: Preterm children (<32 w gestation), classified as bronchopulmonary dysplasia (BPD) or non BPD, and healthy term controls were studied. Lung function was measured by forced oscillation technique (respiratory resistance [Rrs] and reactance [Xrs]) and spirometry. Respiratory symptom questionnaires were administered. RESULTS: One hundred and fifty children (74 BPD, 44 non-BPD, 32 controls) 4-8 years were studied. Lung function (median Z-score [10,90th centile]) was significantly impaired in preterm children compared to controls for FVC (0.00 [-1.18, 1.76], 0.69 [-0.17,1.86]), FEV1 (-0.44 [-1.94, 1.11], 0.49 [-0.83, 2.51]), Xrs (-1.26 [ 3.31, 0.11], -0.11 [-0.97, 0.73]), and Rrs (0.55 [-0.48, 1.82], 0.28 [-0.99, 0.96]). Only Xrs differed between the BPD and non-BPD (-1.51 [-3.59, -0.41], 0.89 [-2.64, 0.52]). The prevalence of recent respiratory symptoms (range: 32 36%) did not differ between BPD and non-BPD children. Supplemental O2 in hospital was positively associated with worsening Xrs and FEV1 . CONCLUSION: Preterm children have worse lung function than healthy controls. Only respiratory reactance differentiated between preterm children with and without BPD and was influenced by days of O2 in hospital. Pediatr Pulmonol. 2016;51:1347-1355. (c) 2016 Wiley Periodicals, Inc. PMID- 27228467 TI - Structure-Activity Relationship of (18)F-Labeled Phosphoramidate Peptidomimetic Prostate-Specific Membrane Antigen (PSMA)-Targeted Inhibitor Analogues for PET Imaging of Prostate Cancer. AB - A series of phosphoramidate-based prostate specific membrane antigen (PSMA) inhibitors of increasing lipophilicity were synthesized (4, 5, and 6), and their fluorine-18 analogs were evaluated for use as positron emission tomography (PET) imaging agents for prostate cancer. To gain insight into their modes of binding, they were also cocrystallized with the extracellular domain of PSMA. All analogs exhibited irreversible binding to PSMA with IC50 values ranging from 0.4 to 1.3 nM. In vitro assays showed binding and rapid internalization (80-95%, 2 h) of the radiolabeled ligands in PSMA(+) cells. In vivo distribution demonstrated significant uptake in CWR22Rv1 (PSMA(+)) tumor, with tumor to blood ratios of 25.6:1, 63.6:1, and 69.6:1 for [(18)F]4, [(18)F]5, and [(18)F]6, respectively, at 2 h postinjection. Installation of aminohexanoic acid (AH) linkers in the phosphoramidate scaffold improved their PSMA binding and inhibition and was critical for achieving suitable in vivo imaging properties, positioning [(18)F]5 and [(18)F]6 as favorable candidates for future prostate cancer imaging clinical trials. PMID- 27228469 TI - Post-traumatic stress disorder. PMID- 27228470 TI - Diabetic retinopathy. PMID- 27228471 TI - LESA FAIMS Mass Spectrometry for the Spatial Profiling of Proteins from Tissue. AB - We have shown previously that coupling of high field asymmetric waveform ion mobility spectrometry (FAIMS), also known as differential ion mobility, with liquid extraction surface analysis (LESA) mass spectrometry of tissue results in significant improvements in the resulting protein mass spectra. Here, we demonstrate LESA FAIMS mass spectrometry imaging of proteins in sections of mouse brain and liver tissue. The results are compared with LESA mass spectrometry images obtained in the absence of FAIMS. The results show that the number of different protein species detected can be significantly increased by incorporating FAIMS into the workflow. A total of 34 proteins were detected by LESA FAIMS mass spectrometry imaging of mouse brain, of which 26 were unique to FAIMS, compared with 15 proteins (7 unique) detected by LESA mass spectrometry imaging. A number of proteins were identified including alpha-globin, 6.8 kDa mitochondrial proteolipid, macrophage migration inhibitory factor, ubiquitin, beta-thymosin 4, and calmodulin. A total of 40 species were detected by LESA FAIMS mass spectrometry imaging of mouse liver, of which 29 were unique to FAIMS, compared with 24 proteins (13 unique) detected by LESA mass spectrometry imaging. The spatial distributions of proteins identified in both LESA mass spectrometry imaging and LESA FAIMS mass spectrometry imaging were in good agreement indicating that FAIMS is a suitable tool for inclusion in mass spectrometry imaging workflows. PMID- 27228472 TI - Warmer temperature modifies effects of polybrominated diphenyl ethers on hormone profiles in leopard frog tadpoles (Lithobates pipiens). AB - Amphibian populations have been declining, and climate change and exposure to environmental contaminants are thought to be involved. Higher water temperature accelerates larval development; however, its combined effects with contaminants and their influence on hormones during metamorphosis are poorly understood. The authors investigated changes in whole-body triiodothyronine (T3) and corticosterone concentrations in developing leopard frogs reared at 23 degrees C and 28 degrees C on diets with 0 ng g-1 , 6 ng g-1 , and 37 ng g-1 of a technical mixture of polybrominated diphenyl ethers (PBDE; DE-71) from 10 d to 44 d (premetamorphosis to late climax; Gosner Stages 28 to 46). Unlike controls, PBDE-exposed tadpoles (6 ng g-1 ) reared at 23 degrees C failed to show any increase in T3 concentrations throughout metamorphosis, and exposed tadpoles reared at 28 degrees C showed a lower peak at climax compared to controls. Corticosterone levels progressively increased throughout metamorphosis, but the levels were higher in PBDE-exposed tadpoles compared to controls at both temperatures. At the warmer temperature, corticosterone increase occurred earlier (at early climax) in controls and exposed tadpoles compared to tadpoles reared at the cooler temperature (late climax), coinciding with the faster development observed at 28 degrees C. Tadpoles reared at 28 degrees C were longer and developed faster than tadpoles reared at 23 degrees C. At both temperatures, PBDE exposure decreased T3 and increased corticosterone concentrations, which can potentially impair developing tadpoles. Environ Toxicol Chem 2017;36:120-127. (c) 2016 SETAC. PMID- 27228473 TI - Axial Mn-CCN Bonds of Cyano Manganese(II) Porphyrin Complexes: Flexible and Weak? AB - Three five-coordinate high-spin (cyano)manganese(II) complexes, utilized tetraphenylporphyrin (TPP), tetratolylporphyrin (TTP), and tetramesitylporphyrin (TMP) as ligands, are prepared and studied by single-crystal X-ray, FT-IR, UV vis, and EPR spectroscopies. The crystal structure studies revealed noteworthy structural features including unexpectedly wide tilting angles of the axial Mn CCN bonds, which is contrasted to the isoelectronic Fe(III)-CCN bonds. Solid state EPR measurements (90 K) and simulations are applied to obtain the ZFS parameters (D, E, and E/D (lambda)), which are compared to Mn(II) porphyrin analogues of hemes to understand the ligand field of the cyanide. The solution EPR studies gave new insights into the chemical equilibrium of four- and five coordinate species, which has been monitored by UV-vis spectroscopy. PMID- 27228474 TI - 15.5 days to decision on your manuscript! PMID- 27228475 TI - Colloidal Synthesis of Quantum Confined Single Crystal CsPbBr3 Nanosheets with Lateral Size Control up to the Micrometer Range. AB - We report the nontemplated colloidal synthesis of single crystal CsPbBr3 perovskite nanosheets with lateral sizes up to a few micrometers and with thickness of just a few unit cells (i.e., below 5 nm), hence in the strong quantum confinement regime, by introducing short ligands (octanoic acid and octylamine) in the synthesis together with longer ones (oleic acid and oleylamine). The lateral size is tunable by varying the ratio of shorter ligands over longer ligands, while the thickness is mainly unaffected by this parameter and stays practically constant at 3 nm in all the syntheses conducted at short-to long ligands volumetric ratio below 0.67. Beyond this ratio, control over the thickness is lost and a multimodal thickness distribution is observed. PMID- 27228476 TI - Choleretic Activity of Turmeric and its Active Ingredients. AB - Turmeric, a rhizome of Curcumin longa L. is widely used as both a spice and an herbal medicine. The traditional use of turmeric in gastroenterology is mainly based on its choleretic activity. The aim of this study is to determine the effects of turmeric on bile flow (BF) and total bile acids (TBAs) excretion in a bile fistula rat model after acute duodenal administration. A significant dose dependent enhancement in both BF and TBAs was detected after treatment with the turmeric decoctions which suggested the choleretic activity was bile acid dependent secretion. In order to direct the active group of compounds, aqueous (AE), ethyl acetate (EtOAc), and petroleum ether (PE) extracts were investigated. The EtOAc and PE extracts showing high effects were purified to locate the active ingredients. Three curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin) and 2 sesquiterpenes (bisacurone B and ar-turmerone) were isolated. It was found Bisacurone B was the most potent choleretic ingredient followed by ar-turmerone, bisdemethoxycurcumin demethoxycurcumin, and then curcumin. The amounts of the active ingredients were quantitatively analyzed by high-performance liquid chromatography. The EtOAc and PE extracts had high sesquiterpenes and curcuminoids content, while the AE extract had poor content of sesquiterpenes and curcuminoids which affected neither BF nor TBAs. Based on the results of multiple linear regression analysis, the content of BIS and TUR were dominant factors (P < 0.01) of controlling BL and TBAs in EtOAC and PE extracts. PMID- 27228477 TI - Characterization of Cell-Type-Specific Drug Transport and Resistance of Breast Cancers Using Tumor-Microenvironment-on-Chip. AB - Heterogeneous response and resistance of cancer cells to chemotherapeutic drugs pose a significant challenge for successful cancer treatments. In this study, an integrated experimental and theoretical analysis of cellular drug transport was developed. The experimental platform, called tumor-microenvironment-on-chip (T MOC), is a microfluidic platform where cancer cells were cultured within a three dimensional extracellular matrix perfused with interstitial fluid. Three types of human breast cancer cell lines (MCF-7, MDA-MB-231, and SUM-159PT) were cultured on this T-MOC platform, and their drug response and resistance to doxorubicin were characterized by time-lapse quantitative fluorescence microscopy. To study the effects of nanoparticle-mediated drug delivery, the transport and action of doxorubicin encapsulated nanoparticles were also examined. Based on the experimental data obtained, a theoretical model was developed to quantify and ultimately predict the cellular transport processes of drugs cell-type specifically. The results demonstrate that the cellular drug transport can be cell-type-specifically quantified by rate constants representing the uptake and efflux of doxorubicin across the cellular membrane. PMID- 27228478 TI - Gap between Recommendations and Practice of Palliative Care and Hospice in Cancer Patients. AB - BACKGROUND: Specialty societies recommend patients with advanced cancer receive early exposure to palliative care and exposure to hospice care. OBJECTIVE: We sought to understand real-world practice of care, specifically, the timing of palliative care, and how timing and duration of hospice care varied across Medicare, VA, and VA-Purchased care. DESIGN: We conducted a retrospective analysis of administrative data for veterans aged 65 years or older who died with cancer in 2012. Multilevel logistic regression was used to evaluate the likelihood of receiving palliative care, receiving hospice care, and receiving hospice care for at least three days. SETTING: Medicare, VA, and VA-Purchased care environments. MEASUREMENTS: The receipt and timing of palliative care within VA and the receipt and timing of hospice care across three healthcare environments. RESULTS: Most veterans received hospice care (71%), whereas fewer received palliative care (52%). Among all cancer decedents, 59% received hospice care for their last three days of life. Patients who received hospice care did so a median of 20 days before death (interquartile range [IQR]: 7-46). Patients who received palliative care did so a median of 38 days before death (IQR: 13-94). Adjusted analyses revealed significant differences in receipt of palliative care across cancer type, and significant differences in receipt of hospice care across cancer type. After adjusting for age and cancer type, patients who received VA hospice care were significantly less likely to receive it for at least three days compared with patients who received VA-Purchased or Medicare hospice care. CONCLUSIONS: There remains a gap between recommended timing of supportive services and real-world practice of care. Results suggest that difficulties in prognosticating death are not fully responsible for underexposure to hospice. PMID- 27228479 TI - Prognostic utility of combination of NT-proBNP with high sensitive cTn I in patients with heart failure: Results from retrospective study in an emergency department. AB - BACKGROUND: N-terminal proBNP (NT-proBNP) and cardiac troponin I (cTn I) are widely used for the diagnosis of myocardial injury, but have not been used for routine evaluation in heart failure (HF) population. AIMS: To evaluate the prognostic utility of combination of NT-proBNP and cTn I in patients with HF, including serial NT-proBNP/cTn I measurements and discharge NT-proBNP/cTn I levels. PATIENTS AND METHODS: A total of 610 patients presenting in our emergency department for acute HF were studied. The mortality and HF-related readmission were endpoints in the study. NT-proBNP and cTn I were tested on admission including first 5 consecutive days, and on discharge. RESULTS: A discharge cTn I cut-off value at 24 ng/L and discharge NT-proBNP cut-off value at 350 ng/L were determined. The cTn I level more than 24 ng/L and NT-proBNP level more than 350 ng/L are associated with increased risk for mortality and readmission (p < 0.01). The mortality and HF-related readmission was significantly increased in patients with high cTn I + high NT-proBNP (p < 0.05), high cTn I + low NT-proBNP (p < 0.05), and low cTn I + high NT-proBNP (p < 0.0%). The increased cTn I or increased NT-proBNP measured in the first 5 consecutive days were significantly associated with 60-day HF-related events (p < 0.05), but the serial measurements did not have a predictive value of 1-year HF outcome. CONCLUSION: This study demonstrates that elevations of discharge cTn I and NT-proBNP are associated with increased 1-year mortality and HF-related readmission. Patients with increasing serial cTnI and NT-proBNP had increased risk for 60-day HF-related events. The two markers can act as independent predicators, and complete each other in prognostic utility of HF patients. PMID- 27228480 TI - 3D-QSAR and molecular docking study of LRRK2 kinase inhibitors by CoMFA and CoMSIA methods. AB - Three-dimensional quantitative structure-activity relationship (3D-QSAR) modelling was conducted on a series of leucine-rich repeat kinase 2 (LRRK2) antagonists using CoMFA and CoMSIA methods. The data set, which consisted of 37 molecules, was divided into training and test subsets by using a hierarchical clustering method. Both CoMFA and CoMSIA models were derived using a training set on the basis of the common substructure-based alignment. The optimum PLS model built by CoMFA and CoMSIA provided satisfactory statistical results (q(2) = 0.589 and r(2) = 0.927 and q(2) = 0.473 and r(2) = 0.802, respectively). The external predictive ability of the models was evaluated by using seven compounds. Moreover, an external evaluation set with known experimental data was used to evaluate the external predictive ability of the porposed models. The statistical parameters indicated that CoMFA (after region focusing) has high predictive ability in comparison with standard CoMFA and CoMSIA models. Molecular docking was also performed on the most active compound to investigate the existence of interactions between the most active inhibitor and the LRRK2 receptor. Based on the obtained results and CoMFA contour maps, some features were introduced to provide useful insights for designing novel and potent LRRK2 inhibitors. PMID- 27228481 TI - Molecular mechanism of the susceptibility difference between HLA-B*27:02/04/05 and HLA-B*27:06/09 to ankylosing spondylitis: substitution analysis, MD simulation, QSAR modelling, and in vitro assay. AB - The human leukocyte antigen HLA-B27 is directly involved in the disease pathogenesis of ankylosing spondylitis (AS). HLA-B27 has a high degree of genetic polymorphism, with 105 currently known subtypes; the presence of aspartic acid at residue 116 (Asp116) has been found to play an essential role in AS susceptibility. Here, we systematically investigated the molecular mechanism of the susceptibility difference between the AS-associated subtypes HLA B*27:02/04/05 and AS-unassociated subtypes HLA-B*27:06/09 to AS at sequence, structure, energetic and dynamic levels. In total seven variable residues were identified among the five studied HLA-B27 subtypes, in which Asp116 can be largely stabilized by a spatially vicinal, positively charged His114 through a salt bridge, while five other variable residues seem to have only a marginal effect on AS susceptibility. We also employed a quantitative structure-activity relationship approach to model the statistical correlation between peptide structure and affinity to HLA-B*27:05, a genetic ancestor of all other HLA-B27 subtypes and associated strongly with AS. The built regression predictor was verified rigorously through both internal cross-validation and external blind validation, and was then employed to identify potential HLA-B*27:05 binders from >20,000 cartilage-derived self-peptides. Subsequently, the binding potency of the top five antigenic peptides to HLA-B*27:05 was assayed in vitro using a FACS based MHC stabilization experiment. Consequently, two (QRVGSDEFK and LRGAGTNEK) out of the five peptides were determined to have high affinity (BL50 = 5.5 and 15.8 nM, respectively) and, as expected, both of them possess positively charged Lys at the C-terminus. PMID- 27228483 TI - Comparative Transcriptome Analysis between Low- and High-Cadmium-Accumulating Genotypes of Pakchoi (Brassica chinensis L.) in Response to Cadmium Stress. AB - To reduce cadmium (Cd) pollution of food chains, screening and breeding of low-Cd accumulating cultivars are the focus of much study. Two previously identified genotypes, a low-Cd-accumulating genotype (LAJK) and a high-Cd-accumulating genotype (HAJS) of pakchoi (Brassica chinesis L.), were stressed by Cd (12.5 MUM) for 0 h (T0), 3 h (T3) and 24 h (T24). By comparative transcriptome analysis for root tissue, 3005 and 4343 differentially expressed genes (DEGs) were identified in LAJK at T3 (vs T0) and T24 (vs T3), respectively, whereas 8677 and 5081 DEGs were detected in HAJS. Gene expression pattern analysis suggested a delay of Cd responded transcriptional changes in LAJK compared to HAJS. DEG functional enrichments proposed genotype-specific biological processes coped with Cd stress. Cell wall biosynthesis and glutathione (GSH) metabolism were found to involve in Cd resistance in HAJS, whereas DNA repair and abscisic acid (ABA) signal transduction pathways played important roles in LAJK. Furthermore, the genes participating in Cd efflux such as PDR8 were overexpressed in LAJK, whereas those responsible for Cd transport such as YSL1 were more enhanced in HAJS, exhibiting different Cd transport processes between two genotypes. These novel findings should be useful for molecular assisted screening and breeding of low-Cd accumulating genotypes for pakchoi. PMID- 27228484 TI - Revisiting the Radical Initiation Mechanism of the Diamine-Promoted Transition Metal-Free Cross-Coupling Reaction. AB - Radical chain reactions leading to C-C bond formation are widely used in organic synthesis, and initiation of the radical chain process usually requires thermolabile radical initiators. Recent studies on transition-metal-free cross coupling reactions between aryl halides and arenes have demonstrated an unprecedented initiation system for radical chain reactions, where the combination of simple organic additives and a base was used in place of conventional radical initiators. Among them, the combination of N,N' dimethylethylenediamine (DMEDA) and t-BuOK is one of the most efficient and representative reaction systems, and the radical initiation mechanism of this system has attracted considerable research interest. In this study, through the combination of kinetic studies, deuterium labeling experiments, and DFT calculations, the radical initiation mechanism of the diamine-promoted cross coupling reaction was carefully reinvestigated. In light of the present study, a mechanistic network of radical initiation in the DMEDA/t-BuOK system was revealed, which differs dramatically from the previously realized single radical initiation pathway. In this mechanism, the diamine acts as a hydrogen atom donor and plays a dual role as both "radical amplifier" and "radical regulator" to initiate the radical chain process as well as to control the concentration of reactive radical species. This represents a rare example of a structurally simple molecule playing such a subtle role in the radical chain reaction system. The present study sheds some light on the novel radical initiation mode in transition metal-free cross-coupling reactions following a base-promoted homolytic aromatic substitution (BHAS) mechanism, and may also help to understand the mechanism of relevant reactions. PMID- 27228486 TI - Ciliatonoids A and B, Two Limonoids from Toona ciliata. AB - Three new ring B-seco limonoids, ciliatonoids A-C (1-3), were isolated from Toona ciliate and structurally characterized by spectroscopic data, X-ray crystallography, and electronic circular dichroism analysis. Ciliatonoids A and B feature an unprecedented limonoid architecture, while ciliatonoid C belongs to a rare class of limonoids. Biological evaluation showed that compound 3 exhibited modest activities against the tested tumor cell lines. PMID- 27228487 TI - Rationale for the use of bioresorbable vascular scaffolds. Why bioresorbable technology is the future of endovascular therapeutics. PMID- 27228485 TI - Serum polybrominated diphenyl ether concentrations and thyroid function in young children. AB - Thyroid hormones are essential for proper neurodevelopment in early life. There is evidence that exposure to polybrominated diphenyl ethers (PBDEs) affects thyroid function, but previous studies have been inconsistent, and no studies among children have been conducted in the United States where PBDE levels are particularly high. Serum levels of seven PBDE congeners and thyroid hormones and other thyroid parameters were measured in 80 children aged 1-5 years from the southeastern United States between 2011 and 2012. Parents of the children completed questionnaires with details on demographics and behaviors. Multivariate linear regression models were used to estimate the associations between serum PBDE levels, expressed as quartiles and as log-transformed continuous variables, and markers of thyroid function. BDE-47, 99, 100 and 153 were detected in >60% of samples, and were summed (?PBDE). PBDE congeners and ?PBDE were positively associated with thyroid-stimulating hormone (TSH). A log-unit increase in ?PBDE was associated with a 22.1% increase in TSH (95% CI: 2.0%, 47.7%). Compared with children in the lowest quartile of ?PBDE exposure, children in higher quartiles had greater TSH concentrations as modeled on the log-scale (second quartile: beta=0.32, 95% confidence interval (CI): -0.09, 0.74; third quartile: beta=0.44, 95% CI: 0.04, 0.85; and fourth quartile: beta=0.49, 95% CI: 0.09, 0.89). There was also a tendency toward lower total T4 and higher free T3 with increasing PBDE exposure. Results suggest that exposure to PBDEs during childhood subclinically disrupts thyroid hormone function, with impacts in the direction of hypothyroidism. PMID- 27228488 TI - Failure of old and new anticoagulants to prevent ischemic stroke in high-risk atrial fibrillation: a case report. AB - Rivaroxaban is an oral anticoagulant that acts as a direct, competitive factor Xa inhibitor. Large randomized clinical trials have shown that, at a daily dose of 20 mg, Rivaroxaban is at least as effective as dose-adjusted warfarin for the prevention of stroke or other embolic complications in patients with nonvalvular atrial fibrillation (AF). The safety and efficacy of combining Rivaroxaban with an antiplatelet agent for secondary stroke prevention has not been established. We report the case of an elderly patient with permanent AF and coronary heart disease, who had already suffered an ischemic stroke while on warfarin treatment, and was consequently switched to treatment with an association of Rivaroxaban and Aspirin. Her CHA2DS2-VASc score was 9. The patient developed a severe recurrent disabling ischemic stroke. This case goes to show that the novel direct anticoagulants may fail to prevent recurrent stroke in patients at particularly high risk, even when associated with antiplatelet drugs. PMID- 27228489 TI - Huge positive remodeling and incomplete stent apposition late after Cypher stent implantation: angiography and optical coherence tomography comparison with a Xience V stent in the same patient. PMID- 27228490 TI - Is it ventricular tachycardia or not? Multiple ICD therapies in a patient with ischemic cardiomyopathy. PMID- 27228501 TI - Ice hockey shoulder pad design and the effect on head response during shoulder-to head impacts. AB - Ice hockey body checks involving direct shoulder-to-head contact frequently result in head injury. In the current study, we examined the effect of shoulder pad style on the likelihood of head injury from a shoulder-to-head check. Shoulder-to-head body checks were simulated by swinging a modified Hybrid-III anthropomorphic test device (ATD) with and without shoulder pads into a stationary Hybrid-III ATD at 21 km/h. Tests were conducted with three different styles of shoulder pads (traditional, integrated and tethered) and without shoulder pads for the purpose of control. Head response kinematics for the stationary ATD were measured. Compared to the case of no shoulder pads, the three different pad styles significantly (p < 0.05) reduced peak resultant linear head accelerations of the stationary ATD by 35-56%. The integrated shoulder pads reduced linear head accelerations by an additional 18-21% beyond the other two styles of shoulder pads. The data presented here suggest that shoulder pads can be designed to help protect the head of the struck player in a shoulder-to-head check. PMID- 27228500 TI - Prognostic potential of the MDM2 309T>G polymorphism in stage I lung adenocarcinoma. AB - The MDM2 protein plays an important role in the regulation of cell proliferation and apoptosis via ubiquitination and proteasome-mediated degradation of p53. The genetic polymorphism rs2279744 (c.309T>G) of the MDM2 gene is reportedly associated with susceptibility and/or prognosis in various cancers. In this study, we investigated the risk factors for worse survival in patients with lung adenocarcinoma (AC). We examined the association between c.309T>G and the prognosis of lung cancer by retrospectively reviewing 453 lung cancer patients. We studied both, clinicopathological and genetic characteristics, including the c.309T>G, p53 Arg72Pro, EGFR, KRAS, and p53 mutations. Associations between these factors and survival outcome were analyzed using Cox proportional hazards models. The frequencies of MDM2 polymorphisms were T/T, 20.8%; T/G, 48.6%, and G/G, 30.7%. The overall survival (OS) of AC patients with pathological stage I disease and the MDM2 T/T genotype was significantly shorter than that of those with the T/G or G/G genotypes (P = 0.02). Multivariate analysis revealed that the MDM2 T/T genotype was an independent, significant prognostic factor (hazard ratio [HR] = 2.23; 95% confidence interval [CI]: 1.07-4.65; P = 0.03). The MDM2 T/T genotype was predictive of poorer survival in a Japanese population. Genotyping for this polymorphism might predict the clinical outcomes of stage I AC patients. PMID- 27228502 TI - Electrical and mechanical controlling of the kinetic and magnetic properties of hydrogen atoms on free-standing silicene. AB - Effects of strain, charge doping and external electric field on kinetic and magnetic properties of hydrogen atoms on a free-standing silicene layer are investigated by first-principles density functional theory. It was found that the charge doping and strain are the most effective ways of changing the hydrogen silicene binding energy, but they can only raise its value. The perpendicular external electric field can also lower it albeit in a narrower range. The strain has also the strongest impact on diffusion processes, and the diffusion barrier can be modified up to 50% of its unstrained value. The adsorption of hydrogen atoms results in a locally antiferromagnetic ground state with the effective exchange constant of approximately 1 eV. The system can easily be driven into a nonmagnetic phase by the charge doping and strain. The obtained results are very promising in view of the silicene functionalization and potential applications of silicene in fields of modern nanoelectronics and spintronics. PMID- 27228504 TI - Nonlinear optical microscopy improvement by focal-point axial modulation. AB - Among the most important challenges of microscopy-even more important than the resolution enhancement, especially in biological and neuroscience applications-is noninvasive and label-free imaging deeper into live scattering samples. However, the fundamental limitation on imaging depth is the signal-to-background ratio in scattering biological tissues. Here, using a vibrating microscope objective in conjunction with a lock-in amplifier, we demonstrate the background cancellation in imaging the samples surrounded by turbid and scattering media, which leads to more clear images deeper into the samples. Furthermore, this technique offers the localization and resolution enhancement as well as resolves ambiguities in signal interpretation, using a single-color laser. This technique is applicable to most nonlinear as well as some linear point-scanning optical microscopies. PMID- 27228505 TI - Sinonasal Quality of Life in Children With Cystic Fibrosis. AB - IMPORTANCE: Sinusitis is the most common otolaryngologic complaint in children with cystic fibrosis (CF). However, basic knowledge about the effect of sinusitis on these children is lacking. OBJECTIVE: To evaluate the incidence and quality-of life impact of chronic rhinosinusitis (CRS) in an unbiased cohort of children with CF. DESIGN, SETTING, AND PARTICIPANTS: Survey study of consecutive pediatric patients with CF presenting for routine quarterly evaluation at a tertiary CF clinic at an academic pediatric hospital. Surveys were completed during the period from December 2012 to January 2013. MAIN OUTCOMES AND MEASURES: Surveys designed to assess major criteria for diagnosis of CRS and a validated pediatric sinonasal quality-of-life instrument, the Sinonasal-5 (SN-5). Statistical analysis was performed to evaluate association between demographic features and survey responses. RESULTS: Of the 102 consecutive eligible patients, 47 children (46%) aged 2 to 20 years (mean [SD] age, 12.9 [5.6] years; 24 [51%] female) completed the surveys. Depending on the exact diagnostic criteria used, 5 (11%) to 18 (38%) of children with CF had CRS. Mean domain (2.16; 95% CI, 2.02-2.30) and overall visual-analog scale (8.26; 95% CI, 8.01-8.51) scores on the SN-5 were consistent with minimal effect on quality of life and comparable to historical posttreatment scores. Mean scores on nasal obstruction (3.07; 95% CI, 2.80-3.34) and sinusitis (2.68;; 95% CI, 2.42-2.94) were the most affected domains, whereas allergy (1.83; 95% CI, 1.65-2.01), emotional disturbance (1.76; 95% CI, 1.56 1.96), and activity restriction (1.43; 95% CI, 1.31-1.57) were minimally affected. Children with a diagnosis of CRS had higher mean SN-5 scores (2.60; 95% CI, 2.31-2.89 vs 2.05; 95% CI, 1.90-2.20; difference of 0.55; 95% CI, 0.29-0.80). Twenty-five patients (53%) had undergone some treatment for sinusitis. There was no association between SN-5 score and CRS treatment history. CONCLUSIONS AND RELEVANCE: In this study, the incidence of symptomatic CRS was high, but quality of-life impact was relatively low among children with CF. Use of standardized assessment scales, including consensus diagnostic criteria and validated quality of-life surveys, may be helpful to guide referral and management decisions. PMID- 27228503 TI - Optical coherence tomography for embryonic imaging: a review. AB - Embryogenesis is a highly complex and dynamic process, and its visualization is crucial for understanding basic physiological processes during development and for identifying and assessing possible defects, malformations, and diseases. While traditional imaging modalities, such as ultrasound biomicroscopy, micro magnetic resonance imaging, and micro-computed tomography, have long been adapted for embryonic imaging, these techniques generally have limitations in their speed, spatial resolution, and contrast to capture processes such as cardiodynamics during embryogenesis. Optical coherence tomography (OCT) is a noninvasive imaging modality with micrometer-scale spatial resolution and imaging depth up to a few millimeters in tissue. OCT has bridged the gap between ultrahigh resolution imaging techniques with limited imaging depth like confocal microscopy and modalities, such as ultrasound sonography, which have deeper penetration but poorer spatial resolution. Moreover, the noninvasive nature of OCT has enabled live imaging of embryos without any external contrast agents. We review how OCT has been utilized to study developing embryos and also discuss advances in techniques used in conjunction with OCT to understand embryonic development. PMID- 27228506 TI - Progressive accumulation of mutations in the hepatitis B virus genome and its impact on time to diagnosis of hepatocellular carcinoma. AB - To evaluate how hepatitis B virus (HBV) genetic variation affected progression from chronic carrier state to hepatocellular carcinoma (HCC), we analyzed HBV full-length sequences in blood obtained <1-20 years before diagnosis from 117 HCC cases and 118 controls nested in a cohort of 4,841 HBV carriers, for whom HBV genotypes B and C are predominant. The relationship between each viral single nucleotide polymorphism (SNP) and HCC development was assessed using ordinal logistic models according to five periods of time to diagnosis (TTD). Thirty-one HBV-SNPs showed significant association with TTD after adjustment for HBV genotype, 24 of which could also be analyzed with an extended analysis on the full-length data in conjunction with 512 partial sequences (nucleotides 2,436 1,623) from the cohort. The obtained 10 robust candidate HBV-SNPs (P <= 0.0304), which showed odds ratios ranging from 1.89 to 8.68, were further confirmed in 163 GenBank HBV-HCC sequences from nine Asia regions, assayed after HCC diagnosis, representing the end stage of progressive hepatic diseases. The prevalence of these HBV-SNPs and their cumulative number, presented in terms of mutation score, increased with time approaching HCC diagnosis, with an odds ratio of 2.17, 4.21, 8.15, and 19.15, respectively, for the mutation score of 1, 2, 3, and >=4 versus 0. The mutation score for predicting short-term HCC risk outperformed other factors, including HBV-DNA levels, viral genotype, and various combinations of risk factors, and revealed increasing accuracy with shorter TTD (<4.5 years before diagnosis: area under the curve = 0.83-0.89; sensitivity = 72.7%-94.1%; specificity = 58.3%-70.5%; conditioned on optimized cutoff for genotype B and C, respectively). CONCLUSIONS: Identifying and tracking viral mutations is important for monitoring hepatitis B progression and early detection of HCC. (Hepatology 2016;64:720-731). PMID- 27228507 TI - A well-baby peer counseling program is not associated with human milk receipt in the NICU. AB - OBJECTIVE: Evaluate the impact of a non-neonatal intensive care unit (NICU) specific peer counseling (PC) program on the cessation of human milk receipt at and post-NICU discharge. STUDY DESIGN: A multivariable logistic regression model used data from 400 mother-infant dyads from a level IV NICU to compare cessation of human milk receipt at NICU discharge by PC program status. Kaplan-Meier distributions and a multivariable Cox proportional hazards model assessed the relationship between participants/non-participants and cessation of human milk post-NICU discharge. RESULTS: No statistically significant differences between groups in cessation of human milk either by or post-discharge were observed. Identified variables associated with the outcome(s) of interest included maternal and infant age, length of stay, presence of a breastfeeding duration goal and frequency of NICU lactation consultant contact. CONCLUSION: Exposure to a non NICU-specific PC program was not associated with human milk receipt either by or post-NICU discharge. PMID- 27228508 TI - Should we still use vitamin A to prevent bronchopulmonary dysplasia? AB - Bronchopulmonary dysplasia (BPD) is associated with significant short- and long term morbidity in preterm infants, and it can be prevented in some infants with vitamin A prophylaxis. Vitamin A, once widely used in neonatal intensive care, was scarce for the last few years, but has become available again at a much higher price, leading to dilemmas about its routine use. In this review we discuss experimental, clinical and socioeconomic evidence related to BPD, and provide a framework for clinicians and policy-makers to evaluate the value of vitamin A treatment and make decisions about its use for prevention of BPD. PMID- 27228509 TI - Local Infiltration Analgesia Versus Regional Blockade for Postoperative Analgesia in Total Knee Arthroplasty: A Meta-analysis of Randomized Controlled Trials. AB - BACKGROUND: Total knee arthroplasty (TKA) is one of the most commonly performed procedures while postoperative analgesia still remains challenging. The efficacy and safety of local infiltration analgesia (LIA) versus regional blockade (RB; epidural analgesia and/or peripheral nerve block) for pain management after TKA are controversial. OBJECTIVES: The purpose of this meta-analysis was to determine whether LIA compared with RB would provide better postoperative pain control, consume less morphine, facilitate early functional recovery, entail a differential risk of side effects and complications, and allow a shorter length of stay. STUDY DESIGN: This meta-analysis pooled all data published in randomized controlled trials (RCTs) examining the efficacy and safety of LIA versus RB following TKA. SETTING: The work was performed at Affiliated Cixi Hospital, Wenzhou Medical University. METHODS: Literature in English was searched using EMBASE, Medline, Cochrane Library, CINAHL, Web of Science, and Scopus from inception to April 2015. RCTs that compared LIA and RB for postoperative analgesia following TKA were included. Methodological quality was assessed using the Cochrane Back Review Group checklist, and a sensitivity analysis was performed. Sixteen RCTs with a total of 1,206 patients were finally included in our study. RESULTS: The results of our meta-analysis indicate that patients managed by LIA showed significantly lower numeric rating scale (NRS) score at rest (WMD: -0.40 [-0.72, -0.07]; P = 0.02) when compared with those managed by RB. Difference of morphine consumption was not significant (WMD: -1.39 [-7.21, 4.44]; P = 0.64) between the 2 groups. In terms of early functional recovery, the LIA group showed more straight leg raise (RR: 2.90 [2.15, 3.93]; P < 0.00001) on the first postoperative day; better range of motion within one week (WMD: 4.33 [2.61, 6.05]; P < 0.00001), but not at 3 months (WMD: 1.98 [-0.02, 3.98]; P = 0.05); and comparable knee society score (WMD: -8.79 [-27.05, 9.48]; P = 0.35). Length of hospital stay of the LIA group was marginally shorter (WMD: -0.25 [ 0.49, -0.01]; P = 0.05) than that of the RB group. Risk of side effects and complications were comparable between groups. LIMITATIONS: The lack of a standard criterion regarding the technique details of LIA and heterogeneity resulting from the various analgesic components, dosages, and different administration methods might have posed a bias on the results. CONCLUSION: Our results have indicated that LIA provided better analgesia than RB at rest and preserved quadriceps function in the immediate postoperative period, which may be beneficial to early functional recovery. And its safety profile is reliable. With the biases in our meta-analysis, a rigorous and adequately powered RCT is needed to validate our results. KEY WORDS: Local infiltration analgesia, regional block, peripheral nerve block, epidural analgesia, postoperative analgesia, total knee arthroplasty, meta-analysis, randomized controlled trial. PMID- 27228510 TI - Patient Characteristics and Outcomes in Unintentional, Non-fatal Prescription Opioid Overdoses: A Systematic Review. AB - BACKGROUND: Opioid overdose continues to be a significant and growing cause of preventable mortality and morbidity. Studies suggest that unintentional, non fatal overdose from prescription opioid analgesics constitutes a large portion of total overdose events. The societal burden associated with these events is a frequently overlooked public health concern. OBJECTIVES: To evaluate unintentional, non-fatal prescription opioid overdoses, including the identification of risk factors, societal burden, and knowledge gaps where further study is warranted. STUDY DESIGN: Systematic review of the literature for unintentional, non-fatal opioid overdose. METHODS: Preferred reporting items for systematic reviews and meta-analyses guidelines were used in constructing this systematic review. To determine the scope of the existing literature, a systematic search was conducted using the MEDLINE, CINAHL, PsycINFO, and Web of Science databases. RESULTS: This systematic review analyzes 24 articles (21 retrospective descriptive analyses, 2 prospective analyses, one phase III trial, and one meta-analysis). Articles were reviewed by authors and relevant data examined. Results show that opioid overdose morbidity is significantly more prevalent than mortality and sequelae of non-fatal events should be studied in more detail. LIMITATIONS: The limitations of this systematic review include the range of study populations and opioids discussed and the broad and variable definitions of "opioid overdose" in the literature. CONCLUSIONS: Opioid overdose morbidity and mortality is seen across the entire spectrum of inpatient and outpatient use with significant numbers of adverse events occurring in population segments not identified by high risk indicators. Increased physician awareness and a multi-modal approach could help mitigate the overdose epidemic while maintaining effective pain control for patients. KEY WORDS: Prescription, opioid, accidental drug overdose, unintentional overdose, drug poisoning, fentanyl, oxycodone, hydrocodone, methadone, oxymorphone, hydromorphone. PMID- 27228511 TI - MILD(r) Is an Effective Treatment for Lumbar Spinal Stenosis with Neurogenic Claudication: MiDAS ENCORE Randomized Controlled Trial. AB - BACKGROUND: Lumbar spinal stenosis (LSS) is a common degenerative condition of the spine, which is a major cause of pain and functional disability for the elderly. Neurogenic claudication symptoms are a hallmark of LSS, where patients develop low back or leg pain when walking or standing that is relieved by sitting or lumbar flexion. The treatment of LSS generally begins with conservative management such as physical therapy, home exercise programs, and oral analgesics. Once these therapies fail, patients commonly move forward with interventional pain treatment options such as epidural steroid injections (ESIs) or MILD(r) as the next step. OBJECTIVE: To assess improvement of function and reduction in pain for Medicare beneficiaries following treatment with MILD (treatment group) in LSS patients with neurogenic claudication and verified ligamentum flavum hypertrophy and to compare to a control group receiving ESIs. STUDY DESIGN: Prospective, multi-center, randomized controlled clinical trial. SETTING: Twenty-six US interventional pain management centers. METHODS: Patients in this trial were randomized one to one into 2 study arms. A total of 302 patients were enrolled, with 149 randomized to MILD and 153 to the active control. Outcomes are assessed using the Oswestry Disability Index (ODI), Numeric Pain Rating Scale (NPRS) and Zurich Claudication Questionnaire (ZCQ). Primary efficacy is the proportion of ODI responders, tested for statistical superiority of the MILD group versus the ESI group. ODI responders are defined as patients achieving the validated Minimal Important Change (MIC) of = 10 point improvement in ODI from baseline to follow up. Similarly, secondary efficacy is the proportion of NPRS and ZCQ responders using validated MIC thresholds. Primary safety is the incidence of device- or procedure-related adverse events in each group. This report presents safety and efficacy results at 1-year follow-up. Outcomes at 2 years will be collected and reported for patients in the MILD group only. RESULTS: At 1-year follow-up, ODI, NPRS, and all 3 ZCQ domains (Symptom Severity, Physical Function and Patient Satisfaction) demonstrated statistically significant superiority of MILD versus the active control. For primary efficacy, the 58.0% ODI responder rate in the MILD group was higher than the 27.1% responder rate in the epidural steroid group (P < 0.001). The primary safety endpoint was achieved, demonstrating that there is no difference in safety between MILD and ESIs (P = 1.00). LIMITATIONS: There was a lack of patient blinding due to considerable differences in treatment protocols, and a potentially higher non-responder rate for both groups versus standard-of-care due to adjunctive pain therapy study restrictions. Study enrollment was not limited to patients that had never received ESI therapy. CONCLUSIONS: One-year results of this randomized controlled clinical trial demonstrate that MILD is statistically superior to ESIs in the treatment of LSS patients with neurogenic claudication and verified central stenosis due to ligamentum flavum hypertrophy. Primary and secondary efficacy outcome measures achieved statistical superiority in the MILD group compared to the control group. With 95% of patients in this study presenting with 5 or more LSS co-factors, it is important to note that patients with spinal co-morbidities also experienced statistically significant improved function that was durable through 1 year. KEY WORDS: MILD, minimally invasive lumbar decompression, interlaminar epidural steroid injections, ESI neurogenic claudication, ligamentum flavum, ENCORE, PILD, CED Study, LSS. PMID- 27228512 TI - Safety and Efficacy of Dexmedetomidine in Treating Post Spinal Anesthesia Shivering: A Randomized Clinically Controlled Dose-Finding Trial. AB - BACKGROUND: The optimum dose of dexmedetomidine for shivering control with the least hemodynamic derangements is still under research. OBJECTIVE: To compare the efficacy, hemodynamic and side effects of dexmedetomidine in 3 different doses with those of meperidine for the treatment of shivering in patients undergoing spinal anesthesia for minor elective lower abdominal surgery. STUDY DESIGN: Prospective double-blind randomized clinically controlled study. SETTING: University hospital. METHODS: One hundred twenty patients who developed shivering under spinal anesthesia.On shivering, patients were randomly allocated to receive an intravenous 2 mL bolus dose of meperidine 0.4 mg/kg (meperidine group, n = 30), dexmedetomidine 0.5 ug/kg (DEX I group, n = 30), 0.3 ug/kg (DEX II group, n = 30), or 0.2ug/kg (DEX III group, n = 30). Control of shivering, time taken for cessation of shivering, response rate, recurrence, hemodynamic changes, sedation score, tympanic temperature, and side effects were noted and compared between groups. RESULTS: The groups were comparable regarding demographic profile, tympanic temperature decline, and shivering onset time (P > 0.05). Lower shivering cessation time (P < 0.001) and higher response rate (P < 0.01) were observed in DEX I and II groups compared with DEX III and meperidine groups, with a nonsignificant difference between DEX I and II groups. Recurrence of shivering activity was higher in DEX III group (36.7%, P < 0.01) compared with DEX I (10%), DEX II (6.7%) and meperidine (16.7%) groups. Lower heart rates, systolic and diastolic blood pressure mean values were recorded in DEX I group (P < 0.05). Nine patients (30%) in DEX I group were in levels 3 - 5 of sedation (P < 0.02) compared with 5 (16.66%), 2 (6.66%), and 4 (13.3) patients in DEX II, DEX III, and meperidine groups, respectively. LIMITATIONS: This study is limited by its small sample size. CONCLUSIONS: Among the 3 doses investigated, dexmedetomidine 0.3ug/kg effectively treated shivering associated with spinal anesthesia with modest hemodynamic and sedation effects. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02382432. KEY WORDS: Dexmedetomidine, hypothermia, shivering, spinal anesthesia. PMID- 27228513 TI - Digital Subtraction Angiography Use During Epidural Steroid Injections Does Not Reliably Distinguish Artery from Vein. AB - BACKGROUND: Epidural steroid injections (ESIs) are among the most common procedures performed in an interventional pain management practice. It is well known that tragic complications may arise from ESIs, most commonly those performed using a transforaminal approach. Digital subtraction angiography (DSA) has been hailed as a fluoroscopic technique that can be used to detect arterial placement of the injection needle, and therefore as a safety measure that can decrease the incidence of catastrophic sequelae of these procedures. OBJECTIVE: The objective of this article was to review existing scientific pain literature to determine if DSA can distinguish arterial vs. venous uptake. STUDY DESIGN: Narrative review. METHODS: The current narrative review of DSA in interventional spine was completed with a PUBMED search using the key words: digital subtraction angiography, epidural, fluoroscopy, intravascular injection, paraplegia, and quadriplegia in accordance with Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) guidelines. RESULTS: After identification of duplicate articles, 383 articles were screened by title, abstract, and/or full article review. Ten of these articles were deemed appropriate, after applying inclusion and exclusion criteria, as they specifically looked at the use of digital subtraction angiography in interventional spine epidural injections. This included 4 case reports, 3 prospective studies, one retrospective analysis, one prospective cohort study, and one meta-analysis. All of the available studies claiming that DSA was capable of detecting vascular spread are likely accurate, but no significant detection of specifically arterial spread has been reported. The known catastrophic complications related to ESIs are purported to be due to arterial injection of insoluble steroids or local anesthetic and detection of arterial spread of contrast during fluoroscopy would be of obvious benefit to the interventionalist. LIMITATIONS: Small study size, non-randomized studies between DSA and real time fluoroscopy. CONCLUSION: Existing studies do not support that DSA can predict arterial spread. In fact, DSA exposes the practitioner and the patient to higher levels of radiation without objective evidence of any safety parameters. KEY WORDS: Digital subtraction angiography, real-time fluoroscopy, transforaminal epidural injection, particulate steroids, cervical radicular artery, lumbar radicular artery, spinal cord injury. PMID- 27228514 TI - High Frequency Spinal Cord Stimulation at 10 kHz for the Treatment of Chronic Pain: 6-Month Australian Clinical Experience. AB - BACKGROUND: High frequency spinal cord stimulation at 10 kHz (HF10 therapy) represents a prominent advance in spinal cord stimulation (SCS) therapy, having demonstrated enhanced efficacy in patients with back and leg pain and pain relief without paresthesia that is sustained at 24 months post implant. OBJECTIVE: To report on the effectiveness HF10 SCS therapy for a wide range of intractable pain conditions in clinical practice. STUDY DESIGN: Retrospective investigation of 256 patients who trialed HF10 SCS for chronic intractable pain of various etiologies. SETTING: Three Australian pain clinics. METHODS: Two hundred fifty-six patients trialed HF10 SCS with view of a permanent implant if successful. Pain distributions included back + leg, back only, head +/- neck, and neck +/- arm/shoulder. About 30% of patients had previously failed traditional low frequency paresthesia-based stimulation, while the remaining cohort were either highly refractory to treatment or not recommended by the pain physician for traditional SCS. Pain scores (numerical pain rating scale - NPRS) and functional outcome measures (Oswestry Disability Index - ODI; and activity tolerance times) were assessed at baseline, post-trial, and at 3 and 6 months post-implant as available in the medical records. RESULTS: Of the 256 patients, 189 (73%) reported a positive trial and were implanted. Patients with back + leg pain demonstrated the highest trial success rate (81%). A mean reduction in pain, among those for whom data were available, of 50% was sustained up to 6 months post-implant across the entire patient population. Sixty-eight percent of patients who failed traditional SCS reported a positive trial and mean pain relief at 6 months was 49% (P < 0.001). An 8.6 point reduction in ODI (21%) at 6 months and improved sitting, standing, and walking tolerances were also reported. LIMITATIONS: As data was collected retrospectively, missing data points were unavoidable; this was primarily due to inconsistent data collection and patients being lost to follow-up. Patient populations were diverse and a control group was not appropriate in this setting. CONCLUSIONS: These retrospective results demonstrate a significant advancement for patients suffering with chronic intractable pain and are consistent with recently published clinical results for HF10 SCS. HF10 SCS appears to be a viable, paresthesia-free alternative to traditional SCS, with high trial success rates, demonstrated effectiveness in a range of pain distributions including those typically difficult to treat with traditional SCS, and the possibility to restore pain control in patients who have previously failed traditional SCS. KEY WORDS: Spinal cord stimulation, high frequency stimulation, HF10, paresthesia-free stimulation, back pain, leg pain, cervical pain, neuromodulation. PMID- 27228515 TI - The Effectiveness of Alcohol Versus Phenol Based Splanchnic Nerve Neurolysis for the Treatment of Intra-Abdominal Cancer Pain. AB - Pancreatic and other upper abdominal organ malignancies can produce intense visceral pain syndromes that are frequently treated with splanchnic nerve neurolysis (SNN) or celiac plexus neurolysis (CPN). Although commonly performed with either alcohol or phenol, there is scant literature on the comparative effectiveness, duration of benefit, and complication profile comparing the 2 agents. This study presents a retrospective chart review of 93 patients who underwent SNN for cancer-related abdominal pain in order to describe patient characteristics, examine comparative efficacy, duration of benefit, and incidence of complications with alcohol vs. those of phenol. Consistent with previous studies, SNN reduced reported pain scores while not significantly reducing opioid consumption. No difference in pain outcomes was found comparing alcohol versus phenol based neurolytic techniques. Celiac axis tumor infiltration and pre procedural local radiation therapy did not change the effectiveness of the procedure. Our data demonstrated that 44.57% of patients had = 30% pain reduction while 43.54% did not have pain reduction. Interestingly, the procedure produced significant improvements in anxiety, depression, difficulty thinking clearly, and feeling of well-being. In addition, no difference in complications was seen between the agents either. SNN was an effective and relatively safe procedure for the treatment of pain associated with pancreatic and other upper abdominal organ malignancies in our sample of patients. Choice of neurolytic agent can appropriately be left to the clinical judgment and local availability of the treating physician. The change in ancillary symptoms has a theoretical basis that supports a biopsychosocial model of pain since changes in one target area (pain) impact other related ones (depression and anxiety). KEY WORDS: Celiac plexus, splanchnic nerves, neurolysis, nerve block, alcohol, ethanol, phenol, pain, cancer pain, abdominal pain, visceral pain, symptom assessment. PMID- 27228516 TI - What Is the Role of Epidural Steroid Injections in Lumbar Spinal Disease with Moderate Disability? AB - Epidural steroid injections have been gaining popularity as an alternative to surgical treatment of radicular pain with associated spinal derangement. To determine the effectiveness and indications of lumbar epidural steroid injections in patients with or without surgery, we performed a prospective observational study. We gathered data from 262 degenerative short-segment spinal disease patients (affected at one or 2 levels) with greater than 12 weeks of medication resistant radicular pain without neurological deficits but with moderate disability (visual analog scale < 6.5; Oswestry Disability Index < 35). All patients received initial fluoroscopically guided transforaminal epidural steroid injections of the affected vertebral level(s) corresponding to their symptoms. Those with inadequate responses or who wanted subsequently surgery underwent decompression surgery. Clinical and demographic characteristics were assessed to compare the differences between the groups. RESULTS: Of the 262 patients who received epidural steroid injections, 204 did not have operations for up to one year. However, 58 patients experienced inadequate relief of pain or wanted operations and therefore underwent surgery. At baseline, the 2 groups had similar mean disability indices and pain scores, as well as gender ratios, ages, and durations of symptoms (P > 0.05). In the patients who underwent surgery, the mean disability and pain scores were not significantly decreased after injection compared to those in the injection-alone group, although the scores for the injection plus surgery patients decreased significantly after surgery (P < 0.05). In contrast, patients who underwent epidural steroid injection alone experienced a significant decrease in disability and pain after injection, and that persisted up to one year of follow-up (P < 0.05). Epidural steroid injection can decrease the pain and disability in the majority of a moderate disability group for up to one year, although a significant number of patients underwent surgery regardless of injection. We recommend epidural steroid injection as a first-line treatment in patients with moderate disability that can be converted to surgery without significant delay. KEY WORDS: Epidural steroid injection, spinal surgery, lumbar spinal disease, lumbar radiculopathy, lumbar radicular pain. PMID- 27228517 TI - Measuring the Quality of Pudendal Nerve Perineural Injections. AB - BACKGROUND: Pudendal neuropathy is a tunnel syndrome characterized by pelvic pain and may include bowel, bladder, or sexual dysfunction or a combination of these. One treatment method, pudendal nerve perineural injections (PNPIs), uses infiltration of bupivacaine and corticosteroid around the nerve to provide symptom relief. Bupivacaine also anesthetizes the skin in the receptive field of the nerve that is injected. Bupivacaine offers rapid pain relief for several hours while corticosteroid provides delayed pain control often lasting 3 to 5 weeks. Not all pudendal nerve blocks may provide complete pain relief but long term pain control from the steroid appears to be associated with immediate response to bupivacaine. We offer a method of evaluating the quality of a pudendal block on the day it is performed using pinprick sensation evaluation. OBJECTIVE: To demonstrate that pinprick sensory changes provide a simple and rapid method of measuring response to local anesthetic and pain reduction provided by a PNPI on the day it is performed. This response defines the quality of each PNPI. STUDY DESIGN: This is a case series based on retrospective review of a private practice database that is maintained by HealthEast hospitals in Minnesota. Database information includes standard physical examination, recording techniques, and treatment processes that had been in place for several years. SETTING: Private practice in United States. METHODS: Patients with a diagnosis of pudendal neuropathy are treated with PNPIs. Two hours after each block, 2 endpoints are measured: response to a sensory pinprick examination of the pudendal territory and difference in patient-reported pain level before and after nerve block. Fifty-three men from a private practice treating only pelvic pain received the treatment in 2005. Reported pain level was not recorded for 2 patients. RESULTS: Bupivacaine in perineural injections produces varying degrees of analgesia or hypalgesia to pinprick. Normal pinprick response suggests pudendal nerves were not penetrated by bupivacaine. Patient responses varied from complete, i.e. all 6 branches anesthetized to none. Most men had 2 - 5 nerve branches anesthetized. One man had a single nerve branch that responded to bupivacaine. Three men failed to respond to local anesthetic.Changes in pre-PNPI to post-PNPI pain scores were significantly decreased (n = 51, P-value < 0.0001), indicating that bupivacaine in the PNPI reduced pain. Forty-one patients (80.4%) indicated less pain after the procedure and only 2 patients (4.0%) indicated more pain. The number of nerve branches successfully anesthetized was also significantly correlated with change in score. On average, an additional successful nerve branch anesthetized corresponded to a drop of about 0.66 in the change score (n = 51, P - value = 0.0005). CONCLUSION: PNPIs relieve pain. Anesthesia affected all 6 pudendal nerve branches in only 13.2% of patients. Complete pain relief occurred in 39.2%. This argues against use of perineural pudendal blockade as a diagnostic test. Pain relief after PNPI is associated with number of nerve branches that are anesthetized. At 2 hours after a PNPI its quality (the number of the 6 nerve branches with reduced response to pinprick from the perineural local anesthetic) is associated with subjective reduction of pain. KEY WORDS: Pudendal neuralgia, chronic perineal pain, pudendal nerve block, sensory examination, neurologic examination, pain management, chronic pelvic pain syndrome. PMID- 27228518 TI - Facetoplasty Using Radiofrequency Thermocoagulation for Facet Joint Hypertrophy. AB - Lumbar spinal stenosis is one of most common pathologic conditions affecting the lumbar spine. Pain and/or disability in the low back and lower extremities with or without neurogenic claudication may occur as a result of compression of dural sac contents or nerve roots in the narrowed space. Bulging and protrusion, facet joint hypertrophy, and disc herniation combined with osteophytes and arthritic changes of facet joints can be the cause of lumbar spinal stenosis. Medical/interventional treatment may be considered as an initial treatment for patients with mild symptoms of lumbar spinal stenosis. Surgery is usually considered when medical/interventional treatment has failed. Even though surgery has been considered to be the definitive treatment for spinal stenosis conventionally, it has potential problems including general anesthesia related complications and failed back surgery syndrome. For that reason, minimally invasive techniques such as percutaneous endoscopic lumbar discectomy (PELD), epiduroscopic laser neural decompression (ELND), and nucleoplasty with radiofrequency have been developed as alternatives to surgery.The authors present a case of treating lumbar spinal stenosis by using radiofrequency thermocoagulation. Radiofrequency therapy is used for spinal pain, usually in forms of neurotomy or nucleoplasty. The patient in this case had leg pain with neurogenic claudication caused by lumbar spinal stenosis from facet joint hypertrophy. His pain did not respond to conservative treatment including epidural steroid injection, but he didn't want to get surgery. As an alternative to surgery, we applied radiofrequency thermocoagulation with high temperatures of electrode to the hypertrophied facet joint for the decompressing of the spinal nerve and the patient's pain was improved without any complications after the treatment. KEY WORDS: Low back pain, neurogenic claudication, lumbar spinal stenosis, facet joint hypertrophy, radiofrequency thermocoagulation, minimally invasive technique. PMID- 27228519 TI - In Memoriam of an Eminent Pain Physician: Phulchand Prithvi Raj. PMID- 27228520 TI - Utilization of Interventional Techniques in Managing Chronic Pain In Medicare Population from 2000 to 2014: An Analysis of Patterns of Utilization. AB - BACKGROUND: The increase in the utilization of various techniques in managing chronic pain, including interventional techniques, is a major concern for policy makers and the public at large. Consequently, multiple regulations have been instituted to reduce health care expenditures in general and expenditures related to interventional techniques in particular. Previous investigations have shown significant increases of utilization of interventional techniques across the board with minor decreases noted in 2007, 2010, 2012 and 2013. OBJECTIVE: To assess the patterns of utilization of interventional techniques in chronic pain management in the fee-for-service (FFS) Medicare population. STUDY DESIGN: Analysis of utilization patterns of interventional techniques from 2000 to 2014 in Fee-for-Services (FFS) Medicare beneficiaries in managing chronic pain. METHODS: The analyzed data was derived from the Centers for Medicare and Medicaid Services (CMS) Physician/Supplier Procedure Summary Master Data from 2000 to 2014. RESULTS: The analysis of data from 2000 to 2014 in FFS Medicare beneficiaries showed overall utilization of interventional techniques increasing at a rate of 153% and an annual average growth rate of 6.9% per 100,000 Medicare population with increase in services of 242%. This showed a 3% decrease per 100,000 Medicare population, compared to the data from 2000 through 2013, even though services increased by 6% due to the increase in the number of Medicare recipients in the FFS beneficiary group. The overall increases in epidural and adhesiolysis procedures were 165% with a rate of 96% per 100,000 Medicare population with an average annual increase of 4.9%. Facet joint interventions and sacroiliac joint blocks increased at a rate of 313% per 100,000 population with an annual average increase of 10.7%. Disc procedures and other types of nerve blocks increased at a much lesser pace than epidural and adhesiolysis procedures or facet joint interventions with an increase of 54% per 100,000 Medicare population and annual increase of 3.1%. A decrease in utilization was noted in 5 of 14 years ranging from 1.2% to 3.8%. LIMITATIONS: The limitations of this updated utilization patterns of interventional techniques in managing chronic pain are multiple with lack of inclusion of participants from Medicare Advantage Plans, lack of complete and accurate data for statewide utilization, and potential errors in coding, billing, and documentation. CONCLUSION: This overall analysis of patterns of utilization in managing chronic pain with interventional techniques showed a continued and significant increase in FFS Medicare beneficiaries from 2000 to 2014 with an increase of 153% per 100,000 Medicare population and at a rate of 6.9% on average per year. However, there were decreases of 2.9% in 2007, 3.8% in 2010, and 1.3%, 3.4%, and 1.2% from 2012 to 2014. KEY WORDS: Interventional pain management, chronic spinal pain, interventional techniques, epidural injections, adhesiolysis, facet joint interventions, sacroiliac joint injections, disc procedures, other types of nerve blocks. PMID- 27228521 TI - Factors Associated with the Outcome of Ultrasound-Guided Trochanteric Bursa Injection in Greater Trochanteric Pain Syndrome: A Retrospective Cohort Study. AB - BACKGROUND: Trochanteric bursa injections of corticosteroids and local anesthetics have been shown to provide pain relief for the treatment of greater trochanteric pain syndrome (GTPS). However, symptom recurrence and incomplete symptom relief are common. The reason for the variation in response is unclear but may be related to disease-, treatment-, or patient-related factors. OBJECTIVE: To determine whether there are factors related to patient, treatment, or disease that can predict either the magnitude or duration of response to ultrasound-guided trochanteric bursa injections for GTPS. STUDY DESIGN: Retrospective evaluation. SETTING: A university hospital outpatient center. METHODS: Potential study participants were patients who underwent ultrasound guided trochanteric bursa injection at an outpatient rehabilitation department. Follow-up interviews were performed in a hospital visit at 1, 3, and 6 months after injection. The Harris Hip Score and the Verbal Numeric Pain Scale were used to evaluate clinical effectiveness of pain reduction and functional improvement at baseline, 1, 3, and 6 months after treatment. Clinical data and ultrasound findings were obtained to assess the possible predictive factors for a good and durable response to ultrasound-guided trochanteric bursa injection. RESULTS: Patients receiving ultrasound-guided trochanteric bursa injections had a statistically significant improvement in pain and hip function at 1, 3, and 6 months after the last injections. Of the 137 patients, 110 (80.3%), 95 (64.9%), and 77 (56.2%) patients achieved successful outcomes according to their 1, 3, and 6-month follow-up evaluations, respectively. Univariate analysis showed that patients with knee osteoarthritis and lumbar facet joint or sacroiliac joint pain experienced less therapeutic effect than those without the conditions at 6 months post-injection. Logistic regression analysis showed that the significant outcome predictors at the 6-month follow-up were facet joint or S-I joint pain (odds ratio = 0.304, P = .014) and knee osteoarthritis (odds ratio = 0.329, P = .021). Age, gender, body mass index, and pain duration were not independent predictors of a clinically successful outcome. There was no statistically significant association between effective treatment and the ultrasound findings of tendinosis, bursitis, partial or full-thickness tear, and enthesopathic changes. LIMITATIONS: Retrospective chart review without a control group. CONCLUSIONS: This study suggests that knee osteoarthritis and lower back pain might be associated with a poor outcome of ultrasound-guided trochanteric bursa injection for GTPS. Assessment of these clinical factors should be incorporated into the evaluation and counseling of patients with GTPS who are candidates for ultrasound guided trochanteric bursa injection. KEY WORDS: Bursa injection, corticosteroid, greater trochanteric pain syndrome, knee osteoarthritis, lower back pain, lumbar facet joint, ultrasonography, S-I joint pain. PMID- 27228522 TI - Sequential Transarterial Embolization Followed by Percutaneous Vertebroplasty Is Safe and Effective in Pain Management in Vertebral Metastases. AB - BACKGROUND: Vertebral metastases are the most frequent vertebral tumor. Transarterial embolization (TAE) devascularizes the tumor, resulting in tumor necrosis. Percutaneous vertebroplasty (PVP), a minimally invasive procedure, can effectively relieve tumor-related pain and improve spine stability. Unfortunately, the PVP technique is of limited use in controlling the progression of vertebral tumor, especially for paravertebral metastases. TAE combined with PVP may achieve a better control on vertebral metastases with paravertebral extension, but little information regarding the combination is available. OBJECTIVES: The present study is intended to assess the safety and effectiveness of the combination of TAE and PVP in patients suffering from vertebral metastases with paravertebral extension. STUDY DESIGN: Sequential TAE followed by PVP was used in 25 patients with symptomatic vertebral metastases. The safety and effectiveness of the sequential therapy were evaluated. SETTING: Three hospitals' clinical research centers. METHODS: This retrospective study was conducted with 25 consecutive patients (11 women and 14 men; mean age 59.3 years, range 38 - 80 years) with vertebral and paravertebral metastases from March 2009 to March 2014. The patients were treated with TAE, and 5 - 7 days later with the PVP procedure. The clinical outcomes were assessed by the control of pain using visual analog scale (VAS) scores, and computed tomography (CT) imaging. X2 or Fisher exact testing was performed for univariate analysis of variables. The VAS scores between groups were compared using ONE-WAY ANOVA, with a P-value of less than 0.05 considered statistically significant. RESULTS: All the TAE and PVP procedures were successfully done. Mean VAS scores decreased after TAE (from 8.64 +/- 0.58 to 5.32 +/- 1.46, P < 0.05) and further decreased after PVP (from 5.32 +/- 1.46 to 2.36 +/- 0.54, P < 0.05), and the decrease in VAS lasted until the third month (3.08 +/- 1.52, P > 0.05) follow-up. However, VAS scores at the sixth month were statistically higher than those at the third month (4.8 +/- 1.24 versus 3.08 +/- 1.52, P < 0.05), VAS scores at the twelfth month were statistically higher than those at the sixth month (6.29 +/- 1.07 versus 4.8 +/- 1.24, P < 0.05). We found paravertebral cement leakage in 6 cases. No clinical or symptomatic complications were observed. In the follow-up, no patient showed further vertebral compression or spinal canal compromise. LIMITATIONS: This is a retrospective clinical study of a small number of patients. CONCLUSION: The sequential TAE followed by PVP is safe and effective in treating vertebral metastases with paravertebral extension. KEY WORDS: Spine, metastases, pain, embolization, vertebroplasty, interventional radiology, PVP, TAE. PMID- 27228523 TI - What Is the Prevalence of Symptomatic Obstructive Sleep Apnea Syndrome in Chronic Spinal Pain Patients? An Assessment of the Correlation of OSAS with Chronic Opioid Therapy, Obesity, and Smoking. AB - BACKGROUND: In modern medicine, obstructive sleep apnea syndrome (OSAS) is a commonly described sleep disorder with airway obstruction, disrupted sleep, and excessive daytime sleepiness. Since its description in 1976 by Guilleminault et al, numerous epidemiologic studies and systematic reviews, with multiple comorbidities related to cardiovascular sequelae, altered cognitive function, and multiple other potential complications have been described. Multiple risk factors have been identified included obesity, smoking, alcohol consumption, and other factors. Chronic pain and chronic opioid therapy also have been described to contribute to a large proportion of patients with OSAS. Chronic pain, obesity, smoking, and chronic opioid therapy are often found together, yet there is a paucity of literature describing OSAS in chronic pain patients. OBJECTIVES: To assess the prevalence of symptomatic OSAS in chronic spinal pain patients receiving chronic opioid therapy and determine the association of OSAS with multiple risk factors and comorbidities. STUDY DESIGN: A retrospective assessment of patients who attend a single interventional pain management practice from January 1, 2010to December 31, 2014. SETTING: A private interventional pain management practice in the United States. METHODS: The data were collected from 4,036 consecutive patients presenting for assessment to a pain management center from January 1, 2010 to December 31, 2014. All assessments were comprehensive and performed by 2 physicians. The comprehensive assessment included a complete history, a physical examination, and a review of records. RESULTS: The prevalence of OSAS in patients with chronic spinal pain was 13.8%. The results showed a higher prevalence in males compared to females (15.1% versus 12.8%), a higher prevalence in those aged 45 or older compared to those 25-45 years and those 18 25 years (16.3% versus 10.7% or 2.5%), higher prevalence in Hispanics and Asians compared to African Americans and whites (23.7% versus 16.2% versus 13.4%), higher prevalence in patients with combined back and neck pain compared to patients with thoracic pain only or back pain only (16.3% versus 8.2% to 11%). Prevalence also varied by body mass index (BMI): 32.4% in morbidly obese patients, 20.3% in severely obese patients, 15.7% in obese patients, 9.2% in those who were overweight, and only 5.7% in those with normal weight. A significant correlation with OSAS was also observed in patients smoking more than 40 pack years and multiple respiratory symptoms except for chronic bronchitis and multiple cardiovascular ailments. LIMITATIONS: The retrospective nature of the assessment. CONCLUSION: This retrospective assessment of over 4,000 patients suffering from chronic pain and receiving chronic opioid therapy indicated a prevalence of sleep apnea syndrome as 13.8%. Multiple risk factors including obesity, chronic obstructive pulmonary disease (COPD), chronic sinus and nasal discharge, and multiple comorbidities including cardiovascular and related ailments have been identified. KEY WORDS: Obstructive sleep apnea syndrome, chronic pain, chronic spinal pain, chronic opioid therapy, obesity, smoking, cardiovascular risk factors, pulmonary risk factors. PMID- 27228524 TI - The Role of Immunoglobulin E in the Pathogenesis of Ketamine Related Cystitis and Ulcerative Interstitial Cystitis: An Immunohistochemical Study. AB - BACKGROUND: A previous study revealed elevated serum Immunoglobulin E (IgE) in ketamine related cystitis (KC) patients. IgE might participate the pathogenesis of different types of bladder pain syndromes, including KC and interstitial cystitis (IC). OBJECTIVES: To investigate the IgE expression in KC and IC bladder tissue. STUDY DESIGN: Prospective evaluation. SETTING: The study was conducted in a tertiary teaching hospital, Hualien Tzu Chi Hospital. METHODS: We investigated the bladder IgE with immunofluorescence staining and quanti?cation. The active mast cells were measuring using tryptase. The symptoms and urodynamic study results were recorded. Double immunofluorescence staining of tryptase and IgE was also performed. Sixteen KC patients, 10 ulcerative IC patients, and 20 non ulcerative IC patients participated. The history and urodynamic parameters were investigated in these patients. The bladder mucosa was biopsied during cystoscopic hydrodistention. Bladder biopsies were also taken from 22 patients with bacterial cystitis and 12 healthy controls. RESULTS: Bladder IgE was positive in 15 (93.8%) KC patients, 9 (90%) ulcerative IC patients, one (5%) non ulcer IC patient, 8 (36.4%) bacterial cystitis patients, and 2 (16.7%) controls (P < .001). The bladder IgE was greater in the patients with KC than in the others (P < .001). After excluding KC patients, bladder IgE was significantly higher in the patients with ulcerative IC than the others (P < .001). The bladder IgE was significantly correlated with pain on a visual analogue scale (r2 = 0.156, P = .017) and maximum bladder capacity (r2 = 0.423, P < .001). Tryptase expression did not show a significant difference between KC, ulcer IC, and non ulcer IC (P = 0.222). Double immunofluorescence staining showed co-expression of tryptase and IgE. CONCLUSIONS: IgE-mediated inflammation played a significant role in the pathogenesis of KC and ulcerative IC. KEY WORDS: Immunoglobulin E, ketamine cystitis, interstitial cystitis. PMID- 27228525 TI - Pentoxifylline Ameliorates Mechanical Hyperalgesia in a Rat Model of Chemotherapy Induced Neuropathic Pain. AB - BACKGROUND: Chemotherapy-induced neuropathic pain is difficult to treat. Pentoxifylline inhibits the production of inflammatory cytokines including tumor necrosis factor alpha(TNF- alpha) and interleukin 1beta (IL-1beta). OBJECTIVE: The aims of our study were to investigate the analgesic and preventive effects of pentoxifylline on paclitaxel-induced neuropathic pain in rats and to identify its mechanisms of action. STUDY DESIGN: Controlled animal study. METHODS: Neuropathic pain was induced with intraperitoneally injected paclitaxel on 4 alternate days in male Sprague-Dawley rats. Pentoxifylline was administered systemically as a single injection and a continuous infusion before or after the injection of paclitaxel. The mechanical threshold for allodynia was measured by using von Frey filaments. Protein levels and localization of inflammatory cytokines were performed by using Western blotting and immunohistochemistry, respectively. RESULTS: After the rats developed neuropathic pain behavior, a single intraperitoneal injection and continuous infusion of pentoxifylline ameliorated paclitaxel-induced mechanical allodynia. In addition, systemic infusion of pentoxifylline in the early phase of the development of pain behavior delayed the onset of paclitaxel-induced pain behavior. Paclitaxel increased the levels of the catalytic subunit alpha of protein kinase A, phosphorylated nuclear factor ;kappaB, TNF- alpha, and IL-1kappa in the lumbar dorsal root ganglia. Pentoxifylline decreased the paclitaxel-induced TNF- alpha and IL-1beta levels. In addition, IL-1beta was expressed in neurons and satellite cells in the lumbar dorsal root ganglia after paclitaxel. LIMITATIONS: Although this study was performed in the animal model by well-designed manner, clinical study will be needed to confirm the analgesic effect of pentoxifylline. CONCLUSION: Pentoxifylline alleviated chemotherapy-induced neuropathic pain in rats by reducing the levels of inflammatory cytokines in dorsal root ganglia and may be effective chemotherapy-induced neuropathic pain in patients. PMID- 27228526 TI - Microstructural Abnormalities in Gray Matter of Patients with Postherpetic Neuralgia: A Diffusional Kurtosis Imaging Study. AB - BACKGROUND: Changes in functional activity and connectivity have been shown in patients experiencing postherpetic neuralgia (PHN) pain. However, PHN-induced structural changes, particularly in the gray matter of which volume and density was widely reported to be altered by other chronic pain, have not been well characterized. OBJECTIVE: In this study, we aimed to detect the difference in the microstructure of gray matter of PHN patients as compared to the healthy controls, and to analyze the correlation between microstructural alterations and clinical features of PHN patients. STUDY DESIGN: Observational study. SETTING: University hospital. METHODS: Diffusional kurtosis imaging (DKI) was performed in 19 patients with PHN and in 19 age- and gender-matched healthy controls. Maps of axial kurtosis (K//), mean kurtosis (MK), radial kurtosis (K) in gray matter were calculated and compared between the 2 groups. Correlations between kurtosis metrics in the regions where between-group difference was detected and pain intensity as well as lesion duration were tested by Pearson's correlation. RESULTS: Compared with healthy controls, PHN patients exhibited significantly decreased DKI parameters in the bilateral insula and superior temporal gyrus, left middle frontal gyrus and occipital lobe, right cerebellum anterior lobe, right thalamus, caudate and parahippocampal gyrus. K// in the bilateral insula and MK in the right insula were negatively correlated with visual analogue scale (VAS) scores of PHN patients, whereas no correlation was found between DKI parameters and lesion duration of PHN pain. LIMITATION: Relatively small sample size. We still cannot determine the causal and effect relationship between the microstructural abnormalities in the gray matter and PHN. CONCLUSIONS: DKI can specifically reflect pathophysiological microstructural alterations in the cerebral gray matters of PHN patients. This feature enables magnetic resonance imaging (MRI) to be a potentially valuable technique for objectively estimating the severity of PHN pain, which would provide an opportunity for elucidating the central mechanisms underlying PHN as well. KEY WORDS: Postherpetic neuralgia, diffusional kurtosis imaging, insula cortex, gray matter, voxel-based analysis. PMID- 27228527 TI - Comparison of Intrathecal Concentrations of Acyclovir following Epidural and Intravenous Administration in Rats. AB - BACKGROUND: Herpes zoster is a disease caused by reactivation of varicella-zoster virus in sensory cranial nerves and dorsal root ganglion. Our presumption was that epidural administration of acyclovir near the viral burden could be more advantageous than intravenous (IV) administration. The cerebrospinal fluid concentration of acyclovir after epidural administration was determined to be higher than that after IV administration in rats. OBJECTIVE: In this study, we tested the hypothesis that the concentration of acyclovir in CSF after epidural administration is higher than that achieved after IV administration in rats. STUDY DESIGN: A randomized controlled animal trial. METHODS: A total of 30 adult male Sprague-Dawley rats were used. The rats were randomly divided into 2 equal groups, epidural (Group Epi) and IV (Group IV) administration groups (n = 15). Group Epi was further subdivided into 3 groups according to acyclovir dosage; each group comprised 5 animals receiving injections at dosages of 0.3 mg, 0.6 mg, and 0.9 mg. Group IV was also subdivided into 3 groups receiving dosages of 3 mg, 6 mg, and 9 mg. We measured CSF and plasma acyclovir concentrations one hour after administration. RESULTS: In Group Epi, the median plasma concentrations of acyclovir were lower than that in CSF (P < 0.05). In Group IV, the median plasma concentrations of acyclovir were significantly higher than that in CSF (P < 0.05). The CSF concentrations of acyclovir in Group Epi were significantly higher than that in Group IV (P < 0.05). The plasma concentrations of acyclovir in Group Epi were significantly lower than that in Group IV (P < 0.05). LIMITATIONS: There were no references of equivalent dosages of acyclovir between IV and epidural administration. However, it is obvious in this study that epidural administration of a low dose of acyclovir can more effectively increase its concentration in the intrathecal space than IV administration. CONCLUSIONS: Epidural administration of acyclovir provides superior drug concentrations in the intrathecal space compared to IV administration. KEY WORDS: Acyclovir, epidural injection, herpes zoster, varicella zoster virus. PMID- 27228528 TI - Near Death Experience from Placement of an Intrathecal Catheter. AB - The management of pain due to cancer is challenging and often requires invasive therapy in addition to medication management. Intrathecal drug delivery is a form of advanced therapy that delivers medication locally in the intrathecal space while reducing systemic side effects associated with high doses of opioids. Although risks associated with intrathecal drug delivery are low, some common complications include dislodgement, kinking, or fracture of the catheter, bleeding, neurological injury, infection, and cerebrospinal leaks. We present a case of a 38-year-old woman with a medical history significant for stage IV breast cancer, L2 metastatic lesion, opioid tolerance, and chronic neck and low back pain who was admitted to the hospital for intractable pain. She had failed multiple interventional procedures in the past including lumbar medial nerve radiofrequency ablation, epidural steroid injection, and trigger point injections as well as a kyphoplasty at the L2 level. Failing both oral and parenteral opioid treatments, the decision was made to place an intrathecal pump in the patient. After placement of the intrathecal catheter and prior to any bolus of medication being given, the patient became bradycardic with a heart rate in the 20s and experienced a 10 second pause. The patient had intermittent bradycardia over the following days and symptoms resolved only after removal of the intrathecal catheter itself. To our knowledge, this is the first reported case with a complication of recurrent bradycardic and asystolic episodes prior to the administration of intrathecal opioid but shortly after placement of the intrathecal catheter itself. KEY WORDS: Intrathecal drug delivery, complications, cancer pain, intrathecal analgesia, bradycardia, opioids. PMID- 27228529 TI - Fluoroscopically Guided C2 Percutaneous Vertebroplasty: A Surgical Technique Note on an Anterior Ascending Approach. AB - BACKGROUND: C2 vertebroplasty is more challenging than transpedicular percutaneous vertebroplasty in the thoracic and lumbar spine. OBJECTIVE: We report an anterior ascending approach for C2 percutaneous vertebroplasty to avoid potential injury to vital structures surrounding the C2 vertebra. STUDY DESIGN: A technique note with 5 consecutive cases. SETTING: Neurosurgery department of a university hospital. METHODS: Fluoroscopically guided manual compression was applied using 3 fingers at the C5 level between the muscle and trachea. The larynx and trachea were displaced medially and the carotid artery laterally. The anterior cervical spine was palpated, and a 15-gauge 4-inch bone marrow biopsy needle was introduced through an anterior ascending approach. When the tip touched the intervertebral disc between C2 and C3, the needle was pushed through the disc until it penetrated into the C2 vertebral body. After confirming adequate needle insertion, vertebroplasty was performed. RESULTS: Pain relief was achieved in 4/5 (80%) patients. One patient possibly did not benefit from percutaneous vertebroplasty, and asymptomatic cement extravasation was detected in 2 patients. LIMITATIONS: Sample size; impossibility of placebo control. CONCLUSION: An anterior ascending approach for C2 percutaneous vertebroplasty is a valuable alternative for relieving pain caused by metastatic spinal tumors. This approach is familiar to surgeons performing anterior cervical discectomies, percutaneous nucleoplasty, or odontoid screw placement surgeries. KEY WORDS: Vertebroplasty, pain, axis, cement leak, metastases, palliative medicine, spine, fracture. PMID- 27228530 TI - Pain Relief in CRPS-II after Spinal Cord and Motor Cortex Simultaneous Dual Stimulation. AB - We describe a case of a 30-year-old woman who suffered a traumatic injury of the right brachial plexus, developing severe complex regional pain syndrome type II (CRPS-II). After clinical treatment failure, spinal cord stimulation (SCS) was indicated with initial positive pain control. However, after 2 years her pain progressively returned to almost baseline intensity before SCS. Additional motor cortex electrode implant was then proposed as a rescue therapy and connected to the same pulse generator. This method allowed simultaneous stimulation of the motor cortex and SCS in cycling mode with independent stimulation parameters in each site. At 2 years follow-up, the patient reported sustained improvement in pain with dual stimulation, reduction of painful crises, and improvement in quality of life. The encouraging results in this case suggests that this can be an option as add-on therapy over SCS as a possible rescue therapy in the management of CRPS-II. However, comparative studies must be performed in order to determine the effectiveness of this therapy. KEY WORDS: Chronic neuropathic pain, Complex regional pain syndrome Type II, brachial plexus injury, motor cortex stimulation, spinal cord stimulation. PMID- 27228531 TI - Chronic Bilateral Sphenopalatine Ganglion Stimulation for Intractable Bilateral Chronic Cluster Headache: A Case Report. AB - A cluster headache (CH) is an excruciating pain centered on the periorbital region and is accompanied by autonomic symptoms. Despite the best currently available medical therapy, many patients still suffer from these headaches. Some patients also experience CH with side shift of attacks, which makes treatment more difficult. In light of the pathophysiological mechanism of CH, the sphenopalatine ganglion (SPG) is a promising therapeutic target for its management. SPG ablation and non-ablation techniques have been the preferred treatment for CH in recent decades. However, few articles have reported the effectiveness of acute SPG stimulation for CH, and no studies have demonstrated the safety and efficacy of bilateral continuous SPG stimulation for CH. In this article, we report on a 59-year-old chronic cluster headache (CCH) patient who had side shifts of attacks and was treated with bilateral continuous SPG stimulation. The patient suffered from CCH for 9 years, and the intensity of pain and the frequency of attacks had gradually increased over time. At the time of admission, he experienced daily attacks. Medical therapy and SPG blocks were offered, but he only achieved transient pain relief. After a careful preoperative examination and discussion with the patient, we provided bilateral SPG stimulation. The electrode was implanted under C-arm fluoroscopic guidance. After continuous stimulation, the patient experienced significant reductions in headache severity. The frequency of attacks was reduced from daily to less than once per week. He also discontinued all of the related drugs that he was taking. This is the first report of bilateral continuous SPG stimulation for CCH. This report indicates that continuous SPG stimulation is a feasible therapeutic option for CCH. However, large-scale and long-term studies are required to elucidate the efficacy of SPG stimulation. KEY WORDS: Cluster headache, sphenopalatine ganglion, SPG, neuromodulation, side shift, stimulation. PMID- 27228532 TI - Novel Single Puncture Approach for Simplicity 3 Sacral Plexus Radiofrequency Ablation: Technical Note. AB - Radiofrequency (RF) ablation of the lateral sacral plexus has been used for the treatment of sacroiliac joint pain including as an adjunct to other palliative therapies for the treatment of painful osseous metastasis. The treatment goal is targeted ablation of the dorsal lateral branches of S1-S4. Though several techniques have been described, the Simplicity III (Neurotherm, Middleton, MA) system allows for ablation to be achieved with a single RF probe by utilizing a multi-electrode curved RF probe to create a continuous ablation line across all sacral nerves. In the standard approach, there is sequential introduction of a spinal needle along the desired ablation tract for local anesthesia followed by separate placement of the ablation probe. Though fluoroscopic guidance is utilized, multiple needle passes increase the risk of complication such as bowel perforation or probe insertion through a neural foramen. It may also extend procedure time and increase radiation dose. We illustrate a technique for Simplicity III RF ablation of the dorsal sacral plexus using a modified Seldinger approach for treatment of a patient with sacroiliac joint pain due to osseous renal cell carcinoma metastasis. The desired ablation tract is initially anesthetized via a hollow micropuncture needle. The needle is then exchanged for a peelaway sheath. The RF probe is inserted through the peelaway sheath thus ensuring the probe is placed precisely along the previously anesthetized tract allowing the procedure to be completed using a single percutaneous puncture. We believe that this approach decreases the risks of bowel perforation, patient discomfort as a result of multiple percutaneous punctures, and procedure time. KEY WORDS: Simplicity 3, sacral plexus ablation, image-guided approach, modified Seldinger, chronic sacral pain, thin wall introducer needle. PMID- 27228533 TI - Ultrasound-Guided Phrenic Nerve Block for Intractable Hiccups following Placement of Esophageal Stent for Esophageal Squamous Cell Carcinoma. AB - Hiccups are actions consisting of sudden contractions of the diaphragm and intercostals followed by a sudden inspiration and transient closure of the vocal cords. They are generally short lived and benign; however, in extreme and rare cases, such as esophageal carcinoma, they can become persistent or intractable, up to and involving significant pain, dramatically impacting the patient's quality of life. This case involves a 60-year-old man with a known history of squamous cell carcinoma of the esophagus. He was considered to have high surgical risk, and therefore he received palliative care through the use of fully covered metallic esophageal self-expandable stents due to a spontaneous perforated esophagus, after which he developed intractable hiccups and associated mediastinal pain. Conservative treatment, including baclofen, chlorpromazine, metoclopramide, and omeprazole, provided no relief for his symptoms. The patient was referred to pain management from gastroenterology for consultation on pain control. He ultimately received an ultrasound-guided left phrenic nerve block with bupivacaine and depomedrol, and 3 days later underwent the identical procedure on the right phrenic nerve. This led to complete resolution of his hiccups and associated mediastinal pain. At follow-up, 2 and 4 weeks after the left phrenic nerve block, the patient was found to maintain complete alleviation of the hiccups. Esophageal dilatation and/or phrenic or vagal afferent fiber irritation can be suspected in cases of intractable hiccups secondary to esophageal stenting. Regional anesthesia of the phrenic nerve through ultrasound guidance offers a long-term therapeutic option for intractable hiccups and associated mediastinal pain in selected patients with esophageal carcinoma after stent placement. KEY WORDS: Esophageal stent, esophageal stenting, intractable hiccups, intractable singultus, phrenic nerve block, phrenic nerve, ultrasound, palliative care, esophageal carcinoma. PMID- 27228534 TI - In Defense of the Meticulous: A Case Against Ambiguity, and a Time to Standardize. PMID- 27228535 TI - Evaluation of Somatosensory Evoked Potential and Pain Rating Index in a Patient with Spinal Cord Injury Accepted Cell Therapy. AB - Spinal cord injury (SCI) causes a high incidence of motor and sensory dysfunctions accompanied with neuropathic pain. No effective treatment is available. Both somatosensory evoked potential (SSEP) and neuropathic pain (NPP) are transmitted via myelinated large diameter fibers of deep sensory pathways. Here we aimed to evaluate whether SSEP can consistently and objectively assess transmission of deep sensory pathways, and to examine the effects of umbilical cord mesenchymal stem cell (UCMSC) transplantation on SSEP and NPP as assessed by the pain rating index (PRI) in a patient with a 2-year history of complete cervical SCI. We demonstrate that SSEP can directly reflect physiological function of myelinated large fibers in deep sensory pathway transmission (NPP is also transmitted by the same pathway). One year after UCMSC transplantation, the SSEP parameter, PRI, and clinical presentations of NPP significantly improved. KEY WORDS: Spinal cord, neuropathic pain, somatosensory evoked potential, umbilical cord mesenchymal stem cells. PMID- 27228536 TI - Ultrasound-Guided Diagnosis and Treatment of Meralgia Paresthetica. AB - Meralgia paresthetica refers to the entrapment of the lateral femoral cutaneous nerve at the level of the inguinal ligament. The lateral femoral cutaneous nerve a purely sensory nerve - arises from the L2 and L3 spinal nerve roots, travels downward lateral to the psoas muscle, and then crosses the iliacus muscle. Close to the anterior superior iliac spine, the nerve courses in contact with the lateral aspect of the inguinal ligament and eventually innervates the lateral thigh. The entrapment syndrome is usually idiopathic but can also ensue due to trauma/overuse, pelvic and retroperitoneal tumors, stretching of the nerve due to prolonged leg/trunk hyperextension, leg length discrepancies, prolonged standing, external compression by belts, weight gain, and tight clothing. The diagnosis of Meralgia paresthetica is usually clinical, i.e., based on the following symptoms: paresthesia, numbness, burning sensation, dysesthesia, and pain over the anterolateral aspects of the thigh. These complaints may be worsened by walking or prolonged standing and typically disappear after weight loss, abdominal muscle strengthening, or elimination of the underlying cause. Although there are several reports on the confirmatory role of electrodiagnostic studies in the diagnosis of Meralgia paresthetica, electromyographers would usually prefer/suggest not to perform nerve conduction studies in daily clinical practice. Herewith, due to its several advantages, ultrasound imaging has been proposed as an alternative diagnostic method in the recent literature. It not only confirms the entrapment morphologically, but also uncovers a likely underlying cause and provides immediate interventional guidance. The pertinent sonographic findings would be hypoechoic and swollen lateral femoral cutaneous nerve. PMID- 27228537 TI - Late Extrusion of an Implantable Pulse Generator of a Spinal Cord Stimulator. AB - The objective of this manuscript was to report a case of a patient with extruded pulse generator 3 years after implantation of a spinal cord stimulator system.With the increasing incidence of chronic pain, spinal cord stimulation (SCS) is becoming more commonly utilized by pain physicians. SCS is a generally safe intervention with minimal adverse effects; however, there are risks of complications which practitioners should be aware of prior to and after placement of the SCS. We present a case of a patient with a late complication of extrusion of an implantable pulse generator (IPG) of a SCS that was promptly identified and successfully removed without any complications. A 60-year-old male truck driver with history of failed back syndrome and diabetes underwent a SCS system implanted with excellent relief of his pain. The SCS was implanted with 2 leads with the IPG being sutured 3 cm in depth in the superior gluteal region. Three years after the implantation, he developed pain over the site of the generator and presented to our clinic with extrusion of the non-rechargeable pulse generator from his gluteal region.The pulse generator was successfully removed with the battery not being infected. This late complication may have been related to his ongoing profession of daily driving with pressure necrosis from prolonged sitting and constant vibration during long rides associated. Structural size and design of the pulse generator may have had an important contribution as well. To our knowledge this complication has not been reported in the literature.Physicians that place or manage patients with SCSs should be aware of this rare complication and maintain vigilance even after remote implantation of the SCS systems. KEY WORDS: Spinal cord stimulator, complication, extrusion, implantable pulse generator, neuromodulation, failed back syndrome, battery complication. PMID- 27228538 TI - Percutaneous Endoscopic Lumbar Discectomy for Far-Migrated Disc Herniation through Two Working Channels. AB - The technique of percutaneous endoscopic lumbar discetomy (PELD) in the transforaminal approach has evolved over the years due to the advances in endoscopic photology and instrumentation and become the most popular technique for lumbar disc herniation. Although PELD offers many advantages, the indications of PELD are limited mostly to non-migrated or low-migrated disc herniation. It is very difficult for PELD in the transforaminal approach to remove the highly migrated disc fragment successfully due to the anatomic barrier. Nowadays, with the advances of instruments and technique, it might be possible for PELD in the transforaminal approach to remove these high-grade migrated disc fragments. The purpose of this study was to describe a technique to effectively treat highly migrated disc herniation via 2 working channels. KEY WORDS: Percutaneous endoscopic lumbar discectomy, far-migrated disc herniation, working channels. PMID- 27228539 TI - Comments on Effect of High-Volume Injectate in Lumbar Transforaminal Epidural Steroid Injections. PMID- 27228540 TI - In Response to Letter to Editor: Use of High Volume Injectate for Lumbar Epidural Steroid Injection via Transforaminal Approach Might Not Be Justifiable. PMID- 27228541 TI - Continuous Analgesia Using a Multi-Holed Catheter in Serratus Plane for Thoracic Surgery. PMID- 27228542 TI - In Response to Font et al. PMID- 27228543 TI - Demystify the Insidious Role of Lumbar Disc Degeneration In Low Back Pain. PMID- 27228544 TI - Production of an in Vitro Low-Digestible Starch via Hydrothermal Treatment of Amylosucrase-Modified Normal and Waxy Rice Starches and Its Structural Properties. AB - We investigated dual modification of normal and waxy rice starch, focusing on digestibility. Amylosucrase (AS) was applied to maximize the slowly digestible and resistant starch fractions. AS-modified starches were adjusted to 25-40% moisture levels and heated at 100 degrees C for 40 min. AS-modified starches exhibited a B-type crystalline structure, and hydrothermal treatment (HTT) significantly (p < 0.05) increased the relative crystallinity with moisture level. The thermal transition properties of modified starches were also affected by the moisture level. The contents of rapidly digestible starch fraction in AS modified normal and waxy starches (43.3 +/- 3.9 and 18.1 +/- 0.6%) decreased to 13.0 +/- 1.0 and 0.3 +/- 0.3% after HTT, accordingly increasing the low digestible fractions. Although the strengthened crystalline structures of AS modified starches by HTT were not stable enough to maintain their rigidity under cooking, application of AS and HTT was more effective in waxy rice starch than normal rice starch when lowering digestibility. PMID- 27228545 TI - IL-10 gene polymorphism is associated with preschool atopy and early-life recurrent wheezing after bronchiolitis in infancy. AB - BACKGROUND: Variations in the genes that regulate innate immunity responses may be associated with susceptibility to asthma or atopy after early-life bronchiolitis. The aim of this study was to evaluate the association between four different polymorphisms of the IL-10 gene at rs1800871, rs1800872, rs1800890, and rs1800896, either alone or in combination, and post-bronchiolitis asthma or allergies at 5-7 years of age. METHODS: Data on single nucleotide polymorphisms (SNP) of IL-10 rs1800896 (-1082G/A), rs1800871 (-819C/T), rs1800872 (-592C/A), and IL-10 rs1800890 (-3575T/A) were available for 135 children. Polymorphisms and their associations with asthma and allergies were studied in 135 preschool-aged children who had been hospitalized for bronchiolitis at age 0-6 months. Their parents were interviewed to record the children's history with asthma and allergies from infancy to the present. RESULTS: At 6.4 years (mean), asthma was present in 17 children (12.6%), while recurrent wheezing during the first 7 years of life was present in 39 (28.9%) children. Fifty-three (39.3%) study participants had current atopy (atopic eczema or allergic rhinitis). Eight (72%) of 11 children with the IL-10 rs1800896, IL-10 rs1800871, and IL-10 rs1800872 combination AA + CT + CA had current atopy (P = 0.02 vs. 38% in other genotype combinations). Twenty-three (56%) children with the IL-10 rs1800871C/T or IL-10 rs1800872C/A genotype had present atopy versus 34 (38%) with other IL-10 genotypes (P = 0.03). Between 2 years and 3 years of age, 27% of ATA haplotype carriers had asthma versus 13.7% of other haplotype carriers (P = 0.02). CONCLUSIONS: IL-10 polymorphisms at rs1800871, rs1800872, rs1800890, and rs1800896 seem to be associated with elevated allergies and/or recurrent wheezing risk in later childhood, after early-life bronchiolitis. Pediatr Pulmonol. 2017;52:14-20. (c) 2016 Wiley Periodicals, Inc. PMID- 27228547 TI - Alzheimer's disease. PMID- 27228546 TI - Gonad development and hermaphroditism in the ascidian Botryllus schlosseri. AB - The colonial ascidian Botryllus schlosseri is an ideal model organism for studying gonad development and hermaphroditism. B. schlosseri has been reared in laboratories for over half a century, and its unique biology allows investigators to probe the processes of germ cell migration and gonad formation, resorption, and regeneration. Following metamorphosis, colonies of B. schlosseri show a synchronized and sequential fertility program that, under standard laboratory conditions, begins with a juvenile stage with no visible gonads and subsequently develops testes at 9 weeks followed later by the production of oocytes-thus resulting in hermaphroditic individuals. The timing of oocyte production varies according to the season, and adult B. schlosseri colonies can cycle among infertile and both male and hermaphrodite fertile states in response to changing environmental conditions. Thus, these acidians are amenable to studying the molecular mechanisms controlling fertility, and recent genomic and transcriptomic databases are providing insight to the key genes involved. Here, we review the techniques and approaches developed to study germ cell migration and gonad formation in B. schlosseri, and include novel videos showing processes related to oocyte ovulation and sperm discharge. In the future, this valuable invertebrate model system may help understand the mechanisms of gonad development and regeneration in a chordate. Mol. Reprod. Dev. 84: 158-170, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27228548 TI - Photochemical Cleavage of Benzylic C-N Bond To Release Amines. AB - The 3-(diethylamino)benzyl (DEABn) group has been studied for releasing primary, secondary, and tertiary amines by direct photochemical breaking of the benzylic C N bond. While photochemical release of primary and secondary amines provides high yields in methanol, release of tertiary amines in MeCN/water can improve yields and reduce the undesired dealkylation side reaction. PMID- 27228549 TI - Long-term exercise training prevents mammary tumorigenesis-induced muscle wasting in rats through the regulation of TWEAK signalling. AB - AIM: Exercise training has been suggested as a non-pharmacological approach to prevent skeletal muscle wasting and improve muscle function in cancer cachexia. However, little is known about the molecular mechanisms underlying such beneficial effect. In this study, we aimed to, firstly, examine the contribution of TWEAK signalling to cancer-induced skeletal muscle wasting and, secondly, evaluate whether long-term exercise alters TWEAK signalling and prevents muscle wasting. METHODS: Female Sprague-Dawley rats were randomly assigned to control and exercise groups. Fifteen animals from each group were exposed to N-Methyl-N nitrosourea carcinogen. Animals in exercise groups were submitted to moderate treadmill exercise for 35 weeks. After the experimental period, animals were killed and gastrocnemius muscles were harvested for morphological and biochemical analysis. RESULTS: We verified that exercise training prevented tumour-induced TWEAK/NF-kappaB signalling in skeletal muscle with a beneficial impact in fibre cross-sectional area and metabolism. Indeed, 35 weeks of exercise training promoted the upregulation of PGC-1alpha and oxidative phosphorylation complexes. This exercise-induced muscle remodelling in tumour-bearing animals was associated with less malignant mammary lesions. CONCLUSION: Data support the benefits of an active lifestyle for the prevention of muscle wasting secondary to breast cancer, highlighting TWEAK/NF- kappaB signalling as a potential therapeutic target for the preservation of muscle mass. PMID- 27228550 TI - A Set of Organelle-Localizable Reactive Molecules for Mitochondrial Chemical Proteomics in Living Cells and Brain Tissues. AB - Protein functions are tightly regulated by their subcellular localization in live cells, and quantitative evaluation of dynamically altered proteomes in each organelle should provide valuable information. Here, we describe a novel method for organelle-focused chemical proteomics using spatially limited reactions. In this work, mitochondria-localizable reactive molecules (MRMs) were designed that penetrate biomembranes and spontaneously concentrate in mitochondria, where protein labeling is facilitated by the condensation effect. The combination of this selective labeling and liquid chromatography-mass spectrometry (LC-MS) based proteomics technology facilitated identification of mitochondrial proteomes and the profile of the intrinsic reactivity of amino acids tethered to proteins expressed in live cultured cells, primary neurons and brain slices. Furthermore, quantitative profiling of mitochondrial proteins whose expression levels change significantly during an oxidant-induced apoptotic process was performed by combination of this MRMs-based method with a standard quantitative MS technique (SILAC: stable isotope labeling by amino acids in cell culture). The use of a set of MRMs represents a powerful tool for chemical proteomics to elucidate mitochondria-associated biological events and diseases. PMID- 27228551 TI - Fetal Alcohol Syndrome and Maternal Alcohol Biomarkers in Sera: A Register-Based Case-Control Study. AB - BACKGROUND: Fetal alcohol syndrome (FAS) is a well-known consequence of prenatal alcohol exposure. However, women tend to deny or underreport their alcohol use during pregnancy. The aim of this study was to explore the usability of various alcohol biomarkers for FAS screening in a data set without information on self reported alcohol use. METHODS: A nationwide register study with a case-control design was conducted. The target population consisted of all live births in Finland from 1987 to 2005. FAS cases (n = 565) were identified from the Finnish Register of Congenital Malformations. Mothers of FAS cases and their controls were selected in a ratio of 1 to 2 from the Finnish Maternity Cohort (FMC). Background information was obtained from the Finnish Medical Birth Register. Serum samples, collected at the mother's first visit to the maternity care, were obtained from the national FMC biobank. Biomarkers of alcohol consumption, gamma glutamyltransferase (GGT), carbohydrate-deficient transferrin (%CDT), combination of GGT and CDT (GGT-CDT), and ethylglucuronide (EtG) were analyzed from mothers of FAS cases (n = 385) and their controls (n = 745). RESULTS: Median levels of all biomarkers were significantly higher among the mothers of FAS children than in control mothers. Using previously validated cutoffs for EtG, GGT, %CDT, and GGT-CDT, nearly half (46%) of the mothers with affected offspring could be identified. The predictive association was highest for GGT-CDT combination and significant also for all the other biomarkers. CONCLUSIONS: In this explorative case-control study, we demonstrate that the FMC biobank can be used to screen alcohol biomarkers for epidemiological research purposes. According to our results, the use of alcohol biomarkers during the first trimester may help to identify the high-risk pregnancies for FAS. A more systematic use of alcohol biomarkers at maternity care may open new possibilities for screening and intervention of alcohol use among pregnant mothers. PMID- 27228552 TI - Role of SEP15 Gene Polymorphisms in the Time of Progression to AIDS. AB - AIMS: HIV infection is a chronic disease that requires intensive treatment in its later phases, including dietary supplementation. Several studies have suggested clinical improvements in patients with high levels of selenium, linking these levels with a longer progression to AIDS. The objective of this study was to verify the association of two polymorphisms in the SEP15 gene, which encodes a selenoprotein that is responsible for the transport of selenium in cells, with the time of progression to AIDS in HIV-1-infected patients. METHODS: Blood samples were obtained from 139 HIV-1-positive individuals after they provided informed consent. DNA was isolated and genotyped using real-time polymerase chain reaction for the presence of SEP15 single nucleotide polymorphisms (rs5859 and rs561104). Questionnaires on sociodemographic features and behavior were answered, and the time of progression to AIDS was estimated based on a medical chart analysis. RESULTS: The allelic and genotypic frequencies did not differ between rapid and nonrapid progressors; however, the presence of the AA genotype of the rs5859 polymorphism was associated with a shorter time of progression to AIDS compared with GG homozygotes (hazard ratio = 3.62, 95% CI = 1.55-8.43, p = 0.003). CONCLUSION: These findings show the importance of genetic analysis of the SEP15 gene in individual patients with regard to predicting time of progression to AIDS. PMID- 27228555 TI - Multidrug-resistant organisms in liver transplant: Mitigating risk and managing infections. AB - Liver transplant (LT) recipients are vulnerable to infections with multidrug resistant (MDR) pathogens. Risk factors for colonization and infection with resistant bacteria are ubiquitous and unavoidable in transplantation. During the past decade, progress in transplantation and infection prevention has contributed to the decreased incidence of infections with methicillin-resistant Staphylococcus aureus. However, even in the face of potentially effective antibiotics, vancomycin-resistant enterococci continue to plague LT. Gram negative bacilli prove to be more problematic and are responsible for high rates of both morbidity and mortality. Despite the licensure of novel antibiotics, there is no universal agent available to safely and effectively treat infections with MDR gram-negative organisms. Currently, efforts dedicated toward prevention and treatment require involvement of multiple disciplines including transplant providers, specialists in infectious diseases and infection prevention, and researchers dedicated to the development of rapid diagnostics and safe and effective antibiotics with novel mechanisms of action. Liver Transplantation 22 1143-1153 2016 AASLD. PMID- 27228558 TI - Hybrid Perovskite/Perovskite Heterojunction Solar Cells. AB - Recently developed organic-inorganic hybrid perovskite solar cells combine low cost fabrication and high power conversion efficiency. Advances in perovskite film optimization have led to an outstanding power conversion efficiency of more than 20%. Looking forward, shifting the focus toward new device architectures holds great potential to induce the next leap in device performance. Here, we demonstrate a perovskite/perovskite heterojunction solar cell. We developed a facile solution-based cation infiltration process to deposit layered perovskite (LPK) structures onto methylammonium lead iodide (MAPI) films. Grazing-incidence wide-angle X-ray scattering experiments were performed to gain insights into the crystallite orientation and the formation process of the perovskite bilayer. Our results show that the self-assembly of the LPK layer on top of an intact MAPI layer is accompanied by a reorganization of the perovskite interface. This leads to an enhancement of the open-circuit voltage and power conversion efficiency due to reduced recombination losses, as well as improved moisture stability in the resulting photovoltaic devices. PMID- 27228557 TI - Dynamic changes in immune cell profile in head and neck squamous cell carcinoma: Immunomodulatory effects of chemotherapy. AB - Tumor cells have evolved sophisticated means of escape from the host immune system. To date, several important immunological phenomena have been revealed in peripheral blood as well as within tumors. In the present study, we first investigated the proportion and activation status of peripheral immune regulatory cells and CD8(+) T-cell subsets in patients with head and neck squamous cell carcinoma (HNSCC) using a multicolor flow cytometer, and then evaluated how therapy with docetaxel, cisplatin, and 5-fluorouracil modulated the immune cell profile in peripheral blood. The proportion of naive T cells was lower and that of effector memory T cells (TEM ) was higher in HNSCC patients than in healthy donors. Moreover, the proportions of activated TEM cells and effector T cells (TEFF ) were dramatically increased in patients with advanced stage disease. The proportion of regulatory T cells and CD14(+) HLA-DR(-) myeloid-derived suppressor cells was elevated in HNSCC patients. Of note, after therapy, in addition to the transient reduction in immune regulatory cells, decreases in central memory T cells and increases in TEFF cells were observed among CD8(+) T-cell subsets, suggesting differentiation from central memory T cells into TEFF cells. Our results suggested that, despite the immunosuppressive status in HNSCC patients, tumor-specific immune responses mediated by CD8(+) T cells might be induced and maintained. Moreover, chemotherapy can trigger not only a transient reduction in immune regulatory cells but also further activation of CD8(+) T cells. PMID- 27228556 TI - Neuronal Hyperactivity Disturbs ATP Microgradients, Impairs Microglial Motility, and Reduces Phagocytic Receptor Expression Triggering Apoptosis/Microglial Phagocytosis Uncoupling. AB - Phagocytosis is essential to maintain tissue homeostasis in a large number of inflammatory and autoimmune diseases, but its role in the diseased brain is poorly explored. Recent findings suggest that in the adult hippocampal neurogenic niche, where the excess of newborn cells undergo apoptosis in physiological conditions, phagocytosis is efficiently executed by surveillant, ramified microglia. To test whether microglia are efficient phagocytes in the diseased brain as well, we confronted them with a series of apoptotic challenges and discovered a generalized response. When challenged with excitotoxicity in vitro (via the glutamate agonist NMDA) or inflammation in vivo (via systemic administration of bacterial lipopolysaccharides or by omega 3 fatty acid deficient diets), microglia resorted to different strategies to boost their phagocytic efficiency and compensate for the increased number of apoptotic cells, thus maintaining phagocytosis and apoptosis tightly coupled. Unexpectedly, this coupling was chronically lost in a mouse model of mesial temporal lobe epilepsy (MTLE) as well as in hippocampal tissue resected from individuals with MTLE, a major neurological disorder characterized by seizures, excitotoxicity, and inflammation. Importantly, the loss of phagocytosis/apoptosis coupling correlated with the expression of microglial proinflammatory, epileptogenic cytokines, suggesting its contribution to the pathophysiology of epilepsy. The phagocytic blockade resulted from reduced microglial surveillance and apoptotic cell recognition receptor expression and was not directly mediated by signaling through microglial glutamate receptors. Instead, it was related to the disruption of local ATP microgradients caused by the hyperactivity of the hippocampal network, at least in the acute phase of epilepsy. Finally, the uncoupling led to an accumulation of apoptotic newborn cells in the neurogenic niche that was due not to decreased survival but to delayed cell clearance after seizures. These results demonstrate that the efficiency of microglial phagocytosis critically affects the dynamics of apoptosis and urge to routinely assess the microglial phagocytic efficiency in neurodegenerative disorders. PMID- 27228559 TI - Racial disparities in renal cell carcinoma: a single-payer healthcare experience. AB - Significant racial disparities in survival for renal cell carcinoma (RCC) exist between white and black patients. Differences in access to care and comorbidities are possible contributors. To investigate if racial disparities persist when controlling for access to care, we analyzed data from a single-payer healthcare system. As part of a case-control study within the Kaiser Permanente Northern California system, pathologic and clinical records were obtained for RCC cases (2152 white, 293 black) diagnosed from 1998 to 2008. Patient demographics, comorbidities, tumor characteristics, and treatment status were compared. Overall survival and disease-specific survival (DSS) were calculated by the Kaplan-Meier method. A Cox proportion hazards model estimated the independent associations of race, comorbidity, and clinicopathologic variables with DSS. We found that compared to white patients, black patients were diagnosed at a younger age (median 62 vs. 66 years, P < 0.001), were more likely to have papillary RCC (15% vs. 5.2%, P < 0.001), and had similar rates of surgical treatment (78.8% vs. 77.9%, P = 0.764). On multivariate analysis, advanced American Joint Committee on Cancer (AJCC) stage, lack of surgical treatment, larger tumor size, and higher grade were predictors of worse DSS. Race was not an independent predictor of survival. Therefore, we conclude that within a single healthcare system, differences in characteristics of black and white patients with RCC persist; black patients had different comorbidities, were younger, and had decreased tumor stage. However, unlike other series, race was not an independent predictor of DSS, suggesting that survival differences in large registries may result from barriers to healthcare access and/or comorbidity rather than disease biology. PMID- 27228561 TI - Tracheotomy Outcomes in Super Obese Patients. AB - IMPORTANCE: Surgeons need to understand the expected outcomes for super obese patients undergoing tracheotomy to appropriately counsel patients and families about likely risks and benefits. OBJECTIVE: To determine the outcomes, complications, and mortality after tracheotomy in super obese patients (those with a body mass index [BMI] greater than 50). DESIGN, SETTING, AND PARTICIPANTS: A retrospective review was conducted of billing records from a tertiary care academic medical center from November 1, 2010, through June 30, 2013, to identify patients undergoing tracheotomy. Medical records were reviewed to identify patients with a BMI (calculated as weight in kilograms divided by height in meters squared) greater than 50 and a control group with a BMI of 30 to 50. Patient characteristics, including BMI, age, race/ethnicity, primary diagnosis for hospitalization, medical comorbidities, and surgical technique, were measured. MAIN OUTCOMES AND MEASURES: The primary outcome measure was dependence on tracheostomy at discharge. Secondary outcomes included rates of ventilator dependence, mortality, postoperative complications, and discharge disposition. RESULTS: The super obese population included 31 patients and was predominantly African American (20 patients [65%]) and female (21 patients [68%]). Mean BMI of super obese patients was 64.0 (range, 50.2-95.5). The obese patient population was mainly African American (25 patients [74%]) and female (17 patients [50%]). Twenty-five of 31 super obese patients (81%) were discharged with a tracheotomy tube in place, compared with 16 of 34 obese patients (52%). Seven patients (23%) in the super obese group were ventilator dependent at discharge, compared with 4 patients (13%) in the obese group. Only 2 of the super obese patients (3%) were decannulated before discharge, compared with 15 (44%) in the obese group. In hospital mortality was similar for the 2 groups (super obese, 4 patients [13%] and obese, 3 patients [9%]). The overall complication rate was 19% in the super obese group (6 patients) compared with 6% in the obese group (2 patients). Super obese patients were less likely to be discharged to a health care facility (17 patients [55%]) compared with patients in the obese group (22 patients [65%]). CONCLUSIONS AND RELEVANCE: Tracheotomy in super obese patients is a safe and effective strategy for airway management. Critically ill, super obese patients have a high likelihood of remaining dependent on a tracheotomy or ventilator at the time of discharge. PMID- 27228562 TI - eNOS Activity in CAV1 Knockout Mouse Eyes. AB - PURPOSE: To investigate endothelial nitric oxide synthase (eNOS) activity and the response of conventional outflow facility to nitric oxide donors and a nitric oxide synthase (NOS) inhibitor in caveolin-1 (CAV1) knockout (KO) mice. METHODS: Intraocular pressure (IOP) was measured in both CAV1 KO and wild-type (WT) mice by rebound tonometry. The expressions of caveolin-2 (CAV2), eNOS, eNOS-phospho Ser1177, eNOS-phospho Thr495, Akt, Akt-phospho Ser473, and nitrotyrosin were measured by Western blot analysis. Nitric oxide donor sodium nitroprusside (SNP), S-nitroso-N-acetyl-D,L-penicillamine (SNAP), or the NOS inhibitor L-NG Nitroarginine Methyl Ester (L-NAME) were administered topically. The outflow facility was measured by perfusing enucleated mouse eyes at multiple pressure steps. RESULTS: CAV1 KO mice have elevated IOP and reduced conventional outflow facility when compared with WT mice. CAV2 expression was absent in CAV1 KO mice, but we observed increased expressions of eNOS, eNOS-phospho Ser1177, Akt, Akt phospho Ser473, and nitrotyrosin and reduced expression of eNOS-phospho Thr495. Topical application of SNP significantly reduced IOP in WT and KO mice by 1.6 fold (n = 6, P < 0.05), but SNAP did not change IOP significantly (n = 6, P > 0.05). In comparison, the NOS inhibitor L-NAME significantly increased IOP by 50% in KO mice (n = 6, P < 0.05). SNP and SNAP significantly increased, whereas L NAME significantly reduced pressure-dependent drainage in KO animals. CONCLUSIONS: Although CAV1 KO mice had elevated IOP and decreased outflow facility, CAV1 deficiency (and possibly the loss of CAV2) resulted in increased eNOS activity. The pressure elevation may be a result of increased tyrosine nitration of protein kinase K and impairment of its activity in KO mice. PMID- 27228563 TI - Intrinsic "Vacancy Point Defect" Induced Electrochemiluminescence from Coreless Supertetrahedral Chalcogenide Nanocluster. AB - A deep understanding of distinct functional differences of various defects in semiconductor materials is conducive to effectively control and rationally tune defect-induced functionalities. However, such research goals remain a substantial challenge due to great difficulties in identifying the defect types and distinguishing their own roles, especially when various defects coexist in bulk or nanoscale material. Hereby, we subtly selected a molecular-type semiconductor material as structural mode composed of supertetrahedral chalcogenide Cd-In-S nanoclusters (NCs) with intrinsic vacancy point defect at the core site and antisite point defects at the surface of supertetrahedron and successfully established the correlation of those point defects with their own electrochemiluminescence (ECL) behaviors. The multichannel ECL properties were recorded, and the corresponding reaction mechanisms were also proposed. The predominant radiation recombination path of ECL emission peak at 585 nm was significantly distinguished from asymmetrically broad PL emission with a peak at 490 nm. In addition, the ECL performance of the coreless supertetrahedral chalcogenide nanocluster can be modulated by atomically precise doping of monomanganese ion at the core vacant site. A relatively high ECL efficiency of 2.1% was also gained. Actually, this is the first investigation of ECL behavior of semiconductor materials based on supertetrahedral chalcogenide nanocluster in aqueous solution. Current research may open up a new avenue to probe the roles of various different defects with defined composition and position in the NC. The versatile and bright ECL properties of Cd-In-S NC combined with tunable ECL potential and ECL peak suggest that the new kind of NC-based ECL material may hold great promising for its potential applications in electrochemical analysis, sensing, and imaging. PMID- 27228564 TI - Ultrasound in EMG-Guided Biopsies: A Prospective, Randomized Pilot Trial. AB - INTRODUCTION: At our institution, core muscle biopsies are performed on muscles selected using electromyography (EMG). Ultrasound (US) guidance is not used routinely. The aim of this study was to determine if US guidance of EMG selected muscles would increase the diagnostic yield of the biopsy as compared to the current practice standards. METHODS: Two trained physicians performed 40 randomized biopsies (US guided or traditional approach). The amount of tissue obtained in each biopsy was recorded (volume and mass), along with the final pathologic diagnosis in each case and incidence of complications. RESULTS: Forty patients were studied. Sixteen muscle biopsies were done with US guidance; 50% had a definitive diagnosis, and 38% did not. In the non-US guidance group, 58% had a definitive diagnosis, and 33% did not. CONCLUSIONS: US did not provide any additive advantage when used to guide biopsy in a muscle previously selected for biopsy with EMG. Muscle Nerve 54: 786-788, 2016. PMID- 27228560 TI - Crystal Nucleation in Liquids: Open Questions and Future Challenges in Molecular Dynamics Simulations. AB - The nucleation of crystals in liquids is one of nature's most ubiquitous phenomena, playing an important role in areas such as climate change and the production of drugs. As the early stages of nucleation involve exceedingly small time and length scales, atomistic computer simulations can provide unique insights into the microscopic aspects of crystallization. In this review, we take stock of the numerous molecular dynamics simulations that, in the past few decades, have unraveled crucial aspects of crystal nucleation in liquids. We put into context the theoretical framework of classical nucleation theory and the state-of-the-art computational methods by reviewing simulations of such processes as ice nucleation and the crystallization of molecules in solutions. We shall see that molecular dynamics simulations have provided key insights into diverse nucleation scenarios, ranging from colloidal particles to natural gas hydrates, and that, as a result, the general applicability of classical nucleation theory has been repeatedly called into question. We have attempted to identify the most pressing open questions in the field. We believe that, by improving (i) existing interatomic potentials and (ii) currently available enhanced sampling methods, the community can move toward accurate investigations of realistic systems of practical interest, thus bringing simulations a step closer to experiments. PMID- 27228565 TI - Relationship between oxygen saturation of the retinal vessels and visual field defect in glaucoma patients: comparison with each hemifield. AB - PURPOSE: This study aimed to elucidate the relationship between visual field defects in the upper and lower hemifields and the corresponding oxygen saturation of the retinal vessels in patients with glaucoma. METHODS: Patients with glaucoma (n = 44) exhibiting more than a 10 dB difference between the upper and lower total deviation (TD) were enrolled in the study. After measuring the retinal vessel oxygen saturation by a non-invasive spectrophotometric retinal oximeter, the hemifields in one eye of each patient were divided into worse (worse TD) and better (better TD) hemifield areas. We additionally evaluated a separate group of 40 patients with glaucoma who exhibited less than a 5 dB difference between the upper and lower TD. Statistical analysis was performed using a Student's t-test. RESULTS: A higher mean venous saturation of oxygen (SaO2 ) was observed in the worse (59.0 +/- 8.0%) hemifield compared to the better (55.4 +/- 7.2%) hemifield (p < 0.01). The mean arteriovenous difference in the SaO2 was lower in the worse (44.4 +/- 9.0%) hemifield compared to the better (48.6 +/- 11.4%) hemifield (p = 0.02). However, when we evaluated the worse and better hemifields in the patients who had less than a 5 dB difference in the upper and lower hemifield TD, we found no statistically significant differences for either the retinal SaO2 in the venous vessels or the arteriovenous difference. CONCLUSIONS: Advanced glaucomatous visual field defects were associated with increased SaO2 in the venous vessels and a decreased arteriovenous difference in the SaO2 . The present results suggest there is a reduced retinal oxygen extraction in eyes with glaucomatous damage due to retinal ganglion cell loss. PMID- 27228566 TI - HIV infection. PMID- 27228568 TI - Liver Transplantation in Brazil. AB - Over 1700 liver transplantations (LTs) are performed annually in Brazil. In absolute terms, the country performs more LT surgeries than anywhere else in Latin America and is third worldwide. However, due to its increasing population and inadequate donor organ supply, the country averages 5-10 LTs per million population, far lower than required. There is a marked heterogeneity in organ donation and LT activity throughout the country. Access to LT in the underprivileged North, Midwest, and Northeast regions of Brazil is scarce. Major challenges for the future of LT in Brazil will be to increase organ donation and access to LT. The reduction of those geographical disparities in donation, organ procurement, and LT due to political and financial constraints is of utmost importance. Liver Transplantation 22 1254-1258 2016 AASLD. PMID- 27228567 TI - Hypoxia induces myeloid-derived suppressor cell recruitment to hepatocellular carcinoma through chemokine (C-C motif) ligand 26. AB - A population of stromal cells, myeloid-derived suppressor cells (MDSCs), is present in tumors. Though studies have gradually revealed the protumorigenic functions of MDSCs, the molecular mechanisms guiding MDSC recruitment remain largely elusive. Hypoxia, O2 deprivation, is an important factor in the tumor microenvironment of solid cancers, whose growth often exceeds the growth of functional blood vessels. Here, using hepatocellular carcinoma as the cancer model, we show that hypoxia is an important driver of MDSC recruitment. We observed that MDSCs preferentially infiltrate into hypoxic regions in human hepatocellular carcinoma tissues and that hypoxia-induced MDSC infiltration is dependent on hypoxia-inducible factors. We further found that hypoxia-inducible factors activate the transcription of chemokine (C-C motif) ligand 26 in cancer cells to recruit chemokine (C-X3-C motif) receptor 1-expressing MDSCs to the primary tumor. Knockdown of chemokine (C-C motif) ligand 26 in cancer cells profoundly reduces MDSC recruitment, angiogenesis, and tumor growth. Therapeutically, blockade of chemokine (C-C motif) ligand 26 production in cancer cells by the hypoxia-inducible factor inhibitor digoxin or blockade of chemokine (C-X3-C motif) receptor 1 in MDSCs by chemokine (C-X3-C motif) receptor 1 neutralizing antibody could substantially suppress MDSC recruitment and tumor growth. CONCLUSION: This study unprecedentedly reveals a novel molecular mechanism by which cancer cells direct MDSC homing to primary tumor and suggests that targeting MDSC recruitment represents an attractive therapeutic approach against solid cancers. (Hepatology 2016;64:797-813). PMID- 27228569 TI - Immunotherapy, asthma and community allergic reactions to food. PMID- 27228570 TI - What do we mean by oral tolerance? PMID- 27228571 TI - Depression or anxiety in adult twins is associated with asthma diagnosis but not with offspring asthma. AB - BACKGROUND: Asthma is common in both children and adults in the Western world, just like anxiety and depression. While some research has revealed that these diseases might share important environmental and pathophysiological aspects, the exact mechanisms still remain unclear. OBJECTIVE: To study the correlation firstly between depression or anxiety and asthma diagnosis in adult twins and secondly the association between parental depression or anxiety and offspring asthma in children of twins. METHODS: In total, 24 685 adult twins aged 20-47 years were interviewed or completed a Web-based questionnaire and their children were identified through the Multi-Generation Register. Asthma diagnosis was obtained from the Patient Register and the Prescribed Drug Register. Assessment of depression and anxiety was obtained from questionnaires using Center for Epidemiologic Studies Depression Scale (CES-D), major depression and generalized anxiety disorder (GAD) from DSM-IV. The association between depression or anxiety and asthma was analyzed with logistic regression adjusting for confounders in twins and offspring. To address genetic and familial environmental confounding, we performed a cotwin analysis using disease-discordant twin pairs. RESULTS: We found an association between asthma and CES-D, major depression and GAD, for example adjusted OR for major depression and register-based asthma 1.56 (1.36 1.79). Most of the point estimates remained in the co-twin control analysis, indicating that the association was likely not due to genetic or familial environmental factors. There was no association between parental depression and/or anxiety and asthma diagnosis in the offspring which implies lack of genetic confounding. CONCLUSIONS: We found an association between own asthma diagnosis and anxiety or depression, but not with offspring asthma. Our results indicate that the associations were not due to confounding from genes or environment shared by the twins. PMID- 27228572 TI - A proteomics analysis reveals that A2M might be regulated by STAT3 in persistent allergic rhinitis. AB - BACKGROUND: Proteomics tools can be used to identify the differentially expressed proteins related to allergic rhinitis (AR). However, the large numbers of proteins related to AR have not yet been explored using an advanced quantitative proteomics approach, known as isobaric tags for relative and absolute quantitation (iTRAQ). OBJECTIVES: To identify differentially expressed proteins in persistent AR patients and to explore the regulatory signalling pathways involving the identified proteins. METHODS: Forty-five persistent AR patients and 20 healthy controls were recruited for this study. iTRAQ was used to identify the proteins that were differentially expressed between these two groups, and a bioinformatics analysis was then conducted to identify the signalling pathways associated with the identified proteins. Immunofluorescence labelling was performed to detect alpha-2-macroglobulin (A2M), STAT3, p-STAT3 and IL17 in the nasal mucosa. RESULTS: A total of 133 differentially expressed proteins were identified. We then determined the top 10 regulatory pathways associated with these proteins and found that the blood coagulation pathway had the most significant association. A2M, a protein involved in the blood coagulation pathway, was found to be differentially expressed in the serum of AR patients. The bioinformatics analysis indicated that STAT3 is an upstream transcription factor that might regulate A2M expression. An immunofluorescence study further confirmed that STAT3 and A2M are co-localized in nasal mucosa cells. Additionally, A2M, STAT3, p-STAT3, and IL17 are elevated in AR patients. The expressional level of A2M is positively related to IL17 and the symptom of the congestion in AR subjects. CONCLUSIONS: The blood coagulation pathway may be a key regulatory network pathway contributing to the allergic inflammatory response in AR patients. A2M, which is regulated by STAT3, may be an important protein in the pathogenesis of allergic rhinitis in AR patients. PMID- 27228574 TI - Genomic Imprinting: A New Epigenetic Perspective of Sleep Regulation. PMID- 27228575 TI - The effect of amifostine on differentiation of the human megakaryoblastic Dami cell line. AB - Amifostine is a cytoprotective drug that was initially used to control and treat nuclear radiation injury and is currently used to provide organ protection in cancer patients receiving chemotherapy. Clinical studies have also found that amifostine has some efficacy in the treatment of cytopenia caused by conditions such as myelodysplastic syndrome and immune thrombocytopenia, both of which involve megakaryocyte maturation defects. We hypothesized that amifostine induced the differentiation of megakaryocytes and investigated this by exposing the human Dami megakaryocyte leukemia cell line to amifostine (1 mmol/L). After 12 days of amifostine exposure, optical microscopy showed that the proportion of Dami cells with diameters >20 MUm had increased to 24.63%. Transmission electron microscopy identified the development of a platelet demarcation membrane system, while flow cytometry detected increased CD41a expression and decreased CD33 expression on the Dami cell surface. Ploidy analysis found that the number of polyploid cells with >4N DNA content increased to 27.96%. We did not detect any elevation in the mRNA or protein levels of megakaryocytic differentiation-associated transcription factors GATA-binding factor 1 (GATA-1) and nuclear factor, erythroid 2 (NF-E2), but nuclear import assay revealed an increased nuclear translocation of these proteins. These findings indicate that amifostine induced the differentiation of Dami cells into mature megakaryocytes via a mechanism involving increased nuclear translocation of the transcription factors, NF-E2 and GATA-1. PMID- 27228576 TI - Managing Work Across Shifts: Not All Shifts Are Equal. AB - PURPOSE: Despite the prevalence of shiftwork, the mechanisms underlying its effects on nurses' well-being and adaptation to the shifts are not fully understood. This study examines whether the characteristics of the person, particularly chronotype, and aspects of the situation (i.e., shift schedule and the nature of work on each shift for each work context) affect job-specific and general well-being above and beyond potential confounds such as age and negative affectivity (NA). DESIGN: Primarily surveys of Australian nurses (N = 446) in three contexts (general acute hospital, maternity hospital, aged care). CONCLUSIONS: The findings highlight the role of nurses' dispositional characteristics, especially NA and in certain contexts chronotype, as well as the need to consider the nature of the work conducted on each shift within a context. CLINICAL RELEVANCE: Nurse managers need to consider the nature of the work conducted on each shift, whether to look at balancing workloads or setting up processes for handling spikes in workload, especially administration. PMID- 27228577 TI - Rapid evolutionary dynamics in a 2.8-Mb chromosomal region containing multiple prolamin and resistance gene families in Aegilops tauschii. AB - Prolamin and resistance gene families are important in wheat food use and in defense against pathogen attacks, respectively. To better understand the evolution of these multi-gene families, the DNA sequence of a 2.8-Mb genomic region, representing an 8.8 cM genetic interval and harboring multiple prolamin and resistance-like gene families, was analyzed in the diploid grass Aegilops tauschii, the D-genome donor of bread wheat. Comparison with orthologous regions from rice, Brachypodium, and sorghum showed that the Ae. tauschii region has undergone dramatic changes; it has acquired more than 80 non-syntenic genes and only 13 ancestral genes are shared among these grass species. These non-syntenic genes, including prolamin and resistance-like genes, originated from various genomic regions and likely moved to their present locations via sequence evolution processes involving gene duplication and translocation. Local duplication of non-syntenic genes contributed significantly to the expansion of gene families. Our analysis indicates that the insertion of prolamin-related genes occurred prior to the separation of the Brachypodieae and Triticeae lineages. Unlike in Brachypodium, inserted prolamin genes have rapidly evolved and expanded to encode different classes of major seed storage proteins in Triticeae species. Phylogenetic analyses also showed that the multiple insertions of resistance-like genes and subsequent differential expansion of each R gene family. The high frequency of non-syntenic genes and rapid local gene evolution correlate with the high recombination rate in the 2.8-Mb region with nine-fold higher than the genome-wide average. Our results demonstrate complex evolutionary dynamics in this agronomically important region of Triticeae species. PMID- 27228579 TI - Correlation and linear regression. PMID- 27228578 TI - The genome of black raspberry (Rubus occidentalis). AB - Black raspberry (Rubus occidentalis) is an important specialty fruit crop in the US Pacific Northwest that can hybridize with the globally commercialized red raspberry (R. idaeus). Here we report a 243 Mb draft genome of black raspberry that will serve as a useful reference for the Rosaceae and Rubus fruit crops (raspberry, blackberry, and their hybrids). The black raspberry genome is largely collinear to the diploid woodland strawberry (Fragaria vesca) with a conserved karyotype and few notable structural rearrangements. Centromeric satellite repeats are widely dispersed across the black raspberry genome, in contrast to the tight association with the centromere observed in most plants. Among the 28 005 predicted protein-coding genes, we identified 290 very recent small-scale gene duplicates enriched for sugar metabolism, fruit development, and anthocyanin related genes which may be related to key agronomic traits during black raspberry domestication. This contrasts patterns of recent duplications in the wild woodland strawberry F. vesca, which show no patterns of enrichment, suggesting gene duplications contributed to domestication traits. Expression profiles from a fruit ripening series and roots exposed to Verticillium dahliae shed insight into fruit development and disease response, respectively. The resources presented here will expedite the development of improved black and red raspberry, blackberry and other Rubus cultivars. PMID- 27228580 TI - [No. 34 GOA applies more often than one thinks]. PMID- 27228581 TI - [Send collection agency to defaulting debtors?]. PMID- 27228582 TI - Regeneration and Carcinogenesis. AB - INTRODUCTION: Once people reach 40 years of age, they have a decrease in their pool of pluripotent stem cells, and an increased risk for development of oncological diseases. MATERIALS AND METHODS: The first part of the study was conducted in 11 patients aging 54 to 76 years old with cancer of the kidney, bladder, or prostate in stages III-IV of the disease. The second part of the study was conducted in four patients aged 60-82 years old, who were given from 4 to 7 transfusions of mononuclear fraction of peripheral blood from young donors 19-23 years old, with the same sex and blood types as the recipients, in order to restore cell regeneration. RESULTS: In the first part of the study, 1 month after chemotherapy or targeted therapy, all 11 cancer patients had leukopenia accompanied by an increase in the contents of FGFb in the blood by 1.74 times on average. Four of these patients had an increase in the level of human VEGF-A of 1.25 times on average, while three patients had an increase in the level of human EGF of 1.13 times on average. In the second part of the study, 3-6 months after the completion of a cycle of 4-7 blood transfusions of mononuclear fraction of periphery blood, four patients had an in increase in the contents of hematopoietic progenitor cells CD34+ of periphery blood by 3.25 times on average, to the level normal in young people, while the level of FGFb decreased by 1.78 times on average. Among two patients, the level of human VEGF-A decreased by 1.48 times on average, while for three patients the level of human EGF decreased by 4.12 times on average. In the buccal epithelium, all four patients had a decrease in the expression of p53 by 6.02 times on average, while three of them had a decrease in the expression of Bcl-2 by 60.0 times on average. CONCLUSION: Violation of tissue renewal is a major cause of carcinogenesis in people older than 40 years old. Excessive stimulation of mitotic activity among people over 40 can be reduced to normal levels by restoring the pool of pluripotent stem cells through transfusion of mononuclear fraction of peripheral blood from young donors 18-23 years old with the same blood groups and sex as the recipient (RF patent number 2350340). PMID- 27228583 TI - [No immunosuppressants in IgA nephritis]. PMID- 27228584 TI - [Peppermint oil solution is convincing in an observational study]. PMID- 27228585 TI - [Anti-angina fixed combination is available]. PMID- 27228586 TI - [Characteristics of CO2 flux in an old growth mixed forest in Tianmu Mountain, Zhejiang, China]. AB - The old-growth, multiple ages, multispecies natural forest has played an important role in terrestrial ecosystem dynamics model and the global carbon budget. However, carbon fluxes of old forests in subtropical regions are rarely reported in China. In the present study, the CO2 flux of an old-growth subtropical evergreen and deciduous broad-leaved mixed forest was observed using eddy covariance technique in Tianmu Mountain of Zhejiang Province. Based on the data sets which were observed from July 2013 to June 2014, the variations of net ecosystem exchange (NEE), eco-system respiration (Re), and gross ecosystem exchange (GEE) were analyzed. The results showed that during the study period, the monthly NEE all had a negative value (acted as a carbon sink) except for December and February (acted as a carbon source). The average monthly NEE was 61.52 g C . m-2, the monthly carbon sequestration showed a double-peak curve and the maximum carbon sink was -149.40 g C . m-2, which occurred in June while the maximum carbon source was 23.45 g C . m-2, which occurred in February. The maximum of monthly mean CO2 flux occurred in June with a value of -0.98 mg . m-2 . s-1, while the minimum value occurred in December with a value of -0.35 mg . m 2 . s-1. The NEE at the time point of positive and negative conversion had typical seasonal characteristics. The yearly NEE, Re, and GEE were -738.18, 931.05 and -1669.23 g C . m-2, respectively. Compared with other forest ecosystems located at the similar latitude, the carbon fixation of the old-growth forest was larger, likely due to its complicated structure within the canopy and the presence of young-growth regeneration and successional stands. This showed that other than in carbon neutral, old-growth forests of Tianmu Mountain in subtropical China had a strong capability in carbon sequestration. PMID- 27228587 TI - [Seasonal dynamics of soil organic carbon mineralization for two forest types in Xiaoxing'an Mountains, China]. AB - To investigate the seasonal dynamics of soil organic carbon (SOC) mineralization in Xiaoxing'an Mountain, we incubated soil samples collected from virgin Korean pine forest and broad-leaved secondary forest in different seasons in the laboratory and measured the SOC mineralization rate and cumulative SOC mineralization (Cm). We employed simultaneous reaction model to describe C mineralization kinetics and estimated SOC mineralization parameters including soil easily mineralizable C (C1), potentially mineralizable C (C0). We also analyzed the relations between Cm, C1and their influencing factors. Results showed that the incubated SOC mineralization rate and Cm for 0-5 cm soil layer decreased from early spring to late autumn, while for 5-10 cm soil layer the seasonal variation was not statistically significant for both forest types. The C1 in 0-5 and 5-10 cm soil layers varied from 42.92-92.18 and 19.23-32.95 mg kg 1, respectively, while the C0 in 0-5 and 5-10 cm soil layers varied from 863.92 3957.15 and 434.15-865.79 mg . kg-1, respec- tively. Both C1 and C0 decreased from early spring to late autumn. The proportions of C0 in SOC for two forest types were 0.74%-2.78% and 1.11%-1.84% in 0-5 and 5-10 cm soil layers, respectively, and decreased from early spring to late autumn, indicating that SOC tended to become more stable as a whole from spring to autumn. The Cm and C0 were significantly positively correlated to in situ soil water content and hot water extractable carbohydrate content, but were not correlated to in situ soil temperature and cool water-extractable carbohydrate content. We concluded that soil labile organic carbon, soil physical and chemical properties contributed to the seasonal dynamics of SOC mineralization in the forests. PMID- 27228588 TI - [Temperature sensitivity of soil organic carbon mineralization and beta glucosidase enzymekinetics in the northern temperate forests at different altitudes, China]. AB - Soil samples, which were collected from three typical forests, i.e., Betula ermanii forest, coniferous mixed broad-leaved forest, and Pinus koraiensis forest, at different altitudes along the southern slope of Laotuding Mountain of Changbai Mountain range in Liaoning Province of China, were incubated over a temperature gradient in laboratory. Soil organic carbon mineralization rates (Cmin), soil beta-1,4-glucosidase (betaG) kinetics and their temperature sensitivity (Q10) were measured. The results showed that both altitude and temperature had significant effects on Cmin . Cmin increased with temperature and was highest in the B. ermanii forest. The temperature sensitivity of Cmin [Q10(Cmin)] ranked in order of B. ermanii forest > P. koraiensis forest > coniferous mixed broad-leaved forest, but did not differ significantly among the three forests. Both the maximum activity (Vmax) and the Michaelis constant (Km) of the betaG responded positively to temperature for all the forests. The temperature sensitivity of Vmax [Q10(Vmax)] ranged from 1.78 to 1.90, and the temperature sensitivity of Km [Q10(Km)] ranged from 1.79 to 2.00. The Q10(Vmax)/Q10(Km) ratios were significantly greater in the B. ermanii soil than in the other two forest soils, suggesting that the betaG kinetics-dependent impacts of the global warming or temperature increase on the decomposition of soil organic carbon were temperature sensitive for the forests at the higher altitudes. PMID- 27228589 TI - [Impact of micro-landform on grassland plant comniunity structure and function in the hilly Loess Plateau region, China]. AB - In order to analyze the impact of micro-landform on grassland plant community structure and function, species composition, aboveground and belowground biomass, and annual fine root production at different slope aspects (sunny slope and shady slope) and different slope positions (top, upper, middle and lower) were investigated in the hilly Loess Plateau region. The results showed that grassland communities were mainly composed of plants species belonging to Compositae, Poaceae and Leguminosae. The aboveground and belowground biomass and annual fine root production of community were 164.12 g . m-2, 1044.87 g . m-2 and 731.77 g . m-2 . a-1, respectively. Aboveground biomass, belowground biomass and annual fine root production of community were in the order of shady slope > sunny slope > top slope. In shady slope, the biomass of community under different positions were in the order of lower > middle > upper > top, but it exhibited different orders in the sunny slope compared with shady slope. Fine root mainly concentrated in the 0 20 cm top soil layer and decreased with soil depth. The average turnover time of root was 0.75 a-1 and changed with soil layers and micro-landform. PMID- 27228590 TI - [Difference of anti-fracture mechanical characteristics between lateral-root branches and adjacent upper straight roots of four plant species in vigorous growth period]. AB - Taking four plant species, Caragana korshinskii, Salix psammophila, Hippophae rhamnides and Artemisia sphaerocephala, which were 3-4 years old and in vigorous growth period, as test materials, the anti-fracture forces of lateral-root branches and adjacent upper straight roots were measured with the self-made fixture and the instrument of TY 8000. The lateral-root branches were vital and the diameters were 1-4 mm. The results showed that the anti-fracture force and anti-fracture strength of lateral-root branches were lesser than those of the adjacent upper straight roots even though the average diameter of lateral-root branches was greater. The ratios of anti-fracture strength of lateral-root branches to the adjacent upper straight roots were 71.5% for C. korshinskii, 62.9% for S. psammophila, 45.4% for H. rhamnides and 35.4% for A. sphaerocephala. For the four plants, the anti-fracture force positively correlated with the diameter in a power function, while the anti-fracture strength negatively correlated with diameter in a power function. The anti-fracture strengths of lateral-root branches and adjacent upper straight roots for the four species followed the sequence of C. korshinskii (33.66 and 47.06 MPa) > S. psammophila (17.31 and 27.54 MPa) > H. rhamnides (3.97 and 8.75 MPa) > A. sphaerphala (2.18 and 6.15 MPa). PMID- 27228591 TI - [Early selection of drought-resistant superior families of Reaumuria soongorica based on the analysis of osmoregulation substances and chlorophyll]. AB - By using 77 families of 3 year-old Reaumuria soongorica seedlings that grew well without injection of any pests and diseases as experimental material, the contents of soluble protein (SP), soluble sugar (SS), proline (Pro) and chlorophyll (Chl) were measured, and their drought resistance was evaluated with principal component analysis and subordinate function method. The results showed that there were great differences in leaf osmolytes and chlorophyll among the 77 families. The soluble protein content varied from 2.14 to 8.60 mg . g-1 FM, the soluble sugar content was from 6.82 to 21.86 mg . g-1 FM, the proline content was from 118.73 to 1494.30 ug . g-1 FM, the chlorophyll a content was from 321.88 to 897.37 ug . g-1 FM, the chlorophyll b content was from 53.65 to 249.04 ug . g-1 FM, chlorophyll (a+b) was from 387.39 to 1146.40 ug . g-1 FM, and the chlorophyll a/b was from 3.46 to 6.42. All drought-resistant indices had significant difference among R. soongorica families, among which the proline content varied most, followed by the soluble sugar content. Evaluated by using the synthesized multi-index, it was found that 12 families showed good drought resistance, with Zhazigou 1-2 and Zhazigou 1-1 performing the best. PMID- 27228592 TI - [Retrieval of leaf net photosynthetic rate of moso bamboo forests using hyperspectral remote sen-sing based on wavelet transform]. AB - This study focused on retrieval of net photosynthetic rate (Pn) of moso bamboo forest based on analysis of wavelet transform on hyperspectral reflectance data of moso bamboo forest leaf. The result showed that the accuracy of Pn retrieved by the ideal high frequency wavelet vegetation index ( VI) was higher than that retrieved by low frequency wavelet VI and spectral VI. Normalized difference vegetation index of wavelet (NDVIw), simple ratio vegetation index of wavelet (SRw) and difference vegetation index of wavelet (Dw) constructed by the first layer of high frequency coefficient through wavelet decomposition had the highest relationship with Pn, with the R2 of 0.7 and RMSE of 0.33; low frequency wavelet VI had no advantage compared with spectral VI. Significant correlation existed between Pn estimated by multivariate linear model constructed by the ideal wavelet VI and the measured Pn, with the R2 of 0.77 and RMSE of 0.29, and the accuracy was significantly higher than that of using the spectral VI. Compared with the fact that sensitive spectral bands of the retrieval through spectral VI were limited in the range of visible light, the wavelength of sensitive bands of wavelet VI ranged more widely from visible to infrared bands. The results illustrated that spectrum of wavelet transform could reflect the Pn of moso bamboo more in detail, and the overall accuracy was significantly improved than that using the original spectral data, which provided a new alternative method for retrieval of Pn of moso bamboo forest using hyper spectral remotely sensed data. PMID- 27228593 TI - [Effects of rootstocks on the growth and berry quality of Vitis vinifera cv. Cabernet Sauvignon grapevine in Changli zone, Hebei Province, China]. AB - Cabernet Sauvignon grafted onto seven rootstocks 188-08, 5BB, SO4, 3309C, 110R, 5C and 101-14M, with the own-rooted vines as control, were investigated to study the effects of different rootstocks on the growth, fruit quality and yield of Cabernet Sauvignon in Changli zone, Hebei Province, China. The results showed that Cabernet Sauvignon grafted on 5BB and 5C significantly increased the trunk diameter, and 5C significantly increased one-year-old shoot diameter. 188-08, 5BB and 5C as rootstock obviously improved berry soluble solid content, in addition 188- 08 and 5BB significantly increased berry reducing sugar content. The vines on 101-14M and 3309C significantly decreased berry titratable acid content. The rootstock 5C and 101-14M significantly raised grape skin phenol and anthocyanin contents, and rootstock 101-14M significantly increased tannin content in grape skin. Cabernet Sauvignon grafted onto 3309C, 110R, 5C and 101-14M obviously got higher yield per vine than own-rooted vines. Growing parameter, grape quality index and yield per vine grafted on seven rootstocks and own-rooted vine were synthetically evaluated by fuzzy evaluation method, and the synthetical effects of vine grafted on seven rootstocks were better than own-rooted vine, with the order of scores from high to low as 5C, 101-14M, 3309C, 5BB, 188-08, 110R and SO4 under Changli unique climate and environment conditions. PMID- 27228594 TI - [Soil anti-erodibility of abandoned lands during different succession stages of plant community in hilly-gullied region of the Loess Plateau: Take Fangta small watershed as an example]. AB - Field survey and laboratory experiment were conducted to study the soil anti erodibility of abandoned croplands during different vegetation succession stages in hilly-gullied region of the Loess Plateau, based on the analysis of soil particle composition, size distribution and group characteristics, soil aggregate fractal dimensions and stability. The results showed that in the earlier stages of succession from annual to perennial herbs in abandoned croplands, soil size distribution changed a little bit, the fractal dimension of soil particle increased, soil structure improved, fractal dimension and damage percent of soil aggregate structure decreased, soil stability increased, thus soil anti erodibility increased. Therefore, natural restoration of vegetation is of great significance to improve the soil structure, increase soil erosion resistance, reduce soil erosion and promote sustainable development of regional ecological environment. PMID- 27228595 TI - [Spatio-temporal change of sand-fixing function and its driving forces in desertification control ecological function area of Hunshandake, China]. AB - Soil erosion is an important ecological and environmental problem in Hunshandake Desert, and the sand-fixing function determines the degree of ecological security in the entire region. In order to clarify the situation of windbreak and sand fixation in Hunshandake area, and to guide the prevention and treatment of desertification on regional scale, based on the meteorological and remote sensing data, this paper quantitatively analyzed the temporal and spatial pattern of windbreak and sand fixation ability between 2000-2010 by the revised wind erosion equation (RWEQ) model, meanwhile, the driving forces for each county ( or banner) in the functional zone were analyzed with the method of principal component analysis. The results showed that there was a fluctuation of the sand fixing capacity in Hunshandake over time, generally rendering a decline trend. The coniferous forest and grassland had strong windbreak and sand fixation capacity in unit area among the various land categories. In terms of spatial distribution, the windbreak and sand fixation function in western and southeastern region was weak and needed to be strengthened with ecological restoration efforts. Through the study of the social driving forces of each administrative region in the function zone, there were 3 main social driving forces of soil erosion in the administrative functions: the intensity of input-output, the level of economic development and the level of agriculture-husbandry development. PMID- 27228596 TI - [Distribution characteristics of soil organic carbon under different forest restoration modes on opencast coal mine dump]. AB - The content and storage of soil organic carbon (SOC) were compared in six wood restoration modes and adjacent abandoned land on opencast coal mine dump, and the mechanisms behind the differences and their influencing factors were analyzed. Results showed that the contents of SOC in six wood lands were significantly higher (23.8%-53.2%) than that of abandoned land (1.92 g . kg-1) at 0-10 cm soil depth, the index were significantly higher (5.8%-70.4%) at 10-20 cm soil depth than the abandoned land (1.39 g . kg-1), and then the difference of the contents of SOC in the deep soil (20-100 cm) were not significant. The contents of SOC decreased with increase of soil depth, but the decreasing magnitude of the topsoil (0-20 cm) was higher than that of the deep soil (20-100 cm). Compared with the deep soil, the topsoil significant higer storage of SOC in different woods, the SOC storage decreased with the soil depth. Along the 0-100 cm soil layer, the storage of SOC in six wood lands higher (18.1%-42.4%) than that of the abandoned land (17.52 t . hm-2). The SOC storage of Amorpha fruticosa land (24.95 t . hm-2) was obviously higher than that in the other wood lands. The SOC storage in the shrub lands was 12.4% higher than that of the arbor woods. There were significantly positive correlations among forest litter, fine root biomass, soil water content and SOC on the dump. Consequently, different plantation restorations significantly improved the SOC level on the dump in 0-100 cm soil, especially the topsoil. But there was still a big gap about SOC level between the wood restoration lands and the original landform. To improve the SOC on opencast coal mine dump, A. fruticosa could be selected as the main wood vegetation. PMID- 27228597 TI - [Effects of different re-vegetation patterns on soil organic carbon and total nitrogen in the wind-water erosion crisscross region, China]. AB - This study was conducted to analyze the responses of soil organic carbon (SOC) and total nitrogen (TN) to three typical re-vegetation patterns, i.e., grassland, alfalfa land and peashrub land on the Loess Plateau of China, and also to assess the dynamics of SOC and TN with re-vegetation age. The results showed that all the three re-vegetation practices increased the concentrations of SOC and TN in the 0-10 cm soil layer, but their effects differed with re-vegetation age. Compared with adjacent croplands, the concentrations of SOC and TN in the 0-10 cm soil layer in grassland did not change within 10 years of succession, but increased after 20 years of succession. In alfalfa land, the concentrations of SOC and TN increased by 51.6%-82.9% and 43.4%-67.0% in the 0-10 cm soil layer, with the increasing rates of stocks of SOC and TN being 0.17-0.46 and 0.015-0.043 t . hm-2 . a-1, respectively. However, SOC and TN were not affected by re vegetation age in alfalfa land. The increases of concentrations of SOC and TN remained high in the first 20 years after conversion of cropland to peashrub land, but decreased after 40 years of conversion. In conclusion, the conversion of croplands to peashrub or alfalfa land could be better in contributing to high stocks of SOC and TN than natural succession of grassland. However, their positive effects on the enrichment of SOC and TN may not be sustainable due to the scarcity of soil moisture and high water consumption of these two re vegetation plants. PMID- 27228598 TI - [Effects of different rotation systems on greenhouse gas (CH4 and N2O) emissions in the Taihu Lake region, China]. AB - We conducted a greenhouse gas emissions study of different rice-based cropping systems in the Taihu Lake region. The results indicated that the seasonal CH4 emission initially increased, but declined over time. CH4emission mainly occurred during the early stages of rice growth and decreased after the paddy soil dried. N2O emission mainly occurred during the fertilizer application and paddy field drying stages. Compared with N20 emission, CH4 emission contributed significantly more to the global warming potential (GWP) during the rice season. The proportion of CH4 emission to the total greenhouse gas emissions, which this study aimed to reduce, ranged from 94.7%-99.6%. CH4emissions and their GWP during the rice season varied significantly under different rotation systems, with the order of wheat-rice rotation>Chinese milk vetch-rice rotation>fallow-rice rotation, while the N2O emissions and their GWP exhibited no significant differences. Compared with no nitrogen fertilization, applying N fertilizer significantly reduced CH4 emission and GWP of the Chinese milk vetch-rice rotation. However, CH4 emission and GWP did not vary with N application rates. The rice yield was largest when the N application rate was 240 kg . hm-2. Taking economic and environmental benefits into account, we found that a N application rate of 240 kg . hm-2 and a straw-return application of Chinese milk vetch not only reduced greenhouse gas emissions but also achieved the highest rice grain yield, which was recommended as a suitable cropping system for the Taihu Lake region. PMID- 27228599 TI - [Influences of water-saved and nitrogen-reduced practice on soil microbial and microfauna assemblage in paddy field]. AB - The resource and environmental problems caused by excessive consumption of water and fertilizer in rice production have recently aroused widespread concern. This study investigated the effects of irrigation modes (conventional irrigation and 25% water-saved irrigation) and different N application rates (conventional high nitrogen fertilization and 40% nitrogen-reduced fertilization) on microbial and microfauna assemblages at tillering and ripening stages in paddy field. The results showed that compared with conventional irrigation (CF), water-saved irrigation (WS) decreased the soil pH at tillering stage. Soil dissolved organic matter (dissolved organic C and N) and microbial biomass C and N were significantly affected by irrigation, nitrogen fertilizer and their interactions. WS or N-reduced fertilization (LN) decreased the contents of dissolved organic matter; WS increased microbial biomass C but decreased microbial biomass N. Nitrate was significantly higher in WS than CF, while ammonium showed reverse pattern. At tillering stage, the soil microbial biomass from bacteria, fungi, actinomy and protozoa was higher in WS than in CF, but the trend was opposite at ripening stage. There was a significant interation between irrigation and fertilization on soil rotifer numbers and microbial-feeding nematodes. At tillering stage, WS increased the numbers of rotifer and nematode, and also the proportion of bacterial-feeding nematode; LN increased the abundance of rotifer but decreased the abundance of nematode. In summary, soil microbial and microfauna assemblages showed different response to water-saved and nitrogen reduced agricultural managements, which depended on different crop growth stages, but also the complex interactions of water and nitrogen and between biological groups in food webs. PMID- 27228600 TI - [Relationships of water conservation through mulching in fallow period with wheat nitrogen transportation and crop yield in dryland]. AB - Field experiments were carried out to study the effects of different mulching times (30 or 60 d after previous wheat harvest) and mulching methods (whole mulching, half-mulching and no- mulching) on wheat plant N absorption and assimilation after deep plowing in fallow period on dryland. The results showed that mulching improved water storage efficiency in fallow period and soil water storage of 0-300 cm at sowing stage significantly. Mulching in fallow period, especially the whole-mulching, increased the N accumulation amount of each growth stage, N translocation amount and rate before anthesis (NABA) , and N accumulation amount after anthesis (NAAA) and grain N. Yield, N uptake efficiency (NUPE), N partial factor productivity (NPFP) and N harvest index (NHI) were all significantly increased under mulching, and whole-mulching had better effects. Mulching at 30 d after previous wheat harvest significantly increased the soil water storage of 0-300 cm at sowing stage and the water storage efficiency in fallow period compared with mulching at 60 d after previous wheat harvest. Compared with mulching at 60 d after previous wheat harvest, mulching at 30 d increased the N accumulation amount of each growth stage, the N accumulation amount in leaf and shoot at maturity, the NABA of stem + sheath, leaf and shoot and the yield. The soil water at the depth of 0-300 cm at sowing stage was positively correlated to N mobilization amount before anthesis and N accumulation amount after anthesis. The N mobilization amount of stem + sheath had a remarkable direct effect on its yield with the direct path coefficient of 0.619. In summary, mulching in fallow period increased the soil moisture at sowing stage to promote N absorption and utilization, increase yield and improve quality, and whole-mulching in advance had better effects. PMID- 27228601 TI - [Effects of different fertilization regimes on weed communities in wheat fields under rice-wheat cropping system]. AB - To reveal the effects of different fertilization regimes on weed communities in wheat fields under a rice-wheat rotation system, a survey was conducted before wheat harvest in 2014 after a 4-year long-term recurrent fertilization scheme. Weed species types, density, height and diversity index under different fertilization and straw-returning schemes in wheat fields were studied and complemented with a canonical correspondence analysis on weed community distribution and soil nutrient factors. Twenty weed species were recorded among 36 wheat fields belonging to 19 genera and 11 families. Beckmannia syzigachne, Hemistepta lyrata, Malachium aquaticum and Cnidium monnieri were widely distributed throughout the sampled area. Long-term fertilization appeared to reduce weed species richness and density, particularly for broadleaf weeds, but increased weed height. Diversity and evenness indices of weed communities were lower and dominance indices were higher in fields where chemical fertilizers were applied alone or combined with organic fertilizers, especially, where organic inorganic compound fertilizer was used, in which it readily caused the outbreak of a dominant species and severe damage. Conversely, diversity and evenness indices of weed communities were higher and dominance indices were lower when the straw was returned to the field combined with chemical or organic fertilizers, in which weed community structures were complex and stable with lower weed density. Under these conditions weeds only caused slight reduction of wheat growth. PMID- 27228602 TI - [Flag leaf photosynthetic characteristics, change in chlorophyll fluorescence parameters, and their relationships with yield of winter wheat sowed in spring]. AB - With five good winter wheat cultivars selected from the middle and lower reaches of Yangtze River and Southwest China as test materials, a field experiment in Xinding basin area of Shanxi Province was conducted to study the photosynthetic characteristics, chlorophyll content, and chlorophyll fluorescence parameters of flag leaf at different sowing dates, as well as the correlations between these indices and yield for two years (2013-2014). The results showed that the difference in most fluorescence parameters except chlorophyll content among cultivars was significant. The correlations between these fluorescence parameters and yield were significant. The variation coefficient of chlorophyll (Chl) content was low (0.12-0.17), and that of performance index based on absorption (PIabs) was high (0.32-0.39), with the partial correlation coefficients of them with grain yield from 2013 to 2014 ranged in 0.70-0.81. Under the early sowing condition, the grain yield positively correlated with PIabs at flowering and filling stages and chlorophyll content at grain filling stage, but negatively correlated with the relative variable fluorescence at I point (Vi) at grain filling stage. About 81.1%-82.8% of grain yield were determined by the variations of PIabs, Chl, and Vi. Wheat cultivars had various performances in the treatments with different sowing dates and a consistent trend was observed in the two experimental years. Among these 5 cultivars, Yangmai 13 was suitable for early sowing, with the flag leaf photosynthetic rate (Pn), Chl, most fluorescence parame-ters, and grain yield showed obviously high levels. In conclusion, under early sowing condition chlorophyll content at grain filling stages, PIabs at flowering and filling stages, and Pn were important indices for selecting wheat cultivars with high photosynthetic efficiency. PMID- 27228603 TI - [Effects of water-potassium interaction on stalk structure and function of high yield summer maize]. AB - The effects of water-potassium interaction on stalk structure and function of high-yield summer maize were studied in the waterproof cultivation pools with Zhengdan 958 (ZD958) as the experimental material. The results showed that the quantity of bleeding sap in stalk was significantly improved by irrigation. Potassium (K) application could reduce the influence of drought stress on the quantity of bleeding sap in stalk to a certain extent. The quantity of bleeding sap in stalks during different growth periods were significantly improved in the treatment of 2250 m3 . hm-22 irrigation amount with K application. The stalk rind penetration strength and stem diameter were significantly improved by water potassium interactions. Under the irrigation amount of 2250 m3 . hm-2, the stalk rind penetration strength and stem diameter with K application were respectively increased by 46.0% and 36.4% compared with no K application. Under K application, the stalk rind penetration strength and stem diameter in the irrigation amount 2250 m3 . hm-2 were respectively increased by 30.7% and 8.6% compared with 450 m3 . hm-2. The number, area of vascular bundle and the thickness of thick-walled cell, cortex and rind, were significantly improved by the irrigation amount 2250 m3 . hm-2 with K application. In conclusion, application of 180 kg K2O . hm-2 and increasing the irrigation amount properly could increase the lodging resistance and yield of summer maize in this field experiment condition. PMID- 27228604 TI - [Effects of brassinolide on leaf physiological characteristics and differential gene expression profiles of NaCl-stressed cotton]. AB - This study analyzed the effects of brassinolide (BL) on Na+ accumulation, leaf physiological characteristics and differentially expressed genes (DEGs) of cotton leaves under NaCl stress. The results showed that NaCl stress increased the Na+, proline and MDA content in the leaves of Sumian 12 and Sumian 22, and changed the expression level of genes in cotton leaves. The application of BL counteracted the NaCl stress-induced growth inhibition in the two tested cotton cultivars. It reduced the accumulation of Na+, enhanced proline content, and resulted in a decrease in the MDA content of NaCl-stressed leaves, and the influence of BL on salt-stressed Sumian 12 plants was more pronounced than that on Sumian 22. The digital gene expression analysis in Sumian 12 indicated that BL application significantly influenced the gene expression in NaCl-stressed cotton leaves, the gene expression pattern as a result of the root applied BL on NaCl-stressed cotton treatment (BL+NaCl) was similar to the normal cotton plants (CK). Our results indicated that brassinolide alleviated NaCl stress on cotton through improving leaf physiological characteristics and gene expression, and resulted in an increase in biomass of NaCl-stressed cotton. PMID- 27228605 TI - [Effects of nitrogen application rates on nitrogen uptake and utilization of direct-seeded cotton after wheat harvest]. AB - An experiment was carried out to study the effects of different nitrogen application rates (0, 60, 120, 150, 180 and 240 kg N . hm-2) on the nitrogen uptake, utilization and distribution of short season cotton cultivar (CCRI-50) which was directly seeded after wheat harvest. Results showed that nitrogen application increased the nitrogen uptake of cotton at different growth stages, with the highest increment at the peak flowering-boll opening stage. Nitrogen application changed the percentages of nitrogen uptake among different growth stages. The percentages of nitrogen uptake decreased from seedling to peak flowering stage, but increased from peak flowering to boll maturing stage. In addition, nitrogen application reduced the decreasing speed of nitrogen concentration in middle and upper fruiting branches at later growth stages. Direct-seeded cotton had nitrogen and biomass accumulation in the lower and middle reproductive branches. With the nitrogen application of 150-180 kg . hm-2, the lint yield, NARE (nitrogen apparent recovery efficiency) and the economic coefficient of biomass and nitrogen were relatively higher, and the eigenvalues of dynamic model of nitrogen content and nitrogen accumulation were relatively coordinate. Excessively high nitrogen application (over 180 kg N . hm-2) decreased biomass and nitrogen amount of reproductive organ in lower and middle branches, narrow rise of yield, and lower nitrogen use efficiency. However, excessively low nitrogen application (lower than 150 kg N . hm-2) also resulted in lower economic coefficient of biomass and nitrogen and yield. These results suggested the optimum nitrogen application rate 150-180 kg N . hm-2 for direct seeded cotton after wheat harvest in lower reaches of Yangtze River. PMID- 27228606 TI - [Diagnosis method of cotton water status based on infrared thermal imaging]. AB - Canopy temperature is one of promising signals for evaluating crop water status. The infrared thermal imager can provide real-time temperature distributions over larger areas with high spatial resolution. The main factors (the observation orientation, angle and distance) controlling the accuracy of measuring canopy temperature with the infrared thermal imaging were investigated in a cotton field. Moreover, the correlation relationships between the crop water stress index (CWSI), which was observed using different methods, and soil water content (SWC), leaf water potential (LWP), and stomatal conductance (g(s)) of cotton in different water treatments were analyzed. Results indicated that the CWSI, which was measured in the opposite direction of the sun with the observation angle of 45 degrees , was in good correlation with LWP, g(s) and SWC, indicating it was a suitable observing method of canopy temperature. The canopy temperature gradually decreased with the increasing observation distance, so the calibration was necessary for long-distance measurement. By analyzing the relationship between the temperature at the dry/wet reference surface and the canopy temperature, we developed a suitable and simplified model of CWSI for cotton in the North China Plain. PMID- 27228607 TI - [Effects of cotton stalk biochar on microbial community structure and function of continuous cropping cotton rhizosphere soil in Xinjiang, China]. AB - In this study, field trials were conducted to examine the effects of cotton stalk biochar on microbial population, function and structural diversity of microorganisms in rhizosphere soil of continuous cotton cropping field in Xinjiang by plate count, Biolog and DGGE methods. The experiment was a factorial design with four treatments: 1) normal fertilization with cotton stalk removed (NPK); 2) normal fertilization with cotton stalk powdered and returned to field (NPKS); 3) normal fertilization plus cotton stalk biochar at 22.50 t . hm-2 (NPKB1); and 4) normal fertilization plus cotton stalk biochar at 45.00 t . hm-2 (NPKB2). The results showed that cotton stalk biochar application obviously increased the numbers of bacteria and actinomycetes in the rhizospheric soil. Compared with NPK treatment, the number of fungi was significantly increased in the NPKB1treatment, but not in the NPKB2 treatment. However, the number of fungi was generally lower in the biochar amended (NPKB1, NPKB2) than in the cotton stalk applied plots (NPKS). Application of cotton stalk biochar increased values of AWCD, and significantly improved microbial richness index, suggesting that the microbial ability of utilizing carbohydrates, amino acids and carboxylic acids, especially phenolic acids was enhanced. The number of DGGE bands of NPKB2 treatment was the greatest, with some species of Gemmatimonadetes, Acidobacteria, Proteobacteria and Actinobacteria being enriched. UPGMC Cluster analysis pointed out that bacterial communities in the rhizospheric soil of NPKB2 treatment were different from those in the NPK, NPKS and NPKB1treatments, which belonged to the same cluster. These results indicated that application of cotton stalk biochar could significantly increase microbial diversity and change soil bacterial community structure in the cotton rhizosphere soil, thus improving the health of soil ecosystem. PMID- 27228608 TI - [Effects of different tillage methods on photosynthetic characteristics, dry matter production and economic benefit of double cropping soybean]. AB - In order to explore suitable mode of high yield cultivation of double cropping soybean after wheat under drip irrigation in northern Xinjiang, field trials were set in 2013-2014 to investigate physiological indices and agronomic traits of double cropping soybean under different tillage methods under drip irrigation. The results showed that leaf area index (LAI), chlorophyll content (SPAD), leaf net photosynthetic rate (Pn), transpiration rate (Tr) and stomatal conductance (g(s)) during the determination period under different tillage methods were in the order of tillage plus film covering (TP)> tillage (T)> rotary tillage (RT) > no-tillage (NT) , and the concentration of intercellular CO2(Ci) was the opposite. LAI, SPAD, Pn, Tr, and g(s) of TP were higher than that with NT by 55.0%, 9.1%, 41.8%, 37.5% and 56.4%, respectively, and Ci was decreased by 22.1%. TP enhanced the photosynthetic efficiency of soybean and improved the ability of CO2assimilation, consequently leading to the increase of soybean yield under TP compared to NT. The plant dry matter accumulation of TP treatment was improved greatly, with the pod number and seeds number per plant, 100-seed mass and yield of quadric sowing soybean being increased by 50.3%, 48.1%, 11.8% and 20.8% compared with that under NT, and the differences were significant. Therefore, the plastic film mulching combined with tillage under drip irrigation technology was suitable for double cropping soybean after wheat in northern Xinjiang under this experimental condition. PMID- 27228609 TI - [Comparison of precision in retrieving soybean leaf area index based on multi source remote sensing data]. AB - With the innovation of remote sensing technology, remote sensing data sources are more and more abundant. The main aim of this study was to analyze retrieval accuracy of soybean leaf area index (LAI) based on multi-source remote sensing data including ground hyperspectral, unmanned aerial vehicle (UAV) multispectral and the Gaofen-1 (GF-1) WFV data. Ratio vegetation index (RVI), normalized difference vegetation index (NDVI), soil-adjusted vegetation index (SAVI), difference vegetation index (DVI), and triangle vegetation index (TVI) were used to establish LAI retrieval models, respectively. The models with the highest calibration accuracy were used in the validation. The capability of these three kinds of remote sensing data for LAI retrieval was assessed according to the estimation accuracy of models. The experimental results showed that the models based on the ground hyperspectral and UAV multispectral data got better estimation accuracy (R2 was more than 0.69 and RMSE was less than 0.4 at 0.01 significance level), compared with the model based on WFV data. The RVI logarithmic model based on ground hyperspectral data was little superior to the NDVI linear model based on UAV multispectral data (The difference in E(A), R2 and RMSE were 0.3%, 0.04 and 0.006, respectively). The models based on WFV data got the lowest estimation accuracy with R2 less than 0.30 and RMSE more than 0.70. The effects of sensor spectral response characteristics, sensor geometric location and spatial resolution on the soybean LAI retrieval were discussed. The results demonstrated that ground hyperspectral data were advantageous but not prominent over traditional multispectral data in soybean LAI retrieval. WFV imagery with 16 m spatial resolution could not meet the requirements of crop growth monitoring at field scale. Under the condition of ensuring the high precision in retrieving soybean LAI and working efficiently, the approach to acquiring agricultural information by UAV remote sensing could yet be regarded as an optimal plan. Therefore, in the case of more and more available remote sensing information sources, agricultural UAV remote sensing could become an important information resource for guiding field-scale crop management and provide more scientific and accurate information for precision agriculture research. PMID- 27228610 TI - [Physiological responses of sugar beet (Beta vulgaris) to drought stress during vegetative development period under drip irrigation]. AB - Sugar beet (Beta vulgaris cv. Beta 356) was subjected to drought stress during vegetative development by maintaining the soil water content in the 0-40 cm soil depth at 70%, 50% or 30% of field capacity to study the physiological traits of the leaves. Results showed that the compensation index was the highest in the 50% field capacity treatment. Malonaldehyde (MDA) content, relative conductivity, catalase (CAT) activity, and soluble sugar content began to increase 24 h after rehydration. Proline content began to increase 48 h after rehydration. In contrast, no compensation effect was observed in peroxidase (POD) activity after rehydration. Among the active oxygen scavenging enzymes, CAT was most sensitive to drought stress. Supplemental irrigation should be carried out promptly when the soil water content dropped to 50% of field capacity during vegetative development. Rehydration could promote self-repair functions in leaves, thus reducing the effects of drought on sugar beet yield and sugar content. PMID- 27228611 TI - [Temporal and spatial variability of livestock and poultry productions and manure nutrients in Shanxi Province, China]. AB - China's livestock and poultry productions have changed significantly in the last three decades, from mainly traditional and small-scale systems in early 1980s towards more intensive and industrialized ones in recent years, due to the booming economy and the changes in people' diet. There is an urgent need to increase the understanding of the changes in the livestock and poultry productions and the impact of manure recycle on the environment. Here, we reported on a systematic and quantitative analysis on the temporal and spatial variability of livestock and poultry productions and manure nutrients in Shanxi Province, China, using a large database and a coupled food chain nutrient flow model (NUFER) with GIS. In the period of 1978 to 2012, total animal manure production increased from 1.61 x 107 t to 2.75 x 107 t by 171%. The manure N increased from 7.74 x 104 t to 17.32 x 104 t, and the manure P from 1.09x104 t to 3.39x104 t. Besides the huge increase in total animal manure production, the distribution of animal manure was much uneven among regions, with high amounts of manure N and P per unit land in the north, middle and southeastern regions and low values in the north-central and southwestern regions, based on the results of 2012. The uneven distribution of manure was the combined effect of regional specializations in livestock and poultry productions and related policies. Our findings suggested that optimizing the structure of livestock and poultry productions and enhancing interregional collaborations on nutrient management could be two effective measures for reducing pollution and environmental risks, while achieving efficient and sustainable use of manure nutrient in the long term. PMID- 27228612 TI - [Calculation on ecological security baseline based on the ecosystem services value and the food security]. AB - The rapid development of coastal economy in Hebei Province caused rapid transition of coastal land use structure, which has threatened land ecological security. Therefore, calculating ecosystem service value of land use and exploring ecological security baseline can provide the basis for regional ecological protection and rehabilitation. Taking Huanghua, a city in the southeast of Hebei Province, as an example, this study explored the joint point, joint path and joint method between ecological security and food security, and then calculated the ecological security baseline of Huanghua City based on the ecosystem service value and the food safety standard. The results showed that ecosystem service value of per unit area from maximum to minimum were in this order: wetland, water, garden, cultivated land, meadow, other land, salt pans, saline and alkaline land, constructive land. The order of contribution rates of each ecological function value from high to low was nutrient recycling, water conservation, entertainment and culture, material production, biodiversity maintenance, gas regulation, climate regulation and environmental purification. The security baseline of grain production was 0.21 kg . m-2, the security baseline of grain output value was 0.41 yuan . m-2, the baseline of ecosystem service value was 21.58 yuan . m-2, and the total of ecosystem service value in the research area was 4.244 billion yuan. In 2081 the ecological security will reach the bottom line and the ecological system, in which human is the subject, will be on the verge of collapse. According to the ecological security status, Huanghua can be divided into 4 zones, i.e., ecological core protection zone, ecological buffer zone, ecological restoration zone and human activity core zone. PMID- 27228613 TI - [Assessment on the ecological suitability in Zhuhai City, Guangdong, China, based on minimum cumulative resistance model]. AB - Urban landscape has the characteristics of spatial heterogeneity. Because the expansion process of urban constructive or ecological land has different resistance values, the land unit stimulates and promotes the expansion of ecological land with different intensity. To compare the effect of promoting and hindering functions in the same land unit, we firstly compared the minimum cumulative resistance value of promoting and hindering functions, and then looked for the balance of two landscape processes under the same standard. According to the ecology principle of minimum limit factor, taking the minimum cumulative resistance analysis method under two expansion processes as the evaluation method of urban land ecological suitability, this research took Zhuhai City as the study area to estimate urban ecological suitability by relative evaluation method with remote sensing image, field survey, and statistics data. With the support of ArcGIS, five types of indicators on landscape types, ecological value, soil erosion sensitivity, sensitivity of geological disasters, and ecological function were selected as input parameters in the minimum cumulative resistance model to compute urban ecological suitability. The results showed that the ecological suitability of the whole Zhuhai City was divided into five levels: constructive expansion prohibited zone (10.1%), constructive expansion restricted zone (32.9%), key construction zone (36.3%), priority development zone (2.3%), and basic cropland (18.4%). Ecological suitability of the central area of Zhuhai City was divided into four levels: constructive expansion prohibited zone (11.6%), constructive expansion restricted zone (25.6%), key construction zone (52.4%), priority development zone (10.4%). Finally, we put forward the sustainable development framework of Zhuhai City according to the research conclusion. On one hand, the government should strictly control the development of the urban center area. On the other hand, the secondary urban center area such as Junchang and Doumen need improve the public infrastructure to relieve the imbalance between eastern and western development in Zhuhai City. PMID- 27228614 TI - [Landscape ecological risk assessment and its spatio-temporal variations in Ebinur Lake region of inland arid area]. AB - The typical region of the Ebinur Lake Basin was chosen as study area. Landsat TM/OLI images for 1998, 2011 and 2013 were obtained. In the study area, landscape was classified into six types, including cropland, woodland, grassland, water body, bare lake bed, salinized land and unutilized land. Landscape indices and ecological risk index were calculated and spatially interpolated for the whole region, which was divided into five different risk zones: extremely low, low, moderate, high and extremely high ecological risk. They were carried out for assessing the spatio-temporal changes in ecological risk for each landscape pattern. The results showed that the regional landscape patterns had experienced significant changes, and the increase in the area of croplands was the main trend in landscape evolution from 1998-2013. The main part of the regional ecosystem faced extremely high risk in 1998, high risk in 2011 and low risk in 2013. The ecological risk level of the study area was significantly decreased in the overall period, and the total area of change from high to low risk was much greater than those from low to high risk. PMID- 27228615 TI - [Effects of land use change on landscape pattern vulnerability in Yinchuan Basin, Northwest China]. AB - Landscape pattern vulnerability reflects the instability and sensitivity of ecological system to external disturbances and helps to understand the status and trend of ecological environment. This paper used landscape sensitivity index and landscape adaptability index to construct the landscape pattern vulnerability index of Yinchuan Basin, and got the distribution of the landscape pattern vulnerability in 2001 and 2013. Our study explored the effect of the land use degree composite index, the integrated land use dynamic degree, the importance index of land use change and various types of land transfer on landscape pattern vulnerability. Results showed that the land use degree composite index was mainly caused by the increase of the arable land, forest and the construction land. The higher proportion of the arable land or forest, the lower the vulnerability was, and the construction land had the opposite effect. With the increase of integrated land use dynamic degree, the construction land significantly increased the vulnerability, followed by grassland, and the forest significantly decreased the vulnerability, followed by the arable land. As the importance index of land use change increasing, the arable land could significantly decrease the vulnerability, followed by the forest, the grassland had a weaker trend with no obvious pattern, and the construction land significantly increased the vulnerability. When the arable land, forest and the grassland were the maintypes of land use transfer, the increasing proportion of the construction land increased the vulnerability. When the construction land was the main type of land use transfer, the grassland and forest improved the vulnerability and the arable land had the opposite effect. Changes in the number of land use types influenced the spatial structure of land use to a certain extent, which could offer a reference on using and developing the land resources scientifically. The ternary diagram could reflect the impact of various types of and use change on the landscape vulnerability, which diagram enriched the content of the research on the land use and change. PMID- 27228616 TI - [Efficiency of Trichoderma longibrachiatum T6 in the control of Meloidogyne incognita and its rhizosphere colonization in cucumber]. AB - Efficiency of different concentrations of Trichoderma longibrachiatum T6 against Meloidogyne incognita and its rhizosphere colonization in cucumber were determined in greenhouse experiments. The results of rhizosphere colonization experiments showed that the number of colonies in cucumber soil and root increased significantly ten weeks after inoculation with the second stage juveniles of M. incognita and different concentrations of T. longibrachiatum T6, and there was significant difference in different concentrations of T. longibrachiatum T6, e.g., the maximum numbers of colonies in soil and root were 7.8 x 107 and 6.3 x 105 CFU . mL-1 respectively after treated with the spore suspension of 1.5 x 107 CFU . mL-1. Greenhouse experiments results showed that different concentrations of T. longibrachiatum T6 had significant control effect on different life stages of M. incognita, and the control effect increased with the concentration of T. longibrachiatum T6. T. longibrachiatum T6 significantly increased plant height, root length, above-ground and root fresh mass o cucumber inoculated by M. incognita. T. longibrachiatum T6 could colonize in cucumber rhizosphere, had control effect on M. incognita, and significantly improved the growth of cucumber. PMID- 27228617 TI - [Resistance risk, cross-resistance and biochemical resistance mechanism of Laodelphax striatellus to buprofezin]. AB - In order to investigate the resistance development law and biochemical resistance mechanism of Laodelphax striatellus to buprofezin, spraying rice seedlings was used to continuously screen resistant strains of L. striatellus and dipping rice seedlings was applied to determine the toxicity and cross-resistance of L. striatellus to insecticides. After 32-generation screening with buprofezin, L. striatellus developed 168.49 folds resistance and its reality heritability (h2) was 0.11. If the killing rate was 80%-90%, L. striatellus was expected to develop 10-fold resistance to buprofezin only after 5 to 6 generations breeding. Because the actual reality heritability of field populations was usually lower than that of the resistant strains, the production of field populations increasing with 10 fold resistance would need much longer time. The results of cross-resistance showed that resistant strain had high level cross-resistance with thiamethoxam and imidacloprid, low level cross-resistance with acetamiprid, and no cross resistance with pymetrozine and chlorpyrifos. The activity of detoxification enzymes of different strains and the syergism of synergist were measured. The results showed that cytochrome P450 monooxygenase played a major role in the resistance of L. striatellus to buprofezin, the esterase played a minor role and the GSH-S-transferase had no effect. Therefore, L. striatellus would have high risk to develop resistance to buprofezin when used in the field and might be delayed by using pymetrozine and chlorpyrifos. PMID- 27228618 TI - [Influences of biochar and nitrogen fertilizer on soil nematode assemblage of upland red soil]. AB - The use of biochar as soil remediation amendment has received more and more concerns, but little attention has been paid to its effect on soil fauna. Based on the field experiment in an upland red soil, we studied the influences of different application rates of biochar (0, 10, 20, 30, 40 t . hm-2) and nitrogen fertilizer (60, 90, 120 kg N . hm-2) on soil basic properties and nematode assemblages during drought and wet periods. Our results showed that the biochar amendment significantly affect soil moisture and pH regardless of drought or wet period. With the increasing of biochar application, soil pH significantly increased, while soil moisture increased first and then decreased. Soil microbial properties (microbial biomass C, microbial biomass N, microbial biomass C/N, basal respiration) were also significantly affected by the application of biochar and N fertilizer. Low doses of biochar could stimulate the microbial activity, while high doses depressed microbial activity. For example, averaged across different N application rates, biochar amendment at less than 30 t . hm-2 could increase microbial activity in the drought and wet periods. Besides, the effects of biochar also depended on wet or drought period. When the biochar application rate higher than 30 t . hm-2, the microbial biomass C was significantly higher in the drought period than the control, but no differences were observed in the wet period. On the contrary, microbial biomass N showed a reverse pattern. Dissolved organic matter and mineral N were affected by biochar and N fertilizer significantly in the drought period, however, in the wet period they were only affected by N fertilizer rather than biochar. There was significant interaction between biochar and N fertilizer on soil nematode abundance and nematode trophic composition independent of sampling period. Combined high doses of both biochar and N fertilization promoted soil nematode abundance. Moreover, the biochar amendment increased the proportion of fungivores especially in the drought period, suggesting the biochar was the preferred fungal energy channel in comparison to soil without biochar addition. In summary, complex patterns occurred not only due to the application rate of biochar as well as their interactions with N fertilization but also due to the drought and wet periods. It is, therefore, necessary to consider different ecological factors when evaluating the effects of biochar in future. PMID- 27228619 TI - [Activity patterns and foraging behavior of Apis cerana cerana in the urban gardens in winter]. AB - Bees and other pollinating insects are the important parts of biodiversity due to their great role in plant reproduction and crop production. To explore the role of city garden in native bees conservation, activity patterns, visiting behaviors and flowering plants with nectar or pollen were recorded in south Sichuan in winter. The results showed that, worker bees (Apis cerana cerana) were active to collect food out hive under suitable weather conditions, the duration of working was long. Peaks of the number of outgoing, entrance and foragers without pollen appeared at 14:00-15:00, and bimodal patterns were observed. While, peak of bees with pollen appeared at 11:00, and a unimodal pattern was observed. Time significantly affected the activity of workers. The workload of honey bees on nectar and pollen collection were different, just less than twenty percent foragers carrying pollen. Temperature and humidity also affected flights of bees to some degree, and bee activities showed similar patterns on different days. However, the activities had diverse characteristics in some time. Though a less number of plants were in flowering, most of them could be utilized by A. cerana cerana, and colonies could effectively get the food resource by behavior adjustment. In addition, visiting activities of bees on the flowers of main garden plants, such as Camellia japonica, showed obvious rhythm. Increasing the flowering plants with nectar and pollen in winter by scientific management of urban gardens would facilitate the creation of suitable habitats for A. cerana cerana and maintaining the wild population. PMID- 27228620 TI - [Effects of starvation on the consumption of energy sources and swimming performance in juvenile Gambusia affinis and Tanichthys albonubes]. AB - To explore the consumption of energy sources and swimming performance of juvenile Gambusia affinis and Tanichthys albonubes after starvation, contents of glycogen, lipid and protein, burst swimming speeds (Uburst), and critical swimming speeds (Ucrit) at different starvation times (0, 10, 20, 30 and 40 days) were evaluated. The results showed that, at 0 day, contents of glycogen and lipid were significantly lower in G. affinis than those in T. albonubes, whereas no significant difference in content of protein between two experimental fish was found. Swimming speeds in G. affinis were significantly lower than those in T. albonubes for all swimming performances. After different starvation scenarios, content of glycogen both in G. affinis and T. albonubes decreased significantly in power function trend with starvation time and were close to zero after starvation for 10 days, whereas the contents of lipid and protein were linearly significantly decreased. The slope of line regression equation between content of lipid and starvation time in G. affinis was significantly lower than that in T. albonubes, whereas there was a significantly higher slope of line equation between content of protein and starvation time in G. affinis. 40 days later, the consumption rate of glycogen both in G. affinis and T. albonubes were significantly higher than that of lipid, while the consumption rate of protein was the least. Consumption amounts of glycogen in all experimental fish were the least, G. affinis consumed more protein than lipid, and T. albonubes consumed more lipid than protein. Uburst and Ucrit decreased significantly linearly with starvation time for all experimental fish. Slope of linear equation between Uburst and starvation time was not significantly different between G. affinis and T. albonubes. However, the straight slope between Ucrit and starvation time was significantly lower in G. affinis than that in T. albonubes. These findings indicated that there was close relationship between the consumption of energy sources and swimming performance in starvation. Although the store amounts of energy sources and swimming performance were lower in G. affinis than those in T. albonubes, G. affinis mainly used protein during starvation. The result of more stable lipid content and Ucrit in G. affinis in starvation compared with that in T. albonubes indicated that G. affinis had a fair endurance to starvation, which helped them to adapt to the poor nutrition environment in stream habitat. PMID- 27228621 TI - [Diet composition and seasonal variation in feeding habits of Collichthy lucidus in Yangtze Estuary, China]. AB - Spiny head croaker (Collichthy lucidus) is an important bottom fish distributing from the East China Sea to the Yellow Sea. In order to investigate the seasonal variation in diet composition and feeding habits, a total of 270 specimens were collected in the Yangtze Estuary from November, 2013 to August, 2014, and analyzed by using the stomach contents analysis method. The importance of different prey items was evaluated by the frequency of occurrence, abundance and mass followed by using these data to calculate the index of relative importance (IRI) and the index of preponderance (Ip) for each taxonomic category. The results showed that the diet of C. lucidus consisted of 30 species belonging to 8 orders, in which shrimps, with 38.5 IRI% and 79.1 Ip values, was the most important prey species. The followings were Mysidacea and Amphipoda. The dominant species in the diet of C. lucidus were Palaemon gravieri, Exopalaemon annandalei, E. carinicauda, Acanthomysis longirostris, A. brevirostris, Synidotea laevidorsalis and Calanus sinicus. The dominant species in the diet varied in different seasons. P. gravieri, E. annandalei and A. brevirostris were dominant species in spring and summer, A. longirostris, A. brevirostris and E. carinicauda in autumn, and P. gravieri, C. sinicus and Pesudeuphausia sinica in winter. There was 10.4% of total samples with empty stomachs, and the highest percent appeared in winter, and the lowest in autumn. The mean stomach fullness index of the whole samples was 0.6%, with the highest found in spring, the lowest in winter, indicating the feeding activity of C. lucidus varied significantly among seasons. PMID- 27228622 TI - [Release and supplement of carbon, nitrogen and phosphorus from jellyfish (Nemopilema nomurai) decomposition in seawater]. AB - Abstract: Jellyfish bloom has been increasing in Chinese seas and decomposition after jellyfish bloom has great influences on marine ecological environment. We conducted the incubation of Nemopilema nomurai decomposing to evaluate its effect on carbon, nitrogen and phosphorus recycling of water column by simulated experiments. The results showed that the processes of jellyfish decomposing represented a fast release of biogenic elements, and the release of carbon, nitrogen and phosphorus reached the maximum at the beginning of jellyfish decomposing. The release of biogenic elements from jellyfish decomposition was dominated by dissolved matter, which had a much higher level than particulate matter. The highest net release rates of dissolved organic carbon and particulate organic carbon reached (103.77 +/- 12.60) and (1.52 +/- 0.37) mg . kg-1 . h-1, respectively. The dissolved nitrogen was dominated by NH4+-N during the whole incubation time, accounting for 69.6%-91.6% of total dissolved nitrogen, whereas the dissolved phosphorus was dominated by dissolved organic phosphorus during the initial stage of decomposition, being 63.9%-86.7% of total dissolved phosphorus and dominated by PO43--P during the late stage of decomposition, being 50.4% 60.2%. On the contrary, the particulate nitrogen was mainly in particulate organic nitrogen, accounting for (88.6 +/- 6.9) % of total particulate nitrogen, whereas the particulate phosphorus was mainly in particulate. inorganic phosphorus, accounting for (73.9 +/-10.5) % of total particulate phosphorus. In addition, jellyfish decomposition decreased the C/N and increased the N/P of water column. These indicated that jellyfish decomposition could result in relative high carbon and nitrogen loads. PMID- 27228623 TI - [Nutrient composition changes in coastal waters of Tangshan Bay, Hebei, China under anthropogenic influence]. AB - Based on the principal component analysis (PCA), data from 25 marine monitoring stations in Tangshan Bay from 1995 to 2012 were collected to study the change of nutrient composition in Tangshan Bay under anthropogenic influence. Results showed that the inorganic nitrogen (DIN) presented an obvious increase trend in the near 20 years, while the PO43--P and SiO32--Si presented a decrease trend. The average N:P ratio increased from 3.0 in 1995 to 26.0 in 2012, but the average Si:N ratio decreased, indicating the nutrient structure in seawater had substantially changed in the near 20 years. According to the results of PCA, the change of water quality was identified. The analysis extracted the first two principal components (PC). PC1 was associated with DIN, NO3--N, NH4+-N, PO43--P and NO2--N, which explained 71.5% of the variance. PC2 was characterized by Chl a and SiO32--Si, which explained 21.8% of the variance. It indicated that the water quality of Tangshan bay was closely related to DIN and PO43--P. The two principal component scores revealed the interannual change trend of water quality in the Tangshan Bay under anthropogenic influence, which changed from the N limitation before development and at early stage of development (1995-2005) to the P limitation after development (since 2007). The nutrient composition in Tangshan Bay had changed significantly under anthropogenic influence, therefore, special attention is needed on the the change of nutrients in seawater of Tangshan Bay, especially the increase of inorganic nitrogen content. PMID- 27228624 TI - [Applications of nuclear magnetic resonance in the study of soil-plant-atmosphere continuum]. AB - Status and transport of water in plant body are the main contents of study of soil-plant-atmosphere continuum (SPAC), as well as the base for use and regulation of agricultural water. The process of water transport in plant can be deeply influenced by the environments. Thus, plant needs to adjust its water status to accommodate the environmental change to sustain its own growth and development. Traditional methods for plant water monitoring, such as evaporation flux, pressure chamber, high pressure flow meter, heat pulse, and so on, usually cause damage or even destruction of plant body and disturb the original water status. Thus, they are not able to truly and precisely detect and reflect the real water status of plant. Nuclear magnetic resonance (NMR) is a non-destructive and non-invasive technique which can be used for the measurement of water molecular displacement, and transportation. This study aimed to provide an overview of the applications of NMR technique in the study of water distribution and transport in plant roots and stems, as well as the water content in plant cells and tissues. In addition, the existing main problems and possible solutions were analyzed for the applications of NMR in SPAC studies. Several important issues were proposed for the acquisition of more precise and reliable detection signals. It was suggested that the NMR technique would probably make important progress in the relevant fields such as plant water physiology, plantenvironment interactions, and water metabolism. In general, the application of NMR in SPAC system study was still in its infancy in China. The deeper application and expansion of NMR in SPAC study would depend on the development of portable and open NMR equipment that could be easily applied for different plants in field. PMID- 27228625 TI - [Concept and connotation development of niche and its ecological orientation]. AB - Proceeding from the niche concept; the article commented the main points of each concept's connotation basing on a systematic review of development on niche concepts, and divided the process into four phases including germination, standardization, quantification and perfection, with two main academic schools. Questions and challenges during niche's development and advancement were presented to extract the characteristics and components of niche concept. On these bases, we explored the orientation of niche concept in ecology, and suggested to position it as a macro concept and detail it in specific applications. Further research points and application perspectives were stated in the end. PMID- 27228626 TI - The Fourth Israel-Italy Meeting: Updates in Rheumatology and Autoimmunity. PMID- 27228627 TI - Are Helminths to be Trusted as Allies in the War against Autoimmunity and Chronic Inflammation? PMID- 27228628 TI - A New Way of Thinking about Systemic Sclerosis: The Opportunity for a Very Early Diagnosis. AB - Systemic sclerosis (SSc) is a heterogeneous chronic autoimmune disease that it is extremely difficult to diagnose in the early phase, resulting in a critical delay in therapy which is often begun when internal organ involvement is already irreversible. The ACR or LeRoy criteria have a low sensitivity for the early phases; these criteria were replaced by the ACR/EULAR 2013 criteria which improved the disease classification. Therefore, the SSc diagnosis may be delayed for several years after the onset of Raynaud's phenomenon (RP) and even after the onset of the first non-RP symptom. RP, antinuclear antibodies (ANA) positivity, and puffy fingers were recently indicated as "red flags" (by the VEDOSS project)- that is, the main elements for suspicion of SSc in the very early phase of the disease. Confirming the diagnosis requires further tests, particularly nailfold videocapillaroscopy and evaluation of specific disease antibodies (anti centromere and anti-topoisomerase I). In this way, the VEDOSS project identified patients in the very early phase of disease enabling a "window of opportunity" whereby the physician can act with effective drugs to block or at least slow the progression of the disease. The principal challenge in the fight against SSc is to detect valid predictors of disease evolution in order to treat patients in the early stage of disease. While waiting to find valid predictors, a close follow-up of the patients with the VEDOSS red flags is essential, as is a close collaboration between rheumatologists and general practitioners in order to identify all potential SSc patients as soon as possible. PMID- 27228629 TI - Quality of Life, Coping and Depression in Systemic Lupus Erythematosus. AB - Physical, mental and social well-being are important outcomes in patients with chronic rheumatic diseases, including systemic lupus erythematosus (SLE). The MOS SF-36 and the WHO QoL Bref are appropriate for assessing quality of life (QoL) in patients with SLE. The QoL of patients with SLE is impaired compared with that of controls. Fibromyalgia adversely affects the QoL of SLE patients. Women with SLE had significantly lower scores on subscales of the sense of coherence (SoC) compared with matched controls. This reduced SoC in SLE women represents impaired adaptive coping and is independently associated with reduced QoL in women with SLE. Depression and anxiety are common among SLE patients, and the frequency is similar to that in patients with rheumatoid arthritis. A reciprocal longitudinal relationship between depression and illness intrusiveness was found in patients with SLE. Disease activity and damage are not associated with depression. The subjective experience, not the illness per se, causes depression. PMID- 27228630 TI - Antiphospholipid Antibodies and Infertility: A Gene Expression Study in Decidual Stromal Cells. AB - BACKGROUND: Antiphospholipid antibodies (aPL) have been advocated as potential mediators of unexplained female infertility, but no evidence has yet been raised to support such an association. OBJECTIVES: To test the hypothesis that aPL might interfere with uterine decidualization, a gene expression study was performed on decidual stromal cells treated with different aPL preparations. METHODS: Decidual stromal cells were isolated from first-trimester deciduas obtained from two women undergoing elective abortion, and treated with: (i) a beta2GPI-dependent aPL monoclonal antibody (IS3); (ii) IS3 plus TIFI, a synthetic peptide mimicking PL binding region of beta2GPI; and (iii) IgG from healthy subjects (NHS). Gene expression data were acquired using human HT-12 v3 beadchip arrays (Illumina). Differential expression analysis was performed by fitting a gene-wise linear model using the treatment group and decidual source as covariates. RESULTS: In the comparison of IS3 versus IgG NHS-treated decidual cells, gene ontology (GO) enrichment was expressed in terms relating to well-characterized aPL-mediated cellular effects: "inflammatory response," "immune response," "response to stress," "oxydoreductase activity," "metalloendopeptidase activity," and "cytokine/chemokine activity." As expected, almost all genes were up-regulated by IS3 treatment. The same GO categories appeared to be differentially expressed when IS3 treatment was compared to IS3 + TIFI, but with most genes being down regulated. CONCLUSIONS: Given the inflammatory response evinced on gene expression analysis of decidual stromal cells treated with a beta2GPI -dependent aPL monoclonal antibody, it is feasible that aPL might interfere with uterine decidualization, affecting the early stages of implantation and ultimately resulting in female infertility. PMID- 27228631 TI - Autoimmune/Inflammatory Syndrome Induced by Adjuvants and Sjogren's Syndrome. AB - Sjogren's syndrome (SS), a chronic systemic autoimmune inflammatory condition involving the exocrine glands, has been suggested to be part of the spectrum of the Autoimmune/ inflammatory Syndrome Induced by Adjuvants (ASIA). ASIA incorporates an umbrella of clinical conditions including siliconosis, macrophage myofasciitis syndrome, and post-vaccination phenomena that occur after the exposure to a substance, namely the adjuvant. Interestingly, SS and ASIA share several common features. Firstly, a shared pathogenic mechanism involving a disruption of the immune system balance, with B cell proliferation, cytokine production and tissue infiltration, has been proposed. Patients with ASIA often present clinical features resembling those of SS; dry mouth and dry eyes have also been included in the proposed classification criteria for ASIA. Finally, several case reports have suggested that both vaccines and silicone may trigger the development of SS. Unveiling these common pathways will contribute considerably to our understanding and management of both conditions. PMID- 27228632 TI - Do Anti-TNF Blockers Increase the Risk of Lung Involvement in Patients with Ankylosing Spondylitis or Psoriatic Arthritis? A Systematic Review. AB - Lung involvement is a well-recognized extra-articular manifestation of ankylosing spondylitis (AS). Anecdotal reports suggest that the use of anti-TNF drugs may be related to lung disease and pulmonary fibrosis. To examine the association between anti-TNF drugs and the development of lung disease in patients with AS or psoriatic arthritis (PsA) we conducted a systematic review. Of the 670 papers identified by means of key word and hand search, only one full-text paper was considered potentially relevant but had to be discarded as it did not meet the eligibility criteria. Although no conclusion was reached, this is the first systematic review to examine this problem which is becoming increasingly important as these drugs are widely prescribed in patients with spondyloarthritis. PMID- 27228633 TI - Can Cannabinoids Modulate Fibrotic Progression in Systemic Sclerosis? PMID- 27228634 TI - Increased T and B Regulatory Cell Function Contributes to the Persistence of HCV and Other Viral Infections. PMID- 27228635 TI - Chikungunya Fever Presenting as a Systemic Disease with Fever. Arthritis and Rash: Our Experience in Israel. AB - Chikungunya fever (CHIK-F) has been increasingly documented among Western travelers returning from areas with chikungunya virus transmission, which are also popular tourist sites. We present three Israeli travelers who developed fever, maculopapular rash and long-standing arthralgias while visiting northern Indian states not known to be involved in the chikungunya fever epidemic. We also present an epidemiological review of the chikungunya epidemic over the past decades. Rare systemic manifestations of this disorder, like catastrophic antiphospholipid syndrome (CAPS) and adult-onset Still's syndrome, are discussed. The present era of international travel poses a new diagnostic and epidemiologic challenge that demands increased awareness to the possibility of an exotic tropical infectious disease. PMID- 27228636 TI - Infections and Biological Therapy in Patients with Rheumatic Diseases. AB - Long-term extension studies and observational drug registers have revealed an increased risk of serious infections in patients treated with anti-tumor necrosis factor agents, particularly infliximab, etanercept and adalimumab. The same may be true for the newer biological drugs rituximab, tocilizumab and abatacept, although this has yet to be confirmed by long-term observational studies. We review the risk of tuberculosis, herpes zoster and other opportunistic infections, and the recommendations for screening for tuberculosis and hepatitis B and C infections in patients with rheumatoid arthritis, with the aim of informing patients and encouraging greater awareness among physicians. PMID- 27228637 TI - Churg-Strauss Syndrome: Singulair or Silicone (or both?). PMID- 27228638 TI - Interleukin-1 Inhibition in Behcet's disease. AB - Behcet's disease (BD) is a systemic inflammatory disorder characterized by a protean clinical spectrum and an enigmatic pathogenesis. After being classified as an autoimmune disorder, spondyloarthritis and vasculitis, today BD is considered at the crossroad between autoimmune and auto-inflammatory syndromes. Many pathogenetic, clinical and therapeutic clues support this recent interpretation, enabling novel treatment choices such as interleukin (IL)-1 inhibition. Thus, in the last decade the IL-1 receptor antagonist anakinra and the anti-IL-1beta monoclonal antibody canakinumab were increasingly administered in BD patients resistant to standard therapies, leading to interesting results and intriguing new pathogenetic implications. However, further studies are essential to both establish how the innate and acquired immune systems interact in BD patients and identify the best way of administering anti-IL-1 agents with regard to dosage, interval of administration, and organ response. PMID- 27228639 TI - Vitamin D and Systemic Lupus Erythematosus: Myth or Reality? AB - There is growing interest in the contribution of vitamin D deficiency to autoimmunity. Several studies have shown an association between low levels of vitamin D and autoimmune disorders, including multiple sclerosis, rheumatoid arthritis, type 1 diabetes, autoimmune thyroid diseases, celiac disease, and systemic lupus erythematosus (SLE). Vitamin D receptor ligands can mediate immunosuppressive effects. It has been suggested that low levels of this hormone contribute to the immune activation in lupus and other autoimmune diseases. This review updates and summarizes the literature on the association between vitamin D and SLE, and discusses the various correlations between vitamin D and SLE activity, clinical expressions, serology, and gene polymorphisms of vitamin D receptors. PMID- 27228640 TI - Management of Gender-Related Problems in Women with Autoimmune Rheumatic Diseases. AB - Autoimmune rheumatic diseases (ARD) affect mainly young women during their reproductive years. Fertility is usually not diminished but the time it takes to conceive is usually longer. Factors related to an ARD or to its treatment are responsible for this effect. In addition, contraception counseling is required to prevent negative fetal outcome and exacerbation of disease symptoms. In recent years, advances in therapies, clarification of risk factors for adverse pregnancy outcomes, and a multidisciplinary approach have vastly improved obstetric management, increasing the possibility of successful pregnancy with a high likelihood of favorable outcome. PMID- 27228641 TI - Melatonin for Prevention of Breast Radiation Dermatitis: A Phase II, Prospective, Double-Blind Randomized Trial. AB - BACKGROUND: Radiation-induced dermatitis is commonly seen during radiotherapy for breast cancer. Melatonin-based creams have shown a protective effect against ultraviolet-induced erythema and a radioprotective effect in rats. OBJECTIVES: To evaluate the efficacy of melatonin-containing cream in minimizing acute radiation dermatitis. METHODS: In this phase II, prospective, randomized, placebo controlled double-blind study, patients who underwent breast-conserving surgery for stage 0-2 breast cancer were randomly allocated to melatonin emulsion (26 women) or placebo (21 women) for twice daily use during radiation treatment and 2 weeks following the end of radiotherapy. All women received 50 Gy whole breast radiation therapy with 2 Gy/fx using computed tomography-based 3D planning. Patients were examined and completed a detailed questionnaire weekly and 2 weeks following the end of treatment. RESULTS: The occurrence of grade 1/2 acute radiation dermatitis was significantly lower (59% vs. 90%, P = 0.038) in the melatonin group. Women older than 50 had significantly less dermatitis than younger patients (56% vs. 100%, P = 0.021). The maximal radiation dermatitis in the study group was grade 2 in 15% of the treated patients. CONCLUSIONS: Patients treated with melatonin-containing emulsion experienced significantly reduced radiation dermatitis compared to patients receiving placebo. PMID- 27228642 TI - Salivary Gland Ultrasonography in Sjogren's Syndrome: Clinical Usefulness and Future Perspectives. AB - In recent years, salivary gland ultrasonography (SGUS) has emerged as a promising tool for the diagnosis and prognostic stratification of patients with primary and secondary Sjogren's syndrome. Several studies have emphasized that salivary ultrasonography could be a highly specific tool for the diagnosis of the disease. However, before it can be used in daily clinical practice the SGUS procedure needs standardization and validation in larger disease-control groups. In this review we provide an update on the role of SGUS in the diagnostic algorithm of primary Sjogren's syndrome. PMID- 27228643 TI - Sarcoidosis and Autoimmunity: From Genetic Background to Environmental Factors. AB - Sarcoidosis is a chronic multisystem disease with variable course resulting from the interaction between environmental factors and the immune system of individuals genetically predisposed. The evidence linking sarcoidosis with environmental triggers such as metals is increasing. We describe the case of a 44 year old female with a history. of smoking since age 30 and previous mercury dental filling who presented at physical examination with numerous subcutaneous nodules. Laboratory data showed accelerated erythrocyte sedimentation rate and high titer of anti-U1 ribonucleoprotein antibodies (U1 RNP). Skin biopsy and chest X-ray suggested the diagnosis of sarcoidosis. In this report we illustrate the different causes involved in the onset of sarcoidosis. PMID- 27228644 TI - Sex Differences in the Treatment of Psoriatic Arthritis: A Systematic Literature Review. AB - Psoriatic arthritis (PsA) is a chronic inflammatory condition associated with skin psoriasis and manifests a wide clinical phenotype, with proposed differences between sexes. Current treatments are based on traditional disease-modifying anti rheumatic drugs (DMARD), and biologic agents and studies have reported different clinical response patterns depending on sex factors. We aimed to identify sex differences in drug retention rate in patients with PsA and performed a systematic research on MEDLINE, EMBASE and Cochrane databases (1979 to June 2015) for studies regarding effectiveness (measured as drug retention rate) in PsA in both traditional DMARDs and biologics. Demographic data as well as retention rates between sexes were extracted. From a total 709 retrieved references, we included 9 articles for the final analysis. Only one study reported data regarding DMARDs, while eight studies reported retention rate for anti-tumor necrosis factor (TNF) biologics, mainly infliximab, adalimumab and etanercept. No differences were reported in retention rates between sexes for methotrexate, while women manifested lower retention rates compared to men with regard to anti TNF. We highlight the need to include sex differences in the management flow chart of patients with PsA. PMID- 27228645 TI - Fishing for Genes in Autoimmunity. AB - Autoimmune diseases are classic examples of multifactorial disorders in which a large number of genes interact with environmental factors to form the final phenotype. Identification of the genes involved in these diseases is a daunting challenge. Initially the search involved the candidate approach where polymorphisms in suspected genes were tested for association in large cohorts of patients and controls. Today, the most widely used method is genome-wide association studies (GWAS), a method based on screening large panels of patients and controls with hundreds of thousands of single nucleotide polymorphisms (SNPs), using microarray-based technology. Unique families in which autoimmune diseases are caused by single genes are another alternative. The identification of candidate genes is often followed by studies that provide biologic plausibility for the findings. The widely expanding list of genes involved in autoimmune conditions show that the same genes frequently underlie the pathogenesis of different autoimmune diseases. Despite all available resources, the main void of heritability in autoimmune conditions is yet to be discovered. Identification of these genes will help define new biological pathways and identify novel targets for the development of new therapeutic drugs. PMID- 27228646 TI - The Importance of an Early Diagnosis in Systemic Lupus Erythematosus. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease with a high degree of variability at onset, making it difficult to reach a correct and prompt diagnosis. OBJECTIVES: To present the difficulties faced by the clinician in making a SLE diagnosis, based on the characteristics at study entry of an Italian cohort of SLE patients with recent onset as compared to two similar cohorts. METHODS: Beginning on 1 January 2012 all patients with a diagnosis of SLE (1997 ACR criteria) and disease duration of less than 12 months were consecutively enrolled in a multicenter prospective study. Information on clinical and serological characteristics was collected at study entry and every 6 months thereafter. RESULTS: Our cohort consisted of 122 patients, of whom 103 were females. Among the manifestations included in the 1997 American College of Rheumatology (ACR) criteria, cutaneous, articular and hematologic symptoms were the most prevalent symptoms at study entry. CONCLUSIONS: Data from the literature confirm that the diagnosis of SLE is challenging, and that SLE is a severe disease even at onset when a prompt diagnosis is necessary for initiating the appropriate therapy. PMID- 27228647 TI - The Safety of Adjuvanted Vaccines Revisited: Vaccine-Induced Narcolepsy. AB - Despite the very high benefit-to-risk ratio of vaccines, the fear of negative side effects has discouraged many people from getting vaccinated, resulting in the reemergence of previously controlled diseases such as measles, pertussis and diphtheria. This fear has been amplified more recently by multiple epidemiologic studies that confirmed the link of an AS03-adjuvanted pandemic influenza vaccine (Pandemrix, GlaxoSmithKline Biologicals, Germany) used in Europe during the 2009 H1N1 influenza pandemic [A(H1N1) pdm09] with the development of narcolepsy, a chronic sleep disorder, in children and adolescents. However, public misperceptions of what adjuvants are and why they are used in vaccines has created in some individuals a closed "black box" attitude towards all vaccines. The focus of this review article is to revisit this "black box" using the example of narcolepsy associated with the European AS03-adjuvanted pandemic influenza vaccine. PMID- 27228648 TI - Update on Auto-Inflammatory Diseases and Familial Mediterranean Fever. PMID- 27228649 TI - What Can We Learn From Large Databases? Lessons From Autoimmunity. AB - The increasing use of computerized medical records has made the clinical data of the entire population available for epidemiological research. The resultant accessibility to this information mandates careful adaptions of ethical guidelines regarding the handling of clinical data. At the same time it grants a unique opportunity to explore the clinical nature of health and disease in large populations across all of society's strata, socioeconomic levels, ethnicities, and geographic locations regardless of their vicinity or distance to tertiary care centers. Analysis of large databases allows us to learn the public's behavior towards medical services and to investigate how medical interventions affect outcomes overtime. Moreover, the interaction between different co morbidities can be better understood by large population studies. The huge numbers of patients involved in these studies provide a good model of multivariate analysis, a statistical tool that by following proper population adjustments underlines the true independent associations between different conditions. Nevertheless, the limitations of these studies should be borne in mind, such as in-built imprecision of diagnoses, incompleteness of the medical data, and the fact that these databases were initially planned for clinical and not investigational use. PMID- 27228650 TI - Antiphospholipid and Antinuclear Antibodies in Young Patients after Myocardial Revascularization Procedures. AB - BACKGROUND: The role of autoimmune factors in the etiology of coronary artery disease (CAD) was suggested in numerous studies but has not been definitively determined. OBJECTIVES: To assess the possible influence of antiphospholipid and antinuclear antibodies on atherosclerosis development in young patients after myocardial revascularization procedures. METHODS: The study group included 39 patients younger than 45 years with CAD who underwent myocardial revascularization. Serum levels of antiphospholipid (aPL), antinuclear (ANA) and antineutrophil cytoplasmatic (ANCA) antibodies were tested within 1 month after the procedure. RESULTS: All three types of aPL were significantly higher in CAD patients when compared to healthy controls: anti-beta2-glycoprotein I (abeta2GPI), both immunoglobulin (Ig)G and IgM classes (median 4.10 SGU, range 3.45-21.63 vs. 0.76, 0.12-6.01, P < 0.001, and 2.82 SGU, 1.44-11.70 vs. 1.08, 0.44-3.64, P < 0.001, respectively); anticardiolipin antibodies (aCL) both IgG and IgM classes (3.13 GPL, 1.32-14.03 vs. 2.42, 0.96-18.45, P = 0.0037, and 6.94 MPL, 1.90-26.40 vs. 4.32, 1.9-28.73, P < 0.008, respectively); and lupus anticoagulant (LA) (27.7% vs. 0%, P = 0.005). ANA were elevated in one patient and ANCA in 23 (60%). The levels of aPL did not correlate with the presence of a clot in a coronary vessel detected during angiography or with exacerbation of coronary artery atherosclerosis. CONCLUSIONS: In young patients with CAD who underwent myocardial revascularization the levels of aPL were significantly higher than in young healthy subjects. Thus, besides the classic risk factors for CAD, autoimmunity may play an important role in atherosclerotic plaque formation and progression. PMID- 27228651 TI - Effect of Mud-Bath Therapy on Serum Biomarkers in Patients with Knee Osteoarthritis: Results from a Randomized Controlled Trial. AB - BACKGROUND: Balneotherapy is one of the most commonly used non-pharmacological approaches for osteoarthritis (OA). Recent data indicate that some biomarkers could be useful to predict OA progression and to assess therapeutic response. OBJECTIVES: To evaluate the effects of mud-bath therapy on serum biomarkers in patients with knee OA. METHODS: The study group comprised 103 patients with primary symptomatic bilateral knee OA who were randomly assigned to receive a cycle of mud-bath therapy over a period of 2 weeks or to continue their standard therapy alone. Clinical and biochemical parameters were assessed at baseline and after 2 weeks. Clinical assessments included global pain score on a visual analogue scale (VAS) and the Western Ontario and McMaster Universities Index (WOMAC) subscores for knee OA. Cartilage oligomeric matrix protein (COMP), C terminal cross-linked telopeptide type II collagen (CTX-II), myeloperoxidase (MPO) and high sensitivity C-reactive protein (hsCRP) serum levels were assessed by ELISA. RESULTS: At the end of mud-bath therapy we observed a statistically significant improvement in VAS and WOMAC subscores. Serum levels of COMP, MPO and hsCRP did not show any significant modification in either group, while a significant increase (P < 0.001) in CTX-II serum levels was observed in the mud bath group after the treatment. CONCLUSIONS: A cycle of mud-bath therapy added to the usual treatment had a beneficial effect on pain and function in patients with knee OA. The evaluation of serum biomarkers showed a significant increase of CTX II only, perhaps due to an increase of cartilage turnover induced by thermal stress. PMID- 27228652 TI - Efficacy and Safety of Intravenous Immunoglobulin Treatment in Refractory Behcet's Disease with Different Organ Involvement: A Case Series. AB - Behcet's disease (BD) is a multi-systemic disorder of unknown etiology characterized by relapsing oral-genital ulcers, uveitis, and involvement of the articular, gastrointestinal, neurologic, and vascular systems. The choice of treatment is based on the severity of systemic involvement, clinical presentation and the site affected, and includes corticosteroids, azathioprine, interferon, cyclophosphamide, methotrexate or tumor necrosis factor-alpha and interleukin-1 blockers. We present a case series of four refractory BD patients successfully treated with intravenous immunoglobulins (IVIG). All patients fulfilled International Study Group criteria. The patients' mean age was 38.75 +/- 12.09 years and mean disease duration 10.25 +/- 8.5 years. Human leukocyte antigen B51 was positive in two of four patients. In addition to oral aphthosis, all patients suffered from genital ulcers and cutaneous BD-related manifestations; central nervous system involvement and arthralgia were found in two patients. Peripheral nervous system, gastrointestinal and eye involvement occurred in 25% of cases. In all patients, previously treated according to EULAR recommendations without reaching satisfactory results, IVIG induced immediate and sustained response over time without incurring any side effects. We propose IVIG administration as an additional effective and safe treatment option in patients with severe and resistant BD. PMID- 27228653 TI - [PRODUCT OF THE BMI1--A KEY COMPONENT OF POLYCOMB--POSITIVELY REGULATES ADIPOCYTE DIFFERENTIATION OF MOUSE MESENCHYMAL STEM CELLS]. AB - Bmil is a key component of Polycomb (PcG), which in mammals controls the basic functions of mammalian somatic stem cells (SSC) such as self-renewal and differentiation. Bmi1 supports SSC via transcriptional suppression of genes associated with cell cycle and differentiation. The most studied target genes of Bmi1 are the genes of Ink4 locus, CdkI p16(Ink4a) and p1(Arf), suppression of which due to activating mutations of the BMI1 results in formation of cancer stem cells (CSC) and carcinomas in various tissues. In contrast, inactivation of BMI1 results in cell cycle arrest and cell senescence. Although clinical phenomena of hypo- and hyperactivation of BMI1 are well known, its targets and mechanisms of regulation of tissue specific SSC are still obscure. The goal of this study was to evaluate the regulatory role of BMI1 in adipocyte differentiation (AD) of mouse mesenchymal stem cells (MSC). Induction of AD in mouse MSC of the C3H10T1/2 cell line was associated with an increase in the expression levels of BMI1, the genes of pRb family (RB, p130) and demethylase UTX, but not methyltransferase EZH2, whose products regulate the methylation levels of H3K27. It was observed earlier that H3K27me3 may play the role of the epigenetic switch by promoting AD of human MSC via activating expression of the PPARgamma2, the master gene of AD (Hemming et al., 2014). Here we show that inactivation of BMI1 using specific siRNA slows and decreases the levels of AD, but does not abolish it. This is associated with a complete inhibition of the expression of adipogenic marker genes--PPARgamma2, ADIPOQ and a decrease in the expression of RB, p130, but not UTX. The results obtained give evidence that the epigenetic mechanism regulating AD differentiation in mouse and human MSC is different. PMID- 27228654 TI - [NEURONAL DIFFERENTIATION OF PC12 CELL LINE AND MURINE NEURAL STEM CELLS ON THE CARBON NANOTUBES FILMS]. AB - The study of the interaction of nerve cells with specially designed substrates (scaffolds) with different surface characteristics at the nanoscale is a necessary step in the development of methods of stimulation of regeneration of nervous tissues, as well as to create next generation of bioelectronic devices. A promising material for such scaffolds may be carbon nanotubes (CNT) that are flexible films of graphene rolled into nano-sized cylindrical tubes. CNT were produced by chemical deposition from the gas phase. The analysis of the PC12 cells cultivated on quartz glass coated by carbon nanotubes films using electron and light microscopy has shown that CNT stimulate the proliferation and do not inhibit neuronal differentiation of PC12 cells. We have found that it is possible to obtain differentiated neurons from murine neural stem cells on the quartz glasses covered with CNT films. The data obtained indicate that the CNT films produced by chemical deposition from the gas phase onto quartz glass may be used as the electro conductive scaffold to obtain and study the functions of neural cells and possibly of mature neurons. PMID- 27228655 TI - [SNCA rs356219 AND rs356165 VARIANTS ARE ASSOCIATED WITH PARKINSON'S DISEASE AND INCREASED ALPHA-SYNUCLEIN GENE EXPRESSION IN THE CD45(+)-BLOOD CELLS]. AB - Impaired metabolism of alpha-synuclein (SNCA) and its aggregation are now implicated in the pathogenesis of Parkinson's disease (PD). Previous studies have found association between PD and gene locus, containing the SNCA gene. Meta analysis have shown high significant association of single nucleotide polymorphisms (SNPs) rs356165 (A/G) and rs356219 (A/G) in the SNCA gene with PD. We genotyped these SNPs in 260 PD patients and 262 controls from north-western region of Russia. Alleles "G" of rs356165 and rs356219 were associated with increased risk of PD development. Linkage disequilibrium was shown between associated marker alleles. We studied the relationship between rs356165 and rs356219 and levels of mRNA SNCA and alpha-synuclein in CD45+ peripheral blood cells in drug-naive PD patients (n = 43) and controls (n = 39). Alleles "G" of rs356165 and rs356219 were associated with increased levels of SNCA expression (p = 0.046) and high alpha-synuclein levels (p = 0.039) in controls. Our data suggest that rs356165 and rs356219 variants might influence on PD development by upregulating SNCA expression. PMID- 27228656 TI - [STRUCTURAL CHARACTERIZATION OF PLATELETS AND PLATELET-DERIVED MICROVESICLES]. AB - Platelets are the anucleated blood cells, wich together with the fibrin stop bleeding (hemostasis). Cellular microvesicles are membrane-surrounded microparticles released into extracellular space upon activation and/or apoptosis of various cells. Platelet-derived macrovesicles from the major population of circulating blood microparticles that play an important role in hemostasis and thrombosis. Despite numerous studies on the pathophysiology of platelet-derived macrovesicles, mechanisms of their formation and structural details remain poorly understood. Here we investigated the ultrastructure of parental platelets and platelet-derived microvesicles formed in vitro by quiescent cells as well as by cells stimulated with one of the following activators: arachidonic acid, ADP, thrombin, calcium ionophore A23187. Using transmission electron microscopy of human platelets and isolated microvesicles, we analyzed the intracellular origin, steps of formation, structural diversity, and size distributions of the subcellular particles. We have revealed that thrombin, unlike other stimuli, not only induced vesiculation of the plasma membrane but also caused break-up of the cells followed by formation of microparticles that are comparable with microvesicles by size. A fraction of these microparticles contained cellular organelles surrounded by a thin membrane. The size of platelet-derived macrovesicles varied from 30 nm to 500 nm, however, the size distributions depended on the nature of a cell-activating stimulus. The results obtained provide new information about the formation of platelet-derived macrovesicles and their structural diversity, wich is important to understand their multiple functions in normal and disease states. PMID- 27228657 TI - [COMPARATIVE ANALYSIS OF SEROTONIN LEVELS IN RAT PLATELETS, SERUM AND BRAIN ON THE AGING]. AB - Serotonin functions as neurotransmitter in central nervous system and is involved in the regulation of vascular tone, gastro-intestinal motility and blood coagulation in the periphery. The appearance of new data on the significant correlation between serotonin levels in platelets and cerebrospinal fluid (Audhya et al., 2012) renewed interest in the hypothesis in which the platelet is seen as a model of cerotoninergic neuron. In our study, the levels of serotonin in platelets, serum and various brain regions of rats aged 6 and 24 months have been determined and comparatively analyzed. The method of high performance liquid chromatography was used. The decrease of serotonin level in platelets from 0.768 to 0.359 MUg per 10(9) cells and its increase in the middle brain from 0.260 to 0.439 MUg per 1 of wet weight have been clearly demonstrated in aging of animals. The differences in the content of serotonin in other parts of the brain and in the blood serum of young and old animals were statistically insignificant. Therefore, despite the attractiveness of the concept of platelet as a model of a neuron, the extrapolation of the data on platelet serotonin transport into neuronal ones requires caution, especially in the study of aging. PMID- 27228658 TI - [CHARACTERIZATION OF THE DIFFERENCE IN THE MORPHOLOGY OF DETERGENT RESISTANT MEMBRANES DOMAINS ISOLATED FROM DIFFERENT CELL TYPES BY ATOMIC FORCE MICROSCOPY]. AB - Planar raft and caveolae are specific membrane clusters with high concentration of cholesterol and lipids with saturated fatty acid. These clasters are resistant to detergents and are denoted as detergent resistant membranes domains (DRMs). Their morphology and size have been studied by atomic force microscopy. The size of planar rafts isolated by Librol from monocytes of healthy volunteers was 150.6 +/- 68.6 nm--diameters and 5.7 +/- 2.9 nm--height, the size of caveolae was 87.3 +/- 46.1 nm--diameters and 9.4 +/- 5.4 nm--height. Significant difference have been found morphology and size of DRMs isolated from monocytes of healthy volunteers and patients suffering from myocardial infarction as well as between DRMs isolated from endothelial cells. The study of time-dependent changes in the morphology of isolated planar rafts and caveolae has shown that they quickly aggregate during keeping. Therefore, to asses the actual size and morphology of the DRMS, they should be investigated immediately after isolation. PMID- 27228659 TI - [ATRIAL AND BRAIN NATRIURETIC PEPTIDES OF CARDIAC MUSCLE CELLS IN POSTREPERFUSION PERIOD IN RATS]. AB - Accumulation and release of atrial and brain natriuretic peptides (ANP and BNP) in right atrial cardiac muscle cells has been investigated in rats after 60 minutes and 60 days after the reperfusion start. The total ischemia was simulated by the method of V. G. Korpachev. Immunocytochemical localization of peptides in cardiomyocytes was performed in ultrathin sections using polyclonal antibodies. The intensity of accumulation/excretion of ANP and BNP were analyzed by the method of counting the number of granules (A- and B-types) with immunoreactive labels in 38 x 38 mkm2 visual fields in transmission electron microscope Morgagni 268D (FEI). The results were assessed using Mann-Whitney U-test (p < 0.05). After 60 minutes and 60 days post-reperfusion period, we detected an increase in the synthesis and release of ANP and BNP. The reaction of BNP was more pronounced than ANP. This is due to the fact that ANP is the main hormone of the natriuretic peptide system involved in the regulation of blood pressure in normal conditions, while BNP is the principal regulator of pressure in cardiovascular pathology. PMID- 27228660 TI - [CO-CULTURE OF BOAR SPERMATOGONIAL CELLS WITH SERTOLI CELLS]. AB - In the present study, we developed in vitro culture conditions using co-culture of boar spermatogonial cells with Sertoli cells. Testes from 60-day-old crossbred boar were used. A spermatogonia-enriched culture was achieved by enzymatic digestion method and purification by density gradient centrifugation using a discontinuous Percoll gradient and differentiated adherence technique. Lipid drops were detected in isolated Sertoli cells by Oil Red O staining. We have found that the cultivation of boar spermatogonia in the presence of Sertoli cells (up to 35 days) leads to their differentiation as well as in vivo in testis. Association of cells in groups, formation of chains and suspension clusters of the spermatogenic cells were observed on the 10th day. Spermatogonial cellular colonies were noted at the same time. These cellular colonies were analyzed for the expression of genes: Nanog and Plzf in RT PCR. The expression of the Nanog gene in the experimental cellular clones obtained by short-term culture of spermatogonial cells in the presence of Sertoli cells was 200 times higher than the expression of this gene in the freshly isolated spermatogonial cells expression was found in freshly isolated germ cells and in cellular clones derived in vitro. We have found that, in the case of longer cultivation of these cells on Sertoli cells, in vitro process of differentiation of germ cells and formation of single mobile boar spermatozoa occurs at 30-33 days. Cellular population is heterogeneous at this stage. Spermatogenic differentiation in vitro without Sertoli cells stays on the 7th day of cultivation. The results show that co-culture of boar spermatogonia-enriched cells with Sertoli cells can induce their differentiation into spermatozoa in vitro and facilitate obtaining of porcine germ cell culture. PMID- 27228662 TI - [WEAK COMBINED MAGNETIC FIELDS ADJUSTED TO THE PARAMETRIC RESONANCE FOR Ca2+ INTENSIFY DYSTROPHIN SYNTHESIS IN MDX MICE SKELETAL MUSCLES AFTER CELL THERAPY]. AB - The mdx mice are an X-linked myopathic mutants, an animal model for human Duchenne muscular dystrophy (DMD). Mdx mice muscles are characterized by high level of striated muscle fibers (SMF) death followed by regeneration. As a result most SMFs of mdx mice have centrally located nuclei. The possibility of using stem cells therapy for the correction of DMD is actively being studied. One of the approaches to the usage of bone marrow stem cells for cellular therapy of DMD is the replacement of bone marrow after irradiation by X-rays. This method however does not give significant increase of dystrophin synthesis in mdx mice muscles fibers. We have tried to affect the mice after bone marrow transplantation by weak combined magnetic fields adjusted to the parametric resonance for Ca2+(Ca(2+)-MF) based on the data that the weak combined magnetic fields influence on tissues regeneration. We observed a significant increase in the proportion of dystrophin-positive SMFs in group of mdx mice radiation chimera 5 Gy and 3 Gy which was additionally exposed in Ca(2+)-MF in comparison with the control mdx mice and the group of mdx mice radiation chimera 5 Gy and 3 Gy which was kept in terrestrial magnetic field 2 months after chimera preparation--up to 15.8 and 18.3%, respectively. Also, there was an accumulation of SMFs without central nuclei. These data indicate a significanly increased efficacy of cell therapy in the case of additional exposition in Ca(2+)-MF. Thus, the efficiency of bone marrow transplantation mdx mice after both in doses 3 and 5 Gy was considerably enhanced by additional exposition to Ca(2+)-MF. Apparently, such magnetic field can intensify functioning of donor's nuclei which had been incorporated into muscle fibers. PMID- 27228661 TI - [NUCLEAR STRUCTURE IN THE SECRETORY CELLS OF MAMMARY GLANDS IN LACTATING AND NON LACTATING RATS]. AB - The features of structural and functional organization of the main nuclear compartments and distribution of their key molecular components (chromatin remodeling protein ATRX, RNA polymerase I and II, and the splicing factor SC35) has been studied in the nuclei of mammary gland cells at different functional states. No significant differences between the nuclei of the cells in the lactating and non-lactating mammary glands have been revealed at the ultrastructural level. At the same time, photometric analysis has revealed higher intensity of nucleoplasmic immunofluorescent staining of mammary glands in the lactating animals when antibodies against the proteins ATRX and SC35 were used. Apparently, this observation reflects the changes of the structural and functional status of chromatin as well as the redistribution of splicing factors between the sites of their deposition and transcription. PMID- 27228663 TI - [INTERACTION OF THE DYE CONGO RED WITH FIBRILS OF LYSOZYME, BETA2-MICROGLOBULIN AND TRANSTHYRETIN]. AB - By means of spectrophotometric assay we investigated interaction of the dye Congo red (CR) with fibrils of model proteins--hen egg white lysozyme, recombinant human beta2-microglobulin (b2M) and recombinant human transthyretin (TTR). The commercial dye sample was found to contain a significant amount of impurities. Methods for the dye purification are disclosed and CR molar extinction coefficient at 490 nm (epsilon490) was determined to be 3.3 x 10(4) M(-1) x cm( 1) at pH above 6.0. Formation of the CR-fibril complex results in changes in the dye visible absorption spectrum. According to the data on titration of fibril solutions with excess of the dye, CR binds to lysozyme fibrils at a ratio of about 5 molecules per protein monomer within fibril structure, to b2M fibrils- about 4 molecules per monomer, to TTR fibrils--about 4 molecules per subunit of the protein. PMID- 27228664 TI - [COMPARATIVE ANALYSIS OF TIGHT JUNCTIONS OF EPITHELIUM OF RATS JEJUNUM UNDER THE EFFECT OF LIPOPOLYSACCHARIDE AND CHOLERA TOXIN]. AB - AIM: Comparative study of tight junctions and ultrastructure alterations of enterocytes of mucous membranes of jejunum of rats under the effect of lipopolysaccharides and cholera toxin. MATERIALS AND METHODS: Lipopolysaccharides (Sigma-Aldrich, Germany) and cholera toxin (Sigma-Aldrich, Germany) were used. The study was carried out in Wistar line rats. Effect of lipopolysaccharides and cholera toxin on epitheliocytes was carried out by a method of withdrawal of segments of rat jejunum and their incubation with the specified substances. Comparative analysis of ultrathin sections of enterocytes of jejunum of rats and tight junctions between them was carried out in control and under the effect of lipopolysaccharides and cholera toxin. RESULTS: Effect of lipopolysaccharides on ultrastructure of enterocytes of rat jejunum manifested in the change of cell form as a result of increase of intercellular space without destruction of tight junctions. Disappearance of desmosomes, increase of nuclei and more pronounced ER were noted in some epitheliocytes. Effect of cholerogen on epitheliocytes of mucous membrane of rat jejunum by a number of signs is similar to the effect of lipopolysaccharides, that manifested in an alteration of ultrastructure of cell, the form of those also transformed as a result of an increase of intercellular space, this process was not accompanied by destruction of tight junctions. Disappearance of folding of the lateral region of plasmatic membrane of cells and a reduction of a number of microvilli was observed under the effect of cholera toxin. CONCLUSION: A similar character of effect of lipopolysaccharides and cholera toxins on ultrastructure of cells and region of tight junctions of enterocytes of rat jejunum was detected, both substances caused an increase of intercellular space without the destruction of tight junctions. PMID- 27228665 TI - [A NOVEL APPROACH TO GENOTYPING OF HOSPITAL ISOLATES OF CLOSTRIDIUM DIFFICILE]. AB - AIM: Development of a novel approach in genotyping of Clostridium difficile and its testing on the example of 140 hospital isolates. MATERIALS AND METHODS: The approach is based on an idea of double digest and selective label (DDSL), used previously during genotyping of other bacterial pathogens. Selection of optimal enzymes for restriction of MluI and Mph1103I was carried out, condition of DDSL reaction execution were optimized. RESULTS: Genotyping of C. difficile hospital isolates was carried out, index of strain discrimination was calculated, conclusions regarding possibilities of the method in elucidation of spread pathways and identification of infection sources were made. CONCLUSION: The developed method of genotyping has a number of advantages over the existing method and can be used to'address issues in epidemiology of infections caused by C. difficile. PMID- 27228666 TI - [CHARACTERISTICS OF BIOLOGICAL AND MOLECULAR-GENETIC PROPERTIES OF LACTOBACILLUS FERMENTUM 90 TC-4 PROBIOTIC STRAIN]. AB - AIM: Confirmation of taxonomic position of Lactobacillus fermentum 90 TC-4 strain using phenotypic (classic microbiological, MALDI TOF mass-spectrometry) and genetic (16S rRNA gene segment sequencing and full genome sequencing) methods. MATERIALS AND METHODS: Object of the study--Lactobacillus fermentum 90 TC-4 strains from various collections. Mass-spectrometric analysis was carried out using Autoflex MALDI TOF mass-spectrometer (Bruker Daltonics, Germany), study of biochemical properties of the strain was carried out using API 50 CHL strips (Biomerueux, France), "DNA-sorb B" kitwas used for isolation ofgenome DNA (CRIE, Moscow). Sequencing of the accumulated fragments of 16S rRNA gene was carried out using GenomeLab GeXP sequencing (Beckman Coulter, USA), full genome sequencing was carried out in MiSeq platform (Illumina). Assembly of genome and bioinformation analysis was carried out using BLAST program (www.blast.ncbi.nlm.nih.gov/blast.cgi), "CLC Bio Assembly" and genome server RAST (rast.nmpdr.org). RESULTS: L. fermentum 90 TC-4 strain was established to be contaminated by L. plantarum culture in a series of cases. As a result of identification of a pure culture of L. fermentum 90 TC-4 strain using a specter of high-technology methods, membership of the strain in L. fer- mentum species has been proven. CONCLUSION: Taxonomic status of L. fermentum 90 TC-4 strain was confirmed. PMID- 27228667 TI - [BIOLOGICAL ACTIVITY OF ANTIMICROBIAL PEPTIDES FROM CHICKENS THROMBOCYTES]. AB - AIM: Isolation and study of biological activity of antimicrobial peptides from chickens thrombocytes. MATERIALS AND METHODS: Peptides from chickens thrombocytes, obtained by reverse-phase high-performance liquid chromatography method with stepped and linear gradients of concentration increase of the organic solvent were used in the study. Their antimicrobial activity was determined by microtitration method in broth; mechanism of biological effect--by using fluorescent spectroscopy method with DNA-tropic dyes. RESULTS: Individual fractions of peptides were isolated from chickens thrombocytes, that possess antimicrobial activity against Staphylococcus aureus P209 and Escherichia coli K12. A disruption of integrity of barrier structures of microorganisms under the effect of thrombocyte antimicrobial peptides and predominance of cells with damaged membrane in the population of E. coli was established. CONCLUSION: The data obtained on antimicrobial activity and mechanism of bactericidal effect of the peptide fractions from chickens thrombocytes isolated for the first time expand the understanding of functional properties of chickens thrombocytes and open a perspective for their further study with the aim of use as antimicrobial means. PMID- 27228668 TI - [MICROBIAL COMPOSITION OF VARIOUS SURFACES OF SKIN DURING DEVELOP- MENT OF ATOPIC DERMATITIS BASED ON DATA FROM MALDI-TOF MASS-SPECTROMETRY IDENTIFICATION METHOD]. AB - AIM: Study transformation of skin microflora during development of atopic dermatitis. MATERIALS AND METHODS: 45 patients with various forms of atopic dermatitis (AtD) were examined. Control group consisted of 26 healthy individuals. The strains were cultivated on elective nutrient media. Identification ofthe isolated strains was carried out by MALDI-TOF mass spectrometry method. RESULTS: A low frequency of occurrence of taxon Staphylococcus epidermidis on face skin and high frequency of occurrence of Staphylococcus aureus on upper and lower limb skin was established for AtD patients compared with healthy individuals. The frequency of occurrence of proteolyti-cally active isolates of S. aureus in AtD patients was 3 times higher than in healthy carriers of this taxon. Taxons of microorganisms not inherent to healthy individuals such as Bacillus mycoides, Pseudomonas putida, Pseudomonas radiobacter were isolated on lower limb and neck skin of AtD patients. A high frequency of occurrence of Cryptococcus satoi, Candida albicans, Malassezia globosa fungi was noted. CONCLUSION: A decrease of barrier functions of skin during AtD facilitates contamination of patients' skin with rare bacterial taxons and fungi. One of the possible mechanisms of suppression of immune competent cell functions could be proteolytic enzymes of S. aureus. PMID- 27228669 TI - [EPIDEMIC SITUATION FOR HIV-INFECTION IN SIBERIAN FEDERAL REGION IN 2014]. AB - AIM: Analyze main epidemiologic indicators for HIV-infection on the territory of SFR for the period from 2012 to 2014 with allotment of contributions of regions into the epidemic for development of personalized regional program for further containment of HIV spread. MATERIALS AND METHODS: Data of main statistical forms and monthly reports of all the regions situated on the territory of the district were used. RESULTS: At large, on both the studied territory and some regions a tendency of growth of HIV-infection morbidity with predominant parenteral transmission was detected. HIV-infection continues to be detected most frequently in young able-bodied population. The number of patients detected for the first time at AIDS stage increases annually, and an increase of lethality among HIV infected was noted. CONCLUSION: Prognostic data for the next year are indicated. PMID- 27228670 TI - [N-ACETYL-beta-D-GLUCOSAMINIDASE OF VIBRIO CHOLERAE]. AB - AIM: Study N-acetyl-beta-D-glucosaminidase (chitobiase) (EC 3.2.1.30) in strains of Vibrio cholerae of O1/non-O1 serogroups of various origin, that is a component of chitinolytic complex taking into account object of isolation and epidemiologic significance of strains. MATERIALS AND METHODS: Cultures of V. cholerae O1/non-O1 serogroup strains were obtained from the museum of live culture of Rostov RIPC. Enzymatic activity analysis was carried out in Hitachi F-2500 fluorescent spectrophotometer using FL Solutions licensed software. NCBI databases were used during enzyme characteristics. RESULTS: N-acetyl-beta-D-glucosaminidase in Vcholerae O1/non-O1 serogroup strains was detected, purified by column chromatography, studied and characterized by a number of physical-chemical and biological properties. Comparative computer analysis of amino acid sequence of N acetyl-beta-D-glucosaminidases of V. cholerae (VC2217 gene), Serratia marcescens etc. has allowed. to attribute the enzyme from V. cholerae to glycosyl-hydrolases (chitobiases) of family 20 and classify it according to enzyme nomenclature as EC 3.2.1.30. CONCLUSION: N-acetyl-beta-D-glucosaminidase in V. cholerae of O1/non-O1 serogroups of various origin and epidemiologic significance, participating in chitin utilization was studied and characterized for the first time, and its possible role in biology of cholera causative agent was shown. PMID- 27228671 TI - [MECHANISMS OF ATTENUATION OF COLD-ADAPTED STRAIN A/KRASNO- DAR/101/35/59 (H2N2)]. AB - AIM: Study of mechanisms of attenuation of cold-adapted (ca) influenza virus strain A/ Krasnodar/101/35/59 (H2N2), associated with disruption of NS1 protein functions. MATERIALS AND METHODS: Study of interferonogenic activity of ca strain A/Krasnodar/101/35/59 (H2N2), its parent variant A/Krasnodar/101/59 (H2N2), virulent strain A/WSN/33 (H1N1) and a number of single gene and multiple gene reassortants between these strains, obtained using reverse genetics, was carried out. Study of dynamics of IFNbeta gene expression was carried out by using a methodical approach of RT-PCR in real time mode. RESULTS: Inclusion of PB-1 gene of ca strain A/ Krasnodar/101/35/59 (H2N2) with reversion to wild type into genome composition of virulent strain A/WSN/33 (H1N1) does not result in a sharp change of interferonogenic activity of the reassortant. At the same time, similar inclusion of PB-1 gene of ca strain resulted in an incredible growth of interferonogenic activity of the reassortant. On the other hand, inclusion of NP gene of wild type strain A/Krasnodar/101/59 (H2N2) into genome composition of the wild type strain A/WSN/33 did not differ by effect on interferonogenicity of the reassortant from inclusion of NP-gene of ca strain. CONCLUSION: Both constellations of genes of parent variants and mutations localized in these genes could affect formation of attenuation phenotype of reassortants. The data obtained allow to assume possible mechanisms of attenuation of ca strains, associated with disruption.of NS gene function. PMID- 27228672 TI - [THERMAL STABILITY AS A PROGNOSTIC INDICATOR OF CONSERVATION OF LIVE EMBRYONIC SMALLPOX VACCINE (TEOVAC) DURING STORAGE]. AB - AIM: Determination of values of coefficients of thermal stability of TEOVac for prognosis of conservation of the vaccine (specific biological activity) during the process of warranty period storage. MATERIALS AND METHOD: TEOVac (masticatory tablets) in primary packaging was kept at increased temperature (accelerated and stress-tests) and at the conditions established by PAP for the preparation (long term tests). Biological activity of the vaccine was determined by titration on 12 day chicken embryos. RESULTS: A correlation between the value of coefficients of thermal stability and conservation of the prepared series of the condition preparation at the final date of storage was experimentally established. CONCLUSION: Coefficients of thermal stability could be used as a prognostic indicator of quality of the produced pelleted formulation of the preparation for evaluation of conservation of the vaccine during warranty period storage. PMID- 27228673 TI - [EPIDEMIOLOGIC SITUATION BY NATURAL-FOCI INFECTIONS IN THE CRIMEA FEDERAL DISTRICT IN 2014-2015]. AB - AIM: Analysis of epidemic manifestations of natural-foci infections (NFI), clarification of spectrum of their causative agents, determination of epizootic activity of natural foci in the Crimea Federal District (KFD). MATERIALS AND METHODS: Epizootologic examination of 10 administrative districts of KDF was carried out. 291 pools (2705 specimens) of ixodes ticks and 283 samples of organs of small mammals were studied by PCRmethod for the presence of DNA/RNA of causative agents of a number of NFI. RESULTS: Morbidity by NFI in KFD was registered by 6 nosologies: Lyme borreliosis, Marseilles fever, leptospirosis; tularemia, intestine yersiniosis and tick-borne viral encephalitis, wherein, transmissive infections made up 91.6%. Circulation of causative agents of Crimea hemorrhagic fever, Q fever, group of tick-borne spotted fever, Lyme borreliosis, human granulocytic anaplasmosis, human monocytic ehrlichiosis, hemorrhagic fever with renal syndrome, West Nile fever, tularemia and leptospirosis was established. CONCLUSION: Due to activity of natural foci of NFI further monitoring of epidemiologic and epizootologic manifestations of these infections in the Crimea, including using genetic methods of analysis, is necessary for ensuring sanitary-epidemiologic welfare of KFD population. PMID- 27228674 TI - [EPIDEMIOLOGIC FEATURES OFNOROVIRUS INFECTION OUTBREAK IN THE REPUBLIC OF NORTH OSSETIA-ALANIA]. AB - AIM: Analysis of epidemiologic features of a norovirus outbreak in Alagir city of the Republic of North Ossetia-Alania and effectiveness of measures of its liquidation. MATERIALS AND METHODS: Data from maps-schemes of water supply system of Alagir city and statistical documentation of Centre of Hygiene and Epidemiology in the Republic of North Ossetia-Alania were used in the study. Indication of norovirus in clinical material and water samples was carried out bypolymerase chain reaction method. RESULTS: Etiological agent of outbreak disease was established--genotype II norovirus. Realization of fecal-oral mechanisms of water transmission pathway of the causative agent of norovirus infection was detected. Conditions facilitating emergence and development of the indicated outbreak were determined--non-satisfactory sanitary-technical condition of water. supply system of the city. CONCLUSION: The studied water outbreak of norovirus infection was caused by GII.17 genotype virus, that currently gradually displaces GII.IV genotype, and was characterized by an intensive start, involvement of all population age groups into the epidemic process (with primary infection of adults), low family focality, predominance of average severity disease forms in the clinical presentation. The counter-epidemic measures carried out ensured rapid localization and liquidation of the norovirus infection outbreak. PMID- 27228675 TI - [CLINICAL-EPIDEMIOLOGICAL CHARACTERISTIC OF WEST NILE FEVER IN KRASNODAR REGION]. AB - AIM: Clinical-epidemiological characteristic of West Nile fever on the territory of Krasnodar Region in multi-year dynamics. MATERIALS AND METHODS: Manifestations of epidemic process and clinical symptoms of West Nile fever (WNF) on the territory of Krasnodar Region were analyzed retrospectively from 1988 to 2013. Results of epidemiologic observations wiih inclusion of monitoring of arbovirus circulation, carried out by Prichernomorskaya Station of Plague Control and Centre of Hygiene and Epidemiology in Krasnodar Region were used. Clinical course of verified WNFwas studied in 62 patients, treated in the Specialized Clinical Infectious Hospital ofKrasnodar in 1999-2012. RESULTS: Clinical-epidemiologic characteristic of cases of West Nile fever morbidity on the territory of Krasnodar Region is presented. The presence of acting foci of arbovirus infections was noted. Clinical signs of the disease are established, patients allocated into groups that require examination for West Nile fever. CONCLUSION: Complex of entomologic-virologic monitoring, prophylactic and counter-epidemic measures was determined, that allow to prevent emergence of dangerous epidemiologic manifestations of foci of the disease in the future. PMID- 27228676 TI - [DETECTION OF DEGREE OF MICROECOLOGICAL DISTURBANCE OF INTESTINE BASED ON CALCULATION OF LOCAL ANTIOXIDANT INDEX]. AB - AIM: Evaluation of dysbiotic condition of intestine based on determination of local antioxidant index (LAI). MATERIALS AND METHODS: 155 patients with bacteriologically confirmed intestine dysbacteriosis were examined: 20 individuals with normobiocenosis of the intestine served as control. Feces dilution 10-2 was used for biochemical study. Catalase, superoxide-dismutase activity and level of malonic dialdehyde was evaluated photometrically by the value of optical density of the samples. Microbial landscape of feces was studied by a bacteriologic method with parallel determination in samples of coprofiltrates of activity of the indicated enzymes and content of malonic dialdehyde. Evaluation of disturbances of microecology of the intestine was carried out by a biochemical method by calculating local antioxidant index in juxtaposition with microbial map data. RESULTS: LAI parameter was significantly higher than 20 in coprofiltrates of people with intestine normobiocenosis. In patients with detected intestine dysbacteriosis, depending on its degree, LAI parameter, changes were registered in the range from negative to 20. Dysbacteriosis in a part of patients had a prolonged character, LAI was lower than 14, that reflected the presence of a persistent inflammation. A tendency of normalization of microbial ecology and growth of LAI was observed during administration of a probiotic preparation. CONCLUSION: A screening criteria is proposed, that differentiates the degree of severity of intestine dysbacteriosis based on calculation of local antioxidant index. PMID- 27228677 TI - [POSSIBILITIES OF APPLICATION OF MALDI-TOF MASS-SPECTROMETRY FOR STUDY OF CARBOHYDRATE-SPECIFIC RECEPTORS FOR DIAGNOSTIC BACTERIOPHAGE EL TOR]. AB - AIM: Study mechanisms of interaction of diagnostic bacteriophage El Tor with sensitive strain Vibrio cholerae El Tor 18507 using direct protein profiling, identification of constant and variable proteins, taking part in interaction of the phage and cell, as well as carbohydrate-specific phage receptors. MATERIALS AND METHODS: . A commercial preparation of cholera diagnostic bacteriophage El Tor, strain V. cholerae El Tor 18507 were used. Effect of carbohydrates on bacteriophage activity was determined in experiments with phage by a classic and modified by us method. Protein profiles of the studied objects were studied using MSP-analysis method. RESULTS: Sucrose was shown to inhibit lytic activity of bacteriophage. Proteome profiles of El Tor bacteriophage and sensitive indicator strains were studied, identification of constant and variable proteins of the studied objects by MSP Peak-list program was carried out. CONCLUSION: Analysis of changes of profiles of phage and microbial cell during interaction with sucrose gave a basis for assuming, that sucrose in the mixture of culture-phage enters interaction namely with phage protein receptors, blocking receptors specific for cholera vibrio, that subsequently manifests in a sharp decrease of phage activity against the sensitive strain. PMID- 27228678 TI - [CONTEMPORARY MOLECULAR-GENETIC METHODS USED FOR ETIOLOGIC DIAGNOSTICS OF SEPSIS]. AB - Etiologic diagnostics of sepsis is one of the most difficult problems of contemporary medicine due to a wide variety of sepsis causative agents, many of which are components of normal human microflora. Disadvantages of contemporary "golden standard" of microbiologic diagnostics of sepsis etiology by seeding of blood for sterility are duration of cultivation, limitation in detection of non cultivable forms of microorganisms, significant effect of preliminary empiric antibiotics therapy on results of the analysis. Methods of molecular diagnostics that are being actively developed and integrated during the last decade are deprived of these disadvantages. Main contemporary methods of molecular biological diagnostics are examined in the review, actualdata on their diagnostic characteristic are provided. Special attention is given to methods of PCR diagnostics, including novel Russian developments. Methods of nucleic acid hybridization and proteomic analysis are examined in comparative aspect. Evaluation of application and perspectives of development of methods of molecular diagnostics of sepsis is given. PMID- 27228679 TI - [ROLE OF INNATE IMMUNITY FACTORS IN PERIODONTITIS PATHOGENESIS]. AB - Chronic generalized periodontitis (CGP) is a disease of periodontium tissues supporting tooth induced by bacteria, that is characterized by the presence of processes of inflammation with destruction of bone tissue. The knowledge of molecular mechanisms of CGP pathogenesis facilitates creation of the most effective methods of therapy of this disease. Bacterial infection is a primary factor in periodontitis etiology, however is not sufficient for its start and subsequent development. It is known, that bacterial factors induce alocal inflammationreaction and.activate the system of innate immunity through activation of Toll-like receptors (TLR), located on the surface of resident cells and leukocytes. Activation of these cells results in production of pro inflammatory cytokines and recruitment of phagocytes and lymphocytes into the inflammation zone. In review we examined the known data regarding factors of immune protection of periodontium including cell populations and cytokines, as well as mechanisms of tissue destruction, that support the tooth. Perspectives of therapy are also discussed PMID- 27228680 TI - [ROLE OF PURINERGIC RECEPTORS IN IMMUNE RESPONSE]. AB - Purine receptors are located on immune and somatic cells of animal and human organisms. Summation of signals from purine and TOLL-like receptors takes place on the level of inflammasome formation and results in summation of the first and second signals of innate immunity. The first signal--from PAMPs (pathogen associated molecular patterns), the second--from DAMPs (danger associated molecular patterns). Adenosine triphosphate (ATP) is the most studied DAMP. ATP connects with purine receptors which include P2 (P2X7 receptors are the best described), that results in opening of channels of these receptors and transit of ATP into the cell. In parallel exit of K+ from cells and entrance of Ca2+ and Na+ into the cells is observed, that is associated with activation of the immune competent cell. Damaged cells dying via necrosis or apoptosis are the source of extracellular ATP, as well as activated immunocytes. Signals from P2 and TOLL like receptors are summarized in effectors of immune response, and activation of P2 receptors in lymphocytes makes a contribution into activation of cells, mediated by T-cell receptor. Negative side of purine receptor activation is a stimulating effect on proliferation and metastasis of malignant cells. The practical output of knowledge on functioning of purine receptors for clinical immunology is the application of agonists and antagonists of purine receptors, as well as explanation of effect of immune modulators from the position of launch of K+/Na+-pump; resulting in prolonged activation of immune competent cells. PMID- 27228681 TI - [MOLECULAR BIOLOGY OF HEPATITIS B VIRUS AND IMMUNOPATHOGENESIS OF CHRONIC VIRAL HEPATITIS B]. AB - Chronic hepatitis B belongs to a category of socially significant diseases due to its wide abundance in the world and high frequency of unfavourable outcomes of this disease. Features of interaction of hepatitis B virus with human immune system, accompanying development of mechanisms of escape from immunological control, is the basis of development of chronic hepatitis B. Molecular-biological features of hepatitis B virus are the basis of the indicated mechanisms, and the content of this review is their examination. Herewith, stages of immunopathogenesis of this disease is the basis of characteristics of interaction of viral proteins with cells of immune system, and isolation of those is accepted in contemporary foreign literature. PMID- 27228682 TI - Foetal Injury in Clinical Trials and Accountability to the Child Once Born. AB - Sponsors of clinical trials have excluded pregnant women from trial participation mainly because of the fear of legal liability for foetal injury. Yet, to prevent untested treatments exposing foetuses generally to unwarranted risks, it is necessary that pregnant women are included in clinical trials. Despite sponsors' fears there are, however, major stumbling blocks for the child once born claiming compensation under English law. Neither the new EU Regulation 536/2014 on clinical trials nor tort law or statutory regulations have achieved a clear and fair avenue for the compensation of children injured in utero. There are also inadequacies with the voluntary pharmaceutical industry guidelines regarding such compensation. Greater clarity and fairness regarding tort and civil liability might encourage sponsors to conduct more trials in pregnant women and more pregnant women to volunteer taking part in research in the knowledge that their children will be compensated if they sustain injuries in utero. PMID- 27228683 TI - Vincent Lambert, Dignity in Dying and the European Court: A Critical Evaluation and the Global Reflections. AB - In this article I analyse the verdict of the European Court of Human Rights in the Case of Lambert and Others v. France, delivered on 5 June 2015, affirming the Conseil d'Etat's decision holding that the withdrawal of artificial nutrition and hydration from Vincent Lambert, a French national lying in tetraplegia and persistent vegetative state, was consistent with French domestic law and the European Convention for the Protection of Human Rights and Fundamental Freedoms. In order to make a comparative evaluation I give an account of judicial decisions across the world and find that the European Court's decision is an affirmative pronouncement, in the prevailing milieu of judicial heterogeneity, as it recognizes a person's right to die with dignity in the face of conflicting claims and arguments, by giving supremacy to a person's autonomy and right of self determination over the deep-rooted religious beliefs and undue paternalistic postures. I conclude that right to die with dignity is a profound area where judge-made law is not the answer. The situation calls for greater consensus and uniformity by evolving suitable legislative strategies. PMID- 27228684 TI - Integrating Advance Research Directives into the European Legal Framework. AB - The possibility of using advance directives to prospectively consent to research participation in the event of dementia remains largely unexplored in Europe. Moreover, the legal status of advance directives for research is unclear in the European regulations governing biomedical research. The article explores the place that advance research directives have in the current European legal framework, and considers the possibility of integrating them more explicitly into the existing regulations. Special focus is placed on issues regarding informed consent, the role of proxies, and the level of acceptable risks and burdens. PMID- 27228685 TI - Using Patient Avatars to Promote Health Data Sharing Applications: Perspectives and Regulatory Challenges. AB - The potential of ICT to address problems in modern healthcare is considerable, and an ICT-driven revolution in healthcare appears imminent. Such developments maybe viewed largely in positive terms. Thus they should result in enhanced treatment and care options, empowering patients--including by permitting greater self-management of illness outside hospital, while offering economic benefits and costs savings over traditional healthcare provision. However, the new possibilities also present manifold risks, such as of data breaches, encroachments on subject autonomy, as well as of other harms. This article considers some of the key regulatory challenges against the background of the progress of the current EU Commission-sponsored 'MyHealthAvatar' project. PMID- 27228686 TI - European Court of Human Rights. ECHR 2016/5 Case of Bergmann v. Germany, 7 January 2016, no. 2327914 (Fifth Section). PMID- 27228688 TI - European Court of Human Rights. ECHR 2016/7 Case of Tavirlau v. Romania, 2 February 2016, no. 43753/10 (Fourth Section). PMID- 27228687 TI - European Court of Human Rights. ECHR 2016/6 Case of Khayletdinov v. Russia, 12 January 2016, no. 2763/13 (Third Section). PMID- 27228689 TI - European Court of Human Rights. ECHR 2016/8 Case of Karpylenko v. Ukraine, 11 February 2016, no. 15509/12 (Fifth Section). PMID- 27228690 TI - European Court of Human Rights. ECHR 2016/9 Case of Arztekammer fur Wien and Dorner v. Austria, 16 February 2016, no. 8895/10 (Fourth Section). PMID- 27228691 TI - European Court of Human Rights. ECHR 2016/10 Case of Bluhdorn v. Germany, 18 February 2016, no. 62054/12 (Fifth Section). PMID- 27228692 TI - European Court of Human Rights. ECHR 2016/11 Case of Y.Y.v. Russia, 23 February 2016, no. 40378/06 (Third Section). PMID- 27228693 TI - European Court of Human Rights. ECHR 2016/12 Case of Klinkenbuss v. Germany, 25 February 2016, no. 53157/11 (Fifth Section). PMID- 27228694 TI - European Court of Human Rights. ECHR 2016/13 Case of Andrey Lavrov v. Russia, 1 March 2016, no. 66252/14 (Third Section). PMID- 27228695 TI - European Court of Justice. ECJ 2016/3, Consorzio Artigiano Servizio Taxi e Autonoleggio (CASTA) and Others v. Azienda Sanitaria Locale di Cirie, Chivasso e Ivrea (ASL TO4), Regione Piemonte, 28 January 2016 (Case C-50/14). PMID- 27228696 TI - [Modern conceptions about the possible impact of palm oil on human health]. AB - Review of the scientific literature on the evidence of the relationship between palm oil (PO) and its components and adverse effects on human health, on the mechanisms of cholesterol control and risks for development of cardiovascular diseases. PO is solid or semisolid at room temperature and often is used as a natural substitute for partially hydrogenated vegetable oils containing trans fatty acids which increase risks of hypercholesteremia. PO contains both saturated and unsaturated fats as well as substances with antioxidant activity. Taking into account the lipid theory of atherosclerosis pathogenesis, and sn-2 hypothesis, PO was compared with other vegetable oils, like olive, sunflower or soybean oils, and did not show great differences in changes of LDL, HDL or total cholesterol levels. Comparison of diets rich in PO with diets rich in trans fatty acids shows improvement of lipid profiles in groups with PO, and serves as a basis for replacement of trans fatty acids in food with PO and its fractions. In addition to fatty acids content, PO contains several phytonutrients including 4 forms of tocopherols and tocotrienols, carotenoids, sterols, and some others. Most of these compounds are considered beneficial for human health, mainly on account of their antioxidant activity. It is concluded that PO is safe component of food, when we pay attention to the rather high content of saturated fats in it. PMID- 27228697 TI - [Types of digestion in breast feeding: returning to the problem]. AB - During the breast feeding the hydrolysis of breast milk nutrients in natural conditions provides by milk enzymes, digestive gland secrets and intestinal epitheliocyte as autolytic induced digestion with following including and development of auto-digestion in hydrolysis of milk lipids and proteins. Milk lactose is hydrolyzed as a type of auto-intestinal digestion. Breast glands release enzymes according to a year lactation dynamics. The mechanism of hydrolase recreation from the mother's blood takes part in milk hudrolase origin. PMID- 27228698 TI - [The study of biochemical mechanisms of mitochondrial dysfunction in rats' hepatocytes during experimental hyperhomocysteinemia]. AB - Methionine is an essential proteinogenic amino acid found in many foods. During its metabolism homocysteine is formed. With elevated level of homocysteine in the blood--hyperhomocysteinemia--increased risk of developing certain diseases, such as non-alcoholic fatty liver disease, is associated. There is evidence that the homocysteine is able to reduce the effect of nitric oxide and induce mitochondrial dysfunction. The present study investigates the relationship of the functional state of the liver cells mitochondria and the level of nitric oxide metabolites in them in experimental hyperhomocysteinemia caused by excessive intake of methionine. The experiment was conducted on 17 male Wistar rats with an initial weight of 220-270 g, rats were divided into 2 groups. A 25%. suspension of methionine was administered (in a dose of 1.5 g of methionine per kg body weight) two times a day for 21 days intragastrically (by gavage) to rats of the first group (n=9) while instead of drinking water animals received a 1% aqueous solution of methionine. Drinks daily volume of methionine solution was 17.2 [15.5; 18.1] ml. In the experiment 8 animals were used, in which severe hyperhomocysteinemia (> 100 mmol/l) was developed. The second group (n = 8) served as a control. These rats were administered suspension base containing no methionine (10% Tween-80, 1% starch, 89% water). The total homocysteine concentration was measured in blood serum by ELISA. In the suspension of liver mitochondria total protein was measured by Lowry method; the concentration of NO metabolites by screening method; succinate dehydrogenase activity--under the reaction of hexacyanoferrate (III) potassium reduction; lactate dehydrogenase activity--by decrease of NADH concentration in the reaction of pyruvate's reduction; activity of H(+)-ATPase--by measuring the inorganic phosphate; superoxide dismutase--by inhibition of quercetin auto-oxidation, the level of Ca(2+)--by reaction with Arsenazo III. Oxidative modification of proteins was evaluated based on the reaction between carbonyl and imino groups of the amino acid residues oxidized with 2,4-dinitrophenylhydrazine to form 2,4 dinitrophenylhydrazone having a specific absorption spectrum in the ultraviolet and visible regions of the spectrum. During three weeks of the experiment the body weight of rats treated with methionine increased from 246 (229; 262) to 302 (283; 311) g, and of control animals--from 256 (231; 264) to 307 (275; 314) g. The difference in body weight gain was not statistically significant. In the study it was revealed that intragastric administration of the methionine for 3 weeks with the addition of this amino acid in the drinking water caused hyperhomocysteinemia. On the one hand it lead to an intensification of energy metabolism in rat liver mitochondria, resulted in increase of lactate dehydrogenase (by 63.0%), succinate dehydrogenase (by 76.1%) and H(+) -ATPase (by 62.5%) activities. On the other hand it lead to the disruption of the Ca2+ deposit (Ca2+ level in mitochondria was reduced by 68.2%) and to enhance of mitochondrial protein carbonylation (by 52.2%) with a predominance of the aggregation process and a reduction of the reserve-adaptive capacity, despite an increase in superoxide dismutase activity (by 87.7%). The reason for these changes in the mitochondria can be the decrease in production of nitric oxide (the level of its metabolites decreased by 21.3%). PMID- 27228699 TI - [The study of the relationship between rates of carnitine exchange and fat mass in young swimmers]. AB - The study of the state of carnitine metabolism is an actual problem for the specialists who are interested in the investigating of children's health, involved in sport. Indicators of carnitine metabolism reflect mitochondrial capacity and the state of energy of the cell, which in it's turn effect on the level of physical performance of athletes and their health status. The aim of our study was to identify the characteristics of carnitine metabolism in young athletes, as well as the establishment of correlation between carnitine metabolism and body fat mass. The study included 46 young athletes 12-17 years old involved in swimming. The average age of the athletes was 15.9 +/- 0.2 years. Carnitine metabolism has been studied by gas chromatography-tandem mass spectrometry, the content of body fat mass has been established by bioimpedance. The free carnitine didn't significantly differ in males (36.3 +/- 1.1 mmol/l) and females (36.3 +/- 1.3 mmol/l). Content of related carnitine was higher in boys- 17.4 +/- 0.8 mmol/l (vs 14.0 +/- 0.9 mmol/l in girls, p < 0.05). Value of related carnitine/free carnitine (AC/C0) was significantly 22.5% higher in boys (0.49 +/- 0.03), because of higher content of related carnitine. The content of body fat mass in boys was 9.6 +/- 0.87%, and in girls--22.24 +/- 1.0%. There was found a significant correlation between indicators of carnitine metabolism and fat body mass. The findings may suggest a higher mitochondrial potential of girls engaged in swimming. PMID- 27228700 TI - [Dynamics of violations of intravascular platelet activity in rats during the formation of metabolic syndrome using fructose models]. AB - Objective: To trace the development of disorders intravascular platelet activity in experimental form of the metabolic syndrome. The study included 61 rat male Wistar rats at the age of 2.5-3 months. Animals were divided into 2 groups: 32 rats were given free access to drink 10% solution of fructose for 8 weeks and 29 rats were the control group. The level of the total cholesterol, high density lipoprotein cholesterol (HDLD cholesterol) and triglycerides were determined using colorimetric enzymatic method. The blood plasma content of endothelin-1 was determined by radioimmunoassay, thromboxane B2 and 6-keto-prostaglandin F(1alpha) -by ELISA. The total content of nitrogen oxide metabolites was revealed in blood. Intravascular platelet activity was assessed using phase contrast microscopy. In terms of fructose load in rats simultaneously with the increase of body weight and the development of biochemical disorders that are characteristic for the metabolic syndrome, there comes a marked progressive increase in intravascular platelet activity [reduction of the number of discocytes from 81.0 +/- 0.1 to 61.3 +/- 0.2%, increase in the number of reactive platelets from 19.0 +/- 0.1 to 38.7 +/- 0.2%, an increase in the number of freely moving in the blood of small units from 2.4 +/- 0.0 to 14.6 +/- 0.1 per 100 free platelets, and of medium and large units (from 4 or more cells) from 0.1 +/- 0.03 to 2.3 +/- 0.06 per 100 free platelets], largely due to the increase (p < 0.01) of the synthesis of thromboxane B2 (from 145.9 +/- 0.2 to 232.6 +/- 0.7 pg/ml), endothelin-4 (from 6.9 +/- 0.2 to 12.5 +/- 0.4 pg/ml) and reduction (p < 0.01) of the generation of 6-keto-prostaglandin F1alpha (from 75.9 +/- 0.2 to 62.3 +/- 0.4 pg/ml), and the total amount of nitric oxide metabolites (from 27.9 +/- 0.3 to 23.2 +/- 0.1 mmol/l). PMID- 27228701 TI - [Toxicological evaluation of nanosized colloidal silver, stabilized with polyvinylpyrrolidone, in 92-day experiment on rats. II. Internal organs morphology]. AB - The aim of the study was to evaluate the safe doses of commercially available nanosized colloidal silver (NCS), stabilized with polyvinilpirrolidone (PVP, food additive E1201) when administered in gastrointestinal tract of rats in the 92-day experiment in terms of the morphological changes in the internals of animals. The sample studied contained non-aggregated nanoparticles (NPs) of silver belonging to size fractions with a diameter of less than 5 nm, 10-20 nm or 50-80 nm. 80% of NPs were inside the range of hydrodynamic diameters 10.6-61.8 nm. The preparation of NCS was administered to growing male Wistar rats. (initial body weight 80 +/- 10 g) for 1 month by intragastric gavage and then consumed with food at doses of 0.1, 1.0 and 10 mg/kg of body weight based on silver. The control animals received water or vehicle of nanomaterial--water solution of PVP. After withdrawal of animals from the experiment by exsanguination under ether anesthesia organs (liver, spleen, kidney, ileum) were isolated and their slides were prepared by standard methods following 'by staining with hematoxylin-eosin. Analysis was performed in light optical microscope equipped with a digital camera at a magnification from 1 x 100 to 1 x 1000. It was shown that the experimental animals treated with the NCS developed series of morphological changes in the tissues of the internal organs (liver, spleen and kidney) with the elevation of the range and severity of structural changes with increasing doses of silver. The most sensitive target of NCS action was apparently liver, which has already shown at a dose of 0.1 mg of silver NP/kg of body weight marked eosinophilic infiltration of portal tracts, which was accompanied at doses of 1.0 and 10.0 mg/kg by the emergence of medium and large-drop fat vacuoles in the cytoplasm of hepatocytes, swelling and lympho-macrophage. infiltration of the portal tracts. Detectable changes can be regarded as symptoms of inflammation of hepatocytes, at least, at a dose nanomaterial of 1.0 mg/kg body weight or more. Relative intensity of morphological changes in the internal organs correlated with published data on the biodistribution of silver NP administered to the gastrointestinal tract. It is concluded that the threshold dose corresponding to the minimum adverse effect of NCS is, according to the study of the above, no more than 1.0 mg/kg of body weight based on silver. PMID- 27228702 TI - [Yogurt consumption and reduced risk of overweight and obesity in adults]. AB - Fermented dairy products comprise a large food group in Russia and are an important source of dietary nutrients like protein, calcium, fat. Obesity is a rising public health issue in Russia. Observing the role of fermented dairy in the maintenance of healthy weights is important. Current study objective was to explore the association between obesity/overweight prevalence and yogurt consumption in Russian adults. Data from RLMS-HSE 1994-2012 was used. Primary materials are available on http://www.cpc.unc.edu/projects/rlms-hse, http://www. hse.ru/org/hse/rlms. Data collected included dietary intake by single 24h recalls and anthropometric measures for 72.400 adults (>= 19 y.o.). Logistic regression models were used to explore the relationships between yogurt consumption and obesity prevalence (BMI > 30.0 compared with. 18.5-25.0), controlling for age and gender. Daily average intake (g/day) of yogurt significantly increased from 1994 to 2012. Yogurt consumption decreased over 40 y.o. in both gender. Women yogurt consumption is inversely correlated with the magnitude of the BMI: the consumption of yogurt in women with normal BMI values (> 18.5-25.0) was significantly higher than in women who are overweight and/or obese (BMI > 25.0; or > 30.0). The mean values of BMI in women who ate yogurt, were significantly lower than in women not consuming yogurt. In men, the relationship between consumption of yogurt and BMI is not revealed. Thus, among women, a significant inverse association was observed between yogurt consumption and obesity (OR 0.582, CI 95% 0.497, 0.680; p < 0.001). The observed association between yogurt intake and prevalence of obesity is dependent on gender: yogurt is associated with lower obesity prevalence only in women. PMID- 27228703 TI - [The study of influence of stresses on virulence genes expression in foodborne pathogens Campylobacter jejuni]. AB - The study of the responses to cold exposure in Campylobacterjejuni (C. jejuni)- one of the most common foodborne pathogens is important for elucidating the mechanisms of acquisition of products contaminated with campylobacter, hazardous properties. These data are also necessary to create effective systems of microbiological controls at all stages of production and storage of food. 5 pairs of oligonucleotide primers were selected for detecting of genes cadF, cdtB, ciaB, flaA, iamA, encoding the main factors of pathogenicity of foodborne pathogens Campylobacter jejuni--adhesion and invasion of epithelial cells, production of CDT-toxin and mobility. To quantify the expression levels of target genes of C. jejuni a comparative method of determining the amount of amplification products of genes encoding pathogenicity factors of Campylobacter spp. has been developed using real-time PCR with intercalating dyes. To calculate and quantify gene expression the mathematical models have been obtained that allow extrapolation of threshold cycles of amplification to the initial number of copies of RNA/DNA in the tested samples. It has been established that exposure of C. jejuni at low temperatures +4 degrees C did not lead to increased levels of expression of genes cdtB and ciaB. However, in the populations of C. jejuni subjected to freezing, followed by incubation at optimum for the pathogen temperature of +42 degrees C, the increase in expression of mRNA encoding protein subunit B of CDT-toxin and antigenic marker of invasion took place. The number of copies of RNA in C. jejuni after stress exposure increased by 1.14-2.6 lg in comparison with intact cultures. CdtB and ciaB gene expression in C. jejuni can serve as an indicator of cell response to stress and helps to restore the functions of the bacterial cells after the termination of cold exposure and return of the pathogen in conditions favourable to the realization of its pathogenic potential. PMID- 27228704 TI - [Phenotypes of food allergy in children]. AB - Questions of food allergy heterogeneity, approaches to allocation of various phenotypes on the basis of clinical signs and immunological markers taking into account an etiology and immune mechanisms of the disease are considered in the article. Allocation of phenotypes contributes the best understanding of essence and it expedient for development of individual approach to diet and therapy. PMID- 27228705 TI - [The complexes of copper, manganese and chromium with enzymatic hydrolysate of pig spleen: research in vitro]. AB - This report describes the preparation and the results of physical and chemical analysis of complexes of enzymatic hydrolysate of pig spleen (EHPS) with manganese, copper and chromium. The complexes were prepared using schemes including the reaction of complexation of inorganic cations with EHPS-peptides structures and application of membrane technology. The process of microfiltration of the resulting mixtures was carried out in tangential flow and low molecular weight fractions were collected. Solutions of copper and manganese complexes with EHPS were subjected to nanofiltration to remove inorganic ions from the reaction mixture. The obtained preparations were lyophilic dried and the molecular weight distribution of the protein fractions in Cu-EHPS, Mn-EHPS and Cr-EHPS complexes was analyzed by exclusion medium pressure liquid chromatography. The percentage relation of fractions with specific molecular weight range was calculated by applying the weighted integration of chromatograms. The determination of copper, manganese and chromium levels in the complexes was performed by atomic absorption method. The content of microelements in the preparations is for copper 16.5 +/- 0.3 mg/g, for manganese--24.9 +/- 0.5 mg/g and for chromium--2.5 +/- 0.2 mg/g. PMID- 27228706 TI - [Enrichment of fruits and berries with selenium and prospects for their using in the preventive nutrition]. AB - The method of producing enriched with selenium berries and fruits has been investigated. The objects of research were plants and berries of edible honeysuckle variety Kingfisher, of garden strawberry variety Korona, of Actinidia kolomikta variety Soroka, the fruits of a field ash variety Sorbinka and the black chokeberry's fruits variety Chernookaya. Enrichment with the selenium of berries and fruits of these cultures has been performed by the method of single and double foliar treatment of plants with aqueous sodium selenate (concentration of 1. 2 and 3 mg/l) during the formation of fruits and berries. Reprocessing had been performed in 10 days after the first one. It was found out that the use of plants' re-processing didn't contribute to greater accumulation of selenium in berries and fruits, according to the single treatment, that's why it is inefficient. Using enrichment, providing the maximum concentration of selenium in the working solution--3 mg/l is the most optimal to increase its content in the honeysuckle--by 5.2 fold; in the strawberry--by 3.9 fold; in Actinidia--3 fold; in the field ash and black chokeberry's fruits--by 2.7 fold. The content of selenium (MUg/100 g) in enriched berries of the honeysuckle was 32.3-35.2; the strawberry--11.7-13.1; Actinidia kolomikta--3.5-4.1; the fruits of the field ash ordinary--4.6-5.1, Aronia--2.8-3.2. Eating fortified fruit and berries will contribute to the prevention of selenium deficiency in the body. Thus, intake of 100 g honeysuckle's berries helps cover the daily requirement of selenium in 47.9 60.9%, the strawberry--in 18.0-22.9%, actinidia' berries, the field ash and black chokeberry's fruits--in 4.3-8.7%. PMID- 27228707 TI - [Micronutrient structure of food parts of a trade bivalve mollusc of Anadara broughtoni]. AB - The content of micronutrients in food parts of a bivalve mollusk of the Far East region of Anadara broughtoni has been defined. It is established that in a muscle the prevailing mineral is potassium, in a cloak with a adductor--sodium. In Anadara broughtoni muscle concentration of potassium reaches 490 mg/100 g of crude tissue that is 2-3 fold higher than the content of this element in combs and oysters and 4 fold above, than in a cloak. For sodium inverse relationship is observed: its contents in a cloak (439 mg/100 g) is 3 fold more, than in a muscle. The low content of sodium in an adductor should be noted. For all food parts of a mollusk of Anadara broughtoni the dominating trace elements are iron and zinc. The content of iron is maximum in a muscle (4.84 mg/100 g) and exceeds that in an adductor by 1.84 fold. The content of zinc in food parts differs insignificantly, the maximum contents is defined in a cloak (2.12 mg/100 g), in comparison with an adductor excess makes only 15%. It should be noted the high content of manganese--especially in a cloak (1.12 mg/100 g)--in comparison with an adductor 43.5% more. Chromium content in a muscle (0.018 mg/100 g) exceeds that in an adductor 2.25 times. The high content of copper in a muscle (0.04 mg/100 g)--4 times old higher than in an adductor is defined. The content of selenium and of iodine is maximum in a muscle (0.03 mg/100 g). For a cloak and a muscle the prevailing class of lipids are phospholipids, for an adductor- cholesterol. The content of cholesterol in an adductor is 2 7-37% more, than in other food parts of a mollusk. The level of total carotenoids in a motive muscle (5.7 mg/100 g) 1.78 fold exceeds the contents in an adductor and by 1.5 fold elevates the contents in a cloak. The main share of carotenoids is concentrated in a motive muscle. PMID- 27228708 TI - [The antioxidant activity of the products of processing of red grape of Cabernet Sauvignon, Merlot, Saperavi]. AB - Experimental data on the antioxidant activity of grape juice, grape concentrates and wine from grapes of Cabernet Sauvignon, Merlot and Saperavi from Crimea and Krasnodar regions was presented. Flavonoids are presented in the form of glycosides of such anthocyanins as delphinidin, malvidin, cyanidin, petunidin, peonidin and also by quercetin and its glycoside, (+)-D-catechin and (-) epicatechin. Oligomeric procyanidins, which are condensed catechol units (2-6) soluble in water, are presented in significant amounts, and polymeric procyanidins with the amount catechin units greater than 7, insoluble in water, constituted the bulk of polyphenols od wine and concentrates from red grapes (no juice). Among non-flavonoid polyphenols hydroxybenzoic (gallic, syringic) and hydroxycinnamic (caftaric, cautaric) acids are identified, the relative content of which in the amount of polyphenols in the juice is maximum, and minimum is in concentrates. It was found that antioxidant activity for all products in standard Trolox method can be estimated by the equation: Y = 0.53627+0.1395X+0.080439X2 0.00064708X3, with a correlation coefficient r = 0.9952; where: Y--antioxidant activity, g/dm3 by Trolox method; X--mass concentration of phenolic substances on the Folin-Ciocalteu, g/dm3. The equation is valid for Y = 0.76-196.22; X = 1.0 82.67. The results of biological testing of wines Cabernet Sauvignon, Merlot, Saperavi and polyphenol concentrates from grape on the biological model of bioluminescent bacteria Photobacterium leiognathi Sh1 demonstrated the applicability of bioassay to assess the antioxidant activity, which correlates well with the polyphenols content and antioxidant activity by trolox method. PMID- 27228709 TI - [On improvement of the mechanism for establishing and changing indicators of quality and food safety in the regulatory and legal acts of the Eurasian Economical Union]. AB - In accordance with the Treaty on the Eurasian Economic Union (EAEU) to ensure the sanitary and epidemiological welfare of the population within the Union, a coordinated policy in agreed policy in the sphere of application of sanitary measures is carried out. Sanitary measures are the obligatory requirements and procedures, including requirements for the final product, processing methods, production, transportation, storage and disposal, sampling procedures, methods of research (tests), risk assessment, the state registration, requirements for packaging directly aimed at ensuring the safety of products (goods) in order to protect human welfare, and they should be applied on the basis having a scientific explanation, and only to the extent that is necessary to protect human welfare. Sanitary measures applied within the Union should be based on international and regional standards, guidelines and (or) the recommendations, except when they based on appropriate scientific studies and explanations. In this case sanitary measures which could provide a higher level of sanitary protection are introduced. At present, the mechanism of the development, justification and approval of common sanitary and epidemiological requirements (ESR) and procedures of the Eurasian Economic Commission (the Commission) is not installed. The absence of a clear mechanism for the development, approval and implementation of the ESR to the products (goods) on the basis having a scientific explanation on the one hand could lead to the creation of unjustified barriers to foreign and mutual trade, on the other--to weaken the level of safety for human life and health of products (goods) placed on markets of the Union. In order to bring the regulatory legal acts of the Customs Union in accordance with the Treaty on the Eurasian Economic Union the Commission in cooperation with the competent authorities of the Member States in the field of sanitary and epidemiological welfare developed the project of Guidelines for development, approval, modification and application of common sanitary epidemiological and hygienic requirements and procedures (hereinafter--Guidelines) which is currently undergoing approval procedures. The project envisages that the Uniform sanitary requirements are established on the basis of scientific research, including the evaluation of the risk of harmful effects of the environment on the human factors, taking into consideration the analysis of international experience in order to harmonize common sanitary requirements with international standards, guidelines and (or) recommendations. Adoption of the draft Guidelines, as well as the application of common methodologies of risk assessment and the hygienic standardization in establishing and justifying safety performance of products (goods) in the Eurasian Economic Union allow quickly and transparently develop, validate, coordinate and approve the Uniform sanitary and epidemiological and hygienic requirements and procedures for sanitary inspection (control) of products (goods) and include them into technical regulations Union. PMID- 27228710 TI - [Healthy eating: implementation of a practice-oriented training program]. AB - Health professionals need to have current knowledge and skills in nutrition. The knowledge and skills have to be acquired in programs of continuing medical education, but also in undergraduate medical education. The main purpose of this work was to develop and implement a practice-oriented training program in nutrition and healthy eating for medical students. The subject named "Nutrition" was implemented into second-year medical curriculum. We defined a theoretical framework and terms such as nutrition, healthy eating, and evidence-based nutrition. In order to get learning outcomes we constructed a method of patients counseling and training "Individual food pyramid". The making of "Individual food pyramid" is a key integrate element of the program. It helps to memorize, understand and apply the basic principles of healthy eating in real life contexts. The final program consists of two sections: "General Nutrition" and "Special Nutrition". The most important intended learning outcome is student's lifestyle improvement. The program is practice-oriented and outcome-based. PMID- 27228711 TI - [Catering for client groups during the XXII Olympic winter games and XI Paralympic winter games of 2014 in Sochi]. AB - The problems of catering control various client groups during the XXII Olympic Winter Games and XI Paralympic Winter Games of 2014 in Sochi is one of the priorities of the sanitary and epidemiological welfare of the population during mass events. The data on the order of nutrition of guests and participants of the games, control of food items, sanitary and microbiological monitoring of drinking water, food raw materials and products are presented. It is noted that the ongoing supervisory activities contributed to the sanitary and epidemiological well-being during the Games. The purpose of this study was to lighting modern achievements in the field of nutrition and food microbiology in the period of the Olympic Games and the determination of their value to the further improvement and use at when conducting mass gatherings. PMID- 27228712 TI - [Antioxidant activity of different types of red grape wines]. AB - This article represented the data about antioxidant activity in the red table and liqueurfaults, prepared from the types of grapes of Cabernet, Merlot and Saperavi. The antioxidant activity of faults in the conversion to TROLOX, the synthetic analog of gallic acid, was determined by voltammetric method. The determination of antioxidant activity was conducted in the young faults (through 2 month after the completion of fermentation) and through half a year the storage without the air inlet. It has been established that the value of antioxidant activity depended on the type of grapes and technology of the production of wine. It was shown that the addition of ethyl alcohol in the production of wines such as Cahors ensured an increase in the extraction of phenol connections from the skin of grapes. This lead to an increase of the antioxidant activity in the Cahors wines in the comparison with the table wine. During the storage of faults the value of antioxidant activity decreased. In the fault cahors wine it remained at the higher level. PMID- 27228713 TI - [Valvular Heart Disease: Current Treatment and Future Perspectives. Editorial: Paradigm shift and future aspect of the treatment of valvular heart disease]. PMID- 27228714 TI - [Valvular Heart Disease: Current Treatment and Future Perspectives. Topics: I. Diagnosis; 1. Physical examination for valvular heart disease]. PMID- 27228715 TI - [Valvular Heart Disease: Current Treatment and Future Perspectives. Topics: I. Diagnosis; 2. Recent progress in echocardiography for valvular heart disease]. PMID- 27228716 TI - [Valvular Heart Disease: Current Treatment and Future Perspectives. Topics: II. Usefulness and limitation of drug therapy for heart valve disease]. PMID- 27228717 TI - [Valvular Heart Disease: Current Treatment and Future Perspectives. Topics: III. Current Treatment: Surgical vs. Medical; Aortic valve, 1) Surgical treatment for aortic valve disease]. PMID- 27228718 TI - [Valvular Heart Disease: Current Treatment and Future Perspectives. Topics: III. Current Treatment: Surgical vs. Medical; 1. Aortic valve, 2) Transcatheter aortic valve implantation]. PMID- 27228719 TI - [Valvular Heart Disease: Current Treatment and Future Perspectives. Topics: III. Current Treatment: Surgical vs. Medical; 2. Mitral valve, 1) Surgery for mitral valve disease]. PMID- 27228720 TI - [Valvular Heart Disease: Current Treatment and Future Perspectives. Topics: III. Current Treatment: Surgical vs. Medical; 2. Mitral valve, 2) Medical therapy]. PMID- 27228721 TI - [Valvular Heart Disease: Current Treatment and Future Perspectives. Topics: III. Current Treatment: Surgical vs. Medical; 3. Infective endocarditis, 1) Surgical intervention for active infective endocarditis]. PMID- 27228722 TI - [Valvular Heart Disease: Current Treatment and Future Perspectives. Topics: III. Current Treatment: Surgical vs. Medical; 3. Infective endocarditis, 2) Infectious endocarditis, medical therapy]. PMID- 27228723 TI - [Discussion meeting on future perspective of valvular heart disease]. PMID- 27228724 TI - [Case Report: Atypical posterior reversible encephalopathy syndrome (PRES) and thrombotic microangiopathy (TMA) in a hemodialysis patient with ANCA-associated vasculitis: a case report]. PMID- 27228725 TI - [Case Report; A case of lipoid pneumonia mimicking lung cancer]. PMID- 27228726 TI - [Case Report; Polyuria and polydipsia as presenting symptoms of sarcoidosis, an elderly case]. PMID- 27228727 TI - [Case Report; A case of bleeding from bile duct caused by tuberculous aneurysm]. PMID- 27228728 TI - [The Cutting-edge of Medicine; Molecular basis of salt-sensitivity and renal injury]. PMID- 27228729 TI - [Research on On-Line Calibration Based Photoacoustic Spectrometry System for Monitoring the Concentration of CO2 in Atmosphere]. AB - Resonate frequency and cell constant of photoacoustic spectrum system are usually calibrated by using standard gas in laboratory, whereas the resonate frequency and cell constant will be changed in-situ, leading to measurement accuracy errors, caused by uncertainties of standard gas, differences between standard and measured gas components and changes in environmental condition, such as temperature and humidity. As to overcome the above problems, we have proposed an on-line atmospheric oxygen-based calibration technology for photoacoustic spectrum system and used in measurement of concentration of carbon dioxide in atmosphere. As the concentration of atmospheric oxygen is kept as constant as 20.96%, the on-line calibration for the photoacoustic spectrum system can be realized by detecting the swept-frequency and peak signal at 763.73 nm. The cell of the PAS has a cavity with length of 100 mm and an inner diameter of 6 mm, and worked in a first longitudinal resonant mode. The influence of environmental temperature and humidity, gas components on the photoacoustic cell's performance has been theoretically analyzed, and meanwhile the resonant frequencies and cell constants were calibrated and acquired respectively using standard gas, indoor air and outdoor air. Compared with calibrated gas analyzer, concentration of carbon dioxide is more accurate by using the resonant frequency and cell constant calculated by oxygen in tested air, of which the relative error is less than 1%, much smaller than that calculated by the standard gas in laboratory. The innovation of this paper is that using atmospheric oxygen as photoacoustic spectrum system's calibration gas effectively reduces the error caused by using standard gas and environmental condition changes, and thus improves the on-line measuring accuracy and reliability of the photoacoustic spectrum system. PMID- 27228730 TI - [The Effect of the Phase on Characteristic Energy of All-Trans-beta-Carotene]. AB - All-trans-beta-carotene has important functions of light collection and light protection, and it is also an important electrooptical material. The Raman spectra of polyenes are a result of the modulation effect of the pi electron energy gap on the vibration of CC bonds, which associate with the external field. So it has higher theoretical significance and practical value to study the molecular structure and properties change under the external field. Ultraviolet visible absorption spectra and resonant Raman spectra of all-trans-beta-carotene in cyclohexanol were measured from 341 to 275 K. The liquid-solid phase transition of the sample appears at 295 K. The characteristic energy describes the conformational change of all-trans-beta-carotene molecule. After the solution phase transition, the characteristic energy epsilon of all-trans-beta-carotene molecule becomes bigger. And when temperature decreasing, the rate of change of the Huang-Rhys, the wavelength of UV absorption peak, electron-phonon Parameter, RSCSs of the CC bond increase. the Huang-Rhys in solid phase is an order of magnitude higher then liquid phase. The characteristic energy of liquid is 0.206 7 eV. The characteristic energy of liquid is 0.559 6 eV. The increasing of the characteristic energy epsilon makes the rate of increasing of the effectively conjugated length becomes bigger. The decreasing of the pi electric energy gap quickens. The function of moderation from electron energy gap to all-trans-beta carotene molecule enhances. Electron-phonon Parameter increases. RSCSs of the CC bond substantially increases. PMID- 27228731 TI - [Research on the Time-Histories of Exited Radicals during the Combustion of Methylcyclohexane by Emission Spectroscopy]. AB - By using three monochromator! detecting systems, the light emissions of excited state OH*, CH* and C* radicals during the transient combustion of methylcyclohexane at high temperatures behind the reflected shock wave have been measured. The dependence of the time-history and the relative intensity of excited radicals on the temperature have been obtained. The reflected shock temperatures are 1 200-1 700 K, the shock pressure is 1.5 atm, the mole fraction of methylcyclohexane is 0.1% and the equivalence ratio is 1.0. At the beginning of the combustion process, these three radicals were produced at the same time. The durations of these radicals became shorter when the temperature increases. At the same ignition temperature, the durations of CH* and OH* are longer than that of C2*. The C2* signal disappears below 1 400 K. The emission intensities of OH* and CH* are not sensitive to the temperature at T < 1 400 K. However, at high temperature (T > 1 400 K), the peak intensity of CH* increases rapidly as temperature increases, while C2* and OH* increase slowly. Current results were compared to the simulation results of corresponding chemical reaction mechanism. The obtained time-history of OH* radical matches well with the prediction of mechanism at low temperatures, but shows difference at high temperatures. The time-history of CH* radical matches well between experimental and simulated results at high temperatures, however, the simulated durations of CH* are longer than the experimental results at low temperatures. Current work provides experimental data to validate and optimize corresponding chemical reaction mechanism containing excited-state species. PMID- 27228732 TI - [The Spectral Analysis of Laser-Induced Plasma in Laser Welding with Various Protecting Conditions]. AB - The shielding gas plays an important role in the laser welding process and the variation of the protecting conditions has an obvious effect on the welding quality. This paper studied the influence of the change of protecting conditions on the parameters of laser-induced plasma such as electron temperature and electron density during the laser welding process by designing some experiments of reducing the shielding gas flow rate step by step and simulating the adverse conditions possibly occurring in the actual Nd : YAG laser welding process. The laser-induced plasma was detected by a fiber spectrometer to get the spectral data. So the electron temperature of laser-induced plasma was calculated by using the method of relative spectral intensity and the electron density by the Stark Broadening. The results indicated that the variation of protecting conditions had an important effect on the electron temperature and the electron density in the laser welding. When the protecting conditions were changed, the average electron temperature and the average electron density of the laser-induced plasma would change, so did their fluctuation range. When the weld was in a good protecting condition, the electron temperature, the electron density and their fluctuation were all low. Otherwise, the values would be high. These characteristics would have contribution to monitoring the process of laser welding. PMID- 27228733 TI - [A Methane Detection System Using Distributed Feedback Laser at 1 654 nm]. AB - A methane (CH4) detection system based on tunable diode laser absorption spectroscopy (TDLAS) technique was experimentally demonstrated. A distributed feedback (DFB) laser around 1 654 nm, an open reflective sensing probe and two InGaAs photodiodes were adopted in the system. The electrical part of the system mainly includes the laser temperature control & modulation module and the orthogonal lock-in amplifier module. Temperature and spectrum tests on the DFB laser indicate that, the laser temperature fluctuation can be limited to the range of -0.02-0.02 degrees C, the laser's emitting wavelength varies linearly with the temperature and injection current, and also good operation stability of the laser was observed through experiments. Under a constant working temperature, the center wavelength of the laser is varied linearly by adjusting the driving current. Meanwhile, a 5 kHz sine wave signal and a 10 Hz saw wave signal were provided by the driving circuit for the harmonic extraction purpose. The developed orthogonal lock-in amplifier can extract the If and 2f harmonic signals with the extraction error of 3.55% and 5% respectively. By using the open optical probe, the effective optical pass length was doubled to 40 cm. Gas detection experiment was performed to derive the relation between the harmonic amplitude and the gas concentration. As the concentration increases from 1% to 5%, the amplitudes of the 1f harmonic and the 2f harmonic signal were obtained, and good linear ration between the concentration and the amplitude ratio was observed, which proves the normal function of the developed detection system. This system is capable to detect other trace gases by using relevant DFB lasers. PMID- 27228734 TI - [Optical Properties of ZnO Films Fabricated by Atomic Layer Deposition]. AB - The ZnO films were deposited by atomic layer deposition method using water and diethylzinc as precursors at different temperatures (110 and 190 degrees C). X ray photoelectron spectroscopy, spectroscopic ellipsometry and photoluminescence spectra (PL) were used to investigate the elemental composition and optical properties of ZnO films. Our results showed that with the increasing of the growth temperature, the amount of -OH groups in the ZnO film decreased, which indicated that the reactions went to completion at high processing temperatures. The PL spectra of the ZnO film deposited at 110 degrees C exhibited two emission bands, one in the UV region and the other in the visible region. When the deposition temperature increased to 190 degrees C, the emission bands in the visible region disappeared, which indicated that the deep level defect in ZnO became less. The carrier mobility improved from 25 to 32 cm2 x (V x S)(-1) with the reduction of the defects in the ZnO film. The refractive index of the ZnO films decreased from 2.33 to 1.9 in the 375-800 nm region. The optical absorption edge (E(g)) values of the ZnO films deposited at different temperature were about 3.27 eV. PMID- 27228735 TI - [Impact of Light Polarization on the Measurement of Water Particulate Backscattering Coefficient]. AB - Particulate backscattering coefficient is a main inherent optical properties (IOPs) of water, which is also a determining factor of ocean color and a basic parameter for inversion of satellite ocean color remote sensing. In-situ measurement with optical instruments is currently the main method for obtaining the particulate backscattering coefficient of water. Due to reflection and refraction by the mirrors in the instrument optical path, the emergent light source from the instrument may be partly polarized, thus to impact the measurement accuracy of water backscattering coefficient. At present, the light polarization of measuring instruments and its impact on the measurement accuracy of particulate backscattering coefficient are still poorly known. For this reason, taking a widely used backscattering coefficient measuring instrument HydroScat6 (HS-6) as an example in this paper, the polarization characteristic of the emergent light from the instrument was systematically measured, and further experimental study on the impact of the light polarization on the measurement accuracy of the particulate backscattering coefficient of water was carried out. The results show that the degree of polarization(DOP) of the central wavelength of emergent light ranges from 20% to 30% for all of the six channels of the HS-6, except the 590 nm channel from which the DOP of the emergent light is slightly low (-15%). Therefore, the emergent light from the HS-6 has significant polarization. Light polarization has non-neglectable impact on the measurement of particulate backscattering coefficient, and the impact degree varies with the wave band, linear polarization angle and suspended particulate matter (SPM) concentration. At different SPM concentrations, the mean difference caused by light polarization can reach 15.49%, 11.27%, 12.79%, 14.43%, 13.76%, and 12.46% in six bands, 420, 442, 470, 510, 590, and 670 nm, respectively. Consequently, the impact of light polarization on the measurement of particulate backscattering coefficient with an optical instrument should be taken into account, and the DOP of the emergent light should be reduced as much as possible. PMID- 27228736 TI - [Precise Temperature Measurement with Imaged Spectral Technique]. AB - A new method for temperature measurement is established based on the gray-body radiation, which can not only determine the real-time temperature of thermal source, but also conduct non-contacted temperature measurement with high precision. First, a wide-band emission spectrum of the given radiation source is measured precisely with a multi-channel CCD image spectrometer, which is served as its spectral fingerprints for establishing a gray-body radiation model; Secondly, the coefficients introduced in the gray-body radiation model are determined by fitting the measured emission spectrum; Finally, a combination of spectroscopic technique and the gray-body radiation model is employed to measure any temperature of the given radiation source. Having tested on both types of radiation sources, with and without a flame, the present work has demonstrated that the imaged spectral approach mentioned above can be utilized as a real-time, high precision and non-contacted technique for temperature measurement. PMID- 27228737 TI - [Modeling and Simulation of Spectral Polarimetric BRDF]. AB - Under the conditions of the polarized light, The reflective surface of the object is affected by many factors, refractive index, surface roughness, and so the angle of incidence. For the rough surface in the different wavelengths of light exhibit different reflection characteristics of polarization, a spectral polarimetric BRDF based on Kirchhof theory is proposee. The spectral model of complex refraction index is combined with refraction index and extinction coefficient spectral model which were got by using the known complex refraction index at different value. Then get the spectral model of surface roughness derived from the classical surface roughness measuring method combined with the Fresnel reflection function. Take the spectral model of refraction index and roughness into the BRDF model, then the spectral polarimetirc BRDF model is proposed. Compare the simulation results of the refractive index varies with wavelength, roughness is constant, the refraction index and roughness both vary with wavelength and origin model with other papers, it shows that, the spectral polarimetric BRDF model can show the polarization characteristics of the surface accurately, and can provide a reliable basis for the application of polarization remote sensing, and other aspects of the classification of substances. PMID- 27228738 TI - [Chiral Transformation of PARC18 Assemblies on NaOH Solution Subphase]. AB - Achiral molecules with conjugated structures can form chiral supramolecules through interfacial self-assembly. These spontaneous symmetry breaking processes may help elucidate the origin of life and are thus of great importance. So far, the mechanism of interfaciam self-assembly has been discussed in detail. However, dynamics of the chiral assemblies was rarely investigated. In order to clarify whether the chiral structures are stable or dynamic, we employed second harmonic generation linear dichroism (SHG-LD) to investigate the supramolecular chirality of PARC18 at air/aqueous interface. It was shown that PARC18 formed chiral structures with stable chiral state at air/water interface. While at air/NaOH solution interface, the chiral state changed with time. In addition, on NaOH solution subphase, contributions of magnetic dipole to second harmonic signals were dominant. We suggest that this is due to isomerization of PARC18 molecules on NaOH solution subphase. As a result, the two chromophores coupled with each other and the magnetic dipole contribution was enhanced. PMID- 27228739 TI - [State Recognition of Solid Fermentation Process Based on Near Infrared Spectroscopy with Adaboost and Spectral Regression Discriminant Analysis]. AB - In order to achieve the rapid monitoring of process state of solid state fermentation (SSF), this study attempted to qualitative identification of process state of SSF of feed protein by use of Fourier transform near infrared (FT-NIR) spectroscopy analysis technique. Even more specifically, the FT-NIR spectroscopy combined with Adaboost-SRDA-NN integrated learning algorithm as an ideal analysis tool was used to accurately and rapidly monitor chemical and physical changes in SSF of feed protein without the need for chemical analysis. Firstly, the raw spectra of all the 140 fermentation samples obtained were collected by use of Fourier transform near infrared spectrometer (Antaris II), and the raw spectra obtained were preprocessed by use of standard normal variate transformation (SNV) spectral preprocessing algorithm. Thereafter, the characteristic information of the preprocessed spectra was extracted by use of spectral regression discriminant analysis (SRDA). Finally, nearest neighbors (NN) algorithm as a basic classifier was selected and building state recognition model to identify different fermentation samples in the validation set. Experimental results showed as follows: the SRDA-NN model revealed its superior performance by compared with other two different NN models, which were developed by use of the feature information form principal component analysis (PCA) and linear discriminant analysis (LDA), and the correct recognition rate of SRDA-NN model achieved 94.28% in the validation set. In this work, in order to further improve the recognition accuracy of the final model, Adaboost-SRDA-NN ensemble learning algorithm was proposed by integrated the Adaboost and SRDA-NN methods, and the presented algorithm was used to construct the online monitoring model of process state of SSF of feed protein. Experimental results showed as follows: the prediction performance of SRDA-NN model has been further enhanced by use of Adaboost lifting algorithm, and the correct recognition rate of the Adaboost-SRDA-NN model achieved 100% in the validation set. The overall results demonstrate that SRDA algorithm can effectively achieve the spectral feature information extraction to the spectral dimension reduction in model calibration process of qualitative analysis of NIR spectroscopy. In addition, the Adaboost lifting algorithm can improve the classification accuracy of the final model. The results obtained in this work can provide research foundation for developing online monitoring instruments for the monitoring of SSF process. PMID- 27228740 TI - [The Use of FTIR Coupled with Partial Least Square for Quantitative Analysis of the Main Composition of Bamboo/Polypropylene Composites]. AB - The biomass to plastic ratio in wood plastic composites (WPCs) greatly affects the physical and mechanical properties and price. Fast and accurate evaluation of the biomass to plastic ratio is important for the further development of WPCs. Quantitative analysis of the WPC main composition currently relies primarily on thermo-analytical methods. However, these methods have some inherent disadvantages, including time-consuming, high analytical errors and sophisticated, which severely limits the applications of these techniques. Therefore, in this study, Fourier Transform Infrared (FTIR) spectroscopy in combination with partial least square (PLS) has been used for rapid prediction of bamboo and polypropylene (PP) content in bamboo/PP composites. The bamboo powders were used as filler after being dried at 105 degrees C for 24 h. PP was used as matrix materials, and some chemical regents were used as additives. Then 42 WPC samples with different ratios of bamboo and PP were prepared by the methods of extrusion. FTIR spectral data of 42 WPC samples were collected by means of KBr pellets technique. The model for bamboo and PP content prediction was developed by PLS-2 and full cross validation. Results of internal cross validation showed that the first derivative spectra in the range of 1 800-800 cm(-1) corrected by standard normal variate (SNV) yielded the optimal model. For both bamboo and PP calibration, the coefficients of determination (R2) were 0.955. The standard errors of calibration (SEC) were 1.872 for bamboo content and 1.848 for PP content, respectively. For both bamboo and PP validation, the R2 values were 0.950. The standard errors of cross validation (SECV) were 1.927 for bamboo content and 1.950 for PP content, respectively. And the ratios of performance to deviation (RPD) were 4.45 for both biomass and PP examinations. The results of external validation showed that the relative prediction deviations for both biomass and PP contents were lower than +/- 6%. FTIR combined with PLS can be used for rapid and accurate determination of bamboo and PP content in bamboo/PP composites. PMID- 27228741 TI - [The Study on Infrared Spectra of 7-Hydroxycoumarin by Density Functional Theory]. AB - Infrared spectroscopy is an important source of information for the identification of the compounds structure and it is great significant for biological activity research of natural and organic drug molecules. With the theoretical calculation method is more reasonable and calculation accuracy continues to improve, Theoretical calculate advantage is more obvious in the infrared spectrum simulation and vibration modes attributable identified. And it has important reference value for experimental study of infrared spectral analysis. Using density functional theory, geometry optimizations and frequencies calculation of 7-Hydroxycoumarin were performed at the level of B3LYP/6-311G(d, p), the stable structure and all vibration modes of 7-Hydroxycoumarin were attained. The results show that the infrared absorption peak of 7-hydroxycoumarin is mainly distributed in the several regions in wave number of 3 700-3 500, 3 150 3 000, 1 750-1 400, 1 400-1 000, 1 000-50 cm(-1). In addition to the vibration in a wave number range of 3 700-3 500, 3 150-3 000 cm(-1) is relatively independent, and were attributed to OH stretching vibration and benzene ring CH stretching vibration, the other several vibration regions are more complex, the different degree of spectral peaks is composed of multiple vibration modes. Finally, based on the theoretical analysis of the vibration mode, the vibration modes of 7 Hydroxycoumarin molecule were assigned, and in order to discuss the reliability of theoretical calculation method, the correlation diagram of the main absorption peak of 7-hydroxyl group was drawn from the theoretical value of X axis and the experimental value of Y axis, the correlation between experimental IR data and calculated IR data of 7-Hydroxycoumarin was analyzed through the linear regression method. Results show that they have good correlation, correlation coefficient values "r" equals 0.998 5, and the theory calculation of 7 Hydroxycoumarin IR by density functional theory at the base set level is reliable. PMID- 27228742 TI - [Prediction of Cellulose, Hemicellulose, Lignin and Ash Content of Four Miscanthus Bio-Energy Crops Using Near-Infrared Spectroscopy]. AB - Biomass energy is being industrialized rapidly in China in recent years, whereas, research on energy grass is still in primary stage. Only if near-infrared spectroscopy mode was constructed which was used to predict the lignin, cellulose and hemicellulose contents in energy crop, the varieties screening, performance evaluation and on-line control of industrialization would be facilitated. In this study, the prediction model for quality indices (cellulose, hemicellulose, lignin and ash) of four energy grass (Miscanthus) was built using Fourier transform near infrared (FT-NIR) spectroscopy combined with partial least squares regression (PLSR), and the impacts exerted by particle size on the model were also revealed. The results showed that (1) the root mean error of cross validation (RMSECV) of cellulose, hemicelluloses and lignin contents were 1.35% (R = 0.88), 0.39% (R = 0.91) and 0.35 (R2 = 0.80), respectively in stalk and 0.72% (R = 0.88), 0.85% (R2 = 0.85) and 0.44 (R2 = 0.87), respectively in leaf. The model showed good performance in prediction of corresponding contents in unknown samples, however, no satisfying performance in ash content. (2) Both 2 mm and 0.5 mm grades of particle size can meet accuracy requirements of the model. But considering the time and labor cost, 2 mm grade was suggested for model building. PMID- 27228743 TI - [Determination of Alcoholysis Degree and Volatile Matter of Poly-Vinyl Alcohol Using Diffuse-Reflection Near Infrared Spectroscopy]. AB - A new method using reflection NIR technology was developed to determine the alcoholysis degree and volatile matter of Poly-vinyl alcohol (PVA). 120 samples were used in this research. NIR spectra of the sample were scanned by the spectrometer from 1 000 to 1 800 nm. The alcoholysis degree and volatile matter were determined by the national standard method of volumetric and gravimetric method respectivily. Partial least squares (PLS1) was used to establish the quantitative correction model of alcoholysis degree and volatile matter of PVA. The corrected relationship (Rc) of alcoholysis degree and volatile matter was 0.976 and 0.981 respectively. The corrected standard deviation(SEC) was 0.176 and 0.197. The predicted relationship (R(p)) was 0.967 and 0.969. The predicted deviation(SEP) was 0.202 and 0.193. The test for actual samples showed that the NIR method was fitted for the requirement of PVA analysis. PMID- 27228744 TI - [Identification of Microalgae Species Using Visible/Near Infrared Transmission Spectroscopy]. AB - At present, the identification and classification of the microalgae and its biochemical analysis have become one of the hot spots on marine biology research. Four microalgae species, including Chlorella vulgaris, Chlorella pyrenoidosa, Nannochloropsis oculata, Chlamydomonas reinhardtii, were chosen as the experimental materials. Using an established spectral acquisition system, which consists of a portable USB 4000 spectrometer having transmitting and receiving fiber bundles connected by a fiber optic probe, a halogen light source, and a computer, the Vis/NIR transmission spectral data of 120 different samples of the microalgae with different concentration gradients were collected, and the spectral curves of fourmicroalgae species were pre-processed by different pre treatment methods (baseline filtering, convolution smoothing, etc. ). Based on the pre-treated effects, SPA was applied to select effective wavelengths (EWs), and the selected EWs were introduced as inputs to develop and compare PLS, Least Square Support Vector Machines (LS-SVM), Extreme Learning Machine (ELM)models, so as to explore the feasibility of using Vis/NIR transmission spectroscopy technology for the rapid identification of four microalgae species in situ. The results showed that: the effect of Savitzky-Golay smoothing was much better than the other pre-treatment methods. Six EWs selected in the spectraby SPA were possibly relevant to the content of carotenoids, chlorophyll in the microalgae. Moreover, the SPA-PLS model obtained better performance than the Full-Spectral PLS model. The average prediction accuracy of three methods including SPA-LV-SVM, SPA-ELM, and SPA-PLS were 80%, 85% and 65%. The established method in this study may identify four microalgae species effectively, which provides a new way for the identification and classification of the microalgae species. The methodology using Vis/NIR spectroscopy with a portable optic probe would be applicable to a diverse range of microalgae species and proves to be a rapid, real-time, non destructive, precise method for the physiological and biochemical detection for microalgae. PMID- 27228745 TI - [Identification of Animal Whole Blood Based on Near Infrared Transmission Spectroscopy]. AB - The inspection and classification for blood products are important but complicated in import-export ports or inspection and quarantine departments. For the inspection of whole blood products, open sampling can cause pollution and virulence factors in bloods samples may even endanger inspectors. Thus non contact classification and identification methods for whole bloods of animals are needed. Spectroscopic techniques adopted in the flowcytometry need sampling blood cells during the detection; therefore they can not meet the demand of non-contact identification and classification for whole bloods of animals. Infrared absorption spectroscopy is a technique that can be used to analyze the molecular structure and chemical bonds of detected samples under the condition of non contact. To find a feasible spectroscopic approach of non-contact detection for the species variation in whole blood samples, a near infrared transmitted spectra (NITS, 4 497.669 - 7 506.4 cm(-1)) experiment of whole blood samples of three common animals including chickens, dogs and cats has been conducted. During the experiment, the spectroscopic resolution is 5 cm(-1), and each spectrogram is an average of 5 measured spectral data. Experimental results show that all samples have a sharp absorption peak between 5 184 and 5 215 cm(-1), and a gentle absorption peak near 7 000 cm(-1). Besides, the NITS curves of different samples of same animals are similar, and only have slight differences in the whole transmittance. A correlation coefficient (CC) is induced to distinguish the differences of the three animals' whole bloods in NITS curves, and the computed CCs between NITS curves of different samples of the same animals, are greater than 0.99, whereas CCs between NITS curves of the whole bloods of different animals are from 0.509 48 to 0.916 13. Among which CCs between NITS curves of the whole bloods of chickens and cats are from 0.857 23 to 0.912 44, CCs between NITS curves of the whole bloods of chickens and dogs are from 0.509 48 to 0.664 82, and CCs between NITS curves of the whole bloods of cats and dogs are from 0.872 75 to 0.916 13. The cat and the dog belong to the class of mammal, and the CCs between their whole bloods NITS curves are greater than those between chickens and cats, or chickens and dogs, which are hetero-class animals. Namely, the whole bloods NITS curves of the cat and the dog have higher similarity. These results of NITS provide a feasible method of non-contact identification of animal whole bloods. PMID- 27228746 TI - [The Near Infrared Spectral Bands Optimal Selection in the Application of Liquor Fermented Grains Composition Analysis]. AB - In order to improve the technical level of the rapid detection of liquor fermented grains, in this paper, use near infrared spectroscopy technology to quantitative analysis moisture, starch, acidity and alcohol of liquor fermented grains. Using CARS, iPLS and no information variable elimination method (UVE), realize the characteristics of spectral band selection. And use the multiple scattering correction (MSC), derivative and standard normal variable transformation (SNV) pretreatment method to optimize the models. Establish models of quantitative analysis of fermented grains by PLS, and in order to select the best modeling method, using R2, RMSEP and optimal number of main factors to evaluate models. The results showed that the band selection is vital to optimize the model and CARS is the best optimization of the most significant effect. The calculation results showed that R2 of moisture, starch, acidity and alcohol were 0.885, 0.915, 0.951, 0.885 respectively and RMSEP of moisture, starch, acidity and alcohol were 0.630, 0.519, 0.228, 0.234 respectively. After optimization, the model prediction effect is good, the models can satisfy the requirement of the rapid detection of liquor fermented grains, which has certain reference value in the practical. PMID- 27228747 TI - [Measurement of Soil Total N Based on Portable Short Wave NIR Spectroscopy Technology]. AB - Near infrared spectroscopy analysis as a reliable, rapid, little sample preparation requirement, low-cost, convenient, nondestructive and green technique becomes more and more important in the area of soil nutrition measurement. Near infrared spectroscopy are highly sensitive to C-H, O-H and N-H bonds of soil components such as total nitrogen (TN) making their use in the agricultural and environmental sciences particularly appropriate. The analytical abilities of near infrared spectroscopy depend on the repetitive and broad absorption of light by C H, O-H and N-H bonds. A total of 243 soil samples were collected from wencheng, Zhejiang province. Raw spectra and wavelength-reduced spectra with 3 different pretreatment methods (Savitzky-Golay smoothing (SG), Reduce (RD), and Wavelet Transform (WT)) were compared to determine the optimal wavelength range and pretreatment method for analysis. 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 preprocessed spectra were then used to select sensitive wavelengths by competitive adaptive reweighted sampling (CARS), Random frog and Successive Projections Algorithm (SPA) methods. Different numbers of sensitive wavelengths were selected by different variable selection methods with Wavelet Transform (WT) preprocessing method. Partial least squares (PLS) was used to build models with the full spectra, and Extreme Learning Machine (ELM) and LS-SVM were applied to build models with the selected wavelength variables. The overall results showed that PLS and LS-SVM models performed better than ELM models, and the LS-SVM models with the selected wavelengths based on SPA obtained the best results with the determination coefficient (R2), RMSEP and RPD were 0.63, 0.007 9 and 1.58 for prediction set. The results indicated that it was feasible to use portable short wave near-infrared spectral technology to predict soil total nitrogen and wavelengths selection could be very useful to reduce redundancy of spectra. PMID- 27228748 TI - [Raman Signal Enhancement for Gas Detection Using a Hollow Core Optical Fiber]. AB - Raman spectroscopy has been widely used for gas detection due to the advantages of simultaneous multiple species recognition, rapid analysis, and no sample preparation, etc. Low sensitivity is still a great limitation for Raman application. In this work a Raman system based on a hollow core optical fiber (HCOF) was built and the detection sensitivity for the gas was significantly improved. Also a comparison was carried out between the HCOF Raman system and back-scattering Raman system. The obtained results indicated that the HCOF Raman system could well enhance the signal while also for the background and noise. Using HCOF system, 60 folds signal enhancement was achieved with SNR improvement of 6 times for the N2 and O2 in air when comparing to the back-scattering system. While for the same signal intensity, with HCOF system the exposure time was well shortened to 1/60 and the noise was decreased to 1/2 than the back-scattering system. PMID- 27228749 TI - [Synthesis of Ultra-Uniform Gold Spherical Nanoparticles with Different Sizes and Their SERS Effects Study]. AB - A series of ultra-uniform gold spherical nanoparticles with different sizes were synthesized using gold chloride acid as precursor, ascorbic acid as reductant and sodium citrate hydrate as surfactant. The prepared Au nanoparticles were characterized by scanning electron microscope (SEM) and UV-visible spectroscopy. The results showed that the absorption peak of UV-Vis spectroscopy red-shifted along with size increasing of the nanoparticles and finally appeared a quadrupole peak. To further explore the mechanism of surface enhanced Raman spectroscopy (SERS) effect and optimize the sensitivity, SERS on Au nanoparticles with different sizes were measured using Rhodamine 6G (R6G) as probe molecule. We found the SERS signals of R6G on the Au nanoaprtciles were highly size dependent. When the particles sizes are close to -120 nm, it will generate the highest enhancement, the enhancement factor is about 1.1 x 10(7). The 3D-FDTD simulation results correlated with the experimental data very well. PMID- 27228750 TI - [Raman Characterization of Hydrate Crystal Structure Influenced by Mine Gas Concentration]. AB - CH4 /C2H6/N2 mixed hydrate formation experiments were performed at 2 degrees C and 5 MPa for three different mine gas concentrations (CH4/C2H6/N2, G1 = 54 : 36 : 10, G2 = 67.5 : 22.5 : 10, G3 = 81 : 9 : 10). Raman spectra for hydration products were obtained by using Microscopic Raman Spectrometer. Hydrate structure is determined by the Raman shift of symmetric C-C stretching vibration mode of C2H6 in the hydrate phase. This work is focused on the cage occupancies and hydration numbers, calculated by the fitting methods of Raman peaks. The results show that structure I (s I) hydrate forms in the G1 and G2 gas systems, while structure II (s II) hydrate forms in the G3 gas system, concentration variation of C2H6 in the gas samples leads to a change in hydrate structure from s I to s II; the percentages of CH4 and C2H6 in s I hydrate phase are less affected by the concentration of gas samples, the percentages of CH4 are respectively 34.4% and 35.7%, C2H6 are respectively 64.6% and 63.9% for gas systems of G1 and G2, the percentages of CH4 and 2 H6 are respectively 73.5% and 22.8% for gas systems of G3, the proportions of object molecules largely depend on the hydrate structure; CH4 and C2H6 molecules occupy 98%, 98% and 92% of the large cages and CH4 molecules occupy 80%, 60% and 84% of the small cages for gas systems of G1, G2 and G3, respectively; additionally, N2 molecules occupy less than 5% of the small cages is due to its weak adsorption ability and the lower partial pressure. PMID- 27228751 TI - [Study on Raman Spectra of Some Clinical Medicine]. AB - Aiming at the shortage of the Raman spectra of drugs and the current situation of drug testing, we have applied Raman spectroscopic technique to several kinds of medicine, such as antibiotics, antihistamine, hemocoagulase and antiemetics. The spectral properties for the samples with high Raman activity are investigated by observing their Raman spectra to yield the shift, intensity, and line width of the Raman peaks, as well as the line shape of Raman envelope. For those samples with weak Raman activity or complex structures that are hard to be identified, we have also made some tentative measurements or raise some suggestions for future measurement. Comparing the similarities or differences among many Raman spectra of drugs, it is evident that drugs with small molecule have apparent spectral characteristics, by which to recognize them is very feasible, while those with large molecule usually have weak peaks or complex envelope in their spectra, leading to a difficult recognition and uncertain peak positions. This work not only proposes to identify chemical ingredients of drugs by observing and analyzing their Raman spectra, but also provides experimental evidences for medical workers doing so. The present results lay the foundation for establish the database of Raman spectra for drugs, and point out the prospect for rapid identification and detection of drugs, promoting the application of Raman spectroscopy technology on drug detection to a certain extent. PMID- 27228752 TI - [Characteristics of Raman Spectra of Polyethylene Terephthalate]. AB - Raman spectrometry was employed to study the characteristics of Raman spectra of polyethylene terephthalate (PET), which were treated with sodium hydroxide, sulfuric acid and copper sulfate, respectively. Raman spectra under different conditions were obtained and the characteristics of the Raman spectra were analyzed. The morphology structures were observed under different conditions using Atomic Force Microscope. The results show that the spectral intensity of PET treated with sodium hydroxide is higher than that untreated between 200-1 750 cm(-1), while the intensity of PET treated with sodium hydroxide is lower than that untreated beyond 1 750 cm(-1) and the fluorescence background of Raman spectra is decreased. The spectral intensity of PET treated with sulfuric acid is remarkably reduced than that untreated, and the intensity of PET treated with copper sulphate is much higher than that untreated. The research results obtained by Atomic Force Microscopy show that the variations of the Raman spectra of PET fibers are closely related to. the chemical bonds and molecular structures of PET fibers. The surface of the PET treated with sodium hydroxide is rougher than that untreated, the surface roughness of the PET treated with sulfuric acid is reduced as compared to that untreated, while the surface roughness of the PET treated with copper sulphate is increased. The results obtained by Raman spectroscopy are consistent with those by Atomic Force Microscopy, indicating that the combination of Raman spectroscopy and Atomic Force Microscopy is expected to be a promising characterization technology for polymer characteristics. PMID- 27228753 TI - [In Vivo Study of Chitin in Fungal Hyphae Based on Confocal Raman Microscopy]. AB - Chitin is an important structural polysaccharide of fungal cell wall. In this paper, aerial hyphae of Colletotrichum camelliae Massee was first studied by confocal Raman microscopy in vivo. Firstly, the optimal experimental parameters of hyphae for collecting the Raman spectra were determined, and the typical Raman spectra of hyphae, chitin standard and background were acquired. By comparing analysis, characteristic peaks of chitin were found in hyphae. Then, a region of interesting on hyphae was selected for Raman scanning. Through principal component analysis, the Raman signal of hyphae and background in the scanning area can be separated clearly. Combined with loading weight plot, two main characteristic peaks of hyphae were obtained, 1 622 cm(-1) was belong to chitin and 1 368 cm(-1) was assigned to pectic polysaccharide. Finally, two and three dimension chemical images of fungal hyphae were realized based on Raman fingerprint spectra of chitin in a nondestructive way. PMID- 27228754 TI - [Lipid Composition of Different Breeds of Milk Fat Globules by Confocal Raman Microscopy]. AB - Different breeds of cows affect the form of fat exist in dairy products and the final functionality, which depended mainly on the composition of the milk fat globules(MFG). However, the relationship between the composition and breeds has not been illuminated. In our study, differences in the lipid content and fatty acid composition of native bovine, buffalo and yak MFG were investigated by confocal Raman spectroscopy. The research offers the possibility of acquisition and analysis of the Raman signal without disruption of the structure of fat globule. The results showed that yak MFG had a higher ratio of band intensities at 2 885/2 850 cm(-1), indicating yak MFG tend to have a triglyceride core in a fluid state with a milk fat globule membrane in a crystalline state. The buffalo and yak MFG had a higher level of unsaturation compared to bovine MFG, shown by a higher ratio of band intensities at 1 655/1 744 cm(-1). The results indicate that small MFG of buffalo is more unsaturated than yak, while the large MFG of buffalo is less unsaturated than the yak. Thus, selective use of cream with yak MFG would allow a harder and more costly churning process but lead to a softer butter. Buffalo milk which contains larger MFG is more suitable for cream and MFG membrane separation. PMID- 27228755 TI - [Fluorescent Characteristics of Strontium Tetraborate (SrB4O7) Doped with Divalent Lanthanide Elements]. AB - Strontium borate doping with different lanthanide bivalent ions and concentration (SrB4O : Re2+) were synthesized by the high-temperature solid state method. The fluorescent spectral characteristics of SrB4O7 : Re2+ were investigated by the non-polarization con-foucus fluorescence/raman measurement system built by us. The results indicate that the fluorescent spectral characteristics of SrB4O7 : Re2+ is very similar to that of SrB4O7 : Sm2+. The most strong fluorescence line (0-0 line) arises from 5D0 - 7F0 electron transition and the wavelength is 685.41 nm. In addition, two fluorescent bands coming from 5D0 - 7F1 and 5D0 -7F2 electron transition are observed near 700 and 730 nm, respectively. The intensity of 0-0 line of SrB4O7 : Re2+ is at least a magnitude smaller than that of SrB4O7 : Sm2+. A further study on the fluorescent spectrums of SrB4O7 : Re2+ shows that the doping elements and concentration both are the key points that affect the intensity of the fluorescent peaks, which directly decide the amount of Re2+ concerned with irradiance. PMID- 27228756 TI - [Study of Reaction Dynamics between Bovine Serum Albumin and Folic Acid by Stopped-Flow/Fluorescence]. AB - As a kind of coenzyme of one-carbon enzymes in vivo, folic acid belongs to B vitamins, which can interact with other vitamins and has great significance for converting among amino acids, dividing growth of cells and protein synthesis reactions. Half-life, concentration and reaction rate constant of drugs are important parameters in pharmacokinetic study. In this paper, by utilizing fluorescence spectrophotometer and stopped-flow spectrum analyzer, reaction kinetic parameters between bovine serum albumin(BSA) and folic acid in a bionic system have been investigated, which provide references for parameters of drug metabolism related to folic acid. By using Stern-Volmer equation dealing with fluorescence quenching experiments data, we concluded that under 25, 30, and 37 degrees C, the static quenching constants of folic acid to intrinsic fluorescence from bovine serum albumin were 2.455 x 10(10), 4.900 x 10(10) and 6.427 x 10(10) L x mol(-1) x s(-1) respectively; The results of kinetic reaction rate have shown that the reaction rate of BSA and folic acid are greater than 100 mol x L(-1) x s(-1) at different temperatures, pH and buffering media, illustrating that the quenching mechanism between BSA and folic acid is to form composite static quenching process. Reaction concentration of bovine serum albumin and its initial concentration were equal to the secondary reaction formula, and the correlation coefficient was 0.998 7, while the half-life (t1/2) was 0.059 s at physiological temperature. With the increase of folic acid concentration, the apparent rate constant of this reaction had a linear increasing trend, the BSA fluorescence quenching rate constant catalyzed by folic acid was 3.174 x 10(5) mol x L(-1) x s(-1). Furthermore, with different buffer, the apparent rate constant and reaction rate constant of BSA interacting with folic acid were detected to explore the influence on the reaction under physiological medium, which is of great significance to determine the clinical regimen, forecast the efficacy and toxicity of drugs and rational drug. PMID- 27228757 TI - [Research on the Fluorescence Enhancement Effect of Silver Nanoparticles on the Cholesterol]. AB - Based on traditional fluorescence spectroscopy and metal nanoparticles-enhanced fluorescence technology, this research explores a method of improving the accuracy and resolution of cholesterol detected by fluorescence spectroscopy in human whole blood solution. In experiment, an adult blood with silver nanoparticles is radiated by a laser pulse with wavelength of 407 nm, the fluorescence enhancement effect of cholesterol in blood is studied. The results show that, colloidal silver nanoparticles can enhance the fluorescence intensity of cholesterol in human blood with low concentration significantly. With the increase of the amount of silver colloids, the enhanced efficiency of fluorescence peaks at different positions increases first, and then decreases. However, the strongest enhanced efficiency of fluorescence peaks is different corresponding to different amount of silver colloids. According to the experimental results and the distribution of cholesterol molecules and silver nanoparticles in solution, molecular spatial distribution model is established by theoretical analyses, and the optimal distance for efficient fluorescence enhancement between cholesterol molecules and silver nanoparticles is calculated, the range is 12.19-25 nm, and the result is in good agreement with the theoretical values in other literatures. In summary, the fluorescence intensity of cholesterol in human blood can be enhanced by colloidal silver nanoparticles, and the results also provide a valuable reference on improving the sensitivity and accuracy of cholesterol detection. PMID- 27228758 TI - [Research on the Relationship between Surface Structure and Fluorescence Intensity of Ca(1-x)Al2Si2O8 : Eu(x)]. AB - Ca(1-x)Al2Si2O8 : Eu(x)(x = 0, 0.01, 0.05, 0.15) were synthesized by solid-state reaction respectively at 1 150, 1 250 1350 and 1 450 degrees C. With X-ray diffraction(XRD), Raman spectroscopy(Raman), photoluminescence spectroscopy(PL) and X-ray fluorescence spectrometer(XRF), the relationship between surface structure and fluorescence intensity of Ca(1-x) Al2Si2O8: Eu(x) were studied. XRD and Raman results show that, CaAl2Si2O8 anorthite single-phase has formed gradually along with the temperature rising in the process of synthesis. Raman spectroscopy is clear that when the Eu doping amount is the same, Si-O amorphous phase disappear gradually and the CaAl2Si2O8 phase form gradually with the temperature increases. As the temperature increases, vibration peaks position silicon oxygen tetrahedron shift to lower wave number. When 1 450 degrees C, the temperature is too high to destroy the structure of silicon oxygen tetrahedron. At the same time, there is a broadening amorphous peak appears in Raman spectroscopy. The procedure of Al to replace Si is hindered with Eu doped in. It is the result that the peak at 1 620 cm(-1) decreases after the first increases. The change of surface structure associated with the scattering amount of Eu. PL and XRF results show that: as the temperature increases, the amount of Eu atom scattering on the material surface increases gradually, this change lead to the fluorescence intensity raise. Therefore, there is proportional relationship between the fluorescence intensity of the samples and the number of samples per unit surface area of Eu atoms. PMID- 27228759 TI - [Aggregation Behavior of Collagen-Based Surfactant Molecules in Aqueous Solutions Based on Synchronization Fluorescence Spectrum Technology]. AB - Due to the intrinsic fluorescence characteristic of tyrosine (Tyr) and phenylalanine (Phe), synchronization fluorescence spectrum technology which adopted the constant wavelength difference (Deltalambda = 15 nm) was selected to investigate the effects of collagen-based surfactant (CBS) concentration, pH, NaCt concentration and temperature on the aggregation state of CBS molecules in aqueous solutions. Meanwhile, temperature-dependent two-dimensional (2D) synchronization fluorescence correlation analyses was used to investigate the variation order of Tyr and Phe residues in CBS molecules with the change of temperature. The results showed that the characteristic absorption peaks located at 261 and 282 nm were attributed to Phe and Tyr, respectively. With the increase of CBS concentration, the amount of Phe and Tyr residues increased gradually which resulted in the increase of aggregate degree of CBS molecules and then led to the increase of fluorescence intensity. When the pH value (pH 5.0) of CBS solutions was close to the isoelectric point of CBS, the aggregate degree of CBS molecules increased due to the increase of the hydrophobic interaction and the formation ability of hydrogen bond. Additionally, with the increase of NaCl concentration, the repulsion force for inter/intra-molecules of CBS decreased, which helped to improve the aggregation behavior of CBS molecules. However, with the increase of temperature, the aggregation state of CBS was changed to be monomolecular state, and then resulted in the decrease of the fluorescence intensity gradually due to the quenching, the denaturation and the decrease of hydrogen bond formation ability. Furthermore, temperature-dependent 2D synchronization fluorescence correlation spectroscopy demonstrated that at lower temperature (10-40 degrees C), the aggregate state of CBS changed to be loose state and then Phe residues located in the inside of the aggregate varied before Tyr residues; while in the heating process of 45-70 degrees C, the monomolecular state of CBS changed to be random coil conformation, the separation distance between Tyr residues increased and the hydrogen bond formation ability reduced strongly, which led to Tyr residues changed before Phe residues. PMID- 27228760 TI - [The Ion Identification and Molecular Logic Gate of a Thiacalix[4]arene Fluorescent Probe]. AB - A disubstituted phthalimide-based thiacalix[4] arene derivative (probe s1) was synthesized from cone 1, 3-thiacalix[4] arene and hydroxyethyl phthalimide, with benzyl appended the lower edge of thiacalix[4]-arene by triazole ring in the 2,4 position. The relative fluorescence quantum yield of probe s1 is 0.43 in CH3CN solvent. The strong fluorescence emission of probe s1 at 390 nm wavelength can be selectively quenched by Fe3+ in DMF/H2O solution. Similarly, the presence of I- also induced a significant fluorescence quenching of probe s1 at 310 nm wavelength in CH3CN solution. Spectral titration and isothermal titration calorimetry were showed that probe s1 with Fe3+ or I- both form 1 : 1 complexes, the binding constants up to 10(5) and coordinate process were spontaneous. The linear ranges of fluorescence detect Fe3+ or I- were 1.0 x 10(-7) - 1.6 x 10(-4) mol x L(-1) and 1.0 x 10(-7) - 8.5 x 10(-5) mol x L(-1), detection limits were up to 2.30 x 10(-8) mol x L(-1) and 1.17 x 10(-8) mol x L(-1), respectively. Meanwhile, take advantage of identification and coordination action, a logic circuit constructed at the molecular level by controlling two input signals of Fe3+ and F-, which causing probe s1 cycling of fluorescence emission or quenching. IR spectrum speculated that the nitrogen atoms of triazole groups are involved in the complexation with Fe3+, while the hydrogen atoms of triazole groups were complexed with I- by hydrogen bonding. PMID- 27228761 TI - [Study on the Interaction in Resveratrol-Hordein Nanoparticle]. AB - In order to clarify the interaction mechanism of the formation of the resveratrol hordein nanoparticle, the fluorescence, UV-Vis spectroscopic, FTIR and DSC were used to study the binding reaction between resveratrol and hordein. The fluorescent emission of hordein was inhibited by resveratrol in a dose dependent manner. Fluorescence spectroscopy and DSC indicated that resveratrol interacted with hordein and formed a new complex by a static process. The binding constant (K(A(298 K)) = 2.21 x 10(5) L x mol(-1), K(A(310 K)) =1.53 x 10(4) L x mol(-1)) and the number of binding sites ((n298 K) = 1.23, (n310 K) 0.94) were calculated based on the quenching effect of resveratrol on hordein. Thermodynamic parameter and FTIR indicated that the interaction force between resveratrol and hordein was mainly hydrogen binding and van der Waals force. The binding distance (r0 = 3. 25 nm) between resveratrol and hordein and the energy transfer efficiency (E = 0.227) were obtained according to non-radiative energy transfer theory. The effect of resveratrol on the conformation of hordein was further analyzed by using synchronous fluorescence spectrometry. The results indicated that resveratrol changed the hydrophobicity of tryptophan residue, which caused an obvious influence on the conformation of hordein. PMID- 27228762 TI - [Research on Spectral Scale Effect in the Estimation of Vegetation Leaf Chlorophyll Content]. AB - Spectral indices (SIs) method has been widely applied in the prediction of vegetation biochemical parameters. Take the diversity of spectral response of different sensors into consideration, this study aimed at researching spectral scale effect of SIs for estimating vegetation chlorophyll content (VCC). The 5 nm leaf reflectance data under 16 levels of chlorophyll content was got by the radiation transfer model PROSPECT and then simulated to multiple bandwidths spectrum (10-35 nm), using Gaussian spectral response function. Firstly, the correlation between SIs and VCC was studied. And then the sensitivity of SIs to VCC and bandwidth were analyzed and compared. Lastly, 112 samples were selected to verify the results above mentioned. The results show that Vegetation Index Based on Universal Pattern Decomposition Method (VIUPD) is the best spectral index due to its high sensitivity to VCC but low sensitivity to bandwidth, and can be successfully used to estimate VCC with coefficient of determination R2 of 0.99 and RMSE of 3.52 MUg x cm(-2). Followed by VIUPD, Normalized Difference Vegetation Index (NDVI) and Simple Ratio Index (SRI) presented a comparatively good performance for VCC estimation (R2 > 0.89) with their prediction value of chlorophyll content was lower than the true value. The worse accuracy of other indices were also tested. Results demonstrate that spectral scale effect must be well-considered when estimating chlorophyll content, using SIs method. VIUPD introduced in the present study has the best performance, which reaffirms its special feature of comparatively sensor-independent and illustrates its potential ability in the area of estimating vegetation biochemical parameters based on multiple satellite data. PMID- 27228763 TI - [Measurement of Water COD Based on UV-Vis Spectroscopy Technology]. AB - Ultraviolet/visible (UV/Vis) spectroscopy technology was used to measure water COD. A total of 135 water samples were collected from Zhejiang province. Raw spectra with 3 different pretreatment methods (Multiplicative Scatter Correction (MSC), Standard Normal Variate (SNV) and 1st Derivatives were compared to determine the optimal pretreatment method for analysis. 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 preprocessed spectra were then used to select sensitive wavelengths by competitive adaptive reweighted sampling (CARS), Random frog and Successive Genetic Algorithm (GA) methods. Different numbers of sensitive wavelengths were selected by different variable selection methods with SNV preprocessing method. Partial least squares (PLS) was used to build models with the full spectra, and Extreme Learning Machine (ELM) was applied to build models with the selected wavelength variables. The overall results showed that ELM model performed better than PLS model, and the ELM model with the selected wavelengths based on CARS obtained the best results with the determination coefficient (R2), RMSEP and RPD were 0.82, 14.48 and 2.34 for prediction set. The results indicated that it was feasible to use UV/Vis with characteristic wavelengths which were obtained by CARS variable selection method, combined with ELM calibration could apply for the rapid and accurate determination of COD in aquaculture water. Moreover, this study laid the foundation for further implementation of online analysis of aquaculture water and rapid determination of other water quality parameters. PMID- 27228764 TI - [High Resolution Remote Sensing Monitoring and Assessment of Secondary Geological Disasters Triggered by the Lushan Earthquake]. AB - The secondary geological disasters triggered by the Lushan earthquake on April 20, 2013, such as landslides, collapses, debris flows, etc., had caused great casualties and losses. We monitored the number and spatial distribution of the secondary geological disasters in the earthquake-hit area from airborne remote sensing images, which covered areas about 3 100 km2. The results showed that Lushan County, Baoxing County and Tianquan County were most severely affected; there were 164, 126 and 71 secondary geological disasters in these regions. Moreover, we analyzed the relationship between the distribution of the secondary geological disasters, geological structure and intensity. The results indicate that there were 4 high-hazard zones in the monitored area, one focused within six kilometers from the epicenter, and others are distributed along the two main fault zones of the Longmen Mountain. More than 97% secondary geological disasters occurred in zones with a seismic intensity of VII to IX degrees, a slope between 25 A degrees and 50 A degrees, and an altitude of between 800 and 2 000 m. At last, preliminary suggestions were proposed for the rehabilitation and reconstruction planning of Lushan earthquake. According to the analysis result, airborne and space borne remote sensing can be used accurately and effectively in almost real-time to monitor and assess secondary geological disasters, providing a scientific basis and decision making support for government emergency command and post-disaster reconstruction. PMID- 27228765 TI - [Errors Analysis and Correction in Atmospheric Methane Retrieval Based on Greenhouse Gases Observing Satellite Data]. AB - High precision retrieval of atmospheric CH4 is influenced by a variety of factors. The uncertainties of ground properties and atmospheric conditions are important factors, such as surface reflectance, temperature profile, humidity profile and pressure profile. Surface reflectance is affected by many factors so that it is difficult to get the precise value. The uncertainty of surface reflectance will cause large error to retrieval result. The uncertainties of temperature profile, humidity profile and pressure profile are also important sources of retrieval error and they will cause unavoidable systematic error. This error is hard to eliminate only using CH4 band. In this paper, ratio spectrometry method and CO2 band correction method are proposed to reduce the error caused by these factors. Ratio spectrometry method can decrease the effect of surface reflectance in CH4 retrieval by converting absolute radiance spectrometry into ratio spectrometry. CO2 band correction method converts column amounts of CH4 into column averaged mixing ratio by using CO2 1.61 MUm band and it can correct the systematic error caused by temperature profile, humidity profile and pressure profile. The combination of these two correction methods will decrease the effect caused by surface reflectance, temperature profile, humidity profile and pressure profile at the same time and reduce the retrieval error. GOSAT data were used to retrieve atmospheric CH4 to test and validate the two correction methods. The results showed that CH4 column averaged mixing ratio retrieved after correction was close to GOSAT Level2 product and the retrieval precision was up to -0.24%. The studies suggest that the error of CH4 retrieval caused by the uncertainties of ground properties and atmospheric conditions can be significantly reduced and the retrieval precision can be highly improved by using ratio spectrometry method and CO2 hand correction method. PMID- 27228766 TI - [Preparation of Human Serum Albumin Micro/Nanotubes]. AB - In this research, protein micro/nanotubes were fabricated by alternate layer-by layer (LbL) assembly of human serum albumin (HSA) and polyethyleneimine (PEI) into polycarbonate (PC) membranes. The experimental conditions of pH values, ionic strength, the depositions cycles and the diameter of porous membrane were discussed. The morphology and composition of tubes were characterized by scanning electron microscope (SEM), transmission electron microscope (TEM), fourier transform infrared spectroscopy (FTIR) and energy dispersive spectroscopy (EDS). The results show that pH and ionic strength of the solution are the key factors that influence the effect of assembly. Micro/nanotubes with good opening hollow tubular structure were obtained when pH 7.4 HSA solution and pH 10.3 PEI solution without NaCl were used in synthesis procedure. The outer diameter of tube was dependent on the PC template, thus the micro/nanotubes size was controlled by the wall thickness, which can be adjusted by the number of layers of the HSA and PEI deposited along the pore walls. To avoid the thin wall being damaged in dissolving the template and vacuum drying, the PEI/HSA bilayer number should not be less than 3. The polar solvent N,N-dimethylformamide (DMF) can dissolve PC template to release the micro/nanotubes. PMID- 27228767 TI - [New Method of Measuring Arterial Oxygen Saturation]. AB - The traditional method of measuring arterial oxygen saturation is that R value, the ratio of alternating component of the logarithmic photoplethysmography, is firstly computed and then the linear regression model is established by experiment. The R value computation is a dimension reduction process based on Lambert-beer law, which aims at eliminating the influence of optical path and minimizing the impact of individual differences. When taking scattering into consideration, the dimension reduction process loses information, introduces the system error and limits the precision of measurement. In order to reduce the measurement error resulting from the scattering effects, this paper presents a new method that the peak and valley values of dual-wavelength logarithmic photoplethysmography waves are used as the independent variables to develop a linear regression model to predict the arterial oxygen saturation. During the experiment, the in-vivo measurements were carried out on 23 healthy volunteer and 133 samples of photoplethysmography waves and the reference value of oxygen saturation were recorded. To compare the predictive performance between the new method and the R value method, 90 samples were randomly selected as modeling sets and the remaining 43 samples were used as prediction sets. Random selection of modeling sets and prediction are executed 10 times. The average related coefficients of the prediction sets of the new method and the R value method are 0.890 6 and 0.846 8, and the average root mean square errors are 0.889 6% and 1.037 3% respectively. Results indicate that the performance of the new method is better than the one of the R value method, and the predictivemodel based on 4 parameters can improve the stability and accuracy of measurement. And the new method has guiding significance to the measurement of human body's blood physiological information based on limited wavelength spectrum data. PMID- 27228768 TI - [Iterated Tikhonov Regularization for Spectral Recovery from Tristimulus]. AB - Reflective spectra in a multispectral image can objectively and originally represent color information due to their high dimensionality, illuminant independent and device independent. Aiming to the problem of loss of spectral information when the spectral data reconstructed from three-dimensional colorimetric data in the trichromatic camera-based spectral image acquisition system and its subsequent problem of loss of color information, this work proposes an iterated Tikhonov regularization to reconstruct the reflectance spectra. First of all, according to relationship between the colorimetric value and the reflective spectra in the colorimetric theory, this work constructs a spectral reconstruction equation which can reconstruct high dimensional spectral data from three dimensional colorimetric data acquired by the trichromatic camera. Then, the iterated Tikhonov regularization, inspired by the idea of the pseudo inverse Moore-Penrose, is used to cope with the linear ill-posed inverse problem during solving the equation of reconstructing reflectance spectra. Meanwhile, the work also uses the L-curve method to obtain an optimal regularized parameter of the iterated Tikhonov regularization by training a set of samples. Through these methods, the ill condition of the spectral reconstruction equation can be effectively controlled and improved, and subsequently loss of spectral information of the reconstructed spectral data can be reduced. The verification experiment is performed under another set of training samples. The experimental results show that the proposed method reconstructs the reflective spectra with less spectral information loss in the trichromatic camera-based spectral image acquisition system, which reflects in obvious decreases of spectral errors and colorimetric errors compared with the previous method. PMID- 27228769 TI - [Evolution of Dissolved Organic Matter Properties in a Constructed Wetland of Xiao River, Hebei]. AB - The evolution of water DOC and COD, and the source, chemical structure, humification degree and redox of dissolved organic matter (DOM) in a constructed wetland of Xiao River, Hebei, was investigated by 3D excitation--emission matrix fluorescence spectroscopy coupled with ultraviolet spectroscopy and chemical reduction, in order to explore the geochemical processes and environmental effects of DOM. Although DOC contributes at least 60% to COD, its decrease in the constructed wetland is mainly caused by the more extensive degradation of elements N, H, S, and P than C in DOM, and 65% is contributed from the former. DOM is mainly consisted of microbial products based on proxies f470/520 and BIX, indicating that DOM in water is apparently affected by microbial degradation. The result based on PARAFAC model shows that DOM in the constructed wetland contains protein-like and humus-like components, and Fulvic- and humic-like components are relatively easier to degrade than protein-like components. Fulvic- and humic-like components undergo similar decomposition in the constructed wetland. A common source of chromophoric dissolved organic matter (CDOM) and fluorescent dissolved organic matter (FDOM) exists; both CDOM and FDOM are mainly composed of a humus like material and do not exhibit selective degradation in the constructed wetland. The proxies E2 /E3, A240-400, r(A, C) and HIX in water have no changes after flowing into the constructed wetland, implying that the humification degree of DOM in water is hardly affected by wet constructed wetland. However, the constructed wetland environment is not only beneficial in forming the reduced state of DOM, but also facilitates the reduction of ferric. It can also improve the capability of DOM to function as an electron shuttle. This result may be related to the condition that the aromatic carbon of DOM can be stabilized well in the constructed wetland. PMID- 27228770 TI - [Method of Background Elimination for Wheat Leaves Based on the BPLT Model]. AB - In order to precisely acquire leaf reflectance spectra (400-1 000 nm), influence of background on leaf reflectance spectra was studied. Experiment was conducted to discriminate the characteristics of wheat leaves based on 8 background materials and leaf chlorophyll concentration. BPLT (Background Plate) model, based on the Plate model, was promoted and applied to remove the influence of leave background. The BPLT model needed "2-3-1"variables, which were input variables R0 (reflectance of the interaction of leaves and background), sigma(reflectance of background alone), intermediate variables R12 (reflectance of interacting interface from air to a compact leaf), R21 (reflectance of interacting interface from a compact leaf to air), tau (the transmissivity of the plate), and ultimate variable R (reflectance of a compact leaf alone). To verify this model, Analysis of Variance (ANOVA) was conducted to compare ten vegetation indices under different background influences. The results indicated that percent of variation in background reflectance associated with spectral vegetation indices was 5% lower after using the BPLT model. Meanwhile, wheat leaf chlorophyll concentration at different levels could be effectively estimated by the means of BPLT model with determined coefficients (DC) greater than 0.9 and residual sum of squares (SSE) less than 1. As with the ANOVA, vegetation indices NIX and MCARI were better than the other 8 ones. The slope of NDI&-MCARI plotted as a function of mean wheat leaf chlorophyll concentration. R2 ranged from 0.847 8 to 0.977 8 with the applied method of BPLT model. The BPLT model is a powerful and accurate method for the acquisition of wheat leaf reflectance information. PMID- 27228771 TI - [Long-Term Different Fertilizations Changed the Chemical and Spectrum Characteristics of DOM of the Irrigation-Desert Soil in North-Western China]. AB - By using Ultraviolet-visible Spectrometry, Fourier Transform Infrared Spectrometer and Elemental Analyzer, spectrum and chemical characteristics of soil DOM affected by long-term different fertilizations were investigated in irrigation-desert soil in North-western China based on an experiment started from 1988. Four different fertilization treatments were included, i. e., organic fertilizer (OF), green manure (GM), chemical fertilizer (CF) and a control of no fertilization (CK). The results showed that fertilization could increase the contents of DOM. Compared to CK, the treatments of OF, GM, CF increased the dissolved organic carbon (DOC) by 37%, 29%, 16%; increased the dissolved nitrogen (DON) by 334%, 257%, 182%; increased the total carbohydrate (TCs) by 90%, 25%, 2%; and increased the total organic acids (TOAs) by 195%, 116%, 58%; respectively. Furthermore, DOC, DON, TCs, and TOAs in the OF treatment were significantly higher than those in CK, they were also significantly higher in the GM and CF treatments except for TCs. The ultraviolet-visible analysis showed that fertilizations enhanced the SUVA(254), SUVA(260), SUVA(272) and SUVA(280) of DOM, indicating that fertilizations increased the aromatic and hydrophobic percentage, humification degree, and average molecular weight, and thus resulting in more stability of DOM. Same trends were showed for all the 4 ultraviolet spectrum absorption values in different fertilizations, i. e., the strongest effect was found in the OF treatment, and then was the GM treatment and CF treatment successively. From the results by the Fourier Transform Infrared Spectrometry, the characteristic peak of aromatic in the OF treatment was observed shifting from 1 625 to 1 649 cm(-1), which was close to the characteristic peak of humin, suggesting that the aromaticity of DOM in the OF treatment was higher than the other treatments. The characteristic peaks of C-O at 1 260-1 000 cm(-1) belonging to sugar, alcohol, and carboxylic acid were highest in the GM treatment, showing that the green manure could increase rich oxygen radicals. The highest characteristic peaks of N-H at 3 559, 3 419 and 1 456 cm(-1) were observed in the CF treatment, indicating that the chemical fertilizer could increase amine substances. The contents of C, O and N in the OF, GM, CF treatments were also increased respectively according to the elemental analysis. PMID- 27228772 TI - [Selection of Characteristic Wavelengths Using SPA and Qualitative Discrimination of Mildew Degree of Corn Kernels Based on SVM]. AB - The feasibility of Fourier transform near infrared (FT-NIR) spectroscopy with spectral range between 833 and 2 500 nm to detect the moldy corn kernels with different levels of mildew was verified in this paper. Firstly, to avoid the influence of noise, moving average smoothing was used for spectral data preprocessing after four common pretreatment methods were compared. Then to improve the prediction performance of the model, SPXY (sample set partitioning based on joint x-y distance) was selected and used for sample set partition. Furthermore, in order to reduce the dimensions of the original spectral data, successive projection algorithm (SPA) was adopted and ultimately 7 characteristic wavelengths were extracted, the characteristic wave-lengths were 833, 927, 1 208, 1 337, 1 454, 1 861, 2 280 nm. The experimental results showed when the spectrum data of the 7 characteristic wavelengths were taken as the input of SVM, the radial basic function (RBF) used as the kernel function, and kernel parameter C = 7 760 469, gamma = 0.017 003, the classification accuracies of the established SVM model were 97.78% and 93.33% for the training and testing sets respectively. In addition, the independent validation set was selected in the same standard, and used to verify the model. At last, the classification accuracy of 91.11% for the independent validation set was achieved. The result indicated that it is feasible to identify and classify different degree of moldy corn grain kernels using SPA and SVM, and characteristic wavelengths selected by SPA in this paper also lay a foundation for the online NIR detection of mildew corn kernels. PMID- 27228773 TI - [Establishment of The Crop Growth and Nitrogen Nutrition State Model Using Spectral Parameters Canopy Cover]. AB - In order to explore a non-destructive monitoring technique, the use of digital photo pixels canopy cover (CC) diagnosis and prediction on maize growth and its nitrogen nutrition status. This study through maize canopy digital photo images on relationship between color index in the photo and the leaf area index (LAI), shoot dry matter weight (DM), leaf nitrogen content percentage (N%). The test conducted in the Chinese Academy of Agricultural Science from 2012 to 2013, based on Maize canopy Visual Image Analysis System developed by Visual Basic Version 6.0, analyzed the correlation of CC, color indices, LAI, DM, N% on maize varieties (Zhongdan909, ZD 909) under three nitrogen levels treatments, furthermore the indicators significantly correlated were fitted with modeling, The results showed that CC had a highly significant correlation with LAI (r = 0.93, p < 0.01), DM (r = 0. 94, p < 0.01), N% (r = 0.82, p < 0.01). Estimating the model of LAI, DM and N% by CC were all power function, and the equation respectively were y = 3.281 2x(0.763 9), y = 283.658 1x(0.553 6) and y = 3.064 5x(0.932 9); using independent data from modeling for model validation indicated that R2, RMSE and RE based on 1 : 1 line relationship between measured values and simulated values in the model of CC estimating LAI were 0.996, 0.035 and 1.46%; R2, RMSE and RE in the model of CC estimating DM were 0.978, 5.408 g and 2.43%; R2, RMSE and RE in the model of CC estimating N% were 0.990, 0.054 and 2.62%. In summary, the model can comparatively accurately estimate the LAI, DM and N% by CC under different nitrogen levels at maize grain filling stage, indicating that it is feasible to apply digital camera on real-time undamaged rapid monitoring and prediction for maize growth conditions and its nitrogen nutrition status. This research finding is to be verified in the field experiment, and further analyze the applicability throughout the growing period in other maize varieties and different planting density. PMID- 27228774 TI - [The Analysis of Traditional Lime Mortars from Zhejiang Province, China]. AB - The components of ancient mortars have always been an important research field in historic building conservation. It has been well known that using traditional mortars in conservation projects have many advantages, such as compatibility and stability. So, developing new binding materials based on traditional mortar has become an international study hotspot. With China's economic development, the protection of ancient buildings also began to put on the agenda, but the understanding on Chinese traditional mortar is limited, and rare literatures are reported. In the present work, the authors investigate seven ancient city wall sites in Zhejiang Province in situ, and subsequently laboratory analysis were carried out on collected mortar samples. The characterizations of mortar samples were made by multi-density gauge, XRD, FTIR, TG-DSC and wet chemical analysis. The experimental results showed that: the main component of masonry mortars is calcium carbonate, the content between 75% - 90%, and they should be made from relatively pure lime mortar. The raw materials of mortar samples were mainly calcareous quick lime, and sample from Taizhou city also contained magnesium quick lime. There are four city walls were built by sticky-rice mortars. It suggests that the technology of adding the sticky rice soup into mortar was universal in the Ming Dynasties. These mortars have lower density between 1.2 and 1.9 g x cm(-3); this outcome should be the result of long-term natural erosion. We have also analyzed other chemical and physical characteristics of these masonry mortars. The results can afford the basic data for the future repairmen programs, development of new protective materials, and comparative study of mortars. PMID- 27228775 TI - [Research on the Source Identification of Mine Water Inrush Based on LIF Technology and SIMCA Algorithm]. AB - Rapid source identification of mine water inrush is of great significance for early warning and prevention in mine water hazard. According to the problem that traditional chemical methods to identify source takes a long time, put forward a method for rapid source identification of mine water inrush with laser induced fluorescence (LIF) technology and soft independent modeling of class analogy (SIMCA) algorithm. Laser induced fluorescence technology has the characteristics of fast analysis, high sensitivity and so on. With the laser assisted, fluorescence spectrums can be collected real-time by the fluorescence spectrometer. According to the fluorescence spectrums, the type of water samples can be identified. If the database is completed, it takes a few seconds for coal mine water source identification, so it is of great significance for early warning and post-disaster relief in coal mine water disaster. The experiment uses 405 nm laser emission laser into the 5 kinds of water inrush samples and get 100 groups of fluorescence spectrum, and then put all fluorescence spectrums into preprocessing. Use 15 group spectrums of each water inrush samples, a total of 75 group spectrums, as the prediction set, the rest of 25 groups spectrums as the test set. Using principal component analysis (PCA) to modeling the 5 kinds of water samples respectively, and then classify the water samples with SIMCA on the basis of the PCA model. It was found that the fluorescence spectrum are obvious different of different water inrush samples. The fluorescence spectrums after preprocessing of Gaussian-Filter, under the condition of the principal component number is 2 and the significant level alpha = 5%, the accuracy of prediction set and testing set are all 100% with the SIMCA to classify the water inrush samples. PMID- 27228776 TI - [Soil Salinity Estimation Based on Near-Ground Multispectral Imagery in Typical Area of the Yellow River Delta]. AB - This study chooses the core demonstration area of 'Bohai Barn' project as the study area, which is located in Wudi, Shandong Province. We first collected near ground and multispectral images and surface soil salinity data using ADC portable multispectral camera and EC110 portable salinometer. Then three vegetation indices, namely NDVI, SAVI and GNDVI, were used to build 18 models respectively with the actual measured soil salinity. These models include linear function, exponential function, logarithmic function, exponentiation function, quadratic function and cubic function, from which the best estimation model for soil salinity estimation was selected and used for inverting and analyzing soil salinity status of the study area. Results indicated that all models mentioned above could effectively estimate soil salinity and models using SAVI as the dependent variable were more effective than the others. Among SAVI models, the linear model (Y = -0.524x + 0.663, n = 70) is the best, under which the test value of F is the highest as 141.347 at significance test level, estimated R2 0.797 with a 93.36% accuracy. Soil salinity of the study area is mainly around 2.5 per thousand - 3.5 per thousand, which gradually increases from southwest to northeast. The study has probed into soil salinity estimation methods based on near-ground and multispectral data, and will provide a quick and effective technical soil salinity estimation approach for coastal saline soil of the study area and the whole Yellow River Delta. PMID- 27228777 TI - [Decomposition of Interference Hyperspectral Images Using Improved Morphological Component Analysis]. AB - As the special imaging principle of the interference hyperspectral image data, there are lots of vertical interference stripes in every frames. The stripes' positions are fixed, and their pixel values are very high. Horizontal displacements also exist in the background between the frames. This special characteristics will destroy the regular structure of the original interference hyperspectral image data, which will also lead to the direct application of compressive sensing theory and traditional compression algorithms can't get the ideal effect. As the interference stripes signals and the background signals have different characteristics themselves, the orthogonal bases which can sparse represent them will also be different. According to this thought, in this paper the morphological component analysis (MCA) is adopted to separate the interference stripes signals and background signals. As the huge amount of interference hyperspectral image will lead to glow iterative convergence speed and low computational efficiency of the traditional MCA algorithm, an improved MCA algorithm is also proposed according to the characteristics of the interference hyperspectral image data, the conditions of iterative convergence is improved, the iteration will be terminated when the error of the separated image signals and the original image signals are almost unchanged. And according to the thought that the orthogonal basis can sparse represent the corresponding signals but cannot sparse represent other signals, an adaptive update mode of the threshold is also proposed in order to accelerate the computational speed of the traditional MCA algorithm, in the proposed algorithm, the projected coefficients of image signals at the different orthogonal bases are calculated and compared in order to get the minimum value and the maximum value of threshold, and the average value of them is chosen as an optimal threshold value for the adaptive update mode. The experimental results prove that whether LASIS and LAMIS image data, the traditional MCA algorithm can separate the interference stripes signals and background signals very well, and make the interference hyperspectral image decomposition perfectly, and the improved MCA algorithm not only keep the perfect results of the traditional MCA algorithm, but also can reduce the times of iteration and meet the iterative convergence conditions much faster than the traditional MCA algorithm, which will also provide a very good solution for the new theory of compressive sensing. PMID- 27228778 TI - [Joint Analyses of Na2SO4 Solution by Laser Induced Breakdown Spectroscopy and Raman Spectroscopy]. AB - Spectroscopic sensor is becoming an important issue for the deep-sea exploration due to the advantages of multi-specie, multi-phases and stand-off detection. Different approach have been developing in recent years based on LIBS (Laser Induced Breakdown Spectroscopy) and Raman spectroscopy since Raman-LIBS are complementary techniques with the similar components and the capability of molecular and elementary analysis. In this work, we built a LIBS-Raman system and detected Na2SO4 in aqueous solution to evaluate the potential ocean application. With the same laser, spectrometer and detector, a hybrid of Raman and LIBS system was developed to realize the detection of anions and cations in the seawater. The optics was composed by two parts. Raman channel and LIBS channel, and the signal was collected by a Y type optical fiber bundle. The signal from two channels was separated by imaging on different arrays of the CCD detector. The Raman spectra of SO4(2-) and LIBS spectra of Na was successfully detected simultaneously when the pulse energy was above 3.6 mJ. However, due to the strong bremsstrahlung radiation of LIBS, the signal to noise ratio of Raman was significantly decreased as the laser energy increasing. The results manifested the great potential of Raman-LIBS combination for the underwater detection. PMID- 27228779 TI - [Application of ICP-MS to Identify the Botanic Source of Characteristic Honey in South Yunnan]. AB - By adopting inductively coupled plasma mass spectrometry (ICP-MS) combined with chemometric analysis technology, 23 kinds of minerals in four kinds of characteristic honey derived from Yunnan province were analyzed. The result showed that 21 kinds of mineral elements, namely Na, Mg, K, Ca, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Sr, Mo, Cd, Sb, Ba, Tl and Pb, have significant differences among different varieties of honey. The results of principal component analysis (PCA) showed that the cumulative variance contribution rate of the first four main components reached 77.74%, seven kinds of elements (Mg, Ca, Mn, Co, Sr, Cd, Ba) from the first main component contained most of the honey information. Through the stepwise discriminant analysis, seven kinds of elements (Mg, K, Ca, Cr, Mn, Sr, Pb) were filtered. out and used to establish the discriminant function model, and the correct classification rates of the proposed model reached 90% and 86.7%, respectively, which showed elements contents could be effectively indicators to discriminate the four kinds characteristic honey in southern Yunnan Province. In view of all the honey samples were harvested from apiaries located at south Yunnan Province where have similar climate, soil and other environment conditions, the differences of the mineral elements contents for the honey samples mainly due to their corresponding nectariferous plant. Therefore, it is feasible to identify honey botanical source through the differences of mineral elements. PMID- 27228780 TI - [Analysis of Influence of Pushroom Erros on The Data Reconstruction of Computational Imaging Spectrometer]. AB - The technology of computational spectral imaging changes the traditional imaging modalities by introducing a coded aperture in the optical path to achieve transformation of the targets spectral imformation, then we can get the spectral data cube by reverse transform. This paper introduces the principle of a push broom imaging coded aperture computational spectral imager. In practical applications, the matching error between the push speed and the frame rate can affect the accuracy of the spectral data reconstruction. The error terms are deduced based on the model of pushroom, the influences of matching errors to the spectral data reconstruction are anlyzed. And the second spectra derivative and strehl ratio are introduced as the evaluation parameters to, respectively, evaluate the reconstructed spectral and spatial image in the data simulation analysis. It showed that, when the accumulated error of a complete set of data is more than one pixel, the shading dramaticly area's reconstructed results are relatively poor, but the relatively homogeneous regions are affected small; when cumulative error does not exceed half pixel, strehlretio of each channel were above 0.9, and the lower of the spectral energy, the channels strehl ratio smaller, so the more the ranks of the coding template, the higher the platform's stability required. PMID- 27228781 TI - [Research on Small-Type and High-Spectral-Resolution Grating Monochromator]. AB - Monochromator is the necessary equipment for spectral imager to calibrate the spectrum continuously. In order to calibrate the hyperspectral imaging spectrometer continuously, a small-type and high-spectral-resolution grating monochromator is designed. The grating monochromator with horizontal Czerny Turner structure is designed with high-spectral-resolution as a starting point, and the design idea is discussed in detail from choosing the grating, calculating the focal length, the sizes of entrance slit and exit slit, among others. Using this method, the necessary structure parameters are determined, and the impact of the necessary structure parameters for spectral resolution and volume is given. According to the optical characteristics of the grating monochromator, the mechanical structures of the instrument are designed for small and handy from the components of the entrance slit, the collimator lens and imaging objective lens, the scanning structures, the fuselage and so on. The relationship of the sine mechanism parameters for output wavelength and wavelength scanning accuracy is given. The design and adjustment of the instrument are completed. The visible spectrums of mercury lamp are used as calibration lines, and the calibration curve is acquired by using least square method. This paper gives a method that combining the limit error of the step number and the calibration curve to evaluate the wavelength repeatability and wavelength precision. The datum of experiment shows that the spectral resolution of the instrument is better than 0.1 nm in the wavelength band from 400 to 800 nm. Simultaneously the wave-length repeatability reach to +/- 0.96 6 nm and the precision reach to +/- 0.096 9 nm. PMID- 27228782 TI - [The Trace Methane Sensor Based on TDLAS-WMS]. AB - Methane is a colorless, odorless, flammable and explosive gas, which not only is the cause to induce significant security risk in coal mining operation, but also one of the important greenhouse gases, so the monitoring of methane is extremely critical. A trace methane gas sensor is designed and developed using the combination of tunable diode laser absorption spectroscopy (TDLAS) and wavelength modulation spectroscopy (WMS) detection technology, which is based on the methane R(3) absorption branch in 2v3 second harmonic band. Through tuning parameters 0.591 cm(-1) x K(-1), using the method that change the working temperature of distributed feedback (DFB) laser to obtain the best absorption wavelength of methane at 1.654 MUm. When the mid-wavelength of DFB laser is selected, the appropriate emitting intension can be obtained via adjusting the amplitude of inject current of DFB laser. Meanwhile, combining the frequency modulation technology to move the bandwidth of detection signal from low frequency to high frequency to reduce the 1/f noise. With aspect to the optical structure, utilizing herriott cell with 76 m effective optical path to guarantee the detection of trace methane is successful. Utilizing the proposed trace methane sensor to extract the second harmonic signal of detected methane in the range of 50 to 5 000 MUmol x mol(-1), and adopting minimum mean square error criterion to fit the relationship between methane concentration and signal noise ratio, harmonic peak signal and methane concentration, respectively. In addition, the minimum detection limit is 1.4 MUmol x mol(-1). The experiment results show the symmetry of harmonic waveform is good, no intensity modulation, and the factor of intensity-modulated impacts on harmonic detection is eliminated. PMID- 27228783 TI - [Research on Temperature Detection System Based on Improved Fiber Bragg Grating]. AB - Traditional temperature detection system based on Fiber Bragg Grating is suitable for large-scale, real-time multi-point temperature detection field. But its stability of temperature response is poor, shift amount of Bragg grating center wavelength is poor linearity with temperature variation. In order to improve the stability for system and temperature detection accuracy of the system, an improved temperature detection system based on Fiber Bragg Grating was designed. The method of dual fiber parallel acquisition for temperature data was used on the same point, and then center wavelength data was differentially processed. It was realized that the random errors of the system were effectively real-time eliminated in the process temperature. The function relationships of center wavelength shift amount of Fiber Bragg Grating and temperature variation was derived in this mode, and the new structure of the probes for Fiber Bragg Grating was designed. In the experiments, measurement data of Improved temperature detection system based on Fiber Bragg Grating was compared with the data of traditional system. Experimental results show that temperature measurement accuracy of improved system was up to 0.5 degrees C, and its accuracy has been improved compared to conventional systems. Meanwhile, the measurement error was significantly better than traditional systems. It proved that the design can improve the stability of temperature detection for the system. PMID- 27228784 TI - [Study of the Detecting System of CH4 and SO2 Based on Spectral Absorption Method and UV Fluorescence Method]. AB - According to the spectral absorption characteristics of polluting gases and fluorescence characteristics, a time-division multiplexing detection system is designed. Through this system we can detect Methane (CH4) and sulfur dioxide (SO2) by using spectral absorption method and the SO2 can be detected by using UV fluorescence method. The system consists of four parts: a combination of a light source which could be switched, the common optical path, the air chamber and the signal processing section. The spectral absorption characteristics and fluorescence characteristics are measured first. Then the experiment of detecting CH4 and SO2 through spectral absorption method and the experiment of detecting SO2 through UV fluorescence method are conducted, respectively. Through measuring characteristics of spectral absorption and fluorescence, we get excitation wavelengths of SO2 and CH4 measured by spectral absorption method at the absorption peak are 280 nm and 1.64 MUm, respectively, and the optimal excitation wavelength of SO2 measured by UV fluorescence method is 220 nm. we acquire the linear relation between the concentration of CH4 and relative intensity and the linear relation between the concentration of SO2 and output voltage after conducting the experiment of spectral absorption method, and the linearity are 98.7%, 99.2% respectively. Through the experiment of UV fluorescence method we acquire that the relation between the concentration of SO2 and the voltage is linear, and the linearity is 99.5%. Research shows that the system is able to be applied to detect the polluted gas by absorption spectrum method and UV fluorescence method. Combing these two measurement methods decreases the costing and the volume, and this system can also be used to measure the other gases. Such system has a certain value of application. PMID- 27228785 TI - Identification of Haploid Maize Kernel Using NIR Spectroscopy in Reflectance and Transmittance Modes: A Comparative Study. AB - The spectra measurements mode that suitable for haploid maize kernel identification was explored using MicroNIR-1700 series of miniature near infrared spectrometer by JDSU company. Based on Near Infrared Spectroscopy (NIRS) qualitative analysis techniques, we conducted a comparative study using reflectance and transmittance spectra to identify haploid maize kernels. Partial least squares-discriminant analysis (PLS-OLDA) was used to compress the pretreated spectral data, and then the identification models were built based on Support Vector Machine (SVM). The measured data were recorded in reflectance and transmittance modes and the recognition correct rates were calculated. For measurements taken in reflectance mode, the average recognition rate was less than 60% regardless of embryo side positions. In transmittance mode, however, the average recognition rate reached 93.2%. The experiment results show that diffuse reflection spectrum could only obtain corn grain surface information, so embryo side positions severely affect haploid maize kernel identification effect when reflectance measurements mode have been employed, but they have far less impact on transmittance mode. The near infrared diffuse transmittance spectra analyzes non-uniform samples can achieve the analysis of optical path depth information accumulation, all information of the sample interior can be obtained, so transmittance spectra could identify haploid maize effectively and be desensitized to kernel positions. NIRS qualitative analysis techniques with features of rapid, nondestructive could identify the haploid and Micro-NIR spectrometer scan fast and cost less, which have utility for automatically selecting haploid maize kernels from hybrid kernels. PMID- 27228786 TI - Determination of Component Contents of Blend Oil Based on Characteristics Peak Value Integration. AB - Edible blend oil market is confused at present. It has some problems such as confusing concepts, randomly named, shoddy and especially the fuzzy standard of compositions and ratios in blend oil. The national standard fails to come on time after eight years. The basic reason is the lack of qualitative and quantitative detection of vegetable oils in blend oil. Edible blend oil is mixed by different vegetable oils according to a certain proportion. Its nutrition is rich. Blend oil is eaten frequently in daily life. Different vegetable oil contains a certain components. The mixed vegetable oil can make full use of their nutrients and make the nutrients more balanced in blend oil. It is conducive to people's health. It is an effectively way to monitor blend oil market by the accurate determination of single vegetable oil content in blend oil. The types of blend oil are known, so we only need for accurate determination of its content. Three dimensional fluorescence spectra are used for the contents in blend oil. A new method of data processing is proposed with calculation of characteristics peak value integration in chosen characteristic area based on Quasi-Monte Carlo method, combined with Neural network method to solve nonlinear equations to obtain single vegetable oil content in blend oil. Peanut oil, soybean oil and sunflower oil are used as research object to reconcile into edible blend oil, with single oil regarded whole, not considered each oil's components. Recovery rates of 10 configurations of edible harmonic oil is measured to verify the validity of the method of characteristics peak value integration. An effective method is provided to detect components content of complex mixture in high sensitivity. Accuracy of recovery rats is increased, compared the common method of solution of linear equations used to detect components content of mixture. It can be used in the testing of kinds and content of edible vegetable oil in blend oil for the food quality detection, and provide an effective reference for the creation of national standards. PMID- 27228787 TI - De novo Families: Lesbian Motherhood. AB - The aim of this recent Australian study was to explore the experiences of lesbian women choosing motherhood. Participants included 30 self-identifying lesbian mothers. Data were collected via interviews, data collection sheets, and online journaling. The interview and journaling data were analyzed using constant comparative analysis and subsequently illuminated three main themes: becoming mothers, constructing motherhood, and legitimizing our family. These papers described the journey to motherhood and specifically explored the various methods of conception and other decisions that participants made when planning their family, the challenge of heteronormativity in health care, and legitimizing the role of the non-birth mother in de novo families. This article aims to present the participants' experiences of motherhood that was a constant topic found woven throughout all three of the identified themes. Participants identified that they had a unique opportunity to create their own mothering roles in the absence of significant "lesbian mother" role models and that they were able to adjust and to adapt their roles depending on fluctuating circumstances. PMID- 27228788 TI - Endoscopic Spatulation of the Intramural Ureter: A Technique to Prevent Stenosis of the Ureterovesical Junction in Patients Undergoing Resection of the Ureteral Orifice. AB - AIM: Wide resection of the ureteral orifice (UO) may result in scarring and stenosis of the ureterovesical junction (UVJ). We aimed to describe a technique of endoscopic spatulation of the intramural ureter in patients undergoing resection of the UO at the time of transurethral resection of bladder tumor (TURBT) and compare the surgical and oncological outcomes of this procedure with those of patients undergoing conventional UO resection. METHODS: The clinical records of patients who underwent TURBT at a single institution were retrospectively analyzed. Patients who underwent conventional UO resection or UO resection followed by endoscopic spatulation of the intramural ureter were included in the analysis. The two groups were compared in terms of intra- and postoperative outcomes. RESULTS: A total of 227 patients were included in the final comparative analyses. Of them, 104 underwent conventional UO resection and 123 underwent UO resection followed by endoscopic spatulation of the intramural ureter. The two groups were comparable for demographic and clinical features. There were not statistically significant differences in terms of mean operative times. The incidence of transient postoperative hydronephrosis as well as UVJ scarring and stenosis was significantly lower in patients undergoing endoscopic spatulation of the intramural ureter. The two groups were similar in terms of incidence of vesicoureteral reflux (VUR) and upper urinary tract cancer recurrence. CONCLUSION: Endoscopic spatulation of the intramural ureter after UO resection is a safe and quick procedure that significantly reduces the incidence of transient early postoperative hydronephrosis and late UVJ stricture if compared with UO resection alone. This procedure is quick to perform, safe, and does not increase the risk of VUR. PMID- 27228789 TI - Organochlorine pesticide distribution in an organic production system for cow's milk in Chiapas, Mexico. AB - The objective of this study was to evaluate the presence of organochlorine pesticides in samples of forage, soil, water, and milk in four units of an organic production system for cow's milk (samples of forage, milk, soil, and water) in Tecpatan, Chiapas, Mexico. The organochlorine pesticides were extracted from forage, soil and water based on the USEPA (2005) guideline and from milk based on the IDF 1991 guideline. The pesticides were identified and quantified by gas chromatography with electron capture detector (CG-ECD). In general, the highest average concentration of total pesticides was found in the samples of milk and forage (311 +/- 328 and 116.5 +/-77 ng g(-1) respectively). Although, the production systems analyzed are organic, organochlorine pesticides were detected in all environmental samples (forage, soil, water, and organic milk). Although no values surpassed the defined limits of Mexican and International regulation it is advisable that a monitoring program of contaminants in these production systems is continued. PMID- 27228790 TI - Sleep, anxiety and psychiatric symptoms in children with Tourette syndrome and tic disorders. AB - OBJECTIVE: The current study evaluated the relationship between tic, sleep disorders and specific psychiatric symptoms (anxiety, depression, obsessive compulsive symptoms). METHODS: Assessment of 36 consecutive children and adolescents with tic disorders included: the Yale Global Tic Severity Scale (YGTSS) to assess the severity of tic symptoms; the Self-administered scale for children and adolescents (SAFA) to evaluate the psychopathological profile; a specific sleep questionnaire consisting of 45 items to assess the presence of sleep disorders. An age and sex-matched control group was used for comparisons. RESULTS: Sleep was significantly more disturbed in patients with tic disorders than in controls. Difficulties in initiating sleep and increased motor activity during sleep were the most frequent sleep disturbances found in our sample. Patients showed also symptoms of anxiety (SAFA A), depressed mood (SAFA D) and doubt-indecision (SAFA O). Additionally, difficulties in initiating sleep resulted associated with other SAFA subscales relative to obsessive-compulsive symptoms and depression symptoms. Furthermore, anxiety symptoms (SAFA A) resulted associated with increased motor activity during sleep. CONCLUSIONS: Findings confirm literature studies reporting high frequency of sleep problems, anxiety and other psychopathological symptoms in patients with tic disorders, and support the hypothesis that intrusive thoughts and other emotional disturbances might disrupt the sleep onset of these patients. These results suggest the importance of a thorough assessment of sleep and psychiatric disturbances in patients with tic disorders. PMID- 27228791 TI - [An abdominal mass]. PMID- 27228897 TI - Simvastatin and artesunate impact the structural organization of adult Schistosoma mansoni in hypercholesterolemic mice. AB - Experimental data have shown that simvastatin and artesunate possess activity against Schistosoma mansoni worms in mice fed standard chow. However, little is known regarding the roles of these drugs in mice fed high-fat chow. We have extended past studies by measuring the effects of these drugs on the structural organization of adult schistosomes in hypercholesterolemic mice. For this purpose, mice were gavaged with either simvastatin or artesunate at nine weeks post-infection and were euthanized by cervical dislocation at two weeks post treatment. Adult worms were then collected and examined by conventional light microscopy, morphometry and confocal laser scanning microscopy. Plasma total cholesterol and worm reduction rates were significantly increased in mice fed high-fat chow compared with their respective control groups. Simvastatin and artesunate caused changes in the tegument, tubercles, and reproductive system (testicular lobes, vitelline glands and ovarian cells), particularly when administered to mice fed high-fat chow. In particular, the tegument and tubercles were significantly thinner in artesunate-treated worms in mice fed high-fat chow compared with mice fed standard chow. This study thus demonstrated that simvastatin and artesunate have several novel effects on the structural organization of adult worms. Together, these results show, for the first time, that simvastatin and artesunate display antischistosomal activity in hypercholesterolemic mice. PMID- 27228898 TI - Inducing an Order-Order Morphological Transition via Chemical Degradation of Amphiphilic Diblock Copolymer Nano-Objects. AB - The disulfide-based cyclic monomer, 3-methylidene-1,9-dioxa-5,12,13 trithiacyclopentadecane-2,8-dione (MTC), is statistically copolymerized with 2 hydroxypropyl methacrylate to form a range of diblock copolymer nano-objects via reversible addition-fragmentation chain transfer (RAFT) polymerization. Poly(glycerol monomethacrylate) (PGMA) is employed as the hydrophilic stabilizer block in this aqueous polymerization-induced self-assembly (PISA) formulation, which affords pure spheres, worms or vesicles depending on the target degree of polymerization for the core-forming block. When relatively low levels (<1 mol %) of MTC are incorporated, high monomer conversions (>99%) are achieved and high blocking efficiencies are observed, as judged by (1)H NMR spectroscopy and gel permeation chromatography (GPC), respectively. However, the side reactions that are known to occur when cyclic allylic sulfides such as MTC are statistically copolymerized with methacrylic comonomers lead to relatively broad molecular weight distributions. Nevertheless, the worm-like nanoparticles obtained via PISA can be successfully transformed into spherical nanoparticles by addition of excess tris(2-carboxyethyl)phosphine (TCEP) at pH 8-9. Surprisingly, DLS and TEM studies indicate that the time scale needed for this order-order transition is significantly longer than that required for cleavage of the disulfide bonds located in the worm cores indicated by GPC analysis. This reductive degradation pathway may enable the use of these chemically degradable nanoparticles in biomedical applications, such as drug delivery systems and responsive biomaterials. PMID- 27228900 TI - Physical health issues in adults with severe or profound intellectual and motor disabilities: a systematic review of cross-sectional studies. AB - BACKGROUND: People with severe or profound intellectual and motor disabilities (SPIMD) encounter several risk factors associated with higher mortality rates. They are also likely to experience a cluster of health problems related to the severe brain damage/dysfunction. In order to earlier detect physical health problems in people with SPIMD, first of all, knowledge regarding the prevalence of physical health problems is necessary. The aim of this systematic review was to methodically review cross-sectional studies on the prevalence of various types of physical health problems in adults with SPIMD. METHOD: MedLine/PubMed, CINAHL, Embase, PsycINFO and Web of Science were searched for studies published between 2004 and 2015. The quality of the incorporated studies was assessed utilising an adjusted 'risk of bias tool' for cross-sectional studies. To estimate the prevalence of the health problems, the proportion and corresponding confidence interval were calculated. A random effect meta-analysis was performed when at least three studies on a specific health problem were available. RESULTS: In total, 20 studies were included and analysed. In the meta-analysis, a homogeneous prevalence rate of 70% (CI 65-75%) was determined for epilepsy. Heterogeneous results were ascertained in the meta-analysis for pulmonary/respiratory problems, hearing problems, dysphagia, reflux disease and visual problems. For the health problems identified in two studies or in a single study, the degree of evidence was low. As expected, higher prevalence rates were found in the current review compared with people with ID for visual problems, epilepsy and spasticity. CONCLUSION: This review provides an overview of the current state of the art research on the prevalence of health problems in adults with SPIMD. There is a substantial need for comprehensive epidemiological data in order to find clusters of health problems specific for people with SPIMD. This would provide insight into the excess morbidity associated with SPIMD. PMID- 27228899 TI - Teaching primary care physicians the 5 A's for discussing weight with overweight and obese adolescents. AB - OBJECTIVE: We developed an online intervention to teach physicians both MI (addressed in outcomes paper) and the 5 A's (Ask, Advise, Assess, Assist, and Arrange) when discussing weight with overweight/obese adolescents. METHODS: We audio recorded 527 encounters between adolescents and physicians and coded the 5 A's during weight/BMI discussions. Half of physicians were randomized to receive a tailored, intervention that included their own audio-recorded clips. To examine arm differences, we used multilevel linear mixed-effects models for sum of 5 A's and generalized estimating equations (GEE) models with a logit link for each of the A's separately. RESULTS: Intervention arm physicians used more A's than control physicians (estimated difference=0.6; 95%CI(0.2,1.0);p=0.001). Intervention physicians used Assess (p=0.004), Assist (p=0.001) and Arrange (p=0.02) more when compared to control arm physicians. CONCLUSION: An online intervention increased physicians' use of the 5 A's when discussing weight with overweight adolescents. These results are promising as the online intervention improved performance for the three A's that are infrequently used (Assess, Assist, and Arrange) yet have the most impact. PRACTICE IMPLICATIONS: A tailored online program can increase physicians' use of the 5 A's behavioral counseling approach in clinical practice with adolescents. PMID- 27228901 TI - Association of clinical outcomes and complications with obesity in patients who have undergone abdominal myomectomy. AB - BACKGROUND: This study aimed to evaluate the association between complications and clinical parameters with obesity in 273 women who have undergone abdominal myomectomy during the study period. METHODS: The patients were classified into two groups according to body mass index (BMI) (<=30 kg/m(2) and >30 kg/m(2)). Demographic, preoperative and postoperative clinical parameters were evaluated. RESULTS: Demographic, preoperative and postoperative clinical parameters were evaluated. The results showed statistically significant differences between the obese and non-obese groups in terms of age, gravidity, diameter of fibroid (DOF), postoperative hemoglobin, duration of hospital stay, and complications. Patients in the obese group had greater DOF and complications such as hemorrhage, postoperative fever, wound infection and ileus (p < 0.05). CONCLUSION: Based on our results, we conclude that obesity adversely affects the clinical outcomes of patients who undergo abdominal myomectomy. PMID- 27228792 TI - Heterogeneity in Cancer Metabolism: New Concepts in an Old Field. AB - SIGNIFICANCE: In the last years, metabolic reprogramming, fluctuations in bioenergetic fuels, and modulation of oxidative stress became new key hallmarks of tumor development. In cancer, elevated glucose uptake and high glycolytic rate, as a source of adenosine triphosphate, constitute a growth advantage for tumors. This represents the universally known Warburg effect, which gave rise to one major clinical application for detecting cancer cells using glucose analogs: the positron emission tomography scan imaging. Recent Advances: Glucose utilization and carbon sources in tumors are much more heterogeneous than initially thought. Indeed, new studies emerged and revealed a dual capacity of tumor cells for glycolytic and oxidative phosphorylation (OXPHOS) metabolism. OXPHOS metabolism, which relies predominantly on mitochondrial respiration, exhibits fine-tuned regulation of respiratory chain complexes and enhanced antioxidant response or detoxification capacity. CRITICAL ISSUES: OXPHOS dependent cancer cells use alternative oxidizable substrates, such as glutamine and fatty acids. The diversity of carbon substrates fueling neoplastic cells is indicative of metabolic heterogeneity, even within tumors sharing the same clinical diagnosis. Metabolic switch supports cancer cell stemness and their bioenergy-consuming functions, such as proliferation, survival, migration, and invasion. Moreover, reactive oxygen species-induced mitochondrial metabolism and nutrient availability are important for interaction with tumor microenvironment components. Carcinoma-associated fibroblasts and immune cells participate in the metabolic interplay with neoplastic cells. They collectively adapt in a dynamic manner to the metabolic needs of cancer cells, thus participating in tumorigenesis and resistance to treatments. FUTURE DIRECTIONS: Characterizing the reciprocal metabolic interplay between stromal, immune, and neoplastic cells will provide a better understanding of treatment resistance. Antioxid. Redox Signal. 26, 462-485. PMID- 27228902 TI - Physicochemical properties of engineered nanomaterials that influence their nervous system distribution and effects. AB - This critical review examines in vitro and in vivo evidence for the influence of engineered nanomaterial (ENM) physicochemical properties on their distribution into, and effects on, the nervous system. Nervous system applications of ENMs; exposure routes and potential for uptake; the nervous system and its barriers to ENM uptake; and the mechanisms of uptake into the nervous system and overcoming those barriers are summarized. The findings of English-language publications of studies that included at least two variations of an ENM physicochemical property and reported results of their pharmacokinetic and/or pharmacodynamic interaction with the nervous system that differed as a function of ENM physicochemical property(ies) are summarized in Supplementary Materials. A summary conclusion is drawn for each of the physicochemical properties on the strength of the evidence that it influences ENM-nervous system interaction. PMID- 27228903 TI - Observation of the quantum Hall effect in delta-doped SrTiO3. AB - The quantum Hall effect is a macroscopic quantum phenomenon in a two-dimensional electron system. The two-dimensional electron system in SrTiO3 has sparked a great deal of interest, mainly because of the strong electron correlation effects expected from the 3d orbitals. Here we report the observation of the quantum Hall effect in a dilute La-doped SrTiO3-two-dimensional electron system, fabricated by metal organic molecular-beam epitaxy. The quantized Hall plateaus are found to be solely stemming from the low Landau levels with even integer-filling factors, nu=4 and 6 without any contribution from odd nu's. For nu=4, the corresponding plateau disappears on decreasing the carrier density. Such peculiar behaviours are proposed to be due to the crossing between the Landau levels originating from the two subbands composed of d orbitals with different effective masses. Our findings pave a way to explore unprecedented quantum phenomena in d-electron systems. PMID- 27228904 TI - Integrating Social Media Monitoring Into Public Health Emergency Response Operations. AB - Social media monitoring for public health emergency response and recovery is an essential response capability for any health department. The value of social media for emergency response lies not only in the capacity to rapidly communicate official and critical incident information, but as a rich source of incoming data that can be gathered to inform leadership decision-making. Social media monitoring is a function that can be formally integrated into the Incident Command System of any response agency. The approach to planning and required resources, such as staffing, logistics, and technology, is flexible and adaptable based on the needs of the agency and size and scope of the emergency. The New York City Department of Health and Mental Hygiene has successfully used its Social Media Monitoring Team during public health emergency responses and planned events including major Ebola and Legionnaires' disease responses. The concepts and implementations described can be applied by any agency, large or small, interested in building a social media monitoring capacity. (Disaster Med Public Health Preparedness. 2016;page 1 of 6). PMID- 27228905 TI - Teaching biochemistry online at Oregon State University. AB - A strategy for growing online biochemistry courses is presented based on successes in ecampus at Oregon State University. Four free drawing cards were key to the effort-YouTube videos, iTunes U online free course content, an Open Educational Resource textbook-Biochemistry Free and Easy, and a fun set of educational songs known as the Metabolic Melodies. (c) 2016 by The International Union of Biochemistry and Molecular Biology, 45(1):25-30, 2017. PMID- 27228906 TI - Robotic-assisted surgery versus open surgery in the treatment of rectal cancer: the current evidence. AB - The aim of this meta-analysis was to comprehensively compare the safety and efficacy of robotic-assisted rectal cancer surgery (RRCS) and open rectal cancer surgery (ORCS). Electronic database (PubMed, EMBASE, Web of Knowledge, and the Cochrane Library) searches were conducted for all relevant studies that compared the short-term and long-term outcomes between RRCS and ORCS. Odds ratios (ORs), mean differences, and hazard ratios were calculated. Seven studies involving 1074 patients with rectal cancer were identified for this meta-analysis. Compared with ORCS, RRCS is associated with a lower estimated blood loss (mean difference [MD]: -139.98, 95% confidence interval [CI]: -159.11 to -120.86; P < 0.00001), shorter hospital stay length (MD: -2.10, 95% CI: -3.47 to -0.73; P = 0.003), lower intraoperative transfusion requirements (OR: 0.52, 95% CI: 0.28 to 0.99, P = 0.05), shorter time to flatus passage (MD: -0.97, 95% CI = -1.06 to -0.88, P < 0.00001), and shorter time to resume a normal diet (MD: -1.71.95% CI = -3.31 to 0.12, P = 0.04). There were no significant differences in surgery-related complications, oncologic clearance, disease-free survival, and overall survival between the two groups. However, RRCS was associated with a longer operative time. RRCS is safe and effective. PMID- 27228907 TI - Natural lecithin promotes neural network complexity and activity. AB - Phospholipids in the brain cell membranes contain different polyunsaturated fatty acids (PUFAs), which are critical to nervous system function and structure. In particular, brain function critically depends on the uptake of the so-called "essential" fatty acids such as omega-3 (n-3) and omega-6 (n-6) PUFAs that cannot be readily synthesized by the human body. We extracted natural lecithin rich in various PUFAs from a marine source and transformed it into nanoliposomes. These nanoliposomes increased neurite outgrowth, network complexity and neural activity of cortical rat neurons in vitro. We also observed an upregulation of synapsin I (SYN1), which supports the positive role of lecithin in synaptogenesis, synaptic development and maturation. These findings suggest that lecithin nanoliposomes enhance neuronal development, which may have an impact on devising new lecithin delivery strategies for therapeutic applications. PMID- 27228909 TI - Presidential address. PMID- 27228908 TI - Dramatically decreased magnetoresistance in non-stoichiometric WTe2 crystals. AB - Recently, the layered semimetal WTe2 has attracted renewed interest owing to the observation of a non-saturating and giant positive magnetoresistance (~10(5)%), which can be useful for magnetic memory and spintronic devices. However, the underlying mechanisms of the giant magnetoresistance are still under hot debate. Herein, we grew the stoichiometric and non-stoichiometric WTe2 crystals to test the robustness of giant magnetoresistance. The stoichiometric WTe2 crystals have magnetoresistance as large as 3100% at 2 K and 9-Tesla magnetic field. However, only 71% and 13% magnetoresistance in the most non-stoichiometry (WTe1.80) and the highest Mo isovalent substitution samples (W0.7Mo0.3Te2) are observed, respectively. Analysis of the magnetic-field dependent magnetoresistance of non stoichiometric WTe2 crystals substantiates that both the large electron-hole concentration asymmetry and decreased carrier mobility, induced by non stoichiometry, synergistically lead to the decreased magnetoresistance. This work sheds more light on the origin of giant magnetoresistance observed in WTe2. PMID- 27228910 TI - BDA presidential valediction. PMID- 27228911 TI - Antibiotic prescribing: Embrace antimicrobial stewardship. PMID- 27228912 TI - Oral cancer: Another challenge for the dental team? PMID- 27228913 TI - Dental radiography: CBCT scrutiny. PMID- 27228914 TI - Careers: The absence of restorative dentistry. PMID- 27228915 TI - Bridging to medicine. PMID- 27228916 TI - Misleading association. PMID- 27228919 TI - 'Amazing endeavour' opened in Essex. PMID- 27228920 TI - Personal account: 'These patients were the fortunate ones'. PMID- 27228921 TI - Tooth decay among five-year-olds continues decline. PMID- 27228924 TI - BOS launches new guide to empower adult patients. PMID- 27228926 TI - Aditi Desai: 'I want dental sleep medicine to be taken seriously'. PMID- 27228927 TI - Brexit and dentistry. AB - On 23 June 2016, eligible UK voters will be asked to decide whether to vote in the EU referendum. The EU impacts on our daily lives in more ways than many people realise. Dentistry is affected by EU legislation. Examples include the movement of dental professionals, the import of dental equipment and materials, as well as health and safety legislation. Many more EU dentists and DCPs come to the UK to work than vice versa. These numbers have increased markedly since 2004. The result of the vote may affect how dentistry operates in the UK in future years. In addition, a vote to stay would not necessarily prevent change. There are attempts underway to increase the ease by which professionals can work in other member states, especially on a temporary basis. This too is likely affect dentistry at some point. Workforce planners and policy makers should factor in the impact of the EU in future dental policy. PMID- 27228928 TI - How will I be after my operation for oral cancer? AB - '...give clinicians a better understanding of their patients' needs.' PMID- 27228929 TI - Managing carious lesions; consensus recommendations on terminology. AB - If biofilm control is considered insufficient, the integrity of a fissure sealant should be monitored until more is known of the 'trampoline' effect (the sealant may not be able to resist occlusal forces when there is softened dentine beneath the weakened enamel). PMID- 27228930 TI - Incidence and survival trends of lip, intra-oral cavity and tongue base cancers in south-east England. AB - Despite an increasing incidence, the 'mortality from oral cancer appears to remain static...' (five-year relative survival = ca. 60%). PMID- 27228931 TI - Service evaluation of a nurse-led dental anxiety management service for adult patients. AB - Objective Evaluate patients' and professionals' experiences of a nurse-led dental anxiety management service (NDAMS).Design Service evaluation.Setting The NDAMS operates as part of the Sheffield Salaried Primary Dental Care Service.Subjects and methods Questionnaire survey of anxious patients and qualitative interviews with patients and professionals.Interventions Dental nurses delivered low-level psychological interventions as part of an integrated care pathway (ICP) for dental anxiety.Main outcome measures Dental anxiety and oral health-related quality of life (OHRQoL) questionnaires were completed by patients before and following NDAM.Results A total of 187 patients were assessed as suitable for NDAM (mean age = 33.7, 77% female) and 33 had completed it at the time of the service evaluation. Of those patients who had completed the intervention, significant improvements in dental anxiety and OHRQoL were reported. Professionals highlighted the importance of integrated working, adequate support and training, and assessing the suitability of patients for NDAM.Conclusion ICPs that combine pharmacological and psychological management approaches can help meet the needs of dentally anxious patients; however, early identification of patients most likely to benefit from psychological intervention should be a priority. PMID- 27228932 TI - Two-week wait false alarms? A prospective investigation of 2WW head and neck cancer referrals. AB - Objectives i) To prospectively explore patients' experience through the two-week wait (2WW) referral process; ii) To compare the relative true malignancy diagnostic rate between general medical practitioners (GMPs) and general dental practitioners (GDPs) over a six-month period; iii) To compare management of 2WW referral cases between GMPs and GDPs before the referral and during the 2 weeks in regards to symptomatic support, investigations in primary care, and information communicated to patients and secondary care clinicians; iv) To investigate the benign conditions that comprise 2WW referrals by finding out the final diagnoses of all cases included in the study.Method The patient inclusion criteria were all 2WW referral patients who attended consultation clinics during the six-month study period in Royal Cornwall Hospital NHS Trust. We prospectively distributed patient questionnaires and clinician's referral assessment forms. We obtained the final diagnoses of all participants electronically, and also identified all malignancies diagnosed via routine referral route during the study period from the cancer services team.Results Two hundred and twenty patients referred via 2WW pathway participated in the study. Of these, 148 referrals were from GMPs and 72 from GDPs. The overall malignancy diagnostic yield was 6.2%; markedly higher from GMPs (9.5%) than GDPs (1.4%), and higher number than those from routine pathway. The GMPs and GDPs showed similar levels of clinical management and information exchange judging from the participants' responses. We also identified the top nine most commonly urgently referred benign conditions.Conclusion We reiterate the need for improved communication between clinicians and patients and between clinicians. We also suggest more focus on education in commonly encountered conditions as well as malignant lesions. The number of 2WW referrals we received from GMPs was nearly twice as many as those from GDPs, highlighting the importance of delivering oral medicine education to medical students, trainees and GMPs. PMID- 27228934 TI - Reducing health inequalities in people with learning disabilities: a multi disciplinary team approach to care under general anaesthesia. AB - Background There remains significant inequality in health and healthcare in people with learning disabilities (LD). A lack of coordination and the episodic nature of care provision are contributory factors. Recognising the need to improve outcomes for this group, we evaluate a multi-disciplinary team (MDT) approach to care whereby additional medical procedures are carried out under the same episode of general anaesthesia (GA) as dental treatment for people with severe LD. This is the first published evaluation of its kind in the UK.Aim To evaluate the need and outcomes of an MDT approach to care among people with severe LD receiving dental treatment under GA.Method One hundred patients with severe LD and behaviour that challenges attended Barts Health Dental Hospital for dental assessment and subsequent treatment under GA. Details of failed or forthcoming medical interventions were determined. Where appropriate, care was coordinated with the relevant medical team.Findings Twenty-one percent (n = 21/100) had recent medical interventions attempted that had been abandoned, and 7.0% (n = 7/100) had future investigations or treatment planned under GA with medical specialties. An MDT approach was indicated in 28.0% (n = 28/100). For such complex cases, a successful MDT outcome was achieved in 89.3% (n = 25/28). This included ophthalmological/orthoptic, ENT and gastroenterological interventions in addition to medical imaging.Conclusion An MDT approach to care for people with LD offers improved patient-centred outcomes in addition to financial and resource efficiency. It requires a high level of cooperation between specialties, with consideration of the practicalities of a shared surgical space and equipment needs. Re-shaping of services and contractual flexibility are essential to support the future implementation of MDTs and to ensure long-term sustainability. Adoption of a holistic culture in the care of this vulnerable patient group is encouraged. PMID- 27228933 TI - Can dental registrants use the Index of Orthodontic Treatment Need accurately? Part 1: Knowledge of IOTN among dental registrants. AB - Aim To determine whether dental registrants can use the dental health component (DHC) and aesthetic component (AC) of the Index of Orthodontic Treatment Need (IOTN) 'accurately' to an acceptable level of agreement and diagnostic validity.Method Participants from six different registrant groups were asked to score the IOTN for 14 cases based on study models and photographs as well as completing a short questionnaire. Participants in the study were all recruited at study days and annual conferences. The main outcome measures include the different registrant groups IOTN scores compared to expert panel scores using kappa statistics. To assess for diagnostic validity, individual participants sensitivity and specificity scores were calculated.Result Overall, 229 registrants took part in the study. For the DHC the specialist orthodontist (SO), postgraduate orthodontic student (PGOS) and the qualified orthodontic therapist (QOT) groups achieved a mean kappa >=0.60 indicating 'acceptable' agreement with the expert panel scores. The dental foundation trainee (DFT) and general dental practitioner (GDP) group achieved a mean kappa of 0.20 and 0.22 respectively indicating poor and fair agreement. The student orthodontic therapist (SOT) group achieved a mean kappa of 0.55 indicating moderate agreement. For the AC none of the registrant groups achieved an acceptable level of agreement with the mean kappa scores for the different groups ranging from kappa 0.13-0.21, indicating poor to fair agreement.Conclusion Overall agreement for the DHC was varied for the different registrant groups ranging from fair to substantial agreement. Registrants were better at applying the DHC compared to the AC with agreement ranging from poor to fair. More needs to done to help registrants use the IOTN more 'accurately'. PMID- 27228935 TI - Belongingness in undergraduate dental education. AB - Objective To undertake a detailed educational evaluation into dental students' experience of the concept of belongingness and their development as 'safe beginners' on an outreach placement at the University of Portsmouth Dental Academy (UPDA).Method The participants were asked two questions: Did you feel belongingness at UPDA?; and When in your year rotation did you feel this? They completed the educational evaluation anonymously in their last week of attendance. The quantitative data was handled with descriptive statistics and the qualitative data was analysed for recurring themes.Results A 95% response rate was achieved. Eighty six percent of respondents strongly agreed to feeling belongingness and 56% felt it after their first two weeks. Four themes were identified: 'Interaction with the preexisting people environment' (1a. Initial welcoming and warmth 1b. Continued interest in me as an individual); 'Developing collegiality' (2a. My group of fellow students 2b. Working with the dental team as a dentist 2c. The team of everyone at UPDA); 'In the clinical environment' (3a. Being a dentist with responsibility and respect 3b. The physical environment 3c. Becoming a reflective independent practitioner); and 'Leadership'.Conclusion Belongingness in dental education should be defined as:- a deeply personal and contextually mediated experience in which a student becomes an essential and respected part of the dental educational environment where all are accepted and equally valued by each other and which allows each individual student to develop autonomy, self-reflection and self-actualisation as a clinician. PMID- 27228936 TI - Volunteer-led free dental outreach clinics in semi-urban Uganda: a feasibility study. AB - Background The global burden of dental disease remains a key global public health issue, with the prevalence of common pathologies grossly unchanged over the last two decades. Poor oral health impacts individuals on a personal and economic level and incurs a significant cost globally. The role of dental aid organisations in strategies to deliver dental health services has long been debated.Methods We launched a dental clinic at the premises of an established non governmental organisation. All patients were taught a locally developed oral hygiene educational module before receiving a thorough examination. Treatments offered included simple scaling, fluoride application, treatment of infection and extraction.Results Three dental clinics were conducted. A total of 93 patients registered. Thirty nine (42%) were male, with an average age of 20 years (range 5 70 years). Eighty-six percent of patients presented in pain. Five (5.4%) of the patients were found to have sound teeth. Forty-three (46%) patients had at least one tooth extraction. Twenty-six percent of patients were referred for restorations. The treatment provided equated to 178 units of dental activity (UDAs). The total cost per patient was L1.82, regardless of treatment, or L0.95 per UDA.Discussion and conclusion We demonstrated a distinct need for dental healthcare in this area, an acceptability of our service, potential for sustainability, and a dedication towards providing a basic package of oral care. We call for a reignition of debate regarding the role of dental aid organisations in the provision of global oral healthcare. PMID- 27228946 TI - Pericarditis and Pericardial Effusions in End-Stage Renal Disease. AB - Pericarditis and pericardial effusions are not uncommon in patients with end stage renal disease (ESRD). Etiologies include those found in the general population along with two entities unique to patients with kidney disease, namely uremic and dialysis-associated pericarditis. Uremic pericarditis has been arbitrarily defined as pericarditis that develops before or within 8 weeks of initiation of dialysis, while dialysis-associated pericarditis is used to define pericarditis in patients on dialysis for more than 8 weeks. Retention of uremic toxins is likely a major contributor to uremic and dialysis-associated pericarditis although their exact cause is not known. Indeed, whether they are actually distinct entities is uncertain. Symptoms and signs of pericarditis differ in patients with ESRD compared to the non-ESRD population. Management has not been well studied and ranges from initiation and intensification of dialysis to percutaneous or open drainage for large effusions. This review covers the literature on this topic but emphasizes that most of the data are old and of relatively poor quality, and therefore additional research is needed. PMID- 27228945 TI - Three proliferating cell nuclear antigen homologues from Metallosphaera sedula form a head-to-tail heterotrimer. AB - Proliferating cell nuclear antigen (PCNA) is a sliding clamp that plays a key role in DNA metabolism. Genome sequence analysis has revealed that some crenarchaea possess three PCNA genes in their genome, but it has been reported that three PCNAs do not always form a unique heterotrimer composed of one of each molecule. The thermoacidophilic archaeon, Metallosphaera sedula, has three PCNA homologue genes. Here, we demonstrated that the three PCNA homologues, MsePCNA1, MsePCNA2 and MsePCNA3, exclusively form a heterotrimer in a stepwise fashion; MsePCNA1 and MsePCNA2 form a heterodimer, and then MsePCNA3 binds to the heterodimer. We determined that the dissociation constants between MsePCNA1 and MsePCNA2, and between MsePCNA3 and the MsePCNA1:MsePCNA2 heterodimer are 0.29 and 43 nM, respectively. Moreover, the MsePCNA1, MsePCNA2 and MsePCNA3 heterotrimer stimulated M. sedula DNA ligase 1 activity, suggesting that the heterotrimer works as a DNA sliding clamp in the organism. The stable and stepwise heterotrimerization of M. sedula PCNA homologues would be useful to generate functional protein-based materials such as artificial multi-enzyme complexes, functional hydrogels and protein fibres, which have recently been achieved by protein self-assembly. PMID- 27228947 TI - Antibodies derived from an enterotoxigenic Escherichia coli (ETEC) adhesin tip MEFA (multiepitope fusion antigen) against adherence of nine ETEC adhesins: CFA/I, CS1, CS2, CS3, CS4, CS5, CS6, CS21 and EtpA. AB - Diarrhea continues to be a leading cause of death in children younger than 5 years in developing countries. Enterotoxigenic Escherichia coli (ETEC) is a leading bacterial cause of children's diarrhea and travelers' diarrhea. ETEC bacteria initiate diarrheal disease by attaching to host receptors at epithelial cells and colonizing in small intestine. Therefore, preventing ETEC attachment has been considered the first line of defense against ETEC diarrhea. However, developing vaccines effectively against ETEC bacterial attachment encounters challenge because ETEC strains produce over 23 immunologically heterogeneous adhesins. In this study, we applied MEFA (multiepitope fusion antigen) approach to integrate epitopes from adhesin tips or adhesive subunits of CFA/I, CS1, CS2, CS3, CS4, CS5, CS6, CS21 and EtpA adhesins and to construct an adhesin tip MEFA peptide. We then examined immunogenicity of this tip MEFA in mouse immunization, and assessed potential application of this tip MEFA for ETEC vaccine development. Data showed that mice intraperitoneally immunized with this adhesin tip MEFA developed IgG antibody responses to all nine ETEC adhesins. Moreover, ETEC and E. coli bacteria expressing these nine adhesins, after incubation with serum of the immunized mice, exhibited significant reduction in attachment to Caco-2 cells. These results indicated that anti-adhesin antibodies induced by this adhesin tip MEFA blocked adherence of the most important ETEC adhesins, suggesting this multivalent tip MEFA may be useful for developing a broadly protective anti adhesin vaccine against ETEC diarrhea. PMID- 27228948 TI - Determinants of the N content of Quercus wutaishanica leaves in the Loess Plateau: a structural equation modeling approach. AB - Most terrestrial ecosystems are nitrogen (N)-limited. The elucidation of the multivariate relationships among environmental drivers, leaf morphological traits, and foliar N of dominant species which are critical to the functioning of forests remains a critical challenge for ecologists. We sampled leaves of Quercus wutaishanica across a broad natural gradient in the Loess Plateau, China, and employed structural equation modelling to evaluate the causal pathways and the relative importance of drivers of the foliar N per unit area (Narea) and per unit mass (Nmass). We found that (1) Nmass and Narea were primarily affected by leaf morphological traits instead of environmental variables and that leaf morphological traits accounted for most of their variations; (2) the total soil potassium and phosphorus and mean annual precipitation had different effects on Nmass and Narea via different pathways and path coefficients, whereas the mean annual temperature and total soil N had non-significant effects on Nmass and Narea. Our results demonstrated that variations in Nmass and Narea within Quercus wutaishanica were strongly linked to their leaf morphological traits and that the leaf N was also influenced by mean annual precipitation and soil phosphorus and potassium instead of soil N in the Loess Plateau, China. PMID- 27228949 TI - Tunable Band-Stop Filters for Graphene Plasmons Based on Periodically Modulated Graphene. AB - Tunable band-stop filters based on graphene with periodically modulated chemical potentials are proposed. Periodic graphene can be considered as a plasmonic crystal. Its energy band diagram is analyzed, which clearly shows a blue shift of the forbidden band with increasing chemical potential. Structural design and optimization are performed by an effective-index-based transfer matrix method, which is confirmed by numerical simulations. The center frequency of the filter can be tuned in a range from 37 to 53 THz based on the electrical tunability of graphene, while the modulation depth (-26 dB) and the bandwidth (3.1 THz) of the filter remain unchanged. Specifically, the bandwidth and modulation depth of the filters can be flexibly preset by adjusting the chemical potential ratio and the period number. The length of the filter (~750 nm) is only 1/9 of the operating wavelength in vacuum, which makes the filter a good choice for compact on-chip applications. PMID- 27228950 TI - A method for assessing real time rates of dissolution and absorption of carbohydrate and other food matrices in human subjects. AB - We prepared pasta of differing physical dimensions but identical chemical composition that contained two monosaccharide probes (lactulose and mannitol) that are absorbed passively and promptly excreted in urine. We showed that the rates of their liberation from the pasta under simulated gastric and small intestinal conditions largely depended upon the rate of digestion of the starchy matrix. We showed, in 20 female subjects, that excretion of mannitol was slower from the pasta with the larger particle size. Hence, after consumption of either the powdered pasta or the simple solution of probe sugars, the mass of mannitol excreted between 1 and 21/2 hours was greater than that excreted between 21/2 and 4 hours. However these masses did not differ significantly after consumption of the pasta pellets. These differences were not reflected in the concurrent patterns of variation in either serum glucose or insulin taken over 120 minutes, their levels being similar for pasta pellets and powder with their peak values occurring synchronously during the first hour. Hence feeding test foods impregnated with lactulose and mannitol probes provided a reproducible and practical means of assessing the timing of digestion of the carbohydrate matrix and showed that this was more protracted than suggested by post prandial glucose levels. Further, the transit times calculated on a basis of the ratios of the two marker sugars could identify that the prolongation of digestion of larger particles was not accompanied by retention of digesta in particular segments of the gut. PMID- 27228951 TI - Length of winter coat in horses depending on husbandry conditions. AB - This paper analyzes changes in the length of coat on selected body areas in horses and ponies kept under different husbandry (stable) conditions during the winter-spring period. The study included 12 Malpolski geldings and 12 geldings of Felin ponies aged 10-15 years. Horses were kept in two stables (six horses and six ponies in each stable). The type of performance, husbandry conditions and feeding of the studied animals were comparable. As of December 1, samples of hair coat from the scapula, sternum, back and abdomen areas of both body sides were collected seven times. The lengths of 20 randomly selected hair fibers were measured. Daily measurements of air temperature in the stables were also taken. An analysis of variance (ANOVA) was performed using the following factors: the body part from where the coat was sampled, the subsequent examination and the stable as well as the interaction between these factors. The significance of differences between means was determined with a t-Tukey test. The relations between air temperature in the stable and hair length were calculated using Pearson's correlation. It was found that air temperature in the stable impacts the length of winter coat in horses and ponies. The effect of this factor is more pronounced in ponies; as in the stables with lower temperatures it produces a longer hair coat which is more evenly distributed over the body in comparison with horses. Keeping horses and ponies in stables with a low air temperature accelerates coat shedding by approximately 25 days. Coat shedding begins from the scapula area. PMID- 27228952 TI - Using structural modularity in cocrystals to engineer properties: elasticity. AB - Cocrystal formation of heterocyclic bases with halogenated aromatic acids increases the tendency for stacking and with this, an increase in structural isotropy occurs that leads to crystal elasticity. PMID- 27228953 TI - Overcoming obstacles in obtaining individual participant data for meta-analysis. AB - Individual participant data (IPD) is the backbone of scientific inquiry and important to a meta-analysis for a variety of reasons. It is therefore important to be able to access IPD, and yet, obstacles persist that make it difficult for meta-analysts, as well as interested primary study analysts, to obtain it. In this paper, we discuss the barriers to obtaining IPD via online repositories or contacting primary study authors and provide an example data sharing agreement that can be used to ameliorate a few of these issues. We also discuss the ethics of data sharing. The goal of this paper is to help meta-analysts anticipate these potential barriers at the outset of their studies and hopefully increase the likelihood of producing thorough IPD syntheses and foster collaborative partnerships with primary study researchers. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27228954 TI - The Age of Cortical Neural Networks Affects Their Interactions with Magnetic Nanoparticles. AB - Despite increasing use of nanotechnology in neuroscience, the characterization of interactions between magnetic nanoparticles (MNPs) and primary cortical neural networks remains underdeveloped. In particular, how the age of primary neural networks affects MNP uptake and endocytosis is critical when considering MNP based therapies for age-related diseases. Here, primary cortical neural networks are cultured up to 4 weeks and with CCL11/eotaxin, an age-inducing chemokine, to create aged neural networks. As the neural networks are aged, their association with membrane-bound starch-coated ferromagnetic nanoparticles (fMNPs) increases while their endocytic mechanisms are impaired, resulting in reduced internalization of chitosan-coated fMNPs. The age of the neurons also negates the neuroprotective effects of chitosan coatings on fMNPs, attributing to decreased intracellular trafficking and increased colocalization of MNPs with lysosomes. These findings demonstrate the importance of age and developmental stage of primary neural cells when developing in vitro models for fMNP therapeutics targeting age-related diseases. PMID- 27228956 TI - A nanoplasmonic probe as a triple channel colorimetric sensor array for protein discrimination. AB - The salt-induced aggregation, nanoparticle regrowth and self-assembly behaviors of gold nanoparticles (AuNPs) and DNA conjugates could be changed after interaction with different proteins, generating various color changes and a unique fingerprint pattern for each protein. The triple-channel colorimetric signals have been employed for protein discrimination with the naked eye. PMID- 27228955 TI - Relationship of Serum Trimethylamine N-Oxide (TMAO) Levels with early Atherosclerosis in Humans. AB - Circulating trimethylamine N-Oxide (TMAO) levels predict cardiovascular disease (CVD), possibly by impacting on cholesterol metabolism and oxidative stress. Because hepatic TMAO production is regulated by insulin signalling and it is unclear whether and to what extent circulating TMAO levels associate with CVD risk, independently of insulin resistance and its important determinants fatty liver and visceral obesity, we have now addressed this question in 220 subjects who participated in the Tubingen Lifestyle Intervention Program. Visceral fat mass (r = 0.40, p < 0.0001), liver fat content (r = 0.23, p = 0.0005) and TMAO levels (r = 0.26, p < 0.0001) associated positively, and insulin sensitivity associated negatively (r = -0.18, p = 0.009) with carotid intima-media thickness (cIMT). Higher TMAO levels (std.-Beta 0.11, p = 0.03) predicted increased cIMT, independently of age, sex and visceral fat mass. While during the lifestyle intervention most cardiovascular risk parameters improved, mean TMAO levels did not change (p = 0.18). However, cIMT decreased significantly (p = 0.0056) only in subjects in the tertile with the largest decrease of TMAO levels (>20%). We provide novel information that increased serum TMAO levels associate with increased cIMT, independently of established cardiovascular risk markers, including insulin resistance, visceral obesity and fatty liver. Furthermore, the decrease of cIMT during a lifestyle intervention may be related to the decrease of TMAO levels. PMID- 27228957 TI - Is Nephron Sparing Surgery Justified in Wilms Tumor With Beckwith-Wiedemann Syndrome or Isolated Hemihypertrophy? AB - BACKGROUND: Patients with Beckwith-Wiedemann syndrome (BWS) or isolated hemihypertrophy (HH) treated for a Wilms tumor (WT) carry an increased risk of developing metachronous lesion. There are no guidelines on precise indications for nephron sparing surgery (NSS) in unilateral WT (UWT). The objective of this retrospective study was to delineate the indications of NSS in patients with BWS/HH treated for WT and to evaluate their outcome. PROCEDURE: All cases of BWS/HH treated for a WT according to SIOP protocols from 1980 to 2013 were reviewed. Patients were divided into two groups (G): isolated UWT (G1) and bilateral lesions (G2) with two subgroups: bilateral tumors suspected of malignancy (G2a), and unilateral tumor suspected of malignancy with contralateral nephroblastomatosis (G2b). RESULTS: Forty-six patients were included (34 G1, three G2a, and nine G2b). Nine NSS and 25 total nephrectomies (TN) were performed in G1, two bilateral NSS and one NSS with contralateral TN in G2a, and eight NSS and one TN in G2b. The 3-year event-free survival was 92.3% (95% CI [77.9 97.5%]). One death occurred after a local relapse following a TN for a stage III stromal WT (G1) and another after a combined local and distant relapse following a NSS for a stage I diffuse anaplastic WT (G2b). There were two metachronous WT (4%), 3 years after a TN (G1) and 12 years after a NSS (G2b). CONCLUSIONS: NSS is recommended in bilateral WT and may be an option in selected UWT patients with BWS/HH because it was not associated with an increased risk of local relapse. PMID- 27228958 TI - Genetic polymorphisms in genes related to risk-taking behaviours predicting body mass index trajectory among Mexican American adolescents. AB - OBJECTIVES: Obesity is associated with multiple health problems and often originates in childhood. The purpose is to investigate the associations of genetic polymorphisms in genes related to risk-taking behaviours with body mass index (BMI) trajectory over adolescence among Mexican Americans. METHODS: This study included 1229 Mexican American adolescents who participated in a large population-based cohort study in Houston, Texas. BMI data were obtained at baseline and two follow-ups. The median follow-up time was 59 months. Participants were genotyped for 672 functional and tagging variants in genes involved in the dopamine, serotonin and cannabinoid pathways. RESULTS: After adjusting for multiple comparisons, three genetic variants, namely, rs933271 and rs4646310 in COMT gene, and rs9567733 in HTR2A gene were significantly associated with BMI growth over adolescence. Using those three variants, we created an allelic score, and the allelic score was associated with BMI growth over adolescence (P < 0.001). With the increase number of variant allele, the rate of BMI growth over adolescence was slower. Finally, we identified another two genetic variants, namely, rs17069005 in HTR2A gene and rs3776511 in SLC6A3A gene were associated with obesity at last follow-up. CONCLUSIONS: The results suggest that genetic variants in selected genes involved in dopamine and serotonin pathways have noticeable effects on BMI over adolescence. PMID- 27228959 TI - A randomised clinical trial comparing the flexible fibrescope and the Pentax Airway Scope (AWS)((r)) for awake oral tracheal intubation. AB - We compared awake fibreoptic intubation with awake intubation using the Pentax Airway Scope((r)) in 40 adult patients. Sedation was achieved using a target controlled remifentanil infusion of 1-5 ng.ml(-1) and midazolam. The airway was anaesthetised with lidocaine spray and gargle. The total procedure time - a composite of sedation time, topical anaesthesia time and intubation time - was recorded. The operator's impression of the ease of the procedure and the patients' reported comfort were recorded on a 0-100 mm visual analogue scale. The median (IQR [range]) for total procedure time was 900 (739-1059 [616-1215]) s with the fibrescope and 651 (601-720 [498-900]) s with the Pentax Airway Scope (p = 0.0001). The median (IQR [range]) intubation time was 420 (283-480 [120-608]) s with the fibrescope and 183 (144-220 [107-420]) s with the Pentax Airway Scope (p = 0.0002). The median (IQR [range]) visual analogue scores for the operator's ease of intubation for the fibrescope and Pentax Airway Scope were 83.6 (72.0 98.0 [49.0-100.0]) and 86.8 (84.0-91.0 [61.0-100.0]), respectively (p = 0.3507). The median (IQR [range]) visual analogue score for patient comfort was 85.5 (81.0 97.0 [69.0-100.0]) and 79.4 (74.0-85.0 [59.0-100.0]) for the fibrescope and Pentax Airway Scope, respectively (p = 0.06). Total procedure time was significantly shorter with the Pentax Airway Scope compared with the fibrescope, with no difference in procedure difficulty or patient discomfort. PMID- 27228960 TI - The soda dipstick: A convenient and cost-effective means of identifying the sugar content of soft drinks. PMID- 27228961 TI - Extra-medial thickness of carotid artery in patients with Behcet's disease: evaluation of atherosclerotic vessel wall changes with a novel carotid artery ultrasound index. AB - OBJECTIVES: Chronic inflammation and endothelial dysfunction are the characteristic features of Behcet's disease (BD). We researched carotid extra medial thickness (cEMT), a novel ultrasound parameter for atherosclerotic vessel wall changes, and carotid intima media thickness (cIMT), a widely accepted marker of subclinical atherosclerosis, in patients with BD, and we evaluated the relationship between these two parameters. MATERIALS AND METHODS: In total, 31 patients with BD were matched to 26 control subjects based on age, gender, and major cardiovascular risk factors. Laboratory parameters, including lipid profile, were measured for both patients and controls. B-mode ultrasonography was used to assess the cEMT and cIMT. RESULTS: There was no significant difference in the cEMT values between the patients with BD and the control group (P = 0.90). cIMT in the BD group was significantly higher compared with the control group (P = 0.021). There was a significant positive correlation between cIMT and cEMT (r = 0.585, P = 0.001). Both cEMT and cIMT were positively correlated with age and the presence of arthritis. There was linear correlation with sedimentation, C reactive protein, and cEMT. CONCLUSIONS: To the best of our knowledge, this is the first study to evaluate both cEMT and cIMT in BD. This study presents morphological evidence of subclinical atherosclerosis in terms of cIMT. Although there was no significant increment in cEMT, it has the potential to assess endothelial dysfunction in BD. Further studies are required to confirm this finding. PMID- 27228962 TI - Use of the retrograde limb of the internal mammary vein to avoid venous congestion in DIEP flap breast reconstruction: Further evidences of a reliable and time-sparing procedure. AB - AIM: Venous congestion is a common cause of DIEP flap failure. When identified intraoperatively, an additional venous anastomosis can improve the venous outflow and prevent flap failure. The aim of this study was to assess if the retrograde limb of the internal mammary vein (IMV) could be considered a good recipient vessel to be used when persistent flap congestion is present, and a second venous anastomosis is required. PATIENTS AND METHODS: A retrospective study was conducted in 74 patients who had undergone DIEP flap breast reconstruction. Patients were classified into two groups: SVA (single venous anastomosis) and DVA (dual venous anastomosis). In the SVA group (n = 38), the IMV antegrade limb was used for venous drainage. A single DIEV (Deep Inferior Epigastric Vein) was anastomosed to the superior arm of the IMV. In the DVA group (n = 36), both the antegrade (superior) and retrograde (inferior) stumps of the IMV were used, connecting the larger DIEV to the antegrade IMV and the other DIEV or the SIEV (Superficial Inferior Epigastric Vein) to the IMV retrograde limb. RESULTS: No venous congestion or flap loss was observed when two venous anastomoses were performed using both the IMV antegrade and retrograde limbs (P = 0.3271). In the DVA group, no major complication occurred (P = 0.0453). Operative explorations were significantly reduced in the DVA group (P = 0.0242). CONCLUSION: These findings suggest that when an additional venous outflow is required, the use of the IMV retrograde limb may help to avoid flap venous congestion. (c) 2016 Wiley Periodicals, Inc. Microsurgery 36:447-452, 2016. PMID- 27228963 TI - Dynamic cerebral autoregulation is unrelated to decrease in external carotid artery blood flow during acute hypotension in healthy young men. AB - NEW FINDINGS: What is the central question of this study? Dynamic cerebral autoregulation (CA) is impaired by sympathetic blockade, and the external carotid artery (ECA) vascular bed may prevent adequate internal carotid artery blood flow. We examined whether alpha1 -receptor blockade-induced attenuation of dynamic CA is related to reduced ECA vasoconstriction. What is the main finding and its importance? alpha1 -Receptor blockade attenuated dynamic CA, but in contrast to our hypothesis did not affect the ECA blood flow response to acute hypotension. These findings suggest that the recovery of cerebral blood flow during acute hypotension is unrelated to vasoconstriction within the ECA territory. External carotid artery (ECA) vasoconstriction may defend internal carotid artery (ICA) blood flow during acute hypotension. We hypothesized that the alpha1 -receptor blockade-induced delay in ICA recovery to the baseline level from acute hypoperfusion is related to attenuated ECA vasoconstriction. The ICA and ECA blood flow were determined by duplex ultrasound during thigh-cuff release induced acute hypotension while the alpha1 -receptor blocker prazosin [1 mg (20 kg)(-1) ] was administered to nine seated young healthy men. Both ICA (mean +/- SD; by 17 +/- 8%, P = 0.005) and ECA (by 37 +/- 15%, P < 0.001) blood flow decreased immediately after occluded thigh-cuff release, with a more rapid ICA blood flow recovery to the baseline level (9 +/- 5 s) than for the ECA blood flow (17 +/- 5 s; P = 0.019). The ICA blood flow recovery from hypoperfusion was delayed with prazosin (17 +/- 4 s versus control 9 +/- 5 s, P = 0.006), whereas ECA recovery remained unchanged (P = 0.313) despite a similar reduction in mean arterial pressure (-20 +/- 4 mmHg versus control -23 +/- 7 mmHg, P = 0.148). These findings suggest that alpha1 -receptor blockade-induced attenuation of the ICA blood flow response to acute hypotension is unrelated to the reduction in ECA blood flow. The sympathetic nervous system via the ECA vascular bed does not contribute to dynamic CA during acute hypotension. PMID- 27228965 TI - Stiff-stilbene photoswitch ruptures bonds not by pulling but by local heating. AB - The photochemical cis->trans-isomerization of stiff-stilbene (1-(1 indanyliden)indan) was previously used to trigger the ring opening of cyclobutene, i.e. the retro [2+2] cycloaddition leading to butadiene, mechanically. However, the forces generated by stiff-stilbene during photoisomerization are limited, so it is unclear in how far the mechanical properties of stiff-stilbene determine the efficiency of the bond rupture. Here we present a computational study in which we investigate the mechanochemical properties of this reaction. We show that the mechanical work transmitted from stiff-stilbene to cyclobutene is much too low to account for the observed facilitation of the ring opening. Hence, local heating resulting from the absorption of a photon by stiff-stilbene and efficient non-radiative decay are the key elements initiating this reaction. PMID- 27228964 TI - Intensity-dependent timing and precision of startle response latency in larval zebrafish. AB - KEY POINTS: Using high-speed videos time-locked with whole-animal electrical recordings, simultaneous measurement of behavioural kinematics and field potential parameters of C-start startle responses allowed for discrimination between short-latency and long-latency C-starts (SLCs vs. LLCs) in larval zebrafish. Apart from their latencies, SLC kinematics and SLC field potential parameters were intensity independent. Increasing stimulus intensity increased the probability of evoking an SLC and decreased mean SLC latencies while increasing their precision; subtraction of field potential latencies from SLC latencies revealed a fixed time delay between the two measurements that was intensity independent. The latency and the precision in the latency of the SLC field potentials were linearly correlated to the latencies and precision of the first evoked action potentials (spikes) in hair-cell afferent neurons of the lateral line. Together, these findings indicate that first spike latency (FSL) is a fast encoding mechanism that can serve to precisely initiate startle responses when speed is critical for survival. ABSTRACT: Vertebrates rely on fast sensory encoding for rapid and precise initiation of startle responses. In afferent sensory neurons, trains of action potentials (spikes) encode stimulus intensity within the onset time of the first evoked spike (first spike latency; FSL) and the number of evoked spikes. For speed of initiation of startle responses, FSL would be the more advantageous mechanism to encode the intensity of a threat. However, the intensity dependence of FSL and spike number and whether either determines the precision of startle response initiation is not known. Here, we examined short-latency startle responses (SLCs) in larval zebrafish and tested the hypothesis that first spike latencies and their precision (jitter) determine the onset time and precision of SLCs. We evoked startle responses via activation of Channelrhodopsin (ChR2) expressed in ear and lateral line hair cells and acquired high-speed videos of head-fixed larvae while simultaneously recording underlying field potentials. This method allowed for discrimination between primary SLCs and less frequent, long-latency startle responses (LLCs). Quantification of SLC kinematics and field potential parameters revealed that, apart from their latencies, they were intensity independent. We found that increasing stimulus intensity decreased SLC latencies while increasing their precision, which was significantly correlated with corresponding changes in field potential latencies and their precision. Single afferent neuron recordings from the lateral line revealed a similar intensity-dependent decrease in first spike latencies and their jitter, which could account for the intensity-dependent changes in timing and precision of startle response latencies. PMID- 27228966 TI - The association of change in medication regimen and use of inappropriate medication based on beers criteria with adverse outcomes in Japanese long-term care facilities. AB - AIM: To describe medication use including potentially inappropriate medication (PIM) and examine the association between adverse outcomes and patient factors including PIM use in Japanese elderly patients in long-term care facilities. METHODS: This was a retrospective cohort study of 470 patients in 53 Geriatric Health Service Facilities and 44 Sanatorium Type Medical Care Facilities for the Elderly Requiring Long Term Care. Standardized forms were used to collect information including oral and parenteral medication use on admission, and 1 month and 3 months after admission. PIMs were determined by the 2003 or 2012 Beers criteria. Adverse outcomes were any medical events leading to emergency department transfer, hospitalization to acute care hospitals or death. RESULTS: A total of 2,227 oral medications and 197 parenteral medications were prescribed for 470 patients on admission. PIM exposure based on the 2003 and 2012 Beers criteria was observed in 11.9% and 37.5%, respectively. Adverse outcomes within 3 months after admission were observed in 8.9% of the entire cohort, and were associated with age, sex, facility type and number of parenteral medications on admission. Adverse outcomes between one and three months after admission were associated with age, sex, number of parenteral medications at one month, and a change in the number of oral and parenteral medications within one month after admission. PIM exposure was not associated with adverse outcomes in any models. CONCLUSIONS: Use of PIM was prevalent in long-term care facilities. Our findings support the importance of comprehensive assessment of medication regimens including parenteral medication. Geriatr Gerontol Int 2017; 17: 591-597. PMID- 27228967 TI - Task interspersal for individuals with autism and other neurodevelopmental disorders. AB - This paper reviews recent studies on task interspersal (TI) for increasing skill acquisition in children who have been diagnosed with autism spectrum disorders and other neurodevelopmental disorders. We highlight some limitations of these studies and provide specific recommendations for future research on TI procedures. PMID- 27228969 TI - A case of rivaroxaban-induced subacute lupus erythematosus. PMID- 27228971 TI - The Prevalence of Amblyopia, Strabismus, and Ptosis in Schoolchildren of Dezful. AB - Purpose To determine the prevalence of amblyopia, strabismus, and ptosis among schoolchildren in Dezful in the west of Iran. Methods In this cross-sectional study, 1,375 schoolchildren of Dezful were selected through multistage cluster sampling. After obtaining written consents, participants had uncorrected and corrected visual acuity tests, cycloplegic refraction, and the cover test, and were examined for ptosis at the school site. Results Of the 1,151 study participants (83.7%), examinations were completed for 1,130 schoolchildren. Prevalence rates of amblyopia, strabismus, and ptosis were 2.7% (95% confidence interval [CI] 0.8-4.7), 1.9% (95% CI: 0.2-3.8), and 0.8%, respectively. Anisometropia was the most common cause of amblyopia; 45.2% of cases had anisometropic amblyopia. Among cases with strabismus, 63.6% were exotropic and 36.4% were esotropic. Conclusion The present study indicated that the prevalence of amblyopia and strabismus in Dezful schoolchildren falls in the average range. Since the Amblyopia Screening Program has been running for years, we expected lower rates compared to previous years, but this was not observed. Correcting refractive errors can significantly reduce amblyopic cases. PMID- 27228970 TI - The involvement of medical doctors in hospital governance and implications for quality management: a quick scan in 19 and an in depth study in 7 OECD countries. AB - BACKGROUND: Hospital governance is broadening its orientation from cost and production controls towards 'improving performance on clinical outcomes'. Given this new focus one might assume that doctors are drawn into hospital management across OECD countries. Hospital performance in terms of patient health, quality of care and efficiency outcomes is supposed to benefit from their involvement. However, international comparative evidence supporting this idea is limited. Just a few studies indicate that there may be a positive relationship between medical doctors being part of hospital boards, and overall hospital performance. More importantly, the assumed relationship between these so-called doctor managers and hospital performance has remained a 'black-box' thus far. However, there is an increasing literature on the implementation of quality management systems in hospitals and their relation with improved performance. It seems therefore fair to assume that the relation between the involvement of doctors in hospital management and improved hospital performance is partly mediated via quality management systems. The threefold aim of this paper is to 1) perform a quick scan of the current situation with regard to doctor managers in hospital management in 19 OECD countries, 2) explore the phenomenon of doctor managers in depth in 7 OECD countries, and 3) investigate whether doctor involvement in hospital management is associated with more advanced implementation of quality management systems. METHODS: This study draws both on a quick scan amongst country coordinators in OECD's Health Care Quality Indicator program, and on the DUQuE project which focused on the implementation of quality management systems in European hospitals. RESULTS: This paper reports two main findings. First, medical doctors fulfil a broad scope of managerial roles at departmental and hospital level but only partly accompanied by formal decision making responsibilities. Second, doctor managers having more formal decision making responsibilities in strategic hospital management areas is positively associated with the level of implementation of quality management systems. CONCLUSIONS: Our findings suggest that doctors are increasingly involved in hospital management in OECD countries, and that this may lead to better implemented quality management systems, when doctors take up managerial roles and are involved in strategic management decision making. PMID- 27228972 TI - Microincision, aspiration cutter-assisted multifocal iris biopsy for melanoma. AB - PURPOSE: To describe a minimally invasive method to create multifocal full thickness surgical iridectomy biopsies. METHODS: Seven patients suspected to have diffuse iris melanoma underwent multifocal surgical iridectomy biopsy through a single 1.0-mm clear corneal incision. A 25-G inked trocar was used to create one visible corneal portal, through which the anterior chamber was filled with sodium hyaluronate 1%. Then, a 25-G aspiration cutter probe was introduced through the corneal incision such that the aspiration portal was occluded by the iris biopsy sites. Then aspiration (600 mm Hg) cutting (300 cuts per minute) was used to create full- and partial-thickness surgical iridectomy biopsies at multiple locations. After each biopsy the probe was removed, and its contents aspirated into a separate 3-mL syringe (marked by clock hour location). The sodium hyaluronate 1% was removed and wound checked for leakage. RESULTS: Diagnostic specimens were obtained in all cases. Five were found to be diffuse iris melanomas and 2 were indeterminate iris melanocytic proliferations. No patients developed a secondary increase in intraocular pressure, hyphema, infection, cataract, or vision loss. No cases of intraocular tumor dissemination were observed. No patient complained of glare or monocular diplopia. Three of 7 corneal wounds were self-sealing. CONCLUSIONS: Multifocal surgical iridectomy biopsy can be minimally invasive and effective allowing for partial- and full thickness iris biopsy. Use of a 25-G aspiration cutting probe allowed for small incision surgery, rapid rehabilitation, and no significant complications. PMID- 27228968 TI - Connexinopathies: a structural and functional glimpse. AB - Mutations in human connexin (Cx) genes have been related to diseases, which we termed connexinopathies. Such hereditary disorders include nonsyndromic or syndromic deafness (Cx26, Cx30), Charcot Marie Tooth disease (Cx32), occulodentodigital dysplasia and cardiopathies (Cx43), and cataracts (Cx46, Cx50). Despite the clinical phenotypes of connexinopathies have been well documented, their pathogenic molecular determinants remain elusive. The purpose of this work is to identify common/uncommon patterns in channels function among Cx mutations linked to human diseases. To this end, we compiled and discussed the effect of mutations associated to Cx26, Cx32, Cx43, and Cx50 over gap junction channels and hemichannels, highlighting the function of the structural channel domains in which mutations are located and their possible role affecting oligomerization, gating and perm/selectivity processes. PMID- 27228973 TI - Comment to: Retinal and vitreous hemorrhage after traumatic impact of dexamethasone implant in a vitrectomized eye. PMID- 27228974 TI - Human Basic Fibroblast Growth Factor Inhibits Tau Phosphorylation via the PI3K/Akt-GSK3beta Signaling Pathway in a 6-Hydroxydopamine-Induced Model of Parkinson's Disease. AB - BACKGROUND: Basic fibroblast growth factor (bFGF) has been increasingly investigated due to its neuroprotection in neurodegenerative disorders. Because there are still no cures for any of these disorders, it is crucial to identify new therapeutic targets and screen potential drugs. The increased phosphorylation of tau at Ser396 leads to intracellular tau accumulation, which forms neurofibrillary tangles in Parkinson's disease (PD). In this study, neuroprotection by bFGF was observed, and the mechanisms related to its regulation of phosphorylated tau were investigated. METHODS: bFGF-loaded liposome carriers were intranasally administered to rats. The neuroprotective effects of bFGF were assessed in a PD model induced by 6-hydroxydopamine (6-OHDA) in vivo and in vitro. The phosphorylation of tau was measured, and the PI3K/Akt-GSK3beta signaling pathway was investigated. RESULTS: Our study demonstrated that liposomes markedly assisted in the delivery of bFGF to the striatum and substantia nigra of rats and enhanced the neuroprotective effects of bFGF on dopaminergic neurons. bFGF treatment significantly ameliorated the behavioral deficits induced by 6-OHDA, rescued the loss of tyrosine hydroxylase-positive neurons and increased the number of Nissl bodies. bFGF reduced the phosphorylation of tau and GSK3beta and increased the phosphorylation of PI3K/Akt. CONCLUSION: Liposomes markedly assisted in the delivery of bFGF to the brain and enhanced the neuroprotective effects of bFGF by inhibiting the phosphorylation of tau. bFGF down-regulated the phosphorylation of tau by increasing the phosphorylation of GSK3beta via the PI3K/Akt signaling pathway. These findings provide a new vision of bFGF as a potential therapy for PD. PMID- 27228975 TI - How storytelling can help scientists to write better abstracts. PMID- 27228976 TI - Obstructive sleep apnea combined dyslipidemia render additive effect on increasing atherosclerotic cardiovascular diseases prevalence. AB - BACKGROUND: Current study was designed to investigate the effects of obstructive sleep apnea (OSA) combined dyslipidemia on the prevalence of atherosclerotic cardiovascular diseases (ASCVD). METHODS: This was a cross-sectional study and subjects with documented dyslipidemia and without previous diagnosis of OSA were enrolled. Polysomnography was applied to evaluate apnea-hypopnea index (AHI). Based on AHI value, subjects were classified into four groups: without OSA, mild, moderate and severe OSA groups. Clinical characteristics and laboratory examination data were recorded. Relationship between AHI event and lipid profiles was analyzed, and logistic regression analysis was used to evaluate the effects of OSA combined dyslipidemia on ASCVD prevalence. RESULTS: Totally 248 subjects with dyslipidemia were enrolled. Compared to the other 3 groups, subjects with severe OSA were older, male predominant and had higher smoking rate. In addition, subjects with severe OSA had higher body mass index, waist-hip ratio, blood pressure, and higher rates of overweight and obesity. Serum levels of fasting plasma glucose, glycated hemoglobin, LDL-C and CRP were all significantly higher. ASCVD prevalence was considerably higher in subjects with severe OSA. AHI event in the severe OSA group was up to 35.4 +/- 5.1 events per hour which was significantly higher than the other groups (P < 0.05 for trend). Pearson correlation analysis showed that only LDL-C was positively correlated with AHI events (r = 0.685, P < 0.05). Logistic regression analysis revealed that in unadjusted model, compared to dyslipidemia plus no-OSA group (reference group), OSA enhanced ASCVD risk in subjects with dyslipidemia, regardless of OSA severity. After extensively adjusted for confounding variables, the odds of dyslipidemia plus mild-OSA was reduced to insignificance. While the effects of moderate- and severe-OSA on promoting ASCVD risk in subjects with dyslipidemia remained significant, with severe-OSA most prominent (odds ratio: 1.52, 95% confidence interval: 1.13-2.02). CONCLUSION: OSA combined dyslipidemia conferred additive adverse effects on cardiovascular system, with severe-OSA most prominent. PMID- 27228977 TI - Primary skeletal muscle myoblasts from chronic heart failure patients exhibit loss of anti-inflammatory and proliferative activity. AB - BACKGROUND: Peripheral skeletal muscle wasting is a common finding with adverse effects in chronic heart failure (HF). Whereas its clinical relevance is beyond doubt, the underlying pathophysiological mechanisms are not yet fully elucidated. We aimed to introduce and characterize the primary culture of skeletal muscle cells from individual HF patients as a supportive model to study this muscle loss. METHODS AND RESULTS: Primary myoblast and myotubes cultures were successfully propagated from the m. vastus lateralis of 6 HF patients with reduced ejection fraction (HFrEF; LVEF <45 %) and 6 age and gender-matched healthy donors. HFrEF cultures were not different from healthy donors in terms of morphology, such as myoblast size, shape and actin microfilament. Differentiation and fusion indexes were identical between groups. Myoblast proliferation in logarithmic growth phase, however, was attenuated in the HFrEF group (p = 0.032). In addition, HFrEF myoblasts are characterized by a reduced TNFR2 expression and IL-6 secretion (p = 0.017 and p = 0.016; respectively). CONCLUSION: Biopsy derived primary skeletal muscle myoblasts of HFrEF patients produce similar morphological and myogenic differentiation responses as myoblasts of healthy donors, though demonstrate loss of anti-inflammatory and proliferative activity. PMID- 27228978 TI - Ginsenoside Rg1 protects starving H9c2 cells by dissociation of Bcl-2-Beclin1 complex. AB - BACKGROUND: Autophagy can result in cellular adaptation, as well as cell survival or cell death. We investigated how ginsenoside Rg1(G-Rg1) regulates the relationship between autophagy and apoptosis induced by continuous starvation. METHODS: H9c2 cells under continuous starvation were treated with or without ginsenoside Rg1, and autophagy and apoptosis related proteins were assessed over a continuous time course by Western blot. Dynamic fluorescence intensity of green fluorescent protein (GFP)-LC3 was used to assess autophagosome formation by live cell imaging. Cyan fluorescent protein (CFP) -Beclin1(BECN1) and yellow fluorescent protein (YFP) -Bcl-2 were co-transfected into cells to observe ginsenoside Rg1 regulation of BECN1/Bcl-2 interaction using Fluorescence Resonance Energy Transfer (FRET). Immunoprecipitation was also used to assess BECN1/Bcl-2 interaction over a continuous time course. RESULTS: In H9c2 cells, starvation induced both apoptosis and autophagy. Cell apoptosis was significantly attenuated in ginsenoside Rg1-treated conditions, while autophagy was promoted. Ginsenoside Rg1 weakened the interaction between Beclin1 and Bcl-2, inhibiting apoptosis while promoting autophagy. Our results suggest that autophagy is beneficial to starved cardiac cells over a period of time. Furthermore, we describe the effect of ginsenoside Rg1 on the relationship between autophagy and apoptosis during starvation. CONCLUSIONS: Our findings provide valuable evidence for employing ginsenoside Rg1 as a specific promoter of autophagy and inhibitor of apoptosis. PMID- 27228980 TI - Building a recruitment database for asthma trials: a conceptual framework for the creation of the UK Database of Asthma Research Volunteers. AB - BACKGROUND: Randomised clinical trials are the 'gold standard' for evaluating the effectiveness of healthcare interventions. However, successful recruitment of participants remains a key challenge for many trialists. In this paper, we present a conceptual framework for creating a digital, population-based database for the recruitment of asthma patients into future asthma trials in the UK. Having set up the database, the goal is to then make it available to support investigators planning asthma clinical trials. METHODS: The UK Database of Asthma Research Volunteers will comprise a web-based front-end that interactively allows participant registration, and a back-end that houses the database containing participants' key relevant data. The database will be hosted and maintained at a secure server at the Asthma UK Centre for Applied Research based at The University of Edinburgh. Using a range of invitation strategies, key demographic and clinical data will be collected from those pre-consenting to consider participation in clinical trials. These data will, with consent, in due course, be linkable to other healthcare, social, economic, and genetic datasets. To use the database, asthma investigators will send their eligibility criteria for participant recruitment; eligible participants will then be informed about the new trial and asked if they wish to participate. A steering committee will oversee the running of the database, including approval of usage access. Novel communication strategies will be utilised to engage participants who are recruited into the database in order to avoid attrition as a result of waiting time to participation in a suitable trial, and to minimise the risk of their being approached when already enrolled in a trial. RESULTS: The value of this database will be whether it proves useful and usable to researchers in facilitating recruitment into clinical trials on asthma and whether patient privacy and data security are protected in meeting this aim. CONCLUSIONS: Successful recruitment is fundamental to the success of a clinical trial. The UK Database of Asthma Research Volunteers, the first of its kind in the context of asthma, presents a novel approach to overcoming recruitment barriers and will facilitate the catalysing of important clinical trials on asthma in the UK. PMID- 27228979 TI - Filling the treatment gap: developing a task sharing counselling intervention for perinatal depression in Khayelitsha, South Africa. AB - BACKGROUND: Perinatal depression is a major public health issue especially in low income settings in South Africa, where there is a shortage of mental health professionals. New psychological interventions delivered by non-specialists are needed to fill the treatment gap. This paper describes the process of developing a manual based task sharing counselling intervention for perinatal depression in Khayelitsha, Cape Town. METHODS: Qualitative semi-structured interviews were conducted with 26 participants, including service providers and service users at a clinic in Khayelitsha in order to explore the feasibility, acceptability and content of a task sharing counselling intervention. The interviews were recorded, translated and transcribed. Themes were identified using the framework analysis approach and were coded and analysed using NVivo v10. After the semi-structured interviews, a workshop was conducted with mental health experts on evidence-based psychological interventions for depression, together with a document review of counselling manuals for community health workers in South Africa. RESULTS: The findings indicate that a task sharing counselling intervention was acceptable and feasible for depressed women in Khayelitsha, under the following conditions: (1) respondents preferred a female counsellor and felt that clinic based individual sessions should be provided at least once a month by an experienced Xhosa speaking counsellor from the community; and (2) the content of a counselling intervention should include psycho-education on cognitive and behavioural effects of depression, how to cope with interpersonal problems, and financial stressors. Based on these conditions, the review of manuals and expert consultation, key components of the counselling intervention were identified as: psycho-education, problem solving, healthy thinking and behaviour activation. These were included in the final counselling manual. CONCLUSION: The development of task sharing counselling interventions for perinatal depression should be informed by the views and needs of local service users and service providers. The study illustrates the manner in which these views can be incorporated for the development of evidence-based psychological interventions, within a task sharing framework in low and middle-income countries. PMID- 27228981 TI - Effects of the prospective payment system on anemia management in maintenance dialysis patients: implications for cost and site of care. AB - BACKGROUND: The 2011 expanded Prospective Payment System (PPS) and contemporaneous Food and Drug Administration label revision for erythropoiesis stimulating agents (ESAs) were associated with changes in ESA use and mean hemoglobin levels among patients receiving maintenance dialysis. We aimed to investigate whether these changes coincided with increased red blood cell transfusions or changes to Medicare-incurred costs or sites of anemia management care in the period immediately before and after the introduction of the PPS, 2009 2011. METHODS: From US Medicare end-stage renal disease (ESRD) data (Parts A and B claims), maintenance hemodialysis patients from facilities that initially enrolled 100 % into the ESRD PPS were identified. Dialysis and anemia-related costs per-patient-per-month (PPPM) were calculated at the facility level, and transfusion rates were calculated overall and by site of care (outpatient, inpatient, emergency department, observation stay). RESULTS: More than 4100 facilities were included. Transfusions in both the inpatient and outpatient environments increased. In the inpatient environment, PPPM use increased by 11-17 % per facility in each quarter of 2011 compared with 2009; in the outpatient environment, PPPM use increased overall by 5.0 %. Site of care for transfusions appeared to have shifted. Transfusions occurring in emergency departments or during observation stays increased 13.9 % and 26.4 %, respectively, over 2 years. CONCLUSIONS: Inpatient- and emergency-department-administered transfusions increased, providing some evidence for a partial shift in the cost and site of care for anemia management from dialysis facilities to hospitals. Further exploration into the economic implications of this increase is necessary. PMID- 27228982 TI - Genetic polymorphisms analysis of CYP2D6 in the Uygur population. AB - BACKGROUND: This study aimed to investigate genetic polymorphisms of CYP2D6 among healthy Uygur individuals. Genetic polymorphisms of CYP2D6 could greatly affect CYP2D6 activity and lead to differences among individuals in drug efficacy or side effects. To investigate genetic polymorphisms of CYP2D6 in the Uygur population, we directly sequenced the whole gene in 96 unrelated, healthy Uygur volunteers from the Xinjiang Uygur Autonomous Region and screened for genetic variants in the promoter, intron, exons, and 3'UTR. RESULTS: We detected 62 genetic polymorphisms of CYP2D6, 16 of which were novel SNP with three novel non synonymous mutations detected for the first time. The allelic frequencies of CYP2D6*1, *10, *39, and *48 were 0.542, 0.156, 0.068, 0.229, and 0.073, respectively. The frequency of CYP2D6*1/*10 which decreased CYP2D6 enzyme activity was 31.3 %. CONCLUSIONS: Our results provided basic information about CYP2D6 polymorphisms, suggested that the enzymatic activities of CYP2D6 might be different within the Uygur ethnic group, and provide a basis for safer drug administration and better therapeutic treatment of Uygur individuals. PMID- 27228983 TI - The Relationship Between Burnout and Occupational Stress in Genetic Counselors. AB - Burnout represents a critical disruption in an individual's relationship with work, resulting in a state of exhaustion in which one's occupational value and capacity to perform are questioned. Burnout can negatively affect an individual's personal life, as well as employers in terms of decreased work quality, patient/client satisfaction, and employee retention. Occupational stress is a known contributor to burnout and occurs as a result of employment requirements and factors intrinsic to the work environment. Empirical research examining genetic counselor-specific burnout is limited; however, existing data suggests that genetic counselors are at increased risk for burnout. To investigate the relationship between occupational stress and burnout in genetic counselors, we administered an online survey to members of three genetic counselor professional organizations. Validated measures included the Maslach Burnout Inventory-General Survey (an instrument measuring burnout on three subscales: exhaustion, cynicism, and professional efficacy) and the Occupational Stress Inventory-Revised (an instrument measuring occupational stress on 14 subscales). Of the 353 respondents, more than 40 % had either considered leaving or left their job role due to burnout. Multiple regression analysis yielded significant predictors for burnout risk. The identified sets of predictors account for approximately 59 % of the variance in exhaustion, 58 % of the variance in cynicism, and 43 % of the variance in professional efficacy. Our data confirm that a significant number of genetic counselors experience burnout and that burnout is correlated with specific aspects of occupational stress. Based on these findings, practice and research recommendations are presented. PMID- 27228984 TI - The Impact of Angelina Jolie (AJ)'s Story on Genetic Referral and Testing at an Academic Cancer Centre in Canada. AB - In May 2013, Angelina Jolie revealed to the media that she had undergone preventive double mastectomy after testing positive for a BRCA1 gene mutation. Media coverage has been extensive, but it is not clear how such a personal story affected the public and cancer genetics clinics. We conducted a retrospective review using data from the clinical database of the Familial Cancer Program at our centre. The impact of Ms. Jolie's story on genetic counseling referrals and the appropriateness of such referrals were assessed and reported. The number of women referred for genetic counseling increased by 90 % after 6 months and remained high one year after AJ's story with an increase of 88 % from baseline. The number of women who qualified for genetic testing increased by 105 % after 6 months; this increase persisted but was somewhat lower after one year with an increase of 68 % from baseline. Furthermore the number of BRCA1/2 carriers identified increased by 110 % after 6 months and by 42 % after one year.The effect of Mrs. Jolie's story persisted one year after its release; however in the latter half of the year, the hereditary cancer risk of referred women was significantly lower than initially observed. The next challenge for our health care system will not only be to meet the increased demand for cancer genetic services in our region, but also to ensure that referrals and hence use of genetic counseling resources are appropriate. PMID- 27228985 TI - Presentations due to acute toxicity of psychoactive substances in an urban emergency department in Switzerland: a case series. AB - BACKGROUND: Although the recreational use of psychoactive substances is common there is only limited systematic collection of data on acute drug toxicity or hospital presentations, in particular regarding novel psychoactive substances (NPS) that have emerged on the illicit market in the last years. METHODS: We included all cases presenting at the emergency department (ED) of the University Hospital of Basel, Switzerland, between October 2014 and September 2015 with acute toxicity due to self-reported recreational drug use or with symptoms/signs consistent with acute toxicity. Intoxications were confirmed using immunoassays and LC-MS/MS, detecting also novel psychoactive substances. RESULTS: Among the 50'624 attendances at the ED, 210 were directly related to acute toxicity of recreational drugs. The mean patient age was 33 years and 73 % were male. Analytical drug confirmation was available in 136 cases. Most presentations were reportedly related to cocaine (33 %), cannabis (32 %), and heroin (14 %). The most commonly analytically detected substances were cannabis (33 %), cocaine (27 %), and opioids excluding methadone (19 %). There were only two NPS cases; a severe intoxication with paramethoxymethamphetamine (PMMA) in combination with other substances and an intoxication of minor severity with 2,5-dimethoxy-4 propylphenethylamine (2C-P). The most frequent symptoms were tachycardia (28 %), anxiety (23 %), nausea or vomiting (18 %), and agitation (17 %). Severe complications included two fatalities, two acute myocardial infarctions, seizures (13 cases), and psychosis (six cases). Most patients (76 %) were discharged home, 10 % were admitted to intensive care, and 2 % were referred to psychiatric care. CONCLUSION: Most medical problems related to illicit drugs concerned cocaine and cannabis and mainly included sympathomimetic toxicity and/or psychiatric disorders confirming data from the prior year. Importantly, despite the dramatic increase in various NPS being detected in the last years, these substances were infrequently associated with ED presentations compared with classic recreational drugs. PMID- 27228987 TI - Primary Angiosarcoma of the Pancreas. PMID- 27228986 TI - Use of antenatal corticosteroids at health facilities and communities in low-and middle income countries. AB - BACKGROUND: Antenatal corticosteroids (ACS) for women at high risk of preterm birth is an effective intervention to reduce neonatal mortality among preterm babies delivered in hospital settings, but has not been widely used in low-middle resource settings. We sought to assess the rates of ACS use at all levels of health care in low and middle income countries (LMIC). METHODS: We assessed rates of ACS in 7 sites in 6 LMIC participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development's Global Network for Women and Children's Health Research Antenatal Corticosteroids Trial (ACT), a cluster randomized trial to assess the feasibility, effectiveness, and safety of a multifaceted intervention designed to increase the use of ACS. We conducted this analysis using data from the control clusters, which did not receive any components of the intervention and intended to follow usual care. We included women who delivered an infant with a birth weight <5th percentile, a proxy for preterm birth, and were enrolled in the Maternal Newborn Health (MNH) Registry between October 2011 and March 2014 in all clusters. A survey of the site investigators regarding existing policies on ACS in health facilities and for health workers in the community was part of pre-trial activities. RESULTS: Overall, of 51,523 women delivered in control clusters across all sites, the percentage of <5th percentile babies ranged from 3.5 % in Kenya to 10.7 % in Pakistan. There was variation among the sites in the use of ACS at all hospitals and among those hospitals having cesarean section and neonatal care capabilities (bag and mask and oxygen or mechanical ventilation). Rates of ACS use for <5th percentile babies in all hospitals ranged from 3.8 % in the Kenya sites to 44.5 % in the Argentina site, and in hospitals with cesarean section and neonatal care capabilities from 0 % in Zambia to 43.5 % in Argentina. ACS were rarely used in clinic or home deliveries at any site. Guidelines for ACS use at all levels of the health system were available for most of the sites. CONCLUSION: Our study reports an overall low utilization of ACS among mothers of <5th percentile infants in hospital and clinic deliveries in LMIC. TRIAL REGISTRATION: clinicaltrials.gov ( NCT01084096 ). PMID- 27228988 TI - Lentiviral Delivery of Proteins for Genome Engineering. AB - Viruses have evolved to traverse cellular barriers and travel to the nucleus by mechanisms that involve active transport through the cytoplasm and viral quirks to resist cellular restriction factors and innate immune responses. Virus-derived vector systems exploit the capacity of viruses to ferry genetic information into cells, and now - more than three decades after the discovery of HIV - lentiviral vectors based on HIV-1 have become instrumental in biomedical research and gene therapies that require genomic insertion of transgenes. By now, the efficacy of lentiviral gene delivery to stem cells, cells of the immune system including T cells, hepatic cells, and many other therapeutically relevant cell types is well established. Along with nucleic acids, HIV-1 virions carry the enzymatic tools that are essential for early steps of infection. Such capacity to package enzymes, even proteins of nonviral origin, has unveiled new ways of exploiting cellular intrusion of HIV-1. Based on early findings demonstrating the packaging of heterologous proteins into virus particles as part of the Gag and GagPol polypeptides, we have established lentiviral protein transduction for delivery of DNA transposases and designer nucleases. This strategy for delivering genome engineering proteins facilitates high enzymatic activity within a short time frame and may potentially improve the safety of genome editing. Exploiting the full potential of lentiviral vectors, incorporation of foreign protein can be combined with the delivery of DNA transposons or a donor sequence for homology directed repair in so-called 'all-in-one' lentiviral vectors. Here, we briefly describe intracellular restrictions that may affect lentiviral gene and protein delivery and review the current status of lentiviral particles as carriers of tool kits for genome engineering. PMID- 27228989 TI - Research protocol for an epidemiological study on estimating disease burden of pediatric HIV in Belgaum district, India. AB - BACKGROUND: Pediatric HIV is poised to become a major public health problem in India with the rising trend of HIV infection in pregnant women (Department of AIDS Control, Ministry of Health and Family Welfare, http://www.naco.gov.in). There is lack of information on the epidemiology of pediatric HIV infection in India. Existing surveillance systems tend to underestimate the Pediatric burden. The overall aim of the present study is to estimate the disease burden of pediatric HIV among children in Belgaum district in the state of Karnataka in Southern India. An innovative multipronged epidemiological approach to comb the district is proposed. METHODS: The primary objectives of the study would be attained under three strategies. A prospective cohort design for objective (i) to determine the incidence rate of HIV by early case detection in infants and toddlers (0-18 months) born to HIV infected pregnant women; and cross sectional design for objectives (ii) to determine the prevalence of HIV infection in children (0-14 years) of HIV infected parents and (iii) to determine the prevalence of HIV in sick children (0-14 years) presenting with suspected signs and symptoms using age specific criteria for screening. Burden of pediatric HIV will be calculated as a product of cases detected in each strategy multiplied by a net inflation factor for each strategy. Study participants (i) (ii) (iii): HIV infected pregnant women and their live born children (ii) Any HIV-infected man/woman, of age 18-49 years, having a biological child of age 0-14 years (iii) Sick children of age 0-14 years presenting with suspected signs and symptoms and satisfying age-specific criteria for screening. Setting and conduct: Belgaum district which is a Category 'A' district (with more than 1 % antenatal prevalence in the district over the last 3 years before the study). Age appropriate testing is used to detect HIV infection. DISCUSSION: There is a need to strengthen existing pediatric HIV estimation methods in India and other developing countries. We hope that the novel methodology emanating from this study would be applicable for estimating the burden of HIV in other settings and it would be adaptable for estimating the burden of other infectious/chronic diseases. Findings from this study will give future direction to the national program for prevention and control of HIV in India and other developing countries. PMID- 27228990 TI - The McGill Brisbane Symptom Score in relation to survival in pancreatic adenocarcinoma: a validation study. AB - PURPOSE: The McGill Brisbane Symptom Score (MBSS) is a clinical score for pancreatic cancer patients upon initial presentation that takes into account four variables (weight loss, abdominal pain, jaundice, and history of smoking) to stratify them into two MBSS intensity categories. Several studies have suggested that these categories are strongly associated with eventual survival in patients with resectable (rPCa) and unresectable (uPCa) pancreatic cancer. This study aimed to validate the MBSS in a cohort of patients with pancreatic cancer from a single institution. METHODS: Survival time by resection status and MBSS intensity category were analyzed among 633 patients from our institution between 2001 and 2010. Hazard ratios for death using Cox proportional hazards models, with age as the timescale, adjustment for sex and year of diagnosis, and stratified by adjuvant chemotherapy status were estimated. RESULTS: Median survival time was the longest in patients with low-intensity MBSS and rPCa (817 days), whereas the shortest survival time was found among patients with uPCa regardless of MBSS status (144-147 days). After consideration of age and chemotherapy status, high intensity MBSS was associated with poorer survival for both rPCa (HR 1.64; 95 % CI 1.07-2.52) and uPCa (HR 1.35; 95 % CI 1.06-1.72). CONCLUSIONS: Preoperative MBSS intensity is a useful prognostic indicator of survival in resectable as well as unresectable pancreatic cancer. PMID- 27228991 TI - Diagnostic colonoscopy following a positive fecal occult blood test in community health center patients. AB - PURPOSE: Fecal occult blood testing (FOBT) is a pragmatic screening option for many community health centers (CHCs), but FOBT screening programs will not reduce mortality if patients with positive results do not undergo diagnostic colonoscopy (DC). This study was conducted to investigate DC completion among CHC patients. METHODS: This retrospective cohort study used data from three CHCs in the Midwest and Southwest. The primary study outcome was DC completion within 6 months of positive FOBT among adults age 50-75. Patient data was collected using automated electronic queries. Manual chart reviews were conducted if queries produced no evidence of DC. Poisson regression models described adjusted relative risks (RRs) of DC completion. RESULTS: The study included 308 patients; 63.3 % were female, 48.7 % were Spanish speakers and 35.7 % were uninsured. Based on combined query and chart review findings, 51.5 % completed DC. Spanish speakers were more likely than English speakers to complete DC [RR 1.19; 95 % confidence interval (CI) 1.04 1.36; P = 0.009], and DC completion was lower among patients with 0 visits than those with 1-2 visits (RR 2.81; 95% CI 1.83-4.33; P < 0.001) or >=3 visits (RR 3.06; 95% CI 1.57-5.95; P = 0.001). CONCLUSIONS: DC completion was low overall, which raises concerns about whether FOBT can reduce CRC mortality in practice. Further research is needed to understand whether CHC navigator programs can achieve very high DC rates. If organizations use FOBT as their primary CRC screening approach and a substantial number of patients receive positive results, both screening rates and DC rates should be measured. PMID- 27228992 TI - Obesity, Renin-Angiotensin System Blockade and Risk of Adverse Renal Outcomes: A Population-Based Cohort Study. AB - BACKGROUND: Obesity substantially increases the risk of the development of chronic kidney disease. Adipose tissue expresses all of the components of the renin-angiotensin system (RAS), contributing to the high prevalence of hypertension in obese patients and driving renal hyperfiltration and subsequent glomerular injury. METHODS: We performed a retrospective cohort study using a United Kingdom primary care database, evaluating the effect of time-updated exposure to RAS blockade versus all other antihypertensive medications in obese, hypertensive, non-diabetic patients. We used Cox proportional hazards modeling with and without marginal structural modeling to assess the hazards of developing a primary outcome of 50% reduction in estimated glomerular filtration rate (eGFR) (across 2 consecutive values), end stage renal disease or death. RESULTS: A total of 219,701 patients met inclusion criteria, with a median 7.2 years of follow-up. Median baseline eGFR was 72.6 ml/min/1.73 m2. Compared to other antihypertensive medications, patients treated with RAS blockade had a modestly elevated hazard of adverse renal outcomes using traditional Cox regression (hazard ratio (HR) 1.04, 95% CI 1.01-1.07) and no significantly increased hazard by marginal structural modeling (HR 1.02, 95% CI 0.97-1.08). Patients treated with RAS blockade had a significantly reduced hazard of incident diabetes, but no significant difference in mortality. CONCLUSION: This study, conducted in a large real-world cohort, provides evidence that RAS blockade may not provide benefit with regard to longitudinal renal outcomes in obese, hypertensive patients. Further research is needed to elucidate the hemodynamic and renoprotective role of antihypertensive medications in obese patients. PMID- 27228993 TI - Root transcriptomes of two acidic soil adapted Indica rice genotypes suggest diverse and complex mechanism of low phosphorus tolerance. AB - Low phosphorus (P) tolerance in rice is a biologically and agronomically important character. Low P tolerant Indica-type rice genotypes, Sahbhagi Dhan (SD) and Chakhao Poreiton (CP), are adapted to acidic soils and show variable response to low P levels. Using RNAseq approach, transcriptome data was generated from roots of SD and CP after 15 days of low P treatment to understand differences and similarities at molecular level. In response to low P, number of genes up-regulated (1318) was more when compared with down-regulated genes (761). Eight hundred twenty-one genes found to be significantly regulated between SD and CP in response to low P. De novo assembly using plant database led to further identification of 1535 novel transcripts. Functional annotation of significantly expressed genes suggests two distinct methods of low P tolerance. While root system architecture in SD works through serine-threonine kinase PSTOL1, suberin mediated cell wall modification seems to be key in CP. The transcription data indicated that CP relies more on releasing its internally bound Pi and coping with low P levels by transcriptional and translational modifications and using dehydration response-based signals. Role of P transporters seems to be vital in response to low P in CP while sugar- and auxin-mediated pathway seems to be preferred in SD. At least six small RNA clusters overlap with transcripts highly expressed under low P, suggesting role of RNA super clusters in nutrient response in plants. These results help us to understand and thereby devise better strategy to enhance low P tolerance in Indica-type rice. PMID- 27228994 TI - Defective small intestinal anion secretion, dipeptide absorption, and intestinal failure in suckling NBCe1-deficient mice. AB - The electrogenic Na(+)HCO3 (-) cotransporter NBCe1 (Slc4a4) is strongly expressed in the basolateral enterocyte membrane in a villous/surface predominant fashion. In order to better understand its physiological function in the intestine, isolated mucosae in miniaturized Ussing chambers and microdissected intestinal villi or crypts loaded with the fluorescent pH-indicator BCECF were studied from the duodenum, jejunum, and colon of 14- to 17-days-old slc4a4-deficient (KO) and WT mice. NBCe1 was active in the basal state in all intestinal segments under study, most likely to compensate for acid loads imposed upon the enterocytes. Upregulation of other basolateral base uptake mechanism occurs, but in a segment specific fashion. Loss of NBCe1 resulted in severely impaired Cl(-) and fluid secretory response, but not HCO3 (-) secretory response to agonist stimulation. In addition, NBCe1 was found to be active during transport processes that load the surface enterocytes with acid, such as Slc26a3 (DRA)-mediated luminal Cl( )/HCO3 (-) exchange or PEPT1-mediated H(+)/dipeptide uptake. Possibly because of the high energy demand for hyperventilation in conjunction with the fluid secretory and nutrient absorptive defects and the relative scarcity of compensatory mechanisms, NBCe1-deficient mice developed progressive jejunal failure, worsening of metabolic acidosis, and death in the third week of life. Our data suggest that the electrogenic influx of base via NBCe1 maintains enterocyte anion homeostasis and pHi control. Its loss impairs small intestinal Cl(-) and fluid secretion as well as the neutralization of acid loads imposed on the enterocytes during nutrient and electrolyte absorption. PMID- 27228996 TI - Putative role of the H(+)/sucrose symporter SLC45A3 as an osmolyte transporter in the kidney. AB - The solute carrier family 45 a3 member (SLC45A3), known also as prostein, has been implicated with prostate cancer and the regulation of lipid metabolism in oligodendrocytes. Recently, we expressed SLC45A3 in yeast cells and characterised it as a proton-coupled sucrose symporter. However, the physiological functions of SLC45A3 were still unknown. Here, we report that SLC45A3 occurs in the kidney and is highly expressed in the medullary collecting duct (IMCD), a part of the kidney responsible for final urine concentration and faced to hyperosmotic environment. Moreover, messenger RNA (mRNA) expression of endogenous SLC45A3 in rat IMCD cells as well as in NRK52E cells increased up to four-fold under hyperosmotic conditions at 600 mOsmol/kg. Using NRK52E cells as an experimental model, we investigated the proton-coupled sugar transport and found that the uptake of sucrose or glucose was enhanced by hyperosmolarity. Down-regulation of expression by small interfering RNA (siRNA) decreased the osmotically inducible part of sucrose uptake and confirmed the involvement of SLC45A3 in this process. Furthermore, we observed an up to four-fold elevation of sucrose uptake triggered by hyperosmolarity across the apical membrane of NRK52E cells, while uptake across the basolateral membrane was not affected. Due to this finding, we conclude that SLC45A3 may occur at the luminal side of kidney epithelial cells and thus may take up solutes from the tubular fluid. Altogether, we show that SLC45A3 is a novel sugar transporter in kidney and hypothesise that the disaccharide sucrose, and probably the monosaccharides glucose and fructose, may serve as compatible osmolytes in urine. PMID- 27228995 TI - Bidirectional signalling between EphA2 and ephrinA1 increases tubular cell attachment, laminin secretion and modulates erythropoietin expression after renal hypoxic injury. AB - Acute kidney injury (AKI) is common in hospitalized patients and has a poor prognosis, the severity of AKI being linked to progression to chronic kidney disease. This stresses the need to search for protective mechanisms during the acute phase. We investigated kidney repair after hypoxic injury using a rat model of renal artery branch ligation, which led to an oxygen gradient vertical to the corticomedullary axis. Three distinct zones were observed: tubular necrosis, infarction border zone and preserved normal tissue. EphA2 is a receptor tyrosine kinase with pivotal roles in cell architecture, migration and survival, upon juxtacrine contact with its membrane-bound ligand EphrinA1. Following hypoxia, EphA2 was up-regulated in cortical and medullary tubular cells, while EphrinA1 was up-regulated in interstitial cells adjacent to peritubular capillaries. Moreover, erythropoietin (EPO) messenger RNA (mRNA) was strongly expressed in the border zone of infarcted kidney within the first 6 h. To gain more insight into the biological impact of EphA2 and EphrinA1 up-regulation, we activated the signalling pathways in vitro using recombinant EphrinA1/Fc or EphA2/Fc proteins. Stimulation of EphA2 forward signalling in the proximal tubular cell line HK2 increased cell attachment and laminin secretion at the baso-lateral side. Conversely, activation of reverse signalling through EphrinA1 expressed by Hep3B cells promoted EPO production at both the transcriptional and protein level. Strikingly, in co-culture experiments, juxtacrine contact between EphA2 expressing MDCK and EphrinA1 expressing Hep3B was sufficient to induce a significant up-regulation of EPO mRNA production in the latter cells, even in the absence of hypoxic conditions. The synergistic effects of EphA2 and hypoxia led to a 15-20-fold increase of EPO expression. Collectively, our results suggest an important role of EphA2/EphrinA1 signalling in kidney repair after hypoxic injury through stimulation of (i) tubular cell attachment, (ii) secretion of basal membrane proteins and (iii) EPO production. These findings could thus pave the way to new therapeutic approaches. PMID- 27228997 TI - Acute Angioedema Triggered by Daptomycin. AB - INTRODUCTION: Daptomycin is a cyclic lipopeptide antibiotic, frequently administered for Staphylococcus aureus bloodstream infections. Numerous studies have shown that daptomycin is relatively safe and well tolerated. Serious adverse events possibly related to this antimicrobial compound are rare. We report a case of acute angioedema triggered by daptomycin. CASE REPORT: A 60-year-old woman with S. aureus bacteremia without identified source was treated intravenously with high-dose beta-lactams at our institution. Because S. aureus bacteremia persisted on day 6, and in parallel, acute kidney injury developed, antimicrobial treatment was switched to a combination therapy with daptomycin and ceftriaxone. Shortly after completion of the first daptomycin administration, the patient developed lip and tongue swelling and dyspnea. Acute angioedema was clinically evident. Antibiotic therapy was switched to vancomycin, and the further clinical course was favorable. An intradermal test showed a significant wheal diameter for daptomycin, but negative results for ceftriaxone. CONCLUSION: The association with daptomycin in this case is either probable or certain. Clinicians should be aware that daptomycin can cause immediate-type hypersensitivity reactions, including acute angioedema, even upon first administration. PMID- 27228998 TI - Boceprevir Plus Peginterferon Alfa-2a/Ribavirin in Treatment-Naive Hepatitis C Virus Genotype 1 Patients: International Phase IIIb/IV TriCo Trial. AB - INTRODUCTION: Boceprevir was not previously studied with peginterferon alfa 2a/ribavirin in phase III trials in treatment-naive chronic hepatitis C patients. The international phase IIIb/IV TriCo study was, therefore, designed to evaluate boceprevir in combination with peginterferon alfa-2a/ribavirin in treatment-naive genotype 1 patients. METHODS: A total of 165 treatment-naive genotype 1 patients were assigned to boceprevir plus peginterferon alfa-2a/ribavirin therapy according to the label. All patients received a 4-week lead-in with peginterferon alfa-2a/ribavirin, after which boceprevir (2400 mg/day) was introduced. The total duration of treatment ranged from 28 to 48 weeks depending on the virological response at Weeks 4, 8, and 24, and on fibrosis status. The primary efficacy outcome was sustained virological response (SVR) [undetectable hepatitis C virus (HCV) ribonucleic acid (RNA) 12 weeks after actual end of treatment, SVR12]. RESULTS: The overall SVR12 rate was 81% (133/165, 95% confidence interval 74 86%). After 8 weeks of treatment, 61% of patients had undetectable HCV RNA, and 78 patients (47%) had an early response (undetectable HCV RNA at Weeks 8 and 24) and were eligible to stop all therapy at Week 28. Among early responders the SVR12 rate was 95% (74/78), and among patients with cirrhosis assigned to 48 weeks' treatment, the SVR12 rate was 67% (14/21). The overall relapse rate was 7% (10/143), and was 4% (3/77) among early responders. The most common adverse events were anemia (41%), neutropenia (32%), and dysgeusia (31%). CONCLUSION: High SVR12 rates can be achieved with boceprevir plus peginterferon alfa 2a/ribavirin in treatment-naive HCV genotype 1 patients, including patients with well-compensated cirrhosis. Treatment is well tolerated when label restrictions are taken into account. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT01591460. FUNDING: F. Hoffmann-La Roche Ltd. PMID- 27228999 TI - The kidney stone and increased water intake trial in steel workers: results from a pilot study. AB - Preventing dehydration in subjects at risk may provide a means of primary prevention of kidney stones. The purpose of this pilot study was to assess the hydration status of an at-risk group of steel plant workers based on end-of-shift ('post-shift') spot urine osmolality and 24-h urinary stone risk parameters. 100 volunteers were recruited from Gerdau Midlothian steel mill in Texas on 11/14/14 and 12/5/14. Clinical data were recorded and post-shift spot urine sample was used to measure urine osmolality. Participants were invited to submit a 24-h urine sample within 4 weeks of enrollment. The mean age was 41 years and 95 % were men. The majority of subjects were white (75 %), followed by 10 % Hispanic and 9 % black. The mean body mass index was 30.1 kg/m2 and overall 16 % had a past history of stone disease. Mean post-shift urine spot osmolality was 704.5 mOsm (169-1165 mOsm) and was >800 and >700 mOsm in 39 and 57 %, respectively. Among 59 24-h urines samples, the mean volume was 1.89 +/- 0.92 l/day, with 56 % < 2 L and 17 % < 1 L. Elevated levels of urinary analytes were found in 29 % of subjects for calcium (>250 mg/TV), 39 % for uric acid (>700 mg/TV), 25 % for oxalate (>45 mg/TV) and 50 % for sodium (>200 meq/TV). The prevalence of stone disease in this population of steel workers was higher than the published prevalence of stone disease in the general population. A significant number of workers had concentrated post-shift and 24-h urines and elevated levels of urinary analytes. PMID- 27229001 TI - Getting to the 'Why' of Behavior Change. PMID- 27229000 TI - Trajectories of Diabetes Medication Adherence and Hospitalization Risk: A Retrospective Cohort Study in a Large State Medicaid Program. AB - BACKGROUND: Numerous interventions are available to boost medication adherence, but the targeting of these interventions often relies on crude measures of poor adherence. Group-based trajectory models identify individuals with similar longitudinal prescription filling patterns. Identifying distinct adherence trajectories may be more useful for targeting interventions, although the association between adherence trajectories and clinical outcomes is unknown. OBJECTIVE: To examine the association between adherence trajectories for oral hypoglycemics and subsequent hospitalizations among diabetes patients. DESIGN: Retrospective cohort study. PATIENTS: A total of 16,256 Pennsylvania Medicaid enrollees, non-dually eligible for Medicare, initiating oral hypoglycemics between 2007 and 2009. MAIN MEASURES: We used group-based trajectory models to identify trajectories of oral hypoglycemics in the 12 months post-treatment initiation, using monthly proportion of days covered (PDC) as the adherence measure. Multivariable Cox proportional hazard models were used to examine the association between trajectories and time to first diabetes-related hospitalization/emergency department (ED) visits in the following year. We used the C-index to compare prediction performance between adherence trajectories and dichotomous cutpoints (annual PDC <80 vs. >=80 %). RESULTS: The mean annual PDC was 0.58 (SD 0.32). Seven trajectories were identified: perfect adherers (9 % of the cohort), nearly perfect adherers (31.4 %), moderate adherers (21.0 %), low adherers (11.0 %), late discontinuers (6.8 %), early discontinuers (9.7 %), and non-adherers with only one fill (11.1 %). Compared to perfect adherers, trajectories of moderate adherers (HR = 1.48, 95 % CI 1.25, 1.75), low adherers (HR = 1.51, 95 % CI 1.25, 1.83), and non-adherers with only one fill (HR = 1.35, 95 % CI 1.09, 1.67) had greater risk of diabetes-related hospitalizations/ED visits. Predictive accuracy was improved using trajectories compared to dichotomized cutpoints (C-index = 0.714 vs. 0.652). CONCLUSIONS: Oral hypoglycemic treatment trajectories were highly variable in this large Medicaid cohort. Low and moderate adherers and those filling only one prescription had a modestly higher risk of hospitalizations/ED visits compared to perfect adherers. Trajectory models may be valuable in identifying specific non-adherence patterns for targeting interventions. PMID- 27229002 TI - Comparing Distortion Product Otoacoustic Emissions to Intracochlear Distortion Products Inferred from a Noninvasive Assay. AB - The behavior of intracochlear distortion products (iDPs) was inferred by interacting a probe tone (f3) with the iDP of interest to produce a "secondary" distortion product otoacoustic emission termed DPOAE(2ry). Measures of the DPOAE(2ry) were then used to deduce the properties of the iDP. This approach was used in alert rabbits and anesthetized gerbils to compare ear-canal 2f1-f2 and 2f2-f1 DPOAE f2/f1 ratio functions, level/phase (L/P) maps, and interference response areas (IRAs) to their simultaneously collected DPOAE(2ry) counterparts. These same measures were also collected in a human volunteer to demonstrate similarities with their laboratory animal counterparts and their potential applicability to humans. Results showed that DPOAEs and inferred iDPs evidenced distinct behaviors and properties. That is, DPOAE ratio functions elicited by low level primaries peaked around an f2/f1 = 1.21 or 1.25, depending on species, while the corresponding inferred iDP ratio functions peaked at f2/f1 ratios of ~1. Additionally, L/P maps showed rapid phase variation with DPOAE frequency (fdp) for the narrow-ratio 2f1-f2 and all 2f2-f1 DPOAEs, while the corresponding DPOAE(2ry) measures evidenced relatively constant phases. Common features of narrow-ratio DPOAE IRAs, such as large enhancements for interference tones (ITs) presented above f2, were not present in DPOAE(2ry) IRAs. Finally, based on prior experiments in gerbils, the behavior of the iDP directly measured in intracochlear pressure was compared to the iDP inferred from the DPOAE(2ry) and found to be similar. Together, these findings are consistent with the notion that under certain conditions, ear-canal DPOAEs provide poor representations of iDPs and thus support a "beamforming" hypothesis. According to this concept, distributed emission components directed toward the ear canal from the f2 and basal to f2 regions can be of differing phases and thus cancel, while these same components directed toward fdp add in phase. PMID- 27229003 TI - Linked Lives: Dyadic Associations of Mastery Beliefs With Health (Behavior) and Health (Behavior) Change Among Older Partners. AB - Objectives: Mastery beliefs are known to contribute to healthy aging. However, it is an open question whether individual mastery-health associations impact the health of close long-term partners. Method: We applied actor-partner interdependence models to 4-wave, 6-year longitudinal dyadic data from married and cohabitating partners in the Health and Retirement Study (N = 1,981 partners; age at baseline: M = 67 years, SD = 8.93, range 50-94 years). Results: Higher individual mastery beliefs were associated with better individual physical health and health behaviors. Higher mastery beliefs were associated with subsequent increases in light physical activity. Having a partner with higher levels of mastery was uniquely associated with fewer functional limitations, better self rated health, and more physical activity. Actor * Partner interaction effects for functional limitations indicated multiplicative associations of actor and partner mastery with health. Of note, mastery-health associations for individuals and their partners were invariant across age, gender, education, employment status, perceived stress over one's own and partner's health, and cognition. Discussion: Findings suggest that partner mastery beliefs matter for the health (behaviors) of older adults. We discuss possible mechanisms underlying partner interrelations in mastery and health, their age invariance, and consider implications arising from our results. PMID- 27229004 TI - Management considerations of massive hemoptysis while on extracorporeal membrane oxygenation. AB - BACKGROUND: Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is a life-saving procedure in patients with both respiratory and cardiac failure. Bleeding complications are common since patients must be maintained on anticoagulation. Massive hemoptysis is a rare complication of ECMO; however, it may result in death if not managed thoughtfully and expeditiously. METHODS: A retrospective chart review was performed of consecutive ECMO patients from 7/2010 8/2014 to identify episodes of massive hemoptysis. The management of and the outcomes in these patients were studied. Massive hemoptysis was defined as an inability to control bleeding (>300 mL/day) from the endotracheal tube with conventional maneuvers, such as bronchoscopy with cold saline lavage, diluted epinephrine lavage and selective lung isolation. All of these episodes necessitated disconnecting the ventilator tubing and clamping the endotracheal tube, causing full airway tamponade. RESULTS: During the period of review, we identified 118 patients on ECMO and 3 (2.5%) patients had the complication of massive hemoptysis. One case was directly related to pulmonary catheter migration and the other two were spontaneous bleeding events that were propagated by antiplatelet agents. All three patients underwent bronchial artery embolization in the interventional radiology suite. Anticoagulation was held during the period of massive hemoptysis without any embolic complications. There was no recurrent bleed after appropriate intervention. All three patients were successfully separated from ECMO. CONCLUSIONS: Bleeding complications remain a major issue in patients on ECMO. Disconnection of the ventilator and clamping the endotracheal tube with full respiratory and cardiac support by V-A ECMO is safe. Early involvement of interventional radiology to embolize any potential sources of the bleed can prevent re-hemoptysis and enable continued cardiac and respiratory recovery. PMID- 27229005 TI - Integration of genetic and clinical risk factors improves prognostication in relapsed childhood B-cell precursor acute lymphoblastic leukemia. AB - Somatic genetic abnormalities are initiators and drivers of disease and have proven clinical utility at initial diagnosis. However, the genetic landscape and its clinical utility at relapse are less well understood and have not been studied comprehensively. We analyzed cytogenetic data from 427 children with relapsed B-cell precursor ALL treated on the international trial, ALLR3. Also we screened 238 patients with a marrow relapse for selected copy number alterations (CNAs) and mutations. Cytogenetic risk groups were predictive of outcome postrelapse and survival rates at 5 years for patients with good, intermediate-, and high-risk cytogenetics were 68%, 47%, and 26%, respectively (P < .001). TP53 alterations and NR3C1/BTG1 deletions were associated with a higher risk of progression: hazard ratio 2.36 (95% confidence interval, 1.51-3.70, P < .001) and 2.15 (1.32-3.48, P = .002). NRAS mutations were associated with an increased risk of progression among standard-risk patients with high hyperdiploidy: 3.17 (1.15 8.71, P = .026). Patients classified clinically as standard and high risk had distinct genetic profiles. The outcome of clinical standard-risk patients with high-risk cytogenetics was equivalent to clinical high-risk patients. Screening patients at relapse for key genetic abnormalities will enable the integration of genetic and clinical risk factors to improve patient stratification and outcome. This study is registered at www.clinicaltrials.org as #ISCRTN45724312. PMID- 27229006 TI - Genome-wide investigation of the NAC transcription factor family in melon (Cucumis melo L.) and their expression analysis under salt stress. AB - KEY MESSAGE: 82 melon NAC (CmNAC) genes were identified in melon. We putatively identified the function of CmNAC gene in melon under salt stress. NAC transcription factor proteins play important roles in many biological processes, including plant development and stress responses. To date, few full-length melon NAC proteins have been identified. In this study, 82 melon NAC (CmNAC) genes were identified in the Cucumis melo L. genome. By interrogating our cDNA libraries and transcriptome data from melon under salt stress, and comparison of their phylogenetic relationship with Arabidopsis NAC salt stress-related genes, we putatively identified that the fourth clade of CmNAC genes were involved in the salt stress response, especially the second clade of the group IV of the phylogenetic tree. Expression analysis confirmed that eleven of the twelve CmNAC genes from the group IV were induced in melon seedling roots by salt stress; the other gene was down regulated by salt stress. The expression of CmNAC14 continually increased in 12 h under salt stress, and was selected for transformation into Arabidopsis for functional verification. Overexpression of CmNAC14 increased the sensitivity of transgenic Arabidopsis lines to salt stress, which were simultaneously demonstrated by reduced expression of abiotic stress response genes and variation in several physiological indices. This study increases our knowledge and may enable further characterization of the roles of CmNAC family in the response to salt stress. PMID- 27229007 TI - Diagnosis and Management of Drooling in Children With Progressive Dystonia: A Case Series of Patients With MEGDEL Syndrome. AB - Drooling is a common problem in children with progressive dystonia. The authors noted a 58% incidence of drooling in 22/38 children with MEGDEL, a rare neurodegenerative cause of dystonia and report on the clinical course of four patients. Drooling of varying severity and subsequent respiratory problems were treated at the authors' multidisciplinary saliva-control outpatient clinic. One patient improved on antireflux medication, the second after medication with drooling as side effect was changed. Two other patients underwent salivary gland surgery, one of whom significantly improved; the other died shortly after surgery. The heterogeneity of the cases presented shows the need for stepwise and personalized treatment. The authors recommend the following: (1) optimize the treatment of the underlying neurological condition and replace medication that stimulates saliva secretion; (2) treat constipation, scoliosis, and gastroesophageal reflux if there is still a risk of chronic aspiration of saliva; (3) perform more intense/invasive treatment (botulinum toxin, salivary gland surgery). PMID- 27229008 TI - Association Between Perinatal Hypoxic-Ischemic Conditions and Attention Deficit/Hyperactivity Disorder: A Meta-Analysis. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common neuropsychiatric disorder worldwide, but its etiology is still not fully understood. Previous studies have reported that perinatal hypoxic-ischemic conditions may be a potential cause of ADHD. METHODS: An online search of potential English studies published before September 2015 was conducted using the PsycINFO, EMBASE, Web of Science, and PubMed databases. The combined odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with random-effects models. RESULTS: Ten studies were included, with 45 821 cases and 9 207 363 controls. The metaresults found that the following were associated with ADHD: preeclampsia (OR 1.31; 95% CI 1.26-1.37), an Apgar score <7 at 5 minutes (OR 1.31; 95% CI 1.12-1.54), breech/transverse presentations (OR 1.14; 95% CI 1.06 1.23), and a prolapsed/nuchal cord (OR 1.10; 95% CI 1.06-1.15). CONCLUSION: Our results support that perinatal hypoxia-ischemia may contribute to ADHD. However, more clinical studies are warranted. PMID- 27229009 TI - The association of grip strength from midlife onwards with all-cause and cause specific mortality over 17 years of follow-up in the Tromso Study. AB - BACKGROUND: Grip strength has consistently been found to predict all-cause mortality rates. However, few studies have examined cause-specific mortality or tested age differences in these associations. METHODS: In 1994, grip strength was measured in the population-based Tromso Study, covering the ages 50-80 years (N=6850). Grip strength was categorised into fifths, and as z-scores. In this cohort study, models with all-cause mortality and deaths from specific causes as the outcome were performed, stratified by sex and age using Cox regression, adjusting for lifestyle-related and health-related factors. RESULTS: During 17 years of follow-up, 2338 participants died. A 1 SD reduction in grip strength was associated with HR=1.17 (95% CI 1.12 to 1.22) for all-cause mortality in a model adjusted for age, gender and body size. This association was similar across all age groups, in men and women, and robust to adjustment for a range of lifestyle related and health-related factors. Results for deaths due to cardiovascular disease (CVD), respiratory diseases and external causes resembled those for all cause mortality, while for cancer, the association was much weaker and not significant after adjustment for lifestyle-related and health-related factors. CONCLUSIONS: Weaker grip strength was associated with increased all-cause mortality rates, with similar effects on deaths due to CVD, respiratory disease and external causes, while a much weaker association was observed for cancer related deaths. These associations were similar in both genders and across age groups, which supports the hypothesis that grip strength might be a biomarker of ageing over the lifespan. PMID- 27229010 TI - Effects of deregulation of the driving licence application process on road safety in Korea: an interrupted time-series analysis. AB - BACKGROUND: Road traffic deaths (RTDs) remain the 9th most common cause of mortality in South Korea despite their decreasing trends in high-income countries. In 2010 and 2011, the Korean government deregulated the process for obtaining a driving licence, and there has been significant concern that such deregulation of the driving licence policy could reduce road safety. This study aimed to explore the effects of the deregulation of driving licence policy on road safety by examining the incidence of road traffic collisions (RTCs), road traffic injuries (RTIs) and RTDs. METHODS: The monthly incidence of RTCs, RTIs and RTDs was generated by using numbers of RTCs, RTIs and RTDs as numerators and numbers of registered vehicles as denominators. Changes in incidence since the deregulation implementation in February 2010 (phase I) and June 2011 (phase II) were evaluated via interrupted time-series analysis. RESULTS: The second deregulation phase demonstrated significant changes in numbers of RTCs and RTIs: numbers of RTCs and RTIs decreased until they began to increase in November 2011. Since then, the monthly incidence of RTCs and RTIs have increased by 133.5 and 123.8 per 100 000 vehicles per month, respectively (p<0.05). RTD secular trends began to increase consecutively at rates of 0.024 (June 2010), 0.018 (between July 2010 and June 2011) and 0.273 (July 2011 onward) per 100 000 vehicles per month. Over the entire study period, the RTD incidence rate increased by 0.018 deaths per month on average subsequent to the first deregulation phase (p<0.05). CONCLUSIONS: The deregulation policies that simplified the driving licence process were associated with increased incidence of RTCs, RTIs and RTDs in Korea. PMID- 27229011 TI - Rg1 Attenuates alcoholic hepatic damage through regulating AMP-activated protein kinase and nuclear factor erythroid 2-related factor 2 signal pathways. AB - Rg1 has shown multiple pharmacological activities and been considered to be evaluated for hepatic protective activity, as Rg1 could modulate different pathways in various diseases. Herein we assessed its effect and potential mechanism in a newly modified ethanol model. C57BL/6 mice were fed with Lieber DeCarli liquid diet containing ethanol or isocaloric maltose dextrin as control diet with or without Rg1. Meanwhile, bicyclol was treated as positive drug to compare the efficacy of Rg1 against alcoholic hepatotoxicity. According to our data, Rg1 indeed improved the survival rate and lowered the abnormal high levels of serum parameters. H&E and Oil Red O staining indicated that the condition of liver damage was mitigated by Rg1 administration. Furthermore, AMPK and Nrf2 pathways were all modulated at both RNA and protein levels. In accordance with these findings, Rg1 effectively protected against alcoholic liver injury, possibly by modulating metabolism, suppressing oxidative stress, and enhancing oxidant defense systems of Nrf2 pathway. In vitro, Rg1 has no cell toxicity and promotes Nrf2 translocate into nuclear. In summary, we demonstrate that Rg1 is a potent activator of Nrf2 pathway, and could therefore be applied for prevention of hepatic damage. PMID- 27229095 TI - Dual venous outflow improves lower extremity trauma free flap reconstructions. AB - BACKGROUND: Venous outflow problems are the most common reasons for perioperative flap complications. The benefit of a second venous anastomosis, however, remains unclear in lower extremity trauma free flap reconstruction and warrants further investigation. MATERIALS AND METHODS: Retrospective review of our institutional flap registry from 1979 to 2014 identified 464 free flaps performed for lower leg trauma reconstruction. Patient demographics, flap characteristics, and outcomes were examined. RESULTS: A total of 219 flaps were randomly selected for preliminary analysis. Single-vein outflow was more common (72.6%) than dual-vein (27.4%); most of the recipients were in deep venous system (83.6%) versus superficial (11.9%) or both (4.6%). Two-vein anastomoses were more likely in fasciocutaneous flaps than muscle flaps (P = 0.001) and in smaller (<300 cm(2)) flaps (P = 0.002). Complications occurred in 98 flaps (44.7%); with 54 partial flap losses (24.7%), and 11 complete flap losses (5.0%). Multivariable regression analysis controlling for age, sex, flap type, presence of bone gap, flap size, vein size mismatch, and time since injury demonstrated dual-vein outflow to be protective against complications (relative risk [RR] = 0.269, P = 0.001), partial flap failure (RR = 0.351, P = 0.031), and any flap failure (RR = 0.31, P = 0.010). No significant difference in operative time was found (P = 0.664). CONCLUSIONS: Dual-vein outflow demonstrated 73% reduction in overall complications and 69% reduction in flap failure rate compared to single-vein flaps. These results suggest a protective effect of a dual-vein outflow system, and when considered together with our findings of unchanged operative time, provide evidence for preferential use of two venous anastomoses when possible for free flap reconstruction of lower extremity trauma. PMID- 27229096 TI - Are appendectomy outcomes in level I trauma centers as good as we think? AB - BACKGROUND: Designated trauma centers improve outcomes for severely injured patients. However, major trauma workload can disrupt other care pathways and some patient groups may compete ineffectively for resources with higher priority trauma cases. This study tested the hypothesis that treatment at a higher-level trauma center is an independent predictor for worse outcome after appendectomy. METHODS: An observational study was undertaken using an all-payer longitudinal data set (California State Inpatient Database 2007-2011). All patients with an ICD-90-CM diagnosis of "acute appendicitis" (International Classification of Diseases, Ninth Revision, Clinical Modification code 540) that subsequently underwent appendectomy were included. Patients transferred between hospitals were excluded to minimize selection bias. The outcome measures were days to the operating room, length of stay, unplanned 30-d readmission (to any hospital in California), and in-hospital mortality. Logistic and generalized linear regression models were used to adjust for patient- (age, sex, payer status, race, Charlson comorbidity index, weekend admission, and generalized peritonitis) and hospital-level (teaching status and bed size) factors. RESULTS: There were 119,601 patients treated in 278 individual hospitals. Patients in level I trauma centers (L1TCs) reached the operating room later (predicted mean difference 0.25 d [95% confidence interval 0.14-0.36]), stayed in hospital longer (0.83 d [0.36 1.31]), and had higher adjusted odds of generalized peritonitis (odds ratio 1.63 [95% confidence interval 1.13-2.36]) than those in nontrauma centers. There were no differences in mortality or unplanned 30-d readmissions to hospital; or between level II trauma centers and nontrauma centers across any of the measured outcomes. CONCLUSIONS: Odds of generalized peritonitis are higher and hospital length of stay is longer in L1TCs, although we found no evidence that patients come to serious harm in such institutions. Further work is necessary to determine whether pressure for resources in L1TCs can explain these findings. PMID- 27229097 TI - A pancreatic cancer multidisciplinary clinic: insights and outcomes. AB - BACKGROUND: The purpose of this study was to evaluate the impact of a multidisciplinary clinic (MDC) on the treatment of pancreatic ductal adenocarcinoma. We hypothesized that an MDC would improve trial participation, multimodality therapy, neoadjuvant therapy, time to treatment, and survival. MATERIALS AND METHODS: Pancreatic ductal adenocarcinoma cancer registry patients from 2008-2012 were analyzed. Outcomes of patients evaluated at the MDC were compared with patients not evaluated at the MDC (non-MDC). RESULTS: A total of 1408 patients were identified, 557 (40%) MDC and 851 (60%) non-MDC. MDC were more likely to be an earlier stage than non-MDC (P = 0.0005): I - 4% versus 4%, II - 54% versus 43%, III - 11% versus 9%, and IV - 32% versus 44%. MDC were younger than non-MDC (68 versus 70; P = 0.005); however, younger (<75) and older (>=75) patients were more likely to receive treatment in MDC than non-MDC. MDC were more likely to participate in trials than non-MDC (28% versus 14%; P < 0.0001). MDC were more likely to receive treatment than non-MDC (90% versus 71%; P < 0.0001). MDC were more likely to receive two (38% versus 24%; P < 0.0001) or three (12% versus 9%; P = 0.02) therapies than non-MDC. No difference in time to first treatment in MDC than non-MDC (0.95 versus 0.92 mo; P = 0.69). After adjusting for age, stage, and therapy, there was a trend; however, no statistical difference in disease-free survival (hazard ratio [HR] of non-MDC versus MDC 0.80; 95% confidence interval [95% CI] 0.61-1.05; P = 0.11), time to recurrence (HR of non-MDC versus MDC 0.69; 95% CI 0.45-1.04; P = 0.07), or overall survival (HR of non-MDC versus MDC 0.81; 95% CI, 0.62-1.07; P = 0.13). CONCLUSIONS: Patients evaluated in an MDC were more likely to receive any treatment, receive multimodality therapy, neoadjuvant therapy, and participate in a clinical trial. PMID- 27229098 TI - Are self-identified "disadvantaged" students less likely to enter surgical residencies? A single-institution study. AB - BACKGROUND: Given more emphasis on training primary care physicians for underserved areas, we hypothesized that students self-identifying as "disadvantaged" would be less likely to pursue surgical training. METHODS: We retrospectively reviewed medical school data on students graduating 2005-2014. Students were stratified into "disadvantaged" and "nondisadvantaged". Data were recorded on age, grade point average, Medical College Admission Test (MCAT), gender, surgery grade, United States Medical Licensing Examination step 1 score, and residency match into a surgical field. A comparison of the proportion of students matching into a surgical field was assessed with chi-square test. Multivariate logistic regression was performed to assess the factors that predict the choice of general surgery versus another surgical field. RESULTS: Of the 1140 students who graduated during the study period, 219 (19.2%) students self identified as "disadvantaged". Of all students, 158 (13.9%) chose a surgical field. The disadvantaged group was older at entry and had lower grade point average and total MCAT scores. Twenty-seven (12.3%) disadvantaged students chose a surgical residency versus 130 (14.1%) nondisadvantaged students (P = 0.56). On multivariate logistic regression, female gender (odds ratio [OR] = 3.9; 95% confidence interval = [1.9-8.3], P < 0.01), disadvantaged status (OR = 2.8 [1.1 7.1], P = 0.03), and United States Medical Licensing Examination step 1 score >= 227 (OR = 0.43 [0.21-0.88], P = 0.02) were significantly associated with matching into general surgery versus another surgical specialty. DISCUSSION: Although the disadvantaged cohort was older and had lower undergraduate GPAs and MCAT scores, the proportion of disadvantaged students matching into a surgical residency was not statistically different. To address the future shortage of general surgeons in underserved areas, increasing enrollment of "disadvantaged" students may alleviate the "surgical desert". PMID- 27229099 TI - The impact of frailty on outcomes of paraesophageal hernia repair. AB - BACKGROUND: Frailty is a measure of physiological reserve that has been used to predict outcomes after surgical procedures in the elderly. We hypothesized that frailty would be associated with outcomes after paraesophageal hernia (PEH) repair. METHODS: The National Surgical Quality Improvement Program database (2011 2013) was queried for International Classification of Diseases, Version 9 and Current Procedural Terminology codes associated with PEH repair in patients aged >= 60 y. A previously described modified frailty index (mFI), based on 11 clinical variables in National Surgical Quality Improvement Program was used to quantify frailty. Multivariate logistic regression was used to determine the relationship between frailty, complications, and mortality. RESULTS: Of the 4434 PEH repairs that met inclusion criteria, 885 records were included in the final analysis (20%). Excluded patients were missing one or more variables in the mFI. The rate of complications that were Clavien-Dindo Grade >= 3 was 6.1%. Mortality was 0.9%. The readmission rate was 8.2%, and 10.9% of patients were discharged to a facility other than home. Relative to mFI scores of 0, 1, 2, and >=3, the respective occurrence percentages were as follows; Grade >=3 complication: 3.2%, 4.7%, 9.8%, and 23.3% (P < 0.0001; odds ratio [OR] 3.51; confidence interval [CI] 1.46-8.46); mortality: 0.0%, 0.9%, 1.8%, and 2.3% (P = 0.0974); discharge to facility other than home: 4.4%, 10.9%, 15.7%, and 31.7% (P < 0.0001; OR 4.07; CI 1.29-12.82); and readmission: 8.9%, 6.8%, 8.5%, and 16.3% (P = 0.1703; OR 1.01; CI 0.36-2.84). Complications and discharge destination were significantly correlated with the mFI. CONCLUSIONS: Frailty, as assessed by the mFI, is correlated with postoperative complications and discharge to a facility other than home after PEH repair. PMID- 27229100 TI - Effect of ukrain on ischemia/reperfusion-induced kidney injury in rats. AB - BACKGROUND: The aim of this study was to investigate the potential protective effect of ukrain on an experimental kidney injury model induced by ischemia and reperfusion (IR) in rats. MATERIAL AND METHODS: A total of 24 male Sprague-Dawley rats were equally and randomly separated into three groups as follows: group-1: controls (C; only laparotomy); group 2: renal ischemia-reperfusion (IR; occlusion of the renal artery for 30 min and 2 h of reperfusion); and group 3: ukrain treatment and IR applied group (U + IR; occlusion of the renal artery for 30 min and 2 h of reperfusion; ukrain was intraperitoneally administered 1 h before the IR process). RESULTS: Serum total oxidant status (TOS) and total antioxidant status (TAS) levels were measured. The oxidative stress index was determined by calculating the TOS/TAS ratio. TAS serum levels significantly increased, and TOS serum levels also prominently decreased in U + IR group, when compared with the IR group (P < 0.001). Mean NGAL level was remarkably higher in IR group, when compared with the U + IR group (P < 0.001). Caspase-3 messenger RNA (mRNA) expression level increased in IR and decreased in U + IR group (P < 0.001). Bcl xL serum and mRNA expression levels increased in the U + IR group (P < 0.001). In addition, serum iNOS and mRNA expression levels increased in IR group and decreased in U + IR group (P < 0.001). CONCLUSIONS: Data established from the present study suggest that ukrain may exhibit protective effect against IR induced kidney injury and that antioxidant activity primarily modulates this effect. PMID- 27229102 TI - Lymphocyte-to-monocyte ratios predict gastric cancer surgical outcomes. AB - BACKGROUND: The prognostic role of the preoperative lymphocyte-to-monocyte ratio (LMR) in patients with gastric adenocarcinoma (GC) remains unclear. The aim of this study was to explore the prognostic potential of the preoperative LMR in patients with resectable GC. MATERIALS AND METHODS: The medical records of 926 consecutive patients with resectable GC between 2005 and 2010 were retrospectively reviewed and analyzed. Patients were stratified into two groups based on the preoperative LMR with a cutoff value of 4.8 (group 1: LMR <= 4.8; group 2: LMR > 4.8). Clinicopathologic factors potentially affecting patient outcomes were collected prospectively and analyzed. RESULTS: Compared to group 2, in group 1, there was a higher percentage of men, patients aged >48 y, total gastrectomy, tumor size > 4.8 cm, T4 lesions, N3 disease, metastatic tumors, advanced stage, ratio of metastatic to examined lymph nodes > 0.18, R1 resection, and occurrence of vascular or lymphatic invasion. Group 1 also had a higher 30-d surgical mortality rate (groups 1 versus 2 at 2.9% versus 0.5%; P = 0.006) and lower 3-y and 5-y overall survival (53.6% versus 71.9% and 46.4% versus 63.3%, respectively; P < 0.0001). Multivariate analysis showed that preoperative low LMR was an unfavorable prognostic factor for resectable GC. CONCLUSIONS: Patients with lower LMR had more aggressive tumor behavior, higher surgical mortality rates, and worse long-term survival. The preoperative LMR may serve as an independent prognostic factor for prediction of surgical outcomes and for assisting clinicians in determining future treatment plans. PMID- 27229101 TI - Measure of pancreas transection and postoperative pancreatic fistula. AB - BACKGROUND: In pancreaticoduodenectomy (PD), a standard protocol for pancreas transection has not been established although the method of pancreas transection might be involved in the occurrence of postoperative pancreatic fistula (POPF). This study aimed to compare whether pancreas transection by ultrasonically activated shears (UAS) or that by scalpel contributed more to POPF development. METHODS: A prospective database of 171 patients who underwent PD for periampullary tumor at National Cancer Center Hospital East between January 2010 and June 2013 was reviewed. Among the 171 patients, 93 patients with soft pancreas were specifically included in this study. Surgical results and background were compared between patients with pancreas transection by UAS and scalpel to evaluate the effectiveness of UAS on reducing POPF. RESULTS: Body mass index, main pancreatic duct diameter, or other clinicopathologic factors that have been reported as predictive factors for POPF were not significantly different between the two groups. The incidence of all grades of POPF and that of grade B were significantly lower in the scalpel group (52%, 4%) than in the UAS group (74%, 42%). Postoperative complications >= grade III were also significantly fewer in the scalpel group. CONCLUSIONS: Scalpel transection was less associated with POPF than UAS transection in patients who underwent PD for soft pancreas. The method of pancreas transection plays an important role in the prevention of clinical POPF. PMID- 27229103 TI - Effects of hydrogen-rich saline on aquaporin 1, 5 in septic rat lungs. AB - Aquaporin 1(AQP1) and AQP5 have an important role in eliminating extravascular lung water, an increase of which contributes to lung injury in patients with sepsis and its consequent mortality. It has been reported that hydrogen-rich saline (HRS) has protective effects against sepsis-related lung injury. In this study, we hypothesized that the protective effect occurred by preserving the expression of AQP1 and AQP5. To test this hypothesis, male Sprague-Dawley rats received intratracheal administration of lipopolysaccharide (LPS) followed by intraperitoneal injection of HRS. Lung function, wet-to-dry weight ratio, and histopathology scores were determined. The expression of AQP1 and AQP5 at the messenger RNA and protein levels, as well as the involved pathways, was explored by quantitative polymerase chain reaction and Western blot. LPS significantly impaired lung function and downregulated the expression of AQP1 and AQP5 in the rat lung, all of which were attenuated by HRS treatment. Moreover, HRS treatment inhibited LPS-induced activation of p38 mitogen-activated protein kinase and jun N-terminal kinase, which is associated with LPS-induced downregulation of AQP1 and AQP5. PMID- 27229104 TI - Minimally invasive surgery and sphincter preservation in rectal cancer. AB - BACKGROUND: National adoption of sphincter-preserving surgery (SPS) and minimally invasive surgery (MIS) has not been well documented. We examined national trends in use of SPS and MIS. MATERIALS AND METHODS: The National Inpatient Sample was used to evaluate open, laparoscopic, and robotic low anterior resection (LAR) or abdominoperineal resection (APR) for patients undergoing rectal cancer surgery from 2009 to 2011. Trends in SPS and MIS were stratified by hospital volume. Propensity score matching was used. RESULTS: A total of 24,999 (62.0%) patients underwent LAR, and 15,288 (38.0%) underwent APR from 2009 to 2011. A total of 22,310 (89.2%) LARs were open and 2689 (10.8%) MIS. A total of 11,600 (75.9%) APRs were open and 3688 (24.1%) MIS. Most procedures were at high-volume centers. In propensity-matched analysis, length of stay for LAR was longer in open surgery (6 versus 5 d; P = 0.01); in APR, MIS patients were less likely to have wound, infectious, urinary, and gastrointestinal complications, and length of stay was shorter (6 versus 8 d; P < 0.01). CONCLUSIONS: SPS and MIS rates have increased nationally, especially in high-volume centers. In addition, the perioperative benefits seen in randomized clinical trials are maintained in a national database. Further studies should focus on understanding differences in survival and oncologic outcomes with MIS techniques. PMID- 27229105 TI - Emodin alleviates lung injury in rats with sepsis. AB - BACKGROUND: Sepsis has high morbidity and mortality. The aim of this study was to investigate whether emodin, an anthraquinone derived from Chinese herb, exerts protective effects on lung injury in rat model of sepsis. MATERIALS AND METHODS: Forty-eight male Wistar rats were randomly divided into four groups (n = 12): normal group, sham-operated group, cecal ligation and puncture (CLP) model group, and emodin-treated group. Saline or emodin (25 mg/kg) was injected intraperitoneally 0.5 h before CLP. The rats were sacrificed 48 h after CLP. Lung wet-to-dry weight ratio and pathologic changes in the lung were examined, the contents of malondialdehyde and myeloperoxidase in lung tissue were detected, serum tumor necrosis factor alpha and interleukin 6 levels were measured by enzyme-linked immunosorbent assay, and the phosphorylation of p38 mitogen activated protein kinase (p38 MAPK) was detected by Western blot analysis. RESULTS: Compared with control group, CLP group exhibited higher wet-to-dry weight ratio and water content in the lung (P < 0.01), but these indexes were reduced and pathologic changes in the lung were relieved in the emodin-treated group. In addition, lung malondialdehyde and myeloperoxidase contents, serum levels of tumor necrosis factor alpha and interleukin 6, and phosphorylation of p38 MAPK increased in the CLP group but decreased in the emodin-treated group (P < 0.05). CONCLUSIONS: Emodin exerts protective effects on lung injury in septic rats, which is related to the inhibition of p38 MAPK pathway and the reduction of oxidative stress and inflammation response during sepsis. PMID- 27229106 TI - RAGE-mediated inflammation in patients with septic shock. AB - BACKGROUND: The receptor for advanced glycation end-products (RAGE)-pathway is described to be a crucial component of the innate immune response in sepsis. The aims of the present study were, therefore, to delineate the kinetics of membrane bound RAGE expression, to quantify its soluble isoforms, and to determine the extent of metabolic (e.g., AGE-CML) as well as immunologic (e.g., S100A8/A9) ligands in different inflammatory settings in humans. MATERIALS AND METHODS: The presented data result from secondary analyses of an observational clinical pilot study, including patients with septic shock (n = 60), postoperative controls (n = 30), and healthy volunteers (n = 30). Surface-bound expression of RAGE by peripheral blood leukocytes was determined by flow cytometry. In addition, plasma levels of sRAGE, esRAGE, AGE-CML, S100A8/A9, S100A8/A9-CML, RBP, RBP-CML, HSA CML, HMBG-1, and beta-Amyloid were measured using ELISA. RESULTS: In patients with septic shock, RAGE expression was significantly increased in comparison to both control groups, which was paralleled by a significant increase in sRAGE plasma levels. Formation of AGE-CML was shown to be dependent on the availability of the unmodified protein. However, the total amount of AGE-CML did not differ significantly between septic patients and healthy volunteers at early stages or was even lower in patients with sepsis at later stages. In contrast, immunologic ligands (e.g., S100A8/A9) were shown to be significantly elevated in septic patients within the entire study period. CONCLUSIONS: Activation of the RAGE pathway was shown to be of relevance in patients with septic shock, mainly driven by an increase in immunologic (e.g., S100A8/A9) rather than metabolic ligands (e.g., CML-derived AGE-formation). PMID- 27229107 TI - Risks of adverse events in colorectal patients: population-based study. AB - BACKGROUND: Postoperative (PO) outcomes are rapidly being integrated into value based purchasing programs and associated penalties are slated for inclusion in the near future. Colorectal surgery procedures are extremely common and account for a high proportion of morbidity among general surgery. We sought to assess adverse events in colorectal surgical patients. METHODS: We performed a retrospective study using the Nationwide Inpatient Sample database, 2008-2012. Patients were identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes and classified based on procedure indication: colon cancer, benign polyps, diverticulitis, inflammatory bowel disease, and ischemic colitis. The outcome of interest was inpatient adverse event identified by Agency for Healthcare Research and Quality's patient safety indicators (PSIs). RESULTS: We identified 1,100,184 colorectal patients who underwent major surgery; 2.7% developed a PSI during their hospital stay. Compared to all colorectal patients, those with ischemic colitis had significantly higher risk-adjusted rates per 1000 case for pressure ulcer (50.20), failure to rescue (211.30), central line bloodstream infection (2.33) and PO DE/deep vein thrombosis (16.02), and sepsis (46.99), whereas benign polyps were associated with significantly lower risk-adjusted rates per 1000 cases for pressure ulcer (11.48), failure to rescue (84.79), central line bloodstream infection (0.97) and PO pulmonary embolism/deep vein thrombosis (4.81), and sepsis (11.23). Compared to both patient demographic and clinical characteristics, the procedure indication was the strongest predictor of any PSI relevant to colorectal surgery; patients with ischemic colitis had higher odds of experiencing a PSI (odds ratio, 1.84; 95% confidence interval, 1.71-1.99) compared with cancer patients. CONCLUSIONS: Among colorectal surgery patients, inpatient events were not uncommon. We found important differential rates of adverse events by diagnostic category, with the highest odds ratio occurring in patients undergoing surgery for ischemic colitis. Our work elaborates the need for rigorous risk adjustment, quality improvement strategies for high-risk populations, and attention to detail in calculating financial incentives in emerging value-based purchasing programs. PMID- 27229108 TI - Trends in the management of pelvic fractures, 2008-2010. AB - BACKGROUND: Bleeding from pelvic fractures can be lethal. Angioembolization (AE) and external fixation (EXFIX) are common treatments to control bleeding, but it is not known how frequently they are used. We hypothesized that AE would be increasingly more common compared with EXFIX over time. METHODS: The National Trauma Data Bank for the years from 2008-2010 were used. Patients were included in the study if they had an International Classification of Diseases, ninth edition, Clinical Modification codes for pelvic fractures and were aged >=18 y. Patients were excluded if they had isolated acetabular fractures, were not admitted, or had minor injuries. Outcomes included receiving a procedure and in hospital mortality. RESULTS: A total of 22,568 patients met study criteria. AE and EXFIX were performed in 746 (3.3%) and 663 (2.9%) patients, respectively. AE was performed more often as the study period progressed (2.5% in 2007 to 3.7% in 2010; P < 0.001). This remained significant in adjusted analysis (odds ratio per year 1.15; P = 0.008). Having a procedure was associated with higher mortality in unadjusted analyses compared with those with no procedure (11.0% for no procedure versus 20.5% and 13.4% for AE or EXFIX, respectively; P < 0.001). In adjusted analyses, only AE remained associated with higher mortality (odds ratio 1.63; P < 0.001). CONCLUSIONS: AE in severely injured pelvic fracture patients is increasing. AE is associated with higher mortality, which may reflect the fact that it is used for patients at higher risk of death. The role of AE for bleeding should be examined in future studies. PMID- 27229109 TI - In-depth analysis of clotting dynamics in burn patients. AB - BACKGROUND: Studies associating coagulopathic changes with burn injury have relied on limited tests such as partial thromboplastin time (PTT) and international normalized ratio (INR). Understanding the clotting dynamics and associated risk factors after burn injury could influence management. This work aimed to identify real-time changes in coagulation after burn injury not indicated by PTT or INR alone. MATERIALS AND METHODS: Nine burn-injured patients at a regional burn center were enrolled for blood collection at admission and set intervals over 96 h. Patient demographics, management, and laboratory data (PTT and INR) were collected. Plasma assays determined factors II, V, VII, VIII, IX, X, XI, antithrombin, and protein C functional activity as well as PAP, D-Dimer, fibrin monomer, TFPI, IL-1b, IL-6, IL-10, IL-12p.70, and TNF-alpha concentrations. RESULTS: Overall, five patients died. These patients had higher mortality scores and were more acidotic. All patients had normal coagulation studies (INR < 1.5, PTT < 45 s) within 24 h of admission, and only two were abnormal after. Increased factor VIII and IX activity were identified in seven patients at admission. Decreased antithrombin and protein C activity were seen in all patients. Patients had increased PAP, D-Dimer, and fibrin monomer concentrations throughout their hospital course. At admission, increased fold changes were seen in IL-6 (2.5-117) and IL-10 (2.4-32), whereas IL-1b and TNF alpha levels were depressed in all patients. CONCLUSIONS: Extensive changes not identified by PTT or INR were seen after burn injury that may explain perturbed coagulation in these patients. This approach further characterizes the impact thermal injury has on coagulation. PMID- 27229110 TI - CCL2-CCR2 signaling promotes hepatic ischemia/reperfusion injury. AB - BACKGROUND: Liver ischemia/reperfusion (I/R) injury is a type of uncontrolled inflammatory cascade in which neutrophils, an early infiltrating immune cell population, elicit significant tissue damage. However, the precise mechanism for neutrophil recruitment and infiltration remains to be fully characterized. METHODS: A hepatic partial I/R model was reproduced in wild-type, CCL2(-/-) and CCR2(-/-) mice. Tissue damage was evaluated by serum enzyme analysis, hematoxylin eosin staining, and cytokine production measurement. Mobilization of neutrophils from the bone marrow and subsequent infiltration into the liver were measured by flow cytometry. C-C motif chemokine receptor 2 (CCR2) expression on neutrophils and C-C motif chemokine ligand 2 (CCL2) chemotaxis were measured using flow cytometry. The cellular source of CCL2 in the liver was determined by deleting specific cell groups and performing intracellular staining. RESULTS: Liver damage was ameliorated, and neutrophil recruitment and accumulation were decreased in both CCL2(-/-) and CCR2(-/-) mice compared with wild-type mice. Neutrophils displayed upregulated expression of CCR2 during I/R, and these cells were required for CCL2-induced chemotaxis. Depletion of Kupffer cells protected the liver from I/R injury. Furthermore, genetic ablation of CCL2 reduced liver injury, as demonstrated by decreases in the levels of alanine aminotransferase and aspartate aminotransferase and subsequent reductions in neutrophil recruitment and accumulation. CONCLUSIONS: Kupffer cells secrete CCL2 to promote CCR2-expressing neutrophil recruitment from the bone marrow and subsequent infiltration into the liver during I/R. These findings reveal a novel pro inflammatory role of cell-mediated CCL2-CCR2 interactions during this sterile insult. PMID- 27229111 TI - Physiologic effects of continuous-flow left ventricular assist devices. AB - BACKGROUND: Within the past 10 years, continuous-flow left ventricular assist devices (LVADs) have replaced pulsatile-flow LVADs as the standard of care for both destination therapy and bridging patients to heart transplantation. Despite the rapid clinical adoption of continuous-flow LVADs, an understanding of the effects of continuous-flow physiology, as opposed to more natural pulsatile-flow physiology, is still evolving. MATERIALS AND METHODS: A thorough review of the relevant scientific literature regarding the physiological and clinical effects of continuous-flow physiology was performed. These effects were analyzed on an organ system basis and include an evaluation of the cardiovascular, respiratory, hematologic, gastrointestinal, renal, hepatic, neurologic, immunologic, and endocrine systems. RESULTS: Continuous-flow physiology is, generally speaking, well tolerated over the long term. However, several changes are manifest at the organ system level. Although many of these changes are without appreciable clinical significance, other changes, such as an increased rate of gastrointestinal bleeding, appear to be associated with continuous-flow physiology. CONCLUSIONS: Continuous-flow LVADs confer a significant advantage over their pulsatile-flow counterparts with regard to size and durability. From a physiological standpoint, continuous-flow physiology has limited clinical effects at the organ system level. Although improved over previous generations, challenges with this technology remain. Approaching these problems with a combination of clinical and engineering solutions may be needed to achieve continued progression in the field of durable mechanical circulatory support. PMID- 27229112 TI - Severe burn increased skeletal muscle loss in mdx mutant mice. AB - BACKGROUND: Severe burn causes muscle mass loss and atrophy. The balance between muscle cell death and growth maintains tissue homeostasis. We hypothesize that preexisting cellular structural defects will exacerbate skeletal muscle mass loss after burn. Using a Duchenne muscular dystrophy (mdx) mutant mouse, we investigated whether severe burn caused more damage in skeletal muscle with preexisting muscle disease. METHODS: The mdx mice and wild-type (WT) mice received 25% total body surface area scald burn. Gastrocnemius (GM), tibialis anterior, and gluteus muscles were obtained at days 1 and 3 after burn. GM muscle function was measured on day 3. Animals without burn served as controls. RESULTS: Wet tissue weight significantly decreased in tibialis anterior and gluteus in both mdx and WT mice after burn (P < 0.05). The ratio of muscle to body weight decreased in mdx mutant mice (P < 0.05) but not WT. Isometric force was significantly lower in mdx GM, and this difference persisted after burn (P < 0.05). Caspase-3 activity increased significantly after burn in both the groups, whereas HMGB1 expression was higher in burn mdx mice (P < 0.05). Proliferating cell nuclear antigen decreased significantly in mdx mice (P < 0.05). Myogenic markers pax7, myoD, and myogenin increased after burn in both the groups and were higher in mdx mice (P < 0.05). CONCLUSIONS: More muscle loss occurred in response to severe burn in mdx mutant mice. Cell turnover in mdx mice after burn is differed from WT. Although markers of myogenic activation are elevated in mdx mutant mice, the underlying muscle pathophysiology is less tolerant of traumatic injury. PMID- 27229113 TI - Delayed gastric emptying after pancreaticoduodenectomy. AB - BACKGROUND: Delayed gastric emptying (DGE) remains an unsolved complication after pancreaticoduodenectomy (PD) with conflicting reports of its cause. We aimed to compare the effect of surgical techniques involving the stomach in PD in lowering the risk of postoperative DGE. METHODS: Online search and review of key bibliographies in PubMed, Medline, Embase, Scopus, Cochrane, and Google Scholar was performed. Studies comparing PD surgical techniques were identified. Primary outcome was postoperative DGE. Methodological quality was assessed using Strengthening the Reporting of Observational Studies in Epidemiology and Consolidated Standards of Reporting Trials. Calculated pooled relative risk and odds ratios (ORs) with the corresponding 95% confidence interval (CI) were used in the meta-analyses. RESULTS: Overall, 376 studies were reviewed, of which 22 studies were selected including a total of 5172 patients. The incidence of DGE was lower in antecolic compared with retrocolic gastrojejunostomy (risk ratio [RR], 0.260; CI, 0.157-0.431; P < 0.001; n = 1067 patients) and in subtotal stomach preserving PD compared with pylorus preserving PD (RR, 0.527; CI, 0.363 0.763; P < 0.001; n = 663 patients). There was no significant difference between classic PD versus pylorus preserving PD (OR, 0.64; CI, 0.40-1.00; P = 0.05; n = 1209 patients), pancreaticogastrostomy versus pancreaticojejunostomy (RR, 1.02; CI, 0.62-1.68; P = 0.94; n = 961 patients), Roux-en-Y versus Billroth II gastrojejunostomy (RR, 0.946; CI, 0.788-1.136; P = 0.5513; n = 470 patients), or minimally invasive PD versus open PD (OR, 0.99; CI, 0.62-1.56; P = 0.96; n = 802). CONCLUSIONS: In PD, surgical techniques using antecolic reconstruction route and subtotal stomach preserving PD seem to be associated with a lower risk of DGE. Further randomized controlled trials are necessary to evaluate these results taking other causes into consideration. PMID- 27229114 TI - The effect of early goal-directed therapy on mortality in patients with severe sepsis and septic shock: a meta-analysis. AB - BACKGROUND: The Surviving Sepsis Campaign has recommended early goal-directed therapy (EGDT) as an essential strategy to decrease mortality among patients with severe sepsis and septic shock. However, three latest multicenter trials failed to show its benefit in the patients with severe sepsis and septic shock. This article was to evaluate the effect of EGDT on the mortality of patients with severe sepsis and septic shock. METHODS: Relevant studies from PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials were identified from January 1, 2001 to June 13, 2015. With both randomized controlled trials (RCTs) and non-RCTs selected, a meta-analysis on the effects of EGDT on all identified trials was performed. The primary outcome was the inhospital mortality. In subgroup, RCTs and non-RCTs were analyzed, respectively. RESULTS: A total of five RCTs and 10 non-RCTs involving 3285 patients in EGDT group and 3233 patients in the control group were identified. Pooled analyses of all studies showed significant difference in the inhospital mortality between the EGDT group and the control group (risk ratio [RR], 0.84; 95% confidence interval [CI], 0.74 0.94; P = 0.003) with substantial heterogeneity (chi2 = 24.93, P = 0.04, I(2) = 44%). In subgroup analysis, there were no significant difference in inhospital mortality between the EGDT group and the control group (RR, 0.95; 95% CI, 0.83 1.10; P = 0.51) with no significant difference in heterogeneity (chi2 = 6.62, P = 0.16, I(2) = 40%) in RCTs. In non-RCTs, EGDT significantly reduced inhospital mortality (RR, 0.75; 95% CI, 0.65-0.88; P = 0.0003) with no significant difference in heterogeneity (chi2 = 11.96, P = 0.22, I(2) = 25%). CONCLUSIONS: This meta-analysis suggests that EGDT can significantly reduce the mortality among patients with severe sepsis and septic shock. PMID- 27229115 TI - Utility of colon leakage score in left-sided colorectal surgery. AB - BACKGROUND: The aim of the study was to evaluate the clinical utility of the colon leakage score (CLS) in predicting the risk of anastomotic leakage (AL) after left-sided colorectal surgery. MATERIALS AND METHODS: This investigation was designed as a retrospective study of 304 patients who underwent left-sided colorectal surgery. The patients were classified into two groups as those who developed AL and those who did not develop AL, and the CLSs of the two groups were compared. The predictive value and the cutoff value of the CLS were assessed by receiver operating characteristic and logistic regression analysis. RESULTS: A significant difference was noted in the mean CLSs of the groups with and without AL (P < 0.001). The values of the area under the receiver operating characteristic curve (0.965; confidence interval, 0.913-1.00) and the odds ratio (2.9; confidence interval, 1.59-4.83; P < 0.001) indicated that CLS was a good predictor of AL. A CLS of 11 was found to be the best cutoff value, with a sensitivity and specificity of 84.6% and 87.2%, respectively. CONCLUSIONS: Our findings indicate that CLS can effectively predict the risk of AL after left sided colorectal surgery and that a CLS of 11 can be used as a cutoff value for the risk level. PMID- 27229116 TI - The clinical correlation of phosphatase and tensin homolog on chromosome 10, phosphorylation of AKT to an activated state, and odontogenic ameloblast associated protein in gastrointestinal stromal tumors. AB - BACKGROUND: Approximately 15% of gastrointestinal stromal tumors (GISTs) will not respond to tyrosine kinase inhibitors and drug resistance can develop over time. For refractory tumors, additional therapies are needed. Odontogenic ameloblast associated protein (ODAM) is expressed in some epithelial malignancies and can correlate with clinical outcomes. This study evaluated ODAM and its relationship to phosphatase and tensin homolog on chromosome 10 (PTEN) and phosphorylation of AKT to an activated state (pAKT) in GISTs. MATERIALS AND METHODS: Ninety-five distinct tumor specimens from 79 patients were identified. Morphologic features and clinical data were recorded for all tumors. Risk of recurrence was calculated using the Memorial Sloan-Kettering nomogram. Immunohistochemistry was performed using antibodies to ODAM, PTEN, and pAKT. Immunoreactivity was assessed for both cytoplasmic and nuclear expression. Staining patterns were correlated with clinical outcomes. RESULTS: Increasing cytoplasmic ODAM staining correlated with a lower recurrence score (P = 0.002), a lower mitotic rate (P = 0.0001), and smaller tumor size (P = 0.038). Increasing pAKT cytoplasmic staining correlated with a higher recurrence score (P = 0.037) and a higher mitotic rate (P = 0.036). ODAM and pAKT expression in the nucleus was associated with tumor origin. PTEN nuclear expression increased with increasing mitotic rate. pAKT expression increased in the cytoplasm and nucleus in high-risk tumors. CONCLUSIONS: Risk of recurrence correlated with cytoplasmic expression of ODAM and pAKT, whereas nuclear expression did not predict recurrence. The staining pattern for ODAM and pAKT in the cytoplasm may further clarify the risk of recurrence beyond the available nomograms. The increased expression of pAKT in the cytoplasm and nucleus of high-risk tumors suggests a potential target for systemic therapy. PMID- 27229118 TI - Disease progression of acute pancreatitis in pediatric patients. AB - BACKGROUND: Approximately 10% of patients with acute pancreatitis (AP) progress to chronic pancreatitis. Little is known about the factors that affect recurrence of pancreatitis after an initial episode. We retrospectively investigated patients with AP, focusing on their outcomes and the predictors for disease progression. METHODS: Between July 2003 and June 2015, we retrospectively enrolled first-time AP patients with medical records on disease etiology, severity (according to the Atlanta classifications), and recurrence of AP. Independent predictors of recurrent AP (RAP) and chronic pancreatitis were identified using the logistic regression model. RESULTS: Of the total 159 patients, 45 (28.3%) developed RAP, including two episodes of RAP in 19 patients, and 9 (5.7%) developed chronic pancreatitis. The median duration from the time of AP to the onset of RAP was 5.6 +/- 2.3 months. RAP patients were identified as more common among patients with idiopathic first-time AP. The presence of severe ascites, pancreatic necrosis, and systemic complications was independent predictors of RAP in pediatric patients. Experiencing over two RAP episodes was the predictor for developing chronic pancreatitis. No influence of age or number of AP episodes was found on the occurrence of abdominal pain, pain severity, and the prevalence of any pain. CONCLUSIONS: Severity of first-time AP and idiopathic first-time AP are related to RAP. Recurrence increases risk for progression to chronic pancreatitis. The risk of recurrence increased with increasing numbers of AP episodes. PMID- 27229117 TI - Nitric oxide differentially affects proteasome activator 28 after arterial injury in type 1 and type 2 diabetic rats. AB - BACKGROUND: Diabetic patients display aggressive restenosis after vascular interventions, likely because of proproliferative influences of hyperglycemia and hyperinsulinemia. We have shown that nitric oxide (NO) inhibits neointimal hyperplasia in type 2, but not in type 1, diabetic rats. Here, we examined proteasome activator 28 (PA28) after arterial injury in different diabetic environments, with or without NO. We hypothesize that NO differentially affects PA28 levels based on metabolic environment. MATERIALS AND METHODS: Vascular smooth muscle cell (VSMC) lysates from male, nondiabetic Lean Zucker (LZ) and Zucker Diabetic Fatty (ZDF) rats were assayed for 26S proteasome activity with or without PA28 and S-nitroso-N-acetylpenicillamine. LZ and ZDF VSMCs were treated with (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate for 24 h. Balloon-injured carotid arteries from LZ, streptozotocin-injected LZ (STZ, type 1), and ZDF (type 2) rats treated with disodium 1-[2-(carboxylato)pyrrolidin 1-iyl]diazen-1-ium-1,2-diolate were harvested at 3 or 14 d. PA28alpha was assessed by Western blotting and immunofluorescent staining. RESULTS: S-nitroso-N acetylpenicillamine reversed PA28-stimulated increases in 26S proteasome activity in LZ and ZDF VSMCs. Increased (Z)-1-[N-(2-aminoethyl)-N-(2 ammonioethyl)amino]diazen-1-ium-1,2-diolate lowered PA28alpha in LZ VSMCs but increased PA28alpha in ZDF VSMCs. At 3 d after injury, disodium 1-[2 (carboxylato)pyrrolidin-1-iyl]diazen-1-ium-1,2-diolate potentiated injury-induced PA28alpha decreases in LZ, STZ, and ZDF rats, suggesting VSMCs, depleted at this early time point, are major sources of PA28alpha. At 14 d after injury, total PA28alpha staining returned to baseline. However, although intimal and medial PA28alpha staining increased in injured STZ rats, adventitial PA28alpha staining increased in injured ZDF rats. CONCLUSIONS: PA28 dysregulation may explain the differential ability of NO to inhibit neointimal hyperplasia in type 1 versus type 2 diabetes. PMID- 27229119 TI - The impact of age on nodal metastases and survival in gastric cancer. AB - BACKGROUND: In gastric adenocarcinoma, the disparity in lymph node involvement between different age groups has not been thoroughly investigated. The objective of our study was to compare age-associated differences in adequate lymph node harvest and nodal involvement in gastric adenocarcinoma patients. METHODS: We analyzed data extracted from the Surveillance, Epidemiology and End Results database on 13,165 patients diagnosed with stage I-III gastric adenocarcinoma between 2004 and 2011. All patients underwent surgical resection. Statistical comparisons between various age groups were done using the chi-square test and Cox regression. RESULTS: Among 13,165 gastrectomy patients, proportion of patients that had >15 lymph nodes examined decreases significantly with increasing age (P < 0.0001). When adequately staged, older patients had a significantly lower proportion of node-positive tumors (P < 0.0001). Adequate nodal staging was also associated with improved 5-y disease-specific survival across all age groups. CONCLUSIONS: In gastric adenocarcinoma, older patients are less likely to be adequately staged. However, when adequately staged, they are less likely to have node-positive tumors. Adherence to national guidelines, regardless of age, is associated with improved survival outcomes and may alter multimodality management of gastric cancer in the elderly. PMID- 27229120 TI - Yes-associated protein impacts adherens junction assembly through regulating actin cytoskeleton organization. AB - The Hippo pathway effector Yes-associated protein (YAP) regulates liver size by promoting cell proliferation and inhibiting apoptosis. However, recent in vivo studies suggest that YAP has important cellular functions other than controlling proliferation and apoptosis. Transgenic YAP expression in mouse hepatocytes results in severe jaundice. A possible explanation for the jaundice could be defects in adherens junctions that prevent bile from leaking into the blood stream. Indeed, immunostaining of E-cadherin and electron microscopic examination of bile canaliculi of Yap transgenic livers revealed abnormal adherens junction structures. Using primary hepatocytes from Yap transgenic livers and Yap knockout livers, we found that YAP antagonizes E-cadherin-mediated cell-cell junction assembly by regulating the cellular actin architecture, including its mechanical properties (elasticity and cortical tension). Mechanistically, we found that YAP promoted contractile actin structure formation by upregulating nonmuscle myosin light chain expression and cellular ATP generation. Thus, by modulating actomyosin organization, YAP may influence many actomyosin-dependent cellular characteristics, including adhesion, membrane protrusion, spreading, morphology, and cortical tension and elasticity, which in turn determine cell differentiation and tissue morphogenesis. PMID- 27229121 TI - Identification of intestinal ion transport defects in microvillus inclusion disease. AB - Loss of function mutations in the actin motor myosin Vb (Myo5b) lead to microvillus inclusion disease (MVID) and death in newborns and children. MVID results in secretory diarrhea, brush border (BB) defects, villus atrophy, and microvillus inclusions (MVIs) in enterocytes. How loss of Myo5b results in increased stool loss of chloride (Cl(-)) and sodium (Na(+)) is unknown. The present study used Myo5b loss-of-function human MVID intestine, polarized intestinal cell models of secretory crypt (T84) and villus resembling (CaCo2BBe, C2BBe) enterocytes lacking Myo5b in conjunction with immunofluorescence confocal stimulated emission depletion (gSTED) imaging, immunohistochemical staining, transmission electron microscopy, shRNA silencing, immunoblots, and electrophysiological approaches to examine the distribution, expression, and function of the major BB ion transporters NHE3 (Na(+)), CFTR (Cl(-)), and SLC26A3 (DRA) (Cl(-)/HCO3 (-)) that control intestinal fluid transport. We hypothesized that enterocyte maturation defects lead villus atrophy with immature secretory cryptlike enterocytes in the MVID epithelium. We investigated the role of Myo5b in enterocyte maturation. NHE3 and DRA localization and function were markedly reduced on the BB membrane of human MVID enterocytes and Myo5bKD C2BBe cells, while CFTR localization was preserved. Forskolin-stimulated CFTR ion transport in Myo5bKD T84 cells resembled that of control. Loss of Myo5b led to YAP1 nuclear retention, retarded enterocyte maturation, and a cryptlike phenotype. We conclude that preservation of functional CFTR in immature enterocytes, reduced functional expression of NHE3, and DRA contribute to Cl(-) and Na(+) stool loss in MVID diarrhea. PMID- 27229122 TI - Loss of intestinal O-glycans promotes spontaneous duodenal tumors. AB - Mucin-type O-glycans, primarily core 1- and core 3-derived O-glycans, are the major mucus barrier components throughout the gastrointestinal tract. Previous reports identified the biological role of O-glycans in the stomach and colon. However, the biological function of O-glycans in the small intestine remains unknown. Using mice lacking intestinal core 1- and core 3-derived O-glycans [intestinal epithelial cell C1galt1(-/-);C3GnT(-/-) or double knockout (DKO)], we found that loss of O-glycans predisposes DKO mice to spontaneous duodenal tumorigenesis by ~1 yr of age. Tumor incidence did not increase with age; however, tumors advanced in aggressiveness by 20 mo. O-glycan deficiency was associated with reduced luminal mucus in DKO mice before tumor development. Altered intestinal epithelial homeostasis with enhanced baseline crypt proliferation characterizes these phenotypes as assayed by Ki67 staining. In addition, fluorescence in situ hybridization analysis reveals a significantly lower bacterial burden in the duodenum compared with the large intestine. This phenotype is not reduced with antibiotic treatment, implying O-glycosylation defects, rather than bacterial-induced inflammation, which causes spontaneous duodenal tumorigenesis. Moreover, inflammatory responses in DKO duodenal mucosa are mild as assayed with histology, quantitative PCR for inflammation-associated cytokines, and immunostaining for immune cells. Importantly, inducible deletion of intestinal O-glycans in adult mice leads to analogous spontaneous duodenal tumors, although with higher incidence and heightened severity compared with mice with O-glycans constitutive deletion. In conclusion, these studies reveal O glycans within the small intestine are critical determinants of duodenal cancer risk. Future studies will provide insights into the pathogenesis in the general population and those at risk for this rare but deadly cancer. PMID- 27229123 TI - Colonic macrophage polarization in homeostasis, inflammation, and cancer. AB - Our review focuses on the colonic macrophage, a monocyte-derived, tissue-resident macrophage, and the role it plays in health and disease, specifically in inflammatory conditions such as inflammatory bowel disease and cancer of the colon and rectum. We give special emphasis to macrophage polarization, or phenotype, in these different states. We focus on macrophages because they are one of the most numerous leukocytes in the colon, and because they normally contribute to homeostasis through an anti-inflammatory phenotype. However, in conditions such as inflammatory bowel disease, proinflammatory macrophages are increased in the colon and have been linked to disease severity and progression. In colorectal cancer, tumor cells may employ anti-inflammatory macrophages to promote tumor growth and dissemination, whereas proinflammatory macrophages may antagonize tumor growth. Given the key roles that this cell type plays in homeostasis, inflammation, and cancer, the colonic macrophage is an intriguing therapeutic target. As such, potential macrophage-targeting strategies are discussed. PMID- 27229124 TI - Axonal localization and mitochondrial association of precursor microRNA 338. AB - MicroRNAs (miRNAs) selectively localize to subcompartments of the neuron, such as dendrites, axons, and presynaptic terminals, where they regulate the local protein synthesis of their putative target genes. In addition to mature miRNAs, precursor miRNAs (pre-miRNAs) have also been shown to localize to somatodendritic and axonal compartments. miRNA-338 (miR-338) regulates the local expression of several nuclear-encoded mitochondrial mRNAs within axons of sympathetic neurons. Previous work has shown that precursor miR-338 (pre-miR-338) introduced into the axon can locally be processed into mature miR-338, where it can regulate local ATP synthesis. However, the mechanisms underlying the localization of pre-miRNAs to the axonal compartment remain unknown. In this study, we investigated the axonal localization of pre-miR-338. Using proteomic and biochemical approaches, we provide evidence for the localization of pre-miR-338 to distal neuronal compartments and identify several constituents of the pre-miR-338 ribonucleoprotein complex. Furthermore, we found that pre-miR-338 is associated with the mitochondria in axons of superior cervical ganglion (SCG) neurons. The maintenance of mitochondrial function within axons requires the precise spatiotemporal synthesis of nuclear-encoded mRNAs, some of which are regulated by miR-338. Therefore, the association of pre-miR-338 with axonal mitochondria could serve as a reservoir of mature, biologically active miRNAs, which could coordinate the intra-axonal expression of multiple nuclear-encoded mitochondrial mRNAs. PMID- 27229126 TI - The behavior of dietary fiber in the gastrointestinal tract determines its physiological effect. AB - A diet rich in dietary fiber (DF) is considered healthy and recommended dietary intake of DF is established all over the world. The physiological effect of DF is mostly related to its behavior during digestion. In this review, the behavior of DF in the human digestive tract is discussed and linked to its physiological effect with special attention to four aspects of such behavior: (i) the modulation of bioavailability by the plant cell walls, (ii) the effect of DF on the rheological and colloidal state of digesta, (iii) the binding of DF with phenolic compounds, bile salts, mineral ions, and digestive enzymes, and (iv) DF fermentation in the large intestine and the corresponding effect on microbiota composition. It is stressed that the detailed chemical characterization of DF is crucial to explain its effect on health and that DF behavior in the digestive tract can be modulated by interactions with other food and meal components so that information of the bare content in DF of food is not sufficient to predict its physiological effect. PMID- 27229125 TI - A structural perspective of RNA recognition by intrinsically disordered proteins. AB - Protein-RNA recognition is essential for gene expression and its regulation, which is indispensable for the survival of the living organism at one hand, on the other hand, misregulation of this recognition may lead to their extinction. Polymorphic conformation of both the interacting partners is a characteristic feature of such molecular recognition that promotes the assembly. Many RNA binding proteins (RBP) or regions in them are found to be intrinsically disordered, and this property helps them to play a central role in the regulatory processes. Sequence composition and the length of the flexible linkers between RNA binding domains in RBPs are crucial in making significant contacts with its partner RNA. Polymorphic conformations of RBPs can provide thermodynamic advantage to its binding partner while acting as a chaperone. Prolonged extensions of the disordered regions in RBPs also contribute to the stability of the large cellular machines including ribosome and viral assemblies. The involvement of these disordered regions in most of the significant cellular processes makes RBPs highly associated with various human diseases that arise due to their misregulation. PMID- 27229127 TI - High-Performance Perovskite Solar Cells Engineered by an Ammonia Modified Graphene Oxide Interfacial Layer. AB - The introduction of an ammonia modified graphene oxide (GO:NH3) layer into perovskite-based solar cells (PSCs) with a structure of indium-tin oxide (ITO)/poly(3,4-ethylene-dioxythiophene):poly(4-styrenesulfonate) ( PEDOT: PSS) GO: NH3/CH3NH3PbI3-xClx/phenyl C61-butyric acid methyl ester (PCBM)/(solution Bphen) sBphen/Ag improves their performance and perovskite structure stability significantly. The fabricated devices with a champion PCE up to 16.11% are superior in all the performances in comparison with all the reference devices without the GO:NH3 layer. To understand the improved device performances, synchrotron-based grazing incidence X-ray diffraction (GIXRD), scanning electron microscopy (SEM), ultraviolet photoelectron spectroscopy (UPS), X-ray photoelectron spectroscopy (XPS), and UV-visible absorption measurements have been conducted on perovskite films on different substrates. It was found that these improvements should be partially attributed to the improved crystallization and preferred orientation order of peovskite structure, partially to the improved morphology with nearly complete coverage, partially to the enhanced optical absorption caused by the PEDOT: PSS-GO:NH3 layer, and partially to the better matched energy-level-alignment at the perovskite interface. Furthermore, the device was shown to be more stable in the ambient condition, which is clearly associated with the improved peovskite structure stability by the GO:NH3 layer observed by the GIXRD measurements. All these achievements will promote more applications of chemically modified graphene oxide interfacial layer in the PSCs as well as other organic multilayer devices. PMID- 27229129 TI - Is It Facebook Official? Coming Out and Passing Strategies of Young Adult Gay Men on Social Media. AB - The rapid proliferation of social media, mobile applications, and Internet technologies has shifted a wide variety of social interaction from physical spaces to an online environment. Drawing from 42 semistructured, in-depth interviews with gay college-aged men between the ages of 18 and 27, this article explores these changing patterns of social interaction among gay men. I discuss three strategies of identity management college-aged gay men use to disclose or conceal their sexual identity to others. The first group of men, "Out and Proud," uses Facebook as a way to celebrate and reaffirm their sexual identity, in addition to actively coming out to others on the social media Web site. The second group, "Out and Discreet," uses Facebook to indirectly come out to some of their friends while hiding this information from others. The men in the last group I identify, "Facebook Closeted," actively manage their online profiles to ensure their sexual identity is not exposed. Facebook is both transformative and risky for college-aged gay men, as it represents a new platform for them to come out as gay to friends and family, as well as other areas of their lives where they must actively manage the presentation of their sexual identity. PMID- 27229128 TI - Evasion of cell senescence in SHH medulloblastoma. AB - The mechanisms leading to brain tumor formation are poorly understood. Using Ptch1+/- mice as a medulloblastoma model, sequential mutations were found to shape tumor evolution. Initially, medulloblastoma preneoplastic lesions display loss of heterozygosity of the Ptch1 wild-type allele, an event associated with cell senescence in preneoplasia. Subsequently, p53 mutations lead to senescence evasion and progression from preneoplasia to medulloblastoma. These findings are consistent with a model where high levels of Hedgehog signaling caused by the loss of the tumor suppressor Ptch1 lead to oncogene-induced senescence and drive p53 mutations. Thus, cell senescence is an important characteristic of a subset of SHH medulloblastoma and might explain the acquisition of somatic TP53 mutations in human medulloblastoma. This mode of medulloblastoma formation contrasts with the one characterizing Li-Fraumeni patients with medulloblastoma, where TP53 germ-line mutations cause chromothriptic genomic instability and lead to mutations in Hedgehog signaling genes, which drive medulloblastoma growth. Here we discuss in detail these 2 alternative mechanisms leading to medulloblastoma tumorigenesis. PMID- 27229130 TI - Sonography for Complete Evaluation of Neonatal Intensive Care Unit Central Support Devices: A Pilot Study. AB - OBJECTIVES: Neonates in the neonatal intensive care unit often require considerable support with endotracheal tubes, umbilical arterial and venous catheters, and peripherally inserted central venous catheters. Support device evaluation with radiography exposes neonates to ionizing radiation. This study evaluated the effectiveness of sonographic localization for endotracheal tubes, umbilical arterial and venous catheters, and peripherally inserted central venous catheters. METHODS: This blinded prospective Institutional Review Board-approved, Health Insurance Portability and Accountability Act-compliant study with informed consent compared sonography to radiography for endotracheal tube, umbilical arterial and venous catheter, and peripherally inserted central venous catheter localization. Participants were consecutively recruited NICU patients of any weight, gestation, and chronologic age who had an endotracheal tube, umbilical arterial catheter, umbilical venous catheter, or peripherally inserted central venous catheter placed or adjusted and had subsequent radiographic confirmation within 24 hours. Sonographic evaluation was obtained as soon as possible, without prior review of the radiograph, and results were compared. RESULTS: Thirty sonographic studies were performed in 25 patients (14 male and 11 female), for a total of 50 lines and tubes: 18 umbilical venous catheters, 12 umbilical arterial catheters, 11 peripherally inserted central venous catheters, and 9 endotracheal tubes. Forty-nine support devices (98%) were visualized with sonography, all concordant with radiography. Forty-four were correctly positioned, and 6 were malpositioned. Sonography identified the location of umbilical venous catheters in all 18 cases (100%), umbilical arterial catheters in all 12 (100%), peripherally inserted central venous catheters in 10 (91%), and endotracheal tubes in 9 (100%). CONCLUSIONS: The effectiveness of sonography was excellent for evaluation of umbilical arterial and venous catheters, endotracheal tubes, and peripherally inserted central venous catheters. These results support the goal of further point-of-care training and accreditation to use sonography as a primary modality for complete evaluation of NICU support devices. PMID- 27229131 TI - Magnetic Resonance Imaging and Sonography in the Diagnosis of Placental Invasion. AB - OBJECTIVES: To compare older and newer magnetic resonance imaging (MRI) criteria for placental invasion and to compare the sensitivity, specificity, and accuracy of MRI and sonography in determining the depth of placental invasion. METHODS: Forty pregnant patients at high risk for morbidly adherent placenta based on prenatal sonography underwent MRI evaluations. Two reviewers, who were blinded to the original MRI and sonographic interpretations, clinical history, and obstetric/pathologic findings, reviewed the MRI examinations. The MRI and sonographic scans were analyzed for the presence and depth of invasion. The MRI scans were tabulated for the presence of dark intraplacental T2 bands, bulging of the myometrium, increased vascularity, and indistinct myometrium, loss of the dark T2 myometrial/placental interface, and a thin myometrium. The obstetric/pathologic results served as the reference standards. RESULTS: Eighteen of 40 patients had a morbidly invasive placenta. The sensitivity, specificity, and accuracy of MRI and sonography were not significantly different. The accuracy rates for determining the depth of placental invasion by readers 1 and 2 were 0.65 and 0.55, respectively (P > .05). According to the Cohen kappa statistic, there was a good inter-reader agreement between the MRI readers in assessing the depth of placental invasion (kappa = 0.45). The features most commonly seen were dark T2 bands, bulging of the uterus, and loss of the dark T2 interface, which were all associated with the presence of placental invasion. CONCLUSIONS: The diagnosis of placental invasion remains challenging on sonography and MRI, which perform similarly. The presence of 2 or more criteria adds specificity to the diagnosis of placental invasion on MRI. PMID- 27229132 TI - Utility of Shear Wave Elastography for Differentiating Biliary Atresia From Infantile Hepatitis Syndrome. AB - OBJECTIVES: The purpose of this study was to investigate the potential utility of shear wave elastography (SWE) for diagnosis of biliary atresia and for differentiating biliary atresia from infantile hepatitis syndrome by measuring liver stiffness. METHODS: Thirty-eight patients with biliary atresia and 17 patients with infantile hepatitis syndrome were included, along with 31 healthy control infants. The 3 groups underwent SWE. The hepatic tissue of each patient with biliary atresia had been surgically biopsied. Statistical analyses for mean values of the 3 groups were performed. Optimum cutoff values using SWE for differentiation between the biliary atresia and control groups were calculated by a receiver operating characteristic (ROC) analysis. RESULTS: The mean SWE values +/- SD for the 3 groups were as follows: biliary atresia group, 20.46 +/- 10.19 kPa; infantile hepatitis syndrome group, 6.29 +/- 0.99 kPa; and control group, 6.41 +/- 1.08 kPa. The mean SWE value for the biliary atresia group was higher than the values for the control and infantile hepatitis syndrome groups (P < .01). The mean SWE values between the control and infantile hepatitis syndrome groups were not statistically different. The ROC analysis showed a cutoff value of 8.68 kPa for differentiation between the biliary atresia and control groups. The area under the ROC curve was 0.997, with sensitivity of 97.4%, specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 96.9%. Correlation analysis suggested a positive correlation between SWE values and age for patients with biliary atresia, with a Pearson correlation coefficient of 0.463 (P < .05). CONCLUSIONS: The significant increase in liver SWE values in neonates and infants with biliary atresia supports their application for differentiating biliary atresia from infantile hepatitis syndrome. PMID- 27229133 TI - Quantitative Cardiac Assessment in Fetal Tetralogy of Fallot. AB - OBJECTIVES: The purpose of this study was to quantitatively assess cardiac function and biometric parameters in fetuses with a diagnosis of tetralogy of Fallot and compare them to those in healthy fetuses. METHODS: Two hundred healthy fetuses and 20 fetuses with a diagnosis of classic tetralogy of Fallot were quantitatively assessed for 16 cardiac parameters, including morphologic characteristics and functions. All recruited fetuses were in the second trimester with correct gestational ages. The measured values that were out of normal reference ranges were considered abnormal. Rates of abnormalities of these parameters were compared between the groups. The significant parameters were further analyzed for their sensitivity, specificity, and likelihood ratio. RESULTS: Of the 16 parameters, rates of abnormalities in 7 parameters, including right ventricular wall thickness, peak systolic velocities (PSVs) in the pulmonary artery and aorta, time to peak velocity, or acceleration time, in the pulmonary artery, aortic valve diameter, pulmonary valve diameter, and aortic-to pulmonary valve diameter ratio, were significantly higher in fetuses with tetralogy of Fallot (P < .001). The pulmonary artery PSV, pulmonary artery time to peak velocity, aortic valve diameter, pulmonary valve diameter, and aortic-to pulmonary valve diameter ratio had high sensitivities (80.0%, 75.0%, 90.0%, 90.0%, and 100.0%, respectively) and specificities (95.5%, 97.0%, 94.5%, 96.0%, and 84.5%). CONCLUSIONS: In addition to a routine anatomic examination, quantitative assessment of fetal hemodynamics, especially an abnormally high PSV in the pulmonary artery, as well as a shortened acceleration time and abnormal valve size, might be very helpful for confirmation of the diagnosis in cases of suspected tetralogy of Fallot. PMID- 27229134 TI - Kinetic Control of O2 Reactivity in H-NOX Domains. AB - Transient absorption, resonance Raman, and vibrational coherence spectroscopies are used to investigate the mechanisms of NO and O2 binding to WT Tt H-NOX and its P115A mutant. Vibrational coherence spectra of the oxy complexes provide clear evidence for the enhancement of an iron-histidine mode near 217 cm(-1) following photoexcitation, which indicates that O2 can be dissociated in these proteins. However, the quantum yield of O2 photolysis is low, particularly in the wild type (?3%). Geminate recombination of O2 and NO in both of these proteins is very fast (~1.4 * 10(11) s(-1)) and highly efficient. We show that the distal heme pocket of the H-NOX system forms an efficient trap that limits the O2 off rate and determines the overall affinity. The distal pocket hydrogen bond, which appears to be stronger in the P115A mutant, may help retard the O2 ligand from escaping into the solvent following either photoinduced or thermal dissociation. This, along with a strengthening of the Fe-O2 bond that is correlated with the significant heme ruffing and saddling distortions, explains the unusually high O2 affinity of WT Tt H-NOX and the even higher affinity found in the P115A mutant. PMID- 27229135 TI - Dissipation kinetics of alpha-cypermethrin and lambda-cyhalothrin residues in aboveground part of white mustard (Sinapis alba L.). AB - Dissipation of simultaneously applied insecticides alpha-cypermethrin and lambda cyhalothrin was studied in a minor crop, aboveground part of white mustard (Sinapis alba L.). A validated gas chromatographic method (GC-ECD/NPD) was used to determine insecticide residues. Analytical performances were very satisfactory, with expanded uncertainties not higher than 14% (coverage factor k = 2, confidence level 95%). Dissipation of alpha-cypermethrin and lambda cyhalothrin in white mustard followed first-order kinetics (R(2) between 0.953 and 0.995), with half-lives of 3.1-4.6 and 2.9-3.7 days respectively. Based on the results of this two-year study and the relevant residue regulation, alpha cypermethrin and lambda-cyhalothrin treatments can be considered safe for crop protection, feeding animals and the environment. PMID- 27229136 TI - G9a promotes proliferation and inhibits cell cycle exit during myogenic differentiation. AB - Differentiation of skeletal muscle cells, like most other cell types, requires a permanent exit from the cell cycle. The epigenetic programming underlying these distinct cellular states is not fully understood. In this study, we provide evidence that the lysine methyltransferase G9a functions as a central axis to regulate proliferation and differentiation of skeletal muscle cells. Transcriptome analysis of G9a knockdown cells revealed deregulation of many cell cycle regulatory genes. We demonstrate that G9a enhances cellular proliferation by two distinct mechanisms. G9a blocks cell cycle exit via methylation-dependent transcriptional repression of the MyoD target genes p21(Cip/Waf1) and Rb1. In addition, it activates E2F1-target genes in a methyltransferase activity independent manner. We show that G9a is present in the E2F1/PCAF complex, and enhances PCAF occupancy and histone acetylation marks at E2F1-target promoters. Interestingly, G9a preferentially associates with E2F1 at the G1/S phase and with MyoD at the G2/M phase. Our results provide evidence that G9a functions both as a co-activator and a co-repressor to enhance cellular proliferation and inhibit myogenic differentiation. PMID- 27229137 TI - Examining cooperative binding of Sox2 on DC5 regulatory element upon complex formation with Pax6 through excess electron transfer assay. AB - Functional cooperativity among transcription factors on regulatory genetic elements is pivotal for milestone decision-making in various cellular processes including mammalian development. However, their molecular interaction during the cooperative binding cannot be precisely understood due to lack of efficient tools for the analyses of protein-DNA interaction in the transcription complex. Here, we demonstrate that photoinduced excess electron transfer assay can be used for analysing cooperativity of proteins in transcription complex using cooperative binding of Pax6 to Sox2 on the regulatory DNA element (DC5 enhancer) as an example. In this assay, (Br)U-labelled DC5 was introduced for the efficient detection of transferred electrons from Sox2 and Pax6 to the DNA, and guanine base in the complementary strand was replaced with hypoxanthine (I) to block intra-strand electron transfer at the Sox2-binding site. By examining DNA cleavage occurred as a result of the electron transfer process, from tryptophan residues of Sox2 and Pax6 to DNA after irradiation at 280 nm, we not only confirmed their binding to DNA but also observed their increased occupancy on DC5 with respect to that of Sox2 and Pax6 alone as a result of their cooperative interaction. PMID- 27229138 TI - Accurate detection for a wide range of mutation and editing sites of microRNAs from small RNA high-throughput sequencing profiles. AB - Various types of mutation and editing (M/E) events in microRNAs (miRNAs) can change the stabilities of pre-miRNAs and/or complementarities between miRNAs and their targets. Small RNA (sRNA) high-throughput sequencing (HTS) profiles can contain many mutated and edited miRNAs. Systematic detection of miRNA mutation and editing sites from the huge volume of sRNA HTS profiles is computationally difficult, as high sensitivity and low false positive rate (FPR) are both required. We propose a novel method (named MiRME) for an accurate and fast detection of miRNA M/E sites using a progressive sequence alignment approach which refines sensitivity and improves FPR step-by-step. From 70 sRNA HTS profiles with over 1.3 billion reads, MiRME has detected thousands of statistically significant M/E sites, including 3'-editing sites, 57 A-to-I editing sites (of which 32 are novel), as well as some putative non-canonical editing sites. We demonstrated that a few non-canonical editing sites were not resulted from mutations in genome by integrating the analysis of genome HTS profiles of two human cell lines, suggesting the existence of new editing types to further diversify the functions of miRNAs. Compared with six existing studies or methods, MiRME has shown much superior performance for the identification and visualization of the M/E sites of miRNAs from the ever-increasing sRNA HTS profiles. PMID- 27229139 TI - Human mutations affect the epigenetic/bookmarking function of HNF1B. AB - Bookmarking factors are transcriptional regulators involved in the mitotic transmission of epigenetic information via their ability to remain associated with mitotic chromatin. The mechanisms through which bookmarking factors bind to mitotic chromatin remain poorly understood. HNF1beta is a bookmarking transcription factor that is frequently mutated in patients suffering from renal multicystic dysplasia and diabetes. Here, we show that HNF1beta bookmarking activity is impaired by naturally occurring mutations found in patients. Interestingly, this defect in HNF1beta mitotic chromatin association is rescued by an abrupt decrease in temperature. The rapid relocalization to mitotic chromatin is reversible and driven by a specific switch in DNA-binding ability of HNF1beta mutants. Furthermore, we demonstrate that importin-beta is involved in the maintenance of the mitotic retention of HNF1beta, suggesting a functional link between the nuclear import system and the mitotic localization/translocation of bookmarking factors. Altogether, our studies have disclosed novel aspects on the mechanisms and the genetic programs that account for the mitotic association of HNF1beta, a bookmarking factor that plays crucial roles in the epigenetic transmission of information through the cell cycle. PMID- 27229141 TI - Spatiotemporal coordination of stem cell commitment during epidermal homeostasis. AB - Adult tissues replace lost cells via pools of stem cells. However, the mechanisms of cell self-renewal, commitment, and functional integration into the tissue remain unsolved. Using imaging techniques in live mice, we captured the lifetime of individual cells in the ear and paw epidermis. Our data suggest that epidermal stem cells have equal potential to either divide or directly differentiate. Tracking stem cells over multiple generations reveals that cell behavior is not coordinated between generations. However, sibling cell fate and lifetimes are coupled. We did not observe regulated asymmetric cell divisions. Lastly, we demonstrated that differentiating stem cells integrate into preexisting ordered spatial units of the epidermis. This study elucidates how a tissue is maintained by both temporal and spatial coordination of stem cell behaviors. PMID- 27229140 TI - The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas. AB - More than 90% of chondroblastomas contain a heterozygous mutation replacing lysine-36 with methionine-36 (K36M) in the histone H3 variant H3.3. Here we show that H3K36 methylation is reduced globally in human chondroblastomas and in chondrocytes harboring the same genetic mutation, due to inhibition of at least two H3K36 methyltransferases, MMSET and SETD2, by the H3.3K36M mutant proteins. Genes with altered expression as well as H3K36 di- and trimethylation in H3.3K36M cells are enriched in cancer pathways. In addition, H3.3K36M chondrocytes exhibit several hallmarks of cancer cells, including increased ability to form colonies, resistance to apoptosis, and defects in differentiation. Thus, H3.3K36M proteins reprogram the H3K36 methylation landscape and contribute to tumorigenesis, in part through altering the expression of cancer-associated genes. PMID- 27229142 TI - A mechanism for the elimination of the female gamete centrosome in Drosophila melanogaster. AB - An important feature of fertilization is the asymmetric inheritance of centrioles. In most species it is the sperm that contributes the initial centriole, which builds the first centrosome that is essential for early development. However, given that centrioles are thought to be exceptionally stable structures, the mechanism behind centriole disappearance in the female germ line remains elusive and paradoxical. We elucidated a program for centriole maintenance in fruit flies, led by Polo kinase and the pericentriolar matrix (PCM): The PCM is down-regulated in the female germ line during oogenesis, which results in centriole loss. Perturbing this program prevents centriole loss, leading to abnormal meiotic and mitotic divisions, and thus to female sterility. This mechanism challenges the view that centrioles are intrinsically stable structures and reveals general functions for Polo kinase and the PCM in centriole maintenance. We propose that regulation of this maintenance program is essential for successful sexual reproduction and defines centriole life span in different tissues in homeostasis and disease, thereby shaping the cytoskeleton. PMID- 27229143 TI - Designer nanoscale DNA assemblies programmed from the top down. AB - Scaffolded DNA origami is a versatile means of synthesizing complex molecular architectures. However, the approach is limited by the need to forward-design specific Watson-Crick base pairing manually for any given target structure. Here, we report a general, top-down strategy to design nearly arbitrary DNA architectures autonomously based only on target shape. Objects are represented as closed surfaces rendered as polyhedral networks of parallel DNA duplexes, which enables complete DNA scaffold routing with a spanning tree algorithm. The asymmetric polymerase chain reaction is applied to produce stable, monodisperse assemblies with custom scaffold length and sequence that are verified structurally in three dimensions to be high fidelity by single-particle cryo electron microscopy. Their long-term stability in serum and low-salt buffer confirms their utility for biological as well as nonbiological applications. PMID- 27229144 TI - Whole-organism lineage tracing by combinatorial and cumulative genome editing. AB - Multicellular systems develop from single cells through distinct lineages. However, current lineage-tracing approaches scale poorly to whole, complex organisms. Here, we use genome editing to progressively introduce and accumulate diverse mutations in a DNA barcode over multiple rounds of cell division. The barcode, an array of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 target sites, marks cells and enables the elucidation of lineage relationships via the patterns of mutations shared between cells. In cell culture and zebrafish, we show that rates and patterns of editing are tunable and that thousands of lineage-informative barcode alleles can be generated. By sampling hundreds of thousands of cells from individual zebrafish, we find that most cells in adult organs derive from relatively few embryonic progenitors. In future analyses, genome editing of synthetic target arrays for lineage tracing (GESTALT) can be used to generate large-scale maps of cell lineage in multicellular systems for normal development and disease. PMID- 27229145 TI - Top-down cortical input during NREM sleep consolidates perceptual memory. AB - During tactile perception, long-range intracortical top-down axonal projections are essential for processing sensory information. Whether these projections regulate sleep-dependent long-term memory consolidation is unknown. We altered top-down inputs from higher-order cortex to sensory cortex during sleep and examined the consolidation of memories acquired earlier during awake texture perception. Mice learned novel textures and consolidated them during sleep. Within the first hour of non-rapid eye movement (NREM) sleep, optogenetic inhibition of top-down projecting axons from secondary motor cortex (M2) to primary somatosensory cortex (S1) impaired sleep-dependent reactivation of S1 neurons and memory consolidation. In NREM sleep and sleep-deprivation states, closed-loop asynchronous or synchronous M2-S1 coactivation, respectively, reduced or prolonged memory retention. Top-down cortical information flow in NREM sleep is thus required for perceptual memory consolidation. PMID- 27229146 TI - Hybrid management, organizational configuration, and medical professionalism: evidence from the establishment of a clinical directorate in Portugal. AB - BACKGROUND: The need of improving the governance of healthcare services has brought health professionals into management positions. However, both the processes and outcomes of this policy change highlight differences among the European countries. This article provides in-depth evidence that neither quantitative data nor cross-country comparisons have been able to provide regarding the influence of hybrids in the functioning of hospital organizations and impact on clinicians' autonomy and exposure to hybridization. METHODS: The study was designed to witness the process of institutional change from the inside and while that process was underway. It reports a case study carried out in a public hospital in Portugal when the establishment of a clinical directorate was being negotiated. Data collection comprises semi-structured interviews with general managers and surgeons complemented with observations. RESULTS: The clinical directorate under study illustrates a divisionalized professional bureaucracy model that combines features of professional bureaucracies and divisionalized forms. The hybrid manager is key to understand the extent to which practising clinicians are more accountable and to whom given that managerial tools of control have not been strengthened, and trust-based relations allow them to keep professional autonomy untouched. In sum, clinicians are allowed to profit from their activity and to perform autonomously from the hospital's board of directors. The advantageous conditions enjoyed by the clinical directorate intensify internal re-stratification in medicine, thus suggesting forms of divisionalized medical professionalism grounded in organizational dynamics. CONCLUSION: It is discussed the extent to which policy change to the governance of health organizations regarding the relationship between medicine and management is subject to specific constraints at the workplace level, thus conditioning the expected outcomes of policy setting. The study also highlights the role of hybrid managers in determining the extent to which practising professionals are more accountable to managerial criteria. The overall conclusion is that although medical and managerial values link to each other, clinicians reconfigure managerial criteria according to specific interests. Ultimately, medical autonomy and authority may be reinforced in organizational settings subject to NPM-driven reforms. PMID- 27229148 TI - A mechanistic approach to anti-nociceptive potential of Artemisia macrocephala Jacquem. AB - BACKGROUND: Artemisia macrocephala Jacquem (A. macrocephala), locally known as "Tarkha", is a perennial plant found abundantly in northern areas of Pakistan. It is widely used in traditional medicine to treat fever, pain, gastrointestinal disorders and diabetes. Till date, no published studies are available regarding the in-vivo antinociceptive potential of the crude extract and sub-fractions from the aerial parts of A. macrocephala. METHODS: Antinociceptive effects of the crude methanolic extract and its sub-fractions were assessed using experimental pain models, including chemical nociception induced by intraperitoneal acetic acid or subplantar formalin injection and thermal nociception like tail immersion test in-vivo. RESULTS: The administration of various doses of crude extract and its fractions showed a dose-dependent indomethacin like antinociceptive effect in acetic acid induced writhing, subplantar formalin injection animal model suggesting the involvement of central mechanism of pain inhibition. Moreover, the crude extract and sub-fractions, on tail flick model (thermal nociception) demonstrated the involvement of central mechanism and significantly increased the latency time to 66.54, 82.94 and 70.53 %. The antagonistic study proposed the possible involvement of opioid receptor using naloxone as non-selective antagonist. The pharmacologically active chloroform and ethyl acetate fractions were further subjected to column chromatography that lead to the isolation four compounds. These isolated compounds were then subjected to various spectroscopic techniques upon which they were confirmed to be one sterol and three flavonoid derivatives. These findings suggest that Artemisia macrocephala possesses peripheral and central analgesic potentials partially associated with opioid system that support its folkloric use for the management of pain. The isolated compounds are currently under investigation in our laboratory for analgesic activity and its possible mechanism of action. CONCLUSION: The results in this study provide evidences that A. macrocrphala has anticonciceptive effects and can be used for treatment of pain in traditional therapies. This study opens a new channel for isolation of analgesic compounds from the specie that is used traditionally for the management of pain. PMID- 27229147 TI - Connexins: substrates and regulators of autophagy. AB - Connexins mediate intercellular communication by assembling into hexameric channel complexes that act as hemichannels and gap junction channels. Most connexins are characterized by a very rapid turn-over in a variety of cell systems. The regulation of connexin turn-over by phosphorylation and ubiquitination events has been well documented. Moreover, different pathways have been implicated in connexin degradation, including proteasomal and lysosomal based pathways. Only recently, autophagy emerged as an important connexin degradation pathway for different connexin isoforms. As such, conditions well known to induce autophagy have an immediate impact on the connexin-expression levels. This is not only limited to experimental conditions but also several pathophysiological conditions associated with autophagy (dys)function affect connexin levels and their presence at the cell surface as gap junctions. Finally, connexins are not only substrates of autophagy but also emerge as regulators of the autophagy process. In particular, several connexin isoforms appear to recruit pre-autophagosomal autophagy-related proteins, including Atg16 and PI3K-complex components, to the plasma membrane, thereby limiting their availability and capacity for regulating autophagy. PMID- 27229149 TI - Lithium carbonate as a treatment for paliperidone extended-release-induced leukopenia and neutropenia in a patient with schizoaffective disorder; a case report. AB - BACKGROUND: Antipsychotic drug treatment can potentially lead to adverse events such as leukopenia and neutropenia. Although these events are rare, they represent serious and life-threatening hematological side effects. CASE PRESENTATION: We present a case study of a patient with schizoaffective disorder in a 50-year-old woman. We report a case of paliperidone extended-release (ER) induced leukopenia and neutropenia in a female patient with schizoaffective disorder. Initiating lithium carbonate treatment and decreasing the dose of valproic acid improved the observed leukopenia and neutropenia. This treatment did not influence psychotic symptoms. CONCLUSION: The combination of paliperidone ER and valproic acid induces increased paliperidone ER plasma levels. Lithium carbonate was successfully used to treat paliperidone ER-induced leukopenia and neutropenia. PMID- 27229150 TI - Protective effect of sildenafil on the genotoxicity and cytotoxicity in apolipoprotein E-deficient mice bone marrow cells. AB - BACKGROUND: The pharmacological inhibitor of phosphodiesterase 5 (PDE5), sildenafil, is a promising candidate for antioxidant therapy that can result in cardiovascular protection. In addition to its known effects on the cardiovascular system, hypercholesterolemia leads to increased oxidative stress and DNA damage in the bone marrow, which is a non-classical target organ of atherosclerosis. In the present study, we evaluate oxidative stress and assess the effect of genomic instability on cell cycle kinetics in atherosclerotic animals and determine if sildenafil reverses these detrimental effects in bone marrow cells. METHODS: Experiments were performed in male wild-type (WT) and apolipoprotein E knockout mice (apoE(-/-)) (9 weeks of age). apoE(-/-) mice were randomly distributed into the following 2 groups: sildenafil-treated (40 mg/kg/day for 3 weeks, n = 8) and vehicle-treated (n = 8), by oral gavage. After treatment, bone marrow cells were isolated to assess the production of superoxide anions and hydrogen peroxide, determine cell cycle kinetics and evaluate the presence of micronucleated cells. RESULTS: Sildenafil treatment reduced the cytoplasmic levels of superoxide anion (~95% decrease, p < 0.05) and decreased hydrogen peroxide (~30% decrease, p < 0.05). Moreover, we observed protective effects on the DNA of bone marrow cells, including normal cell cycling, decreased DNA fragmentation and a diminished frequency of micronucleated cells. CONCLUSION: Our data reveal that the excessive production of ROS in atherosclerotic mice overcome the DNA repair pathways in bone marrow cells. The novelty of the present study is that the administration of sildenafil reduced ROS to baseline levels and, consequently, reverted the DNA damage and its outcomes in bone marrow cells. PMID- 27229151 TI - Genome-wide resequencing of KRICE_CORE reveals their potential for future breeding, as well as functional and evolutionary studies in the post-genomic era. AB - BACKGROUND: Rice germplasm collections continue to grow in number and size around the world. Since maintaining and screening such massive resources remains challenging, it is important to establish practical methods to manage them. A core collection, by definition, refers to a subset of the entire population that preserves the majority of genetic diversity, enhancing the efficiency of germplasm utilization. RESULTS: Here, we report whole-genome resequencing of the 137 rice mini core collection or Korean rice core set (KRICE_CORE) that represents 25,604 rice germplasms deposited in the Korean genebank of the Rural Development Administration (RDA). We implemented the Illumina HiSeq 2000 and 2500 platform to produce short reads and then assembled those with 9.8 depths using Nipponbare as a reference. Comparisons of the sequences with the reference genome yielded more than 15 million (M) single nucleotide polymorphisms (SNPs) and 1.3 M INDELs. Phylogenetic and population analyses using 2,046,529 high-quality SNPs successfully assigned rice accessions to the relevant rice subgroups, suggesting that these SNPs capture evolutionary signatures that have accumulated in rice subpopulations. Furthermore, genome-wide association studies (GWAS) for four exemplary agronomic traits in the KRIC_CORE manifest the utility of KRICE_CORE; that is, identifying previously defined genes or novel genetic factors that potentially regulate important phenotypes. CONCLUSION: This study provides strong evidence that the size of KRICE_CORE is small but contains high genetic and functional diversity across the genome. Thus, our resequencing results will be useful for future breeding, as well as functional and evolutionary studies, in the post-genomic era. PMID- 27229152 TI - Case control feasibility study assessing the association between severity of coronary artery disease with Glutathione Peroxidase-1 (GPX-1) and GPX-1 polymorphism (Pro198Leu). AB - BACKGROUND: Glutathione peroxidase-1 (GPX-1) activity was reported to be useful marker for monitoring cardiovascular disease. However, accurate assessment of coronary artery disease (CAD) using GPX-1 polymorphism is limited for South Asian population. Present study aim to assess GPX-1activity and GPX-1 polymorphismin patients with coronary artery disease (CAD) who were confirmed with coronary angiography findings and in apparently healthy subjects. METHODS: Case control study was carried out with 85 patients (58 males and 27 females) 40-60 years of age confirmed as having CAD on coronary angiography findings and 85 age and sex matched healthy volunteers as controls. Blood samples were analyzed for erythrocyte GPX-1 activity and GPX-1 polymorphism in both groups and the severity of CAD was assessed using coronary angiography scoring system based on vessel, stenosis and extent score. RESULTS: Coronary angiography scores indicated that erythrocyteGPX-1 cutoff value of 23.9 U/gHb showed a high sensitivity and negative predictive value in ruling out major vessel disease. The GPX-1 Pro198Leu (CT) polymorphism was higher in patients with CAD (25.3 %) when compared to controls (10.7 %). Pro198Leu (CT) genotype showed a 2.84 fold risk for CAD [odds ratio 2.84 (95 % CI 1.15-6.98), p = 0.019]. CONCLUSION: Coronary angiography findings indicated that individuals possessing Pro198Leu (CT) polymorphism were found to be associated with low erythrocyte GPX-1 activity and increased susceptibility for CAD. PMID- 27229153 TI - A review of approaches to improve participation of culturally and linguistically diverse populations in clinical trials. AB - The under-representation of culturally and linguistically diverse participants in clinical trials is an ongoing concern for medical researchers and the community. The aim of this review is to examine the complex issue of recruiting culturally and linguistically diverse (CALD) older people to medical research and to examine responses to these issues. The review focuses on (1) trends in the existing literature on barriers to and strategies for recruiting CALD and older people to clinical research, (2) issues with informed consent for CALD populations, and (3) the efficacy of innovative approaches, including approaches incorporating multimedia in research and consent processes. The literature indicates that predominant barriers to greater involvement of CALD patients in clinical trials are communication, including literacy and health literacy considerations; English language competence; and cultural factors in the research setting such as mistrust of consent processes, as well as considerable practical and logistical barriers, including mobility considerations. Some evidence exists that incorporating multimedia resources into the informed consent process can improve patient understanding and is preferred by patients, yet these findings are inconclusive. A multi-methodological approach, including the use of culturally and linguistically sensitive multimedia tools, may help address the issue of low inclusion of CALD groups in clinical research. Researcher education needs to be taken into account to address preconceptions about CALD resistance to research participation and to raise awareness of cultural concerns in regard to research participation. PMID- 27229154 TI - Accidents and undetermined deaths: re-evaluation of nationwide samples from the Scandinavian countries. AB - BACKGROUND: National mortality statistics should be comparable between countries that use the World Health Organization's International Classification of Diseases. Distinguishing between manners of death, especially suicides and accidents, is a challenge. Knowledge about accidents is important in prevention of both accidents and suicides. The aim of the present study was to assess the reliability of classifying deaths as accidents and undetermined manner of deaths in the three Scandinavian countries and to compare cross-national differences. METHODS: The cause of death registers in Norway, Sweden and Denmark provided data from 2008 for samples of 600 deaths from each country, of which 200 were registered as suicides, 200 as accidents or undetermined manner of deaths and 200 as natural deaths. The information given to the eight experts was identical to the information used by the Cause of Death Register. This included death certificates, and if available external post-mortem examinations, forensic autopsy reports and police reports. RESULTS: In total, 69 % (Sweden and Norway) and 78 % (Denmark) of deaths registered in the official mortality statistics as accidents were confirmed by the experts. In the majority of the cases where disagreement was seen, the experts reclassified accidents to undetermined manner of death, in 26, 25 and 19 % of cases, respectively. Few cases were reclassified as suicides or natural deaths. Among the extracted accidents, the experts agreed least with the official mortality statistics concerning drowning and poisoning accidents. They also reported most uncertainty in these categories of accidents. In a second re-evaluation, where more information was made available, the Norwegian psychiatrist and forensic pathologist increased their agreement with the official mortality statistics from 76 to 87 %, and from 85 to 88 %, respectively, regarding the Norwegian and Swedish datasets. Among the extracted undetermined deaths in the Swedish dataset, the two experts reclassified 22 and 51 %, respectively, to accidents. CONCLUSION: There was moderate agreement in reclassification of accidents between the official mortality statistics and the experts. In the majority of cases where there was disagreement, accidents were reclassified as undetermined manner of death, and only a small proportion as suicides. PMID- 27229155 TI - The Effect of Stevia on the Chicken Embryo Heart. AB - BACKGROUND: Stevioside is one of the most important food additives that has become well known for its sweetness. The aim of this study was to evaluate the impact of Stevioside on the heart. METHODS: 4-day-old embryonated chickens eggs were inoculated with Stevioside and kept until hatching. Shortly after, the heart tissue samples were taken to examine organ Oxidative stresses by measuring Malondialdehyde (MDA) and glutathione (GSH) levels, ferric reducing /antioxidant power (FRAP) and cupric ion reducing assay (CUPRIC). RESULTS: There was no significant difference in glutathione level, lipid peroxidation, FRAP, and cupric assay. CONCLUSION: It was suggested that stevioside did not cause marked damages to heart tissues in chicken embryo model. PMID- 27229156 TI - Brain perfusion imaging with voxel-based analysis in secondary progressive multiple sclerosis patients with a moderate to severe stage of disease: a boon for the workforce. AB - BACKGROUND: The present study was carried out to evaluate cerebral perfusion in multiple sclerosis (MS) patients with a moderate to severe stage of disease. Some patients underwent hyperbaric oxygen therapy (HBOT) and brain perfusion between before and after that was compared. METHODS: We retrospectively reviewed 25 secondary progressive (SP)-MS patients from the hospital database. Neurological disability evaluated by Expanded Disability Status Scale Score (EDSS). Brain perfusion was performed by (99 m) Tc-labeled bicisate (ECD) brain SPECT and the data were compared using statistical parametric mapping (SPM). In total, 16 patients underwent HBOT. Before HBOT and at the end of 20 sessions of oxygen treatment, 99mTc-ECD brain perfusion single photon emission computed tomography (SPECT) was performed again then the results were evaluated and compared. Brain perfusion was performed by (99 m) Tc-labeled bicisate (ECD) brain SPECT and the data were compared using statistical parametric mapping (SPM). RESULTS: A total of 25 SP-MS patients, 14 females (56 %) and 11 males (44 %) with a mean age of 38.92 +/- 11.28 years included in the study. The mean disease duration was 8.70 +/- 5.30 years. Of the 25 patients, 2 (8 %) had a normal SPECT and 23 (92 %) had abnormal brain perfusion SPECT studies. The study showed a significant association between severity of perfusion impairment with disease duration and also with EDSS (P <0.05). There was a significant improvement in pre- and post treatment perfusion scans (P <0.05), but this did not demonstrate a significant improvement in the clinical subjective and objective evaluation of patients (P >0.05). CONCLUSIONS: This study depicted decreased cerebral perfusion in SP-MS patients with a moderate to severe disability score and its association with clinical parameters. Because of its accessibility, rather low price, practical ease, and being objective quantitative information, brain perfusion SPECT can be complementing to other diagnostic modalities such as MRI and clinical examinations in disease surveillance and monitoring. The literature on this important issue is extremely scarce, and follow up studies are required to assess these preliminary results. PMID- 27229158 TI - Evidence for the role of microRNA 374b in acquired cisplatin resistance in pancreatic cancer cells. AB - Recent evidence has implicated microRNAs (miRNAs) as potentially significant players in the acquisition of cancer-drug resistance in pancreatic and other cancers. To evaluate the potential contribution of miRNAs in acquired resistance to cisplatin in pancreatic cancer, we compared levels of more than 2000 human miRNAs in a cisplatin-resistant cell line (BxPC3-R) derived from parental (BxPC3) cells by step-wise exposure to increasing concentrations of the drug over more than 20 passages. The acquired drug resistance was accompanied by significant changes in the expression of 57 miRNAs, of which 23 were downregulated and 34 were upregulated. Employing a hidden Markov model (HMM) algorithm, we identified downregulation of miR-374b as likely being directly involved in acquisition of the drug-resistant phenotype. Consistent with this prediction, ectopic overexpression of miR-374b in the resistant BxPC3-R cells restored cisplatin sensitivity to levels approaching those displayed by the BxPC3 parental cells. The results are consistent with a growing body of evidence implicating miRNAs in acquired cancer-drug resistance and with the potential therapeutic value of these small regulatory RNAs in blocking and/or reversing the process. PMID- 27229160 TI - Multiscale architectured materials with composition and grain size gradients manufactured using high-pressure torsion. AB - The concept of multiscale architectured materials is established using composition and grain size gradients. Composition-gradient nanostructured materials are produced from coarse grained interstitial free steels via carburization and high-pressure torsion. Quantitative analyses of the dislocation density using X-ray diffraction and microstructural studies clearly demonstrate the gradients of the dislocation density and grain size. The mechanical properties of the gradient materials are compared with homogeneous nanostructured carbon steel without a composition gradient in an effort to investigate the gradient effect. Based on the above observations, the potential of multiscale architecturing to open a new material property is discussed. PMID- 27229159 TI - Evaluation of CD46 re-targeted adenoviral vectors for clinical ovarian cancer intraperitoneal therapy. AB - Ovarian cancer accounts for >140 000 deaths globally each year. Typically, disease is asymptomatic until an advanced, incurable stage. Although response to cytotoxic chemotherapy is frequently observed, resistance to conventional platinum-based therapies develop rapidly. Improved treatments are therefore urgently required. Virotherapy offers great potential for ovarian cancer, where the application of local, intraperitoneal delivery circumvents some of the limitations of intravenous strategies. To develop effective, adenovirus (Ad) based platforms for ovarian cancer, we profiled the fluid and cellular components of patient ascites for factors known to influence adenoviral transduction. Levels of factor X (FX) and neutralizing antibodies (nAbs) in ascitic fluid were quantified and tumor cells were assessed for the expression of coxsackie virus and adenovirus receptor (CAR) and CD46. We show that clinical ascites contains significant levels of FX but consistently high CD46 expression. We therefore evaluated in vitro the relative transduction of epithelial ovarian cancers (EOCs) by Ad5 (via CAR) and Ad5 pseudotyped with the fiber of Ad35 (Ad5T*F35++) via CD46. Ad5T*F35++ achieved significantly increased transduction in comparison to Ad5 (P<0.001), independent of FX and nAb levels. We therefore propose selective transduction of CD46 over-expressing EOCs using re-targeted, Ad35-pseudotyped Ad vectors may represent a promising virotherapy for ovarian cancer. PMID- 27229157 TI - DNA methylation analysis of paediatric low-grade astrocytomas identifies a tumour specific hypomethylation signature in pilocytic astrocytomas. AB - Low-grade gliomas (LGGs) account for about a third of all brain tumours in children. We conducted a detailed study of DNA methylation and gene expression to improve our understanding of the biology of pilocytic and diffuse astrocytomas. Pilocytic astrocytomas were found to have a distinctive signature at 315 CpG sites, of which 312 were hypomethylated and 3 were hypermethylated. Genomic analysis revealed that 182 of these sites are within annotated enhancers. The signature was not present in diffuse astrocytomas, or in published profiles of other brain tumours and normal brain tissue. The AP-1 transcription factor was predicted to bind within 200 bp of a subset of the 315 differentially methylated CpG sites; the AP-1 factors, FOS and FOSL1 were found to be up-regulated in pilocytic astrocytomas. We also analysed splice variants of the AP-1 target gene, CCND1, which encodes cell cycle regulator cyclin D1. CCND1a was found to be highly expressed in both pilocytic and diffuse astrocytomas, but diffuse astrocytomas have far higher expression of the oncogenic variant, CCND1b. These findings highlight novel genetic and epigenetic differences between pilocytic and diffuse astrocytoma, in addition to well-described alterations involving BRAF, MYB and FGFR1. PMID- 27229162 TI - Good mid- to long-term THA outcomes with a modified cementless rectangular biconical stem design. AB - PURPOSE: Second- and third-generation cementless Zweymuller stems have achieved good long-term outcomes in total hip arthroplasty (THA). The PPF cementless proximal press-fit femoral stem (Biomet Inc.) is based on the Zweymuller stem, with some prominent design differences. This study was designed to assess its performance in terms of survivorship, clinical function, and radiographic outcomes. METHODS: We retrospectively analysed 250 patients (303 hips) who underwent THA between 1998 and 2011. Patients attended a follow-up visit a mean 10.9 +/- 2.6 years after the procedure. All patients underwent radiographic examination and were clinically assessed for Forgotten Joint Score (FJS) and pain visual analogue scale (VAS). Survivorship was calculated using Kaplan-Meier analysis. RESULTS: Clinical data were available for 142 patients (192 hips) and radiographic data for 79 patients (109 hips). Stem survival was 99.1% (95% confidence interval [CI] 96.6%-99.8%) at 10 years and 95.6% (95% CI 96.6%-99.8%) at 15 years. The median postoperative FJS was 91 (interquartile range [IQR], 75 100). The median VAS score was 0 (IQR, 0-2). Radiolucent lines were observed in 47 hips (43.1%). 25 hips (22.9%) had Grade I ossification, 17 (15.6%) Grade II, and 2 (1.8%) Grade III. 12 hips (11.0%) had osteolysis in at least 1 femoral zone. CONCLUSIONS: The cementless proximal press-fit femoral stem was associated with good mid- to long-term survival and functional outcomes. The current design can be considered equivalent to the second- and third-generation Zweymuller stems. PMID- 27229161 TI - Trabecular TitaniumTM cups and augments in revision total hip arthroplasty: clinical results, radiology and survival outcomes. AB - BACKGROUND: Large acetabular defects remain a challenge in hip revision arthroplasty. Experience with Trabecular TitaniumTM (TT) cups (Limacorporate S.p.a.) has not been widely reported. Therefore, we assessed the survivorship and clinical and radiological outcomes of patients receiving TT cups, with or without supplementary trabecular titanium hemispherical modules for acetabular reconstruction, in primary and revision total hip arthroplasty (THA). METHODS: Between January 2009 and July 2014, we performed 67 revisions and 5 primary THAs using TT cups in 69 patients. To achieve stability and/or restore the hip's centre of rotation, hemispherical modules were used in 17 cases based on preoperative templating and/or intraoperative findings. Mean follow-up was 30.5 months. Acetabular bone defects were classified according to the Paprosky classification. Survivorship, functional outcomes (Merle d'Aubigne) and radiological outcomes were analysed. RESULTS: 8 patients underwent cup revision: 2 for loosening, 3 for infection, and 3 for hip dislocation. The remaining cases did not present radiological signs of loosening. None of the cases with Paprosky type I classifications needed revision, while 4 with type II and 4 with type III needed revision (p = 0.028). The respective mean values for pain, walking, and range of motion (Merle d'Aubigne scores +/- standard deviation) were 3.6 +/- 1.4, 3.7 +/- 0.7, and 3.8 +/- 0.6 preoperatively, and 5.7 +/- 0.7, 5.3 +/- 0.7, and 5.6 +/- 0.7 at the latest follow-up (p<0.001). CONCLUSIONS: In the short term, results with TT cups appear to be encouraging, with satisfactory survival rates for both simple and complex cases. PMID- 27229163 TI - Neutrophil to lymphocyte ratio may be a predictive marker of poor prognosis in Legg-Calve-Perthes disease. AB - BACKGROUND: Legg-Calve-Perthes disease (LCPD) is the idiopathic avascular necrosis of the femoral head in childhood. The pathologic changes seen in the femoral head are likely a result of vascular factors. Blood neutrophil to lymphocyte (N/L) ratio is a simple marker of subclinical inflammation. This study aims to to analyse the predictive ability of N/L ratio for the prognosis in LCPD patients. METHODS: Patients who had been diagnosed as LCPD from 2008 to 2014 were investigated retrospectively and 40 LCPD patients (33 male and 7 female) and 25 healthy age and sex-matched children (controls) were included in the study. LCPD patients were divided into 2 groups according to expected prognosis (good prognosis expected Herring A and B patients as Group I and poor prognosis expected Herring B-C and C patients as Group II) and healthy children (control) were included in Group III. All the patients' hematological markers were analysed. RESULTS: Mean age was 7.1 +/- 2.0 years in group I (4.9-12 years), 8.3 +/- 2.2 years (4-12.5 years) in group II and 7.8 +/- 1.3 years (6-12 years) in group III. Mean values for Groups I, II and III for neutrophil to lymphocyte (N/L) ratio were 1.13 +/- 0.65, 1.75 +/- 0.95, 1.08 +/- 0.37, respectively. The mean neutrophil to lymphocyte (N/L) ratio of Group II was higher than the other 2 groups (p = 0.003). CONCLUSIONS: N/L ratio may give us information about the natural course of LCPD and may be used as independent predictor of prognosis in patients with LCPD. PMID- 27229164 TI - Patient-reported outcomes in cemented and uncemented total hip replacements. AB - INTRODUCTION: Data from national registries have favored the use of cemented fixation in total hip replacement (THR) while other reports show no significant differences in implant survival between cemented and uncemented fixation using modern implants. It is important to investigate whether the method of fixation itself may affect patient-reported outcomes. Hence, this study sought to analyse if patient-reported outcomes measures (PROMs) differ depending on the type of fixation. METHODS: Data was used from the follow-up programme of the Swedish Hip Arthroplasty Register which comprises the EQ-5D, a visual analogue scale (VAS) on hip pain, as well as a VAS addressing satisfaction with the outcome of the hip replacement.3,118 patients with uncemented THR due to primary osteoarthritis performed from 2002 to 2011 with complete 1-year follow-up were included in the study. A control group of patients with cemented THR (n = 3,118) were selected by matching on age, gender, Charnley class, and preoperative health-related quality of life. RESULTS: After adjusting for age, gender, Charnley class, and baseline PROMs, multivariate linear regression analyses showed that uncemented fixation is associated with a larger improvement in EQ-5D index (B = 0.03, 95% CI 0.019, 0.041), EQ VAS (B = 2.58, 95% CI 1.65, 3.51), greater pain relief (B = -2.68, 95% CI -3.54, -1.82) and superior patient satisfaction (B = -2.56, 95% CI -3.52, 1.60) (all p<0.001). DISCUSSIONS: This study demonstrates that uncemented fixation is associated with better patient-reported outcomes. Factors unrelated to implant fixation, such as performance or selection bias, may also contribute to the difference. PMID- 27229165 TI - The effect of unilateral osteoarthritis of the hip on postural balance disorders. AB - BACKGROUND: Postural stability is of great importance because imbalances and muscle weakness are significant risk factors for falls experienced by the elderly. Hip arthrosis, which causes pain and gait disorders that affect balance control, is common in the ageing population. AIM: The aim of this study was to assess postural stability in patients with unilateral hip arthrosis before total hip arthroplasty. METHODS: The study population consisted of 52 patients with hip arthrosis (study group) and 47 subjects with no history of clinical symptoms of hip pain. The groups did not differ statistically in terms of age and BMI. Static balance was assessed by conducting a quantitative analysis of balance reaction parameters in a quiet standing position with the eyes open and closed. RESULTS: Analysis of the collected data revealed numerous statistically significant differences between patients with unilateral hip arthrosis before total hip arthoplasty and the asymptomatic group for parameters tested with eyes closed (p<0.05). We observed higher values of total length of centre of pressure (COP), sway path (SP), length of COP path in the medial-lateral plane (SPML), maximal amplitude between the 2 most distant points in the medial-lateral plane (MaxML), mean COP velocity (MV), and mean COP velocity in medial-lateral (MVML) in the study group. PMID- 27229166 TI - Acetabuloplasty at the anatomic centre for treating Crowe class III and IV developmental hip dysplasia: a case series. AB - INTRODUCTION: Total hip replacement in patients with developmental dysplasia of the hip (DDH) is a difficult technical procedure for surgeons to perform because of the potential for these patients to have severe anomalies in their bones and soft tissues. MATERIALS AND METHODS: We performed acetabuloplasty in 54 hips from 44 patients by reaming the posterior wall of the native acetabulum and medialising the acetabular component to restore the anatomic centre of hip rotation using a small cup without bone grafting. Median time to post-surgery follow-up was 5 (range 2-14) years. RESULTS: Prosthetic survival rates in patients after 2 and 5 years post hip replacement were 93% (50/54) and 89% (48/54), respectively. 4 patients required early revision because of malposition and instability of the acetabular cup. 3 patients with Crowe type IV dislocations had transient sciatic nerve palsy and 3 had deep vein thrombosis. CONCLUSIONS: Placement of the acetabular shell using posterior bone stock to provide normal hip rotation is a successful alternative technique for acetabuloplasty in patients with DDH. PMID- 27229167 TI - Late correction of neck deformity in healed severe slipped capital femoral epiphysis: short-term clinical outcomes. AB - PURPOSE: Contemporary methods for the management of neck deformity following a healed severe slipped capital femoral epiphysis (SCFE) include subcapital neck osteotomy. METHODS: 18 patients with chronic severe SCFE in the oblique plane (mean slip angle = 70 degrees ) constituted the study group. 6 patients with an open physis underwent modified Dunn capital realignment and 12 patients with a closed physis underwent surgical dislocation with a corrective neck osteotomy. 10 patients already had an in-situ pinning. RESULTS: The mean follow-up was 4.5 years (3-6 years). The mean preoperative modified Harris Hip Score (mHHS) and nonarthritic hip score (NAHS) were 24 and 40 respectively, followed by a score of 89 and 92 respectively at the last follow-up (p = 0.0002). Radiologically, all the parameters showed a significant correction. The mean pre- and postoperative values of alpha angle were 79.8 and 34.5 respectively (p = 0.0002); AP slip angle being 36.7 and 14.8 (p = 0.002); lateral slip angle being 54.2 and 13.6 (p = 0.0002); oblique plane slip angle being 70.7 and 20.8 (p = 0.0002) and centre trochanter distance being -6.9 and 1.2 (p = 0.002). The major complications seen were nonunion of the neck osteotomy (n = 1/12) and chondrolysis (n = 1/6) in the modified Dunn's group. The overall complication rate was 11%. There was no statistically significant difference in outcome between the 2 groups clinically and radiologically. CONCLUSIONS: Femoral neck osteotomy is a potentially rewarding technique to correct severe neck deformities and restoring hip function in the short term. PMID- 27229168 TI - Nonunion paediatric femoral neck fracture treatment without open reduction. AB - OBJECTIVES: Fractures of the proximal femur account for less than 1% of all children's fractures. Because of this, most orthopaedic surgeons lack enough experience in treating them. This adds to the rather high incidence of complications especially nonunion. At the time of this review there is no consensus on which method of treatment of the nonunion is the best. The objective of this study is to present our method of treatment to correct the nonunion without open reduction of the nonunion sites. METHOD: 9 children with nonunion of the proximal femur with an average age of 10.2 years (2-14 years old) were included in the study. There were 7 males and 2 females. All of them underwent at least 1 operation to treat the initial fractures and the nonunion. The nonunion in all these 9 cases was treated with valgus intertrochanteric osteotomy without open reduction of the nonunion site. The healing time of the nonunion, the postoperative neck-shaft angle and the functional outcome were evaluated. RESULTS: All the nonunion cases had coxa vara and had bone resorption of the femoral neck with x-ray evidences of avascular necrosis (AVN). Ratliff classification was used to classify the AVN, Ratliff type 3 was found in 4 cases, Ratliff 2 in 1 case and Ratliff 1 in 4 cases. Patients were followed for an average of 68 (range 36-156) months. All patients had x-ray evidence of solid union of the nonunion in an average time of 15.4 (range 13-18) weeks and union of the osteotomy sites within10.6 (range 9-12) weeks. The postoperative neck-shaft angle averaged 135 degrees (range 125 degrees -150 degrees ) compared to 98 degrees before the surgery. The increase in the amount of neck-shaft angle was statistically significant (p<0.001). Using Harris Hip Score, 2 patients were graded as excellent, 3 patients were graded as good and 4 patients were graded as fair. Harris Hip Score was significantly improved compared to the preoperative status (p<0.001). CONCLUSIONS: Nonunion paediatric femoral neck fracture treatment could be successfully treated without open reduction by using valgus intertrochanteric osteotomy. All patients obtained union of the nonunion site and the osteotomy site in this study. Harris Hip Score showed significant improvement. This technique can be used to treat nonunion with associated coxa vara, bone resorption and AVN with satisfactory results even in cases who had received several operations before. PMID- 27229169 TI - Outcome after cementless total hip arthroplasty for arthritic hip in patients with residual poliomyelitis: a case series. AB - PURPOSE: In this case series, we investigated the outcome of cementless total hip arthroplasty (THA) for advanced hip osteoarthritis in patients with residual poliomyelitis to evaluate its clinical usefulness for these patients. METHODS: 11 unilateral cementless primary THA were performed to arthritic hips in patients with residual poliomyelitis. 7 were in paralytic and 4 were in nonparalytic limbs. The mean follow-up duration was 79.9 months. Retrospective clinical evaluations with various scores and radiological evaluations were made. RESULTS: Harris Hip Score, Western Ontario and McMaster Universities Arthritis Index (WOMAC) and Short-form (SF)-36 physical scales were significantly improved after the surgery. However, UCLA activity score and SF-36 mental scale were not. Because of remaining leg length discrepancies, all but 1 noted a residual limp. In nonparalytic hip, functional acetabular cup inclination during weight bearing significantly increased from installed inclination. Other than 1 case of posterior dislocation, no complications were observed. CONCLUSIONS: Although the overall result itself is excellent, THA for these patients cannot improve limp, physical activity and mental status. Surgeons should be aware of the change of the inclination of acetabular cup during mobilisation, especially for THA in contralateral hip. PMID- 27229170 TI - A new stem extractor with specific multigrip pliers for revision hip arthroplasty - a biomechanical investigation. AB - INTRODUCTION: It was the aim of this biomechanical study to test a new extractor with 2 specific multigrip pliers on different stem designs and to compare it to a commonly used prefabricated one (UnMod). METHODS: The new extractor comprises 2 specific multigrip pliers, 1 neck-pliers and 1 shoulder-pliers. The tests were performed on a tapered and a nontapered neck stem. They were fixed in specific moulds allowing torque adjustability. The first endpoint was maximum grip with the extractors being tested up to 70 hits or failure (pliers off) in maximally fixed stems. The second endpoint was hits/attempts until stem extraction or failure (pliers off > than 5 times) in moderately fixed stems. RESULTS: The best grip on the tapered neck was achieved by the neck-pliers without failure, whereas the others failed consistently (shoulder-pliers: mean 42.9 hits, SD: 3.5/UnMod: 40.1, SD: 5.4; p<0.01). The shoulder-pliers had the best grip on the nontapered neck withstanding more hits (11.9, SD: 1.9) than the others (neck-pliers: 4.8, SD: 1.7/UnMod: 2.8, SD 1.0; p<0.01). None of the devices failed to extract the tapered neck (UnMod best: 4, SD: 1.3). The shoulder-pliers were able to extract the nontapered neck in 60% of the tests, whereas the others failed 100%. CONCLUSIONS: The new extractor with specific pliers for neck/shoulder grip seems to be a valuable tool for stem extraction in revision hip arthroplasty. Compared to UnMod, the neck-pliers showed better grip on the tapered neck and the shoulder pliers performed the best on the nontapered neck. PMID- 27229171 TI - Osteopontin as a biochemical marker and severity indicator for idiopathic hip osteoarthritis. AB - INTRODUCTION: A diagnostic evaluation of the severity and progression of hip osteoarthritis (OA) using biochemical markers is lacking in the current medical literature. Osteopontin (OPN) has been proved to correlate with the progression and severity of knee OA. Therefore, the examination of plasma OPN levels in patients with idiopathic hip OA and its correlation with disease severity and progression was necessary. METHODS: Our study included 21 patients displaying symptomatic severe idiopathic hip OA; the diagnosis of the disease was based on the checklist of the American College of Rheumatology and the severity was evaluated according to the K-L grading (Kellgran and Lawrence score). RESULTS: 14 patients showed radiological changes according K-L grade 3 (66.66%), and 7 patients showed radiological changes according K-L grade 4 (33.33%). We observed a highly statistically significant increase of plasma OPN levels in comparison with normal referenced values, the cut off value for differentiating between normal people and patients with hip OA was 193.6 ng/ml. Furthermore, the mean of plasma OPN levels in idiopathic hip osteoarthritis patients with K-L grade 4 (362.51 +/- 83.31 ng/mL) was greater than those with K-L grade 3 (283.41 +/- 56.31 ng/mL), the difference being statistically significant. CONCLUSIONS: plasma OPN levels are increased in idiopathic hip OA and are correlated with the severity of the disease. PMID- 27229172 TI - Transcriptome analysis of human ageing in male skin shows mid-life period of variability and central role of NF-kappaB. AB - Age is well-known to be a significant factor in both disease pathology and response to treatment, yet the molecular changes that occur with age in humans remain ill-defined. Here, using transcriptome profiling of healthy human male skin, we demonstrate that there is a period of significantly elevated, transcriptome-wide expression changes occurring predominantly in middle age. Both pre and post this period, the transcriptome appears to undergo much smaller, linear changes with increasing age. Functional analysis of the transient changes in middle age suggest a period of heightened metabolic activity and cellular damage associated with NF-kappa-B and TNF signaling pathways. Through meta analysis we also show the presence of global, tissue independent linear transcriptome changes with age which appear to be regulated by NF-kappa-B. These results suggest that aging in human skin is associated with a critical mid-life period with widespread transcriptome changes, both preceded and proceeded by a relatively steady rate of linear change in the transcriptome. The data provides insight into molecular changes associated with normal aging and will help to better understand the increasingly important pathological changes associated with aging. PMID- 27229173 TI - Haem-assisted dityrosine-cross-linking of fibrinogen under non-thermal plasma exposure: one important mechanism of facilitated blood coagulation. AB - Although blood coagulation facilitated by non-thermal plasma has been reported several years ago, the insight to the involved mechanisms is still rather limited. In this work, we report our discovery of a new mechanism for the haem promoted blood-coagulation caused by non-thermal plasma treatment. The reason for the haem role is due to that its oxidized form, namely, hematin, can promote the dityrosine cross-linking of fibrinogen, the most important coagulation protein, to form a membrane-like layer on the surface of the treated blood with plasma exposure. Both haem and non-thermal-plasma generated hydrogen peroxide are requisite for the cross-linking process. We confirmed that fibrinogen can coordinate with the haem iron to form a protein-haem complex which shows pseudo peroxidase activity, and in the presence of hydrogen peroxide, the complex can induce the dityrosine formation between fibrinogen molecules, leading to the fibrin network necessary for the blood coagulation. Understanding of such an underlying mechanism can be useful to guide more efficient application of non thermal plasma in the management of hemostasis, thrombosis and etc. PMID- 27229174 TI - Enhanced Flexible Tubular Microelectrode with Conducting Polymer for Multi Functional Implantable Tissue-Machine Interface. AB - Implantable biomedical microdevices enable the restoration of body function and improvement of health condition. As the interface between artificial machines and natural tissue, various kinds of microelectrodes with high density and tiny size were developed to undertake precise and complex medical tasks through electrical stimulation and electrophysiological recording. However, if only the electrical interaction existed between electrodes and muscle or nerve tissue without nutrition factor delivery, it would eventually lead to a significant symptom of denervation-induced skeletal muscle atrophy. In this paper, we developed a novel flexible tubular microelectrode integrated with fluidic drug delivery channel for dynamic tissue implant. First, the whole microelectrode was made of biocompatible polymers, which could avoid the drawbacks of the stiff microelectrodes that are easy to be broken and damage tissue. Moreover, the microelectrode sites were circumferentially distributed on the surface of polymer microtube in three dimensions, which would be beneficial to the spatial selectivity. Finally, the in vivo results confirmed that our implantable tubular microelectrodes were suitable for dynamic electrophysiological recording and simultaneous fluidic drug delivery, and the electrode performance was further enhanced by the conducting polymer modification. PMID- 27229175 TI - Pharmacokinetically guided algorithm of 5-fluorouracil dosing, a reliable strategy of precision chemotherapy for solid tumors: a meta-analysis. AB - Precision medicine characterizes a new era of cancer care and provides each patient with the right drug at the right dose and time. However, the practice of precision dosing is hampered by a lack of smart dosing algorithms. A pharmacokinetically guided (PKG) dosing algorithm is considered to be the leading strategy for precision chemotherapy, although the effects of PKG dosing are not completely confirmed. Hence, we conducted a meta-analysis to evaluate the effects of the PKG algorithm of 5-fluorouracil (5-FU) dosing on patients with solid tumors. A comprehensive retrieval was performed to identify all of the prospective controlled studies that compared the body surface area (BSA)-based algorithm with the PKG algorithm of 5-FU in patients with solid tumors. Overall, four studies with 504 patients were included. The PKG algorithm significantly improved the objective response rate of 5-FU-based chemotherapy compared with the BSA-based algorithm. Furthermore, PKG dosing markedly decreased the risk of total grade 3/4 adverse drug reactions, especially those related to hematological toxicity. Overall, the PKG algorithm may serve as a reliable strategy for individualized dosing of 5-FU. PMID- 27229176 TI - Ciguatoxin reduces regenerative capacity of axotomized peripheral neurons and delays functional recovery in pre-exposed mice after peripheral nerve injury. AB - Ciguatera fish poisoning (CFP) results from consumption of tropical reef fish containing ciguatoxins (CTXs). Pacific (P)-CTX-1 is among the most potent known CTXs and the predominant source of CFP in the endemic region responsible for the majority of neurological symptoms in patients. Chronic and persistent neurological symptoms occur in some CFP patients, which often result in incomplete functional recovery for years. However, the direct effects of exposure to CTXs remain largely unknown. In present study, we exposed mice to CTX purified from ciguatera fish sourced from the Pacific region. P-CTX-1 was detected in peripheral nerves within hours and persisted for two months after exposure. P-CTX 1 inhibited axonal regrowth from axotomized peripheral neurons in culture. P-CTX 1 exposure reduced motor function in mice within the first two weeks of exposure before returning to baseline levels. These pre-exposed animals exhibited delayed sensory and motor functional recovery, and irreversible motor deficits after peripheral nerve injury in which formation of functional synapses was impaired. These findings are consistent with reduced muscle function, as assessed by electromyography recordings. Our study provides strong evidence that the persistence of P-CTX-1 in peripheral nerves reduces the intrinsic growth capacity of peripheral neurons, resulting in delayed functional recovery after injury. PMID- 27229178 TI - Efficacy and safety of sitagliptin/metformin fixed-dose combination compared with glimepiride in patients with type 2 diabetes: A multicenter randomized double blind study. AB - BACKGROUND: Early initiation of combination therapy using antihyperglycemic agents is recommended for treating type 2 diabetes (T2D). The present multicenter double-blind randomized parallel-group study examined the efficacy and safety of a sitagliptin and metformin fixed-dose combination (Sita/Met) compared with glimepiride in T2D patients as initial treatment. METHODS: Type 2 diabetes patients (aged >=18 years) were randomized to Sita/Met or glimepiride for 30 weeks after a wash-off run-in period. The primary endpoint was change from baseline (CFB) in HbA1c. Secondary endpoints included the proportion of patients achieving target goal (HbA1c < 7.0 % [53 mmol/mol]) and CFB in fasting plasma glucose (FPG). Safety assessments comprised weight gain from baseline and the incidence of adverse events (AEs). RESULTS: In total, 292 patients were randomized to Sita/Met (n = 147) or glimepiride (n = 145). After 30 weeks, Sita/Met demonstrated superiority over glimepiride in reducing HbA1c (-1.49 % vs 0.71 %, respectively; between-group difference - 0.78 %; P < 0.001). A significantly higher proportion of patients achieved the target goal with Sita/Met (81.2 %) than with glimepiride (40.1 %; P < 0.001). Greater reduction in FPG occurred with Sita/Met than with glimepiride (least-squares mean difference - 23.5 mg/dL; P < 0.001). Both drugs were generally well tolerated. Hypoglycemia events and weight gain were significantly lower in patients with Sita/Met than with glimepiride (5.5 % vs 20.1 % and -0.83 vs +0.90 kg, respectively; both P < 0.001). No serious drug-related AEs or deaths were reported. CONCLUSIONS: Compared with glimepiride, Sita/Met as an initial treatment led to significantly greater improvements in glycemic control and body weight changes, with a lower incidence of hypoglycemia, over 30 weeks. PMID- 27229177 TI - NAMPT knockdown attenuates atherosclerosis and promotes reverse cholesterol transport in ApoE KO mice with high-fat-induced insulin resistance. AB - NAMPT has been suggested association with atherosclerosis and insulin resistance. However, the impact of NAMPT on atherosclerosis remained unknown. Therefore, the objective of this study was to use a NAMPT loss-of-function approach to investigate the effect of NAMPT on atherosclerosis in hypercholesterolemic mice. We demonstrated that a specific NAMPT knockdown increased plasma HDL-C levels, reduced the plaque area of the total aorta en face and the cross-sectional aortic sinus, decreased macrophage number and apoptosis, and promoted RCT in HFD-fed ApoE KO mice. These changes were accompanied by increased PPARalpha, LXRalpha, ABCA1 and ABCG1 expressions in the liver. NAMPT knockdown also facilitated cholesterol efflux in RAW264.7 cells. We further investigated the effect of NAMPT knockdown on the PPARalpha-LXRalpha pathway of cholesterol metabolism with MK886 (a selective inhibitor of PPARalpha) in RAW264.7 macrophages. MK886 abolished the ability of NAMPT knockdown to decrease intracellular cholesterol levels to enhance the rate of (3)H-cholesterol efflux and to increase ABCA1/G1 and LXRalpha expressions in RAW264.7 macrophages. Our observations demonstrate that NAMPT knockdown exerted antiatherogenic effects by promoting cholesterol efflux and macrophage RCT through the PPARalpha- LXRalpha- ABCA1/G1pathway in vitro and in vivo. PMID- 27229179 TI - Structure of the intact ATM/Tel1 kinase. AB - The ataxia-telangiectasia mutated (ATM) protein is an apical kinase that orchestrates the multifaceted DNA-damage response. Normally, ATM kinase is in an inactive, homodimer form and is transformed into monomers upon activation. Besides a conserved kinase domain at the C terminus, ATM contains three other structural modules, referred to as FAT, FATC and N-terminal helical solenoid. Here we report the first cryo-EM structure of ATM kinase, which is an intact homodimeric ATM/Tel1 from Schizosaccharomyces pombe. We show that two monomers directly contact head-to-head through the FAT and kinase domains. The tandem N terminal helical solenoid tightly packs against the FAT and kinase domains. The structure suggests that ATM/Tel1 dimer interface and the consecutive HEAT repeats inhibit the binding of kinase substrates and regulators by steric hindrance. Our study provides a structural framework for understanding the mechanisms of ATM/Tel1 regulation as well as the development of new therapeutic agents. PMID- 27229181 TI - The Future of Antibiotics: Emerging Technologies and Stewardship. AB - Antibiotic resistance is on the rise while the number of antibiotics being brought to market continues to drop. While this is a dire situation, a number of emerging technologies have the potential to reverse this trend. These, and supporting legislative initiatives, promise to stave off the post-antibiotic era. PMID- 27229182 TI - Statins, renal function and homocysteine. PMID- 27229180 TI - The International Association for the Study of Lung Cancer Consensus Statement on Optimizing Management of EGFR Mutation-Positive Non-Small Cell Lung Cancer: Status in 2016. AB - Mutations in the epidermal growth factor receptor gene (EGFR) represent one of the most frequent "actionable" alterations in non-small cell lung cancer (NSCLC). Typified by high response rates to targeted therapies, EGFR tyrosine kinase inhibitors (TKIs) are now established first-line treatment options and have transformed the treatment paradigm for NSCLC. With the recent breakthrough designation and approval of the third-generation EGFR TKI osimertinib, available systemic and local treatment options have expanded, requiring new clinical algorithms that take into account individual patient molecular and clinical profiles. In this International Association for the Study of Lung Cancer commissioned consensus statement, key pathologic, diagnostic, and therapeutic considerations, such as optimal choice of EGFR TKI and management of brain metastasis, are discussed. In addition, recommendations are made for clinical guidelines and research priorities, such as the role of repeat biopsies and use of circulating free DNA for molecular studies. With the rapid pace of progress in treating EGFR-mutant NSCLC, this statement provides a state-of-the-art review of the contemporary issues in managing this unique subgroup of patients. PMID- 27229183 TI - Diphenylphosphino Styrene-Containing Homopolymers: Influence of Alkylation and Mobile Anions on Physical Properties. AB - Conventional free radical polymerization and post-alkylation of 4 diphenylphosphino styrene (DPPS) generate a new class of high-molecular-weight phosphonium-containing homopolymers with tunable thermal, viscoelastic, and wetting properties. Post-alkylation and subsequent anion exchange provide an effective method for tuning Tg values and thermal stability as a function of alkyl chain length and counteranion selection (X(-) , BF4 (-) , TfO(-) , and Tf2 N(-) ). Rheological characterization facilitates the generation of time temperature-superposition (TTS) pseudomaster curves and subsequent analysis of frequency sweeps at various temperatures reveals two relaxation modes corresponding to long-range segmental motion and the onset of viscous flow. Contact angle measurements reveal the influence of counteranion selection on wetting properties, revealing increased contact angles for homopolymers containing nucleophilic counteranions. These investigations provide fundamental insight into phosphonium-containing polymers, aiming to guide future research and applications involving electro-active polymeric devices. PMID- 27229185 TI - Pet dogs and child physical activity: the role of child-dog attachment. AB - BACKGROUND: Dog ownership has been associated with increased physical activity in children which in turn may mitigate childhood obesity. OBJECTIVE: To measure the association between child-dog attachment and child physical activity and screen time. METHODS: Cross-sectional study including 370 children (ages 4-10) who had pet dogs in the home. Parents completed the DartScreen, a web-based screener, before a well-child visit. Screener domains included child body mass index (BMI), physical activity, screen time and dog-related questions. The Companion Animal Bonding Scale (CABS) was used to measure child attachment to the dog. Clinic nurses weighed and measured the children. Associations between CABS, BMI z-score, screen time and physical activity were estimated. RESULTS: CABS was strongly associated with time spent being active with the dog (F = 22.81, p < 0.0001), but not with BMI z-score or screen time. CONCLUSIONS: A higher level of child attachment to a pet dog is associated with increased child physical activity. PMID- 27229184 TI - Dynamin-1 deletion enhances post-tetanic potentiation and quantal size after tetanic stimulation at the calyx of Held. AB - KEY POINTS: Post-tetanic potentiation (PTP) is attributed mainly to an increase in release probability (Pr ) and/or readily-releasable pool (RRP) in many synapses, but the role of endocytosis in PTP is unknown. Using the calyx of Held synapse from tissue-specific dynamin-1 knockout (cKO) mice (P16-20), we report that cKO synapses show enhanced PTP compared to control. We found significant increases in both spontaneous excitatory postsynaptic current (spEPSC) amplitude and RRP size (estimated by a train of 30 APs at 100 Hz) in cKO over control during PTP. Actin depolymerization blocks the increase in spEPSC amplitude in both control and cKO, and it abolishes the enhancement of PTP in cKO. PTP is sensitive to the PKC inhibitor GF109203X in both control and cKO. We conclude that an activity-dependent quantal size increase contributes to the enhancement of PTP in cKO over control and an altered endocytosis affects short-term plasticity through quantal size changes. ABSTRACT: High-frequency stimulation leads to post-tetanic potentiation (PTP) at many types of synapses. Previous studies suggest that PTP results primarily from a protein kinase C (PKC) dependent increase in release probability (Pr ) and/or readily-releasable pool (RRP) of synaptic vesicles (SVs), but the role of SV endocytosis in PTP is unknown. Using the mature calyx of Held (P16-20), we report that tissue-specific ablation of dynamin-1 (cKO), an endocytic protein crucial for SV regeneration, enhances PTP in cKO over control. To explore the mechanism of this enhancement, we estimated the changes in paired-pulse ratios (PPRs) and RRP size during PTP. RRP was estimated by the back-extrapolation of cumulative EPSC amplitudes during a train of 30 action potentials at 100 Hz (termed RRPtrain ). We found an increase in RRPtrain during PTP in both control and cKO, but no significant changes in the PPR. Moreover, the amplitude and frequency of spontaneous excitatory postsynaptic currents (spEPSCs) increased during PTP in both control and cKO; however, the spEPSC amplitude in cKO during PTP was significantly larger than in control. Actin depolymerization reagent latrunculin-B (Lat-B) abolished the activity-dependent increase in spEPSC amplitude in both control and cKO, but selectively blocked the enhancement of PTP in cKO, without affecting PTP in control. PKC inhibitor GF109203X nearly abolished PTP in both control and cKO. These data suggest that the quantal size increase contributes to the enhancement of PTP in dynamin-1 cKO, and this change depends on strong synaptic activity and actin polymerization. PMID- 27229186 TI - Quantifying the Impact of Floods on Bacillary Dysentery in Dalian City, China, From 2004 to 2010. AB - OBJECTIVE: Studies quantifying relationships between floods and diarrheal diseases have mainly been conducted in low-latitude regions. It's therefore increasingly important to examine these relationships in midlatitude regions, where they may have significant public health implications. This study aimed to examine the association between floods and bacillary dysentery in the city of Dalian, China. METHODS: A generalized additive mixed model was applied to examine the association between floods and bacillary dysentery. The relative risk (RR) of flood impact on bacillary dysentery was estimated. RESULTS: A total of 18,976 cases of bacillary dysentery were reported in Dalian during the study period. Two weeks' lagged effect was detected from the impact of floods on bacillary dysentery. The RR of flood impact on bacillary dysentery was 1.17 (95% CI: 1.03 1.33). CONCLUSIONS: Floods have significantly increased the risk of bacillary dysentery in Dalian. More studies should focus on the association between floods and infectious diseases in different regions. Our findings have significant implications for managing the negative health impact of floods in the midlatitude region of China. (Disaster Med Public Health Preparedness. 2017;11:190-195). PMID- 27229188 TI - Department of Error. PMID- 27229187 TI - Yellow fever: the resurgence of a forgotten disease. PMID- 27229189 TI - Teenage Pregnancy Strategy for England. PMID- 27229191 TI - England's Teenage Pregnancy Strategy: a hard-won success. PMID- 27229190 TI - Changes in conceptions in women younger than 18 years and the circumstances of young mothers in England in 2000-12: an observational study. AB - BACKGROUND: In 2000, a 10-year Teenage Pregnancy Strategy was launched in England to reduce conceptions in women younger than 18 years and social exclusion in young parents. We used routinely collected data and data from Britain's National Surveys of Sexual Attitudes and Lifestyles (Natsal) to examine progress towards these goals. METHODS: In this observational study, we used random-effects meta regression to analyse the change in conception rates from 1994-98 to 2009-13 by top-tier local authorities in England, in relation to Teenage Pregnancy Strategy related expenditure per head, socioeconomic deprivation, and region. Data from similar probability sample surveys: Natsal-1 (1990-91), Natsal-2 (1999-2001), and Natsal-3 (2010-12) were used to assess the prevalence of risk factors and their association with conception in women younger than 18 years in women aged 18-24 years; and the prevalence of participation in education, work, and training in young mothers. FINDINGS: Conception rates in women younger than 18 years declined steadily from their peak in 1996-98 and more rapidly from 2007 onwards. More deprived areas and those receiving greater Teenage Pregnancy Strategy-related investment had higher rates of conception in 1994-98 and had greater declines to 2009-13. Regression analyses assessing the association between Teenage Pregnancy Strategy funding and decline in conception rates in women younger than 18 years showed an estimated reduction in the conception rate of 11.4 conceptions (95% CI 9.6-13.2; p<0.0001) per 1000 women aged 15-17 years for every L100 Teenage Pregnancy Strategy spend per head and a reduction of 8.2 conceptions (5.8-10.5; p<0.0001) after adjustment for socioeconomic deprivation and region. The association between conception in women younger than 18 years and lower socioeconomic status weakened slightly between Natsal-2 and Natsal-3. The prevalence of participation in education, work, or training among young women with a child conceived before age 18 years was low, but the odds of them doing so doubled between Natsal-2 and Natsal-3 (odds ratio 1.99, 95% CI 0.99-4.00). INTERPRETATION: A sustained, multifaceted policy intervention involving health and education agencies, alongside other social and educational changes, has probably contributed to a substantial and accelerating decline in conceptions in women younger than 18 years in England since the late 1990s. FUNDING: Medical Research Council, Wellcome Trust, Economic and Social Research Council, and Department of Health. PMID- 27229192 TI - Welcome to the Eighth World Congress of Veterinary Dermatology and to the historical city of Bordeaux! PMID- 27229193 TI - Abstracts from the 8th World Congress of Veterinary Dermatology, May 31 - June 4 2016, Bordeaux, France. PMID- 27229194 TI - A Series of COX-2 Inhibitors Endowed with NO-Releasing Properties: Synthesis, Biological Evaluation, and Docking Analysis. AB - Herein we report the synthesis, biological evaluation, and docking analysis of a class of cyclooxygenase-2 (COX-2) inhibitors with nitric oxide (NO)-releasing properties. In an earlier study, a number of selective COX-2 inhibitors/NO donors were developed by conjugating a diarylpyrrole scaffold endowed with selective COX 2 inhibitory properties with various nitrooxyalkyl side chains such as esters, alpha-amino esters, amides, alpha-amino amides, ethers, beta-amino ethers, inverse esters, and amides. These candidates were found to have high in vitro potencies (COX-2 inhibition at 10 MUm: >=96 %), great efficacy in determining NO vasorelaxing responses, and good antinociceptive activity in an abdominal writhing test. Among the compounds synthesized in the present work, derivative 2 b [2-(2-(1-(3-fluorophenyl)-2-methyl-5-(4-sulfamoylphenyl)-1H-pyrrol-3 yl)acetamido)ethyl nitrate] showed particularly outstanding activity, with efficacy similar to that of celecoxib even at very low concentrations. PMID- 27229264 TI - Evidence-based (S3) Guideline on (anogenital) Lichen sclerosus. PMID- 27229265 TI - Functionalized nanoparticles based solid-phase membrane micro-tip extraction and high-performance liquid chromatography analyses of vitamin B complex in human plasma. AB - Iron nanoparticles were prepared by a green method following functionalization using 1-butyl-3-methylimidazolium bromide. 1-Butyl-3-methylimidazole iron nanoparticles were characterized using FTIR spectroscopy, energy dispersive X-ray fluorescence, X-ray diffraction, scanning electron microscopy and transmission electron microscopy. The nanoparticles were used in solid-phase membrane micro tip extraction to separate vitamin B complex from plasma before high-performance liquid chromatography. The optimum conditions obtained were sorbent (15 mg), agitation time (30 min), pH (9.0), desorbing solvent [water (5 mL) + methanol (5 mL) + sodium hydroxide (0.1 N) + acetic acid (d = 1.05 kg/L, pH 5.5), desorbing volume (10 mL) and desorption time (30 min). The percentage recoveries of all the eight vitamin B complex were from 60 to 83%. A high-performance liquid chromatography method was developed using a PhE column (250 * 4.6 mm, 5.0 MUm) and water/acetonitrile (95:5, v/v; pH 4.0 with 0.1% formic acid) mobile phase. The flow rate was 1.0 mL/min with detection at 270 and 210 nm. The values of the capacity, separation and resolution factor were 0.57-39.47, 1.12-6.00 and 1.84 26.26, respectively. The developed sample preparation and chromatographic methods were fast, selective, inexpensive, economic and reproducible. The developed method can be applied for analyzing these drugs in biological and environmental matrices. PMID- 27229266 TI - Using an FPLC to promote active learning of the principles of protein structure and purification. AB - The concepts of protein purification are often taught in undergraduate biology and biochemistry lectures and reinforced during laboratory exercises; however, very few reported activities allow students to directly gain experience using modern protein purification instruments, such as Fast Protein Liquid Chromatography (FPLC). This laboratory exercise uses size exclusion chromatography (SEC) and ion exchange (IEX) chromatography to separate a mixture of four different proteins. Students use an SEC chromatogram and corresponding SDS-PAGE gel to understand how protein conformations change under different conditions (i.e. native and non-native). Students explore strategies to separate co-eluting proteins by IEX chromatography. Using either cation or anion exchange, one protein is bound to the column while the other is collected in the flow through. In this exercise, undergraduate students gain hands-on experience with experimental design, buffer and sample preparation, and implementation of instrumentation that is commonly used by experienced researchers while learning and applying the fundamental concepts of protein structure, protein purification, and SDS-PAGE. (c) 2016 by The International Union of Biochemistry and Molecular Biology, 45(1):60-68, 2017. PMID- 27229267 TI - Laennec's melanosis: The first published description of metastatic melanoma. AB - Melanomas are a common skin condition in Australia. The authors decided to examine the history of melanomas and its metastases with particular reference to the description of Laennec and the controversy between him and his teacher Dupuytren, who challenged his pupil as to who was the first to describe melanomatous metastases to the lungs. The rivalry between teacher and student continued, with each describing a similar system of pathological classification. PMID- 27229268 TI - New conjugates of mycophenolic acid and their antiproliferative activity. AB - The new conjugates of mycophenolic acid (MPA) were obtained in the reaction of N(6)-(omega-aminoalkyl)adenosines with MPA in the presence of EDCI as a coupling reagent. New compounds 4a-h were evaluated on leukemia cell line (Jurkat) and PBMC from healthy donors. Length of the linker influenced observed activity. The compound 4b possessing 1,3-diamine spacer exhibited the most promising results and can be considered to further investigations. PMID- 27229270 TI - Primary Cutaneous Lymphomas in Children and Adolescents. AB - Primary cutaneous lymphomas are rare in children and mostly represented by mycosis fungoides and CD30(+) lymphoproliferative disorders. Most pediatric cutaneous lymphomas have similar clinical/pathological features as their adult counterparts, particularly the T-cell subtypes. With regard to outcome, adult cutaneous mature T-cell lymphomas have a tendency to progression, while this appears to be relatively infrequent in children. The outcome of cutaneous B-cell lymphomas depends on subtype, with the B-lymphoblastic entity being associated with similar outcomes to precursor B acute lymphoblastic leukemia, while there are insufficient data on other entities. The diagnosis and treatment of these patients require a close collaboration between experienced pediatric pathologists, dermatologists, and oncologists. Prospective collection of longitudinal clinical and biological data from children with these rare lymphomas is needed to better understand their biological and clinical behavior and to ultimately discover the best therapeutic strategies. PMID- 27229271 TI - Predisposing factors for eruptive cherry angiomas: New insights from an observational study. PMID- 27229272 TI - Technological Advances in Psychiatric Nursing: An update. AB - Understanding and treating mental illness has improved in many ways as a result of the fast pace of technological advances. The technologies that have the greatest potential impact are those that (1) increase the knowledge of how the brain functions and changes based on interventions, (2) have the potential to personalize interventions based on understanding genetic factors of drug metabolism and pharmacodynamics, and (3) use information technology to provide treatment in the absence of an adequate mental health workforce. Technologies are explored for psychiatric nurses to consider. Psychiatric nurses are encouraged to consider the experiences of psychiatric patients, including poor health, stigmatization, and suffering. PMID- 27229269 TI - Long non-coding RNA: Functional agent for disease traits. AB - In recent years, long non-coding RNAs (lncRNAs) have attracted the attention of researchers with their involvement in all facets of life. LncRNAs are transcripts of more than 200 nucleotides which lack defined protein coding potential. Although they do not code for proteins, a large number of them are involved in regulating gene expression and translation. The presence of numerous lncRNAs in the human genome has prompted us to investigate the contribution of these molecules to human biology and medicine. In this review, we present the potential role of lncRNAs interlinked to different human diseases and genetic disorders. We also describe their role in cellular differentiation and aging and discuss their potential importance as biomarkers and as therapeutic agents. PMID- 27229273 TI - Legal Considerations of Psychiatric Nursing Practice. AB - There are major legal issues that affect psychiatric nursing and guidelines for practicing in a legal and responsible manner. Advances in understanding of psychiatric conditions and developments in how nurses care for psychiatric patients result in changes in regulations, case law, and policies that govern nursing practice. Professional development, keeping abreast of current research and literature regarding clinical practice and trends, and involvement in professional organizations are some of the ways that psychiatric nurses can meet the challenges of their profession. PMID- 27229274 TI - Caring for the Patient with an Anxiety Disorder. AB - Anxiety disorders are among the most prevalent and disabling psychiatric disorders. Patients and their families have a plethora of evidence-based treatment options to manage these potentially incapacitating and costly disorders. Nurses in various settings can assess symptoms of anxiety disorder and initiate or refer patients for treatment. Families play a critical role in treatment planning and must be part of the health care team. Primary nursing interventions must be person centered and recovery based to ensure accurate diagnosis, initiation of appropriate person-centered treatment, and facilitate an optimal level of functioning and quality of life. PMID- 27229275 TI - Assessing and Treating the Patient with Acute Psychotic Disorders. AB - Patients with acute psychosis often present to emergency departments. Management of acute agitation and psychosis can be a challenge for the staff. Medical stabilization, appropriate assessment, and diagnosis are important. Verbal de escalation and other psychosocial interventions are helpful in creating a safe and therapeutic environment. Psychiatric and emergency room nurses are poised to treat patients presenting with acute psychosis and must be knowledgeable of evidence-based approaches to treat these complex disorders. PMID- 27229276 TI - Treatment Approaches to Attention Deficit Hyperactivity Disorder. AB - Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children, adolescents, and adults, with a prevalence estimated from 5% to 7% across cultures and approximately 2% to 5% in adults. This lifelong disorder challenges nurses to understand the basis of ADHD, analyze symptoms, differentiate coexisting disorders, gather health information from varied sources, and implement person-centered multimodal treatment. Nurses are poised to plan, and work with patients, families, and teachers in the community and school systems to optimize academic and occupational performance and improve quality of life. Pharmacotherapy, psychoeducation, and behavioral therapies are strong components of multimodal treatment planning. PMID- 27229277 TI - Nursing Care Considerations for the Hospitalized Patient with an Eating Disorder. AB - Eating disorders are chronic psychiatric illnesses with significant medical complications, psychological distress, and psychiatric comorbidity. Although many patients are treated on an outpatient basis, inpatient care for the more severely ill hospitalized patient can be challenging given the severity of illness and concurrent issues requiring intervention. This article provides an overview of the clinical characteristics of eating disorders typically seen for inpatient care, focusing primarily on anorexia nervosa and bulimia nervosa, and the associated key areas for nursing assessment, diagnoses, and plan of care during hospitalization. PMID- 27229278 TI - Dual Diagnosis: Coexisting Substance Use Disorders and Psychiatric Disorders. AB - Dual diagnosis is a prevalent and serious health problem. These disorders challenge psychiatric mental health and addiction nurses to treat 2 distinct disorders. Despite advances in the treatment of these disorders, there remains a void in the ideal approach. This article offers psychiatric nurses opportunities to improve their expertise in the identification of vulnerable or high-risk populations by using integrated screening and brief interventions to discern treatment options. Patients who require comprehensive treatment to stabilize 1 or both disorders further challenge nurses to have a basic understanding of the powerful effects of substance use on psychiatric conditions and vice versa. PMID- 27229279 TI - Evidenced-Based Care of Adolescents and Families in Crisis. AB - This article examines the challenges faced by adolescents and their families as the young person matures into adulthood. Crises are the result of unpredictable situations or events that overwhelm the individual or individuals and render their resources and coping skills ineffective in mediating the stress. Crises can be situational, maturational, or adventitious. Nurses of all specialties may encounter the individual or family in crisis and need to provide crisis interventions services while assisting them to access the services of a skilled mental health professional. PMID- 27229280 TI - Managing the Care of the Older Patient with Delirium and Dementia. AB - As the population ages, nurses in various clinical settings must identify high risk groups that are vulnerable to delirium and dementia. They also must be able to provide psychosocial and pharmacologic interventions that promote comfort and safety for patients and their families experiencing these distressful medical conditions. Efforts to facilitate health resolution and restore the patient and caregivers to an optimal level of functioning must be priorities. PMID- 27229281 TI - Suicide: Across the Life Span. AB - Suicide remains a major public health issue. There have been more than 40,000 deaths by suicide in 2014. Understanding both the neuroscience and psychological development is key for nursing care so adequate interventions and treatment strategies are developed when working with people thinking about suicide. It is critical to assess and recognize risk and protective factors to ensure patient safety. The older adult, children, and adolescent populations remain vulnerable to suicide. A discussion regarding the psychiatric, psychosocial, and treatment considerations for these populations is included. An overview of communication, suicide assessment, and safety planning is discussed. PMID- 27229282 TI - Psychosocial Recovery and Rehabilitation. AB - This article discusses a psychosocial recovery and rehabilitation recovery model that uses an intensive case management approach. The approach offers an interdisciplinary model that integrates pharmacotherapy, social skills training, cognitive remediation, family involvement, and community integration. This evidence-based plan of care instills hope and nurtures one's capacity to learn and improve function and quality of life. It is cost-effective and offers psychiatric nurses opportunities to facilitate symptomatic remission, facilitate self-efficacy, and improve communication and social cognition skills. Nurses in diverse practice settings must be willing to plan and implement innovative treatment models that provide seamless mental health care across the treatment continuum. PMID- 27229283 TI - Evidence-Based Care of the Patient with Borderline Personality Disorder. AB - Borderline personality disorder (BPD) is a complex, serious, and high-cost psychiatric disorder. The high prevalence of patients with BPD and co-occurring depression, eating disorders, and substance-use disorders in primary care and mental health settings contribute to their high use of resources in these practice settings. Regardless of treatment challenges associated with BPD, researchers suggest a more positive outlook in the treatment of this complex psychiatric condition. This article focuses on areas in which nurses can strengthen their understanding of underpinnings and multimodal approaches, assess the patient's immediate needs, and manage distressful emotional states and impulsivity. PMID- 27229284 TI - Adverse Drug Reactions Associated with Antipsychotics, Antidepressants, Mood Stabilizers, and Stimulants. AB - The advent of psychotropic medications in the 1950s greatly impacted the practice of psychiatry. Since then, efforts have been made to produce effective medications with few side effects (SEs) or adverse drug reactions (ADRs). Newer psychotropics have been developed but are not without risk. ADRs and SEs can lead to medication noncompliance, morbidity, and mortality. In many cases, ADRs can be prevented and common SEs relieved through proper interventions. Nursing interventions are vital to improving patient safety and outcomes in mental health populations. This article discusses ADRs and SEs of antipsychotics, antidepressants, mood stabilizers, and stimulants. PMID- 27229285 TI - Caring for Trauma Survivors. AB - Although trauma exposure is common, few people develop acute and chronic psychiatric disorders. Those who develop posttraumatic stress disorder likely have coexisting psychiatric and physical disorders. Psychiatric nurses must be knowledgeable about trauma responses, implement evidence-based approaches to conduct assessments, and create safe environments for patients. Most researchers assert that trauma-focused cognitive-behavioral approaches demonstrate the most efficacious treatment outcomes. Integrated approaches, offer promising treatment options. This article provides an overview of clinical factors necessary to help the trauma survivor begin the process of healing and recovery and attain an optimal level of functioning. PMID- 27229286 TI - Contemporary Treatment Approaches to Major Depression and Bipolar Disorders. AB - Mood disorders have a high incidence of coexisting psychiatric, substance use, and physical disorders. When these disorders are unrecognized and left untreated, patients are likely to have a reduced life expectancy and experience impaired functional and psychosocial deficits and poor quality of life. Psychiatric nurses are poised to address the needs of these patients through various approaches. Although the ideal approach for mood disorders continues to be researched, there is a compilation of data showing that integrated models of treatment that reflect person-centered, strength, and recovery-based principles produce positive clinical outcomes. PMID- 27229287 TI - Patients with Mental Health Issues Transcend Centralized Care Settings. PMID- 27229288 TI - Psychiatric Mental Health Nursing: An Update. PMID- 27229289 TI - Effects of stocking density, light and perches on broiler growth. AB - The aim of this study was to determine the effect of stocking density, light intensity and light color on broiler growth. The experiment consisted of four 35 day phases during each of which 320 chickens were surveyed. The research was performed at stocking densities of four and six birds/m2 . Illuminances of 15 and 30 lx were obtained through commercial lamps with 4000 K and 6000 K color temperatures. Lighting was used 17 h a day, between 06.00 and 23.00 hours (17 L:7 D). The results showed a decrease in body, carcass, breast and thighs weight (P < 0.05) with the increase in stocking density. Body weight decreased by 10.5% and carcass weight decreased by 9.4% at six birds/m2 stocking density. Contrastingly, no differences were found for the tested light colors. Increasing illuminance from 15 to 30 lx caused a 1.9% decrease in body weight. The analysis of the effect of perches revealed that using perches significantly increased body (2.5%) and breast weight (11.8%). The interactions between light intensity or color and stocking density and between light intensity and light color were analyzed. PMID- 27229290 TI - Chemical bonding and dynamic fluxionality of a B15(+) cluster: a nanoscale double axle tank tread. AB - A planar, elongated B15(+) cationic cluster is shown to be structurally fluxional and functions as a nanoscale tank tread on the basis of electronic structure calculations, bonding analyses, and molecular dynamics simulations. The outer B11 peripheral ring behaves like a flexible chain gliding around an inner B4 rhombus core, almost freely at the temperature of 500 K. The rotational energy barrier is only 1.37 kcal mol(-1) (0.06 eV) at the PBE0/6-311+G* level, further refined to 1.66 kcal mol(-1) (0.07 eV) at the single-point CCSD(T)/6-311G*//CCSD/6-311G* level. Two soft vibrational modes of 166.3 and 258.3 cm(-1) are associated with the rotation, serving as double engines for the system. Bonding analysis suggests that the "island" electron clouds, both sigma and pi, between the peripheral ring and inner core flow and shift continuously during the intramolecular rotation, facilitating the dynamic fluxionality of the system with a small rotational barrier. The B15(+) cluster, roughly 0.6 nm in dimension, is the first double axle nanoscale tank tread equipped with two engines, which expands the concepts of molecular wheels, Wankel motors, and molecular tanks. PMID- 27229291 TI - Hollow K0.27MnO2 Nanospheres as Cathode for High-Performance Aqueous Sodium Ion Batteries. AB - Hollow K0.27MnO2 nanospheres as cathode material were designed for aqueous sodium ion batteries (SIBs) using polystyrene (PS) as a template. The samples were systematically studied by X-ray diffraction, field emission scanning electron microscopy, and transmission electron microscopy. As cathode materials for aqueous SIBs, the hollow structure can effectively improve the sodium storage property. A coin cell with hollow K0.27MnO2 as cathode and NaTi2(PO4)3 as anode exhibits a specific capacity of 84.9 mA h g(-1) at 150 mA g(-1), and the capacity of 56.6 mA h g(-1) is still maintained at an extremely high current density of 600 mA g(-1). For full cell measurement at the current density of 200 mA g(-1), 83% capacity retention also can be attained after 100 cycles. The as-designed hollow K0.27MnO2 nanospheres demonstrate long cyclability and high rate capability, which grant the potential for application in advanced aqueous SIBs. PMID- 27229293 TI - A high-resolution method to assess cell multinucleation with cytoplasm-localized fluorescent probes. AB - Cell multinucleation is closely related to chromosomal instability. We report a simple, convenient method to assess cell multinucleation with cytoplasm-localized fluorescent probes (CLFP) which is superior to conventional nuclear staining methods. The CLFP method provides high-resolution images that enable the accurate calculation of the number of nuclear fragments. PMID- 27229292 TI - Pro-fibrotic pathway activation in trabecular meshwork and lamina cribrosa is the main driving force of glaucoma. AB - While primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide, it still does not have a clear mechanism that can explain all clinical cases of the disease. Elevated IOP is associated with increased accumulation of extracellular matrix (ECM) proteins in the trabecular meshwork (TM) that prevents normal outflow of aqueous humor (AH) and has damaging effects on the fine mesh like lamina cribrosa (LC) through which the optic nerve fibers pass. Applying a pathway analysis algorithm, we discovered that an elevated level of TGFbeta observed in glaucoma-affected tissues could lead to pro-fibrotic pathway activation in TM and in LC. In turn, activated pro-fibrotic pathways lead to ECM remodeling in TM and LC, making TM less efficient in AH drainage and making LC more susceptible to damage from elevated IOP via ECM transformation in LC. We propose pathway targets for potential therapeutic interventions to delay or avoid fibrosis initiation in TM and LC tissues. PMID- 27229294 TI - Plasma metabolomic profile and potential biomarkers for missed abortion. AB - A missed abortion (MA) is an in utero death of the embryo or fetus before the 20th week of gestation with retained products of conception, and this condition is currently common in China. In order to discover novel biomarkers for MA, ultrahigh performance liquid chromatography was applied to study plasma metabolite profiles for 33 patients with MA and 29 control subjects. Thirty-seven differential plasma metabolites were found to discriminate between the two groups in the initial cohort (15 subjects with MA and 15 healthy controls). The feasibility of using these potential biomarkers to predict MA was further evaluated in the validation cohort (18 subjects with MA and 14 healthy controls) and 15 had an area under the receiver operating characteristic curve of >0.80, making them satisfactory. Tryptophan metabolism and sphingolipid metabolism were identified as important potential target pathways for MA using metabolic pathway impact analysis. Furthermore, three of the 15 satisfactory metabolites (glyceric acid, indole and sphingosine) were combined to establish a predictive model with 100% sensitivity and 100% specificity in the validation cohort. Taken together, these results suggest that MA results in significant disturbance of metabolism and those various novel biomarkers have satisfactory diagnostic and predictive power for MA. PMID- 27229295 TI - Chemical constituents and biological research on plants in the genus Curcuma. AB - Curcuma, a valuable genus in the family Zingiberaceae, includes approximately 110 species. These plants are native to Southeast Asia and are extensively cultivated in India, China, Sri Lanka, Indonesia, Peru, Australia, and the West Indies. The plants have long been used in folk medicine to treat stomach ailments, stimulate digestion, and protect the digestive organs, including the intestines, stomach, and liver. In recent years, substantial progress has been achieved in investigations regarding the chemical and pharmacological properties, as well as in clinical trials of certain Curcuma species. This review comprehensively summarizes the current knowledge on the chemistry and briefly discusses the biological activities of Curcuma species. A total of 720 compounds, including 102 diphenylalkanoids, 19 phenylpropene derivatives, 529 terpenoids, 15 flavonoids, 7 steroids, 3 alkaloids, and 44 compounds of other types isolated or identified from 32 species, have been phytochemically investigated. The biological activities of plant extracts and pure compounds are classified into 15 groups in detail, with emphasis on anti-inflammatory and antitumor activities. PMID- 27229296 TI - Role of enteroscopy in the diagnosis and management of adult small-bowel intussusception. PMID- 27229297 TI - Simultaneous performance of one-tunnel per-oral endoscopic myotomy, submucosal tunneling endoscopic resection, and diverticulotomy. PMID- 27229298 TI - Intracellular delivery of chemical probes using a glutathione-responsive traceless tag. AB - A new glutathione (GSH)-responsive traceless tag that facilitates intracellular delivery of small molecule chemical probes has been developed. PMID- 27229299 TI - Spin-Driven Multiferroic Properties of PbMn7O12 Perovskite. AB - We synthesize PbMn7O12 perovskite under high-pressure (6 GPa) and high temperature (1373 K) conditions and investigate its structural, magnetic, dielectric, and ferroelectric properties. We find that PbMn7O12 exhibits rich physical properties from interplay among charge, orbital, and spin degrees of freedom and rich structural properties. PbMn7O12 crystallizes in space group R3 near room temperature and shows a structural phase transition at TCO = 397 K to a cubic structure in space group Im3; the Im3-to-R3 transition is associated with charge ordering. Below TOO = 294 K, a structural modulation transition associated with orbital ordering takes place. There are two magnetic transitions with Neel temperatures of TN1 = 83 K and TN2 = 77 K and probably a lock-in transition at TN3 = 43 K (on cooling). There is huge hysteresis on specific heat (between ~37 and 65 K at 0 Oe), dielectric constant (between ~20 and 70 K at 0 Oe), and dc and ac magnetic susceptibilities around the lock-in transition. Sharp dielectric constant, dielectric loss, and pyroelectric current anomalies are observed at TN2, indicating that electric polarization is developed at this magnetic transition, and PbMn7O12 perovskite is a spin-driven multiferroic. Polarization of PbMn7O12 is measured to be ~4 MUC/m(2). Field-induced transitions are detected at ~63 and ~170 kOe at 1.6-2 K; similar high-magnetic field properties are also found for CdMn7O12, CaMn7O12, and SrMn7O12. PbMn7O12 exhibits a quite small magnetodielectric effect, reaching approximately -1.3 to -1.7% at 10 K and 90 kOe. PMID- 27229300 TI - Label-free whole blood cell differentiation based on multiple frequency AC impedance and light scattering analysis in a micro flow cytometer. AB - We developed a microfluidic sensor for label-free flow cytometric cell differentiation by combined multiple AC electrical impedance and light scattering analysis. The measured signals are correlated to cell volume, membrane capacity and optical properties of single cells. For an improved signal to noise ratio, the microfluidic sensor incorporates two electrode pairs for differential impedance detection. One-dimensional sheath flow focusing was implemented, which allows single particle analysis at kHz count rates. Various monodisperse particles and differentiation of leukocytes in haemolysed samples served to benchmark the microdevice applying combined AC impedance and side scatter analyses. In what follows, we demonstrate that AC impedance measurements at selected frequencies allow label-free discrimination of platelets, erythrocytes, monocytes, granulocytes and lymphocytes in whole blood samples involving dilution only. Immunofluorescence staining was applied to validate the results of the label-free cell analysis. Reliable differentiation and enumeration of cells in whole blood by AC impedance detection have the potential to support medical diagnosis for patients with haemolysis resistant erythrocytes or abnormally sensitive leucocytes, i.e. for patients suffering from anaemia or leukaemia. PMID- 27229301 TI - Cutaneous melanoma: A current overview. AB - Cutaneous melanoma continues to increase in frequency, for unknown reasons, and it can pose considerable diagnostic challenges to clinician and pathologists alike. This review considers current concepts pertaining to that tumor, including those concerning epidemiology, clinical diagnosis, histologic findings, adjunctive diagnostic studies, and prognosis. PMID- 27229302 TI - Effectiveness of a cooling jacket with reference to physiological responses in iron foundry workers. AB - Personal cooling garments (PCGs) have gained increased attention in recent years due to heat stress and strain in the working environment. The present study was conducted in hot environments of an iron foundry to evaluate the efficacy of a battery-operated PCG. Twenty-four workers were exposed to climatic conditions of 35.89 +/- 1.25 degrees C, 35% relative humidity during 90-min work with PCG and habitual clothing (HC). Mean weighted skin temperature was significantly lower by 4.84 +/- 1.05 degrees C compared with HC 0.38 +/- 1.02 degrees C (p < 0.05). A statistically significant difference was also observed for 0.492 +/- 0.26 g mean sweat loss in the PCG group compared with 0.775 +/- 0.42 g in the HC group (p < 0.05). Heart rate, and back and chest skin temperatures were comparatively more reduced in the PCG group compared with the HC group. PCG provides a practical and economical way of alleviating the physiological effects of heat stress when environmental control is not feasible. PMID- 27229303 TI - Distribution and ecotoxicological concerns of persistent organic pollutants in sediment from creek ecosystem. AB - In order to study the distribution and ecotoxicological concerns of persistent organic pollutants, grab sediment samples were collected from different locations across Thane creek, India. Analyses of samples were carried out using gas chromatography (GC)-electron capture detector and GC-mass spectrometry techniques. In organochlorine pesticides (OCPs), DDT (1,1,1,-trichloro-2,2-bis(p chlorophenyl) ethane), DDE (1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene), DDD (1-chloro-4-(2,2-dichloro-1-(4-chlorophenyl)ethyl) benzene) and alpha, beta, and gamma conformer of hexachlorocyclohexane (HCH), and 9 polychlorinated biphenyls (PCBs) congeners were analyzed in surface sediment samples. Concentrations of these pollutants in grab sediment samples may indicate their current use and impact on marine ecosystem. Average concentrations of total DDT (including DDD and DDE), HCH, and Sigma9PCBs were found to be 4.9, 12.5, and 2.9 ug kg(-1)(dry weight) respectively. High concentrations of OCPs and PCBs were found at discharge locations in creek compared to other locations. Location-wise distribution of OCPs and PCBs indicates their high concentrations at the waste water receiving point. Data were compared for ecotoxicological impacts based on the levels specified in the sediment quality standards of the US Environmental Protection Agency and the Canadian Council of Ministers of the Environment. gamma HCH was found to have maximum potential to induce ecotoxicological impacts. PMID- 27229304 TI - Effects of glucose on lactose synthesis in mammary epithelial cells from dairy cow. AB - BACKGROUND: Lactose, as the primary osmotic component in milk, is the major determinant of milk volume. Glucose is the primary precursor of lactose. However, the effect of glucose on lactose synthesis in dairy cow mammary glands and the mechanism governing this process are poorly understood. RESULTS: Here we showed that glucose has the ability to induce lactose synthesis in dairy cow mammary epithelial cells, as well as increase cell viability and proliferation. A concentration of 12 mM glucose was the optimum concentration to induce cell growth and lactose synthesis in cultured dairy cow mammary epithelial cells. In vitro, 12 mM glucose enhanced lactose content, along with the expression of genes involved in glucose transportation and the lactose biosynthesis pathway, including GLUT1, SLC35A2, SLC35B1, HK2, beta4GalT-I, and AKT1. In addition, we found that AKT1 knockdown inhibited cell growth and lactose synthesis as well as expression of GLUT1, SLC35A2, SLC35B1, HK2, and beta4GalT-I. CONCLUSIONS: Glucose induces cell growth and lactose synthesis in dairy cow mammary epithelial cells. Protein kinase B alpha acts as a regulator of metabolism in dairy cow mammary gland to mediate the effects of glucose on lactose synthesis. PMID- 27229306 TI - Facilitators and barriers of herbal medicine use in Accra, Ghana: an inductive exploratory study. AB - BACKGROUND: The use of complementary and alternative medicine including herbal medicine is increasing in many countries including Ghana. However, there is paucity of research on the perspectives of patrons of herbal medicine regarding the facilitators and barriers of herbal medicine use. This study sought to investigate the facilitators and barriers of herbal medicine among Ghanaian adults who use one form of herbal medicine or the other. METHODS: The study employed an inductive exploratory qualitative approach. It was conducted at a private herbal clinic in Accra. Purposive sampling was employed to recruit 16 participants. Data collection was through individual face-to-face interviews and these were transcribed and analysed using content analysis procedures. RESULTS: It was realized that the factors that enhanced the use of herbal medicine included use of convincing information to enhance the initiation of herbal medicine use, effectiveness of herbal medicine, personal preference for herbal medicine, perceived ineffectiveness of western medicine and integration of spirituality in herbal medicine. The factors that hindered herbal medicine use included negative perceptions and attitudes about herbal medicine, poor vending environment, poor knowledge of vendors, high cost of herbal products at credible herbal clinics and inconsistent effectiveness of some herbal products. Participants desired that the national health insurance scheme will cover the cost of herbal medicine to alleviate the financial burden associated with herbal medicine use. CONCLUSION: Although some Ghanaians patronize herbal medicine, the negative perceptions about herbal medicine resulting from deceitful producers and vendors call for enhanced education and monitoring to ensure that effective herbal products are used. PMID- 27229307 TI - Delirium diagnosis defined by cluster analysis of symptoms versus diagnosis by DSM and ICD criteria: diagnostic accuracy study. AB - BACKGROUND: Information on validity and reliability of delirium criteria is necessary for clinicians, researchers, and further developments of DSM or ICD. We compare four DSM and ICD delirium diagnostic criteria versions, which were developed by consensus of experts, with a phenomenology-based natural diagnosis delineated using cluster analysis of delirium features in a sample with a high prevalence of dementia. We also measured inter-rater reliability of each system when applied by two evaluators from distinct disciplines. METHODS: Cross sectional analysis of 200 consecutive patients admitted to a skilled nursing facility, independently assessed within 24-48 h after admission with the Delirium Rating Scale-Revised-98 (DRS-R98) and for DSM-III-R, DSM-IV, DSM-5, and ICD-10 criteria for delirium. Cluster analysis (CA) delineated natural delirium and nondelirium reference groups using DRS-R98 items and then diagnostic systems' performance were evaluated against the CA-defined groups using logistic regression and crosstabs for discriminant analysis (sensitivity, specificity, percentage of subjects correctly classified by each diagnostic system and their individual criteria, and performance for each system when excluding each individual criterion are reported). Kappa Index (K) was used to report inter rater reliability for delirium diagnostic systems and their individual criteria. RESULTS: 117 (58.5 %) patients had preexisting dementia according to the Informant Questionnaire on Cognitive Decline in the Elderly. CA delineated 49 delirium subjects and 151 nondelirium. Against these CA groups, delirium diagnosis accuracy was highest using DSM-III-R (87.5 %) followed closely by DSM IV (86.0 %), ICD-10 (85.5 %) and DSM-5 (84.5 %). ICD-10 had the highest specificity (96.0 %) but lowest sensitivity (53.1 %). DSM-III-R had the best sensitivity (81.6 %) and the best sensitivity-specificity balance. DSM-5 had the highest inter-rater reliability (K =0.73) while DSM-III-R criteria were the least reliable. CONCLUSIONS: Using our CA-defined, phenomenologically-based delirium designations as the reference standard, we found performance discordance among four diagnostic systems when tested in subjects where comorbid dementia was prevalent. The most complex diagnostic systems have higher accuracy and the newer DSM-5 have higher reliability. Our novel phenomenological approach to designing a delirium reference standard may be preferred to guide revisions of diagnostic systems in the future. PMID- 27229308 TI - The association of NR1H3 gene with lipid deposition in the pig. AB - BACKGROUND: Nuclear receptor subfamily 1, group H, member 3 (NR1H3, an alias for Liver X receptor alpha, LXRalpha) is a member of the LXR nuclear receptor super family and is an important regulator of lipid and fatty acid accumulation in the liver, adipose and skeletal muscle. METHODS: In this study, single-nucleotide polymorphisms (SNPs) from six populations of pig (Sus scrofa) were screened by PCR-sequencing and genotyped, and its association with backfat thickness was analyzed in a population of New Huai line (NHP, n = 117). In addition, quantitative real-time PCR and western blot were used to measure expression of NR1H3 in the liver tissue, backfat and longissimus dorsi muscle of DSP (n = 10), TP (n = 10) and YY (n = 10) pigs. RESULTS: Three SNPs (exon2-C105T, exon2-G106C, and exon5-A201C) were screened and exon5-A201C was identified; the genotype frequencies were significantly different between indigenous and introduced breeds. The CC genotype was associated with higher backfat thickness than the AA and AC genotypes in the NYP. NR1H3 mRNA and protein expression were higher in the liver and longissimus dorsi of DSP and TP than in those of YY. This increased NR1H3 expression might be associated with higher lipid deposition. NR1H3 expression in the backfat of YY was not lower than that in DSP or TP, which might because NR1H3 has an alternative regulatory function for lipid metabolism in the subcutaneous fat of pigs. CONCLUSIONS: Our results suggest that allele A of the exon5-A201C in NR1H3 may promote a reduction in backfat thickness, and differences in NR1H3 expression may be associated with differences in lipid deposition capacity among pigs. PMID- 27229305 TI - Connexin and pannexin channels in cancer. AB - Communication among cells via direct cell-cell contact by connexin gap junctions, or between cell and extracellular environment via pannexin channels or connexin hemichannels, is a key factor in cell function and tissue homeostasis. Upon malignant transformation in different cancer types, the dysregulation of these connexin and pannexin channels and their effect in cellular communication, can either enhance or suppress tumorigenesis and metastasis. In this review, we will highlight the latest reports on the role of the well characterized connexin family and its ability to form gap junctions and hemichannels in cancer. We will also introduce the more recently discovered family of pannexin channels and our current knowledge about their involvement in cancer progression. PMID- 27229309 TI - Molecular phylogeny and dynamic evolution of disease resistance genes in the legume family. AB - BACKGROUND: Legumes are the second-most important crop family in agriculture for its economic and nutritional values. Disease resistance (R-) genes play an important role in responding to pathogen infections in plants. To further increase the yield of legume crops, we need a comprehensive understanding of the evolution of R-genes in the legume family. RESULTS: In this study, we developed a robust pipeline and identified a total of 4,217 R-genes in the genomes of seven sequenced legume species. A dramatic diversity of R-genes with structural variances indicated a rapid birth-and-death rate during the R-gene evolution in legumes. The number of R-genes transiently expanded and then quickly contracted after whole-genome duplications, which meant that R-genes were sensitive to subsequent diploidization. R proteins with the Coiled-coil (CC) domain are more conserved than others in legumes. Meanwhile, other types of legume R proteins with only one or two typical domains were subjected to higher rates of loss during evolution. Although R-genes evolved quickly in legumes, they tended to undergo purifying selection instead of positive selection during evolution. In addition, domestication events in some legume species preferentially selected for the genes directly involved in the plant-pathogen interaction pathway while suppressing those R-genes with low occurrence rates. CONCLUSIONS: Our results provide insights into the dynamic evolution of R-genes in the legume family, which will be valuable for facilitating genetic improvements in the disease resistance of legume cultivars. PMID- 27229310 TI - Measurement and control of bias in patient reported outcomes using multidimensional item response theory. AB - BACKGROUND: Patient-reported outcome (PRO) measures play a key role in the advancement of patient-centered care research. The accuracy of inferences, relevance of predictions, and the true nature of the associations made with PRO data depend on the validity of these measures. Errors inherent to self-report measures can seriously bias the estimation of constructs assessed by the scale. A well-documented disadvantage of self-report measures is their sensitivity to response style (RS) effects such as the respondent's tendency to select the extremes of a rating scale. Although the biasing effect of extreme responding on constructs measured by self-reported tools has been widely acknowledged and studied across disciplines, little attention has been given to the development and systematic application of methodologies to assess and control for this effect in PRO measures. METHODS: We review the methodological approaches that have been proposed to study extreme RS effects (ERS). We applied a multidimensional item response theory model to simultaneously estimate and correct for the impact of ERS on trait estimation in a PRO instrument. Model estimates were used to study the biasing effects of ERS on sum scores for individuals with the same amount of the targeted trait but different levels of ERS. We evaluated the effect of joint estimation of multiple scales and ERS on trait estimates and demonstrated the biasing effects of ERS on these trait estimates when used as explanatory variables. RESULTS: A four-dimensional model accounting for ERS bias provided a better fit to the response data. Increasing levels of ERS showed bias in total scores as a function of trait estimates. The effect of ERS was greater when the pattern of extreme responding was the same across multiple scales modeled jointly. The estimated item category intercepts provided evidence of content independent category selection. Uncorrected trait estimates used as explanatory variables in prediction models showed downward bias. CONCLUSIONS: A comprehensive evaluation of the psychometric quality and soundness of PRO assessment measures should incorporate the study of ERS as a potential nuisance dimension affecting the accuracy and validity of scores and the impact of PRO data in clinical research and decision making. PMID- 27229311 TI - Signature motif-guided identification of receptors for peptide hormones essential for root meristem growth. AB - Peptide-mediated cell-to-cell signaling has crucial roles in coordination and definition of cellular functions in plants. Peptide-receptor matching is important for understanding the mechanisms underlying peptide-mediated signaling. Here we report the structure-guided identification of root meristem growth factor (RGF) receptors important for plant development. An assay based on a signature ligand recognition motif (Arg-x-Arg) conserved in a subfamily of leucine-rich repeat receptor kinases (LRR-RKs) identified the functionally uncharacterized LRR RK At4g26540 as a receptor of RGF1 (RGFR1). We further solved the crystal structure of RGF1 in complex with the LRR domain of RGFR1 at a resolution of 2.6 A, which reveals that the Arg-x-Gly-Gly (RxGG) motif is responsible for specific recognition of the sulfate group of RGF1 by RGFR1. Based on the RxGG motif, we identified additional four RGFRs. Participation of the five RGFRs in RGF-induced signaling is supported by biochemical and genetic data. We also offer evidence showing that SERKs function as co-receptors for RGFs. Taken together, our study identifies RGF receptors and co-receptors that can link RGF signals with their downstream components and provides a proof of principle for structure-based matching of LRR-RKs with their peptide ligands. PMID- 27229313 TI - Electrophysiologist shows a cation channel function of MLKL. AB - Whether mixed lineage kinase domain-like (MLKL) mediates necroptosis by forming ion channel, none-selective pore, or simply by disrupting plasma membrane is unclear. In a paper published in recent issue of Cell Research, Xia et al. showed that MLKL functions as a novel class of cation channel. PMID- 27229312 TI - RGF1 INSENSITIVE 1 to 5, a group of LRR receptor-like kinases, are essential for the perception of root meristem growth factor 1 in Arabidopsis thaliana. AB - RGF1, a secreted peptide hormone, plays key roles in root meristem development in Arabidopsis. Previous studies indicated that a functional RGF1 needs to be sulfated at a tyrosine residue by a tyrosylprotein sulfotransferase and that RGF1 regulates the root meristem activity mainly via two downstream transcription factors, PLETHORA 1 (PLT1) and PLT2. How extracellular RGF1 is perceived by a plant cell, however, is unclear. Using genetic approaches, we discovered a clade of leucine-rich repeat receptor-like kinases, designated as RGF1 INSENSITIVE 1 (RGI1) to RGI5, serving as receptors of RGF1. Two independent rgi1 rgi2 rgi3 rgi4 rgi5 quintuple mutants display a consistent short primary root phenotype with a small size of meristem. An rgi1 rgi2 rgi3 rgi4 quadruple mutant shows a significantly reduced sensitivity to RGF1, and the quintuple mutant is completely insensitive to RGF1. The expression of PLT1 and PLT2 is almost undetectable in the quintuple mutant. Ectopic expression of PLT2 driven by an RGI2 promoter in the quintuple mutant greatly rescued its root meristem defects. One of the RGIs, RGI1, was subsequently analyzed biochemically in detail. In vitro dot blotting and pull-down analyses indicated that RGI1 can physically interact with RGF1. Exogenous application of RGF1 can quickly and simultaneously induce the phosphorylation and ubiquitination of RGI1, indicating that RGI1 can perceive and transduce the RGF1 peptide signal. Yet, the activated RGI1 is likely turned over rapidly. These results demonstrate that RGIs, acting as the receptors of RGF1, play essential roles in RGF1-PLT-mediated root meristem development in Arabidopsis thaliana. PMID- 27229314 TI - Peer engagement in harm reduction strategies and services: a critical case study and evaluation framework from British Columbia, Canada. AB - BACKGROUND: Engaging people with drug use experience, or 'peers,' in decision making helps to ensure harm reduction services reflect current need. There is little published on the implementation, evaluation, and effectiveness of meaningful peer engagement. This paper aims to describe and evaluate peer engagement in British Columbia from 2010-2014. METHODS: A process evaluation framework specific to peer engagement was developed and used to assess progress made, lessons learned, and future opportunities under four domains: supportive environment, equitable participation, capacity building and empowerment, and improved programming and policy. The evaluation was conducted by reviewing primary and secondary qualitative data including focus groups, formal documents, and meeting minutes. RESULTS: Peer engagement was an iterative process that increased and improved over time as a consequence of reflexive learning. Practical ways to develop trust, redress power imbalances, and improve relationships were crosscutting themes. Lack of support, coordination, and building on existing capacity were factors that could undermine peer engagement. Peers involved across the province reviewed and provided feedback on these results. CONCLUSION: Recommendations from this evaluation can be applied to other peer engagement initiatives in decision-making settings to improve relationships between peers and professionals and to ensure programs and policies are relevant and equitable. PMID- 27229315 TI - Is a woolen cap effective in maintaining normothermia in low-birth-weight infants during kangaroo mother care? Study protocol for a randomized controlled trial. AB - BACKGROUND: Neonatal hypothermia is an important challenge associated with morbidity and mortality. Preventing neonatal hypothermia is important in high resource countries, but is of fundamental importance in low-resource settings where supportive care is limited. Kangaroo mother care (KMC) is a low-cost intervention that, whenever possible, is strongly recommended for temperature maintenance. During KMC, the World Health Organization (WHO) guidelines recommend the use of a cap/hat, but its effect on temperature control during KMC remains to be established. In the hospitals participating in the projects of the non governmental organization CUAMM, KMC represents a standard of care, but the heads of the babies often remain uncovered due to local habits or to the unavailability of a cap. The aim of the present study will be to assess the effectiveness and safety of using a woolen cap in maintaining normothermia in low-birth-weight infants (LBWI) during KMC. METHODS/DESIGN: This is a multicenter (three hospitals), multicountry (three countries), prospective, unblinded, randomized controlled trial of KMC treatment with and without a woolen cap in LBWI. After obtaining parental consent, all infants with a birth weight below 2500 g and who are candidates for KMC, based on the clinical decision of the attending physician, will be assigned to the KMC with a woolen cap group or to the KMC without a woolen cap group in a 1:1 ratio according to a computer-generated, randomized sequence. The duration of the study will be until the patient's discharge, with a maximum treatment duration of 7 days. The primary outcome measure will be whether the infants' temperatures remain within the normal range (36.5-37.5 degrees C) in the course of KMC during the intervention. In all participants, axillary temperature will be measured with a digital thermometer four times per day. In addition, maternal and room temperature will be recorded. Secondary outcome measures will be: episodes of apnea; sepsis; mortality before hospital discharge; in-hospital growth; and age at discharge. DISCUSSION: The findings of this study will be important for other units/settings in high- as well low-resource countries where KMC is routinely performed. Based on the results of the present study, we could speculate whether the use of a woolen cap may help to maintain the neonate within the normal thermal range. Furthermore, potential complications such as hyperthermia will be strictly monitored and collected. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02645526 (registered on 31 December 2015). PMID- 27229316 TI - Histone methyltransferase Ash1L mediates activity-dependent repression of neurexin-1alpha. AB - Activity-dependent transcription is critical for the regulation of long-term synaptic plasticity and plastic rewiring in the brain. Here, we report that the transcription of neurexin1alpha (nrxn1alpha), a presynaptic adhesion molecule for synaptic formation, is regulated by transient neuronal activation. We showed that 10 minutes of firing at 50 Hz in neurons repressed the expression of nrxn1alpha for 24 hours in a primary cortical neuron culture through a transcriptional repression mechanism. By performing a screening assay using a synthetic zinc finger protein (ZFP) to pull down the proteins enriched near the nrxn1alpha promoter region in vivo, we identified that Ash1L, a histone methyltransferase, is enriched in the nrxn1alpha promoter. Neuronal activity triggered binding of Ash1L to the promoter and enriched the histone marker H3K36me2 at the nrxn1alpha promoter region. Knockout of Ash1L in mice completely abolished the activity dependent repression of nrxn1alpha. Taken together, our results reveal that a novel process of activity-dependent transcriptional repression exists in neurons and that Ash1L mediates the long-term repression of nrxn1alpha, thus implicating an important role for epigenetic modification in brain functioning. PMID- 27229317 TI - NHERF1/EBP50 and NF2 as diagnostic markers for choroid plexus tumors. AB - The adaptor protein NHERF1 (Na/H exchanger-3 regulatory factor-1) and its associated ezrin-radixin-moesin-merlin/neurofibromin-2 (ERM-NF2) family proteins are required for epithelial morphogenesis and have been implicated in cancer progression. NHERF1 is expressed in ependymal cells and constitutes a highly sensitive diagnostic marker for ependymoma, where it labels membrane polarity structures. Since NHERF1 and ERM-NF2 proteins show polarized expression in choroid plexus (CP) cells, we tested their diagnostic utility in CP neoplasms. NHERF1 immunohistochemistry in 43 adult and pediatric tumors with papillary morphology revealed strong apical plasma membrane staining in CP papilloma (WHO grade I) and cytoplasmic expression in CP carcinoma (WHO grade III). Ezrin and moesin showed similar but less distinctive staining. NHERF1 also labeled papillary tumors of the pineal region in a microlumen and focal apical membrane pattern, suggestive of a transitional morphology between CP papilloma and ependymoma. CP tumors of all grades could be differentiated from metastatic carcinomas with papillary architecture by NF2, which showed polarized membranous staining in CP tumors. NHERF1 and NF2 immunohistochemistry showed enhanced sensitivity and specificity for CP tumors compared to commonly used markers, including cytokeratins and Kir7.1, emerging as reliable diagnostic tools for the differential diagnosis of papillary tumors of the central nervous system. PMID- 27229318 TI - Reasons for accepting or declining Down syndrome screening in Dutch prospective mothers within the context of national policy and healthcare system characteristics: a qualitative study. AB - BACKGROUND: Uptake rates for Down syndrome screening in the Netherlands are low compared to other European countries. To investigate the low uptake, we explored women's reasons for participation and possible influences of national healthcare system characteristics. Dutch prenatal care is characterised by an approach aimed at a low degree of medicalisation, with pregnant women initially considered to be at low risk. Prenatal screening for Down syndrome is offered to all women, with a 'right not to know' for women who do not want to be informed on this screening. At the time this study was performed, the test was not reimbursed for women aged 35 and younger. METHODS: We conducted a qualitative study to explore reasons for participation and possible influences of healthcare system characteristics. Data were collected via ten semi-structured focus groups with women declining or accepting the offer of Down syndrome screening (n = 46). All focus groups were audio- and videotaped, transcribed verbatim, coded and content analysed. RESULTS: Women declining Down syndrome screening did not consider Down syndrome a condition severe enough to justify termination of pregnancy. Young women declining felt supported in their decision by perceived confirmation of their obstetric caregiver and reassured by system characteristics (costs and age restriction). Women accepting Down syndrome screening mainly wanted to be reassured or be prepared to care for a child with Down syndrome. By weighing up the pros and cons of testing, obstetric caregivers supported young women who accepted in the decision-making process. This was helpful, although some felt the need to defend their decision to accept the test offer due to their young age. For some young women accepting testing, costs were considered a disincentive to participate. CONCLUSIONS: Presentation of prenatal screening affects how the offer is attended to, perceived and utilised. By offering screening with age restriction and additional costs, declining is considered the preferred choice, which might account for low Dutch uptake rates. Autonomous and informed decision making in Down syndrome screening should be based on the personal interest in knowing the individual risk of having a child with Down syndrome and system characteristics should not influence participation. PMID- 27229319 TI - Ratio of surface roughness to flow scale as additional parameter for shear induced hemolysis. AB - BACKGROUND: In addition to the conventional knowledge that shear stress and its exposure time should have a large impact on hemolysis, it became obvious through Dr. Maruyama's study that surface roughness would be the additional factor for high shear-induced hemolysis. Concerning this new information, we hypothesized that the ratio of surface roughness to the flow scale should play a role as the additional factor for shear-induced hemolysis. The purpose of this study was to develop a constant shear generator as the method to provide a controlled shear flow field with the combination between the controlled surface roughness and the flow scale to the blood cells. Its preliminary application was to validate our hypothesis. METHODS: We prototyped the constant shear stress generator with the cylindrical cone-cup structure made from the acrylic material. This chamber had 3 flow scales of 1.00, 1.25, and 1.5 mm according to the change of the inner stationary cone, at which the surface roughness was distributed into the several levels between 0.14 and 0.92 micrometers in arithmetic average roughness. Using this shear chamber, we examined what effect the flow scale and the surface roughness had on hemolysis. RESULTS: Our experimental data showed the tendency of a positive correlation between the ratio of surface roughness to the flow scale and the induced hemolysis levels, validating our hypothesis. CONCLUSIONS: The ratio of the surface roughness to the flow scale should be the additional parameter for shear-induced hemolysis. PMID- 27229320 TI - Peritoneal dialysis use within the context of the population and healthcare systems of Europe - differences, trends and future challenges. AB - INTRODUCTION: Peritoneal dialysis (PD) and haemodialysis (HD) are complementary therapies in end-stage renal disease (ESRD). Despite survival benefit, PD remains an underused therapy with variable utilisation and a common descriptive framework for this variation is not established. We reviewed the renal literature, general population and healthcare data to examine factors leading to variable PD use in Europe and possible changes in the future. METHODS: ERA-EDTA data were used to examine PD distribution in Europe. Statistics and descriptive data about population structure and living conditions published by Eurostat, the World Health Organization (WHO) and the European Observatory were examined. Published literature (Pubmed), health system data (formal internet search approach) and professional body data (internet and personal communication) were examined to describe the factors that may explain PD variation. RESULTS: PD usage varies across Europe and analysis of contributing factors enabled the development of a descriptive framework. PD variation cannot be entirely explained by the reimbursement system. It appears that factors specific to countries and centres as well as personalised ones involving patient-physician interaction are the most influential. The current and projected European population demographics and living conditions will lead to more elderly patients who live alone being on dialysis. DISCUSSION: Factors relating to the patient-physician interaction are prime determinants around the utilization of PD. Population demographic change will lead to additional challenges to renal services. The descriptive framework postulated should be considered in strategic dialysis service planning and future product design to meet the needs of future dialysis patients and deliver patient choice. PMID- 27229321 TI - Veno-arterial ECMO for rescue of severe airway hemorrhage with rigid bronchoscopy after pulmonary artery thromboendarterectomy. AB - Pulmonary endarterectomy (PEA) is the treatment of choice to relieve pulmonary artery obstruction in patients with chronic thromboembolic pulmonary hypertension (CTEPH). We present a patient with airway obstruction and acute respiratory failure due to large blood clots obstructing the trachea and main left bronchus. This condition was accompanied by right ventricle failure and cardiogenic shock. A venoarterial ECMO system was used for cardiopulmonary support before extracting the clots and clearing the airway by rigid bronchoscopy. PMID- 27229322 TI - Achieving optimal cancer outcomes in East Africa through multidisciplinary partnership: a case study of the Kenyan National Retinoblastoma Strategy group. AB - BACKGROUND: Strategic, interdisciplinary partnerships are essential to addressing the complex drivers of health inequities that result in survival disparities worldwide. Take for example the aggressive early childhood eye cancer retinoblastoma, where survival reaches 97 % in resource-rich countries, but is as low 30 % in some resource-limited nations, where 92 % of the burden lies. This suggests a need for a multifaceted approach to achieve a tangible and sustainable increase in survival. METHODS: We assembled the history the Kenyan National Retinoblastoma Strategy (KNRbS), using information documented in NGO reports, grant applications, news articles, meeting agendas and summaries. We evaluated the KNRbS using the principles found in the guide for transboundary research partnerships developed by the Swiss Commission for Research Partnerships with Developing Countries. RESULTS: A nationally co-ordinated approach drawing input and expertise from multiple disciplines and sectors presented opportunities to optimise cure of children with retinoblastoma. Annual meetings were key to achieving the over 40 major outputs of the group's efforts, related to Awareness, Medical Care, Family Support and Resource Mobilization. Three features were found to be critical to the KNRbS success: multidisciplinarity, consistency and flexibility. CONCLUSION: The KNRbS has achieved a number of key outputs with limited financial investment. As a partnership, the KNRbS meets most of the criteria identified for success. Challenges remain in securing the long-term sustainability of its achievements. Elements of the Kenyan National Retinoblastoma Strategy may be useful to other developing countries struggling with limited survival of retinoblastoma and other cancers or rare diseases. PMID- 27229323 TI - Pathogenesis and Subtype of Intracerebral Hemorrhage (ICH) and ICH Score Determines Prognosis. AB - CDATA[Whether original intracerebral hemorrhage (ICH) score can be used to predict clinical outcomes in patients with SMASH-U (structural vascular lesions, medication, cerebral amyloid angiopathy, systemic disease, hypertension, or undetermined) classification remains an open question. This study obtained data related to consecutive acute patients with ICH from 21 tertiary hospitals in China during January 2012 to December 2014. Using the SMASH-U method, patients were classified into 6 subtypes. Favorable functional outcome and mortality was obtained after ICH at the 3 months. We used logistic regression to evaluate the effectiveness of each risk model in predicting clinical outcome and under the receiver operating characteristic curves (ROC) to assess performance. A total of 3475 patients were included, the most common cause was hypertensive angiopathy (n=1279, 36.81%), followed by undetermined (n=1168, 33.61%), cerebral amyloid angiopathy (CAA) (n=507, 14.59%), structural vascular lesions (n=368, 10.59%), medication (n=96, 2.76%), and systemic disease (n=57, 1.64%). For good clinical outcome (mRS<=2), the ROC values of original ICH score were 0.781, 0.701, 0.718, 0.722, 0.788, and 0.771, while for the mortality in 3-month, the ROC values of original ICH score were 0.840, 0.734, 0.836, 0.722, 0.785, 0.820, and 0.734 according to SMASH-U pathogenic classification, respectively. The ability of original ICH score may be well differentiated among the 6 ICH pathogeneses. Thus, physicians should select different risk score according to different etiological ICH. PMID- 27229324 TI - The Balance between Conventional DCs and Plasmacytoid DCs Is Pivotal for Immunological Tolerance during Pregnancy in the Mouse. AB - Dendritic cells (DCs), which can shape their functions depending on the microenvironment, are crucial for the delicate balance of immunity and tolerance during pregnancy. However, the mechanism underlying the microenvironment-educated plasticity of DC differentiation during pregnancy remains largely unclear. Here, we found that the differentiation of conventional DCs (cDCs) and plasmacytoid DCs (pDCs) is regulated in a tissue-specific manner during pregnancy. The ratio of cDCs and pDCs remained constant in the spleen. However, the ratio changed in the para-aortic lymph nodes (LNs), where cDC percentages were significantly reduced concurrent with an increase in pDCs from E8.5 to E16.5. Moreover, the expansion of pDCs and T regulatory (Treg) cells was correlated in the para-aortic LNs, and pDCs had more potential to induce regulatory T cells (Tregs) compared with cDCs (independent of IDO expression). Notably, the balance between cDCs and pDCs is disrupted in IFN-gamma-induced abnormal pregnancy, accompanied by lower Treg percentages in the para-aortic LNs and decidua. To further identify the underlying mechanism, we found that elevated IFN-gamma can increase the levels of GM-CSF to alter the differentiation of pDCs into cDCs in vivo. Therefore, we provide a novel regulatory mechanism underlying pregnancy-related immune tolerance that involves the balance of DC subsets, which may offer a new target for the prevention of human spontaneous abortion. PMID- 27229325 TI - A new family of bizarre durophagous carnivorous marsupials from Miocene deposits in the Riversleigh World Heritage Area, northwestern Queensland. AB - A new specimen of the bizarrely specialised Malleodectes mirabilis from middle Miocene deposits in the Riversleigh World Heritage Area provides the first and only information about the molar dentition of this strange group of extinct marsupials. Apart from striking autapomorphies such as the enormous P3, other dental features such as stylar cusp D being larger than B suggest it belongs in the Order Dasyuromorphia. Phylogenetic analysis of 62 craniodental characters places Malleodectes within Dasyuromorphia albeit with weak support and without indication of specific relationships to any of the three established families (Dasyuridae, Myrmecobiidae and Thylacinidae). Accordingly we have allocated Malleodectes to the new family, Malleodectidae. Some features suggest potential links to previously named dasyuromorphians from Riversleigh (e.g., Ganbulanyi) but these are too poorly known to test this possibility. Although the original interpretation of a steeply declining molar row in Malleodectes can be rejected, it continues to seem likely that malleodectids specialised on snails but probably also consumed a wider range of prey items including small vertebrates. Whatever their actual diet, malleodectids appear to have filled a niche in Australia's rainforests that has not been occupied by any other mammal group anywhere in the world from the Miocene onwards. PMID- 27229327 TI - Women With Cardiogenic Shock Derive Greater Benefit From Early Mechanical Circulatory Support: An Update From the cVAD Registry. AB - OBJECTIVES: The aim of this analysis was to assess survival differences between men and women supported with Impella 2.5 (Abiomed Inc., Danvers) in the setting of acute myocardial infarction (AMI) complicated by cardiogenic shock (CS). BACKGROUND: Data on sex differences in outcomes of CS with mechanical circulatory support are sparse. METHODS: Patients enrolled in the cVAD Registry who underwent percutaneous coronary intervention (PCI) and Impella 2.5 support for CS complicating an AMI were included. Differences between men and women were examined. RESULTS: In total, 180 patients were analyzed. Women (n = 49, 27.2%) were older (71.0 +/- 12.8 years vs 63.8 +/- 13.0, P = 0.001), smaller (BSA 1.82 +/- 0.22 vs 2.04 +/- 0.24 m(2) , P < 0.001), and had a higher STS mortality risk score than men (27.9 +/- 17.0 vs. 20.8 +/- 16.8 P = 0.01). There was no difference in survival to discharge (P = 0.3). Patients receiving the Impella 2.5 pre-PCI had significantly lower inpatient mortality than those who received support post-PCI (P = 0.003). However, the magnitude of the survival benefit was significantly greater in women who received the Impella pre-PCI as compared to men. Overall, 68.8% of women survived with pre-PCI Impella 2.5 versus 24.2% post PCI (P = 0.005) whereas 54.2% of men survived with pre-PCI Impella 2.5 versus 40.3% post-PCI (P = 0.1, p-interaction = 0.07). No differences in timing to intervention were found between men and women. CONCLUSIONS: Early initiation of hemodynamic support prior to PCI with Impella 2.5, in the setting of AMI complicated by CS, was associated with a greater survival benefit to hospital discharge in women compared to men, despite a higher predicted risk of mortality and a greater revascularization failure rate for women. (J Interven Cardiol 2016;29:248-256). PMID- 27229326 TI - Protein rethreading: A novel approach to protein design. AB - Protein engineering is an important tool for the design of proteins with novel and desirable features. Templates from the protein databank (PDB) are often used as initial models that can be modified to introduce new properties. We examine whether it is possible to reconnect a protein in a manner that generates a new topology yet preserves its structural integrity. Here, we describe the rethreading of dihydrofolate reductase (DHFR) from E. coli (wtDHFR). The rethreading process involved the removal of three native loops, and the introduction of three new loops with alternate connections. The structure of the rethreaded DHFR (rDHFR-1) was determined to 1.6 A, demonstrating the success of the rethreading process. Both wtDHFR and rDHFR-1 exhibited similar affinities towards methotrexate. However, rDHFR-1 showed no reducing activity towards dihydrofolate, and exhibited about ~6-fold lower affinity towards NADPH than wtDHFR. This work demonstrates that protein rethreading can be a powerful tool for the design of a large array of proteins with novel structures and topologies, and that by careful rearrangement of a protein sequence, the sequence to structure relationship can be expanded substantially. PMID- 27229329 TI - Erratum to: Variability of State School-Based Hearing Screening Protocols in The United States. PMID- 27229328 TI - Efficient suilysin-mediated invasion and apoptosis in porcine respiratory epithelial cells after streptococcal infection under air-liquid interface conditions. AB - Streptococci may colonize the epithelium in the airways and other entry sites. While local infection often remains asymptomatic, severe or even fatal diseases occur when streptococci become invasive and spread to different sites in the infected host. We have established porcine respiratory air-liquid interface cultures (ALI) from the porcine lung to analyze the interaction of streptococci with their primary target cells. As representative of the streptococcal family we chose Streptococcus suis (S. suis) that is not only a major swine respiratory pathogen but can also infect humans. Suilysin, a cholesterol-dependent cytolysin (CDC), is an important virulence factor. By comparing a S. suis wt strain with a suilysin-deficient mutant, we demonstrate that suilysin contributes to (i) adherence to airway cells (ii) loss of ciliated cells (iii) apoptosis, and (iv) invasion. Furthermore, we show that cytolytic activity of suilysin is crucial for these effects. A striking result of our analysis was the high efficiency of S. suis-induced apoptosis and invasion upon infection under ALI conditions. These properties have been reported to be less efficient when analyzed with immortalized cells. We hypothesize that soluble effectors such as suilysin are present at higher concentrations in cells kept at ALI conditions and thus more effective. These results should be relevant also for infection of the respiratory tract by other respiratory pathogens. PMID- 27229330 TI - A look inside the mechanistic black box: Are red blood cells the critical effectors of RRx-001 cytotoxicity? AB - The therapeutic potential of epi-immunotherapeutic anticancer agent RRx-001 in cancer has been validated with preclinical and clinical studies, since RRx-001 has successfully completed a phase 1 trial and multiple single-agent and combination phase 2 trials with preliminary evidence of promising activity are underway. Previous experimental work has implicated diverse anticancer mechanisms such as oxidative stress, ATP and NADPH depletion, anti-angiogenesis and epigenetic modulation in the overall antitumor effect of RRx-001. The hypothesis of this study was that the RRx-001 red blood cells are the essential and de facto intermediaries responsible for the reprograming of tumor behavior via transfer of their intracellular and membrane contents. To test this hypothesis, and thereby resolve the "black box" incompleteness in the continuity of the mechanism, the fate of red blood cells incubated with RRx-001 was explored in vitro and in vivo both in healthy animals and in tumor-bearing mice. The collective results establish that RRx-001-derivatized red blood cells are the critical "missing links" to explain the specificity and anticancer activity of RRx-001, including its immunomodulatory effects on tumor-associated macrophages. These experimental results delineate a novel erythrocyte-based mechanism without precedent in the annals of oncology and open the door to rational combination strategies with RRx 001 both in cancer therapy and beyond, particularly in disease states that affect red blood cell and vascular function such as malaria, leishmaniasis, sickle-cell disease and hemorrhagic shock. PMID- 27229331 TI - A tribute to the memory of Dr. Kenji Honda. PMID- 27229332 TI - Cerebral Microemboli Detection and Differentiation During Transcatheter Closure of Patent Ductus Arteriosus. AB - The aim of this prospective study was to determine the frequency and composition of cerebral microemboli in a pediatric population, during transcatheter closure of patent ductus arteriosus (PDA). Multifrequency transcranial Doppler was used to monitor cerebral blood flow velocity (CBFV) and detect microembolic signals (MES) in the middle cerebral artery in 23 patients (median age 18 months). MES were automatically identified and differentiated according to composition; gaseous or solid. The procedure was divided into five periods: Arterial catheterization; venous catheterization; ductal catheterization; angiography; device placement and release. Timing of catheter manipulations and MES were registered and compared. MES were detected in all patients. The median number of signals was 7, (minimum 1, maximum 28). Over 95 % of all MES were gaseous. 11 % were detected during device placement while 64 % were detected during angiographic studies, significantly higher than during any other period (P < 0.001). There was a moderate correlation between the number of MES and volume of contrast used, (R = 0.622, P < 0.01). There was no correlation with fluoroscopic time or duration of procedure. This is the first study to investigate the timing and composition of cerebral microemboli during PDA occlusion. Microemboli were related to specific catheter manipulations and correlated with the amount of contrast used. PMID- 27229333 TI - Heparin-induced thrombocytopenia: reducing misdiagnosis via collaboration between an inpatient anticoagulation pharmacy service and hospital reference laboratory. AB - Misdiagnosis of heparin-induced thrombocytopenia (HIT) is common and exposes patients to high-risk therapies and potentially serious adverse events. The primary objective of this study was to evaluate the impact of collaboration between an inpatient pharmacy-driven anticoagulation management service (AMS) and hospital reference laboratory to reduce inappropriate HIT antibody testing via pharmacist intervention and use of the 4T pre-test probability score. Secondary objectives included clinical outcomes and cost-savings realized through reduced laboratory testing and decreased unnecessary treatment of HIT. This was a single center, pre-post, observational study. The hospital reference laboratory contacted the AMS when they received a blood sample for an enzyme-linked immunosorbent HIT antibody (HIT Ab). Trained pharmacists prospectively scored each HIT Ab ordered by using the 4T score with subsequent communication to physicians recommending for or against processing and reporting of lab results. Utilizing retrospective chart review and a database for all patients with a HIT Ab ordered during the study period, we compared the incidence of HIT Ab testing before and after implementation of the pharmacy-driven 4T score intervention. Our intervention significantly reduced the number of inappropriate HIT Ab tests processed (176 vs. 63, p < 0.0001), with no increase in thrombotic or hemorrhagic events. Overall incidence of suspected and confirmed HIT was <3 and <0.005 %, respectively. Overall cost savings were $75,754 (US) or 62 % per patient exposed to heparin between the pre and post intervention groups. Collaboration between inpatient pharmacy AMS and hospital reference laboratories can result in reduction of misdiagnosis of HIT and significant cost savings with similar safety. PMID- 27229334 TI - In dubious battle: bleeding versus ischemic events. PMID- 27229335 TI - The National Osteoporosis Foundation's methods and processes for developing position statements. AB - The methods and processes described in this manuscript have been approved and adopted by the NOF Board of Trustees on November 11, 2015. This manuscript has been peer-reviewed by the NOF Research Committee and Osteoporosis International. The National Osteoporosis Foundation frequently publishes position statements for the benefit of educating healthcare professionals and the general public on a particular issue and/or concern related to preventing osteoporosis and/or promoting strong bones throughout the lifespan. This manuscript represents the official methods and processes adopted by the NOF Board of Trustees for the purpose developing future position statements in a transparent and unbiased manner. PMID- 27229336 TI - Inhibition of tyrosine phenol-lyase by tyrosine homologues. AB - We have designed, synthesized, and evaluated tyrosine homologues and their O methyl derivatives as potential inhibitors for tyrosine phenol lyase (TPL, E.C. 4.1.99.2). Recently, we reported that homologues of tryptophan are potent inhibitors of tryptophan indole-lyase (tryptophanase, TIL, E.C. 4.1.99.1), with K i values in the low uM range (Do et al. Arch Biochem Biophys 560:20-26, 2014). As the structure and mechanism for TPL is very similar to that of TIL, we postulated that tyrosine homologues could also be potent inhibitors of TPL. However, we have found that homotyrosine, bishomotyrosine, and their corresponding O-methyl derivatives are competitive inhibitors of TPL, which exhibit K i values in the range of 0.8-1.5 mM. Thus, these compounds are not potent inhibitors, but instead bind with affinities similar to common amino acids, such as phenylalanine or methionine. Pre-steady-state kinetic data were very similar for all compounds tested and demonstrated the formation of an equilibrating mixture of aldimine and quinonoid intermediates upon binding. Interestingly, we also observed a blue shift for the absorbance peak of external aldimine complexes of all tyrosine homologues, suggesting possible strain at the active site due to accommodating the elongated side chains. PMID- 27229337 TI - Assessments of pulmonary vein and left atrial anatomical variants in atrial fibrillation patients for catheter ablation with cardiac CT. AB - OBJECTIVES: To provide a road map of pulmonary vein (PV) and left atrial (LA) variants in patients with atrial fibrillation (AF) before catheter ablation procedure using cardiac CT. METHODS: Cardiac CT was performed in 1420 subjects for accurate anatomical information, including 710 patients with AF and 710 matched controls without AF. PV variants, PV ostia and spatial orientation, LA enlargement, and left atrial diverticulum (LAD) were measured, respectively. Differences between these two groups were also respectively compared. Some risk factors for the occurrence of LAD were analyzed. RESULTS: In total, PV variants were observed in 202 (28.5 %) patients with AF patients and 206 (29.0 %) controls without AF (p = 0.8153). The ostial sizes of all accessory veins were generally smaller than those of the typical four PVs (p = 0.0153 to 0.3958). There was a significant difference of LA enlargement between the AF and control groups (36.3 % vs. 12.5 %, p < 0.0001), while the prevalence of LAD was similar in these two groups (43.2 % vs. 41.9 %, p = 0.6293). CONCLUSION: PV variants are common. Detailed knowledge of PVs and LA variants are helpful for providing anatomical road map to determine ablation strategy. KEY POINTS: * PVs variants are helpful for providing anatomical road map to ablation. * PV variants are common. * DSCT could recognize these anatomic features before ablation as a non-invasive imaging. PMID- 27229339 TI - CT measurement of breast glandular tissue and its association with testicular cancer. AB - OBJECTIVES: To evaluate the associations between breast glandular tissues diameters as determined by CT and b-hCG levels, histological types, tumour spread and prognosis in patients with testicular germ cell tumour. METHODS: Ninety-four patients with pre-treatment CT scan and markers (b-hCG, AFP, LDH) were retrospectively collected. A radiologist measured diameters in all CT examinations and correlation between diameters and log (b-hCG) was assessed (Pearson's coefficient). The ability of measured diameters to predict lymphatic and distant haematogenous metastatic spread was evaluated (ROC curves). The associations between measured diameter cut-off values of 20 and 25 mm and International Germ Cell Cancer Collaborative Group (IGCCCG) classification, lymphatic and distant haematogenous metastatic spread and histological subtypes were evaluated (chi squared test). RESULTS: Breast glandular diameters correlated to log(b-hCG) (r = 0.579) and predicted distant haematogenous metastatic spread (AUC = 0.78). Worse prognosis (intermediate or poor IGCCCG) was shown for 20 mm (27.3 vs. 4.2 %, p = 0.005) and 25 mm (33.3 vs. 6.1 %, p = 0.014). A diameter of 25 mm was associated with non-seminoma (91.7 vs. 48.8 %, p = 0.005). CONCLUSION: Breast glandular tissue diameters correlated with log(b-hCG) and predicted distant haematogenous metastases. Twenty and 25 mm were associated with worse prognosis and 25 mm was able to distinguish between seminoma and non-seminoma. KEY POINTS: * CT breast glandular tissue diameter correlates with log(b-HCG) * Gynaecomastia in CT is associated with worse prognosis * Gynaecomastia in CT is associated with non-seminoma histological subtype. PMID- 27229338 TI - Short & long term adverse outcomes after arterial embolisation for the treatment of postpartum haemorrhage: a systematic review. AB - OBJECTIVES: Arterial embolisation (AE) plays a major role in current practice in the management of postpartum haemorrhage (PPH) that fails to respond to conservative treatment. While its benefit is well known, long-term outcomes of AE have been poorly investigated. The objective of this review is to assess its potential complications and long-term effects on the patients' quality of life. METHODS: Using the terms "embolisation" and "postpartum haemorrhage", we searched the Cochrane Central Register of Controlled Trials, Medline and PubMed for published studies. We limited the search to articles in English and French reporting "complications", "fertility", "menstruation" or "menstrual cycle" in humans. To ensure completeness, the references of extracted articles and review articles were also searched. RESULTS: The fertility rate in patients attempting another pregnancy reaches 70-80 %. Pregnancies following AE for PPH are not associated with a higher rate of intrauterine growth restriction. Pathological placentation (placenta accreta/increta/percreta) occurs more frequently after AE than in the general population. Psychological wellbeing, post-traumatic stress and sexual dysfunction after a life-threatening PPH requiring AE will require further investigation. CONCLUSION: AE does not appear to adversely affect menstrual cycle, fertility and subsequent pregnancies, but may affect placentation. The experience of a life-threatening PPH, however, might prevent couples from pursuing another pregnancy. KEY POINTS: * Embolisation for PPH does not adversely affect menstrual cycle and fertility * Experience of life threatening PPH might prevent couples from pursuing another pregnancy * Pathological placentation seems to occur more frequently after embolisation for PPH. PMID- 27229340 TI - Altered signal intensity of active enhancing inflammatory lesions using post contrast double inversion recovery MR sequence. AB - OBJECTIVES: We aimed at establishing the impact upon gadolinium administration on the conspicuity of active enhancing multiple sclerosis (MS) lesions using double inversion recovery (DIR) at 3T. METHODS: 15 consecutive patients with MS (n=8) or a clinically isolated syndrome (n=7) underwent pre and post-contrast DIR in addition to T2-weighted, FLAIR, pre and post-contrast T1-weighted sequences. First, two neuroradiologists located and marked all the enhancing MS lesions visible in consensus. Second, two other neuroradiologists, blinded to other sequences than DIR, independently assessed the SI changes from pre to post contrast DIR images for each enhancing lesion, according to a 4-point-scale: increased SI (grade 1), absence of change (grade 2), lesion being partially (grade 3) or completely masked on post-contrast DIR images (grade 4). RESULTS: 246 MS lesions were detected including 26 enhancing on post-contrast T1-weighted images in 9 patients. The two blinded readers concluded to a decreased signal intensity on post-contrast DIR images for all the 26 enhancing MS lesions (14 of grade 3 and 12 of grade 4). Inter-observer agreement was excellent, Kappa=0.85 (0.75 - 0.94). Using DIR post-contrast leads to altered signal-intensity of enhancing active MS lesions, ranging from partial to complete signal-loss. CONCLUSION: Our study strongly suggests the use of DIR before gadolinium administration. KEY POINTS: * DIR has gained widespread use in MS. * MRI protocols for MS patients usually contain several post-contrast sequences. * Signal-intensity of enhancing MS lesions is altered using DIR post-contrast. * Our study strongly suggests the use of DIR before gadolinium administration. PMID- 27229341 TI - Impact of coronary revascularization vs medical therapy on ischemia among stable patients with or suspected coronary artery disease undergoing serial myocardial perfusion scintigraphy. AB - BACKGROUND: Randomized trials have challenged the role of revascularization in stable coronary artery disease. We aimed to appraise the impact of revascularization on ischemia in patients undergoing serial myocardial perfusion scintigraphy (MPS). METHODS: We queried our institutional database for stable subjects undergoing serial MPS and appraised the impact of revascularization on changes in ischemia. RESULTS: A total of 3631 patients were included: 967 (27%) undergoing revascularization and 2664 (73%) receiving medical therapy only. Patients treated with revascularization had a significantly lower burden of myocardial ischemia at follow-up (odds ratio = 0.577 [95% confidence interval 0.483-0.689] vs medical therapy, P < .001). Among all those having moderate or severe ischemia at baseline, revascularization was associated with a follow-up prevalence of 80% for no, minimal, or mild ischemia and 20% for moderate or severe ischemia, vs 43% and 57% for medical therapy (P < .001). Even at multivariable analysis and propensity-adjusted, and propensity-matched analyses, revascularization was associated with a significantly lower prevalence of moderate or severe ischemia at follow-up (respectively P < .001, P = .001, and P = .042). CONCLUSIONS: Revascularization appears superior to medical therapy in reducing ischemic burden and normalizing myocardial perfusion among subjects with moderate or severe ischemia at baseline. PMID- 27229342 TI - Budget impact of applying appropriateness criteria for myocardial perfusion scintigraphy: The perspective of a developing country. AB - Myocardial perfusion imaging is widely used for the risk stratification of coronary artery disease. In view of its cost, besides radiation issues, judicious evaluation of the appropriateness of its indications is essential to prevent an unnecessary economic burden on the health system. We evaluated, at a tertiary care, public Brazilian hospital, the appropriateness of myocardial perfusion scintigraphy indications, and estimated the budget impact of applying appropriateness criteria. An observational, cross-sectional study of 190 patients with suspected or known coronary artery disease referred for myocardial perfusion imaging was conducted. The appropriateness of myocardial perfusion imaging indications was evaluated with the Appropriate Use Criteria for Cardiac Radionuclide Imaging published in 2009. Budget impact analysis was performed with a deterministic model. The prevalence of appropriate requests was 78%; of inappropriate indications, 12%; and of uncertain indications, 10%. Budget impact analysis showed that the use of appropriateness criteria, applied to the population referred to myocardial perfusion scintigraphy within 1 year, could generate savings of $ 64,252.04 dollars. The 12% inappropriate requests for myocardial perfusion scintigraphy at a tertiary-care hospital suggest that a reappraisal of MPI indications is needed. Budget impact analysis estimated resource savings of 18.6% with the establishment of appropriateness criteria for MPI. PMID- 27229343 TI - Topical issue on Multi-scale phenomena in complex flows and flowing matter. PMID- 27229344 TI - Applying the Model of Goal-Directed Behavior, Including Descriptive Norms, to Physical Activity Intentions: A Contribution to Improving the Theory of Planned Behavior. AB - The theory of planned behavior (TPB) has received its fair share of criticism lately, including calls for it to retire. We contribute to improving the theory by testing extensions such as the model of goal-directed behavior (MGDB, which adds desire and anticipated positive and negative emotions) applied to physical activity (PA) intention. We also test the inclusion of a descriptive norms construct as an addition to the subjective norms construct, also applied to PA, resulting in two additional models: TPB including descriptive norms (TPB + DN) and MGDB including descriptive norms (MGDB + DN). The study is based on an online survey of 400 young adult Internet users, previously enrolled in a subject pool. Confirmatory factor analysis (CFA) showed that TPB and TPB + DN were not fit for purpose, while MGDB and MGDB + DN were. Structural equation modelling (SEM) conducted on MGDB and MGDB + DN showed that the inclusion of descriptive norms took over the significance of injunctive norms, and increased the model's account of total variance in intention to be physically active. PMID- 27229347 TI - Vitamin D in Kidney Transplant Recipients: Mechanisms and Therapy. AB - Chronic kidney disease-mineral and bone disorder (CKD-MBD) is common in kidney transplant recipients (KTRs), where secondary hyperparathyroidism (HPTH) and post transplantation bone disease (PTBD) are potential effectors of both graft and vascular aging. Reduced 25(OH)D levels are highly prevalent in KTRs. Experimental and clinical evidence support the direct involvement of deranged vitamin D metabolism in CKD-MBD among KTRs. This review analyzes the pathophysiology of vitamin D derangement in KTRs and its fall out on patient and graft outcome, highlighting the roles of both nutritional and active vitamin D compounds to treat PTBD, cardiovascular disease (CVD) and graft dysfunction. Fibroblast growth factor-23-parathyroid hormone (PTH)-vitamin D axis, immunosuppressive therapy and previous bone status have been associated with PTBD. Although several studies reported reduced PTH levels in KTRs receiving nutritional vitamin D, its effects on bone mineral density (BMD) remain controversial. Active vitamin D reduced PTH levels and increased BMD after transplantation, but paricalcitol treatment was not accompanied by benefits on osteopenia. Vitamin D is considered protective against CVD due to the widespread pleiotropic effects, but data among KTRs remain scanty. Although vitamin deficiency is associated with lower glomerular filtration rate (GFR) and faster estimated GFR decline and data on the anti proteinuric effects of vitamin D receptor activation (VDRA) in KTRs sound encouraging, reports on related improvement on graft survival are still lacking. Clinical data support the efficacy of VDRA against HPTH and show promising evidence of VDRA's effect in counteracting post-transplant proteinuria. New insights are mandatory to establish if the improvement of surrogate outcomes will translate into better patient and graft outcome. PMID- 27229346 TI - Post-translational modification profiling - A novel tool for mapping the protein modification landscape in cancer. AB - The ubiquitin system plays an important role in essentially every cellular process, regulating numerous pathways ranging from development, transcription, DNA damage response, cell cycle, and signal transduction. Its best studied role involves removal of faulty proteins or those that are not necessary anymore. Aberrations in the ubiquitin system have been implicated in various pathologies including cancer, where specific mutations in E3 ligases such as Mdm2, pVHL, and BRCA1 have been linked to disease progression, prognosis, and resistance to drugs. Yet, there are hundreds of E3 ligases in the human genome and our knowledge of their target proteins and their dynamic regulation in the cellular environment is largely limited. In addition, fundamental questions related to recognition and specificity in ubiquitin conjugation remain unanswered. It is thus of major importance to characterize the ubiquitin landscape under various cellular conditions, and study how the regulatory network is altered in health and disease. To do so, analytical tools that allow identification of ubiquitin substrates, the conjugation and removal of ubiquitin, and the nature of specific ubiquitin linkages that are formed are needed. In this mini-review, we discuss common proteomic methodologies applied to studying the ubiquitome, and specifically focus on our recently developed post-translational modification (PTM) profiling approach. PTM profiling is a functional assay, amenable to biochemical manipulation, which allows the detection of protein modifications in a high-throughput manner. We discuss in detail the advantages and limitations of this system, focusing primarily on examples for analyzing the ubiquitin system in cancer. Uncovering the intricate signaling dynamics governed by and regulating ubiquitin modifications should clearly evolve into a new paradigm in understanding the molecular basis of malignant transformation and the development of novel therapeutic modalities. PMID- 27229348 TI - Agomelatine Improves Apathy in Frontotemporal Dementia. AB - BACKGROUND/AIMS: Apathy is the most common initial symptom of frontotemporal dementia (FTD) and has been linked to frontal-subcortical dopaminergic system dysfunction. No pharmacological therapy has been approved for the treatment of apathy, but, on the basis of its physiopathological mechanism, we suspected that increasing prefrontal dopaminergic innervation could improve this disabling symptom. METHODS: We evaluated a group of 24 nondepressed patients with a diagnosis of the behavioral variant of FTD, in order to determine the effectiveness on apathy of agomelatine, an antidepressant with MT1 and MT2 receptor agonism and 5-HT2C receptor antagonism; the latter leads to an increase in prefrontal dopaminergic and noradrenergic tone. To try to tease out the effects of 5-HT2C antagonism on apathy, patients were randomized, using a cross over design, to receive either agomelatine 50 mg/day or sustained release melatonin 10 mg/day for 10 weeks in a double-blind procedure. At the end of the follow-up period, subjects receiving melatonin switched to agomelatine for the following 10 weeks. RESULTS: Agomelatine, but not melatonin, was associated with a significant reduction of apathy in FTD subjects and of caregiver distress due to patients' apathy. The switch from melatonin to agomelatine was associated with a reduction in apathetic behavior. Agomelatine was well-tolerated by all enrolled subjects. CONCLUSIONS: Our data, albeit preliminary, suggest that agomelatine could represent a novel useful approach to the treatment of apathy in FTD patients. PMID- 27229349 TI - Comparison of angiographic and IVUS derived coronary geometric reconstructions for evaluation of the association of hemodynamics with coronary artery disease progression. AB - Wall shear stress (WSS) has been investigated as a prognostic marker for the prospective identification of rapidly progressing coronary artery disease (CAD) and atherosclerotic lesions likely to gain high-risk (vulnerable) characteristics. The goal of this study was to compare biplane angiographic vs. intravascular ultrasound (IVUS) derived reconstructed coronary geometries to evaluate agreement in geometry, computed WSS, and association of WSS and CAD progression. Baseline and 6-month follow-up angiographic and IVUS imaging data were collected in patients with non-obstructive CAD (n = 5). Three-dimensional (3D) reconstructions of the coronary arteries were generated with each technique, and patient-specific computational fluid dynamics models were constructed to compute baseline WSS values. Geometric comparisons were evaluated in arterial segments (n = 9), and hemodynamic data were evaluated in circumferential sections (n = 468). CAD progression was quantified from serial IVUS imaging data (n = 277), and included virtual-histology IVUS (VH-IVUS) derived changes in plaque composition. There was no significant difference in reconstructed coronary segment lengths and cross-sectional areas (CSA), however, IVUS derived geometries exhibited a significantly larger left main CSA than the angiographic reconstructions. Computed absolute time-averaged WSS (TAWSSABS) values were significantly greater in the IVUS derived geometries, however, evaluations of relative TAWSS (TAWSSREL) values revealed improved agreement and differences within defined zones of equivalence. Associations between VH-IVUS defined CAD progression and angiographic or IVUS derived WSS exhibited poor agreement when examining TAWSSABS data, but improved when evaluating the association with TAWSSREL data. We present data from a small cohort of patients highlighting strong agreement between angiographic and IVUS derived coronary geometries, however, limited agreement is observed between computed WSS values and associations of WSS with CAD progression. PMID- 27229350 TI - Should the General Practitioner Consider Mesotherapy (Intradermal Therapy) to Manage Localized Pain? AB - Wide variations in the types of pain and response to analgesic pharmacotherapy mean that a variety of treatment strategies are needed. One approach is mesotherapy (intradermal therapy). This consists of microinjections into the skin and is ideally suited to the management of localized pain. Advantages include increasing the duration of drug activity, reduced risk of adverse events and interactions, and possible synergy with other therapies. Mesotherapy provides general practitioners with another tool for the treatment of local pain. However, it is important to provide patients with full details of the pros and cons of this approach and obtain informed patient consent. PMID- 27229351 TI - Ocular morphology and visual function in relation to general growth in moderate to-late preterm school-aged children. AB - PURPOSE: To study ocular morphology and visual function in relation to general growth in moderate-to-late preterm (MLP) children. METHODS: Visual acuity (VA), refraction, optic disc parameters, biometric values and anthropometric measures were obtained from 50 eight-year-old MLP and 43 full-term children. Macular parameters were examined by optical coherence tomography. Serum insulin-like growth factor I (IGF-I) levels were analysed at birth and at assessment and delta IGF-I was calculated. RESULTS: Total macular volume was significantly less in MLP than in controls (both eyes p < 0.01). Macular volume correlated with head circumference (HCF) at assessment [right eye (RE) p = 0.002, r = 0.67; left eyes (LE) p = 0.01, r = 0.54] and refraction (both eyes p < 0.05, r = 0.4) in the MLP children. Furthermore, central retinal thickness correlated significantly with delta IGF-I (RE p = 0.03, r = -0.51, LE p = 0.006, r = -0.59) and refraction (both eyes p < 0.01, r = 0.5) and optic disc areas correlated with weight and height at assessment (all p < 0.05, r = 0.4). Total axial length correlated with HCF at assessment (both eyes p < 0.01, r = 0.5) and VA logMAR (both eyes p < 0.02, r = -0.4). CONCLUSIONS: Macular volume was significantly less in MLP children than in controls examined at 8 years of age. General growth of children and IGF-I levels seem to be involved in development of ocular growth and morphology. PMID- 27229353 TI - Free tissue transfer in Ehlers-Danlos Syndrome. PMID- 27229354 TI - A Randomized Controlled Trial With Mean 16-Year Follow-up Comparing Hamstring and Patellar Tendon Autografts in Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND: There is no consensus in the current literature on which surgical options render the best long-term results after anterior cruciate ligament (ACL) reconstruction in terms of clinical outcomes and the development of radiographic osteoarthritis (OA). PURPOSE: To investigate the long-term clinical and radiographic results after ACL reconstruction using either a patellar tendon (PT) autograft or a hamstring tendon (HT) autograft. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: This multicenter study was based on 2 previous randomized cohorts consisting of 193 patients who underwent unilateral primary ACL reconstruction using either a PT autograft or an HT autograft. The index surgical procedure was performed between September 1995 and January 2000. Clinical assessments, including knee laxity measurements, functional outcomes, patient-reported outcomes, and bilateral standing radiographs, were performed at the final follow-up examination. RESULTS: At the long-term follow-up, 147 (76%) patients were examined: 61 in the PT group and 86 in the HT group. The mean (+/-SD) follow-up time was 191.9 +/-15.1 months for the HT group and 202.6 +/- 10.4 months for the PT group. Knee laxity measurements revealed significantly more patients with a normal pivot-shift test finding in the HT group compared with the PT group (71% vs 51%, respectively; P = .048); however, no significant differences were found in terms of the manual Lachman test or the KT-1000 arthrometer manual maximum test. The patients in the PT group had significantly more difficulty knee walking (P = .049). There were no significant differences between the study groups in terms of patient-reported outcomes or range of motion in the reconstructed knee. In both groups, significantly more signs of radiographic OA were found in the reconstructed knee than in the contralateral healthy knee. However, there were no significant differences between the groups in terms of radiographic OA. CONCLUSION: Only minor and mostly insignificant differences were found between the PT and HT autograft groups in this long-term randomized controlled trial. In both groups, significantly more signs of radiographic OA were found in the reconstructed knee than in the contralateral knee. PMID- 27229355 TI - Prolonged length of stay after posterior surgery for cervical spondylotic myelopathy in patients over 65years of age. AB - Prolonged length of stay (PLOS) has been associated with increased hospital resource utilization and worsened patient outcomes in multiple studies. In this study, we defined and identified factors associated with PLOS after posterior surgery for cervical spondylotic myelopathy in patients over the age of 65. PLOS was defined as length of stay beyond the "prolongation point" (that is, the day after which discharge rates begin to decline). Using the United States Nationwide Inpatient Sample database, 2742 patients met inclusion criteria, out of whom 16.5% experienced PLOS (stay beyond 6days). After multivariate analysis, increasing age was independently associated with PLOS (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.02-1.06). Multiple comorbid conditions were associated with PLOS, including alcohol abuse (OR 3.85, 95% CI 1.87-7.94), congestive heart failure (OR 1.72, 95% CI 1.11-2.64), obesity (OR 1.70, 95% CI 1.14-2.55), and deficiency anemia (OR 1.44, 95% CI 1.01-2.05); the strongest associated operative parameter was blood transfusion (OR 2.39, 95% CI 1.75-3.28). Major complications independently associated with PLOS were deep vein thrombosis (OR 18.32, 95% CI 6.50-51.61), myocardial infarction (OR 8.98, 95% CI 2.92-27.56), pneumonia (OR 6.67, 95% CI 3.17-14.05), acute respiratory failure (OR 6.27, 95% CI 3.43-11.45), hemorrhage/hematoma (OR 5.04, 95% CI 2.69-9.44), and implant-related complications (OR 2.49, 95% CI 1.24-4.98). Average total hospital charges for patients who experienced PLOS were $122,965 US dollars, compared to $76,870 for the control group (p<0.001). Mortality for patients who experienced PLOS was 2.7% versus 0.5% for patients who did not epxerience PLOS (p<0.001). In conclusion, patients over the age of 65 who underwent posterior surgery for cervical myelopathy and stayed over 6days in hospital were defined as having PLOS. Hospital charges and mortality rates were significantly higher for patients who experienced PLOS. Potentially modifiable and/or preventable risk factors were also identified. PMID- 27229356 TI - Topiramate associated non-glaucomatous visual field defects. AB - We report a 34-years-old woman who presented with bilateral incongruous inferior visual field defects after the commencement of topiramate for management of migraine. Investigations did not reveal any underlying angle closure glaucoma, reported in current literature to be associated commonly with topiramate associated visual field defects. The changes in the peripheral visual fields gradually improved over several months after the medication was withdrawn. There were only minor changes persistent on the left side on a background of pre existing myopia and keratoconus. Visual field deficits secondary to topiramate are more commonly attributed to angle closure glaucoma due to ciliochoroidal effusion syndrome. In such instance, the visual field defects are associated with considerable pain due to raised intra-ocular pressure. There have also been reports of visual scotomas due to retinal damage and maculopathy in patients taking topiramate. It is worthwhile to obtain a baseline perimetry in patients being considered for topiramate therapy in order to gauge any changes in their peripheral field of vision during the treatment. Changes in visual fields during the course of medication use and after cessation can be easily compared especially if there are other possible confounders such as refractive errors or a history of migraine. PMID- 27229357 TI - Interconnection of post-transcriptional regulation: The RNA-binding protein Hfq is a novel target of the Lon protease in Pseudomonas aeruginosa. AB - Besides being a major opportunistic human pathogen, Pseudomonas aeruginosa can be found in a wide range of environments. This versatility is linked to complex regulation, which is achieved through the action of transcriptional regulators, and post-transcriptional regulation by intracellular proteases including Lon. Indeed, lon mutants in this species show defects in motility, biofilm formation, pathogenicity and fluoroquinolone resistance. Here, the proteomic approach stable isotope labeling by amino acids in cell culture (SILAC) was used to search for novel proteolytic targets. One of the proteins that accumulated in the lon mutant was the RNA-binding protein Hfq. Further experiments demonstrated the ability of Lon to degrade Hfq in vitro. Also, overexpression of the hfq gene in the wild type strain led to partial inhibition of swarming, swimming and twitching motilities, indicating that Hfq accumulation could contribute to the phenotypes displayed by Lon mutants. Hfq overexpression also led to the upregulation of the small regulatory RNA PhrS. Analysis of the phenotypes of strains lacking or overexpressing this sRNA indicated that the Lon protease might be indirectly regulating the levels and activity of sRNAs via Hfq. Overall, this study revealed new links in the complex regulatory chain that controls multicellular behaviours in P. aeruginosa. PMID- 27229352 TI - Effect of CLU genetic variants on cerebrospinal fluid and neuroimaging markers in healthy, mild cognitive impairment and Alzheimer's disease cohorts. AB - The Clusterin (CLU) gene, also known as apolipoprotein J (ApoJ), is currently the third most associated late-onset Alzheimer's disease (LOAD) risk gene. However, little was known about the possible effect of CLU genetic variants on AD pathology in brain. Here, we evaluated the interaction between 7 CLU SNPs (covering 95% of genetic variations) and the role of CLU in beta-amyloid (Abeta) deposition, AD-related structure atrophy, abnormal glucose metabolism on neuroimaging and CSF markers to clarify the possible approach by that CLU impacts AD. Finally, four loci (rs11136000, rs1532278, rs2279590, rs7982) showed significant associations with the Abeta deposition at the baseline level while genotypes of rs9331888 (P = 0.042) increased Abeta deposition. Besides, rs9331888 was significantly associated with baseline volume of left hippocampus (P = 0.014). We then further validated the association with Abeta deposition in the AD, mild cognitive impairment (MCI), normal control (NC) sub-groups. The results in sub-groups confirmed the association between CLU genotypes and Abeta deposition further. Our findings revealed that CLU genotypes could probably modulate the cerebral the Abeta loads on imaging and volume of hippocampus. These findings raise the possibility that the biological effects of CLU may be relatively confined to neuroimaging trait and hence may offer clues to AD. PMID- 27229359 TI - The evolution of sustainable remediation in Australia and New Zealand: A storyline. AB - This article describes the 'storyline' of the early and recent growth of sustainable remediation (SR) practice in Australia and New Zealand (ANZ), in order to inform and support other SR stakeholders, and to identify some lessons learned. Achievement of full acceptance and consistency across relevant ANZ regulatory jurisdictions and industry sectors will take time and will require publication of successful examples of SR application. The article describes the respective policy and regulatory contexts for sustainable remediation practice in Australia and in New Zealand; several milestone activities and events in the growth of SR in ANZ; and example SR methodologies and policies produced by stakeholders and remediation practitioners including the Sustainable Remediation Forum of Australia and New Zealand (SuRF ANZ). PMID- 27229358 TI - Surgical protocol violations in children with renal tumors provides an opportunity to improve pediatric cancer care: a report from the Children's Oncology Group. AB - BACKGROUND: The purpose of this study was to evaluate the frequency and characteristics of surgical protocol violations (SPVs) among children undergoing surgery for renal tumors who were enrolled on the Children's Oncology Group (COG) renal tumor biology and classification study AREN03B2. METHODS: AREN03B2 was opened in February 2006, and as on March 31, 2013, there were 3,664 eligible patients. The surgical review forms for 3,536 patients with unilateral disease were centrally reviewed for SPVs. The frequency, type, number of violations, institutional prevalence, and quartiles for SPVs were assessed. RESULTS: Of the 3,536 patients, there were a total of 505 with at least one SPV (564 total SPVs reported), for an overall incidence of 14.28%. The types of SPVs included a lack of lymph node sampling in 365 (64.7%), avoidable spill in 61 (10.8%), biopsy immediately before nephrectomy in 89 (15.8%), an incorrect abdominal incision in 32 (5.7%), and unnecessary resection of organs in 17 (3.0%). The SPVs occurred in 163 of 215 participating institutions (75.8%). For centers with at least one SPV, the mean number of SPVs reported was 3.10 +/- 2.39 (mean +/- standard deviation). The incidence of protocol violation per institution ranged from 0 to 67%. Centers with an average of <=1 case/year had an incidence of SPVs of 12.2 +/- 3.8%, those with an average of >1 to <4 cases/year had an incidence of SPVs of 16.4 +/- 3.6%, and those with an average of >=4 cases/year had an incidence of SPVs of 12.6 +/- 5.5% (P > 0.05). CONCLUSIONS: SPVs that potentially result in additional exposure to chemotherapy and radiation therapy are not uncommon in children undergoing resection of renal malignancies. PMID- 27229360 TI - Enhancement of chromate reduction in soils by surface modified biochar. AB - Chromium (Cr) is one of the common metals present in the soils and may have an extremely deleterious environmental impact depending on its redox state. Among two common forms, trivalent Cr(III) is less toxic than hexavalent Cr(VI) in soils. Carbon (C) based materials including biochar could be used to alleviate Cr toxicity through converting Cr(VI) to Cr(III). Incubation experiments were conducted to examine Cr(VI) reduction in different soils (Soil 1: pH 7.5 and Soil 2: pH 5.5) with three manures from poultry (PM), cow (CM) and sheep (SM), three respective manure-derived biochars (PM biochar (PM-BC), CM biochar (CM-BC) and SM biochar (SM-BC)) and two modified biochars (modified PM-BC (PM-BC-M) and modified SM-BC (SM-BC-M)). Modified biochar was synthesized by incorporating chitosan and zerovalent iron (ZVI) during pyrolysis. Among biochars, highest Cr(VI) reduction was observed with PM-BC application (5%; w/w) (up to 88.12 mg kg-1; 45% reduction) in Soil 2 (pH 5.5). The modified biochars enhanced Cr(VI) reduction by 55% (SM-BC-M) compared to manure (29%, SM) and manure-derived biochars (40% reduction, SM-BC). Among the modified biochars, SM-BC-M showed a higher Cr(VI) reduction rate (55%) than PM-BC-M (48%) in Soil 2. Various oxygen-containing surface functional groups such as phenolic, carboxyl, carbonyl, etc. on biochar surface might act as a proton donor for Cr(VI) reduction and subsequent Cr(III) adsorption. This study underpins the immense potential of modified biochar in remediation of Cr(VI) contaminated soils. PMID- 27229361 TI - Reactive oxygen species, Ca(2+) stores and acute pancreatitis; a step closer to therapy? AB - Disruption of Ca(2+) homeostasis can lead to severe damage of the pancreas, resulting in premature activation of digestive enzymes, vacuolisation and necrotic cell death, features typical of acute pancreatitis (AP). Therefore a fine balance between Ca(2+) release from internal stores, Ca(2+) entry and extrusion mechanisms is necessary to avoid injury. Precipitants of AP induce Ca(2+) overload of the pancreatic acinar cell that causes mitochondrial dysfunction, via formation of the mitochondrial permeability transition pore (MPTP), loss of ATP production and consequent necrosis. Oxidative stress has been shown to occur in the development of AP and may modify Ca(2+) signalling events in the acinar cell. However, the precise pathophysiological involvement is currently unclear and antioxidant therapy in the clinic has largely proved ineffective. Possible reasons for this are discussed, including evidence that ROS generation may determine cell death patterns. In contrast, recent evidence has indicated the potential for AP therapy via the prevention of Ca(2+)-dependent mitochondrial damage. Multiple approaches are indicated from preclinical findings; 1) inhibition of Ca(2+) release by IP3R blockade, 2) inhibition of Ca(2+) entry through Orai1 blockade and 3) prevention of MPTP formation. Clinical trials of drugs which prevent mitochondrial dysfunction induced by Ca(2+) overload of pancreatic acinar cells are imminent and may provide patient benefit for a disease that currently lacks specific therapy. PMID- 27229362 TI - Transdiagnostic assessment of anxiety symptoms using the Anxiety Disorder Diagnostic Questionnaire - weekly version. AB - BACKGROUND: Norton and Robinson [2010. Development and evaluation of the anxiety disorder diagnostic questionnaire. Cognitive Behaviour Therapy, 39(2), 137-149. doi: 10.1080/16506070903140430 ] developed the Anxiety Disorder Diagnostic Questionnaire (ADDQ) as a transdiagnostic assessment of fear and anxiety to address problems in using diagnosis-specific measures as well as limitations with the extant transdiagnostic measures of anxiety. The present study validated a weekly version of the ADDQ, the Anxiety Disorder Diagnostic Questionnaire - Weekly (ADDQ-W) allowing session-by-session transdiagnostic assessment of anxiety. METHOD: Data were a secondary analysis of 49 treatment-seeking outpatient adults from a previous clinical trial. The ADDQ-W was administered weekly over the course of 12-group therapy sessions. RESULTS: The ADDQ-W was a valid weekly measure and neither scores, F(2, 37) = 2.70, p = .08, nor trajectories of change, F(2, 37) = 0.31, p = .73, differed by primary diagnosis, though power was limited. Rate of ADDQ-W change was predictive of change in both primary diagnosis severity, t = 2.40, p = .02, beta = 0.32, and overall severity, t = 3.01, p < .01, beta = 0.36, at post-treatment. CONCLUSIONS: This study has established initial support for the use of the brief, easily scored, ADDQ-W for repeated assessment over treatment using a diagnostically heterogeneous clinical sample of treatment-seeking individuals. PMID- 27229363 TI - Gigantic vascular anomaly in a PHACE syndrome patient managed with photodynamic therapy. PMID- 27229364 TI - [ESMO ECCO 2015: The highlights of immunotherapy and targeted therapies]. AB - The ESMO/ECC congress (European Society for Medical Oncology/European Cancer Congress) took place in Vienna, Austria, September 25-29. The main topic of the conference was immunotherapies especially in advanced kidney cancer with nivolumab in phase III and in metastatic lung cancer with atezolizumab in phase II. Targeted therapies were also highlighted with cabozantinib proposed in advanced renal cancer or everolimus in differenciated neuroendocrine tumors grade 1 or 2. Furthermore the current challenges remain unchanged: improving patients' care through better selection and finding biomarkers using simple samples (blood or urine). Also early phases and personalized medicine found their place in the different presentations and were highlighted largely bringing new approaches in the treatment of metastatic patients. PMID- 27229365 TI - Parental monitoring may protect impulsive children from overeating. AB - BACKGROUND: Research has highlighted links between impulsivity and weight in children and adults. Nevertheless, little is known about the nature of this link in very young children or about the underlying mechanism by which impulsivity leads to greater adiposity. OBJECTIVE: The present study aimed to explore relationships between impulsivity, weight and eating behaviour in a sample of 95 2 to 4-year-olds. METHOD: Parent-child dyads visited the laboratory and consumed a meal after which parents completed measures of child impulsivity, eating behaviour and parental feeding, whilst children completed impulsivity tasks measuring the impulsivity facet delay of gratification (Snack Delay task), motor impulsivity (Line Walking task) and inhibitory control (Tower task). RESULTS: Pearson's correlations showed that girls with greater motor impulsivity were heavier. Additionally, monitoring moderated the relationship between impulsivity and food approach behaviour, indicating that monitoring may protect more impulsive children from displaying problematic eating behaviours. CONCLUSIONS: The motor impulsivity facet appears particularly relevant to child weight; parents can modulate the impact of impulsivity on child eating behaviour through their feeding style. PMID- 27229366 TI - A Redox-Dependent Electrochromic Material: Tetri-EDOT Substituted Thieno[3,2 b]thiophene. AB - Organic electrochromic materials change color rapidly under applied potential. A butterfly-shaped compound, 5,5',-5",-5'"-(thieno[3,2-b]thiophene-2,3,5,6-tetrayl) tetrakis-(2,3-dihydrothieno[3,4-b][1,4]dioxine) (t-EDOT-TT) is synthesized for the first time and polymerized at different potentials via electropolymerization technique. By applying different polymerization potentials, the optical and electrochromic properties of this newly synthesized polymer can be tuned. Owing to the dependence of functional group position in the polymer structure on the redox potential, this polymer can be utilized in very interesting organic optoelectronic applications. PMID- 27229367 TI - Prompt gamma ray imaging for verification of proton boron fusion therapy: A Monte Carlo study. AB - PURPOSE: The purpose of this study was to verify acquisition feasibility of a single photon emission computed tomography image using prompt gamma rays for proton boron fusion therapy (PBFT) and to confirm an enhanced therapeutic effect of PBFT by comparison with conventional proton therapy without use of boron. METHODS: Monte Carlo simulation was performed to acquire reconstructed image during PBFT. We acquired percentage depth dose (PDD) of the proton beams in a water phantom, energy spectrum of the prompt gamma rays, and tomographic images, including the boron uptake region (BUR; target). The prompt gamma ray image was reconstructed using maximum likelihood expectation maximisation (MLEM) with 64 projection raw data. To verify the reconstructed image, both an image profile and contrast analysis according to the iteration number were conducted. In addition, the physical distance between two BURs in the region of interest of each BUR was measured. RESULTS: The PDD of the proton beam from the water phantom including the BURs shows more efficient than that of conventional proton therapy on tumour region. A 719keV prompt gamma ray peak was clearly observed in the prompt gamma ray energy spectrum. The prompt gamma ray image was reconstructed successfully using 64 projections. Different image profiles including two BURs were acquired from the reconstructed image according to the iteration number. CONCLUSION: We confirmed successful acquisition of a prompt gamma ray image during PBFT. In addition, the quantitative image analysis results showed relatively good performance for further study. PMID- 27229368 TI - Study of commercial detector responses in non-equilibrium small photon fields of a 1000MU/min CyberKnife system. AB - PURPOSE: The purpose of this study was to analyze the detector responses in non equilibrium small photon fields. METHODS: Five detectors (PTW 31014 ionization chamber, PTW 60016, PTW 60017 and Sun Nuclear EDGE diodes and PTW 60003 diamond detector) and one passive dosimeter (Harshaw micro-LiF) as well as a 1000MU/min CyberKnife were modeled with the PENELOPE Monte Carlo code. Field factors, [Formula: see text] were calculated and perturbations due to volume averaging effect, active material effect and coating effect were quantified for the five detectors and passive dosimeter. RESULTS: The PTW 31014 ionization chamber under response is mainly due to the fluence perturbation caused by the presence of air as detecting material. Regarding diodes, the high density materials used in their active volume and in their coating is responsible for their over-response. Regarding the PTW 60003 diamond, its under-response for the 5mm field size is due to a large volume averaging effect whereas for largest field sizes a nearly perfect compensation between the volume averaging effect and the material effect due to the diamond density occurs. Despite its small size, a volume averaging effect was observed for the micro-LiF for the 5mm field size. CONCLUSION: Perturbations due to volume averaging effect, active material effect and coating effect were investigated and quantified for five active detectors. Since these perturbations can cause opposite effects, wrong conclusions may be drawn regarding the radiological water-equivalence of detectors. Thus, we recommend performing such a study for each novel detector available on the market. PMID- 27229369 TI - Determinants of increased acute postoperative pain after autologous breast reconstruction within an enhanced recovery after surgery protocol: A prospective cohort study. PMID- 27229371 TI - Association of nonmelanoma skin cancer with second noncutaneous malignancy in the Women's Health Initiative. PMID- 27229370 TI - The CsrA-FliW network controls polar localization of the dual-function flagellin mRNA in Campylobacter jejuni. AB - The widespread CsrA/RsmA protein regulators repress translation by binding GGA motifs in bacterial mRNAs. CsrA activity is primarily controlled through sequestration by multiple small regulatory RNAs. Here we investigate CsrA activity control in the absence of antagonizing small RNAs by examining the CsrA regulon in the human pathogen Campylobacter jejuni. We use genome-wide co immunoprecipitation combined with RNA sequencing to show that CsrA primarily binds flagellar mRNAs and identify the major flagellin mRNA (flaA) as the main CsrA target. The flaA mRNA is translationally repressed by CsrA, but it can also titrate CsrA activity. Together with the main C. jejuni CsrA antagonist, the FliW protein, flaA mRNA controls CsrA-mediated post-transcriptional regulation of other flagellar genes. RNA-FISH reveals that flaA mRNA is expressed and localized at the poles of elongating cells. Polar flaA mRNA localization is translation dependent and is post-transcriptionally regulated by the CsrA-FliW network. Overall, our results suggest a role for CsrA-FliW in spatiotemporal control of flagella assembly and localization of a dual-function mRNA. PMID- 27229372 TI - Ultrafast Nanocrystalline-TiO2 (B)/Carbon Nanotube Hyperdispersion Prepared via Combined Ultracentrifugation and Hydrothermal Treatments for Hybrid Supercapacitors. AB - Anisotropically grown (b-axis short) single-nano TiO2 (B), uniformly hyper dispersed on the surface of multiwalled carbon nanotubes (MWCNT), was successfully synthesized via an in situ ultracentrifugation (UC) process coupled with a follow-up hydrothermal treatment. The uc-TiO2 (B)/MWCNT composite materials enable ultrafast Li(+) intercalation especially along the b-axis, resulting in a capacity of 235 mA h g(-1) per TiO2 (B) even at 300C (1C = 335 mA g(-1) ). PMID- 27229373 TI - A ten-week biochemistry lab project studying wild-type and mutant bacterial alkaline phosphatase. AB - This work describes a 10-week laboratory project studying wild-type and mutant bacterial alkaline phosphatase, in which students purify, quantitate, and perform kinetic assays on wild-type and selected mutants of the enzyme. Students also perform plasmid DNA purification, digestion, and gel analysis. In addition to simply learning important techniques, students acquire novel biochemical data in their kinetic analysis of mutant enzymes. The experiments are designed to build on students' work from week to week in a way that requires them to apply quantitative analysis and reasoning skills, reinforcing traditional textbook biochemical concepts. Students are assessed through lab reports focused on journal style writing, quantitative and conceptual question sheets, and traditional exams. (c) 2016 by The International Union of Biochemistry and Molecular Biology, 44(6):555-564, 2016. PMID- 27229374 TI - EXTRA SPINDLE POLES (Separase) controls anisotropic cell expansion in Norway spruce (Picea abies) embryos independently of its role in anaphase progression. AB - The caspase-related protease separase (EXTRA SPINDLE POLES, ESP) plays a major role in chromatid disjunction and cell expansion in Arabidopsis thaliana. Whether the expansion phenotypes are linked to defects in cell division in Arabidopsis ESP mutants remains elusive. Here we present the identification, cloning and characterization of the gymnosperm Norway spruce (Picea abies, Pa) ESP. We used the P. abies somatic embryo system and a combination of reverse genetics and microscopy to explore the roles of Pa ESP during embryogenesis. Pa ESP was expressed in the proliferating embryonal mass, while it was absent in the suspensor cells. Pa ESP associated with kinetochore microtubules in metaphase and then with anaphase spindle midzone. During cytokinesis, it localized on the phragmoplast microtubules and on the cell plate. Pa ESP deficiency perturbed anisotropic expansion and reduced mitotic divisions in cotyledonary embryos. Furthermore, whilst Pa ESP can rescue the chromatid nondisjunction phenotype of Arabidopsis ESP mutants, it cannot rescue anisotropic cell expansion. Our data demonstrate that the roles of ESP in daughter chromatid separation and cell expansion are conserved between gymnosperms and angiosperms. However, the mechanisms of ESP-mediated regulation of cell expansion seem to be lineage specific. PMID- 27229375 TI - Algorithm-driven optimization of cryopreservation protocols for transfusion model cell types including Jurkat cells and mesenchymal stem cells. AB - This investigation describes the use of a differential evolution (DE) algorithm to optimize cryopreservation solution compositions and cooling rates for specific cell types. Jurkat cells (a lymphocyte model cell type) and mesenchymal stem cells (MSCs) were combined with non-DMSO solutions at concentrations dictated by a DE algorithm. The cells were then frozen in 96-well plates at DE algorithm dictated cooling rates in the range 0.5-10 degrees C/min. The DE algorithm was iterated until convergence resulted in identification of an optimum solution composition and cooling rate, which occurred within six to nine generations (seven to 10 experiments) for both cell types. The optimal composition for cryopreserving Jurkat cells included 300 mm trehalose, 10% glycerol and 0.01% ectoine (TGE) at 10 degrees C/min. The optimal composition for cryopreserving MSCs included 300 mm ethylene glycol, 1 mm taurine and 1% ectoine (SEGA) at 1 degrees C/min. High-throughput concentration studies verified the optimum identified by the DE algorithm. Vial freezing experiments showed that experimental solutions of TGE at 10 degrees C/min resulted in significantly higher viability for Jurkat cells than DMSO at 1 degrees C/min, while experimental solutions of SEGA at 10 degrees C/min resulted in significantly higher recovery for MSCs than DMSO at 1 degrees C/min; these results were solution- and cell type-specific. Implementation of the DE algorithm permits optimization of multicomponent freezing solutions in a rational, accelerated fashion. This technique can be applied to optimize freezing conditions, which vary by cell type, with significantly fewer experiments than traditional methods. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27229376 TI - Identification and pharmacological analyses of eight naturally occurring caprine melanocortin-1 receptor mutations in three different goat breeds. AB - The melanocortin-1 receptor (MC1R) belongs to the family of seven transmembrane G protein-coupled receptors and plays a central role in animal coat color. We have sequenced the full coding region of 954bp of the MC1R gene in 72 goats of three breeds with different coat colors and identified five missense mutations (K226E, F250V, G255D, V265I, and C267W) and one silent mutation (A61A), among which two haplotypes with complete linkage disequilibrium (A61A and F250V, G255D and V265I) were found. We performed detailed functional studies on the six single and two double mutations in transiently transfected HEK293T cells. We found that none of the mutants had decreased cell surface expression. However, all the mutants except A61A had decreased constitutive activities in the cAMP pathway. Five mutations (F250V, G255D, G267W, A61A/F250V, G255D/V265I) exhibited significant defects in ligand binding and consequent agonist-induced cAMP signaling and ERK1/2 activation. Additionally, K226E, with normal ligand binding affinity and cAMP signaling, showed a significant defect in ERK1/2 activation, exhibiting biased signaling. Co-expression studies showed that the five defective mutants did not affect wild-type MC1R signaling, hence they were not dominant negative. In summary, we provided detailed data of these goat MC1R mutations leading to a better understanding of the role of MC1R mutation and coat color in goats. PMID- 27229377 TI - Penetration of topically applied nanocarriers into the hair follicles of dog and rat dorsal skin and porcine ear skin. AB - BACKGROUND: In humans, topically applied nanocarriers penetrate effectively into the hair follicles where they can be exploited for the localized and targeted treatment of skin disorders. OBJECTIVE: The objective of the present study was to examine the applicability of particle-based systems for follicular drug delivery in companion animals and livestock, which have a large follicular reservoir. ANIMALS: Skin samples from 10 beagle dogs, 14 Wistar rats and four ears from freshly slaughtered cross-bred pigs were used. METHODS: Fluoresceinamine labelled poly (L-lactide-co-glycolide) nanocarriers (256 or 430 nm) were applied on the different skin samples. After penetration, skin biopsies were removed and cryohistological cross sections prepared and investigated with regard to the follicular penetration depths (in MUm +/- standard deviation) of the nanocarriers using confocal laser scanning microscopy. RESULTS: In canine, rat and porcine hair follicles, the smaller nanoparticles were detected at mean follicular penetration depths of 630.16 +/- 135.75 MUm, 253.55 +/- 47.36 MUm and 653.40 +/- 94.71 MUm, respectively. The larger particles were observed at average follicular depths of 604.79 +/- 132.42 MUm; 262.87 +/- 55.25 MUm and 786.81 +/- 121.73 MUm, respectively, in canine, rat and porcine hair follicles. Statistically significant differences (P < 0.05) in the mean follicular penetration depths of the differently sized nanocarriers could be determined for the canine and porcine skin samples. CONCLUSION: The mean follicular penetration depths of the differently sized nanocarriers were mostly significantly different between the different species, which might be due to different species-specific follicular dimensions. This issue needs to be addressed specifically in further studies. PMID- 27229378 TI - Regulation of monocyte induced cell migration by the RNA binding protein, FXR1. AB - FXR1 belongs to a family of RNA-binding proteins that play critical roles in post transcriptional regulation of gene expression in immunity, development and cancer. FXR1 is associated with regulation of specific mRNAs in myocytes and macrophages. In quiescent cells (> 24 h of extended serum-starvation, ~30-48 h or more), a spliced isoform of FXR1, FXR1a, promotes translation of the cytokine TNFalpha, independent of the effects of RNA levels. Here we examined the role of FXR1 in THP1 human monocytic leukemic cells that were grown in serum, as well as in early (24 h) serum-starvation conditions that demonstrates differences in gene expression mechanisms and is distinct from quiescent (> 24 h extended serum starvation) cells. Global RNA profiling, conducted to investigate the role of FXR1 on mRNA levels, revealed that FXR1 affects levels of specific mRNAs in serum grown and in early 24 h serum-starvation conditions. FXR1 decreases levels of several mRNAs, including as previously identified, CDKN1A (p21CIP1 or p21) mRNA in serum-grown cells. Interestingly, we find that FXR1 positively regulates mRNA levels of specific cytokines and chemokines in serum-grown and in early 24 h serum-starvation conditions. These include IL1beta and CCL2 that control cell migration. Accordingly, depletion and overexpression of FXR1 decreased and increased levels of CCL2 mRNA. Consistent with the reduced levels of IL1beta, CCL2 and other chemokines upon FXR1 depletion, our data reveal that depletion of FXR1 decreases the ability of these cells to induce cell migration of neighboring monocytic cells. These data reveal a new role of FXR1 in controlling induction of monocyte migration. PMID- 27229379 TI - Ocular Inflammatory Disorders in Autoimmune Lymphoproliferative Syndrome (ALPS). AB - PURPOSE: To describe inflammatory ocular findings in patients with autoimmune lymphoproliferative syndrome (ALPS). METHODS: A retrospective review of medical records for ALPS patients seen at the National Eye Institute between 2003 and 2013. RESULTS: A total of 29 ALPS patients previously referred for ocular or visual symptoms or with a history of prolonged corticosteroid use, were identified. Mean age was 20 years (range: 4-66 years). The majority were male (n = 21, 72.4%) and Caucasian (n = 24, 82.8%). Ten (34.5%) had abnormal ocular findings, the most common of which was an ocular inflammatory disorder (n = 4, 13.8%). Uveitis was seen in two patients with ALPS-FAS and one with ALPS-U, all of whom required long-term systemic immunosuppression. One patient with ALPS-FAS had a history of optic neuritis. CONCLUSIONS: ALPS can have intraocular inflammatory manifestations that require routine follow-up to ensure appropriate and timely treatment of intraocular disease. Long-term immunosuppression may be needed for patients with ALPS-associated uveitis. PMID- 27229440 TI - Improving the fermentation quality of wheat straw silage stored at low temperature by psychrotrophic lactic acid bacteria. AB - This study aimed to explore the feasible approaches to develop a silage production technique in regions with low temperatures. An effective low temperature silage technology system was constructed and two frigostable Lactobacillus (L.) strains isolated from alpine pastures were selected and proved to be available for wheat straw silage at 5 degrees C. The strains QZ227 and QZ887 were both identified as L. plantarum according to the phenotype, 16S rRNA, and RecA gene analysis. QZ227, QZ887 and a commercial inoculant FG1 consisting of L. plantarum were effective for improving the fermentation quality of wheat straws silage at 5 degrees C for 30 days as indicated by the higher content of lactic acid and for 60 days by lower pH values, while the control with sterile water instead conferred reduced benefits. Additionally, silages fermented at low temperature proved to be acceptable for feeding livestock after being placed in a simulated environmental temperature of 20 degrees C for 14 days to detect its edibility during the early spring when the temperature begins to rise. Both QZ227 and QZ887 showed potential applications of silage making in frigid areas and were effective inoculants in a low-temperature silage technology system. PMID- 27229441 TI - Rapid acquisition of high-volume microscopic images using predicted focal plane. AB - For an automated microscopic imaging system, the image acquisition speed is one of the most critical performance features because many applications require to analyse high-volume images. This paper illustrates a novel approach for rapid acquisition of high-volume microscopic images used to count blood cells automatically. This approach firstly forms a panoramic image of the sample slide by stitching sequential images captured at a low magnification, selects a few basic points (x, y) indicating the target areas from the panoramic image, and then refocuses the slide at each of the basic points at the regular magnification to record the depth position (z). The focusing coordinates (x, y, z) at these basic points are used to calculate a predicted focal plane that defines the relationship between the focus position (z) and the stage position (x, y). Via the predicted focal plane, the system can directly focus the objective lens at any local view, and can tremendously save image-acquisition time by avoiding the autofocusing function. The experiments showed how to determine the optimal number of the basic points at a given imaging condition, and proved that there is no significant difference between the images captured using the autofocusing function or the predicted focal plane. PMID- 27229442 TI - A case of acquired port wine stain: an association with repeated sunburn? AB - BACKGROUND: Unlike congenital port wine stain (PWS), an acquired PWS is a rare vascular lesion that develops later in life. Although solar damage is associated with acquired PWS, there is no reported case of acquired PWS after sunburn in the literature. METHODS: We report a case of a 54-year-old man diagnosed with acquired PWS possibly caused by repeated sunburn. RESULTS: We recommended laser treatment to our patient; however, the patient did not chose to receive any treatment. CONCLUSIONS: Our case demonstrates a possible rare occurrence of an acquired PWS after sunburn with larger lesions and more diffuse distribution. For this reason, our case differs from other acquired PWS cases. PMID- 27229443 TI - Effective isolation of exosomes with polyethylene glycol from cell culture supernatant for in-depth proteome profiling. AB - Exosomes are secreted nanovesicles shed by almost all kinds of cells. Recently, increased interest has been focused on these extracellular vesicles as natural carriers transporting biological contents for intercellular communication. However, current isolation techniques, such as ultracentrifugation, are not convenient and often require specialized equipment. Herein, we describe a polyethylene glycol (PEG)-based approach, which could permit facile, low-cost and effective isolation of exosomes from cell culture supernatant. High-resolution electron microscopes clearly visualized the size and morphology of isolated exosome aggregates, implying the mechanism of PEG-based precipitation. Combined with tandem mass spectrometry analysis, 6299 protein groups encoded by 5120 genes were successfully characterized from HeLa cell culture supernatant, including numerous exosome proteins which could overlap 97% of the Top 100 exosome marker proteins recorded in the ExoCarta database, as well as a series of low-abundance cytokines and biomarkers. Furthermore, we found a higher ratio of neo-cleavage sites in proteins identified from exosomes compared with cellular proteins, revealing the potential roles of exosomes in accumulation and transportation of protein degradation intermediates. PMID- 27229444 TI - ZrO2-Nanoparticle-Modified Graphite Felt: Bifunctional Effects on Vanadium Flow Batteries. AB - To improve the electrochemical performance of graphite felt (GF) electrodes in vanadium flow batteries (VFBs), we synthesize a series of ZrO2-modified GF (ZrO2/GF) electrodes with varying ZrO2 contents via a facile immersion precipitation approach. It is found that the uniform immobilization of ZrO2 nanoparticles on the GF not only significantly promotes the accessibility of vanadium electrolyte, but also provides more active sites for the redox reactions, thereby resulting in better electrochemical activity and reversibility toward the VO(2+)/VO2(+) and V(2+)/V(3+) redox reactions as compared with those of GF. In particular, The ZrO2/GF composite with 0.3 wt % ZrO2 displays the best electrochemical performance with voltage and energy efficiencies of 71.9% and 67.4%, respectively, which are much higher than those of 57.3% and 53.8% as obtained from the GF electrode at 200 mA cm(-2). The cycle life tests demonstrate that the ZrO2/GF electrodes exhibit outstanding stability. The ZrO2/GF-based VFB battery shows negligible activity decay after 200 cycles. PMID- 27229446 TI - Nanocrystallinity and direct cross-linkage as key-factors for the assembly of gold nanoparticle-superlattices. AB - We report here how the crystallinity of AuNPs and the choice of binding sites of molecular cross-linkers control their aggregation. The combination of different binding moieties (N-oxides, ArF-I) and the reactivity of the particles' facets allow control over the organization and crystallinity of the AuNP assemblies. PMID- 27229447 TI - Unravelling the working junction of aqueous-processed polymer-nanocrystal solar cells towards improved performance. AB - Hybrid solar cells (HSCs) based on aqueous polymers and nanocrystals are attractive due to their environmental friendliness and cost effectiveness. In this study, HSCs are fabricated from a series of water-soluble polymers with different highest occupied molecular orbital (HOMO) levels and nanocrystals with different Fermi levels. We demonstrate that the working principle of the aqueous processed HSCs follows a p-n junction instead of a type-II heterojunction. The function of the polymer is to provide an interface dipole which can improve the build-in potential of the HSCs. Subsequently, the aqueous-processed HSCs are optimized following a p-n junction and an improved PCE of 5.41% is achieved, which is the highest for aqueous-processed HSCs. This study will provide instructive guidelines for the development of aqueous-processed HSCs. PMID- 27229445 TI - Multiple on-line HPLC coupled with biochemical detection methods to evaluate bioactive compounds in Danshen injection. AB - On-line high performance liquid chromatography (HPLC) coupled with three biochemical detection (BCD) methods was applied to evaluate bioactive components in Danshen injection. On-line HPLC-photo-diode array-fluorescence detection based on the fluorogenic substrate 7-acetoxy-1-methyl quinolinium iodide, was built to search acetylcholinesterase (AChE) inhibitors in Danshen injection. On-line HPLC coupled with the scavenging assay of 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) free radicals was developed to screen antioxidants. The three active profiles were obviously different. Radical scavenging profiles revealed seven strong peaks in the chromatographic fingerprint possessing obvious free radical inhibition effects, while some minor peaks exhibited stronger AChE inhibition activities. The main radical scavengers and AChE inhibitors were identified by HPLC-MS. Several unknown ingredients showing strong AChE inhibition activities needed further identification except protocatechuic aldehydrate, salvianolic acid H or I and lithospermic acid. The on-line multiple on-line HPLC-BCD methods will provide powerful tools in the field of pharmacognosy for fast-track identification of interesting and/or novel bioactive compounds. PMID- 27229448 TI - Preparation and Characterization of Cysteine Adducts of Deoxynivalenol. AB - Conjugation with the biologically relevant thiol glutathione is one of the metabolic pathways for the mycotoxin deoxynivalenol (DON) in wheat. The occurrence of putative DON-cysteine conjugates has also been shown in wheat, likely in part as a result of degradation of the glutathione conjugates. It was reported that thiols react in vitro with DON at two positions: reversibly at C-10 of the alpha,beta-unsaturated ketone and irreversibly at C-13 of the epoxy group. We synthesized pure DON-cysteine adducts and made analytical standards using quantitative NMR experiments. Compounds were characterized using NMR and LC HRMS/MS and tested in vitro for toxicity. Cysteine conjugates were much less toxic than DON at the same concentration, and LC-HRMS analysis demonstrated that there was no detectable metabolism of the conjugates in human monocytes or human macrophages. PMID- 27229449 TI - Preliminary validation of a brief measure of the frequency and severity of nightmares: The Trauma-Related Nightmare Survey. AB - Nightmares and sleep disturbances are gaining attention as targets of treatment interventions for trauma-exposed populations. Measures in trials evaluating these interventions tend to utilize proprietary measures of nightmare characteristics, which makes it challenging to compare findings across studies. The Trauma-Related Nightmare Survey is a questionnaire that was initially developed for utilization in efficacy studies of Exposure, Relaxation, and Rescripting Therapy. Preliminary examinations of the psychometric properties have demonstrated good test-retest reliability and convergent validity. The present brief report provides an updated examination of these properties and offers the first open publication of the measure for general use. Results support previous findings that the Trauma Related Nightmare Survey demonstrates good test-retest reliability (r = .73) and moderate to strong convergent validity (rs = .44-.78) with other commonly utilized measures of sleep and mood symptoms. PMID- 27229451 TI - [Hypertension and pregnancy: Post-partum period]. AB - Post-partum period is associated with specific characteristics in women with gestational disorders or preeclampsia. For breastfeeding women, the choice of antihypertensive treatment should take into account the impact on child health. The impact of breastfeeding on health mother must be also discussed. Moreover, for lactation inhibition, bromocriptine should not be used, especially in the context of gestational disorders. In post-partum period, the best contraceptive strategy is only-progestin contraception or non-hormonal contraceptives use. However, this choice will depend on the stabilization or normalization of blood pressure in early post-partum period. Finally, several consultations should be suggested: an information and announcement to explain the consequences of these gestational disorders and organize their multidisciplinary management and follow up. A preconceptional consultation takes its place to anticipate potential recurrent preeclampsia or gestational hypertension and to schedule a future pregnancy in optimal conditions. PMID- 27229452 TI - [Letter on the article: "Cannabis use: What to do in general practice?"]. PMID- 27229450 TI - A microphysiological model of the human placental barrier. AB - During human pregnancy, the fetal circulation is separated from maternal blood in the placenta by two cell layers - the fetal capillary endothelium and placental trophoblast. This placental barrier plays an essential role in fetal development and health by tightly regulating the exchange of endogenous and exogenous materials between the mother and the fetus. Here we present a microengineered device that provides a novel platform to mimic the structural and functional complexity of this specialized tissue in vitro. Our model is created in a multilayered microfluidic system that enables co-culture of human trophoblast cells and human fetal endothelial cells in a physiologically relevant spatial arrangement to replicate the characteristic architecture of the human placental barrier. We have engineered this co-culture model to induce progressive fusion of trophoblast cells and to form a syncytialized epithelium that resembles the syncytiotrophoblast in vivo. Our system also allows the cultured trophoblasts to form dense microvilli under dynamic flow conditions and to reconstitute expression and physiological localization of membrane transport proteins, such as glucose transporters (GLUTs), critical to the barrier function of the placenta. To provide a proof-of-principle for using this microdevice to recapitulate native function of the placental barrier, we demonstrated physiological transport of glucose across the microengineered maternal-fetal interface. Importantly, the rate of maternal-to-fetal glucose transfer in this system closely approximated that measured in ex vivo perfused human placentas. Our "placenta-on-a-chip" platform represents an important advance in the development of new technologies to model and study the physiological complexity of the human placenta for a wide variety of applications. PMID- 27229453 TI - Letter to the Editor, "Dentin Bonding Testing Using a Mini-interfacial Fracture Toughness Approach". PMID- 27229454 TI - Response to Letter to the Editor, "Dentin Bonding Testing Using a Mini interfacial Fracture Toughness Approach". PMID- 27229455 TI - Influence of an oblique path of staircase descent on toe placement and foot clearance. AB - During their commute, pedestrians encounter a variety of staircase designs. One such design is the oblique staircase that allows pedestrians to descend at an angle. The purpose of this study was to assess the influence of an oblique path of descent on heel and toe clearance, and toe placement on a step. Sixteen participants descended a staircase on an angled path at three angles: 0 degrees (perpendicular), 25 degrees , and 45 degrees . Toe placement and foot clearances were compared between the descent angles and feet. An increase in descent angle demonstrated increased clearance of the heel apex compared with straight descent; however, the aspect of the foot closest to the stair changes in angled descent, moving from the apex to the side of the heel. A greater portion of the foot was placed on the stair tread during angled descent. Future work should address the influence of angled descent on fall risk. PMID- 27229456 TI - Gaussian Process Modeling of Protein Turnover. AB - We describe a stochastic model to compute in vivo protein turnover rate constants from stable-isotope labeling and high-throughput liquid chromatography-mass spectrometry experiments. We show that the often-used one- and two-compartment nonstochastic models allow explicit solutions from the corresponding stochastic differential equations. The resulting stochastic process is a Gaussian processes with Ornstein-Uhlenbeck covariance matrix. We applied the stochastic model to a large-scale data set from (15)N labeling and compared its performance metrics with those of the nonstochastic curve fitting. The comparison showed that for more than 99% of proteins, the stochastic model produced better fits to the experimental data (based on residual sum of squares). The model was used for extracting protein-decay rate constants from mouse brain (slow turnover) and liver (fast turnover) samples. We found that the most affected (compared to two exponent curve fitting) results were those for liver proteins. The ratio of the median of degradation rate constants of liver proteins to those of brain proteins increased 4-fold in stochastic modeling compared to the two-exponent fitting. Stochastic modeling predicted stronger differences of protein turnover processes between mouse liver and brain than previously estimated. The model is independent of the labeling isotope. To show this, we also applied the model to protein turnover studied in induced heart failure in rats, in which metabolic labeling was achieved by administering heavy water. No changes in the model were necessary for adapting to heavy-water labeling. The approach has been implemented in a freely available R code. PMID- 27229457 TI - Variability of pesticide residues in cauliflower units collected from a field trial and market places in Greece. AB - To estimate the variability of pesticide residue levels present in cauliflower units, a total of 142 samples were collected from a field trial of a cooperative farmer, and 120 samples were collected from different market places in Thessaloniki, Greece. The collected samples were extracted using the quick, easy, cheap, effective, rugged, and safe (QuEChERS) extraction technique, and the residues were determined by liquid chromatography-tandem mass spectrometry. The developed method was validated by evaluating the accuracy, precision, linearity, limit of detection (LOD), and limit of quantification (LOQ). The average recoveries for all the analytes, derived from the data of control samples fortified at 0.01, 0.05, 0.1, and 0.2 mg/kg, ranged from 74 to 110% with a relative standard deviation of <=8%. The correlation coefficient (R(2)) was >=0.997 for all the analytes using matrix-matched calibration standards. The LOD values ranged from 0.001 to 0.003 mg/kg, and the LOQ was determined at 0.01 mg/kg for all the sought analytes. The matrix effect was found to be at a considerable level, especially for cypermethrin and deltamethrin, amounting to +90% and +145%, respectively. For the field samples, the unit-to-unit variability factors (VFs) calculated for cypermethrin and deltamethrin were 2.38 and 2.32, respectively, while the average VF for the market basket samples was 5.11. In the market basket samples, residues of cypermethrin, deltamethrin, chlorpyrifos, and indoxacarb were found at levels >=LOQ and their respective VFs were 7.12, 5.67, 5.28, and 2.40. PMID- 27229458 TI - Lipocalin-2 deficiency or blockade protects against aortic abdominal aneurysm development in mice. AB - AIMS: To study the role of lipocalin-2 (Lcn2) and the effect of Lcn2 blockade via anti-Lcn2 antibody in the development of abdominal aortic aneurysm (AAA). METHODS AND RESULTS: Expression mRNA and protein levels of Lcn2 and its human orthologue neutrophil gelatinase-associated lipocalin (NGAL) in aortic wall samples from experimental mouse and human AAA samples, respectively, were analysed by real time PCR and immunohistochemistry. Experimental AAA was induced by aortic elastase perfusion in wild-type mice (WT) and Lcn2-deficient mice (Lcn2-/-). NGAL/Lcn2 mRNA and protein levels in human and murine AAA samples were increased compared with healthy aortas. Decreased AAA incidence and reduced aortic expansion were observed in Lcn2-/- mice or mice preoperative treated with a polyclonal anti-Lcn2 antibody compared with WT mice or mice treated with control IgG, respectively, at Day 14 after elastase perfusion. Moreover, immunohistochemical analysis of AAA tissues from Lcn2-/- or anti-Lcn2-treated mice showed diminished elastin damage, reduced microvessels and polymorphonuclear neutrophil (PMN) infiltration, and enhanced preservation of vascular smooth muscle cells compared with WT aortas. Fluorescent molecular tomography revealed decreased MMP activity in AAA of Lcn2-/- mice compared with WT controls. Therapeutic administration of anti-Lcn2 antibody to WT mice 3 days after elastase perfusion decreased aortic dilatation and PMN infiltration compared with WT mice treated with control IgG. CONCLUSION: Either Lcn2 deficiency or anti-Lcn2 antibody blockade limits AAA expansion in mice by decreasing PMN infiltration in the aorta. Lcn2 modulation may therefore be a viable new therapeutic option for the treatment of AAA. PMID- 27229459 TI - Ryanodine receptor-2: a necessity for gating store-operated Ca2+ channels. PMID- 27229460 TI - Induced NCX1 overexpression attenuates pressure overload-induced pathological cardiac remodelling. AB - AIMS: Although increased Na(+)/Ca(2+) exchanger 1 (NCX1) expression is observed during heart failure (HF), the pathological role of NCX1 during the progression of HF remains unclear. We examined alterations of NCX1 expression and activity in hearts after transverse aortic constriction (TAC) surgery and explored whether NCX1 influences pressure overload-induced pathological cardiac remodelling. METHODS AND RESULTS: We generated novel transgenic mice in which NCX1 expression is controlled by a cardiac-specific, doxycycline (DOX)-dependent promoter. In the absence of DOX, TAC surgery caused substantial chamber dilation with a gradual decrease in contractility by 16 weeks. Cardiomyocytes showed a decline in contractility with abnormal Ca(2+) handling during excitation-contraction (E-C) coupling. Reduced NCX1 activity was observed 8 weeks after TAC and was still apparent at 17 weeks. Induced NCX1 overexpression by DOX treatment starting 8 weeks after TAC returned NCX1 activity to pre-TAC levels and prevented chamber dilation with cardiac dysfunction. DOX treatment not only upregulated NCX1 expression in TAC-operated hearts but also returned L-type Ca(2+) channel and sarcoplasmic reticulum (SR) Ca(2+) ATPase expression levels to those in sham operated hearts. In DOX-treated myocytes, contractility, T-tubule integrity, synchrony of Ca(2+) release from the SR, and Ca(2+) handling during E-C coupling was preserved 16 weeks after TAC surgery. In addition, DOX treatment attenuated the down-regulation of survival signalling and up-regulation of apoptosis signalling 16 weeks after TAC surgery. CONCLUSION: Induced overexpression of NCX1 attenuated pressure overload-induced pathological cardiac remodelling. Thus, maintaining NCX1 activity may be a potential therapeutic strategy for preventing the progression of HF. PMID- 27229461 TI - Primary sex determination of placental mammals: a modelling study uncovers dynamical developmental constraints in the formation of Sertoli and granulosa cells. AB - BACKGROUND: Primary sex determination in placental mammals is a very well studied developmental process. Here, we aim to investigate the currently established scenario and to assess its adequacy to fully recover the observed phenotypes, in the wild type and perturbed situations. Computational modelling allows clarifying network dynamics, elucidating crucial temporal constrains as well as interplay between core regulatory modules. RESULTS: Relying on a comprehensive revision of the literature, we define a logical model that integrates the current knowledge of the regulatory network controlling this developmental process. Our analysis indicates the necessity for some genes to operate at distinct functional thresholds and for specific developmental conditions to ensure the reproducibility of the sexual pathways followed by bi-potential gonads developing into either testes or ovaries. Our model thus allows studying the dynamics of wild type and mutant XX and XY gonads. Furthermore, the model analysis reveals that the gonad sexual fate results from the operation of two sub-networks associated respectively with an initiation and a maintenance phases. At the core of the process is the resolution of two connected feedback loops: the mutual inhibition of Sox9 and beta-catenin at the initiation phase, which in turn affects the mutual inhibition between Dmrt1 and Foxl2, at the maintenance phase. Three developmental signals related to the temporal activity of those sub networks are required: a signal that determines Sry activation, marking the beginning of the initiation phase, and two further signals that define the transition from the initiation to the maintenance phases, by inhibiting the Wnt4 signalling pathway on the one hand, and by activating Foxl2 on the other hand. CONCLUSIONS: Our model reproduces a wide range of experimental data reported for the development of wild type and mutant gonads. It also provides a formal support to crucial aspects of the gonad sexual development and predicts gonadal phenotypes for mutations not tested yet. PMID- 27229463 TI - Herbal medicine use and linked suspected adverse drug reactions in a prospective cohort of Ugandan inpatients. AB - BACKGROUND: Clinical history-taking can be employed as a standardized approach to elucidate the use of herbal medicines and their linked suspected adverse drug reactions (ADRs) among hospitalized patients. We sought to identify herbal medicines nominated by Ugandan inpatients; compare nomination rates by ward and gender; confirm the herbs' known pharmacological properties from published literature; and identify ADRs linked to pre-admission use of herbal medicines. METHODS: Prospective cohort of consented adult inpatients designed to assess medication use and ADRs on one gynaecological and three medical wards of 1790-bed Mulago National Referral Hospital. Baseline and follow-up data were obtained on patients' characteristics, including pre-admission use of herbal medicines. RESULTS: Fourteen percent (26/191) of females in Gynaecology nominated at least one specific herbal medicine compared with 20 % (114/571) of inpatients on medical wards [20 % (69/343) of females; 20 % (45/228) of males]. Frequent nominations were Persea americana (30), Mumbwa/multiple-herb clay rods (23), Aloe barbadensis (22), Beta vulgaris (12), Vernonia amygdalina (11), Commelina africana (7), Bidens pilosa (7), Hoslundia opposita (6), Mangifera indica (4), and Dicliptera laxata (4). Four inpatients experienced 10 suspected ADRs linked to pre-admission herbal medicine use including Commelina africana (4), multiple herb-mumbwa (1), or unspecified local-herbs (5): three ADR-cases were abortion related and one kidney-related. CONCLUSIONS: The named herbal medicines and their nomination rates generally differed by specialized ward, probably guided by local folklore knowledge of their use. Clinical elicitation from inpatients can generate valuable safety data on herbal medicine use. However, larger routine studies might increase the utility of our method to assess herbal medicine use and detect herb-linked ADRs. Future studies should take testable samples of ADR implicated herbal medicines for further analysis. PMID- 27229462 TI - Expression and function of pannexins in the inner ear and hearing. AB - Pannexin (Panx) is a gene family encoding gap junction proteins in vertebrates. So far, three isoforms (Panx1, 2 and 3) have been identified. All of three Panx isoforms express in the cochlea with distinct expression patterns. Panx1 expresses in the cochlea extensively, including the spiral limbus, the organ of Corti, and the cochlear lateral wall, whereas Panx2 and Panx3 restrict to the basal cells of the stria vascularis in the lateral wall and the cochlear bony structure, respectively. However, there is no pannexin expression in auditory sensory hair cells. Recent studies demonstrated that like connexin gap junction gene, Panx1 deficiency causes hearing loss. Panx1 channels dominate ATP release in the cochlea. Deletion of Panx1 abolishes ATP release in the cochlea and reduces endocochlear potential (EP), auditory receptor current/potential, and active cochlear amplification. Panx1 deficiency in the cochlea also activates caspase-3 cell apoptotic pathway leading to cell degeneration. These new findings suggest that pannexins have a critical role in the cochlea in regard to hearing. However, detailed information about pannexin function in the cochlea and Panx mutation induced hearing loss still remain largely undetermined. Further studies are required. PMID- 27229465 TI - Dialysis and pregnancy: no longer the impossible. PMID- 27229464 TI - Effect of a sport-for-health intervention (SmokeFree Sports) on smoking-related intentions and cognitions among 9-10 year old primary school children: a controlled trial. AB - BACKGROUND: Preventing children from smoking is a public health priority. This study evaluated the effects of a sport-for-health smoking prevention programme (SmokeFree Sports) on smoking-related intentions and cognitions among primary school children from deprived communities. METHODS: A non-randomised-controlled trial targeted 9-10 year old children from Merseyside, North-West England. 32 primary schools received a programme of sport-for-health activities over 7 months; 11 comparison schools followed usual routines. Data were collected pre intervention (T0), and at 8 months (T1) and one year post-intervention (T2). Smoking-related intentions and cognitions were assessed using an online questionnaire. Intervention effects were analysed using multi-level modelling (school, student), adjusted for baseline values and potential confounders. Mixed sex focus groups (n = 18) were conducted at T1. RESULTS: 961 children completed all assessments and were included in the final analyses. There were no significant differences between the two study groups for non-smoking intentions (T1: beta = 0.02, 95 % CI = -0.08-0.12; T2: beta = 0.08, 95 % CI = -0.02-0.17) or for cigarette refusal self-efficacy (T1: beta = 0.28, 95 % CI = -0.11-0.67; T2: beta = 0.23, 95 % CI = -0.07-0.52). At T1 there was a positive intervention effect for cigarette refusal self-efficacy in girls (beta = 0.72, 95 % CI = 0.21 1.23). Intervention participants were more likely to 'definitely' believe that: 'it is not safe to smoke for a year or two as long as you quit after that' (RR = 1.19, 95 % CI = 1.07-1.33), 'it is difficult to quit smoking once started' (RR = 1.56, 95 % CI = 1.38-1.76), 'smoke from other peoples' cigarettes is harmful' (RR = 1.19, 95 % CI = 1.20-2.08), 'smoking affects sports performance' (RR = 1.73, 95 % CI = 1.59-1.88) and 'smoking makes 'no difference' to weight' (RR = 2.13, 95 % CI = 1.86-2.44). At T2, significant between-group differences remained just for 'smoking affects sports performance' (RR = 1.57, 95 % CI = 1.43-1.72). Focus groups showed that SFS made children determined to remain smoke free and that the interactive activities aided children's understanding of smoking harms. CONCLUSION: SFS demonstrated short-term positive effects on smoking attitudes among children, and cigarette refusal self-efficacy among girls. Although no effects were observed for non-smoking intentions, children said that SFS made them more determined not to smoke. Most children had strong intentions not to smoke; therefore, smoking prevention programmes should perhaps target early adolescents, who are closer to the age of smoking onset. PMID- 27229466 TI - Hedgehog Gli signalling in kidney fibrosis. AB - Kidney fibrosis is the common final pathway of virtually all progressive injury to the kidney and a promising therapeutic target in chronic kidney disease (CKD). The Hedgehog pathway has been reported to be critical in kidney development, and recent evidence suggests a role in kidney injury and fibrosis. This review provides an overview of recent data suggesting an important role of Gli transcriptional activators in kidney injury and repair. We have reported that the hedgehog transcriptional activator Gli1 specifically marks perivascular mesenchymal stem cells, which are an important source of kidney myofibroblasts. Genetic ablation of these cells ameliorated kidney and heart fibrosis and stabilized organ function after injury. Recent data suggest that Gli2 is an important driver of myofibroblast cell cycle progression and a promising therapeutic target in kidney fibrosis progression and CKD. However, the non canonical mechanism of Gli activation in kidney fibrosis remains an open question, and further studies are needed to elucidate the role of Hedgehog Gli and Gli1+ perivascular cells in human kidney fibrosis. PMID- 27229468 TI - Comprehensive left ventricular mechanics analysis by speckle tracking echocardiography in Chagas disease. AB - BACKGROUND: Chagas disease (CD) is a frequent cause of dilated cardiomyopathy (CMP) in developing countries, leading to clinical heart failure and worse prognosis. Therefore, the development and evolution of this CMP has always been a major topic in numbers of previous studies. A comprehensive echocardiographic study of left ventricular (LV) mechanics, fully assessing myocardial contraction, has never been done before. This could help characterize and improve the understanding of the evolution of this prevalent CMP. METHODS: A total of 47 chagasic and 84 control patients were included in this study and allocated in groups according to LV ejection fraction. 2D-Echocardiogram was acquired for LV mechanics analysis by speckle tracking echocardiography. RESULTS: Mean age of chagasic individuals was 55y and 16 (34 %) were men. Significant difference was found in global longitudinal velocity analysis, with lower values in indeterminate form. In the group with severe systolic dysfunction, a paradoxical increase in longitudinal and apical radial displacements were demonstrated. In parallel, segmental analyzes highlighted lower values of radial displacement, strain and strain rate into inferior and inferolateral walls, with increase of these values in septal and anterior walls. CONCLUSION: Chagasic CMP has a vicarious pattern of contraction in the course of its evolution, defined by reduced displacement and strain into inferior and posterior walls with paradoxical increase in septal and anterior segments. Also, lower longitudinal velocities were demonstrated in CD indeterminate form, which may indicate an incipient myocardial injury. PMID- 27229469 TI - The essential genome of Streptococcus agalactiae. AB - BACKGROUND: Next-generation sequencing of transposon-genome junctions from a saturated bacterial mutant library (Tn-seq) is a powerful tool that permits genome-wide determination of the contribution of genes to fitness of the organism under a wide range of experimental conditions. We report development, testing, and results from a Tn-seq system for use in Streptococcus agalactiae (group B Streptococcus; GBS), an important cause of neonatal sepsis. METHODS: Our method uses a Himar1 mini-transposon that inserts at genomic TA dinucleotide sites, delivered to GBS on a temperature-sensitive plasmid that is subsequently cured from the bacterial population. In order to establish the GBS essential genome, we performed Tn-seq on DNA collected from three independent mutant libraries-with at least 135,000 mutants per library-at serial 24 h time points after outgrowth in rich media. RESULTS: After statistical analysis of transposon insertion density and distribution, we identified 13.5 % of genes as essential and 1.2 % as critical, with high levels of reproducibility. Essential and critical genes are enriched for fundamental cellular housekeeping functions, such as acyl-tRNA biosynthesis, nucleotide metabolism, and glycolysis. We further validated our system by comparing fitness assignments of homologous genes in GBS and a close bacterial relative, Streptococcus pyogenes, which demonstrated 93 % concordance. Finally, we used our fitness assignments to identify signal transduction pathway components predicted to be essential or critical in GBS. CONCLUSIONS: We believe that our baseline fitness assignments will be a valuable tool for GBS researchers and that our system has the potential to reveal key pathogenesis gene networks and potential therapeutic/preventative targets. PMID- 27229470 TI - Adhesive capsulitis of the shoulder, treatment with corticosteroid, corticosteroid with distension or treatment-as-usual; a randomised controlled trial in primary care. AB - BACKGROUND: Optimal management for adhesive shoulder capsulitis (frozen shoulder) is currently unclear. We intended to explore whether treatment by intra-articular injections with corticosteroid and distension is more effective than treating with corticosteroids alone or treatment-as-usual in a primary care setting in Norway. METHODS: In this prospective randomised intention to treat parallel study, 106 patients were block randomised to three groups; 36 (analysed 35) receiving steroid injection and Lidocaine (IS), 34 receiving steroid and additional saline as distension (ISD) and 36 had treatment-as-usual (TAU). Intervention groups received four injections within 8 weeks, assessed on 1st visit, at the 4th and 8th week. Outcomes were Shoulder Pain and Disability Index (SPADI), Numerical pain rating scale (NPRS) and passive range of motion (PROM). Postal assessment was repeated after 1 year for SPADI. Patients in the IS and ISD groups were "blinded" for intervention received and the assessor was "blinded" to group allocation. RESULTS: At baseline there were no differences between groups in outcome measures. There were no statistical significant differences between the intervention groups in SPADI, NPRS and PROM at baseline, at short-term (4-and 8 weeks) or long-term (12 months). There were statistically significant differences (p < 0.01) in change scores at short-term for SPADI when comparing the IS and TAU groups (-20.8; CI-28.9 to -12.7), and the ISD and TAU groups ( 21.7; CI-29.4 to -14.0), respectively for NPRS (-2.0; CI-2.8 to -1.1 and -2.2; CI 3.0 to -1.4), and for PROM, but not at long-term for SPADI (p > 0.05). Effect size (ES) at 8 weeks was large between both injection groups and TAU (ES 1.2). At 12 months ES was reduced to 0.3 and 0.4 respectively. Transitory side effects as flushing and after-pain were reported by 14 % in intervention groups. CONCLUSION: This intention to treat RCT in primary care indicates that four injections with corticosteroid with or without distension, given with increasing intervals during 8 weeks, were better than treatment-as-usual in treatment of adhesive shoulder capsulitis. However, in the long run no difference was found between any of the groups, indicating that natural healing takes place independent of treatment or not. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov/ identifier: NCT01570985. PMID- 27229472 TI - Separating underwater ambient noise from flow noise recorded on stereo acoustic tags attached to marine mammals. AB - Sound-recording acoustic tags attached to marine animals are commonly used in behavioural studies. Measuring ambient noise is of interest to efforts to understand responses of marine mammals to anthropogenic underwater sound, or to assess their communication space. Noise of water flowing around the tag reflects the speed of the animal, but hinders ambient noise measurement. Here, we describe a correlation-based method for stereo acoustic tags to separate the relative contributions of flow and ambient noise. The uncorrelated part of the noise measured in digital acoustic recording tag (DTAG) recordings related well to swim speed of a humpback whale (Megaptera novaeangliae), thus providing a robust measure of flow noise over a wide frequency bandwidth. By removing measurements affected by flow noise, consistent ambient noise estimates were made for two killer whales (Orcinus orca) with DTAGs attached simultaneously. The method is applicable to any multi-channel acoustic tag, enabling application to a wide range of marine species. PMID- 27229471 TI - Molecular identification of Anaplasma marginale in two autochthonous South American wild species revealed an identical new genotype and its phylogenetic relationship with those of bovines. AB - BACKGROUND: Anaplasma marginale is a well-known cattle pathogen of tropical and subtropical world regions. Even though, this obligate intracellular bacterium has been reported in other host species different than bovine, it has never been documented in Myrmecophaga tridactyla (giant anteater) or Hippocamelus antisense (taruca), which are two native endangered species. METHODS: Samples from two sick wild animals: a Myrmecophaga tridactyla (blood) and a Hippocamelus antisense (blood and serum) were studied for the presence of A. marginale DNA through msp5 gene fragment amplification. Further characterization was done through MSP1a tandem repeats analysis and MLST scheme and the genetic relationship among previously characterized A. marginale sequences were studied by applying, eBURST algorithm and AMOVA analysis. RESULTS: Anaplasma marginale DNA was identified in the Myrmecophaga tridactyla and Hippocamelus antisense samples. Through molecular markers, we identified an identical genotype in both animals that was not previously reported in bovine host. The analysis through eBURST and AMOVA revealed no differentiation between the taruca/anteater isolate and the bovine group. CONCLUSIONS: In the present publication we report the identification of A. marginale DNA in a novel ruminant (Hippocamelus antisense) and non-ruminant (Myrmecophaga tridactyla) host species. Genotyping analysis of isolates demonstrated the close relatedness of the new isolate with the circulation population of A. marginale in livestock. Further analysis is needed to understand whether these two hosts contribute to the anaplasmosis epidemiology. PMID- 27229473 TI - Reproductive consequences of female size in haematophagous ectoparasites. AB - To test relationships between maternal size, egg size and size of new offspring, we studied (a) the effect of maternal size on egg size and number, and maternal survival after oviposition and (b) the effect of egg size on the duration of development and new imago size in three flea species (Xenopsylla ramesis, Synosternus cleopatrae, Parapulex chephrenis) with varying host and habitat specificity. In general, the number and size of eggs as well as total egg volume appeared to be independent of maternal body size. There was no trade-off between egg number and size. However, female body size was related to post-oviposition survival, with larger females surviving longer after oviposition than smaller females. In addition, females that produced more eggs died faster after oviposition in X. ramesis but not in the two other species. There were no significant size differences between eggs that developed into new imagoes and eggs that did not survive. Survivorship of male and female eggs did not differ; however, new adult females were significantly larger than new adult males. Female, but not male, new imagoes exhibited a significant positive relationship between egg size and duration of preimaginal development in all three species, with larger eggs developing faster than smaller eggs. In X. ramesis and S. cleopatrae, faster developing eggs also developed into larger new imagoes. We conclude that these patterns were largely consistent among the three flea species, suggesting that they result from the same mechanisms and are weakly affected by the ecological specialization of a given species. PMID- 27229474 TI - A subset of neurons controls the permeability of the peritrophic matrix and midgut structure in Drosophila adults. AB - The metazoan gut performs multiple physiological functions, including digestion and absorption of nutrients, and also serves as a physical and chemical barrier against ingested pathogens and abrasive particles. Maintenance of these functions and structures is partly controlled by the nervous system, yet the precise roles and mechanisms of the neural control of gut integrity remain to be clarified in Drosophila Here, we screened for GAL4 enhancer-trap strains and labeled a specific subsets of neurons, using Kir2.1 to inhibit their activity. We identified an NP3253 line that is susceptible to oral infection by Gram-negative bacteria. The subset of neurons driven by the NP3253 line includes some of the enteric neurons innervating the anterior midgut, and these flies have a disorganized proventricular structure with high permeability of the peritrophic matrix and epithelial barrier. The findings of the present study indicate that neural control is crucial for maintaining the barrier function of the gut, and provide a route for genetic dissection of the complex brain-gut axis in adults of the model organism Drosophila. PMID- 27229475 TI - Parental thermal environment alters offspring sex ratio and fitness in an oviparous lizard. AB - The environment experienced by parents can impact the phenotype of their offspring (parental effects), a critical component of organismal ecology and evolution in variable or changing environments. Although temperature is a central feature of the environment for ectotherms, its role in parental effects has been little explored until recently. Here, parental basking opportunity was manipulated in an oviparous lizard with temperature-dependent sex determination, the jacky dragon (Amphibolurus muricatus). Eggs were incubated at a temperature that typically produces a 50:50 sex ratio, and hatchlings were reared in a standard thermal environment. Offspring of parents in short bask conditions appeared to have better fitness outcomes in captive conditions than those of parents in long bask conditions - they had greater growth and survival as a function of their mass. In addition, the sex of offspring (male or female) depended on the interaction between parental treatment and egg mass, and treatment impacted whether sons or daughters grew larger in their first season. The interactive effects of treatment on offspring sex and growth are consistent with adaptive explanations for the existence of temperature-dependent sex determination in this species. Moreover, the greater performance recorded in short bask offspring may represent an anticipatory parental effect to aid offspring in predicted conditions of restricted thermal opportunity. Together, these responses constitute a crucial component of the population response to spatial or temporal variation in temperature. PMID- 27229476 TI - Potential role of p21 Activated Kinase 1 (PAK1) in the invasion and motility of oral cancer cells. AB - BACKGROUND: Oral cancer malignancy consists of uncontrolled division of cells primarily in and around the floor of the oral cavity, gingiva, oropharynx, lower lip and base of the tongue. According to GLOBOCAN 2012 report, oral cancer is one of the most common cancers among males and females in India. Even though significant advancements have been made in the field of oral cancer treatment modalities, the overall prognosis for the patients has not improved in the past few decades and hence, this demands a new thrust for the identification of novel therapeutic targets in oral cancer. p21 Activated Kinases (PAKs) are potential therapeutic targets that are involved in numerous physiological functions. PAKs are serine-threonine kinases and they serve as important regulators of cytoskeletal dynamics and cell motility, transcription through MAP kinase cascades, death and survival signalling, and cell-cycle progression. Although PAKs are known to play crucial roles in cancer progression, the role and clinical significance of PAKs in oral cancer remains poorly understood. RESULTS: Our results suggest that PAK1 is over-expressed in oral cancer cell lines. Stimulation of Oral Squamous Cell Carcinoma (OSCC) cells with serum growth factors leads to PAK1 re-localization and might cause a profound cytoskeletal remodelling. PAK1 was also found to be involved in the invasion, migration and cytoskeletal remodelling of OSCC cells. CONCLUSIONS: Our study revealed that PAK1 may play a crucial role in the progression of OSCC. Studying the role of PAK1 and its substrates is likely to enhance our understanding of oral carcinogenesis and potential therapeutic value of PAKs in oral cancer. PMID- 27229477 TI - Thermotolerant yeasts selected by adaptive evolution express heat stress response at 30 degrees C. AB - Exposure to long-term environmental changes across >100s of generations results in adapted phenotypes, but little is known about how metabolic and transcriptional responses are optimized in these processes. Here, we show that thermotolerant yeast strains selected by adaptive laboratory evolution to grow at increased temperature, activated a constitutive heat stress response when grown at the optimal ancestral temperature, and that this is associated with a reduced growth rate. This preventive response was perfected by additional transcriptional changes activated when the cultivation temperature is increased. Remarkably, the sum of global transcriptional changes activated in the thermotolerant strains when transferred from the optimal to the high temperature, corresponded, in magnitude and direction, to the global changes observed in the ancestral strain exposed to the same transition. This demonstrates robustness of the yeast transcriptional program when exposed to heat, and that the thermotolerant strains streamlined their path to rapidly and optimally reach post-stress transcriptional and metabolic levels. Thus, long-term adaptation to heat improved yeasts ability to rapidly adapt to increased temperatures, but this also causes a trade-off in the growth rate at the optimal ancestral temperature. PMID- 27229479 TI - MgZnO/ZnO heterostructures with electron mobility exceeding 1 * 10(6) cm(2)/Vs. AB - The inherently complex chemical and crystallographic nature of oxide materials has suppressed the purities achievable in laboratory environments, obscuring the rich physical degrees of freedom these systems host. In this manuscript we provide a systematic approach to defect identification and management in oxide molecular beam epitaxy grown MgZnO/ZnO heterostructures which host two dimensional electron systems. We achieve samples displaying electron mobilities in excess of 1 * 10(6) cm(2)/Vs. This data set for the MgZnO/ZnO system firmly establishes that the crystalline quality has become comparable to traditional semiconductor materials. PMID- 27229478 TI - Comparison of qualitative and semiquantitative strain elastography in breast lesions for diagnostic accuracy. AB - BACKGROUND: Strain elastography can be purely qualitative or semiquantitative using both strain score and strain ratio. The aim of this study was to establish the accuracy of semiquantitative elastography using both strain score and strain ratio in differentiating benign from malignant breast masses. The diagnostic performance of the two methods was analysed for any statistically significant difference. METHODS: A prospective study was carried out from May to December 2014 in the University of Nairobi, Department of Diagnostic Imaging and Radiation Medicine. One hundred and eighteen patients referred for breast ultrasound following clinical detection of masses certified the inclusion criteria. All solid masses identified on grey scale imaging were subjected to strain elastography. Elastographic findings were represented in both strain score and strain ratio. Comparison of diagnostic performance with histological findings as the gold standard for all detected solid masses was done. Fisher's exact test and receiver operating characteristics curves were applied for statistical analysis to look for any significant differences between the diagnostic performance of strain score and strain ratio. RESULTS: Out of the 118, three patients did not attend for all the examinations and three biopsy results were misplaced therefore analysis was done for 112 subjects. The sensitivity, specificity, positive predictive value and negative predictive value of elasticity strain (Ueno) score were 0.86, 0.96, 0.89 and 0.96 respectively. For the strain ratio the values were 0.93, 0.96, 0.90 and 0.96 respectively. Fisher's exact test P values comparing the sensitivity and specificity were 0.69 and 1.00 respectively not considered significant at p 0.05 levels. The areas under the curve (AUCs) from the receiver operating characteristic (ROC) curves were 0.972 and 0.976 for strain score and ratio respectively with a strong Pearson's correlation coefficient, r 0.79 indicating a high diagnostic accuracy for both methods but no statistically significant difference in performance. CONCLUSION: Semiquantitative ultrasound elastography has good diagnostic accuracy in differentiating benign and malignant breast solid lesions and there is no statistically significant difference between strain score and strain ratio in sensitivity, specificity and accuracy. PMID- 27229480 TI - Proteomic analysis of novel targets associated with the enhancement of TrkA induced SK-N-MC cancer cell death caused by NGF. AB - Nerve growth factor (NGF) is known to regulate both cancer cell survival and death signaling, depending on the cellular circumstances, in various cell types. In this study, we showed that NGF strongly upregulated the protein level of tropomyosin-related kinase A (TrkA) in TrkA-inducible SK-N-MC cancer cells, resulting in increases in various TrkA-dependent cellular processes, including the phosphorylation of c-Jun N-terminal kinase (JNK) and caspase-8 cleavage. In addition, NGF enhanced TrkA-induced morphological changes and cell death, and this effect was significantly suppressed by the JNK inhibitor SP600125, but not by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin. To investigate novel targets associated with the enhancement of TrkA-induced SK-N-MC cell death caused by NGF, we performed Coomassie Brilliant Blue staining and two-dimensional (2D) proteomic analysis in TrkA-inducible SK-N-MC cells. We identified 31 protein spots that were either greatly upregulated or downregulated by TrkA during NGF treatment using matrix-associated laser desorption/ionization time of flight/time of flight mass spectrometry, and we analyzed the effects of SP600125 and wortmannin on the spots. Interestingly, 11 protein spots, including heterogeneous nuclear ribonucleoprotein K (hnRNP K), lamin B1 and TAR DNA-binding protein (TDP43), were significantly influenced by SP600125, but not by wortmannin. Moreover, the NGF/TrkA-dependent inhibition of cell viability was significantly enhanced by knockdown of hnRNP K using small interfering RNA, demonstrating that hnRNP K is a novel target associated with the regulation of TrkA-dependent SK-N MC cancer cell death enhanced by NGF. PMID- 27229481 TI - p16INK4a is not a reliable screening marker of HPV infection in esophageal squamous cell carcinoma: evidence from a meta-analysis. AB - BACKGROUND: The role of p16INK4a as a surrogate marker for screening human papillomavirus (HPV) in esophageal squamous cell carcinoma (ESCC) remains controversial. METHODS: A comprehensive search of EMBASE, PubMed, China National Knowledge Infrastructure and China Biology Medicine was performed from inception to December 27, 2015. A random-effects model was applied to the pooled odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Ten studies were identified (985 cases). The pooled results showed no significant relationship between p16INK4a expression and HPV infection in ESCC based on overall HPV types (OR: 1.79, 95% CI: 0.69-4.66, p = 0.235). Subgroup analysis by HPV detection method showed no statistical significance in either the polymerase chain reaction (PCR) (OR: 1.65, 95% CI: 0.83-3.30, p = 0.154) or in situ hybridization (ISH) group (OR: 2.58, 95% CI: 0.03-268.14, p = 0.689). The pooled OR of the sensitivity analysis ranged from 1.27 (95% CI: 0.58-2.84) to 2.32 (95% CI: 0.95 5.64). Of these studies, 6 involved only high-risk human papillomavirus types (HR HPV), HPV16 or HPV18. However, similar observations were made for HR-HPV (OR = 1.31, 95% CI: 0.26-6.59, p = 0.741). Subgroup analysis again showed no statistical significance in the PCR group (OR: 0.95, 95% CI: 0.25-3.64, p = 0.940) and ISH group (OR: 2.58, 95% CI: 0.03-268.14, p = 0.689). Sensitivity analysis showed that the pooled OR ranged from 0.69 (95% CI: 0.21-2.22) to 1.89 (95% CI: 0.33-10.86). CONCLUSIONS: p16INK4a is not a reliable screening marker of HPV infection in ESCC. Further multicenter, large-sample and well-matched prospective studies are still required to illuminate the possible etiological roles of HPV in ESCC. PMID- 27229482 TI - Evaluation of proinflammatory cytokine and neopterin levels in women with papillary thyroid carcinoma. AB - INTRODUCTION: Papillary thyroid cancer is a disease that has been associated with chronic inflammation. The purpose of this study is to measure the production of the proinflammatory cytokines IL-1beta, IL-6 and IL-8 and neopterin, which is a novel biomarker for cellular immune response in papillary thyroid cancer. MATERIALS AND METHODS: The serum IL-1beta, IL-6, IL-8 and neopterin values of 31 papillary thyroid cancer patients undergoing bilateral total thyroidectomy were measured before and 20 days after surgery. The values were compared with those of 39 healthy controls. RESULTS: Serum IL-1beta levels were similar across groups. IL-6 (p<0.001), IL-8 (p = 0.015) and neopterin levels (p = 0.002) were higher in presurgical samples and returned to normal following surgery. CONCLUSIONS: The proinflammatory cytokines IL-6 and IL-8, but not IL-1beta, were produced in greater amounts in papillary thyroid cancer. Serum neopterin seems to be a valid biological marker supporting the presence of papillary thyroid cancer. PMID- 27229483 TI - Arhgap17, a RhoGTPase activating protein, regulates mucosal and epithelial barrier function in the mouse colon. AB - Coordinated regulation of the actin cytoskeleton by the Rho GTPase family is required for the maintenance of polarity in epithelial cells as well as for their proliferation and migration. A RhoGTPase-activating protein 17 (Arhgap17) is known to be involved in multiple cellular processes in vitro, including the maintenance of tight junctions and vesicle trafficking. However, the function of Arhgap17 has not been studied in the physiological context. Here, we generated Arhgap17-deficient mice and examined the effect in the epithelial and mucosal barriers of the intestine. Reporter staining revealed that Arhgap17 expression is limited to the luminal epithelium of intestine. Arhgap17-deficient mice show an increased paracellular permeability and aberrant localization of the apical junction complex in the luminal epithelium, but do not develop spontaneous colitis. The inner mucus layer is impervious to the enteric bacteria irrespective of Tff3 downregulation in the Arhgap17-deficient mice. Interestingly however, treatment with dextran sulfate sodium (DSS) causes an increased accumulation of DSS and TNF production in intraluminal cells and rapid destruction of the inner mucus layer, resulting in increased severity of colitis in mutant mice. Overall, these data reveal that Arhgap17 has a novel function in regulating transcellular transport and maintaining integrity of intestinal barriers. PMID- 27229486 TI - Topological triple-vortex lattice stabilized by mixed frustration in expanded honeycomb Kitaev-Heisenberg model. AB - The expanded classical Kitaev-Heisenberg model on a honeycomb lattice is investigated with the next-nearest-neighboring Heisenberg interaction considered. The simulation shows a rich phase diagram with periodic behavior in a wide parameter range. Beside the double 120 degrees ordered phase, an inhomogeneous phase is uncovered to exhibit a topological triple-vortex lattice, corresponding to the hexagonal domain structure of vector chirality, which is stabilized by the mixed frustration of two sources: the geometrical frustration arising from the lattice structure as well as the frustration from the Kitaev couplings. PMID- 27229484 TI - Genome-wide differential expression of genes and small RNAs in testis of two different porcine breeds and at two different ages. AB - Some documented evidences proved small RNAs (sRNA) and targeted genes are involved in mammalian testicular development and spermatogenesis. However, the detailed molecular regulation mechanisms of them remain largely unknown so far. In this study, we obtained a total of 10,716 mRNAs, 67 miRNAs and 16,953 piRNAs which were differentially expressed between LC and LW pig breeds or between the two sexual maturity stages. Of which, we identified 16 miRNAs and 28 targeted genes possibly related to spermatogenesis; 14 miRNA and 18 targeted genes probably associated with cell adhesion related testis development. We also annotated 579 piRNAs which could potentially regulate cell death, nucleosome organization and other basic biology process, which implied that those piRNAs might be involved in sexual maturation difference. The integrated network analysis results suggested that some differentially expressed genes were involved in spermatogenesis through the ECM-receptor interaction, focal adhesion, Wnt and PI3K-Akt signaling pathways, some particular miRNAs have the negative regulation roles and some special piRNAs have the positive and negative regulation roles in testicular development. Our data provide novel insights into the molecular expression and regulation similarities and diversities of spermatogenesis and testicular development in different pig breeds at different stages of sexual maturity. PMID- 27229485 TI - Integration of (68)Ga-PSMA-PET imaging in planning of primary definitive radiotherapy in prostate cancer: a retrospective study. AB - BACKGROUND: Prostate cancer (PC) is one of the most commonly treated cancer entities with radiation therapy (RT). Risk group-adapted treatment and avoidance of unnecessary toxicities relies primarily on accurate tumor staging. Thus, the introduction of prostate-specific membrane antigen (PSMA) in diagnosis and treatment of PC is a highly interesting development in radiation oncology of urologic tumors. The present work is to evaluate the integration of (68)Ga-PSMA PET imaging into standard radiation planning of primary definitive treatment of PC and to determine the impact of PSMA imaging on tumor staging. METHODS: The data of 15 patients treated for PC between August 2013 and April 2015 were evaluated. Treatment planning included (68)Ga-PSMA-PET imaging. We analyzed whether the use of PSMA-imaging led to a change of the TNM stage and if it influenced the RT treatment approach or the target volume, due to changes in the gross tumor volume (GTV) or clinical target volume (CTV), in the final treatment plan. RESULTS: In 53.3 % of the analyzed patients a change occurred in the TNM stage based on (68)Ga-PSMA-PET examination. The RT concept changed in 33.3 % of all patients, leading to relevant changes in the planning target volume. Among these, an additional irradiation of the pelvic lymph drainage due to tracer uptake in lymph nodes was performed in 25 %. Furthermore, boost volumes of PET positive lymph nodes were added in 80 % of these cases. A down staging due to the (68)Ga-PSMA-PET examination occurred in 13.3 % of all cases. CONCLUSIONS: The integration of (68)Ga-PSMA-PET-imaging into the RT treatment planning process can be useful for detailed target volume planning. The performance of a (68)Ga-PSMA PET frequently leads to changes in the TNM stage, altering the RT treatment regimen and the target volume. A prospective trial is underway to evaluate the impact of (68)Ga-PSMA-PET based treatment planning on outcome. PMID- 27229487 TI - Analysis of the association of HOTAIR single nucleotide polymorphism (rs920778) and risk of cervical cancer. AB - We recently demonstrated that overexpression of HOTAIR (Hox transcript antisense intergenic RNA) was associated with tumor progression and radio-resistance in human cervical cancer. Considering the single nucleotide polymorphism (SNP) rs920778 (C>T) could influence HOTAIR expression and cancer predisposition in other malignancies, we herein investigated the association between rs920778 status and cervical cancer susceptibility in a Chinese population. Using the specific TaqMan PCR assay, we genotyped rs920778 in 215 cervical cancer patients and 430 age-matched healthy controls. As shown in our data, TT genotype of rs920778 was significantly correlated with the upregulation of HOTAIR (p = 0.008). Compared with the healthy control, TT genotype and T allele notably indicated a much higher risk of cervical cancer [TT genotype: odds ratio (OR) = 2.186, 95% confidence interval (CI) = 1.378-3.466, p = 0.003; T allele: OR = 1.556, 95% CI = 1.221-1.981]. In addition, we also found that the TT genotype of rs920778 was correlated with advanced tumor stage (p = 0.039), highly histological grade (p = 0.013), lympho node metastasis (p < 0.001) and positive infection of high risk HPV (p < 0.001). Among the patients who underwent concurrent chemo-radiotherapy, TT genotype carriers present notably resistance to the combination of EBRT + ICBT + cisplatin (p = 0.023). In conclusion, we firstly reported that TT genotype of HOTAIR rs920778 was significantly associated with the cervical cancer susceptibility. Moreover, the TT genotype of rs920778 might be a potent prognostic marker in cervical cancer patients. PMID- 27229488 TI - Targeting Cancer with Epi-Drugs: A Precision Medicine Perspective. AB - Recent pan-cancer studies have shown the importance of coupling DNA methylation patterns with transcriptome profiles to reveal tumor subgroups with clinically relevant distinct characteristics. While the coupling patterns remain in most cases matter for further study and/or interpretation, it is emerging that all associations between epigenetic changes and specific cancer histotypes can facilitate the development of novel epidrugs. In particular, together with chemotherapy and chemoprevention of cancer, these epidrugs will target specific enzymes involved in the complex regulation of gene expression. This perspective surveys recent cancer epigenetic findings on target drugs and therapeutic strategies, and focuses on the epigenetic modifications that can reverse a stable differentiated state of adult cell towards neoplastic phenotypes. The relevance of such developments may thus pave the way for patient's customized personalized therapies. PMID- 27229489 TI - Neonatal Jaundice Detection System. AB - Neonatal jaundice is a common condition that occurs in newborn infants in the first week of life. Today, techniques used for detection are required blood samples and other clinical testing with special equipment. The aim of this study is creating a non-invasive system to control and to detect the jaundice periodically and helping doctors for early diagnosis. In this work, first, a patient group which is consisted from jaundiced babies and a control group which is consisted from healthy babies are prepared, then between 24 and 48 h after birth, 40 jaundiced and 40 healthy newborns are chosen. Second, advanced image processing techniques are used on the images which are taken with a standard smartphone and the color calibration card. Segmentation, pixel similarity and white balancing methods are used as image processing techniques and RGB values and pixels' important information are obtained exactly. Third, during feature extraction stage, with using colormap transformations and feature calculation, comparisons are done in RGB plane between color change values and the 8-color calibration card which is specially designed. Finally, in the bilirubin level estimation stage, kNN and SVR machine learning regressions are used on the dataset which are obtained from feature extraction. At the end of the process, when the control group is based on for comparisons, jaundice is succesfully detected for 40 jaundiced infants and the success rate is 85 %. Obtained bilirubin estimation results are consisted with bilirubin results which are obtained from the standard blood test and the compliance rate is 85 %. PMID- 27229490 TI - Characterization of Brain-Heart Interactions in a Rodent Model of Sepsis. AB - Loss of heart rate variability (HRV) and autonomic dysfunction are associated with poor outcomes in critically ill patients. Neuronal networks comprising brainstem and hypothalamus are involved in the "flight-or-fight" response via control over the autonomic nervous system and circulation. We hypothesized that sepsis-induced inflammation in brain regions responsible for autonomic control is associated with sympathovagal imbalance and depressed contractility. Sepsis was induced by fecal slurry injection in fluid-resuscitated rats. Sham-operated animals served as controls. Echocardiography-derived peak velocity (PV) was used to separate septic animals into good (PV >=0.93 m/s, low 72-h mortality) and bad (PV <0.93, high 72-h mortality) prognosis. Cytokine protein levels were assessed by ELISA. All experiments were performed at 24 h post-insult. Increased levels of inflammation and oxidative injury were observed in the hypothalamus (TNF-alpha, IL-10, nitrite and nitrate and carbonyl groups) and brainstem (IL-1, IL-6, IL-10, nitrite and nitrate and carbonyl groups) of the septic animals (p < 0.05 vs. sham), but not in the pre-frontal cortex, an area not directly implicated in control of the autonomic nervous system. Good prognosis septic animals had increased sympathetic output and increased left ventricular contractility (p < 0.05 vs. sham). There was a significant inverse correlation between high frequency power (a marker of parasympathetic outflow) and contractility (r = 0.73, p < 0.05). We found no correlation between the degree of inflammation or injury to autonomic centers and cardiovascular function. In conclusion, control of autonomic centers and cardiac function in our long-term rodent model of sepsis was related to clinical severity but not directly to the degree of inflammation. PMID- 27229492 TI - Introduction: pediatric body MRI course supplement. PMID- 27229491 TI - Chronic Treatment with Paraquat Induces Brain Injury, Changes in Antioxidant Defenses System, and Modulates Behavioral Functions in Zebrafish. AB - Paraquat (PQ) administration consists in a chemical model that mimics phenotypes observed in Parkinson's disease (PD), due to its ability to induce changes in dopaminergic system and oxidative stress. The aim of this study was to evaluate the actions of PQ in behavioral functions of adult zebrafish and its influence on oxidative stress biomarkers in brain samples. PQ (20 mg/kg) was administered intraperitoneally with six injections for 16 days (one injection every 3 days). PQ-treated group showed a significant decrease in the time spent in the bottom section and a shorter latency to enter the top area in the novel tank test. Moreover, PQ-exposed fish showed a significant decrease in the number and duration of risk assessment episodes in the light-dark test, as well as an increase in the agonistic behavior in the mirror-induced aggression (MIA) test. PQ induced brain damage by decreasing mitochondrial viability. Concerning the antioxidant defense system, PQ increased catalase (CAT) and glutathione peroxidase (GPx) activities, as well as the non-protein sulfhydryl content (NPSH), but did not change ROS formation and decreased lipid peroxidation. We demonstrate, for the first time, that PQ induces an increase in aggressive behavior, alters non-motor patterns associated to defensive behaviors, and changes redox parameters in zebrafish brain. Overall, our findings may serve as useful tools to investigate the interaction between behavioral and neurochemical impairments triggered by PQ administration in zebrafish. PMID- 27229493 TI - Appropriate selection of MRI sequences for common scenarios in clinical practice. AB - Knowledge about sequence properties is essential to plan and acquire a diagnostic MRI examination. The broad four categories of sequences include spin echo (SE), gradient echo (GRE), inversion recovery (IR) and echoplanar imaging (EPI). Varieties of sequences from these four categories are available for clinical application. They have different contrast mechanisms, spatial and contrast resolution and speed of acquisition. Choice of sequence differs in various scenarios in clinical practice such as solid organ imaging, moving target imaging, bone and bone marrow imaging, cartilage imaging and vessel imaging, taking into consideration properties of sequences to answer the clinical question. Broad classification of sequences and differences in their contrast, spatial and contrast resolution, and speed of acquisition are discussed in this review. A few common clinical scenarios of MRI imaging are illustrated, along with reasons for the given sequence choices. PMID- 27229494 TI - Body MR angiography in children: how we do it. AB - Vascular pathology is ubiquitous in children. Common indications for angiographic imaging in the body include congenital anomalies, portal hypertension, assessing resectability of neoplasms, renovascular hypertension, vascular malformations, vasculitis, systemic vein thrombosis, and trauma. MR angiography, with or without the use of intravenous contrast agents, is therefore a mainstay in the repertoire of MR imaging in children. Pediatric contrast-enhanced MR angiography has benefited from several innovations in recent years, including improved hardware options like high-field-strength scanners and integrated high-density coil arrays, new sequences that combine parallel imaging, innovative k-space sampling and Dixon fat suppression with time-resolved imaging, new contrast agents with longer blood-pool residence time, and advanced post-processing solutions like image fusion. This article focuses on the principles of contrast-enhanced MR angiography of the body as it pertains to the physiologies and pathologies encountered in children. It also discusses tools to adapt the MR angiographic technique to the clinical indication, as well as pitfalls of post-processing and interpretation in commonly encountered vascular imaging scenarios in the pediatric body. PMID- 27229495 TI - Magnetic resonance imaging of primary pediatric liver tumors. AB - Although primary hepatic neoplasms are less common than other intra-abdominal tumors in children, these neoplasms are a significant source of morbidity and mortality in the pediatric population. MRI is increasingly relied upon in the diagnostic evaluation of these lesions, both before and after treatment, and familiarity with the MRI findings associated with these neoplasms is a must for pediatric radiologists. Advances in MRI technology, particularly the advent of hepatocyte-specific gadolinium-based MRI contrast agents, have allowed for accurate characterization of several types of hepatic neoplasms on the basis of imaging appearance. In this review, we provide an overview of the approach to imaging hepatic neoplasms in children using MRI, including a sample imaging protocol. We also discuss the relevant clinical features and MRI findings of the most clinically relevant entities, including their appearance on post-contrast imaging using hepatocyte-specific gadolinium-based MRI contrast agents. PMID- 27229496 TI - Magnetic resonance imaging of pancreaticobiliary diseases in children: from technique to practice. AB - Magnetic resonance imaging is useful for evaluating pancreaticobiliary diseases in children after initial sonography, obviating the use of ionizing radiation or invasive procedures such as endoscopic retrograde cholangiopancreatography (ERCP) or transhepatic biliary procedures. Advanced MRI applications have improved depiction of pediatric pancreaticobiliary anatomy and have greatly impacted management of biliary and pancreatic diseases in children. In this article, we review current MRI and magnetic resonance cholangiopancreatography (MRCP) techniques and discuss their role in the assessment of common pancreatic and biliary disorders in children. PMID- 27229497 TI - Magnetic resonance urography in the pediatric population: a clinical perspective. AB - Diagnostic imaging in pediatric urology has traditionally relied upon multiple modalities based on availability, use of ionizing radiation, and invasiveness to evaluate urological anomalies. These modalities include ultrasonography, voiding cystourethrography, fluoroscopy and radionuclide scintigraphy. Magnetic resonance urography (MRU) has become increasingly useful in depicting more detailed abdominal and pelvic anatomy, specifically in duplex collecting systems, ectopic ureter, ureteropelvic junction (UPJ) obstruction, megaureter and congenital pelvic anomalies. Here we discuss the clinical role of MRU in the pediatric population and its future direction. PMID- 27229498 TI - Magnetic resonance imaging of Mullerian duct anomalies in children. AB - Mullerian duct anomalies encompass a wide variety of disorders resulting from abnormalities in the embryological development of the Mullerian ducts. In the prepubertal pediatric population, Mullerian duct anomalies are often incidental findings on studies obtained for other reasons. The onset of menses can prompt more clinical symptoms. Proper characterization of Mullerian duct anomalies is important because these anomalies can affect the development of gynecological disorders as well as fertility. Mullerian duct anomalies also carry a high association with other congenital anomalies, particularly renal abnormalities. MRI is widely considered the best modality for assessing Mullerian duct anomalies; it provides multiplanar capability, clear anatomical detail and tissue characterization without ionizing radiation. MRI allows for careful description of Mullerian duct anomalies, often leading to classification into the most widely accepted classification system for Mullerian duct anomalies. This system, developed by the American Society of Reproductive Medicine, includes seven subtypes: uterine agenesis/hypoplasia, unicornuate, didelphys, bicornuate, septate, arcuate, and diethylstilbestrol (DES) drug-related uterus. In cases of complex anomalies that defy classification, MRI allows detailed depiction of all components of the anatomical abnormality, allowing for proper management and surgical planning. PMID- 27229499 TI - Magnetic resonance imaging of acquired disorders of the pediatric female pelvis other than neoplasm. AB - Transabdominal US remains the primary screening imaging modality of the pediatric female pelvis. However, MRI has become an invaluable adjunct to US in recent years. MRI offers superb soft-tissue contrast resolution that allows for detailed evaluation, particularly of the ovaries and their associated pathology. MRI can yield diagnostic information that is similar to or even better than that of US, especially in nonsexually active girls in whom transvaginal US would be contraindicated. MRI is generally a second-line examination and is preferred over CT because it does not involve the use of ionizing radiation. MRI might be underutilized in this population, particularly in differentiating surgical from nonsurgical conditions. This article reviews the relevant anatomy and discusses imaging of acquired conditions that involve the pediatric female genital tract, illustrating associated pathology with case examples. PMID- 27229500 TI - How we do it: MR enterography. AB - Magnetic resonance enterography (MRE) now plays a central role in diagnosing pediatric inflammatory bowel disease (IBD), and its role in other intestinal pathologies such as scleroderma is gradually expanding. MRE helps distinguish between Crohn disease and ulcerative colitis, defining extent and severity. Standard MRE protocols can be optimized in children and adolescents to be diagnostic and well tolerated, both of which are important with increasing use of serial MRE in pediatric IBD for monitoring treatment response and evaluating complications. MRI is especially suited to this role given its lack of ionizing radiation. MRE compliance can be improved through patient education. Differing from adult MRE, pediatric MRE protocols use weight-based formulas to calculate oral and intravenous contrast media and antispasmodic agent doses, using either hyoscine-N-butylbromide or glucagon. Nausea is more commonly experienced with glucagon; however vomiting occurs in <10% of children with either agent. Standard and advanced sequences applied in adults are also used in children and adolescents. These include static and cinematic balanced steady-state free precession sequences, single-shot T2-weighted sequences, diffusion-weighted imaging and pre- and post-contrast 3-D T1-weighted gradient echo sequences. Magnetization transfer imaging and quantitative assessment of bowel to distinguish inflammation and fibrosis are not yet standard in pediatric MRE, but show promise. PMID- 27229501 TI - Magnetic resonance imaging of perianal Crohn disease in children. AB - Perianal penetrating complications of Crohn disease are among the most important causes of symptoms in the pediatric population. High-quality diagnostic imaging of the perianal region is crucial for treatment planning and therapeutic response assessment. MRI, with its absence of ionizing radiation and high soft-tissue resolution, provides an excellent noninvasive tool for evaluation of perianal fistulae and associated abscesses, as well as their anatomical relationship to the anal sphincter complex. In this review we discuss the role of MRI in initial diagnosis and follow-up of perianal fistulizing Crohn disease in the pediatric population. PMID- 27229502 TI - Diffusion-weighted imaging in pediatric body magnetic resonance imaging. AB - Diffusion-weighted MRI is being increasingly used in pediatric body imaging. Its role is still emerging. It is used for detection of tumors and abscesses, differentiation of benign and malignant tumors, and detection of inflamed bowel segments in inflammatory bowel disease in children. It holds great promise in the assessment of therapy response in body tumors, with apparent diffusion coefficient (ADC) value as a potential biomarker. Significant overlap of ADC values of benign and malignant processes and less reproducibility of ADC measurements are hampering its widespread use in clinical practice. With standardization of the technique, diffusion-weighted imaging (DWI) is likely to be used more frequently in clinical practice. We discuss the principles and technique of DWI, selection of b value, qualitative and quantitative assessment, and current status of DWI in evaluation of disease processes in the pediatric body. PMID- 27229504 TI - Current role of body MRI in pediatric oncology. AB - Magnetic resonance imaging (MRI) plays an important role in the imaging of children with non-central nervous system malignancies, and it is increasingly replacing or complementing CT in many cases. MRI has several advantages over CT, including superior contrast resolution as well as superior tissue characterization with the use of novel pulse sequences and functional or organ specific contrast agents. In addition, the lack of ionizing radiation - an important consideration in children - allows for multiphase dynamic post-contrast imaging, which can be useful for lesion detection and characterization. Several challenges remain in the performance of MRI in pediatric oncology patients, including the frequent need for sedation or anesthesia in young children because of long imaging times, as well as the suboptimal imaging of the lungs in the evaluation for pulmonary metastatic disease. However, despite these challenges, with continued improvements in MRI image quality and the development of novel sequences, contrast agents and quantitative imaging techniques, MRI is expected to play an ever increasing role in the imaging of pediatric oncology patients. PMID- 27229503 TI - Whole-body magnetic resonance imaging in children: technique and clinical applications. AB - Whole-body MR imaging is being increasingly used in children to evaluate the extent of various oncologic and non-oncologic entities. The lack of exposure to ionizing radiation, excellent soft-tissue contrast (even without the use of contrast agents), and functional imaging capabilities make it especially suitable for screening and surveillance in the pediatric population. Technical developments such as moving table platforms, multi-channel/multi-element surface coils, and parallel imaging allow imaging of the entire body with multiple sequences in a reasonable 30- to 40-min time frame, which has facilitated its acceptance in routine clinical practice. The initial investigations in whole-body MR imaging were primarily focused on oncologic applications such as tumor screening and staging. The exquisite sensitivity of fluid-sensitive MR sequences to many different types of pathology has led to new applications of whole-body MR imaging in evaluation of multifocal rheumatologic conditions. Availability of blood pool contrast agents has allowed whole-body MR angiographic imaging of vascular malformations, vasculitides and vasculopathies. Whole-body MRI is being applied for delineating the extent and distribution of systemic and multifocal diseases, establishing diagnoses, assessing treatment response, and surveillance imaging. This article reviews the technique and clinical applications of whole body MR imaging in children. PMID- 27229505 TI - What MRI can tell us about neurogenic tumors and rhabdomyosarcoma. AB - This review focuses on the MRI features of neurogenic tumors and rhabdomyosarcoma in children. Neurogenic tumors include those arising from a nerve sheath and neuroblastic tumors that arise from the sympathetic nervous system. Nerve sheath tumors can be benign or malignant and occur sporadically or in association with neurofibromatosis type 1. Neuroblastic tumors comprise a spectrum of tumors ranging from highly malignant neuroblastoma to the benign ganglioneuroma. These neurogenic tumors arise in typical locations within the chest, abdomen and pelvis and have distinctive and characteristic imaging features that should suggest their diagnosis. Rhabdomyosarcoma encompasses a variety of histological subtypes that exhibit varying degrees of aggressiveness and biological behavior. While some abdominal and pelvic locations are well known to give rise to rhabdomyosarcoma, this tumor can arise in any tissue in the body except bone. The paper reviews the MRI and clinical features of neurogenic tumors and rhabdomyosarcoma and the imaging findings that can aid in clinical management. PMID- 27229506 TI - Magnetic resonance imaging of pediatric soft-tissue vascular anomalies. AB - Magnetic resonance (MR) imaging can be used in the management of pediatric soft tissue vascular anomalies for diagnosing and assessing extent of lesions and for evaluating response to therapy. MR imaging studies often involve a combination of T1- and T2-weighted images in addition to MR angiography and fat-suppressed post contrast sequences. The MR imaging features of these vascular anomalies when combined with clinical findings can aid in diagnosis. In cases of complex vascular malformations and syndromes associated with vascular anomalies, MR imaging can be used to evaluate accompanying soft-tissue and bone anomalies. This article reviews the MR imaging protocols and appearances of the most common pediatric soft-tissue vascular anomalies. PMID- 27229507 TI - Magnetic resonance imaging of the mediastinum, chest wall and pleura in children. AB - The acceptance of applications for the use of chest MRI in children has been somewhat slow and selective. The use of MRI to image chest wall lesions is likely the most common and widely used indication, aside from the widespread and somewhat sophisticated use of MRI in imaging the cardiovascular structures of the chest. In this respect, fairly standard variations of T1-W, T2-W and contrast enhanced imaging can be used, similar to the sequences used for musculoskeletal lesions elsewhere in the body. Imaging of the anterior mediastinal masses should be performed in conjunction with a detailed pre-test clinical examination to determine potential cardiovascular compromise. MRI in the setting of middle mediastinal adenopathy, congenital mediastinal cysts or posterior mediastinal masses, however, has been shown to be more effective and more comprehensive than multidetector CT. Although sonographic imaging is the initial modality of choice for pleural abnormalities, MR imaging is extremely effective and clinically useful in the setting of a potentially ambiguous sonographic examination. Faster imaging protocols are likely to increase the acceptance of MRI to replace multidetector CT for many pediatric chest lesions. PMID- 27229508 TI - Strategies to minimize sedation in pediatric body magnetic resonance imaging. AB - The high soft-tissue contrast of MRI and the absence of ionizing radiation make it a valuable tool for assessment of body pathology in children. Infants and young children are often unable to cooperate with awake MRI so sedation or general anesthesia might be required. However, given recent data on the costs and potential risks of anesthesia in young children, there is a need to try to decrease or avoid sedation in this population when possible. Child life specialists in radiology frequently use behavioral techniques and audiovisual support devices, and they practice with children and families using mock scanners to improve child compliance with MRI. Optimization of the MR scanner environment is also important to create a child-friendly space. If the child can remain inside the MRI scanner, a variety of emerging techniques can reduce the effect of involuntary motion. Using sequences with short acquisition times such as single shot fast spin echo and volumetric gradient echo can decrease artifacts and improve image quality. Breath-holding, respiratory triggering and signal averaging all reduce respiratory motion. Emerging techniques such as radial and multislice k-space acquisition, navigator motion correction, as well as parallel imaging and compressed sensing reconstruction methods can further accelerate acquisition and decrease motion. Collaboration among radiologists, anesthesiologists, technologists, child life specialists and families is crucial for successful performance of MRI in young children. PMID- 27229509 TI - Magnetic resonance imaging in pediatric appendicitis: a systematic review. AB - Magnetic resonance imaging for the evaluation of appendicitis in children has rapidly increased recently. This change has been primarily driven by the desire to avoid CT radiation dose. This meta-analysis reviews the diagnostic performance of MRI for pediatric appendicitis and discusses current knowledge of cost effectiveness. We used a conservative Haldane correction statistical method and found pooled diagnostic parameters including a sensitivity of 96.5% (95% confidence interval [CI]: 94.3-97.8%), specificity of 96.1% (95% CI: 93.5-97.7%), positive predictive value of 92.0% (95% CI: 89.3-94.0%) and negative predictive value of 98.3% (95% CI: 97.3-99.0%), based on 11 studies. Assessment of patient outcomes associated with MRI use at two institutions indicates that time to antibiotics was 4.7 h and 8.2 h, time to appendectomy was 9.1 h and 13.9 h, and negative appendectomy rate was 3.1% and 1.4%, respectively. Alternative diagnoses were present in ~20% of cases, most commonly adnexal cysts and enteritis/colitis. Regarding technique, half-acquisition single-shot fast spin-echo (SSFSE) pulse sequences are crucial. While gadolinium-enhanced T1-weighted pulse sequences might be helpful, any benefit beyond non-contrast MRI has not been confirmed. Balanced steady-state free precession (SSFP) sequences are generally noncontributory. Protocols do not need to exceed five sequences; four-sequence protocols are commonly utilized. Sedation generally is not indicated; patients younger than 5 years might be attempted based on the child's ability to cooperate. A comprehensive pediatric cost-effectiveness analysis that includes both direct and indirect costs is needed. PMID- 27229510 TI - BAC mediated transgenic Large White boars with FSHalpha/beta genes from Chinese Erhualian pigs. AB - Follicle-stimulating hormone (FSH) is a critical hormone regulating reproduction in mammals. Transgenic mice show that overexpression of FSH can improve female fecundity. Using a bacterial artificial chromosome (BAC) system and somatic cell nuclear transfer, we herein generated 67 Large White transgenic (TG) boars harboring FSHalpha/beta genes from Chinese Erhualian pigs, the most prolific breed in the world. We selected two F0 TG boars for further breeding and conducted molecular characterization and biosafety assessment for F1 boars. We showed that 8-9 copies of exogenous FSHalpha and 5-6 copies of exogenous FSHbeta were integrated into the genome of transgenic pigs. The inheritance of exogenous genes conforms to the Mendel's law of segregation. TG boars had higher levels of serum FSH, FSHalpha mRNA in multiple tissues, FSHbeta protein in pituitary and more germ cells per seminiferous tubule compared with their wild-type half sibs without any reproductive defects. Analysis of growth curve, hematological and biochemical parameters and histopathology illustrated that TG boars grew healthily and normally. By applying 16S rRNA gene sequencing, we demonstrated that exogenous genes had no impact on the bacterial community structures of pig guts. Moreover, foreign gene drift did not occur as verified by horizontal gene transfer. Our findings indicate that overexpression of FSH could improve spermatogenesis ability of boars. This work provides insight into the effect of FSHalpha/beta genes on male reproductive performance on pigs by a BAC-mediated transgenic approach. PMID- 27229512 TI - A realistic in silico model for structure/function studies of molybdenum-copper CO dehydrogenase. AB - CO dehydrogenase (CODH) is an environmentally crucial bacterial enzyme that oxidizes CO to CO2 at a Mo-Cu active site. Despite the close to atomic resolution structure (1.1 A), significant uncertainties have remained with regard to the protonation state of the water-derived equatorial ligand coordinated at the Mo center, as well as the nature of intermediates formed during the catalytic cycle. To address the protonation state of the equatorial ligand, we have developed a realistic in silico QM model (~179 atoms) containing structurally essential residues surrounding the active site. Using our QM model, we examined each plausible combination of redox states (Mo(VI)-Cu(I), Mo(V)-Cu(II), Mo(V)-Cu(I), and Mo(IV)-Cu(I)) and Mo-coordinated equatorial ligands (O(2-), OH(-), H2O), as well as the effects of second-sphere residues surrounding the active site. Herein, we present a refined computational model for the Mo(VI) state in which Glu763 acts as an active site base, leading to a MoO2-like core and a protonated Glu763. Calculated structural and spectroscopic data (hyperfine couplings) are in support of a MoO2-like core in agreement with XRD data. The calculated two electron reduction potential (E = -467 mV vs. SHE) is in reasonable agreement with the experimental value (E = -558 mV vs. SHE) for the redox couple comprising an equatorial oxo ligand and protonated Glu763 in the Mo(VI)-Cu(I) state and an equatorial water in the Mo(IV)-Cu(I) state. We also suggest a potential role of second-sphere residues (e.g., Glu763, Phe390) based on geometric changes observed upon exclusion of these residues in the most plausible oxidized states. PMID- 27229511 TI - Crystal structure of CmlI, the arylamine oxygenase from the chloramphenicol biosynthetic pathway. AB - The diiron cluster-containing oxygenase CmlI catalyzes the conversion of the aromatic amine precursor of chloramphenicol to the nitroaromatic moiety of the active antibiotic. The X-ray crystal structures of the fully active, N-terminally truncated CmlIDelta33 in the chemically reduced Fe(2+)/Fe(2+) state and a cis MU 1,2(eta (1):eta (1))-peroxo complex are presented. These structures allow comparison with the homologous arylamine oxygenase AurF as well as other types of diiron cluster-containing oxygenases. The structural model of CmlIDelta33 crystallized at pH 6.8 lacks the oxo-bridge apparent from the enzyme optical spectrum in solution at higher pH. In its place, residue E236 forms a MU-1,3(eta (1):eta (2)) bridge between the irons in both models. This orientation of E236 stabilizes a helical region near the cluster which closes the active site to substrate binding in contrast to the open site found for AurF. A very similar closed structure was observed for the inactive dimanganese form of AurF. The observation of this same structure in different arylamine oxygenases may indicate that there are two structural states that are involved in regulation of the catalytic cycle. Both the structural studies and single crystal optical spectra indicate that the observed cis MU-1,2(eta (1):eta (1))-peroxo complex differs from the MU-eta (1):eta (2)-peroxo proposed from spectroscopic studies of a reactive intermediate formed in solution by addition of O2 to diferrous CmlI. It is proposed that the structural changes required to open the active site also drive conversion of the u-1,2-peroxo species to the reactive form. PMID- 27229514 TI - Biochemical and spectroscopic characterization of the catalytic domain of MMP16 (cdMMP16). AB - Membrane-bound matrix metalloproteinase 16 (MMP16/MT3-MMP) is considered a drug target due to its role(s) in disease processes such as cancer and inflammation. Biochemical characterization of MMP16 is critical for developing new generation MMP inhibitors (MMPi), which exhibit high efficacies and selectivities. Herein, a modified over-expression and purification protocol was used to prepare the catalytic domain of MMP16 (cdMMP16). The resulting recombinant enzyme exhibited steady-state kinetic constants of K m = 10.6 +/- 0.7 MUM and k cat = 1.14 +/- 0.02 s(-1), when using FS-6 as substrate, and the enzyme bound 1.8 +/- 0.1 eq of Zn(II). The enzymatic activity of cdMMP16 is salt concentration-dependent, and cdMMP16 exhibits autoproteolytic activity under certain conditions, which may be related to an in vivo regulatory mechanism of MMP16 and of other membrane-type MMPs (MT-MMPs). Co(II)-substituted analogs (Co2- and ZnCo) of cdMMP16 were prepared and characterized using several spectroscopic techniques, such as UV Vis, (1)H NMR, and EXAFS spectroscopies. A well-characterized cdMMP16 is now available for future inhibitor screening efforts. PMID- 27229515 TI - Cyanide binding to ferrous and ferric microperoxidase-11. AB - Microperoxidase-11 (MP11) is an undecapeptide derived from horse heart cytochrome c (cytc). MP11 is characterized by a covalently linked solvent-exposed heme group, the heme-Fe atom being axially coordinated by a histidyl residue. Here, the reactions of ferrous and ferric MP11 (MP11-Fe(II) and MP11-Fe(III), respectively) with cyanide have been investigated from the kinetic and thermodynamic viewpoints, at pH 7.0 and 20.0 degrees C. Values of the second order rate constant for cyanide binding to MP11-Fe(II) and MP11-Fe(III) are 4.5 M(-1) s(-1) and 8.9 * 10(3) M(-1) s(-1), respectively. Values of the first-order rate constant for cyanide dissociation from ligated MP11-Fe(II) and MP11-Fe(III) are 1.8 * 10(-1) s(-1) and 1.5 * 10(-3) s(-1), respectively. Values of the dissociation equilibrium constant for cyanide binding to MP11-Fe(II) and MP11 Fe(III) are 3.7 * 10(-2) and 1.7 * 10(-7) M, respectively, matching very well with those calculated from kinetic parameters so that no intermediate species seem to be involved in the ligand-binding process. The pH-dependence of cyanide binding to MP11-Fe(III) indicates that CN(-) is the only binding species. Present results have been analyzed in parallel with those of several heme-proteins, suggesting that (1) the ligand accessibility to the metal center and cyanide ionization may modulate the formation of heme-Fe-cyanide complexes, and (2) the general polarity of the heme pocket and/or hydrogen bonding of the heme-bound ligand may affect cyanide exit from the protein matrix. Microperoxidase-11 (MP11) is an undecapeptide derived from horse heart cytochrome c. Penta-coordinated MP11 displays a very high reactivity towards cyanide, whereas the reactivity of hexa coordinated horse heart cytochrome c is very low. PMID- 27229516 TI - Epithelioid angiosarcoma of the thyroid gland without distant metastases at diagnosis: report of six cases with a long follow-up. AB - We present six cases of epithelioid angiosarcomas (EAS) of the thyroid gland without distant metastases at diagnosis and with a long follow-up. We retrieved the six consecutive cases of thyroid EAS between 2005 and 2011. Gender was equally represented; median age was 60 years (range 53-68). One case was post irradiation and another post-exposure to vinyl chloride. Median diameter was 6 cm (range 5-13). Regional nodal metastases were present at onset in two cases. All the cases expressed CD31 in a membranous pattern. CD34 was always negative. All the patients underwent complete surgical resection. Neoadjuvant chemotherapy was applied in one case and adjuvant chemotherapy in four cases with adjuvant radiation therapy in one case. Follow-up until June 2015 was available in five cases. Median follow-up was 59 months (range 9-82). Three patients relapsed. Two patients (the post-irradiation and post vinyl chloride exposure cases) died of disease after 36 and 9 months, after a local relapse soon followed by distant metastases. Three patients are alive and well after 59, 70, and 82 months, including a patient with a relapse treated with neoadjuvant chemotherapy and surgery. In conclusion, thyroid EAS without distant metastases at diagnosis are very rare tumors. They all expressed CD31, while CD34 was always negative. Distant metastases developed together with local relapse, rapidly followed by death. Inadequate surgery contributed to poor outcome. Cases with previous exposure to irradiation and vinyl chloride showed a particularly poor behavior. PMID- 27229513 TI - Mono- and binuclear non-heme iron chemistry from a theoretical perspective. AB - In this minireview, we provide an account of the current state-of-the-art developments in the area of mono- and binuclear non-heme enzymes (NHFe and NHFe2) and the smaller NHFe(2) synthetic models, mostly from a theoretical and computational perspective. The sheer complexity, and at the same time the beauty, of the NHFe(2) world represents a challenge for experimental as well as theoretical methods. We emphasize that the concerted progress on both theoretical and experimental side is a conditio sine qua non for future understanding, exploration and utilization of the NHFe(2) systems. After briefly discussing the current challenges and advances in the computational methodology, we review the recent spectroscopic and computational studies of NHFe(2) enzymatic and inorganic systems and highlight the correlations between various experimental data (spectroscopic, kinetic, thermodynamic, electrochemical) and computations. Throughout, we attempt to keep in mind the most fascinating and attractive phenomenon in the NHFe(2) chemistry, which is the fact that despite the strong oxidative power of many reactive intermediates, the NHFe(2) enzymes perform catalysis with high selectivity. We conclude with our personal viewpoint and hope that further developments in quantum chemistry and especially in the field of multireference wave function methods are needed to have a solid theoretical basis for the NHFe(2) studies, mostly by providing benchmarking and calibration of the computationally efficient and easy-to-use DFT methods. PMID- 27229517 TI - Growth of Well-Aligned InN Nanorods on Amorphous Glass Substrates. AB - The growth of well-aligned nanorods on amorphous substrates can pave the way to fabricate large-scale and low-cost devices. In this work, we successfully prepared vertically well-aligned c-axis InN nanorods on amorphous glass substrate by metal-organic chemical vapor deposition. The products formed directly on bare glass are randomly oriented without preferential growth direction. By inserting a GaN/Ti interlayer, the nanowire alignment can be greatly improved as indicated by scanning electron microscopy and X-ray diffraction. PMID- 27229518 TI - Photocatalytic Oxidation of Propylene on Pd-Loaded Anatase TiO2 Nanotubes Under Visible Light Irradiation. AB - TiO2 nanotubes attract much attention because of their high photoelectron chemical and photocatalytic efficiency. But their large band gap leads to a low absorption of the solar light and limits the practical application. How to obtain TiO2 nanotubes without any dopant and possessing visible light response is a big challenge nowadays. Orthorhombic titanic acid nanotubes (TAN) are a special precursor of TiO2, which possess large Brunauer-Emmett-Teller (BET) surface areas and strong ion exchange and adsorption capacity. TAN can transform to a novel TiO2 with a large amount of single-electron-trapped oxygen vacancies (SETOV) during calcination, while their nanotubular structure would be destroyed, and a BET surface area would decrease remarkably. And interestingly, SETOV can lead to a visible light response for this kind of TiO2. Herein, glucose was penetrated into TAN by the vacuum inhalation method, and TAN would dehydrate to anatase TiO2, and glucose would undergo thermolysis completely in the calcination process. As a result, the pure TiO2 nanotubes with visible light response and large BET surface areas were obtained. For further improving the photocatalytic activity, Pd nanoparticles were loaded as the foreign electron traps on TiO2 nanotubes and the photocatalytic oxidation efficiency of propylene was as high as 71 % under visible light irradiation, and the photostability of the catalyst kept over 90 % after 4 cyclic tests. PMID- 27229519 TI - Epigenetic perturbations in aging stem cells. AB - Stem cells maintain homeostasis in all regenerating tissues during the lifespan of an organism. Thus, age-related functional decline of such tissues is likely to be at least partially explained by molecular events occurring in the stem cell compartment. Some of these events involve epigenetic changes, which may dictate how an aging genome can lead to differential gene expression programs. Recent technological advances have made it now possible to assess the genome-wide distribution of an ever-increasing number of epigenetic marks. As a result, the hypothesis that there may be a causal role for an altered epigenome contributing to the functional decline of cells, tissues, and organs in aging organisms can now be explored. In this paper, we review recent developments in the field of epigenetic regulation of stem cells, and how this may contribute to aging. PMID- 27229520 TI - The Individual, Joint, and Additive Interaction Associations of Aerobic-Based Physical Activity and Muscle Strengthening Activities on Metabolic Syndrome. AB - PURPOSE: Previous research has demonstrated that physical activity and muscle strengthening activities are independently and inversely associated with metabolic syndrome. Despite a number of studies examining the individual associations, only a few studies have examined the joint associations, and to our knowledge, no previous studies have examined the potential additive interaction of performing muscle strengthening activities and aerobic-based physical activity and their association with metabolic syndrome. METHOD: Using data from the 2003 to 2006 National Health and Nutrition Examination Survey (NHANES), we computed three separate multivariable logistic regression models to examine the individual, combined, and additive interaction of meeting guidelines for accelerometer-assessed physical activity and self-reported muscle strengthening activities, and their association with metabolic syndrome. RESULTS: We found that individuals meeting physical activity and muscle strengthening activity guidelines, respectively, were at 61 and 25 % lower odds of having metabolic syndrome. Furthermore, individuals meeting both guidelines had the lowest odds of having metabolic syndrome (70 %), in part due to the additive interaction of performing both modes of exercise. CONCLUSION: In this national sample, accelerometer-assessed physical activity and muscle strengthening activities were synergistically associated with metabolic syndrome. PMID- 27229522 TI - GPs achieve dramatic cut in antibiotic prescriptions. PMID- 27229521 TI - The Association of Type D personality with Heart Rate Variability and Lipid Profiles Among Patients with Coronary Artery Disease. AB - PURPOSE: Characteristics of the distressed (Type D) personality include negative affectivity (NA) and social inhibition (SI), which are associated with an increased risk of major adverse cardiac events and mortality among patients with coronary artery disease (CAD). The aims of this study were to examine: (1) the correlation of NA and SI with psychological characteristics, heart rate variability (HRV) indices, and lipids profiles and (2) the differences in psychological characteristics, HRV indices, and lipid profiles between patients with CAD with Type D personality and those with non-Type D personality. METHOD: A cross-sectional study was conducted on 168 patients with CAD. The Taiwanese 14 item Type D Scale, Chinese Hostility Inventory-Short Form, Beck Depression Inventory-II, Beck Anxiety Inventory, and Anger Rumination Scale were administered to all of the participants. The raw signals of electrocardiograms were recorded over a 5-min baseline resting period and then transformed to HRV indices representing short-term cardiac autonomic activations. Lipid profiles were acquired from patients' medical records. RESULTS: NA was positively correlated with hostility, depression, anxiety, and anger rumination. With respect to pathophysiological mechanisms for CAD with Type D personality, NA was negatively correlated with standard deviation of all normal-to-normal intervals (SDNN) and total power of HRV and positively correlated with total cholesterol. SI was positively correlated with suppressive hostility behavior and anger rumination; however, SI was not significantly correlated with expressive hostility behavior, or HRV indices and lipid profiles. CONCLUSION: Pathophysiological mechanisms leading to higher rates of adverse outcomes in CAD in individuals with Type D personalities may involve cardiac autonomic imbalance and lipid dysregulation. PMID- 27229523 TI - Gesture Performance in First- and Multiple-Episode Patients with Schizophrenia Spectrum Disorders. AB - BACKGROUND/AIM: Gesturing plays an important role in social behavior and social learning. Deficits are frequent in schizophrenia and may contribute to impaired social functioning. Information about deficits during the course of the disease and presence of severity and patterns of impairment in first-episode patients is missing. Hence, we aimed to investigate gesturing in first- compared to multiple episode schizophrenia patients and healthy controls. METHODS: In 14 first-episode patients, 14 multiple-episode patients and 16 healthy controls matched for age, gender and education, gesturing was assessed by the comprehensive Test of Upper Limb Apraxia. Performance in two domains of gesturing - imitation and pantomime - was recorded on video. Raters of gesture performance were blinded. RESULTS: Patients with multiple episodes had severe gestural deficits. For almost all gesture categories, performance was worse in multiple- than in first-episode patients. First-episode patients demonstrated subtle deficits with a comparable pattern. CONCLUSIONS: Subjects with multiple psychotic episodes have severe deficits in gesturing, while only mild impairments were found in first-episode patients independent of age, gender, education and negative symptoms. The results indicate that gesturing is impaired at the onset of disease and likely to further deteriorate during its course. PMID- 27229524 TI - Does an Acid-Milieu in Chronic Kidney Disease Contribute to Its Increased Cardiovascular Mortality? PMID- 27229526 TI - Allergen Quantification by Use of Electrostatic Dust Collectors (EDCs): Influence of Deployment Time, Extraction Buffer, and Storage Conditions on the Results. AB - Sampling of endotoxin, beta-glucan, or allergens on electrostatic dust collectors (EDCs) is a convenient method for exposure assessment. However, especially for allergens few experiments on validation of this method concerning deployment time or storage and extraction procedure have been performed. The aim of study was to optimize the EDC procedure for sampling of allergens in indoor environments. EDCs were placed in households or day-care centers and after extraction, allergens were quantified by six immunoassays detecting mite antigens (Domestic mites DM, Dermatophagoides pteronyssinus Dp, Tyrophagus putrescentiae Tp) or the main allergens from cat (Fel d 1), dog (Can f 1) and mouse (Mus m 1). For 20 EDC holders, deployment times of cloths were varied between 7 and 28 days, 36 EDCs were used to test reproducibility, and for 28 EDCs extraction buffers were varied (with or without 0.05% Tween 20, borate, or phosphate buffer). The influence of storage of cloths at room temperature (2-629 days) or extracts at -80 degrees C (7-639 days), and variation of extract storage temperature (-20 degrees C and -80 degrees C) for long time storage (1.5 years) on the outcome of allergen quantification were tested for about 150 EDCs. The allergens on EDC cloths increased proportionally with deployment time, and allergen loads on parallel sampled tissues were significantly correlated (P < 0.0001, Pearson of log transformed values 0.91-0.99). Extraction without Tween reduced all results (P < 0.0001, -51% DM, -85% Dp, -60% Tp, -99% Fel d 1, -86% Can f 1, -52% Mus m 1), and borate buffer resulted in lower yields of Mus m 1 (-53%), DP (-45%), and Tp ( 27%) than phosphate buffer. Storage of cloths at room temperature significantly decreased Can f 1 levels (P < 0.0001, -4.8% loss for every 30 days), whereas storage of extracts at -80 degrees C decreased DM results (P < 0.0001, -1.2% loss for every 30 days). Extracts stored at -20 degrees C gave at mean 12% higher DM results compared to extracts stored at -80 degrees C for 1.5 years. Several mammalian allergens and also DM antigens could be quantified reproducibly on EDCs from indoor environments. Allergen levels on EDC cloths increased proportionally with deployment time in a period of 4 weeks. Allergen yields are strongly influenced by the extraction procedure; the use of detergent Tween 20 and phosphate buffer is recommended. PMID- 27229525 TI - The Long-Term Safety of S-Flurbiprofen Plaster for Osteoarthritis Patients: An Open-Label, 52-Week Study. AB - BACKGROUND AND OBJECTIVES: The newly developed S-flurbiprofen plaster (SFPP) is a tape-type patch that shows innovative percutaneous absorption. This study was designed to evaluate the safety of a long-term 52-week SFPP application to osteoarthritis (OA) patients. METHODS: This was a multi-center, open-label, uncontrolled prospective study that included 201 OA patients. SFPP at 40 mg/day was applied to the site of pain in 101 patients and at 80 mg/day (2 patches) in 100 patients at a total of 301 sites for 52 weeks. The affected sites assessed included the knee (192), lumbar spine (66), cervical spine (26), and others (17). Drug safety was evaluated by medical examination, laboratory tests, and examination of vital signs. Efficacy was evaluated by the patient's and clinician's global assessments and clinical symptoms. RESULTS: Most patients (80.1 %) completed the 52-week SFPP application. The majority of drug-related adverse events (AEs) included mild dermatitis at the application sites and occurred in 46.8 % of the sites. No photosensitive dermatitis was observed. Systemic AEs occurred in 9.0 % of the patients; a serious AE (gastric ulcer hemorrhage) occurred in one patient. No clinically significant changes in the laboratory tests and vital signs were observed. The efficacy evaluation showed an improvement from 2 weeks after the SFPP application, which continued during the 52 weeks' treatment. CONCLUSIONS: No apparent safety concerns were observed, even during the long-term SFPP application. Therefore, SFPP could be an additional pharmacotherapy in OA treatment. PMID- 27229527 TI - Using Whole Exome Sequencing to Identify Candidate Genes With Rare Variants In Nonsyndromic Cleft Lip and Palate. AB - Studies suggest that nonsyndromic cleft lip and palate (NSCLP) is polygenic with variable penetrance, presenting a challenge in identifying all causal genetic variants. Despite relatively high prevalence of NSCLP among Amerindian populations, no large whole exome sequencing (WES) studies have been completed in this population. Our goal was to identify candidate genes with rare genetic variants for NSCLP in a Honduran population using WES. WES was performed on two to four members of 27 multiplex Honduran families. Genetic variants with a minor allele frequency > 1% in reference databases were removed. Heterozygous variants consistent with dominant disease with incomplete penetrance were ascertained, and variants with predicted functional consequence were prioritized for analysis. Pedigree-specific P-values were calculated as the probability of all affected members in the pedigree being carriers, given that at least one is a carrier. Preliminary results identified 3,727 heterozygous rare variants; 1,282 were predicted to be functionally consequential. Twenty-three genes had variants of interest in >=3 families, where some genes had different variants in each family, giving a total of 50 variants. Variant validation via Sanger sequencing of the families and unrelated unaffected controls excluded variants that were sequencing errors or common variants not in databases, leaving four genes with candidate variants in >=3 families. Of these, candidate variants in two genes consistently segregate with NSCLP as a dominant variant with incomplete penetrance: ACSS2 and PHYH. Rare variants found at the same gene in all affected individuals in several families are likely to be directly related to NSCLP. PMID- 27229529 TI - Dynamic contrast-enhanced MRI coupled with a subtraction technique is useful for treatment response evaluation of malignant melanoma hepatic metastasis. AB - PURPOSE: To determine whether contrast-enhanced MRI including subtraction sequences can predict the treatment response of melanoma liver metastasis. RESULTS: High precontrast T1 signal intensity (SI) of melanoma lesions obscured detection of enhancement after contrast injection. It was impossible to determine whether or not enhancement occurred in the majority of lesions (85.4%, n = 35/41) without including the subtraction technique. Positive enhancement was identified in 14.6% (n = 6/41) of patients without subtraction images, but increased to 68.3% (n = 28/41) by including subtraction images. Follow-up studies determined lesion progression in 34.1% (n = 14/41) of patients. Positive enhancement on the subtraction image (odds ratio = 12.1, P = 0.048) and intermediate high T2 SI (odds ratio = 8.16, P = 0.040) were significantly associated with higher risk of lesion progression. MATERIALS AND METHODS: Patients who underwent MRI for melanoma liver metastases between January 2007 and February 2015 were enrolled. The study analyzed 41 liver metastases in 15 patients [11 male and four female; median age 56 years (range 21-81)] for size, lesion enhancement with and without subtraction images, and T2 SI. Follow-up imaging studies were used to determine treatment response. Data were analyzed with generalized estimating equations. CONCLUSIONS: MRI including the subtraction technique is useful for determining the treatment response of melanoma liver metastases. Lesion contrast enhancement and intermediate high T2 SI increased the risk of lesion progression. PMID- 27229528 TI - Downregulation of miR-101 contributes to epithelial-mesenchymal transition in cisplatin resistance of NSCLC cells by targeting ROCK2. AB - Chemoresistance and epithelial-mesenchymal transition (EMT) in cancer are linked phenomena. EMT contributes to chemoresistance, however, little is known about whether chemotherapy can induce EMT in cancer cells. Here, we found that miR-101 expression was downregulated in cisplatin-resistant non-small cell lung cancer (NSCLC) cells. Restoration of miR-101 expression inhibited EMT and increased the sensitivity of cisplatin-resistant NSCLC cells to cisplatin in vitro by targeting ROCK2. Furthermore, ROCK2 protein level was inversely correlated with miR-101 level in NSCLC tissue samples. Kaplan-Meier analysis revealed that low miR-101 expression in NSCLC was correlated with poor survival time. In summary, our results provide novel mechanistic insights into the role of miR-101/ROCK2 signaling in the cisplatin resistance of NSCLC cells. Targeting of miR-101 is a potential therapeutic approach for NSCLC. PMID- 27229530 TI - High throughput chemical library screening identifies a novel p110-delta inhibitor that potentiates the anti-myeloma effect of bortezomib. AB - Multiple myeloma (MM) remains an incurable plasma cell malignancy and drug resistance persists as the major cause of treatment failure leading to fatal outcomes. The phosphatidyl-inositol-3-kinase (PI3K) pathway is constitutively hyperactivated in MM to promote disease progression and drug resistance. While inhibiting PI3K induces apoptosis in MM and is predicted to increase tumor susceptibility to anticancer therapy, early-generation pan-PI3K inhibitors display poor clinical efficacy as well as intolerable side effects. Here, we found that PI3K activity is significantly upregulated in MM cell lines and patient tumor cells resistant to bortezomib and that the majority of PI3K activity in MM cells is dependent upon the p110-delta isoform. Genetic or pharmacologic inhibition of p110-delta substantially reduced myeloma viability and enhanced cellular sensitivity to bortezomib. Chemical library screens then identified a novel compound, DT97, that potently inhibited p110-delta kinase activity and induced apoptosis in MM cells. DT97 was evaluated in the NCI-60 panel of human cancer cell types and anticancer activity was greatest against MM, leukemia and lymphoma cells. Co-treatment with DT97 and bortezomib synergistically induced apoptosis in MM patient cells and overcame bortezomib resistance. Although bone marrow stromal cells (BMSCs) promote MM growth, the pro survival effects of BMSCs were significantly reduced by DT97 treatment. Co treatment with bortezomib and DT97 reduced the growth of myeloma xenotransplants in murine models and prolonged host survival. Taken together, the results provide the basis for further clinical evaluation of p110-delta inhibitors, as monotherapy or in synergistic combinations, for the benefit of MM patients. PMID- 27229531 TI - Identification of prognostic biomarkers in glioblastoma using a long non-coding RNA-mediated, competitive endogenous RNA network. AB - Glioblastoma multiforme (GBM) is a highly malignant brain tumor associated with a poor prognosis. Cross-talk between competitive endogenous RNAs (ceRNAs) plays a critical role in tumor development and physiology. In this study, we present a multi-step computational approach to construct a functional GBM long non-coding RNA (lncRNA)-mediated ceRNA network (LMCN) by integrating genome-wide lncRNA and mRNA expression profiles, miRNA-target interactions, functional analyses, and clinical survival analyses. LncRNAs in the LMCN exhibited specific topological features consistent with a regulatory association with coding mRNAs across GBM pathology. We determined that the lncRNA MCM3AP-AS was involved in RNA processing and cell cycle-related functions, and was correlated with patient survival. MCM3AP-AS and MIR17HG acted synergistically to regulate mRNAs in a network module of the competitive LMCN. By integrating the expression profile of this module into a risk model, we stratified GBM patients in both the The Cancer Genome Atlas and an independent GBM dataset into distinct risk groups. Finally, survival analyses demonstrated that the lncRNAs and network module are potential prognostic biomarkers for GBM. Thus, ceRNAs could accelerate biomarker discovery and therapeutic development in GBM. PMID- 27229532 TI - Basic fibroblast growth factor promotes VEGF-C-dependent lymphangiogenesis via inhibition of miR-381 in human chondrosarcoma cells. AB - A chondrosarcoma is a common, primary malignant bone tumor that can grow to destroy the bone, produce fractures and develop soft tissue masses. Left untreated, chondrosarcomas metastasize through the vascular system to the lungs and ultimately lead to large metastatic deposits of the malignant cartilage taking over lung volume and function. Vascular endothelial growth factor (VEGF)-C has been implicated in tumor-induced lymphangiogenesis and elevated expression of VEGF-C has been found to correlate with cancer metastasis. bFGF (basic fibroblast growth factor), a secreted cytokine, regulates biological activity, including angiogenesis and metastasis. We have previously reported on the important role of bFGF in angiogenesis in chondrosarcomas. However, the effect of bFGF in VEGF-C regulation and lymphangiogenesis in chondrosarcomas is poorly understood. In this investigation, we demonstrate a correlation exists between bFGF and VEGF-C in tissue specimens from patients with chondrosarcomas. To examine the lymphangiogenic effect of bFGF, we used human lymphatic endothelial cells (LECs) to mimic lymphatic vessel formation. We found that bFGF-treated chondrosarcomas promoted LEC tube formation and cell migration. In addition, bFGF knockdown inhibited lymphangiogenesis in vitro and in vivo. We also found that bFGF-induced VEGF-C is mediated by the platelet-derived growth factor receptor (PDGFR) and c Src signaling pathway. Furthermore, bFGF inhibited microRNA-381 expression via the PDGFR and c-Src cascade. Our study is the first to describe the mechanism of bFGF-promoted lymphangiogenesis by upregulating VEGF-C expression in chondrosarcomas. Thus, bFGF could serve as a therapeutic target in chondrosarcoma metastasis and lymphangiogenesis. PMID- 27229533 TI - Big data and computational biology strategy for personalized prognosis. AB - The era of big data and precision medicine has led to accumulation of massive datasets of gene expression data and clinical information of patients. For a new patient, we propose that identification of a highly similar reference patient from an existing patient database via similarity matching of both clinical and expression data could be useful for predicting the prognostic risk or therapeutic efficacy.Here, we propose a novel methodology to predict disease/treatment outcome via analysis of the similarity between any pair of patients who are each characterized by a certain set of pre-defined biological variables (biomarkers or clinical features) represented initially as a prognostic binary variable vector (PBVV) and subsequently transformed to a prognostic signature vector (PSV). Our analyses revealed that Euclidean distance rather correlation distance measure was effective in defining an unbiased similarity measure calculated between two PSVs.We implemented our methods to high-grade serous ovarian cancer (HGSC) based on a 36-mRNA predictor that was previously shown to stratify patients into 3 distinct prognostic subgroups. We studied and revealed that patient's age, when converted into binary variable, was positively correlated with the overall risk of succumbing to the disease. When applied to an independent testing dataset, the inclusion of age into the molecular predictor provided more robust personalized prognosis of overall survival correlated with the therapeutic response of HGSC and provided benefit for treatment targeting of the tumors in HGSC patients.Finally, our method can be generalized and implemented in many other diseases to accurately predict personalized patients' outcomes. PMID- 27229534 TI - MicroRNA-320a inhibits breast cancer metastasis by targeting metadherin. AB - Dysregulated microRNAs play important pathological roles in carcinogenesis that are yet to be fully elucidated. This study was performed to investigate the biological functions of microRNA-320a (miR-320a) in breast cancer and the underlying mechanisms. Function analyses for cell proliferation, cell cycle, and cell invasion/migration, were conducted after miR-320a silencing and overexpression. The specific target genes of miR-320a were predicted by TargetScan algorithm and then determined by dual luciferase reporter assay and rescue experiment. The relationship between miR-320a and its target genes was explored in human breast cancer tissues. We found that miR-320a overexpression could inhibit breast cancer invasion and migration abilities in vitro, while miR 320a silencing could enhance that. In addition, miR-320a could suppress activity of 3'-untranslated region luciferase of metadherin (MTDH), a potent oncogene. The rescue experiment revealed that MTDH was a functional target of miR-320a. Moreover, we found that MTDH was negatively correlated with miR-320a expression, and it was related to clinical outcomes of breast cancer. Further xenograft experiment also showed that miR-320a could inhibit breast cancer metastasis in vivo. Our findings clearly demonstrate that miR-320a suppresses breast cancer metastasis by directly inhibiting MTDH expression. The present study provides a new insight into anti-oncogenic roles of miR-320a and suggests that miR-320a/MTDH pathway is a putative therapeutic target in breast cancer. PMID- 27229535 TI - Cellular prion protein controls stem cell-like properties of human glioblastoma tumor-initiating cells. AB - Prion protein (PrPC) is a cell surface glycoprotein whose misfolding is responsible for prion diseases. Although its physiological role is not completely defined, several lines of evidence propose that PrPC is involved in self-renewal, pluripotency gene expression, proliferation and differentiation of neural stem cells. Moreover, PrPC regulates different biological functions in human tumors, including glioblastoma (GBM). We analyzed the role of PrPC in GBM cell pathogenicity focusing on tumor-initiating cells (TICs, or cancer stem cells, CSCs), the subpopulation responsible for development, progression and recurrence of most malignancies. Analyzing four GBM CSC-enriched cultures, we show that PrPC expression is directly correlated with the proliferation rate of the cells. To better define its role in CSC biology, we knocked-down PrPC expression in two of these GBM-derived CSC cultures by specific lentiviral-delivered shRNAs. We provide evidence that CSC proliferation rate, spherogenesis and in vivo tumorigenicity are significantly inhibited in PrPC down-regulated cells. Moreover, PrPC down-regulation caused loss of expression of the stemness and self renewal markers (NANOG, Sox2) and the activation of differentiation pathways (i.e. increased GFAP expression). Our results suggest that PrPC controls the stemness properties of human GBM CSCs and that its down-regulation induces the acquisition of a more differentiated and less oncogenic phenotype. PMID- 27229536 TI - Haemonchus contortus excretory and secretory proteins (HcESPs) suppress functions of goat PBMCs in vitro. AB - Excretory and secretory products (ESPs) of nematode contain various proteins which are capable of inducing the instigation or depression of the host immune response and are involved in the pathogenesis of the worms. In the present study, Haemonchus contortus excretory and secretory products (HcESPs) were collected from the adult worms. Binding of HcESPs to goat peripheral blood mononuclear cells (PBMCs) was confirmed by immune-fluorescence assay. Effects of the HcESPs on cytokine production, cell proliferation, cell migration and nitric oxide (NO) production of PBMCs were checked by co-incubation of HcESPs with goat PBMCs. The results indicated that the production of IL-4 and IFN-gamma were significantly decreased by HcESPs in dose dependent manner. On the contrary, the production of IL-10 and IL-17 were increased. Cell migration was significantly enhanced by HcESPs, whereas, HcESPs treatment significantly suppressed the cell proliferation and NO production. These results indicated that the HcESPs played important suppressive regulatory roles on PBMCs and provided highlights to the understanding of the host-parasite interactions. PMID- 27229538 TI - Addressing epidemiological and public health analytic challenges in outcome and impact research: a commentary on 'Prechewing Infant Food, Consumption of Sweets and Dairy and Not Breastfeeding are Associated with Increased Diarrhea Risk of Ten Month Old Infants'. AB - Based on a paper by Conkle et al 2016, in which the authors use a descriptive epidemiological design to examine the relationship of premastication and other dietary behavioral variables to childhood diarrhea in the US, we address larger issues of "plausible causality" and the challenges involved in moving from epidemiological studies to public health policy. Drawing on examples from breastfeeding research and water, sanitation and hygiene (WASH) research, we discuss the following propositions: 1. Effective outcome analyses require simultaneous investigation of different, even contradictory, pathways; 2. Outcome versus impact assessments require different analytic procedures including context analysis; 3. Impact analysis requires understanding the trade-offs between detrimental and beneficial outcomes in relation to potential interventions; 4. No estimates exist for the likely detrimental and beneficial impacts of banning premastication, much less for their trade-offs. PMID- 27229539 TI - Risk factors and outcomes of carbapenem-resistant Acinetobacter baumannii ventilator-associated pneumonia in the neonate: A case-case-control study. AB - BACKGROUND: Carbapenem-resistant and susceptible Acinetobacter baumannii (CRAB and CSAB) have emerged as serious threats among critically ill neonates. We aimed to identify the risks and outcomes for CRAB and CSAB ventilator-associated pneumonia (VAP) compared with a control group. METHODS: We performed a retrospective and case-case-control study in a neonatal intensive care unit between 2009 and 2014. RESULTS: The numbers of patients in the CRAB VAP, CSAB VAP, and control groups were 63, 13, and 25, respectively. The mean gestational ages and median birthweights of CRAB VAP, CSAB VAP, and control groups were 33.2, 35.0, and 32.6 weeks and 1800, 2230, and 2245 g, respectively. By multivariate analysis, infants who had a birthweight of 1000-1499 g (P = 0.04), cesarean section (P = 0.01), history of cephalosporin use (P = 0.02), and surfactant replacement (P = 0.01) in CRAB VAP were significantly higher than in the control group. Inborn infant (P = 0.01), reintubation (P = 0.04), and umbilical artery catheterization (P = 0.04) in the CRAB VAP group were significantly more than in the CSAB VAP group. The crude mortality rates (CMRs) of CRAB VAP and CSAB VAP were 15.9% and 7.7%, respectively. By univariate analysis, the CMR, septic shock, and bronchopulmonary dysplasia in CRAB VAP were higher than in the control group. CONCLUSIONS: There are very high mortality and short-term morbidity rates in CRAB VAP. Surfactant replacement therapy, fewer cesarean sections, and the reduced use of cephalosporin in very preterm infants may reduce CRAB VAP. PMID- 27229537 TI - Impaired macrophage autophagy induces systemic insulin resistance in obesity. AB - Obesity-induced insulin resistance and diabetes are significantly associated with infiltrates of inflammatory cells in adipose tissue. Previous studies recognized the involvement of autophagy in the regulation of metabolism in multiple tissues, including beta-cells, hepatocytes, myocytes, and adipocytes. However, despite the importance of macrophages in obesity-induced insulin resistance, the role of macrophage autophagy in regulating insulin sensitivity is seldom addressed. In the present study, we show that macrophage autophagy is important for the regulation of systemic insulin sensitivity. We found that macrophage autophagy is downregulated by both acute and chronic inflammatory stimuli, and blockade of autophagy significantly increased accumulation of reactive oxygen species (ROS) in macrophages. Macrophage-specific Atg7 knockout mice displayed a shift in the proportion to pro-inflammatory M1 macrophages and impairment of insulin sensitivity and glucose homeostasis under high-fat diet conditions. Furthermore, inhibition of ROS in macrophages with antioxidant recovered adipocyte insulin sensitivity. Our results provide evidence of the underlying mechanism of how macrophage autophagy regulates inflammation and insulin sensitivity. We anticipate our findings will serve as a basis for development of therapeutics for inflammatory diseases, including diabetes. PMID- 27229540 TI - Metabolic engineering of anthocyanins in dark tobacco varieties. AB - In this study, we investigate the metabolic engineering of anthocyanins in two dark tobacco crops (Narrow Leaf Madole and KY171) and evaluate the effects on physiological features of plant photosynthesis. Arabidopsis PAP1 (production of anthocyanin pigment 1) gene (AtPAP1) encodes a R2R3-type MYB transcript factor that is a master component of regulatory complexes controlling anthocyanin biosynthesis. AtPAP1 was introduced to Narrow Leaf Madole and KY171 plants. Multiple transgenic plants developed red/purple pigmentation in different tissues. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis showed that the expression levels of six pathway genes were increased two- to eight-fold in AtPAP1 transgenic plants compared with vector control plants. Dihydroflavonol reductase and anthocyanidin synthase genes that were not expressed in wild-type plants were activated. Spectrophotometric measurement showed that the amount of anthocyanins in AtPAP1 transgenic plants were 400-800 ug g-1 fresh weight (FW). High-performance liquid chromatography (HPLC) analysis showed that one main anthocyanin molecule accounted for approximately 98% of the total anthocyanins. Tandem MS/MS analysis using HPLC coupled to electrospray ionization and quadrupole time-of-flight mass spectrometry identified the main anthocyanin as cyanidin 3-O-rutinoside, an important medicinal anthocyanin. Analysis of photosynthesis rate, chlorophylls and carotenoids contents showed no differences between red/purple transgenic and control plants, indicating that this metabolic engineering did not alter photosynthetic physiological traits. This study shows that AtPAP1 is of significance for metabolic engineering of anthocyanins in crop plants for value-added traits. PMID- 27229541 TI - Disseminated granulomatous skin lesions associated with myelodysplastic syndrome treated successfully with tranilast: a case report and review of the literature. PMID- 27229616 TI - HLA-B*40:329, a novel HLA-B*40 variant, identified in a Taiwanese individual. AB - One nucleotide substitution at codon 254 of HLA-B*40:01:01 results in a new allele, HLA-B*40:329. PMID- 27229618 TI - Novel free fatty acid receptor 1 (GPR40) agonists based on 1,3,4-thiadiazole-2 carboxamide scaffold. AB - Free fatty acid receptor 1 (FFA1), previously known as GPR40 is a G protein coupled receptor and a new target for treatment of type 2 diabetes. Two series of FFA1 agonists utilizing a 1,3,4-thiadiazole-2-caboxamide scaffold were synthetized. Both series offered significant improvement of the potency compared to the previously described 1,3,4-thiadiazole-based FFA1 agonists and high selectivity for FFA1. Molecular docking predicts new aromatic interactions with the receptor that improve agonist potency. The most potent compounds from both series were profiled for in vitro ADME properties (plasma and metabolic stability, LogD, plasma protein binding, hERG binding and CYP inhibition). One series suffered very rapid degradation in plasma and in presence of mouse liver microsomes. However, the other series delivered a lead compound that displayed a reasonable ADME profile together with the improved FFA1 potency. PMID- 27229617 TI - Increased expression of SIRT2 is a novel marker of cellular senescence and is dependent on wild type p53 status. AB - Sirtuins (SIRT) belonging to the NAD+ dependent histone deacetylase III class of enzymes have emerged as master regulators of metabolism and longevity. However, their role in prevention of organismal aging and cellular senescence still remains controversial. In the present study, we now report upregulation of SIRT2 as a specific feature associated with stress induced premature senescence but not with either quiescence or cell death. Additionally, increase in SIRT2 expression was noted in different types of senescent conditions such as replicative and oncogene induced senescence using multiple cell lines. Induction of SIRT2 expression during senescence was dependent on p53 status as depletion of p53 by shRNA prevented its accumulation. Chromatin immunoprecipitation revealed the presence of p53 binding sites on the SIRT2 promoter suggesting its regulation by p53, which was also corroborated by the SEAP reporter assay. Overexpression or knockdown of SIRT2 had no effect on stress induced premature senescence, thereby indicating that SIRT2 increase is not a cause of senescence; rather it is an effect linked to senescence-associated changes. Overall, our results suggest SIRT2 as a promising marker of cellular senescence at least in cells with wild type p53 status. PMID- 27229620 TI - A retrospective study on the effectiveness of curettage and electrodesiccation for clinically suspected primary nodular basal cell carcinoma. PMID- 27229621 TI - A method to rapidly create protein aggregates in living cells. AB - The accumulation of protein aggregates is a common pathological hallmark of many neurodegenerative diseases. However, we do not fully understand how aggregates are formed or the complex network of chaperones, proteasomes and other regulatory factors involved in their clearance. Here, we report a chemically controllable fluorescent protein that enables us to rapidly produce small aggregates inside living cells on the order of seconds, as well as monitor the movement and coalescence of individual aggregates into larger structures. This method can be applied to diverse experimental systems, including live animals, and may prove valuable for understanding cellular responses and diseases associated with protein aggregates. PMID- 27229619 TI - Autoinflammation and HLA-B27: Beyond Antigen Presentation. AB - HLA-B27 associated disorders comprise a group of inflammatory conditions which have in common an association with the HLA class I molecule, HLA-B27. Given this association, these diseases are classically considered disorders of adaptive immunity. However, mounting data are challenging this assumption and confirming that innate immunity plays a more prominent role in pathogenesis than previously suspected. In this review, the concept of autoinflammation is discussed and evidence is presented from human and animal models to support a key role for innate immunity in HLA-B27 associated disorders. PMID- 27229622 TI - Lateral inhibition-induced pattern formation controlled by the size and geometry of the cell. AB - Pattern formation in development biology is one of the fundamental processes by which cells change their functions. It is based on the communication of cells via intra- and intercellular dynamics of biochemicals. Thus, the cell is directly involved in biochemical interactions. However, many theoretical approaches describing biochemical pattern formation have usually neglected the cell's role or have simplified the subcellular process without considering cellular aspects despite the cell being the environment where biochemicals interact. On the other hand, recent experimental observations suggest that a change in the physical conditions of cell-to-cell contact can result in a change in cell fate and tissue patterning in a lateral inhibition system. Here we develop a mathematical model by which biochemical dynamics can be directly observed with explicitly expressed cell structure and geometry in higher dimensions, and reconsider pattern formation by lateral inhibition of the Notch-Delta signaling pathway. We explore how the physical characteristic of cell, such as cell geometry or size, influences the biochemical pattern formation in a multi-cellular system. Our results suggest that a property based on cell geometry can be a novel mechanism for symmetry breaking inducing cell asymmetry. We show that cell volume can critically influence cell fate determination and pattern formation at the tissue level, and the surface area of the cell-to-cell contact can directly affect the spatial range of patterning. PMID- 27229623 TI - The Association Between Low Back Pain and Composition of IgG Glycome. AB - Low back pain (LBP) is a common debilitating condition which aetiology and pathogenesis are poorly understood. We carried out a first so far analysis of associations between LBP and plasma IgG N-glycome in a sample of 4511 twins from TwinsUK database assessed for LBP, lumbar disc degeneration (LDD) as its possible cause, and IgG-glycan levels. Using weighted correlation network analysis, we established a correlation between LBP and glycan modules featured by glycans that either promote or block antibody-dependent cell-mediated cytotoxicity (ADCC). The levels of four glycan traits representing two of those modules were statistically significantly different in monozygotic twins discordant for LBP. Also, the trend to higher prevalence of systemic inflammatory disorders was shown for twins with low level of fucosylated glycans and high level of non-fucosylated glycans. Core fucosylation of IgG is a "safety switch" reducing ADCC, thus our results suggest the involvement of ADCC and associated inflammation in pathogenesis of LBP. No correlation between LDD scores and glycans was found assuming that the inflammation may not be a part of LDD. These data provide a new insight into understanding the complex pathophysiology of LBP and suggest glycan levels as a possible biomarker for inflammation-related subtypes of LBP. PMID- 27229624 TI - Ocean acidification reverses the positive effects of seawater pH fluctuations on growth and photosynthesis of the habitat-forming kelp, Ecklonia radiata. AB - Ocean acidification (OA) is the reduction in seawater pH due to the absorption of human-released CO2 by the world's oceans. The average surface oceanic pH is predicted to decline by 0.4 units by 2100. However, kelp metabolically modifies seawater pH via photosynthesis and respiration in some temperate coastal systems, resulting in daily pH fluctuations of up to +/-0.45 units. It is unknown how these fluctuations in pH influence the growth and physiology of the kelp, or how this might change with OA. In laboratory experiments that mimicked the most extreme pH fluctuations measured within beds of the canopy-forming kelp Ecklonia radiata in Tasmania, the growth and photosynthetic rates of juvenile E. radiata were greater under fluctuating pH (8.4 in the day, 7.8 at night) than in static pH treatments (8.4, 8.1, 7.8). However, pH fluctuations had no effect on growth rates and a negative effect on photosynthesis when the mean pH of each treatment was reduced by 0.3 units. Currently, pH fluctuations have a positive effect on E. radiata but this effect could be reversed in the future under OA, which is likely to impact the future ecological dynamics and productivity of habitats dominated by E. radiata. PMID- 27229625 TI - pH-Activated Targeting Drug Delivery System Based on the Selective Binding of Phenylboronic Acid. AB - Phenylboronic acid (PBA) is a tumor-targeting molecule, but its nonspecific interaction with normal cells or other components containing cis-diol residues undoubtedly limits its potential application in tumor-targeting drug delivery. Herein, we developed fructose-coated mixed micelles via PBA-terminated polyethylene glycol monostearate (PBA-PEG-C18) and Pluronic P123 (PEG20-PPG70 PEG20) to solve this problem, as the stability of borate formed by PBA and fructose was dramatically dependent on pH. The fluorescence spectroscopic results indicated that the borate formed by PBA and fructose decomposed at a decreased pH, and better binding between PBA and sialic acid (SA) was observed at a low pH. These results implied that the fructose groups decorated on the surface of the micelles could be out-competed by SA at a low pH. In vitro uptake and cytotoxicity studies demonstrated that the fructose coating on the mixed micelles improved the endocytosis and enhanced the cytotoxicity of drug-loaded mixed micelles in HepG2 cells but reduced the cytotoxicity in normal cells. These results demonstrate that a simple decorating strategy may facilitate PBA-targeted nanoparticles for tumor-specific drug delivery. PMID- 27229626 TI - A pneumatic pressure-driven multi-throughput microfluidic circulation culture system. AB - Here, we report a pneumatic pressure-driven microfluidic device capable of multi throughput medium circulation culture. The circulation culture system has the following advantages for application in drug discovery: (i) simultaneous operation of multiple circulation units, (ii) use of a small amount of circulating medium (3.5 mL), (iii) pipette-friendly liquid handling, and (iv) a detachable interface with pneumatic pressure lines via sterile air-vent filters. The microfluidic device contains three independent circulation culture units, in which human umbilical vein endothelial cells (HUVECs) were cultured under physiological shear stress induced by circulation of the medium. Circulation of the medium in the three culture units was generated by programmed sequentially applied pressure from two pressure-control lines. HUVECs cultured in the microfluidic device were aligned under a one-way circulating flow with a shear stress of 10 dyn cm(-2); they exhibited a randomly ordered alignment under no shear stress and under reciprocating flow with a shear stress of 10 dyn cm(-2). We also observed 2.8- to 4.9-fold increases in expression of the mRNAs of endothelial nitric oxide synthase and thrombomodulin under one-way circulating flow with a shear stress of 10 dyn cm(-2) compared with conditions of no shear stress or reciprocating flow. PMID- 27229627 TI - Pre- and intraretinal haemorrhages in a 22-week-old fetus of a mother suffering from HELLP syndrome and factor V Leiden mutation with deep vein thrombosis. PMID- 27229629 TI - Ultrastructural features of dentinoenamel junction revealed by focused gallium ion beam milling. AB - To take full advantage of focused ion beam (FIB) in preparation of ultrathin sections of biological tissues, we have used a cryo-milling process. In this study, extracted human teeth were scanned by optical coherence tomography to inspect the samples for intactness and to determine the area of interest. Then, the selected area of interest was cross-sectioned for examination under a confocal laser scanning microscope to determine the target location of the dentinoenamel junction (DEJ) that was later milled by cryo-FIB at preset parameters, followed by transmission electron microscope examination of the final sliced specimens for ultrastructural characterization. The proposed technique was able to outline the DEJ and to identify the different tooth layers in a single section, without artefacts or tissue damage. The DEJ was outlined as fine longitudinal projections intermingling between the solid electron-dense enamel and intricate electron-lucent hollow dentin. In conclusion, this study has shown the great potential of cryo-FIB in handling different biological tissues having different physical properties, with great precision and accuracy and minimum artefacts. PMID- 27229628 TI - Vitrectomy Before Intravitreal Injection of AAV2/2 Vector Promotes Efficient Transduction of Retinal Ganglion Cells in Dogs and Nonhuman Primates. AB - Recombinant adeno-associated virus (AAV) has emerged as a promising vector for retinal gene delivery to restore visual function in certain forms of inherited retinal dystrophies. Several studies in rodent models have shown that intravitreal injection of the AAV2/2 vector is the optimal route for efficient retinal ganglion cell (RGC) transduction. However, translation of these findings to larger species, including humans, is complicated by anatomical differences in the eye, a key difference being the comparatively smaller volume of the vitreous chamber in rodents. Here, we address the role of the vitreous body as a potential barrier to AAV2/2 diffusion and transduction in the RGCs of dogs and macaques, two of the most relevant preclinical models. We intravitreally administered the AAV2/2 vector carrying the CMV-eGFP reporter cassette in dog and macaque eyes, either directly into the vitreous chamber or after complete vitrectomy, a surgical procedure that removes the vitreous body. Our findings suggest that the vitreous body appears to trap the injected vector, thus impairing the diffusion and transduction of AAV2/2 to inner retinal neurons. We show that vitrectomy before intravitreal vector injection is an effective means of overcoming this physical barrier, improving the transduction of RGCs in dog and macaque retinas. These findings support the use of vitrectomy in clinical trials of intravitreal gene transfer techniques targeting inner retinal neurons. PMID- 27229630 TI - Composition in portraits: Selfies and wefies reveal similar biases in untrained modern youths and ancient masters. AB - Previous analyses suggest that artists prefer poses showing the left side of the subject's face when composing a portrait, but showing the right side when composing their own self-portrait. There is also some evidence that artists may prefer compositions with key features on the right of the picture. Do these findings generalize to spontaneous, pseudo-artistic productions by individuals with no formal training in painting and art history? To investigate this issue, we tested a sample of 104 British schoolchildren and teenagers (mean age = 13.8 years; 80 females). We analysed posing biases in individual photographic self portraits ("selfies") as well as of self-portraits including also the portrait of a friend ("wefies"). Our results document a bias for showing the left cheek in selfies, a bias for placing the selfie-taker on the right in wefies, and a bias for showing two left cheeks over two right cheeks, again in wefies. These biases are reminiscent of what has been reported for selfies in adult non-artists and for portraits and self-portraits by artists in the 16th-18th centuries. Thus, these results provide new evidence in support of a biological basis for side biases in portraits and self-portraits independently of training and expertise. PMID- 27229631 TI - Genotoxicity and immunotoxic effects of 1,2-dichloroethane in Wistar rats. AB - Dichloroethane is widely used as a solvent, degreasing agent and in a variety of commercial products, and is known for being a ubiquitous contaminant in the environment. Important sources principally include the emissions from industrial processes, improper consumption, storage, and disposal methods. In view of the fact that the mechanism of its genotoxicity has not been satisfactorily elucidated, the acute in vivo toxicological impact is assessed in Rattus norvegicus. A systematic investigation has been made involving the use of conventional methods along with molecular and flow cytometric approaches. The micronucleus and chromosomal aberration frequencies were significantly elevated in bone marrow cells exposed to three concentrations at multiple treatment durations indicating positive time- and dose-response relationships. The mitotic index significantly decreased in similar concentrations in contrast to normal control. Separate studies were performed on blood cells for comet assay. It revealed dichloroethane-induced DNA damage in all exposures readily explainable in a dose- and time-dependent manner. Recent molecular techniques were further employed using leukocytes for the cell apoptosis/cycle and mitochondrial membrane potential employing propidium iodide staining and rhodamine-123, respectively. The effect on mitochondrial membrane permeability, cell cycle phases, and the DNA damage was analyzed through flow cytometry. These indicators revealed dichloroethane treatment decreased the mitochondrial membrane potential, affected the cell cycle, and confirmed the DNA damage, leading to apoptosis of the cells of the immune system responsible for immunotoxic effects of dichloroethane on rat leukocytes. PMID- 27229632 TI - Integration of a zebrafish research project into a molecular biology course to support critical thinking and course content goals. AB - Engaging undergraduates in research is essential for teaching them to think like scientists, and it has become a desired component of classroom and laboratory instruction. Research projects that span an entire semester expose students to a variety of concepts and techniques and allow students to use experiments to learn scientific principles, understand why specific techniques are applicable, critically analyze varied data, and examine how experimentation leads to acquiring knowledge. To provide an experience with these features, a semester long research project was integrated into a combined lecture and laboratory course, Molecular Biology. The project utilized the zebrafish model to examine gene expression during embryonic development and required students to develop and test hypotheses about the timing of expression of previously uncharacterized genes. The main goals for the project were to provide opportunities for students to develop critical thinking skills required for conducting research and to support the content goals of the course. To determine whether these goals were met, student performance on the steps of the project and related pre-test and post-test questions was examined. (c) 2016 by The International Union of Biochemistry and Molecular Biology, 44(6):565-573, 2016. PMID- 27229633 TI - Reactive force field development for magnesium chloride hydrates and its application for seasonal heat storage. AB - MgCl2 hydrates are considered as high-potential candidates for seasonal heat storage materials. These materials have high storage capacity and fast dehydration kinetics. However, as a side reaction to dehydration, hydrolysis may occur. Hydrolysis is an irreversible reaction, which produces HCl gas thus affecting the durability of heat storage systems. In this study, we present the parameterization of a reactive force field (ReaxFF) for MgCl2 hydrates to study the dehydration and hydrolysis kinetics of MgCl2.H2O and MgCl2.2H2O. The ReaxFF parameters have been derived by training against quantum mechanics data obtained from Density Functional Theory (DFT) calculations consisting of bond dissociation curves, angle bending curves, reaction enthalpies, and equation of state. A single-parameter search algorithm in combination with a Metropolis Monte Carlo algorithm is successfully used for this ReaxFF parameterization. The newly developed force field is validated by examining the elastic properties of MgCl2 hydrates and the proton transfer reaction barrier, which is important for the hydrolysis reaction. The bulk moduli of MgCl2.H2O and MgCl2.2H2O obtained from ReaxFF are in close agreement with the bulk moduli obtained from DFT. A barrier of 20.24 kcal mol(-1) for the proton transfer in MgCl2.2H2O is obtained, which is in good agreement with the barrier (19.55 kcal mol(-1)) obtained from DFT. Molecular dynamics simulations using the newly developed ReaxFF on 2D-periodic slabs of MgCl2.H2O and MgCl2.2H2O show that the dehydration rate increases more rapidly with temperature in MgCl2.H2O than in MgCl2.2H2O, in the temperature range 300-500 K. The onset temperature of HCl formation, a crucial design parameter in seasonal heat storage systems, is observed at 340 K for MgCl2.H2O, which is in agreement with experiments. The HCl formation is not observed for MgCl2.2H2O. The diffusion coefficient of H2O through MgCl2.H2O is lower than through MgCl2.2H2O, and can become a rate-limiting step. The diffusion coefficient increases with temperature and follows the Arrhenius law both for MgCl2.H2O and MgCl2.2H2O. These results indicate the validity of the ReaxFF approach for studying MgCl2 hydrates and provide important atomistic-scale insight of reaction kinetics and H2O transport in these materials. PMID- 27229634 TI - Bioinspired Interface Engineering in Elastomer/Graphene Composites by Constructing Sacrificial Metal-Ligand Bonds. AB - It remains a huge challenge to create advanced elastomers combining high strength and great toughness. Despite enhanced strength and stiffness, elastomeric nanocomposites suffer notably reduced extensibility and toughness. Here, inspired by the concept of sacrificial bonding associated with many natural materials, a novel interface strategy is proposed to fabricate elastomer/graphene nanocomposites by constructing a strong yet sacrificial interface. This interface is composed of pyridine-Zn(2+) -catechol coordination motifs, which is strong enough to ensure uniform graphene dispersion and efficient stress transfer from matrix to fillers. Moreover, they are sacrificial under external stress, which dissipates much energy and facilitates chain orientation. As a result, the strength, modulus, and toughness of the elastomeric composites are simultaneously strikingly enhanced relative to elastomeric bulk. This work suggests a promising methodology of designing advanced elastomers with exceptional mechanical properties by engineering sacrificial bonds into the interface. PMID- 27229636 TI - Therapeutic Targets in Sepsis: Past, Present, and Future. AB - Antibiotics and fluids have been standard treatment for sepsis since World War II. Many molecular mediators of septic shock have since been identified. In models of sepsis, blocking these mediators improved organ injury and decreased mortality. Clinical trials, however, have failed. The absence of new therapies has been vexing to clinicians, clinical researchers, basic scientists, and the pharmaceutical industry. This article examines the evolution of sepsis therapy and theorizes about why so many well-reasoned therapies have not worked in human trials. We review new molecular targets for sepsis and examine trial designs that might lead to successful treatments for sepsis. PMID- 27229635 TI - The Changing Epidemiology and Definitions of Sepsis. AB - This article describes the trends in the incidence of and mortality from sepsis in the United States and globally. The article then discusses the known factors associated with increased risk for developing sepsis and the limitations of the current clinical definition and the clinical correlations of the current epidemiology. PMID- 27229637 TI - Early Identification and Treatment of Pathogens in Sepsis: Molecular Diagnostics and Antibiotic Choice. AB - Sepsis and septic shock are serious conditions associated with high morbidity and mortality. Rapid molecular methods for detection of microorganisms and antimicrobial resistance genes from positive blood cultures or whole blood have evolved over the past 10 years. Such diagnostic methods coupled with therapeutic interventional programs are desirable to improve the overall clinical outcome and mortality. This article discusses the usefulness of current molecular test methods for the diagnosis of sepsis and their potential to enhance the success of antimicrobial stewardship programs. Clinicians and laboratories alike must appreciate key factors influencing the appropriate use and potential impact of these methods. PMID- 27229638 TI - Risk Stratification and Prognosis in Sepsis: What Have We Learned from Microarrays? AB - Sepsis mortality rates have decreased in recent years but remain unacceptably high. Risk stratification and prognostication is of particular importance because high-risk patients may benefit from earlier clinical interventions, whereas low risk patients may benefit from not undergoing unnecessary procedures. Prognostication is currently done mostly via clinical criteria and blood lactate levels. This article summarizes the literature on the complexity of changes at the molecular level for the casual reader. PMID- 27229640 TI - Goal-Directed Resuscitation in Septic Shock: A Critical Analysis. AB - The Early Goal-Directed Therapy versus Standard Care for Sepsis trial by Rivers and colleagues in 2001 suggested that a significant mortality reduction may be realized through goal-directed interventions early in the care of patients with septic shock. However, the recent publication of the Protocol-Based Care for Early Septic Shock (ProCESS), Australasian Resuscitation in Sepsis Evaluation (ARISE), and Protocolised Management in Sepsis (ProMISE) trials did not demonstrate the superiority of early goal-directed therapy over usual care. If usual care includes timely and meticulous care, a protocol may not be needed to realize the continued lowering mortality rates. PMID- 27229639 TI - Development and Implementation of Sepsis Alert Systems. AB - Development and implementation of sepsis alert systems is challenging, particularly outside the monitored intensive care unit (ICU) setting. Barriers to wider use of sepsis alerts include evolving clinical definitions of sepsis, information overload, and alert fatigue, due to suboptimal alert performance. Outside the ICU, barriers include differences in health care delivery models, charting behaviors, and availability of electronic data. Current evidence does not support routine use of sepsis alert systems in clinical practice. Continuous improvement in the afferent and efferent aspects will help translate theoretic advantages into measurable patient benefit. PMID- 27229641 TI - Sepsis Resuscitation: Fluid Choice and Dose. AB - Sepsis is a common and life-threatening inflammatory response to severe infection treated with antibiotics and fluid resuscitation. Despite the central role of intravenous fluid in sepsis management, fundamental questions regarding which fluid and in what amount remain unanswered. Recent advances in understanding the physiologic response to fluid administration, and large clinical studies examining resuscitation strategies, fluid balance after resuscitation, colloid versus crystalloid solutions, and high- versus low-chloride crystalloids, inform the current approach to sepsis fluid management and suggest areas for future research. PMID- 27229642 TI - Vasopressors During Sepsis: Selection and Targets. AB - Clinicians have greatly improved care for septic shock. Urgent resuscitation using intravenous fluids and vasopressors as well as rapid administration of broad spectrum antibiotics are probably the most basic and universally accepted interventions. Various trials have compared different types of vasopressors, associations of vasopressors and inotropes, and pressure targets. End goal directed therapy algorithms are designed to optimize oxygen delivery by use of fluids, vasopressors, inotropes, and blood products. Patients who have a poor response to resuscitation and patients with known severe ventricular dysfunction might merit advanced hemodynamic monitoring. This review examines important vasopressor and septic shock trials. PMID- 27229644 TI - Management of Acute Kidney Injury and Acid-Base Balance in the Septic Patient. AB - Acute kidney injury (AKI) is an abrupt decrease in kidney function that takes place over hours to days. Sepsis is the leading cause of AKI and portends a particularly high morbidity and mortality, although the severity may vary from a transient rise in serum creatinine to end-stage renal disease. With regard to acid-base management in septic AKI, caution should be used with hyperchloremic crystalloid solutions, and dialysis is often used in the setting of severe acidosis. In the future, biomarkers may help clinicians identify AKI earlier and allow for potential interventions before the development of severe AKI. PMID- 27229645 TI - Cardiac Function and Dysfunction in Sepsis. AB - Cardiac function and dysfunction are important in the clinical outcomes of sepsis and septic shock. Cardiac dysfunction is not a single entity, but is a broad spectrum of syndromes that result in biventricular cardiac dysfunction manifested by both systolic and diastolic dysfunction and is influenced by cardiac loading conditions (ie, preload and afterload). Elucidating the underlying pathophysiology has proved to be complex. This article emphasizes the underlying pathophysiology of cardiac dysfunction and explores recent evidence related to diagnosis, including the utility of biomarkers, the role of echocardiography, and management goals and treatment. PMID- 27229646 TI - The Use of Ultrasound in Caring for Patients with Sepsis. AB - Echocardiography is a noninvasive and accurate tool used in the intensive care unit to assess cardiac function and monitor hemodynamics in shocked patients. During severe sepsis or septic shock, several mechanisms can lead to hemodynamic failure and have to be quickly and precisely diagnosed to propose adequate, personalized, and timely hemodynamic therapy. Echocardiography truly provides intensivists with this diagnostic possibility, whether or not there is fluid responsiveness, cardiac dysfunction, or persistent vasoplegia. Acquiring skills in critical care echocardiography is mandatory in improving management and monitoring of patients with sepsis at the bedside. How critical care echocardiography in managing patients with septic shock improves prognosis remains to be elucidated. PMID- 27229643 TI - Endothelial and Microcirculatory Function and Dysfunction in Sepsis. AB - The microcirculation is a series of arterioles, capillaries, and venules that performs essential functions of oxygen and nutrient delivery, customized to the unique physiologic needs of the supplied organ. The homeostatic microcirculatory response to infection can become harmful if overactive and/or dysregulated. Pathologic microcirculatory dysfunction can be directly visualized by intravital microscopy or indirectly measured via detection of circulating biomarkers. Although several treatments have been shown to protect the microcirculation during sepsis, they have not improved patient outcomes when applied indiscriminately. Future outcomes-oriented studies are needed to test sepsis therapeutics when personalized to a patient's microcirculatory dysfunction. PMID- 27229647 TI - Dysglycemia and Glucose Control During Sepsis. AB - Sepsis predisposes to disordered metabolism and dysglycemia; the latter is a broad term that includes hyperglycemia, hypoglycemia, and glycemic variability. Dysglycemia is a marker of illness severity. Large randomized controlled trials have provided considerable insight into the optimal blood glucose targets for critically ill patients with sepsis. However, it may be that the pathophysiologic consequences of dysglycemia are dynamic throughout the course of a septic insult and also altered by premorbid glycemia. This review highlights the relevance of hyperglycemia, hypoglycemia, and glycemic variability in patients with sepsis with an emphasis on a rational approach to management. PMID- 27229649 TI - Neuroanatomy and Physiology of Brain Dysfunction in Sepsis. AB - Sepsis-associated encephalopathy (SAE), a complication of sepsis, is often complicated by acute and long-term brain dysfunction. SAE is associated with electroencephalogram pattern changes and abnormal neuroimaging findings. The major processes involved are neuroinflammation, circulatory dysfunction, and excitotoxicity. Neuroinflammation and microcirculatory alterations are diffuse, whereas excitotoxicity might occur in more specific structures involved in the response to stress and the control of vital functions. A dysfunction of the brainstem, amygdala, and hippocampus might account for the increased mortality, psychological disorders, and cognitive impairment. This review summarizes clinical and paraclinical features of SAE and describes its mechanisms at cellular and structural levels. PMID- 27229648 TI - Metabolism, Metabolomics, and Nutritional Support of Patients with Sepsis. AB - Sepsis is characterized by profound changes in systemic and cellular metabolism that disrupt normal metabolic homeostasis. These metabolic changes can serve as biomarkers for disease severity. Lactate, a metabolite of anaerobic metabolism, is the most widely used ICU biomarker and it is incorporated into multiple management algorithms. Technological advances now make broader metabolic profiling possible, with early studies identifying metabolic changes associated with sepsis mortality. Finally, given the marked changes in metabolism in sepsis and the association of worse prognosis in patients with severe metabolic derangements, we summarize the seminal trials conducted to optimize nutrition in the ICU. PMID- 27229650 TI - Beyond the Golden Hours: Caring for Septic Patients After the Initial Resuscitation. AB - Recognition and management of agitation, delirium, and pain are key areas. Reduced use of sedatives is an important measure that must be coupled with increased patient engagement, mobilization, and exercise. Use of low tidal volumes and low mean airway pressures during mechanical ventilation is helpful. A key hemodynamic principle following early aggressive volume resuscitation is subsequent careful assessment to avoid unnecessary additional volume administration and adverse consequences of frank volume overload. Substantial evidence now supports a lower hemoglobin transfusion threshold of 7 g/dL. A rush to initiate enteral or parenteral feeds is not clearly supported by the current evidence. PMID- 27229651 TI - Short-term Gains with Long-term Consequences: The Evolving Story of Sepsis Survivorship. AB - Sepsis is an acute, life-threatening condition that afflicts millions of patients annually. Advances in care and heightened awareness have led to substantial declines in short-term mortality. An expanding body of literature describes the long-term impact of sepsis, revealing long-term cognitive and functional impairments, sustained inflammation and immune dysfunction, increased healthcare resource use, reduced health-related quality of life, and increased mortality. The evidence challenges the notion that sepsis is an acute, transient illness, revealing rather that sepsis is an acute illness with lingering consequences. This article provides a state-of-the-art review of the emerging literature of the long-term consequences of sepsis. PMID- 27229652 TI - Sepsis. PMID- 27229653 TI - Reaction of Paprika Carotenoids, Capsanthin and Capsorubin, with Reactive Oxygen Species. AB - The reaction of paprika carotenoids, capsanthin and capsorubin, with reactive oxygen species (ROS), such as superoxide anion radical (.O2(-)), hydroxyl radical (.OH), and singlet oxygen ((1)O2), was analyzed by LC/PDA ESI-MS and ESR spectrometry. Capsanthin formed both the 5,6-epoxide and 5,8-epoxide by reaction with .O2(-) and .OH. Furthermore, capsanthin also formed 5,6- and 5,8 endoperoxide on reaction with (1)O2. The same results were obtained in the case of capsanthin diacetate. On the other hand, capsorubin showed higher stability against these ROS. Capsorubin formed 7,8-epoxide on reaction with .O2(-) and .OH and 7,8-endoperoxide on reaction with (1)O2. PMID- 27229654 TI - Anti-ageing glycoprotein promotes long-term survival of transplanted neurosensory precursor cells. AB - Cell therapy, to replace lost tissue, is a promising approach for the treatment of various neurodegenerative diseases. Many studies suggest, however, that the percentage of transplanted cells that survive and undergo functional integration remains low as a result of immune rejection, suboptimal precursor cell type, trauma during cell transplantation, toxic compounds released by dying tissues or nutritional deficiencies. We recently developed an ex vivo system to facilitate identification of factors contributing to the death of transplanted neuronal (photoreceptor) cells and compounds that block these toxic effects. In this system, photoreceptor precursor cells (PPCs) are sandwiched between a neurosensory retinal explant and retinal pigment epithelium derived from human embryonic stem cells. Explant medium was collected to identify toxic components and PPC survival was assessed by flow cytometry. We also assessed the potential for AAGPTM, a cryopreservative molecule, to improve PPC survival. We identified elevated prostaglandin E2 (PGE2) in the explant medium and demonstrated that AAGPTM reduced PGE2 levels by 2.6-fold. A pro-inflammatory stress assay suggested that this may result from AAGPTM inhibition of cyclo-oxygenase-2 (COX-2) expression. We confirmed that PGE2 reduced the viability of cultured PPCs by 44% and found that the survival rate of PPCs pretreated with AAGPTM was 2.8-fold higher than in untreated PPCs. These data suggest that PGE2 release from necrotic tissue may be one factor that reduces the survival of transplanted precursor cells and that the pro-survival molecule AAGPTM may improve long-term transplanted cell viability. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27229655 TI - Reliability, validity and cutoff score of the Intra-Oral Injection Fear scale. AB - BACKGROUND: A proper assessment tool is needed to gain more knowledge about fear of intraoral injections in children. AIM: The aims of this study were to evaluate the reliability and validity of the novel Intra-Oral Injection Fear scale (IOIF s) and to establish a cutoff score for a high level of such fear. METHODS: Data were obtained from two samples of 10- to 16-year-olds in Hordaland, Norway. Sample I, 1460 pupils attending elementary and high schools, provided questionnaire-based data. The survey instruments used were IOIF-s, Children's Fear Survey Schedule-Dental Subscale (CFSS-DS), Mutilation Questionnaire for Children (MQ-c) and Injection phobia Scale for Children (IS-c). Sample II was 67 patients, diagnosed with intraoral injection phobia at the Center for Odontophobia, Oral Health Center of Expertise in Western Norway-Hordaland, who provided IOIF-s data. RESULTS: Cronbach's alpha was 0.95. The IOIF-s discriminated between subjects with and without intraoral injection phobia and was associated with the other survey instruments of similar construct. Principal component analysis revealed a two-component solution, characterized as 'Contact Fear' and 'Distal Fear'. Receiver-operating characteristic (ROC) curve indicated that a cutoff score of 38 was appropriate. CONCLUSION: The IOIF-s showed satisfying psychometric properties in terms of reliability and validity. PMID- 27229656 TI - Decarboxylative dearomatization and mono-alpha-arylation of ketones. AB - We report the first example of a palladium-catalyzed decarboxylative dearomatization reaction that occurs via Pd-pi-benzyl intermediates. In fact, the Pd-catalyzed decarboxylative cross-coupling reaction of benzyl enol carbonates can lead to either the dearomatized alicyclic ketones or alpha-monoarylated ketone products depending on the catalyst and ligand employed. PMID- 27229657 TI - Setting of an endoscopic nasal reference point for surgical access to the anterior base through an anatomical study on cadavers. AB - INTRODUCTION: Diseases of paranasal sinuses, nasal cavity, and skull base can be treated by endonasal operations using a nasal rigid endoscope. When conducting this kind of surgery, anatomical references are critical for safety. OBJECTIVE: To measure the distance from the posterior wall of the maxillary sinus to the skull base, according to socio-demographic characteristics, and to detail an anatomical reference point for paranasal sinus operations and for an access to the anterior skull base, comparing anatomical variations between right and left sides, gender, height, weight, age, and ethnicity in cadavers. METHODS: Measures were taken from the 90 degrees angle (the starting point where deflection of the skull base begins to form the anterior wall of the sphenoid, also known as Delta90 degrees ) to the upper, middle, and lower points of the posterior wall of the maxillary sinus. This study used 60 cadavers aged over 17 years, and evaluated these bodies with respect to age, height, BMI, weight, gender, and ethnicity, comparing measurements of right and left sides. RESULTS: The measurements were >1.5cm in all cadavers and did not vary with age, height, weight, gender, and ethnicity on their right and left sides. The lack of association between the measurement from Delta90 degrees to the upper, middle, and lower posterior walls of the maxillary sinus (categorical or quantitative) is noteworthy, considering the characteristics studied. CONCLUSION: The methodology defined the nasal point of reference, considering an absence of variation in the cadavers' characteristics. PMID- 27229658 TI - Assessment of hearing threshold in adults with hearing loss using an automated system of cortical auditory evoked potential detection. AB - INTRODUCTION: The use of hearing aids by individuals with hearing loss brings a better quality of life. Access to and benefit from these devices may be compromised in patients who present difficulties or limitations in traditional behavioral audiological evaluation, such as newborns and small children, individuals with auditory neuropathy spectrum, autism, and intellectual deficits, and in adults and the elderly with dementia. These populations (or individuals) are unable to undergo a behavioral assessment, and generate a growing demand for objective methods to assess hearing. Cortical auditory evoked potentials have been used for decades to estimate hearing thresholds. Current technological advances have lead to the development of equipment that allows their clinical use, with features that enable greater accuracy, sensitivity, and specificity, and the possibility of automated detection, analysis, and recording of cortical responses. OBJECTIVE: To determine and correlate behavioral auditory thresholds with cortical auditory thresholds obtained from an automated response analysis technique. METHODS: The study included 52 adults, divided into two groups: 21 adults with moderate to severe hearing loss (study group); and 31 adults with normal hearing (control group). An automated system of detection, analysis, and recording of cortical responses (HEARLab(r)) was used to record the behavioral and cortical thresholds. The subjects remained awake in an acoustically treated environment. Altogether, 150 tone bursts at 500, 1000, 2000, and 4000Hz were presented through insert earphones in descending-ascending intensity. The lowest level at which the subject detected the sound stimulus was defined as the behavioral (hearing) threshold (BT). The lowest level at which a cortical response was observed was defined as the cortical electrophysiological threshold. These two responses were correlated using linear regression. RESULTS: The cortical electrophysiological threshold was, on average, 7.8dB higher than the behavioral for the group with hearing loss and, on average, 14.5dB higher for the group without hearing loss for all studied frequencies. CONCLUSION: The cortical electrophysiological thresholds obtained with the use of an automated response detection system were highly correlated with behavioral thresholds in the group of individuals with hearing loss. PMID- 27229659 TI - Lichen sclerosis: clinicopathological study of 60 cases from Lebanon. AB - BACKGROUND: Lichen sclerosus (LS) is an uncommon idiopathic chronic inflammatory debilitating disease with predilection for the genital region. Our recent encounter with an LS case exhibiting perineural inflammation microscopically prompted us to assess the features of all patients diagnosed with LS at our institution. MATERIALS AND METHODS: All cases of LS diagnosed between 1990 and 2014 were retrospectively reviewed. Diagnosis was confirmed with demonstration of microscopic features typical of LS. RESULTS: Sixty patients (42 women and 18 men) with 65 biopsy specimens of LS were identified, of which 41 were extragenital, 16 genital, and three had both. Histopathologically, significantly higher proportions of follicular plugging, atrophy, and vacuolar interface changes were observed in extragenital LS cases, while angiokeratoma-like, mycosis fungoides like, and pseudoepitheliomatous changes were only seen in genital LS. Perineural inflammation was observed as a novel finding in 22 cases (33.8%) of LS. CONCLUSION: Features of patients with LS in this study are generally comparable to those published in the literature, with some differences. In contrast to the literature, extragenital LS was more frequently encountered. Histopathologically, perineural inflammation was not an uncommon feature of LS and thus may serve as a clue in the differentiation of LS from its mimickers. PMID- 27229660 TI - Mesoporous Titanium Nitride-Enabled Highly Stable Lithium-Sulfur Batteries. AB - The TiN-S composite cathode exhibits superior performance because of higher electrical conductivity and the capture of the soluble intermediate species of the electrode reactions by 2-5 nm mesopores and strong N-S surface bonding. PMID- 27229661 TI - Effect of heat stress on adipokines and some blood metabolites in goats from Jordan. AB - To date and to the best of our knowledge, there have been no available data on the interaction between heat stress (HS) and secretion of adipokines and some blood metabolites in Baladi goats from Jordan. Therefore, this study aimed at evaluating the changes in leptin, adiponectin, non-ester fatty acid (NEFA) and beta-hydroxybutyrate (BHB) concentrations in Baladi goats under HS conditions in Jordan. Six goats were exposed to direct solar radiation versus six goats exposed to shade regimen. Blood samples were collected and serum concentrations of leptin, adiponectin, NEFA and BHB were measured. Ambient temperature, relative humidity (RH) and body weight (BW) were recorded. Results indicated that leptin and adiponectin concentrations were significantly increased under HS. The concentration of NEFA was significantly increased under HS at the 7th and 14th days of the experiment, while mean total concentration of NEFA was not significantly affected by HS. Neither weekly nor mean total concentrations of BHB were significantly affected by HS during the experimental period. In conclusion, HS is associated with changes in leptin and adiponectin concentrations in Baladi goats. Heat-stressed goats were able to keep their blood NEFA and BHB concentrations similar to those of thermo-neutral goats. PMID- 27229662 TI - In vivo target bio-imaging of Alzheimer's disease by fluorescent zinc oxide nanoclusters. AB - Alzheimer's disease (AD) is an irreversible neurodegenerative disease which is difficult to cure. When Alzheimer's disease occurs, the level of zinc ions in the brain changes, and the relevant amount of zinc ions continue decreasing in the cerebrospinal fluid and plasma of Alzheimer's patients with disease exacerbation. In view of these considerations, we have explored a new strategy for the in vivo rapid fluorescence imaging of Alzheimer's disease through target bio-labeling of zinc oxide nanoclusters which were biosynthesized in vivo in the Alzheimer's brain via intravenous injection of zinc gluconate solution. By using three-month old and six-month-old Alzheimer's model mice as models, our observations demonstrate that biocompatible zinc ions could pass through the blood-brain barrier of the Alzheimer's disease mice and generate fluorescent zinc oxide nanoclusters (ZnO NCs) through biosynthesis, and then the bio-synthesized ZnO NCs could readily accumulate in situ on the hippocampus specific region for the in vivo fluorescent labeling of the affected sites. This study provides a new way for the rapid diagnosis of Alzheimer's disease and may have promising prospects in the effective diagnosis of Alzheimer's disease. PMID- 27229663 TI - Susceptibility of Australian Redfin Perch Perca fluviatilis Experimentally Challenged with Epizootic Hematopoietic Necrosis Virus (EHNV). AB - The ranavirus epizootic hematopoietic necrosis virus (EHNV) is endemic to Australia and is listed by the Office International des Epizooties. Clinical outbreaks have only been observed in wild populations of Redfin Perch Perca fluviatilis (also known as Eurasian Perch) and farmed populations of Rainbow Trout Oncorhynchus mykiss. The initial outbreaks of EHNV describe all age-classes of Redfin Perch as being susceptible and can lead to epidemic fish kills. Subsequently, experimental challenge studies using either cohabitation with the virus or injection exposures resulted in mixed susceptibilities across various age-groupings of Redfin Perch. We used an experimental bath challenge model to investigate the susceptibility of Redfin Perch collected from areas with and without a history of EHNV outbreaks. The median survival time for fish from Blowering Dam in New South Wales, a zone with a history of EHNV outbreaks, was 35 d, compared with fish from other areas, which had a median survival between 12 and 28 d postexposure. Redfin Perch from Blowering Dam demonstrated an increased mortality associated with epizootic hematopoietic necrosis up to approximately day 14 after exposure, and then there was a significantly reduced risk of mortality until the end of the trial compared with all other fish. Redfin Perch from Blowering Dam had markedly decreased susceptibility to EHNV, and less than 40% became infected following a bath challenge. In contrast, Redfin Perch from neighboring (e.g., Bethungra Dam and Tarcutta Creek) and distant water bodies (e.g., in Western Australia) with no previous history of EHNVdisplayed moderate to high susceptibility when given a bath challenge. Potential factors for the observed changes in the host-pathogen relationship include intense positive selection pressure for resistant fish following epizootic hematopoietic necrosis outbreaks and subsequent attenuation of the virulence of the virus in resistant fish. Received August 22, 2015; accepted February 13, 2016. PMID- 27229664 TI - Complete remodelling after iatrogenic Stanford type A acute aortic dissection. PMID- 27229665 TI - No difference between aspirin and warfarin after extracardiac Fontan in a propensity score analysis of 475 patients. AB - OBJECTIVES: The most effective method of long-term thromboprophylaxis after the Fontan procedure is not clear. We compared the rates of thromboembolic events between patients receiving aspirin and warfarin after an extracardiac conduit Fontan procedure in a bi-national registry. METHODS: All patients who underwent an extracardiac conduit Fontan procedure from 1997 to 2010 in Australia and New Zealand were identified. Medication status and routine follow-up and echocardiographic data were obtained from all patients. Survival analysis with propensity score matching and adjustment was performed to determine the treatment effect of warfarin compared with that of aspirin beyond the first year of follow up, after which time patients had settled on their long-term thromboprophylaxis strategy. RESULTS: Of 570 eligible patients, the data of 475 patients who were regularly followed up without mechanical valve replacement were available for analysis. Long-term thromboprophylaxis consisted of warfarin in 301 patients (63%), aspirin in 157 (33%) and none in 17 (4%). The 10-year rate of freedom from all thromboembolic events was 91% [95% confidence interval (CI) 88-94%]. Thromboembolic events beyond the first year of follow-up occurred in 18 patients (6 on aspirin and 12 on warfarin). After (i) propensity score adjustment and (ii) matching yielding 164 pairs, the hazard rates of thromboembolic events beyond the first year were not statistically different between the warfarin and aspirin groups [(i) hazard ratio (HR) 2.3, 95% CI 0.7-7.4, P = 0.2 and (ii) HR 1.5, 95% CI 0.5-4.7, P = 0.5, respectively]. CONCLUSIONS: No difference in the hazard rates of late thromboembolic events was observed between aspirin and warfarin beyond the first year after the extracardiac conduit Fontan procedure. PMID- 27229666 TI - Total aortic arch repair: risk factor analysis and follow-up in 199 patients. AB - OBJECTIVES: Aortic arch surgery is associated with substantial perioperative risks. New prostheses as well as novel perfusion techniques have been developed to reduce the risks of these procedures. The routine application of these new techniques warrants reassessment of risk factors of aortic arch repair. METHODS: Between April 2010 and December 2015, 199 patients [61% male, median age 63 years (interquartile range 52-70 years)] underwent total aortic arch repair in our institution. Forty-four per cent of the patients presented with acute aortic dissections (ADs, 32% with malperfusion), 22% with chronic aortic dissections (CDs), 34% with degenerative aneurysms, 24% underwent reoperations. Our surgical technique involved cold blood cardioplegia for cardiac procedures, non cardioplegic continuous myocardial blood perfusion during aortic arch repair and early lower body reperfusion after distal aortic arch reconstruction. Anastomosis of head vessels is performed at the end of the procedure. RESULTS: Forty-four per cent of patients underwent aortic root surgery, 90% received a classical elephant trunk (ET) or frozen elephant trunk (FET). Median (interquartile range) cardiopulmonary bypass time, cardiac ischaemia time, hypothermic circulatory arrest time and selective antegrade cerebral perfusion time were 248 min (204 302), 105 min (51-150), 47 min (35-61) and 93 min (72-115), respectively. Operative mortality was 16%, stroke occurred in 10%, dialysis in 21% and spinal cord injury in 5%. Independent risk factors for mortality were age, rethoracotomy for bleeding, postoperative dialysis, maximum lactate value and maximum creatinine kinase-MB (CK-MB) value. 'Beating heart' aortic arch surgery significantly reduced the risk of mortality. Malperfusion syndrome and coronary artery bypass grafting were preoperative predictors of stroke. CD, preoperative renal dysfunction, operation time, rethoracotomy for bleeding and low cardiac output syndrome were risk factors for postoperative dialysis. Freedom from aortic reoperation was 91% (AD), 66% (CD) and 70% (aneurysm) after 2 years. CONCLUSIONS: Aortic arch repair remains a high-risk procedure, especially in multisegment aortic disease. Several peri- and postoperative factors predicted adverse outcome, indicating the need to further improve perioperative management (e.g. organ protection). Indications for FET treatment have to be thoroughly investigated (e.g. FET in CDs). PMID- 27229667 TI - Reply to Riquet et al. PMID- 27229668 TI - Microscopic pN2 in lung cancer: a better prognosis? PMID- 27229669 TI - Bilateral mammary artery grafting increases postoperative mediastinitis without survival benefit in obese patients. AB - OBJECTIVES: The prevalence of obesity has risen in the last decade, increasing the percentage of obese patients who undergo cardiac surgery. Deep sternal wound infection (DSWI) is a rare but devastating postoperative complication, more often encountered in the obese population. DSWI is also associated with the use of bilateral internal mammary artery (BIMA), particularly in this high-risk population. The aim of this study is to determine the short-term and long-term outcomes following BIMA revascularization in obese patients. METHODS: This is a single-centre retrospective cohort study using prospectively collected data including all obese patients who underwent coronary artery bypass grafting (CABG) surgery between April 1991 and April 2014. Preoperative demographic characteristics, operative and postoperative variables were taken from the computerized database of the hospital. A propensity score matching was conducted for the short- and long-term outcomes in the entire study population. RESULTS: Results showed that 5608 patients with a body mass index of >=30 kg/m2 underwent CABG during the studied period. After propensity scoring, 494 patients receiving BIMA were matched to 5089 patients receiving single internal mammary artery (SIMA). All preoperative characteristics were comparable except for a higher prevalence of left ventricular dysfunction and left main disease as well as higher mean EuroSCORE in the SIMA group. In the postoperative period, short-term mortality was comparable in the two groups (P = 0.68). In-hospital DSWI was also comparable (P = 0.10). However, when considering DSWI occurring after hospitalization (median time; 19 days), the latter was significantly lower in the SIMA than in the BIMA group (1.1 vs 3.2%; P < 0.0001). For long-term survival, no difference was observed between the BIMA and SIMA groups after appropriate matching (P = 0.22). CONCLUSIONS: In obese patients, CABG surgery using BIMA instead of SIMA increased the risk of postoperative DSWI, without improving survival. According to our results, short-term postoperative risks of infection associated with BIMA are not offset by longer-term benefits in that patient population. Special care should be exerted when selecting conduits for myocardial revascularization in obese patients. PMID- 27229670 TI - Is beating heart coronary artery bypass grafting on or off? PMID- 27229671 TI - Over 20 years experience with aortic homograft in aortic valve replacement during acute infective endocarditis. AB - OBJECTIVES: Despite the controversy, the aortic homograft is supposedly the best option in acute infective endocarditis (AIE), due to its resistance to reinfection. However, the technical complexity and the risk of structural deterioration over time have limited its utilization. The aim of this study was to evaluate the long-term results of aortic homograft for the treatment of infective endocarditis in our institution with particular attention to predictors of survival and homograft reoperation. METHODS: The cohort includes 112 patients who underwent aortic valve replacement with an aortic homograft for AIE between January 1990 and December 2014. RESULTS: Fifteen patients (13.4%) died during the first 30 days after the operation. Two patients were lost to follow-up after discharge from the hospital; therefore, 95 patients were available for long-term analysis. The median duration of follow-up was 7.8 years (IQR 4.7-17.6). Five patients (5.3%) suffered a recurrence of infective endocarditis (1 relapse and 4 new episodes). Sixteen patients (16.8%) were reoperated for structural valve degeneration (SVD; n = 14, 87.5%) or for infection recurrence (n = 2, 12.5%). Freedom from homograft reoperation for infective endocarditis or structural homograft degeneration at 10 and 15 years postoperatively was 86.3 +/- 5.5 and 47.3 +/- 11.0%, respectively. For patients requiring homograft reoperation, the median interval to reintervention was 11.6 years (IQR 8.3-14.5). Long-term survival was 63.6% (95% CI 52.4-72.8%) and 53.8% (95% CI 40.6-65.3%) at 10 and 15 years, respectively. CONCLUSIONS: The use of aortic homograft in acute aortic valve endocarditis is associated with a remarkably low risk of relapsing infection and very acceptable long-term survival. The risk of reoperation due to SVD is significant after one decade especially in young patients. The aortic homograft seems to be ideally suited for reconstruction of the aortic valve and cardiac structures damaged by the infective process especially in early surgery. PMID- 27229672 TI - Obstructed prosthetic valve thrombosis of a pure carbon bi-leaflet aortic valve. AB - Obstruction of a prosthetic valve is a severe complication and can result in congestive heart failure or cardiac shock. We present an extremely rare case of obstructed prosthetic aortic valve thrombosis of a pure pyrolytic carbon valve. The patient was successfully treated with complete surgical thrombectomy. PMID- 27229673 TI - Long-term follow-up after aortic root replacement with the Shelhigh(r) biological valved conduit: a word of caution! AB - OBJECTIVES: The aim of this study was to analyse long-term results of aortic root replacement with the Shelhigh(r) NR-2000C conduit. METHODS: From January 2001 to October 2005, 63 patients with a median age of 62 years underwent aortic root replacement with a Shelhigh(r) conduit. Aneurysm (27%), aortic valve endocarditis (30%) and acute type A aortic dissection (33%) were the predominant indications for the surgery. Fifty-four patients (86%) were entered in the follow-up study with the end-points of death, aortic root-related reoperation and endocarditis. RESULTS: The overall 30-day mortality rate was 8% (n = 5). The median follow-up was 9.5 years (range 0-14.2 years). In total, 13 (24%) deaths occurred during follow-up; of these, 4 were directly conduit-related. The overall estimated survival rates at 1, 5 and 10 years were 85 +/- 5, 79 +/- 6 and 71 +/- 7%, respectively. Reoperation was necessary in 10 (19%) patients due to endocarditis (n = 5), aortic stenosis (n = 3), pseudoaneurysm due to detachment of the right coronary artery (n = 1) and detachment of the non-coronary leaflet (n = 1). The overall estimated rate of freedom from aortic root-related reoperation at 1, 5 and 10 years was 83 +/- 5, 79 +/- 6 and 64 +/- 7%, respectively. Endocarditis of the prosthesis was reported in 9 (17%) patients; of whom, 5 patients required reoperation and 4 were treated medically. In 1 patient with endocarditis, a stroke was reported due to a thromboembolic event. CONCLUSIONS: The first long term follow-up after aortic root replacement with the Shelhigh(r) BioConduit revealed a relatively high rate of death and very high rate of reoperations due to endocarditis, aorto-ventricular disconnection and structural valve failure. This may be potentially connected to the nature of the implanted valved conduit. PMID- 27229674 TI - A rapid NGS strategy for comprehensive molecular diagnosis of Birt-Hogg-Dube syndrome in patients with primary spontaneous pneumothorax. AB - BACKGROUND: Primary spontaneous pneumothorax (PSP) or pulmonary cysts is one of the manifestations of Birt-Hogg-Dube syndrome (BHDS) that is caused by heterozygous mutations in FLCN gene. Most of the mutations are SNVs and small indels, and there are also approximately 10 % large intragenic deletions and duplications of the mutations. These molecular findings are generally obtained by disparate methods including Sanger sequencing and Multiple Ligation-dependent Probe Amplification in the clinical laboratory. In addition, as a genetically heterogeneous disorder, PSP may be caused by mutations in multiple genes include FBN1, COL3A1, CBS, SERPINA1 and TSC1/TSC2 genes. For differential diagnosis, these genes should also be screened which makes the diagnostic procedure more time-consuming and labor-intensive. METHODS: Forty PSP patients were divided into 2 groups. Nineteen patients with different pathogenic mutations of FLCN previously identified by conventional Sanger sequencing and MLPA were included in test group, 21 random PSP patients without any genetic screening were included in blinded sample group. 7 PSP genes including FLCN, FBN1, COL3A1, CBS, SERPINA1 and TSC1/TSC2 were designed and enriched by Haloplex system, sequenced on a Miseq platform and analyzed in the 40 patients to evaluate the performance of the targeted-NGS method. RESULTS: We demonstrated that the full spectrum of genes associated with pneumothorax including FLCN gene mutations can be identified simultaneously in multiplexed sequence data. Noteworthy, by our in-house copy number analysis of the sequence data, we could not only detect intragenic deletions, but also determine approximate deletion junctions simultaneously. CONCLUSIONS: NGS based Haloplex target enrichment technology is proved to be a rapid and cost-effective screening strategy for the comprehensive molecular diagnosis of BHDS in PSP patients, as it can replace Sanger sequencing and MLPA by simultaneously detecting exonic and intronic SNVs, small indels, large intragenic deletions and determining deletion junctions in PSP-related genes. PMID- 27229675 TI - Psychologically Adjusted Persons Are Less Aware of How They Are Perceived by Others. AB - Focusing on individual differences, we studied three influences on the accuracy of meta-perceptions of personality: (a) projection, that is, relying on one's self-perception; (b) normative meta-insight, that is, relying on the perception of the typical person by others; and (c) distinctive meta-insight, that is, relying on others' perception of one's unique personality attributes. Using a round-robin design, 52 groups of four acquainted students described themselves, three acquaintances, and their meta-perceptions on the Big-Five factors of personality, and provided self-reports of psychological adjustment. Projection, normative, and distinctive meta-insight contributed uniquely to meta-perception, yet qualified by systematic individual differences: Psychologically adjusted meta perceivers projected more and relied on distinctive meta-insight less. Moreover, acquaintance raised projection. Thus, psychologically adjusted meta-perceivers were less aware of discrepancies between their self-perceptions and their actual perceptions by others, and the better people knew another person, the more strongly they expected that this other person perceived them like they perceived themselves. PMID- 27229676 TI - When It's Okay That I Don't Play: Social Norms and the Situated Construal of Social Exclusion. AB - Being excluded and ignored has been shown to threaten fundamental human needs and cause pain. Such reflexive reactions to social exclusion have been conceptualized as direct and unmoderated (temporal need threat model of ostracism). Here, we propose an extension and argue that reflexive reactions depend on how social exclusion situations are construed. If being excluded is understood as a violation of an inclusion norm, individuals will react with pain and threat. In contrast, if being excluded is consistent with the prevailing norm, the exclusion situation is interpreted as less threatening, and negative reflexive reactions to ostracism should be attenuated. Four studies empirically support this conceptual model. Studies 3 and 4 further show that to guide situated construal, the norm has to be endorsed by the individual. In both Studies 1 and 3, the effect of the norm is mediated by the objective situation's subjective construal. PMID- 27229677 TI - Narcissistic Reactions to Subordinate Role Assignment: The Case of the Narcissistic Follower. AB - Narcissists aspire to be leaders and consequently may react negatively to being assigned a subordinate role, even though such roles may be integral to group functioning. In the first three studies, participants were assigned to a low status role (i.e., "employee"), high status role (i.e., "project manager"), or (in Studies 2 and 3) control condition. More narcissistic participants were less satisfied and discredited the role assignment more in the employee condition than in the project manager condition. Furthermore, more narcissistic participants displayed greater self-interest in the employee condition, relative to the project manager condition (Study 2), and less willingness to engage in behaviors to benefit the group in the employee condition, relative to the project manager and control conditions (Study 3). In Study 4, these findings were replicated in sports teams. Although there is nothing inherently negative about subordinate roles, narcissists perceive them negatively and react poorly to occupying them. PMID- 27229678 TI - Directionality of Person-Situation Transactions: Are There Spillovers Among and Between Situation Experiences And Personality States? AB - To elucidate temporal sequences among and between person and situation variables, this work examines cross-measurement spillovers between situation experiences S (on the Situational Eight DIAMONDS characteristics [Duty, Intellect, Adversity, Mating, pOsitivity, Negativity, Deception, Sociality]) and personality states P (on the Big Six HEXACO dimensions [Honesty/Humility, Emotionality, eXtraversion, Agreeableness, Conscientiousness, Openness to Experience]) in experience sampling data. Multi-level modeling of lagged data at tn -1 and non-lagged data at tn grants the opportunity to examine (a) the stability (P -> P, S -> S), (b) cross sectional associations (S <-> P), and (c) cross-lagged associations among and between situation experiences and personality states (S -> P, P -> S). Findings indicated that there were (a) moderate stability paths, (b) small to moderate cross-sectional paths, and (c) only very small cross-lagged paths (though the different situation characteristics and personality states showed differential tendencies toward no directionality, S -> P or P -> S unidirectionality, or bidirectionality). Findings are discussed in light of refining studies on dynamic person-situation transactions. PMID- 27229679 TI - Prosocial Conformity: Prosocial Norms Generalize Across Behavior and Empathy. AB - Generosity is contagious: People imitate others' prosocial behaviors. However, research on such prosocial conformity focuses on cases in which people merely reproduce others' positive actions. Hence, we know little about the breadth of prosocial conformity. Can prosocial conformity cross behavior types or even jump from behavior to affect? Five studies address these questions. In Studies 1 to 3, participants decided how much to donate to charities before learning that others donated generously or stingily. Participants who observed generous donations donated more than those who observed stingy donations (Studies 1 and 2). Crucially, this generalized across behaviors: Participants who observed generous donations later wrote more supportive notes to another participant (Study 3). In Studies 4 and 5, participants observed empathic or non-empathic group responses to vignettes. Group empathy ratings not only shifted participants' own empathic feelings (Study 4), but they also influenced participants' donations to a homeless shelter (Study 5). These findings reveal the remarkable breadth of prosocial conformity. PMID- 27229680 TI - The absence of dysferlin induces the expression of functional connexin-based hemichannels in human myotubes. AB - BACKGROUND: Mutations in the gene encoding for dysferlin cause recessive autosomal muscular dystrophies called dysferlinopathies. These mutations induce several alterations in skeletal muscles, including, inflammation, increased membrane permeability and cell death. Despite the fact that the etiology of dysferlinopathies is known, the mechanism that explains the aforementioned alterations is still elusive. Therefore, we have now evaluated the potential involvement of connexin based hemichannels in the pathophysiology of dysferlinopathies. RESULTS: Human deltoid muscle biopsies of 5 Chilean dysferlinopathy patients exhibited the presence of muscular connexins (Cx40.1, Cx43 and Cx45). The presence of these connexins was also observed in human myotubes derived from immortalized myoblasts derived from other patients with mutated forms of dysferlin. In addition to the aforementioned connexins, these myotubes expressed functional connexin based hemichannels, evaluated by ethidium uptake assays, as opposed to myotubes obtained from a normal human muscle cell line, RCMH. This response was reproduced in a knock-down model of dysferlin, by treating RCMH cell line with small hairpin RNA specific for dysferlin (RCMH-sh Dysferlin). Also, the presence of P2X7 receptor and the transient receptor potential channel, TRPV2, another Ca(2+) permeable channels, was detected in the myotubes expressing mutated dysferlin, and an elevated resting intracellular Ca(2+) level was found in the latter myotubes, which was in turn reduced to control levels in the presence of the molecule D4, a selective Cx HCs inhibitor. CONCLUSIONS: The data suggests that dysferlin deficiency, caused by mutation or downregulation of dysferlin, promotes the expression of Cx HCs. Then, the de novo expression Cx HC causes a dysregulation of intracellular free Ca(2+) levels, which could underlie muscular damage associated to dysferlin mutations. This mechanism could constitute a potential therapeutical target in dysferlinopathies. PMID- 27229681 TI - Wound healing potential of lavender oil by acceleration of granulation and wound contraction through induction of TGF-beta in a rat model. AB - BACKGROUND: Although previous studies have suggested that lavender oil promote wound healing, no study has examined the molecular mechanisms of its effect. In this study, we investigated the effect of lavender oil on various steps of wound healing and its molecular mechanism, focusing on transforming growth factor-beta (TGF-beta). METHODS: Circular full-thickness skin wounds were produced on rats. Control solution or lavender oil was topically applied to the wounds on alternating days for 14 days. RESULTS: The area of wounds topically treated with lavender oil was significantly decreased as compared to that of wounds of control rats at 4, 6, 8, and 10 days after wounding. Topical application of lavender oil induced expression of type I and III collagen at 4 days after wounding, accompanied by an increased number of fibroblasts, which synthesize collagen. Induced expression of type III collagen by topical application of lavender oil was reduced to control level at 7 days after wounding although increased expression of type I collagen still continued even at 7 days, suggesting rapid collagen replacement from type III to type I in wounds treated with lavender oil. Importantly, expression of TGF-beta in wounds treated with lavender oil was significantly increased as compared to control. Moreover, an increased number of myofibroblasts was observed in wounds treated with lavender oil at 4 days after wounding, suggesting promotion of differentiation of fibroblasts through induction of TGF-beta, which is needed for wound contraction. CONCLUSION: This study demonstrated that topical application of lavender oil promoted collagen synthesis and differentiation of fibroblasts, accompanied by up-regulation of TGF beta. These data suggest that lavender oil has the potential to promote wound healing in the early phase by acceleration of formation of granulation tissue, tissue remodeling by collagen replacement and wound contraction through up regulation of TGF-beta. The beneficial effect of lavender oil on wound healing may raise the possibility of new approaches as complementary treatment besides conventional therapy. PMID- 27229682 TI - 'Let's Move It' - a school-based multilevel intervention to increase physical activity and reduce sedentary behaviour among older adolescents in vocational secondary schools: a study protocol for a cluster-randomised trial. AB - BACKGROUND: Physical activity (PA) has been shown to decline during adolescence, and those with lower education have lower levels of activity already at this age, calling for targeted efforts for them. No previous study has demonstrated lasting effects of school-based PA interventions among older adolescents. Furthermore, these interventions have rarely targeted sedentary behaviour (SB) despite its relevance to health. The Let's Move It trial aims to evaluate the effectiveness and the cost-effectiveness of a school-based, multi-level intervention, on PA and SB, among vocational school students. We hypothesise that the intervention is effective in increasing moderate-to-vigorous-intensity physical activity (MVPA), particularly among those with low or moderate baseline levels, and decreasing SB among all students. METHODS: The design is a cluster-randomised parallel group trial with an internal pilot study. The trial is conducted in six vocational schools in the Helsinki Metropolitan area, Finland. The intervention is carried out in 30 intervention classes, and 27 control classes retain the standard curriculum. The randomisation occurs at school-level to avoid contamination and to aid delivery. Three of the six schools, randomly allocated, receive the 'Let's Move It' intervention which consists of 1) group sessions and poster campaign targeting students' autonomous PA motivation and self-regulation skills, 2) sitting reduction in classrooms via alterations in choice architecture and teacher behaviour, and 3) enhancement of PA opportunities in school, home and community environments. At baseline, student participants are blind to group allocation. The trial is carried out in six batches in 2015-2017, with main measurements at pre-intervention baseline, and 2-month and 14-month follow-ups. Primary outcomes are for PA, MVPA measured by accelerometry and self-report, and for SB, sedentary time and breaks in sedentary time (accelerometry). Key secondary outcomes include measured body composition, self-reported well-being, and psychological variables. Process variables include measures of psychosocial determinants of PA (e.g. autonomous motivation) and use of behaviour change techniques. Process evaluation also includes qualitative interviews. Intervention fidelity is monitored. DISCUSSION: The study will establish whether the Let's Move It intervention is effective in increasing PA and reducing SB in vocational school students, and identify key processes explaining the results. TRIAL REGISTRATION: ISRCTN10979479 . Registered: 31.12.2015. PMID- 27229683 TI - An optimized protocol for generation and analysis of Ion Proton sequencing reads for RNA-Seq. AB - BACKGROUND: Previous studies compared running cost, time and other performance measures of popular sequencing platforms. However, comprehensive assessment of library construction and analysis protocols for Proton sequencing platform remains unexplored. Unlike Illumina sequencing platforms, Proton reads are heterogeneous in length and quality. When sequencing data from different platforms are combined, this can result in reads with various read length. Whether the performance of the commonly used software for handling such kind of data is satisfactory is unknown. RESULTS: By using universal human reference RNA as the initial material, RNaseIII and chemical fragmentation methods in library construction showed similar result in gene and junction discovery number and expression level estimated accuracy. In contrast, sequencing quality, read length and the choice of software affected mapping rate to a much larger extent. Unspliced aligner TMAP attained the highest mapping rate (97.27 % to genome, 86.46 % to transcriptome), though 47.83 % of mapped reads were clipped. Long reads could paradoxically reduce mapping in junctions. With reference annotation guide, the mapping rate of TopHat2 significantly increased from 75.79 to 92.09 %, especially for long (>150 bp) reads. Sailfish, a k-mer based gene expression quantifier attained highly consistent results with that of TaqMan array and highest sensitivity. CONCLUSION: We provided for the first time, the reference statistics of library preparation methods, gene detection and quantification and junction discovery for RNA-Seq by the Ion Proton platform. Chemical fragmentation performed equally well with the enzyme-based one. The optimal Ion Proton sequencing options and analysis software have been evaluated. PMID- 27229684 TI - Arterial adaptations to training among first time marathoners. AB - BACKGROUND: Exercise training favorably alters arterial anatomy in trained limbs, though the simultaneous effects on passively trained arteries are unclear. Thus, brachial (non-trained limb), popliteal (trained limb) and carotid total wall thickness (TWT), wall-to-lumen ratios (W:L), intima-media thickness (IMT) and lumen diameters (LD) were compared between experimental (n = 14) and control (n = 11) participants before and after the experimental participants participated in marathon training. METHODS: Arterial dimensions were measured with B-mode ultrasonography. Initial and final testing of VO2max and running speed at 3.5 mmol lactate were measured in the experimental group. RESULTS: VO2max was unchanged by training, but running speed at 3.5 mmol lactate increased by 5 % (p = .008). Time by group interactions were observed for the brachial and popliteal measures (p < 0.05), but not the carotid. No changes were observed in the control group. Prior to the intervention the experimental group had larger LD in the brachial (p = .002) and popliteal arteries (p = .007) than controls; no other pre testing differences were found. Following training, TWT declined in the brachial (pre = .99 +/- .16 mm; post = .84 +/- .10 mm; p = .007) and popliteal (pre = .96 +/- .09 mm; post = .86 +/- .11 mm; p = .005) arteries, characterized by a 0.07 mm decrease in brachial IMT (p = .032) and a non-significant 0.03 mm reduction in popliteal IMT. LD increased in the brachial (pre = 3.38 +/- .35 mm; post = 3.57 +/- .41 mm; p = .015) and popliteal (pre = 4.73 +/- .48 mm; post = 5.11 +/- .72 mm; p = .002) arteries. CONCLUSIONS: These data suggest that exercise-induced alterations in arterial dimensions occur in trained and non-trained limbs, and that adaptations may be dose dependent. PMID- 27229685 TI - Antibody response to pneumococcal and influenza vaccination in patients with rheumatoid arthritis receiving abatacept. AB - BACKGROUND: Patients with rheumatoid arthritis (RA), including those treated with biologics, are at increased risk of some vaccine-preventable infections. We evaluated the antibody response to standard 23-valent pneumococcal polysaccharide vaccine (PPSV23) and the 2011-2012 trivalent seasonal influenza vaccine in adults with RA receiving subcutaneous (SC) abatacept and background disease-modifying anti-rheumatic drugs (DMARDs). METHODS: Two multicenter, open-label sub-studies enrolled patients from the ACQUIRE (pneumococcal and influenza) and ATTUNE (pneumococcal) studies at any point during their SC abatacept treatment cycle following completion of >=3 months' SC abatacept. All patients received fixed dose abatacept 125 mg/week with background DMARDs. A pre-vaccination blood sample was taken, and after 28 +/- 3 days a final post-vaccination sample was collected. The primary endpoint was the proportion of patients achieving an immunologic response to the vaccine at Day 28 among patients without a protective antibody level to the vaccine antigens at baseline (pneumococcal: defined as >=2-fold increase in post-vaccination titers to >=3 of 5 antigens and protective antibody level of >=1.6 MUg/mL to >=3 of 5 antigens; influenza: defined as >=4-fold increase in post-vaccination titers to >=2 of 3 antigens and protective antibody level of >=1:40 to >=2 of 3 antigens). Safety and tolerability were evaluated throughout the sub-studies. RESULTS: Pre- and post-vaccination titers were available for 113/125 and 186/191 enrolled patients receiving the PPSV23 and influenza vaccine, respectively. Among vaccinated patients, 47/113 pneumococcal and 121/186 influenza patients were without protective antibody levels at baseline. Among patients with available data, 73.9 % (34/46) and 61.3 % (73/119) met the primary endpoint and achieved an immunologic response to PPSV23 or influenza vaccine, respectively. In patients with pre- and post-vaccination data available, 83.9 % in the pneumococcal study demonstrated protective antibody levels with PPSV23 (titer >=1.6 MUg/mL to >=3 of 5 antigens), and 81.2 % in the influenza study achieved protective antibody levels (titer >=1:40 to >=2 of 3 antigens) at Day 28 post-vaccination. Vaccines were well tolerated with SC abatacept with background DMARDs. CONCLUSIONS: In these sub-studies, patients with RA receiving SC abatacept and background DMARDs were able to mount an appropriate immune response to pneumococcal and influenza vaccines. TRIAL REGISTRATION: NCT00559585 (registered 15 November 2007) and NCT00663702 (registered 18 April 2008). PMID- 27229686 TI - Spread and establishment of Aedes albopictus in southern Switzerland between 2003 and 2014: an analysis of oviposition data and weather conditions. AB - BACKGROUND: The Asian tiger mosquito, Aedes albopictus, is a highly invasive mosquito species of public health importance. In the wake of its arrival in neighbouring Italy the authorities of the canton of Ticino in southern Switzerland initiated a surveillance programme in 2000 that is still on-going. Here we explored the unique data set, compiled from 2003 to 2014, to analyse the local dynamic of introduction and establishment of Ae. albopictus, its relative density in relation to precipitation and temperature, and its potential distribution at the passage from southern to northern Europe. METHODS: The presence of Ae. albopictus was recorded by ovitraps placed across Ticino. In addition to presence-absence, the relationship between relative egg densities and year, month, temperature and precipitation was analysed by a generalised linear mixed model. RESULTS: Since its first detection in 2003 at Ticino's border with Italy Ae. albopictus has continuously spread north across the lower valleys, mainly along the trans-European motorway, E35. Detailed local analysis showed that industrial areas were colonised by the mosquito before residential areas and that, afterwards, the mosquito was more present in residential than in industrial areas. Ae. albopictus appeared sporadically and then became more present in the same places the following years, suggesting gradual establishment of locally reproducing populations that manage to overwinter. This trend continues as witnessed by both a growing area being infested and increasing egg counts in the ovitraps. There was a clear South-North gradient with more traps being repeatedly positive in the South and fewer eggs laid during periods of intensive precipitation. In the North, the mosquito appeared repeatedly through the years, but never managed to establish, probably because of unfavourable weather conditions and low road traffic. CONCLUSIONS: Given the present results we assume that additional areas may still become infested. While the current study provides good estimates of relative egg densities and shows the local and regional dynamics of Ae. albopictus invasion, additional parameters ought to be measured to make an objective risk assessment for epidemic disease transmission. The likelihood of Ae. albopictus to further spread and increase in densities calls for continued surveillance. PMID- 27229688 TI - [Systemic mastocytosis: a heterogeneous disease]. AB - Systemic mastocytosis (SM) is an acquired myeloproliferative disease, which is caused by an uncontrolled proliferation of aberrant mast cells. SM patients can have very different clinical phenotypes and may therefore initially present to different specialties. Diagnosis is often delayed because many physicians are unfamiliar with this illness. This can lead to substantial morbidity and puts patients at risk of complications such as severe anaphylaxis. Measurement of serum tryptase levels is always a sensible first step in the diagnostic work-up, but a normal serum tryptase does not rule out SM completely, and a bone marrow biopsy is essential for a conclusive diagnosis. Here, we describe two patient cases to illustrate the heterogeneous nature of this disease, and provide an overview of the symptoms, diagnostic work-up and current treatments options for SM. PMID- 27229687 TI - Importance of hereditary and selected environmental risk factors in the etiology of inflammatory breast cancer: a case-comparison study. AB - BACKGROUND: To assess the importance of heredity in the etiology of inflammatory breast cancer (IBC), we compared IBC patients to several carefully chosen comparison groups with respect to the prevalence of first-degree family history of breast cancer. METHODS: IBC cases (n = 141) were compared to non-inflammatory breast cancer cases (n = 178) ascertained through George Washington University (GWU) with respect to the prevalence of first-degree family history of breast cancer and selected environmental/lifestyle risk factors for breast cancer. Similar comparisons were conducted with subjects from three case-control studies: breast cancer cases (n = 1145) and unaffected controls (n = 1142) from the Cancer Genetic Markers of Susceptibility (CGEMS) study, breast cancer cases (n = 465) and controls (n = 9317) from the Women's Health Initiative (WHI) study, and ovarian cancer cases (n = 260) and controls (n = 331) from a study by University of Toronto (UT). RESULTS: The frequency of first-degree breast cancer family history among IBC cases was 17.0 % compared to 24.4 % for GWU breast cancer cases, 23.9 % and 17.9 % for CGEMS breast cancer cases and controls, respectively, 16.9 % and 12.6 % for WHI breast cancer cases and controls, respectively, and 24.2 % and 11.2 % for UT ovarian cancer cases and controls, respectively. IBC cases had a significantly lower prevalence of parous women than WHI breast cancer cases (OR = 0.46, 95 % CI:0.27-0.81) and controls (OR = 0.31, 95 % CI:0.20-0.49). Oral contraceptive use was significantly higher among IBC cases compared to WHI breast cancer cases (OR = 7.77, 95 % CI:4.82-12.59) and controls (OR = 8.14, 95 % CI:5.28-12.61). IBC cases had a significantly higher frequency of regular alcohol consumption (>=1 drink per day) compared to WHI controls (OR = 1.84, 95 % CI:1.20-2.82) and UT controls (OR = 1.86, 95 % CI:1.07 3.22) and higher (statistically non-significant) prevalence (21.3 %) compared to breast cancer cases from GWU (18.2 %) and WHI (15.2 %). CONCLUSIONS: The prevalence of first-degree breast cancer family history among IBC cases was lower compared to breast and ovarian cancer cases but higher than unaffected individuals. Our multiple-case inflammatory and non-inflammatory breast cancer families may reflect aggregation of common genetic and/or environmental factors predisposing to both types of breast cancer. Our findings that oral contraceptive use and regular alcohol consumption may be associated with IBC warrant further investigations. PMID- 27229689 TI - [Acute appendicitis or colon cancer? Difference in elderly patients not always clear]. AB - Three elderly patients presented with acute abdominal pain in the right lower quadrant and leukocytosis. CT-imaging of the abdomen supported the suspicion of acute appendicitis. The patients underwent appendectomy. After pathological examination, two patients were found to have a colon carcinoma. The third patient had a normal appendix; however, adenocarcinoma of the cecum was found four weeks later. The patients underwent a second operation, a right hemicolectomy, within two months. In patients older than 65 years with symptoms of acute appendicitis, colon cancer should be considered in the differential diagnosis. Distinguishing between appendicitis and colon cancer based on clinical symptoms and imaging is difficult. However, this distinction is important for the prognosis and choice of surgical treatment. If no direct evidence of malignancy is present in elderly patients with symptoms of appendicitis, a colonoscopy should be performed postoperatively to exclude colon cancer. PMID- 27229690 TI - [A rare cause of abdominal pain in children]. AB - A 4-year-old boy was admitted to our hospital with abdominal pain, vomiting and weight loss. After a period of diarrhoea, he was now constipated. Micturition was painful but there were no abnormalities in the urine. Blood test showed no signs of infection or elevated liver enzymes. Signs of cholecystitis were seen on abdominal ultrasound, but this diagnosis was ignored because of the low incidence of cholecystitis in children and the absence of abnormal liver enzymes and infection parameters. Other diagnostic investigations were carried out, but no cause could be found for his symptoms. His condition worsened during the hospital stay, and liver enzymes and infection parameters became abnormal. An abdominal laparoscopy was finally performed, and a perforation in the presence of a necrotizing cholecystitis was seen. This case shows that one should never ignore a diagnostic report even if the diagnosis has low prevalence. PMID- 27229691 TI - [Extended abstractCutaneous Adverse Reactions to Tattoos]. AB - INTRODUCTION: Tattooing involves the introduction of exogenous pigment into the dermis. Worldwide, tattoos are one of the most popular forms of permanent body art. In the Netherlands, 8-10% of the population older than 12 years old has a tattoo. A wide variety of cutaneous adverse effects can occur in tattoos, these can cause serious symptoms. However, recognition and appropriate knowledge of diagnosis and treatment is still frequently insufficient in many medical practitioners. CASE DESCRIPTION: The first case concerns a 57-year-old female, who developed an itching swelling in the red part of a tattoo on the left arm. Histology of a punch biopsy showed a pseudolymphomatous reaction. This plaque like allergic reaction was successfully treated with intralesional injection of corticosteroids. CONCLUSION: Here we described four cases of cutaneous adverse reactions to tattoos. Allergic reactions in tattoos can present in a wide variety of clinical and histological patterns. The symptoms are often chronic itch and can appear weeks, months or years after placing the tattoo. Allergic reactions are uniformly manifested in one particular colour. Clinically, the reactions can present in a plaque-like, hyperkeratotic or rarely ulcerative or generalised reaction. In spite of changes to the compounds in tattoo inks, allergic reactions are still mostly observed to red ink. Treatment options are topical corticosteroids, intralesional injection of corticosteroids, laser treatment or dermatome shaving. PMID- 27229692 TI - [Health care usage by minimum income citizens in Amsterdam; a cross-sectional study into claims within the Dutch basic health insurance scheme]. AB - OBJECTIVE: Gaining more insight into any differences in care expenses between minimum and higher income groups. DESIGN: Cross-sectional study among 6,709 citizens of Amsterdam aged 19 years and over. METHOD: Data on declared health care expenses from 2012 were linked to personal income and to public health survey data. Through weighted logistic regression analysis, differences in expenses for primary care, hospital care, mental health care and other care were compared for minimum and higher income groups, controlling for demographic characteristics, educational level and health status. RESULTS: Minimum income groups claimed more often for mental health care costs (11%) than higher income groups (7%). However, after controlling for demographic characteristics, educational level and health status this difference was not significant. Further, minimum income groups claimed fewer expenses for hospital care, but this difference was not significant. The number of claims for other care did not differ. The size of the expenses differed between income groups. Expenses for primary care among minimum income groups were lower versus those for higher earners. Expenses for hospital care, mental health care and other care were higher, but not to a statistically significant level. CONCLUSION: Minimum income groups claim lower costs for primary care. On the other hand, the number of claims for mental health care, hospital care and other care is equal or higher than that of higher income citizens, as is the size of the claimed expenses. PMID- 27229693 TI - [Shock-induced ischemic optic neuropathy]. AB - BACKGROUND: Shock can lead to ischemic injury of organs. Ischemic injury of the optic nerve may even cause blindness. CASE DESCRIPTION: A 61-year-old female patient was admitted to ICU with septic shock. When recovering, she was only able to determine the difference between light and dark; before admission her vision was good. Ophthalmologic examination revealed slow pupillary reflexes and pale, atrophic optic discs. The diagnosis of bilateral shock-induced ischemic optic neuropathy was made. The patient was permanently blind and traumatised by her experiences during her hospital stay when her blindness was not yet recognised. CONCLUSION: Blindness caused by ischemic optic neuropathy is a rare and severe complication of shock that is usually irreversible. Early recognition is important in order to allow appropriate communication with, and approach of the patient to prevent traumatic experiences and promote rehabilitation. PMID- 27229694 TI - [Persistently elevated hepatic transaminases: a patient with late-onset Pompe disease]. AB - BACKGROUND: Pompe disease is a rare hereditary glycogen storage disease. Disease progression can be delayed by enzyme replacement therapy, which makes early identification important. Sometimes, the clinical presentation can be atypical, which may result in late recognition. CASE DESCRIPTION: A 23-year-old male presented with mild fatigue and persistently elevated liver transaminase levels. Biochemical, metabolic, viral, autoimmune, and toxicological examination, augmented with imaging and liver biopsy, initially did not result in a diagnosis. During follow-up, alongside the known liver test abnormalities, increased CK levels were observed. A muscle biopsy demonstrated abnormal glycogen accumulation, indicative of Pompe disease. CONCLUSION: Persistently elevated levels of transaminases are not limited to liver pathology. In patients with this phenomenon, one should also consider extrahepatic causes. PMID- 27229695 TI - [An infant with a black hairy tongue]. AB - At the outpatient clinic, an 8-month-old girl presented with a black hairy tongue. Since 2,5 weeks she used antibiotics because of osteomyelitis in her right humerus. There was no proper oral hygiene. She had no other complaints or abnormalities. The diagnosis 'lingua villosa nigra' was made. This is a benign, self-limiting disorder. PMID- 27229696 TI - [Guillain-Barre syndrome following infection with the Zika virus]. AB - BACKGROUND: Guillain-Barre syndrome (GBS) has been identified as a possible complication of infections with the Zika virus (ZIKV) in the current epidemic in Central and South America. Here we describe the first case of GBS in the Netherlands following a ZIKV infection. CASE DESCRIPTION: A 60-year-old woman presented with diarrhoea, fever and an unsteady gait after returning from Surinam. As creatine kinase levels were raised the initial diagnosis was rhabdomyolysis associated with myositis or medication use. However, creatine kinase levels normalized rapidly and the patient developed muscle weakness, sensory disturbances, hyporeflexia in her limbs and facial diplegia. The diagnosis GBS was considered, which was supported by spinal fluid investigation and electromyography. ZIKV was detected in serum and urine. The patient was treated with intravenous immunoglobulins, and recovered. CONCLUSION: This patient developed GBS following a recent ZIKV infection acquired in Suriname. A causal relation between ZIKV infection and GBS, however, has not yet been demonstrated. PMID- 27229697 TI - [A man with 2 painful feet]. AB - A 25-year-old man landed a jump with both feet against a vertical rock. He experienced a sharp pain in both ankles and was unable to walk without support. Active plantar flexion could not be performed and the Thompson test was abnormal. The diagnosis bilateral Achilles tendon rupture was made. PMID- 27229698 TI - [Orthopaedic surgeons can also treat their patients verbally: conservative treatment of osteoarthritis of the knee and hip using careful explanation]. AB - A recent study of factors that stimulate or hinder conservative treatment of osteoarthritis of the hip or knee concluded that orthopaedic surgeons' beliefs might obstruct application of conservative treatment. Orthopaedic surgeons, along with general practitioners, may play a key role in providing patient-specific conservative treatment. Patients who demand arthroplasty and who are not willing to try conservative treatment may be more problematic. An appreciable percentage of patients are not satisfied after total hip or total knee arthroplasty, so it is of the utmost importance that orthopaedic surgeons provide comprehensive information for all patients, including explaining potential complications and managing expectations. Orthopaedic surgeons should, therefore, treat patients both actively and conservatively. PMID- 27229699 TI - Mechanism of impaired microtubule-dependent peroxisome trafficking and oxidative stress in SPAST-mutated cells from patients with Hereditary Spastic Paraplegia. AB - Hereditary spastic paraplegia (HSP) is an inherited neurological condition that leads to progressive spasticity and gait abnormalities. Adult-onset HSP is most commonly caused by mutations in SPAST, which encodes spastin a microtubule severing protein. In olfactory stem cell lines derived from patients carrying different SPAST mutations, we investigated microtubule-dependent peroxisome movement with time-lapse imaging and automated image analysis. The average speed of peroxisomes in patient-cells was slower, with fewer fast moving peroxisomes than in cells from healthy controls. This was not because of impairment of peroxisome-microtubule interactions because the time-dependent saltatory dynamics of movement of individual peroxisomes was unaffected in patient-cells. Our observations indicate that average peroxisome speeds are less in patient-cells because of the lower probability of individual peroxisome interactions with the reduced numbers of stable microtubules: peroxisome speeds in patient cells are restored by epothilone D, a tubulin-binding drug that increases the number of stable microtubules to control levels. Patient-cells were under increased oxidative stress and were more sensitive than control-cells to hydrogen peroxide, which is primarily metabolised by peroxisomal catalase. Epothilone D also ameliorated patient-cell sensitivity to hydrogen-peroxide. Our findings suggest a mechanism for neurodegeneration whereby SPAST mutations indirectly lead to impaired peroxisome transport and oxidative stress. PMID- 27229700 TI - Clinical efficacy of modified partial pars plana vitrectomy combined with phacoemulsification for malignant glaucoma. AB - ObjectiveThe objective of this study was to evaluate the clinical effects of modified partial pars plana vitrectomy together with phacoemulsification, intraocular lens (IOL) implantation, posterior capsulectomy, and zonulohyaloidectomy for patients with malignant glaucoma after trabeculectomy or cataract surgery.DesignRetrospective, cohort study.ParticipantsThirty consecutive patients (30 eyes) with malignant glaucoma after trabeculectomy surgery or ultrasonic phacoemulsification of cataract between January 2008 and September 2014 were enrolled.MethodsA retrospective analysis of 30 eyes with malignant glaucoma after trabeculectomy surgery for angle-closure glaucoma or ultrasonic phacoemulsification of cataract was performed. All patients underwent modified partial pars plana vitrectomy with zonulohyaloidectomy. Phacoemulsification and IOL implantation was performed in 25 patients with no previous cataract surgery. Pre-operative and post-operative ocular parameters were recorded in detail.Main outcome measuresClinical features, anterior chamber depth, best-corrected visual acuity, and intraocular pressure (IOP).ResultsIn these 30 patients, 25 had undergone trabeculectomy surgery and 5 had undergone cataract surgery. The mean axial length was 21.3+/-0.8 mm. After surgery, mean IOP decreased from 34+/-8.3 mm Hg to 10.5+/-4.1 mm Hg (P<0.001), and mean anterior chamber depth increased from 0.8+/-0.4 mm to 2.7+/-0.3 mm (P<0.001). No severe complications occurred.ConclusionsModified partial pars plana vitrectomy combined with phacoemulsification, IOL implantation, posterior capsulectomy, and zonulohyaloidectomy not only simplifies the process of traditional vitrectomy, but effectively resolves the ciliary block and corrects the misdirection of aqueous humor in malignant glaucoma. PMID- 27229701 TI - Aflibercept in persistent neovascular AMD: comparison of different treatment strategies in switching therapy. AB - PurposeTo evaluate the effects of aflibercept administered according to a pro re nata (PRN) or Fixed Regimen to patients with neovascular AMD and persistent intraretinal/subretinal fluid (IRF/SRF) despite three consecutive ranibizumab injections.MethodsPatients were switched to aflibercept injection (IVA) administered according to a PRN or to a fixed regimen for 1 year in two different retina centers. At baseline each patient underwent a complete ophthalmologic evaluation, including best-corrected visual acuity assessment (BCVA ETDRS chart), fluorescein, and indocyanine green angiography and OCT.ResultsEach group included 36 eyes. After 1 year the PRN group showed BCVA stabilization (63 vs 60 letters, P=0.33), whereas fixed regimen group showed significant BCVA improvement (68 vs 71, P=0.008). The median central retinal thickness decreased by 94 MUm in the PRN (P=0.002) and by 148 MUm in the fixed regimen group (P<=0.001). Complete IRF/SRF reabsorption was found in 58% of eyes in the PRN and in 42% of eyes in the fixed regimen group. At 1-year visit, the percentage of eyes with pigment epithelium detachment did not significantly decrease, but a height reduction was recorded in both groups. The median number of IVA was 3.5 in the PRN and 7 in the fixed regimen group.ConclusionThe switch to aflibercept with both treatment strategies enabled improvement in morphological parameters and stabilization of visual acuity. BCVA improvement and reduction in vision loss with reduction in retinal thickness, fluid and PED height was achieved with the fixed regimen in previously treated nAMD after 1 year. PMID- 27229702 TI - Correlation between anterior chamber characteristics and laser flare photometry immediately after femtosecond laser treatment before phacoemulsification. AB - PurposeTo assess the anterior chamber (AC) characteristics and its correlation to laser flare photometry immediately after femtosecond laser-assisted capsulotomy and photodisruption.Patients and methodsThe study included 97 cataract eyes (n=97, mean age 68.6 years) undergoing femtosecond laser-assisted cataract surgery (FLACS). Three cohorts were analysed relating to the flare photometry directly post femtosecond laser treatment (flare <100 n=28, 69.6+/-7 years; flare 100-249 n=47, 67.7+/-8 years; flare >249 photon counts per ms cohort n=22, 68.5+/ 10 years). Flare photometry (KOWA FM-700), corneal topography (Oculus Pentacam, Germany: AC depth, volume, angle, pachymetry), axial length, pupil diameter, and endothelial cells were assessed before FLACS, immediately after femtosecond laser treatment and 1 day postoperative (LenSx Alcon, USA). Statistical data were analysed by SPSS v19.0, Inc.ResultsThe AC depth, AC volume, AC angle, central and thinnest corneal thickness showed a significant difference between flare <100 vs flare 100-249 10 min post femtosecond laser procedure (P=0.002, P=0.023, P=0.007, P=0.003, P=0.011, respectively). The AC depth, AC volume, and AC angle were significantly larger (P=0.001, P=0.007, P=0.003, respectively) in the flare <100 vs flare >249 cohort 10 min post femtosecond laser treatment.ConclusionsA flat AC, low AC volume, and a narrow AC angle were parameters associated with higher intraocular inflammation. These criteria could be used for patient selection in FLACS to reduce postoperative intraocular inflammation. PMID- 27229704 TI - Triple bottom line: sustainability in amblyopia care. PMID- 27229703 TI - Delayed vitreous haemorrhage after paediatric cataract surgery in Lowe syndrome. PMID- 27229705 TI - Rate of intraoperative complications during cataract surgery following intravitreal injections. AB - PurposeTo investigate the effect of prior intravitreal injections on intraoperative and postoperative complication rates associated with cataract surgery.MethodsA retrospective cohort analysis reviewed 10 105 cataract surgery procedures performed by experienced surgeons at the Duke Eye Center from 1 January 2005 to 10 December 2012. A group of 197 eyes with prior intravitreal injections was compared with an equal number of matched control eyes without prior injection using the Fisher's exact test of difference in proportions and the Wilcoxon rank-sum test of difference in means. Outcomes analyzed included baseline demographic information, preoperative clinical characteristics, prevalence of intraoperative complications, and postoperative intraocular pressure, glaucoma surgery, and glaucoma medication requirement through 1 year following cataract surgery.ResultsAn increased rate of intraoperative complications was identified during cataract surgery in eyes with prior intravitreal injections compared with control eyes (3 vs 0%, P=0.030). Injection eyes required more glaucoma medications at 1 year, but no difference was identified if steroid injections were excluded. No difference in postoperative IOP or glaucoma surgery was identified. No cases of endophthalmitis were reported.ConclusionsA history of intravitreal injections may be a risk factor for cataract surgery-related intraoperative complications. We hypothesize this may be due to unidentified iatrogenic lens trauma during intravitreal injections. Particular attention to the posterior capsule during preoperative assessment and intraoperatively is recommended in eyes undergoing cataract surgery with a prior history of intravitreal injections. PMID- 27229706 TI - Angle closure glaucoma in the Northern Ireland Diabetic Retinopathy Screening Programme. AB - PurposeTo ascertain the risk of angle closure glaucoma associated with mydriasis in the Northern Ireland Diabetic Retinopathy Screening Programme.MethodsA retrospective case note review was carried out, cross referencing hospital records with those of the screening programme, to identify episodes of angle closure glaucoma, which occurred within 14 days of a retinopathy screening episode involving pharmacological mydriasis.ResultsThree cases of angle closure following mydriasis for screening were identified. The incidence of angle closure within the screening programme was calculated to be 1 in 31 755 patients dilated or 0.75 patients per year.ConclusionAngle closure is a rare complication of mydriasis used in photographic screening for diabetic retinopathy. We advocate the provision of clear instructions to patients in screening programmes on when and how to access emergency ophthalmic care following dilation to prevent loss of vision in this rare event. PMID- 27229707 TI - Combination therapy of intravitreal bevacizumab with single simultaneous posterior subtenon triamcinolone acetonide for macular edema due to branch retinal vein occlusion. AB - PurposeTo evaluate efficacy and safety of combination therapy of intravitreal bevacizumab (IVB) with single simultaneous posterior subtenon triamcinolone acetonide (STA) for treatment of macular edema (ME) secondary to branch retinal vein occlusion (BRVO).MethodsThis was a prospective, randomized, interventional comparative study conducted in 45 eyes with ME secondary to BRVO who were treated primarily with IVB 1.25 mg (23 eyes, IVB group) or combination therapy of IVB 1.25 mg with a single simultaneous STA 40 mg (18 eyes, IVB/STA group). Reinjections were performed with IVB if optical coherence tomography (OCT) showed recurrent ME associated with decreased visual acuity. The main outcome measurement was the number of additional IVB injections, and changes of best corrected visual acuity (BCVA) and central macular thickness (CMT) during a 6 month follow-up period were compared.ResultsBCVA showed significant improvement in two groups at 6 months. In addition, CMT showed significant decrease in two groups at 6 months. No significant differences in the change of BCVA and CMT at 6 months after injection (P=0.973, P=0.639) were observed between the two groups. A statistically significant difference was found regarding the number of additional IVB injections (IVB group 0.96+/-0.83; IVB/STA group 0.44+/-0.70, P=0.034).ConclusionAlthough combination therapy of IVB with a single simultaneous STA for treatment of ME secondary to BRVO did not affect the visual outcomes compared with IVB monotherapy, it had a benefit of reducing the number of additional IVB injections. PMID- 27229708 TI - Variation in rod and cone density from the fovea to the mid-periphery in healthy human retinas using adaptive optics scanning laser ophthalmoscopy. AB - PurposeTo characterize the rod and cone photoreceptor mosaic at retinal locations spanning the central 60 degrees in vivo using adaptive optics scanning laser ophthalmoscopy (AO-SLO) in healthy human eyes.MethodsAO-SLO images (0.7 * 0.9 degrees ) were acquired at 680 nm from 14 locations from 30 degrees nasal retina (NR) to 30 degrees temporal retina (TR) in 5 subjects. Registered averaged images were used to measure rod and cone density and spacing within 60 * 60 MUm regions of interest. Voronoi analysis was performed to examine packing geometry at all locations.ResultsAverage peak cone density near the fovea was 164 000+/-24 000 cones/mm(2) and decreased to 6700+/-1500 and 5400+/-700 cones/mm(2) at 30 degrees NR and 30 degrees TR, respectively. Cone-to-cone spacing increased from 2.7+/-0.2 MUm at the fovea to 14.6+/-1.4 MUm at 30 degrees NR and 16.3+/-0.7 MUm at 30 degrees TR. Rod density peaked at 25 degrees NR (124 000+/-20 000 rods/mm(2)) and 20 degrees TR (120 000+/-12 000 rods/mm(2)) and decreased at higher eccentricities. Center-to-center rod spacing was lowest nasally at 25 degrees (2.1+/-0.1 MUm). Temporally, rod spacing was lowest at 20 degrees (2.2+/-0.1 MUm) before increasing to 2.3+/-0.1 MUm at 30 degrees TR.ConclusionsBoth rod and cone densities showed good agreement with histology and prior AO-SLO studies. The results demonstrate the ability to image at higher retinal eccentricities than reported previously. This has clinical importance in diseases that initially affect the peripheral retina such as retinitis pigmentosa. PMID- 27229710 TI - Renal atrophy after stereotactic body radiotherapy for renal cell carcinoma. AB - BACKGROUND: Renal atrophy is observed in an irradiated kidney. The aim of this study was to determine dose-volume histogram parameters and other factors that predict renal atrophy after 10-fraction stereotactic body radiotherapy (SBRT) for primary renal cell carcinoma (RCC). METHODS: A total of 14 patients (11 males, 3 females) who received SBRT for RCC at Tohoku University Hospital between April 2010 and February 2014 were analyzed. The median serum creatinine level was 1.1 mg/dl and two patients had a single kidney. Nine patients were implanted with fiducial markers. The median tumor diameter was 30 mm. SBRT was delivered at 70 Gy in 10 fractions for 7 tumors, at 60 Gy in 10 fractions for 2 tumors, and at 50 Gy in 10 fractions for 5 tumors with 6 and/or 15 MV X-ray using 5 to 8 multi static beams. Renal atrophy was assessed using post-SBRT CT images after 12-24 months intervals. Correlations were examined by Spearman rank correlation analysis. Differences between two groups were evaluated by the Mann-Whitney test, and pairwise comparisons were made by the Wilcoxon signed-rank test. RESULTS: The median tumor volume shrunk from 14.8 cc to 10.6 cc (p = 0.12), and the median irradiated kidney volume changed from 160.4 cc to 137.1 cc (p < .01). The median peak creatinine level was 1.6 mg/dl after treatment (p < .01). Percentage volumes of the irradiated kidney receiving at least 10 Gy (V10, p = 0.03), V20 (p < .01), V30(p < .01), V40 (p = 0.01), mean irradiated kidney dose (p < .01), and magnitude of overlap between PTV and kidney volume (p = 0.03) were significantly correlated with post-treatment irradiated kidney volume in percent, and V20-V30 had strong correlation (r < -0.70, p < .01). Patients with implanted fiducial markers showed a significantly lower ratio of renal atrophy (p = 0.02). CONCLUSIONS: Significant renal atrophic change was observed. Dose distribution of SBRT at 20-30 Gy had a strong correlation with renal atrophy when irradiation was performed in 10 fractions. PMID- 27229709 TI - Endoscopic mucosal resection (EMR) versus endoscopic submucosal dissection (ESD) for resection of large distal non-pedunculated colorectal adenomas (MATILDA trial): rationale and design of a multicenter randomized clinical trial. AB - BACKGROUND: Endoscopic mucosal resection (EMR) is currently the most used technique for resection of large distal colorectal polyps. However, in large lesions EMR can often only be performed in a piecemeal fashion resulting in relatively low radical (R0)-resection rates and high recurrence rates. Endoscopic submucosal dissection (ESD) is a newer procedure that is more difficult resulting in a longer procedural time, but is promising due to the high en-bloc resection rates and the very low recurrence rates. We aim to evaluate the (cost )effectiveness of ESD against EMR on both short (i.e. 6 months) and long-term (i.e. 36 months). We hypothesize that in the short-run ESD is more time consuming resulting in higher healthcare costs, but is (cost-) effective on the long-term due to lower patients burden, a higher number of R0-resections and lower recurrence rates with less need for repeated procedures. METHODS: This is a multicenter randomized clinical trial in patients with a non-pedunculated polyp larger than 20 mm in the rectum, sigmoid, or descending colon suspected to be an adenoma by means of endoscopic assessment. Primary endpoint is recurrence rate at follow-up colonoscopy at 6 months. Secondary endpoints are R0-resection rate, perceived burden and quality of life, healthcare resources utilization and costs, surgical referral rate, complication rate and recurrence rate at 36 months. Quality-adjusted-life-year (QALY) will be estimated taking an area under the curve approach and using EQ-5D-indexes. Healthcare costs will be calculated by multiplying used healthcare services with unit prices. The cost-effectiveness of ESD against EMR will be expressed as incremental cost-effectiveness ratios (ICER) showing additional costs per recurrence free patient and as ICER showing additional costs per QALY. DISCUSSION: If this trial confirms ESD to be favorable on the long-term, the burden of extra colonoscopies and repeated procedures can be prevented for future patients. TRIAL REGISTRATION: NCT02657044 (Clinicaltrials.gov), registered January 8, 2016. PMID- 27229711 TI - Restrictive influence of SAMHD1 on Hepatitis B Virus life cycle. AB - Deoxynucleotide triphosphates (dNTPs) are essential for efficient hepatitis B virus (HBV) replication. Here, we investigated the influence of the restriction factor SAMHD1, a dNTP hydrolase (dNTPase) and RNase, on HBV replication. We demonstrated that silencing of SAMHD1 in hepatic cells increased HBV replication, while overexpression had the opposite effect. SAMHD1 significantly affected the levels of extracellular viral DNA as well as intracellular reverse transcription products, without affecting HBV RNAs or cccDNA. SAMHD1 mutations that interfere with the dNTPase activity (D137N) or in the catalytic center of the histidine aspartate (HD) domain (D311A), and a phospho-mimetic mutation (T592E), abrogated the inhibitory activity. In contrast, a mutation diminishing the potential RNase but not dNTPase activity (Q548A) and a mutation disabling phosphorylation (T592A) did not affect antiviral activity. Moreover, HBV restriction by SAMHD1 was rescued by addition of deoxynucleosides. Although HBV infection did not directly affect protein level or phosphorylation of SAMHD1, the virus upregulated intracellular dATPs. Interestingly, SAMHD1 was dephosphorylated, thus in a potentially antiviral-active state, in primary human hepatocytes. Furthermore, SAMHD1 was upregulated by type I and II interferons in hepatic cells. These results suggest that SAMHD1 is a relevant restriction factor for HBV and restricts reverse transcription through its dNTPase activity. PMID- 27229712 TI - Altered heme-mediated modulation of dendritic cell function in sickle cell alloimmunization. AB - Transfusions are the main treatment for patients with sickle cell disease. However, alloimmunization remains a major life-threatening complication for these patients, but the mechanism underlying pathogenesis of alloimmunization is not known. Given the chronic hemolytic state characteristic of sickle cell disease, resulting in release of free heme and activation of inflammatory cascades, we tested the hypothesis that anti-inflammatory response to heme is compromised in alloimmunized sickle patients, increasing their risk of alloimmunization. Heme exposed monocyte-derived dendritic cells from both non-alloimmunized sickle patients and healthy donors inhibited priming of pro-inflammatory CD4(+) type 1 T cells, and exhibited significantly reduced levels of the maturation marker CD83. In contrast, in alloimmunized patients, heme did not reverse priming of pro inflammatory CD4(+) cells by monocyte-derived dendritic cells or their maturation. Furthermore, heme dampened NF-kappaB activation in non-alloimmunized, but not in alloimmunized monocyte-derived dendritic cells. Heme-mediated CD83 inhibition depended on Toll-like receptor 4 but not heme oxygenase 1. These data suggest that extracellular heme limits CD83 expression on dendritic cells in non alloimmunized sickle patients through a Toll-like receptor 4-mediated pathway, involving NF-kappaB, resulting in dampening of pro-inflammatory responses, but that in alloimmunized patients this pathway is defective. This opens up the possibility of developing new therapeutic strategies to prevent sickle cell alloimmunization. PMID- 27229713 TI - A randomized phase II trial of azacitidine +/- epoetin-beta in lower-risk myelodysplastic syndromes resistant to erythropoietic stimulating agents. AB - The efficacy of azacitidine in patients with anemia and with lower-risk myelodysplastic syndromes, if relapsing after or resistant to erythropoietic stimulating agents, and the benefit of combining these agents to azacitidine in this setting are not well known. We prospectively compared the outcomes of patients, all of them having the characteristics of this subset of lower-risk myelodysplastic syndrome, if randomly treated with azacitidine alone or azacitidine combined with epoetin-beta. High-resolution cytogenetics and gene mutation analysis were performed at entry. The primary study endpoint was the achievement of red blood cell transfusion independence after six cycles. Ninety eight patients were randomised (49 in each arm). Median age was 72 years. In an intention to treat analysis, transfusion independence was obtained after 6 cycles in 16.3% versus 14.3% of patients in the azacitidine and azacitidine plus epoetin beta arms, respectively (P=1.00). Overall erythroid response rate (minor and major responses according to IWG 2000 criteria) was 34.7% vs. 24.5% in the azacitidine and azacitidine plus epoetin-beta arms, respectively (P=0.38). Mutations of the SF3B1 gene were the only ones associated with a significant erythroid response, 29/59 (49%) versus 6/27 (22%) in SF3B1 mutated and unmutated patients, respectively, P=0.02. Detection of at least one "epigenetic mutation" and of an abnormal single nucleotide polymorphism array profile were the only factors associated with significantly poorer overall survival by multivariate analysis. The transfusion independence rate observed with azacitidine in this lower-risk population, but resistant to erythropoietic stimulating agents, was lower than expected, with no observed benefit of added epoetin, (clinicaltrials.gov identifier: 01015352). PMID- 27229714 TI - Characterization of leukemias with ETV6-ABL1 fusion. AB - To characterize the incidence, clinical features and genetics of ETV6-ABL1 leukemias, representing targetable kinase-activating lesions, we analyzed 44 new and published cases of ETV6-ABL1-positive hematologic malignancies [22 cases of acute lymphoblastic leukemia (13 children, 9 adults) and 22 myeloid malignancies (18 myeloproliferative neoplasms, 4 acute myeloid leukemias)]. The presence of the ETV6-ABL1 fusion was ascertained by cytogenetics, fluorescence in-situ hybridization, reverse transcriptase-polymerase chain reaction and RNA sequencing. Genomic and gene expression profiling was performed by single nucleotide polymorphism and expression arrays. Systematic screening of more than 4,500 cases revealed that in acute lymphoblastic leukemia ETV6-ABL1 is rare in childhood (0.17% cases) and slightly more common in adults (0.38%). There is no systematic screening of myeloproliferative neoplasms; however, the number of ETV6 ABL1-positive cases and the relative incidence of acute lymphoblastic leukemia and myeloproliferative neoplasms suggest that in adulthood ETV6-ABL1 is more common in BCR-ABL1-negative chronic myeloid leukemia-like myeloproliferations than in acute lymphoblastic leukemia. The genomic profile of ETV6-ABL1 acute lymphoblastic leukemia resembled that of BCR-ABL1 and BCR-ABL1-like cases with 80% of patients having concurrent CDKN2A/B and IKZF1 deletions. In the gene expression profiling all the ETV6-ABL1-positive samples clustered in close vicinity to BCR-ABL1 cases. All but one of the cases of ETV6-ABL1 acute lymphoblastic leukemia were classified as BCR-ABL1-like by a standardized assay. Over 60% of patients died, irrespectively of the disease or age subgroup examined. In conclusion, ETV6-ABL1 fusion occurs in both lymphoid and myeloid leukemias; the genomic profile and clinical behavior resemble BCR-ABL1-positive malignancies, including the unfavorable prognosis, particularly of acute leukemias. The poor outcome suggests that treatment with tyrosine kinase inhibitors should be considered for patients with this fusion. PMID- 27229715 TI - Immune thrombocytopenia in adults: a prospective cohort study of clinical features and predictors of outcome. AB - This prospective observational cohort study aimed to explore the clinical features of incident immune thrombocytopenia in adults and predictors of outcome, while determining if a family history of autoimmune disorder is a risk factor for immune thrombocytopenia. All adults, 18 years of age or older, recently diagnosed with immune thrombocytopenia were consecutively recruited across 21 hospital centers in France. Data were collected at diagnosis and after 12 months. Predictors of chronicity at 12 months were explored using logistic regression models. The association between family history of autoimmune disorder and the risk of developing immune thrombocytopenia was explored using a conditional logistic regression model after matching each case to 10 controls. One hundred and forty-three patients were included: 63% female, mean age 48 years old (Standard Deviation=19), and 84% presented with bleeding symptoms. Median platelet count was 10*10(9)/L. Initial treatment was required in 82% of patients. After 12 months, only 37% of patients not subject to disease-modifying interventions achieved cure. The sole possible predictor of chronicity at 12 months was a higher platelet count at baseline [Odds Ratio 1.03; 95%CI: 1.00, 1.06]. No association was found between outcome and any of the following features: age, sex, presence of either bleeding symptoms or antinuclear antibodies at diagnosis. Likewise, family history of autoimmune disorder was not associated with incident immune thrombocytopenia. Immune thrombocytopenia in adults has been shown to progress to a chronic form in the majority of patients. A lower platelet count could be indicative of a more favorable outcome. PMID- 27229716 TI - Outcomes of unrelated cord blood transplantation in patients with multiple myeloma: a survey on behalf of Eurocord, the Cord Blood Committee of Cellular Therapy and Immunobiology Working Party, and the Chronic Leukemia Working Party of the EBMT. AB - Although allogeneic stem cell transplantation is not a standard therapy for multiple myeloma, some patients can benefit from this intense therapy. There are few reports on outcomes after umbilical cord blood transplantation in multiple myeloma, and investigation of this procedure is warranted. We retrospectively analyzed 95 patients, 85 with multiple myeloma and 10 with plasma cell leukemia, receiving single or double umbilical cord blood transplantation from 2001 to 2013. Median follow up was 41 months. The majority of patients received a reduced intensity conditioning. The cumulative incidence of neutrophil engraftment was 97%+/-3% at 60 days, and that of 100-day acute graft-versus-host disease grade II IV was 41%+/-5%. Chronic graft-versus-host disease at two years was 22%+/-4%. Relapse and non-relapse mortality was 47%+/-5% and 29%+/-5% at three years, respectively. Three-year progression-free survival and overall survival were 24%+/-5% and 40%+/-5%, respectively. Anti-thymocyte globulin was associated with decreased incidence of acute graft-versus-host disease, higher non-relapse mortality, decreased overall and progression-free survival. Patients with high cytogenetic risk had higher relapse, and worse overall and progression-free survival. In conclusion, umbilical cord blood transplantation is feasible for multiple myeloma patients. PMID- 27229720 TI - DNA Methylation: An Epigenetic Insight into Type 2 Diabetes Mellitus. AB - DNA methylation, a major regulator of epigenetic modifications has been shown to alter the expression of genes that are involved in aspects of glucose metabolism such as glucose intolerance, insulin resistance, beta-cell dysfunction and other conditions, and it ultimately leads to the pathogenesis of type 2 diabetes mellitus (T2DM). Current evidences indicate an association of DNA methylation with T2DM. This review provides an overview of how various factors play crucial roles in T2DM pathogenesis and how DNA methylation interacts with these factors. Additionally, an update on current techniques of DNA methylation analysis with their pros and cons is provided as a basis for the adoption of suitable techniques in future DNA methylation research towards better management of T2DM. To elucidate the mechanistic relationship between vital environmental factors and the development of T2DM, a better understanding of the changes in gene expression associated with DNA methylation at the molecular level is still needed. PMID- 27229721 TI - Type 2 Diabetes Mellitus and Alzheimer's Disease: Bridging the Pathophysiology and Management. AB - Although type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are two independent diseases, evidences from epidemiological, pathophysiological and animal studies have indicated a close pathophysiological relationship between these diseases. Due to the pathophysiological similarity of T2DM and AD, which includes insulin resistance and deficiency, protein aggregation, oxidative stress, inflammation, autophagocytosis and advanced glycation end products; AD is often referred to as "type 3 diabetes". In addition to the targeted regimens usually used for treating T2DM and AD individually, currently, anti-diabetic drugs are successfully used to reduce the cognitive decline in AD patients. Therefore, if a common pathophysiology of T2DM and AD could be clearly determined, both diseases could be managed more efficiently, possibly by shared pharmacotherapy in addition to understanding the broader spectrum of preventive strategies. The aim of this review is to discuss the pathophysiological bridge between T2DM and AD to lay the foundation for the future treatment strategies in the management of both diseases. PMID- 27229719 TI - Expression Profiles of IGF-1R Gene and Polymorphisms of its Regulatory Regions in Different Pig Breeds. AB - Insulin like growth factor 1 receptor (IGF-1R) is a candidate gene for growth and carcass traits in regulating animal growth, metabolism and endocrine. It is widely expressed in liver, muscle, bone tissues where the IGF-1R functions as a factor that promotes cell growth. In this study, the protein expression level of IGF-1R gene in liver and muscle tissues of three periods (birth, weaning and adult) of three pig breeds (BamaXiang pigs (BM), Tibetan pigs (TM) and Junmu No.1 pigs (JM)) were tested by western blot. SNPs within the regulatory region of pig IGF-1R gene were detected using direct sequencing and then the genotypes were identified through AS-PCR approach. Results showed expression profiles of IGF-1R gene between liver and muscle tissues were different and significant differences were also found among pig breeds. In the same time, four SNPs were detected in the regulatory region of IGF-1R gene, among which the genotype frequency of three (g.-1468G > C, g.-1192 C > T and g.330,424 C > T) were significantly different among the pig breeds. BM tended to heterozygous (GC/CT) of the anterior two loci, while TM and JM preferred the other two homozygotes respectively. For the g.330,424 C > T, all pig breeds were tended to be the heterozygous. In conclusion, the SNPs with different genotype distribution among the three pig breeds may explain the gene expression difference between the different pig breeds. PMID- 27229722 TI - Antiphospholipid Antibody-Mediated Thrombotic Mechanisms in Antiphospholipid Syndrome: Towards Pathophysiology-Based Treatment. AB - Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by a persistently high titer of antiphospholipid antibodies (aPLs). In addition to pregnancy morbidity, arterial and/or venous thrombosis is another clinical feature of APS. Regardless of the type of APS, the thrombi formed by the induction of aPLs can lead to deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke and gangrene. Although the concept of APS was introduced approximately 32 years ago, its thrombogenic pathophysiology is still unclear. Therefore, patients are treated with anticoagulant and/or antiplatelet regimens just as in other thrombotic disorders even though the thrombotic pathophysiology is mainly aPLs-mediated. In this review, we provided an update of the cellular, auto-immune and genetic factors known to play important roles in the generation of thrombi. Current successful regimens are also outlined along with potential emerging treatment strategies that may lead to the optimum management of thrombotic APS patients. PMID- 27229723 TI - Difluorinated Curcumin: A Promising Curcumin Analogue with Improved Anti-Tumor Activity and Pharmacokinetic Profile. AB - BACKGROUND: Curcumin, a polyphenol from turmeric, is a dietary phytochemical with a diversity of health benefits including strong anti-tumor effects. Curcumin undergoes a rapid metabolism resulting in a low oral bioavailability. 3, 4 difluorobenzylidene curcumin or (CDF) is a novel fluorinated curcumin analogue which has been shown to be about 3 times more bioavailable than curcumin. This review aimed to summarize the findings of studies related to pharmacokinetic and pharmacological characteristics of CDF. METHODS: A systematic literature search was prformed in Scopus and Medline to identify all published articles dealing with CDF. RESULTS: Biodistribution assays have revealed that curcumin is mostly distributed to the heart and lung tissues while CDF is preferentially accumulated in pancreas where its tissue concentrations reach two folds higher than that of curcumin. Moreover, CDF has been reported to possess stronger cytotoxic effects compared with CMN in both monolayer and spheroid cultures of different tumor cell lines including chemo-resistant ones. CDF can promote tumor suppression through multiple mechanisms including inhibition of self-renewal capacity of cancer stem/stem-like cells, clonogenicity invasiveness and angiogenesis of tumor cells, while increasing the sensitivity of cells to chemotherapy. These effects are the results of the modulatory action of CDF on diverse targets, such as miRNAs (miR 21, miR-101, miR-210, miR34a and miR34c), PTEN, CD44, EGFR, EpCAM, EZH2, HIF 1alpha, and VEGF. CONCLUSION: This review presents an overview of the findings on metabolism and pharmacological activities of CDF, and also highlights potential opportunities to use this novel curcumin analogue in the treatment of cancer. PMID- 27229718 TI - APASL consensus statements and recommendations for hepatitis C prevention, epidemiology, and laboratory testing. AB - The Asian Pacific Association for the Study of the Liver (APASL) convened an international working party on "APASL consensus statements and recommendations for management of hepatitis C" in March 2015 to revise the "APASL consensus statements and management algorithms for hepatitis C virus infection" (Hepatol Int 6:409-435, 2012). The working party consisted of expert hepatologists from the Asian-Pacific region gathered at the Istanbul Congress Center, Istanbul, Turkey on 13 March 2015. New data were presented, discussed, and debated during the course of drafting a revision. Participants of the consensus meeting assessed the quality of the cited studies. The finalized recommendations for hepatitis C prevention, epidemiology, and laboratory testing are presented in this review. PMID- 27229724 TI - Novel zero-valent iron-assembled reactor for strengthening anammox performance under low temperature. AB - To further expand the application of anammox biotechnology, a novel zero-valent iron-assembled upflow anaerobic sludge bed reactor was employed to strengthen anammox performance under low temperature and shock load. Packed with sponge iron and polyester sponge, this novel reactor could speed up the recovery of anammox activity in 12 days and improve the adaptability of anammox bacteria at the temperature of 10-15 degrees C. The high nitrogen loading rate of 1109.2 mg N/L/day could be adapted in 27 days and the new nitrogen pathway under the effect of sponge iron was clarified by batch experiment. Moreover, the real-time quantitative PCR analysis and Illumina MiSeq sequencing verified the dominant status of Candidatus Kuenenia stuttgartiensis and planctomycete KSU-1, as well as demonstrated the positive role of sponge iron on anammox microorganisms' proliferation. The findings might be beneficial to popularize anammox-related processes in municipal and industrial wastewater engineering. PMID- 27229725 TI - Exploring the transferase activity of Ffase from Schwanniomyces occidentalis, a beta-fructofuranosidase showing high fructosyl-acceptor promiscuity. AB - The beta-fructofuranosidase from the yeast Schwanniomyces occidentalis (Ffase) produces the prebiotic sugars 6-kestose and 1-kestose by transfructosylation of sucrose, which makes it of biotechnological interest. In this study, the hydrolase and transferase activity of this enzyme was kinetically characterized and its potential to synthesize new fructosylated products explored. A total of 40 hydroxylated compounds were used as potential fructosyl-acceptor alternatives to sucrose. Only 17 of them, including some monosaccharides, disaccharides, and oligosaccharides as well as alditols and glycosides were fructosylated. The best alternative acceptors were the alditols. The major transfer product of the reaction including mannitol was purified and characterized as 1-O-beta-D fructofuranosyl-D-mannitol, whose maximum concentration reached 44 g/L, representing about 7.3 % of total compounds in the mixture and 89 % of all products generated by transfructosylation. The reactions including erythritol produced 35 g/L of an isomer mixture comprising 1- and 4-O-beta-D-fructofuranosyl D-erythritol. In addition, Ffase produced 24 g/L of the disaccharide blastose by direct fructosylation of glucose, which makes it the first enzyme characterized from yeast showing this ability. Thus, novel fructosylated compounds with potential applications in food and pharmaceutical industries can be obtained due to the Ffase fructosyl-acceptor promiscuity. PMID- 27229726 TI - The E. coli pET expression system revisited-mechanistic correlation between glucose and lactose uptake. AB - Therapeutic monoclonal antibodies are mainly produced in mammalian cells to date. However, unglycosylated antibody fragments can also be produced in the bacterium Escherichia coli which brings several advantages, like growth on cheap media and high productivity. One of the most popular E. coli strains for recombinant protein production is E. coli BL21(DE3) which is usually used in combination with the pET expression system. However, it is well known that induction by isopropyl beta-D-1-thiogalactopyranoside (IPTG) stresses the cells and can lead to the formation of insoluble inclusion bodies. In this study, we revisited the pET expression system for the production of a novel antibody single-chain variable fragment (scFv) with the goal of maximizing the amount of soluble product. Thus, we (1) investigated whether lactose favors the recombinant production of soluble scFv compared to IPTG, (2) investigated whether the formation of soluble product can be influenced by the specific glucose uptake rate (q s,glu) during lactose induction, and (3) determined the mechanistic correlation between the specific lactose uptake rate (q s,lac) and q s,glu. We found that lactose induction gave a much greater amount of soluble scFv compared to IPTG, even when the growth rate was increased. Furthermore, we showed that the production of soluble protein could be tuned by varying q s,glu during lactose induction. Finally, we established a simple model describing the mechanistic correlation between q s,lac and q s,glu allowing tailored feeding and prevention of sugar accumulation. We believe that this mechanistic model might serve as platform knowledge for E. coli. PMID- 27229727 TI - Fluoride and calcium concentrations in the biofilm fluid after use of fluoridated dentifrices supplemented with polyphosphate salts. AB - OBJECTIVES: The present study evaluated fluoride (F) and calcium (Ca) concentrations in the biofilm fluid formed in situ under cariogenic challenge after using F dentifrices supplemented or not with sodium trimetaphosphate (TMP) or calcium glycerophosphate (CaGP). METHODS: Volunteers (n = 12) were randomly divided into 5 groups according to the toothpastes used: placebo (without F, CaGP or TMP), 1100 ppm F (1100F) and low-fluoride dentifrice (LFD, 550 ppm F) with no supplementation (550F) or supplemented with 1 % TMP (550F-TMP) or 0.25 % CaGP (550F-CaGP). In each phase, volunteers wore palatal appliances containing 4 bovine enamel blocks. Cariogenic challenge was performed with 30 % sucrose solution, 6 times/day. On the morning of the eigth day, biofilm samples were collected 12 h and 1 h after brushing and cariogenic challenge. F and Ca analyses in the biofilm fluid were performed with the inverted electrode after buffering with TISAB III and using the Arsenazo III method, respectively. Data were submitted to two-way ANOVA (repeated measures) and Student-Newman-Keuls test (p < 0.05). RESULTS: A dose-response relationship was verified between F concentrations in the dentifrices and in the biofilm fluid. Significant differences were observed among placebo, 550F, and 1100F only 1 h after brushing, without statistical differences among 550F, 550F-TMP, and 550F-CaGP. No defined trend was observed among the groups regarding Ca concentrations, with the highest values seen for placebo and 550F-CaGP. CONCLUSION: The anticaries effect of LFDs supplemented with CaGP or TMP cannot be related to an increased availability of F and Ca in the biofilm fluid. CLINICAL SIGNIFICANCE: The better performance of LFDs containing CaGP or TMP shown in previous studies should be attributed to their ability to interact with tooth enamel and with the biofilm, rather to their effect on the biofilm fluid. PMID- 27229728 TI - Diagnosis of adverse events after hysterectomy with postoperative self-care web applications: A pilot study. AB - Increased pressures from multiple sources are leading to earlier patient discharge following surgery. Our objective was to test the feasibility of self care web applications to inform women if, when, and where to seek help for symptoms after hysterectomy. We asked 31 women recovering at home after hysterectomy at two centers to sign into a website on a schedule. For each session, the website informed them about normal postoperative symptoms and prompted them to complete an interactive symptom questionnaire that provided detailed information on flagged responses. We interviewed eight women who experienced an adverse event. Six of these women had used the web application regularly, each indicating they used the information to guide them in seeking care for their complications. These data support that self-care applications may empower patients to manage their own care and present to appropriate health care providers and venues when they experience abnormal symptoms. PMID- 27229729 TI - The psychosocial effect of web-based information in fast-track surgery. AB - The psychosocial effects of web-based information have yet to be tested for patients joining a fast-track total hip arthroplasty programme. This study compared and evaluated the psychosocial impact of standard total hip arthroplasty programme, with and without supplementation with a web-based information platform (E-total hip arthroplasty programme). Totally, 299 patients were enrolled in an un-controlled, before-and-after study, 117 in the S-total hip arthroplasty programme group and 182 in the E-total hip arthroplasty programme group. Psychosocial outcomes before and during admission and then 3 months post-surgery were evaluated, with analyses conducted between and within groups. All outcomes improved significantly from pre-admission to 3 months post-surgery, with no between-group differences. In all, 112 of the 182 E-total hip arthroplasty programme patients accessed the learning platform. A subgroup analysis showed no significant differences between users and non-users, either at baseline or in terms of outcome. This study found no positive psychosocial effect between groups, but a significant effect within groups. PMID- 27229730 TI - eHealth and the use of individually tailored information: A systematic review. AB - Tailored messages are those that specifically target individuals following an assessment of their unique characteristics. This systematic review assesses the evidence regarding the effectiveness of tailoring within eHealth interventions aimed at chronic disease management. OVID Medline/Embase databases were searched for randomised control trials, controlled clinical, trials, before -after studies, and time series analyses from inception - May 2014. Objectively measured clinical processes/outcomes were considered. Twenty-two papers were eligible for inclusion: 6/22 used fully tailored messaging and 16/22 used partially tailored messages. Two studies isolated tailoring as the active component. The remainder compared intervention with standard care. In all, 12/16 studies measuring clinical processes and 2/6 studies reporting clinical outcomes showed improvements, regardless of target group. Study quality was low and design did not allow for identification of interventions' active component. Heterogeneity precluded meta-analysis. This review has demonstrated that there is a lack of evidence to suggest that tailoring within an eHealth context confers benefit over non-tailored eHealth interventions. PMID- 27229731 TI - Significance of oral cancer-associated fibroblasts in angiogenesis, lymphangiogenesis, and tumor invasion in oral squamous cell carcinoma. AB - BACKGROUND: Cancer-associated fibroblasts (CAFs) are recognized as a pivotal promoter in cancer initiation and development. However, the role of CAFs in the progression and metastasis of oral squamous cell carcinoma (OSCC) has not been fully elucidated. MATERIALS AND METHODS: Lymphatic vessel density (LVD) and microvessel density (MVD) and the expression of alpha-smooth muscle actin (alpha SMA) and matrix metalloproteinase-9 (MMP-9) were evaluated by immunohistochemistry in 86 cases of OSCC. The correlations between alpha-SMA expression and MMP-9 expression, LVD, MVD, and other clinicopathological parameters were analyzed. In vitro invasion assay was performed to assess the effect of CAFs on the invasion of OSCC cells. We also investigated the effect of CAFs on the angiogenesis and lymphangiogenesis by inoculating CAFs with OSCC cells into nude mice subcutaneously. RESULTS: Positive expression of alpha-SMA protein was detected in 69.8% of the tumors. Increased alpha-SMA expression was correlated strongly with enhanced tumor invasion, higher tumor grade, increased risk of recurrence, lymph node involvement, and higher peritumoral lymphatic vessel density and microvessel density (P < 0.05). CAFs induced more cancer cells to invade relative to normal fibroblasts (NFs) (P < 0.05). Compared with co injection of OSCC cells and NFs or injection of tumor cells alone, co-injection of OSCC cells and CAFs resulted in earlier tumor formation and bigger tumor volume accompanied with increased angiogenesis and lymphangiogenesis (P < 0.05). CONCLUSION: CAFs may play critical roles in OSCC progression as an inducer of tumor invasion, angiogenesis, and lymphangiogenesis. Therapeutic strategies targeting CAFs against OSCC is promising and need further exploration. PMID- 27229732 TI - Overexpression of wheat gene TaMOR improves root system architecture and grain yield in Oryza sativa. AB - Improved root architecture is an effective strategy to increase crop yield. We demonstrate that overexpression of transcription factor gene MORE ROOT (TaMOR) from wheat (Triticum aestivum L.) results in more roots and higher grain yield in rice (Oryza sativa). TaMOR, encoding a plant-specific transcription factor belonging to the ASYMMETRIC LEAVES2/LATERAL ORGAN BOUNDARIES (AS2/LOB) protein family, is highly conserved in wheat and its wild relatives. In this study, tissue expression patterns indicated that TaMOR mainly localizes to root initiation sites. The consistent gene expression pattern suggests that TaMOR is involved in root initiation. Exogenous auxin treatment induced TaMOR expression without de novo protein biosynthesis. Both in vivo and in vitro experiments demonstrated that TaMOR interacts with TaMOR-related protein TaMRRP, which contains a four-tandem-pentatricopeptide repeat motif. Overexpression of TaMOR led to more lateral roots in Arabidopsis thaliana, and TaMOR-overexpressing rice plants had more crown roots, a longer main panicle, a higher number of primary branches on the main panicle, a higher grain number per plant, and higher yield per plant than the plants of wild type. In general, TaMOR-D-overexpressing lines had larger root systems in Arabidopsis and rice, and produce a higher grain yield per plant. TaMOR therefore offers an opportunity to improve root architecture and increase yield in crop plants. PMID- 27229733 TI - CLE peptides and their signaling pathways in plant development. AB - Cell-to-cell communication is crucial for the coherent functioning of multicellular organisms, and they have evolved intricate molecular mechanisms to achieve such communication. Small, secreted peptide hormones participate in cell to-cell communication to regulate various physiological processes. One such family of plant peptide hormones is the CLAVATA3 (CLV3)/EMBRYO SURROUNDING REGION related (CLE) family, whose members play crucial roles in the differentiation of shoot and root meristems. Recent biochemical and genetic studies have characterized various CLE signaling modules, which include CLE peptides, transmembrane receptors, and downstream intracellular signaling components. CLE signaling systems are conserved across the plant kingdom but have divergent modes of action in various developmental processes in different species. Moreover, several CLE peptides play roles in symbiosis, parasitism, and responses to abiotic cues. Here we review recent studies that have provided new insights into the mechanisms of CLE signaling. PMID- 27229734 TI - Shared and distinct functions of the pseudokinase CORYNE (CRN) in shoot and root stem cell maintenance of Arabidopsis. AB - Stem cell maintenance in plants depends on the activity of small secreted signaling peptides of the CLAVATA3/EMBRYO SURROUNDING REGION (CLE) family, which, in the shoot, act through at least three kinds of receptor complexes, CLAVATA1 (CLV1) homomers, CLAVATA2 (CLV2) / CORYNE (CRN) heteromers, and CLV1/CLV2/CRN multimers. In the root, the CLV2/CRN receptor complexes function in the proximal meristem to transmit signals from the CLE peptide CLE40. While CLV1 consists of an extracellular receptor domain and an intracellular kinase domain, CLV2, a leucine-rich repeat (LRR) receptor-like protein, and CRN, a protein kinase, have to interact to form a receptor-kinase complex. The kinase domain of CRN has been reported to be catalytically inactive, and it is not yet known how the CLV2/CRN complex can relay the perceived signal into the cells, and whether the kinase domain is necessary for signal transduction at all. In this study we show that the kinase domain of CRN is actively involved in CLV3 signal transduction in the shoot apical meristem of Arabidopsis, but it is dispensable for CRN protein function in root meristem maintenance. Hence, we provide an example of a catalytically inactive pseudokinase that is involved in two homologous pathways, but functions in distinctively different ways in each of them. PMID- 27229735 TI - Answer to: Micronutrient Supplementation after Biliopancreatic Diversion with Duodenal Switch in the Long Term: Using Refill Bypass Is the Solution. PMID- 27229736 TI - Understanding the Capacity for Exercise in Post-Bariatric Patients. AB - PURPOSE: The aim of this study is to conduct a pilot randomized trial testing an exercise program specifically adapted for post-bariatric patients. METHODS: A total of 51 post-bariatric patients, 6-24 months post-surgery, were randomly assigned to usual care control (n = 25) or the exercise intervention (n = 26). The intervention included twice weekly 60-min group exercise classes with functional strength, flexibility, and aerobic activities; at least 3 days per week of self-directed exercise; daily pedometer; recording of steps and activities; and weekly telephone counseling. There was also a 6-month maintenance period. RESULTS: Patients were 49 +/- 12 years old, 84 % female, 59 % non Hispanic white, with a BMI of 32.9 +/- 5.7 kg/m2 and percent excess BMI loss since surgery of 56 +/- 35 %. Patients were 14 +/- 5 months post-surgery. A total of 44 patients (86 %) completed both phases of the program and all assessments. The following measures improved significantly for intervention participants with no significant change in control participants: yards walked in 6 min, seconds for 8-foot up-and-go, number of arm curls, and distance in inches for chair sit-and reach. Intervention changes remained after 6 months of maintenance. CONCLUSIONS: When compared to patients in usual care, a specially adapted exercise program for post-bariatric patients resulted in significant improvements in objectively monitored health outcomes. This program was delivered in a clinical setting and could be implemented in a variety of settings to improve health outcomes for post bariatric patients. PMID- 27229737 TI - Weight gain in anorexia nervosa does not ameliorate the faecal microbiota, branched chain fatty acid profiles, and gastrointestinal complaints. AB - The gut microbiota not only influences host metabolism but can also affect brain function and behaviour through the microbiota-gut-brain axis. To explore the potential role of the intestinal microbiota in anorexia nervosa (AN), we comprehensively investigated the faecal microbiota and short-chain fatty acids in these patients before (n = 55) and after weight gain (n = 44) in comparison to normal-weight participants (NW, n = 55) along with dietary intake and gastrointestinal complaints. We show profound microbial perturbations in AN patients as compared to NW participants, with higher levels of mucin-degraders and members of Clostridium clusters I, XI and XVIII and reduced levels of the butyrate-producing Roseburia spp. Branched-chain fatty acid concentrations, being markers for protein fermentation, were elevated. Distinct perturbations in microbial community compositions were observed for individual restrictive and binge/purging AN-subtypes. Upon weight gain, microbial richness increased, however perturbations in intestinal microbiota and short chain fatty acid profiles in addition to several gastrointestinal symptoms did not recover. These insights provide new leads to modulate the intestinal microbiota in order to improve the outcomes of the standard therapy. PMID- 27229738 TI - An osteoarthritis triple play. PMID- 27229739 TI - A mathematical model for the simulation of the formation and the subsequent regression of hypertrophic scar tissue after dermal wounding. AB - A continuum hypothesis-based model is presented for the simulation of the formation and the subsequent regression of hypertrophic scar tissue after dermal wounding. Solely the dermal layer of the skin is modeled explicitly and it is modeled as a heterogeneous, isotropic and compressible neo-Hookean solid. With respect to the constituents of the dermal layer, the following components are selected as primary model components: fibroblasts, myofibroblasts, a generic signaling molecule and collagen molecules. A good match with respect to the evolution of the thickness of the dermal layer of scars between the outcomes of simulations and clinical measurements on hypertrophic scars at different time points after injury in human subjects is demonstrated. Interestingly, the comparison between the outcomes of the simulations and the clinical measurements demonstrates that a relatively high apoptosis rate of myofibroblasts results in scar tissue that behaves more like normal scar tissue with respect to the evolution of the thickness of the tissue over time, while a relatively low apoptosis rate results in scar tissue that behaves like hypertrophic scar tissue with respect to the evolution of the thickness of the tissue over time. Our ultimate goal is to construct models with which the properties of newly generated tissues that form during wound healing can be predicted with a high degree of certainty. The development of the presented model is considered by us as a step toward their construction. PMID- 27229741 TI - Home run for integrated primary care? PMID- 27229740 TI - Effect of the Interaction of Veratrum Nigrum with Panax Ginseng on Estrogenic Activity In Vivo and In Vitro. AB - Panax ginseng (GS) and Veratrum nigrum (VN) are representative of incompatible pairs in "eighteen antagonistic medicaments" that have been recorded in the Chinese medicinal literature for over 2,000 years. However, evidence linking interference effects with combination use is scare. Based on the estrogen-like effect of GS described in our previous studies, we undertake a characterization of the interaction on estrogenic activity of GS and VN using in vivo models of immature and ovariectomized (OVX) mice and in vitro studies with MCF-7 cells for further mechanism. VN decreased the estrogenic efficacy of GS on promoting the development of the uterus and vagina in immature mice, and reversing the atrophy of reproductive tissues in OVX mice. VN interfered with the estrogenic efficacy of GS by decreasing the increase of the serum estradiol and the up-regulation of ERalpha and ERbeta expressions by treatment with GS. And VN antagonized the estrogenic efficacy of GS on promoting the viability of MCF-7 cells and up regulation of protein and gene expressions of ERs. In conclusion, this study provided evidence that GS and VN decreased effects on estrogenic activity, which might be related to regulation of estrogen secretion and ERs. PMID- 27229742 TI - A Phase II Study of Third-Line Combination Chemotherapy with Bevacizumab Plus S-1 for Metastatic Colorectal Cancer with Mutated KRAS (SAVIOR Study). AB - OBJECTIVE: No salvage treatment had been established for metastatic colorectal cancer (mCRC) with mutated KRAS before the emergence of the new drugs regorafenib and TAS-102. We performed a phase II study of third-line chemotherapy with combined bevacizumab and S-1 for mCRC. METHODS: Subjects were mCRC patients with mutated KRAS who showed disease aggravation even after two regimens with oxaliplatin and irinotecan. Bevacizumab was given intravenously every 2 weeks, and S-1 was administered orally on days 1-28 of a 42-day cycle. The primary endpoint was disease control rate (DCR). RESULTS: In total, 31 subjects were enrolled between August 2009 and June 2011. Three subjects in whom antitumor effects could not be evaluated were excluded. The median follow-up period was 8.6 months. The DCR was 67.9%, the response rate 0%, median progression-free survival 3.7 months, and overall survival 8.6 months. In 30 subjects evaluated for safety, there was no treatment-related death. The most common adverse events were anorexia (grade >=3, 20%), diarrhea (grade 3, 10%), and decreased hemoglobin (grade >=3, 17%). CONCLUSIONS: The results suggest that third-line chemotherapy with combined bevacizumab and S-1 is safe and may delay the progression of mCRC resistant to oxaliplatin and irinotecan with mutated KRAS. PMID- 27229743 TI - Defining and estimating causal direct and indirect effects when setting the mediator to specific values is not feasible. AB - Natural direct and indirect effects decompose the effect of a treatment into the part that is mediated by a covariate (the mediator) and the part that is not. Their definitions rely on the concept of outcomes under treatment with the mediator 'set' to its value without treatment. Typically, the mechanism through which the mediator is set to this value is left unspecified, and in many applications, it may be challenging to fix the mediator to particular values for each unit or patient. Moreover, how one sets the mediator may affect the distribution of the outcome. This article introduces 'organic' direct and indirect effects, which can be defined and estimated without relying on setting the mediator to specific values. Organic direct and indirect effects can be applied, for example, to estimate how much of the effect of some treatments for HIV/AIDS on mother-to-child transmission of HIV infection is mediated by the effect of the treatment on the HIV viral load in the blood of the mother. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27229744 TI - Dexamethasone Is One of the Factors Minimizing the Inner Ear Damage from Electrode Insertion in Cochlear Implantation. AB - The aim of this study was to investigate the efficacy of preoperative and intraoperative steroid administration for inner ear protection in cochlear implantation (CI). Nineteen subjects who underwent CI were included in the study, and 10 subjects were enrolled as controls (steroid-administered group, n = 19; control group, n = 10). Dexamethasone (dexamethasone sodium phosphate, 5 mg/ml) was systemically administered preoperatively (1 ml) and topically applied during CI (0.5 ml). The extent of hearing preservation (HP) after CI and the change in the bithermal caloric response were evaluated. Hearing level was calculated using mean thresholds [(250 Hz + 500 Hz + 1,000 Hz + 2,000 Hz)/4]. Preoperative hearing thresholds were similar in the steroid-administered and control groups (100.92 +/ 12.60 vs. 103.29 +/- 14.39 dB, p = 0.650). The mean thresholds significantly increased in both groups after surgery (108.46 +/- 14.08 dB, p = 0.006, for the steroid-administered group; 117.50 +/- 6.34 dB, p = 0.027, for the control group), and the difference between the groups was also significant (p = 0.027). The postoperative shift in the hearing thresholds at frequencies of 500 and 1,000 Hz was significant in the steroid-administered group and that at the frequencies of 500, 1,000 and 2,000 Hz was significant in the control group. However, the extent of the shift in hearing threshold levels at each frequency was not significantly different between the groups. Preservation of hearing thresholds was compared between the groups, and there were significantly more subjects with complete and partial HP in the steroid-administered group than in the control group (p = 0.008). The preoperative caloric response was maintained after CI in the steroid-administered group. This study suggests that the perioperative use of a steroid could minimize the inner ear damage after CI. PMID- 27229746 TI - Life-threatening angio-oedema after the first dose of an ACE inhibitor-not an anaphylactic reaction. AB - We present a case of a 60-year-old Caucasian woman, with no prior history of swellings, who was admitted to a hospital due to life-threatening angio-oedema. She had, the previous day, been prescribed an ACE inhibitor for her essential hypertension. She had taken one tablet at night-time, and awoke in the morning with a swollen face progressing to involve the tongue and throat within a few hours. On arrival at her doctor's office, her voice had altered. Corticosteroids and antihistamine were administered while awaiting an ambulance. Arriving at the emergency department, she had dyspnoea due to increasingly severe angio-oedema of the upper airways. Neither adrenaline inhalations, intravenously administrated corticosteroids, atropine nor furosemide were effective and the patient soon become bradycardic. A tracheotomy was performed and the patient was placed on a ventilator. She eventually made a full recovery. It was concluded that she had suffered from life-threatening angio-oedema due to her new medication. PMID- 27229745 TI - Cancer Treatment with Anti-PD-1/PD-L1 Agents: Is PD-L1 Expression a Biomarker for Patient Selection? AB - Strategies to help improve the efficacy of the immune system against cancer represent an important innovation, with recent attention having focused on anti programmed death (PD)-1/PD-ligand 1 (L1) monoclonal antibodies. Clinical trials have shown objective clinical activity of these agents (e.g., nivolumab, pembrolizumab) in several malignancies, including melanoma, non-small-cell lung cancer, bladder cancer, squamous head and neck cancer, renal cell cancer, ovarian cancer, microsatellite-unstable colorectal cancer, and Hodgkin's lymphoma. Expression of PD-L1 in the tumor microenvironment appears to be crucial for therapeutic activity, and initial trials suggested positive PD-L1 tumor expression was associated with higher response rates. However, subsequent observations have questioned the prospect of using PD-L1 expression as a biomarker for selecting patients for therapy, especially since many patients considered PD-L1-negative experience a benefit from treatment. Importantly, there is not yet a definitive test for determination of PD-L1 and a cut-off reference for PD-L1-positive status has not been established. Immunohistochemistry with different antibodies and different thresholds has been used to define PD-L1 positivity (1-50 %), with no clear superiority of one threshold over another for identifying which patients respond. Moreover, the type of cells on which PD-L1 expression is most relevant is not yet clear, with immune infiltrate cells and tumor cells both being used. In conclusion, while PD-L1 expression is often a predictive factor for treatment response, it must be complemented by other biomarkers or histopathologic features, such as the composition and amount of inflammatory cells in the tumor microenvironment and their functional status. Multi-parameter quantitative or semi-quantitative algorithms may become useful and reliable tools to guide patient selection. PMID- 27229747 TI - Sigmoid volvulus: an uncommon complication of Hirschsprung's disease. AB - Sigmoid volvulus is a rare and potentially life-threatening condition that is usually seen in adults, however, when diagnosed in children, it is often associated with Hirschsprung's disease (HD). We report a case of an 11-year-old boy who presented with a history of constipation since 1.5 months of age, with acute onset of severe abdominal pain and marked distention of the abdomen. Sigmoid volvulus was suspected, detected and successfully managed with resection of the sigmoid colon and primary Scott Boley's pull-through. This report underscores the importance of suspecting sigmoid volvulus in the pertinent clinical setting; also, a primary definitive procedure can be performed in select cases. PMID- 27229748 TI - Percutaneous transcatheter embolisation of active haemorrhage following radiofrequency ablation of hepatocellular carcinoma. AB - A 72-year-old woman with hepatitis C virus cirrhosis underwent a surveillance ultrasound examination which identified a new hepatic lesion. A workup triphasic CT examination demonstrated a 3.7 cm lesion at the hepatic dome with arterial enhancement and portal venous washout consistent with hepatocellular carcinoma. She subsequently proceeded for treatment with radiofrequency ablation (RFA). RFA was technically successful, but the patient became hypotensive and tachycardic postprocedure. A CT angiogram demonstrated active arterial intraperitoneal haemorrhage from the RFA site. The patient returned to the interventional suite for catheter angiography which confirmed the presence of active haemorrhage from the hepatic arterial branch supplying segment VIII. The bleeding vessel was selectively catheterised with a microcatheter, and successfully embolised with 250-355 um polyvinyl alcohol particles. PMID- 27229749 TI - Two similar cases of elderly women with moderate abdominal pain and pneumoperitoneum of unknown origin: a surgeon's successful conservative management. AB - Patients presenting with abdominal pain and pneumoperitoneum in radiological examination usually require emergency explorative laparoscopy or laparotomy. Pneumoperitoneum mostly associates with gastrointestinal perforation. There are very few cases where surgery can be avoided. We present 2 cases of pneumoperitoneum with unknown origin and successful conservative treatment. Both patients were elderly women presenting to our emergency unit, with moderate abdominal pain. There was neither medical intervention nor trauma in their medical history. Physical examination revealed mild abdominal tenderness, but no clinical sign of peritonitis. Cardiopulmonary examination remained unremarkable. Blood studies showed only slight abnormalities, in particular, inflammation parameters were not significantly increased. Finally, obtained CTs showed free abdominal gas of unknown origin in both cases. We performed conservative management with nil per os, nasogastric tube, total parenteral nutrition and prophylactic antibiotics. After 2 weeks, both were discharged home. PMID- 27229750 TI - Pulmonary function tests, interstitial lung disease and lung function decline in outpatients with classic and clinically amyopathic dermatomyositis. PMID- 27229751 TI - Corosolic acid inhibits the proliferation of glomerular mesangial cells and protects against diabetic renal damage. AB - Diabetic nephropathy (DN) is one of the major complications of diabetes mellitus (DM). This study aimed to explore the effects of corosolic acid (CA) on the renal damage of DM and the mechanisms behind these effects. The renoprotective effect of CA was investigated in type 1 diabetic rats and db/db mice. The kidneys and glomerular mesangial cells (GMCs) were used to study the proliferation of GMCs by immunostaining and MTT assay. Further immunoblotting, siRNA, qPCR analysis, and detecting of NADPH oxidase activity and reactive oxygen species (ROS) generation were performed to explore relevant molecular mechanisms. In CA-treated diabetic animals, diabetes-induced albuminuria, increased serum creatinine and blood urea nitrogen were significantly attenuated, and glomerular hypertrophy, mesangial expansion and fibrosis were ameliorated. Furthermore, CA significantly inhibited proliferation of GMCs and phosphorylation of ERK1/2 and p38 MAPK in both diabetic animals and high glucose (HG)-induced GMCs. CA also normalized Deltapsim and inhibited HG-induced NADPH oxidase activity, ROS generation and NOX4, NOX2, p22(phox) and p47(phox) expression. More importantly, CA inhibited GMC proliferation mediated by NADPH/ERK1/2 and p38 MAPK signaling pathways. These findings suggest that CA exert the protective effect on DN by anti-proliferation resulted from inhibition of p38 MAPK- and NADPH-mediated inactivation of ERK1/2. PMID- 27229752 TI - A Critical Look at Entropy-Based Gene-Gene Interaction Measures. AB - Several entropy-based measures for detecting gene-gene interaction have been proposed recently. It has been argued that the entropy-based measures are preferred because entropy can better capture the nonlinear relationships between genotypes and traits, so they can be useful to detect gene-gene interactions for complex diseases. These suggested measures look reasonable at intuitive level, but so far there has been no detailed characterization of the interactions captured by them. Here we study analytically the properties of some entropy-based measures for detecting gene-gene interactions in detail. The relationship between interactions captured by the entropy-based measures and those of logistic regression models is clarified. In general we find that the entropy-based measures can suffer from a lack of specificity in terms of target parameters, i.e., they can detect uninteresting signals as interactions. Numerical studies are carried out to confirm theoretical findings. PMID- 27229753 TI - 2-D steering and propelling of acoustic bubble-powered microswimmers. AB - This paper describes bi-directional (linear and rotational) propelling and 2-D steering of acoustic bubble-powered microswimmers that are achieved in a centimeter-scale pool (beyond chip level scale). The core structure of a microswimmer is a microtube with one end open in which a gaseous bubble is trapped. The swimmer is propelled by microstreaming flows that are generated when the trapped bubble is oscillated by an external acoustic wave. The bubble oscillation and thus propelling force are highly dependent on the frequency of the acoustic wave and the bubble length. This dependence is experimentally studied by measuring the resonance behaviors of the testing pool and bubble using a laser Doppler vibrometer (LDV) and by evaluating the generated streaming flows. The key idea in the present 2-D steering is to utilize this dependence. Multiple bubbles with different lengths are mounted on a single microswimmer with a variety of arrangements. By controlling the frequency of the acoustic wave, only frequency-matched bubbles can strongly oscillate and generate strong propulsion. By arranging multiple bubbles of different lengths in parallel but with their openings opposite and switching the frequency of the acoustic wave, bi directionally linear propelling motions are successfully achieved. The propelling forces are calculated by a CFD analysis using the Ansys Fluent(r) package. For bi directional rotations, a similar method but with diagonal arrangement of bubbles on a rectangular swimmer is also applied. The rotation can be easily reversed when the frequency of the acoustic wave is switched. For 2-D steering, short bubbles are aligned perpendicular to long bubbles. It is successfully demonstrated that the microswimmer navigates through a T-junction channel under full control with and without carrying a payload. During the navigation, the frequency is the main control input to select and resonate targeted bubbles. All of these operations are achieved by a single piezoelectric actuator. PMID- 27229754 TI - Comment on "Evaluation of the Choroid, Fovea, and Retinal Nerve Fiber Layer in Patients with Rheumatoid Arthritis". PMID- 27229755 TI - Assessment of the impact of Aluminum on germination, early growth and free proline content in Lactuca sativa L. AB - Aluminum (Al) toxicity is a major problem in crop production on acid soils. The use of industrial or municipal wastewaters, which may be contaminated with metals, for irrigation in agriculture is common over the world. This action can increase the concentration of these agents in the soil and decrease crops yields. In order to evaluate the toxicological effects of recommended Al levels in irrigation water, under acidic conditions, on lettuce, seeds of two cultivars ("cv Reine de Mai" and "cv White Boston") were exposed to five different Al concentrations (0, 0.05, 0.5, 5 and 20mg/L) and germination percentage, root and shoot lengths were measured. Also, the germination rate and the vigor index were calculated, and the proline content was estimated for all concentrations. Results showed that seed germination was not negatively affected by Al, but the germination rate decreased in both cultivars. For the other factors analyzed, with the exception of 20mg/L concentration for "cv White Boston", Al induced, in general, negative effects including the content of proline that increased in the seeds that were exposed to this metal. The "cv Reine de Mai" was more sensitive for the analyzed concentrations than the other cultivar.. The results indicated that even recommended Al concentrations for irrigation, under acidic conditions, can interfere negatively in seed germination and seedling establishment and possibly with crop production. PMID- 27229756 TI - Changes in choroidal thickness after vitrectomy for epiretinal membrane combined with vitreomacular traction. AB - PURPOSE: To compare choroidal thickness after vitrectomy between epiretinal membrane (ERM) with and without vitreomacular traction (VMT). METHODS: In this retrospective study, 228 consecutive participants with ERM who underwent vitrectomy were categorized into two groups according to the presence of VMT on spectral domain-optical coherence tomography: VMT group (ERM with VMT, n = 21) and non-VMT group (ERM without VMT, n = 207). The primary outcome was the mean subfoveal choroidal thickness (SFCT) at baseline, and at 3 and 6 months postsurgery. RESULTS: At baseline, the prevalence of VMT in eyes with ERM was 9.6% (21/228), and mean SFCT was greater in the VMT than in the non-VMT group (270.3 +/- 93.4 vs. 223.7 +/- 82.1 MUm; p = 0.015). After surgery, mean SFCT decreased in the VMT group (241.7 +/- 92.3 MUm at 3 months and 228.8 +/- 86.4 MUm at 6 months; p < 0.001), but remained unchanged in the non-VMT group (223.6 +/- 78.9 MUm at 3 months and 223.3 +/- 82.6 MUm at 6 months; p = 0.696). There were no differences in mean SFCT between the groups at 3 and 6 months after surgery (p = 0.339 and p = 0.772, respectively). CONCLUSION: Choroidal thickness was greater in ERM eyes with than without VMT possibly due to direct anteroposterior traction on the retina and choroid, increased vascular endothelial growth factor associated with stress on retinal pigment epithelial cells and inflammation. After vitrectomy, mean SFCT reduced in the eyes with VMT, but not in those without VMT. PMID- 27229757 TI - Intrathyroidal oxyphilic parathyroid carcinoma: A potential diagnostic caveat in cytology? AB - Oxyphilic (oncocytic) parathyroid lesions are very uncommon and their cytological features are rarely described. Due to the similarities in anatomical location and indistinguishable cytomorphological features, these lesions are easily confused with neoplastic and non-neoplastic thyroid lesions on fine needle aspiration (FNA). The diagnosis becomes more challenging in cases of unusual intrathyroidal location of the parathyroid lesions in the absence of clinical evidence of hyperparathyroidism, which simulate thyroid nodules clinically. We describe a case of intrathyroidal oxyphilic parathyroid carcinoma in a 66-year-old female, who presented with a dominant left "thyroid" nodule. FNA smears were cellular, comprising predominantly of oxyphilic cells arranged in papillary-like architecture with occasional nuclear grooves, which was mistaken for oncocytic variant of papillary carcinoma of the thyroid. The histological diagnosis of oxyphilic parathyroid "adenoma" was made following total thyroidectomy. The tumor, unfortunately, recurred 7 years later with associated multiple lung metastases. When dealing with thyroid lesions comprising predominantly of oncocytic cells, one should consider oxyphilic parathyroid neoplasms as one of the differential diagnosis. In difficult equivocal cases, a panel of immunocytochemical stains (PTH, GATA3, TTF-1, PAX8, and thyroglobulin) can be helpful. In addition, a combination of valuable clinical, radiological, and laboratory data, including serum calcium and parathyroid hormone levels are key to arriving at an accurate cytological diagnosis. Diagn. Cytopathol. 2016;44:688 692. (c) 2016 Wiley Periodicals, Inc. PMID- 27229758 TI - The water maze paradigm in experimental studies of chronic cognitive disorders: Theory, protocols, analysis, and inference. AB - An instrumental step in assessing the validity of animal models of chronic cognitive disorders is to document disease-related deficits in learning/memory capacity. The water maze (WM) is a popular paradigm because of its low cost, relatively simple protocol and short procedure time. Despite being broadly accepted as a spatial learning task, inference of generalized, bona fide "cognitive" dysfunction can be challenging because task accomplishment is also reliant on non-cognitive processes. We review theoretical background, testing procedures, confounding factors, as well as approaches to data analysis and interpretation. We also describe an extended protocol that has proven useful in detecting early performance deficits in murine models of neuropsychiatric lupus and Alzheimer's disease. Lastly, we highlight the need for standardization of inferential criteria on "cognitive" dysfunction in experimental rodents and exclusion of preparations of a limited scientific merit. A deeper appreciation for the multifactorial nature of performance in WM may also help to reveal other deficits that herald the onset of neurodegenerative brain disorders. PMID- 27229759 TI - Cortisol awakening response in patients with psychosis: Systematic review and meta-analysis. AB - The cortisol awakening response (CAR), defined as the increase in cortisol release in response to waking up, shows associations with social and environmental risk factors of schizophrenia and has been studied as a potential biomarker in schizophrenia. We report a systematic review and meta-analysis of 11 studies and 879 participants focusing on the CAR of patients with schizophrenia, first-episode psychosis, and at-risk mental states. Random-effects meta-analysis showed that CAR is attenuated in patients with psychosis compared to healthy controls (g=-0.426, 95% CI -0.585 to -0.267, p<0.001, 11 between-group comparisons, n=879). Subgroup analysis showed flattened CAR in patients with schizophrenia (g=-0.556, 95% CI -1.069 to -0.044, p<0.05, 2 between-group comparisons, n=114) and first-episode psychosis (g=-0.544, 95% CI -0.731 to 0.358, p<0.001, 6 between-group comparisons, n=505), but not in individuals with at-risk mental states. These distinctive alterations of hypothalamic-pituitary adrenal axis function may have important implications for CAR as a marker for transition risk. However, the lack of objective verification of sampling adherence in these studies may limit the interpretation of the results. PMID- 27229760 TI - Natriuretic peptides in the central nervous system: Novel targets for cognitive impairment. AB - Natriuretic peptides (NPs) are traditionally known as cardiac hormones with diuretic, natriuretic and blood pressure lowering properties. Evidence indicates that NPs and their receptors are abundant in the central nervous system, suggesting their involvement in regulation of various brain functions. It has been shown that NPs are involved in the regulation of neurovascular and blood brain barrier integrity, neuro-inflammation, neuroprotection, synaptic transmission and brain fluid homeostasis. In addition, NPs might contribute to the brain's inhibitory control over the hypothalamic-pituitary-adrenal axis. Studies have also shown that high systemic levels of NPs are associated with cognitive impairment independent of cardiovascular risk factors. In this review we discuss the potential roles of NPs in regulating structural and functional integrity of the brain. Based on the available neurobiological and clinical evidence, we propose that NPs might represent as potential novel diagnostic and therapeutic targets for cognitive impairment. PMID- 27229761 TI - Toxicology of freshwater cyanobacteria. AB - Many chemical contaminants in drinking water have been shown to cause adverse health effects in humans after prolonged exposure. Cyanobacteria are one of the most potent and diverse groups of photosynthetic prokaryotes. One key component of cyanobacterial success in the environment is the production of potent toxins as secondary metabolites, which have been responsible for numerous adverse health impacts in humans. Anthropogenic activities have led to the increase of eutrophication in freshwater bodies' worldwide, causing cyanobacterial blooms to become more frequent. The present article will discuss about harmful cyanobacteria and their toxicology with special references to microcystin, nodularin, and cylindrospermopsin. PMID- 27229762 TI - Genetic scores based on risk-associated single nucleotide polymorphisms (SNPs) can reveal inherited risk of renal cell carcinoma. AB - The objective of this study was to evaluate whether renal cell carcinoma (RCC) risk-associated single nucleotide polymorphisms (SNPs) could reflect the individual inherited risks of RCC. A total of 346 RCC patients and 1,130 controls were recruited in this case-control study. Genetic scores were calculated for each individual based on the odds ratios and frequencies of risk-associated SNPs. Four SNPs were significantly associated with RCC in Chinese population. Two genetic score models were established, genetic score 1 (rs10054504, rs7023329 and rs718314) and genetic score 2 (rs10054504, rs7023329 and rs1049380). For genetic score 1, the individual likelihood of RCC with low (<0.8), medium (0.8-1.2) and high (>=1.2) genetic score 1 was 15.61%, 22.25% and 33.92% respectively (P trend=6.88*10(-7)). For genetic score 2, individual with low (<0.8), medium (0.8 1.2) and high (>=1.2) genetic score 2 would have likelihood of RCC as 14.39%, 24.54% and 36.48%, respectively (P-trend=1.27*10(-10)). The area under the receiver operating curve (AUC) of genetic score 1 was 0.626, and AUC of genetic score 2 was 0.658. We concluded that genetic score can reveal personal risk and inherited risk of RCC, especially when family history is not available. PMID- 27229763 TI - Negative Oxygen Ions Production by Superamphiphobic and Antibacterial TiO2/Cu2O Composite Film Anchored on Wooden Substrates. AB - According to statistics, early in the 20th century, the proportion of positive and negative air ions on the earth is 1 : 1.2. However, after more than one century, the equilibrium state of the proportion had an obvious change, which the proportion of positive and negative air ions became 1.2 : 1, leading to a surrounding of positive air ions in human living environment. Therefore, it is urgent to adopt effective methods to improve the proportion of negative oxygen ions, which are known as "air vitamin". In this study, negative oxygen ions production by the TiO2/Cu2O-treated wood under UV irradiation was first reported. Anatase TiO2 particles with Cu2O particles were doped on wooden substrates through a two-step method and further modification is employed to create remarkable superamphiphobic surface. The effect of Cu2O particles dopant on the negative oxygen ions production of the TiO2-treated wood was investigated. The results showed that the production of negative oxygen ions was drastically improved by doping with Cu2O particles under UV irradiation. The wood modified with TiO2/Cu2O composite film after hydrophobization is imparted with superamphiphobicity, antibacterial actions against Escherichia coli, and negative oxygen ions production under UV irradiation. PMID- 27229764 TI - Pre-bilaterian origin of the blastoporal axial organizer. AB - The startling capacity of the amphibian Spemann organizer to induce naive cells to form a Siamese twin embryo with a second set of body axes is one of the hallmarks of developmental biology. However, the axis-inducing potential of the blastopore-associated tissue is commonly regarded as a chordate feature. Here we show that the blastopore lip of a non-bilaterian metazoan, the anthozoan cnidarian Nematostella vectensis, possesses the same capacity and uses the same molecular mechanism for inducing extra axes as chordates: Wnt/beta-catenin signaling. We also demonstrate that the establishment of the secondary, directive axis in Nematostella by BMP signaling is sensitive to an initial Wnt signal, but once established the directive axis becomes Wnt-independent. By combining molecular analysis with experimental embryology, we provide evidence that the emergence of the Wnt/beta-catenin driven blastopore-associated axial organizer predated the cnidarian-bilaterian split over 600 million years ago. PMID- 27229765 TI - The value of preoperative functional cortical mapping using navigated TMS. AB - The surgical removal of brain tumours in so-called eloquent regions is frequently associated with a high risk of causing disabling postoperative deficits. Among the preoperative techniques proposed to help neurosurgical planning and procedure, navigated transcranial magnetic stimulation (nTMS) is increasingly performed. A high level of evidence is now available in the literature regarding the anatomical and functional accuracy of this mapping technique. This article presents the principles and facts demonstrating the value of using nTMS in clinical practice to preserve motor or language functions from deleterious lesions secondary to brain tumour resection or epilepsy surgery. PMID- 27229766 TI - Roles of Hcp family proteins in the pathogenesis of the porcine extraintestinal pathogenic Escherichia coli type VI secretion system. AB - Hcp (hemolysin-coregulated protein) is considered a vital component of the functional T6SS (Type VI Secretion System), which is a newly discovered secretion system. Our laboratory has previously sequenced the whole genome of porcine extraintestinal pathogenic E. coli (ExPEC) strain PCN033, and identified an integrated T6SS encoding three different hcp family genes. In this study, we first identified a functional T6SS in porcine ExPEC strain PCN033, and demonstrated that the Hcp family proteins were involved in bacterial competition and the interactions with other cells. Interestingly, the three Hcp proteins had different functions. Hcp2 functioned predominantly in bacterial competition; all three proteins were involved in the colonization of mice; and Hcp1 and Hcp3 were predominantly contributed to bacterial-eukaryotic cell interactions. We showed an active T6SS in porcine ExPEC strain PCN033, and the Hcp family proteins had different functions in their interaction with other bacteria or host cells. PMID- 27229767 TI - Correcting the record of structural publications requires joint effort of the community and journal editors. AB - Seriously flawed and even fictional models of biomolecular crystal structures, although rare, still persist in the record of structural repositories and databases. The ensuing problems of database contamination and persistence of publications based on incorrect structure models must be effectively addressed. The burden cannot be simply left to the critical voices who take the effort to contribute dissenting comments that are mostly ignored. The entire structural biology community, and particularly the journal editors who exercise significant power in this respect, must engage in a constructive dialog lest structural biology lose its credibility as an evidence-based empirical science. PMID- 27229769 TI - Cellular localization of Sun4p and its interaction with proteins in the yeast birth scar. AB - Yeast harbor several proteins with predicted glucanase activity that are potentially involved in cell wall remodeling during different processes, including mitosis. Here, we showed that 2 of these putative glucanases, Sun4p and Dse2p, co-localize to the yeast birth scar, dependently on presence of the third glucanase, Egt2p. The absence of these glucanases results in inefficient mother daughter cell separation. The Sun4p, Dse2p and Egt2p localize to the daughter side of the bud neck, possibly forming a complex, and are involved in the separation of the virgin daughter from the mother cell during mitosis. The formation of properly assembled birth scars that delimitate cell wall area restricted in the next budding is dependent on the presence of Aim44p and its transcriptional regulator, Swi5p. AIM44 or SWI5 deletion caused the "budding within the birth scar" phenotype, together with altered localization of the birth scar proteins Sun4p and Dse2p, indicating the impairment of birth scar protein complexes. PMID- 27229768 TI - Whole-gene sequencing investigation of SAT1 in attempted suicide. AB - Suicidal behavior imposes a tremendous cost, with current US estimates reporting approximately 1.3 million suicide attempts and more than 40,000 suicide deaths each year. Several recent research efforts have identified an association between suicidal behavior and the expression level of the spermidine/spermine N1 acetyltransferase 1 (SAT1) gene. To date, several SAT1 genetic variants have been inconsistently associated with altered gene expression and/or directly with suicidal behavior. To clarify the role SAT1 genetic variation plays in suicidal behavior risk, we present a whole-gene sequencing effort of SAT1 in 476 bipolar disorder subjects with a history of suicide attempt and 473 subjects with bipolar disorder but no suicide attempts. Agilent SureSelect target enrichment was used to sequence all exons, introns, promoter regions, and putative regulatory regions identified from the ENCODE project within 10 kb of SAT1. Individual variant, haplotype, and collapsing variant tests were performed. Our results identified no variant or assessed region of SAT1 that showed a significant association with attempted suicide, nor did any assessment show evidence for replication of previously reported associations. Overall, no evidence for SAT1 sequence variation contributing to the risk for attempted suicide could be identified. It is possible that past associations of SAT1 expression with suicidal behavior arise from variation not captured in this study, or that causal variants in the region are too rare to be detected within our sample. Larger sample sizes and broader sequencing efforts will likely be required to identify the source of SAT1 expression level associations with suicidal behavior. (c) 2016 Wiley Periodicals, Inc. PMID- 27229770 TI - Predicting the adoption of evidence-based practice using "Rogers diffusion of innovation model". AB - INTRODUCTION: Predicting the significant determinants of adopting evidence-based practice (EBP) by nursing students has received little attention in the nursing education literature. The purpose of this study was to investigate the predictors of EBP adoption among Iranian nursing students and to evaluate the fitness of the research model derived from Rogers' model. METHODS: The study was a cross sectional survey of 170 nursing students. A path analysis was conducted to predict the determinants of EBP in nursing students. Also, direct and indirect effects of the variables were calculated. RESULTS: The results indicated that knowledge of EBP as well as its perceived complexity, observability and trialability significantly predicted the adoption of EBP. Among the variables, knowledge of EBP had the greatest total impact on the adoption of EBP (P < .05). Also, the results of indices (chi(2) = 30.06, P = .000; GFI = 0.96; CFI = 0.97; RMSEA = 0.11) indicated an adequate model fit to the data. CONCLUSION: Nursing educators can identify the predictors of EBP in order to enhance the education and adoption of EBP. The results of this study can be used by health professionals such as nursing managers and educators for teaching any new concept in clinical and educational settings such as EBP. PMID- 27229771 TI - Physiological and microbiological verification of the benefit of hair washing in patients with skin conditions of the scalp. AB - BACKGROUND: It is unclear whether hair washing is effective against scalp eruption and pruritus caused by seborrheic dermatitis or psoriasis vulgaris. AIMS: To assess whether a proper hair-washing regimen, including the use of antibacterial shampoo, can ameliorate scalp eruption symptoms and alter the composition of the scalp microflora. METHODS: Eighteen patients with seborrheic dermatitis or psoriasis vulgaris scalp eruptions were instructed in proper techniques of daily hair washing, rinsing, and shampooing, which they underwent for 12 weeks. They used control shampoo in weeks 1-4 and 9-12, and an antibacterial shampoo during weeks 5-8. At the start of the test period and at weeks 4, 8, and 12, we assessed scalp symptoms (erythema, scaling/desquamation, dryness, itchiness, and scratching scars); microbial DNA levels from lesion and nonlesion areas; and levels of interleukin (IL)-1alpha, IL-1ra, and total protein in the scalp's horny layer. RESULTS: Compared to baseline values, scaling/desquamation and itchiness improved significantly at weeks 8 and 12. Other observed skin symptoms also improved over time. Malassezia colonization levels in lesion and nonlesion areas decreased gradually; the decrease was significant at week 8 in lesion areas and at weeks 4 and 8 in nonlesion areas. Bacterial colonization levels also decreased gradually, achieving significance in lesion areas at week 4. Gradual decreases in IL-1ra/IL-1alpha level showed statistical significance at weeks 4 and 12, while the protein quantity significantly decreased at week 12. CONCLUSION: Proper hair washing improved scalp condition symptoms, and possibly the underlying etiology. PMID- 27229773 TI - Development and Optimization of AAV hFIX Particles by Transient Transfection in an iCELLis((r)) Fixed-Bed Bioreactor. AB - Adeno-associated virus (AAV) vectors are increasingly popular in gene therapy because they are unassociated with human disease, replication dependent, and less immunogenic than other viral vectors and can infect a variety of cell types. These vectors have been used in over 130 clinical trials, and one AAV product has been approved for treatment of lipoprotein lipase deficiency in Europe. To meet the demand for the increasing quantities of AAV required for clinical trials and treatment, a scalable high-capacity technology is required. Bioreactors meet these requirements but limited options are available for adherent HEK 293T/17 cells. Here we optimize the transient transfection of HEK293T/17 cells for the production of AAV human factor IX in a disposable fixed-bed bioreactor, the iCELLis((r)) Nano (PALL Corporation). A fixed bed in the center of the iCELLis bioreactor is surrounded by culture medium that is pumped through the bed from the bottom of the bioreactor so that a thin film of the medium overflows the bed and is replenished with oxygen and depleted of CO2 as it returns to the surrounding medium reservoir. We show that this fixed-bed bioreactor can support as many as 2.5 * 10(8) cells/ml of fixed bed (1.9 * 10(6) cells/cm(2)). By optimizing culture and transfection parameters such as the concentration of DNA for transfection, day of harvest, size of PEI/DNA particles, and transfection medium, and adding an additional medium change to the process, we increased our yield to as high as 9.0 * 10(14) viral particles per square meter of fixed bed. We also show an average GFP transfection of 97% of cells throughout the fixed bed. These yields make the iCELLis a promising scalable technology for the clinical production of AAV gene therapy products. PMID- 27229772 TI - Crave-Out: A Distraction/Motivation Mobile Game to Assist in Smoking Cessation. AB - BACKGROUND: Smoking is still the number one preventable cause of death. Cravings an intense desire or longing for a cigarette-are a major contributor to quit attempt failure. New tools to help smokers' manage their cravings are needed. OBJECTIVE: To present a case study of the development process and testing of a distraction/motivation game (Crave-Out) to help manage cravings. METHODS: We used a phased approach: in Phase 1 (alpha testing), we tested and refined the game concept, using a Web-based prototype. In Phase 2 (beta testing), we evaluated the distraction/motivation potential of the mobile game prototype, using a prepost design. After varying duration of abstinence, smokers completed the Questionnaire of Smoking Urge-Brief (QSU-Brief) measurement before and after playing Crave-Out. Paired t tests were used to compare pregame and postgame QSU-Brief levels. To test dissemination potential, we released the game on the Apple iTunes App Store and tracked downloads between December 22, 2011, and May 5, 2014. RESULTS: Our concept refinement resulted in a multilevel, pattern memory challenge game, with each level increasing in difficulty. Smokers could play the game as long as they wanted. At the end of each level, smokers were provided clear goals for the next level and rewards (positive reinforcement using motivational tokens that represented a benefit of quitting smoking). Negative reinforcement was removed in alpha testing as smokers felt it reminded them of smoking. Measurement of QSU Brief (N=30) resulted in a pregame mean of 3.24 (SD 1.65) and postgame mean of 2.99 (SD 1.40) with an overall decrease of 0.25 in cravings (not statistically significant). In a subset analysis, the QSU-Brief decrease was significant for smokers abstinent for more than 48 hours (N=5) with a pregame mean of 2.84 (SD 1.16) and a postgame mean of 2.0 (SD 0.94; change=0.84; P =.03). Between December 22, 2011, and May 29, 2014, the game was downloaded 3372 times from the App Store, with 1526 smokers visiting the online resource www.decide2quit.org linked to the game. CONCLUSIONS: Overall, playing the game resulted in small, but nonsignificant decreases in cravings, with changes greater for those had already quit for more than 48 hours. Lessons learned can inform further development. Future research could incorporate mHealth games in multicomponent cessation interventions. TRIAL REGISTRATION: Clinicaltrials.gov NCT00797628; https://clinicaltrials.gov/ct2/show/NCT00797628 (Archived by WebCite at http://www.webcitation.org/6hbJr6LWG). PMID- 27229847 TI - Third-harmonic generation imaging of breast tissue biopsies. AB - We demonstrate for the first time the imaging of unstained breast tissue biopsies using third-harmonic generation (THG) microscopy. As a label-free imaging technique, THG microscopy is compared to phase contrast and polarized light microscopy which are standard imaging methods for breast tissues. A simple feature detection algorithm is applied to detect tumour-associated lymphocyte rich regions in unstained breast biopsy tissue and compared with corresponding regions identified by a pathologist from bright-field images of hematoxylin and eosin stained breast tissue. Our results suggest that THG imaging holds potential as a complementary technique for analysing breast tissue biopsies. PMID- 27229848 TI - Probing the correlations between the defects in metal-organic frameworks and their catalytic activity by an epoxide ring-opening reaction. AB - Seven Zr/Hf-based MOFs with different degrees of defects were obtained by modulating the synthetic conditions. The number of missing linkers in these MOFs was calculated based on potentiometric acid-base titration. The number of defects was found to correlate quantitatively with the catalytic activity of UiO-type MOFs for an acid-catalyzed epoxide ring-opening reaction. More importantly, we were able to identify a MOF with inherent defective Zr6 nodes, which showed great activity and regio-selectivity for the epoxide ring-opening reaction. PMID- 27229849 TI - Bioinspired 1D Superparamagnetic Magnetite Arrays with Magnetic Field Perception. AB - Superparamagnetic magnetite nanoparticles can be assembled into 1D arrays by a capillary-bridge mediate assembly approach, inspired by the Earth's magnetic field perception in nature. These 1D arrays possess strict alignment, precise position and high aspect ratio, yielding highly anisotropic magnetization characteristic. PMID- 27229851 TI - Evaluating the pragmatic language skills of children with ADHD and typically developing playmates following a pilot parent-delivered play-based intervention. AB - BACKGROUND/AIM: Children with attention deficit hyperactivity disorder (ADHD) often present with pragmatic language deficits and difficulties with peer-peer friendships. Parents and typically developing peers (TDPs) may be able to assist via parent and peer-mediated intervention approaches when adequately supported by trained adult facilitators. This study investigated whether a parent-delivered play-based intervention supported by occupational therapists and speech language pathologists was feasible and improved the pragmatic language skills of children with ADHD and their TDPs. METHODS: Nine children with ADHD paired with nine TDPs (mean age = 8.2 years) participated. The seven-week intervention was delivered by parents of children with ADHD at their home and consisted of weekly assigned home based modules, supported play-dates between the pairs of children and supplemented by three clinic visits. Parent adherence to intervention activity was monitored on a weekly basis. Blinded ratings of observed peer-peer play interactions were used to detect changes in pragmatic language from pre-post intervention and one month follow-up using the Pragmatic Observation Measure (POM). RESULTS: All parents reported completing the seven weekly home-based modules and attended all clinic visits. Significant improvements in observed pragmatic language skills were found from pre-follow-up for both the ADHD and TDP children and pre-post for the ADHD children. CONCLUSION: The preliminary findings suggest that using parents to facilitate their child's pragmatic language skills was a feasible intervention approach with parents acting as agents of change to improve the pragmatic language of their children. This exploratory study identifies the need for further large-scale research to address the pragmatic language skills of children with ADHD using parent-delivery in a play-based, peer peer context. PMID- 27229850 TI - Therapeutic effect of budesonide/formoterol, montelukast and N-acetylcysteine for bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation. AB - BACKGROUND: Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic stem cell transplantation (HSCT) is currently treated with systemic corticosteroids despite poor efficacy and side effects. This study investigated the therapeutic effect of budesonide/formoterol, montelukast and n acetylcysteine, which are suggested as treatment options for BOS after HSCT. METHODS: After diagnosis of BOS, 61 patients were treated with budesonide/formoterol, montelukast and n-acetylcysteine for 3 months. Pulmonary function test and COPD assessment test (CAT) were performed before and after the combination therapy. Therapeutic response was evaluated by changes in forced expiratory volume in 1 s (FEV1) or CAT score. RESULTS: After 3 months of combination treatment, mean FEV1 increased by 220 mL (p < 0.001) and residual volume decreased by 200 mL (p =0 .005). Median CAT score also significantly decreased from 15.5 to 11.0 (p = 0.001). The overall response rate to combination therapy was 82 %. Comparing the no-response group and the response group, the forced vital capacity (% predicted) decline between pre-HSCT and BOS diagnosis was significantly greater in the response group (p = 0.036). CONCLUSION: Combination treatment with budesonide/formoterol, montelukast and n acetylcysteine significantly improved lung function and respiratory symptoms in patients with BOS after allogeneic HSCT without serious side effects. PMID- 27229852 TI - Effect of drying on the bioactive compounds, antioxidant, antibacterial and antityrosinase activities of pomegranate peel. AB - BACKGROUND: The use of pomegranate peel is highly associated with its rich phenolic concentration. Series of drying methods are recommended since bioactive compounds are highly sensitive to thermal degradation. The study was conducted to evaluate the effects of drying on the bioactive compounds, antioxidant as well as antibacterial and antityrosinase activities of pomegranate peel. METHODS: Dried pomegranate peels with the initial moisture content of 70.30 % wet basis were prepared by freeze and oven drying at 40, 50 and 60 degrees C. Difference in CIE LAB, chroma (C*) and hue angle (h degrees ) were determined using colorimeter. Individual polyphenol retention was determined using LC-MS and LC-MS(E) while total phenolics concentration (TPC), total flavonoid concentration (TFC), total tannins concentration (TTC) and vitamin C concentration were measured using colorimetric methods. The antioxidant activity was measured by radical scavenging activity (RSA) and ferric reducing antioxidant power (FRAP). Furthermore, the antibacterial activity of methanolic peel extracts were tested on Gram negative (Escherichia coli and Klebsiella pneumonia) and Gram positive bacteria (Staphylococcus aureus and Bacillus subtilis) using the in vitro microdilution assays. Tyrosinase enzyme inhibition was investigated against monophenolase (tyrosine) and diphenolase (DOPA), with arbutin as positive controls. RESULTS: Oven drying at 60 degrees C resulted in high punicalin concentration (888.04 +/- 141.03 mg CE/kg dried matter) along with poor red coloration (high hue angle). Freeze dried peel contained higher catechin concentration (674.51 mg/kg drying matter) + catechin and -epicatechin (70.56 mg/kg drying matter) compared to oven dried peel. Furthermore, freeze dried peel had the highest total phenolic, tannin and flavonoid concentrations compared to oven dried peel over the temperature range studied. High concentration of vitamin C (31.19 MUg AAE/g dried matter) was observed in the oven dried (40 degrees C) pomegranate peel. Drying at 50 degrees C showed the highest inhibitory activity with the MIC values of 0.10 mg/ml against Gram positive (Staphylococcus aureus and Bacillus subtili. Likewise, the extracts dried at 50 degrees C showed potent inhibitory activity concentration (22.95 mg/ml) against monophenolase. Principal component analysis showed that the peel colour characteristics and bioactive compounds isolated the investigated drying method. CONCLUSIONS: The freeze and oven dried peel extracts exhibited a significant antibacterial and antioxidant activities. The freeze drying method had higher total phenolic, tannin and flavonoid concentration therefore can be explored as a feasible method for processing pomegranate peel to ensure retention of the maximum amount of their naturally occurring bioactive compounds. TRIAL REGISTRATION: Not relevant for this study. PMID- 27229853 TI - The case of #arseniclife: Blogs and Twitter in informal peer review. AB - Using the "#arseniclife" controversy as a case study, we examine the roles of blogs and Twitter in post-publication review. The controversy was initiated by a scientific article about bacteria able to substitute arsenic for phosphorus in its genetic material. We present the debate chronologically, using prominent online media to reconstruct the events. Using tweets that discussed the controversy, we conducted quantitative sentiment analysis to examine skeptical and non-skeptical tones on Twitter. Critiques of and studies refuting the arsenic life hypothesis were publicized on blogs before formal publication in traditional academic spaces and were shared on Twitter, influencing issue salience among a range of audiences. This case exemplifies the role of new media in informal post publication peer review, which can complement traditional peer review processes. The implications drawn from this case study for future conduct and transparency of both formal and informal peer review are discussed. PMID- 27229854 TI - Auditing the socio-environmental determinants of motivation towards physical activity or sedentariness in work-aged adults: a qualitative study. AB - BACKGROUND: There is a lack of understanding of work aged adults' (30-60 years old) perspectives on the motivation of physical activity versus sedentariness. This study aims to: (1) identify which socio-environmental factors motivate physical activity and/or sedentary behavior, in adults aged 30-60 years; and (2) explore how these motivators interact and combine. METHOD: Fifteen work-aged adults who, were able to engage in physical activity (Mean age = 43.9 years; SD 9.6, range 31-59), participated in semi-structured interviews. Inductive content analysis was used to generate an inventory of socio-environmental factors and their specific influences on motivation towards physical activity or sedentariness. RESULTS: Key socio-environmental agents found to influence motivation included: Spouse/partner, parents, children, siblings, whole family, grandchildren, friends, work-mates, neighbors, strangers, team-mates and class mates, instructors, health care professionals, employers, gyms and health companies, governments, media and social media, cultural norms, and the physical environment. Mechanisms fell into five broad themes of socio-environmental motivation for both physical activity and sedentariness: (1) competence and progress; (2) informational influences, (3) emotional influences, (4) pragmatics and logistics, and (5) relationships. Similar socio-environmental factors were frequently reported as able to motivate both activity and sedentariness. Likewise, individual categories of influence could also motivate both behaviors, depending on context. CONCLUSION: The findings of this paper 'unpack' theoretical concepts into specific and targeted behavioral recommendations. The data suggested no simple solutions for promoting physical activity or reducing sedentariness, but rather complex and interacting systems surrounding work-aged adults. Findings also suggest that health professionals should be encouraged to support adults' health by examining the socio-environmental motivational influences, or 'motivational atmosphere'. PMID- 27229855 TI - Rivaroxaban versus warfarin and dabigatran in atrial fibrillation: comparative effectiveness and safety in Danish routine care. AB - PURPOSE: To evaluate effectiveness and safety of rivaroxaban versus warfarin or dabigatran etexilate in a prospective cohort of routine care non-valvular atrial fibrillation (AF) patients during February 2012 to August 2014. METHODS: We identified in nationwide health registries a cohort of AF patients who were new users of rivaroxaban 15 mg (R15) or 20 mg (R20); dabigatran 110 mg (D110) or 150 mg (D150); or warfarin. Propensity-adjusted Cox regression was used to compare outcome rates in four settings: 'R15 vs. warfarin'; 'R15 vs. D110'; 'R20 vs. warfarin'; and 'R20 vs. D150'. RESULTS: Rivaroxaban users (R15: n = 776; R20: n = 1629) were older and with more comorbidities than warfarin (n = 11 045) and dabigatran users (D110: n = 3588; D150: n = 5320). Rivaroxaban 15-mg users had the overall highest crude mortality rate. After propensity adjustment, rivaroxaban had lower stroke rates vs. warfarin (R15: hazard ratio [HR] 0.46, 95% confidence interval [CI]: 0.26-0.82; R20 HR: 0.72, 95%CI: 0.51-1.01), and similar stroke rates vs. dabigatran. The bleeding rate was similar to warfarin and moderately higher vs. dabigatran (R15 vs. D110 HR: 1.28, 95%CI: 0.82-2.01; R20 vs. D150 HR: 1.81, 95%CI: 1.25-2.62). The mortality rate was higher vs. dabigatran (R15 vs. D110 HR: 1.43, 95%CI: 1.13-1.81; R20 vs. D150 HR: 1.52, 95%CI: 1.06-2.19). CONCLUSIONS: Rivaroxaban was associated with similar or lower stroke rates, but higher bleeding and mortality rates. Channeling of rivaroxaban towards elderly and less healthy patients may have generated residual confounding. In particular, our findings cannot stand alone when deciding which oral anticoagulant to prescribe. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27229856 TI - Mesenchymal stem cell therapy in the treatment of osteoarthritis: reparative pathways, safety and efficacy - a review. AB - Osteoarthritis is a leading cause of pain and disability across the world. With an aging population its prevalence is likely to further increase. Current accepted medical treatment strategies are aimed at symptom control rather than disease modification. Surgical options including joint replacement are not without possible significant complications. A growing interest in the area of regenerative medicine, led by an improved understanding of the role of mesenchymal stem cells in tissue homeostasis and repair, has seen recent focused efforts to explore the potential of stem cell therapies in the active management of symptomatic osteoarthritis. Encouragingly, results of pre-clinical and clinical trials have provided initial evidence of efficacy and indicated safety in the therapeutic use of mesenchymal stem cell therapies for the treatment of knee osteoarthritis. This paper explores the pathogenesis of osteoarthritis and how mesenchymal stem cells may play a role in future management strategies of this disabling condition. PMID- 27229858 TI - The effect of miR-340 over-expression on cell-cycle-related genes in triple negative breast cancer cells. AB - Breast cancer is a heterogeneous disease, and among all types, triple-negative breast cancer (TNBC) is characterised by high risk of recurrence. The discovery of microRNAs (miRNA) has opened the door for targeted therapy of TNBC. miR-340 down-regulation and sub-G1-accumulated cells in flowcytometry were observed in metastatic TNBC cells (data in publication), leading us to investigate the potential tumour suppressive role of this miRNA on cell-cycle-related genes. A lentiviral vector containing miR-340 was applied to over-express miR-340 in TNBC cell line, MDA-MB-231. Then, the expression of some cell-cycle-regulating genes including cyclin A2 (cyclin A2), Cyclin-dependent kinases 2 (CDK2), cyclin dependent kinase inhibitors (P16, P18 and P27), Retinoblastoma (RB) and transcription factors (SMAD 4, SOX2 and SOX17) was investigated using quantitative RT-PCR. The results showed a decline in the expression of SOX2, P16 and P27 after miR-340 over-expression, whereas we observed an increase in the expression of cyclin A2, CDK2, SOX17, P18, SMAD 4 and RB. The over-expression of tumour suppressor genes such as RB and SOX17 and down-regulation of an oncogene such as SOX2 were in accordance to the inhibitory role of miR-340 that causes blockage of breast cancer metastasis which should be further investigated. PMID- 27229860 TI - Proceedings of the International Gap Junction Conference 2015. PMID- 27229857 TI - Recent insights in nanotechnology-based drugs and formulations designed for effective anti-cancer therapy. AB - The rapid development of nanotechnology provides alternative approaches to overcome several limitations of conventional anti-cancer therapy. Drug targeting using functionalized nanoparticles to advance their transport to the dedicated site, became a new standard in novel anti-cancer methods. In effect, the employment of nanoparticles during design of antineoplastic drugs helps to improve pharmacokinetic properties, with subsequent development of high specific, non-toxic and biocompatible anti-cancer agents. However, the physicochemical and biological diversity of nanomaterials and a broad spectrum of unique features influencing their biological action requires continuous research to assess their activity. Among numerous nanosystems designed to eradicate cancer cells, only a limited number of them entered the clinical trials. It is anticipated that progress in development of nanotechnology-based anti-cancer materials will provide modern, individualized anti-cancer therapies assuring decrease in morbidity and mortality from cancer diseases. In this review we discussed the implication of nanomaterials in design of new drugs for effective antineoplastic therapy and describe a variety of mechanisms and challenges for selective tumor targeting. We emphasized the recent advantages in the field of nanotechnology based strategies to fight cancer and discussed their part in effective anti cancer therapy and successful drug delivery. PMID- 27229859 TI - Selective mode of action of plumbagin through BRCA1 deficient breast cancer stem cells. AB - BACKGROUND: Studies over the past decade and half have identified cancer stem cells (CSCs) to be responsible for tumorigenesis, invasion, sustenance of metastatic disease, radio- and chemo-resistance and tumor relapse. Recent reports have described the plasticity of breast CSCs (BCSCs) to shift between the epithelial and mesenchymal phenotypes via Epithelial-Mesenchymal Transition (EMT) and Mesenchymal-Epithelial Transition (MET) states as the reason for their invasive capabilities. Additionally, BRCA1 has been found to be a mammary stem cell fate determinant. However, it is not clear what would be the best marker that can be used for identifying CSCs in BRCA1 mutated cancers. Also, anticancer agents that can reduce CSC population in a BRCA1 defective condition have not been addressed so far. METHODS: Putative BCSCs were identified based on Hoechst exclusion, CD44(+)/24(-/low) expression and Aldehyde Dehydrogenase 1 (ALDH1) positivity using flow cytometry. The 'stemness' of the isolated ALDH1+ cells were analysed by immunofluorescence, western blotting for stem cell and EMT markers as well as in vitro mammosphere assays. Induction of Reactive Oxygen Species (ROS) by Plumbagin (PB) in BCSCs was assayed by Dichloro-dihydro-fluorescein diacetate (DCF-DA) staining. Ovarian cancer xenografts treated with PB were subjected to immunohistochemical analysis to study the ability of PB to target CSCs. RESULTS: We have confirmed that ALDH1 positivity is the best marker for the identification of BCSCs in BRCA1-defective breast cancer cell lines when compared to the CD marker profile and Side Population (SP) analysis. BRCA1 status was observed to be a determinant of the abundance of epithelial-like (ALDH1+) or mesenchymal-like (CD44(+)/24(-/low)) BCSCs, and the reconstitution of a full length, wild type BRCA1 in HCC1937 breast cancer cells possessing a mutated BRCA1, transforms them from 'stem-like' to more 'mesenchymal'. For the first time we have shown that Plumbagin (PB), a naturally occurring naphthoquinone which is predominantly a ROS inducer, could reduce BCSCs specifically in BRCA1-defective, basal-like cancer cells. CONCLUSIONS: The best marker for identifying BCSCs in BRCA1 defective condition could be ALDH1 and that BRCA1 mutated BCSCs would be mostly 'stem like' than 'mesenchymal'. Also ROS inducers like PB could reduce BCSCs in BRCA1 defective cancers. PMID- 27229861 TI - Prediction of peptidoglycan hydrolases- a new class of antibacterial proteins. AB - BACKGROUND: The efficacy of antibiotics against bacterial infections is decreasing due to the development of resistance in bacteria, and thus, there is a need to search for potential alternatives to antibiotics. In this scenario, peptidoglycan hydrolases can be used as alternate antibacterial agents due to their unique property of cleaving peptidoglycan cell wall present in both gram positive and gram-negative bacteria. Along with a role in maintaining overall peptidoglycan turnover in a cell and in daughter cell separation, peptidoglycan hydrolases also play crucial role in bacterial pathophysiology requiring development of a computational tool for the identification and classification of novel peptidoglycan hydrolases from genomic and metagenomic data. RESULTS: In this study, the known peptidoglycan hydrolases were divided into multiple classes based on their site of action and were used for the development of a computational tool 'HyPe' for identification and classification of novel peptidoglycan hydrolases from genomic and metagenomic data. Various classification models were developed using amino acid and dipeptide composition features by training and optimization of Random Forest and Support Vector Machines. Random Forest multiclass model was selected for the development of HyPe tool as it showed up to 71.12 % sensitivity, 99.98 % specificity, 99.55 % accuracy and 0.80 MCC in four different classes of peptidoglycan hydrolases. The tool was validated on 24 independent genomic datasets and showed up to 100 % sensitivity and 0.94 MCC. The ability of HyPe to identify novel peptidoglycan hydrolases was also demonstrated on 24 metagenomic datasets. CONCLUSIONS: The present tool helps in the identification and classification of novel peptidoglycan hydrolases from complete genomic or metagenomic ORFs. To our knowledge, this is the only tool available for the prediction of peptidoglycan hydrolases from genomic and metagenomic data. AVAILABILITY: http://metagenomics.iiserb.ac.in/hype/ and http://metabiosys.iiserb.ac.in/hype/ . PMID- 27229863 TI - Dynamic monitoring of platelet activation and its role in post-dissection inflammation in a canine model of acute type A aortic dissection. AB - BACKGROUND: To confirm the activation of platelets (PLT) and explore the role of activated PLT in post-dissection inflammation. METHOD: An acute type A aortic dissection (AAD) canine model was established. Mean platelet volume/platelet count (MPV/PTC), platelet size distribution width (PDW), and inflammatory cytokines (tumor necrosis factor-alpha [TNF-alpha] and interleukin-6 [IL-6]) were measured between anesthetization and thoracotomy (T1), at the end of the operation (T2), and at 2 h (T3), 4 h (T4), and 6 h (T5) after the operation. Bivariate analysis was used to determine the correlations between the peak MPV/PTC, PDW, and inflammatory cytokines at T4. RESULT: An AAD canine model was successfully established. Both MPV/PTC and PDW values were significantly higher at T3-T5 than at T1 (P < 0.05). Both were also significantly higher at T3-T5 in the dissection group than in the sham operation (SO) group (P < 0.05). Inflammatory cytokine levels were remarkably higher at T3-T5 than at T1, and were higher at T3-T5 in both the dissection and the SO group (P < 0.05). Bivariate analysis demonstrated positive correlations between MPV/PTC and both TNF-alpha (r = 0.826, P = 0.011) and IL-6 (r = 0.806, P = 0.016). CONCLUSION: Activated PLT were identified after AAD, and played a critical role in the initiation of post dissection inflammation. PMID- 27229864 TI - Erratum to: Formula diet alters small intestine morphology, microbial abundance and reduces VE-cadherin and IL-10 expression in neonatal porcine model. PMID- 27229862 TI - Human fascioliasis endemic areas in Argentina: multigene characterisation of the lymnaeid vectors and climatic-environmental assessment of the transmission pattern. AB - BACKGROUND: In South America, fascioliasis stands out due to the human endemic areas in many countries. In Argentina, human endemic areas have recently been detected. Lymnaeid vectors were studied in two human endemic localities of Catamarca province: Locality A beside Taton and Rio Grande villages; Locality B close to Recreo town. METHODS: Lymnaeids were characterised by the complete sequences of rDNA ITS-2 and ITS-1 and fragments of the mtDNA 16S and cox1. Shell morphometry was studied with the aid of a computer image analysis system. Climate analyses were made by nearest neighbour interpolation from FAO data. Koeppen & Budyko climate classifications were used. De Martonne aridity index and Gorczynski continentality index were obtained. Lymnaeid distribution was assessed in environmental studies. RESULTS: DNA sequences demonstrated the presence of Lymnaea neotropica and L. viator in Locality A and of L. neotropica in Locality B. Two and four new haplotypes were found in L. neotropica and L. viator, respectively. For interspecific differentiation, ITS-1 and 16S showed the highest and lowest resolution, respectively. For intraspecific analyses, cox1 was the best marker and ITS-1 the worst. Shell intraspecific variability overlapped in both species, except maximum length which was greater in L. viator. The desertic arid conditions surrounding Locality A, the semiaridity-aridity surrounding Locality B, and the very low yearly precipitation in both localities, are very different from the typical fascioliasis transmission foci. Lymnaeids are confined to lateral river side floodings and small man-made irrigation systems. Water availability only depends on the rivers flowing from neighbouring mountains. All disease transmission factors are concentrated in small areas where humans and animals go for water supply, vegetable cultures and livestock farming. CONCLUSIONS: The unusually high number of DNA haplotypes and the extreme climate unsuitable for F. hepatica and lymnaeid development, demonstrate that the transmission foci are isolated. Seasonal transmission may depend on the timely overlap of appropriate temperature and river water availability. Lymnaeids and F. hepatica have probably reached these localities by livestock introduction. DNA differences regarding other populations of L. neotropica and L. viator in Argentina suggest an introduction independent from the spreading movements which allowed these two lymnaeids to expand throughout the country. PMID- 27229865 TI - Neurospora crassa tox-1 Gene Encodes a pH- and Temperature-Tolerant Mini Cellulase. AB - Cellulases that endure extreme conditions are essential in various industrial sectors. This study reports a mini-cellulase gene tox-1 from Neurospora crassa. The gene tox-1 was cloned in Escherichia coli after chimerization with the YebF gene and substitutions of certain isoleucine and valine with leucine residues. The yeast transformants could grow on rice straw-agar medium. The 44-amino acid peptide and its two mutant variants displayed potent cellulase activities in Congo Red assay and enzymatic assays. Conservative replacements with leucine have substantially increased the stabilities and half-lives of the peptides at alkaline pH and low and high temperatures and also the tolerance to organic solvents and surfactants, on the basis of activities toward cellose. The small size of the mini-cellulase would allow for commercially viable automatic chemical peptide synthesis. This work suggests that conservative leucine replacements may serve as a general strategy in the engineering of more robust enzymes with special features with little loss of activities. PMID- 27229867 TI - Rapid green assembly of antimicrobial nanobunches. AB - Antimicrobial nanobunches with different amounts of chitosan-capped Ag were prepared by continuous gas-liquid green route under ultrasound irradiation. Spark produced aerosol Cu nanoparticles were directly injected into an ultrasound Ag(I) chitosan reaction cell for efficient hydrosolization of the Cu particles and the subsequent incorporation of Ag and chitosan on Cu. Subsequently, electrospraying was used to form of chitosan-capped Cu-Ag nanobunch coatings. The time required for reducing the bacterial proliferation to 50% dropped to ~1 h at a nanobunch concentration of 10 MUg mL(-1) from the 2.0 min Ag(I) reaction time, and was further decreased to ~0.5 h by increasing the concentration of the nanobunches to 90 MUg mL(-1). The nanobunches were directly coated onto the substrate using an electrospray device to fabricate transparent films and composite fibers. The antimicrobial activity of the composite carbon fibers was then evaluated via the disc diffusion method. PMID- 27229866 TI - Protective effect of in ovo treatment with the chicken cathelicidin analog D-CATH 2 against avian pathogenic E. coli. AB - Increasing antibiotic resistance and ever stricter control on antibiotic use are a driving force to develop alternatives to antibiotics. One such strategy is the use of multifunctional Host Defense Peptides. Here we examined the protective effect of prophylactic treatment with the D analog of chicken cathelicidin-2 (D CATH-2) against a respiratory E. coli infection. Chickens were treated with D CATH-2 in ovo at day 18 of embryonic development or intramuscularly at days 1 and 4 after hatch. At 7 days of age, birds were challenged intratracheally with avian pathogenic E. coli. Protection was evaluated by recording mortality, morbidity (Mean Lesion Score) and bacterial swabs of air sacs at 7 days post-infection. In ovo D-CATH-2 treatment significantly reduced morbidity (63%) and respiratory bacterial load (>90%), while intramuscular treatment was less effective. D-CATH-2 increased the percentage of peripheral blood lymphocytes and heterophils by both administration routes. E. coli specific IgM levels were lower in in ovo treated animals compared to intramuscular D-CATH-2 treatment. In short, in ovo treatment with the Host Defense Peptide derived D-CATH-2 can partially protect chickens from E. coli infection, making this peptide an interesting starting point to develop alternatives to antibiotics for use in the poultry sector. PMID- 27229868 TI - Negative information-seeking experiences of long-term prostate cancer survivors. AB - PURPOSE: Many prostate cancer survivors have lasting symptoms and disease-related concerns for which they seek information. To understand survivors' information seeking experiences, we examined the topics of their information searches, their overall perceptions of the search, and perceptions of their health information seeking self-efficacy (i.e., confidence in their ability to obtain information). We hypothesized that negative search experiences and lower health information seeking self-efficacy would be associated with certain survivor characteristics such as non-white race, low income, and less education. METHODS: This was a retrospective study using data from the Michigan Prostate Cancer Survivor Study (state-based survey of long-term prostate cancer survivor outcomes, N = 2499, response rate = 38 %). Participants recalled their last search for information and reported the topics and overall experience. We conducted multivariable regression to examine the association between survivor characteristics and the information-seeking experience. RESULTS: Nearly a third (31.7 %) of prostate cancer survivors (median age of 76 years and 9 years since diagnosis) reported having negative information-seeking experiences when looking for information. However, only 13.4 % reported having low health information-seeking self efficacy. Lower income and less education were both significantly associated with negative information-seeking experiences. CONCLUSIONS: Our findings suggest that many long-term prostate cancer survivors have negative experiences when searching for information, and lower income and less education were survivor factors related to negative information-seeking experiences. IMPLICATIONS FOR CANCER SURVIVORS: We advocate for ongoing, information needs assessment at the point-of care as the survivorship experience progresses to assess and potentially improve survivors' quality of life. PMID- 27229869 TI - Chronic condition clusters and functional impairment in older cancer survivors: a population-based study. AB - PURPOSE: The purpose of the study is to identify chronic condition clusters at pre- and post-cancer diagnosis, evaluate predictors of developing clusters post cancer, and examine the impact on functional impairment among older cancer survivors. METHODS: We identified 5991 survivors age 65 and older of prostate, breast, colorectal, lung, bladder, kidney, head and neck, and gynecologic cancer and non-Hodgkin lymphoma from the Surveillance, Epidemiology and End Results Medicare Health Outcomes Survey resource. Survivors completed surveys pre- and post-cancer diagnosis on 13 chronic conditions and functional status. Among those with >=2 conditions, exploratory factor analysis identified clusters of conditions. Differences in cluster frequency from pre- to post-cancer diagnosis were evaluated across the top five cancer types using chi-square tests. Modified Poisson regression models estimated the relative risk of developing clusters post diagnosis. Chi-square tests evaluated associations between function and clusters. RESULTS: Clusters included the following: cardiovascular disease cluster (pre 6.1 % and post 7.7 %), musculoskeletal cluster (28.2 % and 29.3 %), metabolic cluster (14.9 % and 17.6 %), and the major depressive disorder risk (MDDr) + gastrointestinal (GI) + pulmonary condition cluster (5.8 % and 8.7 %). Increases in MDDr + GI + Pulmonary cluster from pre- to post-cancer diagnosis were observed for prostate, lung, and colorectal cancer survivors. Functional impairment was more prevalent in survivors with defined clusters, especially in MDDr + GI + pulmonary, compared to survivors with >=2 un-clustered conditions. CONCLUSIONS: Distinct condition clusters of two or more chronic conditions are prevalent among older cancer survivors. Cluster prevalence increases from pre- to post-cancer diagnosis and these clusters have a significant impact on functional limitations. IMPLICATIONS FOR CANCER SURVIVORS: Tailored management on specific multimorbidity patterns will have implications for functional outcomes among older survivors. PMID- 27229870 TI - Modern ab initio valence bond theory calculations reveal charge shift bonding in protic ionic liquids. AB - The nature of bonding interactions between the cation and the anion of an ionic liquid is at the heart of understanding ionic liquid properties. A particularly interesting case is a special class of ionic liquids known as protic ionic liquids. The extent of proton transfer in protic ionic liquids has been observed to vary according to the interacting species. Back proton transfer renders protic ionic liquids volatile and to be considered as inferior ionic liquids. We try to address this issue by employing modern ab initio valence bond theory calculations. The results indicate that the bonding in the cation and the anion of a prototypical ionic liquid, ethylammonium nitrate, is fundamentally different. It is neither characteristic of covalent/polar covalent bonding nor ionic bonding but rather charge shift bonding as a resonance hybrid of two competing ionic molecular electronic structure configurations. An investigation of other analogous protic ionic liquids reveals that this charge shift bonding seems to be a typical characteristic of protic ionic liquids while the ionic solid analogue compound ammonium nitrate has less charge shift bonding character as compared to protic ionic liquids. Further the extent of charge shift bonding character has been found to be congruent with the trends in many physicochemical properties such as melting point, conductivity, viscosity, and ionicity of the studied ionic liquids indicating that percentage charge shift character may serve as a key descriptor for large scale computational screening of ionic liquids with desired properties. PMID- 27229871 TI - Interaction Between Syntactic Structure and Information Structure in the Processing of a Head-Final Language. AB - The effects of syntactic and information structures on sentence processing load were investigated using two reading comprehension experiments in Japanese, a head final SOV language. In the first experiment, we discovered the main effects of syntactic and information structures, as well as their interaction, showing that interaction of these two factors is not restricted to head-initial languages. The second experiment revealed that the interaction between syntactic structure and information structure occurs at the second NP (O of SOV and S of OSV), which, crucially, is a pre-head position, suggesting the incremental nature of the processing of both syntactic structure and information structure in head-final languages. PMID- 27229872 TI - Effects of over-the-counter sales restriction of antibiotics on substitution with medicines for symptoms relief of cold in Mexico and Brazil: time series analysis. AB - We evaluated changes in the use of non-steroidal anti-inflammatory drugs (NSAIDs), non-opioid analgesics and cough and cold medicines and its relation with the use of antibiotics after the over-the-counter (OTC) antibiotic sales restrictions in Mexico and Brazil. IMS Health provided retail quarterly data from the private sectors in Mexico and Brazil from the first quarter of 2007 to the first quarter of 2013. Data of each active substance of antibiotics, easily accessible medicines perceived as antibiotics substitutes (cough and cold medicines, analgesics and NSAIDs-the latter two being combined in the analyses), and medicines to control for external factors that can affect the medicines usage trend (antihypertensives) were converted from kilograms to defined daily doses per 1000 inhabitants days (DDD/TID). Interrupted time series were used to estimate changes in level of medicines use at the intervention point and slope after the regulation. The Gregory-Hansen cointegration test was used to explore the relation between the use of antibiotics and perceived substitutes. After the regulation in Mexico NSAIDs-analgesics usage level increased by 1.1 DDD/TID with a slope increase of 0.2 DDD/TID per quarter and the cough and cold medicines usage level increased by 0.4 DDD/TID. In Brazil NSAIDs-analgesics usage level increased by 1.9 DDD/TID, and cough and cold medicines did not change. In the two countries, NSAIDs-analgesics usage changes were related with antibiotic usage changes; in Mexico cough and cold medicines usage changes had a relation with the antibiotics usage changes. These results showed a substitution effect on the use of other medicines, especially NSAIDs and analgesics, after reinforcement of OTC antibiotics sales restrictions. These regulations aimed to improve the antibiotics use and as a consequence reduce antimicrobial resistance; however, this type of policies should be comprehensive and take into account the potential substitution effects on the use of other medicines. PMID- 27229873 TI - Service delivery: subspecialisation, emergencies, sharps injuries, personality traits and the ENT surgeon. PMID- 27229874 TI - Percent slope analysis of dynamic magnetic resonance imaging for assessment of chemotherapy response of osteosarcoma or Ewing sarcoma: systematic review and meta-analysis. AB - OBJECTIVE: The objective of this systematic review is to provide an up-to-date and unprecedented summary of percent slope analysis of dynamic magnetic resonance imaging (MRI) for the preoperative evaluation of the chemotherapy response of osteosarcoma or Ewing sarcoma. MATERIALS AND METHOD: Studies evaluating dynamic MRI for the preoperative evaluation of the chemotherapy response of osteosarcoma or Ewing sarcoma were systematically searched for in MEDLINE, EMBASE, and Web of Science. More than 60 % reduction of the slope of the time intensity curve derived from dynamic MRI was defined as a positive response. Pooled sensitivity and specificity for each study were calculated into 2 * 2 contingency tables. The DerSimonian-Laird random-effects method was used for determining the pooled diagnostic odds ratio and the area under curve (AUC) of the summary receiver operating characteristic (SROC) curve. RESULTS: A total of six studies with 66 patients who fulfilled all of the inclusion criteria were considered for the meta analysis. The pooled sensitivity and specificity were 0.73 (95 % CI, 0.54-0.88) and 0.83 (95 % CI, 0.67-0.94), respectively. A significant difference was found between the good and poor responders in the diagnostic odds ratio. The SROC curve showed that the AUC was 0.839, indicating diagnostic accuracy in estimating good therapy response. CONCLUSION: The slope of the time intensity curve derived from dynamic MRI was useful for evaluating the histological response of patients to neoadjuvant chemotherapy in osteosarcoma or Ewing sarcoma. PMID- 27229875 TI - Subtle radiographic findings of acute, isolated distal radioulnar joint dislocation. AB - Distal radioulnar dislocations typically occur in association with fractures of the distal radius and/or ulna. Rare isolated dislocations or subluxations are more difficult to diagnose and are initially missed in up to 50 % of cases. We present two cases of missed isolated volar rotatory dislocation of the distal radioulnar joint. Subtle, overlooked radiographic findings of abnormal radioulnar alignment and ulnar styloid projection are highlighted. The supplemental role of cross-sectional imaging is reviewed. Adequate clinical information, appropriate radiographic technique, and high index of suspicion are necessary for the accurate and timely diagnosis of this rare injury pattern. PMID- 27229876 TI - Electronic interactions of i, i + 1 dithioamides: increased fluorescence quenching and evidence for n-to-pi* interactions. AB - Thioamide residues can be effective, minimally-perturbing fluorescence quenching probes for studying protein folding and proteolysis. In order to increase the level of quenching, we have here explored the use of adjacent dithioamides. We have found that they are more effective fluorescence quenchers, as expected, but we have also observed unexpected changes in the thioamide absorption spectra that may arise from n-to-pi* interactions of the thiocarbonyls. We have made use of the increased quenching to improve the fluorescence turn-on of thioamide protease sensors. PMID- 27229877 TI - Two different dengue virus strains in the Japanese epidemics of 2014. AB - In late August 2014, dengue cases were reported in Japan, and a total of 162 cases were confirmed. In the present study, the envelope (E) gene sequences of 12 specimens from the dengue patients were determined. A dengue virus serotype 1 (DENV1) strain (D1/Hu/Shizuoka/NIID181/2014), which was clearly different from the first reported strain (D1/Hu/Saitama/NIID100/2014), was identified, although the other 11 specimens showed the same nucleotide sequences as D1/Hu/Saitama/NIID100/2014. The E gene sequences of two different strains were compared with those of nine DENV1 strains of imported cases in Japan in 2014. Phylogenetic analysis based on the E gene sequences showed that the D1/Hu/Saitama/NIID100/2014 strain was closely related to a strain isolated from an imported case from Singapore. Although no strain closely related to D1/Hu/Shizuoka/NIID181/2014 was found in these imported strains, the strain was closely related to isolates in Thailand and Taiwan in 2009. These data indicate that the dengue cases in Japan were caused by two different dengue virus strains that entered Japan through different means. PMID- 27229878 TI - IARS mutation causes prenatal death in Japanese Black cattle. AB - Isoleucyl-tRNA synthetase (IARS) c.235G > C (p.V79L) is a causative mutation for a recessive disease called IARS disorder in Japanese black cattle. The disease is involved in weak calf syndrome and is characterized by low birth weight, weakness and poor suckling. The gestation period is often slightly extended, implying that intrauterine growth is retarded. In a previous analysis of 2597 artificial insemination (AI) procedures, we suggested that the IARS mutation might contribute toward an increase in the incidence of prenatal death. In this study, we extended this analysis to better clarify the association between the IARS mutation and prenatal death. The IARS genotypes of 92 animals resulting from crosses between carrier (G/C) * G/C were 27 normal (G/G), 55 G/C and 10 affected animals (C/C) (expected numbers: 23, 46 and 23, respectively). Compared to the expected numbers, there were significantly fewer affected animals in this population (P < 0.05), suggesting that more than half of the affected embryos died prenatally. When the number of AI procedures examined was increased to 11 580, the frequency of re-insemination after G/C * G/C insemination was significantly higher at 61-140 days (P < 0.001). The findings suggested that the homozygous IARS mutation not only causes calf death, but also embryonic or fetal death. PMID- 27229879 TI - Correlation of intratumoral lymphatic microvessel density, vascular endothelial growth factor C and cell proliferation in salivary gland tumors. AB - Lymphatic dissemination is one of the most important pathways for metastasis in many solid tumors, including head and neck carcinomas. The lymphatic growth of cancer has been used as a significant independent adverse prognostic factor and provides information about tumor progression. Salivary gland tumors present different prognoses and have the ability to develop metastases; however, this information regarding the lymphatic spread is scarce. This paper quantifies the lymphatic microvessel density (LMD) in benign and malignant salivary gland tumors and analyzes the relationship between LMD and tumor expression of vascular endothelial growth factors C (VEGF-C) and the proliferative index. The results show that there is no correlation between LMD, VEGF-C and the proliferative index in the majority of salivary gland tumors analyzed, apart from polymorphous low grade carcinoma which exhibits statistical correlation between LMD and the proliferative index (p < 0.05). This correlation probably does not indicate a poor prognosis for this PLGA, since this is a low metastasizing carcinoma of the salivary glands. Different from other solid tumors, such as breast or prostatic carcinomas, there is no correlation between VEGF-C and LMD in salivary gland tumors, and so these traits are not able to estimate the metastatic risk or the prognosis of these tumors. PMID- 27229880 TI - Dutch food bank parcels do not meet nutritional guidelines for a healthy diet. AB - Nutritional intakes of food bank recipients and consequently their health status largely rely on the availability and quality of donated food in provided food parcels. In this cross-sectional study, the nutritional quality of ninety-six individual food parcels was assessed and compared with the Dutch nutritional guidelines for a healthy diet. Furthermore, we assessed how food bank recipients use the contents of the food parcel. Therefore, 251 Dutch food bank recipients from eleven food banks throughout the Netherlands filled out a general questionnaire. The provided amounts of energy (19 849 (sd 162 615) kJ (4744 (sd 38 866) kcal)), protein (14.6 energy percentages (en%)) and SFA (12.9 en%) in a single-person food parcel for one single day were higher than the nutritional guidelines, whereas the provided amounts of fruits (97 (sd 1441) g) and fish (23 (sd 640) g) were lower. The number of days for which macronutrients, fruits, vegetables and fish were provided for a single-person food parcel ranged from 1.2 (fruits) to 11.3 (protein) d. Of the participants, only 9.5 % bought fruits and 4.6 % bought fish to supplement the food parcel, 39.4 % used all foods provided and 75.7 % were (very) satisfied with the contents of the food parcel. Our study shows that the nutritional content of food parcels provided by Dutch food banks is not in line with the nutritional guidelines. Improving the quality of the parcels is likely to positively impact the dietary intake of this vulnerable population subgroup. PMID- 27229881 TI - Mathematical-based modeling and prediction of the effect of external stimuli on human gait. AB - Human gait is defined as human locomotion that is achieved through the movement of limbs. Different limb movement patterns result in different gait patterns. Different internal and external stimuli can affect the human gait. During the years, scientists have worked on the analysis of the effect of external stimuli on human gait, but no work has been reported yet that suggests a mathematical model for analysis of this effect by linking to the nervous system. Considering the diffusion of external stimuli to the nervous system on one side and fractality of human gait on another side, in this research, for the first time, we develop a model for prediction of human gait using fractional diffusion equation. Using this model, we will predict the effect of auditory stimuli on human gait. The model developed in this research is useful not only for analysis of the effect of auditory stimuli on human gait but can be used also for analysis of different types of stimuli on subjects with healthy conditions or having some types of diseases. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27229882 TI - Experimental evidence for beneficial effects of projected climate change on hibernating amphibians. AB - Amphibians are the most threatened vertebrates today, experiencing worldwide declines. In recent years considerable effort was invested in exposing the causes of these declines. Climate change has been identified as such a cause; however, the expectable effects of predicted milder, shorter winters on hibernation success of temperate-zone Amphibians have remained controversial, mainly due to a lack of controlled experimental studies. Here we present a laboratory experiment, testing the effects of simulated climate change on hibernating juvenile common toads (Bufo bufo). We simulated hibernation conditions by exposing toadlets to current (1.5 degrees C) or elevated (4.5 degrees C) hibernation temperatures in combination with current (91 days) or shortened (61 days) hibernation length. We found that a shorter winter and milder hibernation temperature increased survival of toads during hibernation. Furthermore, the increase in temperature and shortening of the cold period had a synergistic positive effect on body mass change during hibernation. Consequently, while climate change may pose severe challenges for amphibians of the temperate zone during their activity period, the negative effects may be dampened by shorter and milder winters experienced during hibernation. PMID- 27229883 TI - beta-Ecdysterone Protects SH-SY5Y Cells Against 6-Hydroxydopamine-Induced Apoptosis via Mitochondria-Dependent Mechanism: Involvement of p38(MAPK)-p53 Signaling Pathway. AB - Parkinson's disease (PD) is a neurological disorder pathologically characterized by loss of dopaminergic neurons in the substantia nigra. No curative therapy is available for PD. We recently found that phytoestrogen beta-ecdysterone (beta Ecd) is able to reduce MPP(+)-induced apoptosis in PC12 cells. This study investigated the potential of beta-Ecd to protect against SH-SY5Y cell apoptosis induced by the PD-related neurotoxin 6-hydroxydopamine (6-OHDA) and the underlying mechanism for this cytoprotection. In the present study, pretreatment with beta-Ecd significantly reduced 6-OHDA-induced apoptosis of SH-SY5Y cells by a mitochondria-dependent pathway, as indicated by downregulation of Bax and PUMA (p53 upregulated modulator of apoptosis) expression, suppressing DeltaPsim loss, inhibiting cytochrome c release, and attenuating caspase-9 activation. Furthermore, we showed that the inhibition of p38 mitogen-activated protein kinase (p38(MAPK))-dependent p53 promoter activity contributed to the protection of SH-SY5Y cells from apoptosis, which was validated by the use of SB203580 or p38beta dominant negative (DN) mutants. Additionally, knock-down apoptosis signal regulating kinase 1 (ASK1) by specific shRNA and blockade reactive oxygen species (ROS) by pharmacological inhibitor competently prevented beta-Ecd-mediated inhibition of p38(MAPK) and ASK1 phosphorylation, respectively. These data provide the first evidence that beta-Ecd protects SH-SY5Y cells against 6-OHDA induced apoptosis, possibly through mitochondria protection and p53 modulation via ROS-dependent ASK1-p38(MAPK) pathways. The neuroprotective effects of beta Ecd make it a promising candidate as a therapeutic agent for PD. PMID- 27229885 TI - Rhabdomyosarcoma in a Silver Carp. AB - Rhabdomyosarcoma is a primitive neoplasm that originates from skeletal muscle progenitor cells. In a routine inspection of a cyprinid farm in southwestern Iran, an approximately 2-year-old female Silver Carp was observed to have a raised mass located on the dorsolateral surface just caudal to the head. Macroscopic examination revealed a firm irregular fleshy pink mass (5 * 4 cm, depth = 3 cm) that appeared to arise from the subcutaneous musculature. Histologic sections were prepared using routine methods and separate sections were stained with hematoxylin-eosin and Massons' trichrome. Microscopically, the tumor mass was composed of spindle cells that were densely packed and arranged in long interwoven bundles. The nuclei were vesicular and oval to elongated or cigar shaped. Nuclear pleomorphism and multinucleate tumor giant cells were clearly evident. The neoplastic cell cytoplasm was eosinophilic with indistinct cell margins, and clear cross striations were observed in fibrils. The striated fibrils stained diffusely red with Masson's trichrome. This account represents the first reported occurrence of rhabdomyosarcoma in Silver Carp Hypophthalmichthys molitrix. Received July 10, 2015; accepted February 4, 2016. PMID- 27229884 TI - The potential role of in vivo reflectance confocal microscopy for evaluating oral cavity lesions: a systematic review. AB - BACKGROUND: Since the early 2000s, several studies have examined the application of reflectance confocal microscopy (RCM) to the oral cavity. This review gives an overview of the literature on reflectance confocal microscopy analysis of the oral cavity in vivo and identifies flaws in the studies, providing guidance to improve reflectance confocal microscopy applications and inform the design of future studies. METHODS: The PubMed, ISI, Scopus, and Cochrane Library databases were searched for publications on RCM using the terms 'reflectance confocal microscopy' in combination with 'mouth' and other terms related to the topic of interest. RESULTS: The search gave 617 results. Seventeen studies were included in our final analysis. We decided to organize the selected articles according to four topics: healthy mucosa, autoimmune diseases, cancer and precancerous lesions, and hard dental tissues. CONCLUSION: Although reflectance confocal microscopy is promising for diagnosing and monitoring oral pathology, it has shortcomings and there are still too few publications on this topic. Further studies are needed to increase the quantity and quality of the results, to translate research into clinical practice. PMID- 27229887 TI - Insulin clearance: an underappreciated modulator of plasma insulin concentration. AB - Plasma glucose concentrations are tightly regulated and maintained within a narrow range in non-diabetic individuals. Maintenance of this physiological state is primarily a function of the ability of the pancreatic beta-cells to modify insulin secretion rate (ISR), thus preventing wide-swings in plasma glucose concentrations. As a consequence, and in contrast to plasma glucose concentrations, plasma insulin concentrations vary substantially in non-diabetic individuals. Although differences in ISR are primarily responsible for the variability in plasma insulin concentration, there is increasing evidence that differences in insulin clearance rate (ICR) also play a role in regulation of plasma insulin concentration. The goal of this mini-review is to highlight situations that demonstrate the important role of ICR in both insulin and glucose homeostasis. PMID- 27229888 TI - Sexual harassment and emotional and behavioural symptoms in adolescence: stronger associations among boys than girls. AB - PURPOSE: To study the associations between subjection to sexual harassment and emotional (depression) and behavioural (delinquency) symptoms among 14-to-18-year old adolescents, and gender differences within these associations. METHODS: 90,953 boys and 91,746 girls aged 14-18 participated in the School Health Promotion Study (SHPS), a school-based survey designed to examine the health, health behaviours, and school experiences of teenagers. Experiences of sexual harassment were elicited with five questions addressing five separate forms of harassment. Depression was measured by the 13-item Beck Depression Inventory and delinquency with a modified version of the International Self-Report Delinquency Study (ISRD) instrument. Data were analysed using cross-tabulations with Chi square statistics and logistic regression. RESULTS: All sexual harassment experiences studied were associated with both depression (adjusted odds ratios varied from 2.2 to 2.7 in girls and from 2.0 to 5.1 in boys) and delinquency (adjusted odds ratios 3.1-5.0 in girls and 1.7-6.9 in boys). Sexual name-calling had a stronger association with depression and with delinquency in girls (adjusted odds ratios, respectively, 2.4 and 4.2), than in boys (adjusted odds ratios, respectively, 2.0 and 1.7), but otherwise stronger associations with emotional and behavioural symptoms were seen in boys. CONCLUSIONS: Subjection to sexual harassment is associated with both emotional and behavioural symptoms in both girls and boys. The associations are mostly stronger for boys. Boys subjected to sexual harassment may feel particularly threatened regarding their masculinity, and there may be less support available for boys traumatised due to sexual harassment. PMID- 27229889 TI - Real-life clinical practice of onabotulinum toxin A intravesical injections for overactive bladder wet: an Italian consensus statement. AB - PURPOSE: We developed a consensus on best practice in the real-life management of patients with overactive bladder (OAB) with onabotulinumtoxin A (Onabot/A). METHODS: In March 2015, an interdisciplinary conference was convened. Eleven panelists were invited to review the literature, to present their personal experience and to respond to a number of questions from: "when do we propose Onabot/A treatment" to "when do you decide to re-inject a patient?" A summary of findings of the meeting was provided to all panelists for review and approval. RESULTS: The following statements were agreed. Refractory OAB can be defined based on lack of adherence to first- and second-line treatments for OAB regardless of the underlying cause. Onabot/A treatment can be proposed to refractory OAB patients provided they are willing to perform intermittent catheterization if needed. Before treatment, uroflowmetry with post-void residual evaluation is needed to rule out voiding dysfunction, while urodynamics should be done in cases of complicated OAB wet. Urinary tract infection should be ruled out or treated before the injection. The injection can be performed in the endoscopy room, in an out-patient basis, with local anesthesia. Antibiotic prophylaxis should be initiated with oral drugs. A first follow-up visit should be planned 10 15 days after treatment and residual urine checked. Retreatment can be decided on patients' request, when symptoms worsen. CONCLUSIONS: This consensus document provides a guide for the management of refractory OAB patients with Onabot/A in real life. A number of questions about the effectiveness of Onabot/A in real life remain open. PMID- 27229886 TI - The novel compound Sul-121 inhibits airway inflammation and hyperresponsiveness in experimental models of chronic obstructive pulmonary disease. AB - COPD is characterized by persistent airflow limitation, neutrophilia and oxidative stress from endogenous and exogenous insults. Current COPD therapy involving anticholinergics, beta2-adrenoceptor agonists and/or corticosteroids, do not specifically target oxidative stress, nor do they reduce chronic pulmonary inflammation and disease progression in all patients. Here, we explore the effects of Sul-121, a novel compound with anti-oxidative capacity, on hyperresponsiveness (AHR) and inflammation in experimental models of COPD. Using a guinea pig model of lipopolysaccharide (LPS)-induced neutrophilia, we demonstrated that Sul-121 inhalation dose-dependently prevented LPS-induced airway neutrophilia (up to ~60%) and AHR (up to ~90%). Non-cartilaginous airways neutrophilia was inversely correlated with blood H2S, and LPS-induced attenuation of blood H2S (~60%) was prevented by Sul-121. Concomitantly, Sul-121 prevented LPS-induced production of the oxidative stress marker, malondialdehyde by ~80%. In immortalized human airway smooth muscle (ASM) cells, Sul-121 dose-dependently prevented cigarette smoke extract-induced IL-8 release parallel with inhibition of nuclear translocation of the NF-kappaB subunit, p65 (each ~90%). Sul-121 also diminished cellular reactive oxygen species production in ASM cells, and inhibited nuclear translocation of the anti-oxidative response regulator, Nrf2. Our data show that Sul-121 effectively inhibits airway inflammation and AHR in experimental COPD models, prospectively through inhibition of oxidative stress. PMID- 27229890 TI - Diurnal Variations in Psychological Distress in Chronic Obstructive Pulmonary Disease. AB - PURPOSE: The aim of this study was to investigate the association between depressive symptoms severity and amplitude of diurnal variations in depression symptoms in patients with chronic obstructive pulmonary disease (COPD). DESIGN: Prospective, observational proof-of-concept study. METHODS: Fourteen participants with moderate/severe COPD completed a 20-item Center for Epidemiologic Studies Depression Scale (CES-D) estimating depressive symptoms severity. Throughout one week, the four-item very short version of the CES-D was completed every day in the morning, afternoon, and evening. FINDINGS: Strong positive correlations were observed between depressive severity and the mean range of diurnal variations in positive (r = .61) and depressed affects (r = .67), somatic complaints (r = .82), and disturbed interpersonal relationships (r = .71). CONCLUSION: In COPD patients, a greater diurnal variation in depression symptoms was associated with greater depression severity. This relationship seems independent of COPD severity. CLINICAL RELEVANCE: Diurnal variation in the symptoms of depression is a new method of identifying depression severity in COPD. PMID- 27229891 TI - A pqr2 mutant encodes a defective polyamine transporter and is negatively affected by ABA for paraquat resistance in Arabidopsis thaliana. AB - Despite the paraquat-resistant mutants that have been reported in plants, this study identified a novel A. thaliana mutant (pqr2) from an XVE inducible activation library based on its resistance to 2 MUM paraquat. The pqr2 mutant exhibited a termination mutation in the exon of AT1G31830/PAR1/PQR2, encoded a polyamine uptake transporter AtPUT2/PAR1/PQR2. The PQR2 mutation could largely reduce superoxide accumulation and cell death in the pqr2 plants under paraquat treatment. Moreover, compared with wild type, the pqr2 mutant exhibited much reduced tolerance to putrescine, a classic polyamine compound, which confirmed that PQR2 encoded a defective polyamine transporter. Notably, co-treated with ABA and paraquat, both pqr2 mutant and wild type exhibited a lethal phenotype from seed germination, but the wild type like pqr2 mutant, could remain paraquat resistance while co-treated with high dosage of Na2WO4, an ABA synthesis inhibitor. Gene expression analysis suggested that ABA signaling should widely regulate paraquat-responsive genes distinctively in wild type and pqr2 mutant. Hence, this study has for the first time reported about ABA negative effect on paraquat-resistance in A. thaliana, providing insight into the ABA signaling involved in the oxidative stress responses induced by paraquat in plants. PMID- 27229892 TI - Attention Deficit Hyperactivity Disorder on YouTube: Framing, Anchoring, and Objectification in Social Media. AB - This study investigated videos about Attention Deficit Hyperactivity Disorder (ADHD) on YouTube in terms of issues, sources, and episodic-thematic aspects. A total of 685 videos uploaded onto YouTube between 2006 and 2014 were content analyzed. Results demonstrated that the top three key issues about ADHD were symptom, child, and treatment. Doctor, patient, and supporter were the three most interviewed sources. Videos from the public sector including the government, company representative, and public organizations were relatively rare compared to other sources suggesting the potential for a greater role for the government and public sector contributions to YouTube to provide credible information relevant to public awareness, campaigns, and policy announcements. Meanwhile, many personal videos in the episodic frame advocated social solutions. This result implies that YouTube videos about health information from the private sectors have the potential to affect change at the social level. PMID- 27229893 TI - Safety and Efficacy of Autologous Plasma Rich in Growth Factors Eye Drops for the Treatment of Evaporative Dry Eye. AB - PURPOSE: To provide preliminary information about the safety and efficacy of plasma rich in growth factors (PRGF) in the treatment of evaporative dry eye (EDE) and analyze the influence of certain variables on treatment outcomes. METHODS: This retrospective study included patients with EDE treated between January 2011 and December 2013. Outcome measures including signs and symptoms of the disease were evaluated before and after treatment. The influence of some of the patient's clinical variables on results was assessed. Safety assessment was also performed. RESULTS: Eighty-three patients with a total of 156 eyes were evaluated. Statistically significant reductions in the Ocular Surface Disease Index (38.2%), best-corrected visual acuity (27.4%), Visual Analogue Scale scores for frequency (32%) and severity (34%), and a significant improvement in the Schirmer test scores (177.5%) were observed (p < 0.05). The results were stratified according to the identified potential effect modifiers. Only four adverse events were reported. All of them were mild and resolved within a few days. CONCLUSIONS: Results suggest that PRGF eye drops could be a safe and effective treatment in reducing EDE signs and symptoms. When treating patients, the possible influence of some clinical variables must be taken into account. PMID- 27229894 TI - Hemoglobin Value Is the Most Important Factor in the Development of Hand-Foot Syndrome under the Capecitabine Regimen. AB - BACKGROUND: Hand-foot syndrome (HFS) is a common side effect that has a high occurrence rate with capecitabine (Cape) chemotherapy. However, little is known about the risk factors of developing HFS under the Cape regimen. Our aim was to examine these risk factors. METHODS: A univariate analysis was used to determine the risk factors associated with developing HFS, and we calculated the effect sizes between the patients who developed HFS compared to those who did not. RESULTS: Of the 52 patients enrolled in our research, 24 (46.2%) developed HFS. This group was significantly associated with hemoglobin (Hb) values (p < 0.001), and the effect size (1.21) was more than moderate. The receiver operating characteristic curve analysis confirmed 12 mg/dl Hb as the best diagnostic cut off value for developing HFS. The sensitivity and specificity were 75.5 and 88.2%, respectively. Patients who had Hb values of 12 or below who developed HFS had longer median times without HFS compared to patients with high Hb values (115 vs. 75 days, p = 0.30, hazard ratio = 1.42, 95% CI 0.73-2.76) and a greater area under the Kaplan-Meier curves (p < 0.05). CONCLUSION: This research suggests that the Hb value is an important factor for developing HFS. PMID- 27229895 TI - US senators urge FDA to take action over wasted cancer drugs. PMID- 27229896 TI - An RNA-aptamer-based two-color CRISPR labeling system. AB - The spatial organization and dynamics of chromatin play important roles in essential biological functions. However, direct visualization of endogenous genomic loci in living cells has proven to be laborious until the recent development of CRISPR-Cas9-based chromatin labeling methods. These methods rely on the recognition of specific DNA sequences by CRISPR single-guide RNAs (sgRNAs) and fluorescent-protein-fused catalytically inactive Cas9 to label specific chromatin loci in cells. Previously, multicolor chromatin labeling has been achieved using orthogonal Cas9 proteins from different bacterial species fused to different fluorescent proteins. Here we report the development of an alternative two-color CRISPR labeling method using only the well-characterized Streptococcus pyogenes Cas9, by incorporating MS2 or PP7 RNA aptamers into the sgRNA. The MS2 or PP7 aptamers then recruit the corresponding MS2 or PP7 coat proteins fused with different fluorescent proteins to the target genomic loci. Here we demonstrate specific and orthogonal two-color labeling of repetitive sequences in living human cells using this method. By attaching the MS2 or PP7 aptamers to different locations on the sgRNA, we found that extending the tetraloop and stem loop 2 of the sgRNA with MS2 or PP7 aptamers enhances the signal-to-background ratio of chromatin imaging. PMID- 27229897 TI - A Method by Which to Assess the Scalability of Field-Based Fitness Tests of Cardiorespiratory Fitness Among Schoolchildren. AB - Previous research has reported the validity and reliability of a range of field based tests of children's cardiorespiratory fitness. These two criteria are critical in ensuring the integrity and credibility of data derived through such tests. However, the criterion of scalability has received little attention. Scalability determines the degree to which tests developed on small samples in controlled settings might demonstrate real-world value, and is of increasing interest to policymakers and practitioners. The present paper proposes a method by which the scalability of cardiorespiratory field-based tests suitable for school-aged children might be assessed. We developed an algorithm to estimate scalability based on a six-component model; delivery, evidence of operating at scale, effectiveness, costs, resource requirements and practical implementation. We tested the algorithm on data derived through a systematic review of research that has used relevant fitness tests. A total of 229 studies that had used field based cardiorespiratory fitness tests to measure children's fitness were identified. Initial analyses indicated that the 5-min run test did not meet accepted criteria for reliability, whilst the 6-min walk test likewise failed to meet the criteria for validity. Of the remainder, a total of 28 studies met the inclusion criteria, 22 reporting the 20-m shuttle-run and seven the 1-mile walk/run. Using the scalability algorithm we demonstrate that the 20-m shuttle run test is substantially more scalable than the 1-mile walk/run test, with tests scoring 34/48 and 25/48, respectively. A comprehensive analysis of scalability was prohibited by the widespread non-reporting of data, for example, those relating to cost-effectiveness. Of all sufficiently valid and reliable candidate tests identified, using our algorithm the 20-m shuttle run test was identified as the most scalable. We hope that the algorithm will prove useful in the examination of scalability in either new data relating to existing tests or in data pertaining to new tests. PMID- 27229898 TI - Association Between Absolute Neutrophil Count and Variation at TCIRG1: The NHLBI Exome Sequencing Project. AB - Neutrophils are a key component of innate immunity. Individuals with low neutrophil count are susceptible to frequent infections. Linkage and association between congenital neutropenia and a single rare missense variant in TCIRG1 have been reported in a single family. Here, we report on nine rare missense variants at evolutionarily conserved sites in TCIRG1 that are associated with lower absolute neutrophil count (ANC; p = 0.005) in 1,058 participants from three cohorts: Atherosclerosis Risk in Communities (ARIC), Coronary Artery Risk Development in Young Adults (CARDIA), and Jackson Heart Study (JHS) of the NHLBI Grand Opportunity Exome Sequencing Project (GO ESP). These results validate the effects of TCIRG1 coding variation on ANC and suggest that this gene may be associated with a spectrum of mild to severe effects on ANC. PMID- 27229899 TI - Pneumatic-aided micro-molding for flexible fabrication of homogeneous and heterogeneous cell-laden microgels. AB - Microgels are favorable for numerous applications such as drug delivery, biomaterials science and tissue engineering. Conventionally, photolithographic methods and micro-molding techniques are extensively exploited to prepare microgels; however, they are, respectively, limited to photocrosslinkable polymers and inadequate to generate serially patterned hydrogels due to the static nature of utilized molds. Herein, we proposed a simple and versatile approach, termed pneumatic-aided micro-molding (PAM), to flexibly fabricate microgels with precise control over multiple cell types and microarchitectures of hydrogels through strategically designed pneumatic microvalves. Using the PAM approach, different cells were encapsulated in various hydrogels that had well defined geometries. Additionally, single/multiple micro-channeled cell-laden microgels were fabricated, of which the shape, number and arrangement could be finely tuned by varying microvalve configurations. Moreover, multi-compartmental microgels comprising composite hydrogel structures were engineered following a two-step PAM, which demonstrated the utility for biomimetically constructing a three-dimensional (3D) liver microtissue composed of a radially orchestrated network of hepatic cords and sinusoids. The resulting microtissue resembled the organizational complexity of the liver lobule and was applied for the evaluation of acetaminophen-induced hepatotoxicity. Collectively, the PAM strategy could be a useful and powerful tool in biomedical engineering, in vitro 3D cell culture, and fundamental biological studies. PMID- 27229900 TI - Postherpetic pseudohernia: delayed onset of paresis of abdominal muscles due to herpes zoster causing an ipsilateral abdominal bulge. AB - Postherpetic pseudohernia causes an abdominal bulge as well as an abdominal wall herniation. This disease is one of the neurological complications of herpes zoster and essentially consists of paresis of ipsilateral abdominal muscles. Postherpetic pseudohernia may be mistaken for abdominal wall herniation because it is not well known. We describe two cases presenting an abdominal bulge. The ipsilateral abdominal bulge appeared after recovery from abdominal zoster. Abdominal CT showed no evidence of a herniation or mass. We diagnosed a postherpetic pseudohernia. One of the patients recovered spontaneously 4 months after the onset, and the other partially recovered after 2 months. This disease can be expected to disappear spontaneously, unlike abdominal herniation requiring surgery. It has been reported that 79.3% of patients eventually recovered spontaneously. For surgeons and general practitioners, it is beneficial to keep this disease in mind when examining a patient presenting an abdominal bulge. PMID- 27229901 TI - Nanoparticles and direct immunosuppression. AB - Targeting the immune system with nanomaterials is an intensely active area of research. Specifically, the capability to induce immunosuppression is a promising complement for drug delivery and regenerative medicine therapies. Many novel strategies for immunosuppression rely on nanoparticles as delivery vehicles for small-molecule immunosuppressive compounds. As a consequence, efforts in understanding the mechanisms in which nanoparticles directly interact with the immune system have been overshadowed. The immunological activity of nanoparticles is dependent on the physiochemical properties of the nanoparticles and its subsequent cellular internalization. As the underlying factors for these reactions are elucidated, more nanoparticles may be engineered and evaluated for inducing immunosuppression and complementing immunosuppressive drugs. This review will briefly summarize the state-of-the-art and developments in understanding how nanoparticles induce immunosuppressive responses, compare the inherent properties of nanomaterials which induce these immunological reactions, and comment on the potential for using nanomaterials to modulate and control the immune system. PMID- 27229902 TI - Engineering galectin-glycan interactions for immunotherapy and immunomodulation. AB - Galectins, a 15-member family of soluble carbohydrate-binding proteins, are receiving increasing interest as therapeutic targets for immunotherapy and immunomodulation due to their role as extracellular signals that regulate innate and adaptive immune cell phenotype and function. However, different galectins can have redundant, synergistic, or antagonistic signaling activity in normal immunological responses, such as resolution of inflammation and induction of antigen-specific tolerance. In addition, certain galectins can be hijacked to promote progression of immunopathologies, such as tumor immune privilege, metastasis, and viral infection, while others can inhibit these processes. Thus, eliciting a desired immunological outcome will likely necessitate therapeutics that can precisely enhance or inhibit particular galectin-glycan interactions. Multivalency is an important determinant of the affinity and specificity of natural galectin-glycan interactions, and is emerging as a key design element for therapeutics that can effectively manipulate galectin bioactivity. This minireview surveys current molecular and biomaterial engineering approaches to create therapeutics that can stabilize galectin multivalency or recapitulate natural glycan multivalency (i.e. "the glycocluster effect"). In particular, we highlight examples of using natural and engineered multivalent galectins for immunosuppression and immune tolerance, with a particular emphasis on treating autoimmune diseases or avoiding transplant rejection. In addition, we present examples of multivalent inhibitors of galectin-glycan interactions to maintain or restore T-cell function, with a particular emphasis on promoting antitumor immunity. Finally, we discuss emerging opportunities to further engineer galectin glycan interactions for immunotherapy and immunomodulation. PMID- 27229903 TI - Monocytes and macrophages in tissue repair: Implications for immunoregenerative biomaterial design. AB - Monocytes and macrophages play a critical role in tissue development, homeostasis, and injury repair. These innate immune cells participate in guiding vascular remodeling, stimulation of local stem and progenitor cells, and structural repair of tissues such as muscle and bone. Therefore, there is a great interest in harnessing this powerful endogenous cell source for therapeutic regeneration through immunoregenerative biomaterial engineering. These materials seek to harness specific subpopulations of monocytes/macrophages to promote repair by influencing their recruitment, positioning, differentiation, and function within a damaged tissue. Monocyte and macrophage phenotypes span a continuum of inflammatory (M1) to anti-inflammatory or pro-regenerative cells (M2), and their heterogeneous functions are highly dependent on microenvironmental cues within the injury niche. Increasing evidence suggests that division of labor among subpopulations of monocytes and macrophages could allow for harnessing regenerative functions over inflammatory functions of myeloid cells; however, the complex balance between necessary functions of inflammatory versus regenerative myeloid cells remains to be fully elucidated. Historically, biomaterial-based therapies for promoting tissue regeneration were designed to minimize the host inflammatory response; although, recent appreciation for the roles that innate immune cells play in tissue repair and material integration has shifted this paradigm. A number of opportunities exist to exploit known signaling systems of specific populations of monocytes/macrophages to promote repair and to better understand the biological and pathological roles of myeloid cells. This review seeks to outline the characteristics of distinct populations of monocytes and macrophages, identify the role of these cells within diverse tissue injury niches, and offer design criteria for immunoregenerative biomaterials given the intrinsic inflammatory response to their implantation. PMID- 27229904 TI - Strategies for cell membrane functionalization. AB - The ability to rationally manipulate and augment the cytoplasmic membrane can be used to overcome many of the challenges faced by conventional cellular therapies and provide innovative opportunities when combined with new biotechnologies. The focus of this review is on emerging strategies used in cell functionalization, highlighting both pioneering approaches and recent developments. These will be discussed within the context of future directions in this rapidly evolving field. PMID- 27229905 TI - An introduction to biomaterial-based strategies for curbing autoimmunity. AB - Recently, scientists have made significant progress in the development of immunotherapeutics that correct aberrant, autoimmune responses. Yet, concerns about the safety, efficacy, and wide scale applicability continue to hinder use of contemporary, immunology-based strategies. There is a clear need for therapies that finely control molecular and cellular elements of the immune system. Biomaterial engineers have taken up this challenge to develop therapeutics with selective spatial and temporal control of immune cells. In this review, we introduce the immunology of autoimmune disorders, survey the current therapeutic strategies for autoimmune diseases, and highlight the ongoing research efforts to engineer the immune system using biomaterials, for positive therapeutic outcomes in treatment of autoimmune disorders. PMID- 27229906 TI - The effect of acoustic radiation force on osteoblasts in cell/hydrogel constructs for bone repair. AB - Ultrasound, or the application of acoustic energy, is a minimally invasive technique that has been used in diagnostic, surgical, imaging, and therapeutic applications. Low-intensity pulsed ultrasound (LIPUS) has been used to accelerate bone fracture repair and to heal non-union defects. While shown to be effective the precise mechanism behind its utility is still poorly understood. In this study, we considered the possibility that LIPUS may be providing a physical stimulus to cells within bony defects. We have also evaluated ultrasound as a means of producing a transdermal physical force that could stimulate osteoblasts that had been encapsulated within collagen hydrogels and delivered to bony defects. Here we show that ultrasound does indeed produce a measurable physical force and when applied to hydrogels causes their deformation, more so as ultrasound intensity was increased or hydrogel stiffness decreased. MC3T3 mouse osteoblast cells were then encapsulated within hydrogels to measure the response to this force. Statistically significant elevated gene expression for alkaline phosphatase and osteocalcin, both well-established markers of osteoblast differentiation, was noted in encapsulated osteoblasts (p < 0.05), suggesting that the physical force provided by ultrasound may induce bone formation in part through physically stimulating cells. We have also shown that this osteoblastic response is dependent in part on the stiffness of the encapsulating hydrogel, as stiffer hydrogels resulted in reducing or reversing this response. Taken together this approach, encapsulating cells for implantation into a bony defect that can potentially be transdermally loaded using ultrasound presents a novel regenerative engineering approach to enhanced fracture repair. PMID- 27229907 TI - A Systematic Review of Drug Therapies for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. AB - PURPOSE: The pathogenesis of chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is complex and remains poorly understood. Evidence regarding the use of drug therapies in CFS/ME is currently limited and conflicting. The aim of this systematic review was to examine the existing evidence on the efficacy of drug therapies and determine whether any can be recommended for patients with CFS/ME. METHODS: MEDLINE, EMBASE, and PubMed databases were searched from the start of their records to March 2016 to identify relevant studies. Randomized controlled trials focusing solely on drug therapy to alleviate and/or eliminate chronic fatigue symptoms were included in the review. Any trials that considered graded exercise therapy, cognitive behavior therapy, adaptive pacing, or any other nonpharmaceutical treatment plans were excluded. The inclusion criteria were examined to ensure that study participants met specific CFS/ME diagnostic criteria. Study size, intervention, and end point outcome domains were summarized. FINDINGS: A total of 1039 studies were identified with the search terms; 26 studies met all the criteria and were considered suitable for review. Three different diagnostic criteria were identified: the Holmes criteria, International Consensus Criteria, and the Fukuda criteria. Primary outcomes were identified as fatigue, pain, mood, neurocognitive dysfunction and sleep quality, symptom severity, functional status, and well being or overall health status. Twenty pharmaceutical classes were trialed. Ten medications were shown to be slightly to moderately effective in their respective study groups (P < 0.05). IMPLICATIONS: These findings indicate that no universal pharmaceutical treatment can be recommended. The unknown etiology of CFS/ME, and complications arising from its heterogeneous nature, contributes to the lack of clear evidence for pharmaceutical interventions. However, patients report using a large number and variety of medications. This finding highlights the need for trials with clearly defined CFS/ME cohorts. Trials based on more specific criteria such as the International Consensus Criteria are recommended to identify specific subgroups of patients in whom treatments may be beneficial. PMID- 27229908 TI - Rescue Sedation With Intranasal Dexmedetomidine for Pediatric Ophthalmic Examination After Chloral Hydrate Failure: A Randomized, Controlled Trial. AB - PURPOSE: It is a challenge to rescue ophthalmology examinations performed in children in the sedation room after initial chloral hydrate failure. Intranasal dexmedetomidine can be used in rescue sedation in children undergoing computed tomography. The present study aimed to assess the efficacy and tolerability of intranasal dexmedetomidine use in children undergoing ophthalmic examination after chloral hydrate failure. METHODS: Sixty uncooperative pediatric patients with cataract (aged 5-36 months; weight, 7-15 kg) presented for follow-up ophthalmic examination. Patients who experienced chloral hydrate failure were randomized to 1 of 2 groups to receive intranasal dexmedetomidine 1 or 2 MUg/kg for rescue sedation. Each group contained 30 patients. The primary outcome was the rate of a successful ophthalmic examination. Secondary outcomes included sedation onset time, recovery time, duration of examination, discharge time, and adverse events, including percentage of heart rate reduction, respiratory depression, vomiting, and postsedative agitation. FINDINGS: A successful ophthalmic examination was achieved in 93.3% (28/30) of patients in the 2-MUg/kg dose group and in 66.7% (20/30) of patients in the 1-MUg/kg dose group (P = 0.021). The onset time, recovery time, and discharge time did not significantly differ between the 2 groups. None of the patients required clinical intervention due to heart rate reduction, and none of the patients in either group experienced vomiting, respiratory depression, or agitation after the administration of dexmedetomidine. IMPLICATIONS: In children undergoing ophthalmic examination, intranasal dexmedetomidine can be administered in the sedation room for rescue sedation after chloral hydrate failure, with the 2-MUg/kg dose being more efficacious than the 1-MUg/kg dose, as measured by success rate. ClinicalTrials.gov identifier: NCT02077712. PMID- 27229909 TI - Refining the definition of the choroidal-scleral interface. PMID- 27229910 TI - LC/QTOF-MS fragmentation of N-nitrosodimethylamine precursors in drinking water supplies is predictable and aids their identification. AB - N-Nitrosodimethylamine (NDMA) is carcinogenic in rodents and occurs in chloraminated drinking water and wastewater effluents. NDMA forms via reactions between chloramines and mostly unidentified, N-containing organic matter. We developed a mass spectrometry technique to identify NDMA precursors by analyzing 25 model compounds with LC/QTOF-MS. We searched isolates of 11 drinking water sources and 1 wastewater using a custom MATLAB(r) program and extracted ion chromatograms for two fragmentation patterns that were specific to the model compounds. Once a diagnostic fragment was discovered, we conducted MS/MS during a subsequent injection to confirm the precursor ion. Using non-target searches and two diagnostic fragmentation patterns, we discovered 158 potential NDMA precursors. Of these, 16 were identified using accurate mass combined with fragment and retention time matches of analytical standards when available. Five of these sixteen NDMA precursors were previously unidentified in the literature, three of which were metabolites of pharmaceuticals. Except methadone, the newly identified precursors all had NDMA molar yields of less than 5%, indicating that NDMA formation could be additive from multiple compounds, each with low yield. We demonstrate that the method is applicable to other disinfection by-product precursors by predicting and verifying the fragmentation patterns for one nitrosodiethylamine precursor. PMID- 27229911 TI - The potential of identification of a malignancy-associated biomarker in breast cancer diagnosis and research: hTERT gene DNA methylation. AB - BACKGROUND: DNA hypermethylation has been documented to be prominent at a CpG island rich region about 600 bp upstream the transcription start site of the hTERT gene using qualitative methylation specific PCR on DNA isolated from tumor cell lines. In order to assess the potential significance of this biomarker in breast cancer research and diagnosis, we explored if such findings are reproducible on surgically resected fresh breast tumor cells. METHODS: Using quantitative pyrosequencing technology, we investigated and present methylation status of four CpG islands of this region in a cohort of 77 invasive breast carcinomas using normal breast tissue as controls. RESULTS: Globally, a significant hypermethylation in tumor cells was observed in the four CpG islands as a sum, in comparison to methylation of the normal breast tissue. Individually, certain CpG islands displayed methylation greater than 50% in about 3/4 of the 77 breast cancers, but in none of the normal breast tissue. Our results highlight the value of DNA hypermethylation in the -600 bp region of the hTERT gene as a potential marker for breast cancer diagnosis. CONCLUSIONS: We believe that integration of this novel, malignancy-associated molecular testing with morphology is of significant value in the accurate interpretation of small tumor sample size obtained via fine needle aspiration biopsy, ductal lavage, and nipple fluid aspirates both in clinical practice and in breast cancer research. Diagn. Cytopathol. 2016;44:670-675. (c) 2016 Wiley Periodicals, Inc. PMID- 27229913 TI - Erratum. PMID- 27229912 TI - (p40)2-Fc reduces immune-inflammatory response through the activation of T cells in collagen induced arthritis mice. AB - IL-12p40 homodimer, a natural antagonist of IL-12 and IL-23, performs an important role in the expression of proinflammatory cytokines that is essential for Th1 and Th17 immune responses. Here, we reveal the therapeutic and immunosuppressive effect of the IL-12p40 subunit ((p40)2-Fc) in an experimental autoimmune arthritis model. We hypothesized that (p40)2-Fc may reduce the inflammatory response and the activation of T cells. In this study, we intraperitoneally injected (p40)2-Fc into collagen induced arthritis (CIA) mice to identify whether (p40)2-Fc attenuates CIA severity. (p40)2-Fc reduced the development of CIA, joint inflammation and cartilage destruction. (p40)2-Fc also significantly decreased the concentration of serum immunoglobulin as well as the number of T cells and C II specific T cells. In addition, osteoclastogenesis in (p40)2-Fc treated mice was down-regulated compared to the mice treated with (p40)2-Fc control. We observed that (p40)2-Fc treatment alleviates arthritis in mice with CIA, reducing inflammation and osteoclast differentiation. These findings suggest that (p40)2-Fc can be a potential therapeutic approach for autoimmune arthritis. PMID- 27229914 TI - Serum-based protein profiles of Alzheimer's disease and mild cognitive impairment in elderly Hispanics. AB - AIM: To describe the biomarker profiles in elderly Panamanians diagnosed with Alzheimer's disease (AD), mild cognitive impairment (MCI) or no impairment using serum-based biomarkers. METHODS: Twenty-four proteins were analyzed using an electrochemiluminescence-based multiplex biomarker assay platform. A biomarker profile was generated using random forest analyses. RESULTS: Two proteins differed among groups: IL-18 and T-lymphocyte-secreted protein I-309. The AD profile was highly accurate and independent of age, gender, education and Apolipoprotein E epsilon4 status. AD and MCI profiles had substantial overlap among the top markers, suggesting common functions in AD and MCI but differences in their relative importance. CONCLUSION: Our results underscore the potential influence of genetic and environmental differences within Hispanic populations on the proteomic profile of AD. PMID- 27229917 TI - Erratum: Transcriptomes of parents identify parenting strategies and sexual conflict in a subsocial beetle. PMID- 27229918 TI - The Cycle of Violence Revisited: Childhood Victimization, Resilience, and Future Violence. AB - The individual and social protective factors that help break the cycle of violence are examined. Specifically, this study investigates (a) the individual and social protective factors that reduce violent offending among previously victimized children, and (b) whether certain protective factors are more or less important depending on the type and frequency of childhood victimization experienced. Data on young adults from Wave III of the National Longitudinal Study of Adolescent to Adult Health are used (N = 13,116). Negative binomial regression models are estimated to examine the protective factors that promote resiliency to violent offending among individuals who reported being physically and sexually victimized as children. Results indicate that a number of individual and social protective factors reduce violent offending in young adulthood. With a few exceptions, these factors are specific to the type, frequency, and comorbidity of abuse experienced. The results suggest a number of promising approaches to break the cycle of violence among previously victimized children. Future research should move beyond explaining the cycle of violence to examine how the cycle may be broken. PMID- 27229916 TI - Major Histocompatibility Complex class I proteins are critical for maintaining neuronal structural complexity in the aging brain. AB - Major histocompatibility complex class I (MHCI) proteins have been implicated in neuronal function through the modulation of neuritogenesis, synaptogenesis, synaptic plasticity, and memory consolidation during development. However, the involvement of MHCI in the aged brain is unclear. Here we demonstrate that MHCI deficiency results in significant dendritic atrophy along with an increase in thin dendritic spines and a reduction in stubby spines in the hippocampus of aged (12 month old) mice. Ultrastructural analyses revealed a decrease in spine head diameter and post synaptic density (PSD) area, as well as an increase in overall synapse density, and non-perforated, small spines. Interestingly, we found that the changes in synapse density and morphology appear relatively late (after the age of 6 months). Finally, we found a significant age dependent increase in the levels of the glutamate receptor, GluN2B in aged MHCI knockout mice, with no change in GluA2/3, VGluT1, PSD95 or synaptophysin. These results indicate that MHCI may be also be involved in maintaining brain integrity at post-developmental stages notably in the modulation of neuronal and spine morphology and synaptic function during non-pathological aging which could have significant implications for cognitive function. PMID- 27229919 TI - "I Will Never Know the Person Who I Could Have Become": Perceived Changes in Self Identity Among Adult Survivors of Clergy-Perpetrated Sexual Abuse. AB - Clergy-perpetrated sexual abuse (CPSA) during childhood represents a tragic betrayal of trust that inflicts damage on the survivor, the family, and the parish community. Survivors often report CPSA has a disturbing impact on their self-identity. Despite intense media coverage of clergy abuse globally in the Catholic Church (and other faith communities) over several decades, relatively few empirical studies have been conducted with survivors. Beyond clinical observations and advocacy group reports, very little is known about survivors' perceptions of how the abuse impacted their long-term self-identity. Using data collected during the 2010 Health and Well-Being Survey, this qualitative analysis represents one of the first large-scale studies with a non-clinical sample of adult male survivors of CPSA from childhood (N = 205). The negative effects of the sexual abuse on participants were expressed across six domains of self identity: (a) total self, (b) psychological self, (c) relational self, (d) gendered self, (e) aspirational self, and (f) spiritual self. These findings highlight the range and depth of self-suffering inflicted by this pernicious form of sexual violence. The findings are useful for developing clinical services for survivors, shaping public and institutional policies to address clergy perpetrated sexual abuse, and guiding future research with this population. PMID- 27229920 TI - Beyond Advocacy: Mapping the Contours of Victim Work. AB - In contrast to works on victim advocacy in specific organizational contexts, this article introduces the term "victim work" to capture the vast array of victim related roles and tasks that have proliferated in recent decades. Data are derived from in-depth interviews with 30 "victim workers" in public and private agencies in two Midwestern states. The interviews revealed diverse work experiences that spanned hotlines, crisis response, legal proceedings, and postconviction support. Three themes emerged that characterize "victim work": flexibility, emotions, and the challenge of "fit"-the multifaceted difficulties of interacting with victims and agents of the justice system. Based on the findings, we offer a revised model of criminal justice vis-a-vis victims and implications for practice and future research. PMID- 27229915 TI - Alzheimer disease research in the 21st century: past and current failures, new perspectives and funding priorities. AB - Much of Alzheimer disease (AD) research has been traditionally based on the use of animals, which have been extensively applied in an effort to both improve our understanding of the pathophysiological mechanisms of the disease and to test novel therapeutic approaches. However, decades of such research have not effectively translated into substantial therapeutic success for human patients. Here we critically discuss these issues in order to determine how existing human based methods can be applied to study AD pathology and develop novel therapeutics. These methods, which include patient-derived cells, computational analysis and models, together with large-scale epidemiological studies represent novel and exciting tools to enhance and forward AD research. In particular, these methods are helping advance AD research by contributing multifactorial and multidimensional perspectives, especially considering the crucial role played by lifestyle risk factors in the determination of AD risk. In addition to research techniques, we also consider related pitfalls and flaws in the current research funding system. Conversely, we identify encouraging new trends in research and government policy. In light of these new research directions, we provide recommendations regarding prioritization of research funding. The goal of this document is to stimulate scientific and public discussion on the need to explore new avenues in AD research, considering outcome and ethics as core principles to reliably judge traditional research efforts and eventually undertake new research strategies. PMID- 27229921 TI - The Development of Attitudes Toward Intimate Partner Violence: An Examination of Key Correlates Among a Sample of Young Adults. AB - Social learning theory remains one of the leading explanations of intimate partner violence (IPV). Research on attitudes toward IPV represents a logical extension of the social learning tradition, as it is intuitive to expect that individuals exposed to violence in the family of origin may internalize behavioral scripts for violence and adopt attitudes accepting of IPV. Yet despite this assumed link between family violence and attitudes toward IPV, few studies have empirically examined factors associated with the development of such attitudes. Using data from the Toledo Adolescent Relationship Study (TARS), we examine the role of family violence on the adoption of attitudes accepting of IPV among a sample of young adults (n = 928). The current investigation contributes to existing literature on attitudes toward IPV by (a) providing an empirical examination of factors associated with attitudes toward IPV in predictive models; (b) relying on a multifaceted index, describing specific conditions under which IPV may be deemed justifiable; (c) examining extra-familial factors, in addition to family violence exposure, to provide a more comprehensive account of factors associated with attitudes toward IPV; and (d) focusing particular attention on the role of gender, including whether the factors associated with attitudinal acceptance of IPV are similar for men and women. Findings indicated considerable variation in overall endorsement of attitudes regarding the use of violence across conditions, with greater endorsement among women. Consistent with social learning approaches to IPV, exposure to violence in the family of origin was associated with attitudes toward IPV. Yet findings also signaled the salience of factors beyond the family, including a range of sociodemographic, relationship, and adult status characteristics. We discuss the relevance of our findings for future theorizing and research in the area of attitudes toward IPV. PMID- 27229922 TI - Convergent Validity of Three Measures of Sexual Sadism: Value of a Dimensional Measure. AB - Sexual sadism can be described as the sexual pleasure produced by acts of cruelty and bodily punishment. The most common method for evaluating sexual sadism is clinical evaluation, that is, evaluation based on the diagnostic criteria of nosological instruments such as the Diagnostic and Statistical Manual of Mental Disorders ( DSM) or the International Classification of Diseases (ICD). It is also possible to evaluate sadistic sexual preferences by phallometry, which provides a physiological measure of sexual excitation by deviant and nondeviant scenarios. The most recently developed evaluation method is the Severe Sexual Sadism Scale (SESAS), a dimensional instrument that has been empirically validated. Despite the availability of all these measurement techniques, very little research has been conducted on their degree of convergence. Consequently, the aim of the current study was to assess the relationship between these three measures of sexual sadism. Our analyses were conducted on a sample of rapists ( N = 72), assessed in a maximum-security penitentiary. There was no significant relation between phallometric scores and other measures of sexual sadism. There was, however, an important correlation between SESAS scores and Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) sexual sadism diagnosis. Our results are consistent with other phallometric studies, which reported no difference in the penile responses of individuals diagnosed as sadists and those not diagnosed as sadists. Results and implications for future research are discussed. PMID- 27229923 TI - Statin use and cardiovascular risk factors in diabetic patients developing a first myocardial infarction. AB - BACKGROUND: The risk for a first myocardial infarction (MI) in people with diabetes has been shown to be as high as the risk for a new MI in non-diabetic patients with a prior MI. Consequently, risk-reducing statin therapy is recommended for nearly all patients with diabetes 40 years of age or older, regardless of cholesterol level. The purpose of this study was to assess the recommended and real-life use of statins for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in diabetic patients who develop ASCVD. METHODS: In a cross-sectional multicenter study of consecutive patients without previous ASCVD hospitalized with a first MI in 2010-2012, we obtained information on diabetic status, statin use, and cardiovascular risk factors prior to MI. RESULTS: The study population consisted of 1622 patients with first MI (63 % men), 228 of whom had known diabetes before MI. All but three of the diabetic patients were >=40 years of age. Diabetic patients were older (70 vs 68, p = 0.006), were more often women (43 vs 36 %, p = 0.05) and had a higher prevalence of statin use (47 vs 11 %, p < 0.001) compared with non-diabetic patients. Despite a high risk factor burden, the majority (53 %) of patients with known diabetes was not treated with statins before MI, and there was no relationship between the number of high-risk markers and statin use. Nearly all diabetic patients not treated with statins before first MI had at least one marker of very high cardiovascular risk, including hypertension (71 %), current smoking (37 %), and nephropathy (33 %). CONCLUSIONS: Primary prevention with statins had been initiated in less than half of diabetic patients destined for a first MI, despite the presence of one or more markers of very high cardiovascular risk in nearly all. These results highlight an urgent need for optimizing statin therapy and global risk factor control in diabetic patients. PMID- 27229924 TI - Addressing obesity in the management of knee and hip osteoarthritis - weighing in from an economic perspective. AB - BACKGROUND: Obesity is one of the only modifiable risk factors for both incidence and progression of Osteoarthritis (OA). So there is increasing interest from a public health perspective in addressing obesity in the management of OA. While evidence of the efficacy of intereventions designed to address obesity in OA populations continues to grow, little is known about their economic credentials. The aim of this study is to conduct a scoping review of: (i) the published economic evidence assessing the economic impact of obesity in OA populations; (ii) economic evaluations of interventions designed to explicitly address obesity in the prevention and management of OA in order to determine which represent value for money. Besides describing the current state of the literature, the study highlights research gaps and identifies future research priorities. METHODS: In July 2014, a search of the peer reviewed literature, published in English, was undertaken for the period January 1975 - July 2014 using Medline Complete (Ebscohost), Embase, Econlit, Global Health, Health Economics Evaluation Database (HEED), all Cochrane Library databases as well as the grey literature using Google and reference lists of relevant studies. A combination of key search terms was used to identify papers assessing the economic impact of obesity in OA or economic evaluations conducted to assess the efficiency of obesity interventions for the prevention or management of OA. RESULTS: 14 studes were identified; 13 were cost burden studies assessing the impact of obesity as a predictor for higher costs in Total Joint Arthroplasty (TJA) patients and one a cost-effectiveness study of an intervention designed to address obesity in the managment of mild to moderate OA patients. CONCLUSION: The majority of the economic studies conducted are cost burden studies. While there is some evidence of the association between severe obesity and excess hospital costs for TJA patients, heterogeneity in studies precludes definitive statements about the strength of the association. With only one economic evaluation to inform policy and practice, there is a need for future research into the cost-effectiveness of obesity interventions designed both for prevention or management of OA along the disease spectrum and over the life course. PMID- 27229927 TI - Chemical composition and in vitro antibacterial activity of Pistacia terebinthus essential oils derived from wild populations in Kosovo. AB - BACKGROUND: Plant material from different organs of Pistacia terebinthus L., (Anacardiaceae) were collected in Kosovo with aim to analyze the chemical variability of the essential oils among native populations and to test them for potential antibacterial activity against Staphylococcus aureus. METHODS: Essential oils obtained from leaves, pedicels, fruits and galls were analyzed by GC-FID and GC/MS. Minimum inhibitory concentration (MIC) against three clinically relevant strains of S. aureus (NRS385, LAC and UAMS-1) were used to evaluate the antibacterial activity of essential oils. RESULTS: In total, 33 different compounds were identified. The main constituents were alpha-pinene (12.58-66.29 %), D-limonene (13.95-46.29 %), beta-ocimene (0.03-40.49 %), beta-pinene (2.63 20.47 %), sabinene (0.00-5.61 %) and (Z)-beta-ocimene (0.00-44.85 %). Antibacterial testing of the essential oils against three clinical isolates of S. aureus revealed that seven of the eight samples had some activity at the concentration range tested (0.04-0.512 % v/v). The gall tissues from both sites produced the highest yield of essential oil (3.24 and 6 %), and both exhibited growth inhibitory activity against S. aureus. The most bioactive essential oils, which exhibited MIC90 values ranging from 0.032-0.128 % v/v, obtained from the fruits of the Ura e Shejte collection site. Likewise, the leaf and pedicel essential oil from the same site was highly active with MIC90 values of 0.064 0.128 and 0.032-0.256 % v/v, respectively. CONCLUSIONS: Principle Component Analyses demonstrated that there is a variation in the chemical composition of essential oil depending on the plant organs from which essential oil are obtained and the geographical origin of the plant populations. The highest variability regarding the chemical composition of essential oil was found between oils obtained from different organs originating from the Prizren site. The MIC90 activity of Pistacia terebinthus was on par or superior compared with Tea Tree Oil control (0.128 % v/v), suggesting that essential oils from this species may have some potential for development as an antibacterial agent for S. aureus infections. PMID- 27229925 TI - Regulation of gap junction channels and hemichannels by phosphorylation and redox changes: a revision. AB - Post-translational modifications of connexins play an important role in the regulation of gap junction and hemichannel permeability. The prerequisite for the formation of functional gap junction channels is the assembly of connexin proteins into hemichannels and their insertion into the membrane. Hemichannels can affect cellular processes by enabling the passage of signaling molecules between the intracellular and extracellular space. For the intercellular communication hemichannels from one cell have to dock to its counterparts on the opposing membrane of an adjacent cell to allow the transmission of signals via gap junctions from one cell to the other. The controlled opening of hemichannels and gating properties of complete gap junctions can be regulated via post translational modifications of connexins. Not only channel gating, but also connexin trafficking and assembly into hemichannels can be affected by post translational changes. Recent investigations have shown that connexins can be modified by phosphorylation/dephosphorylation, redox-related changes including effects of nitric oxide (NO), hydrogen sulfide (H2S) or carbon monoxide (CO), acetylation, methylation or ubiquitination. Most of the connexin isoforms are known to be phosphorylated, e.g. Cx43, one of the most studied connexin at all, has 21 reported phosphorylation sites. In this review, we provide an overview about the current knowledge and relevant research of responsible kinases, connexin phosphorylation sites and reported effects on gap junction and hemichannel regulation. Regarding the effects of oxidants we discuss the role of NO in different cell types and tissues and recent studies about modifications of connexins by CO and H2S. PMID- 27229926 TI - Factors influencing changes in health related quality of life of caregivers of persons with multiple chronic conditions. AB - BACKGROUND: The majority of care for older adults with multiple chronic conditions (MCC) is provided by family (including friends) caregivers. Although caregivers have reported positive benefits to caregiving they also experience decreases in their physical and mental health. As there is a critical need for supportive interventions for this population, it is important to know what influences the health of family caregivers of persons with MCC. This research examined relationships among the changes from baseline to 6 months in health related quality of life (SF12v2) of family caregivers caring for older adults with multiple chronic conditions and the following factors: a) demographic variables, b) gender identity [Bem Sex Role Inventory (BSRI)] c) changes in general self-efficacy [General Self Efficacy Scale (GSES) (baseline to 6 months) and d)) changes in caregiver burden [Zarit Burden Inventory (ZBI)] baseline to 6 months. Specific hypothesis were based on a conceptual framework generated from a literature review. METHODS: This is a secondary analysis of a study of 194 family caregivers who were recruited from two Canadian provinces Alberta and Ontario. Data were collected in-person, by telephone, by Skype or by mail at two time periods spaced 6 months apart. The sample size for this secondary analysis was n = 185, as 9 participants had dropped out of the study at 6 months. Changes in the scores between the two time periods were calculated for SF12v2 physical component score (PCS) and mental component score (MCS) and the other main variables. Generalized Linear Modeling was then used to determine factors associated with changes in HRQL. RESULTS: Participants who had significantly positive increases in their MCS (baseline to 6 months) reported lower burden (ZBI, p < 0.001), and higher general self-efficacy (GSES, p < 0.001) and Masculine BSRI (p = 0.025). There were no significant associations among variables and changes in PCS (baseline to 6 months). CONCLUSIONS: Our findings suggest that a masculine gender identity (which incorporates assertive and instrumental approaches to caregiving), and confidence in the ability to deal with difficult situations was positively related to improvement in mental health for caregivers of persons with MCC. Decreases in perceptions of burden in this populations was also associated with improvements in mental health. Further research is needed to explore ways to support caregivers of older persons with multiple chronic conditions living at home. PMID- 27229928 TI - Gender relations, sexual behaviour, and risk of contracting sexually transmitted infections among women in union in Uganda. AB - BACKGROUND: Sexually transmitted infections (STIs) are a major reproductive and public health concern, especially in the era of HIV/AIDS. This study examined the relationship between sexual empowerment and STI status of women in union (married or cohabiting) in Uganda, controlling for sexual behaviour, partner factors, and women's background characteristics. METHODS: The study, based on data from the 2011 Uganda Demographic and Health Survey (UDHS), analysed 1307 weighted cases of women age 15-49 in union and selected for the domestic violence module. Chi squared tests and multivariate logistic regressions were used to examine the predicators of STI status. The main explanatory variables included sexual empowerment, involvement in decision making on own health, experience of any sexual violence, condom use during last sex with most recent partner, number of lifetime partners and partner control behaviours. Sexual empowerment was measured with three indicators: a woman's reported ability to refuse sex, ability to ask her partner to use a condom, and opinion regarding whether a woman is justified to refuse sex with her husband if he is unfaithful. RESULTS: Results show that 28 % of women in union reported STIs in the last 12 months. Sexual violence and number of lifetime partners were the strongest predictors of reporting STIs. Women's sexual empowerment was a significant predictor of their STI status, but, surprisingly, the odds of reporting STIs were greater among women who were sexually empowered. Reporting of STIs was negatively associated with a woman's participation in decision-making with respect to her own health, and was positively associated with experience of sexual violence, partner's controlling behaviour, and having more than one life partner. CONCLUSIONS: Our findings suggest that, with respect to STIs, sexual empowerment as measured in the study does not protect women who have sexually violent and controlling partners. Interventions promoting sexual health must effectively address negative masculine attitudes and roles that perpetuate unhealthy sexual behaviours and gender relations within marriage. It is also important to promote marital fidelity and better communication within union and to encourage women to take charge of their health jointly with their partners. PMID- 27229930 TI - Dual targeting of EGFR and ERBB2 pathways produces a synergistic effect on cancer cell proliferation and migration in vitro. AB - Members of the epidermal growth factor receptor (EGFR/ERBB) gene family are frequently dysregulated in a range of human cancers, and therapeutics targeting these proteins are in clinical use. We hypothesized that similar pathways are involved in feline and canine tumours and that the same drugs may be of clinical use in veterinary patients. We investigated EGFR and ERBB2 targeting using a panel of feline and canine cell lines. EGFR and ERBB2 were targeted with siRNAs or tyrosine kinase inhibitors (TKIs) and their effect on cellular proliferation, colony formation and migration was investigated in vitro. Here we report that EGFR and ERBB2 combined siRNA targeting produced synergistic effects in feline and canine cell lines similar to that reported in human cell lines. We conclude that dual EGFR and ERBB2 targeting using TKIs should be further evaluated as a potential new therapeutic strategy in feline head and neck and mammary tumours and canine mammary tumours. PMID- 27229929 TI - Systematic interactome mapping of acute lymphoblastic leukemia cancer gene products reveals EXT-1 tumor suppressor as a Notch1 and FBWX7 common interactor. AB - BACKGROUND: Perturbed genotypes in cancer can now be identified by whole genome sequencing of large number of diverse tumor samples, and observed gene mutations can be used for prognosis and classification of cancer subtypes. Although mutations in a few causative genes are directly linked to key signaling pathways perturbation, a global understanding of how known cancer genes drive oncogenesis in human is difficult to assess. METHODS: We collected available information about mutated genes in Acute Lymphoblastic Leukemia (ALL). Validated human protein interactions (PPI) were collected from IntAct, HPRD and BioGRID interactomics databases, or obtained using yeast two-hybrid screening assay. RESULTS: We have mapped interconnections between 116 cancer census gene products associated with ALL. Combining protein-protein interactions data and cancer specific gene mutations information, we observed that 63 ALL-gene products are interconnected and identified 37 human proteins interacting with at least 2 ALL gene products. We highlighted exclusive and coexistence genetic alterations in key signaling pathways including the PI3K/AKT and the NOTCH pathways. We then used different cell lines and reporter assay systems to validate the involvement of EXT1 in the Notch pathway. CONCLUSION: We propose that novel ALL-gene candidates can be identified based on their functional association with well known cancer genes. We identified EXT1, a gene not previously linked to ALL via mutations, as a common interactor of NOTCH1 and FBXW7 regulating the NOTCH pathway in an FBXW7-dependend manner. PMID- 27229931 TI - Dietary breadth is positively correlated with venom complexity in cone snails. AB - BACKGROUND: Although diet is believed to be a major factor underlying the evolution of venom, few comparative studies examine both venom composition and diet across a radiation of venomous species. Cone snails within the family, Conidae, comprise more than 700 species of carnivorous marine snails that capture their prey by using a cocktail of venomous neurotoxins (conotoxins or conopeptides). Venom composition across species has been previously hypothesized to be shaped by (a) prey taxonomic class (i.e., worms, molluscs, or fish) and (b) dietary breadth. We tested these hypotheses under a comparative phylogenetic framework using ecological data from past studies in conjunction with venom duct transcriptomes sequenced from 12 phylogenetically disparate cone snail species, including 10 vermivores (worm-eating), one molluscivore, and one generalist. RESULTS: We discovered 2223 unique conotoxin precursor peptides that encoded 1864 unique mature toxins across all species, >90 % of which are new to this study. In addition, we identified two novel gene superfamilies and 16 novel cysteine frameworks. Each species exhibited unique venom profiles, with venom composition and expression patterns among species dominated by a restricted set of gene superfamilies and mature toxins. In contrast with the dominant paradigm for interpreting Conidae venom evolution, prey taxonomic class did not predict venom composition patterns among species. We also found a significant positive relationship between dietary breadth and measures of conotoxin complexity. CONCLUSIONS: The poor performance of prey taxonomic class in predicting venom components suggests that cone snails have either evolved species-specific expression patterns likely as a consequence of the rapid evolution of conotoxin genes, or that traditional means of categorizing prey type (i.e., worms, mollusc, or fish) and conotoxins (i.e., by gene superfamily) do not accurately encapsulate evolutionary dynamics between diet and venom composition. We also show that species with more generalized diets tend to have more complex venoms and utilize a greater number of venom genes for prey capture. Whether this increased gene diversity confers an increased capacity for evolutionary change remains to be tested. Overall, our results corroborate the key role of diet in influencing patterns of venom evolution in cone snails and other venomous radiations. PMID- 27229932 TI - Intra-operative device closure of perimembranous ventricular septal defect without cardiopulmonary bypass under guidance of trans-epicardial echocardiography: a single center experience. AB - BACKGROUND: Intraoperative device closure of perimembranous ventricular septal defect(VSD) through a lower mini-sternotomy is safe, less invasive, and has excellent surgical and cosmetic outcomes. Our study is to evaluate the feasibility of closing VSD under guidance of trans-epicardial echocardiography. METHODS: We reviewed the clinical course of 41 patients referred to our institution for minimally invasive closure of perimembranous VSD. The trans epicardial echocardiography(TEE) was used to monitor the whole procedure to guide the positioning of device and evaluate the operative effect instantly after operation. RESULT: The procedure was successfully done in 38 patients(92.6 %) with mean age of 1.2 +/- 1.5 years(range 0.5-6.1 years),mean weight of 10.78 +/- 6.87 kg(range 5.2 ~ 26 kg) and VSD size of 5.1 +/- 1.13 mm(range 5 ~ 10 mm). Three cases failed, including two cases whose guide-wires could not pass through VSDs and one case whose occluder could not repair VSD well. Three patients had tiny residual shunts because of the shifting of occluders. There were no major complications such as arrhythmia, valve regurgitation and the failure of occluder during follow-up(Mean 2.3 +/- 1.2 years). TEE provided superior imaging of shapes and surrounding structures of the VSDs, and guide-wires passing through VSDs. CONCLUSIONS: Intraoperative device closure of perimembranous VSD through a lower mini-sternotomy without cardiopulmonary bypass appears to be a safe and effective procedure. The use of trans-epicardial echocardiography provides useful information for intraoperative device closure of VSD. PMID- 27229933 TI - Risk factors for subsequent endocrine-related cancer in childhood cancer survivors. AB - Long-term adverse health conditions, including secondary malignant neoplasms, are common in childhood cancer survivors. Although mortality attributable to secondary malignancies declined over the past decades, the risk for developing a solid secondary malignant neoplasm did not. Endocrine-related malignancies are among the most common secondary malignant neoplasms observed in childhood cancer survivors. In this systematic review, we describe risk factors for secondary malignant neoplasms of the breast and thyroid, since these are the most common secondary endocrine-related malignancies in childhood cancer survivors. Radiotherapy is the most important risk factor for secondary breast and thyroid cancer in childhood cancer survivors. Breast cancer risk is especially increased in survivors of Hodgkin lymphoma who received moderate- to high-dosed mantle field irradiation. Recent studies also demonstrated an increased risk after lower dose irradiation in other radiation fields for other childhood cancer subtypes. Premature ovarian insufficiency may protect against radiation-induced breast cancer. Although evidence is weak, estrogen-progestin replacement therapy does not seem to be associated with an increased breast cancer risk in premature ovarian-insufficient childhood cancer survivors. Radiotherapy involving the thyroid gland increases the risk for secondary differentiated thyroid carcinoma, as well as benign thyroid nodules. Currently available studies on secondary malignant neoplasms in childhood cancer survivors are limited by short follow-up durations and assessed before treatment regimens. In addition, studies on risk modifying effects of environmental and lifestyle factors are lacking. Risk modifying effects of premature ovarian insufficiency and estrogen-progestin replacement therapy on radiation-induced breast cancer require further study. PMID- 27229934 TI - Current and Emerging Aspects of Diabetes Mellitus in Acromegaly. AB - Diabetes mellitus is a frequent complication of acromegaly, a disease characterized by chronic hypersecretion of growth hormone (GH) by a pituitary adenoma. Diabetes occurs commonly but not only as a consequence of an insulin resistant state induced by GH excess. The development of diabetes in patients with acromegaly is clinically relevant, since such a complication is thought to increase the already elevated cardiovascular morbidity and mortality risk of the disease. Emerging data suggest that a specific cardiomyopathy can be identified in acromegaly patients with diabetes. Moreover, the presence of diabetes may also influence therapeutic decision making in acromegaly, since traditional and newly developed drugs used in this clinical setting may impact glucose metabolism regardless of control of GH hypersecretion. PMID- 27229935 TI - Erratum to: Pretreatment gut microbiome predicts chemotherapy-related bloodstream infection. PMID- 27229936 TI - How to Choose the Best Metabolic Procedure? AB - Bariatric/metabolic surgery has proven to be effective in inducing and maintaining diabetes remission-although with a percentage of patients undergoing hyperglycemia relapse-weight loss, and improvement of the cardiovascular risk. It is, however, associated with mortality, although low, and early and late complications. In particular, metabolic complications are related to vitamin deficiency due to the erratic absorption of the supplemented vitamins and to the unpredictable compliance of patients to vitamin and trace element supplementation. In addition, often, the general practitioners and even the specialists are unaware of the clinical effects of metabolic dysfunction following malabsorptive surgery. The choice of the surgical procedure should be the balance between benefits and risks. Our review addresses this important question trying to give some suggestions. PMID- 27229937 TI - Validation of the Erlangen Test of Activities of Daily Living in Persons with Mild Dementia or Mild Cognitive Impairment (ETAM). AB - BACKGROUND: There are currently no valid, fast, and easy-to-administer performance tests that are designed to assess the capacities to perform activities of daily living in persons with mild dementia and mild cognitive impairment (MCI). However, such measures are urgently needed for determining individual support needs as well as the efficacy of interventions. The aim of the present study was therefore to validate the Erlangen Test of Activities of Daily Living in Persons with Mild Dementia and Mild Cognitive Impairment (ETAM), a performance test that is based on the International Classification of Functioning and Health (ICF), which assesses the relevant domains of living in older adults with MCI and mild dementia who live independently. METHODS: The 10 ICF-based items on the research version of the ETAM were tested in a final sample of 81 persons with MCI or mild dementia. The items were selected for the final version in accordance with 6 criteria: 1) all domains must be represented and have equal weight, 2) all items must load on the same factor, 3) item difficulties and item discriminatory powers, 4) convergent validity (Bayer Activities of Daily Living Scale [B-ADL]) and discriminant validity (Mini Mental State Examination [MMSE], Geriatric Depression Scale 15 [GDS-15]), 5) inter-rater reliabilities of the individual items, 6) as little material as possible. Retest reliability was also examined. Cohen's ds were calculated to determine the magnitudes of the differences in ETAM scores between participants diagnosed with different grades of severity of cognitive impairment. RESULTS: The final version of the ETAM consists of 6 items that cover the five ICF domains communication, mobility, self care, domestic life (assessed by two 3-point items), and major life areas (specifically, the economic life sub-category) and load on a single factor. The maximum achievable score is 30 points (6 points per domain). The average administration time was 35 min, 19 of which were needed for pure item performance. The internal consistency was alpha = .71. The three-week test-retest reliability was r = .78, and the inter-rater reliability was r = .97. The ETAM also provided satisfactory discrimination between healthy individuals and persons with MCI or mild dementia as well as between persons with mild and moderate dementia. CONCLUSIONS: The 6-item final version of the ETAM shows satisfactory psychometric characteristics and can be administered quickly. It is therefore suitable for use in both clinical practice and research. PMID- 27229938 TI - Acute Toxicity and Gastroprotection Studies of a New Schiff Base Derived Manganese (II) Complex against HCl/Ethanol-Induced Gastric Ulcerations in Rats. AB - Manganese is a crucial element for health. In this study, the gastroprotective efficacy of Mn (II) complex (MDLA) against acidified ethanol (HCl/Ethanol) induced gastric ulceration in rats was evaluated. The animals were distributed into 5 groups. Groups 1 and 2 received carboxymethylcellulose (CMC), group 3 was pretreated with omeprazole, and groups 4 and 5 were given 10 and 20 mg/kg of MDLA, respectively. After one hour, CMC and HCl/Ethanol were given to groups 2-5 whilst the animals in group 1 were ingested with CMC. After sacrifice, gastric lesions were evaluated by wall mucus, gross appearance, histology, antioxidant enzymes and immunohistochemistry. Group 2 displayed severe gastric damage with a significant reduction in wall mucus. Conversely, gastric lesions were reduced in groups 3-5 by 85.72%, 56.51% and 65.93%, respectively. The rats in groups 3-5 showed up-regulation of heat shock protein 70 (Hsp70) with down-regulation of Bcl 2-associated protein x (Bax). Pretreatment with omeprazole or MDLA led to an increase in the uptake of Periodic Acid Schiff (PAS) stain in the glandular part of the gastric tissue, raised levels of prostaglandin E2 (PGE2) and superoxide dismutase (SOD), and a reduction in malondialdehyde (MDA) concentrations. These results suggested the gastroprotective action of Mn (II) complex. PMID- 27229939 TI - Religiosity and Health Risk Behaviour Among University Students in 26 Low, Middle and High Income Countries. AB - The aim of this study was to assess religiosity and health risk behaviours among university students from 26 low, middle and high income countries. Using anonymous questionnaires, data were collected from 20,222 undergraduate university students (mean age 20.8, SD = 2. 8) from 27 universities in 26 countries across Asia, Africa and the Americas. Among all students, 41.1 % engaged at least once a week in organized religious activity, 35.8 % practised a non-organized religious activity daily or more than once daily, and more or less two-thirds of the students agreed to the three different statements on intrinsic of subjective religiosity. In multivariate logistic regression analysis, higher reported involvement in organized religious activity was associated with addictive, injury, sexual and oral health risk behaviour, while lower reported involvement in organized religious activity was associated with physical inactivity and oral health risk behaviour. Lower reported involvement in non organized religious activity was associated with addictive, nutrition risk, injury, sexual and oral health risk behaviour, while higher reported involvement in non-organized religious activity was associated with physical inactivity. Finally, lower reported intrinsic religiosity was associated with addictive and sexual risk behaviour, while higher reported intrinsic religiosity was associated with nutrition risk behaviour, physical inactivity and oral health risk behaviour. PMID- 27229940 TI - Port-site transversus abdominis fascia closure reduced the incidence of incisional hernia following retroperitoneal laparoscopic nephrectomy. AB - PURPOSE: The incidence of incisional hernia after laparoscopic surgery is reportedly 0-5.2 %; there are only a few reports of that following retroperitoneal laparoscopic nephrectomy. We evaluated the incidence of and risk factors for incisional hernia after retroperitoneal laparoscopic nephrectomy, and the efficacy of our novel prophylaxis technique. METHODS: A total of 207 renal cell carcinoma patients who underwent laparoscopic nephrectomy at Chiba University Hospital were retrospectively enrolled in this study. We compared the incidences of incisional hernia following the transperitoneal vs. retroperitoneal approaches, and, among the latter group, the incidences with vs. without use of our prophylaxis method. Also among the retroperitoneal-approach group, we evaluated selected patient characteristics as potential hernia risk factors. RESULTS: The rate of incisional hernias was 14 (8.7 %) after 161 retroperitoneal laparoscopic nephrectomies and one (2.2 %) after 46 transperitoneal laparoscopic nephrectomies (P = 0.132). For those undergoing the retroperitoneal approach, 14 (11.3 %) hernias were identified in 124 non-prophylaxed patients and none in 37 prophylaxed patients. Transversus abdominis fascia closure was a statistically significant factor for reducing the incidence of incisional hernia after retroperitoneal laparoscopic nephrectomy (P = 0.0324): rectus abdominis muscle thickness <=7 mm and perioperative blood loss >100 ml were statistically significant independent risk factors, by multivariate analysis. CONCLUSIONS: To prevent incisional hernia after retroperitoneal laparoscopic nephrectomy in the patients with risk factors, it is useful to close the transversus abdominis fascia at the port sites from inside the surgical cavity, through the open specimen-removal trocar port site, under direct observation. PMID- 27229941 TI - Highlights lecture EANM 2015: the search for nuclear medicine's superheroes. AB - The EANM 2015 Annual Congress, held from October 10th to 14th in Hamburg, Germany, was outstanding in many respects. With 5550 participants, this was by far the largest European congress concerning nuclear medicine. More than 1750 scientific presentations were submitted, with more than 250 abstracts from young scientists, indicating that the future success of our discipline is fuelled by a high number of young individuals becoming involved in a multitude of scientific activities. Significant improvements have been made in molecular imaging of cancer, particularly in prostate cancer. PSMA-directed PET/CT appears to become a new gold standard for staging and restaging purposes. Novel tumour specific compounds have shown their potential for target identification also in other solid neoplasms and further our understanding of tumour biology and heterogeneity. In addition, a variety of nuclear imaging techniques guiding surgical interventions have been introduced. A particular focus of the congress was put on targeted, radionuclide based therapies. Novel theranostic concepts addressing also tumour entities with high incidence rates such as prostate cancer, melanoma, and lymphoma, have shown effective anti-tumour activity. Strategies have been presented to improve further already established therapeutic regimens such as somatostatin receptor based radio receptor therapy for treating advanced neuroendocrine tumours. Significant contributions were presented also in the neurosciences track. An increasing number of target structures of high interest in neurology and psychiatry are now available for PET and SPECT imaging, facilitating specific imaging of different subtypes of dementia and movement disorders as well as neuroinflammation. Major contributions in the cardiovascular track focused on further optimization of cardiac perfusion imaging by reducing radiation exposure, reducing scanning time, and improving motion correction. Besides coronary artery disease, many contributions focused on cardiac inflammation, cardiac sarcoidosis, and specific imaging of large vessel vasculitis. The physics and instrumentation track included many highlights such as novel, high resolution scanners. The most noteworthy news and developments of this meeting were summarized in the highlights lecture. Only 55 scientific contributions were mentioned, and hence they represent only a brief summary, which is outlined in this article. For a more detailed view, all presentations can be accessed by the online version of the European Journal of Nuclear Medicine and Molecular Imaging (Volume 42, Supplement 1). PMID- 27229942 TI - Workplace bullying among Nurses in South Taiwan. AB - AIMS AND OBJECTIVES: This study was to investigate bullying among hospital nurses and its correlates. BACKGROUND: Chinese people were unlikely to express their opinions or pursue individual rights. Workplace bullying took place more easily among the educated people within Chinese culture. However, studies related to workplace bullying among hospital nurses in Taiwan were still limited. DESIGN: A cross-sectional design. METHODS: Two hundred and eighty-five nurses who worked in the regional teaching hospital in south Taiwan were recruited. The significant predictors of workplace bullying were identified by using linear regression analysis. RESULTS: The mean of overall bullying was 1.47, showing that the frequency of the nurses having experienced workplace bullying was between 'never' and 'now and then'. The most frequent bullying item was 'being yelled at or being the target of anger', followed by 'being the objects of untruthful criticism' and 'having views ignored'. Hospital nurses working in the Emergency room would gain 10.888 points more in the overall bullying scale compared with those who worked in operation rooms or haemodialysis rooms. They were more likely to be bullied. Hospital nurses with one year increase in nursing experience were 0.207 points less likely to be bullied. CONCLUSIONS: Reducing workplace bullying among hospital nurses was an essential method to provide quality assurance to health care. Nurse managers should build up zero tolerance policy to decrease nurses' exposure to workplace bullying. RELEVANCE TO CLINICAL PRACTICE: Training programmes related to bullying prevention are suggested to avoid workplace bullying. The contents of the educational training programmes or workshops should incorporate the characteristics and consequences of the workplace bullying, and the strategies to deal with bullying. PMID- 27229943 TI - Health economic burden that different wound types impose on the UK's National Health Service. AB - The aim of this study was to estimate the patterns of care and annual levels of health care resource use attributable to the management of different wound types by the UK's National Health Service (NHS) in 2012/2013 and the annual costs incurred by the NHS in managing them. This was a retrospective cohort analysis of the records of 2000 patients in The Health Improvement Network (THIN) Database. Patients' characteristics, wound-related health outcomes and all health care resource use were quantified, and the total NHS cost of patient management was estimated at 2013/2014 prices. The NHS managed an estimated 2.2 million patients with a wound during 2012/2013. Patients were predominantly managed in the community by general practitioners (GPs) and nurses. The annual NHS cost varied between L1.94 billion for managing 731 000 leg ulcers and L89.6 million for managing 87 000 burns, and associated comorbidities. Sixty-one percent of all wounds were shown to heal in an average year. Resource use associated with managing the unhealed wounds was substantially greater than that of managing the healed wounds (e.g. 20% more practice nurse visits, 104% more community nurse visits). Consequently, the annual cost of managing wounds that healed in the study period was estimated to be L2.1 billion compared with L3.2 billion for the 39% of wounds that did not heal within the study year. Within the study period, the cost per healed wound ranged from L698 to L3998 per patient and that of an unhealed wound ranged from L1719 to L5976 per patient. Hence, the patient care cost of an unhealed wound was a mean 135% more than that of a healed wound. Real world evidence highlights the substantial burden that wounds impose on the NHS in an average year. Clinical and economic benefits to both patients and the NHS could accrue from strategies that focus on (a) wound prevention, (b) accurate diagnosis and (c) improving wound-healing rates. PMID- 27230012 TI - Is obstructive sleep apnea syndrome in children season dependent? AB - INTRODUCTION: The most common cause of obstructive sleep apnea (OSA) in children is an enlargement of tonsils and/or adenoids. Previous studies have shown that the size of adenoids and tonsils is influenced by upper respiratory tract infections and exposure to allergens. The rate of exposure to bacteria, viruses, and allergens fluctuates from season to season. Therefore, we hypothesized that the rate of polysomnograms positive for OSA may vary according to season. OBJECTIVE: The objective of this study is to determine whether the prevalence of OSA in children, as determined by polysomnography, is affected by the season during which the study was performed. METHODS: We retrospectively reviewed polysomnography tests of 296 children, ages 0-12 years, referred for suspected OSA. We compared the Obstructive Apnea Hypopnea Index (OAHI) between the seasons and the rates of abnormal tests in each season according to the degree of severity. RESULTS: The mean OAHI did not significantly differ among the seasons (winter, 3.0 +/- 5.0; spring, 3.0 +/- 4.9; summer, 4.0 +/- 6.3; fall, 3.4 +/- 5.7, p = 0.183). When dividing the OAHI by levels of severity, no seasonality was found in moderate (winter, 13.8 %; spring, 6.7 %; summer, 11.7 %; fall, 14.1 %, p = NS) and severe OSA (winter, 8.8 %; spring, 11.2 %; summer, 10 %; fall, 7.8 %, p = NS). There was a small increase in the frequency of mild OSA diagnoses in the summer compared to the other seasons. CONCLUSION: In this study, season does not appear to affect the rate of diagnosis of significant OSA in children. Re evaluation during a different season is unlikely to provide different results and may postpone surgery unnecessarily. PMID- 27230013 TI - The association between ophthalmologic diseases and obstructive sleep apnea: a systematic review and meta-analysis. AB - PURPOSE: The purpose of this study was to evaluate the association between obstructive sleep apnea (OSA) and ophthalmologic diseases, specifically glaucoma, nonarteritic anterior ischemic optic neuropathy (NAION), retinal vein occlusion (RVO), central serous chorioretinopathy (CSR), and floppy eyelid syndrome (FES), by performing a systematic review and meta-analysis of published studies. METHODS: PubMed, Embase, and Scopus databases were searched for observational studies on OSA and its association with select ophthalmologic diseases. Data was pooled for random-effects modeling. The association between OSA and ophthalmologic diseases was summarized using an estimated pooled odds ratio with a 95 % confidence interval. RESULTS: Relative to non-OSA subjects, OSA subjects have increased odds of diagnosis with glaucoma (pooled odds ratio (OR) = 1.242; P < 0.001) and floppy eyelids syndrome (pooled OR = 4.157; P < 0.001). In reverse, the overall pooled OR for OSA was 1.746 (P = 0.002) in the glaucoma group, 3.126 (P = 0.000) in the NAION group, and 2.019 (P = 0.028) in the CSR group. For RVO, one study with 5965 OSA patients and 29,669 controls demonstrated a 1.94-fold odds increase in OSA patients. CONCLUSIONS: Our results suggest significant associations between OSA and glaucoma, NAION, CSR, and FES. Screening for OSA should be considered in patients with glaucoma, NAION, CSR, or FES. PMID- 27230015 TI - Occurrence and first multilocus microsatellite genotyping of Neospora caninum from naturally infected dogs in dairy farms in Henan, Central China. AB - Neospora caninum is one of the important causes of abortion in dairy cattle worldwide. The dog is known as a definitive host of N. caninum and can transmit the parasite to cattle by shedding oocysts. The aim of the present study is to detect the presence of N. caninum in feces of dairy farm dogs and determine the genetic characteristics of N. caninum in Central China. A total of 78 fecal samples were collected from dogs in dairy farms from May to November 2014 and examined by microscopy and nested PCR based on Nc5 gene. Neospora-like oocysts were microscopically detected in two fecal samples, of which only one (Nc-LY1) was confirmed to be N. caninum by nested PCR. Seven out of 78 fecal samples (9.0 %) were N. caninum DNA positive, of which Neospora-like oocysts were simultaneously microscopically detected only in one sample (Nc-LY1). No statistical associations were found between the positive rates and age or sex of dogs (P > 0.05). The N. caninum-positive DNA samples were further analyzed by multilocus microsatellite (MS) genotyping for MS4, MS5, MS6A, MS7, MS8, MS10, MS12, and Cont-14. Only the fecal sample in which oocysts were detected was successfully genotyped at all genetic loci, and a new genotype was identified. To our knowledge, this study is the first report of genetic characterization of N. caninum isolates from naturally infected dogs based on multilocus microsatellites in China. PMID- 27230014 TI - Repriming by PrimPol is critical for DNA replication restart downstream of lesions and chain-terminating nucleosides. AB - PrimPol is a DNA damage tolerance enzyme possessing both translesion synthesis (TLS) and primase activities. To uncover its potential role in TLS-mediated IgVlambda hypermutation and define its interplay with other TLS polymerases, PrimPol(-/-) and PrimPol(-/-)/Poleta(-/-)/Polzeta (-/-) gene knockouts were generated in avian cells. Loss of PrimPol had no significant impact on the rate of hypermutation or the mutation spectrum of IgVlambda. However, PrimPol(-/-) cells were sensitive to methylmethane sulfonate, suggesting that it may bypass abasic sites at the IgVlambda segment by repriming DNA synthesis downstream of these sites. PrimPol(-/-) cells were also sensitive to cisplatin and hydroxyurea, indicating that it assists in maintaining / restarting replication at a variety of lesions. To accurately measure the relative contribution of the TLS and primase activities, we examined DNA damage sensitivity in PrimPol(-/-) cells complemented with polymerase or primase-deficient PrimPol. Polymerase-defective, but not primase-deficient, PrimPol suppresses the hypersensitivity of PrimPol(-/ ) cells. This indicates that its primase, rather than TLS activity, is pivotal for DNA damage tolerance. Loss of TLS polymerases, Poleta and Polzeta has an additive effect on the sensitivity of PrimPol(-/-) cells. Moreover, we found that PrimPol and Poleta-Polzeta redundantly prevented cell death and facilitated unperturbed cell cycle progression. PrimPol(-/-) cells also exhibited increased sensitivity to a wide variety of chain-terminating nucleoside analogs (CTNAs). PrimPol could perform close-coupled repriming downstream of CTNAs and oxidative damage in vitro. Together, these results indicate that PrimPol's repriming activity plays a central role in reinitiating replication downstream from CTNAs and other specific DNA lesions. PMID- 27230016 TI - Aelurostrongylus abstrusus in wild felids of South Africa. AB - The increasing interest on respiratory nematodes of domestic cats (Felis silvestris catus) has recently stimulated several studies on their epidemiology and geographic distribution. At the same time, there are still important gaps in our knowledge of the infections caused by respiratory nematodes in wild felids. The present study investigated the occurrence of pulmonary parasites in wild hosts housed in sanctuaries and protected areas of South Africa. Faecal samples collected from seven species of wild felids living in three study sites were copromicroscopically and genetically examined. Of twenty-one samples six, i.e. three from caracals (Caracal caracal), two from lions (Panthera leo) and one from a serval (Leptailurus serval), scored positive for the metastrongyloid Aelurostrongylus abstrusus at copromicroscopic and/or molecular tests. No other lungworms were recorded. The occurrence of the cosmopolitan cat lungworm A. abstrusus in wild hosts has been so far questioned. Importantly, the present findings represent an unequivocal evidence of the capability of A. abstrusus to infect some species of wild felids. Further studies are warranted to understand the epidemiological patterns of lungworms in wild and domestic felids, and to better investigate the impact of these parasitoses on health and welfare of wild animals. PMID- 27230017 TI - Derivatives of biarylalkyl carboxylic acid induce pleiotropic phenotypes in adult Schistosoma mansoni in vitro. AB - Schistosomes and other parasitic platyhelminths cause infectious diseases of worldwide significance for humans and animals. Despite their medical and economic importance, vaccines are not available and the number of drugs is alarmingly limited. For most platyhelminths including schistosomes, Praziquantel (PZQ) is the commonly used drug. With respect to its regular application in mass treatment programs, however, there is increasing concern about resistance development.Previous studies demonstrated that inhibitors used to treat non parasitic human diseases may be useful to be tested for their effects on parasites. To this end, we focused on biarylalkyl carboxylic acids (BACAs) as basis, which had been shown before to be interesting candidates in the context of finding alternative approaches to treat diabetes mellitus. We tested 32 chemically modified derivatives of these substances (biarylalkyl carboxylic acid derivatives (BACADs)) for their effects on adult Schistosoma mansoni in vitro. Treatment with 18 BACADs resulted in egg production-associated phenotypes and reduced pairing stability. In addition, 12 of these derivatives affected vitality and/or caused severe tegument damage, gut dilatation, or other forms of tissue disintegration which led to the death of worms. In most cases (10/12), one derivative caused more than one phenotype at a time. In vitro experiments in the presence of serum albumin (SA) and alpha-acidic glycoprotein (AGP) indicated a varying influence of these blood components on the effects of two selected derivatives. The variety of observed phenotypes suggested that different targets were hit. The results demonstrated that BACADs are interesting substances with respect to their anti-schistosomal effects. PMID- 27230019 TI - High prevalence of Eucoleus boehmi (syn. Capillaria boehmi) in foxes from western Austria. AB - Eucoleus boehmi (syn. Capillaria boehmi) is a canine trichuroid nematode affecting the upper respiratory airways (i.e., nasal cavity and paranasal sinuses) of dogs, foxes, and wolves. In the past few years, reports in dogs and wild canids have increased from across Europe, but data on its occurrence and distribution in Austria is scanty. A total of 47 red foxes (Vulpes vulpes) from the two westernmost provinces (Tyrol and Vorarlberg) of Austria were therefore examined for the presence of E. boehmi at necropsy. Eggs and adult nematodes were identified morphologically and molecularly (cox1) as E. boehmi. These nematodes were found in 26 (78.8 %) and 13 (92.9 %) foxes from Tyrol and Vorarlberg, respectively, with an overall prevalence of 83.0 % (39/47). The prevalence rate of infection recorded in this study is among the highest in Europe. These results suggest that foxes may represent an important source of infection for dogs and other canids, but further studies are needed to elucidate the transmission dynamics. PMID- 27230018 TI - Photosensitizers in the fight against ticks: safranin as a novel photodynamic fluorescent acaricide to control the camel tick Hyalomma dromedarii (Ixodidae). AB - Ticks transmit more pathogen species than any other group of blood-feeding arthropods worldwide, affecting humans, livestock, and companion animals. Hyalomma dromedarii is the predominant tick species infesting camels, and its effective control is of pivotal importance. In this research, we compared the phytoefficacy of safranin (SF), a fluorescent dye applied as an acaricide for the first time, to that of tetramethrin (TM) against engorged females of H. dromedarii through in vitro immersion bioassays. Furthermore, the effect of SF exposure was evaluated on the reproductive potential of surviving tick females. Different concentrations of SF (0.03, 0.06, 0.3, 1, and 4 % w:v) and TM (0.03, 0.13, 0.5, 2, and 4 %) were prepared in distilled water and administered to engorged females of H. dromedarii. SF-treated ticks were illuminated with a light source for 30 min post-treatment (PT). Photophysical properties of SF were studied, and the relative efficacy of the used light source and sunlight was calculated. Results showed that the minimum least concentration that causes 100 % acaricidal effect was 4 % PT with SF and TM, for 8 and 48 h, respectively. LC50 values 8 and 24 h PT were 0.08, 0.03 and 0.78, 0.20 %, respectively. Comparing LC50 and LC90 2 h PT, SF was 33 and 22 times more potent than TM. LT50 of 4 % SF and TM were 0.80 and 2.17 h, respectively. Treatment with the lowest concentrations of SF and TM induced reduction of the number of ovipositing females, eggs per female, ticks laying viable eggs, and hatched eggs. Overall, our results highlighted that SF is highly effective if compared to TM, allowing use to candidate it for the development of novel and safer acaricides. PMID- 27230020 TI - Impact of short-term high altitude exposure on exercise capacity and symptoms in Fontan patients. PMID- 27230022 TI - Impact of multi-modal web-based rehabilitation on occupational performance and upper limb outcomes: pilot randomized trial in children with acquired brain injuries. AB - AIMS: To determine whether the multi-modal web-based rehabilitation 'Move it to improve it' (Mitii) is more effective than wait list control (usual care) to improve occupational performance, upper limb function, and visual perception in children with acquired brain injury (ABI). METHOD: Fifty-eight randomly allocated children (53% males; mean age 11y 11mo, SD 2y 6mo; Manual Abilities Classification Scale equivalent I=32, II=24, III=2; mean Full-scale IQ 75.8, SD 16.2) received either 20 weeks of Mitii (n=29) or usual care (n=29). Mitii comprised upper limb, cognitive, visual perception, and gross motor tasks, recommended for 30 minutes per day, 6 days per week, over 20 weeks. Outcomes were the Assessment of Motor and Process Skills (AMPS), Melbourne Assessment of Unilateral Upper Limb Function, Jebsen-Taylor Test of Hand Function, Test of Visual Perceptual Skills, Assisting Hand Assessment (AHA), and Canadian Occupational Performance Measure. The primary comparison at 20 weeks between groups on the AMPS process and motor measures used generalized estimating equations. RESULTS: Groups were equivalent at baseline. Participants completed on average 17.6 hours (range 0-46h) of Mitii. There were no differences between groups on the primary outcome (AMPS process: estimated mean difference -0.1, 95% CI -0.3 to 0.2, p=0.589; and AMPS motor: estimated mean difference 0.2, 95% CI 0.1 to 0.5, p=0.192). There were no differences between groups on overall visual perception, upper limb, and occupational performance outcomes. INTERPRETATION: Mitii led to negligible changes on all primary and secondary outcomes compared with usual care. This likely reflects the small dose achieved and poses questions around the acceptability and feasibility of home-delivered Mitii in this population of children with ABI. PMID- 27230023 TI - Enhanced light-driven catalytic performance of cytochrome P450 confined in macroporous silica. AB - A light-driven approach combined with a macroporous reactor for the enzymatic biocatalytic reaction has been developed by confining the enzyme/photosensitizer nanohybrids in a macroporous material, which exhibits high bio-conversion efficiency due to the fast diffusion and collision between the enzyme/photosensitizer nanohybrid and the substrate in the reactor. PMID- 27230021 TI - Testing for the mediating role of endophenotypes using molecular genetic data in a twin study of ADHD traits. AB - Family and twin studies have identified endophenotypes that capture familial and genetic risk in attention-deficit/hyperactivity disorder (ADHD), but it remains unclear if they lie on the causal pathway. Here, we illustrate a stepwise approach to identifying intermediate phenotypes. First, we use previous quantitative genetic findings to delineate the expected pattern of genetically correlated phenotypes. Second, we identify overlapping genetic associations with ADHD-related quantitative traits. Finally, we test for the mediating role of associated endophenotypes. We applied this approach to a sample of 1,312 twins aged 7-10. Based on previous twin model-fitting analyses, we selected hyperactivity-impulsivity, inattention, reading difficulties (RD), reaction time variability (RTV) and commission errors (CE), and tested for association with selected ADHD risk alleles. For nominally significant associations with both a symptom and a cognitive variable, matching the expected pattern based on previous genetic correlations, we performed mediation analysis to distinguish pleiotropic from mediating effects. The strongest association was observed for the rs7984966 SNP in the serotonin receptor gene (HTR2A), and RTV (P = 0.007; unadjusted for multiple testing). Mediation analysis suggested that CE (38%) and RTV (44%) substantially mediated the association between inattention and the T-allele of SNP rs3785157 in the norepinephrine transporter gene (SLC6A2) and the T-allele of SNP rs7984966 in HTR2A, respectively. The SNPs tag risk-haplotypes but are not thought to be functionally significant. While these exploratory findings are preliminary, requiring replication, this study demonstrates the value of this approach that can be adapted to the investigation of multiple genetic markers and polygenic risk scores. (c) 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc. PMID- 27230024 TI - Regulation of Hydroxylation and Nitroreduction Pathways during Metabolism of the Neonicotinoid Insecticide Imidacloprid by Pseudomonas putida. AB - Imidacloprid (IMI) is mainly metabolized via nitroreduction and hydroxylation pathways, which produce different metabolites that are toxic to mammals and insects. However, regulation of IMI metabolic flux between nitroreduction and hydroxylation pathways is still unclear. In this study, Pseudomonas putida was found to metabolize IMI to 5-hydroxy and nitroso IMI and was therefore used for investigating the regulation of IMI metabolic flux. The cell growth time, cosubstrate, dissolved oxygen concentration, and pH showed significant effect on IMI degradation and nitroso and 5-hydroxy IMI formation. Gene cloning and overexpression in Escherichia coli proved that P. putida KT2440 aldehyde oxidase mediated IMI nitroreduction to nitroso IMI, while cytochrome P450 monooxygenase (CYP) failed to improve IMI hydroxylation. Moreover, E. coli cells without CYP could hydroxylate IMI, demonstrating the role of a non-CYP enzyme in IMI hydroxylation. Thus, the present study helps to further understand the environmental fate of IMI and its underlying mechanism. PMID- 27230025 TI - Correlation Among Soil Enzyme Activities, Root Enzyme Activities, and Contaminant Removal in Two-Stage In Situ Constructed Wetlands Purifying Domestic Wastewater. AB - Two-stage in situ wetlands (two vertical flow constructed wetlands in parallel and a horizontal flow constructed wetland) were constructed for studying domestic wastewater purification and the correlations between contaminant removal and plant and soil enzyme activities. Results indicated the removal efficiency of NH4 (+) and NO3 (-) were significantly correlated with both urease and protease activity, and the removal of total phosphorus was significantly correlated with phosphatase activity. Chemical oxygen demand removal was not correlated with enzyme activity in constructed wetlands. Plant root enzyme (urease, phosphatase, protease and cellulose) activity correlation was apparent with all contaminant removal in the two vertical flow constructed wetlands. However, the correlation between the plant root enzyme activity and contaminant removal was poor in horizontal flow constructed wetlands. Results indicated that plant roots clearly played a role in the removal of contaminants. PMID- 27230026 TI - Acute Toxicity of Gamma Radiation to the Monogonont Rotifer Brachionus koreanus. AB - We examined the tolerance of the monogonont rotifer Brachionus koreanus in response to gamma radiation. In order to determine the median lethal dose (LD50) of rotifers against gamma radiation, we irradiated B. koreanus with gamma rays from 0 to 7000 grays (Gy). The LD50s were 2900 and 2300 Gy at 24 h (LD50-24 h) and 96 h (LD50-96 h) after irradiation, respectively. In addition, the no observed effect levels (NOEL) were 1500 and 1000 Gy at 24 and 96 h, respectively. This is the first determination of lethal doses of gamma radiation for B. koreanus, which could be useful in ecological assessment of gamma radiation toward aquatic life and could be useful for understanding toxic mechanisms over sublethal doses. PMID- 27230027 TI - Nickel and Copper Toxicity and Plant Response Mechanisms in White Birch (Betula papyrifera). AB - Nickel (Ni) and copper (Cu) are the most prevalent metals found in the soils in the Greater Sudbury Region (Canada) because of smelting emissions. The main objectives of the present study were to (1) determine the toxicity of nickel (Ni) and copper (Cu) at different doses in Betula papyrifera (white birch), (2) Characterize nickel resistance mechanism, and (3) assess segregating patterns for Ni and Cu resistance in B. papyrifera populations. This study revealed that B. papyrifera is resistant to Ni and Cu concentrations equivalent to the levels reported in metal-contaminated stands in the GSR. Resistant genotypes (RG) accumulate Ni in roots but not in leaves. Moderately susceptible (MSG) and susceptible genotypes (SG) show a high level of Ni translocation to leaves. Gene expression analysis showed differential regulation of genes in RG compared to MSG and SG. Analysis of segregation patterns suggests that resistance to Ni and Cu is controlled by single recessive genes. PMID- 27230028 TI - Effects of a Dam Reservoir on the Distribution of Heavy Metals in Two Chilean Native Freshwater Fish Species. AB - In order to determine the effect of a dam on metal concentrations in riverine fish species, we studied fish inhabiting the influent (Cachapoal River) and effluent (Rapel River) of the Rapel Reservoir in central Chile. Heavy metals were quantified in gills, liver and muscle of the catfish Trichomycterus areolatus and the silverside Basilichthys microlepidotus. Also, the bioaccumulation index (BAI) was estimated by considering heavy metal concentrations obtained from water and sediment. Results showed the presence of Al, Cu, Fe, Mn, Pb and Zn in the fish organs. The analysis showed high metal concentrations in catfish inhabiting the influent compared to those collected in the effluent. These results indicate a possible filter effect of the dam for most of the metals identified in the fish organs, because metal concentrations decreased in the effluent. Finally, catfish exhibited a larger BAI for most metals analyzed. PMID- 27230029 TI - Testing Direct and Indirect Effects of Identity, Media Use, Cognitions, and Conversations on Self-Reported Physical Activity Among a Sample of Hispanic Adults. AB - This article presents the results of a study testing the direct and indirect effects of identity, media use, cognitions and conversations on physical activity (PA). The study was guided by the O-S-O-R model (Markus & Zajonc, 1985), and it used data collected from a sample of Hispanic adults (N = 268) living in the U.S. Southwest. Exercise identity and ethnic identity were defined as pre-orientations (O1); use of PA-related media content was defined as the stimulus (S); reflective integration and conversations about PA-related media were post-orientations (O2); and self-reported physical activity was the behavioral response (R). Structural equation modeling was used to analyze the data, and several compelling results emerged. Exercise identity had a significant positive direct effect on PA and PA related media use, as well as a significant positive indirect effect on conversations about PA-related media. PA-related media use exerted a strong and significant positive effect on conversations about PA-related media, as well as a significant positive indirect effect on PA. Finally, conversations about PA related media content had a significant positive direct effect on PA. The results indicate that identity acts as a filter influencing what media content are selected and that cognitions and conversations about media content can serve as a link between media use and health behavior. Key words: O-S-O-R model, physical activity, Hispanic adults, identity, media use, conversation. PMID- 27230031 TI - Successful treatment continuation with a single mild partial splenic embolization for thrombocytopenia caused by oxaliplatin-based chemotherapy for advanced colon cancer. AB - We report the case of a patient with advanced colon cancer receiving oxaliplatin based chemotherapy that was able to continue systemic chemotherapy by performing mild partial splenic embolization (PSE) for thrombocytopenia caused by splenomegaly due to oxaliplatin. Mild PSE may be useful for thrombocytopenia due to splenomegaly in cancer patients because it provides more treatment opportunities. PMID- 27230030 TI - Soluble TNF-related apoptosis induced ligand (sTRAIL) is augmented by Post Conditioning and correlates to infarct size and left ventricle dysfunction in STEMI patients: a substudy from a randomized clinical trial. AB - Low levels of Soluble TNF-related apoptosis induced ligand (sTRAIL) seem to be related to worse prognosis after an acute coronary syndrome. PostConditioning (PostCond) may protect the heart from reperfusion injury. We sought to evaluate the impact of PostCond on sTRAIL in relationship to infarct size (area under the curve of Troponin T, AUCTnT) and left ventricle ejection fraction (LVEF) in a series of patients undergoing primary coronary intervention for ST-segment elevation myocardial infarction (STEMI). In a substudy of a randomized trial that tested the effects of PostCond in STEMI-patients, sTRAIL was measured 24 h after reperfusion (PostCond n = 39, Control n = 39). Correlations between sTRAIL and both AUCTnT and LVEF were studied for each study arm. At 24 h, sTRAIL was higher for PostCond vs Controls (46.4 +/- 30.6 vs 32.9 +/- 23.4, p = 0.031), was negatively related to AUCTnT [B = -0.09, 95 % CI (-0.15 to -0.30), p = 0.005] and was positively related to both in-hospital [B = 0.10, 95 % CI (0.02-0.17), p = 0.018], and follow-up LVEF [B = 0.21, 95 % (0.10-0.32), p = 0.001]. No significant relationship was found for Controls. On multivariate analysis, PostCond was an independent predictor for sTRAIL [B = 12.13 95 % CI (0.40-23.87), p = 0.043]. In conclusion, PostCond positively influenced sTRAIL, which was related to reduced infarct size and better LVEF. Further studies are needed to understand potential mechanisms elicited by PostCond in infarct size reduction. PMID- 27230032 TI - Risk factors for consecutive exotropia after esotropia surgery. AB - PURPOSE: To evaluate the risk factors in development of postoperative exotropia following bilateral medial rectus (BMR) recession for esotropia. METHODS: 108 patients who underwent BMR recession for esotropia between November 1996 and July 2010 were enrolled. 54 patients who required surgery for consecutive exotropia were compared to 54 controls whose angle of deviation showed less than five prism diopters of esotropia at all periods after BMR recession. Amblyopia, dissociated vertical deviation (DVD), refractive error, inferior oblique overaction, and multiple surgery history were evaluated as risk factors for the development of consecutive exotropia. The postoperative changes of angle of deviation were calculated. RESULTS: Amblyopia was found in 27 patients (50.5 %) in the exotropia group, and in six patients (11.1 %) in the control group (P < 0.001) before esotropia surgery. DVD was detected in 16 (29.06 %) patients in the exotropia group as compared to 4 (7.4 %) in the control group (P = 0.003). With logistic regression analysis, the odds ratio of DVD was 5.27 (95 % CI 1.63-17.03; P = 0.006) and of amblyopia, 8.00 (95 % CI 2.94-21.80; P < 0.001). There were no significant differences between the two groups with regards to the pre-operative deviation, follow up periods, degree of hyperopia, presence of anisometropia or inferior oblique overaction, and history of multiple surgery. Using linear mixed model analysis, the exotropic shift across time was higher in the consecutive exotropia group relative to the controls (P < 0.001). CONCLUSIONS: The presence of amblyopia before esotropia surgery and DVD correlated with risk of consecutive exotropia. PMID- 27230033 TI - Isolation of the Fathead Minnow Nidovirus from Muskellunge Experiencing Lingering Mortality. AB - In 2011, the Fathead Minnow nidovirus (FHMNV; Genus Bafinivirus, Family Coronaviridae, Order Nidovirales) was isolated from pond-raised juvenile Muskellunge Esox masquinongy suffering from lingering mortality at the Wild Rose Hatchery in Wild Rose, Wisconsin. Moribund Muskellunge exhibited tubular necrosis in the kidneys as well as multifocal coalescing necrotizing hepatitis. The FHMNV was also isolated from apparently healthy juvenile Muskellunge at the Wolf Lake State Fish Hatchery in Mattawan, Michigan. The identity of the two syncytia forming viruses (designated MUS-WR and MUS-WL from Wild Rose Hatchery and Wolf Lake State Fish Hatchery, respectively) as strains of FHMNV was determined based on multiple-gene sequencing and phylogenetic analyses. The pathogenicity of the MUS-WL FHMNV strain was determined by experimentally infecting naive juvenile Muskellunge through intraperitoneal injection with two viral concentrations (63 and 6.3 * 10(3) TCID50/fish). Both doses resulted in 100% mortality in experimentally infected fish, which exhibited severely pale gills and petechial hemorrhaging in eyes, fins, and skin. Histopathological alterations in experimentally infected fish were observed mainly in the hematopoietic tissues in the form of focal areas of necrosis. Phylogenetic analysis of concatenated partial spike glycoprotein and helicase gene sequences revealed differences between the MUS-WL FHMNV, MUS-WR FHMNV, and two other FHMNV originally isolated from moribund Fathead Minnows Pimephales promelas including the index FHMNV strain (GU002364). Based on a partial helicase gene sequence, a reverse transcriptase PCR assay was developed that is specific to FHMNV. These results give evidence that the risks posed to Muskellunge by FHMNV should be taken seriously. Received May 1, 2015; accepted February 8, 2016. PMID- 27230034 TI - Prediction of response to everolimus in neuroendocrine tumors: evaluation of clinical, biological and histological factors. AB - Objectives Several targeted therapies are available for metastatic neuroendocrine tumours (NETs) but no predictive factor of response to these treatments has been identified yet. Our aim was to identify and evaluate clinical, biological, histological and functional markers of response to everolimus. Methods We retrospectively reviewed 53 patients with NETs treated with everolimus (68 % in clinical trials). Clinical, biological and histological data were analyzed. The functional marker p-p70S6K, a main effector of the mTOR pathway, was studied by immunohistochemistry in 43 cases. Prognostic factors of progression-free survival (PFS) were studied by Kaplan Meier analysis. Results All patients had metastatic and progressive disease before everolimus treatment. Objective response was 9 % and median PFS was 8.1 (4.7-11.5) months. Hypercholesterolemia (HR = 0.13, p < 0.0001) was associated with longer PFS, whereas presence of bone metastases (HR = 3.1, p < 0.001) and overexpression of p-p70S6K by tumor cells (HR = 2.5, p = 0.01) were associated with shorter PFS under everolimus at multivariate analysis. Conclusion Clinical markers are not useful to predict response to everolimus. However, occurrence of hypercholesterolemia under treatment may be an early marker of response. Prospective studies are required to confirm these results and to assess whether p-p70S6K immunostaining is a prognostic or predictive marker of no-response to everolimus. PMID- 27230035 TI - MiR-221 Promotes Capan-2 Pancreatic Ductal Adenocarcinoma Cells Proliferation by Targeting PTEN-Akt. AB - BACKGROUND/AIMS: MicroRNAs (miRNAs, miRs) have emerged as critical regulators of cancer cell proliferation. The effect of miR-221 on cancer cell growth could be significantly changeable in different cell lines. Although miR-221 was reported to promote the cell growth of pancreatic ductal adenocarcinoma (PDAC) cells, its role in Capan-2 cell line is largely unknown. METHODS: Capan-2 cells were transfected with miR-221 mimics, inhibitors, or negative controls. Cell Counting Kit-8 was used to determine cell viability. EdU staining and cell cycle analysis were used to measure cell proliferation. Western blotting was used to detect the expression levels of PTEN and phospho-Akt. The PI3K-Akt pathway activator SC-79 and inhibitor LY294002 were used to perform the rescue experiment in determining cell proliferation. RESULTS: Overexpressing miR-221 significantly increased cell vitality and promoted cell proliferation and G1-to-S phase transition of the cell cycle in Capan-2 cells, while inhibition of miR-221 decreased that. The protein level of PTEN in Capan-2 cells was downregulated by overexpressing miR-221, while upregulated by inhibiting miR-221. Consistently, enhanced phosphorylation of AktSer473 was observed in miR-221 overexpressed Capan-2 cells, and the opposite result was found in miR-221 inhibited cells. LY294002 restored the pro proliferation effect of miR-221 on Capan-2 cells, while SC-79 had no additional effect on cell proliferation in Capan-2 cells transfected with miR-221 mimics. CONCLUSION: Our study indicates that miR-221 is an oncogenic miRNA which promotes Capan-2 cells proliferation by targeting PTEN-Akt pathway. PMID- 27230037 TI - More older patients are stuck in hospitals. PMID- 27230036 TI - Repeated salivary daytime cortisol and onset of mood episodes in offspring of bipolar parents. AB - BACKGROUND: Differences in cortisol secretion may differentiate individuals at high compared to low genetic risk for bipolar disorder (BD) and predict the onset or recurrence of mood episodes. The objectives of this study were to determine if salivary cortisol measures are: (1) different in high-risk offspring of parents with BD (HR) compared to control offspring of unaffected parents (C), (2) stable over time, (3) associated with the development of mood episode onset/recurrence, and (4) influenced by comorbid complications. METHODS: Fifty-three HR and 22 C completed salivary cortisol sampling annually for up to 4 years in conjunction with semi-structured clinical interviews. The cortisol awakening response (CAR), daytime cortisol [area under the curve (AUC)], and evening cortisol (8:00 p.m.) were calculated. RESULTS: There were no differences in baseline CAR, AUC and evening cortisol between HR and C (p = 0.38, p = 0.30 and p = 0.84), respectively. CAR, AUC and evening cortisol were stable over yearly assessments in HR, while in Cs, evening cortisol increased over time (p = 0.008), and CAR and AUC remained stable. In HR, AUC and evening cortisol increased the hazard of a new onset mood disorder/recurrence by 2.7 times (p = 0.01), and 3.5 times (p = 0.01), respectively, but this was no longer significant after accounting for multiple comparisons. CONCLUSIONS: Salivary cortisol is stable over time within HR offspring. However, between individuals, basal salivary cortisol is highly variable. More research is needed, with larger samples of prospectively studied HR youth using a more reliable method of cortisol measurement, to determine the potential role of cortisol in the development of mood disorders. PMID- 27230038 TI - Comparison of Amplitude-Integrated EEG and Conventional EEG in a Cohort of Premature Infants. AB - OBJECTIVE: To compare amplitude-integrated EEG (aEEG) and conventional EEG (EEG) activity in premature neonates. METHODS: Biweekly aEEG and EEG were simultaneously recorded in a cohort of infants born less than 34 weeks gestation. aEEG recordings were visually assessed for lower and upper border amplitude and bandwidth. EEG recordings were compressed for visual evaluation of continuity and assessed using a signal processing software for interburst intervals (IBI) and frequencies' amplitude. Ten-minute segments of aEEG and EEG indices were compared using regression analysis. RESULTS: A total of 189 recordings from 67 infants were made, from which 1697 aEEG/EEG pairs of 10-minute segments were assessed. Good concordance was found for visual assessment of continuity between the 2 methods. EEG IBI, alpha and theta frequencies' amplitudes were negatively correlated to the aEEG lower border while conceptional age (CA) was positively correlated to aEEG lower border ( P < .001). IBI and all frequencies' amplitude were positively correlated to the upper aEEG border ( P <= .001). CA was negatively correlated to aEEG span while IBI, alpha, beta, and theta frequencies' amplitude were positively correlated to the aEEG span. CONCLUSIONS: Important information is retained and integrated in the transformation of premature neonatal EEG to aEEG. SIGNIFICANCE: aEEG recordings in high-risk premature neonates reflect reliably EEG background information related to continuity and amplitude. PMID- 27230039 TI - Diagnostic Value of the CD103+CD4+/CD4+ Ratio to Differentiate Sarcoidosis from Other Causes of Lymphocytic Alveolitis. AB - BACKGROUND: The CD103 integrin is present on CD4+ lymphocytes of the bronchial mucosa, but not on peripheral blood CD4+ lymphocytes. It has been hypothesized that CD4+ lymphocytes in pulmonary sarcoidosis originate from redistribution from the peripheral blood to the lung, and therefore do not bear the CD103 integrin. Some data suggest that a low CD103+ percentage among bronchoalveolar lavage fluid (BALF) CD4+ lymphocytes discriminates between sarcoidosis and other diagnoses. OBJECTIVE: To determine the diagnostic value of BALF CD103+ to identify sarcoidosis among other causes of alveolar lymphocytosis in a large retrospective case series. METHODS: Among 391 consecutive bronchoalveolar lavages performed at our institution and analyzed by flow cytometry, we identified 207 cases, which were grouped into nine diagnostic categories: sarcoidosis, tuberculosis, non tuberculous infections, hypersensitivity pneumonitis, non-specific interstitial pneumonia, organizing pneumonia, drug-induced lung diseases, other interstitial lung diseases (ILDs), and other diagnoses. To assess the discriminative value of the CD103+CD4+/CD4+ ratio to distinguish sarcoidosis from other entities, areas under ROC curves (AUC) were calculated. RESULTS: Sarcoidosis patients (n = 53) had significantly lower CD103+CD4+/CD4+ ratios than patients in other diagnostic categories. The AUC was 62% for sarcoidosis compared to all other diagnoses, and 69% for sarcoidosis compared to other ILDs. When combining CD103+CD4+/CD4+ and CD4+/CD8+ ratios, the AUC increased to 76 and 78%, respectively. When applying previously published cut-offs to our population, the AUC varied between 54 and 73%. CONCLUSIONS: The CD103+CD4+/CD4+ ratio does not accurately discriminate between sarcoidosis and other causes of lymphocytic alveolitis, neither alone nor in combination with the CD4+/CD8+ ratio, and is not a powerful marker for the diagnosis of sarcoidosis. PMID- 27230040 TI - The astrocytic response to the dopaminergic denervation of the striatum. AB - Increasing evidence suggests that the dopaminergic degeneration which characterizes Parkinson's disease starts in the striatal dopamine terminals and progresses retrogradely to the body of dopamine cells in the substantia nigra. The role of striatal astrocytes in the striatal initiation of the dopaminergic degeneration is little known. This work was aimed at studying the astrocytic response to the dopaminergic denervation of the striatum. The injection of 6 hydroxydopamine (25 MUg) in the lateral ventricle of adult Sprague-Dawley rats induced a fast (4 h) and selective (unaccompanied by unspecific lesions of striatal tissue or microgliosis) degeneration of the dopaminergic innervation of the striatum which was followed by a selective astrocytosis unaccompanied by microgliosis. This astrocytosis was severe and had a specific profile which included some (e.g. up-regulation of glial fibrillary acidic protein, GS, S100beta, NDRG2, vimentin) but not all (e.g. astrocytic proliferation or differentiation from NG2 cells, astrocytic scars, microgliosis) the characteristics observed after the non-selective lesion of the striatum. This astrocytosis is similar to those observed in the parkinsonian striatum and, because it is was unaccompanied by changes in other striatal cells (e.g. by microgliosis), it may be suitable to study the role of striatal astrocytes during the dopaminergic denervation which characterizes the first stages of Parkinson's disease. The dopaminergic denervation of the striatum induced a severe astrogliosis with a specific profile which included some (e.g. up-regulation of GFAP, GS, S100beta, NDRG2, vimentin) but not all (e.g. astrocytic proliferation or differentiation from NG2 cells, astrocytic scars, microgliosis) the characteristics observed after the non-selective striatal lesions. This response may help to understand the role of striatal astrocytes during the dopaminergic denervation which characterizes the first stages of PD. Cover Image for this issue: doi: 10.1111/jnc.13336. PMID- 27230041 TI - Short Telomere Load, Telomere Length, and Subclinical Atherosclerosis: The PESA Study. AB - BACKGROUND: Leucocyte telomere length (LTL) shortening is associated with cardiovascular ischemic events and mortality in humans, but data on its association with subclinical atherosclerosis are scarce. Whether the incidence and severity of subclinical atherosclerosis are associated with the abundance of critically short telomeres, a major trigger of cellular senescence, remains unknown. OBJECTIVES: The authors conducted a cross-sectional exploration of the association between subclinical atherosclerosis burden and both average LTL and the abundance of short telomeres (%LTL<3 kb). METHODS: Telomere length was assessed by high-throughput quantitative fluorescence in situ hybridization in circulating leukocytes from 1,459 volunteers without established cardiovascular disease (58% men, 40 to 54 years of age) from the PESA (Progression of Early Subclinical Atherosclerosis) study. Subclinical atherosclerosis was evaluated by coronary artery calcium scan and 2-dimensional/3-dimensional ultrasound in different aortic territories. Statistical significance of differences among multiple covariates was assessed with linear regression models. Independent associations of telomere parameters with plaque presence were evaluated using general linear models. RESULTS: In men and women, age was inversely associated with LTL (Pearson's r = -0.127, p < 0.001) and directly with %LTL<3 kb (Pearson's r = 0.085; p = 0.001). Short LTL reached statistical significance as a determinant of total and femoral plaque in men, but not in women. However, this association was not sustained after adjustment for age or additional adjustment for cardiovascular risk factors. No significant independent association was found between %LTL<3 kb and plaque burden. Serum-oxidized low-density lipoprotein levels were directly associated with %LTL<3 kb in men (p = 0.008) and women (p < 0.001). CONCLUSIONS: In a cross-sectional study of a middle-aged population, average LTL and short telomere load are not significant independent determinants of subclinical atherosclerosis. Longitudinal follow-up of PESA participants will assess long-term associations between telomere length and progression of subclinical atherosclerosis. PMID- 27230042 TI - Telomeres and Atherosclerosis: The Attrition of an Attractive Hypothesis. PMID- 27230044 TI - Cholesterol Efflux Capacity: Choke Point of Reverse Cholesterol Traffic? PMID- 27230043 TI - Beyond Coronary Calcification, Family History, and C-Reactive Protein: Cholesterol Efflux Capacity and Cardiovascular Risk Prediction. AB - BACKGROUND: Cholesterol efflux capacity (CEC), which is a key step in the reverse cholesterol transport pathway, is independently associated with atherosclerotic cardiovascular disease (ASCVD). However, whether it predicts ASCVD beyond validated novel risk markers is unknown. OBJECTIVES: This study assessed if CEC improved ACSVD risk prediction beyond using coronary artery calcium (CAC), family history (FH), and high-sensitivity C-reactive protein (hs-CRP). METHODS: CEC, CAC, self-reported FH, and hs-CRP were assessed among participants without baseline ASCVD who were enrolled in the Dallas Heart Study (DHS). ASCVD was defined as a first nonfatal myocardial infarction (MI) or stroke, coronary revascularization, or cardiovascular death, assessed over a median 9.4 years. Risk prediction was assessed using various modeling techniques and improvements in the c-statistic, the integrated discrimination index (IDI), and the net reclassification index (NRI). RESULTS: The mean age of the population (N = 1,972) was 45 years, 52% had CAC (>0), 31% had FH, and 58% had elevated hs-CRP (>=2 mg/l). CEC greater than the median was associated with a 50% reduced incidence of ASCVD in those with CAC (5.4% vs. 10.5%; p = 0.003), FH (5.8% vs. 10%; p = 0.05), and elevated hs-CRP (3.8% vs. 7.9%; p = 0.004). CEC improved all metrics of discrimination and reclassification when added to CAC (c-statistic, p = 0.004; IDI, p = 0.02; NRI: 0.38; 95% confidence interval [CI]: 0.13 to 0.53), FH (c statistic, p = 0.006; IDI, p = 0.008; NRI: 0.38; 95% CI: 0.13 to 0.55), or elevated hs-CRP (c-statistic p = 0.008; IDI p = 0.02; NRI: 0.36; 95% CI 0.12 to 0.52). CONCLUSIONS: CEC improves ASCVD risk prediction beyond using CAC, FH, and hs-CRP and warrants consideration as a novel ASCVD risk marker. PMID- 27230045 TI - DAPT Duration After Coronary Stenting: Assessing Risk-Benefit Tradeoffs in Individual Patients. PMID- 27230047 TI - The Evolution of Contrast Ultrasound: From Diagnosis to Therapy. PMID- 27230046 TI - Diagnostic Ultrasound Impulses Improve Microvascular Flow in Patients With STEMI Receiving Intravenous Microbubbles. AB - BACKGROUND: Pre-clinical trials have demonstrated that, during intravenous microbubble infusion, high mechanical index (HMI) impulses from a diagnostic ultrasound (DUS) transducer might restore epicardial and microvascular flow in acute ST-segment elevation myocardial infarction (STEMI). OBJECTIVES: The purpose of this study was to test the safety and efficacy of this adjunctive approach in humans. METHODS: From May 2014 through September 2015, patients arriving with their first STEMI were randomized to either DUS intermittent HMI impulses (n = 20) just prior to emergent percutaneous coronary intervention (PCI) and for an additional 30 min post-PCI (HMI + PCI), or low mechanical index (LMI) imaging only (n = 10) for perfusion assessments before and after PCI (LMI + PCI). All studies were conducted during an intravenous perflutren lipid microsphere infusion. A control reference group (n = 70) arrived outside of the time window of ultrasound availability and received emergent PCI alone (PCI only). Initial epicardial recanalization rates prior to emergent PCI and improvements in microvascular flow were compared between ultrasound-treated groups. RESULTS: Median door-to-dilation times were 82 +/- 26 min in the LMI + PCI group, 72 +/- 15 min in the HMI + PCI group, and 103 +/- 42 min in the PCI-only group (p = NS). Angiographic recanalization prior to PCI was seen in 12 of 20 HMI + PCI patients (60%) compared with 10% of LMI + PCI and 23% of PCI-only patients (p = 0.002). There were no differences in microvascular obstructed segments prior to treatment, but there were significantly smaller proportions of obstructed segments in the HMI + PCI group at 1 month (p = 0.001) and significant improvements in left ventricular ejection fraction (p < 0.005). CONCLUSIONS: HMI impulses from a diagnostic transducer, combined with a commercial microbubble infusion, can prevent microvascular obstruction and improve functional outcome when added to the contemporary PCI management of acute STEMI. (Therapeutic Use of Ultrasound in Acute Coronary Artery Disease; NCT02410330). PMID- 27230049 TI - Dystrophin-Deficient Cardiomyopathy. AB - Dystrophinopathies are a group of distinct neuromuscular diseases that result from mutations in the structural cytoskeletal Dystrophin gene. Dystrophinopathies include Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), X linked dilated cardiomyopathy, as well as DMD and BMD female carriers. The primary presenting symptom in most dystrophinopathies is skeletal muscle weakness. However, cardiac muscle is also a subtype of striated muscle and is similarly affected in many of the muscular dystrophies. Cardiomyopathies associated with dystrophinopathies are an increasingly recognized manifestation of these neuromuscular disorders and contribute significantly to their morbidity and mortality. Recent studies suggest that these patient populations would benefit from cardiovascular therapies, annual cardiovascular imaging studies, and close follow-up with cardiovascular specialists. Moreover, patients with DMD and BMD who develop end-stage heart failure may benefit from the use of advanced therapies. This review focuses on the pathophysiology, cardiac involvement, and treatment of cardiomyopathy in the dystrophic patient. PMID- 27230050 TI - ABIM Maintenance of Certification: Current Status. PMID- 27230048 TI - Heparin-Induced Thrombocytopenia: A Comprehensive Clinical Review. AB - Heparin-induced thrombocytopenia is a profoundly dangerous, potentially lethal, immunologically mediated adverse drug reaction to unfractionated heparin or, less commonly, to low-molecular weight heparin. In this comprehensive review, the authors highlight heparin-induced thrombocytopenia's risk factors, clinical presentation, pathophysiology, diagnostic principles, and treatment. The authors place special emphasis on the management of patients requiring procedures using cardiopulmonary bypass or interventions in the catheterization laboratory. Clinical vigilance of this disease process is important to ensure its recognition, diagnosis, and treatment. Misdiagnosis of the syndrome, as well as misunderstanding of the disease process, continues to contribute to its morbidity and mortality. PMID- 27230051 TI - Our Personal Relationships From Training to Practice: Defining True Success. PMID- 27230052 TI - Haptoglobin Genotype as a Determinant of Benefit or Harm From Niacin for Participants With Diabetes. PMID- 27230053 TI - Effects of Milrinone on Rest and Exercise Hemodynamics in Heart Failure With Preserved Ejection Fraction. PMID- 27230054 TI - Elevated Serum Fibrinogen Is Associated With 12-Month Major Adverse Cardiovascular Events Following Percutaneous Coronary Intervention. PMID- 27230055 TI - The Importance of Global Health Experiences During Clinical Training. PMID- 27230056 TI - Genetic Scores and Prediction of Atherosclerotic Cardiovascular Disease: Moving From Short-Term to Lifetime Risk Assessment. PMID- 27230057 TI - Hospitalizations, Therapies, and Outcomes of Pulmonary Embolism in Medicare Beneficiaries: Trends Are Similar to Europe. PMID- 27230058 TI - Cautionary Pulmonary Insufficiency in Ablation of Ventricular Arrhythmias From Pulmonary Sinus Cusps. PMID- 27230060 TI - Correction. PMID- 27230059 TI - Reply: Cautionary Pulmonary Insufficiency in Ablation of Ventricular Arrhythmias From Pulmonary Sinus Cusps. PMID- 27230061 TI - Correction. PMID- 27230064 TI - Current management of the neck in salivary gland carcinomas. AB - Salivary gland cancers include a diverse group of tumours with many histological subtypes which occur in both major and minor salivary glands. As a result of this heterogeneity and different sites of presentation, there have been no randomised controlled trials to evaluate the indications and efficacy of neck treatments by either surgery or radiotherapy for occult or apparent neck node metastases. Neck dissection is an important treatment strategy for neck metastases arising from major and minor salivary gland malignancy as well as being useful for disease staging. However, there is considerable controversy in how to manage the neck in these patients. In this review, we discuss the management of neck metastases relating to malignant salivary gland tumours. PMID- 27230062 TI - A pancreatic exocrine-like cell regulatory circuit operating in the upper stomach of the sea urchin Strongylocentrotus purpuratus larva. AB - BACKGROUND: Digestive cells are present in all metazoans and provide the energy necessary for the whole organism. Pancreatic exocrine cells are a unique vertebrate cell type involved in extracellular digestion of a wide range of nutrients. Although the organization and regulation of this cell type is intensively studied in vertebrates, its evolutionary history is still unknown. In order to understand which are the elements that define the pancreatic exocrine phenotype, we have analyzed the expression of genes that contribute to specification and function of this cell-type in an early branching deuterostome, the sea urchin Strongylocentrotus purpuratus. RESULTS: We defined the spatial and temporal expression of sea urchin orthologs of pancreatic exocrine genes and described a unique population of cells clustered in the upper stomach of the sea urchin embryo where exocrine markers are co-expressed. We used a combination of perturbation analysis, drug and feeding experiments and found that in these cells of the sea urchin embryo gene expression and gene regulatory interactions resemble that of bona fide pancreatic exocrine cells. We show that the sea urchin Ptf1a, a key transcriptional activator of digestive enzymes in pancreatic exocrine cells, can substitute for its vertebrate ortholog in activating downstream genes. CONCLUSIONS: Collectively, our study is the first to show with molecular tools that defining features of a vertebrate cell-type, the pancreatic exocrine cell, are shared by a non-vertebrate deuterostome. Our results indicate that the functional cell-type unit of the vertebrate pancreas may evolutionarily predate the emergence of the pancreas as a discrete organ. From an evolutionary perspective, these results encourage to further explore the homologs of other vertebrate cell-types in traditional or newly emerging deuterostome systems. PMID- 27230063 TI - Medicine and management in European hospitals: a comparative overview. AB - BACKGROUND: Since the early 1980s all European countries have given priority to reforming the management of health services. A distinctive feature of these reforms has also been the drive to co-opt professionals themselves into the management of services, taking on full time or part time (hybrid) management or leadership roles. However, although these trends are well documented in the literature, our understanding of the nature and impact of reforms and how they are re-shaping the relationship between medicine and management remains limited. Most studies have tended to be nationally specific, located within a single discipline and focused primarily on describing new management practices. This article serves as an Introduction to a special issue of BMC Health Services Research which seeks to address these concerns. It builds on the work of a European Union funded COST Action (ISO903) which ran between 2009 and 2013, focusing specifically on the changing relationship between medicine and management in a European context. MAIN TEXT: Prior to describing the contributions to the special issue, this Introduction sets the scene by exploring four main questions which have characterised much of the recent literature on medicine and management. First is the question of what we understand by the changing relationship between medicine and management and in particular which this means for the emergence of so called 'hybrid' clinical leader roles? A second question concerns the forces that have driven change, in particular those relating to the wider project of management reforms. Third, we raise questions of how medical professionals have responded to these changes and what factors have shaped their responses. Lastly we consider what some of the outcomes of greater medical involvement in management and leadership might be, both in terms of intended and unintended outcomes. CONCLUSIONS: The paper concludes by summarising the contributions to the special issue and highlighting the need to extend research in this area by focusing more on comparative dimensions of change. It is argued that future research would also benefit theoretically by drawing together insights from health policy and management literatures. PMID- 27230065 TI - The incidence risk of type 2 diabetes mellitus in female nurses: a nationwide matched cohort study. AB - BACKGROUND: Diabetes is one of the most common chronic illnesses worldwide. This study was to assess whether the incidence risk of type 2 diabetes mellitus between female nurses and female non-nurses. METHODS: Study data were obtained from the Longitudinal Health Insurance Research Database, and nurses were sampled from the Registry for medical personnel. Nurses and non-nurses with similar traits and health conditions were selected via 1:1 propensity score matching. A total of 111,670 subjects were selected (55,835 nurses and 55,835 non-nurses). Stages of diabetes development were monitored until December 31, 2009. The Cox proportional hazards model was used to discuss risks and influencing factors related to diabetes. Poisson distribution methods were used to examine the incidence rate of diabetes per 1,000 person-years. RESULTS: The propensity matching results show that on average, female nurses who were diagnosed with diabetes were younger compared with the non-nurses (46.98 +/- 10.80 vs. 48.31 +/- 10.43, p <0.05). However, the results of the Cox proportional hazards model show that the nurses showed a lower risk of developing diabetes compared with the non nurses (Adj. HR = 0.84, 95 % CI: 0.79-0.90). Factors influencing diabetes development risks among the nurses include advanced age and high Charlson Comorbidity Index levels. CONCLUSION: The low degree of diabetes development among the nurses may be attributable to the fact that nurses possess substantial knowledge on health care and on healthy behaviors. The results of this study can be used as a reference to assess occupational risks facing nursing staff, to prevent diabetes development, and to promote health education. PMID- 27230067 TI - Exploring the relationship between population mobility and HIV risk: Evidence from Tanzania. AB - Migration and population mobility has long been regarded as an important structural driver of HIV. Following initial concerns regarding the spatial spread of the disease, mobile populations are viewed to engage in higher levels of risky sexual behaviours than non-mobile groups. However, beyond the case studies of mineworkers and truck drivers, the statistical evidence is inconclusive, suggesting that the relationship between mobility and risk is not well understood. This study investigated how engaging in specific livelihoods that involve mobility influences sexual behaviour and HIV risk. A qualitative research project, including focus groups and in-depth interviews with key mobile groups, was conducted in Northern Tanzania. The findings show that the patterns and conditions of moving related to the requirements of each different economic activity influence the nature of relationships that mobile groups have whilst away, how and where local sexual networks are accessed, and the practicalities of having sex. This has further implications for condom use. Risk behaviours are also shaped by local sexual norms related to transactional sex, emphasising that the roles of mobility and gender are interrelated, overlapping and difficult to disentangle. PMID- 27230066 TI - Associations between nasopharyngeal carriage of Group B Streptococcus and other respiratory pathogens during early infancy. AB - BACKGROUND: In West Africa, the carriage of Group B Streptococcus (GBS), among infants is poorly characterised. We investigated co-carriage of GBS with other respiratory pathogens in the infants' nasopharynx in The Gambia. METHODS: We assessed the carriage, serotypes and antibiotic susceptibility of Beta-haemolytic Streptococci (BHS) groups A-G; along with the carriage of Streptococcus pneumoniae; Haemophilus influenzae; Staphylococcus aureus and Moraxella catarrhalis in 1200 two-month old infants. RESULTS: The BHS prevalence was 20.0 % and GBS dominated (13.8 %), particularly serotypes V and II; serotype V being negatively associated with H. Influenzae carriage (OR 0.41 [95 % CI: 0.18-0.93], p = 0.033). Although co-colonization of GBS and other BHS was not seen, colonization with GBS was positively associated with S. aureus (OR 1.89 [95 % CI: 1.33-2.69], P < 0.001) and negatively associated with S. pneumoniae (OR 0.47 [95 % CI: 0.33-0.67], p < 0.001) and M. catarrhalis (OR 0.61 [95 % CI: 0.40-0.92], p = 0.017). >= 89 % of GBS isolates were susceptible to most antibiotics tested, except for tetracycline resistance, which was 89 %. CONCLUSION: This study provides baseline data on the carriage of GBS in two month old infants from West Africa. The dominant serotypes of GBS in this setting are serotypes V and II. This may be important for future GBS vaccine development for the West African sub region. PMID- 27230069 TI - Several cases of undesirable effects caused by methacrylate ultraviolet-curing nail polish for non-professional use. AB - BACKGROUND: Ultraviolet (UV)-curing nail polishes based on acrylates or methacrylates are currently also available for non-professional use. The Swedish Medical Products Agency recently prohibited one brand of UV-curing polish, because several consumers reported undesirable effects after using it. OBJECTIVES: To investigate whether consumers with undesirable effects after using the UV-curing nail polish that was later prohibited were contact allergic to the polish and its individual ingredients. MATERIALS/METHODS: Eight patients who had reported severe skin reactions after the use of the UV-curing polish were patch tested with two coatings of the nail polish and its ingredients at five dermatology departments in Sweden. RESULTS: All patients tested except one showed contact allergic reactions to one or several of the acrylate-based or methacrylate-based ingredients in the nail polish. CONCLUSIONS: The non professional use of UV-curing nail polishes poses a risk of sensitization from acrylates and methacrylates. PMID- 27230068 TI - Nociceptive transmission and modulation via P2X receptors in central pain syndrome. AB - Painful sensations are some of the most frequent complaints of patients who are admitted to local medical clinics. Persistent pain varies according to its causes, often resulting from local tissue damage or inflammation. Central somatosensory pathway lesions that are not adequately relieved can consequently cause central pain syndrome or central neuropathic pain. Research on the molecular mechanisms that underlie this pathogenesis is important for treating such pain. To date, evidence suggests the involvement of ion channels, including adenosine triphosphate (ATP)-gated cation channel P2X receptors, in central nervous system pain transmission and persistent modulation upon and following the occurrence of neuropathic pain. Several P2X receptor subtypes, including P2X2, P2X3, P2X4, and P2X7, have been shown to play diverse roles in the pathogenesis of central pain including the mediation of fast transmission in the peripheral nervous system and modulation of neuronal activity in the central nervous system. This review article highlights the role of the P2X family of ATP receptors in the pathogenesis of central neuropathic pain and pain transmission. We discuss basic research that may be translated to clinical application, suggesting that P2X receptors may be treatment targets for central pain syndrome. PMID- 27230071 TI - Implementation of coordinated global serotype 2 oral poliovirus vaccine cessation: risks of potential non-synchronous cessation. AB - BACKGROUND: The endgame for polio eradication involves coordinated global cessation of oral poliovirus vaccine (OPV) with cessation of serotype 2 OPV (OPV2 cessation) implemented in late April and early May 2016 and cessation of serotypes 1 and 3 OPV (OPV13 cessation) currently planned for after 2018. The logistics associated with globally switching all use of trivalent OPV (tOPV) to bivalent OPV (bOPV) represent a significant undertaking, which may cause some complications, including delays that lead to different timing of the switch across shared borders. METHODS: Building on an integrated global model for long term poliovirus risk management, we consider the expected vulnerability of different populations to transmission of OPV2-related polioviruses as a function of time following the switch. We explore the relationship between the net reproduction number (Rn) of OPV2 at the time of the switch and the time until OPV2-related viruses imported from countries still using OPV2 can establish transmission. We also analyze some specific situations modeled after populations at high potential risk of circulating serotype 2 vaccine-derived poliovirus (cVDPV2) outbreaks in the event of a non-synchronous switch. RESULTS: Well implemented tOPV immunization activities prior to the tOPV to bOPV switch (i.e., tOPV intensification sufficient to prevent the creation of indigenous cVDPV2 outbreaks) lead to sufficient population immunity to transmission to cause die out of any imported OPV2-related viruses for over 6 months after the switch in all populations in the global model. Higher Rn of OPV2 at the time of the switch reduces the time until imported OPV2-related viruses can establish transmission and increases the time during which indigenous OPV2-related viruses circulate. Modeling specific connected populations suggests a relatively low vulnerability to importations of OPV2-related viruses that could establish transmission in the context of a non-synchronous switch from tOPV to bOPV, unless the gap between switch times becomes very long (>6 months) or a high risk of indigenous cVDPV2s already exists in the importing and/or the exporting population. CONCLUSIONS: Short national discrepancies in the timing of the tOPV to bOPV switch will likely not significantly increase cVDPV2 risks due to the insurance provided by tOPV intensification efforts, although the goal to coordinate national switches within the globally agreed April 17-May 1, 2016 time window minimized the risks associated with cross-border importations. PMID- 27230070 TI - New Agents in Treatment of Hyperkalemia: an Opportunity to Optimize Use of RAAS Inhibitors for Blood Pressure Control and Organ Protection in Patients with Chronic Kidney Disease. AB - PURPOSE OF REVIEW: The overactive renin-angiotensin-aldosterone system (RAAS) plays an important part in many pathologic conditions including hypertension, heart failure, and renal disease. Hyperkalemia, a potentially life-threatening side effect of RAAS inhibitors, limits their use. The recent introduction of new hyperkalemia treatments provides opportunities to take full benefit of RAAS inhibitors. RECENT FINDINGS: Optimizing RAAS inhibition is an important therapeutic goal, particularly in chronic kidney disease. Different strategies have been investigated to achieve this goal, including inhibiting the pathway at multiple steps and using maximum or even supramaximal doses. Hyperkalemia is one of the most significant barriers to all of the strategies mentioned above. Up until the recent past, there have been limited therapeutic options available for the prevention and treatment of hyperkalemia in the long term. New promising agents to treat hyperkalemia in outpatient settings, namely, patiromer and sodium zirconium, may provide a solution. This article will review the benefits and risks of RAAS inhibitors, strategies to optimize their use, and the new hyperkalemia treatments that can lower the risk associated with RAAS inhibiting therapies. PMID- 27230072 TI - Reliability of quantifying the spatial distribution of fatty infiltration in lumbar paravertebral muscles using a new segmentation method for T1-weighted MRI. AB - BACKGROUND: To our knowledge, there are no methods allowing for quantification of the spatial distribution of lumbar paravertebral muscle fatty infiltration (FI) in the transverse plane. There is an increasing emphasis on muscle tissues as modifiable factors in lumbar spine health. Population datasets based on conventional T1-weighted (T1-W) magnetic resonance imaging (MRI) represent a valuable resource for examining all spinal tissues, and methods with reliability are needed. The aim of our study was to determine the reliability of a novel method quantifying lumbar paravertebral muscle fat content based on conventional T1-W MRI. METHODS: Axial 3-Tesla T1W MRIs from ten adult subjects (3W, 7M; mean age 52.8 +/- SD 7.2 years) were randomly selected from the large prospective cross-sectional Hong Kong Population-based Disc Degeneration Cohort study examining lumbar spine degeneration. The selected sample included subjects with mixed imaging-determined disc degeneration and low back pain history. Two raters with MRI lumbar paravertebral muscle analysis experience (R1 > 250 h and R2 > 1000 h) repeat-measured the image-set a week apart. Multifidus and erector spinae (spinalis, longissimus and iliocostalis) were manually outlined together on a single-slice from the inferior vertebral end-plates of L1 to L5 using a semi automated, quartile-defining (Q1-4 (medial to lateral) and Qmean) MatLab-based programme. Bland-Altman plots and intra-class correlation coefficients (ICC) with 95 % confidence intervals (CI) describe intra- and inter-rater reliability according to lumbar level, quartile, and side, and combined level and quartile. RESULTS: There was good intra- (ICC = 0.88; CI: 0.87-0.90) and inter-rater agreement (ICC = 0.82; CI: 0.80-0.84). Intra-rater values for Qmean (ICC; CI) were higher at L5 (0.89; 0.79-0.94) than L1 (0.61; 0.37-0.78). Higher intra-rater values for L1-5 were shown at Q1 (0.93; 0.91-0.95) than Q3 (0.83; 0.78-0.87) or Q4 (0.81; 0.76-0.85), and on the right (0.91; 0.90-0.93) than left (0.85; 0.83 0.88). Similar observations were made for inter-rater values in terms of lumbar level and quartile, with no differences between sides shown. CONCLUSIONS: In our study of ten cases we demonstrate a reliable method to quantify the spatial distribution of fat content in lumbar paravertebral muscles based on T1W MRI. Understanding the geography of fat content in these muscles may offer additional insight in determining and improving spinal health. The clinical relevance and application of this method require testing across various populations to build on the early feasibility established in this study. PMID- 27230074 TI - NPS Versus CDC: Scylla, Charybdis and the "Number Needed to [Under-] Treat". PMID- 27230073 TI - A case of multicentric gliomas in both supra- and infratentorial regions with different histology: a case report. AB - BACKGROUND: Multicentric gliomas are well-separated tumors in different locations of the brain, without anatomical continuity between lesions. We report a rare case of multicentric gliomas that occurred in both supra- and infratentorial regions with different histopathology. CASE PRESENTATION: A 27-year-old man was admitted to our hospital with mild motor weakness of the right leg. Magnetic resonance imaging (MRI) showed a large tumor occupying the left insula, extending to the left basal ganglia, so tumor resection was performed. Histological diagnosis was diffuse astrocytoma. Tumor cells showed sporadic immunoreactivity for p53 and negative immunostaining for epidermal growth factor receptor (EGFR). Postoperative course was uneventful, and adjuvant therapy was not performed. At 7 months after surgery, MRI disclosed a left cerebellar tumor displaying an irregular ring formation on enhancement with gadolinium (Gd) and marked peritumoral edema. MRI studies including T2-weighted imaging demonstrated that this paravermian tumor had no contact with the initial left insular tumor. In addition, MRI studies of the whole neuraxis, cytological examination of the cerebrospinal fluid, and neurological findings demonstrated that no dissemination had occurred through the subarachnoid space or as intracerebral metastases. Therefore, the second surgery was performed. Histological diagnosis was glioblastoma. Immunohistochemistry revealed that most tumor cells were positively stained for both p53 and EGFR but negatively stained for isocitrate dehydrogenase 1 (IDH1). CONCLUSIONS: We reported a case of multicentric gliomas occurring in both supra- and infratentorial regions with different histopathology. Immunohistochemical examinations suggest that different genetic pathways may participate in the occurrence of these tumors. PMID- 27230075 TI - Integrative Medicine as Standard Care for Pain Management: The Need for Rigorous Research. PMID- 27230076 TI - The Relationship Between Pain Catastrophizing and Outcomes of a 3-Week Comprehensive Pain Rehabilitation Program. AB - OBJECTIVE : Pain catastrophizing is an important predictor of functioning and disability among individuals with chronic pain, and modification of catastrophic interpretations of pain is a proposed treatment mechanism of pain rehabilitation. The purpose of the current study is to examine the relationship between changes in catastrophic thinking and treatment outcomes for a large sample of patients with chronic pain. METHODS : 648 adult patients with chronic pain completed a 3 week intensive outpatient comprehensive pain rehabilitation program. Measures of pain severity, pain-related life interference, depression, and pain catastrophizing were completed at admission and discharge. RESULTS : Consistent with prior research, pain catastrophizing was associated with several negative pain-related outcomes. Results of a within-subjects mediational analysis indicated that pain catastrophizing not only improved during the treatment program, but also accounted for a significant portion of the variance in the reduction of pain severity, pain interference, and depression at the end of treatment. CONCLUSIONS : This study adds further support to the position that pain catastrophizing has a detrimental role in adaptation to chronic pain, and that this construct can be successfully modified in treatment to improve patient outcomes. PMID- 27230078 TI - Discovering causal interactions using Bayesian network scoring and information gain. AB - BACKGROUND: The problem of learning causal influences from data has recently attracted much attention. Standard statistical methods can have difficulty learning discrete causes, which interacting to affect a target, because the assumptions in these methods often do not model discrete causal relationships well. An important task then is to learn such interactions from data. Motivated by the problem of learning epistatic interactions from datasets developed in genome-wide association studies (GWAS), researchers conceived new methods for learning discrete interactions. However, many of these methods do not differentiate a model representing a true interaction from a model representing non-interacting causes with strong individual affects. The recent algorithm MBS IGain addresses this difficulty by using Bayesian network learning and information gain to discover interactions from high-dimensional datasets. However, MBS-IGain requires marginal effects to detect interactions containing more than two causes. If the dataset is not high-dimensional, we can avoid this shortcoming by doing an exhaustive search. RESULTS: We develop Exhaustive-IGain, which is like MBS-IGain but does an exhaustive search. We compare the performance of Exhaustive-IGain to MBS-IGain using low-dimensional simulated datasets based on interactions with marginal effects and ones based on interactions without marginal effects. Their performance is similar on the datasets based on marginal effects. However, Exhaustive-IGain compellingly outperforms MBS-IGain on the datasets based on 3 and 4-cause interactions without marginal effects. We apply Exhaustive-IGain to investigate how clinical variables interact to affect breast cancer survival, and obtain results that agree with judgements of a breast cancer oncologist. CONCLUSIONS: We conclude that the combined use of information gain and Bayesian network scoring enables us to discover higher order interactions with no marginal effects if we perform an exhaustive search. We further conclude that Exhaustive-IGain can be effective when applied to real data. PMID- 27230079 TI - Consistency of Cluster Analysis for Cognitive Diagnosis: The Reduced Reparameterized Unified Model and the General Diagnostic Model. AB - The asymptotic classification theory of cognitive diagnosis (ACTCD) provided the theoretical foundation for using clustering methods that do not rely on a parametric statistical model for assigning examinees to proficiency classes. Like general diagnostic classification models, clustering methods can be useful in situations where the true diagnostic classification model (DCM) underlying the data is unknown and possibly misspecified, or the items of a test conform to a mix of multiple DCMs. Clustering methods can also be an option when fitting advanced and complex DCMs encounters computational difficulties. These can range from the use of excessive CPU times to plain computational infeasibility. However, the propositions of the ACTCD have only been proven for the Deterministic Input Noisy Output "AND" gate (DINA) model and the Deterministic Input Noisy Output "OR" gate (DINO) model. For other DCMs, there does not exist a theoretical justification to use clustering for assigning examinees to proficiency classes. But if clustering is to be used legitimately, then the ACTCD must cover a larger number of DCMs than just the DINA model and the DINO model. Thus, the purpose of this article is to prove the theoretical propositions of the ACTCD for two other important DCMs, the Reduced Reparameterized Unified Model and the General Diagnostic Model. PMID- 27230080 TI - Subfoveal choroidal thickness changes in carotid cavernous fistula following spontaneous resolution. AB - BACKGROUND: We report the enhanced depth imaging optical coherence tomography (EDI-OCT) characteristics and variations in a patient with subretinal fluid secondary to a carotid cavernous fistula. CASE PRESENTATION: A 59-year-old man presented with blurred vision in his right eye. Venous congestion of the epiescleral and retinal vessels were observed. EDI-OCT disclosed macular subretinal fluid with an increase of choroidal thickness up to 341 MUm. Brain and orbital computerized tomography showed an enlarged right superior ophthalmic vein. Orbital magnetic resonance imaging and angiography disclosed a decrease in blood flow, an indirect sign of carotid cavernous fistula. After a 3 months follow-up, spontaneous closure of the fistula occurred. Both the dilation of the conjunctiva and retinal veins improved. EDI-OCT showed resolution of the subfoveal fluid and a reduction of the subfoveal choroidal thickness to 271 MUm after a 3 months follow-up and 168 MUm after a 8 months follow-up. CONCLUSION: Serous retinal detachment has been described as a rare complication of carotid cavernous fistula. In our patient, EDI-OCT examinations revealed a thicker choroidal thickness when subretinal fluid was present as compared to that observed in the contralateral eye or after subretinal fluid resolution. PMID- 27230081 TI - Public Access Bleeding Control: Enhancing Local Resilience. AB - Levy MJ . Public Access Bleeding Control: enhancing local resilience. Prehosp Disaster Med. 2016;31(3):235-236. PMID- 27230082 TI - Impact of Hurricane Sandy on the Staten Island University Hospital Emergency Department. AB - Introduction On October 29, 2012, Hurricane Sandy touched down in New York City (NYC; New York USA) causing massive destruction, paralyzing the city, and destroying lives. Research has shown that considerable damage and loss of life can be averted in at-risk areas from advanced preparation in communication procedures, evacuation planning, and resource allocation. However, research is limited in describing how natural disasters of this magnitude affect emergency departments (EDs). Hypothesis/Problem The aim of this study was to identify and describe trends in patient volume and demographics, and types of conditions treated, as a result of Hurricane Sandy at Staten Island University Hospital North (SIUH-N; Staten Island, New York USA) site ED. METHODS: A retrospective chart review of patients presenting to SIUH-N in the days surrounding the storm, October 26, 2012 through November 2, 2012, was completed. Data were compared to the same week of the year prior, October 28, 2011 through November 4, 2011. Daily census, patient age, gender, admission rates, mode of arrival, and diagnoses in the days surrounding the storm were observed. RESULTS: A significant decline in patient volume was found in all age ranges on the day of landfall (Day 0) with a census of 114; -55% compared to 2011. The daily volume exhibited a precipitous drop on the days preceding the storm followed by a return to usual volumes shortly after. A notably larger percentage of patients were seen for medication refills in 2012; 5.8% versus 0.4% (P<.05). Lacerations and cold exposure also were increased substantially in 2012 at 7.6% versus 2.8% (P<.05) and 3.8% versus 0.0% (P<.05) of patient visits, respectively. A large decline in admissions was observed in the days prior to the storm, with a nadir on Day +1 at five percent ( 22%). Review of admitted patients revealed atypical admissions for home care service such as need for supplemental oxygen or ventilator. In addition, a drop in Emergency Medical Services (EMS) utilization was seen on Days 0 and +1. The SIUH-N typically sees 18% of patients arriving via EMS. On Day +1, only two percent of patients arrived by ambulance. CONCLUSION: The daily ED census saw a significant decline in the days preceding the storm. In addition, the type of conditions treated varied from baseline, and a considerable drop in hospital admissions was seen. Data such as these presented here can help make predictions for future scenarios. Greenstein J , Chacko J , Ardolic B , Berwald N . Impact of Hurricane Sandy on the Staten Island University Hospital emergency department. Prehosp Disaster Med. 2016;31(3):335-339. PMID- 27230083 TI - Validation of claims-based algorithms for gout flares. AB - PURPOSE: Gout is a common inflammatory arthritis characterized by repeated acute flares. The ability to accurately identify gout flares is critical for comparative effectiveness studies of gout treatments. We developed and examined the accuracy of a claims-based algorithm to identify gout flares. METHODS: Patients receiving care at an academic medical center between 2006 and 2010 with a diagnosis of gout or hyperuricemia were selected using an electronic medical record-Medicare claims linked dataset. Gout flares were identified by several claims-based algorithms using a diagnosis of gout combined with gout-related medication claims and/or procedure codes for arthrocentesis or joint injection. We calculated positive predictive value of these algorithms based on physician documentation of gout flare in medical record as the gold standard. Negative predictive value of the gout flare algorithm was calculated in a randomly selected subgroup of 200 patients with gout. RESULTS: Among 3952 subjects with gout or hyperuricemia, 503 flares were identified using the medication-based algorithm, and 290 were identified using the procedure-based algorithm. The positive predictive value for gout flares ranged from 50-54% for the medication based algorithms and 59-68% for the procedure-based algorithms. The negative predictive value of the algorithm combining both medication and procedure claims was high (85.2%). CONCLUSION: Use of gout diagnosis codes in combination with medication dispensing or procedure codes did not appear to accurately capture gout flares in patients with gout in a claims database. However, the claims-based flare algorithm could be useful in identifying a cohort of gout patients with no flares. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27230084 TI - Attitude towards diabetes and social and family support among type 2 diabetes patients attending a tertiary-care hospital in Bangladesh: a cross-sectional study. AB - BACKGROUND: Bangladesh has been suffering from an epidemiological transition from infectious and maternal diseases to non-communicable lifestyle-related diseases like diabetes, cardiovascular diseases, cancers etc. The burden of diabetes has been increasing rapidly due to high incidence as well as poor glycemic control leading to various macro and micro-vascular complications. In this study, we aim to assess the attitude towards diabetes and social and family support among the Bangladeshi type 2 diabetic mellitus (T2DM) patients. METHODS: This was a cross sectional study among 144 patients with T2DM at the medicine outpatient department of Dhaka Medical College Hospital (DMCH) in Dhaka, Bangladesh between 1 July and 31 July 2014. Data collection was done by interviewing patients using structured questionnaire. Understanding diabetes, education/advice received, attitude towards diabetes, family and friend support were measured by validated scales adapted from diabetes care profile. RESULTS: This study includes a total of 144 patients (101 males and 43 females) with type 2 diabetes aged between 20 and 84 years. 87 % of the patients had inadequate blood glucose control (fasting blood sugar >7.2 mmol/L or >130 mg/dl). Statistically significant differences were observed in the mean scores of various attitude scales (i.e. positive, negative, care ability and self-care adherence scale) among patients with adequate and inadequate blood glucose control (p < 0.05). Statistically significant positive correlations were found between these three categories of social and family support. Self-satisfaction with diabetic care was significantly associated with adequate blood glucose control (p = 0.05). CONCLUSIONS: Positive attitude towards diabetes management and support from friends and family were associated with adequate diabetes management. Appropriate public health interventions should be designed to educate and motivate the family members to offer greater support to the diabetes patients. PMID- 27230085 TI - Development of a stent-biovalve with round-shaped leaflets: in vitro hydrodynamic evaluation for transcatheter pulmonary valve implantation (TPVI). AB - This study evaluates a newly designed autologous heart valve-shaped tissue with a stent [stent-biovalve (SBV)] for transcatheter pulmonary valve implantation using the "in-body tissue architecture" technology. In the previously developed SBV with flat-shaped leaflets (FS-SBV), the valve could not close rapidly, because the leaflets were fixed in the open position, which induced regurgitant volume in the closing phase. Therefore, a novel mold to fabricate an SBV with round-shaped leaflets (RS-SBV) was developed, and its hydrodynamic performance with different valve diameters was evaluated in this study. A specially designed, self expandable, stent-mounted, acrylic mold, which has 3 hemispheres, was placed in dorsal subcutaneous pouches of goats for 2 months. After extraction, the acrylic mold was removed from the implant, and a tubular tissue impregnated with the stent strut was obtained. Half of the tubular tissue with 3 hemispheres was completely folded in half inwards. The acrylic mold was designed, such that the folded half of the tubular tissue became the round-shaped leaflets. The 3 commissure parts were connected to form 3 leaflets, resulting in the preparation of the RS-SBV (internal diameter 25 mm). The RS-SBV closed more rapidly than the FS-SBV in a pulsatile mock circulation circuit under the pulmonary circulation conditions. The regurgitant fraction of the RS-SBV was approximately 6 %, which was lower than that of the FS-SBV. The appropriate pulmonary annulus diameter of the RS-SBV was from 24 to 25 mm based on the pressure difference and effective orifice area. PMID- 27230086 TI - Opening-closing pattern of four pericardial prostheses: results from an in vitro study of leaflet kinematics. AB - Pericardial and porcine stented aortic valves have different leaflet kinematics. To study the biomechanics of a prosthesis thoroughly, the in vitro setting is the most appropriate. The aim of our study was to find out whether the prosthesis design in which the pericardial sheet is outside the stent post might influence the opening and closing patterns of the leaflets. Four pericardial prostheses (Magna Ease [MG] 21, Trifecta [TRI] 21, Soprano-Armonia [SA] 20 and Mitroflow [MF] 23) that fitted aortic roots with a native annulus diameter of 2.1 cm were implanted and their leaflet kinematics was studied by a high-speed digital camera. In the opening phase, MG showed the shortest RVOT and the highest RVOVI, with values of 12 +/- 2 and 209 +/- 17 ms, respectively. The RVOT of MG was significantly shorter than that of MF (p < 0.01), but not than that of TRI (p = 0.286). Both TRI and SA showed similar opening patterns (TRI: RVOT of 15 +/- 3 ms and RVOVI of 132 +/- 25 ms; SA: 17 +/- 2 ms and 126 +/- 19 ms), without statistically significant difference. Conversely, MF showed the slowest profile, with an RVOT of 23 +/- 3 ms and an RVOVI of 94 +/- 8 ms (Table 1; Fig. 3). The opening/closing profile is not influenced by the position of the pericardial leaflets, but depends on other intrinsic structural characteristics related to the material used for the stent and leaflets. Moreover, the kinematics does not affect the valve performance. Table 1 Kinematics and hydrodynamic results, reported as means and standard deviations, evaluated over the tested heart samples TRI SA MG MF ANOVA TRI versus SA TRI versus MG TRI versus MF SA versus MG SA versus MF MG versus MF p Value p Value p Value p Value p Value p Value p Value ET (ms) 1.0 1.0 1.0 1.0 RVOT (ms) 15 +/- 3 17 +/- 2 12 +/- 2 23 +/- 3 <0.01 1.0 0.286 <0.01 0.03 <0.01 <0.01 SVCT (ms) 247 +/- 14 231 +/- 15 256 +/- 26 241 +/- 11 0.170 0.463 0.853 0.931 0.213 1.0 1.0 RVCT (ms) 35 +/- 19 52 +/- 13 32 +/- 17 52 +/- 4 0.07 0.474 1.0 0.494 0.236 1.0 0.247 TVCT (ms) 283 +/- 10 283 +/- 19 289 +/- 10 293 +/- 11 0.584 1.00 1.0 1.0 1.0 1.0 1.0 RVOVI (ms-1) 132 +/- 25 126 +/- 19 209 +/- 17 94 +/- 8 <0.01 0.959 <0.01 0.02 <0.01 0.07 <0.01 SVCVI (ms-1) -0.9 +/- 0.3 -1.1 +/- 0.4 -0.57 +/- 0.1 -0.55 +/- 0.1 <0.01 1.0 0.353 0.292 0.045 0.04 1.0 RVCVI (ms-1) -16 +/- 4 -10 +/- 2 -18 +/- 6 -10 +/- 1 <0.01 0.396 1.0 0.513 0.025 1.0 0.03 Deltap (mmHg) 6.7 +/- 3.6 10.6 +/- 5.5 15.2 +/- 7.9 10.7 +/- 6.1 <0.01 0.01 <0.01 0.01 0.04 1.0 <0.01 EOA (cm2) 2.2 +/- 1.2 1.7 +/- 0.9 1.5 +/- 0.8 1.7 +/- 0.9 <0.01 0.03 <0.01 0.01 0.261 0.617 0.11 El % 7.3 +/- 1 11.9 +/- 1 15.4 +/- 2 11.8 +/- 3 <0.01 <0.01 <0.01 <0.01 0.04 1.00 0.03 CO (L/min) 3.1 +/- 0.4 2.8 +/- 0.5 3.1 +/- 0.3 3.0 +/- 0.5 0.534 0.282 0.792 0.702 0.106 0.552 0.559 ET ejection time, RVOT rapid valve-opening time, SVCT slow valve-closing time, RVCT rapid valve-closing time, TVCT total valve-closing time, RVOVI rapid valve opening velocity index, SVCVI slow valve-closing velocity index, RVCVI rapid valve-closing velocity index, Deltap mean pressure drop, EOA effective orifice area, El % energy loss, CO cardiac output. PMID- 27230087 TI - Preliminary report on a cost-utility analysis of revascularization by percutaneous coronary intervention for ischemic heart disease. AB - Few socioeconomic studies have so far reported on revascularization for stable ischemic heart disease in Japan. This study aimed to validate the sensitivity of the health-related quality of life (HRQOL) scale for determining the pathology and medical technology to be used and to validate the application of a cost utility analysis model. We studied 32 patients who had undergone percutaneous coronary intervention (PCI) (mean age 67.9 +/- 7.3 years). For HRQOL, utility and quality of life (QOL) were examined using the EuroQol 5 Dimension (EQ-5D) and EuroQol Visual Analogue Scale (EQ-VAS), respectively. The changes in the utility index before and after PCI were compared between the PCI and coronary angiography (CAG) groups to determine the sensitivity of the EQ-5D that was used to calculate quality-adjusted life years (QALY). Additionally, to estimate the cost-utility of PCI 120 months after the procedure, we analyzed our study results and the results of previous reports using the Markov chain model. The utility index was found to improve in the PCI group (0.08 +/- 0.15), whereas it decreased in the CAG group ( 0.02 +/- 0.11) (p = 0.049). The estimated result of the cost-utility analysis as the increase in utility above baseline level was the expected value, that is, 70,000 US$/QALY. Our findings suggest that QALY may be valid as a utility index in the clinical and economic evaluation of PCI in Japan. PMID- 27230088 TI - Changes in muscle fiber type and expression of mRNA of myosin heavy chain isoforms in porcine muscle during pre- and postnatal development. AB - The purpose of this study is to elucidate developmental changes in muscle fiber type in the pig during pre- and postnatal development. For this purpose, we performed a histochemical analysis for myosin adenosine triphosphatase activity to assess muscle fiber type and determined abundances of messenger RNA (mRNA) of myosin heavy chain (MHC) isoforms. Samples of Longissimus dorsi (LD) muscle were taken from fetuses on day 90 of the fetal stage. Further, samples of LD, Rhomboideus and Biceps femoris (B. femoris) muscles were taken from pigs when they were 1, 12, 26, 45 or 75 days old. Expression of MHC 2b mRNA in the LD and the B. femoris muscles rapidly and considerably increased from the late fetal stage to the early postnatal stage and this increase was associated with the development of type 2b fibers at least in the LD muscle. As shown by the rapid and considerable changes in expression of MHC 2b mRNA, it seems that a certain plasticity of muscle fiber type still remains in this developmental stage. PMID- 27230089 TI - Sex Differences in the Risk of Developing Acute Coronary Syndrome in Patients With Sleep Disorders: A Population-Based Cohort Study. AB - Studies that focus on the relationship between sex and the risk of acute coronary syndrome (ACS) are scant. The current study investigated the effects of sex differences in the risk of developing ACS in patients with sleep disorders (SDs). This longitudinal population-based cohort study evaluated the incidence and risk of ACS development in 40,232 men and 65,519 women newly diagnosed with SDs between 2002 and 2008 from the Longitudinal Health Insurance Database. The follow up period began from the entry date and ended on the date of an ACS event or December 31, 2010. Univariable and multivariable Cox proportional hazard regression models were conducted to estimate the sex differences in the risk of ACS. Men with SDs exhibited an increased incidence of ACS compared with women with SDs in all age- and comorbidity-specific subgroups. After covariates were adjusted, the men with SDs exhibited a 1.48-fold adjusted hazard ratio (aHR) of ACS compared with the women with SDs (95% confidence interval [CI] = 1.36-1.60). After age group stratification, the men with SDs in the young adult group exhibited the highest risk of subsequent ACS development compared with the women with SDs (aHR = 2.07, 95% CI = 1.69-2.55), followed by those in middle-aged adults (aHR = 1.52, 95% CI = 1.32-1.76) and older adults groups (aHR = 1.24, 95% CI = 1.11-1.39). This study determined that men with SDs, particularly young men, are at a higher risk of subsequent ACS development compared with women with SDs. PMID- 27230090 TI - Modulators of J-Shaped Association of HbA1c Levels with Mortality in Adults. PMID- 27230091 TI - Corrigendum: A General Method for N-Methylation of Amines and Nitro Compounds with Dimethylsulfoxide. PMID- 27230092 TI - Corrigendum: An Iron(III) Catalyst with Unusually Broad Substrate Scope in Regioselective Alkylation of Diols and Polyols. PMID- 27230094 TI - Web-based Discussion Forums on Pregnancy Complaints and Maternal Health Literacy in Norway: A Qualitative Study. AB - BACKGROUND: The Internet is one of the fastest growing information sources for pregnant women and seems to be used across social and economic strata. However, we still lack knowledge on how interaction in Web-based discussion forums influence maternal health literacy, in terms of how pregnant women access, appraise, and apply information to promote and maintain good health. OBJECTIVE: The aim of this study was to understand how Web-based discussion forums influence maternal health literacy; hence, we explored the role of interactions in Web based discussion forums among women who experienced health problems during pregnancy. More specifically, we explored why media-literate women experiencing the medically unexplained condition, pelvic girdle pain (PGP), during pregnancy participated in Web-based discussion forums and how they appraised and applied the information and advice that they gained from the Web-based interaction with other women. METHODS: Women were invited to participate in the study via postings on 3 different open websites for pregnant women and mothers. The sample included 11 Norwegian women who participated in open Web-based discussion forums when experiencing PGP in pregnancy. The data were collected using synchronous qualitative email interviews and were analyzed using thematic analysis. RESULTS: In our study sample, interaction in Web-based discussion forums influenced maternal health literacy in terms of increased health-related knowledge and competencies, increased awareness of health promotion and health protection, and increased system navigation. The women appraised and selectively applied information and advice that resonated with their own experiences. For many, the information provided online by other women in the same situation was valued more highly than advice from health professionals. Women reported that they used their knowledge and competency in encounters with health professionals but hesitated to disclose the origin of their knowledge. Those with a high level of education in medicine-related fields raised a concern about the Internet as a source of horror stories and erroneous information and were actively engaged in trying to minimize potential negative effects, by providing biomedical information. CONCLUSIONS: The popularity of Web-based discussion forums among pregnant women suggests that this group needs additional sources of information and support to complement traditional consultations with the health professionals. The professionals need to recognize that pregnant women access Web-based discussion forums for support and information to increase their ability to take better health decisions for themselves. This is a potential resource that health professionals may find useful in consultations with pregnant women. PMID- 27230095 TI - The usefulness of a computer-aided diagnosis scheme for improving the performance of clinicians to diagnose non-mass lesions on breast ultrasonographic images. AB - PURPOSE: The purpose of this study was to evaluate the usefulness of a computer aided diagnosis (CAD) scheme for improving the performance of clinicians to diagnose non-mass lesions appearing as hypoechoic areas on breast ultrasonographic images. METHODS: The database included 97 ultrasonographic images with hypoechoic areas: 48 benign cases [benign lesion with benign mammary tissue or fibrocystic disease (n = 20), fibroadenoma (n = 11), and intraductal papilloma (n = 17)] and 49 malignant cases [ductal carcinoma in situ (n = 17) and invasive ductal carcinoma (n = 32)]. Seven clinicians, three expert breast surgeons, and four general surgeons participated in the observer study. They were asked their confidence level concerning the possibility of malignancy in all 97 cases with and without the use of the CAD scheme. Receiver operating characteristic (ROC) analysis was performed to evaluate the usefulness of the CAD scheme. RESULTS: The areas under the ROC curve (AUC) improved for all observers when they used the CAD scheme and increased from 0.649 to 0.783 (P = 0.0167). Notably, the AUC for the general surgeon group increased from 0.625 to 0.793 (P = 0.045). CONCLUSIONS: This study showed that the performance of clinicians to diagnose non-mass lesions appearing as hypoechoic areas on breast ultrasonographic images was improved by the use of a CAD scheme. PMID- 27230096 TI - Trophic restructuring (Wieser 1953) of free-living nematode in marine sediment experimentally enriched to increasing doses of pharmaceutical penicillin G. AB - Trophic structure of free living nematode from Bizerte lagoon was tested by a microcosmic study after 30 days of exposure with 5 increasing doses of pharmaceutical penicillin G (D1: 3 mg L(-1), D2: 30 mg L(-1), D3: 300 mg L(-1), D4: 600 mg L(-1), D5: 700 mg L(-1)). Results showed significant differences between nematode assemblages from undisturbed controls and those from penicillin G treatments. Selective deposit-feeders (1A) or nonselective deposit-feeders (1B), very abundant in the control microcosm, were significantly affected and their dominance declined significantly. Epistrate feeders (2A) were significantly gradual increase for all microcosms treated with penicillin G, appeared to be more tolerant to the antibiotic and to take advantage of the growing scarcity of other trophic groups. Compared to the control microcosms, omnivorous-carnivorous (2B) was found to be higher in all treated microcosms, with the exception of those treated with D5. Trophic index (Sigmatheta(2)) was significantly reduced in all microcosms treated whereas trophic ratio 1B/2A appears to be insignificant. PMID- 27230097 TI - Future of clinical coding. PMID- 27230098 TI - Familial Aggregation and Heritability of Wuchereria bancrofti Infection. AB - BACKGROUND: The familial recurrence risk of lymphatic filariasis (LF) is unknown. This case study aimed to evaluate the familial susceptibility to infection with Wuchereria bancrofti and to microfilaremia in a village of the Republic of Congo. METHODS: The heritability and intrafamilial correlation coefficients were assessed for both W. bancrofti infection and microfilaremia by controlling for individual risk factors, environmental influence, and household effects. RESULTS: Pedigree charts were constructed for 829 individuals, including 143 individuals with a diagnosis of W. bancrofti circulating filarial antigens (CFAs) and 44 who also had microfilariae (MF). There was no intrafamilial correlation regarding CFA levels. However, the presence of MF (rho = 0.45) and microfilarial density (rho = 0.44) were significantly correlated among parent-offspring pairs. Heritability estimates for CFA positivity and intensity were 0.23 and 0.18, respectively. Heritability estimates were high for microfilarial positivity (h(2) = 0.74) and microfilarial density traits (h(2) = 0.81). CONCLUSIONS: Our study suggests that the acquisition of LF is mainly driven by environmental factors and habits and that genetic factors are moderately involved in the regulation of infection. By contrast, genetic factors play a major role in both the presence and intensity of microfilaremia. PMID- 27230099 TI - Association of Microvascular Function and Endothelial Biomarkers With Clinical Outcome in Dengue: An Observational Study. AB - BACKGROUND: The hallmark of severe dengue is increased microvascular permeability, but alterations in the microcirculation and their evolution over the course of dengue are unknown. METHODS: We conducted a prospective observational study to evaluate the sublingual microcirculation using side-stream dark-field imaging in patients presenting early (<72 hours after fever onset) and patients hospitalized with warning signs or severe dengue in Vietnam. Clinical findings, microvascular function, global hemodynamics assessed with echocardiography, and serological markers of endothelial activation were determined at 4 time points. RESULTS: A total of 165 patients were enrolled. No difference was found between the microcirculatory parameters comparing dengue with other febrile illnesses. The proportion of perfused vessels (PPV) and the mean flow index (MFI) were lower in patients with dengue with plasma than those without leakage (PPV, 88.1% vs 90.6% [P = .01]; MFI, 2.1 vs 2.4 [P = .007]), most markedly during the critical phase. PPV and MFI were correlated with the endothelial activation markers vascular cell adhesion molecule 1 (P < .001 for both) and angiopoietin 2 (P < .001 for both), negatively correlated. CONCLUSIONS: Modest microcirculatory alterations occur in dengue, are associated with plasma leakage, and are correlate with molecules of endothelial activation, angiopoietin 2 and vascular cell adhesion molecule 1. PMID- 27230100 TI - Forewing color pattern in Micropterigidae (Insecta: Lepidoptera): homologies between contrast boundaries, and a revised hypothesis for the origin of symmetry systems. AB - BACKGROUND: Despite the great importance of lepidopteran wing patterns in various biological disciplines, homologies between wing pattern elements in different moth and butterfly lineages are still not understood. Among other reasons, this may be due to an incomplete understanding of the relationship between color pattern and wing venation; many individual wing pattern elements have a known relationship with venation, but a framework to unite all wing pattern elements with venation is lacking. Though plesiomorphic wing veins are known to influence color patterning even when not expressed in the adult wing, most studies of wing pattern evolution have focused on derived taxa with a reduced suite of wing veins. RESULTS: The present study aims to address this gap through an examination of Micropterigidae, a very early-diverged moth family in which all known plesiomorphic lepidopteran veins are expressed in the adult wing. The relationship between wing pattern and venation was examined in 66 species belonging to 9 genera. The relationship between venation and pattern element location, predicted based on moths in the family Tortricidae, holds for Sabatinca just as it does for Micropterix. However, the pattern elements that are lightly colored in Micropterix are dark in Sabatinca, and vice-versa. When plotted onto a hypothetical nymphalid wing in accordance with the relationship between pattern and venation discussed here, the wing pattern of Sabatinca doroxena very closely resembles the nymphalid groundplan. CONCLUSIONS: The color difference in pattern elements between Micropterix and Sabatinca indicates that homologies exist among the contrast boundaries that divide wing pattern elements, and that color itself is not a reliable indicator of homology. The similarity between the wing pattern of Sabatinca doroxena and the nymphalid groundplan suggests that the nymphalid groundplan may have originated from a Sabatinca-like wing pattern subjected to changes in wing shape and reduced expression of venation. PMID- 27230101 TI - Uncomfortable realities: the challenge of creating real change in Europe's consolidating hospital sector. AB - BACKGROUND: This article examines uncomfortable realities that the European hospital sector currently faces and the potential impact of wide-spread rationalization policies such as (hospital) payment reform and privatization. METHODS: Review of relevant international literature. RESULTS: Based on the evidence we present, rationalization policies such as (hospital) payment reform and privatization will probably fall short in delivering better quality of care and lower growth in health expenses. Reasons can be sought in a mix of evidence on the effectiveness of these rationalization policies. Nevertheless, pressures for different business models will gradually continue to increase and it seems safe to assume that more value-added process business and facilitated network models will eventually emerge. CONCLUSIONS: The overall argument of this article holds important implications for future research: how can policymakers generate adequate leverage to introduce such changes without destroying necessary hospital capacity and the ability to produce quality healthcare. PMID- 27230102 TI - Evaporation of Ethanol-Water Binary Mixture Sessile Liquid Marbles. AB - Liquid marble is a liquid droplet coated with particles. Recently, the evaporation process of a sessile liquid marble using geometric measurements has attracted great attention from the research community. However, the lack of gravimetric measurement limits further insights into the physical changes of a liquid marble during the evaporation process. Moreover, the evaporation process of a marble containing a liquid binary mixture has not been reported before. The present paper investigates the effective density and the effective surface tension of an evaporating liquid marble that contains aqueous ethanol at relatively low concentrations. The effective density of an evaporating liquid marble is determined from the concurrent measurement of instantaneous mass and volume. Density measurements combined with surface profile fitting provide the effective surface tension of the marble. We found that the density and surface tension of an evaporating marble are significantly affected by the particle coating. PMID- 27230103 TI - Synthesis, magnetism and spectral studies of six defective dicubane tetranuclear {M4O6} (M = Ni(II), Co(II), Zn(II)) and three trinuclear Cd(II) complexes with polydentate Schiff base ligands. AB - A series of Ni(II), Co(II), Zn(II) and Cd(II) complexes with polytopic Schiff base ligands have been synthesized. The single-crystal X-ray crystallography results show that tetranuclear complexes have common face-shared defective dicubane cores, whereas trinuclear Cd(II) complexes are almost linear entities. Synthesis methods (solvent evaporation and hydrothermal synthesis), reaction conditions (pH, solvents and dosage) and coligands (azide, methanol, chloride and acetate) play vital roles in determining the final structure of the complexes and therefore their magnetic properties. In complexes , the terminal and central M(2+) ions are connected through mixed bridges, MU-phenoxido/MU1,1,1-X and MU Oalphatic/MU1,1,1-X, while central two M(2+) ions are linked by double bridges, MU1,1,1-X (X = azido and methoxido groups for and respectively). For complex , two central Ni(II) ions are connected through two MU1,1,1-N3(-) which is relatively less reported. For complexes , there are two kinds of Cd(II), the centre Cd(II) ions are eight-coordinated with triangle dodecahedral geometries, while the two side Cd(II) ions are six-coordinated with trigonal prism geometries using chlorides or acetates as terminal ligands. Magnetic susceptibility measurements (chiM) for compounds have been performed, and they reveal predominant ferromagnetic exchange interactions in Co(II) and Ni(II) tetramers. The photoluminescence studies show that the Zn(II) complex and three Cd(II) complexes have strong fluorescence, and the lifetimes are measured to be in the 10(2) nanosecond timescale. PMID- 27230104 TI - Erratum: Tracheal Involvement in Crohn Disease: the First Case in Korea. AB - [This corrects the article on p. 202 in vol. 49, PMID: 26879553.]. PMID- 27230105 TI - ProCarDB: a database of bacterial carotenoids. AB - BACKGROUND: Carotenoids have important functions in bacteria, ranging from harvesting light energy to neutralizing oxidants and acting as virulence factors. However, information pertaining to the carotenoids is scattered throughout the literature. Furthermore, information about the genes/proteins involved in the biosynthesis of carotenoids has tremendously increased in the post-genomic era. A web server providing the information about microbial carotenoids in a structured manner is required and will be a valuable resource for the scientific community working with microbial carotenoids. RESULTS: Here, we have created a manually curated, open access, comprehensive compilation of bacterial carotenoids named as ProCarDB- Prokaryotic Carotenoid Database. ProCarDB includes 304 unique carotenoids arising from 50 biosynthetic pathways distributed among 611 prokaryotes. ProCarDB provides important information on carotenoids, such as 2D and 3D structures, molecular weight, molecular formula, SMILES, InChI, InChIKey, IUPAC name, KEGG Id, PubChem Id, and ChEBI Id. The database also provides NMR data, UV-vis absorption data, IR data, MS data and HPLC data that play key roles in the identification of carotenoids. An important feature of this database is the extension of biosynthetic pathways from the literature and through the presence of the genes/enzymes in different organisms. The information contained in the database was mined from published literature and databases such as KEGG, PubChem, ChEBI, LipidBank, LPSN, and Uniprot. The database integrates user friendly browsing and searching with carotenoid analysis tools to help the user. We believe that this database will serve as a major information centre for researchers working on bacterial carotenoids. PMID- 27230106 TI - Human papillomavirus not detected in esophageal adenocarcinoma tumor specimens Letter. PMID- 27230107 TI - A new reassortment of influenza A (H7N9) virus causing human infection in Beijing, 2014. AB - A 73-year-old man was confirmed to have an influenza A (H7N9) virus infection, and the causative agent A/Beijing/02/2014(H7N9) virus was isolated. Genetic and phylogenetic analyses revealed that the virus belonged to a novel genotype, which probably emerged and further reassorted with other H9 or H7 viruses in poultry before transmitting to humans. This virus caused a severe infection with high levels of cytokines and neutralizing antibodies. Eventually, the patient was cured after serially combined treatments. Taken together, our findings indicated that this novel genotype of the human H7N9 virus did not evolve directly from the first Beijing isolate A/Beijing/01/2013(H7N9), suggesting that the H7N9 virus has not obtained the ability for human-to-human transmissibility and the virus only evolves in poultry and then infects human by direct contact. Hence, the major measures to prevent human H7N9 virus infection are still to control and standardize the live poultry trade. Early antiviral treatment with combination therapies, including mechanical ventilation, nutrition support and symptomatic treatment, are effective for H7N9 infection. PMID- 27230108 TI - Beyond sentinel node algorithm. Toward a more tailored surgery for cervical cancer patients. AB - Nowadays cervical cancer is frequently diagnosed at early stage. For these patients lymph node metastasis (LNM) is considered the most important prognostic factor. During the last decade many efforts have been made to reduce rate of complications associated with lymphadenectomy (LND). A great interest has arisen in sentinel lymph node (SLN) biopsy as a technique able to decrease number of LND performed and, at the same time, to assess lymph nodal status. High diagnostic performances have been reached thanks to SLN surgical algorithm. However, despite the efforts, about 25% of these patients undergo at least unilateral LND to meet NCCN recommendations. Data of women with International Federation of Gynecology and Obstetrics stage IA1-IB1/IIA1 cervical carcinoma were retrospectively collected by six Italian institutions. All patients underwent complete preoperative staging workup and were primarily treated by radical hysterectomy and pelvic bilateral LND. A total of 368 patients with early-stage cervical cancer were identified. Among them 333 (90.5%) showed no suspicious enlarged nodes at the preoperative magnetic resonance imaging (MRI). In this subset, tumor diameter >=20 mm was the only independent predictor of LN status (P = 0.003). None of the 106 patients with negative MRI nodal assessment, with squamous and adenosquamous histotype and a tumor diameter less than 2 cm had LNM. Based on these results we propose a new modified SLN surgical algorithm that could safely reduce LND performed in patients with very low-risk early-stage cervical cancer. PMID- 27230109 TI - Population genetic structure and post-LGM expansion of the plant bug Nesidiocoris tenuis (Hemiptera: Miridae) in China. AB - The plant bug, Nesidiocoris tenuis (Hemiptera: Miridae), is one of the most thermophilous dicyphines in agroecosystems and is widely distributed in China. Little is known regarding the genetic structure of N. tenuis and the effect of historical climatic fluctuations on N. tenuis populations. We analyzed partial sequences of three mitochondrial protein-coding genes (COI, ND2 and CytB) and nuclear genes (5.8S, ITS2 and 28S) for 516 specimens collected from 37 localities across China. Analyses of the combined mitochondrial dataset indicated that the Southwestern China group (SWC) was significantly differentiated from the remaining populations, other Chinese group (OC). Asymmetric migration and high level of gene flow across a long distance within the OC group was detected. The long-distance dispersal of N. tenuis might be affected by air currents and human interference. Both the neutrality tests and mismatch distributions revealed the occurrence of historical population expansion. Bayesian skyline plot analyses with two different substitution rates indicated that N. tenuis might follow the post-LGM (the Last Glacial Maximum) expansion pattern for temperate species. Pleistocene climatic fluctuation, complicated topography and anthropogenic factors, along with other ecological factors (e.g. temperature and air current) might have accounted for the current population structure of N. tenuis. PMID- 27230110 TI - Normative equations for central augmentation index: assessment of inter population applicability and how it could be improved. AB - Common reference values of arterial stiffness indices could be effective screening tool in detecting vascular phenotypes at risk. However, populations of the same ethnicity may differ in vascular phenotype due to different environmental pressure. We examined applicability of normative equations for central augmentation index (cAIx) derived from Danish population with low cardiovascular risk on the corresponding Croatian population from the Mediterranean area. Disagreement between measured and predicted cAIx was assessed by Bland-Altman analysis. Both, cAIx-age distribution and normative equation fitted on Croatian data were highly comparable to Danish low-risk sample. Contrarily, Bland-Altman analysis of cAIx disagreement revealed a curvilinear deviation from the line of full agreement indicating that the equations were not equally applicable across age ranges. Stratification of individual data into age decades eliminated curvilinearity in all but the 30-39 (men) and 40-49 (women) decades. In other decades, linear disagreement independent of age persisted indicating that cAIx determinants other than age were not envisaged/compensated for by proposed equations. Therefore, established normative equations are equally applicable to both Nordic and Mediterranean populations but are of limited use. If designed for narrower age ranges, the equations' sensitivity in detecting vascular phenotypes at risk and applicability to different populations could be improved. PMID- 27230111 TI - Quantifying the role of weather on seasonal influenza. AB - BACKGROUND: Improving knowledge about influenza transmission is crucial to upgrade surveillance network and to develop accurate predicting models to enhance public health intervention strategies. Epidemics usually occur in winter in temperate countries and during the rainy season for tropical countries, suggesting a climate impact on influenza spread. Despite a lot of studies, the role of weather on influenza spread is not yet fully understood. In the present study, we investigated this issue at two different levels. METHODS: First, we evaluated how weekly (intra-annual) incidence variations of clinical diseases could be linked to those of climatic factors. We considered that only a fraction of the human population is susceptible at the beginning of a year due to immunity acquired from previous years. Second, we focused on epidemic sizes (cumulated number of clinical reported cases) and looked at how their inter-annual and regional variations could be related to differences in the winter climatic conditions of the epidemic years over the regions. We quantified the impact of fifteen climatic variables in France using the Reseau des GROG surveillance network incidence data over eleven regions and nine years. RESULTS: At the epidemic scale, no impact of climatic factors was highlighted. At the intra annual scale, six climatic variables had a significant impact: average temperature (5.54 +/- 1.09 %), absolute humidity (5.94 +/- 1.08 %), daily variation of absolute humidity (3.02 +/- 1.17 %), sunshine duration (3.46 +/- 1.06 %), relative humidity (4.92 +/- 1.20 %) and daily variation of relative humidity (4.46 +/- 1.24 %). Since in practice the impact of two highly correlated variables is very hard to disentangle, we performed a principal component analysis that revealed two groups of three highly correlated climatic variables: one including the first three highlighted climatic variables on the one hand, the other including the last three ones on the other hand. CONCLUSIONS: These results suggest that, among the six factors that appeared to be significant, only two (one per group) could in fact have a real effect on influenza spread, although it is not possible to determine which one based on a purely statistical argument. Our results support the idea of an important role of climate on the spread of influenza. PMID- 27230112 TI - Glycine confers neuroprotection through microRNA-301a/PTEN signaling. AB - BACKGROUND: Glycine is known to protect against neuronal death. However, the underlying mechanism remains to be elucidated. The microRNA-301a is involved in both biological and pathological processes. But it is not known whether microRNA 301a has a neuroprotective property. In this study, we aimed to determine whether glycine-induced neuroprotection requires microRNA-301a-dependent signaling. RESULTS: We provided the first evidence that glycine increased the expression of microRNA-301a in cultured rat cortical neurons and protected against cortical neuronal death through up-regulation of microRNA-301a after oxygen-glucose deprivation. MicroRNA-301a directly bound the predicted 3'UTR target sites of PTEN and reduced PTEN expression in cortical neurons. We revealed that PTEN down regulation by microRNA-301a mediated glycine-induced neuroprotective effect following oxygen-glucose deprivation. CONCLUSIONS: Our results suggest that 1) microRNA-301a is neuroprotective in oxygen-glucose deprivation-induced neuronal injury; 2) glycine is an upstream regulator of microRNA-301a; 3) glycine confers neuroprotection through microRNA-301a/PTEN signal pathway. PMID- 27230114 TI - Clinically mild encephalitis/encephalopathy with a reversible splenial lesion associated with Mycoplasma pneumoniae infection. AB - BACKGROUND: Clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) is a clinico-radiological syndrome characterized by transient mild symptoms of encephalopathy and a reversible lesion in the splenium of the corpus callosum on magnetic resonance imaging (MRI). It is often triggered by infection. The common pathogens of MERS are viruses, especially influenza virus. However, Mycoplasma pneumoniae (M.pneumoniae) are relatively rare pathogens for MERS. CASE PRESENTATION: Here we report two paediatric cases of M.pneumoniae infection-induced MERS. The diagnosis of M.pneumoniae infection was established based on polymerase chain reaction (PCR) and specific serum antibodies (IgM). Both of the two patients presented with mild encephalopathy manifestations and recovered completely within a few days. The initial MRI showed a lesion in the central portion of the splenium of the corpus callosum, which completely resolved on the seventh and eighth day after admission for case 1 and case 2. Lumbar puncture was performed in both patients, which revealed no pleocytosis. In case 1, the patient had hyponatremia, peripheral facial nerve paralysis, and rash. To the best of our knowledge, it is the first MERS case associated with peripheral nerve damage. In case 2, interleukin-6(IL-6) was moderately increased in the cerebrospinal fluid (CSF). It suggested that IL-6 may play a role in the pathogenesis of M.pneumoniae-induced MERS. CONCLUSION: Our study enriches the available information on the pathogens of MERS and provides valuable data for better understanding of this syndrome. PMID- 27230115 TI - Nanomolar detection of glucose using SERS substrates fabricated with albumin coated gold nanoparticles. AB - This work presents the design of substrates for Surface Enhanced Raman Scattering (SERS) using star-like gold nanoparticles synthesized by a wet chemical method. The SERS substrates were used for glucose detection for concentrations as low as 10(-7) M, which represents an enhancement factor (EF) of 10(9), as a result of the hot spot formed by the spike termination and appropriate distribution of the gold nanoparticles. An improvement of two orders of magnitude was obtained by coating the gold nanoparticles with albumin with the configuration: glass/Au nanoparticles/albumin. In this case the lowest detection was at a concentration of 10(-9) M for an EF of 10(11). The albumin molecule allowed us to enhance the Raman signal because of the formation of peptide bonds (COOH-NH2) generated due to the interaction of glucose with albumin, and the appropriate separation distance between the glucose molecules and gold nanoparticles. The presence of such peptide conjugates was confirmed by FTIR spectra. Thus, our results suggest that our SERS substrates can be useful for the detection of very low concentrations of glucose, which is important for the diagnosis of diabetes in the field of medicine. PMID- 27230113 TI - Neurological Complications of Pregnancy. AB - Physiologic alterations during pregnancy create an environment for the occurrence of disease states that are either unique to pregnancy, occur more frequently in pregnancy, or require special management considerations that may be different from the nonpregnancy state. In the realm of cerebrovascular disease, preeclampsia, eclampsia, reversible cerebral vasoconstriction syndrome, sources of cardiogenic embolization including peripartum cardiomyopathy, cerebral venous thrombosis, pituitary apoplexy, subarachnoid hemorrhage, intracerebral hemorrhage, and special considerations for anticoagulation during pregnancy will be discussed. Management of epilepsy during pregnancy counterbalances maternal freedom from seizures against the potential for major, minor, cognitive, and behavioral fetal deformities. Teratogenic potential of the most common anticonvulsants are described. Considerations for anticonvulsant level monitoring during pregnancy are based upon differences in medication clearance in comparison to the prepregnancy state. The most common neuromuscular disorders of pregnancy are reviewed. PMID- 27230116 TI - High Production of 3-Hydroxypropionic Acid in Klebsiella pneumoniae by Systematic Optimization of Glycerol Metabolism. AB - 3-Hydroxypropionic acid (3-HP) is an important platform chemical proposed by the United States Department of Energy. 3-HP can be converted to a series of bulk chemicals. Biological production of 3-HP has made great progress in recent years. However, low yield of 3-HP restricts its commercialization. In this study, systematic optimization was conducted towards high-yield production of 3-HP in Klebsiella pneumoniae. We first investigated appropriate promoters for the key enzyme (aldehyde dehydrogenase, ALDH) in 3-HP biosynthesis, and found that IPTG inducible tac promoter enabled overexpression of an endogenous ALDH (PuuC) in K. pneumoniae. We optimized the metabolic flux and found that blocking the synthesis of lactic acid and acetic acid significantly increased the production of 3-HP. Additionally, fermentation conditions were optimized and scaled-up cultivation were investigated. The highest 3-HP titer was observed at 83.8 g/L with a high conversion ratio of 54% on substrate glycerol. Furthermore, a flux distribution model of glycerol metabolism in K. pneumoniae was proposed based on in silico analysis. To our knowledge, this is the highest 3-HP production in K. pneumoniae. This work has significantly advanced biological production of 3-HP from renewable carbon sources. PMID- 27230117 TI - Caregiver and Adolescent Discrepancies in Perceptions of Violence and Their Associations with Early Adolescent Aggression. AB - This article examined the role of caregiver messages about violence and exposure to neighborhood violence on adolescent aggression in light of research regarding discrepancies between parents and their children. Drawing upon data from an urban African American sample of 144 caregiver/early adolescent dyads (M = 12.99; SD = 0.93; 58.7 % female) we examined covariates of discrepancies between caregiver and adolescent reports of perceptions of violence as well as their association with adolescent aggression. Analyses suggested that concordance in perceptions of violence was associated with children's attitudes about violence and caregivers' perceptions of family communication. Structural equation modeling indicated a unique role for individual perceptions and suggested that agreement in awareness of neighborhood violence could be protective for early adolescent involvement in aggression. PMID- 27230118 TI - Discrepancies Between Perceptions of the Parent-Adolescent Relationship and Early Adolescent Depressive Symptoms: An Illustration of Polynomial Regression Analysis. AB - Adolescence is a critical period for the development of depressive symptoms. Lower quality of the parent-adolescent relationship has been consistently associated with higher adolescent depressive symptoms, but discrepancies in perceptions of parents and adolescents regarding the quality of their relationship may be particularly important to consider. In the present study, we therefore examined how discrepancies in parents' and adolescents' perceptions of the parent-adolescent relationship were associated with early adolescent depressive symptoms, both concurrently and longitudinally over a 1-year period. Our sample consisted of 497 Dutch adolescents (57 % boys, M age = 13.03 years), residing in the western and central regions of the Netherlands, and their mothers and fathers, who all completed several questionnaires on two occasions with a 1 year interval. Adolescents reported on depressive symptoms and all informants reported on levels of negative interaction in the parent-adolescent relationship. Results from polynomial regression analyses including interaction terms between informants' perceptions, which have recently been proposed as more valid tests of hypotheses involving informant discrepancies than difference scores, suggested the highest adolescent depressive symptoms when both the mother and the adolescent reported high negative interaction, and when the adolescent reported high but the father reported low negative interaction. This pattern of findings underscores the need for a more sophisticated methodology such as polynomial regression analysis including tests of moderation, rather than the use of difference scores, which can adequately address both congruence and discrepancies in perceptions of adolescents and mothers/fathers of the parent-adolescent relationship in detail. Such an analysis can contribute to a more comprehensive understanding of risk factors for early adolescent depressive symptoms. PMID- 27230119 TI - Promoting a Positive Middle School Transition: A Randomized-Controlled Treatment Study Examining Self-Concept and Self-Esteem. AB - The middle school transition is a salient developmental experience impacting adolescents around the world. This study employed a randomized-controlled treatment design, with randomization at the school level, to investigate the impact of a school adjustment program for middle school transition and potential gender differences. Participants included 1147 students (M age = 9.62; SD = 0.30, 45.7 % girls), who were assessed at four time points during the transition, regarding five dimensions of self-concept (academic, social, emotional, physical and family) and self-esteem. Parallel growth curves were employed to analyze the evolution of self-concept. Following the transition to middle school, students reported lower levels of self-concept (academic, emotional and physical) and self esteem, while participation in the intervention led to increases in self-esteem and gains in social self-concept. No gender differences were found. These results provide preliminary evidence supporting such interventions in early middle school transitions. PMID- 27230121 TI - Inter-observer Variability in Scoring Ultra-wide-field Fluorescein Angiography in Patients with Behcet Retinal Vasculitis. AB - PURPOSE: To test inter-observer agreement in applying the scoring system of the Angiography Scoring of Uveitis Working Group (ASUWG) to ultra-wide-field fluorescein angiograms (UWFA) obtained from patients with Behcet retinal vasculitis. METHODS: Both standard FA and UWFA images were obtained from 21 patients with retinal vasculitis associated with Behcet disease. Three graders independently graded 21 series of standard FA and 21 series of UWFA images. Spearman rank correlation and the intra-class correlation coefficient (ICC) were used to analyze the correlations. RESULTS: Total scores of all angiographic signs observed in both UWFA and standard FA images were significantly correlated between each pair of graders and among the three graders (ICC of standard FA = 0.874, p<0.001; ICC of UWFA = 0.928, p<0.001). CONCLUSIONS: The ASUWG scoring system is a reliable method of scoring UWFA images with regard to judging the activity of retinal vasculitis in ocular Behcet disease. PMID- 27230120 TI - The Protective Role of Friendship Quality on the Wellbeing of Adolescents Victimized by Peers. AB - Although studies on peer relations acknowledge that having friends constitutes a protective factor against being victimized by peers at school, it is not enough for this factor to operate. The quality of these friendships does play a role too. The present study explored the moderating role of friendship-quality dimensions (closeness, support, disclosure, and affection) on peer victimization and wellbeing. 614 young adolescents (4th to 6th graders, 50.1 % girls) were assessed three times over 1 year. Analyses were conducted to determine moderation effects, differentiated by gender. Results showed that only disclosure and support interact with victimization and affect wellbeing, especially for girls. Implications for studying peer relations, acknowledging gender differences, are discussed. PMID- 27230122 TI - A case of erythrodermia from exacerbated psoriasis vulgaris due to treatment of acute hepatitis C. AB - BACKGROUND: Skin side effects during interferon-alpha and ribavirin treatment are common, but autoimmune dermatosis triggered by interferon-alpha is rare. We describe a case of erythrodermia from exacerbated psoriasis during the treatment of acute hepatitis C with pegylated-interferon-alpha and ribavirin. The incidence of psoriasis in this circumstance is unknown and only 36 cases are described in the literature, of which only one describes an erythrodermic psoriasis flare. CASE PRESENTATION: A 50-years old healthy white man presented with the complaints of headache, muscle pain, appetite loss, yellow skin complexion and fatigue. The laboratory results showed elevated liver enzymes above 50 times the upper limit of normal and a positive antibody test and RNA for hepatitis C. A screening test 6 months earlier was negative and therefore the diagnosis of an acute hepatitis C infection was most likely. In the absence of spontaneous clearance of the virus a therapy with pegylated- interferon-alpha and ribavirin was initiated. After 3 weeks the patient developed red scaly papular skin lesions that evolved despite treatment with prednisone to a severe erythrodermia. A skin biopsy showed typical signs for psoriasis vulgaris. Treatment with steroids was intensified and the hepatitis C therapy stopped. The patient achieved sustained virological response for hepatitis C, but psoriatic lesions were still present 6 months after treatment. CONCLUSION: Although autoimmune skin reactions under pegylated interferon-alpha and ribavirin treatment are rare it is important to recognise them early to start an adequate treatment to guarantee hepatitis C treatment continuation. PMID- 27230123 TI - How neuropathology can contribute to the understanding of dementia. PMID- 27230125 TI - Complex quantum networks as structured environments: engineering and probing. AB - We consider structured environments modeled by bosonic quantum networks and investigate the probing of their spectral density, structure, and topology. We demonstrate how to engineer a desired spectral density by changing the network structure. Our results show that the spectral density can be very accurately detected via a locally immersed quantum probe for virtually any network configuration. Moreover, we show how the entire network structure can be reconstructed by using a single quantum probe. We illustrate our findings presenting examples of spectral densities and topology probing for networks of genuine complexity. PMID- 27230124 TI - Damage effect of high-intensity focused ultrasound on breast cancer tissues and their vascularities. AB - BACKGROUND: High-intensity focused ultrasound (HIFU) is a noninvasive therapy that makes entire coagulative necrosis of a tumor in deep tissue through the intact skin. There are many reports about the HIFU's efficacy in the treatment of patients with breast cancer, but randomized clinical trials are rare which emphasize on the systematic assessment of histological changes in the ablated tumor vascularities, while clinical trials utilizing bevacizumab and other anti angiogenic drugs in breast cancer have not demonstrated overall survival benefit. The purpose of this study is to evaluate the damage effect of HIFU on breast cancer tissues and their vascularities. METHODS: Randomized clinical trials and the modality of treat-and-resect protocols were adopted. The treated outcome of all patients was followed up in this study. The target lesions of 25 breast cancer patients treated by HIFU were observed after autopsy. One slide was used for hematoxylin-eosin (HE) staining, one slide was used for elastic fiber staining by Victoria blue and Ponceau's histochemical staining, and one slide was used for vascular endothelial cell immunohistochemical staining with biotinylated ulex europaeus agglutinin I (UEAI); all three slides were observed under an optical microscopic. One additional slide was systematically observed by electron microscopy. RESULTS: The average follow-up time was 12 months; no local recurrence or a distant metastatic lesion was detected among treated patients. Histological examination of the HE slides indicated that HIFU caused coagulative necrosis in the tumor tissues and their vascularities: all feeder vessels less than 2 mm in diameter in the insonated tumor were occluded, the vascular elasticity provided by fibrin was lost, the cells were disordered and delaminated, and UEAI staining of the target lesions was negative. Immediately after HIFU irradiation, the tumor capillary ultrastructure was destroyed, the capillary endothelium was disintegrated, the peritubular cells were cavitated, and the plasma membrane was incomplete. CONCLUSIONS: HIFU ablation can destroy all proliferating tumor cells and their growing vascularities simultaneously; this may break interdependent vicious cycle of tumor angiogenesis and neoplastic cell growth that results in infinite proliferation. While it cannot cause tumor resistance to HIFU ablation, it may be a new anti-angiogenic strategy that needs further clinical observation and exploration. Furthermore, the treatment indications of HIFU ablation were reviewed and discussed in this manuscript. PMID- 27230126 TI - Outcome of phacoemulsification and intraocular lens implantion in eyes with pseudoexfoliation and weak zonules. AB - PURPOSE: To evaluate the results of phacoemulsification and intraocular lens (IOL) implantation in eyes with pseudoexfoliation (PEX) and zonular weakness. METHODS: Two hundred and ninety-five patients (295 eyes) were recruited. This study is a retrospective case review of 143 PEX eyes with preoperative (Group 1) and intraoperative (Group 2) signs of zonular weakness, 76 PEX eyes (Group 3) and 76 non-PEX eyes without zonular weakness (Group 4) undergoing phacoemulsification and IOL implantation performed by single surgeon from year 1988 to 2010. Outcome measures included frequency of postoperative pseudophakodonesis, anterior capsule contraction and IOL decentration/dislocation. Postoperative vision, intraocular pressure (IOP) and glaucoma medication requirements were also assessed. A subanalysis on identical postoperative outcomes of capsular tension ring (CTR) implantation was performed. Comparisons were made for 52 PEX eyes with zonular weakness receiving nonsutured CTR implantation (Group A), 91 PEX eyes with zonular weakness not receiving CTR implantation (Group B) and 142 PEX eyes without zonular weakness (Group C). RESULTS: Mean follow-up was 4.08 +/- 0.48 years and maximum was 8.3 years. Both Groups 1 and 2 showed higher incidence of complications than Groups 3 and 4 (p < 0.01). Vision, IOP and glaucoma medication requirements were similar postoperatively for all four groups. Groups A and B had a significantly higher proportion of postoperative complications than Group C (p < 0.01). There was no significant difference in risk of developing these complications between Groups A and B (p = 0.64). CONCLUSION: Postoperative complication rates are higher in PEX eyes with preoperative and/or intraoperative signs of zonular weakness undergoing phacoemulsification. Nonsutured CTR implantation does not prevent IOL and capsular complications postoperatively. PMID- 27230127 TI - A review and comparison of Bayesian and likelihood-based inferences in beta regression and zero-or-one-inflated beta regression. AB - Beta regression is an increasingly popular statistical technique in medical research for modeling of outcomes that assume values in (0, 1), such as proportions and patient reported outcomes. When outcomes take values in the intervals [0,1), (0,1], or [0,1], zero-or-one-inflated beta (zoib) regression can be used. We provide a thorough review on beta regression and zoib regression in the modeling, inferential, and computational aspects via the likelihood-based and Bayesian approaches. We demonstrate the statistical and practical importance of correctly modeling the inflation at zero/one rather than ad hoc replacing them with values close to zero/one via simulation studies; the latter approach can lead to biased estimates and invalid inferences. We show via simulation studies that the likelihood-based approach is computationally faster in general than MCMC algorithms used in the Bayesian inferences, but runs the risk of non-convergence, large biases, and sensitivity to starting values in the optimization algorithm especially with clustered/correlated data, data with sparse inflation at zero and one, and data that warrant regularization of the likelihood. The disadvantages of the regular likelihood-based approach make the Bayesian approach an attractive alternative in these cases. Software packages and tools for fitting beta and zoib regressions in both the likelihood-based and Bayesian frameworks are also reviewed. PMID- 27230128 TI - A novel complete-case analysis to determine statistical significance between treatments in an intention-to-treat population of randomized clinical trials involving missing data. AB - The application of the principle of the intention-to-treat (ITT) to the analysis of clinical trials is challenged in the presence of missing outcome data. The consequences of stopping an assigned treatment in a withdrawn subject are unknown. It is difficult to make a single assumption about missing mechanisms for all clinical trials because there are complicated reactions in the human body to drugs due to the presence of complex biological networks, leading to data missing randomly or non-randomly. Currently there is no statistical method that can tell whether a difference between two treatments in the ITT population of a randomized clinical trial with missing data is significant at a pre-specified level. Making no assumptions about the missing mechanisms, we propose a generalized complete case (GCC) analysis based on the data of completers. An evaluation of the impact of missing data on the ITT analysis reveals that a statistically significant GCC result implies a significant treatment effect in the ITT population at a pre specified significance level unless, relative to the comparator, the test drug is poisonous to the non-completers as documented in their medical records. Applications of the GCC analysis are illustrated using literature data, and its properties and limits are discussed. PMID- 27230129 TI - Low-Density Lipoprotein Receptor Signaling Mediates the Triglyceride-Lowering Action of Akkermansia muciniphila in Genetic-Induced Hyperlipidemia. AB - OBJECTIVE: Akkermansia muciniphila (A muciniphila) is a mucin-degrading bacterium that resides in the mucus layer whose abundance inversely correlates with body weight and the development of diabetes mellitus in mice and humans. The objective of this study was to explore the regulatory effect of A muciniphila on host lipoprotein metabolism, insulin sensitivity, and hepatic metabolic inflammation. APPROACH AND RESULTS: By establishing a novel mouse model that colonized the A muciniphila in the gastrointestinal tract of the cAMP-responsive binding protein H (CREBH)-deficient mouse and in vivo chylomicron assay, we found that increased colonization of A muciniphila in the gastrointestinal tract of wild-type mice protected mice from an acute fat load-induced hyperlipidemia compared with vehicle-treated mice. A muciniphila administration also significantly ameliorated chronic hypertriglyceridemia, improved insulin sensitivity, and prevented overproduction of postprandial chylomicrons in CREBH-null mice. Mechanistic studies revealed that increased A muciniphila colonization induced expression of low-density lipoprotein receptors and apolipoprotein E in the hepatocytes of CREBH-null mice, which facilitated the uptake of intermediate-density lipoprotein via the mediation of apolipoprotein B100 and apolipoprotein E, leading to the increased clearance of triglyceride-rich lipoprotein remnants, chylomicron remnants, and intermediate-density lipoproteins, from the circulation. Treatment with A muciniphila further improved hepatic endoplasmic reticulum stress and metabolic inflammation in CREBH-null mice. CONCLUSIONS: Increased colonization of the disease-protective gut bacteria A muciniphila protected the host from acute and chronic hyperlipidemia by enhancing the low-density lipoprotein receptor expression and alleviating hepatic endoplasmic reticulum stress and the inflammatory response in CREBH-null mice. PMID- 27230131 TI - Intracellular Localization of Endogenous Mouse ABCG1 Is Mimicked by Both ABCG1 L550 and ABCG1-P550-Brief Report. AB - OBJECTIVE: In a recent article in Arteriosclerosis, Thrombosis, and Vascular Biology, it was reported that ATP-binding cassette transporter G1 (ABCG1) containing leucine at position 550 (ABCG1-L550) was localized to the plasma membrane, whereas ABCG1-P550 (proline at position 550) was intracellular. Because the published data on the subcellular localization of ABCG1 are controversial, we performed additional experiments to determine the importance of leucine or proline at amino acid 550. APPROACH AND RESULTS: We transfected multiple cell lines (CHO-K1, Cos-7, and HEK293 [human embryonic kidney]) with untagged or FLAG tagged ABCG1 containing either leucine or proline at position 550. Immunofluorescence studies demonstrated that in all cases, ABCG1 localized to intracellular endosomal vesicles. We also show that both ABCG1-L550 and ABCG1 P550 are equally active in both promoting the efflux of cellular cholesterol to exogenous high-density lipoprotein and in inducing the activity of sterol regulatory element-binding protein-2, presumably as a result of redistributing intracellular sterols away from the endoplasmic reticulum. Importantly, we treated nontransfected primary peritoneal macrophages with a liver X receptor agonist and demonstrate, using immunofluorescence, that although endogenous ABCG1 localizes to intracellular endosomes, none was detectable at the cell surface/plasma membrane. CONCLUSIONS: ABCG1, irrespective of either a leucine or proline at position 550, is an intracellular protein that localizes to vesicles of the endosomal pathway where it functions to mobilize sterols away from the endoplasmic reticulum and out of the cell. PMID- 27230132 TI - Determinants of utilization of antenatal care services among adolescent girls and young women in Indonesia. AB - Due to the high number of maternal deaths, provision of antenatal care services (ANC) in Indonesia is one of the key aims of the post-Millennium Development Goals agenda. This study aimed to assess the key factors determining use of ANC by adolescent girls and young women in Indonesia. Data from the Indonesia Demographic and Health Survey 2012 were used, with a focus on married adolescent girls (aged 15-19 years, n = 543) and young women (20-24 years, n = 2,916) who were mothers. Bivariate and multiple logistic regression analyses were performed to determine the factors associated with ANC use. The findings indicated that adolescents were less likely to make ANC visits than young women. Richer women were more likely to make four ANC visits in both groups compared to the poorer women. Living in urban areas, higher educational attainment, and lower birth order were also all associated with higher levels of receiving ANC among young women. The results showed that socio-economic factors were related to the use of ANC among adolescent girls and young women. Ongoing health-care interventions should thus put a priority on adolescent mothers coming from poor socio-economic backgrounds. PMID- 27230130 TI - Transcriptome-Wide Analysis Reveals Modulation of Human Macrophage Inflammatory Phenotype Through Alternative Splicing. AB - OBJECTIVE: Human macrophages can shift phenotype across the inflammatory M1 and reparative M2 spectrum in response to environmental challenges, but the mechanisms promoting inflammatory and cardiometabolic disease-associated M1 phenotypes remain incompletely understood. Alternative splicing (AS) is emerging as an important regulator of cellular function, yet its role in macrophage activation is largely unknown. We investigated the extent to which AS occurs in M1 activation within the cardiometabolic disease context and validated a functional genomic cell model for studying human macrophage-related AS events. APPROACH AND RESULTS: From deep RNA-sequencing of resting, M1, and M2 primary human monocyte-derived macrophages, we found 3860 differentially expressed genes in M1 activation and detected 233 M1-induced AS events; the majority of AS events were cell- and M1-specific with enrichment for pathways relevant to macrophage inflammation. Using genetic variant data for 10 cardiometabolic traits, we identified 28 trait-associated variants within the genomic loci of 21 alternatively spliced genes and 15 variants within 7 differentially expressed regulatory splicing factors in M1 activation. Knockdown of 1 such splicing factor, CELF1, in primary human macrophages led to increased inflammatory response to M1 stimulation, demonstrating CELF1's potential modulation of the M1 phenotype. Finally, we demonstrated that an induced pluripotent stem cell-derived macrophage system recapitulates M1-associated AS events and provides a high fidelity macrophage AS model. CONCLUSIONS: AS plays a role in defining macrophage phenotype in a cell- and stimulus-specific fashion. Alternatively spliced genes and splicing factors with trait-associated variants may reveal novel pathways and targets in cardiometabolic diseases. PMID- 27230133 TI - Detecting Gene-Environment Interactions for a Quantitative Trait in a Genome-Wide Association Study. AB - A genome-wide association study (GWAS) typically is focused on detecting marginal genetic effects. However, many complex traits are likely to be the result of the interplay of genes and environmental factors. These SNPs may have a weak marginal effect and thus unlikely to be detected from a scan of marginal effects, but may be detectable in a gene-environment (G * E) interaction analysis. However, a genome-wide interaction scan (GWIS) using a standard test of G * E interaction is known to have low power, particularly when one corrects for testing multiple SNPs. Two 2-step methods for GWIS have been previously proposed, aimed at improving efficiency by prioritizing SNPs most likely to be involved in a G * E interaction using a screening step. For a quantitative trait, these include a method that screens on marginal effects [Kooperberg and Leblanc, 2008] and a method that screens on variance heterogeneity by genotype [Pare et al., 2010] In this paper, we show that the Pare et al. approach has an inflated false-positive rate in the presence of an environmental marginal effect, and we propose an alternative that remains valid. We also propose a novel 2-step approach that combines the two screening approaches, and provide simulations demonstrating that the new method can outperform other GWIS approaches. Application of this method to a G * Hispanic-ethnicity scan for childhood lung function reveals a SNP near the MARCO locus that was not identified by previous marginal-effect scans. PMID- 27230134 TI - Anti-arthritic activity of 11-O-(4'-O-methyl galloyl)-bergenin and Crassula capitella extract in rats. AB - OBJECTIVES: Isolation and identification of phytochemicals of Crassula capitella (Thunberg), evaluation of the anti-arthritic potential of the extract and the major isolated compound; 11-O-(4'-O-methyl galloyl)-bergenin and underlying their mechanism on rat model of rheumatoid arthritis (RA). METHODS: Different fractions were subjected to column chromatography giving fourteen compound identified by mass and NMR spectroscopic techniques. RA was induced by intraplantar injection of complete Freund's adjuvant into the right hind paw of rats. Influence of tested samples in comparable to methotrexate on paw oedema, body weight gain, serum diagnostic markers, cartilage and bone degeneration enzymes, pro inflammatory mediators and oxidative stress biomarkers in arthritic rats. KEY FINDINGS: Fourteen phenolic compounds were isolated and identified for the first time from C. capitella. The major compound identified as 11-O-(4'-O-methyl galloyl)-bergenin. Treatment of arthritic rats with extract or 11-O-(4'-O-methyl galloyl)-bergenin with the tested doses can reduce the progression and severity of RA. CONCLUSION: Crassula capitella is a new natural and abundant source for 11 O-(4'-O-methyl galloyl)-bergenin for resolving chronic inflammatory diseases as RA through antioxidant, anti-inflammatory and membrane stabilizing mechanism. PMID- 27230135 TI - Differential item functioning in patient reported outcomes research. PMID- 27230136 TI - SUMO-interacting motifs (SIMs) in Polo-like kinase 1-interacting checkpoint helicase (PICH) ensure proper chromosome segregation during mitosis. AB - Polo-like kinase 1 (Plk1)-interacting checkpoint helicase (PICH) localizes at the centromere and is critical for proper chromosome segregation during mitosis. However, the precise molecular mechanism of PICH's centromeric localization and function at the centromere is not yet fully understood. Recently, using Xenopus egg extract assays, we showed that PICH is a promiscuous SUMO binding protein. To further determine the molecular consequence of PICH/SUMO interaction on PICH function, we identified 3 SUMO-interacting motifs (SIMs) on PICH and generated a SIM-deficient PICH mutant. Using the conditional expression of PICH in cells, we found distinct roles of PICH SIMs during mitosis. Although all SIMs are dispensable for PICH's localization on ultrafine anaphase DNA bridges, only SIM3 (third SIM, close to the C-terminus end of PICH) is critical for its centromeric localization. Intriguingly, the other 2 SIMs function in chromatin bridge prevention. With these results, we propose a novel SUMO-dependent regulation of PICH's function on mitotic centromeres. PMID- 27230137 TI - Electrochemical possibility of iron compounds in used disposable heating pads and their use in lithium ion batteries. AB - In this study, iron oxides obtained from used disposable heating pads are used as an anode material in lithium ion batteries. Fe3O4 and Fe2O3 phases are identified using XRD. Additionally, the existence of other substances, such as carbon and NaCl, are determined using EDS dot mapping. Purified powder (PP) is prepared by washing the obtained powder (OP) with distilled water and ethanol. Heat-treated powder (HP) is prepared by heating PP at 600 degrees C. The electrochemical result shows that PP delivers a discharge capacity of ~700 mAh g(-1) after 50 cycles. HP delivers a higher initial capacity of 1170 mAh g(-1); however, the discharge capacity decreases drastically to 500 mAh g(-1). These results were similar to those determined for commercial iron oxide in previous studies. PMID- 27230138 TI - Application of an integrated biomarker response index to assess ground water contamination in the vicinity of a rare earth mine tailings site. AB - We utilized a multi-biomarker approach (Integrated Biomarker Response version 2, IBRv2) to investigate the scope and dispersion of groundwater contamination surrounding a rare earth mine tailings impoundment. Parameters of SD rat included in our IBRv2 analyses were glutathione levels, superoxide dismutase, catalase, and glutathione peroxidase activities, total anti-oxidative capacity, chromosome aberration, and micronucleus formation. The concentration of 20 pollutants including Cl(-), SO4 (2-), Na(+), K(+), Mg(2+), Ca(2+), TH, CODMn, As, Se, TDS, Be, Mn, Co, Ni, Cu, Zn, Mo, Cd, and Pb in the groundwater were also analyzed. The results of this study indicated that groundwater polluted by tailings impoundment leakage exhibited significant ecotoxicological effects. The selected biomarkers responded sensitively to groundwater pollution. Analyses showed a significant relationship between IBRv2 values and the Nemerow composite index. IBRv2 could serve as a sensitive ecotoxicological diagnosis method for assessing groundwater contamination in the vicinity of rare earth mine tailings. According to the trend of IBRv2 value and Nemerow composite index, the maximum diffusion distance of groundwater pollutants from rare earth mine tailings was approximately 5.7 km. PMID- 27230139 TI - Thermal and spectroscopic analysis of organic matter degradation and humification during composting of pig slurry in different scenarios. AB - In this work, different analytical techniques (thermal analysis, (13)C cross polarization magic angle spinning (CPMAS) NMR and Fourier transform infrared (FT IR) spectroscopy) have been used to study the organic matter changes during the co-composting of pig slurry with cotton gin waste. To ensure the validity of the findings, the composting process was developed in different scenarios: under experimental pilot plant conditions, using the static pile system, and under real conditions on a pig farm, using the turning pile system. Also, the thermal stability index (R1) was determined before and after an extraction with water, to evaluate the effect of eliminating water-soluble inorganic salts on the thermal analysis. The results of the thermal methods showed the degradation of the most labile organic matter during composting; R1 increased during composting in all piles, without any influence of the presence of water-soluble inorganic ions in the sample. The NMR showed a decrease in the abundance of the carbohydrate molecules and an increase in the aliphatic materials during composting, due to a concentration effect. Also, FT-IR spectroscopy was a useful technique to study the trends of polysaccharides and nitrate, as indicators of organic matter transformations during composting. PMID- 27230140 TI - International food trade reduces environmental effects of nitrogen pollution in China. AB - The globalization of agricultural trade has dramatically altered global nitrogen flows by changing the spatial pattern of nitrogen utilization and emissions at a global scale. As a major trading country, China uses a large amount of nitrogen, which has a profound impact on global nitrogen flows. Using data on food production and trade between China and 26 other countries and regions, we calculated nitrogen inputs and outputs in food production ecosystem in each country. We estimated nitrogen flows in international food trade and analyzed their impact on nitrogen pollution in China. We divided nitrogen flows into embodied and virtual nitrogen flows. Embodied nitrogen is taken up by the plant and incorporated into the final food product, whereas virtual nitrogen is lost to the environment throughout the food production process and is not contained in the final food product. Our results show that China mainly imports food products from America and Asia, accounting for 95 % of all imported food. Asia (mainly Japan) and Europe are the main exporters of food from China, with Japan and the EU accounting for 17 and 10 % of all exported food, respectively. Total nitrogen inputs and outputs in food production in China were 55,400 and 61,000 Gg respectively, which were much higher than in other countries. About 1440 and 950 Gg of embodied and virtual nitrogen respectively flow into China through the food trade, mainly from food-exporting countries such as the USA, Argentina, and Brazil. Meanwhile, 177 and 160 Gg of embodied and virtual nitrogen respectively flow out of China from the export of food products, mainly to Japan. China's net food imports have reduced 720 and 458 Gg for nitrogen utilization and outputs, respectively, which accounted for 1.3 and 0.78 % of total nitrogen inputs and outputs in China. These results suggest that food trade in China has a profound effect on nitrogen flows and has greatly reduced environmental impacts on nitrogen pollution in China. PMID- 27230141 TI - The influence of diesel-truck exhaust particles on the kinetics of the atmospheric oxidation of dissolved sulfur dioxide by oxygen. AB - The automobile exhausts are one of the major sources of particulate matter in urban areas and these particles are known to influence the atmospheric chemistry in a variety of ways. Because of this, the oxidation of dissolved sulfur dioxide by oxygen was studied in aqueous suspensions of particulates, obtained by scraping the particles deposited inside a diesel truck exhaust pipe (DEP). A variation in pH showed the rate to increase with increase in pH from 5.22 to about ~6.3 and to decrease thereafter becoming very slow at pH = 8.2. In acetate buffered medium, the reaction rate was higher than the rate in unbuffered medium at the same pH. Further, the rate was found to be higher in suspension than in the leachate under otherwise identical conditions. And, the reaction rate in the blank reaction was the slowest. This appears to be due to catalysis by leached metal ions in leachate and due to catalysis by leached metal ions and particulate surface both in suspensions. The kinetics of dissolved SO2 oxidation in acetate buffered medium as well as in unbuffered medium at pH = 5.22 were defined by rate law: k obs = k 0 + k cat [DEP], where k obs and k 0 are observed rate constants in the presence and the absence of DEP and k cat is the rate constant for DEP catalyzed pathway. At pH = 8.2, the reaction rate was strongly inhibited by DEP in buffered and unbuffered media. Results suggest that the DEP would have an inhibiting effect in those areas where rainwater pH is 7 or more. These results at high pH are of particular significance to the Indian subcontinent, because of high rainwater pH. Conversely, it indicates the DEP to retard the oxidation of dissolved SO2 and control rainwater acidification. PMID- 27230142 TI - Trends in atmospheric particulate matter in Dhaka, Bangladesh, and the vicinity. AB - Dhaka and its neighboring areas suffer from severe air pollution, especially during dry season (November-April). We investigated temporal and directional variations in particulate matter (PM) concentrations in Dhaka, Gazipur, and Narayanganj from October 2012 to March 2015 to understand different aspects of PM concentrations and possible sources of high pollution in this region. Ninety-six hour backward trajectories for the whole dry season were also computed to investigate incursion of long-range pollution into this area. We found yearly PM10 concentrations in this area about three times and yearly PM2.5 concentrations about six times greater than the national standards of Bangladesh. Dhaka and its vicinity experienced several air pollution episodes in dry season when PM2.5 concentrations were 8-13 times greater than the World Health Organization (WHO) guideline value. Higher pollution and great contribution of PM2.5 most of the time were associated with the north-westerly wind. Winter (November to January) was found as the most polluted season in this area, when average PM10 concentrations in Dhaka, Gazipur, and Narayanganj were 257.1, 240.3, and 327.4 MUg m(-3), respectively. Pollution levels during wet season (May October) were, although found legitimate as per the national standards of Bangladesh, exceeded WHO guideline value in 50 % of the days of that season. Trans-boundary source identifications using concentration-weighted trajectory method revealed that the sources in the eastern Indian region bordering Bangladesh, in the north-eastern Indian region bordering Nepal and in Nepal and its neighboring areas had high probability of contributing to the PM pollutions at Gazipur station. PMID- 27230143 TI - The effects of groundwater depth on water uptake of Populus euphratica and Tamarix ramosissima in the hyperarid region of Northwestern China. AB - Knowledge of the water sources used by desert trees and shrubs is critical for understanding how they function and respond to groundwater decline and predicting the influence of water table changes on riparian plants. In this paper, we test whether increased depth to groundwater changed the water uptake pattern of desert riparian species and whether competition for water resources between trees and shrubs became more intense with a groundwater depth gradient. The water sources used by plants were calculated using the IsoSource model, and the results suggested differences in water uptake patterns with varying groundwater depths. At the river bank (groundwater depth = 1.8 m), Populus euphratica and Tamarix ramosissima both used a mixture of river water, groundwater, and deeper soil water (>75 cm). When groundwater depth was 3.8 m, trees and shrubs both depended predominantly on soil water stored at 150-375 cm depth. When the groundwater depth was 7.2 m, plant species switched to predominantly use both groundwater and deeper soil water (>375 cm). However, differences in water acquisition patterns between species were not found. The proportional similarity index (PSI) of proportional contribution to water uptake of different water resources between P. euphratica and T. ramosissima was calculated, and results showed that there was intense water resource competition between P. euphratica and T. ramosissima when grown at shallow groundwater depth (not more than 3.8 m), and the competition weakened when the groundwater depth increased to 7.2 m. PMID- 27230144 TI - Organophosphate flame retardants (OPFRs) in indoor and outdoor air in the Rhine/Main area, Germany: comparison of concentrations and distribution profiles in different microenvironments. AB - The concentrations of 9 organophosphate flame retardants (OPFRs) were determined in 56 indoor and 9 outdoor air samples in the Rhine/Main area in Germany. The indoor samples were collected from seven different indoor microenvironments including private cars, private homes, floor/carpet stores, building material markets, schools, offices, and day care centers, while outdoor samples were simultaneously collected close to the indoor sampling locations. The total OPFR concentrations (?OPFRs) in indoor air ranged from 3.30 to 751.0 ng/m3 with a median of 40.23 ng/m3, which was approximately eight times higher than those in outdoor air (median 5.38 ng/m3), indicating that sources of OPFRs predominate in the indoor environment. Tris(2-chloroisopropyl)phosphate (TCPP), tris(isobutyl)phosphate (TiBP), and tributyl phosphate (TnBP) were the dominating compounds both in indoor and outdoor air. The median concentration of ?OPFRs in private cars (180.3 ng/m3) was significantly higher than that in private homes (12.51 ng/m3), schools (36.23 ng/m3), day care centers (31.80 ng/m3), and building material markets (31.17 ng/m3) (p < 0.05). Distribution profiles of OPFRs varied among different indoor microenvironments, which are evidenced by dominating indoor air concentrations of non-Cl-OPFRs in day care centers, floor/carpet stores, schools, and of Cl-OPFRs in other indoor microenvironments. Multivariate analyses revealed three distinct groups for OPFRs, i.e., TiBP/TnBP, TEP/TCEP/TDCPP, and TCPP, whose concentrations were closely associated with the distribution profiles and pollution characteristics of materials predominating in different indoor microenvironments. PMID- 27230145 TI - Three simple biomarkers useful in conducting water quality assessments with bivalve mollusks. AB - While biomarkers are undeniably key tools in aquatic ecotoxicology to measure adverse effects linked to contamination events, their application is often inhibited by monetary constraints negating the possibility of having access to dedicated equipment, special wares, and/or expensive reagents. To offset this bottleneck, we propose three simple physiological biomarkers, quantifiable in bivalves, that are free of cost considerations and that can provide basic knowledge on animal health and water quality. Indeed, condition index (CI), growth index (GI), and SOS response (air-time survival) comprise measurements straightforward enough to perform by any laboratory or science body on the planet. Long-term monitoring or screening studies can be carried out with these biomarkers and they are able to provide robust information notably after exposure of bivalves to either singular or multiple agents of contamination. By highlighting examples of data generated in aquatic studies conducted in Eastern Canada under both laboratory and field situations with different species of marine and freshwater mollusks, we establish the suitability of these biomarkers for assessing environmental contamination. Their relationships with other biomarkers are also shown which further corroborate their value as reliable indicators of ecosystem health. PMID- 27230146 TI - Changes in bryophyte and lichen communities on Scots pines along an alkaline dust pollution gradient. AB - Dust pollution can cause a significant damage of environment and endanger human health. Our study aimed to investigate epiphytic lichens and bryophytes in relation to long-term alkaline dust pollution and provide new insights into the bioindicators of dust pollution. We measured the bark pH of Scots pines and the species richness and cover of two cryptogam groups in 32 sample plots in the vicinity of limestone quarries (up to ca. 3 km) in northern Estonia. The bark pH decreased gradually with increasing distance from quarries. We recorded the changes in natural epiphytic communities, resulting in diversified artificial communities on pines near the pollution source; the distance over 2 km from the quarries was sufficient to re-establish the normal acidity of the bark and natural communities of both lichens and bryophytes. The cover of lichens and the number of bryophytes are a more promising indicator of environmental conditions than individual species occurrence. We confirmed previously proposed and suggested new bioindicator species of dust pollution (e.g., Lecidella elaeochroma, Opegrapha varia, Schistidium apocarpum). Limestone quarrying activity revealed a "parapositive" impact on cryptogamic communities, meaning that quarrying might, besides disturbances of natural communities, temporarily contribute to the distribution of locally rare species. PMID- 27230147 TI - Combination of wet irrigation and nitrification inhibitor reduced nitrous oxide and methane emissions from a rice cropping system. AB - To conserve water resources and guarantee food security, a new technology termed as "wet irrigation" is developed and practiced in rice fields; thus, its impact on radiative forcing derived from nitrous oxide (N2O) and methane (CH4) emissions merits serious attention. Dicyandiamide (DCD), a kind of nitrification inhibitor, is proposed as a viable means to mitigate greenhouse gas (GHG) emission while enhancing crop productivity. However, little is known about the response of GHG emission and grain yield to DCD application in a rice system under wet irrigation. In these regard, effects of water regime and DCD application on CH4 and N2O emissions, grain yield, global warming potential (GWP), and greenhouse gas intensity (GHGI) from rice fields were studied. For this study, a field experiment, designed: Treatment II (intermittent irrigation), Treatment WI (wet irrigation), Treatment IID (II plus DCD), and Treatment WID (WI plus DCD), was conducted in Jurong, Jiangsu Province, China, from 2011 to 2012. Relative to Treatment II, Treatment WI decreased CH4 emission significantly by 49-71 % while increasing N2O emission by 33-72 %. By integrating CH4 and N2O emissions and grain yield, Treatment WI was 20-28 and 11-15 % lower than Treatment II in GWP and GHGI, respectively. The use of DCD under wet irrigation reduced N2O emission significantly by 25-38 % (p < 0.05) and CH4 emission by 7-8 %, relative to Treatment WI, resulting in a decline of 18-30 % in GWP. Due to the increase in N use efficiency, maximal grain yield (6-7 %) and minimal GHGI (22-34 %) was observed in Treatment WID. These findings indicate that combined application of N fertilizer and DCD is a win-win strategy in water-saving high-yield rice production with less GHG emission. PMID- 27230148 TI - Solar photolysis versus TiO2-mediated solar photocatalysis: a kinetic study of the degradation of naproxen and diclofenac in various water matrices. AB - Given that drugs and their degradation products are likely to occur as concoctions in wastewater, the degradation of a mixture of two nonsteroidal anti inflammatory drugs (NSAIDs), diclofenac (DCF) and naproxen (NPX), was investigated by solar photolysis and titanium dioxide (TiO2)-mediated solar photocatalysis using an immersion-well photoreactor. An equimolar ratio (1:1) of both NSAIDs in distilled water, drinking water, and river water was subjected to solar degradation. Solar photolysis of the DCF and NPX mixture was competitive particularly in drinking water and river water, as both drugs have the ability to undergo photolysis. However, the addition of TiO2 in the mixture significantly enhanced the degradation rate of both APIs compared to solar photolysis alone. Mineralization, as measured by chemical oxygen demand (COD), was incomplete under all conditions investigated. TiO2-mediated solar photocatalytic degradation of DCF and NPX mixtures produced 15 identifiable degradants corresponding to degradation of the individual NSAIDs, while two degradation products with much higher molecular weight than the parent NSAIDs were identified by liquid chromatography mass spectrometry (LC-MS) and Fourier transform-ion cyclotron resonance-mass spectrometry (FT-ICR-MS). This study showed that the solar light intensity and the water matrix appear to be the main factors influencing the overall performance of the solar photolysis and TiO2-mediated solar photocatalysis for degradation of DCF and NPX mixtures. PMID- 27230149 TI - Biochar as possible long-term soil amendment for phytostabilisation of TE contaminated soils. AB - Soils contaminated by trace elements (TEs) pose a high risk to their surrounding areas as TEs can spread by wind and water erosion or leaching. A possible option to reduce TE transfer from these sites is phytostabilisation. It is a long-term and cost-effective rehabilitation strategy which aims at immobilising TEs within the soil by vegetation cover and amendment application. One possible amendment is biochar. It is charred organic matter which has been shown to immobilise metals due to its high surface area and alkaline pH. Doubts have been expressed about the longevity of this immobilising effect as it could dissipate once the carbonates in the biochar have dissolved. Therefore, in a pot experiment, we determined plant metal uptake by ryegrass (Lolium perenne) from three TE contaminated soils treated with two biochars, which differed only in their pH (acidic, 2.80; alkaline, 9.33) and carbonate (0.17 and 7.3 %) content. Root biomass was increased by the application of the alkaline biochar due to the decrease in TE toxicity. Zinc and Cu bioavailability and plant uptake were equally reduced by both biochars, showing that surface area plays an important role in metal immobilisation. Biochar could serve as a long-term amendment for TE immobilisation even after its alkalinity effect has dissipated. PMID- 27230150 TI - Effect of aluminum speciation on fouling mechanisms by pre coagulation/ultrafiltration process with different NOM fractions. AB - Ultrafiltration is an emerging technology for drinking water production, but the membrane fouling is still a challenge. This study was carried out to investigate the effect of aluminum speciation on UF membrane fouling behavior by different NOM fractions-humic substances and proteins, as represented by humic acid (HA) and bovine serum albumin (BSA), respectively. The interesting results showed that the total fouling resistance of the mixture of HA-BSA-kaolinite solution without coagulant demonstrated a slight decrease in comparison with those of the individually filtered substances, indicating a mitigatory fouling effect. The hydrolysis of aluminum products was various as pH and membrane fouling was related to aluminum speciation. The average size of flocs dramatically increased and fractal dimension of flocs decreased with the increasing of pH value independent on water quality, which indicated that aluminum speciation had a significant impact on floc properties. For the mixture of HA-BSA-kaolinte, the slightly larger of flocs average size in comparison with the individual organic fraction after coagulation was probably attributing that BSA was encapsulated by HA to enlarge the molecular length and floc size further increased. The membrane performance also showed that coagulation effluent of HA-BSA-kaolinite mitigated membrane fouling. The strong linear relationship was observed between flocs fractal dimension and final membrane flux in this research. From the results, the control of flocs fractal dimension should be considered as a new technique for traditional hybrid coagulation/ultrafiltration system, which resulted in minimized total and irreversible fouling and has a meaningful engineering application value. PMID- 27230151 TI - Global Mercury Observatory System (GMOS): measurements of atmospheric mercury in Celestun, Yucatan, Mexico during 2012. AB - Within the Global Mercury Observation System (GMOS) project, long-term continuous measurements of total gaseous mercury (TGM) were carried out by a monitoring station located at Celestun, Yucatan, Mexico, a coastal site along the Gulf of Mexico. The measurements covered the period from January 28th to October 17th, 2012. TGM data, at the Celestun site, were obtained using a high-resolution mercury vapor analyzer. TGM data show values from 0.50 to 2.82 ng/m(3) with an annual average concentration of 1.047 +/- 0.271 ng/m(3). Multivariate analyses of TGM and meteorological variables suggest that TGM is correlated with the vertical air mass distribution in the atmosphere, which is influenced by diurnal variations in temperature and relative humidity. Diurnal variation is characterized by higher nighttime mercury concentrations, which might be influenced by convection currents between sea and land. The back trajectory analysis confirmed that local sources do not significantly influence TGM variations. This study shows that TGM monitoring at the Celestun site fulfills GMOS goals for a background site. PMID- 27230152 TI - Distribution and origins of n-alkanes, hopanes, and steranes in rivers and marine sediments from Southwest Caspian coast, Iran: implications for identifying petroleum hydrocarbon inputs. AB - The occurrence of n-alkanes and biomarkers (hopane and sterane) in surface sediments from Southwestern coasts of Caspian Sea and 28 rivers arriving to this lake, determined with a gas chromatography-mass spectrometry method, was used to assess the impacts of anthropogenic activities in the studied area. The concentrations of total n-alkanes (Sigma21 n-alkane) in costal and riverine sediments varied from 249.2 to 3899.5 and 56 to 1622.4 MUg g(-1), respectively. An evaluation of the source diagnostic indices indicated that petroleum related sources (petrogenic) were mainly contributed to n-alkanes in costal and most riverine sediments. Only the hydrocarbons in sediment of 3 rivers were found to be mainly of biogenic origin. Principal component analysis using hopane diagnostic ratios in costal and riverine sediments, and Anzali, Turkmenistan, and Azerbaijan oils were used to identify the sources of hydrocarbons in sediments. It was indicated that the anthropogenic contributions in most of the costal sediment samples are dominated with inputs of oil spills from Turkmenistan and Azerbaijan countries. PMID- 27230153 TI - The relationship between plasma and urinary 8-hydroxy-2-deoxyguanosine biomarkers measured by liquid chromatography tandem mass spectrometry. AB - Although 8-hydroxy-2-deoxyguanosine (8-OHdG) is a widely used promising biomarker of DNA damage, there are concerns about which tissues or body fluids should be sampled. The objective of this study is to evaluate the correlation of DNA oxidative damage biomarkers, 8-OHdG, between blood and urine and risk factors associated with 8OHdG. The study population was recruited from a baseline survey of a worksite lifestyle study including 92 office workers aged 23 to 60 years. A self-administered questionnaire was used to collect information on personal characteristics. The plasma and urinary 8-OHdG was measured by liquid chromatography tandem mass spectrometry (LC-MS/MS). In linear regression, a positive relation was found (p < 0.01) between the log-transformed plasma and urinary 8-OHdG levels adjusted for gender, age, BMI, and smoking status. Our findings showed that age, gender and smoking were significantly associated with plasma 8-OHdG, but not with urinary 8-OHdG. Our results suggest that there is a positive relation between the biomarkers of plasma (steady state DNA damage) and urinary 8-OHdG (total DNA damage). However, the plasma 8-OHdG is more sensitive than urinary 8-OHdG to detect increased oxidative damages induced by risk factors. PMID- 27230154 TI - Influence of UV-B radiation on lead speciation in the presence of natural particles of estuarine waters. AB - The influence of UV-B irradiation on filtered and non-filtered water samples collected in a non-polluted area of Tagus estuary was evaluated in this study. In the laboratory, both samples were titrated with lead (Pb(+2)) followed by differential pulse anodic stripping voltammetry (DPASV), before and after 1 and 10 days under UV-B irradiation. Metal-ligand complexing parameters were obtained based on a macromolecular heterogeneous ligand described by two distinct sites with a labile behavior, and a third small homogeneous weaker group, which concentration was determined from a potentiometric titration. Under UV-B radiation, the complexing strength decreased with time in both (filtered and non filtered) irradiated samples, but this effect was more pronounced in the non filtered water, which might be due to some adsorption of dissolved macromolecular ligands on the particles and/or to further degradation of dissolved organic matter (DOM). Furthermore, the presence of particles favored the break-down of the macromolecular ligand under long UV-B exposure time. These results present ecological implications for the estuarine ecosystems such as bioavailability and toxicity. PMID- 27230155 TI - Assessment of health risk of trace metal pollution in surface soil and road dust from e-waste recycling area in China. AB - Informal recycling of e-waste and the resulting heavy metal pollution has become a serious burden on the ecosystem in Guiyu, China. In this investigation, we evaluated the trace metal concentration of community soil and road dust samples from 11 locations in Guiyu and 5 locations (consisting of residential areas, kindergarten/school, and farm field) in a reference area using graphite furnace atomic absorption spectrophotometer. The study spanned four seasons, 2012-2013, with a view to assess the risk associated with e-waste recycling in the study area. The concentrations of Pb, Cd, Cr, and Mn were 448.73, 0.71, 63.90, and 806.54 mg/kg in Guiyu soil and 589.74, 1.94, 69.71, and 693.74 mg/kg, in the dust, respectively. Pb and Cd values were significantly higher (P <= 0.05) than the reference area, and the mixed model analysis with repeated seasonal measurements revealed soil Pb and Cd levels that were 2.32 and 4.34 times, while the ratios for dust sample were 4.10 and 3.18 times higher than the reference area. Contamination factor, degree of contamination, and pollution load index indicated that all sampling points had a high level of metal contamination except farm land and kindergarten compound. The cumulative hazard index of Pb, Cd, Cr, and Mn for children in exposed area was 0.99 and 1.62 for soil and dust, respectively, suggesting non-cancer health risk potential. The significant accumulation of trace metals in the e-waste recycling area predisposes human life, especially children, to a potentially serious health risk. PMID- 27230156 TI - Health transition after lung transplantation - a grounded theory study. AB - AIMS AND OBJECTIVES: To investigate lung recipients' process of transition from prior the transplantation to one year afterwards, as well as what their main concerns are and how they deal with these concerns. BACKGROUND: During the last three decades, lung transplantation has been established as an effective treatment for patients with end-stage pulmonary disease. Towards the end of the 20th century, the concept of survival expanded to also include improving health related quality of life (HRQoL). Although many studies have been published regarding lung recipients' HRQoL, aspects of health and everyday life remain understudied. Lung transplantation demands some kind of transition. However, very little is known about this transitional process. DESIGN: A qualitative inductive approach using Grounded Theory (GT) was used. METHODS: A total of ten adult males and five adult females (n = 15) with a mean age of 55 years were included in the study and interviewed one year after transplantation. The open-ended interviews were digitally recorded and transcribed verbatim after each interview. The analysis of the material was performed consistent with Charmaz contructivistic approach of GT. RESULTS: The core category Reconstructing daily occupations summarises a process wherein the generated GT is present through four main categories: Restricting, Regaining, Reorganising and Enriching. The process of reconstructing daily occupations is necessary to regain health. CONCLUSIONS: A trajectory of health transition is evident, starting pretransplant with the lung disease and severe illness and proceeding at least up to one year after the transplantation with experienced health. RELEVANCE TO CLINICAL PRACTICE: The result enables a unique possibility to enhance the lung recipients' striving for everyday life and thereby promote health. There is a need for change in the existing multidisciplinary transplant team to also include an occupational therapist to support and guide the lung recipients in changing their occupational patterns. PMID- 27230211 TI - Identification of recurrent focal copy number variations and their putative targeted driver genes in ovarian cancer. AB - BACKGROUND: Genomic regions with recurrent DNA copy number variations (CNVs) are generally believed to encode oncogenes and tumor suppressor genes (TSGs) that drive cancer growth. However, it remains a challenge to delineate the key cancer driver genes from the regions encoding a large number of genes. RESULTS: In this study, we developed a new approach to CNV analysis based on spectral decomposition of CNV profiles into focal CNVs and broad CNVs. We performed an analysis of CNV data of 587 serous ovarian cancer samples on multiple platforms. We identified a number of novel focal regions, such as focal gain of ESR1, focal loss of LSAMP, prognostic site at 3q26.2 and losses of sub-telomere regions in multiple chromosomes. Furthermore, we performed network modularity analysis to examine the relationships among genes encoded in the focal CNV regions. Our results also showed that the recurrent focal gains were significantly associated with the known oncogenes and recurrent losses associated with TSGs and the CNVs had a greater effect on the mRNA expression of the driver genes than that of the non-driver genes. CONCLUSIONS: Our results demonstrate that spectral decomposition of CNV profiles offers a new way of understanding the role of CNVs in cancer. PMID- 27230212 TI - SeGSTo, a novel glutathione S-transferase from the beet armyworm (Spodoptera exigua), involved in detoxification and oxidative stress. AB - Members of the glutathione S-transferase superfamily can protect organisms against oxidative stress. In this study, we characterized an omega glutathione S transferase from Spodoptera exigua (SeGSTo). The SeGSTo gene contains an open reading frame (ORF) of 744 nucleotides encoding a 248-amino acid polypeptide. The predicted molecular mass and isoelectric point of SeGSTo are 29007 Da and 7.74, respectively. Multiple amino acid sequence alignment analysis shows that the SeGSTo sequence is closely related to the class 4 GSTo of Bombyx mori BmGSTo4 (77 % protein sequence similarity). Homologous modeling and molecular docking reveal that Cys35 may play an essential role in the catalytic process. Additionally, the phylogenetic tree indicates that SeGSTo belongs to the omega group of the GST superfamily. During S. exigua development, SeGSTo is expressed in the midgut of the fifth instar larval stage, but not in the epidermis or fat body. Identification of recombinant SeGSTo via SDS-PAGE and Western blot shows that its molecular mass is 30 kDa. The recombinant SeGSTo was able to protect super-coiled DNA from damage in a metal-catalyzed oxidation (MCO) system and catalyze the 1 chloro-2,4-dinitrobenzene (CDNB), but not 1,2-dichloro-4-nitrobenzene (DCNB), 4 nitrophenethyl bromide (4-NPB), or 4-nitrobenzyl chloride (4-NBC). The optimal reaction pH and temperature were 8 and 50 degrees C, respectively, in the catalysis of CDNB by recombinant SeGSTo. The mRNA expression of SeGSTo was up regulated by various oxidative stresses, such as CdCl2, CuSO4, and isoprocarb, and the catalytic activity of recombinant SeGSTo was noticeably inhibited by heavy metals (Cu(2+) and Cd(2+)) and various pesticides. Taken together, these results indicate that SeGSTo plays an important role in the antioxidation and detoxification of pesticides. PMID- 27230214 TI - Recurrent acute angle-closure attack due to plateau iris syndrome after cataract extraction with or without argon laser peripheral iridoplasty: a case report. AB - BACKGROUND: We describe two cases of recurrent acute angle-closure attack in patients with plateau iris syndrome after cataract extraction. Argon laser peripheral iridoplasty and cataract extraction have been used to reduce the occurrence of acute angle-closure attack in plateau iris syndrome although the risk cannot be completely eliminated. There is no consensus on the long term management of plateau iris syndrome. This is, as far as we know, the first case report of recurrent acute angle-closure attack in plateau iris syndrome after cataract extraction. CASE PRESENTATION: We report two cases of recurrent acute angle-closure attack in 2 Chinese patients with plateau iris syndrome. The first patient was a 69 year-old woman who received bilateral argon laser peripheral iridoplasty and cataract extraction 2 years prior to the latest acute angle closure with right eye intraocular pressure 48 mmHg. The attack was aborted medically. Peripheral iridotomy was patent and argon laser peripheral iridoplasty marks were mostly at peripheral 2/3 of the iris. Anterior segment optical coherence tomography confirmed bilateral plateau iris configuration. Use of long term pilocarpine or repeated argon laser peripheral iridoplasty to prevent recurrent angle-closure attack was discussed but she opted for observation. The second patient was a 64 year-old man presented with acute angle-closure after cataract extraction despite placement of laser peripheral iridotomy. Plateau iris syndrome was confirmed by anterior segment optical coherence tomography and he received argon laser peripheral iridoplasty. CONCLUSIONS: Acute angle-closure due to plateau iris syndrome can still occur despite previous cataract extraction and argon laser peripheral iridoplasty. These are the first reported cases of recurrent acute angle-closure attack due to plateau iris syndrome following cataract extraction, with or without previous argon laser peripheral iridoplasty. Repeated treatment with argon laser peripheral iridoplasty or pilocarpine could be considered although the long term efficacy is questionable. Argon laser peripheral iridoplasty should be applied as peripheral as possible so as to open up the drainage angle effectively. PMID- 27230215 TI - Frequency-Selective Attention in Auditory Scenes Recruits Frequency Representations Throughout Human Superior Temporal Cortex. AB - A sound of interest may be tracked amid other salient sounds by focusing attention on its characteristic features including its frequency. Functional magnetic resonance imaging findings have indicated that frequency representations in human primary auditory cortex (AC) contribute to this feat. However, attentional modulations were examined at relatively low spatial and spectral resolutions, and frequency-selective contributions outside the primary AC could not be established. To address these issues, we compared blood oxygenation level dependent (BOLD) responses in the superior temporal cortex of human listeners while they identified single frequencies versus listened selectively for various frequencies within a multifrequency scene. Using best-frequency mapping, we observed that the detailed spatial layout of attention-induced BOLD response enhancements in primary AC follows the tonotopy of stimulus-driven frequency representations-analogous to the "spotlight" of attention enhancing visuospatial representations in retinotopic visual cortex. Moreover, using an algorithm trained to discriminate stimulus-driven frequency representations, we could successfully decode the focus of frequency-selective attention from listeners' BOLD response patterns in nonprimary AC. Our results indicate that the human brain facilitates selective listening to a frequency of interest in a scene by reinforcing the fine-grained activity pattern throughout the entire superior temporal cortex that would be evoked if that frequency was present alone. PMID- 27230213 TI - Inactivation of GABAA receptor is related to heat shock stress response in organism model Caenorhabditis elegans. AB - The mechanisms underlying oxidative stress (OS) resistance are not completely clear. Caenorhabditis elegans (C. elegans) is a good organism model to study OS because it displays stress responses similar to those in mammals. Among these mechanisms, the insulin/IGF-1 signaling (IIS) pathway is thought to affect GABAergic neurotransmission. The aim of this study was to determine the influence of heat shock stress (HS) on GABAergic activity in C. elegans. For this purpose, we tested the effect of exposure to picrotoxin (PTX), gamma-aminobutyric acid (GABA), hydrogen peroxide, and HS on the occurrence of a shrinking response (SR) after nose touch stimulus in N2 (WT) worms. Moreover, the effect of HS on the expression of UNC-49 (GABAA receptor ortholog) in the EG1653 strain and the effect of GABA and PTX exposure on HSP-16.2 expression in the TJ375 strain were analyzed. PTX 1 mM- or H2O2 0.7 mM-exposed worms displayed a SR in about 80 % of trials. GABA exposure did not cause a SR. HS prompted the occurrence of a SR as did PTX 1 mM or H2O2 0.7 mM exposure. In addition, HS increased UNC-49 expression, and PTX augmented HSP-16.2 expression. Thus, the results of the present study suggest that oxidative stress, through either H2O2 exposure or application of heat shock, inactivates the GABAergic system, which subsequently would affect the oxidative stress response, perhaps by enhancing the activity of transcription factors DAF-16 and HSF-1, both regulated by the IIS pathway and related to hsp-16.2 expression. PMID- 27230216 TI - Frequency of Maternal Touch Predicts Resting Activity and Connectivity of the Developing Social Brain. AB - Previous behavioral research points to a positive relationship between maternal touch and early social development. Here, we explored the brain correlates of this relationship. The frequency of maternal touch was recorded for 43 five-year old children during a 10 min standardized play session. Additionally, all children completed a resting-state functional magnetic resonance imaging session. Investigating the default mode network revealed a positive relation between the frequency of maternal touch and activity in the right posterior superior temporal sulcus (pSTS) extending into the temporo-parietal junction. Using this effect as a seed in a functional connectivity analysis identified a network including extended bilateral regions along the temporal lobe, bilateral frontal cortex, and left insula. Compared with children with low maternal touch, children with high maternal touch showed additional connectivity with the right dorso-medial prefrontal cortex. Together these results support the notion that childhood tactile experiences shape the developing "social brain" with a particular emphasis on a network involved in mentalizing. PMID- 27230217 TI - Longitudinal Evidence for Smaller Hippocampus Volume as a Vulnerability Factor for Perceived Stress. AB - Hippocampal volume has been found to be smaller in individuals with stress related disorders, but it remains unclear whether smaller volume is a consequence of stress or rather a vulnerability factor. Here, we examined this issue by relating stress levels to hippocampal volumes in healthy participants examined every 5 years in a longitudinal population-based study. Based on scores of 25- to 60-year-old participants on the perceived stress questionnaire, we defined moderately to high (n = 35) and low (n = 76) stress groups. The groups were re examined after 5 years (at the 6th study wave). Historical data on subjective stress were available up to 10 years prior to Wave 5. At the first MRI session, the moderately to high stress group had a significantly smaller hippocampal volume, as measured by FreeSurfer (version 5.3), compared with the low-stress group. At follow-up, group differences in stress levels and hippocampal volume remained unchanged. In retrospective analyses of subjective stress, the observed group difference in stress was found to be stable. The long-term stability of group differences in perceived stress and hippocampal volume suggests that a small hippocampal volume may be a vulnerability factor for stress-related disorders. PMID- 27230220 TI - The justification of caring science. PMID- 27230218 TI - The Human Brainnetome Atlas: A New Brain Atlas Based on Connectional Architecture. AB - The human brain atlases that allow correlating brain anatomy with psychological and cognitive functions are in transition from ex vivo histology-based printed atlases to digital brain maps providing multimodal in vivo information. Many current human brain atlases cover only specific structures, lack fine-grained parcellations, and fail to provide functionally important connectivity information. Using noninvasive multimodal neuroimaging techniques, we designed a connectivity-based parcellation framework that identifies the subdivisions of the entire human brain, revealing the in vivo connectivity architecture. The resulting human Brainnetome Atlas, with 210 cortical and 36 subcortical subregions, provides a fine-grained, cross-validated atlas and contains information on both anatomical and functional connections. Additionally, we further mapped the delineated structures to mental processes by reference to the BrainMap database. It thus provides an objective and stable starting point from which to explore the complex relationships between structure, connectivity, and function, and eventually improves understanding of how the human brain works. The human Brainnetome Atlas will be made freely available for download at http://atlas.brainnetome.org, so that whole brain parcellations, connections, and functional data will be readily available for researchers to use in their investigations into healthy and pathological states. PMID- 27230221 TI - Correction: A strongly greenish-blue-emitting Cu4Cl4 cluster with an efficient spin-orbit coupling (SOC): fast phosphorescence versus thermally activated delayed fluorescence. AB - Correction for 'A strongly greenish-blue-emitting Cu4Cl4 cluster with an efficient spin-orbit coupling (SOC): fast phosphorescence versus thermally activated delayed fluorescence' by Xu-Lin Chen et al., Chem. Commun., 2016, 52, 6288-6291. PMID- 27230219 TI - Cortical Dependence of Whisker Responses in Posterior Medial Thalamus In Vivo. AB - Cortical layer 5B (L5B) thick-tufted pyramidal neurons have reliable responses to whisker stimulation in anesthetized rodents. These cells drive a corticothalamic pathway that evokes spikes in thalamic posterior medial nucleus (POm). While a subset of POm has been shown to integrate both cortical L5B and paralemniscal signals, the majority of POm neurons are suggested to receive driving input from L5B only. Here, we test this possibility by investigating the origin of whisker evoked responses in POm and specifically the contribution of the L5B-POm pathway. We compare L5B spiking with POm spiking and subthreshold responses to whisker deflections in urethane anesthetized mice. We find that a subset of recorded POm neurons shows early (<50 ms) spike responses and early large EPSPs. In these neurons, the early large EPSPs matched L5B input criteria, were blocked by cortical inhibition, and also interacted with spontaneous Up state coupled large EPSPs. This result supports the view of POm subdivisions, one of which receives whisker signals predominantly via L5B neurons. PMID- 27230222 TI - A novel polymorphic repeat in the upstream regulatory region of the estrogen induced gene EIG121 is not associated with the risk of developing breast or endometrial cancer. AB - BACKGROUND: The estrogen-induced gene 121 (EIG121) has been associated with breast and endometrial cancers, but its mechanism of action remains unknown. In a genome-wide search for tandem repeats, we found that EIG121 contains a short tandem repeat (STR) in its upstream regulatory region which has the potential to alter gene expression. The presence of this STR has not previously been analysed in relation to breast or endometrial cancer risk. RESULTS: In this study, the lengths of this STR were determined by PCR, fragment analysis and sequencing using DNA from 223 breast cancer patients, 204 endometrial cancer patients and 220 healthy controls to determine if they were associated with the risk of developing breast or endometrial cancer. We found this repeat to be highly variable with the number of copies of the AG motif ranging from 27 to 72 and having a bimodal distribution. No statistically significant association was identified between the length of this STR and the risk of developing breast or endometrial cancer or age at diagnosis. CONCLUSIONS: The STR in the upstream regulatory region of EIG121 is highly polymorphic, but is not associated with the risk of developing breast or endometrial cancer in the cohorts analysed here. While this polymorphic STR in the regulatory region of EIG121 appears to have no impact on the risk of developing breast or endometrial cancer, its association with disease recurrence or overall survival remains to be determined. PMID- 27230223 TI - Describing Kawasaki shock syndrome: results from a retrospective study and literature review. AB - Kawasaki shock syndrome (KSS) is a rare manifestation of Kawasaki disease (KD) characterized by systolic hypotension or clinical signs of poor perfusion. The objectives of the study are to describe the main clinical presentation, echocardiographic, and laboratory findings, as well as the treatment options and clinical outcomes of KSS patients when compared with KD patients. This is a retrospective study. All children referred to two pediatric rheumatology units from January 1, 2012, to December 31, 2014, were enrolled. Patients were divided into patients with or without KSS. We compared the two groups according to the following variables: sex, age, type of KD (classic, with less frequent manifestations, or incomplete), clinical manifestations, cardiac involvement, laboratory findings, therapy administered, response to treatment, and outcome. Eighty-four patients with KD were enrolled. Of these, five (6 %) met the criteria for KSS. Patients with KSS had higher values of C-reactive protein (p = 0.005), lower hemoglobin levels (p = 0.003); more frequent hyponatremia (p = 0.004), hypoalbuminemia (p = 0.004), and coagulopathy (p = 0.003); and increase in cardiac troponins (p = 0.000). Among the KSS patients, three had a coronary artery involvement, but none developed a permanent aneurysm. Intravenous immunoglobulin resistance was more frequent in the KSS group, although not significantly so (3/5, 60 % vs. 23/79, 30 %, P = NS). None of the five cases was fatal, and all recovered without sequelae. KSS patients are more likely to have higher rates of cardiac involvement. However, most cardiovascular abnormalities resolved promptly with therapy. PMID- 27230224 TI - Measurement of the hepatitis B core-related antigen is valuable for predicting the pathological status of liver tissues in chronic hepatitis B patients. AB - The objective of this study was to evaluate the validities of serum hepatitis B core-related antigen (HBcrAg) for predicting the pathological status of liver tissues of chronic hepatitis B (CHB). A total of 205 Chinese patients with CHB, including 121 HBeAg-positive and 84 HBeAg-negative patients, were enrolled in this study. In HBeAg-positive patients, AUCs of serum HBcrAg for predicting severe necro-inflammation and advanced fibrosis were greater than 0.70; using serum HBcrAg<=4.81*10(4)kUmL(-1) and <=2.45*10(4)kUmL(-1) as cutoffs, the sensitivities, specificities, accuracies for predicting severe necro-inflammation and advanced fbrosis were 0.697, 0.716, 0.711 and 0.818, 0.778, 0.785, respectively. In HBeAg-negative patients, the AUCs of serum HBcrAg for predicting significant necro-inflammation and significant fibrosis were greater than 0.70; using serum HBcrAg>=1.70*10(2)kUmL(-1) and >=4.02kUmL(-1) as cutoffs, the sensitivities, specificities, accuracies for predicting significant necro inflammation and significant fibrosis were 0.929, 0.964, 0.952 and 1.000, 1.000, 1.000, respectively. These results indicated favorable performances of serum HBcrAg for predicting severe necro-inflammation and advanced fibrosis in HBeAg positive patients and significant necro-inflammation and significant fibrosis in negative patients. PMID- 27230225 TI - Israeli acute paralysis virus associated paralysis symptoms, viral tissue distribution and Dicer-2 induction in bumblebee workers (Bombus terrestris). AB - Although it is known that Israeli acute paralysis virus (IAPV) can cause bee mortality, the symptoms of paralysis and the distribution of the virus in different body tissues and their potential to respond with an increase of the siRNA antiviral immune system have not been studied. In this project we worked with Bombus terrestris, which is one of the most numerous bumblebee species in Europe and an important pollinator for wild flowers and many crops in agriculture. Besides the classic symptoms of paralysis and trembling prior to death, we report a new IAPV-related symptom, crippled/immobilized forelegs. Reverse-transcriptase quantitative PCR showed that IAPV accumulates in different body tissues (midgut, fat body, brain and ovary). The highest levels of IAPV were observed in the fat body. With fluorescence in situ hybridization (FISH) we detected IAPV in the Kenyon cells of mushroom bodies and neuropils from both antennal and optic lobes of the brain in IAPV-infected workers. Finally, we observed an induction of Dicer-2, a core gene of the RNAi antiviral immune response, in the IAPV-infected tissues of B. terrestris workers. According to our results, tissue tropism and the induction strength of Dicer-2 could not be correlated with virus-related paralysis symptoms. PMID- 27230226 TI - Effect of Urea and Thiourea on Generation of Xenogeneic Extracellular Matrix Scaffolds for Tissue Engineering. AB - Effective solubilization of proteins by chaotropes in proteomic applications motivates their use in solubilization-based antigen removal/decellularization strategies. A high urea concentration has previously been reported to significantly reduce lipophilic antigen content of bovine pericardium (BP); however, structure and function of the resultant extracellular matrix (ECM) scaffold were compromised. It has been recently demonstrated that in vivo ECM scaffold fate is determined by two primary outcome measures as follows: (1) sufficient reduction in antigen content to avoid graft-specific adaptive immune responses and (2) maintenance of native ECM structural proteins to avoid graft specific innate responses. In this work, we assessed residual antigenicity, ECM architecture, ECM content, thermal stability, and tensile properties of BP subjected to a gradient of urea concentrations to determine whether an intermediate concentration exists at which both antigenicity and structure function primary outcome measures for successful in vivo scaffold outcome can simultaneously be achieved. Alteration in tissue structure-function properties at various urea concentrations with decreased effectiveness for antigen removal makes use of urea-mediated antigen removal unlikely to be suitable for functional scaffold generation. PMID- 27230227 TI - Assessing a doctor you've rarely worked with: The use of workplace-based assessments in a busy inner city emergency department. AB - OBJECTIVE: Historically, end-of-term assessments for Junior Medical Officers in our ED have been completed by nominated Consultants based on varying amounts of observation in addition to feedback from other health professionals. Our hypothesis is that this system of assessment is both inconsistent and unreliable. Our objective was to increase the validity of our assessment process using workplace-based assessments linked specifically to the domains set out in the Australian Medical Council intern assessment form. METHODS: Current practice was established using an online survey. Workplace-based assessments were then performed on each junior doctor throughout the course of a term. A repeat survey at the end of term was used to audit the use of the workplace-based assessments and their effect on the adequacy of the assessments. RESULTS: Almost three quarters of our Consultants used workplace-based assessments as part of their end of-term assessment. Overall, 80% of Consultants agreed that the Junior Medical Officers assessment process was improved when using workplace-based assessments as an adjunct. CONCLUSION: Workplace-based assessments improve the validity of end-of-term assessments for junior doctors in an ED as perceived by those performing the assessment. PMID- 27230229 TI - Erratum to: The intracellular carboxyl tail of the PAR-2 receptor controls intracellular signaling and cell death. PMID- 27230228 TI - Extrinsic innervation of ileum and pelvic flexure of foals with ileocolonic aganglionosis. AB - Equine ileocolonic aganglionosis, which is also called lethal white foal syndrome (LWFS), is a severe congenital condition characterized by the unsuccessful colonization of neural crest progenitors in the caudal part of the small intestine and the entire large intestine. LWFS, which is attributable to a mutation in the endothelin receptor B gene, is the horse equivalent of Hirschsprung's disease in humans. Affected foals suffer from aganglionosis or hypoganglionosis of the enteric ganglia resulting in intestinal akinesia and colic. In other species with aganglionosis, fibers of extrinsic origin show an abnormal distribution pattern within the gut wall, but we have no information to date regarding this occurrence in horses. Our present aim is to investigate the distribution of extrinsic sympathetic and sensory neural fibers in LWFS, focusing on ileum and the pelvic flexure of the colon of two LWFS foals compared with a control subject. The sympathetic fibers were immunohistochemically identified with the markers tyrosine hydroxylase and dopamine beta-hydroxylase. The extrinsic sensory fibers were identified with the markers Substance P (SP) and calcitonin gene-related peptide (CGRP). Since SP and CGRP are also synthesized by subclasses of horse intramural neurons, LWFS represents a good model for the selective study of extrinsic fiber distribution. Affected foals showed large bundles of extrinsic fibers, compared with the control, as observed in Hirschsprung's disease. Furthermore, altered adrenergic pathways were observed, prominently in the pelvic flexure. The numbers of SP- and CGRP-immunoreactive fibers in the muscle, a target of enteric neurons, were dramatically reduced, whereas fibers deduced to be extrinsic sensory axons persisted around submucosal blood vessels. Fiber numbers in the mucosa were reduced. Thus, extrinsic innervation, contributing to modulate enteric functions, might also be affected during LWFS. PMID- 27230230 TI - Subclinical zinc deficiency impairs pancreatic digestive enzyme activity and digestive capacity of weaned piglets. AB - This study investigated the effects of short-term subclinical Zn deficiency on exocrine pancreatic activity and changes in digestive capacity. A total of forty eight weaned piglets were fed ad libitum a basal diet (maize and soyabean meal) with adequate Zn supply (88 mg Zn/kg diet) during a 2-week acclimatisation phase. Animals were then assigned to eight dietary treatment groups (n 6) according to a complete randomised block design considering litter, live weight and sex. All pigs were fed restrictively (450 g diet/d) the basal diet but with varying ZnSO4.7H2O additions, resulting in 28.1, 33.6, 38.8, 42.7, 47.5, 58.2, 67.8 and 88.0 mg Zn/kg diet for a total experimental period of 8 d. Pancreatic Zn concentrations and pancreatic activities of trypsin, chymotrypsin, carboxypeptidase A and B, elastase and alpha-amylase exhibited a broken-line response to stepwise reduction in dietary Zn by declining beneath thresholds of 39.0, 58.0, 58.0, 41.2, 47.5, 57.7 and 58.0 mg Zn/kg diet, respectively. Furthermore, carboxypeptidase B and alpha-amylase activities were significantly lower in samples with reduced pancreatic Zn contents. Coefficients of faecal digestibility of DM, crude protein, total lipids and crude ash responded similarly to pancreatic enzyme activities by declining below dietary thresholds of 54.7, 45.0, 46.9 and 58.2 mg Zn/kg diet, respectively. In conclusion, (1) subclinical Zn deficiency impaired pancreatic exocrine enzymes, (2) this response was connected to pancreatic Zn metabolism and (3) the decline in catalytic activity impaired faecal digestibility already after 1 week of insufficient alimentary Zn supply and very early before clinical deficiency symptoms arise. PMID- 27230231 TI - Current status of emergency department attending physician ultrasound credentialing and quality assurance in the United States. AB - BACKGROUND: The use of emergency ultrasonography (EUS) has gained much popularity in the past few decades, and is now a mainstay of diagnostic decision-making. This expanded use is now highlighting the substantial issue of individual hospitals in credentialing its emergency medicine attending physicians in EUS in the United States. This issue is also of importance as more hospitals are now requesting reimbursements for emergency ultrasounds. The objective of this study is to gain an understanding of how many emergency departments are currently credentialing its attending staff in EUS, what the internal structure and staffing are of these emergency departments, and how they are currently performing quality assurance of the ultrasounds performed. METHODS: This was a cross-sectional, web-based survey sent to 160 ACGME-accredited EM residency programs from July 2013 to November 2013. The survey consisted of 23 questions regarding: (1) number of emergency medicine attendings on staff, (2) presence of an EUS fellowship, (3) quality assurance (QA) process, and (4) current US credentialing process. RESULTS: There was a 50 % response rate. Fifty percent of the total respondents (n = 40) had an EUS fellowship program. Of the sites with an EUS fellowship, 36 had EUS fellowship-trained attendings. Of the sites without an EUS fellowship, 19 had EUS fellowship-trained faculty, p <= 0.0001. Sites with an EUS fellowship had a greater percentage of staff credentialed to perform EUS as compared to sites with no EUS fellowship, p = 0.0161. All sites with an EUS fellowship had EUS-credentialed attendings. In sites with an EUS fellowship, 35 conducted a formal QA of ED performed EUS scans versus 22 at sites without an EUS fellowship, p = 0.003. CONCLUSIONS: The survey results support hiring emergency attendings that have completed postgraduate training in emergency ultrasonography to aid in credentialing staff. This also seems to be helpful in completing a timelier QA of all ED ultrasounds. PMID- 27230232 TI - Leverage application on Gartland type IV supracondylar humeral fracture in children. AB - PURPOSE: Although the most complex management of Gartland type IV supracondylar humeral fracture (SCHF) due to instability, the gold standard of initial treatment remains closed reduction and percutaneous pinning. However, open reduction was inevitable in most published studies. This study reports the outcome of treatment by leverage-assisted closed reduction. METHOD: Twenty-seven patients were diagnosed as Gartland type IV SCHF during surgery in 214 preoperative Gartland type III fractures. Leverage-assisted reduction with percutaneous lateral pinning was done in these patients after failure of close reduction. Evaluations were performed with radiographic examination, clinical assessment and Flynn's criteria by interview and physical examination. RESULT: All 27 patients obtained acceptable reduction by leverage-assisted close reduction and percutaneous pinning. The average follow-up was 23.6 (18-30 months). There was no neurovascular complication, infection, nonunion, myositis ossificans or Volkmann's contracture. Evaluation of Baumann's angle was towards varus (74-74.2 degrees ). There was no significant difference (p = 0.1876). Flynn's criteria were excellent in 22 (81.5 %) patients, good in four (14.8 %) and fair in one (3.7 %). The rate of excellent and good outcome was 96.3 % and of satisfactory 100 %. CONCLUSION: We recommend leverage-assisted closed reduction as an option before open reduction in type IV SCHF, not only for gold standard management but also because of satisfactory outcomes and the low incidence of major complications. PMID- 27230233 TI - Comments on the paper "Gluteal muscle fibrosis with abduction contracture of the hip," published by Al Bayati M.A. and Kraidy B.K. PMID- 27230234 TI - Low HbA1c Levels and Mortality: The Story Is Not Over Yet.... PMID- 27230235 TI - Phronesis: Beyond the Research Ethics Committee-A Crucial Decision-Making Skill for Health Researchers During Community Research. AB - Health researchers conducting research in the community are often faced with unanticipated ethical issues that arise in the course of their research and that go beyond the scope of ethical approval by the research ethics committee. Eight expert researchers were selected through extreme intensity purposive sampling, because they are representative of unusual manifestations of the phenomenon related to their research in the community. They were selected to take part in a semi-structured focus group discussion on whether practical wisdom (phronesis) is used as a decision-making skill to solve unanticipated ethical issues during research in the community. Although the researchers were not familiar with the concept phronesis, it became obvious that it formed an integral part of their everyday existence and decision making during intervention research. They could balance research ethics with practical considerations. The capacity of practical wisdom as a crucial decision-making skill should be assimilated into a researcher's everyday reality, and also into the process of mentoring young researchers to become phronimos. Researchers should be taught this skill to handle unanticipated ethical issues. PMID- 27230236 TI - Production of para-aminobenzoic acid from different carbon-sources in engineered Saccharomyces cerevisiae. AB - BACKGROUND: Biological production of the aromatic compound para-aminobenzoic acid (pABA) is of great interest to the chemical industry. Besides its application in pharmacy and as crosslinking agent for resins and dyes pABA is a potential precursor for the high-volume aromatic feedstocks terephthalic acid and para phenylenediamine. The yeast Saccharomyces cerevisiae synthesises pABA in the shikimate pathway: Outgoing from the central shikimate pathway intermediate chorismate, pABA is formed in two enzyme-catalysed steps, encoded by the genes ABZ1 and ABZ2. In this study S. cerevisiae metabolism was genetically engineered for the overproduction of pABA. Using in silico metabolic modelling an observed impact of carbon-source on product yield was investigated and exploited to optimize production. RESULTS: A strain that incorporated the feedback resistant ARO4 (K229L) and deletions in the ARO7 and TRP3 genes, in order to channel flux to chorismate, was used to screen different ABZ1 and ABZ2 genes for pABA production. In glucose based shake-flaks fermentations the highest titer (600 uM) was reached when over-expressing the ABZ1 and ABZ2 genes from the wine yeast strains AWRI1631 and QA23, respectively. In silico metabolic modelling indicated a metabolic advantage for pABA production on glycerol and combined glycerol ethanol carbon-sources. This was confirmed experimentally, the empirical ideal glycerol to ethanol uptake ratios of 1:2-2:1 correlated with the model. A (13)C tracer experiment determined that up to 32% of the produced pABA originated from glycerol. Finally, in fed-batch bioreactor experiments pABA titers of 1.57 mM (215 mg/L) and carbon yields of 2.64% could be achieved. CONCLUSION: In this study a combination of genetic engineering and in silico modelling has proven to be a complete and advantageous approach to increase pABA production. Especially the enzymes that catalyse the last two steps towards product formation appeared to be crucial to direct flux to pABA. A stoichiometric model for carbon utilization proved useful to design carbon-source composition, leading to increased pABA production. The reported pABA concentrations and yields are, to date, the highest in S. cerevisiae and the second highest in a microbial production system, underlining the great potential of yeast as a cell factory for renewable aromatic feedstocks. PMID- 27230237 TI - A new quantitative radiographic measurement of patella for patellar instability using the lateral plain radiograph: 'patellar width ratio'. AB - PURPOSE: Patellar width ratio, a new measurement of anterior-posterior patellar width, was developed using lateral radiographs. The hypothesis was that patellar width ratio would increase with increasing patellar tilt angle and that patients with patellar instability would have larger patellar width ratio compared to controls. METHODS: Fifty knees who underwent surgery for patellar instability were enrolled as Group P. The fifty knees without patellar instability were enrolled as controls (Group C). Patellar width ratio was measured using preoperative lateral radiographs. The width between proximal and distal apexes of patella was defined as A. The width between anterior and posterior margins of patella was defined as B. Patellar width ratio was defined as the ratio B/A. Patellar tilt angle was measured on preoperative computed tomography images. Values were compared between groups and their correlation examined, and a receiver operating characteristic (ROC) curve was generated to identify the threshold value. RESULTS: Mean patellar width ratio in Groups C and P was 0.54 +/ 0.04 and 0.66 +/- 0.11 (P < 0.01). Mean patellar tilt angle in Groups C and P was 12.8 degrees +/- 4.9 degrees and 32.0 degrees +/- 10.3 degrees (P < 0.01). Patellar width ratio was strongly correlated with patellar tilt angle (R = 0.83, P < 0.01). For patellar width ratio, the area under ROC curve was 0.86, and the cut-off value was 0.59 (sensitivity 76.0 %, specificity 90.0 %). CONCLUSION: Patellar width ratio in Group P was significantly larger than in Group C. Patellar width ratio would allow clinicians to evaluate patellar tilt on lateral radiographs. LEVEL OF EVIDENCE: III. PMID- 27230239 TI - Do adults aged 70 years or older with acute myeloid leukemia benefit from allogeneic hematopoietic cell transplantation? PMID- 27230238 TI - RhBMP-2 Activates Hippo Signaling through RASSF1 in Esophageal Cancer Cells. AB - Despite that recombinant human bone morphogenetic protein-2 (rhBMP-2) has been reported as a stimulatory effecter of cancer cell growth because of its characteristic like morphogen, the biological functions of rhBMP-2 in human esophageal cancer cells are unknown. The purpose of this study was to investigate whether rhBMP-2 has an inhibitory effect on the growth of human esophageal squamous carcinoma cells (ESCC). RhBMP-2 significantly inhibited proliferation of ESCC cells in a dose-dependent manner in the MTT assay. Cell cycle arrest at the G1 phase was induced 24 h after rhBMP2 treatment. RhBMP-2 also reduced cyclin D1, cyclin-dependent kinase (CDK) 4 and CDK 6 activities, and stimulated p-Smad1/5/8, p53, and p21 levels at 12 h. In contrast, rhBMP-2 diminished poly (ADP-ribose) polymerase (PARP) protein expression levels and activated cleaved PARP, cleaved caspase-7, and cleaved-caspase 9 levels in ESCC cells. In addition, rhBMP-2 increased MST1, MOB1, and p-YAP protein levels and the RASSF1 binds Mst1 more upon treatment with rhBMP2. The induced p-YAP expression in TE-8 and TE-12 cells by rhBMP-2 was reversed by the RASSF1 knockdown. In vivo study, rhBMP-2 decreased tumor volume following subcutaneous implantation and showed higher radiologic score (less bony destruction) after femoral implantation compared to those in a control group. These results suggest that rhBMP-2 inhibits rather than activates proliferation of human esophageal cancer cells which is mediated through activating the hippo signaling pathway. PMID- 27230241 TI - Vitamin D supplementation in children with asthma. PMID- 27230242 TI - Christoph Gruber, 17.05.1960 - 10.01.2016. PMID- 27230243 TI - Experience with the GORE EXCLUDER iliac branch endoprosthesis for common iliac artery aneurysms. AB - OBJECTIVE: In this study, we analyzed the procedural success and early outcome of endovascular treatment of a multicenter cohort of patients with common iliac artery (CIA) aneurysms treated with the new GORE EXCLUDER (W. L. Gore & Associates, Flagstaff, Ariz) iliac branch endoprosthesis (IBE). METHODS: A retrospective cohort analysis was performed in 13 sites in The Netherlands. Anatomic, demographic, procedural, and follow-up data were assessed from hospital records. RESULTS: From November 2013 to December 2014, 51 CIA aneurysms were treated with an IBE in 46 patients. The median diameter of the treated aneurysm was 40.5 (range, 25.0-90.0) mm. The mean procedural time was 198 +/- 56 minutes. All but one implantation were successful; two type Ib endoleaks were noticed, resulting in a procedural success rate of 93.5%. The two type Ib endoleaks spontaneously disappeared at 30 days. There was no 30-day mortality. Ipsilateral buttock claudication was present in only two cases at 30 days and disappeared during follow-up. The incidence of reported erectile dysfunction was low and severe ischemic complications were absent. After a mean follow-up of 6 months, data on 17 treated aneurysms were available. Two showed a stable diameter, whereas 15 showed a mean decrease of 3.9 +/- 2.2 mm (P < .001). Reinterventions were performed in two patients (7.1%). The 6-month primary patency of the internal component of the IBE device was 94%. CONCLUSIONS: The use of the GORE EXCLUDER IBE device for CIA aneurysms is related to high procedural success, high patency rates, and low reintervention rates at short-term follow-up. Prospective data with longer follow-up are awaited to establish the role of the device in the treatment algorithm of CIA aneurysms. PMID- 27230245 TI - Streamliner Multilayer Flow Modulator for subacute complicated type B dissection using the phantom technique. PMID- 27230246 TI - Use of an endovascular graft converter for primary repair of a complex right aortoiliac aneurysm. PMID- 27230244 TI - Worldwide results from the RESTORE II on elective endografting of thoracic aneurysms and dissections. AB - OBJECTIVE: To assess safety, performance, and efficacy of the RELAY thoracic stent graft (Bolton Medical, Barcelona, Spain) in the treatment of patients who require elective thoracic endovascular aortic repair including aneurysms and dissections. METHODS: The RELAY Endovascular Registry for Thoracic Disease II (RESTORE II) is a multicenter, prospective, international cohort study involving 21 centers in 12 countries worldwide. All consecutively included patients underwent elective thoracic endovascular aortic repair with a RELAY or RELAY NBS stent graft (including off the shelf and custom-made devices) to repair thoracic aortic aneurysms or dissections. Demographic, clinical, and aortic parameters were Web-based registers. Safety and efficacy data were collected for a follow-up period of 24 months. RESTORE was a precedent registry involving European sites that used RELAY first-generation devices. RESULTS: A total of 173 patients were enrolled in the registry from October 2010 to September 2014 (aneurysm [n = 99]/dissection [n = 74]). Overall technical success of the intervention reached 97.1% irrespective of the etiology and geographic origin of patients. Baseline clinical heterogeneity was observed between devices concerning the etiology of the disease and certain comorbidities and/or risk factor distribution (diabetes, hypertension, myocardial infarction, angina pectoris). An average of 1.36 stent graft components were used per patient, with mean intended treatment length of 197.0 +/- 87.7/188.7 +/- 103.1 mm and mean access site diameter of 10.3 +/- 8.2/9.7 +/- 1.7 mm in aneurysms/dissections, respectively. The rate of all-cause 30-day mortality was lower than in the RESTORE registry (4.0% vs 7.2%). Perioperative neurologic complications were infrequent: paraplegia/paraparesis (2.9%) and stroke (0.6%) (vs 2.0% and 1.6% in the RESTORE registry). Freedom from all-cause mortality at 2 years was 93.6%. At the final completion angiography, device-associated complications were detected in 4.6% of the patients (vs 5.3% in the RESTORE) and endoleak rate was 6.4% (type I 5.8% and type II 1.7%). CONCLUSIONS: The worldwide results of the RESTORE II registry show the safety and effectiveness of RELAY and RELAY NBS stent grafts for elective endovascular thoracic aortic repair. Compared with the RESTORE registry, the device presents a lower rate of perioperative complications. PMID- 27230247 TI - The ethics of dysfunctional professional relationships. AB - Dr N, the chief surgeon at a large private hospital who has been practicing there for decades, has noted recent changes in the administration that are troubling. Multiple advertisements proclaim awards that have not been achieved and various ads employed actors pretending to be patients experiencing miracle cures. Pressures on medical staff to practice more efficiently have become overbearing. Changes in bundling Medicare postoperative care have raised questions about future patient selection. There is a lack of transparency with minimal physician input. The much respected chief-of-staff has moved into the administrative side and no longer advocates for the professionalism of the staff. When Dr N meets with the chief-of-staff and objects to these changes, the chief of staff calls Dr N a complainer and tells him to forget about it. Nothing is done. PMID- 27230248 TI - Regarding "A randomized controlled trial of interrupted versus continuous suturing techniques for radiocephalic fistulas". PMID- 27230249 TI - Regarding "One-year outcomes from the international multicenter study of the Zenith Alpha Thoracic Endovascular Graft for thoracic endovascular repair". PMID- 27230250 TI - Reply. PMID- 27230251 TI - Regarding "Exploring patient involvement in decision making for vascular procedures". PMID- 27230252 TI - Respiratory hypersensitivity reactions to NSAIDs in Europe: the global allergy and asthma network (GA2 LEN) survey. AB - BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most prevalent drugs inducing hypersensitivity reactions. The aim of this analysis was to estimate the prevalence of NSAID-induced respiratory symptoms in population across Europe and to assess its association with upper and lower respiratory tract disorders. METHODS: The GA2 LEN survey was conducted in 22 centers in 15 European countries. Each of 19 centers selected random samples of 5000 adults aged 15-74 from their general population, and in three centers (Athens, Munich, Oslo), a younger population was sampled. Questionnaires including questions about age, gender, presence of symptoms of asthma, allergic rhinitis, chronic rhinosinusitis, smoking status, and history of NSAID-induced hypersensitivity reactions were sent to participants by mail. Totally, 62 737 participants completed the questionnaires. RESULTS: The mean prevalence of NSAID-induced dyspnea was 1.9% and was highest in the three Polish centers [Katowice (4.9%), Krakow (4.8%), and Lodz (4.4%)] and lowest in Skopje, (0.9%), Amsterdam (1.1%), and Umea (1.2%). In multivariate analysis, the prevalence of respiratory reactions to NSAIDs was higher in participants with chronic rhinosinusitis symptoms (Odds Ratio 2.12; 95%CI 1.78-2.74), asthma symptoms in last 12 months (2.7; 2.18-3.35), hospitalization due to asthma (1.53; 1.22-1.99), and adults vs children (1.53; 1.24-1.89), but was not associated with allergic rhinitis. CONCLUSION: Our study documented significant variation between European countries in the prevalence of NSAID-induced respiratory hypersensitivity reactions, and association with chronic airway diseases, but also with environmental factors. PMID- 27230255 TI - Correction to Semiexperimental Equilibrium Structures for Building Blocks of Organic and Biological Molecules: The B2PLYP Route. PMID- 27230256 TI - Direct Metal-Free Entry to Aminocyclobutenes or Aminocyclobutenols from Ynamides: Synthetic Applications. AB - The [2+2] cycloaddition of ynamides with the highly polarized reagent Tf2 C=CH2 has been developed to regioselectively afford bis(triflyl)aminocyclobutenes in the absence of catalyst under mild conditions. Incidentally, with the ynamides bearing electron-rich aromatic rings at the C-terminal, an interesting reactivity switch was observed; a cyclization/hydroxylation sequence yielded 2-amino-3 (triflyl)cyclobut-2-enols. Aminocyclobutene construction with addition of alcohols resulted in the formation of aminocyclobutenyl ethers through a cyclization/hydroalkoxylation process. Moreover, the utility of functionalized aminocyclobutenes as precursors for further elaboration was demonstrated with the preparation of alpha-amino-beta,gamma-unsaturated ketones and 3-(triflyl)buta-1,3 dien-2-amines through 4 pi-electrocyclic ring opening. PMID- 27230254 TI - How Do Perceived Descriptive Norms Influence Indoor Tanning Intentions? An Application of the Theory of Normative Social Behavior. AB - Indoor tanning bed use is highly influenced by perceived norms about a tanned appearance. The theory of normative social behavior (TNSB) details the many ways in which norms can impact intentions and behavior, but has never been assessed in the context of indoor tanning. Considering this, we conducted a survey among female university students (N = 274) to determine the extent to which the TNSB predicted intentions to use indoor tanning beds. Overall, the path model predicted about 46% of the variance in intentions, and the majority of significant indirect effects were witnessed through the outcome expectation variables included in the TNSB, suggesting that these may be the most salient mechanisms-as predicted by the TNSB-through which norms can impact tanning intentions. In light of these results, theoretical and practical implications are discussed, and specific recommendations are given to extend the predictive utility of the TNSB in the context of indoor tanning. PMID- 27230253 TI - 3D Bioprinting for Vascularized Tissue Fabrication. AB - 3D bioprinting holds remarkable promise for rapid fabrication of 3D tissue engineering constructs. Given its scalability, reproducibility, and precise multi dimensional control that traditional fabrication methods do not provide, 3D bioprinting provides a powerful means to address one of the major challenges in tissue engineering: vascularization. Moderate success of current tissue engineering strategies have been attributed to the current inability to fabricate thick tissue engineering constructs that contain endogenous, engineered vasculature or nutrient channels that can integrate with the host tissue. Successful fabrication of a vascularized tissue construct requires synergy between high throughput, high-resolution bioprinting of larger perfusable channels and instructive bioink that promotes angiogenic sprouting and neovascularization. This review aims to cover the recent progress in the field of 3D bioprinting of vascularized tissues. It will cover the methods of bioprinting vascularized constructs, bioink for vascularization, and perspectives on recent innovations in 3D printing and biomaterials for the next generation of 3D bioprinting for vascularized tissue fabrication. PMID- 27230257 TI - PGE2 maintains self-renewal of human adult stem cells via EP2-mediated autocrine signaling and its production is regulated by cell-to-cell contact. AB - Mesenchymal stem cells (MSCs) possess unique immunomodulatory abilities. Many studies have elucidated the clinical efficacy and underlying mechanisms of MSCs in immune disorders. Although immunoregulatory factors, such as Prostaglandin E2 (PGE2), and their mechanisms of action on immune cells have been revealed, their effects on MSCs and regulation of their production by the culture environment are less clear. Therefore, we investigated the autocrine effect of PGE2 on human adult stem cells from cord blood or adipose tissue, and the regulation of its production by cell-to-cell contact, followed by the determination of its immunomodulatory properties. MSCs were treated with specific inhibitors to suppress PGE2 secretion, and proliferation was assessed. PGE2 exerted an autocrine regulatory function in MSCs by triggering E-Prostanoid (EP) 2 receptor. Inhibiting PGE2 production led to growth arrest, whereas addition of MSC-derived PGE2 restored proliferation. The level of PGE2 production from an equivalent number of MSCs was down-regulated via gap junctional intercellular communication. This cell contact-mediated decrease in PGE2 secretion down-regulated the suppressive effect of MSCs on immune cells. In conclusion, PGE2 produced by MSCs contributes to maintenance of self-renewal capacity through EP2 in an autocrine manner, and PGE2 secretion is down-regulated by cell-to-cell contact, attenuating its immunomodulatory potency. PMID- 27230259 TI - What Donald Trump would do with the US healthcare system. PMID- 27230260 TI - Stabilization of a Zn(ii) hydrosulfido complex utilizing a hydrogen-bond accepting ligand. AB - Hydrogen sulfide (H2S) has gained recent attention as an important biological analyte that interacts with bioinorganic targets. Despite this importance, stable H2S or HS(-) adducts of bioinorganic metal complexes remain rare due to the redox activity of sulfide and its propensity to form insoluble metal sulfides. We report here reversible coordination of HS(-) to Zn(didpa)Cl2, which is enabled by an intramolecular hydrogen bond between the zinc hydrosulfido product and the pendant tertiary amine of the didpa ligand. PMID- 27230258 TI - The use of mass spectrometry for analysing metabolite biomarkers in epidemiology: methodological and statistical considerations for application to large numbers of biological samples. AB - Data quality is critical for epidemiology, and as scientific understanding expands, the range of data available for epidemiological studies and the types of tools used for measurement have also expanded. It is essential for the epidemiologist to have a grasp of the issues involved with different measurement tools. One tool that is increasingly being used for measuring biomarkers in epidemiological cohorts is mass spectrometry (MS), because of the high specificity and sensitivity of MS-based methods and the expanding range of biomarkers that can be measured. Further, the ability of MS to quantify many biomarkers simultaneously is advantageously compared to single biomarker methods. However, as with all methods used to measure biomarkers, there are a number of pitfalls to consider which may have an impact on results when used in epidemiology. In this review we discuss the use of MS for biomarker analyses, focusing on metabolites and their application and potential issues related to large-scale epidemiology studies, the use of MS "omics" approaches for biomarker discovery and how MS-based results can be used for increasing biological knowledge gained from epidemiological studies. Better understanding of the possibilities and possible problems related to MS-based measurements will help the epidemiologist in their discussions with analytical chemists and lead to the use of the most appropriate statistical tools for these data. PMID- 27230261 TI - A dual molecular analogue tuner for dissecting protein function in mammalian cells. AB - Loss-of-function studies are fundamental for dissecting gene function. Yet, methods to rapidly and effectively perturb genes in mammalian cells, and particularly in stem cells, are scarce. Here we present a system for simultaneous conditional regulation of two different proteins in the same mammalian cell. This system harnesses the plant auxin and jasmonate hormone-induced degradation pathways, and is deliverable with only two lentiviral vectors. It combines RNAi mediated silencing of two endogenous proteins with the expression of two exogenous proteins whose degradation is induced by external ligands in a rapid, reversible, titratable and independent manner. By engineering molecular tuners for NANOG, CHK1, p53 and NOTCH1 in mammalian stem cells, we have validated the applicability of the system and demonstrated its potential to unravel complex biological processes. PMID- 27230262 TI - Hospitalization and other risk factors for depressive and anxious symptoms in oncological and non-oncological patients. AB - OBJECTIVE: Depression and anxiety are common in hospitalized patients. In particular, oncological patients might be vulnerable to depression and anxiety. The aim of this study is to assess and compare different variables and the prevalence of anxiety and depression symptoms between oncological and medically ill inpatients and to identify variables that can influence depressive and anxious symptoms during hospitalization of patients. METHODS: A total of 360 consecutive hospitalized patients completed the following questionnaires: Hospital Anxiety and Depression Scale (HADS), Patients Health Questionnaire-9, General Health Questionnaire (GHQ-12), 12-Item Short-Form Survey: physical component summary (PCS), and mental component summary (MCS). Patients were divided into oncological patients and non-oncological patients: groups 1 and 2. RESULTS: Only two significant differences were evident between the groups: the PCS of 12-item Short-form Survey was higher in non-oncological patient (p < 0.000), and the GHQ total score was higher in oncological patients. Variables significantly associated with HADS-D >= 8 were lower MCS, higher GHQ-12 score, lower PCS, more numerous previous hospitalizations, longer duration of hospitalization, and positive psychiatric family history. Variables significantly associated with HADS-A >= 8 were lower MCS, higher GHQ-12 score, positive psychiatric family history, longer duration of hospitalization, and younger age. CONCLUSIONS: Anxiety and depression symptoms in concurrent general medical conditions were associated with a specific sociodemographic profile, and this association has implications for clinical care. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27230263 TI - Carboxy-terminal mutations of bile acid CoA:N-acyltransferase alter activity and substrate specificity. AB - Bile acid CoA:amino acid N-acyltransferase (BAAT) is the terminal enzyme in the synthesis of bile salts from cholesterol and catalyzes the conjugation of taurine or glycine to bile acid CoA thioesters to form bile acid N-acylamidates. BAAT has a dual localization to the cytosol and peroxisomes, possibly due to an inefficient carboxy-terminal peroxisomal targeting signal (PTS), -serine glutamine-leucine (-SQL). Mutational analysis was used to define the role of the carboxy terminus in peroxisomal localization and kinetic activity. Amidation activity of BAAT and BAAT lacking the final two amino acids (AAs) (BAAT-S) were similar, whereas the activity of BAAT with a canonical PTS sequence (BAAT-SKL) was increased >2.5-fold. Kinetic analysis of BAAT and BAAT-SKL showed that BAAT SKL had a lower Km for taurine and glycine as well as a greater Vmax There was no difference in the affinity for cholyl-CoA. In contrast to BAAT, BAAT-SKL forms bile acid N-acylamidates with beta-alanine. BAAT-S immunoprecipitated when incubated with peroxisomal biogenesis factor 5 (Pex5) and rabbit anti-Pex5 antibodies; however, deleting the final 12 AAs prevented coimmunoprecipitation with Pex5, indicating the Pex5 interaction involves more than the -SQL sequence. These results indicate that even small changes in the carboxy terminus of BAAT can have significant effects on activity and substrate specificity. PMID- 27230264 TI - Cross-validation to select Bayesian hierarchical models in phylogenetics. AB - BACKGROUND: Recent developments in Bayesian phylogenetic models have increased the range of inferences that can be drawn from molecular sequence data. Accordingly, model selection has become an important component of phylogenetic analysis. Methods of model selection generally consider the likelihood of the data under the model in question. In the context of Bayesian phylogenetics, the most common approach involves estimating the marginal likelihood, which is typically done by integrating the likelihood across model parameters, weighted by the prior. Although this method is accurate, it is sensitive to the presence of improper priors. We explored an alternative approach based on cross-validation that is widely used in evolutionary analysis. This involves comparing models according to their predictive performance. RESULTS: We analysed simulated data and a range of viral and bacterial data sets using a cross-validation approach to compare a variety of molecular clock and demographic models. Our results show that cross-validation can be effective in distinguishing between strict- and relaxed-clock models and in identifying demographic models that allow growth in population size over time. In most of our empirical data analyses, the model selected using cross-validation was able to match that selected using marginal likelihood estimation. The accuracy of cross-validation appears to improve with longer sequence data, particularly when distinguishing between relaxed-clock models. CONCLUSIONS: Cross-validation is a useful method for Bayesian phylogenetic model selection. This method can be readily implemented even when considering complex models where selecting an appropriate prior for all parameters may be difficult. PMID- 27230265 TI - Comparing medicine and management: methodological issues. AB - BACKGROUND: In the study of medicine and management, there is a strong interest in cross-country comparison. Across healthcare systems in industrialised countries, New Public Management has provided a similar reform template, but new governing arrangements exhibit significant national variations. The comparative perspective also offers a leverage to overcome the resistance focus of earlier studies. Comparison raises two overall questions: in what similar and different ways are relations between medicine and management changing across industrialised countries? Why is change occurring in different ways? The questions reflect exploration and explanation as the two basic rationales for comparison. METHODS: The aim was to provide a critical discussion of different approaches to comparing medicine and management across countries. The analysis was based on a narrative review of relevant studies from several bodies of literature. RESULTS AND DISCUSSION: The majority of studies exploring medicine and management adopt macro level approaches to comparison. Studies draw on a range of notions, including area specific ideal types of professionalism, professionalism as countervailing powers and governmentality. There are much fewer studies exploring relations between medicine and management at the meso level. Analyses treat comparison as a two-dimensional exercise looking across both countries and levels. The majority of studies draws on institutional explanations. These are variations of the path dependency argument and studies include both sector specific and broader political and administrative institutions. There is an emerging body of process based explanations which connect macro level institutions to organisations and which promote more non-linear comparisons. CONCLUSION: The lack of meso level comparisons drawing on process explanations is problematic. Empirically, we need to know more about how relations between medicine and management are different across countries. Theoretically, we need to better understand how we can transpose analytical insights from institutional explanations at macro level to studies that are multi-level and also include the meso level of organisations. Methodologically, we need to address the challenges arising from more non-linear approaches to comparison, especially how to organise close international research collaboration over an extended period of time. PMID- 27230266 TI - Effect of estrogen on visceral sensory function in a non-inflammatory colonic hypersensitivity rat model. AB - BACKGROUND: Increased prevalence of functional gastrointestinal disorders in women and perimenstrually accentuated symptoms imply that sexual hormones play a crucial role in the pathogenesis of such syndromes. The aim of this study was to analyze the selective effect of estrogen on visceral sensitivity in gonadectomized female and male Lewis rats with or without prior treatment with butyrate enemas. METHODS: Following ovariectomy (OVX) or orchiectomy (ORX) estradiol pellets (E2-P) or sham pellets (Sham-P) were implanted. After treatment with butyrate (BUT) or saline (NaCl) enemas, colorectal distensions (CRD) were performed and the visceromotor reflex (VMR) to CRD was measured by electromyography. KEY RESULTS: Gender did not influence VMR to CRD in gonadectomized animals. VMR in E2-P animals compared to Sham-P animals was increased (635 +/- 32 MUVs vs 470 +/- 39 MUVs; p = 0.002). Overall, instillation of butyrate enemas did not influence VMR to CRD. A comparison of CRD clusters showed that butyrate enemas in the E2-P animals resulted in a significant sensitization in both OVX and ORX animals. In female rats, sensitization was also caused by estrogen substitution alone. CONCLUSION & INFERENCES: In our animal model, estrogen is a strong factor for an increase in visceral sensory function. Surprisingly, the treatment with butyrate alone did not evoke a general rise in VMR to CRD. Rats treated with butyrate enemas and under selective estrogen substitution developed visceral sensitization during the series of CRDs. PMID- 27230267 TI - Patient-Reported Safety Events in Chronic Kidney Disease Recorded With an Interactive Voice-Inquiry Dial-Response System: Monthly Report Analysis. AB - BACKGROUND: Monitoring patient-reported outcomes (PROs) may improve safety of chronic kidney disease (CKD) patients. OBJECTIVE: Evaluate the performance of an interactive voice-inquiry dial-response system (IVRDS) in detecting CKD-pertinent adverse safety events outside of the clinical environment and compare the incidence of events using the IVDRS to that detected by paper diary. METHODS: This was a 6-month study of Stage III-V CKD patients in the Safe Kidney Care (SKC) study. Participants crossed over from a paper diary to the IVDRS for recording patient-reported safety events defined as symptoms or events attributable to medications or care. The IVDRS was adapted from the SKC paper diary to record event frequency and remediation. Participants were auto-called weekly and permitted to self-initiate calls. Monthly reports were reviewed by two physician adjudicators for their clinical significance. RESULTS: 52 participants were followed over a total of 1384 weeks. 28 out of 52 participants (54%) reported events using the IVDRS versus 8 out of 52 (15%) with the paper diary; hypoglycemia was the most common event for both methods. All IVDRS menu options were selected at least once except for confusion and rash. Events were reported on 121 calls, with 8 calls reporting event remediation by ambulance or emergency room (ER) visit. The event rate with the IVDRS and paper diary, with and without hypoglycemia, was 26.7 versus 4.7 and 18.3 versus 0.8 per 100 person weeks, respectively (P=.002 and P<.001). The frequent users (ie, >10 events) largely differed by method, and event rates excluding the most frequent user of each were 16.9 versus 2.5 per 100 person weeks, respectively (P<.001). Adjudicators found approximately half the 80 reports clinically significant, with about a quarter judged as actionable. Hypoglycemia was often associated with additional reports of fatigue and falling. Participants expressed favorable satisfaction with the IVDRS. CONCLUSIONS: Use of the IVDRS among CKD patients reveals a high frequency of clinically significant safety events and has the potential to be used as an important supplement to clinical care for improving patient safety. PMID- 27230268 TI - Behavioral Determinants of Switching to Arsenic-Safe Water Wells. AB - More than 100 million people globally are estimated to be exposed to arsenic in drinking water that exceeds the World Health Organization guideline of 10 ug/L. In an effort to develop and test a low-cost sustainable approach for water arsenic testing in Bangladesh, we conducted a randomized controlled trial which found arsenic educational interventions when combined with fee-based water arsenic testing programs led to nearly all households buying an arsenic test for their drinking water sources (93%) compared with only 53% when fee-based arsenic testing alone was offered. The aim of the present study was to build on the findings of this trial by investigating prospectively the psychological factors that were most strongly associated with switching to arsenic-safe wells in response to these interventions. Our theoretical framework was the RANAS (risk, attitude, norm, ability, and self-regulation) model of behavior change. In the multivariate logistic regression model of 285 baseline unsafe well users, switching to an arsenic-safe water source was significantly associated with increased instrumental attitude (odds ratio [OR] = 9.12; 95% confidence interval [CI] = [1.85, 45.00]), descriptive norm (OR = 34.02; 95% CI = [6.11, 189.45]), coping planning (OR = 11.59; 95% CI = [3.82, 35.19]), and commitment (OR = 10.78; 95% CI = [2.33, 49.99]). In addition, each additional minute from the nearest arsenic-safe drinking water source reduced the odds of switching to an arsenic safe well by more than 10% (OR = 0.89; 95% CI = [0.87, 0.92]). Future arsenic mitigation programs should target these behavioral determinants of switching to arsenic-safe water sources. PMID- 27230269 TI - Evaluating the Impact of U.S. Food and Drug Administration-Proposed Nutrition Facts Label Changes on Young Adults' Visual Attention and Purchase Intentions. AB - BACKGROUND: The U.S. Food and Drug Administration (FDA) has proposed modifying the Nutrition Facts Label (NFL) on food packages to increase consumer attention to this resource and to promote healthier dietary choices. AIMS: The present study sought to determine whether the proposed NFL changes will affect consumer attention to the NFL or purchase intentions. METHOD: This study compared purchase intentions (yes/no responses to "would you purchase this food?" for 64 products) and attention to NFLs (measured via high-speed eye-tracking camera) among 155 young adults randomly assigned to view products with existing versus modified NFLs. Attention to all individual components of the NFL (e.g., calories, fats, sugars) were analyzed separately to assess the impact of each proposed NFL modification on attention to that region. Data were collected in 2014; analysis was conducted in 2015. RESULTS: Modified NFLs did not elicit significantly more visual attention or lead to more healthful purchase intentions than did existing NFLs. Relocating the percent daily value component from the right side of the NFL to the left side, as proposed by the FDA, actually reduced participants' attention to this information. The proposed "added sugars" component was viewed on at least one label by a majority (58%) of participants. DISCUSSION: Results suggest that the proposed NFL changes may not achieve FDA's goals. Changes to nutrition labeling may need to take a different form to meaningfully influence dietary behavior. CONCLUSION: Young adults' visual attention and purchase intentions do not appear to be meaningfully affected by the proposed NFL modifications. PMID- 27230270 TI - Temporal Changes in the Correlates of U.S. Adolescent Electronic Cigarette Use and Utilization in Tobacco Cessation, 2011 to 2013. AB - OBJECTIVE: To examine temporal changes in the correlates of experimental and current e-cigarette use and associations with tobacco quit attempts. METHOD: Repeated cross-sectional analyses of data from the 2011 ( n = 17,741), 2012 ( n = 23,194), and 2013 ( n = 16,858) National Youth Tobacco Surveys-a nationally representative sample of U.S. middle and high school students. Respondents were asked about lifetime and past-month e-cigarette use, conventional cigarette use, and number of quit attempts made in the prior year among current smokers. RESULTS: Multinomial logistic regression models indicate higher odds of experimental or current e-cigarette use versus abstinence in the 2012 and 2013 survey years (vs. 2011). Respondents in the 2013 survey were more likely to use e cigarettes in 2012, and they were significantly more likely to be current versus experimental users. Temporal increases in past-month e-cigarette use were uneven across demographic subgroups. Among current smokers of conventional cigarettes, fully adjusted models show that across all survey years the probability of past month e-cigarette use was not significantly different for those who attempted to quit using tobacco in the past year from those who did not. CONCLUSIONS: Adolescent e-cigarette use has become more common between 2011 and 2013 and shows signs of becoming increasingly characterized by current rather than experimental use. Temporal patterns suggest that recent population increases were initially driven by select subgroups (e.g., Whites), with other subgroups contributing to the increase more recently (e.g., Black). Tobacco cessation has remained unrelated to current e-cigarette use over time, suggesting that e-cigarette use may be contributing to increased nicotine use. PMID- 27230271 TI - Longitudinal Associations Between Observed and Perceived Neighborhood Food Availability and Body Mass Index in a Multiethnic Urban Sample. AB - INTRODUCTION: Blacks, Hispanics, and women of lower socioeconomic status tend to have a higher risk of obesity. Numerous studies over the past decade examined the role of the neighborhood food environment in body weight. However, few were longitudinal. PURPOSE: This longitudinal study examined whether multiple measures of neighborhood food availability were associated with body mass index (BMI) in a predominately Black and Hispanic adult sample living in low- to moderate-income urban neighborhoods. METHOD: This longitudinal study used two waves of data (2002, 2008), including interviewer-measured height and weight, from a community survey of adults ( n = 219). In both 2002 and 2008, multiple measures characterized neighborhood food availability: GIS-derived availability of retail food outlets (large grocery store, small grocery store, convenience store, liquor stores), observed fruit and vegetable availability (count of stores selling 10 or more fresh fruit or vegetable varieties), and perceived fruit and vegetable access. Random intercept models estimated multivariable associations, controlling for individual-level demographics and neighborhood median household income. RESULTS: Small grocery store availability was associated with 1.22-unit increase in BMI ( p = .047), while each unit increase in perceived fruit and vegetable access was associated with a 0.69-unit decrease in BMI ( p = .055). BMI was not associated with large grocery store, convenience store, or liquor store availability, or with observed fruit and vegetable availability. CONCLUSIONS: Findings suggest that improving the neighborhood food environment, particularly at small grocery stores, may help urban residents living in low- to moderate income neighborhoods achieve healthier body weights over time. PMID- 27230272 TI - Stakeholder Perspectives on Creating and Maintaining Trust in Community-Academic Research Partnerships. AB - Community-academic research partnerships aim to build stakeholder trust in order to improve the reach and translation of health research, but there is limited empirical research regarding effective ways to build trust. This multisite study was launched to identify similarities and differences among stakeholders' perspectives of antecedents to trust in research partnerships. In 2013-2014, we conducted a mixed-methods concept mapping study with participants from three major stakeholder groups who identified and rated the importance of different antecedents of trust on a 5-point Likert-type scale. Study participants were community members ( n = 66), health care providers ( n = 38), and academic researchers ( n = 44). All stakeholder groups rated "authentic communication" and "reciprocal relationships" the highest in importance. Community members rated "communication/methodology to resolve problems" ( M = 4.23, SD = 0.58) significantly higher than academic researchers ( M = 3.87, SD = 0.67) and health care providers ( M = 3.89, SD = 0.62; p < .01) and had different perspectives regarding the importance of issues related to "sustainability." The importance of communication and relationships across stakeholders indicates the importance of colearning processes that involve the exchange of knowledge and skills. The differences uncovered suggest specific areas where attention and skill building may be needed to improve trust within partnerships. More research on how partnerships can improve communication specific to problem solving and sustainability is merited. PMID- 27230273 TI - Efficacy of Trimetazidine Dihydrochloride for Relieving Chronic Tinnitus: A Randomized Double-Blind Study. AB - OBJECTIVES: To evaluate the efficacy of trimetazidine dihydrochloride as a treatment for chronic tinnitus. METHODS: A total of 97 chronic tinnitus patients were evaluated in this randomized, prospective, double-blind, placebo-controlled trial. After assessing for eligibility, 82 patients were randomly assigned into placebo or trimetazidine groups according to the medication. The trimetazidine group received 20*3 mg/day per oral trimetazidine dihydrochloride and the placebo group received 20*3 mg/day per oral placebo for 3 months. Tinnitus handicap inventory (THI), visual analogue scale (VAS) questionnaires and audiometric results were used to determine the effectiveness of trimetazidine treatment. RESULTS: The study group comprised 82 tinnitus subjects, 42 (51%) of whom received trimetazidine dihydrochloride and 40 (49%) who received placebo. There was no significant difference between placebo and trimetazidine groups in THI grade and VAS (both pre- and posttreatment scores) (P>0.05) and no significant improvement was observed in subjective loudness score in either group (P>0.05). Additionally there was no significant difference between groups in pre- and posttreatment pure tone hearing thresholds at all measured frequencies (P>0.05). CONCLUSION: Trimetazidine dihydrochloride therapy was ineffective for relieving chronic tinnitus. PMID- 27230274 TI - Effect of Septoplasty on Voice Quality: A Prospective-Controlled Trial. AB - OBJECTIVES: The purpose is to investigate effect of septoplasty and widened nasal patency on voice quality. METHODS: Fifty patients who undergone septoplasty were included in the study. Thirty-three people who had similar age and distribution were enrolled as control group. Before and 1 and 3 months after surgery, anterior rhinomanometry, voice analysis by Multi-Dimensional Voice Program, and spectrographic analysis were performed to patients. The recordings of /a/ vowel were used to evaluate average fundamental frequency (F0), jitter percent, and shimmer percent. In spectrographic analyses, F3-F4 values for the vowels /i, e, a, o, and u/, nasal formant frequencies of the consonants /m/ and /n/ in the word /mini/, and 4 formant frequencies (F1, F2, F3, and F4) for nasalized /i/ vowel following a nasal consonant /n/ in the word /mini/ were compared. The differences in nasal resonance were evaluated. All patients were asked whether change in their voices after the surgery. Preoperative and postoperative voice parameters and anterior rhinomanometry results were compared separately with the control group as well as in the patient group itself. RESULTS: Preoperative total nasal resistance (TNR) values of patients were higher than the control group (P=0.001). TNR values of patients measured one day before surgery and after surgery in the 1st and 3rd months were different and these differences were significant statistically (P=0.001). There was no significant difference between the voice analysis parameters in preoperative, postoperative 1st, and 3rd months. As a result of their subjective reviews, 12 patients (36%) noted their voices were better than before surgery and 20 patients (61%) noted no change before and after surgery. CONCLUSION: Providing widened nasal cavity has no effect on voice quality. PMID- 27230275 TI - Recurrent mild cerebral ischemia: enhanced brain injury following acute compared to subacute recurrence in the rat. AB - BACKGROUND: In the current study, a transient cerebral ischemia producing selective cell death was designated a mild ischemic insult. A comparable insult in humans is a transient ischemic attack (TIA) that is associated with functional recovery but can have imaging evidence of minor ischemic damage including cerebral atrophy. A TIA also predicts a high risk for early recurrence of a stroke or TIA and thus multiple ischemic insults are not uncommon. Not well understood is what the effect of differing recovery times between mild ischemic insults has on their pathophysiology. We investigated whether cumulative brain damage would differ if recurrence of a mild ischemic insult occurred at 1 or 3 days after a first insult. RESULTS: A transient episode of middle cerebral artery occlusion via microclip was produced to elicit mild ischemic changes predominantly scattered necrosis. This was followed 1 or 3 days later by a repeat of the same insult. Brain damage assessed histologically 7 days later was substantially greater in the 1 day recurrent group than the 3 days recurrent group, with areas of damage consisting predominantly of regions of incomplete infarction and pannecrosis in the 1 day group but predominantly regions of selective necrosis and smaller areas of incomplete infarction in the 3 days group (P < 0.05). Enhanced injury was reflected by greater number of cells staining for macrophages/microglia with ED1 and greater alterations in GFAP staining of reactive astrocytes in the 1 day than 3 days recurrent groups. The differential susceptibility to injury did not correspond to higher levels of injurious factors present at the time of the second insult such as BBB disruption or increased cytokines (tumor necrosis factor). Microglial activation, with potential for some beneficial effects, appeared greater at 3 days than 1 day. Also blood analysis demonstrated changes that included an acute increase in granulocytes and decrease in platelets at 1 day compared to 3 days post transient ischemia. CONCLUSIONS: Dynamic changes in multiple inflammatory responses likely contribute to the time dependence of the extent of damage produced by recurrent mild ischemic insults. The time of mild stroke recurrence is crucial with early recurrence producing greater damage than subacute recurrence and this supports urgency for determining and implementing optimal stroke management directly after a TIA. PMID- 27230276 TI - Hypofractionated radiation therapy for breast cancer: long-term results in a series of 85 patients. AB - PURPOSE: Whole-breast irradiation after conservative surgery is the standard treatment for early breast cancer. The purpose of this study is to report the late toxicity, cosmetic result, and disease control in a group of patients treated with hypofractionated radiotherapy (RT) comparing results with retrospective data of a control group who underwent conventional RT. METHODS: From 2006 to 2008, 85 patients were treated with hypofractionated schedule to dose of 45 Gy, 2.25 Gy/fr, followed by a boost. We evaluated late toxicity, cosmetic result, and disease control. The data were compared to a control group of 70 patients who underwent conventional RT before 2006. RESULTS: At 8 years of follow-up, the cumulative incidence of late skin toxicity was 6.2 in the hypofractionated RT group and 7.5 in the standard RT group (p = 0.94). The cumulative incidence of late subcutaneous tissue toxicity was 11.6 in the hypofractionated RT group and 18.7 in the standard RT group (p = 0.23). Cosmetic outcome was rated as excellent or good in 84/85 patients of the hypofractionated RT group and in 68/70 patients of the conventional RT group (p = 0.7). No statistically significant differences were found in terms of local control (p = 0.05), disease-free survival (p = 0.06), or overall survival (p = 0.17) between the 2 groups. CONCLUSIONS: The present analysis, focused on long-term effects, disease control, and survival, confirms, in a daily practice setting, the low incidence of skin atrophy and fibrosis, the satisfactory cosmetic outcome, and the high grade of local and distant disease control with hypofractionated schedule. PMID- 27230277 TI - Transthoracically or transabdominally: how to approach adenocarcinoma of the distal esophagus and cardia. A meta-analysis. AB - Esophageal carcinoma is the eighth most frequent cancer worldwide and the sixth cancer-related cause of death. Here we propose a new meta-analysis to identify the most appropriate approach for resectable adenocarcinoma of the distal esophagus and cardia (Siewert 1-2). A systematic literature search was performed independently by 2 of the manuscript's authors using PubMed, EMBASE, Scopus and the Cochrane Library Central. The following criteria were set for inclusion in this meta-analysis: 1) studies comparing transthoracic esophagectomy and transhiatal esophagectomy for adenocarcinoma of the esophagus; 2) studies reporting at least 1 perioperative outcome; and 3) if more than 1 study was reported by the same institute, only the most recent or the highest quality study was included. A total of 6 articles dated between 1996 and 2012 fulfilled the selection criteria and were therefore included in this meta-analysis; this pool of articles consisted of 2 prospective and 4 retrospective studies. A statistically significant difference favoring the transthoracic procedure was noted regarding the number of retrieved lymph nodes, 5-year disease-free survival rate and 5-year overall survival rate (p = 0.001, p = 0.05 and p = 0.03, respectively). In conclusion, transthoracic esophagectomy for adenocarcinoma of the distal esophagus and esophagogastric junction (Siewert 1-2) appears to be superior to the transhiatal approach in terms of oncological outcomes. PMID- 27230278 TI - Reductive nitrosylation of nickel(ii) complex by nitric oxide followed by nitrous oxide release. AB - Ni(ii) complex of ligand ( = bis(2-ethyl-4-methylimidazol-5-yl)methane) in methanol solution reacts with an equivalent amount of NO resulting in a corresponding Ni(i) complex. Adding further NO equivalent affords a Ni(i) nitrosyl intermediate with the {NiNO}(10) configuration. This nitrosyl intermediate upon subsequent reaction with additional NO results in the release of N2O and formation of a Ni(ii)-nitrito complex. Crystallographic characterization of the nitrito complex revealed a symmetric eta(2)-O,O-nitrito bonding to the metal ion. This study demonstrates the reductive nitrosylation of a Ni(ii) center followed by N2O release in the presence of excess NO. PMID- 27230280 TI - Epithelial-mesenchymal transition, proliferation, and angiogenesis in locally advanced cervical cancer treated with chemoradiotherapy. AB - We evaluated the association between epithelial-mesenchymal transition (EMT) derived markers and expression of proteins associated with cell proliferation and tumor growth, as well as their prognostic roles, in 61 patients (mean age 52 +/- 10 years) with locally advanced cervical cancer, all of whom were treated with chemoradiation and intracavitary brachytherapy. We used immunohistochemical analysis to assess the expression of proteins targeted in our investigation. Various statistical analyses were then conducted to assess protein marker associations with survival outcomes. Forty-six percent of the patients were positive for human papilloma virus. Median progression-free survival (PFS) was 6.6 months (95% confidence interval [CI]: 4.0-9.1, whereas overall survival (OS) was 30.0 months (95% CI: 11-48). Multivariate analysis demonstrated that vascular endothelial growth factor (VEGF) (P = 0.002), epidermal growth factor receptor (EGFR) (P = 0.001), and TWIST2 (P = 0.001) expression levels, as well as a tumor size <6 cm (P = 0.02), influenced OS. Changes in TWIST2 levels and loss of E cadherin expression were correlated with VEGF and EGFR levels; furthermore, patients with high TWIST2 expression had shorter OS (P = 0.0001), as those with loss of E-cadherin (P = 0.02). OS was even shorter when positive EGFR or VEGF expression was related with EMT markers (positive EGFR + negative E-cadherin: median 14 months, 95% CI: 3-24; negative EGFR + positive E-cadherin: median 31 months, 95% CI: 14-NA; P = 0.02.). The presence of EMT markers was associated with proliferative and pro-angiogenic protein expression and influenced the prognosis of locally advanced cervical cancer. PMID- 27230279 TI - Elevated MTSS1 expression associated with metastasis and poor prognosis of residual hepatitis B-related hepatocellular carcinoma. AB - BACKGROUND: Hepatectomy generally offers the best chance of long-term survival for patients with hepatocellular carcinoma (HCC). Many studies have shown that hepatectomy accelerates tumor metastasis, but the mechanism remains unclear. METHODS: An orthotopic nude mice model with palliative HCC hepatectomy was performed in this study. Metastasis-related genes in tumor following resection were screened; HCC invasion, metastasis, and some molecular alterations were examined in vivo and in vitro. Clinical significance of key gene mRNA expression was also analyzed. RESULTS: Metastasis suppressor 1 (MTSS1) located in the central position of gene function net of residual HCC. MTSS1 was up-regulated in residual tumor after palliative resection. In hepatitis B-related HCC patients undergone palliative hepatectomy, those with higher MTSS1 mRNA expression accompanied by activation of matrix metalloproteinase 2 (MMP2) in residual HCC, had earlier residual HCC detection after hepatectomy and poorer survival when compared to those with lower MTSS1. In different cell lines, the levels of MTSS1 mRNA increased in parallel with metastatic potential. MTSS1 down regulation via siRNA decreased MMP2 activity, reduced invasive potentials of HCC by 28.9 % in vitro, and averted the deteriorated lung metastatic extent in vivo. CONCLUSIONS: The poor prognosis of hepatitis B-related HCC patients following palliative hepatectomy associates with elevated MTSS1 mRNA expression; therefore, MTSS1 may provide a new research field for HCC diagnosis and treatment. PMID- 27230281 TI - Alcohol in urban streetscapes: a comparison of the use of Google Street View and on-street observation. AB - BACKGROUND: Alcohol-related harm is a major global health issue, and controls on alcohol marketing are one intervention utilized by governments. This study investigated the use of Google Street View (GSV) as a novel research method for collecting alcohol-related data in the urban environment. METHODS: The efficacy of GSV and on-street observation by observer teams was compared by surveying 400 m stretches of 12 streets in Wellington, the capital city of New Zealand. Data on alcohol sale, alcohol-related advertising, health promotion materials, regulatory information and visible alcohol consumption were collected. RESULTS: A total of 403 retailers with evidence of alcohol sales and 1161 items of alcohol-related communication were identified in on-street observation. Of the latter, 1028 items (89 %) were for alcohol marketing and 133 (11 %) were for alcohol-related health promotion and alcohol regulation. GSV was found to be a less sensitive tool than on-street observation with only 50 % of the alcohol venues identified and 52 % of the venue-associated brand marketing identified. A high degree of inter-observer reliability was generally found between pairs of observers e.g., for the detection of alcohol retail venues the intra-class correlation coefficient (ICC) was 0.93 (95 % CI: 0.78 to 0.98) for on-street observation and 0.85 (95 % CI: 0.49 to 0.96) for using GSV. CONCLUSIONS: GSV does not seem suitable for the comprehensive study of the influences on alcohol consumption in the urban streetscape. However, it may still have value for large, static objects in the environment and be more time efficient than traditional on-street observation measures, especially when used to collect data across a wide geographical area. Furthermore, GSV might become a more useful research tool in settings with better image quality (such as more 'footpath views') and with more regularly updated GSV imagery. PMID- 27230282 TI - Late Cardiotoxicity: Issues for Childhood Cancer Survivors. AB - OPINION STATEMENT: Cardiovascular-related morbidity is a substantial health burden in survivors of childhood cancers. This burden is gaining importance as this population increases through advancements in therapy. Anthracyclines are commonly used agents that are known to cause late cardiotoxicity. Cardiotoxicity is also increased by other risk factors, such as concurrent radio- or chemotherapy, younger age at diagnosis, female sex, comorbidities, lifestyle factors, and genetic factors, such as hemochromatosis gene mutations. Treatment of late cardiotoxicity depends on the type of cardiac abnormalities and consists of pharmacotherapy, mechanical support, or heart transplantation. Because cardiotoxicity is progressive and often irreversible, prevention, risk reduction, and early detection are of utmost importance. The cardioprotectant dexrazoxane decreases anthracycline cardiotoxicity. Screening for other risk factors at the time of diagnosis may identify risk that when present, if used to tailor therapy, may reduce the severity of cardiac damage. The effects of exercise and other lifestyle changes in reducing the cardiovascular diseases in cancer survivors are unclear. However, it may be beneficial to encourage survivors to engage in physical activity tailored to survivor medical status, but with close monitoring. PMID- 27230283 TI - Different effects of meteorological factors on hand, foot and mouth disease in various climates: a spatial panel data model analysis. AB - BACKGROUND: Major outbreaks of hand, foot and mouth disease (HFMD) have been reported in China since 2008, posing a great threat to the health of children. Although many studies have examined the effect of meteorological variables on the incidence of HFMD, the results have been inconsistent. This study aimed to quantify the relationship between meteorological factors and HFMD occurrence in different climates of mainland China using spatial panel data models. METHODS: All statistical analyses were carried out according to different climate types. We firstly conducted a descriptive analysis to summarize the epidemic characteristics of HFMD from May 2008 to November 2012 and then detected the spatial autocorrelation of HFMD using a global autocorrelation statistic (Moran's I) in each month. Finally, the association between HFMD incidence and meteorological factors was explored by spatial panel data models. RESULTS: The 353 regions were divided into 4 groups according to climate (G1: subtropical monsoon climate; G2: temperate monsoon climate; G3: temperate continental climate; G4: plateau mountain climate). The Moran's I values were significant with high correlations in most months of group G1 and G2 and some months of group G3 and G4. This suggested the existence of a high spatial autocorrelation with HFMD. Spatial panel data models were more appropriate to describe the data than fixed effect models. The results showed that HFMD incidences were significantly associated with average atmospheric pressure (AAP), average temperature (AT), average vapor pressure (AVP), average relative humidity (ARH), monthly precipitation (MP), average wind speed (AWS), monthly total sunshine hours (MSH), mean temperature difference (MTD), rain day (RD) and average temperature distance (ATD), but the effect of meteorological factors might differ in various climate types. CONCLUSIONS: Spatial panel data models are useful and effective when longitudinal data are available and spatial autocorrelation exists. Our findings showed that meteorological factors were related to the occurrence of HFMD, which were also affected by climate type. PMID- 27230284 TI - Butyrate upregulates endogenous host defense peptides to enhance disease resistance in piglets via histone deacetylase inhibition. AB - Butyrate has been used to treat different inflammatory disease with positive outcomes, the mechanisms by which butyrate exerts its anti-inflammatory effects remain largely undefined. Here we proposed a new mechanism that butyrate manipulate endogenous host defense peptides (HDPs) which contributes to the elimination of Escherichia coli O157:H7, and thus affects the alleviation of inflammation. An experiment in piglets treated with butyrate (0.2% of diets) 2 days before E. coli O157:H7 challenge was designed to investigate porcine HDP expression, inflammation and E. coli O157:H7 load in feces. The mechanisms underlying butyrate-induced HDP gene expression and the antibacterial activity and bacterial clearance of macrophage 3D4/2 cells in vitro were examined. Butyrate treatment (i) alleviated the clinical symptoms of E. coli O157:H7 induced hemolytic uremic syndrome (HUS) and the severity of intestinal inflammation; (ii) reduced the E. coli O157:H7 load in feces; (iii) significantly upregulated multiple, but not all, HDPs in vitro and in vivo via histone deacetylase (HDAC) inhibition; and (iv) enhanced the antibacterial activity and bacterial clearance of 3D4/2 cells. Our findings indicate that butyrate enhances disease resistance, promotes the clearance of E. coli O157:H7, and alleviates the clinical symptoms of HUS and inflammation, partially, by affecting HDP expression via HDAC inhibition. PMID- 27230285 TI - Evaluating the Survival Benefit Following Ovarian Function Suppression in Premenopausal Patients with Hormone Receptor Positive Early Breast Cancer. AB - There are divergent opinions regarding the use of ovarian function suppression or ablation (hereafter, OFS) in hormone receptor positive early breast cancer patients. In order to clarify the survival benefit of OFS, a meta-analysis was performed. The result is that use of OFS was more effective than no OFS on DFS (the pooled relative risk (pRR) = 0.86; 95% CI: 0.75-0.96) and on OS (pRR = 0.79; 95% CI: 0.70-0.89). In subgroup analysis, we found that increased DFS was positively associated with patients who had received chemotherapy (pRR = 0.85; 95% CI: 0.74-0.96), who were lymph node negative (pRR = 0.74; 95% CI: 0.61-0.91) and were less than 40 years old (pRR = 0.71; 95% CI: 0.59-0.83). There was a significant difference in OS between the groups receiving chemotherapy (pRR = 0.73; 95% CI: 0.58-0.89) or for patients less than 40 years old (pRR = 0.52; 95% CI: 0.18-0.87). The use of OFS also produces statistical differences in the occurrence of the side-effects; severe hot flashes (pRR = 2.32; 95% CI: 1.36 3.97), and hypertension (pRR = 1.54; 95% CI: 1.12-2.12). In general, OFS should be considered as one treatment for hormone receptor positive premenopausal early breast cancer patients who have received chemotherapy and are less than 40 years old. We also should pay attention to the side-effects and weigh the advantages and disadvantages before deciding on using OFS. PMID- 27230287 TI - Commentary on Obstetric Care in Rural Georgia. AB - This is an invited commentary on five articles on obstetric care in rural Georgia. PMID- 27230286 TI - Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice. AB - Male C57BL/6J mice raised on high fat diet (HFD) become prediabetic and develop insulin resistance and sensory neuropathy. The same mice given low doses of streptozotocin are a model of type 2 diabetes (T2D), developing hyperglycemia, severe insulin resistance and diabetic peripheral neuropathy involving sensory and motor neurons. Because of suggestions that increased NAD(+) metabolism might address glycemic control and be neuroprotective, we treated prediabetic and T2D mice with nicotinamide riboside (NR) added to HFD. NR improved glucose tolerance, reduced weight gain, liver damage and the development of hepatic steatosis in prediabetic mice while protecting against sensory neuropathy. In T2D mice, NR greatly reduced non-fasting and fasting blood glucose, weight gain and hepatic steatosis while protecting against diabetic neuropathy. The neuroprotective effect of NR could not be explained by glycemic control alone. Corneal confocal microscopy was the most sensitive measure of neurodegeneration. This assay allowed detection of the protective effect of NR on small nerve structures in living mice. Quantitative metabolomics established that hepatic NADP(+) and NADPH levels were significantly degraded in prediabetes and T2D but were largely protected when mice were supplemented with NR. The data justify testing of NR in human models of obesity, T2D and associated neuropathies. PMID- 27230288 TI - Secondary negative symptoms - A review of mechanisms, assessment and treatment. AB - Negative symptoms in schizophrenia may be classified as primary or secondary. Primary negative symptoms are thought to be intrinsic to schizophrenia, while secondary negative symptoms are caused by positive symptoms, depression, medication side-effects, social deprivation or substance abuse. Most of the research on secondary negative symptoms has aimed at ruling them out in order to isolate primary negative symptoms. However, secondary negative symptoms are common and can have a major impact on patient-relevant outcomes. Therefore, the assessment and treatment of secondary negative symptoms are clinically relevant. Furthermore, understanding the mechanisms underlying secondary negative symptoms can contribute to an integrated model of negative symptoms. In this review we provide an overview of concepts, evidence, assessment and treatment for the major causes of secondary negative symptoms. We also summarize neuroimaging research relevant to secondary negative symptoms. We emphasize the relevance of recent developments in psychopathological assessment of negative symptoms, such as the distinction between amotivation and diminished expression, which have only rarely been applied in research on secondary negative symptoms. PMID- 27230289 TI - A systematic review on comorbid post-traumatic stress disorder in schizophrenia. AB - Post-traumatic stress disorder (PTSD) appears to commonly co-occur with schizophrenia, which is widely considered the most disabling mental illness. Both conditions share neurological risk factors, and present with symptoms that are superficially similar, complicating diagnostic accuracy. The presence of comorbid PTSD is also of concern as additional diagnoses tend to worsen functioning and quality of life. In the current review, EMBASE, Medline, and PsycINFO were searched for articles pertaining to PTSD comorbidity in schizophrenia spectrum disorders. Articles went through two stages of review prior to inclusion - one at the abstract level and another at the full-text level. Thirty-four articles were ultimately included in the present review. Prevalence of PTSD in schizophrenia ranged from 0 to 57%, likely due to study heterogeneity. Findings generally indicated that comorbid PTSD was associated with higher levels of positive symptoms, general psychopathology, and neurocognitive impairment, as well as worse functioning and quality of life. As such, it is important for clinicians to differentiate between psychotic and PTSD symptoms, and to pay attention to the associated features of comorbid PTSD in order to provide the most appropriate intervention. Unfortunately, epidemiological and longitudinal studies in this area are lacking. PMID- 27230290 TI - Design and experimental analysis of an advanced static VAR compensator with computer aided control. AB - This study presents integration of a real-time energy monitoring and control system with an advanced reactive power compensation unit based on fixed capacitor thyristor controlled reactor (FC-TCR). Firing angles of the thyristors located in the FC-TCR are controlled by a microcontroller in order to keep the power factor within the limits. Electrical parameters of the system are measured by specially designed circuits and simultaneously transferred to the computer via a data acquisition board. Thus, real time data of the system can be observed through a visual user interface. The data obtained is not only analyzed for control process, but also regularly saved into a database. The system has been tested in laboratory conditions under different load characteristics and experimental results verified that the system successfully and accurately achieves compensation process against the all operational conditions. PMID- 27230292 TI - The value of specialist orthopaedic nurses. PMID- 27230291 TI - Heat-mediated reduction of apoptosis in UVB-damaged keratinocytes in vitro and in human skin ex vivo. AB - BACKGROUND: UV radiation induces significant DNA damage in keratinocytes and is a known risk factor for skin carcinogenesis. However, it has been reported previously that repeated and simultaneous exposure to UV and heat stress increases the rate of cutaneous tumour formation in mice. Since constant exposure to high temperatures and UV are often experienced in the environment, the effects of exposure to UV and heat needs to be clearly addressed in human epidermal cells. METHODS: In this study, we determined the effects of repeated UVB exposure 1 kJ/m(2) followed by heat (39 degrees C) to human keratinocytes. Normal human ex vivo skin models and primary keratinocytes (NHEK) were exposed once a day to UVB and/or heat stress for four consecutive days. Cells were then assessed for changes in proliferation, apoptosis and gene expression at 2 days post-exposure, to determine the cumulative and persistent effects of UV and/or heat in skin keratinocytes. RESULTS: Using ex vivo skin models and primary keratinocytes in vitro, we showed that UVB plus heat treated keratinocytes exhibit persistent DNA damage, as observed with UVB alone. However, we found that apoptosis was significantly reduced in UVB plus heat treated samples. Immunohistochemical and whole genome transcription analysis showed that multiple UVB plus heat exposures induced inactivation of the p53-mediated stress response. Furthermore, we demonstrated that repeated exposure to UV plus heat induced SIRT1 expression and a decrease in acetylated p53 in keratinocytes, which is consistent with the significant downregulation of p53-regulated pro-apoptotic and DNA damage repair genes in these cells. CONCLUSION: Our results suggest that UVB-induced p53 mediated cell cycle arrest and apoptosis are reduced in the presence of heat stress, leading to increased survival of DNA damaged cells. Thus, exposure to UVB and heat stress may act synergistically to allow survival of damaged cells, which could have implications for initiation skin carcinogenesis. PMID- 27230294 TI - Hydrophobic matrix-free graphene-oxide composites with isotropic and nematic states. AB - We demonstrate a novel route to synthesise hydrophobic matrix-free composites of polymer-grafted graphene oxide (GO) showing isotropic or nematic alignment and shape-memory effects. For the first time, a cationic macroinitiator (MI) has been immobilised on anionic GO and subsequently grafted with hydrophobic polymer grafts. Dense grafts of PBA, PBMA and PMMA with a wide range of average graft lengths (MW: 1-440 kDa) were polymerised by surface-initiated controlled radical precipitation polymerisation from the statistical MI. The surface modification is designed similarly to bimodal graft systems, where the cationic MI generates nanoparticle repulsion, similar to dense short grafts, while the long grafts offer miscibility in non-polar environments and cohesion. The state-of-the-art dispersions of grafted GO were in the isotropic state. Transparent and translucent matrix-free GO-composites could be melt-processed directly using only grafted GO. After processing, birefringence due to nematic alignment of grafted GO was observed as a single giant Maltese cross, 3.4 cm across. Permeability models for composites containing aligned 2D-fillers were developed, which were compared with the experimental oxygen permeability data and found to be consistent with isotropic or nematic states. The storage modulus of the matrix free GO-composites increased with GO content (50% increase at 0.67 wt%), while the significant increases in the thermal stability (up to 130 degrees C) and the glass transition temperature (up to 17 degrees C) were dependent on graft length. The tuneable matrix-free GO-composites with rapid thermo-responsive shape memory effects are promising candidates for a vast range of applications, especially selective membranes and sensors. PMID- 27230293 TI - AMP-activated protein kinase modulates tau phosphorylation and tau pathology in vivo. AB - Neurofibrillary tangles (NFTs) are the pathological hallmark of neurodegenerative diseases commonly known as tauopathies. NFTs result from the intracellular aggregation of abnormally and hyperphosphorylated tau proteins. Tau functions, which include the regulation of microtubules dynamics, are dependent on its phosphorylation status. As a consequence, any changes in tau phosphorylation can have major impacts on synaptic plasticity and memory. Recently, it has been demonstrated that AMP-activated protein kinase (AMPK) was deregulated in the brain of Alzheimer's disease (AD) patients where it co-localized with phosphorylated tau in pre-tangle and tangle-bearing neurons. Besides, it was found that AMPK was a tau kinase in vitro. Here, we find that endogenous AMPK activation in mouse primary neurons induced an increase of tau phosphorylation at multiple sites, whereas AMPK inhibition led to a rapid decrease of tau phosphorylation. We further show that AMPK mice deficient for one of the catalytic alpha subunits displayed reduced endogenous tau phosphorylation. Finally, we found that AMPK deficiency reduced tau pathology in the PS19 mouse model of tauopathy. These results show that AMPK regulates tau phosphorylation in mouse primary neurons as well as in vivo, and thus suggest that AMPK could be a key player in the development of AD pathology. PMID- 27230295 TI - The Ex-PRESS Glaucoma Filtration Device Implantation in Uveitic Glaucoma. AB - PURPOSE: To evaluate the outcomes of the Ex-PRESS Filtration Device in patients with uveitic glaucoma. METHODS: We reviewed 23 eyes, comparing control simple glaucoma patients (n = 11) to uveitic glaucoma patients (n = 12). Intraocular pressure (IOP) and glaucoma medications at the preoperative examination were compared with those at the 6-month and 10-14-month postoperative examination. Surgical success was defined as >=25% decrease in intraocular pressure without hypotony, and/or decrease in glaucoma medications at 6 months follow-up. RESULTS: Statistically significant reduction in mean IOP from preoperative levels occurred in both groups at 6 months follow-up (p<0.0001) and 10-14 months follow-up (p = 0.0007) and in the mean number of medications in the uveitic glaucoma (UG) group (p = 0.0313). CONCLUSIONS: Surgical success was seen in 10 eyes in the control group (90.9%) and nine eyes (75%) in the UG group (p = 0.314). Ex-PRESS implantation is an effective surgical intervention for the management of uveitic glaucoma. PMID- 27230296 TI - Abeta immunotherapy for Alzheimer's disease: where are we? PMID- 27230297 TI - Multimodal imaging of the disease progression of birdshot chorioretinopathy. AB - PURPOSE: To study outer retinal deterioration in relation to clinical disease activity in patients with birdshot chorioretinopathy using fundus autofluorescence and spectral-domain optical coherence tomography (OCT). METHODS: A single-centre retrospective cohort study was carried out on 42 eyes of 21 patients with birdshot disease, using a multimodal imaging approach including fundus autofluorescence, OCT, fluorescein angiography and indocyanine green angiography in combination with a patient chart review. The patients' overall clinical activity of retinal vasculitis during the follow-up period was determined by periods of clinical activity as indicated by fluorescein angiography and associated treatment decisions. Image analysis was performed to examine the spatial correspondence between autofluorescence changes and disruption of the photoreceptor inner segment ellipsoid zone on OCT. RESULTS: Three common types of outer retinal lesions were observed in fovea-centred images of 43% of patients: circular patches of chorioretinal atrophy, ellipsoid zone disruption on OCT, and outer retinal atrophy on autofluorescence and OCT. There was good spatial correspondence between ellipsoid zone disruption and areas of diffuse hyper-autofluorescence outside the fovea. Interestingly, the ellipsoid zone disruption recovered in four out of seven patients upon intensified therapeutic immunosuppression. CONCLUSION: Most patients only developed peripapillary atrophy and occasional perivascular hypo-autofluorescence. A multimodal imaging approach with autofluorescence imaging and OCT may help to detect ellipsoid zone disruption in the central retina of patients with birdshot disease. Our results suggest that ellipsoid zone disruption may be related to both the activity and duration of retinal vasculitis, and could help to determine therapeutic success in birdshot disease. PMID- 27230298 TI - A qualitative case study of evaluation use in the context of a collaborative program evaluation strategy in Burkina Faso. AB - BACKGROUND: Program evaluation is widely recognized in the international humanitarian sector as a means to make interventions and policies more evidence based, equitable, and accountable. Yet, little is known about the way humanitarian non-governmental organizations (NGOs) actually use evaluations. METHODS: The current qualitative evaluation employed an instrumental case study design to examine evaluation use (EU) by a humanitarian NGO based in Burkina Faso. This organization developed an evaluation strategy in 2008 to document the implementation and effects of its maternal and child healthcare user fee exemption program. Program evaluations have been undertaken ever since, and the present study examined the discourses of evaluation partners in 2009 (n = 15) and 2011 (n = 17). Semi-structured individual interviews and one group interview were conducted to identify instances of EU over time. Alkin and Taut's (Stud Educ Eval 29:1-12, 2003) conceptualization of EU was used as the basis for thematic qualitative analyses of the different forms of EU identified by stakeholders of the exemption program in the two data collection periods. RESULTS: Results demonstrated that stakeholders began to understand and value the utility of program evaluations once they were exposed to evaluation findings and then progressively used evaluations over time. EU was manifested in a variety of ways, including instrumental and conceptual use of evaluation processes and findings, as well as the persuasive use of findings. Such EU supported planning, decision making, program practices, evaluation capacity, and advocacy. CONCLUSIONS: The study sheds light on the many ways evaluations can be used by different actors in the humanitarian sector. Conceptualizations of EU are also critically discussed. PMID- 27230299 TI - Improve sensitization and corrosion resistance of an Al-Mg alloy by optimization of grain boundaries. AB - The sensitization and subsequent intergranular corrosion of Al-5.3 wt.% Mg alloy has been shown to be an important factor in stress corrosion cracking of Al-Mg alloys. Understanding sensitization requires the review of grain boundary character on the precipitation process which can assist in developing and designing alloys with improved corrosion resistance. This study shows that the degree of precipitation in Al-Mg alloy is dependent on grain boundary misorientation angle, adjacent grain boundary planes and grain boundary types. The results show that the misorientation angle is the most important factor influencing precipitation in grain boundaries of the Al-Mg alloy. Low angle grain boundaries (<=15 degrees ) have better immunity to precipitation and grain boundary acid attack. High angle grain boundaries (>15 degrees ) are vulnerable to grain boundary acid attack. Grain boundaries with adjacent plane orientations near to {100} have potential for immunity to precipitation and grain boundary acid attack. This work shows that low Sigma (Sigma <= 29) coincident site lattice (CSL) grain boundaries have thinner beta precipitates. Modified nitric acid mass loss test and polarization test demonstrated that the global corrosion resistance of sputtered Al-Mg alloy is enhanced. This may be attributed to the increased fractions of low Sigma (Sigma <= 29) CSL grain boundaries after sputtering. PMID- 27230300 TI - Topical formulations of miltefosine for cutaneous leishmaniasis in a BALB/c mouse model. AB - Cutaneous leishmaniasis (CL) is caused by several species of the protozoan parasite Leishmania and affects approximately 10 million people worldwide. Currently available drugs are not ideal due to high cost, toxicity, parenteral administration and suboptimal efficacy. Miltefosine is the only oral treatment (Impavido(r)) available to treat CL, given over a period of 28 days with common side effects such as vomiting and diarrhoea. OBJECTIVE: To explore the local application of miltefosine as a topical formulation to enhance activity and reduce the drug's adverse effects. METHODS: The antileishmanial activity of miltefosine was confirmed in vitro against several Leishmania species. The permeation of miltefosine, in different solvents and solvent combinations, through BALB/c mouse skin was evaluated in vitro using Franz diffusion cells. The topical formulations which enabled the highest drug permeation or skin disposition were tested in vivo in BALB/c mice infected with L. major. KEY FINDINGS: The overall permeation of miltefosine through skin was low regardless of the solvents used. This was reflected in limited antileishmanial activity of the drug formulations when applied topically in vivo. All topical formulations caused skin irritation. CONCLUSIONS: We conclude that miltefosine is not an appropriate candidate for the topical treatment of CL. PMID- 27230301 TI - Pathogenic characteristics of a novel triple-reasserted H1N2 swine influenza virus. AB - A novel triple reasserted H1N2 virus A/swine/Shanghai/1/2007 (SH07) was isolated from nasal swabs of weaned pig showing clinical symptoms of coughing and sneezing. To explore the virus characteristics, mice, chickens and pigs were selected for pathogenicity study. Pigs inoculated intranasally with 10(6) TCID50 SH07 showed clinical symptoms with coughing and sneezing, but no death. The virus nuclear acid was detected in many tissues using real-time PCR, which was mainly distributed in respiratory system particularly in the lungs. The virus was low pathogenic to chickens with 10(6) TCID50 dose inoculation either via intramuscular or intranasal routes. However virus nuclear acid detection and virus isolation confirmed that the virus can also be found in nasal and rectum. When virus was inoculated into mice by intramuscular or intranasal routes we observed 100% and 80% lethality respectively. The third generation of samples passaged on MDCK cell were SIV positive in indirect immunofluorescence assay (IFA) using antiserum against H1N2 SIV. Furthermore, the lungs of mice showed obvious lesion with interstitial pneumonia. Data in our study suggest that SH07 is preferentially pathogenic to mammals rather than birds although it is a reasserting virus with the fragments from swine, human and avian origin. PMID- 27230303 TI - Isoniazid-induced control of Mycobacterium tuberculosis by primary human cells requires interleukin-1 receptor and tumor necrosis factor. AB - Proinflammatory cytokines are critical mediators that control Mycobacterium tuberculosis (Mtb) growth during active tuberculosis (ATB). To further inhibit bacterial proliferation in diseased individuals, drug inhibitors of cell wall synthesis such as isoniazid (INH) are employed. However, whether INH presents an indirect effect on bacterial growth by regulating host cytokines during ATB is not well known. To examine this hypothesis, we used an in vitro human granuloma system generated with primary leukocytes from healthy donors adapted to model ATB. Intense Mtb proliferation in cell cultures was associated with monocyte/macrophage activation and secretion of IL-1beta and TNF. Treatment with INH significantly reduced Mtb survival, but altered neither T-cell-mediated Mtb killing, nor production of IL-1beta and TNF. However, blockade of both IL-1R1 and TNF signaling rescued INH-induced killing, suggesting synergistic roles of these cytokines in mediating control of Mtb proliferation. Additionally, mycobacterial killing by INH was highly dependent upon drug activation by the pathogen catalase peroxidase KatG and involved a host PI3K-dependent pathway. Finally, experiments using coinfected (KatG-mutated and H37Rv strains) cells suggested that active INH does not directly enhance host-mediated killing of Mtb. Our results thus indicate that Mtb-stimulated host IL-1 and TNF have potential roles in TB chemotherapy. PMID- 27230304 TI - O-GlcNAcylation: A sweet thorn in the spindle! PMID- 27230305 TI - Dominance of texture over shape in facial identity processing is modulated by individual abilities. AB - For face recognition, observers utilize both shape and texture information. Here, we investigated the relative diagnosticity of shape and texture for delayed matching of familiar and unfamiliar faces (Experiment 1) and identifying familiar and newly learned faces (Experiment 2). Within each familiarity condition, pairs of 3D-captured faces were morphed selectively in either shape or texture in 20% steps, holding the respective other dimension constant. We also assessed participants' individual face-processing skills via the Bielefelder Famous Faces Test (BFFT), the Glasgow Face Matching Test, and the Cambridge Face Memory Test (CFMT). Using multilevel model analyses, we examined probabilities of same versus different responses (Experiment 1) and of original identity versus other/unknown identity responses (Experiment 2). Overall, texture was more diagnostic than shape for both delayed matching and identification, particularly so for familiar faces. On top of these overall effects, above-average BFFT performance was associated with enhanced utilization of texture in both experiments. Furthermore, above-average CFMT performance coincided with slightly reduced texture dominance in the delayed matching task (Experiment 1) and stronger sensitivity to morph based changes overall, that is irrespective of morph type, in the face identification task (Experiment 2). Our findings (1) show the disproportionate importance of texture information for processing familiar face identity and (2) provide further evidence that familiar and unfamiliar face identity perception are mediated by different underlying processes. PMID- 27230302 TI - An Empirical Comparison of Joint and Stratified Frameworks for Studying G * E Interactions: Systolic Blood Pressure and Smoking in the CHARGE Gene-Lifestyle Interactions Working Group. AB - Studying gene-environment (G * E) interactions is important, as they extend our knowledge of the genetic architecture of complex traits and may help to identify novel variants not detected via analysis of main effects alone. The main statistical framework for studying G * E interactions uses a single regression model that includes both the genetic main and G * E interaction effects (the "joint" framework). The alternative "stratified" framework combines results from genetic main-effect analyses carried out separately within the exposed and unexposed groups. Although there have been several investigations using theory and simulation, an empirical comparison of the two frameworks is lacking. Here, we compare the two frameworks using results from genome-wide association studies of systolic blood pressure for 3.2 million low frequency and 6.5 million common variants across 20 cohorts of European ancestry, comprising 79,731 individuals. Our cohorts have sample sizes ranging from 456 to 22,983 and include both family based and population-based samples. In cohort-specific analyses, the two frameworks provided similar inference for population-based cohorts. The agreement was reduced for family-based cohorts. In meta-analyses, agreement between the two frameworks was less than that observed in cohort-specific analyses, despite the increased sample size. In meta-analyses, agreement depended on (1) the minor allele frequency, (2) inclusion of family-based cohorts in meta-analysis, and (3) filtering scheme. The stratified framework appears to approximate the joint framework well only for common variants in population-based cohorts. We conclude that the joint framework is the preferred approach and should be used to control false positives when dealing with low-frequency variants and/or family-based cohorts. PMID- 27230306 TI - 'That red flag on your file': misinterpreting physical symptoms as mental illness. AB - AIMS AND OBJECTIVES: To ascertain the views and experiences of mental health consumers regarding the availability and quality of care and treatment received for their physical health needs. BACKGROUND: People diagnosed with mental illness have higher occurrence of physical health problems. Responsive health care services are crucial for prevention and management of physical health problems, and for reducing disparities in health between people diagnosed with mental illness and those who are not. There is limited research giving voice to consumer perspectives on their experiences with health care providers. DESIGN: Exploratory qualitative. METHODS: Focus group interviews with mental health consumers accessed via a consumer network group in a region of Australia (n = 31). All interview audio recordings were transcribed professionally. Interviews were thematically analysed. RESULTS: The main themes were: symptomising; failure to act and alertness to prejudice. The first two themes were consumer perceptions of the actions and behaviours of health professionals, and the third describes consumer responses to these behaviours and actions. Consumers described increased risks of illness and death because of undiagnosed physical illness despite their physical health advice-seeking as the reason for the health consultation. CONCLUSION: Health care providers' non-recognition of physical health problems presents a clear example of a significant and potentially life threatening health inequity. The service provider responses described by participants suggest that mental health consumers' physical health needs may not be taken seriously. RELEVANCE TO CLINICAL PRACTICE: Clinicians need to take seriously the physical health needs and concerns of people with mental illness. Nurses can play a crucial role in the prevention of diagnostic overshadowing as part of a broader direction of balancing biomedical perspectives with other approaches to health care. PMID- 27230307 TI - Color-Multiplexing-Based Fluorescent Test Paper: Dosage-Sensitive Visualization of Arsenic(III) with Discernable Scale as Low as 5 ppb. AB - Fluorescent colorimetry test papers are promising for the assays of environments, medicines, and foods by the observation of the naked eye on the variations of fluorescence brightness and color. Unlike dye-absorption-based pH test paper, however, the fluorescent test papers with wide color-emissive variations with target dosages for accurate quantification remain unsuccessful even if the multicolorful fluorescent probes are used. Here, we report the dosage-sensitive fluorescent colorimetry test paper with a very wide/consecutive "from red to cyan" response to the presence and amount of arsenic ions, As(III). Red quantum dots (QDs) were modified with glutathione and dithiothreitol to obtain the supersensitivity to As(III) by the quenching of red fluorescence through the formation of dispersive QDs aggregates. A small amount of cyan carbon dots (CDs) with spectral blue-green components as the photostable internal standard were mixed into the QDs solution to produce a composited red fluorescence. Upon the addition of As(III) into the sensory solution, the fluorescence color could gradually be reversed from red to cyan with a detection limit of 1.7 ppb As(III). When the sensory solution was printed onto a piece of filter paper, surprisingly a serial of color evolution from peach to pink to orange to khaki to yellowish to yellow-green to final cyan with the addition of As(III) was displayed and clearly discerned the dosage scale as low as 5 ppb. The methodology reported here opens a novel pathway toward the real applications of fluorescent test papers. PMID- 27230351 TI - Some ethical challenges regarding self-immolation. PMID- 27230350 TI - Therapist Attitudes Towards Evidence-Based Practice: A Joint Factor Analysis. AB - Despite the accumulated research support for the use of evidence-based practices (EBPs) with youth, these treatment approaches remain underutilized in community settings. Therapist attitudes towards EBPs play a pivotal role in their adoption and implementation of these practices. The present investigation employs joint exploratory factor analysis to evaluate the structure of two measures of therapist attitudes, the Evidence-Based Practices Attitudes Scale and the Modified Practice Attitude Scale. Results suggest three factors including (a) importance of clinical experience over EBPs, (b) clinician openness to change, and (c) problems with EBPs. Recommendations are provided for future evaluation of therapist attitudes and associated characteristics. PMID- 27230354 TI - Implicit bias. PMID- 27230352 TI - Neurobehavioral toxicity of carbon nanotubes in mice. AB - OBJECTIVES: The aim of this study was to evaluate neurobehavioral toxicity of single-walled (SWNTs) and multiwalled carbon nanotubes (MWNTs) in mice. METHODS: Male NMRI mice were randomized into 5 groups ( n = 10 each): Normal control (NC) group was injected intraperitoneally (i.p.) with phosphate-buffered saline (PBS) solution (pH 7.8; ca. 1 mL), MW80 and MW800 groups were injected with either i.p. 80 or 800 mg kg-1 MWNTs suspended in 1 mL of PBS and SW80 and SW800 groups were injected with either i.p. 80 or 800 mg kg-1 SWNTs suspended in 1 mL of PBS. After 2 weeks, five mice from each group were evaluated for brain-derived neurotrophic factor (BDNF) messenger RNA expression and protein content of brain tissues. Locomotion, anxiety, learning and memory, and depression were measured by open field test (OFT), elevated plus-maze (EPM), object recognition test (ORT), and forced swimming test (FST), respectively. RESULTS: Ambulation time and center arena time in the OFT did not change among groups. In the EPM paradigm, SWNTs (800 mg kg-1) and MWNTs (80 and 800 mg kg-1) showed an anxiogenic effect. In ORT, MWNTs (80 mg kg-1) increased the discrimination ratio while in FST, MWNTs showed a depressant effect as compared to vehicle. The BDNF gene expression in mice treated with 80 and 800 mg kg-1 SWNTs or 80 mg kg-1 MWNTs decreased as compared to NC mice although BDNF gene expression increased in mice that were treated with 800 mg kg-1 MWNTs. The whole brain BDNF protein content did not change among groups. CONCLUSION: Our study showed that i.p. exposure to carbon nanotubes (CNTs) may result in behavioral toxicity linked with expression of depression or anxiety that depends on the type of CNTs. In addition, exposure to CNTs changed BDNF gene expression. PMID- 27230356 TI - NUCLEAR SAFETY. Near miss at Fukushima is a warning for U.S. PMID- 27230353 TI - GRIN2A polymorphisms and expression levels are associated with lead-induced neurotoxicity. AB - Lead acts as an antagonist of the N-methyl-d-aspartate receptor (NMDAR). GRIN2A encodes an important subunit of NMDARs and may be a critical factor in the mechanism of lead neurotoxicity. Changes in GRIN2A expression levels or gene variants may be mechanisms of lead-induced neurotoxicity. In this study, we hypothesized that GRIN2A might contribute to lead-induced neurotoxicity. A preliminary HEK293 cell experiment was performed to analyze the association between GRIN2A expression and lead exposure. In addition, in a population-based study, serum GRIN2A levels were measured in both lead-exposed and control populations. To detect further the influence of GRIN2A gene single nucleotide polymorphisms (SNPs) in lead-induced neurotoxicity, 3 tag SNPs (rs2650429, rs6497540, and rs9302415) were genotyped in a case-control study that included 399 lead-exposed subjects and 398 controls. Lead exposure decreased GRIN2A expression levels in HEK293 cells ( p < 0.001) compared with lead-free cells. Lead-exposed individuals had lower serum GRIN2A levels compared with controls ( p < 0.001), and we found a trend of decreasing GRIN2A level with an increase in blood lead level ( p < 0.001). In addition, we found a significant association between rs2650429 CT and TT genotypes and risk of lead poisoning compared with the rs2650429 CC genotype (adjusted odds ratio = 1.42, 95% confidence interval = 1.01-2.00]. Therefore, changes in GRIN2A expression levels and variants may be important mechanisms in the development of lead-induced neurotoxicity. PMID- 27230357 TI - Q&A. Shooting for a star. PMID- 27230358 TI - SOCIAL SCIENCES. Government 'nudges' prove their worth. PMID- 27230359 TI - TRANSGENIC CROPS. India nears putting GM mustard on the table. PMID- 27230360 TI - LATIN AMERICA. Brazilian crisis threatens science and environment. PMID- 27230361 TI - The battery builder. PMID- 27230362 TI - CHEMISTRY. How to break down crystalline cellulose. PMID- 27230363 TI - CANCER. The cancer predisposition revolution. PMID- 27230364 TI - POLYMER SYNTHESIS. Organic photocatalysts for cleaner polymer synthesis. PMID- 27230365 TI - BIOCHEMISTRY. A metal shuttle keeps pathogens well fed. PMID- 27230366 TI - ECONOMICS. Matching markets in the digital age. PMID- 27230367 TI - GENE EXPRESSION. Unwinding inducible gene expression. PMID- 27230368 TI - MEDICINE. Paying for future success in gene therapy. PMID- 27230369 TI - Public participation in China's project plans. PMID- 27230370 TI - Infection and the first eukaryotes. PMID- 27230371 TI - Infection and the first eukaryotes--Response. PMID- 27230372 TI - An ice age recorded in the polar deposits of Mars. AB - Layered ice deposits at the poles of Mars record a detailed history of accumulation and erosion related to climate processes. Radar investigations measure these layers and provide evidence for climate changes such as ice advance and retreat. We present a detailed analysis of observational data showing that ~87,000 cubic kilometers of ice have accumulated at the poles since the end of the last ice age ~370,000 years ago; this volume is equivalent to a global layer of ~60 centimeters. The majority of the material accumulated at the north pole. These results provide both a means to understand the accumulation history of the polar deposits as related to orbital Milankovitch cycles and constraints for better determination of Mars' past and future climates. PMID- 27230373 TI - Enantioselective synthesis of an ophiobolin sesterterpene via a programmed radical cascade. AB - Cyclase enzymes weave simple polyprenyl chains into the elaborate polycyclic ring systems of terpenes, a sequence that is often difficult to emulate under abiotic conditions. Here we report a disparate synthetic approach to complex terpenes whereby simple prenyl-derived chains are cyclized using radical, rather than cationic, reaction pathways. This strategy allowed us to efficiently forge the intricate 5-8-5 fused ring systems found in numerous complex natural product classes and also enabled a nine-step total synthesis of (-)-6-epi-ophiobolin N, a member of the large family of cytotoxic ophiobolin sesterterpenes. A small molecule thiol catalyst was found to override the inherent diastereoselectivity observed during a reductive radical cascade cyclization process. This work lays the foundation for efficient synthesis of terpenoid ring systems of interest in medicinal research, particularly those that have been historically challenging to access. PMID- 27230374 TI - A Schrodinger cat living in two boxes. AB - Quantum superpositions of distinct coherent states in a single-mode harmonic oscillator, known as "cat states," have been an elegant demonstration of Schrodinger's famous cat paradox. Here, we realize a two-mode cat state of electromagnetic fields in two microwave cavities bridged by a superconducting artificial atom, which can also be viewed as an entangled pair of single-cavity cat states. We present full quantum state tomography of this complex cat state over a Hilbert space exceeding 100 dimensions via quantum nondemolition measurements of the joint photon number parity. The ability to manipulate such multicavity quantum states paves the way for logical operations between redundantly encoded qubits for fault-tolerant quantum computation and communication. PMID- 27230375 TI - Experimental reconstruction of the Berry curvature in a Floquet Bloch band. AB - Topological properties lie at the heart of many fascinating phenomena in solid state systems such as quantum Hall systems or Chern insulators. The topology of the bands can be captured by the distribution of Berry curvature, which describes the geometry of the eigenstates across the Brillouin zone. Using fermionic ultracold atoms in a hexagonal optical lattice, we engineered the Berry curvature of the Bloch bands using resonant driving and show a full momentum-resolved measurement of the ensuing Berry curvature. Our results pave the way to explore intriguing phases of matter with interactions in topological band structures. PMID- 27230376 TI - Bloch state tomography using Wilson lines. AB - Topology and geometry are essential to our understanding of modern physics, underlying many foundational concepts from high-energy theories, quantum information, and condensed-matter physics. In condensed-matter systems, a wide range of phenomena stem from the geometry of the band eigenstates, which is encoded in the matrix-valued Wilson line for general multiband systems. Using an ultracold gas of rubidium atoms loaded in a honeycomb optical lattice, we realize strong-force dynamics in Bloch bands that are described by Wilson lines and observe an evolution in the band populations that directly reveals the band geometry. Our technique enables a full determination of band eigenstates, Berry curvature, and topological invariants, including single- and multiband Chern and Z2 numbers. PMID- 27230377 TI - Nuclear-localized cyclic nucleotide-gated channels mediate symbiotic calcium oscillations. AB - Nuclear-associated Ca(2+) oscillations mediate plant responses to beneficial microbial partners--namely, nitrogen-fixing rhizobial bacteria that colonize roots of legumes and arbuscular mycorrhizal fungi that colonize roots of the majority of plant species. A potassium-permeable channel is known to be required for symbiotic Ca(2+) oscillations, but the calcium channels themselves have been unknown until now. We show that three cyclic nucleotide-gated channels in Medicago truncatula are required for nuclear Ca(2+) oscillations and subsequent symbiotic responses. These cyclic nucleotide-gated channels are located at the nuclear envelope and are permeable to Ca(2+) We demonstrate that the cyclic nucleotide-gated channels form a complex with the postassium-permeable channel, which modulates nuclear Ca(2+) release. These channels, like their counterparts in animal cells, might regulate multiple nuclear Ca(2+) responses to developmental and environmental conditions. PMID- 27230378 TI - Biosynthesis of a broad-spectrum nicotianamine-like metallophore in Staphylococcus aureus. AB - Metal acquisition is a vital microbial process in metal-scarce environments, such as inside a host. Using metabolomic exploration, targeted mutagenesis, and biochemical analysis, we discovered an operon in Staphylococcus aureus that encodes the different functions required for the biosynthesis and trafficking of a broad-spectrum metallophore related to plant nicotianamine (here called staphylopine). The biosynthesis of staphylopine reveals the association of three enzyme activities: a histidine racemase, an enzyme distantly related to nicotianamine synthase, and a staphylopine dehydrogenase belonging to the DUF2338 family. Staphylopine is involved in nickel, cobalt, zinc, copper, and iron acquisition, depending on the growth conditions. This biosynthetic pathway is conserved across other pathogens, thus underscoring the importance of this metal acquisition strategy in infection. PMID- 27230379 TI - CRISPR-directed mitotic recombination enables genetic mapping without crosses. AB - Linkage and association studies have mapped thousands of genomic regions that contribute to phenotypic variation, but narrowing these regions to the underlying causal genes and variants has proven much more challenging. Resolution of genetic mapping is limited by the recombination rate. We developed a method that uses CRISPR (clustered, regularly interspaced, short palindromic repeats) to build mapping panels with targeted recombination events. We tested the method by generating a panel with recombination events spaced along a yeast chromosome arm, mapping trait variation, and then targeting a high density of recombination events to the region of interest. Using this approach, we fine-mapped manganese sensitivity to a single polymorphism in the transporter Pmr1. Targeting recombination events to regions of interest allows us to rapidly and systematically identify causal variants underlying trait differences. PMID- 27230381 TI - A force-generating machinery maintains the spindle at the cell center during mitosis. AB - The position and orientation of the mitotic spindle is precisely regulated to ensure the accurate partition of the cytoplasm between daughter cells and the correct localization of the daughters within growing tissue. Using magnetic tweezers to perturb the position of the spindle in intact cells, we discovered a force-generating machinery that maintains the spindle at the cell center during metaphase and anaphase in one- and two-cell Caenorhabditis elegans embryos. The forces increase with the number of microtubules and are larger in smaller cells. The machinery is rigid enough to suppress thermal fluctuations to ensure precise localization of the mitotic spindle, yet compliant enough to allow molecular force generators to fine-tune the position of the mitotic spindle to facilitate asymmetric division. PMID- 27230382 TI - Three strikes and research is out. PMID- 27230380 TI - Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is associated with risk variants in the human genome and dysbiosis of the gut microbiome, though unifying principles for these findings remain largely undescribed. The human commensal Bacteroides fragilis delivers immunomodulatory molecules to immune cells via secretion of outer membrane vesicles (OMVs). We reveal that OMVs require IBD-associated genes, ATG16L1 and NOD2, to activate a noncanonical autophagy pathway during protection from colitis. ATG16L1-deficient dendritic cells do not induce regulatory T cells (T(regs)) to suppress mucosal inflammation. Immune cells from human subjects with a major risk variant in ATG16L1 are defective in T(reg) responses to OMVs. We propose that polymorphisms in susceptibility genes promote disease through defects in "sensing" protective signals from the microbiome, defining a potentially critical gene-environment etiology for IBD. PMID- 27230383 TI - Micturating cystourethrogram as a tool for investigating UTI in children - An institutional audit. AB - BACKGROUND: Micturating cystourethrograms (MCUG) are the gold standard for evaluating vesicoureteric reflux (VUR). There is a growing consensus for increasing the threshold for performing MCUGs following urinary tract infections (UTI) in children. There are several varying guidelines. It is important to detect high-grade reflux in the setting of an UTI because of potential long-term complications. OBJECTIVE: This audit aimed to retrospectively: (1) identify the conformance rate of local guidelines at the Women's and Children's Hospital (WCH); (2) assess predictors for an abnormal MCUG; and (3) compare local guidelines against the Royal Children's Hospital, Melbourne (RCH), National Institute for Healthcare and Excellence (NICE), and American Academy of Pediatrics (AAP) guidelines for selectively detecting high-grade reflux. METHOD: The number of MCUGs performed from 2008 to 2012 at the WCH radiology department was collected. Patients undergoing MCUG during the 2012 calendar year were identified. Only children having an initial MCUG as part of an UTI investigation with prerequisite imaging as per guidelines were included. Each child's age, sex, referral source, reason, renal ultrasound (RUS) prior to the MCUG, MCUG result and VUR grade were recorded. The WCH guidelines were applied to determine conformance, to evaluate predictors for an abnormal MCUG, and compared against other retrospectively applied guidelines (RCH, NICE, AAP). RESULTS/DISCUSSION: There was complete data for 168 children who underwent MCUG as part of an UTI investigation (median age 0.79 years, range 0.12-8.74, male:female 67:101). There were 67/168 abnormal MCUGs (62 children with VUR, five bladder diverticulum), and 97 refluxing renal units (43 high-grade VUR units). No posterior urethral valves (PUV) were identified as part of the UTI investigation. A total of 143/168 patients had prior RUS (normal:abnormal 67:76). The WCH guidelines had 82% conformance. There was no statistically significant association between an abnormal MCUG and age, sex, referral source, reason, or prior RUS result. The WCH guidelines may have missed five children with high-grade VUR (four children had surgery), compared with RCH, APP and NICE, with 8, 15, and 17 children, respectively, having high-grade VUR (two, five, and five children had surgery, respectively) show in the Summary Table. The retrospective study had limitations and possible selection bias (children with UTI without a MCUG). There were no standard treatment approaches for VUR; hence establishing a MCUG guideline is difficult. An alternative is the top-down approach. CONCLUSION: Current institutional guidelines for considering MCUG following UTI in children vary considerably. The MCUG guidelines at any institution must take into account the local management guidelines for high-grade VUR. PMID- 27230384 TI - Crowdsourcing the nodulation gene network discovery environment. AB - BACKGROUND: The Legumes (Fabaceae) are an economically and ecologically important group of plant species with the conspicuous capacity for symbiotic nitrogen fixation in root nodules, specialized plant organs containing symbiotic microbes. With the aim of understanding the underlying molecular mechanisms leading to nodulation, many efforts are underway to identify nodulation-related genes and determine how these genes interact with each other. In order to accurately and efficiently reconstruct nodulation gene network, a crowdsourcing platform, CrowdNodNet, was created. RESULTS: The platform implements the jQuery and vis.js JavaScript libraries, so that users are able to interactively visualize and edit the gene network, and easily access the information about the network, e.g. gene lists, gene interactions and gene functional annotations. In addition, all the gene information is written on MediaWiki pages, enabling users to edit and contribute to the network curation. CONCLUSIONS: Utilizing the continuously updated, collaboratively written, and community-reviewed Wikipedia model, the platform could, in a short time, become a comprehensive knowledge base of nodulation-related pathways. The platform could also be used for other biological processes, and thus has great potential for integrating and advancing our understanding of the functional genomics and systems biology of any process for any species. The platform is available at http://crowd.bioops.info/ , and the source code can be openly accessed at https://github.com/bioops/crowdnodnet under MIT License. PMID- 27230385 TI - A user report on the trial use of gesture commands for image manipulation and X ray acquisition. AB - Touchless environment for image manipulation and X-ray acquisition may enhance the current infection control measure during X-ray examination simply by avoiding any touch on the control panel. The present study is intended at designing and performing a trial experiment on using motion-sensing technology to perform image manipulation and X-ray acquisition function (the activities a radiographer frequently performs during an X-ray examination) under an experimental setup. Based on the author's clinical experience, several gesture commands were designed carefully to complete a single X-ray examination. Four radiographers were randomly recruited for the study. They were asked to perform gesture commands in front of a computer integrated with a gesture-based touchless controller. The translational movements of the tip of their thumb and index finger while performing different gesture commands were recorded for analysis. Although individual operators were free to decide the extent of movement and the speed at which their fingers and thumbs moved while performing these gesture commands, the result of our study demonstrated that all operators could perform our proposed gesture commands with good consistency, suggesting that motion-sensing technology could, in practice, be integrated into radiographic examinations. To summarize, although the implementation of motion-sensing technology as an input command in radiographic examination might inevitably slow down the examination throughput considering that extra procedural steps are required to trigger specific gesture commands in sequence, it is advantageous in minimizing the potential of the pathogen contamination during image operation and image processing that leads to cross infection. PMID- 27230386 TI - Targeting copper(II)-induced oxidative stress and the acetylcholinesterase system in Alzheimer's disease using multifunctional tacrine-coumarin hybrid molecules. AB - Alzheimer's disease is a multifactorial disease that is characterized mainly by Amyloid-beta (A-beta) deposits, cholinergic deficit and extensive metal (copper, iron)-induced oxidative stress. In this work we present details of the synthesis, antioxidant and copper-chelating properties, DNA protection study, cholinergic activity and amyloid-antiaggregation properties of new multifunctional tacrine-7 hydroxycoumarin hybrids. The mode of interaction between copper(II) and hybrids and interestingly, the reduction of Cu(II) to Cu(I) species (for complexes Cu-5e g) were confirmed by EPR measurements. EPR spin trapping on the model Fenton reaction, using 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a spin trap, demonstrated a significantly suppressed formation of hydroxyl radicals for the Cu 5e complex in comparison with free copper(II). This suggests that compound 5e upon coordination to free copper ion prevents the Cu(II)-catalyzed decomposition of hydrogen peroxide, which in turn may alleviate oxidative stress-induced damage. Protective activity of hybrids 5c and 5e against DNA damage in a Fenton system (copper catalyzed) was found to be in excellent agreement with the EPR spin trapping study. Compound 5g was the most effective in the inhibition of acetylcholinesterase (hAChE, IC50=38nM) and compound 5b was the most potent inhibitor of butyrylcholinesterase (hBuChE, IC50=63nM). Compound 5c was the strongest inhibitor of A-beta1-40 aggregation, although a significant inhibition (>50%) was detected for compounds 5b, 5d, 5e and 5g. Collectively, these results suggest that the design and investigation of multifunctional agents containing along with the acetylcholinesterase inhibitory segment also an antioxidant moiety capable of alleviating metal (copper)-induced oxidative stress, may be of importance in the treatment of Alzheimer's disease. PMID- 27230387 TI - G-quadruplex vs. duplex-DNA binding of nickel(II) and zinc(II) Schiff base complexes. AB - Novel nickel(II) (1) and zinc(II) (2) complexes of a Salen-like ligand, carrying a pyrimidine ring on the N,N' bridge, were synthesized and characterized. Their interaction with duplex and G-quadruplex DNA was investigated in aqueous solution through UV-visible absorption, circular dichroism and viscometry measurements. The results obtained point out that, while the zinc(II) complex does not interact with both duplex and G-quadruplex DNA, the nickel(II) complex 1 binds preferentially to G-quadruplex respect to duplex-DNA, with values of the DNA binding constants, Kb, 2.6*10(5)M(-1) and 3.5*10(4)M(-1), respectively. Molecular dynamics simulations provided an atomic level model of the top-stacking binding occurring between 1 and hTelo (a 22-mer sequence oligonucleotide) in G-quadruplex conformation. PMID- 27230388 TI - Intravitreal ranibizumab injection combined trabeculectomy versus Ahmed valve surgery in the treatment of neovascular glaucoma: assessment of efficacy and complications. AB - BACKGROUND: Researches have shown anti-vascular endothelial growth factor (VEGF) agent is effective in treating neovascular eye diseases. The purpose of this study is to evaluate the efficacy and safety of intravitreal ranibizumab (IVR) injection combined trabeculectomy in the treatment of neovascular glaucoma (NVG), and compared it with Ahmed valve surgery. METHODS: Thirty-six NVG patients (37 eyes) from the First Affiliated Hospital of Zhejiang medical college, between January 1, 2014 and January 31, 2015, were included in this prospective, interventional clinical study. Eighteen NVG eyes were given IVR injection one week before trabeculectomy. Ahmed valve implantation surgery was performed in nineteen eyes. Ocular pain, best corrected visual acuity (BCVA), intraocular pressure (IOP) and surgical complications were evaluated before and after the surgery. RESULTS: IOP was significantly decreased following IVR injection combined trabeculectomy treatment (baseline 57.1 +/- 8.9 mmHg; week 1, 15.2 +/- 4.3 mmHg p = 0.000; month 1, 16.9 +/- 2.1 mmHg p = 0.000; month 3, 20.3 +/- 7.7 mmHg p = 0.000; month 6, 19.7 +/- 7.3 mmHg p = 0.000). There was a significant, though modest, BCVA improvement in sighted eyes of IVR group (baseline 2.42 +/- 0.68, W1 1.80 +/- 0.91, P = 0.013; M1 1.77 +/- 0.93, p = 0.011). IVR injection combined trabeculectomy had less postoperative complications and lower failure ratio than Ahmed surgery (IVR 5.6 %, Ahmed 31.6 %). CONCLUSIONS: The study revealed that IVR injection combined trabeculectomy was an effective and safe treatment for NVG. Compared with Ahmed surgery, IVR injection combined trabeculectomy had less complications and higher success ratio. (Chinese Clinical Registry, TRN ChiCTR-OPN-16008147, 3/24/2016, retrospectively registered). PMID- 27230389 TI - Charting a course through the CEAs: diagnosis and management of medullary thyroid cancer. AB - Medullary thyroid cancer (MTC) is an uncommon thyroid cancer that requires a high index of suspicion to facilitate diagnosis of early-stage disease amenable to surgical cure. The challenges of diagnosis, as well as management in the setting of persistent disease, are explored in the context of a case presenting with the incidental finding of elevated carcinoembryonic antigen (CEA) and an (18) F fluorodeoxyglucose positron emission tomography ((18) F-FDG-PET)-positive thyroid incidentaloma detected following treatment of colorectal cancer. Strategies to individualize prognosis, and emerging PET-based imaging modalities, particularly the potential role of (18) F-DOPA-PET in staging, are reviewed. PMID- 27230390 TI - Tracing the origins of transient overshoots for binary mixture diffusion in microporous crystalline materials. AB - Separation of mixtures using microporous crystalline materials is normally achieved by exploiting differences in the adsorption strengths of the constituent species. The focus of the current investigation is on diffusion-selective separations that exploit differences in intra-crystalline diffusivities of guest molecules. A number of experimental investigations report overshoots in intra crystalline loadings of the more mobile species during transient mixture uptake. Analogous overshoots in fluxes occur for mixture permeation across thin microporous membrane layers. The attainment of supra-equilibrium loadings is a common characteristic of diffusion-selective separations; this allows the over riding of adsorption selectivities. The primary objective of the current investigation is to demonstrate that the Maxwell-Stefan diffusion formulation, using chemical potential gradients as driving forces, is capable of providing a quantitative description of the temporal and spatial overshoots found in diverse experimental studies. The origins of the overshoots can be traced to thermodynamic coupling effects that emanate from sizable off-diagonal contributions of the matrix of thermodynamic correction factors. If thermodynamic coupling effects are neglected, the overshoots are not realized. It is also demonstrated that while the transport of the more mobile partner is uphill of its loading gradient, its transport is downhill the gradient of its chemical potential. The deliberate exploitation of uphill diffusion to achieve difficult separations is highlighted. PMID- 27230392 TI - Bacteriological quality of raw camel milk along the market value chain in Fafen zone, Ethiopian Somali regional state. AB - BACKGROUND: The camel is a multipurpose animal with a huge productive potential. Camel milk is a key food in arid and semi-arid areas of the African and Asian countries. The quality of milk is influenced by different bacteria present in milk. This study was conducted to evaluate total bacterial content in raw camel milk along the market chain in Fafen zone, Ethiopian Somali Regional State. METHODS: One hundred twenty-six raw camel milk samples were collected from Gursum (47.1 %) and Babile (52.9 %) districts. The three sampling levels included were udder (14.7 %), milking bucket (29.4 %) and market (55.9 %). Milk samples were analyzed for total bacterial counts (TBC) and coliform counts (CC). Furthermore, major pathogens were isolated and identified. RESULT: 108 (85.7 %) of raw camel milk samples demonstrated bacterial contamination. The overall mean TBC and CC of contaminated raw camel milk samples was 4.75 +/- 0.17 and 4.03 +/- 0.26 log CFU/ml, respectively. TBC increased from udder to market level and was higher in Gursum compared to Babile district (P < 0.05). Around 38.9 % of TBCs and 88.2 % CCs in contaminated raw camel milk samples were in the range considered unsafe for human utility. Staphylococcus spp. (89.8 %), Streptococcus spp. (53.7 %), E. coli (31.5 %), Salmonella spp. (17.6 %), Klebsiella spp. (5.6 %) and Enterobacter spp. (5.6 %) were the major bacterial microorganisms isolated. CONCLUSION: The majority of the bacterial isolates in this study showed high incidence in market as compared to production level. These results indicate a lack of compliance with good production practices and hygiene at milking, transportation and market of raw camel milk. PMID- 27230391 TI - Impact and Effectiveness of the Quadrivalent Human Papillomavirus Vaccine: A Systematic Review of 10 Years of Real-world Experience. AB - Prophylactic human papillomavirus (HPV) vaccination programs constitute major public health initiatives worldwide. We assessed the global effect of quadrivalent HPV (4vHPV) vaccination on HPV infection and disease. PubMed and Embase were systematically searched for peer-reviewed articles from January 2007 through February 2016 to identify observational studies reporting the impact or effectiveness of 4vHPV vaccination on infection, anogenital warts, and cervical cancer or precancerous lesions. Over the last decade, the impact of HPV vaccination in real-world settings has become increasingly evident, especially among girls vaccinated before HPV exposure in countries with high vaccine uptake. Maximal reductions of approximately 90% for HPV 6/11/16/18 infection, approximately 90% for genital warts, approximately 45% for low-grade cytological cervical abnormalities, and approximately 85% for high-grade histologically proven cervical abnormalities have been reported. The full public health potential of HPV vaccination is not yet realized. HPV-related disease remains a significant source of morbidity and mortality in developing and developed nations, underscoring the need for HPV vaccination programs with high population coverage. PMID- 27230393 TI - Effect of repetitive transcranial magnetic stimulation on auditory function following acoustic trauma. AB - Repetitive transcranial magnetic stimulation (rTMS) is one form of non-invasive brain stimulation and increasingly shows neuroprotection in multiple neurological disorders. However, the potential of rTMS for protective action on auditory function following acoustic trauma has not been investigated. Here, we examined effect of TMS on hearing conservation, neurons survival and brain-derived neurotrophin factor (BDNF) expression in the cochlea and auditory cortex following acoustic trauma in rats. Wistar rats were exposed to intense pure tone noise (10 kHz, 120 dB SPL for 2 h) followed by rTMS treatment or sham treatment (handling control) daily for 14 days. Auditory brainstem response revealed there was no significant difference in hearing threshold shifts between rTMS- and sham treated rats, although rTMS-treated rats showed less neuron loss in the auditory cortex in comparison with sham rats. Additionally, acoustic trauma increased BDNF expression in the cochlea and auditory cortex, and this elevation could be attenuated by rTMS treatment. Our results suggest present regiment of rTMS does not protect hearing against acoustic trauma, but maybe have implications for tinnitus treatment. PMID- 27230394 TI - Activation of endocannabinoid system in the rat basolateral amygdala improved scopolamine-induced memory consolidation impairment. AB - The current study was designed to examine the involvement of cannabinoid CB1 receptors in the basolateral amygdala (BLA) in scopolamine-induced memory impairment in adult male Wistar rats. The animals were bilaterally implanted with the cannulas in the BLA and submitted to a step-through type passive avoidance task to measure the memory formation. The results showed that intraperitoneal (i.p.) administration of different doses of scopolamine (0.5-1.5mg/kg) immediately after the training phase (post-training) impaired memory consolidation. Bilateral microinjection of the cannabinoid CB1 receptor agonist, arachydonilcyclopropylamide (ACPA; 1-4ng/rat), into the BLA significantly improved scopolamine-induced memory consolidation impairment. On the other hand, co-administration of AM251, a cannabinoid CB1 receptor antagonist (0.25-1ng/rat, intra-BLA), with an ineffective dose of scopolamine (0.5mg/kg, i.p.), significantly impaired memory consolidation and mimicked the response of a higher dose of scopolamine. It is important to note that post-training intra-BLA microinjections of the same doses of ACPA or AM251 alone had no effect on memory consolidation. Moreover, the blockade of the BLA CB1 receptors by 0.3ng/rat of AM251 prevented ACPA-induced improvement of the scopolamine response. In view of the known actions of the drugs used, the present data pointed to the involvement of the BLA CB1 receptors in scopolamine-induced memory consolidation impairment. Furthermore, it seems that a functional interaction between the BLA endocannabinoid and cholinergic muscarinic systems may be critical for memory formation. PMID- 27230395 TI - Effects of Ayahuasca and its Alkaloids on Drug Dependence: A Systematic Literature Review of Quantitative Studies in Animals and Humans. AB - Recently, the anti-addictive potential of ayahuasca, a dimethyltryptamine(DMT)- and beta-carboline-rich hallucinogenic beverage traditionally used by indigenous groups of the Northwest Amazon and currently by syncretic churches worldwide, has received increased attention. To better evaluate this topic, we performed a systematic literature review using the PubMed database to find quantitative studies (using statistical analysis) that assessed the effects of ayahuasca or its components in drug-related symptoms or disorders. We found five animal studies (using harmaline, harmine, or ayahuasca) and five observational studies of regular ayahuasca consumers. All animal studies showed improvement of biochemical or behavioral parameters related to drug-induced disorders. Of the five human studies, four reported significant reductions of dependence symptoms or substance use, while one did not report significant results. The mechanisms responsible for the anti-addictive properties of ayahuasca and its alkaloids are not clarified, apparently involving both peripheral MAO-A inhibition by the beta carbolines and central agonism of DMT at 5-HT2A receptors expressed in brain regions related to the regulation of mood and emotions. Although results are promising, controlled studies are needed to replicate these preliminary findings. PMID- 27230396 TI - Increased olfactory search costs change foraging behaviour in an alien mustelid: a precursor to prey switching? AB - If generalist predators are to hunt efficiently, they must track the changing costs and benefits of multiple prey types. Decisions to switch from hunting preferred prey to alternate prey have been assumed to be driven by decreasing availability of preferred prey, with less regard for accessibility of alternate prey. Olfactory cues from prey provide information about prey availability and its location, and are exploited by many predators to reduce search costs. We show that stoats Mustela erminea, an alien olfactory predator in New Zealand, are sensitive to the search costs of hunting both their preferred rodent prey (mice) and a less desirable alternate prey (locust). We manipulated search costs for stoats using a novel form of olfactory camouflage of both prey, and found that stoats altered their foraging strategy depending on whether mice were camouflaged or conspicuous, but only when locusts were also camouflaged. Stoats gave up foraging four times more often when both prey were camouflaged, compared to when mice were conspicuous and locusts camouflaged. There were no differences in the foraging strategies used to hunt camouflaged or conspicuous mice when locusts were easy to find. Consequently, camouflaged mice survived longer than conspicuous mice when locusts were hard to find, but not when locusts were easy to find. Our results demonstrate that predators can integrate search costs from multiple prey types when making foraging decisions. Manipulating olfactory search costs to alter foraging strategies offers new methods for understanding the factors that foreshadow prey switching. PMID- 27230397 TI - Double-Gloving Impairs the Quality of Surgical Knot Tying: A Randomised Controlled Trial. AB - BACKGROUND: Double-gloving is endorsed by a number of healthcare authorities worldwide, on the basis that it promotes patient and surgeon safety; adoption of this practice amongst surgeons remains limited, based upon anecdotal reporting that double-gloving may compromise surgical technique due to impaired dexterity and sensation. The aim of this study is to formally investigate and demonstrate the effect of double-gloving upon the quality of knot tying, an essential surgical skill. METHODS: An international cohort of practising general surgeons hand tied surgical knots, under both single-gloved and double-gloved conditions, using monofilament and braided sutures, at two different gauges. Half of the participants tied single-gloved first. The mechanical strength of the knots was determined by tensile testing, and each knot was given a knot quality score (KQS), a validated assessment of knot quality. RESULTS AND CONCLUSIONS: 1466 knots were tested. Double-gloving was shown to reduce KQS for all suture types, compared to knots tied under single-gloved conditions (p = 0.001). There was no difference in the KQS of the double-gloved ties between those who routinely double-gloved and those who did not (p = 0.640). The OR showed that double gloving reduced the KQS by 24 % overall, with the effect being much more prominent when the finer 4.0 suture was used, as knot quality was reduced by almost 50 % (95 % CI 13-93 %). Double-gloving impairs the quality of knot tying, and therefore, surgeons should consider other precautions to ensure patient and surgeon safety. These findings also question the validity of recommendations that surgeons should double-glove as a routine. PMID- 27230399 TI - Basic Statistics for Comparing Categorical Data From 2 or More Groups. PMID- 27230398 TI - Critical Care in a Tertiary Hospital in Malawi. AB - BACKGROUND: The provision of critical care services is essential to healthcare systems and increasingly a global health focus, but many hospitals in sub-Saharan Africa are unable to meet this need. Intensive care unit (ICU) mortality in this region is high, but studies describing the provision of critical care services are scarce. METHODS: This was a retrospective cohort study of all patients admitted to the ICU at Queen Elizabeth Central Hospital (QECH) in Blantyre, Malawi, between September 1, 2013, and October 17, 2014. We summarized demographics, clinical characteristics, and outcomes, and analyzed factors associated with mortality. RESULTS: Of 390 patients admitted to ICU during the study, 44.9 % of patients were male, and the median age was 22 years (IQR 6-35) years. Although most patients (73.1 %) were admitted with surgical diagnoses, the highest mortality was among patients admitted with sepsis (59.3 %), or obstetric (44.7 %) or medical (40.0 %) diagnoses. Overall ICU mortality was high (23.6 %). CONCLUSIONS: There is a shortage of data describing critical care in low-resource settings, particularly in sub-Saharan Africa. Surgical disease comprises the majority of ICU utilization in this study site, but medical and obstetric illness carried higher ICU mortality. These data may guide strategies for improving critical care in the region. PMID- 27230400 TI - MiR-29b suppresses the proliferation and migration of osteosarcoma cells by targeting CDK6. AB - Osteosarcoma is the most common primary sarcoma of bone, and it is a leading cause of cancer death among adolescents and young adults. However, the molecular mechanism underlying osteosarcoma carcinogenesis remains poorly understood. Recently, cyclin-dependent kinase 6 (CDK6) was identified as an important oncogene. We found that CDK6 protein level, rather than CDK6 mRNA level, is much higher in osteosarcoma tissues than in normal adjacent tissues, which indicates a post-transcriptional mechanism involved in CDK6 regulation in osteosarcoma. MiRNAs are small non-coding RNAs that repress gene expression at the post transcriptional level and have widely been shown to play important roles in many human cancers. In this study, we investigated the role of miR-29b as a novel regulator of CDK6 using bioinformatics methods. We demonstrated that CDK6 can be downregulated by miR-29b via binding to the 3'-UTR region in osteosarcoma cells. Furthermore, we identified an inverse correlation between miR-29b and CDK6 protein levels in osteosarcoma tissues. Finally, we examined the function of miR 29b-driven repression of CDK6 expression in osteosarcoma cells. The results revealed that miR-29b acts as a tumor suppressor of osteosarcoma by targeting CDK6 in the proliferation and migration processes. Taken together, our results highlight an important role for miR-29b in the regulation of CDK6 in osteosarcoma and may open new avenues for future osteosarcoma therapies. PMID- 27230401 TI - Fermentation of residual glycerol by Clostridium acetobutylicum ATCC 824 in pure and mixed cultures. AB - The aim of this research was to estimate the production of hydrogen, organic acids and alcohols by the strain of Clostridium acetobutylicum ATCC 824 using residual glycerol as a carbon source. The experiments were carried out in pure and mixed cultures in batch experiments. Three different sources of inocula for mixed culture were used. Ruminal liquid from goats and sludge collected from two upflow anaerobic sludge blanket reactors treating municipal wastewater and brewery effluent were tested for hydrogen, organic acids and alcohols production with or without C. acetobutylicum ATCC 824. The main detected end-products from the glycerol fermentation were hydrogen, organic acids (acetic, propionic, butyric and caproic) and alcohol (ethanol and 1,3-propanediol - 1,3PD). High hydrogen (0.44 mol H2/mol glycerol consumed) and 1,3PD (0.32 mol 1,3PD/mol glycerol consumed) yields were obtained when the strain C. acetobutylicum ATCC 824 was bioaugmented into the sludge from municipal wastewater using 5 g/L of glycerol. Significant concentrations of n-caproic acid were detected in the ruminal liquid when amended with C. acetobutylicum ATCC 824. The results suggest that glycerol can be used for the generation of H2, 1,3PD and n-caproic acid using C. acetobutylicum ATCC 824 as agent in pure or mixed cultures. PMID- 27230402 TI - Occupational commitment and job satisfaction mediate effort-reward imbalance and the intention to continue nursing. AB - AIM: Occupational commitment and job satisfaction are major predictors of the intention to continue nursing. This study's purpose was to verify the mediating effects of job satisfaction and three components of occupational commitment on the relationship between effort-reward imbalance and the intention to continue nursing. METHODS: A self-report questionnaire was distributed to 3977 nurses by the nursing department of 12 hospitals in the Tohoku and Kanto districts of Japan in 2013. Of these, 1531 (response rate: 38.5%) nurses returned the questionnaire by mail and the complete data that were provided by 1241 nurses (valid response rate: 31.2%) were analyzed. RESULTS: Structural equation modeling showed that the effort-reward ratio had negative effects on job satisfaction and affective and normative occupational commitment. Job satisfaction and affective and normative occupational commitment had positive effects on the intention to continue nursing, whereas the effort-reward ratio had no direct effect on the intention to continue nursing. Continuance occupational commitment was not a mediator, but it positively influenced the intention to continue nursing. CONCLUSION: The findings suggest that it is important to increase job satisfaction and affective and normative occupational commitment in order to enhance their buffering effects on the relationship between job stress and the intention to continue nursing. Measures to increase continuance occupational commitment also would be an effective method of strengthening the intention to continue nursing. Improvements in these areas should contribute to an increase in nurses' intention to continue nursing and prevent the loss of this precious human resource from the health sector. PMID- 27230403 TI - Pyrrolidine-Acridine hybrid in Artemisinin-based combination: a pharmacodynamic study. AB - Aiming to develop new artemisinin-based combination therapy (ACT) for malaria, antimalarial effect of a new series of pyrrolidine-acridine hybrid in combination with artemisinin derivatives was investigated. Synthesis, antimalarial and cytotoxic evaluation of a series of hybrid of 2-(3-(substitutedbenzyl)pyrrolidin 1-yl)alkanamines and acridine were performed and mode of action of the lead compound was investigated. In vivo pharmacodynamic properties (parasite clearance time, parasite reduction ratio, dose and regimen determination) against multidrug resistant (MDR) rodent malaria parasite and toxicological parameters (median lethal dose, liver function test, kidney function test) were also investigated. 6 Chloro-N-(4-(3-(3,4-dimethoxybenzyl)pyrrolidin-1-yl)butyl)-2-methoxyacridin-9 amine (15c) has shown a dose dependent haem bio-mineralization inhibition and was found to be the most effective and safe compound against MDR malaria parasite in Swiss mice model. It displayed best antimalarial potential with artemether (AM) in vitro as well as in vivo. The combination also showed favourable pharmacodynamic properties and therapeutic response in mice with established MDR malaria infection and all mice were cured at the determined doses. The combination did not show toxicity at the doses administered to the Swiss mice. Taken together, our findings suggest that compound 15c is a potential partner with AM for the ACT and could be explored for further development. PMID- 27230404 TI - Preoperative Endoscopic Biliary Drainage May Negatively Impact Survival Following Pancreatoduodenectomy for Ampullary Cancer. AB - BACKGROUND/AIMS: Ampullary carcinoma is a rare tumour with a high resectability rate. There is an increasing body of evidence indicating not only tumour-related factors, but also jaundice influence survival following curative resection. Several modalities for preoperative biliary drainage are available; however, routine preoperative endoscopic biliary drainage (PEBD) is not recommended. There is no sufficient data regarding the impact of PEBD on long-term outcomes. The aim of our study was to identify predictive factors of survival with special regard to PEBD in patients undergoing curative resection for ampullary carcinoma. PATIENTS AND METHODS: Data from 64 consecutive patients with adenocarcinoma of the papilla of Vater who have been operated on was analysed. Overall survival was defined from the date of surgery to the date of death, or censored at the last patient contact. Survival analysis was determined by means of the Kaplan-Meier method. The significance of the demographic, clinical and histopathologic factors was ascertained by the log-rank test. A Cox proportional hazard model was used to determine independent prognostic factors of survival. RESULTS: Twenty patients (31.2%) underwent PEBD. Univariate analysis revealed tumour-related factors, age over 70, and PEBD to negatively influence survival. Five of them (excluding T stage) were identified as the independent prognosticators, while PEBD appeared to be the most decisive factor. Median survival for patients who underwent PEBD was 25.3 months as compared to 112.9 months for those who did not. In conclusion, PEBD negatively affected long-term outcomes in our patients with resected ampullary carcinoma. PMID- 27230405 TI - Physiological strain to prolonged exercise bouts at the walk-run transition speeds depends on locomotion mode in healthy untrained men. AB - This study compared the physiological strain induced by prolonged walking and running performed at the walk-run transition speed (WRTS) in healthy untrained men. Twenty volunteers (age: 28 +/- 5.01 years; height: 174.0 +/- 0.3 cm; body mass: 74.5 +/- 0.6 kg) underwent the following: (a) ramp-incremental maximal cardiopulmonary exercise test (CPET); (b) specific protocol to detect the WRTS; and (c) two 30-min walking and running bouts at WRTS (mean +/- SD: 6.9 +/- 0.06 km/h). Expired gases were collected during exercise bouts via the metabolic cart. A significant effect of locomotion mode (F = 4.8, P < 0.001) was observed with running resulting in higher cardiorespiratory responses than walking at the WRTS (oxygen uptake: mean difference = 0.26 L/min; pulmonary ventilation: mean difference = 5.53 L/min; carbon dioxide output: mean difference = 0.32 L/min; heart rate: mean difference = 13 beats/min; total energy expenditure: mean difference = 59 kcal). The rating of perceived exertion was similar across locomotion modes (mean difference = 0.3; P = 0.490). In conclusion, running promoted greater cardiorespiratory responses than walking at the WRTS in untrained healthy men. These data might have practical impact on aerobic training performed at intensities corresponding to WRTS. PMID- 27230406 TI - Prevalence of, and risk factors for, symptomatic pelvic organ prolapse in Rural Bangladesh: a cross-sectional survey study. AB - INTRODUCTION AND HYPOTHESIS: The prevalence of symptomatic pelvic organ prolapse (POP), diagnosed by a pre-tested structured questionnaire, is unknown in Bangladesh. We investigated the prevalence of, and risk factors for, symptomatic POP in women in rural Bangladesh, recruited from the community. METHODS: A cross sectional survey of 787 women aged over 15 years was conducted in four villages in one district in rural Bangladesh. The prevalence of symptomatic POP and the risk factors associated with the condition was investigated, using Chi-squared and multivariate logistic regression. RESULTS: The prevalence of symptomatic POP was 15.6 %. The mean age of participants was 40.1 (+/-9.0) years. Women aged 35 44 years (odds ratio [OR] 1.96, 95 % confidence interval [CI] 1.03-3.73) and >=45 years (OR 2.95, 95 % CI 1.62-5.38) were more likely to have POP compared with women aged <=35 years. Having POP was positively associated with women having >=5 children (OR 4.34, 95 % CI 1.39-13.58), having chronic obstructive pulmonary disease (COPD; OR 2.07, 95 % CI 1.02-4.21), and women having constipation (OR 3.54, 95 % CI 1.87-6.72). Women whose husband had >5 years of schooling were less likely to have POP (OR 0.37, 95 % CI 0.19-0.73) compared with women whose husband had no schooling. CONCLUSIONS: Symptomatic POP affects a substantial proportion of women in rural Bangladesh and increases with age. Parity, COPD, constipation and husband's education are associated with POP, all of which have the potential to be modified. Thus, interventions targeting these risk factors to prevent the condition are urgently needed in Bangladesh. PMID- 27230407 TI - Hungarian language validation of the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR). AB - INTRODUCTION AND HYPOTHESIS: Until now, no valid Hungarian questionnaire has existed to evaluate the sexual quality of life of women with pelvic floor disorders. The aim of this study was to translate the Prolapse/Urinary Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR), into Hungarian and to validate the translated PISQ-IR. METHODS: PISQ-IR was translated and validated using three steps, as guided by the IUGA international protocol: forward translation by two urogynecologists, a community review process consisting of one on-one cognitive interviews with 20 patients, and backward translation by a native English speaker. The final version was approved by the IUGA Working Group comprising the original authors. RESULTS: Among sexually active women, good internal consistency was observed for all scales of the adapted instrument: global quality (Cronbach's alpha = 0.75), condition impact (alpha = 0.87), desire (alpha = 0.82), arousal/orgasm (alpha = 0.67), partner-related (alpha = 0.61) and condition-specific (alpha = 0.67). Among women who were not sexually active, internal consistency was valid for three scales: condition-specific (alpha = 0.70), global quality (alpha = 0.81) and condition impact (alpha = 0.86). Cronbach's alpha could not be determined in the partner-related domain because only two items were included. Criterion validity and reliability showed strong significant correlations with the UI at the Clinical-Q values and the FSFI and PFDI-20 tests. CONCLUSIONS: The PISQ-IR Hungarian version is a valid and reliable tool that is equivalent to the original English questionnaire and assesses sexual function in Hungarian women with pelvic organ prolapse, urinary incontinence and/or fecal incontinence. PMID- 27230408 TI - Measuring the impact of a posterior compartment procedure on symptoms of obstructed defecation and posterior vaginal compartment anatomy. AB - INTRODUCTION AND HYPOTHESIS: We hypothesized that there would be a significant difference in changes in obstructed defecation symptoms and posterior compartment prolapse between women who underwent posterior vaginal wall prolapse repair (PR) and those who did not. METHODS: This was a two-site prospective cohort study of women undergoing prolapse or incontinence surgery in which a PR was, or was not, performed at the discretion of the surgeon. Women were assessed using validated obstructed defecation questionnaires and standardized examination measures (including POP-Q, measurement of transverse gh, and assessment for a rectovaginal pocket and laxity) prior to pelvic surgery and 12 weeks after surgery. RESULTS: Of 68 women who underwent surgery, 43 had PR. The PR group had higher obstructed defecation symptoms and greater posterior compartment prolapse at baseline. At 12 weeks, obstructed defecation symptoms had improved significantly more in the PR group than in the no PR group (all p < 0.03). Anatomic outcomes showed greater improvement in point Bp in the PR group (-3.4 vs. -0.7 no PR, p < 0.001) and resolution of the rectovaginal pocket (86 % vs. 42 %, p = 0.002). There were no significant changes in obstructed defecation symptoms or anatomic outcomes from baseline in the no PR group, while the PR group showed significantly improved obstructed defecation symptoms and anatomic outcomes after repair (p < 0.001 for both). CONCLUSIONS: Significant improvements in obstructed defecation symptoms and posterior compartment prolapse were seen after PR, but not in women who did not receive PR. Obstructed defecation symptoms, Bp and rectovaginal pocket were the measures best able to demonstrate improvement after PR. We recommend the use of these measures to assess the impact of surgery in the posterior compartment. PMID- 27230409 TI - Animal facility videoendoscopic intubation station: tips and tricks from mice to rabbits. AB - Endotracheal intubation of laboratory animals is a common procedure shared by several research fields for different purposes, such as mechanical ventilation of anaesthetized animals, instillation of cytotoxic nanoparticles, infectious agents or tumour cells for induction of disease models, and even for diagnostic and therapeutic purposes. These different research purposes, achieved in different animal models, require technical expertise and equipment that suits every research need from animal facilities. In this short report we propose a videoendoscopic intubation station that could be shared among the most common laboratory animals, namely the mouse, rat, guinea pig and rabbit, from neonates to adult animals. This report aims to contribute to the reduction of animals excluded from experiments due to false paths during direct and blind intubations and to the refinement of procedures by replacing surgical approaches such as tracheotomy. PMID- 27230410 TI - A pharmacokinetic/pharmacodynamic model capturing the time course of torasemide induced diuresis in the dog. AB - A pharmacokinetic/pharmacodynamic modelling approach was used to determine a dosage regimen which maximizes diuretic efficiency of torasemide in dogs. Kinetic profiles of plasma concentration, torasemide excretion rate in urine (TERU) and diuresis were investigated in 10 dogs after single oral administrations at 3 dose levels, 0.2, 0.8 and 1.6 mg/kg, and an intravenous injection of 0.2 mg/kg. Endogenous regulation was evidenced by a proteresis loop between TERU and diuresis. To describe the diuresis-time profile, TERU served as input into a turnover model with inhibition of loss of response, extended by a moderator acting on both loss and production of response. Estimated maximum inhibition of loss of response, Imax , was 0.984 showing that torasemide is an efficacious diuretic able to suppress almost total water reabsorption. A TERU50, value producing half of Imax , of 1.45 MUg/kg/h was estimated from the model. Pharmacokinetic and pharmacodynamic parameters were used to simulate the torasemide dose-effect relationship after oral administration. Model predictions were in good agreement with diuresis measured in a validation study conducted in 10 dogs, which were administered oral doses of 0.15, 0.4, 0.75, 1.5 and 4.5 mg/kg for 5 days. Finally, oral dose associated with the highest daily diuretic efficiency was predicted to be 0.1 mg/kg. PMID- 27230411 TI - Continuity of Monolayer-Bilayer Junctions for Localization of Lipid Raft Microdomains in Model Membranes. AB - We show that the selective localization of cholesterol-rich domains and associated ganglioside receptors prefer to occur in the monolayer across continuous monolayer-bilayer junctions (MBJs) in supported lipid membranes. For the MBJs, glass substrates were patterned with poly(dimethylsiloxane) (PDMS) oligomers by thermally-assisted contact printing, leaving behind 3 nm-thick PDMS patterns. The hydrophobicity of the transferred PDMS patterns was precisely tuned by the stamping temperature. Lipid monolayers were formed on the PDMS patterned surface while lipid bilayers were on the bare glass surface. Due to the continuity of the lipid membranes over the MBJs, essentially free diffusion of lipids was allowed between the monolayer on the PDMS surface and the upper leaflet of the bilayer on the glass substrate. The preferential localization of sphingomyelin, ganglioside GM1 and cholesterol in the monolayer region enabled to develop raft microdomains through coarsening of nanorafts. Our methodology provides a simple and effective scheme of non-disruptive manipulation of the chemical landscape associated with lipid phase separations, which leads to more sophisticated applications in biosensors and as cell culture substrates. PMID- 27230412 TI - FGFR2 in gastric cancer: protein overexpression predicts gene amplification and high H-index predicts poor survival. AB - FGFR2 gene amplification, and resulting FGFR2 protein overexpression, is rare in gastric cancer patients, and development of an accurate and widely available method for mass screening to identify patients who may respond to treatment with fibroblast growth factor receptor (FGFR) inhibitors is important. We first screened 312 gastric cancer patients with known copy number variations by FGFR2b immunohistochemistry using FPR2-D, an isoform-specific antibody. Next, we performed immunohistochemistry on tissue microarrays from 1574 gastric cancer patients. Selected cases were analyzed for FGFR2 amplification by FISH. In addition, FGFR2b overexpression was studied in 88 matched primary and metastatic gastric cancers. In the first cohort, FGFR2b immunohistochemistry results correlated very well with those of copy number variation (r=0.79) and FISH (r=1.0). In total, FGFR2b overexpression was identified in 73 of 1974 gastric cancers (4%). The concordance between immunohistochemistry and FISH was extremely high; all 2+ and 3+ cases identified by immunohistochemistry were FGFR2 amplified. In the matched primary and metastatic gastric cancer pairs, the positivity and percentage of positive tumor cells were significantly higher in metastatic gastric cancers than in primary gastric cancers (8% vs 3% and 75% vs 47%, respectively; P<0.001). FGFR2b overexpression was significantly more frequent in gastric cancers with diffuse subtype (P=0.01) and higher N stage (P=0.006). FGFR2b overexpression with H-score >=150 were independent prognostic factors for overall survival with hazard ratio of 1.836 (95% confidence interval, 1.034-3.261; P=0.038). FGFR2b positivity in immunohistochemistry was strongly correlated with FGFR2 amplification. Given the low frequency of FGFR2 amplification in gastric cancers, FGFRb2 immunohistochemistry is an accurate screening tool to detect FGFR2 amplification, and both primary and metastatic gastric cancer tissues should be tested to select gastric cancer patients for treatment with FGFR2 inhibitors. PMID- 27230413 TI - KCC3 axonopathy: neuropathological features in the central and peripheral nervous system. AB - Hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum (HMSN/ACC) is an autosomal recessive disease of the central and peripheral nervous system that presents as early-onset polyneuropathy. Patients are hypotonic and areflexic from birth, with abnormal facial features and atrophic muscles. Progressive peripheral neuropathy eventually confines them to a wheelchair in the second decade of life, and death occurs by the fourth decade. We here define the neuropathologic features of the disease in autopsy tissues from eight cases. Both developmental and neurodegenerative features were found. Hypoplasia or absence of the major telencephalic commissures and a hypoplasia of corticospinal tracts to half the normal size, were the major neurodevelopmental defects we observed. Despite being a neurodegenerative disease, preservation of brain weight and a conspicuous absence of neuronal or glial cell death were signal features of this disease. Small tumor-like overgrowths of axons, termed axonomas, were found in the central and peripheral nervous system, indicating attempted axonal regeneration. We conclude that the neurodegenerative deficits in HMSN/ACC are primarily caused by an axonopathy superimposed upon abnormal development, affecting peripheral but also central nervous system axons, all ultimately because of a genetic defect in the axonal cotransporter KCC3. PMID- 27230414 TI - The Application of Graphene and Its Derivatives to Energy Conversion, Storage, and Environmental and Biosensing Devices. AB - Graphene (GR) and its derivatives are promising materials on the horizon of nanotechnology and material science and have attracted a tremendous amount of research interest in recent years. The unique atom-thick 2D structure with sp(2) hybridization and large specific surface area, high thermal conductivity, superior electron mobility, and chemical stability have made GR and its derivatives extremely attractive components for composite materials for solar energy conversion, energy storage, environmental purification, and biosensor applications. This review gives a brief introduction of GR's unique structure, band structure engineering, physical and chemical properties, and recent energy related progress of GR-based materials in the fields of energy conversion (e.g., photocatalysis, photoelectrochemical water splitting, CO2 reduction, dye sensitized and organic solar cells, and photosensitizers in photovoltaic devices) and energy storage (batteries, fuel cells, and supercapacitors). The vast coverage of advancements in environmental applications of GR-based materials for photocatalytic degradation of organic pollutants, gas sensing, and removal of heavy-metal ions is presented. Additionally, the use of graphene composites in the biosensing field is discussed. We conclude the review with remarks on the challenges, prospects, and further development of GR-based materials in the exciting fields of energy, environment, and bioscience. PMID- 27230415 TI - Introduction. PMID- 27230416 TI - Correction to iCI: Iterative CI toward Full CI. PMID- 27230417 TI - Aniline-Promoted Cyclization-Replacement Cascade Reactions of 2 Hydroxycinnamaldehydes with Various Carbonic Nucleophiles through In Situ Formed N,O-Acetals. AB - In this study, we report the harnessing of new reactivity of N,O-acetals in an aminocatalytic fashion for organic synthesis. Unlike widely used strategies requiring the use of acids and/or elevated temperatures, direct replacement of the amine component of the N,O-acetals by carbon-centered nucleophiles for C-C bond formation is realized under mild reaction conditions. Furthermore, without necessary preformation of the N,O-acetals, an amine-catalyzed in situ formation of N,O-acetals is developed. Coupling both reactions into a one-pot operation enables the achievement of a catalytic process. We demonstrate the employment of simple anilines as promoters for the cyclization-substitution cascade reactions of trans-2-hydroxycinnamaldehydes with various carbonic nucleophiles including indoles, pyrroles, naphthols, phenols, and silyl enol ethers. The process offers an alternative approach to structurally diverse, "privileged" 2-substituted 2H chromenes. The synthetic power of the new process is furthermore shown by its application in a 2-step synthesis of the natural product candenatenin E and for the facile installation of 2-substituted 2H-chromene moieties into biologically active indoles. PMID- 27230418 TI - Interphase tuning for stronger and tougher composites. AB - The development of composite materials that are simultaneously strong and tough is one of the most active topics of current material science. Observations of biological structural materials show that adequate introduction of reinforcements and interfaces, or interphases, at different scales usually improves toughness, without reduction in strength. The prospect of interphase properties tuning may lead to further increases in material toughness. Here we use evaporation-driven self-assembly (EDSA) to deposit a thin network of multi-wall carbon nanotubes on ceramic surfaces, thereby generating an interphase reinforcing layer in a multiscale laminated ceramic composite. Both strength and toughness are improved by up to 90%, while keeping the overall volume fraction of nanotubes in a composite below 0.012%, making it a most effective toughening and reinforcement technique. PMID- 27230419 TI - Generalizing Contextual Analysis. AB - Okasha, in Evolution and the Levels of Selection, convincingly argues that two rival statistical decompositions of covariance, namely contextual analysis and the neighbour approach, are better causal decompositions than the hierarchical Price approach. However, he claims that this result cannot be generalized in the special case of soft selection and argues that the Price approach represents in this case a better option. He provides several arguments to substantiate this claim. In this paper, I demonstrate that these arguments are flawed and argue that neither the Price equation nor the contextual and neighbour partitionings sensu Okasha are adequate causal decompositions in cases of soft selection. The Price partitioning is generally unable to detect cross-level by-products and this naturally also applies to soft selection. Both contextual and neighbour partitionings violate the fundamental principle of determinism that the same cause always produces the same effect. I argue that a fourth partitioning widely used in the contemporary social sciences, under the generic term of 'hierarchical linear model' and related to contextual analysis understood broadly, addresses the shortcomings of the three other partitionings and thus represents a better causal decomposition. I then defend this model against the argument that because it predicts that there is some organismal selection in some specific cases of segregation distortion then it should be rejected. I show that cases of segregation distortion that intuitively seem to contradict the conclusion drawn from the hierarchical linear model are in fact cases of multilevel selection 2 while the assessment of the different partitionings are restricted to multilevel selection 1. PMID- 27230420 TI - Bipartite electronic superstructures in the vortex core of Bi2Sr2CaCu2O8+delta. AB - The central issue in the physics of cuprate superconductivity is the mutual relationship among superconductivity, pseudogap and broken-spatial-symmetry states. A magnetic field B suppresses superconductivity, providing an opportunity to investigate the competition among these states. Although various B-induced electronic superstructures have been reported, their energy, spatial and momentum space structures are unclear. Here, we show using spectroscopic-imaging scanning tunnelling microscopy on Bi2Sr2CaCu2O8+delta that there are two distinct B induced electronic superstructures, both being localized in the vortex core but appearing at different energies. In the low-energy range where the nodal Bogoliubov quasiparticles are well-defined, we observe the so-called vortex checkerboard that we identify as the B-enhanced quasiparticle interference pattern. By contrast, in the high-energy region where the pseudogap develops, the broken-spatial-symmetry patterns that pre-exist at B=0 T is locally enhanced in the vortex core. This evidences the competition between superconductivity and the broken-spatial-symmetry state that is associated with the pseudogap. PMID- 27230421 TI - A photodegradable hexaaza-pentacene molecule for selective dispersion of large diameter semiconducting carbon nanotubes. AB - Harvesting high-purity semiconducting single-walled carbon nanotubes (s-SWCNTs) with removable dispersants remains a challenge. In this work, we demonstrate that small heteroacene derivatives may serve as promising selective dispersants for sorting s-SWCNTs. A rich N "doped" and thiophene-substituted hexaazapentacene molecule, denoted as 4HP, was found to be more favorable for high-purity s-SWCNTs with large diameters. Importantly, 4HP is photodegradable under 365 nm or blue light, which enables a simple deposition approach for the formation of clean s SWCNT networks. The as-fabricated thin film transistors show excellent performance with a charge-mobility of 30-80 cm(2) V(-1) s(-1) and an on-off ratio of 10(4)-10(6). PMID- 27230422 TI - Natural and human induced factors influencing the abundance of Schistosoma host snails in Zambia. AB - Schistosomiasis remains a global public health problem affecting about 240 million people. In Zambia, 2 million are infected while 3 million live with the risk of getting infected. Research and interventions relating to schistosomiasis are mainly linked to disease epidemiology. Malacological and ecological aspects of the disease are superficially understood. Developing effective control measures requires an understanding of interacting environmental and socioeconomic factors of host snails vis-a-vis schistosomiasis. Therefore, the present work involved collecting social and environmental data in a large field study in two zones in Zambia that are different in terms of temperature and rainfall amounts. Social data collected through questionnaires included demographic, educational and knowledge of schistosomiasis disease dynamics. Environmental data included physicochemical factors, aquatic plants and snails. Gender (P < 0.001) significantly influences livelihood strategies, while age (P = 0.069) and level of education (P = 0.086) have a moderate influence in zone I. In zone III, none of these factors (age, P = 0.378; gender, P = 0.311; education, P = 0.553) play a significant role. Environmental parameters explained 43 and 41 % variation in species composition for zones I and III, respectively. Most respondents' (52 %, 87 %) perception is that there are more cases of bilharzia in hot season than in other seasons (rainy season 23 %, 7 %; cold season 8 %, 0 % and year round 17 %, 6 %) for zone I and zone III, respectively. PMID- 27230423 TI - Assessing ambient ozone injury in olive (Olea europaea L.) plants by using the antioxidant ethylenediurea (EDU) in Saudi Arabia. AB - The antiozonant chemical, ethylenediurea (N-[2-(2-oxo-1-imidazolidinyl)ethyl]-N' phenylurea, abbreviated as EDU), was applied as stem injections or soil drenches to 5-year-old containerized plants of olive (Olea europaea L. cultivar Kalamata) in growth chambers in order to assess its ameliorative effects against realistic ozone (O3) stress. Visible injury symptoms were reduced greatly in individuals treated with EDU, with injection applications having greater protection than soil drenches. EDU application caused increases in the measured ecophysiological parameters compared to untreated individuals. In particular, the stem injection protected plants against photosynthetic impairment (unchanged net photosynthetic rates and intercellular CO2 concentration, in comparison to plants grown in filtered air). EDU application increased the protection of PSII from ambient O3 oxidative stress, although it did not retain the proportion of redox state of QA, pigment composition of photosynthetic apparatus and size of light-harvesting complex of PSII. However, the stem injection of plants with EDU induced lower non photochemical quenching (NPQ) values in comparison to ambient air (-2 %), indicating a better photoprotection of PSII in comparison to soil drench application. EDU application caused increases in the morphological and biometric parameters compared to individuals exposed to ambient air. To the best of our knowledge, this is the first study highlighting the protection of Kalamata olive trees due to EDU in terms of growth, yield, visible injury, and photosynthetic performance. Furthermore, this study proved that EDU could be a low-cost and a low-technology efficient tool for assessing O3 effects on plant performances in the field in Saudi Arabia. PMID- 27230424 TI - The heron that laid the golden egg: metals and metalloids in ibis, darter, cormorant, heron, and egret eggs from the Vaal River catchment, South Africa. AB - Metal pollution issues are afforded the highest priority in developing countries. Only one previous study has addressed metals in African bird eggs. We determined the concentration of metals and metalloids in bird eggs from four sites in the Vaal River catchment (VRC) of South Africa to provide data on the current situation. We analysed 16 pools of 77 heron, ibis, darter, egret, and cormorant eggs for 18 metals and metalloids using ICP-MS. We found high concentrations of gold (Au), uranium (U), thallium (Tl), and platinum (Pt) in Grey Heron eggs from Baberspan. Great white egrets from Bloemhof Dam had high concentrations of mercury (Hg). Multivariate analyses revealed strong associations between Au and U, and between palladium (Pd) and Pt. The toxic reference value (TRV) for Hg was exceeded in seven pools. Selenium exceeded its TRV in one pool; in the same pool, copper (Cu) reached its TRV. Compared with other studies, VRC bird eggs had high concentrations of contaminants. Based on these high concentrations, human health might be at risk as Grey Herons and humans share similar food and are therefore exposed to the same contaminants. PMID- 27230425 TI - Assessment of the toxicity of wastewater from the metalworking industry treated using a conventional physico-chemical process. AB - This article presents results from a toxicity reduction evaluation program intended to describe wastewater from the metalworking industry that was treated using a conventional physico-chemical process. The toxicity of the wastewater for the microcrustacean Daphnia magna was predominantly expressive. Alkaline cyanide wastewater generated from electroplating accounted for the largest number of samples with expressive toxicity. When the raw wastewater concentrations in the batches were repeated, inexpressive toxicity variations were observed more frequently among the coagulated-flocculated samples. At the coagulation flocculation step, 22.2 % of the treatments had reduced acute toxicity, 30.6 % showed increased toxicity, and 47.2 % remained unchanged. The conductivity and total dissolved solids contents of the wastewater indicated the presence of salts with charges that were inappropriate for the survival of daphnid. The wastewaters treated by neutralization and coagulation-flocculation had average metallic compound contents that were greater than the reference toxic concentrations reported in other studies, suggesting that metals likely contributed to the toxic effects of the wastewater on freshwater microcrustaceans. Thus, alternative coagulants and flocculants should be assessed, and feasible doses should be determined to improve wastewater treatment. In addition, advanced treatment processes should be assessed for their abilities to remove dissolved toxic salts and ions. PMID- 27230426 TI - Levels of pesticides residues in the White Nile water in the Sudan. AB - Twenty-two commonly used pesticides were monitored during autumn, winter, and summer of 2004-2005 in 27 water samples from three sites along the White Nile in Sudan (former Sudan). Sites were selected to reflect pesticides gathered from drainage canals in central Sudan and from upstream sources. Collected samples were extracted and subjected to gas chromatographic analysis. Pesticides levels were measured in nanograms per liter. Pesticides residues were detected in 96 % of the samples with a total residue burden of 4132.6 ng L(-1), and an overall mean concentration and range of 50.99 and not detected-1570 ng L(-1), respectively. Ororganochlorines were the most frequently detected contaminants, which were found in 70 % of the samples, causing a total burden of 2852.8 ng L( 1), followed by pyrethroids 15 % of the samples, with a total burden of 926.5 ng L(-1). The tested herbicides were detected in ?4 % of the samples with a total burden of 353.3 ng L(-1), while organophosphorus levels were below the detection limit. The most frequent contaminants were the following: heptachlor and its epoxide (52 % of samples), followed by DDTs (dichlorodiphenyltrichloroethanes) (DDT and DDE, in 19 % of the samples), cypermethrin and fenvalerate (in 11 % of the samples), and pendimethalin (in <4 % of the samples). Residues of hexachlorocyclohexane (HCH) isomers (alpha, beta, gamma and delta), endosulfan (alpha and beta), p, p-DDD, lambda cyhalothrin, deltamethrin, and oxyfluorfen were not detected in the analyzed samples. Generally, levels were least in autumn, and followed by summer and winter. Sources of contamination might include agricultural lands in central Sudan and upstream sources. Both recent and old contaminations were indicated. PMID- 27230427 TI - Development, validation and application of a sensitive analytical method for residue determination and dissipation of imidacloprid in sugarcane under tropical field condition. AB - A simple and sensitive analytical method has been developed and validated for the determination of trace amounts of imidacloprid in/on sugarcane sett, stalk and leaf. The method optimized in the present study requires less volume of organic solvent and time. Hence, this method is suitable for high-throughput analyses involving large number of samples. The limit of detection (LOD) and limit of quantification (LOQ) of the method were 0.003 and 0.01 mg/kg, respectively. The recovery and relative standard deviation were more than 93 % and less than 4 %, respectively. Thus, it is obvious that the analytical method standardized in this study is more precise and accurate enough to determine the residues of imidacloprid in sugarcane sett, stalk and leaf. The dissipation and translocation of imidacloprid residues from treated cane setts to leaf and stalk were studied by adopting this method. In sugarcane setts, the residues of imidacloprid persisted up to 120 days with half-life of 15.4 days at its recommended dose (70 g a.i./ha). The residues of imidacloprid were found to be translocated from setts to stalk and leaf. The imidacloprid residues were detected up to 105 days in both leaf and stalk. Dipping of sugarcane setts in imidacloprid at its recommended dose may result in better protection of cane setts and established crop because of higher initial deposit (>100 mg/kg) and longer persistence (>120 days). PMID- 27230428 TI - A web-based multicriteria evaluation of spatial trade-offs between environmental and economic implications from hydraulic fracturing in a shale gas region in Ohio. AB - Planning of shale gas infrastructure and drilling sites for hydraulic fracturing has important spatial implications. The evaluation of conflicting and competing objectives requires an explicit consideration of multiple criteria as they have important environmental and economic implications. This study presents a web based multicriteria spatial decision support system (SDSS) prototype with a flexible and user-friendly interface that could provide educational or decision making capabilities with respect to hydraulic fracturing site selection in eastern Ohio. One of the main features of this SDSS is to emphasize potential trade-offs between important factors of environmental and economic ramifications from hydraulic fracturing activities using a weighted linear combination (WLC) method. In the prototype, the GIS-enabled analytical components allow spontaneous visualization of available alternatives on maps which provide value-added features for decision support processes and derivation of final decision maps. The SDSS prototype also facilitates nonexpert participation capabilities using a mapping module, decision-making tool, group decision module, and social media sharing tools. The logical flow of successively presented forms and standardized criteria maps is used to generate visualization of trade-off scenarios and alternative solutions tailored to individual user's preferences that are graphed for subsequent decision-making. PMID- 27230429 TI - "Collaborative care" is preferable to "patient centred care". PMID- 27230430 TI - Pediatric Asthma and the Indoor Microbial Environment. AB - The global increase in the prevalence of asthma has been related to several risk factors; many of them linked to the "westernization" process and the characteristics of the indoor microbial environment during early life may play an important role. Living in moisture damaged homes contributes to the exacerbation and development of asthma. However, living in homes with a rich variety and high levels of microbes (e.g., traditional farming environments) may confer protection. While the results of previous research are rather consistent when it comes to observation/report of indoor moisture damage or when comparing farming versus non-farming homes, when actual measures targeting indoor microbial exposure are included, the picture becomes less clear and the associations appear inconsistent. This may partly be due to limitations of sampling and measurement techniques that make comparisons difficult and provide an incomplete picture of the indoor microbial environment and in particular also human exposure. In this regard, new generation sequencing techniques represent a potential revolution in better understanding the impact of the indoor microbiome on human health. PMID- 27230431 TI - Rare intronic variants of TCF7L2 arising by selective sweeps in an indigenous population from Mexico. AB - BACKGROUND: Genetic variations of the TCF7L2 gene are associated with the development of Type 2 diabetes (T2D). The associated mutations have demonstrated an adaptive role in some human populations, but no studies have determined the impact of evolutionary forces on genetic diversity in indigenous populations from Mexico. Here, we sequenced and analyzed the variation of the TCF7L2 gene in three Amerindian populations and compared the results with whole-exon-sequencing of Mestizo populations from Sigma and the 1000 Genomes Project to assess the roles of selection and recombination in diversity. RESULTS: The diversity in the indigenous populations was biased to intronic regions. Most of the variation was low frequency. Only mutations rs77961654 and rs61724286 were located on exon 15. We did not observe variation in intronic region 4-6 in any of the three indigenous populations. In addition, we identified peaks of selective sweeps in the mestizo samples from the Sigma Project within this region. By replicating the analysis of association with T2D between case-controls from the Sigma Project, we determined that T2D was most highly associated with the rs7903146 risk allele and to a lesser extent with the other six variants. All associated markers were located in intronic region 4-6, and their r(2) values of linkage disequilibrium were significantly higher in the Mexican population than in Africans from the 1000 Genomes Project. We observed reticulations in both the haplotypes network analysis from seven marker associates and the neighborNet tree based on 6061 markers in the TCF7L2 gene identified from all samples of the 1000 Genomes Project. Finally, we identified two recombination hotspots in the upstream region and 3' end of the TCF7L2 gene. CONCLUSIONS: The lack of diversity in intronic region 4-6 in Indigenous populations could be an effect of selective sweeps generated by the selection of neighboring rare variants at T2D-associated mutations. The survivors' variants make the intronic region 4-6 the area of the greatest population differentiation within the TCF7L2 gene. The abundance of selective peak sweeps in the downstream region of the TCF7L2 gene suggests that the TCF7L2 gene is part of a region that is in constant recombination between populations. PMID- 27230432 TI - Untangling approaches to management and leadership across systems of medical education. AB - AIMS: How future doctors might be educated and trained in order to meet the population and system needs of countries is currently being debated. Incorporation of a broad range of capabilities, encompassed within categories of management and, increasingly, leadership, form part of this discussion. The purpose of this paper is to outline a framework by which countries' progress in this area might be assessed and compared. METHODS: Key databases and journals related to this area were reviewed. From relevant articles potential factors impacting on the incorporation of aspects of management and leadership within medical education and training were identified. These factors were tested via an online survey during 2013 with six members of a European Association of doctors who promote medical involvement in hospital management, including members from countries less represented in the health management literature. RESULTS: A framework for analysing how management and leadership education is being approached within different systems of healthcare is developed and presented. CONCLUSIONS: More systematic work across a wider range of countries is needed if we are to have a better understanding of how countries within and beyond Europe are approaching and progressing the education of doctors in management and leadership. PMID- 27230433 TI - Do Patients Look Up Their Therapists Online? An Exploratory Study Among Patients in Psychotherapy. AB - BACKGROUND: The use of the Internet as a source of health information is growing among people who experience mental health difficulties. The increase in Internet use has led to questions about online information-seeking behaviors, for example, how psychotherapists and patients use the Internet to ascertain information about each other. The notion of psychotherapists seeking information about their patients online (patient-targeted googling, PTG) has been identified and explored. However, the idea of patients searching for information online about their psychotherapists (therapist-targeted googling, TTG) and the associated motives and effects on the therapeutic relationship remain unclear. OBJECTIVE: This study investigated former and current German-speaking psychotherapy patients' behavior and attitudes relating to TTG. In addition, patients' methods of information gathering, motives, and success in searching for information were examined. Furthermore, patients' experiences and perceptions of PTG were explored. METHODS: Overall, 238 former and current psychotherapy patients responded to a new questionnaire specifically designed to assess the frequency, motives, use, and outcomes of TTG as well as experiences and perceptions of PTG. The study sample was a nonrepresentative convenience sample recruited online via several German-speaking therapy platforms and self-help forums. RESULTS: Of the 238 former and current patients who responded, 106 (44.5%) had obtained information about their therapists; most of them (n=85, 80.2%) had used the Internet for this. Besides curiosity, motives behind information searches included the desire to get to know the therapist better by attempting to search for both professional and private information. TTG appeared to be associated with phases of therapy in which patients felt that progress was not being made. Patients being treated for personality disorders appear to engage more frequently in TTG (rphi = 0.21; P=.004). In general, however, information about therapists sought for online was often not found. Furthermore, most patients refrained from telling their therapist about their information searches. CONCLUSIONS: Patients appear to engage in TTG to obtain both professional and private information about their psychotherapists. TTG can be viewed as a form of client-initiated disclosure. It is therefore important to include TTG as a subject in therapists' education and also to raise awareness within patient education. This investigation provides the first findings into TTG to begin debate on this subject. PMID- 27230434 TI - Bi-directional cannabinoid signalling in the basolateral amygdala controls rewarding and aversive emotional processing via functional regulation of the nucleus accumbens. AB - Functional connections between the basolateral amygdala (BLA) and nucleus accumbens (NAc) are involved critically in opiate-reward processing. In the BLA, inhibitory GABAergic substrates are inhibited by cannabinoid CB1 receptor (CB1R) activation and can modulate BLA projections to various limbic regions, including the NAc. However, the potential role of CB1R transmission in the regulation of opiate-related memory formation via the BLA -> NAc circuit is not understood. Using an unbiased conditioned place preference paradigm in rats, we examined the effects of intra-BLA CB1R modulation by either direct pharmacological activation or blockade of CB1R transmission. We report that intra-BLA CB1R activation switches normally rewarding effects of morphine into strongly aversive effects. In contrast, CB1R blockade strongly potentiates normally subreward threshold effects of morphine. Next, using targeted microinfusions of an NMDA receptor antagonist to either the core or shell (NASh) subdivisions of the NAc, we found that selective blockade of NMDA transmission in the NA shell, but not core, prevented both intra-BLA CB1 blockade-mediated opiate reward potentiation and CB1 activation-mediated aversion effects. Finally, using multi-unit, in vivo electrophysiological recordings in the NASh, we report that the ability of intra BLA CB1R modulation to control opiate reward salience and motivational valence is associated with distinct reward or aversion neuronal activity patterns and bi directional regulation of intra-NASh fast-spiking interneurons versus medium spiny neurons. These findings identify a unique mechanism whereby bi-directional BLA CB1R transmission can regulate opiate-related motivational processing and control affective states through functional modulation of mesolimbic neuronal activity. PMID- 27230435 TI - Characterization of Genetic Variability and Population Structure of the Tick Amblyomma aureolatum (Acari: Ixodidae). AB - The hard tick Amblyomma aureolatum (Pallas) is a vector of the bacterium Rickettsia rickettsii, the etiologic agent of Brazilian spotted fever (BSF) in parts of Brazil. Despite its wide distribution in southeastern South America and its public health importance, there is no information about genetic variation of this species that might help to understand the epidemiology of BSF. Using data from eight microsatellite markers and ticks from six localities, we used a population genetics approach to test the hypothesis that tick populations from areas with the presence of R. rickettsii are genetically different from ticks from areas without R. rickettsii Contrary to expectations, we found low genetic structure between studied regions. Thus, the presence of R. rickettsii in the specific area is more likely correlated with ecological and the environmental conditions or due to unknown gene coding regions of A. aureolatum genome that would be related to R. rickettsii infection resistance. PMID- 27230436 TI - Salinity stress induces the production of 2-(2-phenylethyl)chromones and regulates novel classes of responsive genes involved in signal transduction in Aquilaria sinensis calli. AB - BACKGROUND: Agarwood, is a resinous portion derived from Aquilaria sinensis, has been widely used in traditional medicine and incense. 2-(2-phenylethyl)chromones are principal components responsible for the quality of agarwood. However, the molecular basis of 2-(2-phenylethyl)chromones biosynthesis and regulation remains almost unknown. Our research indicated that salt stress induced production of several of 2-(2-phenylethyl)chromones in A. sinensis calli. Transcriptome analysis of A. sinensis calli treated with NaCl is required to further facilitate the multiple signal pathways in response to salt stress and to understand the mechanism of 2-(2-phenylethyl)chromones biosynthesis. RESULTS: Forty one 2-(2 phenylethyl)chromones were identified from NaCl-treated A. sinensis calli. 93 041 unigenes with an average length of 1562 nt were generated from the control and salt-treated calli by Illmunina sequencing after assembly, and the unigenes were annotated by comparing with the public databases including NR, Swiss-Prot, KEGG, COG, and GO database. In total, 18 069 differentially expressed transcripts were identified by the transcriptome comparisons on the control calli and calli induced by 24 h or 120 h salinity stress. Numerous genes involved in signal transduction pathways including the genes responsible for hormone signal transduction, receptor-like kinases, MAPK cascades, Ca(2+) signal transduction, and transcription factors showed clear differences between the control calli and NaCl-treated calli. Furthermore, our data suggested that the genes annotated as chalcone synthases and O-methyltransferases may contribute to the biosynthesis of 2-(2-phenylethyl)chromones. CONCLUSIONS: Salinity stress could induce the production of 41 2-(2-phenylethyl)chromones in A. sinensis calli. We conducted the first deep-sequencing transcriptome profiling of A. sinensis under salt stress and observed a large number of differentially expressed genes in response to salinity stress. Moreover, salt stress induced dynamic changes in transcript abundance for novel classes of responsive genes involved in signal transduction, including the genes responsible for hormone signal transduction, receptor-like kinases, MAPK cascades, Ca(2+) signal transduction, and transcription factors. This study will aid in selecting the target genes to genetically regulate A. sinensis salt-stress signal transduction and elucidating the biosynthesis of 2-(2 phenylethyl)chromones under salinity stress. PMID- 27230437 TI - e-Monitoring of Asthma Therapy to Improve Compliance in children (e-MATIC): a randomised controlled trial. AB - Real-time medication monitoring (RTMM) is a promising tool for improving adherence to inhaled corticosteroids (ICS), but has not been sufficiently tested in children with asthma. We aimed to study the effects of RTMM with short message service (SMS) reminders on adherence to ICS, asthma control, asthma-specific quality of life and asthma exacerbation rate; and to study the associated cost effectiveness.In a multicentre, randomised controlled trial, children (aged 4-11 years) using ICS were recruited from five outpatient clinics and were given an RTMM device for 12 months. The intervention group also received tailored SMS reminders, sent only when a dose was at risk of omission. Outcome measures were adherence to ICS (RTMM data), asthma control (childhood asthma control test questionnaire), quality of life (paediatric asthma quality of life questionnaire) and asthma exacerbations. Costs were calculated from a healthcare and societal perspective.We included 209 children. Mean adherence was higher in the intervention group: 69.3% versus 57.3% (difference 12.0%, 95% CI 6.7%-17.7%). No differences were found for asthma control, quality of life or asthma exacerbations. Costs were higher in the intervention group, but this difference was not statistically significant.RTMM with tailored SMS reminders improved adherence to ICS, but not asthma control, quality of life or exacerbations in children using ICS for asthma. PMID- 27230438 TI - Annual risk of tuberculosis infection in rural China: a population-based prospective study. AB - Prospective population data on the incidence of tuberculosis (TB) infection has been sparsely reported in the global literature.A population-based prospective study was conducted in rural China to investigate the annual risk of TB infection, and its persistence using serial tuberculin skin tests (TSTs) and an interferon-gamma release assay. In total, 13 580 eligible participants from four rural sites, identified as TST negative (<10 mm) or QuantiFERON-TB Gold In-Tube (QFT) (an interferon-gamma release assay) negative from a baseline survey, were included in the first year's follow-up examination.The annual conversion rate of QFT among the study sites ranged between 2.1% and 4.9% (average 3.1%), and the incidence of TST conversion ranged between 6.0% and 31.1% (average 14.5%). During the second year's follow-up, infection persistence was investigated using 390 subjects with QFT conversions. Among them, 49.7% (164 out of 330) were found to be consistently QFT positive. Both the conversion and the persistence of QFT positivity were found to be significantly increased with increasing age.In conclusion, the annual TB infection rate was suggested to be ~1.5% based on persistent positive results after QFT conversion in rural China. Therefore, infection control among those high-risk populations, including the elderly, should be prioritised for TB control in China. PMID- 27230440 TI - Cessation of long-acting beta2-agonist in children with persistent asthma on inhaled corticosteroids. PMID- 27230439 TI - Hydrogen cyanide emission in the lung by Staphylococcus aureus. PMID- 27230441 TI - Expanded lung T-bet+RORgammaT+ CD4+ T-cells in sarcoidosis patients with a favourable disease phenotype. AB - Disease phenotypes of pulmonary sarcoidosis are distinguished by clinical rather than immunological criteria. We aimed to characterise patterns of CD4(+) T-cell lineage plasticity underlying the differences in clinical presentation and disease course between the acute form, Lofgren's syndrome, and the heterogeneous, potentially progressive "non-Lofgren" form.33 pulmonary sarcoidosis patients and nine controls underwent bronchoscopy with bronchoalveolar lavage. CD4(+) T-cell transcription factor, chemokine receptor and T-cell receptor expression, proliferation and cytokine production were assessed in the lavage fluid and peripheral blood using flow cytometry and multicolour FluoroSpot.CD4(+) T-cells simultaneously expressing the T-helper cell (Th)1 and Th17 transcriptional regulators T-bet and RORgammaT (T-bet(+)RORgammaT(+)) were identified in the lavage, but not blood, of all subjects, and to a significantly higher degree in Lofgren's patients. T-bet(+)RORgammaT(+) cells proliferated actively, produced interferon (IFN)gamma and interleukin (IL)-17A, co-expressed the chemokine receptors CXCR3 and CCR6, and correlated with nonchronic disease. T-cell receptor restricted Valpha2.3(+)Vbeta22(+) T-cells strongly co-expressed T-bet/RORgammaT and CXCR3/CCR6. Cytokine production was more heterogeneous in Lofgren's patients, with significantly higher IL-17A, IL-10, IL-22 and IL-2, but lower IFNgamma.Here we demonstrate the presence of lung T-bet(+)RORgammaT(+)CXCR3(+)CCR6(+) CD4(+) T cells and Th17-associated cytokines especially in sarcoidosis patients with a favourable prognosis, suggesting a Th1/Th17-permissive environment in the lung with implications for disease resolution. PMID- 27230442 TI - Epidemiology and survival of idiopathic pulmonary fibrosis from national data in Canada. AB - Idiopathic pulmonary fibrosis (IPF) is a rare disease, with estimates of prevalence varying considerably across countries due to paucity in data collection. The aim of this study was to investigate the prevalence and incidence of IPF in Canada using administrative data requiring minimal extrapolation.We used mandatory national administrative data from 2007-2011 to identify IPF cases of all ages with an International Classification of Diseases (Version 10, Canadian) diagnosis code of J84.1. We used a broad definition that excluded cases with subsequent diagnosis of other interstitial lung diseases, and a narrow definition that required further diagnostic testing prior to IPF diagnosis. We explored survival and quality of life.For all ages, the broad prevalence of IPF was 41.8 per 100 000 (14 259 cases) and was higher for men. The incidence rate was 18.7 per 100 000 (6390 cases) and was higher for men. The narrow prevalence was 20.0 per 100 000 (6822 cases) and incidence was 9.0 per 100 000 (3057 cases). The 4-year risk of death was 41.0% and the quality of life with IPF after 2 years was lower than for Global Initiative for Chronic Obstructive Lung Disease stage IV chronic obstructive pulmonary disease.Using comprehensive national data, the prevalence of IPF in Canada was higher than other national estimates, suggesting that either IPF may be more common in Canada or that data capture may have been previously limited. PMID- 27230443 TI - Digital health for the End TB Strategy: developing priority products and making them work. AB - In 2014, the World Health Organization (WHO) developed the End TB Strategy in response to a World Health Assembly Resolution requesting Member States to end the worldwide epidemic of tuberculosis (TB) by 2035. For the strategy's objectives to be realised, the next 20 years will need novel solutions to address the challenges posed by TB to health professionals, and to affected people and communities. Information and communication technology presents opportunities for innovative approaches to support TB efforts in patient care, surveillance, programme management and electronic learning. The effective application of digital health products at a large scale and their continued development need the engagement of TB patients and their caregivers, innovators, funders, policy makers, advocacy groups, and affected communities.In April 2015, WHO established its Global Task Force on Digital Health for TB to advocate and support the development of digital health innovations in global efforts to improve TB care and prevention. We outline the group's approach to stewarding this process in alignment with the three pillars of the End TB Strategy. The supplementary material of this article includes target product profiles, as developed by early 2016, defining nine priority digital health concepts and products that are strategically positioned to enhance TB action at the country level. PMID- 27230444 TI - Emphysema- and airway-dominant COPD phenotypes defined by standardised quantitative computed tomography. AB - EvA (Emphysema versus Airway disease) is a multicentre project to study mechanisms and identify biomarkers of emphysema and airway disease in chronic obstructive pulmonary disease (COPD). The objective of this study was to delineate objectively imaging-based emphysema-dominant and airway disease dominant phenotypes using quantitative computed tomography (QCT) indices, standardised with a novel phantom-based approach.441 subjects with COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 1-3) were assessed in terms of clinical and physiological measurements, laboratory testing and standardised QCT indices of emphysema and airway wall geometry.QCT indices were influenced by scanner non-conformity, but standardisation significantly reduced variability (p<0.001) and led to more robust phenotypes. Four imaging-derived phenotypes were identified, reflecting "emphysema-dominant", "airway disease dominant", "mixed" disease and "mild" disease. The emphysema-dominant group had significantly higher lung volumes, lower gas transfer coefficient, lower oxygen (PO2 ) and carbon dioxide (PCO2 ) tensions, higher haemoglobin and higher blood leukocyte numbers than the airway disease-dominant group.The utility of QCT for phenotyping in the setting of an international multicentre study is improved by standardisation. QCT indices of emphysema and airway disease can delineate within a population of patients with COPD, phenotypic groups that have typical clinical features known to be associated with emphysema-dominant and airway-dominant disease. PMID- 27230445 TI - Long-term computed tomographic changes in cystic fibrosis patients treated with ivacaftor. PMID- 27230446 TI - Lung function decline in asthma patients with elevated bronchial CD8, CD4 and CD3 cells. AB - Which inflammatory markers in the bronchial mucosa of asthma patients are associated with decline of lung function during 14 years of prospective follow up?To address this question, 19 mild-to-moderate, atopic asthmatic patients underwent spirometry and bronchoscopy at baseline and after 14 years of follow-up (t=14). Baseline bronchial biopsies were analysed for reticular layer thickness, eosinophil cationic protein (EG2), mast cell tryptase (AA1), CD3, CD4 and CD8. Follow-up biopsies were stained for EG2, AA1, neutrophil elastase, CD3, CD4, CD8, CD20, granzyme B, CD68, DC-SIGN, Ki67 and mucins.Decline in forced expiratory volume in 1 s (FEV1) % predicted was highest in patients with high CD8 (p=0.01, both pre- and post-bronchodilator) or high CD4 counts at baseline (p=0.04 pre bronchodilator, p=0.03 post-bronchodilator). Patients with high CD8, CD3 or granzyme B counts at t=14 also exhibited faster decline in FEV1 (p=0.00 CD8 pre bronchodilator, p=0.04 CD8 post-bronchodilator, p=0.01 granzyme B pre bronchodilator, and p<0.01 CD3 pre-bronchodilator).Long-term lung function decline in asthma is associated with elevation of bronchial CD8 and CD4 at baseline, and CD8, CD3 and granzyme B at follow-up. This suggests that high-risk groups can be identified on the basis of inflammatory phenotypes. PMID- 27230447 TI - Risk of hypersensitivity pneumonitis and interstitial lung diseases among pigeon breeders. AB - We studied the risk of hypersensitivity pneumonitis and other interstitial lung diseases (ILDs) among pigeon breeders.This is a retrospective follow-up study from 1980 to 2013 of 6920 pigeon breeders identified in the records of the Danish Racing Pigeon Association. They were compared with 276 800 individually matched referents randomly drawn from the Danish population. Hospital based diagnoses of hypersensitivity pneumonitis and other ILDs were identified in the National Patient Registry 1977-2013. Stratified Cox regression analyses estimated the hazard ratios (HR) of hypersensitivity pneumonitis and other ILDs adjusted for occupation, residence and redeemed prescription of medication with ILDs as a possible side-effect. Subjects were censored at death, emigration or a diagnosis of connective tissue disease.The overall incidence rate of ILD was 77.4 per 100 000 person-years among the pigeon breeders and 50.0 among the referents. This difference corresponded to an adjusted HR of 1.56 (95% CI 1.26-1.94). The adjusted HRs of hypersensitivity pneumonitis and other ILDs for pigeon breeders were 14.36 (95% CI 8.10-25.44) and 1.33 (95% CI 1.05-1.69), respectively.This study shows an increased risk of ILD among pigeon breeders compared with the referent population. Protective measures are recommended even though ILD leading to hospital contact remains rare among pigeon breeders. PMID- 27230448 TI - Present and future utility of computed tomography scanning in the assessment and management of COPD. AB - Computed tomography (CT) is the modality of choice for imaging the thorax and lung structure. In chronic obstructive pulmonary disease (COPD), it used to recognise the key morphological features of emphysema, bronchial wall thickening and gas trapping. Despite this, its place in the investigation and management of COPD is yet to be determined, and it is not routinely recommended. However, lung CT already has important clinical applications where it can be used to diagnose concomitant pathology and determine which patients with severe emphysema are appropriate for lung volume reduction procedures. Furthermore, novel quantitative analysis techniques permit objective measurements of pulmonary and extrapulmonary manifestations of the disease. These techniques can give important insights into COPD, and help explore the heterogeneity and underlying mechanisms of the condition. In time, it is hoped that these techniques can be used in clinical trials to help develop disease-specific therapy and, ultimately, as a clinical tool in identifying patients who would benefit most from new and existing treatments. This review discusses the current clinical applications for CT imaging in COPD and quantification techniques, and its potential future role in stratifying disease for optimal outcome. PMID- 27230449 TI - Utility of measuring FEV0.75/FVC ratio in preschoolers with uncontrolled wheezing disorder. AB - Uncontrolled wheezing disorder is common in preschoolers and disease control assessment is challenging as parents frequently overestimate the extent to which their child's disease is controlled. This is the first study of forced expiratory volume in t s (FEVt)/forced vital capacity (FVC) ratio measurements (i.e. FEV1/FVC, FEV0.75/FVC and FEV0.5/FVC) in wheezy preschoolers in relation to disease control. Our objective was to evaluate whether FEVt/FVC ratios less than the lower limit of normal (LLN; z-score <-1.64) were associated with uncontrolled wheezing disorder in preschoolers.Valid FVC, FEV1, FEV0.75 and FEV0.5 values were obtained in 92 healthy and 125 wheezy (62% uncontrolled) children (3-5 years). Associations between spirometry value 99th to 5*99th percentile (n=1928), and a group with peak postprocedural troponin T>5*99th percentile upper reference limit (n=793). Advanced age, smaller body mass index, baseline troponin level, complex lesions, bifurcation lesions and stented length were independently associated with elevated troponin T levels after the procedure. The median follow-up was 15.5 months. There were 56 deaths: 5 deaths (1.7%) among patients with peak postprocedural troponin T<=99th percentile, 35 deaths (4.5%) among patients with peak postprocedural troponin T>99th to 5*99th percentile and 16 deaths (4.3%) among patients with peak postprocedural troponin T>5*99th percentile upper reference limit (hazard ratio=1.50; 95% confidence interval, 1.01-2.25; P=.047). After adjustment, peak postprocedural troponin T level was not independently associated with mortality after percutaneous coronary intervention (P=.094). CONCLUSIONS: In patients with stable coronary artery disease and without elevated baseline high-sensitivity troponin T, elevated high-sensitivity troponin T level after percutaneous coronary intervention was not associated with postprocedural mortality. PMID- 27230477 TI - Uniqueness: skews bit occurrence frequencies in randomly generated fingerprint libraries. AB - Requiring that randomly generated chemical fingerprint libraries have unique fingerprints such that no two fingerprints are identical causes a systematic skew in bit occurrence frequencies, the proportion at which specified bits are set. Observed frequencies (O) at which each bit is set within the resulting libraries systematically differ from frequencies at which bits are set at fingerprint generation (E). Observed frequencies systematically skew toward 0.5, with the effect being more pronounced as library size approaches the compound space, which is the total number of unique possible fingerprints given the number of bit positions each fingerprint contains. The effect is quantified for varying library sizes as a fraction of the overall compound space, and for changes in the specified frequency E. The cause and implications for this systematic skew are subsequently discussed. When generating random libraries of chemical fingerprints, the imposition of a uniqueness requirement should either be avoided or taken into account. PMID- 27230476 TI - Vitamin k3 inhibits protein aggregation: Implication in the treatment of amyloid diseases. AB - Protein misfolding and aggregation have been associated with several human diseases such as Alzheimer's, Parkinson's and familial amyloid polyneuropathy etc. In this study, anti-fibrillation activity of vitamin k3 and its effect on the kinetics of amyloid formation of hen egg white lysozyme (HEWL) and Abeta-42 peptide were investigated. Here, in combination with Thioflavin T (ThT) fluorescence assay, circular dichroism (CD), transmission electron microscopy and cell cytotoxicity assay, we demonstrated that vitamin k3 significantly inhibits fibril formation as well as the inhibitory effect is dose dependent manner. Our experimental studies inferred that vitamin k3 exert its neuro protective effect against amyloid induced cytotoxicity through concerted pathway, modifying the aggregation formation towards formation of nontoxic aggregates. Molecular docking demonstrated that vitamin k3 mediated inhibition of HEWL and Abeta-42 fibrillogenesis may be initiated by interacting with proteolytic resistant and aggregation prone regions respectively. This work would provide an insight into the mechanism of protein aggregation inhibition by vitamin k3; pave the way for discovery of other small molecules that may exert similar effect against amyloid formation and its associated neurodegenerative diseases. PMID- 27230478 TI - Dually cross-linked single network poly(acrylic acid) hydrogels with superior mechanical properties and water absorbency. AB - Poly(acrylic acid) (PAA) hydrogels with superior mechanical properties, based on a single network structure with dual cross-linking, are prepared by one-pot free radical polymerization. The network structure of the PAA hydrogels is composed of dual cross-linking: a dynamic and reversible ionic cross-linking among the PAA chains enabled by Fe(3+) ions, and a sparse covalent cross-linking enabled by a covalent cross-linker (Bis). Under deformation, the covalently cross-linked PAA chains remain intact to maintain their original configuration, while the Fe(3+) enabled ionic cross-linking among the PAA chains is broken to dissipate energy and then recombined. It is found that the mechanical properties of the PAA hydrogels are significantly influenced by the contents of covalent cross-linkers, Fe(3+) ions and water, which can be adjusted within a substantial range and thus broaden the applications of the hydrogels. Meanwhile, the PAA hydrogels have excellent recoverability based on the dynamic and reversible ionic cross-linking enabled by Fe(3+) ions. Moreover, the swelling capacity of the PAA hydrogels is as high as 1800 times in deionized water due to the synergistic effects of ionic and covalent cross-linkings. The combination of balanced mechanical properties, efficient recoverability, high swelling capacity and facile preparation provides a new method to obtain high-performance hydrogels. PMID- 27230479 TI - Understanding adherence-related beliefs about medicine amongst patients of South Asian origin with diabetes and cardiovascular disease patients: a qualitative synthesis. AB - BACKGROUND: Prevalence of diabetes and cardiovascular (CVD) disease amongst UK South Asians is higher than in the general population. Non-adherence to medicines may lead to poor clinical outcomes for South Asian patients with diabetes and CVD. To understand the decision making processes associated with taking medicines, a qualitative systematic meta-synthesis exploring medicine taking behaviours, and beliefs was undertaken. METHODS: Four databases (Medline, Embase, Science Citation Index and CINAHL) were searched to identify qualitative studies of South Asian patients taking diabetic medicines. Data were thematic coded and synthesised. RESULTS: The following themes were identified: [1] beliefs about the need for and efficacy of medicines; [2] toxicity of medicines and polypharmacy; [3] the necessity of traditional remedies versus "western medicines"; [4] stigma and social support; and [5] communication. CONCLUSIONS: South Asians described cultural social stigma associated with diabetes and reported fears about drug toxicity as barriers to taking medicines. Cultural beliefs about traditional remedies and interactions with healthcare professionals also appeared to play a role in the way people made decisions about medicines. Advice should be tailored provided to South Asian patients highlighting the long term consequences of diabetes and CVD. PMID- 27230480 TI - Do Demographic Factors Influence Uveitis Patients' Understanding of Uveitis? AB - PURPOSE: To establish how much uveitis patients know about their own condition and to investigate the contribution of demographic factors to that knowledge. METHODS: A self-designed questionnaire, comprising 20 questions about uveitis, was distributed to 200 consecutive patients attending a uveitis clinic. The questionnaire requested demographic details and required responses to uveitis specific knowledge questions. Postcode was used to determine level of social deprivation using Index of Multiple Deprivation 2007. Univariate analyses with the Mann-Whitney test and Kruskal-Wallis test were utilized. Multivariable logistic regression was performed to simultaneously measure the independent influence of demographic variables on the level of patients' understanding of their condition. RESULTS: Of the respondents, 62% were female, 71% aged >40 years and 67% of white ethnic origin, with 41% having been under the care of a uveitis specialist for >10 years and 72% attending >=3 clinic appointments in the preceding 12 months. Median questionnaire score (out of 60) was 27 (interquartile range, IQR 15). Females scored significantly higher than males (30 vs 24; p = 0.001), but there was no difference according to age, ethnicity, or social deprivation quintile, nor the duration patients had been under ophthalmic review or number of clinic attendances in the preceding 12 months. Multivariable analyses determined no independent influence of any of the factors on the uveitis questionnaire score. CONCLUSIONS: Uveitis patients' understanding of their condition is poor. This has relevance for adherence to treatment, follow-up clinic attendance, and eventual outcomes in these patients. PMID- 27230481 TI - Visual function in patients with idiopathic macular telangiectasia type 1. PMID- 27230482 TI - K19 capsular polysaccharide of Acinetobacter baumannii is produced via a Wzy polymerase encoded in a small genomic island rather than the KL19 capsule gene cluster. AB - Polymerization of the oligosaccharides (K units) of complex capsular polysaccharides (CPSs) requires a Wzy polymerase, which is usually encoded in the gene cluster that directs K unit synthesis. Here, a gene cluster at the Acinetobacter K locus (KL) that lacks a wzy gene, KL19, was found in Acinetobacter baumannii ST111 isolates 28 and RBH2 recovered from hospitals in the Russian Federation and Australia, respectively. However, these isolates produced long-chain capsule, and a wzy gene was found in a 6.1 kb genomic island (GI) located adjacent to the cpn60 gene. The GI also includes an acetyltransferase gene, atr25, which is interrupted by an insertion sequence (IS) in RBH2. The capsule structure from both strains was ->3)-alpha-d-GalpNAc-(1->4) alpha-d-GalpNAcA-(1->3)-beta-d-QuipNAc4NAc-(1->, determined using NMR spectroscopy. Biosynthesis of the K unit was inferred to be initiated with QuiNAc4NAc, and hence the Wzy forms the beta-(1->3) linkage between QuipNAc4NAc and GalpNAc. The GalpNAc residue is 6-O-acetylated in isolate 28 only, showing that atr25 is responsible for this acetylation. The same GI with or without an IS in atr25 was found in draft genomes of other KL19 isolates, as well as ones carrying a closely related CPS gene cluster, KL39, which differs from KL19 only in a gene for an acyltransferase in the QuiNAc4NR synthesis pathway. Isolates carrying a KL1 variant with the wzy and atr genes each interrupted by an ISAba125 also have this GI. To our knowledge, this study is the first report of genes involved in capsule biosynthesis normally found at the KL located elsewhere in A. baumannii genomes. PMID- 27230483 TI - Alexithymia in Parkinson's disease: a point of view on current evidence. AB - The risk of alexithymia in individuals with Parkinson's disease (PD) is about double compared with that observed in the general population. This finding indicates that alexithymia may be a relevant phenomenon in PD. However, several issues have to be clarified. The review here proposed outlines two main points. First, available data do not allow the clarification of whether alexithymia is independently associated with PD or if it is secondary to other mood and/or cognitive disorders. Second, it is not well understood how PD-related neurobiological changes may account for alexithymic expression. Our examination of extant literature also evidenced some potential limits of current tools and designs used that should carefully taken into account in further investigations of above issues. PMID- 27230484 TI - A Versatile Multiple Target Detection System Based on DNA Nano-assembled Linear FRET Arrays. AB - DNA molecules have been utilized both as powerful synthetic building blocks to create nanoscale architectures and as inconstant programmable templates for assembly of biosensors. In this paper, a versatile, scalable and multiplex detection system is reported based on an extending fluorescent resonance energy transfer (FRET) cascades on a linear DNA assemblies. Seven combinations of three kinds of targets are successfully detected through the changes of fluorescence spectra because of the three-steps FRET or non-FRET continuity mechanisms. This nano-assembled FRET-based nanowire is extremely significant for the development of rapid, simple and sensitive detection system. The method used here could be extended to a general platform for multiplex detection through more-step FRET process. PMID- 27230486 TI - Deferasirox pharmacokinetic evaluation in beta-thalassaemia paediatric patients. AB - OBJECTIVES: Iron chelation in the transfusion-dependent anaemias management is essential to prevent end-organ damage and to improve survival. Deferasirox is a once-daily orally active tridentate selective iron chelator which pharmacokinetic disposition could influence treatment efficacy and toxicity. Therapeutic drug monitoring is an important tool for optimizing drug utilization and doses. METHODS: A fully validated chromatographic method was used to quantify deferasirox concentration in plasma collected from paediatric patients with beta thalassaemia. Samples obtained after 5 days of washout or in naive patients before and after 2, 4, 6 and 24 h drug administration were evaluated. KEY FINDINGS: Associations between variables were tested using the Pearson test. Twenty paediatric patients were enrolled; they were mainly men (13.65%), with median age of 6.35 years and body mass index of 15.45 kg/m2 . Concerning pharmacokinetic parameters, a higher interindividual variability was shown. A positive, but not significant, correlation (r = 0.363; P = 0.115) was found between deferasirox area under the concentration curve over 24 h (AUC) and drug dose. CONCLUSIONS: Monitoring plasma deferasirox concentrations appears beneficial for guiding appropriate patient treatment, enhancing effectiveness and minimizing toxicity. PMID- 27230485 TI - Similarities and differences between stakeholders' opinions on using Health Technology Assessment (HTA) information across five European countries: results from the EQUIPT survey. AB - BACKGROUND: The European-study on Quantifying Utility of Investment in Protection from Tobacco (EQUIPT) project aimed to study transferability of economic evidence by co-creating the Tobacco Return On Investment (ROI) tool, previously developed in the United Kingdom, for four sample countries (Germany, Hungary, Spain and the Netherlands). The EQUIPT tool provides policymakers and stakeholders with customized information about the economic and wider returns on the investment in evidence-based tobacco control, including smoking cessation interventions. A Stakeholder Interview Survey was developed to engage with the stakeholders in early phases of the development and country adaptation of the ROI tool. The survey assessed stakeholders' information needs, awareness about underlying principles used in economic analyses, opinion about the importance, effectiveness and cost-effectiveness of tobacco control interventions, and willingness to use a Health Technology Assessment (HTA) tool such as the ROI tool. METHODS: A cross sectional study using a mixed method approach was conducted among participating stakeholders in the sample countries and the United Kingdom. The individual questionnaire contained open-ended questions as well as single choice and 7- or 3 point Likert-scale questions. The results corresponding to the priority and needs assessment and to the awareness of stakeholders about underlying principles used in economic analysis are analysed by country and stakeholder categories. RESULTS: Stakeholders considered it important that the decisions on the investments in tobacco control interventions should be supported by scientific evidence, including prevalence of smoking, cost of smoking, quality of life, mortality due to smoking, and effectiveness, cost-effectiveness and budget impact of smoking cessation interventions. The proposed ROI tool was required to provide this granularity of information. The majority of the stakeholders were aware of the general principles of economic analyses used in decision making contexts but they did not appear to have in-depth knowledge about specific technical details. Generally, stakeholders' answers showed larger variability by country than by stakeholder category. CONCLUSIONS: Stakeholders across different European countries viewed the use of HTA evidence to be an important factor in their decision-making process. Further, they considered themselves to be capable of interpreting the results from a ROI tool and were highly motivated to use it. PMID- 27230487 TI - Continuous improvement, burnout and job engagement: a study in a Dutch nursing department. AB - Continuous improvement (CI) programs are potentially powerful means to improve the quality of care. The more positive nurses perceive these programs' effects, the better they may be expected to cooperate. Crucial to this perception is how nurses' quality of working life is affected. We studied this in a nursing department, using the job demands-resources model. We found that two job demands improved, and none of the job resources. Job engagement did not change significantly, while the burnout risk decreased slightly. Overall, the nurses felt the impact to be small yet the changes were in a positive direction. CI can thus be used to improve nurses' working lives and, by restructuring the work processes, the quality of care. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27230489 TI - Sustainable Sizing. AB - OBJECTIVE: To provide a review of sustainable sizing practices that reduce waste, increase sales, and simultaneously produce safer, better fitting, accommodating products. BACKGROUND: Sustainable sizing involves a set of methods good for both the environment (sustainable environment) and business (sustainable business). Sustainable sizing methods reduce (1) materials used, (2) the number of sizes or adjustments, and (3) the amount of product unsold or marked down for sale. This reduces waste and cost. The methods can also increase sales by fitting more people in the target market and produce happier, loyal customers with better fitting products. This is a mini-review of methods that result in more sustainable sizing practices. It also reviews and contrasts current statistical and modeling practices that lead to poor fit and sizing. Fit-mapping and the use of cases are two excellent methods suited for creating sustainable sizing, when real people (vs. virtual people) are used. These methods are described and reviewed. Evidence presented supports the view that virtual fitting with simulated people and products is not yet effective. CONCLUSIONS: Fit-mapping and cases with real people and actual products result in good design and products that are fit for person, fit for purpose, with good accommodation and comfortable, optimized sizing. While virtual models have been shown to be ineffective for predicting or representing fit, there is an opportunity to improve them by adding fit-mapping data to the models. This will require saving fit data, product data, anthropometry, and demographics in a standardized manner. For this success to extend to the wider design community, the development of a standardized method of data collection for fit-mapping with a globally shared fit map database is needed. It will enable the world community to build knowledge of fit and accommodation and generate effective virtual fitting for the future. APPLICATION: A standardized method of data collection that tests products' fit methodically and quantitatively will increase our predictive power to determine fit and accommodation, thereby facilitating improved, effective design. These methods apply to all products people wear, use, or occupy. PMID- 27230490 TI - Perceived Spaciousness and Preference in Sequential Experience. AB - OBJECTIVE: We assessed the perceived spaciousness and preference for a destination space in relation to six attributes (size, lighting, window size, texture, wall mural, and amount of furniture) of it and of the space experienced before it. BACKGROUND: Studies have examined effects of these attributes but not for dynamic experience or preference. METHOD: We created 24 virtual reality walks between each possible pair of two levels of each attribute. For each destination space, 31 students (13 men, 18 women) rated spaciousness and 30 students (16 men, 14 women) rated preference. We conducted separate 2 * 2 repeated-measure ANOVAs across each condition for perceived spaciousness and preference. RESULTS: Participants judged the space that was larger, was more brightly lit, with a larger window, or with less furniture as the more spacious. These attributes also increased preference. Consonant with adaptation-level theory, participants judged offices as higher in spaciousness and preference if preceded by a space that was smaller, was more dimly lit, or had smaller windows. CONCLUSION: The findings suggest that perceived spaciousness varies with size, lightness, window size, and amount of furniture but that perception also depends on the size, lightness, and size of the space experienced before. APPLICATION: Designers could use the findings to manipulate features to make a space appear larger or more desirable. PMID- 27230491 TI - Modeling Driving Performance Using In-Vehicle Speech Data From a Naturalistic Driving Study. AB - OBJECTIVE: We aimed to (a) describe the development and application of an automated approach for processing in-vehicle speech data from a naturalistic driving study (NDS), (b) examine the influence of child passenger presence on driving performance, and (c) model this relationship using in-vehicle speech data. BACKGROUND: Parent drivers frequently engage in child-related secondary behaviors, but the impact on driving performance is unknown. Applying automated speech-processing techniques to NDS audio data would facilitate the analysis of in-vehicle driver-child interactions and their influence on driving performance. METHOD: Speech activity detection and speaker diarization algorithms were applied to audio data from a Melbourne-based NDS involving 42 families. Multilevel models were developed to evaluate the effect of speech activity and the presence of child passengers on driving performance. RESULTS: Speech activity was significantly associated with velocity and steering angle variability. Child passenger presence alone was not associated with changes in driving performance. However, speech activity in the presence of two child passengers was associated with the most variability in driving performance. CONCLUSION: The effects of in vehicle speech on driving performance in the presence of child passengers appear to be heterogeneous, and multiple factors may need to be considered in evaluating their impact. This goal can potentially be achieved within large-scale NDS through the automated processing of observational data, including speech. APPLICATION: Speech-processing algorithms enable new perspectives on driving performance to be gained from existing NDS data, and variables that were once labor-intensive to process can be readily utilized in future research. PMID- 27230488 TI - Generating long-lived CD8(+) T-cell memory: Insights from epigenetic programs. AB - T-cell-based immunological memory has the potential to provide the host with life long protection against pathogen reexposure and thus offers tremendous promise for the design of vaccines targeting chronic infections or cancer. In order to exploit this potential in the design of new vaccines, it is necessary to understand how and when memory T cells acquire their poised effector potential, and moreover, how they maintain these properties during homeostatic proliferation. To gain insight into the persistent nature of memory T-cell functions, investigators have turned their attention to epigenetic mechanisms. Recent efforts have revealed that many of the properties acquired among memory T cells are coupled to stable changes in DNA methylation and histone modifications. Furthermore, it has recently been reported that the delineating features among memory T cells subsets are also linked to distinct epigenetic events, such as permissive and repressive histone modifications and DNA methylation programs, providing exciting new hypotheses regarding their cellular ancestry. Here, we review recent studies focused on epigenetic programs acquired during effector and memory T-cell differentiation and discuss how these data may shed new light on the developmental path for generating long-lived CD8(+) T-cell memory. PMID- 27230492 TI - National Safe Routes to School program and risk of school-age pedestrian and bicyclist injury. AB - PURPOSE: Safe Routes to School (SRTS) was a federally funded transportation program for facilitating physically active commuting to and from school in children through improvements of the built environment. There is evidence that SRTS programs increase walking and bicycling in school-age children, but their impact on pedestrian and bicyclist safety has not been adequately examined. We investigate the impact and effects of the SRTS program on school-age pedestrian and bicyclist injuries in a nationwide sample in the United States. METHODS: Data were crash records for school-age children (5-19 years) and adults (30-64 years), in 18 U.S. states for a 16-year period (1995-2010). Multilevel negative binomial models were used to examine the association between SRTS intervention and the risk of pedestrian and bicyclist injury in children aged 5-19 years. RESULTS: SRTS was associated with an approximately 23% reduction (incidence rate ratio = 0.77, 95% confidence interval = 0.65-0.92) in pedestrian/bicyclist injury risk and a 20% reduction in pedestrian/bicyclist fatality risk (incidence rate ratio = 0.80, 95% confidence interval = 0.68-0.94) in school-age children compared to adults aged 30-64 years. CONCLUSIONS: Implementation of the SRTS program appears to have contributed to improving traffic safety for school-age children in the United States. PMID- 27230494 TI - Does media coverage influence public attitudes towards welfare recipients? The impact of the 2011 English riots. AB - Following the shooting of Mark Duggan by police on 4 August 2011, there were riots in many large cities in the UK. As the rioting was widely perceived to be perpetrated by the urban poor, links were quickly made with Britain's welfare policies. In this paper, we examine whether the riots, and the subsequent media coverage, influenced attitudes toward welfare recipients. Using the British Social Attitudes survey, we use multivariate difference-in-differences regression models to compare attitudes toward welfare recipients among those interviewed before (pre-intervention: i.e. prior to 6 August) and after (post-intervention: 10 August-10 September) the riots occurred (N = 3,311). We use variation in exposure to the media coverage to test theories of media persuasion in the context of attitudes toward welfare recipients. Before the riots, there were no significant differences between newspaper readers and non-readers in their attitudes towards welfare recipients. However, after the riots, attitudes diverged. Newspaper readers became more likely than non-readers to believe that those on welfare did not really deserve help, that the unemployed could find a job if they wanted to and that those on the dole were being dishonest in claiming benefits. Although the divergence was clearest between right-leaning newspaper and non-newspaper readers, we do not a find statistically significant difference between right- and left-leaning newspapers. These results suggest that media coverage of the riots influenced attitudes towards welfare recipients; specifically, newspaper coverage of the riots increased the likelihood that readers of the print media expressed negative attitudes towards welfare recipients when compared with the rest of the population. PMID- 27230493 TI - Screening and direct assessment methodology to determine the prevalence of autism spectrum disorders. AB - PURPOSE: Findings from the Centers for Disease Control and Prevention-sponsored Autism and Developmental Disabilities Monitoring (ADDM) network suggest a growing prevalence of autism spectrum disorders (ASDs). The rigorous ADDM record review methodology has provided valuable insight into the epidemiology of autism spectrum disorder (ASD), but recent studies using alternative methods have reported significantly higher prevalence estimates. The South Carolina Children's Educational Surveillance Study (SUCCESS) was designed to determine ASD prevalence via population-based screening and direct assessment and to compare prevalence results to ADDM and administrative prevalence counts. This article provides an overview of the methods used for this study. METHODS: SUCCESS involved a novel (first in the United States) population-based screening approach combined with direct assessment to determine ASD prevalence. RESULTS: SUCCESS results will be compared to those obtained via records-based surveillance (ADDM) and administrative counts in the same population of children. This article describes the methods for developing and implementing SUCCESS and rationale for major decisions. Procedures used to maximize participation and accurately determine case status are discussed. Study results will be available in 2016. CONCLUSIONS: Accurate reporting of ASD prevalence is important to researchers, health care providers, policy makers, and families. This study will clarify the findings of various methods used to estimate ASD prevalence. PMID- 27230495 TI - AC Electroosmotic Pumping in Nanofluidic Funnels. AB - We report efficient pumping of fluids through nanofluidic funnels when a symmetric AC waveform is applied. The asymmetric geometry of the nanofluidic funnel induces not only ion current rectification but also electroosmotic flow rectification. In the base-to-tip direction, the funnel exhibits a lower ion conductance and a higher electroosmotic flow velocity, whereas, in the tip-to base direction, the funnel has a higher ion conductance and a lower electroosmotic flow velocity. Consequently, symmetric AC waveforms easily pump fluid through the nanofunnels over a range of frequencies, e.g., 5 Hz to 5 kHz. In our experiments, the nanofunnels were milled into glass substrates with a focused ion beam (FIB) instrument, and the funnel design had a constant 5 degrees taper with aspect ratios (funnel tip width to funnel depth) of 0.1 to 1.0. We tracked ion current rectification by current-voltage (I-V) response and electroosmotic flow rectification by transport of a zwitterionic fluorescent probe. Rectification of ion current and electroosmotic flow increased with increasing electric field applied to the nanofunnel. Our results support three dimensional simulations of ion transport and electroosmotic transport through nanofunnels, which suggest the asymmetric electroosmotic transport stems from an induced pressure at the junction of the nanochannel and nanofunnel tip. PMID- 27230496 TI - Lesbian and bisexual women's sexual healthcare experiences. AB - AIMS AND OBJECTIVES: To develop insight into the experiences of lesbian and bisexual women accessing sexual health services and an understanding of their needs within the New Zealand context. BACKGROUND: Lesbian and bisexual women are typically invisible in healthcare settings due to heteronormative assumptions. As lesbian and bisexual women are reluctant to come out to clinicians, opportunities for targeted opportunistic health education are often missed. Lesbian and bisexual women have different needs from both heterosexual women and gay men when seeking healthcare. There has been little exploration of the experiences of lesbian and bisexual women accessing healthcare in the New Zealand context. DESIGN: Qualitative descriptive design. METHODS: Participants (n = 6) were recruited via advertisements and snowball sampling. Those recruited lived in a provincial city in New Zealand; self-identified as lesbian or bisexual; and met the inclusion criteria. Semi-structured, face-to-face interviews were used to obtain narrative data about participants being recipients of healthcare. RESULTS: Five themes were identified within the data set: Heteronormativity; The conundrum of safer sex; Implied and overt homophobia; Engagement with health promotion; and Resilience. CONCLUSION: This study highlighted the difficulties that lesbian and bisexual women face when seeking sexual healthcare, primarily due to clinicians' heteronormative assumptions. Lesbian and bisexual women have found ways of navigating the health system that make them feel safe(r) despite experiencing many adversities such as homophobia. RELEVANCE TO CLINICAL PRACTICE: This study's findings can be used to guide further research to identify ways to optimise clinicians' engagement with lesbian and bisexual women. Recognition of diversity and skilful communication are essential to rectify inequities and effectively target health information. PMID- 27230498 TI - A valley and spin filter based on gapped graphene. AB - We study highly valley- and spin-polarized current in single-layer gapped graphene without spin-orbit coupling. The structure considered is a three-barrier structure with one spin-splitting barrier and two electrical potential barriers with vector potentials. The electrons in the two valleys transmit differently because of the valley-dependent reflection between two adjacent barriers, while the spin-up and spin-down electrons transmit differently because of the spin splitting. The structure is different from other structures in which spin-orbit coupling plays an important role in the observation of valley- and spin-polarized current. We can control the spin and valley polarization by changing the width of the barrier or the strength of the spin splitting. The structure proposed in this paper can be used to make valley and spin devices. PMID- 27230497 TI - Forced KLF4 expression increases the generation of mature plasma cells and uncovers a network linked with plasma cell stage. AB - A role of the transcription factor Kruppel-like factor 4 (KLF4) in the generation of mature plasma cells (PC) is unknown. Indeed, KLF4 is critical in controlling the differentiation of various cell linages, particularly monocytes and epithelial cells. KLF4 is expressed at low levels in pro-B cells and its expression increases as they mature into pre-B cells, resting naive B cells and memory B cells. We show here that KLF4 is expressed in human bone marrow plasma cells and its function was studied using an in vitro model of differentiation of memory B cells into long lived plasma cells. KLF4 is rapidly lost when memory B cells differentiate into highly cell cycling plasmablasts, poorly cycling early plasma cells and then quiescent long-lived plasma cells. A forced expression of KLF4 in plasmablasts enhances the yield of their differentiation into early plasma cell and long lived plasma cells, by inhibiting apoptosis and upregulating previously unknown plasma cell pathways. PMID- 27230499 TI - Development of a compact continuum tubular robotic system for nasopharyngeal biopsy. AB - Traditional posterior nasopharyngeal biopsy using a flexible nasal endoscope has the risks of abrasion and injury to the nasal mucosa and thus causing trauma to the patient. Recently, a new class of robots known as continuum tubular robots (CTRs) provide a novel solution to the challenge with miniaturized size, curvilinear maneuverability, and capability of avoiding collision within the nasal environment. This paper presents a compact CTR which is 35 cm in total length, 10 cm in diameter, 2.15 kg in weight, and easy to be integrated with a robotic arm to perform more complicated operations. Structural design, end effector design, and workspace analysis are described in detail. In addition, teleoperation of the CTR using a haptic input device is developed for position control in 3D space. Moreover, by integrating the robot with three electromagnetic tracking sensors, a navigation system together with a shape reconstruction algorithm is developed. Comprehensive experiments are conducted to test the functionality of the proposed prototype; experiment results show that under teleoperation, the system has an accuracy of 2.20 mm in following a linear path, an accuracy of 2.01 mm in following a circular path, and a latency time of 0.1 s. It is also found that the proposed shape reconstruction algorithm has a mean error of around 1 mm along the length of the tubes. Besides, the feasibility and effectiveness of the proposed robotic system being applied to posterior nasopharyngeal biopsy are demonstrated by a cadaver experiment. The proposed robotic system holds promise to enhance clinical operation in transnasal procedures. PMID- 27230500 TI - Dual agency in critical care nursing: Balancing responsibilities towards colleagues and patients. AB - AIM: To explore critical care nurses' decisions to seek help from doctors. BACKGROUND: Despite their well-documented role in improving critically ill patients' outcomes, research indicates that nurses rarely take decisions about patients' treatment modalities on their own and constantly need to seek advice or authorization for their clinical decisions, even for protocol-guided actions. However, research around the factors related to, and the actual process of, such referrals is limited. DESIGN: A grounded theory study, underpinned by a symbolic interactionist perspective. METHODS: Data collection took place in a general intensive care unit between 2010 - 2012 and involved: 20 hours of non-participant and 50 hours of participant observation; ten informal and ten formal interviews; and two focus groups with ten nurses, selected by purposive and theoretical sampling. Data analysis was guided by the dimensional analysis approach to generating grounded theory. FINDINGS: Nurses' decisions to seek help from doctors involve weighing up several occasionally conflicting motivators. A central consideration is that of balancing their moral obligation to safeguard patients' interests with their duty to respect doctors' authority. Subsequently, nurses end up in a position of dual agency as they need to concurrently act as an agent to medical practitioners and patients. CONCLUSION: Nurses' dual agency relationship with patients and doctors may deter their moral obligation of keeping patients' interest as their utmost concern. Nurse leaders and educators should, therefore, enhance nurses' assertiveness, courage and skills to place patients' interest at the forefront of all their actions and interactions. PMID- 27230501 TI - Improved charge transportation at PbS QDs/TiO2 interface for efficient PEC hydrogen generation. AB - The effect of lead sulfide (PbS) quantum dots (QDs) on the photoelectrochemical properties of TiO2 with a varied number of SILAR cycles has been investigated. The study has also highlighted physical processes including band alignment, charge recombination and transportation for a PbS QDs/TiO2 interface. The inclusion of PbS QDs underneath TiO2 thin film has significantly enhanced the PEC response due to a higher number of photogenerated charge carriers along with the efficient separation and facilitation of these carriers towards their respective electrodes. The uniqueness of the work lies in the high stability of the system as PbS QDs lie beneath the TiO2 thin film, compared to the commonly used QDs sensitization over metal oxide, along with a good photoresponse. PMID- 27230502 TI - Chemical Exacerbation of Light-induced Retinal Degeneration in F344/N Rats in National Toxicology Program Rodent Bioassays. AB - Retinal degeneration due to chronic ambient light exposure is a common spontaneous age-related finding in albino rats, but it can also be related to exposures associated with environmental chemicals and drugs. Typically, light induced retinal degeneration has a central/hemispherical localization whereas chemical-induced retinal degeneration has a diffuse localization. This study was conducted to identify and characterize treatment-related retinal degeneration in National Toxicology Program rodent bioassays. A total of 3 chronic bioassays in F344/N rats (but not in B6C3F1/N mice) were identified that had treatment-related increases in retinal degeneration (kava kava extract, acrylamide, and leucomalachite green). A retrospective light microscopic evaluation of the retinas from rats in these 3 studies showed a dose-related increase in the frequencies of retinal degeneration, beginning with the loss of photoreceptor cells, followed by the inner nuclear layer cells. These dose-related increased frequencies of degenerative retinal lesions localized within the central/hemispherical region are suggestive of exacerbation of light-induced retinal degeneration. PMID- 27230504 TI - Lipid- and Polymer-Based Nanostructures for Cutaneous Delivery of Curcumin. AB - It is well-known that nanoencapsulation may overcome biopharmaceutical limitations of curcumin (CUR), but studies regarding the contribution of the vesicular nature of CUR-loaded nanoparticles on skin permeation are still scarce. Therefore, the effect of three colloidal systems (solid lipid nanoparticles (SLN), nanoemulsion (NE), and polymeric nanoparticles (NP)) on the control of cutaneous permeation of CUR was investigated in porcine ear skin/Franz diffusion cells. Colloidal suspensions were designed to present a similar particle size (+/ 170 nm), narrow size distribution (PdI < 0.2), and high entrapment efficiency (>99%). Zeta potential values were -0.13, -9.68 and -36.7 mV for the CUR-loaded NP, SLN and NE, respectively. Nanoencapsulation resulted in a cumulative amount of CUR in the more superficial layers of the skin. NP significantly enhanced the compound retention in the epidermis, which was approximately 2.49- and 3.32-fold more than SLN and NE, respectively. The CUR levels into the dermis were significantly increased after treatment with NE, which may be associated with repulsion phenomena in surface skin. Therefore, a more superficial or deeper action of CUR on the skin may be obtained depending on nanostructure type. While NPs are more effective in upper skin layers, NE should be prioritized when a dermal action for the CUR is required. PMID- 27230505 TI - Biological mechanisms underlying evolutionary origins of psychotic and mood disorders. AB - Psychotic and mood disorders are brain dysfunctions that are caused by gene environment interactions. Although these disorders are disadvantageous and involve behavioral phenotypes that decrease the reproductive success of afflicted individuals in the modern human society, the prevalence of these disorders have remained constant in the population. Here, we propose several biological mechanisms by which the genes associated with psychotic and mood disorders could be selected for in specific environmental conditions that provide evolutionary bases for explanations of when, why, and where these disorders emerged and have been maintained in humans. We discuss the evolutionary origins of psychotic and mood disorders with specific focuses on the roles of dopamine and serotonin in the conditions of social competitiveness/hierarchy and maternal care and other potential mechanisms, such as social network homophily and symbiosis. PMID- 27230503 TI - Molecular mechanisms regulating formation, trafficking and processing of annular gap junctions. AB - Internalization of gap junction plaques results in the formation of annular gap junction vesicles. The factors that regulate the coordinated internalization of the gap junction plaques to form annular gap junction vesicles, and the subsequent events involved in annular gap junction processing have only relatively recently been investigated in detail. However it is becoming clear that while annular gap junction vesicles have been demonstrated to be degraded by autophagosomal and endo-lysosomal pathways, they undergo a number of additional processing events. Here, we characterize the morphology of the annular gap junction vesicle and review the current knowledge of the processes involved in their formation, fission, fusion, and degradation. In addition, we address the possibility for connexin protein recycling back to the plasma membrane to contribute to gap junction formation and intercellular communication. Information on gap junction plaque removal from the plasma membrane and the subsequent processing of annular gap junction vesicles is critical to our understanding of cell-cell communication as it relates to events regulating development, cell homeostasis, unstable proliferation of cancer cells, wound healing, changes in the ischemic heart, and many other physiological and pathological cellular phenomena. PMID- 27230506 TI - Reading a "negative" study. PMID- 27230507 TI - The pathological features of ectopic lymphoid neogenesis in idiopathic dacryoadenitis. AB - BACKGROUND: Lymphoid neogenesis has been reported in various diseases but not in idiopathic dacryoadenitis. The aim of this paper is to discuss the pathological features of lymphoid neogenesis in idiopathic dacryoadenitis. METHODS: 20 cases of idiopathic dacryoadenitis were collected retrospectively. Lymphoid neogenesis was graded by lymphocytic aggregates and germinal center-like structure formation. T and B cell compartmentalization, follicular dendritic cells and the expression of CXCL13 and CCL21 were analyzed. RESULTS: Grade 1 lymphoid neogenesis was observed in 10 of 20 cases (50 %), grade 2 in 18 of 20 cases (90 %) and grade 3 in 14 of 20 (70 %). The existence of T and B cell compartmentalization and follicular dendritic cells increased in parallel to the grade of lymphoid neogenesis. The expression of CXCL13 significantly increased in the higher grade of lymphoid neogenesis, but no correlation was found between CCL21 and grades of lymphoid neogenesis. CONCLUSIONS: Ectopic lymphoid neogenesis participates in the pathogenesis of idiopathic dacryoadenitis and appears as a dynamic process. PMID- 27230509 TI - Associations between common intestinal parasites and bacteria in humans as revealed by qPCR. AB - Several studies have shown associations between groups of intestinal bacterial or specific ratios between bacterial groups and various disease traits. Meanwhile, little is known about interactions and associations between eukaryotic and prokaryotic microorganisms in the human gut. In this work, we set out to investigate potential associations between common single-celled parasites such as Blastocystis spp. and Dientamoeba fragilis and intestinal bacteria. Stool DNA from patients with intestinal symptoms were selected based on being Blastocystis spp.-positive (B+)/negative (B-) and D. fragilis-positive (D+)/negative (D-), and split into four groups of 21 samples (B+ D+, B+ D-, B- D+, and B- D-). Quantitative PCR targeting the six bacterial taxa Bacteroides, Prevotella, the butyrate-producing clostridial clusters IV and XIVa, the mucin-degrading Akkermansia muciniphila, and the indigenous group of Bifidobacterium was subsequently performed, and the relative abundance of these bacteria across the four groups was compared. The relative abundance of Bacteroides in B- D- samples was significantly higher compared with B+ D- and B+ D+ samples (P < 0.05 and P < 0.01, respectively), and this association was even more significant when comparing all parasite-positive samples with parasite-negative samples (P < 0.001). Additionally, our data revealed that a low abundance of Prevotella and a higher abundance of Clostridial cluster XIVa was associated with parasite negative samples (P < 0.05 and P < 0.01, respectively). Our data support the theory that Blastocystis alone or combined with D. fragilis is associated with gut microbiota characterized by low relative abundances of Bacteroides and Clostridial cluster XIVa and high levels of Prevotella. PMID- 27230508 TI - Use of the neutrophil-to-lymphocyte ratio as a component of a score to predict postoperative mortality after surgery for hip fracture in elderly subjects. AB - BACKGROUND: Hip fracture precedes death in 12-37 % of elderly people. Identification of high risk patients may contribute to target those in whom optimal management, resource allocation and trials efficiency are needed. The aim of this study is to evaluate a predictive score of mortality after hip fracture in older persons on the basis of the objective prognostic factors easily available: age, sex and neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP). PATIENTS AND METHODS: After the ethical committee approval, we analyzed our prospective database including 286 consecutive older patients (>64 years) with hip fracture. A score [range 0-4] was constructed, based on a previous analysis, combining age (1 point per decade above 74 years), sex (1 point for male gender) and NLR at postoperative day +5 (1 point if > 5). A receiver-operating curve (ROC) analysis was performed. Similar analyses were performed with CRP (1 point if > 7.65 mg/dL). RESULTS: In the 286 patients (male 31 %), the median age was 84 (65-102) years, and the mean NLR values were 6.47 +/ 6.07. At 1 year, 82/286 patients died (28.7 %). In the 235 patients with complete data, significant differences in term of mortality risk are observed (P < 0.001). Performance analysis shows an AUC of 0.72[95 % CI 0.65-0.79]. CRP performed less than NLR (AUC for CRP alone: 0.53[95 % CI 0.45-0.61], P = 0.42, with a sensitivity of 58.5 % and a specificity of 57.1 % for a cut-off value of 7.65 mg/dL; and for NLR alone: 0.59 [95 % CI 0.51-0.66]; P = 0.02, with a sensitivity of 55 % and a specificity of 65 % for a cut-off value of 4.9). CONCLUSION: A discrete 0-4 scoring systems based on age, sex and the NLR was shown to be predictive of mortality in elderly patients during the first postoperative year following surgery for hip fracture repair. PMID- 27230510 TI - Colistin combination therapy improves microbiologic cure in critically ill patients with multi-drug resistant gram-negative pneumonia. AB - Currently, in vitro synergy with colistin has not translated into improved clinical outcomes. This study aimed to compare colistin combination therapy to colistin monotherapy in critically ill patients with multi-drug resistant gram negative (MDR-GN) pneumonia. This was a retrospective analysis of critically ill adult patients receiving intravenous colistin for MDR-GN pneumonia comparing colistin combination therapy to colistin monotherapy with a primary endpoint of clinical cure. Combination therapy was defined by administration of another antibiotic to which the MDR-GN pathogen was reported as susceptible or intermediate. Ninety patients were included for evaluation (41 combination therapy and 49 monotherapy). Baseline characteristics were similar between groups. No difference in clinical cure was observed between combination therapy and monotherapy in univariate analysis, nor when adjusted for APACHE II score and time to appropriate antibiotic therapy (57.1 vs. 63.4 %, adjusted OR 1.15, p = 0.78). Microbiological cure was significantly higher for combination therapy (87 vs. 35.5 %, p < 0.001). Colistin combination therapy was associated with a significant improvement in microbiological cure, without improvement in clinical cure. Based on the in vitro synergy and improvement in microbiological clearance, colistin combination therapy should be prescribed for MDR-GN pneumonia. Further research is warranted to determine if in vitro synergy with colistin translates into improved clinical outcomes. PMID- 27230511 TI - The relevance of Tim-3 polymorphisms and F protein to the outcomes of HCV infection. AB - Hepatitis C virus (HCV) is one of the major causes of liver inflammation. The aim of this study was to investigate the associations of T-cell immunoglobulin and mucin domain-3 (Tim-3) polymorphisms and the alternate reading frame protein (F protein) with the outcomes of HCV infection. Three single-nucleotide polymorphisms (SNPs; rs10053538, rs12186731, and rs13170556) of Tim-3 were genotyped in this study, which included 203 healthy controls, 558 hepatitis C anti-F-positive patients, and 163 hepatitis C anti-F-negative patients. The results revealed that the rs12186731 CT and rs13170556 TC and CC genotypes were significantly less frequent in the anti-F-positive patients [odds ratio (OR) = 0.54, 95 % confidence interval (CI) = 0.35-0.83, p = 0.005; OR = 0.26, 95 % CI = 0.18-0.39, p < 0.001; and OR = 0.19, 95 % CI = 0.10-0.35, p < 0.001, respectively), and the rs13170556 TC genotype was more frequent in the chronic HCV (CHC) patients (OR = 1.70, 95 % CI = 1.20-2.40, p = 0.002). The combined analysis of the rs12186731 CT and rs13170556 TC/CC genotypes revealed a locus dosage protective effect in the anti-F-positive patients (OR = 0.22, 95 % CI = 0.14-0.33, p trend < 0.001). Stratified analyses revealed that the frequencies of the rs12186731 (CT + TT) genotypes were significantly lower in the older (OR = 0.31, 95 % CI = 0.15-0.65, p = 0.002) and female (OR = 0.30, 95 % CI = 0.17-0.52, p < 0.001) subgroups, and rs13170556 (TC + CC) genotypes exhibited the same effect in all subgroups (all p < 0.001) in the anti-F antibody generations. Moreover, the rs13170556 (TC + CC) genotypes were significantly more frequent in the younger (OR = 1.86, 95 % CI = 1.18-2.94, p = 0.007) and female (OR = 2.38, 95 % CI = 1.48-3.83, p < 0.001) subgroups of CHC patients. These findings suggest that the rs12186731 CT and rs13170556 TC/CC genotypes of Tim-3 provide potential protective effects with the F protein in the outcomes of HCV infection and that these effects are related to sex and age. PMID- 27230513 TI - Percutaneous Biopsy and Radiofrequency Ablation of Osteoid Osteoma with Excess Reactive New Bone Formation and Cortical Thickening Using a Battery-Powered Drill for Access: A Technical Note. AB - PURPOSE: To report our experience with the use of a battery-powered drill in biopsy and radiofrequency ablation of osteoid osteoma with excess reactive new bone formation. The battery-powered drill enables obtaining the sample while drilling. MATERIALS AND METHODS: During the last 18 months, 14 patients suffering from painful osteoid osteoma with excess reactive new bone formation underwent CT guided biopsy and radiofrequency ablation. In order to assess and sample the nidus of the osteoid osteoma, a battery-powered drill was used. Biopsy was performed in all cases. Then, coaxially, a radiofrequency electrode was inserted and ablation was performed with osteoid osteoma protocol. Procedure time (i.e., drilling including local anesthesia), amount of scans, technical and clinical success, and the results of biopsy are reported. RESULTS: Access to the nidus through the excess reactive new bone formation was feasible in all cases. Median procedure time was 50.5 min. Histologic verification of osteoid osteoma was performed in all cases. Radiofrequency electrode was coaxially inserted within the nidus and ablation was successfully performed in all lesions. Median amount CT scans, performed to control correct positioning of the drill and precise electrode placement within the nidus was 11. There were no complications or material failure reported in our study. CONCLUSIONS: The use of battery-powered drill facilitates access to the osteoid osteoma nidus in cases where excess reactive new bone formation is present. Biopsy needle can be used for channel creation during the access offering at the same time the possibility to extract bone samples. PMID- 27230512 TI - Renal tissue oxygenation in children with chronic kidney disease due to vesicoureteral reflux. AB - BACKGROUND: Vesicoureteral reflux (VUR) is a frequent cause of chronic kidney disease (CKD) in children. Using blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI), we measured cortical and medullary oxygenation in children with CKD due to VUR and compared the results to those obtained on healthy controls. METHOD: The study population comprised 37 children (19 with CKD due to VUR and 18 healthy age-matched controls). BOLD-MRI was performed before and after furosemide treatment. MR images were analyzed with the region-of interest (ROI) technique to assess the mean R2* values (=1/T2*) of the cortex and medulla of each kidney and with the concentric object (CO) technique that divides renal parenchyma in 12 equal layers. RESULTS: R2* values were significantly lower (corresponding to higher oxygenation) in the cortex and medulla of kidneys of children with CKD due to VUR than in those of the healthy controls (cortex 16.4 +/- 1.4 vs. 17.2 +/- 1.6 s(-1) , respectively; medulla 28.4 +/- 3.2 vs. 30.3 +/- 1.9 s(-1) , respectively; P < 0.05), and furosemide-induced changes in medullary R2* were smaller in the former than in the latter (-5.7 +/- 3.0 vs. -6.9 +/- 3.4 s(-1), respectively; P < 0.05). Similar results were found with the CO technique. In children with a history of unilateral reflux (n = 9), the non-affected contralateral kidneys presented similar R2* values as the diseased kidneys, but their response to furosemide was significantly larger (-7.4 +/- 3.2 vs. -5.7 +/- 3.0, respectively; P = 0.05). CONCLUSIONS: Chronic kidney disease due to VUR is not associated with kidney tissue hypoxia in children. The significantly larger furosemide-induced decrease in medullary R2* levels in the healthy group and unaffected contralateral kidneys of the VUR group points towards more intense renal sodium transport in these kidneys. PMID- 27230514 TI - Uncommon Case of a Post-Traumatic Portal Vein Pseudoaneurysm Treated with Percutaneous Transhepatic Stent Grafting. AB - We describe a man who presented with a traumatic portal vein pseudoaneurysm, which was subsequently managed with a percutaneous transhepatic stent graft. This case demonstrates a rarely seen condition in the traumatic population and a novel management strategy, which should be considered in the management of this challenging injury. PMID- 27230515 TI - Pharmacomechanical Thrombectomy in Paget-Schroetter Syndrome. AB - PURPOSE: The purpose of the study was to evaluate feasibility of pharmacomechanical thrombectomy (PMT) in the treatment of Paget-Schroetter syndrome (PSS) followed by thoracoscopic or open surgical decompression of the subclavian vein. METHODS: Twenty-two out of 27 consecutive patients with PSS received PMT using the Trellis-8 peripheral infusion system (Covidien) between 2010 and 2014. Subsequent surgery was performed in 18 of those patients, 9 patients were treated with thoracoscopic, 7 patients with subclavicular, and 2 patients with transaxillary first rib resection, 4 patients were treated with PMT and anticoagulation alone. Technical success, complications, and patency were registered. RESULTS: PMT was successful in 21 (95 %) patients; 1 patient with unsatisfactory lysis received further catheter-directed thrombolysis, which, however, did not improve the result. The mean endovascular procedure time was 105 +/- 33 min (range 70-200 min), and the required median amount of thrombolytic agent was 500,000 international unit (IU; range 250,000-1,000,000 IU). Adjunctive balloon venoplasty and aspiration were used in 18 (82 %) and 7 (32 %) cases, respectively. One patient had an intimal tear of the subclavian vein that was discovered and repaired during surgery. There were no other complications related to the endovascular procedure. At follow-up, 18 of 21 patients (86 %) with follow up imaging available had patent subclavian vein, and all except 1 of the 22 patients were asymptomatic. The mean follow-up time was 25 +/- 17 months. CONCLUSIONS: In experienced hands, PMT is effective for early thrombus removal in PSS. Surgical decompression must be considered after PMT. PMID- 27230516 TI - Reconstructive valve surgery within 10 days of stroke in endocarditis. AB - BACKGROUND: The optimal timing of surgical treatment for infective endocarditis complicated by cerebrovascular events is controversial, largely due to the perceived risk of perioperative intracranial bleeding. Current guidelines suggest waiting 2 weeks between the diagnosis of stroke and surgery. The aim of this study was to investigate the clinical and neurological outcomes of early surgery following a stroke. METHODS: This was a single-center retrospective analysis of 12 consecutive patients requiring surgery for infective endocarditis between 2011 and 2014 at Rush University Medical Center, with either ischemic (n = 6) and/or hemorrhagic (n = 6) cerebrovascular complications. All underwent computed tomographic angiography prior to early valve reconstructive surgery to identify potentially actionable neurological findings. Early valve surgery was performed for ongoing sepsis or persistent emboli. Neurologic risk and outcome were assessed pre- and postoperatively using the National Institutes of Health Stroke Scale and the Glasgow Outcome Scale, respectively. RESULTS: All 12 patients underwent surgical treatment within 10 days of the diagnosis of stroke. Mortality in the immediate postoperative period was 8%. Eleven of the 12 patients exhibited good neurological recovery in the immediate postoperative period, with a Glasgow Outcome Scale score >= 3. There was no correlation between duration of cardiopulmonary bypass and neurological outcomes. CONCLUSION: Early cardiac surgery in patients with infective endocarditis and stroke maybe lifesaving with a low neurological risk. Comprehensive neurovascular imaging may help in identifying patient-related risk factors. PMID- 27230517 TI - Pulse volume recordings to identify falsely elevated ankle brachial index. AB - BACKGROUND: Ankle brachial index can be falsely elevated in cases of medial arterial calcification, and its clinical use should be limited, especially in patients with diabetes. The aim of this study was to evaluate the potential role of pulse volume recording in detecting falsely elevated ankle brachial index. METHODS: Two parameters of the pulse waveform were automatically calculated: upstroke time and percentage mean artery pressure. Pulse volume recordings were retrospectively evaluated in 171 consecutive patients (342 limbs); 73 (43%) had a diagnosis of diabetes. RESULTS: On multivariate analysis, diabetes (hazard ratio = 1.7), ankle brachial index <= 0.90 (hazard ratio = 4.4), upstroke time >= 180 ms (hazard ratio = 2.1), and percentage mean artery pressure >= 45% (hazard ratio = 2.8) were significantly related to toe brachial index < 0.60. Further analysis for falsely elevated ankle brachial index was performed in 196 limbs (146 patients) with ankle brachial index > 0.90. The difference between ankle brachial index and toe brachial index differentiated the limbs of diabetic patients, with percentage mean artery pressure >= 45%, from controls (0.45 +/- 0.17 vs. 0.35 +/- 0.16, p = 0.03); upstroke time was not found to be a discriminating factor. CONCLUSIONS: Although measurement of ankle brachial index remains the gold standard for diagnosing peripheral arterial disease, percentage mean artery pressure, automatically obtained in ankle brachial index measurement, may be useful to detect falsely elevated ankle brachial index, especially in patients with diabetes. PMID- 27230518 TI - The pterygopalatine fossa: imaging anatomy, communications, and pathology revisited. AB - The pterygopalatine fossa (PPF) is a small, clinically inaccessible, fat-filled space located in the deep face that serves as a major neurovascular crossroad between the oral cavity, nasal cavity, nasopharynx, orbit, masticator space, and the middle cranial fossa. Due to its inherent complex location and connections, it can potentially act as a natural conduit for the spread of inflammatory and neoplastic diseases across the various deep spaces in the head and neck. This review aims to acquaint the reader with the imaging anatomy of the PPF, its important communications, and to identify some major pathological conditions that can involve the PPF, especially in conditions where its involvement can have serious diagnostic and therapeutic implications, such as in perineural tumour spread. TEACHING POINTS: * The PPF is a small neurovascular junction in the deep face with important to-and-fro connections. * Awareness of anatomy of the PPF and its communications helps to simplify imaging of its pathology. * Perineural tumour spread is clinically the most important pathology in this region. PMID- 27230519 TI - Feasibility and Success Rate of a Fetal MRI and MR Spectroscopy Research Protocol Performed at Term Using a 3.0-Tesla Scanner. AB - OBJECTIVES: To report the feasibility and main factors affecting the success of a fetal magnetic resonance imaging (MRI) and MR spectroscopy (MRS) research protocol performed at term using a 3-tesla scanner. METHODS: Pregnant patients at term underwent an MRI. Specific measures were taken to prevent maternal discomfort and distress, such as detailed counseling and maternal repositioning if needed. MRS data were acquired from the frontal lobe and basal ganglia, and processed applying quality control criteria. RESULTS: The mean gestational age at MRI was 37.4 +/- 0.9 weeks. From a total of 245 patients that showed up for the MRI, 11 referred claustrophobia which prevented the test from starting, and 30 patients started the test but decided to discontinue due to discomfort. Thus, the examination was complete in 204 patients. MRS data could be obtained in 170 cases from the frontal lobe and 165 cases from the basal ganglia, of which 52.4 and 68.6%, respectively, complied with our defined quality criteria. The mean scanning time was 34:16 +/- 9:30 min:s after excluding those cases presenting initial intolerance to the test. Minor abnormalities were described in 11 MRI reports. CONCLUSIONS: The fetal MRI/MRS protocol was feasible and generally well tolerated at term on a 3-tesla scanner, but a significant number of cases were lost to analysis. The rate of patients that eventually provided usable research information was 95.5% for anatomical examination and 52.4-68.6% for MRS. This information should be taken into account in the design of fetal brain MRI studies. PMID- 27230520 TI - Assessment of Groin Application of Junctional Tourniquets in a Manikin Model. AB - Introduction To aid in preparation of military medic trainers for a possible new curriculum in teaching junctional tourniquet use, the investigators studied the time to control hemorrhage and blood volume lost in order to provide evidence for ease of use. Hypothesis Models of junctional tourniquet could perform differentially by blood loss, time to hemostasis, and user preference. METHODS: In a laboratory experiment, 30 users controlled simulated hemorrhage from a manikin (Combat Ready Clamp [CRoC] Trainer) with three iterations each of three junctional tourniquets. There were 270 tests which included hemorrhage control (yes/no), time to hemostasis, and blood volume lost. Users also subjectively ranked tourniquet performance. Models included CRoC, Junctional Emergency Treatment Tool (JETT), and SAM Junctional Tourniquet (SJT). Time to hemostasis and total blood loss were log-transformed and analyzed using a mixed model analysis of variance (ANOVA) with the users represented as random effects and the tourniquet model used as the treatment effect. Preference scores were analyzed with ANOVA, and Tukey's honest significant difference test was used for all post hoc pairwise comparisons. RESULTS: All tourniquet uses were 100% effective for hemorrhage control. For blood loss, CRoC and SJT performed best with least blood loss and were significantly better than JETT; in pairwise comparison, CRoC-JETT (P .5, all models). CONCLUSION: The CRoC and SJT performed best in having least blood loss, CRoC performed best in having least time to hemostasis, and users did not differ in preference of model. Models of junctional tourniquet performed differentially by blood loss and time to hemostasis. Kragh JF Jr , Lunati MP , Kharod CU , Cunningham CW , Bailey JA , Stockinger ZT , Cap AP , Chen J , Aden JK 3d , Cancio LC . Assessment of groin application of junctional tourniquets in a manikin model. Prehosp Disaster Med. 2016;31(4):358-363. PMID- 27230521 TI - Effectiveness of a minimal resource fracture liaison service. AB - PURPOSE: The purpose of this study was to investigate if a 2-year intervention with a minimal resource fracture liaison service (FLS) was associated with increased investigation and medical treatment and if treatment was related to reduced re-fracture risk. METHODS: The FLS started in 2013 using existing secretaries (without an FLS coordinator) at the emergency department and orthopaedic wards to identify risk patients. All patients older than 50 years of age with a fractured hip, vertebra, shoulder, wrist or pelvis were followed during 2013-2014 (n = 2713) and compared with their historic counterparts in 2011 2012 (n = 2616) at the same hospital. Re-fractures were X-ray verified. A time dependent adjusted (for age, sex, previous fracture, index fracture type, prevalent treatment, comorbidity and secondary osteoporosis) Cox model was used. RESULTS: The minimal resource FLS increased the proportion of DXA-investigated patients after fracture from 7.6 to 39.6 % (p < 0.001) and the treatment rate after fracture from 12.6 to 31.8 %, which is well in line with FLS types using the conventional coordinator model. Treated patients had a 51 % lower risk of any re-fracture than untreated patients (HR 0.49, 95 % CI 0.37-0.65 p < 0.001). CONCLUSIONS: We found that our minimal resource FLS was effective in increasing investigation and treatment, in line with conventional coordinator-based services, and that treated patients had a 51 % reduced risk of new fractures, indicating that also non-coordinator based fracture liaison services can improve secondary prevention of fractures. PMID- 27230522 TI - Risk factors for osteoporotic fractures in persons with spinal cord injuries and disorders. AB - Clinical risk factors for fracture were explored among Veterans with a spinal cord injury. At the end of 11 years of follow-up, the absolute risk of fracture was approximately 20 %. Among the clinical and SCI-related factors explored, a prior history of fracture was strongly associated with incident fracture. INTRODUCTION: Few studies to date have comprehensively addressed clinical risk factors for fracture in persons with spinal cord injury (SCI). The purpose of this study was to identify risk factors for incident osteoporotic fractures in persons with a SCI that can be easily determined at the point of care. METHODS: The Veteran's Affairs Spinal Cord Dysfunction Registry, a national database of persons with a SCI, was used to examine clinical and SCI-related risk factors for fracture. Incident fractures were identified in a cohort of persons with chronic SCI, defined as SCI present for at least 2 years. Cox regression models were used to estimate the risk of incident fractures. RESULTS: There were 22,516 persons with chronic SCI included in the cohort with 3365 incident fractures. The mean observational follow-up time for the overall sample was 6.2 years (median 6.0, IQR 2.9-11.0). The mean observational follow-up time for the fracture group was 3.9 years (median 3.3, IQR 1.4-6.1) and 6.7 years (median 6.7, IQR 3.1-11.0) for the nonfracture group. By the end of the study, which included predominantly older Veterans with a SCI observed for a relatively short period of time, the absolute (i.e., cumulative hazard) for incident fractures was 0.17 (95%CI 0.14 0.21). In multivariable analysis, factors associated with an increased risk of fracture included White race, traumatic etiology of SCI, paraplegia, complete extent of SCI, longer duration of SCI, use of anticonvulsants and opioids, prevalent fractures, and higher Charlson Comorbidity Indices. Women aged 50 and older were also at higher risk of sustaining an incident fracture at any time during the 11-year follow-up period. CONCLUSIONS: There are multiple clinical and SCI-related risk factors which can be used to predict fracture in persons with a SCI. Clinicians should be particularly concerned about incident fracture risk in persons with a SCI who have had a previous fracture. PMID- 27230524 TI - Closing evidence-practice gaps in lung cancer: Results from multi-methods priority setting in the clinical context. AB - AIM: To establish priorities for implementation research to reduce evidence practice gaps in lung cancer care. METHODS: A modified Nominal Group Technique was used to prioritize evidence-practice gaps in lung cancer care with oncology professionals at three clinical study sites: one rural and two metropolitan. A multimethods design was used to gather quantitative and qualitative data. Quantitative data were analyzed with descriptive statistics, while qualitative data were thematically analyzed. RESULTS: Forty-two health professionals participated, representing a multidisciplinary spread across the care trajectory. A standout priority was identified: reducing the time from first presentation of symptoms to diagnosis and referral for treatment (gap 1), as well as significant focus on a number of presented priorities, including: utilization of active treatments; timely referral to palliative care services; screening as a potential diagnostic tool; and focusing on the care needs of our vulnerable population groups. We describe emerging themes from the qualitative analysis, including: patient help-seeking behavior, provider knowledge about lung cancer, service factors, patient and provider factors in not receiving treatment, the "flow on" effect of variations from optimal care, vulnerable populations of patients, psychosocial needs and early referral to palliative care services. CONCLUSION: This study is an example of a priority setting partnership between clinicians and health researchers. The priorities highlighted by this study guide future decision making for collaborative implementation of research in lung cancer care. PMID- 27230523 TI - Adhesion of Plasmodium falciparum infected erythrocytes in ex vivo perfused placental tissue: a novel model of placental malaria. AB - BACKGROUND: Placental malaria occurs when Plasmodium falciparum infected erythrocytes sequester in the placenta. Placental parasite isolates bind to chondroitin sulphate A (CSA) by expression of VAR2CSA on the surface of infected erythrocytes, but may sequester by other VAR2CSA mediated mechanisms, such as binding to immunoglobulins. Furthermore, other parasite antigens have been associated with placental malaria. These findings have important implications for placental malaria vaccine design. The objective of this study was to adapt and describe a biologically relevant model of parasite adhesion in intact placental tissue. RESULTS: The ex vivo placental perfusion model was modified to study adhesion of infected erythrocytes binding to CSA, endothelial protein C receptor (EPCR) or a transgenic parasite where P. falciparum erythrocyte membrane protein 1 expression had been shut down. Infected erythrocytes expressing VAR2CSA accumulated in perfused placental tissue whereas the EPCR binding and the transgenic parasite did not. Soluble CSA and antibodies specific against VAR2CSA inhibited binding of infected erythrocytes. CONCLUSION: The ex vivo model provides a novel way of studying receptor-ligand interactions and antibody mediated inhibition of binding in placental malaria. PMID- 27230525 TI - Recent Advances in the Reactions of 1,2-Allenic Ketones and alpha-Allenic Alcohols. AB - This Personal Account summarizes our recent efforts in searching for novel synthetic strategies for a number of organic molecules by using allene derivatives as valuable substrates. It starts with a concise description of the background of allene-related synthetic chemistry. The second part deals with the reactions of 1,2-allenic ketones, including the reactions of 1,2-allenic ketones with various nucleophiles to afford functionalized benzenes, heterocycles, and fluoroenones, and those of allenic ketones as nucleophiles under the promotion of bases to provide 1,3,4'-triones or functionalized furans. The third part of this account focuses on the reactions of alpha-allenic alcohols. In this section, multicomponent reactions involving alpha-allenic alcohols, and cascade reactions of alpha-allenic alcohols promoted by Bronsted acid or iodine, are presented. PMID- 27230527 TI - Stem cell heterogeneity revealed. AB - The skin forms a protective, water-impermeable barrier consisting of heavily crosslinked epithelial cells. However, the specific role of stem cells in sustaining this barrier remains a contentious issue. A detailed analysis of the interfollicular epidermis now proposes a model for how a composite of cells with different properties are involved in its maintenance. PMID- 27230526 TI - The increasing complexity of the ubiquitin code. AB - Ubiquitylation is essential for signal transduction as well as cell division and differentiation in all eukaryotes. Substrate modifications range from a single ubiquitin molecule to complex polymeric chains, with different types of ubiquitylation often eliciting distinct outcomes. The recent identification of novel chain topologies has improved our understanding of how ubiquitylation establishes precise communication within cells. Here, we discuss how the increasing complexity of ubiquitylation is employed to ensure robust and faithful signal transduction in eukaryotic cells. PMID- 27230528 TI - PGC1alpha drives a metabolic block on prostate cancer progression. AB - Metabolic rewiring is essential for cancer cell survival. PGC1alpha, a transcriptional co-activator that is downregulated in prostate cancer, is now shown to control prostate cancer metabolism by activating an oxidative metabolic program that prevents tumour growth and metastatic dissemination. PMID- 27230529 TI - Primary cilia mechanosensing triggers autophagy-regulated cell volume control. AB - The primary cilium and the process of autophagy are thought to be in a functionally reciprocal relationship. In further support of this link, fluid flow sensing by the primary cilium is now shown to induce autophagy, which in turn regulates the volume of kidney epithelial cells. PMID- 27230530 TI - Replicating repetitive DNA. AB - The function and regulation of repetitive DNA, the 'dark matter' of the genome, is still only rudimentarily understood. Now a study investigating DNA replication of repetitive centromeric chromosome segments has started to expose a fascinating replication program that involves suppression of ATR signalling, in particular during replication stress. PMID- 27230531 TI - Corrigendum: SAS-6 engineering reveals interdependence between cartwheel and microtubules in determining centriole architecture. PMID- 27230532 TI - Corrigendum: A splicing switch from ketohexokinase-C to ketohexokinase-A drives hepatocellular carcinoma formation. PMID- 27230533 TI - Atrial Fibrillation in a Dual-Chamber ICD Recipient with Activation of the Ventricular Intrinsic Preference Algorithm: What Is the Mechanism? PMID- 27230534 TI - Effect of holding a racket on propulsion technique of wheelchair tennis players. AB - The purpose of this study was to determine possible differences in propulsion technique between propelling the wheelchair with and without a racket in the hand. Eight experienced wheelchair tennis players performed three submaximal exercise tests and six sprint tests on a wheelchair ergometer. Torque and velocity were measured during the tests and power output and timing variables were calculated. Differences between the conditions with and without racket were analyzed. When propelling with the racket, the racket side showed a significantly lower push time (P = 0.03), lower percentage push time (P = 0.001), shorter contact angle (P < 0.001), more power loss before (P = 0.006) and after (P = 0.001) the push, a higher peak (P = 0.009) and mean (P = 0.005) power output during the push, and a lower mean overall velocity (P = 0.03). When the same hand is compared when propelling with and without racket or when the sprint data were analyzed, similar significant differences were found. Propelling the wheelchair while holding a racket has negative effects on the propulsion technique and may lead to injuries of the upper extremity. The longer time needed to couple the hand with the racket to the rim leads to higher power losses and subsequently higher power output generation during the shorter push phase. PMID- 27230535 TI - The Prokinetic, Laxative, and Antidiarrheal Effects of Morus nigra: Possible Muscarinic, Ca(2+) Channel Blocking, and Antimuscarinic Mechanisms. AB - Morus nigra Linn. (black mulberry) is used in gastrointestinal ailments. This study demonstrates gut modulatory properties of M. nigra. The prokinetic, laxative, and antidiarrheal activities of M. nigra were assessed in mice, while isolated rabbit jejunum and guinea-pig ileum were used to explore insight into mechanism(s). At 30 and 70 mg/kg, the crude extract of M. nigra (Mn.Cr) exhibited atropine-sensitive prokinetic and laxative effects, similar to carbachol (CCh). While at higher doses (100, 300, and 500 mg/kg), Mn.Cr offered protection against castor oil-induced diarrhea. In rabbit jejunum, Mn.Cr and its chloroform fraction inhibited CCh-induced contractions more potently compared with high K(+) (80 mm). Conversely, petroleum fraction was more potent against high-K(+) -induced contractions. At 0.01 mg/mL, Mn.Cr caused a parallel shift in acetylcholine concentration-response curves (CRCs) followed by a non-parallel shift at 0.03 mg/mL, similar to dicyclomine. At further tested concentrations, Mn.Cr (0.1 and 0.3 mg/mL) and petroleum fraction suppressed Ca(2+) CRCs, similar to verapamil. In guinea-pig ileum, Mn.Cr, its aqueous and ethyl acetate fractions exhibited atropine-sensitive gut stimulant activity along with additional uncharacterized excitatory response in the aqueous fraction only. These results suggest that black mulberry possesses prokinetic, laxative, and antidiarrheal effects, putatively mediated through cholinomimetic, antimuscarinic, and Ca(2+) antagonist mechanisms, respectively. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27230536 TI - Innate immune responses in human hepatocyte-derived cell lines alter genotype 1 hepatitis E virus replication efficiencies. AB - Hepatitis E virus (HEV) is a significant health problem in developing countries causing sporadic and epidemic forms of acute viral hepatitis. Hepatitis E is a self-limiting disease; however, chronic HEV infections are being reported in immunocompromised individuals. The disease severity is more during pregnancy with high mortality (20-25%), especially in third trimester. Early cellular responses after HEV infection are not completely understood. We analyzed innate immune responses associated with genotype-I HEV replication in human hepatoma cell lines (Huh7, Huh7.5 and HepG2/C3A) using HEV replicon system. These cells supported HEV replication with different efficiencies due to the cell type specific innate immune responses. HepG2/C3A cells were less supportive to HEV replication as compared to Huh7.5 and S10-3 cells. Reconstitution of the defective RIG-I and TLR3 signaling in Huh7.5 cells enabled them to induce higher level antiviral responses and restrict HEV replication, suggesting the involvement of both RIG-I and TLR3 in sensing HEV RNA and downstream activation of interferon regulatory factor 3 (IRF3) to generate antiviral responses. Inhibition of IRF3 mediated downstream responses in HepG2/C3A cells by pharmacological inhibitor BX795 significantly improved HEV replication efficiency implying the importance of this study in establishing a better cell culture system for future HEV studies. PMID- 27230537 TI - Porcine pulmonary auto-transplantation for ex vivo therapy as a model for new treatment strategies. AB - OBJECTIVES: Lung auto-transplantation is the surgical key step in experiments involving ex vivo therapy of severe or end-stage lung diseases. Ex vivo therapy has become a clinical reality because of systems such as the Organ Care System (OCS) Lung, which is the only commercially available portable lung perfusion system. However, survival experiments involving porcine lung auto-transplantation pose special surgical and anaesthesiological challenges. This current study was designed to describe the development of surgical techniques and aneasthesiological management strategies that facilitate lung auto transplantation survival surgery including a follow-up period of 4 days. METHODS: Left pneumonectomy was performed in 12 Mini-Lewe miniature pigs. After ex vivo treatment of the harvested lungs within the OCS Lung for 2 h, the lungs were retransplanted into the same animal (auto-transplantation). Four animals were used to develop the optimal techniques and establish an experimental protocol. According to the final protocol, eight additional animals were operated. The follow-up period was 4 days. RESULTS: There were four severe intraoperative surgical complications [anatomical variant of the superior vena cava (two times), a complication related to the bronchial anastomosis and a complication related to the pulmonary arterial anastomosis]. The major postoperative problems were hyperkalaemia, prolonged recovery from anaesthesia and pulmonary oedema after reperfusion. Establishment of the surgical technique showed that using a pericardial tube to facilitate the anastomosis of the thin left superior pulmonary vein should be considered to prevent thrombosis. However, routine use of the patch technique to construct venous and arterial anastomoses is not necessary. Furthermore, traction on the venous anastomoses can be avoided by performing the bronchial anastomosis first. CONCLUSIONS: Lung auto transplantation is a feasible experimental model for ex vivo therapy of lung diseases and is applicable for experimental questions concerning human lung transplantation. PMID- 27230539 TI - Corrigendum: Alcohol intake and cardiovascular risk factors: A Mendelian randomisation study. PMID- 27230538 TI - Surgical correction of a coronary fistula between the left main coronary artery and the coronary sinus in a neonate. AB - We present a rare case of a 6-day old female neonate with a particularly exceptional coronary anatomy encompassing a fistula between the left main coronary artery and the coronary sinus with steal phenomenon, mandating surgical correction. The condition is extremely rare with an estimated incidence of about 0.1-0.2%. We operated this girl early on to prevent ischaemic events and pulmonary overflow with future heart failure. Further, we discuss possible aetiology and pathophysiological mechanisms of coronary artery fistulae and steal phenomena. Depending on specific anatomic characteristics, an interventional approach may be an alternative for surgical closure; however, this was not possible in our case. PMID- 27230540 TI - ssDNA and the Argonautes: The Quest for the Next Golden Editor. AB - Genome engineering has gone mainstream because of breakthroughs in defining and harnessing naturally occurring, customizable DNA recognition cursors (protein or RNA-guided). At present, most gene editing relies on these cursors to direct custom DNA endonucleases to a specific genomic sequence to induce a double-strand break. New tools for genome engineering are continuously being explored, and another advance in DNA targeting has recently been described. Argonaute isolated from Natronobacterium gregoryi (NgAgo) is an ssDNA-based cursor that thus far has no known limitations in sequence recognition, shows promise for high specificity, and for many applications may represent a potentially more accessible genome editing system over prior tools as it requires only a single, 24-base, 5' phosphorylated ssDNA for DNA targeting. Genome engineering is in a remarkable moment of unprecedented growth with exponential reduction in costs reminiscent of Moore's law in electronics. Many questions remain with regard to Argonaute utility in specific systems, but there is no doubt that genome engineering is expanding into new and exciting areas from synthetic biology to gene therapy. PMID- 27230541 TI - 13-Helix folding of a beta/gamma-peptide manifold designed from a "minimal constraint" blueprint. AB - A bottom-up design rationale was adopted to devise beta/gamma-peptide foldamer manifolds which would adopt preferred 13-helix conformations, relying on minimal steric imposition brought by the constituent amino acid residues. In this way, a well-defined 13-helix conformer was revealed for short oligomers of trans-2 aminocyclobutanecarboxylic acid and gamma(4)-amino acids in alternation, which gave good topological superposition upon an alpha-helix motif. PMID- 27230542 TI - RPA and Rad51 constitute a cell intrinsic mechanism to protect the cytosol from self DNA. AB - Immune recognition of cytosolic DNA represents a central antiviral defence mechanism. Within the host, short single-stranded DNA (ssDNA) continuously arises during the repair of DNA damage induced by endogenous and environmental genotoxic stress. Here we show that short ssDNA traverses the nuclear membrane, but is drawn into the nucleus by binding to the DNA replication and repair factors RPA and Rad51. Knockdown of RPA and Rad51 enhances cytosolic leakage of ssDNA resulting in cGAS-dependent type I IFN activation. Mutations in the exonuclease TREX1 cause type I IFN-dependent autoinflammation and autoimmunity. We demonstrate that TREX1 is anchored within the outer nuclear membrane to ensure immediate degradation of ssDNA leaking into the cytosol. In TREX1-deficient fibroblasts, accumulating ssDNA causes exhaustion of RPA and Rad51 resulting in replication stress and activation of p53 and type I IFN. Thus, the ssDNA-binding capacity of RPA and Rad51 constitutes a cell intrinsic mechanism to protect the cytosol from self DNA. PMID- 27230543 TI - A functional neuroimaging study of the clinical reasoning of medical students. AB - As clinical reasoning is a fundamental competence of physicians for good clinical practices, medical academics have endeavored to teach reasoning skills to undergraduate students. However, our current understanding of student-level clinical reasoning is limited, mainly because of the lack of evaluation tools for this internal cognitive process. This functional magnetic resonance imaging (fMRI) study aimed to examine the clinical reasoning processes of medical students in response to problem-solving questions. We recruited 24 2nd-year medical students who had completed their preclinical curriculum. They answered 40 clinical vignette-based multiple-choice questions during fMRI scanning. We compared the imaging data for 20 problem-solving questions (reasoning task) and 20 recall questions (recall task). Compared to the recall task, the reasoning task resulted in significantly greater activation in nine brain regions, including the dorsolateral prefrontal cortex and inferior parietal cortex, which are known to be associated with executive function and deductive reasoning. During the recall task, significant activation was observed in the brain regions that are related to memory and emotions, including the amygdala and ventromedial prefrontal cortex. Our results support that medical students mainly solve clinical questions with deductive reasoning involving prior knowledge structures and executive functions. The problem-solving questions induced the students to utilize higher cognitive functions compared with the recall questions. Interestingly, the results suggested that the students experienced some emotional distress while they were solving the recall questions. In addition, these results suggest that fMRI is a promising research tool for investigating students' cognitive processes. PMID- 27230545 TI - Concordance of Text Message Ecological Momentary Assessment and Retrospective Survey Data Among Substance-Using Men Who Have Sex With Men: A Secondary Analysis of a Randomized Controlled Trial. AB - BACKGROUND: Alcohol and illicit drug use is more prevalent among men who have sex with men (MSM) compared to the general population and has been linked to HIV transmission in this population. Research assessing individual patterns of substance use often utilizes questionnaires or interviews that rely on retrospective self-reported information, which can be subject to recall bias. Ecological momentary assessment (EMA) is a set of methods developed to mitigate recall bias by collecting data about subjects' mental states and behaviors on a near real-time basis. EMA remains underutilized in substance use and HIV research. OBJECTIVE: To assess the concordance between daily reports of substance use collected by EMA text messages (short message service, SMS) and retrospective questionnaires and identify predictors of daily concordance in a sample of MSM. METHODS: We conducted a secondary analysis of EMA text responses (regarding behavior on the previous day) and audio computer-assisted self-interview (ACASI) survey data (14-day recall) from June 2013 to September 2014 as part of a randomized controlled trial assessing a pharmacologic intervention to reduce methamphetamine and alcohol use among nondependent MSM in San Francisco, California. Reports of daily methamphetamine use, alcohol use, and binge alcohol use (5 or more drinks on one occasion) were collected via EMA and ACASI and compared using McNemar's tests. Demographic and behavioral correlates of daily concordance between EMA and ACASI were assessed for each substance, using separate multivariable logistic regression models, fit with generalized estimating equations. RESULTS: Among 30 MSM, a total of 994 days were included in the analysis for methamphetamine use, 987 for alcohol use, and 981 for binge alcohol use. Methamphetamine (EMA 20%, ACASI 11%, P<.001) and alcohol use (EMA 40%, ACASI 35%, P=.001) were reported significantly more frequently via EMA versus ACASI. In multivariable analysis, text reporting of methamphetamine (adjusted odds ratio 0.06, 95% CI 0.04-0.10), alcohol (0.48, 0.33-0.69), and binge alcohol use (0.27, 0.17-0.42) was negatively associated with daily concordance in the reporting of each respective substance. Compared to white participants, African American participants were less likely to have daily concordance in methamphetamine (0.15, 0.05-0.43) and alcohol (0.2, 0.05-0.54) reporting, and other participants of color (ie, Asian, Hispanic, multi-racial) were less likely to have daily concordance in methamphetamine reporting (0.34, 0.12-1.00). College graduates were more likely to have daily concordance in methamphetamine reporting (6.79, 1.84-25.04) compared to those with no college experience. CONCLUSIONS: We found that methamphetamine and alcohol use were reported more frequently with daily EMA texts compared to retrospective ACASI, concordance varied among different racial/ethnic subgroups and education levels, and reported substance use by EMA text was associated with lower daily concordance with retrospective ACASI. These findings suggest that EMA methods may provide more complete reporting of frequent, discrete behaviors such as substance use. PMID- 27230544 TI - Genome Analysis of Pseudoloma neurophilia: A Microsporidian Parasite of Zebrafish (Danio rerio). AB - Microsporidia are highly successful parasites that infect virtually all known animal lineages, including the model Danio rerio (zebrafish). The widespread use of this aquatic model for biomedical research has resulted in an unexpected increase in infections from the microsporidium Pseudoloma neurophilia, which can lead to significant physical, behavioral, and immunological modifications, resulting in nonprotocol variation during experimental procedures. Here, we seek to obtain insights into the biology of P. neurophilia by investigating its genome content, which was obtained from only 29 nanograms of DNA using the MiSeq technology and paired-end Illumina sequencing. We found that the genome of P. neurophilia is phylogenetically and genetically related to other fish microsporidians, but features unique to this intracellular parasite are also found. The small 5.25-Mb genome assembly includes 1,139 unique open-reading frames and an unusually high number of transposable elements for such a small genome. Investigations of intragenomic diversity also provided strong indications that the mononucleate nucleus of this species is diploid. Overall, our study provides insights into the dynamics of microsporidian genomes and a solid sequence reference to be used in future studies of host-parasite interactions using the zebrafish D. rerio and P. neurophilia as a model. PMID- 27230546 TI - Brain CYP2B induction can decrease nicotine levels in the brain. AB - Nicotine can be metabolized by the enzyme CYP2B; brain CYP2B is higher in rats and monkeys treated with nicotine, and in human smokers. A 7-day nicotine treatment increased CYP2B expression in rat brain but not liver, and decreased the behavioral response and brain levels (ex vivo) to the CYP2B substrate propofol. However, the effect of CYP2B induction on the time course and levels of circulating brain nicotine in vivo has not been demonstrated. Using brain microdialysis, nicotine levels following a subcutaneous nicotine injection were measured on day one and after a 7-day nicotine treatment. There was a significant time x treatment interaction (p = 0.01); peak nicotine levels (15-45 minutes post injection) were lower after treatment (p = 0.04) consistent with CYP2B induction. Following a two-week washout period, brain nicotine levels increased to day one levels (p = 0.02), consistent with brain CYP2B levels returning to baseline. Brain pretreatment of the CYP2B inhibitor, C8-xanthate, increased brain nicotine levels acutely and after 7-day nicotine treatment, indicating the alterations in brain nicotine levels were due to changes in brain CYP2B activity. Plasma nicotine levels were not altered for any time or treatment sampled, confirming no effect on peripheral nicotine metabolism. These results demonstrate that chronic nicotine, by increasing brain CYP2B activity, reduces brain nicotine levels, which could alter nicotine's reinforcing effects. Higher brain CYP2B levels in smokers could lower brain nicotine levels; as this induction would occur following continued nicotine exposure it could increase withdrawal symptoms and contribute to sustaining smoking behavior. PMID- 27230547 TI - Supra-physiological rhGH administration induces gender-related differences in the hypothalamus-pituitary-thyroid (HPT) axis in healthy individuals. AB - PURPOSE: The use of recombinant human growth hormone (rhGH) is a common habit among athletes. While the effects of rhGH administration have been described with contrasting results in males, no data exist in females to date. The aim of the present study was to evaluate the effects of rhGH administration on TSH, FT4 and FT3 levels and the time requested to return to baseline values after treatment withdrawal. METHODS: Twenty-one healthy trained male and female athletes were treated with 0.03 mg rhGH/kg body mass 6 days/week for 3 weeks. We collected blood samples immediately before the first daily rhGH administration, at 3, 4, 8, 15 and 21 days of treatment and at 3 and 9 days after rhGH withdrawal. RESULTS: In males, rhGH administration induced a significant (p < 0.01) early and stable TSH decrease and IGF-I increase, and a delayed FT4 reduction without FT3 modification, suggesting a central regulatory mechanism. In females, rhGH administration induced a significant (p < 0.01) early and transient TSH decrease and IGF-I increase, and a transient reduction in FT4 without any changes in FT3 concentrations. rhGH withdrawal was associated with a prompt normalization of TSH and FT4 levels in males, while in females the effects of rhGH treatment had already disappeared during the last period of treatment. CONCLUSION: We suggest that rhGH inhibits TSH at central level both in males and females. The pattern of normalization was different in the two genders probably due to gonadal steroids modulation on GH-IGF-I axis. PMID- 27230549 TI - NHS spends L820m a year keeping older patients in hospital unnecessarily. PMID- 27230548 TI - Mouse chromosome 2 harbors genetic determinants of resistance to podocyte injury and renal tubulointerstitial fibrosis. AB - BACKGROUND: Tensin2 deficiency results in alterations in podocytes and subsequent glomerular and tubulointerstitial injuries. However, this pathology is critically dependent on genetic background. While the Tensin2-deficient podocytes of resistant murine strains, including C57BL/6J mice, remain almost intact, susceptible murine strains with Tensin2 deficency, including ICGN mice, develop chronic kidney disease following alterations in the podocyte foot processes. In a previous study, genome-wide linkage analysis was utilized to identify the quantitative trait loci associated with the disease phenotypes on mouse chromosome 2. This study investigated the disease phenotypes of chromosome 2 consomic and subcongenic strains. RESULTS: ICGN consomic mice introgressed with chromosome 2 from the C57BL/6J mouse were generated and found to exhibit milder renal failure than that in ICGN mice. We developed 6 subcongenic strains that carry C57BL/6J-derived chromosomal segments from the consomic strain. One showed significantly milder albuminuria, another showed significantly milder tubulointerstitial injury, and the both showed significantly milder glomerular injury. CONCLUSIONS: These data indicate that mouse chromosome 2 harbors two major genes associated with the severities of nephropathy induced by Tensin2 deficiency. The proximal region on chromosome 2 contributes to the resistance to tubulointerstitial fibrosis. In contrast, the distal region on chromosome 2 contributes to the resistance to podocyte injury. This study would be helpful to discover the biological mechanism underlying the renal injury, and may lead to the identification of therapeutic targets. PMID- 27230550 TI - Nutritional support for critically ill children. AB - BACKGROUND: Nutritional support in the critically ill child has not been well investigated and is a controversial topic within paediatric intensive care. There are no clear guidelines as to the best form or timing of nutrition in critically ill infants and children. This is an update of a review that was originally published in 2009. . OBJECTIVES: The objective of this review was to assess the impact of enteral and parenteral nutrition given in the first week of illness on clinically important outcomes in critically ill children. There were two primary hypotheses:1. the mortality rate of critically ill children fed enterally or parenterally is different to that of children who are given no nutrition;2. the mortality rate of critically ill children fed enterally is different to that of children fed parenterally.We planned to conduct subgroup analyses, pending available data, to examine whether the treatment effect was altered by:a. age (infants less than one year versus children greater than or equal to one year old);b. type of patient (medical, where purpose of admission to intensive care unit (ICU) is for medical illness (without surgical intervention immediately prior to admission), versus surgical, where purpose of admission to ICU is for postoperative care or care after trauma).We also proposed the following secondary hypotheses (a priori), pending other clinical trials becoming available, to examine nutrition more distinctly:3. the mortality rate is different in children who are given enteral nutrition alone versus enteral and parenteral combined;4. the mortality rate is different in children who are given both enteral feeds and parenteral nutrition versus no nutrition. SEARCH METHODS: In this updated review we searched: the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 2); Ovid MEDLINE (1966 to February 2016); Ovid EMBASE (1988 to February 2016); OVID Evidence-Based Medicine Reviews; ISI Web of Science - Science Citation Index Expanded (1965 to February 2016); WebSPIRS Biological Abstracts (1969 to February 2016); and WebSPIRS CAB Abstracts (1972 to February 2016). We also searched trial registries, reviewed reference lists of all potentially relevant studies, handsearched relevant conference proceedings, and contacted experts in the area and manufacturers of enteral and parenteral nutrition products. We did not limit the search by language or publication status. SELECTION CRITERIA: We included studies if they were randomized controlled trials; involved paediatric patients, aged one day to 18 years of age, who were cared for in a paediatric intensive care unit setting (PICU) and had received nutrition within the first seven days of admission; and reported data for at least one of the pre-specified outcomes (30-day or PICU mortality; length of stay in PICU or hospital; number of ventilator days; and morbid complications, such as nosocomial infections). We excluded studies if they only reported nutritional outcomes, quality of life assessments, or economic implications. Furthermore, we did not address other areas of paediatric nutrition, such as immunonutrition and different routes of delivering enteral nutrition, in this review. DATA COLLECTION AND ANALYSIS: Two authors independently screened the searches, applied the inclusion criteria, and performed 'Risk of bias' assessments. We resolved discrepancies through discussion and consensus. One author extracted data and a second checked data for accuracy and completeness. We graded the evidence based on the following domains: study limitations, consistency of effect, imprecision, indirectness, and publication bias. MAIN RESULTS: We identified only one trial as relevant. Seventy-seven children in intensive care with burns involving more than 25% of the total body surface area were randomized to either enteral nutrition within 24 hours or after at least 48 hours. No statistically significant differences were observed for mortality, sepsis, ventilator days, length of stay, unexpected adverse events, resting energy expenditure, nitrogen balance, or albumin levels. We assessed the trial as having unclear risk of bias. We consider the quality of the evidence to be very low due to there being only one small trial. In the most recent search update we identified a protocol for a relevant randomized controlled trial examining the impact of withholding early parenteral nutrition completing enteral nutrition in pediatric critically ill patients; no results have been published. AUTHORS' CONCLUSIONS: There was only one randomized trial relevant to the review question. Research is urgently needed to identify best practices regarding the timing and forms of nutrition for critically ill infants and children. PMID- 27230551 TI - Medical doctors in healthcare leadership: theoretical and practical challenges. AB - BACKGROUND: While healthcare systems vary in their structure and available resources, it is widely recognized that medical doctors play a key role in their adaptation and performance. In this article, we examine recent government and organizational policies in two different health systems that aim to develop clinical leadership among the medical profession. Clinical leadership refers to the engagement and guiding role of physicians in health system improvement. Three dimensions are defined to conduct our analysis of engaging medical doctors in healthcare leadership: the position and status of medical doctors within the system; the broader institutional context of governmental and organizational policies to engage medical doctors in clinical leadership roles; and the main factors that may facilitate or limit achievements. METHODS: Our aim in this study is exploratory. We selected two contrasting cases according to their level of institutional pluralism: one national health insurance system, Canada, and one etatist social insurance system, the Netherlands. We documented the institutional dynamics of medical doctors' engagement and leadership through secondary sources, such as government websites, key policy reports, and scholarly literature on health policies in both countries. RESULTS: Initiatives across Canadian provinces signal that the medical profession and governments search for alternatives to involve doctors in health system improvement beyond the limitations imposed by their fundamental social contract and formal labour relations. These initiatives suggest an emerging trend toward more joint collaboration between governments and medical associations. In the Dutch system, organizational and legal attempts for integration over the past decades do not yet fit well with the ideas and interests of medical doctors. The engagement of medical doctors requires additional initiatives that are closer to their professional values and interests and that depart from an overly focus on top down performance indicators and competition. CONCLUSIONS: Different institutional contexts have different policy experiences regarding the engagement and leadership of medical doctors but seem to face similar policy challenges. Achieving alignment between soft (trust, collaboration) and hard (financial incentives) levers may require facilitative conditions at the level of the health system, like clarity and stability of broad policy orientations and openness to local experimentation. PMID- 27230552 TI - Prenatal pesticide exposure and PON1 genotype associated with adolescent body fat distribution evaluated by dual X-ray absorptiometry (DXA). AB - Many modern pesticides have endocrine disrupting abilities and early-life exposure may affect growth and disease risk later in life. Previously, we reported associations between prenatal pesticide exposure and higher childhood body fat content measured by anthropometry. The associations were affected by child PON1 Q192R genotype. We aimed to study whether prenatal pesticide exposure was still associated with body fat content and distribution in the children at puberty and the potential impact of both maternal and child PON1 Q192R genotype. In this prospective cohort study of 247 children born by occupationally exposed or unexposed women (greenhouse workers and controls) two follow-up examinations (age 10-15 and 11-16 years) including simple anthropometry, skinfold measurements, pubertal staging and blood sampling were performed. Total and regional fat% was determined by dual X-ray absorptiometry (DXA) at age 10-15. Prenatal pesticide exposure was associated with increased total, android, and gynoid fat percentage (DXA) at age 10-15 years after adjustment for sex, socioeconomic status, and puberty (all beta = 0.5 standard deviation score (SDS) p < 0.05). Stratified by sex, the associations were significant in girls (total fat: beta = 0.7 SDS, android-gynoid ratio: beta = 0.1, both p < 0.05), but not in boys. Carrying the R-allele (child or mother, separately, or both) augmented the differences between exposed and unexposed children (total fat: beta = 1.0 SDS, beta = 0.8 SDS, p < 0.05, respectively, and beta = 1.2 SDS, p < 0.01). No exposure-related differences were found if either the child or mother had the QQ wild-type. At age 11-16, exposed children tended to have a higher total fat% estimated by skinfolds than unexposed children (p = 0.06). No significant associations between prenatal exposure and body mass index or waist circumference were found. Prenatal pesticide exposure was associated with higher adolescent body fat content, including android fat deposition, independent of puberty. Girls appeared more susceptible than boys. Furthermore, the association depended on maternal and child PON1 Q192R genotype. PMID- 27230553 TI - Chiral linker-bridged bis-N-heterocyclic carbenes: design, synthesis, palladium complexes, and catalytic properties. AB - A series of chiral bis(benzimidazolium) salts 10-19 with (1R,2R)-cyclohexene, (1R,2R)-diphenylethylene and (aR)-binaphthylene linkers have been designed and synthesized in 30-94% yield. Ten chiral bis(NHC) palladium complexes 20-28 have been synthesized and characterized by NMR, HRMS, elemental analysis and further confirmed by X-ray single crystal analysis. These bis(NHC)-Pd complexes showed obviously different catalytic properties in the asymmetric Suzuki-Miyaura coupling reactions. The (1R,2R)-cyclohexene-bridged bis(NHC)-Pd complex, (R,R) 23, achieved the highest yield of 90%, while complex (aR)-28, with a binaphthylene linker, showed the best enantioselectivity of 60 ee%. The structural analysis of these complexes suggested that such difference of catalytic performance has a close relationship with their coordination surroundings around metal centres. PMID- 27230554 TI - Early discoid lupus erythematosus protects against renal disease in patients with systemic lupus erythematosus: longitudinal data from a large Latin American cohort. AB - OBJECTIVES: The objective of this study was to examine whether early discoid lupus erythematosus (DLE) would be a protective factor for further lupus nephritis in patients with systemic lupus erythematosus (SLE). METHODS: We studied SLE patients from GLADEL, an inception longitudinal cohort from nine Latin American countries. The main predictor was DLE onset, which was defined as physician-documented DLE at SLE diagnosis. The outcome was time from the diagnosis of SLE to new lupus nephritis. Univariate and multivariate survival analyses were conducted to examine the association of DLE onset with time to lupus nephritis. RESULTS: Among 845 GLADEL patients, 204 (24.1%) developed lupus nephritis after SLE diagnosis. Of them, 10 (4.9%) had DLE onset, compared to 83 (12.9%) in the group of 641 patients that remained free of lupus nephritis (hazard ratio 0.39; P = 0.0033). The cumulative proportion of lupus nephritis at 1 and 5 years since SLE diagnosis was 6% and 14%, respectively, in the DLE onset group, compared to 14% and 29% in those without DLE (P = 0.0023). DLE onset was independently associated with a lower risk of lupus nephritis, after controlling for sociodemographic factors and disease severity at diagnosis (hazard ratio 0.38; 95% confidence interval 0.20-0.71). CONCLUSIONS: Our data indicate that DLE onset reduces the risk of further lupus nephritis in patients with SLE, independently of other factors such as age, ethnicity, disease activity, and organ damage. These findings have relevant prognosis implications for SLE patients and their clinicians. Further studies are warranted to unravel the biological and environmental pathways associated with the protective role of DLE against renal disease in patients with SLE. PMID- 27230556 TI - Correlation between the Modified Systemic Lupus Erythematosus Disease Activity Index 2000 and the European Consensus Lupus Activity Measurement in juvenile systemic lupus erythematosus. AB - Objective The objective of this study was to assess Modified Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and European Consensus Lupus Activity Measurement (ECLAM) disease activity correlation in addition to their respective correlation to Pediatric Systemic Lupus International Collaborative Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (Ped-SDI), in juvenile systemic lupus erythematosus (JSLE). Methods The activity indices were scored retrospectively and summarized by adjusted means during follow-up. The Ped-SDI was scored during the last visit for those with more than six months follow-up. Pearson correlation between the Modified SLEDAI-2K and ECLAM, as well as Spearman correlations between the Modified SLEDAI-2K, ECLAM, and Ped-SDI were calculated. The receiver operating characteristic (ROC) curve was calculated for both activity indices discriminating damage measured by Ped SDI. Results Thirty-seven patients with mean age at diagnosis 11 +/- 2.9 years and mean follow-up time 3.2 +/- 2.4 years were studied. The Modified SLEDAI-2K and ECLAM adjusted means were highly correlated ( r = 0.78, p < 0.001). Similarly, Spearman correlation between the activity indices was also high ( rs > 0.7, p < 0.001), but Modified SLEDAI-2K and ECLAM correlation with Ped-SDI was only moderate. ROC analysis discriminant performance for both activity indices resulted in area under curve (AUC) of 0.74 and 0.73 for Modified SLEDAI-2K and ECLAM, respectively. Conclusion The high correlation found between the Modified SLEDAI-2K and ECLAM adjusted means indicated that both tools can be equally useful for longitudinal estimates of JSLE activity. PMID- 27230557 TI - Euphorikanin A, a Diterpenoid Lactone with a Fused 5/6/7/3 Ring System from Euphorbia kansui. AB - Euphorikanin A (1), an unprecedented diterpenoid lactone which possesses a novel 5/6/7/3-fused tetracyclic ring skeleton, was isolated from the roots of Euphorbia kansui. The chemical structure and absolute stereochemistry were elucidated on the basis of extensive spectroscopic methods and single-crystal X-ray diffraction analysis. Compound 1 exhibited moderate cytotoxicity against two human tumor cell lines HeLa and NCI-446. A proposed biosynthetic pathway of compound 1 is also described. PMID- 27230555 TI - Artesunate inhibits type I interferon-induced production of macrophage migration inhibitory factor in patients with systemic lupus erythematosus. AB - OBJECTIVE: Macrophage migration inhibitory factor (MIF) is a key regulator of both atherosclerosis and systemic lupus erythematosus (SLE), yet factors leading to its overproduction remain unclear. To explore regulation of MIF in SLE, we studied effects and potential mechanisms of type I interferon (IFN) and artesunate (ART), an antimalarial agent extracted from Chinese herbs, on levels of MIF. METHODS: Serum and peripheral blood cells from SLE patients and healthy controls were measured for MIF levels by ELISA and type I IFN-inducible gene expressions by real-time PCR, respectively, and assessed for associations by Spearman correlation. ART was added to human umbilical vein endothelial cell (HUVEC) cultures with or without prior IFNalpha-1b stimulation and to SLE peripheral blood mononuclear cell (PBMC) cultures. Protein levels of STATs and phosphorylated (p-) STATs in HUVECs were determined by Western blotting. RESULTS: Serum MIF levels were elevated in SLE patients and positively associated with disease activity (r = 0.86, p < 0.0001), accumulated damage (r = 0.34, p < 0.05), and IFN scores in SLE PBMCs (r = 0.74, p = 0.0002). The addition of IFNalpha-1b promoted MIF production in a time- and dose-dependent manner in HUVEC cultures. ART could inhibit expressions of IFN-inducible genes (LY6E and ISG15) in both HUVEC and SLE PBMC cultures, and suppress MIF production and over-expression of p STAT1, but not p-STAT3 or STAT5, induced by IFNalpha-1b stimulation. IFNgamma induced expression of p-STAT1 in HUVECs was not inhibited by ART. CONCLUSION: MIF could be regulated by type I IFN in SLE patients. ART counteracts the effect of IFNalpha to inhibit MIF production by blocking STAT1 phosphorylation and thus may have therapeutic potential for SLE-associated atherosclerosis. PMID- 27230559 TI - High-voltage electron microscopy tomography and structome analysis of unique spiral bacteria from the deep sea. AB - Structome analysis is a useful tool for identification of unknown microorganisms that cannot be cultured. In 2012, we discovered a unique deep-sea microorganism with a cell structure intermediate between those of prokaryotes and eukaryotes and described its features using freeze-substitution electron microscopy and structome analysis (quantitative and three-dimensional structural analysis of a whole cell at the electron microscopic level). We named it Myojin parakaryote Here we describe, using serial ultrathin sectioning and high-voltage electron microscopy tomography of freeze-substituted specimens, the structome analysis and 3D reconstruction of another unique spiral bacteria, found in the deep sea off the coast of Japan. The bacteria, which is named as 'Myojin spiral bacteria' after the discovery location and their morphology, had a total length of 1.768 +/ 0.478 um and a total diameter of 0.445 +/- 0.050 um, and showed either clockwise or counter-clockwise spiral. The cells had a cell surface membrane, thick fibrous layer, ribosomes and inner fibrous structures (most likely DNA). They had no flagella. The bacteria had 322 +/- 119 ribosomes per cell. This ribosome number is only 1.2% of that of Escherichia coli and 19.3% of Mycobacterium tuberculosis and may reflect a very slow growth rate of this organism in the deep sea. PMID- 27230558 TI - Repeat Composition of CenH3-chromatin and H3K9me2-marked heterochromatin in Sugar Beet (Beta vulgaris). AB - BACKGROUND: Sugar beet (Beta vulgaris) is an important crop of temperate climate zones, which provides nearly 30 % of the world's annual sugar needs. From the total genome size of 758 Mb, only 567 Mb were incorporated in the recently published genome sequence, due to the fact that regions with high repetitive DNA contents (e.g. satellite DNAs) are only partially included. Therefore, to fill these gaps and to gain information about the repeat composition of centromeres and heterochromatic regions, we performed chromatin immunoprecipitation followed by sequencing (ChIP-Seq) using antibodies against the centromere-specific histone H3 variant of sugar beet (CenH3) and the heterochromatic mark of dimethylated lysine 9 of histone H3 (H3K9me2). RESULTS: ChIP-Seq analysis revealed that active centromeres containing CenH3 consist of the satellite pBV and the Ty3-gypsy retrotransposon Beetle7, while heterochromatin marked by H3K9me2 exhibits heterogeneity in repeat composition. H3K9me2 was mainly associated with the satellite family pEV, the Ty1-copia retrotransposon family Cotzilla and the DNA transposon superfamily of the En/Spm type. In members of the section Beta within the genus Beta, immunostaining using the CenH3 antibody was successful, indicating that orthologous CenH3 proteins are present in closely related species within this section. CONCLUSIONS: The identification of repetitive genome portions by ChIP-Seq experiments complemented the sugar beet reference sequence by providing insights into the repeat composition of poorly characterized CenH3 chromatin and H3K9me2-heterochromatin. Therefore, our work provides the basis for future research and application concerning the sugar beet centromere and repeat rich heterochromatic regions characterized by the presence of H3K9me2. PMID- 27230560 TI - Effect of eplerenone on the severity of obstructive sleep apnea and arterial stiffness in patients with resistant arterial hypertension. AB - INTRODUCTION Obstructive sleep apnea (OSA) is considered to be one of the major causes of resistant arterial hypertension (RAH). Apnea episodes cause hypoxia, which triggers the activation of the renin-angiotensin-aldosterone system. This leads to water retention and swelling in the neck region, exacerbating OSA symptoms. It is assumed that the use of eplerenone may reduce the swelling and thus alleviate the severity of OSA. OBJECTIVES We aimed to prospectively assess the impact of eplerenone on the severity of OSA and arterial stiffness in patients with RAH. PATIENTS AND METHODS The study included 31 patients with RAH and OSA. The exclusion criteria were as follows: secondary hypertension, myocardial infarction, stroke 6 months prior to the study, congestive heart failure, chronic kidney failure, alcohol or drug addiction, and active cancer. In all patients, the following tests were performed: blood pressure (BP) measurement (traditionally and using ambulatory BP measuring [ABPM]), applanation tonometry, polysomnography, and the apnea-hypopnea index (AHI) calculation. The tests were done before and after 3 months of eplerenone therapy. Patients received 50 mg of oral eplerenone daily, along with other hypertensive drugs. RESULTS The mean age of participants was 57.76 +/-6.16 years. After 3 months of eplerenone therapy, we observed a significant reduction in the AHI, neck circumference, BP, aortic pulse wave, and arterial wall stiffness. There were significant correlations between the AHI and mean BP measured by ABPM and between the AHI and arterial stiffness parameters. CONCLUSIONS Our results provide evidence for the clinical significance of eplerenone, not only as an antihypertensive medication but also as a drug that may reduce the severity of OSA and arterial stiffness in patients with RAH and OSA. PMID- 27230561 TI - Influence of automatic frequent pace-timing adjustments on effective left ventricular pacing during cardiac resynchronization therapy. AB - Aims: Cardiac resynchronization therapy (CRT) requires effective left ventricular (LV) pacing (i.e. sufficient energy and appropriate timing to capture). The AdaptivCRTTM (aCRT) algorithm serves to maintain ventricular fusion during LV or biventricular pacing. This function was tested by comparing the morphological consistency of ventricular depolarizations and percentage effective LV pacing in CRT patients randomized to aCRT vs. echo-optimization. Methods and results: Continuous recordings (>=20 h) of unipolar LV electrograms from aCRT (n = 38) and echo-optimized patients (n = 22) were analysed. Morphological consistency was determined by the correlation coefficient between each beat and a template beat. Effective LV pacing of paced beats was assessed by algorithmic analysis of negative initial EGM deflection in each evoked response. The %CRT pacing delivered, %effective LV pacing (i.e. % of paced beats with effective LV pacing), and overall %effective CRT (i.e. product of %CRT pacing and %effective LV pacing) were compared between aCRT and echo-optimized patients. Demographics were similar between groups. The mean correlation coefficient between individual beats and template was greater for aCRT (0.96 +/- 0.03 vs. 0.91 +/- 0.13, P = 0.07). Although %CRT pacing was similar for aCRT and echo-optimized (median 97.4 vs. 98.6%, P = 0.14), %effective LV pacing was larger for aCRT [99.6%, (99.1%, 99.9%) vs. 94.3%, (24.3%, 99.8%), P=0.03]. For aCRT vs. echo-optimized groups, the proportions of patients with >=90% effective LV pacing was 92 vs. 55% (P = 0.002), and with >=90% effective CRT was 79 vs. 45%, respectively (P = 0.018). Conclusion: AdaptivCRTTM significantly increased effective LV pacing over echo optimized CRT. PMID- 27230562 TI - Same pattern, different mechanism: Locking onto the role of key species in seafloor ecosystem process. AB - Seafloor biodiversity is a key mediator of ecosystem functioning, but its role is often excluded from global budgets or simplified to black boxes in models. New techniques allow quantification of the behavior of animals living below the sediment surface and assessment of the ecosystem consequences of complex interactions, yielding a better understanding of the role of seafloor animals in affecting key processes like primary productivity. Combining predictions based on natural history, behavior of key benthic species and environmental context allow assessment of differences in functioning and process, even when the measured ecosystem property in different systems is similar. Data from three sedimentary systems in New Zealand illustrate this. Analysis of the behaviors of the infaunal ecosystem engineers in each system revealed three very different mechanisms driving ecosystem function: density and excretion, sediment turnover and surface rugosity, and hydraulic activities and porewater bioadvection. Integrative metrics of ecosystem function in some cases differentiate among the systems (gross primary production) and in others do not (photosynthetic efficiency). Analyses based on behaviors and activities revealed important ecosystem functional differences and can dramatically improve our ability to model the impact of stressors on ecosystem and global processes. PMID- 27230563 TI - TaMCA1, a regulator of cell death, is important for the interaction between wheat and Puccinia striiformis. AB - Metacaspase orthologs are conserved in fungi, protozoa and plants, however, their roles in plant disease resistance are largely unknown. In this study, we identified a Triticum aestivum metacaspase gene, TaMCA1, with three copies located on chromosomes 1A, 1B and 1D. The TaMCA1 protein contained typical structural features of type I metacaspases domains, including an N-terminal pro domain. Transient expression analyses indicated that TaMCA1 was localized in cytosol and mitochondria. TaMCA1 exhibited no caspase-1 activity in vitro, but was able to inhibit cell death in tobacco and wheat leaves induced by the mouse Bax gene. In addition, the expression level of TaMCA1 was up-regulated following challenge with the Puccinia striiformis f. sp. tritici (Pst). Knockdown of TaMCA1 via virus-induced gene silencing (VIGS) enhanced plant disease resistance to Pst, and the accumulation of hydrogen peroxide (H2O2). Further study showed that TaMCA1 decreased yeast cell resistance similar to the function of yeast metacaspase, and there was no interaction between TaMCA1 and TaLSD1. Based on these combined results, we speculate that TaMCA1, a regulator of cell death, is important during the compatible interaction of wheat and Pst. PMID- 27230564 TI - Diagnosis and management of invasive candidiasis in the ICU: an updated approach to an old enemy. AB - Invasive fungal infections, particularly those caused by Candida species, are not uncommon in critically ill patients and are associated with considerable morbidity and mortality. Diagnosis and management of these infections can be challenging. In this review, we will briefly discuss recent epidemiological data on invasive candidiasis and current diagnostic approaches before concentrating on antifungal treatments. PMID- 27230566 TI - Quantification of short- and medium-chain chlorinated paraffins in environmental samples by gas chromatography quadrupole time-of-flight mass spectrometry. AB - Chlorinated paraffins (CPs) are technical products produced and used in bulk for a number of purposes. However, the analysis of CPs is challenging, as they are complex mixtures of compounds and isomers. We herein report the development of an analytical method for the analysis of short-chain CPs (SCCPs) and medium-chain CPs (MCCPs) using quadrupole time-of-flight high-resolution mass spectrometry (GC NCI-qTOF-HRMS). This method employs gas chromatography with a chemical ionization source working in negative mode. The linear relationship between chlorination and the CP total response factors was applied to quantify the CP content and the congener group distribution patterns. In a single injection, 24 SCCP formula groups and 24 MCCP formula groups were quantified. Extraction of accurate masses using qTOF-HRMS allowed the SCCPs and MCCPs to be distinguished, with interference from other chemicals (e.g., PCBs) being largely avoided. The SCCP and MCCP detection limits were 24-81ng/mL and 27-170ng/mL, respectively. Comparison of the obtained results with analytical results from gas chromatography coupled with electron capture negative ionization low-resolution mass spectrometry (GC-ECNI-LRMS) indicate that the developed technique is a more accurate and convenient method for the analysis of CPs in samples from a range of matrices. PMID- 27230565 TI - Fuel for Fun: a cluster-randomized controlled study of cooking skills, eating behaviors, and physical activity of 4th graders and their families. AB - BACKGROUND: Childhood obesity remains a serious concern in the United States and in many other countries. Direct experience preparing and tasting healthful foods and increasing activity during the school day are promising prevention approaches. Engaging parents and families remains an important challenge. Fuel for Fun: Cooking with Kids Plus Parents and Play is a multi-component school- and family-based intervention for 4th graders and their families intended to promote positive food and activity environments, policies and behaviors at the individual, family and school levels. This paper describes the design and evaluation plan. METHODS/DESIGN: Four cohorts of 4th-graders and their parents from 8 schools in 2 districts in the same Northern Colorado region are participating in a 4-arm cluster randomized controlled trial. Theory-based Fuel for Fun consists of 5 components delivered over 1 school year: 1) Cooking with Kids - Colorado; an experiential classroom-based cooking and tasting curriculum, 2) Cafeteria Connections; cafeteria-based reinforcements of classroom food experiences using behavioral economic strategies, 3) SPARK active recess; a playground intervention to engage children in moderate to vigorous activity, 4) Fuel for Fun Family; multi-element supports targeting parents to reinforce the 3 school-based components at home, and 5) About Eating; an online interactive program for parents addressing constructs of eating competence and food resource management. Outcomes include child and parent measures of fruit and vegetable preferences and intake, cooking, physical activity, sedentary behaviors and attitudes. School level data assess lunch plate waste and physical activity at recess. In-depth diet and accelerometry assessments are collected with a subsample of parent-child dyads. Data are collected at baseline, immediately post intervention at 7 months, and at 12 month follow-up. We anticipate recruiting 1320-1584 children and their parents over the length of the project. DISCUSSION: The Fuel for Fun study design allows for impact assessment of school-, family- and online parent-based intervention components separately and in combination. Study strengths include use of theory- and evidence-based programs, valid child and parent self-report instruments, and objective measures of food, cooking, and physical activity behaviors at the individual, family and school levels. Parent involvement and engagement is examined through multiple strategies. TRIAL REGISTRATION: Clinicaltrials.gov registration number NCT02491294 . Registered 7 July, 2015. PMID- 27230567 TI - Recovery Camp: Assisting consumers toward enhanced self-determination. AB - Mental health consumers are often socially isolated and may lack the basic leisure competencies which serve as a critical building block for community (re)integration. Therapeutic recreation (TR), as a treatment modality for people with mental illness, is yet to be fully embraced in the Australian health-care setting, despite having a strong historical foundation in North America. A team of academics created a TR experience, termed Recovery Camp, which was designed to collectively engage consumers and future health professionals drawn from a range of discipline areas. The 2014 Recovery Camp was staged over a five day period and involved 28 adult consumers living with mental illness. Consumers undertook a diverse range of experiential recreation activities engineered to facilitate individual engagement and to encourage the development of positive therapeutic relationships and teamwork. The camp atmosphere was deliberately community-based and recovery-oriented, valuing the lived experience of mental illness. Using a 2 * 3 design involving a camp and comparison group, the study sought to examine the influence of a TR programme on the self-determination of individuals with a mental illness. Those who participated in the Recovery Camp reported an increase in awareness of self and perceived choice post-camp, relative to the comparison group. While this difference remained significant for awareness of self at three month follow-up, there was no significant difference in perceived choice between the two groups at follow-up. Study findings serve to support the role of recreation within a recovery framework to positively change the health-related behaviour of mental health consumers. PMID- 27230568 TI - Selecting the Best and Brightest: A Structured Approach to Orthopedic Resident Selection. AB - BACKGROUND: Resident selection is integral to the graduate medical educational process and the future of our profession. There is no consensus among residency directors as to how to systematically and consistently screen and select applicants who would perform well as residents. The purpose of this study was to introduce and assess a high volume application screening tool and semistructured interview process. METHODS: This study took place in an academic orthopedic surgery department over 2 years (2013-2014). Overall, 1382 applications were screened in 7 categories, with a maximum score of 100. A total of 14 faculty reviewed applications; 218 interviews were offered; 165 applicants accepted the interview. Overall, 4 interview domains (cognitive, affective, activities, and theme), and an impression score were ranked from 1 (Exceptional) to 6 (Concern). Each room had an assigned "theme" (ethics, affective, cognitive, research, and "fit") with standardized questions. A summary score was generated of all scores to determine the preliminary rank list; the final rank list was determined after group discussion. Correlation between preliminary rank, final rank, and screening scores were assessed. RESULTS: The average screening score was 62.5 (range: 0 100, median = 64). The average interview score was 69.5 (range: 32.24-95.0). Final rank lists correlated most highly with initial rank (0.912, p < 0.001), impression (0.847, p < 0.001), and affective domain (0.834, p < 0.001). Cognitive domain (0.628, p < 0.001) and screening scores (0.264, p < 0.001) less highly correlated with final rank position. CONCLUSIONS: A systematic approach was used to screen and evaluate a large number of orthopedic surgery applicants. Our system demonstrated excellent feasibility, reliability, and predictability for the final rank list. PMID- 27230569 TI - From the New Editor-in-Chief. PMID- 27230570 TI - The Feasibility of Thermophilic Caldimonas manganoxidans as a Platform for Efficient PHB Production. AB - Recently, poly(3-hydroxybutyrate) (PHB) has been found in a few thermophilic strains where several advantages can be gained from running fermentation at high temperatures. Caldimonas manganoxidans, a thermophilic gram-negative bacterium, was investigated for the feasibility as a PHB-producing strain. It is suggested that the best fermentation strategy for achieving the highest PHB concentration of 5.4 +/- 1.1 g/L (from 20 g/L glucose) in 24 h is to use the fermentation conditions that are favored for the bacterial growth, yet temperature and pH should be chosen at conditions that are favored for the PHB content. Besides, the above fermentation conditions produce PHB that has a high molecular weight of 1274 kDa with a low polydispersity index (PDI) of 1.45, where the highest Mw of PHB of 1399 kDa (PDI of 1.32) is obtained in this study. To the best knowledge of authors, C. manganoxidans has the best PHB productivity among the thermophiles and is comparable to those common PHB-producing mesophiles. PMID- 27230572 TI - Slow and long-ranged dynamical heterogeneities in dissipative fluids. AB - A two-dimensional bidisperse granular fluid is shown to exhibit pronounced long ranged dynamical heterogeneities as dynamical arrest is approached. Here we focus on the most direct approach to study these heterogeneities: we identify clusters of slow particles and determine their size, Nc, and their radius of gyration, RG. We show that , providing direct evidence that the most immobile particles arrange in fractal objects with a fractal dimension, df, that is observed to increase with packing fraction phi. The cluster size distribution obeys scaling, approaching an algebraic decay in the limit of structural arrest, i.e., phi >phic. Alternatively, dynamical heterogeneities are analyzed via the four-point structure factor S4(q,t) and the dynamical susceptibility chi4(t). S4(q,t) is shown to obey scaling in the full range of packing fractions, 0.6 <=phi<= 0.805, and to become increasingly long-ranged as phi->phic. Finite size scaling of chi4(t) provides a consistency check for the previously analyzed divergences of chi4(t) ? (phi-phic)(-gammachi) and the correlation length xi? (phi-phic)( gammaxi). We check the robustness of our results with respect to our definition of mobility. The divergences and the scaling for phi->phic suggest a non equilibrium glass transition which seems qualitatively independent of the coefficient of restitution. PMID- 27230571 TI - Different dietary patterns and reduction of lung cancer risk: A large case control study in the U.S. AB - Reducing lung cancer risk by modifying diet is highly desirable. We investigated whether different U.S. dietary patterns were associated with lung cancer risk. Dietary patterns were derived using exploratory factor analysis for 2139 non small cell lung cancer (NSCLC) cases and 2163 frequency-matched controls. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). Highest adherence (highest vs. lowest quintile) to the "Tex Mex", "fruits and vegetables", and "American/Western" patterns was associated with a 55% reduced (OR = 0.45; 95% CI = 0.37-0.56; P < 0.001), 32% reduced (OR = 0.68; 95% CI = 0.55-0.85; P = 0.001), and 45% increased (OR = 1.45; 95% CI = 1.18 1.78; P < 0.001) risk of lung cancer, respectively. The effects were stronger for squamous cell carcinoma and ever smokers for the "fruits and vegetables" pattern, and stronger for other non-small cell lung cancer and never smokers for the "American/Western" pattern. Among six genome-wide association (GWA) studies identified lung cancer susceptibility loci assessed, a variant (rs2808630) of the C-reactive protein gene modified the associations for the "fruits and vegetables" (P for interaction = 0.03) and "American/Western" (P for interaction = 0.02) patterns. Our study first showed that the "Tex-Mex" dietary pattern was associated with a reduced lung cancer risk. Also, the "fruits and vegetables" and "American/Western" patterns affected lung cancer risk, and the effects were further modified by host genetic background. PMID- 27230573 TI - Prognostic value of mid-regional pro-adrenomedullin (MR-proADM) in patients with community-acquired pneumonia: a systematic review and meta-analysis. AB - BACKGROUND: The early identification of patients at risk of dying from community acquired pneumonia (CAP) is critical for their treatment and for defining hospital resource consumption. Mid-regional pro-adrenomedullin (MR-proADM) has been extensively investigated for its prognostic value in CAP. However, the results are conflicting. The purpose of the present meta-analysis was to explore the diagnostic accuracy of MR-proADM for predicting mortality in patients suffering from CAP, particularly emergency department (ED) patients. METHOD: We systematically searched the PubMed, Embase, Web of Knowledge and Cochrane databases. Studies were included if a 2 * 2 contingency table could be constructed based on both the MR-proADM level and the complications or mortality of patients diagnosed with CAP. The prognostic accuracy of MR-proADM in CAP was assessed using the bivariate meta-analysis model. We used the Q-test and I (2) index to evaluate heterogeneity. RESULTS: MR-proADM displayed moderate diagnostic accuracy for predicting complications in CAP, with an overall area under the SROC curve (AUC) of 0.74 (95 % CI: 0.70-0.78). Eight studies with a total of 4119 patients in the emergency department (ED) were included. An elevated MR-proADM level was associated with increased risk of death from CAP (RR 6.16, 95 % CI 4.71 8.06); the I (2) value was 0.0 %, and a fixed-effects model was used to pool RR. The pooled sensitivity and specificity were 0.74 (95 % CI: 0.67-0.79) and 0.73 (95 % CI: 0.70-0.77), respectively. The positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were 2.8 (95 % CI, 2.3-3.3) and 0.36 (95 % CI, 0.29-0.45), respectively. In addition, the diagnostic odds ratio (DOR) was 8 (95 % CI, 5-11), and the overall area under the SROC curve was 0.76 (95 % CI, 0.72 0.80). CONCLUSIONS: Our study has demonstrated that MR-proADM is predictive of increased complications and higher mortality rates in patients suffering from CAP. Future studies are warranted to determine the prognostic accuracy of MR proADM in conjunction with severity scores or other biomarkers and to determine an optimal cut-off level. PMID- 27230574 TI - Relationship between cytosine-adenine repeat polymorphism of ADAMTS9 gene and clinical and radiologic severity of knee osteoarthritis. AB - OBJECTIVE: The aim of this study is to determine the role of cytosine-adenine (CA) micro-satellite repeat sequence of ADAMTS9 gene on the development and progression of osteoarthritis (OA). METHODS: A total of 110 participants, including those with primary knee OA and healthy controls were enrolled in the study. Patients were stratified into two groups using the Kellgren-Lawrence staging (K-L staging) as group 1 for controls and mild OA and group 2 for moderate and severe OA. Genetic analyses were performed to determine the CA repeat length in ADAMTS9 gene. RESULTS: Twenty CA repeats were found to be statistically significant for differentiating groups 1 and 2 (P = 0.020). Age was the most significant risk factor involved, followed by >= 20 CA repeats and body mass index (P < 0.05). CA repeat length of >= 20 showed a 6.1-fold increase in probability for having OA at stage 3 or 4 compared to those of CA repeat length of < 20 (P = 0.004). In conclusion, the CA repeat length of >= 20 has a six-fold increase in probability for having severe OA. CONCLUSION: ADAMTS9 gene CA repeat polymorphism may be used to determine the prognosis for OA radiologic progression. Being the first in the literature reporting the CA repeat in the promotor region of ADAMTS9 gene in patients with OA, our study could be highlighted further in future research with larger sample size. PMID- 27230575 TI - Herpes Simplex Acute Retinal Necrosis Presenting as Unilateral Disc Swelling in Young Immunocompetent Patients. AB - PURPOSE: To report two cases of young immunocompetent males with herpes simplex acute retinal necrosis (HSV ARN) with initial diagnosis of unilateral disc swelling. METHODS: Retrospective case series. RESULTS: Two young immunocompetent males who were diagnosed to have unilateral disc swelling were treated as presumed optic neuritis and started on systemic steroids. On dilated fundal examination, unilateral retinitis and vasculitis was found after 2-3 days of systemic steroids and the diagnosis of ARN was made. Tetraplex vitreous tap subsequently returned as HSV-2 and HSV for the first and second patient, respectively. Both patients had no significant systemic medical history and tested negative for human immunodeficiency virus (HIV). Despite aggressive treatment, both patients developed profound visual morbidity. CONCLUSIONS: Close monitoring of patients with unilateral disc swelling and dilated fundus evaluation is critical, particularly upon initiation of systemic steroid therapy, even if immunocompetent, as misdiagnoses can result in potentially devastating consequences. PMID- 27230576 TI - Molecular cloning and expression profiling of multiple Dof genes of Sorghum bicolor (L) Moench. AB - DNA binding with one finger (Dof) proteins represent a family of plant specific transcription factors associated with diverse biological processes, such as seed maturation and germination, phytohormone and light mediated regulation, and plant responses to biotic and abiotic stresses. In present study, a total of 21 Dof genes from Sorghum bicolor were cloned, sequenced and in silico characterized for homology search, revealing their identity to Dof like proteins. The expression profiling of SbDof genes using quantitative RT-PCR in different tissue types and also under drought and salt stresses was attempted. The SbDof genes displayed differential expression either in their transcript abundance or in their expression patterns under normal growth condition. Two of the SbDof genes namely SbDof8 and SbDof12 showed comparatively high level of transcript abundance in all the tissue types tested; whereas some of the SbDof genes showed a distinct tissue specific expression pattern. Further a total of 13 SbDof genes showed differential expression when subjected to either of the abiotic stress i.e. drought or salinity. Three of the SbDof genes namely SbDof12, SbDof19 and SbDof24 were found to be up-regulated in response to drought and salt stress. Comparative analysis of SbDof genes expression revealed existence of a complex transcriptional and functional diversity across plant growth and developmental stages. PMID- 27230577 TI - High-level expression of a novel recombinant human plasminogen activator (rhPA) in the milk of transgenic rabbits and its thrombolytic bioactivity in vitro. AB - The human tissue-type plasminogen activator (tPA) is a key kinase of fibrinolysis that plays an important role in dissolving fibrin clots to promote thrombolysis. The recombinant human plasminogen activator (rhPA) has more thrombolytic advantages than the wild type tPA. To increase the half-life and thrombolytic activity of tPA, a mutant containing only the essential K2 fibrin-binding and P activating plasminogen domains of the wild type tPA was cloned. This fragment was then inserted into goat beta-casein regulatory sequences. Then, a mammary gland specific expression vector, PCL25/rhPA, was constructed, and the transgenic rabbits were generated. In this study, 18 live transgenic founders (12?, 6?) were generated using pronuclear microinjection. Six transgenic rabbits were obtained, and the expression levels of rhPA in the milk had a range of 15.2-630 ug/ml. A fibrin agarose plate assay of rhPA showed that it had strong thrombolytic bioactivity in vitro, and the highest specific activity was >360 (360 times more than that of alteplase). The results indicated that the rhPA containing only the K2 and P domains is efficiently expressed with higher thrombolytic bioactivity in the milk of transgenic rabbits. Our study also demonstrated a new method for the large-scale production of clinically relevant recombinant pharmaceutical proteins in the mammary glands of transgenic rabbits. PMID- 27230578 TI - Osmotic induction of placental growth factor in retinal pigment epithelial cells in vitro: contribution of NFAT5 activity. AB - One risk factor of neovascular age-related macular degeneration is systemic hypertension; hypertension is mainly caused by extracellular hyperosmolarity after consumption of dietary salt. In retinal pigment epithelial (RPE) cells, high extracellular osmolarity induces vascular endothelial growth factor (VEGF)-A (Hollborn et al. in Mol Vis 21:360-377, 2015). The aim of the present study was to determine whether extracellular hyperosmolarity and chemical hypoxia trigger the expression of further VEGF family members including placental growth factor (PlGF) in human RPE cells. Hyperosmotic media were made up by addition of 100 mM NaCl or sucrose. Chemical hypoxia was induced by CoCl2. Gene expression was quantified by real-time RT-PCR, and secretion of PlGF-2 was investigated with ELISA. Nuclear factor of activated T cell 5 (NFAT5) was depleted using siRNA. Extracellular hyperosmolarity triggered expression of VEGF-A, VEGF-D, and PlGF genes, and secretion of PlGF-2. Hypoosmolarity decreased PlGF gene expression. Hypoxia induced expression of VEGF-A, VEGF-B, VEGF-D, and PlGF genes. Extracellular hyperosmolarity and hypoxia produced additive PlGF gene expression. Both hyperosmolarity and hypoxia induced expression of KDR and FLT-4 receptor genes, while hyperosmolarity caused neuropilin-2 and hypoxia neuropilin-1 gene expression. The hyperosmotic, but not the hypoxic, PlGF gene expression was in part mediated by NFAT5. The expression of PlGF in RPE cells depends on the extracellular osmolarity. The data suggest that high consumption of dietary salt may exacerbate the angiogenic response of RPE cells in the hypoxic retina via transcriptional activation of various VEGF family member genes. PMID- 27230579 TI - Identification of gonadal soma-derived factor involvement in Monopterus albus (protogynous rice field eel) sex change. AB - We studied molecular events and potential mechanisms underlying the process of female-to-male sex transformation in the rice field eel (Monopterus albus), a protogynous hermaphrodite fish in which the gonad is initially a female ovary and transforms into male testes. We cloned and identified a novel gonadal soma derived factor (GSDF), which encodes a member of the transforming growth factor beta superfamily. gsdf expression was measured in gonads of female, intersex and male with reverse transcription-PCR and gsdf's role in sex transformation was studied with qPCR, histological analysis and dual-color in situ hybridization assays and compared to other sex-related genes. gsdf was correlated to Sertoli cell differentiation, indicating involvement in testicular differentiation and sex transformation from female to male in this species. A unique expression pattern reveals a potential role of gsdf essential for the sex transformation of rice field eels. PMID- 27230580 TI - Exploring the Inhibitory Mechanism of Approved Selective Norepinephrine Reuptake Inhibitors and Reboxetine Enantiomers by Molecular Dynamics Study. AB - Selective norepinephrine reuptake inhibitors (sNRIs) provide an effective class of approved antipsychotics, whose inhibitory mechanism could facilitate the discovery of privileged scaffolds with enhanced drug efficacy. However, the crystal structure of human norepinephrine transporter (hNET) has not been determined yet and the inhibitory mechanism of sNRIs remains elusive. In this work, multiple computational methods were integrated to explore the inhibitory mechanism of approved sNRIs (atomoxetine, maprotiline, reboxetine and viloxazine), and 3 lines of evidences were provided to verify the calculation results. Consequently, a binding mode defined by interactions between three chemical moieties in sNRIs and eleven residues in hNET was identified as shared by approved sNRIs. In the meantime, binding modes of reboxetine's enantiomers with hNET were compared. 6 key residues favoring the binding of (S, S)-reboxetine over that of (R, R)-reboxetine were discovered. This is the first study reporting that those 11 residues are the common determinants for the binding of approved sNRIs. The identified binding mode shed light on the inhibitory mechanism of approved sNRIs, which could help identify novel scaffolds with improved drug efficacy. PMID- 27230581 TI - Retinal blood flow is increased in type 1 diabetes mellitus patients with advanced stages of retinopathy. AB - BACKGROUND: Diabetic retinopathy (DRP) is a common microvascular complication seen in patients with type 1 diabetes mellitus (T1DM). The effects of T1DM and concomitant (proliferative) DRP on retinal blood flow are currently unclear. Therefore, we measured retinal vascular blood flow in T1DM patients with and without DRP and non-diabetic controls. We further assessed the acute effects of panretinal photocoagulation on retinal microvascular bloodflow in eight patients with diabetes. METHODS: Thirty-three T1DM patients with proliferative DRP, previously treated with panretinal photocoagulation (pDRP), 11 T1DM patients with untreated non-proliferative retinopathy (npDRP) and 32 T1DM patients without DRP (nDRP) were compared with 44 non-diabetic gender-matched controls. Using scanning laser Doppler flowmetry (HRF, Heidelberg) blood flow in the retinal microvasculature was measured temporal and nasal of the optic disc and averaged into one flow value per eye. The right eye was used as a default for further analyses. Eight patients with novel proliferative retinopathy (4 T1DM and 4 with type 2 diabetes) were measured before and several months after photocoagulation. Between-group differences in retinal blood flow were assessed using ANOVA corrected for multiple comparisons (Bonferroni). RESULTS: Retinal blood flow was higher in the treated pDRP compared with the nDRP group and controls (all P Bonferroni < 0.01). Furthermore, there was a positive linear trend for blood flow with lowest blood flow in the control group and highest in the pDRP group (P-for trend < 0.01). In the eight patients with novel proliferative retinopathy, blood flow did not significantly change before and after panretinal photocoagulation (P > 0.05). Using regression analysis, no variables were found as predictors of retinal blood flow. CONCLUSIONS: In comparison with controls and nDRP patients, retinal blood flow significantly increased in the pDRP group, which previously underwent photocoagulation treatment, but not in the npDRP patients. These changes may be a consequence of a failing vascular autoregulation in advanced diabetic retinopathy. PMID- 27230582 TI - Characterisation of phenolic antioxidants in Scabiosa arenaria flowers by LC-ESI MS/MS and NMR. AB - OBJECTIVES: This work describes the bioguided fractionation of the flower's ethyl acetate fraction of Scabiosa arenaria Forssk. (Dipsacaceae). METHODS: The identification of the pure compound isolated has been studied by mono-dimensional NMR experiments. The mixture of phenolic compounds was analysed by LC-ESI-MS/MS. The antioxidant activity has been evaluated by the 1, 1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay. KEY FINDINGS: The bioguided fractionation of the flower's ethyl acetate fraction of Scabiosa arenaria led to the isolation of a pure compound: luteolin. The mixture of three phenolic compounds was identified as: 1, 4-O-dicaffeoylquinic acid, apigenin 7-O-glucoside and luteolin-7-O glucoside. Two of which are reported here for the first time in Scabiosa genus. Luteolin had the highest antioxidant activity with an IC50 value of 0.02 +/- 0.007 mg/ml, followed by the three phenolic compounds with an IC50 value of 0.025 +/- 0.008 mg/ml. CONCLUSIONS: The results of the present work indicate that S. arenaria flower's ethyl acetate extract could be used as natural antioxidant agents in food preservation and human health. PMID- 27230583 TI - Transcriptomic analysis reveals how a lack of potassium ions increases Sulfolobus acidocaldarius sensitivity to pH changes. AB - Extremely acidophilic microorganisms (optimum growth pH of <=3) maintain a near neutral cytoplasmic pH via several homeostatic mechanisms, including an inside positive membrane potential created by potassium ions. Transcriptomic responses to pH stress in the thermoacidophilic archaeon, Sulfolobus acidocaldarius were investigated by growing cells without added sodium and/or potassium ions at both optimal and sub-optimal pH. Culturing the cells in the absence of added sodium or potassium ions resulted in a reduced growth rate compared to full-salt conditions as well as 43 and 75 significantly different RNA transcript ratios, respectively. Differentially expressed RNA transcripts during growth in the absence of added sodium ions included genes coding for permeases, a sodium/proline transporter and electron transport proteins. In contrast, culturing without added potassium ions resulted in higher RNA transcripts for similar genes as a lack of sodium ions plus genes related to spermidine that has a general role in response to stress and a decarboxylase that potentially consumes protons. The greatest RNA transcript response occurred when S. acidocaldarius cells were grown in the absence of potassium and/or sodium at a sub-optimal pH. These adaptations included those listed above plus osmoregulated glucans and mechanosensitive channels that have previously been shown to respond to osmotic stress. In addition, data analyses revealed two co-expressed IclR family transcriptional regulator genes with a previously unknown role in the S. acidocaldarius pH stress response. Our study provides additional evidence towards the importance of potassium in acidophile growth at acidic pH. PMID- 27230584 TI - Improving the management of chronic inflammatory demyelinating polyradiculoneuropathy. AB - This article considers several issues of current interest relating to the management of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), including diagnostic pitfalls, differences between CIDP patients with and without concurrent diabetes mellitus and how to best measure treatment response in daily practice. Despite the availability of diagnostic criteria, many patients diagnosed with CIDP do not meet these criteria; reasons for misdiagnosis are discussed. There are no definitive predictors of treatment response in CIDP; however, certain clinical and electrophysiological characteristics may be helpful. Patients with CIDP and concurrent diabetes present an additional diagnostic challenge; the differences between these groups, including possible differences in response predictors are discussed. Finally, the most appropriate outcome measures for use in daily practice are considered. PMID- 27230585 TI - Mapping research activity on mental health disorders in Europe: study protocol for the Mapping_NCD project. AB - BACKGROUND: Mental health disorders (MHDs) constitute a large and growing disease burden in Europe, although they typically receive less attention and research funding than other non-communicable diseases (NCDs). This study protocol describes a methodology for the mapping of MHD research in Europe as part of Mapping_NCD, a 2-year project funded by the European Commission which seeks to map European research funding and impact for five NCDs in order to identify potential gaps, overlaps, synergies and opportunities, and to develop evidence based policies for future research. METHODS: The project aims to develop a multi focal view of the MHD research landscape across the 28 European Union Member States, plus Iceland, Norway and Switzerland, through a survey of European funding entities, analysis of research initiatives undertaken in the public, voluntary/not-for-profit and commercial sectors, and expert interviews to contextualize the gathered data. The impact of MHD research will be explored using bibliometric analyses of scientific publications, clinical guidelines and newspaper stories reporting on research initiatives. Finally, these research inputs and outputs will be considered in light of various metrics that have been proposed to inform priorities for the allocation of research funds, including burden of disease, treatment gaps and cost of illness. DISCUSSION: Given the growing burden of MHDs, a clear and broad view of the current state of MHD research is needed to ensure that limited resources are directed to evidence based priority areas. MHDs pose a particular challenge in mapping the research landscape due to their complex nature, high co-morbidity and varying diagnostic criteria. Undertaking such an effort across 31 countries is further challenged by differences in data collection, healthcare systems, reimbursement rates and clinical practices, as well as cultural and socioeconomic diversity. Using multiple methods to explore the spectrum of MHD research funding activity across Europe, this project aims to develop a broad, high-level perspective to inform priority setting for future research. PMID- 27230586 TI - Violence, stigma and mental health among female sex workers in China: A structural equation modeling. AB - Intimate partner violence is prevalent among female sex workers (FSWs) in China, and it is significantly associated with mental health problems among FSWs. However, limited studies have explored the mechanisms/process by which violence affects mental health. The purpose of this study was to explore the relationships among partner violence, internalized stigma, and mental health problems among FSWs. Data were collected using a self-administered cross-sectional survey administered to 1,022 FSWs in the Guangxi Zhuang Autonomous Region (Guangxi), China during 2008-2009. We used structural equation modeling to test the hypothesized relationships. Results indicated that violence perpetrated by either stable sexual partners or clients was directly and positively associated with mental health problems. Violence also had an indirect relation to mental health problems through stigma. Results highlight the need for interventions on counseling and care for FSWs who have experienced violence and for interventions to increase FSWs' coping skills and empowerment strategies. PMID- 27230587 TI - Effects of Pretreatment with Warfarin or Rivaroxaban on Neurovascular Unit Dissociation after Tissue Plasminogen Activator Thrombolysis in Ischemic Rat Brain. AB - BACKGROUND: Warfarin and rivaroxaban are highly effective in reducing stroke risk in patients with atrial fibrillation (AF). However, their effects on anticoagulation and neurovascular unit (NVU) change remain elusive. In this study, we assessed the risks and benefits of pre-treatment with warfarin or rivaroxaban after tissue-type plasminogen activator (tPA) thrombolysis in ischemic rat brain. METHODS: Pre-treatment with warfarin (.2 mg/kg/day), low dose rivaroxaban (60 mg/kg/day), high dose rivaroxaban (120 mg/kg/day) or vehicle was performed for 2 weeks, transient middle cerebral artery occlusion (tMCAO) was induced for 90 min, then followed by reperfusion with tPA. At 24 hours (h) after reperfusion, we observed the changes of matrix metalloproteinase-9 (MMP-9), tissue factor, caspase 3 and NVU dissociation. RESULTS: Prothrombin time (PT) was significantly prolonged in the warfarin and rivaroxaban pretreated groups. MMP-9 expression greatly increased in the warfarin group, and this was reduced in the rivaroxaban groups compared with the vehicle group. Tissue factor expression remarkably decreased in the warfarin and rivaroxaban groups. The number of caspase 3-positive cells had no difference among all the groups. Marked dissociations between astrocyte foot processes and the basal lamina or pericytes were observed in the warfarin pretreated group, but such dissociations were improved in the rivaroxaban groups. CONCLUSIONS: Our present study shows that pre treatment with rivaroxaban was noninferior to warfarin in the anticoagulation, but a lower risk of NVU dysfunction and dissociation after tPA treatment in rivaroxaban. This finding could partly explain the mechanism of reducing hemorrhagic complications by rivaroxaban in clinical studies. PMID- 27230588 TI - Epistatic interactions between ancestral genotype and beneficial mutations shape evolvability in Pseudomonas aeruginosa. AB - The idea that interactions between mutations influence adaptation by driving populations to low and high fitness peaks on adaptive landscapes is deeply ingrained in evolutionary theory. Here, we investigate the impact of epistasis on evolvability by challenging populations of two Pseudomonas aeruginosa clones bearing different initial mutations (in rpoB conferring rifampicin resistance, and the type IV pili gene network) to adaptation to a medium containing l-serine as the sole carbon source. Despite being initially indistinguishable in fitness, populations founded by the two ancestral genotypes reached different fitness following 300 generations of evolution. Genome sequencing revealed that the difference could not be explained by acquiring mutations in different targets of selection; the majority of clones from both ancestors converged on one of the following two strategies: (1) acquiring mutations in either PA2449 (gcsR, an l serine-metabolism RpoN enhancer binding protein) or (2) protease genes. Additionally, populations from both ancestors converged on loss-of-function mutations in the type IV pili gene network, either due to ancestral or acquired mutations. No compensatory or reversion mutations were observed in RNA polymerase (RNAP) genes, in spite of the large fitness costs typically associated with mutations in rpoB. Although current theory points to sign epistasis as the dominant constraint on evolvability, these results suggest that the role of magnitude epistasis in constraining evolvability may be underappreciated. The contribution of magnitude epistasis is likely to be greatest under the biologically relevant mutation supply rates that make back mutations probabilistically unlikely. PMID- 27230589 TI - Community governance in primary health care: towards an international Ideal Type. AB - Against a global background of increased resource management responsibilities for primary health care agencies, general medical practices, in particular, are increasingly being required to demonstrate the legitimacy of their decision making in market oriented environments. In this context a scoping review explores the potential utility for health managers in primary health care of community governance as a policy concept. The review of recent research suggests that applied learning from international health systems with enhanced approaches to public and patient involvement may contribute to meeting this requirement. Such approaches often characterise local health systems in Latin America and North West Europe where innovative models are beginning to respond effectively to the growing demands on general practice. The study design draws on documentary and secondary data analyses to identify common components of community governance from the countries in these regions, supplemented by other relevant international studies and sources where appropriate. Within a comprehensive framework of collaborative governance the components are aggregated in an Ideal Type format to provide a point of reference for possible adaptation and transferable learning across market oriented health systems. Each component is illustrated with international exemplars from recent organisational practices in primary health care. The application of community governance is considered for the particular contexts of GP led Clinical Commissioning Groups in England and Primary Health Networks in Australia. Some components of the Ideal Type possess potentially powerful negative as well as positive motivational effects, with PPI at practice levels sometimes hindering the development of effective local governance. This highlights the importance of careful and competent management of the growing resources attributed to primary health care agencies, which possess an increasingly diverse range of non-governmental status. Future policy and research priorities are outlined. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27230590 TI - Molecular mechanisms of adaptation and speciation: why do we need an integrative approach? AB - Understanding divergent adaptation and ecological speciation requires the synthesis of multiple approaches, including phenotypic characterization, genetics and genomics, realistic assessment of fitness and population genetic modelling. Current research in this field often approaches this problem from one of two directions: either a mechanistic approach-seeking to link phenotype, genotype and fitness, or a genomic approach-searching for signatures of divergence or selection across the genome. In most cases, these two approaches are not synthesized, and as a result, our understanding is incomplete. We argue that research in adaptation and evolutionary genetics needs to integrate these approaches for multiple reasons, including progress towards understanding the architecture and evolutionary history of adaptation and speciation loci, the ability to untangle linkage and pleiotropy, increased knowledge of mechanisms of genomic evolution and insights into parallel evolutionary events. Identifying the genetic underpinnings of adaptation and ecological speciation is not necessarily the end goal of research, but it is an integral part of understanding the evolutionary process. As a result, it is critical to utilize both genetic and genomic approaches. Challenges remain, particularly in nonmodel organisms and in our ability to synthesize results from multiple experimental systems. Nonetheless, advances in genetic and genomic techniques are increasingly available in a diverse array of systems, and the time is ripe to exploit the synthesis of these two approaches to increase our understanding of evolution. PMID- 27230591 TI - Unilateral persistent fetal vasculature coexisting with anterior segment dysgenesia. AB - CASE REPORT: A case is presented of a 4 week-old female neonate with Peters anomaly (PA) and unilateral persistent foetal vasculature (PFV) referred to our centre due to esotropia. At 12 weeks of age, a penetrating keratoplasty and vitrectomy were performed without major complications in the immediate post operative period. The patient is currently under an intensive treatment for amblyopia and secondary glaucoma. DISCUSSION: Surgical treatment of PFV is controversial, with prevention of amblyopia, phthisis, and glaucoma being the main reasons for it. Patients with unilateral PFV and type II PA could be good candidates for this combined surgical procedure. PMID- 27230592 TI - Femtophacovitrectomy. Case series and description of the technique. AB - OBJECTIVE: The aim of this study was to assess the safety and surgical results of combined pars plana vitrectomy and femtosecond laser-assisted cataract surgery (femtophacovitrectomy). MATERIAL AND METHODS: A prospective, non-comparative case series was conducted by selecting patients with cataract and vitreoretinal pathology who underwent femtophacovitrectomy by a single surgeon at the Hospital Central Militar between June 2013 and February 2014. An evaluation was made of the preoperative characteristics, surgical indications, results, and postoperative complications, with a minimum follow-up of 3 months. RESULTS: The study included 35 eyes of 35 patients, of whom 20 (57.1%) were male. The mean age was 60.76+/-4.2 years. Diagnoses included vitreous haemorrhage (19 cases), macular hole (6 cases), epiretinal membrane (7), and tractional detachment (5 cases). The mean best corrected visual acuity was 1.3 LogMAR before surgery, and 0.5 LogMAR at 3-months follow-up (P<.05). No patient had visual loss. The intra operative complication was miosis in 14.28%. In the early postoperative period (<1 month), all had subconjunctival haemorrhage, with moderate corneal oedema in 20% of cases, and only 2.85% (one case) ocular hypertension associated with use of intraocular gas. There were no cases of endophthalmitis. The mean follow-up was 13.3 months (10-16 months). CONCLUSIONS: The use of femtosecond laser in phacovitrectomy is a safe and effective alternative, with similar risk of complications in cases of macular pathology, tractional retinal detachment, and/or vitreous haemorrhage. PMID- 27230593 TI - Public political thought: bridging the sociological-philosophical divide in the study of legitimacy. AB - The study of political legitimacy is divided between prescriptive and descriptive approaches. Political philosophy regards legitimacy as principled justification, sociology regards legitimacy as public support. However, all people can, and occasionally do engage in morally reasoning their political life. This paper thus submits that in studying socio-political legitimation - the legitimacy-making process - the philosophical ought and the sociological is can be bridged. I call this construct 'public political thought' (PPT), signifying the public's principled moral reasoning of politics, which need not be democratic or liberal. The paper lays PPT's foundations and identifies its 'builders' and 'building blocks'. I propose that the edifice of PPT is built by moral agents constructing and construing socio-moral order (nomization). PPT's building blocks are justificatory common beliefs (doxa) and the deliberative language of legitimation. I illustrate the merits of this groundwork through two empirical puzzles: the end of apartheid and the emergence of Quebecois identity. PMID- 27230594 TI - Examining the Effectiveness of the Smoking Prevention Program "I Do Not Smoke, I Exercise" in Elementary and Secondary School Settings. AB - The aim of the study was to examine the effectiveness of the smoking prevention program "I do not smoke, I exercise" implemented with elementary and secondary school students. "I do not smoke, I exercise" is a theory-based smoking prevention program that promotes exercise as an alternative of smoking. The program consists of eight sessions implemented weekly. Participants were 338 Greek students (135 elementary and 203 secondary students) who were pre- and posttested in smoking, program, and exercise-related measures. The results showed that the program had significant effects on elementary students' attitudes toward smoking, intention to smoke, subjective norms, attitudes toward the application of the program, and knowledge about the health consequences of smoking. For secondary students, significant effects were found on students' perceived behavioral control and knowledge about the health consequences of smoking, while very few students reported a smoking experience before and after the intervention. Therefore the program "I do not smoke, I exercise" may have positive effects on variables related with smoking behavior. Differences in the program's impact on elementary and secondary students were identified. All these are discussed with reference to the need of implementing smoking prevention programs in schools contexts. PMID- 27230595 TI - On the Hydrodynamic Nature of DNA Acoustic Sensing. AB - In this work we provide strong experimental evidence for the hydrodynamic nature of the acoustic wave/biomolecule interaction at a solid/liquid interface. By using a wide range of DNAs of various sizes and by assuming DNA attachment as discrete particles through a neutravidin/biotin link, we prove experimentally that the acoustic ratio (dissipation/frequency) is directly related to the molecules' intrinsic viscosity [eta]. The relationship of [eta] to the size and shape of biomolecules is described in general and more specifically for linear dsDNA; equations are derived linking the measured acoustic ratio to the number of dsDNA base pairs for two acoustic sensors, the QCM and Love-wave devices operating at a frequency of 35 and 155 MHz, respectively. Single-stranded DNAs were also tested and shown to fit well to the equation derived for the double stranded molecules while new insight is provided on their conformation on a surface. Other types of DNA are also shown to fit the proposed model. The current work establishes a new way of viewing acoustic sensor data and lays down the groundwork for a surface technique where quantitative information can be obtained at the nanometer scale regarding the shape and size, i.e., conformation of biomolecules at an interface. PMID- 27230596 TI - Magnetic behavior of Gd3Ru4Al12, a layered compound with distorted kagome net. AB - The magnetic behavior of the compound, Gd3Ru4Al12, which was reported about two decades ago to crystallize in a hexagonal structure (space group P63/mmc), has not been investigated in the past literature despite interesting structural features (that is, magnetic layers and triangular as well as kagome-lattice features favoring frustrated magnetism) characterizing this compound. We report here the results of studies of magnetization, heat capacity and magnetoresistance in the temperature range T = 1.8-300 K. The results establish that there is a long-range magnetic order of antiferromagnetic type below (T N =) 18.5 K, despite a much larger value (~80 K) of paramagnetic Curie temperature with a positive sign characteristic of ferromagnetic interaction. We attribute this to geometric frustration. The most interesting finding is that there is an additional magnetic anomaly below ~55 K before the onset of long-range order in the magnetic susceptibility data. Concurrent with this observation, the sign of isothermal change in entropy, DeltaS = S(0) - S(H), where H is the externally applied magnetic field, remains positive above T N, with a broad peak. This observation indicates the presence of ferromagnetic clusters before the onset of long-range magnetic order. Thus, this compound may serve as an example of a situation in which magnetic frustration due to geometrical reasons faces competition from such magnetic precursor effects. There is also a reversal of the sign of -DeltaS in the curves for lower final fields (H < 30 kOe) on entering the magnetically ordered state consistent with the entrance to an antiferromagetic state. The magnetoresistance behavior is consistent with the above conclusions. PMID- 27230597 TI - Strengthening the Case for Professional Assistance to Support a Choice of Dialysis Location in Older Dialysis Patients. PMID- 27230599 TI - New-Onset Diabetes in Peritoneal Dialysis Patients - Which Predictors Really Matter? PMID- 27230598 TI - Is the Effect of Low-GDP Solutions on Residual Renal Function Mediated by Fluid State? An Enigmatic Question which Still Needs to be Solved. PMID- 27230600 TI - Epidemic of Chemical Peritonitis in Patients on Continuous Ambulatory Peritoneal Dialysis: A Report from Western India. AB - While non-infectious etiologies like chemical irritants are rare causes of epidemics of peritonitis, this possibility should be considered when one encounters an unusual clustering of peritonitis cases. We describe here an epidemic of chemical peritonitis at our center. PMID- 27230601 TI - Uninterrupted Peritoneal Dialysis after Robotic-Assisted Total Laparoscopic Hysterectomy. AB - This report describes the first case of uninterrupted peritoneal dialysis (PD) after robotic-assisted laparoscopic hysterectomy. Frequent low-volume PD exchanges in a supine position to minimize intra-abdominal pressure starting on post-operative day 3 successfully provided adequate clearance and ultrafiltration. The patient did not encounter any metabolic or wound complications. Pre-admission PD prescription was resumed on post-operative day 14. Interim hemodialysis was not needed. PMID- 27230602 TI - Hodgkin's Lymphoma Diagnosed from Peritoneal Effluent. AB - In infective cases of peritoneal dialysis (PD) peritonitis, examination of the effluent fluid usually shows a predominance of neutrophils, and a bacterial organism is frequently isolated by culture. Where no organisms are identified, cases are often referred to as culture-negative 'peritonitis,' but non-infective causes for cloudy effluent are rare. We report the unusual finding of cloudy effluent as a presenting sign of recurrent lymphoma, diagnosed by cytological examination of the peritoneal effluent. PMID- 27230603 TI - Appendiceal Incarceration by Peritoneal Dialysis Catheter. PMID- 27230604 TI - Unintentional Removal of a Peritoneal Dialysis Catheter: A Case Report. PMID- 27230605 TI - Weekly nab-Paclitaxel in Combination With Carboplatin as First-Line Therapy in Patients With Advanced Non-Small-Cell Lung Cancer: Analysis of Safety and Efficacy in Patients With Diabetes. AB - PURPOSE: To examine outcomes in a phase 3 trial of nab-paclitaxel plus carboplatin (nab-P/C) versus solvent-based paclitaxel plus carboplatin (sb-P/C) in a subset of patients with advanced non-small-cell lung cancer (NSCLC) and diabetes. PATIENTS AND METHODS: Patients with stage IIIB/IV NSCLC received nab-P 100 mg/m2 on days 1, 8, and 15 or sb-P 200 mg/m2 on day 1, both with C at an area under the curve of 6 mg.min/mL on day 1 every 3 weeks. Overall response rate (ORR) and progression-free survival (PFS) were determined by blinded, independent, centralized review. P values were based on chi-square test for ORR and log-rank test for overall survival (OS) and PFS. RESULTS: Of the 1052 randomized patients in the phase 3 trial, 61 had diabetes according to prespecified terms (nab-P/C, 31; sb-P/C, 30). ORR for nab-P/C versus sb-P/C in this subset was 52% versus 27% (relative risk ratio, 1.935; P = .046), median PFS was 10.9 versus 4.9 months (hazard ratio, 0.420; P = .016), and median OS was 17.5 versus 11.1 months (hazard ratio, 0.550; P = .057). Treatment differences in PFS remained significant (P <= .036) after adjusting for histology, region, stage, race, and age and also remained significant in OS for histology (P = .039). Patients with diabetes experienced lower rates of grade 3 or higher neutropenia and peripheral neuropathy and higher rates of thrombocytopenia and anemia with nab-P/C versus sb-P/C. CONCLUSION: nab-P/C demonstrated improved efficacy and manageable tolerability in patients with advanced NSCLC and diabetes. PMID- 27230607 TI - A re-investigation of (4)JFF and (5)JFF nuclear spin-spin couplings in substituted benzenes, a novel conformational tool. AB - A theoretical analysis of the (4)JFF and (5)JFF couplings in fluorobenzenes separates the sigma and pi components of the substituent coefficients. The pi bond mechanism is dominant but the sigma bond mechanism must be included to give accurate values of the couplings. For monosubstituted difluorobenzenes the (4)JFF and (5)JFF couplings can be predicted from the calculated pi densities by linear equations. The use of additive substituent effects allows the prediction of the meta(4)JFF couplings for multisubstituted compounds. The pi dependence of the (4)JFF coupling in 2,6-difluorobenzenes provides a novel and simple method of determining the torsional angle of the C1 substituent and the benzene ring for non-symmetrical functional groups (acetyl, carboxymethyl, dimethylamino, amide, nitro etc.). This could be used to determine the geometries of such molecules in biological systems. The pi dependence of the (4)JFF coupling is also of importance in the charged species of 2,6-difluoroanilinium ((4)JFF 2.1 Hz) and 2,6-difluoro-N,N,N-trimethylanilinium ((4)JFF 0.0 Hz) due to the very different pi electron densities. PMID- 27230606 TI - Clinical effectiveness of transdiagnostic health management interventions for older people with multimorbidity: a quantitative systematic review. AB - AIM: The aim of this study was to evaluate the clinical effectiveness (improvement in health status and/or functioning and use of health services) of transdiagnostic health management interventions for people aged 65 years and older. BACKGROUND: The care of older people with multimorbidity is of increasing concern for nurses. A transdiagnostic approach to health management interventions (promote self-management or lifestyle) may be apposite for providing older people with the skills to manage symptoms that may or may not be disease-specific. DESIGN: Quantitative systematic review. REVIEW METHODS: Cochrane methods using Cochrane's Effective Practice and Organization of Care Methods (EPOC) for assessing risk of bias and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) for assessing the weight of evidence. DATA SOURCES: Medline, CINAHL, PubMed and PsycINFO 1999-2014. RESULTS: Twelve studies were included in the review (n = 10,393). All 12 studies provided results for health outcomes (health status and functioning) and six provided results for health outcomes and health service utilization. Ten studies reported statistically significant improvements in health outcomes but of these studies only two were of low risk of bias. Three studies identified some statistically significant reductions in health service utilization. The weight of evidence for the health management interventions included in the review, were low/moderate for improvements in health status and low for improvements in health service utilization. CONCLUSION: While there is some very preliminary evidence suggesting that structured transdiagnostic health management interventions may be clinically effective for older people with multimorbidity the effect sizes are small and the quality of this evidence is generally low. PMID- 27230608 TI - A Model for Carrier-Mediated Biological Signal Transduction Based on Equilibrium Ligand Binding Theory. AB - Different variants of a mathematical model for carrier-mediated signal transduction are introduced with focus on the odor dose-electrophysiological response curve of insect olfaction. The latter offers a unique opportunity to observe experimentally the effect of an alteration in the carrier molecule composition on the signal molecule-dependent response curve. Our work highlights the role of involved carrier molecules, which have largely been ignored in mathematical models for response curves in the past. The resulting model explains how the involvement of more than one carrier molecule in signal molecule transport can cause dose-response curves as observed in experiments, without the need of more than one receptor per neuron. In particular, the model has the following features: (1) An extended sensitivity range of neuronal response is implemented by a system consisting of only one receptor but several carrier molecules with different affinities for the signal molecule. (2) Given that the sensitivity range is extended by the involvement of different carrier molecules, the model implies that a strong difference in the expression levels of the carrier molecules is absolutely essential for wide range responses. (3) Complex changes in dose-response curves which can be observed when the expression levels of carrier molecules are altered experimentally can be explained by interactions between different carrier molecules. The principles we demonstrate here for electrophysiological responses can also be applied to any other carrier-mediated biological signal transduction process. The presented concept provides a framework for modeling and statistical analysis of signal transduction processes if sufficient information on the underlying biology is available. PMID- 27230609 TI - On Eigen's Quasispecies Model, Two-Valued Fitness Landscapes, and Isometry Groups Acting on Finite Metric Spaces. AB - A two-valued fitness landscape is introduced for the classical Eigen's quasispecies model. This fitness landscape can be considered as a direct generalization of the so-called single- or sharply peaked landscape. A general, non-permutation invariant quasispecies model is studied, and therefore the dimension of the problem is [Formula: see text], where N is the sequence length. It is shown that if the fitness function is equal to [Formula: see text] on a G orbit A and is equal to w elsewhere, then the mean population fitness can be found as the largest root of an algebraic equation of degree at most [Formula: see text]. Here G is an arbitrary isometry group acting on the metric space of sequences of zeroes and ones of the length N with the Hamming distance. An explicit form of this exact algebraic equation is given in terms of the spherical growth function of the G-orbit A. Motivated by the analysis of the two-valued fitness landscapes, an abstract generalization of Eigen's model is introduced such that the sequences are identified with the points of a finite metric space X together with a group of isometries acting transitively on X. In particular, a simplicial analog of the original quasispecies model is discussed, which can be considered as a mathematical model of the switching of the antigenic variants for some bacteria. PMID- 27230610 TI - Living with appending a scarlet letter: The lifelong suffering of children of alcoholics in South Korea. AB - : Children of alcoholics (COAs) are those who have grown up with parental alcoholism. The purpose of this study was to understand the lives of Korean COAs within a Korean cultural context, influenced by Confucianism. Prior literature has extensively reported about the adverse life experiences of COAs related to their alcohol dependent parents. Indeed, most of these studies assume the U.S.- or Western-centric perspective. However, in order to provide culture-specific care, health professionals who provide care for diverse ethnic families have to understand the cultural influences on the families which have an ill family member. Data were collected from 20 Korean adult children through semi-structured interviews. All interviews were audio-recorded and fully transcribed. Thematic analysis was used for the data analysis. The lives of Korean COAs were described with four themes, namely: "Losing family," "Life with holding a bomb," "My life ruined," and "Being bound." CONCLUSION: In conclusion, the findings of this study demonstrated how cultural components could shape individual's life experiences in a family having an alcohol dependent family member. This study would be helpful for health professionals to deeply understand the alcoholic family members within a specific cultural background as well as to build a cultural-specific care-plans for them. PMID- 27230611 TI - Does impulsivity predict outcome in treatment for binge eating disorder? A multimodal investigation. AB - Multiple dimensions of impulsivity (e.g., affect-driven impulsivity, impulsive inhibition - both general and food-specific, and impulsive decision-making) are associated with binge eating pathology cross-sectionally, yet the literature on whether impulsivity predicts treatment outcome is limited. The present pilot study explored impulsivity-related predictors of 20-week outcome in a small open trial (n = 17) of a novel treatment for binge eating disorder. Overall, dimensions of impulsivity related to emotions (i.e., negative urgency) and food cues emerged as predictors of treatment outcomes (i.e., binge eating frequency and global eating pathology as measured by the Eating Disorders Examination), while more general measures of impulsivity were statistically unrelated to global eating pathology or binge frequency. Specifically, those with higher levels of negative urgency at baseline experienced slower and less pronounced benefit from treatment, and those with higher food-specific impulsivity had more severe global eating pathology at baseline that was consistent at post-treatment and follow-up. These preliminary findings suggest that patients high in negative urgency and with poor response inhibition to food cues may benefit from augmentation of existing treatments to achieve optimal outcomes. Future research will benefit from replication with a larger sample, parsing out the role of different dimensions of impulsivity in treatment outcome for eating disorders, and identifying how treatment can be improved to accommodate higher levels of baseline impulsivity. PMID- 27230613 TI - Prognostic Value of Vascular Invasion in Pediatric Osteosarcomas. AB - Metastatic status, histologic response, and quality of surgical resection are prognostic factors for osteosarcomas. Pathology reports sometimes describe peritumoral vascular invasion on surgical specimens after neoadjuvant chemotherapy but their prognostic significance as an independent parameter has never been reported. The aim of this study was to evaluate how the presence of this peritumoral vascular invasion could influence survival. We retrospectively analyzed histology, demographics, and outcomes of pediatric patients treated for osteosarcoma in our institutions between January 2007 and December 2012. A single pathologist analyzed the resection specimens after neoadjuvant chemotherapy. Fifty-one osteosarcomas were diagnosed over a 6-year period; nine had metastatic disease at diagnosis. Surgery was performed after neoadjuvant chemotherapy in all cases. We identified peritumoral vascular invasion in the surgical specimens in 15 cases. Two-year event-free survival (EFS) was 78 % (CI95%[64;93]) for patients without vascular invasion versus 48 % (CI95% [21;75]) in patients with vascular invasion, and 2-year overall survival (OS) was 94 % (CI95%[86;100]) for those without vascular invasion versus 79 % (CI95%[57;100]) for others. Multivariate analysis demonstrated correlation of metastatic status and presence of vascular invasion with survival. The histopathological description of peritumoral vascular invasion in surgical specimens of osteosarcoma after neoadjuvant chemotherapy can be considered a prognostic factor and could indicate modification of the postoperative therapeutic strategy. PMID- 27230612 TI - Role of connexins and pannexins during ontogeny, regeneration, and pathologies of bone. AB - Electron micrographs revealed the presence of gap junctions in osteoblastic cells over 40 years ago. These intercellular channels formed from connexins are present in bone forming osteoblasts, bone resorbing osteoclasts, and osteocytes (mature osteoblasts embedded in the mineralized bone matrix). More recently, genetic and pharmacologic studies revealed the role of connexins, and in particular Cx43, in the differentiation and function of all bone types. Furthermore, mutations in the gene encoding Cx43 were found to be causally linked to oculodentodigital dysplasia, a condition that results in an abnormal skeleton. Pannexins, molecules with similar structure and single-membrane channel forming potential as connexins when organized as hemichannels, are also expressed in osteoblastic cells. The function of pannexins in bone and cartilage is beginning to be uncovered, but more research is needed to determine the role of pannexins in bone development, adult bone mass and skeletal homeostasis. We describe here the current knowledge on the role of connexins and pannexins on skeletal health and disease. PMID- 27230615 TI - Effect of operating conditions on the performances of multichannel ceramic UF membranes for textile mercerization wastewater treatment. AB - Textile wastewaters are rated as one of the most polluting in all industrial sectors, and membrane separation is the most promising technology for their treatment and reuse of auxiliary chemicals. This study evaluates the performance of three types of tubular ceramic ultrafiltration membranes differing by mean pore size (1, 2 and 500 kDa) treating textile mercerization wastewater from a textile mill at different operating conditions: cross-flow velocity (CFV) and temperature. Acceptable results were obtained with 1 kDa ceramic membrane, with rejection efficiencies 92% for suspended solids, 98% for turbidity, 98% for color and 53% for total organic carbon at 20 degrees C and 3 m s-1 CFV. Highest fouling effect was observed for 500 kDa membrane and lowest CFV. According to the observed results, 1 kDa membrane could be used for the treatment of wastewater from the textile mercerization process in terms of permeate quality. PMID- 27230614 TI - The Associations Between Forced Sex and Severe Mental Health, Substance Use, and HIV Risk Behaviors Among Asian American Women. AB - We examined the association between forced sex history and mental health, sexual health, and substance use among Asian American women ( n = 720); 14.3% of our sample ( n = 103) reported forced sex experiences. Multiple logistic regression analyses revealed that participants with forced sex histories were 2-8 times more likely to have higher rates of mental health problems, HIV risk behavior, and substance use. Qualitative analysis was used to supplement the quantitative results and give depth to our findings. Our results suggest that interventions for Asian American women who experienced forced sex should integrate mental health, substance use, and sexual health treatments. PMID- 27230616 TI - Minimising impairment: Protocol for a multicentre randomised controlled trial of upper limb orthoses for children with cerebral palsy. AB - BACKGROUND: Upper limb orthoses are frequently prescribed for children with cerebral palsy (CP) who have muscle overactivity predominantly due to spasticity, with little evidence of long-term effectiveness. Clinical consensus is that orthoses help to preserve range of movement: nevertheless, they can be complex to construct, expensive, uncomfortable and require commitment from parents and children to wear. This protocol paper describes a randomised controlled trial to evaluate whether long-term use of rigid wrist/hand orthoses (WHO) in children with CP, combined with usual multidisciplinary care, can prevent or reduce musculoskeletal impairments, including muscle stiffness/tone and loss of movement range, compared to usual multidisciplinary care alone. METHODS/DESIGN: This pragmatic, multicentre, assessor-blinded randomised controlled trial with economic analysis will recruit 194 children with CP, aged 5-15 years, who present with flexor muscle stiffness of the wrist and/or fingers/thumb (Modified Ashworth Scale score >=1). Children, recruited from treatment centres in Victoria, New South Wales and Western Australia, will be randomised to groups (1:1 allocation) using concealed procedures. All children will receive care typically provided by their treating organisation. The treatment group will receive a custom-made serially adjustable rigid WHO, prescribed for 6 h nightly (or daily) to wear for 3 years. An application developed for mobile devices will monitor WHO wearing time and adverse events. The control group will not receive a WHO, and will cease wearing one if previously prescribed. Outcomes will be measured 6 monthly over a period of 3 years. The primary outcome is passive range of wrist extension, measured with fingers extended using a goniometer at 3 years. Secondary outcomes include muscle stiffness, spasticity, pain, grip strength and hand deformity. Activity, participation, quality of life, cost and cost-effectiveness will also be assessed. DISCUSSION: This study will provide evidence to inform clinicians, services, funding agencies and parents/carers of children with CP whether the provision of a rigid WHO to reduce upper limb impairment, in combination with usual multidisciplinary care, is worth the effort and costs. TRIAL REGISTRATION: ANZ Clinical Trials Registry: U1111-1164-0572 . PMID- 27230617 TI - A cross sectional evaluation of a total smoking ban at a large Australian university. AB - BACKGROUND: Total smoking bans have been found to contribute positively to the health of non-smokers by reducing exposure to second-hand smoke, and to enhance the likelihood of cessation among smokers. METHODS: Two cross-sectional electronic surveys of staff and students at a large Australian university were conducted prior (n = 969) and 1 year post (n = 670) the implementation of a smoke free campus policy. Demographics, tobacco use, intention to quit, attitudes towards smoking and smoking restrictions and awareness of and attitudes towards the campus smoking policy were measured. RESULTS: Exposure to second-hand smoke (SHS) reduced significantly (p < 0.001) one year after policy implementation. Smoking prevalence was similar at both time periods (T1 9.3 %; T2 8.4 %) and over half of smokers indicated they were planning to quit smoking in the future (T1 65.5 vs T2 62.3 %). There was a significant increase in positive responses to the statement the campus should be totally smoke free including all outdoor areas at T2 compared to T1 (T1 60.8 vs T2 71.4 %; p < 0.001), however respondents felt there should be places on campus for smokers to smoke (T1 53.6 vs T2 47 %; p < 0.05). CONCLUSIONS: This study found a significant positive difference in exposure SHS after implementation of the total ban. Although prevalence of smoking in this study was low, the proportion of respondents who were contemplating smoking cessation suggests support for smokers would be beneficial. Continued awareness raising, education and enforcement is likely to enhance the long term outcomes of the total ban. PMID- 27230618 TI - Characterization of an Alpha Type Carbonic Anhydrase from Paracentrotus lividus Sea Urchin Embryos. AB - Carbonic anhydrases (CA) are zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide to bicarbonate. In the sea urchin, CA has a role in the formation of the calcitic skeleton during embryo development. Here, we report a newly identified mRNA sequence from embryos of the sea urchin Paracentrotus lividus, referred to as Pl-can. The complete coding sequence was identified with the aid of both EST databases and experimental procedures. Pl-CAN is a 447 aa long protein, with an estimated molecular mass of 48.5 kDa and an isoelectric point of 6.83. The in silico study of functional domains showed, in addition to the alpha type CA-specific domain, the presence of an unexpected glycine-rich region at the N-terminal of the molecule. This is not found in any other species described so far, but probably it is restricted to the sea urchins. The phylogenetic analysis indicated that Pl-CAN is evolutionarily closer to human among chordates than to other species. The putative role(s) of the identified domains is discussed. The Pl-can temporal and spatial expression profiles, analyzed throughout embryo development by comparative qPCR and whole-mount in situ hybridization (WMISH), showed that Pl-can mRNA is specifically expressed in the primary mesenchyme cells (PMC) of the embryo and levels increase along with the growth of the embryonic skeleton, reaching a peak at the pluteus stage. A recombinant fusion protein was produced in E. coli and used to raise specific antibodies in mice recognized the endogenous Pl-CAN by Western blot in embryo extracts from gastrula and pluteus. PMID- 27230619 TI - Changing Nomenclature for PBC from "Primary Biliary Cirrhosis" to "Primary Biliary Cholangitis". PMID- 27230621 TI - A comparison of the doses received by normal cranial tissues during different simple model conventional radiotherapeutic approaches to pituitary tumours. AB - This aim of this study was to compare the doses received by critical cranial organs when three different radiation techniques were used to treat pituitary tumours. Cranial computed tomography scans of a RANDO phantom and 30 patients were used for pituitary macroadenoma radiotherapy treatment planning. For each slice, target volumes and other critical organs were contoured and three techniques were applied: (A) two parallel-opposed lateral fields, (B) two oblique fields (45 degrees ) in coronal plane and (C) two parallel-opposed lateral and anterior fields while the head was tilted 45 degrees in the sagittal plane. The doses received by the target volume and the critical organs for each technique were calculated for all patients. Irradiation was repeated three times for each technique. Finally, the doses that reached the organs of interest resulting from these techniques were compared. The dose delivered to the temporal lobes was 105, 9 and 72 % of the prescribed dose using techniques A, B and C, respectively. The dose received by the cochlea was the lowest in technique C (27 % of prescribed dose) compared with techniques A (79 %) and B (48 %). All techniques delivered 100 % of the prescribed dose to the chiasma. Technique A increased the dose to temporal lobes and the cochlea to such an extent that they exceeded the tolerance dose. Technique B spared the temporal lobes better than technique C; however, technique C was preferred since the dose received by the cochlea in this case was the lowest of all techniques. None of the techniques spared the chiasma. PMID- 27230620 TI - Cytogenetic profiles of 2806 patients with acute myeloid leukemia-a retrospective multicenter nationwide study. AB - The cytogenetic and molecular data is recognized as the most valuable prognostic factor in acute myeloid leukemia (AML). Our aim was to systemically analyze the cytogenetics of Korean AML patients and to compare the cytogenetic profiles of various races to identify possible geographic heterogeneity. We retrospectively reviewed medical records of 2806 AML patients diagnosed at 11 tertiary teaching hospitals in Korea between January 2007 and December 2011. The most common recurrent chromosomal abnormality was t(8;21) (8.8 %, 238/2717), but t(15;17) showed an almost same number (8.6 %,235/2717). Among de novo AML, the most frequent aberrations were t(15;17), observed in 229 (10.7 %). The most common French-American-British (FAB) classification type was M2 (32.2 %), and recurrent cytogenetic abnormalities correlated with the FAB subtypes. Among 283 secondary AML cases, myelodysplastic syndrome was the most common predisposing factor. About 67.1 % of the secondary AML cases were associated with chromosomal aberrations, and chromosome 7 abnormalities (n = 45, 15.9 %) were most common. The incidence of FLT3 internal tandem duplication mutation was relatively low at 15 %. Our study reports certain similarities and differences in comparison to previous reports. Such discrepancies call for extensive epidemiological studies to clarify the role of genetic as well as geographic heterogeneity in the pathogenesis of AML. PMID- 27230622 TI - The impact of a failing right heart in patients supported by intra-aortic balloon counterpulsation. AB - BACKGROUND: Intra-aortic balloon pumps (IABPs) provide primarily left ventricular support, yet few data detail the efficacy of this temporary mechanical circulatory support device in patients with concomitant right ventricular failure. We compared the efficacy of IABPs in cardiogenic shock patients with isolated left ventricular versus biventricular failure. METHODS: IABP-treated cardiogenic shock patients were identified from our center between 2006 and 2012, with patients stratified by either isolated left ventricular failure or biventricular failure. We compared baseline characteristics and 72-hour and 30 day outcomes between groups. Outcomes of interest included escalation of mechanical circulatory support, a clinical definition of IABP failure, and death. RESULTS: Among 107 patients, 60 patients (56%) had isolated left ventricular failure compared with 47 patients (44%) having biventricular failure. Patients with isolated left ventricular failure were older and more likely to have coronary artery disease ( p<0.05, both). Patients with biventricular failure more often required escalation of mechanical circulatory support at both 72 hours (21% vs. 2%, p<0.001) and 30 days (36% vs. 30%). However, there was no significant difference between groups for failure of IABP therapy at 72 hours ( p=0.27) or at 30 days ( p=0.62) and death at 30 days ( p=0.98). In adjusted analysis, there was no significant difference between groups with regard to risk for a clinical definition of IABP failure at 30 days (odds ratio=0.85, 95% confidence interval (0.27, 2.69)). CONCLUSIONS: IABP-treated cardiogenic shock patients with biventricular failure more often required early escalation of mechanical circulatory support. However, there were no significant differences by type of ventricular failure with regard to 30-day outcomes. PMID- 27230623 TI - Predictors, Morbidity, and Costs Associated with Pneumothorax during Electronic Cardiac Device Implantation. AB - BACKGROUND: Pneumothorax (PTX) is a major cause of morbidity associated with cardiac implantable electronic devices (CIEDs). We sought to evaluate predictors of PTX at our centers during CIED implantations, including the venous access technique utilized, as well as to determine morbidity and costs associated with PTX. METHODS: We reviewed records of all patients undergoing cardiac device implant or revision with new venous access at our institutions between 2008 and 2014. Common demographic and procedure characteristics were collected including age, sex, body mass index (BMI), comorbidities, and method of venous access (axillary vein vs classic proximal subclavian vein technique). RESULTS: We identified 1,264 patients who met criteria for our analysis, with a total of 21 PTX cases during CIED implantation. The strongest predictor for PTX was the venous access strategy: 0 of 385 (0%) patients with axillary vein approach versus 21 of 879 (2.4%) with traditional subclavian vein approach, P = 0.0006. Additional predictors of PTX included advanced age, female sex, low BMI, and a new device implant (vs device upgrade). The occurrence of PTX was associated with increased length of stay: 3.0 days (median; interquartile range [IQR] 3) versus 1.0 day (median; IQR: 1), P = 0.0001, with a cost increase of 361.4%. CONCLUSION: An axillary vein vascular access strategy was associated with greatly reduced risk of iatrogenic PTX versus the traditional subclavian approach for CIED placement. Similarly, device upgrade with patent vascular access carried less risk of PTX compared to new device implantation. PTX occurrence significantly prolonged hospitalization and increased costs. PMID- 27230624 TI - A visual assay and spectrophotometric determination of LLM-105 explosive using detection of gold nanoparticle aggregation at two pH values. AB - We report a simple, rapid, and sensitive assay for visual and spectrophotometric detection of the 2,6-diamino-3,5-dinitropyrazine-1-oxide (LLM-105) explosive. The assay is based on different interactions between LLM-105 and gold nanoparticle (AuNP) dispersions at two pH values, leading to the formation of dispersed or aggregated AuNPs. Two AuNP dispersions at two pH values were applied to recognize and detect LLM-105 instead of traditional AuNP dispersion under an aptotic pH to improve the anti-interference ability. The developed assay showed excellent sensitivity with a detection limit of 3 ng/mL, and the presence of as low as 0.2 MUg/mL LLM-105 can be directly detected with the bare eye. This sensitivity is about six orders of magnitude higher than that of the reported traditional assays. Additionally, the assay exhibited good selectivity toward LLM-105 over other explosives, sulfur-containing compounds, and amines. Graphical abstract A simple, sensitive, and selective assay for LLM-105 was developed based on the pH dependent interaction between the LLM-105 explosive and gold nanoparticle dispersion. PMID- 27230625 TI - Microscopic visualization of testosterone in mouse testis by use of imaging mass spectrometry. AB - Testosterone is one of the androgens synthesized from cholesterol as a precursor in the Leydig cells of testes. Since the ionization efficiency of testosterone in matrix-assisted laser desorption ionization (MALDI) is quite low, visualization of testosterone by using MALDI-imaging mass spectrometry (MALDI-IMS) has been considered difficult. To overcome this problem, we used two types of on-tissue derivatization techniques, which were achieved by pyridine sulfur trioxide and Girard's T (GT) reagent, to introduce a polar group into testosterone molecule with the aim to increase the sensitivity. Derivatization by use of GT reagent provided excellent results, superior to those obtained with pyridine sulfur trioxide, in terms of ionization efficiency, molecular specificity, and tissue damage. In GT derivatized testis tissues of mice treated with human chorionic gonadotropin (hCG), testosterone was broadly observed both inside and outside the seminiferous tubules by using an iMScope. To evaluate our imaging results, we performed quantification experiments of underivatized testosterone extracted from hCG-treated testes and control testes using LC-MS/MS. We confirmed the 256-fold concentration change between hCG-treated tissues and control tissues. We also confirmed the 228-fold change in detected peak intensities between hCG-treated tissue sections and control tissue sections in imaging results. We consider our tissue preparation methods for IMS provide high sensitivity with high precision. In addition, high-spatial definition IMS was also available, and we confirmed testosterone had mainly accumulated on the surface of the Leydig cells. Graphical abstract Girard's T-testosterone (GT-Ts) provides the fragment ion at m/z 343.24. Clear GT-Ts signal was detected in hCG treated mouse testis not only as spectra but also as a mass image. PMID- 27230626 TI - First evaluation of bendiocarb in experimental huts using different substrates in Madagascar. AB - BACKGROUND: Indoor residual spraying with insecticide is recommended for malaria control in high-transmission settings. Determination of residual activity of insecticides is essential for the selection of appropriate indoor spraying policy. The present study was undertaken to evaluate the residual effect of bendiocarb, a carbamate insecticide used in Madagascar, on different indoor surfaces in order to elaborate future vector control interventions. METHODS: The residual activity of bendiocarb was evaluated in both experimental huts and houses. Tests in experimental huts on different substrates represented a small scale-field trials. The houses IRS performed in parallel of experimental huts IRS, was done to compare semi-field results and field results. Bioassays according to the World Health Organization (WHO) standard protocol were carried out on different substrates impregnated with bendiocarb using susceptible strains of Anopheles arabiensis and Aedes albopictus. RESULTS: Bendiocarb induced significantly high mortality in treated huts against exposed mosquito (p < 0.005) compared to untreated huts. The mortality is up to the WHO threshold of 80 % during 5 months post-treatment. Using a multivariate analysis, Ae. albopictus mortality decreased significantly from the 3rd month post-treatment. However, An. arabiensis mortality decreased significantly from the 4th month after treatment. Comparing mosquito mortality results from the mud experimental huts and the mud houses showed no significant difference regarding the persistence of bendiocarb on wall. CONCLUSIONS: Current data suggest variable persistence of bendiocarb according to the type of wall surfaces, highlighting the importance of testing insecticide for IRS in local context before using them in large scale. Data from this study validate also the importance of using experimental huts as representative tool to evaluate the effectiveness of an insecticide. PMID- 27230627 TI - A 16q12.2q21 deletion identified in a patient with developmental delay, epilepsy, short stature, and distinctive features. AB - Interstitial deletions of the 16q centromeric region are rarely reported. A microdeletion of the 16q12.2q21 region was identified in a patient with intellectual disability, epilepsy, short stature, and distinctive features; including up-slanting palpebral fissures, hypertelorism, epicanthic folds, anteverted nares, simple philtrum, thin upper lip vermilion, high arched palate, posteriorly rotated ears, and overlapping toes in his right foot. Although the deleted region includes the genes responsible for neurological impairments (GNOA1, GPR56, KATNB1, and BBS2), haploinsufficiency of these genes would not be associated with the patient's phenotype. When NDRG4, present in the deleted region, was knocked out in mice, these mice exhibited spatial learning deficits. Thus, we hypothesize that this gene could be a potential candidate underlying the neurological observations of the patient. Because RSPRY1 was been discovered as the cause of progressive skeletal dysplasia, a loss of this gene might explain the skeletal defects observed in the patient. PMID- 27230628 TI - Attenuation of Adhesion, Biofilm Formation and Quorum Sensing of Campylobacter jejuni by Euodia ruticarpa. AB - Thermophilic campylobacters are a major cause of bacterial food-borne diarrhoeal disease. Adherence and biofilm formation are key elements of Campylobacter jejuni persistence in unfavourable environmental conditions. The phytochemical analysis of Euodia ruticarpa fruit ethanol solution extract (EREE) indicated that the major compounds were evodiamine (1), rutaecarpine (2) and evocarpine (9). E. ruticarpa fruit ethanol solution extract, compounds 1 and 2 as well as a mixture of quinolinone alkaloids with 41.7% of 9 were tested for antibacterial, antibiofilm and antiquorum sensing activities against C. jejuni. Minimal inhibitory concentrations varied from 64 to 1024 ug/mL. A mutant strain that lacks the functional gene coding for the CmeB efflux pump protein was the most susceptible. Interestingly, in addition to the wild-type (NCTC 11168) and cmeB mutant, also a mutant that lacks autoinducer-2 production (luxS) was able to adhere (1 h) and to produce a biofilm (24, 48 and 72 h). The subinhibitory concentrations of all preparations at least partly inhibited C. jejuni adhesion and biofilm formation with the most visible effect of the quinolinone alkaloid fraction. Using a Vibrio harveyi luminescence assay, the inhibition of autoinducer-2 production was observed in the wild-type and cmeB mutant after 48 h with the most visible effect of EREE and its fraction Q. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27230629 TI - Breast-feeding perceptions, beliefs and experiences of Marshallese migrants: an exploratory study. AB - OBJECTIVE: To determine perceptions, beliefs and experiences affecting breast feeding in Marshallese mothers residing in Northwest Arkansas, USA. DESIGN: A qualitative, exploratory study using a brief survey and focus groups. Marshallese women, 18 years or older who had a child under 7 years of age, were included in the study. SETTING: Community-based organization in Northwest Arkansas. RESULTS: The majority of mothers viewed breast milk as superior to formula, but had concerns about adequate milk supply and the nutritional value of their milk. The primary barriers to exclusive breast-feeding in the USA included public shaming (both verbal and non-verbal), perceived milk production and quality, and maternal employment. These barriers are not reported in the Marshall Islands and are encountered only after moving to the USA. Breast-feeding mothers rely heavily on familial support, especially the eldest female, who may not reside in the USA. The influence of institutions, including the Special Supplemental Nutrition Program for Women, Infants, and Children, is strong and may negatively affect breast-feeding. CONCLUSIONS: Despite the belief that breast milk is the healthiest option, breast-feeding among Marshallese mothers is challenged by numerous barriers they encounter as they assimilate to US cultural norms. The barriers and challenges, along with the strong desire to assimilate to US culture, impact Marshallese mothers' perceptions, beliefs and experiences with breast-feeding. PMID- 27230630 TI - Clinical features and long-term outcomes of bilateral Wilms tumor treated with Taiwan Pediatric Oncology Group protocols: A single center report. AB - AIMS: Wilms tumor (WT) is rare in Asia. Treatment of bilateral WT is challenging, and the treatment outcome of bilateral WT is rarely reported in low incidence areas. METHODS: We enrolled patients with bilateral WT registered in Chang Gung Memorial Hospital, Taoyuan, Taiwan, between January 1986 and June 2015. They were treated according to the Taiwan Pediatric Oncology Group (TPOG) protocols. The clinical features and long-term outcomes were analyzed. RESULTS: Six patients with histologically-proved bilateral WT were identified for analysis. One additional patient who was diagnosed with unilateral WT-associated intralobar nephrogenic rest, in addition to two small lesions in the contralateral kidney, was also included. There were total of three male patients and four female patients. The median follow-up period was 19 years (range 8-29 years). Five patients underwent initial biopsy and preoperative chemotherapy followed by surgery, whereas two patients underwent initial surgery followed by adjuvant chemotherapy. Local recurrence was found in two patients. The 8-year event-free survival and overall survival rates were 71.4% and 100%, respectively. Two patients developed advanced stage of chronic kidney disease, but none had been diagnosed with secondary malignant neoplasm. Other health issues such as hypertension, scoliosis and unspecified autoimmune disease were also found. CONCLUSIONS: The treatment outcome in this study is comparably superior to other western countries. However, survivors of bilateral WT still have many chronic health issues and thereby need individualized long-term medical care. PMID- 27230631 TI - Functionalized Conjugated Polyelectrolytes for Biological Sensing and Imaging. AB - Conjugated polyelectrolytes (CPEs) are macromolecules with highly delocalized pi conjugated backbones and charged side chains, which are unique types of active materials, with wide applications in optoelectronics, sensing, imaging, and therapy. By attaching specific groups (e.g., recognition elements, magnetic resonance (MR) contrast agents, gene carriers, and drugs) to the side chain or backbone of CPEs, functionalized CPEs have been developed and used for specific biological applications. In this account, we summarize the recent progress of functionalized CPEs with respect to their synthesis and biomedical applications. Future perspectives are also discussed at the end. PMID- 27230633 TI - Overcommitment to the conization volume can be a cause of the both under- and overtreatment. PMID- 27230632 TI - Heterogeneous effects of market integration on sub-adult body size and nutritional status among the Shuar of Amazonian Ecuador. AB - BACKGROUND: Market integration (MI)-increasing production for and consumption from a market-based economy-is drastically altering traditional ways of life and environmental conditions among indigenous Amazonian peoples. The effects of MI on the biology and health of Amazonian children and adolescents, however, remain unclear. AIM: This study examines the impact of MI on sub-adult body size and nutritional status at the population, regional and household levels among the Shuar of Amazonian Ecuador. SUBJECTS AND METHODS: Anthropometric data were collected between 2005-2014 from 2164 Shuar (aged 2-19 years) living in two geographic regions differing in general degree of MI. High-resolution household economic, lifestyle and dietary data were collected from a sub-sample of 631 participants. Analyses were performed to investigate relationships between body size and year of data collection, region and specific aspects of household MI. RESULTS: Results from temporal and regional analyses suggest that MI has a significant and overall positive impact on Shuar body size and nutritional status. However, household-level results exhibit nuanced and heterogeneous specific effects of MI underlying these overarching relationships. CONCLUSION: This study provides novel insight into the complex socio-ecological pathways linking MI, physical growth and health among the Shuar and other indigenous Amazonian populations. PMID- 27230634 TI - Response to the Editor. PMID- 27230635 TI - Removal of fly-ash and dust particulate matters from syngas produced by gasification of coal by using a multi-stage dual-flow sieve plate wet scrubber. AB - In this work, fly-ash water scrubbing experiments were conducted in a three-stage lab-scale dual-flow sieve plate scrubber to observe the performance of scrubber in fly-ash removal at different operating conditions by varying the liquid rate, gas rate and inlet fly-ash loading. The percentage of fly-ash removal efficiency increases with increase in inlet fly-ash loading, gas flow rate and liquid flow rate, and height of the scrubber; 98.55% maximum percentage of fly-ash removal efficiency (etaFA) is achieved at 19.36 * 10(-4) Nm(3)/s gas flow rate (QG) and 48.183 * 10(-6) m(3)/s liquid flow rate (QL) at 25 * 10(-3) kg/Nm(3) inlet fly ash loading (CFA,i). A model has also been developed for the prediction of fly ash removal efficiency of the column using the experimental results. The predicted values calculated using the correlation matched well with the experimental results. Deviations observed between the experimental and the predicted values were less than 20%. PMID- 27230636 TI - Obesity, Diabetes, and Cardiovascular Diseases: A Compendium. PMID- 27230637 TI - Epigenetic Changes in Diabetes and Cardiovascular Risk. AB - Cardiovascular complications remain the leading causes of morbidity and premature mortality in patients with diabetes mellitus. Studies in humans and preclinical models demonstrate lasting gene expression changes in the vasculopathies initiated by previous exposure to high glucose concentrations and the associated overproduction of reactive oxygen species. The molecular signatures of chromatin architectures that sensitize the genome to these and other cardiometabolic risk factors of the diabetic milieu are increasingly implicated in the biological memory underlying cardiovascular complications and now widely considered as promising therapeutic targets. Atherosclerosis is a complex heterocellular disease where the contributing cell types possess distinct epigenomes shaping diverse gene expression. Although the extent that pathological chromatin changes can be manipulated in human cardiovascular disease remains to be established, the clinical applicability of epigenetic interventions will be greatly advanced by a deeper understanding of the cell type-specific roles played by writers, erasers, and readers of chromatin modifications in the diabetic vasculature. This review details a current perspective of epigenetic mechanisms of macrovascular disease in diabetes mellitus and highlights recent key descriptions of chromatinized changes associated with persistent gene expression in endothelial, smooth muscle, and circulating immune cells relevant to atherosclerosis. Furthermore, we discuss the challenges associated with pharmacological targeting of epigenetic networks to correct abnormal or deregulated gene expression as a strategy to alleviate the clinical burden of diabetic cardiovascular disease. PMID- 27230638 TI - Epidemiology of Obesity and Diabetes and Their Cardiovascular Complications. AB - Obesity and diabetes mellitus have reached epidemic proportions in the past few years. During 2011 to 2012, more than one-third of the US population was obese. Although recent trend data indicate that the epidemic has leveled off, prevalence of abdominal obesity continues to rise, especially among adults. As seen for obesity, the past few decades have seen a doubling of the diabetes mellitus incidence with an increasing number of type 2 diabetes mellitus cases being diagnosed in children. Significant racial and ethnic disparities exist in the prevalence and trends of obesity and diabetes mellitus. In general, in both adults and children, non-Hispanic blacks and Mexican Americans seem to be at a high risk than their non-Hispanic white counterparts. Secular changes in agricultural policies, diet, food environment, physical activity, and sleep have all contributed to the upward trends in the diabesity epidemic. Despite marginal improvements in physical activity and the US diet, the food environment has changed drastically to an obesogenic one with increased portion sizes and limited access to healthy food choices especially for disadvantaged populations. Interventions that improve the food environment are critical as both obesity and diabetes mellitus raise the risk of cardiovascular disease by ~2-fold. Among those with type 2 diabetes mellitus, significant sex differences occur in the risk of cardiovascular disease such that diabetes mellitus completely eliminates or attenuates the advantages of being female. Given the substantial burden of obesity and diabetes mellitus, future research efforts should adopt a translational approach to find sustainable and holistic solutions in preventing these costly diseases. PMID- 27230640 TI - Obesity and Cardiovascular Disease. AB - The prevalence of obesity has increased worldwide over the past few decades. In 2013, the prevalence of obesity exceeded the 50% of the adult population in some countries from Oceania, North Africa, and Middle East. Lower but still alarmingly high prevalence was observed in North America (~30%) and in Western Europe (~20%). These figures are of serious concern because of the strong link between obesity and disease. In the present review, we summarize the current evidence on the relationship of obesity with cardiovascular disease (CVD), discussing how both the degree and the duration of obesity affect CVD. Although in the general population, obesity and, especially, severe obesity are consistently and strongly related with higher risk of CVD incidence and mortality, the one-size-fits-all approach should not be used with obesity. There are relevant factors largely affecting the CVD prognosis of obese individuals. In this context, we thoroughly discuss important concepts such as the fat-but-fit paradigm, the metabolically healthy but obese (MHO) phenotype and the obesity paradox in patients with CVD. About the MHO phenotype and its CVD prognosis, available data have provided mixed findings, what could be partially because of the adjustment or not for key confounders such as cardiorespiratory fitness, and to the lack of consensus on the MHO definition. In the present review, we propose a scientifically based harmonized definition of MHO, which will hopefully contribute to more comparable data in the future and a better understanding on the MHO subgroup and its CVD prognosis. PMID- 27230641 TI - Vascular Complications of Diabetes. AB - Over the last several decades, the global incidence and prevalence of diabetes mellitus has increased significantly. The raised incidence rate is projected to continue as greater numbers of persons adopt a Western lifestyle and diet. Patients with diabetes mellitus are at heightened risk of both adverse microvascular and cardiovascular events. Moreover, once cardiovascular disease develops, diabetes mellitus exacerbates progression and worsens outcomes. The medical management of patients with diabetes mellitus mandates comprehensive risk factor modification and antiplatelet therapy. Recent clinical trials of new medical therapies continue to inform the care of patients with diabetes mellitus to reduce both cardiovascular morbidity and mortality. PMID- 27230639 TI - Lipid Use and Misuse by the Heart. AB - The heart utilizes large amounts of fatty acids as energy providing substrates. The physiological balance of lipid uptake and oxidation prevents accumulation of excess lipids. Several processes that affect cardiac function, including ischemia, obesity, diabetes mellitus, sepsis, and most forms of heart failure lead to altered fatty acid oxidation and often also to the accumulation of lipids. There is now mounting evidence associating certain species of these lipids with cardiac lipotoxicity and subsequent myocardial dysfunction. Experimental and clinical data are discussed and paths to reduction of toxic lipids as a means to improve cardiac function are suggested. PMID- 27230644 TI - Heart Failure Considerations of Antihyperglycemic Medications for Type 2 Diabetes. AB - Prevalent and incident heart failure (HF) is increased in people with type 2 diabetes mellitus, with risk directly associated with the severity of hyperglycemia. Furthermore, in patients with type 2 diabetes mellitus, mortality is increased ~10-fold in patients with versus without HF. Reducing HF with antihyperglycemic therapies, however, has been unsuccessful until recently. In fact, HF as an important outcome in patients with type 2 diabetes mellitus seems to be heterogeneously modulated by antihyperglycemic medications, as evidenced by results from cardiovascular outcome trials (CVOTs) and large observational cohort studies. Appropriately powered and executed CVOTs are necessary to truly evaluate cardiovascular safety and efficacy of new antihyperglycemic medications, as reflected by the guidance of the US Food and Drug Administration and other regulatory agencies since 2008. In light of the best available evidence at present, metformin and the sodium-glucose-co-transporter 2-inhibitor empagliflozin seem to be especially advantageous with regard to HF effects, with their use associated with reduced HF events and improved mortality. Acarbose, the dipeptidyl-peptidase 4-inhibitor sitagliptin, the glucagon-like peptide 1 receptor agonist lixisenatide based on presently available CVOT results comprise reasonable additional options, as significant harm in terms of HF has been excluded for those drugs. Additions to this list are anticipated pending results of ongoing CVOTs. Although no HF harm was seen in CVOTs for insulin or sulfonylureas, they should be used only with caution in patients with HF, given their established high risk for hypoglycemia and some uncertainties on their safety in patients with HF derived from epidemiological observations. Pioglitazone is contraindicated in patients with HF>New York Heart Association I, despite some benefits suggested by CVOT subanalyses. PMID- 27230643 TI - Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes. AB - The clinical correlations linking diabetes mellitus with accelerated atherosclerosis, cardiomyopathy, and increased post-myocardial infarction fatality rates are increasingly understood in mechanistic terms. The multiple mechanisms discussed in this review seem to share a common element: prolonged increases in reactive oxygen species (ROS) production in diabetic cardiovascular cells. Intracellular hyperglycemia causes excessive ROS production. This activates nuclear poly(ADP-ribose) polymerase, which inhibits GAPDH, shunting early glycolytic intermediates into pathogenic signaling pathways. ROS and poly(ADP-ribose) polymerase also reduce sirtuin, PGC-1alpha, and AMP-activated protein kinase activity. These changes cause decreased mitochondrial biogenesis, increased ROS production, and disturbed circadian clock synchronization of glucose and lipid metabolism. Excessive ROS production also facilitates nuclear transport of proatherogenic transcription factors, increases transcription of the neutrophil enzyme initiating NETosis, peptidylarginine deiminase 4, and activates the NOD-like receptor family, pyrin domain-containing 3 inflammasome. Insulin resistance causes excessive cardiomyocyte ROS production by increasing fatty acid flux and oxidation. This stimulates overexpression of the nuclear receptor PPARalpha and nuclear translocation of forkhead box O 1, which cause cardiomyopathy. ROS also shift the balance between mitochondrial fusion and fission in favor of increased fission, reducing the metabolic capacity and efficiency of the mitochondrial electron transport chain and ATP synthesis. Mitochondrial oxidative stress also plays a central role in angiotensin II induced gap junction remodeling and arrhythmogenesis. ROS contribute to sudden death in diabetics after myocardial infarction by increasing post-translational protein modifications, which cause increased ryanodine receptor phosphorylation and downregulation of sarco-endoplasmic reticulum Ca(++)-ATPase transcription. Increased ROS also depress autonomic ganglion synaptic transmission by oxidizing the nAch receptor alpha3 subunit, potentially contributing to the increased risk of fatal cardiac arrhythmias associated with diabetic cardiac autonomic neuropathy. PMID- 27230646 TI - Capturing the dynamic nascent transcriptome during acute cellular responses: The serum response. AB - Dynamic regulation of gene expression via signal transduction pathways is of fundamental importance during many biological processes such as cell state transitioning, cell cycle progression and stress responses. In this study we used serum stimulation as a cell response paradigm to apply the nascent RNA Bru-seq technique in order to capture early dynamic changes in the nascent transcriptome. Our data provides an unprecedented view of the dynamics of genome-wide transcription during the first two hours of serum stimulation in human fibroblasts. While some genes showed sustained induction or repression, other genes showed transient or delayed responses. Surprisingly, the dynamic patterns of induction and suppression of response genes showed a high degree of similarity, suggesting that these opposite outcomes are triggered by a common set of signals. As expected, early response genes such as those encoding components of the AP-1 transcription factor and those involved in the circadian clock were immediately but transiently induced. Surprisingly, transcription of important DNA damage response genes and histone genes were rapidly repressed. We also show that RNA polymerase II accelerates as it transcribes large genes and this was independent of whether the gene was induced or not. These results provide a unique genome-wide depiction of dynamic patterns of transcription of serum response genes and demonstrate the utility of Bru-seq to comprehensively capture rapid and dynamic changes of the nascent transcriptome. PMID- 27230645 TI - Treatment of Obesity: Weight Loss and Bariatric Surgery. AB - This review focuses on the mechanisms underlying, and indications for, bariatric surgery in the reduction of cardiovascular disease (CVD), as well as other expected benefits of this intervention. The fundamental basis for bariatric surgery for the purpose of accomplishing weight loss is the determination that severe obesity is a disease associated with multiple adverse effects on health, which can be reversed or improved by successful weight loss in patients who have been unable to sustain weight loss by nonsurgical means. An explanation of possible indications for weight loss surgery as well as specific bariatric surgical procedures is presented, along with review of the safety literature of such procedures. Procedures that are less invasive or those that involve less gastrointestinal rearrangement accomplish considerably less weight loss but have substantially lower perioperative and longer-term risk. The ultimate benefit of weight reduction relates to the reduction of the comorbidities, quality of life, and all-cause mortality. With weight loss being the underlying justification for bariatric surgery in ameliorating CVD risk, current evidence-based research is discussed concerning body fat distribution, dyslipidemia, hypertension, diabetes mellitus, inflammation, obstructive sleep apnea, and others. The rationale for bariatric surgery reducing CVD events is discussed and juxtaposed with impacts on all-cause mortalities. Given the improvement of established obesity-related CVD risk factors after weight loss, it is reasonable to expect a reduction of CVD events and related mortality after weight loss in populations with obesity. The quality of the current evidence is reviewed, and future research opportunities and summaries are stated. PMID- 27230647 TI - Genome-wide analysis of auxin response factor gene family members in medicinal model plant Salvia miltiorrhiza. AB - Auxin response factors (ARFs) can function as transcriptional activators or repressors to regulate the expression of auxin response genes by specifically binding to auxin response elements (AuxREs) during plant development. Based on a genome-wide strategy using the medicinal model plant Salvia miltiorrhiza, 25 S. miltiorrhiza ARF (SmARF) gene family members in four classes (class Ia, IIa, IIb and III) were comprehensively analyzed to identify characteristics including gene structures, conserved domains, phylogenetic relationships and expression patterns. In a hybrid analysis of the phylogenetic tree, microRNA targets, and expression patterns of SmARFs in different organs, root tissues, and methyl jasmonate or indole-3-acetic acid treatment conditions, we screened for candidate SmARFs involved in various developmental processes of S. miltiorrhiza Based on this analysis, we predicted that SmARF25, SmARF7, SmARF16 and SmARF20 are involved in flower, leaf, stem and root development, respectively. With the further insight into the targets of miR160 and miR167, specific SmARF genes in S. miltiorrhiza might encode products that participate in biological processes as described for ARF genes in Arabidopsis Our results provide a foundation for understanding the molecular basis and regulatory mechanisms of SmARFs in S. miltiorrhiza. PMID- 27230648 TI - Sipa1l1 is an early biomarker of liver fibrosis in CCl4-treated rats. AB - At present, several procedures are used for staging liver fibrosis. However, these methods may involve clinical complications and/or present diagnostic uncertainty mainly in the early stages of the disease. Thus, this study was designed to unveil new non-invasive biomarkers of liver fibrosis in an in vivo model of fibrosis/cirrhosis induction by CCl4 inhalation by using a label-free quantitative LC-MS/MS approach. We analyzed 94 serum samples from adult Wistar rats with different degrees of liver fibrosis and 36 control rats. Firstly, serum samples from 18 CCl4-treated rats were clustered into three different groups according to the severity of hepatic and the serum proteome was characterized by label-free LC-MS/MS. Furthermore, three different pooled serum samples obtained from 16 control Wistar rats were also analyzed. Based on the proteomic data obtained, we performed a multivariate analysis which displayed three main cell signaling pathways altered in fibrosis. In cirrhosis, more biological imbalances were detected as well as multi-organ alterations. In addition, hemopexin and signal-induced proliferation-associated 1 like 1 (SIPA1L1) were selected as potential serum markers of liver fibrogenesis among all the analyzed proteins. The results were validated by ELISA in an independent group of 76 fibrotic/cirrhotic rats and 20 controls which confirmed SIPA1L1 as a potential non-invasive biomarker of liver fibrosis. In particular, SIPA1L1 showed a clear diminution in serum samples from fibrotic/cirrhotic rats and a great accuracy at identifying early fibrotic stages. In conclusion, the proteomic analysis of serum samples from CCl4-treated rats has enabled the identification of SIPA1L1 as a non invasive marker of early liver fibrosis. PMID- 27230649 TI - How low can they go when going with the flow? Tolerance of egg and larval fishes to rapid decompression. AB - Egg and larval fish that drift downstream are likely to encounter river infrastructure and consequently rapid decompression, which may result in significant injury. Pressure-related injury (or barotrauma) has been shown in juvenile fishes when pressure falls sufficiently below that at which the fish has acclimated. There is a presumption that eggs and larvae may be at least as, if not more, susceptible to barotrauma injury because they are far less-developed and more fragile than juveniles, but studies to date report inconsistent results and none have considered the relationship between pressure change and barotrauma over a sufficiently broad range of pressure changes to enable tolerances to be properly determined. To address this, we exposed eggs and larvae of three physoclistic species to rapid decompression in a barometric chamber over a broad range of discrete pressure changes. Eggs, but not larvae, were unaffected by all levels of decompression tested. At exposure pressures below ~40 kPa, or ~40% of surface pressure, swim bladder deflation occurred in all species and internal haemorrhage was observed in one species. None of these injuries killed the fish within 24 h, but subsequent mortality cannot be excluded. Consequently, if larval drift is expected where river infrastructure is present, adopting design or operational features which maintain exposure pressures at 40% or more of the pressure to which drifting larvae are acclimated may afford greater protection for resident fishes. PMID- 27230642 TI - Obesity-Induced Changes in Adipose Tissue Microenvironment and Their Impact on Cardiovascular Disease. AB - Obesity is causally linked with the development of cardiovascular disorders. Accumulating evidence indicates that cardiovascular disease is the collateral damage of obesity-driven adipose tissue dysfunction that promotes a chronic inflammatory state within the organism. Adipose tissues secrete bioactive substances, referred to as adipokines, which largely function as modulators of inflammation. The microenvironment of adipose tissue will affect the adipokine secretome, having actions on remote tissues. Obesity typically leads to the upregulation of proinflammatory adipokines and the downregulation of anti inflammatory adipokines, thereby contributing to the pathogenesis of cardiovascular diseases. In this review, we focus on the microenvironment of adipose tissue and how it influences cardiovascular disorders, including atherosclerosis and ischemic heart diseases, through the systemic actions of adipokines. PMID- 27230650 TI - Unveiling the pan-genome of the SXT/R391 family of ICEs: molecular characterisation of new variable regions of SXT/R391-like ICEs detected in Pseudoalteromonas sp. and Vibrio scophthalmi. AB - Integrating conjugative elements (ICEs) of the SXT/R391 family have been identified in fish-isolated bacterial strains collected from marine aquaculture environments of the northwestern Iberian Peninsula. Here we analysed the variable regions of two ICEs, one preliminarily characterised in a previous study (ICEVscSpa3) and one newly identified (ICEPspSpa1). Bacterial strains harboring these ICEs were phylogenetically assigned to Vibrio scophthalmi and Pseudoalteromonas sp., thus constituting the first evidence of SXT/R391-like ICEs in the genus Pseudoalteromonas to date. Variable DNA regions, which confer element-specific properties to ICEs of this family, were characterised. Interestingly, the two ICEs contained 29 genes not found in variable DNA insertions of previously described ICEs. Most notably, variable gene content for ICEVscSpa3 showed similarity to genes potentially involved in housekeeping functions of replication, nucleotide metabolism and transcription. For these genes, closest homologues were found clustered in the genome of Pseudomonas psychrotolerans L19, suggesting a transfer as a block to ICEVscSpa3. Genes encoding antibiotic resistance, restriction modification systems and toxin/antitoxin systems were absent from hotspots of ICEVscSpa3. In contrast, the variable gene content of ICEPspSpa1 included genes involved in restriction/modification functions in two different hotspots and genes related to ICE maintenance. The present study unveils a relatively large number of novel genes in SXT/R391-ICEs, and demonstrates the major role of ICE elements as contributors to horizontal gene transfer. PMID- 27230652 TI - Pathological complete response after percutaneous isolated hepatic perfusion in hepatocellular carcinoma with portal vein tumor thrombosis: a case report. AB - BACKGROUND: Although the effectiveness of perioperative adjuvant therapy in the treatment of hepatocellular carcinoma (HCC) has been investigated, the efficacy of preoperative therapy is unclear. Herein, we report a case of pathological complete response after percutaneous isolated hepatic perfusion (PIHP) for HCC involving portal vein tumor thrombosis (PVTT). CASE PRESENTATION: A 77-year-old woman was referred to our institute with a liver mass detected on a routine health screening. Computed tomography revealed a 28 * 25 mm HCC in the left lobe of the liver and a tumor thrombus in the left and right portal branches (T4N0M0, stage IVA). The patient received a single dose of preoperative PIHP with doxorubicin plus mitomycin C, without severe toxicity. After the chemotherapy, she underwent extended left hepatic lobectomy and thrombectomy of the PVTT. No cancer cells were detected during histopathological analysis, indicating pathological complete response. She remained relapse-free 12 months after the surgery. CONCLUSIONS: We experienced a case of pathological complete response after preoperative PIHP with doxorubicin plus mitomycin C for HCC involving PVTT. PMID- 27230651 TI - Current views on anthracycline cardiotoxicity. AB - Anthracyclines are well established and effective anticancer agents used to treat a variety of adult and pediatric cancers. Unfortunately, these drugs are also among the commonest chemotherapeutic agents that have been recognized to cause cardiotoxicity. In the last years, several experimental and clinical investigations provided new information and perspectives on anthracycline-related cardiotoxicity. In particular, molecular mechanisms of cardiotoxicity have been better elucidated, early diagnosis has improved through the use of advanced noninvasive cardiac imaging techniques, and emerging data indicate a genetic predisposition to develop anthracycline-related cardiotoxicity. In this article, we review established and new knowledge about anthracycline cardiotoxicity, with special focus on recent advances in cardiotoxicity diagnosis and genetic profiling. PMID- 27230653 TI - Single-site laparoscopic right hemicolectomy for acute cecal volvulus: a case report. AB - BACKGROUND: Cecal volvulus is an uncommon cause of acute abdomen in patients. Cecal volvulus is currently treated mostly with right hemicolectomy with laparotomy, which is an invasive surgical procedure. Less invasive techniques, such as endoscopic decompression, have a poor success rate. CASE PRESENTATION: We report a case of cecal volvulus in a 35-year-old male patient. He was successfully treated with single-site laparoscopic decompression by inserting a catheter through the amputated appendix, detorsion, and hemicolectomy. This approach was less invasive than the traditional approach and resulted in satisfactory outcomes and cosmesis. CONCLUSIONS: Application of single-site laparoscopic colectomy to acute cecal volvulus is feasible using decompression of the dilated colon by inserting a catheter through the amputated appendix. To the best of our knowledge, this is the first report of this treatment. PMID- 27230654 TI - Medicine and management: looking inside the box of changing hospital governance. AB - BACKGROUND: Health policy has strengthened the demand for coordination between clinicians and managers and introduced new medical manager roles in hospitals to better connect medicine and management. These developments have created a scholarly debate of concepts and an increasing 'hybridization' of tasks and roles, yet the organizational effects are not well researched. This research introduces a multi-level governance approach and aims to explore the organizational needs of doctors using Sweden as a case study. METHODS: We apply an assessment framework focusing on macro-meso levels and managerial-professional modes of hospital governance (using document analysis, secondary sources, and expert information) and expand the analysis towards the micro-level. Qualitative explorative empirical material gathered in two different studies in Swedish hospitals serves to pilot research into actor-centred perceptions of clinical management from the viewpoint of the 'managed' and the 'managing' doctors in an organization. RESULTS: Sweden has developed a model of integrated hospital governance with complex structural coordination between medicine and management on the level of the organization. In terms of formal requirements, the professional background is less relevant for many management positions but in everyday work, medical managers are perceived primarily as colleagues and not as experts advising on managerial problems. The managers themselves seem to rely more on personal strength and medical knowledge than on management tools. Bringing doctors into management may hybridize formal roles and concepts, but it does not necessarily change the perceptions of doctors and improve managerial professional coordination at the micro-level of the organization. CONCLUSION: This study brings gaps in hospital governance into view that may create organizational weaknesses and unmet management needs, thereby constraining more coordinated and integrated medical management. PMID- 27230656 TI - MiRNA-211 suppresses cell proliferation, migration and invasion by targeting SPARC in human hepatocellular carcinoma. AB - Previous studies have shown that the expression of miR-211 was downregulated in hepatocellular carcinoma (HCC). However, the molecular function and mechanism of miR-211 in HCC growth and invasion are largely unclear. We found that miR-211 is downregulated in HCC tissues and cell lines, respectively. Further results showed that low miR-211 associated with TNM stage, vein invasion status, and poor prognosis. Ectopic expression of miR-211 effectively suppressed HCC cell proliferation, migration and invasion both in vitro and in vivo. We identified SPARC as a bona fide target of miR-211, and overexpression of miR-211 decreased the mRNA and protein expression of SPARC. Finally, we confirmed that the overexpression of SPARC in miR-211-expressing HCC cells can partially restore the inhibitory effect of miR-211. Taken together, our results demonstrated that loss of miR-211 expression and thus uncontrolled SPARC overexpression might drive progression of HCC, which may provide a novel therapeutic strategy for the treatment of HCC. PMID- 27230658 TI - Microbiota-Derived Phenylacetylglutamine Associates with Overall Mortality and Cardiovascular Disease in Patients with CKD. AB - Colonic microbial metabolism substantially contributes to uremic solute production. p-Cresyl sulfate and indoxyl sulfate are the main representatives of solutes of microbial origin and also, protein-bound solutes, exhibiting high protein-binding affinity and dependence on tubular secretion. Phenylacetylglutamine is another microbial metabolite with high dependence on tubular secretion but low protein-binding affinity. The relevance of such solutes is unknown. Therefore, we prospectively followed 488 patients with CKD stages 1-5 and a measurement of serum phenylacetylglutamine by liquid chromatography-mass spectrometry. In a subgroup, we determined 24-hour urinary excretion as a surrogate of intestinal uptake as well as renal clearance of phenylacetylglutamine. We performed outcome analysis for mortality (51 events) and cardiovascular disease (75 events). Serum phenylacetylglutamine level correlated with 24-hour urinary excretion (rho=0.55; P<0.001) and clearance of phenylacetylglutamine (rho=-0.76; P<0.001). Phenylacetylglutamine clearance also correlated with eGFR (rho=0.84; P<0.001). Furthermore, serum phenylacetylglutamine level associated with mortality (hazard ratio per 1-SD increase, 1.77; 95% confidence interval, 1.22 to 2.57; P=0.003) and cardiovascular disease (hazard ratio, 1.79; 95% confidence interval, 1.32 to 2.41; P<0.001) after adjustment for age, sex, presence of diabetes mellitus, prior cardiovascular disease, and eGFR. Thus, serum phenylacetylglutamine level is elevated in patients with more advanced CKD and determined by intestinal uptake and renal clearance, and it is not fully accounted for by differences in eGFR. High serum phenylacetylglutamine level is a strong and independent risk factor for mortality and cardiovascular disease, suggesting the relevance of microbial metabolism and/or tubular dysfunction in CKD, irrespective of protein binding. PMID- 27230657 TI - Genome-wide identification of microRNAs in pomegranate (Punica granatum L.) by high-throughput sequencing. AB - BACKGROUND: MicroRNAs (miRNAs), a class of small non-coding endogenous RNAs that regulate gene expression post-transcriptionally, play multiple key roles in plant growth and development and in biotic and abiotic stress response. Knowledge and roles of miRNAs in pomegranate fruit development have not been explored. RESULTS: Pomegranate, which accumulates a large amount of anthocyanins in skin and arils, is valuable to human health, mainly because of its antioxidant properties. In this study, we developed a small RNA library from pooled RNA samples from young seedlings to mature fruits and identified both conserved and pomegranate-specific miRNA from 29,948,480 high-quality reads. For the pool of 15- to 30-nt small RNAs, ~50 % were 24 nt. The miR157 family was the most abundant, followed by miR156, miR166, and miR168, with variants within each family. The base bias at the first position from the 5' end had a strong preference for U for most 18- to 26-nt sRNAs but a preference for A for 18-nt sRNAs. In addition, for all 24-nt sRNAs, the nucleotide U was preferred (97 %) in the first position. Stem-loop RT qPCR was used to validate the expression of the predominant miRNAs and novel miRNAs in leaves, male and female flowers, and multiple fruit developmental stages; miR156, miR156a, miR159a, miR159b, and miR319b were upregulated during the later stages of fruit development. Higher expression of miR156 in later fruit developmental may positively regulate anthocyanin biosynthesis by reducing SPL transcription factor. Novel miRNAs showed variation in expression among different tissues. These novel miRNAs targeted different transcription factors and hormone related regulators. Gene ontology and KEGG pathway analyses revealed predominant metabolic processes and catalytic activities, important for fruit development. In addition, KEGG pathway analyses revealed the involvement of miRNAs in ascorbate and linolenic acid, starch and sucrose metabolism; RNA transport; plant hormone signaling pathways; and circadian clock. CONCLUSION: Our first and preliminary report of miRNAs will provide information on the synthesis of biochemical compounds of pomegranate for future research. The functions of the targets of the novel miRNAs need further investigation. PMID- 27230659 TI - Acute kidney injury prediction in cardiac surgery patients by a urinary peptide pattern: a case-control validation study. AB - BACKGROUND: Acute kidney injury (AKI) is a prominent problem in hospitalized patients and associated with increased morbidity and mortality. Clinical medicine is currently hampered by the lack of accurate and early biomarkers for diagnosis of AKI and the evaluation of the severity of the disease. In 2010, we established a multivariate peptide marker pattern consisting of 20 naturally occurring urinary peptides to screen patients for early signs of renal failure. The current study now aims to evaluate if, in a different study population and potentially various AKI causes, AKI can be detected early and accurately by proteome analysis. METHODS: Urine samples from 60 patients who developed AKI after cardiac surgery were analyzed by capillary electrophoresis-mass spectrometry (CE-MS). The obtained peptide profiles were screened by the AKI peptide marker panel for early signs of AKI. Accuracy of the proteomic model in this patient collective was compared to that based on urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) ELISA levels. Sixty patients who did not develop AKI served as negative controls. RESULTS: From the 120 patients, 110 were successfully analyzed by CE-MS (59 with AKI, 51 controls). Application of the AKI panel demonstrated an AUC in receiver operating characteristics (ROC) analysis of 0.81 (95 % confidence interval: 0.72-0.88). Compared to the proteomic model, ROC analysis revealed poorer classification accuracy of NGAL and KIM-1 with the respective AUC values being outside the statistical significant range (0.63 for NGAL and 0.57 for KIM-1). CONCLUSIONS: This study gives further proof for the general applicability of our proteomic multimarker model for early and accurate prediction of AKI irrespective of its underlying disease cause. PMID- 27230660 TI - Spatial analysis of gender variation in the prevalence of hypertension among the middle-aged and elderly population in Zhejiang Province, China. AB - BACKGROUND: Previous studies have shown that there may be gender disparities in the prevalence of hypertension; however, these studies do not address the spatial information contained in the sample which may limit the analytical results. Our study extends the existing Shared Component Model (SCM) and compares its utility with a logistic regression model to evaluate the significance of spatial information for identifying risk factors for hypertension and other non-rare diseases. METHODS: A total of 1267 residents aged 45 years of age and over were included in our study, of which 48.1 % were males. The overall prevalence of hypertension was 33.2 %, with females experiencing a higher prevalence than males (35.5 % vs. 30.6 %). The research variables included body mass index (BMI), Waist -to-Height Ratio (WHtR), smoking status, alcohol consumption etc. The extended SCM is employed to investigate regional gender variations in the risk of hypertension and assess the gender variation in the middle-aged and elderly populations of Zhejiang Province in eastern China and then its performance is compared with that of a traditional multiple logistic regression model. RESULTS: Our SCM analysis determined that the spatial pattern of hypertension risk for the middle-aged and elderly populations of Zhejiang Province in eastern China is quite different for males and females. Furthermore, Waist -to-Height Ratio (WHtR) continues to be a simple and effective predictor of hypertension risk for males at the regional level. CONCLUSIONS: We believe that the extended SCM spatial model is a useful tool for identifying risk factors at the regional level. PMID- 27230662 TI - Piglet nasal microbiota at weaning may influence the development of Glasser's disease during the rearing period. AB - BACKGROUND: The microbiota, the ensemble of microorganisms on a particular body site, has been extensively studied during the last few years, and demonstrated to influence the development of many diseases. However, these studies focused mainly on the human digestive system, while the populations in the respiratory tract have been poorly assessed, especially in pigs. The nasal mucosa of piglets is colonized by an array of bacteria, many of which are unknown. Among the early colonizers, Haemophilus parasuis also has clinical importance, since it is also the etiological agent of Glasser's disease. This disease produces economical losses in all the countries with pig production, and the factors influencing its development are not totally understood. Hence, the purpose of this work was to characterize the nasal microbiota composition of piglets, and its possible role in Glasser's disease development. RESULTS: Seven farms from Spain (4 with Glasser's disease and 3 control farms without any respiratory disease) and three farms from UK (all control farms) were studied. Ten piglets from each farm were sampled at 3-4 weeks of age before weaning. The total DNA extracted from nasal swabs was used to amplify the 16S RNA gene for sequencing in Illumina MiSeq. Sequencing data was quality filtered and analyzed using QIIME software. The diversity of the nasal microbiota was low in comparison with other body sites, showing a maximum number of operational taxonomic units (OTUs) per pig of 1,603, clustered in five phyla. Significant differences were found at various taxonomical levels, when the microbiota was compared regarding the farm health status. Healthy status was associated to higher species richness and diversity, and UK farms demonstrated the highest diversity. CONCLUSIONS: The composition of the nasal microbiota of healthy piglets was uncovered and different phylotypes were shown to be significantly altered in animals depending on the clinical status of the farm of origin. Several OTUs at genus level were identified over represented in piglets from control farms, indicating their potential as probiotics. Although we provide relevant data, fully metagenomic approaches could give light on the genes and metabolic pathways involved in the roles of the nasal microbiota to prevent respiratory diseases. PMID- 27230664 TI - Catastrophic surgery and the legal issues. PMID- 27230663 TI - Pharmacologic rationale for the NK1R antagonist, aprepitant as adjunctive therapy in HIV. AB - BACKGROUND: Many HIV infected individuals with suppressed viral loads experience chronic immune activation frequently developing neurological impairment designated as HIV associated neurocognitive disorder (HAND). Adjunctive therapies may reduce HIV associated inflammation and therefore decrease the occurrence of HAND. METHODS: We have conducted in vitro, animal and clinical studies of the neurokinin 1 receptor (NK1R) antagonist aprepitant in HIV/SIV infection. RESULTS: Aprepitant inhibits HIV infection of human macrophages ex vivo with an ED50 ~ 5 uM. When administered at 125 mg once daily for 12 months to SIV-infected rhesus macaques, aprepitant reduced viral load by approximately tenfold and produced anti-anxiolytic effects. The anti-viral and anti-anxiolytic effects occur at approximately the third month of dosing; and the effects are sustained throughout the duration of drug administration. Protein binding experiments in culture media and animal and human plasma indicate that the free fraction of aprepitant is lower than previously reported supporting usage of higher doses in vivo. The analysis of blood samples from HIV positive individuals treated for 2 weeks with aprepitant at doses up to 375 mg demonstrated reduced levels of pro-inflammatory cytokines including G-CSF, IL-6, IL-8 and TNFalpha. Decreased pro-inflammatory cytokines may reduce HIV comorbidities associated with chronic inflammation. CONCLUSIONS: Our results provide evidence for a unique combination of antiretroviral, anti-inflammatory and behavioral modulation properties of aprepitant in vitro and in vivo. These results provide robust support for a clinical exposure target above that recommended for chemotherapy-induced nausea and vomiting. Doses up to 375 mg once daily in HIV-infected patients still elicit sub-therapeutic exposure of aprepitant though effective plasma concentrations can be achievable by proper dose modulation. PMID- 27230665 TI - Hereditary hemorrhagic telangiectasias as a rare cause of recurrent gastrointestinal bleeding. PMID- 27230667 TI - Characterisation of assembly and ubiquitylation by the RBCC motif of Trim5alpha. AB - The post-entry restriction factor Trim5alpha blocks infection of retroviral pathogens shortly after the virus gains entry to the cell, preventing reverse transcription and integration into the host genome. Central to the mechanism of restriction is recognition of the lattice of capsid protein that forms the inner shell of the retrovirus. To recognise this lattice, Trim5alpha has been shown to assemble into a large hexagonal array, complementary to the capsid lattice. Structures of the Trim5alpha coiled-coil region reveal an elongated anti-parallel dimer consistent with the edges of this array placing the Bbox domain at each end of the coiled-coil to facilitate assembly. To investigate the nature of this assembly we have designed and characterised a monomeric version of the TRIM RBCC motif with a truncated coiled-coil. Biophysical characterisation by SEC-MALLS, AUC, and SAXS demonstrate that this construct forms compact folded domain that assembles into a trimer that would support the formation of a hexagonal lattice. Furthermore, the RING domain and elements of the coiled-coil region are shown to contribute to assembly. Ubiquitylation assays demonstrate that this assembly increases ubiquitylation activity providing a link from recognition of the capsid lattice and assembly to the activation of innate immune signalling and restriction. PMID- 27230666 TI - Gaining and sustaining schistosomiasis control: study protocol and baseline data prior to different treatment strategies in five African countries. AB - BACKGROUND: The Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) was established in 2008 to answer strategic questions about schistosomiasis control. For programme managers, a high-priority question is: what are the most cost-effective strategies for delivering preventive chemotherapy (PCT) with praziquantel (PZQ)? This paper describes the process SCORE used to transform this question into a harmonized research protocol, the study design for answering this question, the village eligibility assessments and data resulting from the first year of the study. METHODS: Beginning in 2009, SCORE held a series of meetings to specify empirical questions and design studies related to different schedules of PCT for schistosomiasis control in communities with high (gaining control studies) and moderate (sustaining control studies) prevalence of Schistosoma infection among school-aged children. Seven studies are currently being implemented in five African countries. During the first year, villages were screened for eligibility, and data were collected on prevalence and intensity of infection prior to randomisation and the implementation of different schemes of PZQ intervention strategies. RESULTS: These studies of different treatment schedules with PZQ will provide the most comprehensive data thus far on the optimal frequency and continuity of PCT for schistosomiasis infection and morbidity control. CONCLUSIONS: We expect that the study outcomes will provide data for decision-making for country programme managers and a rich resource of information to the schistosomiasis research community. TRIAL REGISTRATION: The trials are registered at International Standard Randomised Controlled Trial registry (identifiers: ISRCTN99401114 , ISRCTN14849830 , ISRCTN16755535 , ISRCTN14117624 , ISRCTN95819193 and ISRCTN32045736 ). PMID- 27230661 TI - The Diversity of Spine Synapses in Animals. AB - Here we examine the structure of the various types of spine synapses throughout the animal kingdom. Based on available evidence, we suggest that there are two major categories of spine synapses: invaginating and non-invaginating, with distributions that vary among different groups of animals. In the simplest living animals with definitive nerve cells and synapses, the cnidarians and ctenophores, most chemical synapses do not form spine synapses. But some cnidarians have invaginating spine synapses, especially in photoreceptor terminals of motile cnidarians with highly complex visual organs, and also in some mainly sessile cnidarians with rapid prey capture reflexes. This association of invaginating spine synapses with complex sensory inputs is retained in the evolution of higher animals in photoreceptor terminals and some mechanoreceptor synapses. In contrast to invaginating spine synapse, non-invaginating spine synapses have been described only in animals with bilateral symmetry, heads and brains, associated with greater complexity in neural connections. This is apparent already in the simplest bilaterians, the flatworms, which can have well-developed non invaginating spine synapses in some cases. Non-invaginating spine synapses diversify in higher animal groups. We also discuss the functional advantages of having synapses on spines and more specifically, on invaginating spines. And finally we discuss pathologies associated with spine synapses, concentrating on those systems and diseases where invaginating spine synapses are involved. PMID- 27230668 TI - Predictive value of serum testosterone for type 2 diabetes risk assessment in men. AB - BACKGROUND: Effective prevention of type 2 diabetes (T2D) requires early identification of high-risk individuals who might benefit from intervention. We sought to determine whether low serum testosterone, a novel risk factor for T2D in men, adds clinically meaningful information beyond current T2D risk models. METHODS: The Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) study population consists of 2563 community-dwelling men aged 35-80 years in Adelaide, Australia. Of the MAILES participants, 2038 (80.0 %) provided information at baseline (2002-2006) and follow-up (2007-2010). After excluding participants with diabetes (n = 317), underweight (n = 5), and unknown BMI status (n = 11) at baseline; and unknown diabetes status (n = 50) at follow-up; 1655 participants were followed for 5 years. T2D at baseline and follow-up was defined by self-reported diabetes, or fasting plasma glucose (FPG) >=7.0 mmol/L (126.1 mg/dL), or glycated haemoglobin (HbA1c) >=6.5 %, or diabetes medications. Risk models were tested using logistic regression models. Sensitivity, specificity, positive predictive values (PPV) were used to identify the optimal cut-off point for low serum testosterone for incident T2D and the area under the receiver operating characteristic (AROC) curve was used to summarise the predictive power of the model. 15.5 % of men had at least one missing predictor variable; addressed through multiple imputation. RESULTS: The incidence rate of T2D was 8.9 % (147/1655) over a median follow-up of 4.95 years (interquartile range: 4.35 5.00). Serum testosterone level predicted incident T2D (relative risk 0.96 [95 % CI: 0.92,1.00], P = 0.032) independent of current risk models including the AUSDRISK, but did not improve corresponding AROC statistics. A cut-off point of <16 nmol/L for low serum testosterone, which classified about 43 % of men, returned equal sensitivity (61.3 % [95 % CI: 52.6,69.4]) and specificity (58.3 % [95 % CI: 55.6,60.9) for predicting T2D risk, with a PPV of 12.9 % (95 % CI: 10.4,15.8). CONCLUSIONS: Low serum testosterone predicts an increased risk of developing T2D in men over 5 years independent of current T2D risk models applicable for use in routine clinical practice. Screening for low serum testosterone in addition to risk factors from current T2D risk assessment models or tools, including the AUSDRISK, would identify a large subgroup of distinct men who might benefit from targeted preventive interventions. PMID- 27230670 TI - MRI of penile fracture: what should be a tailored protocol in emergency? AB - OBJECTIVES: To conduct a review of literature to summarize the existing MRI protocols for penile trauma, suggesting a tailored protocol to reduce costs and time of examination. MATERIALS AND METHODS: A systematic search was performed in Medline, Embase, Cochrane Library, and Cinahl databases from 1995 to 2015 to identify studies evaluating penis trauma with MRI examination. Studies were included if there was the description of MRI protocol with at least sequences and orthogonal planes used. We chose a systematic approach for data extraction and descriptive synthesis. RESULTS: 12 articles were included in our study. Among the list of 12 articles: 2 were case reports, 3 were clinical series, and 7 were reviews. Clinical trials were not found. There is no unanimous consensus among the authors. Summarizing the data, the most used protocol is characterized by T2 sequences in three orthogonal planes plus T1 sequences in one plane (either axial or sagittal) without contrast medium injection. CONCLUSION: There is a lack of a standard protocol. A tailored protocol to answer the diagnostic question, reducing costs and time of examination, is characterized by T2 sequences in three orthogonal planes plus at least a T1 sequence (either axial or sagittal plane). PMID- 27230669 TI - Resected pN1 non-small cell lung cancer: recurrence patterns and nodal risk factors may suggest selection criteria for post-operative radiotherapy. AB - PURPOSE: To describe the pattern of recurrence in resected pN1 non-small cell lung cancer (NSCLC) and to identify factors predicting an increased risk of locoregional recurrence (LR) or distant metastasis (DM) to define a selected population who may benefit from postoperative radiotherapy (PORT). METHODS: 285 patients with resected pN1 NSCLC were identified. Patients with positive surgical margins, undergoing neoadjuvant treatment or PORT, were excluded. LR was defined as first event of recurrence at the surgical bed, ipsilateral hilum or mediastinum, and other sites were considered as DM. Kaplan-Meier actuarial estimates of overall survival (OS), progression-free survival (PFS), freedom from LR (FFLR) and freedom from DM (FFDM) in different subgroups were compared with the log-rank test. Multivariate analysis was calculated. RESULTS: 202 patients met the inclusion criteria, 24 % received adjuvant chemotherapy. The median follow-up was 39 months. The total number of recurrences was 118 (64.4 %): 44 (24 %) and 74 (40.4 %) for LR and DM, respectively. Five-year OS and PFS rates were 39.2 and 33.3 %, respectively. Extra capsular extension (ECE) (RR 2.10, p = 0.01) and lymph nodal ratio (LNR) >0:15 (RR 1.68, p = 0.015) were associated with a worse PFS. ECE and LNR >0.15 were significantly related to a worst FFLR (RR 3.04 and 4.42, respectively), and adenocarcinoma to an unfavorable FFDM (RR 1.97, p = 0.013). CONCLUSIONS: Nodal factors as high LNR and ECE can predict an increased risk of worse FFLR and PFS. Prospective data on selected patients, treated with modern radiotherapy techniques, need to be collected to re-evaluate the role of radiotherapy. PMID- 27230671 TI - Effect of separate and combined exposure of selenium and diazinon on rat sperm motility by computer assisted semen analysis. AB - Effects of selenium (Se) and diazinon (DZN) on sperm motility parameters in rats were investigated. Male rats received a separate dose of Se (2mgkg-1 b.w., intraperitoneally, 5mgL-1, per os in drinking water), diazinon (20mgkg-1 b.w., intraperitoneally, 40mgL-1, per os in drinking water), and in combination (Se+DZN) with the same dosage as in the separate administration. 36h an intraperitoneal (i.p.) and after 90days of per oral (p.o.) exposure, thirteen parameters of sperm motility were evaluated using a Computer Assisted Sperm Analyzer (CASA). Almost all the evaluated sperm motility parameters significantly decreased in Se p.o. exposed groups. In the Se i.p. group decrease was noted only in beat cross frequency (BCF) and progressive motility. Significant decline in the sperm motility, progressive motility, BCF and increase in amplitude of lateral head displacement (ALH) were recorded after DZN i.p. administration. In DZN p.o. group, significant increase in ALH, velocity average path (VAP) and curvilinear velocity (VCL) but decrease in progressive motility and BCF was detected. Se+DZN i.p. administration caused a significant decrease in motility, progressive motility and BCF. Per oral administration of Se+DZN decreased all motility parameters except LIN, WOB and ALH. Sperm abnormalities increased in all experimental conditions. Se and DZN negatively affected sperm structure and function in separate doses or in combination. No protective effect of Se was observed. PMID- 27230672 TI - Connexins and pannexins in neuronal development and adult neurogenesis. AB - Connexins and pannexins share very similar structures and functions; they also exhibit overlapping expression in many stages of neuronal development. Here, we review evidence implicating connexin- and pannexin-mediated communication in the regulation of the birth and development of neurons, specifically Cx26, Cx30, Cx32, Cx36, Cx43, Cx45, Panx1, and Panx2. We begin by dissecting the involvement of these proteins in the generation and development of new neurons in the embryonic, postnatal, and adult brain. Next we briefly outline common mechanisms employed by both pannexins and connexins in these roles, including modulation of purinergic receptor signalling and signalling nexus functions. Throughout this review we highlight developing themes as well as important gaps in knowledge to be bridged. PMID- 27230673 TI - Lysophospholipid Receptors, as Novel Conditional Danger Receptors and Homeostatic Receptors Modulate Inflammation-Novel Paradigm and Therapeutic Potential. AB - There are limitations in the current classification of danger-associated molecular patterns (DAMP) receptors. To overcome these limitations, we propose a new paradigm by using endogenous metabolites lysophospholipids (LPLs) as a prototype. By utilizing a data mining method we pioneered, we made the following findings: (1) endogenous metabolites such as LPLs at basal level have physiological functions; (2) under sterile inflammation, expression of some LPLs is elevated. These LPLs act as conditional DAMPs or anti-inflammatory homeostasis associated molecular pattern molecules (HAMPs) for regulating the progression of inflammation or inhibition of inflammation, respectively; (3) receptors for conditional DAMPs and HAMPs are differentially expressed in human and mouse tissues; and (4) complex signaling mechanism exists between pro-inflammatory mediators and classical DAMPs that regulate the expression of conditional DAMPs and HAMPs. This novel insight will facilitate identification of novel conditional DAMPs and HAMPs, thus promote development of new therapeutic targets to treat inflammatory disorders. PMID- 27230674 TI - Why QRS Duration Should Be Replaced by Better Measures of Electrical Activation to Improve Patient Selection for Cardiac Resynchronization Therapy. AB - Cardiac resynchronization therapy (CRT) is a well-known treatment modality for patients with a reduced left ventricular ejection fraction accompanied by a ventricular conduction delay. However, a large proportion of patients does not benefit from this therapy. Better patient selection may importantly reduce the number of non-responders. Here, we review the strengths and weaknesses of the electrocardiogram (ECG) markers currently being used in guidelines for patient selection, e.g., QRS duration and morphology. We shed light on the current knowledge on the underlying electrical substrate and the mechanism of action of CRT. Finally, we discuss potentially better ECG-based biomarkers for CRT candidate selection, of which the vectorcardiogram may have high potential. PMID- 27230675 TI - Treatment-seeking patients with binge-eating disorder in the Swedish national registers: clinical course and psychiatric comorbidity. AB - BACKGROUND: We linked extensive longitudinal data from the Swedish national eating disorders quality registers and patient registers to explore clinical characteristics at diagnosis, diagnostic flux, psychiatric comorbidity, and suicide attempts in 850 individuals diagnosed with binge-eating disorder (BED). METHOD: Cases were all individuals who met criteria for BED in the quality registers (N = 850). We identified 10 controls for each identified case from the Multi-Generation Register matched on sex, and year, month, and county of birth. We evaluated characteristics of individuals with BED at evaluation and explored diagnostic flux across eating disorders presentations between evaluation and one year follow-up. We applied conditional logistic regression models to assess the association of BED with each comorbid psychiatric disorder and with suicide attempts and explored whether risk for depression and suicide were differentially elevated in individuals with BED with or without comorbid obesity. RESULTS: BED shows considerable diagnostic flux with other eating disorders over time, carries high psychiatric comorbidity burden with other eating disorders (OR 85.8; 95 % CI: 61.6, 119.4), major depressive disorder (OR 7.6; 95 % CI: 6.2, 9.3), bipolar disorder (OR 7.5; 95 % CI: 4.8, 11.9), anxiety disorders (OR 5.2; 95 % CI: 4.2, 6.4), and post-traumatic stress disorder (OR 4.3; 95 % CI: 3.2, 5.7) and is associated with elevated risk for suicide attempts (OR 1.8; 95 % CI: 1.2, 2.7). Depression and suicide attempt risk were elevated in individuals with BED with and without comorbid obesity. CONCLUSIONS: Considerable flux occurs across BED and other eating disorder diagnoses. The high psychiatric comorbidity and suicide risk underscore the severity and clinical complexity of BED. PMID- 27230677 TI - In reply: Comparing face-to-face intubation with different devices. PMID- 27230676 TI - Lin28A induces energetic switching to glycolytic metabolism in human embryonic kidney cells. AB - BACKGROUND: Loss of a cell's capacity to generate sufficient energy for cellular functions is a key hallmark of the ageing process and ultimately leads to a variety of important age-related pathologies such as cancer, Parkinson's disease and atherosclerosis. Regenerative medicine has sought to reverse these pathologies by reprogramming somatic cells to a more juvenile energetic state using a variety of stem cell factors. One of these factors, Lin28, is considered a candidate for modification in the reprogramming of cellular energetics to ameliorate the ageing process while retaining cell phenotype. RESULTS: Over expression of Lin28A resulted in key changes to cellular metabolism not observed in wild-type controls. Extracellular pH flux analysis indicated that Lin28A over expression significantly increased the rate of glycolysis, whilst high resolution oxygen respirometry demonstrated a reduced oxygen consumption. Western blot and real-time PCR analysis identified Hexokinase II as one of the key modulators of glycolysis in these cells which was further confirmed by increased glucose transport. A metabolic switching effect was further emphasised by Western blot analysis where the oxygen consuming mitochondrial complex IV was significantly reduced after Lin28A over expression. CONCLUSIONS: Results from this study confirm that Lin28A expression promotes metabolic switching to a phenotype that relies predominantly on glycolysis as an energy source, while compromising oxidative phosphorylation. Mechanisms to augment regulated Lin28A in age related pathologies that are characterised by mitochondria dysfunction or in differentiated and aged post-mitotic cells is the future goal of this work. PMID- 27230678 TI - PEG stabilized DNA - poly(ferrocenylsilane) polyplexes for gene delivery. AB - Polycationic poly(ferrocenylsilane)s (PFS) with tunable amounts of PEG side chains were used for the condensation of DNA into polyplexes of 110 nm in 5.0 mM HEPES. The PFS-PEG/DNA polyplexes showed negligible aggregation, a strongly reduced protein adsorption, transfection activities comparable with linear polyethyleneimine and an excellent cytocompatibility. PMID- 27230679 TI - DUSP28 links regulation of Mucin 5B and Mucin 16 to migration and survival of AsPC-1 human pancreatic cancer cells. AB - The prognosis of pancreatic cancer has not improved despite considerable and continuous effort. Dual-specificity phosphatase 28 (DUSP28) is highly expressed in human pancreatic cancers and exerts critical effects. However, knowledge of its function in pancreatic cancers is extremely limited. Here, we demonstrate the peculiar role of DUSP28 in pancreatic cancers. Analysis using the Gene Expression Omnibus public microarray database indicated higher DUSP28, MUC1, MUC4, MUC5B, MUC16 and MUC20 messenger RNA (mRNA) levels in pancreatic cancers compared with normal pancreas tissues. DUSP28 expression in human pancreatic cancer correlated positively with those of MUC1, MUC4, MUC5B, MUC16 and MUC20. In contrast, there were no significant correlations between DUSP28 and mucins in normal pancreas tissues. Decreased DUSP28 expression resulted in down-regulation of MUC5B and MUC16 at both the mRNA and protein levels; furthermore, transfection with small interfering RNA (siRNA) for MUC5B and MUC16 inhibited the migration and survival of AsPC-1 cells. In addition, transfection of siRNA for MUC5B and MUC16 resulted in a significant decrease in phosphorylation of FAK and ERK1/2 compared with transfection with scrambled-siRNA. These results collectively indicate unique links between DUSP28 and MUC5B/MUC16 and their roles in pancreatic cancer; moreover, they strongly support a rationale for targeting DUSP28 to inhibit development of malignant pancreatic cancer. PMID- 27230680 TI - Prostaglandin E2 (PGE2) promotes proliferation and invasion by enhancing SUMO-1 activity via EP4 receptor in endometrial cancer. AB - Prostaglandin E2 (PGE2), a derivative of arachidonic acid, has been identified as a tumorigenic factor in many cancers in recent studies. Prostaglandin E synthase 2 (PTGES2) is an enzyme that in humans is encoded by the PTGES2 gene located on chromosome 9, and it synthesizes PGE2 in human cells. In our study, we selected 119 samples from endometrial cancer patients, with 50 normal endometrium tissue samples as controls, in which we examined the expression of PTGES2. Both immunohistochemistry (IHC) and Western blot analyses demonstrated that synthase PTGES2, which is required for PGE2 synthesis, was highly expressed in endometrium cancer tissues compared with normal endometrium. Stable PTGES2-shRNA transfectants were generated in Ishikawa and Hec-1B endometrial cancer cell lines, and transfection efficiencies were confirmed by RT-PCR and Western blot analyses. We found that PGE2 promoted proliferation and invasion of cells in Ishikawa and Hec-1B cells by cell counting kit-8 tests (CCK8) and transwell assays, respectively. PGE2 stimulation enhanced the expression of SUMO-1, via PGE2 receptor subtype 4 (EP4). Further analysis implicated the Wnt/beta-catenin signaling pathway function as the major mediator of EP4 and SUMO-1. The increase in SUMO-1 activity prompted the SUMOlyation of target proteins which may be involved in proliferation and invasion. These findings suggest SUMO-1 and EP4 as two potential targets for new therapeutic or prevention strategies for endometrial cancers. PMID- 27230682 TI - Purple plants. PMID- 27230681 TI - A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair. AB - Inhibition of the Wnt antagonist sclerostin increases bone mass in patients with osteoporosis and in preclinical animal models. Here we show increased levels of the Wnt antagonist Dickkopf-1 (DKK-1) in animals treated with sclerostin antibody, suggesting a negative feedback mechanism that limits Wnt-driven bone formation. To test our hypothesis that co-inhibition of both factors further increases bone mass, we engineer a first-in-class bispecific antibody with single residue pair mutations in the Fab region to promote efficient and stable cognate light-heavy chain pairing. We demonstrate that dual inhibition of sclerostin and DKK-1 leads to synergistic bone formation in rodents and non-human primates. Furthermore, by targeting distinct facets of fracture healing, the bispecific antibody shows superior bone repair activity compared with monotherapies. This work supports the potential of this agent both for treatment and prevention of fractures and offers a promising therapeutic approach to reduce the burden of low bone mass disorders. PMID- 27230683 TI - The history of the Y chromosome in man. AB - Studies of the Y chromosome over the past few decades have opened a window into the history of our species, through the reconstruction and exploitation of a patrilineal (Y-genealogical) tree based on several hundred single-nucleotide variants (SNVs). A new study validates, refines and extends this tree by incorporating >65,000 Y-linked variants identified in 1,244 men representing worldwide diversity. PMID- 27230684 TI - The carrot genome sequence brings colors out of the dark. AB - The genome sequence of carrot (Daucus carota L.) is the first completed for an Apiaceae species, furthering knowledge of the evolution of the important euasterid II clade. Analyzing the whole-genome sequence allowed for the identification of a gene that may regulate the accumulation of carotenoids in the root. PMID- 27230685 TI - DNA-sequence-specific erasers of epigenetic memory. AB - How epigenetic regulators find their specific targets remains a challenging question. Two parallel studies show that REF6, a plant H3K27me3 demethylase, binds a specific DNA motif via its zinc-finger domains and recruits the SWI/SNF type ATPase BRAHMA, demonstrating a sequence-specific recruitment mechanism for a chromatin-modifying complex. PMID- 27230686 TI - Erratum: Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer. PMID- 27230687 TI - Corrigendum: Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma. PMID- 27230689 TI - DATEL: A Scarless and Sequence-Independent DNA Assembly Method Using Thermostable Exonucleases and Ligase. AB - DNA assembly is a pivotal technique in synthetic biology. Here, we report a scarless and sequence-independent DNA assembly method using thermal exonucleases (Taq and Pfu DNA polymerases) and Taq DNA ligase (DATEL). Under the optimized conditions, DATEL allows rapid assembly of 2-10 DNA fragments (1-2 h) with high accuracy (between 74 and 100%). Owing to the simple operation system with denaturation-annealing-cleavage-ligation temperature cycles in one tube, DATEL is expected to be a desirable choice for both manual and automated high-throughput assembly of DNA fragments, which will greatly facilitate the rapid progress of synthetic biology and metabolic engineering. PMID- 27230688 TI - Corrigendum: The spotted gar genome illuminates vertebrate evolution and facilitates human-teleost comparisons. PMID- 27230690 TI - Laparoendoscopic single-site donor nephrectomy (LESS-DN) versus standard laparoscopic donor nephrectomy. AB - BACKGROUND: Advances in minimally invasive surgery for live kidney donors have led to the development of laparoendoscopic single site donor nephrectomy (LESS DN). At present, laparoscopic donor nephrectomy is the technique of choice for donor nephrectomy globally. Compared with open surgical approaches, laparoscopic donor nephrectomy is associated with decreased morbidity, faster recovery times and return to normal activity, and shorter hospital stays. LESS-DN differs from standard laparoscopic donor nephrectomy; LESS-DN requires a single incision through which the procedure is performed and donor kidney is removed. Previous studies have hypothesised that LESS-DN may provide additional benefits for kidney donors and stimulate increased donor rates. OBJECTIVES: This review looked at the benefits and harms of LESS-DN compared with standard laparoscopic nephrectomy for live kidney donors. SEARCH METHODS: We searched the Cochrane Kidney and Transplant's Specialised Register to 28 January 2016 through contact with the Information Specialist using search terms relevant to this review. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared LESS-DN with laparoscopic donor nephrectomy in adults. DATA COLLECTION AND ANALYSIS: Three authors independently assessed studies for eligibility and conducted risk of bias evaluation. Summary estimates of effect were obtained using a random effects model and results were expressed as risk ratios (RR) or risk difference (RD) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes. MAIN RESULTS: We included three studies (179 participants) comparing LESS-DN with laparoscopic donor nephrectomy. There were no significant differences between LESS-DN and laparoscopic donor nephrectomy for mean operative time (2 studies, 79 participants: MD 6.36 min, 95% CI -11.85 to 24.57), intra-operative blood loss (2 studies, 79 participants: MD -8.31 mL, 95% CI -23.70 to 7.09), or complication rates (3 studies, 179 participants: RD 0.05, 95% CI -0.04 to 0.14). Pain scores at discharge were significantly less in the LESS-DN group (2 studies, 79 participants: MD -1.19, 95% CI -2.17 to -0.21). For all other outcomes (length of hospital stay; length of time to return to normal activities; blood transfusions; conversion to another form of surgery; warm ischaemia time; total analgesic requirement; graft loss) there were no significant differences observed.Although risk of bias was assessed as low overall, one study was assessed at high risk of attrition bias. AUTHORS' CONCLUSIONS: Given the small number and size of included studies it is uncertain whether LESS-DN is better than laparoscopic donor nephrectomy. Well designed and adequately powered RCTs are needed to better define the role of LESS-DN as a minimally invasive option for kidney donor surgery. PMID- 27230691 TI - Dermoscopic Ulceration is a Predictor of Basal Cell Carcinoma Response to Imiquimod: A Retrospective Study. PMID- 27230692 TI - Combinatorial development of antibacterial Zr-Cu-Al-Ag thin film metallic glasses. AB - Metallic alloys are normally composed of multiple constituent elements in order to achieve integration of a plurality of properties required in technological applications. However, conventional alloy development paradigm, by sequential trial-and-error approach, requires completely unrelated strategies to optimize compositions out of a vast phase space, making alloy development time consuming and labor intensive. Here, we challenge the conventional paradigm by proposing a combinatorial strategy that enables parallel screening of a multitude of alloys. Utilizing a typical metallic glass forming alloy system Zr-Cu-Al-Ag as an example, we demonstrate how glass formation and antibacterial activity, two unrelated properties, can be simultaneously characterized and the optimal composition can be efficiently identified. We found that in the Zr-Cu-Al-Ag alloy system fully glassy phase can be obtained in a wide compositional range by co sputtering, and antibacterial activity is strongly dependent on alloy compositions. Our results indicate that antibacterial activity is sensitive to Cu and Ag while essentially remains unchanged within a wide range of Zr and Al. The proposed strategy not only facilitates development of high-performing alloys, but also provides a tool to unveil the composition dependence of properties in a highly parallel fashion, which helps the development of new materials by design. PMID- 27230694 TI - Testing Theories of Transfer Using Error Rate Learning Curves. AB - We analyze naturally occurring datasets from student use of educational technologies to explore a long-standing question of the scope of transfer of learning. We contrast a faculty theory of broad transfer with a component theory of more constrained transfer. To test these theories, we develop statistical models of them. These models use latent variables to represent mental functions that are changed while learning to cause a reduction in error rates for new tasks. Strong versions of these models provide a common explanation for the variance in task difficulty and transfer. Weak versions decouple difficulty and transfer explanations by describing task difficulty with parameters for each unique task. We evaluate these models in terms of both their prediction accuracy on held-out data and their power in explaining task difficulty and learning transfer. In comparisons across eight datasets, we find that the component models provide both better predictions and better explanations than the faculty models. Weak model variations tend to improve generalization across students, but hurt generalization across items and make a sacrifice to explanatory power. More generally, the approach could be used to identify malleable components of cognitive functions, such as spatial reasoning or executive functions. PMID- 27230693 TI - Prolonged mitotic arrest induces a caspase-dependent DNA damage response at telomeres that determines cell survival. AB - A delay in the completion of metaphase induces a stress response that inhibits further cell proliferation or induces apoptosis. This response is thought to protect against genomic instability and is important for the effects of anti mitotic cancer drugs. Here, we show that mitotic arrest induces a caspase dependent DNA damage response (DDR) at telomeres in non-apoptotic cells. This pathway is under the control of Mcl-1 and other Bcl-2 family proteins and requires caspase-9, caspase-3/7 and the endonuclease CAD/DFF40. The gradual caspase-dependent loss of the shelterin complex protein TRF2 from telomeres promotes a DDR that involves DNA-dependent protein kinase (DNA-PK). Suppression of mitotic telomere damage by enhanced expression of TRF2, or the inhibition of either caspase-3/7 or DNA-PK during mitotic arrest, promotes subsequent cell survival. Thus, we demonstrate that mitotic stress is characterised by the sub apoptotic activation of a classical caspase pathway, which promotes telomere deprotection, activates DNA damage signalling, and determines cell fate in response to a prolonged delay in mitosis. PMID- 27230695 TI - Model minority stereotype and the diagnosis of alcohol use disorders: Implications for practitioners working with Asian Americans. AB - This study investigated the priming effects of the model minority stereotype on 122 clinicians in training regarding their diagnostic accuracy on Asian Americans compared to Whites. It was hypothesized that clinicians in training would be less likely to diagnose Asian Americans with alcohol use disorder and would perceive them to have fewer clinical symptoms than Whites due to the model minority stereotype. Consistent with the hypotheses, clinicians in training were less likely to assign alcohol use disorder to Asian Americans compared to Whites, as well as to the unprimed condition versus the condition primed with the stereotype. Implications regarding cultural competence and future research are discussed. PMID- 27230696 TI - Reducing Physical Risk Factors in Construction Work Through a Participatory Intervention: Protocol for a Mixed-Methods Process Evaluation. AB - BACKGROUND: Previous research has shown that reducing physical workload among workers in the construction industry is complicated. In order to address this issue, we developed a process evaluation in a formative mixed-methods design, drawing on existing knowledge of the potential barriers for implementation. OBJECTIVE: We present the design of a mixed-methods process evaluation of the organizational, social, and subjective practices that play roles in the intervention study, integrating technical measurements to detect excessive physical exertion measured with electromyography and accelerometers, video documentation of working tasks, and a 3-phased workshop program. METHODS: The evaluation is designed in an adapted process evaluation framework, addressing recruitment, reach, fidelity, satisfaction, intervention delivery, intervention received, and context of the intervention companies. Observational studies, interviews, and questionnaires among 80 construction workers organized in 20 work gangs, as well as health and safety staff, contribute to the creation of knowledge about these phenomena. RESULTS: At the time of publication, the process of participant recruitment is underway. CONCLUSIONS: Intervention studies are challenging to conduct and evaluate in the construction industry, often because of narrow time frames and ever-changing contexts. The mixed-methods design presents opportunities for obtaining detailed knowledge of the practices intra acting with the intervention, while offering the opportunity to customize parts of the intervention. PMID- 27230698 TI - Kindness in Australia: an empirical critique of moral decline sociology. AB - A new sociological agenda is emerging that interrogates how morality can be established in the absence of the moral certainties of the past but there is a shortage of empirical work on this topic. This article establishes a theoretical framework for the empirical analysis of everyday morality drawing on the work of theorists including Ahmed, Bauman and Taylor. It uses the Australian Survey of Social Attitudes to assess the state and shape of contemporary moralities by asking how kind are Australians, how is its expression socially distributed, and what are the motivations for kindness. The findings demonstrate that Australians exhibit a strong attachment and commitment to kindness as a moral value that is primarily motivated by interiorized sources of moral authority. We argue these findings support the work of theorists such as Ahmed and Taylor who argue authenticity and embodied emotion are legitimate sources of morality in today's secular societies. The research also provides new evidence that generational changes are shaping understandings and practices of kindness in unexpected ways. PMID- 27230697 TI - Nondopaminergic treatments for Parkinson's disease: current and future prospects. AB - Parkinson's disease is primarily caused by dysfunction of dopaminergic neurons, however, nondopaminergic (ND) systems are also involved. ND targets are potentially useful to reduce doses of levodopa or to treat nonlevodopa-responsive symptoms. Recent studies have investigated the role of ND drugs for motor and nonmotor symptoms. Adenosine A2A receptor antagonists, mixed inhibitors of sodium/calcium channels and monoamine oxidase-B have recently been found to improve motor fluctuations. N-methyl-d-aspartate receptor antagonists and serotonin 5HT1B receptor agonists demonstrated benefit in levodopa-induced dyskinesia. Conversely, studies using antiepileptic drugs and adrenoreceptor antagonist had conflicting results. Moreover, metabotropic glutamate receptor antagonists also failed to improve symptoms. The current review summarizes the most recent findings on ND drugs over the last 2 years. PMID- 27230699 TI - Molecular determinant modulates thermal recovery kinetics and structural integrity of the bacterial BLUF photoreceptor. AB - BLUF domains are flavin-based photoreceptors which receive the blue light signal and are involved in the sensory transduction. We report a short BLUF photoreceptor (SnfB) in Stenotrophomonas sp. We have investigated photodynamic properties of C terminus truncated and several mutated SnfB proteins. Deletion of the extended C-terminal residues alters the thermal recovery kinetics and also affects the integrity of the SnfB protein. Mutagenesis studies demonstrated that the conserved residues within and outside the flavin-binding pocket also regulates the photocycle properties of the protein. These studies suggest that the C-terminal residues outside the BLUF domain can tune the photodynamic properties of the BLUF protein. PMID- 27230700 TI - Dialysis and Patient Factors Which Determine Convective Volume Exchange in Patients Treated by Postdilution Online Hemodiafiltration. AB - Recent reports suggest a survival advantage for dialysis patients treated by postdilutional online hemodiafiltration (OL-HDF) who achieve higher volume convective exchanges. As such, the factors associated with achieving higher convective volume exchange were determined. The convective exchange volumes during the midweek OL-HDF session in a cohort of 653 patients with corresponding bio-impedance measurements of volume status and sessional electronic records were audited. Mean patient age was 64.9 +/- 14.9 years, 65.3% male, 47.7% diabetes, with 81.6% dialyzing using fistula access. Sessional substitution volume exchanged was 17.0 +/- 3.5 L (83.8 +/- 13.9 mL/min), with a filtration fraction of 23.3 +/- 4.6%, sessional time of 3.8 +/- 0.5 h, and blood flow 321 +/- 28 mL/min. As expected, convection exchange volume achieved was associated with sessional time (beta 3.24, P < 0.001), blood flow (beta 0.03, P < 0.001), dialysate flow (beta 0.03, P < 0.001), but also patient factors: postsessional intracellular water (ICW) (beta 0.07, P = 0.002), and serum albumin (beta 0.71, P = 0.011). In addition convective exchange was lower for diabetics (16.6 +/- 3.0 vs. 17.3 +/- 3.8 L, P < 0.01), and for patients with higher Davies co-morbidity grades (16.6 +/- 2.8 vs. 17.0 +/- 3.6 vs. 17.9 +/- 4.0 L), P = 0.01 respectively. As expected the convective volume exchanged with OL-HDF was associated with sessional time and blood and dialysate flows. However, the convective volume exchange achieved was also associated with patient factors, including ICW, which is related to body cell mass and also co-morbidity. Although some center practices can be modified to increase convective exchange, patient factors are not so readily remediable. As such, highly comorbid patients may not be able to achieve the higher volume convective exchanges reported to be associated with improved patient survival. PMID- 27230701 TI - Re: Diagnosing Acute Heart Failure in the Emergency Department. PMID- 27230702 TI - Chronic exposures and male fertility: the impacts of environment, diet, and drug use on spermatogenesis. AB - Several recent studies have suggested that sperm concentrations and semen quality have been decreasing over the past several decades in many areas of the world. The etiology of these decreases is currently unknown. Acute events can have significant impacts on spermatogenesis and are often readily identified during the male fertility evaluation. The majority of male factor infertility, however, is idiopathic. Chronic, low-dose exposures to chemicals and nutrients are more difficult to identify, but are extremely prevalent. These exposures have been shown to have dramatic effects on both individual and community health and interest in the cumulative and synergistic impacts of such agents on spermatogenesis has been increasing. While our understanding of these potential hazards is evolving, it is clear that they may significantly influence male reproductive potential. This review explores the literature related to effects of chronic exposures from drug use, dietary intake, and the environment on spermatogenesis in humans and animals. PMID- 27230703 TI - High-amplitude theta wave bursts characterizing narcoleptic mice and patients are also produced by histamine deficiency in mice. AB - Histamine and orexins are wake promoters released by hypothalamic neurons. The activity of histamine neurons is increased by orexin neurons. Recently, it has been shown that orexin deficiency entails high-amplitude theta wave bursts during rapid eye movement sleep and cataplexy in narcoleptic mice. The primary aim of this study was to assess whether histamine system is involved in high-amplitude theta wave burst generation during rapid eye movement sleep. The secondary aim was to assess the effects of combined histamine and orexin deficiency on high amplitude theta wave bursts during rapid eye movement sleep in mice. Twelve histidine-decarboxylase knockout mice with congenital histamine deficiency, seven double mutant mice with combined deficiency of orexin neurons and histamine, and 11 wild-type control mice were studied with electrodes for sleep recordings and a telemetric blood pressure transducer. High-amplitude theta wave bursts during rapid eye movement sleep were detected in each of the histidine-decarboxylase knockout and double mutant mice, whereas only one burst was found in a wild-type control mouse. High-amplitude theta wave bursts occurred significantly more often and were significantly longer in double mutant than in histidine-decarboxylase knockout mice. In conclusion, it was demonstrated that, similarly to orexin, the chronic impairment of histamine entailed high-amplitude theta wave bursts during rapid eye movement sleep. The current data also suggested a synergistic role of orexin and histamine signalling on high-amplitude theta wave bursts during rapid eye movement sleep in mice. PMID- 27230704 TI - Reflecting the transition from pain management services to chronic pain support group attendance: An interpretative phenomenological analysis. AB - OBJECTIVES: Transitioning from clinical care to community-based self-management represents a significant challenge, throughout which social support can facilitate health adjustment and quality of life. However, community-centred, peer-led support structures are often underused. This study aimed to investigate the decision-making processes involved in the choice to attend a chronic pain support group (CPSG) following discharge from a Pain Management Programme. DESIGN: An in-depth, qualitative analysis was undertaken using interpretative phenomenological analysis, exploring participants' subjective experiences, decision-making, and rationale for initial CPSG attendance. METHODS: Twelve participants (four males, eight females) were recruited from a regional CPSG and completed semi-structured interviews lasting between 45 and 120 min. Interviews were transcribed verbatim and analysed idiographically before a cross-case analysis was completed. RESULTS: Analysis of transcripts resulted in three superordinate themes: (1) The thirst for comparative friendship; (2) conjecture and the imminent choice; (3) progressive pain management. These themes reflect a desire for empathic, socially comparative friendships and the search for a forum in which to enhance pain self-management strategies, yet also internal conflict over initial CPSG attendance. CONCLUSION: Social support and associated friendships are attractive to prospective CPSG members and are conceptualized as opportunities to engage in social comparison and nurture self-care. The first visit to the support group presents a significant hurdle, but can be facilitated by managing the transition between therapeutic care and CPSG attendance. Clinicians can challenge preconceptions, foster positive viewpoints regarding the group and support collective decision-making to attend. Following initial attendance, psychosocial well-being was enhanced. Statement of contribution What is already known on this subject? Social support functions as a protective buffer against declining health. Joining a peer-led support group can be initially intimidating and the first visit presents a significant hurdle. What does this study add? Participants are predominantly attracted to support groups due to the opportunity to develop new friendships. Health-related peer groups function as fora for social comparison, enhancing self-esteem and self-efficacy. Experience of pain management programmes primes willingness to attend support groups. The initial decision to attend is difficult but facilitated by collective, group decision-making processes. Health care professionals dynamically prime the transition towards peer support structures. PMID- 27230705 TI - Increased transverse relaxivity in ultrasmall superparamagnetic iron oxide nanoparticles used as MRI contrast agent for biomedical imaging. AB - Synthesis of a contrast agent for biomedical imaging is of great interest where magnetic nanoparticles are concerned, because of the strong influence of particle size on transverse relaxivity. In the present study, biocompatible magnetic iron oxide nanoparticles were synthesized by co-precipitation of Fe2+ and Fe3+ salts, followed by surface adsorption with reduced dextran. The synthesized nanoparticles were spherical in shape, and 12 +/- 2 nm in size as measured using transmission electron microscopy; this was corroborated with results from X-ray diffraction and dynamic light scattering studies. The nanoparticles exhibited superparamagnetic behavior, superior T2 relaxation rate and high relaxivities (r1 = 18.4 +/- 0.3, r2 = 90.5 +/- 0.8 s-1 mM-1 , at 7 T). MR image analysis of animals before and after magnetic nanoparticle administration revealed that the signal intensity of tumor imaging, specific organ imaging and whole body imaging can be clearly distinguished, due to the strong relaxation properties of these nanoparticles. Very low concentrations (3.0 mg Fe/kg body weight) of iron oxides are sufficient for early detection of tumors, and also have a clear distinction in pre- and post-enhancement of contrast in organs and body imaging. Many investigators have demonstrated high relaxivities of magnetic nanoparticles at superparamagnetic iron oxide level above 50 nm, but this investigation presents a satisfactory, ultrasmall, superparamagnetic and high transverse relaxivity negative contrast agent for diagnosis in pre-clinical studies. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27230706 TI - Population-weighted efficiency in transportation networks. AB - Transportation efficiency is critical for the operation of cities and is attracting great attention worldwide. Improving the transportation efficiency can not only decrease energy consumption, reduce carbon emissions, but also accelerate people's interactions, which will become more and more important for sustainable urban living. Generally, traffic conditions in less-developed countries are not so good due to the undeveloped economy and road networks, while this issue is rarely studied before, because traditional survey data in these areas are scarce. Nowadays, with the development of ubiquitous mobile phone data, we can explore the transportation efficiency in a new way. In this paper, based on users' call detailed records (CDRs), we propose an indicator named population weighted efficiency (PWE) to quantitatively measure the efficiency of the transportation networks. PWE can provide insights into transportation infrastructure development, according to which we identify dozens of inefficient routes at both the intra- and inter-city levels, which are verified by several ongoing construction projects in Senegal. In addition, we compare PWE with excess commuting indices, and the fitting result of PWE is better than excess commuting index, which also proves the validity of our method. PMID- 27230707 TI - Phthalic anhydride: Illustrating a conundrum in chemical allergy. AB - Although a substantial number of chemicals has the ability to bind covalently to proteins and thereby, given sufficient exposure, induce a state of sensitization, only a small minority appear to be able to cause allergic hypersensitivity of the respiratory tract; the great majority being exclusively skin sensitizers. The key mechanistic drivers for the differentiation between skin and respiratory sensitization are already well characterized at the cellular/cytokine level. However, at both the chemical level and in terms of predictive toxicology, matters are much less clear. In the present article, phthalic anhydride is used as an exemplar, since it displays a particularly differentiated profile as a chemical allergen. Whereas most respiratory sensitizers are known also to give rise to delayed skin reactions, evidence for phthalic anhydride suggests that it only causes immediate type allergy. Chemically, phthalic anhydride can be presumed to react similar to other respiratory sensitizing anhydrides; in predictive tests for skin sensitization, phthalic anhydride is clearly positive, a property it has in common with all other chemical respiratory allergens. Thus, in the context of interpreting predictive toxicology tests for skin sensitization, the inference is that negative results demonstrate an absence of both skin- and respiratory-sensitizing capacity. PMID- 27230708 TI - Blocking the phosphatidylinositol 3-kinase pathway inhibits neuregulin-1-mediated rescue of neurotoxicity induced by Abeta1-42. AB - OBJECTIVES: Neuregulin-1 (NRG1) has an important role in both the development and the plasticity of the brain as well as neuroprotective properties. In this study, we investigated the downstream pathways of NRG1 signalling and their role in the prevention of Abeta1-42 -induced neurotoxicity. METHODS: Lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) generation, superoxide dismutase (SOD) activity and TUNEL staining were assayed to examine the neuroprotective properties in primary rat cortical neurons. KEY FINDINGS: The inhibition of PI3K/Akt activation abolished the ability of NRG1 to prevent Abeta1-42 -induced LDH release and increased TUNEL-positive cell count and reactive oxygen species accumulation in primary cortical neurons. CONCLUSIONS: Our results demonstrate that NRG1 signalling exerts a neuroprotective effect against Abeta1-42 -induced neurotoxicity via activation of the PI3K/Akt pathway. Furthermore, this suggests that NRG1 has neuroprotective potential for the treatment of AD. PMID- 27230709 TI - Do breast cancer survivors benefit from prophylactic removal of uterus and ovaries? A population-based data linkage replication study. AB - AIM: Our previous population-based research found prophylactic surgery (hysterectomy and bilateral salpingo-oophorectomy [BSO]) halved the mortality risk for premenopausal breast cancer patients. Here we aim to replicate findings in a Western Australia dataset. METHOD: Data from the Western Australia Cancer Registry of 15 395 women 20-79 years diagnosed with primary breast cancer (1997 2011) was categorized into four groups: neither hysterectomy nor BSO, hysterectomy only, BSO only, or hysterectomy + BSO. We fitted flexible parametric breast cancer-specific and overall survival models with 95% confidence intervals (also known as Royston-Parmar models) to assess the impact of prophylactic surgery. RESULTS: A total of 12 630 (82.0%) patients had no surgery, 1799 (11.7%) had a hysterectomy only, 337 (2.2%) had BSO only and 629 (4.1%) had both a hysterectomy and BSO. For all-causes mortality, unadjusted 10-year survival was highest for women who had either a hysterectomy + BSO (84.7%) or a hysterectomy only (84.2%). After adjusting for covariates, the survival advantage compared to women without any surgery remained significant for the hysterectomy only group (hazard ratio [HR] = 0.89; 95% confidence interval [CI], 0.81-0.98; P = 0.02). A similar pattern emerged in breast cancer-specific survival with significantly improved survival for women who had a hysterectomy only (HR = 0.83; 95% CI, 0.74 0.94; P = 0.003). However, for non-breast cancer-related survival, having a BSO alone increased risk of death (HR = 1.83; 95% CI, 1.14-2.93; P = 0.01). CONCLUSION: We observed significantly improved overall and breast cancer-specific survival among women who had a hysterectomy only, but increased non-breast cancer related risk after BSO only. Breast cancer patients must weigh up pros and cons of prophylactic surgery. PMID- 27230710 TI - Use of sociological theories and models in research. PMID- 27230711 TI - Fabrication of CoTiO3-TiO2 composite films from a heterobimetallic single source precursor for electrochemical sensing of dopamine. AB - Cobalt titanate-titania composite oxide films have been grown on FTO-coated glass substrates using a single-source heterometallic complex [Co2Ti4(MU O)6(TFA)8(THF)6].THF () which was obtained in quantitative yield from the reaction of diacetatocobalt(ii) tetrahydrate, tetraisopropoxytitanium(iv), and trifluoroacetic acid from a tetrahydrofuran solution. Physicochemical investigations of complex have been carried out by melting point, FT-IR, thermogravimetric and single-crystal X-ray diffraction analyses. CoTiO3-TiO2 films composed of spherical objects of various sizes have been grown from by aerosol-assisted chemical vapor deposition at different temperatures of 500, 550 and 600 degrees C. Thin films characterized by XRD, Raman and X-ray photoelectron spectroscopy, scanning electron microscopy, energy-dispersive X-ray analysis have been explored for electrochemical detection of dopamine (DA). The cyclic voltammetry with the CoTiO3-TiO2 electrode showed a DA oxidation peak at +0.215 V while linear sweep voltammetry displayed a detection limit (LoD) of 0.083 MUM and a linear concentration range of 20-300 MUM for DA. Thus, the CoTiO3 TiO2 electrode is a potential candidate for the sensitive and selective detection of DA. PMID- 27230712 TI - Long-Term Care Coverage as a Microcosm for Health System Reform. PMID- 27230713 TI - Funding Long-Term Care in Canada: Issues and Options. AB - Canada's aging population is likely to result in increased health and long-term care (LTC) costs. It is estimated that between 2012 and 2046, LTC cost liability could reach almost $1.2 trillion. Many Canadians are unaware of the potential burden of LTC expenditures, and there is no consensus on who should pay for them. There are four possible options: (1) general tax revenues; (2) social insurance (employer/employee contributions); (3) private purchase of LTC insurance; and (4) private savings. This paper reviews these options as they have materialized to date in Canada and other countries. Despite the growing acuity of this issue, it seems unlikely that a universal, publicly funded approach to LTC will emerge in Canada. It is clear that federal and provincial/territorial governments must continue to explore policy options for LTC funding including public education, prevention and mitigation strategies and provision for tax-sheltered savings specifically for LTC. PMID- 27230714 TI - Funding for Long-Term Care: Why Public Insurance Makes Sense. AB - Adams and Vanin (2016) build a strong case for public support for private insurance in long-term care. Their main argument is that public coverage is not politically feasible. I start with summing up and criticizing their argument. The gist of my criticism is that the success of their plan requires some kind of selection (not everybody buys coverage), and selection is precisely why private insurance does not work for long-term care. I then reframe my preferred policy option: a public scheme financed out of a flat rate or sales tax. PMID- 27230716 TI - Long-Term Commitment for Long-Term Care. AB - Adams and Vanin have written a timely policy paper on financing long-term care (LTC). Because the subject is so important, the paper could be even stronger in many ways. First, the Adams and Vanin paper explores the main drivers creating pressure to reform the financing of LTC. While it focuses primarily on population aging, the rising incidence of chronic disease is another crucial factor that will drive the need for LTC. This commentary next examines the relative strengths and weaknesses of the proposed policy options. Financing through general tax revenues may not be politically popular but it is likely the most feasible approach given the scope of funds that will be required in the future. It would also provide the most complete coverage of the population. Finally, the commentary identifies several relevant issues that are missing from the policy conversation. The relationship to the disability agenda is crucial because many components of LTC overlap with the provision of disability supports. Some thoughts on next steps would also be helpful. Although most theoretical papers are not concerned with questions of implementation, the latter are vital when it comes to the complex issue of LTC. PMID- 27230715 TI - Determining the Public/Private Mix: Options for Financing Targeted Universality in Long-Term Care. AB - The way in which we pay for long-term care (LTC) services is going to come under enormous pressure as Canada's baby boomers age. Once baby boomers start to turn 75, in 2021, the demand for LTC services will see a sharp upward trend. A number of independent projections have demonstrated how this will put pressure on the public finances in coming years. It should be concerning to Canadians that we have not publicly discussed how we will make the tough choices to cope with these pressures. Moreover, it's equally troubling that our provincial LTC systems already are unable to cope with the current level of demand for services, with less than a decade before the first wave of boomers enter age groups where demand for LTC is high, and alternate level of care patients, made up mostly of frail elderly, occupying over 15% of Canadian hospital beds on a daily basis as they await care elsewhere. Although we think it is unlikely that Canadian provinces will add LTC to the list of fully subsidized health services (hospitals and doctors), we should do a better job of targeting the existing public subsidies for LTC - and do so while putting LTC financing on a more sustainable footing. PMID- 27230717 TI - Funding Long-Term Care in Canada: Who Is Responsible for What? AB - As Adams and Vanin (2016) have noted, different ways of funding long-term care (LTC) have different implications. Because health is not just healthcare, and LTC is not homogeneous, determining the appropriate public-private mix is complex. We suggest that how issues are framed helps influence policy choices, including who should pay for what, and how things should be financed. In addition, the distribution of expenditures for some services can be highly skewed, affecting the extent to which average cost data are useful in extrapolating their costs. We note that health expenditures fall into multiple categories, each presenting different policy issues. For example, framing LTC as health, as basic costs associated with living or as forced savings (like pensions) affects which funding approaches might be used, and the extent to which changes in the population distribution will affect cost structures. Underlying these discussions are questions of solidarity, and how much we believe that we are our brother's - or grandmother's - keeper. PMID- 27230718 TI - A Fifth Option for Funding Long-Term Care in Canada - Shift the Resources from Medical Treatment and Universal Pension Entitlements. AB - Needs for non-medical residential care services, long-term care (LTC), will increase over the next 30 years as Canada's population ages. Adams and Vanin (2016) explore four options for raising the public and private monies required to meet LTC needs. In this commentary, I raise a fifth option for finding the resources to meet emerging LTC needs. An alternative approach is to divert resources from Canada's well-resourced, but inefficient, medical treatment system. The dividend of provinces pursuing long overdue reforms to medicare is the liberation of public funds to finance emerging priorities for Canadians like LTC. PMID- 27230719 TI - Still-Born Autonomy Insurance Plan in Quebec: An Example of a Public Long-Term Care Insurance System in Canada. AB - Funding long-term care (LTC) is a challenge under the existing Beveridgean universal healthcare system. The Autonomy Insurance (AI) plan developed in Quebec was an attempt to introduce public LTC insurance into our healthcare system. The AI benefit was based on an assessment of the needs of older people and those with disabilities using a disability scale (SMAF) and case-mix classification system (Iso-SMAF Profiles). Under the plan, the benefit would be used to fund public institutions or purchase services from private organizations. Case managers were responsible for assessments and helping users and their families plan services and decide how to use the AI benefit. Funding AI was based on general tax revenues without capitalized funding, under a separate protected budget program. Projections were made for the additional budget needed to support AI, which would have mitigated the forecast increase in LTC spending due to population aging. All the legal, administrative, funding, training and contractual issues were dealt with, for implementation of the plan in April 2015. Unfortunately, the project was still-born for political reasons, but it demonstrates the feasibility of this essential innovation for Canada. PMID- 27230720 TI - Recognizing the Magnitude of the Challenge. AB - "Funding Long-Term Care in Canada: Issues And Options" (Adams and Vanin 2016) is a well-argued paper that grounds its recommendations in learnings from other jurisdictions that have tried to enact major reforms to the funding approach for long-term care (LTC). In particular, the paper considers the experience in both the UK and Quebec. The paper correctly highlights the significant difficulty of implementing large structural reforms to deal with LTC funding challenges. This is not a surprising result. Structural reform in healthcare has proven challenging even when the problems being addressed are immediate and large in scale, let alone for those that will manifest themselves in increments over many years or even decades in the future. The authors are correct, in my view, to focus on the art of the possible and to seek ways to set Canada on a path towards addressing the coming challenges around LTC, rather than proposing a big-bang fix. PMID- 27230721 TI - Initial somatic symptoms are associated with prolonged symptom duration following concussion in adolescents. AB - AIM: To determine which initial postinjury symptom domains are independently associated with symptoms lasting >28 days in youth athletes who sustained sport related concussions. METHODS: Patients who presented for care at a sport concussion clinic completed the postconcussion symptom scale. They were classified into two groups: those who reported symptom resolution within 28 days of injury and those who did not. Logistic regression models were constructed for children and adolescents to determine the independent association between symptom recovery and potential predictor variables: initial symptom scores in 5 postconcussion symptom scale domains (somatic, vestibular-ocular, cognitive, sleep and emotional), sex, loss of consciousness or amnesia at the time of injury, history of prior concussion, prior treatment for headaches or migraines, or family history of concussion. RESULTS: Sixty-eight child (8-12 years of age) and 250 adolescent (13-18 years of age) athletes were included. For adolescents, initial somatic symptom severity was independently associated with prolonged symptom duration (adjusted odds ratio = 1.162; 95% CI: 1.060, 1.275) and no other predictor variables were. No potential predictor variables were independently associated with prolonged symptom duration for children. CONCLUSION: Among adolescent athletes, a high initial somatic symptom burden (e.g. headache, nausea, vomiting, etc.) is associated with increased odds of symptoms beyond 28 days postinjury. PMID- 27230722 TI - The Proof is in the Pudding: Does tDCS Actually Deliver DC Stimulation? PMID- 27230724 TI - Exfoliated beta-Ga2O3 nano-belt field-effect transistors for air-stable high power and high temperature electronics. AB - This study demonstrated the exfoliation of a two-dimensional (2D) beta-Ga2O3 nano belt and subsequent processing into a thin film transistor structure. This mechanical exfoliation and transfer method produces beta-Ga2O3 nano-belts with a pristine surface as well as a continuous defect-free interface with the SiO2/Si substrate. This beta-Ga2O3 nano-belt based transistor displayed an on/off ratio that increased from approximately 10(4) to 10(7) over the operating temperature range of 20 degrees C to 250 degrees C. No electrical breakdown was observed in our measurements up to VDS = +40 V and VGS = -60 V between 25 degrees C and 250 degrees C. Additionally, the electrical characteristics were not degraded after a month-long storage in ambient air. The demonstration of high-temperature/high voltage operation of quasi-2D beta-Ga2O3 nano-belts contrasts with traditional 2D materials such as transition metal dichalcogenides that intrinsically have limited temperature and power operational envelopes owing to their narrow bandgap. This work motivates the application of 2D beta-Ga2O3 to high power nano electronic devices for harsh environments such as high temperature chemical sensors and photodetectors as well as the miniaturization of power circuits and cooling systems in nano-electronics. PMID- 27230723 TI - P-wave complexity in normal subjects and computer models. AB - BACKGROUND: P waves reported in electrocardiology literature uniformly appear smooth. Computer simulation and signal analysis studies have shown much more complex shapes. OBJECTIVE: We systematically investigated P-wave complexity in normal volunteers using high-fidelity electrocardiographic techniques without filtering. METHODS: We recorded 5-min multichannel ECGs in 16 healthy volunteers. Noise and interference were reduced by averaging over 300 beats per recording. In addition, normal P waves were simulated with a realistic model of the human atria. RESULTS: Measured P waves had an average of 4.1 peaks (range 1-10) that were reproducible between recordings. Simulated P waves demonstrated similar complexity, which was related to structural discontinuities in the computer model of the atria. CONCLUSION: The true shape of the P wave is very irregular and is best seen in ECGs averaged over many beats. PMID- 27230725 TI - How clients' during-treatment motivations relate to their perceptions and impressions of methadone maintenance treatment: A multilevel analysis of a cross sectional survey in Guangdong Province, China. AB - BACKGROUND: Much evidence has suggested the positive effect of methadone maintenance treatment (MMT) on mitigating adverse outcomes caused by opioid use. Pretreatment motivations are associated with clients' engagement, retention, and outcomes in drug use treatment. However, motivation is mutable, and few MMT researchers have considered during-treatment motivations and associated multilevel factors. OBJECTIVE: We aimed to investigate during-treatment motivations and clinic- and individual-level associated factors among MMT clients in Guangdong Province, China. METHODS: Stratified random sampling was used to select 12 MMT clinics in Guangdong Province. Between December 2011 and January 2012, a total of 802 respondents were surveyed about their motivation and multilevel factors using the following instruments: the Texas Christian University (TCU) Treatment Motivation Scales, the impression-of-detoxification scale, the National MMT Data Management System of China, and structured questionnaires. Multilevel models were employed to conduct the univariate and multivariate analyses of the factors associated with during-treatment motivations for MMT. RESULTS: The means +/- SD (95% CI) of clients' during-treatment motivations (Desire for Help and Treatment Readiness) were 2.89+/-0.56 (2.85, 2.93) and 2.28+/-0.57 (2.24, 2.32). Multilevel analyses showed that clients' educational level, perceptions, and impressions of MMT; and clinics' supportive family assistance and closing time were significantly associated with during treatment motivations for MMT (P<0.05). CONCLUSIONS: During-treatment motivation may play a significant role in the success of MMT. There is a need for improving motivation among Chinese MMT clients, and the knowledge of associated factors may guide more effective program in the future. PMID- 27230726 TI - Measuring thermal behavior in smaller insects: A case study in Drosophila melanogaster demonstrates effects of sex, geographic origin, and rearing temperature on adult behavior. AB - Measuring thermal behavior in smaller insects is particularly challenging. In this study, we describe a new horizontal thermal gradient apparatus designed to study adult thermal behavior in small insects and apply it using D. melanogaster as a model and case study. Specifically, we used this apparatus and associated methodology to examine the effects of sex, geographic origin, and developmental rearing temperature on temperature preferences exhibited by adults in a controlled laboratory environment. The thermal gradient established by the apparatus was stable over diurnal and calendar time. Furthermore, the distribution of adult flies across thermal habitats within the apparatus remained stable following the period of acclimation, as evidenced by the high degree of repeatability across both biological and technical replicates. Our data demonstrate significant and predictable variation in temperature preference for all 3 assayed variables. Behaviorally, females were more sensitive than males to higher temperatures. Flies originating from high latitude, temperate populations exhibited a greater preference for cooler temperatures; conversely, flies originating from low latitude, tropical habitats demonstrated a relative preference for higher temperatures. Similarly, larval rearing temperature was positively associated with adult thermal behavior: low culture temperatures increased the relative adult preference for cooler temperatures, and this response was distinct between the sexes and for flies from the temperate and subtropical geographic regions. Together, these results demonstrate that the temperature chamber apparatus elicits robust, predictable, and quantifiable thermal preference behavior that could readily be applied to other taxa to examine the role of temperature-mediated behavior in a variety of contexts. PMID- 27230727 TI - Obesity, diet quality and absenteeism in a working population. AB - OBJECTIVE: The relationship between workplace absenteeism and adverse lifestyle factors (smoking, physical inactivity and poor dietary patterns) remains ambiguous. Reliance on self-reported absenteeism and obesity measures may contribute to this uncertainty. Using objective absenteeism and health status measures, the present study aimed to investigate what health status outcomes and lifestyle factors influence workplace absenteeism. DESIGN: Cross-sectional data were obtained from a complex workplace dietary intervention trial, the Food Choice at Work Study. SETTING: Four multinational manufacturing workplaces in Cork, Republic of Ireland. SUBJECTS: Participants included 540 randomly selected employees from the four workplaces. Annual count absenteeism data were collected. Physical assessments included objective health status measures (BMI, midway waist circumference and blood pressure). FFQ measured diet quality from which DASH (Dietary Approaches to Stop Hypertension) scores were constructed. A zero inflated negative binomial (zinb) regression model examined associations between health status outcomes, lifestyle characteristics and absenteeism. RESULTS: The mean number of absences was 2.5 (sd 4.5) d. After controlling for sociodemographic and lifestyle characteristics, the zinb model indicated that absenteeism was positively associated with central obesity, increasing expected absence rate by 72 %. Consuming a high-quality diet and engaging in moderate levels of physical activity were negatively associated with absenteeism and reduced expected frequency by 50 % and 36 %, respectively. Being in a managerial/supervisory position also reduced expected frequency by 50 %. CONCLUSIONS: To reduce absenteeism, workplace health promotion policies should incorporate recommendations designed to prevent and manage excess weight, improve diet quality and increase physical activity levels of employees. PMID- 27230728 TI - Stereoselective Rh-Catalyzed Hydrogenative Desymmetrization of Achiral Substituted 1,4-Dienes. AB - Highly efficient catalytic stereoselective hydrogenative desymmetrization reactions mediated by rhodium complexes derived from enantiopure phosphine phosphite (P-OP) ligands are described. The highest performing ligand, which contains a TADDOL-derived phosphite fragment [TADDOL = (2,2-dimethyl-1,3 dioxolane-4,5-diyl)bis(diphenylmethanol)], presented excellent catalytic properties for the desymmetrization of a set of achiral 1,4-dienes, providing access to the selective formation of a variety of enantioenriched secondary and tertiary alcohols (six examples, up to 92% ee). PMID- 27230729 TI - Effects of maternal folic acid supplementation on gene methylation and being small for gestational age. AB - BACKGROUND: Being small for gestational age (SGA), a foetal growth abnormality, has a long-lasting impact on childhood health. Its aetiology and underlying mechanisms are not well understood. Underlying epigenetic changes of imprinted genes have emerged as a potential pathological pathway because they may be associated with growth, including SGA. As a common methyl donor, folic acid (FA) is essential for DNA methylation, synthesis and repair, and FA supplementation is widely recommended for women planning pregnancy. The present study aimed to investigate the inter-relationships among methylation levels of two imprinted genes [H19 differentially methylated regions (DMRs) and MEST DMRs], maternal FA supplementation and SGA. METHODS: We conducted a case-control study. Umbilical cord blood was taken from 39 SGA infants and 49 controls whose birth weights are appropriate for gestational age (AGA). DNA methylation levels of H19 and MEST DMRs were determined by an analysis of mass array quantitative methylation. RESULTS: Statistically significantly higher methylation levels were observed at sites 7.8, 9 and 17.18 of H19 (P = 0.030, 0.016 and 0.050, respectively) in the SGA infants compared to the AGA group. In addition, the association was stronger in male births where the mothers took FA around conception at six H19 sites (P = 0.004, 0.005, 0.048, 0.002, 0.021 and 0.005, respectively). CONCLUSIONS: Methylation levels at H19 DMRs were higher in SGA infants compared to AGA controls. It appears that the association may be influenced by maternal peri conception FA supplementation and also be sex-specific. PMID- 27230730 TI - Radiation dose distribution in coronary arteries in breast cancer radiotherapy. AB - BACKGROUND: Women irradiated for left-sided breast cancer (BC) have an increased risk of coronary artery disease compared to women with right-sided BC. We describe the distribution of radiation dose in segments of coronary arteries in women receiving adjuvant radiotherapy (RT) for left- or right-sided BC. MATERIAL AND METHODS: Fifteen women with BC, seven left-sided and eight right-sided, who had received three-dimensional conformal radiotherapy (3DCRT), constituted the study base. The heart and the segments of the coronary arteries were defined as separate organs at risk (OAR), and the mean and maximum radiation doses were calculated for each OAR. RESULTS: In women with left-sided BC, irrespective of if regional lymph node RT was given or not, maximum dose in mid and distal left anterior descending artery (mdLAD) was approximately 50 Gy in 6/7 patients, whereas women with right-sided BC mainly received low doses of radiation. In women with left-sided BC, 6/7 patients had substantially higher mean dose to the distal LAD than to the heart, ranging from 30 to 55 Gy and 3 to13 Gy, respectively. CONCLUSION: We found a pronounced difference of radiation dose distribution in the coronary arteries between women with left- and right-sided BC. Women with left-sided BC had almost full treatment dose in parts of mdLAD, regardless of if regional lymph node irradiation was given or not, while women with right-sided BC mainly received low doses to the coronary arteries. PMID- 27230731 TI - Computerized tomography of the acute left upper quadrant pain. AB - The purpose of this study was to evaluate the clinical utility of computerized tomography (CT) of the abdomen in the emergent setting of left upper quadrant pain. One hundred patients (average age: 45, range: 19-93 years, female: 57 %, male: 43 %) who presented to the emergency department (ED) and underwent CT scanning of abdomen with the given indication of left upper quadrant pain were included in this study. The results from CT examinations were compared to final diagnoses determined by either ED physician or clinician on a follow-up visit. Sensitivity of CT was 69 % (95 %CI: 52-83 %) for 39 patients who eventually were diagnosed with an acute abdominal abnormality. Twenty-seven patients had an acute abnormal finding on abdominal CT that represented the cause of the patient's pain (positive predictive value of 100 %, 95 %CI: 87-100 %). Of the remaining 73 patients with negative CT report, 12 were diagnosed clinically (either in the ED or on follow-up visit to specialist) with a pathology that was undetectable on the CT imaging (negative predictive value of 83 %, 95 %CI: 73-91 %). None of the remaining 61 patients with negative CT were found to have pathology by clinical evaluation (specificity of 100 %, 95 %CI: 94-100 %). CT is a useful examination for patients with acute left upper quadrant pain in the emergency department setting with moderate sensitivity and excellent specificity. PMID- 27230732 TI - Pathway Compartmentalization in Peroxisome of Saccharomyces cerevisiae to Produce Versatile Medium Chain Fatty Alcohols. AB - Fatty alcohols are value-added chemicals and important components of a variety of industries, which have a >3 billion-dollar global market annually. Long chain fatty alcohols (>C12) are mainly used in surfactants, lubricants, detergents, pharmaceuticals and cosmetics while medium chain fatty alcohols (C6-C12) could be used as diesel-like biofuels. Microbial production of fatty alcohols from renewable feedstock stands as a promising strategy to enable sustainable supply of fatty alcohols. In this study, we report, for the first time, that medium chain fatty alcohols could be produced in yeast via targeted expression of a fatty acyl-CoA reductase (TaFAR) in the peroxisome of Saccharomyces cerevisiae. By tagging TaFAR enzyme with peroxisomal targeting signal peptides, the TaFAR could be compartmentalized into the matrix of the peroxisome to hijack the medium chain fatty acyl-CoA generated from the beta-oxidation pathway and convert them to versatile medium chain fatty alcohols (C10 &C12). The overexpression of genes encoding PEX7 and acetyl-CoA carboxylase further improved fatty alcohol production by 1.4-fold. After medium optimization in fed-batch fermentation using glucose as the sole carbon source, fatty alcohols were produced at 1.3 g/L, including 6.9% 1-decanol, 27.5% 1-dodecanol, 2.9% 1-tetradecanol and 62.7% 1 hexadecanol. This work revealed that peroxisome could be engineered as a compartmentalized organelle for producing fatty acid-derived chemicals in S. cerevisiae. PMID- 27230733 TI - The triad psoriasis-obesity-adipokine profile. AB - Psoriasis is a chronic inflammatory skin disease, often associated with overweight/obesity. The adipose tissue is a complex organ that secretes several adipokines, involved in the regulation of some metabolic processes, such as lipid metabolism, glucose homeostasis, angiogenesis, blood pressure and inflammation. In obesity, the distribution and function of adipose tissue, and the adipokine profile are altered. The unbalanced production of pro- and anti-inflammatory adipokines in obesity, contributes to the development of a chronic low-grade inflammation state, which seems to favour worsening of psoriasis lesion and a poorer response to treatment. In this review, we will debate published data concerning the current knowledge about the triad psoriasis-obesity-adipokine profile. PMID- 27230734 TI - Transition Metal-Participated Synthesis and Utilization of N-containing Heterocycles: Exploring for Nitrogen Sources. AB - This account aims to describe our recent efforts on the synthesis and utilization of N-containing heterocycles, where transition metals participate in the synthesis. A variety of nitrogen sources, including amines, amides, hydrazones, pyrimidines, isocyanides, and copper nitrate, have been disclosed for the synthesis of diverse bioactive and pharmacologically interesting N-containing heterocycles under the participation of transition metals. The well-known nitrogen sources, such as amines and amides, were used for the construction of indoles, isatins, and quinolones. Dihydrophthalazines, isoquinolines, indazoles, and pyrazoles were obtained from hydrazones, while various pyrimidine-containing heterocycles were afforded through regioselective C-H functionalizations using pyrimidine as the directing group. Recent research has focused on the chemistry of isocyanides to achieve several kinds of heterocyclic compounds with high efficiency under the catalysis of transition metals (Pd, Rh, Mn, Cu), through oxidative cyanation reactions, sequential isocyanide insertions into C-H, N-H, or O-H bonds, and tandem radical annulation. More recently, an efficient route to isoxazolines has been reported using copper nitrate as a novel nitrogen source. PMID- 27230735 TI - Effect of regional competition on heart transplant waiting list outcomes. AB - BACKGROUND: Heterogeneity of risk within heart transplant urgency designations is undesirable. Regional competition for donor hearts may contribute to this variation in risk. In this study we assessed whether an association exists between center competition and variation in event rates within status designations on the waiting list. METHODS: Our study sample included 20,237 adult transplant registrants initially listed between July 1, 2006 and July 1, 2013. Market competition was quantified using the Herfindahl-Hirshman Index (HHI) and number of centers within a donor service area (DSA) per 1 million people. A Cox model was used to assess for variation in waiting list outcomes within status designation by both HHI and DSA density. The primary outcome was death or delisting as too ill. RESULTS: Outcome rates within status designations differed significantly between centers: Status 1A, center p < 0.0001; Status 1B, center p < 0.0001; and Status 2, center p < 0.0001. Market competition (decreasing HHI) was associated with differential outcome rates within higher urgency status designation [Status 1A hazard ratio (HR) 0.94, p = 0.012; Status 1B HR 0.95, p = 0.010; and Status 2 HR 1.02, p = 0.360]. Center density within the DSA was not associated with outcome rates within each status designation (Status 1A HR 0.99, p = 0.961; Status 1B HR 1.03, p = 0.901; and Status 2 HR 1.20, p = 0.399). CONCLUSIONS: The rate of death or delisting as too ill within urgency designations varies between transplant centers and is partially explained by competition between transplant programs. Further methods of normalizing risk within status designations are necessary. PMID- 27230736 TI - The regulatory framework for preventing cross-contamination of pharmaceutical products: History and considerations for the future. AB - Cross-contamination in multi-product pharmaceutical manufacturing facilities can impact both product safety and quality. This issue has been recognized by regulators and industry for some time, leading to publication of a number of continually evolving guidelines. This manuscript provides a historical overview of the regulatory framework for managing cross-contamination in multi-product facilities to provide context for current approaches. Early guidelines focused on the types of pharmaceuticals for which dedicated facilities and control systems were needed, and stated the requirements for cleaning validation. More recent guidelines have promoted the idea of using Acceptable Daily Exposures (ADEs) to establish cleaning limits for actives and other potentially hazardous substances. The ADE approach is considered superior to previous methods for setting cleaning limits such as using a predetermined general limit (e.g., 10 ppm or a fraction of the median lethal dose (LD50) or therapeutic dose). The ADEs can be used to drive the cleaning process and as part of the overall assessment of whether dedicated production facilities are required. While great strides have been made in using the ADE approach, work remains to update good manufacturing practices (GMPs) to ensure that the approaches are clear, consistent with the state-of-the-science, and broadly applicable yet flexible enough for adaptation to unique products and situations. PMID- 27230737 TI - Mercury levels and human health in the Amazon Basin. AB - CONTEXT: Environmental mercury in the Amazon mostly originates from geochemical sources with some from artisanal gold mining (AGM). Geochemical-originated methylmercury (MeHg) reaches the aquatic food chain, ending up in fish. Inorganic Hg used in AGM is responsible for localised environmental contamination and occupational exposure of adults. In addition to this, iatrogenic ethylmercury (EtHg) derived from Thimerosal-containing vaccines (TCVs) exposes immunised infants. OBJECTIVE: To understand Hg exposure in the Amazon in relation to environmental fish-MeHg exposure, occupational AGM activities and low-doses of TCV-EtHg. METHODS: Medline and Thomson-Reuter Web of Science were searched to retrieve and select papers addressing Hg exposure and human health. RESULTS AND CONCLUSION: Environmental-Hg studies addressed health effects associated with birth weight, infant linear growth and neurodevelopment, while, in adults, environmental and occupational studies addressed immune and neurological issues. No widespread clinical toxicity was reported due to fish-MeHg. However, mixed results associated with Hg exposure can be found. Reducing children's exposure to EtHg is possible using Thimerosal-free vaccines, but it is difficult to interfere with fish consumption without consequences to riverine subsistence populations. Policies to diminish Hg exposure should focus on controlling and/or curbing widespread use of Hg (in gold amalgamation) and promotion of Thimerosal-free vaccines for pregnant women and young children. PMID- 27230738 TI - Migration and psychosis in acute inpatient psychiatry. AB - OBJECTIVE: We investigated the role of biological and psychosocial risk factors in the development of psychotic disorders with regards to immigrant status. Our hypothesis was that biological risk factors are more predictive of psychosis in non-immigrants, whereas psychosocial risk factors play a bigger role in immigrants. METHOD: A retrospective audit of admissions between December 2013 and June 2014 in an Australian adult inpatient unit was conducted, focussing on patients with psychotic disorders. We analysed the association between immigrant status, and biological and psychosocial variables. RESULTS: For biological risk factors, non-immigrants had significantly more family history of psychotic disorders (p = 0.021), illicit drug use (p = < 0.001) and alcohol use (p = < 0.001). For psychosocial risk factors, immigrants were more likely to have experienced a traumatic event (p = 0.022). With regards to age of index presentation, age at onset of psychotic disorder, proportion of males and dysfunctional family background, there was no significant difference. CONCLUSION: Retrospective data in this report suggests that the development of psychotic disorders in immigrants and non-immigrants may be different. PMID- 27230740 TI - The importance of the timescale of the fitness metric for estimates of selection on phenotypic traits during a period of demographic change. AB - Although fitness is central to the evolutionary process, metrics vary by timescale. Different timescales may give rise to different estimates of selection, especially during demographic transitions caused by rapid environmental and socioeconomic change. In this study, we used a dataset of a human population in Finland from 1775 to 1950 to compare two fitness metrics and their estimates of selection pressures, before and during a demographic transition. Both metrics, lifetime reproductive success and an annual metric of individual performance, declined while selection on the ages at first and last reproduction remained nearly constant, favouring individuals with wider reproductive windows. The ability to partition the annual metric into contributions from reproduction and survival revealed the short-term effects of a famine and the reversal of selection pressure via the survival component of annual fitness. Although the metrics generally agreed, the annual metric detected the effects of environmental variation and demographic change occurring within a generation. PMID- 27230739 TI - Malaria and other febrile diseases among travellers: the experience of a reference centre located outside the Brazilian Amazon Region. AB - BACKGROUND: Malaria is endemic in countries located in tropical and sub-tropical regions. The increasing flow of domestic and international travellers has made malaria a relevant health problem even in non-endemic regions. Malaria has been described as the main diagnosis among travellers presenting febrile diseases after returning from tropical countries. In Brazil, malaria transmission occurs mainly in the Amazon region. Outside this area, malaria transmission is of low magnitude. METHODS: This cross-sectional study aimed to describe the experience in the diagnosis of malaria in a reference centre located outside the Brazilian Amazon Region, emphasizing the differences in clinical and laboratory markers between cases of malaria and those of other febrile diseases (OFD). Medical charts from adult patients (>=18 years) who underwent a thick smear test (TST) for malaria, between January 2001 and December 2014, were retrospectively reviewed. RESULTS: A total of 458 cases referred to perform the TST were included. Malaria was diagnosed in 193 (42 %) episodes. The remaining 265 episodes (58 %) were grouped as OFD. The majority of malaria episodes were acquired in the Brazilian Amazon Region. The median time between the onset of symptoms and the TST was 7 days. Only 53 (11.5 %) episodes were tested within the first 48 h after symptom onset. Comparing malaria with OFD, jaundice, nausea, vomiting, and reports of fever were more prevalent in the malaria group. Low platelet count and elevated bilirubin levels were also related to the diagnosis of malaria. CONCLUSIONS: The results indicate that outside the endemic area travellers presenting febrile disease suspected of being malaria underwent diagnostic test after considerable delay. The reporting of fever combined with a recent visit to an endemic area should promptly evoke the hypothesis of malaria. In these cases, specific diagnostic tests for malaria should be a priority. For cases that jump this step, the presence of elevated bilirubin or thrombocytopaenia should also indicate a diagnosis of malaria. PMID- 27230741 TI - HBM Mice Have Altered Bone Matrix Composition and Improved Material Toughness. AB - The G171V mutation in the low-density lipoprotein receptor-related protein 5 (LRP5) leads to a high bone mass (HBM) phenotype. Studies using HBM transgenic mouse models have consistently found increased bone mass and whole-bone strength, but little attention has been paid to the composition of the bone matrix. The current study sought to determine if the cortical bone matrix composition differs in HBM and wild-type mice and to determine how much of the variance in bone material properties is explained by variance in matrix composition. Consistent with previous studies, HBM mice had greater cortical area, moment of inertia, ultimate force, bending stiffness, and energy to failure than wild-type animals. The increased energy to failure was primarily caused by a large increase in post yield behavior, with no difference in pre-yield behavior. The HBM mice had increased mineral-to-matrix and collagen cross-link ratios, and decreased crystallinity, carbonate, and acid phosphate substitution as measured by Fourier transform infrared microspectroscopy, but no differences in crystal length, intra fibular strains, and mineral spacing compared to wild-type controls, as measured by X-ray scattering. The largest between genotype difference in material properties was a twofold increase in the modulus of toughness in HBM mice. Step wise regression analyses showed that the specific matrix compositional parameters most closely associated with material properties varied between the wild-type and HBM genotypes. Although the mechanisms controlling the paradoxical combination of more mineralized yet tougher bone in HBM mice remain to be fully explained, the findings suggest that LRP5 represents a target to not only build bone mass but also to improve bone quality. PMID- 27230742 TI - Batch anaerobic co-digestion of waste activated sludge and microalgae (Chlorella sorokiniana) at mesophilic temperature. AB - The microalgae Chlorella sorokiniana are used as co-substrate for waste activated sludge (WAS) anaerobic digestion. The specific objective of this research was to evaluate the feasibility of improving methane production from anaerobic digestion of WAS in co-digestion with this microalga, based on an optimized mixture percentage. Thus, the anaerobic co-digestion of both substrates aims to overcome the drawbacks of the anaerobic digestion of single WAS, simultaneously improving its management. Different co-digestion mixtures (0% WAS-100% microalgae; 25% WAS 75% microalgae; 50% WAS-50% microalgae; 75% WAS-25% microalgae; 100% WAS-0% microalgae) were studied. The highest methane yield (442 mL CH4/g VS) was obtained for the mixture with 75% WAS and 25% microalgae. This value was 22% and 39% higher than that obtained in the anaerobic digestion of the sole substrates WAS and microalgae, respectively, as well as 16% and 25% higher than those obtained for the co-digestion mixtures with 25% WAS and 75% microalgae and 50% WAS and 50% microalgae, respectively. The kinetic constant of the process increased 42%, 42% and 12%, respectively, for the mixtures with 25%, 50% and 75% of WAS compared to the substrate without WAS. Anaerobic digestion of WAS, together with C. sorokiniana, has been clearly improved by ensuring its viability, suitability and efficiency. PMID- 27230743 TI - Direct access to magnetic resonance imaging improved orthopaedic knee referrals in the Netherlands. AB - BACKGROUND: The use of magnetic resonance imaging (MRI) in primary care is under debate, and the majority of GPs have no experience with MRI. OBJECTIVES: To examine for which patients with knee injury an MRI is ordered and does direct access to MRI in primary care influence the GP referral to an orthopaedic surgeon? METHODS: Consecutive patients with knee injury who underwent an MRI examination ordered by their GP were included. On the application form for MRI, the GPs indicated their referral intention in advance, as if MRI had not been available. Six months after the MRI scan, written interviews with the GPs were used to collect data on referrals and orthopaedic intervention. The number of patients finally referred to an orthopaedic surgeon in secondary care after MRI was compared with the number of intended referrals. RESULTS: Of the 588 included, GPs referred fewer patients to the orthopaedic surgeon after receiving the MRI results than they would have done prior to MRI (60% versus 82.8%, P < 0.0001). The reduction was 16.1% for patients older than 50 years and 28.1% for patients younger than 50 years. Orthopaedic intervention was performed in 62.9% of all referred patients. Of the 101 patients whom the GP did not intend to refer prior to MRI, 48 were referred to an orthopaedic surgeon based on the MRI findings. CONCLUSION: In patients with knee injury, direct access to MRI of the knee in a primary care setting significantly reduced referrals to an orthopaedic surgeon. LEVEL OF EVIDENCE: Three prospective cohort. PMID- 27230744 TI - Development of overweight and obesity among primary school children-a longitudinal cohort study. AB - BACKGROUND: School health care is crucial for obesity prevention. Data on constancy of childhood obesity are still scarce, but highly necessary for risk evaluation. OBJECTIVES: We examined from electronic health records (EHRs) the continuity of obesity during primary school and searched for social and behavioural characteristics associated with childhood obesity. METHODS: From randomly selected 2000 Finnish sixth graders (aged 12-14), we identified 402 'ever overweight' and 172 'ever obese' children who were overweight or obese at least once since their first grade. These cohort data of growth measurements and the content of all pre-seventh grade health checks were retrospectively analysed from EHRs. RESULTS: Of the ever obese and ever overweight children, 69.3% (95% CI: 65.2-73.4%) continued to be overweight or obese in sixth grade. Of the ever obese children, nearly 40% were obese in first grade and 56% were obese or overweight in all six grades. Furthermore, 80% were obese or overweight already before school age. Obese children had experienced more bullying than overweight children (43.6% versus 30.8%, P = 0.003), had more frequently special needs for studying (25.6% versus 14.7%, P = 0.002) or had undergone a serious family crisis (20.3% versus 11.4%, P = 0.005). CONCLUSIONS: Electronic data on children's growth and psychosocial characteristics are potentially useful when aiming for early action to counter obesity. Such routinely collected data appear to be underutilized and should be further exploited both in individual and population level to develop screening and treatment processes. PMID- 27230745 TI - C-reactive protein point-of-care testing and associated antibiotic prescribing. AB - BACKGROUND: In clinical trials, the potential of point-of-care (POC) C-reactive protein (CRP) tests was demonstrated in decreasing antibiotic prescribing in adults with acute cough in general practice, but effects of implementation are unknown. OBJECTIVE: To determine the overall effect of POC CRP testing on antibiotic prescribing rate in general practice. METHODS: In an observational study, GPs were instructed to use POC CRP in adults with acute cough following current guidelines. After routine history taking and physical examination, they reported whether they intended to prescribe antibiotics ('pre-test decision'). They reported their revised decision after receiving the POC CRP test result ('post-test decision'). Primary outcome was the percentage of patients in whom the GP changed his or her decision to prescribe antibiotics. Secondary outcome was the difference between 'pre-test' and 'post-test' antibiotic prescribing % at group level. RESULTS: A total of 40 GPs enrolled 939 patients, 78% of whom were tested for CRP. GPs changed their decision after POC CRP testing in 200 patients (27%). Antibiotic prescribing before and after CRP testing did not differ ('pre test' 31%, 'post-test' 28%; 95% confidence interval of difference -7 to 1). In 41% of the tested patients, the indication for testing was in accordance with the guidelines. CONCLUSION: POC CRP influenced GPs to change their decision about antibiotic prescribing in patients with acute cough. POC CRP testing does not reduce overall antibiotic prescribing by GPs who already have a low antibiotic prescribing rate. PMID- 27230746 TI - The impact on post-operative shoulder function of intraoperative nerve monitoring of cranial nerve XI during modified radical neck dissection. AB - Intraoperative monitoring of the cranial nerve XI (CN XI) may decrease shoulder disability following modified radical neck dissection. Prospective study was designed comparing results of Constant Shoulder Score (CSS), Shoulder Pain and Disability Index (SPADI) and EMG score of the trapezius muscle (mT) before and after surgery. One side of the neck was monitored during surgery with intraoperative nerve monitor. EMG scores of the mT 6 months postoperatively were statistically better on monitored as compared to the non-monitored side of the neck (p = 0.041), while the differences of the CSS and SPADI were not statistically significant. Patients with better EMG scores of the mT at 6 weeks recuperated better and with smaller decrease of the CSS. Intraoperative monitoring is beneficial at the beginning of the surgeon's learning curve and in the process of familiarizing with anatomical variation of the CN XI. PMID- 27230747 TI - Longevity-modulating effects of symbiosis: insights from Drosophila-Wolbachia interaction. AB - Microbial communities are known to significantly affect various fitness components and survival of their insect hosts, including Drosophila. The composition of symbiotic microbiota has been shown to change with the host's aging. It is unclear whether these changes are caused by the aging process or, vice versa, they affect the host's aging and longevity. Recent findings indicate that fitness and lifespan of Drosophila are affected by endosymbiotic bacteria Wolbachia. These effects, however, are inconsistent and have been reported both to extend and shorten longevity. The main molecular pathways underlying the lifespan-modulating effects of Wolbachia remain unclear, however insulin/insulin like growth factor, immune deficiency, ecdysteroid synthesis and signaling and c Jun N-terminal kinase pathways as well as heat shock protein synthesis and autophagy have been proposed to play a role. Here we revise the current evidence that elucidates the impact of Wolbachia endosymbionts on the aging processes in Drosophila. PMID- 27230748 TI - Cellular degradation activity is maintained during aging in long-living queen bees. AB - Queen honeybees (Apis mellifera) have a much longer lifespan than worker bees. Whether cellular degradation activity is involved in the longevity of queen bees is unknown. In the present study, cellular degradation activity was evaluated in the trophocytes and oenocytes of young and old queen bees. The results indicated that (i) 20S proteasome activity and the size of autophagic vacuoles decreased with aging, and (ii) there were no significant differences between young and old queen bees with regard to 20S proteasome expression or efficiency, polyubiquitin aggregate expression, microtubule-associated protein 1 light chain 3-II (LC3-II) expression, 70 kDa heat shock cognate protein (Hsc70) expression, the density of autophagic vacuoles, p62/SQSTM1 expression, the activity or density of lysosomes, or molecular target of rapamycin expression. These results indicate that cellular degradation activity maintains a youthful status in the trophocytes and oenocytes of queen bees during aging and that cellular degradation activity is involved in maintaining the longevity of queen bees. PMID- 27230749 TI - Cyst Fluid Telomerase Activity Predicts the Histologic Grade of Cystic Neoplasms of the Pancreas. AB - PURPOSE: Pancreatic cysts frequently pose clinical dilemmas. On one hand, cysts with high-grade dysplasia offer opportunities for cure, on the other hand, those with low-grade dysplasia are easily over treated. Cyst fluid markers have the potential to improve the evaluation of these cysts. Because telomerase activity is commonly activated in malignant cells, we evaluated the diagnostic performance of cyst fluid telomerase activity measurements for predicting histologic grade. EXPERIMENTAL DESIGN: Telomerase activity was measured using telomerase repeat amplification with digital-droplet PCR in surgically aspirated cyst fluid samples from 219 patients who underwent pancreatic resection for a cystic lesion (184 discovery, 35 validation) and 36 patients who underwent endoscopic ultrasound fine-needle aspiration. Methodologic and clinical factors associated with telomerase activity were examined. RESULTS: Telomerase activity was reduced in samples that had undergone prior thawing. Among 119 samples not previously thawed, surgical cyst fluids from cystic neoplasms with high-grade dysplasia +/- associated invasive cancer had higher telomerase activity [median (interquartile range), 1,158 (295.9-13,033)] copies/MUL of cyst fluid than those without [19.74 (2.58-233.6) copies/MUL; P < 0.001)]. Elevated cyst fluid telomerase activity had a diagnostic accuracy for invasive cancer/high-grade dysplasia of 88.1% (discovery), 88.6% (validation), and 88.2% (merged). Among cysts classified preoperatively as having "worrisome features," cyst fluid telomerase activity had high diagnostic performance (sensitivity 73.7%, specificity 90.6%, accuracy, 86.1%). In multivariate analysis, telomerase activity independently predicted the presence of invasive cancer/high-grade dysplasia. CONCLUSIONS: Cyst fluid telomerase activity can be a useful predictor of the neoplastic grade of pancreatic cysts. Clin Cancer Res; 22(20); 5141-51. (c)2016 AACRSee related commentary by Allen et al., p. 4966. PMID- 27230750 TI - Making doctors manage... but how? Recent developments in the Italian NHS. AB - BACKGROUND: Involving doctors in management has been intended as one of the strategies to spread organizational principles in healthcare settings. However, professionals often resist taking on relevant managerial responsibility, and the question concerning by which means to engage doctors in management in a manner that best fit the challenges encountered by different health systems remains open to debate. METHODS: This paper analyzes the different forms of medical management experienced over time in the Italian NHS, a relevant "lab" to study the evolution of the involvement of doctors in management, and provides a framework for disentangling different dimensions of medical management. RESULTS: We show how new means to engage frontline professionals in management spread, without deliberate planning, as a consequence of the innovations in service provision that are introduced to respond to the changes in the healthcare sector. CONCLUSIONS: This trend is promising because such means of performing medical management appear to be more easily compatible with professional logics; therefore, this could facilitate the engagement of a large proportion of professionals rather than the currently limited number of doctors who are "forced" or willing to take formal management roles. PMID- 27230751 TI - Developing and Evaluating a Self-Management Intervention for Women With Breast Cancer. AB - Reports of self-management interventions usually focus on efficacy and do not detail processes of intervention development and evaluation. We describe the development and evaluation of Managing Cancer Care: A Personal Guide, a patient oriented cancer self-management intervention consisting of seven modules on the topics of self-management, care options, transitions, communication, symptom management, and self-efficacy. We developed and evaluated the intervention in stages by partnering with women with breast cancer. Stages were as follows: individual interviews (n = 25), intervention design, focus group (n = 6), pilot testing with metastatic patients (n = 23), and population testing with non metastatic patients (n = 105). We used interpretive description and content analysis for qualitative analyses and used descriptive statistics to analyze module ratings and frequency of use. We report results of each stage and discuss the challenges of creating a self-management intervention that has broad appeal without taking a one-size-fits-all approach and implementing a self-management intervention in a real-world versus research setting. PMID- 27230752 TI - Quality of Life of College Students Living With Type 1 Diabetes: A Qualitative View. AB - The purpose of this phenomenological qualitative study was to examine the quality of life among college students living with Type 1 diabetes (T1D). Inclusion criteria included age 18 to 24, current college student, and a diagnosis of T1D for at least 1 year. Semi-structured interviews were conducted, in-person and by phone. During these interviews, college students shared stories of living with T1D and its impact on their quality of life. Three major themes emerged, which included "planning ahead," "thinking positive," and "seeking support." These findings provide a better understanding of the transitional experience of living with T1D and the impact on perceived quality of life while attending college. Techniques and strategies aimed at the enhancement of perceived quality of life for college students living with T1D were identified. These findings will provide valuable insight for professionals working with this population. PMID- 27230754 TI - When "Bouba" equals "Kiki": Cultural commonalities and cultural differences in sound-shape correspondences. AB - It has been suggested that the Bouba/Kiki effect, in which meaningless speech sounds are systematically mapped onto rounded or angular shapes, reflects a universal crossmodal correspondence between audition and vision. Here, radial frequency (RF) patterns were adapted in order to compare the Bouba/Kiki effect in Eastern and Western participants demonstrating different perceptual styles. Three attributes of the RF patterns were manipulated: The frequency, amplitude, and spikiness of the sinusoidal modulations along the circumference of a circle. By testing participants in the US and Taiwan, both cultural commonalities and differences in sound-shape correspondence were revealed. RF patterns were more likely to be matched with "Kiki" than with "Bouba" when the frequency, amplitude, and spikiness increased. The responses from both groups of participants had a similar weighting on frequency; nevertheless, the North Americans had a higher weighting on amplitude, but a lower weighting on spikiness, than their Taiwanese counterparts. These novel results regarding cultural differences suggest that the Bouba/Kiki effect is partly tuned by differing perceptual experience. In addition, using the RF patterns in the Bouba/Kiki effect provides a "mid-level" linkage between visual and auditory processing, and a future understanding of sound-shape correspondences based on the mechanism of visual pattern processing. PMID- 27230753 TI - Stepwise Progression of Embryonic Patterning. AB - It is long established that the graded distribution of Dorsal transcription factor influences spatial domains of gene expression along the dorsoventral (DV) axis of Drosophila melanogaster embryos. However, the more recent realization that Dorsal levels also change with time raises the question of whether these dynamics are instructive. An overview of DV axis patterning is provided, focusing on new insights identified through quantitative analysis of temporal changes in Dorsal target gene expression from one nuclear cycle to the next ('steps'). Possible roles for the stepwise progression of this patterning program are discussed including (i) tight temporal regulation of signaling pathway activation, (ii) control of gene expression cohorts, and (iii) ensuring the irreversibility of the patterning and cell fate specification process. PMID- 27230755 TI - Transgenic studies reveal the positive role of LeEIL-1 in regulating shikonin biosynthesis in Lithospermum erythrorhizon hairy roots. AB - BACKGROUND: The phytohormone ethylene (ET) is a key signaling molecule for inducing the biosynthesis of shikonin and its derivatives, which are secondary metabolites in Lithospermum erythrorhizon. Although ETHYLENE INSENSITIVE3 (EIN3)/EIN3-like proteins (EILs) are crucial transcription factors in ET signal transduction pathway, the possible function of EIN3/EIL1 in shikonin biosynthesis remains unknown. In this study, by targeting LeEIL-1 (L. erythrorhizon EIN3-like protein gene 1) at the expression level, we revealed the positive regulatory effect of LeEIL-1 on shikonin formation. RESULTS: The mRNA level of LeEIL-1 was significantly up-regulated and down-regulated in the LeEIL-1-overexpressing hairy root lines and LeEIL-1-RNAi hairy root lines, respectively. Specifically, LeEIL-1 overexpression resulted in increased transcript levels of the downstream gene of ET signal transduction pathway (LeERF-1) and a subset of genes for shikonin formation, excretion and/or transportation (LePAL, LeC4H-2, Le4CL-1, HMGR, LePGT 1, LeDI-2, and LePS-2), which was consistent with the enhanced shikonin contents in the LeEIL-1-overexpressing hairy root lines. Conversely, LeEIL-1-RNAi dramatically repressed the expression of the above genes and significantly reduced shikonin production. CONCLUSIONS: The results revealed that LeEIL-1 is a positive regulator of the biosynthesis of shikonin and its derivatives in L. erythrorhizon hairy roots. Our findings gave new insights into the molecular regulatory mechanism of ET in shikonin biosynthesis. LeEIL-1 could be a crucial target gene for the genetic engineering of shikonin biosynthesis. PMID- 27230758 TI - BMA responds to junior doctor committee leak. PMID- 27230756 TI - The Antimetastatic and Antiangiogenesis Effects of Kefir Water on Murine Breast Cancer Cells. AB - BACKGROUND: Kefir is a unique cultured product that contains beneficial probiotics. Kefir culture from other parts of the world exhibits numerous beneficial qualities such as anti-inflammatory, immunomodulation, and anticancer effects. Nevertheless, kefir cultures from different parts of the world exert different effects because of variation in culture conditions and media. Breast cancer is the leading cancer in women, and metastasis is the major cause of death associated with breast cancer. The antimetastatic and antiangiogenic effects of kefir water made from kefir grains cultured in Malaysia were studied in 4T1 breast cancer cells. METHODS: 4T1 cancer cells were treated with kefir water in vitro to assess its antimigration and anti-invasion effects. BALB/c mice were injected with 4T1 cancer cells and treated orally with kefir water for 28 days. RESULTS: Kefir water was cytotoxic toward 4T1 cells at IC50 (half-maximal inhibitory concentration) of 12.5 and 8.33 mg/mL for 48 and 72 hours, respectively. A significant reduction in tumor size and weight (0.9132 +/- 0.219 g) and a substantial increase in helper T cells (5-fold) and cytotoxic T cells (7 fold) were observed in the kefir water-treated group. Proinflammatory and proangiogenic markers were significantly reduced in the kefir water-treated group. CONCLUSIONS: Kefir water inhibited tumor proliferation in vitro and in vivo mainly through cancer cell apoptosis, immunomodulation by stimulating T helper cells and cytotoxic T cells, and anti-inflammatory, antimetastatic, and antiangiogenesis effects. This study brought out the potential of the probiotic beverage kefir water in cancer treatment. PMID- 27230757 TI - Breast Cancer Integrative Oncology Care and Its Costs. AB - BACKGROUND: Naturopathic oncology in conjunction with conventional treatment is commonly referred to as integrative oncology (IO). Clinics directed by oncology board certified NDs (Fellows of the American Board of Naturopathic Oncology or FABNOs) provide high-quality data for describing IO therapies, their costs and measuring clinical outcomes. PURPOSE: To describe the types of IO therapies prescribed to breast cancer patients by ND FABNO physicians. Study participants (n = 324). Women who sought care at 1 of 6 naturopathic oncology clinics in Washington State were asked to enroll in a prospective 5 year observational outcomes study. METHODS: Medical records were abstracted to collect treatment recommendations and cost data. RESULTS: More than 72 oral or topical, nutritional, botanical, fungal and bacterial-based medicines were prescribed to the cohort during their first year of IO care. Trametes versicolor was prescribed to 63% of the women. Mind-body therapy was recommended to 45% of patients, and 49% received acupuncture. Also, 26% were prescribed injectable therapy, including mistletoe, vitamin B complex (12%), IV ascorbate (12%), IV artesunate (7%), and IV nutrition and hydration (4%). Costs ranged from $1594/year for early-stage breast cancer to $6200/year for stage 4 breast cancer patients. Of the total amount billed for IO care for 1 year for breast cancer patients, 21% was out-of pocket. CONCLUSIONS: IO care for women with breast cancer consists of botanical and mushroom oral therapies, parenteral botanical and nutrient therapy, mind-body medicine and acupuncture. IO clinic visits and acupuncture are partially paid for by medical insurance companies. PMID- 27230760 TI - College Students' Knowledge and Attitudes Towards Students on the Autism Spectrum. AB - Young adults with autism spectrum disorder (ASD) are attending university in increasing numbers. The importance of acceptance from peers and integration into the university have been recognized as key factors for success. We examined university students' knowledge and attitudes towards students with ASD, underlying factors that contributed to such attitudes, and whether attitudes changed across two cohorts 5-years apart. The later cohort demonstrated greater knowledge and more positive attitudes toward students with ASD compared to students in the first cohort. However, knowledge was not found to be a significant predictor of attitudes and many students who were knowledgeable about ASD still reported negative attitudes toward participating in university and classroom based activities with students with ASD. PMID- 27230759 TI - Social (Pragmatic) Communication Disorder and Its Relation to the Autism Spectrum: Dilemmas Arising From the DSM-5 Classification. AB - DSM-5 introduced two diagnoses describing neurodevelopmental deficits in social communication (SC); Autism Spectrum Disorder (ASD) and Social (Pragmatic) Communication Disorder (SPCD). These diagnoses are differentiated by Repetitive and Restricted Behaviors (RRB), required for an ASD diagnosis and absent in SPCD. We highlight the gaps between the research into SPCD and DSM-5's diagnostic criteria, and discuss the clinical implications of this diagnostic decision. We argue that DSM-5's demand for full manifestation of both SC and RRB axes when diagnosing ASD, prematurely forced a categorical view on the continual nature of the potentially dependent SC and RRB phenotypes. We conclude by highlighting the implications of this differential diagnostic decision on public health policies, designated therapy, and the need for further research regarding SPCD. PMID- 27230761 TI - Preschool to School in Autism: Neuropsychiatric Problems 8 Years After Diagnosis at 3 Years of Age. AB - The study presents neuropsychiatric profiles of children aged 11 with autism spectrum disorder, assessed before 4.5 years, and after interventions. The original group comprised a community sample of 208 children with ASD. Parents of 128 participated-34 with average intellectual function, 36 with borderline intellectual function and 58 with intellectual disability. They were interviewed using the Autism-Tics, AD/HD and other Comorbidities interview. Criteria for a clinical/subclinical proxy of ASD were met by 71, 89 and 95 %, respectively. Criteria for at least one of ASD, AD/HD, Learning disorder or Developmental Coordination Disorder were met by 82, 94 and 97 %. More than 90 % of children with a preschool diagnosis of ASD have remaining neuropsychiatric problems at 11, despite early intervention. PMID- 27230762 TI - Brief Report: Reduced Restricted and Repetitive Behaviors after Pivotal Response Treatment. AB - Children with ASD show high frequency of restricted and repetitive behaviors (RRBs); however, higher-order RRBs, such as restricted interests, have remained largely resistant to treatment. This study evaluated change in severity of RRBs following a 16-weeks open trial of Pivotal Response Treatment (PRT). Participants included 15 children with ASD ages 4-7 years. RRBs, as measured by the repetitive behavioral scales-revised (RBS-R) and aberrant behaviors checklist, decreased significantly after treatment. These reductions remained significant after controlling for change in social communication skills. PRT shows promise in reducing RRBs; although PRT explicitly addresses pivotal social communication skills, there is a secondary and less direct effect on RRBs. PMID- 27230763 TI - Fast and accurate single-cell RNA-seq analysis by clustering of transcript compatibility counts. AB - Current approaches to single-cell transcriptomic analysis are computationally intensive and require assay-specific modeling, which limits their scope and generality. We propose a novel method that compares and clusters cells based on their transcript-compatibility read counts rather than on the transcript or gene quantifications used in standard analysis pipelines. In the reanalysis of two landmark yet disparate single-cell RNA-seq datasets, we show that our method is up to two orders of magnitude faster than previous approaches, provides accurate and in some cases improved results, and is directly applicable to data from a wide variety of assays. PMID- 27230765 TI - Preventing Exacerbations in Preschoolers With Recurrent Wheeze: A Meta-analysis. AB - CONTEXT: Half of children experience wheezing by age 6 years, and optimal strategies for preventing severe exacerbations are not well defined. OBJECTIVE: Synthesize the evidence of the effects of daily inhaled corticosteroids (ICS), intermittent ICS, and montelukast in preventing severe exacerbations among preschool children with recurrent wheeze. DATA SOURCES: Medline (1946, 2/25/15), Embase (1947, 2/25/15), CENTRAL. STUDY SELECTION: Studies were included based on design (randomized controlled trials), population (children <=6 years with asthma or recurrent wheeze), intervention and comparison (daily ICS vs placebo, intermittent ICS vs placebo, daily ICS vs intermittent ICS, ICS vs montelukast), and outcome (exacerbations necessitating systemic steroids). DATA EXTRACTION: Completed by 2 independent reviewers. RESULTS: Twenty-two studies (N = 4550) were included. Fifteen studies (N = 3278) compared daily ICS with placebo and showed reduced exacerbations with daily medium-dose ICS (risk ratio [RR] 0.70; 95% confidence interval [CI], 0.61-0.79; NNT = 9). Subgroup analysis of children with persistent asthma showed reduced exacerbations with daily ICS compared with placebo (8 studies, N = 2505; RR 0.56; 95% CI, 0.46-0.70; NNT = 11) and daily ICS compared with montelukast (1 study, N = 202; RR 0.59; 95% CI, 0.38-0.92). Subgroup analysis of children with intermittent asthma or viral-triggered wheezing showed reduced exacerbations with preemptive high-dose intermittent ICS compared with placebo (5 studies, N = 422; RR 0.65; 95% CI, 0.51-0.81; NNT = 6). LIMITATIONS: More studies are needed that directly compare these strategies. CONCLUSIONS: There is strong evidence to support daily ICS for preventing exacerbations in preschool children with recurrent wheeze, specifically in children with persistent asthma. For preschool children with intermittent asthma or viral-triggered wheezing, there is strong evidence to support intermittent ICS for preventing exacerbations. PMID- 27230764 TI - Sudden Unexpected Death in Fetal Life Through Early Childhood. AB - In March 2015, the Eunice Kennedy Shriver National Institute of Child Health and Human Development held a workshop entitled "Sudden Unexpected Death in Fetal Life Through Early Childhood: New Opportunities." Its objective was to advance efforts to understand and ultimately prevent sudden deaths in early life, by considering their pathogenesis as a potential continuum with some commonalities in biological origins or pathways. A second objective of this meeting was to highlight current issues surrounding the classification of sudden infant death syndrome (SIDS), and the implications of variations in the use of the term "SIDS" in forensic practice, and pediatric care and research. The proceedings reflected the most current knowledge and understanding of the origins and biology of vulnerability to sudden unexpected death, and its environmental triggers. Participants were encouraged to consider the application of new technologies and "omics" approaches to accelerate research. The major advances in delineating the intrinsic vulnerabilities to sudden death in early life have come from epidemiologic, neural, cardiac, metabolic, genetic, and physiologic research, with some commonalities among cases of unexplained stillbirth, SIDS, and sudden unexplained death in childhood observed. It was emphasized that investigations of sudden unexpected death are inconsistent, varying by jurisdiction, as are the education, certification practices, and experience of death certifiers. In addition, there is no practical consensus on the use of "SIDS" as a determination in cause of death. Major clinical, forensic, and scientific areas are identified for future research. PMID- 27230766 TI - Age at Onset of Puberty and Adolescent Depression: "Children of 1997" Birth Cohort. AB - OBJECTIVE: Timing of onset of puberty has fallen, with profound and detrimental consequences for health. We examined the associations of earlier onset of puberty with the presence of depression in early to middle adolescence. METHODS: The study examined prospective adjusted associations of age at onset of puberty, based on clinically assessed Tanner stage for breast/genitalia and pubic hair development, and self-reported presence of depression, assessed from the 9-item Patient Health Questionnaire on average at 13.6 years (n = 5795 [73%]). These factors were examined by using multivariable logistic regression in a population representative Hong Kong Chinese birth cohort (ie, the "Children of 1997"). We also assessed whether associations varied according to gender. RESULTS: Association of age at onset of breast/genitalia development with the presence of depression varied according to gender. Earlier onset of breast development was associated with higher risk of the presence of depression (odds ratio, 0.83 per 1 year increase in age of onset [95% confidence interval, 0.70 to 0.98]) adjusted for age, socioeconomic position, mother's place of birth, birth order, secondhand smoke exposure, parental age, survey mode, gender-specific birth weight z score, BMI z score at 7 years, and parental marital status. In boys, similarly adjusted, age at onset of genitalia development was unrelated to the presence of depression. Earlier age at onset of pubic hair development was unrelated to the presence of depression in girls and boys. CONCLUSIONS: Early onset of breast development was associated with high risk of the presence of depression. Whether these findings are indicators of the effects of hormones or transient effects of social pressures remain to be determined. PMID- 27230767 TI - Cooling down inflammation in type 2 diabetes: how strong is the evidence for cardiometabolic benefit? AB - Chronic inflammation is supposed to be an important mediator of cardiometabolic dysfunctions seen in type 2 diabetes. In this mini-review, we collected evidence (PubMed) from randomized controlled trials (through March 2016) evaluating the effect of anti-inflammatory drugs on indices of glycemic control and/or cardiovascular events in people with type 2 diabetes. Within the last 25 years, many anti-inflammatory drugs have been tested in type 2 diabetes, including hydroxychloroquine, anti-tumor necrosis factor therapies (etanercept and infliximab), salsalate, interleukin-1 antagonists (anakinra, canakinumab, gevokizumab, LY2189102), and CC-R2 antagonists. Despite being promising, the observed effects on HbA1c or glucose control remain rather modest in most clinical trials, especially with the new drugs. There are many trials underway with anti-inflammatory agents to see whether patients with cardiovascular diseases and/or type 2 diabetes may have clinical benefit from marked reductions in circulating inflammatory markers. Until now, a large trial with losmapimod (a p38 inhibitor) among patients with acute myocardial infarction, including one/third of diabetic patients, showed no reduction in the risk of major ischemic cardiovascular events. Further evidence is warranted in support of the concept that targeting inflammation pathways may ameliorate glycemic control and also reduce cardiovascular complications in type 2 diabetes. PMID- 27230768 TI - How do etiological factors can explain the different clinical features of patients with differentiated thyroid cancer and their histopathological findings? AB - The aim was to retrospectively analyse the clinical-histopathological characteristics of patients with newly diagnosis of differentiated thyroid cancer (DTC) referred to two Italian centres, one in Northern and the other in Southern Italy, between 2000 and 2013. 1081 patients were included and subdivided into two groups: group A (474 patients from Novara) and group B (607 patients from Naples). The group A came from the industrial area of Novara, while the Group B came from the areas around Vesuvius and Campi Flegrei. The two groups were comparable for iodine levels, body mass index, diagnostic timing and clinical procedures. For all patients, demographic and clinical data were collected. No difference was found in gender, whereas the age at diagnosis was later in the group A (group A 53.1 +/- 15.16 years, group B 41.9 +/- 14.25 years, p < 0.001). In both groups, the most frequent histotype was papillary thyroid cancer (PTC) with prevalence of follicular variant in group A (p < 0.0001) and classical variant in group B (p < 0.0001). Aggressive histological features were mainly seen in group A (bilaterality p < 0.0001, multifocality p < 0.0001 and thyroid capsular invasion p < 0.0001). Microcarcinomas were more frequent in group A (p < 0.0001) but mostly characterized by bilaterality (p < 0.001) and multifocality (p < 0.04). In both groups, tumour-associated thyroiditis showed a significant increase over the years (group A p < 0.05, group B p < 0.04). Environmental factors could justify the differences found in our study. These preliminary data should stimulate the need for an Italian Cancer Registry of DTC in order to allow an epidemiological characterization, allowing the identification of specific etiological factors and an improvement in the management of the disease. PMID- 27230770 TI - Screen Time Weight-loss Intervention Targeting Children at Home (SWITCH): process evaluation of a randomised controlled trial intervention. AB - BACKGROUND: The Screen Time Weight-loss Intervention Targeting Children at Home (SWITCH) trial tested a family intervention to reduce screen-based sedentary behaviour in overweight children. The trial found no significant effect of the intervention on children's screen-based sedentary behaviour. To explore these null findings, we conducted a pre-planned process evaluation, focussing on intervention delivery and uptake. METHODS: SWITCH was a randomised controlled trial of a 6-month family intervention to reduce screen time in overweight children aged 9-12 years (n = 251). Community workers met with each child's primary caregiver to deliver the intervention content. Community workers underwent standard training and were monitored once by a member of the research team to assess intervention delivery. The primary caregiver implemented the intervention with their child, and self-reported intervention use at 3 and 6 months. An exploratory analysis determined whether child outcomes at 6 months varied by primary caregiver use of the intervention. RESULTS: Monitoring indicated that community workers delivered all core intervention components to primary caregivers. However, two thirds of primary caregivers reported using any intervention component "sometimes" or less frequently at both time points, suggesting that intervention uptake was poor. Additionally, analyses indicated no effect of primary caregiver intervention use on child outcomes at 6 months, suggesting the intervention itself lacked efficacy. CONCLUSIONS: Poor uptake, and the efficacy of the intervention itself, may have played a role in the null findings of the SWITCH trial on health behaviour and body composition. TRIAL REGISTRATION: The trial was registered in the Australian and New Zealand Clinical Trials Registry (no. ACTRN12611000164998 ); registration date: 10/02/2011. PMID- 27230769 TI - Brain regions associated with telomerase reverse transcriptase promoter mutations in primary glioblastomas. AB - Human telomerase reverse transcriptase (TERT) promoter mutations are important genetic alterations in many kinds of human malignancies, including glioma. The current study aimed to investigate the anatomical specificity of TERT promoter mutations in glioblastomas (GBMs). Clinical information and preoperative magnetic resonance images of 203 patients with GBMs were reviewed. TERT promoter mutation status was assessed by Sanger sequencing in all cases. Tumor lesions were manually segmented and then registered to a standard brain atlas. Then the specific brain regions associated with TERT promoter mutation status were subsequently identified by voxel-based regression analysis. TERT promoter mutations were detected in 94 (46.3 %) of the 203 patients. Voxel-based statistical analysis demonstrated that GBMs with TERT promoter mutations were much more likely to locate in the right temporal lobe, while those with wild-type TERT promoters were more likely to occur in the anterior region of the right lateral ventricle. No significant difference was found in the lesion volumes of the T2-identified tumor or in the contrast enhancement areas between the two groups. The current study demonstrated the anatomic specificity of TERT promoter mutation status in GBM. These findings may provide new insight into the molecular classification of GBM and further our understanding of the associations between tumor-specific molecular alterations and tumor location. PMID- 27230771 TI - Chronic administration of AMD3100 increases survival and alleviates pathology in SOD1(G93A) mice model of ALS. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease, involving both upper and lower motor neurons. The disease is induced by multifactorial pathologies, and as such, it requires a multifaceted therapeutic approach. CXCR4, a chemokine receptor widely expressed in neurons and glial cells and its ligand, CXCL12, also known as stromal-cell derived factor (SDF1), modulate both neuronal function and apoptosis by glutamate release signaling as well as hematopoietic stem and progenitor cells (HSPCs) migration into the blood and their homing towards injured sites. Inhibition approaches towards the CXCR4/CXCL12 signaling may result in preventing neuronal apoptosis and alter the HSPCs migration and homing. Such inhibition can be achieved by means of treatment with AMD3100, an antagonist of the chemokine receptor CXCR4. METHODS: We chronically treated male and female transgenic mice model of ALS, SOD1(G93A) mice, with AMD3100. Mice body weight and motor function, evaluated by Rotarod test, were recorded once a week. The most effective treatment regimen was repeated for biochemical and histological analyses in female mice. RESULTS: We found that chronic administration of AMD3100 to SOD1(G93A) mice led to significant extension in mice lifespan and improved motor function and weight loss. In addition, the treatment significantly improved microglial pathology and decreased proinflammatory cytokines in spinal cords of treated female mice. Furthermore, AMD3100 treatment decreased blood-spinal cord barrier (BSCB) permeability by increasing tight junction proteins levels and increased the motor neurons count in the lamina X area of the spinal cord, where adult stem cells are formed. CONCLUSIONS: These data, relevant to the corresponding disease mechanism in human ALS, suggest that blocking CXCR4 by the small molecule, AMD3100, may provide a novel candidate for ALS therapy with an increased safety. PMID- 27230772 TI - Genomic analysis of Ugandan and Rwandan chicken ecotypes using a 600 k genotyping array. AB - BACKGROUND: Indigenous populations of animals have developed unique adaptations to their local environments, which may include factors such as response to thermal stress, drought, pathogens and suboptimal nutrition. The survival and subsequent evolution within these local environments can be the result of both natural and artificial selection driving the acquisition of favorable traits, which over time leave genomic signatures in a population. This study's goals are to characterize genomic diversity and identify selection signatures in chickens from equatorial Africa to identify genomic regions that may confer adaptive advantages of these ecotypes to their environments. RESULTS: Indigenous chickens from Uganda (n = 72) and Rwanda (n = 100), plus Kuroilers (n = 24, an Indian breed imported to Africa), were genotyped using the Axiom(r) 600 k Chicken Genotyping Array. Indigenous ecotypes were defined based upon location of sampling within Africa. The results revealed the presence of admixture among the Ugandan, Rwandan, and Kuroiler populations. Genes within runs of homozygosity consensus regions are linked to gene ontology (GO) terms related to lipid metabolism, immune functions and stress-mediated responses (FDR < 0.15). The genes within regions of signatures of selection are enriched for GO terms related to health and oxidative stress processes. Key genes in these regions had anti oxidant, apoptosis, and inflammation functions. CONCLUSIONS: The study suggests that these populations have alleles under selective pressure from their environment, which may aid in adaptation to harsh environments. The correspondence in gene ontology terms connected to stress-mediated processes across the populations could be related to the similarity of environments or an artifact of the detected admixture. PMID- 27230774 TI - Relationship between education and cardiovascular risk score. PMID- 27230773 TI - Analysis of mitochondrial alterations in Brazilian patients with sensorineural hearing loss using MALDI-TOF mass spectrometry. AB - BACKGROUND: Mutations in the mitochondrial DNA (mtDNA) have been associated with aminoglycoside-induced and nonsyndromic deafness in different populations. In the present study, we investigated the contribution of mutations in mitochondrial genes to the etiology of hearing loss in a Brazilian sample. METHODS: Using mass spectrometry genotyping technology, combined with direct sequencing, 50 alterations previously described in 14 mitochondrial genes were screened in 152 patients with sensorineural hearing loss and in104 normal hearing controls. RESULTS: Fifteen known mitochondrial alterations were detected (G709A, A735G, A827G, G988A, A1555G, T4363C, T5628C, T5655C, G5821A, C7462T, G8363A, T10454C, G12236A, T1291C, G15927A). Pathogenic mutations in MT-RNR1 and MT-TK genes were detected in 3 % (5/152) of the patients with hearing loss. CONCLUSIONS: This study contributed to show the spectrum of mitochondrial variants in Brazilian patients with hearing loss. Frequency of A1555G was relatively high (2.6 %), indicating that this mutation is an important cause of hearing loss in our population. This work reports for the first time the investigation and the detection of the tRNA(Lys) G8363A mutation in Brazilian patients with maternally inherited sensorineural hearing loss. PMID- 27230775 TI - Evaluating the impact of caries prevention and management by caries risk assessment guidelines on clinical practice in a dental teaching hospital. AB - BACKGROUND: Clinical practice guidelines on 'Dental caries prevention and management by caries risk assessment for pre-school children in Hong Kong' were developed using ADAPTE process and Delphi consensus technique. This study aimed to evaluate the feasibility of disseminating and implementing the guidelines, and to evaluate their effectiveness in changing clinical practice. METHODS: The study was conducted in two phases, examining clinical records of pre-school aged patients being treated by non-academic clinical staff in the Paediatric Dentistry Clinic of a dental teaching hospital in Hong Kong. The clinical guidelines were introduced to the staff in a departmental seminar at the end of pre-intervention phase. Post-intervention phase began one month after the introduction of guidelines. Clinical records for three consecutive months were reviewed against standards and recommendations derived from the newly developed clinical guidelines in both phases. The results were assessed by Chi-square test, ANOVA and regression analyses. RESULTS: A total of 237 and 147 clinical records were reviewed in pre-intervention and post-intervention phases, respectively. Guideline adherence percentage increased significantly on almost all aspects of the guidelines in the post-intervention phase (P < 0.05). There were a significant difference in the mean overall guideline adherence score (pre intervention phase: [Formula: see text] = 14.86 +/- 6.11; post-intervention phase: [Formula: see text] = 28.88 +/- 8.75) and sub-domain adherence scores between the two phases (P < 0.001). The training grade of the clinicians was the factor associated with changes in evidence-based practice (P < 0.001). CONCLUSIONS: The developed guidelines were effective in translating evidence into best practice. The findings have implication for widespread implementation. PMID- 27230777 TI - Recent development of single preparations and fixed-dose combination tablets for the treatment of non-insulin-dependent diabetes mellitus : A comprehensive summary for antidiabetic drugs. AB - As a complex endocrine and metabolic disorder, type 2 diabetes mellitus (non insulin-dependent diabetes mellitus, NIDDM) has become a major threat to human health. Because of the heterogeneous and progressive disorders induced by insulin resistance and pancreatic b-cell dysfunction, the treatment of NIDDM is still challenging. Although antidiabetic drugs with different pharmacological mechanisms of action have been used clinically, different degrees of undesirable glucose control and the incidences of a variety of side effects, including hypoglycemia, cardiovascular complications and weight gain require the better treatment options. This article has overviewed the current literature about commercially available antidiabetic drugs with different pharmacological mechanisms of action in the treatment of NIDDM, and summarized the published data regarding the efficacy, tolerability, and safety of currently available single preparations and fixed-dose combinations, aiming to provide important information for the development and application of antidiabetic drugs in the future. The literature search from 1989 to 2015 was conducted by PubMed, ScienceDirect, Springer, American Diabetes Association, and U.S. FDA Drugs databases. PMID- 27230776 TI - Activity-dependent plasticity of electrical synapses: increasing evidence for its presence and functional roles in the mammalian brain. AB - Gap junctions mediate electrical synaptic transmission between neurons. While the actions of neurotransmitter modulators on the conductance of gap junctions have been extensively documented, increasing evidence indicates they can also be influenced by the ongoing activity of neural networks, in most cases via local interactions with nearby glutamatergic synapses. We review here early evidence for the existence of activity-dependent regulatory mechanisms as well recent examples reported in mammalian brain. The ubiquitous distribution of both neuronal connexins and the molecules involved suggest this phenomenon is widespread and represents a property of electrical transmission in general. PMID- 27230778 TI - Endoperoxy and hydroperoxy cadinane-type sesquiterpenoids from an Okinawan soft coral, Sinularia sp. AB - Three cadinane-type sesquiterpenoids, endoperoxide (1) and hydroperoxides (2, 3) together with three known sesquiterpenoids (4-6) were isolated from an Okinawan soft coral, Sinularia species. Structures of these isolates were elucidated by spectroscopic analyses (NMR, IR and MS) and molecular modeling. In addition, the isolates 1-3 as new compounds were examined for biological activities, resulting that they have antibacterial activity and weak cytotoxicity against HCT116 cells as well as anti-inflammatory effect on LPS/IFN-gamma-stimulated RAW 264.7 macrophage cells. PMID- 27230779 TI - A versatile intensity-based 3D/2D rigid registration compatible with mobile C-arm for endovascular treatment of abdominal aortic aneurysm. AB - PURPOSE: Augmented reality-assisted surgery requires prior registration between preoperative and intraoperative data. In the context of the endovascular aneurysm repair (EVAR) of abdominal aortic aneurysm, no satisfactory solution exists at present for clinical use, in particular in the case of use with a mobile C-arm. The difficulties stem in particular from the diversity of intraoperative images, table movements and changes of C-arm pose. METHODS: We propose a fast and versatile 3D/2D registration method compatible with mobile C-arm that can be easily repeated during an EVAR procedure. Applicable to both vascular and bone structures, our approach is based on an optimization by reduced exhaustive search involving a multi-resolution scheme and a decomposition of the transformation to reduce calculation time. RESULTS: Registration was performed between the preoperative CT-scan and fluoroscopic images for a group of 26 patients in order to confront our method in real conditions of use. The evaluation was completed by also performing registration between an intraoperative CBCT volume and fluoroscopic images for a group of 6 patients to compare registration results with reference transformations. The experimental results show that our approach allows obtaining accuracy of the order of 0.5 mm, a computation time of [Formula: see text] and a higher rate of success in comparison with a classical optimization method. When integrated in an augmented reality navigation system, our approach shows that it is compatible with clinical workflow. CONCLUSION: We presented a versatile 3D/2D rigid registration applicable to all intraoperative scenes and usable to guide an EVAR procedure by augmented reality. PMID- 27230780 TI - Economic evidence for the prevention and treatment of atopic eczema: a protocol for a systematic review. AB - BACKGROUND: Eczema, synonymous with atopic eczema or atopic dermatitis, is a chronic skin disease that has a similar impact on health-related quality of life as other chronic diseases. The proposed research aims to provide a comprehensive systematic assessment of the economic evidence base available to inform economic modelling and decision making on interventions to prevent and treat eczema at any stage of the life course. Whilst the Global Resource of Eczema Trials (GREAT) database collects together the effectiveness evidence for eczema, there is currently no such systematic resource on the economics of eczema. It is important to gain an overview of the current state of the art of economic methods in the field of eczema in order to strengthen the economic evidence base further. METHODS/DESIGN: The proposed study is a systematic review of the economic evidence surrounding interventions for the prevention and treatment of eczema. Relevant search terms will be used to search MEDLINE, EMBASE, Database of Abstracts of Reviews of Effects, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, National Health Service (NHS) Economic Evaluation Database, Health Technology Assessment, Cumulative Index to Nursing and Allied Health Literature, EconLit, Scopus, Cost-Effectiveness Analysis Registry and Web of Science in order to identify relevant evidence. To be eligible for inclusion studies will be primary empirical studies evaluating the cost, utility or full economic evaluation of interventions for preventing or treating eczema. Two reviewers will independently assess studies for eligibility and perform data abstraction. Evidence tables will be produced presenting details of study characteristics, costing methods, outcome methods and quality assessment. The methodological quality of studies will be assessed using accepted checklists. DISCUSSION: The systematic review is being undertaken to identify the type of economic evidence available, summarise the results of the available economic evidence and critically appraise the quality of economic evidence currently available to inform future economic modelling and resource allocation decisions about interventions to prevent or treat eczema. We aim to use the review to offer guidance about how to gather economic evidence in studies of eczema and/or what further research is necessary in order to inform this. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015024633. PMID- 27230781 TI - On the behavior of an eye encircled by a scleral buckle. AB - A mechanics based mathematical model for the behavior of an eye encircled by a scleral buckle, a procedure used by surgeons to correct retinal detachment, is developed. Closed form analytical solutions are obtained, and results of numerical simulations based on those solutions are presented. The effects of material and geometric parameters of the scleral buckle, as well as of the ocular pressure, on the deformation and volume change of the eye are studied. Critical behavior is identified, and correlations are drawn with regard to the properties of the buckle, the associated deformation of the eye, and the ocular pressure. The results indicate that a judicious choice of the buckle parameters is advisable for planning surgery. In particular, the initial (undeformed) radius of the buckle is seen to have the dominant influence with regard to deformation of the eye, while the thickness (height) and width, and hence the shape, of the buckle are seen to have minimal influence and may be chosen for other reasons, such as to maximize the comfort of the patient. PMID- 27230782 TI - Analysis of scientific collaboration in Chinese psychiatry research. AB - BACKGROUND: In recent decades, China has changed profoundly, becoming the country with the world's second-largest economy. The proportion of the Chinese population suffering from mental disorder has grown in parallel with the rapid economic development, as social stresses have increased. The aim of this study is to shed light on the status of collaborations in the Chinese psychiatry field, of which there is currently limited research. METHODS: We sampled 16,224 publications (2003-2012) from 10 core psychiatry journals from Chinese National Knowledge Infrastructure (CNKI) and WanFang Database. We used various social network analysis (SNA) methods such as centrality analysis, and Core-Periphery analysis to study collaboration. We also used hierarchical clustering analysis in this study. RESULTS: From 2003-2012, there were increasing collaborations at the level of authors, institutions and regions in the Chinese psychiatry field. Geographically, these collaborations were distributed unevenly. The 100 most prolific authors and institutions and 32 regions were used to construct the collaboration map, from which we detected the core author, institution and region. Collaborative behavior was affected by economic development. CONCLUSION: We should encourage collaborative behavior in the Chinese psychiatry field, as this facilitates knowledge distribution, resource sharing and information acquisition. Collaboration has also helped the field narrow its current research focus, providing further evidence to inform policymakers to fund research in order to tackle the increase in mental disorder facing modern China. PMID- 27230784 TI - Successfully treated transoral crossbow injury to the axial spine causing mild neurologic deficit: case presentation. AB - PURPOSE: To detail the management, complications and results of a crossbow arrow injury, where the broadhead went through the mouth, tongue, soft palate, C2 vertebra, spinal canal, dural sack, exiting the neck posteriorly and the arrow shaft lodged in the spine causing mild spinal cord injury. METHODS: Case presentation. RESULTS: A penetrating axial cervical spine crossbow injury was treated successfully in spite of the following interdisciplinary complications: meningitis, cerebrospinal fluid leakage, re-bleeding, and cardiac arrest. The shaft was removed from the neck, and C1-3 dorsal stabilization was performed. Controlled Computed Tomography (CT) showed adequate implant position. After 4 months the patient's fine motor skills improved, and he became able to button his shirt on his own, and to eat and drink without any help. Additionally, he was able to walk without any support. At the time of control at the outpatient clinic his behavior was adequate: he cooperated with the examining doctor and answered with short sentences although his psychomotor skills were slightly slower. CONCLUSIONS: Although bow and crossbow spine injuries are rare nowadays they still occur. The removal of a penetrating missile resulting in such a spinal injury required a unique solution. General considerations, such as securing the airway, leaving the penetrating arrow in the neck and immobilizing both the arrow and neck for transport, thorough diagnostic imaging, preventing cerebrospinal fluid leakage, administering prophylactic antibiotics with broad coverage and stabilizing the spine if required, are advised. PMID- 27230783 TI - Narrow cervical canal in 1211 asymptomatic healthy subjects: the relationship with spinal cord compression on MRI. AB - PURPOSE: Narrow cervical canal (NCC) has been a suspected risk factor for later development of cervical myelopathy. However, few studies have evaluated the prevalence in asymptomatic subjects. The purpose of this study was to investigate the prevalence of NCC in a large cohort of asymptomatic volunteers. METHODS: This study was a cross-sectional study of 1211 asymptomatic volunteers. Approximately 100 men and 100 women representing each decade of life from the 20s to the 70s were included in this study. Cervical canal anteroposterior diameters at C5 midvertebral level on X-rays, and the prevalence of spinal cord compression (SCC) and increased signal intensity (ISI) changes on MRI were evaluated. Receiver operating characteristic analysis was performed to determine the cut-off value of the severity of canal stenosis resulting in SCC. RESULTS: NCC (<14 mm) was observed in 123 (10.2 %) subjects. SCC and ISI were found in 64 (5.3 %) and 28 (2.3 %) subjects, respectively. The prevalence of NCC was significantly higher in females and older subjects, but the occurrence of severe NCC (<12 mm) did not increase with age. The canal size in subjects with SCC or ISI was significantly smaller than in those without SCC (p < 0.0001). The cut-off values of cervical canal stenosis resulting in SCC were 14.8 and 13.9 mm in males and females, respectively. CONCLUSIONS: The prevalence of NCC was considerably lower among asymptomatic healthy volunteers; the cervical canal diameter in subjects with SCC or ISI was significantly smaller than in asymptomatic subjects; NCC is a risk factor for SCC. PMID- 27230786 TI - First venous thromboembolism in admitted patients younger than 50years old. PMID- 27230785 TI - Does visual attention drive the dynamics of bistable perception? AB - How does attention interact with incoming sensory information to determine what we perceive? One domain in which this question has received serious consideration is that of bistable perception: a captivating class of phenomena that involves fluctuating visual experience in the face of physically unchanging sensory input. Here, some investigations have yielded support for the idea that attention alone determines what is seen, while others have implicated entirely attention independent processes in driving alternations during bistable perception. We review the body of literature addressing this divide and conclude that in fact both sides are correct-depending on the form of bistable perception being considered. Converging evidence suggests that visual attention is required for alternations in the type of bistable perception called binocular rivalry, while alternations during other types of bistable perception appear to continue without requiring attention. We discuss some implications of this differential effect of attention for our understanding of the mechanisms underlying bistable perception, and examine how these mechanisms operate during our everyday visual experiences. PMID- 27230787 TI - Medial plantar nerve ligation as a novel model of neuropathic pain in mice: pharmacological and molecular characterization. AB - Peripheral neuropathic pain is a consequence of an injury/disease of the peripheral nerves. The mechanisms involved in its pathophysiology are not entirely understood. To better understand the mechanisms involved in the development of peripheral nerve injury-induced neuropathic pain, more experimental models are required. Here, we developed a novel peripheral neuropathic pain model in mice by using a minimally invasive surgery and medial plantar nerve ligation (MPNL). After MPNL, mechanical allodynia was established, and mice quickly recovered from the surgery without any significant motor impairment. MPNL causes an increased expression of ATF-3 in the sensory neurons. At 14 days after surgery, gabapentin was capable of reversing the mechanical allodynia, whereas anti-inflammatory drugs and opioids were ineffective. MPNL induced neuropathic pain was mediated by glial cells activation and the production of TNF-alpha and IL-6 in the spinal cord. These results indicate MPNL as a reasonable animal model for the study of peripheral neuropathic pain, presenting analgesic pharmacological predictivity to clinically used drugs. The results also showed molecular phenotypic changes similar to other peripheral neuropathic pain models, with the advantage of a lack of motor impairment. These features indicate that MPNL might be more appropriate for the study of neuropathic pain than classical models. PMID- 27230788 TI - Donor CD47 controls T cell alloresponses and is required for tolerance induction following hepatocyte allotransplantation. AB - CD47-deficient hepatocyte transplantation induces rapid innate immune cell activation and subsequent associated graft loss in syngeneic recipients. However, the role of donor CD47 in regulation of T-cell alloresponses is poorly understood. We addressed this question by assessing OVA-specific immune responses in mice following hepatocyte transplantation from CD47-competent or -deficient OVA-transgenic donors. Compared to sham-operated controls, intrasplenic transplantation of CD47-deficient OVA(+) hepatocytes significantly accelerated rejection of OVA(+) skin grafted 7 days after hepatocyte transplantation. In contrast, mice receiving CD47-competent OVA(+) hepatocytes showed prolonged and even indefinite survival of OVA(+) skin allografts. T cells from mice receiving CD47-deficient, but not CD47-competent, OVA(+) hepatocytes showed significantly enhanced responses to OVA(+) stimulators compared to sham-operated controls. In contrast to the production of tolerogenic cytokines (IL-4 and IL-10) in the recipients of CD47-competent hepatocytes, mice receiving CD47-deficient hepatocytes showed elevated production of IFN-gamma and IL-1alpha. Moreover, significant expansion of myeloid-derived suppressor cells was detected in the recipients of CD47-competent hepatocytes, which was required for tolerance induction in these mice. Thus, donor CD47 plays an important role in the control of T-cell alloresponses and tolerance induction following hepatocyte transplantation. Our data also suggest that intrasplenic hepatocyte transplantation may provide a means to induce allograft tolerance. PMID- 27230790 TI - Is no evidence of disease activity an achievable goal in MS patients on intramuscular interferon beta-1a treatment over long-term follow-up? AB - BACKGROUND: No evidence of disease activity (NEDA) has been proposed as a new treatment goal in multiple sclerosis (MS). NEDA-3 status is defined as the absence of magnetic resonance imaging (MRI; new/enlarging/enhancing lesions and increased whole brain volume loss in NEDA-4) and clinical disease activity. OBJECTIVES: To investigate the persistence of NEDA status over long-term follow up in MS patients treated with weekly intramuscular interferon beta-1a. METHODS: We included 192 patients after the first demyelinating event suggestive of MS, that is, clinically isolated syndrome (CIS) and 162 relapsing-remitting MS (RRMS) patients. RESULTS: NEDA-3 status was observed in 40.1% of CIS and 20.4% of RRMS patients after 1 year. After 4 years, 10.1% of CIS patients had NEDA-3 status. After 10 years, none of the RRMS patients had NEDA-3 status. Only 4.6% of CIS and 1.0% of RRMS patients maintained NEDA-4 status after 4 years. Loss of NEDA-3 status after the first year was associated with a higher risk of disability progression (hazard ratio (HR) = 2.3-4.0; p = 0.005-0.03) over 6 years. CONCLUSIONS: Despite intramuscular interferon beta-1a treatment, loss of NEDA status occurred in the vast majority of individuals. Loss of NEDA status during the first year was associated with disability progression over long-term follow up; however, specificity for individual patient was low. PMID- 27230789 TI - Natalizumab versus fingolimod in patients with relapsing-remitting multiple sclerosis non-responding to first-line injectable therapies. AB - BACKGROUND: Natalizumab and fingolimod have not been compared in controlled trials but only in observational studies, with inconclusive results. OBJECTIVES: The objective of this study is to compare the effect of natalizumab and fingolimod in reducing disease activity in relapsing-remitting multiple sclerosis (RRMS). METHODS: We included all consecutive RRMS patients switched from first line agents (glatiramer acetate/interferons) to natalizumab or fingolimod, with a follow-up of 24 months. Data of relapses, Expanded Disability Status Scale score and brain magnetic resonance imaging (MRI) scans were collected. We used propensity score (PS) matching and intention-to-treat analysis. RESULTS: We retained 102 patients in each cohort after PS matching, with similar baseline characteristics. More patients discontinued natalizumab compared to fingolimod (33% vs 11%, p < 0.001), mainly for progressive multifocal leukoencephalopathy (PML) concern. No serious adverse events occurred in the two cohorts. Compared to fingolimod, the natalizumab group presented a higher percentage of relapse-free patients (66% vs 80%, p = 0.015), a higher percentage of disability-improved patients (6% vs 15%, p = 0.033), a lower percentage of MRI-active patients (38% vs 14%, p = 0.001) and a higher percentage of patients with no evidence of disease activity (NEDA-3; 44% vs 70%, p < 0.001) after 2 years of follow-up. Disability worsening was not statistically different in the two groups. CONCLUSION: Natalizumab is superior to fingolimod in RRMS patients non-responding to first-line agents. PMID- 27230791 TI - Influence of hypertension, diabetes, hyperlipidemia, and obstructive lung disease on multiple sclerosis disease course. AB - BACKGROUND: Comorbidities are known to affect multiple sclerosis (MS) patients in a number of ways, including delaying time to diagnosis and reducing health related quality of life. OBJECTIVE: To determine the impact of hypertension, hyperlipidemia, diabetes mellitus, and obstructive lung disease on disease course in MS patients. METHODS: The Knowledge Program is a database linked to our electronic medical record allowing capture of patient and clinician reported outcomes. Through Knowledge Program query and chart review, we identified all relapsing-remitting MS patients seen between 1 January 2010 and 29 May 2012 and acquired their magnetic resonance imaging (MRI) results and comorbidities. Linear and logistic regression models with adjustment for important covariates were used to determine whether the comorbidities affected outcomes over a 3-year period. RESULTS: Hypertension, diabetes, and obstructive lung disease, but not hyperlipidemia, impacted clinical outcomes, including walking speed, self reported disability, and depression. Hypertension had the greatest effect. The presence of multiple comorbidities had a cumulative effect on clinical outcomes. MRI outcomes were unaffected by comorbidities. CONCLUSION: This 3-year longitudinal study revealed that all comorbidities tested except hyperlipidemia impacted clinical outcomes and a cumulative effect with multiple comorbidities was observed. Consideration of comorbid conditions is essential in MS patient care. PMID- 27230792 TI - Escherichia coli Harboring mcr-1 and blaCTX-M on a Novel IncF Plasmid: First Report of mcr-1 in the United States. PMID- 27230793 TI - Usefulness of Serum Procalcitonin for Early Discrimination Between Necrotizing Fasciitis and Cellulitis. PMID- 27230794 TI - Governing metal-organic frameworks towards high stability. AB - Metal-organic frameworks (MOFs) constructed with metal ions/clusters and organic ligands have emerged as an important family of porous materials for various applications. However, the stability of this class of materials is crucial for their practical applications, which might be improved by varying their chemical composition and/or structurally tuning them. To fabricate MOFs with high stability, several strategies for enhancing the stability of MOFs have been developed, in which the strength of metal-ligand bonds is especially considered: the use of highly charged cations and higher pKa ligands, and varying the chemical functionality of linkers. On the other hand, the regulation of their structural architectures is also investigated: interpenetrated frameworks, multi walled frameworks, and self-strengthening of the frameworks. In addition, the surface modification can also improve the stability of the materials. In this review, we introduce and summarize these strategies from the viewpoint of structural tuning and component choosing, providing useful instructions for the further design and synthesis of MOFs with high-level stability. PMID- 27230795 TI - Impact of institutional smoking bans on reducing harms and secondhand smoke exposure. AB - BACKGROUND: Smoking bans or restrictions can assist in eliminating nonsmokers' exposure to the dangers of secondhand smoke and can reduce tobacco consumption amongst smokers themselves. Evidence exists identifying the impact of tobacco control regulations and interventions implemented in general workplaces and at an individual level. However, it is important that we also review the evidence for smoking bans at a meso- or organisational level, to identify their impact on reducing the burden of exposure to tobacco smoke. Our review assesses evidence for meso- or organisational-level tobacco control bans or policies in a number of specialist settings, including public healthcare facilities, higher education and correctional facilities. OBJECTIVES: To assess the extent to which institutional smoking bans may reduce passive smoke exposure and active smoking, and affect other health-related outcomes. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE, EMBASE, and the reference lists of identified studies. We contacted authors to identify completed or ongoing studies eligible for inclusion in this review. We also checked websites of state agencies and organisations, such as trial registries. Date of latest searches was 22nd June 2015. SELECTION CRITERIA: We considered studies that reported the effects of tobacco bans or policies, whether complete or partial, on reducing secondhand smoke exposure, tobacco consumption, smoking prevalence and other health outcomes, in public healthcare, higher educational and correctional facilities, from 2005 onwards.The minimum standard for inclusion was having a settings-level policy or ban implemented in the study, and a minimum of six months follow-up for measures of smoking behaviour. We included quasi experimental studies (i.e. controlled before-and-after studies), interrupted time series as defined by the Cochrane Effective Practice and Organization of Care Group, and uncontrolled pre- and post-ban data. DATA COLLECTION AND ANALYSIS: Two or more review authors independently assessed studies for inclusion in the review. Due to variation in the measurement of outcomes we did not conduct a meta analysis for all of the studies included in this review, but carried out a Mantel Haenszel fixed-effect meta-analysis, pooling 11 of the included studies. We evaluated all studies using a qualitative narrative synthesis. MAIN RESULTS: We included 17 observational studies in this review. We found no randomized controlled trials. Twelve studies are based in hospitals, three in prisons and two in universities. Three studies used a controlled before-and-after design, with another site used for comparison. The remaining 14 studies used an uncontrolled before-and-after study design. Five studies reported evidence from two participant groups, including staff and either patients or prisoners (depending on specialist setting), with the 12 remaining studies investigating only one participant group.The four studies (two in prisons, two in hospitals) providing health outcomes data reported an effect of reduced secondhand smoke exposure and reduced mortality associated with smoking-related illnesses. No studies included in the review measured cotinine levels to validate secondhand smoke exposure. Eleven studies reporting active smoking rates with 12,485 participants available for pooling, but with substantial evidence of statistical heterogeneity (I2 = 72%). Heterogeneity was lower in subgroups defined by setting, and provided evidence for an effect of tobacco bans on reducing active smoking rates. An analysis exploring heterogeneity within hospital settings showed evidence of an effect on reducing active smoking rates in both staff (risk ratio (RR) 0.71, 95% confidence interval ( CI) 0.64 to 0.78) and patients (RR 0.86, 95% CI 0.76 to 0.98), but heterogeneity remained in the staff subgroup (I2 = 76%). In prisons, despite evidence of reduced mortality associated with smoking related illnesses in two studies, there was no evidence of effect on active smoking rates (1 study, RR 0.99, 95% CI 0.84 to 1.16).We judged the quality of the evidence to be low, using the GRADE approach, as the included studies are all observational. AUTHORS' CONCLUSIONS: We found evidence of an effect of settings based smoking policies on reducing smoking rates in hospitals and universities. In prisons, reduced mortality rates and reduced exposure to secondhand smoke were reported. However, we rated the evidence base as low quality. We therefore need more robust studies assessing the evidence for smoking bans and policies in these important specialist settings. PMID- 27230796 TI - Sparse serological evidence of Plasmodium vivax transmission in the Ouest and Sud Est departments of Haiti. AB - BACKGROUND: Plasmodium vivax infections, while quite prevalent throughout South and Central America, are virtually non-existent in Haiti, where P. falciparum infections are detected in over 99% of malaria cases. Historically, few cases of P. vivax have been reported in Haiti; all of which were identified by microscopy and none were confirmed by molecular diagnostics. To further examine the transmission of P. vivax in Haiti, a cross-sectional seroepidemiological study was conducted. METHODS: Whole blood was collected from 814 community members and school children ranging in age between 2 and 80 years-of-age from four locations in the Ouest and Sud-Est Departments of Haiti. After separation of serum, samples were screened for antibodies toward P. vivax apical membrane antigen (AMA-1) and merozoite surface protein-119 (MSP-1) using an indirect enzyme-linked immunosorbent assay (ELISA). RESULTS: Of all participants screened, 4.42% (36/814) were seropositive for AMA-1, 4.55% (37/814) were seropositive for MSP-1, 7.99% (65/814) were seropositive to either antigen, and only 0.98% (7/814) were seropositive for both antigens. Seroconversion rates (SCR) for AMA-1, MSP-1, either AMA-1 or MSP-1, and for both AMA-1 and MSP-1 estimated from the cross sectional seroprevalence indicated rates of P. vivax transmission of less than 1% per year. CONCLUSION: Given the lack of historical evidence of P. vivax infections on the island of Hispaniola, the sparse serological evidence of antibodies toward P. vivax identified in the current study further support the notion that the transmission of P. vivax malaria might be extremely low or even completely absent in Haiti. PMID- 27230799 TI - Environmental signaling: from environmental estrogens to endocrine-disrupting chemicals and beyond. AB - The landmark report (Herbst et al. 1971) linking prenatal treatment with a synthetic estrogen, diethylstilbestrol (DES), to cancer at puberty in women whose mothers took the drug while pregnant ushered in an era of research on delayed effects of such exposures on functional outcomes in offspring. An animal model developed in our laboratory at the National Institute of Environmental Health Sciences confirmed that DES was the carcinogen and exposure to DES caused, as well, functional alterations in the reproductive, endocrine, and immune systems of male and female mice treated in utero. DES was also being used in agriculture and we discovered, at the first meeting on Estrogens in the Environment in 1979 (Estrogens in the Environment, 1980), that many environmental contaminants were also estrogenic. Many laboratories sought to discern the basis for estrogenicity in environmental chemicals and to discover other hormonally active xenobiotics. Our laboratory elucidated how DES and other estrogenic compounds worked by altering differentiation through epigenetic gene imprinting, helping explain the transgenerational effects found in mice and humans. At the Wingspread Conference on the Human-Wildlife Connection in 1991 (Advances in Modern Environmental Toxicology, 1992), we learned that environmental disruption of the endocrine system occurred in many species and phyla, and the term endocrine disruption was introduced. Further findings of transgenerational effects of environmental agents that mimicked or blocked various reproductive hormones and the ubiquity of environmental signals, such as bisphenol A increased concern for human and ecological health. Scientists began to look at other endocrine system aspects, such as cardiovascular and immune function, and other nuclear receptors, with important observations regarding obesity and metabolism. Laboratories, such as ours, are now using stem cells to try to understand the mechanisms by which various environmental signals alter cell differentiation. Since 2010, research has shown that trauma and other behavioral inputs can function as 'environmental signals,' can be encoded in gene regulation networks in a variety of cells and organs, and can be passed on to subsequent generations. So now we come full circle: environmental chemicals mimic hormones or other metabolic signaling molecules and now behavioral experience can be transduced into chemical signals that also modify gene expression. PMID- 27230797 TI - Translational regulation in blood stages of the malaria parasite Plasmodium spp.: systems-wide studies pave the way. AB - The malaria parasite Plasmodium spp. varies the expression profile of its genes depending on the host it resides in and its developmental stage. Virtually all messenger RNA (mRNA) is expressed in a monocistronic manner, with transcriptional activation regulated at the epigenetic level and by specialized transcription factors. Furthermore, recent systems-wide studies have identified distinct mechanisms of post-transcriptional and translational control at various points of the parasite lifecycle. Taken together, it is evident that 'just-in-time' transcription and translation strategies coexist and coordinate protein expression during Plasmodium development, some of which we review here. In particular, we discuss global and specific mechanisms that control protein translation in blood stages of the human malaria parasite Plasmodium falciparum, once a cytoplasmic mRNA has been generated, and its crosstalk with mRNA decay and storage. We also focus on the widespread translational delay observed during the 48-hour blood stage lifecycle of P. falciparum-for over 30% of transcribed genes, including virulence factors required to invade erythrocytes-and its regulation by cis-elements in the mRNA, RNA-processing enzymes and RNA-binding proteins; the first-characterized amongst these are the DNA- and RNA-binding Alba proteins. More generally, we conclude that translational regulation is an emerging research field in malaria parasites and propose that its elucidation will not only shed light on the complex developmental program of this parasite, but may also reveal mechanisms contributing to drug resistance and define new targets for malaria intervention strategies. WIREs RNA 2016, 7:772-792. doi: 10.1002/wrna.1365 For further resources related to this article, please visit the WIREs website. PMID- 27230800 TI - Hospital transfers and patterns of mortality in very low birth weight neonates with surgical necrotizing enterocolitis. AB - PURPOSE: The objectives of this study were to evaluate mortality rates in very low birth weight (VLBW) infants with surgical necrotizing enterocolitis (NEC) by level of available surgical resources and to determine the effect of hospital transfer on mortality. METHODS: Mortality among 4328 VLBW neonates with surgical NEC born 2009-2013 was assessed using the Vermont Oxford Network database. NICUs were classified by availability of resources as a marker of overall center capability: type A (restrictions on ventilation or do not routinely perform major neonatal surgery), type B (perform major neonatal surgery but not cardiac bypass), and type C (perform major surgery, including cardiac bypass in infants). RESULTS: Mortality was higher among those who had surgery at type B centers versus type C centers (44.3% vs 36.4%, adjusted prevalence ratio 1.20 (95% CI: 1.08, 1.33)). Neonates who were not transferred between birth and surgery had a higher mortality compared to those transferred (44.6% vs 31.6%, adjusted prevalence ratio 1.39 (95% CI: 1.25, 1.55)). CONCLUSION: Transfer between birth and surgery and a higher level of surgical resources at the operative center were associated with lower mortality. Early transfer of high risk neonates to centers with higher levels of surgical resources may be warranted. PMID- 27230801 TI - Preliminary observations regarding the expression of collagen triple helix repeat containing 1 is an independent prognostic factor for Wilms' tumor. AB - PURPOSE: Overexpression of collagen triple helix-repeat containing 1 (CTHRC1) has been reported in many malignancies, where it plays an important role in tumorigenesis and progression. This study aimed to examine the clinical significance of CTHRC1 expression in patients with Wilms' tumor (WT). METHODS: The expression of CTHRC1, and its correlations with various clinicopathological parameters, was analyzed using immunohistochemistry in 42 WT tissues and 42 adjacent non-cancerous tissues. Samples from 8 patients with WT were examined using Western blotting and quantitative real-time polymerase chain reaction (qRT PCR). Kaplan-Meier analysis and Cox proportional hazards regression models were used to investigate the correlations between CTHRC1 expression and the prognosis of patients with WT. RESULTS: Immunohistochemistry, Western blotting, and qRT-PCR revealed that the expression of CTHRC1 was significantly higher in WT tumors, compared to the expression in the adjacent non-cancerous tissues. Furthermore, high tumor expression of CTHRC1 was associated with tumor size, clinical stage, histopathological type, and vascular invasion/metastasis. Moreover, the proportions of expressing cells in the WT specimens was higher than the proportions in the matched adjacent non-cancerous tissues. Kaplan-Meier analysis revealed that patients with high CTHRC1 expression exhibited a shorter survival, compared to patients with low CTHRC1 expression. Univariate and multivariate analyses also revealed that CTHRC1 expression was an independent prognostic factor for overall survival. CONCLUSIONS: Our preliminary results suggest that CTHRC1 is an independent prognostic factor, which may play an important role in tumorigenesis and progression, and may be a potential biomarker for WT. PMID- 27230802 TI - Quantum annealing for the number-partitioning problem using a tunable spin glass of ions. AB - Exploiting quantum properties to outperform classical ways of information processing is an outstanding goal of modern physics. A promising route is quantum simulation, which aims at implementing relevant and computationally hard problems in controllable quantum systems. Here we demonstrate that in a trapped ion setup, with present day technology, it is possible to realize a spin model of the Mattis type that exhibits spin glass phases. Our method produces the glassy behaviour without the need for any disorder potential, just by controlling the detuning of the spin-phonon coupling. Applying a transverse field, the system can be used to benchmark quantum annealing strategies which aim at reaching the ground state of the spin glass starting from the paramagnetic phase. In the vicinity of a phonon resonance, the problem maps onto number partitioning, and instances which are difficult to address classically can be implemented. PMID- 27230804 TI - Supraventricular Tachycardia Initiated by Couplets of Atrial Extrasystoles but Not by Single Premature Atrial Beats: What Is the Mechanism? AB - The reported electrocardiogram shows several atrial extrasystoles (AEs) sometimes occurring in couplets. The former beat of each couplet is nonconducted, whereas the latter triggers a supraventricular tachycardia with negative P waves in inferior leads and RP > PR. This suggests an atypical atrioventricular nodal reentrant tachycardia involving the fast pathway anterogradely and the slow pathway retrogradely. The tachycardia is never precipitated by single AEs. The blocked AE of each pair is pivotal in tachycardia initiation, allowing the subsequent impulse to conduct down the fast pathway. A concealed slow pathway penetration during the blocked AE is invoked as the key mechanism. PMID- 27230803 TI - Investigation of High-Speed Erythrocyte Flow and Erythrocyte-Wall Impact in a Lab on-a-Chip. AB - To better understand erythrocyte high-speed motion, collision characteristics, and collision-induced hemolysis probability in rotary blood pumps, a visual experimental investigation of high-speed erythrocyte flow and erythrocyte-wall collision in a lab-on-a-chip was performed. The erythrocyte suspension was driven by a microsyringe pump connected to the microchip, and the erythrocyte flow and erythrocyte-wall impact process were observed and imaged by an optical microscope and a high-speed camera. Two types of microchips with different impact surfaces (flat and curved) were employed. The motion and deformation features before and after collision were studied in detail. The results show that erythrocytes not only move along the flow direction in the flow plane but also rotate and roll in three-dimensional space. Erythrocytes keep discoid shape during the movement in the straight channel, but their deformations during collision are mainly classified into two types: erythrocyte structure is still stable and the erythrocyte performance can be ensured to a certain extent in the TypeA deformation, while the TypeB deformation makes the membrane more likely to fracture on the stretched side, increasing the probability of hemolysis. Furthermore, the movements and deformations of the erythrocytes after collision are analyzed and classified into two types: bouncing and slipping. Moreover, a simulation method for the flow in microchip was performed and validated through a comparison of the streamlines and experimental erythrocytes tracks, which can be further employed to predict the high-speed blood flow, associated with collision process in mechanical blood pump. PMID- 27230805 TI - Assessment of the suitability of using a forehead EEG electrode set and chin EMG electrodes for sleep staging in polysomnography. AB - Recently, a number of portable devices designed for full polysomnography at home have appeared. However, current scalp electrodes used for electroencephalograms are not practical for patient self-application. The aim of this study was to evaluate the suitability of recently introduced forehead electroencephalogram electrode set and supplementary chin electromyogram electrodes for sleep staging. From 31 subjects (10 male, 21 female; age 31.3 +/- 11.8 years), sleep was recorded simultaneously with a forehead electroencephalogram electrode set and with a standard polysomnography setup consisting of six recommended electroencephalogram channels, two electrooculogram channels and chin electromyogram. Thereafter, two experienced specialists scored each recording twice, based on either standard polysomnography or forehead recordings. Sleep variables recorded with the forehead electroencephalogram electrode set and separate chin electromyogram electrodes were highly consistent with those obtained with the standard polysomnography. There were no statistically significant differences in total sleep time, sleep efficiency or sleep latencies. However, compared with the standard polysomnography, there was a significant increase in the amount of stage N1 and N2, and a significant reduction in stage N3 and rapid eye movement sleep. Overall, epoch-by-epoch agreement between the methods was 79.5%. Inter-scorer agreement for the forehead electroencephalogram was only slightly lower than that for standard polysomnography (76.1% versus 83.2%). Forehead electroencephalogram electrode set as supplemented with chin electromyogram electrodes may serve as a reliable and simple solution for recording total sleep time, and may be adequate for measuring sleep architecture. Because this electrode concept is well suited for patient's self-application, it may offer a significant advancement in home polysomnography. PMID- 27230806 TI - Investigations on the possible impact of a glyphosate-containing herbicide on ruminal metabolism and bacteria in vitro by means of the 'Rumen Simulation Technique'. AB - AIMS: This study was performed in a well-established in vitro model to investigate whether the application of a glyphosate-containing herbicide might affect the bacterial communities and some biochemical parameters in a cow's rumen. METHODS AND RESULTS: The test item was applied in two concentrations (high and low) for 5 days. In a second trial, fermentation vessels were inoculated with Clostridium sporogenes before the high dose was applied. Effluents were analysed by biochemical, microbiological and genetic methods. A marginal increase in short chain fatty acid production and a reduction in NH3 -N were observed. There were minor and rather equivocal changes in the composition of ruminal bacteria but no indications of a shift towards a more frequent abundance of pathogenic Clostridia species. Clostridium sporogenes counts declined consistently. CONCLUSIONS: No adverse effects of the herbicide on ruminal metabolism or composition of the bacterial communities could be detected. In particular, there was no evidence of a suspected stimulation of Clostridia growth. SIGNIFICANCE AND IMPACT OF THE STUDY: Antibiotic activity of glyphosate resulting in microbial imbalances has been postulated. In this exploratory study, however, intraruminal application of concentrations reflecting potential exposure of dairy cows or beef cattle did not exhibit significant effects on bacterial communities in a complex in vitro system. The low number of replicates (n = 3/dose) may leave some uncertainty. PMID- 27230807 TI - Intracellular calcium signaling regulates glomerular filtration barrier permeability: the role of the PKGIalpha-dependent pathway. AB - Podocytes are dynamic polarized cells that lie on the surface of glomerular capillaries and comprise an essential component of the glomerular filtration barrier. Insulin provoked a sustained, approximately 70%, increase in intracellular calcium concentration in podocytes. RT-PCR revealed the presence of mRNA encoding sarco/endoplasmic reticulum calcium ATPase isoforms 1-3, and plasma membrane Ca(2+) pump (PMCA) isoforms 1,3,4; mRNA levels were depressed by the addition of insulin. Inhibitors of PMCA, and the Na(+) -Ca(2+) exchanger, increased podocyte permeability to albumin, induced dimerization of protein kinase G type I alpha (PKGIalpha), and activation of PKGIalpha-dependent signaling. These data suggest the involvement of calcium and PKGIalpha signaling in insulin-enhanced filtration barrier permeability in podocytes. PMID- 27230808 TI - Reflections on Caring: The White Bike. PMID- 27230798 TI - The next generation of therapeutics for chronic kidney disease. AB - Chronic kidney disease (CKD) represents a leading cause of death in the United States. There is no cure for this disease, with current treatment strategies relying on blood pressure control through blockade of the renin-angiotensin system. Such approaches only delay the development of end-stage kidney disease and can be associated with serious side effects. Recent identification of several novel mechanisms contributing to CKD development - including vascular changes, loss of podocytes and renal epithelial cells, matrix deposition, inflammation and metabolic dysregulation - has revealed new potential therapeutic approaches for CKD. This Review assesses emerging strategies and agents for CKD treatment, highlighting the associated challenges in their clinical development. PMID- 27230809 TI - Pediatric Brain Tumors: An Update. AB - Brain tumors collectively represent the most common solid tumors in childhood and account for significant morbidity and mortality. Until recently, pediatric brain tumors were diagnosed and classified solely based on histologic criteria, and treatments were chosen empirically. Recent research has greatly enhanced our understanding of the diverse biology of pediatric brain tumors, their molecular and genetic underpinnings, leading to improved diagnostic accuracy and risk stratification, as well as the development of novel biomarkers and molecular targeted therapies. For subsets of patients, these new treatment options have already resulted in improved survival and decreased treatment toxicity. In this article, we provide an overview of the most common childhood brain tumors, describe recent key advances in the field, and discuss the therapeutic challenges that remain. PMID- 27230810 TI - Foreword: Pediatric Sarcomas, Leukemias, and Brain Tumors. PMID- 27230811 TI - A simple method for optimising transformation of non-parametric data: an illustration by reference to cortisol assays. AB - Neuroendocrine data are typically positively skewed and rarely conform to the expectations of a Gaussian distribution. This can be a problem when attempting to analyse results within the framework of the general linear model, which relies on assumptions that residuals in the data are normally distributed. One frequently used method for handling violations of this assumption is to transform variables to bring residuals into closer alignment with assumptions (as residuals are not directly manipulated). This is often attempted through ad hoc traditional transformations such as square root, log and inverse. However, Box and Cox (Box & Cox, ) observed that these are all special cases of power transformations and proposed a more flexible method of transformation for researchers to optimise alignment with assumptions. The goal of this paper is to demonstrate the benefits of the infinitely flexible Box-Cox transformation on neuroendocrine data using syntax in spss. When applied to positively skewed data typical of neuroendocrine data, the majority (~2/3) of cases were brought into strict alignment with Gaussian distribution (i.e. a non-significant Shapiro-Wilks test). Those unable to meet this challenge showed substantial improvement in distributional properties. The biggest challenge was distributions with a high ratio of kurtosis to skewness. We discuss how these cases might be handled, and we highlight some of the broader issues associated with transformation. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27230813 TI - Brain stimulation in Huntington's disease. AB - Huntington's disease (HD) is a hereditary neurodegenerative disorder which is associated with severe disturbances of motor function, especially choreatic movements, cognitive decline and psychiatric symptoms. Various brain stimulation methods have been used to study brain function in patients with HD. Moreover, brain stimulation has evolved as an alternative or additive treatment option, besides current symptomatic medical treatment. This article summarizes the results of brain stimulation to better understand the characteristics of cortical excitability and plasticity in HD and gives a perspective on the therapeutic role for noninvasive and invasive neuromodulatory brain stimulation methods. PMID- 27230814 TI - A genomic approach to identify hybrid incompatibility genes. AB - Uncovering the genetic and molecular basis of barriers to gene flow between populations is key to understanding how new species are born. Intrinsic postzygotic reproductive barriers such as hybrid sterility and hybrid inviability are caused by deleterious genetic interactions known as hybrid incompatibilities. The difficulty in identifying these hybrid incompatibility genes remains a rate limiting step in our understanding of the molecular basis of speciation. We recently described how whole genome sequencing can be applied to identify hybrid incompatibility genes, even from genetically terminal hybrids. Using this approach, we discovered a new hybrid incompatibility gene, gfzf, between Drosophila melanogaster and Drosophila simulans, and found that it plays an essential role in cell cycle regulation. Here, we discuss the history of the hunt for incompatibility genes between these species, discuss the molecular roles of gfzf in cell cycle regulation, and explore how intragenomic conflict drives the evolution of fundamental cellular mechanisms that lead to the developmental arrest of hybrids. PMID- 27230815 TI - Novel mutations of the ADAR1 gene in two Chinese families with dyschromatosis symmetrica hereditaria. PMID- 27230812 TI - Genome-wide analysis reveals adaptation to high altitudes in Tibetan sheep. AB - Tibetan sheep have lived on the Tibetan Plateau for thousands of years; however, the process and consequences of adaptation to this extreme environment have not been elucidated for important livestock such as sheep. Here, seven sheep breeds, representing both highland and lowland breeds from different areas of China, were genotyped for a genome-wide collection of single-nucleotide polymorphisms (SNPs). The FST and XP-EHH approaches were used to identify regions harbouring local positive selection between these highland and lowland breeds, and 236 genes were identified. We detected selection events spanning genes involved in angiogenesis, energy production and erythropoiesis. In particular, several candidate genes were associated with high-altitude hypoxia, including EPAS1, CRYAA, LONP1, NF1, DPP4, SOD1, PPARG and SOCS2. EPAS1 plays a crucial role in hypoxia adaption; therefore, we investigated the exon sequences of EPAS1 and identified 12 mutations. Analysis of the relationship between blood-related phenotypes and EPAS1 genotypes in additional highland sheep revealed that a homozygous mutation at a relatively conserved site in the EPAS1 3' untranslated region was associated with increased mean corpuscular haemoglobin concentration and mean corpuscular volume. Taken together, our results provide evidence of the genetic diversity of highland sheep and indicate potential high-altitude hypoxia adaptation mechanisms, including the role of EPAS1 in adaptation. PMID- 27230816 TI - Contrasting 1D tunnel-structured and 2D layered polymorphs of V2O5: relating crystal structure and bonding to band gaps and electronic structure. AB - New V2O5 polymorphs have risen to prominence as a result of their open framework structures, cation intercalation properties, tunable electronic structures, and wide range of applications. The application of these materials and the design of new, useful polymorphs requires understanding their defining structure-property relationships. We present a characterization of the band gap and electronic structure of nanowires of the novel zeta-phase and the orthorhombic alpha-phase of V2O5 using X-ray spectroscopy and density functional theory calculations. The band gap is found to decrease from 1.90 +/- 0.20 eV in the alpha-phase to 1.50 +/ 0.20 eV in the zeta-phase, accompanied by the loss of the alpha-phase's characteristic split-off dxy band in the zeta-phase. States of dxy origin continue to dominate the conduction band edge in the new polymorph but the inequivalence of the vanadium atoms and the increased local symmetry of [VO6] octahedra results in these states overlapping with the rest of the V 3d conduction band. zeta-V2O5 exhibits anisotropic conductivity along the b direction, defining a 1D tunnel, in contrast to alpha-V2O5 where the anisotropic conductivity is along the ab layers. We explain the structural origins of the differences in electronic properties that exist between the alpha- and zeta phase. PMID- 27230817 TI - A family of acetato-diphenoxo triply bridged dimetallic Zn(II)Ln(III) complexes: SMM behavior and luminescent properties. AB - Eleven dimetallic Zn(II)-Ln(III) complexes of the general formula [Zn(u-L)(u OAc)Ln(NO3)2].CH3CN (Ln(III) = Pr (1), Nd (2), Sm (3), Eu (4), Gd (5), Tb (6), Dy (7), Ho (8), Er (9), Tm (10), Yb (11)) have been prepared in a one-pot reaction from the compartmental ligand N,N'-dimethyl-N,N'-bis(2-hydroxy-3-formyl-5-bromo benzyl)ethylenediamine (H2L). In all these complexes, the Zn(II) ions occupy the internal N2O2 site whereas the Ln(III) ions show preference for the O4 external site. Both metallic ions are bridged by an acetate bridge, giving rise to triple mixed diphenoxido/acetate bridged Zn(II)Ln(III) compounds. The Nd, Dy, Er and Yb complexes exhibit field induced single-ion magnet (SIM) behaviour, with Ueff values ranging from 14.12 to 41.55 K. The Er complex shows two relaxation processes, but only the second relaxation process with an energy barrier of 21.0 K has been characterized. The chromophoric L(2-) ligand is able to act as an "antenna" group, sensitizing the near-infrared (NIR) Nd(III) and Yb(III)-based luminescence in complexes 2 and 11 and therefore, both compounds can be considered as magneto-luminescent materials. In addition, the Sm(III), Eu(III) and Tb(III) derivatives exhibit characteristic emissions in the visible region. PMID- 27230818 TI - The needs of siblings of children with a life-threatening illness, part 2: Psychometric validation of the IBesFEMS. AB - OBJECTIVE: Life-threatening illnesses in children have a significant impact on the lives of their brothers and sisters. Consequently, special attention must be paid to the specific needs of these siblings to help them cope with their situations. To address this issue, we developed an inventory of the needs of the adolescent siblings of severely ill children, the Inventaire des Besoins de la Fratrie d'Enfants Malades Severement (IBesFEMS) [Needs Inventory for Siblings of Critically Ill Children]. The present article describes a preliminary validation study of this new instrument. METHOD: In a prospective cohort study, the 48-item instrument was administered via a website or paper to 58 siblings. RESULTS: Our study revealed that the measure has an estimated internal consistency of 0.96 and a temporal stability intraclass correlation coefficient (ICC) of 0.86 (p < 0.01). Its convergence validity is also satisfactory. SIGNIFICANCE OF RESULTS: Our findings suggest that the IBesFEMS is highly relevant for pediatric palliative care clinicians and researchers. Future studies should investigate its factorial structure and predictive validities. PMID- 27230819 TI - Trifolium species - the latest findings on chemical profile, ethnomedicinal use and pharmacological properties. AB - OBJECTIVES: Clovers (Trifolium, Fabaceae) have a long history of use in folk medicine. Furthermore, during last 3 years, a considerable growth in scientific interest in these plants has been observed. This article summarizes and critically reviews an over 3-year progress of knowledge of ethnomedicinal use, phytochemical profile, physiological effects and possible therapeutic action of various clover species. It contains the latest literature (over 80 papers), originated from international databases (MEDLINE/PubMed, Science Direct/Elsevier, Springer Link, Wiley Online Library) and reports from other international and local scientific periodicals. KEY FINDINGS: Traditional uses of T. pratense and T. repens have been confirmed, while the folk medicine recommendations for administration of other clovers such as T. burchellianum, T. fragiferum, T. hybridum, T. minus and T. purpureum were reported for the first time. Furthermore, several other clover species were also investigated in terms of their antioxidant, antimicrobial and phytoestrogenic effects for the first time. Only T. alexandrinum, T. pratense and T. medium were examined in animal studies. SUMMARY: Besides T. pratense, other clovers may be a rich source of bioactive phytochemicals. However, in contradiction to red clover, the therapeutic use of other clovers is still limited by the lack of in-vivo evidence. PMID- 27230820 TI - Exploratory subgroup analysis in clinical trials by model selection. AB - The interest in individualized medicines and upcoming or renewed regulatory requests to assess treatment effects in subgroups of confirmatory trials requires statistical methods that account for selection uncertainty and selection bias after having performed the search for meaningful subgroups. The challenge is to judge the strength of the apparent findings after mining the same data to discover them. In this paper, we describe a resampling approach that allows to replicate the subgroup finding process many times. The replicates are used to adjust the effect estimates for selection bias and to provide variance estimators that account for selection uncertainty. A simulation study provides some evidence of the performance of the method and an example from oncology illustrates its use. PMID- 27230821 TI - Appropriateness of aminoglycoside prescriptions in a French university hospital. AB - INTRODUCTION: Aminoglycosides are a major class of antibiotics. Their use is particularly interesting in the treatment of severe infections but their toxicity is well known. They are mostly prescribed combined with other agents and as first line treatments. We aimed to assess the appropriateness of aminoglycoside prescriptions in a French university hospital on the basis of the latest French recommendations published in 2011. METHOD: We conducted a prospective study between January 17th and February 4th, 2014 to assess prescription modalities of aminoglycosides on the basis of the following criteria: indication, duration of treatment, dosing schedule, administration modalities, and drug level monitoring. Prescriptions were then compared to the 2011 national guidelines. RESULTS: A total of 68 consecutive prescriptions were analyzed and only 47.8% complied with guidelines. Most physicians complied with recommendations, particularly with the indication for severe infections (95.6%), the administration of a single daily dose (92.6%), and the slow intravenous infusion (30minutes) administration (84%). However, physicians tended to prescribe lower doses than recommended (40.3%), especially to patients presenting with renal insufficiency, and drug level monitoring was not optimal. CONCLUSION: Although new and accurate national recommendations were recently published, aminoglycoside prescription is still not optimal, in particular for dosing and plasma concentration monitoring. PMID- 27230822 TI - Hajj-associated infections. AB - BACKGROUND: The Hajj is the largest annual mass gathering event in the world, thus favoring the transmission of various infections: 183 different nationalities, high temperatures, coincidence with the start of the flu season in the Northern hemisphere, a long barefoot walk, tent-type accommodation, communal toilet facilities, absence of food control, and sharing of razors. Infections are the first cause of hospital admission, which often occurs in the home country of pilgrims. METHODS: Literature review on PubMed from 1952 to November 2015 on the epidemiology and prevention of infections contracted during the Hajj, using the keywords "Hajj" and "infections". RESULTS: Respiratory tract infections, ENT infections, influenza, pyogenic pneumonia, whooping cough, and tuberculosis are most frequently observed during the Hajj. Outbreaks of meningococcal meningitis have been reported in pilgrims and their contacts. Waterborne infections such as gastroenteritis and hepatitis A are common, despite the improvement of health conditions. Pyoderma and furuncles are also frequently observed. Recently, dengue fever, Alkhumra hemorrhagic fever, and Rift Valley fever have emerged but no case of MERS-coronavirus, appeared in Saudi Arabia in 2012, have yet been observed during the 2012-2014 Hajj. CONCLUSION: Prevention is based on compulsory meningococcal vaccination, vaccination against seasonal influenza and pneumococcal infections for pilgrims at high risk of contracting the infection, and on vaccination against hepatitis A. Updating immunization for diphtheria/tetanus/poliomyelitis/pertussis and measles/mumps is also crucial and pilgrims must comply with hygiene precautions. PMID- 27230823 TI - Animal Hairs as Water-stimulated Shape Memory Materials: Mechanism and Structural Networks in Molecular Assemblies. AB - Animal hairs consisting of alpha-keratin biopolymers existing broadly in nature may be responsive to water for recovery to the innate shape from their fixed deformation, thus possess smart behavior, namely shape memory effect (SME). In this article, three typical animal hair fibers were first time investigated for their water-stimulated SME, and therefrom to identify the corresponding net points and switches in their molecular and morphological structures. Experimentally, the SME manifested a good stability of high shape fixation ratio and reasonable recovery rate after many cycles of deformation programming under water stimulation. The effects of hydration on hair lateral size, recovery kinetics, dynamic mechanical behaviors and structural components (crystal, disulfide and hydrogen bonds) were then systematically studied. SME mechanisms were explored based on the variations of structural components in molecular assemblies of such smart fibers. A hybrid structural network model with single switch and twin-net-points was thereafter proposed to interpret the water stimulated shape memory mechanism of animal hairs. This original work is expected to provide inspiration for exploring other natural materials to reveal their smart functions and natural laws in animals including human as well as making more remarkable synthetic smart materials. PMID- 27230824 TI - Extending the Substrate Scope for the Asymmetric Iridium-Catalyzed Hydrogenation of Minimally Functionalized Olefins by Using Biaryl Phosphite-Based Modular Ligand Libraries. AB - Asymmetric hydrogenation is one of the most efficient and atom-economical tools to prepare chiral molecules. However, the enantiodiscrimination of simple, minimally functionalized olefins is still challenging and requires more sophisticated ligand design. Herein, we discuss our progress in the successful development of ligand design for the iridium-catalyzed asymmetric hydrogenation of minimally functionalized olefins. PMID- 27230825 TI - Bronchial thermoplasty and biological therapy as targeted treatments for severe uncontrolled asthma. AB - Although a small proportion of patients with asthma have severe disease, it accounts for the majority of morbidity related to the illness. Severe asthma comprises a heterogeneous group of phenotypes. Targeted treatments for these phenotypes represent a major advancement in the management of severe asthma. Omalizumab, a monoclonal antibody to IgE, improves asthma control in patients with a predominant allergic phenotype. Monoclonal antibodies targeted to interleukin 4alpha and interleukin 5 have shown substantial benefit in patients with the eosinophilic asthma phenotype; so too have monoclonal antibodies targeted to interleukin 13 in patients with a type 2 allergic phenotype. Bronchial thermoplasty, a new technique to reduce airway smooth muscle mass, improves symptoms and reduces exacerbations in patients with severe uncontrolled asthma and the chronic airflow obstruction phenotype. While awaiting comparative trials, we can now use a targeted approach with these phenotypes, guiding our treatment selection with the best evidence. This Review will focus on the latest developments in these new treatments and inform the clinician on how to select the appropriate patient for these treatments. PMID- 27230826 TI - Implementation of nutrition risk screening using the Malnutrition Universal Screening Tool across a large metropolitan health service. AB - BACKGROUND: A standardised nutrition risk screening (NRS) programme with ongoing education is recommended for the successful implementation of NRS. This project aimed to develop and implement a standardised NRS and education process across the adult bed-based services of a large metropolitan health service and to achieve a 75% NRS compliance at 12 months post-implementation. METHODS: A working party of Monash Health (MH) dietitians and a nutrition technician revised an existing NRS medical record form consisting of the Malnutrition Universal Screening Tool and nutrition management guidelines. Nursing staff across six MH hospital sites were educated in the use of this revised form and there was a formalised implementation process. Support from Executive Management, nurse educators and the Nutrition Risk Committee ensured the incorporation of NRS into nursing practice. Compliance audits were conducted pre- and post-implementation. RESULTS: At 12 months post-implementation, organisation-wide NRS compliance reached 34.3%. For those wards that had pre-implementation NRS performed by nursing staff, compliance increased from 7.1% to 37.9% at 12 months (P < 0.001). The improved NRS form is now incorporated into standard nursing practice and NRS is embedded in the organisation's 'Point of Care Audit', which is reported 6 monthly to the Nutrition Risk Committee and site Quality and Safety Committees. CONCLUSIONS: NRS compliance improved at MH with strong governance support and formalised implementation; however, the overall compliance achieved appears to have been affected by the complexity and diversity of multiple healthcare sites. Ongoing education, regular auditing and establishment of NRS routines and ward practices is recommended to further improve compliance. PMID- 27230827 TI - Clinical Practice Guideline: Irritable bowel syndrome with constipation and functional constipation in the adult. AB - In this Clinical Practice Guideline we discuss the diagnostic and therapeutic approach of adult patients with constipation and abdominal complaints at the confluence of the irritable bowel syndrome spectrum and functional constipation. Both conditions are included among the functional bowel disorders, and have a significant personal, healthcare, and social impact, affecting the quality of life of the patients who suffer from them. The first one is the irritable bowel syndrome subtype, where constipation represents the predominant complaint, in association with recurrent abdominal pain, bloating, and abdominal distension. Constipation is characterized by difficulties with or low frequency of bowel movements, often accompanied by straining during defecation or a feeling of incomplete evacuation. Most cases have no underlying medical cause, and are therefore considered as a functional bowel disorder. There are many clinical and pathophysiological similarities between both disorders, and both respond similarly to commonly used drugs, their primary difference being the presence or absence of pain, albeit not in an "all or nothing" manner. Severity depends not only upon bowel symptom intensity but also upon other biopsychosocial factors (association of gastrointestinal and extraintestinal symptoms, grade of involvement, and perception and behavior variants). Functional bowel disorders are diagnosed using the Rome criteria. This Clinical Practice Guideline has been made consistent with the Rome IV criteria, which were published late in May 2016, and discuss alarm criteria, diagnostic tests, and referral criteria between Primary Care and gastroenterology settings. Furthermore, all the available treatment options (exercise, fluid ingestion, diet with soluble fiber-rich foods, fiber supplementation, other dietary components, osmotic or stimulating laxatives, probiotics, antibiotics, spasmolytics, peppermint essence, prucalopride, linaclotide, lubiprostone, biofeedback, antidepressants, psychological therapy, acupuncture, enemas, sacral root neurostimulation, surgery) are discussed, and practical recommendations are made regarding each of them. PMID- 27230828 TI - Identifications of novel mechanisms in breast cancer cells involving duct-like multicellular spheroid formation after exposure to the Random Positioning Machine. AB - Many cell types form three-dimensional aggregates (MCS; multicellular spheroids), when they are cultured under microgravity. MCS often resemble the organ, from which the cells have been derived. In this study we investigated human MCF-7 breast cancer cells after a 2 h-, 4 h-, 16 h-, 24 h- and 5d-exposure to a Random Positioning Machine (RPM) simulating microgravity. At 24 h few small compact MCS were detectable, whereas after 5d many MCS were floating in the supernatant above the cells, remaining adherently (AD). The MCS resembled the ducts formed in vivo by human epithelial breast cells. In order to clarify the underlying mechanisms, we harvested MCS and AD cells separately from each RPM-culture and measured the expression of 29 selected genes with a known involvement in MCS formation. qPCR analyses indicated that cytoskeletal genes were unaltered in short-term samples. IL8, VEGFA, and FLT1 were upregulated in 2 h/4 h AD-cultures. The ACTB, TUBB, EZR, RDX, FN1, VEGFA, FLK1 Casp9, Casp3, PRKCA mRNAs were downregulated in 5d-MCS samples. ESR1 was upregulated in AD, and PGR1 in both phenotypes after 5d. A pathway analysis revealed that the corresponding gene products are involved in organization and regulation of the cell shape, in cell tip formation and membrane to membrane docking. PMID- 27230829 TI - Molecular imaging of brain tumors with radiolabeled choline PET. AB - Several positron emission tomography (PET) radiopharmaceuticals have been emerged in the last decade as feasible in the management of brain lesions, due to the low performance in this field of the 18F-fluoro-deoxyglucose (18F-FDG), for its high physiological gradient of distribution in the brain. Beyond its usefulness in prostate cancer imaging, the radiolabeled choline is becoming a promising tool in diagnosing benign and malignant lesions of the brain, due to a very low rate of distribution in normal white and grey matters. The aim of our review was to assess the real impact of the radiolabeled choline PET/CT in the management of brain benign lesions, brain tumors, and metastases. Furthermore, emphasis was given to the comparison between the radiolabeled choline and the other radiopharmaceuticals in this field. A literature review was performed. The radiolabeled choline is useful in the management of patients with suspected brain tumor relapse, especially in association with magnetic resonance imaging (MRI), with caution regarding its intrinsic characteristic of non-tumor-specific tracer. For the same reason, it is not useful in the early evaluation of brain lesions. Similar results are reported for other radiopharmaceuticals. The inclusion of the head in the whole-body scans for somatic tumors is necessary to ensure metastases in the brain or choline-avid benign lesions. PMID- 27230830 TI - Prechiasmatic transection of the optic nerve in optic nerve glioma: technical description and surgical outcome. AB - Optic pathway glioma (OPG) encompasses a spectrum of findings ranging from lesions confined to the optic nerve only, lesions affecting the optic chiasm and hypothalamus, and lesions with diffuse involvement of a large part of the optic pathway and neighboring structures. The majority of pediatric low-grade astrocytomas in the optic/chiasmatic region are typical pilocytic astrocytoma. The rest of them (10 %) may be other gliomas such as fibrillary pilomyxoid astrocytoma (grade 2 WHO). The postsurgical local recurrence rate of 55 to 76 % has been reported in some histological subtypes such as pilomyxoid astrocytoma (grade 2). Performing a prechiasmatic transection might offer a new surgical option to avoid further tumor growth toward the chiasm in the optic nerve glioma with predominantly orbital manifestations. In this retrospective study, four patients (three children, two without neurofibromatosis type 1 (NF1), and one with NF1 and one adult without NF1) with optic nerve glioma without involvement of the chiasm but blindness, disfiguring proptosis, and pain of the affected eye were included. The surgical approach was performed as a combined approach from pterional extradural and intradural. Without any exceptions, vision of the contralateral eye could be preserved and did not show any deterioration after surgery or during the follow-up time between 17 and 106 months. Furthermore, in all patients, gross total tumor resection could be achieved. During follow-up observation in all patients, no further tumor progress or recurrences could be observed. None of the patients were treated postoperatively by radiotherapy or chemotherapy. Prechiasmatic transection of the optic nerve in optic nerve glioma without affecting the chiasm might offer a surgical treatment option to control tumor growth and to preserve vision of the contralateral eye. PMID- 27230831 TI - Acute stress impairs cognitive flexibility in men, not women. AB - Psychosocial stress influences cognitive abilities, such as long-term memory retrieval. However, less is known about the effects of stress on cognitive flexibility, which is mediated by different neurobiological circuits and could thus be regulated by different neuroendocrine pathways. In this study, we randomly assigned healthy adults to an acute stress induction or control condition and subsequently assessed participants' cognitive flexibility using an open-source version of the Wisconsin Card Sort task. Drawing on work in rodents, we hypothesized that stress would have stronger impairing effects on cognitive flexibility in men than women. As predicted, we found that stress impaired cognitive flexibility in men but did not significantly affect women. Our results thus indicate that stress exerts sex-specific effects on cognitive flexibility in humans and add to the growing body of research highlighting the need to consider sex differences in effects of stress. PMID- 27230832 TI - A meta-analysis of reflectance confocal microscopy for the diagnosis of malignant skin tumours. AB - Early diagnosis is extremely important for treatment and prognosis of skin cancer. Reflectance confocal microscopy (RCM) is a recently developed technique used to diagnose skin cancer. This meta-analysis was carried out to assess the accuracy of RCM for the diagnosis of malignant skin tumours. We conducted a systematic literature search of EMBASE, PubMed, the Cochrane Library and Web of Science database for relevant articles in English published up to 24 December 2015. The quality of the included studies was assessed using the QUADAS-2 tool. Statistical analyses were conducted using the software Meta-Disc version 1.4 and STATA version 12.0. A total of 21 studies involving 3108 patients with a total of 3602 lesions were included in the per-lesion analysis. The corresponding pooled results for sensitivity and specificity were 93.6% (95% CI: 0.92-0.95) and 82.7% (95% CI: 0.81-0.84) respectively. Positive likelihood ratio and negative likelihood ratio were 5.84 (95% CI: 4.27-7.98) and 0.08 (95% CI: 0.07-0.10) respectively. Subgroup analysis showed that RCM had a sensitivity of 92.7% (95% CI: 0.90-0.95) and a specificity of 78.3% (95% CI: 0.76-0.81) for detecting melanoma. The pooled sensitivity and specificity of RCM for detecting basal cell carcinoma were 91.7% (95% CI: 0.87-0.95) and 91.3% (95% CI: 0.94-0.96) respectively. RCM is a valid method of identifying malignant skin tumours accurately. PMID- 27230833 TI - Distribution of polymorphisms in the CYP2C9 gene and CYP2C19/CYP2C9 haplotypes among Venezuelan populations. AB - BACKGROUND: Polymorphisms with decreased enzyme activity of their gene products have been reported in region CYP2C with population variations in haplotype structure. AIM: To estimate the allelic and genotypic frequencies of variants CYP2C9*2 and CYP2C9*3 and of CYP2C9/CYP2C19 haplotypes in Venezuelan populations. SUBJECTS AND METHODS: Six hundred and thirty-four individuals from nine admixed populations (AP) and the Warao indigenous group were studied. Allelic frequencies, linkage disequilibrium and genetic distances for haplotypes were calculated and compared within Venezuela and with data available in the literature. RESULTS: Heterogeneity in the distribution of CYP2C9 alleles and CYP2C9/CYP2C19 haplotypes among the AP and the Warao was observed. The joint frequency of haplotypes, with at least one non-functional variant, shows values in AP between 21-41%, while in Warao it reaches 5%. The haplotype that includes the Asian and rare Latin America CYP2C19*3 allele was detected in most AP and in Warao. Pairwise Fst values showed that the Warao was an outlier compared with the AP, while these are closer to European-derived populations. No significant correlation was found between haplotype frequencies and admixture. CONCLUSIONS: These results support the need to understand the distribution of genomic biomarkers related to the metabolism of drugs, for planning national public health strategies. PMID- 27230834 TI - Altered cytokine network in gestational diabetes mellitus affects maternal insulin and placental-fetal development. AB - Pregnancy is characterized by an altered inflammatory profile, compared to the non-pregnant state with an adequate balance between pro-and anti-inflammatory cytokines needed for normal development. Cytokines are small secreted proteins expressed mainly in immunocompetent cells in the reproductive system. From early developmental stages onward, the secretory activity of placenta cells clearly contributes to increase local as well as systemic levels of cytokines. The placental production of cytokines may affect mother and fetus independently. In turn because of this unique position at the maternal fetal interface, the placenta is also exposed to the regulatory influence of cytokines from maternal and fetal circulations, and hence, may be affected by changes in any of these. Gestational diabetes mellitus (GDM) is associated with an overall alteration of the cytokine network. This review discusses the changes that occur in cytokines post GDM and their negative effects on maternal insulin and placental-fetal development. PMID- 27230836 TI - [Pathophysiology of primary hyperparathyroidism]. AB - Primary hyperparathyroidism is a disease with increased cell proliferation and enhanced PTH secretion due to the escape from negative feedback by calcium ion in parathyroid cells for their tumorization. Involvements of several gene abnormalities have been demonstrated in the pathogenesis of parathyroid tumor. First, an activation of cyclin D1 gene by the translocation of 11 chromosome was found as one of the cause of parathyroid tumorigenesis. Moreover, mutation of multiple endocrine type 1 gene is the most frequent as a genetic cause of sporadic parathyroid tumor. Its related tumor is developed by an inactivation mutation of tumor suppressor gene. Parafibromin, calcium-sensing receptor, vitamin D receptor, Klotho and RET might be related to the tumorigeneis of parathyroid tumor. PMID- 27230835 TI - Methylene bisphosphonates as the inhibitors of HIV RT phosphorolytic activity. AB - The structure-function analysis of 36 methylenebisphosphonates (BPs) as inhibitors of the phosphorolytic activity of native and drug-resistant forms of HIV-1 reverse transcriptase (RT) was performed. It was shown that with the increase of the inhibitory potential of BPs towards the phosphorolytic activity raises their ability to inhibit the RT-catalyzed DNA elongation. Herein, we report the impact of the thymidine analog mutations (TAM) on the activity of bisphosphonates, as well as some structural features of the BPs, allowing them to maintain the inhibitory activity on the enzyme resistant to nucleoside analog therapy. We estimated the Mg(2+)-coordinating group structure, the linker and the aromatic pharmacophore influence on the inhibitory potential of the BPs. Based on the 31 BPs SAR, several BPs with improved inhibitory properties were designed and synthesized. PMID- 27230837 TI - [The pathophysiology of secondary hyperparathyroidism]. AB - Secondary hyperparathyroidism (SHPT) is characterized by the acceleration of bone turnover due to the over-secretion of parathyroid hormone, which is accompanied with parathyroid hyperplasia. The pathogenesis includes the reduced production of calcitriol due to the elevated serum fibroblast growth factor 23 (FGF23) level to maintain phosphate (P) homeostasis, and its resultant hypocalcemia. Although the mechanism parathyroid glands sense P remains unknown, the expressions of calcium (Ca) sensing receptor and vitamin D receptor, which sense serum level of Ca and calcitriol respectively, down-regulate in chronic kidney disease. The rapture of feedback system including these, contributes to the development of SHPT. PMID- 27230838 TI - [Pathophysiology of Hypoparathyroidism]. AB - Hypoparathyroidism in a broad sense is caused by a parathyroid hormone (PTH) deficiency or resistance, leading to hypocalcemia and hyperphosphatemia. PTH deficiency can be result from destruction or hypoplasia/agenesis of the parathyroid gland, or the impaired synthesis or secretion of PTH. On the other hand, PTH resistance is based on the disrupted transduction of its signaling and includes pseudohypoparathyroidism, Blomstrand lethal chondrodysplasia and acrodysostosis. There has been a substantial progress in the identification of the pathogenesis for the inherited hypoparathyroidism, and genetic tests for diagnosis are considered when necessary. PMID- 27230839 TI - [Pharmacological characteristics of drugs targeted on calcium-sensing receptor. properties of cinacalcet hydrochloride as allosteric modulator]. AB - Calcimimetics act as positive allosteric modulators of the calcium-sensing receptor (CaSR), thereby decreasing parathyroid hormone (PTH) secretion from the parathyroid glands. On the other hand, negative allosteric modulators of the CaSR with stimulatory effect on PTH secretion are termed calcilytics. The calcimimetic cinacalcet hydrochloride (cinacalcet) is the world's first allosteric modulator of G protein-coupled receptor to enter the clinical market. Cinacalcet just tunes the physiological effects of Ca(2+), an endogenous ligand, therefore, shows high selectivity and low side effects. Calcimimetics also increase cell surface CaSR expression by acting as pharmacological chaperones (pharmacoperones). It is considered that the cinacalcet-induced upper gastrointestinal problems are resulted from enhanced physiological responses to Ca(2+) and amino acids via increased sensitivity of digestive tract CaSR by cinacalcet. While clinical developments of calcilytics for osteoporosis were unfortunately halted or terminated due to paucity of efficacy, it is expected that calcilytics may be useful for the treatment of patients with activating CaSR mutations, asthma, and idiopathic pulmonary artery hypertension. PMID- 27230840 TI - [Nonsurgical management of mild primary hyperparathyroidism]. AB - Primary hyperparathyroidism (PHPT) is one of the common endocrine disorders, which results clinically in nephrolithiasis, osteoporosis, muscle weakness, cardiac and psychiatric abnormalities even in a mild or asymptomatic disease. Parathyroidectomy (PTX) is the only definitive treatment for PHPT, however, some patients with sporadic PHPT refuse surgery, are medically unfit, or have residual or recurrent disease inaccessible to further surgery. These patients may require intervention for management of symptomatic or moderate to severe hypercalcemia, bone loss or kidney calculi. PMID- 27230841 TI - [Role of parathyroid hormone in Klotho-FGF23 system]. AB - Klotho was originally identified as an anti-aging gene that accelerated aging when disrupted and extended life span when overexpressed in mice. The Klotho gene encodes a single-pass transmembrane protein and is expressed in the kidney and parathyroid gland. Klotho protein functions as an obligate subunit of the receptor for fibroblast growth factor 23 (FGF23). FGF23 is a hormone secreted from osteocytes and osteoblasts and acts on renal tubular cells to promote phosphate excretion into the urine and suppress synthesis of active form of vitamin D (1,25-dihydroxyvitamin D3;1,25(OH)(2)D(3)). Decreased Klotho expression due to the kidney damage including CKD might increase the circulating level of FGF23 and trigger disturbed mineral-bone metabolism, leading to CKD-MBD. Characteristic features of CKD-MBD including hyperphosphatemia, hypocalcemia, and decreased serum 1,25(OH)(2)D(3) can be explained by (mal) adaptation of the Klotho-FGF23 system, which also contributes to the pathophysiology of secondary hyperparathyroidism (SHPT). In addition to its function as a receptor for FGF23, the extracellular domain of Klotho is secreted by ectodomain shedding and functions as a humoral factor that regulates multiple ion channels and transporters. Thus, Klotho has emerged as a key regulator of mineral metabolism in health and disease. PMID- 27230842 TI - [Imaging of hyperparathyroidism-Ultrasonography and 99mTc-MIBI scintigraphy-]. AB - Treatments for primary hyperparathyroidism due to adenoma, hyperplasia and carcinoma and secondary hyperparathyroidism are mainly surgical resections of them. Accurate imaging diagnoses of the existences and the regions are very important for reductions of invasiveness. We describe ultrasonography and (99m)Tc MIBI scintigraphy of hyperparathyroidism. We explain an advantage, a disadvantage and diagnosability of these modalities. We mention utilities of SPECT/CT, too. We show echogram and (99m)Tc-MIBI scintigraphy images about 3 cases of hyperparathyroidism. PMID- 27230843 TI - [Bone disease in the field of CKD-MBD]. AB - The pathophysiology and treatment for renal bone disease have made remakable progress. Moreover, osteocyte reseach has made tremendous progress. In the clinical aspect, (1) hyperphosphatemia, (2) hyperparathyroid and hypoparathyroid bone disease in patients with chronic kidney disease, (3) increased serum level of fibroblast growth factor 23 (FGF-23) and(4) reduced level of Klotho should be taken into consideration when analyzing these conditions. On the other hand, hyperphosphatemia must be successfully treated. Hyperparathyroid bone disease has been successfully treated with vitamin D sterol, cinacalcet hydrochloride and parathyroidectomy, however, the treatment of hypoparathyroidism inpatient with diabetes or non-diabetes met with high hurdles. We must treat these patients in thinking about osteocytic perilacunar/canalicular system. PMID- 27230844 TI - [Vascular diseases in CKD-MBD]. AB - Vascular calcification is an important component of CKD-MBD and occurs in association with vascular lesions of CKD-MBD such as atherosclerosis and arteriosclerosis. Atherosclerotic intimal calcification and medial calcification contribute to the development and progression of cardiovascular disease. Epidemiological data suggest that it is not atherothrombotic disease but myocardal disease including left ventricular hypertrophy with fibrosis and diastolic dysfunction which is the principal cause of cardiovascular death in CKD. Arteriosclerosis is characterized by thickening and calcification of the medial arterial layer. Medial calcification results in increased arterial stiffness and contributes to the development of myocardial disease. Therefore, it is important to develop novel therapeutics for medial calcification. PMID- 27230845 TI - [Surgical treatment for patients with hyperparathyroidism]. AB - Although parathyroid surgery is not a complicated surgical procedure, enough knowledge of the surgical anatomy and accurate information for localization of involved gland are required from the fact of the variation in the number and the location of the parathyroid gland. Surgical treatment for patients with hyperparathyroidism has been in the transition state from the era of both sides exploration to minimally invasive surgery. In addition, intraoperative radio guide method, intraoperative iPTH measurement, and intraoperative neuromonitoring have been introduced for the safe and reliable operation. PMID- 27230846 TI - [Treatment of CKD-MBD targeting the parathyroid gland]. AB - Secondary hyperparathyroidism is a major component of chronic kidney disease mineral and bone disorder (CKD-MBD) and has a considerable impact on morbidity and mortality through the development of high-turnover bone disease and vascular calcification. Thus, management of secondary hyperparathyroidism is important for improving the outcomes of CKD patients. Because there is a fundamental difference in the pathogenesis of secondary hyperparathyroidism between predialysis and dialysis patients, different therapeutic approach should be considered for each condition. In this article, we summarize the treatment of CKD-MBD for managing secondary hyperparathyroidism, with a particular focus on the difference between predialysis and dialysis stages of CKD. PMID- 27230847 TI - [The Importance of teriparatide in the treatment of osteoporosis]. AB - The anabolic agent teriparatide (TPTD) clearly increases bone mineral density both in daily and weekly formulations. In addition, the effectiveness of daily TPTD in reducing the risks of vertebral and non-vertebral fractures and of weekly TPTD in reducing the risk of vertebral fractures has been established. TPTD is indicated for severe osteoporosis, such as cases of multiple fractures, hip fractures, and fractures sustained during antiresorptive therapy. TPTD has also been shown to be effective for male osteoporosis and glucocorticoid-induced osteoporosis. Furthermore, TPTD can only be given for a limited duration, and requires sequential antiresorptive therapy following completion of administration. TPTD is the only anabolic agent that is currently available, and more effective methods of use such as combination and sequential therapies are being investigated. Moreover, clinical development of novel anabolic agents such as abaloparatide, a parathyroid hormone-related protein(PTHrP)analog, is being actively undertaken. PMID- 27230848 TI - [Molecular and Cellular Pathogenesis of Cherubism]. AB - Study of rare genetic disorder often provides fundamental insights into the pathology of common diseases. Cherubism is a rare craniofacial disorder in children characterized by the destruction of maxillary and mandibular bones due to expansile fibrous inflammatory lesions. Genetic study of cherubism families discovered that gain-of-function mutations in the signaling adaptor protein SH3BP2 are responsible for cherubism. Analysis of the mouse model revealed that cherubism is an autoinflammatory disorder that is caused by dysregulated signaling pathway mediated by toll-like receptors and spleen tyrosine kinase. Recent study of the SH3BP2-deficient mice showed that SH3BP2 plays important roles in bone resorption in mouse models of inflammatory arthritis. These results establish SH3BP2 as a key player in the osteoimmune system beyond its role in a rare inherited disorder and suggest that the signaling pathway mediated by SH3BP2 is involved in the pathogenesis of common inflammatory bone diseases such as rheumatoid arthritis. PMID- 27230849 TI - Effects of human limb gestures on galvanic coupling intra-body communication for advanced healthcare system. AB - BACKGROUND: Intra-Body Communication (IBC), which utilizes the human body as the transmission medium to transmit signal, is a potential communication technique for the physiological data transfer among the sensors of remote healthcare monitoring system, in which the doctors are permitted to remotely access the healthcare data without interrupt to the patients' daily activities. METHODS: This work investigates the effects of human limb gestures including various joint angles, hand gripping force and loading on galvanic coupling IBC channel. The experiment results show that channel gain is significantly influenced by the joint angle (i.e. gain variation 1.09-11.70 dB, p < 0.014). The extension, as well as the appearance of joint in IBC channel increases the channel attenuation. While the other gestures and muscle fatigue have negligible effect (gain variation <0.77 dB, p > 0.793) on IBC channel. Moreover, the change of joint angle on human limb IBC channel causes significant variation in bit error rate (BER) performance. CONCLUSIONS: The results reveal the dynamic behavior of galvanic coupling IBC channel, and provide suggestions for practical IBC system design. PMID- 27230850 TI - Effect of renal function on the pharmacokinetics of LCZ696 (sacubitril/valsartan), an angiotensin receptor neprilysin inhibitor. AB - PURPOSE: LCZ696 (sacubitril/valsartan), an angiotensin receptor neprilysin inhibitor, is indicated for chronic heart failure (HF) and reduced ejection fraction (HFrEF) to reduce the risk of cardiovascular death and hospitalization for HF. Following oral administration, LCZ696 provides systemic exposure to valsartan and sacubitril (a prodrug), and its metabolite sacubitrilat (the active neprilysin inhibitor, formerly named as LBQ657), which is eliminated primarily via renal route. Since renal dysfunction is a common comorbidity in patients with HF, two open-label studies assessing the effect of mild, moderate, and severe renal impairment were conducted. METHODS: Patients with mild (N = 8; creatinine clearance [CrCl] 50 to <=80 mL/min), moderate (N = 8; CrCl 30 to <50 mL/min), and severe (N = 6; CrCl <30 mL/min) renal impairment and matching healthy subjects (CrCl >80 mL/min) for each severity group were enrolled to assess the pharmacokinetics of LCZ696 analytes following administration of LCZ696 400 mg once daily (QD) on days 1 and 5. RESULTS: The steady-state Cmax and AUC0-24h of sacubitril and valsartan were unchanged in patients with renal impairment compared with healthy subjects. However, the steady-state Cmax of sacubitrilat was increased by ~60 % in patients irrespective of degree of renal impairment; half-life increased from 12 h (in healthy subjects) to 21.1, 23.7, and 38.5 h, respectively; and AUC0-24h was increased 2.10-, 2.24-, and 2.70-fold, respectively, in patients with mild, moderate, and severe renal impairment. CONCLUSION: Renal dysfunction increases exposure to sacubitrilat while not impacting sacubitril and valsartan exposure. LCZ696 was generally well tolerated in patients with renal impairment. PMID- 27230851 TI - Personality disorders and obesity: a systematic review. AB - BACKGROUND: Studies demonstrate an association between personality traits and obesity as well as their prognostic influence on weight course. In contrast, only few studies have investigated the association between personality disorders (PDs) and obesity. OBJECTIVE: The present review summarizes through a comprehensive and critical evaluation the results of 68 studies identified by database research (PubMed and PsycINFO) covering the last 35 years that investigated the association between PDs, overweight and obesity as well as the predictive value of PDs for the development of obesity and the effectiveness of weight reduction treatments. RESULTS: Adults with any PD have a higher risk of obesity. In the female general population, there is an association between avoidant or antisocial PD and severe obesity. Further, women with paranoid or schizotypal PD have a higher risk of obesity. Clinical studies including foremost female participants showed a higher comorbidity of PDs, especially borderline PD and avoidant PD, in binge-eating disorder. Regarding both genders, patients with PD show less treatment success in conservative weight-loss treatment programmes for obesity than patients without PD. CONCLUSIONS: In prevention and conservative weight-loss treatment strategies, more care should be taken to address the special needs of patients with comorbid PDs. PMID- 27230852 TI - Zika virus and neurology: proving cause and effect. PMID- 27230853 TI - Expanding the spectrum of PEX10-related peroxisomal biogenesis disorders: slowly progressive recessive ataxia. AB - Peroxisomal biogenesis disorders (PBDs) consist of a heterogeneous group of autosomal recessive diseases, in which peroxisome assembly and proliferation are impaired leading to severe multisystem disease and early death. PBDs include Zellweger spectrum disorders (ZSDs) with a relatively mild clinical phenotype caused by PEX1, (MIM# 602136), PEX2 (MIM# 170993), PEX6 (MIM# 601498), PEX10 (MIM# 602859), PEX12 (MIM# 601758), and PEX16 (MIM# 603360) mutations. Three adult patients are reported belonging to a non-consanguineous French family affected with slowly progressive cerebellar ataxia, axonal neuropathy, and pyramidal signs. Mental retardation and diabetes mellitus were optional. The age at onset was in childhood or in adolescence (3-15 years). Brain MRI showed marked cerebellar atrophy. Biochemical blood analyses suggested a mild peroxisomal defect. With whole exome sequencing, two mutations in PEX10 were found in the three patients: c.827G>T (novel) causing the missense change p.Cys276Phe and c.932G>A causing the missense change p.Arg311Gln. The phenotypic spectrum related to PEX10 mutations includes slowly progressive, syndromic recessive ataxia. PMID- 27230854 TI - XPR1 mutations are a rare cause of primary familial brain calcification. AB - Mutations in XPR1, a gene encoding an inorganic phosphate exporter, have recently been identified in patients with primary familial brain calcification (PFBC). Using Sanger sequencing, we screened XPR1 in 18 unrelated patients with PFBC and no SLC20A2, PDGFB, or PDGFRB mutation. XPR1 variants were tested in an in vitro physiological complementation assay and patient blood cells were assessed ex vivo for phosphate export. We identified a novel c.260T > C, p.(Leu87Pro) XPR1 variant in a 41-year-old man complaining of micrographia and dysarthria and demonstrating mild parkinsonism, cerebellar ataxia and executive dysfunction. Brain (123)I Ioflupane scintigraphy showed marked dopaminergic neuron loss. Peripheral blood cells from the patient exhibited decreased phosphate export. XPR1 in which we introduced the mutation was not detectable at the cell surface and did not lead to phosphate export. These results confirm that loss of XPR1-mediated phosphate export function causes PFBC, occurring in less than 8 % of cases negative for the other genes, and may be responsible for parkinsonism. PMID- 27230855 TI - PROSPERA: a randomized, controlled trial evaluating rasagiline in progressive supranuclear palsy. AB - To date, pharmacological treatment options for progressive supranuclear palsy (PSP), a neurodegenerative tauopathy, are limited. The MAO-B inhibitor rasagiline has shown neuroprotective effects in preclinical models of neurodegeneration. To evaluate the safety, tolerability and therapeutic effect of rasagiline on symptom progression in PSP. In this 1-year randomized, double-blind, placebo-controlled trial, 44 patients fulfilling the NINDS-PSP criteria were randomized to 1 mg/d rasagiline or placebo. The combined primary endpoint included symptom progression as measured by the PSP rating scale (PSP-RS) and the requirement of L-dopa rescue medication. Secondary endpoints included Schwab and England Activities of Daily Living (SEADL), Montgomery-Asberg Depression Rating Scale, Mini Mental State Examination, Frontal Assessment Battery and posturographic measurements. Of the 44 patients randomized, 26 completed the trial per protocol. Rasagiline was well tolerated, with a slight increase of known side effects (hallucinations, ventricular extrasystoles). No effect on the primary endpoint (p = 0.496) was detected. Symptom progression averaged at 11.2 (rasagiline) and 10.8 (placebo) points per year (DeltaPSP-RS). No difference was seen in SEADL, depression, cognitive function, frontal executive function and posturographic measurements. Post hoc analyses of PSP-RS subdomains indicate a potential beneficial effect in the "limb motor" subdomain, whereas performance appeared lower in the "mentation" and "history" subdomains in the treatment group. While rasagiline is well tolerated in PSP, a beneficial effect on overall symptom progression was not detected. Post hoc analyses suggest the implementation of more specific endpoints in future studies. PMID- 27230856 TI - Subcortical matter in the alpha-synucleinopathies spectrum: an MRI pilot study. AB - alpha-Synucleinopathies, such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB), are characterized by alpha-synuclein accumulation from brainstem structures to the neocortex. PD and DLB are clinically distinguishable, while discrimination between Parkinson Disease Dementia (PDD) and DLB can be subtle and based on the temporal relationship between motor and cognitive symptoms. To explore patterns of subcortical atrophy in PD, PDD and DLB, and assess specific differences between PD and PDD, and between DLB and PDD. 16 PD, 11 PDD and 16 DLB patients were recruited and underwent 1.5 Tesla structural MRI scanning. Segmentation of subcortical structures was performed with a well-validated, fully automated tool, and volume and shape for each structure were compared between groups. PDD and DLB patients showed global subcortical atrophy compared to PD patients. Greater hippocampal atrophy was the specific trait that distinguished PDD from PD, while greater atrophy of the pallidi discriminated DLB from PDD. Vertex analysis revealed specific shape differences in both structures. Our results suggest that automated, time-sparing, subcortical volumetry may provide diagnostically useful information in alpha-synucleinopathies. Future studies on larger samples and with iron-sensitive MRI contrasts are needed. PMID- 27230857 TI - Alterations of functional and structural connectivity of freezing of gait in Parkinson's disease. AB - This study assessed the patterns of functional and structural connectivity abnormalities in patients with Parkinson's disease with freezing of gait (PD FOG+) compared with those without freezing (PD FOG-) and healthy controls (HCs). Resting state functional MRI (rs-fMRI) and diffusion tensor imaging (DTI) scans were obtained from 14 PD FOG+, 16 PD FOG- and 16HCs. Between-group difference in pedunculopontine nucleus (PPN) functional connectivity (FC) was performed to assess FC dysfunction. Tract-based spatial statistics (TBSS) was applied to compare white matter (WM) impairment across the whole brain between groups. PD FOG+ patients exhibited abnormal PPN FC, compared with HCs and with PD FOG-, mainly in the corticopontine-cerebellar pathways (in the bilateral cerebellum and in the pons), as well as the visual temporal areas (in the right middle temporal gyrus and in the right inferior temporal gyrus). Moreover, PD FOG+ patients, showed more pronounced WM abnormalities, relative to controls, including the interhemispheric connections of corpus callosum, the cortico-cortical WM tracts of the cingulum, the superior longitudinal fasciculus and inferior fronto occipital fasciculus, the corticofugal tract (cerebral peduncles, internal capsule, corona radiata), as well as tracts connecting the thalamus (thalamic radiation). This study suggests that FOG in PD is associated with abnormal PPN FC network, mainly affecting the corticopontine-cerebellar pathways as well as visual temporal areas involved in visual processing, and with diffuse WM deficits extending to motor, sensory and cognitive regions. Combining rs-fMRI and DTI method, our study should advance the understanding of neural mechanisms underlying FOG in PD. PMID- 27230858 TI - JNK1 ablation in mice confers long-term metabolic protection from diet-induced obesity at the cost of moderate skin oxidative damage. AB - Obesity and insulin resistance are associated with oxidative stress, which may be implicated in the progression of obesity-related diseases. The kinase JNK1 has emerged as a promising drug target for the treatment of obesity and type 2 diabetes. JNK1 is also a key mediator of the oxidative stress response, which can promote cell death or survival, depending on the magnitude and context of its activation. In this article, we describe a study in which the long-term effects of JNK1 inactivation on glucose homeostasis and oxidative stress in obese mice were investigated for the first time. Mice lacking JNK1 (JNK1(-/-)) were fed an obesogenic high-fat diet (HFD) for a long period. JNK1(-/-) mice fed an HFD for the long term had reduced expression of antioxidant genes in their skin, more skin oxidative damage, and increased epidermal thickness and inflammation compared with the effects in control wild-type mice. However, we also observed that the protection from obesity, adipose tissue inflammation, steatosis, and insulin resistance, conferred by JNK1 ablation, was sustained over a long period and was paralleled by decreased oxidative damage in fat and liver. We conclude that compounds targeting JNK1 activity in brain and adipose tissue, which do not accumulate in the skin, may be safer and most effective.-Becattini, B., Zani, F., Breasson, L., Sardi, C., D'Agostino, V. G., Choo, M.-K., Provenzani, A., Park, J. M., Solinas, G. JNK1 ablation in mice confers long-term metabolic protection from diet-induced obesity at the cost of moderate skin oxidative damage. PMID- 27230859 TI - Carbamazepine behaviour and effects in an urban wastewater MBR working with high sludge and hydraulic retention time. AB - The behaviour and fate of carbamazepine (CBZ) in urban wastewater treatment by a membrane bioreactor (MBR) and its possible effects on the system's efficiency, and on mixed microbial communities, has been studied. The experimental microfiltration MBR system, with capacity to treat 10.8 m(3) d(-1) of urban wastewater, operated with a pre-denitrification configuration with high sludge and hydraulic retention time. The CBZ concentration assayed was higher than in the usual urban wastewater, in order to provoke a strong biomass reaction. Influent, effluent, and all bioreactors of the MBR system were analysed in order to calculate a CBZ balance. Bench-scale experiments and respirometric analyses were performed, with and without the presence of CBZ, to evaluate its influence on the bacterial activity. The respirometric assays showed variations in the oxygen uptake rate (OUR) in the presence of CBZ. Negative effects were detected in the MBR bacterial community during the initial period of dosing. However, the effects were not permanent and the biomass spiked with CBZ had behaviour similar to that of the biomass without CBZ after a few hours. Biodegradation was not detected during the MBR treatment. The system showed an inefficient elimination of CBZ (less than 10%) with a high concentration in the effluent. The small percentage of CBZ removal was associated with the sludge retention and eliminated by the purge. All CBZ present in the influent was accounted for, and even an increase in the total amount of CBZ was registered in the permeate. During and after the experimental process, CBZ did not significantly affect the efficiency of the MBR system, and the quality of the effluent was not affected by the dosing of CBZ in terms of COD and nitrogen removal. PMID- 27230860 TI - The General Neurotic Syndrome: A Re-Evaluation. PMID- 27230861 TI - Group- and Home-Based Cognitive Intervention for Patients with Mild Cognitive Impairment: A Randomized Controlled Trial. AB - BACKGROUND: We examined the efficacy of group-based cognitive intervention (GCI) and home-based cognitive intervention (HCI) in amnestic mild cognitive impairment (aMCI) and intervention effects on serum brain-derived neurotrophic factor (BDNF). METHODS: In this randomized and rater-blinded trial, 293 patients with aMCI from 18 nationwide hospitals were randomized: 96 to the GCI group, 98 to the HCI group and 99 to the control group. For 12 weeks, subjects receiving GCI participated twice per week in group sessions led by trained instructors, and those receiving HCI completed homework materials 5 days per week. They were assessed at baseline, postintervention (PI) and at the 6-month follow-up after the intervention. The primary endpoint was the change from baseline to PI in the modified Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog). RESULTS: In comparison to the controls (a 0.8-point decrease), the subjects receiving GCI (a 2.3-point decrease, p = 0.01) or HCI (a 2.5-point decrease, p = 0.02) showed significant improvements in the modified ADAS-Cog at PI, respectively. By the 6-month follow-up, those receiving GCI or HCI had better scores in the modified ADAS-Cog than the controls. The changes in BDNF levels significantly correlated with the changes in the modified ADAS-Cog in the GCI (r = -0.29, p = 0.02 at PI) and HCI (r = -0.27, p = 0.03 at 6-month follow-up) groups, respectively. CONCLUSIONS: The GCI and HCI resulted in cognitive improvements in aMCI. An enhanced brain plasticity may be a component of the mechanism underpinning the cognitive improvements associated with the cognitive interventions. PMID- 27230862 TI - Cognitive Behavioral Therapy for Patients with Social Anxiety Disorder Who Remain Symptomatic following Antidepressant Treatment: A Randomized, Assessor-Blinded, Controlled Trial. AB - BACKGROUND: Although antidepressants are still a commonly used treatment for social anxiety disorder (SAD), a significant proportion of patients fail to remit following antidepressants. However, no standard approach has been established for managing such patients. This study aimed to examine the effectiveness of cognitive behavioral therapy (CBT) as an adjunct to usual care (UC) compared with UC alone in SAD patients who remain symptomatic following antidepressant treatment. METHODS: This was a prospective randomized open-blinded end-point study with two parallel groups (CBT + UC, and UC alone, both for 16 weeks) conducted from June 2012 to March 2014. SAD patients who remain symptomatic following antidepressant treatment were recruited, and a total sample size of 42 was set based on pilot results. RESULTS: Patients were randomly allocated to CBT + UC (n = 21) or UC alone (n = 21). After 16 weeks, adjusted mean reduction in the Liebowitz Social Anxiety Scale from baseline for CBT + UC and UC alone was 40.87 and 0.68, respectively; the between-group difference was -41.55 (-53.68 to 29.42, p < 0.0001). Response rates were 85.7 and 10.0% for CBT + UC and UC alone, respectively (p < 0.0001). The corresponding remission rates were 47.6 and 0.0%, respectively (p = 0.0005). Significant differences were also found in favor of CBT + UC for social anxiety symptoms, depressive symptoms, and functional impairment. CONCLUSIONS: Our results suggest that in SAD patients who have been ineffectively treated with antidepressants, CBT is an effective treatment adjunct to UC over 16 weeks in reducing social anxiety and related symptoms. PMID- 27230863 TI - Effects of a Psychological Internet Intervention in the Treatment of Mild to Moderate Depressive Symptoms: Results of the EVIDENT Study, a Randomized Controlled Trial. AB - BACKGROUND: Mild to moderate depressive symptoms are common but often remain unrecognized and treated inadequately. We hypothesized that an Internet intervention in addition to usual care is superior to care as usual alone (CAU) in the treatment of mild to moderate depressive symptoms in adults. METHODS: This trial was controlled, randomized and assessor-blinded. Participants with mild to moderate depressive symptoms (Patient Health Questionnaire, PHQ-9, score 5-14) were recruited from clinical and non-clinical settings and randomized to either CAU or a 12-week Internet intervention (Deprexis) adjunctive to usual care. Outcomes were assessed at baseline, 3 months (post-assessment) and 6 months (follow-up). The primary outcome measure was self-rated depression severity (PHQ 9). The main analysis was based on the intention-to-treat principle and used linear mixed models. RESULTS: A total of 1,013 participants were randomized. Changes in PHQ-9 from baseline differed signixFB01;cantly between groups (t825 = 6.12, p < 0.001 for the main effect of group). The post-assessment between-group effect size in favour of the intervention was d = 0.39 (95% CI: 0.13-0.64). It was stable at follow-up, with d = 0.32 (95% CI: 0.06-0.69). The rate of participants experiencing at least minimally clinically important PHQ-9 change at the post-assessment was higher in the intervention group (35.6 vs. 20.2%) with a number needed to treat of 7 (95% CI: 5-10). CONCLUSIONS: The Internet intervention examined in this trial was superior to CAU alone in reducing mild to moderate depressive symptoms. The magnitude of the effect is clinically important and has public health implications. PMID- 27230864 TI - The Items Predicting Non-Remission after 6 Months of Treatment of Patients with Generalized Anxiety Disorder Covered the Eysenck Neuroticism Components of Anxiety, Interpersonal Sensitivity and Depression. PMID- 27230865 TI - Efficacy of Metacognitive Training for Depression: A Randomized Controlled Trial. PMID- 27230866 TI - Long-Term Outcome and Non-Response in Psychotherapy: Are We Short-Sighted. PMID- 27230867 TI - Brain and Behavior Changes following Exposure Therapy Predict Outcome at 8-Year Follow-Up. PMID- 27230868 TI - The Family Assessment Device: A Clinimetric Analysis. PMID- 27230869 TI - Incongruence between Clinicians' Assessment and Self-Reported Functioning Is Related to Psychopathology among Patients Diagnosed with Gastrointestinal Disorders. PMID- 27230870 TI - Autobiographical Memory-Based Intervention for Depressive Symptoms in Young Adults: A Randomized Controlled Trial of Cognitive-Reminiscence Therapy. PMID- 27230871 TI - Angiotensin Converting Enzyme Inhibitors and Risk of Mood Disorders. PMID- 27230873 TI - Clinical leadership and hospital performance: assessing the evidence base. AB - BACKGROUND: A widespread assumption across health systems suggests that greater clinicians' involvement in governance and management roles would have wider benefits for the efficiency and effectiveness of healthcare organisations. However, despite growing interest around the topic, it is still poorly understood how managers with a clinical background might specifically affect healthcare performance outcomes. The purpose of this review is, therefore, to map out and critically appraise quantitatively-oriented studies investigating this phenomenon within the acute hospital sector. METHODS: The review has focused on scientific papers published in English in international journals and conference proceedings. The articles have been extracted through a Boolean search strategy from ISI Web of Science citation and search source. No time constraints were imposed. A manual search by keywords and citation tracking was also conducted concentrating on highly ranked public sector governance and management journals. Nineteen papers were identified as a match for the research criteria and, subsequently, were classified on the basis of six items. Finally, a thematic mapping has been carried out leading to identify three main research sub-streams on the basis of the types of performance outcomes investigated. RESULTS AND CONTRIBUTION: The analysis of the extant literature has revealed that research focusing on clinicians' involvement in leadership positions has explored its implications for the management of financial resources, the quality of care offered and the social performance of service providers. In general terms, the findings show a positive impact of clinical leadership on different types of outcome measures, with only a handful of studies highlighting a negative impact on financial and social performance. Therefore, this review lends support to the prevalent move across health systems towards increasing the presence of clinicians in leadership positions in healthcare organisations. Furthermore, we present an explanatory model summarising the reasons offered in the reviewed studies to justify the findings and provide suggestions for future research. PMID- 27230874 TI - Reference Intervals: Strengths, Weaknesses, and Challenges. PMID- 27230876 TI - Defining and refining sperm selection strategies. PMID- 27230875 TI - Intensive plaque modification with rotational atherectomy and cutting balloon before drug-eluting stent implantation for patients with severely calcified coronary lesions: a pilot clinical study. AB - BACKGROUND: This study investigated whether, for patients with severely calcified coronary lesions, use of a cutting balloon (CB) during rotational atherectomy (RA) before placing a drug-eluting stent will improve periprocedural outcomes, compared to RA with a conventional plain balloon. METHODS: In a randomized controlled trial, patients with severely calcified lesions of calcium arc >=180 degrees were apportioned to receive intensive plaque modification with RA and CB (RA + CB; n = 35) or RA with conventional plain balloon (RA; n = 36). Intravascular ultrasound was applied for quantitative or qualitative analyses of percutaneous coronary intervention outcomes. The primary outcome was acute lumen gain after drug-eluting stent. RESULTS: The RA + CB and RA groups were similar in baseline mean arcs of superficial calcium, and minimum lumen cross-sectional areas (CSAs). The mean minimum stent CSA after percutaneous coronary intervention (PCI) of the RA + CB group (5.9 +/- 1.7 mm(2)) was significantly larger than that of the RA group (5.0 +/- 1.4 mm(2); P = 0.021). Patients in the RA + CB group achieved significantly larger acute CSA gain after PCI (4.5 +/- 1.5 mm(2)) relative to the RA group (3.8 +/- 1.5 mm(2); P = 0.035). The groups were similar in rates of periprocedural complications, but at the 1-year follow-up the RA + CB had a lower rate of revascularization for restenosis of the target vessel and MACE (5.7 %) than did the RA group (22.2 %, P = 0.046). CONCLUSION: Aggressive plaque preparation with RA and CB seems to be safe and effective for patients with severely calcified coronary lesions. TRIAL REGISTRATION: Current Controlled Trials ChiCTR-INR-16008274 . Retrospectively registered 12 April 2016. PMID- 27230878 TI - Collection of pregnancy outcome records following infertility-challenges and possible solutions. AB - PURPOSE: The aim of this study is to report challenges encountered when conducting inter-institutional data collection of obstetric (prenatal and postpartum) and delivery outcomes for research purposes and to propose solutions for enhanced efficiency. METHODS: Data were collected from women who consented to collection of obstetric and delivery records for an observational study of pregnancy and delivery outcomes following infertility treatment. We analyzed key issues relevant to improving efficiency of obstetric and delivery data collection via quantification of effort (such as number of calls and faxes) required to obtain records from different types of obstetric clinics and hospitals before and after utilization of a revised authorization. RESULTS: At time of analysis, records were successfully collected from 320 of the 451 participants who had delivered. The 320 participants received obstetric care at 63 institutions and delivered at 27 hospitals, with 168 (52.5 %) delivering at institutions other than home facility. At time of consent (8 weeks gestation), 155 of 320 (48.5 %) correctly predicted where they would receive obstetric care and 176 (55 %) where they would delivery. Most facilities (nearly 90 %) rejected our original authorization, but most (90 %) accepted the revised authorization described in this manuscript. CONCLUSIONS: Collecting records is time-consuming but important as over 50 % of our participants received care outside of the home facility. To efficiently collect outside records, we recommend that researchers interested in maternal and neonatal outcomes consider the guidelines outlined in this manuscript. This report also provides strong evidence of the need to develop data sharing through electronic health records for research purposes. PMID- 27230879 TI - Computing tumor trees from single cells. AB - Computational methods have been developed to reconstruct evolutionary lineages from tumors using single-cell genomic data. The resulting tumor trees have important applications in cancer research and clinical oncology.Please see related Research articles: http://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-0929-9 and http://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-0936-x . PMID- 27230877 TI - Commonly used fertility drugs, a diet supplement, and stress force AMPK-dependent block of stemness and development in cultured mammalian embryos. AB - PURPOSE: The purpose of the present study is to test whether metformin, aspirin, or diet supplement (DS) BioResponse-3,3'-Diindolylmethane (BR-DIM) can induce AMP activated protein kinase (AMPK)-dependent potency loss in cultured embryos and whether metformin (Met) + Aspirin (Asa) or BR-DIM causes an AMPK-dependent decrease in embryonic development. METHODS: The methods used were as follows: culture post-thaw mouse zygotes to the two-cell embryo stage and test effects after 1-h AMPK agonists' (e.g., Met, Asa, BR-DIM, control hyperosmotic stress) exposure on AMPK-dependent loss of Oct4 and/or Rex1 nuclear potency factors, confirm AMPK dependence by reversing potency loss in two-cell-stage embryos with AMPK inhibitor compound C (CC), test whether Met + Asa (i.e., co-added) or DS BR DIM decreases development of two-cell to blastocyst stage in an AMPK-dependent (CC-sensitive) manner, and evaluate the level of Rex1 and Oct4 nuclear fluorescence in two-cell-stage embryos and rate of two-cell-stage embryo development to blastocysts. RESULT(S): Met, Asa, BR-DIM, or hyperosmotic sorbitol stress induces rapid ~50-85 % Rex1 and/or Oct4 protein loss in two-cell embryos. This loss is ~60-90 % reversible by co-culture with AMPK inhibitor CC. Embryo development from two-cell to blastocyst stage is decreased in culture with either Met + Asa or BR-DIM, and this is either >90 or ~60 % reversible with CC, respectively. CONCLUSION: These experimental designs here showed that Met-, Asa-, BR-DIM-, or sorbitol stress-induced rapid potency loss in two-cell embryos is AMPK dependent as suggested by inhibition of Rex1 and/or Oct4 protein loss with an AMPK inhibitor. The DS BR-DIM or fertility drugs (e.g., Met + Asa) that are used to enhance maternal metabolism to support fertility can also chronically slow embryo growth and block development in an AMPK-dependent manner. PMID- 27230880 TI - Identifying cases of heroin toxicity where 6-acetylmorphine (6-AM) is not detected by toxicological analyses. PMID- 27230882 TI - Alteration of Cytokines Levels in the Striatum of Rats: Possible Participation in Vacuous Chewing Movements Induced by Antipsycotics. AB - Antipsychotic drugs have been used in the treatment of schizophrenia and their long-term use can cause movement disorders, such as tardive dyskinesia (TD) in humans mainly typical ones such as haloperidol. Neuroinflammation has been implicated to the use of antipsychotics besides its participation in TD remains unclear. Thus, the aim of this study was to investigate the relation of cytokines with vacuous chewing movements (VCMs) in rats comparing typical and atypical antipsychotics. Rats were treated with haloperidol or risperidone for 28 days. On day 29, rats were subjected to behavioral analysis (quantification of crossing and rearing numbers and VCMs) with subsequent measurement of cytokines levels in the striatum. Haloperidol, but not risperidone treatment significantly decreased the number of crossing and rearing and increased the VCMs when compared with control group. Both antipsychotics were able to increase the levels of pro inflammatory cytokines (IL-1beta, IL-6, TNF-alpha and IFN-gamma) and decrease the anti-inflammatory cytokine (IL-10) in striatum of rats. However, IL-1beta and IFN gamma levels were higher in animals treated with haloperidol than risperidone. Furthermore, positive correlations were observed between the cytokines (IL-1beta and IFN-gamma) and VCM numbers. Thus, the results suggest a role of inflammatory markers in the development of movement disorders, especially IL-1beta and IFN gamma. PMID- 27230883 TI - Lamotrigine Attenuates Proteasome Inhibition-Induced Apoptosis by Suppressing the Activation of the Mitochondrial Pathway and the Caspase-8- and Bid-Dependent Pathways. AB - Proteasome impairment has been shown to be involved in neuronal degeneration. Antiepileptic lamotrigine has been demonstrated to have a neuroprotective effect. However, the effect of lamotrigine on the proteasome inhibition-induced neuronal cell death has not been studied. Therefore, we assessed the effect of lamotrigine on the proteasome inhibition-induced neuronal cell apoptosis in relation to cell death process using differentiated PC12 cells and SH-SY5Y cells. The proteasome inhibitors MG132 and MG115 induced a decrease in the levels of Bid and Bcl-2 proteins, an increase in the levels of Bax and p53, loss of the mitochondrial transmembrane potential, cytochrome c release and activation of caspases (-8, -9 and -3). The addition of lamotrigine reduced the proteasome inhibitor-induced changes in the apoptosis-related protein levels, production of reactive oxygen species, depletion and oxidation of glutathione (GSH), and cell death in both cell lines. Lamotrigine and N-acetylcysteine alone did not affect the levels of 26S proteasome and activity of 20S proteasome. MG132 did not alter the levels of 26S proteasome but decreased activity of 20S proteasome. Lamotrigine and N acetylcysteine attenuated MG132-induced decrease in the activity of 20S proteasome. The results show that lamotrigine appears to suppress the proteasome inhibitor-induced apoptosis in PC12 cells by suppressing the activation of the mitochondrial pathway and the caspase-8- and Bid-dependent pathways. The suppressive effect of lamotrigine appears to be associated with its inhibitory effect on the production of reactive oxygen species, the depletion and oxidation of GSH and the activity reduction of 20S proteasome. PMID- 27230881 TI - Hypothalamic Proteomic Analysis Reveals Dysregulation of Glutamate Balance and Energy Metabolism in a Mouse Model of Chronic Mild Stress-Induced Depression. AB - Hypothalamus-pituitary-adrenal (HPA) axis hyperactivity is observed in many patients suffering from depression. However, the mechanism underlying the dysfunction of the HPA axis is not well understood. Moreover, dysfunction of the hypothalamus, the key brain region of the HPA axis, has not been well-explored. The aim of our study was to examine possible alterations in hypothalamus protein expression in a model of depression using proteomic analysis. In order to achieve this aim, mice were exposed to chronic unpredictable mild stress (CUMS), as the paradigm results in hyperactivity of the HPA axis. Differential protein expression between the hypothalamic proteomes of CUMS and control mice was then assessed through two-dimensional electrophoresis followed by matrix-assisted laser desorption ionization-time of flight-tandem mass spectrometry. Thirty-seven proteins with a threshold of a 1.5-fold change and a p value <=0.05 were identified as being differentially expressed between CUMS and control mice, and were quantified for bioinformatics analysis. Glycometabolism, citrate cycle (TCA cycle) and oxidation respiratory chain were found to have changed significantly. Glial fibrillary acidic protein and glutamine synthetase were further validated by Western Blot. Our results demonstrated that CUMS mice exhibited a dramatic protein change both in glutamate metabolism and energy mobilization, which may shed some light on the role of the hypothalamus in the pathology of stress induced depression. PMID- 27230884 TI - Effects of Hindlimb Unweighting on MBP and GDNF Expression and Morphology in Rat Dorsal Root Ganglia Neurons. AB - With the development of technology and space exploration, studies on long duration space flights have shown that microgravity induces damage to multiple organs, including the dorsal root ganglia (DRG). However, very little is known about the effects of long-term microgravity on DRG neurons. This study investigated the effects of microgravity on lumbar 5 (L5) DRG neurons in rats using the hindlimb unweighting (HU) model. Male (M) and female (F) Sprague-Dawley rats were randomly divided into M- and F-control (CON) groups and M- and F-HU groups, respectively (n = 10). At the end of HU treatment for 4 weeks, morphological changes were detected. Myelin basic protein (MBP) and degenerated myelin basic protein (dgen-MBP) expressions were analyzed by immunofluorescence and western blot assays. Glial cell line-derived neurotrophic factor (GDNF) protein and mRNA expressions were also analyzed by immunohistochemistry, western blot, and RT-PCR analysis, respectively. Compared with the corresponding CON groups, the HU groups exhibited slightly loose junctions between DRG neurons, some separated ganglion cells and satellite cells, and lightly stained Nissl bodies that were of smaller size and had a scattered distribution. High levels of dgen-MBP and low MBP expressions were appeared and GDNF expressions were significantly decreased in both HU groups. Changes were more pronounced in the F HU group than in the M-HU group. In conclusion, HU treatment induced damage of L5 DRG neurons, which was correlated with decreased total MBP protein expression, increased dgen-MBP expression, and reduced GDNF protein and mRNA expression. Importantly, these changes were more severe in F-HU rats compared with M-HU rats. PMID- 27230886 TI - CRISPR/Cas9: a double-edged sword when used to combat HIV infection. PMID- 27230887 TI - New insights into the transport processes controlling the sulfate-methane transition-zone near methane vents. AB - Over the past years, several studies have raised concerns about the possible interactions between methane hydrate decomposition and external change. To carry out such an investigation, it is essential to characterize the baseline dynamics of gas hydrate systems related to natural geological and sedimentary processes. This is usually treated through the analysis of sulfate-reduction coupled to anaerobic oxidation of methane (AOM). Here, we model sulfate reduction coupled with AOM as a two-dimensional (2D) problem including, advective and diffusive transport. This is applied to a case study from a deep-water site off Nigeria's coast where lateral methane advection through turbidite layers was suspected. We show by analyzing the acquired data in combination with computational modeling that a two-dimensional approach is able to accurately describe the recent past dynamics of such a complex natural system. Our results show that the sulfate methane-transition-zone (SMTZ) is not a vertical barrier for dissolved sulfate and methane. We also show that such a modeling is able to assess short timescale variations in the order of decades to centuries. PMID- 27230885 TI - Global healthcare use by immigrants in Spain according to morbidity burden, area of origin, and length of stay. AB - BACKGROUND: The healthcare of immigrants is an important aspect of equity of care provision. Understanding how immigrants use the healthcare services based on their needs is crucial to establish effective health policy. METHODS: This retrospective, observational study included the total population of Aragon, Spain (1,251,540 individuals, of whom 11.9 % were immigrants). Patient-level data on the use of primary, specialised, hospital, and emergency care as well as prescription drug use in 2011 were extracted from the EpiChron Cohort and compared between immigrants and nationals. Multivariable standard or zero inflated negative binomial regression models were generated, adjusting for age, sex, length of stay, and morbidity burden. RESULTS: The annual visit rates of immigrants were lower than those of nationals for primary care (3.3 vs 6.4), specialised care (1.3 vs 2.7), planned hospital admissions/100 individuals (1.6 vs 3.8), unplanned hospital admissions/100 individuals (2.7 vs 4.7), and emergency room visits/10 individuals (2.3 vs 2.8). Annual prescription drug costs were also lower for immigrants (?47 vs ?318). These differences were only partially attenuated after adjusting for age, sex and morbidity burden. CONCLUSION: In a universal coverage health system offering broad legal access to immigrants, the global use of healthcare services was lower for immigrants than for nationals. These differences may be explained in part by the healthy migration effect, but also reveal possible inequalities in healthcare provision that warrant further investigation. PMID- 27230889 TI - Gas6 protein: its role in cardiovascular calcification. AB - BACKGROUND: Cardiovascular calcifications can be prevented by vitamin K and are accelerated by vitamin K antagonists. These effects are believed to be mainly mediated by the vitamin K-dependent matrix Gla protein. Another vitamin K dependent protein, Gas6, is also expressed in vascular smooth muscle cells (VSMC). In vitro Gas6 expression was shown to be regulated in VSMC calcification and apoptotic processes. METHODS: We investigated the role of Gas6 in vitro using VSMC cultures and in vivo in young and old Gas6-deficient (Gas6(-/-)) and wildtype (WT) mice. In addition, Gas6(-/-) and WT mice were challenged by (a) warfarin administration, (b) uninephrectomy (UniNX) plus high phosphate diet, or (c) UniNX plus high phosphate plus electrocautery of the residual kidney. RESULTS: In vitro VSMC from WT and Gas6(-/-) mice exposed to warfarin showed increased apoptosis and calcified similarly. In vivo, aortic, cardiac and renal calcium content in all groups was similar, except for a lower cardiac calcium content in Gas6(-/-) mice (group a). Von Kossa staining revealed small vascular calcifications in both WT and Gas6(-/-) mice (groups a-c). In aging, non manipulated mice, no significant differences in vascular calcification were identified between Gas6(-/-) and WT mice. Gas6(-/-) mice exhibited no upregulation of matrix Gla protein in any group. Cardiac output was similar in all treatment groups. CONCLUSIONS: Taken together, in our study Gas6 fails to aggravate calcification against the previous assumption. PMID- 27230888 TI - Sixteen kiwi (Apteryx spp) transcriptomes provide a wealth of genetic markers and insight into sex chromosome evolution in birds. AB - BACKGROUND: Kiwi represent the most basal extant avian lineage (paleognaths) and exhibit biological attributes that are unusual or extreme among living birds, such as large egg size, strong olfaction, nocturnality, flightlessness and long lifespan. Despite intense interest in their evolution and their threatened status, genomic resources for kiwi were virtually non-existent until the recent publication of a single genome. Here we present the most comprehensive kiwi transcriptomes to date, obtained via Illumina sequencing of whole blood and de novo assembly of mRNA sequences of eight individuals from each of the two rarest kiwi species, little spotted kiwi (LSK; Apteryx owenii) and rowi (A. rowi). RESULTS: Sequences obtained were orthologous with a wide diversity of functional genes despite the sequencing of a single tissue type. Individual and composite assemblies contain more than 7900 unique protein coding transcripts in each of LSK and rowi that show strong homology with chicken (Gallus gallus), including those associated with growth, development, disease resistance, reproduction and behavior. The assemblies also contain 66,909 SNPs that distinguish between LSK and rowi, 12,384 SNPs among LSK (associated with 3088 genes), and 29,313 SNPs among rowi (associated with 4953 genes). We found 3084 transcripts differentially expressed between LSK and rowi and 150 transcripts differentially expressed between the sexes. Of the latter, 83 could be mapped to chicken chromosomes with 95% syntenic with chromosome Z. CONCLUSIONS: Our study has simultaneously sequenced multiple species, sexes, and individual kiwi at thousands of genes, and thus represents a significant leap forward in genomic resources available for kiwi. The expression pattern we observed among chromosome Z related genes in kiwi is similar to that observed in ostriches and emu, suggesting a common and ancestral pattern of sex chromosome homomorphy, recombination, and gene dosage among living paleognaths. The transcriptome assemblies described here will provide a rich resource for polymorphic marker development and studies of adaptation of these highly unusual and endangered birds. PMID- 27230890 TI - Barriers to essential surgical care experienced by women in the two northernmost regions of Ghana: a cross-sectional survey. AB - BACKGROUND: Women in developing countries might experience certain barriers to care more frequently than men. We aimed to describe barriers to essential surgical care that women face in five communities in Ghana. METHODS: Questions regarding potential barriers were asked during surgical outreaches to five communities in the northernmost regions of Ghana. Responses were scored in three dimensions from 0 to 18 (i.e., 'acceptability,' 'affordability,' and 'accessibility'; 18 implied no barriers). A barrier to care index out of 10 was derived (10 implied no barriers). An open-ended question to elicit gender specific barriers was also asked. RESULTS: Of the 320 participants approached, 315 responded (response rate 98 %); 149 were women (47 %). Women had a slightly lower barriers to surgical care index (median index 7.4; IQR 3.9-9.1) than men (7.9; IQR 3.9-9.4; p = 0.002). Compared with men, women had lower accessibility and acceptability dimension scores (14.4/18 vs 14.4/18; p = 0.001 and 13.5/18 vs 14/18; p = 0.05, respectively), but similar affordability scores (13.5/18 vs 13.5/18; p = 0.13). Factors contributing to low dimension scores among women included fear of anesthesia, lack of social support, and difficulty navigating healthcare, as well as lack of hospital privacy and confidentiality. CONCLUSION: Women had a slightly lower barriers to surgical care index than men, which may indicate greater barriers to surgical care. However, the actual significance of this difference is not yet known. Community-level education regarding the safety and benefits of essential surgical care is needed. Additionally, healthcare facilities must ensure a private and confidential care environment. These interventions might ameliorate some barriers to essential surgical care for women in Ghana, as well as other LMICs more broadly. PMID- 27230891 TI - [Vitreous hemorrhage as the initial manifestation of familial exudative vitreoretinopathy in an eight-year-old child]. AB - PURPOSE: To report vitreous hemorrhage as the initial manifestation of familial exudative vitreoretinopathy (FEVR). METHODS: Case report. RESULTS: An 8-year-old child presented with vitreous hemorrhage leading to the discovery of large neovascularization. Fundus examination and fluorescein angiography showed the typical appearance of FEVR. A genetic study confirmed the diagnosis. Treatment by laser photocoagulation was performed with good recovery of visual acuity. CONCLUSION: Ophthalmologists should be aware of familial exudative vitreoretinopathy (FEVR) so as not to misdiagnose this sight-threatening disease. PMID- 27230892 TI - [Eplerenone treatment in chronic central serous chorioretinopathy]. AB - PURPOSE: To evaluate the efficacy of eplerenone, a mineralocorticoid receptor antagonist, in the treatment of chronic central serous chorioretinopathy (CSCR). MATERIALS AND METHODS: We conducted a retrospective study of 27 patients treated with eplerenone for chronic CSCR of at least 3 months duration. For each patient, visual acuity and macular OCT (central retinal thickness, height of foveal subretinal fluid (SRF), central choroidal thickness) were evaluated before treatment and at 1 month and 3 months. In the case of complete disappearance of SRF at 1 month, treatment was discontinued and follow-up was performed at 3 months. RESULTS: Central retinal thickness was 371.6MUm (266-573MUm) before treatment. A clear decrease in retinal central thickness and height of SRF was observed at 1 month in 74% of patients (20 of 27 patients, central retinal thickness: 322.6MUm at 1 month, P=0.01), with improvement of visual acuity in all of these patients. Follow-up at 3 months also found a decrease in SRF and central retinal thickness (294.3MUm, P=0.002). Six patients had complete resolution of SRF at 1 month, without recurrence at 3 months. Six other patients had complete resolution of SRF at 3 months. No side effects requiring treatment discontinuation were observed. CONCLUSION: In our study, eplerenone was associated with regression of central retinal thickness and height of SRF. Eplerenone appears to be a safe and effective treatment for chronic CSCR, with a probable mechanism of action on the pathophysiology of this disease. PMID- 27230894 TI - The interplay of local attraction, context and domain-general cognitive control in activation and suppression of semantic distractors during sentence comprehension. AB - During sentence comprehension, real-time identification of a referent is driven both by local, context-independent lexical information and by more global sentential information related to the meaning of the utterance as a whole. This paper investigates the cognitive factors that limit the consideration of referents that are supported by local lexical information but not supported by more global sentential information. In an eye-tracking paradigm, participants heard sentences like "She will eat the red pear" while viewing four black-and white (colorless) line-drawings. In the experimental condition, the display contained a "local attractor" (e.g., a heart), which was locally compatible with the adjective but incompatible with the context ("eat"). In the control condition, the local attractor was replaced by a picture which was incompatible with the adjective (e.g., "igloo"). A second factor manipulated contextual constraint, by using either a constraining verb (e.g., "eat"), or a non constraining one (e.g., "see"). Results showed consideration of the local attractor, the magnitude of which was modulated by verb constraint, but also by each subject's cognitive control abilities, as measured in a separate Flanker task run on the same subjects. The findings are compatible with a processing model in which the interplay between local attraction, context, and domain general control mechanisms determines the consideration of possible referents. PMID- 27230895 TI - Integrin-Linked Kinase Senses Hypoxia During Scar Angiogenesis. AB - Integrin-linked kinase (ILK) mediates signal transduction between cells and the extracellular matrix, regulating cell proliferation, migration, angiogenesis, and apoptosis. However, its roles in the formation of hypertrophic scars are not yet clear. In this study, we found that ILK was predominantly expressed on the microvascular endothelial cells and the epidermal basal cells of human hypertrophic scars. The proliferation, migration and angiogenesis of primary human scar microvascular endothelial cells (HSMECs) were significantly inhibited after ILK was silenced. The ILK inhibitor QLT0267 had the same effect of impeding angiogenesis in vitro by blocking ILK activity. Both siRNA and QLT0267 markedly decreased the expression of vascular endothelial growth factor, but not its receptors, such as human vascular endothelial cell growth factor receptor 1 or kinase insert domain-containing receptor. We also showed that the expression of ILK was enhanced by inducing mild hypoxia with CoCl2, but it was suppressed under serious hypoxia. Thus, ILK regulates HSMEC proliferation and angiogenesis and participates in the formation of hypertrophic scars, in which mild hypoxia may be the mechanism of action. PMID- 27230893 TI - Characteristics and plasticity of electrical synaptic transmission. AB - Electrical synapses are an omnipresent feature of nervous systems, from the simple nerve nets of cnidarians to complex brains of mammals. Formed by gap junction channels between neurons, electrical synapses allow direct transmission of voltage signals between coupled cells. The relative simplicity of this arrangement belies the sophistication of these synapses. Coupling via electrical synapses can be regulated by a variety of mechanisms on times scales ranging from milliseconds to days, and active properties of the coupled neurons can impart emergent properties such as signal amplification, phase shifts and frequency selective transmission. This article reviews the biophysical characteristics of electrical synapses and some of the core mechanisms that control their plasticity in the vertebrate central nervous system. PMID- 27230896 TI - Early and Thorough Wound Debridement Is Crucial for Treatment of Patients With Thermal Burns and para-Chloronitrobenzene Poisoning. AB - para-Chloronitrobenzene (p-CNB) is one of the important chemicals with high liposolubility and oxidizing properties. Heated p-CNB liquid can cause thermal injury by absorption over skin and wound and even methemoglobinemia by conversion of hemoglobin into methemoglobin. Severe methemoglobinemia is a life-threatening condition that demands immediate treatment. It is very rare for individuals to be injured by heated p-CNB, but they should be carefully attended to because of the peculiarities of this kind of injury. In the past 10 years, we received 5 patients who were injured by heated p-CNB. In addition to the intravenous administration of methylene blue, prompt and thorough wound management played a crucial role in the treatment of these critically ill patients, indicating the potential value of sufficient information for the clinical practitioners. The purpose of this article is to report our experience in the management of patients with thermal burns and p-CNB poisoning. PMID- 27230897 TI - The Cerebellar System and What it Signifies from a Biological Perspective: a Communication by Christfried Jakob (1866-1956) Before the Society of Neurology and Psychiatry of Buenos Aires, December 1938. PMID- 27230898 TI - The Cerebellar System and What it Signifies from a Biological Perspective, by Professor Christofredo Jakob (English Translation). AB - The paper is an English translation of Christofredo Jakob's 1938 lecture on cerebellar neurobiology, rendered from the original Spanish text. Communicated at the special sessions of the Society of Neurology and Psychiatry of Buenos Aires, December 1938. PMID- 27230899 TI - PSP-CBS with Dopamine Deficiency in a Female with a FMR1 Premutation. AB - Premutations in the fragile X mental retardation 1 (FMR1) gene cause fragile X associated tremor/ataxia syndrome (FXTAS) and FMR1-related primary ovarian insufficiency (POI). Female FMR1 premutation carriers rarely develop motor features. Dual pathology is an emerging phenomenon among FMR1 premutation carriers. Here, we describe a family affected by FMR1-related disorders in which the female index case has developed a rapidly progressive and disabling syndrome of atypical parkinsonism. This syndrome consists of early onset postural instability, echolalia, dystonia, and varying types of apraxia like early onset orobuccal apraxia and oculomotor apraxia. She has also developed supranuclear gaze palsy, increased latency of saccade initiation, and slow saccades. These features are compatible with progressive supranuclear palsy (PSP) of a corticobasal syndrome (CBS) variant. Imaging displays a marked reduction of presynaptic dopaminergic uptake and cerebrospinal fluid analysis showed reduced dopamine metabolism; however, the patient is unresponsive to levodopa. Midbrain atrophy ("hummingbird sign") and mild cerebellar atrophy were found on brain MRI. Her father was affected by a typical FXTAS presentation but also displayed dopamine deficiency along with the hummingbird sign. The mechanisms by which FMR1 premutations predispose to atypical parkinsonism and dopamine deficiency await further elucidation. PMID- 27230901 TI - Editorial: Recent Developments in Pharmaceutical Sciences 11th ISOPS International Symposium on Pharmaceutical Sciences, June 9-12 2015. PMID- 27230900 TI - Commentary on "The Cerebellar System and What it Signifies from a Biological Perspective: A Communication by Christofredo Jakob (1866-1956) Before the Society of Neurology and Psychiatry of Buenos Aires, December 1938". AB - This commentary highlights a "cerebellar classic" by a pioneer of neurobiology, Christfried Jakob. Jakob discussed the connectivity between the cerebellum and mesencephalic, diencephalic, and telencephalic structures in an evolutionary, developmental, and histophysiological perspective. He proposed three evolutionary morphofunctional stages, the archicerebellar, paleocerebellar, and neocerebellar; he attributed the reduced cerebellospinal connections in humans, compared to other primates, to the perfection of the rubrolenticular and thalamocortical systems and the intense ascending pathways to the red nucleus in exchange for the more elementary descending efferent pathways. Jakob hypothesized the convergence of cerebellar pathways in associative cortical regions, insisting on the intimate collaboration of the cerebellum with the frontal lobe. The extensive lines of communication between regions throughout the association cortex substantiate Jakob's intuition and begin to outline the mechanisms for substantial cerebellar involvement in functions beyond the purely motor domain. Atop a foundation of anatomical and phylogenetic mastery, Jakob conceived ideas that were noteworthy, timely, and have much relevance to our current thinking on cerebellar structure and function. PMID- 27230902 TI - Development and Optimization of Self-emulsifying Drug Delivery Systems (SEDDS) for Enhanced Dissolution and Permeability of Rosuvastatin. AB - Rosuvastatin calcium is commonly used statin for treatment of dyslipidemia. It has low bioavailability. The aim of this study was to develop new rosuvastatin calcium self-emulsifying drug delivery systems (SEDDS) as an alternative formulation and to evaluate the permeability of rosuvastatin calcium SEDDS by using Caco-2 cells. Rosuvastatin calcium SEDDSs were developed by using pseudo ternary phase diagram and characterized by using heating cooling cycle, robustness to dilution, stability and in vitro drug release and permeability. The permeability studies of rosuvastatin calcium SEDDS (Papp (A->B) for F1 RS=1.492*10-5+/-0.413*10-5 and Papp (A->B) for F2-RS=1.254*10-5+/-0.19*10-5) across Caco-2 cells showed that permeability value from apical to basolateral was higher than permeability value of commercial formulation (Papp (A->B) =7.13*10 5+/-0.668*10-5). In conclusion, SEDDS as a drug carrier may be used as an effective and alternative hyperlipidemia therapy for oral delivery of rosuvastatin calcium. PMID- 27230903 TI - Short-term effects of the "Together at School" intervention program on children's socio-emotional skills: a cluster randomized controlled trial. AB - BACKGROUND: Together at School is a universal intervention program designed to promote socio-emotional skills among primary-school children. It is based on a whole school approach, and implemented in school classes by teachers. The aim of the present study is to examine the short-term effects of the intervention program in improving socio-emotional skills and reducing psychological problems among boys and girls. We also examine whether these effects depend on grade level (Grades 1 to 3) and intervention dosage. METHODS: This cluster randomized controlled trial design included 79 Finnish primary schools (40 intervention and 39 control) with 3 704 children. The outcome measures were the Strengths and Difficulties Questionnaire (SDQ) and the Multisource Assessment of Social Competence Scale (MASCS) with teachers as raters. The intervention dosage was indicated by the frequencies six central tools were used by the teachers. The data was collected at baseline and 6 months later. Intervention effects were analyzed using multilevel modeling. RESULTS: When analyzed across all grades no intervention effect was observed in improving children's socio-emotional skills or in reducing their psychological problems at 6-month follow-up. Among third (compared to first) graders the intervention decreased psychological problems. Stratified analyses by gender showed that this effect was significant only among boys and that among them the intervention also improved third graders' cooperation skills. Among girls the intervention effects were not moderated by grade. Implementing the intervention with intended intensity (i.e. a high enough dosage) had a significant positive effect on cooperation skills. When analyzed separately among genders, this effect was significant only in girls. CONCLUSIONS: These first, short-term results of the Together at School intervention program did not show any main effects on children's socio-emotional skills or psychological problems. This lack of effects may be due to the relatively short follow-up period given the universal, whole school-based approach of the program. The results suggest that the grade level where the intervention is started might be a factor in the program's effectiveness. Moreover, the results also suggest that for this type of intervention program to be effective, it needs to be delivered with a high enough dosage. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02178332 ; Date of registration: 03-April-2014. PMID- 27230904 TI - Information fusion control with time delay for smooth pursuit eye movement. AB - Smooth pursuit eye movement depends on prediction and learning, and is subject to time delays in the visual pathways. In this paper, an information fusion control method with time delay is presented, implementing smooth pursuit eye movement with prediction and learning as well as solving the problem of time delays in the visual pathways. By fusing the soft constraint information of the target trajectory of eyes and the ideal control strategy, and the hard constraint information of the eye system state equation and the output equation, optimal estimations of the co-state sequence and the control variable are obtained. The proposed control method can track not only constant velocity, sinusoidal target motion, but also arbitrary moving targets. Moreover, the absolute value of the retinal slip reaches steady state after 0.1 sec. Information fusion control method elegantly describes in a function manner how the brain may deal with arbitrary target velocities, how it implements the smooth pursuit eye movement with prediction, learning, and time delays. These two principles allowed us to accurately describe visually guided, predictive and learning smooth pursuit dynamics observed in a wide variety of tasks within a single theoretical framework. The tracking control performance of the proposed information fusion control with time delays is verified by numerical simulation results. PMID- 27230905 TI - Thermoneutrality decreases thermogenic program and promotes adiposity in high-fat diet-fed mice. AB - Brown/beige adipocytes are therapeutic targets to combat obesity due to their abilities to dissipate energy through adaptive thermogenesis. Most studies investigating induction of brown/beige adipocytes were conducted in cold condition (e.g., 4 degrees C); much is unknown about how the thermogenic program of brown/beige adipocytes is regulated in thermoneutral condition (e.g., 30 degrees C), which is within the thermal comfort zone of human dwellings in daily life. Therefore, this study aims to characterize the thermogenic program of brown/beige adipocytes in mice housed under ambient (22 degrees C) versus thermoneutral condition (30 degrees C). Male mice raised at 22 degrees C or 30 degrees C were fed either chow diet or high-fat (HF) diet for 20 weeks. Despite less food intake, chow-fed mice housed at 30 degrees C remained the same body weight compared to mice at 22 degrees C. However, these thermoneutrally housed mice displayed a decrease in the expression of thermogenic program in both brown and white fat depots with larger adipocytes. When pair-fed with chow diet, thermoneutrally housed mice showed an increase in body weight. Moreover, thermoneutrality increased body weight of mice fed with HF diet. This was associated with decreased expression of the thermogenic program in both brown and white fat depots of the thermoneutrally housed mice. The downregulation of the thermogenic program might have resulted from decreased sympathetic drive in the thermoneutrally housed mice evident by decreased expression of tyrosine hydroxylase expression and norepinephrine turnover in both brown and white fat depots. Our data demonstrate that thermoneutrality may negatively regulate the thermogenic program and sympathetic drive, leading to increased adiposity in mice. PMID- 27230906 TI - Perioperative and follow-up results in carotid artery stenting with contralateral carotid occlusion. AB - PURPOSE: Contralateral carotid occlusion (CCO) increases the risk of carotid endarterectomy (CEA). We determined the outcome of carotid angioplasty and stenting (CAS), an alternative to CEA, in the setting of CCO through an independent analysis of imaging and clinical outcome. MATERIALS AND METHODS: Medical records of 26 consecutive patients with CCO who underwent CAS by a single operator using the same procedural protocol (with distal protection and closed cell stents) were retrospectively evaluated. National Institutes of Health Stroke Scale (NIHSS) and Modified Rankin Scale (mRS) scores before and after CAS, periprocedural complications, and the restenosis rate were analyzed by independent stroke neurologists who were not involved in the care of the patients. RESULTS: The median mRS score for the 26 patients was 1 (range 0-5) before and after CAS. All of the patients underwent clinical and imaging follow up (mean 19.5 +/- 14.3 and 11.6 +/- 11.2 months, respectively). Thirty-day mortality/permanent morbidity rates were 0 %. One patient had hyperperfusion syndrome and was managed medically without sequelae; however, he had stent occlusion after 30 days, resulting in a decline in his mRS from 4 (preprocedure) to 5. Otherwise, there was no decline in mRS during the post-discharge follow-up. CONCLUSION: According to an independent analysis of this single-operator series, CAS is safe and effective for the treatment of patients with CCO. PMID- 27230907 TI - The yeast Hsp70 homolog Ssb: a chaperone for general de novo protein folding and a nanny for specific intrinsically disordered protein domains. AB - Activation of the heterotrimeric kinase SNF1 via phosphorylation of a specific residue within the alpha subunit is essential for the release from glucose repression in the yeast Saccharomyces cerevisiae. When glucose is available, SNF1 is maintained in the dephosphorylated, inactive state by the phosphatase Glc7 Reg1. Recent findings suggest that Bmh and Ssb combine their unique client binding properties to interact with the regulatory region of the SNF1 alpha subunit and by that stabilize a conformation of SNF1, which is accessible for Glc7-Reg1-dependent dephosphorylation. Together, the 14-3-3 protein Bmh and the Hsp70 homolog Ssb comprise a novel chaperone module, which is required to maintain proper glucose repression in the yeast S. cerevisiae. PMID- 27230909 TI - LncRNAs, lost in translation or licence to regulate? AB - Over the last decade, advances in transcriptomics have revealed that the pervasive transcription of eukaryotic genomes produces plethora of long noncoding RNAs (lncRNAs), which are now recognized as major regulators of multiple cellular processes. Although they have been thought to lack any protein-coding potential, recent ribosome-profiling data indicate that lncRNAs can interact with the translation machinery, leading to the production of functional peptides in some cases. In this perspective, we have explored the idea that translation can be part of the fate of cytoplasmic lncRNAs, raising the possibility for them to work as bifunctional RNAs, endowed with dual coding and regulatory functions. PMID- 27230908 TI - The slim, the fat, and the obese: guess who lives the longest? AB - In a modern society that is increasingly older and "heavier," it is understandable that the majority favors a slimmer body that helps to sail smoothly into the dusk of life. Given the association between obesity and many metabolic and cardiovascular disorders, there are stern criticisms over such a thought of "good fat". Ironically, a phenomenon called "obesity paradox", that is, the overweight population purportedly enjoys the lowest all-cause mortality, and baffles open-minded clinicians and scientists. Lipids are essential to all life forms. Fat, in particular, triacylglycerol, also exists in different forms and in different locations in the human body, making any simple statement that vilifies all fat invalid. Whether the phenomenon of obesity paradox, indeed, has its root in a hitherto unrealized pro-survival function of fat deserves a serious look. Indeed, a recent publication using yeast as the model showed that elevation in the cellular storage of triacylglycerol extends lifespan in an energy expenditure independent fashion. In stark contrast, lean cells devoid of triacylglycerol biosynthetic capability die upon entering the senescence phase. Together, a new cytoprotective function of fat emerges. This mini-review aims to discuss potential mechanisms for the observed lifespan preservation function of triacylglycerol. PMID- 27230911 TI - WhatsAPP in neurosurgery: the best practice is in our hands. PMID- 27230910 TI - Attitudes towards suicide in urban and rural China: a population based, cross sectional study. AB - BACKGROUND: Suicide intervention programs have been guided by findings that attitude towards suicide and suicidal behavior may be causally linked. These findings also make it imperative to identify the factors that influence attitudes towards suicide. However, there has been little research on attitudes towards suicide among the general population, especially in low-income and middle-income countries. This population-based, cross-sectional study investigated the associated factors of attitudes towards suicide among a representative sample of urban and rural adult residents in China. METHODS: A multi-stage, stratified random sampling approach was implemented to select participants. Data were collected by a survey using the Scale of Public Attitudes about Suicide (SPAS). The survey also collected some socio-demographic factors and suicidal history of participants. Statistical tests were conducted to identify associated factors that account for variations in attitudes towards suicide. RESULTS: The residents in China generally hold a neutral attitude towards suicide. Attitudes towards suicide among Chinese residents were associated with age, duration of formal education, marital status, job and suicidal ideation. Different attitudinal subscales seemed not to share the same risk factors. However, gender, ethnicity, religious belief, housing style and economic status might not influence residents' attitudes towards suicide. Attitudes towards suicide among Chinese urban and rural residents generally had no statistical difference with one notable exception: opinions on whether or not suicides and suicide attempts are different phenomena. CONCLUSIONS: Age, duration of formal education, marital status, job and suicidal ideation seem to have an impact on attitudes towards suicide among residents. Urban and rural residents have similar attitudes towards suicide with the only statistically significance difference being their opinions on whether or not suicides and suicide attempts are different phenomena. PMID- 27230912 TI - Intradural synovial cyst of the atlantoaxial joint: a case report. AB - BACKGROUND: Intradural synovial cysts of the cervical spine represent a rare disease entity, causing stenosis of the spinal canal and thereby leading to progressive myelopathy. In particular, at the cranio-cervical junction early intervention is necessary to prevent permanent neurological dysfunction. We present the case of a 74-year-old man who presented with moderate cervicogenic headache, gait disturbance and progressive left-sided weakness. Magnetic resonance imaging (MRI) of the cervical spine confirmed a left-sided cystic mass located anteriorly at the craniovertebral junction compressing the surrounding structures. METHOD: Surgical decompression was performed by means of a minimal left-sided laminectomy of C1. Postoperatively, the patients symptoms slowly improved, albeit a persistent ataxic gait. RESULTS: Intraoperatively, a large intradural cyst was removed via a minimal suboccipital craniectomy combined with laminectomy of C1. Histopathological evaluation revealed a synovial cyst without any features of neoplasia. Despite not using craniocervical instrumentation, no clinical or radiological signs of atlantoaxial instability were observed up to 2 years after surgery. CONCLUSIONS: Cystic lesions located at the atlanto-axial joint are a rare cause of cervical myelopathy. Preoperative imaging of the cervical spine should include not only MRI and computerised tomography (CT) but also dynamic imaging. Dorsal decompression without instrumentation prevents progressive neurological decline and may allow cord function to recover. If there is additional preoperative instability, instrumentation and fusion may be necessary. PMID- 27230913 TI - Nurse ethical sensitivity: An integrative review. AB - BACKGROUND: Ethical sensitivity has been identified as a foundational component of ethical action. Diminished or absent ethical sensitivity can result in ethically incongruent care, which is inconsistent with the professional obligations of nursing. As such, assessing ethical sensitivity is imperative in order to design interventions to facilitate ethical practice and to ensure nurses recognize the nature and extent of professional ethical obligations. AIM: To review and critique the state of the science of nurse ethical sensitivity and to synthesize findings across studies. RESEARCH DESIGN: Whittemore and Knafl's revised framework for integrative reviews guided the analysis. Research context and data sources: A comprehensive, computer-assisted search of literature published in Cumulative Index of Nursing and Allied Health Literature and PubMed was performed. A systematic approach was used to extract, reduce, and synthesize the data. FINDINGS: Four major conceptualizations of ethical sensitivity emerged from the literature. A sample of 25 reports met inclusion criteria, including 17 empirical reports and 8 theoretical reports. DISCUSSION: Despite the existence of a concept analysis and a validated tool, ethical sensitivity remains a highly theoretical concept with multiple, and at times competing, conceptualizations. Ethical sensitivity has been assessed extensively in the context of ethical dilemmas; however, little attention has been paid to the way the concept operates in day-to-day practice. CONCLUSION: Future research should focus on better ways to operationalize and assess the concept, with particular attention to nurse awareness of the ethical content of everyday practice. PMID- 27230914 TI - Dementia-associated mortality and its predictors among older adults in sub Saharan Africa: results from a 2-year follow-up in Congo (the EPIDEMCA-FU study). AB - BACKGROUND: between 2001 and 2012, we carried out a study of dementia prevalence in central Africa throughout the EPIDEMCA (Epidemiology of Dementia in Central Africa) programme. OBJECTIVE: to assess dementia-related mortality among Congolese older people from the EPIDEMCA study after 2 years of follow-up. DESIGN: longitudinal population-based cohort study. SETTING: Gamboma and Brazzaville, Republic of Congo. METHODS: older participants were traced and interviewed in rural and urban Congo annually between 2012 and 2014. DSM-IV and NINCDS-ADRDA criteria were required for dementia diagnosis. Data on vital status were collected throughout the follow-up. Cox proportional hazards model was used to assess the link between baseline dementia diagnosis and mortality risk. RESULTS: of 1,029 participants at baseline, 910 (88.4%) have a complete cognitive diagnosis. There were 791 participants (76.87%) with normal cognition, 56 (5.44%) with MCI and 63 (6.12%) with dementia. After 2 years of follow-up, 101 (9.8%) participants had died. Compared with participants with normal cognition, patients with dementia had 2.5 times higher mortality risk (HR = 2.53, 95% CI 1.42-4.49, P = 0.001). Among those with dementia, only clinical severity of dementia was associated with an additional increased mortality risk (HR = 1.91; CI 95%, 1.23 2.96; P = 0.004). Age (per 5-year increase), male sex and living in an urban area were independently associated with increased mortality risk across the full cohort. CONCLUSION: among Congolese older adults, dementia is associated with increased mortality risk. Our results highlight the need for targeted health policies and strategies for dementia care in sub-Saharan Africa (SSA). PMID- 27230916 TI - Multi-parametric ultrasound criteria for internal carotid artery disease comparison with CT angiography. AB - INTRODUCTION: The German Society of Ultrasound in Medicine (known by its acronym DEGUM) recently proposed a novel multi-parametric ultrasound approach for comprehensive and accurate assessment of extracranial internal carotid artery (ICA) steno-occlusive disease. We determined the agreement between duplex ultrasonography (DUS) interpreted by the DEGUM criteria and CT angiography (CTA) for grading of extracranial ICA steno-occlusive disease. METHODS: Consecutive patients with acute cerebral ischemia underwent DUS and CTA. Internal carotid artery stenosis was graded according to the DEGUM-recommended criteria for DUS. Independent readers manually performed North American Symptomatic Carotid Endarterectomy Trial-type measurements on axial CTA source images. Both modalities were compared using Spearman's correlation and Bland-Altman analyses. RESULTS: A total of 303 acute cerebral ischemia patients (mean age, 72 +/- 12 years; 58 % men; median baseline National Institutes of Health Stroke Scale score, 4 [interquartile range 7]) provided 593 DUS and CTA vessel pairs for comparison. There was a positive correlation between DUS and CTA (r s = 0.783, p < 0.001) with mean difference in degree of stenosis measurement of 3.57 %. Bland Altman analysis further revealed widely varying differences (95 % limits of agreement -29.26 to 22.84) between the two modalities. CONCLUSION: Although the novel DEGUM criteria showed overall good agreement between DUS and CTA across all stenosis ranges, potential for wide incongruence with CTA underscores the need for local laboratory validation to avoid false screening results. PMID- 27230915 TI - Biological and behavioral factors modify urinary arsenic metabolic profiles in a U.S. population. AB - BACKGROUND: Because some adverse health effects associated with chronic arsenic exposure may be mediated by methylated arsenicals, interindividual variation in capacity to convert inorganic arsenic into mono- and di-methylated metabolites may be an important determinant of risk associated with exposure to this metalloid. Hence, identifying biological and behavioral factors that modify an individual's capacity to methylate inorganic arsenic could provide insights into critical dose-response relations underlying adverse health effects. METHODS: A total of 904 older adults (>=45 years old) in Churchill County, Nevada, who chronically used home tap water supplies containing up to 1850 MUg of arsenic per liter provided urine and toenail samples for determination of total and speciated arsenic levels. Effects of biological factors (gender, age, body mass index) and behavioral factors (smoking, recent fish or shellfish consumption) on patterns of arsenicals in urine were evaluated with bivariate analyses and multivariate regression models. RESULTS: Relative contributions of inorganic, mono-, and di methylated arsenic to total speciated arsenic in urine were unchanged over the range of concentrations of arsenic in home tap water supplies used by study participants. Gender predicted both absolute and relative amounts of arsenicals in urine. Age predicted levels of inorganic arsenic in urine and body mass index predicted relative levels of mono- and di-methylated arsenic in urine. Smoking predicted both absolute and relative levels of arsenicals in urine. Multivariate regression models were developed for both absolute and relative levels of arsenicals in urine. Concentration of arsenic in home tap water and estimated water consumption were strongly predictive of levels of arsenicals in urine as were smoking, body mass index, and gender. Relative contributions of arsenicals to urinary arsenic were not consistently predicted by concentrations of arsenic in drinking water supplies but were more consistently predicted by gender, body mass index, age, and smoking. CONCLUSIONS: These findings suggest that analyses of dose-response relations in arsenic-exposed populations should account for biological and behavioral factors that modify levels of inorganic and methylated arsenicals in urine. Evidence of significant effects of these factors on arsenic metabolism may also support mode of action studies in appropriate experimental models. PMID- 27230918 TI - Evolution of sex-peptide in Drosophila. AB - The Drosophila sex-peptide (SP) has been identified as a seminal fluid component that induces post-mating responses (PMRs) in the inseminated females, such as inhibition of remating and stimulation of egg-laying. SP has been thought to play a central role in sexual conflict and sexually antagonistic co-evolution. Most of the sequenced Drosophila genomes contain SP orthologs, but their functions have been poorly characterized. Recently, we have investigated cross-species activity of D. melanogaster SP by means of injection into virgin females of other species. Among 11 species examined, SP response was observed in 6 species belonging to the D. melanogaster species group only. These species females express SP receptor (SPR) in their oviducts at relatively high levels, which was visualized by using a GFP-tagged SP. Furthermore, females of this species group responded to their own SP orthologs. However, females of the species outside the group did not respond to their own SP orthologs, even though all of them were potent inducers of SP-response in D. melanogaster. Our results suggested that the SP/SPR-mediated PMR was established in the lineage of the D. melanogaster species group. PMID- 27230919 TI - Twelve-month outcomes of treatment using ranibizumab or aflibercept for neovascular age-related macular degeneration: a comparative study. AB - PURPOSE: To compare the 12-month treatment outcome of ranibizumab with that of aflibercept in cases of neovascular age-related macular degeneration (AMD). METHODS: This retrospective single-institution study included patients who had been diagnosed with treatment-naive neovascular AMD and treated using either ranibizumab (ranibizumab group, n = 30) or aflibercept (aflibercept group, n = 21) monotherapy over a 12-month follow-up period. Patients initially received three monthly injections, and were re-treated when neovascularization recurred. The best-corrected visual acuity (BCVA) at diagnosis and at 12 months, as well as the number of injections, were compared between the two groups. RESULTS: In the ranibizumab group, the mean logarithm of the minimum angle of resolution BCVA values at diagnosis and at 12 months were 0.86 +/- 0.45 and 0.72 +/- 0.56, respectively. The equivalent values were 0.73 +/- 0.37 and 0.58 +/- 0.41 in the aflibercept group. The mean number of injections was 4.5 +/- 1.3 in the ranibizumab group and 4.3 +/- 0.9 in the aflibercept group. There was no difference in BCVA between the two groups at either diagnosis (P = 0.560) or 12 months (P = 0.702). There was also no difference between the two groups in the number of injections (P = 0.847). CONCLUSION: The 12-month treatment outcome of intravitreal ranibizumab was similar to that of intravitreal aflibercept, with a comparable injection frequency. Further prospective studies with a more controlled design are needed to confirm our findings. PMID- 27230917 TI - Reduced white matter integrity in amateur boxers. AB - INTRODUCTION: Professional boxing can lead to chronic traumatic encephalopathy, a variant of traumatic brain injury (TBI). Its occurrence in amateur boxers is a matter of debate since amateur boxing is considered to be less harmful due to more strict regulations. However, several studies using different methodological approaches have revealed subtle signs of TBI even in amateurs. Diffusion tensor imaging (DTI) is sensitive to microscopic white matter changes and has been proven useful in TBI when routine MR imaging often is unrevealing. METHODS: DTI, with tract-based spatial statistics (TBSS) together with neuropsychological examination of executive functions and memory, was used to investigate a collective of 31 male amateur boxers and 31 age-matched controls as well as a subgroup of 19 individuals, respectively, who were additionally matched for intellectual performance (IQ). RESULTS: All participants had normal findings in neurological examination and conventional MR. Amateur boxers did not show deficits in neuropsychological tests when their IQ was taken into account. Fractional anisotropy was significantly reduced, while diffusivity measures were increased along central white matter tracts in the boxers group. These changes were in part associated with the number of fights. CONCLUSIONS: TBSS revealed widespread white matter disturbance partially related to the individual fighting history in amateur boxers. These findings closely resemble those in patients with accidental TBI and indicate similar histological changes in amateur boxers. PMID- 27230920 TI - Induction of Neutrophil Extracellular Traps in Shiga Toxin-Associated Hemolytic Uremic Syndrome. AB - Hemolytic uremic syndrome (HUS), a vascular disease characterized by hemolytic anemia, thrombocytopenia, and acute renal failure, is caused by enterohemorrhagic Shiga toxin (Stx)-producing bacteria, which mainly affect children. Besides Stx, the inflammatory response mediated by neutrophils (PMN) is essential to HUS evolution. PMN can release neutrophil extracellular traps (NET) composed of DNA, histones, and other proteins. Since NET are involved in infectious and inflammatory diseases, the aim of this work was to investigate the contribution of NET to HUS. Plasma from HUS patients contained increased levels of circulating free-DNA and nucleosomes in comparison to plasma from healthy children. Neutrophils from HUS patients exhibited a greater capacity to undergo spontaneous NETosis. NET activated human glomerular endothelial cells, stimulating secretion of the proinflammatory cytokines IL-6 and IL-8. Stx induced PMN activation as judged by its ability to trigger reactive oxygen species production, increase CD11b and CD66b expression, and induce NETosis in PMN from healthy donors. During HUS, NET can contribute to the inflammatory response and thrombosis in the microvasculature and thus to renal failure. Intervention strategies to inhibit inflammatory mechanisms mediated by PMN, such as NETosis, could have a potential therapeutic impact towards amelioration of the severity of HUS. PMID- 27230921 TI - Methane turnover and methanotrophic communities in arctic aquatic ecosystems of the Lena Delta, Northeast Siberia. AB - Large amounts of organic carbon are stored in Arctic permafrost environments, and microbial activity can potentially mineralize this carbon into methane, a potent greenhouse gas. In this study, we assessed the methane budget, the bacterial methane oxidation (MOX) and the underlying environmental controls of arctic lake systems, which represent substantial sources of methane. Five lake systems located on Samoylov Island (Lena Delta, Siberia) and the connected river sites were analyzed using radiotracers to estimate the MOX rates, and molecular biology methods to characterize the abundance and the community composition of methane oxidizing bacteria (MOB). In contrast to the river, the lake systems had high variation in the methane concentrations, the abundance and composition of the MOB communities, and consequently, the MOX rates. The highest methane concentrations and the highest MOX rates were detected in the lake outlets and in a lake complex in a flood plain area. Though, in all aquatic systems, we detected both, Type I and II MOB, in lake systems, we observed a higher diversity including MOB, typical of the soil environments. The inoculation of soil MOB into the aquatic systems, resulting from permafrost thawing, might be an additional factor controlling the MOB community composition and potentially methanotrophic capacity. PMID- 27230922 TI - Noninvasive Quantification of Myocardial 11C-Meta-Hydroxyephedrine Kinetics. AB - (11)C-meta-hydroxyephedrine ((11)C-HED) kinetics in the myocardium can be quantified using a single-tissue-compartment model together with a metabolite corrected arterial blood sampler input function (BSIF). The need for arterial blood sampling, however, limits clinical applicability. The purpose of this study was to investigate the feasibility of replacing arterial sampling with imaging derived input function (IDIF) and venous blood samples. METHODS: Twenty patients underwent 60-min dynamic (11)C-HED PET/CT scans with online arterial blood sampling. Thirteen of these patients also underwent venous blood sampling. Data were reconstructed using both 3-dimensional row-action maximum-likelihood algorithm (3DR) and a time-of-flight (TF) list-mode reconstruction algorithm. For each reconstruction, IDIF results were compared with BSIF results. In addition, IDIF results obtained with venous blood samples and with a transformed venous-to arterial metabolite correction were compared with results obtained with arterial metabolite corrections. RESULTS: Correlations between IDIF- and BSIF-derived K1 and VT were high (r(2) > =0.89 for 3DR and TF). Slopes of the linear fits were significantly different from 1 for K1, for both 3DR (slope = 0.94) and TF (slope = 1.06). For VT, the slope of the linear fit was different from 1 for TF (slope = 0.93) but not for 3DR (slope = 0.98). Use of venous blood data introduced a large bias in VT (r(2) = 0.96, slope = 0.84) and a small bias in K1 (r(2) = 0.99, slope = 0.98). Use of a second-order polynomial venous-to-arterial transformation was robust and greatly reduced bias in VT (r(2) = 0.97, slope = 0.99) with no effect on K1 CONCLUSION: IDIF yielded precise results for both 3DR and TF. Venous blood samples can be used for absolute quantification of (11)C-HED studies, provided a venous-to-arterial transformation is applied. A venous-to-arterial transformation enables noninvasive, absolute quantification of (11)C-HED studies. PMID- 27230923 TI - Optimal Acquisition Time Window and Simplified Quantification of Dopamine Transporter Availability Using 18F-FE-PE2I in Healthy Controls and Parkinson Disease Patients. AB - : 18F-(E)-N-(3-iodoprop-2-enyl)-2beta-carbofluoroethoxy-3beta (4'methylphenyl)nortropane (18F-FE-PE2I) is a newly developed dopamine transporter (DAT) PET radioligand. Full quantification methods rely on dynamic acquisition of 18F-FE-PE2I, but in a clinical setting a simplified protocol is preferable. The aims of this study were to identify the optimal acquisition time window for 18F-FE-PE2I and to validate the specific binding ratio (SBR) as a simplified quantification method. METHODS: Ten Parkinson disease (PD) patients and 10 controls were included. Ninety-three-min dynamic PET measurements with 18F FE-PE2I were conducted using the high-resolution research tomograph (HRRT). The dynamic measurement was also smoothed to the resolution of a clinical PET system (HR). Regions of interest for the caudate, putamen, ventral striatum, substantia nigra (SN), and cerebellum were manually drawn on coregistered MR images. The outcome measure was the SBR, and the gold standard was the binding potential obtained with wavelet-aided parametric imaging (WAPI BPND). The cerebellum was used as a reference region. In a preliminary analysis, SBR was computed for 8 time windows (SBRdyn). Linear regression analysis and Bland-Altman plots were used to select the optimal acquisition time window. An average image from the selected time window was created, from which new SBR values (SBR calculated on the average image on the HRRT and SBR calculated on the average image on the simulated HR images) were calculated and compared with WAPI BPND The effect size was calculated. RESULTS: SBRdyn values for the time window between 16.5 and 42 min correlated best with WAPI BPND (r2 = 0.98, P < 0.001). Significant correlations (P < 0.001) were observed between SBRHR and WAPI-BPND (r2 = 0.95 in controls and 0.97 in PD patients). In the striatum, SBRHR values were 37% lower than BPND in controls, 29% in PD patients, whereas in the SN the underestimation was 22% in controls and 15% in PD patients. Similar effect sizes for BPND and SBRHR were found in the caudate (0.6), putamen (1.7 and 1.4), ventral striatum (0.7), and SN (0.5 and 0.4). CONCLUSION: A single 18F-FE-PE2I acquisition between 16.5 and 42 min provides the best outcome measure for simplified DAT quantification. Despite underestimation of the BPND, the SBR can be used in a clinical setting as a valid quantification method for DAT using 18F-FE-PE2I, because it provides differentiation similar to BPND between controls and PD patients. PMID- 27230924 TI - Quantitative Assessment of Breast Parenchymal Uptake on 18F-FDG PET/CT: Correlation with Age, Background Parenchymal Enhancement, and Amount of Fibroglandular Tissue on MRI. AB - : Background parenchymal enhancement (BPE), and the amount of fibroglandular tissue (FGT) assessed with MRI have been implicated as sensitive imaging biomarkers for breast cancer. The purpose of this study was to quantitatively assess breast parenchymal uptake (BPU) on 18F-FDG PET/CT as another valuable imaging biomarker and examine its correlation with BPE, FGT, and age. METHODS: This study included 129 patients with suspected breast cancer and normal imaging findings in one breast (BI-RADS 1), whose cases were retrospectively analyzed. All patients underwent prone 18F-FDG PET/CT and 3-T contrast-enhanced MRI of the breast. In all patients, interpreter 1 assessed BPU quantitatively using SUVmax Interpreters 1 and 2 assessed amount of FGT and BPE in the normal contralateral breast by subjective visual estimation, as recommended by BI-RADS. Interpreter 1 reassessed all cases and repeated the BPU measurements. Statistical tests were used to assess correlations between BPU, BPE, FGT, and age, as well as inter- and intrainterpreter agreement. RESULTS: BPU on 18F-FDG PET/CT varied among patients. The mean BPU SUVmax +/- SD was 1.57 +/- 0.6 for patients with minimal BPE, 1.93 +/- 0.6 for mild BPE, 2.42 +/- 0.5 for moderate BPE, and 1.45 +/- 0.3 for marked BPE. There were significant (P < 0.001) moderate to strong correlations among BPU, BPE, and FGT. BPU directly correlated with both BPE and FGT on MRI. Patient age showed a moderate to strong indirect correlation with all 3 imaging-derived tissue biomarkers. The coefficient of variation for quantitative BPU measurements with SUVmax was 5.6%, indicating a high reproducibility. Interinterpreter and intrainterpreter agreement for BPE and FGT was almost perfect, with a kappa-value of 0.860 and 0.822, respectively. CONCLUSION: The results of our study demonstrate that BPU varied among patients. BPU directly correlated with both BPE and FGT on MRI, and BPU measurements were highly reproducible. Patient age showed a strong inverse correlation with all 3 imaging-derived tissue biomarkers. These findings indicate that BPU may serve as a sensitive imaging biomarker for breast cancer prediction, prognosis, and risk assessment. PMID- 27230925 TI - Preclinical Characterization of 18F-MK-6240, a Promising PET Tracer for In Vivo Quantification of Human Neurofibrillary Tangles. AB - : A PET tracer is desired to help guide the discovery and development of disease modifying therapeutics for neurodegenerative diseases characterized by neurofibrillary tangles (NFTs), the predominant tau pathology in Alzheimer disease (AD). We describe the preclinical characterization of the NFT PET tracer 18F-MK-6240. METHODS: In vitro binding studies were conducted with 3H-MK-6240 in tissue slices and homogenates from cognitively normal and AD human brain donors to evaluate tracer affinity and selectivity for NFTs. Immunohistochemistry for phosphorylated tau was performed on human brain slices for comparison with 3H-MK 6240 binding patterns on adjacent brain slices. PET studies were performed with 18F-MK-6240 in monkeys to evaluate tracer kinetics and distribution in the brain. 18F-MK-6240 monkey PET studies were conducted after dosing with unlabeled MK-6240 to evaluate tracer binding selectivity in vivo. RESULTS: The 3H-MK-6240 binding pattern was consistent with the distribution of phosphorylated tau in human AD brain slices. 3H-MK-6240 bound with high affinity to human AD brain cortex homogenates containing abundant NFTs but bound poorly to amyloid plaque-rich, NFT poor AD brain homogenates. 3H-MK-6240 showed no displaceable binding in the subcortical regions of human AD brain slices and in the hippocampus/entorhinal cortex of non-AD human brain homogenates. In monkey PET studies, 18F-MK-6240 displayed rapid and homogeneous distribution in the brain. The 18F-MK-6240 volume of distribution stabilized rapidly, indicating favorable tracer kinetics. No displaceable binding was observed in self-block studies in rhesus monkeys, which do not natively express NFTs. Moderate defluorination was observed as skull uptake. CONCLUSION: 18F-MK-6240 is a promising PET tracer for the in vivo quantification of NFTs in AD patients. PMID- 27230926 TI - A Cystine Knot Peptide Targeting Integrin alphavbeta6 for Photoacoustic and Fluorescence Imaging of Tumors in Living Subjects. AB - : Photoacoustic imaging is a nonionizing biomedical imaging modality with higher resolution and imaging depth than fluorescence imaging, which has greater sensitivity. The combination of the 2 imaging modalities could improve the detection of cancer. Integrin alphavbeta6 is a cell surface marker overexpressed in many different cancers. Here, we report the development and evaluation of a dye-labeled cystine knot peptide, which selectively recognizes integrin alphavbeta6 with high affinity, for photoacoustic and fluorescence imaging. The new dual-modality probe may find clinical application in cancer diagnosis and intraoperative imaging of integrin alphavbeta6-positive tumors. METHODS: An engineered cystine knot peptide, R01, that recognizes integrin alphavbeta6 was labeled with Atto 740 (A740) and evaluated for its specific cell uptake and its sensitivity threshold. A740-R01 was injected via the tail vein into nude mice xenografted with A431 (integrin alphavbeta6-positive) or 293T (integrin alphavbeta6-negative) tumors. Photoacoustic and fluorescence scans of tumors were acquired before and at 0.5, 1, 2, and 4 h after injection of A740-R01. Dynamic photoacoustic scans of various normal organs were also acquired. Ex vivo fluorescence imaging of tissues was performed 1 h after injection. RESULTS: The A740-R01 demonstrated integrin alphavbeta6-dependent binding to A431 cells in culture. Sensitivity studies indicated that the probe may potentially detect lesions as small as 1 or 6 mm3 by fluorescence or photoacoustic imaging, respectively. The photoacoustic and fluorescence signals of A431 xenografts at 1 h after injection were 1.87 +/- 0.25 arbitrary units (AU) and 8.27 +/- 0.87 AU, respectively. Target specificity was confirmed by low tumor uptake in 293T tumors at 1 h after injection (1.07 +/- 0.15 AU and 1.10 +/- 0.14 AU for photoacoustic and fluorescence signals, respectively). A740-R01 exhibited hepatobiliary clearance marked by high uptake in the liver, spleen, and intestine but low uptake in the kidneys. CONCLUSION: A740-R01 specifically targeted integrin alphavbeta6 with low nanomolar affinity. A740-R01 was able to detect integrin alphavbeta6 both in vitro and in vivo by photoacoustic and fluorescence imaging. A740-R01 is able to detect alphavbeta6-positive tumors in living subjects and may have clinical application in cancer diagnosis and real-time image-guided surgery. PMID- 27230927 TI - Toward (Hybrid) Navigation of a Fluorescence Camera in an Open Surgery Setting. AB - : With the introduction of the hybrid tracer indocyanine green (ICG)-99mTc nanocolloid, a direct relation between preoperative imaging and intraoperative fluorescence guidance was established. However, fluorescence guidance remains limited by its superficial nature. This study evaluated the feasibility of a nuclear medicine-based navigation concept that allowed intraoperative positioning of a fluorescence camera (FC) in the vicinity of preoperatively defined ICG-99mTc nanocolloid containing sentinel nodes (SNs). METHODS: Five patients with penile cancer scheduled for SN biopsy were injected with ICG-99mTc-nanocolloid followed by preoperative SPECT/CT imaging. The navigation device was used to provide a real-time augmented reality overlay of the SPECT/CT images and video output of the FC. This overlay was then used for FC navigation. RESULTS: SPECT/CT identified 13 SNs in 9 groins. FC navigation was successful for all 12 intraoperatively evaluated SNs (average error, 8.8 mm; range, 0-20 mm). CONCLUSION: This study reveals the potential benefits of FC navigation during open surgery procedures. PMID- 27230928 TI - Immuno-PET Using Anticarcinoembryonic Antigen Bispecific Antibody and 68Ga Labeled Peptide in Metastatic Medullary Thyroid Carcinoma: Clinical Optimization of the Pretargeting Parameters in a First-in-Human Trial. AB - : Earlier clinical studies reported a high sensitivity of pretargeted immunoscintigraphy using murine or chimeric anticarcinoembryonic antigen (CEA) bispecific antibody (BsMAb) and peptides labeled with 111In or 131I in medullary thyroid carcinoma (MTC). Preclinical studies showed that new-generation humanized recombinant anti-CEA * antihistamine-succinyl-glycine (HSG) trivalent BsMAb TF2 and radiolabeled HSG peptide (IMP288) present good features for PET. This study aimed at optimizing molar doses and pretargeting interval of TF2 and 68Ga-labeled IMP288 for immuno-PET in relapsed MTC patients with calcitonin serum levels greater than 150 pg/mL. METHODS: Five cohorts (C1-C5) of 3 patients received variable molar doses of TF2 and approximately 150 MBq of 68Ga-IMP288 after different pretargeting time intervals (C1: 120 nmol TF2, 6 nmol IMP288, 24 h; C2: 120 nmol TF2, 6 nmol IMP288, 30 h; C3: 120 nmol TF2, 6 nmol IMP288, 42 h; C4: 120 nmol TF2, 3 nmol IMP288, 30 h; and C5: 60 nmol TF2, 3 nmol IMP288, 30 h). TF2 and 68Ga-IMP288 pharmacokinetics were monitored. Whole-body PET was recorded 60 and 120 min after 68Ga-IMP288 injection. Tumor maximal SUV (T-SUVmax) and T-SUVmax-to mediastinum blood-pool (MBP) SUVmean ratios (T/MBP) were determined. RESULTS: In C1, T-SUVmax and T/MBP ranged from 4.09 to 8.93 and 1.39 to 3.72 at 60 min and 5.14 to 11.25 and 2.73 to 5.38 at 120 min, respectively. Because of the high MBP, the delay was increased to 30 h in C2, increasing T-SUVmax and T/MBP. Further increasing the delay to 42 h in C3 decreased T-SUVmax and T/MBP, showing that 30 h was the most favorable delay. In C4, the TF2-to-peptide mole ratio was increased to 40 (delay 30 h), resulting in high T-SUVmax but with higher MBP than in C2. In C5, the molar dose of TF2 was reduced, resulting in lower imaging performance. Pharmacokinetics demonstrated a fast TF2 clearance and a clear relationship between blood activity clearance and the ratio between the molar amount of injected peptide to the molar amount of circulating TF2 at the time of peptide injection. CONCLUSION: High tumor uptake and contrast can be obtained with pretargeted anti-CEA immuno-PET in relapsed MTC patients, especially using optimized pretargeting parameters: a BsMAb-to-peptide mole ratio of 20 and 30 h pretargeting delay. PMID- 27230929 TI - Quantitative CD3 PET Imaging Predicts Tumor Growth Response to Anti-CTLA-4 Therapy. AB - : Immune checkpoint inhibitors have made rapid advances, resulting in multiple Food and Drug Administration-approved therapeutics that have markedly improved survival. However, these benefits are limited to a minority subpopulation that achieves a response. Predicting which patients are most likely to benefit would be valuable for individual therapy optimization. T-cell markers such as CD3-by examining active recruitment of the T cells responsible for cancer-cell death represent a more direct approach to monitoring tumor immune response than pretreatment biopsy or genetic screening. This approach could be especially effective as numerous different therapeutic strategies emerge, decreasing the need for drug-specific biomarkers and instead focusing on T-cell infiltration, which has been previously correlated with treatment response. METHODS: A CD3 PET imaging agent targeting T cells was synthesized to test the role of such imaging as a predictive marker. The 89Zr-p-isothiocyanatobenzyl-deferoxamine-CD3 PET probe was assessed in a murine tumor xenograft model of anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) immunotherapy of colon cancer. RESULTS: Imaging on day 14 revealed 2 distinct groups of mice stratified by PET signal intensity. Although there was no significant difference in tumor volume on the day of imaging, in the high-uptake group subsequent measurements revealed significantly smaller tumors than in either the low-uptake group or the untreated controls. In contrast, there was no significant difference in the size of tumors between the low-uptake and untreated control mice. CONCLUSION: These findings indicate that high CD3 PET uptake in the anti-CTLA-4-treated mice correlated with subsequent reduced tumor volume and was a predictive biomarker of response. PMID- 27230930 TI - (2S)-2-(3-(1-Carboxy-5-(4-211At-Astatobenzamido)Pentyl)Ureido)-Pentanedioic Acid for PSMA-Targeted alpha-Particle Radiopharmaceutical Therapy. AB - : Alpha-particle emitters have a high linear energy transfer and short range, offering the potential for treating micrometastases while sparing normal tissues. We developed a urea-based, 211At-labeled small molecule targeting prostate specific membrane antigen (PSMA) for the treatment of micrometastases due to prostate cancer (PC). METHODS: PSMA-targeted (2S)-2-(3-(1-carboxy-5-(4-211At astatobenzamido)pentyl)ureido)-pentanedioic acid (211At- 6: ) was synthesized. Cellular uptake and clonogenic survival were tested in PSMA-positive (PSMA+) PC3 PIP and PSMA-negative (PSMA-) PC3 flu human PC cells after 211At- 6: treatment. The antitumor efficacy of 211At- 6: was evaluated in mice bearing PSMA+ PC3 PIP and PSMA- PC3 flu flank xenografts at a 740-kBq dose and in mice bearing PSMA+, luciferase-expressing PC3-ML micrometastases. Biodistribution was determined in mice bearing PSMA+ PC3 PIP and PSMA- PC3 flu flank xenografts. Suborgan distribution was evaluated using alpha-camera images, and microscale dosimetry was modeled. Long-term toxicity was assessed in mice for 12 mo. RESULTS: 211At- 6: treatment resulted in PSMA-specific cellular uptake and decreased clonogenic survival in PSMA+ PC3 PIP cells and caused significant tumor growth delay in PSMA+ PC3 PIP flank tumors. Significantly improved survival was achieved in the newly developed PSMA+ micrometastatic PC model. Biodistribution showed uptake of 211At- 6: in PSMA+ PC3 PIP tumors and in kidneys. Microscale kidney dosimetry based on alpha-camera images and a nephron model revealed hot spots in the proximal renal tubules. Long-term toxicity studies confirmed that the dose limiting toxicity was late radiation nephropathy. CONCLUSION: PSMA-targeted 211At 6: alpha-particle radiotherapy yielded significantly improved survival in mice bearing PC micrometastases after systemic administration. 211At- 6: also showed uptake in renal proximal tubules resulting in late nephrotoxicity, highlighting the importance of long-term toxicity studies and microscale dosimetry. PMID- 27230931 TI - Serial 18F-FDG PET for Monitoring Treatment Response After Allogeneic Stem Cell Transplantation for Myelofibrosis. AB - : Our objective was to assess the feasibility of 18F-FDG PET/CT for noninvasive monitoring of treatment response after allogeneic stem cell transplantation (SCT) for myelofibrosis. METHODS: Twelve patients with myelofibrosis underwent 18F-FDG PET/CT before and after SCT. Bone marrow uptake, spleen uptake, and spleen size were assessed before and after SCT and compared with hematologic response criteria and bone marrow biopsies. RESULTS: All patients who did not achieve complete remission remained PET-positive (P = 0.02). Extent of disease, bone marrow metabolism, spleen metabolism, and spleen volume decreased significantly in patients with complete remission (P = 0.03). PET/CT after SCT had a sensitivity of 1.0 (95% confidence interval [CI], 0.54-1.0), a specificity of 0.83 (95% CI, 0.36-1.0), a negative predictive value of 1.0 (95% CI, 0.48-1.0), and a positive predictive value of 0.86 (95% CI, 0.42-1.0) for diagnosis of residual disease. CONCLUSION: 18F-FDG PET/CT is feasible for noninvasive monitoring of treatment response after allogeneic SCT for myelofibrosis. PMID- 27230932 TI - Prediction of CT Substitutes from MR Images Based on Local Diffeomorphic Mapping for Brain PET Attenuation Correction. AB - : Attenuation correction is important for PET reconstruction. In PET/MR, MR intensities are not directly related to attenuation coefficients that are needed in PET imaging. The attenuation coefficient map can be derived from CT images. Therefore, prediction of CT substitutes from MR images is desired for attenuation correction in PET/MR. METHODS: This study presents a patch-based method for CT prediction from MR images, generating attenuation maps for PET reconstruction. Because no global relation exists between MR and CT intensities, we propose local diffeomorphic mapping (LDM) for CT prediction. In LDM, we assume that MR and CT patches are located on 2 nonlinear manifolds, and the mapping from the MR manifold to the CT manifold approximates a diffeomorphism under a local constraint. Locality is important in LDM and is constrained by the following techniques. The first is local dictionary construction, wherein, for each patch in the testing MR image, a local search window is used to extract patches from training MR/CT pairs to construct MR and CT dictionaries. The k-nearest neighbors and an outlier detection strategy are then used to constrain the locality in MR and CT dictionaries. Second is local linear representation, wherein, local anchor embedding is used to solve MR dictionary coefficients when representing the MR testing sample. Under these local constraints, dictionary coefficients are linearly transferred from the MR manifold to the CT manifold and used to combine CT training samples to generate CT predictions. RESULTS: Our dataset contains 13 healthy subjects, each with T1- and T2-weighted MR and CT brain images. This method provides CT predictions with a mean absolute error of 110.1 Hounsfield units, Pearson linear correlation of 0.82, peak signal-to-noise ratio of 24.81 dB, and Dice in bone regions of 0.84 as compared with real CTs. CT substitute based PET reconstruction has a regression slope of 1.0084 and R2 of 0.9903 compared with real CT-based PET. CONCLUSION: In this method, no image segmentation or accurate registration is required. Our method demonstrates superior performance in CT prediction and PET reconstruction compared with competing methods. PMID- 27230933 TI - Accuracy and Precision of Partial-Volume Correction in Oncological PET/CT Studies. AB - : Accurate quantification of tracer uptake in small tumors using PET is hampered by the partial-volume effect as well as by the method of volume-of-interest (VOI) delineation. This study aimed to investigate the effect of partial-volume correction (PVC) combined with several VOI methods on the accuracy and precision of quantitative PET. METHODS: Four image-based PVC methods and resolution modeling (applied as PVC) were used in combination with several common VOI methods. Performance was evaluated using simulations, phantom experiments, and clinical repeatability studies. Simulations were based on a whole-body 18F-FDG PET scan in which differently sized spheres were placed in lung and mediastinum. A National Electrical Manufacturers Association NU2 quality phantom was used for the experiments. Repeatability data consisted of an 18F-FDG PET/CT study on 11 patients with advanced non-small cell lung cancer and an 18F-fluoromethylcholine PET/CT study on 12 patients with metastatic prostate cancer. RESULTS: Phantom data demonstrated that most PVC methods were strongly affected by the applied resolution kernel, with accuracy differing by about 20%-50% between full-width-at half-maximum settings of 5.0 and 7.5 mm. For all PVC methods, large differences in accuracy were seen among all VOI methods. Additionally, the image-based PVC methods were observed to have variable sensitivity to the accuracy of the VOI methods. For most PVC methods, accuracy was strongly affected by more than a 2.5 mm misalignment of true (simulated) VOI. When the optimal VOI method for each PVC method was used, high accuracy could be achieved. For example, resolution modeling for mediastinal lesions and iterative deconvolution for lung lesions were 99% +/- 1.5% and 99% +/- 0.9% accurate, respectively, for spheres 15-40 mm in diameter. Precision worsened slightly for resolution modeling and to a larger extent for some image-based PVC methods. Uncertainties in delineation propagated into uncertainties in PVC performance, as confirmed by the clinical data. CONCLUSION: The accuracy and precision of the tested PVC methods depended strongly on VOI method, resolution settings, contrast, and spatial alignment of the VOI. PVC has the potential to substantially improve the accuracy of tracer uptake assessment, provided that robust and accurate VOI methods become available. Commonly used delineation methods may not be adequate for this purpose. PMID- 27230934 TI - First results and follow-up of a second-generation circular mapping and ablation catheter. AB - PURPOSE: Pulmonary vein isolation with radiofrequency energy is widely used as a strategy for catheter ablation of atrial fibrillation (AF). Anatomically designed catheters have been developed to increase the efficiency of AF ablation procedures. The second-generation circular ablation catheter, PVAC GOLD, was re designed to improve energy delivery and mitigate emboli. We investigated the procedural efficiency, biophysics, and chronic efficacy of PVAC GOLD in patients with AF. METHODS: We consecutively enrolled 40 patients (60 +/- 11 years) with highly symptomatic, drug refractory AF. The first 20 patients were treated with the first-generation PVAC. The subsequent 20 patients were treated with the second-generation PVAC GOLD catheter. All patients were followed up at 3, 6, and 12 months. RESULTS: All 164 targeted PVs were successfully isolated. Ablations performed with PVAC GOLD showed a significant reduction in total number of ablations needed for PVI, fluoroscopy, and procedure times compared to PVAC (34.7 +/- 7.0 vs. 27.0 +/- 6.5; p = 0.009), fluoroscopy (29.5 +/- 9.5 vs. 23.4 +/- 7.0; p = 0.026), and procedure time (93.8 +/- 18.9 vs. 83.1 +/- 10.6; p = 0.033). PVAC GOLD showed improved biophysics including a reduction of low power ablations and an increase in mean effective energy delivery. At 12 months follow-up, AF recurrence rates were comparable in the two groups (35 vs. 30 %; p = 0.735). There were no adverse events. CONCLUSIONS: The redesigned PVAC GOLD catheter demonstrates a reduction in radiofrequency ablation and procedure time and improved biophysics while maintaining chronic efficacy compared to the first generation PVAC. PMID- 27230935 TI - "You Can't Always Get What You Want": A Novel Research Paradigm to Explore the Relationship between Multiple Intentions and Behaviours. AB - OBJECTIVE: Research investigating cognitive moderators of the intention-behaviour relationship and psychological consequences of failure to enact intentions is usually conducted in a single-behaviour paradigm. A multiple-behaviour paradigm is introduced which overcomes bias inherent to single-behaviour designs and allows testing of novel hypotheses. Two exploratory studies illustrate the utility of this new paradigm by investigating the role of cognitive predictors and psychological correlates of intention-behaviour relationships. METHOD: The proposed method involves measuring multiple intentions across common areas of life activity at baseline and corresponding behaviours at follow-up. In two studies, 51 intentions and behaviours were assessed (49 by self-report, 2 objectively). In Study 1, participants (n = 126) also completed self-reported measures of everyday cognitive failures and dysexecutive behaviours, crystallised intelligence (Mill Hill Vocabulary Scale) at baseline and Quality of Life (QoL; follow-up). In Study 2, objective executive function measures (Stroop, Go/NoGo task and Word Fluency test) were completed by N = 30 participants. RESULTS: The total number of intentions, cognitive, and QoL measures were unrelated to the percentage of intentions enacted. Crystallised intelligence was related to successful intention implementation and problems with emotion regulation were associated with forming fewer intentions and with fewer failed intentions. QoL was strongly related with more intentions, regardless of whether or not these were implemented. Study 2 showed that cognitive flexibility (word fluency) and task errors, rather than Stroop effect and Go/No-Go performance were related, to intention-behaviour congruence. CONCLUSION: Intention-behaviour relationships might be better understood when considering the multiple intentions and behaviours that people are engaged in at once at any one point in time. A multiple-behaviour paradigm suggests novel hypotheses. Preliminary findings reported here require replication. Anticipated applications of the paradigm are outlined and discussed. PMID- 27230937 TI - Functional characterization of germin and germin-like protein genes in various plant species using transgenic approaches. AB - The important role of germins (GER) and genes coding for germin-like proteins (GLP) in responses against various stresses in both homologous and heterologous systems is well validated. This review summarizes the work on their functional validation using various biotechnological approaches. The genes are widely expressed during a specific period of plant growth and development, and exhibit a pattern of evolutionary subfunctionalization at both the intracellular and whole plant level. Their applications against various biotic and abiotic stresses, especially against fungal pathogens, are enormous. Although the validation of these proteins against various stresses has led to the development of commercially and agronomically important transgenic plants, much work is still needed to exploit this ever-expanding repertoire of genes and deploy them for commercial use. Historical progress of genetic engineering in GERs and GLPs is reviewed, and future prospects for their potential role in crop improvement are highlighted. PMID- 27230938 TI - Microbial recovery of vanadium by the acidophilic bacterium, Acidocella aromatica. AB - OBJECTIVE: To investigate the bioreduction of toxic pentavalent vanadium [vanadate; V(V)] in the acidophilic, Fe(III)-reducing obligately heterotrophic bacterium, Acidocella aromatica PFBC. RESULTS: Although the initial lag-phase of growth became extended with increasing initial V(V) concentrations, the final cell density during aerobic growth of A. aromatica PFBC was unaffected by up to 2 mM V(V). While strain PFBC is an aerobe, growth-decoupled PFBC cell suspensions directly reduced V(V) using fructose, both micro-aerobically and anaerobically, under highly acidic (pH 2) and moderately acidic (pH 4.5) conditions. Bio reduced V(IV) was subsequently precipitated even under micro-aerobic conditions, mostly by encrusting the cell surface. An anaerobic condition at pH 4.5 was optimal for forming and maintaining stable V(IV)-precipitates. Recovery of approx. 70 % of V(V) from the solution phase was made possible with V(V) at 1 mM. CONCLUSIONS: The first case of direct V(V) reducing ability and its subsequent V recovery from the solution phase was shown in acidophilic prokaryotes. Possible utilities of V(V) bioreduction in acidic conditions, are discussed. PMID- 27230939 TI - Effects of the level of early productivity on the lifespan of ewes in contrasting flock environments. AB - Selection for high levels of prolificacy has allowed substantial improvements in the production efficiency of New Zealand (NZ) sheep farms, but the consequences on ewe lifetime performance are mostly unknown. In this study, the relationship between the level of prolificacy early in ewes' productive lives and their probability to survive later (i.e. stayability) was evaluated in two contrasting NZ flock environments. Records were obtained from 6605 ewes from four ram breeder flocks representing either a moderate (n=2) or a highly variable (n=2) nutritional environment. All ewes lambed for the first time at 2 years of age and were mated the following year. The number of lambs born during the first 2 years of productive life (NLB2-3) was used as a measure of early prolificacy. Effects of NLB2-3 on stayability to 4, 5, 6, 7 and 8 years old were analysed using logistic regression. Curvilinear effects (logit-transformed) were detected (P<0.05) until stayability to 6 years and to 8 years old in the highly variable and the moderate environment, respectively. The NLB2-3 that resulted in maximum expected stayability to various ages was 3.9 to 4.2, and 4.5 to 4.7 lambs in the highly variable and in the moderate flock environments, respectively. In addition, ewe stayability was reduced when the proportion of the litter that survived from birth to weaning (i.e. ewe rearing ability) was submaximal during the early productive life. High prolific ewes had a low rearing ability whatever the environment whereas the rearing ability of lowly prolific ewes was apparently more sensitive to the nutritional environment. The poor maternal performance of ewes with low levels of NLB2-3 led to a premature culling by breeders whereas the high early reproductive effort associated with high levels of NLB2-3 seemed to be at the cost of ewes' survival, even in the moderate flock environment. In conclusion, the flock environment influenced the level of early prolificacy beyond which ewe longevity was reduced. It is suggested that further selection for high and early prolificacy in NZ flocks is likely to impair ewes' lifetime productivity. PMID- 27230936 TI - Nanoparticles for Targeting Intratumoral Hypoxia: Exploiting a Potential Weakness of Glioblastoma. AB - Extensive hypoxic regions are the daunting hallmark of glioblastoma, as they host aggressive stem-like cells, hinder drug delivery and shield cancer cells from the effects of radiotherapy. Nanotechnology could address most of these issues, as it employs nanoparticles (NPs) carrying drugs that selectively accumulate and achieve controlled drug release in tumor tissues. Methods overcoming the stiff interstitium and scarce vascularity within hypoxic zones include the incorporation of collagenases to degrade the collagen-rich tumor extracellular matrix, the use of multistage systems that progressively reduce NP size or of NP loaded cells that display inherent hypoxia-targeting abilities. The unfavorable hypoxia-induced low pH could be converted into a therapeutical advantage by pH responsive NPs or multilayer NPs, while overexpressed markers of hypoxic cells could be specifically targeted for an enhanced preferential drug delivery. Finally, promising new gene therapeutics could also be incorporated into nanovehicles, which could lead to silencing of hypoxia-specific genes that are overexpressed in cancer cells. In this review, we highlight NPs which have shown promising results in targeting cancer hypoxia and we discuss their applicability in glioblastoma, as well as possible limitations. Novel research directions in this field are also considered. PMID- 27230940 TI - Mapping the electrostatic force field of single molecules from high-resolution scanning probe images. AB - How electronic charge is distributed over a molecule determines to a large extent its chemical properties. Here, we demonstrate how the electrostatic force field, originating from the inhomogeneous charge distribution in a molecule, can be measured with submolecular resolution. We exploit the fact that distortions typically observed in high-resolution atomic force microscopy images are for a significant part caused by the electrostatic force acting between charges of the tip and the molecule of interest. By finding a geometrical transformation between two high-resolution AFM images acquired with two different tips, the electrostatic force field or potential over individual molecules and self assemblies thereof can be reconstructed with submolecular resolution. PMID- 27230941 TI - Following the steps of a reaction by direct imaging of many individual molecules. AB - The dehydrogenation and dechlorination of FeOEP-Cl on Cu(111) has been studied in detail by scanning tunneling microscopy. Although, it is not possible to follow the reaction of an individual molecule, the complete pathway of the reaction with 22 inequivalent intermediate states and the rates of the involved processes are revealed. This is achieved by combining the analysis of a large data set showing thousands of molecules in the different stages of the reaction with numerical simulations. PMID- 27230942 TI - Accurate force fields and methods for modelling organic molecular crystals at finite temperatures. AB - We present an assessment of the performance of several force fields for modelling intermolecular interactions in organic molecular crystals using the X23 benchmark set. The performance of the force fields is compared to several popular dispersion corrected density functional methods. In addition, we present our implementation of lattice vibrational free energy calculations in the quasi harmonic approximation, using several methods to account for phonon dispersion. This allows us to also benchmark the force fields' reproduction of finite temperature crystal structures. The results demonstrate that anisotropic atom atom multipole-based force fields can be as accurate as several popular DFT-D methods, but have errors 2-3 times larger than the current best DFT-D methods. The largest error in the examined force fields is a systematic underestimation of the (absolute) lattice energy. PMID- 27230943 TI - Expression of SOX18 in Mycosis Fungoides. AB - SOX18 is a transcription factor involved in the development of hair follicle, blood and lymphatic vessels, as well as regenerative processes. In addition, accumulated data indicate the role of SOX18 in tumourigenesis. So far, no studies on the role of SOX18 expression in mycosis fungoides (MF), the most common primary cutaneous T-cell lymphoma, have been performed. Therefore, we evaluated SOX18 expression in MF at the mRNA and protein level. SOX18 expression was observed predominantly on the blood and lymphatic vessels, in the intratumoural and peritumoural microenvironment of MF. The intra-tumoural, but not peritumoural, expression of SOX18 correlated positively with the advancement of the disease, cutaneous involvement and extracutaneous meta-stases at the protein level (p < 0.001, p < 0.001, p = 0.004; respectively). Significantly lower SOX18 mRNA expression was correlated with lymph node involvement (p = 0.01). In conclusion, we hypothesize that SOX18, as a marker of neovascularization, may be involved in the progression of MF. PMID- 27230944 TI - High-fidelity spherical cholesteric liquid crystal Bragg reflectors generating unclonable patterns for secure authentication. AB - Monodisperse cholesteric liquid crystal microspheres exhibit spherically symmetric Bragg reflection, generating, via photonic cross communication, dynamically tuneable multi-coloured patterns. These patterns, uniquely defined by the particular sphere arrangement, could render cholesteric microspheres very useful in countless security applications, as tags to identify and authenticate their carriers, mainly physical objects or persons. However, the optical quality of the cholesteric droplets studied so far is unsatisfactory, especially after polymerisation, a step required for obtaining durable samples that can be used for object identification. We show that a transition from droplets to shells solves all key problems, giving rise to sharp patterns and excellent optical quality even after polymerisation, the polymerised shells sustaining considerable mechanical deformation. Moreover, we demonstrate that, counter to prior expectation, cross communication takes place even between non-identical shells. This opens additional communication channels that add significantly to the complexity and unique character of the generated patterns. PMID- 27230945 TI - The expression of tenascin-C and tenascin-W in human ossicles. AB - The ossicles of the middle ear (the malleus, incus and stapes) transmit forces resulting from vibrations of the tympanic membrane to the cochlea where they are coded as sound. Hearing loss can result from diseases such as rheumatoid arthritis (RA) that affect the joints between the ossicles or degenerative processes like otosclerosis that lead to ankylosis of the footplate of the stapes in the oval window of the cochlea. In this study, immunohistochemistry was used to determine if the extracellular matrix glycoproteins tenascin-C or tenascin-W are expressed in the incudomalleolar and incudostapedial joints of ossicles dissected from human cadavers. Tenascin-C, which is expressed during inflammatory conditions including RA, was seen in the articular cartilage of the incudomalleolar joints and the head of the stapes. Tenascin-W, in contrast, was enriched in the annular ligament that anchors the footplate of the stapes into the oval window of the cochlea. PMID- 27230946 TI - Follow-up strategies for women treated for early breast cancer. AB - BACKGROUND: Follow-up examinations are commonly performed after primary treatment for women with breast cancer. They are used to detect recurrences at an early (asymptomatic) stage. This is an update of a Cochrane review first published in 2000. OBJECTIVES: To assess the effectiveness of different policies of follow-up for distant metastases on mortality, morbidity and quality of life in women treated for stage I, II or III breast cancer. SEARCH METHODS: For this 2014 review update, we searched the Cochrane Breast Cancer Group's Specialised Register (4 July 2014), MEDLINE (4 July 2014), Embase (4 July 2014), CENTRAL (2014, Issue 3), the World Health Organization (WHO) International Clinical Trials Registry Platform (4 July 2014) and ClinicalTrials.gov (4 July 2014). References from retrieved articles were also checked. SELECTION CRITERIA: All randomised controlled trials (RCTs) assessing the effectiveness of different policies of follow-up after primary treatment were reviewed for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for eligibility for inclusion in the review and risk of bias. Data were pooled in an individual patient data meta-analysis for the two RCTs testing the effectiveness of different follow-up schemes. Subgroup analyses were conducted by age, tumour size and lymph node status. MAIN RESULTS: Since 2000, one new trial has been published; the updated review now includes five RCTs involving 4023 women with breast cancer (clinical stage I, II or III).Two trials involving 2563 women compared follow-up based on clinical visits and mammography with a more intensive scheme including radiological and laboratory tests. After pooling the data, no significant differences in overall survival (hazard ratio (HR) 0.98, 95% confidence interval (CI) 0.84 to 1.15, two studies, 2563 participants, high quality evidence), or disease-free survival (HR 0.84, 95% CI 0.71 to 1.00, two studies, 2563 participants, low-quality evidence) emerged. No differences in overall survival and disease-free survival emerged in subgroup analyses according to patient age, tumour size and lymph node status before primary treatment. In 1999, 10-year follow-up data became available for one trial of these trials, and no significant differences in overall survival were found. No difference was noted in quality of life measures (one study, 639 participants, high-quality evidence).The new included trial, together with a previously included trial involving 1264 women compared follow-up performed by a hospital-based specialist versus follow-up performed by general practitioners. No significant differences were noted in overall survival (HR 1.07, 95% CI 0.64 to 1.78, one study, 968 participants, moderate-quality evidence), time to detection of recurrence (HR 1.06, 95% CI 0.76 to 1.47, two studies, 1264 participants, moderate-quality evidence), and quality of life (one study, 356 participants, high-quality evidence). Patient satisfaction was greater among patients treated by general practitioners. One RCT involving 196 women compared regularly scheduled follow-up visits versus less frequent visits restricted to the time of mammography. No significant differences emerged in interim use of telephone and frequency of general practitioners's consultations. AUTHORS' CONCLUSIONS: This updated review of RCTs conducted almost 20 years ago suggests that follow-up programs based on regular physical examinations and yearly mammography alone are as effective as more intensive approaches based on regular performance of laboratory and instrumental tests in terms of timeliness of recurrence detection, overall survival and quality of life.In two RCTs, follow-up care performed by trained and not trained general practitioners working in an organised practice setting had comparable effectiveness to that delivered by hospital-based specialists in terms of overall survival, recurrence detection, and quality of life. PMID- 27230947 TI - Risk Factors: Melatonin signalling implicated in the risk of T2DM. PMID- 27230948 TI - Genetics: Healthy ageing, the genome and the environment. PMID- 27230949 TI - The potential of endurance exercise-derived exosomes to treat metabolic diseases. AB - Endurance exercise-mediated multisystemic adaptations are known to mitigate metabolism-related disorders such as obesity and type 2 diabetes mellitus (T2DM). However, the underlying molecular mechanisms that promote crosstalk between organs and orchestrate the pro-metabolic effects of endurance exercise remain unclear. Exercise-induced release of peptides and nucleic acids from skeletal muscle and other organs (collectively termed 'exerkines') has been implicated in mediating these systemic adaptations. Given that the extracellular milieu is probably not a hospitable environment for labile exerkines, a lipid vehicle-based mode of delivery has originated over the course of evolution. Two types of extracellular vesicles, exosomes and microvesicles, have been shown to contain proteins and nucleic acids that participate in a variety of physiological and pathological processes. Exosomes, in particular, have been shown to facilitate the exchange of peptides, microRNA, mRNA and mitochondrial DNA between cells and tissues. Intriguingly, circulatory extracellular vesicle content increases in an intensity-dependant manner in response to endurance exercise. We propose that the systemic benefits of exercise are modulated by exosomes and/or microvesicles functioning in an autocrine, paracrine and/or endocrine manner. Furthermore, we posit that native or modified exosomes, and/or microvesicles enriched with exerkines will have therapeutic utility in the treatment of obesity and T2DM. PMID- 27230950 TI - Adipose tissue: Fat, yet fit. PMID- 27230952 TI - Obesity: Could 13 amino acids combat obesity? PMID- 27230953 TI - Lymphomatoid papulosis associated with multiple myeloma. PMID- 27230951 TI - Osteocytic signalling pathways as therapeutic targets for bone fragility. AB - Osteocytes are differentiated osteoblasts that become surrounded by matrix during the process of bone formation. Acquisition of the osteocyte phenotype is achieved by profound changes in gene expression that facilitate adaptation to the changing cellular environment and constitute the molecular signature of osteocytes. During osteocytogenesis, the expression of genes that are characteristic of the osteoblast are altered and the expression of genes and/or proteins that impart dendritic cellular morphology, regulate matrix mineralization and control the function of cells at the bone surface are ordely modulated. The discovery of mutations in human osteocytic genes has contributed, in a large part, to our understanding of the role of osteocytes in bone homeostasis. Osteocytes are targets of the mechanical force imposed on the skeleton and have a critical role in integrating mechanosensory pathways with the action of hormones, which thereby leads to the orchestrated response of bone to environmental cues. Current, therapeutic approaches harness this accumulating knowledge by targeting osteocytic signalling pathways and messengers to improve skeletal health. PMID- 27230954 TI - Angiotensin II analogues with N-terminal lactam bridge cyclization: an overview on AT1 receptor activation and tachyphylaxis. AB - Angiotensin II (AngII) is the final active product of the renin enzymatic cascade, which is responsible for sustaining blood pressure. To investigate the effect of N-terminal cyclization on AT1 activation and tachyphylaxis, we designed conformationally constrained analogues with an i-(i + 1) lactam bridge. All analogues presented the same binding coefficient and tachyphylactic index, but some of them such as Cyclo (0-1a) [Glu0 , endo-(Lys1a )]-AngII and Cyclo (0-1a) [Asp0 , endo-(Orn1a )]-AngII showed higher potency. The same tachyphylactic index presented by AngII and cyclic analogues was surprising. We expected a variation after the modification of AngII N-terminal region. PMID- 27230955 TI - Investigation of the Levels of Serum Amyloid A, YKL-40, and Pentraxin-3 in Patients with Familial Mediterranean Fever. AB - BACKGROUND: Familial Mediterranean Fever (FMF) is an autosomal recessive form of recurrent episodes of fever and an autoinflammatory disease characterized by inflammation of the serous membranes. The clinical diagnosis is supported by the laboratory findings. This study investigated the relationship of Serum Amyloid A (SAA), YKL-40, and Pentraxin-3 (PTX-3) with the FMF disease. METHODS: About 50 patients with FMF were enrolled in this study. Patients were divided into three groups according to disease severity score (mild, moderate, and severe). Thirty seven healthy individuals were included as the control group. Serum SAA, YKL-40, and PTX-3 concentrations were measured using an ELISA kit. RESULTS: Serum SAA and YKL-40 levels of FMF patients were significantly higher than in the control (P < 0.001). PTX-3 levels were found to be higher in patients even though there was no significant difference (P = 0.113). Whereas the positive predictive value was 71.9% for cut-off point of SAA, the positive predictive value was 83.3% for cut off point of YKL-40. Whereas a significant correlation was detected in SAA and PTX-3 with YKL-40 (respectively; P = 0.036, P < 0.001), there was no correlation between the PTX-3 with SAA (P = 0.219). CONCLUSIONS: YKL-40 can be used together with SAA to support the diagnosis of FMF and to monitor the severity of the disease. In this study, YKL-40 levels were examined for the first time in FMF patients and further studies are necessary using larger patient samples. PMID- 27230956 TI - Identification of lactate dehydrogenase as a mammalian pyrroloquinoline quinone (PQQ)-binding protein. AB - Pyrroloquinoline quinone (PQQ), a redox-active o-quinone, is an important nutrient involved in numerous physiological and biochemical processes in mammals. Despite such beneficial functions, the underlying molecular mechanisms remain to be established. In the present study, using PQQ-immobilized Sepharose beads as a probe, we examined the presence of protein(s) that are capable of binding PQQ in mouse NIH/3T3 fibroblasts and identified five cellular proteins, including l lactate dehydrogenase (LDH) A chain, as potential mammalian PQQ-binding proteins. In vitro studies using a purified rabbit muscle LDH show that PQQ inhibits the formation of lactate from pyruvate in the presence of NADH (forward reaction), whereas it enhances the conversion of lactate to pyruvate in the presence of NAD(+) (reverse reaction). The molecular mechanism underlying PQQ-mediated regulation of LDH activity is attributed to the oxidation of NADH to NAD(+) by PQQ. Indeed, the PQQ-bound LDH oxidizes NADH, generating NAD(+), and significantly catalyzes the conversion of lactate to pyruvate. Furthermore, PQQ attenuates cellular lactate release and increases intracellular ATP levels in the NIH/3T3 fibroblasts. Our results suggest that PQQ, modulating LDH activity to facilitate pyruvate formation through its redox-cycling activity, may be involved in the enhanced energy production via mitochondrial TCA cycle and oxidative phosphorylation. PMID- 27230957 TI - Proteomic analysis of minute amount of colonic biopsies by enteroscopy sampling. AB - Colorectal cancer (CRC) is one of the most common types of malignant tumor worldwide. Currently, although many researchers have been devoting themselves in CRC studies, the process of locating biomarkers for CRC early diagnosis and prognostic is still very slow. Using a centrifugal proteomic reactor-based proteomic analysis of minute amount of colonic biopsies by enteroscopy sampling, 2620 protein groups were quantified between cancer mucosa and adjacent normal colorectal mucosa. Of which, 403 protein groups were differentially expressed with statistic significance between cancer and normal tissues, including 195 up regulated and 208 down-regulated proteins in cancer tissues. Three proteins (SOD3, PRELP and NGAL) were selected for further Western blot validation. And the resulting Western blot experimental results were consistent with the quantitative proteomic data. SOD3 and PRELP are down-regulated in CRC mucosa comparing to adjacent normal tissue, while NGAL is up-regulated in CRC mucosa. In conclusion, the centrifugal proteomic reactor-based label-free quantitative proteomic approach provides a highly sensitive and powerful tool for analyzing minute protein sample from tiny colorectal biopsies, which may facilitate CRC biomarkers discovery for diagnoses and prognoses. PMID- 27230958 TI - Role of AMP-activated protein kinase alpha1 in angiotensin-II-induced renal Tgfbeta-activated kinase 1 activation. AB - Angiotensin-II is a key factor in renal fibrosis. Obstructive nephropathy induces an isoform shift from catalytic Ampkalpha2 towards Ampkalpha1 which contributes to signaling involved in renal tissue injury. The present study explored whether the Ampkalpha1 isoform contributes to the renal effects of angiotensin-II. To this end, angiotensin-II was infused by subcutaneous implantation of osmotic minipumps in gene-targeted mice lacking functional Ampkalpha1 (Ampkalpha1(-/-)) and corresponding wild-type mice (Ampkalpha1(+/+)). Western blotting and qRT-PCR were employed to determine protein abundance and mRNA levels, respectively, in renal tissue. In Ampkalpha1(+/+) mice, angiotensin-II increased renal Ampkalpha1 protein expression without significantly modifying renal Ampkalpha2 protein expression. The renal phosphorylated Ampkalpha (Thr(172)) protein abundance was not affected by angiotensin-II in neither genotypes, but was significantly lower in Ampkalpha1(-/-) mice than Ampkalpha1(+/+) mice. Angiotensin-II increased the phosphorylation of Tak1 (Ser(412)) in renal tissue of Ampkalpha1(+/+) mice, an effect virtually absent in the Ampkalpha1(-/-) mice. Furthermore, angiotensin-II treatment significantly increased renal protein and mRNA expression of alpha smooth muscle actin (alphaSma) as well as Tak1-target gene expression: Cox2, Il6 and Pai1 in Ampkalpha1(+/+) mice, all effects significantly less pronounced in Ampkalpha1(-/-) mice. In conclusion, angiotensin-II up-regulates the Ampkalpha1 isoform in renal tissue. Ampkalpha1 participates in renal Tak1 activation and Tak1-dependent signaling induced by angiotensin-II. PMID- 27230959 TI - Ti/beta-PbO2 versus Ti/Pt/beta-PbO2: Influence of the platinum interlayer on the electrodegradation of tetracyclines. AB - The behaviors of the electrodes Ti/PbO2 and Ti/Pt/PbO2 as anodes in the electro oxidation of two antibiotics-tetracycline and oxytetracycline-were evaluated at different applied current densities, to evaluate the influence of the Pt interlayer. In the preparation of the electrodes, the electrodeposited beta-PbO2 phase was homogeneous; no Ti or Pt peaks were detected in the diffractograms. The beta-PbO2 surface presented significant roughness when deposited over the Pt interlayer, which also conferred significant conductivity to the material. In the electro-oxidation assays, the COD, TOC and absorbance removals increased with the current density due to an increase in the concentration of hydroxyl radicals, for both electrode materials and antibiotics tested. Slightly better results were obtained with Ti/PbO2. The primary differences observed in the antibiotics concentration decay consisted of zero-order kinetics at the Ti/Pt/PbO2 anode and first-order kinetics at the Ti/PbO2 anode with a higher oxytetracycline concentration decay than the tetracycline concentration decay. A greater amount of total nitrogen was eliminated with the Ti/PbO2 electrode. At the Ti/Pt/PbO2 anode, the organic nitrogen primarily transformed into NH4(+) and the total nitrogen remained unchanged. The specific energy consumption with the Ti/Pt/PbO2 anode was significantly lower than the specific energy consumption with the Ti/PbO2 anode due to the higher electrical conductivity of the Ti/Pt/PbO2 anode. Both anode materials were also utilized in the electro-oxidation of a leachate sample collected at sanitary landfill and spiked with tetracycline, and the complete elimination of the antibiotic molecule was observed. PMID- 27230961 TI - Full characterization of an attosecond pulse generated using an infrared driver. AB - The physics of attosecond pulse generation requires using infrared driving wavelength to reach the soft X-rays. However, with longer driving wavelength, the harmonic conversion efficiency drops significantly. It makes the conventional attosecond pulse measurement using streaking very difficult due to the low photoionization cross section in the soft X-rays region. In-situ measurement was developed for precisely this purpose. We use in-situ measurement to characterize, in both space and time, an attosecond pulse produced by ultrafast wavefront rotation of a 1.8 MUm fundamental beam. We confirm what models suggest - that each beamlet is an isolated attosecond pulse in the time domain. We get almost constant flat wavefront curvature through the whole photon energy range. The measurement method is scalable to the soft X-ray spectral region. PMID- 27230962 TI - Diagnostic test accuracy of D-dimer for acute aortic syndrome: systematic review and meta-analysis of 22 studies with 5000 subjects. AB - Diagnostic test accuracy of D-dimer for acute aortic dissection (AAD) has not been evaluated by meta-analysis with the bivariate model methodology. Four databases were electrically searched. We included both case-control and cohort studies that could provide sufficient data concerning both sensitivity and specificity of D-dimer for AAD. Non-English language articles and conference abstract were allowed. Intramural hematoma and penetrating aortic ulcer were regarded as AAD. Based on 22 eligible articles consisting of 1140 AAD subjects and 3860 non-AAD subjects, the diagnostic odds ratio was 28.5 (95% CI 17.6-46.3, I(2) = 17.4%) and the area under curve was 0.946 (95% CI 0.903-0.994). Based on 833 AAD subjects and 1994 non-AAD subjects constituting 12 studies that used the cutoff value of 500 ng/ml, the sensitivity was 0.952 (95% CI 0.901-0.978), the specificity was 0.604 (95% CI 0.485-0.712), positive likelihood ratio was 2.4 (95% CI 1.8-3.3), and negative likelihood ratio was 0.079 (95% CI 0.036-0.172). Sensitivity analysis using data of three high-quality studies almost replicated these results. In conclusion, D-dimer has very good overall accuracy. D-dimer <500 ng/ml largely decreases the possibility of AAD. D-dimer >500 ng/ml moderately increases the possibility of AAD. PMID- 27230960 TI - Nanostructured injectable cell microcarriers for tissue regeneration. AB - Biodegradable polymer microspheres have emerged as cell carriers for the regeneration and repair of irregularly shaped tissue defects due to their injectability, controllable biodegradability and capacity for drug incorporation and release. Notably, recent advances in nanotechnology allowed the manipulation of the physical and chemical properties of the microspheres at the nanoscale, creating nanostructured microspheres mimicking the composition and/or structure of natural extracellular matrix. These nanostructured microspheres, including nanocomposite microspheres and nanofibrous microspheres, have been employed as cell carriers for tissue regeneration. They enhance cell attachment and proliferation, promote positive cell-carrier interactions and facilitate stem cell differentiation for target tissue regeneration. This review highlights the recent advances in nanostructured microspheres that are employed as injectable, biomimetic and cell-instructive cell carriers. PMID- 27230963 TI - Body fat and menstrual resumption in adult females with anorexia nervosa: a 1 year longitudinal study. AB - BACKGROUND: The variables predicting the resumption of menses in anorexia nervosa (AN) after weight restoration have not yet been fully established. We therefore aimed to investigate the association between several clinical parameters at inpatient discharge and the resumption of menses at 1-year follow-up in weight restored adults with AN. METHODS: Demographic, anthropometric, body composition and eating disorder features were assessed in 54 adult females with AN who had restored normal body weight [body mass index (BMI) >= 18.5 kg m(-) 2] at the end of specialist inpatient treatment. These variables were compared between participants who had resumed menses and those who were still amenorrheic 1 year after inpatient discharge. RESULTS: At 1-year follow-up, 35.2% of patients had resumed menstruation. No significant association was found between the resumption of menses and either age, duration of illness or BMI at inpatient admission, nor for BMI, global Eating Disorder Examination score or trunk fat percentage at inpatient discharge. Only total body fat percentage at inpatient discharge was significantly higher in patients who resumed menstruation, as confirmed by combined logistic regression analysis (odds ratio = 1.14, 95% confidence interval = 1.001-1.303, P = 0.049). CONCLUSIONS: A higher total body fat percentage at inpatient discharge is associated with the resumption of menses at 1-year follow up in weight-restored adult females with AN. PMID- 27230965 TI - Patterns of Kidney Function Decline Associated with APOL1 Genotypes: Results from AASK. AB - BACKGROUND AND OBJECTIVES: Trajectories of eGFR in patients with CKD are highly variable. Only a subset of patients with CKD experiences a steady decline in eGFR. The objective of our study was to investigate whether eGFR trajectory patterns differ by APOL1 risk status. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Our study was a longitudinal observational study of 622 participants in the African American Study of Kidney Disease and Hypertension with APOL1 genotyping and sufficient follow-up for estimating GFR trajectories. The predictor was APOL1 high-risk status (having two copies of the G1 or G2 risk alleles) versus low-risk status (zero or one copy of the risk alleles), and the outcome was four eGFR trajectory patterns on the basis of the joint probabilities of linearity and progression: steady decline, unsteady decline, steady stable, and unsteady stable. RESULTS: Over a median follow-up of 9 years, 24.0% of participants experienced steady eGFR decline, 25.9% had an unsteady decline, 25.6% were steady and stable, and 24.6% were unsteady but stable. Those experiencing steady decline had lower eGFR and higher urine protein-to-creatinine ratio at baseline than participants with the other eGFR trajectory patterns. The APOL1 high-risk group was associated with a greater odds for the steady decline pattern than the APOL1 low-risk group (unadjusted odds ratio, 2.45; 95% confidence interval, 1.62 to 3.69). This association remained significant after adjusting for demographic factors, baseline eGFR, urine protein-to-creatinine ratio, treatment assignment, and follow-up time (adjusted odds ratio, 1.59; 95% confidence interval, 1.00 to 2.52). CONCLUSIONS: Among patients with CKD attributed to hypertension, those with the APOL1 high-risk genotype were more likely to experience a steady decline trajectory in eGFR than those without the APOL1 high-risk genotype. These findings suggest a persistent underlying pathophysiologic process in those patients with the APOL1 high-risk genotype. PMID- 27230967 TI - Palliative Care Consultations in the Neuro-ICU: A Qualitative Study. AB - BACKGROUND: Integration of palliative care (PC) into the neurological intensive care unit (neuro-ICU) is increasingly recommended, but evidence regarding the best practice is lacking. We conducted a qualitative analysis exploring current practices and key themes of specialist PC consultations in patients admitted to a single neuro-ICU. METHODS: We retrospectively identified all patients who were admitted to the neuro-ICU for >=24 h and received a PC consultation between January and August 2014. We reviewed PC consultation notes and neuro-ICU progress notes from the electronic health records of these patients. We performed content analysis on the PC notes. RESULTS: Twenty-five neuro-ICU patients (4 %) received a PC consultation over 8 months with the most prevalent reason of clarifying goals of care. The main distinctions between patients with and those without (n = 580) a PC consultation were ICU length of stay (median 8.2 vs. 2.8 days) and death in the neuro-ICU (56 % vs. 11 %). The most prevalent themes addressed in the PC consultation notes were (1) discussing prognosis, (2) eliciting patient and family values, (3) understanding medical options, and (4) identifying conflict. CONCLUSIONS: PC consultations in the neuro-ICU emphasize family coping and decision-making by helping discuss prognosis and exploring patient and family values as well as their ability to understand the medical information. Several features suggest that earlier integration of PC into neuro-ICU care may enhance both coping and the decision-making process. PMID- 27230966 TI - Systemic leukotriene B4 receptor antagonism lowers arterial blood pressure and improves autonomic function in the spontaneously hypertensive rat. AB - KEY POINTS: Evidence indicates an association between hypertension and chronic systemic inflammation in both human hypertension and experimental animal models. Previous studies in the spontaneously hypertensive rat (SHR) support a role for leukotriene B4 (LTB4 ), a potent chemoattractant involved in the inflammatory response, but its mode of action is poorly understood. In the SHR, we observed an increase in T cells and macrophages in the brainstem; in addition, gene expression profiling data showed that LTB4 production, degradation and downstream signalling in the brainstem of the SHR are dynamically regulated during hypertension. When LTB4 receptor 1 (BLT1) receptors were blocked with CP-105,696, arterial pressure was reduced in the SHR compared to the normotensive control and this reduction was associated with a significant decrease in systolic blood pressure (BP) indicators. These data provide new evidence for the role of LTB4 as an important neuro-immune pathway in the development of hypertension and therefore may serve as a novel therapeutic target for the treatment of neurogenic hypertension. ABSTRACT: Accumulating evidence indicates an association between hypertension and chronic systemic inflammation in both human hypertension and experimental animal models. Previous studies in the spontaneously hypertensive rat (SHR) support a role for leukotriene B4 (LTB4 ), a potent chemoattractant involved in the inflammatory response. However, the mechanism for LTB4 -mediated inflammation in hypertension is poorly understood. Here we report in the SHR, increased brainstem infiltration of T cells and macrophages plus gene expression profiling data showing that LTB4 production, degradation and downstream signalling in the brainstem of the SHR are dynamically regulated during hypertension. Chronic blockade of the LTB4 receptor 1 (BLT1) receptor with CP 105,696, reduced arterial pressure in the SHR compared to the normotensive control and this reduction was associated with a significant decrease in low and high frequency spectra of systolic blood pressure, and an increase in spontaneous baroreceptor reflex gain (sBRG). These data provide new evidence for the role of LTB4 as an important neuro-immune pathway in the development of hypertension and therefore may serve as a novel therapeutic target for the treatment of neurogenic hypertension. PMID- 27230969 TI - Immobilization of polyoxometalates in crystalline solids for highly efficient heterogeneous catalysis. AB - Polyoxometalates (POMs) are a unique class of molecular metal-oxygen clusters with attractive architecture and tunable properties. Due to their strong acidity, redox chemistry, photoactivity, charge distribution and multielectron transformation, POMs have been used as efficient catalysts in a variety of chemical reactions. To meet the requirement of sustainable chemistry, great effort has been focused on immobilization of the active POMs on different solid supports to realize heterogeneous catalysis. This short review summarizes the recent progress on immobilization of POM moieties in crystalline solids with defined crystal structures, including organic-inorganic hybrid materials, POM based inorganic crystalline solids and POM-encapsulated metal-organic frameworks (POM@MOFs), and their catalytic properties in oxidation, hydrolysis, cyanosilylation, photocatalysis and electrocatalysis. As illustrated in the text, these crystalline solids exhibit interesting catalytic properties, such as high activity, stability and selectivity, and simple recovery and easy recycling, which are much superior to those of the corresponding constituent species in most cases. PMID- 27230968 TI - Predictors of Functional Outcome After Subdural Hematoma: A Prospective Study. AB - BACKGROUND: Although the incidence of subdural hematoma (SDH) has increased in the US in the last decade, limited prospective data exist examining risk factors for poor outcome. METHODS: A prospective, observational study of consecutive SDH patients was conducted from 7/2008 to 11/2011. Baseline clinical data, hospital and surgical course, complications, and imaging data were compared between those with good versus poor 3-month outcomes (modified Rankin Scores [mRS] 0-3 vs. 4 6). A multivariable logistic regression model was constructed to identify independent predictors of poor outcome. RESULTS: 116 SDH patients (18 acute, 56 mixed acute/subacute/chronic, 42 subacute/chronic) were included. At 3 months, 61 (53 %) patients had good outcomes (mRS 0-3) while 55 (47 %) were severely disabled or dead (mRS 4-6). Of those who underwent surgical evacuation, 54/94 (57 %) had good outcomes compared to 7/22 (32 %) who did not (p = 0.030). Patients with mixed acuity or subacute/chronic SDH had significantly better 3-month mRS with surgery (median mRS 1 versus 5 without surgery, p = 0.002) compared to those with only acute SDH (p = 0.494). In multivariable analysis, premorbid mRS, age, admission Glasgow Coma Score, history of smoking, and fever were independent predictors of poor 3-month outcome (all p < 0.05; area under the curve 0.90), while SDH evacuation tended to improve outcomes (adjusted OR 3.90, 95 % CI 0.96 18.9, p = 0.057). CONCLUSIONS: Nearly 50 % of SDH patients were dead or moderate severely disabled at 3 months. Older age, poor baseline, poor admission neurological status, history of smoking, and fever during hospitalization predicted poor outcomes, while surgical evacuation was associated with improved outcomes among those with mixed acuity or chronic/subacute SDH. PMID- 27230971 TI - Evidence-based (S3) guideline on (anogenital) lichen sclerosus. JEADV. 2015; 29(10):e1-e43. PMID- 27230970 TI - Radiological-pathological correlation of diffusion tensor and magnetization transfer imaging in a closed head traumatic brain injury model. AB - OBJECTIVE: Metrics of diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI) can detect diffuse axonal injury in traumatic brain injury (TBI). The relationship between the changes in these imaging measures and the underlying pathologies is still relatively unknown. This study investigated the radiological pathological correlation between these imaging techniques and immunohistochemistry using a closed head rat model of TBI. METHODS: TBI was performed on female rats followed longitudinally by magnetic resonance imaging (MRI) out to 30 days postinjury, with a subset of animals selected for histopathological analyses. A MRI-based finite element analysis was generated to characterize the pattern of the mechanical insult and estimate the extent of brain injury to direct the pathological correlation with imaging findings. RESULTS: DTI axial diffusivity and fractional anisotropy (FA) were sensitive to axonal integrity, whereas radial diffusivity showed significant correlation to the myelin compactness. FA was correlated with astrogliosis in the gray matter, whereas mean diffusivity was correlated with increased cellularity. Secondary inflammatory responses also partly affected the changes of these DTI metrics. The magnetization transfer ratio (MTR) at 3.5ppm demonstrated a strong correlation with both axon and myelin integrity. Decrease in MTR at 20ppm correlated with the extent of astrogliosis in both gray and white matter. INTERPRETATION: Although conventional T2-weighted MRI did not detect abnormalities following TBI, DTI and MTI afforded complementary insight into the underlying pathologies reflecting varying injury states over time, and thus may substitute for histology to reveal diffusive axonal injury pathologies in vivo. This correlation of MRI and histology furthers understanding of the microscopic pathology underlying DTI and MTI changes in TBI. Ann Neurol 2016;79:907-920. PMID- 27230972 TI - A selected review of abstracts from the 20th Annual Meeting of the Society for Neuro-Oncology (SNO). AB - 20th Annual Meeting of the Society for Neuro-Oncology, San Antonio, TX, USA, 18 22 November 2015 The Society for Neuro-Oncology is the largest neuro-oncology meeting in the USA that meets annually and provides a multiday venue that showcases new brain cancer clinical trial results and basic research primarily pertaining to gliomas. The Society for Neuro-Oncology 2015 meeting comprising one education day, 2 days of premeetings and 3 days of presentation, over 200 oral presentations and 900 abstracts provides an overview of contemporary neuro oncology that includes metastatic disease of the central nervous system as well as primary brain tumors. This review attempts to highlight select abstracts presented at this year's meeting in a short summary that provides a synopsis of a large and multifaceted meeting. PMID- 27230973 TI - Sox2: regulation of expression and contribution to brain tumors. AB - Tumors of the CNS are composed of a complex mixture of neoplastic cells, in addition to vascular, inflammatory and stromal components. Similar to most other tumors, brain tumors contain a heterogeneous population of cells that are found at different stages of differentiation. The cancer stem cell hypothesis suggests that all tumors are composed of subpopulation of cells with stem-like properties, which are capable of self-renewal, display resistance to therapy and lead to tumor recurrence. One of the most important transcription factors that regulate cancer stem cell properties is SOX2. In this review, we focus on SOX2 and the complex network of signaling molecules and transcription factors that regulate its expression and function in brain tumor initiating cells. We also highlight important findings in the literature about the role of SOX2 in glioblastoma and medulloblastoma, where it has been more extensively studied. PMID- 27230975 TI - Acute hemolysis in a patient with a newly diagnosed glioblastoma. AB - We describe a 62-year-old of Egyptian origin who presented with sudden, severe and symptomatic anemia requiring hospitalization shortly after beginning concurrent radiation and temozolomide for his newly diagnosed glioblastoma. He had also recently been started on steroids, anticonvulsants and Pneumocystis jirovecii prophylaxis. He was ultimately diagnosed with G6PD deficiency with an acute hemolytic anemia precipitated by dapsone. Screening for G6PD deficiency should be considered in high-risk patient populations where P. jirovecii prophylaxis is planned. PMID- 27230977 TI - Interaction of a Transapical Miniaturized Ventricular Assist Device With the Left Ventricle: Hemodynamic Evaluation and Visualization in an Isolated Heart Setup. AB - New left ventricular assist devices (LVADs) offer both important advantages and potential hazards. VAD development requires better and expeditious ways to identify these advantages and hazards. We validated in an isolated working heart the hemodynamic performance of an intraventricular LVAD and investigated how its outflow cannula interacted with the aortic valve. Hearts from six pigs were explanted and connected to an isolated working heart setup. A miniaturized LVAD was implanted within the left ventricle (tMVAD, HeartWare Inc., Miami Lakes, FL, USA). In four experiments blood was used to investigate hemodynamics under various loading conditions. In two experiments crystalloid perfusate was used, allowing visualization of the outflow cannula within the aortic valve. In all hearts the transapical miniaturized ventricular assist device (tMVAD) implantation was successful. In the blood experiments hemodynamics similar to those observed clinically were achieved. Pump speeds ranged from 9 to 22 krpm with a maximum of 7.6 L/min against a pressure difference between ventricle and aorta of ~50 mm Hg. With crystalloid perfusate, central positioning of the outflow cannula in the aortic root was observed during full and partial support. With decreasing aortic pressures the cannula tended to drift toward the aortic root wall. The tMVAD could unload the ventricle similarly to LVADs under conventional cannulation. Aortic pressure influenced central positioning of the outflow cannula in the aortic root. The isolated heart is a simple, accessible evaluation platform unaffected by complex reactions within a whole, living animal. This platform allowed detection and visualization of potential hazards. PMID- 27230978 TI - New hypothesis on pontine-frontal eye field connectivity in Kleine-Levin syndrome. AB - Previous studies have indicated involvement of the thalamus and the pons in Kleine-Levin syndrome. In the present study, functional connectivity of the thalamus and the pons was investigated in asymptomatic patients with Kleine-Levin syndrome and healthy controls. Twelve patients and 14 healthy controls were investigated by functional magnetic resonance imaging during rest. Resting state images were analysed using seed regions of interest in the thalamus and the pons. The results showed significantly lower functional connectivity between the pons and the frontal eye field in persons with Kleine-Levin syndrome compared with healthy controls. There were no connectivity differences involving the thalamus. Based on these findings, a relation is proposed between the sleep disorder Kleine Levin syndrome and cerebral control of eye movements, which in turn is related to visual attention and working memory. This hypothesis has to be tested in future studies of oculomotor control in Kleine-Levin syndrome. PMID- 27230974 TI - Anaplastic astrocytoma. AB - Anaplastic astrocytoma (AA) is a diffusely infiltrating, malignant, astrocytic, primary brain tumor. AA is currently defined by histology although future classification schemes will include molecular alterations. AA can be separated into subgroups, which share similar molecular profiles, age at diagnosis and median survival, based on 1p/19q co-deletion status and IDH mutation status. AA with co-deletion of chromosomes 1p and 19q and IDH mutation have the best prognosis. AA with IDH mutation and no 1p/19q co-deletion have intermediate prognosis and AA with wild-type IDH have the worst prognosis and share many molecular alterations with glioblastoma. Treatment of noncodeleted AA based on preliminary results from the CATNON clinical trial consists of maximal safe resection followed by radiotherapy with post-radiotherapy temozolomide (TMZ) chemotherapy. The role of concurrent TMZ and whether IDH1 subgroups benefit from TMZ is currently being evaluated in the recently completed randomized, prospective Phase III clinical trial, CATNON. PMID- 27230979 TI - Combination Therapy of Simeprevir and Sofosbuvir in Recurrent HCV Genotype 4 After Liver Retransplantation: Case Report. AB - BACKGROUND: The treatment of hepatitis C virus (HCV) infection is evolving rapidly. Many studies have been completed during the last 2 years, with more studies still in progress. The management of recurring HCV infection following liver organ transplantation remains very challenging, especially for HCV genotype 4 (GT-4). More research is needed in this area. CASE REPORT: We report on a patient with a recurring HCV infection and fibrosing cholestatic hepatitis following liver retransplantation, who was successfully treated with a combination therapy of simeprevir and sofosbuvir without interferon/ribavirin. As far as we know, this is the first reported case of this kind. CONCLUSIONS: This information may be of importance and inform future management of patients with recurrent HCV infections following liver transplantation. PMID- 27230980 TI - Expression of metallothioneins I and II related to oxidative stress in the liver of aluminium-treated rats. AB - Hepatotoxicity, induced by aluminium chloride (AlCl3), has been well studied but there are no reports about liver metallothionein (MT) genes induction. Therefore, it is of interest to establish the mechanism involving the relation between MT gene expression levels and the oxidative stress status in hepatic cells of aluminium-treated rats. Aluminium (Al) was administered to rats in their drinking water at a dose of 50 mg/kg body weight for three weeks. AlCl3 provoked hepatotoxicity objectified by an increase in malondialdehyde (MDA), hydrogen peroxide (H2O2), advanced oxidation protein products (AOPP), protein carbonyls (PCO) and a decrease in reduced glutathione (GSH), non-protein thiols (NPSH) and vitamin C. CAT and Glutathione peroxidase (GPx) activities were decreased while Mn-SOD gene expression, total Metallothionein content and MT I and MT II genes induction were increased. There are changes in plasma of some trace elements, albumin levels, transaminases, LDH and ALP activities. All these changes were supported by histopathological observations. PMID- 27230981 TI - Microfluidic EDGE emulsification: the importance of interface interactions on droplet formation and pressure stability. AB - The fact that interactions of components with interfaces can influence processes is well-known; e.g. deposit accumulation on heat exchangers and membrane fouling lead to additional resistances against heat and mass transfer, respectively. In microfluidic emulsification, the situation is even more complex. Component accumulation at the liquid/liquid interface is necessary for emulsion stability, while undesired at the solid/liquid interface where it may change wettability. For successful emulsification both aspects need to be controlled, and that is investigated in this paper for o/w emulsification with microfluidic EDGE devices. These devices were characterised previously, and can be used to detect small wettability changes through e.g. the pressure stability of the device. We used various oil/emulsifier combinations (alkanes, vegetable oil, surfactants and proteins) and related droplet size and operational pressure stability to component interactions with the solid surface and liquid interface. Surfactants with a strong interaction with glass always favour emulsification, while surfactants that have week interactions with the surface can be replaced by vegetable oil that interacts strongly with glass, resulting in loss of emulsification. Our findings clearly show that an appropriate combination of construction material and emulsion components is needed to achieve successful emulsification in microfluidic EDGE devices. PMID- 27230982 TI - Same-Sex Sexuality and Educational Attainment: The Pathway to College. AB - Research finds lower levels of academic performance among sexual minority high school students, but some studies suggest sexual minorities have higher levels of educational attainment in adulthood. To further our understanding of how and why sexual orientation is associated with educational success, this study turns attention to the pathways to college completion, examining points along educational trajectories in which sexual minorities fall behind or surpass their heterosexual peers. Using data from the National Longitudinal Study of Adolescent to Adult Health, we find that sexual minority women are less likely than women with no same-sex sexuality to complete college, in part due to their high school performance and transition into college. Men who experience same-sex sexuality only in adolescence struggle in high school, but men who experience same-sex sexuality for the first time in adulthood are more likely to earn a college degree than men who do not experience same-sex sexuality. PMID- 27230983 TI - Elucidation of the mechanism of suppressed steroidogenesis during androgen deprivation therapy of prostate cancer patients using a mouse model. AB - Androgen deprivation therapy (ADT) is the standard medical approach to the management of prostate cancer. Patients switched from a GnRH antagonist to a GnRH agonist, did not experience a testosterone surge in spite of the occurrence of luteinizing hormone (LH) surge in our protocol of clinical study. To clarify this observation, male mice pre-treated with two different doses of the GnRH antagonist degarelix for 28 days were further administered the GnRH agonist leuprolide or chorionic gonadotropin, and testosterone production of the mice was studied. Serum LH and testosterone levels, the size of Leydig cells, and expression level of steroidogenesis-related genes in the testis were analyzed. Treatment of mice with a high dose of degarelix (0.1 MUg/mouse; HDG), but not a low dose (0.05 MUg/mouse; LDG), for 28 days reproduced declined steroidogenesis observed in prostate cancer patients during ADT switched from a GnRH antagonist to a GnRH agonist. The size of the Leydig cells in the HDG mice was not significantly different from that in naive mice. Although expression levels of StAR, P450scc, and 17beta HSD increased significantly in the LDH testis, those in the HDG testis did not change. Treatment of mice with a high dose of degarelix for 28 days reproduced the decline in steroidogenesis observed in prostate cancer patients during ADT. In this animal model, we demonstrated that initial ADT may inhibit the ability of Leydig cells to produce testosterone by suppressing the expression of genes involved in steroidogenesis, such as StAR, P450scc, and 17betaHSD. PMID- 27230985 TI - Sorption of 3,3',4,4'-tetrachlorobiphenyl by microplastics: A case study of polypropylene. AB - Though plastics show good chemical inertness, they could sorb polychlorinated biphenyls (PCBs) and other toxic pollutants from the surrounding environment. Thus, ingestion of microplastics by marine organisms potentially enhances the transport and bioavailability of toxic chemicals. However, there is lack of studies on the sorption capacity, mechanism and factors affecting the sorption behavior. Here, sorption of PCBs by microplastics in the simulated seawater was studied using the batch oscillation equilibration technique, in which polypropylene (PP) and 3,3',4,4'-tetrachlorobiphenyl (PCB77) acted as model plastic and PCB, respectively. Factors including particle size, temperature and solution environment were investigated. Results showed that, equilibrium sorption time is about 8h and sorption capacity increase with decreasing particle size and temperature. Different sorption capacity in three solution environments was observed. Equilibrium data in three solution environments fitted very well to the Langmuir sorption model, indicating chemical sorption is the predominant mechanism. PMID- 27230986 TI - Excess seawater nutrients, enlarged algal symbiont densities and bleaching sensitive reef locations: 1. Identifying thresholds of concern for the Great Barrier Reef, Australia. AB - Here, I contribute new insight into why excess seawater nutrients are an increasingly identified feature at reef locations that have low resistance to thermal stress. Specifically, I link this unfavourable synergism to the development of enlarged (suboptimal) zooxanthellae densities that paradoxically limit the capacity of the host coral to build tissue energy reserves needed to combat periods of stress. I explain how both theoretical predictions and field observations support the existence of species-specific 'optimal' zooxanthellae densities ~1.0-3.0*106 cellscm-2. For the central Great Barrier Reef (GBR), excess seawater nutrients that permit enlarged zooxanthellae densities beyond this optimum range are linked with seawater chlorophyll a>0.45MUg.L-1; a eutrophication threshold previously shown to correlate with a significant loss in species for hard corals and phototrophic octocorals on the central GBR, and herein shown to correlate with enhanced bleaching sensitivity during the 1998 and 2002 mass bleaching events. PMID- 27230987 TI - Monsoonal variations in atmospheric surfactants at different coastal areas of the Malaysian Peninsula. AB - This study determined the effect of monsoonal changes on the composition of atmospheric surfactants in coastal areas. The composition of anions (SO4(2-), NO3(-), Cl(-), F(-)) and the major elements (Ca, K, Mg, Na) in aerosols were used to determine the possible sources of surfactants. Surfactant compositions were determined using a colorimetric method as methylene blue active substances (MBAS) and disulphine blue active substances (DBAS). The anion and major element compositions of the aerosol samples were determined by ion chromatography (IC) and inductively coupled plasma mass spectrometry (ICP-MS), respectively. The results indicated that the concentrations of surfactant in aerosols were dominated by MBAS (34-326pmolm(-3)). Monsoonal changes were found to significantly affect the concentration of surfactants. Using principal component analysis-multiple linear regressions (PCA-MLR), major possible sources for surfactants in the aerosols were motor vehicle emissions, secondary aerosol and the combustion of biomass along with marine aerosol. PMID- 27230988 TI - Comorbidity Burden in Trial-Aligned Patients with Established Gout in Germany, UK, US, and France: a Retrospective Analysis. AB - INTRODUCTION: Patients with gout have numerous comorbidities. We aimed to estimate the prevalence and incidence rates of renal and cardiovascular morbidities in trial-aligned patients with established gout in Germany (DE), the United Kingdom (UK), the United States (US), and France (FR). METHODS: This longitudinal cohort study used retrospective data from IMS Disease AnalyzerTM (DE, FR), Clinical Practice Research Datalink-Hospital Episode Statistics (UK), and IMS' PharMetrics Plus database linked with outpatient laboratory results (US). Included patients were >=18 years at index date (January 1, 2010; all dates +1 year for FR), with continuous enrollment during the pre-index year, had "prevalent established gout" determined by data in the pre-index year, and >=1 documented visit after index date; additional inclusion/exclusion criteria were aligned with recent gout clinical trials. Look-back for comorbidity prevalence extended to January 1, 2003 (US: January 1, 2009). Follow-up for incidence extended from index date to at most March 26, 2013 (FR: May 31, 2014). Events of interest were identified by diagnostic codes and/or laboratory data. RESULTS: The trial-aligned cohorts included 35,118 (DE), 24,607 (UK), 121,591 (US), and 17,338 (FR) patients. Among renal conditions, baseline diagnosis of chronic kidney disease/renal failure was most prevalent in the UK followed by DE; abnormal serum creatinine was most prevalent in the UK. Hypertension was the most prevalent cardiovascular diagnosis in all countries, followed by ischemic heart disease (IHD) and myocardial infarction. Incidence rates (per 100 patient-years) for new/worsening renal impairment ranged from 1.67 (DE) to 4.34 (US) and for nephrolithiasis diagnosis from 0.31 (FR) to 3.79 (US). The incidence rates for hypertension diagnosis were highest among cardiovascular-related events, ranging from 3.23 (UK) to 20.27 (US), followed by IHD. CONCLUSIONS: Patients with established gout such as those included in gout trials have a high burden of established morbidity and new diagnoses of morbid events. Consideration of comorbidities, which greatly exacerbate disease burden, is important in gout management. FUNDING: AstraZeneca. PMID- 27230989 TI - Changes in thalamo-frontal interaction under different levels of anesthesia in rats. AB - Anesthesia is thought to be mediated by inhibiting the integration of information between different areas of the brain. Long-range thalamo-cortical interaction plays a critical role in inducing anesthesia-related unconsciousness. However, it remains unclear how this interaction change according to anesthetic depth. In this study, we aimed to investigate how different levels of anesthesia affect thalamo-frontal interactions. Prior to the experiment, electrodes were implanted to record local field potentials (LFPs). Isoflurane (ISO) was administered and LFPs were measured in rats from four different brain areas (left frontal, right frontal, left thalamus and right thalamus) at four different anesthesia levels: awake, deep (ISO 2.5vol%), light (ISO 1vol%) and recovery. Spectral granger causality (Spectral-GC) were calculated at the measured areas in accordance with anesthetic levels. Anesthesia led to a decrease in connectivity in the thalamo frontal direction and an increase in connectivity in the frontal-thalamic direction. The changes in thalamo-frontal functional connectivity were prominent during deep anesthesia at high frequency bands. The connection strengths between the thalamus and the frontal area changed depending on the depth of anesthesia. The relationships between anesthetic levels and thalamo-frontal activity may shed light on the neural mechanism by which different levels of anesthesia act. PMID- 27230984 TI - Acute kidney injury in the perioperative period and in intensive care units (excluding renal replacement therapies). AB - Acute kidney injury (AKI) is a syndrome that has progressed a great deal over the last 20 years. The decrease in urine output and the increase in classical renal biomarkers, such as blood urea nitrogen and serum creatinine, have largely been used as surrogate markers for decreased glomerular filtration rate (GFR), which defines AKI. However, using such markers of GFR as criteria for diagnosing AKI has several limits including the difficult diagnosis of non-organic AKI, also called "functional renal insufficiency" or "pre-renal insufficiency". This situation is characterized by an oliguria and an increase in creatininemia as a consequence of a reduction in renal blood flow related to systemic haemodynamic abnormalities. In this situation, "renal insufficiency" seems rather inappropriate as kidney function is not impaired. On the contrary, the kidney delivers an appropriate response aiming to recover optimal systemic physiological haemodynamic conditions. Considering the kidney as insufficient is erroneous because this suggests that it does not work correctly, whereas the opposite is occurring, because the kidney is healthy even in a threatening situation. With current definitions of AKI, normalization of volaemia is needed before defining AKI in order to avoid this pitfall. PMID- 27230991 TI - Comparison of males versus females with culture-confirmed early Lyme disease at presentation and at 11-20 years after diagnosis. AB - BACKGROUND: Lyme disease is the most common vector-borne infection in the United States with 300,000 estimated cases per year. OBJECTIVE: The purpose of this study was to compare the presenting clinical features and long-term outcome of males versus females with culture-confirmed early Lyme disease. METHODS: 174 males and 109 females with culture-confirmed erythema migrans were entered into a prospective study with follow-up visits scheduled at six months, 12 months and annually thereafter for up to 20 years. RESULTS: Males and females with early Lyme disease had a similar likelihood of having multiple erythema migrans skin lesions and had a similar number of additional subjective symptoms, such as fatigue, at study entry. Among the 71 males and 57 females able to be followed up for 11-20 years, there were no significant differences in baseline symptoms, rate of seroreactivity to Borrelia burgdorferi, or in frequency of post-treatment symptoms. Females, however, were significantly more likely than males to return for follow-up visits (P = 0.0003). CONCLUSION: Males and females with culture confirmed early Lyme disease had similar clinical features, rates of seropositivity, and long-term outcomes. PMID- 27230990 TI - A systematic review of commercial weight loss programmes' effect on glycemic outcomes among overweight and obese adults with and without type 2 diabetes mellitus. AB - OBJECTIVE: We examined the glycemic benefits of commercial weight loss programmes as compared with control/education or counselling among overweight and obese adults with and without type 2 diabetes mellitus (T2DM). METHODS: We searched MEDLINE, Cochrane Database of Systematic Reviews, and references cited by individual programmes. We included randomized controlled trials of >=12 weeks duration. Two reviewers extracted information on study design, population characteristics, interventions, and mean changes in haemoglobin A1c and glucose. RESULTS: We included 18 randomized controlled trials. Few trials occurred among individuals with T2DM. In this population, Jenny Craig reduced A1c at least 0.4% more than counselling at 12 months, Nutrisystem significantly reduced A1c 0.3% more than counselling at 6 months, and OPTIFAST reduced A1c 0.3% more than counselling at 6 months. Among individuals without T2DM, few studies evaluated glycemic outcomes, and when reported, most did not show substantial reductions. DISCUSSION: Few trials have examined whether commercial weight loss programmes result in glycemic benefits for their participants, particularly among overweight and obese individuals without T2DM. Jenny Craig, Nutrisystem and OPTIFAST show promising glycemic lowering benefits for patients with T2DM, although additional studies are needed to confirm these conclusions. (c) 2016 World Obesity. PMID- 27230992 TI - MAGE-A1-6 expression in patients with head and neck squamous cell carcinoma: impact on clinical patterns and oncologic outcomes. AB - BACKGROUND: Various subtypes of melanoma-associated antigens (MAGEs) are expressed in the tumor tissues of patients with head and neck squamous cell carcinoma (HNSCC). However, little data are currently available on how the gene expression of MAGEs impacts clinical patterns and oncologic outcomes. We have therefore evaluated the expression of MAGE-A1-6 (A1-6) subtypes in tumor tissues of patients with HNSCC and the clinical impact of this expression. METHODS: This was a retrospective review of 53 patients with histologically proven HNSCC of the oral cavity, oropharynx, larynx, or hypopharynx who underwent both treatment and analysis by reverse transcription (RT)-PCR assay with a common primer to identify the expression of MAGE-A1-6 subtypes in the tumor tissue. The clinicopathologic factors and oncologic outcomes of these patients and the correlations of both to MAGE-A1-6 gene expression were analyzed. RESULTS: MAGE-A1-6 subtypes were expressed in the tumor tissues of 37 patients (69.8 %). Patient age of >=65 years [p = 0.031, hazard ratio (HR) 4.866] and advanced American Joint Committee on Cancer stage (p = 0.035, HR 4.291) were independent risk factors for expression of MAGE-A1-6 subtypes. Patients with MAGE-A1-6 expression had lower disease-free survival (p = 0.029), disease-specific survival (p = 0.070), and overall survival (p = 0.017) rates. Overall survival rate was independently associated to chemotherapy (p = 0.011, HR 2.859), while no surgery (p = 0.050, HR 2.400) and MAGE-A1-6 expression (p = 0.050, HR 2.527) showed borderline significance. CONCLUSION: In our patient group the expression of MAGE-A1-6 subtypes in tumor tissues of patients with HNSCC was correlated with advanced clinical stage of cancer and poor oncologic outcomes. We suggest that gene expression of MAGE-A1-6 subtypes may be considered to be a predictive factor to determine patient treatment or follow-up strategy. PMID- 27230994 TI - Symptomatic knee osteonecrosis in patients with systemic lupus erythematosus: a case-control study. AB - To explore the associated risk factors of symptomatic knee osteonecrosis (KON) in patients with systemic lupus erythematosus (SLE), we conducted a retrospective case-control study to compare the clinical and laboratory features between SLE patients with and without symptomatic KON matched by age and gender. Univariate and multivariate regression analyses were used to evaluate possible associated risk factors. Twenty (one male, nineteen females) out of 3941 lupus patients were identified as symptomatic KON, which was confirmed by magnetic resonance imaging. The mean age at KON onset was 34.4 (range 12-67) years, and the median course of lupus at KON onset was 72.5 (range 8-123) months. Univariate and multivariate analyses identified that the prevalence of cutaneous vasculitis (OR 5.23; 95 % CI 1.11-24.70), hyperfibrinogenemia (OR 4.75; 95 % CI 1.08-20.85), and elevated IgG levels (OR 6.05; 95 % CI 1.58-23.16) were statistically higher in KON group, and hydroxychloroquine (HCQ) usage was statistically lower in KON group (OR 0.27; 95 % CI 0.07-0.97). Glucocorticoid usage, in terms of maximal dose, duration of treatment, and the percentage of receiving methylprednisolone pulse therapy, did not show statistical difference between the two groups (p > 0.05). Symptomatic KON is a relatively rare complication of SLE. Cutaneous vasculitis, hyperfibrinogenemia, and elevated IgG levels are possible risk factors, whereas HCQ may provide a protective effect. Our results suggest that lupus activity as well as hypercoagulation status may play a role in the pathogenesis of KON in lupus. PMID- 27230995 TI - Postoperative Medical Management of Crohn's Disease: Prevention and Surveillance Strategies. PMID- 27230993 TI - Exploratory Studies With BT-11: A Proposed Orally Active Therapeutic for Crohn's Disease. AB - Lanthionine synthetase cyclase-like receptor 2 (LANCL2) is a novel therapeutic target for Crohn's disease (CD). BT-11 is a small molecule that binds LANCL2, is orally active, and has demonstrated therapeutic efficacy in 3 validated mouse models of colitis at doses as low as 8 mg/kg/d. Exploratory experiments evaluated BT-11 in male Harlan Sprague Dawley rats with a single oral dose of 500 mg/kg and 80 mg/kg/d for 14 days (n = 10 rats dosed/group). Treated and control rats were observed for behavioral detriments, and blood and tissues were collected for clinical pathology and histopathological examination. A functional observational battery demonstrated no differences between treated and control groups over multiple times of observation for quantal, categorical, and continuous end points, including posture, in cage activity, approach, response to touch, weight, grip strength, body temperature, and time on a rotarod. Histopathological examination of the brain, kidney, liver, adrenal gland, testes, stomach, small and large intestines, duodenum, pancreas, heart, lungs, spleen, thymus, and rib found no significant differences between the groups. Plasma enzymes associated with liver function were transiently elevated 2 to 4 days after the 500 mg/kg single dose but returned to normal values by 8 days and were not observed at any time in rats given 80 mg/kg/d for 14 days. One hour after oral administration of a single dose of 80 mg/kg, BT-11 had a maximal concentration of 21 ng/mL; the half-life was 3 hours. These experimental results demonstrated that BT-11 is well tolerated in rats, and, with further testing, may hold promise as an orally active therapeutic for CD. PMID- 27230996 TI - Routine Cyst Fluid Cytology Is Not Indicated in the Evaluation of Pancreatic Cystic Lesions. AB - BACKGROUND: The work-up of cystic lesions of the pancreas often involves endoscopic ultrasound (EUS) with fine needle aspiration (FNA). In addition to CEA and amylase measurement, fluid is routinely sent for cytologic examination. We evaluated the utility of cytologic findings in clinical decision-making. MATERIALS AND METHODS: Records of patients who underwent EUS-guided pancreatic cyst aspiration were reviewed. Findings from axial imaging and EUS were compared to cyst fluid cytology as well as fluid amylase and CEA. All results were then compared to final diagnosis, determined by clinical analysis for those patients not resected, and surgical pathology report for those who underwent resection. RESULTS: A total of 167 patients were reviewed. Of 48 patients with suspicious findings on imaging, cytology yielded diagnostic information in 89.6 % of cases (43 patients). However, in the 119 patients where no suspicious components were revealed on imaging, fluid cytology yielded no significant diagnostic results in any case. In all cases where mucin was noted on cytologic review, thick fluid was also seen at the time of aspiration. DISCUSSION: In our cohort of patients with cystic pancreatic lesions, cytologic analysis of pancreatic cyst fluid yielded no diagnostic benefit over radiologic findings alone. In such cases where fluid is to be aspirated, specimens that would otherwise be sent for cytologic evaluation would be better served for other purposes, such as molecular analysis or banking for future research. PMID- 27230997 TI - Biodegradable Polymeric Nanoparticles as the Delivery Carrier for Drug. AB - BACKGROUND: Drug research and development has entered into the new epoch of innovation formulation, and the drug delivery system has been in the forefront of pharmaceutical innovation. Nanotechnology is widely used in fiber and textiles, electronics, space, agriculture, forensic science and medical therapeutics. It increasingly plays a significant role in drug delivery system. Compared with traditional delivery system, the nanoparticle drug delivery system has lots of merits, such as the high drug loading ability, the excellent biocompatibility, low toxicity, controlled and targeted drug release. METHODS: We undertook a structured research of biodegradable polymeric nanoparticles used as delivery carrier for drug using a focused review question and inclusion/exclusion criteria. We have searched the bibliographic databases for peerreviewed research literature. The outstanding characteristics of the screened papers were described respectively, and a systematic content analysis methodology was used to analysis the findings. RESULTS: Seventy-three papers were included in the review, the majority defined leadership and governance approaches that had impacted upon the polymeric nanoparticles as the delivery carrier for drug in therapeutic applications and developments. Seven papers outlined the superiority characteristics of polymeric nanoparticles that applied in the field of vaccine. Forty-seven papers overviewed the application prospects of polymeric nanoparticles used as drug delivery carrier for cancer. These included current advances in research and clinical applications of polymeric nanoparticles. The review identified the drug delivery carrier of biodegradable polymeric nanoparticles, and we described the synthesis methods, applications and challenges of polymeric nanoparticles. CONCLUSION: The findings of this review identified that the biodegradable polymeric nanoparticles were used as delivery carrier for drug currently. It also indicates that the biodegradable polymeric nanoparticles play an important role in the drug delivery. PMID- 27230998 TI - Increasing compliance with low tidal volume ventilation in the ICU with two nudge based interventions: evaluation through intervention time-series analyses. AB - OBJECTIVES: Low tidal volume (TVe) ventilation improves outcomes for ventilated patients, and the majority of clinicians state they implement it. Unfortunately, most patients never receive low TVes. 'Nudges' influence decision-making with subtle cognitive mechanisms and are effective in many contexts. There have been few studies examining their impact on clinical decision-making. We investigated the impact of 2 interventions designed using principles from behavioural science on the deployment of low TVe ventilation in the intensive care unit (ICU). SETTING: University Hospitals Bristol, a tertiary, mixed medical and surgical ICU with 20 beds, admitting over 1300 patients per year. PARTICIPANTS: Data were collected from 2144 consecutive patients receiving controlled mechanical ventilation for more than 1 hour between October 2010 and September 2014. Patients on controlled mechanical ventilation for more than 20 hours were included in the final analysis. INTERVENTIONS: (1) Default ventilator settings were adjusted to comply with low TVe targets from the initiation of ventilation unless actively changed by a clinician. (2) A large dashboard was deployed displaying TVes in the format mL/kg ideal body weight (IBW) with alerts when TVes were excessive. PRIMARY OUTCOME MEASURE: TVe in mL/kg IBW. FINDINGS: TVe was significantly lower in the defaults group. In the dashboard intervention, TVe fell more quickly and by a greater amount after a TVe of 8 mL/kg IBW was breached when compared with controls. This effect improved in each subsequent year for 3 years. CONCLUSIONS: This study has demonstrated that adjustment of default ventilator settings and a dashboard with alerts for excessive TVe can significantly influence clinical decision-making. This offers a promising strategy to improve compliance with low TVe ventilation, and suggests that using insights from behavioural science has potential to improve the translation of evidence into practice. PMID- 27230999 TI - Bayesian spatiotemporal modelling for identifying unusual and unstable trends in mammography utilisation. AB - OBJECTIVES: To compare two Bayesian models capable of identifying unusual and unstable temporal patterns in spatiotemporal data. SETTING: Annual counts of mammography screening users from each statistical local area (SLA) in Brisbane, Australia, recorded between 1997 and 2008 inclusive. PRIMARY OUTCOME MEASURES: Mammography screening counts. RESULTS: The temporal trends of 91 SLAs (58%) were dissimilar from the overall common temporal trend. SLAs that followed the common temporal trend also tended to have stable temporal trends. SLAs with unstable temporal trends tended to be situated farther from the city and farther from mammography screening facilities. CONCLUSIONS: This paper demonstrates the usefulness of the two models in identifying unusual and unstable temporal trends, and the synergy obtained when both models are applied to the same data set. An analysis of these models has provided interesting insights into the temporal trends of mammography screening counts and has shown several possible avenues for further research, such as extending the models to allow for multiple common temporal trends and accounting for additional spatiotemporal heterogeneity. PMID- 27231001 TI - Retrospective hepatitis C seroprevalence screening in the antenatal setting should we be screening antenatal women? AB - OBJECTIVES: An unlinked anonymous seroprevalence study was conducted to estimate the prevalence of hepatitis C virus (HCV) infection in samples derived from antenatal clinic attendees at 2 East London Hospitals. An unexpectedly high HCV seroprevalence of 2.6% (1.2% viraemic) had been revealed during an unlinked study of the emergency department at 1 of these hospitals. DESIGN: 1000 stored residual samples were tested for HCV antibody (anti-HCV) and reactive samples were further tested for HCV RNA. The study was reviewed by the East Midland NRES ethics committee project ID 181154, approval number 15/WS/0125. RESULTS: The anti-HCV reactivity rate was 0.5% (5/1000) with 0.1% (1/1000) confirmed viraemic. Prevalence for the other blood-borne viruses was higher: 1% (10/1000) were hepatitis B surface antigen positive and 0.3% were HIV antigen/antibody positive (3/1000). There were no co-infections. CONCLUSIONS: More data to establish the prevalence of HCV in the antenatal population is needed. The addition of anti-HCV testing to the well-established antenatal screening programme provides a unique opportunity to impact on the health of pregnant women, their children, partners and future pregnancies in this new era of treatment for hepatitis C. PMID- 27231000 TI - Effectiveness of a biopsychosocial e-learning intervention on the clinical judgements of medical students and GP trainees regarding future risk of disability in patients with chronic lower back pain: study protocol for a randomised controlled trial. AB - INTRODUCTION: Chronic lower back pain (CLBP) is a major healthcare problem with wide ranging effects. It is a priority for appropriate management of CLBP to get individuals back to work as early as possible. Interventions that identify biopsychosocial barriers to recovery have been observed to lead to successfully reduced pain-related work absences and increased return to work for individuals with CLBP. Modern conceptualisations of pain adopt a biopsychosocial approach, such as the flags approach. Biopsychosocial perspectives have been applied to judgements about future adjustment, recovery from pain and risk of long-term disability; and provide a helpful model for understanding the importance of contextual interactions between psychosocial and biological variables in the experience of pain. Medical students and general practitioner (GP) trainees are important groups to target with education about biopsychosocial conceptualisations of pain and related clinical implications. AIM: The current study will compare the effects of an e-learning intervention that focuses on a biopsychosocial model of pain, on the clinical judgements of medical students and trainees. METHODS AND ANALYSIS: Medical student and GP trainee participants will be randomised to 1 of 2 study conditions: (1) a 20 min e-learning intervention focused on the fundamentals of the flags approach to clinical judgement-making regarding risk of future pain-related disability; compared with a (2) wait-list control group on judgement accuracy and weighting (ie, primary outcomes); flags approach knowledge, attitudes and beliefs towards pain, judgement speed and empathy (ie, secondary outcomes). Participants will be assessed at preintervention and postintervention. ETHICS AND DISSEMINATION: The study will be performed in agreement with the Declaration of Helsinki and is approved by the National University of Ireland Galway Research Ethics Committee. The results of the trial will be published according to the CONSORT statement and will be presented at conferences and reported in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN53670726; Pre-results. PMID- 27231002 TI - Efficacy and safety of acupuncture for chemotherapy-induced leucopoenia: protocol for a systematic review. AB - INTRODUCTION: Many cancer patients experience leucopoenia during chemotherapy. Granulocyte- colony-stimulating factor (G-CSF) is used to treat chemotherapy induced leucopoenia (CIL) but has various limitations. Clinical trials have indicated that acupuncture may prevent bone marrow suppression and increase leucocyte counts after chemotherapy. The objective of this review is to assess the efficacy and safety of acupuncture for treating CIL. METHODS AND ANALYSIS: This systematic review will electronically search the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Library, Medline, EMBASE, the China National Knowledge Infrastructure Database (CNKI), the Chinese Biomedical Literature Database (CBM), the Chinese Scientific Journal Database (VIP Database) and the Wanfang database from their inception to 1 January 2016. Other sources will also be searched including potential grey literature, conference proceedings and the reference lists of identified publications and existing systematic reviews. Two reviewers will independently search the databases, perform data extraction and assess the quality of studies. Data will be synthesised by either the fixed-effects or the random-effects model according to a heterogeneity test. White blood cell counts will be assessed as the primary outcome. Adverse effects, incidence of leucopoenia, quality of life and physical condition will be evaluated as secondary outcomes. RevMan V.5.3 will be employed for data analysis. The results will be expressed as risk ratios for dichotomous data and mean differences for continuous data. ETHICS AND DISSEMINATION: The protocol does not need ethics approval because individuals cannot be identified. The review will be reported in a peer-reviewed publication or at a relevant conference. TRIAL REGISTRATION NUMBER: CRD42015027594. PMID- 27231003 TI - Evaluating the effectiveness of exercise training on elderly patients who require haemodialysis: study protocol for a systematic review and meta-analysis. AB - INTRODUCTION: As the average age of haemodialysis patients rapidly increases around the world, the number of frail, elderly patients has increased. Frailty is well known to be an indicator of disability and a poor prognosis for haemodialysis patients. Exercise interventions have been safely and successfully implemented for middle-aged or younger patients undergoing haemodialysis. However, the benefits of exercise interventions on elderly patients undergoing haemodialysis remain controversial. The main objective of this study is to systematically review the effects of exercise training on the physical function, exercise capacity and quality of life of elderly patients undergoing haemodialysis, and to provide an update on the relevant evidence. METHODS AND ANALYSES: Published randomised controlled trials (RCTs) that assessed the effectiveness of exercise training on haemodialysis patients with respect to physical function, exercise tolerance and quality of life will be included. Bibliographic databases include MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, CINAHL, Web of Science, PsycINFO and PEDro. The risk of bias of the included RCTs will be assessed using the Cochrane Collaboration's tool and TESTEX. The primary outcome will be physical function and exercise tolerance. This review protocol is reported according to the PRISMA-P 2015 checklist. Statistical analysis will be performed using review manager software (RevMan V.5.3, Cochrane Collaboration, Oxford, England). ETHICS AND DISSEMINATION: Ethical approval is not required because this study does not include confidential personal data nor does it perform interventions on patients. This review is expected to inform readers on the effectiveness of exercise training in elderly patients undergoing haemodialysis. Findings will be presented at conferences and submitted to a peer reviewed journal for publication. PROSPERO REGISTRATION NUMBER: CRD42015020701. PMID- 27231004 TI - Using the Consumer Experience with Pharmacy Services Survey as a quality metric for ambulatory care pharmacies: older adults' perspectives. AB - OBJECTIVES: To describe older adults' perceptions of evaluating and comparing pharmacies based on the Consumer Experience with Pharmacy Services Survey (CEPSS), describe older adults' perceived importance of the CEPSS and its specific domains, and explore older adults' perceptions of the influence of specific CEPSS domains in choosing/switching pharmacies. DESIGN: Focus group methodology was combined with the administration of a questionnaire. The focus groups explored participants' perceived importance of the CEPSS and their perception of using the CEPSS to choose and/or switch pharmacies. Then, using the questionnaire, participants rated their perceived importance of each CEPSS domain in evaluating a pharmacy, and the likelihood of using CEPSS to switch pharmacies if their current pharmacy had low ratings. Descriptive and thematic analyses were done. SETTING: 6 semistructured focus groups were conducted in a private meeting room in a Mid-Western state in the USA. PARTICIPANTS: 60 English-speaking adults who were at least 65 years, and had filled a prescription at a retail pharmacy within 90 days. RESULTS: During the focus groups, the older adults perceived the CEPSS to have advantages and disadvantages in evaluating and comparing pharmacies. Older adults thought the CEPSS was important in choosing the best pharmacies and avoiding the worst pharmacies. The perceived influence of the CEPSS in switching pharmacies varied depending on the older adult's personal experience or trust of other consumers' experience. Questionnaire results showed that participants perceived health/medication-focused communication as very important or extremely important (n=47, 82.5%) in evaluating pharmacies and would be extremely likely (n=21, 36.8%) to switch pharmacies if their pharmacy had low ratings in this domain. CONCLUSIONS: The older adults in this study are interested in using patient experiences as a quality metric for avoiding the worst pharmacies. Pharmacists' communication about health and medicines is perceived important and likely to influence older adults' pharmacy selection. PMID- 27231005 TI - Feasibility of improving identification of familial hypercholesterolaemia in general practice: intervention development study. AB - OBJECTIVES: To assess the feasibility of improving identification of familial hypercholesterolaemia (FH) in primary care, and of collecting outcome measures to inform a future trial. DESIGN: Feasibility intervention study. SETTING: 6 general practices (GPs) in central England. PARTICIPANTS: 831 eligible patients with elevated cholesterol >7.5 mmol/L were identified, by search of electronic health records, for recruitment to the intervention. INTERVENTION: Educational session in practice; use of opportunistic computer reminders in consultations or universal postal invitation over 6 months to eligible patients invited to complete a family history questionnaire. Those fulfilling the Simon-Broome criteria for possible FH were invited for GP assessment and referred for specialist definitive diagnosis. OUTCOME MEASURES: Rates of recruitment of eligible patients, identification of patients with possible FH, referral to specialist care, diagnosis of confirmed FH in specialist care; and feasibility of collecting relevant outcome measures for a future trial. RESULTS: Of 173 general practices, 18 were interested in participating and 6 were recruited. From 831 eligible patients, 127 (15.3%) were recruited and completed family history questionnaires: 86 (10.7%) through postal invitation and 41 (4.9%) opportunistically. Among the 127 patients, 32 (25.6%) had a possible diagnosis of FH in primary care. Within 6 months of completing recruitment, 7 patients had had specialist assessment confirming 2 patients with definite FH (28.6%), and 5 patients with possible FH (71.4%). Potential trial outcome measures for lipid tests, statin prescribing and secondary causes of hypercholesterolaemia were extracted using automated data extraction from electronic records alone without recourse to other methods. CONCLUSIONS: The intervention is feasible to implement in GP, and facilitates recruitment of patients with raised cholesterol for targeted assessment and identification of FH. Extracting data directly from electronic records could be used to evaluate relevant outcome measures in a future trial. PMID- 27231006 TI - Analysis of the Mild strain of tomato yellow leaf curl virus, which overcomes Ty 2 gene-mediated resistance in tomato line H24. AB - In tomato line H24, an isolate of the Mild (Mld) strain of tomato yellow leaf curl virus (TYLCV-Mld [JR:Kis]) overcomes Ty-2 gene-mediated resistance and causes typical symptoms of tomato yellow leaf curl disease (TYLCD). No systemic infection with visible symptoms or accumulation of viral DNA in the upper leaves was observed in H24 challenged with another isolate, TYLCV-IL (TYLCV-IL [JR:Osaka]), confirming that H24 is resistant to the IL strain. To elucidate the genomic regions that cause the breakdown of the Ty-2 gene-mediated resistance, we constructed a series of chimeras by swapping genes between the two strains. A chimeric virus that had the overlapping C4/Rep region of the Mld strain in the context of the IL strain genome, caused severe TYLCD in H24 plants, suggesting that the overlapping C4/Rep region of the Mld strain is associated with the ability of this strain to overcome Ty-2 gene-mediated resistance. PMID- 27231007 TI - Characterisation of a novel enterobacteria phage, CAjan, isolated from rat faeces. AB - In this study, we describe the isolation and characterisation of the novel enterobacteria phage CAjan. This phage belongs to the order Caudovirales and the family Siphoviridae. The phage possesses a linear, double-stranded DNA genome consisting of 59,670 bp with a G+C content of 44.7 % and 91 predicted open reading frames (ORFs). Putative functions were assigned to 39 of the ORFs (37.4 %). The phage structural genes were furthermore functionally characterised by LC MS/MS. CAjan, together with Escherichia phage Seurat and Escherichia phage slur01, represent a novel and genetically distinct clade of Siphoviridae phages that could be considered to constitute a new phage genus. Despite limited sequence similarity, the phages in this group share a number of other common features, including genome structure and the presence of queuosine biosynthesis genes. PMID- 27231008 TI - Molecular detection of a novel totivirus from golden shiner (Notemigonus crysoleucas) baitfish in the USA. AB - During regulatory and routine surveillance sampling of apparently healthy baitfish from the state of Minnesota, a novel totivirus (tentatively named "golden shiner totivirus", GSTV) was detected in a homogenate of kidney and spleen of golden shiner (Notemigonus crysoleucas). The nearly complete genome is 7788 nt long with a complete 5' untranslated region (UTR) of 135 nt (1-135 nt position), complete open reading frames (ORFs) and a partial 3' UTR of 54 nt (7734-7788). The sequence is comprised of two ORFs (ORF1 and ORF2). The larger ORF1 encodes a 1659-aa polypeptide in frame +1 from nt position 136 to 5115 (4980 nt) with a start codon at position 136-138 and a stop codon at position 5113 5115. The ORF1 is 54 aa longer than the 1605-aa ORF1-encoded protein of a reference strain of infectious myonecrosis virus (IMNV), ID-EJ-12-1(AIC34743.1). The predicted ORF1 and ORF2 fusion protein sequence was NFQDGG. Hence, an overlapping region of 99 nt was observed, which is shorter than the 172-nt and 199-nt overlapping regions in Armigeres subalbatus totivirus (AsTV) and IMNV, respectively. GSTV formed a separate lineage based on phylogenetic analysis of ORF1-encoded major capsid protein (MCP) and ORF2-encoded RNA-dependent RNA polymerase (RdRp) sequences. Based on ORF1 MCP sequence analysis, GSTV was most closely related to IMNV, with maximum aa sequence identity of 26.42-27.86 %, followed by 26.59, 22.94 and 21.75 % for Drosophila totivirus (DTV), AsTV and Omono River virus (OMRV), respectively. Similar to ORF1, the ORF2 (RdRp) of GSTV formed a separate clade with maximum identity of 38.10 % and 38.50 % to IMNV and DTV, respectively. The virus identified here differs enough from its closest relative that it may represent a new genus in the family Totiviridae. The disease causing potential and management impact of this novel virus is unknown at this time. PMID- 27231009 TI - Is the optimal pH for membrane fusion in host cells by avian influenza viruses related to host range and pathogenicity? AB - Influenza viruses isolated from wild ducks do not replicate in chickens. This fact is not explained solely by the receptor specificity of the hemagglutinin (HA) from such viruses for target host cells. To investigate this restriction in host range, the fusion activities of HA molecules from duck and chicken influenza viruses were examined. Influenza viruses A/duck/Mongolia/54/2001 (H5N2) (Dk/MNG) and A/chicken/Ibaraki/1/2005 (H5N2) (Ck/IBR), which replicate only in their primary hosts, were used. The optimal pH for membrane fusion of Ck/IBR was 5.9, higher than that of Dk/MNG at 4.9. To assess the relationship between the optimal pH for fusion and the host range of avian influenza viruses, the optimal pH for fusion of 55 influenza virus strains isolated from ducks and chickens was examined. No correlation was found between the host range and optimal pH for membrane fusion by the viruses, and this finding applied also to the H5N1 highly pathogenic avian influenza viruses. The optimal pH for membrane fusion for avian influenza viruses was shown to not necessarily be correlated with their host range or pathogenicity in ducks and chickens. PMID- 27231011 TI - Occupational and Environmental Health Risks Associated with Informal Sector Activities-Selected Case Studies from West Africa. AB - Most in the Economic Community of West African States region are employed in the informal sector. While the informal sector plays a significant role in the region's economy, policymakers and the scientific community have long neglected it. To better understand informal-sector work conditions, the goal here is to bring together researchers to exchange findings and catalyze dialogue. The article showcases research studies on several economic systems, namely agriculture, resource extraction, transportation, and trade/commerce. Site specific cases are provided concerning occupational health risks within artisanal and small-scale gold mining, aggregate mining, gasoline trade, farming and pesticide applications, and electronic waste recycling. These cases emphasize the vastness of the informal sector and that the majority of work activities across the region remain poorly documented, and thus no data or knowledge is available to help improve conditions and formulate policies and programs to promote and ensure decent work conditions. PMID- 27231012 TI - Thermoregulation in boys and men exercising at the same heat production per unit body mass. AB - PURPOSE: Child-adult thermoregulatory comparisons may be biased by differences in metabolic heat production ([Formula: see text]). We compared thermoregulatory responses of boys and men exercising at two intensities prescribed to elicit either a fixed [Formula: see text] per unit body mass (BM) or a fixed absolute [Formula: see text]. METHODS: Ten boys (10-12 years) and 10 men (19-25 years) performed 4 * 20-min cycling at a fixed [Formula: see text] per BM (W kg(-1)) at 35 degrees C and 35 % relative humidity (MENREL). Men also cycled (MENABS) at the same absolute [Formula: see text] (in W) as the boys. RESULTS: [Formula: see text] was lower in boys compared with MENREL, but similar to MENABS (mean +/- SD, 233.6 +/- 38.4, 396.5 +/- 72.3, 233.6 +/- 34.1 W, respectively, P < 0.001). Conversely, [Formula: see text] per unit BM was similar between boys and MENREL, and lower in MENABS (5.7 +/- 1.0, 5.6 +/- 0.8 and 3.3 +/- 0.3 W kg(-1), respectively; P < 0.001). The change in rectal temperature was similar between boys and MENREL (0.6 +/- 0.2 vs. 0.7 +/- 0.2 degrees C, P = 0.92) but was lower in MENABS (0.3 +/- 0.2 degrees C, P = 0.004). Sweat volume was lower in boys compared to MENABS (500 +/- 173 vs. 710 +/- 150 mL; P = 0.041), despite the same evaporative heat balance requirement (E req) (199.1 +/- 34.2 vs. 201.0 +/- 32.7 W, P = 0.87). CONCLUSION: Boys and men demonstrated similar thermoregulatory responses to 80 min of exercise in the heat performed at a fixed [Formula: see text] per unit BM. Sweat volume was lower in boys compared to men, despite similarities in absolute [Formula: see text] and E req. PMID- 27231010 TI - Essential role of miRNAs in orchestrating the biology of the tumor microenvironment. AB - MicroRNAs (miRNAs) are emerging as central players in shaping the biology of the Tumor Microenvironment (TME). They do so both by modulating their expression levels within the different cells of the TME and by being shuttled among different cell populations within exosomes and other extracellular vesicles. This review focuses on the state-of-the-art knowledge of the role of miRNAs in the complexity of the TME and highlights limitations and challenges in the field. A better understanding of the mechanisms of action of these fascinating micro molecules will lead to the development of new therapeutic weapons and most importantly, to an improvement in the clinical outcome of cancer patients. PMID- 27231013 TI - Synthesis and Photophysical Studies on Naphthalimide Derived Fluorophores as Markers in Drug Delivery. AB - Derivatives of 4-amino-1,8-naphthalimide containing a free alkyl chain bearing carboxyl group as linker and different substituents at 4-amino function have been synthesized, characterized and studied for their photophysical properties. Steady state fluorescence studies showed quantum yield varied from 0.45 to 0.65 with Stokes shift in the range of 5824-8558 cm(-1). Spectroscopic and physicochemical parameters, like electronic absorption, emission, and extinction coefficient were investigated in order to explore the analytical potential of compounds. Solvatochromic studies demonstrated that all compounds were sensitive towards the polarity of different solvents showing the highest degree of fluorescence in acetonitrile. In addition, the compounds in the presence of ions, viz. Na(+), K(+) and Mg(2+) at concentration of 0.1-2 equivalents, showed a decreasing trend in fluorescence with increasing ionic concentration. TCSPC set - up was used to measure the fluorescence lifetime of compounds, which was found to be bi exponential with longer and shorter component at their respective amplitudes. The average lifetime of compounds was observed to be 5.76-9.96 ns indicating the possibility of their greater utilization in research and diagnosis. PMID- 27231015 TI - Colloidal crystals and water: Perspectives on liquid-solid nanoscale phenomena in wet particulate media. AB - Solid colloidal ensembles inherently contain water adsorbed from the ambient moisture. This water, confined in the porous network formed by the building submicron spheres, greatly affects the ensemble properties. Inversely, one can benefit from such influence on collective features to explore the water behavior in such nanoconfinements. Recently, novel approaches have been developed to investigate in-depth where and how water is placed in the nanometric pores of self-assembled colloidal crystals. Here, we summarize these advances, along with new ones, that are linked to general interfacial water phenomena like adsorption, capillary forces, and flow. Water-dependent structural properties of the colloidal crystal give clues to the interplay between nanoconfined water and solid fine particles that determines the behavior of ensembles. We elaborate on how the knowledge gained on water in colloidal crystals provides new opportunities for multidisciplinary study of interfacial and nanoconfined liquids and their essential role in the physics of utmost important systems such as particulate media. PMID- 27231014 TI - The POU/Oct Transcription Factor Pdm1/nub Is Necessary for a Beneficial Gut Microbiota and Normal Lifespan of Drosophila. AB - Maintenance of a stable gut microbial community relies on a delicate balance between immune defense and immune tolerance. We have used Drosophila to study how the microbial gut flora is affected by changes in host genetic factors and immunity. Flies with a constitutively active gut immune system, due to a mutation in the POU transcriptional regulator Pdm1/nubbin (nub) gene, had higher loads of bacteria and a more diverse taxonomic composition than controls. In addition, the microbial composition shifted considerably during the short lifespan of the nub1 mutants. This shift was characterized by a loss of relatively few OTUs (operational taxonomic units) and a remarkable increase in a large number of Acetobacter spp. and Leuconostoc spp. Treating nub1 mutant flies with antibiotics prolonged their lifetime survival by more than 100%. Immune gene expression was also persistently high in the presence of antibiotics, indicating that the early death was not a direct consequence of an overactive immune defense but rather an indirect consequence of the microbial load and composition. Thus, changes in host genotype and an inability to regulate the normal growth and composition of the gut microbiota leads to a shift in the microbial community, dysbiosis and early death. PMID- 27231016 TI - Microfluidics meets metabolomics to reveal the impact of Campylobacter jejuni infection on biochemical pathways. AB - Microfluidic devices that are currently being used in pharmaceutical research also have a significant potential for utilization in investigating exposure to infectious agents. We have established a microfluidic device cultured with Caco-2 cells, and utilized metabolomics to investigate the biochemical responses to the bacterial pathogen Campylobacter jejuni. In the microfluidic devices, Caco-2 cells polarize at day 5, are uniform, have defined brush borders and tight junctions, and form a mucus layer. Metabolomics analysis of cell culture media collected from both Caco-2 cell culture systems demonstrated a more metabolic homogenous biochemical profile in the media collected from microfluidic devices, compared with media collected from transwells. GeneGo pathway mapping indicated that aminoacyl-tRNA biosynthesis was perturbed by fluid flow, suggesting that fluid dynamics and shear stress impacts the cells translational quality control. Both microfluidic device and transwell culturing systems were used to investigate the impact of Campylobacter jejuni infection on biochemical processes. Caco-2 cells cultured in either system were infected at day 5 with C. jejuni 81-176 for 48 h. Metabolomics analysis clearly differentiated C. jejuni 81-176 infected and non-infected medias collected from the microfluidic devices, and demonstrated that C. jejuni 81-176 infection in microfluidic devices impacts branched-chain amino acid metabolism, glycolysis, and gluconeogenesis. In contrast, no distinction was seen in the biochemical profiles of infected versus non-infected media collected from cells cultured in transwells. Microfluidic culturing conditions demonstrated a more metabolically homogenous cell population, and present the opportunity for studying host-pathogen interactions for extended periods of time. PMID- 27231017 TI - Estrogen-mediated dental tissue regeneration. AB - As the key regulator of hard tissue metabolism in both men and women, estrogen regulates the processes necessary for cell growth, proliferation, and differentiation through estrogen receptor (ER). Estrogen deficiency usually causes systemic osteoporosis not only in long bones but also in jaw bones, and exogenous estrogen can enhance the osteogenic potential of mesenchymal stem cells. Dental mesenchymal stem cells (DMSCs) represent a group of stem cells isolated from different parts of the tooth, including dental pulps, apical papillae and periodontal ligaments. A number of studies have proved that estrogen plays an important role in the proliferation, differentiation and tissue regeneration of human DMSCs. Thus, this review will focus on the effects of estrogen on proliferation, apoptosis, and differentiation of dental stem cells, discuss evidence from studies in rodents that estrogen plays an important role in dental morphogenesis as well as periodontal remodeling, and suggest directions for future studies in estrogen-related tooth regeneration. PMID- 27231018 TI - Vascular Regeneration in Ischemic Hindlimb by Adeno-Associated Virus Expressing Conditionally Silenced Vascular Endothelial Growth Factor. AB - BACKGROUND: Critical limb ischemia (CLI) is the extreme manifestation of peripheral artery disease, a major unmet clinical need for which lower limb amputation is the only option for many patients. After 2 decades in development, therapeutic angiogenesis has been tested clinically via intramuscular delivery of proangiogenic proteins, genes, and stem cells. Efficacy has been modest to absent, and the largest phase 3 trial of gene therapy for CLI reported a worsening trend of plasmid fibroblast growth factor. In all clinical trials to date, gene therapy has used unregulated vectors with limited duration of expression. Only unregulated extended expression vectors such as adeno-associated virus (AAV) and lentivirus have been tested in preclinical models. METHODS AND RESULTS: We present preclinical results of ischemia (hypoxia)-regulated conditionally silenced (CS) AAV-human vascular endothelial growth factor (hVEGF) gene delivery that shows efficacy and safety in a setting where other strategies fail. In a BALB/c mouse model of CLI, we show that gene therapy with AAV-CS hVEGF, but not unregulated AAV or plasmid, vectors conferred limb salvage, protection from necrosis, and vascular regeneration when delivered via intramuscular or intra-arterial routes. All vector treatments conferred increased capillary density, but organized longitudinal arteries were selectively generated by AAV-CS-hVEGF. AAV-CS-hVEGF therapy reversibly activated angiogenic and vasculogenic genes, including Notch, SDF1, Angiopoietin, and Ephrin-B2. Reoxygenation extinguished VEGF expression and inactivated the program with no apparent adverse side effects. CONCLUSIONS: Restriction of angiogenic growth factor expression to regions of ischemia supports the safe and stable reperfusion of hindlimbs in a clinically relevant murine model of CLI. PMID- 27231019 TI - Implantable Loop Recorder Monitoring for Refining Management of Children With Inherited Arrhythmia Syndromes. AB - BACKGROUND: Implantable loop recorders (ILRs) are conventionally utilized to elucidate the mechanism of atypical syncope. The objective of this study was to assess the impact of these devices on management of pediatric patients with known or suspected inherited arrhythmia syndromes. METHODS AND RESULTS: A retrospective chart review was undertaken of all pediatric patients with known or suspected inherited arrhythmia syndromes in whom an ILR was implanted from 2008 to 2015. Captured data included categorization of diagnosis, treatment, transmitted tracings, and the impact of ILR tracings on management. Transmissions were categorized as symptomatic, autotriggered, or routine. Actionable transmissions were abnormal tracings that directly resulted in a change of medical or device therapy. A total of 20 patients met the stated inclusion criteria (long QT syndrome, n=8, catecholaminergic polymorphic ventricular tachycardia,n=9, Brugada syndrome, n=1, arrhythmogenic right ventricular cardiomyopathy, n=2), with 60% of patients being genotype positive. Primary indication for implantation of ILR included ongoing monitoring +/- symptoms (n=15, 75%), suspicion of noncompliance (n=1, 5%), and liberalization of recommended activity restrictions (n=4, 25%). A total of 172 transmissions were received in patients with inherited arrhythmia syndromes, with 7% yielding actionable data. The majority (52%) of symptom events were documented in the long QT syndrome population, with only 1 tracing (5%) yielding actionable data. Automatic transmissions were mostly seen in the catecholaminergic polymorphic ventricular tachycardia cohort (81%), with 21% yielding actionable data. There was no actionable data in routine transmissions. CONCLUSIONS: ILRs in patients with suspected or confirmed inherited arrhythmia syndromes may be useful for guiding management. Findings escalated therapies in 30% of subjects. As importantly, in this high-risk population, the majority of symptom events represented normal or benign rhythms, reassuring patients and physicians that no further intervention was required. PMID- 27231020 TI - Functional Analysis of the TRIB1 Associated Locus Linked to Plasma Triglycerides and Coronary Artery Disease. PMID- 27231021 TI - Binding of Human Fibrinogen to MRP Enhances Streptococcus suis Survival in Host Blood in a alphaXbeta2 Integrin-dependent Manner. AB - The Gram-positive bacterium Streptococcus suis serotype 2 (S. suis 2), an important zoonotic pathogen, induces strong systemic infections in humans; sepsis and meningitis are the most common clinical manifestations and are often accompanied by bacteremia. However, the mechanisms of S. suis 2 survival in human blood are not well understood. In our previous study, we identified muramidase released protein (MRP), a novel human fibrinogen (hFg)-binding protein (FBP) in S. suis 2 that is an important epidemic infection marker with an unknown mechanism in pathogenesis. The present study demonstrates that the N-terminus of MRP (a.a. 283-721) binds to both the Aalpha and Bbeta chains of the D fragment of hFg. Strikingly, the hFg-MRP interaction improved the survival of S. suis 2 in human blood and led to the aggregation and exhaustion of polymorphonuclear neutrophils (PMNs) via an alphaXbeta2 integrin-dependent mechanism. Other Fg binding proteins, such as M1 (GAS) and FOG (GGS), also induced PMNs aggregation; however, the mechanisms of these FBP-hFg complexes in the evasion of PMN-mediated innate immunity remain unclear. MRP is conserved across highly virulent strains in Europe and Asia, and these data shed new light on the function of MRP in S. suis pathogenesis. PMID- 27231022 TI - Vitamin C promotes the proliferation of human adipose-derived stem cells via p53 p21 pathway. AB - Although adipose-derived stem cells (ADSCs) have demonstrated a promising potential for the applications of cell-based therapy and regenerative medicine, excessive reactive oxygen species (ROS) are harmful to ADSCs cell survival and proliferation. Vitamin C is an important antioxidant, and is often added into culture media as an essential micronutrient. However, its roles on the proliferation of human ADSCs have not been studied. Therefore, in this study, human ADSCs were isolated, and detected by flow cytometry for the analysis of their cell surface antigens. Cell proliferation and cell cycle progression were measured with cell counting kit-8 assay and flow cytometry, respectively. Western blotting was used to detect the expression levels of cyclin E1, p53, p21, and CDK2 proteins. The effect of vitamin C pretreatment on the production of hydrogen peroxide (H2O2)-mediated ROS in the ADSCs was evaluated by flow cytometry. Our results indicated that vitamin C treatment significantly increased cell proliferation, and changed the cell cycle distribution of ADSCs by decreasing the percentage of G1 phase, and concurrently increased the percentage of S and G2/M phase. Western blot analysis indicated that vitamin C treatment up-regulated the expression levels of cyclin E1 and CDK2, but down-regulated p53 and p21 proteins expression, which contributed to cell proliferation and cell cycle progression. Vitamin C pretreatment significantly reduced the production of H2O2-induced ROS in the ADSCs. These findings suggest that vitamin C can promote the proliferation and cell cycle progression in the ADSCs possibly through regulation of p53-p21 signal pathway. PMID- 27231024 TI - Configuration-averaged 4f orbitals in ab initio calculations of low-lying crystal field levels in lanthanide(iii) complexes. AB - A successful and commonly used ab initio method for the calculation of crystal field levels and magnetic anisotropy of lanthanide complexes consists of spin adapted state-averaged CASSCF calculations followed by state interaction with spin-orbit coupling (SI-SO). Based on two observations valid for Ln(iii) complexes, namely: (i) CASSCF 4f orbitals are expected to change very little when optimized for different states belonging to the 4f electronic configuration, (ii) due to strong spin-orbit coupling the total spin is not a good quantum number, we show here via a straightforward analysis and direct calculation that the CASSCF/SI-SO method can be simplified to a single configuration-averaged HF calculation and one complete active space CI diagonalization, including spin orbit coupling, on determinant basis. Besides its conceptual simplicity, this approach has the advantage that all spin states of the 4f(n) configuration are automatically included in the SO coupling, thereby overcoming one of the computational limitations of the existing CASSCF/SI-SO approach. As an example, we consider three isostructural complexes [Ln(acac)3(H2O)2], Ln = Dy(3+), Ho(3+), Er(3+), and find that the proposed simplified method yields crystal field levels and magnetic g-tensors that are in very good agreement with those obtained with CASSCF/SI-SO. PMID- 27231023 TI - Screening for SH3TC2 gene mutations in a series of demyelinating recessive Charcot-Marie-Tooth disease (CMT4). AB - Charcot-Marie-Tooth disease type 4C (CMT4C) is an autosomal recessive (AR) demyelinating neuropathy associated to SH3TC2 mutations, characterized by early onset, spine deformities, and cranial nerve involvement. We screened 43 CMT4 patients (36 index cases) with AR inheritance, demyelinating nerve conductions, and negative testing for PMP22 duplication, GJB1 and MPZ mutations, for SH3TC2 mutations. Twelve patients (11 index cases) had CMT4C as they carried homozygous or compound heterozygous mutations in SH3TC2. We found six mutations: three nonsense (p.R1109*, p.R954*, p.Q892*), one splice site (c.805+2T>C), one synonymous variant (p.K93K) predicting altered splicing, and one frameshift (p.F491Lfs*32) mutation. The splice site and the frameshift mutations are novel. Mean onset age was 7 years (range: 1-14). Neuropathy was moderate-to-severe. Scoliosis was present in 11 patients (severe in 4), and cranial nerve deficits in 9 (hearing loss in 7). Scoliosis and cranial nerve involvement are frequent features of this CMT4 subtype, and their presence should prompt the clinician to look for SH3TC2 gene mutations. In our series of undiagnosed CMT4 patients, SH3TC2 mutation frequency is 30%, confirming that CMT4C may be the most common AR CMT type. PMID- 27231026 TI - CuO-Decorated ZnO Hierarchical Nanostructures as Efficient and Established Sensing Materials for H2S Gas Sensors. AB - Highly sensitive hydrogen sulfide (H2S) gas sensors were developed from CuO decorated ZnO semiconducting hierarchical nanostructures. The ZnO hierarchical nanostructure was fabricated by an electrospinning method following hydrothermal and heat treatment. CuO decoration of ZnO hierarchical structures was carried out by a wet method. The H2S gas-sensing properties were examined at different working temperatures using various quantities of CuO as the variable. CuO decoration of the ZnO hierarchical structure was observed to promote sensitivity for H2S gas higher than 30 times at low working temperature (200 degrees C) compared with that in the nondecorated hierarchical structure. The sensing mechanism of the hybrid sensor structure is also discussed. The morphology and characteristics of the samples were examined by scanning electron microscopy (SEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), UV-vis absorption, photoluminescence (PL), and electrical measurements. PMID- 27231025 TI - Stakeholders in support systems for self-care for chronic illness: the gap between expectations and reality regarding their identity, roles and relationships. AB - BACKGROUND AND OBJECTIVE: The spread of self-care holds the promise of containing chronic illness burden. Falling within the framework of a FP7 collaborative research project, this paper reports the views of key informants from six countries regarding who the main stakeholders are at different levels in the support system for self-care for patients with chronic illness (SSSC) and how they accomplish their role and collaborate. METHODS: 90 Interviews with purposefully selected key informants from Bulgaria, Greece, the Netherlands, Norway, Spain and United Kingdom were conducted. Interviews involved government and local authorities, politicians, academics, health professionals and private sector representatives. Interviewers followed an expert opinion-based guide. Analysis involved a cross-country examination with thematic analysis and framework method techniques. RESULTS: Key informants described the ideal SSSC as inclusive, interdependent and patient-centred. The following main stakeholders in SSSC were identified: patients, governments, health-care professionals, associations, private companies and the media. In the current SSSCs, collaboration among stakeholders within and across different levels was said to be lacking. Patients were seen as playing a passive subordinate role based on the following: their own attitudes; the paternalistic and medicalized attitudes of the health-care professionals; their misrepresentation by patient associations; and their exposure to the damaging influences of media and industries. CONCLUSIONS: Making SSSC patient-centred constitutes the greatest challenge for European authorities. Strategies must be revised for promoting patient participation. They should undergo changes so as to promote industry and media social responsibility and patient association advocacy capacity. PMID- 27231027 TI - Diagnostic Accuracy Study of Intraoperative and Perioperative Serum Intact PTH Level for Successful Parathyroidectomy in 501 Secondary Hyperparathyroidism Patients. AB - Parathyroidectomy (PTX) is an effective treatment for severe secondary hyperparathyroidism (SHPT); however, persistent SHPT may occur because of supernumerary and ectopic parathyroids. Here a diagnostic accuracy study of intraoperative and perioperative serum intact parathyroid hormone (iPTH) was performed to predict successful surgery in 501 patients, who received total PTX + autotransplantation without thymectomy. Serum iPTH values before incision (io iPTH0), 10 and 20 min after removing the last parathyroid (io-iPTH10, io-iPTH20), and the first and fourth day after PTX (D1-iPTH, D4-iPTH) were recoded. Patients whose serum iPTH was >50 pg/mL at the first postoperative week were followed up within six months. Successful PTX was defined if iPTH was <300 pg/mL, on the contrary, persistent SHPT was regarded. There were 86.4% patients underwent successful PTX, 9.8% remained as persistent SHPT and 3.8% were undetermined. Intraoperative serum iPTH demonstrated no significant differences in two subgroups with or without chronic hepatitis. Receiver operating characteristic (ROC) curves showed that >88.9% of io-iPTH20% could predict successful PTX (area under the curve [AUC] 0.909, sensitivity 78.6%, specificity 88.5%), thereby avoiding unnecessary exploration to reduce operative complications. D4-iPTH >147.4 pg/mL could predict persistent SHPT (AUC 0.998, sensitivity 100%, specificity 99.5%), so that medical intervention or reoperation start timely. PMID- 27231028 TI - The orthotropic elastic properties of fibrolamellar bone tissue in juvenile white tailed deer femora. AB - Fibrolamellar bone is a transient primary bone tissue found in fast-growing juvenile mammals, several species of birds and large dinosaurs. Despite the fact that this bone tissue is prevalent in many species, the vast majority of bone structural and mechanical studies are focused on human osteonal bone tissue. Previous research revealed the orthotropic structure of fibrolamellar bone, but only a handful of experiments investigated its elastic properties, mostly in the axial direction. Here we have performed for the first time an extensive biomechanical study to determine the elastic properties of fibrolamellar bone in all three orthogonal directions. We have tested 30 fibrolamellar bone cubes (2 * 2 * 2 mm) from the femora of five juvenile white-tailed deer (Odocoileus virginianus) in compression. Each bone cube was compressed iteratively, within its elastic region, in the axial, transverse and radial directions, and bone stiffness (Young's modulus) was recorded. Next, the cubes were kept for 7 days at 4 degrees C and then compressed again to test whether bone stiffness had significantly deteriorated. Our results demonstrated that bone tissue in the deer femora has an orthotropic elastic behavior where the highest stiffness was in the axial direction followed by the transverse and the radial directions (21.6 +/- 3.3, 17.6 +/- 3.0 and 14.9 +/- 1.9 Gpa, respectively). Our results also revealed a slight non-significant decrease in bone stiffness after 7 days. Finally, our sample size allowed us to establish that population variance was much bigger in the axial direction than the radial direction, potentially reflecting bone adaptation to the large diversity in loading activity between individuals in the loading direction (axial) compared with the normal (radial) direction. This study confirms that the mechanically well-studied human transverse-isotropic osteonal bone is just one possible functional adaptation of bone tissue and that other vertebrate species use an orthotropic bone tissue structure which is more suitable for their mechanical requirements. PMID- 27231030 TI - Synthesis and structural studies of 1,4-di(2-pyridyl)-1,2,3-triazole and its transition metal complexes; a versatile and subtly unsymmetric ligand. AB - The synthesis of the 'click' derived 1,4-di(2-pyridyl)-1,2,3-triazole () chelator/ligand from 2-azidopyridine and 2-ethynylpyridine using Cu(i) and TBTA by microwave assisted synthesis is presented. The complexes of the subtly unsymmetric ligand with Cu(i), Pt(ii), Co(ii), and Ag(i) were structurally characterised by using conventional methods, as well as using single crystal and powder diffraction analysis. The results of the studies showed formation of discrete molecules displaying preferential binding of the d-metal cations through the pyridyl nitrogen N1 and the proximal triazolyl nitrogen N2 i.e. the 2-(1H 1,2,3-triazol-4-yl)pyridine or 'regular' chelate moiety despite the presence of a second potential binding pocket i.e. the 2-(1H-1,2,3-triazol-1-yl)pyridine chelate or 'inverse' moiety. This binding selectivity was corroborated through the study of the self-assembly of with Cu(i) and Ag(i) using (1)H NMR titration in CD3CN solution, as well as using UV-Vis absorption titrations; the former showing a broadening of the proton peaks associated with that chelate pocket. PMID- 27231029 TI - Early pulmonary disease manifestations in cystic fibrosis mice. AB - BACKGROUND: Altered pulmonary function is present early in the course of cystic fibrosis (CF), independent of documented infections or onset of pulmonary symptoms. New initiatives in clinical care are focusing on detection and characterization of preclinical disease. Thus, animal models are needed which recapitulate the pulmonary phenotype characteristic of early stage CF. METHODS: We investigated young CF mice to determine if they exhibit pulmonary pathophysiology consistent with the early CF lung phenotype. Lung histology and pulmonary mechanics were examined in 12- to 16-week-old congenic C57bl/6 F508del and R117H CF mice using a forced oscillation technique (flexiVent). RESULTS: There were no significant differences in the resistance of the large airways. However, in both CF mouse models, prominent differences in the mechanical properties of the peripheral lung compartment were identified including decreased static lung compliance, increased elastance and increased tissue damping. CF mice also had distal airspace enlargement with significantly increased mean linear intercept distances. CONCLUSIONS: An impaired ability to stretch and expand the peripheral lung compartment, as well as increased distances between gas exchange surfaces, were present in young CF mice carrying two independent Cftr mutations. This altered pulmonary histopathophysiology in the peripheral lung compartment, which develops in the absence of infection, is similar to the early lung phenotype of CF patients. PMID- 27231031 TI - Tools and Checklists Used for the Evaluation of Hospital Disaster Preparedness: A Systematic Review. AB - Hospitals need to be fully operative during disasters. It is therefore essential to be able to evaluate hospital preparedness. However, there is no consensus of a standardized, comprehensive and reliable tool with which to measure hospital preparedness. The aim of the current study was to perform a systematic review of evaluation tools for hospital disaster preparedness. A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The key words "crisis," "disaster," "disaster medicine," "emergency," "mass casualty," "hospital preparedness," "hospital readiness," "hospital assessment," "hospital evaluation," "hospital appraisal," "planning," "checklist," and "medical facility" were used in combination with the Boolean operators "OR" and "AND." PubMed (National Library of Medicine, Bethesda, MD), ISI Web of Science (Thomson Reuters, New York, NY), and Scopus (Elsevier, New York, NY) were searched. A total of 51,809 publications were screened. The following themes were required for relevance: logistics, planning, human resources, triage, communication, command and control, structural and nonstructural preparedness, training, evacuation, recovery after disaster, coordination, transportation, surge capacity, and safety. The results from 15 publications are presented. Fifteen articles fulfilled the criteria of relevance and considered at least 1 of the 14 predetermined themes. None of the evaluated checklists and tools included all dimensions required for an appropriate hospital preparedness evaluation. The results of the current systematic review could be used as a basis for designing an evaluation tool for hospital disaster preparedness. (Disaster Med Public Health Preparedness. 2016;page 1 of 8). PMID- 27231032 TI - A misleading procedure name may prove dangerous: cautionary note on an article by Har-Shai et al. PMID- 27231033 TI - Catalytic Dinitrogen Fixation to Form Ammonia at Ambient Reaction Conditions Using Transition Metal-Dinitrogen Complexes. AB - This paper presents recent progress in catalytic transformation of molecular dinitrogen into ammonia or its equivalents, such as silylamine, especially using transition metal-dinitrogen complexes under ambient reaction conditions. Several catalytic systems have been recently established using molybdenum-, iron-, and cobalt-dinitrogen complexes or their precursors as catalysts, providing new approaches to the development of novel nitrogen fixation under ambient reaction conditions. PMID- 27231036 TI - Does multitasking mediate the relationships between episodic memory, attention, executive functions and apathetic manifestations in traumatic brain injury? AB - Apathy is frequently described in patients with traumatic brain injury (TBI); its negative consequences particularly affect functional independence. Among apathetic manifestations, lack of initiative and lack of interest have mainly been associated with cognitive impairments. However, few studies have been conducted to precisely identify the underlying cognitive processes. Our aims were (1) to determine the best predictor of apathy from among several cognitive processes, including episodic memory and attention/executive mechanisms and multitasking, and (2) to examine to what extent multitasking could mediate the relationships between specific cognitive processes and lack of initiative/interest. Seventy participants (34 patients with TBI matched with 36 control participants) were given a questionnaire to assess anxio-depressive symptoms, four tasks to assess specific cognitive processes, and one task to assess real-life multitasking. Participants' relatives completed an apathy questionnaire. Multitasking, as assessed by the number of goals not achieved, was the only significant predictor of apathetic manifestations. In addition, the mediation analyses revealed that multitasking performance mediated the relationships between verbal episodic memory and lack of initiative/interest, whereas executive and attentional functions were only indirectly related to lack of initiative/interest due to their significant impacts on multitasking. These results shed new light on the aetiology of apathetic manifestations in patients with TBI, indicating how specific cognitive deficits are expressed in real-life multitasking, and consequently, how they may lead to the development and/or maintenance of apathetic manifestations. PMID- 27231034 TI - ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation. AB - The V-ATPase is the main regulator of intra-organellar acidification. Assembly of this complex has extensively been studied in yeast, while limited knowledge exists for man. We identified 11 male patients with hemizygous missense mutations in ATP6AP1, encoding accessory protein Ac45 of the V-ATPase. Homology detection at the level of sequence profiles indicated Ac45 as the long-sought human homologue of yeast V-ATPase assembly factor Voa1. Processed wild-type Ac45, but not its disease mutants, restored V-ATPase-dependent growth in Voa1 mutant yeast. Patients display an immunodeficiency phenotype associated with hypogammaglobulinemia, hepatopathy and a spectrum of neurocognitive abnormalities. Ac45 in human brain is present as the common, processed ~40-kDa form, while liver shows a 62-kDa intact protein, and B-cells a 50-kDa isoform. Our work unmasks Ac45 as the functional ortholog of yeast V-ATPase assembly factor Voa1 and reveals a novel link of tissue-specific V-ATPase assembly with immunoglobulin production and cognitive function. PMID- 27231035 TI - Glycosylphosphatidylinositol Anchor Deficiency Attenuates the Production of Infectious HIV-1 and Renders Virions Sensitive to Complement Attack. AB - Human immunodeficiency virus type 1 (HIV-1) escapes complement-mediated lysis (CML) by incorporating host regulators of complement activation (RCA) into its envelope. CD59, a key member of RCA, is incorporated into HIV-1 virions at levels that protect against CML. Since CD59 is a glycosylphosphatidylinositol-anchored protein (GPI-AP), we used GPI anchor-deficient Jurkat cells (Jurkat-7) that express intracellular CD59, but not surface CD59, to study the molecular mechanisms underlying CD59 incorporation into HIV-1 virions and the role of host proteins in virus replication. Compared to Jurkat cells, Jurkat-7 cells were less supportive to HIV-1 replication and more sensitive to CML. Jurkat-7 cells exhibited similar capacities of HIV-1 binding and entry to Jurkat cells, but were less supportive to viral RNA and DNA biosynthesis as infected Jurkat-7 cells produced reduced amounts of HIV-1 RNA and DNA. HIV-1 virions produced from Jurkat 7 cells were CD59 negative, suggesting that viral particles acquire CD59, and probably other host proteins, from the cell membrane rather than intracellular compartments. As a result, CD59-negative virions were sensitive to CML. Strikingly, these virions exhibited reduced activity of virus binding and were less infectious, implicating that GPI-APs may be also important in ensuring the integrity of HIV-1 particles. Transient expression of the PIG-A gene restored CD59 expression on the surface of Jurkat-7 cells. After HIV-1 infection, the restored CD59 was colocalized with viral envelope glycoprotein gp120/gp41 within lipid rafts, which is identical to that on infected Jurkat cells. Thus, HIV-1 virions acquire RCA from the cell surface, likely lipid rafts, to escape CML and ensure viral infectivity. PMID- 27231037 TI - Assessment of anxiety levels of patients awaiting surgery for suspected thyroid cancer: A case-control study in a Chinese-Han population. AB - INTRODUCTION: The objective of this study was to evaluate levels and prevalence of anxiety in thyroid tumor patients awaiting surgery and diagnosis and to investigate whether significant differences existed in preoperative anxiety levels between patients with postoperative pathological diagnosis of benign thyroid tumors (BTT) or thyroid cancer (TC) in a Chinese-Han population. METHODS: Five hundred and twenty-nine patients awaiting surgery and diagnosis were chosen as the patient group, and 419 healthy Chinese were chosen as the control group. Anxiety levels were assessed by the State-Trait Anxiety Inventory. RESULTS: The cytological and histopathologic examinations showed BTT in 390 patients and TC in 139 patients. Moderate and high state-anxiety prevalence were 63.3%, 66.9%, and 38.9%, and moderate and high trait-anxiety prevalence were 53.6%, 56.1%, and 20.5% for BTT, TC, and healthy groups, respectively. There were significant differences in sample distributions between low and moderate/high anxiety levels among the three groups (state-anxiety, chi2 = 60.95, P < 0.001; trait-anxiety, chi2 = 111.73, P < 0.001). The mean state-anxiety scores were 41.02 +/- 8.82, 42.71 +/- 8.74, and 37.18 +/- 7.46, and the mean trait-anxiety scores were 41.91 +/- 8.40, 42.69 +/- 9.40, and 38.28 +/- 6.30 for BTT, TC, and healthy groups, respectively. There were significant differences in the state-anxiety (chi2 = 73.43, P < 0.001) and trait-anxiety levels (chi2 = 72.21, P < 0.001) among these three groups. DISCUSSION: This study has demonstrated that patients with BTT or TC have a high level of anxiety. The anxiety level of patients with TC is significantly higher than those with BTT. Our results indicate that anxiety may be a relative risk of thyroid tumor in Han-Chinese. (c) 2016 John Wiley & Sons Australia, Ltd. PMID- 27231038 TI - Interventions for treating oro-antral communications and fistulae due to dental procedures. AB - BACKGROUND: An oro-antral communication is an unnatural opening between the oral cavity and maxillary sinus. When it fails to close spontaneously, it remains patent and is epithelialized to develop into an oro-antral fistula. Various surgical and non-surgical techniques have been used for treating the condition. Surgical procedures include flaps, grafts and other techniques like re implantation of third molars. Non-surgical techniques include allogenic materials and xenografts. OBJECTIVES: To assess the effectiveness and safety of various interventions for the treatment of oro-antral communications and fistulae due to dental procedures. SEARCH METHODS: We searched the Cochrane Oral Health Group's Trials Register (whole database, to 3 July 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2015, Issue 6), MEDLINE via OVID (1946 to 3 July 2015), EMBASE via OVID (1980 to 3 July 2015), US National Institutes of Health Trials Registry (http://clinicaltrials.gov) (whole database, to 3 July 2015) and the World Health Organization (WHO) International Clinical Trials Registry Platform (http://www.who.int/ictrp/en/) (whole database, to 3 July 2015). We also searched the reference lists of included and excluded trials for any randomised controlled trials (RCTs). SELECTION CRITERIA: We included RCTs evaluating any intervention for treating oro-antral communications or oro-antral fistulae due to dental procedures. We excluded quasi-RCTs and cross-over trials. We excluded studies on participants who had oro-antral communications, fistulae or both related to Caldwell-Luc procedure or surgical excision of tumours. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials. Two review authors assessed trial risk of bias and extracted data independently. We estimated risk ratios (RR) for dichotomous data, with 95% confidence intervals (CI). We assessed the overall quality of the evidence using the GRADE approach. MAIN RESULTS: We included only one study in this review, which compared two surgical interventions: pedicled buccal fat pad flap and buccal flap for the treatment of oro-antral communications. The study involved 20 participants. The risk of bias was unclear. The relevant outcome reported in this trial was successful (complete) closure of oro-antral communication.The quality of the evidence for the primary outcome was very low. The study did not find evidence of a difference between interventions for the successful (complete) closure of an oro-antral communication (RR 1.00, 95% Cl 0.83 to 1.20) one month after the surgery. All oro-antral communications in both groups were successfully closed so there were no adverse effects due to treatment failure.We did not find trials evaluating any other intervention for treating oro-antral communications or fistulae due to dental procedures. AUTHORS' CONCLUSIONS: We found very low quality evidence from a single small study that compared pedicled buccal fat pad and buccal flap. The evidence was insufficient to judge whether there is a difference in the effectiveness of these interventions as all oro-antral communications in the study were successfully closed by one month after surgery. Large, well-conducted RCTs investigating different interventions for the treatment of oro-antral communications and fistulae caused by dental procedures are needed to inform clinical practice. PMID- 27231039 TI - Sampling of BTX in Hat Yai city using cost effective laboratory-built PCB passive sampler. AB - A laboratory-built printed circuit board (PCB) passive sampler used for the monitoring of xylene and styrene in copy print shops was re-validated for detecting benzene, toluene and xylene (BTX) and applied for the sampling of ambient air from Hat Yai city, Songkhla, Thailand, in the month of November 2014. For monitoring, the PCB passive samplers were exposed to target analytes in 16 locations covering high to low exposure areas. After sampling, the samplers were thermally desorbed and the analytes were trapped by multi-walled carbon nanotubes packed into a micro-preconcentrator coupled to a gas chromatograph (GC) equipped with a flame ionization detector. At the optimum GC operating conditions, the linear dynamic ranges for BTX were 0.06-5.6 ug for benzene, 0.07-2.2 ug for toluene and 0.23-2.5 ug for xylene with R(2) > 0.99 with the limits of detection being 6.6, 6.8 and 19 ng for benzene, toluene and xylene, respectively. The concentrations of BTX in the 16 sampling sites were in the range of N.D.-1.3 +/- 1.6, 4.50 +/- 0.76-49.6 +/- 3.7 and 1.00 +/- 0.21-39.6 +/- 3.1 ug m(-3), respectively. When compared to past studies, there had been an increase in the benzene concentration. PMID- 27231040 TI - Association between TSHR gene polymorphism and the risk of Graves' disease: a meta-analysis. AB - Thyroid stimulating hormone receptor (TSHR) is thought to be a significant candidate for genetic susceptibility to Graves' disease (GD). However, the association between TSHR gene polymorphism and the risk of GD remains controversial. In this study, we investigated the relationship between the two conditions by meta-analysis. We searched all relevant case-control studies in PubMed, Web of Science, CNKI and Wanfang for literature available until May 2015, and chose studies on two single nucleotide polymorphisms (SNPs): rs179247 and rs12101255, within TSHR intron-1. Bias of heterogeneity test among studies was determined by the fixed or random effect pooled measure, and publication bias was examined by modified Begg's and Egger's test. Eight eligible studies with 15 outcomes were involved in this meta-analysis, including 6,976 GD cases and 7,089 controls from China, Japan, Poland, UK and Brazil. Pooled odds ratios (ORs) for allelic comparisons showed that both TSHR rs179247A/G and rs12101255T/C polymorphism had significant association with GD (OR=1.422, 95%CI=1.353-1.495, P<0.001, Pheterogeneity=0.448; OR=1.502, 95%CI: 1.410-1.600, P<0.001, Pheterogeneity=0.642), and the associations were the same under dominant, recessive and co-dominant models. In subgroup analyses, the conclusions are also consistent with all those in Asian, European and South America subgroups (P<0.001). Our meta-analysis revealed a significant association between TSHR rs179247A/G and rs12101255T/C polymorphism with GD in five different populations from Asia, Europe and South America. Further studies are needed in other ethnic backgrounds to independently confirm our findings. PMID- 27231042 TI - Mobile health: new technologies, new modes and new era. PMID- 27231041 TI - Monitoring cerebral ischemia during cerebrovascular surgery. AB - Patients undergoing intracranial cerebrovascular surgery under general anesthesia are at risk of cerebral ischemia due to the nature of the surgery and/or the underlying cerebrovascular occlusive disease. It is thus imperative to reliably and continuously monitor cerebral perfusion during this type of surgery to timely reverse ischemic processes. The aim of this review is to discuss the techniques currently available for monitoring cerebral ischemia during cerebrovascular surgery with a focus on the advantages and disadvantages of each technique. PMID- 27231043 TI - Internal carotid artery agenesis with stenosed intercavernous anastomosis: a case report. AB - We report a rare case of internal carotid artery agenesis with stenosed intercavernous anastomosis. A 59-year-old male patient presented with a new infarction in the left basal ganglia. Magnetic resonance angiography and cerebral angiography showed that the right internal carotid artery disappeared from the origin to the foramen lacerum segment, and there was an anastomotic artery with severe stenosis passed through the floor of the sella and in front of the cavernous sinus. The right A1 segment of the anterior cerebral artery was absent and A2 segment was supplied by the normal contralateral internal carotid artery via the anterior communicating artery. PMID- 27231045 TI - pH-Degradable Mannosylated Nanogels for Dendritic Cell Targeting. AB - We report on the design of glycosylated nanogels via core-cross-linking of amphiphilic non-water-soluble block copolymers composed of an acetylated glycosylated block and a pentafluorophenyl (PFP) activated ester block prepared by reversible addition-fragmentation (RAFT) polymerization. Self-assembly, pH sensitive core-cross-linking, and removal of remaining PFP esters and protecting groups are achieved in one pot and yield fully hydrated sub-100 nm nanogels. Using cell subsets that exhibit high and low expression of the mannose receptor (MR) under conditions that suppress active endocytosis, we show that mannosylated but not galactosylated nanogels can efficiently target the MR that is expressed on the cell surface of primary dendritic cells (DCs). These nanogels hold promise for immunological applications involving DCs and macrophage subsets. PMID- 27231044 TI - Monitoring cerebral ischemia during carotid endarterectomy and stenting. AB - Current therapy for carotid stenosis mainly includes carotid endarterectomy and endovascular stenting, which may incur procedure-related cerebral ischemia. Several methods have been employed for monitoring cerebral ischemia during surgery, such as awake neurocognitive assessment, electroencephalography, evoked potentials, transcranial Doppler, carotid stump pressure, and near infrared spectroscopy. However, there is no consensus on the gold standard or the method that is superior to others at present. Keeping patient awake for real time neurocognitive assessment is effective and essential; however, not every surgeon adopts it. In patients under general anesthesia, cerebral ischemia monitoring has to rely on non-awake technologies. The advantageous and disadvantageous properties of each monitoring method are reviewed. PMID- 27231046 TI - Cav1.2 and Cav1.3 L-type calcium channels independently control short- and long term sensitization to pain. AB - KEY POINTS: L-type calcium channels in the CNS exist as two subunit forming channels, Cav1.2 and Cav1.3, which are involved in short- and long-term plasticity. We demonstrate that Cav1.3 but not Cav1.2 is essential for wind-up. These results identify Cav1.3 as a key conductance responsible for short-term sensitization in physiological pain transmission. We confirm the role of Cav1.2 in a model of long-term plasticity associated with neuropathic pain. Up regulation of Cav1.2 and down-regultation of Cav1.3 in neuropathic pain underlies the switch from physiology to pathology. Finally, the results of the present study reveal that therapeutic targeting molecular pathways involved in wind-up may be not relevant in the treatment of neuropathy. ABSTRACT: Short-term central sensitization to pain temporarily increases the responsiveness of nociceptive pathways after peripheral injury. In dorsal horn neurons (DHNs), short-term sensitization can be monitored through the study of wind-up. Wind-up, a progressive increase in DHNs response following repetitive peripheral stimulations, depends on the post-synaptic L-type calcium channels. In the dorsal horn of the spinal cord, two L-type calcium channels are present, Cav1.2 and Cav1.3, each displaying specific kinetics and spatial distribution. In the present study, we used a mathematical model of DHNs in which we integrated the specific patterns of expression of each Cav subunits. This mathematical approach reveals that Cav1.3 is necessary for the onset of wind-up, whereas Cav1.2 is not and that synaptically triggered wind-up requires NMDA receptor activation. We then switched to a biological preparation in which we knocked down Cav subunits and confirmed the prominent role of Cav1.3 in both naive and spinal nerve ligation model of neuropathy (SNL). Interestingly, although a clear mechanical allodynia dependent on Cav1.2 expression was observed after SNL, the amplitude of wind-up was decreased. These results were confirmed with our model when adapting Cav1.3 conductance to the changes observed after SNL. Finally, our mathematical approach predicts that, although wind-up amplitude is decreased in SNL, plateau potentials are not altered, suggesting that plateau and wind-up are not fully equivalent. Wind-up and long-term hyperexcitability of DHNs are differentially controlled by Cav1.2 and Cav1.3, therefore confirming that short- and long-term sensitization are two different phenomena triggered by distinct mechanisms. PMID- 27231047 TI - Psychological effects of deep-breathing: the impact of expectancy-priming. AB - Outcome expectancy could mediate the psychological effects of exercise-related interventions, which implies that part of the psychological benefits of physical activity could be ascribed to placebo effects. In this framed field-experiment, 89 healthy participants were studied in three groups, (1) breathing-primed (deep breathing with an exercise-related expectancy), (2) breathing-unprimed (deep breathing with no exercise-related expectancy), and (3) control (no intervention). Deep-breathing lasted for three minutes. Before and after deep breathing, or sitting quietly in the control group, participants completed two questionnaires assessing their positive- and negative affect (NA) and subjective well-being (WB). In contrast to the control group, both the breathing-primed and breathing-unprimed groups showed decreased NA and increased subjective WB. The breathing-primed group reported larger changes in WB than the breathing-unprimed group, in addition to also exhibiting significant increases in positive affect. These findings support the hypothesis of the work that expectations mediate the psychological effects of deep-breathing beyond the intervention's specific effects. Therefore, future research should control for expectations related to an intervention when gauging psychological changes. PMID- 27231048 TI - Neonatal immunity: Maternal IgG promotes intestinal homeostasis. PMID- 27231049 TI - Mucosal immunology: Tryptophan triggers tranquillity. PMID- 27231050 TI - Gut microbiota, metabolites and host immunity. AB - The microbiota - the collection of microorganisms that live within and on all mammals - provides crucial signals for the development and function of the immune system. Increased availability of technologies that profile microbial communities is facilitating the entry of many immunologists into the evolving field of host microbiota studies. The microbial communities, their metabolites and components are not only necessary for immune homeostasis, they also influence the susceptibility of the host to many immune-mediated diseases and disorders. In this Review, we discuss technological and computational approaches for investigating the microbiome, as well as recent advances in our understanding of host immunity and microbial mutualism with a focus on specific microbial metabolites, bacterial components and the immune system. PMID- 27231053 TI - Ligand-controlled gold-catalyzed cycloisomerization of 1,n-enyne esters toward synthesis of dihydronaphthalene. AB - We describe herein a gold-catalyzed rearrangement of propargyl esters followed by allene-ene cyclization to afford substituted bicyclic [4.4.0] dihydronaphthalene compounds. This method is also applied to vinylethers and vinylamines of 1,7 enyne esters to form dihydroquinoline and dihydrobenzopyran structures. The basis of this transformation is the ligand-controlled preferential activation of the alkene over the allene, affording the desired aromatic bicyclic structures in moderate to excellent yields. PMID- 27231051 TI - The influence of skin microorganisms on cutaneous immunity. AB - The skin is a complex and dynamic ecosystem that is inhabited by many microorganisms. Recent evidence highlights the profound reliance of the skin immune system on its resident microbiota for both host defence and tissue repair. This tissue is also a primary target for infections, which are in some cases caused by normal constituents of the microbiota. In the context of infections and genetic predispositions that are associated with barrier or regulatory network defects, microorganism-induced inflammatory cycles can contribute to the initiation and/or amplification of skin disorders. This Review will discuss some of our current understanding of skin-microbiota and skin-pathogen interactions in the context of homeostasis and diseases and highlight current gaps in our understanding of the skin immune ecosystem. PMID- 27231055 TI - Secukinumab in the Treatment of Generalized Pustular Psoriasis: A Case report. PMID- 27231052 TI - Neutrophil migration in infection and wound repair: going forward in reverse. AB - Neutrophil migration and its role during inflammation has been the focus of increased interest in the past decade. Advances in live imaging and the use of new model systems have helped to uncover the behaviour of neutrophils in injured and infected tissues. Although neutrophils were considered to be short-lived effector cells that undergo apoptosis in damaged tissues, recent evidence suggests that neutrophil behaviour is more complex and, in some settings, neutrophils might leave sites of tissue injury and migrate back into the vasculature. The role of reverse migration and its contribution to resolution of inflammation remains unclear. In this Review, we discuss the different cues within tissues that mediate neutrophil forward and reverse migration in response to injury or infection and the implications of these mechanisms to human disease. PMID- 27231056 TI - Maternal supplementation with a megadose of vitamin A reduces colostrum level of alpha-tocopherol: a randomised controlled trial. AB - BACKGROUND: Maternal supplementation with vitamin A is one of the strategies for controlling its deficiency in the mother-child dyad, although studies with animals showed that supplementation with high doses of vitamin A reduces the levels of alpha-tocopherol (vitamin E) in the mother's serum and milk. The objective of the present study was to assess the influence of maternal supplementation with vitamin A on the concentration of retinol and alpha tocopherol in human milk. METHODS: Healthy puerperal women were randomly distributed into a control group (n = 44) and a supplemented group (n = 44). Blood and colostrum samples were collected after delivery, and mature milk samples were collected 30 days later. The supplemented group received 200 000 IU of retinyl palmitate after the first colostrum collection. The retinol and alpha tocopherol levels in the samples were determined by high-performance liquid chromatography. RESULTS: The mean (SD) retinol and alpha-tocopherol levels in the maternal serum were considered adequate at 46.4 (15.9) and 1023.6 (380.4) MUg dL( 1) , respectively. The colostrum retinol levels of the supplemented group increased significantly 24 h after the intervention (P < 0.001). However, the retinol levels in the mature milk of both groups did not differ (P > 0.05). Moreover, after maternal supplementation with vitamin A, the colostrum alpha tocopherol level decreased by 16.4%, which is a significant reduction (P < 0.05). However, vitamin A supplementation did not affect the alpha-tocopherol level of mature milk (P > 0.05). CONCLUSIONS: Maternal supplementation with high doses of vitamin A increased the colostrum level of this nutrient but reduced the bioavailability of alpha-tocopherol, which may harm the newborn's health because newborns have limited vitamin E reserves. PMID- 27231057 TI - Dependences of Q-branch integrated intensity of linear-molecule pendular spectra on electric-field strength and rotational temperature and its potential applications. AB - We calculate the pendular-state spectra of cold linear molecules, and investigated the dependences of "Q-branch" integrated intensity of pendular spectra on both electric-field strength and molecular rotation-temperature. A new multi-peak structure in the "Q-branch" spectrum is appearing when the Stark interaction strength omega = MUE/B equal to or larger than the critical value. Our study shows that the above results can be used not only to measure the electric-field vector and its spatial distribution in some electrostatic devices, such as the Stark decelerator, Stark velocity filter and electrostatic trap and so on, but also to survey the orientation degree of cold linear molecules in a strong electrostatic field. PMID- 27231058 TI - Corrigendum. PMID- 27231054 TI - Lineage-specific genomics: Frequent birth and death in the human genome: The human genome contains many lineage-specific elements created by both sequence and functional turnover. AB - Frequent evolutionary birth and death events have created a large quantity of biologically important, lineage-specific DNA within mammalian genomes. The birth and death of DNA sequences is so frequent that the total number of these insertions and deletions in the human population remains unknown, although there are differences between these groups, e.g. transposable elements contribute predominantly to sequence insertion. Functional turnover - where the activity of a locus is specific to one lineage, but the underlying DNA remains conserved - can also drive birth and death. However, this does not appear to be a major driver of divergent transcriptional regulation. Both sequence and functional turnover have contributed to the birth and death of thousands of functional promoters in the human and mouse genomes. These findings reveal the pervasive nature of evolutionary birth and death and suggest that lineage-specific regions may play an important but previously underappreciated role in human biology and disease. PMID- 27231059 TI - Digital can help with care. AB - Welcome to the June issue of Nursing Older People. This month, Deidre Wild and colleagues ask the digital question in the second part of their article on digital skills training in care homes ( page 31 ). PMID- 27231061 TI - Older patients miss out in access to specialist lung disease services. AB - PEOPLE OVER the age of 75 are less likely than their younger counterparts to receive an assessment from a lung cancer specialist nurse, despite national guidelines calling for direct, personal access for every person diagnosed with the disease. PMID- 27231060 TI - New journal website will keep you updated when on the move. AB - Promotions / new appointments. PMID- 27231062 TI - RCNi Awards recognise nurses' contribution to enhanced patient care. AB - GERALDINE RODGERS has won the Nursing Older People Award, sponsored by Hallmark Care Homes, at the RCNi Nurse Awards 2016 for her work in creating a more homely and safe environment for patients and staff on a mental health ward. PMID- 27231065 TI - Call for extra funds to meet end of life needs. AB - EXTRA FUNDING for end of life community care is needed to help cope with growing numbers of people dying from cancer, a charity has warned. PMID- 27231066 TI - Strokestra hits the right note for recovery. AB - NURSES ARE helping people recovering from stroke to get involved in an orchestra. PMID- 27231064 TI - Care homes are failing residents with dementia. AB - THE NHS is providing a second-class service to care home residents with dementia in England, a report says. PMID- 27231067 TI - Care home nurses may desert rather than face revalidation. AB - TWO MONTHS ago, the Nursing and Midwifery Council launched a revalidation model that all nurses and midwives in the UK will have to undertake to maintain their registration. PMID- 27231069 TI - Hidden Cameras: Everything You Need to Know About Covert Recording, Undercover Cameras and Secret Filming Plomin Joe Hidden Cameras: Everything You Need to Know About Covert Recording, Undercover Cameras and Secret Filming 224pp L12.99 Jessica Kingsley 9781849056434 1849056439 [Formula: see text]. AB - LAST YEAR, the Care Quality Commission issued guidance to families on using hidden cameras if they are concerned that their relatives are being abused or receiving poor care. Filming in care settings has also resulted in high profile prosecutions, and numerous TV documentaries. Joe Plomin, the author, was the undercover producer who exposed the abuse at Winterbourne View, near Bristol, in 2011. PMID- 27231070 TI - Medicines Management for Nurses at a Glance Young Simon and Pitcher Ben Medicines Management for Nurses at a Glance 120pp L26.99 Wiley Blackwell 9781118840726 1118840720 [Formula: see text]. AB - THIS PUBLICATION presents a general introduction to medicines management rather than an in-depth discussion. However, it is a good starting point for expanding your knowledge on the subject. PMID- 27231072 TI - Diary. AB - Our roundup of what's on. PMID- 27231074 TI - Exercise and dance offer multiple benefits after breast operations. AB - Radiotherapy is administered to most women after breast-conserving surgery for cancer and to some women after mastectomy. PMID- 27231071 TI - DeAR-GP aids referrals. AB - UNDIAGNOSED DEMENTIA among care home residents runs into the 'tens of thousands', making it difficult to access appropriate care, relevant treatments, interventions or services. PMID- 27231075 TI - Signs to look for when ageing affects body's glucose levels. AB - A hypoglycaemic episode in an older adult can lead to complications including falls, unconsciousness, seizures, cardiac events or even death. PMID- 27231076 TI - Aspirin can aid bandage as the best treatment for leg ulcers. AB - Best practice for venous leg ulcers is a firm graduated compression bandage to reduce venous hypertension, aid venous return and reduce peripheral oedema. Sadly, many healed ulcers recur within three months, possibly due to prolonged inflammatory response. PMID- 27231077 TI - Saturated fat may not be as bad for us after all. AB - The traditional diet-heart hypothesis predicts that replacing saturated fat with vegetable oil rich in linoleic acid will reduce coronary heart disease events and deaths by lowering serum cholesterol. Older studies have shown that these dietary changes do indeed reduce serum cholesterol, but the clinical benefits of this have never been clearly demonstrated. PMID- 27231078 TI - Advance care planning for nursing home residents with dementia: policy vs. practice. AB - Despite the potential benefits of ACP for nursing home residents with dementia, the authors of this study highlight that hardly any research has focused on the involvement of residents/families in ACP and that ACP is rarely realised for these people. Their research aimed to evaluate the ACP policy for people with dementia in nursing homes and to gain insight into the involvement of residents with dementia and their families in ACP. PMID- 27231079 TI - Advance care planning for people with dementia. AB - Advance care planning (ACP) provides a framework for discussing and documenting care preferences in preparation for situations in which a person loses the cognitive capacity to make decisions. It can be particularly valuable in assisting people in the early stages of living with a dementia, supported by their families, to document their preferences for care at the later stages of their illness. While the potential benefits of ACP are widely acknowledged, there remain gaps in the research evidence on ACP and challenges in implementing ACP in practice. The three recently-published studies described below address these issues. PMID- 27231080 TI - Uptake of a newly implemented advance care planning program in a dementia diagnostic service. AB - Through a three-stage project in a specialist memory clinic in Australia, researchers introduced ACP to clients with mild cognitive impairment or recently diagnosed dementia and their families. Clients and carers were initially posted a survey assessing completed documentation for future care, understanding of the principles of ACP and willingness to receive further information. Those wanting more information were invited to a seminar introducing the ACP programme and service. Participants wanting to complete ACP documentation could make an appointment with the ACP clinicians. PMID- 27231081 TI - Health care professionals' perspectives of advance care planning for people with dementia living in long-term care settings: a narrative review of the literature. AB - This comprehensive synthesis of published literature from a team in Northern Ireland focused on the perspectives of healthcare professionals in relation to ACP for people with dementia living in long-term care settings. From the 14 papers discussed, the authors identified that people with dementia are often not recognised as having a terminal illness. Four key themes were identified: ? Early integration and planning for palliative care in dementia is important. ? Healthcare professionals' perspectives on ACP are influenced by ethical and moral concerns including presumptions regarding capacity of the person with dementia towards ACP and the impact of the increased role of the family in the decision making processes. ? Challenges in communicating with people who have dementia and their families. ? A need for improvement in healthcare professionals' knowledge of the disease trajectory of dementia with emphasis on end of life care, and a greater understanding of the process of ACP itself. This would assist them in engaging in ACP discussions. PMID- 27231083 TI - Comprehensive geriatric assessment of a mental health service user with safeguarding needs. AB - This is the final article in a short series that presents case study examples of the use of comprehensive geriatric assessment (CGA) in different clinical settings. CGA is a holistic model that is used to determine frail older people's medical and mental health status, as well as any functional, social and environmental issues that might affect their care. When undertaken by nurses, it can enable individualised planning for health, safety and wellbeing. This article explores the case of an older woman living in the community who was receiving support from a number of health and social care services and who had significant safeguarding needs. It highlights the complexity of caring for patients with physical and mental health conditions. CGA can link these conditions and needs together to allow a better understanding of their effects on the patient. The risks of significant transitions in care are also highlighted, along with recommendations for the provision of multidisciplinary care in community settings. PMID- 27231082 TI - Overcoming challenges of conducting research in nursing homes. AB - In the UK, one third of the 850,000 people with dementia live in care homes. This article explores the process of carrying out research in nursing homes, identifying barriers and enabling factors, and making recommendations for researchers. The authors' experiences derive from an ongoing study investigating the effect of educational interventions to promote and embed person-centred care, designed for nurses caring for the people with dementia in nursing homes. Design issues arose from the need to use cluster randomisation which requires a large sample size, implementation fidelity, poor compliance and high numbers of participants lost to follow up. Further difficulties included gaining ethical approval, recruitment, raising concerns and the practicalities of participant retention. There are many benefits of conducting research in care homes, for the homes themselves, their staff and residents. These include training and education, networking and empowerment of staff and subsequent improved standards of care. For the research team, benefits include opportunities to contribute to an underserved setting, to advance care standards and improve nurses' working lives. PMID- 27231085 TI - Award-winning care. AB - HAD SHE been 'clever enough', Anita Astle would have liked to have been a paediatrician. But on failing to get the grades for medicine, she embarked on a nursing career that has already spanned 30 years. She has no regrets. PMID- 27231084 TI - Digital skills training in care homes: achievement. AB - This article describes digital skills training (DST) for staff and later, residents, as part of a programme of culture change in a large care home with nursing in Glasgow. It presents the successes and challenges arising from DST from the perspectives of the two volunteer information technology (IT) champions (Thomas Sloan and John Thomson), who were also staff members. Using their written reports, questionnaires and subsequent conversations, the IT champions recall the challenges and gains for staff and residents as a result of their initial training. This is supplemented by a follow-up on IT activities in the 18 months after the introduction period. PMID- 27231086 TI - Pregnancy and melanoma: a European-wide survey to assess current management and a critical literature overview. AB - BACKGROUND: Management of melanoma during pregnancy can be extremely challenging. The reported incidence of melanoma in pregnancy ranges from 2.8 to 5.0 per 100 000 pregnancies. There are no guidelines for the management of melanoma during pregnancy. METHODS: The survey was designed to investigate the opinions of melanoma physicians on decision making in relation to pregnancy and melanoma. A clinical scenario-based survey on management of pregnancy in melanoma was distributed all over Europe via the membership of the EORTC and other European melanoma societies. RESULTS: A total of 290 questionnaires were returned with a larger participation from southern Europe. A large heterogeneity was found for the answers given in the different clinical scenarios with 50% of the answers showing discordance, especially regarding sentinel lymph node biopsy during pregnancy. Discordant answers were also found for the counselling of women about a potential delay in getting pregnant after a high-risk melanoma (35% for a 2 year wait minimum vs. 57% no waiting needed), while for thin melanomas, as expected, there was more concordance with 70% of the physicians recommending no delay. Fifteen per cent of physicians recommended an abortion in stage II melanoma during the third month of pregnancy. Twenty per cent of the responders advised against hormonal replacement therapy in melanoma patients. CONCLUSIONS: The management of melanoma during pregnancy varies widely in Europe. At present, there is a lack of consensus in Europe, which may lead to very important decisions in women with melanoma, and guidelines are needed. PMID- 27231087 TI - Faith-Based Interventions: Pathways to Health Promotion. PMID- 27231088 TI - Relationship Between Physical and Psychological Status of Cancer Patients and Caregivers. AB - The purpose of this study was to describe the relationship between patient physical and emotional status and caregiver mood state for patients with advanced cancer. Data were collected from 299 cancer patients and their caregivers from a cancer center. We used a longitudinal design and collected data through interviews. The relationships between patient and caregiver emotional states over time were moderate and statistically significant at all three points in time (p values = .012-.0001). Patient physical and emotional status predicted caregiver mood state at all points in time (betas = -.22 to -.25) and caregiver mood state at baseline predicted patient emotional status at 3 months (beta = -.16, p = .013). Relationships between patient emotional status and caregiver mood state were moderately strong. Addressing the emotional needs of both patients and caregivers has the potential to yield improved emotional outcomes for both over time. PMID- 27231089 TI - Midwest Nursing Research Society News. PMID- 27231090 TI - Increased Risk for Adhesive Capsulitis of the Shoulder following Cervical Disc Surgery. AB - Shoulder problems are common in patients with a cervical herniated intervertebral disc (HIVD). This study aimed to explore the incidence and risk of shoulder capsulitis/tendonitis following cervical HIVD surgery. We used data from the Taiwan "Longitudinal Health Insurance Database". We identified all patients who were hospitalized with a diagnosis of displacement of a cervical HIVD and who underwent cervical surgery (n = 1625). We selected 8125 patients who received cervical HIVD conservative therapy only as the comparison group matched with study patients. We individually tracked these sampled patients for 6 months to identify all patients who received a diagnosis of shoulder tendonitis/capsulitis. We found that incidence rates of shoulder tendonitis/capsulitis during the 6 month follow-up period were 3.69 (95% CI: 2.49~5.27) per 100 person-years for the study group and 2.33 (95% CI: 1.89~2.86) per 100 person-years for the comparison group. Cox proportional hazard regressions showed that the adjusted hazard ratio for shoulder tendonitis/capsulitis among patients who underwent cervical disc surgery was 1.66 (95% CI = 1.09~2.53) when compared to comparison group. We concluded that patients who underwent surgery for a cervical HIVD had a significantly higher risk of developing shoulder capsulitis/tendonitis in 6 months follow-up compared to patients who received cervical HIVD conservative therapy only. PMID- 27231091 TI - alpha-Terpineol, a monoterpene alcohol, complexed with beta-cyclodextrin exerts antihyperalgesic effect in animal model for fibromyalgia aided with docking study. AB - The anti-hyperalgesic effect of the complex containing alpha-terpineol (alphaTPN) and beta-cyclodextrin (betaCD) was analyzed in a non-inflammatory chronic muscle pain model, as well as its mechanism of action through docking study for a possible interaction with receptors. The alphaTPN-betaCD complex was prepared and characterized through the thermogravimetry/derivate thermogravimetry (TG/DTG), Fourier transform infrared spectroscopy (FTIR) and scanning electron microscope (SEM). The model of chronic muscle pain was induced by two injections of pH 4.0 saline (20 MUl) into the left gastrocnemius 5 days apart. After confirming hyperalgesia, male mice were treated with alphaTPN-betaCD (25, 50 or 100 mg/kg; p.o.) or vehicle (saline 0.9%, p.o.) daily for 10 days. 1 h after the mechanical hyperalgesia, motor performance was evaluated. In addition, the systemic administration of naloxone and ondansetron tested the analgesic effect on the active opioid and serotonin receptors, respectively. The characterization tests indicated that alphaTPN was efficiently incorporated into betaCD. The oral treatment with alphaTPN-betaCD, at all doses tested, produced a significant (p < 0.001) decrease in the mechanical hyperalgesia, without causing any alteration in the force and in motor performance. This analgesic effect was reversed by the systemic administration of naloxone or ondansetron. These findings are corroborated by the docking study described in the present study, which verified a possible interaction of alphaTPN-betaCD with opioid (MU, Kappa, Delta) and 5-HT receptors. Thus, it can be concluded that alphaTPN-betaCD reduced the hyperalgesia followed by the chronic muscle pain model, probably evoked by the descending inhibitory pain system, specifically by opioid and serotoninergic receptors. PMID- 27231093 TI - VEGF-A stimulates podosome-mediated collagen-IV proteolysis in microvascular endothelial cells. AB - Podosomes are dynamic cell-matrix contact structures that combine several key abilities, including adhesion, matrix degradation and mechanosensing. These actin based cytoskeletal structures have been mostly studied in monocytic cells, but much less is known about those formed in other lineages. In this study, we characterise podosomes in capillary-derived microvascular endothelial cells. We identify two types of podosomes: constitutive podosomes that form in the absence of specific stimulation and induced podosomes that arise in response to the angiogenic factor VEGF-A. Constitutive and VEGF-A-induced podosomes share similar components but exhibit marked differences in terms of gelatinolytic activity. We also show that the extracellular matrix proteins laminin and collagen-IV are key determinants of the VEGF-A response, but neither collagen-I nor fibronectin are conducive for podosome induction. Moreover, only collagen-IV elicits the formation of proteolytically active podosomes through a mechanism involving increased Src phosphorylation, p190RhoGAP-B (also known as ARHGAP5) relocalisation and MT1-MMP (also known as MMP14) cell surface exposure at podosome sites. We hypothesise that by promoting podosome formation, VEGF-A enables endothelial cells to overcome the basement membrane barrier to allow sprouting outwards from the existing vasculature. PMID- 27231092 TI - Shot and Patronin polarise microtubules to direct membrane traffic and biogenesis of microvilli in epithelia. AB - In epithelial tissues, polarisation of microtubules and actin microvilli occurs along the apical-basal axis of each cell, yet how these cytoskeletal polarisation events are coordinated remains unclear. Here, we examine the hierarchy of events during cytoskeletal polarisation in Drosophila melanogaster epithelia. Core apical-basal polarity determinants polarise the spectrin cytoskeleton to recruit the microtubule-binding proteins Patronin (CAMSAP1, CAMSAP2 and CAMSAP3 in humans) and Shortstop [Shot; MACF1 and BPAG1 (also known as DST) in humans] to the apical membrane domain. Patronin and Shot then act to polarise microtubules along the apical-basal axis to enable apical transport of Rab11 endosomes by the Nuf-Dynein microtubule motor complex. Finally, Rab11 endosomes are transferred to the MyoV (also known as Didum in Drosophila) actin motor to deliver the key microvillar determinant Cadherin 99C to the apical membrane to organise the biogenesis of actin microvilli. PMID- 27231095 TI - Decompensation: A Novel Approach to Accounting for Stress Arising From the Effects of Ideology and Social Norms. AB - To date, research that has drawn on Meyer's (2003) minority stress model has largely taken for granted the premises underpinning it. In this article we provide a close reading of how "stress" is conceptualized in the model and suggest that aspects of the model do not attend to the institutionalized nature of stressors experienced by people with marginalized identities, particularly lesbian, gay, bisexual, and transgender individuals. As a counter to this, we highlight the importance of a focus on the effects of ideology and social norms in terms of stress, and we argue why an intersectional approach is necessary to ensure recognition of multiple axes of marginalization and privilege. The article then outlines the concept of decompensation and suggests that it may offer one way to reconsider the effects of ideology and social norms. The decompensation approach centers on the need for social change rather than solely relying on individuals to be resilient. PMID- 27231094 TI - The Nim1 kinase Gin4 has distinct domains crucial for septin assembly, phospholipid binding and mitotic exit. AB - In fungi, the Nim1 protein kinases, such as Gin4, are important regulators of multiple cell cycle events, including the G2-M transition, septin assembly, polarized growth and cytokinesis. Compelling evidence has linked some key functions of Gin4 with the large C-terminal non-kinase region which, however, is poorly defined. By systematically dissecting and functionally characterizing the non-kinase region of Gin4 in the human fungal pathogen Candida albicans, we report the identification of three new domains with distinct functions: a lipid binding domain (LBD), a septin-binding domain (SBD) and a nucleolus-associating domain (NAD). The LBD and SBD are indispensable for the function of Gin4, and they alone could sufficiently restore septin ring assembly in GIN4-null mutants. The NAD localizes to the periphery of the nucleolus and physically associates with Cdc14, the ultimate effector of the mitotic exit network. Gin4 mutants that lack the NAD are defective in spindle orientation and exit mitosis prematurely. Furthermore, we show that Gin4 is a substrate of Cdc14. These findings provide novel insights into the roles and mechanisms of Nim1 kinases in the regulation of some crucial cell cycle events. PMID- 27231096 TI - The effect of sleep deprivation on leadership behaviour in military officers: an experimental study. AB - While several studies show that leaders frequently lack sleep, little is known about how this influences leadership behaviour. The present study encompasses an experiment that investigated how three main types of leadership behaviour: transformational (four sub-facets); transactional (two sub-facets); and passive avoidant (two sub-facets) leadership differed across a rested and a long-term, partially sleep-deprived condition. A total of 16 military naval officers participated. In both conditions, the leaders managed a team of three subordinates in a navy navigation simulator, instructed to complete a specific mission (A or B). Both sleep state (rested or sleep deprived) and mission were counterbalanced. Leadership behaviour was video recorded and subsequently rated on the three leadership behaviours. Overall, the scores on transformational leadership (and on two of four sub-facets) and transactional leadership (on both sub-facets) decreased from the rested to sleep-deprived condition, whereas scores on passive-avoidant leadership overall (and on both sub-facets) increased from the rested to sleep-deprived condition. This study underscores the importance of including sleep as a potentially important determinant when assessing leadership effectiveness. PMID- 27231097 TI - Intervention improves assisted conception intracytoplasmic sperm injection outcomes for patients with high levels of sperm DNA fragmentation: a retrospective analysis. AB - Sperm DNA fragmentation (SDF) is used in assisted reproductive technology (ART) programs as an indicator for sperm quality, although there is still a lack of consensus as to its clinical utility. In this retrospective study, we examined intracytoplasmic sperm injection (ICSI) outcomes of 1924 infertile patients who underwent SDF analysis using the sperm chromatin integrity test. ART patients were classified as having low [DNA fragmentation index (DFI) <29%] or high SDF (DFI >=29%) and by whether or not an intervention [physiological intracytoplasmic sperm injection (PICSI), intracytoplasmic morphologically selected sperm injection (IMSI), testicular sperm extraction (TESE)/testicular sperm aspiration (TESA), frequent ejaculation] was performed. High SDF patients who did not have an intervention had a lower fertilization rate and poorer clinical outcomes from blastocyst transfers as compared with low SDF patients; the fertilization rate was 66.0% vs. 70.2% (p = 0.042), single embryo transfer (SET) fetal heart pregnancy rate was 28.5% vs. 45.2% (p = 0.042), and SET live birth rate was 24.9% vs. 40.6% (p = 0.060), respectively. Furthermore, high SDF patients who had an intervention had significantly improved blastocyst transfer outcomes, similar to those of low SDF patients; the SET live birth rate for high SDF intervention patients was 43.8% as compared with 24.9% for high SDF no intervention patients (p = 0.037) and 40.6% for low SDF patients (p = 0.446). Analysis of the three main intervention subgroups for high SDF patients revealed that TESE/TESA patients had the highest SET live birth rate; in comparison with 24.2% for high SDF patients who did not have an intervention, PICSI patients had 38.3% (p = 0.151), IMSI patients had 28.7% (p = 0.680), and TESE/TESA patients had 49.8% (p = 0.020). Our data suggest that SDF results indicate ICSI outcomes and that patients who have high SDF benefit from an intervention. PMID- 27231098 TI - Synthesis and Anticonvulsant Activity of N-(Substituted)-1-methyl-2,4-dioxo-1,2 dihydroquinazoline-3(4H)-carboxamides. AB - A series of new N-(substituted)-1-methyl-2,4-dioxo-1,2-dihydroquinazoline-3(4H) carboxamides were designed, synthesized, and evaluated for their anticonvulsant activity. Most of the synthesized compounds exhibited potent anticonvulsant activities in the maximal electroshock (MES) and pentylenetetrazol (PTZ) test. The most promising compound 4c showed significant anticonvulsant activity with a protective index value of 3.58. The compounds 4a-c were also found to have encouraging anticonvulsant activity in the MES and PTZ screen when compared with the standard drugs, valproate and methaqualone. The same compounds were found to exhibit advanced anticonvulsant activity as well as lower neurotoxicity than the reference drugs. PMID- 27231099 TI - Treatment failure and drug resistance in HIV-positive patients on tenofovir-based first-line antiretroviral therapy in western Kenya. AB - INTRODUCTION: Tenofovir-based first-line antiretroviral therapy (ART) is recommended globally. To evaluate the impact of its incorporation into the World Health Organization (WHO) guidelines, we examined treatment failure and drug resistance among a cohort of patients on tenofovir-based first-line ART at the Academic Model Providing Access to Healthcare, a large HIV treatment programme in western Kenya. METHODS: We determined viral load (VL), drug resistance and their correlates in patients on >=six months of tenofovir-based first-line ART. Based on enrolled patients' characteristics, we described these measures in those with (prior ART group) and without (tenofovir-only group) prior non-tenofovir-based first-line ART using Wilcoxon rank sum and Fisher's exact tests. RESULTS: Among 333 participants (55% female; median age 41 years; median CD4 336 cells/uL), detectable (>40 copies/mL) VL was found in 18%, and VL>1000 copies/mL (WHO threshold) in 10%. Virologic failure at both thresholds was significantly higher in 217 participants in the tenofovir-only group compared with 116 in the prior ART group using both cut-offs (24% vs. 7% with VL>40 copies/mL; 15% vs. 1% with VL>1000 copies/mL). Failure in the tenofovir-only group was associated with lower CD4 values and advanced WHO stage. In 35 available genotypes from 51 participants in the tenofovir-only group with VL>40 copies/mL (69% subtype A), any resistance was found in 89% and dual-class resistance in 83%. Tenofovir signature mutation K65R occurred in 71% (17/24) of the patients infected with subtype A. Patients with K65R had significantly lower CD4 values, higher WHO stage and more resistance mutations. CONCLUSIONS: In this Kenyan cohort, tenofovir-based first line ART resulted in good (90%) virologic suppression including high suppression (99%) after switch from non-tenofovir-based ART. Lower virologic suppression (85%) and high observed resistance levels (89%) in the tenofovir-only group impact future treatment options, support recommendations for widespread VL monitoring in such resource limited settings to identify early treatment failure and suggest consideration of individualized resistance testing to design effective subsequent regimens. PMID- 27231100 TI - Primary Fatty Alcohols Are Major Components of Suberized Root Tissues of Arabidopsis in the Form of Alkyl Hydroxycinnamates. AB - Suberin is a complex hydrophobic polymer that acts as a barrier controlling water and solute fluxes and restricting pathogen infections. Suberin is deposited immediately outside of the plasmalemma in the cell wall of certain tissues such as endodermis of roots, aerial and underground periderms, and seed coats. Suberin consists of a variety of fatty acid derivatives polymerized with glycerol and phenolics. In this study, we show using liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry techniques that most of the fatty alcohols not covalently linked to the suberin polymer are in the form of alkyl hydroxycinnamates (AHCs), with alkyl caffeates predominating. Such compounds are not restricted to the periderm of mature roots but also are present in the endodermis of younger roots, where they are not extracted by rapid dipping in chloroform. Analysis of several mutants affected in key enzymes involved in the biosynthesis and export of suberin monomers suggests that the formation of the suberin polymer and associated waxes involves common pathways and occurs concomitantly in Arabidopsis (Arabidopsis thaliana) roots. Although fatty alcohols represent only minor components of the suberin polymer in Arabidopsis roots, this study demonstrates that they constitute the major aliphatics of suberin-associated waxes in the form of AHCs. Therefore, our results indicate that esterified fatty alcohols, both soluble and polymerized forms, represent major constituents of Arabidopsis root suberized barriers, being as abundant as alpha,omega-dicarboxylic and unsubstituted fatty acids. In addition, our results show that suberized layers represent a major sink for acyl-lipid metabolism in Arabidopsis roots. PMID- 27231101 TI - Cytosolic Glutamine Synthetase Gln1;2 Is the Main Isozyme Contributing to GS1 Activity and Can Be Up-Regulated to Relieve Ammonium Toxicity. AB - Cytosolic GS1 (Gln synthetase) is central for ammonium assimilation in plants. High ammonium treatment enhanced the expression of the GS1 isogene Gln-1;2 encoding a low-affinity high-capacity GS1 protein in Arabidopsis (Arabidopsis thaliana) shoots. Under the same conditions, the expression of the high-affinity low-capacity isoform Gln-1;1 was reduced. The expression of Gln-1;3 did not respond to ammonium treatment while Gln-1;4 and Gln-1;5 isogenes in all cases were expressed at a very low level. Gln-2 was highly expressed in shoots but only at a very low level in roots. To investigate the specific functions of the two isogenes Gln-1;1 and Gln-1;2 in shoots for ammonium detoxification, single and double knock-out mutants were grown under standard N supply or with high ammonium provision. Phenotypes of the single mutant gln1;1 were similar to the wild type, while growth of the gln1;2 single mutant and the gln1;1:gln1;2 double mutant was significantly impaired irrespective of N regime. GS1 activity was significantly reduced in both gln1;2 and gln1;1:gln1;2 Along with this, the ammonium content increased while that of Gln decreased, showing that Gln-1;2 was essential for ammonium assimilation and amino acid synthesis. We conclude that Gln-1;2 is the main isozyme contributing to shoot GS1 activity in vegetative growth stages and can be up-regulated to relieve ammonium toxicity. This reveals, to our knowledge, a novel shoot function of Gln-1;2 in Arabidopsis shoots. PMID- 27231103 TI - Foreword. PMID- 27231102 TI - A GTPase-Dependent Fine ER Is Required for Localized Secretion in Polarized Growth of Root Hairs1. AB - The endoplasmic reticulum (ER) is a cellular network comprising membrane tubules and sheets stretching throughout the cytoplasm. Atlastin GTPases, including Atlastin-1 in mammals and RHD3 in plants, play a role in the generation of the interconnected tubular ER network by promoting the fusion of ER tubules. Root hairs in rhd3 are short and wavy, a defect reminiscent of axon growth in cells with depleted Atlastin-1. However, how a loss in the ER complexity could lead to a defective polarized cell growth of root hairs or neurons remains elusive. Using live-cell imaging techniques, we reveal that, a fine ER distribution, which is found in the subapical zone of growing root hairs of wild-type plants, is altered to thick bundles in rhd3 The localized secretion to the apical dome as well as the apical localization of root hair growth regulator ROP2 is oscillated in rhd3 Interestingly, the shift of ROP2 precedes the shift of localized secretion as well as the fine ER distribution in rhd3 Our live imaging and pharmacologic modification of root hair growth defects in rhd3 suggest that there is interplay between the ER and microtubules in the polarized cell growth of root hairs. We hypothesize that, under the guidance of ROP2, RHD3, together with the action of microtubules, is required for the formation of a fine ER structure in the subapical zone of growing root hairs. This fine ER structure is essential for the localized secretion to the apical dome in polarized cell growth. PMID- 27231104 TI - Histone Deacetylase Inhibitors Modulating Non-epigenetic Players: The Novel Mechanism for Small Molecule Based Therapeutic Intervention. AB - Histone deacetylases (HDACs) play a crucial role in regulating the expression and activity of myriad of proteins involved in tumour onset and progression. HDAC activity results in a nonpermissive chromatin conformation by erasing acetyl moiety from histone substrates culminating in transcriptional repression of those genes having significant role in tumourigenesis. Apart from histones, HDACs deacetylate a variety of non-histone proteins including transcription factors involved in controlling cell growth, differentiation and apoptosis. Histone deacetylase inhibitors (HDACi) are small-molecules restraining HDACs and hence modulating their biological activity. Emerging evidences suggest that acetylation of non-histone proteins plays a critical role in various cellular processes including mRNA stability, protein localization and degradation. Abnormal turnover or expression of non-histone proteins like nuclear factor- kappaB (NF-kappaB), heat shock protein 90 (HSP90) and frataxin fuels various diseases including cancer. The present article explores the therapeutic role of HDACi with special emphasis on modulation of clinically relevant non-histone molecular targets. Extensive details regarding the non-histone proteins and their deregulation in disease states have also been provided. Moreover, the underlying molecular mechanism triggered by HDACi to overcome disease states by modulating the predefined targets has also been illuminated. The article strongly suggests the promising use of HDACi in therapeutic intervention against complications arising due to non-histone protein deregulation. PMID- 27231105 TI - The Connections Among Autophagy, Inflammasome and Mitochondria. AB - BACKGROUND: The molecular crosstalk between inflammation and autophagy is an emerging field of research that is essential for the understanding of multicellular organism homeostasis and how these processes influence a variety of pathological conditions. OBJECTIVE: In this review, we briefly describe the relationship between autophagy and inflammasome activation. The central role that mitochondria play in both cellular processes is also discussed. CONCLUSION: Inflammasome and autophagy often modulate each other by common inhibitory mechanisms that are controlled by different input pathways. Thus, inflammasome components coordinate autophagy and autophagy regulates inflammasome activation, making the balance between both processes a fundamental player in cellular homeostasis. PMID- 27231106 TI - Biologic Therapies in Ulcerative Colitis: Primi Inter Pares? AB - BACKGROUND: In the last decade, the introduction of the first anti-tumor necrosis factor (TNF)-alpha agent infliximab has revolutionized the treatment of ulcerative colitis (UC). However, this drug is not a magic bullet since up to 50% of UC patients do not respond (primary failure) or lose response to infliximab (secondary failure). Hence the demand for novel drugs to fill the unmet medical need. OBJECTIVE: The aim of this review is to discuss the data from randomized controlled trials (RCTs) of available biological agents for the treatment of moderate-to-severe UC in adults, in order to support clinical decision making. RESULTS AND CONCLUSION: New biological agents are now available for the treatment of moderate-tosevere UC. Adalimumab and golimumab are anti-TNF-alpha monoclonal antibodies, as is infliximab, whereas vedolizumab blocks the integrin alpha4beta7/mucosal addressin cell adhesion molucule-1 (MAd- CAM). Additions to the therapeutic arsenal boost the chances of successful treatment of UC, but lead to difficulty choosing the most appropriate biological drug: which biologic to use first and when and how to switch. In the absence of head-to-head trials to answer these questions, a network metaanalysis of the available RCTs can provide estimates of relative efficacy between interventions. Other factors, including convenience and satisfaction for the patient, route of administration, the cost of treatment, and the safety and efficacy profile, should all be considered. PMID- 27231107 TI - Smart Drug-Delivery Systems for Cancer Nanotherapy. AB - BACKGROUND: Despite all the advances achieved in the field of tumor-biology research, in most cases conventional therapies including chemotherapy are still the leading choices. The main disadvantage of these treatments, in addition to the low solubility of many antitumor drugs, is their lack of specificity, which leads to the occurrence of severe side effects due to nonspecific drug uptake by healthy cells. OBJECTIVE: The purpose of this manuscript is to review and analyze the recent progress made in cancer nanotherapy. RESULTS: Progress in nanotechnology and its application in medicine have provided new opportunities and different smart systems. Such systems can improve the intracellular delivery of the drugs due to their multifunctionality and targeting potential. First, we provide a global overview of cancer and different smart nanoparticles currently used in oncology. Then, we analyze in detail the development of drug-delivery strategies in cancer therapy, focusing mainly on the intravenously administered smart nanoparticles. Finally, we discuss the challenges, clinical trials, marketed nanomedicines and future directions of the nanotherapy applied to cancer treatment. CONCLUSION: In this review, we have evidenced the tremendous potential that smart drug-delivery systems have to enhance the therapeutic effect of current standard treatment modalities, including chemotherapies and radiotherapies. PMID- 27231108 TI - New Pharmacological Approaches Using Polyphenols on the Physiopathology of Neuropathic Pain. AB - Polyphenols constitute a group of a paramount importance within the natural products in the plant kingdom, with an approximate amount of 8000 phenolic structures currently known. Fruits, vegetables, whole grains and several other foods and beverages (as tea, chocolate and wine, for instance) are rich and important sources of polyphenols. The scientific literature provides pre-clinical experimental evidence on the antinociceptive effects of polyphenolic compounds, found in plant extracts, in animal models of neuropathic pain. But not only neuropathic pain is attenuated: in fact, nociceptive pain, caused by stimulation of nerve fibers (either somatic or visceral) responding only to stimuli approaching or exceeding harmful intensity thresholds (nociceptors), and also inflammatory pain, which is associated with tissue damage and infiltration of immune cells, are both reduced and alleviated by polyphenols. In the present work, the antinociceptive effects of polyphenols are reviewed. PMID- 27231109 TI - The Smart Programmable CRISPR Technology: A Next Generation Genome Editing Tool for Investigators. AB - BACKGROUND: The present era is fast experiencing rapid innovation in the genome editing technology. CRISPR Cas9-mediated targeted genetic manipulation is an easy, cost-effective and scalable method. As a result, it can be used for a broad range of targeted genome engineering. OBJECTIVE: The main objective of the present review is to highlight the structural signature, classification, its mechanism and application from basic science to medicine and future challenges for this genome editing tool kit. RESULTS: The present review provides a brief description of the recent development of CRISPR-Cas9 genome editing technology. We discuss the paradigms shift for this next generation genome editing technology, CRISPR. The CRISPR structural significance, classification and its different applications are also being discussed. We portray the future challenges for this extraordinary genome in vivo editing tool. We also highlight the role of CRISPR genome editing in curing many diseases. CONCLUSION: Scientists and researchers are constantly looking one genome editing tool that is competent, simple and low-cost assembly of nucleases. It can target any particular site without any off-target mutations in the genome. The CRISPR-Cas9 has all of the above characteristics. The genome engineering technology may be a strong and inspiring technology meant for the next generation of drug development. PMID- 27231110 TI - Ion-Responsive Drug Delivery Systems. AB - BACKGROUND: Some kinds of cations and anions are contained in body fluids such as blood, interstitial fluid, gastrointestinal juice, and tears at relatively high concentration. Ionresponsive drug delivery is available to design the unique dosage formulations which provide optimized drug therapy with effective, safe and convenient dosing of drugs. OBJECTIVE: The objective of the present review was to collect, summarize, and categorize recent research findings on ion-responsive drug delivery systems. RESULTS: Ions in body fluid/formulations caused structural changes of polymers/molecules contained in the formulations, allow formulations exhibit functions. The polymers/molecules responding to ions were ion-exchange resins/fibers, anionic or cationic polymers, polymers exhibiting transition at lower critical solution temperature, self-assemble supramolecular systems, peptides, and metalorganic frameworks. The functions of ion-responsive drug delivery systems were categorized to controlled drug release, site-specific drug release, in situ gelation, prolonged retention at the target sites, and enhancement of drug permeation. Administration of the formulations via oral, ophthalmic, transdermal, and nasal routes has showed significant advantages in the recent literatures. CONCLUSION: Many kinds of drug delivery systems responding to ions have been reported recently for several administration routes. Improvement and advancement of these systems can maximize drugs potential and contribute to patients in the world. PMID- 27231111 TI - Targeting Hsp90-Cdc37: A Promising Therapeutic Strategy by Inhibiting Hsp90 Chaperone Function. AB - BACKGROUND & OBJECTIVE: The Hsp90 chaperone protein regulates the folding, maturation and stability of a wide variety of oncoproteins. In recent years, many Hsp90 inhibitors have entered into the clinical trials while all of them target ATPase showing similar binding capacity and kinds of side-effects so that none have reached to the market. During the regulation progress, numerous protein- protein interactions (PPI) such as Hsp90 and client proteins or cochaperones are involved. With the Hsp90-cochaperones PPI networks being more and more clear, many cancerous proteins have been reported to be tightly correlated to Hsp90 cochaperones PPI. Among them, Hsp90-Cdc37 PPI has been widely reported to associate with numerous protein kinases, making it a novel target for the treatment of cancers. RESULTS AND CONCLUSION: In this paper, we briefly review the strategies and modulators targeting Hsp90-Cdc37 complex including direct and indirect regulation mechanism. Through these discussions we expect to present inspirations for new insights into an alternative way to inhibit Hsp90 chaperone function. PMID- 27231113 TI - Drug interaction between idelalisib and diazepam resulting in altered mental status and respiratory failure. AB - In recent years, several new oral anticancer drugs have been approved, many via an accelerated approval process. These new agents have the potential for drug interactions, but lack of familiarity with these drugs by clinicians may increase the risk for drug interactions. We describe an interaction between the new anticancer agent idelalisib (CYP 3A4 inhibitor) and diazepam (CYP 3A4 substrate) that resulted in altered mental status and type II respiratory failure resulting in hospitalization. After discontinuation of both agents, the patient recovered quickly. Idelalisib was reinitiated after discharge. Lorazepam was substituted for diazepam since it is not metabolized via CYP 3A4. Both agents were tolerated well thereafter. This interaction was only flagged by two of four commonly used drug interaction databases. Clinicians should exercise caution with initiating new oral anticancer agents and consider the potential for drug interactions without solely relying on drug interaction databases. PMID- 27231112 TI - Functional Components from Nature-Derived Drugs for the Treatment of Rheumatoid Arthritis. AB - Rheumatoid arthritis (RA) is a chronic systemic disorder characterized by persistent synovitis and systemic inflammation. Currently, the widely used drugs for the treatment of RA are disease-modifying antirheumatic drugs, biological agents and glucocorticoids. But their clinical use has been limited because of their adverse effects with a high frequency and high cost of treatment. It is essential to find novel candidate agents. Traditional Chinese medicine (TCM) has been used for RA treatment for a long period of time. In recent years, significant amounts of studies have shown that some TCMs and their active ingredients have obvious therapeutic effects on RA. In this review, the compounds in TCMs that have an effect in clinic or animal experiments of RA are critically reviewed and summarized. Moreover, the relationship between chemical structures of the compound and their activities is analyzed. The relevant researches are described from the aspects of source, methods, result, and related mechanism analysis. The existing studies show that most effective compounds in TCM for RA treatment belong to alkaloids, flavonoids, terpenoids, phenols and quinines. It is hoped that the data summarized in this review will be beneficial to the screening of new nature-derived antirheumatic drugs. PMID- 27231114 TI - Scale Changes Provide an Alternative Cue For the Discrimination of Heading, But Not Object Motion. AB - BACKGROUND Understanding the dynamics of our surrounding environments is a task usually attributed to the detection of motion based on changes in luminance across space. Yet a number of other cues, both dynamic and static, have been shown to provide useful information about how we are moving and how objects around us move. One such cue, based on changes in spatial frequency, or scale, over time has been shown to be useful in conveying motion in depth even in the absence of a coherent, motion-defined flow field (optic flow). MATERIAL AND METHODS 16 right handed healthy observers (ages 18-28) participated in the behavioral experiments described in this study. Using analytical behavioral methods we investigate the functional specificity of this cue by measuring the ability of observers to perform tasks of heading (direction of self-motion) and 3D trajectory discrimination on the basis of scale changes and optic flow. RESULTS Statistical analyses of performance on the test-experiments in comparison to the control experiments suggests that while scale changes may be involved in the detection of heading, they are not correctly integrated with translational motion and, thus, do not provide a correct discrimination of 3D object trajectories. CONCLUSIONS These results have the important implication for the type of visual guided navigation that can be done by an observer blind to optic flow. Scale change is an important alternative cue for self-motion. PMID- 27231115 TI - Sitosterolemia Presenting as Pseudohomozygous Familial Hypercholesterolemia. AB - A young girl, age 8.5 years, presented with profound hypercholesterolemia and early xanthomatosis, suggesting homozygous familial (or type II) hypercholesterolemia. The patient's low density lipoprotein (LDL) receptor function and parental lipoprotein profiles were determined to be normal, prompting revision of the initial diagnosis to pseudohomozygous familial hypercholesterolemia. When she subsequently presented with giant platelets, the case was presented to colleagues on an electronic mailing list. It was recommended that plasma and sterol analysis be performed, which led to a diagnosis of sitosterolemia. The presentation of profound hypercholesterolomia in childhood that ultimately is not attributed as due to homozygous or compound heterozygous defects in the LDL receptor gene has been termed pseudohomozygous familial (or type II) hypercholesterolemia (PHT2HC). Patients diagnosed with PHT2HC subsequently confirmed to have sitosterolemia have been previously reported only rarely. The challenge of achieving accurate specific diagnosis and appropriate workup for these conditions in children is discussed in the context of this rare case and review of the historical literature concerning these conditions. PMID- 27231116 TI - Comparison of Two Types of Insoles on Musculoskeletal Symptoms and Plantar Pressure Distribution in a Work Environment: A Randomized Clinical Trial. AB - BACKGROUND: The aim of the present study was to assess plantar pressure distribution and musculoskeletal symptoms following the use of customized insoles among female assembly line workers. METHODS: The study included 29 female assembly line workers (age, 29.76 +/- 5.79 years; weight, 63.79 +/- 12.11 kg) with musculoskeletal symptoms who work predominantly while standing. The Nordic Musculoskeletal Questionnaire was administered to the study population. Plantar pressure was determined using a computerized plantar pressure feedback system. A control group (n=13) used ethylvinylacetate insoles (Podaly(r)) that were individually heat molded and heat glued. The intervention group (n=14) also used the insoles and a strip of the same material was added to the site of greatest plantar pressure as determined by the electronic feedback device. After five weeks, the plantar pressure data were collected again and the questionnaire was administered a second time. RESULTS: There was no significant difference between groups with regard to pain in any anatomic site. However, within each group the lumbar region exhibited a reduction in symptoms in the intervention group (P<0.05), and the feet exhibited a reduction in symptoms in both groups (P<0.05). Mean plantar pressure increased and plantar surface decreased in the intervention group (P<0.05). CONCLUSION: Insoles increased foot comfort in both groups. However, the added strip did not significantly modify either plantar pressure or other symptoms in female workers. PMID- 27231117 TI - Biochemical Testing of the Thyroid: TSH is the Best and, Oftentimes, Only Test Needed - A Review for Primary Care. AB - Disorders of thyroid function are common, and screening, diagnosis, and management are often performed by primary care providers. While management of significant biochemical abnormalities is reasonably straight forward, laboratory tests only slightly outside, or even within, the normal range are becoming more difficult to appropriately manage. A large part of this increasing difficulty in appropriate management is caused by patients requesting, and even demanding, certain tests or treatments that may not be indicated. Symptoms of thyroid dysfunction are non-specific and extremely prevalent in the general population. This, along with a growing body of information available to patients via the lay press and internet suggesting that traditional thyroid function testing is not reliable, has fostered some degree of patient mistrust. Increasingly, when a physician informs a patient that their thyroid is not the cause of their symptoms, the patient is dissatisfied and even angry. This review aims to clarify the interpretation of normal and mild abnormalities of thyroid function tests by describing pituitary-thyroid physiology and through an in depth review of, arguably, the three most important biochemical tests of thyroid function: TSH, free T4, and anti-TPO antibodies. It is important for primary care providers to have an understanding of the shortcomings and proper interpretation of these tests to be better able to discuss thyroid function with their patients. PMID- 27231118 TI - Central Venous Access Device-Related Bacillus Cereus Endocarditis: A Case Report and Review of the Literature. AB - Bacillus cereus typically presents as a gastrointestinal infection, but rarely manifests as systemic disease. This report describes a case of B. cereus-related endocarditis that presented as a sickle cell crisis and bacteremia. Initial clinical suspicion was for laboratory contamination of blood cultures. The case herein described is intended to demonstrate an uncommon presentation of B. cereus infection and highlights the value of an aggressive need to further investigate and interpret unexpected blood culture findings in clinical practice, early adequate antimicrobial therapy, prompt diagnosis, and consideration to urgent surgical interventions in such cases. PMID- 27231119 TI - A radiological and pathological assessment of ileocolic pedicle length as a predictor of lymph node retrieval following right hemicolectomy for caecal cancer. AB - BACKGROUND: In colon cancer, the number of harvested lymph nodes is critical for pathological staging. It has been proposed that the more central the mesenteric vascular ligation, the greater the nodal yield. The aim of the current study was to determine the association of radiological and pathological ileocolic pedicle length on nodal harvest following right hemicolectomy for caecal cancer. METHODS: A series of 50 patients undergoing right hemicolectomy for adenocarcinoma underwent specimen evaluation. Preoperative computed tomography images were reconstructed and analysed to determine the direct (vessel origin to caecum) ileocolic pedicle length. RESULTS: The median pathological distance from the tumour to the high vascular tie was 80 mm, and median nodal yield was 16.5 nodes. Radiological pedicle length did not correlate with the pathological distance from the tumour to the high vascular tie or nodal yield; however, the pathological pedicle length did correlate with the total nodal yield (r (2): 0.343, p = 0.015). The median pathologically determined length of colon resected (r (2): 0.153, p = 0.289), ileum resected (r (2): 0.087, p = 0.568) and total specimen length resected (r (2): 0.182, p = 0.205) did not correlate with the total nodal yield. An ileal specimen length <=25 mm [hazard ratio (HR) 14.8, 95 % confidence interval (CI) 1.1-194.5, p = 0.040] and a well-differentiated tumour (HR 10.5, 95 % CI 1.1-95.9, p = 0.037) increased the likelihood of retrieving <12 lymph nodes. CONCLUSIONS: Based on these data, pathologic pedicle length is a determining factor in lymph node retrieval. Preoperative radiological calculation of pedicle length does not help predict the number of lymph nodes retrieved. PMID- 27231120 TI - Adult attention and interaction can increase moderate-to-vigorous physical activity in young children. AB - Evidence suggests that physical inactivity is prevalent among young children. To combat this, one recommendation for caregivers is to become actively involved in their child's physical activities. However, this general recommendation does not specify how or when a parent should become involved. The purpose of the current study was to conduct a functional analysis to identify a social consequence that would increase the moderate-to-vigorous physical activity (MVPA) exhibited by preschool-aged children, and then to compare the effects of that social consequence when it was provided contingent on MVPA and when provided independent of MVPA. The results of the functional analyses indicated that 3 of 7 children were most active when attention or interactive play was provided contingent on MVPA. Results of the intervention analysis suggested that caregivers of young children should provide attention or interactive play contingent on MVPA when those consequences are identified as reinforcers in a functional analysis. PMID- 27231121 TI - Effect of particle size on their accumulation in an inflammatory lesion in a dextran sulfate sodium (DSS)-induced colitis model. AB - Taking advantage of the enhanced permeation and retention (EPR) effect is a promising approach for delivering macromolecules or nanoparticles to tumors. Recent studies revealed that this strategy is also applicable for targeting other pathological lesions (i.e. inflammatory disease). In the present study, we report the optimal size of a nanoparticle for allowing the higher accumulation of a particle in an inflammatory lesion using a dextran sulfate sodium (DSS)-induced colitis model. As a nanoparticle platform, we utilized a SS-cleavable and pH activated lipid-like material (ssPalm), that can be used to produce particles in a variety of sizes ranging from 50nm to 180nm while using the same lipid composition. In healthy mice, particle accumulation remained low regardless of size. In contrast, the accumulation in inflammatory colon tissue was enhanced depending on the progress of the inflammation. In this situation, the apparent uptake clearance accumulation of a mid-sized particle (113nm on average) was higher than that for smaller and larger (54nm and 183nm in average, respectively) ones. Therefore, controlling particle size is an important parameter for the extensive targeting of inflammatory lesion. PMID- 27231122 TI - Design of cholesterol arabinogalactan anchored liposomes for asialoglycoprotein receptor mediated targeting to hepatocellular carcinoma: In silico modeling, in vitro and in vivo evaluation. AB - We have developed active targeting liposomes to deliver anticancer agents to ASGPR which will contribute to effective treatment of hepatocellular carcinoma. Active targeting is achieved through polymeric ligands on the liposome surface. The liposomes were prepared using reverse phase evaporation method and doxorubicin hydrocholoride, a model drug, was loaded using the ammonium sulphate gradient method. Liposomes loaded with DOX were found to have a particle size of 200nm with more than 90% entrapment efficiency. Systems were observed to release the drug in a sustained manner in acidic pH in vitro. Liposomes containing targeting ligands possessed greater and selective toxicity to ASGPR positive HepG2 cell lines due to specific ligand receptor interaction. Bio-distribution studies revealed that liposomes were concentrated in the liver even after 3h of administration, thus providing conclusive evidence of targeting potential for formulated nanosystems. Tumor regression studies indicated greater tumor suppression with targeted liposomes thereby establishing superiority of the liposomal system. In this work, we used a novel methodology to guide the determination of the optimal composition of the targeting liposomes: molecular dynamics (MD) simulation that aided our understanding of the behaviour of the ligand within the bilayer. This can be seen as a demonstration of the utility of this methodology as a rational design tool for active targeting liposome formulation. PMID- 27231123 TI - Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma. AB - Intrahepatic cholangiocarcinoma (ICC) is an aggressive liver bile duct malignancy exhibiting frequent isocitrate dehydrogenase (IDH1/IDH2) mutations. Through a high-throughput drug screen of a large panel of cancer cell lines, including 17 biliary tract cancers, we found that IDH mutant (IDHm) ICC cells demonstrate a striking response to the multikinase inhibitor dasatinib, with the highest sensitivity among 682 solid tumor cell lines. Using unbiased proteomics to capture the activated kinome and CRISPR/Cas9-based genome editing to introduce dasatinib-resistant "gatekeeper" mutant kinases, we identified SRC as a critical dasatinib target in IDHm ICC. Importantly, dasatinib-treated IDHm xenografts exhibited pronounced apoptosis and tumor regression. Our results show that IDHm ICC cells have a unique dependency on SRC and suggest that dasatinib may have therapeutic benefit against IDHm ICC. Moreover, these proteomic and genome editing strategies provide a systematic and broadly applicable approach to define targets of kinase inhibitors underlying drug responsiveness. SIGNIFICANCE: IDH mutations define a distinct subtype of ICC, a malignancy that is largely refractory to current therapies. Our work demonstrates that IDHm ICC cells are hypersensitive to dasatinib and critically dependent on SRC activity for survival and proliferation, pointing to new therapeutic strategies against these cancers. Cancer Discov; 6(7); 727-39. (c)2016 AACR.This article is highlighted in the In This Issue feature, p. 681. PMID- 27231124 TI - ICOS(+)PD-1(+)CXCR3(+) T follicular helper cells contribute to the generation of high-avidity antibodies following influenza vaccination. AB - The immune mechanism leading to the generation of protective antibody responses following influenza trivalent inactivated vaccine (TIV) vaccinations remains largely uncharacterized. We recently reported that TIV vaccination induced a transient increase of circulating ICOS(+)PD-1(+)CXCR3(+) T follicular helper (cTfh) cells in blood, which positively correlated with the induction of protective antibody responses measured at day 28. However, whether and how these T cells directly contribute to antibody response remains unclear. In this study, we analyzed the changes after TIV vaccination in the amount and the avidity of the polyclonal antibodies specific for the HA1 subunit of the pandemic H1N1 virus, and analyzed the correlation with the increase of ICOS(+)PD-1(+)CXCR3(+) cTfh cells. We found that both the amount and the avidity of specific antibodies rapidly increased during the first 7 days after TIV. Importantly, the increase of ICOS(+)PD-1(+)CXCR3(+) cTfh cells strongly correlated with the increase in the avidity of antibodies, particularly in subjects who did not have high affinity antibodies at baseline. We propose that ICOS(+)PD-1(+)CXCR3(+) Tfh cells directly contribute to the generation of high-avidity antibodies after TIV vaccinations by selectively interacting with high affinity B cells at extrafollicular sites. PMID- 27231125 TI - Clinical Evaluation of Fully Automated Elecsys(r) Syphilis Assay for the Detection of Antibodies of Treponema pallidum. AB - OBJECTIVE: The resurgence of syphilis in recent years has become a serious threat to the public health worldwide, and the serological detection of specific antibodies against Treponema pallidum (TP) remains the most reliable method for laboratory diagnosis of syphilis. The performance of the Elecsys(r) Syphilis assay, a brand new electrochemiluminescene immunoassay (ECLIA), was assessed by large amounts of samples in this study. METHODS: In comparison with InTec assay, the Elecsys(r) Syphilis assay was evaluated in 146 preselected samples from patients with syphilis, 1803 clinical routine samples, and 175 preselected samples from specific populations with reportedly increased rates of false positive syphilis test results. Discrepancy samples must be investigated by Mikrogen Syphilis recomline assay. RESULTS: There was an overall agreement of 99.58% between two assays (Kappa = 0.975). The sensitivity and specificity of the Elecsys(r) Syphilis assay were 100.0% (95% CI, 96.8-100.0%) and 99.8% (95% CI, 99.5-100.0%), respectively. The Elecsys syphilis assay displays better sensitivity (100%), specificity (99.8%), PPV (98.7%), and NPV (100%) in 2124 samples enrolled, compared with the InTec assay. CONCLUSION: Considering the excellent ease of use and automation, high throughput, and its superior sensitivity, especially in primary syphilis, the Elecsys(r) Syphilis assay could represent an outstanding choice for screening of syphilis in high-volume laboratories. However, more attention was still needed, or the results must be confirmed by other treponemal immunoassays. The new Elecsys(r) Syphilis assay is applied to patients with malignant neoplasm or HIV infection. PMID- 27231126 TI - Systematic review of paediatric weight management interventions delivered in the home setting. AB - To increase their accessibility, paediatric weight management interventions are increasingly designed to be delivered in the home setting by trained staff. This systematic review summarizes the available evidence for interventions featuring home visitation and identifies key gaps in the literature. PubMed, CINAHL, Cochrane and PsycINFO were searched for intervention studies that reported change in objectively measured adiposity outcomes in youth ages 2-18 years. Studies published between 1 January 1995 and 12 February 2016 were analysed. Of 15 eligible studies, nine reported that interventions with home visitation were either superior to a control/comparison condition or achieved significant within subjects reductions in adiposity. Interventions in which professional staff (e.g. dietitians and exercise trainers) conducted home visits tended to be more efficacious than those delivered by paraprofessional or community-based staff, as were interventions with more frequent contact. Most studies were judged to have low or unclear risk of bias across various domains. As most studies compared interventions with home visits with less intensive and qualitatively different approaches, it remains unclear whether home visitation per se enhances weight loss efficacy. Overall, paediatric weight management interventions that feature home visitation are promising, but the incremental benefit of the home visitation treatment modality remains to be rigorously evaluated. (c) 2016 World Obesity. PMID- 27231127 TI - Effect of carbon chain length in acyl coenzyme A on the efficiency of enzymatic transformation of okadaic acid to 7-O-acyl okadaic acid. AB - Okadaic acid (OA), a product of dinoflagellate Prorocentrum spp., is transformed into 7-O-acyl OA in various bivalve species. The structural transformation proceeds enzymatically in vitro in the presence of the microsomal fraction from the digestive gland of bivalves. We have been using LC-MS/MS to identify OA transforming enzymes by detecting 7-O-acyl OA, also known as dinophysistoxin 3 (DTX3). However, an alternative assay for DTX3 is required because the OA transforming enzyme is a membrane protein, and surfactants for solubilizing membrane proteins decrease the sensitivity of LC-MS/MS. The present study examined saturated fatty acyl CoAs with a carbon chain length of 10 (decanoyl), 12 (dodecanoyl), 14 (tetradecanoyl), 16 (hexadecanoyl) and 18 (octadecanoyl) as the substrate for the in vitro acylation reaction. Saturated fatty acyl CoAs with a carbon chain length of 14, 16 and 18 exhibited higher yields than those with a carbon chain length of 10 or 12. Acyl CoAs with carbon chain lengths from 14 to 18 and containing either a diene unit, an alkyne unit, or an azide unit in the carbon chain were synthesized and shown to provide the corresponding DTX3 with a yield comparable to that of hexadecanoyl CoA. The three functional units can be conjugated with fluorescent reagents and are applicable to the development of a novel assay for DTX3. PMID- 27231128 TI - New antitumour agents with alpha,beta-unsaturated delta-lactone scaffold: Synthesis and antiproliferative activity of (-)-cleistenolide and analogues. AB - A stereoselective total synthesis of (-)-cleistenolide (1) from d-glucose has been achieved. This new approach for the synthesis of (-)-cleistenolide and analogues involves a one-C-atom degradation of the chiral precursor, (Z) selective Wittig olefination, followed by the final delta-lactonisation. Synthesized compounds showed potent growth inhibitory effects against selected human tumour cell lines, especially 2,4,6-trichlorobenzoyl derivative 12, which in the culture of MDA-MB 231 cells displayed the highest activity (IC50 0.02MUM) of all compounds under evaluation. A preliminary SAR study reveals the structural features that are beneficial for antiproliferative activity of synthesized delta lactones, such as presence of either electron-withdrawing or electron-donating substituents in the aromatic ring, as well as the presence of cinnamoyl functionality instead of benzoyl group at the O-7 position. PMID- 27231130 TI - [Community health in primary health care teams: a management objective]. AB - OBJECTIVE: To describe the process of development of community health in a territory where the Primary Health Care board decided to include it in its roadmap as a strategic line. DESIGN: Evaluative research using qualitative techniques, including SWOT analysis on community health. Two-steps study. LOCATION: Primary care teams (PCT) of the Catalan Health Institute in Barcelona city. PARTICIPANTS AND/OR CONTEXT: The 24 PCT belonging to the Muntanya-Dreta Primary Care Service in Barcelona city, with 904 professionals serving 557,430 inhabitants. METHOD: Application of qualitative methodology using SWOT analysis in two steps (two-step study). Step 1: Setting up a core group consisting of local PCT professionals; collecting the community projects across the territory; SWOT analysis. Step 2: From the needs identified in the previous phase, a plan was developed, including a set of training activities in community health: basic, advanced, and a workshop to exchange experiences from the PCTs. RESULTS: A total of 80 team professionals received specific training in the 4 workshops held, one of them an advanced level. Two workshops were held to exchange experiences with 165 representatives from the local teams, and 22 PCTs presenting their practices. In 2013, 6 out of 24 PCTs have had a community diagnosis performed. CONCLUSIONS: Community health has achieved a good level of development in some areas, but this is not the general situation in the health care system. Its progression depends on the management support they have, the local community dynamics, and the scope of the Primary Health Care. PMID- 27231131 TI - [Cat scratch disease. Presentation of several clinical cases]. PMID- 27231129 TI - Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease. AB - Men have a shorter life expectancy compared with women but the underlying factor(s) are not clear. Late-onset, sporadic Alzheimer disease (AD) is a common and lethal neurodegenerative disorder and many germline inherited variants have been found to influence the risk of developing AD. Our previous results show that a fundamentally different genetic variant, i.e., lifetime-acquired loss of chromosome Y (LOY) in blood cells, is associated with all-cause mortality and an increased risk of non-hematological tumors and that LOY could be induced by tobacco smoking. We tested here a hypothesis that men with LOY are more susceptible to AD and show that LOY is associated with AD in three independent studies of different types. In a case-control study, males with AD diagnosis had higher degree of LOY mosaicism (adjusted odds ratio = 2.80, p = 0.0184, AD events = 606). Furthermore, in two prospective studies, men with LOY at blood sampling had greater risk for incident AD diagnosis during follow-up time (hazard ratio [HR] = 6.80, 95% confidence interval [95% CI] = 2.16-21.43, AD events = 140, p = 0.0011). Thus, LOY in blood is associated with risks of both AD and cancer, suggesting a role of LOY in blood cells on disease processes in other tissues, possibly via defective immunosurveillance. As a male-specific risk factor, LOY might explain why males on average live shorter lives than females. PMID- 27231132 TI - Electricity production from municipal solid waste using microbial fuel cells. AB - The organic content of municipal solid waste has long been an attractive source of renewable energy, mainly as a solid fuel in waste-to-energy plants. This study focuses on the potential to use microbial fuel cells to convert municipal solid waste organics into energy using various operational conditions. The results showed that two-chamber microbial fuel cells with carbon felt and carbon felt allocation had a higher maximal power density (20.12 and 30.47 mW m(-2) for 1.5 and 4 L, respectively) than those of other electrode plate allocations. Most two chamber microbial fuel cells (1.5 and 4 L) had a higher maximal power density than single-chamber ones with corresponding electrode plate allocations. Municipal solid waste with alkali hydrolysis pre-treatment and K3Fe(CN)6 as an electron acceptor improved the maximal power density to 1817.88 mW m(-2) (~0.49% coulomb efficiency, from 0.05-0.49%). The maximal power density from experiments using individual 1.5 and 4 L two-chamber microbial fuel cells, and serial and parallel connections of 1.5 and 4 L two-chamber microbial fuel cells, was found to be in the order of individual 4 L (30.47 mW m(-2)) > serial connection of 1.5 and 4 L (27.75) > individual 1.5 L (20.12) > parallel connection of 1.5 and 4 L (17.04) two-chamber microbial fuel cells . The power density using municipal solid waste microbial fuel cells was compared with information in the literature and discussed. PMID- 27231135 TI - Realizing half-metallicity in K2CoF4 exfoliated nanosheets via defect engineering. AB - Two-dimensional (2D) materials with intriguing electronic characteristics open up tremendous opportunities for application in future nanoelectronic devices, and have become one of the hot subjects of today's research. Here, we firstly predict the possibility of realizing a 2D exfoliated ionic bonding nanosheet, namely the K2CoF4 nanosheet, based on first-principles calculations. Through analysis of the cleavage energy, in-plane stiffness and stability, the free-standing K2CoF4 nanosheet can be exfoliated in experiments. It is shown that the K2CoF4 nanosheet with K vacancy can transform into a ferromagnetic half-metal under moderate tensile strain, whereas the pristine K2CoF4 nanosheet is an antiferromagnetic semiconductor. Monte Carlo simulations based on the Heisenberg model predict that the Curie temperature for the K vacancy K2CoF4 nanosheet under 2% tensile strain is higher than room temperature. Therefore, our results suggest that the K2CoF4 nanosheet may be a promising material for spintronic and nanoelectronic applications. PMID- 27231136 TI - Hyperthermia and Severe Rhabdomyolysis From Synthetic Cannabinoids Am J Emerg Med 2016;34:121.e1-2. Doi: 10.1016/j.Ajem.2015.05.052. Epub 2015 Jun 12. PMID- 27231133 TI - Lactobacillus plantarum WCFS1 and its host interaction: a dozen years after the genome. AB - Lactobacillus plantarum WCFS1 is one of the best studied Lactobacilli, notably as its genome was unravelled over 12 years ago. L. plantarum WCFS1 can be grown to high densities, is amenable to genetic transformation and highly robust with a relatively high survival rate during the gastrointestinal passage. In this review, we present and discuss the main insights provided by the functional genomics research on L. plantarum WCFS1 with specific attention for the molecular mechanisms related to its interaction with the human host and its potential to modify the immune system, and induce other health-related benefits. Whereas most insight has been gained in mouse and other model studies, only five human studies have been reported with L. plantarum WCFS1. Hence NCIMB 8826 (the parental strain of L. plantarum WCFS1) in human trials as to capitalize on the wealth of knowledge that is summarized here. PMID- 27231137 TI - When Health Diplomacy Serves Foreign Policy: Use of Soft Power to Quell Conflict and Crises. AB - OBJECTIVE: Health diplomacy has increasingly become a crucial element in forging political neutrality and conflict resolution and the World Health Organization has strongly encouraged its use. Global turmoil has heightened, especially in the Middle East, and with it, political, religious, and cultural differences have become major reasons to incite crises. METHODS: The authors cite the example of the human stampede and the deaths of over 2000 pilgrims during the 2015 annual Haj pilgrimage in Mecca. RESULTS: The resulting political conflict between Iran and Saudi Arabia had the potential to escalate into a more severe political and military crisis had it not been for the ministers of health from both countries successfully exercising "soft power" options. CONCLUSION: Global health security demands critical health diplomacy skills and training for all health providers. (Disaster Med Public Health Preparedness. 2016;page 1 of 4). PMID- 27231134 TI - The NKD1/Rac1 feedback loop regulates the invasion and migration ability of hepatocarcinoma cells. AB - Hepatocellular carcinoma (HCC) is complicated by aggressive migration and invasion, which contribute to the increased mortality of HCC patients. The NKD1 protein is abnormally expressed in many neoplasms and plays an important role in tumor progression. However, the regulation and underlying molecular mechanisms of NKD1 in HCC cell invasion and migration remain poorly understood. In the present study, ectopic expression of NKD1 in HCC cells attenuated migration and invasion in vitro and in vivo by down-regulating Rac1 expression level and activity, which affected the HCC cell cytoskeleton and E-cadherin expression. Mechanistic studies showed that NKD1 interacted with Rac1 in the cytoplasm and promoted its degradation by the ubiquitin-proteasome pathway. Over-expression of Rac1 enhanced the transcription of the NKD1 gene and protein expression conversely owing to its negative regulation of EZH2. Analysis of clinical samples showed that abnormal expression of NKD1 and Rac1 was associated with the poor prognosis of HCC patients. In summary, our data indicate a new role for NKD1 as a regulator of HCC cell invasion and migration via a feedback loop involving Rac1. PMID- 27231138 TI - Acrodermatitis Continua of Hallopeau with Granuloma-like Vegetation, Osteolysis and IL36RN Mutation. PMID- 27231139 TI - Medial gastrocnemius vein aneurysm development after compressive trauma in the knee. AB - Objectives Venous aneurysms are uncommon. They can involve both superficial and deep venous systems. We hereby present a unique case of gastrocnemius venous aneurysm developed after compressive knee trauma. Report A large venous aneurysm in the left popliteal fossa was detected by chance in a 44-year-old woman one month after a compressive trauma to the posterior surface of the knee. Magnetic resonance-imaging of the same knee had documented normal venous anatomy one year earlier. The venous aneurysm involved the medial gastrocnemius vein near its confluence in the popliteal vein and was surgically resected. Histopathology evidenced a true venous aneurysm. The patient was discharged under oral anticoagulation for three months. At one year follow-up, neither complications nor new venous aneurysm development was detected. Conclusions An accurate evaluation of the venous system is always mandatory after limb traumas which may lead to post-traumatic venous pseudo-aneurysms, as well as more rarely, true venous aneurysms in the lower extremities. PMID- 27231140 TI - Audit of use of stiripentol in adults with Dravet syndrome. AB - OBJECTIVES: There are very few data available in the literature on the use of stiripentol in adults with Dravet syndrome (DS). DS cases are increasingly recognized in adulthood, and more children with DS now survive to adulthood. The aim of the study was to document the effectiveness and tolerability of stiripentol in adults with DS. MATERIAL AND METHODS: We conducted an observational clinical audit in the epilepsy service of the National Hospital for Neurology and Neurosurgery, London (UK). RESULTS: We included 13 adult subjects with DS (eight females, five males). The responder (defined as more than 50% reduction in all seizure types) rate was 3/13 (23%) at 36 months. The following other outcomes were reported: seizure exacerbation (3/13, 23%), no change (3/13, 23%), less than 50% reduction in seizures (2/13, 15%), more than 50% reduction in generalized tonic-clonic seizures but no other seizure types (1/13, 8%), undefined response (1/13, 8%). The retention rate was 62% after 1 year and 31% after 5 years. Adverse effects were reported in 7/13 (54%): the most frequent were anorexia, weight loss, unsteadiness and tiredness. Withdrawal due to adverse effects occurred in 3/13 (23%). CONCLUSIONS: Compared with previous studies on children with DS, our results show a lower responder rate and a similar tolerability profile. Stiripentol can be effective with a good tolerability profile. Our audit is small, but supports the use of stiripentol in adults with DS when first-line treatments are ineffective or not tolerated, in keeping with published guidelines. PMID- 27231141 TI - [Are we doing our best for our patients with hypoxic-ischaemic encephalopathy?] PMID- 27231143 TI - Classical Kaposi sarcoma: case reports with unusual presentation on the penis and scrotum. AB - BACKGROUND: Kaposi sarcoma (KS) is the most common vascular neoplasm. Any skin area could be involved, including the genitalia. Traditionally, classic KS lesions have a general distribution, often involving skin of the feet and legs, and to a lesser extent, that of the hands, arms, and trunk. KS limited to the external genitalia is extremely rare in HIV seronegative individuals. METHODS: We report six patients of classic KS with generalized dermal KS lesions. RESULTS: Two of them presenting with unusual KS lesions on the penis and scrotum beside the other dermal lesions. Patients were HIV negative and human herpes virus eight positive. Histological examination showed classical KS. CONCLUSIONS: Primary KS of the penis and scrotum is rare but could occur in HIV-negative patients. PMID- 27231144 TI - A Reduction in Intracellular Reactive Oxygen Species Due to a Mutation in NCF4 Promotes Autoimmune Arthritis in Mice. AB - AIMS: The mechanisms linking deficits in the phagocytic NADPH oxidase 2 (NOX2) complex to autoimmunity are so far incompletely understood. Deficiency in neutrophil cytosolic factor 1 (NCF1) inactivates the NOX2 complex, leading to a dramatic reduction of intra- and extracellular reactive oxygen species (ROS) and enhanced susceptibility to autoimmune disease. The contribution of intracellular NOX2 activity to autoimmune regulation is, however, unknown. Another component of the NOX2 complex, NCF4, directs the NOX2 complex to phagosomal membranes via binding to phosphatidylinositol 3-phosphate (PtdIns3P) and has been proposed to regulate intracellular ROS levels. To address the impact of NCF4 and selective changes in intracellular ROS production on autoimmune inflammation, we studied collagen-induced arthritis (CIA) and mannan-induced psoriatic arthritis-like disease (MIP) in mice lacking NCF4 and mice with a mutation in the PtdIns3P binding site of NCF4. RESULTS: Targeted deletion of Ncf4 (Ncf4-/-) led to severe defects in overall ROS production due to concomitant reduction of NCF2 and NCF1. These mice displayed delayed neutrophil apoptosis and enhanced innate immune responses, and they developed aggravated CIA and MIP. Disruption of the PtdIns3P binding site by targeted mutation (Ncf4*/*) resulted in selective defects in intracellular NOX2 activity, which entailed milder effects on innate immunity and MIP but clearly promoted susceptibility to CIA. Innovation and Conclusion: This is, to our knowledge, the first study addressing the development of autoimmunity in an organism with selectively compromised NOX2-dependent intracellular ROS levels. Our data reveal a specific role for NCF4-mediated intracellular ROS production in regulating autoimmunity and chronic inflammation. Antioxid. Redox Signal. 25, 983-996. PMID- 27231142 TI - Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia. AB - Although manganese is an essential trace metal, little is known about its transport and homeostatic regulation. Here we have identified a cohort of patients with a novel autosomal recessive manganese transporter defect caused by mutations in SLC39A14. Excessive accumulation of manganese in these patients results in rapidly progressive childhood-onset parkinsonism-dystonia with distinctive brain magnetic resonance imaging appearances and neurodegenerative features on post-mortem examination. We show that mutations in SLC39A14 impair manganese transport in vitro and lead to manganese dyshomeostasis and altered locomotor activity in zebrafish with CRISPR-induced slc39a14 null mutations. Chelation with disodium calcium edetate lowers blood manganese levels in patients and can lead to striking clinical improvement. Our results demonstrate that SLC39A14 functions as a pivotal manganese transporter in vertebrates. PMID- 27231146 TI - A systematic literature review of the physical and psychosocial correlates of Special Olympics participation among individuals with intellectual disability. AB - BACKGROUND: Special Olympics (SO) is commonly cited to play an important role in the lives of individuals with intellectual disabilities (ID). The purpose of the current review was to (a) synthesise key findings regarding the physical, psychological/emotional, social and/or intellectual/cognitive correlates of SO participation for individuals with ID and (b) highlight limitations in the extant research as well as directions for future research. METHOD: A systematic review of electronic databases was undertaken. A total of 46 articles were confirmed to meet study criteria. Quality assessments of included studies were conducted using checklists from the Scottish Intercollegiate Guidelines Network methodology checklists (SIGN 50; SIGN 2008). RESULTS: There was a larger amount of support for physical, psychological/emotional and social outcomes as compared with cognitive/intellectual outcomes; however, many studies were confounded by measurement difficulties, sampling procedures and a lack of replicable methods, which hinder generalisation of results. CONCLUSIONS: This review highlights the need for a continued critical focus on SO programme evaluation research with more rigorous and replicable methods. PMID- 27231147 TI - Physical and emotional well-being of survivors of childhood and young adult allo SCT - A Danish national cohort study. AB - The aim of this investigation was to examine, within a population-based study of a national cohort comprising Danish survivors of allo-SCT (n = 148), the long term effects of allo-SCT in children and young adults. Physical and emotional well-being was assessed using the Short Form 36 (SF-36) and the HADS. Allo-SCT related data were obtained from the participants' medical records. The study includes 148 patients, with an 89% response rate (n = 132). For comparison purposes, norm data from Danish (1994, n = 6000), Swedish (2006, n = 285), and British (2001, n = 1792) population samples were used. Factors negatively influencing the SF-36 subscales included female gender; TBI; stem cells derived from PB; older age at time of questioning; and living alone. Factors significantly (p < 0.05) influencing HADS were transplantation with stem cells derived from PB and being underweight at time of questioning (median values were within normal range). Overall scores of allo-SCT patients were similar to norm data. In conclusion, this national cohort study shows that patients treated with SCT in early life (<25) and whose survival period extended beyond 10 yr (mean) from SCT, showed similar levels of anxiety, depression, and physical and emotional well-being to those of the normal population. PMID- 27231145 TI - Type I interferon licenses enhanced innate recognition and transcriptional responses to Franciscella tularensis live vaccine strain. AB - The innate inflammatory response to Francisella tularensis (Ft) in macrophages is significantly governed by the expression of type I interferon (IFN). Previously, the proteolytic processing and maturation of pro-IL-1beta protein was shown to depend upon type I IFN expression. We show in this report that paracrine type I IFN can profoundly enhance innate recognition and TLR-dependent transcriptional responses to Ft infection upstream of its role in inflammasome regulation in both primary human monocyte-derived macrophages and primary murine peritoneal macrophages but not murine bone marrow-derived macrophages. This type I IFN enhanced response is synergistic with TLR2 transcriptional responses, partially TLR2-independent, but strictly MyD88-dependent. PMID- 27231148 TI - Nutritional intervention as part of functional rehabilitation in older people with reduced functional ability: a systematic review and meta-analysis of randomised controlled studies. AB - BACKGROUND: Nutritional intervention is increasingly recognised as having an important role in functional rehabilitation for older people. Nonetheless, a greater understanding of the functional benefit of nutritional interventions is needed. METHODS: A systematic review and meta-analysis examined randomised controlled trials (RCTs) published between 2007 and 2014 with the aim of determining whether nutritional intervention combined with rehabilitation benefited older people with reduced functional ability. Six electronic databases were searched. RCTs including people aged 65 years and older with reduced physical, social and/or cognitive function were included. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed, and gradepro computer software (http://gradepro.org) was used for the quality assessment of critical and important outcomes. Included studies considered to be clinical homogenous were combined in a meta-analysis. RESULTS: Of the 788 studies screened, five were identified for inclusion. Nutritional intervention given with functional rehabilitation improved energy and protein intake, although it failed to provide any improvement in final body weight, hand grip strength or muscle strength. There was no difference between groups in the critical outcomes; balance, cognition, activities of daily living and mortality at long-term follow-up. Nutritional intervention given with functional rehabilitation was associated with an increased likelihood of both mortality (odds ratio = 1.77; 95% confidence interval = 1.13-2.76) and hospitalisation (odds ratio = 2.29; 95% confidence interval = 1.10-4.79) during the intervention. Meta-analysis of the baseline data showed that, overall, the intervention cohort had a lower body weight and cognition. CONCLUSIONS: This meta-analysis highlights concerns regarding the quality of the randomisation of participants at baseline. Future high-quality research is essential to establish whether older people with loss of functional abilities can benefit from nutritional intervention. PMID- 27231149 TI - Use of Primary Care Services, Care Specialized and Drug Use by Population 65 Years and More in the Community of Madrid, Spain. AB - BACKGROUND: Ageing of the Spanish population results in an increase in health services required. Therefore, determine the frequency of the health services utilization in this age group and analyze their determinants has a great interest.The aim was to analyze the utilization of health services among older people living in two urban neighborhoods of northern Madrid. METHODS: A cross sectional population-based study. It is studied a cohort of 1327 individuals >= 65 years, stratified by age and sex. Nine utilization indicators were defined. For each indicator frequencies and the association of each with the other variables were calculated by multivariate analysis. RESULTS: The distribution of indicators expressed as a percentage of the user population is: GP appoiments/month 64.8% (95%CI 62.3 to 67.4); nursing appoiments/month 44.6% (95% CI 41.2 to 47.2); home medical visits/month 3.1% (95%CI 2.2 to 4.1); home nursing visits/month 3% (95%CI 2.1 to 3.9); hospitalization/year 16.4% (95%CI 14.4 to 18.4); appoiments rheumatologist/orthopedic/year 25.1% (95%CI 22.7 to 27.4); physiotherapist appoiments/year 12.9% (95% CI 11.1 to 14.7); podiatrist appoiments/year 30.6% (95%CI 28.1 to 33.1) and polypharmacy (>=5 drugs) 55.7% (95% CI 53 to 58.4). Comorbidity was the best predictor of health care utilization ranging from OR 4.10 (95%CI: 3.07-5,49) to OR 1.39 (95%CI: 0.97-1.99) in polymedicated and visit the physiotherapist respectively. Cardiovascular disease (OR 1.34; 95%CI 1.03-1,76) and diabetes (OR 1.46; 95%CI: 1.05 -2.02) were independently associated with increased use of family doctor. Dependence was the main determinant for home healthcare (OR 3.38; 95%CI: 1.38-8.28) and nurses (OR 9.71; 95%CI: 4.19-22.48) Mood disorders were associated to polypharmacy (OR 2.06; 95%CI: 1,48-2.86) and to visits to family doctor (OR 1.52; 95%CI: 1,13-2.04). CONCLUSIONS: The comorbidity is the strongest predictor of health services utilization. Cardiovascular diseases and diabetes are independently associated to greater use. Dependence is the main determinant of home care. Mood disorders associated with polypharmacy and increased attendances to the General Practitioner. PMID- 27231150 TI - Bistability of mitotic entry and exit switches during open mitosis in mammalian cells. AB - Mitotic entry and exit are switch-like transitions that are driven by the activation and inactivation of Cdk1 and mitotic cyclins. This simple on/off reaction turns out to be a complex interplay of various reversible reactions, feedback loops, and thresholds that involve both the direct regulators of Cdk1 and its counteracting phosphatases. In this review, we summarize the interplay of the major components of the system and discuss how they work together to generate robustness, bistability, and irreversibility. We propose that it may be beneficial to regard the entry and exit reactions as two separate reversible switches that are distinguished by differences in the state of phosphatase activity, mitotic proteolysis, and a dramatic rearrangement of cellular components after nuclear envelope breakdown, and discuss how the major Cdk1 activity thresholds could be determined for these transitions. PMID- 27231151 TI - Self-assessment of oral health, dental health care and oral health-related quality of life among Parkinson's disease patients. AB - OBJECTIVE: Parkinson's disease (PD) is a common condition in elderly people and can adversely affect oral health (OH). However, the subjective burden of oral symptoms on the quality of life (QoL) of patients with PD is largely unknown and needs to be better understood. The objective of this study was to explore self assessed dental care in patients with PD, including the ability to perform oral hygiene, self-assessed xerostomia, drooling and dysphagia problems, and the impact on OH-related QoL. MATERIALS AND METHODS: A questionnaire was completed by 100 patients with PD in Germany recruited from PD support groups, and included self-assessment of dental care, the Oral Health Impact Profile (OHIP-14) score, the levodopa equivalent daily dose, the Movement Disorder Society Unified Parkinson's Disease Rating Scale-II and the leading OH-related symptoms. RESULTS: Participants experienced xerostomia (49%), drooling (70%) and dysphagia (47%) and suffered from a limited ability to perform oral hygiene (29%). The oral symptoms xerostomia, drooling and dysphagia impaired the OH-related QoL [OHIP total score 14.6 (9.7)-16.8 (11.4) compared to 11.3 (9.9) in participants without symptoms]. In total, 91.8% of participants had their own dentist. Only 6.1% of participants with xerostomia received advice regarding management. CONCLUSION: In this study, patients with PD suffered from OH-related symptoms (xerostomia, drooling, and dysphagia) that impaired their OH-related QoL. Participants felt that they received adequate dental health care; however, dental advice regarding management of PD-related OH problems was often lacking. PMID- 27231152 TI - Single-molecule magnet behavior in an octanuclear dysprosium(iii) aggregate inherited from helical triangular Dy3 SMM-building blocks. AB - An unprecedented octanuclear dysprosium(iii) cluster with the formula [Dy8L6(MU3 OH)4(MU2-CH3O)2(CH3OH)6(H2O)2].6H2O.10CH3OH.2CH3CN () based on a nonlinearly tritopic aroylhydrazone ligand H3L has been isolated, realizing the successful linking of pairwise interesting triangular Dy3 SMMs. It is noteworthy that two enantiomers (Lambda and Delta configurations) individually behaving as a coordination-induced chirality presented in the Dy3 helicate are connected in the meso Dy8 cluster. Remarkably, alternating-current magnetic susceptibility measurements revealed that the Dy8 cluster shows typical SMM behavior inherited from its Dy3 helical precursor. It is one of the rare polynuclear Lnn SMMs (n > 7) under zero dc field. PMID- 27231154 TI - Tolerance to the Diuretic Effects of Cannabinoids and Cross-Tolerance to a kappa Opioid Agonist in THC-Treated Mice. AB - Daily treatment with cannabinoids results in tolerance to many, but not all, of their behavioral and physiologic effects. The present studies investigated the effects of 7-day exposure to 10 mg/kg daily of Delta(9)-tetrahydrocannabinol (THC) on the diuretic and antinociceptive effects of THC and the synthetic cannabinoid AM4054. Comparison studies determined diuretic responses to the kappa opioid agonist U50,488 and furosemide. After determination of control dose response functions, mice received 10 mg/kg daily of THC for 7 days, and dose response functions were re-determined 24 hours, 7 days, or 14 days later. THC and AM4054 had biphasic diuretic effects under control conditions with maximum effects of 30 and 35 ml/kg of urine, respectively. In contrast, antinociceptive effects of both drugs increased monotonically with dose to >90% of maximal possible effect. Treatment with THC produced 9- and 7-fold rightward shifts of the diuresis and antinociception dose-response curves for THC and, respectively, 7- and 3-fold rightward shifts in the AM4054 dose-response functions. U50,488 and furosemide increased urine output to >35 ml/kg under control conditions. The effects of U50,488 were attenuated after 7-day treatment with THC, whereas the effects of furosemide were unaltered. Diuretic effects of THC and AM4054 recovered to near-baseline levels within 14 days after stopping daily THC injections, whereas tolerance to the antinociceptive effects persisted longer than 14 days. The tolerance induced by 7-day treatment with THC was accompanied by a 55% decrease in the Bmax value for cannabinoid receptors (CB1). These data indicate that repeated exposure to THC produces similar rightward shifts in the ascending and descending limbs of cannabinoid diuresis dose-effect curves and to antinociceptive effects while resulting in a flattening of the U50,488 diuresis dose-effect function. PMID- 27231153 TI - Systems genetic and pharmacological analysis identifies candidate genes underlying mechanosensation in the von Frey test. AB - Mechanical sensitivity is commonly affected in chronic pain and other neurological disorders. To discover mechanisms of individual differences in punctate mechanosensation, we performed quantitative trait locus (QTL) mapping of the response to von Frey monofilament stimulation in BXD recombinant inbred (BXD) mice. Significant loci were detected on mouse chromosome (Chr) 5 and 15, indicating the location of underlying polymorphisms that cause heritable variation in von Frey response. Convergent evidence from public gene expression data implicates candidate genes within the loci: von Frey thresholds were strongly correlated with baseline expression of Cacna2d1, Ift27 and Csnk1e in multiple brain regions of BXD strains. Systemic gabapentin and PF-670462, which target the protein products of Cacna2d1 and Csnk1e, respectively, significantly increased von Frey thresholds in a genotype-dependent manner in progenitors and BXD strains. Real-time polymerase chain reaction confirmed differential expression of Cacna2d1 and Csnk1e in multiple brain regions in progenitors and showed differential expression of Cacna2d1 and Csnk1e in the dorsal root ganglia of the progenitors and BXD strains grouped by QTL genotype. Thus, linkage mapping, transcript covariance and pharmacological testing suggest that genetic variation affecting Cacna2d1 and Csnk1e may contribute to individual differences in von Frey filament response. This study implicates Cacna2d1 and Ift27 in basal mechanosensation in line with their previously suspected role in mechanical hypersensitivity. Csnk1e is implicated for von Frey response for the first time. Further investigation is warranted to identify the specific polymorphisms involved and assess the relevance of these findings to clinical conditions of disturbed mechanosensation. PMID- 27231156 TI - Cystic Lung Disease Among Patients With Sjogren Syndrome: Frequency, Natural History, and Associated Risk Factors. AB - BACKGROUND: Cystic lung disease (CLD) in Sjogren syndrome (SS) is a condition with unclear prognostic implications. Our objectives in this study are to determine its frequency, progression over time, and associated risk factors and complications. METHODS: Eighty-four patients with primary or secondary SS and chest imaging, chest radiograph, or CT scan were retrospectively evaluated for CLD. Thirteen patients with cysts were found. Baseline characteristics of all patients were collected. A multivariate logistic regression model was used to look for predictors of CLD in patients with CT scan. Additional imaging, SS activity, and complications from CLD and SS were collected for the patients with cysts. RESULTS: CLD had a frequency of 15.4% for all patients with chest imaging. Not all cysts were evident on radiography, and CLD frequency was 30.9% for the patients with chest CT scan. Six patients had cysts without other radiographic findings. CLD was associated with older age (OR, 1.1; 95% CI, 1.0-1.16), a diagnosis of secondary SS (OR, 12.1; 95% CI, 1.12-130.4), and seropositivity for anti-SS-related antigen A/Ro autoantibodies (OR, 26.9; 95% CI, 1.44-93.61). There was no radiologic progression of CLD for 12 patients after a 4-year median follow up. Lung function did not exhibit temporal worsening. CLD did not correlate with a specific pattern in pulmonary function testing. Two patients had secondary infectious complications of the cysts. CONCLUSIONS: CLD is a relatively common condition in SS that does not progress on serial radiologic and lung function follow-up. CLD, without other radiographic findings, may represent a direct manifestation of SS. PMID- 27231155 TI - Autophagy Inhibition Delays Early but Not Late-Stage Metastatic Disease. AB - The autophagy pathway has been recognized as a mechanism of survival and therapy resistance in cancer, yet the extent of autophagy's function in metastatic progression is still unclear. Therefore, we used murine models of metastatic cancer to investigate the effect of autophagy modulation on metastasis development. Pharmacologic and genetic autophagy inhibition were able to impede cell proliferation in culture, but did not impact the development of experimentally induced 4T1 and B16-F10 metastases. Similarly, autophagy inhibition by adjuvant chloroquine (CQ) treatment did not delay metastasis in an orthotopic 4T1, tumor-resection model. However, neoadjuvant CQ treatment or genetic autophagy inhibition resulted in delayed metastasis development, whereas stimulation of autophagy by trehalose hastened development. Cisplatin was also administered either as a single agent or in combination with CQ. The combination of cisplatin and CQ was antagonistic. The effects of autophagy modulation on metastasis did not appear to be due to alterations in the intrinsic metastatic capability of the cells, as modulating autophagy had no impact on migration, invasion, or anchorage-independent growth in vitro. To explore the possibility of autophagy's influence on the metastatic microenvironment, bone marrow-derived cells (BMDCs), which mediate the establishment of the premetastatic niche, were measured in the lung and in circulation. Trehalose-treated mice had significantly more BMDCs than either vehicle- or CQ-treated mice. Autophagy inhibition may be most useful as a treatment to impede early metastatic development. However, modulating autophagy may also alter the efficacy of platinum-based therapies, requiring caution when considering combination therapies. PMID- 27231158 TI - Shortcomings of an approximate confidence interval for moment-based estimators of the between-study variance in random-effects meta-analysis. PMID- 27231157 TI - Thirdhand smoke beliefs and behaviors among healthcare professionals. AB - Thirdhand smoke (THS) refers to tobacco smoke contaminants and by-products that remain in the environment after a cigarette is extinguished. The purpose of this study was to assess beliefs and behaviors regarding THS among healthcare professionals, and to examine associations among smoking attitudes/beliefs, provider demographics, and THS beliefs and behaviors. Healthcare professionals (N = 204) at a comprehensive cancer center and affiliated general hospital in a northeastern urban area completed online questionnaires. About one third of the respondents had heard of THS before completing the survey, and more than two thirds of the sample believed that THS issues do not receive enough attention. Being female, likelihood of discussing THS with others, endorsing the belief that smoking affects the quality of parenting, and support for government action towards smoking bans were significantly associated with providers' belief that THS is harmful. Endorsing the belief that smoking affects the quality of parenting and belief that THS is harmful were significantly associated with the likelihood of discussing THS with others. Findings shed light on THS beliefs and behaviors of healthcare providers (a group of individuals that could be trained to educate and advise patients about THS) and inform recommendations for new tobacco policies and clinical guidelines for best practices in tobacco control and prevention. PMID- 27231159 TI - Effectiveness of CO2 laser with subcision in patients with acne scars. AB - BACKGROUND: Post-acne facial scarring has always been a challenge to treat. It requires multiple therapeutic modalities as single modality is not hundred percent effective. Therefore, we have combined CO2 laser resurfacing with subcision in patients with acne scars for better results. OBJECTIVES: The aim is to study the effectiveness and side effects of CO2 laser with subcision in patients with atrophic acne scars. METHODS: Fifty patients were selected for the study. Baseline grading was done with Goodman and Baron grading system. Twenty five patients were randomly selected for subcision followed by CO2 laser and the remaining patients were selected for CO2 laser alone. The treatment was done for four sessions at 4-week interval. Clinical photographs were obtained for evaluation. RESULTS: CO2 laser with subcision showed excellent response in grade 2 and -3 acne scars. Statistically there is a significant difference between CO2 laser following subcision and CO2 laser alone at 5% level (p < 0.05). Both procedures were well tolerated with minimal side effects. CONCLUSION: The highly versatile CO2 laser is useful for treating acne scars. Subcision prior to the CO2 laser procedure showed better improvement when compared to CO2 laser alone. Thus, in acne scars, multiple therapeutic modalities achieve better results. PMID- 27231160 TI - Construction of Transjugular Intrahepatic Portosystemic Shunt: Bare Metal Stent/Stent-graft Combination versus Single Stent-graft, a Prospective Randomized Controlled Study with Long-term Patency and Clinical Analysis. AB - BACKGROUND: Balanced adjustment of the portal vein shunt volume during a transjugular intrahepatic portosystemic shunt (TIPS) is critical for maintaining liver perfusion and decreasing the incidence of liver insufficiency. A stent graft is proved to be superior to a bare metal stent (BMS) for the construction of a TIPS. However, the clinical results of the combination application of stents and stent-grafts have not been determined. This study aimed to compare the technique of using a combination of stents and stent-grafts with using a single stent-graft to construct a TIPS. METHODS: From April 2011 to November 2014, a total of fifty patients were randomly assigned to a stents-combination group (Group I, n = 28) or a stent-graft group (Group II, n = 22). Primary patency rates were calculated. Clinical data, including the technical success rate, bleeding control results, incidence of encephalopathy, liver function preservation, and survival rate, were assessed. RESULTS: Technically, the success rate was 100% for both groups. The primary patency rates at 1, 2, and 3 years for Group I were 96%, 84%, and 77%, respectively; for Group II, they were 90%, 90%, and 78%, respectively. The survival rates at 1, 2, and 3 years for Group I were 79%, 74%, and 68%, respectively; for Group II, they were 82%, 82%, and 74%, respectively. The incidence of hepatic encephalopathy was 14.3% for Group I and 13.6% for Group II. The Child-Pugh score in Group I was stable at the end of the follow-up but had significantly increased in Group II (t = -2.474, P = 0.022). CONCLUSIONS: The construction of a TIPS with either the single stent-graft or BMS/stent-graft combination is effective for controlling variceal bleeding. The BMS/stent-graft combination technique is superior to the stent-graft technique in terms of hepatic function preservation indicated by the Child-Pugh score. However, considering the clinical results of the TIPS, the two techniques are comparable in their primary shunt patency, incidence of encephalopathy and patient survival during the long-term follow-up. PMID- 27231161 TI - Long-term Efficacy of Trabeculectomy on Chinese Patients with Pigmentary Glaucoma: A Prospective Case Series Observational Study. AB - BACKGROUND: Though trabeculectomy is often performed on patients with medically refractive pigmentary glaucoma (PG), the clinical outcomes of surgical treatment on PG remain unknown. The aim of this study was to summarize the long-term efficacy and safety of trabeculectomy on PG. METHODS: This was a prospective case series observational study. Eighteen consecutive PG patients were followed up for 8 years after trabeculectomy from May 2006 to April 2007. Visual acuity (VA), best-corrected visual acuity (BCVA), slit lamp biomicroscopy, intraocular pressure (IOP) measurement, Humphrey visual field analysis (VFA), and stereoscopic funduscopy were performed on admission and every 6 months after the surgery. Postoperative IOP, VA, BCVA, VFA, adjunctive anti-glaucoma medication, treatment-related side-effects, changes in blebs, and main clinical findings in the anterior segment of PG were recorded and compared with the baseline. RESULTS: Eighteen PG eyes from 18 patients, with average preoperative IOP of 34.5 +/- 4.7 mmHg (range: 21-47 mmHg, 1 mmHg=0.133 kPa) were enrolled in this study. All enrolled patients completed the follow-up visits and required examinations. Eight years after trabeculectomy, all surgical eyes (18/18) had satisfactory IOP control with an average of 13.7 +/- 2.5 mmHg (range: 9-19 mmHg), which was significantly lower than baseline (P = 0.001). Majority (15/18) of the PG eyes had stable VA, BCVA, VFA, and optic disc cupping parameters. Functional blebs still existed in 12/18 of the PG eyes at the last follow-up visit. Unanimously, pigmentation in the anterior segment attenuated with time after surgical treatment. No severe side-effects were recorded in any of the surgical eyes. CONCLUSIONS: All surgical PG eyes in this study had satisfactory IOP control 8 years after the surgery with well-preserved visual function. The long-term efficacy and safety of trabeculectomy are promising in PG patients. PMID- 27231162 TI - Vitamin D Insufficiency and Its Association with Biochemical and Anthropometric Variables of Young Children in Rural Southwestern China. AB - BACKGROUND: With recognition of the important roles of Vitamin D (VitD) in various physiological processes, increasing attention has been drawn to the status of VitD in early life. However, the VitD status of young children and the related factors in rural areas of Southwestern China remain unclear. This study aimed to explore VitD status and its seasonal variation in 18-month-old children living in rural Southwestern China. The association of VitD with biochemical and anthropometric variables was also investigated. METHODS: A total of 177 18-month old children in a rural area of Yunnan Province, Southwestern China, were enrolled. Serum concentrations of 25-hydroxy Vitamin D (25(OH)D) were measured through high-performance liquid chromatogram-tandem mass spectrometry. Parathyroid hormone (PTH) levels were measured with a chemiluminescence assay. Serum concentrations of calcium, phosphorus, and alkaline phosphatase (ALP) were also measured. Anthropometric data and the outdoor activity time of each participant were collected. RESULTS: The serum 25(OH)D concentration was 26.61 +/ 7.26 ng/ml; concentrations lower than 30 ng/ml accounted for 70.6% of the participants and concentrations lower than 20 ng/ml accounted for 16.4%. The level of serum 25(OH)D was not significantly different among four seasons (P >0.05). A positive relationship was found between 25(OH)D concentration and the time of outdoor activities (r = 0.168, P < 0.05). Serum PTH concentration was negatively correlated with 25(OH)D concentration (r = -0.163, P < 0.05). A positive relationship was found between the serum concentrations of 25(OH)D and calcium (r = 0.154, P < 0.05). No significant association was observed between 25(OH)D and ALP, phosphorus, or anthropometric variables. CONCLUSIONS: The prevalence of VitD insufficiency is high among young children in the rural Southwestern China regardless of the seasons. VitD supplementation is still essential to maintain VitD sufficiency for children living in rural area. PMID- 27231163 TI - Effects of New Rural Cooperative Medical Scheme on Medical Service Utilization and Medical Expense Control of Inpatients: A 3-year Empirical Study of Hainan Province in China. AB - BACKGROUND: The New Rural Cooperative Medical Scheme (NCMS) has been further adjusted and optimized to reduce the financial burden of rural residents and to achieve universal coverage for them. In this study, we aimed to explore the impact of NCMS on medical service utilization and medical expense of inpatients in recent years. METHODS: The research data of Hainan Province were extracted from the Chinese NCMS platform from 2012 to 2014. Detailed information included total expenditure, average inpatients costs, average out-of-pocket payments, actual reimbursement rate, and average annual growth rate of the above indicators. Descriptive analysis was used to gauge the effects of NCMS. RESULTS: In the utilization of medical services, NCMS inpatients in tertiary hospital decreased from 25.49% in 2012 to 20.39% in 2014, inpatients in county hospitals increased from 39.49% to 55.92%, simultaneously. The total expenditure in county hospitals rose steadily from 28.46% to 46.66%, meanwhile, the total expenditure in tertiary hospitals fell from 60.44% to 44.51%.The average out-of-pocket costs of rural inpatients remained stable over the years. Furthermore, the compensation fund of NCMS inpatients grew significantly. The actual inpatient reimbursement rate at township health centers increased from 76.93% to 84.04%. Meanwhile, the rate at county hospitals and tertiary hospitals increased slightly from 59.37% and 46.10% to 61.25% and 47.71%, respectively. CONCLUSIONS: With the improvement of the reimbursement ability, especially after the new health care reform in 2009, the NCMS have been playing a prominent role in alleviating the economic burden of farmers' medical treatment. Meanwhile, more patients go to primary hospitals than tertiary hospitals, and the capability of primary hospitals has been greatly improved. PMID- 27231164 TI - Influence of Occupational Status on the Quality of Life of Chinese Adult Patients with Epilepsy. AB - BACKGROUND: Epilepsy is one of the most common serious neurological disorders. The present study aimed to investigate the influence of occupational status on the quality of life of Chinese adult patients with epilepsy. METHODS: This study surveyed 819 subjects clinically diagnosed with epilepsy for more than 1 year in 11 hospitals in Beijing; 586 were employed (71.55%). All subjects completed the case report form with inquiries on demographic data, social factors, and illness. The patients' quality of life was assessed using the quality of life in patients with epilepsy-31 items (QOLIE-31) questionnaire. RESULTS: The QOLIE-31 score in the employed group was significantly higher than that in the unemployed group. Furthermore, the scores in all the sections (overall quality of life, energy/fatigue, emotional well-being, seizure worry, cognition, social function, and medication effects) of the employed group were higher than those of the unemployed group. Both the employed and unemployed groups achieved the highest difference in social function. The QOLIE-31 score of students was higher than those of farmers and workers. Both the students and workers scored higher in the quality of life compared with the adult peasants living with epilepsy. The students and farmers showed significant differences in QOLIE-31 score, cognition, emotional well-being, overall quality of life, energy/fatigue, and social function. In contrast, no significant difference was noted in seizure worry and medication effects across the three different kinds of occupation. CONCLUSION: Occupational status might affect the quality of life of Chinese adult patients with epilepsy, and social function is the most important contributing factor. PMID- 27231165 TI - Clinical Characteristics of Patients with Diabetic Nephropathy on Maintenance Hemodialysis: A Multicenter Cross-sectional Survey in Anhui Province, Eastern China. AB - BACKGROUND: The incidence of diabetic nephropathy (DN) increases year by year. However, clinical characteristics of DN patients on maintenance hemodialysis (MHD) were rarely reported in China. The purpose of this study was to examine the clinical characteristics of the DN patients on MHD in Anhui Province, Eastern China. METHODS: The clinical data of MHD patients in the hemodialysis centers of 26 hospitals in Anhui Province from January 1, 2014, to March 31, 2014, were examined. The differences between DN patients and non-DN patients were compared regarding vascular access, nutritional status, mineral and bone disorder, and other indexes. RESULTS: Among the selected 2768 adult MHD patients, 427 had DN. The incidence of hypertension, coronary heart disease, and cerebral thrombus in DN patients was 94.1%, 21.5%, and 15.0%, respectively, which were higher than those in non-DN patients (P < 0.001). Category of vascular access for hemodialysis in DN patients was arteriovenous fistula (AVF) (87.4% [373/427]) and tunneled cuffed catheter (TCC) (11.2% [48/427]). The percentage of AVF was significantly lower than that of non-DN patients (P < 0.001), and percentage of TCC was significantly higher than that of non-DN patients (P < 0.001). Hemoglobin achievement rate in DN patients was 32.0%. The incidence of hypoalbuminemia was 24.7%, significantly higher than that in non-DN patients (P < 0.001). The achievement rate of the target range in mineral values was 55.9% in corrected serum calcium level, 30.1% in serum phosphorus level, and 49.3% in intact parathyroid hormone (iPTH) level in DN patients. Compared with non-DN patients, the achievement rate of serum phosphorus was significantly higher in DN patients. CONCLUSIONS: DN patients on MHD in Anhui province exhibited different clinical characteristics compared to non-DN hemodialysis patients. They presented higher percentage in TCC use and cardiovascular complication, lower serum albumin and iPTH levels than those in non-DN patients. PMID- 27231166 TI - Imbalance of Fecal Microbiota at Newly Diagnosed Type 1 Diabetes in Chinese Children. AB - BACKGROUND: Recent studies have indicated that an imbalance of gut microbiota is associated with the development of type 1 diabetes mellitus (T1DM) and there is no literature regarding it in Chinese children yet. The aim of this study was to evaluate the alteration of gut microbiota between children with newly diagnosed T1DM and healthy controls and to determine if gut microbiota could partly explain the etiology of this disease. METHODS: A case-control study was carried out with 15 children with T1DM and 15 healthy children. The fecal bacteria composition was investigated by high-throughput sequencing of the V3-V4 region of the 16S rDNA gene and analyzed by the estimators of community richness (Chao) indexes. RESULTS: There was a notable lower richness of fecal bacteria in T1DM group than controls (156.53 +/- 36.96 vs. 130.0 +/- 32.85, P = 0.047). At the genus level, the composition of Blautia was increased in T1DM group than control group whereas the composition of Haemophilus, Lachnospira, Dialister, and Acidaminococcus was decreased. In addition, we found that the percentage of Blautia was correlated positively with HbA1c (rho = 0.40, P = 0.031), the numbers of T1DM autoantibodies (rho = 0.42, P = 0.023), and the titers of tyrosine phosphatase autoantibodies (IA-2) (rho = 0.82, P = 0.000) in the study. CONCLUSIONS: This study showed that gut microbiota was associated with the development of T1DM by affecting the autoimmunity, and the results suggested a potential therapy for T1DM via modulating the gut microbiota. PMID- 27231167 TI - Single Port Transumbilical Laparoscopic Surgery versus Conventional Laparoscopic Surgery for Benign Adnexal Masses: A Retrospective Study of Feasibility and Safety. AB - BACKGROUND: Single port laparoscopic surgery (SPLS) is an innovative approach that is rapidly gaining recognition worldwide. The aim of this study was to determine the feasibility and safety of SPLS compared to conventional laparoscopic surgery for the treatment of benign adnexal masses. METHODS: In total, 99 patients who underwent SPLS for benign adnexal masses between December 2013 and March 2015 were compared to a nonrandomized control group comprising 104 conventional laparoscopic adnexal surgeries that were performed during the same period. We retrospectively analyzed multiple clinical characteristics and operative outcomes of all the patients, including age, body mass index, size and pathological type of ovarian mass, operative time, estimated blood loss (EBL), duration of postoperative hospital stay, etc. RESULTS: No significant difference was observed between the two groups regarding preoperative baseline characteristics. However, the pathological results between the two groups were found to be slightly different. The most common pathological type in the SPLS group was mature cystic teratoma, whereas endometrioma was more commonly seen in the control group. Otherwise, the two groups had comparable surgical outcomes, including the median operation time (51 min vs. 52 min, P = 0.909), the median decreased level of hemoglobin from preoperation to postoperation day 3 (10 g/L vs. 10 g/L, P = 0.795), and the median duration of postoperative hospital stay (3 days vs. 3 days, P = 0.168). In SPLS groups, the median EBL and the anal exsufflation time were significantly less than those of the conventional group (5 ml vs. 10 ml, P < 0.001; 10 h vs. 22 h, P < 0.001). CONCLUSIONS: SPLS is a feasible and safe approach for the treatment of benign adnexal masses. Further study is required to better determine whether SPLS has significant benefits compared to conventional techniques. PMID- 27231168 TI - Early Changes in Atrial Electromechanical Coupling in Patients with Hypertension: Assessment by Tissue Doppler Imaging. AB - BACKGROUND: Hypertension (HT) is associated with atrial electrophysiological abnormalities. Echocardiographic pulsed wave tissue Doppler imaging (TDI) is one of the noninvasive methods for evaluation of atrial electromechanical properties. The aims of our study were to investigate the early changes in atrial electromechanical conduction in patients with HT and to assess the parameters that affect atrial electromechanical conduction. METHODS: Seventy-six patients with HT (41 males, mean age 52.6 +/- 9.0 years) and 41 controls (22 males, mean age 49.8 +/- 7.9 years) were included in the study. Atrial electromechanical coupling at the right (PRA), left (PLA), interatrial septum (PIS) were measured with TDI. Intra- (right: PIS-PRA, left: PLA-PIS) and inter-atrial (PLA-PRA) electromechanical delays were calculated. Maximum P-wave duration (Pmax) was calculated from 12-lead electrocardiogram. RESULTS: Atrial electromechanical coupling at PLA (76.6 +/- 14.1 ms vs. 82.9 +/- 15.8 ms, P = 0.036), left intra atrial (10.9 +/- 5.0 ms vs. 14.0 +/- 9.7 ms, P = 0.023), right intra-atrial (10.6 +/- 7.8 ms vs. 14.5 +/- 10.1 ms, P = 0.035), and interatrial electromechanical (21.4 +/- 9.8 ms vs. 28.3 +/- 12.7 ms, P = 0.003) delays were significantly longer in patients with HT. The linear regression analysis showed that left ventricular (LV) mass index and Pmax were significantly associated with PLA (P = 0.001 and P = 0.002, respectively), and the LV mass index was the only related factor for interatrial delay (P = 0.001). CONCLUSIONS: Intra- and interatrial electromechanical delay, PLA were significantly prolonged in hypertensive patients. LV mass index and Pmax were significantly associated with PLA, and the LV mass index was the only related factor for interatrial delay. The atrial TDI can be a valuable method to assess the early changes of atrial electromechanical conduction properties in those patients. PMID- 27231170 TI - Intermittent Oxygen Inhalation with Proper Frequency Improves Overall Health Conditions and Alleviates Symptoms in a Population at High Risk of Chronic Mountain Sickness with Severe Symptoms. AB - BACKGROUND: Oxygen inhalation therapy is essential for the treatment of patients with chronic mountain sickness (CMS), but the efficacy of oxygen inhalation for populations at high risk of CMS remains unknown. This research investigated whether oxygen inhalation therapy benefits populations at high risk of CMS. METHODS: A total of 296 local residents living at an altitude of 3658 m were included; of which these were 25 diagnosed cases of CMS, 8 cases dropped out of the study, and 263 cases were included in the analysis. The subjects were divided into high-risk (180 <= hemoglobin (Hb) <210 g/L, n = 161) and low-risk (Hb <180 g/L, n = 102) groups, and the cases in each group were divided into severe symptom (CMS score >=6) and mild symptom (CMS score 0-5) subgroups. Severe symptomatic population of either high- or low-risk CMS was randomly assigned to no oxygen intake group (A group) or oxygen intake 7 times/week group (D group); mild symptomatic population of either high- or low-risk CMS was randomly assigned to no oxygen intake group (A group), oxygen intake 2 times/week group (B group), and 4 times/week group (C group). The courses for oxygen intake were all 30 days. The CMS symptoms, sleep quality, physiological biomarkers, biochemical markers, etc., were recorded on the day before oxygen intake, on the 15th and 30th days of oxygen intake, and on the 15th day after terminating oxygen intake therapy. RESULTS: A total of 263 residents were finally included in the analysis. Among these high-altitude residents, CMS symptom scores decreased for oxygen inhalation methods B, C, and D at 15 and 30 days after oxygen intake and 15 days after termination, including dyspnea, palpitation, and headache index, compared to those before oxygen intake (B group: Z = 5.604, 5.092, 5.741; C group: Z = 4.155, 4.068, 4.809; D group: Z = 6.021, 6.196, 5.331, at the 3 time points respectively; all P < 0.05/3 vs. before intake). However, dyspnea/palpitation (A group: Z = 5.003, 5.428, 5.493, both P < 0.05/3 vs. before intake) and headache (A group: Z = 4.263, 3.890, 4.040, both P < 0.05/3 vs. before intake) index decreased significantly also for oxygen inhalation method A at all the 3 time points. Cyanosis index decreased significantly 30 days after oxygen intake only in the group of participants administered the D method (Z = 2.701, P = 0.007). Tinnitus index decreased significantly in group A and D at 15 days (A group: Z = 3.377, P = 0.001, D group: Z = 3.150, P = 0.002), 30 days after oxygen intake (A group: Z = 2.836, P = 0.005, D group: Z = 5.963, P < 0.0001) and 15 days after termination (A group: Z = 2.734, P = 0.006, D group: Z = 4.049, P = 0.0001), and decreased significantly in the group B and C at 15 days after termination (B group: Z = 2.611, P = 0.009; C group: Z = 3.302, P = 0.001). In the population at high risk of CMS with severe symptoms, oxygen intake 7 times/week significantly improved total symptom scores of severe symptoms at 15 days (4 [2, 5] vs. 5.5 [4, 7], Z = 2.890, P = 0.005) and 30 days (3 [1, 5] vs. 5.5 [2, 7], Z = 3.270, P = 0.001) after oxygen intake compared to no oxygen intake. In the population at high risk of CMS with mild symptoms, compared to no oxygen intake, oxygen intake 2 or 4 times/week did not improve the total symptom scores at 15 days (2 [1, 3], 3 [1, 4] vs. 3 [1.5, 5]; chi2 = 2.490, P = 0.288), and at 30 days (2 [0, 4], 2 [1, 4.5] vs. 3 [2, 5]; chi2 = 3.730, P = 0.155) after oxygen intake. In the population at low risk of CMS, oxygen intake did not significantly change the white cell count and red cell count compared to no oxygen intake, neither in the severe symptomatic population nor in the mild symptomatic population. CONCLUSIONS: Intermittent oxygen inhalation with proper frequency might alleviate symptoms in residents at high altitude by improving their overall health conditions. Administration of oxygen inhalation therapy 2-4 times/week might not benefit populations at high risk of CMS with mild CMS symptoms while administration of therapy 7 times/week might benefit those with severe symptoms. Oxygen inhalation therapy is not recommended for low-risk CMS populations. PMID- 27231169 TI - Efficacy of Postoperative Hormone Replacement Therapy on Prognosis of Patients with Serous Ovarian Carcinoma. AB - BACKGROUND: Ovarian cancer is the most common cause of gynecological cancer associated death. Iatrogenic menopause might adversely affect the quality of life and health outcomes in young female cancer survivors. We evaluated whether postoperative hormone replacement therapy (HRT) had a negative influence on the progression-free survival (PFS) of patients with papillary serous ovarian cancer (SOC). METHODS: We retrospectively reviewed the medical records of patients with papillary SOC, treated from January 1980 to December 2009, who suffered from menopause with or without HRT. Clinical characteristics of patients were compared between the two groups (HRT and non-HRT). Blood samples were collected from all the participants to detect serum cancer antigen (CA) 125. Hazard ratios with 95% confidential intervals for each variable were calculated by univariable and multivariable conditional Logistic regression analyses. RESULTS: Among 112 identified patients, 31 were HRT users and 81 were not. The two groups did not significantly differ in median age at diagnosis (t = 0.652, P = 0.513), International Federation of Gynecology and Obstetrics (FIGO) stage (chi2 = 0.565, P = 0.754), differentiation (chi2 = 1.728, P = 0.422), resection status (chi2 = 0.070, P = 0.791), relapse (chi2 = 0.109, P = 0.741), chemotherapy course (t = 1.079, P = 0.282), follow-up interval (t = 0.878, P = 0.382), or PFS (t = 0.580, P = 0.562). Median Kupperman score at the onset of HRT was 30.81 and 12.19 after the therapy (t = 3.302, P = 0.001). According to the analysis, the strongest independent variables in predicting PFS were FIGO stage and disease that was not optimally debulked. CONCLUSIONS: Postoperative HRT is not a prognostic factor for PFS of patients with papillary SOC. However, multicenter studies are needed to verify and extend our findings. PMID- 27231171 TI - Clinical and Laboratory Diagnosis of Intestinal Tuberculosis. AB - BACKGROUND: Tuberculosis (TB) remains a worldwide problem. Intestinal TB (ITB) constitutes a major public health problem in developing countries and has been associated with significant morbidity and mortality. The aim of this study was to characterize the clinical, radiological, endoscopic, and pathological features of ITB and to define the strategy for establishing the diagnosis. METHODS: A retrospective study (from January 2000 to June 2015) was carried out in Peking Union Medical College Hospital and all hospitalized cases were diagnosed as ITB during the study period were included. The relevant clinical information, laboratory results, microbiological, and radiological investigations were recorded. RESULTS: Of the 85 cases, 61 cases (71.8%) were ranged from 20 to 50 years. The ileocecal region was involved in about 83.5% (71/85) of patients. About 41.2% (35/85) of patients had co-existing extra ITB, especially active pulmonary TB. Abdominal pain (82.4%) was the most common presenting symptom followed by weight loss (72.9%) and fever (64.7%). Both T-cell spot of TB test (T SPOT.TB) and purified protein derivatives (PPD) tests were performed in 26 patients: 20 (76.9%) positive T-SPOT.TB and 13 (50.0%) positive PPD were detected, with a statistical significant difference (P = 0.046). Twenty cases (23.5%) were histopathology and/or pathogen confirmed TB; 27 cases (31.8%) were diagnosed by clinical manifestation consistent with ITB and evidence of active extra ITB; 38 cases (44.7%) were diagnosed by good response to diagnostic anti-TB therapy. CONCLUSIONS: ITB is difficult to diagnose even with modern medical techniques due to its nonspecific clinical and laboratory features. At present, combination of clinical, endoscopic, radiological, and pathological features continues to be the key to the diagnosis of ITB. PMID- 27231172 TI - Results of a Second-generation Constrained Condylar Prosthesis in Complex Primary and Revision Total Knee Arthroplasty: A Mean 5.5-Year Follow-up. AB - BACKGROUND: The application of second-generation constrained condylar knee (CCK) prostheses has not been widely studied. This retrospective study was carried out to evaluate the clinical and radiographic outcomes of a second-generation CCK prosthesis for complex primary or revision total knee arthroplasty (TKA). METHODS: In total, 51 consecutive TKAs (47 patients) were performed between June 2003 and June 2013 using second-generation modular CCK prostheses. The follow-up was conducted at 3rd day, 1st, 6th, and 12th months postoperatively and later annually. Anteroposterior (AP), lateral, skyline, and long-standing AP radiographs of the affected knees were taken. The Hospital for Special Surgery (HSS) Knee Score, the Knee Society Knee Score (KSKS), the Knee Society Function Score (KSFS), and range of motion (ROM) were also recorded. Heteroscedastic two tailed Student's t-tests were used to compare the HSS score and the Knee Society score between primary and revision TKAs. A value of P < 0.05 was considered statistically significant. RESULTS: Four knees (two patients) were lost to follow up, and 47 knees (31 primary TKAs and 16 revision TKAs) had a mean follow-up time of 5.5 years. The mean HSS score improved from 51.1 +/- 15.0 preoperatively to 85.3 +/- 8.4 points at the final follow-up (P < 0.05). Similar results were observed in terms of the KSKS and KSFS, which improved from 26.0 +/- 13.0 to 80.0 +/- 12.2 and from 40.0 +/- 15.0 to 85.0 +/- 9.3 points, respectively (P < 0.05). No significant difference in the HSS, KSKS, KSFS, or ROM was found between primary and revision TKAs (P > 0.05). Two complications were observed in the revision TKA group (one intraoperative distal femur fracture and one recurrence of infection) while one complication (infection) was observed in the primary TKA group. No prosthesis loosening, joint dislocation, patella problems, tibial fracture, or nerve injury were observed. Radiolucent lines were observed in 4% of the knees without progressive osteolysis. CONCLUSIONS: Second-generation modular CCK prostheses are a safe and practical treatment for both primary and revision knees that cannot be balanced. However, further studies focusing on different types of constrained prostheses are required to validate these results. PMID- 27231173 TI - Individualized Immunosuppressive Protocol of Liver Transplant Recipient Should be Made Based on Splenic Function Status. AB - BACKGROUND: Lymphocyte subsets play important roles in rejection in liver transplant recipients, and the effect of splenic function on these roles remains unknown. The aim of this study was to explore the feasibility to adjust immunosuppressive agents based on splenic function status through detecting the lymphocyte subsets in liver transplantBeijing recipients. METHODS: The lymphocyte subsets of 49 liver transplant recipients were assessed in the 309th Hospital of Chinese People's Liberation Army between June 2014 and August 2015. The patients were divided into splenectomy group (n = 9), normal splenic function group (n = 24), and hypersplenism group (n = 16). The percentages and counts of CD4+ T, CD8+ T, natural killer (NK) cell, B-cell, regulatory B-cell (Breg), and regulatory T cell (Treg) were detected by flow cytometer. In addition, the immunosuppressive agents, histories of rejection and infection, and postoperative time of the patients were compared among the three groups. RESULTS: There was no significant difference of clinical characteristics among the three groups. The percentage of CD19+CD24+CD38+ Breg was significantly higher in hypersplenism group than normal splenic function group and splenectomy group (3.29 +/- 0.97% vs. 2.12 +/- 1.08% and 1.90 +/- 0.99%, P = 0.001). The same result was found in CD4+CD25+FoxP3+ Treg percentage (0.97 +/- 0.39% vs. 0.54 +/- 0.31% and 0.56 +/- 0.28%, P = 0.001). The counts of CD8+ T-cell, CD4+ T-cell, and NK cell were significantly lower in hypersplenism group than normal splenic function group (254.25 +/- 149.08 vs. 476.96 +/- 225.52, P= 0.002; 301.69 +/- 154.39 vs. 532.50 +/- 194.42, P= 0.000; and 88.56 +/- 63.15 vs. 188.33 +/- 134.51, P = 0.048). Moreover, the counts of CD4+ T-cell and NK cell were significantly lower in hypersplenism group than splenectomy group (301.69 +/- 154.39 vs. 491.89 +/- 132.31, P= 0.033; and 88.56 +/- 63.15 vs. 226.00 +/- 168.85, P = 0.032). CONCLUSION: Splenic function status might affect the immunity of liver transplant recipients, that should be considered when we make immunosuppressive protocols. PMID- 27231174 TI - Associations of Human Leukocyte Antigen-DRB1 Alleles with Nasopharyngeal Carcinoma and Its Clinical Significance in Xinjiang Uyghur Autonomous Region of China. AB - BACKGROUND: Genetic susceptibility is one of the major etiological factors for nasopharyngeal carcinoma (NPC). Among the genetic predisposing factors, human leukocyte antigen (HLA) genes have been reported to be associated with NPC. This study aimed to investigate the associations of HLA-DRB1 alleles with NPC and the clinical significance of HLA-DRB1 alleles in NPC. METHODS: From January 2009 to December 2013, 140 NPC patients (118 Han patients and 22 Uyghur patients) and 158 healthy controls (81 Han individuals and 77 Uyghur individuals) from Xinjiang Province were genotyped for HLA-DRB1 using the polymerase chain reaction-sequence specific primer technique. Chi-square analysis was used when comparing allele frequencies between groups. The clinical outcomes were evaluated by Kaplan-Meier method and Cox regression model. RESULTS: Compared with healthy controls, the allele frequency of HLA-DRB1*0701 was increased in the Uyghur patients (P = 0.008) but not in the Han patients (P = 0.869). HLA-DRB1*0101 allele was presented with higher frequency in clinical Stage I + II group compared with clinical Stage III + IV group in the Han patients (P = 0.015) but not in the Uyghur patients (P = 1.000). Higher frequency of HLA-DRB1*1501 allele was observed in patients aged <45 years compared with those in patients aged >=45 years (P = 0.002). Neither HLA-DRB1*0701 nor HLA-DRB1*0101 had a statistically significant association with 3-year survival. CONCLUSIONS: This study found HLA DRB1*0701 in Uyghur population was associated with an increased risk of developing NPC. In Han population, we found HLA-DRB1*0101 was associated with protection from disease progression, and HLA-DRB1*1501 was associated with early age of onset. HLA-DRB1 could not be identified as a prognostic indicator for NPC in either Han or Uyghur patients. PMID- 27231175 TI - Epigenetic Silencing of Eyes Absent 4 Gene by Acute Myeloid Leukemia 1-Eight twenty-one Oncoprotein Contributes to Leukemogenesis in t(8;21) Acute Myeloid Leukemia. AB - BACKGROUND: The acute myeloid leukemia 1 (AML1)-eight-twenty-one (ETO) fusion protein generated by the t(8;21)(q22;q22) translocation is considered to display a crucial role in leukemogenesis in AML. By focusing on the anti-leukemia effects of eyes absent 4 (EYA4) gene on AML cells, we investigated the biologic and molecular mechanism associated with AML1-ETO expressed in t(8;21) AML. METHODS: Qualitative polymerase chain reaction (PCR), quantitative reverse transcription PCR (RT-PCR), and Western blotting analysis were used to observe the mRNA and protein expression levels of EYA4 in cell lines. Different plasmids (including mutant plasmids) of dual luciferase reporter vector were built to study the binding status of AML1-ETO to the promoter region of EYA4. Chromatin immunoprecipitation assay was used to study the epigenetic silencing mechanism of EYA4. Bisulfite sequencing was applied to detect the methylation status in EYA4 promoter region. The influence of EYA4 gene in the cell proliferation, apoptosis, and cell clone-forming ability was detected by the technique of Cell Counting Kit 8, flow cytometry, and clonogenic assay. RESULTS: EYA4 gene was hypermethylated in AML1-ETO+ patients and its expression was down-regulated by 6-fold in Kasumi-1 and SKNO-1 cells, compared to HL-60 and SKNO-1-siA/E cells, respectively. We demonstrated that AML1-ETO triggered the epigenetic silencing of EYA4 gene by binding at AML1-binding sites and recruiting histone deacetylase 1 and DNA methyltransferases. Enhanced EYA4 expression levels inhibited cellular proliferation and suppressed cell colony formation in AML1-ETO+ cell lines. We also found EYA4 transfection increased apoptosis of Kasumi-1 and SKNO-1 cells by 1.6-fold and 1.4-fold compared to negative control, respectively. CONCLUSIONS: Our study identified EYA4 gene as targets for AML1-ETO and indicated it as a novel tumor suppressor gene. In addition, we provided evidence that EYA4 gene might be a novel therapeutic target and a potential candidate for treating AML1 ETO+ t (8;21) AML. PMID- 27231177 TI - First Positive Detection of H9 Subtype of Avian Influenza Virus Nucleic Acid in Aerosol Samples from Live Poultry Markets in Guangxi, South of China. PMID- 27231176 TI - High-resolution Magnetic Resonance Vessel Wall Imaging for Intracranial Arterial Stenosis. AB - OBJECTIVE: To discuss the feasibility and clinical value of high-resolution magnetic resonance vessel wall imaging (HRMR VWI) for intracranial arterial stenosis. DATE SOURCES: We retrieved information from PubMed database up to December 2015, using various search terms including vessel wall imaging (VWI), high-resolution magnetic resonance imaging, intracranial arterial stenosis, black blood, and intracranial atherosclerosis. STUDY SELECTION: We reviewed peer reviewed articles printed in English on imaging technique of VWI and characteristic findings of various intracranial vasculopathies on VWI. We organized this data to explain the value of VWI in clinical application. RESULTS: VWI with black blood technique could provide high-quality images with submillimeter voxel size, and display both the vessel wall and lumen of intracranial artery simultaneously. Various intracranial vasculopathies (atherosclerotic or nonatherosclerotic) had differentiating features including pattern of wall thickening, enhancement, and vessel remodeling on VWI. This technique could be used for determining causes of stenosis, identification of stroke mechanism, risk-stratifying patients, and directing therapeutic management in clinical practice. In addition, a new morphological classification based on VWI could be established for predicting the efficacy of endovascular therapy. CONCLUSIONS: This review highlights the value of HRMR VWI for discrimination of different intracranial vasculopathies and directing therapeutic management. PMID- 27231178 TI - Fracture of Extensively Porous-Coated Cylindrical Femoral Stem Following Revision Total Hip Arthroplasty. PMID- 27231179 TI - Preoperative Diagnosis in 46 Cases of Pulmonary Sclerosing Hemangioma. PMID- 27231180 TI - Successful Renal Transplantation in a Patient with Atypical Hemolytic Uremic Syndrome Treated with Eculizumab in China. PMID- 27231181 TI - Cleft Palate Surgical Skills Training Using an Alternative Synthetic Bench Model. PMID- 27231182 TI - A Case of Pulmonary Langerhans Cell Histiocytosis with BRAF V600E-negative and MAP2K1-posivtive Mutations Presenting as Diffuse Nodules in Chest High-resolution Computed Tomography After Smoking Cessation. PMID- 27231183 TI - Impact of delirium on weaning from mechanical ventilation in medical patients. PMID- 27231185 TI - Motor neuron disease: Environmental toxins - modifiable risk factors for ALS? PMID- 27231186 TI - CNS infections: Mouse studies confirm the link between Zika virus infection and microcephaly. PMID- 27231184 TI - Skeletal muscle disorders of glycogenolysis and glycolysis. AB - Skeletal muscle disorders of glycogenolysis and glycolysis account for most of the conditions collectively termed glycogen storage diseases (GSDs). These disorders are rare (incidence 1 in 20,000-43,000 live births), and are caused by autosomal or X-linked recessive mutations that result in a specific enzyme deficiency, leading to the inability to utilize muscle glycogen as an energy substrate. McArdle disease (GSD V) is the most common of these disorders, and is caused by mutations in the gene encoding muscle glycogen phosphorylase. Symptoms of McArdle disease and most other related GSDs include exercise intolerance, muscle contracture, acute rhabdomyolysis, and risk of acute renal failure. Older patients may exhibit muscle wasting and weakness involving the paraspinal muscles and shoulder girdle. For patients with these conditions, engaging with exercise is likely to be beneficial. Diagnosis is frequently delayed owing to the rarity of the conditions and lack of access to appropriate investigations. A few randomized clinical trials have been conducted, some focusing on dietary modification, although the quality of the evidence is low and no specific recommendations can yet be made. The development of EUROMAC, an international registry for these disorders, should improve our knowledge of their natural histories and provide a platform for future clinical trials. PMID- 27231187 TI - Health Literacy Status Affects Outcomes for Patients Referred for Transplant. AB - BACKGROUND: It is hypothesized that limited health literacy affects outcomes for patients referred for transplant; however, research has not examined this for all types of end-stage organ disease. OBJECTIVE: The purpose of this study was to determine whether health literacy and cognitive impairment were related to listing for transplant and posttransplant outcomes. METHODS: Chart reviews were conducted on 398 patients who completed a required psychiatric evaluation before transplant listing. Information gathered from these evaluations included reading ability, math ability, and cognitive functioning. Variables before transplant and 6 months after transplantation were also collected. RESULTS: Patients with limited reading ability were less likely to be listed for transplant (p = .018) and were more likely to be removed from listing (p = .042), to miss appointments prelisting (p = .021), and to experience graft failure (p = .015). Patients with limited math ability were less likely to be listed (p = .010) and receive a transplant (p = 0.031), and more likely to be readmitted posttransplant (p = .029). Patients with cognitive impairment were less likely to be listed (p = .043) and to receive a transplant (p = .010). CONCLUSIONS: To achieve superior transplant access and outcomes, transplant providers should regularly screen patients for limited health literacy and cognitive impairment. Future studies should evaluate whether interventions result in better outcomes for these patients. PMID- 27231188 TI - Asymmetric dual catalysis via fragmentation of a single rhodium precursor complex. AB - A strategy for dual transition metal catalysis and organocatalysis is reported via the in situ disintegration of a single rhodium complex. The hereby generated chiral Lewis acid and l-beta-phenylalanine synergistically catalyze the Michael addition of alpha,alpha-disubstituted aldehydes to alpha,beta-unsaturated 2-acyl imidazoles under the formation of vicinal quaternary/tertiary stereocenters. Conveniently, the chiral-at-metal rhodium catalyst can be synthesized in just two steps starting from rhodium trichloride without the need for any chromatography. PMID- 27231189 TI - [Immunoglobulin G4-related lung disease: Case report and literature review]. AB - We report the case of a 61-year-old man with a pulmonary nodule discovered while staging the metastasis of a squamous cell carcinoma. No primary cancer was found. Histological examination of the resected specimen (lingula) was in favor of IgG4 related inflammatory pseudotumor. Histological criteria were described in 2012, combining a dense lymphoplasmacitic infiltrate rich in IgG4-positive plasma cell, storiform fibrosis and obliterative phlebitis. IgG4/IgG plama cell ratio>40 % is mandatory for histological diagnosis of IgG4-related disease. This is a rare and often underdiagnosed disease. Diagnostic criteria are now defined and consensual, combining clinical signs, biology and histology. PMID- 27231191 TI - The dynamics of neutrophils in zebrafish (Danio rerio) during infection with the parasite Ichthyophthirius multifiliis. AB - Ichthyophthirius multifiliis is a ciliated protozoan parasite infecting the skin and gills of freshwater fish. Neutrophils are attracted to the infection sites, as a part of the innate immune response. In this study a transgenic line of zebrafish (Tg(MPO:GFP)(i114)) with GFP-tagged neutrophils was infected with I. multifiliis and the neutrophil influx in the caudal fin was quantified. Twenty four hours post infection (pi) the neutrophil count had gone up with an average of 3.4 fold. Forty-eight h pi the neutrophil count had dropped 12% and 72 h pi it had dropped to 21% compared to 24 h pi. At 72 h pi the neutrophil count was 2.7 times higher than prior to infection. A few dead parasites were observed, which were disintegrated and covered internally and externally with neutrophils. Live parasites, both surrounded by neutrophils and with no neutrophils in the near vicinity, were found during the infection. Neutrophils interacted directly with the parasites with pseudopod formation projecting towards the pathogen. These results indicate a strong innate immune response immediately following infection and/or a subsequent immune evasion by the parasite. PMID- 27231190 TI - Complement C3 gene: Expression characterization and innate immune response in razor clam Sinonovacula constricta. AB - Complement component 3 (C3) is central to the complement system, playing an important role in immune defense, immune regulation and immune pathology. Several C3 genes have been characterized in invertebrates but very few in shellfish. The C3 gene was identified from the razor clam Sinonovacula constricta, referred to here as Sc-C3. It was found to be highly homologous with the C3 gene of Ruditapes decussatus. All eight model motifs of the C3 gene were found to be included in the thiolester bond and the C345C region. Sc-C3 was widely expressed in all healthy tissues with expression being highest in hemolymph. A significant difference in expression was revealed at the umbo larvae development stage. The expression of Sc-C3 was highly regulated in the hemolymph and liver, with a distinct response pattern being noted after a challenge with Micrococcus lysodeikticus and Vibrio parahemolyticus. It is therefore suggested that a complicated and unique response pathway may be present in S. constricta. Further, serum of S. constricta containing Sc-C3 was extracted. This was activated by LPS or bacterium for verification for function. The more obvious immune function of Sc-C3 was described as an effective membrane rupture in hemocyte cells of rabbit, V. parahemolyticus and Vibrio anguillarum. Thus, Sc-C3 plays an essential role in the immune defense of S. constricta. PMID- 27231192 TI - Characterization of ADP ribosylation factor 1 gene from Exopalaemon carinicauda and its immune response to pathogens challenge and ammonia-N stress. AB - ADP ribosylation factors (Arf), as highly conserved small guanosine triphosphate (GTP)-binding proteins, participates in intracellular trafficking and organelle structure. In this study, a full-length cDNA of Arf1 (designated EcArf1) was cloned from Exopalaemon carinicauda by using rapid amplification of cDNA ends (RACE) approaches. The full-length cDNA of EcArf1 was 1428 bp, which contains an open reading frame (ORF) of 549 bp, encoding a 182 amino-acid polypeptide with the predicted molecular weight of 20.69 kDa and estimated isoelectric point was 7.24. Sequence analysis revealed that the conserved Arf protein family signatures were identified in EcArf1. The deduced amino acid sequence of EcArf1 shared high identity (95%-98%) with that of other species and clustered together with Arf1 of other shrimp in the NJ phylogenetic tree, indicating that EcArf1 should be a member of the Arf1 family. Quantitative real-time RT-qPCR analysis indicated that EcArf1 was expressed in hemocytes, hepatopancreas, gills, muscle, ovary, intestine, stomach and heart, and the most abundant level was in hemocytes and gills, which were also the two main target tissues of pathogen infection and environmental stress. After Vibrio parahaemolyticus challenge, EcArf1 transcripts level significantly increased in hemocytes and hepatopancreas at 3 h and 6 h, respectively. The expression of EcArf1 in hemocytes and hepatopancreas significantly up-regulated at 12 h and 6 h respectively, and down-regulated at 72 h and 48 h, respectively. EcArf1 expression in hepatopancreas and gills both significantly increased at 6 h and decreased at 24 h under ammonia-N stress. The results suggested that EcArf1 might be involved in immune responses to pathogens (V. parahaemolyticus and WSSV) challenge and ammonia-N stress in E. carinicauda. PMID- 27231193 TI - Visual processing during natural reading. AB - Reading is a unique human ability that plays a pivotal role in the development and functioning of our modern society. However, its neural basis remains poorly understood since previous research was focused on reading words with fixed gaze. Here we developed a methodological framework for single-trial analysis of fixation onset-related EEG activity (FOREA) that enabled us to investigate visual information processing during natural reading. To reveal the effect of reading skills on orthographic processing during natural reading, we measured how altering the configural properties of the written text by modifying inter-letter spacing affects FOREA. We found that orthographic processing is reflected in FOREA in three consecutive time windows (120-175 ms, 230-265 ms, 345-380 ms after fixation onset) and the magnitude of FOREA effects in the two later time intervals showed a close association with the participants' reading speed: FOREA effects were larger in fast than in slow readers. Furthermore, these expertise driven configural effects were clearly dissociable from the FOREA signatures of visual perceptual processes engaged to handle the increased crowding (155-220 ms) as a result of decreasing letter spacing. Our findings revealed that with increased reading skills orthographic processing becomes more sensitive to the configural properties of the written text. PMID- 27231195 TI - Subluminal group velocity and dispersion of Laguerre Gauss beams in free space. AB - That the speed of light in free space c is constant has been a pillar of modern physics since the derivation of Maxwell and in Einstein's postulate in special relativity. This has been a basic assumption in light's various applications. However, a physical beam of light has a finite extent such that even in free space it is by nature dispersive. The field confinement changes its wavevector, hence, altering the light's group velocity vg. Here, we report the subluminal vg and consequently the dispersion in free space of Laguerre-Gauss (LG) beam, a beam known to carry orbital angular momentum. The vg of LG beam, calculated in the paraxial regime, is observed to be inversely proportional to the beam's divergence theta0, the orbital order l and the radial order p. LG beams of higher orders travel relatively slower than that of lower orders. As a consequence, LG beams of different orders separate in the temporal domain along propagation. This is an added effect to the dispersion due to field confinement. Our results are useful for treating information embedded in LG beams from astronomical sources and/or data transmission in free space. PMID- 27231194 TI - Characterizing dynamic local functional connectivity in the human brain. AB - Functional connectivity (FC), obtained from functional magnetic resonance imaging (fMRI), brings insights into the functional organization of the brain. Recently, rich and complex behaviour of brain has been revealed by the dynamic fluctuation of FC, which had previously been regarded as confounding 'noise'. While the dynamics of long-distance, inter-regional FC has been extensively studied, the dynamics of local FC within a few millimetres in space remains largely unexplored. In this study, the local FC was depicted by regional homogeneity (ReHo), and the dynamics of local FC was obtained using sliding windows method. We observed a robust positive correlation between ReHo and its temporal variability, which was shown to be an intrinsic feature of the brain rather than a pure stochastic effect. Furthermore, fluctuation of ReHo was associated with global functional organization: (i) brain regions with higher centrality of inter regional FC tended to possess higher ReHo variability; (ii) coherence of ReHo fluctuation was higher within brain's functional modules. Finally, we observed alteration of ReHo variability during a motor task compared with resting-state. Our findings associated the temporal fluctuation of ReHo with brain function, opening up the possibility of dynamic local FC study in the future. PMID- 27231196 TI - Efficacy of Indian polyvalent snake antivenoms against Sri Lankan snake venoms: lethality studies or clinically focussed in vitro studies. AB - In vitro antivenom efficacy studies were compared to rodent lethality studies to test two Indian snake antivenoms (VINS and BHARAT) against four Sri Lankan snakes. In vitro efficacy was tested at venom concentrations consistent with human envenoming. Efficacy was compared statistically for one batch from each manufacturer where multiple vials were available. In binding studies EC50 for all VINS antivenoms were less than BHARAT for D. russelii [553 MUg/mL vs. 1371 MUg/mL;p = 0.016), but were greater for VINS antivenoms compared to BHARAT for N. naja [336 MUg/mL vs. 70 MUg/mL;p < 0.0001]. EC50 of both antivenoms was only slighty different for E. carinatus and B. caeruleus. For procoagulant activity neutralisation, the EC50 was lower for VINS compared to BHARAT - 60 MUg/mL vs. 176 MUg/mL (p < 0.0001) for Russell's viper and 357 MUg/mL vs. 6906MUg/mL (p < 0.0001) for Saw-scaled viper. Only VINS antivenom neutralized in vitro neurotoxicity of krait venom. Both antivenoms partially neutralized cobra and didn't neutralize Russell's viper neurotoxicity. Lethality studies found no statistically significant difference in ED50 values between VINS and BHARAT antivenoms. VINS antivenoms appeared superior to BHARAT at concentrations equivalent to administering 10 vials antivenom, based on binding and neutralisation studies. Lethality studies were inconsistent suggesting rodent death may not measure relevant efficacy outcomes in humans. PMID- 27231198 TI - Metallosupramolecular Structures Derived from a Series of Diphosphine-bridged Digold(I) Metalloligands with Terminal d-Penicillamine. AB - In this report, we describe our recent work on the development of a new family of chiral heteroleptic digold(I) metalloligands with mixed diphosphine and d penicillaminate (d-pen), [Au2 (dppx)(d-pen-S)2 ](2-) (dppx = PPh2 (CH2 )n PPh2 , n = 1-5) and their application for the construction of chiral multinuclear and metallosupramolecular structures. The reactions of the metalloligands with 3d metal ions produce a variety of chiral heterobimetallic structures retaining the digold(I) metalloligand structure, ranging from discrete trinuclear to infinite helix structures that depend on the type of dppx. In addition, monophosphine and triphosphine analogues of the metalloligands were designed, and their coordination behavior is discussed to show the essential properties and potential extensibility of this class of metalloligands. PMID- 27231197 TI - Association between previous history of gout attack and risk of deep vein thrombosis - a nationwide population-based cohort study. AB - Although the association of hyperuricemia and cardiovascular diseases is well established by previous research studies, the relationship between gout and deep vein thrombosis (DVT) remains unclear. We conducted a nationwide longitudinal cohort study to investigate the relationship between gout and DVT. We used the Taiwan National Health Insurance Research Database to identify patients with gout diagnosed in Taiwan during 2000-2011, and we followed up these patients to determine the incidence of DVT among them. The association between gout and DVT was analyzed by cox proportional hazard model. The study cohort included 35,959 patients with history of gout attack and 35,959 matched controls without gout attack. During the median follow-up of 7.5 +/- 3.6 years, the incidence rate of DVT was significantly higher in patients with gout than that in control group (13.48 versus 9.77 per 10(4) person-years, p < 0.001). Kaplan-Meier analysis revealed a tendency toward DVT development in gout patients (log rank test, p < 0.001). In a Cox model, patients with gout were found to have a 1.38-fold (95% confidence interval [CI], 1.18 to 1.62, p < 0.001) higher risk of developing DVT. Hyperuricemia with gout attack could be a possible risk predictor for DVT, but these findings need to be confirmed in future clinical and experimental studies. PMID- 27231199 TI - Metabolic Phenotypes of Carotid Atherosclerotic Plaques Relate to Stroke Risk: An Exploratory Study. AB - OBJECTIVE: Stroke is a major cause of death and disability. That three-quarters of stroke patients will never have previously manifested cerebrovascular symptoms demonstrates the unmet clinical need for new biomarkers able to stratify patient risk and elucidation of the biological dysregulations. In this study, the utility of comprehensive metabolic phenotyping is assessed to provide candidate biomarkers that relate to stroke risk in stenosing carotid plaque tissue samples. METHOD: Carotid plaque tissue samples were obtained from patients with cerebrovascular symptoms of carotid origin (n = 5), and from asymptomatic patients (n = 5). Two adjacent biological replicates were obtained from each tissue. Organic and aqueous metabolite extracts were obtained separately and analysed using two ultra performance liquid chromatography coupled to mass spectrometry metabolic profiling methods. Multivariate and univariate tools were used for statistical analysis. RESULTS: The two study groups demonstrated distinct plaque phenotypes using multivariate data analysis. Univariate statistics also revealed metabolites that differentiated the two groups with a strong statistical significance (p = 10(-4)-10(-5)). Specifically, metabolites related to the eicosanoid pathway (arachidonic acid and arachidonic acid precursors), and three acylcarnitine species (butyrylcarnitine, hexanoylcarnitine, and palmitoylcarnitine), intermediates of the beta-oxidation, were detected in higher intensities in symptomatic patients. However, metabolites implicated in the process of cell death, a process known to be upregulated in the formation of the vulnerable plaque, were unaffected. CONCLUSIONS: Discrimination between symptomatic and asymptomatic carotid plaque tissue is demonstrated for the first time using metabolic profiling technologies. Two biological pathways (eicosanoid and beta-oxidation) were implicated in differentiating symptomatic from asymptomatic patients and will be further investigated. These results indicate that metabolic phenotyping should be further explored to investigate the chemistry of the unstable plaque, in the pursuit of candidate biomarkers for risk stratification and targets for pharmacotherapeutic intervention. PMID- 27231200 TI - The impact of sperm protamine deficiency and sperm DNA damage on human male fertility: a systematic review and meta-analysis. AB - Existing literature suggests evidence that protamine deficiency is related to DNA damage and male fertility. In this meta-analysis, we analyzed the relationship between the ratio of protamine-1 and protamine-2 with male fertility and the association of protamine deficiency with sperm DNA damage. Quality of available cohort studies was evaluated using the Newcastle-Ottawa Scale checklist. Summary effect estimates with 95% confidence intervals (CI) were derived using a random effects model. The effect of the protamine ratio on male fertility was analyzed in nine studies demonstrating a significantly higher value of the protamine ratio in subfertile men (n = 633) when compared with controls (n = 453, SMD = 0.46, 95% CI 0.25-0.66, Z = 4.42, p < 0.00001). Both protamine mRNA (SMD = 0.45, 95% CI 0.11-0.79, Z = 2.63, p = 0.009) and protein ratio (SMD = 0.46, 95% CI 0.25-0.68, Z = 4.22, p < 0.0001) showed significantly increased values in subfertile patients. The association between protamine deficiency and DNA damage was analyzed in 12 studies (n = 845) exhibiting a combined overall correlation coefficient (COR) of 0.53 (95% CI 0.28-0.71, Z = 3.87, p < 0.001). Protamine deficiency measured by CMA3 staining was significantly associated with sperm DNA damage (COR = 0.71, 95% CI 0.48-0.85, Z = 4.87, p < 0.001), whereas the P1/P2 ratio was not (COR = 0.17, 95% CI -0.16 to 0.46, Z = 0.99, p = 0.33). It is concluded that the protamine ratio represents a suitable biomarker for the assessment of sperm quality and protamine deficiency is closely related with sperm DNA damage. PMID- 27231201 TI - Glutamate transporter activity promotes enhanced Na+ /K+ -ATPase-mediated extracellular K+ management during neuronal activity. AB - KEY POINTS: Management of glutamate and K+ in brain extracellular space is of critical importance to neuronal function. The astrocytic alpha2beta2 Na+ /K+ ATPase isoform combination is activated by the K+ transients occurring during neuronal activity. In the present study, we report that glutamate transporter mediated astrocytic Na+ transients stimulate the Na+ /K+ -ATPase and thus the clearance of extracellular K+ . Specifically, the astrocytic alpha2beta1 Na+ /K+ ATPase subunit combination displays an apparent Na+ affinity primed to react to physiological changes in intracellular Na+ . Accordingly, we demonstrate a distinct physiological role in K+ management for each of the two astrocytic Na+ /K+ -ATPase beta-subunits. ABSTRACT: Neuronal activity is associated with transient [K+ ]o increases. The excess K+ is cleared by surrounding astrocytes, partly by the Na+ /K+ -ATPase of which several subunit isoform combinations exist. The astrocytic Na+ /K+ -ATPase alpha2beta2 isoform constellation responds directly to increased [K+ ]o but, in addition, Na+ /K+ -ATPase-mediated K+ clearance could be governed by astrocytic [Na+ ]i . During most neuronal activity, glutamate is released in the synaptic cleft and is re-absorbed by astrocytic Na+ -coupled glutamate transporters, thereby elevating [Na+ ]i . It thus remains unresolved whether the different Na+ /K+ -ATPase isoforms are controlled by [K+ ]o or [Na+ ]i during neuronal activity. Hippocampal slice recordings of stimulus-induced [K+ ]o transients with ion-sensitive microelectrodes revealed reduced Na+ /K+ -ATPase-mediated K+ management upon parallel inhibition of the glutamate transporter. The apparent intracellular Na+ affinity of isoform constellations involving the astrocytic beta2 has remained elusive as a result of inherent expression of beta1 in most cell systems, as well as technical challenges involved in measuring intracellular affinity in intact cells. We therefore expressed the different astrocytic isoform constellations in Xenopus oocytes and determined their apparent Na+ affinity in intact oocytes and isolated membranes. The Na+ /K+ -ATPase was not fully saturated at basal astrocytic [Na+ ]i , irrespective of isoform constellation, although the beta1 subunit conferred lower apparent Na+ affinity to the alpha1 and alpha2 isoforms than the beta2 isoform. In summary, enhanced astrocytic Na+ /K+ -ATPase-dependent K+ clearance was obtained with parallel glutamate transport activity. The astrocytic Na+ /K+ -ATPase isoform constellation alpha2beta1 appeared to be specifically geared to respond to the [Na+ ]i transients associated with activity induced glutamate transporter activity. PMID- 27231202 TI - The E3-ligase E6AP Represses Breast Cancer Metastasis via Regulation of ECT2-Rho Signaling. AB - Metastatic disease is the major cause of breast cancer-related death and despite many advances, current therapies are rarely curative. Tumor cell migration and invasion require actin cytoskeletal reorganization to endow cells with capacity to disseminate and initiate the formation of secondary tumors. However, it is still unclear how these migratory cells colonize distant tissues to form macrometastases. The E6-associated protein, E6AP, acts both as an E3 ubiquitin protein ligase and as a coactivator of steroid hormone receptors. We report that E6AP suppresses breast cancer invasiveness, colonization, and metastasis in mice, and in breast cancer patients, loss of E6AP associates with poor prognosis, particularly for basal breast cancer. E6AP regulates actin cytoskeletal remodeling via regulation of Rho GTPases, acting as a negative regulator of ECT2, a GEF required for activation of Rho GTPases. E6AP promotes ubiquitination and proteasomal degradation of ECT2 for which high expression predicts poor prognosis in breast cancer patients. We conclude that E6AP suppresses breast cancer metastasis by regulating actin cytoskeleton remodeling through the control of ECT2 and Rho GTPase activity. These findings establish E6AP as a novel suppressor of metastasis and provide a compelling rationale for inhibition of ECT2 as a therapeutic approach for patients with metastatic breast cancer. Cancer Res; 76(14); 4236-48. (c)2016 AACR. PMID- 27231204 TI - The translational science training program at NIH: Introducing early career researchers to the science and operation of translation of basic research to medical interventions. AB - Translational science is an emerging field that holds great promise to accelerate the development of novel medical interventions. As the field grows, so does the demand for highly trained biomedical scientists to fill the positions that are being created. Many graduate and postdoctorate training programs do not provide their trainees with sufficient education to take advantage of this growing employment sector. To help better prepare the trainees at the National Institutes of Health for possible careers in translation, we have created the Translational Science Training Program (TSTP). The TSTP is an intensive 2- to 3-day training program that introduces NIH postdoctoral trainees and graduate students to the science and operation of turning basic research discoveries into a medical therapeutic, device or diagnostic, and also exposes them to the variety of career options in translational science. Through a combination of classroom teaching from practicing experts in the various disciplines of translation and small group interactions with pre-clinical development teams, participants in the TSTP gain knowledge that will aid them in obtaining a career in translational science and building a network to make the transition to the field. (c) 2016 by The International Union of Biochemistry and Molecular Biology, 45(1):13-24, 2017. PMID- 27231205 TI - More data along with further definitions are required. PMID- 27231203 TI - Diverse, Biologically Relevant, and Targetable Gene Rearrangements in Triple Negative Breast Cancer and Other Malignancies. AB - Triple-negative breast cancer (TNBC) and other molecularly heterogeneous malignancies present a significant clinical challenge due to a lack of high frequency "driver" alterations amenable to therapeutic intervention. These cancers often exhibit genomic instability, resulting in chromosomal rearrangements that affect the structure and expression of protein-coding genes. However, identification of these rearrangements remains technically challenging. Using a newly developed approach that quantitatively predicts gene rearrangements in tumor-derived genetic material, we identified and characterized a novel oncogenic fusion involving the MER proto-oncogene tyrosine kinase (MERTK) and discovered a clinical occurrence and cell line model of the targetable FGFR3 TACC3 fusion in TNBC. Expanding our analysis to other malignancies, we identified a diverse array of novel and known hybrid transcripts, including rearrangements between noncoding regions and clinically relevant genes such as ALK, CSF1R, and CD274/PD-L1 The over 1,000 genetic alterations we identified highlight the importance of considering noncoding gene rearrangement partners, and the targetable gene fusions identified in TNBC demonstrate the need to advance gene fusion detection for molecularly heterogeneous cancers. Cancer Res; 76(16); 4850 60. (c)2016 AACR. PMID- 27231206 TI - Acute Hemarthrosis of the Knee Caused by Arteriovenous Malformation. PMID- 27231207 TI - Learning Curves for Ultrasound Assessment of Lumbar Puncture Insertion Sites: When is Competency Established? AB - BACKGROUND: Ultrasound (US) can be used to improve lumbar puncture (LP) success. How to achieve competency in LP US has not been defined. Cumulative sum statistics (CUSUM) characterized competency acquisition in other skills. OBJECTIVES: Identify the learning curve for 80% success rate in LP US insertion site (IS) identification among pediatric emergency medicine fellows. METHODS: This prospective study took place in a single pediatric emergency department. Fellows with limited ultrasound experience received didactics, training, and three proctored examinations. Skills were evaluated in three 2-h sessions: using US, subjects identified LP ISs on a convenience sample of patients ages 0-20 years old. Subjects' IS markings were compared to markings by an expert, an emergency US fellowship-trained attending. Successful IS identification was defined as markings within 2 mm or 5 mm of the expert mark in infants and older children, respectively. A second expert marked 17 cases for interrater agreement. CUSUM was used to analyze individual learning curves. RESULTS: Five fellows evaluated 72 patients (mean age 11.4 years [SD = 4, range 3-20], mean body mass index 20.5 [SD = 4.4, range 13.1-37.7]) over a 3-month period. Mean number of attempts per fellow was 14.4 +/- 3.1 (R 11-19); mean time to landmark identification was 72 +/- 46 s (R 27-240). The two experts demonstrated 100% observed agreement. Aggregate success rate for all fellows was 75% (54/72). Four fellows showed learning curves that trended toward, but did not achieve, the acceptable success rate of 80%. CONCLUSIONS: Nineteen attempts are insufficient among fellows to achieve competency in US-guided LP IS identification. PMID- 27231208 TI - Central Nervous System Tuberculosis in an Immigrant Child. PMID- 27231209 TI - Hemolysis Affects C-Peptide Immunoassay. AB - BACKGROUND: C-peptide is used widely as a marker of insulin secretion, and it participates in the inflammatory response and contributes to the development of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). Previous studies have reported that C-peptide measurement was unaffected by hemolysis. However, we found that hemolysis negatively affected C-peptide assay in routine laboratory practice. We further established and validated an individualized hemolysis correction equation to correct and report accurate serum C-peptide results for hemolyzed samples. METHODS: We studied the effects of hemolysis on C-peptide assay by adding lysed self red blood cells (self-RBCs) to serum. An individualized correction equation was derived. Further, we evaluated the performance of this individualized correction equation by artificially hemolyzed samples. RESULTS: C-peptide concentration decreased with increasing degree and exposure time of hemolysis. The individualized hemolysis correction equation derived: C-Pcorr = C-Pmeas /(0.969-1.5Hbserum/plasma -5.394 *10-5 Time), which can correct bias in C-peptide measurement caused by hemolysis. CONCLUSIONS: Hemolysis negatively affects C-peptide measurement. We can correct and report accurate serum C-peptide results for a wide range of degrees of sample hemolysis by individualized hemolysis correction equation for C-peptide assay. This correction would improve diagnostic accuracy and reduce inappropriate therapeutic decisions. PMID- 27231210 TI - Corrigendum. AB - The benefits of using a vacuum-assisted socket system to improve balance and gait in elderly transtibial amputees by C Beatriz Samitier, Lluis Guirao, Maria Costea, Josep M Camos, and Eulogio Pleguezuelos. Prosthetics and Orthotics International 2016; 40: 83-88, DOI: 10.1177/0309364614546927. PMID- 27231211 TI - Towards large scale preparation of graphene in molten salts and its use in the fabrication of highly toughened alumina ceramics. AB - Highly crystalline graphene nanosheets were reproducibly generated by the electrochemical exfoliation of graphite electrodes in molten LiCl containing protons. The graphene product has been successfully applied in several applications. This paper discusses the effect of molten salt produced graphene on the microstructures and mechanical properties of alumina articles produced by slip casting and pressureless sintering, which is one of the most convenient methods for the commercial production of alumina ceramics. In addition to graphene, graphite powder and multi-walled carbon nanotubes (CNTs) were also used to prepare alumina articles for comparative purposes. A graphene strengthening effect was realized through microstructural refinement and by influencing the formation of alumina nanorods during the sintering of alpha-Al2O3 articles. The fracture toughness of the sintered alumina articles increased to an impressive value of 6.98 MPa m(1/2) by adding 0.5 wt% graphene nanosheets. This was attributed to the unique microstructure obtained, comprised of micrometer sized alumina grains separated by alumina nanorods. PMID- 27231212 TI - Corrigendum: (2) H and (139) La NMR Spectroscopy in Aqueous Solutions at Geochemical Pressures. PMID- 27231214 TI - Diagnostic Classification of ADHD Versus Control: Support Vector Machine Classification Using Brief Neuropsychological Assessment. AB - OBJECTIVE: Common methods for clinical diagnosis include clinical interview, behavioral questionnaires, and neuropsychological assessment. These methods rely on clinical interpretation and have variable reliability, sensitivity, and specificity. The goal of this study was to evaluate the utility of machine learning in the prediction and classification of children with ADHD-Combined presentation (ADHD-C) using brief neuropsychological measures (d2 Test of Attention, Children with ADHD-C and typically developing control children completed semi-structured clinical interviews and measures of attention/concentration and parents completed symptom severity questionnaires. METHOD: We used a forward feature selection method to identify the most informative neuropsychological features for support vector machine (SVM) classification and a decision tree model to derive a rule-based model. RESULTS: The SVM model yielded excellent classification accuracy (100%) of individual children with and without ADHD (1.0). Decision tree algorithms identified individuals with and without ADHD-C with 100% sensitivity and specificity. CONCLUSION: This study observed highly accurate statistical diagnostic classification, at the individual level, in a sample of children with ADHD-C. The findings suggest data-driven behavioral algorithms based on brief neuropsychological data may present an efficient and accurate diagnostic tool for clinicians. PMID- 27231215 TI - Study of the Mechanical Behavior of Radially Grown Fivefold Twinned Nanowires on the Atomic Scale. AB - In situ bending tests and dynamic modeling simulations are for the first time revealing the mechanical behavior of copper nanowires (NW) with radially grown fivefold twin structures on the atomic scale. Combining the simulations with the experimental results it is shown that both the twin boundaries (TBs) and the twin center act as dislocation sources. TB migration and L-locks are readily observed in these types of radially grown fivefold-twin structures. PMID- 27231216 TI - beta-Taxilin participates in differentiation of C2C12 myoblasts into myotubes. AB - Myogenesis is required for the development of skeletal muscle. Accumulating evidence indicates that the expression of several genes are upregulated during myogenesis and these genes play pivotal roles in myogenesis. However, the molecular mechanism underlying myogenesis is not fully understood. In this study, we found that beta-taxilin, which is specifically expressed in the skeletal muscle and heart tissues, was progressively expressed during differentiation of C2C12 myoblasts into myotubes, prompting us to investigate the role of beta taxilin in myogenesis. In C2C12 cells, knockdown of beta-taxilin impaired the fusion of myoblasts into myotubes, and decreased the diameter of myotubes. We also found that beta-taxilin interacted with dysbindin, a coiled-coil-containing protein. Knockdown of dysbindin conversely promoted the fusion of myoblasts into myotubes and increased the diameter of myotubes in C2C12 cells. Furthermore, knockdown of dysbindin attenuated the inhibitory effect of beta-taxilin depletion on myotube formation of C2C12 cells. These results demonstrate that beta-taxilin participates in myogenesis through suppressing the function of dysbindin to inhibit the differentiation of C2C12 myoblasts into myotubes. PMID- 27231217 TI - The problem with unregulated botanicals. PMID- 27231218 TI - Genes, dopamine pathways, and sociality in primates. PMID- 27231219 TI - Superresolved multiphoton microscopy with spatial frequency-modulated imaging. AB - Superresolved far-field microscopy has emerged as a powerful tool for investigating the structure of objects with resolution well below the diffraction limit of light. Nearly all superresolution imaging techniques reported to date rely on real energy states of fluorescent molecules to circumvent the diffraction limit, preventing superresolved imaging with contrast mechanisms that occur via virtual energy states, including harmonic generation (HG). We report a superresolution technique based on spatial frequency-modulated imaging (SPIFI) that permits superresolved nonlinear microscopy with any contrast mechanism and with single-pixel detection. We show multimodal superresolved images with two photon excited fluorescence (TPEF) and second-harmonic generation (SHG) from biological and inorganic media. Multiphoton SPIFI (MP-SPIFI) provides spatial resolution up to 2eta below the diffraction limit, where eta is the highest power of the nonlinear intensity response. MP-SPIFI can be used to provide enhanced resolution in optically thin media and may provide a solution for superresolved imaging deep in scattering media. PMID- 27231220 TI - Reply to Piper: Aquilonifer's kites are not mites. PMID- 27231221 TI - Offspring or phoronts? An alternative interpretation of the "kite-runner" fossil. PMID- 27231222 TI - Impact of delirium on weaning from mechanical ventilation in medical patients - Reply. PMID- 27231223 TI - In Vivo T1 of Blood Measurements in Children with Sickle Cell Disease Improve Cerebral Blood Flow Quantification from Arterial Spin-Labeling MRI. AB - BACKGROUND AND PURPOSE: Children with sickle cell disease have low hematocrit and elevated CBF, the latter of which can be assessed with arterial spin-labeling MR imaging. Quantitative CBF values are obtained by using an estimation of the longitudinal relaxation time of blood (T1blood). Because T1blood depends on hematocrit in healthy individuals, we investigated the importance of measuring T1blood in vivo with MR imaging versus calculating it from hematocrit or assuming an adult fixed value recommended by the literature, hypothesizing that measured T1blood would be the most suited for CBF quantification in children with sickle cell disease. MATERIALS AND METHODS: Four approaches for T1blood estimation were investigated in 39 patients with sickle cell disease and subsequently used in the CBF quantification from arterial spin-labeling MR imaging. First, we used 1650 ms as recommended by the literature (T1blood-fixed); second, T1blood calculated from hematocrit measured in patients (T1blood-hematocrit); third, T1blood measured in vivo with a Look-Locker MR imaging sequence (T1blood-measured); and finally, a mean value from T1blood measured in this study in children with sickle cell disease (T1blood-sickle cell disease). Quantitative flow measurements acquired with phase-contrast MR imaging served as reference values for CBF. RESULTS: T1blood-measured (1818 +/- 107 ms) was higher than the literature recommended value of 1650 ms, was significantly lower than T1blood-hematocrit (2058 +/- 123 ms, P < .001), and, most interesting, did not correlate with hematocrit measurements. Use of either T1blood-measured or T1blood-sickle cell disease provided the best agreement on CBF between arterial-spin labeling and phase contrast MR imaging reference values. CONCLUSIONS: This work advocates the use of patient-specific measured T1blood or a standardized value (1818 ms) in the quantification of CBF from arterial spin-labeling in children with SCD. PMID- 27231224 TI - MR Imaging of the Cervical Spine in Nonaccidental Trauma: A Tertiary Institution Experience. AB - BACKGROUND AND PURPOSE: Cervical MR imaging has demonstrated a utility for detecting soft tissue injury in nonaccidental trauma. The purpose of this study was to identify the incidence and types of cervical spine injury on MR imaging in nonaccidental trauma and to correlate cervical spine injury with parenchymal injury on brain MR imaging and findings on head CT. MATERIALS AND METHODS: A retrospective review of children diagnosed with nonaccidental trauma in a tertiary referral pediatric hospital over 8 years was performed. Inclusion criteria were children younger than 5 years of age, a confirmed diagnosis of nonaccidental trauma, and cervical spine MR imaging within 1 week of presentation. Brain and cervical spine MR imaging, head CT, cervical radiographs, and skeletal surveys were reviewed. RESULTS: There were 89 patients included in this study (48 males; mean age, 9.1 months [range, 1-59 months]). Cervical spine injury on MR imaging was found in 61 patients (69%). Ligamentous injury was seen in 60 patients (67%), with interspinous ligaments being most commonly involved. Abnormal capsular fluid (atlanto-occipital and atlantoaxial) was present in 28 patients (32%). Cervical spine injury on MR imaging was significantly associated with parenchymal restricted diffusion on brain MR imaging and parenchymal injury on head CT (P = .0004 and P = .0104, respectively). Children with restricted diffusion on brain MR imaging were 6.22 (point estimate) times more likely to have cervical spine injury on MR imaging. CONCLUSIONS: There is a high incidence of cervical spine injury in pediatric nonaccidental trauma. Positive findings may affect management and suggest a traumatic etiology. PMID- 27231225 TI - Dynamic Susceptibility Contrast-Enhanced MR Perfusion Imaging in Assessing Recurrent Glioblastoma Response to Superselective Intra-Arterial Bevacizumab Therapy. AB - BACKGROUND AND PURPOSE: Recurrent glioblastoma currently has no established standard of care. We evaluated the response of recurrent glioblastoma to superselective intra-arterial cerebral infusion of bevacizumab by using dynamic susceptibility contrast-enhanced MR perfusion imaging. We hypothesized that treatment response would be associated with decreased relative CBV and relative CBF. MATERIALS AND METHODS: Patients were accrued for this study from larger ongoing serial Phase I/II trials. Twenty-five patients (14 men, 11 women; median age, 55 years) were analyzed. Four distinct ROIs were chosen: 1) normal-appearing white matter on the contralateral side, 2) the location of the highest T1 enhancement in the lesion (maximum enhancing), 3) the location of highest relative CBV in the lesion (maximum relative CBV), and 4) nonenhancing T2 hyperintense signal abnormality surrounding the tumor (nonenhancing T2 hyperintensity). RESULTS: There was a statistically significant median percentage change of -32.34% (P = .001) in relative CBV in areas of maximum relative CBV following intra-arterial bevacizumab therapy. There was also a statistically significant median percentage decrease in relative CBF of -30.67 (P = .001) and 27.25 (P = .037) in areas of maximum relative CBV and maximum tumor enhancement, respectively. Last, a trend toward statistical significance for increasing relative CBV in nonenhancing T2 hyperintense areas (median percent change, 30.04; P = .069) was noted. CONCLUSIONS: Dynamic susceptibility contrast-enhanced MR perfusion imaging demonstrated a significant decrease in tumor perfusion metrics within recurrent glioblastomas in response to superselective intra-arterial cerebral infusion of bevacizumab; however, these changes did not correlate with time to progression or overall survival. PMID- 27231226 TI - Volumetric Description of Brain Atrophy in Neuronal Ceroid Lipofuscinosis 2: Supratentorial Gray Matter Shows Uniform Disease Progression. AB - BACKGROUND AND PURPOSE: Experimental therapies for ceroid lipofuscinosis, neuronal, 2 (CLN2), a genetic disorder of childhood associated with progressive brain atrophy, are currently being developed. Because quantitative descriptions of the natural course of brain volume loss are needed to evaluate novel therapies, we performed MR imaging volumetry of patients with CLN2 to identify a suitable MR imaging marker of disease progression. MATERIALS AND METHODS: Thirteen patients (8 females, 5 males) were recruited from a prospective natural disease cohort of patients with neuronal ceroid lipofuscinosis. Repeated MR imaging volumetric analysis (29 datasets) was performed by using the FreeSurfer Software Suite. Follow-up time ranged from 8 months to 5.3 years. MR imaging segmented brain volumes were correlated to patient age and clinical scores. RESULTS: Segmented brain volumes correlated significantly with patient age (lateral ventricles, r = 0.606, P = .001; supratentorial cortical GM, r = -0.913, P < .001; supratentorial WM, r = -0.865, P < .001; basal ganglia/thalamus, r = 0.832, P < .001; cerebellar GM, r = -0.659, P < .001; cerebellar WM, r = -0.830, P < .001) and clinical scores (lateral ventricles, r = -0.692, P < .001; supratentorial cortical GM, r = 0.862, P < .001; supratentorial WM, r = 0.735, P < .001; basal ganglia/thalamus, r = 0.758, P < .001; cerebellar GM, r = 0.609, P = .001; cerebellar WM, r = 0.638, P < .001). Notably, supratentorial cortical GM showed a uniform decline across the patient cohort. During late stages of the disease when the clinical score was zero, segmented brain volumes still correlated with patient age; this finding suggests that MR imaging volumetry allows quantitative assessment of disease progression at stages when it cannot be detected by clinical assessment alone. CONCLUSIONS: Automated MR imaging volumetry, as a nonsubjective and highly sensitive tool, is feasible in CLN2 disease and provides a quantitative basis to evaluate novel experimental therapies. PMID- 27231227 TI - Clinical Significance of the Champagne Bottle Neck Sign in the Extracranial Carotid Arteries of Patients with Moyamoya Disease. AB - BACKGROUND AND PURPOSE: The champagne bottle neck sign represents a rapid reduction in the extracranial ICA diameters and is a characteristic feature of Moyamoya disease. However, the clinical significance of the champagne bottle neck sign is unclear. We investigated the relationship between the champagne bottle neck sign and the clinical and hemodynamic stages of Moyamoya disease. MATERIALS AND METHODS: We analyzed 14 patients with Moyamoya disease before revascularization (5 men, 9 women; age, 43.2 +/- 19.3 years). The ratio of the extracranial ICA and common carotid artery diameters was determined using carotid ultrasonography or cerebral angiography; a ratio of < 0.5 was considered champagne bottle neck sign-positive. The clinical disease stage was determined using the Suzuki angiographic grading system. CBF and cerebral vasoreactivity also were measured. RESULTS: The ICA/common carotid artery ratio (expressed as median [interquartile range]) decreased as the clinical stage advanced (stages I II, 0.71 [0.60-0.77]; stages III-IV, 0.49 [0.45-0.57]; stages V-VI, 0.38 [0.34 0.47]; P < .001). Lower ICA/common carotid artery ratio tended to occur in symptomatic versus asymptomatic arteries (0.47 [0.40-0.53] versus 0.57 [0.40 0.66], respectively; P = .06). Although the ICA/common carotid artery ratio was not related to cerebral perfusion, it decreased as cerebral vasoreactivity decreased (P < .01). All champagne bottle neck sign-positive arteries were classified as Suzuki stage >=III, 73% were symptomatic, and 89% exhibited reduced cerebral vasoreactivity. In contrast, all champagne bottle neck sign-negative arteries were Suzuki stage <=III, 67% were asymptomatic, and all showed preserved cerebral vasoreactivity. CONCLUSIONS: The champagne bottle neck sign was related to advanced clinical stage, clinical symptoms, and impaired cerebral vasoreactivity. Thus, detection of the champagne bottle neck sign might be useful in determining the clinical and hemodynamic stages of Moyamoya disease. PMID- 27231228 TI - Ocular Signs Caused by Dural Arteriovenous Fistula without Involvement of the Cavernous Sinus: A Case Series with Review of the Literature. AB - Carotid cavernous fistula is a well-known clinical and angiographic entity responsible for ocular signs and symptoms. On the contrary, ocular signs are unusual in the presentation of cranial dural arteriovenous fistulas at locations other than the cavernous sinus. We retrospectively analyzed data focusing on the pathophysiology of ophthalmologic signs and their angiographic explanations. Thirteen patients were included with a mean age of 50 years. The most common signs were chemosis (61.5%), loss of visual acuity (38.5%), exophthalmia (38.5%), and ocular hypertension (7.7%). Dural arteriovenous fistulas presenting with ocular signs could be classified into 4 types due to their pathologic mechanism (local venous reflux into the superior ophthalmic vein, massive venous engorgement of the cerebrum responsible for intracranial hypertension, compression of an oculomotor nerve by a venous dilation, or intraorbital fistula with drainage into the superior ophthalmic vein). PMID- 27231229 TI - Measures of Neuroradiologic Activities in the "Air du Temps". PMID- 27231231 TI - Facile synthesis of symmetric bundle-like Sb2S3 micron-structures and their application in lithium-ion battery anodes. AB - A novel two-step oxidation-sulfuration route is developed to fabricate the symmetric bundle-like Sb2S3 micron-structure, in which hundreds of one dimensional Sb2S3 nanowires are tied. As an anode material for lithium-ion batteries, the bundle-like Sb2S3 delivers a discharge capacity of 548 mA h g(-1) after 100 cycles, much higher than the rod-like one. PMID- 27231230 TI - Biology and survival of extremely halophilic archaeon Haloarcula marismortui RR12 isolated from Mumbai salterns, India in response to salinity stress. AB - Haloarchaea are unique microorganism's resistant to environmental and osmotic stresses and thrive in their habitats despite extreme fluctuating salinities. In the present study, haloarchaea were isolated from hypersaline thalossohaline salterns of Bhandup, Mumbai, India and were identified as Haloferax prahovense, Haloferax alexandrines, Haloferax lucentense, Haloarcula tradensis, Haloarcula marismortui and Haloarcula argentinensis. The mechanism of adaptation to contrasting salinities (1.5 M and 4.5 M) was investigated in the extreme haloarchaeon, Hal. marismortui RR12. Hal. marismortui RR12 increased the intracellular sequestration of K(+) and Cl(-) ions in hypo salinity and hyper salinity respectively as detected by Energy-dispersive X-ray spectroscopy microanalysis (EDAX) and Inductively Coupled Plasma- atomic Emission Spectroscopy (ICP-AES) indicating the presence of 'salt-in' strategy of osmoadaptation. As a cellular response to salinity stress, it produced small heat shock like proteins (sHSP) identified using MALDI-TOF MS and increased the production of protective red carotenoid pigment. This is the first report on the study of the concomitant cellular, molecular and physiological mechanism adapted by Hal. marismortui RR12 when exposed to contrasting salinities in external environment. PMID- 27231232 TI - Fine-Needle Aspiration with Immunohistochemistry Using a Modified Scrape Cell Block Technique for the Diagnosis of Thyroid and Parathyroid Nodules. AB - OBJECTIVE: To evaluate the diagnostic accuracy of a modified scrape cell block (SCB) technique in a large series of patients. The technique was especially developed and tested for fine-needle aspiration of thyroid and parathyroid nodules. STUDY DESIGN: Eighty-two ultrasound-guided fine-needle aspiration specimens with the sonographic aspect of a thyroid (n = 33) or a possible parathyroid nodule (n = 49) were studied. Immunohistochemistry (IHC) was used on cell blocks containing plasma, thromboplastin, and selected 3-dimensional cell aggregates scraped off Papanicolaou-stained smears. Antibodies for chromogranin A, thyroglobulin, parathyroid hormone, calcitonin, and carcinoembryonic antibody (CEA) were used. In cases of reduced immunosensitivity or suspected metastases or rare primary tumors, additional IHC markers were employed. RESULTS: Chromogranin A was expressed in all 28 parathyroid adenomas (PA), in 7 of 8 hyperplastic parathyroid glands, and in 13 of 14 medullary thyroid carcinomas (MTC). When combining positivity for chromogranin A and calcitonin/CEA, the specificity for the detection of MTC was 100%. Parathyroid hormone was expressed in 26 of 36 parathyroid nodules (72.2%). When combining follicular microarchitecture and expression of chromogranin A, the specificity for the detection of parathyroid tissue was 97%. CONCLUSION: With the modified SCB technique, accurate cytological diagnoses were obtained in 97.6% of 82 patients. PMID- 27231234 TI - Different Strategies for the Stabilization of Acenes and Acene Analogues. AB - Acenes, a type of polycyclic aromatic hydrocarbon containing linearly fused benzene rings, have received much attention from organic chemists, physical chemists, and materials scientists, due to their intriguing properties and potential applications in organic electronics. Without doubt, acene chemistry has been one of the hottest topics among the pi-conjugated systems. However, poor stability of acenes is the prominent issue that limits their applications. In this personal account, we summarize different strategies developed in our group to construct and stabilize acenes and acene analogues. In addition, the unique properties and applications of some molecules will be discussed. PMID- 27231233 TI - A melanosomal two-pore sodium channel regulates pigmentation. AB - Intracellular organelles mediate complex cellular functions that often require ion transport across their membranes. Melanosomes are organelles responsible for the synthesis of the major mammalian pigment melanin. Defects in melanin synthesis result in pigmentation defects, visual deficits, and increased susceptibility to skin and eye cancers. Although genes encoding putative melanosomal ion transporters have been identified as key regulators of melanin synthesis, melanosome ion transport and its contribution to pigmentation remain poorly understood. Here we identify two-pore channel 2 (TPC2) as the first reported melanosomal cation conductance by directly patch-clamping skin and eye melanosomes. TPC2 has been implicated in human pigmentation and melanoma, but the molecular mechanism mediating this function was entirely unknown. We demonstrate that the vesicular signaling lipid phosphatidylinositol bisphosphate PI(3,5)P2 modulates TPC2 activity to control melanosomal membrane potential, pH, and regulate pigmentation. PMID- 27231235 TI - Farnesiferol c induces apoptosis via regulation of L11 and c-Myc with combinational potential with anticancer drugs in non-small-cell lung cancers. AB - Though Farnesiferol c (FC) has been reported to have anti-angiogenic and antitumor activity, the underlying antitumor mechanism of FC still remains unclear. Thus, in the present study, we investigated the apoptotic mechanism of FC in human H1299 and H596 non-small lung cancer cells (NSCLCs). FC significantly showed cytotoxicity, increased sub-G1 accumulation, and attenuated the expression of Bcl-2, Bcl-xL, Survivin and procaspase 3 in H1299 and H596 cells. Furthermore, FC effectively suppressed the mRNA expression of G1 arrest related genes such as Cyclin D1, E2F1 transcription factor and CDC25A by RT-PCR. Interestingly, FC inhibited the expression of c-Myc, ribosomal protein L11 (L11) and nucleolin (NCL) in H1299 and H596 cells. Of note, silencing of L11 by siRNA transfection enhanced the expression of c-Myc through a negative feedback mechanism, while c Myc knockdown downregulated L11 in H1299 cells. Additionally, combined treatment of FC and puromycin/doxorubicin promoted the activation of caspase 9/3, and attenuated the expression of c-Myc, Cyclin D1 and CDK4 in H1299 cells compared to single treatment. Taken together, our findings suggest that FC induces apoptosis and G1 arrest via regulation of ribosomal protein L11 and c-Myc and also enhances antitumor effect of puromycin or doxorubicin in NSCLCs. PMID- 27231236 TI - Two-year follow-up of a primary care-based intervention to prevent and manage childhood obesity: the High Five for Kids study. AB - BACKGROUND: The obesity epidemic has spared no age group, even young infants. Most childhood obesity is incident by the age of 5 years, making prevention in preschool years a priority. OBJECTIVE: To examine 2-year changes in age- and sex specific BMI z-scores and obesity-related behaviours among 441 of the 475 originally recruited participants in High Five for Kids, a cluster randomized controlled trial in 10 paediatric practices. METHODS: The intervention included a more intensive 1-year intervention period (four in-person visits and two phone calls) followed by a less intensive 1-year maintenance period (two in-person visits) among children who were overweight or obese and age 2-6 years at enrolment. The five intervention practices restructured care to manage these children including motivational interviewing and educational modules targeting television viewing and intakes of fast food and sugar-sweetened beverages. RESULTS: After 2 years, compared with usual care, intervention participants had similar changes in BMI z-scores (-0.04 units; 95% CI -0.14, 0.06), television viewing (-0.20 h/d; -0.49 to 0.09) and intakes of fast food (-0.09 servings/week; -0.34 to 0.17) and sugar-sweetened beverages (-0.26 servings/day; -0.67 to 0.14). CONCLUSION: High Five for Kids, a primarily clinical-based intervention, did not affect BMI z-scores or obesity-related behaviours after 2 years. PMID- 27231238 TI - Increased expression of genes involved in uptake and degradation of murein tripeptide under nitrogen starvation in Escherichia coli. AB - Peptidoglycan (also known as murein) is an important envelope component of bacteria, and its turnover usually takes place at considerable levels during normal growth. Amino sugars and murein tripeptide resulting from murein degradation are used for resynthesis of peptidoglycan or as self-generated nutrients or energy sources for cell growth. PgrR (regulator of peptide glycan recycling; formerly YcjZ) was recently identified as a repressor of several genes participating in uptake and degradation of murein tripeptide. In this study, we identified the ycjG gene involved in murein tripeptide degradation as a new direct target of PgrR. The expression of PgrR-regulated genes including ycjY, mppA, mpaA and ycjG was repressed in the presence of a good nitrogen source, but their expression increased under poor nitrogen conditions. Under nitrogen starvation, the pgrR mutant cells exhibited faster growth than wild-type cells, implying that derepression of genes under the control of PgrR may help cells overcome nitrogen limitation. Therefore, these results suggest that nitrogen starvation induces derepression of PgrR-controlled genes involved in uptake and degradation of murein tripeptide, and this may stimulate the utilization of murein tripeptide as a nitrogen source. PMID- 27231239 TI - In vitro and in vivo downregulation of C3 by lipoteichoic acid isolated from Lactobacillus plantarum K8 suppressed cytokine-mediated complement system activation. AB - Complement component 3 (C3) is one of the proteins associated with complement cascades. C3 plays an essential role in three different pathways-the alternative, classical and lectin pathways. It is well known that cytokines activate complement system and increase complement component C3 production. In the current study, we found that lipoteichoic acid isolated from Lactobacillus plantarum K8 (pLTA) inhibited tumor necrosis factor-alpha (TNF-alpha) or interferon-gamma (IFN gamma)-mediated C3 mRNA and protein expression in HaCaT cells. pLTA inhibited C3 expression through the inhibition of the phosphorylation of p65 and p38 in the TNF-alpha-treated cells, while the inhibition of STAT1/2 and JAK2 phosphorylation by pLTA contributed to the reduction of C3 in IFN-gamma-treated cells. When mice were pre-injected with pLTA followed by re-injection of TNF-alpha, serum C3 level was decreased as compared to TNF-alpha-injected only. Further studies revealed that membrane attack complex (MAC) increased by TNF-alpha injection was lessened in pLTA-pre-injected mice. A bactericidal assay using mouse sera showed that MAC activity in pLTA-pre-injected mice was lower than in TNF-alpha only-injected mice. These results suggest that pLTA can suppress inflammatory cytokine-mediated complement activation through the inhibition of C3 synthesis. pLTA application has the potential to alleviate complement-mediated diseases caused by excessive inflammation. PMID- 27231237 TI - Increase of genetic diversity and clonal replacement of epidemic methicillin resistant Staphylococcus aureus strains in South-East Austria. AB - Spa-typing and microarray techniques were used to study epidemiological changes in methicillin-resistant Staphylococcus aureus (MRSA) in South-East Austria. The population structure of 327 MRSA isolated between 2002 and 2012 was investigated. MRSA was assigned to 58 different spa types and 14 different MLST CC (multilocus sequence type clonal complexes); in particular, between 2007 and 2012, an increasing diversity in MRSA clones could be observed. The most abundant clonal complex was CC5. On the respective SCCmec cassettes, the CC5 isolates differed clearly within this decade and CC5/SCCmecI, the South German MRSA, predominant in 2002, was replaced by CC5/SCCmecII, the Rhine-Hesse MRSA in 2012. Whereas in many European countries MLST CC22-MRSA (EMRSA 15, the Barnim epidemic MRSA) is predominant, this clone occurred in Austria nearly 10 years later than in neighbouring countries. CC45, the Berlin EMRSA, epidemic in Germany, was only sporadically found in South-East Austria. The Irish ST8-MRSA-II represented by spa-type t190 was frequently found in 2002 and 2007, but disappeared in 2012. Our results demonstrate clonal replacement of MRSA clones within the last years in Austria. Ongoing surveillance is warranted for detection of changes within the MRSA population. PMID- 27231240 TI - Modular projects and 'mean questions': best practices for advising an International Genetically Engineered Machines team. AB - In the yearly Internationally Genetically Engineered Machines (iGEM) competition, teams of Bachelor's and Master's students design and build an engineered biological system using DNA technologies. Advising an iGEM team poses unique challenges due to the inherent difficulties of mounting and completing a new biological project from scratch over the course of a single academic year; the challenges in obtaining financial and structural resources for a project that will likely not be fully realized; and conflicts between educational and competition-based goals. This article shares tips and best practices for iGEM team advisors, from two team advisors with very different experiences with the iGEM competition. PMID- 27231241 TI - Analysis of a new cluster of genes involved in the synthesis of the unique volatile organic compound sodorifen of Serratia plymuthica 4Rx13. AB - The rhizobacterium Serratia plymuthica 4Rx13 emits the novel and unique volatile sodorifen (C16H26), which has a polymethylated bicyclic structure. Transcriptome analysis revealed that gene SOD_c20750 (annotated as terpene cyclase) is involved in the biosynthesis of sodorifen. Here we show that this gene is located in a small cluster of four genes (SOD_c20750 - SOD_c20780), and the analysis of the knockout mutants demonstrated that SOD_c20760 (annotated as methyltransferase) and SOD_c20780 (annotated as isopentenyl pyrophosphate (IPP) isomerase) are needed for the biosynthesis of sodorifen, while a sodorifen-negative phenotype was not achieved with the SOD_c20770 (annotated as deoxy-xylulose-5-phosphate (DOXP) synthase) mutant. Altogether, the function of this new gene cluster was assigned to the biosynthesis of this structurally unusual volatile compound sodorifen. PMID- 27231242 TI - Effects of dietary fibre source on microbiota composition in the large intestine of suckling piglets. AB - This study aimed to investigate the effects of dietary fibre sources on the gut microbiota in suckling piglets, and to test the hypothesis that a moderate increase of dietary fibre may affect the gut microbiota during the suckling period. Suckling piglets were fed different fibre-containing diets or a control diet from postnatal day 7 to 22. Digesta samples from cecum, proximal colon and distal colon were used for Pig Intestinal Tract Chip analysis. The data showed that the effects of fibre-containing diet on the gut microbiota differed in the fibre source and gut location. The alfalfa diet increased Clostridium cluster XIVb and Sporobacter termitidis in the cecum compared to the pure cellulose diet. Compared to the control diet, the alfalfa diet also increased Coprococcus eutactus in the distal colon, while the pure cellulose diet decreased Eubacterium pyruvativorans in the cecum. The pure cellulose diet increased Prevotella ruminicola compared to the wheat bran diet. Interestingly, the alfalfa group had the lowest abundance of the potential pathogen Streptococcus suis in the cecum and distal colon. These results indicated that a moderate increase in dietary fibres affected the microbial composition in suckling piglets, and that the alfalfa inclusion produced some beneficial effects on the microbial communities. PMID- 27231243 TI - Furosemide Increases the Risk of Hyperparathyroidism in Chronic Kidney Disease. AB - BACKGROUND: Diuretics are widely used in patients with chronic kidney disease (CKD). While thiazide-like diuretics limit urinary calcium excretion, loop diuretics (LD) promote calcium wasting, which might facilitate the development of secondary hyperparathyroidism (HPT2). We sought to investigate, in CKD patients not on dialysis, the influence of either hydrochlorothiazide (Hydro) or furosemide (Furo) on circulating parathyroid hormone (PTH) and whether such actions are determined by the effects of these compounds on calcium excretion. METHODS: Electronic charts of all nephrology outpatients (CKD stages 2-5) who were given Hydro or Furo were included. We assessed estimated glomerular filtration rate (eGFR), biochemical parameters and 24-hour calcium excretion. Hyperparathyroidism was defined as PTH >65 pg/ml. RESULTS: Out of 275 patients, 108 (29%) were taking Hydro and 167 (61%) Furo. Patients on Hydro were younger, mostly female and had higher eGFR. The median 24-hour urinary calcium excretion in the overall cohort was 41 (22, 76), being lower in Furo than in Hydro patients (37 (16, 68) vs. 47 (26, 88) mg/24 h, respectively, p = 0.016). Logistic regression showed that, after adjustment for eGFR, calcium excretion rate was found not to increase the risk ratio for HPT2, whereas Furo was a strong predictor of HPT2. CONCLUSION: Furo increased the risk of HPT2 among CKD patients compared to Hydro. This effect was independent of eGFR or calcium excretion. The use of LD in CKD, currently preferred in advanced stages, should be reappraised. PMID- 27231244 TI - A Systematic Review of Financial Exploitation Measures in Prevalence Studies. AB - The financial exploitation of older adults has garnered the attention of society as well as state and federal governments in a way that elder abuse has never been able to achieve. It is frequently asserted that financial exploitation deserves this attention in part because it is the most prevalent form of elder abuse. This article systematically reviews the measurement of financial exploitation in comparison with other forms of elder abuse and concludes that its measurement is considerably more variable than other forms of abuse. Consequently, improvements in the measurement of financial exploitation are warranted. PMID- 27231245 TI - Trajectories of Leisure Activity and Disability in Older Adults Over 11 Years in Taiwan. AB - We aimed to identify leisure activity (LA) trajectories and examined the association among baseline characteristics, LA trajectories, and the later disability among older Taiwanese adults. Data were from the Taiwan Longitudinal Study on Aging Survey for the years 1996-2007 ( N = 3,186). LA trajectories were identified by using latent class growth curve modeling. Regression analyses were applied to predict the relationships among baseline characteristics, LA trajectories, and disability. Four LA trajectories-consistent high, consistent low, increasing, and decreasing-were identified. Lower depressive symptom was related to consistently active in LAs. Younger age and fewer comorbidities were related to develop an increasing LA trajectory. Participants in the consistent high or increasing LA trajectories were more likely to be functionally independent, but those in the decreasing LA subgroup were more at risk of developing disability. The findings suggested that long-term changes in LA over time have benefits on physical health in older population. PMID- 27231246 TI - eComment. Atrial fibrillation surgery: less invasive techniques, less efficient results. PMID- 27231247 TI - eComment: Aortic-root enlargement procedures: an invaluable surgical technique. PMID- 27231248 TI - eComment. Thoracoscopic maze: unresolved issues. PMID- 27231249 TI - eComment. Iterative metastasectomy for recurrent pulmonary disease from colorectal cancer: a challenging issue. PMID- 27231250 TI - eComment. Atrial septal defect closure with a composite check-valved patch in pulmonary hypertensive patients. PMID- 27231251 TI - eReply re: Atrial septal defect closure with a composite check-valved patch in pulmonary hypertensive patients. PMID- 27231252 TI - eComment: How to define operability in pulmonary hypertension secondary to congenital heart disease? PMID- 27231253 TI - Myeloid-derived suppressor cells contribute to systemic lupus erythaematosus by regulating differentiation of Th17 cells and Tregs. AB - Although major advancements have made in investigating the aetiology of SLE (systemic lupus erythaematosus), the role of MDSCs (myeloid-derived suppressor cells) in SLE progression remains confused. Recently, some studies have revealed that MDSCs play an important role in lupus mice. However, the proportion and function of MDSCs in lupus mice and SLE patients are still poorly understood. In the present study, we investigated the proportion and function of MDSCs using different stages of MRL/lpr lupus mice and specimens from SLE patients with different activity. Results showed that splenic granulocytic (G-)MDSCs were significantly expanded by increasing the expression of CCR1 (CC chemokine receptor 1) in diseased MRL/lpr lupus mice and in high-disease-activity SLE patients. However, the proportion of monocytic (M-)MDSCs remains similar in MRL/lpr lupus mice and SLE patients. G-MDSCs produce high levels of ROS (reactive oxygen species) through increasing gp91(phox) expression, and activated TLR2 (Toll-like receptor 2) and AIM2 (absent in melanoma 2) inflammasome in M-MDSCs lead to IL-1beta (interleukin 1beta) expression in diseased MRL/lpr mice and high disease-activity SLE patients. Previous study has revealed that MDSCs could alter the plasticity of Th17 (T helper 17) cells and Tregs (regulatory T-cells) via ROS and IL-1beta. Co-culture experiments showed that G-MDSCs impaired Treg differentiation via ROS and M-MDSCs promoted Th17 cell polarization by IL-1beta in vitro Furthermore, adoptive transfer or antibody depletion of MDSCs in MRL/lpr mice confirmed that MDSCs influenced the imbalance of Tregs and Th17 cells in vivo Our results indicate that MDSCs with the capacity to regulate Th17 cell/Treg balance may be a critical pathogenic factor in SLE. PMID- 27231254 TI - Nitroxyl (HNO) reduces endothelial and monocyte activation and promotes M2 macrophage polarization. AB - Nitroxyl anion (HNO) donors are currently being assessed for their therapeutic utility in several cardiovascular disorders including heart failure. Here, we examine their effect on factors that precede atherosclerosis including endothelial cell and monocyte activation, leucocyte adhesion to the endothelium and macrophage polarization. Similar to the NO donor glyceryl trinitrate (GTN), the HNO donors Angeli's salt (AS) and isopropylamine NONOate (IPA/NO) decreased leucocyte adhesion to activated human umbilical vein endothelial cells (HUVECs) and mouse isolated aorta. This reduction in adhesion was accompanied by a reduction in intercellular adhesion molecule-1 (ICAM-1) and the cytokines monocyte chemoattractant protein 1 (MCP-1) and interleukin 6 (IL-6) which was inhibitor of nuclear factor kappaB (NFkappaB) alpha (IkappaBalpha)- and subsequently NFkappaB-dependent. Intriguingly, the effects of AS on leucocyte adhesion, like those on vasodilation, were found to not be susceptible to pharmacological tolerance, unlike those observed with GTN. As well, HNO reduces monocyte activation and promotes polarization of M2 macrophages. Taken together, our data demonstrate that HNO donors can reduce factors that are associated with and which precede atherosclerosis and may thus be useful therapeutically. Furthermore, since the effects of the HNO donors were not subject to tolerance, this confers an additional advantage over NO donors. PMID- 27231255 TI - Wide range of body composition measures are associated with cognitive function in community-dwelling older adults. AB - AIM: Studies of the association between body composition, both body fat and body muscle, and cognitive function are rarely reported. The aim of the present study was to determine the association between a wide range of body composition measures with cognitive function in older adults. METHODS: A total of 2322 Malaysian older adults aged 60 years and older were recruited using multistage random sampling in a population-based cross-sectional study. Out of 2322 older adults recruited, 2309 (48% men) completed assessments on cognitive function and body composition. Cognitive functions were assessed using the Malay version of the Mini-Mental State Examination, the Bahasa Malaysia version of Montreal Cognitive Assessment, Digit Span Test, Digit Symbol Test and Rey Auditory Verbal Learning Test. Body composition included body mass index, mid-upper arm circumference, waist circumference, calf circumference, waist-to-hip ratio, percentage body fat and skeletal muscle mass. RESULTS: The association between body composition and cognitive functions was analyzed using multiple linear regression. After adjustment for age, education years, hypertension, hypercholesterolemia, diabetes mellitus, depression, smoking status and alcohol consumption, we found that calf circumference appeared as a significant predictor for all cognitive tests among both men and women (P < 0.05), except for the Rey Auditory Verbal Learning Test. Waist-to-hip ratio was detected as a significant predictor for all cognitive tests among women (P < 0.05), but was only a significant predictor for the Bahasa Malaysia version of Montreal Cognitive Assessment among men (P < 0.05). CONCLUSIONS: These results suggest that there is a need to maintain muscle mass and lower adipose tissue among older adults for optimal cognitive function. Geriatr Gerontol Int 2017; 17: 554-560. PMID- 27231257 TI - Erratum. PMID- 27231256 TI - Which Cognitive Domains are Improved by Treatment with Vortioxetine? AB - BACKGROUND: These post hoc analyses evaluated vortioxetine efficacy on cognitive dysfunction in depression. Data were from a double-blind, randomized, fixed-dose, placebo-controlled, 8-week depression study in adults aged 18-65 years (n = 602) with DSM-IV-defined major depressive disorder (MDD). Subjects were randomized (1:1:1) to vortioxetine 10mg/day or 20mg/day or placebo. METHODS: Cognitive function was assessed at baseline, Week 1 (10mg/day only) and Week 8 using Digit Symbol Substitution Test (DSST) number of correct symbols, Rey Auditory Verbal Learning Test, Trail Making Test, Stroop test, Simple Reaction Time, and Choice Reaction Time tests. The cognition variables were standardized and used for constructing composite Z-scores for the cognitive domains of executive function, attention/speed of processing, and memory. RESULTS: At Week 1, vortioxetine 10mg/day separated from placebo for attention/speed of processing (standardized composite Z-score = 0.21; p = 0.0238) and DSST number of correct symbols (standardized effect size = 0.18; p = 0.0458) and for executive function (standardized composite Z-score = 0.20; p = 0.0274). At Week 8, vortioxetine 10mg/day and 20mg/day separated from placebo for executive function and attention/speed of processing, with standardized composite Z-scores ranging from 0.35 to 0.49 (all p < 0.01). Standardized composite Z-scores for memory were 0.31 (p = 0.0036, 10mg/day) and 0.22 (p = 0.0349, 20mg/day). Standardized effect sizes for DSST were 0.51 (p < 0.0001, 10mg/day) and 0.52 (p < 0.0001, 20mg/day). Results are limited by the post hoc nature of the analyses and the absence of an active reference in the original study. CONCLUSIONS: Vortioxetine (10 and 20mg/day) had a multi-domain beneficial effect on cognitive performance, as evidenced by improvements in measures of executive function, attention/speed of processing, and memory. The effect on the DSST may be due to improvements in several cognitive skills. PMID- 27231258 TI - Volatile and Within-Needle Terpene Changes to Douglas-fir Trees Associated With Douglas-fir Beetle (Coleoptera: Curculionidae) Attack. AB - Mass attack by tree-killing bark beetles (Curculionidae: Scolytinae) brings about large chemical changes in host trees that can have important ecological consequences. For example, mountain pine beetle (Dendroctonus ponderosae Hopkins) attack increases emission of terpenes by lodgepole pine (Pinus contorta Dougl. ex Loud.), affecting foliage flammability with consequences for wildfires. In this study, we measured chemical changes to Douglas-fir (Pseudotsuga menziesii var. glauca (Mirb.) Franco) foliage in response to attack by Douglas-fir beetles (Dendroctonus pseudotsugae Hopkins) as trees die and crowns transitioned from green/healthy, to green-infested (year of attack), to yellow (year after attack), and red (2 yr after attack). We found large differences in volatile and within needle terpene concentrations among crown classes and variation across a growing season. In general, emissions and concentrations of total and individual terpenes were greater for yellow and red needles than green needles. Douglas-fir beetle attack increased emissions and concentrations of terpene compounds linked to increased tree flammability in other conifer species and compounds known to attract beetles (e.g., [Formula: see text]-pinene, camphene, and D-limonene). There was little relationship between air temperature or within-needle concentrations of terpenes and emission of terpenes, suggesting that passive emission of terpenes (e.g., from dead foliage) does not fully explain changes in volatile emissions. The potential physiological causes and ecological consequences of these bark beetle-associated chemical changes are discussed. PMID- 27231259 TI - Explorations in statistics: statistical facets of reproducibility. AB - Learning about statistics is a lot like learning about science: the learning is more meaningful if you can actively explore. This eleventh installment of Explorations in Statistics explores statistical facets of reproducibility. If we obtain an experimental result that is scientifically meaningful and statistically unusual, we would like to know that our result reflects a general biological phenomenon that another researcher could reproduce if (s)he repeated our experiment. But more often than not, we may learn this researcher cannot replicate our result. The National Institutes of Health and the Federation of American Societies for Experimental Biology have created training modules and outlined strategies to help improve the reproducibility of research. These particular approaches are necessary, but they are not sufficient. The principles of hypothesis testing and estimation are inherent to the notion of reproducibility in science. If we want to improve the reproducibility of our research, then we need to rethink how we apply fundamental concepts of statistics to our science. PMID- 27231260 TI - Brazilian actions to promote physiology learning and teaching in secondary and high schools. AB - Members of the Education Committee of the Brazilian Society of Physiology have developed multiple outreach models to improve the appreciation of science and physiology at the precollege level. The members of this committee act in concert with important Brazilian governmental strategies to promote training of undergraduate students in the teaching environment of secondary and high schools. One of these governmental strategies, the Programa Institucional de Bolsas de Iniciacao a Docencia, a Brazilian public policy of teaching enhancement implemented by the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) since 2007, represents a well-articulated public policy that can promote the partnership between University and Schools (7). Furthermore, the Program "Novos Talentos" (New Talents)/CAPES/Ministry of Education is another government initiative to bring together university and high-level technical training with the reality of Brazilian schools. Linked to the New Talents Program, in partnership with the British Council/Newton Fund, CAPES recently promoted the visit of some university professors that coordinate New Talents projects to formal and informal educational science spaces in the United Kingdom (Science, Technology, Engineering, and Mathematics, Brazil-United Kingdom International Cooperation Program) to qualify the actions developed in this area in Brazil, and one of us had the opportunity to participate with this. PMID- 27231261 TI - Apoptosis as the focus of an authentic research experience in a cell physiology laboratory. AB - Curriculum-embedded independent research is a high-impact teaching practice that has been shown to increase student engagement and learning. This article describes a multiweek laboratory project for an upper-division undergraduate cell physiology laboratory using apoptosis via the mitochondrial pathway as the overarching theme. Students did literature research on apoptotic agents that acted via the mitochondrial pathway. Compounds ranged from natural products such as curcumin to synthetic compounds such as etoposide. Groups of two to three students planned a series of experiments using one of three cultured cell lines that required them to 1) learn to culture cells; 2) determine treatment conditions, including apoptotic agent solubility and concentration ranges that had been reported in the literature; 3) choose two methods to validate/quantify apoptotic capacity of the reagent; and 4) attempt to "rescue" cells from undergoing apoptosis using one of several available compounds/methods. In essence, given some reagent and equipment constraints, students designed an independent experiment to highlight the effects of different apoptotic agents on cells in culture. Students presented their experimental designs as in a laboratory group meeting and their final findings as a classroom "symposium." This exercise can be adapted to many different types of laboratories with greater or lesser equipment and instrumentation constraints, incorporates several core cell physiology methods, and encourages key experimental design and critical thinking components of independent research. PMID- 27231262 TI - An instructional design process based on expert knowledge for teaching students how mechanisms are explained. AB - In biology and physiology courses, students face many difficulties when learning to explain mechanisms, a topic that is demanding due to the immense complexity and abstract nature of molecular and cellular mechanisms. To overcome these difficulties, we asked the following question: how does an instructor transform their understanding of biological mechanisms and other difficult-to-learn topics so that students can comprehend them? To address this question, we first reviewed a model of the components used by biologists to explain molecular and cellular mechanisms: the MACH model, with the components of methods (M), analogies (A), context (C), and how (H). Next, instructional materials were developed and the teaching activities were piloted with a physical MACH model. Students who used the MACH model to guide their explanations of mechanisms exhibited both improvements and some new difficulties. Third, a series of design-based research cycles was applied to bring the activities with an improved physical MACH model into biology and biochemistry courses. Finally, a useful rubric was developed to address prevalent student difficulties. Here, we present, for physiology and biology instructors, the knowledge and resources for explaining molecular and cellular mechanisms in undergraduate courses with an instructional design process aimed at realizing pedagogical content knowledge for teaching. Our four-stage process could be adapted to advance instruction with a range of models in the life sciences. PMID- 27231263 TI - Chitosan-functionalised single-walled carbon nanotube-mediated drug delivery of SNX-2112 in cancer cells. AB - Delivery of amphiphobic drugs (insoluble in both water and oil) has been a great challenge in drug delivery. SNX-2112, a novel inhibitor of Hsp90, is a promising drug candidate for treating various types of cancers; however, the insolubility greatly limits its clinical application. This study aimed to build a new type of drug delivery system using single-walled carbon nanotubes (SWNTs) for controllable release of SNX-2112; chitosan (CHI) was non-covalently added to SWNTs to improve their biocompatibility. SWNTs-CHI demonstrated high drug-loading capability; the release of SNX-2112 was pH triggered and time related. The intracellular reactive oxygen species of SWNTs-CHI increased, compared with that of SWNTs, leading to higher mitogen-activated protein kinase and cell apoptosis. The results of western-blotting, lactate dehydrogenase (LDH) release assay, and cell viability assay analyses indicated that apoptosis-related proteins were abundantly expressed in K562 cells and that the drug delivery system significantly inhibited K562 cells. Thus, SWNT-CHI/SNX-2112 shows great potential as a drug delivery system for cancer therapy. PMID- 27231264 TI - Genipin-crosslinked O-carboxymethyl chitosan-gum Arabic coacervate as a pH sensitive delivery system and microstructure characterization. AB - The possibility of genipin-crosslinked O-carboxymethyl chitosan-gum Arabic coacervate as a pH-sensitive delivery vehicle was investigated. O-carboxymethyl chitosan-gum Arabic coacervates separated in pH 3.0, 4.5, and 6.0 were crosslinked by genipin for different durations and the crosslinked products were subjected to crosslinking degree, swelling behavior, bovine serum albumin release profile, and microstructure characterization. Genipin-crosslinking greatly improved the stability of the coacervates against the simulated gastric solution and created certain pH-sensitivity. The coacervates displayed higher swelling ratios in the simulated gastric solution than in the simulated intestine and colon solutions; meanwhile, the coacervates prepared in pH 4.5 and 6.0 swelled more severely than the complex separated in pH 3.0. Nevertheless, the bovine serum albumin release in the simulated gastric solution from the microcapsules prepared in pH 6.0 was much lower than those prepared in pH 4.5 and 3.0, whose cumulative release percentages in the three simulated solutions were 17.14%, 55.23%, and 79.79%, respectively, in crosslinking duration 2 h. X-ray diffraction, scanning electron microscopy, and transmission electron microscopy analysis revealed that genipin-crosslinking improved the regularity and compactness of coacervate structure, whereas confocal laser scanning microscopy observation indicated that O-carboxymethyl chitosan content was possibly the major reason for the different swelling and bovine serum albumin release behavior of the coacervates. It was concluded that the genipin-crosslinked O-carboxymethyl chitosan-gum Arabic coacervate was a potential intestine-targeted delivery system and its delivery performance could be tailored by varying the crosslinking degree and coacervation acidity. PMID- 27231265 TI - Bioactivity of Y2O3 and CeO2 doped SiO2-SrO-Na2O glass-ceramics. AB - The bioactivity of yttrium and cerium are investigated when substituted for Sodium (Na) in a 0.52SiO2-0.24SrO-0.24-xNa2O-xMO glass-ceramics (where x = 0.08 and MO = Y2O3 or CeO2). Bioactivity is monitored through pH and inductively coupled plasma-optical emission spectrometry where pH of simulated body fluid ranged from 7.5 to 7.6 and increased between 8.2 and 10.0 after 14-day incubation with the glass-ceramic disks. Calcium (Ca) and phosphorus (P) levels in simulated body fluid after incubation with yttrium and cerium containing disks show a continual decline over the 14-day period. In contrast, Con disks (not containing yttrium or cerium) caused the elimination of Ca in solution after 1 day and throughout the incubation period, and initially showed a decline in P levels followed by an increase at 14 days. Scanning electron microscopy and energy dispersive spectroscopy confirmed the presence of Ca and P on the surface of the simulated body fluid-incubated disks and showed precipitates on Con and HCe (8 mol% cerium) samples. Cell viability of MC3T3 osteoblasts was not significantly affected at a 9% extract concentration. Optical microscopy after 24 h cell incubation with disks showed that Con samples do not support osteoblast or Schwann cell growth, while all yttrium and cerium containing disks have direct contact with osteoblasts spread across the wells. Schwann cells attached in all wells, but only showed spreading with the HY-S (8 mol% yttrium, heated to sintering temperature) and YCe (4 mol% yttrium and cerium) disks. Scanning electron microscopy of the compatible disks shows osteoblast and sNF96.2 Schwann cells attachment and spreading directly on the disk surfaces. PMID- 27231268 TI - New consumption and production models for a circular economy. PMID- 27231267 TI - A modified echocardiographic approach improves reliability of superior vena caval flow quantification. AB - OBJECTIVE: To assess accuracy and repeatability of a modified echocardiographic approach to quantify superior vena cava (SVC) flow volume that uses a short-axis view to directly measure SVC area and a suprasternal view to measure flow velocity, both at the level of the right pulmonary artery. SETTING: Three tertiary-level neonatal intensive care units. DESIGN: This was a multicentre, prospective, observational study. Accuracy of the traditional and modified approach was first assessed by comparing echo measurements according to both techniques with Phase contrast MRI (PCMRI) assessments, in a cohort of 10 neonates. In a second cohort of 40 neonates, intraobserver scan-rescan repeatability and interobserver analysis-reanalysis repeatability were assessed by repeated SVC flow echo measurements, according to both techniques. RESULTS: The traditional echocardiographic approach to assessment of SVC flow had a moderate agreement with PCMRI (r2 0.259), a scan-rescan intraobserver repeatability index (RI) of 37% (limits of agreement (LOA) -47/+51 mL/kg/min) and an interobserver analysis-reanalysis RI of 31% (LOA -38/+40 mL/kg/min). The modified approach showed a stronger agreement with PCMRI (r2 0.775), an improved intraobserver scan-rescan repeatability (RI 22%, LOA -24/+18 mL/kg/min) and improved interobserver analysis-reanalysis repeatability (RI 18%, LOA -18/+20 mL/kg/min). CONCLUSIONS: Echocardiographic assessment of SVC flow volume by tracing area from a short-axis view and measuring velocity-time integral from a suprasternal view offered an improvement in accuracy and repeatability, building on the traditional approach previously described. PMID- 27231269 TI - Should Atrial Fibrillation Patients With Only 1 Nongender-Related CHA2DS2-VASc Risk Factor Be Anticoagulated? AB - BACKGROUND AND PURPOSE: There is some uncertainty about treating patients with atrial fibrillation (AF) with 1 nongender-related (NGR) stroke risk factor (CHA2DS2-VASc [ie, congestive heart failure, hypertension, age (>=75 years; 2 points), diabetes, stroke/transient ischemic attack (2 points), vascular disease, age (65-74 years), sex (female)] score of 1 in males and 2 in females) with oral anticoagulation (OAC). METHODS: We investigated adverse outcomes and calculated the net clinical benefit of OAC use in a community-based cohort of unselected AF patients with 0 compared with 1 NGR stroke risk factor (CHA2DS2-VASc 0 versus 1 in males; and 1 versus 2 in females). Among 8962 patients with AF, 2208 (25%) had 0 or 1 NGR stroke risk factors, of which 45% were not prescribed OAC. RESULTS: During a follow-up of 1028+/-1189 days (median, 495; interquartile range, 5-1882 days), the yearly rate of the combined end point of stroke/systemic embolism in nonanticoagulated AF patients with 1 NGR stroke risk factor was 2.09% (95% confidence interval, 1.37-3.18). This corresponded to an adjusted hazard ratio of 2.82 (95% confidence interval, 1.32-6.04) relative to the group with 0 NGR stroke risk factor. When the benefit of ischemic stroke reduction was balanced against the increased risk of intracranial hemorrhage among patients with 1 NGR stroke risk factor, the net clinical benefit was positive in favor of OAC use versus no antithrombotic therapy or antiplatelet therapy use. The net clinical benefit was negative for antiplatelet therapy use versus no antithrombotic therapy. CONCLUSIONS: Among AF patients with 1 NGR stroke risk factor (ie, CHA2DS2-VASc 1 in males or 2 in females), OAC use as indicated according to the guidelines was associated with a positive net clinical benefit for the prevention of stroke and thromboembolic events. PMID- 27231266 TI - Diabetes in pregnancy and infant adiposity: systematic review and meta-analysis. AB - OBJECTIVE: Maternal glycaemia and anthropometry-derived newborn adiposity are strongly correlated. The children of mothers with diabetes are at greater risk of adverse metabolic health, and increased adiposity is a plausible mediator. We undertook a systematic review and meta-analysis to compare adiposity in infants of diabetic mothers (IDM) and infants of mothers without diabetes (NIDM). DESIGN: We identified observational studies reporting adiposity in IDM and NIDM. We searched references, traced forward citations and contacted authors for additional data. We considered all body composition techniques and compared fat mass, fat-free mass, body fat % and skinfold thickness. We used random effects meta-analyses and performed subgroup analyses by maternal diabetes type (type 1, type 2 and gestational) and infant sex. We examined the influence of pre pregnancy body mass index (BMI) and conducted sensitivity analyses. RESULTS: We included data from 35 papers and over 24 000 infants. IDM have greater fat mass than NIDM (mean difference (95% CI)): 83 g (49 to 117). Fat mass is greater in infants of mothers with gestational diabetes: 62 g (29 to 94) and type 1 diabetes: 268 g (139 to 397). Insufficient studies reported data for type 2 diabetes separately. Compared with NIDM, fat mass was greater in IDM boys: 87 g (30 to 145), but not significantly different in IDM girls: 42 g (-33 to 116). There was no attenuation after adjustment for maternal BMI. CONCLUSIONS: IDM have significantly greater adiposity in comparison with NIDM. These findings are justification for studies to determine whether measures to reduce infant adiposity will improve later health. PMID- 27231270 TI - Fast-growing Acer rubrum differs from slow-growing Quercus alba in leaf, xylem and hydraulic trait coordination responses to simulated acid rain. AB - We investigated the effects of historic soil chemistry changes associated with acid rain, i.e., reduced soil pH and a shift from nitrogen (N)- to phosphorus (P) limitation, on the coordination of leaf water demand and xylem hydraulic supply traits in two co-occurring temperate tree species differing in growth rate. Using a full-factorial design (N * P * pH), we measured leaf nutrient content, water relations, leaf-level and canopy-level gas exchange, total biomass and allocation, as well as stem xylem anatomy and hydraulic function for greenhouse grown saplings of fast-growing Acer rubrum (L.) and slow-growing Quercus alba (L.). We used principle component analysis to characterize trait coordination. We found that N-limitation, but not P-limitation, had a significant impact on plant water relations and hydraulic coordination of both species. Fast-growing A. rubrum made hydraulic adjustments in response to N-limitation, but trait coordination was variable within treatments and did not fully compensate for changing allocation across N-availability. For slow-growing Q. alba, N-limitation engendered more strict coordination of leaf and xylem traits, resulting in similar leaf water content and hydraulic function across all treatments. Finally, low pH reduced the propensity of both species to adjust leaf water relations and xylem anatomical traits in response to nutrient manipulations. Our data suggest that a shift from N- to P-limitation has had a negative impact on the water relations and hydraulic function of A. rubrum to a greater extent than for Q. alba We suggest that current expansion of A. rubrum populations could be tempered by acidic N-deposition, which may restrict it to more mesic microsites. The disruption of hydraulic acclimation and coordination at low pH is emphasized as an interesting area of future study. PMID- 27231271 TI - Measurement Properties of the Quebec Back Pain Disability Scale in Patients With Nonspecific Low Back Pain: Systematic Review. AB - BACKGROUND: The Quebec Back Pain Disability Scale (QBPDS) has been translated into different languages, and several studies on its measurement properties have been done. PURPOSE: The purpose of this review was to critically appraise and compare the measurement properties, when possible, of all language versions of the QBPDS by systematically reviewing the methodological quality and results of the available studies. METHOD: Bibliographic databases (PubMed, Embase, CINAHL, and PsycINFO) were searched for articles with the key words "Quebec," "back," "pain," and "disability" in combination with a methodological search filter for finding studies on measurement properties concerning the development or evaluation of the measurement properties of the QBPDS in patients with nonspecific low back pain. Assessment of the methodological quality was carried out by the reviewers using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist for both the original language version of the QBPDS in English and French and all translated versions. The results of the measurement properties were rated based on criteria proposed by Terwee et al. RESULTS: The search strategy resulted in identification of 1,436 publications, and 27 articles were included in the systematic review. There was limited-to-moderate evidence of good reliability, validity, and responsiveness of the QBPDS for the different language versions, but for no language version was evidence available for all measurement properties. CONCLUSION: For research and clinical practice, caution is advised when using the QBPDS to measure disability in patients with nonspecific low back pain. Strong evidence is lacking on all measurement properties for each language version of the QBPDS. PMID- 27231272 TI - Structural Validity of the Mini-Balance Evaluation Systems Test (Mini-BESTest) in People With Mild to Moderate Parkinson Disease. AB - BACKGROUND: The Mini-Balance Evaluation Systems Test (Mini-BESTest) is a clinical balance test comprising 14 items assumed to reflect the unidimensional construct "dynamic balance." OBJECTIVE: The study objective was to examine the dimensionality of the test and the properties of each item and their interrelationships in elderly people with mild to moderate Parkinson disease (PD). DESIGN: This was a cross-sectional study in a laboratory setting. METHODS: A total of 112 participants (mean age=73 years) with idiopathic PD (Hoehn and Yahr stages 1-3) were assessed by physical therapists. Local independence among items was examined with Rasch modeling. Unidimensionality was tested by running a principal component analysis on the residuals. An exploratory factor analysis was used to examine the structure of the test, and a confirmatory factor analysis was used to evaluate the fit of the derived model. RESULTS: The first residual component of the principal component analysis, with an eigenvalue of greater than 2, superseded the assumption of unidimensionality. After the omission of item 7 because of convergence problems, the exploratory factor analysis suggested that a 3-factor solution best fit the data. A confirmatory factor analysis demonstrated acceptable fit of the final model, although item 14 loaded poorly on its factor. LIMITATIONS: The sample size was on the lower end of what is generally recommended. CONCLUSIONS: This study could not confirm that the Mini-BESTest is unidimensional. Gait items were dispersed over all factors, indicating that they may reflect different constructs. Nonetheless, as there arguably is no clinical balance test superior to the Mini-BESTest today, we recommend using the total score for assessing gross balance in this population and individual items to identify specific weaknesses. Moreover, dual tasks should be assessed separately because they are an important aspect of balance control in people with PD, reflected in only one item of the test. PMID- 27231273 TI - Outcome Measure Recommendations From the Spinal Cord Injury EDGE Task Force. PMID- 27231274 TI - Delay of antifungal therapy influences the outcome of invasive aspergillosis in experimental models of infection. AB - OBJECTIVES: The aim of the present study was to evaluate the effects of delayed antifungal therapy on the outcome of invasive aspergillosis due to Aspergillus fumigatus in experimental models of infection. METHODS: A clinical isolate of A. fumigatus susceptible to amphotericin B (MIC 0.5 mg/L) and micafungin [minimum effective concentration (MEC) 0.03 mg/L] was used in all experiments. Two models of infection were investigated in immunosuppressed mice: disseminated infection and pulmonary infection. Twenty-four hours (early therapy) and 48 h (delayed therapy) post-infection, the mice were given vehicle, liposomal amphotericin B, micafungin or liposomal amphotericin B plus micafungin (combination). Drug efficacy was assessed by either survival or tissue burden experiments. RESULTS: In disseminated infection, any drug regimen given early significantly prolonged survival. When therapy was delayed, only micafungin and the combination were effective. In pulmonary infection, although there was a trend towards a prolongation of survival of mice treated early with liposomal amphotericin B, only the combination was effective. Similarly, when therapy was delayed, only the combination was effective. In disseminated infection, any drug regimen given early was effective at reducing the cfu in kidney tissue. In pulmonary infection, only liposomal amphotericin B and the combination given early were effective at reducing the cfu in lung tissue. Conversely, when therapy was delayed, no regimen was effective at reducing the tissue burden, regardless of the type of infection. CONCLUSIONS: Our data indicate that delayed initiation of antifungal therapy is deleterious in experimental models of invasive aspergillosis. A combination regimen seems to have some advantages over a single-drug approach when the therapy is started late. PMID- 27231275 TI - Comment on: A systematic review of the public's knowledge and beliefs about antibiotic resistance. PMID- 27231277 TI - Pharmacokinetic/pharmacodynamic-based optimization of levofloxacin administration in the treatment of MDR-TB. AB - The emergence of MDR-TB and XDR-TB has complicated TB treatment success. Among many factors that contribute to the development of resistance, low drug exposure is not the least important. This review summarizes the available information on pharmacokinetic properties of levofloxacin in relation to microbial susceptibilities, in order to optimize the dose and make general treatment recommendations. A total of 37 studies on adult (32 studies) and paediatric (5 studies) MDR-TB patients were included. Among the 32 adult studies, 19 were on susceptibility of Mycobacterium tuberculosis isolates to levofloxacin by MIC, 1 was on susceptibility of M. tuberculosis isolates to levofloxacin by MBC, 1 was on susceptibility of M. tuberculosis isolates to levofloxacin by mutant prevention concentration and 4 were on pharmacokinetics of levofloxacin, and 7 others were included. Likewise, out of five studies on children, two dealt with levofloxacin pharmacokinetic parameters, one reviewed CSF concentrations and two dealt with background information. In adult MDR-TB patients, standard dosing of once-daily 1000 mg levofloxacin in TB treatment did not consistently attain the target concentration (i.e. fAUC/MIC >100 and fAUC/MBC >100) in 80% of the patients with MIC and MBC of 1 mg/L, leaving them at risk of developing drug resistance. However, with an MIC of 0.5 mg/L, 100% of the patients achieved the target concentration. Similarly, paediatric patients failed consistently in achieving given pharmacokinetic/pharmacodynamic targets due to age-related differences, demanding a shift towards once daily dosing of 15-20 mg/kg. Therefore, we recommend therapeutic drug monitoring for patients with strains having MICs of >=0.5 mg/L and suggest revising the cut-off value from 2 to 1 mg/L. PMID- 27231276 TI - Reduction in post-operative acute kidney injury following a change in antibiotic prophylaxis policy for orthopaedic surgery: an observational study. AB - OBJECTIVES: Evidence has shown that a prophylactic antibiotic regimen of flucloxacillin and gentamicin for orthopaedic surgery was associated with increased rates of post-operative acute kidney injury (AKI). This resulted in changes in the national antibiotic policy recommendation for orthopaedic surgical prophylaxis. This study aimed to assess whether this change from flucloxacillin and gentamicin to co-amoxiclav was associated with changes in the rates of AKI and Clostridium difficile infection (CDI). METHODS: An observational study and interrupted time series analyses were used to assess rates of post-operative AKI separately in patients undergoing neck of femur (NOF) repair and other orthopaedic operations that required antibiotic prophylaxis. Incidence rate ratios were used to evaluate changes in CDI rates. RESULTS: Following the change in policy, from flucloxacillin and gentamicin to co-amoxiclav, there was a relative change in rates of post-operative AKI of -63% (95% CI -77% to -49%) at 18 months in the other orthopaedic operations group. In the NOF repair group, there was no change in the rate of post-operative AKI [-10% (95% CI -35%-15%)] at 18 months. The incident rate ratio for CDI in the other orthopaedic operations group was 0.29 (95% CI 0.09-0.96) and in the NOF repair group was 0.76 (95% CI 0.28-2.08). CONCLUSIONS: The use of co-amoxiclav for antibiotic prophylaxis in orthopaedic surgery was associated with a decreased rate of post-operative AKI compared with flucloxacillin and gentamicin and was not associated with increased rates of CDI. PMID- 27231278 TI - Effect of different renal function on antibacterial effects of piperacillin against Pseudomonas aeruginosa evaluated via the hollow-fibre infection model and mechanism-based modelling. AB - BACKGROUND: Pathophysiological changes in critically ill patients can cause severely altered pharmacokinetics and widely varying antibiotic exposures. The impact of altered pharmacokinetics on bacterial killing and resistance has not been characterized in the dynamic hollow-fibre in vitro infection model (HFIM). METHODS: A clinical Pseudomonas aeruginosa isolate (piperacillin MIC 4 mg/L) was studied in the HFIM (inoculum ~10(7) cfu/mL). Pharmacokinetic profiles of three piperacillin dosing regimens (4 g 8-, 6- and 4-hourly, 30 min intravenous infusion) as observed in critically ill patients with augmented renal clearance (ARC), normal renal function or impaired renal function (creatinine clearances of 250, 110 or 30 mL/min, respectively) were simulated over 7 days. The time courses of total and less-susceptible populations and MICs were determined. Mechanism based modelling was performed in S-ADAPT. RESULTS: For all regimens with ARC and regimens with 8- or 6-hourly dosing with normal renal function, initial killing of <=~2 log10 was followed by regrowth to 10(8)-10(9) cfu/mL at 48 h. For 8- and 6-hourly dosing at normal renal function, the proportion of less-susceptible colonies increased ~10-100-fold above those in ARC and control arms. Regimens achieving an fCmin of >=5* MIC resulted in bacterial killing of 3-4 log10 without regrowth and suppressed less-susceptible populations to <=~2 log10. The mechanism based model successfully quantified the time course of bacterial growth, killing and regrowth. CONCLUSIONS: Only high piperacillin concentrations prevented regrowth of P. aeruginosa. Individualized dosing regimens that account for altered pharmacokinetics and aim for higher-than-standard antibiotic exposures to achieve an fCmin of >=5* MIC were required to maximize bacterial killing and suppress emergence of resistance. PMID- 27231279 TI - Engineered cationic antimicrobial peptide (eCAP) prevents Pseudomonas aeruginosa biofilm growth on airway epithelial cells. AB - OBJECTIVES: Chronic infections with the opportunistic pathogen Pseudomonas aeruginosa are responsible for the majority of the morbidity and mortality in patients with cystic fibrosis (CF). While P. aeruginosa infections may initially be treated successfully with standard antibiotics, chronic infections typically arise as bacteria transition to a biofilm mode of growth and acquire remarkable antimicrobial resistance. To address the critical need for novel antimicrobial therapeutics that can effectively suppress chronic bacterial infections in challenging physiological environments, such as the CF lung, we have rationally designed a de novo engineered cationic antimicrobial peptide, the 24-residue WLBU2, with broad-spectrum antibacterial activity for pan-drug-resistant P. aeruginosa in liquid culture. In the current study, we tested the hypothesis that WLBU2 also prevents P. aeruginosa biofilm growth. METHODS: Using abiotic and biotic biofilm assays, co-culturing P. aeruginosa with polarized human airway epithelial cells, we examined the ability of WLBU2 to prevent biofilm biogenesis alone and in combination with currently used antibiotics. RESULTS: We observed a dose-dependent reduction in biofilm growth on an abiotic surface and in association with CF airway epithelial cells. WLBU2 prevented P. aeruginosa biofilm formation when co-cultured with mucus-producing primary human CF airway epithelial cells and using CF clinical isolates of P. aeruginosa, even at low pH and high salt conditions that mimic the CF airway. When used in combination, WLBU2 significantly increases killing by the commonly used antibiotics tobramycin, ciprofloxacin, ceftazidime and meropenem. CONCLUSIONS: While other studies have demonstrated the ability of natural and synthetic antimicrobial peptides to prevent abiotic bacterial biofilm formation, the current studies for the first time demonstrate the effective peptide treatment of a biotic bacterial biofilm in a setting similar to the CF airway, and without negative effects on human airway epithelial cells, thus highlighting the unique potential of this engineered cationic antimicrobial peptide for treatment of human respiratory infections. PMID- 27231281 TI - Radiology double reads. PMID- 27231280 TI - Usefulness of an HIV DNA resistance genotypic test in patients who are candidates for a switch to the rilpivirine/emtricitabine/tenofovir disoproxil fumarate combination. AB - OBJECTIVES: In the context of a rilpivirine/emtricitabine/tenofovir disoproxil fumarate switch in HIV-1-infected patients with at least 1 year of virological success, we determined whether proviral DNA is an alternative to plasma HIV RNA for resistance genotyping. METHODS: Resistance-associated mutations (RAMs) in DNA after at least 1 year of virological success [viral load (VL) <50 copies/mL] were compared with those identified in the last plasma RNA genotype available. Rilpivirine/emtricitabine/tenofovir disoproxil fumarate RAMs studied were K65R, L100I, K101E/P, E138A/G/K/R/Q, V179L, Y181C/I/V, M184V/I, Y188L, H221Y, F227C and M230I/L in the RT. We studied patients without virological failure (VF) and with at least 1 VF (two consecutive VLs >50 copies/mL). Kappa's coefficient was used to measure agreement between the DNA and RNA genotypes. RESULTS: In patients without VF (n = 130) and with VF (n = 114), RNA and DNA showed resistance to at least one drug of the rilpivirine/emtricitabine/tenofovir disoproxil fumarate combination in 8% and 9% and in 60% and 45%, respectively. For rilpivirine RAMs, correlation between RNA and DNA was higher in patients without VF than in patients with VF (kappa = 0.60 versus 0.19, P = 0.026). Overall, the prevalence of RAMs was lower in DNA than in RNA. CONCLUSIONS: Incomplete information provided by the DNA genotypic test is more notable in patients with VF, suggesting that all resistance mutations associated with prior VF have not been archived in the proviral DNA or decreased to a level below the threshold of detection. In the case where no historical plasma genotypic test is available, DNA testing might be useful to rule out switching to rilpivirine/emtricitabine/tenofovir disoproxil fumarate. PMID- 27231283 TI - Foreword. PMID- 27231284 TI - Foreign Medical Teams in support of the Ebola outbreak: a UK military model of pre-deployment training and assurance. AB - We discuss the training methodology developed and utilised to prepare UK military medical teams to establish an Ebola Treatment Centre in Sierra Leone. We highlight the process of identifying and mitigating nosocomial risk in the Pre Deployment Training process, encompassing the challenges of developing, training and assuring a capability at pace, which deployed to deliver high quality clinical care to patients with Ebola Virus Disease. PMID- 27231285 TI - Fundamental Flaws. PMID- 27231286 TI - Giving voice to the voiceless: how to involve vulnerable migrants in healthcare research. PMID- 27231287 TI - The physical health of people who inject drugs: complexities, challenges, and continuity. PMID- 27231288 TI - Preventing radicalisation and terrorism: is there a GP response? PMID- 27231289 TI - In defence of the 'tick-box approach': why end-of-life care is no exception. PMID- 27231290 TI - GP training programmes. PMID- 27231291 TI - NSAIDs and chickenpox. PMID- 27231292 TI - Telephone triage for new GP consultations. PMID- 27231293 TI - GP attitudes to migrant health care across Europe. PMID- 27231294 TI - The role of GPs in the world's poorest country: health care in Malawi. PMID- 27231295 TI - Bad medicine: the menopause. PMID- 27231296 TI - Yonder: Advance care planning, osteopathy, HPV vaccination, and international medical graduates. PMID- 27231297 TI - Exhibition: Scholar, Courtier, Magician: The Lost Library of John Dee: Master of Divine Secrets. PMID- 27231298 TI - Can religious fundamentalism reform for the benefit of public health? PMID- 27231299 TI - Books: Compassion: Compassion, Continuity and Caring in the NHS: Intelligent Kindness. PMID- 27231300 TI - Books: ABC of Domestic and Sexual Violence: No Quick Fix - Aim to Recognise, Respond, and Refer. PMID- 27231301 TI - Books: Mind Over Mood: Change How You Feel by Changing the Way You Think: Think Better, Feel Better. PMID- 27231302 TI - Regression is good. PMID- 27231303 TI - How can general practice respond to the needs of street-based prostitutes? PMID- 27231304 TI - Hand manifestations of neurological disease: some alternatives to consider. PMID- 27231305 TI - Evolving health policy for primary care in the Asia Pacific region. PMID- 27231306 TI - Safeguarding adults in primary care: making a safeguarding adults referral. PMID- 27231307 TI - When to consider a diagnosis of MODY at the presentation of diabetes: aetiology matters for correct management. PMID- 27231309 TI - Physiological phenotyping of pediatric chronic obstructive airway diseases. AB - Inert tracer gas washout (IGW) measurements detect increased ventilation inhomogeneity (VI) in chronic lung diseases. Their suitability for different diseases, such as cystic fibrosis (CF) and primary ciliary dyskinesia (PCD), has already been shown. However, it is still unclear if physiological phenotypes based on different IGW variables can be defined independently of underlying disease. Eighty school-age children, 20 with CF, 20 with PCD, 20 former preterm children, and 20 healthy children, performed nitrogen multiple-breath washout, double-tracer gas (DTG) single-breath washout, and spirometry. Our primary outcome was the definition of physiological phenotypes based on IGW variables. We applied principal component analysis, hierarchical Ward's clustering, and enrichment analysis to compare clinical characteristics between the clusters. IGW variables used for clustering were lung clearance index (LCI) and convection dependent [conductive ventilation heterogeneity index (Scond)] and diffusion convection-dependent variables [acinar ventilation heterogeneity index (Sacin) and carbon dioxide and DTG phase III slopes]. Three main phenotypes were identified. Phenotype I (n = 38) showed normal values in all IGW outcome variables. Phenotype II (n = 21) was characterized by pronounced global and convection-dependent VI while diffusion-dependent VI was normal. Phenotype III (n = 21) was characterized by increased global and diffusion- and convection dependent VI. Enrichment analysis revealed an overrepresentation of healthy children and former preterm children in phenotype I and of CF and PCD in phenotypes II and III. Patients in phenotype III showed the highest proportion and frequency of exacerbations and hospitalization in the year prior to the measurement. IGW techniques allow identification of clinically meaningful, disease-independent physiological clusters. Their predictive value of future disease outcomes remains to be determined. PMID- 27231308 TI - Pitch and Duration Mismatch Negativity and Premorbid Intellect in the First Hospitalized Schizophrenia Spectrum. AB - Mismatch negativity (MMN) is a robustly abnormal brainwave in chronically ill schizophrenia that has generated interest as a disease presence biomarker. Reports of MMN reduction in first-episode schizophrenia have been equivocal, raising uncertainty about its reduction at first psychotic break. Here we tested 29 schizophrenia-spectrum participants under 1 year from their first hospitalization for psychosis and 40 age-, gender-, parental socioeconomic status , and Wechsler Adult Intelligence Scales III Information-matched healthy controls on both pitch and duration MMN. Participants performed a visual checkerboard tracking task while standard (1kHz, 50ms, 80%), pitch-deviant (1.2kHz, 50ms, 10%) and duration-deviant (1kHz, 100ms, 10%) tones were presented over headphones (75 dB) and EEG was recorded. Independent component analysis was used to remove eye movements and visual stimulus processing activity. Groups did not differ in pitch MMN or duration MMN amplitudes. Smaller pitch and duration MMN amplitudes were associated with lower estimates of premorbid intellect in all participants and independently with greater positive symptoms in first hospitalized schizophrenia. Overall MMN reduction was not present in these relatively high functioning individuals at the first episode of schizophrenia, and therefore is not a good disease presence biomarker for this sample. Future research is warranted to determine the degree of MMN reduction at the first episode of psychosis across a greater range of cognitive impairment, the utility of MMN as an indicator of risk or diagnosis, and its role for understanding pathophysiological mechanisms in emerging psychosis. PMID- 27231310 TI - Segmental extracellular and intracellular water distribution and muscle glycogen after 72-h carbohydrate loading using spectroscopic techniques. AB - Body water content increases during carbohydrate loading because 2.7-4-g water binds each 1 g of glycogen. Bioelectrical impedance spectroscopy (BIS) allows separate assessment of extracellular and intracellular water (ECW and ICW, respectively) in the whole body and each body segment. However, BIS has not been shown to detect changes in body water induced by carbohydrate loading. Here, we aimed to investigate whether BIS had sufficient sensitivity to detect changes in body water content and to determine segmental water distribution after carbohydrate loading. Eight subjects consumed a high-carbohydrate diet containing 12 g carbohydrates.kg body mass(-1).day(-1) for 72 h after glycogen depletion cycling exercise. Changes in muscle glycogen concentration were measured by (13)C magnetic resonance spectroscopy, and total body water (TBW) was measured by the deuterium dilution technique (TBWD2O). ICW and ECW in the whole body (wrist-to ankle) and in each body segment (arm, trunk, and leg) were assessed by BIS. Muscle glycogen concentration [72.7 +/- 10.0 (SD) to 169.4 +/- 55.9 mmol/kg wet wt, P < 0.001] and TBWD2O (39.3 +/- 3.2 to 40.2 +/- 3.0 kg, P < 0.05) increased significantly 72 h after exercise compared with baseline, respectively. Whole body BIS showed significant increases in ICW (P < 0.05), but not in ECW. Segmental BIS showed significant increases in ICW in the legs (P < 0.05), but not in the arms or trunk. Our results suggest that increase in body water after carbohydrate loading can be detected by BIS and is caused by segment-specific increases in ICW. PMID- 27231312 TI - Comparison of high-intensity vs. high-volume resistance training on the BDNF response to exercise. AB - This study compared the acute and chronic response of circulating plasma brain derived neurotrophic factor (BDNF) to high-intensity low-volume (HI) and low intensity high volume (HV) resistance training. Twenty experienced resistance trained men (23.5 +/- 2.6 y, 1.79 +/- 0.05 m, 75.7 +/- 13.8 kg) volunteered for this study. Before the resistance training program (PRE), participants performed an acute bout of exercise using either the HI [3-5 reps; 90% of one repetition maximum (1RM)] or HV (10-12 reps; 70% 1RM) training paradigm. The acute exercise protocol was repeated after 7 wk of training (POST). Blood samples were obtained at rest (BL), immediately (IP), 30 min (30P), and 60 min (60P) post exercise at PRE and POST. A three-way repeated measure ANOVA was used to analyze acute changes in BDNF concentrations during HI and HV resistance exercise and the effect of 7 wk of training. No training * time * group interaction in BDNF was noted (P = 0.994). Significant main effects for training (P = 0.050) and time (P < 0.001) in BDNF were observed. Significant elevations in BDNF concentrations were seen from BL at IP (P = 0.001), 30P (P < 0.001), and 60P (P < 0.001) in both HI and HV combined during PRE and POST. BDNF concentrations were also observed to increase from PRE to POST when collapsed across groups and time. No significant group * training interaction (P = 0.342), training (P = 0.105), or group (P = 0.238) effect were noted in the BDNF area under the curve response. Results indicate that BDNF concentrations are increased after an acute bout of resistance exercise, regardless of training paradigm, and are further increased during a 7 wk training program in experienced lifters. PMID- 27231311 TI - Exercise training reverses myocardial dysfunction induced by CaMKIIdeltaC overexpression by restoring Ca2+ homeostasis. AB - Several conditions of heart disease, including heart failure and diabetic cardiomyopathy, are associated with upregulation of cytosolic Ca(2+)/calmodulin dependent protein kinase II (CaMKIIdeltaC) activity. In the heart, CaMKIIdeltaC isoform targets several proteins involved in intracellular Ca(2+) homeostasis. We hypothesized that high-intensity endurance training activates mechanisms that enable a rescue of dysfunctional cardiomyocyte Ca(2+) handling and thereby ameliorate cardiac dysfunction despite continuous and chronic elevated levels of CaMKIIdeltaC CaMKIIdeltaC transgenic (TG) and wild-type (WT) mice performed aerobic interval exercise training over 6 wk. Cardiac function was measured by echocardiography in vivo, and cardiomyocyte shortening and intracellular Ca(2+) handling were measured in vitro. TG mice had reduced global cardiac function, cardiomyocyte shortening (47% reduced compared with WT, P < 0.01), and impaired Ca(2+) homeostasis. Despite no change in the chronic elevated levels of CaMKIIdeltaC, exercise improved global cardiac function, restored cardiomyocyte shortening, and reestablished Ca(2+) homeostasis to values not different from WT. The key features to explain restored Ca(2+) homeostasis after exercise training were increased L-type Ca(2+) current density and flux by 79 and 85%, respectively (P < 0.01), increased sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA2a) function by 50% (P < 0.01), and reduced diastolic SR Ca(2+) leak by 73% (P < 0.01), compared with sedentary TG mice. In conclusion, exercise training improves global cardiac function as well as cardiomyocyte function in the presence of a maintained high CaMKII activity. The main mechanisms of exercise-induced improvements in TG CaMKIIdeltaC mice are mediated via increased L-type Ca(2+) channel currents and improved SR Ca(2+) handling by restoration of SERCA2a function in addition to reduced diastolic SR Ca(2+) leak. PMID- 27231313 TI - Predicting outcomes to anti-vascular endothelial growth factor (VEGF) therapy in diabetic macular oedema: a review of the literature. AB - Diabetic macular oedema affects visual acuity to a varying degree. The current treatment of choice is intravitreal anti-vascular endothelial growth factor (VEGF) that has proven both its anatomical and visual efficacy in several large randomised clinical trials (RCTs). Although most patients respond well to anti VEGF agents, some, however, show a moderate or even poor response. There is no clear consensus as to how to manage these patients, or define them. In addition, identifying early in the course of treatment which patients will respond and which patients will not is paramount to any personalised treatment regimen. Most large RCTs such as RESTORE and Protocol I have attempted post hoc analyses to identify demographic, clinical, optical coherence tomography (OCT) and fluorescein angiography findings that might predict patient response. Although some factors were found to be predictive, the lack of uniformity between the different RCTs means that no consensus exists as to which of these factors can be reliably used. This review looks at the large diabetic macular oedema RCTs such as RESTORE, Protocol I, READ-2 and BOLT in an attempt to identify common prognostic indicators between the various studies. We also attempted to look at several other OCT parameters such as the inner segment-outer segment (IS-OS) layer, the external limiting membrane layer, and choroidal thickness to help determine whether they can truly predict visual outcomes in patients being treated with anti-VEGF therapy. Finally, we provide a simplified summary about which factors might be relevant in clinical practice to help guide physicians in treatment decisions. PMID- 27231314 TI - PyQuant: A Versatile Framework for Analysis of Quantitative Mass Spectrometry Data. AB - Quantitative mass spectrometry data necessitates an analytical pipeline that captures the accuracy and comprehensiveness of the experiments. Currently, data analysis is often coupled to specific software packages, which restricts the analysis to a given workflow and precludes a more thorough characterization of the data by other complementary tools. To address this, we have developed PyQuant, a cross-platform mass spectrometry data quantification application that is compatible with existing frameworks and can be used as a stand-alone quantification tool. PyQuant supports most types of quantitative mass spectrometry data including SILAC, NeuCode, (15)N, (13)C, or (18)O and chemical methods such as iTRAQ or TMT and provides the option of adding custom labeling strategies. In addition, PyQuant can perform specialized analyses such as quantifying isotopically labeled samples where the label has been metabolized into other amino acids and targeted quantification of selected ions independent of spectral assignment. PyQuant is capable of quantifying search results from popular proteomic frameworks such as MaxQuant, Proteome Discoverer, and the Trans Proteomic Pipeline in addition to several standalone search engines. We have found that PyQuant routinely quantifies a greater proportion of spectral assignments, with increases ranging from 25-45% in this study. Finally, PyQuant is capable of complementing spectral assignments between replicates to quantify ions missed because of lack of MS/MS fragmentation or that were omitted because of issues such as spectra quality or false discovery rates. This results in an increase of biologically useful data available for interpretation. In summary, PyQuant is a flexible mass spectrometry data quantification platform that is capable of interfacing with a variety of existing formats and is highly customizable, which permits easy configuration for custom analysis. PMID- 27231317 TI - Lurasidone. PMID- 27231316 TI - Expert leadership - why psychiatrists should lead mental health services. PMID- 27231319 TI - The relationship between environment and mental health: How does geographic information systems (GIS) help? PMID- 27231315 TI - Proteomics Analysis with a Nano Random Forest Approach Reveals Novel Functional Interactions Regulated by SMC Complexes on Mitotic Chromosomes. AB - Packaging of DNA into condensed chromosomes during mitosis is essential for the faithful segregation of the genome into daughter nuclei. Although the structure and composition of mitotic chromosomes have been studied for over 30 years, these aspects are yet to be fully elucidated. Here, we used stable isotope labeling with amino acids in cell culture to compare the proteomes of mitotic chromosomes isolated from cell lines harboring conditional knockouts of members of the condensin (SMC2, CAP-H, CAP-D3), cohesin (Scc1/Rad21), and SMC5/6 (SMC5) complexes. Our analysis revealed that these complexes associate with chromosomes independently of each other, with the SMC5/6 complex showing no significant dependence on any other chromosomal proteins during mitosis. To identify subtle relationships between chromosomal proteins, we employed a nano Random Forest (nanoRF) approach to detect protein complexes and the relationships between them. Our nanoRF results suggested that as few as 113 of 5058 detected chromosomal proteins are functionally linked to chromosome structure and segregation. Furthermore, nanoRF data revealed 23 proteins that were not previously suspected to have functional interactions with complexes playing important roles in mitosis. Subsequent small-interfering-RNA-based validation and localization tracking by green fluorescent protein-tagging highlighted novel candidates that might play significant roles in mitotic progression. PMID- 27231321 TI - Routine testing for thyroid problems. PMID- 27231320 TI - The Millennium series and The Girl With the Dragon Tattoo - featuring yet another criminal psychiatrist: a screenplay psychiatrists should be aware of. PMID- 27231324 TI - Talking with Professor Anne Buist. PMID- 27231322 TI - From the President. PMID- 27231325 TI - Official opening of the new premises of the College's South Australian Branch. PMID- 27231327 TI - Newly updated College policy documents in 2016. PMID- 27231326 TI - College releases new position statement on LGBTI mental health. PMID- 27231331 TI - Sagittal alignment of the spine-pelvis-lower extremity axis in patients with severe knee osteoarthritis: A radiographic study. AB - OBJECTIVES: Normal sagittal spine-pelvis-lower extremity alignment is crucial in humans for maintaining an ergonomic upright standing posture, and pathogenesis in any segment leads to poor balance. The present study aimed to investigate how this sagittal alignment can be affected by severe knee osteoarthritis (KOA), and whether associated changes corresponded with symptoms of lower back pain (LBP) in this patient population. METHODS: Lateral radiograph films in an upright standing position were obtained from 59 patients with severe KOA and 58 asymptomatic controls free from KOA. Sagittal alignment of the spine, pelvis, hip and proximal femur was quantified by measuring several radiographic parameters. Global balance was accessed according to the relative position of the C7 plumb line to the sacrum and femoral heads. The presence of chronic LBP was documented. Comparisons between the two groups were carried by independent samples t-tests or chi-squared test. RESULTS: Patients with severe KOA showed significant backward femoral inclination (FI), hip flexion, forward spinal inclination, and higher prevalence of global imbalance (27.1% versus 3.4%, p < 0.001) compared with controls. In addition, patients with FI of 10 degrees (n = 23) showed reduced lumbar lordosis and significant forward spinal inclination compared with controls, whereas those with FI > 10 degrees (n = 36) presented with significant pelvic anteversion and hip flexion. A total of 39 patients with KOA (66.1%) suffered from LBP. There was no significant difference in sagittal alignment between KOA patients with and without LBP. CONCLUSIONS: The sagittal alignment of spine-pelvis-lower extremity axis was significantly influenced by severe KOA. The lumbar spine served as the primary source of compensation, while hip flexion and pelvic anteversion increased for further compensation. Changes in sagittal alignment may not be involved in the pathogenesis of LBP in this patient population.Cite this article: W. J. Wang, F. Liu, Y.W. Zhu, M.H. Sun, Y. Qiu, W. J. Weng. Sagittal alignment of the spine-pelvis-lower extremity axis in patients with severe knee osteoarthritis: A radiographic study. Bone Joint Res 2016;5:198-205. DOI:10.1302/2046-3758.55.2000538. PMID- 27231332 TI - Determination of Polycyclic Aromatic Hydrocarbons in the Presence of Humic Acid in water. AB - The presence of humic acid (HA) makes it extremely difficult to determine and quantify accurately polycyclic aromatic hydrocarbons (PAHs) in aquatic environment because of their complex and strong interaction. To solve this problem, a new method was developed in this work through the combination of PARAFAC and fluorescence spectroscopy, which mainly includes: (1) the fluorescence quantum yield acquisition of PAHs with and without HA by PARAFAC; (2) the concentration score correction of PAHs in validation and test sets using the fluorescence quantum yields; and (3) the prediction of PAHs concentration in the validation and test sets in the presence of HA by corrected concentration. Using this method, the PAHs concentration on the level of ug L(-1) in the test samples with HA of 2.5 mg/L and 5.0 mg/L can be successfully predicted with the root mean square error below 0.15 ug L(-1), relative error of prediction below 4% for validation samples, recoveries of each PAH between 82.5% and 102.6% for test samples. PMID- 27231330 TI - Glutamate Delta-1 Receptor Regulates Metabotropic Glutamate Receptor 5 Signaling in the Hippocampus. AB - The delta family of ionotropic glutamate receptors consists of glutamate delta-1 (GluD1) and glutamate delta-2 receptors. We have previously shown that GluD1 knockout mice exhibit features of developmental delay, including impaired spine pruning and switch in the N-methyl-D-aspartate receptor subunit, which are relevant to autism and other neurodevelopmental disorders. Here, we identified a novel role of GluD1 in regulating metabotropic glutamate receptor 5 (mGlu5) signaling in the hippocampus. Immunohistochemical analysis demonstrated colocalization of mGlu5 with GluD1 punctas in the hippocampus. Additionally, GluD1 protein coimmunoprecipitated with mGlu5 in the hippocampal membrane fraction, as well as when overexpressed in human embryonic kidney 293 cells, demonstrating that GluD1 and mGlu5 may cooperate in a signaling complex. The interaction of mGlu5 with scaffold protein effector Homer, which regulates mechanistic target of rapamycin (mTOR) signaling, was abnormal both under basal conditions and in response to mGlu1/5 agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) in GluD1 knockout mice. The basal levels of phosphorylated mTOR and protein kinase B, the signaling proteins downstream of mGlu5 activation, were higher in GluD1 knockout mice, and no further increase was induced by DHPG. We also observed higher basal protein translation and an absence of DHPG-induced increase in GluD1 knockout mice. In accordance with a role of mGlu5-mediated mTOR signaling in synaptic plasticity, DHPG-induced internalization of surface alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunits was impaired in the GluD1 knockout mice. These results demonstrate that GluD1 interacts with mGlu5, and loss of GluD1 impairs normal mGlu5 signaling potentially by dysregulating coupling to its effector. These studies identify a novel role of the enigmatic GluD1 subunit in hippocampal function. PMID- 27231333 TI - Using Pyridinium Styryl Dyes as the Standards of Time-Resolved Instrument Response. AB - In this paper, two pyridinium styryl dyes, [2-(4-dimethylamino-phenyl)-vinyl]-1 methylpyridinium iodide (DASPMI), were synthesized and characterized by steady state fluorescence spectroscopy as well as picosecond and femtosecond time resolved fluorescence spectroscopies. Both dyes exhibit large Stokes shifts and fluorescence decays equivalent to the instrument response function (IRF) standards employed in time-correlated single-photon counting. Due to their styryl and pyridinium moieties, DASPMIs have higher peak fluorescence intensity and shorter excited-state lifetimes than iodide ion-quenched fluorophores. The fluorescence lifetimes of o-DASPMI and p-DASPMI were measured to be 6.6 ps and 12.4 ps, respectively. The fluorescence transients of these DASPMIs were used as the IRFs for iterative reconvolution fitting of the time-resolved fluorescence decay profiles of Rhodamine B (RhB), sulforhodamine B (SRB), and the SRB-SRB2m RNA aptamer complex. The quality of the fits employing the DASPMI-derived IRFs are consistently equivalent to those employing IRFs obtained from light scattering. These results indicate that DASPMI-derived IRFs may be suited for a broad range of applications in time-resolved spectroscopy and fluorescence lifetime imaging microscopy (FLIM), especially in the visible emission range. PMID- 27231334 TI - Time to be honest regarding outcomes of ACL reconstructions: should we be quoting 55-65% success rates for high-level athletes? PMID- 27231335 TI - Cardiovascular diseases in Paralympic athletes. AB - BACKGROUND: Sport participation (SP) of individuals with impairments has recently grown exponentially. Scarce scientific data, however, exist regarding cardiovascular (CV) risk associated with competitive SP. OBJECTIVE: Assessing the prevalence of CV abnormalities and the risk for SP in Paralympic athletes (PA). METHODS: PA (n=267; 76% men), aged 35+/-9 years, engaged in 18 sport disciplines, with a spectrum of lesions including: spinal cord injury (paraplegia and spina bifida) (n=116); amputation, poliomyelitis, cerebral palsy and other neuromuscular and/or skeletal disorders (Les autres) or visual impairment (n=151) entered the study. CV evaluation included history, PE, 12-lead and exercise ECG, echocardiography. Of these, 105 participated in >=2 consecutive games, and had evaluations available over a 6+/-4 year follow-up. RESULTS: Structural CV abnormalities were identified in 33 athletes (12%), including arrhythmogenic cardiomyopathies in 3, aortic root dilation in 3, valvular diseases in 7 (mitral valve prolapse in 4, bicuspid aortic valve in 3) and systemic hypertension in 11 (4%). In addition, ventricular (polymorphic, couplets or non-sustained ventricular tachycardia) or supraventricular tachyarrhythmias (atrial flutter, paroxysmal atrial fibrillation or SVT) were identified in 9 others. Over a 6-year follow-up, 6 of the 105 athletes (6%) developed CV diseases, including dilated cardiomyopathy in 1 and systemic hypertension in 5. CONCLUSIONS: PA present an unexpected high prevalence of CV abnormalities (12%), including a non-trivial proportion of diseases at risk for sudden death (2%), such as arrhythmogenic cardiomyopathies and dilated aortic root. This observation suggests that tailored recommendations for preparticipation screening and safe SP in this special athletic population are timely and appropriate. PMID- 27231336 TI - Translation and cultural appropriateness of the Autism Diagnostic Observation Schedule-2 in Afrikaans. AB - Autism Diagnostic Observation Schedule-2 is the 'gold standard' autism spectrum disorder observational assessment, and it is increasingly used in South Africa. However, its use is limited to English speakers, as it has not been translated into the country's other 10 official languages. Moreover, the cultural appropriateness of this tool has not been explored in South Africa. The Autism Diagnostic Observation Schedule-2 was translated into Afrikaans and assessed for cultural appropriateness to the 'coloured' population from low-middle socioeconomic status backgrounds in the Western Cape Province. Using a mixed methods approach, three components associated with method bias in the Autism Diagnostic Observation Schedule-2 were investigated: language used, social interactions and activities, and materials. An ethnographic investigation of play, social interaction and social activities was conducted in a community sample ( n = 40), and the Afrikaans Autism Diagnostic Observation Schedule-2 was pre-piloted in a clinical sample ( n = 7). Results highlighted unique aspects of the language ('Kaaps') that need to be considered during Autism Diagnostic Observation Schedule-2 administration. The social interaction demands of the Autism Diagnostic Observation Schedule-2 appeared appropriate, and sufficient familiarity with Autism Diagnostic Observation Schedule-2 materials and activities was found to support the use of the Autism Diagnostic Observation Schedule-2. Guidelines for administration of the Autism Diagnostic Observation Schedule-2 to this population were generated to improve cultural sensitivity and cultural appropriateness and to reduce method bias. PMID- 27231338 TI - The missing voices of Indigenous Australians with autism in research. AB - The purpose of this Letter to the Editor is to raise awareness among those who read Autism about the limited amount of peer-reviewed literature on Aboriginal and Torres Strait Islander Australians living on the autism spectrum. This letter summarises the results of our search on Pubmed and Google Scholar for peer reviewed literature on this subject. It then concludes by explaining why more research should be conducted on Aboriginal and Torres Strait Islander Australians living on the autism spectrum. PMID- 27231337 TI - Use of complementary and alternative medicine in children and adolescents with autism spectrum disorder: A systematic review. AB - Despite limited evidence, complementary and alternative medicine treatments are popular in autism spectrum disorder. The aim of this review was to summarize the available evidence on complementary and alternative medicine use frequency in autism spectrum disorder. A systematic search of three electronic databases was performed. All research studies in English or German reporting data on the frequency of complementary and alternative medicine use in individuals with autism spectrum disorder were included. Two independent reviewers searched the literature, extracted information on study design and results, and assessed study quality using an established quality assessment tool. Twenty studies with a total of 9540 participants were included. The prevalence of any complementary and alternative medicine use ranged from 28% to 95% (median: 54%). Special diets or dietary supplements (including vitamins) were the most frequent complementary and alternative medicine treatments, ranking first in 75% of studies. There was some evidence for a higher prevalence of complementary and alternative medicine use in autism spectrum disorder compared to other psychiatric disorders and the general population. Approximately half of children and adolescents with autism spectrum disorder use complementary and alternative medicine. Doctors should be aware of this and should discuss complementary and alternative medicine use with patients and their carers, especially as the evidence is mixed and some complementary and alternative medicine treatments are potentially harmful. PMID- 27231339 TI - Cluster headache: When to worry? Two case reports. AB - Background The clinical criteria for cluster headache (CH) are included in Chapter 3 of the International Classification of Headache Disorders, 3rd beta edition (ICHD-III). CH may sometimes be secondary to other pathologies. Case reports We report two patients in whom the clinical features of CH initially fulfilled the ICHD-III criteria, but who later presented some radical modifications in headache natural history as a result of a secondary pathology. The first case of CH was secondary to a pontine cavernous angioma and the second to a cerebral venous thrombosis. Conclusion We highlight the importance of clinical modifications of CH that could suggest clinical investigations should be performed or repeated to exclude a secondary pathology in a previously diagnosed cluster headache. Some of the pathological mechanisms of CH and brain lesions are discussed. PMID- 27231340 TI - Sweet Marjoram: A Review of Ethnopharmacology, Phytochemistry, and Biological Activities. AB - Origanum majorana L. commonly known as sweet marjoram has been used for variety of diseases in traditional and folklore medicines, including gastrointestinal, ocular, nasopharyngeal, respiratory, cardiac, rheumatologic, and neurological disorders. Essential oil containing monoterpene hydrocarbons and oxygenated monoterpenes as well as phenolic compounds are chemical constituents isolated and detected in O majorana Wide range of pharmacological activities including antioxidant, hepatoprotective, cardioprotective, anti-platelet, gastroprotective, antibacterial and antifungal, antiprotozoal, antiatherosclerosis, anti inflammatory, antimetastatic, antitumor, antiulcer, and anticholinesterase inhibitory activities have been reported from this plant in modern medicine. This article summarizes comprehensive information concerning traditional uses, phytochemistry, and pharmacological activities of sweet marjoram. PMID- 27231341 TI - Tankyrase Inhibitor Sensitizes Lung Cancer Cells to Endothelial Growth Factor Receptor (EGFR) Inhibition via Stabilizing Angiomotins and Inhibiting YAP Signaling. AB - YAP signaling pathway plays critical roles in tissue homeostasis, and aberrant activation of YAP signaling has been implicated in cancers. To identify tractable targets of YAP pathway, we have performed a pathway-based pooled CRISPR screen and identified tankyrase and its associated E3 ligase RNF146 as positive regulators of YAP signaling. Genetic ablation or pharmacological inhibition of tankyrase prominently suppresses YAP activity and YAP target gene expression. Using a proteomic approach, we have identified angiomotin family proteins, which are known negative regulators of YAP signaling, as novel tankyrase substrates. Inhibition of tankyrase or depletion of RNF146 stabilizes angiomotins. Angiomotins physically interact with tankyrase through a highly conserved motif at their N terminus, and mutation of this motif leads to their stabilization. Tankyrase inhibitor-induced stabilization of angiomotins reduces YAP nuclear translocation and decreases downstream YAP signaling. We have further shown that knock-out of YAP sensitizes non-small cell lung cancer to EGFR inhibitor Erlotinib. Tankyrase inhibitor, but not porcupine inhibitor, which blocks Wnt secretion, enhances growth inhibitory activity of Erlotinib. This activity is mediated by YAP inhibition and not Wnt/beta-catenin inhibition. Our data suggest that tankyrase inhibition could serve as a novel strategy to suppress YAP signaling for combinatorial targeted therapy. PMID- 27231342 TI - alphaT-Catenin Is a Constitutive Actin-binding alpha-Catenin That Directly Couples the Cadherin.Catenin Complex to Actin Filaments. AB - alpha-Catenin is the primary link between the cadherin.catenin complex and the actin cytoskeleton. Mammalian alphaE-catenin is allosterically regulated: the monomer binds the beta-catenin.cadherin complex, whereas the homodimer does not bind beta-catenin but interacts with F-actin. As part of the cadherin.catenin complex, alphaE-catenin requires force to bind F-actin strongly. It is not known whether these properties are conserved across the mammalian alpha-catenin family. Here we show that alphaT (testes)-catenin, a protein unique to amniotes that is expressed predominantly in the heart, is a constitutive actin-binding alpha catenin. We demonstrate that alphaT-catenin is primarily a monomer in solution and that alphaT-catenin monomer binds F-actin in cosedimentation assays as strongly as alphaE-catenin homodimer. The beta-catenin.alphaT-catenin heterocomplex also binds F-actin with high affinity unlike the beta catenin.alphaE-catenin complex, indicating that alphaT-catenin can directly link the cadherin.catenin complex to the actin cytoskeleton. Finally, we show that a mutation in alphaT-catenin linked to arrhythmogenic right ventricular cardiomyopathy, V94D, promotes homodimerization, blocks beta-catenin binding, and in cardiomyocytes disrupts localization at cell-cell contacts. Together, our data demonstrate that alphaT-catenin is a constitutively active actin-binding protein that can physically couple the cadherin.catenin complex to F-actin in the absence of tension. We speculate that these properties are optimized to meet the demands of cardiomyocyte adhesion. PMID- 27231343 TI - Modulation of Macrophage Inflammatory Nuclear Factor kappaB (NF-kappaB) Signaling by Intracellular Cryptococcus neoformans. AB - Cryptococcus neoformans (Cn) is a common facultative intracellular pathogen that can cause life-threatening fungal meningitis in immunocompromised individuals. Shortly after infection, Cn is detectable as both extra- and intracellular yeast particles, with Cn being capable of establishing long-lasting latent infections within host macrophages. Although recent studies have shown that shed capsular polysaccharides and intact extracellular Cn can compromise macrophage function through modulation of NF-kappaB signaling, it is currently unclear whether intracellular Cn also affects NF-kappaB signaling. Utilizing live cell imaging and computational modeling, we find that extra- and intracellular Cn support distinct modes of NF-kappaB signaling in cultured murine macrophages. Specifically, in RAW 264.7 murine macrophages treated with extracellular glucuronoxylomannan (GXM), the major Cn capsular polysaccharide, LPS-induced nuclear translocation of p65 is inhibited, whereas in cells with intracellular Cn, LPS-induced nuclear translocation of p65 is both amplified and sustained. Mathematical simulations and quantification of nascent protein expression indicate that this is a possible consequence of Cn-induced "translational interference," impeding IkappaBalpha resynthesis. We also show that long term Cn infection induces stable nuclear localization of p65 and IkappaBalpha proteins in the absence of additional pro-inflammatory stimuli. In this case, nuclear localization of p65 is not accompanied by TNFalpha or inducible NOS (iNOS) expression. These results demonstrate that capsular polysaccharides and intact intracellular yeast manipulate NF-kappaB via multiple distinct mechanisms and provide new insights into how Cn might modulate cellular signaling at different stages of an infection. PMID- 27231344 TI - Discovery of a Novel Alginate Lyase from Nitratiruptor sp. SB155-2 Thriving at Deep-sea Hydrothermal Vents and Identification of the Residues Responsible for Its Heat Stability. AB - Extremophiles are expected to represent a source of enzymes having unique functional properties. The hypothetical protein NIS_0185, termed NitAly in this study, was identified as an alginate lyase-homolog protein in the genomic database of epsilon-Proteobacteria Nitratiruptor sp. SB155-2, which was isolated from deep-sea hydrothermal vents at a water depth of 1,000 m. Among the characterized alginate lyases in the polysaccharide lyase family 7 (PL-7), the amino acid sequence of NitAly showed the highest identity (39%) with that of red alga Pyropia yezoensis alginate lyase PyAly. Recombinant NitAly (rNitAly) was successfully expressed in Escherichia coli Purified rNitAly degraded alginate in an endolytic manner. Among alginate block types, polyM was preferable to polyG and polyMG as a substrate, and its end degradation products were mainly tri-, tetra-, and penta-saccharides. The optimum temperature and pH values were 70 degrees C and around 6, respectively. A high concentration of NaCl (0.8-1.4 m) was required for maximum activity. In addition, a 50% loss of activity was observed after incubation at 67 degrees C for 30 min. Heat stability was decreased in the presence of 5 mm DTT, and Cys-80 and Cys-232 were identified as the residues responsible for heat stability but not lyase activity. Introducing two cysteines into PyAly based on homology modeling using Pseudomonas aeruginosa alginate lyase PA1167 as the template enhanced its heat stability. Thus, NitAly is a functional alginate lyase, with its unique optimum conditions adapted to its environment. These insights into the heat stability of NitAly could be applied to improve that of other PL-7 alginate lyases. PMID- 27231345 TI - Structure of a Potential Therapeutic Antibody Bound to Interleukin-16 (IL-16): MECHANISTIC INSIGHTS AND NEW THERAPEUTIC OPPORTUNITIES. AB - Interleukin-16 (IL-16) is reported to be a chemoattractant cytokine and modulator of T-cell activation, and has been proposed as a ligand for the co-receptor CD4. The secreted active form of IL-16 has been detected at sites of TH1-mediated inflammation, such as those seen in autoimmune diseases, ischemic reperfusion injury (IRI), and tissue transplant rejection. Neutralization of IL-16 recruitment to its receptor, using an anti-IL16 antibody, has been shown to significantly attenuate inflammation and disease pathology in IRI, as well as in some autoimmune diseases. The 14.1 antibody is a monoclonal anti-IL-16 antibody, which when incubated with CD4(+) cells is reported to cause a reduction in the TH1-type inflammatory response. Secreted IL-16 contains a characteristic PDZ domain. PDZ domains are typically characterized by a defined globular structure, along with a peptide-binding site located in a groove between the alphaB and betaB structural elements and a highly conserved carboxylate-binding loop. In contrast to other reported PDZ domains, the solution structure previously reported for IL-16 reveals a tryptophan residue obscuring the recognition groove. We have solved the structure of the 14.1Fab fragment in complex with IL-16, revealing that binding of the antibody requires a conformational change in the IL 16 PDZ domain. This involves the rotation of the alphaB-helix, accompanied movement of the peptide groove obscuring tryptophan residue, and consequent opening up of the binding site for interaction. Our study reveals a surprising mechanism of action for the antibody and identifies new opportunities for the development of IL-16-targeted therapeutics, including small molecules that mimic the interaction of the antibody. PMID- 27231346 TI - Crystal Structure and Function of PqqF Protein in the Pyrroloquinoline Quinone Biosynthetic Pathway. AB - Pyrroloquinoline quinone (PQQ) has received considerable attention due to its numerous important physiological functions. PqqA is a precursor peptide of PQQ with two conserved residues: glutamate and tyrosine. After linkage of the Cgamma of glutamate and Cepsilon of tyrosine by PqqE, these two residues are hypothesized to be cleaved from PqqA by PqqF. The linked glutamate and tyrosine residues are then used to synthesize PQQ. Here, we demonstrated that the pqqF gene is essential for PQQ biosynthesis as deletion of it eliminated the inhibition of prodigiosin production by glucose. We further determined the crystal structure of PqqF, which has a closed clamshell-like shape. The PqqF consists of two halves composed of an N- and a C-terminal lobe. The PqqF-N and PqqF-C lobes form a chamber with the volume of the cavity of ~9400 A(3) The PqqF structure conforms to the general structure of inverzincins. Compared with the most thoroughly characterized inverzincin insulin-degrading enzyme, the size of PqqF chamber is markedly smaller, which may define the specificity for its substrate PqqA. Furthermore, the 14-amino acid-residue-long tag formed by the N terminal tag from expression vector precisely protrudes into the counterpart active site; this N-terminal tag occupies the active site and stabilizes the closed, inactive conformation. His-48, His-52, Glu-129 and His-14 from the N terminal tag coordinate with the zinc ion. Glu-51 acts as a base catalyst. The observed histidine residue-mediated inhibition may be applicable for the design of a peptide for the inhibition of M16 metalloproteases. PMID- 27231347 TI - O-Linked N-Acetylglucosamine (O-GlcNAc) Transferase and O-GlcNAcase Interact with Mi2beta Protein at the Agamma-Globin Promoter. AB - One mode of gamma-globin gene silencing involves a GATA-1.FOG-1.Mi2beta repressor complex that binds to the -566 GATA site relative to the (A)gamma-globin gene cap site. However, the mechanism of how this repressor complex is assembled at the 566 GATA site is unknown. In this study, we demonstrate that the O-linked N acetylglucosamine (O-GlcNAc) processing enzymes, O-GlcNAc-transferase (OGT) and O GlcNAcase (OGA), interact with the (A)gamma-globin promoter at the -566 GATA repressor site; however, mutation of the GATA site to GAGA significantly reduces OGT and OGA promoter interactions in beta-globin locus yeast artificial chromosome (beta-YAC) bone marrow cells. When WT beta-YAC bone marrow cells are treated with the OGA inhibitor Thiamet-G, the occupancy of OGT, OGA, and Mi2beta at the (A)gamma-globin promoter is increased. In addition, OGT and Mi2beta recruitment is increased at the (A)gamma-globin promoter when gamma-globin becomes repressed in postconception day E18 human beta-YAC transgenic mouse fetal liver. Furthermore, we show that Mi2beta is modified with O-GlcNAc, and both OGT and OGA interact with Mi2beta, GATA-1, and FOG-1. Taken together, our data suggest that O-GlcNAcylation is a novel mechanism of gamma-globin gene regulation mediated by modulating the assembly of the GATA-1.FOG-1.Mi2beta repressor complex at the -566 GATA motif within the promoter. PMID- 27231348 TI - Structural, Functional, and Immunological Characterization of Profilin Panallergens Amb a 8, Art v 4, and Bet v 2. AB - Ragweed allergens affect several million people in the United States and Canada. To date, only two ragweed allergens, Amb t 5 and Amb a 11, have their structures determined and deposited to the Protein Data Bank. Here, we present structures of methylated ragweed allergen Amb a 8, Amb a 8 in the presence of poly(l-proline), and Art v 4 (mugwort allergen). Amb a 8 and Art v 4 are panallergens belonging to the profilin family of proteins. They share significant sequence and structural similarities, which results in cross-recognition by IgE antibodies. Molecular and immunological properties of Amb a 8 and Art v 4 are compared with those of Bet v 2 (birch pollen allergen) as well as with other allergenic profilins. We purified recombinant allergens that are recognized by patient IgE and are highly cross reactive. It was determined that the analyzed allergens are relatively unstable. Structures of Amb a 8 in complex with poly(l-proline)10 or poly(l-proline)14 are the first structures of the plant profilin in complex with proline-rich peptides. Amb a 8 binds the poly(l-proline) in a mode similar to that observed in human, mouse, and P. falciparum profilin.peptide complexes. However, only some of the residues that form the peptide binding site are conserved. PMID- 27231349 TI - Loss of Mouse P2Y6 Nucleotide Receptor Is Associated with Physiological Macrocardia and Amplified Pathological Cardiac Hypertrophy. AB - The study of the mechanisms leading to cardiac hypertrophy is essential to better understand cardiac development and regeneration. Pathological conditions such as ischemia or pressure overload can induce a release of extracellular nucleotides within the heart. We recently investigated the potential role of nucleotide P2Y receptors in cardiac development. We showed that adult P2Y4-null mice displayed microcardia resulting from defective cardiac angiogenesis. Here we show that loss of another P2Y subtype called P2Y6, a UDP receptor, was associated with a macrocardia phenotype and amplified pathological cardiac hypertrophy. Cardiomyocyte proliferation and size were increased in vivo in hearts of P2Y6 null neonates, resulting in enhanced postnatal heart growth. We then observed that loss of P2Y6 receptor enhanced pathological cardiac hypertrophy induced after isoproterenol injection. We identified an inhibitory effect of UDP on in vitro isoproterenol-induced cardiomyocyte hyperplasia and hypertrophy. The present study identifies mouse P2Y6 receptor as a regulator of cardiac development and cardiomyocyte function. P2Y6 receptor could constitute a therapeutic target to regulate cardiac hypertrophy. PMID- 27231350 TI - Peroxisome Proliferator-activated Receptor gamma Coactivator-1 alpha Isoforms Selectively Regulate Multiple Splicing Events on Target Genes. AB - Endurance and resistance exercise training induces specific and profound changes in the skeletal muscle transcriptome. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1alpha) coactivators are not only among the genes differentially induced by distinct training methods, but they also participate in the ensuing signaling cascades that allow skeletal muscle to adapt to each type of exercise. Although endurance training preferentially induces PGC-1alpha1 expression, resistance exercise activates the expression of PGC-1alpha2, -alpha3, and -alpha4. These three alternative PGC-1alpha isoforms lack the arginine/serine rich (RS) and RNA recognition motifs characteristic of PGC-1alpha1. Discrete functions for PGC-1alpha1 and -alpha4 have been described, but the biological role of PGC-1alpha2 and -alpha3 remains elusive. Here we show that different PGC 1alpha variants can affect target gene splicing through diverse mechanisms, including alternative promoter usage. By analyzing the exon structure of the target transcripts for each PGC-1alpha isoform, we were able to identify a large number of previously unknown PGC-1alpha2 and -alpha3 target genes and pathways in skeletal muscle. In particular, PGC-1alpha2 seems to mediate a decrease in the levels of cholesterol synthesis genes. Our results suggest that the conservation of the N-terminal activation and repression domains (and not the RS/RNA recognition motif) is what determines the gene programs and splicing options modulated by each PGC-1alpha isoform. By using skeletal muscle-specific transgenic mice for PGC-1alpha1 and -alpha4, we could validate, in vivo, splicing events observed in in vitro studies. These results show that alternative PGC 1alpha variants can affect target gene expression both quantitatively and qualitatively and identify novel biological pathways under the control of this system of coactivators. PMID- 27231352 TI - Complete Genome Sequences of Five Bacteriophages That Infect Rhodobacter capsulatus. AB - Five bacteriophages that infect the Rhodobacter capsulatus strain YW1 were isolated from stream water near Bloomington, Illinois, USA. Two distinct genome types are represented in the newly isolated bacteriophages. These genomes are different from other bacteriophage genomes previously described. PMID- 27231351 TI - A Cyclic di-GMP-binding Adaptor Protein Interacts with Histidine Kinase to Regulate Two-component Signaling. AB - The bacterial messenger cyclic di-GMP (c-di-GMP) binds to a diverse range of effectors to exert its biological effect. Despite the fact that free-standing PilZ proteins are by far the most prevalent c-di-GMP effectors known to date, their physiological function and mechanism of action remain largely unknown. Here we report that the free-standing PilZ protein PA2799 from the opportunistic pathogen Pseudomonas aeruginosa interacts directly with the hybrid histidine kinase SagS. We show that PA2799 (named as HapZ: histidine kinase associated PilZ) binds directly to the phosphoreceiver (REC) domain of SagS, and that the SagS-HapZ interaction is further enhanced at elevated c-di-GMP concentration. We demonstrate that binding of HapZ to SagS inhibits the phosphotransfer between SagS and the downstream protein HptB in a c-di-GMP-dependent manner. In accordance with the role of SagS as a motile-sessile switch and biofilm growth factor, we show that HapZ impacts surface attachment and biofilm formation most likely by regulating the expression of a large number of genes. The observations suggest a previously unknown mechanism whereby c-di-GMP mediates two-component signaling through a PilZ adaptor protein. PMID- 27231353 TI - Genome Sequence of Psychrobacter cibarius Strain W1. AB - Here, we report the draft genome sequence of Psychrobacter cibarius strain W1, which was isolated at a slaughterhouse in Denmark. The 3.63-Mb genome sequence was assembled into 241 contigs. PMID- 27231354 TI - Draft Genome Sequences of Five Rapidly Growing Mycobacterium Species, M. thermoresistibile, M. fortuitum subsp. acetamidolyticum, M. canariasense, M. brisbanense, and M. novocastrense. AB - We report here the draft genome sequences of five rapidly growing Mycobacterium (RGM) species potentially pathogenic to humans, M. thermoresistibile, M. fortuitum subsp. acetamidolyticum, M. canariasense, M. brisbanense, and M. novocastrense As the clinical importance of RGMs is increasingly being recognized worldwide, these sequences would contribute to further advances in RGM research. PMID- 27231355 TI - Complete Genome Sequence of a Reference Stock of Simian Immunodeficiency Virus RNA (SIVmac251/32H/L28) Determined by Deep Sequencing. AB - A reference preparation for simian immunodeficiency virus (SIV) RNA nucleic acid assays was characterized by complete genome deep sequencing. The entire coding sequence and flanking long terminal repeats, including minority species, were determined. This information will inform SIV research investigations and aid evaluation and development of amplification assays for SIV RNA quantification. PMID- 27231356 TI - Complete Genome Sequence of the Mycobacterium immunogenum Type Strain CCUG 47286. AB - Here, we report the complete genome sequence of Mycobacterium immunogenum type strain CCUG 47286, a nontuberculous mycobacterium. The whole genome has 5,573,781 bp and covers as many as 5,484 predicted genes. This genome contributes to the task of closing the still-existing gap of genomes of rapidly growing mycobacterial type strains. PMID- 27231357 TI - Variable Genome Sequences of the Murine Pneumotropic Virus (Polyomaviridae) Regulatory Region Isolated from an Infected Mouse Tissue Viral Suspension. AB - The murine pneumotropic virus genome, isolated from an infected murine tissue homogenate, was sequenced to completion. The lungs, liver, spleen, and kidneys were the source of the tissue homogenate in order to mirror the heterogeneity of the virus population in vivo The regulatory region sequence was found to be highly variable. PMID- 27231358 TI - Complete Genome Sequence of Porcine Deltacoronavirus Isolated in Thailand in 2015. AB - In Thailand, porcine deltacoronavirus (PDCoV) was first identified in November 2015. The virus was isolated from piglets experiencing diarrhea outbreak. Herein, the full-length genome sequence of the Thai PDCoV isolate P23_15_TT_1115 is reported. The results provide a clearer understanding of the molecular characteristics of PDCoV in Thailand. PMID- 27231359 TI - Complete Genome Sequences of the Carlavirus Sweet potato chlorotic fleck virus from East Timor and Australia. AB - We present here the first complete genome sequences of Sweet potato chlorotic fleck virus (SPCFV) from sweet potato in Australia and East Timor, and we compare these with four complete SPCFV genomes from South Korea and one from Uganda. The Australian, East Timorese, South Korean, and Ugandan genomes differed considerably from each other. PMID- 27231360 TI - Whole-Genome Sequence of Rummeliibacillus stabekisii Strain PP9 Isolated from Antarctic Soil. AB - The whole genome of Rummeliibacillus stabekisii PP9, isolated from a soil sample from Antarctica, consists of a circular chromosome of 3,412,092 bp and a circular plasmid of 8,647 bp, with 3,244 protein-coding genes, 12 copies of the 16S-23S-5S rRNA operon, 101 tRNA genes, and 6 noncoding RNAs (ncRNAs). PMID- 27231361 TI - Genome Sequence of Madurella mycetomatis mm55, Isolated from a Human Mycetoma Case in Sudan. AB - We present the first genome sequence for a strain of the main mycetoma causative agent, Madurella mycetomatis This 36.7-Mb genome sequence will offer new insights into the pathogenesis of mycetoma, and it will contribute to the development of better therapies for this neglected tropical disease. PMID- 27231362 TI - Draft Genome Sequence of a Multidrug-Resistant Klebsiella quasipneumoniae subsp. similipneumoniae Isolate from a Clinical Source. AB - We report here the draft genome sequence of a multidrug-resistant clinical isolate of Klebsiella quasipneumoniae subsp. similipneumoniae, KP_Z4175. This strain, isolated as part of a hospital infection-control screening program, is resistant to multiple beta-lactam antibiotics, aminoglycosides, and trimethoprim sulfamethoxazole. PMID- 27231363 TI - Draft Genome Sequence of Bacillus subtilis subsp. natto Strain CGMCC 2108, a High Producer of Poly-gamma-Glutamic Acid. AB - Here, we report the 4.1-Mb draft genome sequence of Bacillus subtilis subsp. natto strain CGMCC 2108, a high producer of poly-gamma-glutamic acid (gamma-PGA). This sequence will provide further help for the biosynthesis of gamma-PGA and will greatly facilitate research efforts in metabolic engineering of B. subtilis subsp. natto strain CGMCC 2108. PMID- 27231364 TI - Complete Genome Sequence and Methylome Analysis of Bacillus globigii ATCC 49760. AB - Bacillus subtilis (Ehrenburg) Cohn ATCC 49760, deposited as Bacillus globigii, is the source strain for the restriction enzymes BglI and BglII. Its complete sequence and full methylome were determined using single-molecule real-time (SMRT) sequencing. PMID- 27231365 TI - Improved High-Quality Draft Genome Sequence of Pseudomonas fluorescens KENGFT3. AB - Pseudomonas sp. strain KENGFT3 inhibits the growth of Phytophthora infestans and is a potentially useful biopesticide for plant diseases, including potato late blight. We sequenced the 6.2-Mbp genome of this strain and assembled it into a single scaffold with 9 contigs. KENGFT3 is related to previously sequenced strains of P. fluorescens. PMID- 27231366 TI - Genome Sequence of the Fish Pathogen Flavobacterium columnare Genomovar II Strain 94-081. AB - Flavobacterium columnare causes columnaris disease in fresh and brackish water worldwide. F. columnare strain 94-081 was isolated from a diseased channel catfish in 1994; its genome sequence is the first completed genomovar II sequence. PMID- 27231367 TI - Draft Genome Sequence of Aeromonas hydrophila TN97-08. AB - Aeromonas hydrophila is an opportunistic pathogen residing in freshwater environments that causes infection in fish and mammals. Here, we report the draft genome sequence of A. hydrophila strain TN97-08 isolated from a diseased bluegill (Lepomis macrochirus) in 1997. PMID- 27231369 TI - Complete Genome Sequence of Klebsiella quasipneumoniae subsp. similipneumoniae Strain ATCC 700603. AB - Klebsiella quasipneumoniae subsp. similipneumoniae strain ATCC 700603, formerly known as K. pneumoniae K6, is known for producing extended-spectrum beta lactamase (ESBL) enzymes that can hydrolyze oxyimino-beta-lactams, resulting in resistance to these drugs. We herein report the complete genome of strain ATCC 700603 and show that the ESBL genes are plasmid-encoded. PMID- 27231368 TI - Draft Genome Sequence of Frankia Strain G2, a Nitrogen-Fixing Actinobacterium Isolated from Casuarina equisetifolia and Able To Nodulate Actinorhizal Plants of the Order Rhamnales. AB - Frankia sp. strain G2 was originally isolated from Casuarina equisetifolia and is characterized by its ability to nodulate actinorhizal plants of the Rhamnales order, but not its original host. It represents one of the largest Frankia genomes so far sequenced (9.5 Mbp). PMID- 27231370 TI - Complete Genome Sequence of Pseudorabies Virus Reference Strain NIA3 Using Single Molecule Real-Time Sequencing. AB - Pseudorabies virus (PRV) is the causative agent of Aujeszky's disease in pigs. PRV strains are also used as model organisms for the study of alphaherpesvirus biology or for neuronal pathway studies. We present here the complete genome of the virulent wild-type PRV reference strain NIA3, determined by single-molecule real-time sequencing. PMID- 27231371 TI - Draft Genome Sequence of Mycobacterium houstonense Strain ATCC 49403T. AB - Mycobacterium houstonense is a nontuberculous species rarely responsible for human infection. The draft genome of M. houstonense ATCC 49403(T) comprises 6,451,020 bp, exhibiting a 66.96% G+C content, 5,881 protein-coding genes, and 65 predicted RNA genes. PMID- 27231372 TI - Genome Sequence of the Acetogenic Bacterium Moorella mulderi DSM 14980T. AB - Here, we report the draft genome sequence of Moorella mulderi DSM 14980(T), a thermophilic acetogenic bacterium, which is able to grow autotrophically on H2 plus CO2 using the Wood-Ljungdahl pathway. The genome consists of a circular chromosome (2.99 Mb). PMID- 27231373 TI - Complete Genome Sequence of Pseudomonas fluorescens LBUM636, a Strain with Biocontrol Capabilities against Late Blight of Potato. AB - Herein provided is the full-genome sequence of Pseudomonas fluorescens LBUM636. This strain is a plant growth-promoting rhizobacterium (PGPR) which produces phenazine-1-carboxylic acid, an antibiotic involved in the biocontrol of numerous plant pathogens, including late blight of potato caused by the plant pathogen Phytophthora infestans. PMID- 27231374 TI - Draft Genome Sequences of Six Novel Bacterial Isolates from Chicken Ceca. AB - The chicken is the most common domesticated animal and the most abundant bird in the world. However, the chicken gut is home to many previously uncharacterized bacterial taxa. Here, we report draft genome sequences from six bacterial isolates from chicken ceca, all of which fall outside any named species. PMID- 27231375 TI - First Complete Genome Sequence of Pepper vein yellows virus from Australia. AB - We present here the first complete genomic RNA sequence of the polerovirus Pepper vein yellows virus (PeVYV) obtained from a pepper plant in Australia. We compare it with complete PeVYV genomes from Japan and China. The Australian genome was more closely related to the Japanese than the Chinese genome. PMID- 27231376 TI - Draft Genome Sequence of Mycobacterium interjectum Strain ATCC 51457T. AB - Mycobacterium interjectum is a nontuberculosis species rarely responsible for human infection. The draft genome of M. interjectum ATCC 51457(T) comprises 5,927,979 bp, exhibiting 67.91% G+C content, 5,314 protein-coding genes, and 51 predicted RNA genes. PMID- 27231377 TI - Complete Coding Sequences of Six Toscana Virus Strains Isolated from Human Patients in France. AB - Toscana virus (TOSV) is an arthropod-borne phlebovirus belonging to the Sandfly fever Naples virus species (genus Phlebovirus, family Bunyaviridae). Here, we report the complete coding sequences of six TOSV strains isolated from human patients having acquired the infection in southeastern France during a 12-year period. PMID- 27231378 TI - Whole-Genome Sequencing of a Campylobacter jejuni Strain Isolated from Retail Chicken Meat Reveals the Presence of a Megaplasmid with Mu-Like Prophage and Multidrug Resistance Genes. AB - Genome sequencing of Campylobacter jejuni strain T1-21 isolated from retail chicken meat revealed the presence of a chromosome of 1,565,978 bp and a megaplasmid of 82,732 bp that contains Mu-like prophage and multidrug resistance genes. This is the first reported sequence of a Campylobacter megaplasmid >55 kb. PMID- 27231379 TI - First Complete Genome Sequence of a Subdivision 6 Acidobacterium Strain. AB - Although ubiquitous and abundant in soils, acidobacteria have mostly escaped isolation and remain poorly investigated. Only a few cultured representatives and just eight genomes of subdivisions 1, 3, and 4 are available to date. Here, we determined the complete genome sequence of strain HEG_-6_39, the first genome of Acidobacterium subdivision 6. PMID- 27231380 TI - Erratum for Abdul Majid et al., Draft Whole-Genome Sequence of Urease-Producing Sporosarcina koreensis. PMID- 27231381 TI - Erratum for Walker et al., Full Genome of Phialocephala scopiformis DAOMC 229536, a Fungal Endophyte of Spruce Producing the Potent Anti-Insectan Compound Rugulosin. PMID- 27231382 TI - Promoting our expertise: State of the art and the science. PMID- 27231383 TI - Faire valoir notre expertise: l'etat actuel de l'art et de la science. PMID- 27231384 TI - Contribution of occupational therapy to the assessment of competence: A case study AB - INTRODUCTION: Many occupational therapists contribute to the assessment of competence to take care of oneself and manageone's affairs, but few guidelines exist regarding this practice with adults who have experienced a traumatic brain injury (TBI). PURPOSE: This study explored the ability of the Instrumental Activities of Daily Living Profile (IADL Profile) to capturecompetence following a TBI. METHOD: Task performance on the IADL Profile of a 46-year-old man (ML) who was found to be incompetent following a severe TBI was compared to eight control subjects (mean age 49.3 +/- 4.2 years). The IADL Profile scores, observable behaviours, and verbalizations were compared using descriptive statistics (M, SD) and qualitative analyses. RESULTS: The independence level of ML was lower than that of the control subjects on seven of the eight tasks of the IADL Profile (p < .05), especially for preparing a hot meal and creating a budget. ML demonstrated difficulties that impacted his performance on many tasks, and he had difficulty critiquing his results. IMPLICATIONS: The IADL Profile could be used as part of a functional assessment to document competence. PMID- 27231386 TI - Stanford Chronic Disease Self-Management Program in myotonic dystrophy: New opportunities for occupational therapists: Stanford Chronic Disease Self Management Program dans la dystrophie myotonique : De nouvelles opportunites pour les ergotherapeutes. AB - BACKGROUND: Chronic disease self-management is a priority in health care. Personal and environmental barriers for populations with neuromuscular disorders might diminish the efficacy of self-management programs, although they have been shown to be an effective intervention in many populations. Owing to their occupational expertise, occupational therapists might optimize self-management program interventions. PURPOSE: This study aimed to adapt the Stanford Chronic Disease Self-Management Program (CDSMP) for people with myotonic dystrophy type 1 (DM1) and assess its acceptability and feasibility in this population. METHOD: Using an adapted version of the Stanford CDSMP, a descriptive pilot study was conducted with 10 participants (five adults with DM1 and their caregivers). A semi-structured interview and questionnaires were used. FINDINGS: The Stanford CDSMP is acceptable and feasible for individuals with DM1. However, improvements are required, such as the involvement of occupational therapists to help foster concrete utilization of self-management strategies into day-to-day tasks using their expertise in enabling occupation. IMPLICATIONS: Although adaptations are needed, the Stanford CDSMP remains a relevant intervention with populations requiring the application of self-management strategies. PMID- 27231387 TI - The Single-Case Reporting Guideline In Behavioural Interventions (SCRIBE) 2016 statement AB - We developed a reporting guideline to provide authors with guidance about what should be reported when writing a paper for publication in a scientific journal using a particular type of research design: the single-case experimental design. This report describes the methods used to develop the Single-Case Reporting guideline In BEhavioural interventions (SCRIBE) 2016. As a result of 2 online surveys and a 2-day meeting of experts, the SCRIBE 2016 checklist was developed, which is a set of 26 items that authors need to address when writing about single case research. This article complements the more detailed SCRIBE 2016 Explanation and Elaboration article (Tate et al., 2016) that provides a rationale for each of the items and examples of adequate reporting from the literature. Both these resources will assist authors to prepare reports of single-case research with clarity, completeness, accuracy, and transparency. They will also provide journal reviewers and editors with a practical checklist against which such reports may be critically evaluated. We recommend that the SCRIBE 2016 is used by authors preparing manuscripts describing single-case research for publication, as well as journal reviewers and editors who are evaluating such manuscripts.Reporting guidelines, such as the Consolidated Standards of Reporting Trials (CONSORT) Statement, improve the reporting of research in the medical literature (Turner et al., 2012). Many such guidelines exist and the CONSORT Extension to Nonpharmacological Trials (Boutron et al., 2008) provides suitable guidance for reporting between-groups intervention studies in the behavioral sciences. The CONSORT Extension for N-of-1 Trials (CENT 2015) was developed for multiple crossover trials with single individuals in the medical sciences (Shamseer et al., 2015; Vohra et al., 2015), but there is no reporting guideline in the CONSORT tradition for single-case research used in the behavioral sciences. We developed the Single-Case Reporting guideline In BEhavioural interventions (SCRIBE) 2016 to meet this need. This Statement article describes the methodology of the development of the SCRIBE 2016, along with the outcome of 2 Delphi surveys and a consensus meeting of experts. We present the resulting 26-item SCRIBE 2016 checklist. The article complements the more detailed SCRIBE 2016 Explanation and Elaboration article (Tate et al., 2016) that provides a rationale for each of the items and examples of adequate reporting from the literature. Both these resources will assist authors to prepare reports of single-case research with clarity, completeness, accuracy, and transparency. They will also provide journal reviewers and editors with a practical checklist against which such reports may be critically evaluated. PMID- 27231388 TI - Prognostic Value of Serum Procalcitonin After Orthopedic Surgery in the Elderly Population. AB - Background: Orthopedic surgery is more and more frequent in the older patients and is associated with a high mortality rate. Although serum procalcitonin levels are associated with prognosis in young adults, data are still lacking in the elderly population, and especially after surgery. The main objective of this study was to determine the prognostic value of procalcitonin levels in a large geriatric orthopedic population, and we compared it with clinical variables and biomarkers. Methods: This is a prospective study including patients admitted in our dedicated geriatric postoperative unit, after orthopedic surgery with immediate postoperative measured procalcitonin levels. Collected data included age, sex, medical history, functional status (activities of daily living [ADL]), fracture type, Cumulative Illness Rating scale (CIRS), postoperative complications, and biological data. The primary endpoint was the 30-day mortality. Results: 436 patients (age 85+/-6 years) were included. Hip fracture surgery was the most frequent (n = 310; 71%), and the 30-day mortality rate was 6.9%. Compared with C-reactive protein (CRP), albumin, CIRS, and ADL, procalcitonin had the highest area under the receiver operating characteristic curve for predicting 30-day mortality (0.74; 95% CI: 0.70-0.78). Using a cutoff at 1 ug/L, procalcitonin was more specific than CIRS to predict 30-day mortality (92 vs 77%; p < .001). In a multivariable analysis, procalcitonin level higher than 0.39 ug/L is a significant predictor of mortality within 30 days (odds ratio 3.84; 95% CI: 1.61-9.14, p = .002). Conclusion: Elevated procalcitonin values were strongly and significantly associated with mortality within 30 days in older patients after orthopedic surgery. PMID- 27231389 TI - Corrigendum. AB - Merman E, Siddha S, Keystone JS, Al Habeeb A, Ghazarian D, Cy A, Rosen CF. Cutaneous strongyloides infection postchemotherapy. J Cutan Med Surg. 2016;20:337 339. Original DOI: 10.1177/1203475416633693. PMID- 27231390 TI - Tanaka KR, Valentine WN, Miwa S. Pyruvate kinase (PK) deficiency hereditary nonspherocytic hemolytic anemia. Blood. 1962;19(3):267-295. PMID- 27231391 TI - Knock-in editing: it functionally corrects! PMID- 27231392 TI - Virus fuels NK cell killing of leukemia. PMID- 27231393 TI - Mouse models of venous thrombosis are not equal. PMID- 27231394 TI - The lived experience of individuals in cardiac rehabilitation who have a positive outlook on their cardiac recovery: A phenomenological inquiry. AB - BACKGROUND: Cardiac rehabilitation is often under-utilized despite its well-known benefits. Individuals with cardiac disease who exhibit a positive outlook often experience improved health outcomes. This study tried to explore the question: "What are the lived experiences of cardiac recovery in cardiac rehabilitation individuals with a predominantly positive outlook in the context of an acute cardiac event?" AIMS: Our primary aim explored the experiences of cardiac recovery in cardiac rehabilitation participants with a predominantly positive outlook, within the context of an acute cardiac event, including exploring barriers and facilitators of cardiac recovery. Our secondary aim explored how a positive outlook impacted completion of phase two of the cardiac rehabilitation program. METHODS: Husserlian phenomenology guided this study. A purposive sample of 10 individuals who had experienced an acute cardiac event and had a predominantly positive outlook were interviewed. Data were analyzed using Colaizzi's method. RESULTS: Three themes emerged from the data. The first was "choosing life over death," where participants discussed how they made a decision to improve their health. The second theme was "learning to live a new self," where participants described the changes they had to make in order to improve their health. The third theme was "a life-transforming cardiac event" where participants shared how the cardiac event had changed their life. CONCLUSION: The participants' decisions to choose to live, led them to embrace their cardiac recovery. It is important for nurses to identify individuals in cardiac rehabilitation that need additional support. In addition, alternative models of cardiac rehabilitation programs need to be explored. PMID- 27231395 TI - Psychometric assessment of the Cardiac Depression Scale Short Form in cardiac outpatients. AB - BACKGROUND: Depression is common in patients with cardiovascular disease and is a risk marker for increased mortality. The valid and reliable detection of depression is fundamental to the appropriate management of these patients. AIM: The aim of this study was to evaluate the psychometric characteristics of the Cardiac Depression Scale Short Form 1 (DS-SF1) and the Cardiac Depression Scale Short Form 2 (DS-SF2) for screening cardiac outpatients in clinical settings. METHODS: Adult cardiac outpatients attending a cardiovascular clinic completed the Cardiac Depression Scale (CDS), two versions of the DS-SF (DS-SF1 and DS-SF2) and the Physical Health Questionnaire 2 (PHQ2-Y/N) prior to their cardiac consultation. RESULTS: Data from 326 patients (224 men; mean+/-SD age 66.25+/ 14.39 years) were analysed. The DS-SF1 (mean score 16.28+/-5.70) had good construct validity with the CDS ( r=0.77; p<0.0001), adequate convergence with the PHQ2-Y/N ( r=0.59; p<0.0001) and good internal consistency (alpha=0.73). The DS-SF2 (mean score 15.80+/-6.80) had a better construct validity with the CDS ( r=0.84; p<0.0001) and the PHQ2-Y/N ( r=0.69; p<0.0001) and better internal consistency (alpha=0.82). The DS-SF2 showed strong criterion validity with the CDS with a DS-SF2 ?15 cut-point yielding 90% sensitivity and 73% specificity (area under the curve 0.92) for detecting depression (CDS ?95). CONCLUSION: These findings confirm the excellent psychometric properties of the DS-SF2 as an ideal tool for screening depression in cardiac patients in clinical practice. The DS SF2 should be regarded as the definitive version of the DS-SF. PMID- 27231396 TI - Development and validation of an instrument to assess patients' appraisal, emotions and action tendencies preceding care-seeking in acute myocardial infarction: The PA-AMI questionnaire. AB - BACKGROUND: Reducing patient delay for patients afflicted by an acute myocardial infarction is a task of great complexity, which might be alleviated if more factors that influence this delay could be identified. Although a number of self reported instruments associated with patient delay exist, none of these taps the content of the appraisal process related to patients' subjective emotions. AIM: The aim of this study was to develop and validate a questionnaire aimed at assessing patients' appraisal, emotions and action tendencies when afflicted by an acute myocardial infarction. METHODS: An item pool was generated based on themes conceptualized in a recent qualitative study of acute myocardial infarction patients' thoughts, feelings and actions preceding the decision to seek medical care. The 'Think-Aloud Protocol' and test-retest analysis at item level were performed. The modified item pool was administered to 96 patients when treated for acute myocardial infarction. Explorative factor analysis and principal component analysis with the non-linear iterative partial least squares algorithm were performed to examine the underlying factor structure of the items. RESULTS: The findings indicated three core dimensions corresponding to three subscales, namely, 'symptom appraisal'; 'perceived inability to act'; 'autonomy preservation'. The results demonstrated acceptable measures of reliability and validity Conclusions: The PA-AMI questionnaire demonstrated satisfactory psychometric properties. Assessment of the included core dimensions may contribute to greater understanding of the appraisal processes for patients afflicted by an acute myocardial infarction. PMID- 27231397 TI - A snapshot in time: Does exercise training impact the muscle circadian clock in patients? PMID- 27231398 TI - In their own words: The experience and needs of children in younger-onset Alzheimer's disease and other dementias families. AB - Because of the age of persons diagnosed with younger-onset Alzheimer's disease or other dementias (YOD), an important and as yet relatively little explored area of YOD, particularly in the United States, is the impact on young children of having a parent with YOD. After reviewing the small but growing research in this area, we report on findings from 12 in-depth interviews with children and well-parents in families with a parent with YOD on the experience and needs of children having a parent with this diagnosis. Children report disruption in many aspects of their lives: their developmental trajectory, emotional and psychological development, familial and broader social relationships, and financial stability. Despite these significant disruptions, and a dearth of information, resources, and services tailored to their individual and familial needs, these children demonstrate remarkable resilience and self-awareness. We discuss implications for interventions with these families. PMID- 27231399 TI - STEM Training and Early Career Outcomes of Female and Male Graduate Students: Evidence from UMETRICS Data linked to the 2010 Census. PMID- 27231400 TI - Lifetime Socioeconomic Status, Historical Context, and Genetic Inheritance in Shaping Body Mass in Middle and Late Adulthood. AB - This study demonstrates body mass in middle and late adulthood as a consequence of the complex interplay among individuals' genes, lifetime socioeconomic experiences, and the historical context in which they live. Drawing on approximately 9,000 genetic samples from the Health and Retirement Study, we first investigate how socioeconomic status (SES) over the life course moderates the impact of 32 established obesity-related genetic variants on body mass index (BMI) in middle and late adulthood. Further, we consider differences across birth cohorts in the genetic influence on BMI and cohort variations in the moderating effects of life-course SES on the genetic influence. Our analyses suggest that persistently low SES over the life course or downward mobility (e.g., high SES in childhood but low SES in adulthood) amplified the genetic influence on BMI, while persistently high SES or upward mobility (e.g., low SES in childhood but high SES in adulthood) compensated for such influence. For more recent birth cohorts, while the genetic influence on BMI became stronger, the moderating effects of lifetime SES on the genetic influence were weaker compared to earlier cohorts. We discuss these findings in light of social changes during the obesity epidemic in the United States. PMID- 27231401 TI - S1-Guideline: Management of Late-term and Post-term Pregnancy: Short version - AWMF Registry Number: 015/065. PMID- 27231402 TI - Ultrasensitive impedimetric lectin based biosensor for glycoproteins containing sialic acid. AB - We report on an ultrasensitive label-free lectin-based impedimetric biosensor for the determination of the sialylated glycoproteins fetuin and asialofetuin. A sialic acid binding agglutinin from Sambucus nigra I was covalently immobilised on a mixed self-assembled monolayer (SAM) consisting of 11-mercaptoundecanoic acid and 6-mercaptohexanol. Poly(vinyl alcohol) was used as a blocking agent. The sensor layer was characterised by atomic force microscopy, electrochemical impedance spectroscopy and X-ray photoelectron spectroscopy. The biosensor exhibits a linear range that spans 7 orders of magnitude for both glycoproteins, with a detection limit as low as 0.33 fM for fetuin and 0.54 fM for asialofetuin. We also show, by making control experiments with oxidised asialofetuin, that the biosensor is capable of quantitatively detecting changes in the fraction of sialic acid on glycoproteins. We conclude that this work lays a solid foundation for future applications of such a biosensor in terms of the diagnosis of diseases such as chronic inflammatory rheumatoid arthritis, genetic disorders and cancer, all of which are associated with aberrant glycosylation of protein biomarkers. PMID- 27231403 TI - The Predictive Validity of Savry Ratings for Assessing Youth Offenders in Singapore: A Comparison With YLS/CMI Ratings. AB - Empirical support for the usage of the SAVRY has been reported in studies conducted in many Western contexts, but not in a Singaporean context. This study compared the predictive validity of the SAVRY ratings for violent and general recidivism against the Youth Level of Service/Case Management Inventory (YLS/CMI) ratings within the Singaporean context. Using a sample of 165 male young offenders (Mfollow-up = 4.54 years), results showed that the SAVRY Total Score and Summary Risk Rating, as well as YLS/CMI Total Score and Overall Risk Rating, predicted violent and general recidivism. SAVRY Protective Total Score was only significantly predictive of desistance from general recidivism, and did not show incremental predictive validity for violent and general recidivism over the SAVRY Total Score. Overall, the results suggest that the SAVRY is suited (to varying degrees) for assessing the risk of violent and general recidivism in young offenders within the Singaporean context, but might not be better than the YLS/CMI. PMID- 27231406 TI - Combined registration and motion correction of longitudinal retinal OCT data. AB - Optical coherence tomography (OCT) has become an important modality for examination of the eye. To measure layer thicknesses in the retina, automated segmentation algorithms are often used, producing accurate and reliable measurements. However, subtle changes over time are difficult to detect since the magnitude of the change can be very small. Thus, tracking disease progression over short periods of time is difficult. Additionally, unstable eye position and motion alter the consistency of these measurements, even in healthy eyes. Thus, both registration and motion correction are important for processing longitudinal data of a specific patient. In this work, we propose a method to jointly do registration and motion correction. Given two scans of the same patient, we initially extract blood vessel points from a fundus projection image generated on the OCT data and estimate point correspondences. Due to saccadic eye movements during the scan, motion is often very abrupt, producing a sparse set of large displacements between successive B-scan images. Thus, we use lasso regression to estimate the movement of each image. By iterating between this regression and a rigid point-based registration, we are able to simultaneously align and correct the data. With longitudinal data from 39 healthy control subjects, our method improves the registration accuracy by 50% compared to simple alignment to the fovea and 22% when using point-based registration only. We also show improved consistency of repeated total retina thickness measurements. PMID- 27231404 TI - Emotional Reactivity and Internalizing Symptoms: Moderating Role of Emotion Regulation. AB - Emotion dysregulation has been associated with increases in many forms of psychopathology in adolescents and adults. The development of effective emotion regulation skills is important during adolescence, especially as stressful life events increase during this time. The current study examined two emotion regulation strategies, cognitive reappraisal and affective suppression, in interaction with self-report and biological measures of emotional reactivity as predictors of internalizing symptoms. A community sample of adolescents (n = 127), at an age of risk for depression and anxiety, completed self-report measures of emotional reactivity and internalizing symptoms. In addition, they completed a modified social stress task and were assessed on biological measures of reactivity and regulation. Findings suggested that the trait tendency to reappraise was associated with a reduced impact of emotional reactivity on depressive, but not anxiety symptoms. Implications for shared and specific aspects of emotional reactivity and regulation are discussed. PMID- 27231405 TI - Recovery of high-quality RNA from laser capture microdissected human and rodent pancreas. AB - Laser capture microdissection (LCM) is a powerful method to isolate specific populations of cells for subsequent analysis such as gene expression profiling, for example, microarrays or ribonucleic (RNA)-Seq. This technique has been applied to frozen as well as formalin-fixed, paraffin-embedded (FFPE) specimens with variable outcomes regarding quality and quantity of extracted RNA. The goal of the study was to develop the methods to isolate high-quality RNA from islets of Langerhans and pancreatic duct glands (PDG) isolated by LCM. We report an optimized protocol for frozen sections to minimize RNA degradation and maximize recovery of expected transcripts from the samples using quantitative real-time polymerase chain reaction (RT-PCR) by adding RNase inhibitors at multiple steps during the experiment. This technique reproducibly delivered intact RNA (RIN values 6-7). Using quantitative RT-PCR, the expected profiles of insulin, glucagon, mucin6 (Muc6), and cytokeratin-19 (CK-19) mRNA in PDGs and pancreatic islets were detected. The described experimental protocol for frozen pancreas tissue might also be useful for other tissues with moderate to high levels of intrinsic ribonuclease (RNase) activity. PMID- 27231407 TI - Characterization and diversity of rhizobia nodulating selected tree legumes in Ghana. AB - The study was conducted to assess the characteristics and diversity of the rhizobia that nodulate some prominent tree legumes in three soils of Ghana. Five introduced and/or indigenous tree legumes were initially assessed for nodulation in three Ghanaian soils. After 12 weeks of growth in nursery pots the 200 rhizobial strains isolated from their nodules were characterized culturally, metabolically and phenotypically. Sixty of these isolates were selected randomly and their genotypic characteristics determined using PCR-RFLP of 16S rRNA and intergenic spacer (ITS) genes. Each tree legume was nodulated by isolates classified as fast or very fast-growers or by isolates classified as slow- or very slow-growers with 54 % of all the 200 isolates belonging to fast- or very fast-growers. Morphologically, eighty five percent of the colonies formed on yeast extract mannitol agar were wet and gummy while 70 % were acid tolerant, i.e. they were able to grow at a pH of 3.5. Combined restriction of the 16S rRNA genes of the 60 rhizobial isolates with five restriction enzymes clearly distinguished seven different clusters at 80 % similarity level. The majority of A. lebbeck isolates were distinct from those of the Acacias and L. leucocephala. The M. thonningii isolates were related to L. leucocephala isolates. Simple PCR of the ITS DNA provided several distinct band sizes indicating great variation among the isolates and restriction of the ITS with three different enzymes did not yield many further differences. Molecular techniques revealed a great diversity among the rhizobia that nodulate tree legumes in the tropics and this may explain why many introduced and/or indigenous trees are able to form nodules with indigenous rhizobia in this region. PMID- 27231408 TI - Weekly fluctuations in nonjudging predict borderline personality disorder feature expression in women. AB - OBJECTIVES: Borderline personality disorder (BPD) features have been linked to deficits in mindfulness, or nonjudgmental attention to present-moment stimuli. However, no previous work has examined the role of fluctuations in mindfulness over time in predicting BPD features. The present study examines the impact of both between-person differences and within-person changes in mindfulness. DESIGN: 40 women recruited to achieve a flat distribution of BPD features completed 4 weekly assessments of mindfulness (Five Facet Mindfulness Questionnaire; FFMQ) and BPD features. Multilevel models predicted each outcome from both 1) a person's average levels of each facet and 2) weekly deviations from a person's average for each facet. RESULTS: Average acting with awareness, nonjudging, and nonreactivity predicted lower BPD features at the between-person level, and weekly deviations above one's average (i.e., higher-than-usual) nonjudging predicted lower BPD feature expression at the within-person level. CONCLUSIONS: Within-person fluctuations in the nonjudging facet of mindfulness may be relevant to the daily expression of BPD features over and above dispositional mindfulness. PMID- 27231409 TI - Executive Functioning and School Adjustment: The Mediational Role of Pre kindergarten Learning-related Behaviors. AB - 164 four-year-old children (14% Latino American, 30% African American, 56% European American; 57% girls) in 22 Head Start classrooms were followed through third grade. Growth curve models were used to estimate the predictive associations between pre-kindergarten executive function (EF) skills and trajectories of academic skill development (math, literacy, overall academic functioning) and social-emotional adjustment at school (social competence, aggression), controlling for child sex, race, verbal IQ, and pre-kindergarten baseline scores. Direct developmental pathways were examined, along with indirect pathways, in which the association between preschool EF and elementary school adjustment was mediated by classroom learning behaviors. Preschool EF significantly predicted later math skills, academic functioning, and social competence, and marginally predicted later literacy skills. Preschool learning behaviors fully mediated the association between EF and later literacy skills and social competence, but did not mediate associations between EF and later math skills or academic functioning. Implications for developmental theory and early education are discussed. PMID- 27231410 TI - Range and niche shifts in response to past climate change in the desert horned lizard (Phrynosoma platyrhinos). AB - During climate change, species are often assumed to shift their geographic distributions (geographic ranges) in order to track environmental conditions - niches - to which they are adapted. Recent work, however, suggests that the niches do not always remain conserved during climate change but shift instead, allowing populations to persist in place or expand into new areas. We assessed the extent of range and niche shifts in response to the warming climate after the Last Glacial Maximum (LGM) in the desert horned lizard (Phrynosoma platyrhinos), a species occupying the western deserts of North America. We used a phylogeographic approach with mitochondrial DNA sequences to approximate the species range during the LGM by identifying populations that exhibit a genetic signal of population stability versus those that exhibit a signal of a recent (likely post-LGM) geographic expansion. We then compared the climatic niche that the species occupies today with the niche it occupied during the LGM using two models of simulated LGM climate. The genetic analyses indicated that P. platyrhinos persisted within the southern Mojave and Sonoran deserts throughout the latest glacial period and expanded from these deserts northwards, into the western and eastern Great Basin, after the LGM. The climatic niche comparisons revealed that P. platyrhinos expanded its climatic niche after the LGM towards novel, warmer and drier climates that allowed it to persist within the southern deserts. Simultaneously, the species shifted its climatic niche towards greater temperature and precipitation fluctuations after the LGM. We concluded that climatic changes at the end of the LGM promoted both range and niche shifts in this lizard. The mechanism that allowed the species to shift its niche remains unknown, but phenotypic plasticity likely contributes to the species ability to adjust to climate change. PMID- 27231411 TI - Gender Moderates the Progression from Fearful Temperament to Social Withdrawal through Protective Parenting. AB - Child gender may exert its influence on development, not as a main effect, but as a moderator among predictors and outcomes. We examined this notion in relations among toddler fearful temperament, maternal protective parenting, maternal accuracy in predicting toddler distress to novelty, and child social withdrawal. In two multi-method, longitudinal studies of toddlers (24 months at Time 1; ns = 93 and 117, respectively) and their mothers, few main effect gender differences occurred. Moderation existed in both studies: only for highly accurate mothers of boys, fearful temperament related to protective parenting, which then predicted later social withdrawal. Thus, studying only main-effect gender differences may obscure important differences in how boys and girls develop from fearful temperament to later social withdrawal. PMID- 27231412 TI - A New Provocative Test for Glaucoma. AB - PURPOSE: To compare the effects of the water-drinking test (WDT) with the 30 degrees inverted body position test on intraocular pressure (IOP) in normal patients, suspected glaucoma patients and glaucoma patients. MATERIALS AND METHODS: Based on clinical evaluation of the optic disk, IOP, and standard achromatic perimetry (SAP) of 71 eyes, 18 were "normal" (normal SAP and optic disk evaluation, and IOP < 21 mm Hg), 30 were "glaucoma suspect" (GS; normal SAP, cup/disk (C/D) ratio > 0.5 or asymmetry > 0.2 and/or ocular hypertension), and 31 had "early glaucoma" (MD < -6 dB, glaucomatous optic neuropathy). Standard achromatic perimetry was performed with the Octopus 3.1.1 Dynamic 24-2 program. Patients fasted before the WDT, and four measurements were performed at basal, 15', 30, and 45' after drinking 1 liter of water (WDT) in 5 minutes. In the 30 degrees inverted position, IOP measurement with Perkins applanation tonometer was taken after 5 minutes lying down. RESULTS: There was a statistical difference in all groups between the basal IOP and peak IOP during the WDT (p < 0.001) and in the inverted position IOP (p < 0.001). Controls (p = 0.50), suspects (p = 0.41) and glaucoma patients (p = 1.0) did not exhibit a difference between WDT IOP and inverted position IOP. CONCLUSION: The 30 degrees inverted position test was as efficient as WDT in detecting peak IOP. This new provocative test is easier, faster and more comfortable for both patients and doctors. How to cite this article: Kanadani FN, Moreira TCA, Campos LF, Vianello MP, Corradi J, Dorairaj SK, Freitas ALA, Ritch R. A New Provocative Test for Glaucoma. J Curr Glaucoma Pract 2016;10(1): 1-3. PMID- 27231413 TI - Diurnal Curve of the Ocular Perfusion Pressure. AB - PURPOSE: To describe the diurnal variation of the ocular perfusion pressure (OPP) in normal, suspects and glaucoma patients. MATERIALS AND METHODS: Seventy-nine subjects were enrolled in a prospective study. The diurnal curve of intraocular pressure (IOP) was performed and blood pressure measurements were obtained. Each participant was grouped into one of the following based upon the clinical evaluation of the optic disk, IOP and standard achromatic perimetry (SAP): 18 eyes were classified as normal (normal SAP, normal optic disk evaluation and IOP < 21 mm Hg in two different measurements), 30 eyes as glaucoma suspect (GS) (normal SAP and mean deviation (MD), C/D ration > 0.5 or asymmetry > 0.2 and/or ocular hypertension), 31 eyes as early glaucoma (MD < -6 dB, glaucomatous optic neuropathy and SAP and MDs on SAP. Standard achromatic perimetry was performed with the Octopus 3.1.1 Dynamic 24-2 program. Intraocular pressure and blood pressure measurements were taken at 6 am, 9 am, 12, 3 and 6 pm. The patients stayed in the seated position for 5 minutes prior to blood pressure measurements. RESULTS: The mean IOP values in all groups did not follow any regular pattern. The peak IOP was found to be greater in suspect [18.70 +/- 3.31 (mm Hg +/- SD)] and glaucoma (18.77 +/- 4.30 mm Hg) patients as compared to normal subjects (16.11 +/- 2.27 mm Hg). In studying the diurnal variation of the OPP, we found lower values at 3 pm in normals (34.21 +/- 2.07 mm Hg), at 9 am in suspects (54.35 +/- 3.32 mm Hg) and at 12 pm in glaucoma patients (34.84 +/- 1.44 mm Hg). CONCLUSION: Each group has a specific OPP variation during the day with the most homogeneous group being the suspect one. It is important to keep studying the IOP and OPP variation for increased comprehension of the pathophysiology of glaucomatous optic neuropathy. How to cite this article: Kanadani FN, Moreira TCA, Bezerra BSP, Vianello MP, Corradi J, Dorairaj SK, Prata TS. Diurnal Curve of the Ocular Perfusion Pressure. J Curr Glaucoma Pract 2016;10(1):4-6. PMID- 27231414 TI - The Safety and Efficacy of Two-site Phacotrabeculectomy with Mitomycin C under Retrobulbar and Topical Anesthesia. AB - PURPOSE: To evaluate and compare the safety and efficacy of combined two-site phacoemulsification and trabeculectomy surgery with mitomycin C (MMC) in glaucoma cataract patients with retrobulbar or topical anesthesia. PATIENTS AND METHODS: A retrospective, nonrandomized review of consecutive phacotrabeculectomy patients with a minimum follow-up time of 6 months, no previous glaucoma surgeries, and a preoperative visual acuity (VA) greater than light perception. The main outcome measures were preoperative and postoperative VA, intraocular pressure (IOP), use of glaucoma medications, and complications. A complete surgical success required an IOP from 6 to 18 mm Hg, no visually devastating complications, no return to surgery, and no use of glaucoma medications. Qualified success allowed the use of up to two glaucoma medications. Anesthesia groups were compared by student t tests and log rank comparison of Kaplan-Meier survival rates. RESULTS: Eighty seven eyes (83 patients) met inclusion criteria, with a mean follow-up of 19 +/- 12 months (6-57 months). The average eye gained 3.1 +/- 4.9 lines of VA, lost 4.0 +/- 7.1 mm Hg of IOP, and decreased 1.0 +/- 1.3 glaucoma medications. Retrobulbar and topical anesthesia groups had statistically equivalent mean changes in VA (p = 0.910), IOP (p = 0.268), and use of glaucoma medications (p = 0.964). Postoperative complication rates were also statistically similar (p = 0.580). Complete success was greater in the retrobulbar group (p = 0.006), however, qualified success was equivalent in both groups (p = 0.769). CONCLUSION: Two-site phacotrabeculectomy with MMC in West Indian patients is as safe and effective for glaucoma-cataract patients with topical anesthesia as it is under retrobulbar anesthesia, and without short-term losses in VA and the chance of serious complications from injection. How to cite this article: Rodriguez R, Alburquerque R, Sauer T, Batlle JF. The Safety and Efficacy of Two-site Phacotrabeculectomy with Mitomycin C under Retrobulbar and Topical Anesthesia. J Curr Glaucoma Pract 2016;10(1):7-12. PMID- 27231415 TI - The Suprachoroidal Route in Glaucoma Surgery. AB - Glaucoma surgeries targeting the uveoscleral drainage pathways have been drawing more attention lately. Among all the available techniques, procedures focusing on the supra-choroidal space seem particularly promising, by making use of a presumably efficient and secure outflow route and avoiding subconjunctival filtration blebs. The purpose of this review is to assess the efficacy and the security of the different suprachoroidal drainage implants, namely the CyPass Micro-Stent, the iStent Supra, the SOLX Gold Shunt, the Aquashunt, and the STARflo Glaucoma Implant. Most clinical studies seem to currently point toward the direction that there are actual benefits in suprachoroidal surgeries by avoiding bleb-related complications. Nevertheless, even suprachoroidal implants may be subject to scarring and failure. More data are still needed, especially concerning long-term effects, although the approach does seem appealing. How to cite this article: Gigon A, Shaarawy T. The Suprachoroidal Route in Glaucoma Surgery. J Curr Glaucoma Pract 2016;10(1): 13-20. PMID- 27231417 TI - Endophthalmitis associated with Glaucoma Shunt Intraluminal Stent Exposure. AB - Endophthalmitis post glaucoma drainage implant (GDI) surgery is rare, often associated with tube or plate exposure. We report a case of endophthalmitis following glaucoma shunt intraluminal stent exposure in a patient who underwent Baerveldt glaucoma implant surgery. Endophthalmitis following manipulation of intraluminal stents is a rare complication of GDIs but potentially vision threatening condition that needs to be carefully screened for and treated immediately. How to cite this article: Kwon HJ, Kerr NM, Ruddle JB, Ang GS. Endophthalmitis associated with Glaucoma Shunt Intraluminal Stent Exposure. J Curr Glaucoma Pract 2016;10(1):36-37. PMID- 27231416 TI - Preoperative Preparation and Anesthesia for Trabeculectomy. AB - Preoperative preparation should improve the likelihood of successful trabeculectomy surgery. The team can reconsider the appropriateness of the proposed surgery, and steps can be taken to maximize the chance of a good outcome. For example, adjustments to anti-hypertensive or anti-coagulant medications may be made, and topical ocular medications adjusted. Choice of anesthesia technique is of particular relevance to the trabeculectomy patient. Some anesthesia techniques are more likely to have serious complications, and glaucoma patients may be at higher risk of some sight-threatening complications, because the optic nerve is already damaged and vulnerable. Posterior placement of local anesthesia (retrobulbar, peribulbar, posterior sub-Tenon's techniques) could potentially damage the optic nerve, and thereby cause "wipe-out" of vision. Anesthesia technique may influence the likelihood of vitreous bulge and surgical difficulty. Regarding long-term control of intraocular pressure, there is no good evidence to indicate that any particular anesthesia technique is better than another. There is little high-quality evidence on this topic. The author's preferred technique for trabeculectomy is subconjunctival-intracameral anesthesia without sedation. How to cite this article: Eke T. Preoperative Preparation and Anesthesia for Trabeculectomy. J Curr Glaucoma Pract 2016; 10(1):21-35. PMID- 27231418 TI - Experiences With Parents and Youth Physical Health Symptoms and Cortisol: A Daily Diary Investigation. AB - Using daily diary data, this study examined the associations between positive and negative parent-youth experiences and youth cortisol and physical health symptoms among a sample of adolescents (N=132, Mean Age = 13.39). On days when girls reported more negative experiences than usual, they exhibited more physical health symptoms and flatter evening cortisol slopes than usual. Negative experiences with mothers were associated with higher dinner and bedtime youth cortisol levels (between-person). Daily positive experiences with fathers were linked with lower dinner cortisol levels. Youth with high levels of negative experiences, on average, were less sensitive to daily variation in negative experiences than youth who experienced lower parental negativity. We discuss the benefits of a daily diary approach. PMID- 27231419 TI - School Belonging, Generational Status, and Socioeconomic Effects on Mexican Origin Children's Later Academic Competence and Expectations. AB - This study examined factors that relate to academic competence and expectations from elementary to middle school for 674 fifth grade students (50% boys; Mage = 10.86 years) of Mexican origin. Models predicting academic competence and expectations were estimated using a Structural Equation Modeling (SEM) framework, with longitudinal data from fifth to eighth grades. School belonging (i.e., social and emotional connectedness to school) predicted greater academic competence and expectations over time. Findings indicate that student feelings of belonging in school may act as a resource that promotes academic competence and expectations. Furthermore, family income, parent education, and generational status had direct effects on academic competence and expectations to some degree, suggesting the importance of contextual factors in this process. PMID- 27231420 TI - Deflected Pathways: Becoming Aggressive, Socially Withdrawn, or Prosocial with Peers During the Transition to Adolescence. AB - Although research has suggested strong continuity in children's adaptive or maladaptive behavior with peers across the transition to adolescence, less is known about deflected developmental pathways of peer social competence across this transition. This study investigates how mother-child and best friend relationship quality predict the deflection of youth from adaptive to maladaptive behavior with peers or the reverse. Using data from the NICHD Study of Early Child Care and Youth Development (N=1055), high-quality friendships were associated with changes in peer social competence from 3rd to 6th grade. More positive and fewer negative interactions with a friend were linked with becoming more prosocial with peers, whereas less positive interactions with a friend were linked to becoming aggressive or withdrawn. PMID- 27231421 TI - Gender, Generational Status, and Parent-Adolescent Sexual Communication: Implications for Latino/a Adolescent Sexual Behavior. AB - There is little research on how specific parent-adolescent sexual communication topics influence Latino/a youth's sexual behaviors, and how gender and generational status may moderate effects. This study examined effects of three different messages on intercourse and condom use among 1944 Latino/as from the National Longitudinal Study of Adolescent Health (T1 mean age=15.46; sd=1.50). Results indicated discussing health consequences predicted higher odds of intercourse one year later across gender and generation groups. Birth control recommendation effects on subsequent intercourse and condom use differed by generational status and gender. Results indicated that message content is important for understanding effects of parent-adolescent sex communication on adolescents' behavior, and underscored the need to consider gender and generational status in Latino/a parent-adolescent sexual communication studies. PMID- 27231422 TI - Paclitaxel-Coated Balloons: Review of a Promising Interventional Approach to Preventing Restenosis in Femoropopliteal Arteries. AB - Peripheral arterial disease (PAD), a major cause of morbidity and mortality worldwide, is characterized by intermittent claudication and is associated with chronic diseases such as diabetes and hypertension. The goal of treatment is to address the underlying cause and to modify risk factors. Although medical management is the first-line treatment of PAD, some individuals may have severe symptoms and require revascularization with percutaneous transluminal angioplasty with or without stent placement or surgery. Interventional approaches may, however, be associated with high prevalence of restenosis and subsequent complications such as critical limb ischemia and amputation. Drug-eluting balloons (DEBs) are a new interventional technology with the primary goal of preventing restenosis. We review the clinical trials and studies that assessed the efficacy and safety profile of DEB and will focus on the restenosis rate in femoropopliteal arteries including target lesion revascularization (TLR) and late lumen lesion (LLL) using different modalities of intervention such as stents and DEB. Average data collected from the trials reported included restenosis rate of 25%, 0.3 mm LLL, and 14% reduction in TLR with DEB versus uncoated balloons. Below the knee (BTK) only intervention studies were excluded from this review as endovascular approach is usually reserved for critical limb ischemia for BTK disease. Interventional approach to treat PAD with DEB appears to be a promising technology. Additional larger studies are needed to further define safety, efficacy, and longer term outcome with this novel technology. PMID- 27231423 TI - Do Cardiovascular Risk Factors and Severity and Complexity of Coronary Atherosclerosis Predict Aortic Pulse Pressure during Cardiac Catheterization? AB - Pulse pressure (PP), estimated from the peripheral blood pressure measurements, has been linked with adverse cardiovascular events. But, the association of PP and coronary artery disease is not well studied. There is a lack of data on the association of invasively measured aortic PP and cardiovascular risk factors and severity of coronary atherosclerosis. We determined the predictive factors of aortic PP during cardiac catheterization. Electronic medical records from 2010 to 2013 were retrospectively reviewed. A total of 368 patients were eligible. The data on demographics, cardiovascular risk factors, coronary lesion characteristics, and medication use was collected. On multivariable regression analysis, aging (beta = 0.34, p = 0.001, 95% confidence interval [CI] 0.14-0.53) and prior aspirin use (beta = 5.09, p = 0.015, 95% CI 0.99-9.18) were associated with higher aortic PP. Increasing estimated glomerular filtration rate (beta = - 0.52, p = 0.040, 95% CI -0.90 to -0.23) was associated with lower aortic PP. Severity and complexity of coronary lesions, SYNTAX score, and number of obstructed vessels were not associated with aortic PP. Aging, prior aspirin use, and declining renal function were associated with an increase in aortic PP. Aortic PP may not predict the severity and complexity of coronary atherosclerosis. Therefore, the risk of adverse cardiovascular events associated with an elevated aortic PP may not be mediated by the severity of coronary atherosclerosis. PMID- 27231424 TI - Growth Rate of Small Abdominal Aortic Aneurysms and Genetic Polymorphisms of Matrix MetalloProteases-1, -3, and -9. AB - Genetic variants of matrix metalloproteases (MMPs)-1, -3, and 9, together with clinical variables, might predict the growth rate (GR) of abdominal aortic aneurysm (AAA). Genotyping of MMP-1 (-1,607 G+/G-), MMP-3 (- 1,171 6A/5A), and MMP-9 microsatellite (13-26 cytosine-adenosine repeats around -90) from peripheral blood was performed in 137 AAA patients with two AAA diameter measurements (at least 3 months to 1 year apart). When the same technique (either ultrasound or computed tomography) was used for the two measurements, yearly GR was estimated and compared with MMP genotype and clinical features by linear and binary logistic regression. Collectively, 36 patients provided 94 observations, with a median GR of 3 mm/year (interquartile range, 0-5.8); GRs in carriers of MMP-1 polymorphism G-/G-, G-/G+, and G+/G+ genotype were 0.3, 3.5, and 4.7mm/year, respectively (p = 0.008). In linear logistic regression, the main determinant of GR was growth arrest (GA, i.e., GR = 0, occurring in 32 observations, 34%). In turn, GA occurred mainly in G-/G- MMP-1 genotype (odds ratio, 3.9; 95% confidence interval, 1.6-9.7; p = 0.002), while variables accounting for GR > 0 were MMP-1 G + /G+ genotype, intake of any antihypertensive drug, and MMP-3 6A/6A genotype. Carriers of none, one, or two/three of these conditions accounted for a GR of 3, 4, and 9 mm/year, respectively (p = 0.001). MMP-1 (-1,607 G+/-) variant is associated to differential GR in AAA: homozygous G deletion variant shows higher GA prevalence and lower GR, while carriers of G + /G+ MMP-1 genotype, together with intake of antihypertensive drugs, and 6A/6A in MMP-3 present cumulative GR increase. PMID- 27231425 TI - Vascular Complications Associated with Transfemoral Aortic Valve Replacement. AB - Background Transfemoral aortic valve replacement (TAVR) is a novel technique for treating aortic stenosis, yet vascular complications are yet to be delineated. Objectives This study aims to study the vascular complications of TAVR with Edwards Sapien valves (Edwards Lifesciences Corp., Irvine, CA). Methods We performed a retrospective evaluation of TAVR patients. Standard demographics, femoral vessel and sheath size, access type (femoral cut-down [FC], percutaneous access [PFA], and iliac conduit [IC]), and treatment method were recorded. Complications were defined by the Valve Academic Research Consortium Criteria. Logistic regression was used for statistical analysis. Results A total of 99 patients underwent TAVR between February 15, 2012 and July 17, 2013 with an Edwards Sapien valve. Out of which, 48 were males with a mean age of 83 +/- 7 years. Overall, 33 had FC, 58 had PFA, and 6 had an IC. A total of 17 major (2 aortic and 15 iliac) and 38 minor complications (36 access and 2 emboli) occurred. Aortic complications were managed by open repair (OR, 1) or percutaneous repair (PR, 1). Overall, 12 iliac injuries were managed by PR and 3 by OR. Out of the 33 groin complications in FC patients 8 (24%) were treated by OR, whereas 30 (52%) of the 58 groin complications in PTA patients were treated by PR. There were no differences in transfusion requirements or length of stay. Conclusion Vascular complications of TAVR are common with most being minor, related to access site and causing no immediate sequelae. Iliac injury can be managed by PR or OR. Aortic injury is associated with significant mortality. These findings increase vascular surgeons' awareness of these complications and how to manage them. PMID- 27231426 TI - Compression Stockings versus Neuromuscular Electrical Stimulation Devices in the Management of Occupational Leg Swelling. AB - Background Occupational edema is reported to occur in healthy individuals after working in a sitting or standing position for extensive periods of time. It can be associated with feelings of tiredness, heaviness of the legs, and pain. Three licensed medical devices were compared in their management of occupational edema. Subjects and Methods A total of 10 subjects were recruited from a clinical workspace. Right leg volume and great saphenous vein diameter was measured in the morning, and 6 hours later. On subsequent separate days, grade 2 graduated compression stockings (Active Compression Socks, Mediven, United Kingdom), geko (Firstkind Ltd, United Kingdom), and Revitive (Actegy Ltd, United Kingdom) were used bilaterally according to manufacturer's instructions. Results Leg volumes increased by median 41 mL (p < 0.05) with no intervention. Percentage increase in leg volume was found to be significantly reduced by stockings compared with control (-1.7%, p < 0.01), and were more effective than electrical devices. Changes in vein diameter poorly correlate with leg volume changes. Conclusion Occupational edema can occur over as little as 6 hours. All devices were well tolerated and reduced leg swelling. Stockings were the only device to significantly reduce leg swelling in this small trial. PMID- 27231427 TI - Atherosclerosis and the Hypercholesterolemic AGE-RAGE Axis. AB - Background Interaction of advanced glycation end products (AGE) with the receptor for advanced glycation end products (RAGE) has been implicated in the pathogenesis of atherosclerosis. Soluble receptors for advanced glycation end products (sRAGE) act as a decoy for AGE by competing with RAGE and suppressing developing atherosclerosis. Hypercholesterolemia and the oxidative stress are known factors involved in atherosclerosis. High-density lipoprotein cholesterol (HDL-C) is known to exert a protective effect against the development of atherosclerosis. We hypothesize that hypercholesterolemia-induced atherosclerosis may be mediated through the AGE-RAGE axis. Objectives Two objectives to be determined are: (1) if hypercholesterolemia is positively correlated with serum AGE, AGE/sRAGE, and malondialdehyde (MDA: a marker for oxidative stress) and (2) if the protective effect of HDL-C is positively associated with serum sRAGE and negatively correlated with the levels of AGE and AGE/sRAGE. Methods Measurement of serum lipid levels from 100 patients allowed the separation into two groups (hypercholesterolemic and normocholesterolemic). Measurements of serum levels of AGE, sRAGE, and MDA were performed. Results Serum levels of sRAGE were lower, while the levels of AGE and AGE/sRAGE were higher in hypercholesterolemic subjects as compared with normocholesterolemic subjects. sRAGE levels are positively correlated with HDL, while they are negatively correlated with low density lipoprotein, triglycerides, total cholesterol, and MDA in hypercholesterolemic subjects. Conclusions Hypercholesterolemia is positively correlated with serum AGE, AGE/sRAGE, and MDA. The effect of HDL-C may be due to increases in sRAGE and decreases in the levels of AGE and AGE/sRAGE. Hypercholesterolemia-induced atherosclerosis may be mediated through the AGE-RAGE axis; however, more research must be conducted. PMID- 27231428 TI - Study on the Long-Term Results of Endovenous Laser Ablation for Treating Varicose Veins. AB - Background Endovenous laser ablation (EVLA) is widely performed since the early 2000s, but there are few long-term results. Objectives The aim of this study was to evaluate the long-term results of EVLA employed for treating varicose veins of the lower limbs by duplex ultrasonographic study. Methods A total of 24 limbs of 17 patients who underwent EVLA between 2004 and 2007 were examined with duplex ultrasonographic scans. The mean follow-up period was 66.1 months. Results There were five recurrences of saphenofemoral junction reflux. The occlusion rate was 79.2% at a mean follow-up of 66.1 months. There were 14 recanalizations and 5 recurrences of the great saphenous vein. Five partial and nine total recanalizations were observed. Conclusions EVLA is an effective and minimally invasive treatment for varicose veins. Our long-term result was acceptable, but the result was not outstanding. PMID- 27231429 TI - Secondary Varicose Small Pelvic Veins and Their Treatment with Micronized Purified Flavonoid Fraction. AB - The aim of this study was to examine secondary varicose small pelvic veins (VSPV) and their treatment with micronized purified flavonoid fraction (MPFF). We examined 70 patients with a history of acute iliac thrombosis of > 1 year. Patients with urination difficulties associated with other symptoms (n = 24) received MPFF 1,000 mg once daily for 1 month. Clinical manifestations were assessed by collecting complaints and analyzing results of physician examinations. VSPV was identified in 48 (68.6%) patients, the majority (58%) had grade 2 (7.0-9.0 mm) venous dilation. VSPV severity correlated with time since the thrombotic event. In most women, varicosities were found in the parametrial venous plexus (mean vein diameter 7.91 mm); retrograde flow during the Valsalva maneuver was found in 14 (78%). In men, all varicosities occurred in the paraprostatic plexus (mean vein diameter 7.20 mm); retrograde flow was found in 21 (70%). MPFF significantly reduced VSPV dilation in 18 (75%) patients (p = 0.0863) and returned ultrasonic indices to normal values in the remainder. Patients with bilateral varices decreased from 10 to 2. Only four patients had retrograde flow in the SPV plexus after treatment. MPFF decreased mean paraprostatic vein diameter in men and parametrial vein diameter in women to near normal values. Clinical improvement was reported in 13 (54%) patients. Patients with pelvic pain decreased from 8 to 1 and patients with urination disorders from 24 to 9. VSPV is common in patients with a history of iliac vein thrombosis. MPFF decreases the diameter of affected veins, improves retrograde flow and pelvic hemodynamics, and significantly reduces the severity of the clinical manifestations. PMID- 27231430 TI - Giant Subclavian Artery Aneurysm. AB - We report the case of a 37-year-old construction executive presenting with chest pain, shortness of breath, and dizziness on exertion secondary to a giant left subclavian artery aneurysm and aortic valvular disease. PMID- 27231431 TI - Recurrent Myocardial Infarction in a Patient with an Arteriovenous Coronary Fistula and No Coronary Artery Disease. AB - Myocardial infarction in the absence of coronary artery disease is a rare finding. Mechanisms leading to infarction include paradoxical embolism, coronary dissection, coronary spasm, hypercoagulable states, vasculitis, or-in presence of a coronary fistula-a steal phenomenon. We report for the first time a case of a patient with an arteriovenous coronary fistula and no coronary artery disease, suffering from three incidents of myocardial infarction in three different coronary regions-of which only one was located in the area supplied by the coronary artery connected to the fistula. PMID- 27231432 TI - Balloon-Assisted Tracking: A Solution to Severe Subclavian Tortuosity Encountered During Transradial Primary PCI. AB - Radial artery access is preferred over femoral access for primary percutaneous coronary intervention (PCI) in patients with acute ST-segment elevation myocardial infarction because of the reduction in access site complications and mortality associated with the radial artery access. Successful transradial primary PCI requires knowledge of techniques to handle unexpected severe subclavian artery tortuosity. Balloon-assisted tracking (BAT) is one technique developed to negotiate the tortuosity and loops in the upper extremity. However, the use of BAT in dealing with a severe subclavian loop during a transradial primary PCI procedure has never been reported. We described a case of transradial primary PCI with severe subclavian artery loop that was negotiated successfully by the BAT technique. PMID- 27231433 TI - What does Cigarette Smoking do to the Circulating Level of Soluble Receptor for Advanced Glycation End Products? PMID- 27231434 TI - Mental Health Screening of Older Adults in Primary Care. AB - In an effort to document mental health outreach in our primary care clinic, 316 veterans (mean age 72) not currently in psychiatric treatment were screened for multiple mental health symptoms. Depressed mood was reported by 18% of the sample, insomnia by 26%, and morbid/suicidal ideation by 6.9% for at least several days during the past 2 weeks. Of those who experienced a loss over the past year (43%), 36% remained affected by the loss. Also reported were anxiety symptoms (29%) and PTSD symptoms (14%). Two-fifths (39%) of patients reported drinking alcohol in the past week, 18% more than 5 days, and 13% more than 3 drinks per sitting. Twenty-six percent of the patients reported symptoms warranting intervention; of these, only 39% accepted a treatment referral. While screening for depressed mood and alcohol use is now common in primary care, we found it useful to screen for specific symptoms of depression (including insomnia and suicidal ideation), persisting grief reactions, anxiety, and PTSD in this setting. Further research is necessary to determine factors that underlie some patients' refusal to accept mental health treatment. PMID- 27231435 TI - Sexual Coercion, Trauma, and Sex Work in Justice-Involved Women with Substance Use Disorders. AB - Sexual victimization is strongly associated with mental health problems, traumatic responses, earlier onset of substance use and criminal justice involvement. It is well known that multiple forms of sexual victimization and aggression have been experienced by most incarcerated women. Two hundred women with a substance use disorder and involvement with the criminal justice system within the previous two years (parole, probation, arrest, or incarceration) were recruited from multiple sites in metropolitan Chicago. We examined whether empowerment moderates the relationship between trauma symptoms, trading sex and the experience of being forced or coerced to have sex. There was a significant three-way interaction between sexual coercion, trading, and empowerment scores on trauma symptoms. For individuals who have not traded sex, lower levels of empowerment were associated with a larger difference in trauma symptomatology between individuals who have been coerced and those who have not been coerced. For individuals who had been coerced to engage in sexual activity, lower levels of empowerment were associated with a larger difference in trauma symptomatology between those who have traded and those who have not traded. The promotion of empowerment beliefs and attitudes in women disproportionately impacted by violence and sexual trauma may reduce the harm that results from being victimized. Furthermore, providing specific interventions that educate women regarding gender roles and cultural values may help women avoid situations that result in exploitation and coercion. PMID- 27231437 TI - How to report professional practice in nursing? A scoping review. AB - BACKGROUND: Nursing professional practice in different contexts of care has been widely described in evidence-based literature. Currently, there is no consensus on a common structure for these descriptions. Understanding and comparing similar practices is made difficult by the varying nature of descriptions provided in scientific literature. PURPOSE OF THE STUDY: 1) to report research methods found in the scientific literature that were used to describe the practice of different health professionals; 2) to report on the main concepts used to describe the practice of these health professionals; 3) to propose a structure for the description of the practice in nursing. METHODS: A scoping review following a five-stage approach: 1) identifying the research question; 2) identifying relevant studies; 3) selecting studies; 4) charting data; 5) reporting results. The Medline, CINAHL, psychARTICLES, psyCRITIQUES, psycEXTRA, Psychology and Behavioral Science Collection and psycINFO databases were searched. Each study was analyzed and extracted data were classified by categories and structures used to describe the health professional practices. RESULTS: Forty-nine studies were included. In these studies, quantitative, qualitative or mixed methods were used to describe professional practice in different health disciplines. Three major concepts were reported most frequently in describing professional practice: roles, domains and activities. The concepts varied greatly among authors. We found that to define roles or to characterize a professional practice, activities must be described and organized on the basis of different domains. CONCLUSIONS: A promising structure for describing nursing professional practice is proposed by the authors of this review. The structure facilitates the accurate description of all domains and activities performed by nurses in different contexts of practice, and will contribute to the development of knowledge about nursing practice in different contexts based on shared concepts. PMID- 27231438 TI - Induction of G1-phase cell cycle arrest and apoptosis pathway in MDA-MB-231 human breast cancer cells by sulfated polysaccharide extracted from Laurencia papillosa. AB - BACKGROUND: Marine algae consumption is linked to law cancer incidences in countries that traditionally consume marine products. Hence, Phytochemicals are considered as potential chemo-preventive and chemotherapeutic agents against cancer. We investigated the effects of the algal sulfated polysaccharide extract (ASPE) from the red marine alga L. papillosa on MDA-MB-231 human breast cancer cell line. METHODS: Flow cytometry analysis was performed to study the cell viability, cell cycle arrest and apoptosis. Changes in the expression of certain genes associated with cell cycle regulation was conducted by PCR real time analyses. Further investigations on apoptotic molecules was performed by ROS measurement and protein profiling. RESULTS: ASPE at low doses (10 ug/ml), inhibited cell proliferation, and arrested proliferating MDA-MB-231 cells at G1 phase. However, higher doses (50 ug/ml), triggered apoptosis in those cells. The low dose of ASPE also caused up-regulation of Cip1/p21 and Kip1/p27 and down regulation of cyclins D1, D2, and E1 transcripts and their related cyclin dependent kinases: Cdk2, Cdk4, and Cdk6. The higher doses of ASPE initiated a dose-dependent apoptotic death in MDA-MB-231 by induction of Bax transcripts, inhibition of Bcl-2 and cleavage of Caspase-3 protein. Over-generation of reactive oxygen species (ROS) were also observed in MDA-MB-231 treated cells. CONCLUSIONS: These findings indicated that ASPE induces G1-phase arrest and apoptosis in MDA-MB-231 cells. ASPE may serve as a potential therapeutic agent for breast cancer. PMID- 27231439 TI - Effects of powdered Montmorency tart cherry supplementation on acute endurance exercise performance in aerobically trained individuals. AB - BACKGROUND: The purpose of this study was to determine whether short-term supplementation of a powdered tart cherry supplement prior to and following stressful endurance exercise would affect markers of muscle damage, inflammation, oxidative stress, and/or muscle soreness. METHODS: 27 endurance-trained runners or triathlete (21.8 +/- 3.9 years, 15.0 +/- 6.0 % body fat, 67.4 +/- 11.8 kg) men (n = 18) and women (n = 9) were matched based on average reported race pace, age, body mass, and fat free mass. Subjects were randomly assigned to ingest, in a double-blind manner, capsules containing 480 mg of a rice flour placebo (P, n = 16) or powdered tart cherries [CherryPURE(r)] (TC, n = 11). Subjects supplemented one time daily (480 mg/day) for 10-d, including race day, up to 48-hr post-run. Subjects completed a half-marathon run (21.1 km) under 2-hr (111.98 +/- 11.9 min). Fasting blood samples and quadriceps muscle soreness ratings using an algometer with a graphic pain rating scale were taken pre-run, 60-min, 24 and 48 h post-run and analyzed by MANOVA with repeated measures. RESULTS: Subjects in the TC group averaged 13 % faster half-marathon race finish times (p = 0.001) and tended to have smaller deviations from predicted race pace (p = 0.091) compared to P. Attenuations in TC muscle catabolic markers were reported over time for creatinine (p = 0.047), urea/blood urea nitrogen (p = 0.048), total protein (p = 0.081), and cortisol (p = 0.016) compared to P. Despite lower antioxidant activity pre-run in TC compared to P, changes from pre-run levels revealed a linear increase in antioxidant activity at 24 and 48-h of recovery in TC that was statistically different (16-39 %) from P and pre-run levels. Inflammatory markers were 47 % lower in TC compared to P over time (p = 0.053) coupled with a significant difference between groups (p = 0.017). Soreness perception between the groups was different over time in the medial quadriceps (p = 0.035) with 34 % lower pre-run soreness in TC compared to P. Over the 48-h recovery period, P changes in medial quadriceps soreness from pre-run measures were smaller compared to TC. CONCLUSION: Results revealed that short-term supplementation of Montmorency powdered tart cherries surrounding an endurance challenge attenuated markers of muscle catabolism, reduced immune and inflammatory stress, better maintained redox balance, and increased performance in aerobically trained individuals. PMID- 27231441 TI - Liver Transplantation. PMID- 27231440 TI - A SPECIAL MEETING REVIEW EDITION: CCFA/Advances in Inflammatory Bowel Diseases 2015: Highlights in Ulcerative Colitis and Crohn's Disease: A Review of Selected Presentations From the CCFA/Advances in Inflammatory Bowel Diseases 2015 Clinical and Research Conference * December 10-12, 2015 * Orlando, FloridaSpecial Reporting on:* New and Future Adhesion Molecule-Based Therapies in IBD* Efficacy and Safety of Vedolizumab for Inflammatory Bowel Disease in Clinical Practice* A Multicenter, Double-Blind, Placebo-Controlled Phase 3 Study of Ustekinumab, a Human IL-12/23p40 Monoclonal Antibody, in Moderate-Severe Crohn's Disease Refractory to Anti-TNFalpha: UNITI-1* Intravenous Iron Sucrose for Treatment of Iron Deficiency Anemia in Pediatric Inflammatory Bowel Disease* Does Vedolizumab Affect Postoperative Outcomes in Patients Undergoing Abdominal Operations for Inflammatory Bowel Disease?PLUS Meeting Abstract Summaries With Expert Commentary by: Gary R. Lichtenstein, MDProfessor of MedicineDirector, Center for Inflammatory Bowel DiseaseUniversity of Pennsylvania Health SystemHospital of the University of PennsylvaniaPhiladelphia, Pennsylvania. PMID- 27231442 TI - GASTRO-HEP News. PMID- 27231443 TI - Large Fundic Gland Polyps in the Stomach. PMID- 27231445 TI - Current Status of Liver Allocation in the United States. AB - The liver transplant allocation system is currently based upon the Model for End Stage Liver Disease (MELD) score and allocates organs preferentially to patients with the highest scores (ie, the sickest patients) within a defined geographic unit. In addition, certain patient populations, such as patients with hepatocellular carcinoma and portopulmonary hypertension, receive MELD exception points to account for their increased waitlist mortality, which is not reflected by their MELD score. Significant geographic variation in the access to liver transplantation exists throughout the United States. Both the Organ Procurement and Transplant Network Board of Directors and the Health Resources and Services Administration have determined these geographic disparities to be unacceptable. The liver transplant community has worked to develop methods to reduce these geographic disparities and to reexamine how MELD exception points are granted to certain patient populations. As a result, numerous policy changes have been adopted throughout the years that have broadened the sharing of organs through wider geographic sharing. Despite all of these changes, variation in access to liver transplantation continues to exist, and, thus, the liver transplant community continues to examine new ways to address geographic disparities. This paper reviews several of the key changes to the liver allocation system that have occurred since the implementation of MELD allocation in 2002 and provides an overview of potential changes to the system. PMID- 27231444 TI - Update on the Management of Fecal Incontinence for the Gastroenterologist. AB - Many patients with fecal incontinence respond to conservative measures based upon a careful assessment and a multimodality approach that Is within the expertise of the practicing gastroenterologist. However, there Is a need for new and effective strategies when conservative therapy fails. This article reviews established therapies for fecal incontinence, such as biofeedback, as well as new therapies that have been approved by the US Food and Drug Administration (FDA), such as sacral neuromodulation and an injectable bulking agent. Also reviewed are some of the newer approaches that have not yet been approved by the FDA or that have uncertain efficacy. PMID- 27231446 TI - Chronic Constipation and Constipation-Predominant IBS: Separate and Distinct Disorders or a Spectrum of Disease? AB - Rome III diagnostic criteria separate patients with idiopathic chronic constipation into mutually exclusive categories of constipation-predominant irritable bowel syndrome (IBS-C) or functional constipation (FC). However, several experts think that these conditions are not different disorders, but parts of a continuum. To shed light on this issue, we examined studies that compared IBS-C with FC with respect to symptoms, pathophysiologic mechanisms, and treatment response. When the Rome III requirement that patients meeting criteria for IBS cannot also be given a diagnosis of FC is suspended, most patients meet criteria for both, and, contrary to expectation, IBS-C patients have more symptoms of constipation than patients with FC. No symptoms reliably separate IBS C from FC. Physiologic tests are not reliably associated with diagnosis, but visceral pain hypersensitivity tends to be more strongly associated with IBS-C than with FC, and delayed colonic transit tends to be more common in FC. Although some treatments are effective for both IBS-C and FC, such as prosecretory agents, other treatments are specific to IBS-C (eg, antidepressants, antispasmodics, cognitive behavior therapy) or FC (eg, prucalopride, biofeedback). Future studies should permit IBS-C and FC diagnoses to overlap. Physiologic tests comparing these disorders should include visceral pain sensitivity, colonic transit time, time to evacuate a water-filled balloon, and anal pressures or electromyographic activity from the anal canal. To date, differential responses to treatment provide the strongest evidence that IBS-C and FC may be different disorders, rather than parts of a spectrum. PMID- 27231447 TI - Antireflux Surgery in Lung Transplant Patients. PMID- 27231448 TI - The Association of Extrahepatic Cancers With Chronic Hepatitis C Virus Infection. PMID- 27231449 TI - Emerging Trends of Inflammatory Bowel Disease in Asia. PMID- 27231450 TI - Screening Tests for Colon Cancer. PMID- 27231451 TI - Advances in the Field of Gastroenterology and Hepatology. PMID- 27231452 TI - Current Issues in Liver Transplantation. AB - The state of liver transplantation continues to evolve. This article focuses on 3 separate yet important issues within this field. First, there is a proposal to change the allocation of donor livers in the United States. The fundamental premise of this proposal is to equalize access to donor livers across the country. To accomplish this goal, the proposal is to increase the geographic area of liver allocation. As might be expected, there is a great deal of controversy surrounding the possibility of a major change in liver allocation and distribution. A second area of interest, and perhaps the most important therapeutic breakthrough in the field of hepatology, is the introduction of direct-acting antiviral agents against hepatitis C virus (HCV) infection. With cure rates up to 100%, an increasing proportion of liver transplant candidates and recipients are being cured of HCV infection with therapies that have minimal side effects. Consequently, the impact of HCV infection on patient and graft survival will likely improve substantially over the next few years. Finally, this article reviews the role of donor-specific antibodies (DSAs) in antibody-mediated rejection. Long recognized as an important factor in graft survival in renal transplantation, DSAs have recently been shown to be a strong predictor of graft and patient survival in liver transplantation. However, the importance of DSAs in liver transplantation is uncertain, in large part due to the absence of proven therapies. PMID- 27231454 TI - Ringed Esophagus Secondary to Lymphocytic Esophagitis. PMID- 27231455 TI - How Relative Value Units Undervalue the Cognitive Physician Visit: A Focus on Inflammatory Bowel Disease. PMID- 27231456 TI - GASTRO-HEP News. PMID- 27231453 TI - Update on Magnetic Resonance Imaging and Ultrasound Evaluation of Crohn's Disease. AB - Magnetic resonance enterography (MRE) and abdominal ultrasound are integral parts of multimodality assessments for patients with inflammatory bowel disease. Applications include assessing Crohn's disease (CD) extent and severity, differentiating CD from ulcerative colitis, detecting CD complications, evaluating response to therapy, and demonstrating postoperative recurrence. Magnetic resonance imaging protocols are being developed that may reduce or eliminate the need for intravenous contrast agents and better differentiate inflammatory from fibrotic strictures. MRE scoring systems have been created to objectively quantify disease activity and response to therapy. By utilizing advanced sonographic imaging techniques, including ultrasound contrast and Doppler assessments, the role of abdominal ultrasonography in the evaluation and management of CD continues to expand. Abdominal ultrasound may function as a low cost, point-of care assessment tool, especially in CD restricted to the terminal ileum and ileocolic anastomosis. PMID- 27231457 TI - Biomarkers for Hepatocellular Carcinoma. PMID- 27231458 TI - Using Institutional Databases to Study Inflammatory Bowel Disease. PMID- 27231459 TI - Managing Perforations Related to Endoscopic Retrograde Cholangiopancreatography. PMID- 27231460 TI - Targeting the Farnesoid X Receptor in Patients With Cholestatic Liver Disease. PMID- 27231461 TI - Diagnosing Gastroesophageal Reflux Disease With Endoscopic-Guided Mucosal Impedance. PMID- 27231462 TI - Ir-192 Calibration in Air with Farmer Chamber for HDR Brachytherapy. AB - A comprehensive review for the in-air calibration of an Ir-192 high-dose-rate brachytherapy source in terms of air kerma strength (AKS) and reference air kerma rate (RAKR) using the Farmer chamber was conducted. The reviewed calibration methods include the National Physical Laboratory (NPL) calibration standard in the UK, the 7-distance technique with the standard calibration of the National Institute of Standards and Technology and Accredited Dosimetry Calibration Laboratory in the US, the calibration conducted in Australia following recommendations of the International Atomic Energy Agency with the chamber primarily calibrated by the Australian Radiation Protection and Nuclear Safety Agency, the calibration conducted in India following the Deutsche Gesellschaft fur Medizinische Physik recommendation, and the convenient empirical method used in Taiwan. The calibrated AKS (or RAKR) and uncertainty obtained using Farmer chambers are similar to those obtained using well chambers. All reported differences (between measurements obtained using Farmer and well chambers, respectively) and uncertainties (k = 2) were generally less than 1.5 and 2.5 %, respectively. The standard uncertainty of the NPL calibration is approximately half that of all the other proposed approaches, and may become the gold standard calibration procedure. Almost all techniques follow the 7-distance technique basis; however, the services at NPL can calibrate the source with lower uncertainty. Users can calibrate the Ir-192 source more conveniently using the empirical method with only one source-chamber distance. PMID- 27231464 TI - Development of Home-Based Frailty Detection Device Using Wireless Sensor Networks. AB - This study develops a home-based frailty detection device that uses embedded systems and wireless sensing technology. This system helps monitor the impact of aging among the elderly through wireless automatic detection. The detection system consists of four devices. The first device, called eScale, simulates the traditional falling ruler test to measure reaction time. Another device, called eChair, measures the pressure exerted by a test subject through a pressure sensor. It is used to test three symptoms of frailty, namely slowness of movement, physical weakness, and body weight. The third device, called ePad, consists of a soft membrane switch placed on the ground to detect footsteps and is used to test balance. The fourth device, called eReach, measures displacement through ultrasound sensors. It is used to carry out the functional reach test. The sampling rate of each device is the main factor that determines system performance. When the test distance was set to 5 m for Home-Gateway, a 1-Hz sampling rate showed the best performance (98 %). Up to eight devices can be connected simultaneously to the gateway. The proposed system was compared with conventional approaches through testing with test subjects (n = 8). The results of the five tests were as follows: standing forward bend (r = 0.929), balance (r = 0.996), slowness of movement (r = 0.976), and physical weakness (r = 0.991), with p < 0.01. In the reaction time test, r = 0.871, with p < 0.1. All results suggest high correlations. Tests of aging symptoms were performed on 309 people aged over 65 years. Among males, degradation of over 20 % was found in the areas of physical weakness, slowness of movement, and functional reach. Among females, a degradation of 75 % was found in the balance test. PMID- 27231465 TI - A special issue on nanotoxicology. PMID- 27231463 TI - Response of Primary Human Bone Marrow Mesenchymal Stromal Cells and Dermal Keratinocytes to Thermal Printer Materials In Vitro. AB - Advancement in thermal three-dimensional printing techniques has greatly increased the possible applications of various materials in medical applications and tissue engineering. Yet, potential toxic effects on primary human cells have been rarely investigated. Therefore, we compared four materials commonly used in thermal printing for bioengineering, namely thermally printed acrylonitrile butadiene styrene, MED610, polycarbonate, and polylactic acid, and investigated their effects on primary human adult skin epidermal keratinocytes and bone marrow mesenchymal stromal cells (BM-MSCs) in vitro. We investigated indirect effects on both cell types caused by potential liberation of soluble substances from the materials, and also analyzed BM-MSCs in direct contact with the materials. We found that even in culture without direct contact with the materials, the culture with MED610 (and to a lesser extent acrylonitrile butadiene styrene) significantly affected keratinocytes, reducing cell numbers and proliferation marker Ki67 expression, and increasing glucose consumption, lactate secretion, and expression of differentiation-associated genes. BM-MSCs had decreased metabolic activity, and exhibited increased cell death in direct culture on the materials. MED610 and acrylonitrile butadiene styrene induced the strongest expression of genes associated to differentiation and estrogen receptor activation. In conclusion, we found strong cell-type-specific effects of the materials, suggesting that materials for applications in regenerative medicine should be carefully selected not only based on their mechanical properties but also based on their cell-type-specific biological effects. PMID- 27231466 TI - Prognostic signatures of breast cancer: Perou's molecular subtypes and Schmidt's metagenes. PMID- 27231467 TI - Lung and breast cancer research: immunoglobulin Kappa C hits the headlines. PMID- 27231468 TI - EDI3, a key enzyme of choline metabolism controls tumour cell migration. PMID- 27231469 TI - Anticancer compounds from plants. PMID- 27231471 TI - Key messages from Experimental and Clinical Sciences. PMID- 27231470 TI - Haematological parameters of alloxan-induced diabetic rats treated with leaf essential oil of Hoslundia opposita (Vahl). AB - The effect of leaf essential oil of Hoslundia opposita (Vahl) on the haematological parameters of alloxan-induced diabetic rats was investigated. Forty-eight albino rats (Rattus norvegicus), of average weight 132.5 g, were randomly selected into normal and diabetic groups, each with four sub-groups. The rats were treated with 110 and 220 mg/kg body weight (b. wt.) of the essential oil. 14.2 mg/kg body weight of metformin (Glucophage) was used as a reference drug. All treatments were administered, intraperitoneally, once a day for four days. Haematological parameters like haemoglobin (HGB), red blood cell (RBC) count, white blood cell (WBC) count, percentage lymphocytes (LYM) and neutrophils (NEU) were analysed. There were no significant differences (p > 0.05) in the erythrocyte indices of all the normal (non-diabetic) rats, both treated and untreated. However, there was a significant increase (p < 0.05) in the WBC count and a significant reduction (p < 0.05) in the lymphocyte (LYM) percentages of the normal (non-diabetic) rats administered with higher dose of the essential oil. The results also revealed a significant reduction (p < 0.05) and a significant increase (p < 0.05) in the RBC counts of untreated diabetic rats and diabetic rats administered 110 mg/kg b. wt. of the oil respectively. A significant increase (p < 0.05) in the LYM of diabetic untreated rats was also observed, while administration of metformin and 110 mg/kg b. wt. Hoslundia opposita leaf essential oil (HOLEO) to diabetic rats significantly (p < 0.05) reduced the LYM percentages to values within range of the normal control animals. Overall, administration of the oil has significant ameliorative effect on alloxan-induced anaemia in diabetic state and this may be of immense benefits in the management of type 2 diabetes and its associated haematological complications. PMID- 27231473 TI - The Human Bitumen Study. PMID- 27231472 TI - Current developments in toxicology. PMID- 27231474 TI - Genetic variants confer susceptibility to urinary bladder cancer: an updated list of confirmed polymorphisms. PMID- 27231475 TI - The role of glutamatergic pathway between septum and hippocampus in the memory formation. AB - The N-methyl-D-aspartate (NMDA) receptor is a subtype of glutamate receptor that is presented in highest density in the hippocampus and septum. NMDA receptors of the septum and the hippocampus are involved in cognitive performance, especially in learning and memory processes. The septum nucleus and hippocampal formation are two regions of the limbic system. The septum and the hippocampus are anatomically and functionally connected to each other. These areas made the septo hippocampal and hippocampo-septal pathways, which are implicated in the cognitive processes. The activity of septal and hippocampal neurons is modulated by several neurotransmitters such as glutamate. Thus, changes in the glutamatergic transmission in the septum and hippocampus may influence learning and memory processes in these pathways. PMID- 27231476 TI - Recent studies on ursolic acid and its biological and pharmacological activity. PMID- 27231477 TI - Larvicidal activity and structure activity relationship of cinnamoyl amides from Zanthoxylum armatum and their synthetic analogues against diamondback moth, Plutella xylostella. AB - Cinnamoyl amides isolated from Zanthoxylum armatum (Rutaceae) and their synthetic analogues were tested for their insecticidal activity against the second instar larvae of diamondback moth, Plutella xylostella (L.) (Lepidoptera: Yponomeutidae) to determine the promising structures with insecticidal activity. Most of the test compounds showed promising activity against larvae of P. xylostella. However, the activities of different compounds varied depending on the presence of different substituents at various positions of both the aromatic rings A and B. Among the tested compounds, 8, N-(3-bromo-4-methoxyphenethyl)cinnamamide showed best larvicidal activity with an LC50 = 62.13 mg/L followed by 6, N-(3' bromophenethyl)cinnamamide (LC50=128.49 mg/L) and 2 N-(4' methoxyphenylethyl)cinnamamide (LC50 = 225.65 mg/L). PMID- 27231478 TI - Virtual Dual inhibition of COX-2 / 5-LOX enzymes based on binding properties of alpha-amyrins, the anti-inflammatory compound as a promising anti-cancer drug. AB - Hydro-alcoholic fruit extract of Cordia myxa was considerably effective on curing acute inflammation in mouse model. Previous studies suggested significant anti inflammatory activities as well as potential anticancer agent of alpha-amyrins in seeds. Inhibition of Cyclooxygenase-2 (COX-2) and 5-Lipooxygenase (5-LOX) is significant in cancer prevention and therapeutics although this inhibition with chemo-drugs has its own side-effects. It is shown that these enzymes pathways are related to several cancers including colon, breast and lung cancer. This study was conducted based on Cordia species' alpha-amyrins as a safer natural anti cancer compound for inhibition of COX-2 and 5-LOX enzymes by molecular docking. The X-ray crystal structure of COX2 / 5-LOX enzymes and alpha-amyrins was retrieved and energetically minimized respectively. The binding site and surface of enzymes were detected. Docking studies were performed by AutoDock 4.2 using Lamarckian genetic algorithm (LGA). Finally drug likeness, molecular pharmacokinetic properties and toxicity of alpha-amyrins was calculated. Molecular Docking revealed hydrogen and hydrophobic interactions between alpha amyrins with both active sites of COX-2 and 5-LOX enzymes. Interestingly, it covalently bonded to Fe cofactor of 5-LOX enzyme and chelated this molecule. Base on binding energies (?G) alpha-amyrin has more inhibitory effects on 5-LOX ( 10.45 Kcal/mol) than COX-2 (-8.02 Kcal/mol). Analysis of molecular pharmacokinetic parameters suggested that alpha-amyrins complied with most sets of Lipinski's rules, and so it could be a suitable ligand for docking studies. Eventually, bioactivity score showed alpha-amyrins possess considerable biological activities as nuclear receptor, enzyme inhibitor, GPCR and protease inhibitor ligand. These results clearly demonstrate that alpha-amyrins could act as potential highly selective COX-/5-LOX inhibitor. Also, it is a safe compound in comparison with classical non-steroidal anti-inflammatory drugs (NSAIDs) that are known as cancer preventive agents, since it is free of side effects on human body and it can be a promising drug for cancer therapeutics. PMID- 27231479 TI - An experimental study of the effects of electronic cigarette warnings on young adult nonsmokers' perceptions and behavioral intentions. AB - BACKGROUND: Electronic cigarette ("e-cigarette") manufacturers use warning labels on their advertising that vary widely in content and the U.S. Food and Drug Administration has issued a warning label requirement for e-cigarettes. There is limited data on the effects of these warnings on e-cigarette perceptions and other potential predictors of future tobacco use behavior in populations of interest to inform future regulatory requirements. This study examined the effects of e-cigarette warnings on perceptions of e-cigarettes and cigarettes and other cognitive precursors to tobacco use among young adult non-smokers. METHODS: Non-smoking young adults ages 18 to 30 years (n = 436) were recruited through an internet-based crowdsourcing platform for an online experiment. Participants completed pre-exposure measures of demographics, tobacco use, and other relevant constructs and were randomized to view 1 of 9 e-cigarette stimuli in a 3 (Ad/Warning condition: Ad Only, Ad with Warning, Warning Only) x 3 (E-cigarette brand: Blu, MarkTen, Vuse) design. After viewing e-cigarette stimuli, participants reported perceptions of e-cigarettes and behavioral intentions to use e-cigarettes. Participants in the Ad Only and Ad with Warning conditions also completed a heat-mapping task assessing aspects of the ads that captured their attention. Then, participants were randomized to view cigarette ads from 1 of 3 major cigarette brands and reported perceptions of cigarettes and intentions to smoke cigarettes. RESULTS: Participants in the Warning Only condition reported significantly greater perceived harm and addictiveness of e-cigarettes and thoughts about not using e-cigarettes than the Ad Only and Ad with Warning conditions (p's < .05). The Ad Only and Ad with Warning conditions did not differ on these outcomes. Participants in the Warning Only condition also reported the harms of e-cigarettes were closer to those of cigarettes than the Ad Only condition (p < .05), but neither differed from the Ad with Warning condition. Visual inspection of heat-mapping task data indicate warnings drew few participants' attention. There were no significant differences across study conditions on perceptions of cigarettes or intentions to smoke. CONCLUSIONS: Text based warning messages influenced young non-smokers' perceptions in a way that may dissuade e-cigarette use, but warnings appearing on advertisements had little impact. PMID- 27231480 TI - Who walks into vape shops in Southern California?: a naturalistic observation of customers. AB - BACKGROUND: The rising popularity of electronic cigarettes (e-cigarettes) has been accompanied by the proliferation of vape shops in the United States. Vape shops are devoted to the sale of e-cigarettes and e-juices. This study aimed to describe the age, gender, and ethnicity of customers who frequent these shops, determine whether conversations transpire between retailers and customers, as well as identify the types of activities taking place while customers are inside the store. METHODS: A naturalistic observation study of 186 customers in 59 vape shops in Southern California was completed in locations that were relatively high in Korean, Non-Hispanic white, Hispanic, or African American ethnicity. RESULTS: Across all shops, the average estimated age of customers was 30.29 years old (SD = 9.70), 53 % were estimated to be non-Hispanic white, and 79 % were males; few minors entered the shops. Conversations about vaping related topics were prevalent (e.g., sampling e-juices, receiving help on hardware, and talking about vaping). Purchases were commonly observed as well as customers lounging in the shop. CONCLUSION: Vape shops provide consumers a place to purchase and discuss e cigarettes and offer an environment that serves as a place of recreation with customers lounging once inside. Findings should inform local tobacco control efforts and regulatory policies in the future. PMID- 27231481 TI - Multiview video plus depth transmission via virtual-view-assisted complementary down/upsampling. AB - Multiview video plus depth is a popular 3D video format which can provide viewers a vivid 3D feeling. However, its requirements in terms of computational complexity and transmission bandwidth are more than that of conventional 2D video. To mitigate these limitations, some works have proposed to reduce the amount of transmitted data by adopting different resolutions for different views, and consequently, the transmitted video is called mixed resolution video. In order to further reduce the transmitted data and maintain good quality at the decoder side; in this paper, we propose a down/upsampling algorithm for 3D multiview video which systematically takes into account the video encoder and decoder. At the encoder side, the rows of the two adjacent views are downsampled following an interlacing and complementary fashion, whereas, at the decoder side, the discarded pixels are recovered by fusing the virtual view pixels with the directional interpolated pixels from the complementary downsampled views. Moreover, the patterns of the texture surrounding the discarded pixels are used to aid the data fusion, so as to enhance edges recovery. Meanwhile, with the assistance of virtual views, at the decoder side, the proposed approach can effectively recover the discarded high-frequency details. The experimental results demonstrate the superior performance of the proposed framework. PMID- 27231482 TI - Factors associated with prelacteal feeding in the rural population of northwest Ethiopia: a community cross-sectional study. AB - BACKGROUND: Prelacteal feeding has continued as a deep-rooted nutritional malpractice in developing countries. Prelacteal feeding is a barrier for implementation of optimal breastfeeding practices, and increases the risk of neonatal illness and mortality. However, its determinants are not well studied, which are essential to design intervention. This study aimed to assess the prevalence and determinants of prelacteal feeding among mothers with children aged 6-24 months in the rural population of northwest Ethiopia. METHODS: A community based cross-sectional study was conducted in Dabat Health and Demographic Surveillance System site, Dabat district, northwest Ethiopia from May 01 to June 29, 2015. Eight hundred and twenty-two mother-child pairs were included in the study. A pretested and structured questionnaire was used to collect data. Multivariable logistic regression analysis was carried out to identify the determinants of prelacteal feeding. RESULTS: In this community, about 26.8 % of children were given prelacteal feeds. The odds of prelacteal feeding was higher among mothers with a poor knowledge of Infant and Young Child Feeding (IYCF) (Adjusted Odds Ratio [AOR] = 3.82; 95 % Confidence Interval [CI] 2.42, 6.04), who gave birth at home (AOR = 3.74; 95 % CI 2.12, 6.60), and who were in the lowest wealth status (AOR = 2.11; 95 % CI 1.35, 3.31). CONCLUSIONS: Prelacteal feeding was common in the study area, and significantly associated with a poor household wealth status, poor maternal knowledge of IYCF, and giving birth at home. Thus, emphasis should be given to improve mothers IYCF knowledge and utilization of institutional delivery. Moreover, special attention should be given to mothers with poor socio-economic status to reduce the practice of prelacteal feeding. PMID- 27231483 TI - Relationship at work as a cause of occupational stress: the case of academic women in Vietnam. AB - BACKGROUND: The present research paper aims to bring deeper understanding and insight to perceptions and experiences of occupational stress from relationships at work in the cultural context of Vietnam. The paper also examines differences in perceptions, experiences of occupational stress from this problem and makes a comparison with perspectives in other cultures. METHODS: Grounded theory approach is used to study occupational stress by collecting data from in-depth interviews with 42 academic women employed at Vietnamese higher education institutions to understand the meaning, the nature and source of the occupational stress from relationships at work they experience and the impact of occupational stress on their lives. RESULTS: Cultural factors play an important role in occupational stress. Cultural factors such as power distance and hierarchy influence perception, experiences of occupational stress and the ways occupational stress is responded to. The Vietnamese context differs from other cultural contexts in the range of factors perceived as stressors for Vietnamese women. CONCLUSION: This paper is the first grounded theory study of occupational stress among women academics in Vietnam that determines that the natural of the relationship at work play an important role in how women understand and respond to occupational stress and supports the growing evidence that occupational stress is common, global but different in other cultures. PMID- 27231485 TI - Host, pathogen and environment: a bacterial gbpA gene expression study in response to magnesium environment and presence of prawn carapace and commercial chitin. AB - BACKGROUND: Vibrio parahaemolyticus is a Gram-negative halophilic bacterium which is found largely in estuarine and coastal waters. The bacteria has been a main focus in gastro-intestinal infections caused primarily due to the consumption of contaminated seafood. It was shown to survive in magnesium concentrations as high as 300 mM which are toxic to various other micro-organisms. Several genes of V. parahaemolyticus were studied, among which gbpA (N-acetyl glucosamine binding protein) was reported in Vibrio cholerae. METHODS: The current study investigates the V. parahaemolyticus gbpA gene expression at different concentrations of magnesium sulfate heptahydrate (MgSO4.7H2O, chosen as the magnesium environment), in the presence of the host's (prawn) carapace and the mimicked carapace [commercial chitin flakes (Sigma)]. The concentrations of MgSO4.7H2O utilized were approximately 0, 1, 75, 137, 225 and 300 mM. These were selected based upon the survival conditions required by prawn and bacteria, respectively. 0.05 gm/3 ml of carapace (by dry weight) and commercial chitin flakes were used in the experiments. Bacterial count was performed for the biological triplicates for the 3 experimental setups. The genome of Vibrio parahaemolyticus PCV08-7 (VPPCV08-7) was used as a reference, based on whose translated gbpA gene the probable protein chemical interactions were determined on the STITCH database. RESULTS: The GbpA protein was shown to interact with chitin on the STITCH database. In our experiments, the gbpA showed lower gene expression levels at different MgSO4.7H2O concentrations in the presence of chitin and carapace, than with the presence of only MgSO4*7H2O. In addition, the bacterial count for various concentrations of magnesium used, revealed a distinct decrease in bacterial count within and among each of the three experimental setups. CONCLUSION: In the presence of only magnesium, an increase in the gbpA expression with neither chitin nor carapace and vice versa supported by the results from the bacterial counts could help further studies to prove that the moulting phase of prawns may trigger increased expression of the V. parahaemolyticus gbpA gene. PMID- 27231484 TI - Data integration to prioritize drugs using genomics and curated data. AB - BACKGROUND: Genomic alterations affecting drug target proteins occur in several tumor types and are prime candidates for patient-specific tailored treatments. Increasingly, patients likely to benefit from targeted cancer therapy are selected based on molecular alterations. The selection of a precision therapy benefiting most patients is challenging but can be enhanced with integration of multiple types of molecular data. Data integration approaches for drug prioritization have successfully integrated diverse molecular data but do not take full advantage of existing data and literature. RESULTS: We have built a knowledge-base which connects data from public databases with molecular results from over 2200 tumors, signaling pathways and drug-target databases. Moreover, we have developed a data mining algorithm to effectively utilize this heterogeneous knowledge-base. Our algorithm is designed to facilitate retargeting of existing drugs by stratifying samples and prioritizing drug targets. We analyzed 797 primary tumors from The Cancer Genome Atlas breast and ovarian cancer cohorts using our framework. FGFR, CDK and HER2 inhibitors were prioritized in breast and ovarian data sets. Estrogen receptor positive breast tumors showed potential sensitivity to targeted inhibitors of FGFR due to activation of FGFR3. CONCLUSIONS: Our results suggest that computational sample stratification selects potentially sensitive samples for targeted therapies and can aid in precision medicine drug repositioning. Source code is available from http://csblcanges.fimm.fi/GOPredict/. PMID- 27231486 TI - Nanoscale controlled architecture for development of ultrasensitive lectin biosensors applicable in glycomics. AB - In this Minireview the most advanced patterning protocols and transducing schemes for development of ultrasensitive label-free and label-based lectin biosensors for glycoprofiling of disease markers and some cancerous cells are described. Performance of such lectin biosensors with interfacial properties tuned at a nanoscale are critically compared to the most sensitive immunoassay format of analysis and challenges ahead in the field are discussed. Moreover, key elements for future advances of such devices on the way to enhance robustness and practical applicability of lectin biosensors are revealed. PMID- 27231487 TI - Are glycan biosensors an alternative to glycan microarrays? AB - Complex carbohydrates (glycans) play an important role in nature and study of their interaction with proteins or intact cells can be useful for understanding many physiological and pathological processes. Such interactions have been successfully interrogated in a highly parallel way using glycan microarrays, but this technique has some limitations. Thus, in recent years glycan biosensors in numerous progressive configurations have been developed offering distinct advantages compared to glycan microarrays. Thus, in this review advances achieved in the field of label-free glycan biosensors are discussed. PMID- 27231488 TI - Histone acetyltransferases: challenges in targeting bi-substrate enzymes. AB - Histone acetyltransferases (HATs) are epigenetic enzymes that install acetyl groups onto lysine residues of cellular proteins such as histones, transcription factors, nuclear receptors, and enzymes. HATs have been shown to play a role in diseases ranging from cancer and inflammatory diseases to neurological disorders, both through acetylations of histone proteins and non-histone proteins. Several HAT inhibitors, like bi-substrate inhibitors, natural product derivatives, small molecules, and protein-protein interaction inhibitors, have been developed. Despite their potential, a large gap remains between the biological activity of inhibitors in in vitro studies and their potential use as therapeutic agents. To bridge this gap, new potent HAT inhibitors with improved properties need to be developed. However, several challenges have been encountered in the investigation of HATs and HAT inhibitors that hinder the development of new HAT inhibitors. HATs have been shown to function in complexes consisting of many proteins. These complexes play a role in the activity and target specificity of HATs, which limits the translation of in vitro to in vivo experiments. The current HAT inhibitors suffer from undesired properties like anti-oxidant activity, reactivity, instability, low potency, or lack of selectivity between HAT subtypes and other enzymes. A characteristic feature of HATs is that they are bi-substrate enzymes that catalyze reactions between two substrates: the cofactor acetyl coenzyme A (Ac-CoA) and a lysine-containing substrate. This has important-but frequently overlooked-consequences for the determination of the inhibitory potency of small molecule HAT inhibitors and the reproducibility of enzyme inhibition experiments. We envision that a careful characterization of molecular aspects of HATs and HAT inhibitors, such as the HAT catalytic mechanism and the enzyme kinetics of small molecule HAT inhibitors, will greatly improve the development of potent and selective HAT inhibitors and provide validated starting points for further development towards therapeutic agents. PMID- 27231490 TI - Imaging Spectrum of Hydatid Disease: Usual and Unusual Locations. AB - Hydatid disease is a parasitic infection caused by Echinococcus granulosus and Echinococcus multilocularis. It is common in endemic regions and can demonstrate a variety of imaging features that differ according to the affected organ and the stage of the disease. Liver and lungs are the most commonly affected organs. The classic features of hepatic hydatid disease are well known. However, diagnosing hydatid disease at unusual locations may be challenging because of myriad imaging features in each of these locations. Knowledge of the imaging spectrum in systemic hydatidoses in various organs is very valuable in improving the accuracy of radiological interpretation. The purpose of this article is to review the imaging features of hydatid disease at its varied locations. PMID- 27231489 TI - Ultraviolet-B induces ERCC6 repression in lens epithelium cells of age-related nuclear cataract through coordinated DNA hypermethylation and histone deacetylation. AB - BACKGROUND: Ultraviolet-B (UVB) exposure attributes to the formation of age related nuclear cataract (ARNC), which is mediated with DNA damage. DNA damage, an important factor for pathogenesis of ARNC, is induced by UVB, and is generally resolved by the nucleotide excision repair (NER) repair mechanism. Cockayne syndrome complementation group B (CSB) protein coded by ERCC6 is a vital component for NER. However, we found no association between selected ERCC6 polymorphisms and ARNC. In this study, we investigated whether UVB exposure could alter ERCC6 expression and the process could involve epigenetic changes of DNA methylation and/or histone acetylation of ERCC6 in the lens epithelial cells (LECs). We also assessed the involvement of those coordinated changes in lens tissue from ARNC patients. RESULTS: mRNA and protein expression of ERCC6 in lens tissue (LECs) were lower in ARNCs than those in the controls. This reduction corresponded to methylation of a CpG site at the ERCC6 promoter and histone modifications (methylation and acetylation) nearby this site. UVB-treated human lens epithelium B3 (HLE-B3) and 239T cell presented (1) increased apoptosis, suggesting reduced UV-damage repair, (2) hypermethylation of the CpG site located at position -441 (relative to transcription start site) within the binding region for transcriptional factor Sp1 in the ERCC6 promoter, (3) the enhancement of histone H3K9 deacetylation, (4) induction in DNA methyltransferases 3b (DNMT3b) and histone deacetylase1 (HDAC1) associated to the CpG site of ERCC6 by CHIP assay. CONCLUSIONS: These findings suggest an orchestrated mechanism triggered by UVB radiation where the concurrent association of specific hypermethylation CpG site, H3K9 deacetylation of ERCC6, and repression of ERCC6 gene expression. Taken together, with the similar changes in the lens tissue from ARNC patients, our data unveiled a possible mechanism of epigenetic modification of DNA repair gene in the pathogenesis of ARNC. PMID- 27231491 TI - Skeletal Metastasis From Carcinoma of the Gall Bladder: Need for Bone Scintigraphy Justified? AB - BACKGROUND: Carcinoma of the gall bladder has a guarded prognosis with predominant sites of involvement being liver and regional nodes. Osseous metastasis in carcinoma of the gall bladder is rare and hence bone scintigraphy does not form a part of the routine work-up for such patients. CASE REPORTS: We describe two patients with carcinoma of the gall bladder with osteolytic metastasis (stage 4). Conservative treatment was planned but both of them succumbed to the illness. CONCLUSIONS: We thus highlight the importance of performing a bone scan or PET CT in cases of carcinoma of the gall bladder. Besides, our cases challenge Paget's seed - soil theory for sites of metastasis. PMID- 27231492 TI - Anterior Urethral Valve: A Rare But an Important Cause of Infravesical Urinary Tract Obstruction. AB - BACKGROUND: Urethral valves are infravesical congenital anomalies, with the posterior urethral valve (PUV) being the most prevalent one. Anterior urethral valve (AUV) is a rare but a well-known congenital anomaly. AUV and diverticula can cause severe obstruction, whose repercussions on the proximal urinary system can be important. Few cases have been described; both separately and in association with urethral diverticulum. The presentation of such a rare but important case led us to a report with highlighting its classic imaging features. CASE REPORT: We present a case report of AUV with lower urinary tract symptoms in a 6-year-old boy with complaints of a poor stream of urine and strain to void. Unique findings were seen on Retrograde Urethrography (RGU) and Voiding Cysto Urethrography (VCUG), i.e. linear incomplete filling defect in the penile urethra and associated mild dilatation of the anterior urethra ending in a smooth bulge. On cysto-urethroscopy the anterior urethral valve was confirmed and fulguration was done. CONCLUSIONS: Congenital anterior urethral valve is an uncommon but important cause of infravesical lower urinary tract obstruction that is more common in male urethra. It can occur as an isolated AUV or in association with diverticulum and VATER anomalies. Early diagnosis and management of this rare condition is very important to prevent further damage, infection and vesicoureteral reflux. AUV may be associated with other congenital anomalies of the urinary system; therefore a full evaluation of the urinary system is essential. PMID- 27231493 TI - Amygdala Volumetry in Patients with Temporal Lobe Epilepsy and Normal Magnetic Resonance Imaging. AB - BACKGROUND: It has been suggested that the pathophysiology of temporal lobe epilepsy may relate to abnormalities in various brain structures, including the amygdala. Patients with mesial temporal lobe epilepsy (MTLE) without MRI abnormalities (MTLE-NMRI) represent a challenge for diagnosis of the underlying abnormality and for presurgical evaluation. To date, however, only few studies have used quantitative structural Magnetic Resonance Imaging-based techniques to examine amygdalar pathology in these patients. MATERIAL/METHODS: Based on clinical examination, 24-hour video EEG recordings and MRI findings, 50 patients with EEG lateralized TLE and normal structural Magnetic Resonance Imaging results were included in this study. Volumetric magnetic resonance imaging (MRI) studies of the amygdalas and hippocampi were conducted in 50 non-epileptic controls (age 7-79 years) and 50 patients with MTLE with normal MRI on a 1.5-Tesla scanner. Visual assessment and amygdalar volumetry were performed on oblique coronal T2W and T1W MP-RAGE images respectively. The T2 relaxation times were measured using the 16-echo Carr-Purcell-Meiboom-Gill sequence (TE, 22-352). Volumetric data were normalized for variation in head size between individuals. Results were assessed by SSPS statistic program. RESULTS: Individual manual volumetric analysis confirmed statistically significant amygdala enlargement (AE) in eight (16%) patients. Overall, among all patients with AE and a defined epileptic focus, 7 had predominant increased volume ipsilateral to the epileptic focus. The T2 relaxometry demonstrated no hyperintense signal of the amygdala in any patient with significant AE. CONCLUSIONS: This paper presented AE in a few patients with TLE and normal MRI. These findings support the hypothesis that there might be a subgroup of patients with MTLE-NMRI in which the enlarged amygdala could be related to the epileptogenic process. PMID- 27231494 TI - Pelvimetry by Three-Dimensional Computed Tomography in Non-Pregnant Multiparous Women Who Delivered Vaginally. AB - BACKGROUND: We assessed retrospectively the reference values of pelvic dimensions by 3D CT performed for non-obstetrical indications in non-pregnant multiparous women with a successful vaginal delivery. We further aimed to evaluate the impact of maternal short stature on these parameters. MATERIAL/METHODS: The 3D CT pelvimetry was performed retrospectively in 203 non-pregnant women selected consecutively if they had at least one singleton term delivery with head presentation and if there was no history of maternal or fetal birth trauma or cerebral palsy after childbirth. With standard sagittal and reformatted axial oblique views, anteroposterior including three conjugates of pelvic inlet, transverse, posterior sagittal diameters of pelvic inlet, the plane of greatest diameter, the plane of least diameter, and pelvic outlet were measured. Selected obstetric parameters were collected. RESULTS: Overall, the pelvises had transverse oval appearance in inlet and size of the female pelvis. The diagonal conjugate was at least 15 mm longer than the obstetric conjugate. Women with short stature had lower maximal birth weight, and this was in accordance with their somewhat lower pelvic diameters. CONCLUSIONS: The findings of this study present the reference values of the main planes of the true pelvis by 3D CT pelvimetry in a relatively large group of multiparous women who passed a trial of labor successfully. Overall, the pelvises had features of female pelvic bony structure although pelvic diameters were somewhat lower in multiparous women with short stature. The 3D pelvimetry with CT applications may be used as an adjunct to clinical and ultrasonographic examinations to rule out cephalopelvic dystocia in selected cases. PMID- 27231495 TI - Anatomical Evaluation of the Pulmonary Veins and the Left Atrium Using Computed Tomography Before Catheter Ablation: Reproducibility of Measurements. AB - BACKGROUND: Atrial fibrillation (AF) is a common supraventricular arrhythmia. ECG gated MDCT seems to be currently a method of choice for pre-ablation anatomical mapping due to an excellent resolution and truly isotropic three-dimensional nature. The aim of this study was to establish the between-subject variability and inter-observer reproducibility of anatomical evaluation of the pulmonary veins (PV) and the left atrium (LA) using computed tomography. MATERIAL/METHODS: A retrospective analysis included 42 patients with AF, who were scheduled for a cardiac CT for ablation planning. Images were assessed by two independent radiologists using a semi-automatic software tool. The left atrium anatomy (volume, AP diameter), anatomy of the pulmonary veins (number, ostia diameters and surface area) were evaluated. The relative between-subject variability and the inter-observer variability of measurements were calculated. RESULTS: The heart rate during scanning ranged from 50 to 133/min. (mean 79.1/min.) and all examinations were of adequate image quality. Accessory pulmonary veins were found in 24% of patients. Between-subject variability of the PV ostial cross-sectional area ranged from 33% to 48%. The variability of the left atrium size was 21% for the diameter and 35% for the volume. The inter-observer agreement for the detection of accessory pulmonary veins was good (kappa=0.73; 95% CI, 0.54-0.93). CONCLUSIONS: Between-subject variability of the pulmonary vein ostial cross sectional area and the left artial volume is substantial. The anatomical assessment of the pulmonary vein ostia and the left atrium size in computed tomography presents a good inter-observer reproducibility. PMID- 27231497 TI - [Dislocation tibio-talar pure in a young athlete]. PMID- 27231496 TI - CHANGE POINT ANALYSIS OF HISTONE MODIFICATIONS REVEALS EPIGENETIC BLOCKS LINKING TO PHYSICAL DOMAINS. AB - Histone modification is a vital epigenetic mechanism for transcriptional control in eukaryotes. High-throughput techniques have enabled whole-genome analysis of histone modifications in recent years. However, most studies assume one combination of histone modification invariantly translates to one transcriptional output regardless of local chromatin environment. In this study we hypothesize that, the genome is organized into local domains that manifest similar enrichment pattern of histone modification, which leads to orchestrated regulation of expression of genes with relevant biological functions. We propose a multivariate Bayesian Change Point (BCP) model to segment the Drosophila melanogaster genome into consecutive blocks on the basis of combinatorial patterns of histone marks. By modeling the sparse distribution of histone marks with a zero-inflated Gaussian mixture, our partitions capture local BLOCKs that manifest relatively homogeneous enrichment pattern of histone marks. We further characterized BLOCKs by their transcription levels, distribution of genes, degree of co-regulation and GO enrichment. Our results demonstrate that these BLOCKs, although inferred merely from histone modifications, reveal strong relevance with physical domains, which suggests their important roles in chromatin organization and coordinated gene regulation. PMID- 27231498 TI - Reflections on the Addis Ababa Immunization Conference of 2016. PMID- 27231499 TI - [Bilateral giant hydronephrosis in a ureteropelvic junction syndrome]. PMID- 27231500 TI - [Retrograde percutaneous screwing of the scaphoid]. PMID- 27231501 TI - [Unusual location of Ewing's sarcoma of soft parts]. PMID- 27231502 TI - [Villonodular synovitis of the ankle, an uncommon location: a case report]. AB - Pigmented villonodular synovitis (PVNS) is a rare pseudotumoral proliferative benign condition of unknown etiology, affecting synovial joints. It can also develop in the synovial bursae and in the tendon sheaths. It usually affects large joints, such as the knee and the hip. Ankle is a rare location, with only a few cases reported in the literature. We report a case of a 52 year old patient with a PVS of the right ankle. She received a subtotal synovectomy. After 2 years of follow-up there was no clinical recurrence. PMID- 27231503 TI - [Squamous cell carcinoma of the penis]. PMID- 27231504 TI - [Dorsal carpometacarpal dislocations of fourth and fifth metacarpal without fracture]. PMID- 27231505 TI - [Pancreatic serous cystadenoma associated with pancreatic heterotopia]. AB - Pancreatic heterotopias (HP) are rare. They can occur at any age with a slight male predominance. These lesions are usually asymptomatic and they are often found incidentally during upper or lower GI endoscopy or during the anatomo pathological examination of an organ which was resected for other reasons; they can be isolated or associated with a digestive pathology. We report, through observation, the association of HP with serous cystadenoma of the pancreas discovered during examinations to identify the etiology of isolated abdominal pain. The aim of this study is to analyse clinical and histological features of this rare pathology. PMID- 27231506 TI - Urethral hemangioma: case report and review of the literature. AB - Hemangiomas are benign vascular tumors. They are the prerogative of the liver and skin. And genitourinary localizations are rare and have only been rarely reported in the prostat, bladder, ureter or the perineum. In the light of published cases, urethral hemangiomas are mostly found in males. Few cases of hemangioma in the female urethra were reported. We report a cavernous hemangioma of the urethra in a 61 years old patient who presented bleeding from the urethra and micturition disorders. Physical examination revealed a tumor 3 cm x 2 polyploid arising from the terminal urethra (urethral hemangioma). We performed surgical resection of the tumor, along with bladder drainage. The postoperative course was simple. We update through a review of the literature aspects of the diagnostic and therapeutic care of the urethral hemangioma. PMID- 27231507 TI - [Pleuropulmonary metastasis revealing a malignant melanoma of the conjunctiva in a young subject]. AB - Melanoma of the conjunctiva is a rare tumor with incidence from 0,03 to 0,08 cases per 100000 white population. Metastatic malignant melanoma represents approximately 5% of all secondary malignant lung tumors. We report the unexpected discovery of a pulmonary and pleural metastasis from a conjunctival melanoma in a young subject. PMID- 27231508 TI - [Consanguineous marriage and morbi-mortality, short literature review based on an exceptional association: Usher syndrome and Von Recklinghausen neurofibromatosis]. AB - Usher syndrome is defined by the association of a progressive or non-progressive congenital sensorineural hearing loss with variable severity and a gradually blinding pigmentary retinopathy. Von Recklinghausen neurofibromatosis or Neurofibromatosis type 1 is the major clinically form of neurofibromatosis which occurs in approximately 90% of cases. Both types of disease are genetic in origin with very low prevalence. The probability of co-occurrence of these diseases in a single individual is exceptional. Inbreeding, as well as all genetic diseases, increases quite significantly the probability of their occurrence. Consanguineous marriages are still widespread in Maghreb and in some regions of the western African. This observation reports an exceptional case of this association in a 40 year-old man of Mauritanian origin born from a consanguineous union. PMID- 27231510 TI - Rare case of pure medial subtalar dislocation in a basketball player. PMID- 27231509 TI - T cell subset profile in healthy Zambian adults at the University Teaching Hospital. AB - INTRODUCTION: Symptom-free human immunodeficiency virus antibody-negative Zambian adults (51 subjects, aged 20 to 62 years, 33.3% women and 66.7% men) were studied to establish T cell subset reference ranges. METHODS: We carried out across sectional study at the University Teaching Hospital, Lusaka. Blood samples were collected from healthy donor volunteers from hospital health care staff, between February and March 2015. Immunopheno typing was undertaken to characterize Tcell subsets using the markers CD3, CD4, CD8, alpha4beta7, Ki67, CD25, CCR7, CD54RA, CD57, CD28, CD27 and HLA-DR. RESULTS: Among 51 volunteers, Women had significantly higher absolute CD4 count (median 1042; IQR 864, 1270) than in men (671; 545, 899) (p=0.003). Women also had more CD4 cells expressing homing, naive, effector and effector memory T cell subsets compared to men. However, in the CD8 population, only the effector cells were significantly different with women expressing more than the males. CONCLUSION: We provide early reference range for T cell subsets in Zambian adults and conclude that among the African women some T cell subsets are higher than men. PMID- 27231511 TI - [Late-onset pituitary stalk interruption syndrome (PSIS)]. AB - Pituitary stalk interruption syndrome is a fairly common cause of the deficiency of Growth Hormone and hypopituitarism often revealed in the neonatal period and childhood. This observation illustrates the peculiarities of a late clinical onset of this syndrome. We report a case of a 17-year-old patient hospitalized for primary amenorrhoea and impuberism. She had no history of neonatal incident. Clinical examination revealed severe growth retardation Hypophysiogramme showed complete hypopituitarism without diabetes insipidus. Magnetic resonance imaging revealed pituitary stalk interruption and an ectopic posterior pituitary gland. Kidney malformation was objectified, which is in favour of a congenital malformative origin of this syndrome. Hormone replacement was administered to this patient. This late-onset form emphasizes the need for early diagnosis of impuberism and/or stunting, revealing a potentially very serious pathology. PMID- 27231512 TI - Targeted therapy of gastrointestinal stromal tumours. AB - Gastrointestinal stromal tumours (GISTs) are mesenchymal neoplasms originating in the gastrointestinal tract, usually in the stomach or the small intestine, and rarely elsewhere in the abdomen. The malignant potential of GISTs is variable ranging from small lesions with a benign behaviour to fatal sarcomas. The majority of the tumours stain positively for the CD-117 (KIT) and discovered on GIST-1 (DOG-1 or anoctamin 1) expression, and they are characterized by the presence of a driver kinase-activating mutation in either KIT or platelet-derived growth factor receptor alpha. Although surgery is the primary modality of treatment, almost half of the patients have disease recurrence following surgery, which highlights the need for an effective adjuvant therapy. Traditionally, GISTs are considered chemotherapy and radiotherapy resistant. With the advent of targeted therapy (tyrosine kinase inhibitors), there has been a paradigm shift in the management of GISTs in the last decade. We present a comprehensive review of targeted therapy in the management of GISTs. PMID- 27231513 TI - Implications of preoperative hypoalbuminemia in colorectal surgery. AB - Serum albumin has traditionally been used as a quantitative measure of a patient's nutritional status because of its availability and low cost. While malnutrition has a clear definition within both the American and European Societies for Parenteral and Enteral Nutrition clinical guidelines, individual surgeons often determine nutritional status anecdotally. Preoperative albumin level has been shown to be the best predictor of mortality after colorectal cancer surgery. Specifically in colorectal surgical patients, hypoalbuminemia significantly increases the length of hospital stay, rates of surgical site infections, enterocutaneous fistula risk, and deep vein thrombosis formation. The delay of surgical procedures to allow for preoperative correction of albumin levels in hypoalbuminemic patients has been shown to improve the morbidity and mortality in patients with severe nutritional risk. The importance of preoperative albumin levels and the patient's chronic inflammatory state on the postoperative morbidity and mortality has led to the development of a variety of surgical scoring systems to predict outcomes efficiently. This review attempts to provide a systematic overview of albumin and its role and implications in colorectal surgery. PMID- 27231515 TI - Critical appraisal of laparoscopic lavage for Hinchey III diverticulitis. AB - Laparoscopic lavage and drainage is a novel approach for managing patients with Hinchey III diverticulitis. However, this less invasive technique has important limitations, which are highlighted in this systematic review. We performed a PubMed search and identified 6 individual series reporting the results of this procedure. An analysis was performed regarding treatment-related morbidity, success rates, and subsequent elective sigmoid resection. Data was available for 287 patients only, of which 213 (74%) were actually presenting with Hinchey III diverticulitis. Reported success rate in this group was 94%, with 3% mortality. Causes of failure were: (1) ongoing sepsis; (2) fecal fistula formation; and (3) perforated sigmoid cancer. Although few patients developed recurrent diverticulitis in follow-up, 106 patients (37%) eventually underwent elective sigmoid resection. Our data indicate that laparoscopic lavage and drainage may benefit a highly selected group of Hinchey III patients. It is unclear whether laparoscopic lavage and drainage should be considered a curative procedure or just a damage control operation. Failure to identify patients with either: (1) feculent peritonitis (Hinchey IV); (2) persistent perforation; or (3) perforated sigmoid cancer, are causes of concern, and will limit the application of this technique. PMID- 27231514 TI - Inflammatory bowel disease surgery in the biologic era. AB - Anti-tumour necrosis factor (TNF)-alpha therapy has revolutionized inflammatory bowel disease (IBD) treatment. Infliximab and adalimumab either as monotherapy or in combination with an immunomodulator are able to induce clinical and biological remission in patients with moderate and severe Crohn's disease (CD) and ulcerative colitis (UC). These new therapies have led to a shift in the goals of IBD management from just controlling clinical symptoms to preventing disease progression. However, despite these advances in medical therapy, surgery is still required in 30%-40% of patients with CD and 20%-30% of patients with UC at some point during their lifetime. While biologics certainly play a major role in the medical treatment of IBD, there is concern about the effects of these anti-TNF alpha agents on postoperative complications and morbidity. The purpose of this article is to review the role of surgery in the treatment of IBD in the age of biologics and the impact of these medications on per-operative outcomes. In this manuscript we review the relationship between biologic agents and surgery in the treatment of IBD. We also discuss in detail the periopetative risks and complications. PMID- 27231516 TI - Role of laparoscopic common bile duct exploration in the management of choledocholithiasis. AB - Surgical fraternity has not yet arrived at any consensus for adequate treatment of choledocholithiasis. Sequential treatment in the form of pre-operative endoscopic retrograde cholangio-pancreatography followed by laparoscopic cholecystectomy (LC) is considered as optimal treatment till date. With refinements in technique and expertise in field of minimal access surgery, many centres in the world have started offering one stage management of choledocholithiasis by LC with laparoscopic common bile duct exploration (LCBDE). Various modalities have been tried for entering into concurrent common bile duct (CBD) [transcystic (TC) vs transcholedochal (TD)], for confirming stone clearance (intraoperative cholangiogram vs choledochoscopy), and for closure of choledochotomy (T-tube vs biliary stent vs primary closure) during LCBDE. Both TC and TD approaches are safe and effective. TD stone extraction is involved with an increased risk of bile leaks and requires more expertise in intra-corporeal suturing and choledochoscopy. Choice depends on number of stones, size of stone, diameter of cystic duct and CBD. This review article was undertaken to evaluate the role of LCBDE for the management of choledocholithiasis. PMID- 27231517 TI - Enhanced recovery program is safe and improves postoperative insulin resistance in gastrectomy. AB - AIM: To assess the safety of enhanced recovery after surgery (ERAS) program in gastrectomy and influences on nutrition state and insulin-resistance. METHODS: Our ERAS program involved shortening the fasting periods and preoperative carbohydrate loading. Eighty gastrectomy patients were randomly assigned to either the conventional group (CG) or ERAS group (EG). We assessed the clinical characteristics and postoperative outcomes prospectively. The primary endpoint was noninferiority in timely discharge from the hospital within 12 d. Secondary endpoints were the incidence of aspiration at anesthesia induction, incidence of postoperative complications, health related quality of life (HRQOL) using the SF8 Health Survey questionnaire, nutrition state [e.g., albumin, transthyretin (TTR), retinal-binding protein (RBP), and transferrin (Tf)], the homeostasis model assessment-insulin resistance (HOMA-R) index, postoperative urine volume, postoperative weight change, and postoperative oral intake. RESULTS: The ERAS program was noninferior to the conventional program in achieving discharge from the hospital within 12 d (95.0% vs 92.5% respectively; 95%CI: -10.0%-16.0%). There was no significant difference in postoperative morbidity between the two groups. Adverse events such as vomiting and aspiration associated with the induction of general anesthesia were not observed. There were no significant differences with respect to postoperative urine volume, weight change, and oral intake between the two groups. EG patients with preoperative HOMA-R scores above 2.5 experienced significant attenuation of their HOMA-R scores on postoperative day 1 compared to CG patients (P = 0.014). There were no significant differences with respect to rapid turnover proteins (TTR, RBP and Tf) or HRQOL scores using the SF8 method. CONCLUSION: Applying the ERAS program to patients who undergo gastrectomy is safe, and improves insulin resistance with no deterioration in QOL. PMID- 27231518 TI - Therapeutic improvement of colonic anastomotic healing under complicated conditions: A systematic review. AB - AIM: To identify therapeutic agents for the prophylaxis of gastrointestinal anastomotic leakage (AL) under complicated conditions. METHODS: The PubMed and EMBASE databases were searched for English articles published between January 1975 and September 2014. Studies with the primary purpose of improving anastomotic healing in the colon or rectum under complicated preoperative and/or intraoperative conditions were included. We excluded studies investigating the adverse effects or risk assessment of an active intervention. Furthermore, investigations of biophysical materials, sealants, electrical stimulation and nutrients were excluded. The primary study outcome was biomechanical anastomotic strength or AL. The meta-analysis focused on therapeutic agents that were investigated in one animal model using the same outcome by at least three independent research groups. RESULTS: The 65 studies included were divided into 7 different complicated animal models: Bowel ischemia, ischemia/reperfusion, bowel obstruction, obstructive jaundice, peritonitis, chemotherapy and radiotherapy. In total, 48 different therapeutic compounds were examined. The majority of investigated agents (65%) were reported as beneficial for anastomotic healing. Twelve of the agents (25%) were tested more than once in the same model, whereas 13 (27%) of the agents were tested in two or more models of complicated healing. Two therapeutic agents met our inclusion criteria for the meta-analysis. Postoperative hyperbaric oxygen therapy significantly increased anastomotic bursting pressure in ischemic colon anastomoses by a mean of 28 mmHg (95%CI: 17 to 39 mmHg, P < 0.00001). Granulocyte macrophage-colony stimulating factor failed to show a significant increase in anastomotic bursting pressure (95%CI: -20 to 21 mmHg, P = 0.97) vs controls in experimental chemotherapeutic models. CONCLUSION: This systematic review identified potential therapeutic agents, but more studies are needed before concluding that any of these are useful for AL prophylaxis. PMID- 27231519 TI - P2Y12-ADP receptor antagonists: Days of future and past. AB - Antiplatelet therapy is the cornerstone of the therapeutic arsenal in coronary artery disease. Thanks to a better understanding in physiology, pharmacology and pharmacogenomics huge progress were made in the field of platelet reactivity inhibition thus allowing the expansion of percutaneous coronary intervention. Stent implantation requires the combination of two antiplatelet agents acting in a synergistic way. Asprin inhibit the cyclo-oxygenase pathway of platelet activation while clopidogrel is a P2Y12 adenosine diphosphate (ADP)-receptor antagonist. This dual antiplatelet therapy has dramatically improved the prognosis of stented patients. However, due to pharmacological limitations of clopidogrel (interindividual variability in its biological efficacy, slow onset of action, mild platelet reactivity inhibition) ischemic recurrences remained high following stent implantation especially in acute coronary syndrome patients. Thus, more potent P2Y12-ADP receptor inhibitors were developped including prasugrel, ticagrelor and more recently cangrelor to overcome these pitfalls. These new agents reduced the rate of thrombotic events in acute coronary syndrome patients at the cost of an increased bleeding risk. The abundance in antiplatelet agents allow us to tailor our strategy based on the thrombotic/bleeding profile of each patient. Recently, the ACCOAST trial cast a doubt on the benefit of pre treatment in non-ST segment elevation acute coronary syndrome. The aim of the present review is to summarize the results of the main studies dealing with antiplatelet therapy in stented/acute coronary syndromes patients. PMID- 27231520 TI - Mitochondrial vasculopathy. AB - Mitochondrial disorders (MIDs) are usually multisystem disorders (mitochondrial multiorgan disorder syndrome) either on from onset or starting at a point during the disease course. Most frequently affected tissues are those with a high oxygen demand such as the central nervous system, the muscle, endocrine glands, or the myocardium. Recently, it has been shown that rarely also the arteries may be affected (mitochondrial arteriopathy). This review focuses on the type, diagnosis, and treatment of mitochondrial vasculopathy in MID patients. A literature search using appropriate search terms was carried out. Mitochondrial vasculopathy manifests as either microangiopathy or macroangiopathy. Clinical manifestations of mitochondrial microangiopathy include leukoencephalopathy, migraine-like headache, stroke-like episodes, or peripheral retinopathy. Mitochondrial macroangiopathy manifests as atherosclerosis, ectasia of arteries, aneurysm formation, dissection, or spontaneous rupture of arteries. The diagnosis relies on the documentation and confirmation of the mitochondrial metabolic defect or the genetic cause after exclusion of non-MID causes. Treatment is not at variance compared to treatment of vasculopathy due to non-MID causes. Mitochondrial vasculopathy exists and manifests as micro- or macroangiopathy. Diagnosing mitochondrial vasculopathy is crucial since appropriate treatment may prevent from severe complications. PMID- 27231522 TI - Relationship between coronary artery ectasia, cocaine abuse and acute coronary syndromes. AB - Coronary artery ectasia (CAE) often represents a coronary angiography finding casually detected or following the occurrence of an acute coronary syndrome. The pathogenetic role of cocaine abuse in the genesis of CAE is still little known and very few data are available in literature. We describe a case of a 31-year old male cocaine user admitted to our department for typical acute chest pain. Coronary angiography showed diffuse coronary ectasia with slow flows and without hemodynamically significant stenosis. An increasing of matrix metalloproteinases values and a reduction of their tissue inhibitors was showed both during hospitalization and at one month after discharge. This case report emphasizes the close relationship between cocaine abuse, CAE and acute coronary syndromes in patients without hemodynamically significant coronary stenosis. As reported by Satran et al, cocaine abuse should be considered an important risk factor for CAE and these patients appear to be at increased risk of angina and acute myocardial infarct. Further studies that can strengthen this hypothesis would be useful to deepen and better analyze this interesting association. PMID- 27231521 TI - Tenascin C upregulates interleukin-6 expression in human cardiac myofibroblasts via toll-like receptor 4. AB - AIM: To investigate the effect of Tenascin C (TNC) on the expression of pro inflammatory cytokines and matrix metalloproteinases in human cardiac myofibroblasts (CMF). METHODS: CMF were isolated and cultured from patients undergoing coronary artery bypass grafting. Cultured cells were treated with either TNC (0.1 MUmol/L, 24 h) or a recombinant protein corresponding to different domains of the TNC protein; fibrinogen-like globe (FBG) and fibronectin type III-like repeats (TNIII 5-7) (both 1 MUmol/L, 24 h). The expression of the pro-inflammatory cytokines; interleukin (IL)-6, IL-1beta, TNFalpha and the matrix metalloproteinases; MMPs (MMP1, 2, 3, 9, 10, MT1-MMP) was assessed using real time RT-PCR and western blot analysis. RESULTS: TNC increased both IL-6 and MMP3 (P < 0.01) mRNA levels in cultured human CMF but had no significant effect on the other markers studied. The increase in IL-6 mRNA expression was mirrored by an increase in protein secretion as assessed by enzyme-linked immunosorbant assay (P < 0.01). Treating CMF with the recombinant protein FBG increased IL-6 mRNA and protein (P < 0.01) whereas the recombinant protein TNIII 5-7 had no effect. Neither FBG nor TNIII 5-7 had any significant effect on MMP3 expression. The expression of toll-like receptor 4 (TLR4) in human CMF was confirmed by real time RT-PCR, western blot and immunohistochemistry. Pre-incubation of cells with TLR4 neutralising antisera attenuated the effect of both TNC and FBG on IL-6 mRNA and protein expression. CONCLUSION: TNC up-regulates IL-6 expression in human CMF, an effect mediated through the FBG domain of TNC and via the TLR4 receptor. PMID- 27231523 TI - Erratum: Onion peel extract reduces the percentage of body fat in overweight and obese subjects: a 12-week, randomized, double-blind, placebo-controlled study. AB - [This corrects the article on p. 175 in vol. 10, PMID: 27087901.]. PMID- 27231524 TI - Cardiorespiratory Fitness and Body Composition of Soccer Referees; Do These Correlate With Proper Performance? AB - BACKGROUND: The elite-level referee is exposed to similar physical demands to those placed on a midfield soccer player. They have an important responsibility to implement the rules of the game. So, good health and performance of soccer referees have a great importance. OBJECTIVES: The purpose of this study was to assess the cardiorespiratory fitness and body composition of all 78 soccer referees officiating at the Iranian Premier League and determine the correlation between these parameters and performance. PATIENTS AND METHODS: In a cross sectional study, all referees selected for the competitions were enrolled. Participants underwent exercise stress test, pulmonary function test and body composition assessment. Then the weekly scores of each referee, assessed by qualified supervisors of national federation were obtained using the FIFA standard form throughout the season (34 weeks) and registered. RESULTS: Among 78 participants (including 32 center and 46 side referees), mean and standard deviation of age, body mass index, percent of body fat, VO2max and performance scores were 37 +/- 3.8, 23.6 +/- 2.1, 20.7 +/- 3.9, 59.9 +/- 7.1 and 85.8 +/- 0.25, respectively. No significant correlation between referees' mean score and selected parameters were found. CONCLUSIONS: It seems that the acquired scores of top-class referees may be influenced by multiple factors other than the laboratory findings of cardiopulmonary fitness and body composition. PMID- 27231525 TI - The Prevalence of Headache Among Athletic University Students. AB - BACKGROUND: Headache is certainly one of the most common medical complaints of general population and one of the important causes of consumption of drugs. Despite its high overall prevalence, the epidemiology of exertional headache is not clear enough. OBJECTIVES: To determine the prevalence of headache in athletic and non-athletic university students and also estimating its variation between different sports fields including concussion prone sports. MATERIALS AND METHODS: This cross-sectional study comprised 739 subjects (367 athletes and 372 non athletes). The present study was carried out on athletic and non-athletic university students aging between 18 to 28 years. An athlete was defined as a person who had at least one year of experience in sports including football, volleyball, basketball, wrestling, boxing, martial arts, track and field, chess, handball and swimming for three sessions a week each lasting at least 2 hours. The random selection of these participants was done by an independent statistical consultant. A questionnaire was used for data collection which was then analyzed by statistical methods. RESULTS: Our study comprised 739 subjects (367 athletes and 372 non-athletes). Among athletic university students, 152 (41.2%) participants complained of headache. Such a complaint was present in 217 (58.3%) non-athletic university students. This lower prevalence of headache in athletes was statistically significant (P value < 0.001). Among ten different sports fields, the prevalence of headache among wrestlers was significantly higher than others (P value < 0.001). CONCLUSIONS: The prevalence of headache is seemingly lower in athletic university students than non-athletic ones. In addition, among athletes, those who are participating in concussion prone sports especially wrestling experience headache more than athletes of other fields. PMID- 27231526 TI - Potential role of oxidative stress-induced apoptosis in mediating chromosomal rearrangements in nasopharyngeal carcinoma. AB - BACKGROUND: Genetic aberrations have been identified in nasopharyngeal carcinoma (NPC), however, the underlying mechanism remains elusive. There are increasing evidences that the apoptotic nuclease caspase-activated deoxyribonuclease (CAD) is one of the players leading to translocation in leukemia. Oxidative stress, which has been strongly implicated in carcinogenesis, is a potent apoptotic inducer. Most of the NPC etiological factors are known to induce oxidative stress. Although apoptosis is a cell death process, cells possess the potential to survive apoptosis upon DNA repair. Eventually, the surviving cells may carry rearranged chromosomes. We hypothesized that oxidative stress-induced apoptosis may cause chromosomal breaks mediated by CAD. Upon erroneous DNA repair, cells that survive apoptosis may harbor chromosomal rearrangements contributing to NPC pathogenesis. This study focused on the AF9 gene at 9p22, a common deletion region in NPC. We aimed to propose a possible model for molecular mechanism underlying the chromosomal rearrangements in NPC. RESULTS: In the present study, we showed that hydrogen peroxide (H2O2) induced apoptosis in NPC (HK1) and normal nasopharyngeal epithelial (NP69) cells, as evaluated by flow cytometric analyses. Activity of caspases 3/7 was detected in H2O2-treated cells. This activity was inhibited by caspase inhibitor (CI). By nested inverse polymerase chain reaction (IPCR), we demonstrated that oxidative stress-induced apoptosis in HK1 and NP69 cells resulted in cleavages within the breakpoint cluster region (BCR) of the AF9 gene. The gene cleavage frequency detected in the H2O2-treated cells was found to be significantly higher than untreated control. We further found that treatment with CI, which indirectly inhibits CAD, significantly reduced the chromosomal breaks in H2O2-cotreated cells. Intriguingly, a few breakpoints were mapped within the AF9 region that was previously reported to translocate with the mixed lineage leukemia (MLL) gene in acute lymphoblastic leukemia (ALL) patient. CONCLUSIONS: In conclusion, our findings suggested that oxidative stress-induced apoptosis could be one of the mechanisms underlying the chromosomal rearrangements in NPC. CAD may play an important role in chromosomal cleavages mediated by oxidative stress-induced apoptosis. A potential model for oxidative stress-induced apoptosis mediating chromosomal rearrangements in NPC is proposed. PMID- 27231527 TI - Intralymphatic immunotherapy induces allergen specific plasmablasts and increases tolerance to skin prick testing in a pilot study. AB - BACKGROUND: Allergen Immunotherapy is a promising treatment of allergy. Seven patients with rhinoconjunctivitis to grass allergen were treated with intralymphatic immunotherapy (ILIT) to explore whether this treatment could be performed. Effect of treatment was assessed as change in symptom medication score, response in skin prick test and nasal allergen provocation. ILIT deposits allergen in an inguinal lymph node to elicit a strong immune stimulus. This allowed us to monitor appearance of allergen specific plasmablasts 7 days after allergen injection. FINDINGS: In an open trial of seven patients with a history of symptomatic allergic rhinoconjunctivitis due to grass pollen, three injections of allergen into inguinal lymph nodes were performed with monthly intervals. Allergen injections induced grass allergen specific plasmablasts expressing other isotypes than IgE after 7 days, induced a trend toward improvement in symptom and medication score and rhinoconjunctivitis-related quality of life during the grass pollen season 2013 and significantly raised the threshold in nasal allergen challenge and titrated skin prick testing. Mild side-effects were recorded after 3 of the 21 of injections (14 %). CONCLUSIONS: This pilot study shows that ILIT may induce allergen specific plasmablasts, and confirms an effect on provocation of mast cells in skin and nasal mucosa during the ensuing winter. PMID- 27231528 TI - Cryptic diversity in Black rats Rattus rattus of the Galapagos Islands, Ecuador. AB - Human activity has facilitated the introduction of a number of alien mammal species to the Galapagos Archipelago. Understanding the phylogeographic history and population genetics of invasive species on the Archipelago is an important step in predicting future spread and designing effective management strategies. In this study, we describe the invasion pathway of Rattus rattus across the Galapagos using microsatellite data, coupled with historical knowledge. Microsatellite genotypes were generated for 581 R. rattus sampled from 15 islands in the archipelago. The genetic data suggest that there are at least three genetic lineages of R. rattus present on the Galapagos Islands. The spatial distributions of these lineages correspond to the main centers of human settlement in the archipelago. There was limited admixture among these three lineages, and these finding coupled with low rates of gene flow among island populations suggests that interisland movement of R. rattus is rare. The low migration among islands recorded for the species will have a positive impact on future eradication efforts. PMID- 27231529 TI - Effects of a protection gradient on carnivore density and survival: an example with leopards in the Luangwa valley, Zambia. AB - Human activities on the periphery of protected areas can limit carnivore populations, but measurements of the strength of such effects are limited, largely due to difficulties of obtaining precise data on population density and survival. We measured how density and survival rates of a previously unstudied leopard population varied across a gradient of protection and evaluated which anthropogenic activities accounted for observed patterns. Insights into this generalist's response to human encroachment are likely to identify limiting factors for other sympatric carnivore species. Motion-sensitive cameras were deployed systematically in adjacent, similarly sized, and ecologically similar study areas inside and outside Zambia's South Luangwa National Park (SLNP) from 2012 to 2014. The sites differed primarily in the degree of human impacts: SLNP is strictly protected, but the adjacent area was subject to human encroachment and bushmeat poaching throughout the study, and trophy hunting of leopards prior to 2012. We used photographic capture histories with robust design capture recapture models to estimate population size and sex-specific survival rates for the two areas. Leopard density within SLNP was 67% greater than in the adjacent area, but annual survival rates and sex ratios did not detectably differ between the sites. Prior research indicated that wire-snare occurrence was 5.2 times greater in the areas adjacent to the park. These results suggest that the low density of leopards on the periphery of SLNP is better explained by prey depletion, rather than by direct anthropogenic mortality. Long-term spatial data from concurrent lion studies suggested that interspecific competition did not produce the observed patterns. Large carnivore populations are often limited by human activities, but science-based management policies depend on methods to rigorously and quantitatively assess threats to populations of concern. Using noninvasive robust design capture-recapture methods, we systematically assessed leopard density and survival across a protection gradient and identified bushmeat poaching as the likely limiting factor. This approach is of broad value to evaluate the impacts of anthropogenic activities on carnivore populations that are distributed across gradients of protection. PMID- 27231530 TI - Plant density can increase invertebrate postdispersal seed predation in an experimental grassland community. AB - Janzen-Connell effects are negative effects on the survival of a plant's progeny at high conspecific densities or close to its conspecifics. Although the role of Janzen-Connell effects on the maintenance of plant diversity was frequently studied, only few studies targeted Janzen-Connell effects via postdispersal seed predation in temperate grassland systems. We examined effects of conspecific density (abundance of conspecific adult plants) on postdispersal seed predation by invertebrates of three grassland species (Centaurea jacea, Geranium pratense, and Knautia arvensis) in experimental plant communities. Additionally, we examined the impact of plant species richness and different seed predator communities on total and relative seed predation (= seed predation of one plant species relative to others). We offered seeds in an exclusion experiment, where treatments allowed access for (1) arthropods and slugs, (2) arthropods only, (3) small arthropods only, and (4) slugs only. Treatments were placed in plots covering a gradient of abundance of conspecific adults at different levels of plant species richness (1, 2, 3, 4, 8 species). Two of the plant species (C. jacea and K. arvensis) experienced higher rates of seed predation and relative predation with increasing abundance of conspecific adults. For C. jacea, this effect was mitigated with increasing plant species richness. Differences in seed predator communities shifted seed predation between the plant species and changed the magnitude of seed predation of one plant species relative to the others. We exemplify density-dependent increase in seed predation via invertebrates in grassland communities shaping both the total magnitude of species-specific seed predation and seed predation of one species relative to others. Further differences in seed predator groups shift the magnitude of seed predation between different plant species. This highlights the importance of invertebrate seed predation to structure grasslands via density-dependent effects and differing preferences of consumer groups. PMID- 27231531 TI - Evolutionary ecology of pipefish brooding structures: embryo survival and growth do not improve with a pouch. AB - For animals that reproduce in water, many adaptations in life-history traits such as egg size, parental care, and behaviors that relate to embryo oxygenation are still poorly understood. In pipefishes, seahorses and seadragons, males care for the embryos either in some sort of brood pouch, or attached ventrally to the skin on their belly or tail. Typically, egg size is larger in the brood pouch group and it has been suggested that oxygen supplied via the pouch buffers the developing embryos against hypoxia and as such is an adaptation that has facilitated the evolution of larger eggs. Here, using four pipefish species, we tested whether the presence or absence of brood pouch relates to how male behavior, embryo size, and survival are affected by hypoxia, with normoxia as control. Two of our studied species Entelurus aequoreus and Nerophis ophidion (both having small eggs) have simple ventral attachment of eggs onto the male trunk, and the other two, Syngnathus typhle (large eggs) and S. rostellatus (small eggs), have fully enclosed brood pouches on the tail. Under hypoxia, all species showed lower embryo survival, while species with brood pouches suffered greater embryo mortality compared to pouchless species, irrespective of oxygen treatment. Behaviorally, species without pouches spent more time closer to the surface, possibly to improve oxygenation. Overall, we found no significant benefits of brood pouches in terms of embryo survival and size under hypoxia. Instead, our results suggest negative effects of large egg size, despite the protection of brood pouches. PMID- 27231532 TI - Genetic population structure and relatedness in the narrow-striped mongoose (Mungotictis decemlineata), a social Malagasy carnivore with sexual segregation. AB - Information on the genetic structure of animal populations can allow inferences about mechanisms shaping their social organization, dispersal, and mating system. The mongooses (Herpestidae) include some of the best-studied mammalian systems in this respect, but much less is known about their closest relatives, the Malagasy carnivores (Eupleridae), even though some of them exhibit unusual association patterns. We investigated the genetic structure of the Malagasy narrow-striped mongoose (Mungotictis decemlineata), a small forest-dwelling gregarious carnivore exhibiting sexual segregation. Based on mtDNA and microsatellite analyses, we determined population-wide haplotype structure and sex-specific and within-group relatedness. Furthermore, we analyzed parentage and sibship relationships and the level of reproductive skew. We found a matrilinear population structure, with several neighboring female units sharing identical haplotypes. Within-group female relatedness was significantly higher than expected by chance in the majority of units. Haplotype diversity of males was significantly higher than in females, indicating male-biased dispersal. Relatedness within the majority of male associations did not differ from random, not proving any kin-directed benefits of male sociality in this case. We found indications for a mildly promiscuous mating system without monopolization of females by males, and low levels of reproductive skew in both sexes based on parentages of emergent young. Low relatedness within breeding pairs confirmed immigration by males and suggested similarities with patterns in social mongooses, providing a starting point for further investigations of mate choice and female control of reproduction and the connected behavioral mechanisms. Our study contributes to the understanding of the determinants of male sociality in carnivores as well as the mechanisms of female competition in species with small social units. PMID- 27231533 TI - Aging alters interspecific competition between two sympatric insect-parasitic nematode species. AB - Interspecific competition can vary depending on the stage, age, or physiological state of the competitors. Competitive ability often increases with age or size; alternatively, senescence can lead to a loss of viability and reduced competitive success. Differences between species in their age-specific competitive abilities can promote coexistence in the face of substantial niche overlap.We examined two sympatric species of nematodes (genus Steinernema) to determine whether their competitive relationship changes as a function of age. These obligately killing insect parasites are known for their broad host ranges and are transmitted from insect to insect via a juvenile stage propagule that is free-living in the soil. Here, we tested whether the two species differed in the effects of age by examining the mortality of insect hosts infected with young or old transmission stage nematodes of each species. We also performed mixed infections, where an equal ratio of both species was simultaneously exposed to a host, to determine the effect of age on competitiveness.One species showed reduced performance with age, as older propagules were slower at inducing host mortality. In contrast, the other species increased in killing speed with age. In competition, insect mortality rate was predictive of competitive outcome, such that if one species induced considerably faster host death in a single-species infection, it was competitively dominant in the coinfection. Accordingly, we found a shift in the competitive relationship between the two species with age.Our work demonstrates that species differences in the effects of aging can lead to dramatic shifts in reproductive success. As these effects are realized solely in a competitive environment, both spatial patchiness and temporal niche partitioning may be important for promoting coexistence. PMID- 27231534 TI - Nonrandom filtering effect on birds: species and guilds response to urbanization. AB - Using bird survey data taken in three cities in Southern Chile, we evaluated the hypothesis that changes in community composition from periurban to urban areas are not random. Furthermore, the consistency of species and guild loss was assessed across cities. A consistent pattern of difference in community and guild structure between urban and periurban habitats was found. In addition, a nonrandom loss of species was found in urban areas compared to periurban areas, and non-native species dominated urban communities in all cities. The average abundance of omnivores, granivores, and habitat generalists was higher in urban areas, while insectivores and open habitat species were more abundant in periurban areas. These results strongly suggest that urban habitats act as filters offering suitable conditions for only a fraction of the bird species present in a given area, and the lack of suitable conditions may be facilitating local biotic homogenization in the three studied cities. The results of this study not only fill a biogeographical knowledge gap, but the work presented here also aids the general understanding of factors that affect community structure in habitats with varied levels of local and global urbanization. PMID- 27134725 TI - The TOUCH program and natalizumab: Fundamental flaw in patient protection. AB - Many drugs have been approved by the Food and Drug Administration (FDA) since 1993 for treatment of relapsing forms of multiple sclerosis (MS). One such drug is natalizumab (Tysabri, Biogen Idec and Elan pharmaceuticals) which has enjoyed great success in the management of MS since its re-introduction in 2006. One of the complications of using natalizumab is the risk of development of progressive multifocal leukoencephalopathy (PML). To mitigate the risk of PML development, Biogen Idec initiated the TOUCH program - this strategy helps monitor the disease. Clinical vigilance remains key in the early diagnosis of PML but serological testing for the John Cunningham Virus Antibody (JCV) helps with risk stratification of PML. However, some physicians do not test for the JCV Ab and since they are not required to send such data to the company or inform the patient, one red flag for suspicion of PML is lost particularly if the patient is asymptomatic. This undercuts the premise of the TOUCH program. In an ideal world, reporting JCV Ab status should be made mandatory since that ensures a basic tenet of the program is met - to identify patients at increased risk of developing PML and make appropriate recommendations based on that finding. Lack of requirement of reporting of this vital finding opens the door for uncertainty in assessment of risk PML development and everyone remains in the dark till it may be too late. This is unacceptable when the company created the TOUCH program specifically with intent to track PML risk in patients on natalizumab. It makes no scientific sense to let the drug be used without setting stringent criteria given the possibility of PML development. PMID- 27081475 TI - The dream of health information for all. AB - In 2004, an influential report in The Lancet suggested that open health information for all could be achieved by 2015. Unfortunately, this goal has not yet been accomplished. Despite progress in obtaining quality scientific articles in Latin America, it remains difficult to reliably access new and cutting-edge research. As graduating Peruvian medical students, we have confronted many obstacles in obtaining access to quality and up-to-date information and a constant tension between accessing "what is available" rather than "what we need". As we have learned, these limitations affect not only our own education but also the choices we make in the management of our patients. In the following article, we state our point of view regarding limitations in access to scientific articles in Peru and Latin America. PMID- 27158455 TI - Case Report: Multifocal biphasic squamoid alveolar renal cell carcinoma. AB - A multifocal biphasic squamoid alveolar renal cell carcinoma in a 68-year-old man is reported. Four different peripheral tumor nodules were identified on gross examination. A fifth central tumor corresponded to a conventional clear cell renal cell carcinoma. Biphasic squamoid alveolar renal cell carcinoma is a rare tumor that has been very recently characterized as a distinct histotype within the spectrum of papillary renal cell carcinoma. Immunostaining with cyclin D1 seems to be specific of this tumor subtype. This is the first reported case with multifocal presentation. PMID- 27134733 TI - Closing gaps between open software and public data in a hackathon setting: User centered software prototyping. AB - In genomics, bioinformatics and other areas of data science, gaps exist between extant public datasets and the open-source software tools built by the community to analyze similar data types. The purpose of biological data science hackathons is to assemble groups of genomics or bioinformatics professionals and software developers to rapidly prototype software to address these gaps. The only two rules for the NCBI-assisted hackathons run so far are that 1) data either must be housed in public data repositories or be deposited to such repositories shortly after the hackathon's conclusion, and 2) all software comprising the final pipeline must be open-source or open-use. Proposed topics, as well as suggested tools and approaches, are distributed to participants at the beginning of each hackathon and refined during the event. Software, scripts, and pipelines are developed and published on GitHub, a web service providing publicly available, free-usage tiers for collaborative software development. The code resulting from each hackathon is published at https://github.com/NCBI-Hackathons/ with separate directories or repositories for each team. PMID- 27231539 TI - Integration of antenatal care services with health programmes in low- and middle income countries: systematic review. AB - BACKGROUND: Antenatal care (ANC) presents a potentially valuable platform for integrated delivery of additional health services for pregnant women-services that are vital to reduce the persistently high rates of maternal and neonatal mortality in low- and middle-income countries (LMICs). However, there is limited evidence on the impact of integrating health services with ANC to guide policy. This review assesses the impact of integration of postnatal and other health services with ANC on health services uptake and utilisation, health outcomes and user experience of care in LMICs. METHODS: Cochrane Library, MEDLINE, Embase, CINAHL Plus, POPLINE and Global Health were searched for studies that compared integrated models for delivery of postnatal and other health services with ANC to non-integrated models. Risk of bias of included studies was assessed using the Cochrane Effective Practice and Organisation of Care (EPOC) criteria and the Newcastle-Ottawa Scale, depending on the study design. Due to high heterogeneity no meta-analysis could be conducted. Results are presented narratively. FINDINGS: 12 studies were included in the review. Limited evidence, with moderate- to high risk of bias, suggests that integrated service delivery results in improved uptake of essential health services for women, earlier initiation of treatment, and better health outcomes. Women also reported improved satisfaction with integrated services. CONCLUSIONS: The reported evidence is largely based on non randomised studies with poor generalizability, and therefore offers very limited policy guidance. More rigorously conducted and geographically diverse studies are needed to better ascertain and quantify the health and economic benefits of integrating health services with ANC. PMID- 27231540 TI - Patterns and determinants of antenatal care utilization: analysis of national survey data in seven countdown countries. AB - BACKGROUND: Antenatal care (ANC) is critical for improving maternal and newborn health. WHO recommends that pregnant women complete at least four ANC visits. Countdown and other global monitoring efforts track the proportions of women who receive one or more visits by a skilled provider (ANC1+) and four or more visits by any provider (ANC4+). This study investigates patterns of drop-off in use between ANC1+ and ANC4+, and explores inequalities in women's use of ANC services. It also identifies determinants of utilization and describes countries' ANC-related policies, and programs. METHODS: We performed secondary analyses using Demographic Health Survey (DHS) data from seven Countdown countries: Bangladesh, Cambodia, Cameroon, Nepal, Peru, Senegal and Uganda. The descriptive analysis illustrates country variations in the frequency of visits by provider type, content, and by household wealth, women's education and type of residence. We conducted a multivariable analysis using a conceptual framework to identify determinants of ANC utilization. We collected contextual information from countries through a standard questionnaire completed by country-based informants. RESULTS: Each country had a unique pattern of ANC utilization in terms of coverage, inequality and the extent to which predictors affected the frequency of visits. Nevertheless, common patterns arise. Women having four or more visits usually saw a skilled provider at least once, and received more evidence-based content interventions than women reporting fewer than four visits. A considerable proportion of women reporting four or more visits did not report receiving the essential interventions. Large disparities exist in ANC use by household wealth, women's education and residence area; and are wider for a larger number of visits. The multivariable analyses of two models in each country showed that determinants had different effects on the dependent variable in each model. Overall, strong predictors of ANC initiation and having a higher frequency (4+) of visits were woman's education and household wealth. Gestational age at first visit, birth rank and preceding birth interval were generally negatively associated with initiating visits and with having four or more visits. Information on country policies and programs were somewhat informative in understanding the utilization patterns across the countries, although timing of adoption and actual implementation make direct linkages impossible to verify. CONCLUSION: Secondary analyses provided a more detailed picture of ANC utilization patterns in the seven countries. While coverage levels differ by country and sub-groups, all countries can benefit from specific in-country assessments to properly identify the underserved women and the reasons behind low coverage and missed interventions. Overall, emphasis needs to be put on assessing the quality of care offered and identifying women's perception to the care as well as the barriers hindering utilization. Country policies and programs need to be reviewed, evaluated and/or implemented properly to ensure that women receive the recommended number of ANC visits with appropriate content, especially, poor and less educated women residing in rural areas. PMID- 27231541 TI - Assessing the validity of indicators of the quality of maternal and newborn health care in Kenya. AB - BACKGROUND: The measurement of progress in maternal and newborn health often relies on data provided by women in surveys on the quality of care they received. The majority of these indicators, however, including the widely tracked "skilled attendance at birth" indicator, have not been validated. We assess the validity of a large set of maternal and newborn health indicators that are included or have the potential to be included in population-based surveys. METHODS: We compare women's reports of care received during labor and delivery in two Kenyan hospitals prior to discharge against a reference standard of direct observations by a trained third party (n = 662). We assessed individual-level reporting accuracy by quantifying the area under the receiver operating curve (AUC) and estimated population-level accuracy using the inflation factor (IF) for each indicator with sufficient numbers for analysis. FINDINGS: Four of 41 indicators performed well on both validation criteria (AUC>0.70 and 0.75 A mutation in promoter region of NR2F2 gene. Three genotypes were found in Large White, Landrace and Duroc sows. A total of 1847 litter records from 625 sows genotyped at NR2F2 gene were used to analyze the total number born (TNB) and number born alive (NBA). The study of the effect on litter size suggested that sows with genotype CC tend to have higher litter size. CONCLUSIONS: These results showed the expression patterns of genes/proteins involved in PGR paracrine signaling over implantation time. And the candidate gene for litter size was identified from genes involved in this signaling. This study could be a resource for further studies to identify the roles of these genes for embryonic implantation in pigs. PMID- 27231549 TI - A four-drug combination therapy consisting of low-dose tacrolimus, low-dose mycophenolate mofetil, corticosteroids, and mizoribine in living donor renal transplantation: A randomized study. AB - OBJECTIVE: We compared a three-drug combination therapy (control group) consisting of tacrolimus, mycophenolate mofetil, and corticosteroids in living donor renal transplantation with a four-drug combination therapy (study group), in which the doses of tacrolimus and mycophenolate mofetil were halved and the immunosuppressive drug mizoribine was added, in order to determine whether the incidence rates of acute rejection after transplantation between the study group and the control group are similar, whether the study group regimen prevents the occurrence of calcineurin inhibitor-induced renal damage, and whether the study group regimen prevents adverse effects such as diarrhea caused by mycophenolate mofetil. METHODS: We investigated the incidence of acute rejection, serum creatinine levels, and estimated glomerular filtration rate and the incidence of adverse effects such as diarrhea. RESULTS: There was no significant difference between the two groups in the incidence of acute rejection. Renal function (estimated glomerular filtration rate and serum creatinine) was maintained in the control group whereas in the study group renal function gradually improved, with a statistical difference observed at 12 months. The incidence of gastrointestinal symptoms including diarrhea was significantly higher in the control group than in the study group. There was no significant difference in the incidence of cytomegalovirus infection and other adverse effects. CONCLUSION: These results suggest the study group therapy is an effective regimen in preventing acute rejection and the deterioration of renal function. These results also show this therapy can reduce the incidence of adverse effects such as gastrointestinal symptoms. PMID- 27231550 TI - A comparison of the direct medical costs for individuals with or without basal or squamous cell skin cancer: A study from Australia. AB - OBJECTIVES: The composition of the medical costs incurred by people treated for basal cell and squamous cell carcinomas (hereafter keratinocyte cancers) is not adequately understood. We sought to compare the medical costs of individuals with or without keratinocyte cancers. METHODS: We used national health insurance data to analyze the direct medical costs of 2000 cases and 2000 controls nested within the QSkin prospective cohort study (n = 43,794) conducted in Australia. We reconstructed the medical history of patients using medical and pharmaceutical item codes and then compared the health service costs of individuals treated for keratinocyte cancers with those not treated for keratinocyte cancers. RESULTS: Individuals treated for keratinocyte cancers consumed on average AUD$1320 per annum more in medical services than those without keratinocyte cancers. Only 23.2% of costs were attributed to the explicit treatment of keratinocyte cancers. The principal drivers of the residual costs were medical attendances, surgical procedures on the skin, and histopathology services. We found significant positive associations between history of treatment for keratinocyte cancers with treatments for other health conditions, including melanoma, cardiovascular disease, lipidemia, osteoporosis, rheumatoid arthritis, colorectal cancer, prostate cancer, and tuberculosis. CONCLUSION: Individuals treated for keratinocyte cancers have substantially higher medical costs overall than individuals without keratinocyte cancers. The direct costs of skin cancer excision account for only one-fifth of this difference. PMID- 27231551 TI - Associations between maternal anthropometric characteristics and infant birth weight in Iranian population. AB - OBJECTIVE: To examine the (1) normal ranges of anthropometric and insulin resistance/sensitivity indices (homeostatic model assessment for insulin resistance, homeostatic model assessment for insulin sensitivity, and quantitative insulin sensitivity check index) for Iranian pregnant women and their newborns and (2) associations between maternal anthropometric and metabolic values and infants' birth weights among Iranian women. METHODS: Anthropometric and metabolic values of 163 singleton non-diabetic pregnant women in Tehran, Iran (2014) were collected before and during pregnancy and at delivery. Linear regression, multivariable regression, and Student t tests were used to evaluate correlations between birth weight and maternal variables. RESULTS: Linear regression modeling suggested that maternal serum glucose (p = 0.2777) and age (p = 0.6752) were not associated with birth weight. Meanwhile, maternal weight and body mass index before pregnancy (p = 0.0006 and 0.0204, respectively), weight at delivery (p = 0.0036), maternal height (p = 0.0118), and gestational age (p = 0.0016) were positively associated with birth weight, while serum insulin (p = 0.0300) and homeostatic model assessment for insulin resistance (p = 0.0334) were negatively associated with infant's birth weight. Using multivariate modeling, we identified severalconfounders: parity (multipara mothers delivered heavier babies compared to first-time mothers) explained as much as 24% of variation in birth weight (p = 0.005), maternal height explained 20.7% (p = 0.014), gestational age accounted for 19.7% (p = 0.027), and maternal body mass index explained 19.1% (p = 0.023) of the variation in the infant's birth weight. Maternal serum insulin and infant's sex were not observed to be associated with birth weight (p = 0.342 and 0.669, respectively) in the overall model. CONCLUSION: Overweight/obese women may experience higher incidence of delivering larger babies. Multivariable regression analyses showed that maternal body mass index and height, parity, and gestational age are associated with newborn's birth weight. PMID- 27231552 TI - The influence of a telehealth project on healthcare professional recruitment and retention in remote areas in Mali: A longitudinal study. AB - OBJECTIVES: The telehealth project EQUI-ResHuS (in French, Les TIC pour un acces Equitable aux Ressources Humaines en Sante) aimed to contribute to more equitable access to care and support practice in remote regions in Mali. This study explored the evolution of perceptions concerning telehealth among healthcare professionals in the four district health centres that participated in the EQUI ResHus project and identified variables influencing their perceptions of telehealth impact on recruitment and retention of health professionals. METHODS: One year after a first survey (T1), a second data collection (T2) was carried out among healthcare professionals using a 91-item questionnaire. Questions assessing telehealth use and perceptions and perceived impact on recruitment and retention of healthcare professionals were rated on a 5-point Likert scale. A total of 10 independent variables were considered for the analyses. A Wilcoxon signed-rank test was performed to detect differences between T1 and T2, and a bivariate linear regression model for repeated measures was carried out to assess the impact of independent variables on dependent variables. RESULTS: There were no noticeable changes in perceptions related to telehealth influence on recruitment and retention. Only access to information and communication technology significantly differed between T1 and T2 according the Wilcoxon rank test (p = 0.001). Perceived influence of telehealth on recruitment and retention was mostly explained by attitude towards telehealth, perceived effect on recruitment and retention and barriers to recruitment and retention. CONCLUSION: Based on our results, telehealth was perceived as having a positive influence but mostly indirect influence on healthcare professional recruitment and retention. Also, there were no major changes after 1 year of telehealth use. PMID- 27231553 TI - Assessing the allelotypic effect of two aminocyclopropane carboxylic acid synthase-encoding genes MdACS1 and MdACS3a on fruit ethylene production and softening in Malus. AB - Phytohormone ethylene largely determines apple fruit shelf life and storability. Previous studies demonstrated that MdACS1 and MdACS3a, which encode 1 aminocyclopropane-1-carboxylic acid synthases (ACS), are crucial in apple fruit ethylene production. MdACS1 is well-known to be intimately involved in the climacteric ethylene burst in fruit ripening, while MdACS3a has been regarded a main regulator for ethylene production transition from system 1 (during fruit development) to system 2 (during fruit ripening). However, MdACS3a was also shown to have limited roles in initiating the ripening process lately. To better assess their roles, fruit ethylene production and softening were evaluated at five time points during a 20-day post-harvest period in 97 Malus accessions and in 34 progeny from 2 controlled crosses. Allelotyping was accomplished using an existing marker (ACS1) for MdACS1 and two markers (CAPS866 and CAPS870) developed here to specifically detect the two null alleles (ACS3a-G289V and Mdacs3a) of MdACS3a. In total, 952 Malus accessions were allelotyped with the three markers. The major findings included: The effect of MdACS1 was significant on fruit ethylene production and softening while that of MdACS3a was less detectable; allele MdACS1-2 was significantly associated with low ethylene and slow softening; under the same background of the MdACS1 allelotypes, null allele Mdacs3a (not ACS3a-G289V) could confer a significant delay of ethylene peak; alleles MdACS1-2 and Mdacs3a (excluding ACS3a-G289V) were highly enriched in M. domestica and M. hybrid when compared with those in M. sieversii. These findings are of practical implications in developing apples of low and delayed ethylene profiles by utilizing the beneficial alleles MdACS1-2 and Mdacs3a. PMID- 27231554 TI - Gynecologic Oncology Research and Practice: a new journal to meet the needs of a growing field. PMID- 27231555 TI - Dasatinib (BMS-35482) potentiates the activity of gemcitabine and docetaxel in uterine leiomyosarcoma cell lines. AB - BACKGROUND: To explore the activity of dasatinib alone and in combination with gemcitabine and docetaxel in uterine leiomyosarcoma (uLMS) cell lines, and determine if dasatinib inhibits the SRC pathway. METHODS: SK-UT-1 and SK-UT-1B uLMS cells were treated with gemcitabine, docetaxel and dasatinib individually and in combination. SRC and paxcillin protein expression were determined pre- and post-dasatinib treatment using Meso Scale Discovery (MSD) multi-array immunogenicity assay. Dose-response curves were constructed and the coefficient of drug interaction (CDI) and combination index (CI) for drug interaction calculated. RESULTS: Activated phosphorylated levels of SRC and paxillin were decreased after treatment with dasatinib in both cell lines (p < 0.001). The addition of a minimally active concentration of dasatinib (IC25) decreased the IC50 of each cytotoxic agent by 2-4 fold. The combination of gemcitabine docetaxel yielded a synergistic effect in SK-UT-1 (CI = 0.59) and an antagonistic effect in SK-UT-1B (CI = 1.36). Dasatinib combined with gemcitabine or docetaxel revealed a synergistic anti-tumor effect (CDI < 1) in both cell lines. The triple drug combination and sequencing revealed conflicting results with a synergistic effect in SK-UT-1B and antagonistic in SK-UT-1. CONCLUSION: Dasatinib inhibits the SRC pathway and yields a synergistic effect with the two-drug combination with either gemcitabine or docetaxel. The value of adding dasatinib to gemcitabine and docetaxel in a triple drug combination is uncertain, but may be beneficial in select uLMS cell lines. Based on our pre-clinical data and known activity of gemcitabine and docetaxel, further evaluation of dasatinib in combination with these agents for the treatment of uLMS is warranted. PMID- 27231556 TI - Updates on drug discovery in ovarian cancer. AB - Drug discovery in the ovarian cancer arena continues to launch important new clinical trials. Many biologic agents are being studied in phase II and phase III clinical trials for recurrent disease. These agents include compounds that disrupt angiogenesis through a variety of mechanisms. Other oncogenic pathways are also specifically targeted such as PARP, MEK, and topoisomerase inhibitors which are currently being studied in phase III trials. Various cytotoxic agents, as well as therapeutic vaccines, are also under investigation, and continue to demonstrate promising new data. The relevant agents in the treatment of ovarian cancer which have demonstrated positive phase II activity will be discussed. PMID- 27231557 TI - Protein profiling of ovarian cancers by immunohistochemistry to identify potential target pathways. AB - BACKGROUND: To determine the protein expression profile (PEP) of primary and recurrent ovarian cancer patients in order to predict therapeutic targets for chemotherapy. METHODS: Tissue samples were submitted for PEP in two formats, including formalin-fixed paraffin-embedded tissue for immunohistochemistry (IHC) and fresh frozen tissue for oligonucleotide microarray (MA) gene expression assays. Specimens were analyzed for 18 protein markers and 88 MA genes. A series of Generalized Linear Models (GLM) was used to predict the proportion of positive results by histology for each biomarker. RESULTS: Four hundred and twenty-eight specimens were analyzed for IHC and 67 specimens for MA analysis. The majority of specimens, 82%, were serous histology and 35.3% of specimens were poorly differentiated. Sixty percent of specimens were advanced stage, 62% were from a primary diagnosis, and 53% were obtained from a metastatic site. BCRP, ER, MGMT, and RRM1 proteins were overexpressed in 85%, 47%, 93%, and 47% of serous carcinomas, respectively. The MGMT and RRM1 biomarkers were significantly overexpressed in serous (p < .001) and endometrioid (p = .01) histologies when compared to clear cell histology. MGMT was significantly elevated in 93% of serous and endometrioid samples, compared to 62% of samples with clear cell histology. Those proteins most often underexpressed included Her2/neu, SPARC, and c-kit, seen in less than 1%, 4%, and 5% of specimens, respectively. CONCLUSIONS: PEP is a reliable and effective way of analyzing ovarian cancer specimens. PEP target identification does not appear to vary significantly with site evaluated, ovarian or other abdominal pelvic tissue, or primary versus recurrent disease. Variability in the expression of drug targets, including BCRP, ER, MGMT, and RRM1 could impact decision making pertaining to which therapeutic strategies carry the best chances for controlling disease. PMID- 27231558 TI - Differentiating pelvic actinomycosis from advanced ovarian cancer: a report of two cases, management reflections and literature review. AB - Pelvic actinomycosis comprises a rare, subacute to chronic bacterial infection characterised by suppurative and granulomatous inflammation. Diagnosis is difficult as it may simulate pelvic malignancies. Laboratory and radiological findings are non-specific. We reported on 2 cases of pelvic actinomycosis mimicking ovarian malignancy with different management approaches that lead to opposite outcomes. We reviewed the literature on pelvic actinomycosis imitating ovarian cancer with a focus on its surgical management. Despite agreement on the duration of antibiotic therapy following surgical management, consensus regarding surgical approach was rather equivocal. We concluded that pelvic actinomycosis should be strongly suspected in women with presumed ovarian cancer of atypical presentation and a history of intrauterine devices (IUD). PMID- 27231559 TI - Uterine cervix metastasis from a sigmoid adenocarcinoma: a rare presentation of an uncommon tumor. AB - Metastatic carcinoma to the uterine cervix from colorectal cancer, through haematogenous or lymphatic spread, is extremely rare. We report the case of a 59 year old woman in whom cervical metastasis was diagnosed after 13 months of follow-up for a sigmoid adenocarcinoma, confirmed by immunohistochemical study, with a review of the literature. This case illustrates that abnormal gynecologic symptoms can reveal a disease progression on patients who suffer colorectal cancer. PMID- 27231560 TI - In vitro chemoresponse in metachronous pairs of gyneclologic cancers. AB - BACKGROUND: While most gynecologic cancers respond to first-line cytotoxic chemotherapy, treatment of recurrent disease is frequently associated with acquired drug resistance. In order to find an in vitro surrogate of this clinical phenomenon, a tumor chemoresponse assay was studied. METHODS/MATERIALS: Patients who had tissue submitted for repeated chemoresponse testing were identified through a retrospective search. Sixty-three patients met inclusion criteria (chemoresponse testing completed at primary diagnosis and upon recurrence of disease and assays completed >=90 days apart). The Wilcoxon signed-rank test was used to compare chemoresponse, represented as a response index (RI), between primary and recurrent measurements. In a secondary analysis, response was categorized and coded as Responsive = 3, Intermediately Responsive = 2 and Non Responsive = 1, and the paired t-test was used to compare chemoresponse between primary and recurrent measurement. RESULTS: Median time between primary and recurrent tumor testing was 309 days (IQR 208-422). Drugs tested included carboplatin, cisplatin, docetaxel, doxorubicin, gemcitabine, paclitaxel, topotecan, and combination carboplatin/gemcitabine and carboplatin/paclitaxel. There were no differences in chemoresponse between primary and recurrent measurement when chemoresponse was represented by RI scores; although a trend toward increased resistance to paclitaxel upon recurrence was noted. When chemoresponse was analyzed as a continuous variable corresponding to categorized response, a significant shift toward increased resistance to paclitaxel at recurrence, and a marginally significant trend toward increased resistance to carboplatin at recurrence, were observed. CONCLUSIONS: We observed a trend toward increased chemoresistance at recurrence for paclitaxel, and a marginally significant trend toward increased chemoresistance to carboplatin, but no change in chemoresponsiveness between primary diagnosis and recurrence of disease for other common chemotherapy drugs, including common second-line agents such as doxorubicin, gemcitabine, and topotecan. PMID- 27231562 TI - Diagnostic, therapeutic and evolutionary characteristics of cervical cancer in Department of Radiotherapy, Mohamed V Military Hospital - Rabat in Morocco. AB - BACKGROUND: Cancer of uterine cervix is the second most common cause of cancer related deaths among women. The aim of this study is to report the experience of Military Hospital Mohamed V in the management of cervical cancer and their results. METHODS: All cervical cancer managed at the radiotherapy department of Military Hospital Mohamed V between January 2005 and February 2010, were included for investigation of their demographic, histological, therapeutic and follow-up characteristics. Of the 162 cases managed, 151 (93.2 %) cases were treated in our department. RESULTS: In our study the median age was 51.5 years (33-82). The median duration of symptoms before diagnosis was four [3, 7] months. The major presenting complaints were abnormal vaginal bleeding (89.8 %). Squamous cell carcinoma cervix was seen in 86.2 % (n = 137), adenocarcinoma in 11.3 % (n = 18) and adenosquamous carcinoma in 2.4 % (n = 4). One hundred seventeen (84.8 %) cases were seen at late stage. An abdominal and pelvic computed tomography (CT) scan was performed in 34.6 % (n = 56) of cases, magnetic resonance imaging (MRI) in 62.9 % (n = 102). The pelvic lymph nodes were achieved in 16.6 % of cases. Over half of patients 58.3 % (n = 88) were treated with a combination of external beam radiation therapy (EBRT) and a concurrent cisplatin based chemotherapy (40 mg /m2 weekly). With a mean of 51.6 months (2 to 109), we recorded 19 (12.6 %) pelvic relapse and 15 (9.9 %) metastases. The median time to onset was 19.4 months (2-84 months). The local control rate was 63.6 % (n = 96) and 21 (13.9 %) patients were lost to follow-up. The overall survival (OS) at 3 years and 5 years was respectively 78.3 % and 73.6 % and the relapse-free survival (RFS) was respectively 80 % and 77.2 %. CONCLUSION: Most of cervical cancer patients in Morocco are seen at late stage necessitating referral for radiotherapy, chemotherapy or palliative care. This may reflect lack of cervical screening in order to early detect and treat pre-malignant disease stage. PMID- 27231563 TI - Very late recurrence of Diethylstilbestrol - related clear cell carcinoma of the cervix: case report. AB - Clear cell adenocarcinoma of the cervix is a rare tumor of the lower genital tract. It has been described in young women with a history of intra uterine exposure to diethylstilbestrol. This tumor is characterized by a greater tendency for late recurrences. In this article, we report the case of one exposed-patient who developed recurrence as liver metastases, 24 years after the initial treatment. This case demonstrates the need and the importance for continued follow-up in individuals prenatally exposed to diethylstilbestrol. PMID- 27231561 TI - Adenocarcinoma of Mullerian origin: review of pathogenesis, molecular biology, and emerging treatment paradigms. AB - Traditionally, epithelial ovarian, tubal, and peritoneal cancers have been viewed as separate entities with disparate origins, pathogenesis, clinical features, and outcomes. Additionally, previous classification systems for ovarian cancer have proposed two primary histologic groups that encompass the standard histologic subtypes. Recent data suggest that these groupings no longer accurately reflect our knowledge surrounding these cancers. In this review, we propose that epithelial ovarian, tubal, and peritoneal carcinomas represent a spectrum of disease that originates in the Mullerian compartment. We will discuss the incidence, classification, origin, molecular determinants, and pathologic analysis of these cancers that support the conclusion they should be collectively referred to as adenocarcinomas of Mullerian origin. As our understanding of the molecular and pathologic profiling of adenocarcinomas of Mullerian origin advances, we anticipate treatment paradigms will shift towards genomic driven therapeutic interventions. PMID- 27231564 TI - Successful use of next generation genomic sequencing (NGS)-directed therapy of clear cell carcinoma of the ovary (CCCO) with trametinib and metformin in a patient with chemotherapy-refractory disease. AB - PURPOSE: Compared to other subtypes of epithelial ovarian cancer, clear cell carcinoma of the ovary bears an ominous reputation for chemotherapy resistance, increased relapse rate, and diminished survival. Among patients with distinct histopathologic subtypes, molecular analyses have identified a variety of known drivers of the malignant behavior, and depict a striking heterogeneity. METHODS: A patient with rapidly metastatic CCCO that was refractory to taxane, platinum, pemetrexed, and bevacizumab-based strategies underwent molecular profiling which disclosed dual MAPK and PI3K/AKT/mTOR pathway mutations. RESULTS: Combined targeted therapy with trametinib and metformin resulted in a dramatic disease regression without toxicity. CONCLUSION: The case highlights the utility of precision medicine combining individual molecular diagnosis with rational therapeutic intervention with targeted agents. PMID- 27231565 TI - Opportunistic salpingectomy for ovarian cancer prevention. AB - Recently accumulated evidence has strongly indicated that the fallopian tube is the site of origin for the majority of high-grade serous ovarian or peritoneal carcinomas. As a result, recommendations have been made to change surgical practice in women at general population risk for ovarian cancer and perform bilateral salpingectomy at the time of hysterectomy without oophorectomy and in lieu of tubal ligation, a practice that has been termed opportunistic salpingectomy (OS). Despite suggestions that bilateral salpingectomy may be used as an interim procedure in women with BRCA1/2 mutations, enabling them to delay oophorectomy, there is insufficient evidence to support this practice as a safe alternative and risk-reducing bilateral salpingo-oophorectomy remains the recommended standard of care for high-risk women. While evidence on uptake of OS is sparse, it points toward increasing practice of OS during hysterectomy. The practice of OS for sterilization purposes, although expanding, appears to be less common. Operative and perioperative complications as measured by administered blood transfusions, hospital length of stay and readmissions were not increased with the addition of OS either at time of hysterectomy or for sterilization. Additional operating room time was 16 and 10 min for OS with hysterectomy and OS for sterilization, respectively. Short-term studies of the consequences of OS on ovarian function indicate no difference between women undergoing hysterectomy alone and hysterectomy with OS, but no long-term data exist. There is emerging evidence of effectiveness of excisional sterilization on reducing ovarian cancer rates from Rochester (OR = 0.36 95 % CI 0.13, 1.02), and bilateral salpingectomy from Denmark (OR = 0.58 95 % CI 0.36, 0.95) and Sweden (HR = 0.35, 95 % CI 0.17, 0.73), but these studies suffer from limitations, including that they were performed for pathological rather than prophylactic purposes. Initial cost effectiveness modeling indicates that OS is cost-effective over a wide range of costs and risk estimates. While preliminary safety, efficacy, and cost effectiveness data are promising, further research is needed (particularly long term data on ovarian function) to firmly establish the safety of the procedure. The marginal benefit of OS compared with tubal ligation or hysterectomy alone needs to be established through large prospective studies of OS done for prophylaxis. PMID- 27231566 TI - Willingness and acceptability of cervical cancer screening among women living with HIV/AIDS in Addis Ababa, Ethiopia: a cross sectional study. AB - BACKGROUND: In Ethiopia, cervical cancer (CC) ranks the 2nd most frequent cancer and the country had 27.19 million women at risk of developing the disease though only 0.6 % women age 18-69 years was screened every 3 years. Nearly a quarter (22.1 %) of southern Ethiopia HIV (Human Immunodeficiency Virus) infected Women were positive for precancerous cervical cancer. Doing regular screening can prevent the disease by around half (45 %) of the cases in age of 30s and three quarter (75 %) cases in 50s and 60s.In the presence of high risk for acquiring cervical cancer among HIV patients, willingness and acceptance of the screening is low in Addis Ababa, Ethiopia thus the current study was aimed to assess willingness and acceptability of cervical cancer screening and its determinants among women living with HIV/AIDS in Addis Ababa, Ethiopia. METHOD: A facility based cross sectional study was conducted among HIV positive women attending HIV treatment centers in Addis Ababa. The respondents were identified using systematic random sampling method. Data was collected using pretested questionnaire and were entered in to Epi-info version 3.5.1 software and exported in to SPSS version 20 statistical package for analysis. The criterias for entering independent variables into multivariate analysis were having p-value 0.05 or less at bivariate analysis and not co-linear. RESULT: One third (34.2 %) of participants knew cervical cancer and two third (62.7 %) were willing for the test though only a quarter (24.8 %) were accepted the test. The independent variables significantly associated with acceptance of screening were educational level, source of information, awareness for the test and preventability of the disease. CONCLUSION: In current study willingness and acceptance of CC (cervical cancer) were low thus organizations working on cancer and HIV/AIDS should establish cervical cancer screening program and further enhance awareness creation. PMID- 27231567 TI - Impact of cervical cancer on quality of life: beyond the short term (Results from a single institution): Quality of life in long-term cervical cancer survivors: results from a single institution. AB - BACKGROUND: Cervical cancer (CC) is one of the most widespread gynecological malignancies in women worldwide. Treatment strategies and screening modalities have largely evolved these past years resulting in an improvement of survival. However, treatment modalities are associated with long term side effects that significantly impacts quality of life (QOL) in cervical cancer survivors. The aim of this study is to evaluate QOL (General and sexual QOL) in cervical cancer survivors up to 10 years after the diagnosis. MATERIAL AND METHODS: In a cross sectional descriptive study design, 110 cervical cancer survivors (CCS) and 80 healthy controls completed questionnaires assessing QOL. RESULTS: Participants were Arabic White, sexually active. The mean age at diagnosis was 34 years and was 43 years at the time of the interview. In our series long term CCS have generally a good global QOL comparable with healthy controls. However, issues concerning emotional functioning were over expressed by CCS. As to the sexual impact of cervical cancer; CCS experienced less sexual functioning and enjoyment and less satisfaction with their body image when compared to healthy controls. In a multivariate analysis, spiritual well-being and social support were the predictor factors that statistically affected QOL among the studied cohort, it accounted for 81 % of the variance in QOL scores. CONCLUSIONS: A better understanding of the complexity of the relationship between QOL and cervical cancer sequelae in one hand and socio-demographic factors in the other hand is necessary to improve QOL among cervical cancer survivors. More efforts should make to inform disease free patients about expected side effects and symptoms to face the physical changes that would affect their QOL and sexual activity. PMID- 27231568 TI - Breaking down the evidence for bevacizumab in advanced cervical cancer: past, present and future. AB - Despite the introduction of screening and, latterly, vaccination programs in the developed world, globally cervical cancer remains a significant health problem. For those diagnosed with advanced or recurrent disease even within resource rich communities, prognosis remains poor with an overall survival (OS) of just over 12 months. New therapeutic interventions are urgently required. Advances in our understanding of the mechanisms underlying tumor growth and the downstream effects of human papilloma virus (HPV) infection identified angiogenesis as a rational target for therapeutic intervention in cervical cancer. Anti-angiogenic agents showed promising activity in early phase clinical trials culminating in a randomized phase III study of the humanized monoclonal antibody to vascular endothelial growth factor (VEGF), bevacizumab, in combination with chemotherapy. This pivotal study, the Gynecologic Oncology Group protocol 240, met its primary endpoint demonstrating a significant improvement in OS. Bevacizumab became the first targeted agent to be granted regulatory approval by the United States Food and Drug Administration for use alongside chemotherapy in adults with persistent, recurrent or metastatic carcinoma of the cervix. This review outlines the rationale for targeting angiogenesis in cervical cancer focusing on the current indications for the use of bevacizumab in this disease and future directions. PMID- 27231569 TI - Clinico-epidemiological profile of molar pregnancies in a tertiary care centre of Eastern Nepal: a retrospective review of medical records. AB - BACKGROUND: The incidence of molar pregnancy has demonstrated marked geographic and ethnic differences. The reported data in Nepal is inconsistent with minimal published literature. Thus, we designed a study to determine prevalence of molar pregnancies and demonstrate clinical and epidemiological characteristics of the patients attending a tertiary care center in eastern Nepal. METHODS: A retrospective review of medical records was conducted to determine the prevalence of molar pregnancies at the B.P. Koirala Institute of Health Sciences (BPKIHS) from the year 2008 to 2012. Secondary data from the medical records were analyzed. Annual and 5-year prevalence of molar pregnancy per 1000 live births was calculated. Demographic characteristics, clinical presentation, management methods and complications of molar pregnancy were studied. RESULTS: The 5- year prevalence of molar pregnancy at BPKIHS is 4.17 per 1000 live births with annual prevalence ranging 3.8-4.5 per 1000 live births. More than one third of the patients were in the age group of 20-35 years and majority of them were of Hindu religion. For more than one third (41.7 %) of the patients, it was their first pregnancy while about 10 % gave a positive past history of molar pregnancy. Abnormal uterine bleeding (86.3 %) was the most frequent complaint, suction evacuation was the most common method of treatment and more than half of the patients required prolonged care after initial management. CONCLUSION: There is a need for studies at country level which will give us a national figure on molar pregnancies. Thus, a standardized clinic-epidemiological profile of molar pregnancy in Nepal can be created. PMID- 27231570 TI - Characteristics and outcomes for patients with advanced vaginal or vulvar cancer referred to a phase I clinical trials program: the MD Anderson cancer center experience. AB - BACKGROUND: Early-stage vaginal and vulvar cancer can be cured. But outcomes of patients with metastatic disease are poor. Thus, new therapeutic strategies are urgently required. METHODS: In this retrospective study, we analyzed the clinical outcomes of consecutive patients with metastatic vaginal or vulvar cancer who were referred to a phase I trial clinic between January 2006 and December 2013. Demographic and clinical data were obtained from patients' electronic medical records. RESULTS: Patients with metastatic vaginal (n = 16) and vulvar (n = 20) cancer who were referred for phase I trial therapy had median overall survival durations of 6.2 and 4.6 months, respectively. Among those who underwent therapy (n = 27), one experienced a partial response and three experienced stable disease for at least 6 months. Patients with a body mass index >=30 had a significantly longer median overall survival duration than did those with a body mass index <30 (13.2 months versus 4.4 months, p = 0.04). Preliminary data revealed differences in molecular profiling between patients with advanced vaginal cancer and those with advanced vaginal cancer. CONCLUSIONS: Metastatic vaginal and vulvar cancers remain to be difficult-to-treat diseases with poor clinical outcomes. The currently available phase I trial agents provided little meaningful clinical benefits. Understanding these tumors' molecular mechanisms may allow us to develop more effective therapeutic strategies than are currently available regimens. PMID- 27231571 TI - Immunotherapy in endometrial cancer - an evolving therapeutic paradigm. AB - Endometrial cancer is the only gynecologic malignancy with a rising incidence and mortality. While cure is routinely achieved with surgery alone or in combination with adjuvant pelvic radiotherapy when disease is confined to the uterus, patients with metastatic or recurrent disease exhibit limited response rates to cytotoxic chemotherapy, targeted agents, or hormonal therapy. Given the unmet clinical need in this patient population, exploration of novel therapeutic approaches is warranted, and attention is turning to immunomodulation of the tumor microenvironment. Existing evidence suggests that endometrial cancer is sufficiently immunogenic to be a reasonable candidate for active and/or passive immunotherapy. In this review, we critically examine what is known about the microenvironment in endometrial cancer and what has been learned from preliminary immunotherapy trials that enrolled endometrial cancer patients, encouraging further attempts at immunomodulation in the treatment of aggressive forms of this disease. PMID- 27231572 TI - Lumbosacral plexopathy: A rare long term complication of concomitant chemo radiation for cervical cancer. AB - Radiation induced Lumbosacral plexophaty (RILP) is a rare but severe complication that has a considerable impact on quality of life. Its occurrence is rare but increasing with improved long-term cancer survival. This entity commonly results in different degrees of sensory and motor deficits. The pathophysiological mechanisms are not yet fully understood. Diagnosis of radiation myelopathy in women with gynecologic malignancies may increase with the use of concomitant chemo-radiation. This report describes the effect of this combination therapy in a 64-year-old woman with cervical carcinoma. PMID- 27231573 TI - Surgical safety and personal costs in morbidly obese, multimorbid patients diagnosed with early-stage endometrial cancer having a hysterectomy. AB - BACKGROUND: Many women who develop endometrial cancer (EC) or endometrial hyperplasia with atypia are obese and therefore at high risk of surgical complications. Recently clinical trials have been initiated offering non-surgical treatment to these women, but not all may agree to participate in such trials. This paper aims to describe the patient characteristics, and surgical outcomes of women with suspected early stage endometrial cancer and body mass index (BMI) of 30 or greater, who declined enrolment in the feMMe trial, which offers non surgical hormonal treatment, hormonal plus metformin or hormonal plus weight loss as primary treatment. METHODS: Consecutive case series from a tertiary gynaecological oncology unit. Over the course of the first 2 years of the feMMe trial, 27 patients met the initial eligibility screening, but declined enrolment in the feMMe trial and opted for upfront surgery. The main surgical outcome measures were type of surgical approach, need for conversion from laparoscopic to open approach, length of stay in hospital and adverse events. RESULTS: Patients' median age was 63 years (range 40 to 86); median BMI was 37.3 kg/m2 (range 30.7 to 54.7); median medical co-morbidities were six (range 3-10). Of the 26/27 surgeries planned to be undertaken laparoscopically, 2/26 patients had to be converted (7 %). Overall, the average hospital stay was 4.5 days, and 11/27 (41 %) of the patients developed one or more adverse events grade 2+ rated according to the Common Toxicity Criteria Version 3. CONCLUSIONS: Adverse surgical outcomes are common in multi-morbid, obese or morbidly obese patients diagnosed with early stage EC or endometrial hyperplasia with atypia and who have a hysterectomy. PMID- 27231574 TI - New treatment option for ovarian cancer: PARP inhibitors. AB - Poly(ADP-ribose) polymerase (PARP), which was first described over 50 years ago by Mandel, are a family of protein enzymes involved in DNA damage response and works by recognizing the single-strand DNA break (ssDNA) and then effecting DNA repair. A double-strand DNA (dsDNA) break can be repaired by one of two different pathways: homologous recombination (HR) or non-homologous end joining (NHEJ). Homologous recombination occurs in the G2 or M phase of the cell cycle when a sister chromatid is available to use as a template for repair. Because a template is available, HR is a high fidelity, error-free form of DNA repair. With NHEJ there is not a template and the DNA is trimmed and ligated which is a very error prone process of repair which can lead to genetic instability. Exploiting these mechanism led to development of PARP inhibitors with the idea of utilizing synthetic lethality, where two deficiencies each having no effect on the cellular outcome become lethal when combined, as single agent in BRCA deficient patients or as chemotherapy/radiotherapy combinations to inhibit ssDNA repair. The recent approval of olaparib in BRCA deficient ovarian cancer patients in US and Europe has opened up a whole new treatment option for ovarian cancer patients. This review will discuss the different PARP inhibitors in development and the potential use of this class of agents in the future. PMID- 27231576 TI - A long-term surviving patient with recurrent low-grade serous ovarian carcinoma treated with the MEK1/2 inhibitor, selumetinib. AB - BACKGROUND: Selumetinib is a potent, selective, orally available, and non-ATP competitive small molecule inhibitor of mitogen-activated protein kinase kinase 1/2 (MEK1/2) that has demonstrated single agent activity in a number of solid tumor including recurrent low-grade serous ovarian carcinoma (LGSOC). However, the long-term prognosis of patients who receive selumetinib, as well as the late toxicity of the agent, have not yet been described. CASE PRESENTATION: In this case report, we present a patient with recurrent LGSOC with KRAS mutation whose tumor has not progressed and who has maintained a good general condition without severe toxicities following treatment with selumetinib for more than 7 years. Next generation sequencing of her tumor revealed a G12V mutation in KRAS. MAPK signaling inhibition plays a role in the biology of LGSOC. CONCLUSIONS: Although biomarkers have yet to definitively define patients with LGSOC who are likely to respond to therapy, exploration of specific alterations should be pursued in an excersie to develop a reliable companion diagnostic test. PMID- 27231575 TI - Safety and efficacy of salvage nano-particle albumin bound paclitaxel in recurrent cervical cancer: a feasibility study. AB - BACKGROUND: After platinum and taxane chemotherapy, with or without bevacizumab, active regimens for advanced or recurrent cervical cancer are lacking. Our objective was to review a single institution experience in treating recurrent, refractory cervical cancer with nano-particle albumin bound (NAB) paclitaxel with or without bevacizumab. METHODS: This retrospective case series was conducted in accordance with the regulations set forth by the Institutional Review Board at St. Joseph's Hospital and Medical center. The chemotherapy log at the outpatient infusion center at the University of Arizona Cancer Center was reviewed to identify all advanced cervical cancer patients treated with NAB-paclitaxel from November 2011 until February 2015. The following data points were extracted from patient charts: demographic information, number of cycles, progression free survival (PFS), overall survival (OS), dose reductions and dose-limiting toxicities. In addition the average number of treatment cycles and age at recurrence were calculated. RESULTS: A total of 12 subjects were identified as receiving treatment with NAB-paclitaxel. Mean age at time of recurrence was 47.2 years (36-55). Nine subjects had squamous cell histology and three subjects had adenocarcinoma histology. All subjects had failed treatment with platinum and taxane, or platinum and topotecan chemotherapy. Two subjects were lost to follow up. The Median number of cycles of NAB-paclitaxel was 6.5 (2-19). The total number of cycles of NAB-paclitaxel in the study population was 65. Seven subjects were treated in combination with bevacizumab. Of these, three subjects are still alive and one subject is currently receiving active treatment with NAB paclitaxel. The median PFS and OS for all subjects that met mortality endpoint was 4.8 months and 8.9 months (n = 7), respectively. One subject discontinued NAB paclitaxel secondary to peripheral neuropathy, and one subject developed a vesicovaginal fistula while obtaining combination NAB-paclitaxel and bevacizumab therapy. CONCLUSIONS: NAB-paclitaxel with or without bevacizumab is tolerable and potentially active in treating recurrent cervical cancer after failing platinum taxane or topotecan chemotherapy. This small case series deserves confirmation through prospective clinical trials. PMID- 27231577 TI - Motor fluctuations due to interaction between dietary protein and levodopa in Parkinson's disease. AB - BACKGROUND: The modulation of levodopa transport across the blood brain barrier by large neutral amino acids is well documented. Protein limitation and protein redistribution diets may improve motor fluctuations in patients with Parkinson's disease but the pharmacokinetics and pharmacodynamics of levodopa and amino acids are highly variable. METHODS: Clinical records of 1037 Parkinson's disease patients were analyzed to determine the proportion of patients with motor fluctuations related to protein interaction with levodopa. Motor fluctuations due to protein interaction with levodopa were defined as dietary protein being associated with (i) longer time to levodopa effectiveness, (ii) reduced benefit or duration of benefit, (iii) dose failures or (iv) earlier wearing off from a previously effective dose. Dose failures, sudden, painful or behavioral wearing off periods, gait freezing, nausea, hallucinations, orthostasis, and dyskinesias were taken as markers of motor fluctuations, disease severity, and levodopa side effects potentially influenced by protein. RESULTS: 5.9 % of Parkinson's disease patients on levodopa, and 12.4 % with motor fluctuations on levodopa correlated their fluctuations with the relative timing of levodopa and protein intake. These patients were younger at disease onset, had worse motor fluctuations and had a higher incidence of family members with Parkinson's disease. Early wearing off or decreased dose efficacy were most commonly associated with protein interaction. 60 % of patients who modified their diets had weight loss. CONCLUSIONS: This study suggests that clinically significant protein interaction with levodopa may occur mostly in a subset of Parkinson's disease patients with earlier disease onset and those with familial disease. PMID- 27231579 TI - Barriers to Healthcare Provision for Victims of Sexual Assault: A Grounded Theory Study. AB - BACKGROUND: Victims of sexual assault need comprehensive healthcare services to deal with the consequences of their experience. However, there are still many girls/women that delay seeking healthcare after they experience sexual assault. OBJECTIVES: To explore the process of health care and clinical services for victims of sexual assault in the health care centers of Iran. PATIENTS AND METHODS: This was a qualitative study based on the grounded theory method. The sample consisted of 23 health care providers and 10 victims of sexual violence. Unstructured interviews and observations were used for data collection. Constant comparative analysis was used according to the Strauss and Corbin method. RESULTS: The analysis of all data led to the extraction of four categories: "performing routines", "victims' expectations", "conflict between expectations of victims and existing healthcare services", and the core category of "neglect of healthcare providers to address the needs and expectations of victims". Providers were offering health care to the victims of sexual violence regardless of their needs. Due to this neglect, victims sought illegal solutions to overcome the consequences that led to social stigma. CONCLUSIONS: The findings indicate the lack of mutual understanding between health care providers and victims of sexual violence in relation to the expectations and priorities of victims. PMID- 27231580 TI - Application of Canonical Correlation Analysis for Detecting Risk Factors Leading to Recurrence of Breast Cancer. AB - BACKGROUND: Advances in treatment options of breast cancer and development of cancer research centers have necessitated the collection of many variables about breast cancer patients. Detection of important variables as predictors and outcomes among them, without applying an appropriate statistical method is a very challenging task. Because of recurrent nature of breast cancer occurring in different time intervals, there are usually more than one variable in the outcome set. For the prevention of this problem that causes multicollinearity, a statistical method named canonical correlation analysis (CCA) is a good solution. OBJECTIVES: The purpose of this study was to analyze the data related to breast cancer recurrence of Iranian females using the CCA method to determine important risk factors. PATIENTS AND METHODS: In this cross-sectional study, data of 584 female patients (mean age of 45.9 years) referred to Breast Cancer Research Center (Tehran, Iran) were analyzed anonymously. SPSS and NORM softwares (2.03) were used for data transformation, running and interpretation of CCA and replacing missing values, respectively. Data were obtained from Breast Cancer Research Center, Tehran, Iran. RESULTS: Analysis showed seven important predictors resulting in breast cancer recurrence in different time periods. Family history and loco-regional recurrence more than 5 years after diagnosis were the most important variables among predictors and outcomes sets, respectively. CONCLUSIONS: Canonical correlation analysis can be used as a useful tool for management and preparing of medical data for discovering of knowledge hidden in them. PMID- 27231581 TI - A Randomized Controlled Trial of the Effects of an Almond-enriched, Hypocaloric Diet on Liver Function Tests in Overweight/Obese Women. AB - BACKGROUND: Gradual weight reduction has been shown to be associated with improvements in liver enzymes. However, some evidence demonstrated that liver enzymes may transiently increase immediately after a diet-induced weight loss. OBJECTIVES: This study was designed to assess the effects of a hypocaloric, almond-enriched diet (AED) compared with a hypocaloric nut-free diet (NFD) on liver function tests in the context of a three-month weight reduction program in overweight/obese women. PATIENTS AND METHODS: This randomized controlled clinical trial was registered at Iranian Registry of Clinical Trials with ID number of IRCT2013062313751N1. Overweight and obese Iranian women [n = 108; age = 42.7 y, body mass index = 29.6 kg/m(2)] were randomly assigned to consume an AED or NFD. The carefully planned hypocaloric diets were identical for both groups except for the AED group who consumed 50 grams of almonds daily for three months. Anthropometric measurements and laboratory measurements including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT) were assessed before and immediately after the intervention. RESULTS: Of 108 participants, 50 women in AED group and 50 women in NFD group completed the protocol of the study (response rate: 92.6 %). The AED led to a median weight loss of 3.79 kg (interquartile range: 4.4 kg). Significant decreases within AED and NFD were observed in ALT (-16.6 +/- 16.3 and -11.7 +/- 16.8, P < 0.001, respectively). Similar significant decreases were observed in AST (-13.6 +/- 15.7 and -7.7 +/- 16.1; P < 0.001, respectively). The decrease in GGT was also significant in both groups (-11.4 +/- 21.6 and -6.2 +/- 19.8; P < 0.001 respectively). ALT, AST and GGT decreased significantly in the AED group compared to the NFD group (P < 0.001). CONCLUSIONS: AED improved liver enzymes in obese women. However, mild, transient increases in ALT and AST values can be observed immediately after an NFD in women. PMID- 27231583 TI - Automatic differentiation of color fundus images containing drusen or exudates using a contextual spatial pyramid approach. AB - We developed an automatic system to identify and differentiate color fundus images containing no lesions, drusen or exudates. Drusen and exudates are lesions with a bright appearance, associated with age-related macular degeneration and diabetic retinopathy, respectively. The system consists of three lesion detectors operating at pixel-level, combining their outputs using spatial pooling and classification with a random forest classifier. System performance was compared with ratings of two independent human observers using human-expert annotations as reference. Kappa agreements of 0.89, 0.97 and 0.92 and accuracies of 0.93, 0.98 and 0.95 were obtained for the system and observers, respectively. PMID- 27231582 TI - Can the BASNEF Model Help to Develop Self-Administered Healthy Behavior in Iranian Youth? AB - BACKGROUND: The stage of youth is critical for human development in several ways. On the one hand, it can lead people towards the adoption of a healthy lifestyle during adulthood based on these earlier practices. On the other hand, it can comprise the development of healthy living practices later on in live, an outcome which is often caused by the youth adopting a risky lifestyle early on. OBJECTIVES: The primary objective of this study was to determine the effectiveness of implementing an educational intervention program based on the BASNEF Model (a simplified approach to understanding behavior), designed to cultivate self-administered lifestyle control skills in youths. MATERIALS AND METHODS: This was a quasi-experimental intervention study, implemented during 2010 - 2011. A total of 288 randomly selected high-school students between the ages of 15 and 17 participated in this study. These students were later divided into experimental and control groups. Subjects completed a BASNEF questionnaire at the baseline (pre-test), one month later (post-test) and three months after the educational intervention (follow-up). Four educational sessions were held, each of a 120 - 150 minute duration. After the data had been collected, the ANOVA test was used to compare trends in changes. The Pearson correlation coefficient was then used to analyze the correlation between components of the BASNEF model. Finally, regression analysis was used to determine the predictive power of the study. RESULTS: Results from the intervention study reveal that the beliefs and attitudes about nutrition of the intervention group, calculated in terms of scores, improved significantly for both male and female subjects (P < 0.001) as compared to the control group. The mean BASNEF scores for improvements in beliefs among girls and boys were 79.2% and 70.1%, respectively and for attitudes, 61.2% and 59.4%. The increase was significantly higher in the intervention group (P < 0.001). Furthermore, participation in physical activity was more frequent among members of the intervention group than among those in the control group (P < 0.001). CONCLUSIONS: The BASNEF model could be effective in encouraging the adoption of nutritious eating habits and more active lifestyles at an early age in order to foster long-term health and well-being. PMID- 27231584 TI - PSF engineering in multifocus microscopy for increased depth volumetric imaging. AB - Imaging and localizing single molecules with high accuracy in a 3D volume is a challenging task. Here we combine multifocal microscopy, a recently developed volumetric imaging technique, with point spread function engineering to achieve an increased depth for single molecule imaging. Applications in 3D single molecule localization-based super-resolution imaging is shown over an axial depth of 4 um as well as for the tracking of diffusing beads in a fluid environment over 8 um. PMID- 27231586 TI - Structured illumination temporal compressive microscopy. AB - We present a compressive video microscope based on structured illumination with incoherent light source. The source-side illumination coding scheme allows the emission photons being collected by the full aperture of the microscope objective, and thus is suitable for the fluorescence readout mode. A 2-step iterative reconstruction algorithm, termed BWISE, has been developed to address the mismatch between the illumination pattern size and the detector pixel size. Image sequences with a temporal compression ratio of 4:1 were demonstrated. PMID- 27231585 TI - Tri-modal microscope for head and neck tissue identification. AB - A novel tri-modal microscope combining optical coherence tomography (OCT), spectrally encoded confocal microscopy (SECM) and fluorescence imaging is presented. This system aims at providing a tool for rapid identification of head and neck tissues during thyroid surgery. The development of a dual-wavelength polygon-based swept laser allows for synchronized, co-registered and simultaneous imaging with all three modalities. Further ameliorations towards miniaturization include a custom lens for optimal compromise between orthogonal imaging geometries as well as a double-clad fiber coupler for increased throughput. Image quality and co-registration is demonstrated on freshly excised swine head and neck tissue samples to illustrate the complementarity of the techniques for identifying signature cellular and structural features. PMID- 27231587 TI - Sensitivity of laser speckle contrast imaging to flow perturbations in the cortex. AB - Laser speckle contrast imaging has become a ubiquitous tool for imaging blood flow in a variety of tissues. However, due to its widefield imaging nature, the measured speckle contrast is a depth integrated quantity and interpretation of baseline values and the depth dependent sensitivity of those values to changes in underlying flow has not been thoroughly evaluated. Using dynamic light scattering Monte Carlo simulations, the sensitivity of the autocorrelation function and speckle contrast to flow changes in the cerebral cortex was extensively examined. These simulations demonstrate that the sensitivity of the inverse autocorrelation time, [Formula: see text], varies across the field of view: directly over surface vessels [Formula: see text] is strongly localized to the single vessel, while parenchymal ROIs have a larger sensitivity to flow changes at depths up to 500 MUm into the tissue and up to 200 MUm lateral to the ROI. It is also shown that utilizing the commonly used models the relate [Formula: see text] to flow resulted in nearly the same sensitivity to the underlying flow, but fail to accurately relate speckle contrast values to absolute [Formula: see text]. PMID- 27231588 TI - Fast blood flow monitoring in deep tissues with real-time software correlators. AB - We introduce, validate and demonstrate a new software correlator for high-speed measurement of blood flow in deep tissues based on diffuse correlation spectroscopy (DCS). The software correlator scheme employs standard PC-based data acquisition boards to measure temporal intensity autocorrelation functions continuously at 50 - 100 Hz, the fastest blood flow measurements reported with DCS to date. The data streams, obtained in vivo for typical source-detector separations of 2.5 cm, easily resolve pulsatile heart-beat fluctuations in blood flow which were previously considered to be noise. We employ the device to separate tissue blood flow from tissue absorption/scattering dynamics and thereby show that the origin of the pulsatile DCS signal is primarily flow, and we monitor cerebral autoregulation dynamics in healthy volunteers more accurately than with traditional instrumentation as a result of increased data acquisition rates. Finally, we characterize measurement signal-to-noise ratio and identify count rate and averaging parameters needed for optimal performance. PMID- 27231589 TI - Simulation of speckle patterns with pre-defined correlation distributions. AB - We put forward a method to easily generate a single or a sequence of fully developed speckle patterns with pre-defined correlation distribution by utilizing the principle of coherent imaging. The few-to-one mapping between the input correlation matrix and the correlation distribution between simulated speckle patterns is realized and there is a simple square relationship between the values of these two correlation coefficient sets. This method is demonstrated both theoretically and experimentally. The square relationship enables easy conversion from any desired correlation distribution. Since the input correlation distribution can be defined by a digital matrix or a gray-scale image acquired experimentally, this method provides a convenient way to simulate real speckle related experiments and to evaluate data processing techniques. PMID- 27231590 TI - In vivo Raman measurement of levofloxacin lactate in blood using a nanoparticle coated optical fiber probe. AB - Monitoring drug concentrations in vivo is very useful for adjusting a drug dosage during treatment and for drug research. Specifically, cutting-edge "on-line" drug research relies on knowing how drugs are metabolized or how they interact with the blood in real-time. Thus, this study explored performing in vivo Raman measurements of the model drug levofloxacin lactate in the blood using a nanoparticle-coated optical fiber probe (optical fiber nano-probe). The results show that we were able to measure real-time changes in the blood concentration of levofloxacin lactate, suggesting that this technique could be helpful for performing drug analyses and drug monitoring in a clinical setting without repeatedly withdrawing blood from patients. PMID- 27231591 TI - Projection-resolved optical coherence tomographic angiography. AB - Shadowgraphic projection artifacts from superficial vasculature interfere with the visualization of deeper vascular networks in optical coherence tomography angiography (OCT-A). We developed a novel algorithm to remove this artifact by resolving the ambiguity between in situ and projected flow signals. The algorithm identifies voxels with in situ flow as those where intensity-normalized decorrelation values are higher than all shallower voxels in the same axial scan line. This "projection-resolved" (PR) algorithm effectively suppressed the projection artifact on both en face and cross-sectional angiograms and enhanced depth resolution of vascular networks. In the human macula, the enhanced angiograms show three distinct vascular plexuses in the inner retina and no vessels in the outer retina. We demonstrate that PR OCT-A cleanly removes flow projection from the normally avascular outer retinal slab while preserving the density and continuity of the intermediate and deep retinal capillary plexuses. PMID- 27231592 TI - Label-free Gram-negative bacteria detection using bacteriophage-adhesin-coated long-period gratings. AB - This paper presents a novel application of a highly sensitive sensor based on long-period gratings (LPGs) coated with T4 bacteriophage adhesin for Gram negative bacteria detection. We show here, that the sensor evidently recognizes Escherichia coli K-12 (PCM2560), whereas in the reference tests - ELISA and BIAcore - the results are questionable. For LPGs sensor the resonant wavelength shift observed for E. coli K-12 was approximately half of that measured for E.coli B (positive control). The BIAcore readings (RU) for E. coli K-12 were at 10% level of the signal obtained for E .coli B. These results confirm the improved sensitivity of the LPGs sensor. Moreover, we also show that application of adhesin may allow for efficient detection of E. coli O111 (PCM418), Klebsiella pneumoniae O1 (PCM1) and Yersinia enterocolitica O1 (PCM1879). The specificity of binding bacteria by the adhesin is discussed and it is determined by a distinct region of lipopolysaccharide receptors and/or by the presence of outer-membrane protein C in an outer membrane of Gram-negative bacteria. PMID- 27231593 TI - Functional optical coherence tomography of rat olfactory bulb with periodic odor stimulation. AB - In rodent olfactory bulb (OB), optical intrinsic signal imaging (OISI) is commonly used to investigate functional maps to odorant stimulations. However, in such studies, the spatial resolution in depth direction (z-axis) is lost because of the integration of light from different depths. To solve this problem, we propose functional optical coherence tomography (fOCT) with periodic stimulation and continuous recording. In fOCT experiments of in vivo rat OB, propionic acid and m-cresol were used as odor stimulus presentations. Such a periodic stimulation enabled us to detect the specific odor-responses from highly scattering brain tissue. Swept source OCT operating at a wavelength of 1334 nm and a frequency of 20 kHz, was employed with theoretical depth and lateral resolutions of 6.7 MUm and 15.4 MUm, respectively. We succeeded in visualizing 2D cross sectional fOCT map across the neural layer structure of OCT in vivo. The detected fOCT signals corresponded to a few glomeruli of the medial and lateral parts of dorsal OB. We also obtained 3D fOCT maps, which upon integration across z-axis agreed well with OISI results. We expect such an approach to open a window for investigating and possibly addressing toward inter/intra-layer connections at high resolutions in the future. PMID- 27231594 TI - Multifocus microscopy with precise color multi-phase diffractive optics applied in functional neuronal imaging. AB - Multifocus microscopy (MFM) allows high-resolution instantaneous three dimensional (3D) imaging and has been applied to study biological specimens ranging from single molecules inside cells nuclei to entire embryos. We here describe pattern designs and nanofabrication methods for diffractive optics that optimize the light-efficiency of the central optical component of MFM: the diffractive multifocus grating (MFG). We also implement a "precise color" MFM layout with MFGs tailored to individual fluorophores in separate optical arms. The reported advancements enable faster and brighter volumetric time-lapse imaging of biological samples. In live microscopy applications, photon budget is a critical parameter and light-efficiency must be optimized to obtain the fastest possible frame rate while minimizing photodamage. We provide comprehensive descriptions and code for designing diffractive optical devices, and a detailed methods description for nanofabrication of devices. Theoretical efficiencies of reported designs is ~90% and we have obtained efficiencies of > 80% in MFGs of our own manufacture. We demonstrate the performance of a multi-phase MFG in 3D functional neuronal imaging in living C. elegans. PMID- 27231595 TI - Real-time simultaneous single snapshot of optical properties and blood flow using coherent spatial frequency domain imaging (cSFDI). AB - In this work we present and validate a wide-field method for the real-time mapping of tissue absorption, scattering and blood flow properties over wide regions of tissue (15 cm x 15 cm) with high temporal resolution (50 frames per second). We achieve this by applying Fourier Domain demodulation techniques to coherent spatial frequency domain imaging to extract optical properties and speckle flow index from a single snapshot. Applying this technique to forearm reactive hyperemia protocols demonstrates the ability to resolve intrinsic physiological signals such as the heart beat waveform and the buildup of deoxyhemoglobin associated with oxygen consumption. PMID- 27231596 TI - Nanoscale refractive index fluctuations detected via sparse spectral microscopy. AB - Partial Wave Spectroscopic (PWS) Microscopy has proven effective at detecting nanoscale hallmarks of carcinogenesis in histologically normal-appearing cells. The current method of data analysis requires acquisition of a three-dimensional data cube, consisting of multiple images taken at different illumination wavelengths, limiting the technique to data acquisition on ~30 individual cells per slide. To enable high throughput data acquisition and whole-slide imaging, new analysis procedures were developed that require fewer wavelengths in the same 500-700nm range for spectral analysis. The nanoscale sensitivity of the new analysis techniques was validated (i) theoretically, using finite-difference time domain solutions of Maxwell's equations, as well as (ii) experimentally, by measuring nanostructural alterations associated with carcinogenesis in biological cells. PMID- 27231597 TI - Automated quantitative assessment of three-dimensional bioprinted hydrogel scaffolds using optical coherence tomography. AB - Reconstructing and quantitatively assessing the internal architecture of opaque three-dimensional (3D) bioprinted hydrogel scaffolds is difficult but vital to the improvement of 3D bioprinting techniques and to the fabrication of functional engineered tissues. In this study, swept-source optical coherence tomography was applied to acquire high-resolution images of hydrogel scaffolds. Novel 3D gelatin/alginate hydrogel scaffolds with six different representative architectures were fabricated using our 3D bioprinting system. Both the scaffold material networks and the interconnected flow channel networks were reconstructed through volume rendering and binarisation processing to provide a 3D volumetric view. An image analysis algorithm was developed based on the automatic selection of the spatially-isolated region-of-interest. Via this algorithm, the spatially resolved morphological parameters including pore size, pore shape, strut size, surface area, porosity, and interconnectivity were quantified precisely. Fabrication defects and differences between the designed and as-produced scaffolds were clearly identified in both 2D and 3D; the locations and dimensions of each of the fabrication defects were also defined. It concludes that this method will be a key tool for non-destructive and quantitative characterization, design optimisation and fabrication refinement of 3D bioprinted hydrogel scaffolds. Furthermore, this method enables investigation into the quantitative relationship between scaffold structure and biological outcome. PMID- 27231599 TI - Optically trapping tumor cells to assess differentiation and prognosis of cancers. AB - We report an optical trapping method that may enable assessment of the differentiation status of cancerous cells by determining the minimum time required for cell-cell adhesion to occur. A single, live cell is trapped and brought into close proximity of another; the minimum contact time required for cell-cell adhesion to occur is measured using transformed cells from neural tumor cell lines: the human neuroblastoma SK-N-SH and rat C6 glioma cells. Earlier work on live adult rat hippocampal neural progenitors/stem cells had shown that a contact minimum of ~5 s was required for cells to adhere to each other. We now find the average minimum time for adhesion of cells from both tumor cell lines to substantially increase to ~20-25 s, in some cases up to 45 s. Upon in vitro differentiation of these cells with all-trans retinoic acid the average minimum time reverts to ~5-7 s. This proof-of-concept study indicates that optical trapping may be a quick, sensitive, and specific method for determining differentiation status and, thereby, the prognosis of cancer cells. PMID- 27231600 TI - Lensfree diffractive tomography for the imaging of 3D cell cultures. AB - New microscopes are needed to help realize the full potential of 3D organoid culture studies. In order to image large volumes of 3D organoid cultures while preserving the ability to catch every single cell, we propose a new imaging platform based on lensfree microscopy. We have built a lensfree diffractive tomography setup performing multi-angle acquisitions of 3D organoid culture embedded in Matrigel and developed a dedicated 3D holographic reconstruction algorithm based on the Fourier diffraction theorem. With this new imaging platform, we have been able to reconstruct a 3D volume as large as 21.5 mm (3) of a 3D organoid culture of prostatic RWPE1 cells showing the ability of these cells to assemble in 3D intricate cellular network at the mesoscopic scale. Importantly, comparisons with 2D images show that it is possible to resolve single cells isolated from the main cellular structure with our lensfree diffractive tomography setup. PMID- 27231598 TI - Comparison of amplitude-decorrelation, speckle-variance and phase-variance OCT angiography methods for imaging the human retina and choroid. AB - We compared the performance of three OCT angiography (OCTA) methods: speckle variance, amplitude decorrelation and phase variance for imaging of the human retina and choroid. Two averaging methods, split spectrum and volume averaging, were compared to assess the quality of the OCTA vascular images. All data were acquired using a swept-source OCT system at 1040 nm central wavelength, operating at 100,000 A-scans/s. We performed a quantitative comparison using a contrast-to noise (CNR) metric to assess the capability of the three methods to visualize the choriocapillaris layer. For evaluation of the static tissue noise suppression in OCTA images we proposed to calculate CNR between the photoreceptor/RPE complex and the choriocapillaris layer. Finally, we demonstrated that implementation of intensity-based OCT imaging and OCT angiography methods allows for visualization of retinal and choroidal vascular layers known from anatomic studies in retinal preparations. OCT projection imaging of data flattened to selected retinal layers was implemented to visualize retinal and choroidal vasculature. User guided vessel tracing was applied to segment the retinal vasculature. The results were visualized in a form of a skeletonized 3D model. PMID- 27231601 TI - In vivo bioluminescence and reflectance imaging of multiple organs in bioluminescence reporter mice by bundled-fiber-coupled microscopy. AB - Bioluminescence imaging (BLI) is used in biomedical research to monitor biological processes within living organisms. Recently, fiber bundles with high transmittance and density have been developed to detect low light with high resolution. Therefore, we have developed a bundled-fiber-coupled microscope with a highly sensitive cooled-CCD camera that enables the BLI of organs within the mouse body. This is the first report of in vivo BLI of the brain and multiple organs in luciferase-reporter mice using bundled-fiber optics. With reflectance imaging, the structures of blood vessels and organs can be seen clearly with light illumination, and it allowed identification of the structural details of bioluminescence images. This technique can also be applied to clinical diagnostics in a low invasive manner. PMID- 27231602 TI - Dynamic filtering improves attentional state prediction with fNIRS. AB - Brain activity can predict a person's level of engagement in an attentional task. However, estimates of brain activity are often confounded by measurement artifacts and systemic physiological noise. The optimal method for filtering this noise - thereby increasing such state prediction accuracy - remains unclear. To investigate this, we asked study participants to perform an attentional task while we monitored their brain activity with functional near infrared spectroscopy (fNIRS). We observed higher state prediction accuracy when noise in the fNIRS hemoglobin [Hb] signals was filtered with a non-stationary (adaptive) model as compared to static regression (84% +/- 6% versus 72% +/- 15%). PMID- 27231603 TI - Optical configuration of pigmented lesion detection by frequency analysis of skin speckle patterns. AB - In this paper we present a novel approach of realizing a safe, simple, and inexpensive sensor applicable to pigmented lesions detection. The approach is based on temporal tracking of back-reflected secondary speckle patterns generated while illuminating the affected area with a laser and applying periodic pressure to the surface via a controlled vibration source. When applied to pigmented lesions, the technique is superior to visual examination in avoiding many false positives and resultant unnecessary biopsies. Applying a series of different vibration frequencies at the examined tissue and analyzing the 2-D time varying speckle patterns in response to the applied periodic pressure creates a unique signature for each and different pigmented lesion. Analyzing these signatures is the first step toward detection of malignant melanoma. In this paper we present preliminary experiments that show the validity of the developed sensor for the classification of pigmented lesions. PMID- 27231604 TI - Statistical iterative reconstruction using adaptive fractional order regularization. AB - In order to reduce the radiation dose of the X-ray computed tomography (CT), low dose CT has drawn much attention in both clinical and industrial fields. A fractional order model based on statistical iterative reconstruction framework was proposed in this study. To further enhance the performance of the proposed model, an adaptive order selection strategy, determining the fractional order pixel-by-pixel, was given. Experiments, including numerical and clinical cases, illustrated better results than several existing methods, especially, in structure and texture preservation. PMID- 27231605 TI - Quantitative monitoring of laser-treated engineered skin using optical coherence tomography. AB - Nowadays, laser therapy is a common method for treating various dermatological troubles such as acne and wrinkles because of its efficient and immediate skin enhancement. Although laser treatment has become a routine procedure in medical and cosmetic fields, the prevention of side-effects, such as hyperpigmentation, redness and burning, still remains a critical issue that needs to be addressed. In order to reduce the side-effects while attaining efficient therapeutic outcomes, it is essential to understand the light-skin interaction through evaluation of physiological changes before and after laser therapy. In this study, we introduce a quantitative tissue monitoring method based on optical coherence tomography (OCT) for the evaluation of tissue regeneration after laser irradiation. To create a skin injury model, we applied a fractional CO2 laser on a customized engineered skin model, which is analogous to human skin in terms of its basic biological function and morphology. The irradiated region in the skin was then imaged by a high-speed OCT system, and its morphologic changes were analyzed by automatic segmentation software. Volumetric OCT images in the laser treated area clearly visualized the wound healing progress at different time points and provided comprehensive information which cannot be acquired through conventional monitoring methods. The results showed that the laser wound in engineered skins was mostly recovered from within 1~2 days with a fast recovery time in the vertical direction. However, the entire recovery period varied widely depending on laser doses and skin type. Our results also indicated that OCT guided laser therapy would be a very promising protocol for optimizing laser treatment for skin therapy. PMID- 27231606 TI - Endogenous light scattering as an optical signature of circulating tumor cell clusters. AB - Circulating tumor cell clusters (CTCCs) are significantly more likely to form metastases than single tumor cells. We demonstrate the potential of backscatter based flow cytometry (BSFC) to detect unique light scattering signatures of CTCCs in the blood of mice orthotopically implanted with breast cancer cells and treated with an anti-ADAM8 or a control antibody. Based on scattering detected at 405, 488, and 633 nm from blood samples flowing through microfluidic devices, we identified 14 CTCCs with large scattering peak widths and intensities, whose presence correlated strongly with metastasis. These initial studies demonstrate the potential to detect CTCCs via label-free BSFC. PMID- 27231607 TI - Eye-pupil displacement and prediction: effects on residual wavefront in adaptive optics retinal imaging. AB - This paper studies the effect of pupil displacements on the best achievable performance of retinal imaging adaptive optics (AO) systems, using 52 trajectories of horizontal and vertical displacements sampled at 80 Hz by a pupil tracker (PT) device on 13 different subjects. This effect is quantified in the form of minimal root mean square (rms) of the residual phase affecting image formation, as a function of the delay between PT measurement and wavefront correction. It is shown that simple dynamic models identified from data can be used to predict horizontal and vertical pupil displacements with greater accuracy (in terms of average rms) over short-term time horizons. The potential impact of these improvements on residual wavefront rms is investigated. These results allow to quantify the part of disturbances corrected by retinal imaging systems that are caused by relative displacements of an otherwise fixed or slowy-varying subject-dependent aberration. They also suggest that prediction has a limited impact on wavefront rms and that taking into account PT measurements in real time improves the performance of AO retinal imaging systems. PMID- 27231608 TI - Full 3-D OCT-based pseudophakic custom computer eye model. AB - We compared measured wave aberrations in pseudophakic eyes implanted with aspheric intraocular lenses (IOLs) with simulated aberrations from numerical ray tracing on customized computer eye models, built using quantitative 3-D OCT-based patient-specific ocular geometry. Experimental and simulated aberrations show high correlation (R = 0.93; p<0.0001) and similarity (RMS for high order aberrations discrepancies within 23.58%). This study shows that full OCT-based pseudophakic custom computer eye models allow understanding the relative contribution of optical geometrical and surgically-related factors to image quality, and are an excellent tool for characterizing and improving cataract surgery. PMID- 27231610 TI - Elemental analysis of tissue pellets for the differentiation of epidermal lesion and normal skin by laser-induced breakdown spectroscopy. AB - By laser induced breakdown spectroscopy (LIBS) analysis of epidermal lesion and dermis tissue pellets of hairless mouse, it is shown that Ca intensity in the epidermal lesion is higher than that in dermis, whereas Na and K intensities have an opposite tendency. It is demonstrated that epidermal lesion and normal dermis can be differentiated with high selectivity either by univariate or multivariate analysis of LIBS spectra with an intensity ratio difference by factor of 8 or classification accuracy over 0.995, respectively. PMID- 27231609 TI - Topical MMP beacon enabled fluorescence-guided resection of oral carcinoma. AB - Each year almost 300,000 individuals worldwide are diagnosed with oral cancer, more than 90% of these being oral carcinoma [N. Engl. J. Med.328, 1841993]. Surgical resection is the standard of care, but accurate delineation of the tumor boundaries is challenging, resulting in either under-resection with risk of local recurrence or over-resection with increased functional loss and negative impact on quality of life. This study evaluates, in two pre-clinical in vivo tumor models, the potential of fluorescence-guided resection using molecular beacons activated by metalloproteinases, which are frequently upregulated in human oral cancer. In both models there was rapid (<15 min) beacon activation upon local application, allowing clear fluoresecence imaging in vivo and confirmed by ex vivo fluorescence microscopy and HPLC, with minimal activation in normal oral tissues. Although the tissue penetration was limited using topical application, these findings support further development of this approach towards translation to first-in-human trials. PMID- 27231611 TI - Optically monitored drug delivery patch based on porous silicon and polymer microneedles. AB - Fabrication and characterization of an optically monitored hybrid patch for local administration of drugs, based on polymeric micro-needles and a porous silicon free-standing membrane, are reported. The micro-needles are realized by an innovative photolithographic approach that allows fine tuning of geometrical parameters, using polyethylene glycol and a commercial photo-catalyzer. The porous silicon multilayer not only increases the storage of a relevant amount of the drug, but also offers a continuous, naked-eye monitoring of the drug delivery process. As a proof-of-concept experiment, we report our results on the release of a dye molecule (fluorescein, 332 Da) in a phosphate saline buffer. PMID- 27231612 TI - Remote z-scanning with a macroscopic voice coil motor for fast 3D multiphoton laser scanning microscopy. AB - There is a high demand for 3D multiphoton imaging in neuroscience and other fields but scanning in axial direction presents technical challenges. We developed a focusing technique based on a remote movable mirror that is conjugate to the specimen plane and translated by a voice coil motor. We constructed cost effective z-scanning modules from off-the-shelf components that can be mounted onto standard multiphoton laser scanning microscopes to extend scan patterns from 2D to 3D. Systems were designed for large objectives and provide high resolution, high speed and a large z-scan range (>300 MUm). We used these systems for 3D multiphoton calcium imaging in the adult zebrafish brain and measured odor-evoked activity patterns across >1500 neurons with single-neuron resolution and high signal-to-noise ratio. PMID- 27231613 TI - Using optical trap to measure the refractive index of a single animal virus in culture fluid with high precision. AB - The refractive index (RI) is a fundamental parameter of materials that can be used to distinguish and sort materials of different nature. Although the RI of a virus is required for many optics-based biosensing applications, RIs of animal viruses have never been measured. Here we have developed a technique that can measure the RI of individual viruses in aqueous media with high precision. This technique is based on optical trapping of single virions and works by relating the size and RI of a single virus to the stiffness of an optical trap. We have derived an analytic expression to quantitatively describe the optical trapping of these particles. We have validated this equation using nanoparticles of known RI, and measured the RI of individual human immunodeficiency viruses type-1, which yielded a value of 1.42 at 830 nm with less than 2% coefficient of variation. This value is much lower than the RI typically assumed for viruses, but very close to that of 2.0 M sucrose solution in water. To the best of our knowledge, this is the first report on the experimental measurement of the RI for a single animal virus in aqueous media. This technique does not require prior knowledge on the diameter of the nanoparticles, and can be applied to other viruses or nanoparticles for accurate measurement of RI that is critical for the label-free detection of these particles in various settings. PMID- 27231614 TI - Label-free imaging of metabolism and oxidative stress in human induced pluripotent stem cell-derived cardiomyocytes. AB - In this work we demonstrate a label-free optical imaging technique to assess metabolic status and oxidative stress in human induced pluripotent stem cell derived cardiomyocytes by two-photon fluorescence lifetime imaging of endogenous fluorophores. Our results show the sensitivity of this method to detect shifts in metabolism and oxidative stress in the cardiomyocytes upon pathological stimuli of hypoxia and cardiotoxic drugs. This non-invasive imaging technique could prove beneficial for drug development and screening, especially for in vitro cardiac models created from stem cell-derived cardiomyocytes and to study the pathogenesis of cardiac diseases and therapy. PMID- 27231615 TI - Fast 3D visualization of endogenous brain signals with high-sensitivity laser scanning photothermal microscopy. AB - A fast, high-sensitivity photothermal microscope was developed by implementing a spatially segmented balanced detection scheme into a laser scanning microscope. We confirmed a 4.9 times improvement in signal-to-noise ratio in the spatially segmented balanced detection compared with that of conventional detection. The system demonstrated simultaneous bi-modal photothermal and confocal fluorescence imaging of transgenic mouse brain tissue with a pixel dwell time of 20 MUs. The fluorescence image visualized neurons expressing yellow fluorescence proteins, while the photothermal signal detected endogenous chromophores in the mouse brain, allowing 3D visualization of the distribution of various features such as blood cells and fine structures probably due to lipids. This imaging modality was constructed using compact and cost-effective laser diodes, and will thus be widely useful in the life and medical sciences. PMID- 27231616 TI - Novel microscope-integrated stereoscopic heads-up display for intrasurgical optical coherence tomography. AB - Intra-operative optical coherence tomography (OCT) requires a display technology which allows surgeons to visualize OCT data without disrupting surgery. Previous research and commercial intrasurgical OCT systems have integrated heads-up display (HUD) systems into surgical microscopes to provide monoscopic viewing of OCT data through one microscope ocular. To take full advantage of our previously reported real-time volumetric microscope-integrated OCT (4D MIOCT) system, we describe a stereoscopic HUD which projects a stereo pair of OCT volume renderings into both oculars simultaneously. The stereoscopic HUD uses a novel optical design employing spatial multiplexing to project dual OCT volume renderings utilizing a single micro-display. The optical performance of the surgical microscope with the HUD was quantitatively characterized and the addition of the HUD was found not to substantially effect the resolution, field of view, or pincushion distortion of the operating microscope. In a pilot depth perception subject study, five ophthalmic surgeons completed a pre-set dexterity task with 50.0% (SD = 37.3%) higher success rate and in 35.0% (SD = 24.8%) less time on average with stereoscopic OCT vision compared to monoscopic OCT vision. Preliminary experience using the HUD in 40 vitreo-retinal human surgeries by five ophthalmic surgeons is reported, in which all surgeons reported that the HUD did not alter their normal view of surgery and that live surgical maneuvers were readily visible in displayed stereoscopic OCT volumes. PMID- 27231617 TI - Fast volumetric imaging with patterned illumination via digital micro-mirror device-based temporal focusing multiphoton microscopy. AB - Temporal focusing multiphoton microscopy (TFMPM) has the advantage of area excitation in an axial confinement of only a few microns; hence, it can offer fast three-dimensional (3D) multiphoton imaging. Herein, fast volumetric imaging via a developed digital micromirror device (DMD)-based TFMPM has been realized through the synchronization of an electron multiplying charge-coupled device (EMCCD) with a dynamic piezoelectric stage for axial scanning. The volumetric imaging rate can achieve 30 volumes per second according to the EMCCD frame rate of more than 400 frames per second, which allows for the 3D Brownian motion of one-micron fluorescent beads to be spatially observed. Furthermore, it is demonstrated that the dynamic HiLo structural multiphoton microscope can reject background noise by way of the fast volumetric imaging with high-speed DMD patterned illumination. PMID- 27231618 TI - Motion robust PPG-imaging through color channel mapping. AB - Photoplethysmography (PPG)-imaging is an emerging noninvasive technique that maps spatial blood-volume variations in living tissue with a video camera. In this paper, we clarify how cardiac-related (i.e., ballistocardiographic; BCG) artifacts occur in this imaging modality and address these using algorithms from the remote-PPG literature. Performance is assessed under stationary conditions at the immobilized hand. Our proposal outperforms the state-of-the-art, blood pulsation imaging [Biomed. Opt. Express5, 3123 (2014). ], even in our best attempt to create diffused illumination. BCG-artifacts are suppressed to an order of magnitude below PPG-signal strength, which is sufficient to prevent interpretation errors. PMID- 27231619 TI - Characterisation of the effects of optical aberrations in single molecule techniques. AB - Optical aberrations degrade image quality in fluorescence microscopy, including for single-molecule based techniques. These depend on post-processing to localize individual molecules in an image series. Using simulated data, we show the impact of optical aberrations on localization success, accuracy and precision. The peak intensity and the proportion of successful localizations strongly reduces when the aberration strength is greater than 1.0 rad RMS, while the precision of each of those localisations is halved. The number of false-positive localisations exceeded 10% of the number of true-positive localisations at an aberration strength of only ~0.6 rad RMS when using the ThunderSTORM package, but at greater than 1.0 rad RMS with the Radial Symmetry package. In the presence of coma, the localization error reaches 100 nm at ~0.6 rad RMS of aberration strength. The impact of noise and of astigmatism for axial resolution are also considered. Understanding the effect of aberrations is crucial when deciding whether the addition of adaptive optics to a single-molecule microscope could significantly increase the information obtainable from an image series. PMID- 27231620 TI - Optimizing ultrafast illumination for multiphoton-excited fluorescence imaging. AB - We study the optimal conditions for high throughput two-photon excited fluorescence (2PEF) and three-photon excited fluorescence (3PEF) imaging using femtosecond lasers. We derive relations that allow maximization of the rate of imaging depending on the average power, pulse repetition rate, and noise characteristics of the laser, as well as on the size and structure of the sample. We perform our analysis using ~100 MHz, ~1 MHz and 1 kHz pulse rates and using both a tightly-focused illumination beam with diffraction-limited image resolution, as well loosely focused illumination with a relatively low image resolution, where the latter utilizes separate illumination and fluorescence detection beam paths. Our theoretical estimates agree with the experiments, which makes our approach especially useful for optimizing high throughput imaging of large samples with a field-of-view up to 10x10 cm(2). PMID- 27231621 TI - Multi-modal adaptive optics system including fundus photography and optical coherence tomography for the clinical setting. AB - We present a new compact multi-modal imaging prototype that combines an adaptive optics (AO) fundus camera with AO-optical coherence tomography (OCT) in a single instrument. The prototype allows acquiring AO fundus images with a field of view of 4 degrees x4 degrees and with a frame rate of 10fps. The exposure time of a single image is 10 ms. The short exposure time results in nearly motion artifact free high resolution images of the retina. The AO-OCT mode allows acquiring volumetric data of the retina at 200kHz A-scan rate with a transverse resolution of ~4 um and an axial resolution of ~5 um. OCT imaging is acquired within a field of view of 2 degrees x2 degrees located at the central part of the AO fundus image. Recording of OCT volume data takes 0.8 seconds. The performance of the new system is tested in healthy volunteers and patients with retinal diseases. PMID- 27231622 TI - Compact solid-state CMOS single-photon detector array for in vivo NIR fluorescence lifetime oncology measurements. AB - In near infrared fluorescence-guided surgical oncology, it is challenging to distinguish healthy from cancerous tissue. One promising research avenue consists in the analysis of the exogenous fluorophores' lifetime, which are however in the (sub-)nanosecond range. We have integrated a single-photon pixel array, based on standard CMOS SPADs (single-photon avalanche diodes), in a compact, time-gated measurement system, named FluoCam. In vivo measurements were carried out with indocyanine green (ICG)-modified derivatives targeting the alphavbeta 3 integrin, initially on a genetically engineered mouse model of melanoma injected with ICG conjugated with tetrameric cyclic pentapeptide (ICG-E[c(RGD f K)4]), then on mice carrying tumour xenografts of U87-MG (a human primary glioblastoma cell line) injected with monomeric ICG-c(RGD f K). Measurements on tumor, muscle and tail locations allowed us to demonstrate the feasibility of in vivo lifetime measurements with the FluoCam, to determine the characteristic lifetimes (around 500 ps) and subtle lifetime differences between bound and unbound ICG-modified fluorophores (10% level), as well as to estimate the available photon fluxes under realistic conditions. PMID- 27231624 TI - Targeted Aucore-Agshell nanorods as a dual-functional contrast agent for photoacoustic imaging and photothermal therapy. AB - Optimizing contrast enhancement is essential for producing specific signals in biomedical imaging and therapy. The potential of using Aucore-Agshell nanorods (Au@Ag NRs) as a dual-functional theranostic contrast agent is demonstrated for effective cancer imaging and treatments. Due to its strong NIR absorption and high efficiency of photothermal conversion, effects of both photoacoustic tomography (PAT) and photothermal therapy (PTT) are enhanced significantly. The PAT signal grows by 45.3% and 82% in the phantom and in vivo experiments, respectively, when compared to those using Au NRs. In PTT, The maximum increase of tissue temperature treated with Au@Ag NRs is 22.8 degrees C, twice that with Au NRs. Results of the current study show the feasibility of using Au@Ag NRs for synergetic PAT with PTT. And it will enhance the potential application on real time PAT guided PTT, which will greatly benefit the customized PTT treatment of cancer. PMID- 27231623 TI - Enhanced volumetric visualization for real time 4D intraoperative ophthalmic swept-source OCT. AB - Current-generation software for rendering volumetric OCT data sets based on ray casting results in volume visualizations with indistinct tissue features and sub optimal depth perception. Recent developments in hand-held and microscope integrated intrasurgical OCT designed for real-time volumetric imaging motivate development of rendering algorithms which are both visually appealing and fast enough to support real time rendering, potentially from multiple viewpoints for stereoscopic visualization. We report on an enhanced, real time, integrated volumetric rendering pipeline which incorporates high performance volumetric median and Gaussian filtering, boundary and feature enhancement, depth encoding, and lighting into a ray casting volume rendering model. We demonstrate this improved model implemented on graphics processing unit (GPU) hardware for real time volumetric rendering of OCT data during tissue phantom and live human surgical imaging. We show that this rendering produces enhanced 3D visualizations of pathology and intraoperative maneuvers compared to standard ray casting. PMID- 27231625 TI - Non-invasive dual fluorescence in vivo imaging for detection of macrophage infiltration and matrix metalloproteinase (MMP) activity in inflammatory arthritic joints. AB - Detection and intervention at an early stage is a critical factor to impede arthritis progress. Here we present a non-invasive method to detect inflammatory changes in joints of arthritic mice. Inflammation was monitored by dual fluorescence optical imaging for near-infrared fluorescent (750F) matrix metalloproteinase activatable agent and allophycocyanin-conjugated anti-mouse CD11b. Increased intensity of allophycocyanin (indication of macrophage accumulation) and 750F (indication of matrix-metalloproteinase activity) showed a biological relationship with the arthritis severity score and the histopathology score of arthritic joints. Our results demonstrate that this method can be used to detect early stages of arthritis with minimum intervention in small animal models. PMID- 27231626 TI - Subcellular chemical and morphological analysis by stimulated Raman scattering microscopy and image analysis techniques. AB - The visualization of heterogeneous morphology, segmentation and quantification of image features is a crucial point for nonlinear optics microscopy applications, spanning from imaging of living cells or tissues to biomedical diagnostic. In this paper, a methodology combining stimulated Raman scattering microscopy and image analysis technique is presented. The basic idea is to join the potential of vibrational contrast of stimulated Raman scattering and the strength of imaging analysis technique in order to delineate subcellular morphology with chemical specificity. Validation tests on label free imaging of polystyrene-beads and of adipocyte cells are reported and discussed. PMID- 27231627 TI - In vivo investigation of temporal effects and drug delivery induced by transdermal microneedles with optical coherence tomography. AB - Transdermal drug-delivery systems (TDDS) have been a growing field in drug delivery because of their advantages over parenteral and oral administration. Recent studies illustrate that microneedles (MNs) can effectively penetrate through the stratum corneum barrier to facilitate drug delivery. However, the temporal effects on skin and drug diffusion are difficult to investigate in vivo. In this study, we used optical coherence tomography (OCT) to observe the process by which MNs dissolve and to investigate the temporal effects on mouse skin induced by MNs, including the morphological and vascular changes. Moreover, the recovery process of the skin was observed with OCT. Additionally, we proposed a method to observe drug delivery by estimation of cross-correlation relationship between sequential 2D OCT images obtained at the same location, reflecting the variation in the backscattered intensity due to the diffusion of the rhodamine molecules encapsulated in MNs. Our observations supported the hypothesis that the temporal effects on skin due to MNs, the dissolution of MNs, and the drug diffusion process can be quantitatively evaluated with OCT. The results showed that OCT can be a potential tool for in vivo monitoring of effects and outcomes when MNs are used as a TDDS. PMID- 27231628 TI - Preclinical metrics to predict through-focus visual acuity for pseudophakic patients. AB - This study compares the clinical through-focus visual acuity (VA) in patients implanted with different intraocular lens (IOL) to optical bench testing of the same IOLs to evaluate the suitability of optical metrics of predicting clinical VA. Modulation transfer function and phase transfer function for different spatial frequencies and US Air Force pictures were measured using an optical bench for two monofocal IOLs, three multifocal IOLs and an extended range of vision IOL. Four preclinical metrics were calculated and compared to the clinical through-focus VA collected in three different clinical studies (243 patients in total). All metrics were well correlated (R(2)>=0.89) with clinical data and may be suitable for predicting through-focus VA in pseudophakic eyes. PMID- 27231629 TI - Third harmonic generation imaging for fast, label-free pathology of human brain tumors. AB - In brain tumor surgery, recognition of tumor boundaries is key. However, intraoperative assessment of tumor boundaries by the neurosurgeon is difficult. Therefore, there is an urgent need for tools that provide the neurosurgeon with pathological information during the operation. We show that third harmonic generation (THG) microscopy provides label-free, real-time images of histopathological quality; increased cellularity, nuclear pleomorphism, and rarefaction of neuropil in fresh, unstained human brain tissue could be clearly recognized. We further demonstrate THG images taken with a GRIN objective, as a step toward in situ THG microendoscopy of tumor boundaries. THG imaging is thus a promising tool for optical biopsies. PMID- 27231631 TI - Ultrasound-guided photoacoustic imaging for the selective detection of EGFR expressing breast cancer and lymph node metastases. AB - We assessed the use of ultrasound (US)-guided photoacoustic imaging (PAI) and anti-EGFR antibody-conjugated gold nanorods (anti-EGFR-GNs) to non-invasively detect EGFR-expressing primary tumor masses and regional lymph node (LN) metastases in breast tumor mice generated by injecting MCF-7 (EGFR-negative) or MDA-MB-231 (EGFR-positive) human breast cells using a preclinical Vevo 2100 LAZR Imaging system. Anti-EGFR-GNs provided a significant enhancement in the PA signal in MDA-MB-231 tumor and the axillary LN metastases relative to MCF-7 tumor and non-LN metastases. We demonstrated that US-guided PAI using anti-EGFR-GNs is highly sensitive for the selective visualization of EGFR-expressing breast primary tumors as well as LN micrometastases. PMID- 27231630 TI - Scalable wide-field optical coherence tomography-based angiography for in vivo imaging applications. AB - Recent advances in optical coherence tomography (OCT)-based angiography have demonstrated a variety of biomedical applications in the diagnosis and therapeutic monitoring of diseases with vascular involvement. While promising, its imaging field of view (FOV) is however still limited (typically less than 9 mm(2)), which somehow slows down its clinical acceptance. In this paper, we report a high-speed spectral-domain OCT operating at 1310 nm to enable wide FOV up to 750 mm(2). Using optical microangiography (OMAG) algorithm, we are able to map vascular networks within living biological tissues. Thanks to 2,048 pixel array line scan InGaAs camera operating at 147 kHz scan rate, the system delivers a ranging depth of ~7.5 mm and provides wide-field OCT-based angiography at a single data acquisition. We implement two imaging modes (i.e., wide-field mode and high-resolution mode) in the OCT system, which gives highly scalable FOV with flexible lateral resolution. We demonstrate scalable wide-field vascular imaging for multiple finger nail beds in human and whole brain in mice with skull left intact at a single 3D scan, promising new opportunities for wide-field OCT-based angiography for many clinical applications. PMID- 27231632 TI - Temperature feedback-controlled photothermal treatment with diffusing applicator: theoretical and experimental evaluations. AB - To minimize thermal injury, the current study evaluated the real-time temperature monitoring with a proportional-integrative-derivative (PID) controller during 980 nm photothermal treatment with a radially-diffusing applicator. Both simulations and experiments demonstrated comparable thermal behaviors in temperature distribution and the degree of irreversible tissue denaturation. The PID controlled application constantly maintained the pre-determined temperature of 353 K (steady-state error = < 1 K). Due to constant energy delivery, coagulation volumes linearly increased up to 1.04 +/- 0.02 cm(3) with irradiation time. Integration of temperature feedback with diffuser-assisted photothermal treatments can provide a feasible therapeutic modality to treat pancreatic tumors in an effective manner. PMID- 27231633 TI - Miniature fiber-optic multiphoton microscopy system using frequency-doubled femtosecond Er-doped fiber laser. AB - We report on a miniature fiber-optic multiphoton microscopy (MPM) system based on a frequency-doubled femtosecond Er-doped fiber laser. The femtosecond pulses from the laser source are delivered to the miniature fiber-optic probe at 1.58 um wavelength, where a standard single mode fiber is used for delivery without the need of free-space dispersion compensation components. The beam is frequency doubled inside the probe by a periodically poled MgO:LiNbO3 crystal. Frequency doubled pulses at 786 nm with a maximum power of 80 mW and a pulsewidth of 150 fs are obtained and applied to excite intrinsic signals from tissues. A MEMS scanner, a miniature objective, and a multimode collection fiber are further used to make the probe compact. The miniature fiber-optic MPM system is highly portable and robust. Ex vivo multiphoton imaging of mammalian skins demonstrates the capability of the system in imaging biological tissues. The results show that the miniature fiber-optic MPM system using frequency-doubled femtosecond fiber laser can potentially bring the MPM imaging for clinical applications. PMID- 27231634 TI - Coherent-weighted three-dimensional image reconstruction in linear-array-based photoacoustic tomography. AB - While the majority of photoacoustic imaging systems used custom-made transducer arrays, commercially-available linear transducer arrays hold the benefits of affordable price, handheld convenience and wide clinical recognition. They are not widely used in photoacoustic imaging primarily because of the poor elevation resolution. Here, without modifying the imaging geometry and system, we propose addressing this limitation purely through image reconstruction. Our approach is based on the integration of two advanced image reconstruction techniques: focal line-based three-dimensional image reconstruction and coherent weighting. We first numerically validated our approach through simulation and then experimentally tested it in phantom and in vivo. Both simulation and experimental results proved that the method can significantly improve the elevation resolution (up to 4 times in our experiment) and enhance object contrast. PMID- 27231635 TI - Real-time imaging of action potentials in nerves using changes in birefringence. AB - Polarized light can be used to measure the electrical activity associated with action potential propagation in nerves, as manifested in simultaneous dynamic changes in their intrinsic optical birefringence. These signals may serve as a tool for minimally invasive neuroimaging in various types of neuroscience research, including the study of neuronal activation patterns with high spatiotemporal resolution. A fast linear photodiode array was used to image propagating action potentials in an excised portion of the lobster walking leg nerve. We show that the crossed-polarized signal (XPS) can be reliably imaged over a >=2 cm span in our custom nerve chamber, by averaging multiple-stimulation signals, and also in single-scan real-time "movies". This demonstration paves the way toward utilizing changes in the optical birefringence to image more complex neuronal activity in nerve fibers and other organized neuronal tissue. PMID- 27231636 TI - Solar-thermal complex sample processing for nucleic acid based diagnostics in limited resource settings. AB - The use of point-of-care (POC) devices in limited resource settings where access to commonly used infrastructure, such as water and electricity, can be restricted represents simultaneously one of the best application fits for POC systems as well as one of the most challenging places to deploy them. Of the many challenges involved in these systems, the preparation and processing of complex samples like stool, vomit, and biopsies are particularly difficult due to the high number and varied nature of mechanical and chemical interferents present in the sample. Previously we have demonstrated the ability to use solar-thermal energy to perform PCR based nucleic acid amplifications. In this work demonstrate how the technique, using similar infrastructure, can also be used to perform solar thermal based sample processing system for extracting and isolating Vibrio Cholerae nucleic acids from fecal samples. The use of opto-thermal energy enables the use of sunlight to drive thermal lysing reactions in large volumes without the need for external electrical power. Using the system demonstrate the ability to reach a 95 degrees C threshold in less than 5 minutes and maintain a stable sample temperature of +/- 2 degrees C following the ramp up. The system is demonstrated to provide linear results between 10(4) and 10(8) CFU/mL when the released nucleic acids were quantified via traditional means. Additionally, we couple the sample processing unit with our previously demonstrated solar-thermal PCR and tablet based detection system to demonstrate very low power sample-in answer-out detection. PMID- 27231637 TI - Accommodating volume-constant age-dependent optical (AVOCADO) model of the crystalline GRIN lens. AB - The purpose of this manuscript is to introduce a new age-dependent model of the human lens with two GRIN power distributions (axial and radial) that allow decoupling of its refractive power and axial optical path length. The aspect ratio of the lens core can be held constant under accommodation, as well as the lens volume by varying the asphericity of the lens external surfaces. The spherical aberration calculated by exact raytracing is shown to be in line with experimental data. The proposed model is compared to previous GRIN models from the literature, and it is concluded that the features of the new model will be useful for GRIN reconstruction in future experimental studies; in particular, studies of the accommodation-dependent properties of the ageing human eye. A proposed logarithmic model of the lens core enables decoupling of three fundamental optical characteristics of the lens, namely axial optical path length, optical power and third-order spherical aberration, without changing the external shape of the lens. Conversely, the near-surface GRIN structure conforms to the external shape of the lens, which is necessary for accommodation modelling. PMID- 27231638 TI - Automated analysis of multimodal fluorescence lifetime imaging and optical coherence tomography data for the diagnosis of oral cancer in the hamster cheek pouch model. AB - It is known that the progression of oral cancer is accompanied by changes in both tissue biochemistry and morphology. A multimodal imaging approach combining functional and structural imaging modalities could therefore provide a more comprehensive prognosis of oral cancer. This idea forms the central theme of the current study, wherein this premise is examined in the context of a multimodal imaging system that combines fluorescence lifetime imaging (FLIM) and optical coherence tomography (OCT). Towards this end, in the first part of the present study, the diagnostic advantage obtained by using both fluorescence intensity and lifetime information is assessed. In the second part of the study, the diagnostic potential of FLIM-derived biochemical features is compared with that of OCT derived morphological features. For an objective assessment, several quantitative biochemical and morphological features from FLIM and OCT data, respectively, were obtained using signal and image processing techniques. These features were subsequently used in a statistical classification framework to quantify the diagnostic potential of different features. The classification accuracy for combined FLIM and OCT features was estimated to be 87.4%, which was statistically higher than accuracy based on only FLIM (83.2%) or OCT (81.0%) features. Moreover, the complimentary information provided by FLIM and OCT features, resulted in highest sensitivity and specificity for the combined FLIM and OCT features for discriminating benign (88.2% sens., 92.0% spec.), pre-cancerous (81.5% sens., 96.0% spec.), and cancerous (90.1% sens., 92.0% spec.) classes. PMID- 27231639 TI - Retinal thermal damage threshold dependence on exposure duration for the transitional near-infrared laser radiation at 1319 nm. AB - The retinal damage effects induced by transitional near-infrared (NIR) lasers have been investigated for years. However, the damage threshold dependence on exposure duration has not been revealed. In this paper, the in-vivo retinal damage ED50 thresholds were determined in chinchilla grey rabbits for 1319 nm laser radiation for exposure durations from 0.1 s to 10 s. The incident corneal irradiance diameter was fixed at 5 mm. The ED50 thresholds given in terms of the total intraocular energy (TIE) for exposure durations of 0.1, 1 and 10 s were 1.36, 6.33 and 28.6 J respectively. The ED50 thresholds were correlated by a power law equation, ED50 = 6.31t (0.66) [J] where t is time [s], with correlation coefficient R = 0.9999. There exists a sufficient safety margin (factor of 28~60) between the human ED50 thresholds derived from the rabbit and the maximum permissible exposure (MPE) values in the current laser safety standards. PMID- 27231640 TI - Raman spectroscopy of endoscopic colonic biopsies from patients with ulcerative colitis to identify mucosal inflammation and healing. AB - Raman spectroscopy was used to differentiate between mucosally healed (or quiescent) and inflamed colon tissue, as assessed endoscopically, in patients with ulcerative colitis. From the analysis of the Raman spectra of 60 biopsy tissue samples, clear differences were identified between the spectra of the quiescent and inflamed tissue. Three carotenoid peaks were found to be approximately twice as intense in the inflamed tissue. Two phospholipid peaks were found to be significantly lower in the inflamed tissue. Using multivariate statistical analysis, we show that these five peaks can be used to discriminate between endoscopically quiescent and inflamed tissue. We also correlated the Raman data with a histological assessment of the tissue. Four of the five peaks were found to be significantly different between the spectra of histologically healed (or quiescent) and histologically inflamed tissue. These findings indicate the ability of Raman spectroscopy to accurately classify colon tissue as either quiescent or inflamed, irrespective of whether an endoscopic or histological grading scheme is followed. We thus demonstrate that Raman spectroscopy could potentially be used as an early diagnosis tool for assessing the presence of mucosal healing or inflammation in patients with ulcerative colitis. PMID- 27231641 TI - Automatic detection of cone photoreceptors in split detector adaptive optics scanning light ophthalmoscope images. AB - Quantitative analysis of the cone photoreceptor mosaic in the living retina is potentially useful for early diagnosis and prognosis of many ocular diseases. Non confocal split detector based adaptive optics scanning light ophthalmoscope (AOSLO) imaging reveals the cone photoreceptor inner segment mosaics often not visualized on confocal AOSLO imaging. Despite recent advances in automated cone segmentation algorithms for confocal AOSLO imagery, quantitative analysis of split detector AOSLO images is currently a time-consuming manual process. In this paper, we present the fully automatic adaptive filtering and local detection (AFLD) method for detecting cones in split detector AOSLO images. We validated our algorithm on 80 images from 10 subjects, showing an overall mean Dice's coefficient of 0.95 (standard deviation 0.03), when comparing our AFLD algorithm to an expert grader. This is comparable to the inter-observer Dice's coefficient of 0.94 (standard deviation 0.04). To the best of our knowledge, this is the first validated, fully-automated segmentation method which has been applied to split detector AOSLO images. PMID- 27231642 TI - Development of perturbation Monte Carlo methods for polarized light transport in a discrete particle scattering model. AB - We present a polarization-sensitive, transport-rigorous perturbation Monte Carlo (pMC) method to model the impact of optical property changes on reflectance measurements within a discrete particle scattering model. The model consists of three log-normally distributed populations of Mie scatterers that approximate biologically relevant cervical tissue properties. Our method provides reflectance estimates for perturbations across wavelength and/or scattering model parameters. We test our pMC model performance by perturbing across number densities and mean particle radii, and compare pMC reflectance estimates with those obtained from conventional Monte Carlo simulations. These tests allow us to explore different factors that control pMC performance and to evaluate the gains in computational efficiency that our pMC method provides. PMID- 27231643 TI - Optical fiber LPG biosensor integrated microfluidic chip for ultrasensitive glucose detection. AB - An optical fiber sensor integrated microfluidic chip is presented for ultrasensitive detection of glucose. A long-period grating (LPG) inscribed in a small-diameter single-mode fiber (SDSMF) is employed as an optical refractive index (RI) sensor. With the layer-by-layer (LbL) self-assembly technique, poly (ethylenimine) (PEI) and poly (acrylic acid) (PAA) multilayer film is deposited on the SDSMF-LPG sensor for both supporting and signal enhancement, and then a glucose oxidase (GOD) layer is immobilized on the outer layer for glucose sensing. A microfluidic chip for glucose detection is fabricated after embedding the SDSMF-LPG biosensor into the microchannel of the chip. Experimental results reveal that the SDSMF-LPG biosensor based on such a hybrid sensing film can ultrasensitively detect glucose concentration as low as 1 nM. After integration into the microfluidic chip, the detection range of the sensor is extended from 2 uM to 10 uM, and the response time is remarkablely shortened from 6 minutes to 70 seconds. PMID- 27231644 TI - Feature issue introduction: biophotonic materials and applications. AB - Biophotonics can be defined as the interplay of light and biological matter. The percolation of new optical technology into the realm of biology has literally shed new light into the inner workings of biological systems. This has revealed new applications for optics in biology. In a parallel trend, biomolecules have been investigated for their optical applications. Materials are playing a central role in the development of biophotonics. New materials, fabrication methods, and structures are enabling new biosensors, contrast agents, imaging strategies, and assay methods. Similarly, biologic materials themselves can be used in photonic devices. In this context, two open-access, rapid-publication journals from The Optical Society of America (OSA), Optical Materials Express and Biomedical Optics Express, will publish a joint feature issue covering advances in biophotonics materials. PMID- 27231646 TI - Premature feather loss among common tern chicks in Ontario: the return of an enigmatic developmental anomaly. AB - In July 2014, we observed premature feather loss (PFL) among non-sibling, common tern Sterna hirundo chicks between two and four weeks of age at Gull Island in northern Lake Ontario, Canada. Rarely observed in wild birds, to our knowledge PFL has not been recorded in terns since 1974, despite the subsequent banding of hundreds of thousands of tern chicks across North America alone. The prevalence, 5% of chicks (9/167), and extent of feather loss we report is more extreme than in previous reports for common terns but was not accompanied by other aberrant developmental or physical deformities. Complete feather loss from all body areas (wing, tail, head and body) occurred over a period of a few days but all affected chicks appeared vigorous and quickly began to grow replacement feathers. All but one chick (recovered dead and submitted for post-mortem) most likely fledged 10 20 days after normal fledging age. We found no evidence of feather dystrophy or concurrent developmental abnormalities unusual among affected chicks. Thus, the PFL we observed among common terns in 2014 was largely of unknown origin. There was striking temporal association between the onset of PFL and persistent strong southwesterly winds that caused extensive mixing of near-shore surface water with cool, deep lake waters. One hypothesis is that PFL may have been caused by unidentified pathogens or toxins welling up from these deep waters along the shoreline but current data are insufficient to test this. PFL was not observed among common terns at Gull Island in 2015, although we did observe similar feather loss in a herring gull Larus argentatus chick in that year. Comparison with sporadic records of PFL in other seabirds suggests that PFL may be a rare, but non-specific, response to a range of potential stressors. PFL is now known for gulls, penguins and terns. PMID- 27231645 TI - Phylogenetics and population genetics of Plotosus canius (Siluriformes: Plotosidae) from Malaysian coastal waters. AB - Plotosus canius (Hamilton, 1822) is a significant marine species in Malaysia from nutritional and commercial perspectives. Despite numerous fundamental research on biological characteristics of P. canius, there are various concerns on the level of population differentiation, genomic structure, and the level of genetic variability among their populations due to deficiency of genetic-based studies. Deficiency on basic contexts such as stock identification, phylogenetic relationship and population genetic structure would negatively impact their sustainable conservation. Hence, this study was conducted to characterize the genetic structure of P. canius for the first time through the application of mitochondrial Cytochrome Oxidase I (COI) gene, cross amplification of Tandanus tandanus microsatellites, and a total of 117 collected specimens across five selected populations of Malaysia. The experimental results of the mitochondrial analysis revealed that the haplotype diversity and nucleotide diversity varied from 0.395-0.771 and 0.033-0.65 respectively. Moreover, the statistical analysis of microsatellites addressed a considerable heterozygote insufficiency in all populations, with average observed heterozygosity (Ho ) value of 0.2168, which was lower than the standard heterozygosity in marine populations (Ho = 0.79). This alongside the high Fis values estimation, high pairwise differentiation among populations and low within population variations are supposed to be associated with small sample size, and inbreeding system. Besides, the significant finding of this study was the sharing of common haplotype KR086940, which reflects a historical genetic connectivity between Peninsular Malaysia and Borneo populations due to the geological history of Southeast Asia during Pleistocene era. Demographic analyses showed that all populations were in an equilibrium state with no significant evidence of population expansion. To put it briefly, the current study has managed to provide an initial genomic database toward understanding of the genetic characterization, phylogenetic, molecular diversification and population structure in P. canius, and should be necessary highlighted for appropriate management and conservation of species. Further studies must be carried out involving more geographical and sampling sites, larger population size per site, and utilization of species specific microsatellites loci. PMID- 27231647 TI - Count trends for migratory Bald Eagles reveal differences between two populations at a spring site along the Lake Ontario shoreline. AB - The recovery of Bald Eagles (Haliaeetus leucophalus), after DDT and other organochlorine insecticides were banned in the United States, can be regarded as one of the most iconic success stories resulting from the Endangered Species Act. Interest remains high in the recovery and growth of the Bald Eagle population. Common to evaluating growth and recovery rates are counts at nesting sites and analyses of individuals fledged per season. But this is merely one snapshot that ignores survival rates as eagles grow to maturity. By analyzing indices from migration counts, we get a different snapshot better reflecting the survival of young birds. Different populations of Bald Eagles breed at different sites at different times of the year. Typical migration count analyses do not separate the populations. A separation of two distinct populations can be achieved at spring count sites by taking advantage of the tendency for northern summer breeding birds to migrate north in spring earlier than southern winter breeding birds who disperse north later in spring. In this paper I analyze migratory indices at a spring site along Lake Ontario. The analysis shows that eagles considered to be primarily of the northern summer breeding population showed an estimated growth rate of 5.3 +/- 0.85% (SE) per year with 49% of eagles tallied in adult plumage, whereas the migrants considered to be primarily of the southern breeding population had an estimated growth rate of 14.0 +/- 1.79% with only 22% in adult plumage. Together these results argue that the populations of southern breeding Bald Eagles are growing at a substantially higher rate than northern breeding eagles. These findings suggest that aggregate population indices for a species at migration counting sites can sometimes obscure important differences among separate populations at any given site and that separating counts by time period can be a useful way to check for differences among sub-populations. PMID- 27231648 TI - Transcriptomic analysis reveals distinct resistant response by physcion and chrysophanol against cucumber powdery mildew. AB - Physcion and chrysophanol induce defense responses against powdery mildew in cucumbers. The combination of these two compounds has synergistic interaction against the disease. We performed RNA-seq on cucumber leaf samples treated with physcion and chrysophanol alone and with their combination. We generated 17.6 Gb of high-quality sequencing data (~2 Gb per sample) and catalogued the expressions profiles of 12,293 annotated cucumber genes in each sample. We identified numerous differentially expressed genes that exhibited distinct expression patterns among the three treatments. The gene expression patterns of the Chr and Phy treatments were more similar to each other than to the Phy * Chr treatment. The Phy * Chr treatment induced the highest number of differentially expressed genes. This dramatic transcriptional change after Phy * Chr treatment leaves reflects that physcion combined with chrysophanol treatment was most closely associated with induction of disease resistance. The analysis showed that the combination treatment caused expression changes of numerous defense-related genes. These genes have known or potential roles in structural, chemical and signaling defense responses and were enriched in functional gene categories potentially responsible for cucumber resistance. These results clearly demonstrated that disease resistance in cucumber leaves was significantly influenced by the combined physcion and chrysophanol treatment. Thus, physcion and chrysophanol are appealing candidates for further investigation of the gene expression and associated regulatory mechanisms related to the defense response. PMID- 27231649 TI - Optimization of viral resuspension methods for carbon-rich soils along a permafrost thaw gradient. AB - Permafrost stores approximately 50% of global soil carbon (C) in a frozen form; it is thawing rapidly under climate change, and little is known about viral communities in these soils or their roles in C cycling. In permafrost soils, microorganisms contribute significantly to C cycling, and characterizing them has recently been shown to improve prediction of ecosystem function. In other ecosystems, viruses have broad ecosystem and community impacts ranging from host cell mortality and organic matter cycling to horizontal gene transfer and reprogramming of core microbial metabolisms. Here we developed an optimized protocol to extract viruses from three types of high organic-matter peatland soils across a permafrost thaw gradient (palsa, moss-dominated bog, and sedge dominated fen). Three separate experiments were used to evaluate the impact of chemical buffers, physical dispersion, storage conditions, and concentration and purification methods on viral yields. The most successful protocol, amended potassium citrate buffer with bead-beating or vortexing and BSA, yielded on average as much as 2-fold more virus-like particles (VLPs) g(-1) of soil than other methods tested. All method combinations yielded VLPs g(-1) of soil on the 10(8) order of magnitude across all three soil types. The different storage and concentration methods did not yield significantly more VLPs g(-1) of soil among the soil types. This research provides much-needed guidelines for resuspending viruses from soils, specifically carbon-rich soils, paving the way for incorporating viruses into soil ecology studies. PMID- 27231651 TI - Coral reproduction in Western Australia. AB - Larval production and recruitment underpin the maintenance of coral populations, but these early life history stages are vulnerable to extreme variation in physical conditions. Environmental managers aim to minimise human impacts during significant periods of larval production and recruitment on reefs, but doing so requires knowledge of the modes and timing of coral reproduction. Most corals are hermaphroditic or gonochoric, with a brooding or broadcast spawning mode of reproduction. Brooding corals are a significant component of some reefs and produce larvae over consecutive months. Broadcast spawning corals are more common and display considerable variation in their patterns of spawning among reefs. Highly synchronous spawning can occur on reefs around Australia, particularly on the Great Barrier Reef. On Australia's remote north-west coast there have been fewer studies of coral reproduction. The recent industrial expansion into these regions has facilitated research, but the associated data are often contained within confidential reports. Here we combine information in this grey-literature with that available publicly to update our knowledge of coral reproduction in WA, for tens of thousands of corals and hundreds of species from over a dozen reefs spanning 20 degrees of latitude. We identified broad patterns in coral reproduction, but more detailed insights were hindered by biased sampling; most studies focused on species of Acropora sampled over a few months at several reefs. Within the existing data, there was a latitudinal gradient in spawning activity among seasons, with mass spawning during autumn occurring on all reefs (but the temperate south-west). Participation in a smaller, multi-specific spawning during spring decreased from approximately one quarter of corals on the Kimberley Oceanic reefs to little participation at Ningaloo. Within these seasons, spawning was concentrated in March and/or April, and October and/or November, depending on the timing of the full moon. The timing of the full moon determined whether spawning was split over two months, which was common on tropical reefs. There were few data available for non-Acropora corals, which may have different patterns of reproduction. For example, the massive Porites seemed to spawn through spring to autumn on Kimberley Oceanic reefs and during summer in the Pilbara region, where other common corals (e.g. Turbinaria & Pavona) also displayed different patterns of reproduction to the Acropora. The brooding corals (Isopora & Seriatopora) on Kimberley Oceanic reefs appeared to planulate during many months, possibly with peaks from spring to autumn; a similar pattern is likely on other WA reefs. Gaps in knowledge were also due to the difficulty in identifying species and issues with methodology. We briefly discuss some of these issues and suggest an approach to quantifying variation in reproductive output throughout a year. PMID- 27231650 TI - Cloning and expression analysis of cinnamoyl-CoA reductase (CCR) genes in sorghum. AB - Cinnamoyl-CoA reductase (CCR) is the first enzyme in the monolignol-specific branch of the lignin biosynthetic pathway. In this research, three sorghum CCR genes including SbCCR1, SbCCR2-1 and SbCCR2-2 were cloned and characterized. Analyses of the structure and phylogeny of the three CCR genes showed evolutionary conservation of the functional domains and divergence of function. Transient expression assays in Nicotiana benthamiana leaves demonstrated that the three CCR proteins were localized in the cytoplasm. The expression analysis showed that the three CCR genes were induced by drought. But in 48 h, the expression levels of SbCCR1 and SbCCR2-2 did not differ between CK and the drought treatment; while the expression level of SbCCR2-1 in the drought treatment was higher than in CK. The expression of the SbCCR1 and SbCCR2-1 genes was not induced by sorghum aphid [Melanaphis sacchari (Zehntner)] attack, but SbCCR2-2 was significantly induced by sorghum aphid attack. It is suggested that SbCCR2-2 is involved in the process of pest defense. Absolute quantitative real time PCR revealed that the three CCR genes were mainly expressed in lignin deposition organs. The gene copy number of SbCCR1 was significantly higher than those of SbCCR2-1 and SbCCR2-2 in the tested tissues, especially in stem. The results provide new insight into the functions of the three CCR genes in sorghum. PMID- 27231652 TI - Feasibility and benefits of group-based exercise in residential aged care adults: a pilot study for the GrACE programme. AB - The objective of the study was to examine the feasibility and benefits of a group resistance training exercise programme for improving muscle function in institutionalised older adults. A feasibility and acceptability study was designed for a residential aged care (RAC) facility, based on the Gold Coast, Australia. Thirty-seven adults, mean age 86.8 +/- 6.1 years (30 females) living in a RAC facility. Participants were allocated into an exercise (n = 20) or control (n = 17) group. The exercise group, the Group Aged Care Exercise (GrACE) programme, performed 12 weeks of twice weekly resistance exercises. Feasibility was measured via recruitment rate, measurement (physiological and surveys) completion rate, loss-to-follow-up, exercise session adherence, adverse events, and ratings of burden and acceptability. Muscle function was assessed using gait speed, sit-to-stand and handgrip strength assessments. All intervention participants completed pre- and post-assessments, and the exercise intervention, with 85% (n = 17) of the group attending >= 18 of the 24 sessions and 15% (n = 3) attending all sessions. Acceptability was 100% with exercise participants, and staff who had been involved with the programme strongly agreed that the participants "Benefited from the programme." There were no adverse events reported by any participants during the exercise sessions. When compared to the control group, the exercise group experienced significant improvements in gait speed (F(4.078) = 8.265, p = 0.007), sit to stand performance (F(3.24) = 11.033, p = 0.002) and handgrip strength (F(3.697) = 26.359, p < 0.001). Resistance training via the GrACE programme is feasible, safe and significantly improves gait speed, sit-to-stand performance and handgrip strength in RAC adults. PMID- 27231653 TI - Microsatellite loci discovery from next-generation sequencing data and loci characterization in the epizoic barnacle Chelonibia testudinaria (Linnaeus, 1758). AB - Microsatellite markers remain an important tool for ecological and evolutionary research, but are unavailable for many non-model organisms. One such organism with rare ecological and evolutionary features is the epizoic barnacle Chelonibia testudinaria (Linnaeus, 1758). Chelonibia testudinaria appears to be a host generalist, and has an unusual sexual system, androdioecy. Genetic studies on host specificity and mating behavior are impeded by the lack of fine-scale, highly variable markers, such as microsatellite markers. In the present study, we discovered thousands of new microsatellite loci from next-generation sequencing data, and characterized 12 loci thoroughly. We conclude that 11 of these loci will be useful markers in future ecological and evolutionary studies on C. testudinaria. PMID- 27231654 TI - Biopsychological structure of Yin-Yang using Cloninger's Temperament model and Carver and White's BIS/BAS scale. AB - Introduction. The purpose of this study was to examine the psychological structure of Yin-Yang based on the Sasang Personality Questionnaire (SPQ) in relation to Carver and White's Behavior Inhibition/Behavior Activation System (BIS/BAS) Scale and Cloninger's temperament model of the West. Methods. A total of 188 university students were classified as high (30%), middle (40%), and low (30%) groups based on their SPQ score and their differences in Cloninger's temperaments and BIS/BAS subscales were analyzed using analysis of covariance after controlling the sex. Correlation among SPQ, Cloninger's four temperaments and BIS/BAS subscales was also examined. Results. Significant differences in BAS (F = 11.703, p < .001), Novelty-Seeking (F = 4.945, p < .01), and Harm-Avoidance (F = 10.912, p < .001) were observed between high and low SPQ score groups after controlling for sex. The SPQ showed significant correlation with BAS (r = 0.303), Novelty-Seeking (r = 0.225), and Harm-Avoidance (r = - 0.273). However, BIS showed no significant differences between SPQ groups, and did not show correlation with the SPQ. Discussion. The current study demonstrated that Yin Yang has similarities with and disparities from the Western tradition and may be examined with objective instruments. We showed that the emotionality of the East which is defined as mobility of emotion, not emotional instability as traditionally defined in Western theories, is pivotal for understanding the nature of emotion in the East. Suggestions are made for cross-cultural psychobiological study of the East and West. PMID- 27231655 TI - Nest site selection and nutritional provision through excreta: a form of parental care in a tropical endogeic earthworm. AB - Nest construction is a common form of parental care in soil organisms. However, it is unknown whether the tropical earthworm Pontoscolex corethrurus produces nests in soils with low nutritional quality habitats. Here we studied the reproductive behaviour and nest site selection of P. corethrurus, and tested the hypothesis whether P. corethrurus produces more cocoons in habitats with low nutritional quality. In bidimensional terrariums we evaluated the combined effect of the nutritional quality of habitat: (Poor Quality Habitat = PQH, Medium Quality Habitat = MQH, High Quality Habitat = HQH) and soil depth (Shallow, Intermediate, Deep) in a factorial 3(2) design. The number and biomass of cocoons, progeny and the production of internal and external excreta were evaluated. The quality habitat and depth of soil and their interaction had a significant effect on nest site construction and the deposition of internal excreta. Pontoscolex corethrurus built a higher amount of nests in the PQH Intermediate and MQH-Intermediate treatments while more internal excreta were found in the HQH-Intermediate treatment. Offspring biomass was positively associated with internal excreta in the PQH (soil only) and MQH (soil + grass) treatments, suggesting that this could be a form of parental care. Since P. corethrurus produces more cocoons in low and medium quality habitats, while produces more internal excreta at high quality habitats, there does not seem to be an association between number of offspring and parental care. We suggest P. corethrurus could have two reproductive strategies that act as diversified bet hedging (do not put all cocoons in one basket) behavior in unpredictable environment, and thus build a higher amount of nests in low and medium quality habitats; and another where they produce more internal excreta as a form of parental care in high quality habitats. Parental care in the form of internal excreta may be particularly important in poor and medium quality habitats where offspring biomass increased with internal excreta. Further research is needed on the ecological conditions that favour the evolution of parental care in earthworms according to their ecological category (epigeic, endogeic and anecic). PMID- 27231657 TI - Investigating body patterning in aquarium-raised flamboyant cuttlefish (Metasepia pfefferi). AB - Cuttlefish are known for their ability to quickly alter their total appearance, or body pattern, to camouflage or to communicate with predators, prey and conspecifics. The body patterns of some species have been extensively documented to gain a better understanding of their behaviors. However, the flamboyant cuttlefish (Metasepia pfefferi) is largely unstudied. Recently, aquarists have been able to breed, house and display M. pfefferi, giving researchers ample opportunities to study their behavior under those conditions. This study aimed to identify the dorsally-visible components of the body patterns used by 5 sexually mature, freely-behaving, F5 generation M. pfefferi in their home aquarium at The Seas in Epcot at Walt Disney World Resorts((r)), Lake Buena Vista, FL, USA. Furthermore, we aimed to determine the most probable patterns used by this population of animals and to create a database of components that can be used in future behavioral studies. We found that this population of M. pfefferi use a combination of 7 textural, 14 postural, 7 locomotor and between 42 and 75 chromatic components in their home aquarium. Using maximum likelihood analysis and AutoClass@IJM software, we found that these components combine to generate 11 distinct body patterns. The software was able to sort 98% of the live animal observations into one of the 11 patterns with 90% confidence and 88% of observations with 99% confidence. Unusually for cuttlefish, 8 of the 11 identified patterns contained at least one "traveling" component (i.e., traveling waves or blinking spots) in which the colors on the skin appeared to travel on the animal's mantle. In other species, these components are generally seen during hunting or aggression, but this population of M. pfefferi uses them frequently during a variety of contexts in their home aquarium. With few published data on the behavior of M. pfefferi in their natural environment, we cannot compare the behavior of the tank-raised individuals in this study to animals in the wild. However, this study provides the groundwork necessary for future studies of M. pfefferi body patterning and behavior. PMID- 27231656 TI - Flower, fruit phenology and flower traits in Cordia boissieri (Boraginaceae) from northeastern Mexico. AB - We characterized variations in Cordia boissieri flowers and established if these variations occur between plants or between flowering events. Flowering and fruiting was measured for 256 plants. A GLM test was used to determine the relationship between flowering and fruit set processes and rainfall. We performed measurements of floral traits to detect variations within the population and between flowering events. The position of the anthers with respect to the ovary was determined in 1,500 flowers. Three out of four flowering events of >80% C. boissieri plants occurred after rainfall events. Only one flowering event occurred in a drought. Most plants flowered at least twice a year. The overlapping of flowering and fruiting only occurred after rainfall. Anthesis lasted three-to-five days, and there were two flower morphs. Half of the plants had longistylus and half had brevistylus flowers. Anacahuita flower in our study had 1-4 styles; 2-9 stamens; 6.5-41.5 mm long corolla; sepals from 4.5-29.5 mm in length; a total length from 15.5-59 mm; a corolla diameter from 10.5-77 mm. The nectar guide had a diameter from 5-30.5 mm; 4-9 lobes; and 5 distinguishable nectar guide colors. The highest variation of phenotypic expression was observed between plants. PMID- 27231658 TI - The ontogenetic transformation of the mesosaurid tarsus: a contribution to the origin of the primitive amniotic astragalus. AB - The hypotheses about the origin of the primitive amniotic tarsus are very speculative. Early studies argued that the origin of the astragalus, one of the largest proximal bones in the tarsus of basal amniotes, was produced by either the fusion of two, three, or even four of the original tarsal bones, the intermedium, the tibiale and the proximal centralia (c4 and c3), or that the intermedium alone transforms into the primitive astragalus. More recent studies have shown that the structure of the tarsus in Captorhinus supports the former hypothesis about a fusion of the intermedium, the tibiale, the proximal centrale (c4) and eventually c3, producing a purportedly multipartite structure of the amniotic astragalus, but the issue remained contentious. Very well preserved tarsi of the Early Permian aquatic amniote Mesosaurus tenuidens Gervais, 1864 1865, which represent the most complete ontogenetic succession known for a basal amniote (the other exceptional one is provided by the Late Permian diapsid Hovasaurus boulei Piveteau, 1926), suggest that there is more than one ossification center for the astragalus and that these fuse during late embryonic stages or maybe early after birth. A non-hatched Mesosaurus in an advanced stage of development shows that the tarsus is represented by a single bone, most probably the astragalus, which seems to be formed by the suturing of three bones, here interpreted as being the intermedium, the tibiale, probably already integrated to the c4 in an earlier stage of the development, and the c3. An amniote-like tarsal structure is observed in very basal Carboniferous and Permian tetrapods such as Proterogyrinus, Gephyrostegus, the diadectids Diadectes and Orobates, some microsaurs like Tuditanus and Pantylus and possibly Westlothiana, taxa that were all considered as true amniotes in their original descriptions. Therefore, the structure of the amniotic tarsus, including the configuration of the proximal series formed by the astragalus and the calcaneum, typically a pair of enlarged bones, could have been established well before the first recognized amniote walked on Earth. Accordingly, the tarsus of these taxa does not constitute specialized convergences that appeared in unrelated groups, they might be instead, part of a transformation series that involves taxa closely related to the early amniotes as some hypotheses have suggested. PMID- 27231659 TI - Transcranial sonography findings related to depression in parkinsonian disorders: cross-sectional study in 126 patients. AB - Background. Transcranial sonography (TCS) has emerged as a potential diagnostic tool for Parkinson's disease. Recent research has suggested that abnormal echogenicity of substantia nigra, raphe nuclei and third ventricle is associated with increased risk of depression among these patients. We sought to reproduce these findings in an ongoing larger study of patients with parkinsonian syndromes. Methods. A total of 126 patients with parkinsonian symptoms underwent the Hamilton Depression Scale, and TCS of the substantia nigra (SN) (n = 126), the raphe nuclei (RN) (n = 80) and the third ventricle (n = 57). We then calculated the correlation between depression and hyper-echogenic SN, hypo echogenic RN and a wider third ventricle. Results. In patients with PD we found no significant difference of the SN between non-depressed and depressed patients (46% vs. 22%; p = 0.18). Non-depressed patients with other parkinsonisms more often had hyperechogenicity of the SN than depressed patients (51% vs. 0%; p = 0.01). We found no relation between depression and the echogenicity of the RN or the width of the third ventricle. Conclusions. In patients with parkinsonian syndromes, we found no association between depression and hyper-echogenic SN, hypo-echogenic RN or a wider third ventricle, as determined by transcranial sonography. PMID- 27231660 TI - Development of an angiogenesis-promoting microvesicle-alginate-polycaprolactone composite graft for bone tissue engineering applications. AB - One of the major challenges of bone tissue engineering applications is to construct a fully vascularized implant that can adapt to hypoxic environments in vivo. The incorporation of proangiogenic factors into scaffolds is a widely accepted method of achieving this goal. Recently, the proangiogenic potential of mesenchymal stem cell-derived microvesicles (MSC-MVs) has been confirmed in several studies. In the present study, we incorporated MSC-MVs into alginate polycaprolactone (PCL) constructs that had previously been developed for bone tissue engineering applications, with the aim of promoting angiogenesis and bone regeneration. MSC-MVs were first isolated from the supernatant of rat bone marrow derived MSCs and characterized by scanning electron microscopic, confocal microscopic, and flow cytometric analyses. The proangiogenic potential of MSC-MVs was demonstrated by the stimulation of tube formation of human umbilical vein endothelial cells in vitro. MSC-MVs and osteodifferentiated MSCs were then encapsulated with alginate and seeded onto porous three-dimensional printed PCL scaffolds. When combined with osteodifferentiated MSCs, the MV-alginate-PCL constructs enhanced vessel formation and tissue-engineered bone regeneration in a nude mouse subcutaneous bone formation model, as demonstrated by micro-computed tomographic, histological, and immunohistochemical analyses. This MV-alginate-PCL construct may offer a novel, proangiogenic, and cost-effective option for bone tissue engineering. PMID- 27231661 TI - Isolation and characterization of eight microsatellite loci from Galeocerdo cuvier (tiger shark) and cross-amplification in Carcharhinus leucas, Carcharhinus brevipinna, Carcharhinus plumbeus and Sphyrna lewini. AB - The tiger shark Galeocerdo cuvier (Carcharhinidae) is a large elasmobranch suspected to have, as other apex predators, a keystone function in marine ecosystems and is currently considered Near Threatened (Red list IUCN). Knowledge on its ecology, which is crucial to design proper conservation and management plans, is very scarce. Here we describe the isolation of eight polymorphic microsatellite loci using 454 GS-FLX Titanium pyrosequencing of enriched DNA libraries. Their characteristics were tested on a population of tiger shark (n = 101) from Reunion Island (South-Western Indian Ocean). All loci were polymorphic with a number of alleles ranging from two to eight. No null alleles were detected and no linkage disequilibrium was detected after Bonferroni correction. Observed and expected heterozygosities ranged from 0.03 to 0.76 and from 0.03 to 0.77, respectively. No locus deviated from Hardy-Weinberg equilibrium and the global F IS of the population was of 0.04 (NS) . Some of the eight loci developed here successfully cross-amplified in the bull shark Carcharhinus leucas (one locus), the spinner shark Carcharhinus brevipinna (four loci), the sandbar shark Carcharhinus plumbeus (five loci) and the scalloped hammerhead shark Sphyrna lewini (two loci). We also designed primers to amplify and sequence a mitochondrial marker, the control region. We sequenced 862 bp and found a low genetic diversity, with four polymorphic sites, a haplotype diversity of 0.15 and a nucleotide diversity of 2 * 10(-4). PMID- 27231662 TI - A biofilter for treating toluene vapors: performance evaluation and microbial counts behavior. AB - A lab-scale biofilter packed with mixed packing materials was used for degradation of toluene. Different empty bed residence times, 148.3, 74.2 and 49.4 s, were tested for inlet concentration ranging from 0.2 to 1.2 g/m(3). The maximum elimination capacity of 36.0 g/(m(3) h) occurred at an inlet loading rate of 45.9 g/(m(3) h). The contribution of the lower layer was higher than other layers and always had the highest elimination capacity. The carbon dioxide production rate and distribution of micro-organisms followed toluene elimination capacities. The results of this study indicated that mixed packing materials could be considered as a potential biofilter carrier, with low pressure drop (less than 84.9 Pa/m), for treating air streams containing VOCs. PMID- 27231663 TI - Symbiotic essential amino acids provisioning in the American cockroach, Periplaneta americana (Linnaeus) under various dietary conditions. AB - Insect gut microbes have been shown to provide nutrients such as essential amino acids (EAAs) to their hosts. How this symbiotic nutrient provisioning tracks with the host's demand is not well understood. In this study, we investigated microbial essential amino acid (EAA) provisioning in omnivorous American cockroaches (Periplaneta americana), fed low-quality (LQD) and comparatively higher-quality dog food (DF) diets using carbon stable isotope ratios of EAAs (delta (13)CEAA). We assessed non-dietary EAA input, quantified as isotopic offsets (Delta(13)C) between cockroach (delta (13)CCockroach EAA) and dietary (delta (13)CDietary EAA) EAAs, and subsequently determined biosynthetic origins of non-dietary EAAs in cockroaches using (13)C-fingerprinting with dietary and representative bacterial and fungal delta (13)CEAA. Investigation of biosynthetic origins of de novo non-dietary EAAs indicated bacterial origins of EAA in cockroach appendage samples, and a mixture of fungal and bacterial EAA origins in gut filtrate samples for both LQD and DF-fed groups. We attribute the bacteria derived EAAs in cockroach appendages to provisioning by the fat body residing obligate endosymbiont, Blattabacterium and gut-residing bacteria. The mixed signatures of gut filtrate samples are attributed to the presence of unassimilated dietary, as well as gut microbial (bacterial and fungal) EAAs. This study highlights the potential impacts of dietary quality on symbiotic EAA provisioning and the need for further studies investigating the interplay between host EAA demands, host dietary quality and symbiotic EAA provisioning in response to dietary sufficiency or deficiency. PMID- 27231664 TI - Foraging loads of red wood ants: Formica aquilonia (Hymenoptera: Formicidae) in relation to tree characteristics and stand age. AB - Background. Foraging efficiency is critical in determining the success of organisms and may be affected by a range of factors, including resource distance and quality. For social insects such as ants, outcomes must be considered at the level of both the individual and the colony. It is important to understand whether anthropogenic disturbances, such as forestry, affect foraging loads, independent of effects on the quality and distribution of resources. We asked if ants harvest greater loads from more distant and higher quality resources, how individual efforts scale to the colony level, and whether worker loads are affected by stand age. Methods. First, we performed a fine-scale study examining the effect of distance and resource quality (tree diameter and species) on harvesting of honeydew by red wood ants, Formica aquilonia, in terms of crop load per worker ant and numbers of workers walking up and down each tree (ant activity) (study 1). Second, we modelled what the combination of load and worker number responses meant for colony-level foraging loads. Third, at a larger scale, we asked whether the relationship between worker load and resource quality and distance depended on stand age (study 2). Results. Study 1 revealed that seventy percent of ants descending trees carried honeydew, and the percentage of workers that were honeydew harvesters was not related to tree species or diameter, but increased weakly with distance. Distance positively affected load mass in both studies 1 and 2, while diameter had weak negative effects on load. Relationships between load and distance and diameter did not differ among stands of different ages. Our model showed that colony-level loads declined much more rapidly with distance for small diameter than large diameter trees. Discussion. We suggest that a negative relationship between diameter and honeydew load detected in study 1 might be a result of crowding on large diameter trees close to nests, while the increase in honeydew load with distance may result from resource depletion close to nests. At the colony level, our model suggests that very little honeydew was harvested from more distant trees if they were small, but that more distant larger trees continued to contribute substantially to colony harvest. Although forestry alters the activity and foraging success of red wood ants, study 2 showed that it does not alter the fundamental rules determining the allocation of foraging effort. PMID- 27231665 TI - Yet another new species from one of the best-studied neotropical areas: Plantago humboldtiana (Plantaginaceae), an extremely narrow endemic new species from a waterfall in southern Brazil. AB - This article presents and describes Plantago humboldtiana, an extremely narrow endemic rheophytic new species from a waterfall in Corupa, Santa Catarina state, southern Brazil. The new species is unique in presenting a combination of type-G antrorse trichomes on scapes, pendulous inflorescences and 1-seeded pyxidia. Only one population is known to exist, despite intensive search efforts in nearby, similar environments. Its conservation status is assessed as critically endangered (CR) as the only known population is restricted to a dramatically small area, and is subject to extreme fluctuation due to occasional floods, and also to intense visitation by tourists, which can disturb its fragile habitat. We also present an updated identification key to the species of Plantago that occur in Santa Catarina. The recent description of three narrow endemic, threatened new species of Plantago in Santa Catarina, which is the Brazilian state with its flora best studied, highlights the need for more taxonomic research, especially in the neotropics. PMID- 27231666 TI - Mortality in HIV-infected patients with tuberculosis treated with streptomycin and a two-week intensified regimen: data from an HIV cohort study using inverse probability of treatment weighting. AB - Background. Despite the dramatic scale-up of antiretroviral therapy in low- and middle-income countries, tuberculosis (TB) is still the main cause of death among HIV-infected patients in resource-limited settings. Previous studies in patients with TB meningitis suggest that the use of higher doses of common anti-TB drugs could reduce mortality. Methods. Using clinical data from an HIV cohort study in India, we compared the mortality among HIV-infected patients diagnosed with TB according to the regimen received during the first two weeks of treatment: standard anti-tuberculosis therapy (ATT) (N = 847), intensified ATT (N = 322), and intensified ATT with streptomycin (N = 446). The intensified ATT comprised double dose of rifampicin and substitution of ethambutol with levofloxacin. Multivariate analysis was performed using Cox proportional hazard models and inverse probability of treatment weighting (IPTW) based on propensity scores. Patients with TB meningitis were excluded. Results. The use of intensified ATT alone did not improve survival. However, when streptomycin was added, the use intensified ATT was associated with reduced mortality in Cox models (adjusted hazard ratio 0.72, 95% CI [0.57-0.91]) and after IPTW (hazard ratio 0.77, 95% CI [0.67-0.96]). Other factors associated with improved survival were high serum albumin concentration, high CD4 lymphocyte cell-counts, and high glomerular filtration rates. Factors associated with increased mortality were high urea concentrations, being on antiretroviral therapy at the time of ATT initiation and high BUN/creatinine ratio. In an effect modification analysis, the survival benefits of the intensified ATT with streptomycin disappeared in patients with severe hypoalbuminemia. Conclusion. The results of this study are in accordance with a previous study from our cohort involving patients with TB meningitis, and suggest that an intensified 2-week ATT with streptomycin could reduce mortality in HIV infected patients with TB. As this is an observational study, we should be cautious about our conclusions, but given the high mortality of HIV-related TB, our findings deserve further research. PMID- 27231667 TI - Anticipated resource utilization for injury versus non-injury pediatric visits to emergency departments. AB - BACKGROUND: Childhood injuries are increasingly treated in emergency departments (EDs) but the relationship between injury severity and ED resource utilization has not been evaluated. The objective of this study was to compare resource utilization for pediatric injury-related ED visits across injury-severity levels and with non-injury visits, using standardized, validated scales. METHODS: A retrospective analysis of 2004-2008 ED visits from the Pediatric Emergency Care Applied Research Network Core Data Project. Maximum Abbreviated Injury Scale severity (MAIS) and Severity Classification System (SCS) scores were calculated and compared. MAIS and SCS are ordinal scales from 1 (minor injury) to 6, and 1 (low anticipated resource utilization) to 5, respectively. ED length of stay (LOS) and admission percentages were calculated as comparative proxy measures of resource utilization. RESULTS: There were 763,733 injury visits and 2,328,916 non injury visits, most with SCS of 2 or 3. Of the injured patients, 59.2 % had an MAIS of 1. ED LOS and admission percentage increased with increasing MAIS from 1 5. LOS and admission percentage increased with increasing SCS in both samples. Median LOS was shorter for injured versus non-injured patients with SCS 3-5. Non injured patients with SCS 2-5 were more likely admitted than injured patients. Most injured patients had an SCS 3 with an MAIS 1-2, or an SCS 2 with an MAIS 1, with no correlation between the two scales. CONCLUSION: While admission rates and LOS increase with increasing AIS and SCS severity, these two classification schemas do not reliably correlate. Similarly, ED visit metrics differ between injured and non-injured patients in similar SCS categories. Although AIS and SCS both have value, these differences should be considered when using these schemas in research and quality improvement. PMID- 27231668 TI - The Role of Smoking-Specific Experiential Avoidance in the Relation Between Perceived Stress and Tobacco Dependence, Perceived Barriers to Cessation, and Problems during Quit Attempts Among Treatment-Seeking Smokers. AB - Despite the clinically-significant association between perceived stress and smoking, there is little understanding of the mechanisms underlying this relation. The present study examined smoking-specific experiential avoidance as an explanatory mechanism linking perceived stress and smoking, including nicotine dependence, perceived barriers to cessation, and problems reported during past quit attempts among treatment-seeking daily smokers (n = 365; 48.5% female; Mage = 38.02; SD = 13.10). Results indicated that smoking-specific experiential avoidance had a significant, indirect effect on perceived stress and the studied smoking criterion variables. The present findings provide initial empirical support that smoking-specific experiential avoidance may help explain how perceived stress is associated with smoking. These data suggest that there may be merit to targeting smoking-specific experiential avoidance during smoking cessation among smokers with elevated perceived stress. PMID- 27231669 TI - Does rush hour see a rush of emotions? Driver mood in conditions likely to exhibit congestion. AB - Polls show that a large portion of the public considers traffic congestion to be a problem and believes a number of policy interventions would ameliorate it. However, most of the public rejects new taxes and fees to fund these improvements. This may be because of a disconnect between the public's stated antipathy towards congestion and the recalled emotional costs congestion imposes. To explore this, we use a large and representative sample drawn from the American Time Use Survey to examine how drivers experience four emotions (happiness, sadness, stress, and fatigue), plus a constructed composite mood variable, when they travel in peak periods, in large cities, in city centers, and in combinations of these. We also explore the interactions between these indicators and trip duration. We find evidence that drivers in the largest cities at the very peak of rush hour (5:00pm-6:00pm) are in a less positive mood, presumably because of congestion. However, this effect, though significant, is small, and we find no significant results using broader definitions of the peak period. In all, our findings suggest that congestion's impact on drivers as a group is quite limited. This may help explain why the public's attitude toward painful financial trade-offs to address congestion is lukewarm. PMID- 27231670 TI - Dynamic Regulation of APE1/Ref-1 as a Therapeutic Target Protein. AB - Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional protein that plays a central role in the cellular response to DNA damage and redox regulation against oxidative stress. APE1/Ref-1 functions in the DNA base excision repair pathway, the redox regulation of several transcription factors, and the control of intracellular redox status through the inhibition of reactive oxygen species (ROS) production. APE1/Ref-1 is predominantly localized in the nucleus; however, its subcellular localization is dynamically regulated and it may be found in the mitochondria or elsewhere in the cytoplasm. Studies have identified a nuclear localization signal and a mitochondrial target sequence in APE1/Ref-1, as well as the involvement of the nuclear export system, as determinants of APE1/Ref-1 subcellular distribution. Recently, it was shown that APE1/Ref-1 is secreted in response to hyperacetylation at specific lysine residues. Additionally, post-translational modifications such as phosphorylation, S-nitrosation, and ubiquitination appear to play a role in fine-tuning the activities and subcellular localization of APE1/Ref-1. In this review, we will introduce the multifunctional role of APE1/Ref-1 and its potential usefulness as a therapeutic target in cancer and cardiovascular disease. PMID- 27231671 TI - Altered Nitric Oxide System in Cardiovascular and Renal Diseases. AB - Nitric oxide (NO) is synthesized by a family of NO synthases (NOS), including neuronal, inducible, and endothelial NOS (n/i/eNOS). NO-mediated effects can be beneficial or harmful depending on the specific risk factors affecting the disease. In hypertension, the vascular relaxation response to acetylcholine is blunted, and that to direct NO donors is maintained. A reduction in the activity of eNOS is mainly responsible for the elevation of blood pressure, and an abnormal expression of iNOS is likely to be related to the progression of vascular dysfunction. While eNOS/nNOS-derived NO is protective against the development of atherosclerosis, iNOS-derived NO may be proatherogenic. eNOS derived NO may prevent the progression of myocardial infarction. Myocardial ischemia/reperfusion injury is significantly enhanced in eNOS-deficient animals. An important component of heart failure is the loss of coronary vascular eNOS activity. A pressure-overload may cause severer left ventricular hypertrophy and dysfunction in eNOS null mice than in wild-type mice. iNOS-derived NO has detrimental effects on the myocardium. NO plays an important role in regulating the angiogenesis and slowing the interstitial fibrosis of the obstructed kidney. In unilateral ureteral obstruction, the expression of eNOS was decreased in the affected kidney. In triply n/i/eNOS null mice, nephrogenic diabetes insipidus developed along with reduced aquaporin-2 abundance. In chronic kidney disease model of subtotal-nephrectomized rats, treatment with NOS inhibitors decreased systemic NO production and induced left ventricular systolic dysfunction (renocardiac syndrome). PMID- 27231673 TI - Evaluation of Arterial Stiffness by Echocardiography: Methodological Aspects. AB - As humans age, degenerative changes in the arterial structure gradually progress and result in the stiffening of the arteries, which is called arteriosclerosis. Arterial stiffness is now an established risk factor of cardiovascular disease (CVD). This stiffening has adverse effects for both the general population as well as for patients with CVD. Measurements of pulse wave velocity and pulse wave analysis are the two most commonly used methods in the evaluation of arterial stiffness, but these methods just allow indirect measures of arterial stiffness. Echocardiography is the most widely used imaging modality in the evaluation of cardiac structure and function and with recent technical advances, it has become possible to evaluate the structure, function and blood flow hemodynamics of the arteries using echocardiography. In the present review, we will discuss the current status of echocardiography in the evaluation of arterial stiffness, especially focusing on the methodological aspects. PMID- 27231672 TI - Vilazodone for the Treatment of Depression: An Update. AB - Vilazodone is a novel antidepressant having a selective serotonin (5-HT) reuptake inhibitor and 5-HT1A receptor partial agonist profile, so it has been regarded as a serotonin partial agonist-reuptake inhibitor (SPARI). We aimed to provide Vilazodone's clinical implications mainly by reviewing published clinical trials. Vilazodone has been speculated to have three potential benefits including faster onset of action, greater efficacy, and better tolerability owning to its SPARI properties. However, no studies conducted so far have directly proven the above speculations. Five initial phase II trials failed to distinguish vilazodone from placebo in the treatment of MDD, but 4 randomized clinical trials (RCT), 3 post hoc or pooled analysis, 1 long-term open label study, and a meta-analysis showed vilazodone's superior efficacy over placebo. The studies also showed vilazodone is generally safe and tolerable. However, diarrhea, nausea, headache, dizziness, dry mouth, and insomnia warrant close attention in clinical practice because they have been constantly noted throughout the clinical studies. 2 RCTs recently documented the efficacy and safety of vilazodone in patients with generalized anxiety disorder, which could be a start of broadening vilazodone's usage or FDA approval in diverse anxiety disorders. PMID- 27231674 TI - Evidence-based Medicine versus the Conventional Approach to Journal Club Sessions: Which One Is More Successful in Teaching Critical Appraisal Skills? AB - This study aimed to compare evidence-based medicine (EBM) vs. conventional approaches to journal club sessions in teaching critical appraisal skills in reading papers by emergency medicine residents. This double cut off discontinuation regression quasi-experimental study was conducted among emergency medicine residents. EBM vs. the conventional approach were applied to teach critical appraisal skills for half of the residents as an experimental group and another half as a control group respectively. Both groups participated in one hour monthly journal club sessions for six months. Before and after the study, all participants were examined by two tests: the Fresno Test (FT) [to evaluate their knowledge about EBM] and the Critical Appraisal Skills Test (CAST) [to evaluate their competency with critical appraisal skills]. The allocation of the participants into the experimental or control groups was according to their CAST scores before the study. 50 emergency medicine residents participated. After the study, the scores of both groups in the FT and CAST significantly improved (p<0.01), and the promotion of scores of the FT and CAST in the experimental group were more than that of the conventional group (p<0.0001). The current study indicated that an evidence-based medicine approach in journal club sessions was comparatively more advantageous compared to the conventional approach in teaching critical appraisal skills for reading papers among the residents of emergency medicine. PMID- 27231676 TI - The Prevalence of Chronic Obstructive Pulmonary Disease and the Determinants of Underdiagnosis in Women Exposed to Biomass Fuel in India- a Cross Section Study. AB - BACKGROUND AND OBJECTIVES: Tobacco smoking has been established as a major risk factor for chronic obstructive pulmonary disease (COPD) in women of developing countries, but emerging evidence suggests that biomass fuel is an important risk factor as well. The primary objective of the study was to find the true prevalence of COPD in Indian women exposed to biomass fuel using spirometry. We also aimed to find the determinants of underdiagnosis of COPD in these participants. METHODS: Women with a history of exposure to biomass fuel for >10 years were screened for COPD using spirometry following all standard protocols as per GOLD/ATS/ERS definitions. RESULTS: Of the 2868 women screened, a total of 529 (18.4%) women were confirmed to have COPD in which 123 (4.2%) were "Women with known COPD" and 406 (14.2%) "Women with new COPD". The mean age at the time of Diagnosis was 61+/-5.2 and 47+/-3.6 respectively. The duration of exposure to biomass fuel had a great impact on the risk of COPD with OR 1.2, 95% CI (1.1-1.9) for patients with 10-15 years exposure and OR 2.9, 95% CI (2.5-3.1) for exposure >25 years, p<0.001. CONCLUSION: The prevalence of COPD among women exposed to biomass fuel is very high. A strong correlation was found between the risk of COPD and the duration of exposure along with the age at which the exposure to biomass fuel begins. Underdiagnosis of COPD was frequent in women due to the lack of the availability of spirometry, lack knowledge of hazards of biomass fuel, a low level of education and the ignorance of the health care provider being the important determinants of underdiagnosis. PMID- 27231675 TI - The Relationship between Anger Expression and Its Indices and Oral Lichen Planus. AB - Oral lichen planus (OLP) is a common inflammatory disease with unknown etiology. Depression, stress and anxiety are psychological factors that their influence on the expression of lichen planus by affecting the immune system's function has been confirmed. There is a probable relationship between anger and OLP expression. Therefore, the present study aimed to evaluate the association of "anger" and OLP. In this descriptive study 95 subjects were included in 3 groups. A: patients with oral lichen planus, B: positive control, C: negative control. Anger and its indices were assessed by the State-Trait Anger Expression Inventory 2 (STAXI-2) questionnaire, and pain was measured via the Visual Analogue Scale (VAS). The collected data were analyzed statistically using SPSS 18 software. The lichen planus and positive control groups bore higher total anger index (AX index) values compared with the negative control. Comparing anger expression-in (AXI) among the lichen planus and negative control groups revealed higher grades in lichen planus group. Evaluating the pain severity index (VAS) data and anger indices in lichen planus group, Spearman's Rank Correlation Test revealed a significant correlation between TAngR (reactional anger traits) and pain severity. The findings of this study indicated that there was a significant correlation between anger control and suppression of lichen planus development. On the other hand, the patients with more severe pain mostly expressed their anger physically. Based on the findings, we can make the claim that anger suppression and its control-in (gathering tension) may play a role in the development of lichen planus as a known psychosomatic disorders. PMID- 27231677 TI - Ureteral Stent Insertion in the Management of Renal Colic during Pregnancy. AB - To determine an optimal invasive intervention for renal colic patients during pregnancy after conservative treatments have been found to be unhelpful. Among the available invasive interventions, we investigated the reliability of a ureteral stent insertion, which is considered the least invasive intervention during pregnancy. Between June 2006 and February 2015, a total of 826 pregnant patients came to the emergency room or urology outpatient department, and 39 of these patients had renal colic. The mean patient age was 30.49 years. In this retrospective cohort study, the charts of the patients were reviewed to collect data that included age, symptoms, the lateralities and locations of urolithiasis, trimester, pain following treatment and pregnancy complications. Based on ultrasonography diagnoses, 13 patients had urolithiasis, and 13 patients had hydronephrosis without definite echogenicity of the ureteral calculi. Conservative treatments were successful in 25 patients. Among these treatments, antibiotics were used in 15 patients, and the remaining patients received only hydration and analgesics without antibiotics. Several urological interventions were required in 14 patients. The most common intervention was ureteral stent insertion, which was performed in 13 patients to treat hydronephrosis or urolithiasis. The patients' pain was relieved following these interventions. Only one patient received percutaneous nephrostomy due to pyonephrosis. No pregnancy complications were noted. Ureteral stent insertion is regarded as a reliable and stable first-line urological intervention for pregnant patients with renal colic following conservative treatments. Ureteral stent insertion has been found to be equally effective and safe as percutaneous nephrostomy, which is associated with complications that include bleeding and dislocation, and the inconvenience of using external drainage system. PMID- 27231678 TI - Comparative Effects of Statin Therapy versus Renin-Angiotensin System Blocking Therapy in Patients with Ischemic Heart Failure Who Underwent Percutaneous Coronary Intervention. AB - Statins and renin-angiotensin system (RAS) blockers are key drugs for treating patients with an acute myocardial infarction (AMI). This study was designed to show the association between treatment with statins or RAS blockers and clinical outcomes and the efficacy of two drug combination therapies in patients with ischemic heart failure (IHF) who underwent revascularization for an AMI. A total of 804 AMI patients with a left ventricular ejection fraction <40% who undertook percutaneous coronary interventions (PCI) were analyzed using the Korea Acute Myocardial Infarction Registry (KAMIR). They were divided into four groups according to the use of medications [Group I: combination of statin and RAS blocker (n=611), Group II: statin alone (n=112), Group III: RAS blocker alone (n=53), Group IV: neither treatment (n=28)]. The cumulative incidence of major adverse cardiac and cerebrovascular events (MACCEs) and independent predictors of MACCEs were investigated. Over a median follow-up study of nearly 1 year, MACCEs had occurred in 48 patients (7.9%) in Group I, 16 patients (14.3%) in Group II, 3 patients (5.7%) in Group III, 7 patients (21.4%) in Group IV (p=0.013). Groups using RAS blocker (Group I and III) showed better clinical outcomes compared with the other groups. By multivariate analysis, use of RAS blockers was the most powerful independent predictor of MACCEs in patients with IHF who underwent PCI (odds ratio 0.469, 95% confidence interval 0.285-0.772; p=0.003), but statin therapy was not found to be an independent predictor. The use of RAS blockers, but not statins, was associated with better clinical outcomes in patients with IHF who underwent PCI. PMID- 27231679 TI - Frequency of Diabetes and Thyroid Autoantibodies in Patients with Type 1 Diabetes and Their Siblings. AB - The aim of this study was to better understand the frequency of autoimmune thyroid and diabetes antibodies in patients with type 1 diabetes mellitus (T1DM) compared with their siblings. Glutamic acid decarboxylase antibodies (GADA), islet cell antibodies (ICA), insulin autoantibodies (IAA), and thyroid autoantibodies were studied in all subjects. The rates of positive GADA and IAA were significantly higher in probands compared to in siblings (p<0.001) or controls (p<0.001). All pancreatic autoantibodies were not significantly different between the siblings and the healthy controls. Thyroid antiperoxidase antibody (TPOAb) and antithyroglobulin antibody (TGAb) were significantly different between the probands and the control subjects (p=0.002 and p=0.018, respectively). The rates of TPOAb and TGAb positivity in siblings were higher than in those of the controls, but there was no significant difference between the two groups. However, thyroid autoimmunity (TA) was significantly different among the groups (p=0.004). Siblings of the TA-positive probands were shown to have a greater prevalence of thyroid antibodies than did the controls (p=0.022), but siblings of the TA-negative probands did not have such a prevalence compared with the control subjects. The prevalence of pancreatic and thyroid antibodies positivity in probands was statistically significant compared with the siblings and the controls. Siblings of TA-positive probands revealed a greater prevalence of thyroid antibodies than did the controls. Therefore, the screening for TA in siblings, particularly siblings of TA-positive probands, is as important as it is in probands. PMID- 27231680 TI - Severe Ketoacidosis in a Patient with an Eating Disorder. PMID- 27231681 TI - Renal Cell Carcinoma Recognized Incidentally during Long-term Lithium Treatment. PMID- 27231682 TI - Simple and Efficient Technique for Correction of Unilateral Scissor Bite Using Straight Wire. AB - Unilateral scissor bite is a relatively rare malocclusion. However, its correction is often difficult and a challenge for the clinician. This article presents simple and efficient technique for the correction of severe unilateral scissor bite in a 14 year old boy, using 0.020 S.S. A. J. Wilcock wire (premium plus) out of the spool, with minimal adjustments and placed in mandibular arch. After about six weeks time, good amount of correction was seen in the lower arch and the lower molar had been relieved of scissor bite. PMID- 27231684 TI - Early Stent Removal After Kidney Transplantation: Is it Possible? AB - BACKGROUND: The most important surgical complications of renal transplantation are stenosis and obstruction of the ureterovesical anastomosis. Routine use of ureteral stents can prevent this complication, but the optimal time for ureteral stent use is still controversial. OBJECTIVES: The purpose of this study is to compare the benefits and complications of early and delayed stent removal after surgery. Early ureteral stent removal can decrease some complications, such as urinary tract infections (UTIs), bladder irritation symptoms, persistent hematuria, and the risk of stent crusting; its benefits include easier stent removal and shorter hospitalization time. PATIENTS AND METHODS: All patients who underwent kidney transplantation from May 2011 until March 2012 in Modarres Hospital were included in this study. We classified the patients into three groups, based on time of stent removal (10, 20, and 30 days after transplantation). RESULTS: Ninety-one patients were studied; urologic complications (hydroureteronephrosis and urinoma) in these three groups were analyzed and showed no statistical significant difference. CONCLUSIONS: We can remove the ureteral stent earlier after kidney transplantation with no increase in the prevalence of surgical complications. PMID- 27231683 TI - The effects of Task-Oriented Motor Training on gait characteristics of patients with type 2 diabetes neuropathy. AB - BACKGROUND: It is known that general gait training improves lower extremity muscle strength and endurance in Diabetes Neuropathy (DN). But, it is still unknown whether Task-Oriented (TO) gait training would change gait biomechanics and the risk of falling in DN. TO gait training focuses on promoting timing and coordination of lower extremity movements through goal-directed practices with sufficient repetition. METHODS: A group of 14 patients with DN participated in a time-series study. All subjects participated in four sessions of assessments (Initial, Pre, Post and Follow-Up). Training was twice a week for 12 weeks. Vertical and horizontal Ground Reaction Forces (GRF), Time Get up and Go (TGUG) and Fall Efficacy Scale-International (FES-I) were evaluated. Gait training started with stepping patterns that progressively changed to complicated patterns of walking. Then, training continued combining walking patterns with upper extremity activities and then ended with treadmill-paced practice. RESULTS: DN patients significantly increased Second Vertical Peak Force and Horizontal Propulsive Force in addition decrease in Minimum Vertical Force. TGUG significantly decreased while FES-I reflected significant increase after gait training. DISCUSSION: Conclusively, training not only improved gait performance, confidence in daily activities and attenuated risk of falling, but also helped DN patients to improve feet biomechanics, muscles timing and coordination. CONCLUSIONS: Gait training with respect to principles of motor learning allowed patients to effectively improve through sessions. PMID- 27231685 TI - Benefits and Complications of Removing Ureteral Stent Based on the Elapsed Time After Renal Transplantation Surgery. AB - BACKGROUND: The most important surgical complications of renal transplantation are stenosis and obstruction of anastomosis of the ureter to the bladder. Although the routine use of the ureteral stents to prevent such complications seems rational, the optimal time to keep the ureteral stent is still controversial. OBJECTIVES: This study presents the benefits and complications of removing the ureteral stent based on the elapsed time after the surgery. PATIENTS AND METHODS: All patients who underwent kidney transplantation between May 2011 and August 2014 in Modarres hospital, Tehran, Iran, were enrolled in the study. The patients were classified into three groups. The ureteral stent was removed 10, 20, and 30 days after the transplantation in these groups. RESULTS: A total of 529 patients underwent kidney transplant surgery in our center. Urologic complications among the three groups consisting of hydronephrosis, urinoma and collection did not have statistically significant differences. CONCLUSIONS: Ureteral stent can be picked up with no increased risk of urologic complications at shorter intervals after the kidney transplantation surgery. PMID- 27231686 TI - Prevalence and Management of Lower Urinary Tract Symptoms Related to Benign Prostatic Obstruction in a Contemporary Series of Renal Transplant Recipients. AB - BACKGROUND: The kidney is the most frequently transplanted human organ worldwide. In patients with end-stage renal failure, renal transplantation improves both quality of life and life expectancy. The current literature indicates that the numbers of renal recipients over 60 years of age has increased in recent years. OBJECTIVES: To evaluate the prevalence and management of lower urinary tract symptoms (LUTS) related to benign prostatic obstruction (BPO) in a contemporary series of male renal transplant (RTx) recipients. MATERIALS AND METHODS: We retrospectively evaluated 150 consecutive transplant recipients at the University of Jena 12 months postoperatively for the presence and treatment of LUTS related to BPO. RESULTS: The mean age of the patients was 59 years (range 27 - 82 years). By 12 months postoperatively, 91% (n = 137/150) were off dialysis with a functioning kidney graft. Two patients died during follow up. Six patients had undergone treatment for prostate cancer prior to RTx. Of the remaining 131 patients, 47% (n = 62/131) were considered as patients with BPO 12 months after RTx. Six percent (n = 8/131) of the patients experienced urinary retention due to BPO and 6% (n = 8/131) had a transurethral resection of the prostate (TURP) during the first year after RTx. No major complications were observed in those patients. A significant increase was noted in the use of alpha-blocker therapy after RTx (P = 0.004). CONCLUSIONS: We observed a high prevalence of LUTS related to BPO in our cohort of patients. Due to the increasing age of transplant recipients, more attention should be paid to the evaluation and treatment of BPO prior to RTx. PMID- 27231687 TI - Conjunctival Angioimmunoblastic T-Cell Lymphoma. AB - Angioimmunoblastic T-cell lymphoma (AITL) represents an uncommon variant of T cell lymphomas and most often presents insidiously with systemic symptoms. This report constitutes the first documented case of conjunctival AITL, masquerading as nodular episcleritis, and describes both the clinical and pathological findings. Furthermore, conjunctival T-cell lymphoma in general remains a rare occurrence, and a survey of previously reported cases reveals a wide variation in clinical presentation. A high index of suspicion, thorough examination and conjunctival biopsy are essential to reaching the diagnosis of conjunctival lymphoma. PMID- 27231688 TI - Indocyanine Green-Enhanced Thermotherapy for Retinoblastoma. AB - PURPOSE: To report the outcome of pediatric patients with retinoblastoma refractory to traditional local therapy who were treated with indocyanine green (ICG)-enhanced thermotherapy. MATERIALS AND METHODS: This is a retrospective review of a case series of 3 patients with bilateral retinoblastoma who were treated with ICG-enhanced thermotherapy after showing no response to conventional chemothermotherapy or transpupillary thermotherapy (TTT) alone noted on two consecutive examinations under anesthesia. RESULTS: The 3 patients had had one eye enucleated previously due to advanced disease, and the remaining eye was diagnosed with a large tumor, which showed either a marginal or no response to systemic chemotherapy and TTT. Addition of ICG enhancement during the subsequent TTT session shrunk the tumor to a measurable size that could then be followed by TTT alone as a means of treatment. One patient had tumor recurrence, at which time additional TTT without ICG was successfully applied after the tumor size had decreased; ICG enhancement was then added whenever TTT alone provided no response. CONCLUSIONS: ICG enhancement with TTT led to a measurable tumor regression in lesions that had previously not been responsive to traditional chemothermotherapy or isolated TTT. MESSAGE: These tumors had shown a minimal to no response to previous TTT treatment. However, adding ICG resulted in a measurable regression even though the same TTT treatment parameters were applied. PMID- 27231689 TI - De novo Evolution of a Small Choroidal Melanoma. AB - AIM: To report the evolution of a de novo choroidal melanoma. METHOD: This is a case report of a 22-year-old white male patient who has been undergoing periodic examination for a choroidal 'freckle' since 10 years of age. RESULTS: In 2007, a fundus photograph of the left eye showed a nondescript area of choroidal hyperpigmentation temporal to the fovea. Progressive growth was observed and, by 2012, the lesion had become well circumscribed and raised. One year later, a 4.5 * 4.5 * 1.5 mm, dome-shaped, pigmented, choroidal mass with subretinal fluid and orange pigmentation was evident. The lesion was classified as a small choroidal melanoma. Six months after plaque radiotherapy, tumor regression with total resolution of the subretinal fluid was documented. CONCLUSION: The distinction between small choroidal melanoma and choroidal nevus is not absolute; therefore, some choroidal melanomas may initially be mislabeled as choroidal nevi because of their small size until continued growth identifies them to be small choroidal melanomas. In our case, the documented growth of the choroidal lesion on each consecutive visit and its high-risk features strongly suggest that it had been a melanoma from the beginning. To our knowledge, this is only the second documented case of a de novo evolution of a small choroidal melanoma. PMID- 27231690 TI - Perivascular Epithelioid Cell Tumor Arising from Ciliary Body Treated by Local Resection. AB - AIMS: Perivascular epithelioid cell tumor (PEComa) is a mesenchymal neoplasm originating from perivascular myoid cells. We report a case of PEComa arising from the ciliary body. METHODS: Case report. RESULTS: A 13-year-old girl was referred to our department with a clinical diagnosis of ciliary body melanoma in her right eye. Her visual acuity was 20/600 OD. Slit-lamp examination revealed a brown tumor behind the iris. The ocular fundus could not be observed due to a cataract. Ultrasonography depicted an oval mass approximately 10 mm in diameter at the ciliary body. The tumor was successfully treated by local resection, and the patient's visual acuity improved to 20/20. Histopathological and immunohistochemical findings of the excised tumor were compatible with the diagnosis of PEComa of the ciliary body. No local recurrence of the tumor was observed for over 4 years after surgery. CONCLUSION: A very rare case of PEComa of the ciliary body was successfully treated by local resection, with favorable visual outcome and no recurrence for several years. PEComa can be differentiated from other ciliary body tumors by immunohistochemical study. PMID- 27231691 TI - The need for research-tested smartphone applications for promoting breastfeeding. PMID- 27231692 TI - Pulmonary Renal Syndrome After Streptococcal Pharyngitis: A Case Report. AB - Pulmonary renal syndrome is a class of small vessel vasculitides that are characterized by the dual presentation of diffuse alveolar hemorrhage (DAH) and glomerulonephritis. Pulmonary renal syndrome has multiple etiologies, but its development has been rarely reported following infection with group A streptococcus. We present the case of a 36-year-old Native American male who was transferred to our facility due to refractory hypoxic respiratory failure. He had been diagnosed with streptococcal pharyngitis 2 weeks prior to admission. Given the presence of hemoptysis, bronchoscopy was performed and was consistent with DAH. Urinalysis demonstrated hematuria and proteinuria, in the setting of elevated creatinine and blood urea nitrogen. Additionally, antistreptolysin O titer was positive. Given the constellation of laboratory findings and history of streptococcal pharyngitis, the patient was diagnosed with PRS secondary to streptococcal infection. High-dose methylprednisolone was initiated with concomitant plasmapheresis. He was extubated successfully after his respiratory status improved and was eventually discharged home after making a full recovery within 2 weeks after admission. This case illustrates the importance of clinically relevant sequelae of streptococcal infection as well as the appropriate treatment of PRS secondary to streptococcal pharyngitis with plasmapheresis and intravenous corticosteroids. PMID- 27231693 TI - A Case of Transfusion Error in a Trauma Patient With Subsequent Root Cause Analysis Leading to Institutional Change. AB - A 28-year-old man presented emergently to the operating room following a gun-shot injury to his right groin. Our hospital's Massive Transfusion Protocol was initiated as the patient entered the operating room actively hemorrhaging and severely hypotensive. During the aggressive resuscitation efforts, the patient was inadvertently transfused 2 units of packed red blood cells intended for another patient due to a series of errors. Fortunately, the incorrect product was compatible, and the patient recovered from his near-fatal injuries. Root cause analysis was used to review the transfusion error and develop an action plan to help prevent future occurrences. PMID- 27231694 TI - Spontaneous Iliopsoas Muscle Hemorrhage Secondary to Ibrutinib (Imbruvica; Pharmacyclics): Brief Report. AB - Ibrutinib (Imbruvica; Pharmacyclics) is the first Food and Drug Administration approved inhibitor of Burton's tyrosine kinase (BTK). Attenuation of BTK signaling ultimately leads to inhibition of B-cell proliferation and apoptosis. After a series of clinical trials, the Food and Drug Administration approved ibrutinib in patients with relapsed chronic lymphocytic leukemia in 2014 and Waldenstrom's macroglobulinemia in 2015. Those trials included rare grade 3+ hemorrhagic events associated with ibrutinib. Herein, we report a unique presentation of back pain due to iliopsoas muscle hemorrhage in a patient with Waldenstrom's macroglobulinemia after initiation of ibrutinib. PMID- 27231695 TI - From IBS to DBS: The Dysbiotic Bowel Syndrome. AB - Irritable bowel syndrome is a chronic gastrointestinal disorder characterized by abdominal pain and altered bowel habits in the absence of organic disease. We present 2 cases where diarrhea-predominant irritable bowel syndrome occurred in association with earlier intestinal infection or antibiotic treatment. Both were successfully treated with instillation of an anaerobic cultivated human intestinal microbiota. Thereafter, they were symptom free for at least 12 months. We now introduce the term dysbiotic bowel syndrome covering cases where a disturbed intestinal microbiota is assumed to be present. We recommend that restoration of the dysbiotic gut microbiota should be first-line treatment in these conditions. PMID- 27231696 TI - Anomalous Origin of the Right Pulmonary Artery From the Ascending Aorta in a 10 Month-Old Child: A Case Report From Tanzania. AB - Anomalous origin of the right pulmonary artery from the ascending aorta is a rare congenital deformity associated with poor quality of life and reduced life expectancy. Without a corrective surgery, less than one third of cases will live to see their sixth month. We report a case of a 10-month-old male child from Tanzania who presented with a 6-month history of recurrent respiratory tract infections, mild effort intolerance, and failure to thrive. PMID- 27231697 TI - An Intact Dissecting Baker's Cyst Mimicking Recurrent Deep Vein Thrombosis. AB - We report a case of a 75-year-old female with a history of acute deep vein thrombosis (DVT) 6 years ago who presented with unilateral calf swelling and pain. D-dimer was normal, and compression ultrasound revealed findings typical of DVT, including an incompressible dilated and hypoechoic peroneal vein. Despite 4 months of anticoagulation for supposed recurrent DVT, pain symptoms persisted and repeat D-dimer and compression ultrasound were unchanged. A magnetic resonance imaging scan to investigate the leg demonstrated a 6-cm dissecting Baker's cyst extending posterolaterally resulting in venous compression and distal dilation, which appeared to have been confused with a DVT. Ultrasound-guided aspiration of the cyst provided immediate and sustained relief. Herein we provide a review of the literature for the management of this rare scenario. PMID- 27231698 TI - Does Repair of a Hill-Sachs Defect Increase Stability at the Glenohumeral Joint? AB - BACKGROUND: The effect of osteoallograft repair of a Hill-Sachs lesion and the effect of allograft fit on glenohumeral translations in response to applied force are poorly understood. PURPOSE: To compare the impact of a 25% Hill-Sachs lesion, a perfect osteoallograft repair (PAR) of a 25% Hill-Sachs lesion, and an "imperfect" osteoallograft repair (IAR) of a 25% Hill-Sachs lesion on glenohumeral translations in response to a compressive load and either an anterior or posterior load in 3 clinically relevant arm positions. STUDY DESIGN: Controlled laboratory study. METHODS: A robotic/universal force-moment sensor testing system was used to apply joint compression (22 N) and an anterior or posterior load (44 N) to cadaveric shoulders (n = 9) with the skin and deltoid removed (intact) at 3 glenohumeral joint positions (abduction/external rotation): 0 degrees /0 degrees , 30 degrees /30 degrees , and 60 degrees /60 degrees . The 25% bony defect state, PAR state, and IAR state were created and the loading protocol was performed. Translational motion was measured in each position for each shoulder state. A nonparametric repeated-measures Friedman test with a Wilcoxon signed-rank post hoc test was performed to compare the biomechanical parameters (P < .05). RESULTS: Compared with the defect shoulder, the PAR shoulder had significantly less anterior translation with an anterior load in the 0 degrees /0 degrees (15.3 +/- 8.2 vs 16.6 +/- 9.0 mm, P = .008) and 30 degrees /30 degrees (13.6 +/- 7.1 vs 14.2 +/- 7.0 mm, P = .021) positions. Compared with IAR, the PAR shoulder had significantly less anterior translation with an anterior load in the 0 degrees /0 degrees (15.3 +/- 8.2 vs 16.6 +/- 9.0 mm, P = .008) and 30 degrees /30 degrees (13.6 +/- 7.1 vs 14.4 +/- 7.1 mm, P = .011) positions, and the defect shoulder had significantly less anterior translation with an anterior load in the 30 degrees /30 degrees (14.2 +/- 7.0 vs 14.4 +/- 7.0 mm, P = .038) position. CONCLUSION: PAR resulted in the least translational motion at the glenohumeral joint. The defect shoulder had significantly less translational motion at the joint compared with the IAR. An IAR resulted in the most translational motion at the glenohumeral joint. This demonstrates the biomechanical importance of performing an osteoallograft repair in which the allograft closely matches the Hill-Sachs defect and fully restores the preinjury state of the humeral head. CLINICAL RELEVANCE: This study demonstrates the importance of performing an osteoallograft repair of a Hill-Sachs defect that closely matches the preinjury state and restores normal humeral head anatomy. PMID- 27231699 TI - Biceps Lesion Associated With Rotator Cuff Tears: Open Subpectoral and Arthroscopic Intracuff Tenodesis. AB - BACKGROUND: Various tenodesis methods are being used for long head of the biceps tendon lesions. However, there is no consensus on the most appropriate surgical method. HYPOTHESIS: There are significant differences in incidence of cosmetic deformity and persistent bicipital pain between open subpectoral and arthroscopic intracuff tenodesis groups. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: This study included 72 patients who underwent biceps tenodesis and rotator cuff repair between January 2009 and May 2014 and who were followed for at least 1 year. Open subpectoral tenodesis was performed in 39 patients (group A), and arthroscopic intracuff tenodesis was performed in 33 patients (group B). RESULTS: In group A, the mean visual analog scale (VAS) score for pain during motion and mean University of California, Los Angeles (UCLA) and Constant scores significantly improved from 4.6, 18.6, and 64.5 preoperatively to 1.9, 30.5, and 86.5 at last follow-up, respectively (P < .001 for all). In group B, these scores significantly improved from 5.1, 17.6, and 62.9 preoperatively to 1.8, 31.5, and 85.9 at last follow-up, respectively (P < .001 for all). Popeye deformity was noted in 2 (5.2%) patients from group A and 5 (15.6%) patients from group B (P = .231). Additionally, persistent bicipital tenderness was noted in 1 (2.6%) patient from group A and 8 (24.2%) patients from group B (P = .012). CONCLUSION: Both open subpectoral tenodesis and arthroscopic intracuff tenodesis show good clinical outcomes for long head of the biceps tendon lesions. However, open subpectoral tenodesis may be more appropriate, considering the low incidence of Popeye deformity and tenderness. PMID- 27231700 TI - Concurrent Validation of the Banff Patella Instability Instrument to the Norwich Patellar Instability Score and the Kujala Score in Patients With Patellofemoral Instability. AB - BACKGROUND: The Banff Patella Instability Instrument (BPII) is a disease specific, patient-reported, quality-of-life outcome measure designed to assess patients with patellofemoral instability. The iterative assessment of the validity, reliability, and responsiveness of a health-related patient-reported outcome measure is vital to the development of a high-quality evaluation tool. PURPOSE: To assess the concurrent validity of the BPII to the Norwich Patellar Instability (NPI) score and the Kujala score. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A total of 74 patients with a confirmed diagnosis of recurrent patellofemoral instability completed the BPII, NPI, and Kujala scores at the initial orthopaedic consultation. A Pearson r correlation coefficient was computed to determine the relationship between each of these patient-reported outcomes. RESULTS: There were statistically significant correlations between the BPII and the NPI score (r = -0.53; P < .001) as well as the BPII and the Kujala score (r = 0.50; P < .001). CONCLUSION: This study demonstrated a moderately strong correlation of the BPII to other outcome measures used to evaluate patients with patellofemoral instability. This study adds further validity to the BPII in accordance with the COSMIN (COnsensus-based Standards for the selection of health Measurement INstruments) guidelines. PMID- 27231701 TI - Assessing Human Health Risk to Endocrine Disrupting Chemicals: a Focus on Prenatal Exposures and Oxidative Stress. AB - Understanding the health risk posed by endocrine disrupting chemicals (EDCs) is a challenge that is receiving intense attention. The following study criteria should be considered to facilitate risk assessment for exposure to EDCs: 1) characterization of target health outcomes and their mediators, 2) study of exposures in the context of critical periods of development, 3) accurate estimates of human exposures and use of human-relevant exposures in animal studies, and 4) cross-species comparisons. In this commentary, we discuss the importance and relevance of each of these criteria in studying the effects of prenatal exposure to EDCs. Our discussion focuses on oxidative stress as a mediator of EDC-related health effects due to its association with both EDC exposure and health outcomes. Our recent study (Veiga-Lopez et al. 2015)1 addressed each of the four outlined criteria and demonstrated that prenatal bisphenol-A exposure is associated with oxidative stress, a risk factor for developing diabetes and cardiovascular diseases in adulthood. PMID- 27231702 TI - PAX6, brain structure and function in human adults: advanced MRI in aniridia. AB - OBJECTIVE: PAX6 is a pleiotropic transcription factor essential for the development of several tissues including the eyes, central nervous system, and some endocrine glands. Recently it has also been shown to be important for the maintenance and functioning of corneal and pancreatic tissues in adults. We hypothesized that PAX6 is important for the maintenance of brain integrity in humans, and that adult heterozygotes may have abnormalities of cortical patterning analogous to those found in mouse models. METHODS: We used advanced magnetic resonance imaging techniques, including surface-based morphometry and region-of-interest analysis in adult humans heterozygously mutated for PAX6 mutations (n = 19 subjects and n = 21 controls). Using immunohistochemistry, we also studied PAX6 expression in the adult brain tissue of healthy subjects (n = 4) and patients with epilepsy (n = 42), some of whom had focal injuries due to intracranial electrode track placement (n = 17). RESULTS: There were significant reductions in frontoparietal cortical area after correcting for age and intracranial volume. A greater decline in thickness of the frontoparietal cortex with age, in subjects with PAX6 mutations compared to controls, correlated with age-corrected, accelerated decline in working memory. These results also demonstrate genotypic effects: those subjects with the most severe genotypes have the most widespread differences compared with controls. We also demonstrated significant increases in PAX6-expressing cells in response to acute injury in the adult human brain. INTERPRETATION: These findings suggest a role for PAX6 in the maintenance and consequent functioning of the adult brain, homologous to that found in other tissues. This has significant implications for the understanding and treatment of neurodegenerative diseases. PMID- 27231703 TI - Absence of UCHL 1 function leads to selective motor neuropathy. AB - OBJECTIVE: The aim of this study was to investigate the role of ubiquitin C terminal hydrolase-L1 (UCHL1) for motor neuron circuitry and especially in spinal motor neuron (SMN) health, function, and connectivity. METHODS: Since mutations in UCHL1 gene leads to motor dysfunction in patients, we investigated the role of UCHL1 on SMN survival, axon health, and connectivity with the muscle, by employing molecular and cellular marker expression analysis and electrophysiological recordings, in healthy wild-type and Uchl1 (nm3419) (UCHL1-/ ) mice, which lack all UCHL1 function. RESULTS: There is pure motor neuropathy with selective degeneration of the motor, but not sensory axons in the absence of UCHL1 function. Neuromuscular junctions (NMJ) are impaired in muscle groups that are innervated by slow-twitch or fast-twitch SMN. However, unlike corticospinal motor neurons, SMN cell bodies remain intact with no signs of elevated endoplasmic reticulum (ER) stress. INTERPRETATION: Presence of NMJ defects and progressive retrograde axonal degeneration in the absence of major SMN soma loss suggest that defining pathology as a function of neuron number is misleading and that upper and lower motor neurons utilize UCHL1 function in different cellular events. In line with findings in patients with mutations in UCHL1 gene, our results suggest a unique role of UCHL1, especially for motor neuron circuitry. SMN require UCHL1 to maintain NMJ and motor axon health, and that observed motor dysfunction in the absence of UCHL1 is not due to SMN loss, but mostly due to disintegrated circuitry. PMID- 27231704 TI - Plasma EGF and cognitive decline in Parkinson's disease and Alzheimer's disease. AB - OBJECTIVE: Cognitive decline occurs in multiple neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Shared underlying mechanisms may exist and manifest as shared biomarker signatures. Previously, we nominated plasma epidermal growth factor (EGF) as a biomarker predicting cognitive decline in patients with established PD. Here, we investigate EGF as a predictive biomarker in prodromal PD, as well as AD. METHODS: A cohort of PD patients (n = 236) was recruited to replicate our finding that low baseline EGF levels predict future cognitive decline. Additionally, plasma EGF and cognitive outcome measures were obtained from individuals with normal cognition (NC, n = 58), amnestic mild cognitive impairment (AD-MCI, n = 396), and Alzheimer's disease (AD, n = 112) in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort to investigate whether low EGF levels correlate with cognitive status and outcome in AD-MCI and AD. Third, plasma EGF and cognitive measures were evaluated in the high-risk asymptomatic Parkinson's Associated Risk Study (PARS) cohort (n = 165) to investigate the association of EGF and cognitive performance in a PD prodromal context. RESULTS: In both PD and AD-MCI, low baseline plasma EGF predicted poorer long-term cognitive outcomes. In asymptomatic individuals at highest risk for developing PD from the PARS cohort, low baseline plasma EGF associated with poorer performance in the visuospatial domain but not in other cognitive domains. INTERPRETATION: Low plasma EGF at baseline predicts cognitive decline in both AD and PD. Evidence for this signal may exist in prodromal stages of both diseases. PMID- 27231705 TI - Somatic mutations in GLI3 and OFD1 involved in sonic hedgehog signaling cause hypothalamic hamartoma. AB - OBJECTIVE: Hypothalamic hamartoma (HH) is a congenital anomalous brain tumor. Although most HHs are found without any other systemic features, HH is observed in syndromic disorders such as Pallister-Hall syndrome (PHS) and oral-facial digital syndrome (OFD). Here, we explore the possible involvement of somatic mutations in HH. METHODS: We analyzed paired blood and hamartoma samples from 18 individuals, including three with digital anomalies, by whole-exome sequencing. Detected somatic mutations were validated by Sanger sequencing and deep sequencing of target amplicons. The effect of GLI3 mutations on its transcriptional properties was evaluated by luciferase assays using reporters containing eight copies of the GLI-binding site and a mutated control sequence disrupting GLI binding. RESULTS: We found hamartoma-specific somatic truncation mutations in GLI3 and OFD1, known regulators of sonic hedgehog (Shh) signaling, in two and three individuals, respectively. Deep sequencing of amplicons covering the mutations showed mutant allele rates of 7-54%. Somatic mutations in OFD1 at Xp22 were found only in male individuals. Potential pathogenic somatic mutations in UBR5 and ZNF263 were also identified in each individual. Germline nonsense mutations in GLI3 and OFD1 were identified in each individual with PHS and OFD type I in our series, respectively. The truncated GLI3 showed stronger repressor activity than the wild-type protein. We did not detect somatic mutations in the remaining 9 individuals. INTERPRETATION: Our data indicate that a spectrum of human disorders can be caused by lesion-specific somatic mutations, and suggest that impaired Shh signaling is one of the pathomechanisms of HH. PMID- 27231707 TI - Novel window on early human neurodevelopment via fetal exosomes in maternal blood. AB - Adverse in utero exposures can disrupt fetal brain development, deplete subpopulations of neurons and inhibit formation of normal synaptic connections. A major roadblock to unraveling the precise mechanisms and timing of human neurodevelopmental derangement is the almost complete absence of sensitive noninvasive assessments. We present novel methods for isolating fetal neuronal exosomes from maternal plasma as a noninvasive platform for testing aspects of fetal neurodevelopment as early as the 1st trimester. Our methodology represents an important breakthrough both in understanding mechanisms of injury in vivo in a human system and potentially for monitoring clinical interventions seeking to promote fetal brain health. PMID- 27231708 TI - Diagnostic delay in progressive multifocal leukoencephalopathy. AB - We investigated delay in diagnosing progressive multifocal leukoencephalopathy (PML). The median time from initial symptom to diagnosis was 74 days (range 1 1643) in 111 PML patients seen at our institution from 1993 to 2015. Another diagnosis was considered before PML in nearly two-thirds, and more than three quarters of patients suffered from diagnostic delay greater than 1 month, irrespective of their underlying immunosuppressive condition. Extended diagnostic delay occurred more frequently in patients with possible PML, and among HIV (+) patients with higher CD4(+) T-cell counts at symptom onset. Prompt diagnosis may improve survival of PML in so far as immune reconstitution can be effected, and prevent unnecessary interventions. PMID- 27231706 TI - Efficacy and ototoxicity of different cyclodextrins in Niemann-Pick C disease. AB - OBJECTIVE: Niemann-Pick type C (NPC) disease is a fatal, neurodegenerative, lysosomal storage disorder characterized by intracellular accumulation of unesterified cholesterol (UC) and other lipids. While its mechanism of action remains unresolved, administration of 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) has provided the greatest disease amelioration in animal models but is ototoxic. We evaluated other cyclodextrins (CDs) for treatment outcome and chemical interaction with disease-relevant substrates that could pertain to mechanism. METHODS: NPC disease mice treated for 2 weeks with nine different CDs were evaluated for UC, and GM2 and GM3 ganglioside accumulation using immunohisto/cytochemical and biochemical assays. Auditory brainstem responses were determined in wild-type mice administered CDs. CD complexation with UC, gangliosides, and other lipids was quantified. RESULTS: Four HPbetaCDs varying in degrees of substitution, including one currently in clinical trial, showed equivalent storage reduction, while other CDs showed significant differences in relative ototoxicity and efficacy, with reductions similar for the brain and liver. Importantly, HPgammaCD and two sulfobutylether-CDs showed efficacy with reduced ototoxicity. Complexation studies showed: incomplete correlation between CD efficacy and UC solubilization; an inverse correlation for ganglioside complexation; substantial interaction with several relevant lipids; and association between undesirable increases of UC storage in Kupffer cells and UC solubilization. INTERPRETATION: CDs other than HPbetaCD identified here may provide disease amelioration without ototoxicity and merit long-term treatment studies. While direct interactions of CD-UC are thought central to the mechanism of correction, the data show that this does not strictly correlate with complexation ability and suggest interactions with other NPC disease-relevant substrates should be considered. PMID- 27231709 TI - alpha5GABAA receptor deficiency causes autism-like behaviors. AB - The prevalence of autism spectrum disorders (ASDs), which affect over 1% of the population, has increased twofold in recent years. Reduced expression of GABAA receptors has been observed in postmortem brain tissue and neuroimaging of individuals with ASDs. We found that deletion of the gene for the alpha5 subunit of the GABAA receptor caused robust autism-like behaviors in mice, including reduced social contacts and vocalizations. Screening of human exome sequencing data from 396 ASD subjects revealed potential missense mutations in GABRA5 and in RDX, the gene for the alpha5GABAA receptor-anchoring protein radixin, further supporting a alpha5GABAA receptor deficiency in ASDs. PMID- 27231711 TI - Visualization of Intracellular Tyrosinase Activity in vitro. AB - Melanocytes produce the melanin pigments in melanosomes and these organelles protect the skin against harmful ultraviolet rays. Tyrosinase is the key cuproenzyme which initiates the pigment synthesis using its substrate amino acid tyrosine or L-DOPA (L-3, 4-dihydroxyphenylalanine). Moreover, the activity of tyrosinase directly correlates to the cellular pigmentation. Defects in tyrosinase transport to melanosomes or mutations in the enzyme or reduced intracellular copper levels results in loss of tyrosinase activity in melanosomes, commonly observed in albinism. Here, we described a method to detect the intracellular activity of tyrosinase in mouse melanocytes. This protocol will visualize the active tyrosinase present in the intracellular vesicles or organelles including melanosomes. PMID- 27231710 TI - Plasma neuronal exosomal levels of Alzheimer's disease biomarkers in normal aging. AB - Plasma neuronal exosomal levels of pathogenic Alzheimer's disease (AD) proteins, cellular survival factors, and lysosomal proteins distinguish AD patients from control subjects, but changes in these exosomal proteins associated with normal aging have not been described for cognitively intact subjects. Plasma neuronal exosomal levels of P-T181-tau, P-S396-tau, Abeta 1-42, cathepsin D, repressor element 1-silencing transcription factor, and neurogranin were quantified longitudinally in cognitively intact older adults using two samples collected at 3- to 11-year intervals. Except for P-S396-tau, exosomal protein levels changed significantly with aging, but were largely outside the range observed in AD patients. PMID- 27231712 TI - Laquinimod prevents cuprizone-induced demyelination independent of Toll-like receptor signaling. AB - OBJECTIVE: To test whether Toll-like receptor (TLR) signaling plays a key role for reduced nuclear factor B (NF-kappaB) activation after laquinimod treatment in the model of cuprizone-induced demyelination, oligodendrocyte apoptosis, inflammation, and axonal damage. METHODS: Ten-week-old C57BL/6J, TLR4(-/-), and MyD88(-/-) mice received 0.25% cuprizone for 6 weeks and were treated daily with 25 mg/kg laquinimod or vehicle. After 6 weeks of demyelination, extent of demyelination, oligodendrocyte density, microglia infiltration, and axonal damage were analyzed in the corpus callosum. Additionally, we analyzed primary mouse astrocytes from C57BL/6J, TLR4(-/-), MyD88(-/-), and TRIF(-/-) mice for alteration in NF-kappaB signaling. RESULTS: Vehicle-treated controls from C57BL/6J, TLR4(-/-), and MyD88(-/-) mice displayed extensive callosal demyelination as well as microglial activation. In contrast, mice treated with 25 mg/kg laquinimod showed mainly intact callosal myelin. The demyelination score was significantly higher in all untreated mice compared to mice treated with laquinimod. There were significantly fewer APP-positive axonal spheroids, Mac3 positive macrophages/microglia, and less oligodendrocyte apoptosis in the corpus callosum of laquinimod-treated mice in comparison to untreated controls. Stimulated primary mouse astrocytes from laquinimod-treated groups show reduced NF-kappaB activation compared to vehicle-treated controls. CONCLUSIONS: Our results confirm that laquinimod prevents demyelination in the cuprizone mouse model for multiple sclerosis via downregulation of NF-kappaB activation. This laquinimod effect, however, does not involve upstream Toll-like receptor signaling. PMID- 27231713 TI - Immunologic profiles of multiple sclerosis treatments reveal shared early B cell alterations. AB - OBJECTIVE: We undertook a systems immunology approach of the adaptive immune system in multiple sclerosis (MS), overcoming tradeoffs between scale and level of detail, in order to identify the immunologic signature of MS and the changes wrought by current immunomodulatory treatments. METHODS: We developed a comprehensive flow cytometry platform measuring 38 immunologic cell types in the peripheral blood of 245 individuals in a routine clinical setting. These include patients with MS, untreated or receiving any of 4 current immunomodulatory treatments (interferon-beta, glatiramer acetate, natalizumab, or fingolimod), patients with autoimmune thyroid disease, and healthy controls. RESULTS: An increase in memory CD8(+) T cells and B cells was observed in untreated patients with MS. Interferon-beta and fingolimod induce significant changes upon multiple aspects of the peripheral immune system, with an unexpectedly prominent alteration of B cells. Overall, both treatments push the immune system in different directions, with only 2 significant effects shared across these treatments-an increase in transitional B cells and a decrease in class-switched B cells. We further identified heightened B cell-activating factor (BAFF) levels as regulating this shared B cell pathway. CONCLUSIONS: A systems immunology approach established different immunologic profiles induced by current immunomodulatory MS treatments, offering perspectives for personalized medicine. Pathways shared between the immunologic architecture of existing efficacious treatments identify targets for future treatment design. PMID- 27231714 TI - Multiple sclerosis: Molecular mimicry of an antimyelin HLA class I restricted T cell receptor. AB - OBJECTIVE: To identify target antigens presented by human leukocyte antigen (HLA) A*02:01 to the myelin-reactive human T-cell receptor (TCR) 2D1, which was originally isolated from a CD8+ T-cell clone recognizing proteolipid protein (PLP) in the context of HLA-A*03:01, we employed a new antigen search technology. METHODS: We used our recently developed antigen search technology that employs plasmid-encoded combinatorial peptide libraries and a highly sensitive single cell detection system to identify endogenous candidate peptides of mice and human origin. We validated candidate antigens by independent T-cell assays using synthetic peptides and refolded HLA:peptide complexes. A molecular model of HLA A*02:01:peptide complexes was obtained by molecular dynamics simulations. RESULTS: We identified one peptide from glycerolphosphatidylcholine phosphodiesterase 1, which is identical in mice and humans and originates from a protein that is expressed in many cell types. When bound to HLA-A*02:01, this peptide cross-stimulates the PLP-reactive HLA-A3-restricted TCR 2D1. Investigation of molecular details revealed that the peptide length plays a crucial role in its capacity to bind HLA-A*02:01 and to activate TCR 2D1. Molecular modeling illustrated the 3D structures of activating HLA:peptide complexes. CONCLUSIONS: Our results show that our antigen search technology allows us to identify new candidate antigens of a presumably pathogenic, autoreactive, human CD8+ T-cell-derived TCR. They further illustrate how this TCR, which recognizes a myelin peptide bound to HLA-A*03:01, may cross-react with an unrelated peptide presented by the protective HLA class I allele HLA-A*02:01. PMID- 27231715 TI - Yoga as a treatment for chronic low back pain: A systematic review of the literature. AB - OBJECTIVES: Chronic low back pain (CLBP) affects millions of people worldwide, and appears to be increasing in prevalence. It is associated not only with pain, but also with increased disability, psychological symptoms, and reduced quality of life. There are various treatment options for CLBP, but no single therapy stands out as being the most effective. In the past 10 years, yoga interventions have been studied as a CLBP treatment approach. The objective of this paper is to review the current literature supporting the efficacy of yoga for CLBP. METHODS: A literature search through the beginning of 2015 was conducted in Pub Med for randomized control trials addressing treatment of CLBP with yoga. RESULTS: In this review we evaluate the use of yoga as a treatment for CLBP. Specifically we evaluate how yoga impacts physical functioning and disability, pain, and associated psychological symptoms. We also evaluate possible mediators of the effect of yoga and the safety of yoga. DISCUSSION: With few exceptions, previous studies and the recent randomized control trials (RCTs) indicate that yoga can reduce pain and disability, can be practiced safely, and is well received by participants. Some studies also indicate that yoga may improve psychological symptoms, but these effects are currently not as well established. PMID- 27231716 TI - Sensory and cognitive plasticity: implications for academic interventions. AB - Research in neuroscience has great potential for transforming education. However, the brain systems that support academic and cognitive skills are poorly understood in comparison to the systems that support sensory processing. Decades of basic research have examined the role that brain plasticity plays in the genesis and treatment of developmental visual disorders, which may help to inform how cognitive training approaches can be tailored for students who experience environmental disadvantage. In this review, we draw parallels between visual and cognitive intervention approaches, and suggest research avenues that could inform educational practice in the future. PMID- 27231717 TI - CAR models: next-generation CAR modifications for enhanced T-cell function. AB - T cells genetically targeted with a chimeric antigen receptor (CAR) to B-cell malignancies have demonstrated tremendous clinical outcomes. With the proof in principle for CAR T cells as a therapy for B-cell malignancies being established, current and future research is being focused on adapting CAR technology to other cancers, as well as enhancing its efficacy and/or safety. The modular nature of the CAR, extracellular antigen-binding domain fused to a transmembrane domain and intracellular T-cell signaling domains, allows for optimization by replacement of the various components. These modifications are creating a whole new class of therapeutic CARs. In this review, we discuss the recent major advances in CAR design and how these modifications will impact its clinical application. PMID- 27231718 TI - Cell-Envelope Remodeling as a Determinant of Phenotypic Antibacterial Tolerance in Mycobacterium tuberculosis. AB - The mechanisms that lead to phenotypic antibacterial tolerance in bacteria remain poorly understood. We investigate whether changes in NaCl concentration toward physiologically higher values affect antibacterial efficacy against Mycobacterium tuberculosis (Mtb), the causal agent of human tuberculosis. Indeed, multiclass phenotypic antibacterial tolerance is observed during Mtb growth in physiologic saline. This includes changes in sensitivity to ethionamide, ethambutol, d cycloserine, several aminoglycosides, and quinolones. By employing organism-wide metabolomic and lipidomic approaches combined with phenotypic tests, we identified a time-dependent biphasic adaptive response after exposure of Mtb to physiological levels of NaCl. A first rapid, extensive, and reversible phase was associated with changes in core and amino acid metabolism. In a second phase, Mtb responded with a substantial remodelling of plasma membrane and outer lipid membrane composition. We demonstrate that phenotypic tolerance at physiological concentrations of NaCl is the result of changes in plasma and outer membrane lipid remodeling and not changes in core metabolism. Altogether, these results indicate that physiologic saline-induced antibacterial tolerance is kinetically coupled to cell envelope changes and demonstrate that metabolic changes and growth arrest are not the cause of phenotypic tolerance observed in Mtb exposed to physiologic concentrations of NaCl. Importantly, this work uncovers a role for bacterial cell envelope remodeling in antibacterial tolerance, alongside well documented allterations in respiration, metabolism, and growth rate. PMID- 27231719 TI - ABCA7 frameshift deletion associated with Alzheimer disease in African Americans. AB - OBJECTIVE: To identify a causative variant(s) that may contribute to Alzheimer disease (AD) in African Americans (AA) in the ATP-binding cassette, subfamily A (ABC1), member 7 (ABCA7) gene, a known risk factor for late-onset AD. METHODS: Custom capture sequencing was performed on ~150 kb encompassing ABCA7 in 40 AA cases and 37 AA controls carrying the AA risk allele (rs115550680). Association testing was performed for an ABCA7 deletion identified in large AA data sets (discovery n = 1,068; replication n = 1,749) and whole exome sequencing of Caribbean Hispanic (CH) AD families. RESULTS: A 44-base pair deletion (rs142076058) was identified in all 77 risk genotype carriers, which shows that the deletion is in high linkage disequilibrium with the risk allele. The deletion was assessed in a large data set (531 cases and 527 controls) and, after adjustments for age, sex, and APOE status, was significantly associated with disease (p = 0.0002, odds ratio [OR] = 2.13 [95% confidence interval (CI): 1.42 3.20]). An independent data set replicated the association (447 cases and 880 controls, p = 0.0117, OR = 1.65 [95% CI: 1.12-2.44]), and joint analysis increased the significance (p = 1.414 * 10(-5), OR = 1.81 [95% CI: 1.38-2.37]). The deletion is common in AA cases (15.2%) and AA controls (9.74%), but in only 0.12% of our non-Hispanic white cohort. Whole exome sequencing of multiplex, CH families identified the deletion cosegregating with disease in a large sibship. The deleted allele produces a stable, detectable RNA strand and is predicted to result in a frameshift mutation (p.Arg578Alafs) that could interfere with protein function. CONCLUSIONS: This common ABCA7 deletion could represent an ethnic specific pathogenic alteration in AD. PMID- 27231720 TI - Magnetic Optical Microarray Imager for Diagnosing Type of Diabetes in Clinical Blood Serum Samples. AB - Due to rapidly rising rates of diabetes and prediabetic conditions worldwide and the associated lethal complications, it is imperative to devise new diagnostic tools that reliably and directly measure insulin levels in clinical samples. Herein, we report a simple and sensitive direct imaging of insulin levels in diabetic patient samples using a surface plasmon resonance microarray imager (SPRi). To enhance sensitivity, we utilized magnetic nanoparticles (MNPs) to capture insulin from serum samples either directly or via a capture antibody immobilized on MNPs. The insulin-captured nanoparticles were allowed to bind surface insulin-antibody for detection from pixel intensity increase using a charge coupled device (CCD) built-in with the SPRi. We have compared the analytical figures-of-merit of the SPRi immunoarray on detecting insulin prepared in various percentages of serum solutions. A four parameter logistic model was used to obtain the best fit of microarray responses with insulin concentration and indicated the cooperative binding of insulin-nanoparticle conjugates to surface antibody in both the buffer insulin and the serum insulin conjugates with MNPs. The cooperativity effect is attributed to the greater association of magnetic nanoparticle-bound insulin molecules with increasing concentration of insulin binding to surface antibody. This is the first report of an SPRi immunoarray to accomplish clinical diagnosis of diabetic and prediabetic conditions based on insulin levels with serum matrix effect analysis and comparison between direct and sandwich insulin assay formats. PMID- 27231721 TI - High salt induces anti-inflammatory MPhi2-like phenotype in peripheral macrophages. AB - Macrophages play a critical role in inflammation and antigen-presentation. Abnormal macrophage function has been attributed in autoimmune diseases and cancer progression. Recent evidence suggests that high salt tissue micro environment causes changes in macrophage activation. In our current report, we studied the role of extracellular sodium chloride on phenotype changes in peripheral circulating monocyte/macrophages collected from healthy donors. High salt (0.2 M NaCl vs basal 0.1 M NaCl) treatment resulted in a decrease in MPhi1 macrophage phenotype (CD11b+CD14highCD16low) from 77.4+/-6.2% (0.1 M) to 29.3+/ 5.7% (0.2 M, p<0.05), while there was an increase in MPhi2 macrophage phenotype (CD11b+ CD14lowCD16high) from 17.2+/-5.9% (0.1 M) to 67.4+/-9.4% (0.2 M, p<0.05). ELISA-based cytokine analysis demonstrated that high salt treatment induced decreased expression of in the MPhi1 phenotype specific pro-inflammatory cytokine, TNFalpha (3.3 fold), IL-12 (2.3 fold), CCL-10 (2 fold) and CCL-5 (3.8 fold), but conversely induced an enhanced expression MPhi2-like phenotype specific anti-inflammatory cytokine, IL-10, TGFbeta, CCL-17 (3.7 fold) and CCR-2 (4.3 fold). Further high salt treatment significantly decreased phagocytic efficiency of macrophages and inducible nitric oxide synthetase expression. Taken together, these data suggest that high salt extracellular environment induces an anti-inflammatory MPhi2-like macrophage phenotype with poor phagocytic and potentially reduced antigen presentation capacity commonly found in tumor microenvironment. PMID- 27231722 TI - Antimanic Treatment With Tamoxifen Affects Brain Chemistry: A Double-Blind, Placebo-Controlled Proton Magnetic Resonance Spectroscopy Study. AB - BACKGROUND: The antimanic efficacy of a protein kinase C (PKC) inhibitor, tamoxifen, has been tested in several clinical trials, all reporting positive results. However, mechanisms underlying the observed clinical effects requires further confirmation through studies of biological markers. METHODS: We investigated the effect of tamoxifen versus placebo on brain metabolites via a proton (1H) magnetic resonance spectroscopy (MRS) study. Forty-eight adult bipolar I manic patients (mean Young Mania Rating Scale (YMRS) score of 37.8+/ 5.8) were scanned at baseline and following 3 weeks of double-blind treatment. We hypothesized that manic symptom alleviation would improve the levels of markers associated with brain energy metabolism (creatine plus phosphocreatine [total creatine; tCr]) and neuronal viability (N-acetylaspartate [NAA]). RESULTS: The YMRS scores decreased from 38.6+/-4.5 to 20.0+/-11.1 in the tamoxifen group and increased from 37.0+/-6.8 to 43.1+/-7.8 in the placebo group (p<0.001). 1H MRS measurements revealed a 5.5+/-13.8% increase in the dorsomedial prefrontal cortex (DMPFC) tCr levels in the tamoxifen group and a 5.3+/-13.1% decrease in tCr in the placebo group (p=0.027). A significant correlation between the YMRS score change and tCr percent change was observed in the whole group (Spearman rho=0.341, p=0.029). Both tCr and NAA levels in the responder group were increased by 9.4+/-15.2% and 6.1+/-11.7%, whereas levels in the non-responder group were decreased by 2.1+/-13.2% and 6.5+/-10.5%, respectively (p<0.05). CONCLUSIONS: Tamoxifen effectively treated mania while it also increased brain tCr levels, consistent with involvement of both excessive PKC activation and impaired brain energy metabolism in the development of bipolar mania. CLINICAL TRIAL REGISTRATION: Registry name: ClinicalTrials.gov URL: https://clinicaltrials.gov/ct2/show/NCT00411203?term=NCT00411203&rank=1 Registration number: NCT00411203. PMID- 27231723 TI - Can Hybrid Learning Theory Be Used to Teach Working Sonographers Breast Elastography? AB - Hybrid learning is a combination of on-line learning and face-to-face sessions. This research sought to answer the question of "Can Hybrid Learning be Utilized To Teach Working Sonographers to perform breast Elastography?" We designed a hybrid course entitled "Breast Elastography for Working Sonographers." This course consisted of four on-line training modules, each complete with a post-test and one face-to-face session. After the face-to-face session lectures, participants were interviewed and observed performing elastography on a breast phantom. Our results indicate that this is a successful method for teaching working sonographers breast elastography, in this setting. PMID- 27231724 TI - Redundant safety features in a high-channel-count retinal neurostimulator. AB - Safety features embedded in a 256-channel retinal prosthesis integrated circuit are presented. The biology of the retina and the electrochemistry of the electrode-tissue interface demand careful planning and design of the safety features of an implantable retinal stimulation device. We describe the internal limits and communication safety features of our ASIC, but we focus on monitoring and protection circuits for the electrode-tissue interface. Two independent voltage monitoring circuits for each channel measure the electrode polarization voltage at two different times in the biphasic stimulation cycle. The monitors ensure that the charged electrode stays within the electrochemical water window potentials, and that the discharged electrode is within a small window near the counter electrode potential. A switch to connect each electrode to the counter electrode between pulses protects against a wide range of device failures. Additionally, we describe work on an active feedback system to ensure that the electrode voltage is at zero. PMID- 27231725 TI - On Using Residual Voltage to Estimate Electrode Model Parameters for Damage Detection. AB - Current technology has enabled a significant increase in the number of electrodes for electrical stimulation. For large arrays of electrodes, it becomes increasingly difficult to monitor and detect failures at the stimulation site. In this paper, we propose the idea that the residual voltage from a biphasic electrical stimulation pulse can serve to recognize damage at the electrode tissue interface. We use a simple switch circuit approach to estimate the relaxation time constant of the electrode model, which essentially models the residual voltage in biphasic electrical stimulation, and compare it with standard electrode characterization techniques. Out of 15 electrodes in a polyimide-based SIROF array, our approach highlights 3 damaged electrodes, consistent with measurements made using cyclic voltammetry and electrode impedance spectroscopy. PMID- 27231726 TI - Adhesive and hydrophobic properties of the selected LAB isolated from gastrointestinal tract of farming animals. AB - The aim of this study was to determine the degree of adhesion and hydrophobicity of some strains of lactic acid bacteria (LAB) with proven antagonistic properties against pathogenic bacteria. Studies were performed using-LAB strains isolated from the gastrointestinal tract of calves and piglets. These strains exhibited an antibacterial activity against pathogenic strains of Clostridium perfringens and Escherichia coli. Cell adhesiveness was examined in relation to the porcine and bovine mucin. Our analyses had shown that the tested microorganisms demonstrated a degree of adhesion in the range of 32.00-40.00% for strains isolated from calves, and 34.00-40.00% for strains isolated from pigs. The hydrophobicity of tested bacteria was in the range of 31.00%-44.00% for strains isolated from pigs, and 26.00%-42.00% for strains obtained from calves. The best mucin adhesion ability was found for bacterial strains belonging to the Enterococcus genus isolated from calves. Taking into account porcine isolates, the best adhesion was observed for the Leuconostoc bacterial strains. Among tested strains, the highest hydrophobicity, measured in relation to hexadecane, was recorded for the bacterial strains belonging to the Leuconostoc sp. isolated from piglets and a of Lactobacillus sp. bacterial strain isolated from calves. PMID- 27231727 TI - A micelle mediated extraction as a new method of obtaining the infusion of Bidens tripartita. AB - In this paper, the extracts of three-part beggarticks (Bidens tripartita) were prepared using ultrasonic assisted micelle-mediated extraction method (UAMME). Different kind of surfactants and WPC (whey protein concentrate) were applied. In the B. tripartita extracts twenty polyphenols were identified by UPLC-DAD-MS. Both aqueous and UAMME extracts mainly contained chlorogenic acid, caftaric acid and its derivatives as well as luteolin 7-O-glucoside. The luteolin was extracted with Rokanol B2 and Triton X-100. Furthermore, antioxidative properties of the extracts were analyzed with two methods: reactions with di(phenyl)-(2,4,6 trinitrophenyl)iminoazanium (DPPH) reagent and Follin's method. The DPPH radical scavenging by micellar extracts was in general comparable with the antioxidant activity of conventional extracts. The most active was sample with Tego Care CG90, reducing about 73% of the radical. Obtained results confirmed that the UAMME might be an alternative method, to the liquid-liquid or solid-liquid extraction, of obtaining specified extracts rich in active compounds. Selecting a suitable surfactant may thus provide the expected composition of the extract. PMID- 27231728 TI - Comparative effects of selected plant polyphenols, gallic acid and epigallocatechin gallate, on matrix metalloproteinases activity in multidrug resistant MCF7/DOX breast cancer cells. AB - The aim of the study was to investigate the effect of selected polyphenols: gallic acid (GA) and epigallocatechin gallate (EGCG) on matrix metalloproteinase (MMP-2 and MMP-9) activity in multidrug resistant (MDR) human breast adenocarcinoma cells: MCF7/DOX cells and obtained recently in our laboratory MCF7/DOX500 cells by the permanent selection of MCF7/DOX cells with 500 nM doxorubicin (DOX). The activity of MMP-2 and MMP-9 and the effect of studied polyphenols on these matrix proteases were examined by gelatin zymography assays. We have found that the activity of MMP-2 and MMP-9 significantly increased in resistant MCF7/DOX and MCF7/DOX500 cells whereas they were not detected in sensitive MCF7 cells. It was also observed that GA (30, 60, 100 and 120 uM) and EGCG (5, 10 and 20 uM) caused a comparable concentration-dependent inhibition of MMP-2 and MMP-9 activity in MCF7/DOX and MCF7/DOX500 cells. Control experiments confirmed that examined compounds in these ranges of concentration did not affect the cell growth of MCF7/DOX and MCF7/DOX500 sublines (80-100% of control cell growth was observed in the presence of studied polyphenols). PMID- 27231729 TI - Three dimensional ink-jet printing of biomaterials using ionic liquids and co solvents. AB - 1-Ethyl-3-methylimidazolium acetate ([C2C1Im][OAc]) and 1-butyl-3 methylimidazolium acetate ([C4C1Im][OAc]) have been used as solvents for the dissolution and ink-jet printing of cellulose from 1.0 to 4.8 wt%, mixed with the co-solvents 1-butanol and DMSO. 1-Butanol and DMSO were used as rheological modifiers to ensure consistent printing, with DMSO in the range of 41-47 wt% producing samples within the printable range of a DIMATIX print-head used (printability parameter < 10) at 55 degrees C, whilst maintaining cellulose solubility. Regeneration of cellulose from printed samples using water was demonstrated, with the resulting structural changes to the cellulose sample assessed by scanning electron microscopy (SEM) and white light interferometry (WLI). These results indicate the potential of biorenewable materials to be used in the 3D additive manufacture process to generate single-component and composite materials. PMID- 27231730 TI - Active Lactobacillus rhamnosus LA68 or Lactobacillus plantarum WCFS1 administration positively influences liver fatty acid composition in mice on a HFD regime. AB - Western life style, and high calorie diet in particular is causing major health problems such as insulin resistance, hepatic steatosis and heart disease in the modern age. High fat diet (HFD) induces similar changes in mice, such as increased body weight, hypercholesterolemia and accumulation of triglycerides in the liver. These changes can be ameliorated by the administration of some Lactobacillus species. The focus of this study was to analyze the fatty acid content of liver, heart and brain tissues of mice fed HFD and administered with either Lactobacillus plantarum WCFS1 or Lactobacillus rhamnosus LA68, and to analyze the fatty acid content of these organs after a two months washout period. The fatty acid composition of mouse liver tissue changed significantly due to probiotic administration during a 12 weeks HFD regime and active Lactobacillus administration had a slightly reversing effect toward the standard mouse diet group, but after the washout period these changes disappeared. The fatty acid composition of the heart and brain tissues was significantly changed in the HFD regime but probiotic administration had no significant influence on the fatty acid profile of these two organs. Upon the 8 weeks washout period the only remaining beneficial effect was the significantly lower mouse weight in the supplemented groups compared to the HFD group. PMID- 27231731 TI - Pyristriatins A and B: Pyridino-Cyathane Antibiotics from the Basidiomycete Cyathus cf. striatus. AB - Two novel pyridino-cyathane diterpenoids, pyristriatins A and B (1 and 2), together with striatin C (3) were isolated from cultures of Cyathus cf. striatus, a basidiomycete that was found during a field trip in northern Thailand. The pyristriatins showed antimicrobial effects against Gram-positive bacteria and fungi. The isolation, structure elucidation, relative configuration, and biological and cytotoxic activity are described. Their structures were assigned by HRMS and NMR spectroscopy. We also describe the first 2D NMR assignment of striatin C. Pyristriatins A and B are the first cyathane natural products featuring a pyridine ring. PMID- 27231732 TI - Higher Dietary Energy Density is Associated with Stunting but not Overweight and Obesity in a Sample of Urban Malaysian Children. AB - Although diets with high energy density are associated with increased risk of overweight and obesity, it is not known whether such diets are associated with undernutrition. This study assessed the relationship between dietary energy density (ED) and nutritional status of 745 urban 1- to 10-year-old children. Dietary intakes were obtained using food recall and record for two days. Dietary energy density was based on food and caloric beverages. Higher dietary ED was associated with lower intakes of carbohydrate, sugar, vitamins C and D, and calcium but higher fat, fiber, iron, and folate intakes. While intakes of fruits and milk/dairy products decreased, meat, fish, and legume intakes increased with higher dietary ED. Stunting, but not other growth problems, was associated with higher dietary ED. Future studies should confirm the cause-and-effect relationship between higher dietary ED and stunting. PMID- 27231733 TI - The physician's associate. PMID- 27231734 TI - Meningococcal W outbreak. PMID- 27231735 TI - Optimising the person-centred management of type 2 diabetes. AB - Type 2 diabetes is increasing in prevalence at a worrying rate and has been exacerbated by the worldwide obesity epidemic. The number of people in the UK diagnosed with type 2 diabetes has soared by 60% in the past 10 years. Type 2 diabetes is a very serious condition, with significant associated risks, and is the leading cause of avoidable macro- and microvascular complications. Health professionals have a key role in enabling and optimising person-centred approaches, educating and augmenting the essential skills every person, whatever his or her individual circumstances, requires for the successful self-management of this lifelong condition. This article reviews approaches to care for the management of hyperglycaemia in type 2 diabetes, which includes optimising person centred targets, promoting individualised care, minimising the risk of complications and promoting education from diagnosis onwards. PMID- 27231736 TI - Improving the patient experience with real-time PICC placement confirmation. AB - Peripherally inserted central catheters (PICCs) are now widely used in health care. The use of ultrasound and the micro introducer set have led to an increase in successful insertion rates. However, malposition can still be a problem. This can lead to delays in treatment, increase in procedure time and repeated chest X rays as well as placement failure. Evolving technologies mean that these challenges can now be overcome. This article describes how a tracking and tip confirmation system (Sherlock 3CG Tip Confirmation System, CR Bard) was used to improve the patient experience during PICC placements by preventing malposition and delays in the start of treatment. Of 88 PICCs placed with the system, all were in an acceptable position when confirmed by chest X-ray and therefore none required any further adjustments post insertion. PMID- 27231738 TI - Mental health: early intervention and prevention in children and young people. AB - It is estimated that 10% of children and young people have mental health problems so significant that they impact not only on their day-to-day life but, if left untreated, they will continue into adulthood. In this article, the author discusses mental health issues affecting children and young people and examines evidence-based early intervention and prevention programmes that have been shown to support better outcomes for children, young people and their families. PMID- 27231737 TI - Dysphagia: warning signs and management. AB - Dysphagia is a condition in which patients have difficulty with some or all parts of the swallowing process. It can lead to penetration of food or drink into the larynx, which can cause aspiration. The prevalence varies but it is thought that 10% of acutely hospitalised elderly patients suffer from dysphagia. There are both obvious and less obvious indicators. Dysphagia is caused by a variety of conditions and can be short term or long term. It affects the patient physically, psychologically and socially. Because nurses spend the most time with patients, they are often the first ones to identify a problem. Therefore, it is sensible for nurses to be trained in how to screen patients for swallowing problems. They can then be referred to speech and language therapists for a formal and thorough assessment. There is a variety of national guidelines available to support health professionals in caring for these patients. PMID- 27231739 TI - Graduate-level entry to nursing: international perspectives. PMID- 27231740 TI - Rating course quality using the National Student Survey. PMID- 27231741 TI - Patient safety: the next 15 years. Part 2. PMID- 27231742 TI - Will the end of bursaries lower student nurse applications to UK universities? PMID- 27231743 TI - New financial arrangements for nursing students. PMID- 27231744 TI - Hitting 'go' on the Five Year Forward View. PMID- 27231745 TI - Translational research and symptom management in oncology nursing. AB - In recent years, translational research (TR) has become a new approach for bridging basic research and clinical practice. This article examines studies in which the authors used TR to learn more about the underlying causes of selected symptoms, and to discuss these results in the context of cancer nursing and symptom management. A literature review was undertaken, plus critical analysis of the authors. TR conducted by cancer nursing scholars has been relatively limited in the past, but is becoming more common as nurses complete additional academic work in the basic sciences and develop research teams with colleagues of those areas of knowledge. The goal in these studies is to show how a set of variables explains differential interventional effects. The availability of TR provides new evidence for the management of symptoms experienced by individuals with cancer, which could lead to improvements in the care of cancer patients across the world. PMID- 27231746 TI - The use of scalp cooling for chemotherapy-induced hair loss. AB - Chemotherapy-induced hair loss is a common and distressing side effect of cancer therapy and is one of the major unmet challenges in cancer management. Scalp cooling can prevent chemotherapy-induced hair loss in some cancer patients with solid tumours receiving certain chemotherapy regimens. Recent evidence indicates that this technique does not increase the risk of scalp metastasis. A reduction in post-chemotherapy infusion duration of scalp cooling and the advancement in cool cap technology may assist clinicians in promoting scalp cooling to cancer patients. This article discusses recent research, scalp cooling guidelines, products available and implications for nurses and their organisations in providing scalp cooling. It also considers recent advancements in identifying genes associated with chemotherapy-induced hair loss and international research collaborations including a registry and a 'chemotherapy-induced hair loss action group'--all striving to improve the patient experience of chemotherapy-induced hair loss. PMID- 27231747 TI - Oncology Nurse of the Year Runner up 2016. PMID- 27231748 TI - Going through revalidation. PMID- 27231749 TI - Working collaboratively for our patients. PMID- 27231751 TI - Structural Characterization of Lecithin-Stabilized Tetracosane Lipid Nanoparticles. Part I: Emulsions. AB - The structure of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)-stabilized colloidal tetracosane emulsions was investigated by photon correlation spectroscopy and small-angle X-ray and neutron scattering, using emulsions with different neutron scattering contrasts. Special emphasis was placed on the structure of the DMPC stabilizer layer covering the emulsion droplets. A monolayer, structurally similar to a half DMPC bilayer, with a thickness of 16 A is found. Thereby, the phosphocholine headgroups arrange flat at the oil-water interface. A deep penetration of the tetracosane oil into the stabilizer layer can be ruled out. PMID- 27231750 TI - Management of opioid-induced constipation. AB - Up to 40% of patients taking opioids develop constipation. Opioid-induced constipation (OIC) may limit the adequate dosing of opioids for pain relief and reduce quality of life. Health professionals must therefore inquire about bowel function in patients receiving opioids. The management of OIC includes carefully re-evaluating the necessity, type and dose of opioids at each visit. Lifestyle modification and alteration of aggravating factors, the use of simple laxatives and, when essential, the addition of newer laxatives or opioid antagonists (naloxone, naloxegol or methylnaltrexone) can be used to treat OIC. This review discusses the recent literature regarding the management of OIC and provides a rational approach to assessing and managing constipation in individuals receiving opioids. PMID- 27231752 TI - Nucleotide-Dependent Bioautocatalytic Timer Reaction. AB - We describe a biochemical timer composed of three biocatalytic reactions involving three types of adenylate nucleotides: adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP). The timer is triggered by a small amount of ATP or ADP. An abrupt increase in the ATP concentration (following numerous amplification cycles) leads to a sudden increase of luminescence from the reaction mixture. The time point when the luminescence appears is found to be a function of the initial concentration of the triggering nucleotide (5.0 * 10(-8)-1.0 * 10(-6) M), even in the presence of a complex biological matrix. The mechanism of the observed dependence of the time of luminescence increase on the concentration has been confirmed with simple kinetic models. Due to the biocompatibility of the proposed trienzymatic reaction scheme (sensitivity to common nucleotides and occurrence in a neutral pH aqueous environment), the scheme can be used in bioengineered systems that require modulation of the response time (light emission) by concentration. PMID- 27231753 TI - A New Approach for Removing Anionic Organic Dyes from Wastewater Based on Electrostatically Driven Assembly. AB - A conceptually new approach for an efficient removal of anionic organic dyes from wastewater using layered double hydroxides (LDHs) through their formation is presented. Acid yellow 25 (AY25) was used as anionic organic dye model molecules. As a result of the electrostatic induction, the removal mechanism involved a concurrent incorporation of AY25 molecules into the interlayer of LDHs during their structural arrangement, where Mg(2+) and Al(3+) ions were utilized to construct the base of LDHs in an alkaline solution. It was found that the molar stoichiometry of all precursors was a key factor affecting the removal efficiency. Within 5 min removal time, this method still maintained high removal efficiency of over 97% and provided a removal capacity of ~186 mg g(-1), comparable to that of other LDH-based methods. Also, almost complete dye recovery was simply achieved by anionic exchange with common anions (Cl(-), NO3(-), and CO3(2-)). Additionally, the present technique is straightforward, cost-effective, and environmentally friendly since it avoids the synthesis step of sorbents, thus significantly saving time, chemicals, and energy. Hence, this strategy not only exhibits the alternative exploitation of LDHs, but also provides new insights into the removal of contaminants from wastewater. PMID- 27231754 TI - Time-Dependent Negative Capacitance Effects in Al2O3/BaTiO3 Bilayers. AB - The negative capacitance (NC) effects in ferroelectric materials have emerged as the possible solution to low-power transistor devices and high-charge-density capacitors. Although the steep switching characteristic (subthreshold swing < sub 60 mV/dec) has been demonstrated in various devices combining the conventional transistors with ferroelectric gates, the actual applications of the NC effects are still some way off owing to the inherent hysteresis problem. This work reinterpreted the hysteretic properties of the NC effects within the time domain and demonstrated that capacitance (charge) boosting could be achieved without the hysteresis from the Al2O3/BaTiO3 bilayer capacitors through short-pulse charging. This work revealed that the hysteresis phenomenon in NC devices originated from the dielectric leakage of the dielectric layer. The suppression of charge injection via the dielectric leakage, which usually takes time, inhibits complete ferroelectric polarization switching during a short pulse time. It was demonstrated that a nonhysteretic NC effect can be achieved only within certain limited time and voltage ranges, but that these are sufficient for critical device applications. PMID- 27231755 TI - Synthesis of Highly Functionalized Triarylbismuthines by Functional Group Manipulation and Use in Palladium- and Copper-Catalyzed Arylation Reactions. AB - Organobismuthines are an attractive class of organometallic reagents that can be accessed from inexpensive and nontoxic bismuth salts. Triarylbismuthines are particularly interesting due to their air and moisture stability and high functional group tolerance. We report herein a detailed study on the preparation of highly functionalized triarylbismuth reagents by triple functional group manipulation and their use in palladium- and copper-catalyzed C-, N-, and O arylation reactions. PMID- 27231757 TI - How has treatment changed for blast phase chronic myeloid leukemia patients in the tyrosine kinase inhibitor era? A review of efficacy and safety. AB - INTRODUCTION: Management of chronic myeloid leukemia (CML) patients in advanced phases of disease has drastically changed since the introduction of tyrosine kinase inhibitors (TKIs) which provide tailored treatment strategies. AREAS COVERED: In this review, efficacy data of different TKIs are reported and reviewed when used as single agent or in combination for the management of blast phase (BP) CML. EXPERT OPINION: Although brilliant results were achieved, the outcome of BP patients did not change when TKIs were used as single agents. Newer strategies of association of TKI with intensified chemotherapy or new agents for different pathways are strongly needed as a bridge to possible allogeneic transplant. PMID- 27231767 TI - Effects of Displacement-Distortion of Potential Energy Surfaces on Nonadiabatic Electron Transfers via Conical Intersections: Application to SO2 and trans-1,3,5 Hexatriene. AB - We show that the time-correlation function formalism can be applied to calculate nonadiabatic electronic population dynamics on the two vibronically coupled diabatic displaced-distorted harmonic potential energy surfaces through conical intersection. We present general formulas for the time-evolved electronic populations at finite temperature with initial sampling from both initial thermal equilibrium and nonequilibrium nuclear distributions. The validity of our formalism is verified through comparison with previous work in a certain limit of our results for case of displaced harmonic oscillator. Finally for illustration, the derived expressions have been applied to determine the electronic population dynamics at conical intersections for SO2 and trans-1,3,5-hexatriene molecules. PMID- 27231768 TI - Different Types of Charged-Inverse Micelles in Nonpolar Media. AB - Over the last few years, the electrodynamics of charged inverse micelles (CIMs) in nonpolar liquids and the generation mechanism and properties of newly generated CIMs have been studied extensively for the model system of polyisobutylene succinimide in dodecane. However, the newly generated CIMs, which accumulate at the electrodes when a continuous voltage is applied, behave differently compared to the regular CIMs present in equilibrium in the absence of a field. In this work, we use transient current measurements to investigate the behavior of the newly generated CIMs when the field is reduced to zero or reversed. We demonstrate that the newly generated CIMs do not participate in the diffuse double layer near the electrode formed by the regular CIMs but form an interface layer at the electrode surface. A fraction of the newly generated negative CIMs can be released from this interface layer when the field there becomes zero. The findings of this study provide a better understanding of fundamental processes in nonpolar liquids and are relevant for applications such as electronic ink displays and liquid toner printing. PMID- 27231786 TI - Electrostatic Embedding To Model the Impact of Environment on Photophysical Properties of Molecular Crystals: A Self-Consistent Charge Adjustment Procedure. AB - A case study of 1,8-dihydroxy-2-napthaldehyde (DHNA)-exhibiting an excited-state intramolecular double proton transfer resulting in photophysical properties sensitive to the surrounding environment-has been used to assess the performance of electrostatic embedding approaches designed to accurately recover the effects of a bulk crystalline environment on calculated photophysical properties. The first approach, based on time-dependent density functional theory (TD-DFT) applied in a QM/QM' scheme, makes use of a background point charge distribution which can accurately reproduce the exact ground-state Ewald potential of the bulk crystal. The second approach seeks to "optimize" these charges in a self consistent manner in order to reproduce the electrostatic field produced by the environment at the excited state. Using these two approaches, both absorption and emission properties of molecular crystals, such as the position and the relative shift in the emission bands in the solid state with respect to solution, can be accurately reproduced. More generally, the results obtained show how these computationally affordable approaches can be used to predict the excited-state behavior of molecules in condensed phases, thus allowing their employment to predict or design new molecular materials with enhanced photophysical properties. PMID- 27231787 TI - Singlet oxygen detection in biological systems: Uses and limitations. AB - The study of singlet oxygen in biological systems is challenging in many ways. Singlet oxygen is a relatively unstable ephemeral molecule, and its properties make it highly reactive with many biomolecules, making it difficult to quantify accurately. Several methods have been developed to study this elusive molecule, but most studies thus far have focused on those conditions that produce relatively large amounts of singlet oxygen. However, the need for more sensitive methods is required as one begins to explore the levels of singlet oxygen required in signaling and regulatory processes. Here we discuss the various methods used in the study of singlet oxygen, and outline their uses and limitations. PMID- 27231789 TI - Got CER? Educating Pharmacists for Practice in the Future: New Tools for New Challenges. AB - BACKGROUND: Understanding how treatments work in the real world and in real patients is an important and complex task. In recent years, comparative effectiveness research (CER) studies have become more available for health care providers to inform evidence-based decision making. There is variability in the strengths and limitations of this new evidence, and researchers and decision makers are faced with challenges when assessing the quality of these new methods and CER studies. OBJECTIVES: To (a) describe an online tool developed by the CER Collaborative, composed of the Academy of Managed Care Pharmacy, the International Society for Pharmacoeconomics and Outcomes Research, and the National Pharmaceutical Council, and (b) provide an early evaluation of the training program impact on learners' self-reported abilities to evaluate and incorporate CER studies into their decision making. METHODS: To encourage greater transparency, consistency, and uniformity in the development and assessment of CER studies, the CER Collaborative developed an online tool to assist researchers, new and experienced clinicians, and decision makers in producing and evaluating CER studies. A training program that supports the use of the online tool was developed to improve the ability and confidence of individuals to apply CER study findings in their daily work. Seventy-one health care professionals enrolled in 3 separate cohorts for the training program. Upon completion, learners assessed their abilities to interpret and apply findings from CER studies by completing on online evaluation questionnaire. RESULTS: The first 3 cohorts of learners to complete the training program consisted of 71 current and future health care practitioners and researchers. At completion, learners indicated high confidence in their CER evidence assessment abilities (mean = 4.2). Learners reported a 27.43%-59.86% improvement in capabilities to evaluate various CER studies and identify study design flaws (mean evaluation before CER Certificate Program [CCP] scores = 1.86-3.14 and post-CCP scores = 3.92-4.24). Additionally, 63% of learners indicated that they expected to increase their use of evidence from CER studies in at least 1-2 problem decisions per month. CONCLUSIONS: The CER Collaborative has responded to the need for increased practitioner training to improve understanding and application of new CER studies. The CER Collaborative tool and certificate training program are innovative solutions to help decision makers meet the challenges they face in honing their skills to best incorporate credible and relevant CER evidence into their decision making. DISCLOSURES: The CER Collaborative, the development of the questionnaires and web-based tool, and the development of the CER Certificate Program were supported by grants and in-kind contributions from the Academy of Managed Care Pharmacy (AMCP), the International Society for Pharmacoeconomics and Outcomes Research (ISPOR), and the National Pharmaceutical Council (NPC). The University of Maryland School of Pharmacy conducted its work under a contract with the AMCP Foundation and grant funding from the NPC. Perfetto is employed by the University of Maryland and the National Health Council and serves as assistant editor for the Journal of Managed Care & Specialty Pharmacy, consults for Avelere, and serves as a member of advisory boards for the PQA and CMTP. Pickering received support from the NPC for activities related to this research. Eichelberger is employed by the Academy of Managed Care Pharmacy. Eichelberger and Graff are with the CER Collaborative. Graff is employed by the National Pharmaceutical Council. Study concept and design were primarily contributed by Perfetto, Graff, and Eichelberger, along with Anyanwu and assisted by Pickering and Ward Zaghab. Pickering and Ward Zaghab took the lead in data collection, with assistance from the other authors, and data interpretation was performed by Perfetto, Graff, Pickering, and Ward Zaghab, with assistance from the other authors. The manuscript was written by Perfetto and Anyanwu, with assistance from the other authors, and revised by Graff, Perfetto, Anyanwu, and Pickering, assisted by Eichelberger and Ward Zaghab. PMID- 27231791 TI - Sequential Therapies and the Cost-Effectiveness of Treating Metastatic Colon Cancer Patients. AB - BACKGROUND: Technological advances in colon cancer treatment have significantly increased survival outcomes among metastatic patients. With different chemotherapy and biologic regimens administered in first, second, and subsequent lines of treatments, costs and survival outcomes vary considerably. However, there is little evidence on how the type of regime administered in the first line of treatment affects the costs and survival outcomes of the second line of treatment. OBJECTIVE: To examine how the cost-effectiveness of second-line treatment for elderly metastatic colon cancer patients varies by the type of regimen administered in the first line of treatment. METHODS: The Surveillance, Epidemiology and End Results (SEER) cancer registry was used, which is linked with the Medicare claims database, to study elderly metastatic patients diagnosed between 2003 and 2009. Average survivals are estimated using the robust nonparametric Kaplan-Meier method. Selection bias was adjusted for using inverse probability weighting and censoring using robust nonparametric methods of estimating the average of total health care costs. RESULTS: Mean incremental survival was 6.7 months for patients who received second-line treatment (95% CI = 5.7-7.7) compared with those receiving only first-line treatment. However, the mean incremental survival varied between 4 months (95% CI = 0.0-7.3) and 9 months (95% CI = 6.5-11.0) depending on whether fluorouracil with or without leucovorin, irinotecan, oxaliplatin, or other agents were administered in first-line treatment. The mean incremental cost associated with receipt of second-line treatment was $60,231 (95% CI = 52,461-64,198) but ranged between $55,368 (95% CI = 48,294-61,290) and $71,211 (95% CI = 43,168-99,667), depending on the type of regimen administered in the first-line treatment. Combining survival benefits and costs, the incremental cost-effectiveness ratios per life-year gained associated with the receipt of second-line treatment were $97,368 (95% CI = 80,415-117,965); $110,621 (95% CI = 89,560-133,961); $130,689 (95% CI = 101,459-171,918); and $247,951 (95% CI = 112,629808,976) when irinotican, fluorouracil/leucovorin, oxaliplatin, and "other" combinations were, respectively, administered in first line treatment. In addition, the results varied depending on which statistical method was used. CONCLUSIONS: When therapies are administered in a sequential manner, the cost-effectiveness of the second line of therapy depends on what was administered in the first line of therapy. DISCLOSURES: Bayer Healthcare Pharmaceuticals provided funding for this project. Onukwugha has received research funding from Bayer and Amgen and has a consultant/advisory relationship with Jansen Analytics at Johnson & Johnson. Seal was formerly an employee of Bayer and holds stock in Bayer. Mullins has research funding sponsored by Bayer and Pfizer and has a consultant/advisory relationship with Bayer, Amgen, BMS, Genentech, GSK, Novartis, NovoNordisk, and Pfizer. Woldemichael and Nader report no conflicts of interest. All authors contributed to the concept and design of this study. Onukwugha, Seal, and Mullins collected the data, with assistance from Woldemichael and Hanna, while Woldemichael interpreted the data, assisted by the other authors. The manuscript was written primarily by Woldemichael, with assistance from the other authors, and revised by Seal, Hanna, and Mullins, with assistance from Woldemichael and Onukwugha. PMID- 27231790 TI - Ability and Use of Comparative Effectiveness Research by P&T Committee Members and Support Staff: A 1-Year Follow-up. AB - BACKGROUND: In recent years, comparative effectiveness tools and methods have evolved to assist health care decision makers in identifying optimal therapies. In-person training programs on comparative effectiveness research may be helpful in understanding and applying this information. OBJECTIVE: To provide a follow-up assessment of the use of comparative effectiveness research (CER) in the pharmacy and therapeutics (P&T) committee decision-making process, using information collected from participants 1 year after attending a live continuing education program, in which participants were taught about CER designs and how to access available CER resources through the Agency for Healthcare Research and Quality (AHRQ) Effective Health Care (EHC) Program. METHODS: A retrospective, cross sectional questionnaire was developed and mailed to 2 groups of individuals: CER workshop attendees and interested nonattendees (expressing an interest in attending a workshop but did not attend for unknown reasons). The questionnaire asked respondents to indicate personal and organizational use of CER in the decision-making process. Participants were asked to indicate whether their knowledge, ability, and use of CER studies increased since participating in the program. Data were analyzed using nonparametric tests to compare the responses of attendees and nonattendees, as well as overall reliability of the instrument. RESULTS: A total of 164 respondents completed the questionnaire (63 attendees and 101 nonattendees; overall response rate = 44%). The majority of respondents were pharmacists (n = 157, 95.7%) and were affiliated with a hospital (n = 106, 64.6%). Proportions of attendees and nonattendees differed significantly in the use of EHC research reviews/reports (45% and 28%, respectively; P = 0.02) and EHC executive summaries of research reviews/reports (48% and 29%, respectively; P = 0.01). At 1-year follow-up, the majority of attendees reported an increase ("somewhat" or "very much") in knowledge of CER (91.5%), ability to use CER (83.0%), and use of CER studies (58.7%). CONCLUSIONS: Health professionals attending a continuing education CER program reported higher use of EHC CER materials compared with nonattendees. Additionally, attendees reported increased use of CER in clinical decision making. A continuing education program such as this may provide an effective avenue for introducing CER methods and resources to the P&T committee and clinical decision-making processes. DISCLOSURES: This project was supported by grant number R18HS019220 from the Agency of Healthcare Research and Quality. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency of Healthcare Research and Quality. Augustine has stock in Pfizer. The authors declared no other potential conflicts of interest associated with this study. Study concept and design were primarily contributed by Malone, along with Warholak, Hines, Brown, Hurwitz, and Taylor. Warholak, Hines, Brown, Hurwitz, and Taylor collected the data, assisted by Malone, Brixner, Cobaugh, and Schlaifer. Data interpretation was performed by Malone and Augustine, with assistance from the other authors. The manuscript was written primarily by Augustine, with assistance from Malone, Sun, Warholak, Hines, Brown, Hurwitz, and Taylor. Malone revised the manuscript, assisted by Warholak, Hines, Brown, Hurwitz, Taylor, Brixner, Cobaugh, and Schlaifer. PMID- 27231792 TI - A Systematic Review of PCSK9 Inhibitors Alirocumab and Evolocumab. AB - BACKGROUND: The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a new class of cholesterol-lowering medications that provide significant reductions in lipids but at a large cost relative to statins. With 2 such drugs now on the market, alirocumab and evolocumab, comparing the evidence base for these drugs is necessary for informed decision making. OBJECTIVE: To compare the benefits and harms of the PCSK9 inhibitors alirocumab and evolocumab. METHODS: The databases Ovid MEDLINE, Cochrane Library, SCOPUS, and ClinicalTrials.gov were used to search for randomized controlled trials of alirocumab or evolocumab with any relevant comparator reporting health outcomes, lipid outcomes, or harms through September 2015, and information was requested from manufacturers. Results were reviewed according to standard review methods. RESULTS: The database searches revealed 17 fair- and good-quality trials; however, none had primary health outcomes or directly compared PCSK9 inhibitors. Alirocumab (75 mg to 150 mg subcutaneously every 2 weeks) resulted in significantly greater reductions in low-density lipoprotein cholesterol (LDL-C; -8% to -67%) at 12-24 weeks in patients with (a) heterozygous familial hypercholesterolemia and (b) patients at high or varied cardiovascular (CV) risk who were not at LDL-C goals with statin therapy. The highest strength evidence was for patients with high CV risk not at LDL-C goals. Alirocumab also resulted in high-density lipoprotein cholesterol (HDL-C) increases of 6%-12%. Low- and moderate-strength evidence for adjudicated CV events at 52-78 weeks for a priori analyses indicated no benefit. Low- and moderate-strength evidence also found no differences in harms except possibly slightly more injection-site reactions. Evolocumab (120 mg subcutaneously every 2 weeks to 420 mg every 4 weeks) resulted in significantly greater reductions in LDL-C (-32% to -71%) at 12-52 weeks in patients with heterozygous or homozygous familial hypercholesterolemia, patients intolerant of statins, and patients with varied CV risk not at LDL-C goal with statin therapy. The highest strength evidence was for heterozygous familial hypercholesterolemia and patients not at LDL-C goals. Moderate-strength evidence showed HDL-C increases in the range of 4.5%-6.8%. Harms were not different between groups, except possibly slightly greater overall adverse event reporting. Evidence on adjudicated CV outcomes was insufficient to draw conclusions because of sparseness of events, study limitations, and inability to assess consistency of findings. CONCLUSIONS: Alirocumab and evolocumab have evidence of large improvements in lipid levels. The strength of the evidence is greater for alirocumab than evolocumab in patients with high CV risk who were not at LDL-C target goals, while evidence for evolocumab is stronger in patients with heterogeneous familial hypercholesterolemia and patients with varied CV risk who were not at LDL-C target goals. Evidence on adjudicated CV outcomes for a priori analyses is unable to show benefit for alirocumab and is insufficient to draw conclusions for evolocumab. Important questions remain about the comparative effects on long-term health outcomes. DISCLOSURES: This project was funded by The Drug Effectiveness Review Project. Project participants reviewed the manuscript but had no role in conducting the work or writing the manuscript. Any comments received from the participants during the course of the review were taken at the discretion of the authors independently. All authors had access to the data and a role in writing the manuscript. McDonagh, Peterson, and Holzhammer declare no conflict of interest or financial interest in any therapy discussed in this article. Fazio declares receiving compensation from Sanofi for a presentation on his science to a group of their advisors and has served as a consultant to MSD, BASF, NHP, Sanofi, Ionis Pharmaceuticals, and Kowa. Study concept and design were primarily contributed by McDonagh, along with Peterson and Holzhammer, with assistance from Fazio. Holzhammer took the lead in data collection, with assistance from McDonagh and Peterson. Data interpretation was performed by McDonagh, Peterson, and Fazio. The manuscript was written by McDonagh, Peterson, and Fazio, with assistance from Holzhammer, and revised by all the authors. PMID- 27231793 TI - Cost-Effectiveness of Ivermectin 1% Cream in Adults with Papulopustular Rosacea in the United States. AB - BACKGROUND: Papulopustular rosacea is a chronic skin disease involving central facial erythema in combination with papules and pustules. Papulopustular rosacea is treated with topical, systemic, or a combination of topical and systemic therapies. Currently approved topical therapies include azelaic acid gel/cream/foam twice daily (BID) and metronidazole cream/gel/lotion BID. Ivermectin 1% cream once daily (QD) is a new topical agent for the treatment of papulopustular rosacea that has been approved for the management of inflammatory lesions of rosacea and offers an alternative to current treatments. OBJECTIVE: To evaluate the cost-effectiveness of ivermectin 1% cream QD compared with current topical treatments in order to understand the cost of adding ivermectin as a treatment option that would bring additional clinical benefit for adults with papulopustular rosacea in the United States. METHODS: The cost-effectiveness of ivermectin 1% cream QD was compared with metronidazole 0.75% cream BID and azelaic acid 15% gel BID for adults in the United States with moderate-to-severe papulopustular rosacea using a Markov cohort state transition structure with 2 mutually exclusive health states (rosacea and no rosacea) and 5 phases. Patients could succeed or fail to respond to treatment and experience a relapse after treatment success. The model took a health care payer perspective (direct medical costs of topical and/or systemic therapy plus health care costs for physician and specialist visits) and used a 3-year time horizon. The model was run for a cohort of 1,000 patients. Costs (2014 U.S. dollars) and benefits (disease-free days and quality-adjusted life-years [QALYs]) were discounted at a rate of 3% per annum. Cost-effectiveness was determined by the incremental cost-effectiveness ratio (ICER) and measured in terms of incremental cost per QALY gained (estimated from health state utilities for patients with and without rosacea). Univariate and probabilistic sensitivity analyses (PSA) were conducted to assess the robustness of model outcomes. RESULTS: Compared with metronidazole 0.75% cream BID, ivermectin 1% cream QD was associated with higher costs but provided greater clinical benefit, with an ICER of $13,211 per QALY gained. For a cohort of 1,000 patients, ivermectin 1% cream QD provided an additional 72,922 disease-free days (200 years) over a 3-year period compared with metronidazole 0.75% cream BID, leading to a lower cost per disease-free day for ivermectin 1% cream QD ($4.54) compared with metronidazole 0.75% cream BID ($4.85). Ivermectin 1% cream QD was associated with lower total costs and greater clinical benefit compared with azelaic acid 15% gel BID at year 3 and dominated this treatment. After 3 years, ivermectin 1% cream QD was associated with the lowest health care costs ($62,767 compared with $73,284 for metronidazole 0.75% cream BID and $77,208 for azelaic acid 15% gel BID), reflecting a 15% reduction in physician visit costs, when compared with metronidazole 0.75% cream BID, and almost a 20% reduction, when compared with azelaic acid 15% gel BID. The univariate sensitivity analyses indicated that the results are sensitive to the time horizon selected: the longer the time horizon, the more beneficial the results for ivermectin 1% cream QD relative to the comparators, although even at 1 year, ivermectin 1% cream QD dominated azelaic acid 15% gel BID. The PSA suggested that ivermectin 1% cream QD was the most likely treatment to be cost-effective at a willingness-to-pay threshold of $15,000 and above. CONCLUSIONS: Ivermectin 1% cream QD had favorable incremental cost-effectiveness when compared with metronidazole 0.75% cream BID and dominated azelaic acid 15% gel BID in the treatment of papulopustular rosacea in the United States. Therefore, ivermectin 1% cream QD may be a good first-line treatment for papulopustular rosacea, providing additional clinical benefit at no or low additional cost. DISCLOSURES: This study was sponsored by Galderma Laboratories. The sponsor was involved in the design of the model structure but not in the collection of the data used to populate the model. Manuscript preparation was also funded by Galderma. Taieb is an investigator and advisor for Galderma. Gold is an investigator for Galderma. Feldman is a consultant and speaker for Galderma and has received grants from Galderma. Dansk and Bertranou received a research grant from Galderma to conduct this study. Dansk and Bertranou contributed to the design of the model structure, the sourcing and inputting of the data, and the interpretation of the results. Taieb, Feldman, and Gold contributed to the interpretation of the results. All authors reviewed draft versions of the manuscript and gave permission for the submission of the final version. PMID- 27231794 TI - Comparative Assessment of Medical Resource Use and Costs Associated with Patients with Symptomatic Peripheral Artery Disease in the United States. AB - BACKGROUND: There is growing concern about appropriate disease management for peripheral artery disease (PAD) because of the rapidly expanding population at risk for PAD and the high burden of illness associated with symptomatic PAD. A better understanding of the potential economic impact of symptomatic PAD relative to a matched control population may help improve care management for these patients. OBJECTIVE: To compare the medical resource utilization, costs, and medication use for patients with symptomatic PAD relative to a matched control population. METHODS: In this retrospective longitudinal analysis, the index date was the earliest date of a symptomatic PAD record (symptomatic PAD cohort) or any medical record (control cohort), and a period of 1 year pre-index and 3 years post-index was the study time frame. Symptomatic PAD patients and control patients (aged >= 18 years) enrolled in the MarketScan Commercial and Encounters database from January 1, 2006, to June 30, 2010, were identified. Symptomatic PAD was defined as having evidence of intermittent claudication (IC) and/or acute critical limb ischemia requiring medical intervention. Symptomatic PAD patients were selected using an algorithm comprising a combination of PAD-related ICD-9-CM diagnostic and diagnosis-related group codes, peripheral revascularization CPT-4 procedure codes, and IC medication National Drug Code numbers. Patients with stroke/transient ischemic attack, bleeding complications, or contraindications to antiplatelet therapy were excluded from the symptomatic PAD group but not the control group. A final 1:1 symptomatic PAD to control population with an exact match based on age, sex, index year, and Charlson Comorbidity Index (CCI) was identified. Descriptive statistics comparing patient demographics, comorbidities, medical resource utilization, cost, and medication use outcomes were generated. Generalized linear models were developed to compare the outcomes while controlling for residual difference in demographics, comorbidities, pre-index resource use, and pre-index costs. RESULTS: 3,965 symptomatic PAD and 3,965 control patients were matched. In both cohorts, 54.7% were male, with a mean age (SD) of 69.0 (12.9) years and a CCI score of 1.3 (0.9). Symptomatic PAD patients had more cardiovascular comorbidities than control patients (27.7% vs. 12.6% coronary artery disease, 27.1% vs. 15.9% hyperlipidemia, and 49.8% vs. 28.2% hypertension) in the pre-index period. Post-index rates of ischemic stroke, non ST segment elevation myocardial infarction, unstable angina, and cardiovascular- or PAD-related procedures (limb amputations, endovascular procedures, open surgical procedures, percutaneous coronary intervention, and coronary artery bypass graft) were higher among symptomatic PAD patients versus control patients. All-cause annualized inpatient admissions (0.46 vs. 0.22 admissions), emergency department/urgent care days (0.27 vs. 0.22 days), and office visit days (12.5 vs. 10.2 days) were higher among symptomatic PAD versus control patients post-index. Annualized all-cause inpatient costs ($8,494 vs. $3,778); outpatient costs ($8,459 vs. $5,692); and total costs ($20,880 vs. $12,501) were higher among symptomatic PAD versus control patients post-index. Only 17.8% of symptomatic PAD patients versus 6.6% of control patients were on clopidogrel pre-index. In the post-index period, clopidogrel prescriptions in the symptomatic PAD population increased to 38.0%. Results were consistent in the regression models with the symptomatic PAD population having a higher number of all-cause post-index inpatient admissions, emergency department/urgent care days, office visit days, inpatient costs, outpatient costs, and total costs versus control patients (P <= 0.026). CONCLUSIONS: Symptomatic PAD patients have significantly higher medical resource use and costs when compared with a matched control population. As the prevalence of symptomatic PAD increases, there will be a significant impact on the population and health care system. The rates of use of evidence-based secondary prevention therapies, such as antiplatelet medication, were low. Therefore, greater effort must be made to increase utilization rates of appropriate treatments to determine if the negative economic and clinical impacts of symptomatic PAD can be minimized. DISCLOSURES: This study was funded by Merck & Co., Kenilworth, New Jersey. Chase and Heithoff are employees of Merck & Co., Kenilworth, New Jersey, and Upper Gwynedd, Pennsylvania. Friedman and Navaratnam are paid consultants for Merck & Co. Simpson is a paid consultant for Merck, Pfizer, and Amgen and has received speaker's fees from Merck and Pfizer. Study concept and design were contributed by Chase, Navaratnam, and Heilhoff, along with Simpson and Friedman. Friedman collected the data, which was interpreted by Simpson and Navaratnam, along with Friedman. The manuscript was written by Navaratnam and Friedman, along with Chase, Heilhoff and Simpson, and revised by all of the authors. PMID- 27231795 TI - Pillbox Use and INR Stability in a Prospective Cohort of New Warfarin Users. AB - BACKGROUND: Warfarin, a frequently prescribed oral anticoagulant, is well known for its narrow therapeutic index. Adherence to warfarin may help to achieve a stable international normalized ratio (INR), but little data are available regarding the impact of using a pillbox as a potential adherence aid device. OBJECTIVE: To evaluate the association between pillbox use and time in therapeutic range (TTR) < 60% and INR instability pattern. METHODS: This study was based on a prospective cohort of 1,069 new warfarin users who initiated warfarin between May 2010 and July 2013 within 17 hospitals in Quebec, Canada. Demographic, lifestyle, and clinical data were collected for 3 months to a year after warfarin initiation, and genetic factors were assessed. Patients usingh self-prepared and pharmacist-prepared pillboxes were compared with nonusers for the 3- to 12-month follow-up period. The primary outcome was a TTR < 60%, which represents a low percentage of time in the INR therapeutic range or an unstable patient. The secondary outcome was the INR instability pattern (unstable below range; unstable over range; unstable with erratic pattern; and stable) to better describe patient INR profiles. A multivariate generalized linear mixed model was used for the primary outcome, along with a multivariate multinomial linear mixed model for the secondary outcome. RESULTS: The cohort included patients with a mean age of 70.4 +/- 11.7 years; 61.8% of patients were men; 76.3% had atrial fibrillation as warfarin's primary indication; and 35.6% had a previous history of myocardial infarction or angina. Self-prepared and pharmacist-prepared pillbox use was not associated with TTR < 60% or a specific INR instability pattern. A sensitivity analysis showed that self-prepared pillbox users had a higher TTR than nonusers (3.55% +/- 1.69%; P = 0.036). This effect was greater among patients aged < 70 years (5.48% +/- 2.50%; P = 0.029) than among older patients (1.92% +/- 2.31%; P =0.406). CONCLUSIONS: Pillbox use was not associated with TTR < 60% or a specific INR instability pattern. The impact of self-prepared pillbox use was greater among younger patients, but results were not clinically significant. Future studies adjusting for concomitant drug use are needed to clarify these results. DISCLOSURES: This study was funded by Canadian Institutes of Health Research (CIHR) and the Centre for Excellence in Personalised Medicine. Both funding sources were not involved in the design, conduct, and reporting of this study. The data used for this study came from the Quebec Warfarin Cohort Study (QWCS), which was supported by the CIHR and the Centre for Excellence in Personalised Medicine. Dumas received a doctoral training award from the CIHR. Perreault and Dube received a salary award from the Fonds Quebecois de Recherche en Sante. Study concept and design were contributed by Talajic, Tardif, Dube, and Perreault. Dumas, Rouleau-Mailloux, Bouchama, and Lahcene collected the data, which was interpreted by Dumas, Dube, and Perreault. The manuscript was written and revised by Dumas, Dube, and Perreault. PMID- 27231796 TI - Patterns of Statin Use in a Real-World Population of Patients at High Cardiovascular Risk. AB - BACKGROUND: Widespread use of statins has improved hypercholesterolemia management, yet a significant proportion of patients remain at risk for cardiovascular (CV) events. Analyses of treatment patterns reveal inadequate intensity and duration of statin therapy among patients with hypercholesterolemia, and little is known about real-world statin use, specifically in subgroups of patients at high risk for CV events. OBJECTIVE: To examine patterns of statin use and outcomes among patients with high-risk features who newly initiated statin monotherapy. METHODS: Adult patients (aged > 18 years) at high CV risk who received > 1 prescription for statin monotherapy and who had not received lipid-modifying therapy during the previous 12 months were identified from the Truven MarketScan Commercial and Medicare Supplemental databases (from January 2007 to June 2013). Patients with atherosclerotic cardiovascular disease (ASCVD) or diabetes were hierarchically classified into 5 mutually exclusive CV risk categories (listed here in order from highest to lowest risk): (1) recent CV event (subcategorized by hospitalization for acute coronary syndrome [ACS] or other non-ACS CV event within 90 days of index); (2) coronary heart disease (CHD); (3) history of ischemic stroke; (4) peripheral artery disease (PAD); and (5) diabetes. Outcomes of interest included changes in therapy, proportion of days covered (PDC), time to discontinuation, and proportion of patients with ASCVD-related inpatient visit during the follow-up period. Statin therapy was subdivided into high-intensity treatment (atorvastatin 40 mg or 80 mg, rosuvastatin 20 mg or 40 mg, or simvastatin 80 mg) or moderate- to low-intensity treatment (all other statins and statin dosing regimens). Follow up data were obtained from the index date (statin initiation) until the end of continuous enrollment. RESULTS: A total of 541,221 patients were included in the analysis. The majority of patients were stratified in the diabetes cohort (61.1%), followed in frequency by recent ACS event (15.8%), recent non-ACS CV event (9.9%), PAD (4.7%), CHD (4.4%), and history of ischemic stroke (4.1%). Only 15.0% of the population initiated therapy with a high-intensity statin, and 22.5% of these high-intensity statin initiators switched to a moderate- to low intensity regimen during the follow-up period. Median time to statin discontinuation was approximately 15 months. Duration of treatment was longer among those who were treated with a high-intensity versus a moderate- to low intensity statin regimen (21 and 15 months, respectively). The PDC was highest in the recent ACS hospitalization cohort (66.4%) and lowest in the diabetes cohort (55.5%). The PDC was significantly greater among patients who initiated treatment with a high-intensity statin regimen than with a moderate- to low-intensity statin regimen (62.1% vs. 57.5%, respectively; P< 0.001). At 1 year, Kaplan-Meier estimates of the cumulative rates for ASCVD-related hospitalizations ranged from 3.5% (diabetes) to 21.8% (recent ACS hospitalization). CONCLUSIONS: Patients at high risk for CV events are suboptimally dosed with statins, have high rates of discontinuation, and have low rates of adherence. Despite the use of statin therapy, ASCVD-related inpatient visit rates were high, particularly among those patients at highest risk because of a recent ACS hospitalization. Future interventions are required to ensure that high-risk patients are effectively managed to reduce subsequent morbidity and mortality. DISCLOSURES: Support for this research was provided by Regeneron Pharmaceuticals, Tarrytown, New York, and Sanofi US, Bridgewater, New Jersey. Menzin and Lin are employees of Boston Health Economics, which received consulting fees from Sanofi. Friedman is a consultant to Boston Health Economics. Lin, Friedman, and Menzin have received research support from Sanofi US. Sung, Mallya, Panaccio, and Koren are employees of Sanofi US and also have ownership interest in Sanofi US. Sanchez is an employee of and has ownership interest in Regeneron Pharmaceuticals. Neumann has served on advisory boards for Merck & Co, Takeda Pharmaceutical Company, Genentech, Novartis, Bayer AG, UCB, Sanofi US, Robert Wood Johnson Foundation, and Cubist and serves as consultant for Boston Health Economics, Forrest, P urdue, and Smith and Nephew. This research has been presented in part at the International Society for Pharmacoeconomics and Outcomes Research, 20th Annual International Meeting, May 16-20, 2015, Philadelphia, Pennsylvania. All authors contributed to the study design, protocol development, and results interpretation. Lin and Menzin were responsible for conducting the study analyses. All authors were involved in manuscript development and approved the submitted version. PMID- 27231797 TI - A Systematic Review of Evidence-Based Community Pharmacy Services Aimed at the Prevention of Cardiovascular Disease. AB - BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death worldwide and has a substantial impact on people's health and quality of life. CVD also causes an increased use of health care resources and services, representing a significant proportion of health care expenditure. Integrating evidence-based community pharmacy services is seen as an asset to reduce the burden of CVD on individuals and the health care system. OBJECTIVES: To (a) identify community pharmacy evidence-based services designed to help prevent CVD and (b) provide fundamental information that is needed to assess their potential adaptation to other community pharmacy settings. METHODS: This review used the DEPICT database, which includes 488 randomized controlled trials (RCT) that address the evaluation of pharmacy services. Articles reviewing these RCTs were identified for the DEPICT database through a systematic search of the following databases: MEDLINE, Scopus, SciELO (Scientific Electronic Library Online), and DOAJ (Directory of Open Access Journals). The DEPICT database was reviewed to identify evidence based services delivered in the community pharmacy setting with the purpose of preventing CVD. An evidence-based service was defined as a service that has been shown to have a positive effect (compared with usual care) in a high-quality RCT. From each evidence-based service, fundamental information was retrieved to facilitate adaptation to other community pharmacy settings. RESULTS: From the DEPICT database, 14 evidence-based community pharmacy services that addressed the prevention of CVD were identified. All services, except 1, targeted populations with a mean age above 60 years. Pharmacy services encompassed a wide range of practical applications or techniques that can be classified into 3 groups: activities directed at patients, activities directed at health care professionals, and assessments to gather patient-related information in order to support the previous activities. CONCLUSIONS: This review provides pharmacy service planners and policymakers with a comprehensive list of evidence-based services that have the potential to be adapted to different settings from which they were originally implemented and evaluated in order to reduce the burden of CVD. DISCLOSURES: Funding for this review was provided by the University of Technology Sydney Chancellor's Postdoctoral Fellowship awarded to Sabater Hernandez. No other potential conflict of interest was declared. Study concept and design were contributed by Sabater-Hernandez, Fernandez-Llimos, Rotta, and Correr. Sabater-Galindo and Sabater-Hernandez took the lead in data collection, along with Franco-Trigo and Rotta. Data interpretation was performed by Sabater Hernandez, Durks, and Lopes. The manuscript was written primarily by Sabater Hernandez, along with Hossain, and revised by Fernandez-Llimos, Rotta, and Benrimoj, with assistance from Durks, Sabater-Galindo, Franco-Trigo, and Correr. PMID- 27231798 TI - Access to New Medications for Hepatitis C for Medicaid Members: A Retrospective Cohort Study. AB - BACKGROUND: Sofosbuvir (SOF)- or simeprevir (SIM)-containing regimens are highly effective for treating chronic hepatitis C virus (HCV) infection. These regimens, however, are expensive. Most payers have implemented prior authorization (PA) requirements to ensure that patients who can benefit most have priority for these medications. While many Medicaid programs limit access to those with advanced disease or to members who do not have active substance use disorder (SUD), the Massachusetts Medicaid (MassHealth) Primary Care Clinician (PCC) plan does not limit access based on disease severity or presence of SUD. Evaluating PA requests for SOF and/or SIM among MassHealth members will offer a useful example of early uptake among Medicaid members and will identify patient groups who might face barriers to treatment at the provider or patient level. OBJECTIVES: To (a) evaluate the percentage of MassHealth PCC members with HCV who had a PA request, along with the percentage of requests approved, and (b) identify characteristics associated with PA requests for SOF or SIM among Massachusetts Medicaid (MassHealth) members with HCV. METHODS: This retrospective cohort study used enrollment, medical claims, and PA request data from MassHealth PCC members from December 6, 2012, to July 31, 2014. The sample included members with 1 or more claims with an ICD-9-CM code for HCV during this time who were continuously enrolled from December 6, 2013, to July 31, 2014. Enrollment and medical claims data for the cohort with HCV were linked to a database containing information collected from PA requests. The overall percentage of members with HCV and a PA request for SOF and/or SIM between December 6, 2013, and July 31, 2014, and the percentage of requests approved were calculated. Chi-square statistics were used to compare demographic and clinical characteristics among members with HCV who did and did not have a request. Logistic regression was used to estimate the strength of associations between patient characteristics and a PA treatment request, adjusting for clinical and demographic variables. RESULTS: Of 6,849 members identified with HCV, 346 (5.1%) had a PA request for SOF and/or SIM submitted to MassHealth. Compared with members with HCV who did not have a PA request for SOF or SIM, those with a PA request for these new treatments were more likely to be male (P = 0.01), older (P < 0.001), white race (P = 0.04), have standard MassHealth insurance (P = 0.01), and less likely to be homeless (P < 0.001). Members with a PA request were also more likely to have been treated for HCV in the past year and have advanced disease (hepatic decompensation, cirrhosis, or liver transplant) but less likely to have SUD (P < 0.001 for each). Ninety percent of requests for SOF or SIM were approved; few demographic or clinical characteristics were associated with approval. In adjusted analyses, predictors of PA request were aged 50-64 years (odds ratio (OR) = 2.0, 95% CI = 1.1-3.7 vs. aged < 30 years); hepatic decompensation (OR = 1.6, 95% CI = 1.2 2.3); cirrhosis (OR = 3.0, 95% CI = 2.2-4.1); liver transplant (OR = 3.0, 95% CI = 1.4-6.5); substance use (OR = 0.6, 95% CI = 0.5-0.8); recent HCV treatment (OR = 1.6, 95% CI = 1.0-2.6); comorbidity (OR = 0.95, 95% CI = 0.91-0.98) for 1-unit increase in Diagnostic Cost Group score; and care at a hospital outpatient department (OR = 2.0, 95% CI = 1.2-3.2 vs. group practice). CONCLUSIONS: Antiviral treatment with SOF and/or SIM was requested for a relatively small proportion of MassHealth members with HCV, with nearly all approved. Prescriber prioritization or patient barriers to care, rather than the PA process, determined access to treatment in this Medicaid population. Support may be needed to ensure patients with SUD benefit from advances in HCV treatment. DISCLOSURES: No outside funding supported this research. Internal funding was provided by the Commonwealth of Massachusetts. Lavitas has received compensation from University of Tennessee Advanced Studies in Medicine for development of CPE activity. Graham has consulted for the National Viral Hepatitis Roundtable and the Department of Health and Human Services, has received payment from Medscape for CME development, and is employed by Trek Therapeutics. Jeffrey has received payment for guest lectures at Boston University and Harvard University. Study concept and design were primarily contributed by Clark and Clements, along with Graham, Lenz, and Jeffrey. Kunte collected the data, which were interpreted by Graham, Lenz, and Jeffrey, with assistance from Lavitas, Clark, and Clements. The manuscript was written primarily by Clements, along with O'Connell and assisted by Graham, and revised by all the authors. PMID- 27231799 TI - Real-World Axitinib Use in the United States: A Retrospective Study Using Linked Datasets. AB - BACKGROUND: Axitinib is approved by the FDA for the treatment of advanced renal cell carcinoma (RCC) after failure of 1 previous systemic therapy and is distributed primarily through specialty pharmacies. Although the efficacy and safety of axitinib have been established in clinical trials, information from real-world populations will help to elucidate patients' clinical profiles and utilization patterns. Prescription records alone provide limited information on patient characteristics and other treatment experiences. Expansion of these data with information from medical claims databases should yield observational real world data that may help to optimize therapy for patients with advanced RCC. OBJECTIVE: To link information from a specialty pharmacy database with information from medical and pharmacy claims databases to characterize real-world treatment patterns of axitinib as subsequent systemic therapy in patients with RCC in the United States. METHODS: This retrospective, observational, cohort study linked de-identified patient-level data from 22 specialty pharmacies that dispense axitinib with databases of longitudinal medical and pharmacy claims. Eligible patients had a diagnosis of RCC (> 1 claim for RCC defined as ICD-9-CM code 189.0), previously received > 1 systemic therapy, had the first prescription for axitinib dispensed between May 2012 and April 2013 (index), and had consistent claims reporting by pharmacies and physicians. All treatment data were used to calculate cycle, line of therapy, and duration of therapy; prescription data were used to determine axitinib dose modifications. Multivariate and logistic regression analyses were conducted to assess the effect of patient/prescriber characteristics on duration of axitinib therapy and dose modifications, respectively. RESULTS: In all, 1,175 patients met the study inclusion criteria and had data present in specialty pharmacy and claims databases. Most patients (74%) were male, and 68% were aged 55-74 years. Mean (SD) Charlson Comorbidity Index score was 2.7 (+/- 1.1); the most common comorbidity was hypertension (in 199 patients, 17%). Based on Rx-Risk-V, the most frequent concomitant conditions were pain (40%) and ischemic heart disease/hypertension (30%); the most frequent concomitant medications were antihypertensive medications (46%) and opiates (40%). Most prescribers (63%) were affiliated with an academic center, and all U.S. geographic regions were represented. In all, 847 patients (72%) had commercial insurance. Axitinib was prescribed as second-line therapy in 659 patients (56%), as third-line therapy in 326 patients (28%), and as fourth-line or later therapy in 190 patients (16%). In the overall population, mean (SD) duration of axitinib therapy was 168.6 (+/- 148.4) days. Axitinib treatment duration was 21 days longer in males than females (P = 0.013); 28 days longer in patients in the Northeast than in the Midwest or West (P = 0.010 and P = 0.016, respectively); and 26 days longer in patients receiving baseline hypothyroidism treatment (P = 0.004). In patients receiving second-line axitinib, the most common first-line therapy was sunitinib (56%), followed by pazopanib (16%) and everolimus (12%). Mean (SD) duration of second line axitinib treatment was 172.3 (+/- 150.6) days and ranged from 127 days in patients who previously received temsirolimus to 196 days in those who previously received sorafenib. Of 1,025 patients who initiated axitinib at the standard 5 mg twice daily starting dose, 70% remained at this dose throughout treatment, whereas 10% had a dose increase. Younger age and gender (male) were associated with dose increases (OR = 0.958, 95% CI = 0.941-0.975 and OR = 0.573, 95% CI = 0.364-0.903, respectively). Baseline hypothyroidism treatment was associated with dose decreases and increases (OR = 1.662, 95% CI = 1.088-2.539 and OR = 2.149, 95% CI = 1.353-3.413, respectively). CONCLUSIONS: This analysis demonstrates the feasibility and utility of linking specialty pharmacy data to other longitudinal databases to better understand patient, provider, and reimbursement characteristics. These data provide insight into routine clinical use of axitinib as subsequent RCC therapy in the United States in the period following FDA approval, as well as additional information on sequencing of targeted agents in patients with advanced RCC. DISCLOSURES: This study was sponsored by Pfizer. MacLean and Cisar are employees of and hold stock in Pfizer. At the time of this analysis, Mehle, Eremina, and Quigley were employees of IMS Health who were paid consultants to Pfizer during the conduct of this study and in connection with the development of this manuscript. MacLean and Cisar contributed to study design and manuscript development. Mehle, Eremina, and Quigley contributed to study design, analysis, and manuscript development. PMID- 27231800 TI - Medication Reconciliation in Oncological Patients: A Randomized Clinical Trial. AB - BACKGROUND: Medication reconciliation is considered to be an important strategy for increasing the safety of medication use. However, few studies have been carried out showing the effect of a medication reconciliation program on the incidence of reconciliation errors (REs) in oncological patients treated in the outpatient setting. OBJECTIVE: To measure the effect of a medication reconciliation program on the incidence of reconciliation error that reached the patient (RERP) in cancer patients receiving chemotherapy as outpatients. METHODS: A randomized, prospective, controlled study was carried out to identify the proportion of patients with at least 1 RERP. Medication reconciliation (intervention group) was compared with standard practice (control group) in patients starting new chemotherapy and who were receiving at least 1 home medication before the start of chemotherapy. A prespecified analysis of factors capable of influencing the occurrence of RE in oncological patients was also carried out. RESULTS: A total of 147 patients were included (76 in the intervention group and 71 controls) in this study. There were 3 (4%) patients with RERP (primary endpoint) in the intervention group and 21 (30%) patients in the control group (relative risk [RR] = 0.13, 95% CI = 0.04-0.43; P = 0.0009). The prespecified analysis of the effects of the Eastern Cooperative Oncology Group performance status (ECOG), Charlson Comorbidity Index score, and degree of poly-medication upon the number of patients with RE showed the Charlson Comorbidity Index to be unrelated to RE occurrence. However, the risk of RE was greater in patients with ECOG >= 2 (RR = 2.18, 95% CI = 1.4-3.4; P = 0.018) and among patients with major poly-medication (RR = 2.49, 95% CI = 1.52-4.09; P <0.001). CONCLUSIONS: Medication reconciliation results in a marked decrease in RERP in cancer patients. The factors that may influence RE occurrence in oncological patients have not been fully established, although parameters such as the degree of poly-medication and performance status may play a role. DISCLOSURES: No outside funding supported this study. The authors declare that they have no affiliations with or financial interests in any company, product, or service described in the manuscript. Study concept and design were contributed by Sierra-Sanchez, Martinez-Bautista, Baena-Canada, and Gonzalez-Carrascosa Vega. Martinez-Bautista, Garcia-Martin, Suarez-Carrascosa, and Gonzalez-Carrascosa Vega collected the data, which was interpreted by Sierra-Sanchez, Martinez-Bautista, Baena-Canada, and Gonzalez-Carrascosa Vega. The manuscript was written by Sierra Sanchez and Gonzalez-Carrascosa Vega and revised by Sierra-Sanchez, Martinez Bautista, Baena-Canada, and Gonzalez-Carrascosa Vega. PMID- 27231801 TI - Low-Cost Generic Program Use by Medicare Beneficiaries: Implications for Medication Exposure Misclassification in Administrative Claims Data. AB - BACKGROUND: Administrative claims data are used for a wide variety of research and quality assurance purposes; however, they are prone to medication exposure misclassification if medications are purchased without using an insurance benefit. Low-cost generic drug programs (LCGPs) offered at major chain pharmacies are a relatively new and sparsely investigated source of exposure misclassification. LCGP medications are often purchased out of pocket; thus, a pharmacy claim may never be submitted, and the exposure may go unobserved in claims data. As heavy users of medications, Medicare beneficiaries have much to gain from the affordable medications offered through LCGPs. This use may put them at increased risk of exposure misclassification in claims data. Many high-risk medications (HRMs) and medications tracked for adherence and utilization quality metrics are available through LCGPs, and exposure misclassification of these medications may impact the quality assurance efforts reliant on administrative claims data. Presently, there is little information regarding the use of these programs among a geriatric population. OBJECTIVES: To (a) quantify the prevalence of LCGP users in a nationally representative population of Medicare beneficiaries; (b) compare clinical and demographic characteristics of LCGP users and nonusers; (c) assess determinants of LCGP use and medications acquired through these programs; and (d) analyze patterns of LCGP use during the years 2007-2012. METHODS: This study relied on data from the Medical Expenditure Panel Survey (MEPS) from 2007 to 2012. The first 3 objectives were completed with a cohort of individuals in the most recent MEPS panel, while the fourth objective was completed with a separate cohort composed of individuals who participated in MEPS from 2007 to 2012. Inclusion in either study cohort required that individuals were Medicare beneficiaries aged 65 years or greater, used at least 1 prescription drug during their 2-year panel period, and participated in all 5 rounds of data collection during their panel period. MEPS captures medication utilization by surveying individuals on current and previous medication use and verifies this information at the pharmacy level, so prescription fills can be observed irrespective of payment by an insurer or a filed claim. Pharmaceutical utilization was assessed at the individual level for each year of the study period, and LCGP use was recorded as a binary variable for each individual. An LCGP medication fill was identified if the total cost of the drug was paid out of pocket and matched the cost of medications listed on LCGP formularies available from major pharmacy retailers during these years. Cohort demographics and characteristics of interest included age, gender, race, employment status, marital status, family income level, education level, residence in a metropolitan statistical area, geographic region, prescription drug coverage, Medicare type, comorbidities, number of unique medications used, and number of medication fills. Comparisons were made between users and nonusers using chi-square and t-tests. Multivariable logistic regression was used to identify factors associated with LCGP use. RESULTS: From the most recent MEPS panel, 1,861 individuals were included in the study cohort, of which 53.5% were observed to be LCGP users. The 995 LCGP users in this cohort represented over 20 million Medicare beneficiaries who used LCGPs from 2011 to 2012. Significant differences between LCGP users and nonusers existed in terms of race, educational attainment, comorbidity burden, type of Medicare insurance, number of unique medications used, and number of medication fills. Each additional unique medication filled increased the odds of LCGP use by 12% (95% CI = 1.09-1.14). Individuals with insurance in addition to Medicare (i.e., Tricare/Veteran's Affairs or Medicaid) had less than half the odds of using LCGPs compared with those with Medicare or Medicare managed care insurance coverage only. The proportion of LCGP users and the proportion of LCGP fills out of all medications available through LCGPs increased from 2007 to 2012. CONCLUSIONS: There is a high rate of LCGP use among Medicare beneficiaries aged 65 years or greater. Claims-based research and quality assurance programs focusing on the benefits and harms of medications available through these programs are at risk of underestimating the true medication exposure in this population and should account for this possibility in sensitivity analyses. Managed care organizations should incentivize the reporting of LCGP medication use or make adjustments to generic medication benefit structures to more effectively capture true medication exposure. DISCLOSURES: No direct sources of funding were used to conduct this study. Data acquisition was supported by the University of Kentucky Center for Clinical and Translational Science through funding from NIH NCATS grant #UL1TR000117. Brown is the Humana-Pfizer Research Fellow at the Institute for Pharmaceutical Outcomes & Policy at the University of Kentucky College of Pharmacy and is provided salary from these corporations. However, neither company provided any direct funding for the current study nor provided any input or guidance for the design, methods, or drafting of the manuscript. Pauly has no financial disclosures or conflicts of interest. Portions of these results were presented at the 20th International Society for Pharmacoeconomics and Outcomes Research International Meeting; May 16-20, 2015; Philadelphia, Pennsylvania. Study concept and design were primarily contributed by Brown, along with the other authors. Brown took the lead in data collection and interpretation, along with Pauly and Talbert. All authors participated in the writing and revision of the manuscript. PMID- 27231802 TI - Use of Oritavancin in Moderate-to-Severe ABSSSI Patients Requiring IV Antibiotics: A U.S. Payer Budget Impact Analysis. AB - BACKGROUND: It is estimated that acute bacterial skin and skin structure infections (ABSSSI) account for nearly 10% of hospital admissions and 3.4-3.8 million emergency department visits per year in the United States. Analyses of hospital discharge records indicate 74% of ABSSSI admissions involve empiric treatment with methicillin-resistant Staphylococcus aureus (MRSA) active antibiotics. Analysis has shown that payer costs could be reduced if moderate-to severe ABSSSI patients were treated to a greater extent in the observational unit followed by discharge to outpatient parenteral antibiotic therapy (OPAT). Oritavancin is a lipoglycopeptide antibiotic with bactericidal activity against gram-positive bacteria, including MRSA. OBJECTIVE: To estimate the impact on a U.S. payer's budget of using single-dose oritavancin in ABSSSI patients with suspected MRSA involvement who are indicated for intravenous antibiotics. METHODS: A decision analytic model based on current clinical practice was developed to estimate the economic value of decreased hospital resource consumption by using single-dose oritavancin over a 1-year time horizon. Use of antibiotics was informed by an analysis of the Premier Research Database. Demographic and clinical data were derived from a targeted literature review. Emergency department, observation, laboratory, and administration costs used were Medicare National Limitation amounts. Drug costs were 2014 wholesale acquisition costs. RESULTS: For a hypothetical U.S. payer with 1,000,000 members, it is expected that approximately 14,285 members per year will be diagnosed with ABSSSI severe enough to indicate intravenous antibiotics with MRSA activity. Based on this simulation, use of single-dose oritavancin in 26% of these patients was estimated to reduce the number of inpatient admissions, reduce length of stay for patients requiring admission, and reduce the number of days a patient needs to receive daily infusions in the OPAT clinic. The total patient days decreased from 171,125 to 133,435 with a total annual budget impact of -$12,550,000 or -$1.05 per member per month (PMPM). Total inpatient and outpatient costs were reduced by $9,970,000 (19.7%) and $2,580,000 (4.2%), respectively. Inpatient cost savings were derived from a reduction in admissions, length of stay, and lower drug administration burden. Outpatient costs were reduced by lower drug administration burden in the OPAT setting. A sensitivity analysis demonstrated that the model was most sensitive to population estimates. CONCLUSIONS: Use of single-dose oritavancin in moderate-to-severe ABSSSI patients, including those with suspected MRSA, was projected to deliver an estimated cost reduction to U.S. payers of $1.05 PMPM by avoiding hospitalization in appropriate patients and reducing outpatient costs associated with multiday parenteral antibiotic therapy. DISCLOSURES: This work was funded by The Medicines Company. Jensen, Wu, and Cyr are employees of ICON Health Economics, which provides consulting services to the biopharmaceutical industry, including The Medicines Company. Fan and Sulman are employees and shareholders of The Medicines Company. Dufour and Lodise have provided consulting services to The Medicines Company. Nicolau provided model input but did not receive an honorarium for contributions on this project. Nicolau is a speaker for The Medicines Company. Study concept and design were contributed by Jensen and Wu, along with the other authors. Jensen, Wu, Fan, and Sulham collected the data, with assistance from Cyr. Data interpretation was performed by Sulham, Jensen, Wu, and Fan, assisted by Lodise, Nicolau, and Dufour. The manuscript was written by Jensen, Wu, and Sulham, with assistance from Cyr, and revised by Lodise, Nicolau, and Dufour, with assistance from the other authors. PMID- 27231803 TI - Effects of ladder parameters on asymmetric patterns of force exertion during below-knee amputees climbing ladders. AB - Different from walking, ladder climbing requires four-limb coordination and more energy exertion for below-knee amputees (BKAs). We hypothesized that functional deficiency of a disabled limb shall be compensated by the other three intact limbs, showing an asymmetry pattern among limbs. Hand and foot forces of six below-knee amputees and six able-bodied people were collected. Hand, foot and hand/foot sum force variances between groups (non-BKA, intact side and prosthetic side) were carefully examined. Our hypothesis was validated that there is asymmetry between prosthetic and intact side. Results further showed that the ipsilateral hand of the prosthetic leg is stronger than the hand on the intact side, compensating weakness of the prosthetic leg. Effects of ladder rung separations and ladder slant on asymmetric force distribution of BKAs were evaluated, indicating that rung separation has a more significant interactive effect on hand/foot force of BKAs than ladder slant. PMID- 27231804 TI - Combining allele frequency uncertainty and population substructure corrections in forensic DNA calculations. AB - In forensic DNA calculations of relatedness of individuals and in DNA mixture analyses, at least two sources of uncertainty are present concerning the allele frequencies used for evaluating genotype probabilities when evaluating likelihoods. They are: (i) imprecision in the estimates of the allele frequencies in the population by using an inevitably finite database of DNA profiles to estimate them; and (ii) the existence of population substructure. Green and Mortera [6] showed that these effects may be taken into account individually using a common Dirichlet model within a Bayesian network formulation, but that when taken in combination this is not the case; however they suggested an approximation that could be used. Here we develop a slightly different approximation that is shown to be exact in the case of a single individual. We demonstrate the numerical closeness of the approximation using a published database of allele counts, and illustrate the effect of incorporating the approximation into calculations of a recently published statistical model of DNA mixtures. PMID- 27231805 TI - Stationary mutation models. AB - Probability calculations for relationship inference based on DNA tests are often performed with computer packages such as Familias. When mutations are assumed to be a possibility, one may notice a curious and problematic effect of including untested parents: results tend to change slightly. In this paper, we trace this effect back to fundamental model-formulating issues which can only be resolved by using stationary mutation models. We present several methods for obtaining such stationary mutation matrices from original mutation matrices, and evaluate essential properties of these methods. Our conclusion is that typically, stationary mutation models can be obtained, but for many types of markers, it may be impossible to combine specific biologically reasonable requirements for a mutation matrix with the requirement of stationarity. PMID- 27231806 TI - Isolation and Identification of Saponins from the Natural Pasturage Asterothamnus centrali-asiaticus Employing Preparative Two-Dimensional Reversed-Phase Liquid Chromatography/Hydrophilic Interaction Chromatography. AB - Asterothamnus centrali-asiaticus, a kind of characteristic shrub abundant in grassland and desert areas, has been used as forage fodder for camels and goats in Central Asia, and this plant also plays a critical role in the maintenance of desert grassland ecosystems as a result of its tolerance to poor soils and sand burial. However, its chemical composition has been rarely reported. In this study, phytochemical investigation of this pasturage was performed and three new triterpenoid saponins (1-3) were isolated together with nine known triterpenoid saponins (4-12) using preparative two-dimensional reversed-phase liquid chromatography/hydrophilic interaction chromatography (2D RPLC/HILIC). Their structures were elucidated via diverse spectroscopic analyses, including infrared (IR) spectrometry, high-resolution electrospray ionization mass spectrometry (HR ESIMS), and one-dimensional (1D) and 2D nuclear magnetic resonance (NMR). All isolated triterpenoid saponins (1-12) were reported from this genus for the first time, and they were further evaluated for their cytotoxicity against four cancer cell lines (A549, HepG2, MGC-803, and MFC), which indicated that compound 11 showed potent cytotoxicity against the HepG2 cell line, with an IC50 value of 6.85 MUg/mL. PMID- 27231808 TI - Correction to "Rhodium-Catalyzed Synthesis of Benzosilolometallocenes via the Dehydrogenative Silylation of C(sp(2))-H Bonds". PMID- 27231807 TI - Effects of resistance training on expression of IGF-I splice variants in younger and older men. AB - Insulin-like growth factor-I (IGF-I) and its splice variants Insulin-like growth factor-I isoform Ea (IGF-IEa) and mechano growth factor (MGF) may play an important role in muscular adaptations to resistance training (RT) that may be modulated by ageing. It has been suggested that IGF-I induces cellular responses via AKT8 virus oncogene cellular homolog (Akt) and Extracellular signal-regulated kinase (Erk) signalling pathways. Therefore, resistance exercise-induced changes in skeletal muscle IGF-IEa and MGF messenger ribonucleic acid (mRNA), and MGF, Erk1/2, Akt and p70S6K protein expression were investigated before and after 21 weeks of RT in younger (YM, 20-34 yrs., n = 7) and older men (OM, 51-71 yrs., n = 10). Experimental resistance exercises (RE) of 5 * 10 repetition maximum leg presses were performed pre- and post-RT. Muscle biopsies were obtained before and 48 h after REs, to study the late response to muscle loading. The muscle proteins or mRNAs of interest were not systematically influenced by the REs or RT, except for MGF mRNA expression which was increased (p < .01) following RE before RT in OM. No differences were observed between YM and OM in any variables. This study demonstrated that basal levels or RE-induced responses in skeletal muscle MGF, Erk1/2, Akt and p70S6K protein levels or IGF-IEa and MGF mRNA expression did not differ between YM and OM, nor change systematically due to RT. Thus, ageing appears not to effect expression of the present signalling molecules involved in skeletal muscle hypertrophy. PMID- 27231809 TI - Modern health worries - the dark side of spirituality? AB - Modern health worries (MHWs) are widespread in modern societies. MHWs were connected to both negative and positive psychological characteristics in previous studies. The study aimed to investigate the relationships among intuitive experiential information processing style, spirituality, MHWs, and psychological well-being. Members of the Hungarian Skeptic Society (N = 128), individuals committed to astrology (N = 601), and people from a non-representative community sample (N = 554) completed questionnaires assessing intuitive-experiential information processing style, spirituality, modern health worries (MHWs), and psychological well-being. Astrologers showed higher levels of spirituality, intuitive-experiential thinking, and modern health worries than individuals from the community sample; and skeptics scored even lower than the latter group with respect to all three constructs. Within the community sample, medium level connections between measures of spirituality and the experiential thinking style, and weak to medium level correlations between spirituality and MHWs were found. The connection between MHWs and experiential thinking style was completely mediated by spirituality. Individuals with higher levels of spirituality are particularly vulnerable to overgeneralized messages on health related risks. Official communication of potential risks based on rational scientific reasoning is not appropriate to persuade them as it has no impact on the intuitive experiential system. PMID- 27231810 TI - Intubation biomechanics: laryngoscope force and cervical spine motion during intubation in cadavers-effect of severe distractive-flexion injury on C3-4 motion. AB - OBJECTIVE With application of the forces of intubation, injured (unstable) cervical segments may move more than they normally do, which can result in spinal cord injury. The authors tested whether, during endotracheal intubation, intervertebral motion of an injured C3-4 cervical segment 1) is greater than that in the intact (stable) state and 2) differs when a high- or low-force laryngoscope is used. METHODS Fourteen cadavers underwent 3 intubations using force-sensing laryngoscopes while simultaneous cervical spine motion was recorded with lateral fluoroscopy. The first intubation was performed with an intact cervical spine and a conventional high-force line-of-sight Macintosh laryngoscope. After creation of a severe C3-4 distractive-flexion injury, 2 additional intubations were performed, one with the Macintosh laryngoscope and the other with a low-force indirect video laryngoscope (Airtraq), used in random order. RESULTS During Macintosh intubations, between the intact and the injured conditions, C3-4 extension (0.3 degrees +/- 3.0 degrees vs 0.4 degrees +/- 2.7 degrees , respectively; p = 0.9515) and anterior-posterior subluxation (-0.1 +/- 0.4 mm vs -0.3 +/- 0.6 mm, respectively; p = 0.2754) did not differ. During Macintosh and Airtraq intubations with an injured C3-4 segment, despite a large difference in applied force between the 2 laryngoscopes, segmental extension (0.4 degrees +/- 2.7 degrees vs 0.3 degrees +/- 3.3 degrees , respectively; p = 0.8077) and anterior-posterior subluxation (0.3 +/- 0.6 mm vs 0.0 +/- 0.7 mm, respectively; p = 0.3203) did not differ. CONCLUSIONS The authors' hypotheses regarding the relationship between laryngoscope force and the motion of an injured cervical segment were not confirmed. Motion-force relationships (biomechanics) of injured cervical intervertebral segments during endotracheal intubation in cadavers are not predicted by the in vitro biomechanical behavior of isolated cervical segments. With the limitations inherent to cadaveric studies, the results of this study suggest that not all forms of cervical spine injury are at risk for pathological motion and cervical cord injury during conventional high-force line-of-sight intubation. PMID- 27231811 TI - Surgical outcomes after laminoplasty for cervical spondylotic myelopathy in patients with renal dysfunction and/or aortic arch calcification. AB - OBJECTIVE The authors recently reported that the presence of chronic kidney disease (CKD) and/or extended abdominal aortic calcification was associated with significantly worse clinical outcomes after posterior lumbar interbody fusion. CKD is one of the highest risk factors for systemic atherosclerosis. Therefore, impaired blood flow due to atherosclerosis could exacerbate degeneration of the cervical spine and neural tissue. However, there has been no report of a study evaluating the deleterious effects of CKD and atherosclerosis on the outcomes after decompression surgery for cervical compression myelopathy. The purpose of this study was thus to examine whether CKD and systemic atherosclerosis affect surgical outcomes after laminoplasty for cervical spondylotic myelopathy (CSM). METHODS The authors analyzed data from 127 consecutive cases involving patients who underwent laminoplasty for CSM and met their inclusion criteria. Stage 3-4 CKD was present as a preoperative comorbidity in 44 cases. Clinical status was assessed using the Japanese Orthopaedic Association (JOA) cervical myelopathy evaluation questionnaire before surgery and 2 years postoperatively. As a marker of systemic atherosclerosis, the presence of aortic arch calcification (AoAC) was assessed on preoperative chest radiographs. RESULTS AoAC was found on preoperative chest radiographs in 40 of 127 patients. Neither CKD nor AoAC had a statistically significant deleterious effect on preoperative JOA score. However, CKD and AoAC were significantly associated with reductions in both the JOA score recovery rate (mean 36.1% in patients with CKD vs 44.7% in those without CKD; 26.0% in patients with AoAC vs 48.9% in those without AoAC) and the change in JOA score at 2 years after surgery (mean 2.3 points in patients with CKD vs 3.1 points in those without CKD; 2.1 points for patients with AoAC vs 3.2 points for those without AoAC). A multivariate regression analysis showed that AoAC was a significant independent predictor of poor outcome with respect to both for the difference between follow-up and preoperative JOA scores and the JOA score recovery rate. CONCLUSIONS CKD and AoAC were associated with increased rates of poor neurological outcomes after laminoplasty for CSM, and AoAC was a significant independent predictive factor for poor outcome. PMID- 27231812 TI - Synthetic bone graft versus autograft or allograft for spinal fusion: a systematic review. AB - The purpose of this review was to compare the efficacy and safety of synthetic bone graft substitutes versus autograft or allograft for the treatment of lumbar and cervical spinal degenerative diseases. Multiple major medical reference databases were searched for studies that evaluated spinal fusion using synthetic bone graft substitutes (either alone or with an autograft or allograft) compared with autograft and allograft. Randomized controlled trials (RCT) and cohort studies with more than 10 patients were included. Radiographic fusion, patient reported outcomes, and functional outcomes were the primary outcomes of interest. The search yielded 214 citations with 27 studies that met the inclusion criteria. For the patients with lumbar spinal degenerative disease, data from 19 comparative studies were included: 3 RCTs, 12 prospective, and 4 retrospective studies. Hydroxyapatite (HA), HA+collagen, beta-tricalcium phosphate (beta-TCP), calcium sulfate, or polymethylmethacrylate (PMMA) were used. Overall, there were no differences between the treatment groups in terms of fusion, functional outcomes, or complications, except in 1 study that found higher rates of HA graft absorption. For the patients with cervical degenerative conditions, data from 8 comparative studies were included: 4 RCTs and 4 cohort studies (1 prospective and 3 retrospective studies). Synthetic grafts included HA, beta-TCP/HA, PMMA, and biocompatible osteoconductive polymer (BOP). The PMMA and BOP grafts led to lower fusion rates, and PMMA, HA, and BOP had greater risks of graft fragmentation, settling, and instrumentation problems compared with iliac crest bone graft. The overall quality of evidence evaluating the potential use and superiority of the synthetic biological materials for lumbar and cervical fusion in this systematic review was low or insufficient, largely due to the high potential for bias and small sample sizes. Thus, definitive conclusions or recommendations regarding the use of these synthetic materials should be made cautiously and within the context of the limitations of the evidence. PMID- 27231813 TI - Posterior lumbar interbody fusion with cortical bone trajectory screw fixation versus posterior lumbar interbody fusion using traditional pedicle screw fixation for degenerative lumbar spondylolisthesis: a comparative study. AB - OBJECTIVE Several biomechanical studies have demonstrated the favorable mechanical properties of the cortical bone trajectory (CBT) screw. However, no reports have examined surgical outcomes of posterior lumbar interbody fusion (PLIF) with CBT screw fixation for degenerative spondylolisthesis (DS) compared with those after PLIF using traditional pedicle screw (PS) fixation. The purposes of this study were thus to elucidate surgical outcomes after PLIF with CBT screw fixation for DS and to compare these results with those after PLIF using traditional PS fixation. METHODS Ninety-five consecutive patients underwent PLIF with CBT screw fixation for DS (CBT group; mean followup 35 months). A historical control group consisted of 82 consecutive patients who underwent PLIF with traditional PS fixation (PS group; mean follow-up 40 months). Clinical status was assessed using the Japanese Orthopaedic Association (JOA) scale score. Fusion status was assessed by dynamic plain radiographs and CT. The need for additional surgery and surgery-related complications was also evaluated. RESULTS The mean JOA score improved significantly from 13.7 points before surgery to 23.3 points at the latest follow-up in the CBT group (mean recovery rate 64.4%), compared with 14.4 points preoperatively to 22.7 points at final follow-up in the PS group (mean recovery rate 55.8%; p < 0.05). Solid spinal fusion was achieved in 84 patients from the CBT group (88.4%) and in 79 patients from the PS group (96.3%, p > 0.05). Symptomatic adjacent-segment disease developed in 3 patients from the CBT group (3.2%) compared with 9 patients from the PS group (11.0%, p < 0.05). CONCLUSIONS PLIF with CBT screw fixation for DS provided comparable improvement of clinical symptoms with PLIF using traditional PS fixation. However, the successful fusion rate tended to be lower in the CBT group than in the PS group, although the difference was not statistically significant between the 2 groups. PMID- 27231815 TI - Erratum: Clinical features of spinal schwannomas in 65 patients with schwannomatosis compared with 831 with solitary schwannomas and 102 with neurofibromatosis Type 2: a retrospective study at a single institution. PMID- 27231814 TI - Fulminant spinal cord compression caused by postradiation inflammatory pseudotumor with rapid response to steroids: case report. AB - Radiation therapy continues to play an extremely valuable role in the treatment of malignancy. The effects of radiation therapy on normal tissue can present in a delayed fashion, resulting in localized damage with pseudomalignant transformation, producing a compressive effect on the spinal cord or exiting nerve roots. Infiltration of inflammatory cells and the subsequent fibrotic response can result in the development of an inflammatory pseudotumor (benign tumor-like lesion) with subsequent mass effect. Herein, the authors present a rare case of inflammatory pseudotumor with fulminant cervicothoracic cord compression, developing 7 years after radiation therapy for breast cancer. The lesion recurred following resection but subsequently displayed complete and rapid resolution following steroid therapy. To the best of the authors' knowledge, no previous studies have reported such an incident. PMID- 27231816 TI - Bariatric Bypass Surgery to Resolve Complicated Childhood Morbid Obesity: Case Report Study: Erratum. AB - In the article ''Bariatric Bypass Surgery to Resolve Complicated Childhood Morbid Obesity: Case Report Study'', which appeared in Volume 94, Issue 49 of Medicine, Dr. Elrazek's name was incorrectly presented as Abd Elrazek M. Ali Hussein when it should have read Abd Elrazek Abd Elrazek. The article has since been corrected online. PMID- 27231817 TI - Linking internal and external bacterial community control gives mechanistic framework for pelagic virus-to-bacteria ratios. AB - For more than 25 years, virus-to-bacteria ratios (VBR) have been measured and interpreted as indicators of the importance of viruses in aquatic ecosystems, yet a generally accepted theory for understanding mechanisms controlling VBR is still lacking. Assuming that the denominator (total bacterial abundance) is primarily predator controlled, while viral lysis compensates for host growth rates exceeding this grazing loss, the numerator (viral abundance) reflects activity differences between prokaryotic hosts. VBR is then a ratio between mechanisms generating structure within the bacterial community and interactions between different plankton functional types controlling bacterial community size. We here show how these arguments can be formalized by combining a recently published model for co-evolutionary host-virus interactions, with a previously published "minimum" model for the microbial food web. The result is a framework where viral lysis links bacterial diversity to microbial food web structure and function, creating relationships between different levels of organization that are strongly modified by organism-level properties such as cost of resistance. PMID- 27231818 TI - First-time parents' shared representation of postpartum depressive symptoms: A qualitative analysis. AB - RATIONALE: Maternal postpartum depression (PD) is a common, debilitating mental health problem. Yet despite effective treatments and widespread screening, treatment rates remain low. Previous studies suggest fathers are frequently consulted about maternal PD symptoms, but little is known about the process, content, or outcomes of these consultations. OBJECTIVE: The aim of this work was to explore how couples communicate about PD symptoms. METHODS: A single purposive sample of first-time parents stratified by maternal depression screening scores (Edinburgh Postnatal Depression Scale; EPDS) and partner status was drawn from a prospective survey of 300 parents in the U.S. Midwest. Partnered mothers with an elevated (EPDS>=10) depression screening score at one of four time points in the postpartum year comprised the majority of the sample. Smaller samples of participants with low EPDS scores and single participants were included to provide contrast in the consultation and decision making process. A total of 39 participants (22 married/EPDS-high, 10 married/EPDS-low, 5 single/ EPDS-high, 2 single/EPDS-low) were interviewed at one year postpartum. Mothers and fathers were interviewed separately to promote candid responses and allow comparison of illness conceptualizations. Interviews were transcribed, analyzed, and coded through an iterative process. RESULTS: Couples' conversations about mood changes centered on two overarching questions: How bad is it? and What should we do about it? Answering How bad is it? involved parents comparing maternal mood changes to uncertain depression criteria, and mothers asking partners and female relatives whether changes were normal. Answering What should we do about it? had three themes: Fathers feeling unprepared to respond to depression, mothers and fathers expressing reluctance to seek treatment, and couples working collaboratively to accommodate treatment or self-care. CONCLUSION: Themes suggest partners significantly contribute to women's conceptualization of mood changes and should be actively engaged in education, screening, and referral practices. PMID- 27231819 TI - Electrochemical activation of a tetrathiafulvalene halogen bond donor in solution. AB - The halogen bond donor properties of iodo-tetrathiafulvalene (I-TTF) can be electrochemically switched and controlled via reversible oxidation in the solution phase. Interestingly the activation of only one single halogen bond yielded already a strong and selective interaction, quantified by cyclic voltammetry. The standard potentials of the redox couples I-TTF(0/1+) and I TTF(1+/2+) were observed to shift upon the addition of halides. These anions selectively stabilize the cationic I-TTF species through halogen bonding in polar liquid electrolytes. The thermodynamic affinity constants for chloride and bromide binding to the oxidized species have been determined. Competition in halide binding between I-TTF(1+) and other halogen bond donors allowed for comparing the relative donor strength of the respective electrophilic species. Furthermore it has been shown that halogen bonding can prevail over hydrogen bonding in the investigated system. PMID- 27231820 TI - Photocatalytic reduction of CO2 over Ag/TiO2 nanocomposites prepared with a simple and rapid silver mirror method. AB - The photocatalytic reduction of CO2 over Ag/TiO2 composites prepared with a simple silver mirror reaction method was investigated under UV-visible irradiation in both gas-phase (CO2 + water vapor) and aqueous solution (CO2 saturated NaHCO3 solution) systems. The as-prepared Ag/TiO2 nanocomposite exhibits efficient photocatalytic activity due to the surface plasmonic resonance and electron sink effect of the Ag component, which was found to be closely related to the size and loading amount of Ag. The rapid silver method is effective at curbing the size of Ag, so photocatalytic activity can be improved. Diverse organic chemical products were detected, including mainly methane and methanol as well as a small amount of C2 and C3 species such as acetaldehyde and acetone. Possible photocatalytic mechanisms were proposed. This artificial photosynthesis process may give a prosperous route to the removal of CO2 while simultaneously converting CO2 to valuable fuels based on highly efficient photocatalysts. PMID- 27231822 TI - Racial disparities in health care access among pediatric patients with craniosynostosis. AB - OBJECTIVE Disparities in surgical access and timing to care result from a combination of complex patient, social, and institutional factors. Due to the perception of delayed presentation for overall health care services and treatment in African American patients on the part of the senior author, this study was designed to identify and quantify these differences in access and care between African American and Caucasian children with craniosynostosis. In addition, hypotheses regarding reasons for this difference are discussed. METHODS A retrospective study was conducted of 132 children between the ages of 0 and 17 years old who previously underwent operations for craniosynostosis at a tertiary pediatric care facility between 2010 and 2013. Patient and family characteristics, age at surgical consultation and time to surgery, and distance to primary care providers and the tertiary center were recorded and analyzed. RESULTS Of the 132 patients in this cohort, 88% were Caucasian and 12% were African American. The median patient age was 5 months (interquartile range [IQR] 2-8 months). African Americans had a significantly greater age at consult compared with Caucasians (median 341 days [IQR 192-584 days] vs median 137 days [IQR 62-235 days], respectively; p = 0.0012). However, after being evaluated in consultation, there was no significant difference in time to surgery between African American and Caucasian patients (median 56 days [IQR 36-98 days] vs median 64 days [IQR 43-87 days], respectively). Using regression analysis, race and type of synostoses were found to be significantly associated with a longer wait time for surgical consultation (p = 0.01 and p = 0.04, respectively, using cutoff points of <= 180 days vs > 180 days). Distance traveled to primary care physicians and to the tertiary care facility did not significantly differ between groups. Other factors such as parental education, insurance type, household income, and referring physician type also showed no significant difference between racial groups. CONCLUSIONS This study identified a correlation between race and age at consultation, but no association with time to surgery, distance, or family characteristics such as household income, parental education, insurance type, and referring physician type. This finding implies that delays in early health-seeking behaviors and subsequent referral to surgical specialists from primary care providers are the main reason for this delay among African American craniofacial patients. Future studies should focus on further detail in regards to these barriers, and educational efforts should be designed for the community and the health care personnel caring for them. PMID- 27231821 TI - Morphometric analysis of the developing pediatric cervical spine. AB - OBJECTIVE Our understanding of pediatric cervical spine development remains incomplete. The purpose of this analysis was to quantitatively define cervical spine growth in a population of children with normal CT scans. METHODS A total of 1458 children older than 1 year and younger than 18 years of age who had undergone a cervical spine CT scan at the authors' institution were identified. Subjects were separated by sex and age (in years) into 34 groups. Following this assignment, subjects within each group were randomly selected for inclusion until a target of 15 subjects in each group had been measured. Linear measurements were performed on the midsagittal image of the cervical spine. Twenty-three unique measurements were obtained for each subject. RESULTS Data showed that normal vertical growth of the pediatric cervical spine continues up to 18 years of age in boys and 14 years of age in girls. Approximately 75% of the vertical growth occurs throughout the subaxial spine and 25% occurs across the craniovertebral region. The C-2 body is the largest single-segment contributor to vertical growth, but the subaxial vertebral bodies and disc spaces also contribute. Overall vertical growth of the cervical spine throughout childhood is dependent on individual vertebral body growth as well as vertical growth of the disc spaces. The majority of spinal canal diameter growth occurs by 4 years of age. CONCLUSIONS The authors' morphometric analyses establish parameters for normal pediatric cervical spine growth up to 18 years of age. These data should be considered when evaluating children for potential surgical intervention and provide a basis of comparison for studies investigating the effects of cervical spine instrumentation and fusion on subsequent growth. PMID- 27231823 TI - Intraoperative complications in pediatric neurosurgery: review of 1807 cases. AB - OBJECTIVE Minimal literature exists on the intraoperative complication rate of pediatric neurosurgical procedures with respect to both surgical and anesthesiological complications. The aim of this study, therefore, was to establish intraoperative complication rates to provide patients and parents with information on which to base their informed consent and to establish a baseline for further targeted improvement of pediatric neurosurgical care. METHODS A clinical complication registration database comprising a consecutive cohort of all pediatric neurosurgical procedures carried out in a general neurosurgical department from January 1, 2004, until July 1, 2012, was analyzed. During the study period, 1807 procedures were performed on patients below the age of 17 years. RESULTS Sixty-four intraoperative complications occurred in 62 patients (3.5% of procedures). Intraoperative mortality was 0.17% (n = 3). Seventy-eight percent of the complications (n = 50) were related to the neurosurgical procedures, whereas 22% (n = 14) were due to anesthesiology. The highest intraoperative complication rates were for cerebrovascular surgery (7.7%) and tumor surgery (7.4%). The most frequently occurring complications were cerebrovascular complications (33%). CONCLUSIONS Intraoperative complications are not exceptional during pediatric neurosurgical procedures. Awareness of these complications is the first step in preventing them. PMID- 27231824 TI - Noninvasive epicutaneous transfontanelle intracranial pressure monitoring in children under the age of 1 year: a novel technique. AB - Monitoring of intracranial pressure (ICP) may be indicated in children with traumatic brain injury, premature intraventricular hemorrhage, or hydrocephalus. The standard technique is either a direct measurement with invasive intracranial insertion of ICP probes or indirect noninvasive assessment using transfontanelle ultrasonography to measure blood flow. The authors have developed a new technique that allows noninvasive epicutaneous transfontanelle ICP measurement with standard ICP probes. They compared the ICP measurements obtained using the same type of standard probe used in 2 different ways in 5 infants (age < 1 year) undergoing surgery for craniosynostosis. The first ICP probe was implanted epidurally (providing control measurements) and the second probe was fixed epicutaneously on the skin over the reopened frontal fontanelle. ICP values were measured hourly for the first 24 hours after surgery and the values obtained with the 2 methods were compared using Bland-Altman 2-methods analysis. A total of 110 pairs of measurements were assessed. There was no significant difference between the ICPs measured using the epicutaneous transfontanelle method (mean 13.10 mm Hg, SEM 6.68 mm Hg) and the epidural measurements (mean 12.46 mm Hg, SEM 6.45 mm Hg; p = 0.4643). The results of this analysis indicate that epicutaneous transfontanelle measurement of ICP is a reliable method that allows noninvasive ICP monitoring in children under the age of 1 year. Such noninvasive ICP monitoring could be implemented in the therapy of children with traumatic brain injury or intraventricular hemorrhage or for screening children with elevated ICP without invasive intracranial implantation of ICP probes. PMID- 27231825 TI - Surgeon interrater reliability in the endoscopic assessment of cistern scarring and aqueduct patency. AB - OBJECTIVE The success of endoscopic third ventriculostomy with choroid plexus cauterization may have associations with age, etiology of hydrocephalus, previous shunting, cisternal scarring, and possibly aqueduct patency. This study aimed to measure interrater reliability among surgeons in identifying cisternal scarring and aqueduct patency. METHODS Using published definitions of cistern scarring and aqueduct patency, 7 neuroendoscopists with training from Dr. Warf in Uganda and 7 neuroendoscopists who were not trained by Dr. Warf rated cistern status from 30 operative videos and aqueduct patency from 26 operative videos. Interrater agreement was calculated using Fleiss' kappa coefficient (kappa). Fisher's 2 tailed exact test was used to identify differences in the rates of agreement between the Warf-trained and nontrained groups compared with Dr. Warf's reference answer. RESULTS Aqueduct status, among all raters, showed substantial agreement with kappa = 0.663 (confidence interval [CI] 0.626-0.701); within the trained group and nontrained groups, there was substantial agreement with kappa = 0.677 (CI 0.593-0.761) and kappa = 0.631 (CI 0.547-0.715), respectively. The identification of cistern scarring was less reliable, with moderate agreement among all raters with kappa = 0.536 (CI 0.501-0.571); within the trained group and nontrained groups, there was moderate agreement with kappa = 0.555 (CI 0.477 0.633) and kappa = 0.542 (CI 0.464-0.620), respectively. There was no statistically significant difference in the amount of agreement between groups compared with Dr. Warf's reference. CONCLUSIONS Regardless of training with Dr. Warf, all neuroendoscopists could identify scarred cisterns and aqueduct patency with similar reliability, emphasizing the strength of the published definitions. This makes the identification of this risk factor for failure generalizable for surgical decision making and research studies. PMID- 27231826 TI - Transfusion-related alloimmunization in children: epidemiology and effects of chemotherapy. AB - BACKGROUND & OBJECTIVES: Alloimmunization rates following red blood cell (RBC) transfusion in paediatric oncology are not known. This study aimed to: (1) describe frequency and specificity of alloantibodies in paediatric oncology patients after RBC transfusions; (2) determine the effect of chemotherapy on alloimmunization rate. MATERIALS & METHODS: Retrospective cohort study of paediatric patients at a tertiary care hospital is evaluated by two groups: control group, paediatric patients without cancer; study group, paediatric oncology patients who received chemotherapy. Alloimmunization was defined as clinically significant IgG alloantibody formation against RBC antigens. RESULTS: A total of 1273 children were evaluated including 324 in study group, 909 controls, and 40 haemoglobinopathy patients. Overall, frequency of alloimmunization was 1.5%: 0.3% (95% CI: 0, 1.90) in study group; 1.3% (95% CI: 0.73, 2.32) in control group and 15% in haemoglobinopathies. The association between chemotherapy and alloimmunization was not significant; P value = 0.20 Fisher's exact test, OR 0.23 (95% CI: 0.03, 1.79). CONCLUSION: This is the first study exploring RBC alloimmunization in paediatric patients by diagnosis. Alloimmunization frequency was low. It was not possible to determine an association between chemotherapy and alloimmunization due to the low event rate. PMID- 27231827 TI - Molecular cloning, computational analysis and expression pattern of forkhead box l2 (Foxl2) gene in catfish. AB - Foxl2 belongs to forkhead/HNF-3-related family of transcription factors which is involved in ovarian differentiation and development. In present study, the Foxl2 mRNA was cloned from ovary of C. batrachus. The full length cDNA sequence of the Foxl2 was 1056bp which consists of 5' (41bp) and 3' (106bp) non-coding regions, as well as a 909bp of open reading frame (ORF) that encodes 302 amino acids. The putative protein was having the theoretical molecular weight (MW) of 34.018kD and a calculated isoelectric point (pI) of 9.38. There were 11 serine (Ser), 5 threonine (Thr), and 5 tyrosine (Tyr) phosphorylation sites and 2 putative N glycosylation sites on the predicted protein. The ligand binding sites were predicted to be present on amino acids 42, 49, 50, 91, 92 and 95 respectively. The signal peptide analysis predicted that C. batrachus Foxl2 is a non-secretory protein. The hydropathy profile of Foxl2 protein revealed that this protein is hydrophilic in nature. Protein-protein interaction demonstrated that Foxl2 protein chiefly interacts with cytochrome P450 protein family. The mRNA transcript analysis of various tissues indicated that the C. batrachus Foxl2 mRNA was more expressed in the brain, pituitary and ovary in female while, the former two tissues and testis showed low expression in male. This study provides a basis for further structural and functional exploration of the Foxl2 from C. batrachus, including its deduced protein and its signal transduction function. PMID- 27231828 TI - The promise of intensity modulated radiation therapy. PMID- 27231829 TI - New cholinesterase inhibitors for Alzheimer's disease: Structure Activity Studies (SARs) and molecular docking of isoquinolone and azepanone derivatives. AB - A library of isoquinolinone and azepanone derivatives were screened for both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity. The strategy adopted included (a) in vitro biological assays, against eel AChE (EeAChE) and equine serum BuChE (EqBuChE) in order to determine the compounds IC50 and their dose-response activity, consolidated by (b) molecular docking studies to evaluate the docking poses and interatomic interactions in the case of the hit compounds, validated by STD-NMR studies. Compound (1f) was identified as one of these hits with an IC50 of 89.5MUM for EeAChE and 153.8MUM for EqBuChE, (2a) was identified as a second hit with an IC50 of 108.4MUM (EeAChE) and 277.8MUM (EqBuChE). In order to gain insights into the binding mode and principle active site interactions of these molecules, (R)-(1f) along with 3 other analogues (also as the R-enantiomer) were docked into both RhAChE and hBuChE models. Galantamine was used as the benchmark. The docking study was validated by performing an STD-NMR study of (1f) with EeAChE using galantamine as the benchmark. PMID- 27231830 TI - Identification of novel acetylcholinesterase inhibitors: Indolopyrazoline derivatives and molecular docking studies. AB - The synthesis of novel indolopyrazoline derivatives (P1-P4 and Q1-Q4) has been characterized and evaluated as potential anti-Alzheimer agents through in vitro Acetylcholinesterase (AChE) inhibition and radical scavenging activity (antioxidant) studies. Specifically, Q3 shows AChE inhibition (IC50: 0.68+/ 0.13MUM) with strong DPPH and ABTS radical scavenging activity (IC50: 13.77+/ 0.25MUM and IC50: 12.59+/-0.21MUM), respectively. While P3 exhibited as the second most potent compound with AChE inhibition (IC50: 0.74+/-0.09MUM) and with DPPH and ABTS radical scavenging activity (IC50: 13.52+/-0.62MUM and IC50: 13.13+/-0.85MUM), respectively. Finally, molecular docking studies provided prospective evidence to identify key interactions between the active inhibitors and the AChE that furthermore led us to the identification of plausible binding mode of novel indolopyrazoline derivatives. Additionally, in-silico ADME prediction using QikProp shows that these derivatives fulfilled all the properties of CNS acting drugs. This study confirms the first time reporting of indolopyrazoline derivatives as potential anti-Alzheimer agents. PMID- 27231831 TI - Intraoperative Neuromonitoring in Pediatric and Adult Spine Deformity Surgery. AB - STUDY DESIGN: Review of techniques and description of institutional clinical experience. OBJECTIVE: To provide a historical review and description of key neuromonitoring concepts, focusing on neurogenic motor-evoked potentials and descending neurogenic evoked potentials, and to review the authors' experience with neuromonitoring techniques in children and adults undergoing spinal deformity surgery. SUMMARY OF BACKGROUND DATA: The original form of neuromonitoring, the Stagnara wake-up test, remains the "gold standard" for detecting true neurological deficits. Multiple newer modalities involving cortical and muscular monitoring, such as somatosensory evoked potentials and motor evoked potentials, have been developed and are widely used. Descending and neurogenic evoked potentials are becoming more common for neuromonitoring in patients undergoing spinal deformity surgery. METHODS: A PubMed search for literature related to "neuromonitoring" was performed, and recent, as well as historical, articles were reviewed. Clinical experience regarding the use of neuromonitoring in adult and pediatric spinal deformity surgery was obtained from institutional experts. RESULTS: Although not regularly used, the Stagnara wake-up test remains the gold standard for detecting neurological injury. Somatosensory evoked potentials measure signals transmitted from the periphery to the cortex and have historically been widely used but are limited by delay, poor localization, and the inability to detect damage to motor tracts. Motor evoked potentials continue to be used widely and measure muscular activity after cortical stimulation, but they are difficult to interpret in patients with underlying motor disorders and cannot be continuously monitored. Newer techniques such as descending neurogenic evoked potentials and neurogenic motor evoked potentials monitoring are used at some high-volume centers. CONCLUSIONS: Familiarity with the history of neuromonitoring in spinal deformity surgery and an understanding of the physiological systems used for neuromonitoring provide a framework from which spine surgeons can select appropriate monitoring for their patients. PMID- 27231832 TI - A Novel Scoring System Associated With Surgical Outcome of Distal-type Cervical Spondylotic Amyotrophy. AB - STUDY DESIGN: A single-center retrospective study. OBJECTIVE: To elucidate the pathology of distal-type cervical spondylotic amyotrophy (CSA) and to assess predictive factors and a novel scoring system associated with surgical outcome. SUMMARY AND BACKGROUND: Because of its rarity, the pathophysiology and surgical outcome of distal-type CSA are less well understood compared with proximal-type CSA. METHOD: Surgical procedures were performed in 13 patients with distal-type CSA. Patients were classified into 2 groups: those with good recovery of muscle power (group 1, n=4) and those with fair recovery (group 2, n=9). All patients underwent magnetic resonance imaging. Central motor conduction time was recorded in abductor digit minim and compound muscle action potentials (CMAPs) were recorded in extensor carpi dig. Predictive factors associated with surgical outcome and a scoring system based on clinical, radiologic, and electrophysiological findings were evaluated. Twelve of 13 patients were scored for the following features: (1) duration of symptoms >=13 months, (2) initial manual muscle testing <=1, (3) multiple compressions in magnetic resonance imaging, (4) CMAPs amplitudes on affected side <1 mV, (5) CMAPs amplitudes on normal side <7.2 mV, (6) central motor conduction time longer than 7.4 ms, (7) the ratio of CMAPs amplitudes comparison with the normal side <50%. RESULT: At final follow-up, 2 patients were graded excellent, 2 good, 9 fair, and 0 poor. None of the predictive factors was significantly different between groups 1 and 2. The mean score in group 2 (5.12+/-1.12) was significantly higher than for group 1 (2+/-1.15; P=0.006). Although all 8 patients in group 2 scored >=4 points, all 4 patients in group 1 scored <=3. CONCLUSIONS: Comprehensive assessment using a scoring system is useful for predicting the surgical outcome of distal-type CSA. Surgeons should be aware that a score of >=4 points correlates with poor surgical outcome on motor function. PMID- 27231833 TI - A Comparison of Different Minimally Invasive and Open Posterior Spinal Procedures Using Volumetric Measurements of the Surgical Exposures. AB - STUDY DESIGN: A Prospective observational study. SUMMARY OF THE BACKGROUND DATA: Minimally invasive (MI) spine surgery techniques strive to minimize the damage to paraspinal soft tissues. Previous studies used only the length of the surgical incision to quantify the invasiveness of certain MI procedures. However, this method does not take into account the volume of muscle tissue that is dissected and retracted from the spine to achieve sufficient exposure. To date, no simple method has been reported to measure the volume of the surgical exposure and to quantify the degree of surgery invasiveness. STUDY OBJECTIVES: To obtain and compare volumetric measures of various MI and open posterior-approached spinal surgical exposures. METHODS: The length, the depth, and the volume of the surgical exposure were obtained from 57 patients who underwent either open or MI posterior lumbar surgery. MI procedures included the following: tubular discectomy, laminotomy, and transforaminal interbody fusion. Open procedures included the following: discectomy, laminectomy, transforaminal interbody fusion, or posterior-lateral instrumented fusion. Four attending spine surgeons at our unit performed the surgeries. To reduce variability, only single-level procedures performed between L4 and S1 vertebrae were used. The volume of exposure was obtained by measuring the amount of saline needed to fill the surgical wound completely once the surgical retractors were deployed and opened. RESULTS: The average volumes in mililiters of exposure for a single-level MI procedure ranged from 9.8+/-2.8 to 75+/-11.7 mL and were significantly smaller than the average volumes of exposure for a single level open procedures that ranged from 44+/- 21 to 277+/-47.9 P<0.001. The average skin-incision lengths for single-level MI procedures ranged from 1.7+/-0.2 to 7.7+/-1.6 cm and were significantly smaller than the average skin-incision lengths for open procedures [5.2+/-1.4 (Table 3) to 11.3+/-2 cm, P<0.001]. The measured surgical depths were similar in MI and open groups (P=0.138). MI decompression and posterior fusion procedures yielded 92% and 73% reductions in the volumes of exposure, respectively. However, absolute differences in exposure volumes were larger for fusion (202 mL) compared with decompression alone (110.7 mL). CONCLUSIONS: Direct volumetric measurement of the surgical exposure is obtained easily by measuring the amount of saline needed to fill the exposed cavity. Using this method, the needed surgical exposure of different spinal procedures can be quantified and compared. This volumetric measurement combined with the measure of retraction force, the duration of retraction, and the impact on soft tissue vascularity can help build a model that assesses the relative invasiveness of different spinal procedures. PMID- 27231834 TI - Radiologic and Functional Outcomes in Unstable Thoracolumbar Fractures Treated With Short-segment Pedicle Instrumentation. AB - STUDY DESIGN: A retrospective review of radiographs, clinical charts, and health questionnaires of 40 patients. OBJECTIVE: To evaluate the radiologic and functional results of unstable thoracolumbar fractures treated with short-segment pedicle instrumentation (SSPI). A SUMMARY OF BACKGROUND DATA: Although earlier publications report a risk of correction loss or material failure after short segment fixation in unstable thoracolumbar fractures, more current data suggest that improvements in this technique could offer good clinical and radiologic results. MATERIALS AND METHODS: We undertook a retrospective review of 40 patients with unstable thoracolumbar fractures treated with SSPI. Radiographs and computed tomogrphic scans were analyzed to determine fracture classification and sagittal plane deformity, estimated by the Cobb method. The rates of final kyphosis and correction loss and their relationship with the Load Sharing Classification (LSC) and the AO classification were analyzed. We reviewed the hospital charts to identify complications and outcomes. At the final follow-up, the Short-Form 36 health survey was carried out to evaluate the functional outcome. The relationship between conditions such as polytrauma, neurological compromise or fracture site, and radiological and functional outcomes was also analyzed. RESULTS: We observed mean values of 5.9 degrees of final follow-up kyphosis and 5.1 degrees of correction loss. One case of material failure was seen. The severity in the LSC or the AO classification, polytrauma, neurological compromise, or fracture site had no relationship with worse radiologic or functional outcomes. CONCLUSIONS: SSPI shows good results in fracture reduction, with good functional outcomes despite the loss of correction seen at the final follow-up. Although no investigated variable was found to be predictive of radiographic failure, a trend was identified (P=0.07) that patients with a higher LSC had an increased loss of correction. PMID- 27231835 TI - Nicardipine Effects on Renal Function During Spine Surgery. AB - STUDY DESIGN: Single-center, prospective, randomized, and single-blinded clinical trial was conducted in patients (n=64) undergoing anterior or posterior spinal interbody fusion. OBJECTIVE: To investigate the renal protective effect of nicardipine during deliberate hypotension for spine surgery by measuring creatinine clearance (Ccr), serum cystatin C, urine output, and fractional excretion of sodium (FENa). SUMMARY OF BACKGROUND DATA: Deliberate hypotension during spine surgery may result in ischemic tissue damage of the kidney. Nicardipine is reported to dilate the renal artery and increase glomerular filtration rate. Previous studies reported the renal protective effect of nicardipine during cardiac surgery under cardiopulmonary bypass and robot assisted laparoscopic surgery. MATERIALS AND METHODS: Patients were randomized to receive nicardipine (nicardipine group, n=32) or normal saline (control group, n=32). Deliberate hypotension of mean arterial pressure at 50-65 mm Hg was maintained during surgery. Ccr, serum cystatin C, urine output, and FENa were measured before surgery, after surgery, and postoperative day 1 (POD1). The RIFLE (risk, injury, failure, loss, and end stage renal disease) criteria of the patients were evaluated. RESULTS: In the nicardipine group, Ccr at POD1 was increased compared with that after surgery. In both groups, serum cystatin C at POD1 was decreased compared with that before surgery and urine output at POD1 was decreased compared with that after surgery. FENa at POD1 in the control group was higher than that in the nicardipine group and was increased compared with that after surgery. Using RIFLE criteria, 6 patients in the control group and 2 patients in the nicardipine group were classified as having acute kidney injury. CONCLUSIONS: Nicardipine increased Ccr and attenuated the increase in FENa at POD1 in patients undergoing spine surgery under deliberate hypotension. PMID- 27231836 TI - The Timing of Surgery and Symptom Resolution in Patients Undergoing Transforaminal Lumbar Interbody Fusion for Lumbar Degenerative Disk Disease and Radiculopathy. AB - OBJECTIVE: Success rates of surgical interventions for lumbar disorders vary significantly depending on multiple factors and, among them, the duration of symptoms. It is not clear whether there is a "cutoff" time when decompression and fusion surgery becomes less effective in the conditions with chronic nerve root compression symptomatology. The main objective of this study was to analyze whether duration of symptoms has any effect on clinical outcomes and primarily resolution of radicular pain symptoms due to degenerative disk disease and stenosis with spondylolisthesis in patients undergoing transforaminal lumbar interbody fusion (TLIF). METHODS: The prospective observational study was performed. Eighty-four patients with radicular symptoms due to degenerative disk disease and stenosis with spondylolisthesis with no previous fusion surgeries and undergoing 1- to 3-level TLIF surgery were enrolled. Fifteen patients (18%) were lost to follow-up and were excluded from this analysis leaving a total of 69 patients. Standardized questionnaires were used to analyze clinical outcomes and were administered preoperatively within 3 months of scheduled surgery, and postoperatively at 3, 6, 12, and 24 months. To emphasize the change in clinical outcome scores, the relevant scores were calculated as the ratio of minimal clinically important difference values and change scores. The change scores were calculated by subtracting the postoperative scores from the baseline scores. Multiple regression analyses were conducted to examine the relationship of the duration of symptoms and relevant minimal clinically important difference ratio values while controlling for independent variables. Further, a comparison between 2 groups of patients was performed to analyze the changes of clinical outcomes for the patients who underwent fusion within <24 months versus >=24 months. RESULTS: It was determined that the duration of symptoms was a significant predictor of better leg pain resolution (P=0.018), but not back pain resolution (P=0.27), or improvement in ODI (P=0.10) and SF-36 PCS scores (P=0.19). The patients with shorter duration of symptoms had significantly better radicular symptom resolution (P=0.032) compared with patients who waited at least 24 months or longer to undergo fusion. CONCLUSIONS: A shorter duration of symptoms was found to be a statistically significant predictor for better resolution of radicular symptoms in patients undergoing TLIF for painful degenerative disk disease and stenosis with spondylolisthesis. PMID- 27231837 TI - Single step, bulk synthesis of engineered MoS2 quantum dots for multifunctional electrocatalysis. AB - Bi- or tri- functional catalysts based on atomic layers are receiving tremendous scientific attention due to their importance in various energy technologies. Recent studies on molybdenum disulphide (MoS2) nanosheets revealed that controlling the edge states and doping/modifying with suitable elements are highly important in tuning the catalytic activities of MoS2. Here we report a bulk, single step method to synthesize metal modified MoS2 quantum dots (QDs). Three elements, namely Fe, Mg and Li, are chosen to study the effects of dopants in the catalytic activities of MoS2. Fe and Mg are found to act like dopants in the MoS2 lattice forming respective doped MoS2 QDs, while Li formed an intercalated MoS2 QD. The efficacy and tunability of these luminescent doped QDs towards various electrocatalytic activities (hydrogen evolution reaction, oxygen evolution reaction and oxygen reduction action) are reported here. PMID- 27231838 TI - The volume of cavities in proteins and virus capsids. AB - An improved algorithm for the calculation of the volume of internal cavities within protein structures and virus capsids as well as the volumes occupied by single amino acid residues were presented. The geometrical approach was based on atomic van der Waals radii. The results obtained with two sets of the radii, those proposed by Pauling and those determined by Tsai et al were compared. The main improvement compared with our previous approach is a more elaborate treatment of the regions at the very boundary of the cavities, which yields a more accurate volume estimate. The cavity volume of a number of Plant Pathogenesis-Related proteins of class 10 (PR-10) were reevaluated and the volumes and other geometrical parameters for about 400 capsids of icosahedral viruses were reported. Using the same approach the volumes of amino acid residues in polypeptides as mean values averaged over multiple conformations of the side chain were also estimated. Proteins 2016; 84:1275-1286. (c) 2016 Wiley Periodicals, Inc. PMID- 27231839 TI - Requirement for flap endonuclease 1 (FEN1) to maintain genomic stability and transcriptional gene silencing in Arabidopsis. AB - As a central component in the maturation of Okazaki fragments, flap endonuclease 1 (FEN1) removes the 5'-flap and maintains genomic stability. Here, FEN1 was cloned as a suppressor of transcriptional gene silencing (TGS) from a forward genetic screen. FEN1 is abundant in the root and shoot apical meristems and FEN1 GFP shows a nucleolus-localized signal in tobacco cells. The Arabidopsis fen1-1 mutant is hypersensitive to methyl methanesulfonate and shows reduced telomere length. Interestingly, genome-wide chromatin immunoprecipitation and RNA sequencing results demonstrate that FEN1 mutation leads to a decrease in the level of H3K27me3 and an increase in the expression of a subset of genes marked with H3K27me3. Overall, these results uncover a role for FEN1 in mediating TGS as well as maintaining genome stability in Arabidopsis. PMID- 27231840 TI - Optical twisting to monitor the rheology of single cells. AB - BACKGROUND: Biological cells exhibit complex mechanical properties which determine their responses to applied force. OBJECTIVE: We developed an optical method to probe the temporal evolution of power-law rheology of single cells. METHODS: The method consisted in applying optically a constant mechanical torque to a birefringent microparticle bound to the cell membrane, and observing dynamics of the particle's in-plane rotation. RESULTS: The deformation dynamics of the membrane followed a power law of time, which directly relates to cytoskeletal prestress as reported in the literature. The temporal evolution of this rheological behaviour, over time scales of several minutes, showed strong variations of the exponent on single adherent cells not subject to any specific treatment. CONCLUSIONS: The consistent observation of variations in the exponent suggests that, in their normal activity, living cells modulate their prestress by up to three orders of magnitude within minutes. PMID- 27231841 TI - Prediction of Late-Onset Psychiatric Disorder in Survivors of Severe Injury: Findings of a Latent Transition Analysis. AB - OBJECTIVE: There is a growing body of evidence indicating that late or delayed onset of psychiatric disorder following traumatic injury and other psychological trauma is common. This research, however, has not examined factors that pose risks for delayed development of different types of psychopathology or at different time points. Such research has considerable implications for the development of screening, assessment, and intervention practices. This article investigates risk factors for late-onset disorders up to 72 months after a severe injury. METHODS: In this 6-year longitudinal study, 1,167 hospitalized patients with severe injury recruited between April 2004 and February 2006 were analyzed with repeated measures at 3, 12, and 72 months after injury. The Mini International Neuropsychiatric Interview (MINI) and Clinician-Administered PTSD Scale (CAPS) were employed to complete diagnoses according to DSM-IV. Latent transition analyses with continuous covariates (injury severity, social support, recent life events, and pain) and 1 dichotomous covariate (presence/absence of a psychiatric disorder before injury) were conducted to identify risk factors for transitioning out of a No Disorder class and into one of 3 previously reported psychopathology classes (PTSD [posttraumatic stress disorder]/Depression, Alcohol/Depression, and Alcohol only) between 3 and 12 months (transition 1) and between 12 and 72 months (transition 2) postinjury. RESULTS: Movement into the PTSD/Depression class was predicted by injury severity at transitions 1 (P = .003) and 2 (P = .017) and social support (P = .006) at transition 1. Past psychiatric history increased the likelihood of moving into the PTSD/Depression class, with anxiety or mood disorders specifically implicated in transition 1. Movement into the Alcohol/Depression class was predicted by social support at transitions 1 (P = .008) and 2 (P < .001) and also by injury severity (P < .001) and pain (P < .001) at transition 2. Movement into the Alcohol class was predicted only by pain (P = .011) at transition 2. A history of a substance use or alcohol use disorder before injury was implicated in movement into both of the alcohol-based classes. CONCLUSIONS: Predictors of developing a delayed-onset psychiatric disorder after severe injury differed by duration after injury and class of disorder. These findings highlight the need to offer targeted screening based on these risk factors to severe injury survivors up to 12 months postinjury, even when they present without disorder at 3 months. PMID- 27231843 TI - Low-Fouling Antibacterial Reverse Osmosis Membranes via Surface Grafting of Graphene Oxide. AB - Azide-functionalized graphene oxide (AGO) was covalently anchored onto commercial reverse osmosis (RO) membrane surfaces via azide photochemistry. Surface modification was carried out by coating the RO membrane with an aqueous dispersion of AGO followed by UV exposure under ambient conditions. This simple process produces a hydrophilic, smooth, antibacterial membrane with limited reduction in water permeability or salt selectivity. The GO-RO membrane exhibited a 17-fold reduction in biofouling after 24 h of Escherichia coli contact and almost 2 times reduced BSA fouling after a 1 week cross-flow test compared to its unmodified counterpart. PMID- 27231844 TI - Reformulating the entropic contribution in molecular docking scoring functions. AB - We have derived, in the context of the Rigid Rotor Harmonic Approximation (RRHO), a general mass and Planck's constant h independent expression for the dissociation free energy in ligand-receptor systems, featuring a systematically (anti-binding) additive negative entropic term depending on readily available ligand-receptor quantities. The proposed RRHO expression allows to straightforwardly compute the absolute standard dissociation free energy without resorting to expensive normal mode analysis or other dynamical matrix-based techniques for evaluating the entropic contribution, hence providing an effective scoring function for assessing docking poses with no adjustable parameters. Our RRHO formula was tested on a set of 55 ligand-receptor systems obtaining correlation coefficients and unsigned mean errors comparable to or better than those obtained with computationally demanding techniques for the dissociation entropy assessment. The proposed compact reformulation of the RRHO entropy term could constitute the basis for new and more effective scoring functions in molecular docking-based high-throughput virtual screening for drug discovery. (c) 2016 Wiley Periodicals, Inc. PMID- 27231842 TI - Improving Walking with an Implanted Neuroprosthesis for Hip, Knee, and Ankle Control After Stroke. AB - OBJECTIVE: The objective of this work was to quantify the effects of a fully implanted pulse generator to activate or augment actions of hip, knee, and ankle muscles after stroke. DESIGN: The subject was a 64-year-old man with left hemiparesis resulting from hemorrhagic stroke 21 months before participation. He received an 8-channel implanted pulse generator and intramuscular stimulating electrodes targeting unilateral hip, knee, and ankle muscles on the paretic side. After implantation, a stimulation pattern was customized to assist with hip, knee, and ankle movement during gait.The subject served as his own concurrent and longitudinal control with and without stimulation. Outcome measures included 10-m walk and 6-minute timed walk to assess gait speed, maximum walk time, and distance to measure endurance, and quantitative motion analysis to evaluate spatial-temporal characteristics. Assessments were repeated under 3 conditions: (1) volitional walking at baseline, (2) volitional walking after training, and (3) walking with stimulation after training. RESULTS: Volitional gait speed improved with training from 0.29 m/s to 0.35 m/s and further increased to 0.72 m/s with stimulation. Most spatial-temporal characteristics improved and represented more symmetrical and dynamic gait. CONCLUSIONS: These data suggest that a multijoint approach to implanted neuroprostheses can provide clinically relevant improvements in gait after stroke. TO CLAIM CME CREDITS: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES:: Upon completion of this article, the reader should be able to do the following: (1) Describe the rationale for evaluating a multijoint implanted neuroprosthesis to improvewalkingafter stroke; (2)Understand the study design and conclusions that can be inferred as a result of the design; and (3) Discuss the statistical significance and clinical relevance of changes between (a) volitional walking at baseline, (b) volitional walking after training, and (c) walking with stimulation after training. LEVEL: Advanced ACCREDITATION:: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Association of Academic Physiatrists designates this activity for a maximum of 1.5 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity. PMID- 27231845 TI - Physical activity, self-efficacy and self-esteem in breast cancer survivors: a panel model. AB - PURPOSE: Physical activity (PA) has been consistently associated with improved self-esteem in breast cancer survivors. However, this relationship is poorly understood. The purpose of this study was to examine whether changes in PA and self-efficacy influenced changes in self-esteem in breast cancer survivors across 6 months. Increases in PA were hypothesized to result in increases in self efficacy, which were hypothesized to influence increases in physical self-worth (PSW) and global self-esteem. METHODS: Breast cancer survivors (n = 370; Mage = 56.04) wore accelerometers to measure PA and completed measures of self-efficacy (e.g., exercise and barriers self-efficacy), PSW, and global self-esteem at baseline and 6 months. RESULTS: The hypothesized model provided a good fit to the data (chi2 = 67.56, df = 26, p < 0.001; comparative fit index (CFI) = 0.98; standardized root mean residual = 0.05). Women with higher activity at baseline reported significantly higher levels of barrier (beta = 0.29) and exercise (beta = 0.23) self-efficacy. In turn, more efficacious women reported significantly higher PSW (beta = 0.26, 0.16). Finally, higher PSW was significantly associated with greater global self-esteem (beta = 0.47). Relationships were similar among changes in model constructs over 6 months. After controlling for covariates, the hypothesized model provided an excellent fit to the data (chi2 = 59.93, df = 33, p = 0.003; comparative fit index = 0.99; standardized root mean residual = 0.03). CONCLUSION: Our findings provide support for the role played by PA and self efficacy in positive self-esteem, a key component of well-being. Highlighting successful PA mastery experiences is likely to enhance self-efficacy and improve self-esteem in this population. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27231846 TI - Artificial small RNA for sequence specific cleavage of target RNA through RNase III endonuclease Dicer. AB - CRISPR-Cas9 system uses a guide RNA which functions in conjunction with Cas9 proteins to target a DNA and cleaves double-strand DNA. This phenomenon raises a question whether an artificial small RNA (asRNA), composed of a Dicer-binding RNA element and an antisense RNA, could also be used to induce Dicer to process and degrade a specific RNA. If so, we could develop a new method which is named DICERi for gene silencing or RNA editing. To prove the feasibility of asRNA, we selected MALAT-1 as target and used Hela and MDA-MB-231 cells as experimental models. The results of qRT-PCR showed that the introduction of asRNA decreased the relative expression level of target gene significantly. Next, we analyzed cell proliferation using CCK-8 and EdU staining assays, and then cell migration using wound scratch and Transwell invasion assays. We found that cell proliferation and cell migration were both suppressed remarkably after asRNA was expressed in Hela and MDA-MB-231 cells. Cell apoptosis was also detected through Hoechst staining and ELISA assays and the data indicated that he numbers of apoptotic cell in experimental groups significantly increased compared with negative controls. In order to prove that the gene silencing effects were caused by Dicer, we co-transfected shRNA silencing Dicer and asRNA. The relative expression levels of Dicer and MALAT-1 were both detected and the results indicated that when the cleavage role of Dicer was silenced, the relative expression level of MALAT-1 was not affected after the introduction of asRNA. All the above results demonstrated that these devices directed by Dicer effectively excised target RNA and repressed the target genes, thus causing phenotypic changes. Our works adds a new dimension to gene regulating technologies and may have broad applications in construction of gene circuits. PMID- 27231847 TI - EAAT3 promotes amino acid transport and proliferation of porcine intestinal epithelial cells. AB - Excitatory amino acid transporter 3 (EAAT3, encoded by SLC1A1) is an epithelial type high-affinity anionic amino acid transporter, and glutamate is the major oxidative fuel for intestinal epithelial cells. This study investigated the effects of EAAT3 on amino acid transport and cell proliferation through activation of the mammalian target of the rapamycin (mTOR) pathway in porcine jejunal epithelial cells (IPEC-J2). Anionic amino acid and cystine (Cys) transport were increased (P<0.05) by EAAT3 overexpression and decreased (P<0.05) by EAAT3 knockdown rather than other amino acids. MTT and cell counting assays suggested that IPEC-J2 cell proliferation increased (P<0.05) with EAAT3 overexpression. Phosphorylation of mTOR (Ser2448), ribosomal protein S6 kinase-1 (S6K1, Thr389) and eukaryotic initiation factor 4E-binding protein-1 (4EBP1, Thr70) was increased by EAAT3 overexpression and decreased by EAAT3 knockdown (P<0.05), as were levels of activating transcription factor 4 (ATF4) and cystine/glutamate antiporter (xCT) (P<0.05). Our results demonstrate for the first time that EAAT3 facilitates anionic amino acid transport and activates the mTOR pathway, promoting Cys transport and IPEC-J2 cell proliferation. PMID- 27231848 TI - Phosphatidylserine-targeted liposome for enhanced glioma-selective imaging. AB - Phosphatidylserine (PS), which is normally intracellular, becomes exposed on the outer surface of viable endothelial cells (ECs) of tumor vasculature. Utilizing a PS-targeting antibody, we have recently established a PS-targeted liposomal (PS L) nanoplatform that has demonstrated to be highly tumor-selective. Because of the vascular lumen-exposed PS that is immediately accessible without a need to penetrate the intact blood brain barrier (BBB), we hypothesize that the systemically administered PS-L binds specifically to tumor vascular ECs, becomes subsequently internalized into the cells and then enables its cargos to be efficiently delivered to glioma parenchyma. To test this, we exploited the dual MRI/optical imaging contrast agents-loaded PS-L and injected it intravenously into mice bearing intracranial U87 glioma. At 24 h, both in vivo optical imaging and MRI depicted enhanced tumor contrast, distinct from the surrounding normal brain. Intriguingly, longitudinal MRI revealed temporal and spatial intratumoral distribution of the PS-L by following MRI contrast changes, which appeared punctate in tumor periphery at an earlier time point (4 h), but became clustering and disseminated throughout the tumor at 24 h post injection. Importantly, glioma targeting specificity of the PS-L was antigen specific, since a control probe of irrelevant specificity showed minimal accumulation in the glioma. Together, these results indicate that the PS-L nanoplatform enables the enhanced, glioma-targeted delivery of imaging contrast agents by crossing the tumor BBB efficiently, which may also serve as a useful nanoplatform for anti-glioma drugs. PMID- 27231849 TI - Exosomal cancer immunotherapy is independent of MHC molecules on exosomes. AB - Peptide-loaded exosomes are promising cancer treatment vehicles; however, moderate T cell responses in human clinical trials indicate a need to further understand exosome-induced immunity. We previously demonstrated that antigen loaded exosomes carry whole protein antigens and require B cells for inducing antigen-specific T cells. Therefore, we investigated the relative importance of exosomal major histocompatibility complex (MHC) class I for the induction of antigen-specific T cell responses and tumour protection. We show that ovalbumin loaded dendritic cell-derived exosomes from MHCI-/- mice induce antigen-specific T cells at the same magnitude as wild type exosomes. Furthermore, exosomes lacking MHC class I, as well as exosomes with both MHC class I and II mismatch, induced tumour infiltrating T cells and increased overall survival to the same extent as syngeneic exosomes in B16 melanoma. In conclusion, T cell responses are independent of exosomal MHC/peptide complexes if whole antigen is present. This establishes the prospective of using impersonalised exosomes, and will greatly increase the feasibility of designing exosome-based vaccines or therapeutic approaches in humans. PMID- 27231850 TI - BCL-W is a regulator of microtubule inhibitor-induced mitotic cell death. AB - Microtubule inhibitors including taxanes and vinca alkaloids are among the most widely used anticancer agents. Disrupting the microtubules activates the spindle assembly checkpoint and traps cells in mitosis. Whether cells subsequently undergo mitotic cell death is an important factor for the effectiveness of the anticancer agents. Given that apoptosis accounts for the majority of mitotic cell death induced by microtubule inhibitors, we performed a systematic study to determine which members of the anti-apoptotic BCL-2 family are involved in determining the duration of mitotic block before cell death or slippage. Depletion of several anti-apoptotic BCL-2-like proteins significantly shortened the time before apoptosis. Among these proteins, BCL-W has not been previously characterized to play a role in mitotic cell death. Although the expression of BCL-W remained constant during mitotic block, it varied significantly between different cell lines. Knockdown of BCL-W with siRNA or disruption of the BCL-W gene with CRISPR-Cas9 speeded up mitotic cell death. Conversely, overexpression of BCL-W delayed mitotic cell death, extending the mitotic block to allow mitotic slippage. Taken together, these results showed that BCL-W contributes to the threshold of anti-apoptotic activity during mitosis. PMID- 27231851 TI - Urinary mRNA biomarker panel for the detection of urothelial carcinoma. AB - The early detection of bladder cancer is important as the disease has a high rate of recurrence and progression. The development of accurate, non-invasive urinary assays would greatly facilitate detection. In previous studies, we have reported the discovery and initial validation of mRNA biomarkers that may be applicable in this context. In this study, we evaluated the diagnostic performance of proposed molecular signatures in an independent cohort.Forty-four mRNA transcripts were monitored blindly in urine samples obtained from a cohort of 196 subjects with known bladder disease status (89 with active BCa) using quantitative real-time PCR (RT-PCR). Statistical analyses defined associations of individual biomarkers with clinical data and the performance of predictive multivariate models was assessed using ROC curves. The majority of the candidate mRNA targets were confirmed as being associated with the presence of BCa over other clinical variables. Multivariate models identified an optimal 18-gene diagnostic signature that predicted the presence of BCa with a sensitivity of 85% and a specificity of 88% (AUC 0.935). Analysis of mRNA signatures in naturally micturated urine samples can provide valuable information for the evaluation of patients under investigation for BCa. Additional refinement and validation of promising multi target signatures will support the development of accurate assays for the non invasive detection and monitoring of BCa. PMID- 27231852 TI - Efficient role of IgH 3' regulatory region deficient B-cells in the development of oil granulomas. AB - Functional B-cells are essential for the formation of oil granulomas. The IgH 3' regulatory region (3'RR) activates important check-points during B-cell maturation. We investigated if 3'RR-deficient B-cells remain efficient to develop oil granulomas in response to pristine. B-cells expressing an IgH 3'RR-deficient allele were similarly recruited to wild type allele expressing B-cells in the granuloma. No differences were observed between 3'RR-deficient mice and control mice for granuloma numbers, cellular composition and ability to express mRNA transcripts for several pro- and anti-inflammatory cytokines. Altogether these results suggest a normal role for 3'RR-deficient B-cells in the development of an acute B-cell-mediated inflammatory response. PMID- 27231854 TI - MiR-499-5p protects cardiomyocytes against ischaemic injury via anti-apoptosis by targeting PDCD4. AB - Recent studies have reported that miRNAs might play critical roles in acute myocardial infarction (AMI). The objective of this study is to investigate the role of miR-499-5p in AMI and its potential molecular mechanisms. The expression level of MiR-499-5p was remarkably decreased in the infarcted myocardial tissues and in the cultured neonatal rat cardiomyocytes induced by hypoxia. Overexpression or knockdown of miR-499-5p decreased or increased the apoptotic rates of cultured cardiomyocytes in vitro. In addition, ectopic overexpression of miR-499-5p in the rat AMI models with agomir reduced the myocardial infarct size through decreasing the cardiomyocytes apoptosis in the infarcted area of the rat hearts. PDCD4 (programmed cell death 4) was verified as a direct target of miR 499-5p by luciferase report assay, and ectopic overexpression or inhibition of miR-499-5p could inhibit or increase the PDCD4 expression at both the mRNA and protein levels. Furthermore, we found that ectopic overexpression of PDCD4 without miR-499-5p binding sites reversed miR-499-5p-mediated cardiomyocytes apoptosis. Together, these findings revealed the role of miR-499-5p in protecting the cardiomyocytes against apoptosis induced by AMI via its direct target PDCD4, which providing evidence for the miR-499-5p/PDCD4 pathway as a potential therapeutic target for patients with AMI. PMID- 27231853 TI - Use of estetrol with other steroids for attenuation of neonatal hypoxic-ischemic brain injury: to combine or not to combine? AB - Estetrol (E4), estradiol (E2) and progesterone (P4) have important antioxidative and neuroprotective effects in neuronal system. We aimed to study the consequence of combined steroid therapy in neonatal hypoxic-ischemic encephalopathy (HIE). In vitro the effect of E4 combined with other steroids on oxidative stress and the cell viability in primary hippocampal cultures was evaluated by lactate dehydrogenase and cell survival assays. In vivo neuroprotective and therapeutic efficacy of E4 combined with other steroids was studied in HIE model of immature rats. The rat pups rectal temperature, body and brain weights were evaluated.The hippocampus and the cortex were investigated by histo/immunohistochemistry: intact cell number counting, expressions of markers for early gray matter lose, neuro- and angiogenesis were studied. Glial fibrillary acidic protein was evaluated by ELISA in blood samples. In vitro E4 and combinations of high doses of E4 with P4 and/or E2 significantly diminished the LDH activity and upregulated the cell survival.In vivopretreatment or treatment by different combinations of E4 with other steroids had unalike effects on body and brain weight, neuro- and angiogenesis, and GFAP expression in blood. The combined use of E4 with other steroids has no benefit over the single use of E4. PMID- 27231856 TI - Three Redox States of a Diradical Acceptor-Donor-Acceptor Triad: Gating the Magnetic Coupling and the Electron Delocalization. AB - The diradical acceptor-donor-acceptor triad 1(**), based on two polychlorotriphenylmethyl (PTM) radicals connected through a tetrathiafulvalene(TTF)-vinylene bridge, has been synthesized. The generation of the mixed-valence radical anion, 1(*-), and triradical cation species, 1(***+), obtained upon electrochemical reduction and oxidation, respectively, was monitored by optical and ESR spectroscopy. Interestingly, the modification of electron delocalization and magnetic coupling was observed when the charged species were generated and the changes have been rationalized by theoretical calculations. PMID- 27231857 TI - Orphan Lung Diseases. PMID- 27231858 TI - Genetics and Idiopathic Interstitial Pneumonias. AB - Significant progress has been made in elucidating the genetics of parenchymal lung diseases, particularly idiopathic interstitial pneumonias (IIPs). IIPs are a heterogeneous group of diffuse interstitial lung diseases of uncertain etiology, diagnosed only after known causes of interstitial lung disease have been excluded. Idiopathic pulmonary fibrosis is the most common IIP. Through candidate gene approaches and genome wide association studies, much light has been shed on the genetic origins of IIPs, enhancing our understanding of risk factors and pathogenesis. However, significant work remains to be accomplished in identifying novel genetic variants and characterizing the function of validated candidate genes in lung pathobiology, their interplay with environmental factors, and ultimately translating these discoveries to patient care. PMID- 27231859 TI - Idiopathic Pulmonary Fibrosis: Epidemiology, Clinical Features, Prognosis, and Management. AB - Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic interstitial lung pneumonia associated with the histologic pattern of usual interstitial pneumonia (UIP). Although UIP is a distinct histologic lesion, this histologic pattern is not specific for IPF and can also be found in other diseases (e.g., connective tissue disease and asbestosis). Clinical features of IPF include progressive cough, dyspnea, restrictive ventilatory defect, and progressive fibrosis and destruction of the lung parenchyma. IPF is rare (13-42 cases/100,000), and primarily affects older adults (>50 years of age). The diagnosis of IPF often requires surgical lung biopsy, but the diagnosis can be affirmed with confidence in some patients provided the results of computed tomographic (CT) scans and clinical features are consistent. The clinical course is variable, but inexorable progression (typically over months to years) is typical. Mean survival from the onset of symptoms approximates 3 to 5 years. Medical treatment is only modestly effective, primarily by slowing the rate of disease progression. Lung transplantation is the best therapeutic option. PMID- 27231860 TI - What We Know About the Pathogenesis of Idiopathic Pulmonary Fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease of unknown cause, occurring in adults, limited to the lungs and associated with the pathologic and radiologic pattern of usual interstitial pneumonia. Prognosis is poor, and most patients die of respiratory failure within 3 to 6 years from the onset of symptoms. Although our understanding of the pathogenesis of IPF has improved over the past two decades, the mechanisms responsible for this disorder have not been clearly defined. Aging is the single most important risk factor, but genetic, environmental, and diverse exogenous factors such as smoking, viral infections, chronic tissue injury (i.e., gastroesophageal reflux disease, traction injury) play contributory roles. In this review, we focus on pathogenetic mechanisms that we think are crucial for the initiation of the fibrotic process and for its progressive evolution. In the early stage of the disease, in the context of the permissive genetic background combined with the presence of specific risk factors, alveolar epithelial cells play a leading role. Subsequent evolution of the fibrotic process and its lethal progression is likely due to the abnormal tissue repair process that takes place in the lung and to the inability to counteract this process. In this phase of the disease, fibroblasts assume a crucial role. Current pharmacological treatment strategies for IPF have only modest value, principally by slowing the course of disease progression. Unfortunately, improvement or cure has not yet been achieved with pharmacological agents. The challenge for the future is to improve the comprehension of the mechanisms involved in the inception and evolution of IPF and their articulated interactions. This is fundamental not only to conceive and develop new drugs against this dreadful disease but also to apply different therapeutic approaches such as drug repositioning and personalized therapies in the management of IPF. PMID- 27231861 TI - Medical Therapy in Idiopathic Pulmonary Fibrosis. AB - Medical therapy for idiopathic fibrosis remains controversial. Idiopathic pulmonary fibrosis (IPF) was uniformly a disease that progressed inexorably, typically leading to death within 3 to 5 years from onset of symptoms. Until recently, lung transplantation was the only effective transplant option. Within the past decade, several placebo-controlled trials failed to show benefit in patients with IPF. However, within the past 2 years, two novel antifibrotic agents (pirfenidone and nintedanib) were approved by the Food and Drug Administration (FDA) in the United States and European Medicines Agency (EMA) based upon pivotal studies that showed benefit (specifically slowing of the rate of disease progression) with both agents. Short-term outcomes (12 months) showed less deterioration of physiological parameters (e.g., change in forced vital capacity), although survival benefit has not convincingly been established with either agent. Nonetheless, these agents bring a glimmer of hope to patients with this deadly disease. The appropriate indications for initiating therapy, best candidates for therapy, and possible role for combination therapy remain controversial. Additional studies using agents that attenuate or abrogate profibrotic cytokines and chemokines may provide even further improvement in the future. PMID- 27231862 TI - Nonspecific Interstitial Pneumonia: What Is the Optimal Approach to Management? AB - We reviewed current aspects of the clinical and pathogenic profile of nonspecific interstitial pneumonia (NSIP), to better elucidate the complex issue of management and treatment options for NSIP patients. Recent findings suggest that idiopathic NSIP is a complex clinical entity with a disease spectrum that includes at least three different phenotypes: NSIP associated with autoimmune features, emphysema, and familial interstitial lung disease. This distinction, based mainly on clinical findings, may be of critical importance when it comes to making a decision on patients' management. This hypothesis warrants further studies. Currently, two major radiologic-pathologic different profiles have been well established. First, the "inflammatory type" characterized by prominent lymphocytic inflammation both on biopsy and bronchoalveolar lavage (BAL), and high-resolution computed tomography (HRCT) with mixed NSIP/organizing pneumonia pattern that tends to have a better response to corticosteroid and immunosuppressive treatment. Second, the "highly fibrotic" subgroup that shows prominent reticular changes and traction bronchiectasis by HRCT, high fibrotic background on biopsy, and no lymphocytosis on BAL. The latter fibrotic NSIP is the subgroup with less potential to respond to immunosuppressive treatment and a marginal risk to evolve into "full-blown idiopathic pulmonary fibrosis." The management of patients with fibrotic, progressive, and immunosuppressive treatment, refractory NSIP remains uncertain, and further studies are needed to address the role of antifibrotic drug in this settings. Oxygen therapy, pulmonary rehabilitation, and lung transplantation are of importance in the current management of severe, progressive, and refractory NSIP patients. PMID- 27231863 TI - Hypersensitivity Pneumonitis: Challenges in Diagnosis and Management, Avoiding Surgical Lung Biopsy. AB - This review presents an update of the currently available information related to hypersensitivity pneumonitis, with a particular focus on the contribution of several techniques in the diagnosis of this condition. The methods discussed include proper elaboration of a complete medical history, targeted auscultation, detection of specific immunoglobulin G antibodies against the most common antigens causing this disease, skin tests, antigen-specific lymphocyte activation assays, bronchoalveolar lavage, and cryobiopsy. Special emphasis is placed on the relevant contribution of specific inhalation challenge (bronchial challenge test). Surgical lung biopsy is presented as the ultimate recourse, to be used when the diagnosis cannot be reached through the other methods covered. PMID- 27231864 TI - Lymphoid Interstitial Pneumonia and Other Benign Lymphoid Disorders. AB - Benign pulmonary lymphoid disorders include a variety of rare lymphoid abnormalities characterized by a polyclonal lymphoid infiltrate with differing histopathologic patterns and clinicoradiologic features that may overlap. Histological examination is essential to reach a correct diagnosis and to exclude alternative causes, although this task can at times prove difficult. Further studies and clinical trials are needed to provide additional insights on pathogenesis and to guide the therapeutic management of these disorders. The purpose of this article is to review the histopathological, epidemiological, and clinicoradiologic features of several benign pulmonary lymphoid disorders, including lymphoid interstitial pneumonia, follicular bronchiolitis, nodular lymphoid hyperplasia (pulmonary pseudolymphoma), inflammatory pseudotumor, immunoglobulin G4-related disease, Castleman disease, posttransplantation lymphoproliferative disease, and drug-induced lymphoid disorders. PMID- 27231865 TI - Many Faces of Bronchiolitis and Organizing Pneumonia. AB - As the bronchioles have a strategic position between the airways and the alveolar structures, they are at a site where disorders of many origins may develop, including infections, inflammatory and/or fibrosing processes of immune, occupational, environmental, tumoral, and iatrogenic origin, which may result in predominant bronchiolitis and/or organizing pneumonia. This etiologic variety results in many distinct entities and syndromes, common or rare, with new or renewed faces such as bronchiolocentric interstitial pneumonia or organizing pneumonia primed by radiation to the breast. PMID- 27231866 TI - Current Approach to Diagnosis and Management of Pulmonary Eosinophilic Syndromes: Eosinophilic Pneumonias, Eosinophilic Granulomatosis with Polyangiitis, and Hypereosinophilic Syndrome. AB - Eosinophils play a key role in orchestrating the complex clinicopathological pulmonary and extrapulmonary disease features in patients with eosinophilic syndromes. Eosinophilic pulmonary syndromes consist of a heterogeneous group of disorders characterized by the presence of peripheral blood eosinophilia and/or eosinophilic-related pulmonary impairment. These disorders can present with varying degrees of organ involvement, and while their presentation may be similar, it is important to define the disease state, as management and prognosis differ. In this article, we discuss acute and chronic eosinophilic pneumonias, eosinophilic granulomatosis with polyangiitis, and the hypereosinophilic syndromes. The mainstay of therapy for these disorders has been corticosteroids; however, recent and ongoing studies have provided strong grounds for optimism for specific targeted treatment approaches. PMID- 27231867 TI - Diffuse Cystic Lung Diseases: Diagnostic Considerations. AB - Diffuse cystic lung disease (DCLD) is a group of heterogeneous diseases that present as diffuse cystic changes in the lung on computed tomography of the chest. Most DCLD diseases are rare, although they might resemble common diseases such as emphysema and bronchiectasis. Main causes of DCLD include lymphangioleiomyomatosis, Birt-Hogg-Dube syndrome, pulmonary Langerhans cell histiocytosis, lymphoid interstitial pneumonia, amyloidosis, light-chain deposition disease, Sjogren syndrome, and primary or metastatic neoplasm. We discuss clinical factors that are helpful in the differential diagnosis of DCLDsuch as sex and age, symptoms and signs, extrapulmonary presentations, cigarette smoking, and family history. Investigations for DCLD include high resolution computed tomography, biochemical and histopathological studies, genetic tests, pulmonary function tests, and bronchoscopic and video-assisted thoracoscopic biopsies. A proposed diagnostic algorithm would enhance ease of diagnosing most cases of DCLD. PMID- 27231868 TI - Connective Tissue Disease-Associated Interstitial Lung Diseases: Unresolved Issues. AB - Interstitial lung disease (ILD) complicating connective tissue disorders, such as scleroderma and rheumatoid arthritis, is associated with significant morbidity and mortality. Progress has been made in our understanding of these collective diseases; however, there are still many unanswered questions. In this review, we describe the current views on epidemiology, clinical presentation, treatment, and prognosis in patients with connective tissue disease (CTD)-associated ILD. We also highlight several areas that remain unresolved and in need of further investigation, including interstitial pneumonia with autoimmune features, histopathologic phenotype, and pharmacologic management. A multidisciplinary and multidimensional approach to diagnosis, management, and investigation of CTD associated ILD patients is essential to advance our understanding of the epidemiology and pathobiology of this challenging group of diseases. PMID- 27231869 TI - Recent Advances and Future Needs in Interstitial Lung Diseases. AB - Interstitial lung diseases (ILDs) are a diverse range of conditions affecting the lung interstitium. The prototypic ILD, idiopathic pulmonary fibrosis (IPF), is a chronic progressive fibrotic lung disease with a median survival of only 3 years from the time of diagnosis. Recently significant progress has been made in both our understanding of the pathogenesis and of the therapeutic targeting of IPF. This culminated in the worldwide approval of the first antifibrotic therapies nintedanib and pirfenidone. While an important first step, patients continue to progress and better therapies are urgently required. The aim of this article is to highlight some of the recent advances that have been made in our understanding of genetics, disease classification, clinical trial design, and novel antifibrotic therapy in IPF. It discusses future priorities if we are to continue to increase the length and quality of life of patients with IPF, and considers possible approaches to translate the progress made in IPF to other progressive fibrotic lung diseases where our understanding remains limited. PMID- 27231870 TI - Rapid infant weight gain and early childhood obesity in low-income Latinos and non-Latinos. AB - OBJECTIVE: To examine the growth of infants and toddlers in a population that is both under-represented in the literature and at high risk for childhood obesity. DESIGN: Weight and height measurements were extracted from all visits for a sample of 0-4-year-old, low-income, Latino and non-Latino patients of an urban, academic general paediatric practice. Early growth was characterized as change in weight-for-length Z-score (WLZ) from birth to 3 years. The outcome of interest was BMI Z-score (BMIZ) at age 3 years. Mixed-effects models and multivariate linear regression were used to analyse the association between infant growth and early childhood obesity. SETTING: Baltimore, MD, USA. SUBJECTS: Latino (n 210) and non-Latino (n 253) children, born in 2003-2004. RESULTS: An increase in WLZ from birth to 2 years was observed for this cohort as well as a high incidence of overweight and obesity. WLZ at birth and change in WLZ from birth to 2 years were both significantly and positively associated with increases in BMIZ at 3 years of age. The effect of the change in WLZ was twofold higher than the effect of WLZ at birth. CONCLUSIONS: An increase in WLZ during the first 2 years of life increased the risk of early childhood obesity. Latino children had a higher incidence of early childhood obesity than non-Latino children in this low-income sample. PMID- 27231871 TI - A Dosimetric Study of Using Fixed-Jaw Volumetric Modulated Arc Therapy for the Treatment of Nasopharyngeal Carcinoma with Cervical Lymph Node Metastasis. AB - PURPOSE: To study the dosimetric difference between fixed-jaw volumetric modulated radiotherapy (FJ-VMAT) and large-field volumetric modulated radiotherapy (LF-VMAT) for nasopharyngeal carcinoma (NPC) with cervical lymph node metastasis. METHODS: Computed tomography (CT) datasets of 10 NPC patients undergoing chemoradiotherapy were used to generate LF-VMAT and FJ-VMAT plans in the Eclipse version 10.0 treatment planning system. These two kinds of plans were then compared with respect to planning-target-volume (PTV) coverage, conformity index (CI), homogeneity index (HI), organ-at-risk sparing, monitor units (MUs) and treatment time (TT). RESULTS: The FJ-VMAT plans provided lower D2% of PGTVnd (PTV of lymph nodes), PTV1 (high-risk PTV) and PTV2 (low-risk PTV) than did the LF-VMAT plans, whereas no significant differences were observed in PGTVnx (PTV of primary nasopharyngeal tumor). The FJ-VMAT plans provided lower doses delivered to the planning organ at risk (OAR) volumes (PRVs) of both brainstem and spinal cord, both parotid glands and normal tissue than did the LF-VMAT plans, whereas no significant differences were observed with respect to the oral cavity and larynx. The MUs of the FJ-VMAT plans (683 +/- 87) were increased by 22% +/- 12% compared with the LF-VMAT plans (559 +/- 62). In terms of the TT, no significant difference was found between the two kinds of plans. CONCLUSIONS: FJ-VMAT was similar or slightly superior to LF-VMAT in terms of PTV coverage and was significantly superior in terms of OAR sparing, at the expense of increased MUs. PMID- 27231872 TI - Remote Control of Intestinal Stem Cell Activity by Haemocytes in Drosophila. AB - The JAK/STAT pathway is a key signaling pathway in the regulation of development and immunity in metazoans. In contrast to the multiple combinatorial JAK/STAT pathways in mammals, only one canonical JAK/STAT pathway exists in Drosophila. It is activated by three secreted proteins of the Unpaired family (Upd): Upd1, Upd2 and Upd3. Although many studies have established a link between JAK/STAT activation and tissue damage, the mode of activation and the precise function of this pathway in the Drosophila systemic immune response remain unclear. In this study, we used mutations in upd2 and upd3 to investigate the role of the JAK/STAT pathway in the systemic immune response. Our study shows that haemocytes express the three upd genes and that injury markedly induces the expression of upd3 by the JNK pathway in haemocytes, which in turn activates the JAK/STAT pathway in the fat body and the gut. Surprisingly, release of Upd3 from haemocytes upon injury can remotely stimulate stem cell proliferation and the expression of Drosomycin-like genes in the intestine. Our results also suggest that a certain level of intestinal epithelium renewal is required for optimal survival to septic injury. While haemocyte-derived Upd promotes intestinal stem cell activation and survival upon septic injury, haemocytes are dispensable for epithelium renewal upon oral bacterial infection. Our study also indicates that intestinal epithelium renewal is sensitive to insults from both the lumen and the haemocoel. It also reveals that release of Upds by haemocytes coordinates the wound-healing program in multiple tissues, including the gut, an organ whose integrity is critical to fly survival. PMID- 27231873 TI - Molecular cloning and functional analysis of a 10-epi-junenol synthase from Inula hupehensis. AB - Junenol based-eudesmanolides have been detected in many compositae plant species and were reported to exhibit various pharmacological activities. So far, the gene encoding junenol synthase has never been isolated. Here we report the molecular cloning and functional analysis of a 10-epi-junenol synthase from Inula hupehensis (designated IhsTPS1). IhsTPS1 converts the substrate farnesyl diphosphate into multiple sesquiterpenes with the product 10-epi-junenol being predominant. The transcript levels of IhsTPS1 correlate well with the accumulation pattern of 10-epi-junenol in I. hupehensis organs, supporting its biochemical roles in vivo. PMID- 27231874 TI - Rhizosphere associated bacteria trigger accumulation of terpenes in leaves of Vitis vinifera L. cv. Malbec that protect cells against reactive oxygen species. AB - It has been proposed that plant growth promoting rhizobacteria (PGPR) stimulate plant growth and development by inducing the biosynthesis of secondary metabolites, like terpenes, which reduce stress incidence. Three bacteria previously isolated from grapevine roots and adjacent soil (Microbacterium imperiale Rz19M10, Kocuria erythromyxa Rt5M10 and Terribacillus saccharophilus Rt17M10) were tested as PGPR. After 30 days since root inoculation of in vitro grown Vitis vinifera cv. Malbec plants, the monoterpenes alpha-pinene, terpinolene and 4-carene, and the sesquiterpene nerolidol were detected only in bacterized-plant leaves. Also, the concentrations of the diterpenes alpha and gamma-tocopherol, and the sterols sitosterol and lupeol were significantly enhanced compared to controls. The leaf extracts of bacterized plants showed photoprotective properties since they decreased the oxygen consumption (that is photo-oxidation) of the amino acid tryptophan in a sensitized solution, thus indicating an increment of the antioxidant capacity of the tissues. In addition, experiments with alpha-pinene and nerolidol standards showed the capability to intercept reactive oxygen species in the sensitized solution. Moreover, bacterized plants infected with the pathogen Botrytis cinerea showed a reduction in the lesion diameter compared with non-bacterized plants. The results suggest that M. imperiale, K. erythromyxa and mainly T. saccharophilus are able to induce a systemic response that trigger increases on monoterpenes, sesquiterpenes, tocopherols and membrane sterols. These compounds enhance the antioxidant capacity in leaf tissues that may help grapevine to cope with stresses. PMID- 27231875 TI - The influence of photoperiod and light intensity on the growth and photosynthesis of Dunaliella salina (chlorophyta) CCAP 19/30. AB - The green microalga Dunaliella salina survives in a wide range of salinities via mechanisms involving glycerol synthesis and degradation and is exploited for large amounts of nutraceutical carotenoids produced under stressed conditions. In this study, D. salina CCAP 19/30 was cultured in varying photoperiods and light intensities to study the relationship of light with different growth measurement parameters, with cellular contents of glycerol, starch and carotenoids, and with photosynthesis and respiration. Results show CCAP 19/30 regulated cell volume when growing under light/dark cycles: cell volume increased in the light and decreased in the dark, and these changes corresponded to changes in cellular glycerol content. The decrease in cell volume in the dark was independent of cell division and biological clock and was regulated by the photoperiod of the light/dark cycle. When the light intensity was increased to above 1000 MUmol photons m(-2) s(-1), cells displayed evidence of photodamage. However, these cells also maintained the maximum level of photosynthesis efficiency and respiration possible, and the growth rate increased as light intensity increased. Significantly, the intracellular glycerol content also increased, >2-fold compared to the content in light intensity of 500 MUmol photons m(-2) s(-1), but there was no commensurate increase in the pool size of carotenoids. These data suggest that in CCAP 19/30 glycerol stabilized the photosynthetic apparatus for maximum performance in high light intensities, a role normally attributed to carotenoids. PMID- 27231877 TI - The natural chlorine cycle - Formation of the carcinogenic and greenhouse gas compound chloroform in drinking water reservoirs. AB - Chlorine cycle in natural ecosystems involves formation of low and high molecular weight organic compounds of living organisms, soil organic matter and atmospherically deposited chloride. Chloroform (CHCl3) and adsorbable organohalogens (AOX) are part of the chlorine cycle. We attempted to characterize the dynamical changes in the levels of total organic carbon (TOC), AOX, chlorine and CHCl3 in a drinking water reservoir and in its tributaries, mainly at its spring, and attempt to relate the presence of AOX and CHCl3 with meteorological, chemical or biological factors. Water temperature and pH influence the formation and accumulation of CHCl3 and affect the conditions for biological processes, which are demonstrated by the correlation between CHCl3 and SigmaAOX/Cl(-) ratio, and also by CHCl3/SigmaAOX, CHCl3/AOXLMW, CHCl3/SigmaTOC, CHCl3/TOCLMW and CHCl3/Cl(-) ratios in different microecosystems (e.g. old spruce forest, stagnant acidic water, humid and warm conditions with high biological activity). These processes start with the biotransformation of AOX from TOC, continue via degradation of AOX to smaller molecules and further chlorination, and finish with the formation of small chlorinated molecules, and their subsequent volatilization and mineralization. The determined concentrations of chloroform result from a dynamic equilibrium between its formation and degradation in the water; in the Hamry water reservoir, this results in a total amount of 0.1-0.7 kg chloroform and 5.2-15.4 t chloride. The formation of chloroform is affected by Cl(-) concentration, by concentrations and ratios of biogenic substrates (TOC and AOX), and by the ratios of the substrates and the product (feedback control by chloroform itself). PMID- 27231876 TI - Prokaryotic Soluble Overexpression and Purification of Human VEGF165 by Fusion to a Maltose Binding Protein Tag. AB - Human vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis and plays a central role in the process of tumor growth and metastatic dissemination. Escherichia coli is one of the most common expression systems used for the production of recombinant proteins; however, expression of human VEGF in E. coli has proven difficult because the E. coli-expressed VEGF tends to be misfolded and forms inclusion bodies, resulting in poor solubility. In this study, we successfully produced semi-preparative amounts of soluble bioactive human VEGF165 (hVEGF). We created seven N-terminal fusion tag constructs with hexahistidine (His6), thioredoxin (Trx), glutathione S transferase (GST), maltose-binding protein (MBP), N-utilization substance protein A (NusA), human protein disulfide isomerase (PDI), and the b'a' domain of PDI (PDIb'a'), and tested each construct for soluble overexpression in E. coli. We found that at 18 degrees C, 92.8% of the MBP-tagged hVEGF to be soluble and that this tag significantly increased the protein's solubility. We successfully purified 0.8 mg of pure hVEGF per 500 mL cell culture. The purified hVEGF is stable after tag cleavage, contains very low levels of endotoxin, and is 97.6% pure. Using an Flk1+ mesodermal precursor cell (MPC) differentiation assay, we show that the purified hVEGF is not only bioactive but has similar bioactivity to hVEGF produced in mammalian cells. Previous reports on producing hVEGF in E. coli have all been based on refolding of the protein from inclusion bodies. To our knowledge, this is the first report on successfully expressing and purifying soluble hVEGF in E. coli. PMID- 27231878 TI - Complete biodegradation of chlorpyrifos by engineered Pseudomonas putida cells expressing surface-immobilized laccases. AB - The long-term abuse use of chlorpyrifos-like pesticides in agriculture and horticulture has resulted in significant soil or water contamination and a worldwide ecosystem threat. In this study, the ability of a solvent-tolerant bacterium, Pseudomonas putida MB285, with surface-displayed bacterial laccase, to biodegrade chlorpyrifos was investigated. The results of compositional analyses of the degraded products demonstrate that the engineered MB285 was capable of completely eliminating chlorpyrifos via direct biodegradation, as determined by high-performance liquid chromatography and gas chromatography-mass spectrometry assays. Two intermediate metabolites, namely 3,5,6-trichloro-2-pyridinol (TCP) and diethyl phosphate, were temporarily detectable, verifying the joint and stepwise degradation of chlorpyrifos by surface laccases and certain cellular enzymes, whereas the purified free laccase incompletely degraded chlorpyrifos into TCP. The degradation reaction can be conducted over a wide range of pH values (2-7) and temperatures (5-55 degrees C) without the need for Cu(2+). Bioassays using Caenorhabditis elegans as an indicator organism demonstrated that the medium was completely detoxified of chlorpyrifos by degradation. Moreover, the engineered cells exhibited a high capacity of repeated degradation and good performance in continuous degradation cycles, as well as a high capacity to degrade real effluents containing chlorpyrifos. Therefore, the developed system exhibited a high degradation capacity and performance and constitutes an improved approach to address chlorpyrifos contamination in chlorpyrifos-remediation practice. PMID- 27231879 TI - Iodine binding to humic acid. AB - The rate of reactions between humic acid (HA) and iodide (I(-)) and iodate (IO3( )) have been investigated in suspensions spiked with (129)I at concentrations of 22, 44 and 88 MUg L(-1) and stored at 10 degrees C. Changes in the speciation of (129)I(-), (129)IO3(-) and mixed ((129)I(-) + (129)IO3(-)) spikes were monitored over 77 days using liquid chromatography inductively coupled plasma mass spectrometry (LC-ICP-MS). In suspensions spiked with (129)I(-) 25% of the added I(-) was transformed into organic iodine (Org-(129)I) within 77 days and there was no evidence of (129)IO3(-) formation. By contrast, rapid loss of (129)IO3(-) and increase in both (129)I(-) and Org-(129)I was observed in (129)IO3(-)-spiked suspensions. However, the rate of Org-(129)I production was greater in mixed systems compared to (129)IO3(-)-spiked suspensions with the same total (129)I concentration, possibly indicating IO3(-)I(-) redox coupling. Size exclusion chromatography (SEC) demonstrated that Org-(129)I was present in both high and low molecular weight fractions of the HA although a slight preference to bond with the lower molecular weight fractions was observed indicating that, after 77 days, the spiked isotope had not fully mixed with the native (127)I pool. Iodine transformations were modelled using first order rate equations and fitted rate coefficients determined. However, extrapolation of the model to 250 days indicated that a pseudo-steady state would be attained after ~200 days but that the proportion of (129)I incorporated into HA was less than that of (127)I indicating the presence of a recalcitrant pool of (127)I that was unavailable for isotopic mixing. PMID- 27231880 TI - Effect of gas-liquid flow pattern and microbial diversity analysis of a pilot scale biotrickling filter for anoxic biogas desulfurization. AB - Hydrogen sulfide removal from biogas was studied under anoxic conditions in a pilot-scale biotrickling filter operated under counter- and co-current gas-liquid flow patterns. The best performance was found under counter-current conditions (maximum elimination capacity of 140 gS m(-3) h(-1)). Nevertheless, switching conditions between co- and counter-current flow lead to a favorable redistribution of biomass and elemental sulfur along the bed height. Moreover, elemental sulfur was oxidized to sulfate when the feeding biogas was disconnected and the supply of nitrate (electron acceptor) was maintained. Removal of elemental sulfur was important to prevent clogging in the packed bed and, thereby, to increase the lifespan of the packed bed between maintenance episodes. The larger elemental sulfur removal rate during shutdowns was 59.1 gS m(-3) h( 1). Tag-encoded FLX amplicon pyrosequencing was used to study the diversity of bacteria under co-current flow pattern with liquid recirculation and counter current mode with a single-pass flow of the liquid phase. The main desulfurizing bacteria were Sedimenticola while significant role of heterotrophic, opportunistic species was envisaged. Remarkable differences between communities were found when a single-pass flow of industrial water was fed to the biotrickling filter. PMID- 27231881 TI - The effectiveness of coagulation for water reclamation from a wastewater treatment plant that has a long hydraulic and sludge retention times: A case study. AB - Coagulation is a feasible process to reclaim municipal wastewater, however, the role of coagulation in removing effluent organic matter (EfOM) from underutilized wastewater treatment plants (WWTPs) has not been fully explored. We identified the characteristics of the EfOM from a typical underutilized WWTP (i.e., the ratio of actual capacity to design capacity is 50%-70%), and investigated the performance of coagulation on suspended solids (SS) and dissolved organic matter (DOM) removal. The effluent could even satisfy the highest national standard of China (Class 1 A) for WWTP effluent, as evaluated by the traditional parameters such as SS and chemical oxygen demand (COD). However, the DOM in the EfOM we studied contained considerable biomass-associated products (BAPs), which were dominated by proteins with a molecular weight of approximately 150 kDa. In addition, protein also dominated the DOM after coagulation. Fulvic acid and humic like acid organics were poorly removed by either AlCl3 or polyaluminum chloride (PAC) coagulation, even with a dosage as high as 24 mg Al L(-1). Biodegradability was very poor, as the ratio of biological oxygen demand (BOD5) to COD was less than 0.17. After coagulation the typical BAPs, protein and polysaccharide, remained as high as 1.6 mg L(-1) and 1.2 mg L(-1) respectively. In this study we found coagulation was ineffective for removal of recalcitrant BAPs. PMID- 27231882 TI - Endocrine disrupting compounds reduction and water quality improvement in reclaimed municipal wastewater: A field-scale study along Jialu River in North China. AB - Several ecological restoration projects have been constructed along urban rivers in North China to purify reclaimed municipal wastewater and improve the water quality of urban rivers. These projects attempt to address several environmental issues, including treating water contamination that is not fully remediated through standard wastewater treatment. This study investigated the efficiency of reducing endocrine disrupting compounds (EDCs) and estrogenic activity in reclaimed municipal wastewater along an 18.5 km field-scale ecological restoration project in Jialu River. The river only receives reclaimed municipal wastewater without natural effluent in North China. Data show that the chemical oxygen demand (COD) and ammonia nitrogen (NH3-N) of reclaimed municipal effluent improved when compared to the Chinese surface water standard, and natural estrogens, such as estrone (E1) and estradiol (E2), were effectively removed during ecological restoration purification processes. The estradiol activity based on measured EDCs concentrations (SigmaEEQEDC) was less than 0.01 ng/L after the ecological purification of restoration river; however, synthetic endocrine disrupting compounds in reclaimed municipal wastewater, such as octylphenol (OP), bisphenol A (BPA), and dibutyl phthalate (DBP), were difficult to eliminate. The bioassays of MDA-kb2 cells and recombinant yeast in vitro showed no direct androgen response and estrogen effect in reclaimed municipal effluent after the purification processes. However, a chorionic long-term (21d) exposure in vivo test showed that exposure to the reclaimed municipal effluents, even after river purification, still significantly induced yolk protein vitellogenin (Vtg) in male zebrafish, leading to abnormal expression of testosterone (T) and E2. This indicates continued potent estrogenic activity to aquatic organisms, even after treatment and purification. PMID- 27231883 TI - Correction: Comprehensive, Population-Based Sensitivity Analysis of a Two-Mass Vocal Fold Model. AB - [This corrects the article DOI: 10.1371/journal.pone.0148309.]. PMID- 27231884 TI - Development and Application of an Alert System to Detect Cases of Food Poisoning in Japan. AB - Recent public health concerns regarding commercial food products have increased the need to develop an automated method to detect food product-related health events. We developed and verified a method for the early detection of potentially harmful events caused by commercial food products. We collected data from daily internet-based questionnaires examining the presence or absence of symptoms and information about food purchased by the respondents. Using these data, we developed a method to detect possible health concerns regarding commercialized food products. To achieve this, we combined the signal detection method used in the reporting system of adverse effects of pharmaceutical products and the Early Aberration Reporting System (EARS) used by the United States Centers for Disease Control. Whiteleg shrimp (Litopenaeus vannamei), which had odds ratio and Odds(-) of 8.99 and 4.13, respectively, was identified as a possible causative food product for diarrhea and vomiting. In conclusion, this study demonstrated that food distributors can implement post-marketing monitoring of the safety of food products purchased via the internet. PMID- 27231885 TI - Psychometric Properties of the Consensus Sleep Diary in Those With Insomnia Disorder. AB - The Consensus Sleep Diary (CSD) is a standardized, prospective tool for tracking nightly subjective sleep. The current study evaluated the validity and utility of the CSD, with consideration for challenges inherent to psychometric evaluation of diary measures. Results showed that the CSD indices differentiated good sleepers from those with insomnia and were associated with similar objective indices and a subjective insomnia severity measure. The ability to detect treatment improvements after cognitive behavior therapy for insomnia (CBT-I) was tested by comparing pre- and post-CBT-I CSD indices with a subjective rating of insomnia symptom severity. Improvement in insomnia symptom severity was significantly related to improvement on the CSD indices. Completion rate of the CSD amongst participants across all 14 days was 99.8%. These findings provide support for the validity, clinical utility, and usability of the CSD. PMID- 27231887 TI - Ethanolic Extract of Acanthopanax koreanum Nakai Alleviates Alcoholic Liver Damage Combined with a High-Fat Diet in C57BL/6J Mice. AB - Alcoholic and nonalcoholic liver steatosis have an indistinguishable spectrum of histological features and liver enzyme elevations. In this study, we investigated the potential of the ethanolic extract of Acanthopanax koreanum Nakai (AK) to protect against experimental alcoholic liver disease in a mouse model that couples diet and daily ethanol bolus gavage. Fifty-six C57BL/6J mice were randomly divided into seven groups: normal control (NC), alcohol control (AC), alcohol/HFD control (AH), low-dose (1%) AK in alcohol group (ACL), high-dose (3%) AK in alcohol group (ACH), low-dose AK in alcohol/HFD group (AHL), and high-dose AK in alcohol/HFD group (AHH). The AH group showed more severe damage than the AC group in terms of biochemical and molecular data that were observed in this study. The administration of AK exerted remarkable effects in: plasma ALT (p < 0.0001), total lipid (p = 0.014), TG (p = 0.0037) levels; CPT-1alpha (p = 0.0197), TLR4 (p < 0.0001), CD14 (p = 0.0002), IL-6 (p = 0.0264) and MCP-1 (p = 0.0045) gene expressions; and ALDH (p < 0.0001) and CAT (p = 0.0076) activities. The data suggested that at least the high dose AK might confer protection against alcoholic liver damage combined with an HFD by accelerating lipid oxidation and alcohol metabolism and by suppressing the inflammatory response, including the TLR pathway. PMID- 27231886 TI - Topoisomerase 1 Regulates Gene Expression in Neurons through Cleavage Complex Dependent and -Independent Mechanisms. AB - Topoisomerase 1 (TOP1) inhibitors, including camptothecin and topotecan, covalently trap TOP1 on DNA, creating cleavage complexes (cc's) that must be resolved before gene transcription and DNA replication can proceed. We previously found that topotecan reduces the expression of long (>100 kb) genes and unsilences the paternal allele of Ube3a in neurons. Here, we sought to evaluate overlap between TOP1cc-dependent and -independent gene regulation in neurons. To do this, we utilized Top1 conditional knockout mice, Top1 knockdown, the CRISPR Cas9 system to delete Top1, TOP1 catalytic inhibitors that do not generate TOP1cc's, and a TOP1 mutation (T718A) that stabilizes TOP1cc's. We found that topotecan treatment significantly alters the expression of many more genes, including long neuronal genes, immediate early genes, and paternal Ube3a, when compared to Top1 deletion. Our data show that topotecan has a stronger effect on neuronal transcription than Top1 deletion, and identifies TOP1cc-dependent and independent contributions to gene expression. PMID- 27231888 TI - Catalysts with Cerium in a Membrane Reactor for the Removal of Formaldehyde Pollutant from Water Effluents. AB - We report the synthesis of cerium oxide, cobalt oxide, mixed cerium, and cobalt oxides and a Ce-Co/Al2O3 membrane, which are employed as catalysts for the catalytic wet oxidation (CWO) reaction process and the removal of formaldehyde from industrial effluents. Formaldehyde is present in numerous waste streams from the chemical industry in a concentration low enough to make its recovery not economically justified but high enough to create an environmental hazard. Common biological degradation methods do not work for formaldehyde, a highly toxic but refractory, low biodegradability substance. The CWO reaction is a recent, promising alternative that also permits much lower temperature and pressure conditions than other oxidation processes, resulting in economic benefits. The CWO reaction employing Ce- and Co-containing catalysts was carried out inside a slurry batch reactor and a membrane reactor. Experimental results are reported. Next, a mixed Ce-Co oxide film was supported on an gamma-alumina membrane used in a catalytic membrane reactor to compare formaldehyde removal between both types of systems. Catalytic materials with cerium and with a relatively large amount of cerium favored the transformation of formaldehyde. Cerium was present as cerianite in the catalytic materials, as indicated by X-ray diffraction patterns. PMID- 27231889 TI - Bioactive Constituents of Zanthoxylum rhetsa Bark and Its Cytotoxic Potential against B16-F10 Melanoma Cancer and Normal Human Dermal Fibroblast (HDF) Cell Lines. AB - Zanthoxylum rhetsa is an aromatic tree, known vernacularly as "Indian Prickly Ash". It has been predominantly used by Indian tribes for the treatment of many infirmities like diabetes, inflammation, rheumatism, toothache and diarrhea. In this study, we identified major volatile constituents present in different solvent fractions of Z. rhetsa bark using GC-MS analysis and isolated two tetrahydrofuran lignans (yangambin and kobusin), a berberine alkaloid (columbamine) and a triterpenoid (lupeol) from the bioactive chloroform fraction. The solvent fractions and purified compounds were tested for their cytotoxic potential against human dermal fibroblasts (HDF) and mouse melanoma (B16-F10) cells, using the MTT assay. All the solvent fractions and purified compounds were found to be non-cytotoxic to HDF cells. However, the chloroform fraction and kobusin exhibited cytotoxic effect against B16-F10 melanoma cells. The presence of bioactive lignans and alkaloids were suggested to be responsible for the cytotoxic property of Z. rhetsa bark against B16-F10 cells. PMID- 27231890 TI - ESeroS-GS Protects Neuronal Cells from Oxidative Stress by Stabilizing Lysosomes. AB - gamma-l-glutamyl-S-[2-[[[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12 trimethyltridecyl)-2H-1-benzopyran-6-yl]oxy]carbonyl]-3-[[2-(1H-indol-3 yl)ethyl]amino]-3-oxopropyl]-l-cysteinylglycine sodium salt (ESeroS-GS) is a water-soluble derivative of alpha-tocopherol (vitamin E). We reported previously that ESeroS-GS can act as an anti-inflammatory agent and can induce cell death in breast cancer cells. However, the potential antioxidant capacities of ESeroS-GS remain elusive. Here, we measured its scavenging effects on free radicals and evaluated its protective effects on neuronal cells against oxidative stress. The results indicated that ESeroS-GS effectively scavenged both 2,2'-azinobis(3 ethylbenzothiazoline)-6-sulfonate free radicals (ABTS(*+)) and 2,2-diphenyl-1 picrylhydrazyl (DPPH) free radicals, and attenuated H2O2-induced neuronal cell death. H2O2 treatment induced lysosomal membrane permeabilization rapidly, and caused the redistribution of lysosomal proteases, which were responsible for the neuronal cell death. ESeroS-GS abolished the interaction between tBid and the lysosomal membranes, blocked the translocation of tBid to the lysosomal membranes, decreased its oligomerization within the membrane circumstances, prevented the lysosomal membrane permeabilization, and thus attenuated the neuronal cell death. These data suggest that ESeroS-GS protected the neuronal cells from oxidative stress by stabilizing lysosomal membranes, and thus might act as a novel neuroprotector for neuronal diseases associated with oxidative stress. PMID- 27231892 TI - Current Status of Bioinks for Micro-Extrusion-Based 3D Bioprinting. AB - Recent developments in 3D printing technologies and design have been nothing short of spectacular. Parallel to this, development of bioinks has also emerged as an active research area with almost unlimited possibilities. Many bioinks have been developed for various cells types, but bioinks currently used for 3D printing still have challenges and limitations. Bioink development is significant due to two major objectives. The first objective is to provide growth- and function-supportive bioinks to the cells for their proper organization and eventual function and the second objective is to minimize the effect of printing on cell viability, without compromising the resolution shape and stability of the construct. Here, we will address the current status and challenges of bioinks for 3D printing of tissue constructs for in vitro and in vivo applications. PMID- 27231891 TI - Synthesis and Characterization of Glutamic-Chitosan Hydrogel for Copper and Nickel Removal from Wastewater. AB - Chitosan was reacted with four concentrations (2.5, 5, 10 and 20 mmol) of glutamic acid resulting in four types of glutamic-chitosan hydrogels (GCs), the activity of the resulted compounds on the removal of copper(II) and nickel(II) from wastewater were tested. The results indicated that by increasing glutamic acid concentration from GCs-1 to GCs-4, the efficiency of removing Cu(II) and Ni(II) were decreased, which may be due to a decrease in the pore size of the hydrogels as a result of the increased degree of crosslinking. PMID- 27231893 TI - Synthesis, Biological Activity, and Apoptotic Properties of NO-Donor/Enmein-Type ent-Kauranoid Hybrids. AB - Herein, we reported on a series of synthetic nitric oxide-releasing enmein-type diterpenoid hybrids (9a-i). All the target compounds showed potent antibacterial activity against selected Gram-positive bacteria S. aureus and B. subtilis. The antiproliferative activity against human tumor K562, MGC-803, CaEs-17 and Bel 7402 cells, and human normal liver cells L-02 was tested and the structure activity relationships (SARs) were also concluded. Compounds 9b and 9d showed the best activity against S. aureus and B. subtilis with the same minimal inhibitory concentrations (MICs) of 4 and 2 MUg/mL, respectively. The derivative 9f displayed IC50 values of 1.68, 1.11, 3.60 and 0.72 MUM against the four cancer cell lines above and 18.80 MUM against normal liver cells L-02; meanwhile, 9f also released a high level of NO at the time point of 60 min of 22.24 MUmol/L. Furthermore, it was also found that 9f induced apoptosis via the mitochondria related pathway and arrested cell cycle of Bel-7402 cells at S phase. These findings might be important to explore new chemical entities for the main causes of in-hospital mortality of S. aureus infection, combined with a solid tumor. PMID- 27231894 TI - Cardiac Stem Cell Secretome Protects Cardiomyocytes from Hypoxic Injury Partly via Monocyte Chemotactic Protein-1-Dependent Mechanism. AB - Cardiac stem cells (CSCs) were known to secrete diverse paracrine factors leading to functional improvement and beneficial left ventricular remodeling via activation of the endogenous pro-survival signaling pathway. However, little is known about the paracrine factors secreted by CSCs and their roles in cardiomyocyte survival during hypoxic condition mimicking the post-myocardial infarction environment. We established Sca-1+/CD31- human telomerase reverse transcriptase-immortalized CSCs (Sca-1+/CD31- CSCs(hTERT)), evaluated their stem cell properties, and paracrine potential in cardiomyocyte survival during hypoxia induced injury. Sca-1+/CD31- CSCs(hTERT) sustained proliferation ability even after long-term culture exceeding 100 population doublings, and represented multi differentiation potential into cardiomyogenic, endothelial, adipogenic, and osteogenic lineages. Dominant factors secreted from Sca-1+/CD31- CSCs(hTERT) were EGF, TGF-beta1, IGF-1, IGF-2, MCP-1, HGF R, and IL-6. Among these, MCP-1 was the most predominant factor in Sca-1+/CD31- CSCs(hTERT) conditioned medium (CM). Sca 1+/CD31- CSCs(hTERT) CM increased survival and reduced apoptosis of HL-1 cardiomyocytes during hypoxic injury. MCP-1 silencing in Sca-1+/CD31- CSCs(hTERT) CM resulted in a significant reduction in cardiomyocyte apoptosis. We demonstrated that Sca-1+/CD31- CSCs(hTERT) exhibited long-term proliferation capacity and multi-differentiation potential. Sca-1+/CD31- CSCs(hTERT) CM protected cardiomyocytes from hypoxic injury partly via MCP-1-dependent mechanism. Thus, they are valuable sources for in vitro and in vivo studies in the cardiovascular field. PMID- 27231895 TI - MicroRNA-24 Attenuates Neointimal Hyperplasia in the Diabetic Rat Carotid Artery Injury Model by Inhibiting Wnt4 Signaling Pathway. AB - The long-term stimulation of hyperglycemia greatly increases the incidence of vascular restenosis (RS) after angioplasty. Neointimal hyperplasia after vascular injury is the pathological cause of RS, but its mechanism has not been elucidated. MicroRNA-24 (miR-24) has low expression in the injured carotid arteries of diabetic rats. However, the role of miR-24 in the vascular system is unknown. In this study, we explore whether over-expression of miR-24 could attenuate neointimal formation in streptozotocin (STZ)-induced diabetic rats. Adenovirus (Ad-miR-24-GFP) was used to deliver the miR-24 gene to injured carotid arteries in diabetic rats. The level of neointimal hyperplasia was examined by hematoxylin-eosin (HE) staining. Vascular smooth muscle cell (VSMC) proliferation in the neointima was evaluated by immunostaining for proliferating cell nuclear antigen (PCNA). The mRNA levels of miR-24, PCNA, wingless-type MMTV integration site family member 4 (Wnt4), disheveled-1 (Dvl-1), beta-catenin and cell cycle associated molecules (Cyclin D1, p21) were determined by Quantitative Real-Time PCR (qRT-PCR). PCNA, Wnt4, Dvl-1, beta-catenin, Cyclin D1 and p21 protein levels were measured by Western blotting analysis. STZ administration decreased plasma insulin and increased fasting blood glucose in Sprague-Dawley (SD) rats. The expression of miR-24 was decreased in the carotid artery after a balloon injury in diabetic rats, and adenoviral transfection (Ad-miR-24-GFP) increased the expression of miR-24. Over-expression of miR-24 suppressed VSMC proliferation and neointimal hyperplasia in diabetic rats at 14 days. Furthermore, compared with Sham group, the mRNA and protein levels of PCNA, Wnt4, Dvl-1, beta-catenin, and Cyclin D1 were strikingly up-regulated in the carotid arteries of diabetic rats after a balloon injury. Interestingly, up-regulation of miR-24 significantly reduced the mRNA and protein levels of these above molecules. In contrast, the change trend in p21 mRNA and protein levels was opposite after a balloon injury. However, over-expression of miR-24 after gene delivery increased the mRNA and protein levels of p21. We conclude that over-expression of miR-24 could attenuate VSMC proliferation and neointimal hyperplasia after vascular injuries in diabetic rats. This result is possibly related to the regulation of the expression of Cyclin D1 and p21 through the Wnt4/Dvl-1/beta-catenin signaling pathway. PMID- 27231897 TI - Biological Rhythms in the Skin. AB - Circadian rhythms, ~24 h oscillations in behavior and physiology, are reflected in all cells of the body and function to optimize cellular functions and meet environmental challenges associated with the solar day. This multi-oscillatory network is entrained by the master pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus, which directs an organism's rhythmic expression of physiological functions and behavior via a hierarchical system. This system has been highly conserved throughout evolution and uses transcriptional-translational autoregulatory loops. This master clock, following environmental cues, regulates an organism's sleep pattern, body temperature, cardiac activity and blood pressure, hormone secretion, oxygen consumption and metabolic rate. Mammalian peripheral clocks and clock gene expression have recently been discovered and are present in all nucleated cells in our body. Like other essential organ of the body, the skin also has cycles that are informed by this master regulator. In addition, skin cells have peripheral clocks that can function autonomously. First described in 2000 for skin, this review summarizes some important aspects of a rapidly growing body of research in circadian and ultradian (an oscillation that repeats multiple times during a 24 h period) cutaneous rhythms, including clock mechanisms, functional manifestations, and stimuli that entrain or disrupt normal cycling. Some specific relationships between disrupted clock signaling and consequences to skin health are discussed in more depth in the other invited articles in this IJMS issue on Sleep, Circadian Rhythm and Skin. PMID- 27231896 TI - Adverse Biological Effect of TiO2 and Hydroxyapatite Nanoparticles Used in Bone Repair and Replacement. AB - The adverse biological effect of nanoparticles is an unavoidable scientific problem because of their small size and high surface activity. In this review, we focus on nano-hydroxyapatite and TiO2 nanoparticles (NPs) to clarify the potential systemic toxicological effect and cytotoxic response of wear nanoparticles because they are attractive materials for bone implants and are widely investigated to promote the repair and reconstruction of bone. The wear nanoparticles would be prone to binding with proteins to form protein-particle complexes, to interacting with visible components in the blood including erythrocytes, leukocytes, and platelets, and to being phagocytosed by macrophages or fibroblasts to deposit in the local tissue, leading to the formation of fibrous local pseudocapsules. These particles would also be translocated to and disseminated into the main organs such as the lung, liver and spleen via blood circulation. The inflammatory response, oxidative stress, and signaling pathway are elaborated to analyze the potential toxicological mechanism. Inhibition of the oxidative stress response and signaling transduction may be a new therapeutic strategy for wear debris-mediated osteolysis. Developing biomimetic materials with better biocompatibility is our goal for orthopedic implants. PMID- 27231898 TI - The Protective Effect of Grape-Seed Proanthocyanidin Extract on Oxidative Damage Induced by Zearalenone in Kunming Mice Liver. AB - Although grape-seed proanthocyanidin extract (GSPE) demonstrates strong anti oxidant activity, little research has been done to clearly reveal the protective effects on the hepatotoxicity caused by zearalenone (ZEN). This study is to explore the protective effect of GSPE on ZEN-induced oxidative damage of liver in Kunming mice and the possible protective molecular mechanism of GSPE. The results indicated that GSPE could greatly reduce the ZEN-induced increase of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. GSPE also significantly decreased the content of MDA but enhanced the activities of antioxidant enzymes SOD and GSH-Px. The analysis indicated that ZEN decreased both mRNA expression levels and protein expression levels of nuclear erythroid2 related factor2 (Nrf2). Nrf2 is considered to be an essential antioxidative transcription factor, as downstream GSH-Px, gamma-glutamyl cysteine synthetase (gamma-GCS), hemeoxygenase-1 (HO-1), and quinone oxidoreductase 1 (NQO1) decreased simultaneously, whereas the pre-administration of GSPE groups was shown to elevate these expressions. The results indicated that GSPE exerted a protective effect on ZEN-induced hepatic injury and the mechanism might be related to the activation of the Nrf2/ARE signaling pathway. PMID- 27231899 TI - Kidney Injury Molecule-1 Is Specifically Expressed in Cystically-Transformed Proximal Tubules of the PKD/Mhm (cy/+) Rat Model of Polycystic Kidney Disease. AB - Expression of kidney injury molecule-1 (Kim-1) is rapidly upregulated following tubular injury, constituting a biomarker for acute kidney damage. We examined the renal localization of Kim-1 expression in PKD/Mhm (polycystic kidney disease, Mannheim) (cy/+) rats (cy: mutated allel, +: wild type allel), an established model for autosomal dominant polycystic kidney disease, with chronic, mainly proximal tubulointerstitial alterations. For immunohistochemistry or Western blot analysis, kidneys of male adult heterozygously-affected (cy/+) and unaffected (+/+) littermates were perfusion-fixed or directly removed. Kim-1 expression was determined using peroxidase- or fluorescence-linked immunohistochemistry (alone or in combination with markers for tubule segments or differentiation). Compared to (+/+), only in (cy/+) kidneys, a chronic expression of Kim-1 could be detected by Western blot analysis, which was histologically confined to an apical cellular localization in areas of cystically-transformed proximal tubules with varying size and morphology, but not in distal tubular segments. Kim-1 was expressed by cystic epithelia exhibiting varying extents of dedifferentiation, as shown by double labeling with aquaporin-1, vimentin or osteopontin, yielding partial cellular coexpression. In this model, in contrast to other known molecules indicating renal injury and/or repair mechanisms, the chronic renal expression of Kim-1 is strictly confined to proximal cysts. Its exact role in interfering with tubulo-interstitial alterations in polycystic kidney disease warrants future investigations. PMID- 27231901 TI - Relevance of Endoplasmic Reticulum Stress Cell Signaling in Liver Cold Ischemia Reperfusion Injury. AB - The endoplasmic reticulum (ER) is involved in calcium homeostasis, protein folding and lipid biosynthesis. Perturbations in its normal functions lead to a condition called endoplasmic reticulum stress (ERS). This can be triggered by many physiopathological conditions such as alcoholic steatohepatitis, insulin resistance or ischemia-reperfusion injury. The cell reacts to ERS by initiating a defensive process known as the unfolded protein response (UPR), which comprises cellular mechanisms for adaptation and the safeguarding of cell survival or, in cases of excessively severe stress, for the initiation of the cell death program. Recent experimental data suggest the involvement of ERS in ischemia/reperfusion injury (IRI) of the liver graft, which has been considered as one of major problems influencing outcome after liver transplantation. The purpose of this review is to summarize updated data on the molecular mechanisms of ERS/UPR and the consequences of this pathology, focusing specifically on solid organ preservation and liver transplantation models. We will also discuss the potential role of ERS, beyond the simple adaptive response and the regulation of cell death, in the modification of cell functional properties and phenotypic changes. PMID- 27231902 TI - Crystal Structure of Cytochrome P450 (CYP105P2) from Streptomyces peucetius and Its Conformational Changes in Response to Substrate Binding. AB - Cytochrome P450 monooxygenases (CYP, EC 1.14.14.1) belong to a large family of enzymes that catalyze the hydroxylation of various substrates. Here, we present the crystal structure of CYP105P2 isolated from Streptomyces peucetius ATCC27952 at a 2.1 A resolution. The structure shows the presence of a pseudo-ligand molecule in the active site, which was co-purified fortuitously and is presumed to be a biphenyl derivative. Comparison with previously determined substrate bound CYP structures showed that binding of the ligand produces large and distinctive conformational changes in alpha2-alpha3, alpha7-alpha9, and the C terminal loop regions. This structural flexibility confirms our previous observation that CYP105P2 can accommodate a broad range of ligands. The structure complexed with a pseudo-ligand provides the first molecular view of CYP105P2 ligand interactions, and it indicates the involvement of hydrophobic residues (Pro82, Ala181, Met187, Leu189, Leu193, and Ile236) in the interactions between hydrophobic ligands and CYP105P2. These results provide useful insights into the structural changes involved in the recognition of different ligands by CYP105P2. PMID- 27231900 TI - The Role of Cell-Penetrating Peptide and Transferrin on Enhanced Delivery of Drug to Brain. AB - The challenge of effectively delivering therapeutic agents to brain has led to an entire field of active research devoted to overcome the blood brain barrier (BBB) and efficiently deliver drugs to brain. This review focusses on exploring the facets of a novel platform designed for the delivery of drugs to brain. The platform was constructed based on the hypothesis that a combination of receptor targeting agent, like transferrin protein, and a cell-penetrating peptide (CPP) will enhance the delivery of associated therapeutic cargo across the BBB. The combination of these two agents in a delivery vehicle has shown significantly improved (p < 0.05) translocation of small molecules and genes into brain as compared to the vehicle with only receptor-targeting agents. The comprehensive details of the uptake mechanisms and properties of various CPPs are illustrated here. The application of this technology, in conjunction with nanotechnology, can potentially open new horizons for the treatment of central nervous system disorders. PMID- 27231904 TI - Effects of Endobacterium (Stenotrophomonas maltophilia) on Pathogenesis-Related Gene Expression of Pine Wood Nematode (Bursaphelenchus xylophilus) and Pine Wilt Disease. AB - Pine wilt disease (PWD) caused by the pine wood nematode (PWN), Bursaphelenchus xylophilus, is responsible for devastating epidemics in pine trees in Asia and Europe. Recent studies showed that bacteria carried by the PWN might be involved in PWD. However, the molecular mechanism of the interaction between bacteria and the PWN remained unclear. Now that the whole genome of B. xylophilus (Bursaphelenchus xylophilus) is published, transcriptome analysis is a unique method to study the role played by bacteria in PWN. In this study, the transcriptome of aseptic B. xylophilus, B. xylophilus treated with endobacterium (Stenotrophomonas maltophilia NSPmBx03) and fungus B. xylophilus were sequenced. We found that 61 genes were up-regulated and 830 were down-regulated in B. xylophilus after treatment with the endobacterium; 178 genes were up-regulated and 1122 were down-regulated in fungus B. xylophilus compared with aseptic B. xylophilus. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were used to study the significantly changed biological functions and pathways for these differentially expressed genes. Many pathogenesis-related genes, including glutathinone S-transferase, pectate lyase, ATP-binding cassette transporter and cytochrome P450, were up-regulated after B. xylophilus were treated with the endobacterium. In addition, we found that bacteria enhanced the virulence of PWN. These findings indicate that endobacteria might play an important role in the development and virulence of PWN and will improve our understanding of the regulatory mechanisms involved in the interaction between bacteria and the PWN. PMID- 27231903 TI - Applications of Fourier Transform Ion Cyclotron Resonance (FT-ICR) and Orbitrap Based High Resolution Mass Spectrometry in Metabolomics and Lipidomics. AB - Metabolomics, along with other "omics" approaches, is rapidly becoming one of the major approaches aimed at understanding the organization and dynamics of metabolic networks. Mass spectrometry is often a technique of choice for metabolomics studies due to its high sensitivity, reproducibility and wide dynamic range. High resolution mass spectrometry (HRMS) is a widely practiced technique in analytical and bioanalytical sciences. It offers exceptionally high resolution and the highest degree of structural confirmation. Many metabolomics studies have been conducted using HRMS over the past decade. In this review, we will explore the latest developments in Fourier transform mass spectrometry (FTMS) and Orbitrap based metabolomics technology, its advantages and drawbacks for using in metabolomics and lipidomics studies, and development of novel approaches for processing HRMS data. PMID- 27231905 TI - Role of Mitochondrial DNA Copy Number Alteration in Human Renal Cell Carcinoma. AB - We investigated the role of mitochondrial DNA (mtDNA) copy number alteration in human renal cell carcinoma (RCC). The mtDNA copy numbers of paired cancer and non cancer parts from five resected RCC kidneys after radical nephrectomy were determined by quantitative polymerase chain reaction (Q-PCR). An RCC cell line, 786-O, was infected by lentiviral particles to knock down mitochondrial transcriptional factor A (TFAM). Null target (NT) and TFAM-knockdown (TFAM-KD) represented the control and knockdown 786-O clones, respectively. Protein or mRNA expression levels of TFAM; mtDNA-encoded NADH dehydrogenase subunit 1 (ND1), ND6 and cytochrome c oxidase subunit 2 (COX-2); nuclear DNA (nDNA)-encoded succinate dehydrogenase subunit A (SDHA); v-akt murine thymoma viral oncogene homolog 1 gene (AKT)-encoded AKT and v-myc myelocytomatosis viral oncogene homolog gene (c MYC)-encoded MYC; glycolytic enzymes including hexokinase II (HK-II), glucose 6 phosphate isomerase (GPI), phosphofructokinase (PFK), and lactate dehydrogenase subunit A (LDHA); and hypoxia-inducible factors the HIF-1alpha and HIF-2alpha, pyruvate dehydrogenase kinase 1 (PDK1), and pyruvate dehydrogenase E1 component alpha subunit (PDHA1) were analyzed by Western blot or Q-PCR. Bioenergetic parameters of cellular metabolism, basal mitochondrial oxygen consumption rate (mOCRB) and basal extracellular acidification rate (ECARB), were measured by a Seahorse XF(e)-24 analyzer. Cell invasiveness was evaluated by a trans-well migration assay and vimentin expression. Doxorubicin was used as a chemotherapeutic agent. The results showed a decrease of mtDNA copy numbers in resected RCC tissues (p = 0.043). The TFAM-KD clone expressed lower mtDNA copy number (p = 0.034), lower mRNA levels of TFAM (p = 0.008), ND1 (p = 0.007), and ND6 (p = 0.017), and lower protein levels of TFAM and COX-2 than did the NT clone. By contrast, the protein levels of HIF-2alpha, HK-II, PFK, LDHA, AKT, MYC and vimentin; trans-well migration activity (p = 0.007); and drug resistance to doxorubicin (p = 0.008) of the TFAM-KD clone were significantly higher than those of the NT clone. Bioenergetically, the TFAM-KD clone expressed lower mOCRB (p = 0.009) but higher ECARB (p = 0.037) than did the NT clone. We conclude that a reduction of mtDNA copy number and decrease of respiratory function of mitochondria in RCC might be compensated for by an increase of enzymes and factors that are involved in the upregulation of glycolysis to confer RCC more invasive and a drug-resistant phenotype in vitro. PMID- 27231906 TI - NAFLD and NASH in HCV Infection: Prevalence and Significance in Hepatic and Extrahepatic Manifestations. AB - The aim of this paper is to review and up to date the prevalence of hepatitis C virus (HCV)-associated non-alcoholic fatty liver disease (NAFLD) and non alcoholic steatohepatitis (NASH) and their significance in both accelerating progression of HCV-related liver disease and development of HCV-associated extrahepatic diseases. The reported mean prevalence of HCV-related NAFLD was 55%, whereas NASH was reported in 4%-10% of cases. HCV genotype 3 directly induces fatty liver deposition, namely "viral steatosis" and it is associated with the highest prevalence and degree of severity, whereas, HCV non-3 genotype infection showed lower prevalence of steatosis, which is associated with metabolic factors and insulin resistance. The host's genetic background predisposes him or her to the development of steatosis. HCV's impairment of lipid and glucose metabolism causes fatty liver accumulation; this seems to be a viral strategy to optimize its life cycle. Irrespective of insulin resistance, HCV-associated NAFLD, in a degree-dependent manner, contributes towards accelerating the liver fibrosis progression and development of hepatocellular carcinoma by inducing liver inflammation and oxidative stress. Furthermore, NAFLD is associated with the presence of metabolic syndrome, type 2 diabetes, and atherosclerosis. In addition, HCV-related "metabolic steatosis" impairs the response rate to interferon-based treatment, whereas it seems that "viral steatosis" may harm the response rate to new oral direct antiviral agents. In conclusion, a high prevalence of NAFLD occurs in HCV infections, which is, at least in part, induced by the virus, and that NAFLD significantly impacts progression of the liver disease, therapeutic response, and some extrahepatic diseases. PMID- 27231909 TI - A Fast Strategy for Determination of Vitamin B9 in Food and Pharmaceutical Samples Using an Ionic Liquid-Modified Nanostructure Voltammetric Sensor. AB - Vitamin B9 or folic acid is an important food supplement with wide clinical applications. Due to its importance and its side effects in pregnant women, fast determination of this vitamin is very important. In this study we present a new fast and sensitive voltammetric sensor for the analysis of trace levels of vitamin B9 using a carbon paste electrode (CPE) modified with 1,3 dipropylimidazolium bromide (1,3-DIBr) as a binder and ZnO/CNTs nanocomposite as a mediator. The electro-oxidation signal of vitamin B9 at the surface of the 1,3 DIBr/ZnO/CNTs/CPE electrode appeared at 800 mV, which was about 95 mV less positive compared to the corresponding unmodified CPE. The oxidation current of vitamin B9 by square wave voltammetry (SWV) increased linearly with its concentration in the range of 0.08-650 MUM. The detection limit for vitamin B9 was 0.05 MUM. Finally, the utility of the new 1,3-DIBr/ZnO/CNTs/CPE electrode was tested in the determination of vitamin B9 in food and pharmaceutical samples. PMID- 27231907 TI - Nutritional and Hormonal Regulation of Citrate and Carnitine/Acylcarnitine Transporters: Two Mitochondrial Carriers Involved in Fatty Acid Metabolism. AB - The transport of solutes across the inner mitochondrial membrane is catalyzed by a family of nuclear-encoded membrane-embedded proteins called mitochondrial carriers (MCs). The citrate carrier (CiC) and the carnitine/acylcarnitine transporter (CACT) are two members of the MCs family involved in fatty acid metabolism. By conveying acetyl-coenzyme A, in the form of citrate, from the mitochondria to the cytosol, CiC contributes to fatty acid and cholesterol synthesis; CACT allows fatty acid oxidation, transporting cytosolic fatty acids, in the form of acylcarnitines, into the mitochondrial matrix. Fatty acid synthesis and oxidation are inversely regulated so that when fatty acid synthesis is activated, the catabolism of fatty acids is turned-off. Malonyl-CoA, produced by acetyl-coenzyme A carboxylase, a key enzyme of cytosolic fatty acid synthesis, represents a regulator of both metabolic pathways. CiC and CACT activity and expression are regulated by different nutritional and hormonal conditions. Defects in the corresponding genes have been directly linked to various human diseases. This review will assess the current understanding of CiC and CACT regulation; underlining their roles in physio-pathological conditions. Emphasis will be placed on the molecular basis of the regulation of CiC and CACT associated with fatty acid metabolism. PMID- 27231908 TI - EIYMNVPV Motif is Essential for A1CF Nucleus Localization and A1CF (-8aa) Promotes Proliferation of MDA-MB-231 Cells via Up-Regulation of IL-6. AB - Apobec-1 complementation factor (A1CF) is a heterogeneous nuclear ribonuceloprotein (hnRNP) and mediates apolipoprotein-B mRNA editing. A1CF can promote the regeneration of the liver by post-transcriptionally stabilizing Interleukin-6 (IL-6) mRNA. It also contains two transcriptional variants-A1CF64 and A1CF65, distinguished by the appearance of a 24-nucleotide motif which contributes to the corresponding eight-amino acid motif of EIYMNVPV. For the first time, we demonstrated that the EIYMNVPV motif was essential for A1CF nucleus localization, A1CF deficient of the EIYMNVPV motif, A1CF (-8aa) showed cytoplasm distribution. More importantly, we found that A1CF (-8aa), but not its full-length counterpart, can promote proliferation of MDA-MB-231 cells accompanied with increased level of IL-6 mRNA. Furthermore, silencing of IL-6 attenuated A1CF (-8aa)-induced proliferation in MDA-MB-231 cells. In conclusion, notably, these findings suggest that A1CF (-8aa) promoted proliferation of MDA-MB 231 cells in vitro viewing IL-6 as a target. Thus, the EIYMNVPV motif could be developed as a potential target for basal-like breast cancer therapy. PMID- 27231910 TI - Optimal Magnetic Sensor Vests for Cardiac Source Imaging. AB - Magnetocardiography (MCG) non-invasively provides functional information about the heart. New room-temperature magnetic field sensors, specifically magnetoresistive and optically pumped magnetometers, have reached sensitivities in the ultra-low range of cardiac fields while allowing for free placement around the human torso. Our aim is to optimize positions and orientations of such magnetic sensors in a vest-like arrangement for robust reconstruction of the electric current distributions in the heart. We optimized a set of 32 sensors on the surface of a torso model with respect to a 13-dipole cardiac source model under noise-free conditions. The reconstruction robustness was estimated by the condition of the lead field matrix. Optimization improved the condition of the lead field matrix by approximately two orders of magnitude compared to a regular array at the front of the torso. Optimized setups exhibited distributions of sensors over the whole torso with denser sampling above the heart at the front and back of the torso. Sensors close to the heart were arranged predominantly tangential to the body surface. The optimized sensor setup could facilitate the definition of a standard for sensor placement in MCG and the development of a wearable MCG vest for clinical diagnostics. PMID- 27231911 TI - Visualized Multiprobe Electrical Impedance Measurements with STM Tips Using Shear Force Feedback Control. AB - Here we devise a multiprobe electrical measurement system based on quartz tuning forks (QTFs) and metallic tips capable of having full 3D control over the position of the probes. The system is based on the use of bent tungsten tips that are placed in mechanical contact (glue-free solution) with a QTF sensor. Shear forces acting in the probe are measured to control the tip-sample distance in the Z direction. Moreover, the tilting of the tip allows the visualization of the experiment under the optical microscope, allowing the coordination of the probes in X and Y directions. Meanwhile, the metallic tips are connected to a current voltage amplifier circuit to measure the currents and thus the impedance of the studied samples. We discuss here the different aspects that must be addressed when conducting these multiprobe experiments, such as the amplitude of oscillation, shear force distance control, and wire tilting. Different results obtained in the measurement of calibration samples and microparticles are presented. They demonstrate the feasibility of the system to measure the impedance of the samples with a full 3D control on the position of the nanotips. PMID- 27231912 TI - Sensitive Adsorptive Voltammetric Method for Determination of Bisphenol A by Gold Nanoparticle/Polyvinylpyrrolidone-Modified Pencil Graphite Electrode. AB - A novel electrochemical sensor gold nanoparticle (AuNP)/polyvinylpyrrolidone (PVP) modified pencil graphite electrode (PGE) was developed for the ultrasensitive determination of Bisphenol A (BPA). The gold nanoparticles were electrodeposited by constant potential electrolysis and PVP was attached by passive adsorption onto the electrode surface. The electrode surfaces were characterized by electrochemical impedance spectroscopy (EIS) and scanning electron microscopy (SEM). The parameters that affected the experimental conditions were researched and optimized. The AuNP/PVP/PGE sensor provided high sensitivity and selectivity for BPA recognition by using square wave adsorptive stripping voltammetry (SWAdSV). Under optimized conditions, the detection limit was found to be 1.0 nM. This new sensor system offered the advantages of simple fabrication which aided the expeditious replication, low cost, fast response, high sensitivity and low background current for BPA. This new sensor system was successfully tested for the detection of the amount of BPA in bottled drinking water with high reliability. PMID- 27231913 TI - Analysis of the Appropriateness of the Use of Peltier Cells as Energy Sources. AB - The article describes the possibilities of using Peltier cells as an energy source to power the telemetry units, which are used in large-scale monitoring systems as central units, ensuring the collection of data from sensors, processing, and sending to the database server. The article describes the various experiments that were carried out, their progress and results. Based on experiments evaluated, the paper also discusses the possibilities of using various types depending on the temperature difference of the cold and hot sides. PMID- 27231914 TI - Nonlinear-Based MEMS Sensors and Active Switches for Gas Detection. AB - The objective of this paper is to demonstrate the integration of a MOF thin film on electrostatically actuated microstructures to realize a switch triggered by gas and a sensing algorithm based on amplitude tracking. The devices are based on the nonlinear response of micromachined clamped-clamped beams. The microbeams are coated with a metal-organic framework (MOF), namely HKUST-1, to achieve high sensitivity. The softening and hardening nonlinear behaviors of the microbeams are exploited to demonstrate the ideas. For gas sensing, an amplitude-based tracking algorithm is developed to quantify the captured quantity of gas. Then, a MEMS switch triggered by gas using the nonlinear response of the microbeam is demonstrated. Noise analysis is conducted, which shows that the switch has high stability against thermal noise. The proposed switch is promising for delivering binary sensing information, and also can be used directly to activate useful functionalities, such as alarming. PMID- 27231915 TI - Synchronous OEIC Integrating Receiver for Optically Reconfigurable Gate Arrays. AB - A monolithically integrated optoelectronic receiver with a low-capacitance on chip pin photodiode is presented. The receiver is fabricated in a 0.35 MUm opto CMOS process fed at 3.3 V and due to the highly effective integrated pin photodiode it operates at MUW. A regenerative latch acting as a sense amplifier leads in addition to a low electrical power consumption. At 400 Mbit/s, sensitivities of -26.0 dBm and -25.5 dBm are achieved, respectively, for lambda = 635 nm and lambda = 675 nm (BER = 10(-9) ) with an energy efficiency of 2 pJ/bit. PMID- 27231916 TI - Energy-Efficient Collaborative Outdoor Localization for Participatory Sensing. AB - Location information is a key element of participatory sensing. Many mobile and sensing applications require location information to provide better recommendations, object search and trip planning. However, continuous GPS positioning consumes much energy, which may drain the battery of mobile devices quickly. Although WiFi and cell tower positioning are alternatives, they provide lower accuracy compared to GPS. This paper solves the above problem by proposing a novel localization scheme through the collaboration of multiple mobile devices to reduce energy consumption and provide accurate positioning. Under our scheme, the mobile devices are divided into three groups, namely the broadcaster group, the location information receiver group and the normal participant group. Only the broadcaster group and the normal participant group use their GPS. The location information receiver group, on the other hand, makes use of the locations broadcast by the broadcaster group to estimate their locations. We formulate the broadcaster set selection problem and propose two novel algorithms to minimize the energy consumption in collaborative localization. Simulations with real traces show that our proposed solution can save up to 68% of the energy of all of the participants and provide more accurate locations than WiFi and cellular network positioning. PMID- 27231917 TI - A Highly Reliable and Cost-Efficient Multi-Sensor System for Land Vehicle Positioning. AB - In this paper, we propose a novel positioning solution for land vehicles which is highly reliable and cost-efficient. The proposed positioning system fuses information from the MEMS-based reduced inertial sensor system (RISS) which consists of one vertical gyroscope and two horizontal accelerometers, low-cost GPS, and supplementary sensors and sources. First, pitch and roll angle are accurately estimated based on a vehicle kinematic model. Meanwhile, the negative effect of the uncertain nonlinear drift of MEMS inertial sensors is eliminated by an Hinfinity filter. Further, a distributed-dual-Hinfinity filtering (DDHF) mechanism is adopted to address the uncertain nonlinear drift of the MEMS-RISS and make full use of the supplementary sensors and sources. The DDHF is composed of a main Hinfinity filter (MHF) and an auxiliary Hinfinity filter (AHF). Finally, a generalized regression neural network (GRNN) module with good approximation capability is specially designed for the MEMS-RISS. A hybrid methodology which combines the GRNN module and the AHF is utilized to compensate for RISS position errors during GPS outages. To verify the effectiveness of the proposed solution, road-test experiments with various scenarios were performed. The experimental results illustrate that the proposed system can achieve accurate and reliable positioning for land vehicles. PMID- 27231918 TI - The Antistaphylococcal Activity of Citropin 1.1 and Temporin A against Planktonic Cells and Biofilms Formed by Isolates from Patients with Atopic Dermatitis: An Assessment of Their Potential to Induce Microbial Resistance Compared to Conventional Antimicrobials. AB - Staphylococcus aureus (SA) colonizes the vast majority of patients with atopic dermatitis (AD). Its resistance to antibiotics and ability to form biofilms are the main origins of therapeutic complications. Endogenous antimicrobial peptides (AMPs) exhibit strong activity against SA, including antibiotic resistant strains as well as bacteria existing in biofilm form. The purpose of the present work was to determine the antistaphylococcal activity of two amphibian peptides against SA isolated from patients with AD. The AMPs demonstrated permanent activity towards strains exposed to sublethal concentrations of the compounds and significantly stronger antibiofilm activity in comparison to that of conventional antimicrobials. The results suggest the potential application of amphibian AMPs as promising antistaphylococcal agents for the management of skin infections. PMID- 27231919 TI - Exploitable Lipids and Fatty Acids in the Invasive Oyster Crassostrea gigas on the French Atlantic Coast. AB - Economic exploitation is one means to offset the cost of controlling invasive species, such as the introduced Pacific oyster (Crassostrea gigas Thunberg) on the French Atlantic coast. Total lipid and phospholipid (PL) fatty acids (FAs) and sterols were examined in an invasive population of C. gigas in Bourgneuf Bay, France, over four successive seasons, with a view to identify possible sources of exploitable substances. The total lipid level (% dry weight) varied from 7.1% (winter) to 8.6% (spring). Of this, PLs accounted for 28.1% (spring) to 50.4% (winter). Phosphatidylcholine was the dominant PL throughout the year (up to 74% of total PLs in winter). Plasmalogens were identified throughout the year as a series of eleven dimethylacetals (DMAs) with chain lengths between C16 and C20 (up to 14.5% of PL FAs + DMAs in winter). Thirty-seven FAs were identified in the PL FAs. Eicosapentaenoic acid (20:5n-3 EPA/7.53% to 14.5%) and docosahexaenoic acid (22:6n-3 DHA/5.51% to 9.5%) were the dominant polyunsaturated FAs in all seasons. Two non-methylene-interrupted dienoic (NMID) FAs were identified in all seasons: 7,13-docosadienoic and 7,15-docosadienoic acids, the latter being present at relatively high levels (up to 9.6% in winter). Twenty free sterols were identified, including cholesterol at 29.9% of the sterol mixture and about 33% of phytosterols. C. gigas tissues thus contained exploitable lipids for health benefits or as a potential source of high-quality commercial lecithin. PMID- 27231921 TI - Preconceptional Iron Intake and Gestational Diabetes Mellitus. AB - Our objective was to assess the impact of preconceptional heme and non-heme iron on gestational diabetes mellitius (GDM) in the Boston University Slone Epidemiology Birth Defects Study (BDS). This retrospective cohort analysis included 7229 participants enrolled in the BDS between 1998 and 2008 who gave birth to non-malformed infants and were free of pre-existing diabetes. All data were collected through structured interviews conducted within 6 months of delivery. Calorie-adjusted and multivariable odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression models. Preconceptional dietary heme iron was modestly associated with an elevated risk of GDM among those (multivariable OR comparing the fifth quintile to the first: 1.55; 95% CI 0.98, 2.46). Conversely, preconceptional dietary non-heme iron was associated with a decreased risk of GDM among those in the fifth quintile of intake compared to the first (multivariable OR: 0.48; 95% CI 0.28, 0.81). Women who consumed supplemental iron during preconception also had a decreased risk of GDM (multivariable OR: 0.78; 95% CI 0.60, 1.02). In conclusion, our data support a positive association between preconceptional heme iron intake and GDM and an inverse association between preconceptional non-heme iron intake from foods and preconceptional intake from supplements. PMID- 27231922 TI - Urolithiasis, Urinary Cancer, and Home Drinking Water Source in the United States Territory of Guam, 2006-2010. AB - We reviewed patient records with a first-listed diagnosis of urolithiasis-also known as urinary tract or kidney stone disease, nephrolithiasis-upon discharge from Guam's sole civilian hospital during 2006 to 2010 and urinary cancer mortality records from the Guam Cancer Registry for 1970 to 2009 to determine the source of municipal water supplied to the patients' residence. The objective was to investigate a possible relationship between the sources of municipal water supplied to Guam villages and the incidence of urolithiasis and urinary cancer. We analyzed hospital discharge diagnoses of urolithiasis or renal calculi by calculating the incidence of first-mentioned discharge for urolithiasis or renal calculi and comparing rates across demographic or geographic categories while adjusting by age, sex, and ethnicity/race. We reviewed cancer registry records of urinary cancer deaths by patient residence. The annual incidence of hospitalization for urolithiasis was 5.22 per 10,000. Rates adjusted for sex or age exhibited almost no change. The rate of 9.83 per 10,000 among Chamorros was significantly higher (p < 0.05) than the rates among any other ethnic group or race. When villages were grouped by water source, rates of patients discharged with a first-listed diagnosis of urolithiasis, adjusted for ethnicity/race, were similar for villages using either well water (5.44 per 10,000) or mixed source water (5.39 per 10,000), and significantly greater than the rate for villages using exclusively reservoir water (1.35 per 10,000). No statistically significant differences were found between the water source or village of residence and urinary cancer mortality. Some Guam residents living in villages served completely or partly by deep well water high in calcium carbonate may be at increased risk for urolithiasis compared with residents living in villages served by surface waters. Although the risk appears to be highest in villagers of Chamorro ethnicity, residents should be aware of other contributing risk factors and steps to take to avoid developing this health problem. PMID- 27231923 TI - Dutch Primary Schoolchildren's Perspectives of Activity-Friendly School Playgrounds: A Participatory Study. AB - School playgrounds are important physical activity (PA) environments for children, yet only a small number of children reaches the target of 40% of moderate-to-vigorous PA time during recess. The aim of this study was to explore children's perspectives (i.e., child-identified determinants) of activity friendly school playgrounds. We conducted participatory research with children as co-researchers, framed as a project to give children the opportunity to discuss their views and ideas about their school playgrounds. At three schools, six children (9-12 years old) met over five to seven group meetings. Data analysis included children's conclusions obtained during the project and the researcher's analysis of written reports of all meetings. Children indicated a strong desire for fun and active play, with physical playground characteristics and safety, rules and supervision, peer-interactions, and variation in equipment/games as important determinants. Our results indicate that improving activity-friendliness of playgrounds requires an integrated and multi-faceted approach. It also indicates that children, as primary users, are able to identify barriers for active play that are easily overlooked, unknown or differently perceived by adults. Hence, we believe that structural involvement of children in designing, developing and improving playgrounds may increase children's' active play and consequently PA levels during recess. PMID- 27231920 TI - Alcoholic Beverage Consumption and Chronic Diseases. AB - Epidemiological and experimental studies have consistently linked alcoholic beverage consumption with the development of several chronic disorders, such as cancer, cardiovascular diseases, diabetes mellitus and obesity. The impact of drinking is usually dose-dependent, and light to moderate drinking tends to lower risks of certain diseases, while heavy drinking tends to increase the risks. Besides, other factors such as drinking frequency, genetic susceptibility, smoking, diet, and hormone status can modify the association. The amount of ethanol in alcoholic beverages is the determining factor in most cases, and beverage types could also make an influence. This review summarizes recent studies on alcoholic beverage consumption and several chronic diseases, trying to assess the effects of different drinking patterns, beverage types, interaction with other risk factors, and provide mechanistic explanations. PMID- 27231924 TI - Prevalence of Hypertension among Adults in Remote Rural Areas of Xinjiang, China. AB - OBJECTIVE: The present study aimed to estimate prevalence of hypertension among adults in rural remote areas of Xinjiang, China and evaluate the associated factors of hypertension. METHODS: The survey was based on questionnaire interviews and clinical measurements of 11,340 individuals (>=18 years old), and was conducted during 2009-2010 via a stratified cluster random sampling method in the remote rural areas of Xinjiang, about 4407 km away from the capital Beijing. Hypertension was defined according to WHO/ISH criteria. RESULTS: Systolic blood pressure (SBP) and diastolic blood pressure (DBP) of the population were (126.3 +/- 21.4) and (80.9 +/- 13.4) mmHg. Compared with Han nationality subjects, SBP and DBP of Kazakh nationality subjects were significantly high (p < 0.05), while the SBP and DBP of Uyghur subjects were significantly low (Kazakh: (128.7 +/- 23.9) and (83.0 +/- 14.6) mmHg, Uyghur: (123.6 +/- 19.3) and (77.4 +/- 12.7) mmHg, Han: (126.5 +/- 20.5) and (82.6 +/- 11.9) mmHg, p < 0.05). Prevalence of hypertension of the population was 32.1%, and was greater among Kazakhs and lower among Uyghur than Han (Kazakh: 36.9%, Uyghur: 26.1%, Han: 33.7%, p < 0.05). The age-standardized prevalence of hypertension was 30.2%, and was greater among Kazakhs while lower among Uyghurs than Han subjects (Kazakh: 37.0%, Uyghur: 26.0%, Han: 33.8%, p < 0.05, p < 0.05). Multivariate logistic regression analyses showed Gender (OR = 1.324), age (OR = 2.098, 3.681, 6.794, 9.473, 14.646), nationality (OR = 1.541), occupation (OR = 1.659, 1.576), education (OR = 1.260), BMI (OR = 1.842), WC (OR = 1.585), WHR (OR = 1.188), WHR (OR = 1.188), diabetes (OR = 1.879), hypertriglyceridemia (OR = 1.361), hypercholesterolemia (OR = 1.131) and high blood low density lipoprotein cholesterol (LDL-C) (OR = 1.956) were all positively correlated with hypertension, while low blood high density lipoprotein cholesterol (HDL-C) (OR = 0.765) was negatively correlated with hypertension. CONCLUSIONS: Prevalence of hypertension among adults in remote rural areas of Xinjiang was higher than the national average. Prevalence of hypertension was greater among Kazakhs and lower among Uyghurs than Han nationals, thus indicating significant differences between regions and nationalities. Gender, age, nation, occupation, education, overweight or obesity, abdominal obesity, diabetes, hyperlipidemia, hypercholesterolemia, high LDL-C were positively correlated with hypertension, low HDL-C was negatively correlated with hypertension. PMID- 27231925 TI - Both Direct and Vicarious Experiences of Nature Affect Children's Willingness to Conserve Biodiversity. AB - Children are becoming less likely to have direct contact with nature. This ongoing loss of human interactions with nature, the extinction of experience, is viewed as one of the most fundamental obstacles to addressing global environmental challenges. However, the consequences for biodiversity conservation have been examined very little. Here, we conducted a questionnaire survey of elementary schoolchildren and investigated effects of the frequency of direct (participating in nature-based activities) and vicarious experiences of nature (reading books or watching TV programs about nature and talking about nature with parents or friends) on their affective attitudes (individuals' emotional feelings) toward and willingness to conserve biodiversity. A total of 397 children participated in the surveys in Tokyo. Children's affective attitudes and willingness to conserve biodiversity were positively associated with the frequency of both direct and vicarious experiences of nature. Path analysis showed that effects of direct and vicarious experiences on children's willingness to conserve biodiversity were mediated by their affective attitudes. This study demonstrates that children who frequently experience nature are likely to develop greater emotional affinity to and support for protecting biodiversity. We suggest that children should be encouraged to experience nature and be provided with various types of these experiences. PMID- 27231926 TI - Systolic Blood Pressure Lower than Heart Rate upon Arrival at and Departure from the Emergency Department Indicates a Poor Outcome for Adult Trauma Patients. AB - BACKGROUND: Hemorrhage is a leading cause of preventable trauma death. In this study, we used the reverse shock index (RSI), a ratio of systolic blood pressure (SBP) to heart rate (HR), to evaluate the hemodynamic stability of trauma patients. As an SBP lower than the HR (RSI < 1) may indicate hemodynamic instability, the objective of this study was to assess the associated complications in trauma patients with an RSI < 1 upon arrival at the emergency department (ED) (indicated as (A)RSI) and at the time of departure from the ED (indicated as (L)RSI) to the operative room or for admission. METHODS: Data obtained from all 16,548 hospitalized patients recorded in the trauma registry system at a Level I trauma center between January 2009 and December 2013 were retrospectively reviewed. A total of 10,234 adult trauma patients aged >=20 were enrolled and subsequently divided into four groups: Group I, (A)RSI >= 1 and (L)RSI >= 1 (n = 9827); Group II, (A)RSI >= 1 and (L)RSI < 1 (n = 76); Group III, (A)RSI < 1 and (L)RSI >= 1 (n = 251); and Group IV, (A)RSI < 1 and (L)RSI < 1 (n = 80). Pearson's chi2 test, Fisher's exact test, or independent Student's t-test was conducted to compare trauma patients in Groups II, III, and IV with those in Group I. RESULTS: Patients in Groups II, III, and IV had a higher injury severity score and underwent a higher number of procedures, including intubation, chest tube insertion, and blood transfusion, than Group I patients. Additionally, patients of these groups had increased hospital length of stay (16.3 days, 14.9 days, and 22.0 days, respectively), proportion of patients admitted to the intensive care unit (ICU) (48.7%, 43.0%, and 62.5%, respectively), and in hospital mortality (19.7%, 7.6%, and 27.5%, respectively). Although the trauma patients who had a SBP < 90 mmHg either upon arrival at or departure from the ED also present a more severe injury and poor outcome, those patients who had a SBP >= 90 mmHg but an RSI < 1 had a more severe injury and poor outcome than those patients who had a SBP >= 90 mmHg and an RSI >= 1. CONCLUSIONS: SBP lower than heart rate (RSI < 1) either upon arrival at or departure from the ED may indicate a detrimental sign of poor outcome in adult trauma patients even in the absence of noted hypotension. PMID- 27231927 TI - Weight Gain Prevention among Midlife Women: A Randomized Controlled Trial to Address Needs Related to the Physical and Social Environment. AB - Women tend to gain weight at midlife (40-60 years) increasing risk of obesity related chronic diseases. Within specific eating occasions, needs related to the physical and social environment may result in less healthy eating behavior, which can lead to weight gain over time. The purpose of this study was to determine if a dietitian-delivered nutrition counseling intervention tailored to eating occasion needs could improve diet and prevent weight gain among midlife women over two years. A randomized controlled trial was conducted with healthy midlife women (n = 354) in one U.S. metropolitan area. The intervention group (n = 185) received ten hours of individual nutrition counseling from dietitians over six months, while women in a control group (n = 169) received no counseling. Measured height, weight and waist circumference, and dietary intakes were collected at baseline and every six months over two years. Mixed linear models were used to test for intervention effect on change in outcome variables over time. Dietary intakes of fruit, reduced/low-fat dairy foods and refined grains were significantly improved over time in the intervention compared to control group. However, the intervention had no effect on weight over time (p = 0.48). Nutrition counseling tailored to address eating occasion needs improved self-reported diet but did not significantly affect weight change. PMID- 27231928 TI - Comments on Li et al. Effects of in Utero Exposure to Dicyclohexyl Phthalate on Rat Fetal Leydig Cells. Int. J. Environ. Res. Public Health 2016, 13, 246. AB - Profiling the expression levels of genes or proteins in tissues comprising two or more cell types is commonplace in biological sciences. Such analyses present particular challenges, however, for example a potential shift in cellular composition, or 'cellularity', between specimens. That is, does an observed change in expression level represent what occurs within individual cells, or does it represent a shift in the ratio of different cell types within the tissue? This commentary attempts to highlight the importance of considering cellularity when interpreting quantitative expression data, using the mammalian testis and a recent study on the effects of phthalate exposure on testis function as an example. PMID- 27231929 TI - Response to the Svingen Comments on Li et al. Effects of in Utero Exposure to Dicyclohexyl Phthalate on Rat Fetal Leydig Cells. Int. J. Environ. Res. Public Health, 2016, 13, 246. AB - Referring to the comments of Svingen [1] on our latest publication about Effects of in utero Exposure to Dicyclohexyl Phthalate on Rat Fetal Leydig Cells [2], we would like to give some comments.[...]. PMID- 27231930 TI - Lessons from the Bone Chapter of the Malaysian Aging Men Study. AB - Male osteoporosis in Malaysia is a largely neglected problem. Therefore, a bone health study in men using quantitative ultrasonometry was launched as part of the Malaysian Aging Men Study in 2009-2012. This review aimed to summarize the findings of the aforementioned bone health study. The study examined the bone health of Chinese and Malaysian men aged 20 years and above living in Kuala Lumpur using a quantitative ultrasound device. Participants answered a questionnaire on their demographic details and physical activity status. Body anthropometry of the participants was measured and their blood collected for biochemical analysis. Results showed that a significant proportion of the Malaysian Chinese and Malay men had suboptimal bone health indicated by calcaneal speed of sound and vitamin D status. Age-related decline of the calcaneal speed of sound in these men was gradual and biphasic without ethnic difference. Body anthropometry such as height, weight, body mass index, and body fat percentage contributed to the variation of the calcaneal speed of sound in Malaysian men. Age-related changes in testosterone, insulin-like growth factor 1, and thyroid stimulating hormone also influenced the calcaneal speed of sound in these men. This study serves as a reminder that male osteoporosis in Malaysia should be an issue of concern. It is also a basis for a more comprehensive study on bone health in men in the future. PMID- 27231931 TI - Mutational Analysis of the Rift Valley Fever Virus Glycoprotein Precursor Proteins for Gn Protein Expression. AB - The Rift Valley fever virus (RVFV) M-segment encodes the 78 kD, NSm, Gn, and Gc proteins. The 1st AUG generates the 78 kD-Gc precursor, the 2nd AUG generates the NSm-Gn-Gc precursor, and the 3rd AUG makes the NSm'-Gn-Gc precursor. To understand biological changes due to abolishment of the precursors, we quantitatively measured Gn secretion using a reporter assay, in which a Gaussia luciferase (gLuc) protein is fused to the RVFV M-segment pre-Gn region. Using the reporter assay, the relative expression of Gn/gLuc fusion proteins was analyzed among various AUG mutants. The reporter assay showed efficient secretion of Gn/gLuc protein from the precursor made from the 2nd AUG, while the removal of the untranslated region upstream of the 2nd AUG (AUG2-M) increased the secretion of the Gn/gLuc protein. Subsequently, recombinant MP-12 strains encoding mutations in the pre-Gn region were rescued, and virological phenotypes were characterized. Recombinant MP-12 encoding the AUG2-M mutation replicated slightly less efficiently than the control, indicating that viral replication is further influenced by the biological processes occurring after Gn expression, rather than the Gn abundance. This study showed that, not only the abolishment of AUG, but also the truncation of viral UTR, affects the expression of Gn protein by the RVFV M-segment. PMID- 27231933 TI - Current Trends in Development of Liposomes for Targeting Bacterial Biofilms. AB - Biofilm targeting represents a great challenge for effective antimicrobial therapy. Increased biofilm resistance, even with the elevated concentrations of very potent antimicrobial agents, often leads to failed therapeutic outcome. Application of biocompatible nanomicrobials, particularly liposomally-associated nanomicrobials, presents a promising approach for improved drug delivery to bacterial cells and biofilms. Versatile manipulations of liposomal physicochemical properties, such as the bilayer composition, membrane fluidity, size, surface charge and coating, enable development of liposomes with desired pharmacokinetic and pharmacodynamic profiles. This review attempts to provide an unbiased overview of investigations of liposomes destined to treat bacterial biofilms. Different strategies including the recent advancements in liposomal design aiming at eradication of existing biofilms and prevention of biofilm formation, as well as respective limitations, are discussed in more details. PMID- 27231934 TI - Liposomes in Drug Delivery: How It All Happened. AB - Effective delivery of drugs via liposomes in the treatment or prevention of disease is the aim of numerous researchers worldwide.[...]. PMID- 27231932 TI - Adapting the Stress Response: Viral Subversion of the mTOR Signaling Pathway. AB - The mammalian target of rapamycin (mTOR) is a central regulator of gene expression, translation and various metabolic processes. Multiple extracellular (growth factors) and intracellular (energy status) molecular signals as well as a variety of stressors are integrated into the mTOR pathway. Viral infection is a significant stress that can activate, reduce or even suppress the mTOR signaling pathway. Consequently, viruses have evolved a plethora of different mechanisms to attack and co-opt the mTOR pathway in order to make the host cell a hospitable environment for replication. A more comprehensive knowledge of different viral interactions may provide fruitful targets for new antiviral drugs. PMID- 27231935 TI - Cuminaldehyde from Cinnamomum verum Induces Cell Death through Targeting Topoisomerase 1 and 2 in Human Colorectal Adenocarcinoma COLO 205 Cells. AB - Cinnamomum verum, also called true cinnamon tree, is employed to make the seasoning cinnamon. Furthermore, the plant has been used as a traditional Chinese herbal medication. We explored the anticancer effect of cuminaldehyde, an ingredient of the cortex of the plant, as well as the molecular biomarkers associated with carcinogenesis in human colorectal adenocarcinoma COLO 205 cells. The results show that cuminaldehyde suppressed growth and induced apoptosis, as proved by depletion of the mitochondrial membrane potential, activation of both caspase-3 and -9, and morphological features of apoptosis. Moreover, cuminaldehyde also led to lysosomal vacuolation with an upregulated volume of acidic compartment and cytotoxicity, together with inhibitions of both topoisomerase I and II activities. Additional study shows that the anticancer activity of cuminaldehyde was observed in the model of nude mice. Our results suggest that the anticancer activity of cuminaldehyde in vitro involved the suppression of cell proliferative markers, topoisomerase I as well as II, together with increase of pro-apoptotic molecules, associated with upregulated lysosomal vacuolation. On the other hand, in vivo, cuminaldehyde diminished the tumor burden that would have a significant clinical impact. Furthermore, similar effects were observed in other tested cell lines. In short, our data suggest that cuminaldehyde could be a drug for chemopreventive or anticancer therapy. PMID- 27231936 TI - Early Genotoxic and Cytotoxic Effects of the Toxic Dinoflagellate Prorocentrum lima in the Mussel Mytilus galloprovincialis. AB - Okadaic acid (OA) and dinophysistoxins (DTXs) are the main toxins responsible for diarrhetic shellfish poisoning (DSP) intoxications during harmful algal blooms (HABs). Although the genotoxic and cytotoxic responses to OA have been evaluated in vitro, the in vivo effects of these toxins have not yet been fully explored. The present work fills this gap by evaluating the in vivo effects of the exposure to the DSP-toxin-producing dinoflagellate Prorocentrum lima during the simulation of an early HAB episode in the mussel Mytilus galloprovincialis. The obtained results revealed that in vivo exposure to this toxic microalgae induced early genotoxicity in hemocytes, as a consequence of oxidative DNA damage. In addition, the DNA damage observed in gill cells seems to be mainly influenced by exposure time and P. lima concentration, similarly to the case of the oxidative damage found in hemocytes exposed in vitro to OA. In both cell types, the absence of DNA damage at low toxin concentrations is consistent with the notion suggesting that this level of toxicity does not disturb the antioxidant balance. Lastly, in vivo exposure to growing P. lima cell densities increased apoptosis but not necrosis, probably due to the presence of a high number of protein apoptosis inhibitors in molluscs. Overall, this work sheds light into the in vivo genotoxic and cytotoxic effects of P. lima. In doing so, it also demonstrates for the first time the potential of the modified (OGG1) comet assay for assessing oxidative DNA damage caused by marine toxins in marine invertebrates. PMID- 27231937 TI - Advances in Biosensors, Chemosensors and Assays for the Determination of Fusarium Mycotoxins. AB - The contaminations of Fusarium mycotoxins in grains and related products, and the exposure in human body are considerable concerns in food safety and human health worldwide. The common Fusarium mycotoxins include fumonisins, T-2 toxin, deoxynivalenol and zearalenone. For this reason, simple, fast and sensitive analytical techniques are particularly important for the screening and determination of Fusarium mycotoxins. In this review, we outlined the related advances in biosensors, chemosensors and assays based on the classical and novel recognition elements such as antibodies, aptamers and molecularly imprinted polymers. Application to food/feed commodities, limit and time of detection were also discussed. PMID- 27231939 TI - Occurrence of 26 Mycotoxins in the Grain of Cereals Cultivated in Poland. AB - The levels of 26 mycotoxins were determined in 147 samples of the grain of cereals cultivated in five regions of Poland during the 2014 growing season. The HPLC-HRMS (time-of-flight) analytical technique was used. An analytical procedure to simultaneously determine 26 mycotoxins in grain was developed, tested and verified. Samples from eastern and southern Poland were more contaminated with mycotoxins than the samples from northern and western Poland. Toxins produced by Fusarium fungi were the main contaminants found. Some deoxynivalenol (DON) was found in 100% of the tested samples of wheat (Osiny, Borusowa, Werbkowice), triticale, winter barley and oats, while the maximum permissible DON level (as defined in the EU Commission Regulation No. 1881/2006) was exceeded in 10 samples. Zearalenone (ZEN), DON metabolites and enniatins were also commonly found. The presence of mycotoxins in grain reflected the prevailing weather conditions during the plant flowering/earing stages, which were favorable for the development of blight. Among all investigated wheat genotypes, cv. Fidelius was the least contaminated, while Bamberka, Forkida and Kampana were the most contaminated. However, the single-factor ANOVA analysis of variance did not reveal (at a statistical significance level alpha = 0.05) any differences between levels of mycotoxins in individual genotypes. Triticale was the most contaminated grain among all of the tested varieties. ZEN, DON and the sum of 3 acetyldexynivalenol and 15-acetyldeoxynivalenol (3- and 15-ADON) were found in 100% of the tested triticale samples at concentrations within the 4-86, 196-1326 and 36-374 ug.kg(-1) range, respectively. Of particular concern was the fact that some "emerging mycotoxins" (enniatins) (in addition to commonly-known and legally regulated mycotoxins) were also found in the tested triticale samples (enniatin B (Enn-B), enniatin B1 (Enn-B1), enniatin A-1 (Enn-A1), 100% of samples, and enniatin A (Enn-A), 70% of samples). Depending on the toxin, they were found at levels between 8 and 3328 ug.kg(-1). PMID- 27231941 TI - Letter to the Editor Re: Ogawa, Y. Cancers 2016, 8, 28. AB - We read with interest the recently published paper by Dr. Ogawa "Paradigm Shift in Radiation Biology/Radiation Oncology-Exploitation of the H2O2 Effect" for Radiotherapy Using Low-LET (Linear Energy Transfer) Radiation such as X-rays and High-Energy Electrons".[...]. PMID- 27231940 TI - Effects of OnabotulintoxinA on Habituation of Laser Evoked Responses in Chronic Migraine. AB - Onabotulintoxin A (BontA) is an efficacious preventive treatment for chronic migraine, though the specific mechanism of action is still under discussion. The study aims: (1) To evaluate pain processing modifications in chronic migraine patients (CM) under single BontA administration in pericranial muscles, by means of CO2 Laser Evoked Potentials (LEPs) obtained by the stimulation of the skin over the right frontal and trapezius injection sites and hand dorsum, in a double blind placebo controlled crossover design. (2) To correlate main LEPs findings with clinical outcome after one year of BontA treatment. Twenty refractory CM patients were included in the analysis. The LEPs were recorded in basal conditions and seven days after BontA (PREEMPT protocol) and saline solution injection. The N1, N2 and P2 amplitude and latencies and N2P2 habituation index were evaluated and correlated with the percent change of headache frequency after one year of toxin treatment. After seven days of BontA treatment, a normalization of the trigeminal habituation index was observed, which was correlated with the clinical outcome after one year of BontA therapy. Patients displaying trigeminal LEPs facilitation at T0 time showed a more efficient therapeutic outcome. Neurotoxin may exert a modulating effect on trigeminal nociception, normalizing central neurotransmission. PMID- 27231938 TI - Roles of Dietary Phytoestrogens on the Regulation of Epithelial-Mesenchymal Transition in Diverse Cancer Metastasis. AB - Epithelial-mesenchymal transition (EMT) plays a key role in tumor progression. The cells undergoing EMT upregulate the expression of cell motility-related proteins and show enhanced migration and invasion. The hallmarks of EMT in cancer cells include changed cell morphology and increased metastatic capabilities in cell migration and invasion. Therefore, prevention of EMT is an important tool for the inhibition of tumor metastasis. A novel preventive therapy is needed, such as treatment of natural dietary substances that are nontoxic to normal human cells, but effective in inhibiting cancer cells. Phytoestrogens, such as genistein, resveratrol, kaempferol and 3,3'-diindolylmethane (DIM), can be raised as possible candidates. They are plant-derived dietary estrogens, which are found in tea, vegetables and fruits, and are known to have various biological efficacies, including chemopreventive activity against cancers. Specifically, these phytoestrogens may induce not only anti-proliferation, apoptosis and cell cycle arrest, but also anti-metastasis by inhibiting the EMT process in various cancer cells. There have been several signaling pathways found to be associated with the induction of the EMT process in cancer cells. Phytoestrogens were demonstrated to have chemopreventive effects on cancer metastasis by inhibiting EMT-associated pathways, such as Notch-1 and TGF-beta signaling. As a result, phytoestrogens can inhibit or reverse the EMT process by upregulating the expression of epithelial phenotypes, including E-cadherin, and downregulating the expression of mesenchymal phenotypes, including N-cadherin, Snail, Slug, and vimentin. In this review, we focused on the important roles of phytoestrogens in inhibiting EMT in many types of cancer and suggested phytoestrogens as prominent alternative compounds to chemotherapy. PMID- 27231942 TI - A Field Trip to the Archaean in Search of Darwin's Warm Little Pond. AB - Charles Darwin's original intuition that life began in a "warm little pond" has for the last three decades been eclipsed by a focus on marine hydrothermal vents as a venue for abiogenesis. However, thermodynamic barriers to polymerization of key molecular building blocks and the difficulty of forming stable membranous compartments in seawater suggest that Darwin's original insight should be reconsidered. I will introduce the terrestrial origin of life hypothesis, which combines field observations and laboratory results to provide a novel and testable model in which life begins as protocells assembling in inland fresh water hydrothermal fields. Hydrothermal fields are associated with volcanic landmasses resembling Hawaii and Iceland today and could plausibly have existed on similar land masses rising out of Earth's first oceans. I will report on a field trip to the living and ancient stromatolite fossil localities of Western Australia, which provided key insights into how life may have emerged in Archaean, fluctuating fresh water hydrothermal pools, geological evidence for which has recently been discovered. Laboratory experimentation and fieldwork are providing mounting evidence that such sites have properties that are conducive to polymerization reactions and generation of membrane-bounded protocells. I will build on the previously developed coupled phases scenario, unifying the chemical and geological frameworks and proposing that a hydrogel of stable, communally supported protocells will emerge as a candidate Woese progenote, the distant common ancestor of microbial communities so abundant in the earliest fossil record. PMID- 27231943 TI - Animal Welfare: Freedoms, Dominions and "A Life Worth Living". AB - This opinion paper considers the relative validity and utility of three concepts: the Five Freedoms (FF), Five Domains (FD) and Quality of Life (QoL) as tools for the analysis of animal welfare. The aims of FF and FD are different but complementary. FD seeks to assess the impact of the physical and social environment on the mental (affective) state of a sentient animal, FF is an outcome-based approach to identify and evaluate the efficacy of specific actions necessary to promote well-being. Both have utility. The concept of QoL is presented mainly as a motivational framework. The FD approach provides an effective foundation for research and evidence-based conclusions as to the impact of the things we do on the mental state of the animals in our care. Moreover, it is one that can evolve with time. The FF are much simpler. They do not attempt to achieve an overall picture of mental state and welfare status, but the principles upon which they are based are timeless. Their aim is to be no more than a memorable set of signposts to right action. Since, so far as the animals are concerned, it is not what we think but what we do that counts, I suggest that they are likely to have a more general impact. PMID- 27231944 TI - Analysis of Failure to Finish a Race in a Cohort of Thoroughbred Racehorses in New Zealand. AB - The objective was to describe the incidence of failure to finish a race in flat racing Thoroughbreds in New Zealand as these are summary indicators of falls, injuries and poor performance. Retrospective data on six complete flat racing seasons (n = 188,615 race starts) of all Thoroughbred flat race starts from 1 August 2005 to 31 July 2011 were obtained. The incidence of failure to finish events and binomial exact 95% confidence intervals were calculated per 1000 horse starts. The association between horse-, rider- and race-level variables with the outcomes failure to finish, pulled-up/fell and lost rider were examined with a mixed effects Poisson regression model. A total of 544 horses failed to finish in 188,615 race starts with an overall incidence of 2.88 per 1000 horse starts (95% CI 2.64-3.12). The incidence of failure to finish horses across each race year showed little variability. In the univariable analysis race distance, larger field size, season, and ratings bands showed association with failing to finish a race. The overall failure to finish outcome was associated with season, race distance and ratings bands (horse experience and success ranking criteria). In the multivariable analysis, race distance and ratings bands were associated with horses that pulled-up/fell; season, apprentice allowances and ratings bands were associated with the outcome lost rider. The failure to finish rate was lower than international figures for race day catastrophic injury. Racing and environmental variables were associated with failure to finish a race highlighting the multifactorial nature of race-day events. Further investigation of risk factors for failure to finish is required to better understand the reasons for a low failure to finish rate in Thoroughbred flat races in New Zealand. PMID- 27231945 TI - Production of Fluconazole-Loaded Polymeric Micelles Using Membrane and Microfluidic Dispersion Devices. AB - Polymeric micelles with a controlled size in the range between 41 and 80 nm were prepared by injecting the organic phase through a microengineered nickel membrane or a tapered-end glass capillary into an aqueous phase. The organic phase was composed of 1 mg.mL(-1) of PEG-b-PCL diblock copolymers with variable molecular weights, dissolved in tetrahydrofuran (THF) or acetone. The pore size of the membrane was 20 MUm and the aqueous/organic phase volumetric flow rate ratio ranged from 1.5 to 10. Block copolymers were successfully synthesized with Mn ranging from ~9700 to 16,000 g.mol(-1) and polymeric micelles were successfully produced from both devices. Micelles produced from the membrane device were smaller than those produced from the microfluidic device, due to the much smaller pore size compared with the orifice size in a co-flow device. The micelles were found to be relatively stable in terms of their size with an initial decrease in size attributed to evaporation of residual solvent rather than their structural disintegration. Fluconazole was loaded into the cores of micelles by injecting the organic phase composed of 0.5-2.5 mg.mL(-1) fluconazole and 1.5 mg.mL(-1) copolymer. The size of the drug-loaded micelles was found to be significantly larger than the size of empty micelles. PMID- 27231946 TI - Broadband 120 MHz Impedance Quartz Crystal Microbalance (QCM) with Calibrated Resistance and Quantitative Dissipation for Biosensing Measurements at Higher Harmonic Frequencies. AB - We developed an impedance quartz crystal microbalance (QCM) approach with the ability to simultaneously record mass changes and calibrated energy dissipation with high sensitivity using an impedance analyzer. This impedance QCM measures frequency shifts and resistance changes of sensing quartz crystals very stable, accurately, and calibrated, thus yielding quantitative information on mass changes and dissipation. Resistance changes below 0.3 Omega were measured with corresponding dissipation values of 0.01 uU (micro dissipation units). The broadband impedance capabilities allow measurements between 20 Hz and 120 MHz including higher harmonic modes of up to 11th order for a 10 MHz fundamental resonance frequency quartz crystal. We demonstrate the adsorbed mass, calibrated resistance, and quantitative dissipation measurements on two biological systems including the high affinity based avidin-biotin interaction and nano-assemblies of polyelectrolyte layers. The binding affinity of a protein-antibody interaction was determined. The impedance QCM is a versatile and simple method for accurate and calibrated resistance and dissipation measurements with broadband measurement capabilities for higher harmonics measurements. PMID- 27231947 TI - The Oligopeptide Permease Opp Mediates Illicit Transport of the Bacterial P-site Decoding Inhibitor GE81112. AB - GE81112 is a tetrapeptide antibiotic that binds to the 30S ribosomal subunit and specifically inhibits P-site decoding of the mRNA initiation codon by the fMet tRNA anticodon. GE81112 displays excellent microbiological activity against some Gram-positive and Gram-negative bacteria in both minimal and complete, chemically defined, broth, but is essentially inactive in complete complex media. This is due to the presence of peptides that compete with the antibiotic for the oligopeptide permease system (Opp) responsible for its illicit transport into the bacterial cells as demonstrated in the cases of Escherichia coli and Bacillus subtilis. Mutations that inactivate the Opp system and confer GE81112 resistance arise spontaneously with a frequency of ca. 1 * 10(-6), similar to that of the mutants resistant to tri-l-ornithine, a known Opp substrate. On the contrary, cells expressing extrachromosomal copies of the opp genes are extremely sensitive to GE81112 in rich medium and GE81112-resistant mutations affecting the molecular target of the antibiotic were not detected upon examining >108 cells of this type. However, some mutations introduced in the 16S rRNA to confer kasugamycin resistance were found to reduce the sensitivity of the cells to GE81112. PMID- 27231949 TI - Epigenetic Inheritance and Its Role in Evolutionary Biology: Re-Evaluation and New Perspectives. AB - Epigenetics increasingly occupies a pivotal position in our understanding of inheritance, natural selection and, perhaps, even evolution. A survey of the PubMed database, however, reveals that the great majority (>93%) of epigenetic papers have an intra-, rather than an inter-generational focus, primarily on mechanisms and disease. Approximately ~1% of epigenetic papers even mention the nexus of epigenetics, natural selection and evolution. Yet, when environments are dynamic (e.g., climate change effects), there may be an "epigenetic advantage" to phenotypic switching by epigenetic inheritance, rather than by gene mutation. An epigenetically-inherited trait can arise simultaneously in many individuals, as opposed to a single individual with a gene mutation. Moreover, a transient epigenetically-modified phenotype can be quickly "sunsetted", with individuals reverting to the original phenotype. Thus, epigenetic phenotype switching is dynamic and temporary and can help bridge periods of environmental stress. Epigenetic inheritance likely contributes to evolution both directly and indirectly. While there is as yet incomplete evidence of direct permanent incorporation of a complex epigenetic phenotype into the genome, doubtlessly, the presence of epigenetic markers and the phenotypes they create (which may sort quite separately from the genotype within a population) will influence natural selection and, so, drive the collective genotype of a population. PMID- 27231951 TI - Identification of Comprehensive Geriatric Assessment Based Risk Factors for Malnutrition in Elderly Asian Cancer Patients. AB - PURPOSE: Elderly cancer patients are at increased risk for malnutrition. We aim to identify comprehensive geriatric assessment (CGA) based clinical factors associated with increased nutritional risk and develop a clinical scoring system to identify nutritional risk in elderly cancer patients. PATIENTS AND METHODS: CGA data was collected from 249 Asian patients aged 70 years or older. Nutritional risk was assessed based on the Nutrition Screening Initiative (NSI) checklist. Univariate and multivariate logistic regression analyses were applied to assess the association between patient clinical factors together with domains within the CGA and moderate to high nutritional risk. Goodness of fit was assessed using Hosmer-Lemeshow test. Discrimination ability was assessed based on the area under the receiver operating characteristics curve (AUC). Internal validation was performed using simulated datasets via bootstrapping. RESULTS: Among the 249 patients, 184 (74%) had moderate to high nutritional risk. Multivariate logistic regression analysis identified stage 3-4 disease (Odds Ratio [OR] 2.54; 95% CI, 1.14-5.69), ECOG performance status of 2-4 (OR 3.04; 95% CI, 1.57-5.88), presence of depression (OR 5.99; 95% CI, 1.99-18.02) and haemoglobin levels <12 g/dL (OR 3.00; 95% CI 1.54-5.84) as significant independent factors associated with moderate to high nutritional risk. The model achieved good calibration (Hosmer-Lemeshow test's p = 0.17) and discrimination (AUC = 0.80). It retained good calibration and discrimination (bias-corrected AUC = 0.79) under internal validation. CONCLUSION: Having advanced stage of cancer, poor performance status, depression and anaemia were found to be predictors of moderate to high nutritional risk. Early identification of patients with these risk factors will allow for nutritional interventions that may improve treatment tolerance, quality of life and survival outcomes. PMID- 27231948 TI - The Function of Fish Cytokines. AB - What is known about the biological activity of fish cytokines is reviewed. Most of the functional studies performed to date have been in teleost fish, and have focused on the induced effects of cytokine recombinant proteins, or have used loss- and gain-of-function experiments in zebrafish. Such studies begin to tell us about the role of these molecules in the regulation of fish immune responses and whether they are similar or divergent to the well-characterised functions of mammalian cytokines. This knowledge will aid our ability to determine and modulate the pathways leading to protective immunity, to improve fish health in aquaculture. PMID- 27231952 TI - Diagnostic significance of circulating multiple miRNAs in breast cancer: a systematic review and meta-analysis. AB - AIMS: To determine whether circulating multiple miRNAs can be used as novel biomarkers for the diagnosis in breast cancer, we performed a systematic review and meta-analysis. MATERIALS & METHODS: After searching the databases of PubMed, EMBASE and Web of Science, we used the bivariate meta-analysis model to summarize the diagnostic indices and plot the summary receiver operator characteristic curve. RESULTS: The summary estimates revealed that the pooled sensitivity was 88% (95% CI: 82-93%); specificity was 84% (95% CI: 74-91%); positive likelihood ratio was 4.69 (95% CI: 2.93-7.51); negative likelihood ratio was 0.15 (95% CI: 0.09-0.25); diagnostic odds ratio was 38.21 (95% CI: 13.41-108.85); and the area under the curve was 0.93 (95% CI: 0.90-0.95). CONCLUSION: These results suggested that circulating multiple miRNAs might serve as novel biomarkers for breast cancer, with a relatively high level of accuracy. PMID- 27231950 TI - The Kinome of Pacific Oyster Crassostrea gigas, Its Expression during Development and in Response to Environmental Factors. AB - Oysters play an important role in estuarine and coastal marine habitats, where the majority of humans live. In these ecosystems, environmental degradation is substantial, and oysters must cope with highly dynamic and stressful environmental constraints during their lives in the intertidal zone. The availability of the genome sequence of the Pacific oyster Crassostrea gigas represents a unique opportunity for a comprehensive assessment of the signal transduction pathways that the species has developed to deal with this unique habitat. We performed an in silico analysis to identify, annotate and classify protein kinases in C. gigas, according to their kinase domain taxonomy classification, and compared with kinome already described in other animal species. The C. gigas kinome consists of 371 protein kinases, making it closely related to the sea urchin kinome, which has 353 protein kinases. The absence of gene redundancy in some groups of the C. gigas kinome may simplify functional studies of protein kinases. Through data mining of transcriptomes in C. gigas, we identified part of the kinome which may be central during development and may play a role in response to various environmental factors. Overall, this work contributes to a better understanding of key sensing pathways that may be central for adaptation to a highly dynamic marine environment. PMID- 27231953 TI - Preparation of [(68)Ga]PSMA-11 for PET-CT imaging using a manual synthesis module and organic matrix based (68)Ge/(68)Ga generator. AB - INTRODUCTION: [(68)Ga]PSMA-11 is a relatively recently introduced radiopharmaceutical for PET-CT imaging of prostate cancer patients. The availability of (68)Ge/(68)Ga generator and PSMA-11 ligand from commercial sources is facilitating the production of the radiopharmaceutical in-house. This paper describes our experience on the preparation of ~200 batches of [(68)Ga]PSMA 11 for conducting PET-CT imaging in patients suspected/suffering from prostate cancer. METHODS: The radiosynthesis of [(68)Ga]PSMA-11 was done in a hospital based nuclear medicine department using (68)Ge/(68)Ga generator and a manual synthesis module, both supplied by Isotope Technologies Garching (ITG), Germany. The production involved the reaction of 5MUg (5.3nmol) of PSMA-11 ligand in 1 ml of 0.25M sodium acetate buffer with 4ml of (68)GaCl3 in 0.05M HCl for 5min at 105 degrees C; followed by purification in a C18 cartridge and collection through a 0.22MUm pore size filter. RESULTS: The radiochemical yields obtained were consistently high, 93.19%+/-3.76%, and there was hardly any batch failure. The radiochemical purity of the product was >99% and the product was stable for over 2h; however it was used in patients immediately after preparation. About 200 batches of [(68)Ga]PSMA-11 were prepared during the period and more than 300 patients received the tracer during the 14months of study. No adverse reaction was observed in any of the patients and the image qualities were consistent with literature reports. CONCLUSION: [(68)Ga]PSMA-11 with high radiochemical and radionuclidic purity is conveniently prepared by using a (68)Ge/(68)Ga generator and manual synthesis module. The radiochemical yields are very high; and activity sufficient for 3-4 patients can be prepared in a single batch; multiple batches can be done on the same day and when needed after a gap of 1.5-2h. PMID- 27231956 TI - Essentials of Advocacy in Case Management: Part 1: Ethical Underpinnings of Advocacy-Theories, Principles, and Concepts. AB - PURPOSE/OBJECTIVES: This article describes the meaning and underpinnings of advocacy in the field of case management and shares essential principles and concepts for effective client advocacy. PRIMARY PRACTICE SETTING(S): All practice settings across the continuum of health and human services and case managers of diverse professional backgrounds. FINDINGS AND CONCLUSION: Advocacy is vital to case management practice and a primary role of the professional case manager. It is rooted in ethical theory and principles. Successful case managers apply advocacy at every step of the case management process and in every action they take. Part I of this 2-part article explores the ethical theories and principles of advocacy, the perception of case management-related professional organizations of advocacy, and types of advocacy. Part II then presents a client advocacy model for case managers to apply in their practice, describes the role of advocacy in client engagement, and identifies important strategies and a set of essential competencies for effective case management advocacy. IMPLICATIONS FOR CASE MANAGEMENT: Acquiring foundational knowledge, skills, and competencies in what advocacy is equips case managers with the ability and confidence to enact advocacy-related behaviors in the provision of care to achieve desired outcomes for both the clients and health care agencies/providers alike. Case management leaders may use the knowledge shared in this article to develop advocacy training and competency programs for their case managers. PMID- 27231955 TI - The Evolution of Ethics. AB - Ethical issues and dilemmas span from conception to the grave. The interconnectedness of advocacy, ethics, and end of life/death with dignity are woven into this issue of the Professional Case Management journal. Case management is a critical member of the team when these discussions arise. And knowledge of the issues, along with legal, ethical, and professional codes, is highlighted. PMID- 27231954 TI - Curcumin Promotes Osteosarcoma Cell Death by Activating miR-125a/ERRalpha Signal Pathway. AB - Curcumin has demonstrated valuable therapeutic potential against a variety of human cancers including osteosarcoma. However, the molecular mechanisms underlying its anti-tumor effect remain to be poorly understood. By RNA sequence profiling, we found that curcumin significantly down-regulates the expression of estrogen-related receptor alpha (ERRalpha) in osteosarcoma cells. Overexpression of ERRalpha diminished curcumin-activated apoptotic cell death and scavenged curcumin-induced reactive oxygen species (ROS), while ERRalpha silencing sensitized osteosarcoma cells to curcumin, resulting in increased inhibition of cell proliferation. In addition, we found that curcumin suppressed the ERRalpha gene expression through upregulation of miR-125a. Data from this study revealed a novel mechanism for curcumin-mediated apoptotic cell death, which involves tumor cell killing via activating miR-125a/ERRalpha pathway. Our studies also provide further support for osteosarcoma therapy by targeting ERRalpha alone or in combination with curcumin. J. Cell. Biochem. 118: 74-81, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27231957 TI - The Evolution of End-of-Life Care: Ethical Implications for Case Management. AB - PURPOSE AND OBJECTIVES: This article: PRIMARY PRACTICE SETTINGS(S): : Applicable to all health care sectors where case management is practiced. FINDINGS/CONCLUSION: Few topics are more intimate and multifaceted for case managers than engaging with today's culturally diverse patient populations around end-of-life processes. The already prominent focus of this issue has been further elevated by a series of events to receive public attention. These include the Institute of Medicine's 2014 report-Dying in America: Improving Quality and Honoring Individual Preferences Near the End of Life, rising numbers of patients around the globe requesting to end life on their own terms, and corresponding death with dignity initiatives and legislation.Another vital factor in the end-of life equation involves how the latest generation of shared decision making influences the management of treatment dialogues among practitioners, patients, as well as insurance companies. Case managers are at the intersection of these complex interactions, working to achieve ethical, as well as legal accountability to the patient, employer, and profession while balancing personal perspectives. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: Professionals strive to effectively intervene with patients and their support systems facing end-of-life care decisions. It is essential case managers actively consider the intricacies of ethical practice and current contexts including death with dignity legislation, shared decision making, and shifts in regulations and reimbursement for end-of life care.Case management's ethical envelope will continue to be pushed. To that end amid shifting societal constructs, professionals must have mastery of applicable codes, standards, principles, and rules essential for adherence to ethical practice. PMID- 27231958 TI - Case Management Ethics: High Professional Standards for Health Care's Interconnected Worlds. AB - PURPOSE: The purpose of this discussion is to draw attention to the considerable pressure on professional case managers today to coordinate with multiple stakeholders, with responsibilities that put them at the forefront of contact with payers and providers. This discussion raises awareness of how case managers, and board-certified case managers in particular, must demonstrate that they adhere to the highest ethical standards, as codified by the Commission for Case Manager Certification's Code of Professional Conduct for Case Managers. PRIMARY PRACTICE SETTINGS: This discussion applies to case management practices and work settings across the full continuum of health care. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: As advocates for clients (individuals receiving case management services) and their families/support systems, case managers must adhere to the highest of ethical and professional standards. The Code of Professional Conduct for Case Managers is an indispensable resource for case managers to ensure that they place the public interest above their own, respect the rights and inherent dignity of clients, maintain objectivity in their relationships with clients, and act with integrity and fidelity with clients and others, as stipulated by the code. PMID- 27231960 TI - Title Protection for Professional Case Management: Social Work's Intricacies and Opportunities. PMID- 27231959 TI - The Music Never Stops. PMID- 27231961 TI - The Case Manager's "Touchstone": The Code of Professional Conduct. PMID- 27231962 TI - "Time-Out" in the Operating Room. PMID- 27231963 TI - Essentials of Advocacy in Case Management: Part 1-Ethical Underpinnings of Advocacy-Theories, Principles, and Concepts. PMID- 27231964 TI - The Evolution of End-of-Life Care: Ethical Implications for Case Management. PMID- 27231965 TI - Two-Step, One-Flask Synthesis of a Meso-Substituted Phlorin. AB - A two-step, one-flask reaction of pyrrole with pentafluorobenzaldehyde and acetone was investigated to determine the potential for a streamlined synthesis of a phlorin and/or 5-isocorrole as an alternative to stepwise, dipyrromethanecarbinol routes. Analytical-scale reactions were performed examining the effect of reactant concentration, reactant ratio, acid catalyst (TFA or BF3.OEt2), concentration of acid catalyst, oxidant quantity, and reaction time on the distribution of phlorin and 5-isocorrole as well as three additional porphyrinoids (porphodimethene, porphyrin, and corrole). Phlorin was observed ubiquitously in yields up to 20-26%, whereas 5-isocorrole was not detected. Promising reaction conditions for the one-flask synthesis of the phlorin were performed on a preparative scale. The best reaction condition afforded the phlorin in an isolated yield of 20-21% (249-268 mg). Preliminary attempts to extend the methodology to the preparation of phlorins derived from other ketones resulted in a low yield of phlorin from acetophenone (5%) and no detectable phlorin from benzophenone. The discovery of reaction conditions for the two-step, one-flask synthesis of a phlorin provides easier access to this interesting compound, and provides encouragement for the further study of reactions of pyrrole with an aldehyde and a ketone. PMID- 27231967 TI - Anatomy education for the YouTube generation: Technical, ethical, and educational considerations. PMID- 27231966 TI - Management of non-muscle invasive bladder cancer: A comprehensive analysis of guidelines from the United States, Europe and Asia. AB - Bladder cancer is the 8th most common cancer with 74,000 new cases in the United States in 2015. Non-muscle invasive bladder cancer (NMIBC) accounts for 75% of all bladder cancer cases. Transurethral resection and intravesical treatments remain the main treatment modality. Up to 31-78% of cases recur, hence the need for intensive treatment and surveillance protocols which makes bladder cancer one of the most expensive cancers to manage. The purpose of this review is to compare contemporary guidelines from Europe, (European Association of Urology), the United States (National Comprehensive Cancer Network), the United Kingdom (National Institute for Health and Care Excellence), Japan (Japanese Urological Association) and the International Consultation on Bladder Cancer (ICUD). We compare and contrast the different guidelines and the evidence on which their recommendations are based. PMID- 27231968 TI - Toward "metalloMOFzymes": Metal-Organic Frameworks with Single-Site Metal Catalysts for Small-Molecule Transformations. AB - Metal-organic frameworks (MOFs) are being increasingly studied as scaffolds and supports for catalysis. The solid-state structures of MOFs, combined with their high porosity, suggest that MOFs may possess advantages shared by both heterogeneous and homogeneous catalysts, with few of the shortcomings of either. Herein, efforts to create single-site catalytic metal centers appended to the organic ligand struts of MOFs will be discussed. Reactions important for advanced energy applications, such as H2 production and CO2 reduction, will be highlighted. Examining how these active sites can be introduced, their performance, and their existing limitations should provide direction for design of the next generation of MOF-based catalysts for energy-relevant, small-molecule transformations. Finally, the introduction of second-sphere interactions (e.g., hydrogen bonding via squaramide groups) as a possible route to enhancing the activity of these metal centers is reported. PMID- 27231969 TI - Ligand Release Pathways Obtained with WExplore: Residence Times and Mechanisms. AB - The binding of ligands with their molecular receptors is of tremendous importance in biology. Although much emphasis has been placed on characterizing binding sites and bound poses that determine the binding thermodynamics, the pathway by which a ligand binds importantly determines the binding kinetics. The computational study of entire unbiased ligand binding and release pathways is still an emerging field, made possible only recently by advances in computational hardware and sampling methodologies. We have developed one such method (WExplore) that is based on a weighted ensemble of trajectories, which we apply to ligand release for the first time, using a set of three previously characterized interactions between low-affinity ligands and the protein FKBP-12 (FK-506 binding protein). WExplore is found to be more efficient that conventional sampling, even for the nanosecond-scale unbinding events observed here. From a nonequilibrium ensemble of unbinding trajectories, we obtain ligand residence times and release pathways without using biasing forces or a Markovian assumption of transitions between regions. We introduce a set of analysis tools for unbinding transition pathways, including using von Mises-Fisher distributions to model clouds of ligand exit points, which provide a quantitative proxy for ligand surface diffusion. Differences between the transition pathway ensembles of the three ligands are identified and discussed. PMID- 27231970 TI - A Nonempirical Approach for Direct Determination of the Absolute Configuration of 1,2-Diols and Amino Alcohols Using Mg(II)bisporphyrin. AB - We report here a simple, facile, and direct nonempirical protocol for determining the absolute stereochemistry of a variety of chiral 1,2-diols and amino alcohols at room temperature with no chemical derivatization using Mg(II)bisporphyrin as a host. Addition of excess substrates resulted in the formation of a 1:2 host-guest complex in which two substrates bind in an unusual endo-endo fashion because of interligand H-bonding within the bisporphyrin cavity leading to the formation of a unidirectional screw in the bisporphyrin moiety that allowed us an accurate absolute stereochemical determination of the chiral substrate via exciton-coupled circular dichroism (ECCD). The sign of the CD couplet has also been found to be inverted when the stereogenic center is moved by one C atom simply from the bound to an unbound functionality and thus able to discriminate between them successfully. Strong complexation of the alcoholic oxygen with Mg(II)bisporphyrin rigidifies the host-guest complex, which eventually enhances its ability to stereochemically differentiate the asymmetric center. The ECCD sign of a large number of substrates has followed consistent and predictable trends; thus, the system is widely applicable. Moreover, computational calculations clearly support the experimental observations along with the absolute stereochemistry of the chiral substrate. PMID- 27231971 TI - NOTCH4 gene polymorphisms as potential risk factors for brain arteriovenous malformation development and hemorrhagic presentation. AB - OBJECTIVE Arteriovenous malformations (AVMs) of the brain are a frequent and important cause of intracranial hemorrhage in young adults. Little is known about the molecular-genetic pathomechanisms underlying AVM development. Genes of the NOTCH family control the normal development of vessels and proper arteriovenous specification. Transgenic mice with constitutive expression of active NOTCH4 frequently develop AVMs. Here, the authors report a genetic association study investigating possible associations between NOTCH4 gene polymorphisms and formation and clinical presentation of AVMs. METHODS After PCR amplification and direct DNA sequencing or restriction digests, 10 single-nucleotide polymorphisms (SNPs) of the NOTCH4 gene were used for genotyping 153 AVM patients and 192 healthy controls (i.e., blood donors). Pertinent clinical data were available for 129 patients. Uni- and multivariate single-marker and explorative haplotype analyses were performed to identify potential genetic risk factors for AVM development and for hemorrhagic or epileptic presentation. RESULTS Eleven calculated haplotypes consisting of 3-4 SNPs (most of which were located in the epidermal growth factor-like domain of the NOTCH4 gene) were observed significantly more often among AVM patients than among controls. Univariate analysis indicated that rs443198_TT and rs915895_AA genotypes both were significantly associated with hemorrhage and that an rs1109771_GG genotype was associated with epilepsy. The association between rs443198_TT and AVM bleeding remained significant in the multivariate regression analysis. CONCLUSIONS The authors' results suggest NOTCH4 SNPs as possible genetic risk factors for the development and clinical presentation of AVMs and a role of NOTCH4 in the pathogenesis of this disease. PMID- 27231972 TI - Helmet efficacy against concussion and traumatic brain injury: a review. AB - Helmets are one of the earliest and most enduring methods of personal protection in human civilization. Although primarily developed for combat purposes in ancient times, modern helmets have become highly diversified to sports, recreation, and transportation. History and the scientific literature exhibit that helmets continue to be the primary and most effective prevention method against traumatic brain injury (TBI), which presents high mortality and morbidity rates in the US. The neurosurgical and neurotrauma literature on helmets and TBI indicate that helmets provide effectual protection against moderate to severe head trauma resulting in severe disability or death. However, there is a dearth of scientific data on helmet efficacy against concussion in both civilian and military aspects. The objective of this literature review was to explore the historical evolution of helmets, consider the effectiveness of helmets in protecting against severe intracranial injuries, and examine recent evidence on helmet efficacy against concussion. It was also the goal of this report to emphasize the need for more research on helmet efficacy with improved experimental design and quantitative standardization of assessments for concussion and TBI, and to promote expanded involvement of neurosurgery in studying the quantitative diagnostics of concussion and TBI. Recent evidence summarized by this literature review suggests that helmeted patients do not have better relative clinical outcome and protection against concussion than unhelmeted patients. PMID- 27231973 TI - Reappearance of arteriovenous malformations after complete resection of ruptured arteriovenous malformations: true recurrence or false-negative early postoperative imaging result? AB - OBJECTIVE Ruptured arteriovenous malformations (AVMs) are often obliterated after emergency microsurgical treatment. However, some studies have reported AVM recurrence after the obliteration of ruptured AVMs. The authors report their experience with AVM recurrence after successful microsurgical treatment of ruptured AVMs. METHODS The authors reviewed the medical data of 139 consecutive patients who underwent microsurgery at the authors' institution for ruptured AVM between 2002 and 2012. Each patient underwent a conventional cerebral angiography examination immediately after the surgery. Subsequent follow-ups were performed with MR angiography after 6 months, and, if there was no indication of AVM recurrence, patients were followed up with conventional cerebral angiography between 1 and 2 years after the treatment; pediatric patients were followed up until age 18 years. Recurrence was defined as new radiological evidence of an AVM at the site of a ruptured AVM or a new hemorrhage in patients with angiographically documented AVM obliteration on postoperative angiograms. RESULTS The mean age of the patients at the time of ruptured AVM diagnosis was 30.8 years (SD +/- 5, range 4-69 years), and 44 of the patients were younger than 18 years (the mean age at diagnosis in this pediatric subgroup was 11.4 years [range 4 17.9 years]). Complete AVM obliteration after the initial microsurgery was observed in 123 patients (89.5%). Reappearance of an AVM was noted in 7 patients between 12 and 42 months after the treatment, and all of these patients were younger than 18 years. The recurrent AVM was located in an eloquent zone in 4 patients, and deep venous drainage was noted in 3 patients. Radiosurgery was performed in 6 of these patients, and 1 patient underwent another microsurgical procedure. The authors noted only one rebleeding due to an AVM recurrence during the latency period after radiosurgery. CONCLUSIONS The recurrence of an AVM is fairly rare and affects mostly pediatric patients. Therefore, especially in children, long-term angiographic follow-up is required to detect AVM recurrence or an AVM remnant. The authors stress the need for discussion involving a multidisciplinary neurosurgical team to decide on treatment in cases of any AVM recurrence or remnant. PMID- 27231974 TI - Continuous intranigral infusion is not associated with observable behavioral deficits or marked pathology: a preclinical safety study. AB - OBJECTIVE A better understanding of the effects of chronically delivering compounds to the substantia nigra and nearby areas is important for the development of new therapeutic approaches to treat alpha-synucleinopathies, like Parkinson's disease. Whether chronic intranigral delivery of an infusate could be achieved without causing motor dysfunction or marked pathology remains unclear. The authors evaluated the tolerability of continuously delivering an infusate directly into the rhesus monkey substantia nigra via a programmable pump coupled to a novel intraparenchymal needle-tip catheter surgically implanted using MRI guided techniques. METHODS The MRI contrast agent gadopentetate dimeglumine (Magnevist, 5 mM) was used to noninvasively evaluate catheter patency and infusion volume associated with 2 flow rates sequentially tested in each of 3 animals: 0.1 ul/min for 14 days into the right substantia nigra and 0.1 ul/min for 7 days plus 0.2 ul/min for an additional 7 days into the left substantia nigra. Flow rate tolerability was assessed via clinical observations and a microscopic examination of the striatum and midbrain regions. RESULTS Evaluation of postsurgical MRI indicated that all 6 catheters remained patent throughout the study and that the volume of distribution achieved in the left midbrain region at a rate of up to 0.2 ul/min (2052 +/- 168 mm3) was greater than that achieved in the right midbrain region at a constant rate of 0.1 ul/min (1225 +/- 273 mm3) by nearly 2-fold. Both flow rates provided sufficient infusate coverage of the rhesus (and possibly the human) midbrain region. There were no indications of observable deficits in behavior. Histopathological evaluations confirmed that all catheter tips were placed in or near the pars compacta region of the substantia nigra in all animals. There was no evidence of infection at any of the 6 catheter sites. Mild to moderate microglial reactions were observed at most catheter track sites and were comparable between the 2 infusion rates. Finally, there was neither observable decrease of tyrosine hydroxylase staining in the striatum nor detectable necrosis of neurons in the pars compacta region of the substantia nigra in any of the animals. CONCLUSIONS The data from this study support the feasibility of using a pump-and-catheter system for chronic intranigral infusion and lay the foundation for using this approach to treat Parkinson's disease or other related degenerative diseases that would benefit from targeted drug delivery to the substantia nigra or to other brainstem regions. PMID- 27231975 TI - Ultra-early angiographic vasospasm associated with delayed cerebral ischemia and infarction following aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE The clinical significance of cerebral ultra-early angiographic vasospasm (UEAV), defined as cerebral arterial narrowing within the first 48 hours of aneurysmal subarachnoid hemorrhage (aSAH), remains poorly characterized. The authors sought to determine its frequency, predictors, and impact on functional outcome. METHODS The authors prospectively studied UEAV in a cohort of 1286 consecutively admitted patients with aSAH between August 1996 and June 2013. Admission clinical, radiographic, and acute clinical course information was documented during patient hospitalization. Functional outcome was assessed at 3 months using the modified Rankin Scale. Logistic regression and Cox proportional hazards models were generated to assess predictors of UEAV and its relationship to delayed cerebral ischemia (DCI) and outcome. Multiple imputation methods were used to address data lost to follow-up. RESULTS The cohort incidence rate of UEAV was 4.6%. Multivariable logistic regression analysis revealed that younger age, sentinel bleed, and poor admission clinical grade were significantly associated with UEAV. Patients with UEAV had a 2-fold increased risk of DCI (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.4-3.9, p = 0.002) and cerebral infarction (OR 2.0, 95% CI 1.0-3.9, p = 0.04), after adjusting for known predictors. Excluding patients who experienced sentinel bleeding did not change this effect. Patients with UEAV also had a significantly higher hazard for DCI in a multivariable model. UEAV was not found to be significantly associated with poor functional outcome (OR 0.8, 95% CI 0.4-1.6, p = 0.5). CONCLUSIONS UEAV may be less frequent than has been reported previously. Patients who exhibit UEAV are at higher risk for refractory DCI that results in cerebral infarction. These patients may benefit from earlier monitoring for signs of DCI and more aggressive treatment. Further study is needed to determine the long-term functional significance of UEAV. PMID- 27231976 TI - Outcomes of chronic subdural hematoma with preexisting comorbidities causing disturbed consciousness. AB - OBJECTIVE Chronic subdural hematoma (CSDH) is widely treated by drainage through a bur hole opening. However, whether and how preexisting comorbidities causing disturbance of consciousness affect patient outcomes remains unclear. METHODS The authors analyzed 188 consecutive patients with CSDH who were surgically treated at the Neurosurgery Institute of the Kyorin University School of Medicine between 2010 and 2012 and followed them for more than 90 days. The mean patient age was 77.0 years (range 33-101 years) and 56 were women. Patient outcomes including modified Rankin Scale (mRS) score, postoperative morbidity and mortality, and recurrence 90 days after initial surgery were analyzed according to preexisting comorbidities causing disturbance of consciousness. The comorbidities observed in 46 patients (24%) included dementia (30 patients), history of ischemic stroke (10 patients), psychiatric disorders (3 patients), and others (3 patients). RESULTS Background characteristics of patients with comorbidities showed older patient age (p < 0.001), lower preoperative Glasgow Coma Scale score (p < 0.001), and higher preoperative mRS score (p < 0.001). The mean mRS score 90 days after the neurosurgical procedure was 1.2 in all 188 patients, which was significantly higher in those with comorbidities (p < 0.001). By 1-way ANOVA with repeated measures, interaction existed between the presence of comorbidities and mRS score, and improvement of mRS score was observed in smaller proportions of patients with comorbidities (p = 0.002). By multivariate logistic regression analysis, the presence of comorbidities, patient age, reoperation for recurrence, and preoperative mRS score were significantly related to poor outcomes, defined as mRS score of 3 or more at 90 days after surgery. Postoperative morbidity (p < 0.01) and mortality (p < 0.01) were significantly higher in those with comorbidities, whereas the rate of recurrence of CSDH was not significantly different. CONCLUSIONS The preexistence of comorbidities causing disturbance of consciousness affected severity and outcomes 90 days after surgical treatment of CSDH, and comorbidities were also correlated with aging. PMID- 27231977 TI - Language pathway tracking: comparing nTMS-based DTI fiber tracking with a cubic ROIs-based protocol. AB - OBJECTIVE Diffusion tensor imaging (DTI) fiber tracking (FT) has been widely used in glioma surgery in recent years. It can provide helpful information about subcortical structures, especially in patients with eloquent space-occupying lesions. This study compared the newly developed navigated transcranial magnetic stimulation (nTMS)-based DTI FT of language pathways with the most reproducible protocol for language pathway tractography, using cubic regions of interest (ROIs) for the arcuate fascicle. METHODS Thirty-seven patients with left-sided perisylvian lesions underwent language mapping by repetitive nTMS. DTI FT was performed using the cubic ROIs-based protocol and the authors' nTMS-based DTI FT approach. The same minimal fiber length and fractional anisotropy were chosen (50 mm and 0.2, respectively). Both protocols were performed with standard clinical tractography software. RESULTS Both methods visualized language-related fiber tracts (i.e., corticonuclear tract, arcuate fascicle, uncinate fascicle, superior longitudinal fascicle, inferior longitudinal fascicle, arcuate fibers, commissural fibers, corticothalamic fibers, and frontooccipital fascicle) in all 37 patients. Using the cubic ROIs-based protocol, 39.9% of these language-related fiber tracts were detected in the examined patients, as opposed to 76.0% when performing nTMS-based DTI FT. For specifically tracking the arcuate fascicle, however, the cubic ROIs-based approach showed better results (97.3% vs 75.7% with nTMS-based DTI FT). CONCLUSIONS The cubic ROIs-based protocol was designed for arcuate fascicle tractography, and this study shows that it is still useful for this intention. However, superior results were obtained using the nTMS-based DTI FT for visualization of other language-related fiber tracts. PMID- 27231978 TI - Impact of the radiosurgery prescription dose on the local control of small (2 cm or smaller) brain metastases. AB - OBJECTIVE The impact of the stereotactic radiosurgery (SRS) prescription dose (PD) on local progression and radiation necrosis for small (<= 2 cm) brain metastases was evaluated. METHODS An institutional review board-approved retrospective review was performed on 896 patients with brain metastases <= 2 cm (3034 tumors) who were treated with 1229 SRS procedures between 2000 and 2012. Local progression and/or radiation necrosis were the primary end points. Each tumor was followed from the date of radiosurgery until one of the end points was reached or the last MRI follow-up. Various criteria were used to differentiate tumor progression and radiation necrosis, including the evaluation of serial MRIs, cerebral blood volume on perfusion MR, FDG-PET scans, and, in some cases, surgical pathology. The median radiographic follow-up per lesion was 6.2 months. RESULTS The median patient age was 56 years, and 56% of the patients were female. The most common primary pathology was non-small cell lung cancer (44%), followed by breast cancer (19%), renal cell carcinoma (14%), melanoma (11%), and small cell lung cancer (5%). The median tumor volume and median largest diameter were 0.16 cm3 and 0.8 cm, respectively. In total, 1018 lesions (34%) were larger than 1 cm in maximum diameter. The PD for 2410 tumors (80%) was 24 Gy, for 408 tumors (13%) it was 19 to 23 Gy, and for 216 tumors (7%) it was 15 to 18 Gy. In total, 87 patients (10%) had local progression of 104 tumors (3%), and 148 patients (17%) had at least radiographic evidence of radiation necrosis involving 199 tumors (7%; 4% were symptomatic). Univariate and multivariate analyses were performed for local progression and radiation necrosis. For local progression, tumors less than 1 cm (subhazard ratio [SHR] 2.32; p < 0.001), PD of 24 Gy (SHR 1.84; p = 0.01), and additional whole-brain radiation therapy (SHR 2.53; p = 0.001) were independently associated with better outcome. For the development of radiographic radiation necrosis, independent prognostic factors included size greater than 1 cm (SHR 2.13; p < 0.001), location in the corpus callosum (SHR 5.72; p < 0.001), and uncommon pathologies (SHR 1.65; p = 0.05). Size (SHR 4.78; p < 0.001) and location (SHR 7.62; p < 0.001)-but not uncommon pathologies-were independent prognostic factors for the subgroup with symptomatic radiation necrosis. CONCLUSIONS A PD of 24 Gy results in significantly better local control of metastases measuring < 2 cm than lower doses. In addition, tumor size is an independent prognostic factor for both local progression and radiation necrosis. Some tumor pathologies and locations may also contribute to an increased risk of radiation necrosis. PMID- 27231979 TI - Traumatic hemorrhagic brain injury: impact of location and resorption on cognitive outcome. AB - OBJECTIVE Hemorrhagic contusions are often the most visible lesions following traumatic brain injury. However, the incidence, location, and natural history of traumatic parenchymal hemorrhage and its impact on neurological outcome have been understudied. The authors sought to examine the location and longitudinal evolution of traumatic parenchymal hemorrhage and its association with cognitive outcome. METHODS Sixteen patients with hemorrhagic contusions due to acceleration deceleration injuries underwent MRI in the acute (mean 6.3 days postinjury) and chronic (mean 192.9 days postinjury) phases. ImageJ was used to generate GRE and FLAIR volumes. To account for the effect of head-size variability across individuals, the authors calculated each patient's total brain tissue volume using SIENAX. GRE and FLAIR volumes were normalized to the total brain tissue volume, and values for absolute and percent lesion volume and total brain volume change were generated. Spearman's rank correlations were computed to determine associations between neuroimaging and 6-month postinjury neuropsychological testing of attention (Symbol Digit Modalities Test [SDMT], oral [O] and written [W] versions), memory (Selective Reminding Test, total learning and delayed recall), and executive function (Trail Making Test Part B [TMT-B]). RESULTS The patients' mean age was 31.4 +/- 14.0 years and their mean Glasgow Coma Scale score at admission was 7.9 +/- 2.8. Lesions were predominantly localized to the frontal (11 lesions) and temporal (9 lesions) lobes. The average percent reductions in GRE and FLAIR volumes were 44.2% +/- 46.1% and 80.5% +/- 26.3%, respectively. While total brain and frontal lesion volumes did not correlate with brain atrophy, larger temporal lobe GRE and FLAIR volumes were associated with larger volumes of atrophy (GRE: acute, -0.87, p < 0.01, chronic, -0.78, p < 0.01; FLAIR: acute, -0.81, p < 0.01, chronic, -0.88, p < 0.01). Total percent volume change of GRE lesions correlated with TMT-B (0.53, p < 0.05) and SDMT-O (0.62, p < 0.05) scores. Frontal lobe lesion volume did not correlate with neuropsychological outcome. However, robust relationships were seen in the temporal lobe, with larger acute temporal lobe GRE volumes were associated with worse scores on both oral and written versions of the SDMT (SDMT-W, -0.85, p < 0.01; SDMT-O, -0.73, p < 0.05). Larger absolute change in temporal GRE volume was strongly associated with worse SDMT scores (SDMT-W, 0.88, p < 0.01; SDMT-O, 0.75, p < 0.05). The same relationships were also seen between temporal FLAIR lesion volumes and neuropsychological outcome. CONCLUSIONS Traumatic parenchymal hemorrhages are largely clustered in the frontal and temporal lobes, and significant residual blood products are present at 6 months postinjury, a potential source of ongoing secondary brain injury. Neuropsychological outcome is closely tied to lesion volume size, particularly in the temporal lobe, where larger GRE and FLAIR volumes are associated with more brain atrophy and worse SDMT scores. Interestingly, larger volumes of hemorrhage resorption were associated with worse SDMT and TMT-B scores, suggesting that the initial tissue damage had a lasting impact on attention and executive function. PMID- 27231980 TI - Thermal Stability and Anisotropic Sublimation of Two-Dimensional Colloidal Bi2Te3 and Bi2Se3 Nanocrystals. AB - The structural and compositional stabilities of two-dimensional (2D) Bi2Te3 and Bi2Se3 nanocrystals, produced by both colloidal synthesis and by liquid phase exfoliation, were studied by in situ transmission electron microscopy (TEM) during annealing at temperatures between 350 and 500 degrees C. The sublimation process induced by annealing is structurally and chemically anisotropic and takes place through the preferential dismantling of the prismatic {0110} type planes, and through the preferential sublimation of Te (or Se). The observed anisotropic sublimation is independent of the method of nanocrystal's synthesis, their morphology, or the presence of surfactant molecules on the nanocrystals surface. A thickness-dependent depression in the sublimation point has been observed with nanocrystals thinner than about 15 nm. The Bi2Se3 nanocrystals were found to sublimate below 280 degrees C, while the Bi2Te3 ones sublimated at temperatures between 350 and 450 degrees C, depending on their thickness, under the vacuum conditions in the TEM column. Density functional theory calculations confirm that the sublimation of the prismatic {0110} facets is more energetically favorable. Within the level of modeling employed, the sublimation occurs at a rate about 700 times faster than the sublimation of the {0001} planes at the annealing temperatures used in this work. This supports the distinctly anisotropic mechanisms of both sublimation and growth of Bi2Te3 and Bi2Se3 nanocrystals, known to preferentially adopt a 2D morphology. The anisotropic sublimation behavior is in agreement with the intrinsic anisotropy in the surface free energy brought about by the crystal structure of Bi2Te3 or Bi2Se3. PMID- 27231981 TI - Perinatal Iron Deficiency-Induced Hypothyroxinemia Impairs Early Brain Development Regardless of Normal Iron Levels in the Neonatal Brain. AB - BACKGROUND: Both perinatal hypothyroxinemia and perinatal iron deficiency (ID) are associated with poor neurodevelopment in offspring. Iron is an important component of thyroid peroxidase, a key enzyme in the synthesis of thyroid hormone. The authors' previous study demonstrated that perinatal ID can lead to maternal hypothyroxinemia during pregnancy. The goal of this study was to determine whether perinatal ID-associated hypothyroxinemia can cause brain defects prior to neonatal brain iron depletion. METHODS: Two rat models were established to imitate the two common types of maternal ID (mild ID with anemia [ID + A] and ID without anemia [ID - A]), and iron limitation was initiated two weeks before pregnancy. Maternal and neonatal thyroid hormones in serum were analyzed at postnatal day (P) 0 and P10. Neonatal thyroid hormone, as well as mRNA expression of some thyroid hormone-responsive genes in the cerebral cortex and hippocampus, were measured at P10. Serum iron and brain iron concentrations were analyzed by inductively coupled plasma mass spectrometry. Liver iron concentration was determined using graphite furnace atomic absorption spectroscopy. Hemoglobin was analyzed with an automated blood coagulation analyzer. Surface righting reflex and vibrissae-evoked forelimb placing were measured to assess the sensorimotor behaviors. RESULTS: It was found that pre pregnant mild ID resulted in maternal hypothyroxinemia, which lasted from gestation day 13 to P10. Pre-pregnant mild ID decreased the neonatal brain total triiodothyronine level at P10. Consistent with a low total triiodothyronine level, the mRNA expression of some thyroid hormone-responsive genes (Mbp, RC3, and Srg1) were significantly reduced in the neonatal cerebral cortex and hippocampus in both ID rat models at P10. Furthermore, ID rat pups at P10 showed retarded sensorimotor skills. No significant difference was found between the control and the ID pups in terms of iron concentrations in the neonatal brain at P10. CONCLUSIONS: This study demonstrates that perinatal ID-associated hypothyroxinemia is sufficient to impair early brain development, regardless of whether the neonatal brain iron level is normal, and monitoring thyroid hormone level is indicated in ID pregnant women. PMID- 27231983 TI - Magnetic Coupling Constants in Three Electrons Three Centers Problems from Effective Hamiltonian Theory and Validation of Broken Symmetry-Based Approaches. AB - In the most general case of three electrons in three symmetry unrelated centers with S1 = S2 = S3 = 1/2 localized magnetic moments, the low energy spectrum consists of one quartet (Q) and two doublet (D1, D2) pure spin states. The energy splitting between these spin states can be described with the well-known Heisenberg-Dirac-Van Vleck (HDVV) model spin Hamiltonian, and their corresponding energy expressions are expressed in terms of the three different two-body magnetic coupling constants J12, J23, and J13. However, the values of all three magnetic coupling constants cannot be extracted using the calculated energy of the three spin-adapted states since only two linearly independent energy differences between pure spin states exist. This problem has been recently investigated by Reta et al. (J. Chem. Theory Comput. 2015, 11, 3650), resulting in an alternative proposal to the original Noodleman's broken symmetry mapping approach. In the present work, this proposal is validated by means of ab initio effective Hamiltonian theory, which allows a direct extraction of all three J values from the one-to-one correspondence between the matrix elements of both effective and HDVV Hamiltonian. The effective Hamiltonian matrix representation has been constructed from configuration interaction wave functions for the three spin states obtained for two model systems showing a different degree of delocalization of the unpaired electrons. These encompass a trinuclear Cu(II) complex and a pi-conjugated purely organic triradical. PMID- 27231982 TI - Hybrid MPI/OpenMP Implementation of the ORAC Molecular Dynamics Program for Generalized Ensemble and Fast Switching Alchemical Simulations. AB - We present a new release (6.0beta) of the ORAC program [Marsili et al. J. Comput. Chem. 2010, 31, 1106-1116] with a hybrid OpenMP/MPI (open multiprocessing message passing interface) multilevel parallelism tailored for generalized ensemble (GE) and fast switching double annihilation (FS-DAM) nonequilibrium technology aimed at evaluating the binding free energy in drug-receptor system on high performance computing platforms. The production of the GE or FS-DAM trajectories is handled using a weak scaling parallel approach on the MPI level only, while a strong scaling force decomposition scheme is implemented for intranode computations with shared memory access at the OpenMP level. The efficiency, simplicity, and inherent parallel nature of the ORAC implementation of the FS-DAM algorithm, project the code as a possible effective tool for a second generation high throughput virtual screening in drug discovery and design. The code, along with documentation, testing, and ancillary tools, is distributed under the provisions of the General Public License and can be freely downloaded at www.chim.unifi.it/orac . PMID- 27231984 TI - Serum bilirubin: a simple routine surrogate marker of the progression of chronic kidney disease. AB - BACKGROUND: Studies suggest that Chronic Kidney Disease (CKD) is a global burden health associated with significant comorbid conditions. Few biochemical parameters have gained significance in predicting the disease progression. The present work aimed to study the association of the simple biochemical parameter of serum bilirubin level with the estimated glomerular filtration rate (eGFR), and to assess their association with the co-morbid conditions in CKD. METHODS: We recruited 188 patients with CKD who attended a Nephrology out-patient department. eGFR values were calculated based on the serum creatinine levels using CKD-EPI formula. Various biochemical parameters including glucose, creatinine, uric acid, total and direct bilirubin were assayed in all study subjects. Study subjects were categorized into subgroups based on their eGFR values and their diabetic status and the parameters were compared among the different subgroups. RESULTS: We observed a significantly decreased serum bilirubin levels (p < 0.001) in patients with lower eGFR values, compared to those with higher eGFR levels. There was a significant positive correlation between the eGFR levels and the total bilirubin levels (r = 0.92). We also observed a significant positive correlation between the eGFR levels and the direct bilirubin levels (r = 0.76). On multivariate linear regression analysis, we found that total and direct bilirubin independently predict eGFR, after adjusting for potential confounders (p < 0.001). CONCLUSIONS: Our results suggest that there is significant hypobilirubinemia in CKD, especially with increasing severity and co-existing diabetes mellitus. This finding has importance in the clinical setting, as assay of simple routine biochemical parameters such as serum bilirubin may help in predicting the early progression of CKD and more so in diabetic CKD. PMID- 27231985 TI - Human mesenchymal stem cells attenuate early damage in a ventilated pig model of acute lung injury. AB - Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a major cause of global morbidity and mortality. Mesenchymal stem cells (MSC) have shown promise in treating inflammatory lung conditions. We hypothesised that human MSC (hMSC) can improve ALI/ARDS through their anti-inflammatory actions. We subjected pigs (n=6) to intravenous oleic acid (OA) injury, ventilation and hMSC infusion, while the controls (n=5) had intravenous OA, ventilation and an infusion vehicle control. hMSC were infused 1h after the administration of OA. The animals were monitored for additional 4h. Nuclear translocation of nuclear factor-light chain enhancer of activated B cells (NF-kappaB), a transcription factor that mediates several inflammatory pathways was reduced in hMSC treated pigs compared to controls (p=0.04). There was no significant difference in lung injury, assessed by histological scoring in hMSC treated pigs versus controls (p=0.063). There was no difference in neutrophil counts between hMSC-treated pigs and controls. Within 4h, there was no difference in the levels of IL-10 and IL-8 pre- and post treatment with hMSC. In addition, there was no difference in hemodynamics, lung mechanics or arterial blood gases between hMSC treated animals and controls. Subsequent studies are required to determine if the observed decrease in inflammatory transcription factors will translate into improvement in inflammation and in physiological parameters over the long term. PMID- 27232006 TI - UGT1A6- and UGT2B7-related valproic acid pharmacogenomics according to age groups and total drug concentration levels. AB - AIM: The role of UGT1A6 and UGT2B7 polymorphisms and the impact of total drug plasma concentration in valproic acid (VPA) pharmacogenomics. PATIENTS & METHODS: A total of 134 Greek patients were recruited (76 adults). Patients were genotyped for UGT1A6 19T>G, 541A>G and 552A>C and UGT2B7 802T>C polymorphisms. Patients' demographic and clinical data were registered. Natural logarithm of concentration to-dose ratio (CDR) was also calculated as the final outcome. RESULTS: No significant genotype-related differences in VPA metabolism were noted among various subgroups. An increased lnCDR ratio was noted in children patients compared with adults suggesting increased metabolic capability in younger ages. CONCLUSION: UGT1A6 and UGT2B7 genotypes were not related to significant changes in VPA metabolism, even after controlling for total drug concentration levels. Younger ages were associated with increased VPA clearance rate. PMID- 27232007 TI - Atomic Force Microscopic Analysis of the Effect of Lipid Composition on Liposome Membrane Rigidity. AB - Mechanical rigidity of the liposome membrane is often defined by the membrane bending modulus and is one of the determinants of liposome stability, but the quantitative experimental data are still limited to a few kinds of liposomes. Here, we used atomic force microscopy to investigate the membrane bending moduli of liposomes by immobilizing them on bovine serum albumin-coated glass in aqueous medium. The following lipids were used for liposome preparation: egg yolk phosphatidylcholine, dioleoylphosphatidylcholine, hydrogenated soybean phosphatidylcholine, dipalmitoylphosphatidylcholine, 1,2-dioleoyl-3 trimethylammonium-propane, cholesterol, and N-(carbonylmethoxypoly(ethylene glycol) 2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine. By using liposomes of various compositions, we showed that the thermodynamic phase state of the membrane rather than the electric potential or liposome surface modification with poly(ethylene glycol) is the predominant determinant of the bending modulus, which decreased in the following order: solid ordered > liquid ordered > liquid disordered. By using the generalized polarization value of the Laurdan fluorescent probe, we investigated membrane rigidity in terms of membrane fluidity. Atomic force microscopic analysis was superior to the Laurdan method, especially in evaluating the membrane rigidity of liposomes containing hydrogenated soybean phosphatidylcholine and cholesterol. Positively charged liposomes with a large bending modulus were taken up by cells more efficiently than those with a small bending modulus. These findings offer a quantitative method of analyzing the membrane rigidity of nanosized liposomes with different lipid compositions and will contribute to the control of liposome stability and cellular uptake efficiency of liposomal formulations intended for clinical use. PMID- 27232008 TI - Entanglement Entropy across the Superfluid-Insulator Transition: A Signature of Bosonic Criticality. AB - We study the entanglement entropy and entanglement spectrum of the paradigmatic Bose-Hubbard model, describing strongly correlated bosons on a lattice. The use of a controlled approximation-the slave-boson approach-allows us to study entanglement in all regimes of the model (and, most importantly, across its superfluid-Mott-insulator transition) at a minimal cost. We find that the area law scaling of entanglement-verified in all the phases-exhibits a sharp singularity at the transition. The singularity is greatly enhanced when the transition is crossed at fixed, integer filling, due to a richer entanglement spectrum containing an additional gapless mode, which descends from the amplitude (Higgs) mode of the global excitation spectrum-while this mode remains gapped at the generic (commensurate-incommensurate) transition with variable filling. Hence, the entanglement properties contain a unique signature of the two different forms of bosonic criticality exhibited by the Bose-Hubbard model. PMID- 27232009 TI - Resource-Efficient Measurement-Device-Independent Entanglement Witness. AB - Imperfections in experimental measurement schemes can lead to falsely identifying, or over estimating, entanglement in a quantum system. A recent solution to this is to define schemes that are robust to measurement imperfections-measurement-device-independent entanglement witness (MDI-EW). This approach can be adapted to witness all entangled qubit states for a wide range of physical systems and does not depend on detection efficiencies or classical communication between devices. Here we extend the theory to remove the necessity of prior knowledge about the two-qubit states to be witnessed. Moreover, we tested this model via a novel experimental implementation for MDI-EW that significantly reduces the experimental complexity. By applying it to a bipartite Werner state, we demonstrate the robustness of this approach against noise by witnessing entanglement down to an entangled state fraction close to 0.4. PMID- 27232010 TI - Demonstration of Light-Matter Micro-Macro Quantum Correlations. AB - Quantum mechanics predicts microscopic phenomena with undeniable success. Nevertheless, current theoretical and experimental efforts still do not yield conclusive evidence that there is or is not a fundamental limitation on the possibility to observe quantum phenomena at the macroscopic scale. This question prompted several experimental efforts producing quantum superpositions of large quantum states in light or matter. We report on the observation of quantum correlations, revealed using an entanglement witness, between a single photon and an atomic ensemble of billions of ions frozen in a crystal. The matter part of the state involves the superposition of two macroscopically distinguishable solid state components composed of several tens of atomic excitations. Assuming the insignificance of the time ordering our experiment indirectly shows light-matter micro-macro entanglement. Our approach leverages from quantum memory techniques and could be used in other systems to expand the size of quantum superpositions in matter. PMID- 27232011 TI - Maxwell Demon Dynamics: Deterministic Chaos, the Szilard Map, and the Intelligence of Thermodynamic Systems. AB - We introduce a deterministic chaotic system-the Szilard map-that encapsulates the measurement, control, and erasure protocol by which Maxwellian demons extract work from a heat reservoir. Implementing the demon's control function in a dynamical embodiment, our construction symmetrizes the demon and the thermodynamic system, allowing one to explore their functionality and recover the fundamental trade-off between the thermodynamic costs of dissipation due to measurement and those due to erasure. The map's degree of chaos-captured by the Kolmogorov-Sinai entropy-is the rate of energy extraction from the heat bath. Moreover, an engine's statistical complexity quantifies the minimum necessary system memory for it to function. In this way, dynamical instability in the control protocol plays an essential and constructive role in intelligent thermodynamic systems. PMID- 27232012 TI - Precessing Ferromagnetic Needle Magnetometer. AB - A ferromagnetic needle is predicted to precess about the magnetic field axis at a Larmor frequency Omega under conditions where its intrinsic spin dominates over its rotational angular momentum, Nh?IOmega (I is the moment of inertia of the needle about the precession axis and N is the number of polarized spins in the needle). In this regime the needle behaves as a gyroscope with spin Nh maintained along the easy axis of the needle by the crystalline and shape anisotropy. A precessing ferromagnetic needle is a correlated system of N spins which can be used to measure magnetic fields for long times. In principle, by taking advantage of rapid averaging of quantum uncertainty, the sensitivity of a precessing needle magnetometer can far surpass that of magnetometers based on spin precession of atoms in the gas phase. Under conditions where noise from coupling to the environment is subdominant, the scaling with measurement time t of the quantum- and detection-limited magnetometric sensitivity is t^{-3/2}. The phenomenon of ferromagnetic needle precession may be of particular interest for precision measurements testing fundamental physics. PMID- 27232013 TI - Holographic Complexity Equals Bulk Action? AB - We conjecture that the quantum complexity of a holographic state is dual to the action of a certain spacetime region that we call a Wheeler-DeWitt patch. We illustrate and test the conjecture in the context of neutral, charged, and rotating black holes in anti-de Sitter spacetime, as well as black holes perturbed with static shells and with shock waves. This conjecture evolved from a previous conjecture that complexity is dual to spatial volume, but appears to be a major improvement over the original. In light of our results, we discuss the hypothesis that black holes are the fastest computers in nature. PMID- 27232014 TI - New Limits on Extragalactic Magnetic Fields from Rotation Measures. AB - We take advantage of the wealth of rotation measures data contained in the NRAO VLA Sky Survey catalog to derive new, statistically robust, upper limits on the strength of extragalactic magnetic fields. We simulate the extragalactic magnetic field contribution to the rotation measures for a given field strength and correlation length, by assuming that the electron density follows the distribution of Lyman-alpha clouds. Based on the observation that rotation measures from distant radio sources do not exhibit any trend with redshift, while the extragalactic contribution instead grows with distance, we constrain fields with Jeans' length coherence length to be below 1.7 nG at the 2sigma level, and fields coherent across the entire observable Universe below 0.65 nG. These limits do not depend on the particular origin of these cosmological fields. PMID- 27232016 TI - Perturbation Theory at Eight Loops: Novel Structures and the Breakdown of Manifest Conformality in N=4 Supersymmetric Yang-Mills Theory. AB - We use the soft-collinear bootstrap to construct the 8-loop integrand for the 4 point amplitude and 4-stress-tensor correlation function in planar maximally supersymmetric Yang-Mills theory. Both have a unique representation in terms of planar, conformal integrands grouped according to a hidden symmetry discovered for correlation functions. The answer we find exposes a fundamental tension between manifest locality and planarity with manifest conformality not seen at lower loops. For the first time, the integrand must include terms that are finite even on-shell and terms that are divergent even off-shell (so-called pseudoconformal integrals). We describe these novelties and their consequences in this Letter, and we make the full correlator and amplitude available as part of the Supplemental Material. PMID- 27232017 TI - Effective Field Theory for Jet Processes. AB - Processes involving narrow jets receive perturbative corrections enhanced by logarithms of the jet opening angle and the ratio of the energies inside and outside the jets. Analyzing cone-jet processes in effective field theory, we find that in addition to soft and collinear fields their description requires degrees of freedom that are simultaneously soft and collinear to the jets. These collinear-soft particles can resolve individual collinear partons, leading to a complicated multi-Wilson-line structure of the associated operators at higher orders. Our effective field theory provides, for the first time, a factorization formula for a cone-jet process, which fully separates the physics at different energy scales. Its renormalization-group equations control all logarithmically enhanced higher-order terms, in particular also the nonglobal logarithms. PMID- 27232018 TI - Unified Description of Electron-Nucleus Scattering within the Spectral Function Formalism. AB - The formalism based on factorization and nuclear spectral functions has been generalized to treat transition matrix elements involving two-nucleon currents, whose contribution to the nuclear electromagnetic response in the transverse channel is known to be significant. We report the results of calculations of the inclusive electron-carbon cross section, showing that the inclusion of processes involving two-nucleon currents appreciably improves the agreement between theory and data in the dip region, between the quasielastic and Delta-production peaks. The relation to approaches based on the independent particle of the nucleus and the implications for the analysis of flux-integrated neutrino-nucleus cross sections are discussed. PMID- 27232020 TI - Angle-Resolved Auger Spectroscopy as a Sensitive Access to Vibronic Coupling. AB - In the angle-averaged excitation and decay spectra of molecules, vibronic coupling may induce the usually weak dipole-forbidden transitions by the excitation intensity borrowing mechanism. The present complementary theoretical and experimental study of the resonant Auger decay of core-to-Rydberg excited CH_{4} and Ne demonstrates that vibronic coupling plays a decisive role in the formation of the angle-resolved spectra by additionally involving the decay rate borrowing mechanism. Thereby, we propose that the angle-resolved Auger spectroscopy can in general provide very insightful information on the strength of the vibronic coupling. PMID- 27232019 TI - Steering Proton Migration in Hydrocarbons Using Intense Few-Cycle Laser Fields. AB - Proton migration is a ubiquitous process in chemical reactions related to biology, combustion, and catalysis. Thus, the ability to manipulate the movement of nuclei with tailored light within a hydrocarbon molecule holds promise for far reaching applications. Here, we demonstrate the steering of hydrogen migration in simple hydrocarbons, namely, acetylene and allene, using waveform-controlled, few cycle laser pulses. The rearrangement dynamics is monitored using coincident 3D momentum imaging spectroscopy and described with a widely applicable quantum dynamical model. Our observations reveal that the underlying control mechanism is due to the manipulation of the phases in a vibrational wave packet by the intense off-resonant laser field. PMID- 27232021 TI - Energy Scaling of Cold Atom-Atom-Ion Three-Body Recombination. AB - We study three-body recombination of Ba^{+}+Rb+Rb in the mK regime where a single ^{138}Ba^{+} ion in a Paul trap is immersed into a cloud of ultracold ^{87}Rb atoms. We measure the energy dependence of the three-body rate coefficient k_{3} and compare the results to the theoretical prediction, k_{3}?E_{col}^{-3/4}, where E_{col} is the collision energy. We find agreement if we assume that the nonthermal ion energy distribution is determined by at least two different micromotion induced energy scales. Furthermore, using classical trajectory calculations we predict how the median binding energy of the formed molecules scales with the collision energy. Our studies give new insights into the kinetics of an ion immersed in an ultracold atom cloud and yield important prospects for atom-ion experiments targeting the s-wave regime. PMID- 27232022 TI - Anderson Mobility Gap Probed by Dynamic Coherent Backscattering. AB - We use dynamic coherent backscattering to study one of the Anderson mobility gaps in the vibrational spectrum of strongly disordered three-dimensional mesoglasses. Comparison of experimental results with the self-consistent theory of localization allows us to estimate the localization (correlation) length as a function of frequency in a wide spectral range covering bands of diffuse transport and a mobility gap delimited by two mobility edges. The results are corroborated by transmission measurements on one of our samples. PMID- 27232023 TI - Slippery but Tough: The Rapid Fracture of Lubricated Frictional Interfaces. AB - We study the onset of friction for rough contacting blocks whose interface is coated with a thin lubrication layer. High speed measurements of the real contact area and stress fields near the interface reveal that propagating shear cracks mediate lubricated frictional motion. While lubricants reduce interface resistances, surprisingly they significantly increase the energy dissipated Gamma during rupture. Moreover, lubricant viscosity affects the onset of friction but has no effect on Gamma. Fracture mechanics provide a new way to view the otherwise hidden complex dynamics of the lubrication layer. PMID- 27232024 TI - Coupling between Buoyancy Forces and Electroconvective Instability near Ion Selective Surfaces. AB - Recent investigations have revealed that ion transport from aqueous electrolytes to ion-selective surfaces is subject to electroconvective instability that stems from coupling of hydrodynamics with electrostatic forces. These systems inherently involve fluid density variation set by salinity gradients. However, the coupling between the buoyancy effects and electroconvective instability has not yet been investigated although a wide range of electrochemical systems are naturally prone to these interplaying effects. In this study we thoroughly examine the interplay of gravitational convection and chaotic electroconvection. Our results reveal that buoyant forces can significantly influence the transport rates, otherwise set by electroconvection, when the Rayleigh number Ra of the system exceeds a value Ra~1000. We show that buoyancy forces can significantly alter the flow patterns in these systems. When the buoyancy acts in the stabilizing direction, it limits the extent of penetration of electroconvection, but without eliminating it. When the buoyancy destabilizes the flow, it alters the electroconvective patterns by introducing upward and downward fingers of respectively light and heavy fluids. PMID- 27232025 TI - Transition from Beam-Target to Thermonuclear Fusion in High-Current Deuterium Z Pinch Simulations. AB - Fusion yields from dense, Z-pinch plasmas are known to scale with the drive current, which is favorable for many potential applications. Decades of experimental studies, however, show an unexplained drop in yield for currents above a few mega-ampere (MA). In this work, simulations of DD Z-Pinch plasmas have been performed in 1D and 2D for a constant pinch time and initial radius using the code Lsp, and observations of a shift in scaling are presented. The results show that yields below 3 MA are enhanced relative to pure thermonuclear scaling by beamlike particles accelerated in the Rayleigh-Taylor induced electric fields, while yields above 3 MA are reduced because of energy lost by the instability and the inability of the beamlike ions to enter the pinch region. PMID- 27232026 TI - Observation of an Alfven Wave Parametric Instability in a Laboratory Plasma. AB - A shear Alfven wave parametric instability is observed for the first time in the laboratory. When a single finite omega/Omega_{i} kinetic Alfven wave (KAW) is launched in the Large Plasma Device above a threshold amplitude, three daughter modes are produced. These daughter modes have frequencies and parallel wave numbers that are consistent with copropagating KAW sidebands and a low frequency nonresonant mode. The observed process is parametric in nature, with the frequency of the daughter modes varying as a function of pump wave amplitude. The daughter modes are spatially localized on a gradient of the pump wave magnetic field amplitude in the plane perpendicular to the background field, suggesting that perpendicular nonlinear forces (and therefore k_{?} of the pump wave) play an important role in the instability process. Despite this, modulational instability theory with k_{?}=0 has several features in common with the observed nonresonant mode and Alfven wave sidebands. PMID- 27232027 TI - Body-Centered Orthorhombic C_{16}: A Novel Topological Node-Line Semimetal. AB - We identify by ab initio calculations a novel topological semimetal carbon phase in all-sp^{2} bonding networks with a 16-atom body-centered orthorhombic unit cell, termed bco-C_{16}. Total-energy calculations show that bco-C_{16} is comparable to solid fcc-C_{60} in energetic stability, and phonon and molecular dynamics simulations confirm its dynamical stability. This all-sp^{2} carbon allotrope can be regarded as a three-dimensional modification of graphite, and its simulated x-ray diffraction (XRD) pattern matches well a previously unexplained diffraction peak in measured XRD spectra of detonation and chimney soot, indicating its presence in the specimen. Electronic band structure calculations reveal that bco-C_{16} is a topological node-line semimetal with a single nodal ring. These findings establish a novel carbon phase with intriguing structural and electronic properties of fundamental significance and practical interest. PMID- 27232028 TI - Discovery of an Unconventional Charge Density Wave at the Surface of K_{0.9}Mo_{6}O_{17}. AB - We use angle resolved photoemission spectroscopy, Raman spectroscopy, low energy electron diffraction, and x-ray scattering to reveal an unusual electronically mediated charge density wave (CDW) in K_{0.9}Mo_{6}O_{17}. Not only does K_{0.9}Mo_{6}O_{17} lack signatures of electron-phonon coupling, but it also hosts an extraordinary surface CDW, with T_{S_CDW}=220 K nearly twice that of the bulk CDW, T_{B_CDW}=115 K. While the bulk CDW has a BCS-like gap of 12 meV, the surface gap is 10 times larger and well in the strong coupling regime. Strong coupling behavior combined with the absence of signatures of strong electron phonon coupling indicates that the CDW is likely mediated by electronic interactions enhanced by low dimensionality. PMID- 27232029 TI - Ultrafast and Gigantic Spin Injection in Semiconductors. AB - The injection of spin currents in semiconductors is one of the big challenges of spintronics. Motivated by the ultrafast demagnetization and spin injection into metals, we propose an alternative femtosecond route based on the laser excitation of superdiffusive spin currents in a ferromagnet such as Ni. Our calculations show that even though only a fraction of the current crosses the Ni-Si interface, the laser-induced creation of strong transient electrical fields at a ferromagnet semiconductor interface allows for the injection of chargeless spin currents with record spin polarizations of 80%. Beyond that they are pulsed on the time scale of 100 fs which opens the door for new experiments and ultrafast spintronics. PMID- 27232030 TI - Giant Room Temperature Interface Spin Hall and Inverse Spin Hall Effects. AB - The spin Hall angle (SHA) is a measure of the efficiency with which a transverse spin current is generated from a charge current by the spin-orbit coupling and disorder in the spin Hall effect (SHE). In a study of the SHE for a Pt|Py (Py=Ni_{80}Fe_{20}) bilayer using a first-principles scattering approach, we find a SHA that increases monotonically with temperature and is proportional to the resistivity for bulk Pt. By decomposing the room temperature SHE and inverse SHE currents into bulk and interface terms, we discover a giant interface SHA that dominates the total inverse SHE current with potentially major consequences for applications. PMID- 27232031 TI - Correlated Coulomb Drag in Capacitively Coupled Quantum-Dot Structures. AB - We study theoretically Coulomb drag in capacitively coupled quantum dots (CQDs)-a bias-driven dot coupled to an unbiased dot where transport is due to Coulomb mediated energy transfer drag. To this end, we introduce a master-equation approach that accounts for higher-order tunneling (cotunneling) processes as well as energy-dependent lead couplings, and identify a mesoscopic Coulomb drag mechanism driven by nonlocal multielectron cotunneling processes. Our theory establishes the conditions for a nonzero drag as well as the direction of the drag current in terms of microscopic system parameters. Interestingly, the direction of the drag current is not determined by the drive current, but by an interplay between the energy-dependent lead couplings. Studying the drag mechanism in a graphene-based CQD heterostructure, we show that the predictions of our theory are consistent with recent experiments on Coulomb drag in CQD systems. PMID- 27232032 TI - Current-Controlled Spin Precession of Quasistationary Electrons in a Cubic Spin Orbit Field. AB - Space- and time-resolved measurements of spin drift and diffusion are performed on a GaAs-hosted two-dimensional electron gas. For spins where forward drift is compensated by backward diffusion, we find a precession frequency in the absence of an external magnetic field. The frequency depends linearly on the drift velocity and is explained by the cubic Dresselhaus spin-orbit interaction, for which drift leads to a spin precession angle twice that of spins that diffuse the same distance. PMID- 27232033 TI - Quantum Diffusion on Molecular Tubes: Universal Scaling of the 1D to 2D Transition. AB - The transport properties of disordered systems are known to depend critically on dimensionality. We study the diffusion coefficient of a quantum particle confined to a lattice on the surface of a tube, where it scales between the 1D and 2D limits. It is found that the scaling relation is universal and independent of the temperature, disorder, and noise parameters, and the essential order parameter is the ratio between the localization length in 2D and the circumference of the tube. Phenomenological and quantitative expressions for transport properties as functions of disorder and noise are obtained and applied to real systems: In the natural chlorosomes found in light-harvesting bacteria the exciton transfer dynamics is predicted to be in the 2D limit, whereas a family of synthetic molecular aggregates is found to be in the homogeneous limit and is independent of dimensionality. PMID- 27232034 TI - Three-particle correlation from a Many-Body Perspective: Trions in a Carbon Nanotube. AB - Trion states of three correlated particles (e.g., two electrons and one hole) are essential to understand the optical spectra of doped or gated nanostructures, like carbon nanotubes or transition-metal dichalcogenides. We develop a theoretical many-body description for such correlated states using an ab initio approach. It can be regarded as an extension of the widely used GW method and Bethe-Salpeter equation, thus allowing for a direct comparison with excitons. We apply this method to a semiconducting (8,0) carbon nanotube, and find that the lowest optically active trions are redshifted by ~130 meV compared to the excitons, confirming experimental findings for similar tubes. Moreover, our method provides detailed insights in the physical nature of trion states. In the prototypical carbon nanotube we find a variety of different excitations, discuss the spectra, energy compositions, and correlated wave functions. PMID- 27232035 TI - Unconventional High-Energy-State Contribution to the Cooper Pairing in the Underdoped Copper-Oxide Superconductor HgBa_{2}Ca_{2}Cu_{3}O_{8+delta}. AB - We study the temperature-dependent electronic B_{1g} Raman response of a slightly underdoped single crystal HgBa_{2}Ca_{2}Cu_{3}O_{8+delta} with a superconducting critical temperature T_{c}=122 K. Our main finding is that the superconducting pair-breaking peak is associated with a dip on its higher-energy side, disappearing together at T_{c}. This result reveals a key aspect of the unconventional pairing mechanism: spectral weight lost in the dip is transferred to the pair-breaking peak at lower energies. This conclusion is supported by cellular dynamical mean-field theory on the Hubbard model, which is able to reproduce all the main features of the B_{1g} Raman response and explain the peak dip behavior in terms of a nontrivial relationship between the superconducting gap and the pseudogap. PMID- 27232036 TI - Coexistence of Midgap Antiferromagnetic and Mott States in Undoped, Hole- and Electron-Doped Ambipolar Cuprates. AB - We report the first observation of the coexistence of a distinct midgap state and a Mott state in undoped and their evolution in electron and hole-doped ambipolar Y_{0.38}La_{0.62}(Ba_{0.82}La_{0.18})_{2}Cu_{3}O_{y} films using spectroscopic ellipsometry and x-ray absorption spectroscopies at the O K and Cu L_{3,2} edges. Supported by theoretical calculations, the midgap state is shown to originate from antiferromagnetic correlation. Surprisingly, while the magnetic state collapses and its correlation strength weakens with dopings, the Mott state in contrast moves toward a higher energy and its correlation strength increases. Our result provides important clues to the mechanism of electronic correlation strengths and superconductivity in cuprates. PMID- 27232038 TI - Transition from Sign-Reversed to Sign-Preserved Cooper-Pairing Symmetry in Sulfur Doped Iron Selenide Superconductors. AB - An essential step toward elucidating the mechanism of superconductivity is to determine the sign or phase of the superconducting order parameter, as it is closely related to the pairing interaction. In conventional superconductors, the electron-phonon interaction induces attraction between electrons near the Fermi energy and results in a sign-preserved s-wave pairing. For high-temperature superconductors, including cuprates and iron-based superconductors, prevalent weak coupling theories suggest that the electron pairing is mediated by spin fluctuations which lead to repulsive interactions, and therefore that a sign reversed pairing with an s_{+/-} or d-wave symmetry is favored. Here, by using magnetic neutron scattering, a phase sensitive probe of the superconducting gap, we report the observation of a transition from the sign-reversed to sign preserved Cooper-pairing symmetry with insignificant changes in T_{c} in the S doped iron selenide superconductors K_{x}Fe_{2-y}(Se_{1-z}S_{z})_{2}. We show that a rather sharp magnetic resonant mode well below the superconducting gap (2Delta) in the undoped sample (z=0) is replaced by a broad hump structure above 2Delta under 50% S doping. These results cannot be readily explained by simple spin fluctuation-exchange pairing theories and, therefore, multiple pairing channels are required to describe superconductivity in this system. Our findings may also yield a simple explanation for the sometimes contradictory data on the sign of the superconducting order parameter in iron-based materials. PMID- 27232037 TI - Strain Control of Fermiology and Many-Body Interactions in Two-Dimensional Ruthenates. AB - Here we demonstrate how the Fermi surface topology and quantum many-body interactions can be manipulated via epitaxial strain in the spin-triplet superconductor Sr_{2}RuO_{4} and its isoelectronic counterpart Ba_{2}RuO_{4} using oxide molecular beam epitaxy, in situ angle-resolved photoemission spectroscopy, and transport measurements. Near the topological transition of the gamma Fermi surface sheet, we observe clear signatures of critical fluctuations, while the quasiparticle mass enhancement is found to increase rapidly and monotonically with increasing Ru-O bond distance. Our work demonstrates the possibilities for using epitaxial strain as a disorder-free means of manipulating emergent properties, many-body interactions, and potentially the superconductivity in correlated materials. PMID- 27232039 TI - Topological Aspects of Symmetry Breaking in Triangular-Lattice Ising Antiferromagnets. AB - Using a specially designed Monte Carlo algorithm with directed loops, we investigate the triangular lattice Ising antiferromagnet with coupling beyond the nearest neighbors. We show that the first-order transition from the stripe state to the paramagnet can be split, giving rise to an intermediate nematic phase in which algebraic correlations coexist with a broken symmetry. Furthermore, we demonstrate the emergence of several properties of a more topological nature such as fractional edge excitations in the stripe state, the proliferation of double domain walls in the nematic phase, and the Kasteleyn transition between them. Experimental implications are briefly discussed. PMID- 27232040 TI - Dimensional Reduction in Quantum Dipolar Antiferromagnets. AB - We report ac susceptibility, specific heat, and neutron scattering measurements on a dipolar-coupled antiferromagnet LiYbF_{4}. For the thermal transition, the order-parameter critical exponent is found to be 0.20(1) and the specific-heat critical exponent -0.25(1). The exponents agree with the 2D XY/h_{4} universality class despite the lack of apparent two-dimensionality in the structure. The order parameter exponent for the quantum phase transitions is found to be 0.35(1) corresponding to (2+1)D. These results are in line with those found for LiErF_{4} which has the same crystal structure, but largely different T_{N}, crystal field environment and hyperfine interactions. Our results therefore experimentally establish that the dimensional reduction is universal to quantum dipolar antiferromagnets on a distorted diamond lattice. PMID- 27232041 TI - Space Group Symmetry Fractionalization in a Chiral Kagome Heisenberg Antiferromagnet. AB - The anyonic excitations of a spin liquid can feature fractional quantum numbers under space group symmetries. Detecting these fractional quantum numbers, which are analogs of the fractional charge of Laughlin quasiparticles, may prove easier than the direct observation of anyonic braiding and statistics. Motivated by the recent numerical discovery of spin-liquid phases in the kagome Heisenberg antiferromagnet, we theoretically predict the pattern of space group symmetry fractionalization in the kagome lattice SO(3)-symmetric chiral spin liquid. We provide a method to detect these fractional quantum numbers in finite-size numerics which is simple to implement in the density matrix renormalization group. Applying these developments to the chiral spin liquid phase of a kagome Heisenberg model, we find perfect agreement between our theoretical prediction and numerical observations. PMID- 27232043 TI - Strong-Field Resonant Dynamics in Semiconductors. AB - We predict that a direct band gap semiconductor (GaAs) resonantly excited by a strong ultrashort laser pulse exhibits a novel regime: kicked anharmonic Rabi oscillations. In this regime, Rabi oscillations are strongly coupled to intraband motion, and interband transitions mainly take place when electrons pass near the Brillouin zone center where electron populations undergo very rapid changes. The asymmetry of the residual population distribution induces an electric current controlled by the carrier-envelope phase of the driving pulse. The predicted effects are experimentally observable using photoemission and terahertz spectroscopies. PMID- 27232042 TI - Verification of Anderson Superexchange in MnO via Magnetic Pair Distribution Function Analysis and ab initio Theory. AB - We present a temperature-dependent atomic and magnetic pair distribution function (PDF) analysis of neutron total scattering measurements of antiferromagnetic MnO, an archetypal strongly correlated transition-metal oxide. The known antiferromagnetic ground-state structure fits the low-temperature data closely with refined parameters that agree with conventional techniques, confirming the reliability of the newly developed magnetic PDF method. The measurements performed in the paramagnetic phase reveal significant short-range magnetic correlations on a ~1 nm length scale that differ substantially from the low temperature long-range spin arrangement. Ab initio calculations using a self interaction-corrected local spin density approximation of density functional theory predict magnetic interactions dominated by Anderson superexchange and reproduce the measured short-range magnetic correlations to a high degree of accuracy. Further calculations simulating an additional contribution from a direct exchange interaction show much worse agreement with the data. The Anderson superexchange model for MnO is thus verified by experimentation and confirmed by ab initio theory. PMID- 27232044 TI - Stopping Narrow-Band X-Ray Pulses in Nuclear Media. AB - A control mechanism for stopping x-ray pulses in resonant nuclear media is investigated theoretically. We show that narrow-band x-ray pulses can be mapped and stored as nuclear coherence in a thin-film planar x-ray cavity with an embedded ^{57}Fe nuclear layer. The pulse is nearly resonant to the 14.4 keV Mossbauer transition in the ^{57}Fe nuclei. The role of the control field is played here by a hyperfine magnetic field which induces interference effects reminiscent of electromagnetically induced transparency. We show that, by switching off the control magnetic field, a narrow-band x-ray pulse can be completely stored in the cavity for approximately 100 ns. Additional manipulation of the external magnetic field can lead to both group velocity and phase control of the pulse in the x-ray cavity sample. PMID- 27232046 TI - Enhanced Tunneling Electroresistance in Ferroelectric Tunnel Junctions due to the Reversible Metallization of the Barrier. AB - Realizing a large tunneling electroresistance (TER) effect is crucial for device application of ferroelectric tunnel junctions (FTJs). FTJs are typically composed of a thin ferroelectric layer sandwiched by two metallic electrodes, where TER generally results from the dependence of the effective tunneling barrier height on the ferroelectric polarization. Since the resistance depends exponentially not only on barrier height but also on barrier width, TER is expected to be greatly enhanced when one of the electrodes is a semiconductor where the depletion region near the interface can be controlled via ferroelectric polarization. To explore this possibility, we perform studies of SrRuO_{3}/BaTiO_{3}/n-SrTiO_{3} FTJs, where n-SrTiO_{3} is an electron doped SrTiO_{3} electrode, using first principles density functional theory. Our studies reveal that, in addition to modulation of the depletion region in n-SrTiO_{3}, the BaTiO_{3} barrier layer becomes conducting near the interface for polarization pointing into n-SrTiO_{3}, leading to dramatic enhancement of TER. The effect is controlled by the band alignment between the semiconductor and the ferroelectric insulator and opens the way for experimental realization of enhanced TER in FTJs through the choice of a semiconducting electrode and interface engineering. PMID- 27232045 TI - One- and Two-Dimensional Nuclear Magnetic Resonance Spectroscopy with a Diamond Quantum Sensor. AB - We report on Fourier spectroscopy experiments performed with near-surface nitrogen-vacancy centers in a diamond chip. By detecting the free precession of nuclear spins rather than applying a multipulse quantum sensing protocol, we are able to unambiguously identify the NMR species devoid of harmonics. We further show that, by engineering different Hamiltonians during free precession, the hyperfine coupling parameters as well as the nuclear Larmor frequency can be selectively measured with up to five digits of precision. The protocols can be combined to demonstrate two-dimensional Fourier spectroscopy. Presented techniques will be useful for mapping nuclear coordinates in molecules deposited on diamond sensor chips, en route to imaging their atomic structure. PMID- 27232047 TI - Complex Contact-Based Dynamics of Microsphere Monolayers Revealed by Resonant Attenuation of Surface Acoustic Waves. AB - Contact-based vibrations play an essential role in the dynamics of granular materials. Significant insights into vibrational granular dynamics have previously been obtained with reduced-dimensional systems containing macroscale particles. We study contact-based vibrations of a two-dimensional monolayer of micron-sized spheres on a solid substrate that forms a microscale granular crystal. Measurements of the resonant attenuation of laser-generated surface acoustic waves reveal three collective vibrational modes that involve displacements and rotations of the microspheres, as well as interparticle and particle-substrate interactions. To identify the modes, we tune the interparticle stiffness, which shifts the frequency of the horizontal-rotational resonances while leaving the vertical resonance unaffected. From the measured contact resonance frequencies we determine both particle-substrate and interparticle contact stiffnesses and find that the former is an order of magnitude larger than the latter. This study paves the way for investigating complex contact-based dynamics of microscale granular crystals and yields a new approach to studying micro- to nanoscale contact mechanics in multiparticle networks. PMID- 27232048 TI - Helicobacter pylori Couples Motility and Diffusion to Actively Create a Heterogeneous Complex Medium in Gastric Mucus. AB - Helicobacter pylori swims through mucus gel by generating ammonia that locally neutralizes the acidic gastric environment, turning nearby gel into a fluid pocket. The size of the fluid zone is important for determining the physics of the motility: in a large zone swimming occurs as in a fluid through hydrodynamic principles, while in a very small zone the motility could be strongly influenced by nonhydrodynamic cell-mucus interactions including chemistry and adhesion. Here, we calculate the size of the fluid pocket. We model how swimming depends on the de-gelation range using a Taylor sheet swimming through a layer of Newtonian fluid bounded by a Brinkman fluid. Then, we model how the de-gelation range depends on the swimming speed by considering the advection-diffusion of ammonia exuded from a translating sphere. Self-consistency between both models determines the values of the swimming speed and the de-gelation range. We find that H. pylori swims through mucus as if unconfined, in a large pocket of Newtonian fluid. PMID- 27232049 TI - Erratum: Spin Chirality Tuning and Topological Semimetals in Strained HgTe_{x}S_{1-x} [Phys. Rev. Lett. 114, 236805 (2015)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.114.236805. PMID- 27232050 TI - Publisher's Note: Observation of Geometric Parametric Instability Induced by the Periodic Spatial Self-Imaging of Multimode Waves [Phys. Rev. Lett. 116, 183901 (2016)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.116.183901. PMID- 27232051 TI - Quantitative Understanding of van der Waals Interactions by Analyzing the Adsorption Structure and Low-Frequency Vibrational Modes of Single Benzene Molecules on Silver. AB - The combination of a sub-Kelvin scanning tunneling microscope and density functional calculations incorporating van der Waals (vdW) corrections has been used successfully to probe the adsorption structure and low-frequency vibrational modes of single benzene molecules on Ag(110). The inclusion of optimized vdW functionals and improved C6-based vdW dispersion schemes in density functional theory is crucial for obtaining the correct adsorption structure and low-energy vibrational modes. These results demonstrate the emerging capability to quantitatively probe the van der Waals interactions between a physisorbed molecule and an inert substrate. PMID- 27232052 TI - Efficacy and Safety of Vilazodone in Patients With Generalized Anxiety Disorder: A Randomized, Double-Blind, Placebo-Controlled, Flexible-Dose Trial. AB - OBJECTIVE: To evaluate the efficacy, safety, and tolerability of vilazodone as an acute treatment for generalized anxiety disorder (GAD). Vilazodone is a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist approved for the treatment of major depressive disorder in adults. METHODS: This was a randomized, placebo-controlled, parallel-group, multicenter, flexible-dose study conducted from May 2013-March 2014. Adult patients (18-70 years, inclusive) who met DSM-IV TR criteria for GAD were randomized (1:1) to placebo or vilazodone 20-40 mg/d for 8 weeks of double-blind treatment. Primary and secondary efficacy parameters were change from baseline to week 8 in the Hamilton Anxiety Rating Scale (HARS) total score and in the Sheehan Disability Scale (SDS) total score, respectively, analyzed using a mixed-effects model for repeated measures approach on a modified intent-to-treat population. Safety outcomes were summarized descriptively. RESULTS: Efficacy analyses were based on 400 patients (placebo = 200, vilazodone = 200); 76% completed the study (placebo = 81%, vilazodone = 71%). The least squares mean difference (95% CI) in total score change from baseline to week 8 was statistically significant for vilazodone versus placebo on the HARS (-2.20 [ 3.72 to -0.68]; P = .0048) and on the SDS (-1.89 [-3.52 to -0.26]; P = .0236). Treatment-emergent adverse events reported in >= 5% of vilazodone patients and at least twice the rate of placebo were nausea, diarrhea, dizziness, fatigue, delayed ejaculation, and erectile dysfunction. CONCLUSION: Statistically significant differences in favor of vilazodone 20-40 mg/d versus placebo were seen on all measures of anxiety and functional impairment in patients with GAD. Vilazodone was generally well tolerated, and no new safety concerns were noted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01844115. PMID- 27232015 TI - Measurement of the Difference of Time-Integrated CP Asymmetries in D^{0}->K^{ }K^{+} and D^{0}->pi^{-}pi^{+} Decays. AB - A search for CP violation in D^{0}->K^{-}K^{+} and D^{0}->pi^{-}pi^{+} decays is performed using pp collision data, corresponding to an integrated luminosity of 3 fb^{-1}, collected using the LHCb detector at center-of-mass energies of 7 and 8 TeV. The flavor of the charm meson is inferred from the charge of the pion in D^{*+}->D^{0}pi^{+} and D^{*-}->D[over -]^{0}pi^{-} decays. The difference between the CP asymmetries in D^{0}->K^{-}K^{+} and D^{0}->pi^{-}pi^{+} decays, DeltaA_{CP}=A_{CP}(K^{-}K^{+})-A_{CP}(pi^{-}pi^{+}), is measured to be [-0.10+/ 0.08(stat)+/-0.03(syst)]%. This is the most precise measurement of a time integrated CP asymmetry in the charm sector from a single experiment. PMID- 27232053 TI - Chiral liquid chromatography-mass spectrometry (LC-MS/MS) method development for the detection of salbutamol in urine samples. AB - A sequential solid-phase extraction (SPE) method was developed and validated using liquid chromatography-electrospray ionization tandem mass spectrometry (LC ESI-MS/MS) for the detection and quantification of salbutamol enantiomers in porcine urine. Porcine urine samples were hydrolysed with beta glucuronidase/arylsulfatase from Helix pomatia and then subjected to a double solid-phase extraction (SPE) first using the Abs-Elut Nexus SPE and then followed by the Bond Elut Phenylboronic Acid (PBA) SPE. The salbutamol enantiomers were separated using the Astec CHIROBIOTICTM T HPLC column (3.0mm*100mm; 5MUm) maintained at 15 degrees C with a 15min isocratic run at a flow rate of 0.4mL/min. The mobile phase constituted of 5mM ammonium formate in methanol. Salbutamol and salbutamol-tert-butyl-d9 (internal standard, IS) was monitored and quantified with the multiple reaction monitoring (MRM) mode. The method showed good linearity for the range of 0.1-10ng/mL with limit of quantification at 0.3ng/mL. Analysis of the QC samples showed intra- and inter-assay precisions to be less than 5.04%, and recovery ranging from 83.82 to 102.33%. PMID- 27232055 TI - Functional reversal of (-)-Stepholidine analogues by replacement of benzazepine substructure using the ring-expansion strategy. AB - (-)-Stepholidine is an active ingredient of the Chinese herb Stephania and naturally occurring tetrahydroprotoberberine alkaloid with mixed dopamine receptor D1 agonistic and dopamine receptor D2 antagonistic activities. In this work, a series of novel hexahydrobenzo[4,5]azepino [2,1-a]isoquinolines were designed and synthesized as ring-expanded analogues of (-)-Stepholidine. Initial pharmacological assays demonstrated that a benzazepine replacement was associated with significant increase in selectivity and functional reversal at dopamine receptor D1 . Compound-(-)-15e (Ki = 5.32 +/- 0.01 nm) is more potent than (-) Stepholidine (Ki = 13 nm) and was identified as a selective dopamine receptor D1 antagonist (IC50 = 0.14 MUm). Moreover, molecular modeling suggested that (-) 15e might exert its dopamine receptor D1 antagonistic activities through interacting with the transmembrane helix 7 of dopamine receptor D1 . PMID- 27232056 TI - GC-MS profile of antimicrobial and antioxidant fractions from Cordia rothii roots. AB - CONTEXT: An ethnobotanical survey of Cordia rothii Roem. & Schult. (Boraginaceae) reveals it as a medicinal plant. OBJECTIVE: Antimicrobial and antioxidant potential evaluation and identification of chemical constituents via GC-MS of C. rothii roots fractions. To the best of our knowledge, this is the first systematic investigation of the roots exploiting GC-MS. MATERIALS AND METHODS: Extraction and fractionation of C. rothii roots furnished various fractions using solvents of varying polarity, i.e., n-hexane, chloroform, ethyl acetate, acetone and methanol. In vitro antimicrobial and antioxidant screening was performed using disk diffusion and DPPH methods, respectively. MIC of active fractions was also determined using disk diffusion method. GC-MS was used to identify constituents which may be responsible for these activities. RESULTS: Among various fractions from C. rothii roots, fraction KA-C showed strong antibacterial activity against 17 microorganisms tested, with MIC ranging from 250-31.25 MUg/mL. Fractions KA-A, KM and KM-A exhibited significant antioxidant potential with EC50 46.875 MUg/mL, while fractions KEA-PE, KM-PE and KM-M were good with EC50 93.750 MUg/mL. Forty-five phytochemicals were identified in GC-MS studies including eight hydrocarbons, six free fatty acids, 11 fatty acids esters, two phenylpropanoids, four aromatics, four terpenoid quinones/hydroquinones, three triterpenes, four phytosterols, two hexose metabolites and a DNA base. Of these, 32 constituents have been reported for the first time from C. rothii, 24 from genus Cordia and 15 from Boraginaceae. DISCUSSION AND CONCLUSION: Strong antibacterial and antioxidant potential of C. rothii roots may be due to the contribution of phytoconstituents identified through GC-MS studies. PMID- 27232057 TI - Building resilience with the Stress Resilience Training System: Design validation and applications. AB - BACKGROUND: Resilience to stress is critical in today's military service. Past work has shown that experts handle stress in more productive ways compared to novices. Training that specifically addresses stress regulation, such as the Graduated Stress Exposure paradigm, can build individual and unit resilience as well as adaptability so that stressors trigger effective stress coping skills rather than stress injury. OBJECTIVE: We developed the Stress Resilience Training System (SRTS), a product of Perceptronics Solutions Inc., to demonstrate that a software training app can provide an effective individualized method for mitigating the negative effects of situational and mission-related stress, at the same time eliciting potentially positive effects on performance. METHODS: Seven separate evaluations including a usability study, controlled experiments, and field evaluations have been conducted to date. RESULTS: These studies have shown that the SRTS program effectively engages users to manage their stress, effectively reduces stress symptoms, and improves job performance. CONCLUSIONS: The SRTS system is a highly effective method for individualized training to inoculate professionals against the negative consequences of stress, while teaching them to harness its positive effects. SRTS is a technology that can be widely applied to many professions that are concerned with well-being. We discuss applications to law enforcement, athletics, personal fitness and healthcare in the Appendix. PMID- 27232054 TI - A single method for detecting 11 organophosphate pesticides in human plasma and breastmilk using GC-FPD. AB - Organophosphate (OP) pesticides are widely used for crop protection in many countries including Thailand. Aside from causing environmental contamination, they affect human health especially by over-stimulating of the neurotransmission system. OP pesticides, as with other non-persistent pesticides, degrade quickly in the environment as well as are metabolized quite rapidly in humans. Assessing human exposures to these compounds requires analytical methods that are sensitive, robust, and most importantly, suitable for specific laboratory settings. The aim of this study was to develop and validate an analytical method for measuring 11 OP pesticide residues in human plasma and breast milk. Analytes in both plasma and breast milk samples were extracted with acetone and methylene chloride, cleaned-up using aminopropyl solid phase extraction cartridges, and analyzed by gas chromatography with flame photometric detection. The optimized method exhibited good linearity, with the coefficients of determination of 0.996 0.999 and <7% error about the slope. Extraction recoveries from spiked plasma and breast milk samples at low and medium concentrations (0.8-5.0 and 1.6-10ngmL(-1), respectively) ranged from 59.4% (ethion) to 94.0% (chlorpyrifos). Intra-batch and inter-batch precisions ranged from 2.3-18.9% and 5.8-19.5%, respectively. Method detection limits of plasma and breast milk ranged from 0.18-1.36 and 0.09 2.66ngmL(-1), respectively. We analyzed 63 plasma and 30 breastmilk samples collected from farmworkers in Chiang Mai Province to determine the suitability of this method for occupational exposure assessment. Of the 11 pesticides measured, seven were detected in plasma samples and five were detected in breast milk samples. Mass spectrometry was used to confirm results. Overall, this method is rapid and reliable. It offers the laboratories with limited access to mass spectrometry a capacity to investigate levels OP pesticides in plasma and breastmilk in those occupationally exposed for health risk assessment. PMID- 27232058 TI - Organizational resilience and enrollment trends of independent, for-profit higher education institutions. AB - BACKGROUND: From 2010 to 2012, the for-profit sector of higher education in the United States (otherwise known as career colleges) existed in a turbulent environment, characterized by regulatory, media, and public scrutiny. While virtually all career colleges experienced enrollment declines during this period, by 2012 some colleges were starting to see this trend stabilize or reverse, whereas others did not. OBJECTIVE: The purpose of this study was to determine if the differences in career colleges' enrollment trends could be attributed to organizational resilience. METHODS: A quantitative correlation study using a multiple regression analysis was conducted to determine the nature of the relationship between organizational resilience and the enrollment fluctuations of 59 career colleges located throughout the United States. RESULTS: The correlation between organizational resilience levels and enrollment fluctuations was fair to moderate and significant, r = 0.40, p < 0.05. A multiple-regression analysis revealed that the model significantly explained the impact of the six organizational resilience factors on enrollment fluctuations, F = 4.15, p < 0.01. The R2 for the model was 0.32, and the adjusted R2 was 0.25. In terms of individual organizational resilience factors, two tested either significantly or moderately significantly: avoidance-skepticism and critical understanding or sensemaking. CONCLUSIONS: Recommendations for college leaders include monitoring the level of avoidance to ensure a healthy balance of skepticism regarding new situations and incorporating strategies to help organizational members increase their levels of critical understanding or sensemaking. PMID- 27232059 TI - Personal resilience and coping with implications for work. Part I: A review. AB - BACKGROUND: Interest in resilience has increased in recent years. The U.S. military focus is on personal health and adaptation following exposure to battle, while the civilian interest centers on adjustments subsequent to disastrous events. Coping skills are also relevant, yet the relationships between coping and resilience are unclear. OBJECTIVE: This brief review examines personal resilience and individual coping strategies, exploring definitions of each, along with their potential relationships to one another. Their potential contributions within a work setting are described. METHODS: A literature review was conducted using search terms of resilience, resiliency, personal resilience, coping and resilient coping. RESULTS: Coping refers to one's using purposeful actions to handle life situations. Coping techniques can be functional or dysfunctional and the situations one copes with may be acute or long term, severe or minor. Resilience refers to positive and functional handling of oneself and ones' life, referring to the ability to recover, recuperate, and regenerate following tragic events. CONCLUSIONS: While coping and resilience are related to one another, they are distinct concepts. Positive coping techniques may contribute to resilience. However, which coping techniques improve resilience, and in what circumstances, are questions for future research. PMID- 27232060 TI - Organizational resilience: Nonprofit organizations' response to change. AB - BACKGROUND: Organizational resilience refers to the ability to respond productively to significant disruptive change and transform challenges into opportunities. There is a gap in the literature about resilient nonprofit organizations and its application for identifying organizational conditions for successful adaption to external variables that threaten their existence. OBJECTIVE: The aim of this study was to identify organizational characteristics that point to the resilience of nonprofit behavioral healthcare organizations as they successfully adapt to funding changes. METHODS: A multiple case study of two behavioral health nonprofit organizations was conducted. Data was collected through interviews and focus groups, and analyzed through a qualitative content analysis. RESULTS: Using the framework of resilience, six themes that equipped these organizations to successfully adapt to funding changes were identified. They included: commitment to the mission, improvisation, community reciprocity, servant and transformational leadership, hope and optimism, and fiscal transparency. CONCLUSIONS: The findings suggest that incorporating these qualities into an organizational system equips it to systematically adapt to funding changes and other disruptive challenges. Using resilience as a process and not simply an outcome after recovery, nonprofit organizations can have the capacity to continuously respond to challenges and provide uninterrupted and valuable services to society. PMID- 27232061 TI - Energetic, Structural, and Vibrational Properties of 4,4'-Methylenediphenyl Diisocyanate with Relevance for Adhesion. AB - Through a polymerization process, the monomer 4,4'-methylenediphenyl diisocyanate can participate in glueing, whereby strong covalent bonds between the monomer and the substrates that will be glued have to be formed. In the present work, we use density functional theory (DFT) calculations to study a group of properties that are important for the initial steps of this process and for its experimental characterization. We focus on energetic and structural properties of a single monomer of 4,4'-methylenediphenyl diisocyanate as obtained using different theoretical approaches. We demonstrate that the molecule is chiral and that for each chirality, three different structures, differing in the orientations of the isocyanate groups, can be identified. The molecule is soft against certain geometry transformations and can, accordingly, easily take a structure that is optimal for the formation of covalent bonds with a substrate. Infrared spectroscopy may be used in identifying these covalent bonds, and therefore, these spectra were calculated, and we identify the most relevant vibrations in this context. Finally, changes in the properties when the monomer was modified or when it was allowed to interact with other molecules were studied, too. PMID- 27232062 TI - Water at Interfaces. AB - The interfaces of neat water and aqueous solutions play a prominent role in many technological processes and in the environment. Examples of aqueous interfaces are ultrathin water films that cover most hydrophilic surfaces under ambient relative humidities, the liquid/solid interface which drives many electrochemical reactions, and the liquid/vapor interface, which governs the uptake and release of trace gases by the oceans and cloud droplets. In this article we review some of the recent experimental and theoretical advances in our knowledge of the properties of aqueous interfaces and discuss open questions and gaps in our understanding. PMID- 27232064 TI - Where next with theory and research on how the school environment influences young people's substance use? AB - Substance use (smoking, drinking and illicit drug use) remains, a serious problem for young people living in industrialised countries. There is increasing interest in interventions to modify the school, environment, addressing the multiple upstream determinants of young, people's health. This article provides an overview of current theory, about how secondary school environments influence young people's, substance use before focusing on the Theory of Human Functioning and, School Organisation. It critically examines the extent to which this, theory is substantiated by quantitative and qualitative evidence and, considers how the theory might be elaborated to better inform future, empirical research. PMID- 27232063 TI - Parkinson's disease and colorectal cancer risk-A nested case control study. AB - BACKGROUND: A pro-inflammatory gut microbiota was described in both Parkinson's disease and colorectal cancer (CRC) and recently alpha-synuclein was demonstrated in the enteric nervous system. We sought to evaluate the association between Parkinson's disease and CRC. METHODS: We conducted a nested case-control study using a large primary-care database. Cases were defined as all individuals with CRC. Up to 4 controls were matched with each case based on age, sex, practice site and duration of follow-up. The primary exposure of interest was diagnosis of Parkinson's disease prior to CRC as well as disease duration, and Parkinson's specific therapies. The primary analysis was a conditional logistic-regression to estimate odds ratios (ORs) and 95% confidence interval (95%CI). RESULTS: The study included 22,093 CRC cases and 85,833 matched controls. Past medical history of Parkinson's disease >1 year before index-date was associated with lower CRC risk (OR 0.74, 95%CI 0.59-0.94). The inverse association was more prominent among females compared to males (0.64, 95%CI 0.42-0.96 and 0.8, 95%CI 0.60-1.07, respectively). While patients who received no therapy or therapy with dopamine agonists had a non-significant decrease in cancer risk, patients who were treated with dopamine had a non-significant elevated cancer risk. CONCLUSION: Parkinson's disease is inversely associated with CRC risk. PMID- 27232065 TI - The clinical spectrum of IgM monoclonal gammopathy: A single center retrospective study of 377 patients. AB - OBJECTIVES: We retrospectively evaluated the clinical features, serum levels of IgM, and prevalence of IgM related diseases in patients with serum immunofixation electrophoresis (sIFE) confirmed IgM monoclonal gammopathy at our center. METHODS: We included patients with sIFE confirmed IgM monoclonal gammopathy between January 2008 and December 2014 in this retrospective study. We evaluated clinical data, sIFE, serum IgM levels, and diagnosis. RESULTS: In total, 7107 patients had sIFE confirmed monoclonal gammopathy, with 377 (5.3%) patients having the IgM type. The median age was 62 years (range, 19-105 years). The median level of serum IgM is 8.3g/L (range, 0.24-150g/L). The diagnosis included monoclonal gammopathy of undetermined significance (MGUS, 157 patients, 41.6%), Waldenstrom macroglobulinemia (WM, 105 patients, 27.9%), B cell non-Hodgkin's lymphoma (69 patients, 18.3%), primary cold agglutinin disease (pCAD, 16 patients, 4.2%), primary amyloidosis (14 patients, 3.7%), cryoglobulinaemia (six patients, 1.6%), IgM MGUS associated neuropathy (five patients, 1.3%), multiple myeloma (three patients, 0.8%), and POEMS syndrome (two patients, 0.5%). Levels of serum IgM>15.5g/L were 80.6% sensitive and 89.2% specific for the diagnosis of WM. Kappa type light chain indicated the diagnosis of WM, pCAD, IgM MGUS associated neuropathy and cryoglobulinaemia, while lambda type light chain indicated POEMS and amyloidosis. There were 41/157 (26.1%) MGUS patients diagnosed with complications due to IgM-unrelated autoimmune diseases. CONCLUSION: IgM monoclonal gammopathy contains a broad spectrum of diseases. Levels of serum IgM and the type of light chain can be used to help with differential diagnosis. The association between MGUS and some autoimmune diseases requires further investigation. PMID- 27232066 TI - The Ingegerd and Viking Olov Bjork Scholarship for Thoracic and Cardiovascular Research. PMID- 27232067 TI - Drug-induced hepatotoxicity in cancer patients - implication for treatment. AB - INTRODUCTION: All anticancer drugs can cause idiosyncratic liver injury. Therefore, hepatoprotective agents assume particular importance to preserve liver function. Hepatic injury represents 10% of cases of acute hepatitis in adults; drug-related damage is still misjudged because of relative clinical underestimation and difficult differential diagnosis. Chemotherapeutic agents can produce liver toxicity through different pathways, resulting in different categories of liver injuries, but these drugs are not homogeneously hepatotoxic. Frequently, anticancer-induced hepatotoxicity is idiosyncratic and influenced by multiple factors. AREAS COVERED: The aim of this paper is to perform a review of the literature regarding anticancer-induced liver toxicity. We described hepatotoxicity mechanisms of principal anticancer agents and respective dose reductions. Furthermore, we reviewed studies on hepatoprotectors and their optimal use. Tiopronin, magnesium isoglycyrrhizinate and S-Adenosylmethionine (AdoMet) demonstrated, in some small studies, a potential hepatoprotective activity. EXPERT OPINION: Actually, in the literature only small experiences are reported. Even though hepatoprotective agents seem to be useful in the oncologic setting, the lack of well-designed prospective Phase III randomized controlled trials is a major limit in the introduction of hepatoprotectors in cancer patients and these kind of studies are warranted to support their use and to give further recommendations for the clinical practice. PMID- 27232068 TI - "If those tears could talk, what would they say?" Multi-method analysis of a corrective experience in brief dynamic therapy. AB - We analyzed master theorist/therapist Hanna Levenson's six-session work with "Ann" in American Psychological Association's Theories of Psychotherapy video series to determine if and how this client had a corrective experience in Brief Dynamic Therapy. First, we identified indicators of a corrective experience in the therapist's and client's own words. Complementing this analysis, we used observational coding to identify, moment by moment, narrative-emotion markers of shifts in Ann's "same old story"; the frequency, type, and depth of immediacy; and the client's and therapist's behavioral contributions to the working alliance. Additionally, we qualitatively analyzed Levenson's session-by-session accounts of the therapy from two sources. Convergent evidence from these multi method analyses suggested how the intertwined relational and technical change processes seemed to bring about this client's corrective experience. Through consistent attention to the alliance and increasingly deep immediacy, Levenson created a safe space for Ann to "bring down the wall"-by allowing herself to cry and be deeply understood and cared for in a way that she had never before experienced. Concurrently, Ann began seeing herself quite differently, signified by self-identity narrative change. Then, following Session 4, she took Levenson's suggestion to risk behaving more authentically with a friend and with her romantic partner. PMID- 27232069 TI - Test-Retest Reliability of the Binaural Interaction Component of the Auditory Brainstem Response. AB - OBJECTIVES: The binaural interaction component (BIC) is the residual auditory brainstem response (ABR) obtained after subtracting the sum of monaurally evoked from binaurally evoked ABRs. The DN1 peak-the first negative peak of the BIC-has been postulated to have diagnostic value as a biomarker for binaural hearing abilities. Indeed, not only do DN1 amplitudes depend systematically upon binaural cues to location (interaural time and level differences), but they are also predictive of central hearing deficits in humans. A prominent issue in using BIC measures as a diagnostic biomarker is that DN1 amplitudes not only exhibit considerable variability across subjects, but also within subjects across different measurement sessions. DESIGN: In this study, the authors investigate the DN1 amplitude measurement reliability by conducting repeated measurements on different days in eight adult guinea pigs. RESULTS: Despite consistent ABR thresholds, ABR and DN1 amplitudes varied between and within subjects across recording sessions. However, the study analysis reveals that DN1 amplitudes varied proportionally with parent monaural ABR amplitudes, suggesting that common experimental factors likely account for the variability in both waveforms. Despite this variability, the authors show that the shape of the dependence between DN1 amplitude and interaural time difference is preserved. The authors then provide a BIC normalization strategy using monaural ABR amplitude that reduces the variability of DN1 peak measurements. Finally, the authors evaluate this normalization strategy in the context of detecting changes of the DN1 amplitude-to-interaural time difference relationship. CONCLUSIONS: The study results indicate that the BIC measurement variability can be reduced by a factor of two by performing a simple and objective normalization operation. The authors discuss the potential for this normalized BIC measure as a biomarker for binaural hearing. PMID- 27232071 TI - Effects of Age and Working Memory Capacity on Speech Recognition Performance in Noise Among Listeners With Normal Hearing. AB - OBJECTIVES: This study aimed to determine if younger and older listeners with normal hearing who differ on working memory span perform differently on speech recognition tests in noise. Older adults typically exhibit poorer speech recognition scores in noise than younger adults, which is attributed primarily to poorer hearing sensitivity and more limited working memory capacity in older than younger adults. Previous studies typically tested older listeners with poorer hearing sensitivity and shorter working memory spans than younger listeners, making it difficult to discern the importance of working memory capacity on speech recognition. This investigation controlled for hearing sensitivity and compared speech recognition performance in noise by younger and older listeners who were subdivided into high and low working memory groups. Performance patterns were compared for different speech materials to assess whether or not the effect of working memory capacity varies with the demands of the specific speech test. The authors hypothesized that (1) normal-hearing listeners with low working memory span would exhibit poorer speech recognition performance in noise than those with high working memory span; (2) older listeners with normal hearing would show poorer speech recognition scores than younger listeners with normal hearing, when the two age groups were matched for working memory span; and (3) an interaction between age and working memory would be observed for speech materials that provide contextual cues. DESIGN: Twenty-eight older (61 to 75 years) and 25 younger (18 to 25 years) normal-hearing listeners were assigned to groups based on age and working memory status. Northwestern University Auditory Test No. 6 words and Institute of Electrical and Electronics Engineers sentences were presented in noise using an adaptive procedure to measure the signal-to-noise ratio corresponding to 50% correct performance. Cognitive ability was evaluated with two tests of working memory (Listening Span Test and Reading Span Test) and two tests of processing speed (Paced Auditory Serial Addition Test and The Letter Digit Substitution Test). RESULTS: Significant effects of age and working memory capacity were observed on the speech recognition measures in noise, but these effects were mediated somewhat by the speech signal. Specifically, main effects of age and working memory were revealed for both words and sentences, but the interaction between the two was significant for sentences only. For these materials, effects of age were observed for listeners in the low working memory groups only. Although all cognitive measures were significantly correlated with speech recognition in noise, working memory span was the most important variable accounting for speech recognition performance. CONCLUSIONS: The results indicate that older adults with high working memory capacity are able to capitalize on contextual cues and perform as well as young listeners with high working memory capacity for sentence recognition. The data also suggest that listeners with normal hearing and low working memory capacity are less able to adapt to distortion of speech signals caused by background noise, which requires the allocation of more processing resources to earlier processing stages. These results indicate that both younger and older adults with low working memory capacity and normal hearing are at a disadvantage for recognizing speech in noise. PMID- 27232070 TI - Changes in the Compressive Nonlinearity of the Cochlea During Early Aging: Estimates From Distortion OAE Input/Output Functions. AB - OBJECTIVES: The level-dependent growth of distortion product otoacoustic emissions (DPOAEs) provides an indirect metric of cochlear compressive nonlinearity. Recent evidence suggests that aging reduces nonlinear distortion emissions more than those associated with linear reflection. Therefore, in this study, we generate input/output (I/O) functions from the isolated distortion component of the DPOAE to probe the effects of early aging on the compressive nonlinearity of the cochlea. DESIGN: Thirty adults whose ages ranged from 18 to 64 years participated in this study, forming a continuum of young to middle-age subjects. When necessary for analyses, subjects were divided into a young-adult group with a mean age of 21 years, and a middle-aged group with a mean age of 52 years. All young-adult subjects and 11 of the middle-aged subjects had normal hearing; 4 middle-aged ears had slight audiometric threshold elevation at mid-to high frequencies. DPOAEs (2f1 - f2) were recorded using primary tones swept upward in frequency from 0.5 to 8 kHz, and varied from 25 to 80 dB sound pressure level. The nonlinear distortion component of the total DPOAE was separated and used to create I/O functions at one-half octave intervals from 1.3 to 7.4 kHz. Four features of OAE compression were extracted from a fit to these functions: compression threshold, range of compression, compression slope, and low-level growth. These values were compared between age groups and correlational analyses were conducted between OAE compression threshold and age with audiometric threshold controlled. RESULTS: Older ears had reduced DPOAE amplitude compared with young-adult ears. The OAE compression threshold was elevated at test frequencies above 2 kHz in the middle-aged subjects by 19 dB (35 versus 54 dB SPL), thereby reducing the compression range. In addition, middle-aged ears showed steeper amplitude growth beyond the compression threshold. Audiometric threshold was initially found to be a confound in establishing the relationship between compression and age; however, statistical analyses allowed us to control its variance. Correlations performed while controlling for age differences in high-frequency audiometric thresholds showed significant relationships between the DPOAE I/O compression threshold and age: Older subjects tended to have elevated compression thresholds compared with younger subjects and an extended range of monotonic growth. CONCLUSIONS: Cochlear manifestations of nonlinearity, such as the DPOAE, weaken during early aging, and DPOAE I/O functions become linearized. Commensurate changes in high-frequency audiometric thresholds are not sufficient to fully explain these changes. The results suggest that age-related changes in compressive nonlinearity could produce a reduced dynamic range of hearing, and contribute to perceptual difficulties in older listeners. PMID- 27232072 TI - How Can Public Health Approaches and Perspectives Advance Hearing Health Care? AB - This commentary explores the role of public health programs and themes on hearing health care. Ongoing engagement within the hearing professional community is needed to determine how to change the landscape and identify important features in the evolution of population hearing health care. Why and how to leverage existing public health programs and develop new programs to improve hearing health in older individuals is an important topic. Hearing professionals are encouraged to reflect on these themes and recommendations and join the discussion about the future of hearing science on a population level. PMID- 27232074 TI - Association Between Osteoporosis/Osteopenia and Vestibular Dysfunction in South Korean Adults. AB - OBJECTIVE: The associations of osteoporosis/osteopenia with vestibular dysfunction have not been well evaluated and conflicting results have been reported. The purpose of this study is to examine the relation of low bone mineral density (BMD) with vestibular dysfunction. DESIGN: The authors conducted a cross-sectional study in 3579 Korean adults aged 50 years and older who participated in the 2009 to 2010 Korea National Health and Nutrition Examination Survey. BMD was measured by dual energy X ray absorptiometry. Vestibular dysfunction was evaluated using the modified Romberg test of standing balance on firm and compliant support surfaces. Data were analyzed in 2015. Multiple logistic regression analysis was used to compute odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The prevalence of vestibular dysfunction was 4.3 +/- 0.5%. After adjustment for potential confounders, the adjusted ORs for vestibular dysfunction based on BMD were 1.00 (reference) for normal BMD, 2.21 (95% CI: 1.08, 4.50) for osteopenia, and 2.47 (95% CI: 1.05, 5.81) for osteoporosis (p < 0.05). We also observed relationships within each age group. The adjusted ORs were as follows: for age <65 years, the values were 1.00 (reference) for normal BMD, 2.91 (95% CI: 1.02, 8.31) for osteopenia, and 2.12 (95% CI: 0.28, 16.14) for osteoporosis (p < 0.05). For age >=65 years, the values were 1.00 (reference) for normal BMD, 2.17 (95% CI: 0.96, 4.90) for osteopenia, and 2.77 (95% CI: 1.18, 6.47) for osteoporosis (p < 0.05). CONCLUSION: Osteoporosis or osteopenia were associated with an increased risk of vestibular dysfunction among South Korean adults, especially in older ones. PMID- 27232073 TI - Hearing Instruments for Unilateral Severe-to-Profound Sensorineural Hearing Loss in Adults: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: A systematic review of the literature and meta-analysis was conducted to assess the nature and quality of the evidence for the use of hearing instruments in adults with a unilateral severe to profound sensorineural hearing loss. DESIGN: The PubMed, EMBASE, MEDLINE, Cochrane, CINAHL, and DARE databases were searched with no restrictions on language. The search included articles from the start of each database until February 11, 2015. Studies were included that (a) assessed the impact of any form of hearing instrument, including devices that reroute signals between the ears or restore aspects of hearing to a deaf ear, in adults with a sensorineural severe to profound loss in one ear and normal or near normal hearing in the other ear; (b) compared different devices or compared a device with placebo or the unaided condition; (c) measured outcomes in terms of speech perception, spatial listening, or quality of life; (d) were prospective controlled or observational studies. Studies that met prospectively defined criteria were subjected to random effects meta-analyses. RESULTS: Twenty-seven studies reported in 30 articles were included. The evidence was graded as low-to moderate quality having been obtained primarily from observational before-after comparisons. The meta-analysis identified statistically significant benefits to speech perception in noise for devices that rerouted the speech signals of interest from the worse ear to the better ear using either air or bone conduction (mean benefit, 2.5 dB). However, these devices also degraded speech understanding significantly and to a similar extent (mean deficit, 3.1 dB) when noise was rerouted to the better ear. Data on the effects of cochlear implantation on speech perception could not be pooled as the prospectively defined criteria for meta-analysis were not met. Inconsistency in the assessment of outcomes relating to sound localization also precluded the synthesis of evidence across studies. Evidence for the relative efficacy of different devices was sparse but a statistically significant advantage was observed for rerouting speech signals using abutment-mounted bone conduction devices when compared with outcomes after preoperative trials of air conduction devices when speech and noise were colocated (mean benefit, 1.5 dB). Patients reported significant improvements in hearing-related quality of life with both rerouting devices and following cochlear implantation. Only two studies measured health-related quality of life and findings were inconclusive. CONCLUSIONS: Devices that reroute sounds from an ear with a severe to profound hearing loss to an ear with minimal hearing loss may improve speech perception in noise when signals of interest are located toward the impaired ear. However, the same device may also degrade speech perception as all signals are rerouted indiscriminately, including noise. Although the restoration of functional hearing in both ears through cochlear implantation could be expected to provide benefits to speech perception, the inability to synthesize evidence across existing studies means that such a conclusion cannot yet be made. For the same reason, it remains unclear whether cochlear implantation can improve the ability to localize sounds despite restoring bilateral input. Prospective controlled studies that measure outcomes consistently and control for selection and observation biases are required to improve the quality of the evidence for the provision of hearing instruments to patients with unilateral deafness and to support any future recommendations for the clinical management of these patients. PMID- 27232075 TI - Comparing the Accuracy and Speed of Manual and Tracking Methods of Measuring Hearing Thresholds. AB - OBJECTIVES: The reliability of hearing thresholds obtained using the standard clinical method (modified Hughson-Westlake) has been the focus of previous investigation given the potential for tester bias (). In recent years, more precise methods in laboratory studies have been used that control for sources of bias, often at the expense of longer test times. The aim of this pilot study was to compare test-retest variability and time requirement to obtain a full set of hearing thresholds (0.125 - 20 kHz) of the clinical modified Hughson-Westlake (manual) method with that of the automated, modified (single frequency) Bekesy tracking method (). DESIGN: Hearing thresholds from 10 subjects (8 female) between 19 to 47 years old (mean = 28.3; SD = 9.4) were measured using two methods with identical test hardware and calibration. Thresholds were obtained using the modified Hughson-Westlake (manual) method and the Bekesy method (tracking). Measurements using each method were repeated after one-week. Test retest variability within each measurement method was computed across test sessions. Results from each test method as well as test time across methods were compared. RESULTS: Test-retest variability was comparable and statistically indistinguishable between the two test methods. Thresholds were approximately 5 dB lower when measured using the tracking method. This difference was not statistically significant. The manual method of measuring thresholds was faster by approximately 4 minutes. Both methods required less time (~ 2 mins) in the second session as compared to the first. CONCLUSION: Hearing thresholds obtained using the manual method can be just as reliable as those obtained using the tracking method over the large frequency range explored here (0.125 - 20 kHz). These results perhaps point to the importance of equivalent and valid calibration techniques that can overcome frequency dependent discrepancies, most prominent at higher frequencies, in the sound pressure delivered to the ear. PMID- 27232076 TI - Better Visuospatial Working Memory in Adults Who Report Profound Deafness Compared to Those With Normal or Poor Hearing: Data From the UK Biobank Resource. AB - Experimental work has shown better visuospatial working memory (VSWM) in profoundly deaf individuals compared to those with normal hearing. Other data, including the UK Biobank resource shows poorer VSWM in individuals with poorer hearing. Using the same database, the authors investigated VSWM in individuals who reported profound deafness. Included in this study were 112 participants who were profoundly deaf, 1310 with poor hearing and 74,635 with normal hearing. All participants performed a card-pair matching task as a test of VSWM. Although variance in VSWM performance was large among profoundly deaf participants, at group level it was superior to that of participants with both normal and poor hearing. VSWM in adults is related to hearing status but the association is not linear. Future study should investigate the mechanism behind enhanced VSWM in profoundly deaf adults. PMID- 27232079 TI - InAs/GaSb core-shell nanowires grown on Si substrates by metal-organic chemical vapor deposition. AB - We report the growth of InAs/GaSb core-shell heterostructure nanowires with smooth sidewalls on Si substrates using metal-organic chemical vapor deposition with no assistance from foreign catalysts. Sb adatoms were observed to strongly influence the morphology of the GaSb shell. In particular, Ga droplets form on the nanowire tips when a relatively low TMSb flow rate is used, whereas the droplets are missing and the radial growth of the GaSb is enhanced due to a reduction in the diffusion length of the Ga adatoms when the TMSb flow rate is increased. Moreover, transmission electron microscopy measurements revealed that the GaSb shell coherently grew on the InAs core. The results obtained here show that the InAs/GaSb core-shell nanowires grown using the Si platform have strong potential in the fabrication of future nanometer-scale devices and in the study of fundamental quantum physics. PMID- 27232080 TI - Diffusion tensor imaging and deep brain stimulation. PMID- 27232081 TI - Aortic calcification was associated with risk of fractures: A meta-analysis. AB - OBJECTIVE: The objective of this meta-analysis was to systematically assess the association between aortic calcification (AC) and fractures. METHOD: Relevant studies were identified through searching PubMed, EMBASE and Cochrane databases before August 2014. Two investigators extracted data independently from the included studies. A random-effects model was derived to composite the pooled HRs or ORs for association of aortic calcification with fractures. RESULTS: A total of 15 articles (21927 subjects) were included in the final meta-analyses. Comparing with non-calcification subjects, patients with aortic calcification were associated with increased risk of fractures (OR = 2.97, 95% CI: 1.98-4.42). Stratified analysis indicated that patients with aortic calcification showed a higher risk of fractures in hemodialysis patients (OR = 1.89, 95% CI: 1.33-2.67; I2 = 0.0%, p= 0.781) and general population (OR = 2.90, 95% CI: 1.80-4.80; I2 = 33.0%, p= 0.225), respectively. Similar significant association between severe aortic calcification and fractures were also observed. CONCLUSIONS: Patients with aortic calcification or severe aortic calcification were associated with higher risk of fractures. PMID- 27232077 TI - The Physiological Basis and Clinical Use of the Binaural Interaction Component of the Auditory Brainstem Response. AB - The auditory brainstem response (ABR) is a sound-evoked noninvasively measured electrical potential representing the sum of neuronal activity in the auditory brainstem and midbrain. ABR peak amplitudes and latencies are widely used in human and animal auditory research and for clinical screening. The binaural interaction component (BIC) of the ABR stands for the difference between the sum of the monaural ABRs and the ABR obtained with binaural stimulation. The BIC comprises a series of distinct waves, the largest of which (DN1) has been used for evaluating binaural hearing in both normal hearing and hearing-impaired listeners. Based on data from animal and human studies, the authors discuss the possible anatomical and physiological bases of the BIC (DN1 in particular). The effects of electrode placement and stimulus characteristics on the binaurally evoked ABR are evaluated. The authors review how interaural time and intensity differences affect the BIC and, analyzing these dependencies, draw conclusion about the mechanism underlying the generation of the BIC. Finally, the utility of the BIC for clinical diagnoses are summarized. PMID- 27232082 TI - Kinesio taping in patients with lateral epicondylitis. AB - BACKGROUND: Lateral epicondylitis (LE) is a painful condition that affects the tendinous tissue of the lateral epicondyle of the humerus and leads to loss of function of the affected limb. Therefore it can have a major impact on the patient's social and personal life. Many treatments are recommended for lateral epicondylitis; unfortunately the evidence is limited. OBJECTIVES: The aim of study was to investigate the effect of kinesio taping (KT) on pain, grip strength and function in patients LE. METHODS: Thirty-one (23 females, 8 males) patients with LE were included. KT was applied twice a week for 2 weeks. Pain at rest, activity of daily living (ADL), night and palpation on lateral epicondyle was evaluated with the visual analog scale (VAS 0-10 cm), and the grip strength was measured with a hand held dynamometer. The stage of the disease was evaluated by the Nirschl score and the functional status was assessed with Patient-Rated Forearm Evaluation Questionnaire (PRTEQ) score. These parameters were evaluated before, at 2 weeks and 6 weeks after treatment. Patients' satisfaction was also recorded on a Likert scale after treatment at 2 weeks and 6 weeks. RESULTS: The average age of the patients was 43.58 +/- 9.02. The dominant limb was affected in 64.5% (20) of the patients. After the application of KT on lateral epicondyle, there was a significant improvement in all parameters in terms of pain, Nirschl score, hand grip strength, patient satisfaction, and PRTEQ scores at 2 and 6 weeks. CONCLUSIONS: Kinesio taping can be an effective treatment method in LE. This application improves pain, grip strength and functional status of the patients with LE. PMID- 27232083 TI - Fatigue-related differences in erector spinae between prepubertal children and young adults using surface electromyographic power spectral analysis. AB - BACKGROUND: The erector spinae is more resistant to fatigue in adult women than men. However, no study has reported the sex differences in back muscle fatigue in children. OBJECTIVE: The aim of this study was to evaluate the fatigability of erector spinae in prepubertal children and adults, in both males and females. METHODS: Fourteen prepubertal boys, 13 prepubertal girls, 14 adult men, and 13 adult women performed the Sorensen back isometric endurance test until exhaustion. The results of electromyographic (EMG) power spectral analysis of erector spinae were compared between both age groups and sexes. RESULTS: The slopes of EMG power spectral median and mean power frequency were significantly higher in males than in females, in both age groups. Furthermore, the slopes were significantly lower in prepubertal children than in adults, in both males and females. CONCLUSIONS: Our results showed major differences in the fatigue threshold of the erector spinae between boys and girls and children and adults. The muscle fatigued faster in prepubertal boys and adult men than in prepubertal girls and adult women. In both sexes, a lower slope of EMG power spectrum parameters of the erector spinae was noted during endurance test in prepubertal children compared to adults. PMID- 27232084 TI - A new method of calculating the rotation angle in pediatric forearm fractures using direct radiographs. AB - BACKGROUND: The aim of this study was to measure the rotational angle defect between fracture ends in paediatric forearm diaphyseal fractures on radiographs. METHODS: Evaluations were performed on 78 paediatric patients who presented at the emergency department with a diaphyseal forearm fracture during 2013-2014. Thirty-two patients who underwent conservative treatment and had < 10 degrees of angulation and translation of not more than half the bone diameter after application of a plaster cast were included in the study. A rotational formula was used with diameter values to determine changes. The degree of rotation of both ends of the fracture line and the forearm rotational defect of the fracture line were calculated. FINDINGS: Fractures included an isolated radius in 16 cases, an isolated ulna in four cases, and both bones in 12 cases. The mean lateral angular (LAT-theta) value was 26.13 +/- 5.93 degrees on the proximal fracture end, and the distal mean LAT-theta was 30.29 +/- 6.24 degrees (p = 0.037).The mean proximal anteroposterior angular (AP-theta) value was 26.83 +/- 5.75 degrees , and the distal mean AP-theta was 30.58 +/- 7.27 degrees (p = 0.008). A significant correlation was detected between the AP-Delta and LAT-Delta measurements (p = 0.883). INTERPRETATION: The rotational defect was mathematically calculated directly from radiographs using a rotational measurement formula. PMID- 27232085 TI - Extracorporeal shock-wave therapy effectively reduces calcaneal spur length and spur-related pain in overweight and obese patients. AB - OBJECTIVE: We aimed to evaluate the effects of extra corporeal shock-wave therapy (ESWT) on the calcaneal spur length and pain severity in overweight and obese patients with symptomatic calcaneal spur. METHODS: In eighty patients with symptomatic calcaneal spur, ESWT was administered on days 0 and 7, and visual analog scale (VAS) scores and calcaneal spur lengths (CSLs) before and 3 months later after treatment were recorded. A lateral heel radiograph was used for computer-aided linear measurements of CSL. RESULTS: Of 80 patients, 59 (73.7%) were female and 21 were male (26.3%); age was 45.9 +/- 8.3 years; BMI was 31.6 +/ 4.4 kg/m2; and symptom duration was 2.3 +/- 2.4 years. The CSL and VAS score after treatment were significantly lower than those before treatment (CSL before vs. after: 5.7 +/- 1.0 vs. 4.4 +/- 0.9, p = 0.001; VAS score before vs. after: 8.3 +/- 1.4 vs. 4.6 +/- 2.2; p = 0.03). The CSLs before and after treatment had a significant strong correlation (r = 0.832, p = 0.001). The VAS scores before and after treatment presented a significant mild correlation (r = 0.242, p = 0.03). CONCLUSIONS: In overweight and obese patients with symptomatic calcaneal spur, ESWT reduces the CSL and pain severity during a follow-up of three-month duration. PMID- 27232086 TI - Effect of a stress management program on subjects with neck pain: A pilot randomized controlled trial. AB - BACKGROUND: Studies have shown that stress is implicated in the cause of neck pain (NP). OBJECTIVES: The purpose of this study is to examine the effect of a simple, zero cost stress management program on patients suffering from NP. METHODS: This study is a parallel-type randomized clinical study. People suffering from chronic non-specific NP were chosen randomly to participate in an eight week duration program of stress management (N= 28) (including diaphragmatic breathing, progressive muscle relaxation) or in a no intervention control condition (N= 25). Self-report measures were used for the evaluation of various variables at the beginning and at the end of the eight-week monitoring period. Descriptive and inferential statistic methods were used for the statistical analysis. RESULTS: At the end of the monitoring period, the intervention group showed a statistically significant reduction of stress and anxiety (p= 0.03, p= 0.01), report of stress related symptoms (p= 0.003), percentage of disability due to NP (p= 0.000) and NP intensity (p= 0.002). At the same time, daily routine satisfaction levels were elevated (p= 0.019). No statistically significant difference was observed in cortisol measurements. CONCLUSIONS: Stress management has positive effects on NP patients. PMID- 27232087 TI - Painful and painless shoulder magnetic resonance imaging comparisons in hemodialysis patients and correlation with clinical findings. AB - BACKGROUND: Shoulder pain is frequently observed in haemodialysis patients. OBJECTIVE: To compare haemodialysis patients with or without shoulder pain in terms of shoulder motion ranges, beta2 microglobulin levels and magnetic resonance imaging findings. METHODS: Forty-three patients undergoing dialysis were enrolled, of which 23 patients had explicit shoulder pain at night, which appeared during dialysis. Range of joint motion and impingement tests were evaluated. beta 2 microglobulin value was recorded. MRI was used to evaluate rotator cuff tendons for thickness, homogeneity, integrity and presence of effusion. RESULTS: Ranges of motion were significantly lower in the painful shoulder group. Supraspinatus tendon thickness and the number of areas with effusion were higher in the painful group. There was a positive correlation between the beta 2 microglobulin level and supraspinatus (r:0.352 p< 0.05) and subscapular (r:0.454 p< 0.05) tendon thicknesses. While effusion areas and pain (r:0.351 p< 0.05) showed positive correlation, there was a negative correlation between pain and shoulder motion ranges. CONCLUSIONS: Shoulder pain in dialysis patients can be related with tendon thickness and effusion. While the beta 2 microglobulin level affects tendon thickness, it has no relation to pain and movement constraint. PMID- 27232088 TI - Forecasting the Future: Expert Opinions on the Next Decade for Adult Speech and Language Disorders. PMID- 27232089 TI - Crystal Ball Gazing: Research and Clinical Work in Fluency Disorders in 2026. AB - In this article, the authors (with the assistance of colleagues from whom they solicited comments), provide a forward-looking perspective on research and clinical work in fluency disorders in the next 10-15 years. Issues discussed include neurology, genetics, early intervention, and clinical training in stuttering. PMID- 27232090 TI - Making It Right? Some Thoughts about the Future of Treatment for Right Hemisphere Cognitive-Communication Disorders. AB - This article reflects on the future of intervention for language and communication disorders that follow unilateral damage to the right cerebral hemisphere. The author first introduces some of the challenges inherent in this task: a very small and preliminary evidence base and a limited number of investigators conducting treatment research for most of the consequences of these disorders, more general difficulties of translating evidence to practice, and limited graduate training in the area. The article then addresses some predictions and hopes for the future. The author foresees progress in defining the disorders and in clinicians' knowledge of the heterogeneity of the population, the multifaceted nature of complex impairments, and the expanding range of well-justified treatment options. The article next discusses the potential of noninvasive brain stimulation techniques, virtual reality-based approaches to intervention, and the promise of telerehabilitation. Finally, the author voices a concern that undeniably important new trends in health care, such as emphases on patient-reported outcomes and patient satisfaction measures, could penalize the subset of the client population that lacks awareness of or minimizes their deficits, and calls for vigilant clinician advocates in such cases. PMID- 27232091 TI - The Next 10 Years in Voice Evaluation and Treatment. AB - Voice disorders are thought to affect approximately one third of all individuals within the United States during their lifetime. Individuals who require the use of their voice as part of their occupations are at highest risk for developing voice problems. Unfortunately, efficient diagnosis and effective management of voice disorders can be challenged by difficulty accessing professionals with the necessary expertise to diagnose and treat voice problems efficiently. Within the next decade, technological advancements show promise for improving the efficiency and effectiveness of intervention for voice disorders. Exciting developments in laryngeal imaging, modeling of patient-specific vocal patterns, and implementation of smart mobile technology and telehealth will greatly improve the accuracy of diagnosing voice problems and enhance implementation and carryover of effective voice treatment methods to daily communication demands. PMID- 27232092 TI - Aphasia Practice in the Year 2026. AB - The purpose of this article is to envision how the clinical practice of aphasia management might be done 10 years in the future. The vision of how an individual clinician's daily tasks are changed is built on current trends, including the aging of the population, the life participation approach to aphasia, development and use of evidence-based practices, person-centered care, and technology. To be prepared for the future of these trends, we will need to develop clinical capacity, not only in the number of speech-language pathologists but also most importantly in their competence for using evidence-based practices and training others to support effective communication, including other health care providers. Research needs that will support the future are also described. PMID- 27232093 TI - Beyond Tracheostomy: Noninvasive Ventilation and Potential Positive Implications for Speaking and Swallowing. AB - For more than a decade, there has been a trend toward increased use of noninvasive positive pressure ventilation (NPPV) via mask or mouthpiece as a means to provide ventilatory support without the need for tracheostomy. All indications are that use of NPPV will continue to increase over the next decade and beyond. In this article, we review NPPV, describe two common forms of NPPV, and discuss the potential benefits and challenges of NPPV for speaking and swallowing based on the available literature, our collective clinical experience, and interviews with NPPV users. We also speculate on how future research may inform clinical practice on how to best maximize speaking and swallowing abilities in NPPV users over the next decade. PMID- 27232094 TI - Will You Still Need Me When I'm 64, or 84, or 104? The Importance of Speech Language Pathologists in Promoting the Quality of Life of Aging Adults in the United States into the Future. AB - In the next two decades, there will be advances in the diagnosis and treatment of the disorders of aging that have the potential to change the way speech-language pathologists (SLPs) are trained and provide services to individuals with a continuum of cognitive communication challenges. SLPs will address the needs of the aging adult who continues to reside in the community and desires to maintain an independent and meaningful life, as well as those who require a supportive residential setting to achieve a satisfying quality of life. Evidence-based strategies and intervention approaches for the range of goals that will address the desired functions of a meaningful life for individuals faced with cognitive communicative challenges are outlined. Institutional barriers to the implementation of documented evidence-based approaches will need to be reduced through a variety of organizational and systems changes. The projected outcome of these changes will be the creation of a person-centered culture of care that promotes dignity, choice, and engagement in meaningful activities through the end of life. PMID- 27232095 TI - Dysphagia Practice in 2035: Beyond Fluorography, Thickener, and Electrical Stimulation. AB - Dysphagia evaluation and management has rapidly become the primary practice area of medical speech pathologists since its adoption in our field less than three decades ago. As a specialty, swallowing and swallowing disorders comprise the largest represented discipline with 10,059 specialty interest group members within the American Speech-Language-Hearing Association and 298 board-certified specialists in the American Speech Hearing Association. There are national and international organizations, such as the Dysphagia Research Society and its interdisciplinary journal Dysphagia, that provide continuing education for clinicians and a platform for dysphagia researchers. Despite this rapid growth, herein we identify some significant needs for improving the science and practice of dysphagia clinical care, including a deeper understanding of physiology and neurophysiology, standardization of evaluation, consensus on core sets of dysphagia parameters for clinical and research reporting, personalized algorithms for implementation of evidenced-based practice, metrics for therapy efficacy, and increased buy-in and funding from agencies. The goals of this article are to summarize the status quo of dysphagia research, evaluation, and treatment as well as to make predictions about the future. Medical trends that we speculate will influence dysphagia research and care in the future include, among others, imaging advances, personalized medicine, regenerative medicine, and telehealth. PMID- 27232096 TI - Motor Speech Disorders: Where Will We Be in 10 Years? AB - Research and practice in the area of motor speech disorders (MSDs) will change in the next 10 years, most likely in evolutionary rather revolutionary ways. We are likely to see an increase in the understanding of the underpinnings of MSDs and refinements in assessment and diagnosis. Management approaches probably will be refined, as will how outcomes are measured. The evidence base for treatment efficacy will grow. Technology and changes in the health care system will have strong and overarching, but not easily predicted, influences. This article provides a broad overview of these and related issues, with some cautious predictions. PMID- 27232097 TI - Rehabilitation for Adults with Traumatic Brain Injury: Where Will We Be Clinically in 2026? AB - In 10 years, there might be fewer adults who need rehabilitation after traumatic brain injury because of advances in injury prevention and very early treatment. For adults who do need rehabilitation, assessment might include biosensor recordings in their everyday communication contexts, and home practice might be delivered by a robot that can be programmed to mimic target characteristics of human behavior. These advances in science and technology will enhance rehabilitation, but it will always be our responsibility as speech-language pathologists to advocate for our patients and clients and support them in achieving the best possible quality of communication life. PMID- 27232098 TI - Twisted Thiophene-Based Chromophores with Enhanced Intramolecular Charge Transfer for Cooperative Amplification of Third-Order Optical Nonlinearity. AB - Exploiting synergistic cooperation between multiple sources of optical nonlinearity, we report the design, synthesis, and nonlinear optical properties of a series of electron-rich thiophene-containing donor-acceptor chromophores with condensed pi-systems and sterically regulated inter-aryl twist angles. These structures couple two key mechanisms underlying optical nonlinearity, namely, (i) intramolecular charge transfer, greatly enhanced by increased electron density and reduced aromaticity at chromophore thiophene rings and (ii) a twisted chromophore geometry, producing a manifold of close-lying excited states and dipole moment changes between ground and excited states that are nearly twice that of untwisted systems. Spectroscopic, electrochemical, and nonlinear Z-scan measurements, combined with quantum chemical calculations, illuminate relationships between molecular structure and mechanisms of enhancement of the nonlinear refractive index. Experiment and calculations together reveal ground state structures that are strongly responsive to the solvent polarity, leading to substantial negative solvatochromism (Deltalambda ~ 10(2) nm) and prevailing zwitterionic/aromatic structures in the solid state and in polar solvents. Ground to-excited-state energy gaps below 2.0 eV are obtained in condensed pi-systems, with lower energy gaps for twisted versus untwisted systems. The real part of the second hyperpolarizability in the twisted structures is much greater than the imaginary part, with the highest twist angle chromophore giving |Re(gamma)/Im(gamma)| ~ 100, making such chromophores very promising for all optical-switching applications. PMID- 27232100 TI - Nanometer-Thick Gold on Silicon as a Proxy for Single-Crystal Gold for the Electrodeposition of Epitaxial Cuprous Oxide Thin Films. AB - Single-crystal Au is an excellent substrate for electrochemical epitaxial growth due to its chemical inertness, but the high cost of bulk Au single crystals prohibits their use in practical applications. Here, we show that ultrathin epitaxial films of Au electrodeposited onto Si(111), Si(100), and Si(110) wafers can serve as an inexpensive proxy for bulk single-crystal Au for the deposition of epitaxial films of cuprous oxide (Cu2O). The Au films range in thickness from 7.7 nm for a film deposited for 5 min to 28.3 nm for a film deposited for 30 min. The film thicknesses are measured by low-angle X-ray reflectivity and X-ray Laue oscillations. High-resolution TEM shows that there is not an interfacial SiOx layer between the Si and Au. The Au films deposited on the Si(111) substrates are smoother and have lower mosaic spread than those deposited onto Si(100) and Si(110). The mosaic spread of the Au(111) layer on Si(111) is only 0.15 degrees for a 28.3 nm thick film. Au films deposited onto degenerate Si(111) exhibit ohmic behavior, whereas Au films deposited onto n-type Si(111) with a resistivity of 1.15 Omega.cm are rectifying with a barrier height of 0.85 eV. The Au and the Cu2O follow the out-of-plane and in-plane orientations of the Si substrates, as determined by X-ray pole figures. The Au and Cu2O films deposited on Si(100) and Si(110) are both twinned. The films grown on Si(100) have twins with a [221] orientation, and the films grown on Si(110) have twins with a [411] orientation. An interface model is proposed for all Si orientations, in which the -24.9% mismatch for the Au/Si system is reduced to only +0.13% by a coincident site lattice in which 4 unit meshes of Au coincide with 3 unit meshes of Si. Although this study only considers the deposition of epitaxial Cu2O films on electrodeposited Au/Si, the thin Au films should serve as high-quality substrates for the deposition of a wide variety of epitaxial materials. PMID- 27232099 TI - Blue dye can be safely omitted in most sentinel node procedures for melanoma. AB - Sentinel node biopsy is a widely used staging procedure in melanoma. It is usually performed using the triple technique: lymphatic mapping after injection of a radiopharmaceutical, blue dye injection, and the use of a gamma probe. Blue dye offers visual confirmation of the location of the sentinel lymph node (SN). There are some disadvantages such as blurring of the surgical field, skin coloring, and possible anaphylactic reactions. We aimed to answer the question whether patent blue is truly necessary for correct intraoperative identification of the SN. One day preoperatively, lymphoscintigraphy (with or without single photon emission computed tomography with integrated computed tomography) is performed and the location of the SN is marked on the skin. Perioperatively, patent blue is injected around the tumor. A handheld gamma-ray detection probe is used to determine the location of the incision and detect the SN during the operation. SNs are pursued in all regions indicated by imaging. In only six of the 681 patients (0.9%) a blue, not radioactive, sentinel node was removed. In one of them (0.15%), this was the only node excised. None of these lymph nodes harbored metastases. This study suggests that blue dye has no additional value in finding the sentinel node and is of low significance in detecting metastases. Therefore, blue dye can be safely omitted from the standardized triple technique. It may be useful in selected cases according to the surgeon's discretion. PMID- 27232101 TI - Evofosfamide, a new horizon in the treatment of pancreatic cancer. AB - Evofosfamide, also formerly known as TH-302, is an investigational hypoxia activated prodrug and is used to target cancerous cells under hypoxic conditions, which is a feature possessed by multiple solid tumors including pancreatic tumors. Gemcitabine, a cytotoxic agent, has for many years been the standard first-line treatment for metastatic pancreatic cancer in patients. In recent years, combination chemotherapeutic therapies have provided a new avenue for molecular targeting by increasing the probability of eliminating the cancer and minimizing the likelihood of resistance. We have evaluated multiple studies in an effort to shed light on an emerging prodrug, evofosfamide, which operates by selectively targeting the tumor hypoxic compartment. A web-based literature search was performed through PubMed and Google Scholar using the keywords 'evofosfamide', 'TH-302,' and 'pancreatic tumor.' Of the available results, 53 relevant studies were reviewed and summarized. Chemotherapeutic agents such as evofosfamide, which targets tumor hypoxia, are new agents against cancer cells. Current experience with these agents is limited as additional and longer prospective studies are needed to further evaluate the clinical efficacy and postmarketing safety profile. PMID- 27232102 TI - The effect of negative experiences on delinquent behavior of youth in a social withdrawal situation. AB - This study examines the relationship between negative experiences, negative emotions, and delinquent behavior among young people in a social withdrawal situation. There were 533 participants in this study and various quantitative analyses were utilized. Results showed that participants with a longer period of social withdrawal were generally less affected by negative experiences, while those with a higher level of social withdrawal were more affected by negative experiences, particularly negative relationships with other people. Also, both negative emotions and higher level of social withdrawal mediated the relationship between negative experiences and involvement in delinquent behavior, with negative emotions displaying a higher mediating effect. This reflects that the root of delinquent behavior is the negative experiences which arouse negative emotions, rather than the social withdrawal behavior itself. Results imply that practitioners should first explore the negative experiences suffered by these young people, so as to provide them the most appropriate support. PMID- 27232103 TI - Family economic hardship and Chinese adolescents' sleep quality: A moderated mediation model involving perceived economic discrimination and coping strategy. AB - The association between family economic hardship and adolescent adjustment outcomes, including sleep quality, is well-established. Few studies, however, have examined the mediating and moderating mechanisms underlying the relation between family economic hardship and adolescents' sleep quality. The aim of this study was to investigate the effect of family economic hardship on Chinese adolescents' sleep quality, as well as the role of perceived economic discrimination as a mediator and the role of coping strategy as a moderator. Survey data from a cross-sectional sample of 997 Chinese adolescents (45% male, mean age = 15.04 years) were analyzed using path analysis in Mplus 7.0. The results of this study indicated that family economic hardship was significantly associated with adolescents' sleep quality. This association was mediated by adolescents' perceived economic discrimination. In addition, adolescents' coping strategy significantly moderated the path from perceived economic discrimination to sleep quality, with the "shift" coping strategy as a protective factor. The present study contributes to our understanding of key mechanisms underlying the association between family economic hardship and adolescent sleep quality and highlights the importance of improving sleep quality for adolescents exposed to economic hardship. PMID- 27232104 TI - Two-dimensional GeS with tunable electronic properties via external electric field and strain. AB - Experimentally, GeS nanosheets have been successfully synthesized using vapor deposition processes and the one-pot strategy. Quite recently, GeS monolayer, the isoelectronic counterpart of phosphorene, has attracted much attention due to promising properties. By means of comprehensive first-principles calculations, we studied the stability and electronic properties of GeS monolayer. Especially, electric field and in-plane strain were used to tailor its electronic band gap. Upon applying electric field, the band gap of GeS monolayer greatly reduces and a semiconductor-metal transition happens under the application of a certain external electric field. Our calculations reveal that the band gaps of GeS monolayer are rather sensitive to the external electric field. On the other hand, for GeS under external strain, quite interestingly, we found that the band gap presents an approximately linear increase not only under compression strain but also under tensile strain from -10% to 10%. For biaxial compressive and tensile strains, the band gap follows the same trend as that of the uniaxial in the zigzag x direction. The present results provide a simple and effective route to tune the electronic properties of GeS monolayer over a wide range and also facilitate the design of GeS-based two-dimensional devices. PMID- 27232105 TI - High-Intensity Chemotherapy is Associated with Better Prognosis in Young Patients with High-Risk Diffuse Large B-Cell Lymphoma: A 10-Year Single-Center Retrospective Cohort Study. AB - BACKGROUND Patients <60 years old with high-risk diffuse large B-cell lymphoma (DLBCL) receiving standard RCHOP(E) treatment display high relapse rates. Here, we compared this standard regimen to a high-intensity regimen in terms of recurrence and long-term survival. MATERIAL AND METHODS Newly diagnosed DLBCL patients <60 years old who were treated at the Second Hospital Affiliated with Xi'an Jiaotong University between January 2004 and December 2013 (n=198, 18-60 years) were included in the study. The high-intensity group included 107 patients (54.0%) who received >8 courses of chemotherapy (high-dose CHOP, CHOP-E, EPOCH, MAED, MMED, and HyperCVAD). The control group included 91 patients (46.0%) who received 6-8 courses of CHOP-based treatment. Response rate (RR), survival, relapse, and adverse effects were compared. RESULTS Baseline characteristics of the patients were similar between the 2 groups. Median follow-up was 64.5 months. RR in the high-intensity and control groups was 88.8% and 84.6% (P=0.387), respectively; 5-year overall survival was 66.4% and 36.3% (P<0.001), respectively; 5-year progression-free survival was 56.1% and 28.6% (P<0.001), respectively; 5-year disease-free survival was 54.2% and 24.2% (P<0.001), respectively; and relapse rate during follow-up was 29.5% and 67.5% (P<0.001), respectively. There were no significant differences in adverse effects between the 2 groups. CONCLUSIONS High-intensity chemotherapy is associated with better prognosis of patients <60 years old with newly diagnosed high-risk DLBCL. PMID- 27232106 TI - Detection of erythroblast antibodies in mitogen-stimulated bone marrow cultures from patients with myelodysplastic syndromes. AB - BACKGROUND: Low-risk myelodysplastic syndromes (MDS) show several immunologic abnormalities, including increased frequency of autoimmune manifestations and/or overt autoimmune diseases, whose prognostic significance still remains controversial. STUDY DESIGN AND METHODS: We studied the presence of erythroblast antibodies in mitogen-stimulated bone marrow (BM) cultures of 70 patients with early-stage MDS (refractory anemia and refractory anemia with ringed sideroblasts). RESULTS: Sixty-six percent of patients showed positive erythroblast antibodies, along with BM erythroid hyperplasia and a hemolytic picture in the peripheral blood. Supernatants from positive cultures induced an increase of overall cellularity, the appearance of erythroblastic clustering, and dyserythropoietic signs in normal BM. We identified CD45(dim) Gly-A(dim) CD71(bright) cells (red blood cell precursors at different maturation stage) as the target of the antibodies. Erythropoietin (EPO) levels were reduced and EPO receptors (EPO-R) increased in BM culture supernatants from positive patients. However, flow cytometric analysis showed that neither EPO nor EPO-R was involved in an abnormal stimulation driven by these autoantibodies. Values of the proapoptotic protein Bax were increased in positive patients and Bcl-2 levels were decreased, although not significantly. CONCLUSION: MDS patients with anti erythroblast autoimmunity showed increased BM apoptosis, suggesting that the autoimmune reaction may contribute to an unfavorable BM microenvironment for optimal erythropoiesis. PMID- 27232107 TI - Surface reaction dynamics. PMID- 27232108 TI - Asymmetric aza-Morita-Baylis-Hillman reactions of chiral N-phosphonyl imines with acrylates via GAP chemistry/technology. AB - Chiral N-phosphonyl imines have been proven to be efficient electrophilic acceptors for asymmetric aza-Morita-Baylis-Hillman (aza-MBH) reactions with acrylates under convenient conditions. Thirty examples of beta-amino acrylates were generated in high yields (up to 99.4%) and diastereoselectivity (up to >99 : 1 dr) in an atom-economical fashion. The synthesis was proved to follow the GAP (group-assisted purification) chemistry, i.e., the pure products can be obtained simply by washing the crude products with hexane/ethyl acetate (v/v, 10/1) without the use of chromatography or recrystallization. DFT calculations were also conducted to support an asymmetric induction model accounting for high diastereoselectivity. PMID- 27232109 TI - SSRs as genetic markers in the human genome and their observable relationship to hereditary diseases. PMID- 27232111 TI - The costs of avoiding environmental impacts from shale-gas surface infrastructure. AB - Growing energy demand has increased the need to manage conflicts between energy production and the environment. As an example, shale-gas extraction requires substantial surface infrastructure, which fragments habitats, erodes soils, degrades freshwater systems, and displaces rare species. Strategic planning of shale-gas infrastructure can reduce trade-offs between economic and environmental objectives, but the specific nature of these trade-offs is not known. We estimated the cost of avoiding impacts from land-use change on forests, wetlands, rare species, and streams from shale-energy development within leaseholds. We created software for optimally siting shale-gas surface infrastructure to minimize its environmental impacts at reasonable construction cost. We visually assessed sites before infrastructure optimization to test whether such inspection could be used to predict whether impacts could be avoided at the site. On average, up to 38% of aggregate environmental impacts of infrastructure could be avoided for 20% greater development costs by spatially optimizing infrastructure. However, we found trade-offs between environmental impacts and costs among sites. In visual inspections, we often distinguished between sites that could be developed to avoid impacts at relatively low cost (29%) and those that could not (20%). Reductions in a metric of aggregate environmental impact could be largely attributed to potential displacement of rare species, sedimentation, and forest fragmentation. Planners and regulators can estimate and use heterogeneous trade offs among development sites to create industry-wide improvements in environmental performance and do so at reasonable costs by, for example, leveraging low-cost avoidance of impacts at some sites to offset others. This could require substantial effort, but the results and software we provide can facilitate the process. PMID- 27232110 TI - State of the science on prevention and screening to reduce melanoma incidence and mortality: The time is now. AB - Answer questions and earn CME/CNE Although overall cancer incidence rates are decreasing, melanoma incidence rates continue to increase about 3% annually. Melanoma is a significant public health problem that exacts a substantial financial burden. Years of potential life lost from melanoma deaths contribute to the social, economic, and human toll of this disease. However, most cases are potentially preventable. Research has clearly established that exposure to ultraviolet radiation increases melanoma risk. Unprecedented antitumor activity and evolving survival benefit from novel targeted therapies and immunotherapies are now available for patients with unresectable and/or metastatic melanoma. Still, prevention (minimizing sun exposure that may result in tanned or sunburned skin and avoiding indoor tanning) and early detection (identifying lesions before they become invasive or at an earlier stage) have significant potential to reduce melanoma incidence and melanoma-associated deaths. This article reviews the state of the science on prevention and early detection of melanoma and current areas of scientific uncertainty and ongoing debate. The US Surgeon General's Call to Action to Prevent Skin Cancer and US Preventive Services Task Force reviews on skin cancer have propelled a national discussion on melanoma prevention and screening that makes this an extraordinary and exciting time for diverse disciplines in multiple sectors-health care, government, education, business, advocacy, and community-to coordinate efforts and leverage existing knowledge to make major strides in reducing the public health burden of melanoma in the United States. CA Cancer J Clin 2016. (c) 2016 American Cancer Society. PMID- 27232113 TI - Crystal structure of norcoclaurine-6-O-methyltransferase, a key rate-limiting step in the synthesis of benzylisoquinoline alkaloids. AB - Growing pharmaceutical interest in benzylisoquinoline alkaloids (BIA) coupled with their chemical complexity make metabolic engineering of microbes to create alternative platforms of production an increasingly attractive proposition. However, precise knowledge of rate-limiting enzymes and negative feedback inhibition by end-products of BIA metabolism is of paramount importance for this emerging field of synthetic biology. In this work we report the structural characterization of (S)-norcoclaurine-6-O-methyltransferase (6OMT), a key rate limiting step enzyme involved in the synthesis of reticuline, the final intermediate to be shared between the different end-products of BIA metabolism, such as morphine, papaverine, berberine and sanguinarine. Four different crystal structures of the enzyme from Thalictrum flavum (Tf 6OMT) were solved: the apoenzyme, the complex with S-adenosyl-l-homocysteine (SAH), the complexe with SAH and the substrate and the complex with SAH and a feedback inhibitor, sanguinarine. The Tf 6OMT structural study provides a molecular understanding of its substrate specificity, active site structure and reaction mechanism. This study also clarifies the inhibition of Tf 6OMT by previously suggested feedback inhibitors. It reveals its high and time-dependent sensitivity toward sanguinarine. PMID- 27232112 TI - PharmGKB summary: isoniazid pathway, pharmacokinetics. PMID- 27232114 TI - Safety and efficacy of recombinant factor VIIa by pediatric age cohort: reassessment of compassionate use and trial data supporting US label. AB - BACKGROUND: The relative safety and efficacy of recombinant activated coagulation factor VII (rFVIIa, NovoSeven(r) RT) across pediatric age cohorts is poorly defined. The objective of this analysis was to assess the safety and efficacy of rFVIIa in pediatric patients with congenital hemophilia with inhibitors (CHwI) in the clinical studies supporting the U.S. labeling. PROCEDURE: Pediatric data were derived from seven studies (five acute and two perioperative treatments) and pooled. All data were stratified by age (<2, 2 to <6, 6 to <12, and 12-16 years) and study category (acute treatment of bleeding episodes or surgery). RESULTS: The pediatric dataset included 172 patients; 144 received rFVIIa for the treatment of bleeding episodes and 28 for the control of bleeding perioperatively. Recombinant FVIIa was effective for 95.4% (1,026/1,076) of the evaluable bleeding episodes and had similar treatment effectiveness across pediatric age groups (range, 94.1-97.2%). The majority received doses of 90 mcg/kg. rFVIIa was effective in achieving perioperative hemostasis across pediatric age groups (range, 91-100%), with greater efficacy observed with the recommended (90 mcg/kg) versus lower dose (35 mcg/kg). A total of 88 pediatric patients experienced a total of 285 adverse drug reactions, similar in type to those reported among adult patients. A total of seven thrombotic events were recorded in seven pediatric patients; only one was confirmed related to rFVIIa upon individual case review. CONCLUSIONS: rFVIIa is safe and effective in the treatment of bleeding episodes and prevention of periprocedure bleeding in CHwI with no apparent differences observed among pediatric age groups. PMID- 27232115 TI - Comparative biochemical studies of fresh frozen plasma and pooled solvent/detergent-treated plasma (octaplasLG(r) ) with focus on protein S and its impact in different thrombin generation assay set-ups. AB - BACKGROUND AND OBJECTIVES: The solvent/detergent treatment enables effective and robust inactivation of all lipid-enveloped viruses, but also inactivates partly sensitive plasma proteins such as protein S. The aim of this study was to investigate the thrombin generation capacity of octaplasLG(r) , in particular focusing on the function of protein S in thrombin generation assay and the impact of assay settings. MATERIALS AND METHODS: Sixteen octaplasLG(r) batches and 32 units of single donor fresh frozen plasma (FFP) were investigated. For protein S, both functional activity and free antigen levels were measured. Thrombin generation assay was performed using two fluorogenic tests with different triggers. Finally, rotational thromboelastometry was performed. RESULTS: Mean protein S levels were lower in octaplasLG(r) , but a wider range of values was found for FFP. Clotting parameters and thrombin generation capacities overlapped between the two plasma groups as demonstrated using both thrombin generation assays and different triggers. Spiking studies with protein S-depleted plasma, human purified protein S or antibodies against protein S confirmed a correlation between protein S and thrombin generation capacity under specific assay conditions, especially in an assay with low tissue factor concentration. CONCLUSION: Correlation between protein S and thrombin generation capacity was demonstrated in the TGA. Due to higher variability in protein S content in the FFP group, overlapping haemostatic potentials of the two plasma groups were found. PMID- 27232117 TI - Assessing the accuracy of improved force-matched water models derived from Ab initio molecular dynamics simulations. AB - The accuracy of water models derived from ab initio molecular dynamics simulations by means on an improved force-matching scheme is assessed for various thermodynamic, transport, and structural properties. It is found that although the resulting force-matched water models are typically less accurate than fully empirical force fields in predicting thermodynamic properties, they are nevertheless much more accurate than generally appreciated in reproducing the structure of liquid water and in fact superseding most of the commonly used empirical water models. This development demonstrates the feasibility to routinely parametrize computationally efficient yet predictive potential energy functions based on accurate ab initio molecular dynamics simulations for a large variety of different systems. (c) 2016 Wiley Periodicals, Inc. PMID- 27232116 TI - Efficacy and Safety Outcomes of Extended Criteria Donor Kidneys by Subtype: Subgroup Analysis of BENEFIT-EXT at 7 Years After Transplant. AB - The phase III Belatacept Evaluation of Nephroprotection and Efficacy as First Line Immunosuppression Trial-Extended Criteria Donors Trial (BENEFIT-EXT) study compared more or less intensive belatacept-based immunosuppression with cyclosporine (CsA)-based immunosuppression in recipients of extended criteria donor kidneys. In this post hoc analysis, patient outcomes were assessed according to donor kidney subtype. In total, 68.9% of patients received an expanded criteria donor kidney (United Network for Organ Sharing definition), 10.1% received a donation after cardiac death kidney, and 21.0% received a kidney with an anticipated cold ischemic time >=24 h. Over 7 years, time to death or graft loss was similar between belatacept- and CsA-based immunosuppression, regardless of donor kidney subtype. In all three donor kidney cohorts, estimated mean GFR increased over months 1-84 for belatacept-based treatment but declined for CsA-based treatment. The estimated differences in GFR significantly favored each belatacept-based regimen versus the CsA-based regimen in the three subgroups (p < 0.0001 for overall treatment effect). No differences in the safety profile of belatacept were observed by donor kidney subtype. PMID- 27232118 TI - Effects of temperature on the life cycle, expansion, and dispersion of Aedes aegypti (Diptera: Culicidae) in three cities in Paraiba, Brazil. AB - The mosquito Aedes aegypti is the primary vector of dengue and is common throughout tropical and subtropical regions. Its distribution is modulated by environmental factors, such as temperature. This study aimed to evaluate the influence of temperature on the life cycle and expansion of Ae. aegypti populations in the cities of Campina Grande, Joao Pessoa, and Patos. Samples of Ae. aegypti were collected in the three cities and raised in the laboratory. We assessed the life cycles of the three Ae. aegypti populations under six constant temperatures (16, 22, 28, 33, 36, and 39 degrees C), selected on the basis of historical temperature tendencies of each city. We also used existing climate data to calculate projected temperature increases for all three areas. Our results suggest that Campina Grande, Joao Pessoa, and Patos will experience, respectively, maximum temperature increases of 0.030 degrees C/year, 0.069 degrees C/year, and 0.061 degrees C/year, and minimum temperature increases of 0.019 degrees C/year, -0.047 degrees C/year, and -0.086 degrees C/year. These projected increases will result in temperatures favorable to the Ae. aegypti life cycle, causing rapid population growth. Therefore, Ae. aegypti populations are likely to expand in the mesoregions represented by these cities. PMID- 27232119 TI - Assessment of Aedes albopictus (Skuse) (Diptera: Culicidae) clutch size in wild and laboratory populations. AB - Aedes albopictus (Skuse) is an invasive mosquito species found across the southern U.S. with range expansion into many northern states. Intra- and interspecific larval competition have been evaluated for Ae. albopictus with respect to subsequent adult size, immature and adult survivability, and its capacity to vector pathogens as an adult. However, limited data are available on egg production as related to larval rearing conditions. Because Ae. albopictus is a container-inhabiting mosquito that oviposits in resource-limited habitats, it is found under variable density-dependent conditions. Therefore, we examined the impact of specific rearing conditions on Ae. albopictus clutch size and adult body size; comparing the egg production values and wing lengths from known developmental densities to those from field-collected populations. Field populations varied significantly among collection sites in mean clutch size (23 to 46). These clutch sizes were comparable to the mean clutch sizes of females reared at the larval densities of nine (20 eggs) and three (53 eggs) larvae per 3 ml of water in the laboratory. Field populations experienced density-dependent effects impacting adult mosquito size. Mosquitoes from the four sample sites had mean wing lengths of 1.99, 2.47, 2.51, and 2.54 mm, which were less than the mean wing length of mosquitoes reared at larval densities of three larvae per 3 ml of water (2.57 mm). PMID- 27232120 TI - Vertical oviposition activity of mosquitoes in the Atlantic Forest of Brazil with emphasis on the sylvan vector, Haemagogus leucocelaenus (Diptera: Culicidae). AB - This study aimed to assess the vertical patterns of oviposition and temporal changes in the distribution of mosquito species in an area of the Atlantic Forest in Rio de Janeiro State, Brazil, and in particular, the behavior and oviposition of potential yellow fever virus vectors. Mosquito samples were collected from the Ecological Reserve Guapiacu (REGUA, Brazil), which includes a somewhat disturbed forest, with a large diversity of plants and animals. In all, 5,458 specimens (ten species from seven genera) were collected. Haemagogus leucocelaenus was the most frequently captured species, representing 73% of the specimens collected. Species richness and diversity were the highest in the samples collected from the ground-level ovitraps and decreased with height. Species composition also differed significantly among heights. The largest species differences were detected between ovitraps set at the ground level and those set at 7 m and 9 m; Hg. leucocelaenus, Limatus durhamii, and Limatus paraensis contributed most to these differences. Sampling month and climatic variables had significant effects on species richness and diversity. Species diversity and richness decreased with height, suggesting that the conditions for mosquito breeding are more favorable closer to the ground. Species composition also showed vertical differences. PMID- 27232121 TI - What is the 'true' effect of Trypanosoma rangeli on its triatomine bug vector? AB - The phrase, "T. rangeli is pathogenic to its insect vector," is commonly found in peer-reviewed publications on the matter, such that it has become the orthodox view of this interaction. In a literature survey, we identified over 20 papers with almost the exact phrase and several others alluding to it. The idea is of particular importance in triatomine population dynamics and the study of vector borne T. cruzi transmission, as it could mean that triatomines infected with T. rangeli have lower fitness than uninfected insects. Trypanosoma rangeli pathogenicity was first observed in a series of studies carried out over fifty years ago using the triatomine species Rhodnius prolixus. However, there are few studies of the effect of T. rangeli on its other vector species, and several of the studies were carried out with R. prolixus under non-physiological conditions. Here, we re-evaluate the published studies that led to the conclusion that T. rangeli is pathogenic to its vector, to determine whether or not this indeed is the "true" effect of T. rangeli on its triatomine vector. PMID- 27232122 TI - Indirect evidence that agricultural pesticides select for insecticide resistance in the malaria vector Anopheles gambiae. AB - We investigated the possible relationship between the agricultural use of insecticides and the emergence of insecticide resistance. Bioassays were conducted using simulated mosquito larval habitats and well known Anopheles gambiae strains. Soil samples were collected from vegetable production areas in Benin, including one site with insecticide use, one site where insecticides had not been used for two months, and a third where insecticides had not been used. Pupation and emergence rates were very low in pyrethroid-susceptible strains when exposed to soil that had been recently exposed to insecticides. Pupation and emergence rates in strains with the kdr mutation alone or both the kdr and Ace-1 mutations were much higher. Overall, strains with the kdr mutation survived at higher rates compared to that without kdr mutation. Although this study is observational, we provide indirect evidence indicating that soils from agricultural areas contain insecticide residues that can play a role in the emergence of insecticide resistance in Anopheles. This aspect should be taken into account to better utilize the insecticide in the context of integrated pest management programs. PMID- 27232123 TI - Diversity of rickettsial pathogens in Columbian black-tailed deer and their associated keds (Diptera: Hippoboscidae) and ticks (Acari: Ixodidae). AB - Cervids host multiple species of ixodid ticks, other ectoparasites, and a variety of rickettsiae. However, diagnostic test cross-reactivity has precluded understanding the specific role of deer in rickettsial ecology. In our survey of 128 Columbian black-tailed deer (Odocoileus hemionus columbianus (Richardson)) and their arthropod parasites from two northern Californian herds, combined with reports from the literature, we identified four distinct Anaplasma spp. and one Ehrlichia species. Two keds, Lipoptena depressa (Say) and Neolipoptena ferrisi Bequaert, and two ixodid ticks, Ixodes pacificus Cooley and Kohls and Dermacentor occidentalis Marx, were removed from deer. One D. occidentalis was PCR-positive for E. chaffeensis; because it was also PCR-positive for Anaplasma sp., this is an Anaplasma/Ehrlichia co-infection prevalence of 4.3%. 29% of L. depressa, 23% of D. occidentalis, and 14% of deer were PCR-positive for Anaplasma spp. DNA sequencing confirmed A. bovis and A. ovis infections in D. occidentalis, A. odocoilei in deer and keds, and Anaplasma phagocytophilum strain WI-1 in keds and deer. This is the first report of Anaplasma spp. in a North America deer ked, and begs the question whether L. depressa may be a competent vector of Anaplasma spp. or merely acquire such bacteria while feeding on rickettsemic deer. PMID- 27232124 TI - Vector capacity of members of Triatoma brasiliensis species complex: The need to extend Chagas disease surveillance to Triatoma melanica. AB - We conducted a lab-based comparative study on vector capacity features of two species of triatomines: Triatoma brasiliensis and T. melanica. Both are members of the T. brasiliensis species complex. The former is the most important Chagas disease vector in the northeastern region of Brazil. To date, no transmission via T. melanica has been recorded. Immature insects exhibited distinct intermoult periods without a direct relationship to a given species. Females of T. brasiliensis consumed an average of 1.9 times more meals (mean = 12.92 vs 6.63) and survived for a shorter period (mean =330.8 days) than T. melanica (mean = 365.2 days), probably due to the cost of reproduction (all significant at P<0.05). These data support the idea that T. brasiliensis is more adapted to lab conditions and is more able to infest domiciles than T. melanica. We also found significant distinctions in other features between these species, such as the elapsed time without eating before molting, which was higher for the second, third, and fifth nymph stages of T. melanica. Regarding features analyzed related to vector capacity, insects of all life stages of both species were considered competent to transmit Trypanosoma cruzi because they needed many feedings (mean =1.5-3.82) to moult and because a high proportion (>39%) of insects defecated rapidly (<30 s) after feeding. Overall, results highlight the need to extend vector surveillance to T. melanica. PMID- 27232125 TI - Desiccation survival time for eggs of a widespread and invasive Australian mosquito species, Aedes (Finlaya) notoscriptus (Skuse). AB - The Australian native mosquito Aedes (Finlaya) notoscriptus (Skuse) is closely associated with natural and artificial water holding receptacles. Eggs are laid in habitats where they are exposed to drying conditions as water levels fluctuate. Withstanding desiccation enables survival in challenging environments and increases the potential for establishment in non-native habitats. Until now, the desiccation resistance of Ae. notoscriptus eggs has been unknown despite the historical invasive success of this important dog heartworm and arbovirus vector. Viability and mean survival times of eggs from two Ae. notoscriptus populations (metropolitan areas of Sydney, NSW and Adelaide, SA) were evaluated, with eggs stored under three dryness conditions for up to 367 days. Our results revealed that Ae. notoscriptus eggs can withstand desiccation for extended periods, under a variety of conditions, with approximately 9-13% egg viability recorded after one year. This prolonged egg survival reflects the widespread distribution of this mosquito in Australia and its history of incursions and subsequent establishment in non-native habitats. Differences in mean egg volume were recorded in addition to significantly different egg length to width ratios for the two populations, which may reflect adaptation to biotope of origin and an associated likelihood of drought and drying conditions. The results of this study suggest that the desiccation resistant eggs of Ae. notoscriptus make this species highly adaptable, increasing the risk of movement to non-endemic regions of the world. PMID- 27232126 TI - Assessment of esterase gene expression as a risk marker for insecticide resistance in Florida Culex nigripalpus (Diptera: Culicidae). AB - Esterases are enzymatic proteins known to play a role in insecticide resistance formation. To further our understanding of the development of insecticide resistance, we tested the gene expression level of a gene implicated in insecticide resistance (Temsha est-1) from Culex nigripalpus Theobald (Diptera: Culicidae) in field mosquitoes. We found that the level of expression of TE-1 differed depending on the frequency of exposure to organophosphate insecticide through expression studies. Temsha est-1 cDNA is 1,808 base pairs and fully sequenced with up to 96% nucleotide sequence identity to esterase B genes of other mosquito species. The genes from five different species, including TE-1, were closely related by genetic distance and phylogenetic analysis. Differential expression of this gene that is correlated to differences in susceptibility towards organophosphate would provide the ability to use Temsha est-1 as an indicator of the formation of tolerance/resistance. This would greatly enhance mosquito control efforts by allowing targeted application of insecticides to mosquito populations that are most susceptible. Also, it would provide resistance information so that a rational design could be used for insecticide rotation schedules. PMID- 27232127 TI - Population differentiation of the Chagas disease vector Triatoma maculata (Erichson, 1848) from Colombia and Venezuela. AB - The emerging vector of Chagas disease, Triatoma maculata (Hemiptera, Reduviidae), is one of the most widely distributed Triatoma species in northern South America. Despite its increasing relevance as a vector, no consistent picture of the magnitude of genetic and phenetic diversity has yet been developed. Here, several populations of T. maculata from eleven Colombia and Venezuela localities were analyzed based on the morphometry of wings and the mitochondrial NADH dehydrogenase subunit 4 (ND4) gene sequences. Our results showed clear morphometric and genetic differences among Colombian and Venezuelan populations, indicating high intraspecific diversity. Inter-population divergence is suggested related to East Cordillera in Colombia. Analyses of other populations from Colombia, Venezuela, and Brazil from distinct eco-geographic regions are still needed to understand its systematics and phylogeography as well as its actual role as a vector of Chagas disease. PMID- 27232128 TI - Suitability of monotypic and mixed diets for Anopheles hermsi larval development. AB - The developmental time and survival to eclosion of Anopheles hermsi Barr & Guptavanij fed monotypic and mixed diets of ten food types were examined in laboratory studies. Larvae fed monotypic diets containing animal detritus (freeze dried rotifers, freeze-dried Daphnia pulicaria, and TetraMin(r) fish food flakes) and the mixotrophic protistan Cryptomonas ovata developed faster and survived better than larvae that were fed other monotypic diets. Survival to adulthood of larvae fed several concentrations of the diatom Planothidium (=Achnanthes) lanceolatum was poor (<13%) and larval development time was approximately twice that of larvae fed TetraMin(r) fish food flakes, the standard laboratory diet. Larvae fed monotypic diets containing prokaryotes (bacteria [Bacillus cereus] and cyanobacteria [Oscillatoria prolifera]) and brewer's yeast (Saccharomyces cerevisiae) failed to survive beyond the 1(st) and 2(nd) instar, respectively. Larvae fed only chlorophytes, single-celled Chlamydomonas reinhardtii and filamentous Spirogyra communis, failed to complete larval development, regardless of the concentration tested. Cohorts fed a combination of food types (mixed diets) usually developed better than cohorts fed monotypic diets. Food types that failed to support complete development when fed alone often facilitated development to adulthood when fed in combination with food types containing >1% C20 polyunsaturated fatty acids as total fat, but regardless of essential fatty acid content, algae that produced mucilage and filaments that sank out of the feeding zone were poor quality diets. PMID- 27232129 TI - Active dispersal of Triatoma infestans and other triatomines in the Argentinean arid Chaco before and after vector control interventions. AB - Peridomestic structures are considered the main sites where Triatoma infestans (Hemiptera: Reduviidae) remain and disperse, representing the first risk factor for intradomestic invasion, even after vector control activities. This study analyzed T. infestans dispersal during vector control interventions in six rural houses of the arid Chaco (La Rioja, Argentina). Flying and walking dispersers were captured during five months of two consecutive warm seasons after insecticide spraying of intra- and peridomiciles. These data were compared with previous published data in the same scenario but without insecticide spraying in peridomiciles. Recorded climatic conditions were favorable for active dispersion during the study. Total number of T. infestans dispersers moving among domestic habitats decreased after insecticide spraying. Sylvatic triatomines T. guasayana, T. eratyrusiformis, T. garciabesi, and T. platensis, not targeted by insecticide spraying, were captured simultaneously within peridomestic areas and showed higher invasion pressure than T. infestans. Adult T. infestans peridomestic populations showed high nutritional status, indicating low dispersion probability. Some peridomiciles remained infested at the end of the study. However, no intradomiciles were recolonized. These results suggest that there is a low probability of intradomestic recolonization by active dispersion from peridomiciles during 15 months post-spraying. PMID- 27232130 TI - Invasion of rural houses by wild Triatominae in the arid Chaco. AB - Triatomines are the vectors of Trypanosoma cruzi, the etiologic agent of Chagas disease, the main endemic disease affecting five to seven million people in Latin America. Besides Triatoma infestans, the most important T. cruzi vector in the Gran Chaco region, other triatomine species associated with sylvatic birds and mammals are responsible for the maintenance of the wild cycle of T. cruzi. The present study aimed at evaluating the house invasion by sylvatic triatomine species in rural communities of the Los Llanos region (La Rioja, Argentina) and its association with environmental variables. House invasion by flying adult triatomines was recorded by trained collectors that surveyed over 377 houses distributed over 73 localities in a 56,600 km(2) study region, between October, 2014 and February, 2015. The result of the study showed the frequent house invasion by adult triatomines: 26.3% houses were infested in 53% of the localities. Seven sylvatic triatomine species were collected, with T. guasayana and T. garciabesi among the most abundant. House invasion by triatomine species showed no spatial aggregation and was not associated with temperature, precipitation, or vegetation cover at the spatial scale considered in the present study. House invasion by the epidemiologically important T. infestans is a concern of rural communities. Besides constituting a latent, although low, risk, the presence of these species negatively interferes with the vigilance activities of the provincial Chagas disease program. PMID- 27232131 TI - Spatial distribution of sand fly species (Psychodidae: Phlebtominae), ecological niche, and climatic regionalization in zoonotic foci of cutaneous leishmaniasis, southwest of Iran. AB - Cutaneous leishmaniasis (CL) is a complex vector-borne disease caused by Leishmania parasites that are transmitted by the bite of several species of infected female phlebotomine sand flies. Monthly factor analysis of climatic variables indicated fundamental variables. Principal component-based regionalization was used for recognition of climatic zones using a clustering integrated method that identified five climatic zones based on factor analysis. To investigate spatial distribution of the sand fly species, the kriging method was used as an advanced geostatistical procedure in the ArcGIS modeling system that is beneficial to design measurement plans and to predict the transmission cycle in various regions of Khuzestan province, southwest of Iran. However, more than an 80% probability of P. papatasi was observed in rainy and temperate bio climatic zones with a high potential of CL transmission. Finding P. sergenti revealed the probability of transmission and distribution patterns of a non native vector of CL in related zones. These findings could be used as models indicating climatic zones and environmental variables connected to sand fly presence and vector distribution. Furthermore, this information is appropriate for future research efforts into the ecology of Phlebotomine sand flies and for the prevention of CL vector transmission as a public health priority. PMID- 27232132 TI - Infestation and seasonal activity of Ixodes vespertilionis Koch, 1844 (Acari: Ixodidae) on the Maghreb mouse-eared bat, Myotis punicus Felten, 1977, in northeastern Algeria. AB - Infestation of Ixodes vespertilionis Koch, 1844 on Myotis punicus Felten, 1977 from two sites (Trios Tunnel and Sidi Trad cave) in northeastern Algeria was studied. An overall infestation of 41.4% for all stages was found among bats collected from both sites. By stage, a total of eight females, 70 nymphs, and 107 larvae were recovered from both populations. The number of females recovered per bat at Sidi Trad ranged from 0-1, for nymphs 0-2, and for larvae 0-2. While no female ticks were collected at Trios Tunnel, the number of nymphs ranged from 0-2 and for larvae 0-2. At Trios Tunnel, the number of nymphs was significantly higher during April and June but not for July and September. On the other hand, the number of larvae increased from July to November, while at Sidi Trad cave, female ticks were recovered during April and May and then disappeared until the end of the study period. Significant differences were noted during all the months when compared with all stages. Nymphs infested bats significantly during April and May, declined in June and July, and then became steady until October. Larvae peaked in July, with low frequency in April, and then fluctuated from August to November. PMID- 27232133 TI - Fine-scale distribution modeling of avian malaria vectors in north-central Kansas. AB - Infectious diseases increasingly play a role in the decline of wildlife populations. Vector-borne diseases, in particular, have been implicated in mass mortality events and localized population declines are threatening some species with extinction. Transmission patterns for vector-borne diseases are influenced by the spatial distribution of vectors and are therefore not uniform across the landscape. Avian malaria is a globally distributed vector-borne disease that has been shown to affect endemic bird populations of North America. We evaluated shared habitat use between avian malaria vectors, mosquitoes in the genus Culex and a native grassland bird, the Greater Prairie-Chicken (Tympanuchus cupido), by (1) modeling the distribution of Culex spp. occurrence across the Smoky Hills of north-central Kansas using detection data and habitat variables, (2) assessing the occurrence of these vectors at nests of female Greater Prairie-Chickens, and (3) evaluating if shared habitat use between vectors and hosts is correlated with malarial infection status of the Greater Prairie-Chicken. Our results indicate that Culex occurrence increased at nest locations compared to other available but unoccupied grassland habitats; however the shared habitat use between vectors and hosts did not result in an increased prevalence of malarial parasites in Greater Prairie-Chickens that occupied habitats with high vector occurrence. We developed a predictive map to illustrate the associations between Culex occurrence and infection status with malarial parasites in an obligate grassland bird that may be used to guide management decisions to limit the spread of vector-borne diseases. PMID- 27232134 TI - Bioinsecticide and leaf litter combination increases oviposition and reduces adult recruitment to create an effective ovitrap for Culex mosquitoes. AB - Mosquito egg traps, aquatic habitats baited with oviposition attractant and insecticide, are important tools for surveillance and control efforts in integrated vector management programs. The bioinsecticide Bacillus thuringiensis subsp. israelensis (Bti) is increasingly used as an environmentally friendly alternative to chemical insecticides and the combination of Bti with a simple oviposition attractant like leaf litter to create an effective egg trap seems appealing. However, previous research suggests that Bti may itself alter oviposition, and that leaf litter may dramatically reduce Bti toxicity. Here we present results from field experiment designed to link the effects of litter and Bti on mosquito oviposition habitat selection and post-colonization survival to production of adult mosquitoes. Tripling litter increased Culex spp. oviposition nearly nine-fold, while Bti had no effect on oviposition. Neither factor altered egg survival, thus larval abundance reflected the effects of litter on oviposition. Both Bti and litter reduced larval survival by ~60%. We found no evidence that increased litter reduced Bti toxicity. Adult production was dependent upon both litter and Bti. In the absence of Bti, effects of litter on oviposition translated into three-fold more adults. However, in the presence of Bti, initial increases in oviposition were erased by the combined negative effects of Bti and litter on post-colonization survival. Thus, our study provides field evidence that combined litter and Bti application creates an effective ovitrap. This combined treatment had the highest oviposition and the lowest survival, and thus removed the greatest number of mosquitoes from the landscape. PMID- 27232135 TI - Hyalomma ticks on northward migrating birds in southern Spain: Implications for the risk of entry of Crimean-Congo haemorrhagic fever virus to Great Britain. AB - Crimean-Congo haemorrhagic fever virus (CCHFV) is a zoonotic virus transmitted by Hyalomma ticks, the immature stages of which may be carried by migratory birds. In this study, a total of 12 Hyalomma ticks were recovered from five of 228 migratory birds trapped in Spring, 2012 in southern Spain along the East Atlantic flyway. All collected ticks tested negative for CCHFV. While most birds had zero Hyalomma ticks, two individuals had four and five ticks each and the statistical distribution of Hyalomma tick counts per bird is over-dispersed compared to the Poisson distribution, demonstrating the need for intensive sampling studies to avoid underestimating the total number of ticks. Rates of tick exchange on migratory birds during their northwards migration will affect the probability that a Hyalomma tick entering Great Britain is positive for CCHFV. Drawing on published data, evidence is presented that the latitude of a European country affects the probability of entry of Hyalomma ticks on wild birds. Further data on Hyalomma infestation rates and tick exchange rates are required along the East Atlantic flyway to further our understanding of the origin of Hyalomma ticks (i.e., Africa or southern Europe) and hence the probability of entry of CCHFV into GB. PMID- 27232136 TI - Comparative egg morphology of six Meccus species and Triatoma recurva (Stal, 1868) Hemiptera: Reduviidae. AB - We investigated the morphology and morphometry of eggs from the colonies of the Entomology Laboratory at ENCB-IPN belonging to six species of the genus Meccus and Triatoma recurva, using both light and scanning electron microscopy. Egg ornamentation is an important parameter to consider in the differentiation of species. Samples were observed under a scanning electron microscope. Measurements of fifty eggs per species included length, width, and opercular diameter, which were used for the morphometric analysis. The results showed that the seven species display a polygonal ornamentation dominated by hexagons; the operculum shows also a polygonal ornamental characteristic in each species. Morphometry provided valuable information for discriminating between closely related species of the genus Meccus and Triatoma recurva, a species akin to this group, thereby facilitating the complete discrimination of these species. PMID- 27232137 TI - Effects of diapause and cold acclimation on egg ultrastructure: new insights into the cold hardiness mechanisms of the Asian tiger mosquito Aedes (Stegomyia) albopictus. AB - The Asian tiger mosquito, Aedes albopictus (Diptera: Culicidae, SKUSE), is an important threat to public health due to its rapid spread and its potential as a vector. The eggs of Ae. albopictus are the most cold resistant life stage and thus, the cold hardiness of eggs is used to predict the future occurrence of the species in distribution models. However, the mechanism of cold hardiness has yet to be revealed. To address this question, we analyzed the layers of diapausing and cold acclimatized eggs of a temperate population of Ae. albopictus in a full factorial test design using transmission electron microscopy. We reviewed the hypotheses that a thickened wax layer or chorion is the cause of cold hardiness but found no evidence. As a result of the induced diapause, the thickness of the dark endochorion as a layer of high electron density and thus an assumed location for waxes was decreasing. We therefore hypothesized a qualitative alteration of the wax layer due to compaction. Cold acclimation was causing an increase in the thickness of the middle serosa cuticle indicating a detachment of serosa membrane from the endochorion as a potential adaptation strategy to isolate inoculating ice formations in the inter-membranous space. PMID- 27232138 TI - Distribution pattern and genetic structure of Aedes zammitii (Diptera: Culicidae) along the Mediterranean and Aegean coasts of Turkey. AB - The Mariae species complex, consisting of Aedes mariae, Aedes phoeniciae, and Aedes zammitii, has a limited distribution worldwide. All three species are found in rocky habitats on the coastal areas of Mediterranean countries. Aedes phoeniciae and Ae. zammitii are two members of the Mariae complex that exist in Turkey. The aim of this study was to determine the distribution pattern and genetic structure of Ae. zammitii along the Mediterranean and Aegean regions. For this purpose, larval and adult samples of Ae. zammitii were collected from 19 different rocky habitats along the coastal regions of Antalya, Mugla, Aydin, Izmir, Balikesir, and Canakkale provinces. DNA isolation was performed primarily from collected samples, and mitochondrial NADH dehydrogenase 4 (ND4) gene was amplified by polymerase chain reaction. Based on ND4 sequence analyses, 21 haplotypes were detected along the distribution range of the species. Analyses of molecular variance (AMOVA) and spatial analyses of molecular variance (SAMOVA) indicated six groups, and most of the variation was among groups, demonstrating the population structuring at group level. Isolation by distance analyses (IBD) showed a correlation between geographic and genetic distances. PMID- 27232139 TI - Genetic and phenotypic variation in central and northern European populations of Aedes (Aedimorphus) vexans (Meigen, 1830) (Diptera, Culicidae). AB - The floodwater mosquito Aedes vexans can be a massive nuisance in the flood plain areas of mainland Europe, and is the vector of Tahyna virus and a potential vector of Dirofilaria immitis. This epidemiologically important species forms three subspecies worldwide, of which Aedes vexans arabiensis has a wide distribution in Europe and Africa. We quantified the genetic and phenotypic variation in Ae. vexans arabiensis in populations from Sweden (northern Europe), Hungary, and Serbia (central Europe). A landscape genetics approach (FST , STRUCTURE, BAPS, GENELAND) revealed significant differentiation between northern and southern populations. Similar to genetic data, wing geometric morphometrics revealed two different clusters, one made by Swedish populations, while another included Hungarian and Serbian populations. Moreover, integrated genetic and morphometric data from the spatial analysis suggested groupings of populations into three clusters, one of which was from Swedish and Hungarian populations. Data on spatial analysis regarding an intermediate status of the Hungarian population was supported by observed Isolation-by-Distance patterns. Furthermore, a low proportion of interpopulation vs intrapopulation variance revealed by AMOVA and low-to-moderate FST values on a broader geographical scale indicate a continuous between-population exchange of individuals, including considerable gene flow on the regional scale, are likely to be responsible for the maintenance of the observed population similarity in Ae. vexans. We discussed data considering population structure in the light of vector control strategies of the mosquito from public health importance. PMID- 27232140 TI - DNA-based identification and OspC serotyping in cultures of Borrelia burgdorferi s.l. isolated from ticks collected in the Moravia (Czech Republic). AB - Two different genetic loci, flaB and ospC, were employed to assign genospecies and OspC phylogenetic type to 18 strains isolated from ticks collected in Pisarky, a suburban park in the city of Brno, Czech Republic. The RFLP analysis revealed three different genospecies (B. afzelii, B. garinii, and B. valaisiana). Three samples from the collection contained more than one genospecies. In the other 15 strains, nucleotide sequences of flaB and ospC were determined. The following phylogenetic analysis assigned 12 isolates to genospecies B. garinii and three to B. afzelii. These isolates were further subdivided into seven distinct ospC groups. The most related OspC types were G2, G4, and G5 (B. garinii) and A3 and A8 (B. afzelii). PMID- 27232141 TI - Detection of African horse sickness virus in Culicoides imicola pools using RT qPCR. AB - African horse sickness (AHS) is an infectious, non-contagious arthropod-borne disease of equids, caused by the African horse sickness virus (AHSV), an orbivirus of the Reoviridae family. It is endemic in sub-Saharan Africa and thought to be the most lethal viral disease of horses. This study focused on detection of AHSV in Culicoides imicola (Diptera: Ceratopogonidae) pools by the application of a RT-qPCR. Midges were fed on AHSV-infected blood. A single blood engorged female was allocated to pools of unfed nulliparous female midges. Pool sizes varied from 1 to 200. RNA was extracted and prepared for RT-qPCR. The virus was successfully detected and the optimal pool size for the limit of detection of the virus was determined at a range between 1 to 25. Results from this investigation highlight the need for a standardized protocol for AHSV investigation in Culicoides midges especially for comparison among different studies and for the determination of infection rate. PMID- 27232143 TI - A taxonomic checklist of the mosquitoes of Harris County, Texas. PMID- 27232142 TI - Sand flies on Parana River Islands and natural infection of Nyssomyia neivai by Leishmania in southern Brazil. PMID- 27232144 TI - The spread of Culex coronator (Diptera: Culicidae) throughout Florida. PMID- 27232145 TI - An effective sampling tool for adult crabhole inhabiting Deinocerites mosquitoes. PMID- 27232146 TI - Synthesis and structure of new tetracopper(II) complexes with N-benzoate-N'-[3 (diethylamino)propyl]oxamide as a bridging ligand: The influence of hydrophobicity on enhanced DNA/BSA-binding and anticancer activity. AB - Two new tetracopper(II) complexes bridged by N-benzoate-N'-[3 (diethylamino)propyl]oxamide (H3bdpox), and ended with 4,4'-dimethyl-2,2' bipyridine (Me2bpy) or 2,2'-bipyridine (bpy), namely [Cu4(bdpox)2(Me2bpy)2](pic)2 (1) and [Cu4(bdpox)2(bpy)2](pic)2.2H2O (2) (where pic denotes the picrate anion) have been synthesized and characterized by X-ray single-crystal diffraction and other methods. In both complexes, four copper(II) ions are bridged alternately by the cis-oxamido and the carboxylato groups of two bdpox(3-) ligands to form a centrosymmetric cyclic tetranuclear cation, in which, the copper(II) ions at the endo- and exo-sites of cis-bdpox(3-) ligand have square-planar and square pyramidal coordination geometries, respectively. The reactivity towards DNA/BSA suggests that these complexes can interact with HS-DNA through the intercalation mode and the binding affinity varies as 1>2 depending on the hydrophobicity, and effectively quench the fluorescence of protein BSA via a static mechanism. In vitro anticancer activities showed that the two complexes are active against the selected tumor cell lines, and the anticancer activities are consistent with their DNA-binding affinity. PMID- 27232147 TI - Modulation of gamma-irradiation and carbon tetrachloride induced oxidative stress in the brain of female rats by flaxseed oil. AB - The activity of flaxseed oil (FSO) on gamma-irradiation (7Gy) and/or carbon tetrachloride (CCl4) induced acute neurotoxicity in rats' brain was investigated. The results revealed a significant decrease (p<0.05) in superoxide dismutase (SOD), catalase (CAT), glutathione-peroxidase (GSH-Px) activities, reduced glutathione (GSH) and manganese (Mn) contents. Further, a significant elevation (p<0.05) in malondialdehyde, nitric oxide (NO), Tumor Necrosis Factor-alpha (TNF alpha), Interleukin-1-beta (IL-1beta), Interleukin-6 (IL-6), transforming growth factor-beta-1 (TGF-beta1), iron (Fe), calcium (Ca), copper (Cu) and magnesium (Mg) levels were observed. Furthermore, the relative ratio of xanthine oxidase (XO) and inducible nitric-oxide synthase (iNOS) gene expression levels were elevated in the brain tissues of gamma-irradiated and CCl4 intoxicated animals. Those effects were augmented due to the effect of CCl4-induced toxicity in gamma irradiated rats. The treatment of FSO displayed significant amendment of the studied parameters in the brain tissues of gamma-irradiated and CCl4 intoxicated animals. FSO has a neuroprotective effect against CCl4-induced brain injury in gamma-irradiated rats. This effect is interrelated to the ability of FSO to scavenges the free radicals, enhances the antioxidant enzymes activity, increases GSH contents, down-regulates the inflammatory responses, ameliorates the iron, calcium, copper, magnesium, manganese levels and inhibiting the gene expression level of XO and iNOS in the brain tissues of intoxicated animals. In conclusion, this study demonstrated that the potent antioxidant and anti-inflammatory activities of FSO have the ability to improve the antioxidant status, suppress the inflammatory responses, and regulate the trace elements in the brain tissues of gamma-irradiated, CCl4, and their combined effect in intoxicated animals. Consequently, FSO exhibited neuroprotective activity on gamma-irradiated, CCl4, and their combined effect induced brain injury in rats. PMID- 27232148 TI - Photodynamic evaluation of tetracarboxy-phthalocyanines in model systems. AB - The present work reports the synthesis, photophysical and photochemical characterization and photodynamic evaluation of zinc, aluminum and metal free base tetracarboxy-phthalocyanines (ZnPc, AlPc and FbPc, respectively). To evaluate the possible application of phthalocyanines as a potential photosensitizer the photophysical and photochemical characterization were performed using aqueous (phosphate-buffered solution, PBS) and organic (dimethyl sulfoxide, DMSO) solvents. The relative lipophilicity of the compounds was estimated by the octanol-water partition coefficient and the photodynamic activity evaluated through the photooxidation of a protein and photohemolysis. The photooxidation rate constants (k) were obtained and the hemolytic potential was evaluated by the maximum percentage of hemolysis achieved (Hmax) and the time (t50) to reach 50% of the Hmax. Although these phthalocyanines are all hydrophilic and possess very low affinity for membranes (log PO/W=-2.0), they led to significant photooxidation of bovine serum albumin (BSA) and photohemolysis. Our results show that ZnPc was the most efficient photosensitizer, followed by AlPc and FbPc; this order is the same as the order of the triplet and singlet oxygen quantum yields (ZnPc>AlPc>FbPc). Furthermore, together, the triplet, fluorescence and singlet oxygen quantum yields of zinc tetracarboxy phthalocyanines suggest their potential for use in theranostic applications, which simultaneously combines photodiagnosis and phototherapy. PMID- 27232149 TI - 20 years experience with appendicovesicostomy in paediatric patients: Complications and their re-interventions. AB - AIMS: To evaluate the long-term outcome of appendicovesicostomies and to present the frequency and timing of complications needing re-intervention. METHODS: In this retrospective study we included patients in whom an appendicovesicostomy was created at our institution between 1993 and 2011. Patients with a follow-up less than 1 year were excluded. Patient characteristics and conduit-related complications requiring re-intervention were collected. RESULTS: One hundred and twenty-eight patients were included with mean age at initial surgery of 10.1 +/- 3.9 years. Two thirds of the children had underlying neurogenic disease. The mean follow-up was 10.1 +/- 4.8 years. All but one patient continued to use the catheterizable channel. Re-intervention for conduit-related complications was necessary in 32.0% of the patients. A second, third, and fourth re-intervention was required in respectively 10.9%, 2.3%, and 1.6%. The commonest complications were cutaneous/fascial stenosis in 14.8%, stenosis at conduit-bladder level in 9.4%, and stomal incontinence in 6.3% of the patients. The most performed re interventions were stoma revision (in 16.4% of the patients), conduit revision (10.2%), and dilatation of a stenotic tract (4.7%). 63.3% of the re-interventions was superficial and/or endoscopic. The peak incidence of re-interventions was in the 1st year after conduit construction and decreased yearly. CONCLUSIONS: Our study gives an overview of patients and their conduits developing from prepubertal children to young adults. During a mean follow-up of 10.1 years, roughly one third of the patients needed a re-intervention. We conclude that an appendicovesicostomy is an effective and durable treatment for whom transurethral clean intermittent catheterization is not feasible. Neurourol. Urodynam. 36:1325 1329, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27232150 TI - Ultrapressure liquid chromatography-tandem mass spectrometry assay using atmospheric pressure photoionization (UPLC-APPI-MS/MS) for quantification of 4 methoxydiphenylmethane in pharmacokinetic evaluation. AB - 4-Methoxydiphenylmethane (4-MDM), a selective augmenter of Leukotriene A4 Hydrolase (LTA4H), is a new anti-inflammatory compound for potential treatment of chronic obstructive pulmonary disease (COPD). Currently, there is no liquid chromatography tandem mass spectrometric (LC-MS/MS) method for the quantification of 4-MDM. A major barrier for developing the LC-MS/MS method is the inability of electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) to ionize 4-MDM due to its hydrophobicity and lack of any functional group for ionization. With the advent of atmospheric pressure photoionization (APPI) technique, many hydrophobic compounds have been demonstrated to ionize by charge transfer reactions. In this study, a highly sensitive ultrapressure liquid chromatography tandem mass spectrometry assay using atmospheric pressure photoionization (UPLC-APPI-MS/MS) for the quantifications of 4-MDM in rat plasma has been developed and validated. 4-MDM was extracted from the plasma by solid phase extraction (SPE) and separated chromatographically using a reverse phase C8 column. The photoionization (PI) was achieved by introducing anisole as a dopant to promote the reaction of charge transfer. The assay with a linear range of 5 (LLOQ)-400ngmL(-1) met the regulatory requirements for accuracy, precision and stability. The validated assay was employed to quantify the plasma concentrations of 4-MDM after an oral dosing in Sprague Dawley (SD) rats. PMID- 27232151 TI - Identification and quantification of psychoactive drugs in whole blood using dried blood spot (DBS) by ultra-performance liquid chromatography tandem mass spectrometry. AB - A procedure based on ultra-high-pressure liquid chromatography tandem mass spectrometry has been developed for the determination of twenty three psychoactive drugs and metabolites in whole blood using dried blood spot (DBS). Chromatographic separation was achieved at ambient temperature using a reverse phase column and a linear gradient elution with two solvents: 0.1% formic acid in acetonitrile and 5mM ammonium formate at pH 3. The mass spectrometer was operated in positive ion mode, using multiple reaction monitoring via positive electro spray ionization. The method was linear from the limit of quantification (5ng/ml for all the analytes apart from 15ng/ml for Delta-9-tetrahydrocannabinol and metabolites) to 500ng/ml, and showed good correlation coefficients (r(2)=0.990) for all substances. Analytical recovery of analytes under investigation was always higher than 75% and intra-assay and inter-assay precision and accuracy always better than 15%. Using the validated method, ten DBS samples, collected at the hospital emergency department in cases of acute drug intoxication, were found positive to one or more psychoactive drugs. Our data support the potential of DBS sampling for non invasive monitoring of exposure/intoxication to psychoactive drugs. PMID- 27232152 TI - Development and validation of sensitive and rapid UPLC-MS/MS method for quantitative determination of daclatasvir in human plasma: Application to a bioequivalence study. AB - A rapid and sensitive UPLC-MS/MS method was developed and validated for determination of daclatasvir (DAC) in human plasma using sofosbuvir (SOF) as an internal standard (IS). The Xevo TQD LC-MS/MS was operated under the multiple reaction monitoring mode using electrospray ionization. Precipitation with acetonitrile was used in sample preparation. The prepared samples were chromatographed on Acquity UPLC HSS C18 (50*2.1mm, 1.8MUm) column by pumping 10mM ammonium formate (pH 3.5) and acetonitrile in an isocratic mode at a flow rate of 0.30ml/min. Method validation was performed as per the FDA guidelines and the standard curves were found to be linear in the range of 5-4000ng/ml for DAC. The intra-day and inter-day precision and accuracy results were within the acceptable limits. A very short run time of 1.2min made it possible to analyze more than 500 human plasma samples per day. The wider range of quantification of DAC allowed the applicability of the developed method for its determination in a bioequivalence study in human volunteers. PMID- 27232153 TI - A rapid and sensitive LC-MS/MS method for determination of lercanidipine in human plasma and its application in a bioequivalence study in Chinese healthy volunteers. AB - A rapid and highly sensitive liquid chromatography-tandem mass spectrometry (LC MS/MS) method has been developed and validated for the determination of lercanidipine (LER) in human plasma. The plasma sample was deproteinized with methanol after addition of diazepam (internal standard, IS) and separated on a 38 degrees C Hedera ODS-2 analytical column with a mobile phase of methanol and 5mM ammonium acetate buffer solution containing 0.1% formic acid at an isocratic flow rate of 400MUL/min. The detection was performed on an API 4000 tandem mass spectrometer coupled with electrospray ionization (ESI) source in positive ESI mode. Quantification was conducted by multiple reaction monitoring (MRM) of the transitions of m/z 612.2->280.2 for LER and m/z 285.1->193.1 for IS, respectively. The method exhibited high sensitivity (LLOQ of 0.015ng/mL) and good linearity over the concentration range of 0.015-8.0ng/mL. No matrix effect and carry-over effect were observed. The values on both the occasions (intra- and inter-day) were all within 15% at three concentration levels. This robust method was successfully applied in a bioequivalence study to evaluate the pharmacokinetics of LER in 59 healthy male Chinese volunteers after a single oral administration of 10mg LER. PMID- 27232154 TI - The first reported fatality associated with the synthetic opioid 3,4-dichloro-N [2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) and implications for forensic analysis. PMID- 27232155 TI - Alkene Epoxidation Catalyzed by Ti-Containing Polyoxometalates: Unprecedented beta-Oxygen Transfer Mechanism. AB - A DFT study revealed that the mechanism of alkene epoxidation with hydrogen peroxide catalyzed by Ti-containing polyoxometalates (POMs) depends on the Ti coordination environment: For rigid and hindered Ti centers, the unprecedented beta-oxygen transfer from the titanium hydroperoxo species becomes favored over the alpha-oxygen one. Improving the model for catalyst description, the calculations were able to reproduce the Arrhenius activation energy values determined in kinetic studies. Unlike protonation, the possible ion-pairing between POMs and countercations has a minor effect on the electrophlicity of the catalyst and, consequently, on the activity of epoxidation. PMID- 27232156 TI - Synthesis of 2-Sulfenylindenones via One-Pot Tandem Meyer-Schuster Rearrangement and Radical Cyclization of Arylpropynols with Disulfides. AB - A tandem annulation of arylpropynols with disulfides has been developed for the synthesis of 2-sulfenylindenone derivatives. The reaction pathway involves one pot tandem Meyer-Schuster rearrangement of arylpropynols and successive radical cyclization with disulfides. Various arylpropynols and disulfides with a number of functional groups are compatible in this reaction that affords the corresponding 2-sulfenylindenones in moderate to good yields. PMID- 27232158 TI - Aryl-Allene Cyclization via a Hg(OTf)2-Catalytic Pathway. AB - Hg(OTf)2-catalyzed aryl-allene cyclization accompanied by formation of a quaternary carbon center has been realized. Deuterium-labeling experiments and computational modeling were used to propose a novel catalytic pathway involving direct H-transfer from the aromatic ring to the vinyl mercury moiety followed by mercury 1,2-migration. PMID- 27232157 TI - Prognostic significance of monocarboxylate transporter expression in oral cavity tumors. AB - BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of cancer. The majority of patients present advanced stage disease and has poor survival. Therefore, it is imperative to search for new biomarkers and new alternative and effective treatment options. Most cancer cells rely on aerobic glycolysis to generate energy and metabolic intermediates. This phenotype is a hallmark of cancer, characterized by an increase in glucose consumption and production of high amounts of lactate. Consequently, cancer cells need to up regulate many proteins and enzymes related with the glycolytic metabolism. Thus, the aim of this study was to characterize metabolic phenotype of oral cavity cancers (OCC) by assessing the expression pattern of monocarboxylate transporters (MCTs) 1, 2 and 4 and other proteins related with the glycolytic phenotype. MATERIAL AND METHODS: We evaluated the immunohistochemical expression of MCT1, MCT4, CD147, GLUT1 and CAIX in 135 human samples of OCC and investigated the correlation with clinicopathological parameters and the possible association with prognosis. RESULTS: We observed that all proteins analyzed presented significantly higher plasma membrane expression in neoplastic compared to non neoplastic samples. MCT4 was significantly associated with T-stage and advanced tumoral stage, while CD147 was significantly correlated with histologic differentiation. Interestingly, tumors expressing both MCT1 and MCT4 but negative for MCT2 were associated with shorter overall survival. CONCLUSION: Overexpression of MCT1/4, CD147, GLUT1 and CAIX, supports previous findings of metabolic reprograming in OCC, warranting future studies to explore the hyper glycolytic phenotype of these tumors. Importantly, MCT expression revealed to have a prognostic value in OCC survival. PMID- 27232159 TI - Atomic Spectral Methods for Ab Initio Molecular Electronic Energy Surfaces: Transitioning From Small-Molecule to Biomolecular-Suitable Approaches. AB - Continuing attention has addressed incorportation of the electronically dynamical attributes of biomolecules in the largely static first-generation molecular mechanical force fields commonly employed in molecular-dynamics simulations. We describe here a universal quantum-mechanical approach to calculations of the electronic energy surfaces of both small molecules and large aggregates on a common basis which can include such electronic attributes, and which also seems well-suited to adaptation in ab initio molecular-dynamics applications. In contrast to the more familiar orbital-product-based methodologies employed in traditional small-molecule computational quantum chemistry, the present approach is based on an "ex-post-facto" method in which Hamiltonian matrices are evaluated prior to wave function antisymmetrization, implemented here in the support of a Hilbert space of orthonormal products of many-electron atomic spectral eigenstates familiar from the van der Waals theory of long-range interactions. The general theory in its various forms incorporates the early semiempirical atoms- and diatomics-in-molecules approaches of Moffitt, Ellison, Tully, Kuntz, and others in a comprehensive mathematical setting, and generalizes the developments of Eisenschitz, London, Claverie, and others addressing electron permutation symmetry adaptation issues, completing these early attempts to treat van der Waals and chemical forces on a common basis. Exact expressions are obtained for molecular Hamiltonian matrices and for associated energy eigenvalues as sums of separate atomic and interaction-energy terms, similar in this respect to the forms of classical force fields. The latter representation is seen to also provide a long-missing general definition of the energies of individual atoms and of their interactions within molecules and matter free from subjective additional constraints. A computer code suite is described for calculations of the many electron atomic eigenspectra and the pairwise-atomic Hamiltonian matrices required for practical applications. These matrices can be retained as functions of scalar atomic-pair separations and employed in assembling aggregate Hamiltonian matrices, with Wigner rotation matrices providing analytical representations of their angular degrees of freedom. In this way, ab initio potential energy surfaces are obtained in the complete absence of repeated evaluations and transformations of the one- and two-electron integrals at different molecular geometries required in most ab inito molecular calculations, with large Hamiltonian matrix assembly simplified and explicit diagonalizations avoided employing partitioning and Brillouin-Wigner or Rayleigh-Schrodinger perturbation theory. Illustrative applications of the important components of the formalism, selected aspects of the scaling of the approach, and aspects of "on the-fly" interfaces with Monte Carlo and molecular-dynamics methods are described in anticipation of subsequent applications to biomolecules and other large aggregates. PMID- 27232160 TI - Assessment of cervical range of motion, cervical core strength and scapular dyskinesia in violin players. AB - BACKGROUND: Playing the violin can lead to asymmetric postures which can affect the cervical range of motion, cervical core strength and scapular stability. OBJECTIVE: The objective of the study was to assess the cervical range of motion, cervical core strength and scapular dyskinesia in violin players and non-players of the same age group. METHODS: An inclinometer was used to assess the cervical range of motion, pressure biofeedback was used to assess cervical core strength and scapular dyskinesia was also assessed in 30 professional violin players (18 40 years) compared with 30 age-matched non-players. Analysis was done using an unpaired t test. RESULTS: Significant change was seen with respect to extension (p = 0.051), cervical core strength (p = 0.005), right (Rt) superior angle 0 degrees (p = 0.004), Rt superior angle 45 degrees (p = 0.015) and Rt inferior angle 90 degrees (p = 0.013). CONCLUSION: This study shows a significant difference in extension range of motion and cervical core strength of violin players. Also, there was scapular dyskinesia seen at 0 degrees and 45 degrees right-side superior angle of the scapula and 90 degrees right-side inferior angle of the scapula. PMID- 27232162 TI - The length of words reflects their conceptual complexity. AB - Are the forms of words systematically related to their meaning? The arbitrariness of the sign has long been a foundational part of our understanding of human language. Theories of communication predict a relationship between length and meaning, however: Longer descriptions should be more conceptually complex. Here we show that both the lexicons of human languages and individual speakers encode the relationship between linguistic and conceptual complexity. Experimentally, participants mapped longer words to more complex objects in comprehension and production tasks and across a range of stimuli. Explicit judgments of conceptual complexity were also highly correlated with implicit measures of study time in a memory task, suggesting that complexity is directly related to basic cognitive processes. Observationally, judgments of conceptual complexity for a sample of real words correlate highly with their length across 80 languages, even controlling for frequency, familiarity, imageability, and concreteness. While word lengths are systematically related to usage-both frequency and contextual predictability-our results reveal a systematic relationship with meaning as well. They point to a general regularity in the design of lexicons and suggest that pragmatic pressures may influence the structure of the lexicon. PMID- 27232163 TI - Building ensemble representations: How the shape of preceding distractor distributions affects visual search. AB - Perception allows us to extract information about regularities in the environment. Observers can quickly determine summary statistics of a group of objects and detect outliers. The existing body of research has, however, not revealed how such ensemble representations develop over time. Moreover, the correspondence between the physical distribution of features in the external world and their potential internal representation as a probability density function (PDF) by the visual system is still unknown. Here, for the first time we demonstrate that such internal PDFs are built during visual search and show how they can be assessed with repetition and role-reversal effects. Using singleton search for an oddly oriented target line among differently oriented distractors (a priming of pop-out paradigm), we test how different properties of previously observed distractor distributions (mean, variability, and shape) influence search times. Our results indicate that observers learn properties of distractor distributions over and above mean and variance; in fact, response times also depend on the shape of the preceding distractor distribution. Response times decrease as a function of target distance from the mean of preceding Gaussian distractor distributions, and the decrease is steeper when preceding distributions have small standard deviations. When preceding distributions are uniform, however, this decrease in response times can be described by a two-piece function corresponding to the uniform distribution PDF. Moreover, following skewed distributions response times function is skewed in accordance with the skew in distributions. Indeed, internal PDFs seem to be specifically tuned to the observed feature distribution. PMID- 27232180 TI - Response of Swelling Behavior of Weak Branched Poly(ethylene imine)/Poly(acrylic acid) Polyelectrolyte Multilayers to Thermal Treatment. AB - Weak polyelectrolyte multilayers (PEMs) prepared by the layer-by-layer technique have attracted a great deal of attention as smart responsive materials for biological and other applications in aqueous medium, but their dynamic behavior as a function of exposure to a wide temperature range is still not well understood. In this work, the thermally dependent swelling behavior of PEMs consisting of branched poly(ethylenimine) and poly(acrylic acid) is studied by temperature controlled in situ spectroscopic ellipsometry. Because of diffusion and interpenetration of polyelectrolytes during film deposition, the PEMs densify with increasing bilayer number, which further affects their water uptake behavior. Upon heating to temperatures below 60 degrees C, the worsened solvent quality of the PEM in water causes deswelling of the PEMs. However, once heated above this critical temperature, the hydrogen bonds within the PEMs are weakened, which allows for chain rearrangement within the film upon cooling, resulting in enhanced water uptake and increased film thickness. The current work provides fundamental insight into the unique dynamic behavior of weak polyelectrolyte multilayers in water at elevated temperatures. PMID- 27232181 TI - A Tubular Biomaterial Construct Exhibiting a Negative Poisson's Ratio. AB - Developing functional small-diameter vascular grafts is an important objective in tissue engineering research. In this study, we address the problem of compliance mismatch by designing and developing a 3D tubular construct that has a negative Poisson's ratio nuxy (NPR). NPR constructs have the unique ability to expand transversely when pulled axially, thereby resulting in a highly-compliant tubular construct. In this work, we used projection stereolithography to 3D-print a planar NPR sheet composed of photosensitive poly(ethylene) glycol diacrylate biomaterial. We used a step-lithography exposure and a stitch process to scale up the projection printing process, and used the cut-missing rib unit design to develop a centimeter-scale NPR sheet, which was rolled up to form a tubular construct. The constructs had Poisson's ratios of -0.6 <= nuxy <= -0.1. The NPR construct also supports higher cellular adhesion than does the construct that has positive nuxy. Our NPR design offers a significant advance in the development of highly-compliant vascular grafts. PMID- 27232183 TI - Stability and Instability of Subjective Well-Being in the Transition from Adolescence to Young Adulthood: Longitudinal Evidence from 20991 Young Australians. AB - PURPOSE: This study assessed the long-term stability and instability of subjective well-being during post-school transition (i.e., transition from adolescence to young adulthood) and evaluated the determinants of transition stability. METHODS: Using two cohorts from a national representative longitudinal study, the Longitudinal Study of Australian Youth (N = 20991), latent profile analysis and latent transition analysis were conducted to examine transition patterns among subjective well-being profiles for youth from age 17 to 25. Multinomial logistic regressions were conducted to evaluate whether key socio demographic variables were associated with transition stability. RESULTS: We identified: (1) three subjective well-being profiles: Low (30%), Moderate (50%), and High (20%); and (2) three major transition patterns among these subjective well-being profiles: stable, partially-stable, and unstable. The majority of youth had stable transition patterns during the transition from adolescence to adulthood. A large percentage of youth (52%) started low in subjective well-being profile and remained in the low subjective-wellbeing profile. Our examination also revealed gender was the most pronounced indicator for transition stability during this time period, with males more likely to have unstable transition patterns than females. CONCLUSIONS: Results suggest that different subjective well-being status and transition patterns can be identified in the post-high school transition to adulthood, including unstable transitions. By targeting those groups more vulnerable to transition, mental health promotion and interventions may be delivered more effectively. PMID- 27232182 TI - The Gene Expression Program for the Formation of Wing Cuticle in Drosophila. AB - The cuticular exoskeleton of insects and other arthropods is a remarkably versatile material with a complex multilayer structure. We made use of the ability to isolate cuticle synthesizing cells in relatively pure form by dissecting pupal wings and we used RNAseq to identify genes expressed during the formation of the adult wing cuticle. We observed dramatic changes in gene expression during cuticle deposition, and combined with transmission electron microscopy, we were able to identify candidate genes for the deposition of the different cuticular layers. Among genes of interest that dramatically change their expression during the cuticle deposition program are ones that encode cuticle proteins, ZP domain proteins, cuticle modifying proteins and transcription factors, as well as genes of unknown function. A striking finding is that mutations in a number of genes that are expressed almost exclusively during the deposition of the envelope (the thin outermost layer that is deposited first) result in gross defects in the procuticle (the thick chitinous layer that is deposited last). An attractive hypothesis to explain this is that the deposition of the different cuticle layers is not independent with the envelope instructing the formation of later layers. Alternatively, some of the genes expressed during the deposition of the envelope could form a platform that is essential for the deposition of all cuticle layers. PMID- 27232184 TI - A New Ligand-Based Method for Purifying Active Human Plasma-Derived Ficolin-3 Complexes Supports the Phenomenon of Crosstalk between Pattern-Recognition Molecules and Immunoglobulins. AB - Despite recombinant protein technology development, proteins isolated from natural sources remain important for structure and activity determination. Ficolins represent a class of proteins that are difficult to isolate. To date, three methods for purifying ficolin-3 from plasma/serum have been proposed, defined by most critical step: (i) hydroxyapatite absorption chromatography (ii) N-acetylated human serum albumin affinity chromatography and (iii) anti-ficolin-3 monoclonal antibody-based affinity chromatography. We present a new protocol for purifying ficolin-3 complexes from human plasma that is based on an exclusive ligand: the O-specific polysaccharide of Hafnia alvei PCM 1200 LPS (O-PS 1200). The protocol includes (i) poly(ethylene glycol) precipitation; (ii) yeast and l fucose incubation, for depletion of mannose-binding lectin; (iii) affinity chromatography using O-PS 1200-Sepharose; (iv) size-exclusion chromatography. Application of this protocol yielded average 2.2 mg of ficolin-3 preparation free of mannose-binding lectin (MBL), ficolin-1 and -2 from 500 ml of plasma. The protein was complexed with MBL-associated serine proteases (MASPs) and was able to activate the complement in vitro. In-process monitoring of MBL, ficolins, and total protein content revealed the presence of difficult-to-remove immunoglobulin G, M and A, in some extent in agreement with recent findings suggesting crosstalk between IgG and ficolin-3. We demonstrated that recombinant ficolin-3 interacts with IgG and IgM in a concentration-dependent manner. Although this association does not appear to influence ficolin-3-ligand interactions in vitro, it may have numerous consequences in vivo. Thus our purification procedure provides Ig ficolin-3/MASP complexes that might be useful for gaining further insight into the crosstalk and biological activity of ficolin-3. PMID- 27232185 TI - Tuberculosis, before and after Antiretroviral Therapy among HIV-Infected Children in Nigeria: What Are the Risk Factors? AB - INTRODUCTION: In Nigeria, there is a dearth of pediatric data on the risk factors associated with tuberculosis (TB), before and after antiretroviral therapy (ART). METHODOLOGY: A retrospective observational cohort study, between October 2010 and December 2013, at the Federal Medical Centre, Makurdi, Nigeria. TB was noted among children less than 15 years of age at ART enrolment (prevalent TB-PrevTB), within 6 months (early incident tuberculosis-EITB) and after 6 months (late incident tuberculosis-LITB) of a 12-month follow-up on ART. Potential risk factors for PrevTB and incident TB were assessed using the multivariate logistic and Cox regression models respectively. RESULTS: Among 368 HIV-1 infected children, PrevTB was diagnosed in 73 children (19.8%). Twenty-eight EITB cases were diagnosed among 278 children over 132 person-years (py) with an EITB rate of 21.2/100 py. Twelve LITB cases were seen among 224 children over 221.9 py with a LITB rate of 5.4/100 py. A significant reduction in the incidence rates of TB was found over time (75%, p? 0.001). Young age of children (12-35 months, aOR; 24, 95% CI; 4.1-146.6, p ? 0.001; 36-59 months, aOR;21, 95%CI;4.0-114.3, p ? 0.001); history of TB in children (aOR; 29, 95% CI; 7.3-119.4, P? 0.001); severe immunosuppression (aOR;38, 95% CI;12-123.2,p ? 0.001); oropharyngeal candidiasis (aOR;3.3, 95% CI; 1.4-8.0, p = 0.009) and sepsis (aOR; 3.2, 95% CI;1.0-9.6, p = 0.043) increased the risk of PrevTB. Urban residency was protective against EITB (aHR; 0.1, 95% CI; 0.0-0.4, p = 0.001). Virological failure (aHR; 4.7, 95% CI; 1.3-16.5, p ? 0.001) and sepsis (aHR; 26, 95% CI; 5.3-131.9, p ? 0.001) increased the risk of LITB. CONCLUSIONS: In our cohort of HIV-infected children, a significant reduction in cases of incident TB was seen following a 12-month use of ART. After ART initiation, TB screening should be optimized among children of rural residency, children with sepsis, and those with poor virological response to ART. PMID- 27232187 TI - Angiotensin-converting enzyme (ACE-I/D) polymorphism frequency in Brazilian soccer players. AB - This study aimed to analyze the angiotensin-converting enzyme (ACE-I/D) allelic and genotypic frequencies in Brazilian soccer players of different ages. The study group comprised 353 players from first-division clubs in the under (U)-14, U-15, U-17, U-20, and professional categories. The allelic and genotypic frequencies did not differ significantly in any of the categories between the group of players and the control group. This was the first study of ACE-I/D polymorphism in Brazilian soccer players. PMID- 27232186 TI - Population-Based Assessment of Hypertension Epidemiology and Risk Factors among HIV-Positive and General Populations in Rural Uganda. AB - BACKGROUND: Antiretroviral therapy scale-up in Sub-Saharan Africa has created a growing, aging HIV-positive population at risk for non-communicable diseases such as hypertension. However, the prevalence and risk factors for hypertension in this population remain incompletely understood. METHODS: We measured blood pressure and collected demographic data on over 65,000 adults attending multi disease community health campaigns in 20 rural Ugandan communities (SEARCH Study: NCT01864603). Our objectives were to determine (i) whether HIV is an independent risk factor for hypertension, and (ii) awareness and control of hypertension in HIV-positive adults and the overall population. RESULTS: Hypertension prevalence was 14% overall, and 11% among HIV-positive individuals. 79% of patients were previously undiagnosed, 85% were not taking medication, and 50% of patients on medication had uncontrolled blood pressure. Multivariate predictors of hypertension included older age, male gender, higher BMI, lack of education, alcohol use, and residence in Eastern Uganda. HIV-negative status was independently associated with higher odds of hypertension (OR 1.2, 95% CI: 1.1 1.4). Viral suppression of HIV did not significantly predict hypertension among HIV-positives. SIGNIFICANCE: The burden of hypertension is substantial and inadequately controlled, both in HIV-positive persons and overall. Universal HIV screening programs could provide counseling, testing, and treatment for hypertension in Sub-Saharan Africa. PMID- 27232189 TI - Polycyclic Aromatic Hydrocarbons in Sediments and Bivalves on the Pacific Coast of Japan: Influence of Tsunami and Fire. AB - Surface sediments and at least one edible bivalve species (Ruditapes philippinarum, Mytilus galloprovincialis, and Crassostrea gigas) were collected from each of seven intertidal sites in Japan in 2013. The sites had experienced varying levels of tsunami and fire disturbance following the major earthquake of 2011. Eight polycyclic aromatic hydrocarbons (PAHs) were identified and analyzed by gas chromatography-mass spectrometry. Total sediment PAH concentration (CT), the sum of the average concentrations of the eight PAHs, was 21-1447 MUg kg-1 dry. Relative to the average level of one type of PAH in sediments collected around Japan in 2002 (benzo[a]pyrene = 21 MUg kg-1-dry), five of the seven sites showed concentrations significantly lower than this average in 2013. The CTs for the three bivalves (134-450 MUg kg-1-dry) were within the range of the previous reports (2.2-5335 MUg kg-1-dry). The data suggest that the natural disaster did not increase PAH concentrations or affect the distribution within sediment or bivalves in Tohoku district. Although PAH concentrations at the sites pose no risk to human health, the findings highlight that the observed PAH levels derive from pre- rather than post-quake processes. PMID- 27232188 TI - Immunopotentiators Improve the Efficacy of Oil-Emulsion-Inactivated Avian Influenza Vaccine in Chickens, Ducks and Geese. AB - Combination of CVCVA5 adjuvant and commercial avian influenza (AI) vaccine has been previously demonstrated to provide good protection against different AI viruses in chickens. In this study, we further investigated the protective immunity of CVCVA5-adjuvanted oil-emulsion inactivated AI vaccine in chickens, ducks and geese. Compared to the commercial H5 inactivated vaccine, the H5-CVCVA5 vaccine induced significantly higher titers of hemaglutinin inhibitory antibodies in three lines of broiler chickens and ducks, elongated the antibody persistence periods in geese, elevated the levels of cross serum neutralization antibody against different clade and subclade H5 AI viruses in chicken embryos. High levels of mucosal antibody were detected in chickens injected with the H5 or H9 CVCA5 vaccine. Furthermore, cellular immune response was markedly improved in terms of increasing the serum levels of cytokine interferon-gamma and interleukine 4, promoting proliferation of splenocytes and upregulating cytotoxicity activity in both H5- and H9-CVCVA5 vaccinated chickens. Together, these results provide evidence that AI vaccines supplemented with CVCVA5 adjuvant is a promising approach for overcoming the limitation of vaccine strain specificity of protection. PMID- 27232190 TI - Dynamical and Phase Behavior of a Phospholipid Membrane Altered by an Antimicrobial Peptide at Low Concentration. AB - The mechanism of action of antimicrobial peptides is traditionally attributed to the formation of pores in the lipid cell membranes of pathogens, which requires a substantial peptide to lipid ratio. However, using incoherent neutron scattering, we show that even at a concentration too low for pore formation, an archetypal antimicrobial peptide, melittin, disrupts the regular phase behavior of the microscopic dynamics in a phospholipid membrane, dimyristoylphosphatidylcholine (DMPC). At the same time, another antimicrobial peptide, alamethicin, does not exert a similar effect on the DMPC microscopic dynamics. The melittin-altered lateral motion of DMPC at physiological temperature no longer resembles the fluid phase behavior characteristic of functional membranes of the living cells. The disruptive effect demonstrated by melittin even at low concentrations reveals a new mechanism of antimicrobial action relevant in more realistic scenarios, when peptide concentration is not as high as would be required for pore formation, which may facilitate treatment with antimicrobial peptides. PMID- 27232193 TI - Altruistic and economic measurements used for prevention health services: Faith community nursing program. PMID- 27232192 TI - Social Security Disability Insurance May Reduce Benefits by 2016: Population at Financial Risk from Reductions. AB - In the United States, 10.9 million people are receiving Social Security Disability Insurance (SSDI) benefits with an average pay of $12,000 per year. If the U.S. House of Congress fails to enact a new bill by the end of fiscal-year 2016, SSDI benefits are estimated to be reduced by $2,300 per-person per year. In the pass, the U.S. Congress has always found a way to enact new bills capable of maintains benefits at existing levels. The specific aim of this project was to report the number of people potentially at risk for experiencing an economic impact if SSDI benefits are reduced. The cross-sectional analysis used data from the American Community Survey, 2009-2013 Public Use Microdata Sample file. Characteristics on a total of 153,627 actual survey participants were used to generalize findings to 2,748,735 residents of the United States. Results indicate non-Hispanic Whites, the Pacific and South Atlantic geographic divisions are at the largest risk for being affected by changes to SSDI benefits. PMID- 27232194 TI - Prevalence and Mental Health Treatment of Suicidal Ideation and Behavior Among College Students Aged 18-25 Years and Their Non-College-Attending Peers in the United States. AB - OBJECTIVE: College students have been the focus of many studies on suicidal ideation with or without suicidal behavior. Little attention has been given to their non-college-attending peers on these issues. We examined the 12-month prevalence and mental health treatment of suicidal ideation with or without suicidal behavior among college students aged 18-25 years and their non-college attending peers in the United States. METHODS: We assessed data from 135,300 persons aged 18-25 years who participated in the 2008-2013 National Surveys on Drug Use and Health. Descriptive analyses and multivariate logistic regression models were applied. RESULTS: Compared with full-time college students, high school students, those not enrolled in a school or college, and part-time college students were more likely to attempt suicide with a plan (model-adjusted prevalence = 0.67% vs 1.09%, 1.06%, and 1.07%, respectively). The mental health treatment rate among full-time college students with suicidal ideation with or without suicidal behavior was similar to the rates among the other 3 counterparts. The effects of race/ethnicity and serious mental illness on receipt of mental health treatment were significantly larger among those who did not perceive unmet treatment need than among those who perceived unmet treatment need (P = .019 and P = .001, respectively). CONCLUSIONS: Compared to full-time college students, non-college-attending young adults and part-time college students were at higher risk for attempting suicide with a plan. Suicide prevention and intervention strategies should emphasize increasing access to mental health treatment among both college students with suicidal ideation with or without suicidal behavior and their non-college-attending peers (particularly among minorities and those who seem to be at low risk because they are without serious mental illness and report no need for mental health treatment). PMID- 27232191 TI - Mechanism and biological role of Dnmt2 in Nucleic Acid Methylation. AB - A group of homologous nucleic acid modification enzymes called Dnmt2, Trdmt1, Pmt1, DnmA, and Ehmet in different model organisms catalyze the transfer of a methyl group from the cofactor S-adenosyl-methionine (SAM) to the carbon-5 of cytosine residues. Originally considered as DNA MTases, these enzymes were shown to be tRNA methyltransferases about a decade ago. Between the presumed involvement in DNA modification-related epigenetics, and the recent foray into the RNA modification field, significant progress has characterized Dnmt2-related research. Here, we review this progress in its diverse facets including molecular evolution, structural biology, biochemistry, chemical biology, cell biology and epigenetics. PMID- 27232195 TI - Unusual venous bullet embolism - Case report. AB - Bullet embolism is rare complication of penetrating gunshot trauma. We are presenting a case of a single gunshot with entrance wound located on external side of a left thigh. The upward directed trajectory extends to the left lateral side of the neck, but the bullet has been recovered from right external iliac vein. The bullet migration was explained due to one rare variation of the mouth of vena cava superior and inferior. PMID- 27232196 TI - Systematic Reviews and Meta-analyses for Cardiology Fellows. AB - Participating in a scholarly activity is one of the training requirements for cardiology fellows. However, it can be very challenging to complete a research project during such a busy period of clinical training. To help the cardiology fellows in choosing and starting off a research project, a light has been shed on the process of conducting a systematic review, and the importance of this research activity, as well as its limitations. PMID- 27232197 TI - Review for Disease of the Year: Epidemiology of HLA-B27 Associated Ocular Disorders. AB - Acute anterior uveitis is generally recognized as the most common form of uveitis. An association with HLA-B27 is seen in approximately half of cases of acute anterior uveitis. The prevalence of HLA-B27 varies widely between ethnic populations, with an approximate 8-10% prevalence in non-Hispanic whites and lower prevalence in Mexican- (4%) and African- (2-4%) Americans. A group of systemic inflammatory diseases, the spondyloarthropathies, similarly demonstrates a strong association with HLA-B27. The strength of association varies, depending on the specific spondyloarthropathy, with the strongest association found in patients with ankylosing spondylitis. The majority of patients with HLA-B27 associated uveitis will have an underlying spondyloarthropathy. Suspicion for HLA B27 associated uveitis should prompt a careful clinical history to assess for features of a spondyloarthropathy as the characteristics of any associated uveitis may vary. PMID- 27232198 TI - Modelling the penumbra in Computed Tomography1. AB - BACKGROUND: In computed tomography (CT), the spot geometry is one of the main sources of error in CT images. Since X-rays do not arise from a point source, artefacts are produced. In particular there is a penumbra effect, leading to poorly defined edges within a reconstructed volume. Penumbra models can be simulated given a fixed spot geometry and the known experimental setup. OBJECTIVE: This paper proposes to use a penumbra model, derived from Beer's law, both to confirm spot geometry from penumbra data, and to quantify blurring in the image. METHODS: Two models for the spot geometry are considered; one consists of a single Gaussian spot, the other is a mixture model consisting of a Gaussian spot together with a larger uniform spot. RESULTS: The model consisting of a single Gaussian spot has a poor fit at the boundary. The mixture model (which adds a larger uniform spot) exhibits a much improved fit. The parameters corresponding to the uniform spot are similar across all powers, and further experiments suggest that the uniform spot produces only soft X-rays of relatively low-energy. CONCLUSIONS: Thus, the precision of radiographs can be estimated from the penumbra effect in the image. The use of a thin copper filter reduces the size of the effective penumbra. PMID- 27232199 TI - A mixed reality approach for stereo-tomographic quantification of lung nodules. AB - To reduce the radiation dose and the equipment cost associated with lung CT screening, in this paper we propose a mixed reality based nodule measurement method with an active shutter stereo imaging system. Without involving hundreds of projection views and subsequent image reconstruction, we generated two projections of an iteratively placed ellipsoidal volume in the field of view and merging these synthetic projections with two original CT projections. We then demonstrated the feasibility of measuring the position and size of a nodule by observing whether projections of an ellipsoidal volume and the nodule are overlapped from a human observer's visual perception through the active shutter 3D vision glasses. The average errors of measured nodule parameters are less than 1 mm in the simulated experiment with 8 viewers. Hence, it could measure real nodules accurately in the experiments with physically measured projections. PMID- 27232200 TI - Image reconstruction from few-view CT data by gradient-domain dictionary learning. AB - BACKGROUND: Decreasing the number of projections is an effective way to reduce the radiation dose exposed to patients in medical computed tomography (CT) imaging. However, incomplete projection data for CT reconstruction will result in artifacts and distortions. OBJECTIVE: In this paper, a novel dictionary learning algorithm operating in the gradient-domain (Grad-DL) is proposed for few-view CT reconstruction. Specifically, the dictionaries are trained from the horizontal and vertical gradient images, respectively and the desired image is reconstructed subsequently from the sparse representations of both gradients by solving the least-square method. METHODS: Since the gradient images are sparser than the image itself, the proposed approach could lead to sparser representations than conventional DL methods in the image-domain, and thus a better reconstruction quality is achieved. RESULTS: To evaluate the proposed Grad-DL algorithm, both qualitative and quantitative studies were employed through computer simulations as well as real data experiments on fan-beam and cone-beam geometry. CONCLUSIONS: The results show that the proposed algorithm can yield better images than the existing algorithms. PMID- 27232201 TI - Positron Binding Properties of Glycine and Its Aqueous Complexes. AB - We investigate positron binding to glycine and its aqueous complexes by first principles calculation. We show that while glycine in its ground state (Gly) does not bind positrons, several of its strongly polar conformers do, and in particular, its zwitterion form (GlyZI) binds positrons strongly. Aqueous complexes Gly.nH2O and GlyZI.nH2O also bind positrons, if their dipole moment MU > MUcr. However, MU is not a sufficient quantity to describe positron binding to these complexes. We show that in addition to MU, positron binding strongly depends on the intramolecular bonding of glycine. In Gly.nH2O, positrons are weakly bound to the nitrogen in Gly, whereas in GlyZI.nH2O, the ionic oxygen in GlyZI is a strong "positron attractor". PMID- 27232202 TI - Microbial interactions and community assembly at microscales. AB - In most environments, microbial interactions take place within microscale cell aggregates. At the scale of these aggregates (~100MUm), interactions are likely to be the dominant driver of population structure and dynamics. In particular, organisms that exploit interspecific interactions to increase ecological performance often co-aggregate. Conversely, organisms that antagonize each other will tend to spatially segregate, creating distinct micro-communities and increased diversity at larger length scales. We argue that, in order to understand the role that biological interactions play in microbial community function, it is necessary to study microscale spatial organization with enough throughput to measure statistical associations between taxa and possible alternative community states. We conclude by proposing strategies to tackle this challenge. PMID- 27232203 TI - Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Ecological Study in the Basque Country, Spain (2000-2011). AB - Chronic obstructive pulmonary disease (COPD) is a prevalent condition in adults aged >=40 years characterized by progressive airflow limitation associated with chronic inflammatory response to noxious particles in the airways and lungs. Smoking, genetics, air pollution, nutrition and other factors may influence COPD development. Most hospitalizations and deaths for COPD are caused by its acute exacerbations, which greatly affect the health and quality of life of COPD patients and pose a high burden on health services. The aims of this project were to identify trends, geographic patterns and risk factors for COPD exacerbations, as revealed by hospitalizations and deaths, in the Basque Country, Spain, over a period of 12 years (2000-2011). Hospitalization and mortality rates for COPD were 262 and 18 per 100,000 population, respectively, with clusters around the biggest cities. Hospital mortality was 7.4%. Most hospitalized patients were male (77.4%) and accounted for 72.1% of hospital mortality. Hospitalizations decreased during the study period, except for 50-64 year-old women, peaking significantly. Using a multivariate modeling approach it was shown that hospitalizations were positively correlated with increased atmospheric concentrations of NO2, CO, PM10, and SO2, and increased influenza incidence, but were negatively associated with increased temperatures and atmospheric O3 concentration. COPD exacerbations decreased in the Basque Country during 2000-2011, but not among 50-64-year-old women, reflecting the high smoking prevalence among Spanish women during the 1970-1990s. The main metropolitan areas were those with the highest risk for COPD exacerbations, calling attention to the role of heavy car traffic. Influenza virus, cold temperatures, and increased atmospheric NO2, CO, PM10, and SO2 (but decreased O3) concentrations were identified as potential contributors to the burden of COPD exacerbations in the community. These findings are important for both the understanding of the disease process and in providing potential targets for COPD-reducing initiatives and new avenues for research. PMID- 27232204 TI - Valorization of biosorbent obtained from a forestry waste: Competitive adsorption, desorption and transport of Cd, Cu, Ni, Pb and Zn. AB - Bark from Pinus pinaster is one of the most abundant forestry wastes in Europe, and among the proposed technologies for its reutilization, the removal of heavy metals from wastewater has been gaining increasing attention. In this work, we have studied the performance of pine bark for heavy metal biosorption on competitive systems. Pb, Cu, Ni, Zn and Cd sorption and desorption at equilibrium were studied in batch experiments, whereas transport was studied in column experiments. Batch experiments were performed adding simultaneously different concentrations (0.08-3.15mM) of two or more metals in solution to pine bark samples. Column experiments were performed with 10mM solutions of two metals or a 5mM solution of the five metals. In general, the results under competitive conditions were different to those obtained in monoelemental experiments. The multi-metal batch experiments showed the adsorption sequence Pb~Cu>Cd>Zn>Ni for lower metal doses, Pb>Cu>Cd>Zn>Ni for intermediate doses, and Pb>Cu>Cd~Zn~Ni for high metal doses. Desorption followed the sequence PbCu>Zn>Cd>Ni. The presence of a second metal affected the transport of all the elements studied except Pb, and confirmed the strong influence of Pb and Cu on the retention of the other metals. These results can help to appropriately design decontamination systems using this forestry waste. PMID- 27232205 TI - Influence of saponins on the biodegradation of halogenated phenols. AB - Biotransformation of aromatic compounds is a challenge due to their low aqueous solubility and sorptive losses. The main obstacle in this process is binding of organic pollutants to the microbial cell surface. To overcome these, we applied saponins from plant extract to the microbial culture, to increase pollutants solubility and enhance diffusive massive transfer. This study investigated the efficiency of Quillaja saponaria and Sapindus mukorossi saponins-rich extracts on biodegradation of halogenated phenols by Raoultella planticola WS2 and Pseudomonas sp. OS2, as an effect of cell surface modification of tested strains. Both strains display changes in inner membrane permeability and cell surface hydrophobicity in the presence of saponins during the process of halogenated phenols biotransformation. This allows them to more efficient pollutants removal from the environment. However, only in case of the Pseudomonas sp. OS2 the addition of surfactants to the culture improved effectiveness of bromo-, chloro- and fluorophenols biodegradation. Also introduction of surfactant allowed higher biodegradability of halogenated phenols and can shorten the process. Therefore this suggests that usage of plant saponins can indicate more successful halogenated phenols biodegradation for selected strains. PMID- 27232206 TI - Pathological and histometric analysis of the gills of female Hyphessobrycon eques (Teleostei:Characidae) exposed to different concentrations of the insecticide Dimilin((r)). AB - Female individuals of Hyphessobrycon eques were exposed to Diflubenzuron (Dimilin((r))) in order to determine whether exposure to sublethal levels of this insecticide causes changes in gill morphology. Fish were exposed to 0.01, 0.1 and 1.0mgL(-1) for 96h and 17 days and then submitted to pathological and histometric evaluation. Pathological lesions, such as hyperplasia, lamellar fusion, vascular congestion, secondary lamellar disarray, vasodilatation, hemorrhage and increased lamellar epithelium, were significantly more common in the gills of fish exposed to Dimilin((r)) than the control. Histometric analysis documented significant changes in blood vessel diameter, primary lamellae width and secondary lamellae length, and the appearance of hemorrhage foci in all concentrations tested. Even at low Dimilin((r)) concentrations, the histopathological alteration index was mild to moderate, thereby indicating that the function of this tissue was compromised. These findings indicate that indiscriminate use of Dimilin((r)) can adversely affect the structural integrity of the gills of H. eques, which can cause numerous problems for fish farming systems. PMID- 27232207 TI - Serenoa repens, selenium and lycopene to manage lower urinary tract symptoms suggestive for benign prostatic hyperplasia. AB - INTRODUCTION: Benign prostatic hyperplasia (BPH) is a disease affecting most of the elderly male. alpha1-blockers and 5-alpha reductase inhibitors are currently used to target lower urinary tract symptoms (LUTS). Moreover phytotherapeutic agents, including Serenoa Repens (SeR), have shown to have a role in ameliorating BPH/LUTS alone or in combination of other elements like Selenium (Se) and Lycopene (Ly). Areas covered: A literature review was performed using data from articles assessing the role of of SeR+Se+Ly in the management of LUTS secondary to BPH. Diverging evidence on SeR's efficacy is available. On one hand several studies have shown SeR efficacy in treating BPH/LUTS. SeR is effective in reducing prostate size, urinary frequency, dysuria, nocturia and in improving maximum urine flow-rate. On the other hand two long-term trials reported that SeR did not improve prostate size or urinary flow. SeR+Se+Ly in combination with tamsulosin is more effective than single therapies in improving IPSS and increasing maximal urinary flow-rate in patients affected by LUTS/BPH. Expert opinion: Despite great amount of preclinical and clinical studies, the use of SeR in BPH/LUTS is not sustained by clear evidence for a therapeutic efficacy but current data hint higher efficacy of of SeR+Se+Ly compared to SeR alone. PMID- 27232208 TI - Investigating treatment characteristics and first-session relationship variables as predictors of dropout in the treatment of traumatized youth. AB - OBJECTIVE: Attrition is a common problem in youth trauma treatment, but there is currently little knowledge of why so many youths drop out. In this study, treatment variables (caregiver attendance in the first session and exposure vs. non-exposure-based treatment) and first-session process variables (the therapeutic alliance and youths' perceptions of parental treatment approval) were investigated as predictors of dropout. METHOD: Participants (N = 156, mean age = 15.1) were randomly assigned to trauma-focused cognitive behavioral therapy or therapy as usual in a community trial. RESULTS: Dropout (n = 39, 25.0%) was predicted by a lack of caregiver attendance, lower rates of youth-perceived parental treatment approval, and weaker therapist-rated youth alliance. Neither type of treatment, youth-rated alliance or caregiver alliance, predicted dropout. CONCLUSIONS: The findings indicate that in addition to caregivers' actual participation in the first session, youths' perception of their parents' approval of treatment seems to influence treatment attendance. This finding implies that therapists should engage caregivers in therapy and address possible discordance in treatment goals and tasks. Furthermore, consistent with adult studies, exposure-based treatments do not appear to increase dropout rates. PMID- 27232209 TI - Chromosome aberrations in peripheral blood lymphocytes of lung cancer patients exposed to radon and air pollution. AB - Lung cancer is one of the most common forms of cancer. The aim of this study was to validate chromosome aberrations in peripheral blood lymphocytes of lung cancer patients living in a region with high air pollution and increased background radon levels as a biomarker of cancer risk. A total of 417 lung cancer patients and 468 control participants were analysed using a chromosome aberration assay in peripheral blood lymphocytes. The results showed that chromatid-type aberrations (2.26+/-1.58 vs. 1.60+/-1.58) and chromosome-type aberrations (CSAs) (0.96+/-1.36 vs. 0.42+/-0.70) in lung cancer patients were increased significantly in comparison with the controls. The most significant two-fold increase was detected for CSAs (nonsmoking patients: 0.84+/-1.54 vs. 0.41+/-0.73%, smoking patients: 0.99+/-1.31 vs. 0.44+/-0.67%). The frequency of dicentric and ring chromosomes, double minutes and rogue cells was significantly higher (P=0.002, 0.00002, 0.01, 0.0007) in the lung cancer patients. As both analysed groups lived in the same environment, our results show that increased radon levels were not the only source for the detected genome damage. Using binomial logistic regression, the estimated odds ratios and 95% confidence intervals adjusted for the main confounders (smoking, occupational exposure, age) were 1.31 (1.20-1.40) for chromatid-type aberrations, 1.28 (1.17-1.33), and 1.68 (1.49-1.88) for CSAs. It may be suggested that lung cancer patients show a significant increase in genome damage that may be caused by an interplay between exposure and individual low capacity of DNA repair, leading to genome instability. PMID- 27232210 TI - Carbon-nanotube-assisted nanoepitaxy of Si-doped GaN for improved performance of InGaN/GaN light-emitting diodes. AB - Using single-walled carbon nanotubes (SWCNTs) as nanomasks on an undoped GaN template, a significant biaxial stress relaxation was achieved in the subsequently-grown Si-doped n-GaN layer. Enhanced near band edge (NBE) emission intensity, similar free carrier concentrations, and the reduced peak width of the asymmetric (102) crystallographic plane all confirmed the suppression of threading dislocations due to the nanoepitaxial growth process. Temperature dependent photoluminescence (PL) revealed improved internal quantum efficiency (IQE) of InGaN/GaN multi-quantum wells (MQWs) grown on this n-GaN layer. Furthermore, enhanced light output power and a remarkable reduction in efficiency droop were observed for the blue light-emitting diodes (LEDs), especially at higher injection currents. Our results emphasize the strong potential for SWCNTs as nanomasks in the heteroepitaxy of GaN-based devices without the exploitation of complicated lithography or etching processes. PMID- 27232211 TI - Patient and healthcare professional satisfaction with a new, high accuracy blood glucose meter with color range indicator and wireless connectivity. AB - Accurate self-monitoring of blood glucose is a key component of effective self management of glycemic control. The OneTouch VerioFlex(TM) (OTVF) blood glucose monitoring system (BGMS) was evaluated for accuracy in a clinical setting. Patients also used OTVF for a 1-wk trial period and reported their level of satisfaction with meter features. In a separate study, healthcare professionals used an on-line simulator of the BGMS and answered questions about its potential utility to their patients. OTVF was accurate over a wide glucose range and met lay user and system accuracy blood glucose standards described in ISO15197:2013 as well as the accuracy requirements to fulfill US FDA expectations for 510(k) clearance of BGMS. Patients and healthcare professionals felt the features of OTVF, which has the capability to connect wirelessly to mobile devices and interact wirelessly with diabetes management software, could provide significant benefits to them or their patients. PMID- 27232212 TI - How to manage a child with difficult asthma? AB - INTRODUCTION: Children with difficult asthma have significant morbidity and fail to achieve asthma control despite being prescribed high dose maintenance treatment. If control remains poor after diagnostic confirmation, detailed assessments of the reasons for asthma being difficult-to-control are needed. Underlying modifiable factors including non-adherence to medication, persistent environmental exposures that trigger asthma symptoms and psychosocial factors contribute to poor control in these patients. AREAS COVERED: The focus of this review is to provide a practical approach to the diagnosis and management of difficult asthma including an overview of long term assessments to identify potential progression to true, severe asthma. A multi-disciplinary team is critical to enable modifiable factors to be identified and addressed. Significant resources are required to manage paediatric difficult asthma optimally and only specialist centres should be tasked with the assessment of these patients. Although this may have an impact on healthcare resources, long term benefits for lung health are significant. Expert commentary: The management of paediatric difficult asthma is not simple and involves numerous professionals with varied expertise. However, if it is not undertaken with the appropriate skills, there is a significant risk of children receiving inappropriate invasive investigations and therapies that will have no impact on morbidity. PMID- 27232213 TI - A Potential VEP Biomarker for Mild Cognitive Impairment: Evidence from Selective Visual Deficit of Higher-Level Dorsal Pathway. AB - Visual dysfunctions are common in Alzheimer's disease (AD). Our aim was to establish a neurophysiological biomarker for amnestic mild cognitive impairment (aMCI). Visual evoked potentials (VEPs) were recorded in aMCI patients who later developed AD (n = 15) and in healthy older (n = 15) and younger controls (n = 15). Visual stimuli were optimized to separately activate lower and higher levels of the ventral and dorsal streams. We compared VEP parameters across the three groups of participants and conducted a linear correlation analysis between VEPs and data from neuropsychological tests. We then used a receiver operating characteristic (ROC) analysis to discriminate those with aMCI from those who were healthy older adults. The latency and phase of VEPs to lower-level stimuli (chromatic and achromatic gratings) were significantly affected by age but not by cognitive decline. Conversely, VEP latencies for higher-ventral (faces and kanji words) and dorsal (kana-words and optic flow motion) stimuli were not affected by age, but they were significantly prolonged in aMCI patients. Interestingly, VEPs for higher-dorsal stimuli were related to outcomes of neuropsychological tests. Furthermore, the ROC analysis showed that the highest areas under the curve were obtained for VEP latencies in response to higher-dorsal stimuli. These results suggest aMCI-related functional impairment specific to higher-level visual processing. Further, dysfunction in the higher-level of the dorsal stream could be an early indicator of cognitive decline. Therefore, we conclude that VEPs associated with higher-level dorsal stream activity can be a sensitive biomarker for early detection of aMCI. PMID- 27232214 TI - Modulation of Amyloid-beta1-40 Transport by ApoA1 and ApoJ Across an in vitro Model of the Blood-Brain Barrier. AB - Amyloid-beta (Abeta) accumulation in Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) is likely caused by the impairment of its brain clearance that partly occurs through the blood-brain barrier (BBB). In this context, an in vitro BBB model is a valuable tool for studying the molecular mechanisms that regulate this process. This study assessed brain Abeta elimination across the BBB and its modulation by the natural chaperones Apolipoprotein A1 (ApoA1) and Apolipoprotein J/Clusterin (ApoJ). The model was based on primary cerebral endothelial cells that were cultured on Matrigel-coated Transwells and treated with fluorescently labeled-Abeta1-40 to track its efflux across the BBB, which corresponds to trafficking from the basolateral (brain) to apical (blood) compartments. We observed that the transport of basolateral Abeta1 40 was enhanced when it was complexed to rApoJ, whereas the complex formed with rApoA1 did not influence Abeta1-40 efflux. However, the presence of rApoA1 in the apical compartment was able to mobilize Abeta1-40 from the basolateral side. We also observed that both rApoA1 and rApoJ moderately crossed the monolayer (from blood to brain) through a mechanism involving the LDL receptor-related protein family. In contrast to the increased rApoJ efflux when complexed to Abeta1-40, rApoA1 trafficking was restricted when it was bound to the Abeta peptide. In summary, the present study highlights the role of ApoJ and ApoA1 in the in vitro modulation of Abeta elimination across the BBB. PMID- 27232215 TI - AVN-101: A Multi-Target Drug Candidate for the Treatment of CNS Disorders. AB - Lack of efficacy of many new highly selective and specific drug candidates in treating diseases with poorly understood or complex etiology, as are many of central nervous system (CNS) diseases, encouraged an idea of developing multi modal (multi-targeted) drugs. In this manuscript, we describe molecular pharmacology, in vitro ADME, pharmacokinetics in animals and humans (part of the Phase I clinical studies), bio-distribution, bioavailability, in vivo efficacy, and safety profile of the multimodal drug candidate, AVN-101. We have carried out development of a next generation drug candidate with a multi-targeted mechanism of action, to treat CNS disorders. AVN-101 is a very potent 5-HT7 receptor antagonist (Ki = 153 pM), with slightly lesser potency toward 5-HT6, 5-HT2A, and 5HT-2C receptors (Ki = 1.2-2.0 nM). AVN-101 also exhibits a rather high affinity toward histamine H1 (Ki = 0.58 nM) and adrenergic alpha2A, alpha2B, and alpha2C (Ki = 0.41-3.6 nM) receptors. AVN-101 shows a good oral bioavailability and facilitated brain-blood barrier permeability, low toxicity, and reasonable efficacy in animal models of CNS diseases. The Phase I clinical study indicates the AVN-101 to be well tolerated when taken orally at doses of up to 20 mg daily. It does not dramatically influence plasma and urine biochemistry, nor does it prolong QT ECG interval, thus indicating low safety concerns. The primary therapeutic area for AVN-101 to be tested in clinical trials would be Alzheimer's disease. However, due to its anxiolytic and anti-depressive activities, there is a strong rational for it to also be studied in such diseases as general anxiety disorders, depression, schizophrenia, and multiple sclerosis. PMID- 27232216 TI - Impacts of Illiteracy on the Risk of Dementia: A Global Health Perspective. AB - Despite its significance as a contributing factor for late-life dementia risk, illiteracy is frequently underappreciated in the management of dementia. In this study, we estimated the proportion of dementia cases attributable to illiteracy using the population attributable fraction (PAF), and calculated to what extent the monetary cost of dementia could be saved in the future by reducing illiteracy from the South Korean, Latin American, South Asian/Middle Eastern, and African populations. We collected necessary data from the 2011 United Nations Human Development Report and prevalence studies conducted in these regions. Additional variables not included in the above sources were estimated using a logit model under a "trend scenario"-based assumption. Around 16% of the total number of dementia cases in South Korea in 2015 can be attributed to illiteracy, with this figure predicted to decline to around 2% by 2050. This translates to a saving in dementia care costs of approximately 52 billion USD, providing we are successful in theoretically eradicating illiteracy as of 2015, in the population aged 65 years or under. Likewise, reducing illiteracy to 50% in Latin America, South Asia/The Middle East, and Africa by 2050 could generate further cost savings of between 71 and 244 billion, 13 and 94 billion, and 17 and 78 billion USD, respectively. Even public policies aimed solely at reducing illiteracy in the childhood, adolescent, or middle-aged population could potentially have a role in the primary prevention of dementia. Moving forward, governments will need to address this issue in a purposeful and systematic manner. PMID- 27232218 TI - Technology and Continuously Learning Health Systems. PMID- 27232217 TI - Patients with Amyloid-Negative Mild Cognitive Impairment have Cortical Hypometabolism but the Hippocampus is Preserved. AB - BACKGROUND: Patients with mild cognitive impairment (MCI) are at risk for Alzheimer's dementia but the presence of amyloid (Abeta) strongly increases this risk. In clinical settings, when Abeta status is not available, different neurodegenerative markers are used to characterize MCI. The accuracy of these markers to discriminate between Abeta-and Abeta+ MCI is not yet determined. OBJECTIVE: To compare different markers of neurodegeneration in Abeta-and Abeta+ MCI, with an Abeta-elderly control (EC) group. METHODS: Patients with MCI (n = 39) and EC (n = 28) underwent MRI, 18F-FDG PET, and Abeta PET (18F-flutemetamol). We compared FDG and MRI biomarker values in cortical and hippocampal regions of interest, and using voxel-wise surface maps. We computed ROC curves discriminating between the three groups for each biomarker. RESULTS: All biomarker values were reduced in Abeta+ MCI compared to EC (p < 0.001). Abeta-MCI had low cortical metabolism (p = 0.002), but hippocampal volume, cortical thickness, and hippocampal metabolism were not significantly different between Abeta-MCI and EC (p > 0.40). Cortical metabolism best discriminated between MCI and EC (AUC = 0.92/0.86, Abeta+/Abeta-) while hippocampal volume best discriminated between Abeta-MCI and Abeta+ MCI (AUC = 0.79). CONCLUSIONS: Cortical hypometabolism was observed in both Abeta-MCI and Abeta+ MCI whereas hippocampal atrophy was mostly found in Abeta+ MCI. For MCI patients without available Abeta information, hippocampal atrophy is thus more informative about Abeta status than cortical hypometabolism. PMID- 27232219 TI - Planning CNE: Putting It All Together. AB - Continuing nursing education programs are most successful when a series of interconnected steps are followed. This column will show how a thoroughly evaluated practice gap and a clearly defined outcome can guide the planning process so that identified practice gaps can most effectively be closed. J Contin Educ Nurs. 2016;47(6):246-247. PMID- 27232220 TI - Beyond Program Objectives. AB - Graduate students in eight diverse health care professional programs participated together in a pilot course entitled, "An Interprofessional Approach to Patient Care." Through postcourse discussions with the clinical nurse leader students, faculty discovered that beyond meeting program objectives, the nursing learners gained numerous unexpected insights about interprofessional collaborative practice. J Contin Educ Nurs. 2016;47(6):248-249. PMID- 27232221 TI - Developing a Leadership Program Trajectory. AB - From a program development perspective, leadership goals and content are best developed over time, with an aim to help nurses mature into their capacity to lead. Leadership often is encouraged in new nurses or in those who seek management positions. Professional development educators are encouraged to enact leadership development across a career continuum. J Contin Educ Nurs. 2016;47(6):250-252. PMID- 27232222 TI - Moving on From Millennials: Preparing for Generation Z. AB - Much has been written about teaching Millennials; however, little has been discussed about Generation Z-those just entering college. Nursing instructors must adapt to the upcoming generation's mobile tech-savviness and self-directed learning, which often is accompanied by a lack of critical thinking skills. Teaching strategies and incorporating technology are highlighted. J Contin Educ Nurs. 2016;47(6):253-254. PMID- 27232223 TI - Simulation Training in Early Emergency Response (STEER). AB - HOW TO OBTAIN CONTACT HOURS BY READING THIS ISSUE Instructions: 1.3 contact hours will be awarded by Villanova University College of Nursing upon successful completion of this activity. A contact hour is a unit of measurement that denotes 60 minutes of an organized learning activity. This is a learner-based activity. Villanova University College of Nursing does not require submission of your answers to the quiz. A contact hour certificate will be awarded after you register, pay the registration fee, and complete the evaluation form online at http://goo.gl/gMfXaf. In order to obtain contact hours you must: 1. Read the article, "Simulation Training in Early Emergency Response (STEER)," found on pages 255-263, carefully noting any tables and other illustrative materials that are included to enhance your knowledge and understanding of the content. Be sure to keep track of the amount of time (number of minutes) you spend reading the article and completing the quiz. 2. Read and answer each question on the quiz. After completing all of the questions, compare your answers to those provided within this issue. If you have incorrect answers, return to the article for further study. 3. Go to the Villanova website to register for contact hour credit. You will be asked to provide your name, contact information, and a VISA, MasterCard, or Discover card number for payment of the $20.00 fee. Once you complete the online evaluation, a certificate will be automatically generated. This activity is valid for continuing education credit until May 31, 2019. CONTACT HOURS This activity is co-provided by Villanova University College of Nursing and SLACK Incorporated. Villanova University College of Nursing is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. OBJECTIVES Define the purpose of the Simulation Training in Early Emergency Response (STEER) study. Review the outcome of the STEER study. DISCLOSURE STATEMENT Neither the planners nor the author have any conflicts of interest to disclose. Little has been published about nurses' responses in the first 5 minutes of in-hospital emergencies. This study aimed to test a simulation curriculum based on institutional priorities using high-intensity, short-duration, frequent in situ content delivery based on deliberate practice. The study design was a prospective, single-center, mixed methods quasi-experimental study. Scenarios used in this study were ventricular fibrillation, opiate-related respiratory depression, syncopal fall, and hemorrhagic stroke. The convenience sample included 41 teams (147 participants). Improvements were noted in initiating chest compressions (p = .018), time to check blood glucose (p = .046), and identification of heparin as a contributor to stroke (p = .043). Establishing in situ simulation-based teaching program is feasible and well received. This approach appears effective in increasing confidence, initiating life-saving measures, and empowering nurses to manage emergencies. Future studies should evaluate and improve on the curriculum, on data collection tools quantitatively, and on overcoming barriers to high-quality emergency care. J Contin Educ Nurs. 2016;47(6):255-263. PMID- 27232225 TI - Evaluation of an Evidence-Based Practice Tutorial for Nurses: A Useful Tool and Some Lessons Learned. AB - Although evidence-based practice (EBP) and research is important to hospitals and nursing staff interested in achieving Magnet status, a more important purpose is the improvement of patient care. As the nursing staff of UConn Health and its John Dempsey Hospital began its initial assessment prior to embarking on the journey for Magnet status, staff nurses were found to lack skills in searching vetted sources of EBP literature and appraising the results of a search. To address this need, a librarian at UConn Health, in collaboration with the hospital's Nursing Research steering committee, developed an online, self-paced EBP tutorial. The EBP tutorial used the iterative (Analysis, Design, Development, Implementation, and Evaluation) model of instructional design in development and assessment. This article describes the development and implementation of the tutorial, its evaluation, and lessons learned. J Contin Educ Nurs. 2016;47(6):266 271. PMID- 27232226 TI - Continuing Education for Mentors and a Mentoring Program for RN-to-BSN Students. AB - Mentoring programs have been used effectively with graduate and undergraduate nursing students and newly licensed nurses. There are few publications about mentoring for the RN enrolled in a bachelor of science in nursing (RN-to-BSN) program. To address low graduation rates in the public RN-to-BSN nursing programs, the Montana Center to Advance Health Through Nursing designed a mentoring program to help these nurses achieve their BSN. This voluntary program was initiated at an RN-to-BSN program in a 4-year college with six RN students who were paired with a mentor. An interactive, continuing education workshop on mentoring also was developed to prepare experienced nurses for their role as a mentor. This workshop was held nine times across Montana, with a total of 156 attendees. Workshop evaluations were consistently positive. Participants identified time and personality issues as barriers to successful mentoring and recommended expansion of the workshop to a distance-learning format so more nurses could attend. J Contin Educ Nurs. 2016;47(6):272-277. PMID- 27232227 TI - Framework for Teaching Psychomotor and Procedural Skills in Nursing. AB - The development of psychomotor and procedural skills requires opportunities for repetitive practice combined with specific, informational feedback from the teacher, another expert, or simulator to correct performance errors. Practice enables learners to refine skills and progress through the phases of motor learning: cognitive, associative, and autonomous. Practice should be spaced over time, can occur in dyads, and can rapidly cycle between practicing and receiving feedback and coaching until skills are mastered. The purpose of this article is to examine psychomotor skill learning in nursing and to suggest strategies for nurse educators in teaching motor and procedural skills in nursing programs, as well as in clinical settings. J Contin Educ Nurs. 2016;47(6):278-282. PMID- 27232228 TI - Better Care Teams: A Stepwise Skill Reinforcement Model. AB - The Building Healthy Urban Communities initiative presents a path for organizations partnering to improve patient outcomes with continuing education (CE) as a key component. Components of the CE initiative included traditional CE delivery formats with an essential element of adaptability and new methods, with rigorous evaluation over time that included evaluation prior to the course, immediately following the CE session, 6 to 8 weeks after the CE session, and then subsequent monthly "testlets." Outcome measures were designed to allow for ongoing adaptation of content, reinforcement of key learning objectives, and use of innovative concordant testing and retrieval practice techniques. The results after 1 year of programming suggest the stepwise skill reinforcement model is effective for learning and is an efficient use of financial and human resources. More important, its design is one that could be adopted at low cost by organizations willing to work in close partnership. J Contin Educ Nurs. 2016;47(6):283-288. PMID- 27232229 TI - The Role of Fibrinogen and Factor XIII in Hemostasis, and the Identification and Treatment of Associated Disorders. PMID- 27232230 TI - Volatile Single-Source Precursors for the Low-Temperature Preparation of Sodium Rare Earth Metal Fluorides. AB - Heterometallic single-source precursors for the preparation of sodium-rare earth metal fluorides are reported. Fluorinated beta-diketonates NaRE(hfac)4 (RE = Y (1), Er (2), and Eu (3); hfac = hexafluoroacetylacetonate) have been obtained on a large scale, in high yield, via one-pot reaction that utilizes commercially available starting reagents. The solid-state structures of the title complexes consist of 1D polymeric chains with alternating [Na] and [RE(hfac)4] units. Compounds 1-3 are highly volatile and exhibit a fair stability in open air. Mass spectrometric investigation indicates the presence of heterometallic fragments in the gas phase. The presence of heterometallic species in solutions of coordinating solvents has also been confirmed. Decomposition of heterometallic precursors in argon atmosphere was shown to yield phase-pure sodium-rare earth metal fluorides. Low decomposition temperature effectively allows for a high degree of control over the formation of both kinetic alpha-phases and thermodynamic beta-phases of target NaREF4 (RE = Y, Er, and Eu) materials. PMID- 27232231 TI - The Importance and Power of Networks in Health Research, Practice and Policy. PMID- 27232232 TI - Health, Wealth and the Price of Oil. AB - The correlation between health and wealth is arguably a very solidly established relationship. Yet that relationship may be reversing. Falling oil prices have raised (average) per capita incomes, worldwide. But from a long-run perspective they are a public health disaster. The latter is easy to see: low oil reduces the incentive to develop alternative energy sources and "bend the curve" of global warming. Their principal impact on incomes has been redistributional - Alberta and Russia lose, Ontario and Germany gain, etc. Zero net gain. But the price has fallen because technical progress in extracting American shale oil has forced the Saudis' hand. These efficiencies have real benefits for (average) incomes, but costs for long-run health. A compensating carbon tax is an obvious response. PMID- 27232233 TI - Accountability for Community Benefit: A Reasonable Expectation for Canadian Hospitals. AB - North American hospitals have historically struggled to engage in prevention and health promotion activities because they have not been incentivized or held accountable for doing so. However, in order to be exempt from federal taxes, 3,000 non-profit hospitals in the US must now regularly assess the health status of the communities they serve, and take action to address identified health needs. This is called "accountability for community benefit," and it is required under the Patient Protection and Affordable Care Act (commonly known as Obamacare). A modified version of accountability for community benefit warrants exploration in the Canadian context, as it may support Canadian hospitals to direct resources towards prevention and health promotion activities - something many Canadian hospitals want to do, but struggle with in the current accountability environment. This is an important health policy topic because even a small shift in focus by hospitals towards prevention and health promotion has the potential to improve population health and reduce healthcare demand. PMID- 27232234 TI - The Council of Academic Hospitals of Ontario (CAHO) Adopting Research to Improve Care (ARTIC) Program: Reach, Sustainability, Spread and Lessons Learned from an Implementation Funding Model. AB - Despite evidence on what works in healthcare, there is a significant gap in the time it takes to bring research into practice. The Council of Academic Hospitals of Ontario's Adopting Research to Improve Care program addresses this research-to practice gap by incorporating the following components into its funding program: strategic selection of evidence for implementation, education and training for implementation, implementation supports, executive champions and governance, and evaluation. Funded projects have been sustained (76% reported full sustainability) and spread to over 200 new sites. Lessons learned include the following: assess readiness, develop tailored implementation materials, consider characteristics of implementation supports, protect champion time and consider evaluation feasibility. PMID- 27232235 TI - An Experiment with Public-Oriented Knowledge Transfer: A Video on Quebec's Bill 10. AB - When decision-makers are engaged in a polarized discourse and leaving aside evidence-based recommendations, is there a role for researchers in the dissemination of this scientific evidence to the general public as a means to counterbalance the debate? In response to the controversial Bill 10 in Quebec, we developed and posted a knowledge transfer video on YouTube to help stimulate critical public debate. This article explains our approach and methodology, and the impact of the video, which, in the space of two weeks, had more than 9,500 views, demonstrating the pertinence of such initiatives. We conclude with recommendations for other research groups to engage in public debates. PMID- 27232236 TI - Effectiveness of Reablement: A Systematic Review. AB - The ageing of the population and the increasing need for long-term care services are global issues. Some countries have adapted homecare programs by introducing an intervention called reablement, which is aimed at optimizing independence. The effectiveness of reablement, as well as its different service models, was examined. A systematic literature review was conducted using MEDLINE, CINAHL, PsycINFO and EBM Reviews to search from 2001 to 2014. Core characteristics and facilitators of reablement implementation were identified from international experiences. Ten studies comprising a total of 14,742 participants (including four randomized trials, most of excellent or good quality) showed a positive impact of reablement, especially on health-related quality of life and service utilization. The implementation of reablement was studied in three regions, and all observed a reduction in healthcare service utilization. Considering its effectiveness and positive impact observed in several countries, the implementation of reablement is a promising avenue to be pursued by policy makers. PMID- 27232237 TI - The Search is on for Coherent Performance Measurement in Healthcare Organizations. Has Quebec Reached a Crossroads? AB - OBJECTIVE: This research looks back at a 10-year period (2004-2014) to understand the development and outlook for healthcare organization performance measurement in the Quebec healthcare system, in an attempt to objectivize relationships within the configuration of its principal institutional actors. METHODS: This is a qualitative study combining the use of official publications and fieldwork based on 13 semi-directed interviews, conducted in 2014, with informers in key performance measurement positions within the Quebec healthcare system. RESULTS: Performance measurement has generated tensions, both internally between different branches of the Department of Health and externally against a strong coalition of external institutional actors, which were defending a shared homogeneous vision of performance. Four major types of political power plays, owing to the power struggles around performance models and indicators, converged around the same implicit issue of the need to attain greater legitimacy in order to impose an authoritative frame of reference. PMID- 27232238 TI - Some Numbers behind Canada's Decision to Adopt an Orphan Drug Policy: US Orphan Drug Approvals in Canada, 1997-2012. AB - We examined whether access to US-approved orphan drugs in Canada has changed between 1997 (when Canada chose not to adopt an orphan drug policy) and 2012 (when Canada reversed its policy decision). Specifically, we looked at two dimensions of access to US-approved orphan drugs in Canada: (1) regulatory access; and (2) temporal access. Whereas only 63% of US-approved orphan drugs were granted regulatory approval in 1997, we found that regulatory access to US approved orphan drugs in Canada increased to 74% between 1997 and 2012. However, temporal access to orphan drugs is slower in Canada: in a head-on comparison of 40 matched drugs, only two were submitted and four were approved first in Canada; moreover, the mean review time in Canada (423 days) was longer than that in the US (mean = 341 days), a statistically significant difference (t[39] = 2.04, p = 0.048). These results raise questions about what motivated Canada's apparent shift in orphan drug policy. PMID- 27232239 TI - Examining Privacy Regulatory Frameworks in Canada in the Context of HIV. AB - In the process of receiving perinatal care, women living with HIV (WLWH) in Canada have experienced disclosure of their HIV status without their express consent. This disclosure often occurs by well-intentioned healthcare providers; however, from the perspective of WLWH, it is a breach of confidentiality and leaves WLWH to manage the consequences. This paper is a critical review of the regulatory and legislative infrastructure that exists to protect the personal health information of WLWH in Ontario and Canada; the recourse that WLWH have in the event that their confidentiality is breached; and potential approaches that could be applied to organize the system differently to decrease the chance of a privacy breach and to facilitate appropriate collection, use and disclosure of personal health information. PMID- 27232240 TI - A Decade Lost: Primary Healthcare Performance Reporting across Canada under the Action Plan for Health System Renewal. AB - In 2004, Canada's First Ministers committed to reforms that would shape the future of the Canadian healthcare landscape. These agreements included commitments to improved performance reporting within the primary healthcare system. The aim of this paper was to review the state of primary healthcare performance reporting after the public reporting mandate agreed to a decade ago in the Action Plan for Health System Renewal of 2003 expired. A grey literature search was performed to identify reports released by the governmental and independent reporting bodies across Canada. No province, or the federal government, met their performance reporting obligations from the 2004 accords. Although the indicators required to report on in the 2004 Accord no longer reflect the priorities of patients, policy makers and physicians, provinces are also failing to report on these priorities. Canada needs better primary healthcare performance reporting to enable accountability and improvement within and across provinces. Despite the national mandate to improve public health system reporting, an opportunity to learn from the diverse primary healthcare reforms, underway across Canada for the past decade, has already been lost. PMID- 27232241 TI - Cardiovascular and Renal Effects of Birdseed Associated with Aerobic Exercise in Rats. AB - INTRODUCTION: Phalaris canariensis L. (Pc), known as birdseed, is rich in tryptophan. The aqueous extract of Pc (AEPc) treatment reduced systolic blood pressure (SBP) in spontaneously hypertensive rats (SHR) via mechanisms mediated by the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase (IDO). Hypertension is a risk factor to cardiovascular and renal diseases. Considering that physical exercise improves hypertension and cardiovascular function, the aim of this study was to evaluate whether the benefits of exercise (Ex) would be enhanced by concomitant AEPc treatment (400 mg.kg.d p.o.). METHODS: Vascular reactivity was assessed in aorta rings from SHR treated with AEPc for 4 wk. Training intensity was based on maximal lactate steady state obtained during the 2-wk adaptation period in a treadmill running. Then exercised (60 min running, five times per week during 8 wk) or sedentary SHR were untreated or treated with AEPc during 8 wk. SBP was estimated by plethysmograph. Heart mass and body mass were used to obtain the index of cardiac hypertrophy. Glucose tolerance test was evaluated by oral glucose overload, and the mRNA expressions of indoleamine 2,3 dioxygenase, interleukin 1beta (IL-1beta), and IL-10 in the kidney were obtained by real time polymerase chain reaction. RESULTS: AEPc induced endothelial mediated vascular relaxation. AEPc or Ex alone reduced SBP, the index of cardiac hypertrophy and ventricular fibrosis, improved glucose metabolism, and attenuated proteinuria and the renal expression of the proinflammatory IL-1beta with an overexpression in the anti-inflammatory IL-10. AEPc potentiated the benefits of the Ex on the cardiovascular system, metabolic parameters, and renal inflammation. CONCLUSION: Birdseed reduced cardiovascular risk related to hypertension and had positive effects when associated to physical exercise. PMID- 27232242 TI - Diaphragm Contractility in Individuals with Chronic Ankle Instability. AB - INTRODUCTION/PURPOSE: Previous investigations have identified impaired trunk and postural stability in individuals with chronic ankle instability (CAI). The diaphragm muscle contributes to trunk and postural stability by modulating the intra-abdominal pressure. A potential mechanism that could help to explain trunk and postural stability deficits may be related to altered diaphragm function due to supraspinal sensorimotor changes with CAI. The purpose of this study was to examine the diaphragm contractility in individuals with CAI and healthy controls. METHODS: Twenty-seven participants with self-reported CAI and 28 healthy control participants volunteered. A portable ultrasound unit was used to visualize and measure the right and left hemidiaphragm thickness at the end of resting inspiration and expiration in supine while breathing quietly. The diaphragm movement was imaged and recorded on B-mode ultrasonography. The degree of diaphragm contractility was calculated from the mean of three images from the end of resting inspiration and expiration. Independent t-tests were used to compare the degree of diaphragm thickness of right and left sides between the CAI and the control groups. RESULTS: The CAI group had a smaller degree of left hemidiaphragm contractility compared with the control group (P = 0.03). There was no between group difference in other diaphragm variables. CONCLUSION: Individuals with CAI appear to have altered diaphragm contractility, which may be an illustration of diaphragm dysfunction and central nervous system changes in CAI population. The association between CAI and altered diaphragm contractility provides clinicians a more comprehensive awareness of proximal impairments associated with CAI. Future investigation is needed to determine whether altered contractility of the diaphragm contributes to functional impairments, activity limitations, and participant restrictions commonly observed in patients with CAI. PMID- 27232243 TI - Injury Profile of American Women's Rugby-7s. AB - PURPOSE: The objective of this study is to determine incidence (injuries/1000 playing hours (ph)), severity (days of absence), and cause of match injuries in US women's Rugby-7s. METHODS: We performed a prospective epidemiological study (2010-2013) of injury of 3876 under-19 to elite/national female Rugby-7s players (nonelite = 3324, elite = 552) on 323 teams (nonelite = 277, elite = 46), applying methodology and injury definitions compliant with the international consensus statement on rugby research. Injuries occurred in USA Rugby-sanctioned tournament series: USA Rugby Local Area (2010), Territorial Union (2011-2013), National and All-Star Sevens Series, and USA Sevens Invitational (2011-2012) and Collegiate Rugby Championships (2012). RESULTS: One hundred and twenty time-loss injuries were encountered (elite, n = 15; 13%) with an injury rate of 46.3 injuries/1000 ph. Injury rates in nonelite were 49.3/1000 ph, and in national level (elite) candidates, 32.6/1000 ph (RR = 1.5, P = 0.130). Mean days missed found elite level players at 74.9 d per injury, whereas nonelite at 41.8 d (P = 0.090). Acute injuries were significant (95%, RR = 1.9, P < 0.001), resulting in immediate removal from the pitch (56%, P < 0.001). The main mechanism of injury occurred when tackling players (73%, P < 0.001). The most common type of injury seen were ligament sprains (37%, 13.9/1000 ph), involving the lower extremity (45%, 20.5/1000 ph). The most common body parts injured were the knee and head/face (16%, 7.3/1000 ph). CONCLUSIONS: Time-loss injuries occurred with frequency in the US women's Rugby-7s tournaments. Overall injury rates in US women are lower than those in international elite men and women's Rugby-7s. The head and neck area in our female players was injured at greater rates (16%) than in international male Rugby-7s (5%). Injury prevention in US women's Rugby-7s must focus on injuries of the knee, head, and neck. Understanding risk factors will allow safe return-to-play decisions and formulate injury prevention protocols. PMID- 27232244 TI - Neutrophil Dysfunction, Immature Granulocytes, and Cell-free DNA are Early Biomarkers of Sepsis in Burn-injured Patients: A Prospective Observational Cohort Study. AB - OBJECTIVE: The aim of this study was to measure neutrophil function longitudinally following burn injury and to examine the relationship between neutrophil dysfunction and sepsis. BACKGROUND: Sepsis prevalence and its associated mortality is high following burn injury, and sepsis diagnosis is complicated by the ongoing inflammatory response. Previous studies have suggested that neutrophil dysfunction may underlie high infection rates and sepsis postburn; however, neutrophil dysfunction has not been thoroughly characterized over time in burns patients. METHODS: Neutrophil phagocytosis, oxidative burst capacity, and neutrophil extracellular trap (NET) generation (NETosis) were measured from 1 day to up to 1 year postburn injury in 63 patients with major burns (>=15% total body surface area). In addition, immature granulocyte (IG) count, plasma cell-free DNA (cfDNA), and plasma citrullinated histone H3 (Cit H3) levels were measured. RESULTS: Neutrophil function was reduced for 28 days postburn injury and to a greater degree in patients who developed sepsis, which was also characterized by elevated IG counts. Plasma cfDNA and Cit-H3, a specific marker of NETosis, were elevated during septic episodes. The combination of neutrophil phagocytic capacity, plasma cfDNA levels, and IG count at day 1 postinjury gave good discriminatory power for the identification of septic patients. CONCLUSION: Neutrophil function, IG count, and plasma cfDNA levels show potential as biomarkers for the prediction/early diagnosis of sepsis postburn injury and neutrophil dysfunction may actively contribute to the development of sepsis. Targeting neutrophil dysfunction and IG release may be a viable therapeutic intervention to help reduce the incidence of nosocomial infections and sepsis postburn. PMID- 27232246 TI - Transhepatic Feeding: Safe and Effective. PMID- 27232245 TI - MicroRNAs for Detection of Pancreatic Neoplasia: Biomarker Discovery by Next generation Sequencing and Validation in 2 Independent Cohorts. AB - OBJECTIVE: The aim of our study was to analyze the miRNome of pancreatic ductal adenocarcinoma (PDAC) and its preneoplastic lesion intraductal papillary mucinous neoplasm (IPMN), to find new microRNA (miRNA)-based biomarkers for early detection of pancreatic neoplasia. OBJECTIVE: Effective early detection methods for PDAC are needed. miRNAs are good biomarker candidates. METHODS: Pancreatic tissues (n = 165) were obtained from patients with PDAC, IPMN, or from control individuals (C), from Hospital Clinic of Barcelona. Biomarker discovery was done using next-generation sequencing in a discovery set of 18 surgical samples (11 PDAC, 4 IPMN, 3 C). MiRNA validation was carried out by quantitative reverse transcriptase PCR in 2 different set of samples. Set 1-52 surgical samples (24 PDAC, 7 IPMN, 6 chronic pancreatitis, 15 C), and set 2-95 endoscopic ultrasound guided fine-needle aspirations (60 PDAC, 9 IPMN, 26 C). RESULTS: In all, 607 and 396 miRNAs were significantly deregulated in PDAC and IPMN versus C. Of them, 40 miRNAs commonly overexpressed in both PDAC and IPMN were selected for further validation. Among them, significant up-regulation of 31 and 30 miRNAs was confirmed by quantitative reverse transcriptase PCR in samples from set 1 and set 2, respectively. CONCLUSIONS: miRNome analysis shows that PDAC and IPMN have differential miRNA profiles with respect to C, with a large number of deregulated miRNAs shared by both neoplastic lesions. Indeed, we have identified and validated 30 miRNAs whose expression is significantly increased in PDAC and IPMN lesions. The feasibility of detecting these miRNAs in endoscopic ultrasound guided fine-needle aspiration samples makes them good biomarker candidates for early detection of pancreatic cancer. PMID- 27232247 TI - Considering Value in Rectal Cancer Surgery: An Analysis of Costs and Outcomes Based on the Open, Laparoscopic, and Robotic Approach for Proctectomy. AB - OBJECTIVE: The aim of the study was to compare value (outcomes/costs) of proctectomy in patients with rectal cancer by 3 approaches: open, laparoscopic, and robotic. BACKGROUND: The role of minimally invasive proctectomy in rectal cancer is controversial. In the era of value-based medicine, costs must be considered along with outcomes. METHODS: Primary rectal cancer patients undergoing curative intent proctectomy at our institution between 2010 and 2014 were included. Patients were grouped by approach [open surgery, laparoscopic surgery, and robotic surgery (RS)] on an intent-to-treat basis. Groups were compared by direct costs of hospitalization for the primary resection, 30-day readmissions, and ileostomy closure and for short-term outcomes. RESULTS: A total of 488 patients were evaluated; 327 were men (67%), median age was 59 (27-93) years, and restorative procedures were performed in 333 (68.2%). Groups were similar in demographics, tumor characteristics, and treatment details. Significant outcome differences between groups were found in operative and anesthesia times (longer in the RS group), and in estimated blood loss, intraoperative transfusion, length of stay, and postoperative complications (all higher in the open surgery group). No significant differences were found in short term oncologic outcomes. Direct cost of the hospitalization for primary resection and total direct cost (including readmission/ileostomy closure hospitalizations) were significantly greater in the RS group. CONCLUSIONS: The laparoscopic and open approaches to proctectomy in patients with rectal cancer provide similar value. If robotic proctectomy is to be widely applied in the future, the costs of the procedure must be reduced. PMID- 27232248 TI - History of the Innovation of Damage Control for Management of Trauma Patients: 1902-2016. AB - OBJECTIVE: To review the history of the innovation of damage control (DC) for management of trauma patients. BACKGROUND: DC is an important development in trauma care that provides a valuable case study in surgical innovation. METHODS: We searched bibliographic databases (1950-2015), conference abstracts (2009 2013), Web sites, textbooks, and bibliographies for articles relating to trauma DC. The innovation of DC was then classified according to the Innovation, Development, Exploration, Assessment, and Long-term study model of surgical innovation. RESULTS: The "innovation" of DC originated from the use of therapeutic liver packing, a practice that had previously been abandoned after World War II because of adverse events. It then "developed" into abbreviated laparotomy using "rapid conservative operative techniques." Subsequent "exploration" resulted in the application of DC to increasingly complex abdominal injuries and thoracic, peripheral vascular, and orthopedic injuries. Increasing use of DC laparotomy was followed by growing reports of postinjury abdominal compartment syndrome and prophylactic use of the open abdomen to prevent intra abdominal hypertension after DC laparotomy. By the year 2000, DC surgery had been widely adopted and was recommended for use in surgical journals, textbooks, and teaching courses ("assessment" stage of innovation). "Long-term study" of DC is raising questions about whether the procedure should be used more selectively in the context of improving resuscitation practices. CONCLUSIONS: The history of the innovation of DC illustrates how a previously abandoned surgical technique was adapted and readopted in response to an increased understanding of trauma patient physiology and changing injury patterns and trauma resuscitation practices. PMID- 27232249 TI - Avoiding Futility in Simultaneous Liver-kidney Transplantation: Analysis of 331 Consecutive Patients Listed for Dual Organ Replacement. AB - OBJECTIVE: We sought to evaluate outcomes and predictors of renal allograft futility (RAF-patient death or need for renal replacement therapy at 3 months) after simultaneous liver-kidney transplantation (SLKT). BACKGROUND: Model for End Stage Liver Disease (MELD) prioritization of liver recipients with renal dysfunction has significantly increased utilization of SLKT. Data on renal outcomes after SLKT in the highest MELD recipients are scarce, as are accurate predictors of recovery of native kidney function. Without well-established listing guidelines, SLKT potentially wastes renal allografts in both high-acuity liver recipients at risk for early mortality and recipients who may regain native kidney function. METHODS: A retrospective single-center multivariate regression analysis was performed for adult patients undergoing SLKT (January 2004 to August 2014) to identify predictors of RAF. RESULTS: Of 331 patients dual-listed for SLKT, 171 (52%) expired awaiting transplant, 145 (44%) underwent SLKT, and 15 (5%) underwent liver transplantation alone. After SLKT, 39% experienced delayed graft function and 20.7% had RAF. Compared with patients without RAF, RAF recipients had greater MELD scores, length of hospitalization, intraoperative base deficit, incidence of female donors, kidney and liver donor risk indices, kidney cold ischemia, and inferior overall survival. Multivariate predictors of RAF included pretransplant dialysis duration, kidney cold ischemia, kidney donor risk index, and recipient hyperlipidemia. CONCLUSIONS: With 20% short-term loss of transplanted kidneys after SLKT, our data strongly suggest that renal transplantation should be deferred in liver recipients at high risk for RAF. Consideration for a kidney allocation variance to allow for delayed renal transplantation after liver transplantation may prevent loss of scarce renal allografts. PMID- 27232250 TI - Reply to the Letter: Improving the Safety of ALPPS Procedure: The Optimal Compromise Between Drop-out and Mortality Risk? Comment on: Schadde E et al Prediction of Mortality After ALPPS Stage-1: An Analysis of 320 Patients From the International ALPPS Registry. Ann Surg. 2015;262: 780-786. PMID- 27232251 TI - Percutaneous Transhepatic Feeding Tube Placement: Single-center Experience In 40 Consecutive Patients. PMID- 27232253 TI - Potential Pitfalls of Reporting and Bias in Observational Studies With Propensity Score Analysis Assessing a Surgical Procedure: A Methodological Systematic Review. AB - OBJECTIVE: To describe the evolution of the use and reporting of propensity score (PS) analysis in observational studies assessing a surgical procedure. BACKGROUND: Assessing surgery in randomized controlled trials raises several challenges. Observational studies with PS analysis are a robust alternative for comparative effectiveness research. METHODS: In this methodological systematic review, we identified all PubMed reports of observational studies with PS analysis that evaluated a surgical procedure and described the evolution of their use over time. Then, we selected a sample of articles published from August 2013 to July 2014 and systematically appraised the quality of reporting and potential bias of the PS analysis used. RESULTS: We selected 652 reports of observational studies with PS analysis. The publications increased over time, from 1 report in 1987 to 198 in 2013. Among the 129 reports assessed, 20% (n = 24) did not detail the covariates included in the PS and 77% (n = 100) did not report a justification for including these covariates in the PS. The rate of missing data for potential covariates was reported in 9% of articles. When a crossover by conversion was possible, only 14% of reports (n = 12) mentioned this issue. For matched analysis, 10% of articles reported all 4 key elements that allow for reproducibility of a PS-matched analysis (matching ratio, method to choose the nearest neighbors, replacement and method for statistical analysis). CONCLUSIONS: Observational studies with PS analysis in surgery are increasing in frequency, but specific methodological issues and weaknesses in reporting exist. PMID- 27232252 TI - Differential Prognostic Implications of Gastric Signet Ring Cell Carcinoma: Stage Adjusted Analysis From a Single High-volume Center in Asia. AB - OBJECTIVE: The aim of this study was to analyze the clinicopathologic characteristics and prognosis of signet ring cell carcinoma (SRC) according to disease status (early vs advanced gastric cancer) in gastric cancer patients. BACKGROUND: The prognostic implication of gastric SRC remains a subject of debate. METHODS: A retrospective analysis was performed using the clinical records of 7667 patients including 1646 SRC patients who underwent radical gastrectomy between 2001 and 2010. A further analysis was also performed after dividing patients into three groups according to histologic subtype: SRC, well-to moderately differentiated (WMD), and poorly differentiated adenocarcinoma. RESULTS: SRC patients have younger age distribution and female predominance compared with other histologic subtypes. Notably, the distribution of T stage of SRC patients was distinct, located in extremes (T1: 66.2% and T4: 20%). Moreover, the prognosis of SRC in early gastric cancer and advanced gastric cancer was contrasting. In early gastric cancer, SRC demonstrated more favorable prognosis than WMD after adjusting for age, sex, and stage. In contrast, SRC in advanced gastric cancer displayed worse prognosis than WMD. As stage increased, survival outcomes of SRC continued to worsen compared with WMD. CONCLUSIONS: Although conferring favorable prognosis in early stage, SRC has worse prognostic impact as disease progresses. The longstanding controversy of SRC on prognosis may result from disease status at presentation, which leads to differing prognosis compared with tubular adenocarinoma. PMID- 27232254 TI - Reply to: Does MRI Restaging of Rectal Cancer After Chemoradiotherapy Actually Permit a Change in Surgical Management? PMID- 27232255 TI - Alvimopan in Enhanced Recovery Colorectal Surgery? PMID- 27232257 TI - Does MRI Restaging of Rectal Cancer After Chemoradiotherapy Actually Permit a Change in Surgical Management? PMID- 27232256 TI - Computed Tomography Screening for Lung Cancer: Mediastinal Lymph Node Resection in Stage IA Nonsmall Cell Lung Cancer Manifesting as Subsolid and Solid Nodules. AB - OBJECTIVE: To compare long-term survival rates of patients with first, primary, clinical stage IA nonsmall cell lung cancer from a large cohort undergoing computed tomography screening with and without mediastinal lymph node resection (MLNR) under an Institutional Review Board-approved common protocol from 1992 to 2014. BACKGROUND: Assessing survival differences of patients with and without MLNR manifesting as solid and subsolid nodules. METHODS: Long-term Kaplan-Meier (K-M) survival rates for those with and without MLNR were compared and Cox regression analyses were used to adjust for demographic, computed tomography, and surgical covariates. RESULTS: The long-term K-M rates for 462 with and 145 without MLNR was 92% versus 96% (P = 0.19), respectively. For 203 patients with a subsolid nodule, 151 with and 52 without MLNR, the rate was 100%. For the 404 patients with a solid nodule, 311 with and 93 without MLNR, the rate was 87% versus 94% (P = 0.24) and Cox regression showed no statistically significant difference (P = 0.28) when adjusted for all covariates. Risk of dying increased significantly with increasing decades of age (hazard ratio [HR] 2.3, 95% confidence interval [CI] 1.4-3.8), centrally located tumor (HR 2.5, 95% CI 1.2 5.2), tumor size 21 to 30 mm (HR 2.7, 95% CI 1.2-6.0), and invasion beyond the lung stroma (HR 3.0, 95% CI 1.4-6.1). For the 346 patients with MLNR, tumor size was 20 mm or less; K-M rates for the 269 patients with and 169 patients without MLNR were also not significantly different (HR 2.1, P = 0.24). CONCLUSIONS: It is not mandatory to perform MLNR when screen-diagnosed nonsmall cell lung cancer manifests as a subsolid nodule. PMID- 27232258 TI - Reply to Letter: "A Different Approach to the Use of C-reactive Protein and Procalcitonin in Postoperative Infectious Complications". PMID- 27232259 TI - Improving the Safety of ALPPS Procedure: The Optimal Compromise Between Dropout and Mortality Risk. Comment on Schadde E et al Prediction of Mortality After ALPPS Stage-1: An Analysis of 320 Patients From the International ALPPS Registry. Ann Surg. 2015;262: 780-786. PMID- 27232260 TI - Incorporation of Procedure-specific Risk Into the ACS-NSQIP Surgical Risk Calculator Improves the Prediction of Morbidity and Mortality After Pancreatoduodenectomy. AB - OBJECTIVE: This multicenter study sought to evaluate the accuracy of the American College of Surgeons National Surgical Quality Improvement Program's (ACS-NSQIP) surgical risk calculator for predicting outcomes after pancreatoduodenectomy (PD) and to determine whether incorporating other factors improves its predictive capacity. BACKGROUND: The ACS-NSQIP surgical risk calculator has been proposed as a decision-support tool to predict complication risk after various operations. Although it considers 21 preoperative factors, it does not include procedure specific variables, which have demonstrated a strong predictive capacity for the most common and morbid complication after PD - clinically relevant pancreatic fistula (CR-POPF). The validated Fistula Risk Score (FRS) intraoperatively predicts the occurrence of CR-POPF and serious complications after PD. METHODS: This study of 1480 PDs involved 47 surgeons at 17 high-volume institutions. Patient complication risk was calculated using both the universal calculator and a procedure-specific model that incorporated the FRS and surgeon/institutional factors. The performance of each model was compared using the c-statistic and Brier score. RESULTS: The FRS was significantly associated with 30-day mortality, 90-day mortality, serious complications, and reoperation (all P < 0.0001). The procedure-specific model outperformed the universal calculator for 30-day mortality (c-statistic: 0.79 vs 0.68; Brier score: 0.020 vs 0.021), 90-day mortality, serious complications, and reoperation. Neither surgeon experience nor institutional volume significantly predicted mortality; however, surgeons with a career PD volume >450 were less likely to have serious complications (P < 0.001) or perform reoperations (P < 0.001). CONCLUSIONS: Procedure-specific complication risk influences outcomes after pancreatoduodenectomy; therefore, risk adjustment for performance assessment and comparative research should consider these preoperative and intraoperative factors along with conventional ACS-NSQIP preoperative variables. PMID- 27232261 TI - Prevalence of Barrett Esophagus in Adolescents and Young Adults With Esophageal Atresia. PMID- 27232262 TI - Reverse osmosis desalination of chitosan cross-linked graphene oxide/titania hybrid lamellar membranes. AB - With excellent mass transport properties, graphene oxide (GO)-based lamellar membranes are believed to have great potential in water desalination. In order to quantify whether GO-based membranes are indeed suitable for reverse osmosis (RO) desalination, three sub-micrometer thick GO-based lamellar membranes: GO-only, reduced GO (RGO)/titania (TO) nanosheets and RGO/TO/chitosan (CTS) are prepared, and their RO desalination performances are evaluated in a home-made RO test apparatus. The photoreduction of GO by TO improves the salt rejection, which increases slowly with the membrane thickness. The RGO/TO/CTS hybrid membranes exhibit higher rejection rates of only about 30% (greater than threefold improvement compared with a GO-only membrane) which is still inferior compared to other commercial RO membranes. The low rejection rates mainly arise from the pressure-induced weakening of the ion-GO interlayer interactions. Despite the advantages of simple, low-cost preparation, high permeability and selectivity of GO-based lamellar membranes, as the current desalination performances are not high enough to afford practical application, there still remains a great challenge to realize high performance separation membranes for water desalination applications. PMID- 27232263 TI - Relationship Between Diffusion Tensor Imaging (DTI) Findings and Cognition Following Pediatric TBI: A Meta-Analytic Review. AB - This study meta-analyzed research examining relationships between diffusion tensor imaging and cognition following pediatric traumatic brain injury (TBI). Data from 14 studies that correlated fractional anisotropy (FA) or apparent diffusion coefficient/mean diffusivity with cognition were analyzed. Short-term (<4 weeks post-TBI) findings were inconsistent, but, in the medium to long term, FA values for numerous large white matter tracts and the whole brain were related to cognition. However, the analyses were limited by the diversity of brain regions and cognitive outcomes that have been examined; all in relatively small samples. Moreover, additional data are needed to investigate the impact of age and injury severity on these findings. PMID- 27232264 TI - Non-muscle myosin-IIA is critical for podocyte f-actin organization, contractility, and attenuation of cell motility. AB - Several glomerular pathologies resulting from podocyte injury are linked to genetic variation involving the MYH9 gene, which encodes the heavy chain of non muscle myosin-IIA (NM-IIA). However, the functional role of NM-IIA has not been studied extensively in podocytes. We hypothesized that NM-IIA is critical for maintenance of podocyte structure and mechanical function. To test this hypothesis, we studied murine podocytes in vitro subjected to blebbistatin inhibition of NM-II activity, or RNA interference-mediated, isoform-specific ablation of Myh9 gene and protein (NM-IIA) or its paralog Myh10 gene and protein (NM-IIB). Using quantitative immunofluorescence microscopy, traction force microscopy, and attachment and "wound healing" assays, we found that NM-IIA ablation altered podocyte actin cytoskeletal structure and focal adhesion distribution, decreased cell attachment and contractility, and increased cell motility. Blebbistatin treatment had similar effects. NM-IIB ablation produced cells that exhibited poor attachment, but cytoskeletal structural organization, contractility and motility were maintained. These findings indicate that NM-IIA is essential for maintenance of podocyte cytoskeletal structure and mechanical function in vitro, and NM-IIB does not replace it in this role when NM-IIA expression is altered. We conclude that critical podocyte functions may be affected by MYH9 mutations or disease-associated haplotypes. (c) 2016 Wiley Periodicals, Inc. PMID- 27232265 TI - A review of the venous thrombotic issues associated with multiple myeloma. AB - INTRODUCTION: Patients with multiple myeloma (MM) have an increased risk of venous thromboembolic (VTE) complications. The first reports of high VTE rates date back to 1999 but became more apparent with the introduction of novel agents in the treatment of MM and mostly with immunomodulatory drugs (IMiDs; thalidomide, lenalidomide and pomalidomide). AREAS COVERED: Currently thromboprophylaxis is recommended for patients who receive IMiDs-based regimens and the type of thrombophrophylaxis is based on patient-, disease- and treatment related risk factors. Making the distinction between the intrinsic risk of thrombosis in MM and the effect of therapy is crucial. The use of aspirin, low molecular weight heparins and warfarin are the recommended drugs but despite their appropriate use the rates of VTE are not completely eliminated. Expert commentary: Research into biomarkers of increased coagulability and their incorporation in risk assessment models could identify patients most likely to benefit from thromboprophylaxis but such models are not widely used in myeloma. PMID- 27232266 TI - Neutral Mononuclear Copper(I) Complexes: Synthesis, Crystal Structures, and Photophysical Properties. AB - Neutral green-emitting four-coordinate Cu(I) complexes with general formula POPCu(NN), where POP = bis[2-(diphenylphosphino)phenyl]ether and NN = substituted 2-pyridine-1,2,4-triazole ligands, were synthesized. The crystal structures of (POPCuMeCN)(+)(PF6)(-) (1), POPCuPhPtp (2a, PhPtp = 2-(5-phenyl-2H-[1,2,4]triazol 3-yl)-pyridine), and POPCu(3,5-2FPhPtp) (2d, 3,5-2FPhPtp = 2-(5-(3,5 difluorophenyl)-2H-1,2,4-triazol-3-yl)pyridine) were determined by single-crystal X-ray diffraction analysis. The electronic and photophysical properties of the complexes were examined by UV-vis, steady-state, and time-resolved spectroscopy. At room temperature, weak emission was observed in solution, while in the solid state, all complexes exhibit intense green emission with quantum yield up to 0.54. The electronic and photophysical properties were further supported by calculation performed at the (time-dependent) density functional theory level. One of the complexes was also tested as dopant in electroluminescent devices. PMID- 27232267 TI - Transition-Metal-Free TBAI-Facilitated Addition-Cyclization of N-Methyl-N arylacrylamides with Arylaldehydes or Benzenesulfonohydrazides: Access to Carbonyl- and Sulfone-Containing N-Methyloxindoles. AB - A highly efficient addition-cyclization of N-methyl-N-arylacrylamides with arylaldehydes or benzenesulfonohydrazides was developed using a catalytic amount of the quaternary ammonium salt (TBAI) under metal-free conditions, leading to the carbonyl- and sulfone-containing oxindoles. Compared to previous methods, which require excessive amounts of explosive organic peroxides and precious or toxic metal reagents, the present protocol, which gave access to 3,3 disubstituted oxindoles, is a safe and green approach, resulting in the formation of various useful carbonyl- and sulfone-containing oxindoles in yields of 40-94%. PMID- 27232268 TI - Well, at least it is better than death.... PMID- 27232269 TI - Polyspermic fertilization resulting in multipolarity in a sea star zygote. PMID- 27232270 TI - Total Synthesis of the GRP78-Downregulatory Macrolide (+)-Prunustatin A, the Immunosuppressant (+)-SW-163A, and a JBIR-04 Diastereoisomer That Confirms JBIR 04 Has Nonidentical Stereochemistry to (+)-Prunustatin A. AB - A unified total synthesis of the GRP78-downregulator (+)-prunustatin A and the immunosuppressant (+)-SW-163A based upon [1 + 1 + 1 + 1]-fragment condensation and macrolactonization between O(4) and C(5) is herein described. Sharpless asymmetric dihydroxylation was used to set the C(2) stereocenter present in both targets. In like fashion, coupling of the (+)-prunustatin A macrolide amine with benzoic acid furnished a JBIR-04 diastereoisomer whose NMR spectra did not match those of JBIR-04, thus confirming that it has different stereochemistry than (+) prunustatin A. PMID- 27232271 TI - Cellulose Nanofibril Film as a Piezoelectric Sensor Material. AB - Self-standing films (45 MUm thick) of native cellulose nanofibrils (CNFs) were synthesized and characterized for their piezoelectric response. The surface and the microstructure of the films were evaluated with image-based analysis and scanning electron microscopy (SEM). The measured dielectric properties of the films at 1 kHz and 9.97 GHz indicated a relative permittivity of 3.47 and 3.38 and loss tangent tan delta of 0.011 and 0.071, respectively. The films were used as functional sensing layers in piezoelectric sensors with corresponding sensitivities of 4.7-6.4 pC/N in ambient conditions. This piezoelectric response is expected to increase remarkably upon film polarization resulting from the alignment of the cellulose crystalline regions in the film. The CNF sensor characteristics were compared with those of polyvinylidene fluoride (PVDF) as reference piezoelectric polymer. Overall, the results suggest that CNF is a suitable precursor material for disposable piezoelectric sensors, actuators, or energy generators with potential applications in the fields of electronics, sensors, and biomedical diagnostics. PMID- 27232272 TI - Predictors of high-quality cord blood units. AB - BACKGROUND: Analysis of umbilical cord blood (UCB) transplants shows a correlation between engraftment and total number of infused cells. Thus, it is worth evaluating what maternal and neonatal characteristics and collection techniques may affect the quality of UCB units. STUDY DESIGN AND METHODS: A cross sectional study was performed with 7897 donors sequentially selected in three health care institutions in Brazil from October 2004 to March 2012, in which both quantitative and qualitative approaches were applied. All donors were considered suitable for cord blood collection. RESULTS: The maternal and neonatal characteristics and techniques of collection that influenced the total number of nucleated cells (TNCs; p < 0.001) were type of delivery, newborn weight and sex, and institution of UCB collection. The TNC count was associated with gestational age (p = 0.008), type of delivery (p < 0.001), newborn sex (p < 0.001), newborn weight (p < 0.001), and UCB collection technique (p = 0.003). Center B presented the largest number of nucleated cells in its results (p < 0.001), followed by Center A (p = 0.001). Other characteristics, such as maternal age, were analyzed but were not relevant for the nucleated cell number. CONCLUSION: This study provides elements for a model that allows an efficient selection of UCB donors, prioritizing candidates who have a better chance to lead to an optimized use of cord blood cells units. PMID- 27232273 TI - Acute lymphoblastic leukemia in a patient with MonoMAC syndrome/GATA2 haploinsufficiency. AB - Patients with GATA2 haploinsufficiency have a significant predisposition to developing cytopenias, unique infectious manifestations, and myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). We report a unique case of a patient who presented with B-cell acute lymphoblastic leukemia (B-ALL) and was subsequently diagnosed with monocytopenia and mycobacterium avium complex (MonoMAC) syndrome/GATA2 haploinsufficiency. The development of MDS/AML in patients with GATA2 haploinsufficiency is well described, however, the development of ALL has not been reported in the literature. ALL may be associated with GATA2 haploinsufficiency. Clinicians should be attuned to the features of the MonoMAC syndrome in patients with ALL that would prompt additional testing and alter treatment. PMID- 27232274 TI - Influence of vanadium-doping on the magnetism of FeCo/SiO2 nanoparticle. AB - FeCo nanoparticles (4 +/- 1 nm), encapsulated by SiO2, were synthesized with and without a 2% (atomic ratio) vanadium doping. The impact from the presence of vanadium, an additive often used in the bulk to alter both physical and mechanical properties, on the nanomagnetism was probed by element-specific X-ray spectroscopy and magnetometry techniques. While the nanostructure was unaffected by the addition of 2% vanadium, the temperature dependent magnetic properties were altered significantly, such as the increased coercivity and an exchange bias field shift. PMID- 27232275 TI - beta-Lactamases: Why and How. AB - The targets of beta-lactam antibiotics are bacterial DD-peptidases that catalyze the final steps of peptidoglycan biosynthesis. Bacterial resistance to beta lactams is achieved by the production of beta-lactamases, enzymes that catalyze beta-lactam hydrolysis. Structural studies of both of these groups of enzymes, their substrates and of beta-lactams have led to the conclusion that beta lactamases have evolved from a DD-peptidase ancestor. Thus, the active sites of DD-peptidases and serine beta-lactamases are very similar. Why is it then that the active site of a serine beta-lactamase can catalyze hydrolysis of a beta lactam while that of a DD-peptidase cannot? In view of the active site similarities, why was it necessary for beta-lactamases to evolve at all? The aim of this review is to examine our current understanding of these issues in terms of the crystal structures of the relevant enzymes that are now available, rounding off the analysis with speculation where necessary. PMID- 27232276 TI - The distribution of MNS hybrid glycophorins with Mur antigen expression in Chinese donors including identification of a novel GYP.Bun allele. AB - BACKGROUND AND OBJECTIVES: MNS hybrid glycophorins are identified by characteristic antigen profiles. One of these is the Mur antigen, which is expressed on red cell hybrid glycophorins of several phenotypes of the 'Miltenberger' series found predominantly in East Asian population. The aim of this study was to investigate the distribution of Mur-positive hybrid glycophorins and clarify the genetic basis in the donors from southern China. MATERIALS AND METHODS: Blood samples from 528 donors were collected for Mur antigen serological typing. Sequencing of GYPB pseudoexon 3 and MNS phenotyping were conducted in Mur-positive samples. The multiplex ligation-dependent probe amplification (MLPA) was used to confirm the zygosity of the GYP.Mur allele and determine the MNSs genotype. The expression of Mur antigen was evaluated by flow cytometry. RESULTS: Fifty-one Mur-positive samples were identified by serological testing. Sequencing analysis showed 50 donors (50/528, 9.5%) with the GYP.Mur allele (48 heterozygotes and two homozygotes), which were confirmed by the MLPA genotyping analysis, and one donor (1/528, 0.19%) with a novel GYP.Bun allele. Flow cytometry analysis revealed higher Mur antigen expression on GP.Mur (Mi.III) homozygotes than heterozygotes. For the GYP.Mur homozygotes, an incorrect 'N' positive typing with anti-N lectin was obtained. CONCLUSION: GP.Mur (Mi.III) is the main Mur-positive hybrid glycophorin in Guangzhou donors. The dosage effect of Mur antigen observed provides a basis for selecting the homozygous GP.Mur RBCs as the reagent cells to avoid neglecting weak antibodies. A separate GYP.Bun lineage found in the southern China provides evidence for further complexity in the MNS system. PMID- 27232278 TI - High-sensitivity troponin and extubation failure after successful spontaneous breathing trial. PMID- 27232279 TI - Failure of statins in ARDS: the quest for the Holy Grail continues. AB - Experimental and clinical observational studies have shown potential benefits of statin administration in the acute respiratory distress syndrome (ARDS) by modulating inflammation and preventing worsening respiratory function. More recently, two randomized clinical trials failed to demonstrate an improved survival of ARDS patients treated with statins. In the first study, conducted by the ARDS Network, 745 patients with sepsis-associated ARDS were randomized within 48-hours of onset to receive either rosuvastatin or placebo. There was no significant difference between the rosuvastatin and placebo groups for hospital mortality (primary outcome, 29% vs. 25%, P=0.21) or ventilator-free days (15+/-11 vs. 15+/-11, respectively; P=0.96). In rosuvastatin-treated patients, renal and hepatic failure free-days were significantly lower than in the placebo group, raising serious safety concerns. In the second study (HARP-2 trial), 540 patients with ARDS were randomized within 48-hours of onset to receive either simvastatin (80 mg/day) or placebo. There was no significant difference between the study groups for number of ventilator-free days (primary outcome, 13+/-10 in the simvastatin vs. 12+/-10 in the placebo group, P=0.21) or 28-day mortality (22% vs. 27%, respectively; P=0.23). No significant difference in serious adverse events was reported between groups. Herein, we discuss the main reasons for these negative findings and consider where there could be a role for statins in ARDS patients. PMID- 27232280 TI - Cervical emphysema and pneumomediastinum due to isolated pharyngeal perforation after blunt trauma. PMID- 27232277 TI - Residual neuromuscular blockade in the postanesthesia care unit: observational cross-sectional study of a multicenter cohort. AB - BACKGROUND: Residual neuromuscular blockade after general anesthesia using nondepolarizing neuromuscular blocking agents has pathophysiological, clinical, and economic consequences. A significant number of patients under muscle relaxation sustain residual curarization. METHODS: Observational, prospective, multicenter study of a cohort of patients (Residual Curarization in Spain Study, ReCuSS). Residual blockade was defined as TOFr<0.9. Patients >18 years-old under general anesthesia, including at least one dose of non-depolarizing neuromuscular blocking agents, and transferred extubated and spontaneously ventilating to the postanesthesia care unit were included. Pre- and intraoperative data were recorded, including, patient characteristics, ASA physical status, experience of the anesthesiologist, type of surgery, temperature monitoring, surgery duration, neuromuscular blockade-related parameters, type of anesthesia (halogenated balanced, intravenous propofol-based, other), and use of neuromuscular monitoring. RESULTS: A total of 763 patients from 26 hospitals were included, 190 patients (26.7%) showing residual paralysis. Female patients were more prone to residual neuromuscular blockade. Length of surgery, type of relaxant used (benzylisoquinolines), halogenated anesthesia, absence of intraoperative specific monitoring, avoidance of drug reversal, and neostigmine reversal (vs. sugammadex), were significantly related to residual blockade. In the postanesthesia care unit, patients with residual neuromuscular blockade had an increased incidence of respiratory events and tracheal reintubation. CONCLUSIONS: The incidence of residual blockade in Spain is similar to that published in other settings and countries. Female gender, longer duration of surgery, and halogenated drugs for anesthesia maintenance were related to residual paralysis, as were NMBA specific items, such as the use of benzylisoquinoline drugs, and the absence of reversal or reversal with neostigmine. PMID- 27232281 TI - Potential diagnostic and prognostic biomarkers for cholangiocarcinoma in serum and bile. AB - Cholangiocarcinoma (CCA) is a devastating malignancy that is difficult to treat because of its insensitivity to conventional therapies and the inability to detect early tumor formation. Novel molecular techniques have enabled the use of serum and bile markers for CCA diagnosis and prognosis. Herein, we summarize the principal characteristics of serum and bile markers of CCA. Biomarkers such as interleukin-6, matrix metalloproteinases, serotonin (5-hydroxytryptamine) and bile acids have shown promise for improving CCA diagnosis. Several markers such as CYFRA 21-1, MK-1 and C-reactive protein were recently shown to be effective for CCA prognosis. PMID- 27232282 TI - The use of Masson's trichrome staining, second harmonic imaging and two-photon excited fluorescence of collagen in distinguishing intestinal tuberculosis from Crohn's disease. AB - AIM: Differentiation between Crohn's disease (CD) and intestinal tuberculosis (ITB) continues to be difficult. The present study investigated the collagen fibre characteristics of CD and ITB using Masson's trichrome staining, second harmonic generation (SHG) imaging and two-photon excited fluorescence (TPEF) imaging with the aim of distinguishing between them. METHOD: The characteristics of collagen fibres in intestinal specimens from patients with CD, ITB and healthy controls were compared using Masson's trichrome staining and SHG and TPEF imaging. RESULTS: Masson's trichrome staining showed that the content of collagen fibre (540.92 [139.61-1681.93] vs 236.17 [72.94-1108.32], P < 0.05) and fibre deposits (888.92 [315.89-3172.9] vs 498.98 [38.82-5802.31], P < 0.05) were both higher in ITB than in CD. The content of collagen fibre (594.677 [139.61-1681.93] vs 107.425 [4.66-988.7], P < 0.05) and fibre deposits (1118.4661 [315.89-5802.31] vs 340.575 [29.62-1188.87], P < 0.05) were significantly higher in lesions with granulomata than in those without. The SHG/TPEF images demonstrated that the percentage of fibrosis in ITB was also significantly higher than in CD (P < 0.05), in both surgical (13.363% +/- 5.303% vs 8.322% +/- 5.078%, P = 0.044) and endoscopic specimens (mean rank 13.5 vs 7.5, P = 0.023). The SHG/TPEF imaging described different distribution patterns of collagen between CD and ITB; in the former this was irregular in clumps while in ITB the collagen was arranged around caseating granulomata. CONCLUSION: The evaluation of fibrosis in CD and ITB by Masson's trichrome staining and SHG and TPEF imaging appears to distinguish between these two diseases. PMID- 27232284 TI - An unusual condition during internal jugular vein catheterisation: vertebral artery catheterisation. AB - Vertebral artery cannulation is an unusual complication during internal jugular vein cannulation. We report a case of vertebral artery cannulation, which occurred during an attempt to cannulate the right internal jugular vein, and we discuss the management of such a rare complication. PMID- 27232286 TI - First-line use of rituximab correlates with increased overall survival in late post-transplant lymphoproliferative disorders: retrospective, single-centre study. AB - This retrospective study evaluates the impact of rituximab on PTLD response and survival in a single-centre cohort. PTLD cases between 1984 and 2009, including heart, kidney, liver and lung transplant recipients, were included. Survival was analysed taking into account the type of PTLD (monomorphic vs. polymorphic), EBV infection status, IPI score, Ann Arbor stage and use of rituximab. Among 1335 transplanted patients, 24 developed PTLD. Median age was 54 yr (range 29-69), median time to diagnosis 50 months (range 0-100). PTLD type was predominantly late/monomorphic (79% and 75%), mostly diffuse large B-cell type. Overall response rate (ORR) was 62% (66% rituximab vs. 50% non-rituximab; P = 0.5). R CHOP-like regimens were used most frequently (72% of patients treated with rituximab). Median overall survival was 64 months (CI 95% 31-96). OS was significantly increased in patients treated with rituximab (P = 0.01; CI 95% rituximab 58-79 months; non-rituximab 1-30 months). Post-transplant immunosuppression regimen had no effect on survival or time to PTLD, except for cyclosporine A (CyA), which associated with increased time to PTLD (P = 0.02). Rituximab was associated with increased survival in our single-centre series, and it should be considered as first-line therapy for PTLD patients. The possible protective effect of CyA for development of PTLD should be prospectively evaluated. PMID- 27232287 TI - Parents Plus Systemic, Solution-Focused Parent Training Programs: Description, Review of the Evidence Base, and Meta-Analysis. AB - Parents Plus (PP) programs are systemic, solution-focused, group-based interventions. They are designed for delivery in clinical and community settings as treatment programs for families with child-focused problems, such as behavioral difficulties, disruptive behavior disorders, and emotional disorders in young people with and without developmental disabilities. PP programs have been developed for families of preschoolers, preadolescent children, and teenagers, as well as for separated or divorced families. Seventeen evaluation studies involving over 1,000 families have shown that PP programs have a significant impact on child behavior problems, goal attainment, and parental satisfaction and stress. The effect size of 0.57 (p < .001) from a meta-analysis of 10 controlled studies for child behavior problems compares favorably with those of meta-analyses of other well-established parent training programs with large evidence bases. In controlled studies, PP programs yielded significant (p < .001) effect sizes for goal attainment (d = 1.51), parental satisfaction (d = 0.78), and parental stress reduction (d = 0.54). PP programs may be facilitated by trained front-line mental health and educational professionals. PMID- 27232288 TI - MID-PREGNANCY CORTICOTROPIN-RELEASING HORMONE LEVELS IN ASSOCIATION WITH POSTPARTUM DEPRESSIVE SYMPTOMS. AB - BACKGROUND: Peripartum depression is a common cause of pregnancy- and postpartum related morbidity. The production of corticotropin-releasing hormone (CRH) from the placenta alters the profile of hypothalamus-pituitary-adrenal axis hormones and may be associated with postpartum depression. The purpose of this study was to assess, in nondepressed pregnant women, the possible association between CRH levels in pregnancy and depressive symptoms postpartum. METHODS: A questionnaire containing demographic data and the Edinburgh Postnatal Depression Scale (EPDS) was filled in gestational weeks 17 and 32, and 6 week postpartum. Blood samples were collected in week 17 for assessment of CRH. A logistic regression model was constructed, using postpartum EPDS score as the dependent variable and log transformed CRH levels as the independent variable. Confounding factors were included in the model. Subanalyses after exclusion of study subjects with preterm birth, newborns small for gestational age (SGA), and women on corticosteroids were performed. RESULTS: Five hundred thirty-five women without depressive symptoms during pregnancy were included. Logistic regression showed an association between high CRH levels in gestational week 17 and postpartum depressive symptoms, before and after controlling for several confounders (unadjusted OR = 1.11, 95% CI 1.01-1.22; adjusted OR = 1.13, 95% CI 1.02-1.26; per 0.1 unit increase in log CRH). Exclusion of women with preterm birth and newborns SGA as well as women who used inhalation corticosteroids during pregnancy did not alter the results. CONCLUSIONS: This study suggests an association between high CRH levels in gestational week 17 and the development of postpartum depressive symptoms, among women without depressive symptoms during pregnancy. PMID- 27232285 TI - Alarmins and Their Receptors as Modulators and Indicators of Alloimmune Responses. AB - Cell damage and death releases alarmins, self-derived immunomodulatory molecules that recruit and activate the immune system. Unfortunately, numerous processes critical to the transplantation of allogeneic materials result in the destruction of donor and recipient cells and may trigger alarmin release. Alarmins, often described as damage-associated molecular patterns, together with exogenous pathogen-associated molecular patterns, are potent orchestrators of immune responses; however, the precise role that alarmins play in alloimmune responses remains relatively undefined. We examined evolving concepts regarding how alarmins affect solid organ and allogeneic hematopoietic cell transplantation outcomes and the mechanisms by which self molecules are released. We describe how, once released, alarmins may act alone or in conjunction with nonself materials to contribute to cytokine networks controlling alloimmune responses and their intensity. It is becoming recognized that this class of molecules has pleotropic functions, and certain alarmins can promote both inflammatory and regulatory responses in transplant models. Emerging evidence indicates that alarmins and their receptors may be promising transplantation biomarkers. Developing the therapeutic ability to support alarmin regulatory mechanisms and the predictive value of alarmin pathway biomarkers for early intervention may provide opportunities to benefit graft recipients. PMID- 27232289 TI - Laparoscopic resection of a hepatic mucinous cystic neoplasm: A case report. AB - INTRODUCTION: We aimed to present a case of hepatic mucinous cystic neoplasm (MCN H) that was completely resected by laparoscopy. PRESENTATION OF CASE: A 47-year old female exhibited mild elevation of serum liver enzyme levels. Abdominal computed tomography revealed a 45-mm multilocular cystic tumor in segment IV of the liver, along with intermittent border calcification and minimal wall thickness. Magnetic resonance imaging revealed fluid-to-fluid level in the cystic tumor, thereby increasing the suspicion of a mild hemorrhage. The patient underwent laparoscopic liver resection (LLR) with a diagnosis of suspected mucinous cystic neoplasm of the liver. The entire tumor was successfully resected with a laparoscopic approach. The resected specimen was a 4.2*3.3*2.2-cm cystic tumor. Histological findings revealed mucin-producing singular epithelium and ovarian-like stroma. The tumor was diagnosed as a MCN-H with no malignancy. DISCUSSION: This is the first report in which a MCN-H was completely resected by laparoscopy. MCN-H is rare and is observed in only<5% of liver cystic tumors. MCN H has been reported to have the malignant potential. And complete resection might be a good treatment option. Along with technical development, LLR has been indicated for benign liver tumors to date. Benign liver tumors are commonly observed in young females. The smaller incisions of the laparoscopic approach might provide cosmetic advantages for patients. CONCLUSION: We presented the first case of a MCN-H completely resected by laparoscopy. Benign tumors and tumors with malignant potential might be good indications for a laparoscopic surgery. PMID- 27232290 TI - Complex gunshot injury to the heart as a consequence of suicide attempt in a schizophrenic patient. AB - INTRODUCTION: Self-inflicted gunshot injury to the heart is uncommon in Western Europe countries. However it is considered to have a high mortality through cardiac tamponade or exsanguination and concomitant chest or abdominal cavity injury. CASE PRESENTATION: We present a 39-year-old schizophrenic woman who attempted suicide with the aid of a 6.35mm caliber handgun, after self discontinuing of antipsychotic treatment. Lower third of sternum, right heart atrium and ventricle and inferior caval vein were hit by the bullet which consequently got lodged in the right paravertebral muscle mass at the lower thoracic vertebral level. As she was hemodynamically unstable due to hemopericardium and a huge right hemothorax, she underwent emergent surgery. Heart and inferior vena caval injuries were repaired on extracorporeal circulation. The postoperative course was uneventful and she was transferred to a psychiatric facility on the 7th postoperative day. One year after the surgery she is well, compliant to antipsychotic medications and on periodic follow-up by psychiatrists. CONCLUSION: This case represents management of complex self inflicted gunshot cardiac injury in a schizophrenic patient who discontinued antipsychotic medication. Liaison between themedical rescue service and high level trauma center essentially reduced injury-to-surgery time. Complex heart injury was successfully repaired on extracorporeal circulation. PMID- 27232291 TI - Adrenal extramedullary hematopoiesis associated with beta-thalassemia trait in an adult woman: a case report and review of literature. AB - INTRODUCTION: Adrenal myelolipoma with extramedullary hematopoiesis (EMH) is a rare condition. CASE PRESENTATION: We report a case of 48-year-old woman suffering from recurrent right hypochondrial pain for two years. Laboratory work up revealed chronic microcytic iron deficiency anemia with beta thalassemia trait, right adrenal myelolipoma with histopathological evidence of hematopoietic cells (EMH). The patient underwent open resection of the adrenal gland and the post-operative course was uneventful. CONCLUSIONS: EMH could be presented with several clinical hematological disorders. Surgical management becomes inevitable in certain adrenal EMH cases especially in the presence of a large adrenal mass. PMID- 27232292 TI - Large pneumothorax in blunt chest trauma: Is a chest drain always necessary in stable patients? A case report. AB - INTRODUCTION: Pneumothorax is the most common potentially life-threatening blunt chest injury. The management of pneumothorax depends upon the etiology, its size and hemodynamic stability of the patient. Most clinicians agree that chest drainage is essential for the management of traumatic large pneumothorax. Herein, we present a case of large pneumothorax in blunt chest trauma patient that resolved spontaneously without a chest drain. PRESENTATION OF CASE: A 63- year- old man presented to the Emergency Department complaining of left lateral chest pain due to a fall on his chest at home. On examination, he was hemodynamically stable. An urgent chest X-ray showed evidence of left sided pneumothorax. CT scan of the chest showed pneumothorax of more than 30% of the left hemithorax (around 600ml of air) with multiple left ribs fracture. Patient refused tube thoracostomy and was admitted to surgical department for close observation. The patient was managed conservatively without chest tube insertion. A repeat CT scan of the chest has shown complete resolution of the pneumothorax. DISCUSSION: The clinical spectrum of pneumothorax varies from asymptomatic to life threatening tension pneumothorax. In stable patients, conservative management can be safe and effective for small pneumothorax. To the best of our knowledge, this is the second reported case in the English literature with large pneumothorax which resolved spontaneously without chest drain. CONCLUSION: Blunt traumatic large pneumothorax in a clinically stable patient can be managed conservatively. Current recommendations for tube placement may need to be reevaluated. This may reduce morbidity associated with chest tube thoracostomy. PMID- 27232293 TI - An angry cat causing Pasteurella multocida endocarditis and aortic valve replacement-A case report. AB - INTRODUCTION: Cat bite infections usually involve a mix of anaerobic and aerobic bacteria including species of Pasteurella, Streptococcus, Staphylococcus, Bacteroides, and Fusobacterium. We report a case of Pasteurella multocida infection from cat bites leading to endocarditis and subsequent aortic valve replacement. PRESENTATION OF CASE: A 70-year-old male was admitted because of fever, tachycardia, and malaise. He had a history of alcohol abuse and was living alone with a cat in a rural area. A sepsis of unknown origin was suspected, and intravenous treatment with gentamicin and cefotaxime was initiated. Blood cultures yielded Pasteurella multocida, and the patient history revealed repeated cat bites. After four days, the patient was discharged with oral penicillin V treatment. Two weeks later, the patient returned with fever and a new systolic murmur. An aortic valve endocarditis was diagnosed, and it became clear that the patient had not completed the prescribed penicillin V treatment. The patient underwent a biological aortic valve replacement with debridement of an annular abscess, and the postoperative course was uneventful. DISCUSSION: Endocarditis due to Pasteurella is extremely rare, and there are only a few reports in the literature. Predisposing factors in the present case were alcohol abuse and reduced compliance to treatment. CONCLUSION: Cat bites are often deep, and in rare circumstances can lead to life-threatening endocarditis. Proper surgical revision, antibiotic treatment, and patient compliance are necessary components in patient care to avoid this complication. PMID- 27232294 TI - Concomitantly intra-articular fracture of proximal condylar second and third proximal phalanges: A rare case report. AB - INTRODUCTION: A rare case of proximal phalange fractures has been presented in this study. PRESENTATION OF CASE: A 29-year-old male patient from Turkey was admitted to the orthopedics and traumatology clinic with a complaint of left hand pain, which had persisted for 10days. He described a rotational trauma that had occurred right after hitting his hand on the wheel of a car as a result of an in car traffic accident 10days ago. Radiological work-ups were requested. In the anteroposterior (AP) graph of the case in which the fracture line could not be observed in the oblique graph, unicondylar fractures in the proximal section of the second and third proximal phalanges have been observed. Surgical treatment was not planned because 10days had passed since the trauma. In the control graphs taken after 3 weeks, healing at the fracture site was observed, and he was referred to physiotherapy after the removal of the splint. A good result was observed after physiotherapy. DISCUSSION: Because of the extension of tendons is important over the bone, the goal of the treatment is not only to heal the fracture, but also to preserve the sliding mechanism of these tendons. Regarding to lack of soft tissue trauma, favored joint movements after the healing of the fracture can be achieved more easily with conservative treatment; however, the fracture must be closely followed up. CONCLUSION: Condylar fractures of proximal phalanges those nondisplaced can be conservatively treated with closed methods. PMID- 27232295 TI - Primary breast angiosarcoma in a young woman. AB - INTRODUCTION: Angiosarcomas of the breast are a rare subtype of sarcomas that frequently are diagnosed after radiation therapy for primary breast cancer. Primary angiosarcomas are rare entities accounting 0.05% of all malignant breast neoplasm. PRESENTATION OF CASE: We report a case of primary angiosarcoma of the breast in a 25 years woman, with no previous radiotherapy, treated with a total mastectomy followed by radio-chemotherapy. DISCUSSION: Total mastectomy appears to be the only treatment known that has proven to benefit these patients. Adjuvant treatment has not proven value up until today. The 5-year disease free survival for grade 1 tumors can be as high as 76%, and up to 15% for grade 3. CONCLUSION: Due to the rarity of these tumors there is no standard therapies approach. PMID- 27232296 TI - Disaster-related prenatal maternal stress explains increasing amounts of variance in body composition through childhood and adolescence: Project Ice Storm. AB - BACKGROUND: The increasing prevalence of childhood obesity worldwide has become a public health issue. While many factors are involved in the development of obesity, stress during pregnancy has been linked to adiposity. However, research involving stressors that are independent of pregnant women's socioeconomic and psychological characteristics is rare. The present study made use of a natural disaster (1998 Quebec ice storm) to determine which aspect of the women's disaster experience (objective hardship, subjective stress, and/or cognitive appraisal) were associated with body mass index levels and/or waist to height ratio across childhood and adolescence. METHODS: Measure of objective hardship, subjective stress, and cognitive appraisal were obtained following the 1998 Quebec ice storm. We measured height, weight, and waist circumference in children at ages 51/2, 81/2, 111/2, 131/2, and 151/2. RESULTS: Our results show that higher prenatal maternal stress was associated with higher body mass index levels and central adiposity in children of ages 51/2, 81/2, 131/2, and 151/2. The effects of prenatal maternal stress on anthropometric measurements tend to increase as the children grew older. DISCUSSION: The findings of this study highlight the long-lasting effect of prenatal stress on body composition, and are compatible with the current theory of fetal programming. Hopefully, our increased knowledge of the effects of prenatal stress on the fetus will lead to improved awareness and the creation of early intervention programs, ultimately improving women's and children's health in the future. PMID- 27232297 TI - Noise sensitivity: Symptoms, health status, illness behavior and co-occurring environmental sensitivities. AB - Epidemiological evidence on the symptomatic profile, health status and illness behavior of people with subjective sensitivity to noise is still scarce. Also, it is unknown to what extent noise sensitivity co-occurs with other environmental sensitivities such as multi-chemical sensitivity and sensitivity to electromagnetic fields (EMF). A cross-sectional study performed in the Netherlands, combining self-administered questionnaires and electronic medical records of non-specific symptoms (NSS) registered by general practitioners (GP) allowed us to explore this further. The study sample consisted of 5806 participants, drawn from 21 general practices. Among participants, 722 (12.5%) responded "absolutely agree" to the statement "I am sensitive to noise", comprising the high noise-sensitive (HNS) group. Compared to the rest of the sample, people in the HNS group reported significantly higher scores on number and duration of self-reported NSS, increased psychological distress, decreased sleep quality and general health, more negative symptom perceptions and higher prevalence of healthcare contacts, GP-registered NSS and prescriptions for antidepressants and benzodiazepines. These results remained robust after adjustment for demographic, residential and lifestyle characteristics, objectively measured nocturnal noise exposure from road-traffic and GP-registered morbidity. Co-occurrence rates with other environmental sensitivities varied between 9% and 50%. Individuals with self-declared sensitivity to noise are characterized by high prevalence of multiple NSS, poorer health status and increased illness behavior independently of noise exposure levels. Findings support the notion that different types of environmental sensitivities partly overlap. PMID- 27232302 TI - Self-assembly of pH-responsive biodegradable mixed micelles based on anionic and cationic polycarbonates for doxorubicin delivery. AB - Poly(5-propyl-1,3-dioxan-2-one)-b-dimethylamine modified polycarbonate (PC(MPpC MMA)) and poly(ethylene glycol)-b-carboxylated polycarbonate (PEG-PCCOOH) diblock copolymers were prepared to construct a pH responsive, highly stable and biodegradable mixed micelle. The two copolymers self-assembled into the mixed micelle in pH 7.4 PBS driven by electrostatic and hydrophobic interactions. PC(MPpC-MMA) with hydrophobic inner core was used for carrying drug and the dimethylamine part was designed as a trigger to disassemble the mixed micelle. PEG-PCCOOH could shield the positive character of the micelle which might show disadvantage to normal tissue. In addition, the free carboxyl groups could further increase the loading efficiency of positive charged drugs. The size and zeta potential of the micelle gradually decreased with increasing the molar ratio of PEG-PCCOOH to PC(MPpC-MMA). These mixed micelles could withstand high ionic strength of plasma and were rather stable for long time storage. However, via decrease of pH value from 7.4 to 5.0, they could undergo dissociation into smaller nanoparticles which were in a diameter of 20nm and showed positive surface nature. In vitro drug delivery studies showed a faster release rate at pH 5.0 than that at pH 7.4. The MTT assays demonstrated potent cytotoxic activity against HepG2 cells. All these results indicate that the newly mixed polycarbonate micelle can show great potential in biomedical field. PMID- 27232303 TI - pH-responsive zwitterionic polypeptide as a platform for anti-tumor drug delivery. AB - In this paper, a doxorubicin delivery system is reported based on a pH-responsive zwitterionic polypeptide derivative. To improve the anti-protein-fouling capacity, the poly(amino acid) was modified by grafting short-chain zwitterions via aminolysis reaction of polysuccinimide with l-lysine. As a result, both positively and negatively charged moieties were introduced onto the same side chain in a simultaneous fashion, providing a nano-scale homogenous mixture of balanced charges. The zwitterionic side chains serve as hydrophilic segments in the copolymer and feature excellent resistance to nonspecific protein adsorption. Doxorubicin was chemically grafted onto the poly(amino acid) moiety through acid labile hydrazone linkages, providing removable hydrophobic segments and driving the polymer self-assembly. Free doxorubicin could be encapsulated into the self assembled micelles via hydrophobic interactions and molecular pi-pi stacking. The results obtained show that the drug loaded nanoparticles exhibit excellent stabilities in protein solutions at pH=7.4 and significantly enhanced drug release characteristics under acidic conditions. The cytotoxicity characteristics of the zwitterionic copolymer and drug-loaded nanoparticles at different pH values were investigated in vitro and feature an excellent biocompatibility and anti-cancer activity, respectively. PMID- 27232304 TI - Controlling mesenchymal stem cells differentiate into contractile smooth muscle cells on a TiO2 micro/nano interface: Towards benign pericytes environment for endothelialization. AB - Building healthy and oriented smooth muscle cells (SMCs) environment is an effective method for improving the surface endothelialization of the cardiovascular implants. However, a long-term and stable source of SMCs for implantation without immune rejection and inflammation has not been solved, and mesenchymal stem cells (MSCs) differentiation may be a good choice. In this work, two types of TiO2 micro/nano interfaces were fabricated on titanium surface by photolithography and anodic oxidation. These TiO2 micro/nano interfaces were used to regulate the differentiation of the MSCs. The X-ray diffraction (XRD) detection showed that the TiO2 micro/nano interfaces possessed the anatase crystal structure, suggesting good cytocompatibility. The CCK-8 results indicated the TiO2 micro/nano interfaces improved MSC proliferation, further immunofluorescence staining and calculation of the cell morphology index proved the micro/nano surfaces also elongated MSCs and regulated MSCs oriented growth. The specific staining of alpha-SMA, CNN-1, vWF, CD44 and CD133 markers revealed that the micro/nano surfaces induced MSCs differentiation to contractile SMCs, and the endothelial cells (ECs) culture experiment indicated that the MSCs induced by micro/nano interfaces contributed to the ECs attachment and proliferation. This method will be further studied and applied for the surface modification of the cardiovascular implants. PMID- 27232305 TI - Synergistic effect of topography, surface chemistry and conductivity of the electrospun nanofibrous scaffold on cellular response of PC12 cells. AB - Electrospun nanofibrous nerve implants is a promising therapy for peripheral nerve injury, and its performance can be tailored by chemical cues, topographical features as well as electrical properties. In this paper, a surface modified, electrically conductive, aligned nanofibrous scaffold composed of poly (lactic acid) (PLA) and polypyrrole (Ppy), referred to as o-PLAPpy_A, was fabricated for nerve regeneration. The morphology, surface chemistry and hydrophilicity of nanofibers were characterized by Scanning Electron Microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS) and water contact angle, respectively. The effects of these nanofibers on neuronal differentiation using PC12 cells were evaluated. A hydrophilic surface was created by Poly-ornithine coating, which was able to provide a better environment for cell attachment, and furthermore aligned fibers were proved to be able to guide PC12 cells grow along the fiber direction and be beneficial for neurite outgrowth. The cellular response of PC12 cells to pulsed electrical stimulation was evaluated by NF 200 and alpha tubulin expression, indicating that electrical stimulation with a voltage of 40mV could enhance the neurite outgrowth. The PC12 cells stimulated with electrical shock showed greater level of neurite outgrowth and smaller cell body size. Moreover, the PC12 cells under electrical stimulation showed better viability. In summary, the o-PLAPpy_A nanofibrous scaffold supported the attachment, proliferation and differentiation of PC12 cells in the absence of electrical stimulation, which could be potential candidate for nerve regeneration applications. PMID- 27232306 TI - Rheological behavior of aqueous dispersions containing blends of rhamsan and welan polysaccharides with an eco-friendly surfactant. AB - Small amplitude oscillatory shear and steady shear flow properties of rhamsan gum and welan gum dispersions containing an eco-friendly surfactant (a polyoxyethylene glycerol ester) formulated to mimic the continuous phase of O/W emulsions were studied using the surface response methodology. A second order polynomial equation fitted the influence of surfactant concentration, rhamsan/welan mass ratio and total concentration of polysaccharides. Systems containing blends of rhamsan and welan did not show synergism but thermodynamic incompatibility and made it possible to adjust the linear viscoelastic and low shear rate flow properties to achieve values in between those of systems containing either rhamsan or welan as the only polysaccharide. All the systems studied exhibited weak gel rheological properties as the mechanical spectra displayed the plateau or rubber-like relaxation zone, the linear viscoelastic range was rather narrow and flow curves presented shear thinning behavior, which fitted the power-law equation. While mechanical spectra of the systems studied demonstrated that they did not control the linear viscoelastic properties of the corresponding emulsions, the blend of rhamsan and welan gums was able to control the steady shear flow properties. PMID- 27232307 TI - A new composite scaffold of bioactive glass nanoparticles/graphene: Synchronous improvements of cytocompatibility and mechanical property. AB - This study presents a simple method of synthesizing bioactive glass nanoparticles/graphene nanosheets composite (BGs/GNS) scaffolds using the sol-gel and mold-compressing strategies. Characterizations of BGs/GNS scaffold revealed that BGs with an average diameter of 28.75nm were densely anchored onto both sides of GNS. When the mass ratio of BGs to graphene oxide was set as 10, this scaffold showed better cytocompatibility and higher osseointegration ability with surrounding tissues than the other scaffolds. The introduction of GNS also significantly enhanced the hardness and Young's modulus of BGs. Given the excellent performance of this scaffold, it has potential applications in bone regeneration and implantation. PMID- 27232308 TI - Room temperature aqueous self-assembly of poly(ethylene glycol)-poly(4-vinyl pyridine) block copolymers: From spherical to worm-like micelles. AB - The solution self-assembly and the formation, at room temperature, of a wide range of nanostructures based on monomethyl ether poly(ethylene glycol)-b-poly(4 vinyl pyridine) (mPEG-b-P4VP) block copolymer is reported. Copolymers with different compositions and molecular weights were synthesized through Atom Transfer Radical Polymerization (ATRP) method. The solution self-assembly of the block copolymers was studied by transmission electron microscopy (TEM) for different solution pHs. It was found that the formation of non-spherical nanostructures, such as rod- and worm-like micelles can be easily achieved, at room temperature, by simply varying the molecular weight of the different segments as well as the mPEG to P4VP ratio in the block copolymer structure. Because P4VP segments are known to form strong complexes with metals, the nanostructures prepared in this manuscript can find innovative applications in the biomedical field and be used as nano-templates for inorganic materials. PMID- 27232309 TI - Sucrose ester based cationic liposomes as effective non-viral gene vectors for gene delivery. AB - As sucrose esters (SEs) are natural and biodegradable excipients with excellent drug dissolution and drug absorption/permeation in controlled release systems, we firstly incorporated SE into liposomes for gene delivery in this article. A peptide-based lipid (CDO14), Gemini-based quaternary ammonium-based lipid (CTA14), and mono-head quaternary ammonium lipid (CPA14), and SE as helper lipid, were prepared into liposomes which could enhance the interactions between liposomes and pDNA. Most importantly, the liposomes with helper lipid SE showed higher transfection and lower cytotoxicity than those without SE in Hela and A549 cells. It was also found that the transfection efficiency increased with the increase of SE content. The selected liposome, CDO14/SE, was able to deliver siRNA against luciferase for silencing gene in lung tumors of mice, with little in vivo toxicity. The results convincingly demonstrated SEs could be highly desirable candidates for gene delivery systems. PMID- 27232327 TI - Cell cycle re-entry sensitizes podocytes to injury induced death. AB - Podocytes are terminally differentiated renal cells, lacking the ability to regenerate by proliferation. However, during renal injury, podocytes re-enter into the cell cycle but fail to divide. Earlier studies suggested that re-entry into cell cycle results in loss of podocytes, but a direct evidence for this is lacking. Therefore, we established an in vitro model to test the consequences of re-entry into the cell cycle on podocyte survival. A mouse immortalized podocyte cell line was differentiated to non-permissive podocytes and stimulated with e.g. growth factors. Stimulated cells were analyzed for mRNA-expression or stained for cell cycle analysis using flow cytometry and immunocytofluorescence microscopy. After stimulation to re-entry into cell cycle, podocytes were stressed with puromycin aminonucleoside (PAN) and analyzed for survival. During permissive stage more than 40% of immortalized podocytes were in the S-phase. In contrast, S phase in non-permissive differentiated podocytes was reduced to 5%. Treatment with b-FGF dose dependently induced re-entry into cell cycle increasing the number of podocytes in the S-phase to 10.7% at an optimal bFGF dosage of 10 ng/ml. Forty eight hours after stimulation with bFGF the number of bi-nucleated podocytes significantly increased. A secondary injury stimulus significantly reduced podocyte survival preferentially in bi-nucleated podocytes In conclusion, stimulation of podocytes using bFGF was able to induce re-entry of podocytes into the cell cycle and to sensitize the cells for cell death by secondary injuries. Therefore, this model is appropriate for testing new podocyte protective substances that can be used for therapy. PMID- 27232328 TI - Urban Dust Microbiome: Impact on Later Atopy and Wheezing. AB - BACKGROUND: Investigations in urban areas have just begun to explore how the indoor dust microbiome may affect the pathogenesis of asthma and allery. OBJECTIVE: We aimed to investigate the early fungal and bacterial microbiome in house dust with allergic sensitization and wheezing later in childhood. METHODS: Individual dust samples from 189 homes of the LISAplus birth cohort study were collected shortly after birth from living room floors and profiled for fungal and bacterial microbiome. Fungal and bacterial diversity was assessed with terminal restriction fragment length polymorphism (tRFLP) and defined by Simpson's Diversity Index. Information on wheezing outcomes and covariates until the age of 10 years was obtained by parent questionnaires. Information on specific allergic sensitization was available at child's age 6 and 10 years. Logistic regression and general estimation equation (GEE) models were used to examine the relationship between microbial diversity and health outcomes. RESULTS: Adjusted logistic regression analyses revealed a significantly reduced risk of developing sensitization to aero-allergens at 6 years and ever wheezing until the age of 10 years for exposure to higher fungal diversity [adjusted odds ratio (aOR) = 0.26 (95% CI: 0.10, 0.70), and 0.42 (95% CI: 0.18, 0.96), respectively]. The associations were attenuated for the longitudinal analyses (GEE) until the age of 10 years. There was no association between higher exposure to bacterial diversity and the tested health outcomes. CONCLUSION: Higher early exposure to fungal diversity might help to prevent a child from developing sensitization to aero allergens in early childhood, but the reasons for attenuated effects in later childhood require further prospective studies. Citation: Tischer C, Weikl F, Probst AJ, Standl M, Heinrich J, Pritsch K. 2016. Urban dust microbiome: impact on later atopy and wheezing. Environ Health Perspect 124:1919-1923; http://dx.doi.org/10.1289/EHP158. PMID- 27232329 TI - Resistance to combination BRAF and MEK inhibition in metastatic melanoma: Where to next? AB - Treatment of BRAF-mutant metastatic melanoma with mitogen-activated protein kinase (MAPK) pathway targeted therapies (BRAF/MEK inhibitors) and immune checkpoint inhibitors has revolutionised management and improved outcomes for patients with advanced stage disease. However, acquired resistance to MAPK inhibitor therapy develops in the majority of patients at approximately 12 months and multiple mechanisms lead to resistance. Understanding the mechanisms of resistance is therefore critical for the development of more effective therapeutic strategies in BRAF-mutant melanoma. Recently, several distinct mechanisms of resistance to BRAF-inhibition have been proposed based on data obtained in experimental melanoma cell models and small series of human tumour samples. These include reactivation of the MAPK pathway resulting in continued extracellular signal-regulated kinase activation and activation of parallel signalling pathways including the PI3K-mTOR (phosphoinositide 3-kinase-mammalian target of rapamycin) pathway. Alterations in how the cells of the immune system respond to melanoma cells treated with targeted therapy may also influence response and progression. In this review, we discuss these mechanisms and identify potential therapeutic strategies to overcome resistance which, in turn, will lead to improved outcomes for patients with metastatic melanoma. PMID- 27232330 TI - Nomograms for survival prediction in patients undergoing liver resection for hepatitis B virus related early stage hepatocellular carcinoma. AB - BACKGROUND: The long-term outcomes of patients who underwent liver resection (LR) for early-stage hepatitis B virus (HBV)-related hepatocellular carcinomas (HCCs) are difficult to predict. This study aimed to develop two nomograms to predict postoperative disease-free survival (DFS) and overall survival (OS), respectively. METHODS: Data on a primary cohort of 1328 patients who underwent LR for HBV-related HCCs within Milan criteria at the Eastern Hepatobiliary Surgery Hospital (EHBH) from 2000 to 2006 were used to develop the nomograms by the Cox regression analyses. An internal validation cohort of 442 patients operated from 2006 to 2011 at the EHBH and an external validation cohort of 474 patients operated from 2007 to 2009 at the Zhongshan Hospital were used for validation studies. Discrimination and calibration were measured using concordance index (C index), calibration plots and Kaplan-Meier curves. RESULTS: The independent predictors of DFS or OS which included tumour stage factors, biomarker and HBV DNA level were respectively incorporated into the two nomograms. In the primary cohort, the C-indexes of the models in predicting DFS and OS were 0.76 (95% confidence interval: 0.75-0.78) and 0.79 (0.77-0.81), respectively. The calibration curves fitted well. Both nomograms accurately stratify patients into four distinct incremental prognostic subgroups. The C-indexes of the nomogram for OS prediction was significantly higher than those of the six conventional staging systems (0.65-0.71, all P<0.001). These results were verified by the internal and external validations. CONCLUSION: The proposed nomograms showed good prognostication for patients with early HBV-related HCCs after hepatectomy. PMID- 27232331 TI - Adults' retractions of childhood sexual abuse allegations: high-stakes and the (in)validation of recollection. AB - Retractors are individuals who have repudiated their earlier claims of having been sexually abused. There has been relatively little research conducted with this population. The growing literature on memory verification strategies and non believed memories provide a conceptual and empirical lens through which to revisit the accounts of these individuals to try and learn more about the process of making and retracting high stake, consequential beliefs or recollections about the past. Do people attempt to validate or invalidate beliefs and recollections of such events in the same way as they do for the moderately significant events studied to date? The paper concludes by re-emphasising the social and contextual nature of remembering and argues for the primacy of belief over recollection. PMID- 27232332 TI - Application of Machine Learning Techniques to High-Dimensional Clinical Data to Forecast Postoperative Complications. AB - OBJECTIVE: To compare performance of risk prediction models for forecasting postoperative sepsis and acute kidney injury. DESIGN: Retrospective single center cohort study of adult surgical patients admitted between 2000 and 2010. PATIENTS: 50,318 adult patients undergoing major surgery. MEASUREMENTS: We evaluated the performance of logistic regression, generalized additive models, naive Bayes and support vector machines for forecasting postoperative sepsis and acute kidney injury. We assessed the impact of feature reduction techniques on predictive performance. Model performance was determined using the area under the receiver operating characteristic curve, accuracy, and positive predicted value. The results were reported based on a 70/30 cross validation procedure where the data were randomly split into 70% used for training the model and the 30% for validation. MAIN RESULTS: The areas under the receiver operating characteristic curve for different models ranged between 0.797 and 0.858 for acute kidney injury and between 0.757 and 0.909 for severe sepsis. Logistic regression, generalized additive model, and support vector machines had better performance compared to Naive Bayes model. Generalized additive models additionally accounted for non linearity of continuous clinical variables as depicted in their risk patterns plots. Reducing the input feature space with LASSO had minimal effect on prediction performance, while feature extraction using principal component analysis improved performance of the models. CONCLUSIONS: Generalized additive models and support vector machines had good performance as risk prediction model for postoperative sepsis and AKI. Feature extraction using principal component analysis improved the predictive performance of all models. PMID- 27232333 TI - High-Efficiency Capture of Drug Resistant-Influenza Virus by Live Imaging of Sialidase Activity. AB - Influenza A and B viruses possess a neuraminidase protein that shows sialidase activity. Influenza virus-specific neuraminidase inhibitors (NAIs) are commonly used for clinical treatment of influenza. However, some influenza A and B viruses that are resistant to NAIs have emerged in nature. NAI-resistant viruses have been monitored in public hygiene surveys and the mechanism underlying the resistance has been studied. Here, we describe a new assay for selective detection and isolation of an NAI-resistant virus in a speedy and easy manner by live fluorescence imaging of viral sialidase activity, which we previously developed, in order to achieve high-efficiency capture of an NAI-resistant virus. An NAI-resistant virus maintains sialidase activity even at a concentration of NAI that leads to complete deactivation of the virus. Infected cells and focuses (infected cell populations) of an oseltamivir-resistant virus were selectively visualized by live fluorescence sialidase imaging in the presence of oseltamivir, resulting in high-efficiency isolation of the resistant viruses. The use of a combination of other NAIs (zanamivir, peramivir, and laninamivir) in the imaging showed that the oseltamivir-resistant virus isolated in 2008 was sensitive to zanamivir and laninamivir but resistant to peramivir. Fluorescence imaging in the presence of zanamivir also succeeded in selective live-cell visualization of cells that expressed zanamivir-resistant NA. Fluorescence imaging of NAI resistant sialidase activity will be a powerful method for study of the NAI resistance mechanism, for public monitoring of NAI-resistant viruses, and for development of a new NAI that shows an effect on various NAI-resistant mutations. PMID- 27232334 TI - Inhibition of Nuclear Transport of NF-KB p65 by the Salmonella Type III Secretion System Effector SpvD. AB - Salmonella enterica replicates in macrophages through the action of effector proteins translocated across the vacuolar membrane by a type III secretion system (T3SS). Here we show that the SPI-2 T3SS effector SpvD suppresses proinflammatory immune responses. SpvD prevented activation of an NF-KB-dependent promoter and caused nuclear accumulation of importin-alpha, which is required for nuclear import of p65. SpvD interacted specifically with the exportin Xpo2, which mediates nuclear-cytoplasmic recycling of importins. We propose that interaction between SpvD and Xpo2 disrupts the normal recycling of importin-alpha from the nucleus, leading to a defect in nuclear translocation of p65 and inhibition of activation of NF-KB regulated promoters. SpvD down-regulated pro-inflammatory responses and contributed to systemic growth of bacteria in mice. This work shows that a bacterial pathogen can manipulate host cell immune responses by interfering with the nuclear transport machinery. PMID- 27232335 TI - Mental Suffering in Protracted Political Conflict: Feeling Broken or Destroyed. AB - PURPOSE: This mixed-methods exploratory study identified and then developed and validated a quantitative measure of a new construct of mental suffering in the occupied Palestinian territory: feeling broken or destroyed. METHODS: Group interviews were conducted in 2011 with 68 Palestinians, most aged 30-40, in the West Bank, East Jerusalem, and the Gaza Strip to discern local definitions of functioning. Interview participants articulated of a type of suffering not captured in existing mental health instruments used in regions of political conflict. In contrast to the specific difficulties measured by depression and PTSD (sleep, appetite, energy, flashbacks, avoidance, etc.), participants elaborated a more existential form of mental suffering: feeling that one's spirit, morale and/or future was broken or destroyed, and emotional and psychological exhaustion. Participants articulated these feelings when describing the rigors of the political and economic contexts in which they live. We wrote survey items to capture these sentiments and administered these items-along with standard survey measures of mental health-to a representative sample of 1,778 32 43 year olds in the occupied Palestinian territory. The same survey questions also were administered to a representative subsample (n = 508) six months earlier, providing repeated measures of the construct. RESULTS: Across samples and time, the feeling broken or destroyed scale: 1) comprised a separate factor in exploratory factor analyses, 2) had high inter-item consistency, 3) was reported by both genders and in all regions, 4) showed discriminate validity via moderate correlations with measures of feelings of depression and trauma-related stress, and 5) was more commonly experienced than either feelings of depression or trauma-related stress. CONCLUSIONS: Feeling broken or destroyed can be reliably measured and distinguished from conventional measures of mental health. Such locally grounded and contextualized measures should be identified and included in assessments of the full impact of protracted political conflict on functioning. PMID- 27232336 TI - Feasibility Study of NMR Based Serum Metabolomic Profiling to Animal Health Monitoring: A Case Study on Iron Storage Disease in Captive Sumatran Rhinoceros (Dicerorhinus sumatrensis). AB - A variety of wildlife species maintained in captivity are susceptible to iron storage disease (ISD), or hemochromatosis, a disease resulting from the deposition of excess iron into insoluble iron clusters in soft tissue. Sumatran rhinoceros (Dicerorhinus sumatrensis) is one of the rhinoceros species that has evolutionarily adapted to a low-iron diet and is susceptible to iron overload. Hemosiderosis is reported at necropsy in many African black and Sumatran rhinoceroses but only a small number of animals reportedly die from hemochromatosis. The underlying cause and reasons for differences in susceptibility to hemochromatosis within the taxon remains unclear. Although serum ferritin concentrations have been useful in monitoring the progression of ISD in many species, there is some question regarding their value in diagnosing hemochromatosis in the Sumatran rhino. To investigate the metabolic changes during the development of hemochromatosis and possibly increase our understanding of its progression and individual susceptibility differences, the serum metabolome from a Sumatran rhinoceros was investigated by nuclear magnetic resonance (NMR)-based metabolomics. The study involved samples from female rhinoceros at the Cincinnati Zoo (n = 3), including two animals that died from liver failure caused by ISD, and the Sungai Dusun Rhinoceros Conservation Centre in Peninsular Malaysia (n = 4). Principal component analysis was performed to visually and statistically compare the metabolic profiles of the healthy animals. The results indicated that significant differences were present between the animals at the zoo and the animals in the conservation center. A comparison of the 43 serum metabolomes of three zoo rhinoceros showed two distinct groupings, healthy (n = 30) and unhealthy (n = 13). A total of eighteen altered metabolites were identified in healthy versus unhealthy samples. Results strongly suggest that NMR-based metabolomics is a valuable tool for animal health monitoring and may provide insight into the progression of this and other insidious diseases. PMID- 27232337 TI - Alpha 1 Antitrypsin Inhibits Dendritic Cell Activation and Attenuates Nephritis in a Mouse Model of Lupus. AB - Systemic lupus erythematosus (SLE) is an autoimmune disorder with a worldwide distribution and considerable mortality and morbidity. Although the pathogenesis of this disease remains elusive, over-reactive dendritic cells (DCs) play a critical role in the disease development. It has been shown that human alpha-1 antitrypsin (hAAT) has protective effects in type 1 diabetes and rheumatoid arthritis mouse models. In the present study, we tested the effect of AAT on DC differentiation and functions, as well as its protective effect in a lupus-prone mouse model. We showed that hAAT treatment significantly inhibited LPS (TLR4 agonist) and CpG (TLR9 agonist) -induced bone-marrow (BM)-derived conventional and plasmacytoid DC (cDC and pDC) activation and reduced the production of inflammatory cytokines including IFN-I, TNF-alpha and IL-1beta. In MRL/lpr mice, hAAT treatment significantly reduced BM-derived DC differentiation, serum autoantibody levels, and importantly attenuated renal pathology. Our results for the first time demonstrate that hAAT inhibits DC activation and function, and it also attenuates autoimmunity and renal damage in the MRL/lpr lupus model. These results imply that hAAT has a therapeutic potential for the treatment of SLE in humans. PMID- 27232338 TI - Molecular Epidemiology and Antibiotic Susceptibility of Vibrio cholerae Associated with a Large Cholera Outbreak in Ghana in 2014. AB - BACKGROUND: Ghana is affected by regular cholera epidemics and an annual average of 3,066 cases since 2000. In 2014, Ghana experienced one of its largest cholera outbreaks within a decade with more than 20,000 notified infections. In order to attribute this rise in cases to a newly emerging strain or to multiple simultaneous outbreaks involving multi-clonal strains, outbreak isolates were characterized, subtyped and compared to previous epidemics in 2011 and 2012. METHODOLOGY/PRINCIPAL FINDINGS: Serotypes, biotypes, antibiotic susceptibilities were determined for 92 Vibrio cholerae isolates collected in 2011, 2012 and 2014 from Southern Ghana. For a subgroup of 45 isolates pulsed-field gel electrophoresis, multilocus sequence typing and multilocus-variable tandem repeat analysis (MLVA) were performed. Eighty-nine isolates (97%) were identified as ctxB (classical type) positive V. cholerae O1 biotype El Tor and three (3%) isolates were cholera toxin negative non-O1/non-O139 V. cholerae. Among the selected isolates only sulfamethoxazole/trimethoprim resistance was detectable in 2011, while 95% of all 2014 isolates showed resistance towards sulfamethoxazole/trimethoprim, ampicillin and reduced susceptibility to ciprofloxacin. MLVA achieved the highest subtype discrimination, revealing 22 genotypes with one major outbreak cluster in each of the three outbreak years. Apart from those clusters genetically distant genotypes circulate during each annual epidemic. CONCLUSIONS/SIGNIFICANCE: This analysis suggests different endemic reservoirs of V. cholerae in Ghana with distinct annual outbreak clusters accompanied by the occurrence of genetically distant genotypes. Preventive measures for cholera transmission should focus on aquatic reservoirs. Rapidly emerging multidrug resistance must be monitored closely. PMID- 27232340 TI - Large Work Function Modulation of Monolayer MoS2 by Ambient Gases. AB - Although two-dimensional monolayer transition-metal dichalcogenides reveal numerous unique features that are inaccessible in bulk materials, their intrinsic properties are often obscured by environmental effects. Among them, work function, which is the energy required to extract an electron from a material to vacuum, is one critical parameter in electronic/optoelectronic devices. Here, we report a large work function modulation in MoS2 via ambient gases. The work function was measured by an in situ Kelvin probe technique and further confirmed by ultraviolet photoemission spectroscopy and theoretical calculations. A measured work function of 4.04 eV in vacuum was converted to 4.47 eV with O2 exposure, which is comparable with a large variation in graphene. The homojunction diode by partially passivating a transistor reveals an ideal junction with an ideality factor of almost one and perfect electrical reversibility. The estimated depletion width obtained from photocurrent mapping was ~200 nm, which is much narrower than bulk semiconductors. PMID- 27232339 TI - Expression and Characterization of a Potent Long-Acting GLP-1 Receptor Agonist, GLP-1-IgG2sigma-Fc. AB - Human GLP-1 (glucagon-like peptide-1) can produce a remarkable improvement in glycemic control in patients with type 2 diabetes. However, its clinical benefits are limited by its short half-life, which is less than 2 min because of its small size and rapid enzymatic inactivation by dipeptidyl peptidase IV. We engineered GLP-1-IgG2sigma-Fc, a 68-kDa fusion protein linking a variant human GLP-1 (A8G/G26E/R36G) to a human IgG2sigma constant heavy-chain. A stably transfected Chinese hamster ovary cell line was obtained using electroporation. Western blotting showed that the expressed protein was immunoreactive to both GLP-1 and IgG antibodies. GLP-1-IgG2sigma-Fc stimulated insulin secretion from INS-1 cells in a dose- and glucose-dependent manner and increased insulin mRNA expression. The half-life of GLP-1-IgG2sigma-Fc in cynomolgus monkeys was approximately 57.1 +/- 4.5 h. In the KKAy mouse model of diabetes, one intraperitoneal injection of GLP-1-IgG2sigma-Fc (1 mg/kg) reduced blood glucose levels for 5 days. A 4-week repeat-administration study identified sustained effects on blood glucose levels. Oral glucose tolerance tests conducted at the beginning and end of this 4-week period showed that GLP-1-IgG2sigma-Fc produced a stable glucose lowering effect. In addition, KKAy mice treated with GLP-1-IgG2sigma-Fc showed statistically significant weight loss from day 23. In conclusion, these properties of GLP-1 IgG2sigma-Fc demonstrated that it represented a potential long-acting GLP-1 receptor agonist for the treatment of type 2 diabetes. PMID- 27232341 TI - Normalization of qPCR in platelets - YWHAE a potential genericreference gene. AB - The mRNA of human platelets has been extensively studied and it is generally appreciated that platelets contain mRNA transcripts derived from the megakaryocytes, and they have the ability to translate it into proteins. Additionally, platelets contain microRNA (miRNA) that has been shown to potentially regulate the translation of certain proteins. When quantifying gene expression by quantitative real-time polymerase chain reaction (qPCR), a valid normalization method is required and the use of reference genes is a common and robust approach. It is recommended to perform a proper validation of potential reference genes for each individual experimental setup. Previous studies have mainly been performed using commonly used reference genes for nucleated cells, and to our knowledge there are no global evaluations of the stability of transcripts in platelets. Finding a stable transcript would be valuable for inter study comparisons, and the aim of this study was to identify one or more stable mRNA transcripts suitable as generic reference genes for mRNA gene expression studies in platelets. Platelets were incubated for 24 h and microarray of platelet mRNA revealed that the levels of YWHAE, B2M, ITM2B, H3F3A, PF4V1 remained similar between 0 and 24 h. Further validation of the stability of these genes together with GAPDH, RN18S1, and PPIA, genes frequently used as reference genes in platelet studies, was performed using qPCR after different in vitro conditions. In addition, inter-individual stability of the genes was analyzed in diabetic patients compared with healthy matched controls. Analysis of gene stability by the software RefFinder revealed that YWHAE, PF4V1, and B2M were the most stable genes in platelets from healthy donors. In addition, YWHAE was stable between subjects. Furthermore, the potential influence of miRNA on the selected genes was investigated by knockdown of Dicer1 in the megakaryocytic cell line MEG01. YWHAE, H3F3A, B2M, and GAPDH remained unchanged over time in MEG01 cells indicating that these genes are not regulated by miRNA and hence are more stably expressed. In conclusion, YWHAE is a stable transcript in platelets and we suggest the use of YWHAE as a generic reference gene in mRNA gene expression studies. PMID- 27232342 TI - Forging into the Future: Archives Continues to Grow. PMID- 27232344 TI - Neonatal Unit Hemolysis Rates From an Academic Medical Center: A Quality Improvement Project. PMID- 27232343 TI - Testing PD-1/PD-L1 Expression in Cancer Therapy: Pathologic Insights and Economic Sustainability. PMID- 27232345 TI - Reviving the Hospital Autopsy. PMID- 27232346 TI - Variability in Testing for Antineutrophil Cytoplasmic Antibodies: A Survey of Participants in the College of American Pathologists Proficiency Testing Program. AB - CONTEXT: -Variability in testing for antineutrophil cytoplasmic antibodies (ANCAs) contributes to confusion and controversy related to testing for vasculitis and other ANCA-associated diseases. OBJECTIVES: -To survey laboratory testing practices regarding ANCA testing and to investigate differences in testing algorithms. DESIGN: -Supplemental questions were sent to the 333 laboratories participating in the College of American Pathologists proficiency testing program for ANCA as part of the Special Immunology S2 Survey. RESULTS: -A total of 315 laboratories submitted responses to the supplemental questions. Only 88 of 315 participants (28%) reported using a combination of indirect immunofluorescence (IFA) and enzyme immunoassay (EIA) techniques as recommended by current guidelines, with a few additional labs using IFA and multiplex bead assay as an acceptable alternative to EIA. Other labs reported using only IFA, EIA, or multiplex bead assays. CONCLUSIONS: -A wide variety of testing algorithms are in use for ANCA testing despite evidence to suggest that a combination of IFA and EIA testing provides the most comprehensive information. Laboratories should inform clinicians clearly about testing practices and utility of testing in specific disease states. PMID- 27232347 TI - Role of Tetrasomy for the Diagnosis of Urothelial Carcinoma Using UroVysion Fluorescent In Situ Hybridization. AB - CONTEXT: -UroVysion fluorescent in situ hybridization (FISH) is routinely used to detect urothelial carcinoma (UC). A positive threshold is defined as chromosome polysomy in 4 or more cells, which also includes tetrasomy, a natural product of cell division. OBJECTIVES: -To evaluate tetrasomy for UC detection and explore the relation to the surgical diagnosis or patient history. DESIGN: -The FISH was performed on 1532 urine samples from patients with cytology results and 4 or more years of follow-up. We created separate polysomy and tetrasomy categories and constructed receiver operating curves to determine appropriate thresholds using biopsy (n = 194) as the gold standard. Standard FISH and a novel assay integrating cytomorphology and FISH (Target-FISH) were compared. Matching tissue biopsies of urine samples with 10 or more tetrasomy cells were analyzed. RESULTS: -No significant threshold was found for tetrasomy cells. Exclusion of tetrasomy from the polysomy category changed the threshold from 8.5 to 4.5 cells, increased specificity (59.2% to 78.9%), but reduced sensitivity (78.9% to 65.9%). In Target FISH, the same approach yielded a specificity of 93.7% and sensitivity of 65.2%. Similarly, specificity improved significantly for low- and high-grade UC, but sensitivity decreased for low-grade UC. No evidence of UC was observed in 95% (52 of 55) of the patients referred for screening who had 10 or more tetrasomy cells by FISH. Matching biopsies for urines containing 10 or more tetrasomy cells showed few or no tetrasomy cells. CONCLUSIONS: -Tetrasomy is a nonspecific finding frequently encountered in urine FISH and should be excluded from the polysomy classification. Target-FISH is an optimal approach, offering the ability to detect rare tetrasomy tumors. PMID- 27232348 TI - Monitoring of the Clonal Fraction by Fluorescence In Situ Hybridization in Myelodysplastic Syndrome: Comparison With International Working Group Treatment Response Criteria. AB - CONTEXT: -At the initial diagnosis of myelodysplastic syndrome (MDS) and/or during follow-up, the evaluation of chromosomal abnormalities is based on standard G-banding, whereas the utility of fluorescence in situ hybridization (FISH) is still debated. OBJECTIVES: -To investigate whether interphase fluorescence in situ hybridization (iFISH) clone size at initial diagnosis of MDS is correlated with survival and whether changes in clonal fraction by iFISH are concordant with the MDS International Working Group response criteria during follow-up. DESIGN: -A tailored FISH panel (-5/5q-, -7/7q-, +8, -20/20q-, and +1/1q+), based on reported cytogenetic changes in Korean patients with MDS, was performed in 81 patients with MDS at initial diagnosis and in 28 patients during follow-up. RESULTS: -During follow-up, absolute increases in the clone size by iFISH by 20% or more, with relative increases of 50% or more, compared with previous specimens, were associated with transformation to acute myeloid leukemia (P = .001 and P = .002, respectively). Of the 28 patients with abnormal iFISH results, 7 (25%) showed discordance between iFISH and MDS International Working Group responses. Concordance between clone size by G-banding and iFISH was higher in the refractory cytopenia with unilineage dysplasia/refractory cytopenia with multilineage dysplasia group during follow-up, whereas the group with refractory anemia with excess blasts showed higher correlation at initial diagnosis. CONCLUSIONS: -We conclude that iFISH can provide additional prognostic information and can predict the response to therapy in MDS. PMID- 27232349 TI - Clinicopathologic Threshold of Acute Colorectal Graft-versus-Host Disease. AB - CONTEXT: -Colon biopsies are often used to determine the presence and severity of acute gastrointestinal graft-versus-host disease following bone marrow transplant. OBJECTIVE: -To establish a threshold consensus within our institution on the number of crypt apoptotic bodies (CAB) indicative of grade 1 acute colorectal graft-versus-host disease, we retrospectively reviewed colon biopsies from posttransplant patients and incorporated clinical and endoscopic findings to validate recently proposed minimum criteria for grade 1 graft-versus-host disease as 7 or more CAB per 10 contiguous crypts. DESIGN: -Eighty-one biopsies performed for suspected graft-versus-host disease from 74 individual patients were initially stratified based on their prior (prestudy) diagnoses: no significant abnormality, grade 1 graft-versus-host disease, and descriptive diagnoses mentioning increased apoptosis. A chart review was performed to assess the clinical and endoscopic impression at the time of biopsy and to determine the subsequent management and outcome. RESULTS: -Twenty-six biopsies with an average of 3 CAB were considered true-negative cases, and 32 biopsies with an average of 9.75 CAB were considered true-positive cases (t = 3.95999, P < .001). True negative cases had an average density of 1.36 CAB per crypt, and true-positive cases had an average density of 2.97 CAB per crypt (t = 3.950178, P < .001). CONCLUSIONS: -A threshold of 7 or more CAB per 10 contiguous crypts promotes appropriate treatment of grade 1 acute graft-versus-host disease after other diagnostic entities are excluded. Although this threshold is 100% specific to grade 1 acute colorectal graft-versus-host disease after other histologic mimics are excluded, this threshold has a low sensitivity (59.4%) as patients with less than 7 CAB per 10 contiguous crypts constitute a heterogeneous group. PMID- 27232350 TI - College of American Pathologists Cancer Protocols: Optimizing Format for Accuracy and Efficiency. AB - CONTEXT: -The data in College of American Pathologists cancer protocols have to be presented effectively to health care providers. There is no consensus on the format of those protocols, resulting in various designs among pathologists. Cancer protocols are independently created by site-specific experts, so there is inconsistent wording and repetition of data. This lack of standardization can be confusing and may lead to interpretation errors. OBJECTIVE: -To define a synopsis format that is effective in delivering essential pathologic information and to evaluate the aesthetic appeal and the impact of varying format styles on the speed and accuracy of data extraction. DESIGN: -We queried individuals from several health care backgrounds using varying formats of the fallopian tube protocol of the College of American Pathologists without content modification to investigate their aesthetic appeal, accuracy, efficiency, and readability/complexity. Descriptive statistics, an item difficulty index, and 3 tests of readability were used. RESULTS: -Columned formats were aesthetically more appealing than justified formats (P < .001) and were associated with greater accuracy and efficiency. Incorrect assumptions were made about items not included in the protocol. Uniform wording and short sentences were associated with better performance by participants. CONCLUSIONS: -Based on these data, we propose standardized protocol formats for cancer resections of the fallopian tube and the more-familiar colon, employing headers, short phrases, and uniform terminology. This template can be easily and minimally modified for other sites, standardizing format and verbiage and increasing user accuracy and efficiency. Principles of human factors engineering should be considered in the display of patient data. PMID- 27232351 TI - Chorangiosis of Chorionic Villi: What Does It Really Mean? AB - CONTEXT: -Chorangiosis has been regarded as a result of low-grade placental hypoxia associated with pregnancy risk factors and abnormal outcomes. It is unknown whether these are a consequence of chorangiosis itself or of associated other placental pathology. OBJECTIVE: -To prove that chorangiosis itself does not portend an increased risk for pregnancy unless associated with other placental pathology. DESIGN: -This retrospective statistical study analyzes 1231 consecutive placentas with diffuse or focal hypervascularity of chorionic villi: 328 with preuterine pattern of chronic hypoxic placental injury (group 1), 297 with uterine type of chronic hypoxic placental injury (group 2), and 606 cases with chorangiosis (group 3) not fulfilling the inclusion criteria for groups 1 or 2. RESULTS: -Group 2, with 33 cases of chorangiosis (11.1%), featured 10 and 11 statistically significant highest percentages of abnormal clinical and placental variables, respectively; group 3 featured the highest percentages of multiple pregnancy, the heaviest placentas, and the most common acute chorioamnionitis, fetal inflammatory response; and group 1 had the highest proportion of mild erythroblastosis of fetal blood. When comparing groups 1 and 3, 21 of 29 clinical risk factors/outcomes (72.4%) and 30 of 41 placental variables (73.2%) were more common in group 1. CONCLUSIONS: -Presence of diffuse hypoxic patterns of placental injury adds prognostically negative significance to increased vascularity of chorionic villi. Chorangiosis without those patterns portends minimal risk for the pregnancy, and is associated with significantly fewer pregnancy risk factors, abnormal outcomes, and other placental abnormalities. PMID- 27232352 TI - Angiomyolipoma With Epithelial Cysts. AB - Angiomyolipoma with epithelial cysts is a rare mesenchymal tumor of the kidney that enters in the differential diagnosis of adult cystic renal neoplasms. These tumors demonstrate a slight female predominance and can present either incidentally or with symptoms, commonly flank pain and hematuria. Unlike conventional angiomyolipoma, this variant is characterized grossly by both solid and cystic areas, and histologically by the presence of single or multiple cysts lined by epithelial cells, a subepithelial "cambium-like" layer of small stromal cells with a prominent capillary vasculature, and a thick exterior wall composed of poorly formed fascicles of smooth muscle and thick-walled dysplastic blood vessels. Tumors show a distinct immunohistochemical profile and are often reactive for melanocytic markers (HMB-45 and Melan-A), as well as estrogen receptor and progesterone receptor. These tumors have an indolent clinical course, with no reports of progression or metastasis in reported cases thus far. PMID- 27232353 TI - Metastatic Renal Cell Carcinoma to the Pancreas: A Review. AB - The pancreas is an unusual site for tumor metastasis, accounting for only 2% to 5% of all malignancies affecting the pancreas. The more common metastases affecting the pancreas include renal cell carcinomas, melanomas, colorectal carcinomas, breast carcinomas, and sarcomas. Although pancreatic involvement by nonrenal malignancies indicates widespread systemic disease, metastatic renal cell carcinoma to the pancreas often represents an isolated event and is thus amenable to surgical resection, which is associated with long-term survival. As such, it is important to accurately diagnose pancreatic involvement by metastatic renal cell carcinoma on histology, especially given that renal cell carcinoma metastasis may manifest more than a decade after its initial presentation and diagnosis. In this review, we discuss the clinicopathologic findings of isolated renal cell carcinoma metastases of the pancreas, with special emphasis on separating metastatic renal cell carcinoma and its various differential diagnoses in the pancreas. PMID- 27232354 TI - Oxidative stress biomarkers in endometrial secretions: A comparison between successful and unsuccessful in vitro fertilization cycles. AB - A potential role of oxidative stress has been implicated in the outcome of various steps of assisted reproductive technology (ART). In a prospective cohort study, a total of 100 patients undergoing IVF/ICSI procedure due to male factor infertility were recruited based on the inclusion criteria. In all patients, 1 2ml of endometrial secretions was aspirated prior to embryo transfer. The oxidative stress markers in endometrial secretions, including superoxide dismutase (SOD), catalase (CAT) activities, lipid peroxidation (LPO), total thiol groups (TTG), and total antioxidant power (TAP) were investigated and compared among study groups including term pregnancy, failed IVF cycle, and miscarriage. P<0.05 was considered statistically different. Of the 100 patients, 28 cases (28%) resulted in ongoing pregnancy (biochemical pregnancy followed by clinical pregnancy), 11 cases (11%) resulted in miscarriage, and 61 cases (61%), resulted in failed IVF cycle. SOD, LPO, CAT, and TAP levels in the endometrial secretions of the three groups were statistically different (P-value <0.01, <0.001, <0.001, and <0.001, respectively). TTG levels in endometrial secretion of three groups were not statistically different (P-value=0.837). Our results indicated that higher levels of antioxidants such as SOD, CAT, or TAP, and lower levels of oxidative stress markers such as LPO in the endometrial secretions were associated with successful IVF outcome. PMID- 27232355 TI - Soluble HLA-G concentrations in maternal blood and cervical vaginal fluid of pregnant women with preterm premature rupture of membranes. AB - OBJECTIVE: To evaluate soluble HLA-G (sHLA-G) concentrations in maternal blood serum and cervical vaginal fluid in pregnancies complicated by preterm premature rupture of membranes (PPROM) compared to controls. STUDY DESIGN: Case-control study of 24 women with PPROM and 40 controls. MAIN OUTCOME MEASURES: Vaginal and serum sHLA-G and IL-6 concentrations. FINDINGS: Women with PPROM had significantly higher serum and vaginal sHLA-G concentrations compared to controls (respectively median 31.48U?ml versus 13.9U?ml p<0.001 and 1.7U?ml versus 0.1U?ml p<0.001). Vaginal expression of IL-6 was higher in PPROM cases compared to controls (respectively, median 31.19pg?ml versus 6.67pg?ml; p<0.001). Higher serum and vaginal sHLA-G were associated with both a shorter length of pregnancy and histological chorioamnionitis in the PPROM group. CONCLUSIONS: Higher vaginal and serum sHLA-G in PPROM cases may be a sign of local and systemic inflammation. PMID- 27232356 TI - Structural features important for the U12 snRNA binding and minor spliceosome assembly of Arabidopsis U11/U12-small nuclear ribonucleoproteins. AB - Although seven proteins unique to U12 intron-specific minor spliceosomes, denoted as U11/U12-65K, -59K, -48K, -35K, -31K, -25K, and -20K, have been identified in humans and the roles of some of them have been demonstrated, the functional role of most of these proteins in plants is not understood. A recent study demonstrated that Arabidopsis U11/U12-65K is essential for U12 intron splicing and normal plant development. However, the structural features and sequence motifs important for 65 K binding to U12 snRNA and other spliceosomal proteins remain unclear. Here, we demonstrated by domain-deletion analysis that the C terminal region of the 65 K protein bound specifically to the stem-loop III of U12 snRNA, whereas the N-terminal region of the 65 K protein was responsible for interacting with the 59 K protein. Analysis of the interactions between each snRNP protein using yeast two-hybrid analysis and in planta bimolecular fluorescence complementation and luciferase complementation imaging assays demonstrated that the core interactions among the 65 K, 59 K, and 48 K proteins were conserved between plants and animals, and multiple interactions were observed among the U11/U12-snRNP proteins. Taken together, these results reveal that U11/U12-65K is an indispensible component of the minor spliceosome complex by binding to both U11/U12-59K and U12 snRNA, and that multiple interactions among the U11/U12-snRNP proteins are necessary for minor spliceosome assembly. PMID- 27232357 TI - Insulin-like growth factor-II mRNA binding protein-3 and podoplanin expression are associated with bone invasion and prognosis in oral squamous cell carcinoma. AB - OBJECTIVE: This study aimed to evaluate the prognostic implications of insulin like growth factor-II mRNA binding protein-3 (IMP3) and podoplanin (PDPN) as therapeutic targets against oral squamous cell carcinoma (OSCC) with bone invasion. STUDY DESIGN: We elucidated the correlation of IMP3 and PDPN expression with bone invasion in 160 OSCC tissue specimens, and assessed a mouse calvarium xenograft model using an IMP3- and PDPN-depleted OSCC cell line. RESULTS: The retrospective analysis revealed that the expression of IMP3 and PDPN is significantly correlated with T stage, lymph node metastasis, and the overall survival of OSCC patients. In addition, the dual expression of IMP3 and PDPN but not the single expression of either IMP3 or PDPN was associated with bone invasion and the number of osteoclasts in patients with OSCC. In support of these findings, IMP3 or PDPN depletion inhibited the invasive capacity of OSCC cells in a three-dimensional culture system, tumorigenesis, and regional bone destruction in a xenograft mouse model. In addition, IMP3 or PDPN depletion inhibited the expression of interleukin (IL)-6 and IL-8 in OSCC cells, and decreased the expression of receptor activator of NF-kappaB ligand (RANKL) in xenograft tumor tissues of OSCC. CONCLUSIONS: These results suggest that IMP3 and PDPN may have strong influence on the pathogenesis of OSCC, especially in bone invasion, and may serve as novel therapeutic targets with prognostic implications for bone invasive OSCC. PMID- 27232358 TI - Initial oral biofilm formation on titanium implants with different surface treatments: An in vivo study. AB - OBJECTIVE: The aim of this study was to examine in vivo the initial bacterial adhesion on titanium implants with different surface treatments. DESIGN: Ten subjects wore oral splints containing machined pure titanium disks (Ti-M), acid etched titanium (Ti-AE) and anodized and laser irradiated disks (Ti-AL) for 24h. After this period, disks were removed from the splints and adherent bacteria were quantified by an enzymatic assay to assess total viable bacteria and by Real Time PCR to evaluate total bacteria and Streptococcus oralis levels. Additionally, the initial adherent microorganisms were visualized by scanning electron microscopy (SEM). Titanium surface morphology was verified using SEM, and roughness was evaluated by profilometer analysis. RESULTS: Regarding titanium surface roughness, Ti-AL (1.423+/-0.397) showed significantly higher Ra values than did Ti-M (0.771+/-0.182) and Ti-AE (0.735+/-0.196) (p<0.05, ANOVA - Tahame). Ti-AE and Ti-AL presented roughened micro-structure surfaces characterized by open pores, whereas Ti-M showed long grooves alternating with planed areas. Comparing the Ti-M, Ti-AE and Ti-AL groups for viable bacteria (MTT assay), total bacteria and S. oralis quantification (qPCR), no significant differences were observed among these three groups (p>0.05, ANOVA - Tahame). SEM images showed similar bacterial adhesion on the three titanium surfaces, predominantly characterized by cocci and several bacilli, indicating an initial colonization of the oral biofilm. CONCLUSION: In conclusion, roughness and microtopography did not stimulate initial biofilm formation on titanium surfaces with different surface treatments. PMID- 27232359 TI - Antimicrobial peptides in saliva of children with severe early childhood caries. AB - OBJECTIVE: Controversies exist regarding the relationship between the concentrations of antimicrobial peptides (AMPs) and presence of dental caries in children. Thus, the aim of this study was to examine levels of AMPs in saliva of caries-free (CF), early childhood caries (ECC) and severe early childhood caries (S-ECC) children to determine if the levels of these salivary peptides individually or in combinations were related to caries severity and mutans streptococci levels. DESIGN: 36 to 60 month-old children were selected to participate in this study. Children were grouped into CF group (n=29), ECC group (n=25) and S-ECC group (n=29). Saliva was collected from children for microbiological analysis by culture. Salivary concentrations of cathelicidin LL 37, human beta-defensin 2 (hBD-2), human beta-defensin 3 (hBD-3) and histatin-5 (HTN-5) were determined by ELISA. RESULTS: Salivary concentrations of AMPs did not differ among CF, ECC and S-ECC groups. Data showed positive correlations between mutans streptococci levels and salivary hBD-2 or HTN-5. Positive correlations were found between hBD-2, hBD-3, LL-37 and HTN-5. Combinations among AMPs, mainly LL-37, were positively associated with caries levels. CONCLUSIONS: Salivary concentrations of AMPs individually were not associated with the severity of early childhood caries. The stimulus of caries appears to trigger a biological response, however, with a combination of these peptides. PMID- 27232360 TI - Rapid and Sustained Reductions in Current Suicidal Ideation Following Repeated Doses of Intravenous Ketamine: Secondary Analysis of an Open-Label Study. AB - BACKGROUND: Ketamine rapidly reduces thoughts of suicide in patients with treatment-resistant depression who are at low risk for suicide. However, the extent to which ketamine reduces thoughts of suicide in depressed patients with current suicidal ideation remains unknown. METHODS: Between April 2012 and October 2013, 14 outpatients with DSM-IV-diagnosed major depressive disorder were recruited for the presence of current, stable (>= 3 months) suicidal thoughts. They received open-label ketamine infusions over 3 weeks (0.5 mg/kg over 45 minutes for the first 3 infusions; 0.75 mg/kg over 45 minutes for the last 3). In this secondary analysis, the primary outcome measures of suicidal ideation (Columbia-Suicide Severity Rating Scale [C-SSRS] and the Suicide Item of the 28 item Hamilton Depression Rating Scale [HDRS28-SI]) were assessed at 240 minutes postinfusion and for 3 months thereafter in a naturalistic follow-up. RESULTS: Over the course of the infusions (acute treatment phase), 7 of 14 patients (50%) showed remission of suicidal ideation on the C-SSRS Ideation scale (even among patients whose depression did not remit). There was a significant linear decrease in this score over time (P < .001), which approached significance even after controlling for severity of 6-item Hamilton Depression Rating Scale (HDRS6) core depression items (P = .05). Similarly, there were significant decreases in the C SSRS Intensity (P < .01) and HDRS28-SI (P < .001) scores during the acute treatment phase. Two of the 7 patients who achieved remission during the acute treatment phase (29%) maintained their remission throughout a 3-month naturalistic follow-up. CONCLUSIONS: In this preliminary study, repeated doses of open-label ketamine rapidly and robustly decreased suicidal ideation in pharmacologically treated outpatients with treatment-resistant depression with stable suicidal thoughts; this decrease was maintained for at least 3 months following the final ketamine infusion in 2 patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01582945. PMID- 27232361 TI - Sarcopenia and two types of presarcopenia in Japanese patients with chronic liver disease. AB - BACKGROUND/AIM: The frequency of sarcopenia, defined as loss of both muscle volume and strength, was analyzed in chronic liver disease (CLD). METHODS AND MATERIALS: From April to September 2015, 807 Japanese CLD patients treated as outpatients were enrolled (67.1+/-10.0 years, men : women=466 : 341, hepatitis C virus : hepatitis B virus : hepatitis B and C virus : alcohol : other=511 : 134 : 3 : 45 : 114). Sarcopenia was diagnosed when the patient showed muscle volume loss and reduced handgrip strength, whereas those with only muscle volume loss were classified as 'v-presarcopenia' and those with only reduced handgrip strength were classified as 's-presarcopenia'. Muscle volume loss was determined using computed tomography findings and a previously reported index (psoas index), and cut-off values for reduced handgrip strength presented by the Asia Working Group for Sarcopenia (AWGS) (AWGS/grip criteria) and European Working Group on Sarcopenia in Older People (EWGSOP) (EWGSOP/grip criteria) (men; 26 and 30 kg, women; 18 and 20 kg, respectively) were used. Clinical features were analyzed for diagnoses of chronic hepatitis (CH, n=381), liver cirrhosis Child-Pugh A (n=330), and liver cirrhosis Child-Pugh B/C (n=96). RESULTS: When the AWGS/grip criteria were used, the frequencies of sarcopenia, v-presarcopenia, and s-presarcopenia in CH were 3.9, 7.9, and 19.4%, whereas those in Child-Pugh A were 4.8, 17.6, and 21.8% and those in Child-Pugh B/C were 16.7, 11.5, and 39.6%, respectively. When the EWGSOP/grip criteria were used, these frequencies were 7.1, 4.7, and 33.1%, in CH, 11.8, 10.6, and 32.7%, in Child-Pugh A, and 21.9, 6.3, and 49.0%, in Child Pugh B/C, respectively. The incidence rates of sarcopenia and both types of presarcopenia increased with progression of CLD. CONCLUSION: Evaluation of handgrip strength and psoas index is an easy and effective method for the detection of sarcopenia and presarcopenia. PMID- 27232362 TI - The Treatment of Localized Prostate Cancer in Everyday Practice in Germany. AB - BACKGROUND: Prostate cancer is now often diagnosed in the localized, welldifferentiated stage. In the HAROW study, we investigated the care situation with respect to the various treatment options for localized prostate cancer in everyday clinical practice in Germany. METHODS: Study physicians for this prospective, multicenter observational study were recruited through the Federation of German Urologists. At six-month intervals, clinical variables were recorded (T category, prostate-specific antigen [PSA], Gleason score, d'Amico risk profile, Charlson Comorbidity Index [CCI]) and patients filled out questionnaires (QLQ-C30) regarding their indicationrelated quality of life (QoL). Covariance analysis was used to adjust for the variable distribution of patient features among the treatment groups. RESULTS: Data from 2957 patients were available for analysis. The mean followup time was 28.4 months overall, and 47.6 months in the active surveillance (AS) group. Younger patients and patients with a CCI of 0 or 1 predominated in the AS and surgery groups; older patients and patients with a CCI of 2 or above predominated in the groups in which palliative treatment strategies such as hormone therapy (HT) and watchful waiting were applied. The HT group had the highest percentage of patients with a Gleason score of 8 or above (21.2%), while the AS group had the highest percentage of patients with a Gleason score of 6 or below (92.5%), as well as the lowest mean PSA value (5.8 +/- 3.4 ng/mL) and the highest percentage of patients with a low-risk profile (82.5%). Of 468 patients in the AS group, 170 (36.3%) underwent a change of treatment strategy. After adjustment for the severity of disease, no significant difference with respect to the global quality of life was found between AS and the curative treatment options over the long term. CONCLUSION: The study physicians drew a clear distinction between curative and palliative treatment strategies, and the inclusion criteria for AS were largely respected. The observed preference for surgery in low-risk patients indicates overtreatment in this patient group. PMID- 27232364 TI - Creatine Kinase Levels After Exercise. PMID- 27232365 TI - Coenzyme Q10 Deficiency. PMID- 27232363 TI - Lichen Sclerosus-Presentation, Diagnosis and Management. AB - BACKGROUND: Lichen sclerosus is a chronic inflammatory skin disease. It is thought to be underdiagnosed and undertreated. If it is not treated, lichen sclerosus is associated with a greater degree of scarring and an elevated risk of cancer in the genital area. METHODS: This review is based on pertinent articles published up to October 2015 that were retrieved by a selective search in PubMed, Embase, and the Cochrane Library and on the European S3 guideline for lichen sclerosus. RESULTS: Lichen sclerosus is mainly found in the anogenital area but can also be generalized. Extragenital involvement is reportedly present in 6% to 20% of patients. Neighboring mucous membranes, such as the vaginal or oral mucosa, are not typically affected. The disease is more common in women than in men, and occurs more often in adults than in children. About 10% of patients have other family members with the same condition. Anogenital lichen sclerosus often causes itching and pain. Functional impairment due to fissures and scars can arise over the course of the condition. The treatment of first choice is the local application of high-potency corticosteroids as early as possible (1/A). For boys and men in whom the condition does not remit after steroid treatment, circumcision is indicated (3/D). CONCLUSION: Anogenital itching and clinical features such as erythema, white skin changes (such as hyperkeratosis and sclerosis), and fissures should arouse suspicion of lichen sclerosus. The diagnosis should be confirmed with a skin biopsy, and early, thorough treatment should be initiated. In this way, a mutilating disease course can be averted, and the risk of cancer can be lessened. PMID- 27232366 TI - Statins Impede a Healthy Lifestyle. PMID- 27232367 TI - In Reply. PMID- 27232369 TI - Assessment of Genomic Literacy Among Baccalaureate Nursing Students in the United States: A Feasibility Study. AB - The implementation of genomic nursing education should be based on evidence, comparing what students know about genetics and genomics with what they need to know. In this multisite feasibility study, a standardized inventory of genetic genomic knowledge was administered to students in 14 baccalaureate nursing programs. Data contribute to instrument validation, provide a snapshot of genetic genomic knowledge among US nursing students, and inform planning for a large, multisite study. PMID- 27232370 TI - Shadowing in Early Baccalaureate Nursing Education and Its Influence on Professional Role Perspectives. AB - Nursing students often experience a discrepancy between their ideal views of nursing obtained while in school and the realities of practice. Using a phenomenological research design, sophomore-level students reflected on their perceptions of the professional nursing role before and after shadowing a nurse. Students' perceptions changed from a focus of the nurse as the primary caregiver in a hierarchy to a broader understanding of the complexity of nursing and what it means to care. PMID- 27232368 TI - Benzyl [(11)C]Hippurate as an Agent for Measuring the Activities of Organic Anion Transporter 3 in the Brain and Multidrug Resistance-Associated Protein 4 in the Heart of Mice. AB - Multidrug resistance-associated protein 4 (MRP4) and organic anion transporter 3 (OAT3) mediate the efflux of organic anions from the brain and heart. In this study, we have developed a probe for estimating the activity of these transporters in these tissues using positron emission tomography. Several (11)C labeled hippuric acid ester derivatives were screened with the expectation that they would be hydrolyzed in situ to form the corresponding (11)C-labeled organic acids in target tissues. Among the compounds screened, benzyl [(11)C]hippurate showed favorable hydrolysis rates and uptake properties in the target tissues of mice. Subsequent evaluation using transporter knockout mice revealed that radioactivity was retained in the brain and heart of Oat3(-/-) and Mrp4(-/-) mice, respectively, compared with that of control mice after the intravenous administration of benzyl [(11)C]hippurate. Benzyl [(11)C]hippurate could therefore be used as a probe for estimating the activities of OAT3 and MRP4 in mouse brain and heart, respectively. PMID- 27232371 TI - Transforming the Classroom With Tablet Technology. AB - Identifying the most effective models for integrating new technology into the classroom and understanding its effects on educational outcomes are essential for nurse educators. This article describes an educational intervention with tablet technology (iPads) using an innovative case-based learning model in a nursing program. Students reported positive learning outcomes when using the tablet technology for learning course content. PMID- 27232372 TI - Improving Performance of Organic-Silicon Heterojunction Solar Cells Based on Textured Surface via Acid Processing. AB - Poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) ( PEDOT: PSS) is widely applied in organic-photoelectronic devices due to its excellent transparency and conductivity. However, when it is used in the organic-silicon heterojunction solar cells with traditional pyramid texturing surface, the device performance is limited by the contact between the PEDOT: PSS and silicon wafer at the bottom of the pyramids. We optimized the structure of the bottom of the pyramids via acid isotropic etching (AIE) method with mixed acid solution to ensure that the silicon wafer is fully covered by the PEDOT: PSS. In addition, hydrogenated amorphous silicon thin films were deposited with PEVCD method as the passivation and back surface field (BSF) layer to decrease the rear surface recombination rate, thus increasing the long wavelength response. Finally, a power conversion efficiency of 13.78% was achieved after depositing MoO3 on the front of the device as the antireflection layer. PMID- 27232374 TI - Enhancing Perovskite Electrocatalysis through Strain Tuning of the Oxygen Deficiency. AB - Oxygen vacancies in transition-metal oxides facilitate catalysis critical for energy storage and generation. However, promoting vacancies at the lower temperatures required for operation in devices such as metal-air batteries and portable fuel cells has proven elusive. Here we used thin films of perovskite based strontium cobaltite (SrCoOx) to show that epitaxial strain is a powerful tool for manipulating the oxygen content under conditions consistent with the oxygen evolution reaction, yielding increasingly oxygen-deficient states in an environment where the cobaltite would normally be fully oxidized. The additional oxygen vacancies created through tensile strain enhance the cobaltite's catalytic activity toward this important reaction by over an order of magnitude, equaling that of precious-metal catalysts, including IrO2. Our findings demonstrate that strain in these oxides can dictate the oxygen stoichiometry independent of ambient conditions, allowing unprecedented control over oxygen vacancies essential in catalysis near room temperature. PMID- 27232373 TI - "Coming Out" of Prison: An Exploratory Study of LGBT Elders in the Criminal Justice System. AB - This two-phase qualitative study explores the experiences of 10 formerly incarcerated LGBT elders' experiences prior to, during, and after release from prison. A core theme of self and the social mirror emerged from the data that represented LGBT elders ongoing coming-out process of unearthing their "true selves" despite managing multiple stigmatized identities or social locations, such as being LGBT, elderly, HIV positive, formerly incarcerated, and a racial/ethnic minority. These findings further our awareness of an overlooked population of LGBT who are older and involved in the criminal justice system. Recommendations that incorporate suggestions from formerly incarcerated LGBT elders for services and policy reform are presented. PMID- 27232375 TI - Computational Replication of the Primary Isotope Dependence of Secondary Kinetic Isotope Effects in Solution Hydride-Transfer Reactions: Supporting the Isotopically Different Tunneling Ready State Conformations. AB - We recently reported a study of the steric effect on the 1 degrees isotope dependence of 2 degrees KIEs for several hydride-transfer reactions in solution (J. Am. Chem. Soc. 2015, 137, 6653). The unusual 2 degrees KIEs decrease as the 1 degrees isotope changes from H to D, and more in the sterically hindered systems. These were explained in terms of a more crowded tunneling ready state (TRS) conformation in D-tunneling, which has a shorter donor-acceptor distance (DAD) than in H-tunneling. To examine the isotopic DAD difference explanation, in this paper, following an activated motion-assisted H-tunneling model that requires a shorter DAD in a heavier isotope transfer process, we computed the 2 degrees KIEs at various H/D positions at different DADs (2.9 A to 3.5 A) for the hydride-transfer reactions from 2-propanol to the xanthylium and thioxanthylium ions (Xn(+) and TXn(+)) and their 9-phenyl substituted derivatives (Ph(T)Xn(+)). The calculated 2 degrees KIEs match the experiments and the calculated DAD effect on the 2 degrees KIEs fits the observed 1 degrees isotope effect on the 2 degrees KIEs. These support the motion-assisted H-tunneling model and the isotopically different TRS conformations. Furthermore, it was found that the TRS of the sterically hindered Ph(T)Xn(+) system does not possess a longer DAD than that of the (T)Xn(+) system. This predicts a no larger 1 degrees KIE in the former system than in the latter. The observed 1 degrees KIE order is, however, contrary to the prediction. This implicates the stronger DAD-compression vibrations coupled to the bulky Ph(T)Xn(+) reaction coordinate. PMID- 27232376 TI - Lithium attenuates the proconvulsant effect of adolescent social isolation stress via involvement of the nitrergic system. AB - In this study, we tested whether acute administration of lithium mitigates the deleterious effect of adolescent social isolation stress (SIS) on seizure susceptibility. In comparison with socially conditioned (SC) mice, isolated conditioned (IC) mice exhibited an increase in seizure susceptibility to pentylenetetrazole. Acute administration of lithium (10mg/kg) reversed the proconvulsant effect of SIS in IC mice, but this effect was not observed in SC mice. Coadministration of subthreshold doses of lithium (3mg/kg) with nitric oxide synthase (NOS) inhibitors reversed the effect of SIS on seizure susceptibility and decreased hippocampal nitrite levels in IC animals. In addition, a subthreshold dose of a nitric oxide precursor reduced the protective effect of lithium on seizure susceptibility and increased nitrite levels in the hippocampus of IC mice. These results suggest that lithium exerts a protective influence against the proconvulsant effect of adolescent SIS via a nitrergic system that includes activation of neuronal NOS in the hippocampus. PMID- 27232377 TI - Age at onset and seizure frequency affect white matter diffusion coefficient in patients with mesial temporal lobe epilepsy. AB - In mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS), structural abnormalities are present not only in the hippocampus but also in the white matter with ipsilateral predominance. Although the timing of epilepsy onset is commonly associated with clinical and semiological dissimilarities, limited data exist regarding white matter diffusion changes with respect to age at epilepsy onset. The aim of this study was to investigate diffusion changes in the white matter of patients with unilateral MTLE-HS with respect to clinical parameters and to compare them with an age- and sex-matched healthy control group. Apparent diffusion coefficients (ADCs) were derived using monoexponential approaches from 22 (11 early and 11 late age at onset) patients with unilateral MTLE-HS and 22 age- and sex-matched control subjects after acquiring diffusion-weighted images on a 3T MRI system. Data were analyzed using two-tailed t-tests and multiple linear regression models. In the group with early onset MTLE-HS, ADC was significantly elevated in the ipsilateral hemispheric (p=0.04) and temporal lobe white matter (p=0.01) compared with that in controls. These differences were not detectable in late onset MTLE-HS patients. Apparent diffusion coefficient of the group with early onset MTLE-HS was negatively related to age at epilepsy onset in the ipsilateral hemispheric white matter (p=0.03) and the uncinate fasciculus (p=0.03), while in patients with late onset MTLE-HS, ADC was no longer dependent on age at epilepsy onset itself but rather on the seizure frequency in the ipsilateral uncinate fasciculus (p=0.03). Such diffusivity pattern has been associated with chronic white matter degeneration, reflecting myelin loss and higher extracellular volume which are more pronounced in the frontotemporal regions and also depend on clinical features. In the group with early onset MTLE HS, the timing of epilepsy seems to be the major cause of white matter abnormalities while in late onset disease, it has a secondary role in provoking diffusion changes. PMID- 27232378 TI - Phase II trial of everolimus in patients with previously treated recurrent or metastatic head and neck squamous cell carcinoma. AB - BACKGROUND: Patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) demonstrate aberrant activation of the phosphotidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. We examined the efficacy of everolimus, an mTOR inhibitor, in patients with recurrent or metastatic HNSCC. METHODS: This single-arm phase II study enrolled biomarker unselected patients with recurrent or metastatic HNSCC who failed at least 1 prior therapy. Everolimus was administered until progressive disease or unacceptable toxicity. Primary endpoint was clinical benefit rate (CBR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and evaluation of tissue and serum biomarkers related to the PIK3CA pathway. RESULTS: Seven of 9 patients treated in the first stage were evaluable. No objective responses were seen; CBR was 28%. Three patients discontinued everolimus because of toxicity. Median PFS and OS were 1.5 and 4.5 months, respectively. No activating PI3K mutations were identified in available tumor tissue. CONCLUSION: Everolimus was not active as monotherapy in unselected patients with recurrent/metastatic HNSCC. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: 1759-1764, 2016. PMID- 27232379 TI - Effect of dietary organic selenium on muscle proteolytic activity and water holding capacity in pork. AB - This study evaluates the effect of dietary selenium (Se) supplementation source (organic, Se-enriched yeast; SY vs. inorganic, sodium selenite; SS), dose (0.2: L vs. 0.4: H mg/kg) and the combination of Se and vitamin E (VITE+SS) for 26days on drip loss, TBARS, colour changes, myofibrillar protein pattern and proteolysis in pork. The lowest water losses were observed in the SY-H group when compared to the others. SY-H and VITE+SS groups presented lower myofibrillar protein hydrolysis/oxidation. VITE+SS supplementation also resulted in higher PRO, TRP and PHE content at days 2 and 7, whereas the SY group showed increased GLY and CAR and tended to have higher TAU and ANS at day 2. The myofibrillar fragmentation index was not modified by the dietary treatment; however, at day 8, it tended to be higher in groups supplemented with SeY and VITE+SS. The results of the present study might indicate a possible relation between muscle proteolysis and water loss. PMID- 27232380 TI - The relationship between adipocyte size and the transcript levels of SNAP23, BSCL2 and COPA genes in pigs. AB - Breed-specific differences in fat tissue accumulation in the pig provide an opportunity to study the genetic background of this process. In the present study three pig breeds, differing in fatness, were analyzed in terms of the size of adipocytes derived from three tissues (subcutaneous, visceral and longissimus dorsi muscle) in relation to transcript levels of genes (SNAP23, BSCL2 and COPA), which encode proteins involved in lipid droplet formation. The analysis of adipocyte size revealed significant effects of breed and tissue and confirmed earlier reports that an elevated backfat thickness in some pig breeds is correlated with a larger adipocyte size. Variability in the transcript abundance of the studied genes among breeds and tissues was observed. We found a positive correlation between the abundance of the SNAP23 transcript and adipocyte diameter. The obtained results indicate that SNAP23 may be considered as an interesting candidate gene involved in adipose tissue growth in the pig. PMID- 27232381 TI - The diversity of insect antiviral immunity: insights from viruses. AB - Insects represent over 70% of all animal species. Recent virome analyses reveal unprecedented genetic diversity of insect viruses, which appears to match that of their hosts. Thus, insect-virus interactions may provide information on a vast repertoire of antiviral immune mechanisms. Tapping into this diversity is challenging because of several constraints imposed by the uniqueness of each insect model. Nevertheless, it is clear that many conserved and divergent pathways participate in the control of viral infection in insects. Co-evolution between hosts and viruses favors the development of immune evasion mechanisms by the pathogen. Viral suppressors can offer unique perspective on host pathways and emphasize the importance of RNA interference, apoptosis, but also NF-kappaB pathways and translation control in insect antiviral immunity. PMID- 27232382 TI - Extracellular vesicles are the Trojan horses of viral infection. AB - Extracellular vesicles have recently emerged as a novel mode of viral propagation exploited by both enveloped and non-enveloped viruses. In particular non enveloped viruses utilize the hosts' production of extracellular vesicles to exit from cells non-lytically and to hide and manipulate the immune system. Moreover, challenging the long held idea that viruses behave as independent genetic units, extracellular vesicles enable multiple viral particles and genomes to collectively traffic in and out of cells, which can promote genetic cooperativity among viral quasispecies and enhance the fitness of the overall viral population. PMID- 27232383 TI - Treatment with or without plasma exchange for patients with acquired thrombotic microangiopathy not associated with severe ADAMTS13 deficiency: a propensity score-matched study. AB - BACKGROUND: Therapeutic plasma exchange (TPE) is a proven treatment for thrombotic thrombocytopenic purpura (TTP) characterized by severe ADAMTS13 deficiency, but the efficacy of TPE in suspected TTP with an ADAMTS13 activity level of more than 10% remains controversial. STUDY DESIGN AND METHODS: We conducted a propensity score (PS)-matched study of 186 adult patients included in the Harvard Thrombotic Microangiopathy (TMA) Research Collaborative registry who presented with TMA suggestive of TTP but an ADAMTS13 activity level of more than 10%. RESULTS: Before matching, patients treated with TPE (n = 71) differed from untreated patients (n = 115) by several clinical measures. PS matching was performed to address clinical disparities between the two groups and resulted in a well-balanced cohort of 59 TPE-treated patients paired with 59 untreated controls, all of whom had TMA. After matching, we observed no significant difference in the primary outcome of 90-day survival between the treated and untreated groups (hazard ratio, 0.88; 95% confidence interval [CI], 0.44-1.77; p = 0.72). In-hospital mortality (odds ratio [OR], 0.77; 95% CI, 0.34-1.75; p = 0.53) and the percentage of patients with platelet count recovery (OR, 1.58; 95% CI, 0.77-3.26; p = 0.21) also did not differ significantly between the two matched groups. CONCLUSION: Our data suggest that routine use of TPE in the diverse group of TMA patients without severe ADAMTS13 deficiency may not significantly improve outcomes. PMID- 27232384 TI - Enzyme-Immobilized 3D-Printed Reactors for Online Monitoring of Rat Brain Extracellular Glucose and Lactate. AB - In this study we constructed a highly sensitive system for in vivo monitoring of the concentrations of rat brain extracellular glucose and lactate. This system involved microdialysis (MD) sampling and fluorescence determination in conjunction with a novel sample derivatization scheme in which glucose oxidase and lactate oxidase were immobilized in ABS flow bioreactors (manufactured through low-cost three-dimensional printing (3DP)), via fused deposition modeling, for online oxidization of sampled glucose and lactate, respectively, in rat brain microdialysate. After optimizing the experimental conditions for MD sampling, the manufacture of the designed flow reactors, the enzyme immobilization procedure, and the online derivatization scheme, the available sampling frequency was 15 h(-1) and the system's detection limits reached as low as 0.060 mM for glucose and 0.059 mM for lactate, based on a 20-MUL conditioned microdialysate; these characteristics were sufficient to reliably determine the concentrations of extracellular glucose and lactate in the brains of living rats. To demonstrate the system's applicability, we performed (i) spike analyses of offline-collected rat brain microdialysate and (ii) in vivo dynamic monitoring of the extracellular glucose and lactate in living rat brains, in addition to triggering neuronal depolarization by perfusing a high-K(+) medium from the implanted MD probe. Our analytical results and demonstrations confirm that postprinting functionalization of analytical devices manufactured using 3DP technology can be a powerful strategy for extending the diversity and adaptability of currently existing analytical configurations. PMID- 27232386 TI - Effect of Vitamin K Intake on the Stability of Treatment with Vitamin K Antagonists: A Systematic Review of the Literature. AB - Vitamin K antagonists (VKA) are highly effective for the primary and secondary prevention of arterial and venous thromboembolic events. However, patients treated with VKA have on average only 60% of their international normalized ratio (INR) values within the therapeutic range and INR instability is associated with an increased risk of thrombosis and bleeding events. Recent evidence suggests that poor dietary vitamin K intake may affect anticoagulation control, but the role of vitamin K in INR stability remains to be established. We performed a systematic review of the literature to assess the role of vitamin K dietary intake on the stability of VKA and the potential effect of daily vitamin K supplementation on VKA therapy. After a search in Medline and EMBASE databases, 15 studies for a total of 1,838 patients were included in our systematic review. Observational studies suggest an increased risk of unstable anticoagulation control in patients with lower daily vitamin K intake. On the other hand, the role of daily vitamin K supplementation or a diet with controlled vitamin K content in patients on VKA treatment remains to be established. Use of daily vitamin K supplementation may be associated with a clinically relevant increase in the time in therapeutic range in patients with unstable anticoagulation control. Conversely, this effect appears small and not clinically relevant when vitamin K was administered to an unselected population receiving VKA. Other large prospective studies are necessary to confirm our preliminary findings. PMID- 27232385 TI - A Redox Active [2Fe-2S] Cluster on the Hydrogenase Maturase HydF. AB - [FeFe]-hydrogenases are nature's most prolific hydrogen catalysts, excelling at facilely interconverting H2 and protons. The catalytic core common to all [FeFe] hydrogenases is a complex metallocofactor, referred to as the H-cluster, which is composed of a standard [4Fe-4S] cluster linked through a bridging thiolate to a 2Fe subcluster harboring dithiomethylamine, carbon monoxide, and cyanide ligands. This 2Fe subcluster is synthesized and inserted into [FeFe]-hydrogenase by three maturase enzymes denoted HydE, HydF, and HydG. HydE and HydG are radical S adenosylmethionine enzymes and synthesize the nonprotein ligands of the H cluster. HydF is a GTPase that functions as a scaffold or carrier for 2Fe subcluster production. Herein, we utilize UV-visible, circular dichroism, and electron paramagnetic resonance spectroscopic studies to establish the existence of redox active [4Fe-4S] and [2Fe-2S] clusters bound to HydF. We have used spectroelectrochemical titrations to assign iron-sulfur cluster midpoint potentials, have shown that HydF purifies with a reduced [2Fe-2S] cluster in the absence of exogenous reducing agents, and have tracked iron-sulfur cluster spectroscopic changes with quaternary structural perturbations. Our results provide an important foundation for understanding the maturation process by defining the iron-sulfur cluster content of HydF prior to its interaction with HydE and HydG. We speculate that the [2Fe-2S] cluster of HydF either acts as a placeholder for HydG-derived Fe(CO)2CN species or serves as a scaffold for 2Fe subcluster assembly. PMID- 27232389 TI - Nature versus nurture: A systematic approach to elucidate gene-environment interactions in the development of myopic refractive errors. AB - Myopia is the most common eye disorder and major cause of visual impairment worldwide. As the incidence of myopia continues to rise, the need to further understand the complex roles of molecular and environmental factors controlling variation in refractive error is of increasing importance. Tkatchenko and colleagues applied a systematic approach using a combination of gene set enrichment analysis, genome-wide association studies, and functional analysis of a murine model to identify a myopia susceptibility gene, APLP2. Differential expression of refractive error was associated with time spent reading for those with low frequency variants in this gene. This provides support for the longstanding hypothesis of gene-environment interactions in refractive error development. PMID- 27232390 TI - Efficient fluorescence quenching in electrochemically exfoliated graphene decorated with gold nanoparticles. AB - High surface area graphene sheets were obtained by electrochemical exfoliation of graphite in an acid medium under constant potential conditions. Filtration and centrifugation processes played an important role in order to obtain stable dispersions in water. Scanning electron microscopy and transmission electron microscopy imaging revealed highly exfoliated crystalline samples of ~5 MUm. Raman, Fourier transform infrared and x-ray photoelectron spectroscopy further confirmed the high quality of the exfoliated material. The electrochemically exfoliated graphene (EEG) was decorated with gold nanoparticles (AuNPs) using sodium cholate as a buffer layer. This approach allowed for a non-covalent functionalization without altering the desirable electronic properties of the EEG. The AuNP-EEG samples were characterized with various techniques including absorbance and fluorescence spectroscopy. These samples displayed a fluorescence signal using an excitation wavelength of 290 nm. The calculated quantum yield (Phi) for these samples was 40.04%, a high efficiency compared to previous studies using solution processable graphene. PMID- 27232392 TI - Parametric and energy consumption optimization of Basic Red 2 removal by electrocoagulation/egg shell adsorption coupling using response surface methodology in a batch system. AB - In this study, response surface methodology (RSM) model was applied for optimization of Basic Red 2 (BR2) removal using electrocoagulation/eggshell (ES) coupling process in a batch system. Central composite design was used to evaluate the effects and interactions of process parameters including current density, reaction time, initial pH and ES dosage on the BR2 removal efficiency and energy consumption. The analysis of variance revealed high R(2) values (>=85%) indicating that the predictions of RSM models are adequately applicable for both responses. The optimum conditions when the dye removal efficiency of 93.18% and energy consumption of 0.840 kWh/kg were observed were 11.40 mA/cm(2) current density, 5 min and 3 s reaction time, 6.5 initial pH and 10.91 g/L ES dosage. PMID- 27232393 TI - Successful reduction of diffuse nitrogen emissions at catchment scale: example from the pilot River Odense, Denmark. AB - Land-based total nitrogen (N) loadings to Danish coastal waters have been markedly reduced since 2000. This has been achieved by general measures reducing discharges from all point sources and N leaching from farmed land supplemented with more local and targeted mitigation measures such as restoration of wetlands to increase the catchment-specific N retention. In the catchment of River Odense, restoration of wetlands has been extensive. Thus, in the major gauged catchment (485 km(2)) eleven wetlands (860 ha) have been restored since 2000. A comparison of data on N concentrations and loss from a gauging station in the River Odense with data from a control catchment (772 km(2)), in which a significantly less intensive wetland restoration programme has been undertaken, showed an excess downward trend in N, amounting to 124 t N yr(-1), which can be ascribed to the intensive wetland restoration programme carried out in the River Odense catchment. In total, the N load in the River Odense has been reduced by 377 t N yr(-1) (39%) since 2000. The observed downward trend is supported by monitoring data from two wetlands restored in 2001 and 2004 in the River Odense catchment. PMID- 27232394 TI - Investigation into the bacterial pollution levels at various sites along the Diep and Plankenburg river systems, 3 Western Cape, South Africa. AB - This study sought to investigate and compare bacterial contamination levels at six different sites along the Diep and Plankenburg river systems in the Western Cape, South Africa. Surface water and sediment samples were collected monthly from the six selected sampling sites along both river courses between January 2014 and December 2014 and were evaluated for bacterial contaminants. Microbial isolation, characterisation and identification were done using conventional techniques (serial dilution, Gram staining, and biochemical testing) and molecular identification techniques (polymerase chain reaction and DNA sequencing). A total of 19 bacterial isolates belonging to the genera Raoultella, Bacillus, Pseudomonas, Klebsiella, Escherichia, Enterobacter, Exiguobacterium, Acinetobacter, Serratia, Aeromonas, Staphylococcus and Citrobacter were isolated from the surface water and sediment samples at the end of the survey. Higher microbial load was obtained from sediment samples compared to surface water samples. Seasonal variation was also observed in terms of microbial counts. Higher microbial counts were obtained during summer sampling time compared to winter sampling time. The most contaminated site was located on Plankenburg River with average bacterial counts ranging between 3.1 * 10(5)-6.9 * 10(8) CFU/ml and 3.9 * 10(6)-2.88 * 10(9) CFU/ml from surface water and sediment, respectively, recorded at this site during winter and summer. Although lower microbial counts were recorded along the Diep River course, most of the bacterial counts recorded along both rivers exceeded the acceptable maximum limits for river water. PMID- 27232395 TI - Isolation, identification, and algicidal activity of aerobic denitrifying bacterium R11 and its effect on Microcystis aeruginosa. AB - Recently, algicidal bacteria have attracted attention as possible agents for the inhibition of algal water blooms. In this study, an aerobic denitrifying bacterium, R11, with high algicidal activity against the toxic Microcystis aeruginosa was isolated from lake sediments. Based on its physiological characteristics and 16S rRNA gene sequence, it was identified as Raoultella, indicating that the bacterium R11 has a good denitrifying ability at 30 degrees C and can reduce the concentration of nitrate-N completely within 36 h. Additionally, different algicidal characteristics against Microcystis aeruginosa were tested. The results showed that the initial bacterial cell density and algal cell densities strongly influence the removal rates of chlorophyll a. Algicidal activity increased with an increase in the bacterial cell density. With densities of bacterial culture at over 2.4 * 10(5) cell/mL, algicidal activity of up to 80% was obtained in 4 days. We have demonstrated that, with the low initial algal cell density (OD680 less than 0.220), the algicidal activity reached was higher than 90% after 6 days. PMID- 27232396 TI - Response surface methodology for cadmium biosorption on Pseudomonas aeruginosa. AB - In this research the effects of various physicochemical factors on Cd(2+) biosorption such as initial metal concentration, pH and contact exposure time were studied. This study has shown a Cd(2+) biosorption, equilibrium time of about 5 min for Pseudomonas aeruginosa and the adsorption equilibrium data were well described by Langmuir equation. The maximum capacity for biosorption has been extrapolated to 0.56 mmol.g(-1) for P. aeruginosa. The thermodynamic properties DeltaG(0), DeltaH(0), and DeltaS(0) of Cd(2+) for biosorption were analyzed by the equilibrium constant value obtained from experimented data at different temperatures. The results show that biosorption of Cd(2+) by P. aeruginosa are endothermic and spontaneous with DeltaH value of 36.35 J.mol(-1). By response surface methodology, the quadratic model has adequately described the experimental data based on the adjusted determination coefficient (R(2) = 0.98). The optimum conditions for maximum uptake onto the biosorbent were established at 0.5 g.l(-1) biosorbent concentration, pH 6 for the aqueous solution, and a temperature of 30 degrees C. PMID- 27232397 TI - Can constructed wetlands treat wastewater for reuse in agriculture? Review of guidelines and examples in South Europe. AB - South Europe is one of the areas negatively affected by climate change. Issues with water shortage are already visible, and are likely to increase. Since agriculture is the biggest freshwater consumer, it is important to find new water sources that could mitigate the climate change impact. In order to overcome problems and protect the environment, a better approach towards wastewater management is needed. That includes an increase in the volume of wastewater that is treated and a paradigm shift towards a more sustainable system where wastewater is actually considered as a resource. This study evaluates the potential of constructed wetlands (CWs) to treat domestic wastewater and produce effluent that will be suitable for reuse in agriculture. In South Europe, four countries (Greece, Italy, Portugal and Spain) have national standards that regulate wastewater reuse in agriculture. Wastewater treatment plants (WWTPs) that are based on CWs in these four countries were analysed and their effluents compared with the quality needed for reuse. In general, it was found that CWs have trouble reaching the strictest standards, especially regarding microbiological parameters. However, their effluents are found to be suitable for reuse in areas that do not require water of the highest quality. PMID- 27232398 TI - Macrolide antibiotics removal using a circulating TiO2-coated paper photoreactor: parametric study and hydrodynamic flow characterization. AB - The present work investigates the photocatalytic degradation efficiency of biorecalcitrant macrolide antibiotics in a circulating tubular photoreactor. As target pollutants, spiramycin (SPM) and tylosin (TYL) were considered in this study. The photoreactor leads to the use of an immobilized titanium dioxide on non-woven paper under artificial UV-lamp irradiation. Maximum removal efficiency was achieved at the optimum conditions of natural pH, low pollutant concentration and a 0.35 L min(-1) flow rate. A Langmuir-Hinshelwood model was used to fit experimental results and the model constants were determined. Moreover, the total organic carbon analysis reveals that SPM and TYL mineralization is not complete. In addition, the study of the residence time distribution allowed us to investigate the flow regime of the reactor. Electrical energy consumption for photocatalytic degradation of macrolides using circulating TiO2-coated paper photoreactor was lower compared with some reported photoreactors used for the elimination of pharmaceutic compounds. A repetitive reuse of the immobilized catalyst was also studied in order to check its photoactivity performance. PMID- 27232399 TI - The effects of microwave regeneration on adsorptive performance of functionalized carbon nanotubes. AB - In this study, the microwave regeneration method was applied to investigate the properties and adsorptive performance of functionalized carbon nanotubes (f-CNTs) in different cycles of regeneration/reuse. For this purpose, an organic and hazardous dye (Reactive Blue 19) was chosen as a widely used pollutant. N2 adsorption/desorption isotherms, scanning electron microscopy and Fourier transform infrared spectroscopy were used to characterize f-CNTs during the regeneration/reuse procedure. The morphology, specific surface area and pore volume of f-CNT samples were not significantly altered. However, the functional groups present on the f-CNTs' surface were gradually removed after successive cycles of regeneration/reuse. A sudden decrease of adsorption capacity (about 20%) after the first cycle of regeneration/reuse was attributed to the elimination of functional groups interacting with the dye molecules because of the molecular-level heating. Relatively high regeneration efficiencies (73.30 to 80.16%) proved that the microwave regeneration method was successful. Very high step stripping efficiencies (80.16 to 98.02%) in four cycles of regeneration/reuse demonstrated that the microwave regeneration method could be utilized in consecutive cycles. After four cycles of regeneration/reuse, the CNTs could not be considered as functionalized. PMID- 27232400 TI - Characterizing phosphorus removal from polluted urban river water by steel slags in a vertical flow constructed wetland. AB - Phosphorus (P) removal in constructed wetlands (CWs) is often low unless special substrates with high sorption capacities are used. However, the use of special substrates in vertical flow (VF) CWs has not been proved to enhance P sorption. Thus, two VF wetlands were designed to evaluate the potential for enhanced P removal from polluted urban river water, one with slag as substrate and the other as a control with gravel as substrate. Findings from batch experiments showed P sorption capacities of 3.15 gP/kg and 0.81 gP/kg, respectively, for steel slag and gravel. Different organic matter fractions played different roles in P sorption, the effects of which were significant only at high concentrations. Over a 220 days' operation, the VF-slag removed 76.0% of the influent total phosphorus (TP) at 0.159 g/m(2).d and PO4-P of 70.9% at 0.063 g/m(2).d, whereas the VF gravel removed 65.0% at 0.136 g/m(2).d and 48.6% at 0.040 g/m(2).d, respectively. Therefore, the merit of using a steel slag substrate in VF wetlands can be significant for the removal of PO4-P. PMID- 27232402 TI - Effects of chemical oxygen demand (COD)/N ratios on pollutants removal in the subsurface wastewater infiltration systems with/without intermittent aeration. AB - The matrix oxidation reduction potential level, organic pollutants and nitrogen removal performances of eight subsurface wastewater infiltration systems (SWISs) (four with intermittent aeration, four without intermittent aeration) fed with influent chemical oxygen demand (COD)/N ratio of 3, 6, 12 and 18 were investigated. Nitrification of non-aerated SWISs was poor due to oxygen deficiency while higher COD/N ratios further led to lower COD and nitrogen removal rate. Intermittent aeration achieved almost complete nitrification, which successfully created aerobic conditions in the depth of 50 cm and did not change anoxic or anaerobic conditions in the depth of 80 and 110 cm. The sufficient carbon source in high COD/N ratio influent greatly promoted denitrification in SWISs with intermittent aeration. High average removal rates of COD (95.68%), ammonia nitrogen (NH4(+)-N) (99.32%) and total nitrogen (TN) (89.65%) were obtained with influent COD/N ratio of 12 in aerated SWISs. The results suggest that intermittent aeration was a reliable option to achieve high nitrogen removal in SWISs, especially with high COD/N ratio wastewater. PMID- 27232401 TI - Preparation of activated carbon from corn cob and its adsorption behavior on Cr(VI) removal. AB - Operation experiments were conducted to optimize the preparation of activated carbons from corn cob. The Cr(VI) adsorption capacity of the produced activated carbons was also evaluated. The impact of the adsorbent dosage, contact time, initial solution pH and temperature was studied. The results showed that the produced corn cob activated carbon had a good Cr(VI) adsorptive capacity; the theoretical maximum adsorption was 34.48 mg g(-1) at 298 K. The Brunauer-Emmett Teller and iodine adsorption value of the produced activated carbon could be 924.9 m(2) g(-1) and 1,188 mg g(-1), respectively. Under the initial Cr(VI) concentration of 10 mg L(-1) and the original solution pH of 5.8, an adsorption equilibrium was reached after 4 h, and Cr(VI) removal rate was from 78.9 to 100% with an adsorbent's dosage increased from 0.5 to 0.7 g L(-1). The kinetics and equilibrium data agreed well with the pseudo-second-order kinetics model and the Langmuir isotherm model. The equilibrium adsorption capacity improved with the increment of the temperature. PMID- 27232403 TI - Pb(II) adsorption by biomass from chemically modified aquatic macrophytes, Salvinia sp. and Pistia stratiotes. AB - This study used two biosorbents obtained from the aquatic plants Salvinia sp. and Pistia stratiotes to establish a sustainable and alternative treatment for industrial wastewater and other water bodies that contain Pb(II). The biosorbent named Salvinia with NaOH (SOH) was obtained from Salvinia sp., and Salvinia and Pistia mixture with NaOH (SPOH) was obtained from a mixture of the two plants in a 1:1 ratio. The biosorbents were characterized by zeta potential, infrared (IR) spectroscopy, scanning electron microscopy (SEM), energy-dispersive spectroscopy and Boehm titration. The results of Boehm titration and IR analysis indicated the presence of basic functional groups, whereas those of SEM analysis indicated that the biosorbents have a structure conducive to adsorption. Batch adsorption experiments were performed to observe the effects of pH, contact time, initial lead concentration and temperature on the metal removal process. The results revealed that the biosorbents efficiently removed Pb(II) from aqueous solutions, with a maximum observed adsorption capacity (saturation limits, qmax) of 202 mg g(-1) and 210.1 mg g(-1) for SPOH and SOH, respectively. The Freundlich, Langmuir and Dubinin-Radushkevich models were applied to the data; these biosorbent studies did not satisfactorily adjust to either of the models, but the information obtained helped us understand the adsorption mechanism. PMID- 27232404 TI - Assessment of the removal mechanism of hexavalent chromium from aqueous solutions by olive stone. AB - The objectives of this study were to study the removal mechanism of Cr(VI) by natural olive stone (OS) and to present a sequential-batch process for the removal of total chromium (original Cr(VI) and Cr(III) derived from reduction of Cr(VI) during biosorption at acidic conditions). First, experiments were conducted varying pH from 1 to 4, and showed that a combined effect of biosorption and reduction is involved in the Cr(VI) removal. Then, X-ray photoelectron spectroscopy and desorption tests were employed to verify the oxidation state of the chromium bound to OS and to elucidate the removal mechanism of Cr(VI) by this material. The goal of these tests was to confirm that Cr(III) is the species mainly absorbed by OS. Finally, the possibility of total chromium removal by biosorption in a sequential-batch process was analyzed. In the first stage, 96.38% of Cr(VI) is removed by OS and reduced to Cr(III). In the second stage, approximately 31% of the total Cr concentration was removed. However, the Cr(III) released in the first stage is not completely removed, and it could suggest that the Cr(III) could be in a hydrated compound or a complex, which could be more difficult to remove under these conditions. PMID- 27232405 TI - Reduction of highly concentrated phosphate from aqueous solution using pectin nanoscale zerovalent iron (PNZVI). AB - Pectin-nanoscale zerovalent iron (PNZVI) has been studied as an effective phosphate adsorption material to remove highly concentrated phosphate from aqueous solution. Batch phosphate removal and equilibrium experiments were conducted in order to evaluate the effects of environmental factors such as pH, coexisting anions and ionic strengths on phosphate removal by PNZVI. The scanning electron microscope images of nanoscale zerovalent iron (NZVI) and PNZVI demonstrated that PNZVI exhibited larger specific surface areas than NZVI so that PNZVI had higher phosphate removal efficiency than NZVI. Equilibrium experiments showed that phosphate adsorption by PNZVI was well fitted with the Freundlich and Langmuir models. In addition, the maximum adsorption capacity reached 277.38 mgP/gPNZVI. The ionic strengths and common anions showed no significant effects on the process of phosphate adsorption by PNZVI. The phosphate removal efficiency increased to a peak value with pH increased from 2.0 to 5.0, then decreased with pH further increased from 5.0 to 10.0. The Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy analyses of PNZVI and P-loaded PNZVI indicated that adsorption, rather than redox reaction, was the dominant mechanism for the removal of phosphate by PNZVI. PMID- 27232406 TI - Catalytic reduction of nitrate in secondary effluent of wastewater treatment plants by Fe(0) and Pd-Cu/gamma-Al2O3. AB - Total nitrogen, in which NO3(-) is dominant in the effluent of most wastewater treatment plants, cannot meet the requirements of the Chinese wastewater discharge standard (<15 mg/L), making nitrate (NO3(-)) elimination attract considerable attention. In this study, reductant iron (Fe(0)) and gamma-Al2O3 supported palladium-copper bimetallic catalysts (Pd-Cu/gamma-Al2O3) were innovatively used for the chemical catalytic reduction of nitrate in wastewater. A series of specific operational conditions (such as mass ratio of Pd:Cu, catalyst amounts, reaction time and pH of solution) were optimized for nitrate reduction in the artificial solution, and then the selected optimal conditions were further applied for investigating the nitrate elimination of secondary effluent of a wastewater treatment plant in Beijing, China. Results indicated that a better catalytic performance (74% of nitrate removal and 62% of N2 selectivity) could be obtained under the optimal condition: 5 g/L Fe(0), 3:1 mass ratio (Pd:Cu), 4 g/L catalyst, 2 h reaction time and pH 5.1. It is noteworthy to point out that nitrogen gas (N2) predominated in the byproducts without another system to treat ammonium and nitrite. Therefore, the chemical catalytic reduction combining Fe(0) with Pd-Cu/gamma-Al2O3 could be regarded as a better alternative for nitrate removal in wastewater treatment. PMID- 27232407 TI - Polishing of treated palm oil mill effluent (POME) from ponding system by electrocoagulation process. AB - As the ponding system used to treat palm oil mill effluent (POME) frequently fails to satisfy the discharge standard in Malaysia, the present study aimed to resolve this problem using an optimized electrocoagulation process. Thus, a central composite design (CCD) module in response surface methodology was employed to optimize the interactions of process variables, namely current density, contact time and initial pH targeted on maximum removal of chemical oxygen demand (COD), colour and turbidity with satisfactory pH of discharge POME. The batch study was initially designed by CCD and statistical models of responses were subsequently derived to indicate the significant terms of interactive process variables. All models were verified by analysis of variance showing model significances with Prob > F < 0.01. The optimum performance was obtained at the current density of 56 mA/cm(2), contact time of 65 min and initial pH of 4.5, rendering complete removal of colour and turbidity with COD removal of 75.4%. The pH of post-treated POME of 7.6 was achieved, which is suitable for direct discharge. These predicted outputs were subsequently confirmed by insignificant standard deviation readings between predicted and actual values. This optimum condition also permitted the simultaneous removal of NH3-N, and various metal ions, signifying the superiority of the electrocoagulation process optimized by CCD. PMID- 27232408 TI - Comparison between Brazilian agro-wastes and activated carbon as adsorbents to remove Ni(II) from aqueous solutions. AB - This research was performed to find an alternative, low-cost, competitive, locally available and efficient adsorbent to treat nickel (Ni) containing effluents. For this purpose, several Brazilian agro-wastes like sugarcane bagasse (SCB), passion fruit wastes (PFW), orange peel (OP) and pineapple peel (PP) were compared with an activated carbon (AC). The adsorbents were characterized. Effects of fundamental factors affecting the adsorption were investigated using batch tests. Kinetic and equilibrium studies were performed using conventional models. It was verified that the adsorption was favored at pH of 6.0 for all agro wastes, being dependent of the Ni speciation, point of zero charge and surface area of the adsorbents. The Ni removal percentage was in the following order: SCB > OP > AC > PFW > PP. From the kinetic viewpoint, the Elovich model was appropriate to fit the Ni adsorption onto SCB, while for the other adsorbents, the pseudo-first-order model was the most suitable. For all adsorbents, the Langmuir model was the more adequate to represent the equilibrium data, being the maximum adsorption capacities of 64.1 mg g(-1), 60.7 mg g(-1), 63.1 mg g(-1), 48.1 mg g(-1) and 64.3 mg g(-1) for SCB, PFW, OP, PP and AC, respectively. These results indicated that mainly SCB and OP can be used as alternative adsorbents to treat Ni containing effluents. PMID- 27232409 TI - Bacterial composition and nutrient removal with a novel PIA-A(2)/O sewage treatment. AB - A novel post intermittent aeration anaerobic-anoxic-oxic (PIA-A(2)/O) process was developed to integrate shortcut nitrification-denitrification with denitrifying phosphorus (P) removal for domestic sewage treatment. With the transformation in configuration and phased start-up strategy, the nitritation rate and the ratio of denitrifying phosphorus accumulating organisms to phosphorus accumulating organisms (DPAO/PAO) were enhanced greatly to 88.2% and 83.9-91.7% in the PIA A(2)/O process, respectively. Improved total nitrogen and phosphorus removal were achieved at long sludge retention time and low aeration. High sludge activity was maintained through the periodic selection of the additional intermittent aeration zone. High-throughput sequencing revealed that Bacteroidetes (38.96%), Proteobacteria (33.59%), TM7 (4.53%), Chloroflexi (3.09%), and Firmicutes (2.49%) were the dominant phyla in the resultant bacterial community. Abundant anaerobic and facultative bacteria conducive to excess sludge reduction were generated by this process. Potential DPAOs involve the genera of Brevundimonas, Brachymonas, Steroidobacter, Haliscomenobacter, and Rhodocyclus. PMID- 27232410 TI - Characterizing cell surface of blooming Microcystis in Lake Taihu, China. AB - Microcystis occurs as colonies in the natural environment but disaggregates into single cells in laboratory cultures. In order to explore the mechanism of how Microcystis forms colonies, the zeta potentials of Microcystis cells from the laboratory and the field were studied, and the hydrophobicity of Microcystis colonies in different sizes was investigated in Lake Taihu. The incubation experiment indicated that the zeta potentials of Microcystis cells were affected by growth phase and species. The absolute values in exponential phase were lower than those in stationary phase, suggesting that the cells with rapid growth easily formed colonies due to more instability on the cell surface. The values of Microcystis aeruginosa were higher than those of Microcystis flos-aquae, which confirmed that M. aeruginosa prevailed in waters for a longer time and at a larger size compared with M. flos-aquae. In another aspect, the absolute zeta potentials of Microcystis spp. at pH 7.0 decreased from spring to autumn in the field; the values in spring were higher than those in summer, suggesting that a large-sized Microcystis colony would more easily form in summer. Additionally, differences in hydrophobicity exist among Microcystis colonies of various sizes. The surface hydrophobicity of colonies in the <20 MUm size class was higher than that of larger colonies. This characteristic allowed small colonies to easily form large colonies to survive better. These results would be helpful to understand the mechanism of the bloom formation, especially the colony formation, in Microcystis. PMID- 27232411 TI - Removal of micropollutants with coarse-ground activated carbon for enhanced separation with hydrocyclone classifiers. AB - One key technology to eliminate organic micropollutants (OMP) from wastewater effluent is adsorption using powdered activated carbon (PAC). To avoid a discharge of highly loaded PAC particles into natural water bodies a separation stage has to be implemented. Commonly large settling tanks and flocculation filters with the application of coagulants and flocculation aids are used. In this study, a multi-hydrocyclone classifier with a downstream cloth filter has been investigated on a pilot plant as a space-saving alternative with no need for a dosing of chemical additives. To improve the separation, a coarser ground PAC type was compared to a standard PAC type with regard to elimination results of OMP as well as separation performance. With a PAC dosing rate of 20 mg/l an average of 64.7 wt% of the standard PAC and 79.5 wt% of the coarse-ground PAC could be separated in the hydrocyclone classifier. A total average separation efficiency of 93-97 wt% could be reached with a combination of both hydrocyclone classifier and cloth filter. Nonetheless, the OMP elimination of the coarse ground PAC was not sufficient enough to compete with the standard PAC. Further research and development is necessary to find applicable coarse-grained PAC types with adequate OMP elimination capabilities. PMID- 27232413 TI - Removal of nitrogen and phosphorus from the secondary effluent in tertiary denitrifying biofilters combined with micro-coagulation. AB - Effective control of nitrogen and phosphorus in secondary effluent can reduce or avoid the eutrophication of receiving water bodies. Two denitrifying biofilters (DNBFs) packed with different sizes of quartz sands combined with micro coagulation were operated for simultaneous removal of nitrogen and phosphorus from the secondary effluent. The quartz sand size in one DNBF was 2-4 mm (DNBFS), and in the other was 4-6 mm (DNBFL). In both DNBFs, methanol was used as the electron donor and different organic carbon to nitrogen (C/N) ratios were applied. Under C/N ratios of 1.5, 1.25, and 0.75 g/g, the nitrate nitrogen (NO3( )-N) removal percentages were 73%, 77%, and 50% in DNBFS, and 43%, 25%, and 21% in DNBFL; the effluent total phosphorus concentrations were 0.15, 0.14, and 0.18 mg/L in DNBFS, and 0.29, 0.35, and 0.24 mg/L in DNBFL. The performance of both biofilters was quite stable within a backwashing cycle. The NO3(-)-N reduction rates were 1.31, 1.10, and 0.48 mg/(L.min) in DNBFS, and 0.97, 0.27, and 0.10 mg/(L.min) in DNBFL. For biomass detached from both biofilters, their denitrifying activities were similar. Biofilm biomass in DNBFS was higher than that in DNBFL, inducing a high denitrification efficiency in DNBFS. PMID- 27232412 TI - Property of Cu2O-CuO/ZSM-5 nanocomposite and degradation process of azo dye AO7 without sacrificial agent (H2O2). AB - In this study, Cu2O-CuO/ZSM-5 nanocomposite was synthesized by the impregnation method, and its catalytic performance for the destruction of AO7 in aqueous solutions was investigated. The morphology, structure and surface element valence state of Cu2O-CuO/ZSM-5 were characterized by transmission electron microscopy, X ray diffraction and X-ray photoelectron spectroscopy. The operating conditions on the degradation of AO7 by Cu2O-CuO/ZSM-5, such as initial pH values, concentration of AO7 and catalyst dosage were investigated and optimized. The results showed that the sample had good catalytic activity for destruction of AO7 in the absence of a sacrificial agent (e.g. H2O2): it could degrade 91% AO7 in 140 min at 25 degrees C and was not restricted by the initial pH of the AO7 aqueous solutions. Cu2O-CuO/ZSM-5 exhibited stable catalytic activity with little loss after three successive runs. The total organic carbon and chemical oxygen demand removal efficiencies increased rapidly to 69.36% and 67.3% after 120 min of treatment by Cu2O-CuO/ZSM-5, respectively. PMID- 27232414 TI - Application of annealed red mud to Mn(2+) ion adsorption from aqueous solution. AB - Physicochemical characteristics and Mn(2+) adsorption of annealed red mud were investigated in this study. The annealing temperature (105-900 degrees C) changed the mineralogical components and the point of zero charge of red mud. By comparison, annealed red mud at 700 degrees C (ARM700) had a better adsorption effect than other annealed samples, associated with the activated components of available Fe2O3, Al2O3, SiO2 and Na5Al3(SiO4)3CO3 (natrodavyne). The removal efficiency of Mn(2+) by ARM700 was dependent on initial pH, contact time, and initial Mn(2+) concentration of aqueous solution and was ~56.5% with initial Mn(2+) concentration 385 mg/L at initial pH > 5. The kinetics process was predicted better by the pseudo-second-order model. The Langmuir isotherm displayed a better fitting model than the Freundlich isotherm and the Mn(2+) maximum adsorption capacity of ARM700 was 88.3 mg/g. The competing effects of Cu(2+) and Zn(2+) on Mn(2+) removal were most obvious. There was efficient Mn(2+) removal at the application of ARM700 to the leachate of electrolytic manganese residue. PMID- 27232415 TI - Cytotoxic and genotoxic activities of waters and sediments from highway and parking lot runoffs. AB - The genotoxicity of water and sediment samples from stormwater treatment systems and water from urban highway runoff was tested in the Salmonella/microsome assays with Salmonella typhimurium, micronucleus assay (Trad-MN) with plants and with human-derived liver cells (HepG2), or comet assay with HepG2. Cytotoxicity of water samples was studied using either reactive oxygen species (ROS) generation, cell proliferation or dye exclusion assay in HepG2. Concentrations of several contaminants in the tested samples were also measured. Results suggested that urban highway runoff exposed to severe vehicle traffic emissions caused genotoxic effects in comet assay and in Trad-MN assays. Sediments induced either mutagenic effects in strain YG1024 or genotoxic effects in Trad-MN assay. These effects could be due to the presence of nitro-polycyclic aromatic hydrocarbons (NPAHs) which possess carcinogenic and mutagenic properties. Influent and effluents of stormwater treatment systems did not induce genotoxic activity or effects on HepG2 cell viability; however, the influents were able to induce ROS generation and cell proliferation in HepG2 cells. As the methods require a sterile filtration of the water samples, this could have also removed particulate associated polycyclic aromatic hydrocarbons (PAHs) and resulted in a less pronounced induction of genotoxicity, as would be expected by PAH contamination. PMID- 27232416 TI - Vortex-assisted surfactant-enhanced-emulsification liquid-liquid microextraction with solidification of floating organic droplet combined with flame atomic absorption spectrometry for the fast determination of cadmium in water samples. AB - A novel vortex-assisted surfactant-enhanced-emulsification liquid-liquid microextraction with solidification of floating organic droplet (VSLLME-SFO) was developed for the fast, simple and efficient determination of cadmium (Cd) in water samples followed by flame atomic absorption spectrometry (FAAS). In the VSLLME-SFO process, the addition of surfactant (as an emulsifier), could enhance the mass transfer from the aqueous solution into the extraction solvent. The extraction solvent could be dispersed into the aqueous phase under vigorous shaking with the vortex. In this paper, we investigated the influences of analytical parameters, including pH, extraction solvent type and its volume, surfactant type and its volume, concentration of chelating agent, salt effect and vortex time, on the extraction efficiency of Cd. Under the optimized conditions, the limit of detection was 0.16 MUg/L. The analyte enrichment factor was 37.68. The relative standard deviation was 3.2% (10 MUg/L, n = 10) and the calibration graph was linear, ranging from 0.5 to 30 MUg/L. The proposed method was successfully applied for the analysis of ultra-trace Cd in river water and wastewater samples. PMID- 27232417 TI - Comparison of sidestream treatment technologies: post aerobic digestion and Anammox. AB - Post aerobic digestion (PAD) and anaerobic ammonium oxidation (Anammox) are sidestream treatment technologies which are both excellent options for the reduction of nitrogen recycled back to the liquid stream without the need for supplemental carbon or alkalinity. However, the achievement of this goal is where the similarities between the two technologies end. PAD is an advanced digestion process where aerobic digestion is designed to follow anaerobic digestion. Other benefits of PAD include volatile solids reduction, odor reduction, and struvite formation reduction. Anammox harnesses a specific species of autotrophic bacteria that can help achieve partial nitritation/deammonification. Other benefits of Anammox include lower energy consumption due to requiring less oxygen compared with conventional nitrification. This manuscript describes the unique benefits and challenges of each technology. Example installations are presented with a narrative of how and why the technology was selected. A whole plant simulator is used to compare and contrast the mass balances and net present value costs on an 'apples to apples' basis. The discussion includes descriptions of conditions under which each technology would potentially be the most beneficial and cost effective against a baseline facility without sidestream treatment. PMID- 27232418 TI - A high-efficient batch-recirculated photoreactor packed with immobilized TiO2-P25 nanoparticles onto glass beads for photocatalytic degradation of phenazopyridine as a pharmaceutical contaminant: artificial neural network modeling. AB - In this study, removal efficiency of phenazopyridine (PhP) as a model pharmaceutical contaminant was investigated in a batch-recirculated photoreactor packed with immobilized TiO2-P25 nanoparticles on glass beads. Influence of various operational parameters such as irradiation time, initial concentration of PhP, volume of solution, volumetric flow rate, pH and power of light source was investigated. Results indicated that removal percentage increases with the rise of irradiation time, volumetric flow rate and power of light source but decreases with the rise of initial concentration of PhP and volume of solution. Highest removal percentage was obtained in the natural pH of PhP solution (pH = 5.9). Results of mineralization studies also showed a decreasing trend of total organic carbon (TOC) and producing mineralization products such as NO3(-), NO2(-) and NH4(+). Modeling of the process using artificial neural network showed that the most effective parameters in the degradation of PhP were volume of solution and power of light source. The packed bed photoreactor with TiO2-P25 nanoparticles coated onto glass beads in consecutive repeats have the proper ability for PhP degradation. Therefore, this system can be a promising alternative for the removal of recalcitrant organic pollutants such as PhP from aqueous solutions. PMID- 27232419 TI - Nanoscale zero-valent iron incorporated with nanomagnetic diatomite for catalytic degradation of methylene blue in heterogeneous Fenton system. AB - Nanoscale zero-valent iron (nZVI) incorporated with nanomagnetic diatomite (DE) composite material was prepared for catalytic degradation of methylene blue (MB) in heterogeneous Fenton system. The material was constructed by two facile steps: Fe3O4 magnetic nanoparticles were supported on DE by chemical co-precipitation method, after which nZVI was incorporated into magnetic DE by liquid-phase chemical reduction strategy. The as-prepared catalyst was characterized by scanning electron microscopy, Fourier-transform infrared spectroscopy, X-ray diffraction, magnetic properties measurement and nitrogen adsorption-desorption isotherm measurement. The novel nZVI@Fe3O4-diatomite nanocomposites showed a distinct catalytic activity and a desirable effect for degradation of MB. MB could be completely decolorized within 8 min and the removal efficiency of total organic carbon could reach to 90% after reaction for 1 h. PMID- 27232420 TI - Modelling runoff on ceramic tile roofs using the kinematic wave equations. AB - Generally, roofs are the best candidates for rainwater harvesting. In this context, the correct evaluation of the quantity and quality of runoff from roofs is essential to effectively design rainwater harvesting systems. This study aims to evaluate the performance of a kinematic wave based numerical model in simulating runoff on sloping roofs, by comparing the numerical results with the ones obtained from laboratory rainfall simulations on a real-scale Lusa ceramic tile roof. For all studied slopes, simulated discharge hydrographs had a good adjust to observed ones. Coefficient of determination and Nash-Sutcliffe efficiency values were close to 1.0. Particularly, peak discharges, times to peak, peak durations and runoff volumes were very well simulated. PMID- 27232421 TI - Removal of methylene blue from aqueous solution by Artist's Bracket fungi: kinetic and equilibrium studies. AB - In this study, adsorption of methylene blue (MB) dye onto Artist's Bracket (AB) fungi was investigated in aqueous solution. Fourier transform infrared and scanning electron microscopy were used to investigate surface characteristic of AB fungi. Influence of operational parameters such as pH, contact time, biosorbent dosage, dye concentration, inorganic salts and temperature was studied on dye removal efficiency. With the increase of pH from 3 to 9, removal efficiency increased from 74.0% to 90.4%. Also, it reduced from 99.8% to 81.8% with increasing initial MB concentration from 25 mg L(-1) to 100 mg L(-1), whereas it increased from 54.7% to 98.7% and from 98.5% to 99.9% with increasing biosorbent dosage from 0.5 g L(-1) to 2 g L(-1) and with increasing temperature from 25 degrees C to 50 degrees C, respectively. Isotherm studies have shown adsorption of MB dye over the AB fungi had a better coefficient of determination (R(2)) of 0.98 for Langmuir isotherm. In addition, the maximum monolayer adsorption capacity (qm) was 100 mg g(-1). Also, the MB dye adsorption process followed pseudo-second-order kinetic. In general, AB fungi particles can be favorable for removal of MB dye from dye aqueous solution with natural pH and high temperature. PMID- 27232422 TI - The Effect of Auditory Information on Patterns of Intrusions and Reductions. AB - PURPOSE: The study investigates whether auditory information affects the nature of intrusion and reduction errors in reiterated speech. These errors are hypothesized to arise as a consequence of autonomous mechanisms to stabilize movement coordination. The specific question addressed is whether this process is affected by auditory information so that it will influence the occurrence of intrusions and reductions. METHODS: Fifteen speakers produced word pairs with alternating onset consonants and identical rhymes repetitively at a normal and fast speaking rate, in masked and unmasked speech. Movement ranges of the tongue tip, tongue dorsum, and lower lip during onset consonants were retrieved from kinematic data collected with electromagnetic articulography. Reductions and intrusions were defined as statistical outliers from movement range distributions of target and nontarget articulators, respectively. RESULTS: Regardless of masking condition, the number of intrusions and reductions increased during the course of a trial, suggesting movement stabilization. However, compared with unmasked speech, speakers made fewer intrusions in masked speech. The number of reductions was not significantly affected. CONCLUSIONS: Masking of auditory information resulted in fewer intrusions, suggesting that speakers were able to pay closer attention to their articulatory movements. This highlights a possible stabilizing role for proprioceptive information in speech movement coordination. PMID- 27232423 TI - Cleaner production in a remanufacturing process of air compressors. AB - This article provides relevant results of a cleaner production program conducted in a company dedicated to remanufacturing air compressors in the city of Hermosillo, Sonora, Mexico. The overall study design was based on an integration of acknowledged cleaner production and pollution prevention programs. Although this kind of program also involves environmental issues, this study focused on occupational health and safety by addressing different aspects of the work environment: ergonomic, physical (noise and lighting), and chemical. Particularly, ergonomic aspects were evaluated through the Modular Arrangement of Predetermined Time Standards (MODAPTS) method. For physical aspects, noise and lighting were addressed through Standard No. NOM-011-STPS-2001 and Standard No. NOM-025-STPS-2008 respectively. In addition, chemical aspects were analyzed through material safety data sheets and different search tools. Root causes of each risk were identified, and options to prevent, eliminate, and/or reduce each risk have been provided. PMID- 27232424 TI - A case of methemoglobinemia after ingestion of a chlorhexidine in alcohol solution in an alcohol-dependent patient. PMID- 27232425 TI - Lifetime prevalence of non-melanoma and melanoma skin cancer in Australian recreational and competitive surfers. AB - BACKGROUND/PURPOSE: Surfing is one of the most popular outdoor aquatic activities in Australia with an estimated 2.7 million recreational surfers; however, Australia has long been recognized as having the highest incidence of melanoma in the world, and it is the most common type of cancer in young Australians. The aim of this study was to investigate the lifetime prevalence of non-melanoma [basal cell carcinoma (BCC), squamous cell carcinoma (SCC)] and melanoma skin cancers in Australian recreational and competitive surfers. METHODS: Australian surfers were invited to complete an online surveillance survey to determine the lifetime prevalence of non-melanoma and melanoma skin cancers. RESULTS: A total of 1348 surfers (56.9% recreational) participated in this study, of which 184 surfers reported a skin cancer (competitive n = 96, recreational n = 87). Of non-melanoma and melanoma cancers reported, BCC was the most common (6.8%), followed by melanoma (1.4%) and SCC (0.6%). The relative risk was higher (P < 0.001) in competitive vs. recreational surfers [OR 1.74 (CI 1.28-2.31)]. There was a higher (P < 0.05) number of skin cancers reported on the face (23.5%), back (16.4%) and arms (12.4%). There were significant trends (P < 0.001) in reported skin cancers between competitive and recreational surfers, as well as significantly (P < 0.001) more skin cancers reported in males (14.6%) than females (9.4%). CONCLUSION: Based upon these findings, individuals who surf are advised to regularly utilize sun protection strategies (avoid peak ultraviolet radiation (10 am-3 pm), rashvest, hat and sunscreen) and primary care physicians are recommended to regularly screen their patients who surf. PMID- 27232426 TI - Why There Is a Need for an International Nomenclature and Classification System for Suicide. PMID- 27232427 TI - Who Goes Online for Suicide-Related Reasons? AB - BACKGROUND: Although people who use the Internet for suicide-related reasons have been found to report significantly higher levels of suicidal ideation, little is known about the characteristics of these users. AIMS: To examine the differences between suicidal people who use the Internet for suicide-related reasons and those who do not. METHOD: Participants were 205 Australian citizens and permanent residents aged 18-24 years who had felt suicidal within the past year. Participants were recruited online through non-mental health-related websites and asked to complete an anonymous online survey. RESULTS: In univariate analyses, suicide-related users reported significantly higher levels of social anxiety and lifetime and past year suicidal ideation than non-suicide-related users, as well as a higher likelihood of future suicide and overall higher risk for suicide. There were no differences on depressive symptoms and perceived social support. Both groups were unlikely to anticipate seeking help from any source and generally perceived similar barriers to offline help-seeking. Multivariate analyses showed that past year suicidal ideation and likelihood of future suicide significantly predicted suicide-related Internet use. CONCLUSIONS: Individuals may choose to go online for alternative methods of coping when their suicidal feelings become more severe, demonstrating the need for more online suicide prevention efforts. PMID- 27232428 TI - Psychological Resilience Provides No Independent Protection From Suicidal Risk. AB - BACKGROUND: Little is known about the role of resilience in the likelihood of suicidal ideation (SI) over time. AIMS: We examined the association between resilience and SI in a young-adult cohort over 4 years. Our objectives were to determine whether resilience was associated with SI at follow-up or, conversely, whether SI was associated with lowered resilience at follow-up. METHOD: Participants were selected from the Personality and Total Health (PATH) Through Life Project from Canberra and Queanbeyan, Australia, aged 28-32 years at the first time point and 32-36 at the second. Multinomial, linear, and binary regression analyses explored the association between resilience and SI over two time points. Models were adjusted for suicidality risk factors. RESULTS: While unadjusted analyses identified associations between resilience and SI, these effects were fully explained by the inclusion of other suicidality risk factors. CONCLUSION: Despite strong cross-sectional associations, resilience and SI appear to be unrelated in a longitudinal context, once risk/resilience factors are controlled for. As independent indicators of psychological well-being, suicidality and resilience are essential if current status is to be captured. However, the addition of other factors (e.g., support, mastery) makes this association tenuous. Consequently, resilience per se may not be protective of SI. PMID- 27232429 TI - Analyzing Language in Suicide Notes and Legacy Tokens. AB - BACKGROUND: Identifying precursors that will aid in the discovery of individuals who may harm themselves or others has long been a focus of scholarly research. AIM: This work set out to determine if it is possible to use the legacy tokens of active shooters and notes left from individuals who completed suicide to uncover signals that foreshadow their behavior. METHOD: A total of 25 suicide notes and 21 legacy tokens were compared with a sample of over 20,000 student writings for a preliminary computer-assisted text analysis to determine what differences can be coded with existing computer software to better identify students who may commit self-harm or harm to others. RESULTS: The results support that text analysis techniques with the Linguistic Inquiry and Word Count (LIWC) tool are effective for identifying suicidal or homicidal writings as distinct from each other and from a variety of student writings in an automated fashion. CONCLUSION: Findings indicate support for automated identification of writings that were associated with harm to self, harm to others, and various other student writing products. This work begins to uncover the viability or larger scale, low cost methods of automatic detection for individuals suffering from harmful ideation. PMID- 27232432 TI - Did you know? Visual adaption causing illusion. PMID- 27232430 TI - Death Ideation and Suicidal Ideation in a Community Sample Who Do Not Meet Criteria for Major Depression. AB - BACKGROUND: Suicide is strongly associated with depression, but many without depression have thoughts of death. AIMS: To characterize persons who did not meet criteria for depressive illness but endorsed death ideation or suicidal ideation over the course of a 10-year follow-up. METHOD: Subjects included 753 participants of the Baltimore sample of the Epidemiologic Catchment Area Program, a population-based 10-year follow-up survey, who neither met criteria for major depressive disorder nor reported death or suicidal ideation in 1994. RESULTS: Persons with death ideation or suicidal ideation in 2004 were generally distressed as measured by the General Health Questionnaire. At baseline, both groups endorsed difficulty with concentration, feeling unhappy, and taking things hard. Functional problems such as social withdrawal were endorsed by both groups. Those with suicidal ideation had a longer lifetime history of social phobia. Persons with death ideation did not use more health services but sought help from persons in their social network. CONCLUSION: Thoughts of death are associated with distress even in persons who do not have depressive illness. This group of persons may have subclinical depressive symptoms that will not be detected by depression screening. Detection of these persons will require broadening our concept of persons at risk. PMID- 27232433 TI - Heterometallic Metal-Organic Frameworks That Catalyze Two Different Reactions Sequentially. AB - A series of copper- and alkaline-earth-metal-based multidimensional metal-organic frameworks, {[CuMg(pdc)2(H2O)4].2H2O}n (1), [CuCa(pdc)2]n (2), [CuSr(pdc)2(H2O)3]n (3), and {[CuBa(pdc)2(H2O)5].H2O}n (4), where H2Pdc = pyridine-2,5-dicarboxylic acid, were hydrothermally synthesized and characterized. Two different metals act as the active center to catalyze two kinds of reactions, viz., olefin to its epoxide followed by epoxide ring opening to afford the corresponding vicinal diol in a sequential manner. PMID- 27232434 TI - Evidence-Based Dentistry - an Ever-Evolving Field of Research and Information. PMID- 27232437 TI - Will producing more dentists solve all the workforce issues in rural and remote areas? PMID- 27232438 TI - Characterization of Extended Spectrum Beta-Lactamase Producing Enterobacteria and Methicillin-Resistant Staphylococcus aureus Isolated from Raw Pork and Cooked Pork Products in South China. AB - In this study, we assessed the co-colonization with extended spectrum beta lactamase producing Enterobacteria (ESBL-E) and methicillin-resistant Staphylococcus aureus (MRSA) in raw pork and cooked pork products in south China. In total, 240 raw pork and 240 cooked pork samples collected from supermarkets (n = 20) and local butcher shops (n = 20) in the city of Guangzhou (China) were investigated. Raw pork and cooked pork was more frequent colonization with ESBL-E (7.5% in raw pork and 0.4% in cooked pork products) than with MRSA (4.2% in raw pork). Two of samples were contaminated with both tested types of multidrug resistant bacteria. High antibiotic-resistance rate with wide spectrums of both ESBL-E and MRSA isolated were observed. In ESBL-E isolates, TEM (n = 15), CTX-M-1 (n = 3), CTX-M-9 (n = 1), and SHV (n = 1) genes were detected. TEM and SHV genes were associated with CTX-M-1 in 2 isolates, respectively. The CTX-M-9 gene of 1 isolate from cooked pork samples was found to be transferred to Escherichia coli J53 by conjugation. Detected MLST-types of MRSA were livestock-associated ST7 (n = 5) and ST9 (n = 4), as well as hospital-acquired ST239 (n = 1), suggesting contamination from human source(s) during meat processing. These findings confirmed a contamination of raw pork and cooked pork with ESBL-E and MRSA and emphasized the necessity of enforcing hygienic practices and specific detection of MRSA and ESBL-producing bacteria in meat processing and storage. PMID- 27232440 TI - Ultrasound-guided subcostal oblique transversus abdominis plane block in canine cadavers. AB - OBJECTIVES: To describe the ultrasound-guided transversus abdominis plane (TAP) block using a subcostal oblique approach in dog cadavers and to evaluate the spread of a methylene blue solution using a multiple-injection technique. STUDY DESIGN: Prospective, descriptive, experimental anatomic study. ANIMALS: Nine adult Beagle cadavers weighing a mean +/- standard deviation of 13 +/- 2 kg. METHODS: Methylene blue solution (10.0 mL) was injected bilaterally within the fascia that overlies the transversus abdominis muscle in dog cadavers under ultrasound guidance. A total of three injections (3.3 mL each) were administered on each side by the same operator. Dissection was performed by a second operator 20 minutes later. Successful nerve staining was defined as the presence of dye on the nerve for a length of >1 cm. RESULTS: Ventral branches of the T9, T10, T11, T12 and T13 nerves innervating the cranial abdominal wall were stained in 72%, 95%, 100%, 95% and 61% of cases, respectively. Ventral branches of L1 and L2 innervating the caudal abdominal wall were stained in only 33% and 11% of cases, respectively. The dye was found only in the fascia between the transversus abdominis and the internal oblique muscles. CONCLUSIONS AND CLINICAL RELEVANCE: The ultrasound-guided subcostal oblique TAP block provided adequate staining of the sensory innervation of the cranial abdominal wall. Further studies are required to evaluate the efficacy of this technique in blocking the nociceptive response in clinical procedures. PMID- 27232441 TI - Photogeneration of H2O2 in Water-Swollen SPEEK/PVA Polymer Films. AB - Efficient reduction of O2 took place via illumination with 350 nm photons of cross-linked films containing a blend of sulfonated poly(ether etherketone) and poly(vinyl alcohol) in contact with air-saturated aqueous solutions. Swelling of the solid macromolecular matrices in H2O enabled O2 diffusion into the films and also continuous extraction of the photogenerated H2O2, which was the basis for a method that allowed quantification of the product. Peroxide formed with similar efficiencies in films containing sulfonated polyketones prepared from different precursors and the initial photochemical process was found to be the rate determining step. Generation of H2O2 was most proficient in the range of 4.9 <= pH <= 8 with a quantum yield of 0.2, which was 10 times higher than the efficiencies determined for solutions of the polymer blend. Increases in temperature as well as [O2] in solution were factors that enhanced the H2O2 generation. H2O2 quantum yields as high as 0.6 were achieved in H2O/CH3CN mixtures with low water concentrations, but peroxide no longer formed when film swelling was suppressed. A mechanism involving reduction of O2 by photogenerated alpha-hydroxy radicals from the polyketone in competition with second-order radical decay processes explains the kinetic features. Higher yields result from the films because cross-links present in them hinder diffusion of the radicals, limiting their decay and enhancing the oxygen reduction pathway. PMID- 27232442 TI - Recent advances in delivery mechanisms for aerosol therapy during pediatric respiratory diseases. AB - The treatment of pediatric surgery diseases via utilization of aerosol delivery mechanisms is in progress for the betterment of pediatric care. Over the years, aerosol therapy has come to play an integral role in the treatment of pediatric respiratory diseases. Inhaled aerosol agents such as bronchodilators, corticosteroids, antibiotics, and mucolytics are commonly delivered to spontaneously breathing pediatric patients with a tracheostomy. Administering therapeutic inhaled aerosols to pediatric patients is challenging. The pediatric population ranges in age, which means patients with different airway sizes, breathing patterns, and cooperation levels. These patient-related factors impact the deposition of aerosol drugs in the lungs. The present review article will discuss the recent advancements in the delivery mechanisms for aerosol therapy in pediatric patients with respiratory diseases. PMID- 27232439 TI - Current state of the art for enhancing urine biomarker discovery. AB - INTRODUCTION: Urine is a highly desirable biospecimen for biomarker analysis because it can be collected recurrently by non-invasive techniques, in relatively large volumes. Urine contains cellular elements, biochemicals, and proteins derived from glomerular filtration of plasma, renal tubule excretion, and urogenital tract secretions that reflect, at a given time point, an individual's metabolic and pathophysiologic state. AREAS COVERED: High-resolution mass spectrometry, coupled with state of the art fractionation systems are revealing the plethora of diagnostic/prognostic proteomic information existing within urinary exosomes, glycoproteins, and proteins. Affinity capture pre-processing techniques such as combinatorial peptide ligand libraries and biomarker harvesting hydrogel nanoparticles are enabling measurement/identification of previously undetectable urinary proteins. Expert commentary: Future challenges in the urinary proteomics field include a) defining either single or multiple, universally applicable data normalization methods for comparing results within and between individual patients/data sets, and b) defining expected urinary protein levels in healthy individuals. PMID- 27232444 TI - Measuring Urban Carbon Footprint from Carbon Flows in the Global Supply Chain. AB - A global multiregional input-output (MRIO) model was built for eight Chinese cities to track their carbon flows. For in-depth understanding of urban carbon footprint from the perspectives of production, consumption, and trade balance, four kinds of footprints and four redefined measurement indicators were calculated. From the global supply chain, urban carbon inflows from Mainland China were larger than outflows, while the carbon outflows to European, principal North American countries and East Asia were much larger than inflows. With the rapid urbanization of China, Construction was the largest consumer and Utilities was the largest producer. Cities with higher consumption (such as Dalian, Tianjin, Shanghai, and Beijing) should change their consumption patterns, while cities with lower production efficiency (such as Dalian, Shanghai, Ningbo, and Chongqing) should improve their technology. The cities of net carbon consumption tended to transfer carbon emissions out of them by trading in carbon-intensive products, while the cities of net carbon production tended to produce carbon intensive products for nonlocal consumers. Our results indicated that urban carbon abatement requires not only rational consumption and industrial symbiosis at the city level, but also tighter collaboration along all stages of the global supply chain. PMID- 27232443 TI - Hepatoprotective effects of lycopene on liver enzymes involved in methionine and xenobiotic metabolism in hyperhomocysteinemic rats. AB - Hyperhomocysteinemia, defined by an increased plasma homocysteine level, is commonly associated with chronic liver diseases. A link between the elevated homocysteine level and oxidative stress has been demonstrated. Indeed the pathogenesis of liver diseases in the case of hyperhomocysteinemia could be due to this production of oxidative stress. Many studies have demonstrated the antioxidative properties of lycopene, a carotenoid. Therefore, the present study was designed to induce hyperhomocysteinemia in male Wistar rats in order to analyze the effect of lycopene supplementation on homocysteine metabolism, on phase I and phase II xenobiotic-metabolizing enzyme activities, and on liver injury by histological examination and analysis of biochemical markers. We found that rats with a high methionine diet showed abnormal histological features, with an increase of serum homocysteine, alanine aminotransferase and aspartate aminotransferase levels, decreased hepatic cystathionine beta synthase and S adenosyl-homocysteine hydrolase activities and an increased hepatic malondialdehyde level. We demonstrated the reversal effect of lycopene supplementation on hyperhomocysteinemia. Taken together, these findings provide additional clues on the hepatoprotective effects of lycopene. PMID- 27232445 TI - Theoretical study of lithium ionic conductors by electronic stress tensor density and electronic kinetic energy density. AB - We analyze the electronic structure of lithium ionic conductors, Li3PO4 and Li3PS4, using the electronic stress tensor density and kinetic energy density with special focus on the ionic bonds among them. We find that, as long as we examine the pattern of the eigenvalues of the electronic stress tensor density, we cannot distinguish between the ionic bonds and bonds among metalloid atoms. We then show that they can be distinguished by looking at the morphology of the electronic interface, the zero surface of the electronic kinetic energy density. (c) 2016 Wiley Periodicals, Inc. PMID- 27232446 TI - Communicating the Ontological Narrative of Ebola: An Emerging Disease in the Time of "Epidemic 2.0". AB - In this article, we critically analyze the implications of "Epidemic 2.0" specifically the formative role of social media (as an exemplar of Web 2.0 technology) in disseminating information during epidemics. We use a narrative analysis framework to study the Ebola-related messaging on the official Facebook pages of the World Health Organization (WHO) and the Center for Disease Control (CDC) in the wake of the recent epidemic in Western Africa. Using as our corpus all the messages on these pages between the period of July 1 and October 15, 2014, our analysis traces the development of an ontological Ebola narrative: a specific, historically contingent, ideological plot that reaffirms contemporary Western anxieties around emerging infections. Our analysis focuses on the evolution of this ontological narrative from a) consulting and containment, to b) an international concern, and c) the possibility of an epidemic in the United States. PMID- 27232447 TI - Visible-Light-Promoted (Phenylsulfonyl)methylation of Electron-Rich Heteroarenes and N-Arylacrylamides. AB - Visible-light-promoted radical (phenylsulfonyl)methylation reactions of electron rich heteroarenes and N-arylacrylamides have been developed starting from bromomethyl phenyl sulfone derivatives. This method provides a mild and efficient access to various (phenylsulfonyl)methylated compounds. PMID- 27232449 TI - A modified Shockley equation taking into account the multi-element nature of light emitting diodes based on nanowire ensembles. AB - In this work we study how the multi-element nature of light emitting diodes (LEDs) based on nanowire (NW) ensembles influences their current voltage (I-V) characteristics. We systematically address critical issues of the fabrication process that can result in significant fluctuations of the electrical properties among the individual NWs in such LEDs, paying particular attention to the planarization step. Electroluminescence (EL) maps acquired for two nominally identical NW-LEDs reveal that small processing variations can result in a large difference in the number of individual nano-devices emitting EL. The lower number of EL spots in one of the LEDs is caused by its inhomogeneous electrical properties. The I-V characteristics of this LED cannot be described well by the classical Shockley model. We are able to take into account the multi-element nature of such LEDs and fit the I-V characteristics in the forward bias regime by employing an ad hoc adjusted version of the Shockley equation. More specifically, we introduce a bias dependence of the ideality factor. The basic considerations of our model should remain valid also for other types of devices based on ensembles of interconnected p-n junctions with inhomogeneous electrical properties, regardless of the employed material system. PMID- 27232448 TI - Gastroschisis and maternal intake of phytoestrogens. AB - The prevalence of gastroschisis has increased significantly in the past few decades. The strongest risks have been observed for women <25 years old or of low body mass index, and maternal diet also been proposed to be associated with risk. The objective of this study was to evaluate whether the risk of gastroschisis is associated with maternal dietary intake of phytoestrogens. The analysis includes data on mothers of 409 gastroschisis cases and 3,007 controls who delivered their infants from 2005 to 2010 and participated in the National Birth Defects Prevention Study, a multistate, population-based, case-control study. Detailed information was obtained from maternal telephone interviews that included a validated food frequency questionnaire. We conducted logistic regression analyses that included each phytoestrogen in its continuous form (to test for linearity) and quadratic form (to test for non-linearity), adjusted for maternal energy intake, age, BMI, race-ethnicity, and smoking in 1st trimester. Logistic regression analysis indicated that biochanin A, formonoetin, and coumestrol had a significant non-linear association with gastroschisis (P-value <0.05 for quadratic term). Lower intakes were associated with increased risk, with somewhat stronger but relatively modest associations at the lower end of the distribution; for example, the ORs for the 10th versus 50th percentiles ranged from 1.1 to 1.2. Associations were not significant for the other phytoestrogens. This study provides some evidence for association with certain phytoestrogens, after adjusting for covariates. The implications of our findings for clinical practice are uncertain pending other studies examining this association. (c) 2016 Wiley Periodicals, Inc. PMID- 27232450 TI - The Effects of Crystal Phase and Particle Morphology of Calcium Phosphates on Proliferation and Differentiation of Human Mesenchymal Stromal Cells. AB - Calcium phosphate (CaP) ceramics are extensively used for bone regeneration; however, their clinical performance is still considered inferior to that of patient's own bone. To improve the performance of CaP bone graft substitutes, it is important to understand the effects of their individual properties on a biological response. The aim of this study is to investigate the effects of the crystal phase and particle morphology on the behavior of human mesenchymal stromal cells (hMSCs). To study the effect of the crystal phase, brushite, monetite, and octacalcium phosphate (OCP) are produced by controlling the precipitation conditions. Brushite and monetite are produced as plate-shaped and as needle-shaped particles, to further investigate the effect of particle morphology. Proliferation of hMSCs is inhibited on OCP as compared to brushite and monetite in either morphology. Brushite needles consistently show the lowest expression of most osteogenic markers, whereas the expression on OCP is in general high. There is a trend toward a higher expression of the osteogenic markers on plate-shaped than on needle-shaped particles for both brushite and monetite. Within the limits of CaP precipitation, these data indicate the effect of both crystal phase and particle morphology of CaPs on the behavior of hMSCs. PMID- 27232451 TI - Phosphine-Catalyzed Intramolecular Cyclizations of alpha-Nitroethylallenoates Forming (Z)-Furanone Oximes. AB - A novel and efficient phosphine-catalyzed intramolecular cyclization of alpha nitroethylallenic esters is reported. This process appears to be practical for the stereoselective syntheses of (Z)-furan-2(3H)-one oxime derivatives in excellent yields. Mechanistically, the reaction involves a phosphine-catalyzed Michael addition of an alkylideneazinate and rearrangement of the cyclic nitronate to the alpha-nitrosodihydrofuran. PMID- 27232452 TI - Cd isotope fractionation during simulated and natural weathering. AB - In practice, stable Cd isotope ratios are being applied to trace pollution sources in the natural environment. However, Cd isotope fractionation during weathering processes is not yet fully understood. We investigated Cd isotope fractionation of PbZn ore in leaching experiments and in the environment under natural weathering processes. Our leaching experiments demonstrated that the leachate was enriched with heavy Cd isotopes, relative to initial and residual samples (Delta(114/110)Cdleachate - initial state = 0.40-0.500/00, Delta(114/110)Cdleachate -residual state = 0.36-0.530/00). For natural samples, delta(114/110)Cd values of stream sediments were higher than those of the corresponding soil samples collected from the riverbank, Delta(114/110)Cdstream sediment -soil can be up to 0.500/00. This observation is consistent with our leaching experiments, which indicate significant Cd isotope fractionation during natural weathering processes. Therefore, natural contributions should be considered when using Cd isotopes to trace anthropogenic pollution in water and sediment systems. PMID- 27232453 TI - Temporal-spatial variation and source apportionment of soil heavy metals in the representative river-alluviation depositional system. AB - The contributions of major driving forces on temporal changes of heavy metals in the soil in a representative river-alluviation area at the lower of Yangtze River were successfully quantified by combining geostatistics analysis with the modified principal component scores & multiple linear regressions approach (PCS MLR). The results showed that the temporal (2003-2014) changes of Cu, Zn, Ni and Cr presented a similar spatial distribution pattern, whereas the Cd and Hg showed the distinctive patterns. The temporal changes of soil Cu, Zn, Ni and Cr may be predominated by the emission of the shipbuilding industry, whereas the significant changes of Cd and Hg were possibly predominated by the geochemical and geographical processes, such as the erosion of the Yangtze River water and leaching because of soil acidification. The emission of metal-bearing shipbuilding industry contributed an estimated 74%-83% of the changes in concentrations of Cu, Zn, Ni and Cr, whereas the geochemical and geographical processes may contribute 58% of change of Cd in the soil and 59% of decrease of Hg. PMID- 27232454 TI - Structural analysis and molecular docking of trypanocidal aryloxy-quinones in trypanothione and glutathione reductases: a comparison with biochemical data. AB - A set of aryloxy-quinones, previously synthesized and evaluated against Trypanosoma cruzi epimastigotes cultures, were found more potent and selective than nifurtimox. One of the possible mechanisms of the trypanocidal activity of these quinones could be inhibition of trypanothione reductase (TR). Considering that glutathione reductase (GR) is the equivalent of TR in humans, biochemical, kinetic, and molecular docking studies in TR and GR were envisaged and compared with the trypanocidal and cytotoxic data of a set of aryloxy-quinones. Biochemical assays indicated that three naphthoquinones (Nq-h, Nq-g, and Nq-d) selectively inhibit TR and the TR kinetic analyses indicated that Nq-h inhibit TR in a noncompetitive mechanism. Molecular dockings were performed in TR and GR in the following three putative binding sites: the catalytic site, the dimer interface, and the nicotinamide adenine dinucleotide phosphate-binding site. In TR and GR, the aryloxy-quinones were found to exhibit high affinity for a site near it cognate-binding site in a place in which the noncompetitive kinetics could be justified. Taking as examples the three compounds with TR specificity (TRS) (Nq-h, Nq-g, and Nq-d), the presence of a network of contacts with the quinonic ring sustained by the triad of Lys62, Met400', Ser464' residues, seems to contribute hardly to the TRS. Compound Nq-b, a naphthoquinone with nitrophenoxy substituent, proved to be the best scaffold for the design of trypanocidal compounds with low toxicity. However, the compound displayed only a poor and non-selective effect toward TR indicating that TR inhibition is not the main reason for the antiparasitic activity of the aryloxy-quinones. PMID- 27232455 TI - Non-linear longitudinal compression effect on dynamics of the transcription bubble in DNA. AB - The dependence of the dynamics of transcription bubble on the parameters of non linear longitudinal compression is presented on the base of simple model of soliton-like conformational switchings in two-component bistable polymer molecules with energetically non-equivalent stable states. It has been shown that under certain conditions the longitudinal compression may be a trap for a conformational switching. PMID- 27232456 TI - Molecular dynamics study of human carbonic anhydrase II in complex with Zn(2+) and acetazolamide on the basis of all-atom force field simulations. AB - Human carbonic anhydrase II (hCAII) represents an ultimate example of the perfectly efficient metalloenzymes, which is capable of catalyzing the hydration of carbon dioxide with a rate approaching the diffusion controlled limit. Extensive experimental studies of this physiologically important metalloprotein have been done to elucidate the fundamentals of its enzymatic actions: what residues anchor the Zn(2+) (or another divalent cation) at the bottom of the binding pocket; how the relevant residues work concertedly with the divalent cation in the reversible conversions between CO2 and HCO3(-); what are the protonation states of the relevant residues and acetazolamide, an inhibitor complexed with hCAII, etc. In this article, we present a detailed computational study on the basis of the all-atom CHARMM force field where Zn(2+) is represented with a simple model of divalent cation using the transferrable parameters available from the current literature. We compute the hydration free energy of Zn(2+), the characteristics of hCAII-Zn(2+) complexation, and the absolute free energy of binding acetazolamide to the hCAII-Zn(2+) complex. In each of these three problems, our computed results agree with the experimental data within the known margin of error without making any case-by-case adjustments to the parameters. The quantitatively accurate insights we gain in this all-atom molecular dynamics study should be helpful in the search and design of more specific inhibitors of this and other carbonic anhydrases. PMID- 27232457 TI - Old Habits Die Hard: Screening for and Treating Asymptomatic Bacteriuria After Kidney Transplantation. PMID- 27232458 TI - BCG lowers plasma cholesterol levels and delays atherosclerotic lesion progression in mice. AB - BACKGROUND AND AIMS: Bacille-Calmette-Guerin (BCG), prepared from attenuated live Mycobacterium bovis, modulates atherosclerosis development as currently explained by immunomodulatory mechanisms. However, whether BCG is pro- or anti-atherogenic remains inconclusive as the effect of BCG on cholesterol metabolism, the main driver of atherosclerosis development, has remained underexposed in previous studies. Therefore, we aimed to elucidate the effect of BCG on cholesterol metabolism in addition to inflammation and atherosclerosis development in APOE*3 Leiden.CETP mice, a well-established model of human-like lipoprotein metabolism. METHODS: Hyperlipidemic APOE*3-Leiden.CETP mice were fed a Western-type diet containing 0.1% cholesterol and were terminated 6 weeks after a single intravenous injection with BCG (0.75 mg; 5 * 10(6) CFU). RESULTS: BCG-treated mice exhibited hepatic mycobacterial infection and hepatomegaly. The enlarged liver (+53%, p = 0.001) coincided with severe immune cell infiltration and a higher cholesterol content (+31%, p = 0.03). Moreover, BCG reduced plasma total cholesterol levels (-34%, p = 0.003), which was confined to reduced nonHDL cholesterol levels (-36%, p = 0.002). This was due to accelerated plasma clearance of cholesterol from intravenously injected [(14)C]cholesteryl oleate labelled VLDL-like particles (t1/2 -41%, p = 0.002) as a result of elevated hepatic uptake (+25%, p = 0.05) as well as reduced intestinal cholestanol and plant sterol absorption (up to -37%, p = 0.003). Ultimately, BCG decreased foam cell formation of peritoneal macrophages (-18%, p = 0.02) and delayed atherosclerotic lesion progression in the aortic root of the heart. BCG tended to decrease atherosclerotic lesion area (-59%, p = 0.08) and reduced lesion severity. CONCLUSIONS: BCG reduces plasma nonHDL-cholesterol levels and delays atherosclerotic lesion formation in hyperlipidemic mice. PMID- 27232460 TI - Use of animals with partially known ancestries in scientifically managed breeding programs. AB - Animals with only partially known ancestry present a problem for population managers because it can be difficult to determine their relative genetic value to the population. So long as their ancestry is not completely unknown, population management software such as PMx can calculate a mean kinship for these animals, but that mean kinship is calculated such that there is no decrease in relative genetic value or "penalty" for only partially known ancestry. However, there is a longer-term genetic cost to having animals with only partially known ancestry in the population, and thus it is appropriate to "penalize" animals with partially known ancestry to some extent. The challenge is determining the correct "penalty" which will serve to decrease the percent unknown ancestry in subsequent generations while not causing excessive selection against the known ancestry of the animal. A new parameter of relative genetic value is developed which takes into account both an animal's mean kinship as well as its percent known ancestry. The method used in PMx to calculate the mean kinships also in general overestimates the inbreeding coefficients of offspring of animals with partially known ancestry when the known parents share a common ancestor, but can underestimate inbreeding if common ancestors exist within the unknown portion of the pedigree. This may result in population managers selecting less suitable pairs for breeding in an attempt to avoid an apparent higher level of inbreeding. A parameter is developed that adjusts the inbreeding coefficient to more accurately reflect the likely inbreeding coefficient of potential offspring. Zoo Biol. 35:319-325, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27232459 TI - Lomitapide affects HDL composition and function. AB - BACKGROUND: Lomitapide reduces low-density lipoprotein-cholesterol (LDL-C) but also high-density lipoprotein-cholesterol (HDL-C) levels. The latter may reduce the clinical efficacy of lomitapide. We investigated the effect of lomitapide on HDL-C levels and on cholesterol efflux capacity (CEC) of HDL in patients with homozygous familial hypercholesterolemia (HoFH). METHODS AND RESULTS: Four HoFH patients were treated with increasing dosages of lomitapide. Lomitapide decreased LDL-C (range -34 to -89%). Total HDL-C levels decreased (range -16 to -34%) with a shift to buoyant HDL. ABCA1-mediated CEC decreased in all patients (range -39 to -99%). The changes of total, ABCG1- and SR-BI-mediated CEC were less consistent. CONCLUSION: Lomitapide decreased LDL-C and HDL-C levels. Our report raises the hypothesis that the anti-atherogenic potential of HDL seems to be unaffected as total CEC did not seem to change consistently. Combined with the reduction of atherogenic lipoproteins, the net effect of lomitapide appears to be beneficial in HoFH patients. PMID- 27232461 TI - Zika virus: oral healthcare implications. AB - Zika virus (ZIKV) infection has been recognised since 1947, but just recently it became a worldwide major public health problem. The most common features of ZIKV infection are fever, cutaneous rash, arthralgia and conjunctivitis but most affected patients with the clinical disease present with only mild symptoms. However, severe neurological complications have been described: there is an occasional association with Guillain-Barre syndrome, and emerging data indicate an association between vertical transmission of ZIKV infection and microcephaly, but no specific orofacial manifestations have yet been reported. ZIKV is present in body fluids and has also been demonstrated in the saliva, but there is as yet no reliable evidence to support ZIKV transmission via this pathway. Transmission in oral health care should be effectively prevented using standard infection control measures. There are currently no specific treatments for Zika virus disease and no vaccines available, so prevention of ZIKV is based on vector control. PMID- 27232466 TI - PARAFOVEAL CAPILLARY DENSITY AFTER PLAQUE RADIOTHERAPY FOR CHOROIDAL MELANOMA: Analysis of Eyes Without Radiation Maculopathy. AB - PURPOSE: To study the parafoveal capillary density using optical coherence tomography angiography (OCTA) in eyes treated with plaque radiotherapy. RESEARCH DESIGN: Retrospective comparative case series. PARTICIPANTS: Ten patients treated with plaque radiotherapy for choroidal melanoma without evident radiation maculopathy on ophthalmoscopy or optical coherence tomography were imaged with OCTA. MAIN OUTCOME MEASURE: Comparison of the parafoveal capillary density in the superficial and deep capillary plexuses in the irradiated versus fellow nonirradiated eye. RESULTS: Overall, mean patient age was 55 years (median: 57, range: 45-65 years), and majority were white (9/10, 90%) and female (9/10, 90%). No patient had diabetes mellitus, and 2 (2/10, 20%) had controlled systemic hypertension. The melanoma was located in the choroid in all patients (10/10, 100%), with 2 (2/10, 20%) in the macular region. The mean largest basal diameter was 11 mm (12, 6-16 mm), and mean thickness was 5 mm (5, 2-10 mm). Mean radiation dose to the tumor apex was 72 Gy (median: 70 Gy, range: 70-85 Gy). Mean foveolar radiation dose was 53 Gy (median: 35 Gy, range: 14-110 Gy). Mean follow-up duration after plaque radiotherapy was 17 months (median: 16 months, range: 5-39 months). There was no ophthalmoscopic evidence of radiation maculopathy throughout the follow-up in every case. Optical coherence tomography demonstrated normal foveal contour without edema or subretinal fluid in every case. On OCTA, there was no significant difference in signal strength (P = 0.1151), central macular thickness (P = 0.9316), and foveal avascular zone area in the superficial (P = 0.1595), and deep (P = 0.1534) capillary plexuses between the irradiated versus fellow eyes. However, there was a statistically significant decrease in capillary density in the parafoveal superficial (P = 0.0005) and deep (P = 0.0067) plexuses in the irradiated eye. In addition, mean logMAR visual acuity was 0.2 (0.1, 0.0-0.5) (Snellen equivalent 20/32) in the irradiated eye and 0.0 (0.0, range: 0.0-0.1) (Snellen equivalent 20/20) in the fellow eye (P = 0.0252). CONCLUSION: Optical coherence tomography angiography allows qualitative and quantitative analysis of parafoveal capillary density. After plaque radiotherapy for choroidal melanoma, in eyes with normal macular features on ophthalmoscopy and optical coherence tomography, there is a statistically significant decrease in parafoveal capillary density and logMAR visual acuity in irradiated eyes compared with fellow eyes. These subclinical ischemic findings represent the commencement of radiation maculopathy. PMID- 27232485 TI - Parallel declines in HIV and hepatitis C virus prevalence, but not in herpes simplex virus type 2 infection: A 10-year, serial cross-sectional study in an inner-city emergency department. AB - BACKGROUND: The Johns Hopkins Hospital Emergency Department (JHHED) has served as an observational window on the HIV epidemic in a socioeconomically depressed, urban population. We previously reported that HIV incidence among JHHED patients is decreasing and that prevalence has declined from 11.4% in 2003-5.6% in 2013. OBJECTIVES: This study sought to observe temporal trends in hepatitis C virus (HCV) and herpes simplex virus type 2 (HSV-2) seroprevalence, which are surrogate markers for parenteral and sexual risk behavior, respectively. STUDY DESIGN: Identity unlinked-serosurveys were conducted over 6-8 weeks in the adult JHHED in 2003, 2007, and 2013. Excess sera from 10,274 patients, previously tested for HIV, were assayed for HSV-2 and HCV antibodies. RESULTS: Overall HCV seroprevalence declined steadily from 22.0% in 2003-13.8% in 2013 (Ptrend<0.01), and was significant by all gender and race strata. Overall HSV-2 prevalence declined from 55.3% in 2003-50.0% in 2013 (Ptrend<0.01), but was non-significant after adjustment for demographics. Among HIV+ individuals<45years of age, there was a significant decrease in the proportion of individuals with HCV co-infection [without HSV-2] (Ptrend=0.02) from 2003 to 2013, however, there was an increase in individuals with HSV-2 co-infection [without HCV] (Ptrend < 0.01). DISCUSSION: Little change in age-specific HSV-2 prevalence suggests the decrease in HIV prevalence was likely not associated with changes in sexual risk behavior. In addition to clinical interventions, strategies to address sexual health disparities and continued parenteral harm-reduction efforts are needed to further drive the decline in HIV. PMID- 27232486 TI - [Research advances on medical genetics in China in 2015]. AB - Steady progress has been achieved in the medical genetics in China in 2015, as numerous original researches were published in the world's leading journals. Chinese scientists have made significant contributions to various fields of medical genetics, such as pathogenicity of rare diseases, predisposition of common diseases, somatic mutations of cancer, new technologies and methods, disease-related microRNAs (miRNAs), disease-related long non-coding RNAs (lncRNAs), disease-related competing endogenous RNAs (ceRNAs), disease-related RNA splicing and molecular evolution. In these fields, Chinese scientists have gradually formed the tendency, from common variants to rare variants, from single omic analyses to multipleomics integration analyses, from genetic discovery to functional confirmation, from basic research to clinical application. Meanwhile, the findings of Chinese scientists have been drawn great attentions of international peers. This review aims to provide an overall picture of the front in Chinese medical genetics, and highlights the important findings and their research strategy. PMID- 27232487 TI - [High-throughput functional screening using CRISPR/Cas9 system]. AB - High-throughput screening, a powerful tool for the discovery of functionally important genes responsible for certain phenotypes, is performed according to loss-of-function or gain-of-function strategies. RNAi technology or knockout approaches have been widely used in high throughput screening due to their advantages of ease use, low cost and so on. However, imcomplete knockdown activity and off-target effect hindered their utility. More recently, CRISPR/Cas9 technology is becoming a robust tool for genome editing in diverse cells or animals, since it could generate a gene mutation in a target-specific manner. In this review, we first summarize the characterization of CRISPR/Cas9 and make comparison with traditional genetic tools, then describe recent achievements of genetic screen in several model organisms using CRISPR/Cas9, finally discuss on its future challenges and opportunities. PMID- 27232488 TI - [Placental developmental defects in cloned mammalian animals]. AB - The cloning technique, also called somatic cell nuclear transfer (SCNT), has been successfully established and gradually applied to various mammalian species. However, the developmental rate of SCNT mammalian embryos is very low, usually at 1% to 5%, which limits the application of SCNT. Placental developmental defects are considered as the main cause of SCNT embryo development inhibition. Almost all of SCNT-derived mammalian placentas exhibit various abnormalities, such as placental hyperplasia, vascular defects and umbilical cord malformation. Mechanistically, these abnormalities result from failure of establishment of correct epigenetic modification in the trophectoderm genome, which leads to erroneous expression of important genes for placenta development-related, particularly imprinted genes. Consequently, aberrant imprinted gene expression gives rise to placental morphologic abnormalities and functional defects, therefore decreases developmental competence of cloned embryos. Currently, although numerous methods that can improve the developmental ability of SCNT derived embryos have been reported, most of them are unable to substantially enhance the success rate of SCNT due to failure to eliminate the placental development defects. In this review, we summarize placental abnormalities and imprinted gene expression in mammalian cloning, and propose directions for the future research aiming to improve the cloning efficiency. PMID- 27232489 TI - [The anti-tumor mechanisms in long-lived rodents]. AB - Rodents, including the nude mice with congenital aplasia of the thymus, cancer resistant naked mole rat (Heterocephalus glaber) and blind mole rat (Spalax galili), are important model organisms that are widely used in biomedical research. The aging process is closely related to cancer incidence in mammals and the aging degree is positively correlated with the risk of cancer. Since rodents account for 40% of mammals, study of the unique antitumor mechanism in long-lived rodents is very important. Replicative senescence is anti-tumor mechanism that prevalently exist in rodents, however, unique anti-tumor mechanisms have been found in naked mole-rats and blind mole-rats. The cancer resistance of Spalax galili is mediated by cell-released IFN-beta which activates p53 and Rb signaling pathway and the cells undergoes concerted cell death while that of Heterocephalus glaber is mediated by high molecular weight hyaluronan (HMW-HA) which causes contact inhibition. In addition, highly expressed pro-cell-death and anti inflammation related genes are found in the genome of both naked mole-rats and blind mole-rats. In this review, we summarize the anti-tumor mechanisms in both Heterocephalus glaber and Spalax galili, which may provide information for related research. PMID- 27232490 TI - [The regulatory roles of small RNAs in phytohormone signaling pathways]. AB - Phytohormones are signaling molecules that control plant growth and development. Recent studies revealed that non-coding small RNAs play critical roles in plant development and stress responses via phytohormone signaling pathways. In this review, we summarize the present knowledge on the microRNAs (miRNAs) and secondary short interfering RNAs (siRNAs) involved in phytohormone signaling pathways, which include auxin, gibberellic acid, brassinosteroid and abscisic acid pathways. We also discuss their possible implications in phytohormone crosstalk during specific developmental processes. PMID- 27232491 TI - [Establishment and identification of the near-infrared fluorescence labeled exosomes in breast cancer cell lines]. AB - Exosomes, a population of extracellular membrane vesicles of 30-100 nm in diameter, play important roles in cell biological functions, intercellular signal transduction and especially in cancer diagnosis and therapy. To better apply exosomes in mechanistic study of breast cancer signal transduction, we constructed recombinant eukaryotic expression vector expressing the near-infrared fluorescence protein and CD63 fusion protein through cloning iRFP682 gene and exosomal marker protein CD63 gene into plasmid containing the ITR of AAV. The constructed plasmids were co-transfected with helper plasmid in AAV-293 cell lines and were packaged into rAAV. After titer measurement, the recombinant plasmids were transfected into breast cancer cell lines. The cell lines that stably expressing near-infrared fluorescence protein were selected by fluorescence. Through isolation, purification and identification, we finally obtained a new biomarker: iRFP682 labeled exosomes secreted by breast cancer cell lines, which could be used in further studies of the distribution and signal transduction of exosomes in breast cancer microenvironment. PMID- 27232492 TI - [Expression and functional analyses of the Arabidopsis QUA1 gene in light signal transduction]. AB - Plants not only use light as an energy source for photosynthesis, but also have to monitor the light quality and quantity input to execute appropriate physiological and developmental responses, such as cell differentiation, structural and functional changes, as well as the formation of tissues and organs. The process is referred to as photomorphogenesis. Arabidopsis QUA1 (QUASIMODO1), which functions in pectin synthesis, is identified as a member of glycosyltransferases. Previously, the hypocotyl elongation of the qua1-1 mutant was shown to be inhibited under dark conditions. In this study, we used the qua1 1/cry1 and qua1-1/phyB double mutants as the materials to study the function of the QUA1 gene in light signal transduction. The results showed that QUA1 not only participated in hypocotyl elongation under dark conditions, but also in blue light, red light and far red light conditions. In qua1-1 mutant seedlings, both the cell length of hypocotyl and the light-regulated gene expression were affected. Compared with cry1 and phyB mutants, qua1-1/cry1 and qua1-1/phyB double mutants had the shorter hypocotyl. Light-regulated gene expression was also affected in the double mutants. These data indicated that QUA1 might participate in the light signal transduction regulated by CRY1 and PHYB. Hence, the QUA1 gene may play multiple roles in light signal transduction by regulating the cell elongation and light-regulated gene expression. PMID- 27232493 TI - [Genome-wide identification, phylogenetic analysis and expression profiling of the WOX family genes in Solanum lycopersicum]. AB - Members of the plant-specific WOX transcription factor family have been reported to play important roles in cell to cell communication as well as other physiological and developmental processes. In this study, ten members of the WOX transcription factor family were identified in Solanum lycopersicum with HMMER. Neighbor-joining phylogenetic tree, maximum-likelihood tree and Bayesian inference tree were constructed and similar topologies were shown using the protein sequences of the homeodomain. Phylogenetic study revealed that the 25 WOX family members from Arabidopsis and tomato fall into three clades and nine subfamilies. The patterns of exon-intron structures and organization of conserved domains in Arabidopsis and tomato were consistent based on the phylogenetic results. Transcriptome analysis showed that the expression patterns of SlWOXs were different in different tissue types. Gene Ontology (GO) analysis suggested that, as transcription factors, the SlWOX family members could be involved in a number of biological processes including cell to cell communication and tissue development. Our results are useful for future studies on WOX family members in tomato and other plant species. PMID- 27232494 TI - [Teaching design and practice of human blood type traits in genetics comprehensive laboratory course]. AB - Comprehensive laboratory courses, which enable students to aptly apply theoretic knowledge and master experiment skills, play an important role in the present educational reform of laboratory courses. We utilized human ABO blood type as the experimental subject, and designed the experiment--"Molecular Genotyping of Human ABO Blood Type and Analysis of Population Genetic Equilibrium". In the experiment, DNA in mucosal cells is extracted from students' saliva, and each student's genotype is identified using a series of molecular genetics technologies, including PCR amplification of target fragments, enzymatic digestion, and electrophoretic separation. Then, taking the whole class as an analogous Mendel population, a survey of genotype frequency of ABO blood type is conducted, followed with analyses of various population genetic parameters using Popgene. Through the open laboratory course, students can not only master molecular genetic experimental skills, but also improve their understanding of theoretic knowledge through independent design and optimization of molecular techniques. After five years of research and practice, a stable experimental system of molecular genetics has been established to identify six genotypes of ABO blood types, namely I(A)I(A), I(A)i, I(B)I(B), I(B)i, I(A)I(B) and ii. Laboratory courses of molecular and population genetics have been integrated by calculating the frequencies of the six genotypes and three multiple alleles and testing population genetic equilibrium. The goal of the open laboratory course with independent design and implementation by the students has been achieved. This laboratory course has proved effective and received good reviews from the students. It could be applied as a genetics laboratory course for the biology majors directly, and its ideas and methods could be promoted and applied to other biological laboratory courses. PMID- 27232495 TI - Erratum to: Immunotherapy in endometrial cancer - an evolving therapeutic paradigm. AB - [This corrects the article DOI: 10.1186/s40661-015-0020-3.]. PMID- 27232497 TI - Scaling Relationships for Spherical Polymer Brushes Revisited. AB - In this short paper, we revisit the scaling relationships for spherical polymer brushes (SPBs), i.e., polymer brushes grafted to rigid, spherical particles. Considering that the brushes can be described to be encased in a series of hypothetical spherical blobs, we identify significant physical discrepancies in the model of Daoud and Cotton (Journal of Physics, 1982), which is considered to be the state of the art in scaling modeling of SPBs. We establish that the "brush" configuration of the polymer molecules forming the SPBs is possible only if the swelling ratio (which is the ratio of the end-to-end length of the blob encased polymer segment to the corresponding coil-like polymer segment) is always less than unity-a notion that has been erroneously overlooked in the model of Daoud and Cotton. We also provide new scaling arguments that (a) establish this swelling (or more appropriately shrinking) ratio as a constant (less than unity) for the case of "good" solvent, (b) recover the scaling predictions for blob dimension and monomer number and monomer concentration distributions within the blob, and PMID- 27232496 TI - Integrated Metabolo-Transcriptomics Reveals Fusarium Head Blight Candidate Resistance Genes in Wheat QTL-Fhb2. AB - BACKGROUND: Fusarium head blight (FHB) caused by Fusarium graminearum not only causes severe losses in yield, but also reduces quality of wheat grain by accumulating mycotoxins. Breeding for host plant resistance is considered as the best strategy to manage FHB. Resistance in wheat to FHB is quantitative in nature, involving cumulative effects of many genes governing resistance. The poor understanding of genetics and lack of precise phenotyping has hindered the development of FHB resistant cultivars. Though more than 100 QTLs imparting FHB resistance have been reported, none discovered the specific genes localized within the QTL region, nor the underlying mechanisms of resistance. FINDINGS: In our study recombinant inbred lines (RILs) carrying resistant (R-RIL) and susceptible (S-RIL) alleles of QTL-Fhb2 were subjected to metabolome and transcriptome profiling to discover the candidate genes. Metabolome profiling detected a higher abundance of metabolites belonging to phenylpropanoid, lignin, glycerophospholipid, flavonoid, fatty acid, and terpenoid biosynthetic pathways in R-RIL than in S-RIL. Transcriptome analysis revealed up-regulation of several receptor kinases, transcription factors, signaling, mycotoxin detoxification and resistance related genes. The dissection of QTL-Fhb2 using flanking marker sequences, integrating metabolomic and transcriptomic datasets, identified 4 Coumarate: CoA ligase (4CL), callose synthase (CS), basic Helix Loop Helix (bHLH041) transcription factor, glutathione S-transferase (GST), ABC transporter 4 (ABC4) and cinnamyl alcohol dehydrogenase (CAD) as putative resistance genes localized within the QTL-Fhb2 region. CONCLUSION: Some of the identified genes within the QTL region are associated with structural resistance through cell wall reinforcement, reducing the spread of pathogen through rachis within a spike and few other genes that detoxify DON, the virulence factor, thus eventually reducing disease severity. In conclusion, we report that the wheat resistance QTL-Fhb2 is associated with high rachis resistance through additive resistance effects of genes, based on cell wall enforcement and detoxification of DON. Following further functional characterization and validation, these resistance genes can be used to replace the genes in susceptible commercial cultivars, if nonfunctional, based on genome editing to improve FHB resistance. PMID- 27232498 TI - Footprints of Fascination: Digital Traces of Public Engagement with Particle Physics on CERN's Social Media Platforms. AB - Although the scientific community increasingly recognizes that its communication with the public may shape civic engagement with science, few studies have characterized how this communication occurs online. Social media plays a growing role in this engagement, yet it is not known if or how different platforms support different types of engagement. This study sets out to explore how users engage with science communication items on different platforms of social media, and what are the characteristics of the items that tend to attract large numbers of user interactions. Here, user interactions with almost identical items on five of CERN's social media platforms were quantitatively compared over an eight-week period, including likes, comments, shares, click-throughs, and time spent on CERN's site. The most popular items were qualitatively analyzed for content features. Findings indicate that as audience size of a social media platform grows, the total rate of engagement with content tends to grow as well. However, per user, engagement tends to decline with audience size. Across all platforms, similar topics tend to consistently receive high engagement. In particular, awe inspiring imagery tends to frequently attract high engagement across platforms, independent of newsworthiness. To our knowledge, this study provides the first cross-platform characterization of public engagement with science on social media. Findings, although focused on particle physics, have a multidisciplinary nature; they may serve to benchmark social media analytics for assessing science communication activities in various domains. Evidence-based suggestions for practitioners are also offered. PMID- 27232499 TI - A Probabilistic Boolean Network Approach for the Analysis of Cancer-Specific Signalling: A Case Study of Deregulated PDGF Signalling in GIST. AB - BACKGROUND: Signal transduction networks are increasingly studied with mathematical modelling approaches while each of them is suited for a particular problem. For the contextualisation and analysis of signalling networks with steady-state protein data, we identified probabilistic Boolean network (PBN) as a promising framework which could capture quantitative changes of molecular changes at steady-state with a minimal parameterisation. RESULTS AND CONCLUSION: In our case study, we successfully applied the PBN approach to model and analyse the deregulated Platelet-Derived Growth Factor (PDGF) signalling pathway in Gastrointestinal Stromal Tumour (GIST). We experimentally determined a rich and accurate dataset of steady-state profiles of selected downstream kinases of PDGF receptor-alpha mutants in combination with inhibitor treatments. Applying the tool optPBN, we fitted a literature-derived candidate network model to the training dataset consisting of single perturbation conditions. Model analysis suggested several important crosstalk interactions. The validity of these predictions was further investigated experimentally pointing to relevant ongoing crosstalk from PI3K to MAPK signalling in tumour cells. The refined model was evaluated with a validation dataset comprising multiple perturbation conditions. The model thereby showed excellent performance allowing to quantitatively predict the combinatorial responses from the individual treatment results in this cancer setting. The established optPBN pipeline is also widely applicable to gain a better understanding of other signalling networks at steady-state in a context specific fashion. PMID- 27232501 TI - Correction: Vestibular Evoked Myogenic Potential (VEMP) Triggered by Galvanic Vestibular Stimulation (GVS): A Promising Tool to Assess Spinal Cord Function in Schistosomal Myeloradiculopathy. AB - [This corrects the article DOI: 10.1371/journal.pntd.0004672.]. PMID- 27232500 TI - Characterization of NF-kappaB Reporter U937 Cells and Their Application for the Detection of Inflammatory Immune-Complexes. AB - Our study tested the hypothesis that immunoglobulins differ in their ability to activate the nuclear factor-kappaB pathway mediated cellular responses. These responses are modulated by several properties of the immune complex, including the ratio of antibody isotypes binding to antigen. Immunoassays allow the measurement of antigen specific antibodies belonging to distinct immunoglobulin classes and subclasses but not the net biological effect of the combination of these antibodies. We set out to develop a biosensor that is suitable for the detection and characterization of antigen specific serum antibodies. We genetically modified the monocytoid U937 cell line carrying Fc receptors with a plasmid encoding NF-kappaB promoter-driven GFP. This clone, U937-NF-kappaB, was characterized with respect to FcR expression and response to solid-phase immunoglobulins. Human IgG3, IgG4 and IgG1 induced GFP production in a time- and dose-dependent manner, in this order of efficacy, while IgG2 triggered no activation at the concentrations tested. IgA elicited no response alone but showed significant synergism with IgG3 and IgG4. We confirmed the importance of activation via FcgammaRI by direct stimulation with monoclonal antibody and by competition assays. We used citrullinated peptides and serum from rheumatoid arthritis patients to generate immune complexes and to study the activation of U937-NF-kappaB, observing again a synergistic effect between IgG and IgA. Our results show that immunoglobulins have distinct pro-inflammatory potential, and that U937-NF-kappaB is suitable for the estimation of biological effects of immune-complexes, offering insight into monocyte activation and pathogenesis of antibody mediated diseases. PMID- 27232502 TI - Correction: Criticism and Depression among the Caregivers of At-Risk Mental State and First-Episode Psychosis Patients. AB - [This corrects the article DOI: 10.1371/journal.pone.0149875.]. PMID- 27232503 TI - Changes in Parthenogenetic Imprinting Patterns during Reprogramming by Cell Fusion. AB - Differentiated somatic cells can be reprogrammed into the pluripotent state by cell-cell fusion. In the pluripotent state, reprogrammed cells may then self renew and differentiate into all three germ layers. Fusion-induced reprogramming also epigenetically modifies the somatic cell genome through DNA demethylation, X chromosome reactivation, and histone modification. In this study, we investigated whether fusion with embryonic stem cells (ESCs) also reprograms genomic imprinting patterns in somatic cells. In particular, we examined imprinting changes in parthenogenetic neural stem cells fused with biparental ESCs, as well as in biparental neural stem cells fused with parthenogenetic ESCs. The resulting hybrid cells expressed the pluripotency markers Oct4 and Nanog. In addition, methylation of several imprinted genes except Peg3 was comparable between hybrid cells and ESCs. This finding indicates that reprogramming by cell fusion does not necessarily reverse the status of all imprinted genes to the state of pluripotent fusion partner. PMID- 27232504 TI - Multimodality Imaging of Liver Infections: Differential Diagnosis and Potential Pitfalls. AB - Imaging plays an important role in the diagnosis, characterization, and management of infectious liver disease. In clinical practice, the main contributions of imaging are in detecting early disease, excluding other entities with a similar presentation, establishing a definitive diagnosis when classic findings are present, and guiding appropriate antimicrobial, interventional, or surgical treatment. The most common imaging features of bacterial, viral, parasitic, and fungal hepatic infections are described, and key imaging and clinical manifestations are reviewed that may be useful to narrow the differential diagnosis and avoid pitfalls in image interpretation. Ultrasonography (US), computed tomography (CT), and magnetic resonance imaging allow accurate detection of most hepatic infections and, in some circumstances, may provide specific signs to identify the underlying pathogen and exclude other entities with similar imaging features. In bacterial and parasitic infections, specific imaging features may be enough to exclude a neoplasm and, occasionally, to identify the underlying infectious agent. US and CT are important means to guide percutaneous aspiration or drainage when needed. In viral infections, imaging is critical to exclude entities that may manifest with similar clinical and laboratory findings. Disseminated fungal infections require early detection at imaging because they can be fatal if not promptly treated. Familiarity with the epidemiology, pathogenesis, clinical manifestations, imaging features, and treatment of hepatic infections can aid in radiologic diagnosis and guide appropriate patient care. ((c))RSNA, 2016. PMID- 27232506 TI - First Case of Zika Virus Infection in a HIV+ Patient. AB - Zika virus is an enveloped, single-stranded RNA virus that belongs to the flavivirus genre. As with arbovirus, it is transmitted by arthropods (mosquitoes), both Aedes aegypti (urban) and albopictus (rural). Zika virus was first isolated in 1947 from monkeys in Uganda. The first human cases were reported in 1952 in East Africa. Outbreaks were reported in Micronesia (2007), Polynesia (2013), and Chile (2014). Both diagnostic procedures and therapeutics are poorly developed. Serological tests cross-react with dengue and there are neither specific antivirals nor vaccines. PMID- 27232505 TI - Bariatric CT Imaging: Challenges and Solutions. AB - The obesity epidemic in the adult and pediatric populations affects all aspects of health care, including diagnostic imaging. With the increasing prevalence of obese and morbidly obese patients, bariatric computed tomographic (CT) imaging is becoming common in day-to-day radiology practice, and a basic understanding of the unique problems that bariatric patients pose to the imaging community is crucial in any setting. Because larger patients may not fit into conventional scanners, having a CT scanner with an adequate table load limit, a large gantry aperture, a large scan field of view, and a high-power generator is a prerequisite for bariatric imaging. Iterative reconstruction methods, high tube current, and high tube voltage can reduce the image noise that is frequently seen in bariatric CT images. Truncation artifacts, cropping artifacts, and ring artifacts frequently complicate the interpretation of CT images of larger patients. If recognized, these artifacts can be easily reduced by using the proper CT equipment, scan acquisition parameters, and postprocessing options. Lastly, because of complex contrast material dynamics, contrast material-enhanced studies of bariatric patients require special attention. Understanding how the rate of injection, the scan timing, and the total mass of iodine affect vascular and parenchymal enhancement will help to optimize contrast-enhanced studies in the bariatric population. This article familiarizes the reader with the challenges that are frequently encountered at CT imaging of bariatric patients, beginning with equipment selection and ending with a review of the most commonly encountered obesity-related artifacts and the technical considerations in the acquisition of contrast-enhanced images. ((c))RSNA, 2016. PMID- 27232507 TI - Does HIV Influence Hepatitis C Cure Rates Using Direct-Acting Antivirals? AB - Approximately one-third of people living with HIV are coinfected with hepatitis C virus (HCV). Coinfected individuals experience more rapid liver disease progression on average, and in the era of interferon-based therapy they do not respond as well to antiviral treatment. However, recent studies have suggested that this disparity in treatment response does not apply to interferon-free direct-acting anti-viral (DAA) regimens. PMID- 27232509 TI - The emerging roles of clusterin on reduction of both blood retina barrier breakdown and neural retina damage in diabetic retinopathy. AB - Previous proteomic studies revealed that intravitreous clusterin was decreased in diabetic retinopathy (DR) patients. We explored the role of clusterin in reduction of both blood retina barrier (BRB) breakdown and neural retina damage in early DR. Immunofluorescent staining of proliferated diabetic retinopathy (PDR) membranes was performed to detect endogenous clusterin, and intravitreous injection of clusterin (CLU group) or PBS (DR group) to streptozotocin-induced diabetic rats was conducted. Both qPCR and immunofluorescent staining were employed to investigate tight junction (TJ) protein. Fundus fluorescein angiography (FFA) and electroretinogram (ERG) were examined. Finally, HE and TUNEL stainings were used for neural retina assessment. Clusterin was expressed in the endothelial cells of PDR membranes. The expressions of several TJ protein genes were decreased in the retina of DR group (p<0.05), but elevated in that of CLU group (p<0.05). FFA revealed that there were several micrangium changes in the rats of the DR group but few in the CLU group. In ERG, the amplitude of b wave in DR group was significantly decreased compared to Control group (p<0.05), and the decreased b wave was partially rescued in CLU group under the highest flashlight level (p<0.05). HE and TUNEL staining of rat retina showed that both dropouts and apoptotic death of neural retina cells in diabetic rats were attenuated in CLU group. Clusterin had a promising role in reducing both BRB breakdown and neural retina damage under high glucose; the mechanism might be keeping TJ protein integrated and maintaining anti-apoptosis in early diabetic rats. PMID- 27232510 TI - Expression profiling and functional prediction of long noncoding RNAs in nasopharyngeal nonkeratinizing carcinoma. AB - Rapidly growing evidence has shown that long noncoding RNAs (lncRNAs) are playing more and more important roles in a variety of biological processes and have been involved in various types of cancer. How to better decode these noncoding transcripts and how to predict their potential roles in tumorigenesis particularly in nasopharyngeal carcinoma (NPC) are still open questions. In this study, we applied our custom-designed lncRNA+mRNA gene expression microarray, which contains probes against 38,141 lncRNA transcripts, to assaying the expression profiling of flash-frozen tumorous and non-tumorous tissue samples from nonkeratinizing carcinoma (NKC), which is the major histologic type of NPC. As a result, 481 differentially expressed (DE) lncRNAs (231 up-regulated and 250 down-regulated) were identified. Moreover, integrated bioinformatics analyses including gene ontology, lncRNA functional prediction based on coding-noncoding gene co-expression network, interactive miRNAs, and transcription factor binding motifs were all carried out to decode the potential functional roles of these newly identified DE-lncRNAs. This work hence offers new resource and insight into lncRNAs for further understanding the molecular mechanisms of tumorigenesis of NKC, and may also define new biomarkers or therapy targets for the translational studies of NKC. PMID- 27232508 TI - Chronic exposure of tilapia (Oreochromis niloticus) to iron oxide nanoparticles: Effects of particle morphology on accumulation, elimination, hematology and immune responses. AB - Effects of chronic exposure to alpha and gamma iron oxide nanoparticles (alpha Fe2O3 and gamma-Fe2O3 NPs) were investigated through exposure of tilapia (Oreochromis niloticus) to 0.1, 0.5 and 1.0mg/L (9.2*10(-4), 4.6*10(-3) and 9.2*10(-3)mM) aqueous suspensions for 60days. Fish were then transferred to NP free freshwater and allowed to eliminate ingested NPs for 30days. The organs, including gills, liver, kidney, intestine, brain, spleen, and muscle tissue of the fish were analyzed to determine the accumulation, physiological distribution and elimination of the Fe2O3 NPs. Largest accumulation occurred in spleen followed by intestine, kidney, liver, gills, brain and muscle tissue. Fish exposed to gamma-Fe2O3 NPs possessed significantly higher Fe in all organs. Accumulation in spleen was fast and independent of NP concentration reaching to maximum levels by the end of the first sampling period (30th day). Dissolved Fe levels in water were very negligible ranging at 4-6MUg/L for alpha-Fe2O3 and 17 21MUg/L for gamma-Fe2O3 NPs (for 1mg/L suspensions). Despite that, Fe levels in gills and brain reflect more dissolved Fe accumulation from metastable gamma Fe2O3 polymorph. Ingested NPs cleared from the organs completely within 30-day elimination period, except the liver and spleen. Liver contained about 31% of alpha- and 46% of gamma-Fe2O3, while spleen retained about 62% of alpha- and 35% of the gamma-polymorph. No significant disturbances were observed in hematological parameters, including hemoglobin, hematocrit, red blood cell and white blood cell counts (p>0.05). Serum glucose (GLU) levels decreased in treatments exposed to 1.0mg/L of gamma-Fe2O3 NPs at day 30 (p<0.05). In contrast, GLU levels increased during the elimination period for 1.0mg/L alpha-Fe2O3 NPs treatments (p<0.05). Transient increases occurred in glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), and lactate dehydrogenase (LDH). Serum Fe levels did not change during exposure (p>0.05), but increased significantly within elimination period due to mobilization of ingested NPs from liver and spleen to blood. Though respiratory burst activity was not affected (p>0.05), lysozyme activity (LA) was suppressed suggesting an immunosuppressive effects from both Fe2O3 NPs (p<0.05). In contrast, myeloperoxidase (MPO) levels increased significantly in treatments exposed to alpha-Fe2O3 NPs (p<0.05), and the effect from gamma-polymorph was marginal (p>=0.05). The results indicate that morphological differences of Fe2O3 NPs could induce differential uptake, assimilation and immunotoxic effects on O. niloticus under chronic exposure. PMID- 27232511 TI - RRx-001, a novel clinical-stage chemosensitizer, radiosensitizer, and immunosensitizer, inhibits glucose 6-phosphate dehydrogenase in human tumor cells. AB - The anti-proliferative effects of RRx-001, a novel RONS-mediated immuno epigenetic and vascular normalizing anticancer agent in Phase 2 clinical trials, are not explainable via a single mechanism. Previous research suggested an association between G6PD inhibition and RRx-001 anticancer activity. The results in this study confirm and extend previous observations that RRx-001 exerts its anti-proliferative effect, at least partially, through interference with glucose 6 phosphate dehydrogenase (G6PD), a key enzyme in the pentose phosphate pathway, responsible for maintaining adequate levels of the major cellular reductant, NADPH. RRx-001 affects glucose and G6PD enzyme activity in three different cancer cell lines namely Hep G2, CACO-2, and HT-29. We observed that in all cancer cell lines tested, RRx-001 induced G6PD inhibition in a concentration dependent fashion. Inhibition of G6PD activity associated with a reduction in ribonucleotide synthesis, glutathione reduction and cell proliferation may represent an important mechanism by which RRx-001 exerts its anticancer effects. PMID- 27232512 TI - Novel approaches in cancer immunotherapy. AB - Our understanding of tumor immunology has exploded in the past 3 decades. The complex relationships between tumor cells, the tumor microenvironment and the immune system cells, especially the cytotoxic and helper T cells and the regulatory T cells are beginning to be elucidated. In this review, we will attempt to provide a brief primer of tumor immunology. Cytokine therapy has historically been the mainstay of immunotherapy in cancers such as melanoma and kidney cancer. We will review some of the advances made with cancer vaccines, with a focus on peptide vaccines, tumor cell vaccines and immune cell vaccines. The pros and cons of nucleic acid-based vaccines including DNA and RNA vaccines will be discussed. Adoptive cell therapy has made significant progress utilizing chimeric antigen-receptor transduced T cells, especially in hematologic malignancies. We will also consider the key targets in checkpoint inhibition, and summarize some of the preclinical and clinical data with respect to checkpoint inhibition. Progress made in the novel immunotherapeutic approach of oncolytic viral therapy will be analyzed. PDL-1 expression by tumor cells and tumor infiltrating lymphocytes has been looked at as a biomarker in clinical trials. Limitations to such an approach and potential candidates for future predictive biomarkers of response to immunotherapy and biomarkers of autoimmunity and adverse reactions will be considered. PMID- 27232513 TI - Neoadjuvant intratumoral immuno-gene therapy for non-small cell lung cancer. AB - Non-small Cell Lung Cancer (NSCLC) remains a deadly disease despite aggressive treatment protocols which incorporate chemotherapy, radiation and surgery. These traditional approaches have reached a plateau in therapeutic benefit. There is emerging evidence suggesting that immunotherapy can serve as an alternative treatment modality for NSCLC. Our group has nearly two decades of experience involving immuno-gene therapy with Ad.hIFN-alpha and Ad.hIFN-beta in human mesothelioma trials, and has observed both safety and efficacy in treatment of Thoracic malignancies. We have expanded the scope of our work and have obtained encouraging pre-clinical evidence suggesting a role for immunotherapy as a surgical adjuvant for NSCLC cancers. By combining immunotherapy with surgery, synergistic results have been observed. Based on these observations, we have prepared a Phase I Clinical Trial that pairs Ad.hIFN-alpha with surgery for patients with resectable NSCLC. Patient enrollment is likely to begin in the Summer of 2016. We hope that this trial will serve as a platform for future trials aimed at pairing immunotherapy with surgery for patients diagnosed with NSCLC. PMID- 27232514 TI - Novel gene and cellular therapy approaches for treating HIV. AB - Advances in HIV drug therapy have drastically decreased mortality and significantly improved quality of life for HIV infected patients since the early days of the epidemic. However, HIV drug-resistance, drug toxicities, therapy adherence, and the need for life-long treatment remain major challenges that continue to contribute to HIV-related global health concerns. Recent advances in cancer immunotherapy have proven the potency of cellular gene therapies. An ever growing toolbox of methods of gene manipulation, cell modification, and clinical cell manufacturing, will enable moving beyond continuous drug therapy for more effective and durable treatments, including the possibility of inducing permanent resistance to HIV. These approaches, which target both host and viral factors, capitalize on points of vulnerability in the virus life cycle. Cellular and gene therapy has the potential to be an effective one-time therapy with less toxicity. Here, we review several promising strategies currently in pre-clinical development and clinical trials. PMID- 27232515 TI - Novel targeted therapies in uterine serous carcinoma, an aggressive variant of endometrial cancer. AB - Uterine serous carcinoma (USC) is a rare but aggressive subtype of endometrial cancer. Although it represents only 10% of all endometrial cancer cases, USC accounts for up to 40% of all endometrial cancer-related recurrences and subsequent deaths. With such a dismal prognosis, there is an expanding role for novel targeted approaches in the treatment of USC. Recent whole-exome sequencing studies have demonstrated gain of function of the HER2/NEU gene, as well as driver mutations in the PIK3CA/AKT/mTOR and cyclin E/FBXW7 oncogenic pathways in a large number of USCs. The results emphasize the relevance of these novel therapeutic targets for biologic therapy of USC, which will be reviewed in this article. PMID- 27232517 TI - Protective effect of delta opioid receptor agonist (D-Ala2, D-Leu5) enkephalin on permanent focal cerebral ischemia in rats. AB - To investigate the effect of delta opioid receptor agonist (D-Ala, D-Leu) enkephalin (DADLE) on the permanent focal cerebral ischemia in rats. Thirty four male Sprague-Dawley rats were assigned randomly into three groups: sham group (group Sham, n=10), artificial cerebrospinal fluid group (group ACSF, n=12), and DADLE group (group DADLE, n=12). Permanent middle cerebral artery occlusion was performed to induce permanent focal cerebral ischemia in rats. Then, the animals in group DADLE and group ACSF were treated with DADLE or ACSF by an intracerebroventricular injection at 45 min after ischemia. Neurologic deficit scores were assessed according to the Garcia criterion at 24 h after ischemia. Infarct volume was determined using the 2,3,5-triphenyltetrazolium chloride staining method. The histological analysis was used to evaluate the extent of cerebral injury. Compared with the control group, the Garcia scores were significantly higher (P=0.000) and the infarct volumes (P=0.018) were significantly smaller in the DADLE treatment group at 24 h after ischemia. These neurologic changes were closely correlated with the outcome of the infarct volumes. In addition, the histological examination showed more intact neurons in rats treated with DADLE than those treated with ACSF at 24 h after ischemia (P=0.000). DADLE by intracerebroventricular administration at 45 min after ischemia can improve neurologic outcome and mitigate cortical neuronal injury induced by permanent focal cerebral ischemia in rats. PMID- 27232516 TI - Recent advances in immunotherapy for kidney cancer. AB - Immunotherapy has been a mainstay of treatment for metastatic renal cell carcinoma (mRCC) since the introduction of high-dose interleukin-2. Recently, improved knowledge of immune regulation and tumor-host immune interactions has led to the development of several novel immunotherapies. Immune checkpoint blockade showed promise in early clinical trials -- eventually leading to FDA approval of nivolumab (anti-PD-1) as a second-line treatment for mRCC. Despite encouraging results, PD-1 blockade alone does not achieve durable responses in the majority of patients treated. Improved biomarkers for patient selection, tumor vaccines and combination therapy may augment the efficacy of existing immunotherapies. This review summarizes recent progress in immunotherapy for RCC, focusing on a discussion of emerging agents. PMID- 27232518 TI - Protective role of miR-23b-3p in kainic acid-induced seizure. AB - Dysregulation of microRNAs has been proposed to contribute toward epilepsy. The miRNA miR-23b-3p has been found to protect against neuronal apoptosis and the production of reactive oxygen species. In this study, we assessed the potential role of miR-23b-3p in the kainic acid (KA)-induced seizure model. We found that miR-23b-3p levels were significantly decreased in the brain cortex of mice and in cultured mouse primary neurons treated with KA. Importantly, supplement of miR 23b-3p agomir by an intacerebroventricular injection alleviated seizure behaviors and abnormal cortical electroencephalogram recordings in KA-treated mice. Together, these results indicate that miR-23b-3p plays a crucial role in suppressing seizure formation in experimental models of epilepsy and that miR-23b 3p supplement may be a potential anabolic strategy for ameliorating seizure. PMID- 27232519 TI - The role of the neural reward system in attention selection. AB - The prefrontal cortex may play a role in attention selection using motivational information from the mesotelencephalic dopamine system, a neural system that responds to reward prediction violations. If so, neural indices of attention selection and reward prediction violation should have overlapping spatiotemporal distributions. Attention selection elicits a frontal event-related potential component around 200-300 ms, the frontal selection positivity. A component with similar spatiotemporal characteristics, the reward positivity is elicited in reward prediction designs to outcomes that are better than expected. The current study used dense sensor array recording in a sample of 41 participants performing visual oddball (attention) and a reward prediction 'slot machine-like' design to compare the spatiotemporal distributions of the frontal selection positivity and the reward positivity. The components did not differ in their peak latencies and had overlapping scalp topographies, supporting the hypothesis that these positivities represent attachment of incentive salience to perceptual representations in the prefrontal cortex. PMID- 27232520 TI - Politeness and the communication of uncertainty. AB - Ambiguity in language derives, in part, from the multiple motivations that underlie the choice to use any particular expression. The use of some lexical items, such as probability expressions and scalar terms, can be motivated by a desire to communicate uncertainty as well as a desire to be polite (i.e., manage face). Research has demonstrated that the interpretation of these items can be influenced by the existence of a potential politeness motive. In general, communications about negative events, relative to positive events, result in higher likelihood estimates whenever politeness can be discerned as a potential motive. With few exceptions, however, this research has focused only on the hearer. In the present research we focused on the dyad and examined whether speakers vary their messages as a function of politeness, and the effect that this has on subsequent judgments made by a recipient. In two experiments we presented participants with situations that varied in terms of face-threat and asked them how they would communicate potentially threatening information. Both experiments included a second set of participants who read these utterances and provided judgments as to the degree of uncertainty conveyed by the utterance. In both experiments, messages in the face-threatening condition conveyed greater uncertainty than messages in the non-face-threatening condition, and the probability estimates made by the second set of participants varied as a function of conveyed uncertainty. This research demonstrates that when examining speakers and hearers together, severe events may be judged less likely (rather than more likely), because speakers tend to hedge the certainty with which they communicate the information. PMID- 27232522 TI - Foreign language affects the contribution of intentions and outcomes to moral judgment. AB - We examine whether the use of a foreign language, as opposed to the native language, influences the relative weight intentions versus outcomes carry in moral evaluations. In Study 1, participants were presented with actions that had positive outcomes but were motivated by dubious intentions, while in Study 2 with actions that had negative outcomes but were motivated by positive intentions. Participants received the materials either in their native or a foreign language. Foreign language prompted more positive moral evaluations in Study 1 and less positive evaluations in Study 2. These results show that foreign language reduces the relative weight placed on intentions versus outcomes. We discuss several theoretical accounts that are consistent with the results such as that foreign language attenuates emotions (triggered by intentions) or it depletes cognitive resources. PMID- 27232521 TI - What is automatized during perceptual categorization? AB - An experiment is described that tested whether stimulus-response associations or an abstract rule are automatized during extensive practice at perceptual categorization. Twenty-seven participants each completed 12,300 trials of perceptual categorization, either on rule-based (RB) categories that could be learned explicitly or information-integration (II) categories that required procedural learning. Each participant practiced predominantly on a primary category structure, but every third session they switched to a secondary structure that used the same stimuli and responses. Half the stimuli retained their same response on the primary and secondary categories (the congruent stimuli) and half switched responses (the incongruent stimuli). Several results stood out. First, performance on the primary categories met the standard criteria of automaticity by the end of training. Second, for the primary categories in the RB condition, accuracy and response time (RT) were identical on congruent and incongruent stimuli. In contrast, for the primary II categories, accuracy was higher and RT was lower for congruent than for incongruent stimuli. These results are consistent with the hypothesis that rules are automatized in RB tasks, whereas stimulus-response associations are automatized in II tasks. A cognitive neuroscience theory is proposed that accounts for these results. PMID- 27232523 TI - Subsurface imaging of silicon nanowire circuits and iron oxide nanoparticles with sub-10 nm spatial resolution. AB - Non-destructive subsurface characterization of nanoscale structures and devices is of significant interest in nanolithography and nanomanufacturing. In those areas, the accurate location of the buried structures and their nanomechanical properties are relevant for optimization of the nanofabrication process and the functionality of the system. Here we demonstrate the capabilities of bimodal and trimodal force microscopy for imaging silicon nanowire devices buried under an ultrathin polymer film. We resolve the morphology and periodicities of silicon nanowire pairs. We report a spatial resolution in the sub-10 nm range for nanostructures buried under a 70 nm thick polymer film. By using numerical simulations we explain the role of the excited modes in the subsurface imaging process. Independent of the bimodal or trimodal atomic force microscopy approach, the fundamental mode is the most suitable for tracking the topography while the higher modes modulate the interaction of the tip with the buried nanostructures and provide subsurface contrast. PMID- 27232524 TI - Infrazygomatico-coronoid fixation in a segmental mandibular reconstruction with a free vascularized flap: A simple and correct repositioning method without interfering with reconstructive and microsurgical procedures. AB - BACKGROUND: In a segmental mandibular reconstruction with a free vascularized flap, reproducing the optimal relationship between the condyle and glenoid fossa, and maintaining correct occlusion are important. We examined the practicality of a repositioning technique that combined bone plate fixation of the infrazygomatic crest and the coronoid process (infrazygomatico-coronoid fixation [IZCF]) with maxillo-mandibular fixation (MMF). METHODS: Eight patients were treated with this method. To investigate masticatory function, the status of the dental and temporomandibular joints were examined, and a food scale questionnaire was administered. RESULTS: IZCF and MMF resulted in correct repositioning of the segmented mandibles and enabled accurate reconstructions. Most patients recovered to be able to ingest the same preoperative food in scale with stable occlusion. CONCLUSION: This method is a simple and correct repositioning method without interfering with reconstructive and microsurgical procedures. We propose this technique as a reliable method for obtaining a functional outcome in mandibular reconstruction. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: 1708-1716, 2016. PMID- 27232525 TI - Lung and gastrointestinal complications are leading causes of death in SCORE, a multi-ethnic Singapore systemic sclerosis cohort. AB - OBJECTIVES: To assess contemporary outcomes and predictors of mortality in the well-characterized multi-ethnic systemic sclerosis cohort Singapore (SCORE). METHOD: From 2008, patients diagnosed with systemic sclerosis (SSc) fulfilling the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) or Very Early Diagnosis of Systemic Sclerosis (VEDOSS) criteria were recruited from three major tertiary rheumatology centres in Singapore. Mortality was verified with the Singapore National Registry of Deaths and in-hospital cause of death was determined by two independent reviewers, up to 10 December 2013. A Cox proportional hazard (PH) regression analysis was used to examine the association between demographic and clinical indices and mortality, controlling for age and race. RESULTS: Of the 349 patients (86.8% female; 77.7% Chinese), 97.4% fulfilled the ACR/EULAR 2013 criteria. The mean age at diagnosis was 46.2 years. The prevalence of limited (lcSSc), diffuse (dcSSc) cutaneous SSc, and SSc overlap syndromes was 34.4, 37.1, and 26.8%, respectively. Thirty-five patients died after a mean follow-up of 2.1 years (743.6 person-years). Fifty-seven per cent of deaths were attributed to SSc, with pulmonary arterial hypertension (PAH), interstitial lung disease (ILD), and gastrointestinal (GI) complications as the leading causes of death. Multivariate analysis (n = 275) showed that smoking [hazard ratio (HR) 4.0, 95% confidence interval (CI) 1.5-10.6], SSc overlap (HR 6.0, 95% CI 1.8-19.1), baseline renal involvement (HR 2.5, 95% CI 1.1 6.0), pulmonary artery systolic pressure (PASP) >= 40 mmHg on echocardiography (HR 5.1, 95% CI 2.2-11.7), treatment for peripheral vasculopathy (HR 2.6, 95% CI 1.1-6.5), and parenteral nutrition (HR 8.8, 95% CI 2.2-34.3) were independent predictors of mortality. CONCLUSIONS: PAH, ILD, and GI complications were leading causes of death in this cohort. We identified a high-risk group of patients who would benefit from closer monitoring and early intervention. PMID- 27232526 TI - Tetrahydroisoquinoline-Derived Urea and 2,5-Diketopiperazine Derivatives as Selective Antagonists of the Transient Receptor Potential Melastatin 8 (TRPM8) Channel Receptor and Antiprostate Cancer Agents. AB - Tetrahydroisoquinoline derivatives containing embedded urea functions were identified as selective TRPM8 channel receptor antagonists. Structure-activity relationships were investigated, with the following conclusions: (a) The urea function and the tetrahydroisoquinoline system are necessary for activity. (b) Bis(1-aryl-6,7dimethoxy-1,2,3,4-tetrahydroisoquinolyl)ureas are more active than compounds containing one tetrahydroisoquinoline ring and than an open phenetylamine ureide. (c) Trans compounds are more active than their cis isomers. (d) Aryl substituents are better than alkyls at the isoquinoline C-1 position. (e) Electron-withdrawing substituents lead to higher activities. The most potent compound is the 4-F derivative, with IC50 in the 10(-8) M range and selectivities around 1000:1 for most other TRP receptors. Selected compounds were found to be active in reducing the growth of LNCaP prostate cancer cells. TRPM8 inhibition reduces proliferation in the tumor cells tested but not in nontumor prostate cells, suggesting that the activity against prostate cancer is linked to TRPM8 inhibition. PMID- 27232528 TI - Conciliatory Inductive Model Explaining the Origin of Changes in the eta(2)-SiH Bond Length Caused by Presence of Strongly Electronegative Atoms X (X = F, Cl) in Cp(OC)2Mn[eta(2)-H(SiH3-nXn)] (n = 0-3) Complexes. AB - Using three theoretical methods, QTAIM, IQA, and NCI, we analyze an influence of halogen atoms X (X = F, Cl) substituted at various positions in the -SiH3-nXn group on the charge density distribution within the eta(2)-SiH bond and on the SiH bond energies in Cp(OC)2Mn[eta(2)-H(SiH3-nXn)] complexes and isolated HSiH3 nXn molecules. It is shown that shortening of the eta(2)-SiH bond in Cp(OC)2Mn[eta(2)-H(SiH3-nXn)] complexes should be considered as a normal inductive result of halogenation. This eta(2)-SiH bond's compression may, however, be overcome by a predominant elongation resulting from a contingent presence of a halogen atom at position trans to the eta(2)-SiH bond. This trans effect is particularly large for bulky and highly polarizable chlorine. Moreover, peculiar properties of the trans chlorine atom are manifested in several ways. To explain the origin of all the observed changes in both the length and the electron charge distribution of the eta(2)-SiH bond in investigated Cp(OC)2Mn[eta(2)-H(SiH3-nXn)] complexes a new model, called the Conciliatory Inductive Model, is being proposed. PMID- 27232527 TI - Estimating the Prevalence of Binge Eating Disorder in a Community Sample From the United States: Comparing DSM-IV-TR and DSM-5 Criteria. AB - OBJECTIVE: To estimate binge eating disorder (BED) prevalence according to DSM-5 and DSM-IV-TR criteria in US adults and to estimate the proportion of individuals meeting DSM-5 BED criteria who reported being formally diagnosed. METHODS: A representative sample of US adults who participated in the National Health and Wellness Survey were asked to respond to an Internet survey (conducted in October 2013). Assessments included 3-month, 12-month, and lifetime BED prevalence based on DSM-5 and DSM-IV-TR criteria and demographics, psychiatric comorbidities, and self-esteem (Rosenberg Self-Esteem Scale). Descriptive statistics are provided. Prevalence estimates were calculated using poststratification sampling weights. RESULTS: Of 22,397 respondents, 344 (women, n = 242; men, n = 102) self-reported symptoms consistent with DSM-5 BED symptom criteria. The 3-month, 12-month, and lifetime DSM-5 prevalence estimates (95% CIs) projected to the US population were 1.19% (1.04%-1.37%), 1.64% (1.45%-1.85%), and 2.03% (1.83%-2.26%), respectively. The 12-month and lifetime projected DSM-IV-TR prevalence estimates were 1.15% (1.00%-1.32%) and 1.52% (1.35%-1.70%), respectively. Of respondents meeting DSM-5 BED criteria in the past 12 months, 3.2% (11/344) reported receiving a formal diagnosis. Compared with non-BED respondents, respondents meeting DSM-5 BED criteria in the past 12 months were younger (mean +/- SD age = 46.01 +/- 14.32 vs 51.59 +/- 15.80 years; P < .001), had a higher body mass index (mean +/- SD = 33.71 +/- 9.36 vs 27.96 +/- 6.68 kg/m2; P < .001), and had lower self-esteem (mean +/- SD score = 16.47 +/- 6.99 vs 23.33 +/- 6.06; P < .001). CONCLUSIONS: DSM-5 BED criteria resulted in higher BED prevalence estimates than with DSM-IV TR criteria. Most BED respondents did not report being formally diagnosed, indicating an unmet need in BED recognition and diagnosis. PMID- 27232529 TI - Challenges of Zika Virus Infection in Pregnant Women. PMID- 27232532 TI - Patient Perspectives on EMS Alternate Destination Models. AB - INTRODUCTION: Studies have shown that a large number of ambulance transports to emergency departments (ED) could have been safely treated in an alternative environment, prompting interest in the development of more patient-centered models for prehospital care. We examined patient attitudes, perspectives, and agreement/comfort with alternate destinations and other proposed innovations in Emergency Medical Services (EMS) care delivery and determined whether demographic, socioeconomic, acuity, and EMS utilization history factors impact levels of agreement. METHODS: We conducted a cross-sectional study on a convenience sample of patients and caregivers presenting to an urban academic ED between July 2012 and May 2013. Respondents were surveyed on levels of agreement with 13 statements corresponding to various aspects of a proposed patient centered emergency response system including increased EMS access to healthcare records, shared decision making with the patient and/or primary care physician, transport to alternative destinations, and relative importance of EMS assessment versus transportation. Information on demographic and socioeconomic factors, level of acuity, and EMS utilization history were also determined via survey and chart review. Responses were analyzed descriptively and compared across patient characteristics using chi-square and regression analyses. RESULTS: A total of 621 patients were enrolled. The percentage of patients who agreed or strongly agreed with each of the 13 statements ranged from 48.2 to 93.8%. About 86% agreed with increased EMS access to healthcare records; approximately 72% agreed with coordinating disposition decisions with a primary physician; and about 58% supported transport to alternative destinations for low acuity conditions. No association was found between levels of agreement and the patient's level of acuity or EMS utilization history. Only Black or Hispanic race showed isolated associations with lower rates of agreement with some aspects of an innovative EMS care delivery model. CONCLUSION: A substantial proportion of patients surveyed in this cross sectional study agreed with a more patient-centered approach to prehospital care where a 9-1-1 call could be met with a variety of treatment and transportation options. Agreement was relatively consistent among a diverse group of patients with varying demographics, levels of acuity and EMS utilization history. MeSH Key words: emergency medical services; triage; telemedicine; surveys and questionnaires; transportation of patients. PMID- 27232530 TI - Shortening the HIV-1 TAR RNA Bulge by a Single Nucleotide Preserves Motional Modes over a Broad Range of Time Scales. AB - Helix-junction-helix (HJH) motifs are flexible building blocks of RNA architecture that help define the orientation and dynamics of helical domains. They are also frequently involved in adaptive recognition of proteins and small molecules and in the formation of tertiary contacts. Here, we use a battery of nuclear magnetic resonance techniques to examine how deleting a single bulge residue (C24) from the human immunodeficiency virus type 1 (HIV-1) transactivation response element (TAR) trinucleotide bulge (U23-C24-U25) affects dynamics over a broad range of time scales. Shortening the bulge has an effect on picosecond-to-nanosecond interhelical and local bulge dynamics similar to that casued by increasing the Mg(2+) and Na(+) concentration, whereby a preexisting two-state equilibrium in TAR is shifted away from a bent flexible conformation toward a coaxial conformation, in which all three bulge residues are flipped out and flexible. Surprisingly, the point deletion minimally affects microsecond-to millisecond conformational exchange directed toward two low-populated and short lived excited conformational states that form through reshuffling of bases pairs throughout TAR. The mutant does, however, adopt a slightly different excited conformational state on the millisecond time scale, in which U23 is intrahelical, mimicking the expected conformation of residue C24 in the excited conformational state of wild-type TAR. Thus, minor changes in HJH topology preserve motional modes in RNA occurring over the picosecond-to-millisecond time scales but alter the relative populations of the sampled states or cause subtle changes in their conformational features. PMID- 27232533 TI - SMARCAD1 knockdown uncovers its role in breast cancer cell migration, invasion, and metastasis. AB - OBJECTIVE: Breast cancer is the most common cancer seen in women worldwide and breast cancer patients are at high risk of recurrence in the form of metastatic disease. Identification of genes associated with invasion and metastasis is crucial in order to develop novel anti-metastasis targeted therapy. It has been demonstrated that the DEAD-BOX helicase DP103 was implicated in breast cancer invasion and metastasis. SMARCAD1 is also a DEAD/H box-containing helicase, suggested to play a role in genetic instability. However, its involvement in cancer migration, invasion, and metastasis has never been explored. RESEARCH DESIGN AND METHODS: Using two different designs of shRNA targeting SMARCAD1, we investigated the impact of SMARCAD1 knockdown on the migration, invasion, and metastasis potential of the breast cancer cells MDA-MB-231 and T47D. RESULTS: We observed that SMARCAD1 knockdown in the invasive breast cancer cells MDA-MB-231, unlike in the non-invasive breast cancer cells T47D, was associated with an increased cell-cell adhesion and a significant decrease in cell migration, invasion, and metastasis due at least in part to a strong inhibition of STAT3 phosphorylation. CONCLUSIONS: These results indicate that SMARCAD1 is involved in breast cancer metastasis and can be a promising target for metastatic breast cancer therapy. PMID- 27232534 TI - pH- and Temperature-Sensitive Hydrogel Nanoparticles with Dual Photoluminescence for Bioprobes. AB - This study demonstrates high contrast and sensitivity by designing a dual emissive hydrogel particle system, whose two emissions respond to pH and temperature strongly and independently. It describes the photoluminescence (PL) response of poly(N-isopropylacrylamide) (PNIPAM)-based core/shell hydrogel nanoparticles with dual emission, which is obtained by emulsion polymerization with potassium persulfate, consisting of the thermo- and pH-responsive copolymers of PNIPAM and poly(acrylic acid) (PAA). A red-emission rare-earth complex and a blue-emission quaternary ammonium tetraphenylethylene derivative (d-TPE) with similar excitation wavelengths are inserted into the core and shell of the hydrogel nanoparticles, respectively. The PL intensities of the nanoparticles exhibit a linear temperature response in the range from 10 to 80 degrees C with a change as large as a factor of 5. In addition, the blue emission from the shell exhibits a linear pH response between pH 6.5 and 7.6 with a resolution of 0.1 unit, while the red emission from the core is pH-independent. These stimuli responsive PL nanoparticles have potential applications in biology and chemistry, including bio- and chemosensors, biological imaging, cancer diagnosis, and externally activated release of anticancer drugs. PMID- 27232537 TI - One-step preparation of Fe3O4/Pd@polypyrrole composites with enhanced catalytic activity and stability. AB - Core/shell Fe3O4/Pd@polypyrrole (PPy) composites with a Fe3O4 core and a PPy shell embedding Pd nanoparticles were prepared in one-step. The diameter of highly dispersed Pd nanoparticles was as small as 2.9nm owing to coordination interaction generated between Pd(2+) ions and amino groups on PPy chains. The outer PPy shell was only 6.8nm: on one hand, the coverage was beneficial to improving the stability of resulting composites; on the other hand, the shell was thin enough to permit free contact between embedding Pd nanoparticles and reactants. Additionally, the as-prepared Fe3O4/Pd@PPy composites displayed good magnetic separation property due to incorporation of Fe3O4 nanospheres. Based on above merits, they served as suitable catalyst candidates. Their catalytic performance and reusability were evaluated by reduction of 4-nitrophenol with sodium borohydride as reducing agent. Compared with traditional Fe3O4/Pd composites, Fe3O4/Pd@PPy composites not only showed superior catalytic activity; but also exhibited much better stability in successive cycling tests. PMID- 27232536 TI - Conjugated polymers nanostructured as smart interfaces for controlling the catalytic properties of enzymes. AB - The search for new molecular architectures to improve the efficiency of enzymes entrapped in ultrathin films is useful to enhance the effectiveness of biosensors. In this present work, conjugated polymers, based on thiophene and fluorine, were investigated to verify their suitability as matrices for the immobilization of urease. The copolymer poly[(9,9-dioctylfluorene)-co-thiophene], PDOF-co-Th was spread on the air-water interface forming stable Langmuir monolayers as determined by surface pressure-area isotherms, polarization modulation reflection-absorption infrared spectroscopy (PM-IRRAS), and Brewster angle microscopy (BAM). Urease was incorporated in the floating monolayers being further transferred to solid supports as mixed Langmuir-Blodgett (LB) films. These films were then characterized with transfer ratio, fluorescence spectroscopy, PM-IRRAS and atomic force microscopy, confirming the co-transfer of the enzyme as well as its structuring in beta-sheets. The catalytic activity was detected for urease, with a lower reaction rate than that encountered for the homogeneous environment. This was attributed to conformational constraints imposed to the biomacromolecule entrapped in the polymeric matrix. PMID- 27232538 TI - Fast and effective quantum-dots encapsulation and protection in PEO based photo cross-linked micelles. AB - Cadmium-based quantum dots (QDs) were easily, quickly and efficiently transferred from an organic medium to water without modification of their surface chemistry by the simple emulsion/solvent evaporation technique using micelles of amphiphilic diblock copolymers based on poly(ethylene oxide) and poly(2 methacryloyloxyethyl acrylate) (PEO-b-PMEA) as hosts. The resulting hybrid micelles were stabilized very rapidly by photo-cross-linking the hydrophobic core around the QDs. The encapsulation and photo-cross-linking process were shown to barely affect the photoluminescence properties. Grafting a short octyl chain at the end of the hydrophobic block enhanced both the colloidal stability of the QDs dispersed in water and prevented the quenching of their fluorescence by copper ions. Grafting a longer hexadecyl chain at the end of the PMEA block decreased the efficiency of the corona cross-linking and led to poorer stabilization and protection. PMID- 27232535 TI - Effect of iron supplementation on iron stores and total body iron after whole blood donation. AB - BACKGROUND: Understanding the effect of blood donation and iron supplementation on iron balance will inform strategies to manage donor iron status. STUDY DESIGN AND METHODS: A total of 215 donors were randomized to receive ferrous gluconate daily (37.5 mg iron) or no iron for 24 weeks after blood donation. Iron stores were assessed using ferritin and soluble transferrin receptor. Hemoglobin (Hb) iron was calculated from total body Hb. Total body iron (TBI) was estimated by summing iron stores and Hb iron. RESULTS: At 24 weeks, TBI in donors taking iron increased by 281.0 mg (95% confidence interval [CI], 223.4-338.6 mg) compared to before donation, while TBI in donors not on iron decreased by 74.1 mg (95% CI, 112.3 to -35.9; p < 0.0001, iron vs. no iron). TBI increased rapidly after blood donation with iron supplementation, especially in iron-depleted donors. Supplementation increased TBI compared to controls during the first 8 weeks after donation: 367.8 mg (95% CI, 293.5-442.1) versus -24.1 mg (95% CI, -82.5 to 34.3) for donors with a baseline ferritin level of not more than 26 ng/mL and 167.8 mg (95% CI, 116.5-219.2) versus -68.1 mg (95% CI, -136.7 to 0.5) for donors with a baseline ferritin level of more than 26 ng/mL. A total of 88% of the benefit of iron supplementation occurred during the first 8 weeks after blood donation. CONCLUSION: Donors on iron supplementation replaced donated iron while donors not on iron did not. Eight weeks of iron supplementation provided nearly all of the measured improvement in TBI. Daily iron supplementation after blood donation allows blood donors to recover the iron loss from blood donation and prevents sustained iron deficiency. PMID- 27232539 TI - Characterization of Al30 in commercial poly-aluminum chlorohydrate by solid-state (27)Al NMR spectroscopy. AB - Investigation of commercially produced hydrolysis salts of aluminum by solid state (27)Al NMR spectroscopy and size-exclusion chromatography (SEC) reveals well-defined and distinct Al environments that can be related to physicochemical properties. (27)Al MAS and MQ-MAS NMR spectroscopic data show that the local structure of the solids is dominated by moieties that closely resemble the Al30 polyoxocation (Al30O8(OH)56(H2O)26(18+)), accounting for 72-85% of the total Al. These Al30-like clusters elute as several size fractions by SEC. Comparison of the SEC and NMR results indicates that the Al30-like clusters includes intact isolated clusters, moieties of larger polymers or aggregates, and possibly fragments resembling delta-Al13 Keggin clusters. The coagulation efficacy of the solids appears to correlate best with the abundance of intact Al30-like clusters and of smaller species available to promote condensation reactions. PMID- 27232540 TI - Solid Electrolyte Interphase Growth and Capacity Loss in Silicon Electrodes. AB - The solid electrolyte interphase (SEI) of the high capacity anode material Si is monitored over multiple electrochemical cycles by (7)Li, (19)F, and (13)C solid state nuclear magnetic resonance spectroscopies, with the organics dominating the SEI. Homonuclear correlation experiments are used to identify the organic fragments -OCH2CH2O-, -OCH2CH2-, -OCH2CH3, and -CH2CH3 contained in both oligomeric species and lithium semicarbonates ROCO2Li, RCO2Li. The SEI growth is correlated with increasing electrode tortuosity by using focused ion beam and scanning electron microscopy. A two-stage model for lithiation capacity loss is developed: initially, the lithiation capacity steadily decreases, Li(+) is irreversibly consumed at a steady rate, and pronounced SEI growth is seen. Later, below 50% of the initial lithiation capacity, less Si is (de)lithiated resulting in less volume expansion and contraction; the rate of Li(+) being irreversibly consumed declines, and the Si SEI thickness stabilizes. The decreasing lithiation capacity is primarily attributed to kinetics, the increased electrode tortuousity severely limiting Li(+) ion diffusion through the bulk of the electrode. The resulting changes in the lithiation processes seen in the electrochemical capacity curves are ascribed to non-uniform lithiation, the reaction commencing near the separator/on the surface of the particles. PMID- 27232541 TI - XI Convegno Nazionale: Firenze, 17-19 marzo 2016, Palazzo dei Congressi - Villa Vittoria. PMID- 27232542 TI - PPAR Modulating Polyketides from a Chinese Plakortis simplex and Clues on the Origin of Their Chemodiversity. AB - Fifteen polyketides, including the first hydroxylated plakortone (12) and plakdiepoxide (15), the first polyketide to embed a vicinal diepoxide, have been isolated from the Chinese sponge Plakortis simplex. The structures of the new metabolites were elucidated by analysis of spectroscopic data, Mosher's derivatization, and DFT computational calculations. The reactivity of the major endoperoxide of this sponge was investigated, suggesting that furan, furanylidene, and plakilactone derivatives, well-known classes of natural products, could actually be chemical degradation products. Plakdiepoxide is a potent and selective modulator of peroxisome proliferator-activated receptor (PPAR)-gamma, while the diunsaturated C12 fatty acid monotriajaponide (13) activates both PPAR-alpha and PPAR-gamma, a dual activity of potential great importance for the treatment of metabolic disorders. PMID- 27232543 TI - Chemical characterization of the main bioactive constituents from fruits of Ziziphus jujuba. AB - The fruit of Ziziphus jujuba Mill., also called hongzao in Chinese, has a long history of cultivation in China. From the fruit of Z. jujuba, twenty-seven known compounds were isolated and identified as the main constituents of these fruits. They were 3-O-(trans-p-coumaroyl)-alphitolic acid (1), 3-O-(cis-p-coumaroyl) alphitolic acid (2), 3beta-O-(trans-p-coumaroyl)-maslinic acid (3), pomonic acid (4), 2-oxo-pomolic acid (5), benthamic acid (6), terminic acid (7), oleanic acid (8), betulinic acid (9), quercetin 3-O-rutinoside (10), quercetin 3-O robinobioside (11), apigenin (12), traumatic acid (13), (Z)-4-oxotetradec-5-enoic acid (14), 7(E)-9-keto-hexadec-7-enoic acid (15), 9(E)-11-oxo-octadecenoic acid (9CI) (16), and magnoflorine (27), etc. The HPLC fingerprint of Z. jujuba fruits was established at the same time. Compounds 4, 5, 7, 11, 14, 15 and 16 were isolated from Z. jujuba for the first time. Compound 14 was isolated from the nature for the first time. Furthermore, cytotoxicity against four human tumor cell lines (MCF-7, A549, HepG2 and HT-29) of the isolated compounds (1-17 and 27) was evaluated. Among these compounds, compounds 1, 2, 3, 6, 7, 9 and 12 had strong growth inhibitory effects on cancer cell lines. These results indicated that jujube extracts exhibited cytotoxicity on these cancer cell lines. PMID- 27232544 TI - U.S. Minority Homeless Youth's Access to and Use of Mobile Phones: Implications for mHealth Intervention Design. AB - Few interventions for homeless youth have leveraged the potential of mHealth technologies, in part because of the limited data on phone behaviors, perceptions, and intervention preferences among youth experiencing homelessness. We conducted 9 focus groups (n = 52 homeless youth) and 41 individual structured interviews also with homeless youth in underserved communities in Baltimore and Washington, DC, to ascertain how youth perceived their mobile phone, acquired and maintained mobile services over time, and thought mHealth programs for this population should be designed. We also measured phone use, functionality, source, duration of ownership, and reasons for changing phones or numbers. Results showed that mobile coverage was high, as most youth self-purchased phones or received gift payments from others. Maintaining mobile connectivity was often challenging because of financial constraints and interpersonal conflict. Youth valued phones to access social support but used several tactics to avoid perceived negative consequences of phone ownership, such as harassment, theft, or relational disputes. Youth most preferred mHealth content relating to sexual, reproductive, and mental health provided that mobile communication was confidential, empowering, and integrated with other digital media. Integrating hidden phones, financial support, and safety management may improve homeless youth's access to and engagement with mHealth strategies over time. PMID- 27232545 TI - Herbal medicines: challenges in the modern world. Part 3. China and Japan. AB - INTRODUCTION: Medicinal plants, and formulations prepared from them, have been used in China and Japan for thousands of years. Nowadays, ancient formulations of Traditional Chinese and Kampo (Japanese) Medicines coexist with Western herbal medicines (HMs) and complement each other. HMs are used for the treatment of mild and chronic diseases, as an adjunct therapy, to improve wellbeing and delay aging, or as healthy (functional) foods. AREAS COVERED: This article, a third part in a series of reviews, is focusing on history, use and regulation of the traditional and modern HMs in Japan and China. Materials available from legislative and governmental websites, PubMed and news media were used. Expert commentary: HMs are heavily regulated in both countries, often in a similar manner as conventional pharmaceutical drugs. The majority of herbal formulations are sold as over-the-counter medications supplied with leaflets describing indications and appropriate dosages for patients of different ages. Medical practitioners prescribe herbal formulations that are tailored to the needs of particular patients. Both countries had problems with adverse drug reactions and toxicity of single herbs and herbal formulations that have been investigated by authorities, and some drugs have been removed from the market. PMID- 27232546 TI - Oxidative mechanisms of biological activity of low-intensity radiofrequency radiation. PMID- 27232547 TI - Nickel(II) Complex of a Hexadentate Ligand with Two o-Iminosemiquinonato(1-) pi Radical Units and Its Monocation and Dication. AB - Aerobic reaction of a hexadentate redox-active o-aminophenol-based ligand, H4L(3) = N,N'-bis(2-hydroxy-3,5-di-tert-butylphenyl)-2,2'-diamino(diphenyldithio) ethane, in CH3OH with Ni(II)(O2CCH3)2.4H2O and Et3N afforded isolation of a reddish-brown crystalline solid [Ni(L(3))] 1. Cyclic voltammetry (CV) experiment exhibits two oxidative responses at E1/2 = 0.09 and 0.53 V vs SCE (saturated calomel electrode). Chemical oxidation of 1 in air by [Fe(III)(eta(5) C5H5)2][PF6] and AgBF4 in CH2Cl2 led to the isolation of one-electron oxidized species [1](1+) as purple [1][PF6].CH2Cl2 and two-electron oxidized species [1](2+) as dark purple [1][BF4]2.CH2Cl2, respectively. X-ray crystallographic analysis at 100(2) K unambiguously established that the ligand is present in [Ni(II){(L(ISQ)O,N)(*-)}{(L(ISQ)O,N)(*-)}{(LS,S)(0)}] 1, [Ni(II){(L(IBQ)O,N)(0)}{(L(ISQ)O,N)(*-)}{(LS,S)(0)}][PF6].CH2Cl2, and [Ni(II){(L(IBQ)O,N)(0)}{(L(IBQ)O,N)(0)}{(LS,S)(0)}][BF4]2.CH2Cl2, as monoanionic o-iminosemiquinonate(1-) pi-radical (Srad = 1/2) (L(ISQ))(*-) and neutral o iminoquinone (L(IBQ))(0) redox-levels. Complexes 1, [1][PF6].CH2Cl2, and [1][BF4]2.CH2Cl2 possess an S = 2, 3/2, and 1 ground-state, respectively, established by temperature-dependent (2-300 K) magnetic behavior of 1 and [1][PF6].CH2Cl2, and a MUeff value of [1][BF4]2.CH2Cl2 at 300 K. Both 1 and [1][PF6].CH2Cl2 exhibit ferromagnetic exchange-coupling between the two electrons of Ni(II) and two/one ligand pi-radicals, respectively. The redox processes are shown to be ligand-based. Spectroscopic and redox properties, and density functional theory (DFT) calculations at the CAM-B3LYP-level of theory adequately describe the electronic structure of 1, [1](1+), and [1](2+). The observed UV-vis NIR absorptions for 1, [1][PF6].CH2Cl2, and [1][BF4]2.CH2Cl2 have been assigned, based on time-dependent (TD)-DFT calculations. PMID- 27232548 TI - Ranking protein-protein docking results using steered molecular dynamics and potential of mean force calculations. AB - Crystallization of protein-protein complexes can often be problematic and therefore computational structural models are often relied on. Such models are often generated using protein-protein docking algorithms, where one of the main challenges is selecting which of several thousand potential predictions represents the most near-native complex. We have developed a novel technique that involves the use of steered molecular dynamics (sMD) and umbrella sampling to identify near-native complexes among protein-protein docking predictions. Using this technique, we have found a strong correlation between our predictions and the interface RMSD (iRMSD) in ten diverse test systems. On two of the systems, we investigated if the prediction results could be further improved using potential of mean force calculations. We demonstrated that a near-native (<2.0 A iRMSD) structure could be identified in the top-1 ranked position for both systems. (c) 2016 Wiley Periodicals, Inc. PMID- 27232549 TI - Emulsifying and Foaming Properties of Different Protein Fractions Obtained from a Novel Lupin Variety AluProt-CGNA((r)) (Lupinus luteus). AB - The use of vegetable proteins as food ingredient is becoming increasingly important due to their high versatility and environmental acceptability. This work describes a chemical characterization and techno-functional properties (emulsifying and foaming properties) of 3 protein fractions obtained from a protein-rich novel lupin variety, AluProt-CGNA((r)) . This nongenetically modified variety have a great protein content in dehulled seeds (60.6 g protein/100 g, dry matter), which is higher than soybean and other lupin varieties. A simple procedure was utilized to obtain 3 different fractions by using alkali solubilization and isoelectric precipitation. Fractions 1 and 3 were mainly composed of protein and polysaccharides (NNE), whereas fraction 2 was mainly composed by protein (97%, w/w). Fraction 3 presented interesting and potential foaming properties in comparison to the other fractions evaluated in the study. Besides, its solubility, foaming and emulsifying capacity were practically not affected by pH variations. The 3 fractions also presented good emulsion stability, reaching values above a 95%. SDS-PAGE showed that fractions 1 and 2 contained mainly conglutin alpha, beta, and delta, but in different ratios, whereas fraction 3 contained mainly conglutin gamma and albumins. The results of this work will provide better understanding for the utilization of each protein fractions as potential ingredients in food industry. PMID- 27232550 TI - Are obstetrical complications really involved in the etiology and course of schizophrenia and mood disorders? AB - The impact of stressful experiences during gestation or early life, leading to increased psychiatric disorders susceptibility, is currently well described in literature, however, few data are available on the association between obstetrical complications and later development of specific diagnoses or clinical features (e.g. psychotic symptoms). Aim of the present paper was to evaluate obstetrical complications frequency in different psychiatric diagnoses and their association with clinical features. Three hundred and eighty-eight patients with a diagnosis of schizophrenia, bipolar disorder or major depressive disorder were compared in terms of clinical presentation according to the presence, type and severity of obstetrical complications. Seventeen percent of the total sample (N=65) had history of at least one obstetrical complication. Patients with a history of at least one obstetrical complication result in an earlier age of onset (F=3.93, p=0.04) and a current higher GAF score (F=6.46, p=0.01). Lewis Murray scale score was directly correlated with GAF scores (t=2.9, p=0.004) and inversely correlated with age at onset (t=-2.77, p=0.006). Obstetrical complications are frequently registered in patients with schizophrenia or mood disorders. In our sample, they appear to have an anticipatory effect on illness onset, but they seem not to be associated with a specific psychiatric diagnosis. PMID- 27232551 TI - Stigma and its correlates among caregivers of schizophrenia: A study from North India. AB - This study aimed to study stigma experienced by caregivers of patients with schizophrenia. One hundred caregivers of patients with schizophrenia were evaluated on Stigma scale for caregivers of people with mental illness (CPMI), Explanatory model interview catalogue stigma scale (EMIC), General health questionnaire-12 (GHQ), Self-report attitude towards medications questionnaire and Knowledge of mental illness scale (KMI). On CPMI the score was higher for affective component (2.3+/-0.5) than for cognitive (1.9+/-0.9) and behavioural (1.8+/-0.6) components. More than half of caregivers 'agreeing' or 'strongly agreeing' on 20 out of 22 items of CPMI indicated high level of stigma. On EMIC the stigma score was 21.7+/-6.3. Higher level of affiliate and/or associative stigma was associated with shorter duration of illness and treatment, shorter duration of being in the caregiver role, younger, female and non-earning caregivers, prescription of higher number of pills, caregivers who less often accompany the patient to the hospital and caregivers experienced more psychological morbidity. To conclude this study suggests that caregivers of patients with schizophrenia experience substantial stigma; hospital and community level programs and services are required to reduce and prevent the same. PMID- 27232553 TI - Manual actions cover symbolic distances at different speed. AB - A privileged way of representing numbers in the human mind is along an oriented mental number line. Activation of this representation has been proposed to account for the impact of numbers on motor tasks, such as on grasping, pointing, and eye movements. Here we evaluated the impact of numbers on motor control, by exploiting the evidence that the speed reached by the manual connection of two points is correlated with their physical distance. We reasoned that, if irrelevant numbers induce a mis-perception of the distance between two points, this should be reflected in the movement speed. Results showed a speed difference in the manual connection of two numerically close numbers (i.e., connected slower) and two numerically distant numbers (i.e., connected faster), placed at equal physical distance. This representational length effect indicates not only that symbolic distance modulates speed movement as physical distance does, but suggests that the impact of numbers on action planning does not only involve action initiation but it extends to the definition of kinematic parameters. More generally, the reported findings show that the representation of numbers along a mental space affects our behaviour in the physical space. PMID- 27232552 TI - Perceived ethnic discrimination and persecutory paranoia in individuals at ultra high risk for psychosis. AB - Despite a consensus that psychosocial adversity plays a role in the onset of psychosis, the nature of this role in relation to persecutory paranoia remains unclear. This study examined the complex relationship between perceived ethnic discrimination and paranoid ideation in individuals at Ultra High Risk (UHR) for psychosis using a virtual reality paradigm to objectively measure paranoia. Data from 64 UHR participants and 43 healthy volunteers were analysed to investigate the relationship between perceived ethnic discrimination and persecutory ideation in a virtual reality environment. Perceived ethnic discrimination was higher in young adults at UHR in comparison to healthy controls. A positive correlation was observed between perceived ethnic discrimination and paranoid persecutory ideation in the whole sample. Perceived ethnic discrimination was not a significant predictor of paranoid persecutory ideation in the VR environment. Elevated levels of perceived ethnic discrimination are present in individuals at UHR and are consistent with current biopsychosocial models in which psychosocial adversity plays a key role in the development of psychosis and attenuated symptomatology. PMID- 27232554 TI - Influence of pacer continuity on continuous and discontinuous visuo-motor synchronisation. AB - Previous research has reported that synchronising movements with an external pacer, known as sensorimotor synchronisation (SMS), is more stable when the movements are discrete/discontinuous rather than continuous. A standard explanation considers that more efficient mechanisms are involved for regulating synchronisation when producing discontinuous movements. To date, however, only discontinuous pacers (e.g., metronomes) have been investigated to compare discontinuous and continuous SMS. We propose an alternative explanation whereby the discontinuous SMS has benefited from the matching between the (dis)continuous nature of the pacer and the (dis)continuous nature of the movements of synchronisation. The present experiment tested this explanation by examining the relative stability of discontinuous and continuous SMS when synchronising with a continuous pacer. Twelve participants finger tapped (discontinuous SMS) or continuously oscillated their forearm (continuous SMS) in synchrony with an oscillatory visual target. The continuity of the pacer was manipulated by varying the kinematic (harmonic to Rayleigh-like oscillations) and the frequency (0.5 and 1Hz) of the target oscillations. Overall, the results showed a more stable continuous than discontinuous SMS. Furthermore, the stability of the discontinuous SMS improved when increasing the discontinuity of the target displacements (high nonlinear kinematic and low frequency), showing an interaction between movement type and pacer continuity in SMS. PMID- 27232555 TI - Sustainability and repeatability of postactivation potentiation. AB - BACKGROUND: This study investigated the duration and repeatability of postactivation potentiation (PAP) benefits within a single exercise session. Specifically examined were the recurring effects, over multiple sets, of heavy back squats on repeated sprint times. METHODS: A partially randomized, counterbalanced, repeated measures design was implemented using 29 college-aged male NCAA varsity field sport athletes participating in PAP and control conditions. Subjects performed four repetitions of back squats (PAP=90% 1RM; control =20% 1RM), rested 8 minutes, performed a set of four 40-m sprints (55 s inter-repetition active recovery) and rested for 8 minutes after the last sprint. This was performed two more times, for a total of three sets (of back squats and sprints) performed 20 minutes apart. Sprint performance was measured using electronic timing gates and a timing pad to capture of reaction time (RT) at the start of each sprint. 2x3 (condition x sets) and 2x4 (condition X repetition) repeated measures ANOVAs were used to analyze both sprint and RT outcomes. RESULTS: Subjects ran significantly faster (P<0.05) after PAP than control. Specifically, sprint times were faster for the first two-three sprints, but not the fourth, across all three sets of sprints over the 51-min exercise session. RT was not affected (P>0.05) by PAP activity. CONCLUSIONS: The PAP effect was sustainable up to 11 minutes after heavy back squats and was repeated successfully three times. These findings can assist coaches and athletes interested in applying PAP to improve performance. PMID- 27232556 TI - Modified stepping exercise improves physical performances and quality of life in healthy elderly subjects. AB - BACKGROUND: Stepping exercise, an aerobic exercise, has been shown to be beneficial to elderly people if performed continuously for at least 12 weeks. This study aimed to evaluate the effects of engaging in modified stepping exercise on stairs with shorter height than the standard stepping platform for a shorter duration (8 weeks) on both physical fitness and quality of life (QoL) in healthy elderly subjects by using a randomized controlled trial. METHODS: The study was conducted at the Elderly Club, Muang District, Khon Kaen, Thailand. The study examined healthy elderly subjects aged 60-80 who had not engaged in regularly exercise in the past two months and no contraindication for exercise. Eligible subjects were randomly assigned to either the stepping exercise group (SG) or control group (CG). The SG performed stepping exercise together in groups three times a week for eight weeks, while the CG received general health education. Stepping exercise was performed for one hour on a one-step platform that was 18 centimeters in height. Physical performance was measured at the baseline and the end of the study. This included a six-minute walk distance test (6MWT), a five times sit to stand test (FTSST), a timed up and go test (TUGT), a functional reach test (FRT) and a QoL assessment. RESULTS: In total, 42 subjects were enrolled, half of which were randomly assigned to the SG and the other half assigned to the CG. The median age of both groups was equal at 69 years. Other baseline characteristics were comparable. None of the outcomes differed between the two groups baseline. However they showed statistically significant differences at the end of study, with the exception of FTSST. After 8 weeks, the SG performed significantly better on the 6MWT (468 vs. 426 m; P=0.01), TUGT (5.96 vs. 8.52 sec; P<0.01), and FRT (28 vs. 21 cm; P<0.01) and had a better QoL score (105 vs. 98; P=0.03) than the CG. CONCLUSIONS: Modified stepping exercise was beneficial to the healthy elderly subjects. Physical functions and QoL significantly improved after the short duration of eight weeks. PMID- 27232557 TI - Prevalence of electrocardiographic abnormalities in young, elite Japanese athletes. AB - BACKGROUND: The question as to whether or not electrocardiogram (ECG) evaluations should be performed in all athletes is still controversial. So, in this study, the prevalence of electrocardiographic abnormalities was evaluated in young, elite Japanese athletes. METHODS: Subjects included 174 male and 101 female Japanese athletes (mean age, 21.5 years). Sports activities included baseball, basketball, diving, fencing, gymnastics, judo, rhythmic gymnastics, soccer, swimming, tennis, track and field, volleyball, and water polo. A 12-lead resting ECG was recorded and evaluated. We used the criteria for distinctly abnormal ECG patterns as defined by Pelliccia et al. Subjects were divided into 2 groups on the basis of their exercise training type: an endurance training group and a static training group. RESULTS: Twenty six of 174 male subjects (14.9%) and 11 of 101 (10.9%) female subjects presented with abnormal ECG results. ECG abnormalities were observed much more frequently in track athletes compared to athletes of other sporting events. Field players did not present with any ECG abnormalities. Overall, the incidences of ECG abnormalities were statistically lower in the static exercise training group than in the endurance training group both in male and female. High voltage of left ventricle was observed in 114 of 175 male subjects (65.1%), and 27 of 101 female subjects (26.7%). CONCLUSIONS: The prevalence of ECG abnormalities in young, elite, Japanese athletes was comparable to that previously reported by both Western and Asian investigators. PMID- 27232558 TI - Tethered 3-min all-out test did not predict the traditional critical force parameters in inexperienced swimmers. AB - BACKGROUND: Critical power model can be performed in tethered swimming (i.e. critical force model). Although critical force can be used to prescribe aerobic training, its determination depends on at least three exhaustive efforts in altered days. In this context, previously studies have demonstrate that critical power model can be estimated by a single 3-min all-out test (3MT), which was not investigated in swimming yet. Thus, the aim of this study was to compare the parameters obtained during the tethered swimming 3MT to those obtained during the traditional critical force model. METHODS: Seven swimmers (four female and three male) underwent a tethered swimming 3MT and three exhaustive efforts to determine the traditional critical force parameters (i.e. critical force [CF] and anaerobic impulse capacity [AIC]). RESULTS: The critical force (CF3-MIN) and force-time integral above the CF3-MIN (AIC3-MIN) determined during the tethered 3MT were not different to CF and AIC, respectively (P value >0.55). However, these parameters were not correlated (P value >0.45). In addition, we verified large limits of agreement between CF3MIN and CF (+/-19.7 N), which was also observed between AIC3MIN and AIC (+/-0.84 Log[N.min]). CONCLUSIONS: These findings demonstrated that tethered 3MTs should not be used to predict traditional critical force parameters, at least when the swimmers are inexperienced in long tethered all-out efforts. PMID- 27232559 TI - The effect of professional dietary counseling: elite basketball players eat healthier during competition days. AB - BACKGROUND: Literature suggests that dietary intake of elite athletes may differ between training and competition days. In addition, despite the importance of nutrition in sports and the popularity of basketball, studies on the diet of basketball players are scarce. Therefore, the aim of the present study was to assess dietary intake and diet quality in training and competition days in a team of elite basketball players receiving daily professional nutritional counseling. METHODS: One elite basketball team (N.=15) participating in EuroLeague volunteered for the study. The team employed a certified dietitian, responsible for providing individualized nutritional evaluation and counseling, dietary planning and supervision of the diet of all the players. Dietary intake was assessed using 24-hour recalls and the Healthy Eating Index (HEI) was then calculated. RESULTS: All players exhibited adequate (i.e., >80) HEI score (raw and adjusted for energy intake [EI]), on both training and competition days. Although daily energy, carbohydrate and protein intakes were greater during training compared to competition days (26.0 [21.7, 26.4] vs. 19.5 [19.3, 22.1] MJ, 7.6+/-1.5 vs. 6.8+/-0.9 g/kg of body weight [BW] and 2.6+/-0.6 vs. 2.2+/-0.2 g/kg BW, respectively; all P<0.05), HEI score (raw and adjusted for EI) was lower in training compared to competition days (92.9 [82.1, 93.2] vs. 94.0 [94.0, 94.0] and 89.7 [88.4, 89.7] vs. 92.7 [91.7, 92.8], respectively; all P<=0.001) due to lower total grains, whole grains and total vegetables consumption and greater saturated fats consumption (P<0.05). CONCLUSIONS: Elite basketball players receiving daily nutritional counseling by certified sports dietitians exhibit adequate diet quality, with the highest possible observed during competition days. PMID- 27232578 TI - Role of transient receptor potential vanilloid 1 in regulating erythropoietin induced activation of endothelial nitric oxide synthase. AB - AIMS: Erythropoietin (EPO), the key hormone involved in erythropoiesis, beneficially affects endothelial cells (ECs), but the detailed mechanisms are yet to be completely understood. In this study, we investigated the role of transient receptor potential vanilloid type 1 (TRPV1), a ligand-gated non-selective calcium (Ca2+ ) channel, in EPO-mediated endothelial nitric oxide synthase (eNOS) activation and angiogenesis. METHODS AND RESULTS: In ECs, EPO time dependently increased intracellular levels of calcium; this increase was abrogated by the Ca2+ chelators and pharmacological inhibitors of TRPV1 in bovine aortic ECs (BAECs) and TRPV1-transfected HEK293 cells. In addition, EPO-induced nitrite oxide (NO) production, phosphorylation of eNOS, Akt and AMP-activated protein kinase (AMPK) and the formation of TRPV1-Akt-AMPK-eNOS complex as well as tube formation were diminished by the pharmacological inhibition of TRPV1 in BAECs. Moreover, EPO time dependently induced the phosphorylation of phospholipase C gamma1 (PLC-gamma1). Inhibition of PLC-gamma1 activity blunted the EPO-induced Ca2+ influx, eNOS phosphorylation, TRPV1-eNOS complex formation and NO production. The phosphorylated level of eNOS increased in the aortas of EPO treated wild-type (WT) mice or EPO-transgenic (Tg) mice but not in those of EPO treated TRPV1-deficient (TRPV1-/- ) mice or EPO-Tg/TRPV1-/- mice. Matrigel plug assay showed that EPO-induced angiogenesis was abrogated in TRPV1 antagonist capsazepine-treated WT mice and TRPV1-/- mice. CONCLUSION: These findings indicate the EPO-induced Ca2+ influx via the activation of the PLC-gamma1 signalling pathway, which leads to TRPV1 activation and consequently increases the association of the TRPV1-Akt-AMPK-eNOS complex, eNOS activation, NO production and angiogenesis. PMID- 27232580 TI - Molecular Order in Buried Layers of TbPc2 Single-Molecule Magnets Detected by Torque Magnetometry. AB - Cantilever torque magnetometry is used to elucidate the orientation of magnetic molecules in thin films. The technique allows depth-resolved investigations by intercalating a layer of anisotropic magnetic molecules in a film of its isotropic analogues. The proof-of-concept is here demonstrated with the single molecule magnet TbPc2 evidencing also an exceptional long-range templating effect on substrates coated by the organic molecule perylene-3,4,9,10-tetracarboxylic dianhydride. PMID- 27232581 TI - Microcephalic primordial dwarfism in an Emirati patient with PNKP mutation. AB - Microcephaly is a rare neurological condition, both in isolation and when it occurs as part of a syndrome. One of the syndromic forms of microcephaly is microcephaly, seizures and developmental delay (MCSZ) (OMIM #613402), a rare autosomal recessive neurodevelopmental disorder with a range of phenotypic severity, and known to be caused by mutations in the polynucleotide kinase 3' phosphatase (PNKP) gene. The PNK protein is a key enzyme involved in the repair of single and double stranded DNA breaks, a process which is particularly important in the nervous system. We describe an Emirati patient who presented with microcephaly, short stature, uncontrollable tonic-clonic seizures, facial dysmorphism, and developmental delay, while at the same time showing evidence of brain atrophy and agenesis of the corpus callosum. We used whole exome sequencing to identify homozygosity for a missense c.1385G > C (p.Arg462Pro) mutation in PNKP in the patient and heterozygosity for this mutation in her consanguineous parents. The Arg 462 residue forms a part of the lid subdomain helix of the P loop Kinase domain. Although our patient's phenotype resembled that of MCSZ, the short stature and evidence of brain atrophy distinguished it from other classic cases of the condition. The report raises the question of whether to consider this case as an atypical variant of MCSZ or as a novel form of microcephalic primordial dwarfism. (c) 2016 Wiley Periodicals, Inc. PMID- 27232579 TI - Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults: results of a 6-month open-label safety trial. AB - BACKGROUND: Chronic liver injury can result in fibrosis that may progress over years to end-stage liver disease. The most effective anti-fibrotic therapy is treatment of the underlying disease, however when not possible, interventions to reverse or slow fibrosis progression are needed. AIM: The aim of this study was to study the safety and tolerability of simtuzumab, a monoclonal antibody directed against lysyl oxidase-like 2 (LOXL2) enzyme, in subjects with hepatitis C virus (HCV), human immunodeficiency virus (HIV), or HCV-HIV co-infection and advanced liver disease. METHODS: Eighteen subjects with advanced liver fibrosis received simtuzumab 700 mg intravenously every 2 weeks for 22 weeks. Transjugular liver biopsies were performed during screening and at the end of treatment to measure hepatic venous pressure gradient (HVPG) and to stage fibrosis. RESULTS: Treatment was well-tolerated with no discontinuations due to adverse events. No significant changes were seen in HVPG or liver biopsy fibrosis score after treatment. Exploratory transcriptional and protein profiling using paired pre- and post-treatment liver biopsy and serum samples suggested up-regulation of TGF beta3 and IL-10 pathways with treatment. CONCLUSION: In this open-label, pilot clinical trial, simtuzumab treatment was well-tolerated in HCV- and HIV-infected subjects with advanced liver disease. Putative modulation of TGF-beta3 and IL-10 pathways during simtuzumab treatment merits investigation in future trials. PMID- 27232582 TI - Complex Orbitals, Multiple Local Minima, and Symmetry Breaking in Perdew-Zunger Self-Interaction Corrected Density Functional Theory Calculations. AB - Implentation of seminumerical stability analysis for calculations using the Perdew-Zunger self-interaction correction is described. It is shown that real valued solutions of the Perdew-Zunger equations for gas phase atoms are unstable with respect to imaginary orbital rotations, confirming that a proper implementation of the correction requires complex-valued orbitals. The orbital density dependence of the self-interaction corrected functional is found to lead to multiple local minima in the case of the acrylic acid, H6, and benzene molecules. In the case of benzene, symmetry breaking that results in incorrect ground state geometry is found to occur, erroneously leading to alternating bond lengths in the molecule. PMID- 27232583 TI - A new method for calculating saddle seat height with an emphasis on optimal posture based on trigonometric relations. AB - INTRODUCTION: Based on the literature, the ergonomic saddle chair provides the most appropriate posture for users. Determination of the seat height is critical to establish the proper posture, carried out using various methods of anthropometry. This study aimed to develop a simple and applied method for determining the saddle seat height with an emphasis on appropriate posture. METHODS: In this study, anthropometric dimensions including weight, body height, popliteal height and seat height at 135 degrees knee angle in 150 male and female dentists were measured. In the laboratory, to determine the 'acetabuloischial number', 25 male and female natural hip bones were measured. The mean saddle-chair height with knee angle of 135 degrees was then compared by two different methods, field measurement and the new calculation method. RESULTS: The results showed a strong correlation between data gathered from the two different methods, the field measurement and the new calculation method (98%), and Cronbach's alpha from the intraclass correlation was equal to 0.994 (p < 0.05). This indicated that the two methods produced similar results. CONCLUSION: The new method can be applied to calculate the optimal height of the saddle seat based on body height and popliteal height. PMID- 27232584 TI - The Patient-Oriented Eczema Measure in young children: responsiveness and minimal clinically important difference. AB - BACKGROUND: The Patient-Oriented Eczema Measure (POEM) has been recommended as the core patient-reported outcome measure for trials of eczema treatments. Using data from the Choice of Moisturiser for Eczema Treatment randomized feasibility study, we assess the responsiveness to change and determine the minimal clinically important difference (MCID) of the POEM in young children with eczema. METHODS: Responsiveness to change by repeated administrations of the POEM was investigated in relation to change recalled using the Parent Global Assessment (PGA) measure. Five methods of determining the MCID of the POEM were employed; three anchor-based methods using PGA as the anchor: the within-patient score change, between-patient score change and sensitivity and specificity method, and two distribution-based methods: effect size estimate and the one half standard deviation of the baseline distribution of POEM scores. RESULTS: Successive POEM scores were found to be responsive to change in eczema severity. The MCID of the POEM change score, in relation to a slight improvement in eczema severity as recalled by parents on the PGA, estimated by the within-patient score change (4.27), the between-patient score change (2.89) and the sensitivity and specificity method (3.00) was similar to the one half standard deviation of the POEM baseline scores (2.94) and the effect size estimate (2.50). CONCLUSIONS: The Patient-Oriented Eczema Measure as applied to young children is responsive to change, and the MCID is around 3. This study will encourage the use of POEM and aid in determining sample size for future randomized controlled trials of treatments for eczema in young children. PMID- 27232585 TI - Concise Enantioselective Total Synthesis of Cardiotonic Steroids 19 Hydroxysarmentogenin and Trewianin Aglycone. AB - The expedient and scalable approach to cardiotonic steroids carrying oxygenation at the C11- and C19-positions has been developed and applied to the total asymmetric synthesis of steroids 19-hydroxysarmentogenin and trewianin aglycone as well as to the assembly of the panogenin core. This new approach features enantioselective organocatalytic oxidation of an aldehyde, diastereoselective Cu(OTf)2-catalyzed Michael reaction/tandem aldol cyclizations, and one-pot reduction/transposition reactions allowing a rapid (7 linear steps) assembly of a functionalized cardenolide skeleton. The ability to quickly set this steroidal core with preinstalled functional handles and diversity elements eliminates the need for difficult downstream functionalizations and substantially improves the accessibility to the entire class of cardenolides and their derivatives for biological evaluation. PMID- 27232586 TI - How Biotransformation Influences Toxicokinetics of Azole Fungicides in the Aquatic Invertebrate Gammarus pulex. AB - Biotransformation is a key process that can greatly influence the bioaccumulation potential and toxicity of organic compounds. In this study, biotransformation of seven frequently used azole fungicides (triazoles: cyproconazole, epoxiconazole, fluconazole, propiconazole, tebuconazole and imidazoles: ketoconazole, prochloraz) was investigated in the aquatic invertebrate Gammarus pulex in a 24 h exposure experiment. Additionally, temporal trends of the whole body internal concentrations of epoxiconazole, prochloraz, and their respective biotransformation products (BTPs) were studied to gain insight into toxicokinetic processes such as uptake, elimination and biotransformation. By the use of high resolution tandem mass spectrometry in total 37 BTPs were identified. Between one (ketoconazole) and six (epoxiconazole) BTPs were identified per parent compound except for prochloraz, which showed extensive biotransformation reactions with 18 BTPs detected that were mainly formed through ring cleavage or ring loss. In general, most BTPs were formed by oxidation and conjugation reactions. Ring loss or ring cleavage was only observed for the imidazoles as expected from the general mechanism of oxidative ring openings of imidazoles, likely affecting the bioactivity of these BTPs. Overall, internal concentrations of BTPs were up to 3 orders of magnitude lower than that of the corresponding parent compound. Thus, biotransformation did not dominate toxicokinetics and only played a minor role in elimination of the respective parent compound, with the exception of prochloraz. PMID- 27232587 TI - Thermal [2 + 2]-Cycloaddition of Ketenes with Chiral Enol Ethers: Route to Densely Substituted Cyclobutanones. AB - Access to chiral polysubstituted cyclobutanones by [2 + 2]-cycloaddition of ketenes with chiral acyclic enol ethers is reported. A wide variety of easily accessible di- and monosubstituted ketenes were found to react with a very high degree of stereoselectivity with chiral, Stericol derived, acyclic enol ethers. This combination of simple reagents provides straightforward entry to highly substituted enantioenriched cyclobutanones. PMID- 27232588 TI - Schottky barrier and contact resistance of InSb nanowire field-effect transistors. AB - Understanding of the electrical contact properties of semiconductor nanowire (NW) field-effect transistors (FETs) plays a crucial role in the use of semiconducting NWs as building blocks for future nanoelectronic devices and in the study of fundamental physics problems. Here, we report on a study of the contact properties of Ti/Au, a widely used contact metal combination, when contacting individual InSb NWs via both two-probe and four-probe transport measurements. We show that a Schottky barrier of height [Formula: see text] is present at the metal-InSb NW interfaces and its effective height is gate-tunable. The contact resistance ([Formula: see text]) in the InSb NWFETs is also analyzed by magnetotransport measurements at low temperatures. It is found that [Formula: see text] in the on-state exhibits a pronounced magnetic field-dependent feature, namely it is increased strongly with increasing magnetic field after an onset field [Formula: see text]. A qualitative picture that takes into account magnetic depopulation of subbands in the NWs is provided to explain the observation. Our results provide solid experimental evidence for the presence of a Schottky barrier at Ti/Au-InSb NW interfaces and can be used as a basis for design and fabrication of novel InSb NW-based nanoelectronic devices and quantum devices. PMID- 27232589 TI - Investigational drugs for treating agitation in persons with dementia. AB - INTRODUCTION: Agitation is common and distressing in persons with dementia, but safe, effective treatments remain elusive. In this review, the authors describe investigational compounds in ongoing or recently completed clinical trials for this indication and provide an opinion on how they may meet current therapeutic needs. AREAS COVERED: Phase II and phase III clinical trials for agitation in persons with dementia were searched in US and EU clinical trial registries and in the medical literature for the period January 2013-February 2016 EXPERT OPINION: The authors searches identified 24 recent clinical trials investigating new treatments for agitation in persons with dementia. Candidate drugs in phase III development included the antipsychotic brexpiprazole, the antidepressant citalopram, the novel compound AVP-786 (deuterated-dextromethorphan/quinidine combination) and the cannabinoid nabilone. Of the compounds in phase II clinical trials, ELND005 (scyllo-inositol) is intended to progress into phase III development, based on evidence from a subgroup analysis and biomarker data. After many years without an FDA/EMA (Food and Drug Administration/European Medicines Agency) approved medication to treat agitation in persons with dementia, we may see the arrival of the first approved drug in the near future. PMID- 27232590 TI - Life after PACE (Program of All-Inclusive Care for the Elderly): A retrospective/prospective, qualitative analysis of the impact of closing a nurse practitioner centered PACE site. AB - BACKGROUND AND PURPOSE: Caring for frail older adults is a significant healthcare concern as the frailest 10% of the population account for over 70% of healthcare expenditures. Research reveals the use of comprehensive models, such as Program of All-Inclusive Care for the Elderly (PACE), leads to improved functional outcomes for participants and cost savings through decreased utilization. This study examines how closing a PACE program impacts health outcomes of previously enrolled participants. METHODS: Data were collected every 6 months for 2 years via phone surveys on 34 former participants enrolled in the program at the time of the closure. The survey included questions regarding satisfaction with care, activities of daily living (ADLs), instrumental ADLs (IADLs), emergency department (ED) visits, hospitalizations, and use of home health services. Deaths and nursing home placements were monitored. Outcomes were compared during and post-PACE. CONCLUSIONS: Higher numbers of ED visits, hospitalizations, and nursing home placements occurred post-PACE. PACE/post-PACE differences in ADL and IADL scores were not significant, nor were death rates. Higher satisfaction existed with PACE versus non-PACE care. IMPLICATIONS FOR PRACTICE: Comprehensive care programs such as PACE are effective in reducing healthcare utilization, thus limiting costs. Further work is required to maintain, develop, and support comprehensive models similar to PACE. PMID- 27232591 TI - Gay Xhosa men's experiences of ulwaluko (traditional male initiation). AB - This paper explores the lives of gay men undergoing traditional initiation in the Eastern Cape. Nine participants aged between 18 and 26 reported their reasons for becoming traditionally circumcised, which included personal validation of cultural manhood, the desire to conform to societal norms and expectations, and pressure from family members to 'convert' them to heterosexuality. While homosexuality remains a target for vilification and abuse both in Southern Africa and across the African continent, practices such as ulwaluko (traditional male initiation) must surely be among the most threatening to a young gay Xhosa man's self-esteem. PMID- 27232592 TI - Analytical method to estimate resin cement diffusion into dentin. AB - This study analyzed the diffusion of two resin luting agents (resin cements) into dentin, with the aim of presenting an analytical method for estimating the thickness of the diffusion zone. Class V cavities were prepared in the buccal and lingual surfaces of molars (n=9). Indirect composite inlays were luted into the cavities with either a self-adhesive or a self-etch resin cement. The teeth were sectioned bucco-lingually and the cement-dentin interface was analyzed by using micro-Raman spectroscopy (MRS) and scanning electron microscopy. Evolution of peak intensities of the Raman bands, collected from the functional groups corresponding to the resin monomer (C?O?C, 1113 cm(-1)) present in the cements, and the mineral content (P?O, 961 cm(-1)) in dentin were sigmoid shaped functions. A Boltzmann function (BF) was then fitted to the peaks encountered at 1113 cm(-1) to estimate the resin cement diffusion into dentin. The BF identified a resin cement-dentin diffusion zone of 1.8+/-0.4 MUm for the self adhesive cement and 2.5+/-0.3 MUm for the self-etch cement. This analysis allowed the authors to estimate the diffusion of the resin cements into the dentin. Fitting the MRS data to the BF contributed to and is relevant for future studies of the adhesive interface. PMID- 27232593 TI - In vivo/ex vivo targeting of Langerhans cells after topical application of the immune response modifier TMX-202: confocal Raman microscopy and histology analysis. AB - The increased ability of TMX-202 (derivative of imiquimod) to penetrate the intact stratum corneum (SC) and the follicular orifices of porcine ear skin was shown ex vivo using confocal Raman microscopy and laser scanning microscopy. Moreover, to assess whether TMX-202 is able to reach the immune cells, Langerhans cells extracted from pretreated human skin were investigated ex vivo using confocal Raman microscopy combined with multivariate statistical methods. Tracking the Raman peak of dimethyl sulfoxide centered at 690 cm(-1), the absorption of TMX-202 containing formulation by Langerhans cells was shown. To answer the question whether the TMX-202 active ingredient is able to reach Langerhans cells, the attraction of immune cells to TMX-202 containing formulation treated skin was measured in the in vivo rodent model Mastomys coucha. The results show that TMX-202 active ingredient is able to reach Langerhans cells after penetrating through the intact skin and subsequently attract immune cells. Both the intercellular/transcellular as well as the follicular pathways allow the penetration through the intact barrier of the SC. PMID- 27232595 TI - Photoacoustic molecular imaging for in vivo liver iron quantitation. AB - A recent study showed that ferritin is a suitable endogenous contrast agent for photoacoustic molecular imaging in cultured mammalian cells. We have therefore tested whether this imaging technique can be used for in vivo quantification of iron in mouse livers. To verify this hypothesis, we used multispectral optoacoustic tomography (MSOT) to image albino CD1 mice before and after experimental iron loading. Postmortem assays showed that the iron treatment caused a 15-fold increase in liver iron and a 40-fold increase in liver ferritin levels, while in vivo longitudinal analysis using MSOT revealed just a 1.6-fold increase in the ferritin/iron photoacoustic signal in the same animals. We conclude that MSOT can monitor changes in ferritin/iron levels in vivo, but its sensitivity is much lower than that of ex vivo iron assays. PMID- 27232594 TI - Widefield imaging of upconverting nanoparticles on epifluorescence microscopes adapted for laser illumination with top-hat profile. AB - We describe a modification of epifluorescence microscopes that allows quantitative widefield imaging of samples labeled by upconverting nanoparticles (UCNP). A top-hat illumination profile on the sample was achieved with a 980-nm laser diode by using tandem microlens arrays, a moving diffuser and a telescope, which adjusts the top-hat area to the field of view. Illumination homogeneity is a critical factor for imaging of UCNP since the intensity of their luminescence typically scales with the second power of the excitation intensity. Our illuminator is combined with the epifluorescence attachment of the microscope, allowing easy switching between observation of UCNP and traditional fluorescent dyes. Illumination profile homogeneity of about 98% was measured for objectives with magnification from 4* to 100*, and the top-hat profile was also obtained with phase contrast objectives. We demonstrate capability of the illuminator by evaluating in vitro uptake of UCNP encapsulated in oleyl-hyaluronan micelles into breast cancer cells. Micelles bearing the targeting peptide were about an order of magnitude more efficient than nontargeted micelles. PMID- 27232596 TI - Effect of neighboring cells on cell stiffness measured by optical tweezers indentation. AB - We report on the modification of mechanical properties of breast cancer cells when they get in contact with other neighboring cells of the same type. Optical tweezers vertical indentation was employed to investigate cell mechanics in isolated and contact conditions, by setting up stiffness as a marker. Two human breast cancer cell lines with different aggressiveness [MCF-7 (luminal breast cancer) and MDA-MB-231 (basal-like breast cancer)] and one normal immortalized breast cell line HBL-100 (normal and myoepithelial) were selected. We found that neighboring cells significantly alter cell stiffness: MDA-MB-231 becomes stiffer when in contact, while HBL-100 and MCF-7 exhibit softer character. Cell stiffness was probed at three cellular subregions: central (above nucleus), intermediate (cytoplasm), and near the leading edge. In an isolated condition, all cells showed a significant regional variation in stiffness: higher at the center and fading toward the leading edge. However, the regional variation becomes statistically insignificant when the cells were in contact with other neighboring cells. The proposed approach will contribute to understand the intriguing temporal sequential alterations in cancer cells during interaction with their surrounding microenvironment. PMID- 27232597 TI - Selective Filter Effect Induced by Cu(2+) Adsorption on the Fluorescence of a GdVO4:Eu Nanoprobe. AB - Human blood contains substantial amounts of metal ions such as Mg(2+), Ca(2+), Fe(2+), Cu(2+), Zn(2+), Cd(2+), Pb(2+), and Al(3+). Most biomedical applications of nanoparticles require understanding the influence of these metal ions because adsorbed metal ions can affect the function of nanoparticles to limit their sensitivity, performance, stability, and/or resolution in applications. In the present work, the adsorption of various metal ions at the surface of GdVO4:Eu nanoparticles was studied to assess their spectral filter effect on the fluorescence of GdVO4:Eu. Due to the negative surface potential, the electrostatic attraction caused an intensive adsorption reaction of GdVO4:Eu nanoparticles with metal cations. Compared to the adsorption of other common metal ions in human blood, the distinct fluorescence quenching of GdVO4:Eu was induced in the presence of Cu(2+) ions. On the basis of the UV-vis absorption spectrum of an aqueous CuCl2 solution and reflectance spectrum of Cu(OH)2, in which the surroundings of Cu(2+) ions are supposedly similar to the hydroxylated surface of GdVO4:Eu nanoparticles, it is proposed that the complementary overlap of the emission band of GdVO4:Eu with the absorption band of Cu(2+) results in the effective filter effect to quench the red emission. Because GdVO4:Eu nanoparticles are attractive candidates for applications as magnetic/fluorescent multimodal nanoprobes, it is important to recognize that the average amount of Cu(2+) ion in human blood is sufficient to interfere with or limit the fluorescence probe function of GdVO4:Eu nanoparticles. PMID- 27232598 TI - Steroid-Responsive Acute Rejection Should Not Be the End Point for Immunosuppressive Trials. PMID- 27232599 TI - Comparative Analysis of Gut Microbiota of Native Tibetan and Han Populations Living at Different Altitudes. AB - The factors driving the composition of gut microbiota are still only partly understood but appear to include environmental, cultural, and genetic factors. In order to obtain more insight into the relative importance of these factors, we analyzed the microbiome composition in subjects of Tibetan or Han descent living at different altitudes. DNA was isolated from stool samples. Using polymerase chain reaction methodology, the 16S rRNA V1-V3 regions were amplified and the sequence information was analyzed by principal coordinates analysis and Lefse analyses. Contrasting the Tibetan and Han populations both living at the 3600 m altitude, we found that the Tibetan microbiome is characterized by a relative abundance of Prevotella whereas the Han stool was enriched in Bacteroides. Comparing the microbiome of Han stool obtained from populations living at different altitudes revealed a more energy efficient flora in samples from those living at higher altitude relative to their lower-altitude counterparts. Comparison of the stool microbiome of Tibetan herders living at 4800 m to rural Tibetans living at 3600 m altitude shows that the former have a flora enriched in butyrate-producing bacteria, possibly in response to the harsher environment that these herders face. Thus, the study shows that both altitude and genetic/cultural background have a significant influence on microbiome composition, and it represents the first attempt to compare stool microbiota of Tibetan and Han populations in relation to altitude. PMID- 27232600 TI - Immune cellular profile of bisphosphonate-related osteonecrosis of the jaw. AB - OBJECTIVES: Characterize the cell profile and immunostaining of proinflammatory markers in an experimental model of bisphosphonate-related osteonecrosis of the jaw (BRONJ). MATERIALS AND METHODS: Male Wistar rats (n = 6-7) were treated chronically with saline solution or zoledronic acid (ZA) at 0.04, 0.20, and 1.00 mg kg(-1) (1.4 * 10(-7) , 6.9 * 10(-6) , and 3.4 * 10(-5) mol kg(-1) ), and subsequently, the first left inferior molar was extracted. Were performed counting of viable and empty osteocyte lacunae, viable and apoptotic osteoclasts, polymorphonuclear neutrophil, mast cells (toluidine blue), and the positive presence cells for CD68, tumor necrosis factor-alpha (TNF-alpha), IL (interleukin)-1beta, inducible nitric oxide synthase (iNOS), nuclear factor-kappa B (NF-kB) and IL-18 binding protein (IL-18 bp). RESULTS: BRONJ was showed in ZA treated with 0.20 and 1.00 mg kg(-1) . There is a dose dependent increase in percentage of empty osteocyte lacunae (P < 0.001) and apoptotic osteoclasts (P < 0.001), counting of total osteoclasts (P = 0.003), polymorphonuclear neutrophil cells (P = 0.009), cytoplasmic-positive cells of CD68 (P < 0.001), TNF-alpha (P = 0.001), IL-1beta (P = 0.001), iNOS (P < 0.001), NF-kB (P = 0.006), and nuclear positive cells of NF-kB (P = 0.011). Consequently, there is no difference in mast cells (P = 0.957), and IL-18 bp immunostaining decreases dose dependently (P = 0.005). CONCLUSIONS: BRONJ is characterized by increases in immunostaining for proinflammatory markers and NF-kB and inversely associated with cells exhibiting IL-18 bp. PMID- 27232601 TI - Promotion of Intestinal Epithelial Cell Turnover by Commensal Bacteria: Role of Short-Chain Fatty Acids. AB - The life span of intestinal epithelial cells (IECs) is short (3-5 days), and its regulation is thought to be important for homeostasis of the intestinal epithelium. We have now investigated the role of commensal bacteria in regulation of IEC turnover in the small intestine. The proliferative activity of IECs in intestinal crypts as well as the migration of these cells along the crypt-villus axis were markedly attenuated both in germ-free mice and in specific pathogen free (SPF) mice treated with a mixture of antibiotics, with antibiotics selective for Gram-positive bacteria being most effective in this regard. Oral administration of chloroform-treated feces of SPF mice to germ-free mice resulted in a marked increase in IEC turnover, suggesting that spore-forming Gram-positive bacteria contribute to this effect. Oral administration of short-chain fatty acids (SCFAs) as bacterial fermentation products also restored the turnover of IECs in antibiotic-treated SPF mice as well as promoted the development of intestinal organoids in vitro. Antibiotic treatment reduced the phosphorylation levels of ERK, ribosomal protein S6, and STAT3 in IECs of SPF mice. Our results thus suggest that Gram-positive commensal bacteria are a major determinant of IEC turnover, and that their stimulatory effect is mediated by SCFAs. PMID- 27232602 TI - Trunk Stability, Trunk Strength and Sport Performance Level in Judo. AB - Although trunk muscle function has been suggested to be a determinant of judo performance, its contribution to high-level performance in this sport has been poorly studied. Therefore, several tests were used to assess the differences in trunk muscle function between 11 international and 14 national level judo practitioners (judokas). Trunk strength and endurance were assessed using isokinetic tests and core stability was assessed using two protocols: 1) sudden loading, to assess trunk responses to unexpected external perturbations; 2) stable and unstable sitting, to assess the participants' ability to control trunk balance. No differences between groups were found for trunk flexor isokinetic strength, trunk responses against lateral and posterior loading and trunk control while sitting. However, international level judokas showed significantly higher trunk extensor isokinetic strength (p <0.05) and lower trunk angular displacement after anterior trunk loading (p <0.05) than national level judokas. Few and low (r < 0.512) significant correlations were found between strength, endurance and stability parameters, which suggests that trunk strength and endurance are not limiting factors for trunk stability in competitive judokas. These results support the importance of trunk extensor strength and trunk stability against forward perturbations in elite judo performance. PMID- 27232603 TI - Correction: Spread of the Invasive Mosquitoes Aedes aegypti and Aedes albopictus in the Black Sea Region Increases Risk of Chikungunya, Dengue, and Zika Outbreaks in Europe. AB - [This corrects the article DOI: 10.1371/journal.pntd.0004664.]. PMID- 27232626 TI - A Single Transcriptome of a Green Toad (Bufo viridis) Yields Candidate Genes for Sex Determination and -Differentiation and Non-Anonymous Population Genetic Markers. AB - Large genome size, including immense repetitive and non-coding fractions, still present challenges for capacity, bioinformatics and thus affordability of whole genome sequencing in most amphibians. Here, we test the performance of a single transcriptome to understand whether it can provide a cost-efficient resource for species with large unknown genomes. Using RNA from six different tissues from a single Palearctic green toad (Bufo viridis) specimen and Hiseq2000, we obtained 22,5 Mio reads and publish >100,000 unigene sequences. To evaluate efficacy and quality, we first use this data to identify green toad specific candidate genes, known from other vertebrates for their role in sex determination and differentiation. Of a list of 37 genes, the transcriptome yielded 32 (87%), many of which providing the first such data for this non-model anuran species. However, for many of these genes, only fragments could be retrieved. In order to allow also applications to population genetics, we further used the transcriptome for the targeted development of 21 non-anonymous microsatellites and tested them in genetic families and backcrosses. Eleven markers were specifically developed to be located on the B. viridis sex chromosomes; for eight markers we can indeed demonstrate sex-specific transmission in genetic families. Depending on phylogenetic distance, several markers, which are sex-linked in green toads, show high cross-amplification success across the anuran phylogeny, involving nine systematic anuran families. Our data support the view that single transcriptome sequencing (based on multiple tissues) provides a reliable genomic resource and cost-efficient method for non-model amphibian species with large genome size and, despite limitations, should be considered as long as genome sequencing remains unaffordable for most species. PMID- 27232629 TI - 'Untreated epilepsy' - A conspiracy of silence? PMID- 27232628 TI - Genetic guidelines for captive breeding and reintroductions of the endangered Black-fronted Piping Guan, Aburria jacutinga (galliformes, cracidae), an Atlantic Forest endemic. AB - The survival of a number of birds rely on captive breeding and reintroduction into the wild, but captive populations are often small and can be exposed to the negative effects of inbreeding and genetic drift. Then, managers are concerned not only with producing as much offspring as possible, but also with the retention of the maximum genetic variability within and between populations. The Black-fronted Piping Guan, Aburria jacutinga, is an endangered cracid endemic to the Atlantic Forest of southeastern South America. Because of its conservation status and functional importance, a captive breeding program started independently, mainly in three aviaries, in the decade of 1980. Although they have supplied animals for reintroductions, genetic variability aspects have never been considered. Here we addressed levels of genetic variability within and between these aviaries. Bayesian clustering analyses revealed two lineages. Inbreeding was not detected, although we found evidences for a recent bottleneck in one of the aviaries. Then, our main management recommendations are: i) reintroducing the species in areas where it has been extinct is more prudent than supplementing natural populations, as it could involve risks of disrupting local adaptive complexes; ii) as far as inbreeding can be avoided, the captive groups should be managed separately to minimize adaptation to captivity; iii) crossbreedings in pre-release generations could improve reintroduction success; and iv) a studbook should be implemented. As populations of Black-fronted Piping Guan from conservation units are progressively declining, these captive genetic repositories may gain importance in a near future. Zoo Biol. 35:313-318, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27232627 TI - Monkey Viperin Restricts Porcine Reproductive and Respiratory Syndrome Virus Replication. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is an important pathogen which causes huge economic damage globally in the swine industry. Current vaccination strategies provide only limited protection against PRRSV infection. Viperin is an interferon (IFN) stimulated protein that inhibits some virus infections via IFN-dependent or IFN-independent pathways. However, the role of viperin in PRRSV infection is not well understood. In this study, we cloned the full-length monkey viperin (mViperin) complementary DNA (cDNA) from IFN-alpha treated African green monkey Marc-145 cells. It was found that the mViperin is up regulated following PRRSV infection in Marc-145 cells along with elevated IRF-1 gene levels. IFN-alpha induced mViperin expression in a dose- and time-dependent manner and strongly inhibits PRRSV replication in Marc-145 cells. Overexpression of mViperin suppresses PRRSV replication by blocking the early steps of PRRSV entry and genome replication and translation but not inhibiting assembly and release. And mViperin co-localized with PRRSV GP5 and N protein, but only interacted with N protein in distinct cytoplasmic loci. Furthermore, it was found that the 13-16 amino acids of mViperin were essential for inhibiting PRRSV replication, by disrupting the distribution of mViperin protein from the granular distribution to a homogeneous distribution in the cytoplasm. These results could be helpful in the future development of novel antiviral therapies against PRRSV infection. PMID- 27232631 TI - Control of Ca2+ Influx and Calmodulin Activation by SK-Channels in Dendritic Spines. AB - The key trigger for Hebbian synaptic plasticity is influx of Ca2+ into postsynaptic dendritic spines. The magnitude of [Ca2+] increase caused by NMDA receptor (NMDAR) and voltage-gated Ca2+ -channel (VGCC) activation is thought to determine both the amplitude and direction of synaptic plasticity by differential activation of Ca2+ -sensitive enzymes such as calmodulin. Ca2+ influx is negatively regulated by Ca2+ -activated K+ channels (SK-channels) which are in turn inhibited by neuromodulators such as acetylcholine. However, the precise mechanisms by which SK-channels control the induction of synaptic plasticity remain unclear. Using a 3-dimensional model of Ca2+ and calmodulin dynamics within an idealised, but biophysically-plausible, dendritic spine, we show that SK-channels regulate calmodulin activation specifically during neuron-firing patterns associated with induction of spike timing-dependent plasticity. SK channel activation and the subsequent reduction in Ca2+ influx through NMDARs and L-type VGCCs results in an order of magnitude decrease in calmodulin (CaM) activation, providing a mechanism for the effective gating of synaptic plasticity induction. This provides a common mechanism for the regulation of synaptic plasticity by neuromodulators. PMID- 27232632 TI - Chemotherapeutic effect of Berberis integerrima hydroalcoholic extract on colon cancer development in the 1,2-dimethyl hydrazine rat model. AB - The aim of this study was to investigate the efficacy of a Berberis integerrima hydroalcoholic extract as a chemotherapeutic agent in colon carcinogenesis in the rat induced by 1,2-dimethyl hydrazine (DMH). Male Wistar rats were divided into five groups: a negative control group without DMH treatment; a control group injected DMH (20 mg/kg b.w); two groups receiving B. integerrima extract (50 and 100 mg/kg b.w), concomitant with injected DMH, as chemotherapeutic groups; a positive control group receiving 5-fluorouracil (5-FU) along with DMH. The effects of the extracts were determined by assessment of hepatic malondialdehyde (MDA), glutathione (GSH), ferric reducing ability of plasma (FRAP), and the activities of hepatic glutathione S-transferase and cytochrome P450 (GST and CYP450). Additionally, colon tissues were assessed for colonic beta-catenin and histopathological analysis. In DMH-treated rats, the extracts partially normalized the levels of FRAP, CYP450, beta-catenin, and GST. Likewise, formation of aberrant crypt foci (ACF) in colon tissue of DMH-treated was reduced by the extracts. Thus, the extracts possess chemotherapeutic activity against colon carcinogenesis. PMID- 27232630 TI - Sex Differences in Serum Markers of Major Depressive Disorder in the Netherlands Study of Depression and Anxiety (NESDA). AB - Women have a consistently higher prevalence of major depressive disorder (MDD) than men. Hypotheses implicating hypothalamic-pituitary -adrenal, -gonadal, and thyroid axes, immune response, genetic factors, and neurotransmitters have emerged to explain this difference. However, more evidence for these hypotheses is needed and new explanations must be explored. Here, we investigated sex differences in MDD markers using multiplex immunoassay measurements of 171 serum molecules in individuals enrolled in the Netherlands Study of Depression and Anxiety (NMDD = 231; Ncontrol = 365). We found 28 sex-dependent markers of MDD, as quantified by a significant interaction between sex and log2-transformed analyte concentration in a logistic regression with diagnosis (MDD/control) as the outcome variable (p<0.05; q<0.30). Among these were a number of male-specific associations between MDD and elevated levels of proteins involved in immune response, including C-reactive protein, trefoil factor 3, cystatin-C, fetuin-A, beta2-microglobulin, CD5L, FASLG receptor, and tumor necrosis factor receptor 2. Furthermore, only male MDD could be classified with an accuracy greater than chance using the measured serum analytes (area under the ROC curve = 0.63). These findings may have consequences for the generalization of inflammatory hypotheses of depression to males and females and have important implications for the development of diagnostic biomarker tests for MDD. More studies are needed to validate these results, investigate a broader range of biological pathways, and integrate this data with brain imaging, genetic, and other relevant data. PMID- 27232633 TI - Regulation of glycosylphosphatidylinositol-anchored proteins and GPI phospholipase D in a c-Myc transgenic mouse model of hepatocellular carcinoma and human HCC. AB - Recent research implicated glycosylphosphatidylinositol-anchored proteins (GPI AP) and GPI-specific phospholipase D (GPI-PLD) in the pathogenesis of fatty liver disease and hepatocellular carcinoma (HCC). Given that c-Myc is frequently amplified in HCC, we investigated their regulation in a c-Myc transgenic disease model of liver cancer and HCC patient samples. Whole genome scans defined 54 significantly regulated genes coding for GPI-AP of which 29 and 14 were repressed in expression in transgenic tumors and steatotic human hepatocyte cultures, respectively, to influence lipid-mediated signal transduction, extracellular matrix and immunity pathways. Analysis of gene specific promoter revealed >95% to carry c-Myc binding sites thus establishing a link between c-Myc activity and transcriptional response. Alike, serum GPI-PLD activity was increased 4-fold in transgenic mice; however its tissue activity was reduced by 70%. The associated repression of the serine/threonine phosphatase 2A (PP2A), i.e. a key player of c Myc proteolysis, indicates co-ordinate responses aimed at impairing tissue GPI PLD anti-proliferative activities. Translational research identified >4-fold increased GPI-PLD serum protein expression though enzyme activities were repressed by 60% in NASH and HCC patients. Taken collectively, c-Myc influences GPI-AP signaling transcriptionally and posttranslational and represses GPI-AP anti-proliferative signaling in tumors. The findings broaden the perspective of molecular targeted therapies and disease monitoring. PMID- 27232636 TI - Improved Contacts to MoS2 Transistors by Ultra-High Vacuum Metal Deposition. AB - The scaling of transistors to sub-10 nm dimensions is strongly limited by their contact resistance (RC). Here we present a systematic study of scaling MoS2 devices and contacts with varying electrode metals and controlled deposition conditions, over a wide range of temperatures (80 to 500 K), carrier densities (10(12) to 10(13) cm(-2)), and contact dimensions (20 to 500 nm). We uncover that Au deposited in ultra-high vacuum (~10(-9) Torr) yields three times lower RC than under normal conditions, reaching 740 Omega.MUm and specific contact resistivity 3 * 10(-7) Omega.cm(2), stable for over four months. Modeling reveals separate RC contributions from the Schottky barrier and the series access resistance, providing key insights on how to further improve scaling of MoS2 contacts and transistor dimensions. The contact transfer length is ~35 nm at 300 K, which is verified experimentally using devices with 20 nm contacts and 70 nm contact pitch (CP), equivalent to the "14 nm" technology node. PMID- 27232635 TI - Multi-locus Test and Correction for Confounding Effects in Genome-Wide Association Studies. AB - Genome-wide association studies (GWAS) examine a large number of genetic variants, e. g., single nucleotide polymorphisms (SNP), and associate them with a disease of interest. Traditional statistical methods for GWASs can produce spurious associations, due to limited information from individual SNPs and confounding effects. This paper develops two statistical methods to enhance data analysis of GWASs. The first is a multiple-SNP association test, which is a weighted chi-square test derived for big contingency tables. The test assesses combinatorial effects of multiple SNPs and improves conventional methods of single SNP analysis. The second is a method that corrects for confounding effects, which may come from population stratification as well as other ambiguous (unknown) factors. The proposed method identifies a latent confounding factor, using a profile of whole genome SNPs, and eliminates confounding effects through matching or stratified statistical analysis. Simulations and a GWAS of rheumatoid arthritis demonstrate that the proposed methods dramatically remove the number of significant tests, or false positives, and outperforms other available methods. PMID- 27232637 TI - The impact of structure dimensions on initial bacterial adhesion. AB - Substrate topography can have profound effects on initial bacterial adhesion during biofilm formation. We applied Staphylococcus epidermidis and Escherichia coli cells onto periodically structured substrates with different structure dimensions, structure types and wetting properties. We found a strong dependence of cell retention on the structure dimensions of the applied substrates. Periodicities in the range of the cell size increased, whereas smaller periodicities decreased cell retention, independent of contact time (minutes to hours) and hydrophobicity. These novel insights on the role of surface topography on bacterial retention might facilitate the development of non-fouling surfaces in the future. PMID- 27232634 TI - Annexin A1: shifting the balance towards resolution and repair. AB - Epithelial barriers play an important role in regulating mucosal homeostasis. Upon injury, the epithelium and immune cells orchestrate repair mechanisms that re-establish homeostasis. This process is highly regulated by protein and lipid mediators such as Annexin A1 (ANXA1). In this review, we focus on the pro-repair properties of ANXA1. PMID- 27232638 TI - Aldosterone-producing Adenoma in Primary Aldosteronism: CT-guided Radiofrequency Ablation-Long-term Results and Recurrence Rate. AB - Purpose To evaluate the long-term biochemical, clinical, and recurrence outcomes of radiofrequency (RF) ablation in treating primary aldosteronism due to aldosterone-producing adenoma (APA). Materials and Methods Institutional review board approval and written informed consent were obtained. The use of computed tomographically (CT) guided percutaneous RF ablation was evaluated in 36 patients (19 men; mean age +/- standard deviation, 52.1 years +/- 10.4) with APA (17 right and 19 left side; mean size, 15.5 mm +/- 5.0). Primary aldosteronism was confirmed by using the oral sodium-loading test. After RF ablation, CT images, aldosterone-to-renin ratio (ARR), serum potassium level, and blood pressure control were assessed at 3 months and at the latest follow-up examination. Long term treatment success was defined as normalization of ARR at the latest assessment. Comparison of ARR, potassium, and blood pressure levels before and after RF ablation was performed by using the Wilcoxon signed-rank test. Results Primary technical success was achieved in 33 (92%) patients who underwent a single RF ablation session. Secondary technical success was achieved in three (8%) patients who required a second RF ablation. At 3-month follow-up, primary aldosteronism was resolved in 33 (92%) patients, with a starting median ARR of 8583 pmol/L per ug/(L . h) that normalized to 97 pmol/L per ug/(L . h) (P < .01). Mean serum potassium levels increased from 2.6 mmol/L +/- 0.4 to 4.0 mmol/L +/- 0.3 (P = .01). At long-term follow-up (mean, 6.2 years +/- 2.5), treatment success was maintained in 33 patients (92%), all of whom had ARRs in the normal range (P < .01). The long-term recurrence rate was 0%. Hypokalemia was resolved in all patients (2.6 mmol/L +/- 0.4 to 4.1 mmol/L +/- 0.3, P = .01). Hypertension was resolved in 13 (36%) patients, and its control was improved in seven (19%) patients. One (3%) patient had major complications and six (17%) had minor complications. Conclusion CT-guided RF ablation is an effective treatment for APA, with high sustainable long-term treatment success. It may serve as a justifiable treatment alternative to surgery and medical therapy for APA. (c) RSNA, 2016. PMID- 27232639 TI - Penetrating Colorectal Injuries: Diagnostic Performance of Multidetector CT with Trajectography. AB - Purpose To determine the diagnostic performance of multidetector computed tomography (CT) with trajectography for penetrating colorectal injuries. Materials and Methods This institutional review board-approved and HIPAA compliant study was a 6-year blinded retrospective review by two independent readers of 182 consecutive patients who preoperatively underwent 40- or 64-row multidetector CT for penetrating torso trauma below the diaphragm and had surgically confirmed findings. Colorectal perforation was present in 42 patients. Trajectory analysis with postprocessing software was used for all studies. Additional signs evaluated were rectal contrast agent leak, collections of extruded fecal material, mural defect, wall thickening, abnormal enhancement, free fluid or stranding, and free air. The quality of the colorectal contrast agent administration was recorded. Sensitivity, specificity, predictive values, areas under the receiver operating characteristic curves (AUCs), and Cohen kappa were determined. Results In patients with rectal contrast agent administration (n = 151), AUCs were 0.90-0.91, which indicated excellent accuracy. Trajectory was sensitive (88%-91%). For single wounds (n = 104), sensitivity of trajectory was 96% for both readers, but was only 80% for multiple wounds (n = 47). Contrast agent leak was highly specific (96%-98%), but insensitive (42%-46%). Improved diagnostic performance was observed in patients with poor colonic distension or opacification. Accuracy remained high (AUC, 0.86-0.99) in the group without rectal contrast agent administration (n = 31). Conclusion Trajectory had excellent sensitivity, while rectal contrast agent leak was specific but insensitive. Sensitivity of trajectory was lower for multiple wounds. Accuracy remained high in patients without rectal contrast agent administration. (c) RSNA, 2016. PMID- 27232640 TI - Perimesencephalic Hemorrhage: Yield of Single versus Multiple DSA Examinations-A Single-Center Study and Meta-Analysis. AB - Purpose To quantify the rate of detection of aneurysms at follow-up digital subtraction angiography (DSA) after initial DSA with results negative for aneurysms in subjects with perimesencephalic (PM) nonaneurysmal subarachnoid hemorrhage. Materials and Methods This single-center retrospective study and meta analysis was approved by the institutional review board. At a single institution from 2000 to 2013, 252 consecutive patients with subarachnoid hemorrhage at computed tomography (CT) and two DSA examinations negative for aneurysm within 10 days were evaluated for inclusion in the study, and 131 met CT criteria for PM nonaneurysmal subarachnoid hemorrhage (53 women; mean age, 53 years [range, 33-88 years]). DS angiographic reports were reviewed for causative abnormalities. Three reviewers searched MEDLINE and electronic databases for studies that reported detection of aneurysm in subjects with PM hemorrhage who had undergone multiple DSA examinations. Main inclusion criteria were PM hemorrhage at CT per van Gijn classification, head CT performed within 72 hours of symptom onset, initial DS angiographic results negative for aneurysm, and two DSA examinations within 10 days. Studies with fewer than 25 subjects were excluded. Methodology was assessed by using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The summary rate of aneurysm detection for subsequent DSA was calculated by using a fixed-effects model. Results Six studies with 298 subjects and a single-institution study with 131 subjects were included. No aneurysms were seen at follow-up DSA in the single-center study (0.0%). Three aneurysms were detected at follow-up DSA in three of six studies from the literature (one of 29 [3.4%], one of 65 [1.5%], and one of 34 [2.9%] patients). Two occurred in cases that likely preceded the use of the current DSA technique. The summary aneurysm detection rate at subsequent DSA was 1.6% (95% confidence interval: 0.7%, 3.8%; range of individual study detection rate: 0.0%-3.4%). Conclusion In patients with PM nonaneurysmal subarachnoid hemorrhage and initial DSA negative for aneurysms, the yield of follow-up DSA for detection of causative aneurysms is very low. (c) RSNA, 2016 Online supplemental material is available for this article. PMID- 27232641 TI - Total Knee Arthroplasty: Diagnostic Accuracy of Patterns of Synovitis at MR Imaging. AB - Purpose To determine the diagnostic accuracy of magnetic resonance (MR) imaging for differentiating synovial patterns in patients with total knee arthroplasty (TKA), whether diagnostic accuracy differs in index versus revision TKA, and interobserver and intraobserver reliability for assessment of synovial patterns at MR imaging. Materials and Methods This retrospective cross-sectional study included 108 consecutive patients with TKAs who underwent MR imaging within 1 year prior to revision surgery from 2012 to 2014. Institutional review board approval was obtained, with waiver of the need to obtain informed consent. MR images were reviewed, and cases were qualitatively categorized by the appearance of the synovium as one of the following: frondlike and hypertrophied (particle induced synovitis), lamellated and hyperintense (infection), and a homogeneous effusion with the signal intensity of fluid (nonspecific synovitis). The MR imaging appearance was compared with surgical and microbiology reports as the reference standard to determine the sensitivity, specificity, and positive and negative predictive values for the index TKA and revision TKA cohorts. Results For all patients combined, MR imaging had 0.907-0.930 sensitivity and 0.723-0.738 specificity for a surgical diagnosis of complications related to polyethylene wear (including osteolysis and loosening); 0.652-0.783 sensitivity and 0.976 0.988 specificity for infection; and 0.643-0.667 sensitivity and 0.894-0.939 specificity for stiffness, instability, and nonspecific pain. Diagnostic accuracy was higher in the index TKA cohort than in the revision TKA cohort. Interobserver and intraobserver reliabilities were almost perfect (kappa = 0.82 and kappa = 0.83, respectively). Conclusion MR imaging can help distinguish qualitative differences in the appearance of the synovium in TKA between particle-induced synovitis, infection, and nonspecific synovitis, with almost perfect interobserver and intraobserver reliability. Diagnostic accuracy is higher for index TKA than for revision TKA. (c) RSNA, 2016. PMID- 27232642 TI - New Insights on the Mechanism of Cyclization in Chromophore Maturation of Wild Type Green Fluorescence Protein: A Computational Study. AB - Cyclization is the first step in the chromophore maturation process of the green fluorescent protein (GFP). In our previous paper [J. Phys. Chem. B 2012, 116, 1426-1436], the results of molecular dynamics simulation suggested the possibility that the amide nitrogen atom of Gly67 attacks the carbonyl carbon of Ser65 directly to complete the cyclization process (one-step mechanism). In this paper, density functional theory (DFT) and quantum mechanical/molecular mechanical (QM/MM) calculations were undertaken to study this step reaction in detail. Three cluster model systems (model A, model B, and model C) and large protein system were set up to investigate the cyclization process. Our results indicate that the one-step mechanism only exists in the two minimum models. However, in model C and the large protein system, the cyclization mechanism involves two steps: the first step is proton of Gly67 amide nitrogen transferring to carbonyl oxygen of Ser65, generating protonated amide, which is stabilized by a hydrogen bond interaction with a crystallographic water molecule, and the second step is Gly67 amide nitrogen attacking the carbonyl carbon of Ser65. Arg96 plays an important role in promoting the cyclization. The energy of cyclized product relative to reactant is about 10.0 kcal/mol endothermic, which is in line with the experimental results. PMID- 27232643 TI - Prospective study of the pattern of lymphatic metastasis in relation to the submandibular gland in patients with carcinoma of the oral cavity. AB - BACKGROUND: The submandibular gland is responsible for 70% to 90% of unstimulated saliva production. Its excision causes a decrease in basal salivary flow resulting in increased symptoms of subjective xerostomia and decreased quality of life. In this study, we have tried to assess the pattern of nodal metastasis in relation to the submandibular gland. With this study, we have tried to find out whether submandibular gland preservation is a viable option in patients with carcinoma of the oral cavity. METHODS: This was a prospective study conducted in a tertiary care cancer center. The fibrofatty tissue surrounding the submandibular gland was divided into 6 parts depending upon its location with the submandibular gland. All these 6 parts along with the submandibular gland were separately sent for histopathological analysis. Metastasis pattern in level Ib region was noted. RESULT: The study included 137 patients with carcinoma of the oral cavity who underwent neck dissections. Eighty-five patients had clinic radiologically N0 neck, 52 patients had cN+ (clinically node positive) neck. Level Ib was involved in 8.2% of the cases with cN0 (clinically node negative neck). In patients with cN+ neck, level Ib metastasis was seen in 40% of the cases. Metastasis in N0 necks in the area deep to the submandibular gland was seen in only 1 case (9% of all pathologically node-positive patients) with cN0 neck. This was the only case in which submandibular gland mobilization would have been required to take out the metastatic node. Even in cases with N+ neck, deep metastasis was seen in 4 cases only (14.8%). None of them had a primary tumor in the tongue. Therefore, there is a possibility of preserving the submandibular gland in cases of carcinoma of the tongue. CONCLUSION: Involvement of level Ib in early tongue cancers is not very common and direct metastases to the submandibular glands are rare. Even when metastasis is present in level Ib, it can be excised without affecting the submandibular gland. In early tongue lesions, submandibular gland mobilization for dissection at level Ib is not required as no metastases deep to the submandibular glands were seen in these patients. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: 1708-1716, 2016. PMID- 27232645 TI - Growth against entropy in bacterial metabolism: the phenotypic trade-off behind empirical growth rate distributions in E. coli. AB - The solution space of genome-scale models of cellular metabolism provides a map between physically viable flux configurations and cellular metabolic phenotypes described, at the most basic level, by the corresponding growth rates. By sampling the solution space of E. coli's metabolic network, we show that empirical growth rate distributions recently obtained in experiments at single cell resolution can be explained in terms of a trade-off between the higher fitness of fast-growing phenotypes and the higher entropy of slow-growing ones. Based on this, we propose a minimal model for the evolution of a large bacterial population that captures this trade-off. The scaling relationships observed in experiments encode, in such frameworks, for the same distance from the maximum achievable growth rate, the same degree of growth rate maximization, and/or the same rate of phenotypic change. Being grounded on genome-scale metabolic network reconstructions, these results allow for multiple implications and extensions in spite of the underlying conceptual simplicity. PMID- 27232646 TI - What Is Pregaming and How Prevalent Is It Among U.S. College Students? An Introduction to the Special Issue on Pregaming. AB - Pregaming (or prepartying) can be defined as drinking before going to an event or gathering. The heavy consumption of alcohol and resulting negative consequences that are associated with pregaming have prompted scholars to investigate this risky drinking practice. Indeed, research on college pregaming has grown considerably within the past decade, with over 80 articles published since the seminal empirical studies on pregaming were published in 2007. This special issue in Substance Use & Misuse seeks to address a number of topics on pregaming among U.S. college students that are not well understood. The articles in this special issue explore pregaming behaviors among particular subgroups of students (i.e., college freshmen; postgraduates) as well as the following topics as they pertain to pregaming: exposure to trauma, emotion regulation, social norms, pregaming motives, protective behavioral strategies, and intervention efforts. This prologue to the special issue will discuss key points regarding the definition of pregaming, present an overview of the prevalence rates of pregaming among U.S. college students within the past decade, and introduce articles that advance the understanding of factors that contribute to the high-risk drinking context of pregaming. PMID- 27232647 TI - Using the Solid Research Base on Pregaming to Begin Intervention Development: An Epilogue to the Special Issue on Pregaming. AB - The pregaming research to date, up to and including the innovative studies included in this special issue, has centered on defining the behavior, learning which students may be most at-risk for pregaming, exploring which contexts may be most risky for pregaming, and quantifying the function of pregaming so that individual-level programs can be developed to target the risky practice. Although there is room for continuing to expand and refine our understanding of pregaming, much of the formative work has been conducted-primarily by the researchers highlighted in this special issue. Now it is time to use the understanding we have of this risky behavior to develop and empirically test programs specifically directed toward reducing or eliminating the behavior, not just at the individual level, but by targeting the social, cultural, economic, environmental, and policy level factors that sustain the behavior in the population. This may include targeting the behavior directly through use of techniques that are shown to be effective for young adult behavior change, but this may also require broadening beyond the psychological literature and utilizing expertise from other domains to affect behavior change. PMID- 27232648 TI - Corrigendum. PMID- 27232650 TI - Methylphenidate in Pregnancy: A Multicenter, Prospective, Comparative, Observational Study. AB - INTRODUCTION: Methylphenidate is a central nervous system stimulant medicinally used in the treatment of attention-deficit disorder with or without hyperactivity (ADD/ADHD). Data on its use in human pregnancy are limited. The primary objective of the study was to evaluate the risk of major congenital anomalies after pregnancy exposure to methylphenidate for medical indications. METHODS: In a prospective, comparative, multicenter observational study performed in 4 participating Teratology Information Services (in Jerusalem, Berlin, Newcastle upon Tyne, and Toronto) between 1996 and 2013, methylphenidate-exposed pregnancies were compared with pregnancies counseled for nonteratogenic exposure (NTE) after matching by maternal age, gestational age, and year at initial contact. RESULTS: 382 methylphenidate-exposed pregnancies (89.5% in the first trimester) were followed up. The overall rate of major congenital anomalies was similar between the groups (10/309 = 3.2% [methylphenidate] vs 13/358 = 3.6% [NTE], P = .780). The rates of major congenital anomalies (6/247 = 2.4% [methylphenidate] vs 12/358 = 3.4% [NTE], P = .511) and cardiovascular anomalies (2/247 = 0.8% [methylphenidate] vs 3/358 = 0.8% [NTE], P = .970) were also similar after exclusion of genetic or cytogenetic anomalies and limiting methylphenidate exposure to the period of organogenesis (weeks 4-13 after the last menstrual period). There was a higher rate of miscarriages and elective terminations of pregnancy in the methylphenidate group. Significant predictors for the miscarriages using Cox proportional hazards model were methylphenidate exposure (adjusted hazard ratio [HR] = 1.98; 95% CI, 1.23-3.20; P = .005) and past miscarriage (adjusted HR = 1.35; 95% CI, 1.18-1.55; P < .001). CONCLUSIONS: The present study suggests that methylphenidate does not seem to increase the risk for major malformations. Further studies are required to establish its pregnancy safety and its possible association with miscarriages. PMID- 27232651 TI - The McLean-Harvard First-Episode Project: Early Course in 114 Cases of First Episode Nonaffective Psychoses. AB - BACKGROUND: Early course in contemporary, clinically treated, nonaffective psychotic disorders other than schizophrenia remains incompletely defined. METHODS: We prospectively, repeatedly, and systematically assessed 114 patients hospitalized for a first episode of DSM-IV-TR nonaffective psychotic illness for >= 2 years (1989-1996) using structured (Structured Clinical Interview for DSM III-R, Patient Edition; Clinical Global Impressions scale; Scale for the Assessment of Negative Symptoms; Scale for the Assessment of Positive Symptoms; and the expanded version of the Brief Psychiatric Rating Scale) and unstructured (best-estimate procedure, life charting) naturalistic follow-up procedures and survival analysis. RESULTS: Duration of untreated psychosis (22 +/- 38 months) was longest with schizophrenia. Within 2 years, syndromal remission sustained for >= 8 weeks (recovery) was attained by 75 subjects (65.8%); median latency to syndromal recovery was 9.4 (95% CI, 5.7-13.3) weeks and was shorter with cycloid features, initial diagnosis of brief psychosis or schizophreniform disorder, and shorter initial hospitalization. Functional recovery within 2 years was achieved by 28 of 68 subjects (41.2%), more often without initial mood-psychomotor instability or homicidal ideation. New episodes occurred in 52 of 114 subjects (45.6%) and were more likely with less affective flattening, younger age, and white race. Median time to new episodes (43.7 [27.9-70.6] weeks) was earlier with initial first-rank auditory hallucinations, substance abuse, and functional nonrecovery. Diagnosis changed to other nonaffective, schizoaffective, or affective disorders within 2 years in 62 of 108 cases (57.4%). CONCLUSIONS: Three quarters of patients presenting in first lifetime, nonaffective psychotic episodes achieved recovery within 2 years, but only 41% returned to baseline functioning, and nearly half experienced new episodes. Patients with schizophrenia had the longest duration of untreated psychosis. A majority changed diagnosis, indicating instability of some DSM psychotic-disorder diagnoses. PMID- 27232652 TI - Experimental and Theoretical Electron Density Determination for Two Norbornene Derivatives: Topological Analysis Provides Insights on Reactivity. AB - The electron density distribution of two substituted norbornene derivatives (cis 5-norbornene-endo-2,3-dicarboxylic anhydride (1) and 7-oxabicylo[2.2.1]hept-5-ene exo-2,3-dicarboxylic anhydride (2) has been determined from low-temperature (20 K) X-ray diffraction data and from DFT calculations with periodic boundary conditions. Topological analysis of the electron density is discussed with respect to exo-selective additions, the partial retro-Diels-Alder (rDA) character of the ground state, and intermolecular interaction energies. PMID- 27232653 TI - Cell-SELEX-based selection and characterization of a G-quadruplex DNA aptamer against mouse dendritic cells. AB - Targeting of dendritic cells (DCs) by aptamers increases antigen capture and presentation to the immune system. Our aim was to produce aptamers against DC molecules using the cell-SELEX procedure. For this purpose, 18 rounds of cell SELEX were performed on mouse macrophage J774A.1 and CT26 as target and control cells, respectively. The selected aptamers were truncated and their binding to mouse macrophages, and immature and mature DCs analyzed. Two macrophage-specific aptamers, Seq6 and Seq7, were identified. A truncated form of Seq7, Seq7-4, 33 nucleotides in length and containing the G-quadruplex, bound macrophages and immature DCs with KD values in the nanomolar range. We anticipate that Seq7-4 has potential as a therapeutic tool in targeting of mouse macrophages and immature DCs to efficiently improve different immunotherapy approaches. PMID- 27232654 TI - miR-709 modulates LPS-induced inflammatory response through targeting GSK-3beta. AB - MicroRNAs (miRNAs) are endogenous small non-coding RNAs which modulate gene expression at the post-transcriptional level by either translational inhibition or mRNA degradation. MicroRNAs play important roles in both innate and adaptive immune response, including TLR-triggered immune response. In this study, we found that the expression of miR-709 was up-regulated in primary macrophage and RAW264.7 cells during the stimulation of LPS. Overexpression of miR-709 in RAW264.7 cells led to reduced production and gene expression of inflammatory cytokines (IL-6, TNF-alpha, IL-1beta) during activation by LPS, whereas knockdown of miR-709 had completely opposite effects. We used bioinformatics and experimental techniques to demonstrate that GSK-3beta is a direct target of miR 709. miR-709 mimics decreased GSK-3beta protein but not mRNA level. We also found that miR-709 regulated the LPS-induced inflammatory response by targeting GSK 3beta and elevating beta-catenin. In conclusion, our data revealed a novel role for miR-709 in regulation of inflammatory response by targeting GSK-3beta. PMID- 27232655 TI - Smoking Prevention in China: A Content Analysis of an Anti-Smoking Social Media Campaign. AB - The China Tobacco Control Media Campaign on Sina Weibo is novel in the context of smoking prevention and cessation in China and has not to date been evaluated. This study draws on health behavior theories and dialogic theory in public relations to analyze microblog campaign postings and their relationships with the outcome of online audience engagement. Microblog postings from May 2011 to January 2015 were content analyzed, showing that the most common persuasive content characteristic was perceived risk, followed by subjective norms and self efficacy. Perceived risk and self-efficacy postings positively influenced online audience engagement, whereas subjective norm postings was a nonsignificant predictor. Postings were more likely to share information than aim to interact with audience members. However, both information sharing and audience interaction postings were positive predictors of online audience engagement. There was also evidence of main and interactive effects of message originality on online audience engagement. The current study has, to the best of our knowledge, broken new ground in 2 regards: (a) using health behavior theories as a basis for analyzing the content of an anti-smoking social media campaign and (b) examining the content of an anti-smoking media campaign of any type in China. PMID- 27232656 TI - Deuterium-Labeled Precursor Feeding Reveals a New pABA-Containing Meroterpenoid from the Mango Pathogen Xanthomonas citri pv. mangiferaeindicae. AB - A new para-aminobenzoic-acid-containing natural product from the mango pathogenic organism Xanthomonas citri pv. mangiferaeindicae is described. By means of stable isotope precursor feeding combined with nontargeted LC-MS/MS, the generated spectra were clustered and visualized in a molecular network. This led to the identification of a new member of the meroterpenoids, termed xanthomonic acid, which is composed of an isoprenylated para-aminobenzoic acid. In vitro cytotoxicity assays demonstrated activity of xanthomonic acid against several human cancer cell lines by induction of autophagy. PMID- 27232657 TI - Determinants for gallstone formation - a new data cohort study and a systematic review with meta-analysis. AB - OBJECTIVE: Only few determinants of gallstone formation have been identified in cohort studies. The aim was to identify further determinants for gallstones in a Danish cohort and to perform a meta-analysis of results from existing cohorts. MATERIAL AND METHODS: Data from a cohort study was used. Gallstone incidence was assessed through repeated ultrasound examinations. Body mass index (BMI), blood pressure, self-rated health, lifestyle variables, blood lipids, and use of female sex hormones were measured at the baseline examination. Statistical analyses included logistic regression. Based on a prospective protocol, a systematic review of the literature was performed identifying all articles dealing with determinants of incident gallstones. Meta-analyses of comparable determinants were performed through fixed effect models. RESULTS: Participants with no gallstones at baseline and with at least one re-examination were followed-up completely (mean 11.6 years, N = 2848). The overall cumulative incidence of gallstones was 0.60% per year. Independent positive determinants for incident gallstones were age, female sex, non-high density lipoprotein (non-HDL) cholesterol, and gallbladder polyps. In addition, BMI was positively associated in men. The systematic review additionally identified associations for comorbidities, parity, and dietary factors. Meta-analysis confirmed the significant associations for incident gallstones and age, female sex, BMI, and non-HDL cholesterol. No significant associations were found for blood pressure, smoking, alcohol consumption, HDL cholesterol, or triglycerides in meta-analyses. CONCLUSIONS: Age, female sex, BMI, non-HDL cholesterol, and polyps are independent determinants for gallstone formation. Incident gallstones and the metabolic syndrome share common risk factors. More studies are needed for further exploration. PMID- 27232658 TI - Self-Assembled Nanostructures Based on Activatable Red Fluorescent Dye for Site Specific Protein Probing and Conformational Transition Detection. AB - Smart and versatile nanostructures have demonstrated their effectiveness for biomolecule analysis and show great potential in digging insights into the structural/functional relationships. Herein, a nanoscale molecular self-assembly was constructed for probing the site-specific recognition and conformational changes of human serum albumin (HSA) with tunable size and emission. A tetraphenylethylene derivative TPE-red-COOH was used as the building block for tailoring fluorescence-silent nanoparticles. The highly specific and sensitive response to HSA was witnessed by the fast turn-on of the red fluorescence and simultaneous disassembly of the nanostructures, whereas various endogenous biomolecules cannot induce such response. The mechanism investigation indicates that the combination of multiple noncovalent interactions is the driving force for disassembling and trapping TPE-red-COOH into HSA. The resultant restriction of intramolecular rotation of TPE-red-COOH in the hydrophobic cavity of HSA induces the significant red emission. By using the fluorescence activatable nanosensor as the structural indicator, the stepwise conformational transitions of HSA during denaturing and the partial refolding of subdomain IIA of HSA were facilely visualized. Benefiting from its activatable signaling, sensitivity, and simplicity, such molecular assembly provides a kind of soft nanomaterial for site specific biomolecule probing and conformational transition detection concerning their structure, function, and biomedical characteristics. PMID- 27232659 TI - Rifamycin Biosynthetic Congeners: Isolation and Total Synthesis of Rifsaliniketal and Total Synthesis of Salinisporamycin and Saliniketals A and B. AB - We describe the isolation, structure elucidation, and total synthesis of the novel marine natural product rifsaliniketal and the total synthesis of the structurally related variants salinisporamycin and saliniketals A and B. Rifsaliniketal was previously proposed, but not observed, as a diverted metabolite from a biosynthetic precursor to rifamycin S. Decarboxylation of rifamycin provides salinisporamycin, which upon truncation with loss of the naphthoquinone ring leads to saliniketals. Our synthetic strategy hinged upon a Pt(II)-catalyzed cycloisomerization of an alkynediol to set the dioxabicyclo[3.2.1]octane ring system and a fragmentation of an intermediate dihydropyranone to forge a stereochemically defined (E,Z)-dienamide unit. Multiple routes were explored to assemble fragments with high stereocontrol, an exercise that provided additional insights into acyclic stereocontrol during stereochemically complex fragment-assembly processes. The resulting 11-14 step synthesis of saliniketals then enabled us to explore strategies for the synthesis and coupling of highly substituted naphthoquinones or the corresponding naphthalene fragments. Whereas direct coupling with naphthoquinone fragments proved unsuccessful, both amidation and C-N bond formation tactics with the more electron-rich naphthalene congeners provided an efficient means to complete the first total synthesis of rifsaliniketal and salinisporamycin. PMID- 27232660 TI - Update on pulmonary arterial hypertension pharmacotherapy. AB - Pulmonary artery hypertension (PAH) refers to several subgroups of disease in which the mean pulmonary artery pressure (mPAP) is elevated to more than 25 mm Hg, pulmonary artery wedge pressure (PAWP) <= 15 mmHg, and an elevated pulmonary vascular resistance (PVR) > 3 Wood units as confirmed by right heart catheterization. The prevalence and geographic distribution of PAH vary depending on the type and etiology of the disease. Despite enormous efforts in the research and development of therapeutic agents in the last twenty years, the disease remains relatively incurable and the overall prognosis remains guarded. Median survival for an untreated patient is 2.8 years. In the last three decades, there have been dramatic advances in understanding the molecular mechanisms and signaling pathways involved in the disease, resulting in emerging new treatment strategies. In the following pages, we will review currently approved treatments for PAH, as well as a new generation of investigational drugs. PMID- 27232661 TI - Elucidation of the Teixobactin Pharmacophore. AB - This paper elucidates the teixobactin pharmacophore by comparing the arginine analogue of teixobactin Arg10-teixobactin to seven homologues with varying structure and stereochemistry. The roles of the guanidinium group at position 10, the stereochemistry of the macrolactone ring, and the "tail" comprising residues 1-5 are investigated. The guanidinium group is not necessary for activity; Lys10 teixobactin is more active than Arg10-teixobactin against Gram-positive bacteria in minimum inhibitory concentration (MIC) assays. The relative stereochemistry of the macrolactone ring is important. Diastereomer l-Thr8,Arg10-teixobactin is inactive, and diastereomer d-allo-Ile11,Arg10-teixobactin is less active. The macrolactone ring is critical; seco-Arg10-teixobactin is inactive. The absolute stereochemistry is not important; the enantiomer ent-Arg10-teixobactin is comparable in activity. The hydrophobic N-terminal tail is important. Truncation of residues 1-5 results in loss of activity, and replacement of residues 1-5 with a dodecanoyl group partially restores activity. These findings pave the way for developing simpler homologues of teixobactin with enhanced pharmacological properties. PMID- 27232649 TI - Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients. AB - BACKGROUND: Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown. METHODS: Patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10+/-4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10+/-4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days. We performed sequential analyses in three prespecified, progressively inclusive cohorts: patients with an elevated d dimer level (cohort 1), patients with an elevated d-dimer level or an age of at least 75 years (cohort 2), and all the enrolled patients (overall population cohort). The statistical analysis plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses would be considered exploratory. The primary efficacy outcome was a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism. The principal safety outcome was major bleeding. RESULTS: A total of 7513 patients underwent randomization. In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P=0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P=0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P=0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P=0.55). CONCLUSIONS: Among acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts. (Funded by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583218.). PMID- 27232662 TI - Decision-tree algorithm for optimized hematopoietic progenitor cell-based predictions in peripheral blood stem cell mobilization. AB - BACKGROUND: Enumerating hematopoietic progenitor cells (HPCs) by using an automated hematology analyzer is a rapid, inexpensive, and simple method for predicting a successful harvest compared with enumerating circulating CD34+ cells. However, the optimal HPC cutoff count and the indicating factors to be considered for improved predicting have not yet been determined. STUDY DESIGN AND METHODS: Between 2007 and 2012, a total of 189 consecutive patients who proceeded to peripheral blood stem cell (PBSC) harvesting were retrospectively recruited. Baseline characteristics were analyzed to identify the risk factors for a failed harvest, which were defined as less than 2 * 10(6) CD34+ cells/kg. Variables identified by multivariate logistic regression and correlation analysis for predicting a successful harvest were subjected to classification and regression tree (CART) analysis. RESULTS: PBSCs were successfully harvested in 154 (81.5%) patients. An age of at least 60 years, a diagnosis of a solid tumor, at least five prior chemotherapy cycles, prior radiotherapy, and mobilization with granulocyte-colony-stimulating factor alone or high-dose cyclophosphamide were independent baseline predictors of poor mobilization. In CART analysis, patients with zero to two host risk factors and either higher HPC (>=28 * 10(6) /L) or mononuclear cell (MNC; >=3.5 * 10(9) /L) counts were categorized as good mobilizers and their harvest success rate was 92.3%. By contrast, 30.3% of harvests were adequate in the patients with three to five host risk factors and lower HPC and MNC counts. CONCLUSION: A CART algorithm incorporating host predictors and HPC and MNC counts improves predictions in a successful harvest and might reduce the necessity of monitoring peripheral CD34+ cells. PMID- 27232663 TI - Dissecting the Binding between Glutamine Synthetase and Its Two Natively Unfolded Protein Inhibitors. AB - Ammonium is incorporated into carbon skeletons by the sequential action of glutamine synthetase (GS) and glutamate synthase (GOGAT) in cyanobacteria. The activity of Synechocystis sp. PCC 6803 GS type I is controlled by protein-protein interactions with two intrinsically disordered inactivating factors (IFs): the 65 residue (IF7) and the 149-residue one (IF17). In this work, we studied both IF7 and IF17 by nuclear magnetic resonance (NMR), and we described their binding to GS by using NMR and biolayer interferometry. We assigned the backbone nuclei of all residues of IF7. Analyses of chemical shifts and the (15)N-{(1)H} NOEs at two field strengths suggest that IF7 region Thr3-Arg13 and a few residues around Ser27 and Phe41 populated helical conformations (although the percentage is smaller around Phe41). The two-dimensional (1)H-(15)N HSQC and CON experiments suggest that IF17 populated several conformations. We followed the binding between GS and IF7 by NMR at physiological pH, and the residues interacting first with IF7 were Gln6 and Ser27, belonging to those regions that appeared to be ordered in the isolated protein. We also determined the kon values and koff values for the binding of both IF7 and IF17 to GS, where the GS protein was bound to a biosensor. The measurements of the kinetic constants for the binding of IF7 to GS suggest that: (i) binding does not follow a kinetic two-state model ([Formula: see text]), (ii) there is a strong electrostatic component in the determined kon, and (iii) the binding is not diffusion-limited. PMID- 27232665 TI - Streamlined bioreactor-based production of human cartilage tissues. AB - Engineered tissue grafts have been manufactured using methods based predominantly on traditional labour-intensive manual benchtop techniques. These methods impart significant regulatory and economic challenges, hindering the successful translation of engineered tissue products to the clinic. Alternatively, bioreactor-based production systems have the potential to overcome such limitations. In this work, we present an innovative manufacturing approach to engineer cartilage tissue within a single bioreactor system, starting from freshly isolated human primary chondrocytes, through the generation of cartilaginous tissue grafts. The limited number of primary chondrocytes that can be isolated from a small clinically-sized cartilage biopsy could be seeded and extensively expanded directly within a 3D scaffold in our perfusion bioreactor (5.4 +/- 0.9 doublings in 2 weeks), bypassing conventional 2D expansion in flasks. Chondrocytes expanded in 3D scaffolds better maintained a chondrogenic phenotype than chondrocytes expanded on plastic flasks (collagen type II mRNA, 18 fold; Sox-9, 11-fold). After this "3D expansion" phase, bioreactor culture conditions were changed to subsequently support chondrogenic differentiation for two weeks. Engineered tissues based on 3D-expanded chondrocytes were more cartilaginous than tissues generated from chondrocytes previously expanded in flasks. We then demonstrated that this streamlined bioreactor-based process could be adapted to effectively generate up-scaled cartilage grafts in a size with clinical relevance (50 mm diameter). Streamlined and robust tissue engineering processes, as the one described here, may be key for the future manufacturing of grafts for clinical applications, as they facilitate the establishment of compact and closed bioreactor-based production systems, with minimal automation requirements, lower operating costs, and increased compliance to regulatory guidelines. PMID- 27232664 TI - The blood-tendon barrier: identification and characterisation of a novel tissue barrier in tendon blood vessels. AB - In the last decade, nanobiotechnology research has emerged as a revolutionising new approach to the 21st century pharmaceutical challenges, offering valuable gains in a vast set of biomedical applications. In the field of bone tissue engineering, a broad range of nanotechnology-based delivery systems have been researched and the most recent developments in high-throughput technology and in silico approaches are creating very high expectations. This review presents a comprehensive overview of the emergent nanotechnology-based materials, processing techniques and research strategies for the delivery of pharmaceutics to bone including the materials general characteristics and the available drug delivery systems to distribute agents systemically or locally. Complementary to what was stated above, it also reviews the latest high-throughput processing techniques and the existent in silico tools (mathematical and computational models) used to help on the design of delivery systems. PMID- 27232666 TI - Stability of housekeeping genes in human intervertebral disc, endplate and articular cartilage cells in multiple conditions for reliable transcriptional analysis. AB - Quantitative gene expression analysis is widely used to evaluate the expression of specific tissue markers. To obtain reliable data it is essential to select stable housekeeping genes whose expression is not influenced by the anatomical origin of cells or by the culture conditions. No studies have evaluated housekeeping gene stability in intervertebral disc (IVD) cells and only few studies using cartilaginous endplate (CEP) and articular cartilage (AC) cells are present in the literature. We analysed the stability of four candidate housekeeping genes (GAPDH, TBP, YWHAZ and RPL13A) in human cells isolated from nucleus pulposus (NP) and annulus fibrosus (AF), CEP and AC. Cell isolation, expansion, cryoconservation, and differentiation in 3D pellets were tested. GeNorm, NormFinder, BestKeeper tools and the comparative DeltaCt method were used to evaluate housekeeping gene stability. In each cell population, TBP alone or combined with YWHAZ was identified as the best normaliser in both monolayer and 3D pellets. GAPDH was the best performer only for AC cells in monolayer. In most culture conditions considering groups of two or more cell types, TBP was the most stable and YWHAZ was the second choice. GAPDH was the best performer only in 3D pellets with factors for AC and AF combined with CEP cells. RPL13A was the most stable only for AF with CEP cells at isolation. Our findings will be useful to properly design the experimental set-up of studies involving IVD, CEP or AC cells in different culture conditions, in order to obtain accurate and high quality data from quantitative gene expression analysis. PMID- 27232667 TI - Mesenchymal stromal cells from human umbilical cords display poor chondrogenic potential in scaffold-free three dimensional cultures. AB - Many researchers world over are currently investigating the suitability of stromal cells harvested from foetal tissues for allogeneic cell transplantation therapies or for tissue engineering purposes. In this study, we have investigated the chondrogenic potential of mesenchymal stromal cells (MSCs) isolated from whole sections of human umbilical cord or mixed cord (UCSCs-MC), and compared them with cells isolated from synovial membrane (SMSCs), Hoffa's fat pad (HFPSCs) and cartilage. All MSCs were positive for surface markers including CD73, CD90, CD105, CD44, CD146 and CD166, but negative for CD11b, CD19, CD34, CD45 and HLA-DR in addition to CD106 and CD271. Chondrogenic potential of all cell sources was studied using 3D pellet cultures incubated in the presence of different combinations of anabolic substances such as dexamethasone, IGF-1, TGF-beta1, TGF beta3, BMP-2 and BMP-7. BMP-2 and dexamethasone in combination with TGF-beta1 or TGF-beta3 excelled at inducing chondrogenesis on SMSCs, HFPSCs and chondrocytes, as measured by glycosaminoglycans and collagen type II staining of pellets, quantitative glycosaminoglycan expression, quantitative PCR of cartilage signature genes and electron microscopy. In contrast, none of the tested growth factor combinations was sufficient to induce chondrogenesis on UCSCs-MC. Moreover, incubation of UCSCs-MC spheroids in the presence of cartilage pieces or synovial cells in co-cultures did not aid chondrogenic induction. In summary, we show that in comparison with MSCs harvested from adult joint tissues, UCSCs-MC display poor chondrogenic abilities. This observation should alert researchers at the time of considering UCSCs-MC as cartilage forming cells in tissue engineering or repair strategies. PMID- 27232668 TI - Rotating-Disk-Based Hybridized Electromagnetic-Triboelectric Nanogenerator for Sustainably Powering Wireless Traffic Volume Sensors. AB - Wireless traffic volume detectors play a critical role for measuring the traffic flow in a real-time for current Intelligent Traffic System. However, as a battery operated electronic device, regularly replacing battery remains a great challenge, especially in the remote area and wide distribution. Here, we report a self-powered active wireless traffic volume sensor by using a rotating-disk-based hybridized nanogenerator of triboelectric nanogenerator and electromagnetic generator as the sustainable power source. Operated at a rotating rate of 1000 rpm, the device delivered an output power of 17.5 mW, corresponding to a volume power density of 55.7 W/m(3) (Pd = P/V, see Supporting Information for detailed calculation) at a loading resistance of 700 Omega. The hybridized nanogenerator was demonstrated to effectively harvest energy from wind generated by a moving vehicle through the tunnel. And the delivered power is capable of triggering a counter via a wireless transmitter for real-time monitoring the traffic volume in the tunnel. This study further expands the applications of triboelectric nanogenerators for high-performance ambient mechanical energy harvesting and as sustainable power sources for driving wireless traffic volume sensors. PMID- 27232669 TI - Agmatine attenuates the discriminative stimulus and hyperthermic effects of methamphetamine in male rats. AB - Methamphetamine abuse remains an alarming public heath challenge, with no approved pharmacotherapies available. Agmatine is a naturally occurring cationic polyamine that has previously been shown to attenuate the rewarding and psychomotor-sensitizing effects of methamphetamine. This study examined the effects of agmatine on the discriminative stimulus and hyperthermic effects of methamphetamine. Adult male rats were trained to discriminate 0.32 mg/kg methamphetamine from saline. Methamphetamine dose dependently increased drug associated lever responding. The nonselective dopamine receptor antagonist haloperidol (0.1 mg/kg) significantly attenuated the discriminative stimulus effects of methamphetamine (5.9-fold rightward shift). Agmatine (10-100 mg/kg) did not substitute for methamphetamine, but significantly attenuated the stimulus effects of methamphetamine, leading to a maximum of a 3.5-fold rightward shift. Acute 10 mg/kg methamphetamine increased the rectal temperature by a maximum of 1.96+/-0.17 degrees C. Agmatine (10-32 mg/kg) pretreatment significantly attenuated the hyperthermic effect of methamphetamine. Agmatine (10 mg/kg) also significantly reversed methamphetamine-induced temperature increase. Together, these results support further exploration of the value that agmatine may have for the treatment of methamphetamine abuse and overdose. PMID- 27232671 TI - Synthesis of Fluorenes Starting from 2-Iodobiphenyls and CH2Br2 through Palladium Catalyzed Dual C-C Bond Formation. AB - A facile and efficient approach is developed for the synthesis of fluorene and its derivatives starting from 2-iodobiphenyls and CH2Br2. A range of fluorene derivatives can be synthesized under relatively mild conditions. The reaction proceeds via a tandem palladium-catalyzed dual C-C bond formation sequence through the key dibenzopalladacyclopentadiene intermediates, which are obtained from 2-iodobiphenyls through palladium-catalyzed C-H activation. PMID- 27232672 TI - FMEA and consideration of real work situations for safer design of production systems. AB - Production equipment designers must ensure the health and safety of future users; in this regard, they augment requirements for standardizing and controlling operator work. This contrasts with the ergonomic view of the activity, which recommends leaving operators leeway (margins for manoeuvre) in performing their task, while safeguarding their health. Following a brief analysis of design practices in the car industry, we detail how the Failure Modes and Effects Analysis (FMEA) approach is implemented in this sector. We then suggest an adaptation that enables designers to consider real work situations. This new protocol, namely, work situation FMEA, allows experience feedback to be used to defend the health standpoint during designer project reviews, which usually only address quality and performance issues. We subsequently illustrate the advantage of this approach using two examples of work situations at car parts manufacturers: the first from the literature and the second from an in-company industrial project. PMID- 27232670 TI - Anorexic response to rapamycin does not appear to involve a central mechanism. AB - The authors have previously demonstrated that a low and intermittent peripheral dose of rapamycin (1 mg/kg three times/week) to rats inhibited mTORC1 signalling, but avoided the hyperlipidemia and diabetes-like syndrome associated with higher doses of rapamycin. The dosing regimen reduced food intake, body weight, adiposity, serum leptin and triglycerides. mTORC1 signalling was inhibited in both liver and hypothalamus, suggesting some of the actions, in particular the decrease in food intake, may be the results of a central mechanism. To test this hypothesis, rapamycin (30 MUg/day for 4 weeks) was infused into 23-25-month-old F344xBN rats by intracerebroventricular (icv) mini pumps. Our results demonstrated that central infusion did not alter food intake or body weight, although there was a tendency for a decrease in body weight towards the end of the study. mTORC1 signalling, evidenced by decreased phosphorylation of S6 protein at end of 4 weeks, was not activated in liver, hypothalamus or hindbrain. Fat and lean mass, sum of white adipose tissues, brown adipose tissue, serum glucose, insulin and leptin levels remained unchanged. Thus, these data suggest that the anorexic and body weight responses evident with peripheral rapamycin are not the result of direct central action. The tendency for decreased body weight towards the end of study, suggests that there is either a slow transport of centrally administered rapamycin into the periphery, or that there is delayed action of rapamycin at sites in the brain. PMID- 27232674 TI - Highly stable perovskite solar cells with an all-carbon hole transport layer. AB - Nano-carbon materials (carbon nanotubes, graphene, and graphene oxide) have potential application for photovoltaics because of their excellent optical and electronic properties. Here, we demonstrate that a single-walled carbon nanotubes/graphene oxide buffer layer greatly improves the photovoltaic performance of organo-lead iodide perovskite solar cells. The carbon nanotubes/graphene oxide buffer layer works as an efficient hole transport/electron blocking layer. The photovoltaic conversion efficiency of 13.3% was achieved in the organo-lead iodide perovskite solar cell due to the complementary properties of carbon nanotubes and graphene oxide. Furthermore, the great improvement of photovoltaic performance stability in the perovskite solar cells using carbon nanotubes/graphene oxide/polymethyl methacrylate was demonstrated in comparison with that using a typical organic hole transport layer of 2,2',7,7'-tetrakis-(N,N-di-4-methoxyphenylamino)-9,9'-spirobifluorene. PMID- 27232673 TI - Alectinib for ALK-positive non-small-cell lung cancer. AB - INTRODUCTION: Anaplastic lymphoma kinase (ALK) rearrangements are present in about 5% of advanced non-small-cell lung cancer (NSCLC) patients. Despite the initial response, after a median of 1-2 years, ALK-positive patients developed an acquired resistance to the ALK-inhibitor crizotinib. Among the most promising second-generation ALK-inhibitors, alectinib is being investigated in crizotinib naive and -resistant ALK-positive NSCLC patients. AREAS COVERED: The current state-of-the-art of ALK-inhibitors treatment, and in particular the role of alectinib in this setting, is reviewed and discussed. A structured search of bibliographic databases for peer-reviewed research literature and of main meetings using a focused review question was undertaken. Expert commentary: Alectinib reports promising results with a good safety profile, becoming a potentially very important option for ALK-translocated NSCLC patients. The preliminary results from the J-ALEX phase III randomized trial performed in ALK rearranged NSCLC Japanese patients showed a better activity and tolerability of alectinib versus crizotinib. PMID- 27232675 TI - CUSUM analysis of learning curves for the head-mounted microscope in phonomicrosurgery. AB - OBJECTIVES/HYPOTHESIS: To observe the learning curve of the head-mounted microscope in a phonomicrosurgery simulator using cumulative summation (CUSUM) analysis, which incorporates a magnetic phonomicrosurgery instrument tracking system (MPTS). STUDY DESIGN: Retrospective case series. METHODS: Eight subjects (6 medical students and 2 surgeons inexperienced in phonomicrosurgery) operated on phonomicrosurgical simulation cutting tasks while using the head-mounted microscope for 400 minutes total. Two 20-minute sessions occurred each day for 10 total days, with operation quality (Qs ) and completion time (T) being recorded after each session. Cumulative summation analysis of Qs and T was performed by using subjects' performance data from trials completed using a traditional standing microscope as success criteria. RESULTS: The motion parameters from the head-mounted microscope were significantly better than the standing microscope (P < 0.01), but T was longer than that from the standing microscope (P < 0.01). No subject successfully adapted to the head-mounted microscope, as assessed by CUSUM analysis. CONCLUSION: Cumulative summation analysis can objectively monitor the learning process associated with a phonomicrosurgical simulator system, ultimately providing a tool to assess learning status. Also, motion parameters determined by our MPTS showed that, although the head-mounted microscope provides better motion control, worse Qs and longer T resulted. This decrease in Qs is likely a result of the relatively unstable visual environment that it provides. Overall, the inexperienced surgeons participating in this study failed to adapt to the head-mounted microscope in our simulated phonomicrosurgery environment. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:2295-2300, 2016. PMID- 27232676 TI - Temporomandibular joint ankylosis as part of the clinical spectrum of Carey Fineman-Ziter syndrome? AB - The Carey-Finema-Ziter syndrome (CFZS, MIM 254940) is an apparently autosomal recessively inherited disorder consisting of the combination of non-progressive congenital myopathy with Moebius and Pierre Robin sequence, facial anomalies and growth delay. Mental development has been described as normal or delayed. Temporomandibular joint (TMJ) ankylosis is the immobility of the joint caused by ankylotic fusion of the mandible to the cranial base or zygoma. It is a serious and disabling condition that may cause problems in mastication, digestion, speech, appearance, and oral hygiene. Most often is a true ankylosis of the TMJ but other pathological mechanisms are described (i.e., the fusion of the coronoid process to temporal bone or with the zygoma, or a variety of soft tissues disorders like Fibrodysplasia Ossificans Progressiva). Here we report a 2-year old girl fitting with a clinical diagnosis of CFZS associated with a limited mouth opening in which temporomandibular joint ankylosis was suspected. Because it has been postulated that many clinical features in CFZS may only be secondary effects of brainstem anomalies and muscle weakness during development, the limited opening of the mouth observed in our patient could represent a rare clinical feature of CFZS itself. (c) 2016 Wiley Periodicals, Inc. PMID- 27232679 TI - From the Editor. PMID- 27232678 TI - Effect of Time-Dependent Sorption on the Dissipation of Water-Extractable Pesticides in Soils. AB - The dissipation behavior of water-extractable pesticides in soils is important when assessing the phytoavailability of pesticides in soils. This process is less understood than pesticide extraction with organic solvents. To elucidate the dissipation behavior of water-extractable pesticides in soils, we conducted an incubation study using 27 pesticides and five Japanese soils. The rate of decrease of the level of pesticides in water extracts was faster in soils than that of total extracts (water extracts and acetone extracts). This suggests that time-dependent sorption contributed to the difference in the dissipation between the pesticides in water and total extracts from soils. Increased apparent sorption coefficients (Kd,app) with time were positively and significantly correlated with Kd,app values of a 0 day incubation [Kd,app(t0)]. This empirical relationship suggests that Kd,app(t0) values can predict the time-dependent increase in Kd,app and the dissipation of water-extractable pesticides in soils. PMID- 27232677 TI - The frequency of influenza and bacterial coinfection: a systematic review and meta-analysis. AB - AIM: Coinfecting bacterial pathogens are a major cause of morbidity and mortality in influenza. However, there remains a paucity of literature on the magnitude of coinfection in influenza patients. METHOD: A systematic search of MeSH, Cochrane Library, Web of Science, SCOPUS, EMBASE, and PubMed was performed. Studies of humans in which all individuals had laboratory confirmed influenza, and all individuals were tested for an array of common bacterial species, met inclusion criteria. RESULTS: Twenty-seven studies including 3215 participants met all inclusion criteria. Common etiologies were defined from a subset of eight articles. There was high heterogeneity in the results (I(2) = 95%), with reported coinfection rates ranging from 2% to 65%. Although only a subset of papers were responsible for observed heterogeneity, subanalyses and meta regression analysis found no study characteristic that was significantly associated with coinfection. The most common coinfecting species were Streptococcus pneumoniae and Staphylococcus aureus, which accounted for 35% (95% CI, 14%-56%) and 28% (95% CI, 16%-40%) of infections, respectively; a wide range of other pathogens caused the remaining infections. An assessment of bias suggested that lack of small-study publications may have biased the results. CONCLUSIONS: The frequency of coinfection in the published studies included in this review suggests that although providers should consider possible bacterial coinfection in all patients hospitalized with influenza, they should not assume all patients are coinfected and be sure to properly treat underlying viral processes. Further, high heterogeneity suggests additional large-scale studies are needed to better understand the etiology of influenza bacterial coinfection. PMID- 27232680 TI - Using Propensity to Succeed Modeling to Increase Utilization and Adherence in a Nurse HealthLine Telephone Triage Program. AB - Propensity to succeed modeling was used to identify characteristics associated with higher utilization of a telephone triage program and adherence to nurse recommendations among callers. Characteristics significantly associated with calling the telephone triage service and engaging in triage services were being female and having an elevated health risk score. Callers most likely to adhere to nurse recommendations were younger than 85 years of age, had called on a weekday, and had received a recommendation to seek care at an emergency department or a doctor's office visit. Additional analyses suggest the propensity to succeed modeling is stable and valid. PMID- 27232681 TI - Demonstration of the Health Literacy Universal Precautions Toolkit: Lessons for Quality Improvement. AB - The Agency for Healthcare Research and Quality Health Literacy Universal Precautions Toolkit was developed to help primary care practices assess and make changes to improve communication with and support for patients. Twelve diverse primary care practices implemented assigned tools over a 6-month period. Qualitative results revealed challenges practices experienced during implementation, including competing demands, bureaucratic hurdles, technological challenges, limited quality improvement experience, and limited leadership support. Practices used the Toolkit flexibly and recognized the efficiencies of implementing tools in tandem and in coordination with other quality improvement initiatives. Practices recommended reducing Toolkit density and making specific refinements. PMID- 27232682 TI - Bridging the Gap: The Role of the Patient-Centered Medical Home in Reducing Time to Follow-Up After Hospital Discharge. AB - Poor transitions in care represent opportunities for improvement. The purpose of this study was to examine whether early follow-up by patients discharged from a hospital varied as a function of patient-centered medical home (PCMH) capacity. The PCMH capacity was not significantly associated with early follow-up; however, higher levels of capacity were associated with early follow-up among patients with more chronic conditions. Policy makers and practitioners should consider how the PCMH may be targeted to maximize its potential to improve transitions in care for these patients and ways it may be modified to improve transitions for other types of patients. PMID- 27232684 TI - Characteristics of Medicare Advantage and Fee-for-Service Beneficiaries Upon Enrollment in Medicare at Age 65. AB - Previous research has found differences in characteristics of beneficiaries enrolled in Medicare fee-for-service versus Medicare Advantage (MA), but there has been limited research using more recent MA enrollment data. We used 1997-2005 National Health Interview Survey data linked to 2000-2009 Medicare enrollment data to compare characteristics of Medicare beneficiaries before their initial enrollment into Medicare fee-for-service or MA at age 65 and whether the characteristics of beneficiaries changed from 2006 to 2009 compared with 2000 to 2005. During this period of MA growth, the greatest increase in enrollment appears to have come from those with no chronic conditions and men. PMID- 27232683 TI - What Ambulatory Care Managers Need to Know About Examination Room Utilization Measurement and Analysis. AB - Demand for ambulatory care visits is projected to increase 22% between 2008 and 2025. Given this growth, ambulatory care managers need to proactively plan for efficient use of scarce resources (ie, space, equipment, and staff). One important component of ambulatory care space (the number of examination rooms) is dependent on multiple factors, including variation in demand, hours of operation, scheduling, and staff. The authors (1) outline common data collection methods, (2) highlight analysis and reporting considerations for examination room utilization, and (3) provide a strategic framework for short- and long-term decision making for facility design or renovation. PMID- 27232685 TI - Effect of Organizational Culture on Patient Access, Care Continuity, and Experience of Primary Care. AB - This study examined relationships between organizational culture and patient centered outcomes in primary care. Generalized least squares regression was used to analyze patient access, care continuity, and reported experiences of care among 357 physicians in 41 primary care departments. Compared with a "Group oriented" culture, a "Rational" culture type was associated with longer appointment wait times, and both "Hierarchical" and "Developmental" culture types were associated with less care continuity, but better patient experiences with care. Understanding the unique effects of organizational culture can enhance the delivery of more patient-centered care. PMID- 27232686 TI - Primary Care Availability, Safety Net Clinics, and Health Insurance Coverage: The Association of These Access Factors With Preventable Hospitalizations. AB - The objective of the study was to examine the relationship between physician/safety net availability and health insurance coverage and preventable hospitalizations (PHs) in nonelderly adults in an urban area. Preventable conditions (PHs) were identified for nonelderly adults in Harris County using the Texas Health Care Information Collection hospital database. Multivariable logistic regression models examined the association of health insurance and patient proximity to physicians and safety net clinics with the risk of a PH. Safety net availability reduced PH risk by 23% (P < .05) but only among the uninsured. Lack of health insurance increased PH risk by 30% (P < .05). PMID- 27232687 TI - Patient-Centered Medical Home Adoption: Lessons Learned and Implications for Health Care System Reform. AB - Case studies of 8 primary care medical homes participating in a Massachusetts based initiative were conducted to understand the approaches they used to operationalize medical home standards and associated barriers. All sites received their National Committee on Quality Assurance recognition as medical homes, yet varied considerably in how components were implemented. Despite this variation, they faced similar challenges to implementing and sustaining medical home standards. Variations and challenges strongly emerged in 4 areas: team-based care, scheduling and online access, identifying and managing high-risk patients, and organizing follow-up care. Our study offers insight into various pathways to medical home success, and notes areas for further study. PMID- 27232688 TI - The Influence of Patient and Provider Communication on Diabetes Care Delivery. AB - PURPOSE: To elicit the perspective of patients with type 2 diabetes, specific to communication with providers and health care teams. METHODS: We conducted 21 focus groups with 115 adults in Midwestern primary care, endocrinology, and bariatric surgery clinics. Facilitators analyzed the transcripts using an iterative coding method. RESULTS: The themes of encouragement and motivation, relationship building, compassion, and communication preferences highlighted effective strategies consistent with the core components of patient-centered care. CONCLUSIONS: Patients and providers benefit from systems in which patients are efficiently and compassionately supported in self-management within their abilities and in partnership with their support networks. PMID- 27232689 TI - What Can Primary Care Learn From Sports Teams? AB - Teams are familiar to sports but relatively new to primary care. In this perspective, we use sports teams to illustrate key principles from team science and extract practical lessons for primary care teams. The most notable lessons include the need for continuous team learning based on presession planning and postsession debriefing, real-world team training focused on identified teamwork needs, and on-site team coaching. Implementation of these principles requires organizational commitment coupled with alignment of continuing medical education and recertification requirements with primary care teamwork competencies. PMID- 27232691 TI - Intramolecular Dehydrogenative Coupling of 2,3-Diaryl Acrylic Compounds: Access to Substituted Phenanthrenes. AB - A simple, facile, and environmentally benign intramolecular dehydrogenative coupling of various 1,2-diarylethylenes for the synthesis of phenanthrenes in excellent yield has been described. This new methodology uses ceric ammonium nitrate (CAN) as a promoter at room temperature and has been extended to intermolecular synthesis of biaryl compounds. The electron transfer from methoxyarene to cerium leads to cationic radical formation, which further proceeds to intramolecular coupling. Preliminary mechanistic investigation by EPR spectroscopy and density functional theory calculation suggested a similar view. PMID- 27232692 TI - Interplay of regulatory RNAs and mobile genetic elements in enteric pathogens. AB - Horizontal transfer of genetic information is a major driving force of evolution. In bacteria, genome plasticity is intimately linked to the ability of the bacterium to integrate novel material into existing gene expression circuits. Small RNAs (sRNAs) are a versatile class of regulatory molecules, and have recently been discovered to perform important tasks in the interplay between core genomic elements and horizontally-acquired DNA. Together with auxiliary proteins such as the RNA-chaperone Hfq and cellular ribonucleases, sRNAs typically act post-transcriptionally to either promote or restrict the expression of multiple target genes. Bacterial sRNAs have been identified in core and peripheral (acquired) genome sequences, and their target suites may likewise include genes from both locations. In this review, we discuss how sRNAs influence the expression of foreign genetic material in enterobacterial pathogens, and outline the processes that foster the integration of horizontally-acquired RNAs into existing regulatory networks. We also consider potential benefits and risks of horizontal gene transfer for RNA-based gene regulation. PMID- 27232694 TI - Firefly Algorithm for Structural Search. AB - The problem of computational structure prediction of materials is approached using the firefly (FF) algorithm. Starting from the chemical composition and optionally using prior knowledge of similar structures, the FF method is able to predict not only known stable structures but also a variety of novel competitive metastable structures. This article focuses on the strengths and limitations of the algorithm as a multimodal global searcher. The algorithm has been implemented in software package PyChemia ( https://github.com/MaterialsDiscovery/PyChemia ), an open source python library for materials analysis. We present applications of the method to van der Waals clusters and crystal structures. The FF method is shown to be competitive when compared to other population-based global searchers. PMID- 27232693 TI - miR-29a associates with viro-immunological markers of HIV infection in treatment experienced patients. AB - MicroRNAs (miRNAs) are small, non-coding RNA species essential for the post translational regulation of gene expression. Several miRNA have been proposed to contribute to Human immunodeficiency virus-1 (HIV-1) infection establishment, progression and latency. Among them, miR-29a seems to be of particular interest. The aim of this study was to investigate the association between miR-29a expression and immunologic and virologic markers of HIV infection progression in long-term antiretroviral-treated individuals. In a homogenous group of 165 young adults, with chronic HIV infection, parenterally acquired during childhood, the expression level of miR-29a was found to be inversely correlated with HIV viral load and the degree of immunosuppression, expressed by both CD4 cell count and the CD4/CD8 ratio. There was a significant difference in miR-29a expression according to the patient's response to treatment, with the lowest levels expressed by patients with treatment failure, defined as detectable viremia and CD4 < 350 cells/mm3 . No significant correlation was found between miRNA level and the nadir CD4 count or zenith HIV viral load. This study establishes the association between miR-29a expression and markers of HIV infection in long-term survivors, treatment-experienced patients, suggesting its potential use as an indicator for the on-treatment disease evolution. J. Med. Virol. 88:2132-2137, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27232695 TI - Scalable Binder-Free Supersonic Cold Spraying of Nanotextured Cupric Oxide (CuO) Films as Efficient Photocathodes. AB - We demonstrate production of nanotextured p-type cupric oxide (CuO) films via a low-cost scalable supersonic cold spray method in open air conditions. Simply sweeping the spray nozzle across a substrate produced a large-scale CuO film. When used as hydrogen evolution photocathodes, these films produced photocurrent densities (PCD) of up to 3.1 mA/cm(2) under AM1.5 illumination, without the use of a cocatalyst or any additional heterojunction layers. Cu2O particles were supersonically sprayed onto an indium tin oxide (ITO) coated soda lime glass (SLG) substrate, without any solvent or binder. Annealing in air converted the Cu2O films to CuO, with a corresponding decrease in the bandgap and increase in the fraction of the solar spectrum absorbed. Annealing at 600 degrees C maximized the PCD. Increasing the supersonic gas velocity from ~450 to ~700 m/s produced denser films with greater surface roughness, in turn producing higher PCD. The nanoscale texture of the films, which resembles the skin of a dinosaur, enhanced their performance, leading to one of the highest PCD values in the literature. We characterized the films by X-ray diffraction, Raman spectroscopy, X-ray photoelectron spectroscopy, atomic force microscopy, scanning electron microscopy, and transmission electron microscopy to elucidate the origins of their outstanding performance. This supersonic cold spraying deposition has the potential to be used on a commercial scale for low cost mass production. PMID- 27232696 TI - The Association of Levels of and Decline in Grip Strength in Old Age with Trajectories of Life Course Occupational Position. AB - BACKGROUND: The study of the influence of life course occupational position (OP) on health in old age demands analysis of time patterns in both OP and health. We study associations between life course time patterns of OP and decline in grip strength in old age. METHODS: We analyze 5 waves from the Survey of Health Ageing and Retirement in Europe (n = 5108, ages 65-90). We use a pattern-mixture latent growth model to predict the level and decline in grip strength in old age by trajectory of life course OP. We extend and generalize the structured regression approach to establish the explanatory power of different life course models for both the level and decline of grip strength. RESULTS: Grip strength declined linearly by 0.70 kg (95% CI -0.74;-0.66) for men and 0.42 kg (95% CI -0.45;-0.39) for women per year. The level of men's grip strength can best be explained by a critical period during midlife, with those exposed to low OP during this period having 1.67 kg (95% CI -2.33;-1.00) less grip strength. These differences remain constant over age. For women, no association between OP and levels of or decline in grip strength was found. CONCLUSIONS: Men's OP in midlife seems to be a critical period for the level of grip strength in old age. Inequalities remain constant over age. The integration of the structured regression approach and latent growth modelling offers new possibilities for life course epidemiology. PMID- 27232697 TI - Evaluation of jejunostomy tube feeding after abdominal surgery in dogs. AB - OBJECTIVE: To describe the use of postoperative intrajejunal feeding and to evaluate the association of preoperative plasma albumin concentrations with intrajejunal feeding-related complications and clinical outcome. DESIGN: Prospective, observational study. SETTING: University veterinary teaching hospital. ANIMALS: Sixty-four dogs. INTERVENTIONS: Jejunostomy tube placement during abdominal surgery. MEASUREMENTS AND MAIN RESULTS: Most dogs (81%) survived. The median intrajejunal feeding period was 2.1 days (range: 1-16 days; n = 64). Only 3 (5%) dogs received their estimated resting energy requirement by intrajejunal feeding. Of dogs that were fed intrajejunally (58 out of 64), most (55 out of 58) received intrajejunal feeding within 24 hours after surgery. Energy provision via the jejunal feeding tube did not differ between dogs with and without complications (P = 0.592), or between nonsurvivors and survivors (P = 0.298). Thirty-five dogs ate voluntarily concurrently with intrajejunal feeding. Of dogs that ate voluntarily concurrently with intrajejunal feeding for <=50% of the postoperative period, most (74%) survived to discharge. Complications were seen in 22% of dogs, and none were life-threatening; gastrointestinal signs were most common. There was no difference in preoperative plasma albumin concentration between dogs with and without complications (P = 0.432) and between nonsurvivors and survivors (P = 0.727). Fecal score was not significantly different between the 2 liquid diets studied (FormulaV Enteral Care HLP and CliniCare Canine/Feline; P = 0.927). CONCLUSIONS: A jejunostomy tube placed during abdominal surgery was likely to be used at the study institution. Few complications were seen and none were life-threatening. Intrajejunal feeding was initiated early after surgery and did not interfere with the initiation of voluntary oral intake. Fecal scores were high and were useful for an objective assessment of fecal consistency in dogs with intrajejunal feeding. PMID- 27232698 TI - Interactions among Lung Cancer Cells, Fibroblasts, and Macrophages in 3D Co Cultures and the Impact on MMP-1 and VEGF Expression. AB - In vitro cell-based models of lung cancer are frequently employed to study invasion and the mechanisms behind metastasis. However, these models often study only one cell type with two-dimensional (2D) monolayer cell cultures, which do not accurately reflect the complexity of inflammation in vivo. Here, a three dimensional (3D) cell co-culture collagen gel model was employed, containing human lung adenocarcinoma cells (HCC), human lung fibroblast cells (MRC-5), and macrophages. Cell culture media and cell images were collected, and matrix metalloproteinase-1 (MMP-1) and vascular endothelial growth factor (VEGF) production was monitored under different cell culture conditions. We found that simulating hypoxia and/or serum starvation conditions induced elevated secretion of VEGF in the 3D co-culture model in vitro, but not MMP-1; the morphology of HCC in the 2D versus the 3D co-culture system was extremely different. MMP-1 and VEGF were secreted at higher levels in mixed cell groups rather than mono-culture groups. Therefore, incorporating lung cancer cells, fibroblasts, and macrophages may better reflect physiological metastasis mechanisms compared to mono-culture systems. Tumour stromal cells, macrophages, and fibroblast cells may promote invasion and metastasis, which also provides a new direction for the design of therapies targeted at destroying the stroma of tumor tissues. PMID- 27232713 TI - Cultural and Environmental Predictors of Pre-European Deforestation on Pacific Islands. AB - The varied islands of the Pacific provide an ideal natural experiment for studying the factors shaping human impact on the environment. Previous research into pre-European deforestation across the Pacific indicated a major effect of environment but did not account for cultural variation or control for dependencies in the data due to shared cultural ancestry and geographic proximity. The relative importance of environment and culture on Pacific deforestation and forest replacement and the extent to which environmental impact is constrained by cultural ancestry therefore remain unexplored. Here we use comparative phylogenetic methods to model the effect of nine ecological and two cultural variables on pre-European Pacific forest outcomes at 80 locations across 67 islands. We show that some but not all ecological features remain important predictors of forest outcomes after accounting for cultural covariates and non independence in the data. Controlling for ecology, cultural variation in agricultural intensification predicts deforestation and forest replacement, and there is some evidence that land tenure norms predict forest replacement. These findings indicate that, alongside ecology, cultural factors also predict pre European Pacific forest outcomes. Although forest outcomes covary with cultural ancestry, this effect disappears after controlling for geographic proximity and ecology. This suggests that forest outcomes were not tightly constrained by colonists' cultural ancestry, but instead reflect a combination of ecological constraints and the short-term responses of each culture in the face of those constraints. PMID- 27232714 TI - Accuracy of Heart Rate Watches: Implications for Weight Management. AB - BACKGROUND: Wrist-worn monitors claim to provide accurate measures of heart rate and energy expenditure. People wishing to lose weight use these devices to monitor energy balance, however the accuracy of these devices to measure such parameters has not been established. AIM: To determine the accuracy of four wrist worn devices (Apple Watch, Fitbit Charge HR, Samsung Gear S and Mio Alpha) to measure heart rate and energy expenditure at rest and during exercise. METHODS: Twenty-two healthy volunteers (50% female; aged 24 +/- 5.6 years) completed ~1-hr protocols involving supine and seated rest, walking and running on a treadmill and cycling on an ergometer. Data from the devices collected during the protocol were compared with reference methods: electrocardiography (heart rate) and indirect calorimetry (energy expenditure). RESULTS: None of the devices performed significantly better overall, however heart rate was consistently more accurate than energy expenditure across all four devices. Correlations between the devices and reference methods were moderate to strong for heart rate (0.67-0.95 [0.35 to 0.98]) and weak to strong for energy expenditure (0.16-0.86 [-0.25 to 0.95]). All devices underestimated both outcomes compared to reference methods. The percentage error for heart rate was small across the devices (range: 1-9%) but greater for energy expenditure (9-43%). Similarly, limits of agreement were considerably narrower for heart rate (ranging from -27.3 to 13.1 bpm) than energy expenditure (ranging from -266.7 to 65.7 kcals) across devices. CONCLUSION: These devices accurately measure heart rate. However, estimates of energy expenditure are poor and would have implications for people using these devices for weight loss. PMID- 27232715 TI - Xenobiotics Produce Distinct Metabolomic Responses in Zebrafish Larvae (Danio rerio). AB - Sensitive and quantitative protocols for characterizing low-dose effects are needed to meet the demands of 21st century chemical hazard assessment. To test the hypothesis that xenobiotic exposure at environmentally relevant concentrations produces specific biochemical fingerprints in organisms, metabolomic perturbations in zebrafish (Danio rerio) embryo/larvae were measured following 24 h exposures to 13 individual chemicals covering a wide range of contaminant classes. Measured metabolites (208 in total) included amino acids, biogenic amines, fatty acids, bile acids, sugars, and lipids. The 96-120 h post fertilization developmental stage was the most appropriate model for detecting xenobiotic-induced metabolomic perturbations. Metabolomic fingerprints were largely chemical- and dose-specific and were reproducible in multiple exposures over a 16-month period. Furthermore, chemical-specific responses were detected in the presence of an effluent matrix; importantly, in the absence of morphological response. In addition to improving sensitivity for detecting biological responses to low-level xenobiotic exposures, these data can aid the classification of novel contaminants based on the similarity of metabolomic responses to well characterized "model" compounds. This approach is clearly of use for rapid, sensitive, and specific analyses of chemical effect on organisms, and can supplement existing methods, such as the Zebrafish Embryo Toxicity assay (OECD TG236), with molecular-level information. PMID- 27232717 TI - 1D versus 3D quantum confinement in 1-5 nm ZnO nanoparticle agglomerations for application in charge-trapping memory devices. AB - ZnO nanoparticles (NPs) have attracted considerable interest from industry and researchers due to their excellent properties with applications in optoelectronic devices, sunscreens, photocatalysts, sensors, biomedical sciences, etc. However, the agglomeration of NPs is considered to be a limiting factor since it can affect the desirable physical and electronic properties of the NPs. In this work, 1-5 nm ZnO NPs deposited by spin- and dip-coating techniques are studied. The electronic and physical properties of the resulting agglomerations of NPs are studied using UV-vis-NIR spectroscopy, atomic force microscopy (AFM), and transmission electron microscopy (TEM), and their application in metal-oxide semiconductor (MOS) memory devices is analyzed. The results show that both dip- and spin-coating techniques lead to agglomerations of the NPs mostly in the horizontal direction. However, the width of the ZnO clusters is larger with dip coating which leads to 1D quantum confinement, while the smaller ZnO clusters obtained by spin-coating enable 3D quantum confinement in ZnO. The ZnO NPs are used as the charge-trapping layer of a MOS-memory structure and the analysis of the high-frequency C-V measurements allow further understanding of the electronic properties of the ZnO agglomerations. A large memory window is achieved in both devices which confirms that ZnO NPs provide large charge-trapping density. In addition, ZnO confined in 3D allows for a larger memory window at lower operating voltages due to the Poole-Frenkel charge-emission mechanism. PMID- 27232716 TI - Efficacy and Safety of the Collagenase of the Bacterium Clostridium Histolyticum for the Treatment of Capsular Contracture after Silicone Implants: Ex-Vivo Study on Human Tissue. AB - BACKGROUND: The fibrotic capsule that surrounds silicone implants consists mainly of collagen. The FDA-approved collagenase of the bacterium clostridium histolyticum provides a reasonable treatment option. Safety and efficacy at the female breast site must be evaluated before clinical utilization. MATERIALS AND METHODS: We incubated 20 samples of fibrotic capsule as well as 12 full thickness skin grafts harvested from the female breast site for 24 hours with different doses of collagenase. Outcome measures involved histological assessment of thickness and density of the capsule tissue as well as the skin grafts. Furthermore, we performed a collagen assay and immunohistochemistry staining for collagen subtypes. RESULTS: Collagenase treatment was able to degrade human capsule contracture tissue ex-vivo. The remaining collagen subtype after degradation was type 4 only. 0.3 mg/ml of collagenase was most effective in reducing capsule thickness when compared with higher concentrations. Of note, effectiveness was inversely related to capsule density, such that there was less reduction in thickness with higher capsule densities and vice versa. Furthermore, the application of 0.3mg/ml collagenase did not lead to thinning or perforation of full thickness skin grafts. CONCLUSION: Adjustment of collagenase dose will depend on thickness and density of the contracted capsule. A concentration of 0.3mg/ml seems to be safe and effective in an ex-vivo setting. The remaining collagen subtype 4 is suitable to serve as a neo-capsule/acellular tissue matrix. Collagenase treatment for capsular contracture may soon become a clinical reality. PMID- 27232718 TI - Which Socio-Ecological Factors Associate with a Switch to or Maintenance of Active and Passive Transport during the Transition from Primary to Secondary School? AB - OBJECTIVES: The aim was to investigate which individual, psychosocial and physical neighborhood environmental factors associate with children's switch to or maintenance of active/passive transport to school and to leisure time destinations during the transition from primary to secondary school. METHODS: Children (n = 313) filled out a questionnaire in the last year of primary school and 2 years later to assess socio-demographic characteristics and self-reported transport. One of their parents completed a questionnaire to assess parental perceptions of psychosocial and physical neighborhood environmental factors. RESULTS: The increase of the home-school distance was significantly associated with children's switch to or maintenance of passive transport to school compared to a switch to (OR = 0.81; p = 0.03) and maintenance (OR = 0.87; p = 0.03) of active transport to school. Low SES was associated with children's switch to active transport to school compared to maintenance of active transport (OR = 3.67; p = 0.07). For transport to leisure time destinations, other factors such as parental perceived neighborhood safety from traffic and crime (OR = 2.78; p = 0.004), a positive social norm (OR = 1.49; p = 0.08), positive attitudes (OR = 1.39; p = 0.08) (i.e. more benefits, less barriers) towards their children's physical activity and poor walking/cycling facilities in the neighborhood (OR = 0.70; p = 0.06) were associated with children's maintenance of active transport to leisure time destinations compared to a switch to or maintenance of passive transport. CONCLUSIONS: This longitudinal study can give directions for interventions promoting children's active transport during the transition to secondary school. It is necessary to promote different possibilities at primary school for children to use active transport when going to secondary school. Walking/cycling a part of the home-school trip can be a possible solution for children who will be living at non-feasible distances from secondary school. Providing safe neighborhoods, combined with programs for parents stimulating a positive social norm and positive attitudes towards physical activity during primary school, can be effective. PMID- 27232719 TI - The mobilization of hazardous elements after a tropical storm event in a polluted estuary. AB - The Tubarao River (Santa Catarina, Brazil) is affected by hazardous elements (HEs) pollution from abandoned coal mines, agricultural activities, urban discharges, industrial and leisure zones, etc. In order to study the distribution and sources of HEs contamination in a polluted estuary after a tropical storm, waters and surface sediments were collected from 15 sampling sites along the Tubarao River. The concentration of 24 elements (Ag, Al, As, Ba, Cd, Co, Cr, Cu, Fe, Hg, Mg, Mn, Mo, Ni, Pb, Sb, Se, Sn, Sr, Ti, Tl, V, W, and Zn) were measured by Inductively Coupled Plasma Mass Spectrometry (ICP-MS) and the mineralogical composition of the sediments by Raman spectroscopy and X-ray diffraction (XRD). The metal concentrations in water and sediment showed wide spatial variation due to the variability in water discharges and anthropogenic inputs after a storm. In general, higher metal concentration in water and lower in sediments were found upstream (closer to coal mining). Downstream sampling sites and the Oratorio River sampling site (one of the eight tributaries of the estuary) showed the highest values in sediment samples. Normalized and Weighed Average Concentrations (NWAC) were calculated, which allow us to identify, in a very simple way, the sampling sites of higher concern (hotspots of contamination) in the studied area. NWAC suggested that the strong rainfall events could affect to the metal distribution in sediments. The results of this study were compared with a previous study in the same area during dry season by Principal Component Analysis (PCA), showing changes in environmental pollution of the sediment after a strong storm event. PMID- 27232720 TI - Canopy level emissions of 2-methyl-3-buten-2-ol, monoterpenes, and sesquiterpenes from an experimental Pinus taeda plantation. AB - Emissions of Biogenic Volatile Organic Compounds (BVOCs) observed during 2007 from an experimental Pinus taeda plantation in Central North Carolina are compared with model estimates from the Model of Emissions of Gases and Aerosols from Nature (MEGAN) version 2.1. Relaxed eddy accumulation (REA) estimates of 2 methyl-3-buten-2-ol (MBO) fluxes are a factor of 3-4 higher than MEGAN estimates. MEGAN monoterpene emission estimates were a factor of approximately two higher than REA flux measurements. MEGAN beta-caryophyllene emission estimates were within 60% of growing season REA flux estimates but were several times higher than REA fluxes during cooler, dormant season periods. The sum of other sesquiterpene emissions estimated by MEGAN was several times higher than REA estimates throughout the year. Model components are examined to understand these discrepancies. Measured summertime leaf area index (LAI) (and therefore foliar biomass) is a factor of two higher than assumed in MEGAN for the P. taeda default. Increasing the canopy mean MBO emission factor from 0.35 to 1.0mgm(-2)h( 1) also reduces MEGAN vs. REA flux differences. This increase is within current MBO emission factor uncertainties. The algorithm within MEGAN which adjusts isoprene emission estimates as a function of the temperature and light of the previous 24h seems also to improve the seasonal MEGAN MBO correlation with REA fluxes. Including the effects of the previous 240h, however, seems to degrade temporal model correlation with fluxes. Monoterpene and sesquiterpene composition data from the REA are compared with MEGAN2.1 estimates and also branch enclosure and needle extract data collected at this site. To our knowledge, the flux data presented here are the first reported for MBO and sesquiterpenes from a P. taeda ecosystem. PMID- 27232723 TI - Novel and facile synthesis of Ba-doped BiFeO3 nanoparticles and enhancement of their magnetic and photocatalytic activities for complete degradation of benzene in aqueous solution. AB - In this work, Bi1-x Bax FeO3 (x=0.05, 0.1 and 0.2mol%) multiferroic materials as visible-light photocatalysts were successfully synthesized via a simple and rapid sol-gel method, at a low temperature and with rapid calcination. Ba loading brought about a distorted structure of BiFeO3 magnetic nanoparticles (BFO MNPs) consisting of small, randomly oriented and non-uniform grains, leading to increased surface area and improved magnetic and photocatalytic activities. Doping of Ba(2+) into pure BFO (Bi1-x Bax FeO3, x=0.2mol%) greatly increased magnetic saturation to 3.0emu/g and significantly decreased the band-gap energy to 1.79eV, as compared to 2.1emu/g and 2.1eV, respectively, for pure BFO. Bi1-xBa xFeO3 of x=0.2mol% exhibited the greatest photocatalytic degradation effect after 60min of visible light irradiation, and reached 97% benzene removal efficiency, leading to production of a high concentration of carbon dioxide (CO2), with 93% and 82% reductions in chemical oxygen demand (COD) and total organic carbon (TOC), respectively. The identified major intermediate products of photodegradation enabled prediction of the proposed benzene degradation pathway. The enhanced photocatalytic activity of benzene removal is due to both mechanisms, photocatalytic and photo-Fenton catalytic degradation. PMID- 27232722 TI - Study on enhanced degradation of atrazine by ozonation in the presence of hydroxylamine. AB - Degradation of atrazine (ATZ) by ozonation in the presence of hydroxylamine (HA) was experimentally investigated in this study. The results showed approximately 80% of ATZ was degraded by ozonation in the presence of HA, while only 20% was degraded by ozonation alone. The obvious inhibition of the ATZ degradation by tert-butanol suggested the enhanced ATZ degradation by ozone/HA was primarily attributed to OH. The OH yield was determined to be 25.8%. Additionally, the optimum HA dosage for the ATZ degradation was 4MUM, when the ozone dosage was 20MUM. The effects of pH, bicarbonate and temperature on ATZ degradation by ozone/HA were investigated in details. Most importantly, the enhanced ATZ degradation by ozonation in the presence of HA was still observed in real water especially at acidic pHs. Furthermore, the potential mechanism of OH formation during the reaction of ozone with HA was proposed herein. Nine products were identified by UPLC/Q-TOF-MS system. The ATZ degradation involved dealkylation, dechlorination-hydroxylation and olefination. The evolutions of the concentrations of three available transformation products including deethylatrazine, deisopropylatrazine and deethyldeisopropylatrazine in ozone/HA were evaluated and compared with that in ozonation alone. PMID- 27232721 TI - Optical clearing of skin enhanced with hyaluronic acid for increased contrast of optoacoustic imaging. AB - Enhanced delivery of optical clearing agents (OCA) through skin may improve sensitivity of optical and optoacoustic (OA) methods of imaging, sensing, and monitoring. This report describes a two-step method for enhancement of light penetration through skin. Here, we demonstrate that topical application of hyaluronic acid (HA) improves skin penetration of hydrophilic and lipophilic OCA and thus enhances their performance. We examined the OC effect of 100% polyethylene and polypropylene glycols (PPGs) and their mixture after pretreatment by HA, and demonstrated significant increase in efficiency of light penetration through skin. Increased light transmission resulted in a significant increase of OA image contrast in vitro. Topical pretreatment of skin for about 30 min with 0.5% HA in aqueous solution offers effective delivery of low molecular weight OCA such as a mixture of PPG-425 and polyethylene glycol (PEG)-400. The developed approach of pretreatment by HA prior to application of clearing agents (PEG and PPG) resulted in a ~ 47-fold increase in transmission of red and near infrared light and significantly enhanced contrast of OA images. PMID- 27232724 TI - Occurrence of drugs of abuse in surface water from four Spanish river basins: Spatial and temporal variations and environmental risk assessment. AB - The present work investigates the occurrence of 22 drugs of abuse (DAs) and metabolites in surface water from four Spanish River basins: Llobregat, Ebro, Jucar and Guadalquivir. To this end, samples were collected from 77 selected sites in two sampling campaigns conducted in 2010 and 2011. Analyses were performed by means of on-line solid phase extraction-liquid chromatography electrospray-tandem mass spectrometry (on-line SPE-LC-ESI-MS/MS). Cocaine, its metabolite benzoylecgonine, ephedrine, MDMA (ecstasy), and methadone and its metabolite EDDP were the most ubiquitous compounds, being present in more than 50% of the samples. Overall, DAs were present at low ng/L levels, showing comparatively higher concentrations in small tributary rivers impacted by wastewater treatment plant effluents. The results obtained did not show a clear relationship between the concentrations of DAs and the hydrological conditions of the river basins. Differences in the occurrence of DAs between river basins were observed, but only for MDMA this finding could be confirmed in both sampling campaigns. These results overall suggest similar drugs consumption in the studied areas. Estimation of potential ecotoxicological effects using Hazard Quotient (HQ) ratios and a concentration addition model showed that in four samples the presence of DAs could represent certain risk to aquatic organisms. PMID- 27232725 TI - Stochastic fuzzy environmental risk characterization of uncertainty and variability in risk assessments: A case study of polycyclic aromatic hydrocarbons in soil at a petroleum-contaminated site in China. AB - Better decisions are made using risk assessment models when uncertainty and variability are explicitly acknowledged. Uncertainty caused by a lack of uniform and scientifically supported environmental quality guidelines and variability in the degree of exposure of environmental systems to contaminants are here incorporated in a stochastic fuzzy environmental risk characterization (SFERC) approach. The approach is based on quotient probability distribution and environmental risk level fuzzy membership function methods. The SFERC framework was used to characterize the environmental risks posed by 16 priority polycyclic aromatic hydrocarbons (PAHs) in soil at a typical petroleum-contaminated site in China. This relied on integrating data from the literature and field and laboratory experiments. The environmental risk levels posed by the PAHs under four risk scenarios were determined using the SFERC approach, using "residential land" and "industrial land" environmental quality guidelines under "loose" and "strict" strictness parameters. The results showed that environmental risks posed by PAHs in soil are primarily caused by oil exploitation, traffic emissions, and coal combustion. The SFERC approach is an effective tool for characterizing uncertainty and variability in environmental risk assessments and for managing contaminated sites. PMID- 27232726 TI - Preparation of a novel graphene oxide/Fe-Mn composite and its application for aqueous Hg(II) removal. AB - A novel graphene oxide/Fe-Mn (GO/Fe-Mn) composite was synthesized (molar ratio of Fe/Mn=3/1 and mass ratio of Fe/GO=1/7.5) and investigated for the sorption characteristics and mechanisms of aqueous mercury (Hg(2+)) as well as the biological effects to wheat and rice. Characterization tests showed that Fe-Mn oxides were impregnated onto GO sheets in an amorphous form through oxygen containing functional groups (i.e., CO, epoxy COC, carboxyl OCO, and CO) and pi pi interactions. GO/Fe-Mn possessed large surface area, surface enhanced Raman scattering with more sp(3) defects, and greater thermal stability than GO. XPS analysis revealed that Fe2O3, FeOOH, MnO2, MnOOH, and MnO were the dominant metal oxides in GO/Fe-Mn. Pseudo-second-order kinetic model and Sips isotherm model fitted well with the sorption kinetic and isotherm data. The maximum sorption capacity for mercury was 32.9mg/g. Ligand exchange and surface complexation were the dominant mechanisms for mercury removal. GO/Fe-Mn greatly reduced the bioavailability of mercury to wheat and rice, even promoted the seedling growth. This work suggests that GO/Fe-Mn can be used as an effective and environmental friendly adsorbent in heavy metal remediation. PMID- 27232727 TI - Self-assembly graphitic carbon nitride quantum dots anchored on TiO2 nanotube arrays: An efficient heterojunction for pollutants degradation under solar light. AB - In this study, an efficient heterojunction was constructed by anchoring graphitic carbon nitride quantum dots onto TiO2 nanotube arrays through hydrothermal reaction strategy. The prepared graphitic carbon nitride quantum dots, which were prepared by solid-thermal reaction and sequential dialysis process, act as a sensitizer to enhance light absorption. Furthermore, it was demonstrated that the charge transfer and separation in the formed heterojunction were significantly improved compared with pristine TiO2. The prepared heterojunction was used as a photoanode, exhibiting much improved photoelectrochemical capability and excellent photo-stability under solar light illumination. The photoelectrocatalytic activities of prepared heterojunction were demonstrated by degradation of RhB and phenol in aqueous solution. The kinetic constants of RhB and phenol degradation using prepared photoelectrode are 2.4 times and 4.9 times higher than those of pristine TiO2, respectively. Moreover, hydroxyl radicals are demonstrated to be dominant active radicals during the pollutants degradation. PMID- 27232728 TI - Chromium speciation in tannery effluent after alkaline precipitation: Isolation and characterization. AB - It is difficult to completely remove Cr(III) from tannery effluent by alkaline precipitation due to the abundance of strong organic ligands. Thereby, the speciation of the residual Cr after alkaline precipitation is of crucial significance to guide the selection and design of further treatment process. For the first time, we revealed the speciation of the residual Cr with the aid of comprehensive analytical techniques. Results showed that the residual Cr(III) mostly located in two size ranges, i.e. the 13-100nm fraction and the <4nm fraction. Combined spectral analyses demonstrated Cr(III) was coordinated by carboxyl groups or hydroxyl groups in both fractions, while the complexation by nitrogen-containing groups was excluded by the total nitrogen and UPLC-MS analysis in the two fractions, respectively. Based on the comprehensive analyses, the structures of Cr(III) complexes in both fractions were proposed. Cr(III) cross-linked the carboxyl groups from polyacrylic acid chains to form the network gel structure in the 13-100nm fraction, while the complex structure of Cr(III) in the <4nm fraction was formed through hydroxyl-carboxyl chelation by masking agents such as tartrate and citrate. Although polyoxyethylene ether was abundantly present, it was responsible for the complexation of Cr(III) in neither fraction. PMID- 27232729 TI - Uncovering microRNA-mediated response to SO2 stress in Arabidopsis thaliana by deep sequencing. AB - Sulfur dioxide (SO2) is a major air pollutant and has significant impacts on plants. MicroRNAs (miRNAs) are a class of gene expression regulators that play important roles in response to environmental stresses. In this study, deep sequencing was used for genome-wide identification of miRNAs and their expression profiles in response to SO2 stress in Arabidopsis thaliana shoots. A total of 27 conserved miRNAs and 5 novel miRNAs were found to be differentially expressed under SO2 stress. qRT-PCR analysis showed mostly negative correlation between miRNA accumulation and target gene mRNA abundance, suggesting regulatory roles of these miRNAs during SO2 exposure. The target genes of SO2-responsive miRNAs encode transcription factors and proteins that regulate auxin signaling and stress response, and the miRNAs-mediated suppression of these genes could improve plant resistance to SO2 stress. Promoter sequence analysis of genes encoding SO2 responsive miRNAs showed that stress-responsive and phytohormone-related cis regulatory elements occurred frequently, providing additional evidence of the involvement of miRNAs in adaption to SO2 stress. This study represents a comprehensive expression profiling of SO2-responsive miRNAs in Arabidopsis and broads our perspective on the ubiquitous regulatory roles of miRNAs under stress conditions. PMID- 27232730 TI - Sex-specific associations of moderate and vigorous physical activity with physical fitness in adolescents. AB - The present study examined the sex-specific associations of moderate and vigorous physical activity (VPA) with physical fitness in 300 Japanese adolescents aged 12 14 years. Participants were asked to wear an accelerometer to evaluate physical activity (PA) levels of various intensities (i.e. moderate PA (MPA), 3-5.9 metabolic equivalents (METs); VPA, >=6 METs; moderate to vigorous PA (MVPA), >=3 METs). Eight fitness items were assessed (grip strength, bent-leg sit-up, sit-and reach, side step, 50 m sprint, standing long jump, handball throw, and distance running) as part of the Japanese standardised fitness test. A fitness composite score was calculated using Japanese fitness norms, and participants were categorised according to their score from category A (most fit) to category E (least fit), with participants in categories D and E defined as having low fitness. It was found that for boys, accumulating more than 80.7 min/day of MVPA may reduce the probability of low fitness (odds ratio (ORs) [95% confidence interval (CI)] = 0.17 [0.06-0.47], p = .001). For girls, accumulating only 8.4 min of VPA could reduce the likelihood of exhibiting low fitness (ORs [95% CI] = 0.23 [0.05-0.89], p = .032). These results reveal that there are sex-specific differences in the relationship between PA and physical fitness in adolescents, suggesting that sex-specific PA recommendation may be needed to improve physical fitness in adolescents. PMID- 27232731 TI - Outcome of infants operated on for congenital pulmonary malformations. AB - INTRODUCTION: Patients operated on for congenital pulmonary malformations (CPM) have excellent survival rates, but little is known about long-term morbidity. Our aim is to report the sequelae in patients operated on for CPM in infancy and to define factors that may influence their outcome. METHODS: All patients operated on for major congenital anomalies are followed in a dedicated outpatient program and evaluated at 6, 24, and 48 months of life (corrected for gestational age) and at school age at 4, 6, 8, and 12 years of life. The data are prospectively collected. Patients operated on for CPM and enrolled in the follow-up clinic between January 2004 and December 2010 are compared with a control group of term infants operated on for inguinal hernia, without other major congenital or acquired abnormalities. The two groups were compared for auxological, respiratory, and orthopedic outcome. RESULTS: In the study period, 76 consecutive patients with CPM attended our dedicated follow-up clinic. Eight non-operated patients were excluded from the study. Age at follow-up was 82.0 (56.1-103.7) months in CPM patients and 83.5 (75.2-90.4) months in controls (P = 0.79). Fifty three patients with CPM (78%) had one or more clinical or radiological abnormality versus six (16%) control patients (OR [95%CI] 16.5 [5.8-47.2]; P < 0.0001). CONCLUSIONS: Over 50% of patients with CPM present long-term sequelae, regardless type of malformation. Therefore, long-term follow-up of patients operated on for CPM is recommended. Further studies are needed to define if, in asymptomatic patients, surgery may modify the natural history of CPM. Pediatr Pulmonol. 2016;51:1367-1372. (c) 2016 Wiley Periodicals, Inc. PMID- 27232750 TI - Pancreas Transplantation: An Alarming Crisis in Confidence. AB - In the past decade, the annual number of pancreas transplantations performed in the United States has steadily declined. From 2004 to 2011, the overall number of simultaneous pancreas-kidney (SPK) transplantations in the United States declined by 10%, whereas the decreases in pancreas after kidney (PAK) and pancreas transplant alone (PTA) procedures were 55% and 34%, respectively. Paradoxically, this has occurred in the setting of improvements in graft and patient survival outcomes and transplanting higher-risk patients. Only 11 centers in the United States currently perform >=20 pancreas transplantations per year, and most centers perform <5 pancreas transplantations annually; many do not perform PAKs or PTAs. This national trend in decreasing numbers of pancreas transplantations is related to a number of factors including lack of a primary referral source, improvements in diabetes care and management, changing donor and recipient considerations, inadequate training opportunities, and increasing risk aversion because of regulatory scrutiny. A national initiative is needed to "reinvigorate" SPK and PAK procedures as preferred transplantation options for appropriately selected uremic patients taking insulin regardless of C-peptide levels or "type" of diabetes. Moreover, many patients may benefit from PTAs because all categories of pancreas transplantation are not only life enhancing but also life extending procedures. PMID- 27232752 TI - Behavioral research as physical enrichment for captive chimpanzees. AB - In this study, we evaluated the potential for a behavioral research study, designed to evaluate chimpanzee decision-making behavior, to also encourage increased activity in a group of zoo-housed chimpanzees. For the behavioral study, the chimpanzees had to carry tokens to different locations such that they always had to travel farther to obtain a more-preferred reward. We recorded the distance travelled by each subject in each of the three phases of the 15-month study. By the final phase, the chimpanzees' rate of travel during test sessions was significantly higher compared to their baseline activity. Importantly, the chimpanzees' increase in locomotion was not dependent on their participation in the study; rate of travel was not correlated with number of tokens exchanged. However, the chimpanzees' activity returned to baseline within 2 hr of the 30-min test sessions. This study emphasizes the role that research can have in providing enrichment, the importance for long-term enrichment plans, and the essential need to evaluate the impact of research on animal participants, just as we evaluate the efficacy of enrichment strategies. Zoo Biol. 35:293-297, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27232753 TI - The Great Migration and African-American Genomic Diversity. AB - We present a comprehensive assessment of genomic diversity in the African American population by studying three genotyped cohorts comprising 3,726 African Americans from across the United States that provide a representative description of the population across all US states and socioeconomic status. An estimated 82.1% of ancestors to African-Americans lived in Africa prior to the advent of transatlantic travel, 16.7% in Europe, and 1.2% in the Americas, with increased African ancestry in the southern United States compared to the North and West. Combining demographic models of ancestry and those of relatedness suggests that admixture occurred predominantly in the South prior to the Civil War and that ancestry-biased migration is responsible for regional differences in ancestry. We find that recent migrations also caused a strong increase in genetic relatedness among geographically distant African-Americans. Long-range relatedness among African-Americans and between African-Americans and European-Americans thus track north- and west-bound migration routes followed during the Great Migration of the twentieth century. By contrast, short-range relatedness patterns suggest comparable mobility of ~15-16km per generation for African-Americans and European Americans, as estimated using a novel analytical model of isolation-by-distance. PMID- 27232754 TI - Prospecting for Energy-Rich Renewable Raw Materials: Sorghum Stem Case Study. AB - Sorghum vegetative tissues are becoming increasingly important for biofuel production. The composition of sorghum stem tissues is influenced by genotype, environment and photoperiod sensitivity, and varies widely between varieties and also between different stem tissues (outer rind vs inner pith). Here, the amount of cellulose, (1,3;1,4)-beta-glucan, arabinose and xylose in the stems of twelve diverse sorghum varieties, including four photoperiod-sensitive varieties, was measured. At maturity, most photoperiod-insensitive lines had 1% w/w (1,3;1,4) beta-glucan in stem pith tissue whilst photoperiod-sensitive varieties remained in a vegetative stage and accumulated up to 6% w/w (1,3;1,4)-beta-glucan in the same tissue. Three sorghum lines were chosen for further study: a cultivated grain variety (Sorghum bicolor BTx623), a sweet variety (S. bicolor Rio) and a photoperiod-sensitive wild line (S. bicolor ssp. verticilliflorum Arun). The Arun line accumulated 5.5% w/w (1,3;1,4)-beta-glucan and had higher SbCslF6 and SbCslH3 transcript levels in pith tissues than did photoperiod-insensitive varieties Rio and BTx623 (<1% w/w pith (1,3;1,4)-beta-glucan). To assess the digestibility of the three varieties, stem tissue was treated with either hydrolytic enzymes or dilute acid and the release of fermentable glucose was determined. Despite having the highest lignin content, Arun yielded significantly more glucose than the other varieties, and theoretical calculation of ethanol yields was 10 344 L ha-1 from this sorghum stem tissue. These data indicate that sorghum stem (1,3;1,4)-beta-glucan content may have a significant effect on digestibility and bioethanol yields. This information opens new avenues of research to generate sorghum lines optimised for biofuel production. PMID- 27232755 TI - Autophagy maintains ubiquitination-proteasomal degradation of Sirt3 to limit oxidative stress in K562 leukemia cells. AB - Sirtuin protein family member 3 (Sirt3) has been suggested as a positive regulator in alleviating oxidative stress by acting on the mitochondrial antioxidant machinery in solid tumors; however, its role and regulation in hematological malignancies has been poorly understood. Here, we show that contrary to what has been reported in solid tumors, in K562 leukemia cells elevated Sirt3 was associated with mitochondrial stress, and depletion of Sirt3 decreased reactive oxygen species (ROS) generation and lipid oxidation, but increased the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG), suggesting an opposite role of Sirt3 in regulating oxidative stress in the leukemia cells. Notably, loss of autophagy by deletion of autophagy essential gene or by pharmacological inhibition on autophagic degradation caused a significant accumulation of Sirt3. However, induced activation of autophagy did not cause autophagic degradation of Sirt3. Furthermore, inhibiting proteasome activity accumulated Sirt3 in autophagy-intact but not autophagy-defective cells, and disrupting functional autophagy either genetically or pharmacologically caused significantly less ubiquitination of Sirt3. Therefore, our data suggest that basal but not enhanced autophagy activity maintains ubiquitination proteasomal degradation of Sirt3 to limit lipid oxidative stress, representing an adaptive mechanism by which autophagy, in collaboration with the ubiquitination proteasomal system, controls oxidative stress by controlling the levels of certain proteins in K562 leukemia cells. PMID- 27232757 TI - The molecular mechanism of G2M cell cycle arrest induced by AFB1 in the jejunum. AB - Aflatoxin B1 (AFB1) has potent hepatotoxic, carcinogenic, genotoxic, immunotoxic and other adverse effects in human and animals. The aim of this study was to investigate the molecular mechanism of G2/M cell cycle arrest induced by AFB1 in the jejunum of broilers. Broilers, as experimental animals, were fed 0.6 mg/kg AFB1 diet for 3 weeks. Our results showed that AFB1 reduced the jejunal villus height, villus height/crypt ratio and caused G2/M cell cycle arrest. The G2/M cell cycle was accompanied by the increase of ataxia telangiectasia mutated (ATM), p53, Chk2, p21 protein and mRNA expression, and the decrease of Mdm2, cdc25C, cdc2, cyclin B and proliferating cell nuclear antigen protein and mRNA expression. In conclusion, AFB1 blocked G2/M cell cycle by ATM pathway in the jejunum of broilers. PMID- 27232756 TI - Dietary phytochemicals and cancer chemoprevention: a review of the clinical evidence. AB - Cancer chemoprevention involves the use of different natural or biologic agents to inhibit or reverse tumor growth. Epidemiological and pre-clinical data suggest that various natural phytochemicals and dietary compounds possess chemopreventive properties, and in-vitro and animal studies support that these compounds may modulate signaling pathways involved in cell proliferation and apoptosis in transformed cells, enhance the host immune system and sensitize malignant cells to cytotoxic agents. Despite promising results from experimental studies, only a limited number of these compounds have been tested in clinical trials and have shown variable results. In this review, we summarize the data regarding select phytochemicals including curcumin, resveratrol, lycopene, folates and tea polyphenols with emphasis on the clinical evidence supporting the efficacy of these compounds in high-risk populations. PMID- 27232758 TI - FBW7 regulates DNA interstrand cross-link repair by modulating FAAP20 degradation. AB - Mutations that deregulate protein degradation lead to human malignancies. The SCF ubiquitin E3 ligase complex degrades key oncogenic regulators, thereby limiting their oncogenic potential. FBW7 is a substrate recognition subunit of SCFFBW7 and is among the most commonly mutated ubiquitin-proteasome system proteins in cancer. FBW7-mutated cancer cells display increased genome instability, but the molecular mechanism by which FBW7 preserves genome integrity remains elusive. Here, we demonstrate that SCFFBW7 regulates the stability of FAAP20, a critical component of the Fanconi anemia (FA) DNA interstrand cross-link (ICL) repair pathway. Phosphorylation of the FAAP20 degron motif by GSK3beta provides a platform for recognition and polyubiquitination of FAAP20 by FBW7, and its subsequent degradation by the proteasome. Accordingly, enhanced GSK3beta-FBW7 signaling disrupts the FA pathway. In cells expressing non-phosphorylatable FAAP20 mutant, the turnover of its binding partner, FANCA, is deregulated in the chromatin during DNA ICL repair, and the FA pathway is compromised. We propose that FAAP20 degradation, which is prompted by its phosphorylation, controls the dynamics of the FA core complex required for completing DNA ICL repair. Together, this study provides insights into how FBW7-mediated proteolysis regulates genome stability and how its deregulation is associated with tumorigenesis. PMID- 27232759 TI - Interferon regulatory factor 4 attenuates Notch signaling to suppress the development of chronic lymphocytic leukemia. AB - Molecular pathogenesis of Chronic Lymphocytic Leukemia (CLL) is not fully elucidated. Genome wide association studies have linked Interferon Regulatory Factor 4 (IRF4) to the development of CLL. We recently established a causal relationship between low levels of IRF4 and development of CLL. However, the molecular mechanism through which IRF4 suppresses CLL development remains unclear. Deregulation of Notch signaling pathway has been identified as one of the most recurrent molecular anomalies in the pathogenesis of CLL. Yet, the role of Notch signaling as well as its regulation during CLL development remains poorly understood. Previously, we demonstrated that IRF4 deficient mice expressing immunoglobulin heavy chain Vh11 (IRF4-/-Vh11) developed spontaneous CLL with complete penetrance. In this study, we show that elevated Notch2 expression and the resulting hyperactivation of Notch signaling are common features of IRF4-/-Vh11 CLL cells. Our studies further reveal that Notch signaling is indispensable for CLL development in the IRF4-/-Vh11 mice. Moreover, we identify E3 ubiquitin ligase Nedd4, which targets Notch for degradation, as a direct target of IRF4 in CLL cells and their precursors. Collectively, our studies provide the first in vivo evidence for an essential role of Notch signaling in the development of CLL and establish IRF4 as a critical regulator of Notch signaling during CLL development. PMID- 27232761 TI - Characterisation of the thermodynamics, structure and dynamics of a water-like model in 2- and 3-dimensions. AB - The physical properties of colloidal particles suspended in an aqueous environment are well-understood when the latter is considered to be a continuum and a structureless medium. However, this approach fails to explain complex phenomena, for example, the critical Casimir forces among colloids and the colloidal self-assembly near critical solvents, and the inertial contribution of the solvent molecules on the diffusion of non-spherical Brownian particles. Therefore, the role played by the solvent on the physical properties of colloidal dispersions is of paramount relevance. Recently, there has been an interest in the (non-trivial) diffusion mechanisms of a nano-colloidal particle in a solvent that undergoes a vapour-liquid transition. Nonetheless, the models typically used to incorporate the solvent details do not capture quantitatively the thermodynamic properties of real substances. It is then important to study the Brownian motion of colloids in more realistic models. To reach such goal, one first has to characterise the thermodynamic states and the microscopic features of the solvent. Hence, in this contribution, we have investigated the coexistence densities of a core-softened potential in two- and three-dimensions, whose potential parameters are able to capture some anomalies of water. We show that in the two-dimensional case, the potential model exhibits, besides the normal vapour liquid coexistence region, additional liquid-liquid coexistence densities. We particularly focus our attention to the structural properties and the dynamical behaviour of the solvent around the liquid-liquid critical point and assess the differences with the three-dimensional case. PMID- 27232760 TI - Utility of a human FcRn transgenic mouse model in drug discovery for early assessment and prediction of human pharmacokinetics of monoclonal antibodies. AB - Therapeutic antibodies continue to develop as an emerging drug class, with a need for preclinical tools to better predict in vivo characteristics. Transgenic mice expressing human neonatal Fc receptor (hFcRn) have potential as a preclinical pharmacokinetic (PK) model to project human PK of monoclonal antibodies (mAbs). Using a panel of 27 mAbs with a broad PK range, we sought to characterize and establish utility of this preclinical animal model and provide guidance for its application in drug development of mAbs. This set of mAbs was administered to both hemizygous and homozygous hFcRn transgenic mice (Tg32) at a single intravenous dose, and PK parameters were derived. Higher hFcRn protein tissue expression was confirmed by liquid chromatography-high resolution tandem mass spectrometry in Tg32 homozygous versus hemizygous mice. Clearance (CL) was calculated using non-compartmental analysis and correlations were assessed to historical data in wild-type mouse, non-human primate (NHP), and human. Results show that mAb CL in hFcRn Tg32 homozygous mouse correlate with human (r(2) = 0.83, r = 0.91, p < 0.01) better than NHP (r(2) = 0.67, r = 0.82, p < 0.01) for this dataset. Applying simple allometric scaling using an empirically derived best-fit exponent of 0.93 enabled the prediction of human CL from the Tg32 homozygous mouse within 2-fold error for 100% of mAbs tested. Implementing the Tg32 homozygous mouse model in discovery and preclinical drug development to predict human CL may result in an overall decreased usage of monkeys for PK studies, enhancement of the early selection of lead molecules, and ultimately a decrease in the time for a drug candidate to reach the clinic. PMID- 27232762 TI - Abnormal mRNA splicing but normal auditory brainstem response (ABR) in mice with the prestin (SLC26A5) IVS2-2A>G mutation. AB - Prestin is critical to OHC somatic motility and hearing sensitivity in mammals. Several mutations of the human SLC26A5 gene have been associated with deafness. However, whether the IVS2-2A>G mutation in the human SLC26A5 gene causes deafness remains controversial. In this study, we created a mouse model in which the IVS2 2A>G mutation was introduced into the mouse Slc26a5 gene by gene targeting. The homozygous Slc26a5 mutant mice were viable and fertile and displayed normal hearing sensitivity by ABR threshold analysis. Whole-mount immunostaining using prestin antibody demonstrated that prestin was correctly targeted to the lateral wall of OHCs, and no obvious hair cell loss occurred in mutant mice. No significant difference in the amount of prestin protein was observed between mutants and controls using western blot analysis. In OHCs isolated from mutants, the NLC was also normal. However, we observed a splicing abnormality in the Slc26a5 mRNA of the mutant mice. Eleven nucleotides were missing from the 5' end of exon 3 in Slc26a5 mRNA, but the normal ATG start codon in exon 3 was still detected. Thus, the IVS2-2A>G mutation in the Slc26a5 gene is insufficient to cause hearing loss in mice. PMID- 27232764 TI - Editorial. PMID- 27232763 TI - Behavior of P85 and P188 Poloxamer Molecules: Computer Simulations Using United Atom Force-Field. AB - To study the interaction between poloxamer molecules and lipid bilayers using molecular dynamics simulation technique with the united-atom resolution, we augmented the GROMOS force-field to include poloxamers. We validated the force field by calculating the radii of gyration of two poloxamers, P85 and P188, solvated in water and by considering the poloxamer density distributions at the air/water interface. The emphasis of our simulations was on the study of the interaction between poloxamers and lipid bilayer. At the water/lipid bilayer interface, we observed that both poloxamers studied, P85 and P188, behaved like surfactants: the hydrophilic blocks of poloxamers became adsorbed at the polar interface, while their hydrophobic block penetrated the interface into the aliphatic tail region of the lipid bilayer. We also observed that when P85 and P188 poloxamers interacted with damaged membranes that contained pores, the hydrophobic blocks of copolymers penetrated into the membrane in the vicinity of the pore and compressed the membrane. Due to this compression, water molecules were evacuated from the pore. PMID- 27232766 TI - Preoperative evaluation using magnetoencephalography: Experience in 382 epilepsy patients. AB - OBJECTIVE: Identifying epilepsy patients for whom clinical MEG is likely to be beneficial avoids or optimizes burdensome ancillary investigations. We determined whether it could be predicted upfront if MEG would be able to generate a hypothesis about the location of the epileptogenic zone (EZ), and in which patients MEG fails to do so. METHODS: MEG recordings of 382 epilepsy patients with inconclusive findings regarding EZ localization prior to MEG were acquired for preoperative evaluation. MEG reports were categorized for several demographic, clinical and MEG variables. First, demographic and clinical variables were associated with MEG localization ability for upfront prediction. Second, all variables were compared between patients with and without MEG location in order to characterize patients without MEG location. RESULTS: Our patient group had often complex etiology and did not contain the (by other means) straightforward and well-localized cases, such as those with concordant tumor and EEG location. For our highly-selected patient group, MEG localization ability cannot be predicted upfront, although the odds of a recording with MEG location were significantly higher in the absence of a tumor and in the presence of widespread MRI abnormalities. Compared to the patients with MEG location, patients without MEG location more often had a tumor, widespread EEG abnormalities, non-lateralizing MEG abnormalities, non-concordant MEG/EEG abnormalities and less often widespread MRI abnormalities or epileptiform MEG activity. In a subgroup of 48 patients with known surgery outcome, more patients with concordant MEG and resection area were seizure-free than patients with discordant results. CONCLUSIONS: MEG potentially adds information about the location of the EZ even in patients with a complex etiology, and the clinical advice is to not withhold MEG in epilepsy surgery candidates. Providing a hypothesis about the location of the EZ using MEG is difficult in patients with inconclusive EEG and MRI findings, and in the absence of specific epileptiform activity. More refined methods are needed for patients where MEG currently does not contribute to the hypothesis about the location of the EZ. PMID- 27232767 TI - Luminal Ca(2+) dynamics during IP3R mediated signals. AB - The role of cytosolic Ca(2+) on the kinetics of Inositol 1,4,5-triphosphate receptors (IP3Rs) and on the dynamics of IP3R-mediated Ca(2+) signals has been studied at large both experimentally and by modeling. The role of luminal Ca(2+) has not been investigated with that much detail although it has been found that it is relevant for signal termination in the case of Ca(2+) release through ryanodine receptors. In this work we present the results of observing the dynamics of luminal and cytosolic Ca(2+) simultaneously in Xenopus laevis oocytes. Combining observations and modeling we conclude that there is a rapid mechanism that guarantees the availability of free Ca(2+) in the lumen even when a relatively large Ca(2+) release is evoked. Comparing the dynamics of cytosolic and luminal Ca(2+) during a release, we estimate that they are consistent with a 80% of luminal Ca(2+) being buffered. The rapid availability of free luminal Ca(2+) correlates with the observation that the lumen occupies a considerable volume in several regions across the images. PMID- 27232768 TI - Comments on Cooper et al.'s review on strategies to mitigate dissociative and psychotomimetic effects from ketamine when used as a fast-acting antidepressant. PMID- 27232769 TI - Kinetic Study of [2]Pseudorotaxane Formation with an Asymmetrical Thread. AB - Kinetic and thermodynamic studies on cyclodextrin (CD)-based [2]pseudorotaxane formation have been carried out by a combination of NMR and calorimetric techniques using bolaform surfactants as axles. Experimental evidence of the formation of an external complex between the trimethylammonium head groups of the axle and the external hydrogen atoms of alpha-cyclodextrin (alpha-CD) is reported. Inclusion of this external complex in the reaction pathway allows us to explain the kinetic behavior as well as the nonlinear dependence of the observed rate constant on CD concentrations. The equilibrium constant for [2]pseudorotaxane formation is strongly affected by the spacer length of the axle. This effect is a consequence of increasing rotaxane stability because the threading rate constant is almost independent of the spacer length, but dethreading strongly decreases on increasing the axle size. Using a nonsymmetrical axle with tripropyl and trimethylammonium cations precludes CD threading by the large head side. CDs will thread this asymmetrical bolaform by both their wide and narrow sides, yielding two isomeric [2]pseudorotaxanes. Threading by the wide side of the CD is 60% more favorable than that by the narrow one, but dethreading rate constants are the same for both isomers. PMID- 27232770 TI - Encapsulins: microbial nanocompartments with applications in biomedicine, nanobiotechnology and materials science. AB - Compartmentalization is one of the defining features of life. Cells use protein compartments to exert spatial control over their metabolism, store nutrients and create unique microenvironments needed for essential physiological processes. Encapsulins are a recently discovered class of protein nanocompartments found in bacteria and archaea that naturally encapsulate cargo proteins. A short C terminal targeting sequence directs the highly specific encapsulation process in vivo. Here, I will initially discuss the properties, diversity and putative function of encapsulins. The unique characteristics and potential uses of the self-sorting cargo-packaging process found in encapsulin systems will then be highlighted. Examples for the application of encapsulins as cell-specific optical nanoprobes and targeted therapeutic delivery systems will be discussed with an emphasis on the ability to integrate multiple functionalities within a single nanodevice. By fusing targeting sequences to non-native proteins, encapsulins can also be used as specific nanocontainers and enzymatic nanoreactors in vivo. I will end by briefly discussing future avenues for encapsulin research related to both basic microbial metabolism and applications in biomedicine, catalysis and materials science. PMID- 27232822 TI - Electrokinetic removal of radionuclides contained in scintillation liquids absorbed in soil type Phaeozem. AB - Control samples of scintillation liquids - Phaeozem soil mixtures were prepared with different scintillation liquids as the support electrolyte, Install Gel(r) XF, (Ultima Gold ABTM and Ultima Gold XRTM), to construct the polarization curves, and to select the cell potential with the highest mass transfer to remove 24Na (15 h) and 99mTc (6 h) as radiotracers from polluted Phaeozem soil. During the electrokinetic treatment (EKT), the removal of radionuclides contained in scintillation liquids absorbed in Phaeozem soil, liquid phase was characterized by Gas Chromatography coupled with a Flame Ionization Detector (GC-FID) and Fourier Transform Infrared Spectrometry (FTIR), solids by FTIR, before and after the application of cell potential. In this sense, the support electrolyte was selected based on the highest current generated (1 mA), as in the case of scintillation liquid 50% Ultima Gold XRTM + 50% Water (1:1), which was used for 6 h in the presence of a mesh and a titanium rod, as anode and cathode, respectively. Finally, the removal percentage accumulated in the liquid phase after the EKT of Phaeozem soil polluted by 99mTc was 61% close to the anode after 4 h. It was also 61% for 24Na close to cathode after 2 h, and after 4 h it was 71.8%. PMID- 27232771 TI - Procedural ultrasound in pediatric patients: techniques and tips for accuracy and safety. AB - Point-of-care ultrasound is becoming more prevalent in pediatric emergency departments as a critical adjunct to both diagnosis and procedure guidance. It is cost-effective, safe for unstable patients, and easily repeatable as a patient's clinical status changes. Point-of-care ultrasound does not expose the patient to ionizing radiation and may care ultrasound in pediatric emergency medicine is relatively new, the body of literature evaluating its utility is small, but growing. Data from adult emergency medicine, radiology, critical care, and anesthesia evaluating the utility of ultrasound guidance must be extrapolated to pediatric emergency medicine. This issue will review the adult literature and the available pediatric literature comparing ultrasound guidance to more traditional approaches. Methods for using ultrasound guidance to perform various procedures, and the pitfalls associated with each procedure, will also be described. PMID- 27232823 TI - Environmental evolution records reflected by radionuclides in the sediment of coastal wetlands: A case study in the Yellow River Estuary wetland. AB - Vertical profiles of environmental radionuclides (210Pb, 137Cs, 238U, 232Th, 226Ra and 40K) in a sediment core (Y1) of the Yellow River Estuary wetland were investigated to assess whether environmental evolutions in the coastal wetland could be recorded by the distributions of radionuclides. Based on 210Pb and 137Cs dating, the average sedimentation rate of core Y1 was estimated to be 1.0 cm y-1. Vertical distributions of natural radionuclides (238U, 232Th, 226Ra and 40K) changed dramatically, reflecting great changes in sediment input. Concentrations of 238U, 232Th, 226Ra and 40K all had significant positive relationships with organic matter and clay content, but their distributions were determined by different factors. Factor analysis showed that 238U was determined by the river sediment input while 226Ra was mainly affected by the seawater erosion. Environmental changes such as river channel migrations and sediment discharge variations could always cause changes in the concentrations of radionuclides. High concentrations of 238U and 226Ra were consistent with high accretion rate. Frequent seawater intrusion decreased the concentration of 226Ra significantly. The value of 238U/226Ra tended to be higher when the sedimentation rate was low and tide intrusion was frequent. In summary, environmental evolutions in the estuary coastal wetland could be recorded by the vertical profiles of natural radionuclides. PMID- 27232824 TI - Evaluating remediation of radionuclide contaminated forest near Iwaki, Japan, using radiometric methods. AB - Radiometric surveys have been conducted in support of a project investigating the potential of biofuel power generation coupled with remediation of forests contaminated with radionuclides following the Fukushima Daiichi accident. Surveys conducted in 2013 and 2014 were used to determine the distribution and time dependence of radionuclides in a cedar plantation and adjacent deciduous forestry subject to downslope radionuclide migration, and a test area where litter removal was conducted. The radiocaesium results confirmed enhanced deposition levels in the evergreen areas compared with adjacent areas of deciduous forestry, implying significant differences in depositional processes during the initial interception period in 2011. Surveys were conducted both with and without a collimator on both occasions, which modified the angular response of the detector to separate radiation signals from above and below the detector. The combined data have been used to define the influence of radionuclides in the forest canopy on dose rate at 1 m, indicating that, in evergreen areas, the activity retained within the canopy even by 2013 contributed less than 5% of ground level dose rate. The time dependent changes observed allow the effect of remediation by litter removal in reducing radionuclide inventories and dose rates to be appraised relative natural redistribution processes on adjacent control areas. A 15 * 45 m area of cedar forest was remediated in September 2013. The work involved five people in a total of 160 person hours. It incurred a total dose of 40-50 MUSv, and generated 2.1 t of waste comprising forest litter and understory. Average dose rates were reduced from 0.31 MUSv h-1 to 0.22 MUSv h-1, with nuclide specific analyses indicating removal of 30 +/- 3% of the local radiocaesium inventory. This compares with annual removal rates of 10-15% where radionuclide migration down-slope over ranges of 10-50 m could be observed within adjacent areas. Local increases were also observed in areas identified as sinks. The results confirm the utility of time-series, collimated, radiometric survey methods to account for the distribution and changes in radionuclide inventory within contaminated forests. The data on litter removal imply that significant activity transfer from canopy to soil had taken place, and provide benchmark results against which such remediation actions can be appraised. PMID- 27232825 TI - The effect of gamma radiation on seed germination and seedling growth of Lathyrus chrysanthus Boiss. under in vitro conditions. AB - The effects of radiation at different doses (0, 50, 100, 150, 200 and 250 Gy) of radioactive cobalt (60Co) gamma rays on seed germination and seedling growth of Lathyrus chrysanthus were investigated under in vitro conditions. The results showed that irradiated seeds had increased seed germination percentage, seedling and root lengths, seedling fresh weight, seedling dry matter content and total chlorophyll content in the leaves of seedlings. However, at higher doses stress was evident and significant decreases in all parameters were observed. The highest seed germination percentage was recorded as 62.4%, 7 days after study initiation when seeds were irradiated with 150 Gy gamma dose, while 100 Gy gamma dose was ranked in second order. Fourteen days after culture initiation, the best shoot growth initiation was again obtained from 150 Gy gamma dose as 75.7% and this was followed by 100 Gy gamma radiation as 74.6%. Gamma doses over 150 Gy resulted in sharp decreases in all parameters examined. On the 14th day, the highest shoot and root lengths were recorded from 150 Gy gamma dose as 1.2 and 2.9 cm, respectively. Twenty eight days after study initiation, the highest values of seedling and root lengths, seedling fresh weight, seedling dry matter content and total chlorophyll content were noted from 50 Gy gamma radiation as 9.7 and 6.3 cm, 0.39, 0.09 g (23.08%) and 471.6 MUg/g fresh tissue, respectively. This study is important from the aspect of showing that stimulatory effect of low gamma doses for germination and seedling growth may not be the same. PMID- 27232826 TI - Repeated Suicide Attempts and Suicide Among Individuals With a First Emergency Department Contact for Attempted Suicide: A Prospective, Nationwide, Danish Register-Based Study. AB - OBJECTIVE: Emergency departments are important, albeit underutilized, sites for suicide prevention. Preventive strategies and interventions could benefit from a greater understanding of factors influencing the course of suicide risk after emergency department contact due to attempted suicide. The aim of our study was 2 fold: to identify predictors of repeated suicide attempts and suicide and to investigate the timing of these events. METHODS: Data from Danish nationwide, longitudinal registers were used in this prospective, population-based study of all individuals first presenting to an emergency department after attempted suicide (index attempt) between January 1, 1996, and December 31, 2011 (N = 11,802). Cox regression analysis identified predictors, and Kaplan-Meier survival analysis modeled the time to repeated suicide attempts and suicide. RESULTS: Sixteen percent of the sample repeated suicide attempt, and 1.4% died by suicide. Repetition was less likely among men than women (adjusted hazard ratio [AHR] = 0.70; 95% CI, 0.63-0.79), whereas those most prone to repeated attempts were individuals with recent psychiatric treatment (AHR = 2.19; 95% CI, 1.97-2.43) and those with recent psychiatric treatment (AHR = 2.19; 95% CI, 1.97-2.43). Predictors of suicide included age over 35 years (AHR = 5.56; 95% CI, 2.89 10.69); hanging, strangling, or suffocation as the method of the index attempt (AHR = 2.55; 95% CI, 1.29-5.01); and receiving psychiatric hospitalization for the index attempt (AHR = 1.74; 95% CI, 1.22-2.49). The cumulative rates of repeated attempts and suicide deaths in the total sample were particularly high within the first week of the index attempt, reaching 3.6% and 0.1%, respectively. CONCLUSIONS: Preventive efforts need to target the period close to discharge from emergency departments. PMID- 27232827 TI - Measurement of J-integral in CAD/CAM dental ceramics and composite resin by digital image correlation. AB - Ceramic and composite resin blocks for CAD/CAM machining of dental restorations are becoming more common. The sample sizes affordable by these blocks are smaller than ideal for stress intensity factor (SIF) based tests. The J-integral measurement calls for full field strain measurement, making it challenging to conduct. Accordingly, the J-integral values of dental restoration materials used in CAD/CAM restorations have not been reported to date. Digital image correlation (DIC) provides full field strain maps, making it possible to calculate the J integral value. The aim of this study was to measure the J-integral value for CAD/CAM restorative materials. Four types of materials (sintered IPS E-MAX CAD, non-sintered IPS E-MAX CAD, Vita Mark II and Paradigm MZ100) were used to prepare beam samples for three-point bending tests. J-integrals were calculated for different integral path size and locations with respect to the crack tip. J integral at path 1 for each material was 1.26+/-0.31*10(-4)MPam for MZ 100, 0.59+/-0.28*10(-4)MPam for sintered E-MAX, 0.19+/-0.07*10(-4)MPam for VM II, and 0.21+/-0.05*10(-4)MPam for non-sintered E-MAX. There were no significant differences between different integral path size, except for the non-sintered E MAX group. J-integral paths of non-sintered E-MAX located within 42% of the height of the sample provided consistent values whereas outside this range resulted in lower J-integral values. Moreover, no significant difference was found among different integral path locations. The critical SIF was calculated from J-integral (KJ) along with geometry derived SIF values (KI). KI values were comparable with KJ and geometry based SIF values obtained from literature. Therefore, DIC derived J-integral is a reliable way to assess the fracture toughness of small sized specimens for dental CAD/CAM restorative materials; however, with caution applied to the selection of J-integral path. PMID- 27232829 TI - Bond strength of a new generation of universal bonding systems to zirconia ceramic. AB - The purpose of this laboratory study was to evaluate the tensile bond strength of a new generation of universal bonding systems to zirconia ceramic and to compare the results with the bond strength of a clinically-established bonding system. Eighty zirconia ceramic test specimens (e.max ZirCAD) were air-abraded and bonded to Plexiglas tubes, filled with an aliphatic dimethacrylate filling material (Clearfil F II), using three so called universal bonding systems of a new generation with different compositions (Monobond Plus/MultilinkAutomix, NX3, Scotchbond Universal/RelyX Ultimate). The latter was used also without the phosphate monomer containing primer Scotchbond Universal. A clinically established phosphate monomer containing adhesive cement served as control group (Panavia F2.0). The specimens were stored in water at 37 degrees C for 3 or 150 days and the long-term storage series were additionally thermal cycled between 5 and 55 degrees C for 37,500 times to simulate oral conditions. All specimens underwent tensile bond strength testing. The statistical analysis was performed using Kruskal-Wallis and Wilcoxon-Test with a Bonferroni-Holm correction for multiple testing. After 150 days the median bond strength of RelyX Ultimate, with and without Scotchbond Universal, and Panavia F2.0 did not differ statistically (range: 21.7-28.8MPa), while the bond strength of Monobond Plus/Multilink Automix was significantly lower (15.4MPa), and that of NX3 the lowest (6.6MPa). After 150 days of water storage with thermal cycling, all adhesive system showed significantly reduced tensile bond strengths compared to that after 3 days. Only RelyX Ultimate was comparable to the established bonding system Panavia F2.0. The additional use of Scotchbond Universal did not result in a significant effect. PMID- 27232828 TI - Advanced zinc-doped adhesives for high performance at the resin-carious dentin interface. AB - The purpose of this study was to evaluate the remineralization ability of an etch and-rinse Zn-doped resin applied on caries-affected dentin (CAD). CAD surfaces were subjected to: (i) 37% phosphoric acid (PA) or (ii) 0.5M ethylenediaminetetraacetic acid (EDTA). 10wt% ZnO nanoparticles or 2wt% ZnCl2 were added into the adhesive Single Bond (SB), to create the following groups: PA+SB, PA+SB-ZnO, PA+SB-ZnCl2, EDTA+SB, EDTA+SB-ZnO, EDTA+SB-ZnCl2. Bonded interfaces were submitted to mechanical loading or stored during 24h. Remineralization of the bonded interfaces was studied by AFM nano-indentation (hardness and Young's modulus), Raman spectroscopy [mapping with principal component analysis (PCA), and hierarchical cluster analysis (HCA)] and Masson's trichrome staining technique. Dentin samples treated with PA+SB-ZnO attained the highest values of nano-mechanical properties. Load cycling increased both mineralization and crystallographic maturity at the interface; this effect was specially noticed when using ZnCl2-doped resin in EDTA-treated carious dentin. Crosslinking attained higher frequencies indicating better conformation and organization of collagen in specimens treated with PA+SB-ZnO, after load cycling. Trichrome staining technique depicted a deeper demineralized dentin fringe that became reduced after loading, and it was not observable in EDTA+SB groups. Multivariate analysis confirmed de homogenizing effect of load cycling in the percentage of variances, traces of centroids and distribution of clusters, especially in specimens treated with EDTA+SB-ZnCl2. PMID- 27232830 TI - Characterization, mechanical properties and corrosion resistance of biocompatible Zn-HA/TiO2 nanocomposite coatings. AB - Biocompatible Zinc-hydroxyapatite-titania and Zinc-hydroxyapatite nanocomposite coatings have been prepared by electrodeposition on NiTi shape memory alloy. Structures of coatings were characterized using X-ray diffraction (XRD). It was found that addition of TiO2 particles cause to reduction of crystallite size of coating. Scanning Electronic Microscope (SEM) observation showed that the Zn HA/TiO2 coating consists of plate-like regions which can express that this plate like structure can facilitate bone growth. X-ray photoelectron microscope (XPS) was performed to investigation of chemical state of composite coating and showed that Zinc matrix was bonded to oxygen. high-resolution transmission electron microscope (HRTEM) result illustrated the crystalline structure of nanocomposite coating. Mechanical behavior of coating was evaluated using microhardness and ball on disk wear test. The TiO2 incorporated composite coatings exhibited the better hardness and anti-wear performance than the Zn-HA coatings. Polarization measurements have been used to evaluate the electrochemical coatings performance. The Zn-HA/TiO2 composite coatings showed the highest corrosion resistance compared with Zn-HA and bare NiTi. PMID- 27232831 TI - Influence of frequency on shear fatigue strength of resin composite to enamel bonds using self-etch adhesives. AB - OBJECTIVES: The purpose of this study was to determine the influence of different frequency rates on of bond durability of self-etch adhesives to enamel using shear fatigue strength (SFS) testing. METHODS: A two-step self-etch adhesive (OX, OptiBond XTR), and two single step self-etch adhesives (GB, G-aenial Bond and SU, Scotchbond Universal) were used in this study. The shear fatigue strength (SFS) to enamel was obtained. A staircase method was used to determine the SFS values with 50,000 cycles or until failure occurred. Fatigue testing was performed at frequencies of 5Hz, 10Hz, and 20Hz. For each test condition, 30 specimens were prepared for the SFS testing. RESULTS: Regardless of the bond strength test method, OX showed significantly higher SFS values than the two single-step self etch adhesives. For each of the three individual self-etch adhesives, there was no significant difference in SFS depending on the frequency rate, although 20Hz results tended to be higher. CONCLUSIONS: Regardless of the self-etch adhesive system, frequencies of 5Hz, 10Hz, and 20Hz produced similar results in fatigue strength of resin composite bonded to enamel using 50,000 cycles or until bond failure. SIGNIFICANCE: Accelerated fatigue testing provides valuable information regarding the long term durability of resin composite to enamel bonding using self-etch adhesive system. PMID- 27232846 TI - How do general practitioners recognize the definition of multimorbidity? A European qualitative study. AB - BACKGROUND: Multimorbidity is a challenging concept for general practice. An EGPRN working group has published a comprehensive definition of the concept of multimorbidity. As multimorbidity could be a way to explore complexity in general practice, it was of importance to explore whether European general practitioners (GPs) recognize this concept and whether they would change it. OBJECTIVES: To investigate whether European GPs recognize the EGPRN concept of multimorbidity and whether they would change it. METHODS: Focus group meetings and semi structured interviews as data collection techniques with a purposive sample of practicing GPs from every country. Data collection continued until saturation was reached in every country. The analysis was undertaken using a grounded theory based method. In each national team, four independent researchers, working blind and pooling data, carried out the analysis. To ensure the internationalization of the data, an international team of 10 researchers pooled the axial and selective coding of all national teams to check the concept and highlight emerging themes. RESULTS: The maximal variation and saturation of the sample were reached in all countries with 211 selected GPs. The EGPRN definition was recognized in all countries. Two additional ideas emerged, the use of Wonca's core competencies of general practice, and the dynamics of the doctor-patient relationship for detecting and managing multimorbidity and patient's complexity. CONCLUSION: European GPs recognized and enhanced the EGPRN concept of multimorbidity. These results open new perspectives regarding the management of complexity using the concept of multimorbidity in general practice. [Box: see text]. PMID- 27232847 TI - In Cellulo Mapping of Subcellular Localized Bilirubin. AB - Bilirubin (BR) is a de novo synthesized metabolite of human cells. However, subcellular localization of BR in the different organelles of human cells has been largely unknown. Here, utilizing UnaG as a genetically encoded fluorescent BR sensor, we report the existence of relatively BR-enriched and BR-depleted microspaces in various cellular organelles of live cells. Our studies indicate that (i) the cytoplasmic facing membrane of the endoplasmic reticulum (ER) and the nucleus are relatively BR-enriched spaces and (ii) mitochondrial intermembrane space and the ER lumen are relatively BR-depleted spaces. Thus, we demonstrate a relationship between such asymmetrical BR distribution in the ER membrane and the BR metabolic pathway. Furthermore, our results suggest plausible BR-transport and BR-regulating machineries in other cellular compartments, including the nucleus and mitochondria. PMID- 27232848 TI - Production and Characterization of Desmalonichrome Relative Binding Affinity for Uranyl Ions in Relation to Other Siderophores. AB - Siderophores are iron (Fe)-binding secondary metabolites that have been investigated for their uranium-binding properties. Previous work has focused on characterizing hydroxamate types of siderophores, such as desferrioxamine B, for their uranyl (UO2)-binding affinity. Carboxylate forms of these metabolites hold potential to be more efficient chelators of UO2, yet they have not been widely studied. Desmalonichrome is a carboxylate siderophore that is not commercially available and so was obtained from the fungus Fusarium oxysporum cultivated under Fe-depleted conditions. The relative affinity for UO2 binding of desmalonichrome was investigated using a competitive analysis of binding affinities between UO2 acetate and different concentrations of Fe(III) chloride using electrospray ionization mass spectrometry. In addition to desmalonichrome, three other siderophores, including two hydroxamates (desferrioxamine B and desferrichrome) and one carboxylate (desferrichrome A), were studied to understand their relative affinities for the UO2(2+) ion at two pH values. The binding affinities of hydroxamate siderophores to UO2(2+) ions were observed to decrease with increasing Fe(III)Cl3 concentration at the lower pH. On the other hand, decreasing the pH has a smaller impact on the binding affinities between carboxylate siderophores and the UO2(2+) ion. Desmalonichrome in particular was shown to have the greatest relative affinity for UO2 at all pH and Fe(III) concentrations examined. These results suggest that acidic functional groups in the ligands are important for strong chelation with UO2 at lower pH. PMID- 27232851 TI - PlncRNA-1 induces apoptosis through the Her-2 pathway in prostate cancer cells. AB - To determine whether PlncRNA-1 induces apoptosis in prostate cancer cells through the Her-2 pathway. The expression of PlncRNA-1, Her-2, and related cyclin proteins in 23 cases of prostate cancer and adjacent normal tissues was analyzed and compared. LNCaP cells were divided into a control group and an LNCaP-PlncRNA 1-siRNA experimental group. Normal prostate RWPE-1 cells were divided into an RWPE-1 control group and an RWPE-1-PlncRNA-1 experimental group. After PlncRNA-1 silencing and overexpression, changes in Her-2 and cyclinD1 expression levels were detected both in vivo and in vitro. In prostate cancer tissues, Her-2 and PlncRNA-1 were highly expressed and significantly correlated. In LNCaP cells, the expression of Her-2 and cyclinD1 decreased following the downregulation of PlncRNA-1 as assessed by real-time PCR and Western blotting. In RWPE-1 cells, the expression of Her-2 and cyclinD1 increased following PlncRNA-1 overexpression. Flow cytometry revealed that the proportion of LNCaP cells in G2/M phase was significantly increased after PlncRNA-1 silencing and that the proportion of RWPE 1 cells in G2/M phase was significantly decreased after PlncRNA-1 overexpression. Furthermore, animal experiments validated these results. In conclusion, in prostate cancer, PlncRNA-1 regulates the cell cycle and cyclinD1 levels and can also regulate proliferation and apoptosis in prostate cancer cells through the Her-2 pathway. PMID- 27232850 TI - Oviductal epithelial cells selected boar sperm according to their functional characteristics. AB - The interaction of oviductal epithelial cells (OECs) with the spermatozoa has beneficial effects on the sperm functions. The aim of this study is to evaluate the in vitro fertilizing capacity of incubating spermatozoa previously selected by density gradient in OEC and determinate some sperm characteristics that could explain the results obtained. In this study, we assessed in vitro fertilization (IVF), tyrosine phosphorylation, phosphatidylserine translocation, nuclear DNA fragmentation, and chromatin decondensation. Three experimental sperm groups, previously selected by Percoll gradient, were established according to the origin of the sperm used for IVF: (i) W30 group: spermatozoa were incubated with oocytes in the absence of OEC; (ii) NB group: after sperm incubation in OEC, the unbound spermatozoa were incubated with oocytes, in the absence of OEC; and (iii) B group: after sperm incubation with OEC, the bound spermatozoa were incubated with oocytes in the OEC plates. The results showed that sperm from the NB group led to a lower IVF yield, accompanied by low penetration rates (NB: 19.6%, B: 94.9%, and W30: 62.9%; P < 0.001) and problems of nuclear decondensation. Moreover, higher levels of tyrosine phosphorylation were observed in the NB group compared with the W30 and B groups (NB: 58.7%, B: 2.5%, and W30: 4.5%; P < 0.01). A similar trend was observed in phosphatidylserine translocation (NB: 93.7%, B: 5.7%, and W30: 44.2%; P < 0.01). These results demonstrate that the OEC exerts a rigorous degree of sperm selection, even within an already highly selected population of spermatozoa, and can capture the best functional spermatozoa for fertilization. PMID- 27232852 TI - Strong association of SLC1A1 and DPF3 gene variants with idiopathic male infertility in Han Chinese. AB - Male infertility is a multifactorial syndrome encompassing a wide variety of disorders. In recent years, several genome-wide single-nucleotide polymorphism (SNP) association studies (GWAS) have been performed on azoospermia and/or oligozoospermia in different populations including two GWAS on nonobstructive azoospermia in China; however, the association of SNPs with idiopathic male infertility, especially asthenozoospermia and oligozoospermia, and their correlation with semen parameters are still not clear. To investigate genetic variants associated with idiopathic male infertility (asthenozoospermia, oligozoospermia, and oligoasthenozoospermia) in Chinese Han people, 20 candidate SNPs were selected from GWAS results and genotyped using the Sequenom MassARRAY assay. A total of 136 subfertile men and 456 healthy fertile men were recruited. rs6476866 in SLC1A1 (P = 1.919E-4, OR = 0.5905, 95% CI: 0.447-0.78) and rs10129954 in DPF3 (P = 0.0023, OR = 2.199, 95% CI: 1.311-3.689) were strongly associated with idiopathic male infertility. In addition, positive associations were observed between asthenozoospermia and rs215702 in LSM5 (P = 0.0016, OR = 1.479, 95% CI: 1.075-2.033) and between oligoasthenozoospermia and rs2477686 in PEX10 (P = 0.0011, OR = 2.935, 95% CI: 1.492-5.775). In addition, six SNPs (rs215702 in LSM5, rs6476866 in SLC1A1, rs10129954 in DPF3, rs1801133 in MTHFR, rs2477686 in PEX10, and rs10841496 in PED3A) were significantly correlated with semen quality alterations. Our results suggest that idiopathic male infertility in different ethnic groups may share the same mechanism or pathway. Cohort expansion and further mechanistic studies on the role of genetic factors that influence spermatogenesis and sperm progressive motility are suggested. PMID- 27232853 TI - No increased risk of dementia in patients receiving androgen deprivation therapy for prostate cancer: a 5-year follow-up study. AB - Prior studies suggested that the use of androgen deprivation therapy (ADT) in patients with prostate cancer (PC) might cause the impairment of cognitive function which is one of the common symptoms of dementia; however, the association between ADT and cognitive impairment still remains controversial. This retrospective cohort study aimed to investigate the relationship between ADT and subsequent risk of dementia using a population-based dataset. Data for this study were taken from the Taiwan (China)Longitudinal Health Insurance Database 2005. We included 755 PC patients who received ADT in the study cohort and 559 PC patients who did not receive ADT in the comparison cohort. Each patient was individually tracked for a 5-year period to define those who subsequently received a diagnosis of dementia. Results show that the incidence rates of dementia per 100 person-years were 2.35 (95% confidence interval [95% CI]: 1.82 2.98) and 1.85 (95% CI: 1.35-2.48) for PC patients who received ADT and those who did not receive ADT, respectively. The adjusted hazard ratio (HR) for dementia for PC patients who received ADT was 1.21 (95% CI: 0.82-1.78, P = 0.333) compared to those who did not receive ADT. In addition, the adjusted HRs for dementia for PC patients receiving ADT with gonadotropin-releasing hormone (GnRH) agonists and without GnRH agonists were 1.39 (95% CI: 0.80-2.40, P = 0.240) and 1.13 (95% CI: 0.75-1.71, P = 0.564), respectively, compared to PC patients not receiving ADT. We concluded that there was no difference in the risk of subsequent dementia between PC patients who did and those who did not receive ADT. PMID- 27232854 TI - PSCA, Cox-2, and Ki-67 are independent, predictive markers of biochemical recurrence in clinically localized prostate cancer: a retrospective study. AB - Prostate cancer is the second most common male cancer, with half of all patients going on to develop metastases. To better identify patients at high risk for prostate cancer progression and reduce prostate cancer-related mortality, improved prognostic factors are required. In this study, we used immunohistochemistry (IHC) to determine the prognostic values of multiple tissue biomarkers in hormone-naomicronve prostatectomy specimens of prostate cancer. Using 510 prostatectomy specimens collected between 2002 and 2012, IHC analysis was performed for Cerb-2, Cyclin D1, VEGF, EGFR, Rb, PSCA, p53, Bcl-2, Cox-2, PMS2, and Ki-67 on formalin-fixed paraffin-embedded sections. The Cox proportional hazard model was used to determine the predictive risk factors for biochemical recurrence (BCR) of prostate cancer. During a median 44-month follow up, 128 (25.1%) patients developed BCR. A multivariate regression analysis revealed that Ki-67 (hazard ratio [HR]: 1.60, P = 0.033), PSCA (HR: 0.42, P < 0.001), and Cox-2 (HR: 2.05, P = 0.003) were the only significant prognostic tissue markers of BCR. Resection margin status (HR: 1.67, P = 0.010), pathologic pT0/1/2 stage (vs pT3/4; HR: 0.20, P = 0.002), preoperative PSA levels (HR: 1.03, P < 0.001), biopsied (HR: 1.30, P = 0.022) and pathologic (HR: 1.42, P = 0.005) Gleason scores, and prostate size (HR: 0.97, P = 0.003) were significant clinicopathologic factors. The expression of Ki-67, PSCA, and Cox-2 biomarkers along with other clinicopathologic factors were prognostic factors for BCR in patients with clinically localized prostate cancer following radical prostatectomy. PMID- 27232856 TI - Evaluating Isolation Behaviors by Nurses Using Mobile Computer Workstations at the Bedside. AB - This secondary analysis from a larger mixed methods study with a sequential explanatory design investigates the clinical challenges for nurses providing patient care, in an airborne and contact isolation room, while using a computer on wheels for medication administration in a simulated setting. Registered nurses, who regularly work in clinical care at the patient bedside, were recruited as study participants in the simulation and debriefing experience. A live volunteer acted as the standardized patient who needed assessment and intravenous pain medication. The simulation was video recorded in a typical hospital room to observe participating nurses conducting patient care in an airborne and contact isolation situation. Participants then reviewed their performance with study personnel in a formal, audio-recorded debriefing. Isolation behaviors were scored by an expert panel, and the debriefing sessions were analyzed. Considerable variation was found in behaviors related to using a computer on wheels while caring for a patient in isolation. Currently, no nursing care guidelines exist on the use of computers on wheels in an airborne and contact isolation room. Specific education is needed on nursing care processes for the proper disinfection of computers on wheels and the reduction of the potential for disease transmission from environmental contamination. PMID- 27232855 TI - Successful management of an asymptomatic bilateral synchronous testicular carcinoid tumor with a testicular-sparing surgery. PMID- 27232858 TI - Synthesis of Demissidine and Solanidine. AB - Demissidine and solanidine, two steroidal alkaloids, are synthesized in eight steps from tigogenin acetate and diosgenin acetate, respectively, which involve the replacement of three C-O bonds with C-N bonds. Key transformations include a cascade ring-switching process of furostan-26-acid, an epimerization of C25, an intramolecular Schmidt reaction, and an imine reduction/intramolecular aminolysis process. PMID- 27232859 TI - The Power of Words: What Can We Learn From the Disabilities Movement? PMID- 27232862 TI - Enhancing Evidence-Based Public Health Policy: Developing and Using Policy Narratives. AB - Academic researchers and clinicians have a critical role in shaping public policies to improve the health of an aging America. Policy narratives that pair personal stories with research statistics are a powerful tool to share knowledge generated in academic and clinical settings with policymakers. Effective policy narratives rely on a trustworthy and competent narrator and a compelling story that highlights the personal impact of policies under consideration and academic research that bolsters the story. Awareness of the cultural differences in the motivations, expectations, and institutional constraints of academic researchers and clinicians as information producers and U.S. Congress and federal agencies as information users is critical to the development of policy narratives that impact policy decisions. The current article describes the development and use of policy narratives to bridge cultures and enhance evidence-based public health policies that better meet the needs of older adults. [Journal of Gerontological Nursing, 42(6), 11-17.]. PMID- 27232857 TI - AKT in cancer: new molecular insights and advances in drug development. AB - The phosphatidylinositol-3 kinase (PI3K)-AKT pathway is one of the most commonly dysregulated pathways in all of cancer, with somatic mutations, copy number alterations, aberrant epigenetic regulation and increased expression in a number of cancers. The carefully maintained homeostatic balance of cell division and growth on one hand, and programmed cell death on the other, is universally disturbed in tumorigenesis, and downstream effectors of the PI3K-AKT pathway play an important role in this disturbance. With a wide array of downstream effectors involved in cell survival and proliferation, the well-characterized direct interactions of AKT make it a highly attractive yet elusive target for cancer therapy. Here, we review the salient features of this pathway, evidence of its role in promoting tumorigenesis and recent progress in the development of therapeutic agents that target AKT. PMID- 27232864 TI - Marvels and Shadows: Science and Education at the University of Puerto Rico School of Tropical Medicine under the Auspices of Columbia University: An Introduction. AB - This essay introduces a series of five historical articles on the scientific and educational contributions of the University of Puerto Rico School of Tropical Medicine (STM), under the auspices of Columbia University (1926-1949), to the fields of tropical medicine and public health. The articles will appear in several consecutive issues, and will address various themes as follows: 1) historical antecedents of the STM, particularly institutional precedents; 2) the educational legacy of the STM; 3) a history of the STM scientific journal ("The Puerto Rico Journal of Public Health and Tropical Medicine"); 4) the scientific practices and representations that prevailed at the institution; and, 5) a brief sociocultural history of malaria in Puerto Rico, mainly from the perspective of the STM's scientific and public health activities. The authors have systematically and comprehensively studied a wide variety of documents from different sources based on multiple archives in Puerto Rico, the United States and England. The authors treat the fluid meanings of the examined historical encounters from a research perspective that privilege complex reciprocal interactions, multiple adaptations and elaborate sociocultural constructs present in a collaborative exemplar of the modernity of medical science in a neocolonial tropical context. PMID- 27232865 TI - The Historical Antecedents of the UPR School of Tropical Medicine. AB - This article deals with the historical antecedents of the University of Puerto Rico (UPR) School of Tropical Medicine (STM) under the auspices of Columbia University. It presents a general view of the social, institutional and conceptual factors that were correlated with the establishment of the STM. The authors start by examining the historical continuities and discontinuities present during the imperial transitions between Spanish colonial and U.S. military medicine at the turn of the 20th century. The clarification of these changes is important for the proper understanding of the emergence of tropical medicine in Puerto Rico, marked by the identification of the biological determinant of the so called "peasants' anemia." The essay focuses on two institutional precursor events: the Puerto Rico Anemia Commissions (1904-1908) and the Institute of Tropical Medicine and Hygiene (1912-1914). Their nature and work paved the way for the establishment of the STM. The notions of tropical medicine and diseases are considered as historical concepts. The support of the Rockefeller Foundation to several significant public health activities in Puerto Rico is also examined. Finally, the social and health conditions which prevailed at the time of the creation of the STM have been summarized. In general, the article provides a sense of historical context deemed essential to understand the emergence and evolution of the STM. PMID- 27232866 TI - Physical Activity in Puerto Rican Breast Cancer Survivors. AB - OBJECTIVE: Breast cancer survivors do not engage in appropriate levels of physical activity, despite the known benefits of such activity. This study aims to describe physical-activity levels and the barriers to it in a group of Puerto Rican breast cancer survivors, as well as detailing their preferences for an intervention. METHODS: Participants who finished their chemotherapy and/or radiotherapy for breast cancer at least 4 months prior to the study were included. Demographic, anthropometric, and clinical data were obtained. The Godin Leisure-Time Exercise Questionnaire (GLTEQ) and questionnaires on exercise self efficacy, barriers to self-efficacy, modeling, and social support were filled out by study participants. Data on access to exercise equipment and preferences regarding a physical-activity intervention were collected. Descriptive statistics and correlation analyses were performed. RESULTS: Fifty breast cancer survivors were recruited. Almost all the participants reported that they did not engage in any kind of strenuous physical activity (94%), with more than three fourths (76%) reporting that they did not even participate in any kind of moderate physical activity. The GLTEQ score was associated with barriers to selfefficacy, while the association with exercise self-efficacy approached significance (p = 0.055). Nearly half of the patients (44%) had access to exercise equipment. Preferred methods for the delivery of physical-activity interventions were participating in group settings (72%) and receiving material in the postal mail (44%). CONCLUSION: The study described herein reports on the low levels of physical activity being practiced by a group of Puerto Rican breast cancer survivors, despite the fact that many of them had access to exercise equipment and facilities. Further studies aimed at understanding breast cancer survivors' barriers to physical activity and at developing culturally competent interventions to increase the levels of such activity are warranted. PMID- 27232867 TI - Use of Complementary and Alternative Medicine in Bayamon, Puerto Rico. AB - OBJECTIVE: To profile complementary and alternative medicine (CAM) utilization patterns in the municipality of Bayamon, Puerto Rico. METHODS: The study consisted of a cross-sectional household survey conducted in 2008. A multi-stage probabilistic sampling method was used to obtain a total of 203 household interviews. The survey used was based on a culturally adapted version of the Complementary and Alternative Medicine Supplement of the 2007 National Health Interview Survey (NHIS), conducted by the U.S. Department of Health and Human Services. The statistical analysis included means, frequency distributions, and a multiple logistic regression model. RESULTS: The prevalence rates of CAM use ranged from 55.7% to 92.1%, depending on the modalities included under CAM. The most frequently reported medical conditions treated with CAM included back problems, headaches, allergies, anxiety, and depression. Sixty-four percent of the respondents had not informed their physicians that they used CAM. The results showed a marginal association 0.0530mm), p53 expression and less proportion of the mucinous component are associated with risk of LN metastasis. CONCLUSION: Based on the results of this study, we conclude that the tumor size, status of LN metastasis, clinical stage, and p53 mutation rate may differ between MMC and PMC patients. The tumor size (>30mm), p53 mutation and less proportion of the mucinous component should be considered risk factors of LN metastasis in MC patients. PMID- 27232882 TI - Transgelin-2 in B-Cells Controls T-Cell Activation by Stabilizing T Cell - B Cell Conjugates. AB - The immunological synapse (IS), a dynamic and organized junction between T-cells and antigen presenting cells (APCs), is critical for initiating adaptive immunity. The actin cytoskeleton plays a major role in T-cell reorganization during IS formation, and we previously reported that transgelin-2, an actin binding protein expressed in T-cells, stabilizes cortical F-actin, promoting T cell activation in response to antigen stimulation. Transgelin-2 is also highly expressed in B-cells, although no specific function has been reported. In this study, we found that deficiency in transgelin-2 (TAGLN2-/-) in B-cells had little effect on B-cell development and activation, as measured by the expression of CD69, MHC class II molecules, and CD80/86. Nevertheless, in B-cells, transgelin-2 accumulated in the IS during the interaction with T-cells. These results led us to hypothesize that transgelin-2 may also be involved in IS stability in B-cells, thereby influencing T-cell function. Notably, we found that transgelin-2 deficiency in B-cells reduced T-cell activation, as determined by the release of IL-2 and interferon-gamma and the expression of CD69. Furthermore, the reduced T cell activation was correlated with reduced B-cell-T-cell conjugate formation. Collectively, these results suggest that actin stability in B-cells during IS formation is critical for the initiation of adaptive T-cell immunity. PMID- 27232883 TI - Cranial Morphology of the Late Oligocene Patagonian Notohippid Rhynchippus equinus Ameghino, 1897 (Mammalia, Notoungulata) with Emphases in Basicranial and Auditory Region. AB - "Notohippidae" is a probably paraphyletic family of medium sized notoungulates with complete dentition and early tendency to hypsodonty. They have been recorded from early Eocene to early Miocene, being particularly diverse by the late Oligocene. Although Rhynchippus equinus Ameghino is one of the most frequent notohippids in the fossil record, there are scarce data about cranial osteology other than the classical descriptions which date back to the early last century. In this context, we describe the exceptionally preserved specimen MPEF PV 695 (based on CT scanning technique and 3D reconstruction) with the aim of improving our knowledge of the species, especially regarding auditory region (petrosal, tympanic and surrounding elements), sphenoidal and occipital complexes. Besides a modular description of the whole skull, osteological correlates identified on the basicranium are used to infer some soft-tissue elements, especially those associated with vessels that supply the head, mainly intracranially. One of the most informative elements was the petrosal bone, whose general morphology matches that expected for a toxodont. The endocranial surface, together with the surrounding parietal, basisphenoid, occipital, and squamosal, enabled us to propose the location and communication of main venous sinuses of the lateral head wall (temporal, inferior and sigmoid sinuses), whereas the tympanic aspect and the identification of a posterior carotid artery canal provided strong evidence in support of an intratympanic course of the internal carotid artery, a controversial issue among notoungulates. Regarding the arrangement of tympanic and paratympanic spaces, the preservation of the specimen allowed us to appreciate the three connected spaces that constitute a heavily pneumatized middle ear; the epitympanic sinus, the tympanic cavity itself, and the ventral expansion of the tympanic cavity through the notably inflated bullae. We hope this study stimulates further inquires and provides potentially informative data for future research involving other representatives of the order. PMID- 27232885 TI - Microbe-triggered arthropathies: reactive arthritis and beyond. PMID- 27232884 TI - Multi-Center Randomized Phase II Study Comparing Cediranib plus Gefitinib with Cediranib plus Placebo in Subjects with Recurrent/Progressive Glioblastoma. AB - BACKGROUND: Cediranib, an oral pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, failed to show benefit over lomustine in relapsed glioblastoma. One resistance mechanism for cediranib is up-regulation of epidermal growth factor receptor (EGFR). This study aimed to determine if dual therapy with cediranib and the oral EGFR inhibitor gefitinib improved outcome in recurrent glioblastoma. METHODS AND FINDINGS: This was a multi-center randomized, two-armed, double-blinded phase II study comparing cediranib plus gefitinib versus cediranib plus placebo in subjects with first relapse/first progression of glioblastoma following surgery and chemoradiotherapy. The primary outcome measure was progression free survival (PFS). Secondary outcome measures included overall survival (OS) and radiologic response rate. Recruitment was terminated early following suspension of the cediranib program. 38 subjects (112 planned) were enrolled with 19 subjects in each treatment arm. Median PFS with cediranib plus gefitinib was 3.6 months compared to 2.8 months for cediranib plus placebo (HR; 0.72, 90% CI; 0.41 to 1.26). Median OS was 7.2 months with cediranib plus gefitinib and 5.5 months with cediranib plus placebo (HR; 0.68, 90% CI; 0.39 to 1.19). Eight subjects (42%) had a partial response in the cediranib plus gefitinib arm versus five patients (26%) in the cediranib plus placebo arm. CONCLUSIONS: Cediranib and gefitinib in combination is tolerated in patients with glioblastoma. Incomplete recruitment led to the study being underpowered. However, a trend towards improved survival and response rates with the addition of gefitinib to cediranib was observed. Further studies of the combination incorporating EGFR and VEGF inhibition are warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT01310855. PMID- 27232886 TI - Stability and Degradation Mechanisms of Radiation-Grafted Polymer Electrolyte Membranes for Water Electrolysis. AB - Radiation-grafted membranes are a promising alternative to commercial membranes for water electrolyzers, since they exhibit lower hydrogen crossover and area resistance, better mechanical properties, and are of potentially lower cost than perfluoroalkylsulfonic acid membranes, such as Nafion. Stability is an important factor in view of the expected lifetime of 40 000 h or more of an electrolyzer. In this study, combinations of styrene (St), alpha-methylstyrene (AMS), acrylonitrile (AN), and 1,3-diisopropenylbenzene (DiPB) are cografted into 50 MUm preirradiated poly(ethylene-co-tetrafluoroethylene) (ETFE) base film, followed by sulfonation to produce radiation-grafted membranes. The stability of the membranes with different monomer combinations is compared under an accelerated stress test (AST), and the degradation mechanisms are investigated. To mimic the conditions in an electrolyzer, in which the membrane is always in contact with liquid water at elevated temperature, the membranes are immersed in water for 5 days at 90 degrees C, so-called thermal stress test (TST). In addition to testing in air atmosphere tests are also carried out under argon to investigate the effect of the absence of oxygen. The water is analyzed with UV-vis spectroscopy and ion chromatography. The ion exchange capacity (IEC), swelling degree, and Fourier transform infrared (FTIR) spectra of the membranes are compared before and after the test. Furthermore, energy-dispersive X-ray (EDX) spectroscopic analysis of the membrane cross-section is performed. Finally, the influence of the TST to the membrane area resistance and hydrogen crossover is measured. The stability increases along the sequence St/AN, St/AN/DiPB, AMS/AN, and AMS/AN/DiPB grafted membrane. The degradation at the weak-link, oxygen induced degradation, and hydrothermal degradation are proposed in addition to the "swelling-induced detachment" reported in the literature. By mitigating the possible paths of degradation, the AMS/AN/DiPB grafted membrane is shown to be the most stable membrane and, therefore, it is a promising candidate for a membrane to be used in a water electrolyzer. PMID- 27232887 TI - Feedback-Related ERP Components Are Modulated by Social Distance during Non Contingent Evaluation of Someone Else's Performance. AB - Performance monitoring depends on cortical structures that are also activated in vicarious monitoring. While many experiments have shown that vicarious and on line monitoring have a similar basis, most such experiments have focused on simple tasks. In order to assess the effect of non-contingent feedback on vicarious monitoring, 23 young volunteer adults were evaluated: in one session, they performed a rule-based category formation task, receiving no feedback on their performance. In a second session, Event Related Potentials (ERPs) were obtained while participants passively reviewed performances attributed to themselves and peers they had previously rated as either socially close or distant. Feedback Related Negativity (FRN) and Feedback Related P300 (fP300) components were analyzed with respect to feedback valence and agent. Results show that both components can be elicited through non-contingent feedback related to prior performance. In addition, FRN waves are modulated by the valence of the feedback, and fP300 is modulated by the agent to whom performance feedback is attributed. This experiment constitutes a novel approach to the evaluation of ERP correlates of vicarious monitoring through non-contingent feedback and its relations to empathy processing. PMID- 27232888 TI - Rhinovirus species and clinical characteristics in the first wheezing episode in children. AB - The clinical data on the first wheezing episodes induced by different rhinovirus (RV) species are still limited. We aimed to investigate the prevalence of RV genotypes, sensitization status, and clinical characteristics of patients having a respiratory infection caused by either different RV species or other respiratory viruses. The study enrolled 111 patients (aged 3-23 months, 79% hospitalized, 76% with RV infection) with the first wheezing episode. RV-specific sequences were identified by partial sequencing of VP4/VP2 and 5' non-coding regions with 80% success rate. The investigated clinical and laboratory variables included atopic characteristics and illness severity, parental atopic illnesses, and parental smoking. Of the study children, 56% percent had >1 atopic characteristic (atopy, eczema and/or blood eosinophil count >0.4 * 109 /L) and 23% were sensitised to allergens. RV-C was detected in 58% of RV positive samples, followed by RV-A (20%) and RV-B (1.2%). Children with RV-A and RV-C induced wheezing were older (P = 0.014) and had more atopic characteristics (P = 0.001) than those with non-RV. RV-A and RV-C illnesses had shorter duration of preadmission symptoms and required more bronchodilator use at the ward than non RV illnesses (both P < 0.05, respectively). RV-C is the most common cause of severe early wheezing. Atopic and illness severity features are associated with children having RV-A or RV-C induced first wheezing episode rather than with children having a non-RV induced wheezing. J. Med. Virol. 88:2059-2068, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27232891 TI - Nontrivial Effect of the Color-Exchange of a Donor/Acceptor Pair in the Engineering of Forster Resonance Energy Transfer (FRET)-Based Indicators. AB - Genetically encoded indicators driven by the Forster resonance energy transfer (FRET) mechanism are reliable tools for live imaging. While the properties of FRET-based indicators have been improved over the years, they often suffer from a poor dynamic range due to the lack of comprehensive understanding about how to apply an appropriate strategy to optimize the FRET parameters. One of the most successful optimizations is the incorporation of circularly permuted fluorescent proteins (cpFPs). To better understand the effects of this strategy, we systematically investigated the properties of the indicators by utilizing a set of FRET backbones consisting of native or one of the most effective cp variants (cp173FPs) with considerations of their order. As a result, the ordering of donor and acceptor FPs, which has been ignored in previous studies, was found to significantly affect the dynamic range of indicators. By utilizing these backbones, we succeeded in improving a cGMP indicator with 3.6-fold increased dynamic range and in generating an ultrasensitive cAMP indicator capable of environmental imaging, demonstrating the practical importance of the ordering of donors and acceptors in the engineering of FRET-based indicators. PMID- 27232890 TI - A Designed A. vinelandii-S. elongatus Coculture for Chemical Photoproduction from Air, Water, Phosphate, and Trace Metals. AB - Microbial mutualisms play critical roles in a diverse number of ecosystems and have the potential to improve the efficiency of bioproduction for desirable chemicals. We investigate the growth of a photosynthetic cyanobacterium, Synechococcus elongatus PCC 7942, and a diazotroph, Azotobacter vinelandii, in coculture. From initial studies of the coculture grown in media with glutamate, we proposed a model of cross-feeding between these organisms. We then engineer a new microbial mutualism between Azotobacter vinelandii AV3 and cscB Synechococcus elongatus that grows in the absence of fixed carbon or nitrogen. The coculture cannot grow in the absence of a sucrose-exporting S. elongatus, and neither organism can grow alone without fixed carbon or nitrogen. This new system has the potential to produce industrially relevant products, such as polyhydroxybutyrate (PHB) and alginate, from air, water, phosphate, trace metals, and sunlight. We demonstrate the ability of the coculture to produce PHB in this work. PMID- 27232893 TI - The Effects of Age, Refractive Status, and Luminance on Pupil Size. AB - PURPOSE: Pupil size is critical for optimal performance of presbyopic contact lenses. Although the effect of luminance is well known, little information is available regarding other contributing factors such as aging and refractive status. METHODS: The cohort population comprised 304 patients (127 male, 177 female) aged 18 to 78 years. Pupils were photographed at three controlled luminance levels 250, 50, and 2.5 cd/m using an infra-red macro video camera. Measurements of pupil diameter were conducted after transforming pixel values to linear values in millimeters. RESULTS: Luminance was the most influential factor with pupil diameter increasing with decreased luminance (p < 0.001, all comparisons). Age was also found to be a significant factor with a smaller diameter in the older groups, but overall the difference was only significant between the pre-presbyopes and the established presbyopes (p = 0.017). Pupil diameter decreased significantly with increasing age, the effect being most marked at low luminance (<0.001). The smallest pupil diameters were measured for hyperopes and the largest for myopes and although refractive error was not a significant factor alone, there was a significant interaction between luminance and refractive error with the greatest differences in pupil diameter between myopes and emmetropes at low luminance (p < 0.001). Pupil diameter changes modeled by multilinear regression (p < 0.001) identified age, luminance, best sphere refraction, and refractive error as significant factors accounting for just over 70% of the average variation in pupil diameter. CONCLUSIONS: Both age and refractive status were found to affect pupil size with larger pupils measured for younger patients and myopes. Designs for multifocal contact lens corrections should take both age and refractive status into consideration; a faster progression from distance to near corrections across the optical zone of the lens is expected to be required for established presbyopes and hyperopes than it is for early presbyopes, myopes, and emmetropes. PMID- 27232892 TI - Avanafil - a further step to tailoring patient needs and expectations. AB - INTRODUCTION: Phosphodiesterase type 5 inhibitors (PDE5Is) represent the first line treatment for erectile dysfunction (ED). Almost one in two patients, however, show some level of treatment dissatisfaction and up to 30% fail to respond to any of the currently available PDE5Is. Recently, the second-generation PDE5I avanafil was launched for the treatment of ED. AREAS COVERED: Pivotal studies of clinical development along with placebo-controlled randomized clinical trials (RCTs) of avanafil in patients with ED were reviewed. Studies concerning the pharmacokinetics and pharmacodynamic of the drug were also analysed. A systematic literature search for English-language studies published up to May 2016 using the Medline database was performed. The search included the terms avanafil and ED. Expert commentary: Avanafil is a potent, highly selective PDE5I whose efficacy is comparable to that of currently available PDE5Is in both naive and previous PDE5I users. Avanafil is effective within approximately 15 minutes of dosing, thus representing the only PDE5I approved for as-needed use, 15 to 30 minutes before sexual activity. Avanafil has high selectivity for the PDE5 isoenzyme, thus resulting in a lower incidence of drug-related side effects compared to other PDE5Is. PMID- 27232889 TI - Angelman Syndrome Protein Ube3a Regulates Synaptic Growth and Endocytosis by Inhibiting BMP Signaling in Drosophila. AB - Altered expression of the E3 ubiquitin ligase UBE3A, which is involved in protein degradation through the proteasome-mediated pathway, is associated with neurodevelopmental and behavioral defects observed in Angelman syndrome (AS) and autism. However, little is known about the neuronal function of UBE3A and the pathogenesis of UBE3A-associated disorders. To understand the in vivo function of UBE3A in the nervous system, we generated multiple mutations of ube3a, the Drosophila ortholog of UBE3A. We found a significantly increased number of total boutons and satellite boutons in conjunction with compromised endocytosis in the neuromuscular junctions (NMJs) of ube3a mutants compared to the wild type. Genetic and biochemical analysis showed upregulation of bone morphogenetic protein (BMP) signaling in the nervous system of ube3a mutants. An immunochemical study revealed a specific increase in the protein level of Thickveins (Tkv), a type I BMP receptor, but not other BMP receptors Wishful thinking (Wit) and Saxophone (Sax), in ube3a mutants. Ube3a was associated with and specifically ubiquitinated lysine 227 within the cytoplasmic tail of Tkv, and promoted its proteasomal degradation in Schneider 2 cells. Negative regulation of Tkv by Ube3a was conserved in mammalian cells. These results reveal a critical role for Ube3a in regulating NMJ synapse development by repressing BMP signaling. This study sheds new light onto the neuronal functions of UBE3A and provides novel perspectives for understanding the pathogenesis of UBE3A-associated disorders. PMID- 27232894 TI - Objective Measures of Pre-lens Tear Film Dynamics versus Visual Responses. AB - PURPOSE: To ascertain whether there is a correlation between objective measures of pre-lens tear film surface quality (TFSQ) dynamics and visual quality responses. METHODS: Thirty one subjects wore a pair of silicone hydrogel lenses for 1 hour before measurements. Acquisition of TFSQ dynamics was conducted for each subject in suppressed blinking conditions. A Placido disk videokeratoscope was fitted with an internal target and a video streaming output. Subjects were asked to focus on the target and indicate the just noticeable decrease in visual quality. The recorded videos and the subjective responses were saved for further analysis, for which a new videokeratoscopy image processing technique, based on calculating a texture feature (homogeneity), was developed. The estimated times of lens dewetting were then associated with the subjective responses. RESULTS: The dewetting point of the lens was identified in 82% of recordings. The group median time of subjective response was 3.5 s post-dewetting point, which corresponded to about 4.3% decrease in TFSQ. In the remaining measurements, either no substantial change in TFSQ or changes related to post-blink slow movement of the lipid layer were observed. The former was not associated with any noticeable change in subjective visual quality whereas the latter usually created visually identifiable temporal disturbance resulting in a subjective response. A small but statistically significant correlation (r = 0.32, p < 0.001) was found between objectively estimated point of dewetting and the subjective response, corresponding to just noticeable change in visual quality. CONCLUSIONS: The new technique proved to be sufficiently sensitive to identify the distinct two-phase process of pre-lens TFSQ dynamics. Changes in objectively determined pre-lens TFSQ can also be identified subjectively, but there exists, in general, a certain lag between the two responses. The estimated times of lens dewetting could be utilized for in vivo assessment of contact lens wetting parameters. PMID- 27232895 TI - Effect of Masking on Subjective Responses to Daily Disposable Contact Lenses. AB - PURPOSE: To explore the effect of masking on subjective responses when wearing daily disposable (DD) contact lenses. METHODS: In an adaptation phase, habitual wearers of Manufacturer-A (MFA) (n = 43) and Manufacturer-B (MFB) (n = 53) wore MFA-brand 1 or MFB-brand 1 DDs, respectively, for 30 days, open-label. Subjects were then randomly assigned to one of two experiments. Each experiment included two, 3-day crossover phases. An enhanced version of MFA and MFB lenses (MFA-brand 2 and MFB-brand 2) were worn contralaterally to evaluate potential differences in masking result between manufacturers. Experiment 1: subjects were fully masked to lens and packaging (FM) then unmasked (UM). Experiment 2: subjects were FM then partially masked using an over-label (PM). Comfort ratings (0-100) were recorded for each lens daily and preference between lenses was recorded on day 3 for each crossover phase. The mean difference between 0-100 ratings or preference when FM or PM versus UM for the same lens was considered a measurement of the effect associated with masking. The purpose of the study was withheld from subjects to minimize bias. RESULTS: The effect associated with masking for habitual wearers of MFA and MFB lenses was less than 1 out of 100 (0 +/- 2.5) in both experiments. Fifty-eight subjects (60%) expressed no preference when FM. This decreased to 29 (30%) when UM or PM (proportion test, p < 0.001). Approximately half the subjects had a change in lens preference when they were UM or PM, primarily in favor of their habitual lens manufacturer. CONCLUSIONS: Masking did not have a measurable impact on 0-100 ratings with the DD lenses used in this study but did have an impact on lens preference. Subjects were more likely to express a preference when they handled the lenses and were exposed to the lens packaging and, in some cases, able to read the lens brand and lens manufacturer. PMID- 27232896 TI - A Survey of Presbyopic Contact Lens Wearers in a University Setting. AB - PURPOSE: To determine why presbyopic patients discontinue contact lens wear and describe their opinions of comfort and visual quality with contact lenses. METHODS: A survey assessing current age, gender, contact lens material/design, and opinions of contact lens comfort and visual quality was mailed to 2400 presbyopic patients (age 40 years and older) that have had eye exams in the Ohio State University College of Optometry's Contact Lens Services over the last 4 years. RESULTS: A total of 496 surveys were analyzed. The mean age of survey respondents was 57 +/- 9 years, and 68% of the sample was female. Permanent discontinuation of contact lens wear was reported by 15%. No association was found between contact lens discontinuation and age (p = 0.7), gender (p = 0.2), age of beginning contact lens wear (p = 0.1), or contact lens material (p = 0.1). Poor vision (38%), discomfort (34%), convenience (20%), and cost (6%) were the primary reported reasons for discontinuation. There was no difference between the proportion of subjects reporting "poor vision" as their primary discontinuation reason and those reporting "discomfort" (p = 0.7). Discontinued wearers had a worse overall opinion of their distance (p = 0.03), intermediate (p = 0.01), and near vision (p = 0.002) compared to subjects who were still wearing their contact lenses. CONCLUSIONS: Discomfort has been reported as the primary reason for contact lens discontinuation. In this presbyopic population, dissatisfaction with vision and discomfort were reported equally as often as primary reasons for discontinuation. As well, subjects who ceased contact lens wear had worse overall opinions of their vision at all distances than current contact lens wearers. The results of this survey suggest that presbyopes have unique demands and opinions related to contact lens wear. PMID- 27232897 TI - Assessing Scleral Contact Lens Satisfaction in a Keratoconus Population. AB - PURPOSE: To assess perceived comfort and related experiences of adapted keratoconic scleral contact lens (17-18.2 mm) wearers with a history of wearing other contact lens modalities and to compare these subjective clinical effects with previous experiences. METHODS: Twenty-four keratocones were recruited, signed an informed consent approved by the University Internal Review Board, and were asked to complete a survey and a dry eye questionnaire. RESULTS: Previous lens wearing experience included soft, piggy back, and hybrid lenses but predominantly was corneal gas permeable. An overwhelming majority strongly preferred the comfort and vision with the scleral contact lenses. This cohort of keratoconus patients were on average dry eye suspects according to a dry eye questionnaire but contained individuals with either normal or significantly dry eye scores. However, patients stated that they experienced less dryness with their scleral lenses, but slightly more than half of these patients experienced, at least occasionally, midday fogging. CONCLUSIONS: The scleral contact lenses are extremely well accepted by keratoconic patients because of comfort and vision these devices provide. For many patients, they offer further relief from dryness symptoms. However, midday fogging remains a limitation for many wearers. PMID- 27232899 TI - Lid Papillae Improvement with Hydrogen Peroxide Lens Care Solution Use. AB - PURPOSE: To assess changes in lid papillae and symptoms after use of a hydrogen peroxide-containing solution (H2O2) for 3 months by symptomatic contact lens wearers. METHODS: This randomized, controlled, investigator-masked, parallel group study enrolled symptomatic lens wearers with at least mild lid papillae who habitually used a biguanide-preserved multipurpose solution (BMPS). Subjects were randomized to habitual BMPS or H2O2 for 3 months to care for their lenses. Lid papillae severity (0-4) was graded in four zones of each eye at baseline and at 30, 60, and 90 days. Subjects rated frequency and intensity of symptoms and completed the Contact Lens Dry Eye Questionnaire (CLDEQ-8) at the same time points. Lens cases used for 1 month were collected from subjects in the H2O2 group, and residual peroxide concentration was analyzed at disinfection time. RESULTS: In all, 131 subjects were randomized to H2O2 (n = 64) or BMPS (n = 67) and underwent post-baseline assessment. The H2O2 group showed significantly greater improvements in lid papillae from baseline to day 90 than the BMPS group (H2O2, least square mean [LSM] difference [baseline-day 90] in maximum score 0.904 [95% CI 0.744-1.064]; BMPS, LSM difference 0.423 [95% CI 0.271-0.576]; p < 0.001). Frequency and intensity of symptoms, including grittiness, end-of-day dryness, irritation, burning/stinging, itchiness, and blurry vision, were significantly lower for H2O2 than for BMPS at days 30, 60, and 90 (all p <= 0.045), as were mean CLDEQ-8 scores (3-mo scores 10.6 +/- 6.30 vs.15.0 +/- 7.29, p < 0.001). Residual peroxide concentration in 61 used lens cases ranged from 6 to 55 ppm (mean, 15 +/- 8 ppm) and 95% of cases had residual peroxide less than 30 ppm. CONCLUSIONS: Symptomatic contact lens wearers using the H2O2 solution showed greater reductions in lid papillae and symptoms at 90 days than did subjects using BMPS. Cases used for 1 month neutralized peroxide at disinfection time to levels below those detectable by ocular tissues. PMID- 27232898 TI - Peripapillary RNFL Thickness Changes after Panretinal Photocoagulation. AB - PURPOSE: To evaluate changes in peripapillary retinal nerve fiber layer (RNFL) thickness as determined by spectral domain optical coherence tomography (SD-OCT) after panretinal photocoagulation (PRP) for proliferative diabetic retinopathy (PDR). METHODS: Forty-two eyes of 42 diabetic patients who were scheduled for PRP were enrolled in this interventional case series. Peripapillary RNFL thickness was measured using SD-OCT (OCT 1000; Topcon Co., Tokyo, Japan) at baseline and 1, 3, and 6 months after PRP. RESULTS: Mean global RNFL thickness was increased significantly by 3 MUm (p = 0.04) 1 month after PRP and was then decreased marginally significantly by 2.4 MUm at 6 months (p = 0.054) as compared to baseline values. After 1 month, RNFL thickness was increased in all quadrants, but only changes in the temporal quadrant were significant (p = 0.009). At 6 months, progressive RNFL thinning occurred in all quadrants; however, only changes in the superior quadrant were significant (p = 0.041). Visual acuity was improved by an average of 0.02 logMAR after 6 months, but this change was not statistically significant. CONCLUSIONS: Shortly after PRP, RNFL thickness (as determined by SD-OCT) increases, but a decrease in RNFL thickness occurs at 6 months post-PRP. RNFL thickness changes based on OCT should be interpreted with caution in diabetic eyes undergoing PRP. PMID- 27232900 TI - Contact Lens-Induced Discomfort and Protein Changes in Tears. AB - PURPOSE: Ocular discomfort is among the main causes of contact lens wear discontinuation. This study investigated the association between subjective ocular comfort ratings and diurnal changes in tear protein concentrations with and without contact lens wear. METHODS: The study was a prospective, open-label, single-group two-staged investigation. Basal tears were collected from 30 experienced contact lens wearers twice a day (morning and evening) using a noninvasive method without lens wear (stage 1) and during wear of Etafilcon A contact lenses (stage 2) for 7 to 10 days. Subjects rated their ocular comfort on a scale of 1 to 100 (with 100 as extremely comfortable) at each time of tear collection. Tears were analyzed using liquid quadrupole mass spectrometry in conjunction with selected reaction monitoring (SRM) method. RESULTS: End-of-day comfort was reduced when wearing lenses (87.8 +/- 14.3 AM vs. 79.2 +/- 16.6 PM) compared to no lens wear (88.3 +/- 12.6 AM vs. 84.7 +/- 13.3 PM) (AM vs. PM, p < 0.05). A greater reduction in comfort over the day was seen during lens wear (p < 0.01). The concentration of prolactin-induced protein increased from morning to evening in both stages (mean +/- SD; 0.08 +/- 0.04 mg/ml, AM vs. 0.09 +/- 0.05 mg/ml, PM, p < 0.05). There was no change in the concentration of lactoferrin (1.20 +/- 0.77 mg/ml), lysozyme (2.11 +/- 1.50 mg/ml), lipocalin 1 (1.75 +/- 0.99 mg/ml), or proline-rich protein 4 (0.80 +/- 0.49 mg/ml). The prolactin-induced protein concentration was negatively associated with discomfort levels in tears (p < 0.05, r = -0.29). CONCLUSIONS: Only the absolute concentration of prolactin induced protein correlated with subjective comfort ratings. Taking into consideration that prolactin-induced protein can be associated with disruption in water transport in lacrimal glands, our findings may indicate that changes to aqueous secretion are associated with contact lens discomfort. PMID- 27232901 TI - The Influence of Different OK Lens Designs on Peripheral Refraction. AB - PURPOSE: To compare peripheral refraction changes along the horizontal and vertical meridians induced by three different orthokeratology (OK) lens designs: BE, Paragon CRT, and Contex lenses. METHODS: Nineteen subjects (6M, 13F, mean age 28 +/- 7 years) were initially fitted with BE OK lenses in both eyes which were worn overnight for 14 days. Central and peripheral refraction and corneal topography were measured at baseline and after 14 nights of lens wear. After a minimum 2-week washout period, one randomly selected eye was re-fitted with a Paragon CRT lens and the other eye with a Contex OK lens. Measurements were repeated before and after 14 nights of lens wear. RESULTS: The three different OK lenses caused significant changes in peripheral refraction along both the horizontal and vertical visual fields (VFs). BE and Paragon CRT lenses induced a significant hyperopic shift within the central +/-20 degrees along the horizontal VF and at all positions along the vertical meridian except at 30 degrees in the superior VF. There were no significant differences in peripheral refraction changes induced between BE and Paragon CRT lenses. When comparing BE and Contex OK lens designs, BE caused greater hyperopic shifts at 10 degrees and 30 degrees in the temporal VF and at center, 10 degrees , and 20 degrees in the superior VF along the vertical meridian. Furthermore, BE lenses caused greater reduction in Flat and Steep K values compared to Contex OK. CONCLUSIONS: OK lenses induced significant changes in peripheral refraction along the horizontal and vertical meridians. Despite the clinically significant difference in central corneal flattening induced by BE and Contex OK lenses, relative peripheral refraction changes differed minimally between the three OK lens designs. If the peripheral retina influences refractive error development, these results suggest that myopia control effects are likely to be similar between different OK lens designs. PMID- 27232902 TI - Optical Assessment of Soft Contact Lens Edge-Thickness. AB - PURPOSE: To assess the edge shape of soft contact lenses using Gabor-Domain Optical Coherence Microscopy (GD-OCM) with a 2-MUm imaging resolution in three dimensions and to generate edge-thickness profiles at different distances from the edge tip of soft contact lenses. METHODS: A high-speed custom-designed GD-OCM system was used to produce 3D images of the edge of an experimental soft contact lens (Bausch + Lomb, Rochester, NY) in four different configurations: in air, submerged into water, submerged into saline with contrast agent, and placed onto the cornea of a porcine eyeball. An algorithm to compute the edge-thickness was developed and applied to cross-sectional images. The proposed algorithm includes the accurate detection of the interfaces between the lens and the environment, and the correction of the refraction error. RESULTS: The sharply defined edge tip of a soft contact lens was visualized in 3D. Results showed precise thickness measurement of the contact lens edge profile. Fifty cross-sectional image frames for each configuration were used to test the robustness of the algorithm in evaluating the edge-thickness at any distance from the edge tip. The precision of the measurements was less than 0.2 MUm. CONCLUSIONS: The results confirmed the ability of GD-OCM to provide high-definition images of soft contact lens edges. As a nondestructive, precise, and fast metrology tool for soft contact lens measurement, the integration of GD-OCM in the design and manufacturing of contact lenses will be beneficial for further improvement in edge design and quality control. In the clinical perspective, the in vivo evaluation of the lens fitted onto the cornea will advance our understanding of how the edge interacts with the ocular surface. The latter will provide insights into the impact of long-term use of contact lenses on the visual performance. PMID- 27232903 TI - Effects of Pigment Location in Tinted Contact Lenses on the Ocular Surface. AB - PURPOSE: To evaluate the effects of the location of pigments in decorative tinted soft contact lenses on the ocular surface. METHODS: Thirty test subjects were enrolled in this study. All subjects wore the following types of contact lenses, classified according to the location of the pigment layer, in one eye in three different testing sessions: conventional clear lenses, tinted lenses with a pigment layer embedded in the lens matrix, and tinted lenses with an exposed pigment layer on the surface. Tear samples were collected, the ocular surface status was evaluated, and subjective symptoms were surveyed after lens wear for 8 hours. RESULTS: The tinted lenses with surface pigments resulted in a greater increase in epidermal growth factor and interleukin-8 levels compared with the clear lenses and tinted lenses with embedded pigments (p < 0.050). Ocular surface parameters and subjective symptom scores were significantly different among three lens types (p < 0.050), with the clear lenses showing superior results compared with the two tinted lenses (p < 0.050). The tinted lenses with exposed pigments resulted in a greater degree of conjunctival redness and ocular surface staining and poorer symptom scores compared with the tinted lens with embedded pigments (p < 0.050). CONCLUSIONS: Our results suggest that the presence of surface pigments in tinted contact lenses increases ocular inflammation and results in a poorer ocular surface status and greater discomfort compared with clear lenses and tinted lenses with an embedded pigment layer. PMID- 27232904 TI - Head Elevation and Intraocular Pressure in Glaucoma. AB - PURPOSE: To investigate the effect of different methods of head elevation on intraocular pressure (IOP) in patients with open-angle glaucoma (OAG). METHODS: Seventy-one patients of OAG were included in this prospective observational study. We measured IOP in the sitting position and in the supine positions with head flat and 30-degree up using two different methods: (1) bed head elevation (BHE) and (2) using multiple pillows (MP). We measured IOP using Tonopen AVIA in both eyes 10 minutes after assuming each position in a randomized sequence. By comparing the mean deviation (MD) of visual field between both eyes of a patient, we classified the eyes into either the better-MD eye or worse-MD eye. RESULTS: Compared with that measured in the supine position with head flat, the mean IOP was significantly lower when measured in the supine position with the head 30 degrees up by BHE, with an average drop of 2.0 mmHg (p < 0.001), whereas the mean IOP did not differ significantly when measured in the supine position with head 30 degrees up using MP (p = 0.081). Twenty-five (35.2%) patients showed IOP elevation when the head was kept up by MP. Compared between the better-MD and worse-MD eye, the IOPs did not differ in all positions. The mean IOP of the better-MD eye was lower in the 30-degree head-up (-1.9 mmHg, BHE; -0.8 mmHg, MP) positions compared with that in the flat-lying position, whereas the mean IOP of the worse-MD eye did not differ between the lying flat position and the head-up position with MP. CONCLUSIONS: Different head-elevating methods had different influences on IOPs of glaucoma patients in the supine position. Although raising the bed head by 30 degrees significantly lowers IOP compared to the supine position, resting on multiple pillows does not appear to offer the same IOP reduction in glaucoma patients. PMID- 27232905 TI - Ir-Catalyzed Regio- and Stereoselective Hydrosilylation of Internal Thioalkynes: A Combined Experimental and Computational Study. AB - Iridium complexes are known catalysts for a range of silylation reactions. However, the exploitation for selective hydrosilylation of unsymmetrical internal alkynes has been limitedly known. Described here is a new example of this type. Specifically, [(cod)IrCl]2 catalyzes the efficient and mild hydrosilylation of thioalkynes by various silanes with excellent regio- and stereoselectivity. DFT studies suggested a new mechanism involving Ir(I) hydride as the key intermediate. PMID- 27232906 TI - Coronary artery bifurcation with chronic total occlusion: A "biodegradable" strategy for a challenging treatment with optical coherence tomography analysis. PMID- 27232907 TI - Catheter closure of atrial septal defect in the elderly (>=65years). A worthwhile procedure. AB - BACKGROUND: Secundum atrial septal defect (ASD2) is one of the most common cardiac malformations diagnosed in adult life. Catheter closure has made treatment possible even in patients of high age. However, published outcome data for elderly patients is limited. The aim of this study was to report, on a national basis, the long-term outcome of ASD2 catheter closure in the elderly. MATERIAL AND RESULTS: We report the clinical and echocardiographic outcome of catheter closure of ASD2 in 148 patients aged 65-87years. Data was obtained from a national registry, medical records and a questionnaire. The proportion of patients in NYHA I increased from 34% to 61% (p<0.001) one year after closure and remained stable at the latest follow-up 4,4 (SD 2,6) years post-closure. The proportion of patients with moderate/severe enlargement of the right ventricle and atrium fell from 77% and 76% to 25% and 40%, respectively, (p<0.001) and right ventricular systolic pressure dropped significantly. Improvement of NYHA class was associated with reduced right ventricular systolic pressure but not with remodelling of the right heart. NYHA deteriorated in 9 patients, despite reduced right ventricular size. Overall, the prevalence of atrial fibrillation was unchanged after closure. Major complication rate was 2% and there was no procedure- or device-related mortality. CONCLUSION: Catheter closure of ASD2 in the elderly is a worthwhile procedure since it improves symptoms and has a low complication rate. However, a subset of patients do not improve, in which we suggest that concealed left ventricular dysfunction may play a causative role. PMID- 27232908 TI - Frame rate required for speckle tracking echocardiography: A quantitative clinical study with open-source, vendor-independent software. AB - OBJECTIVES: To determine the optimal frame rate at which reliable heart walls velocities can be assessed by speckle tracking. BACKGROUND: Assessing left ventricular function with speckle tracking is useful in patient diagnosis but requires a temporal resolution that can follow myocardial motion. In this study we investigated the effect of different frame rates on the accuracy of speckle tracking results, highlighting the temporal resolution where reliable results can be obtained. MATERIAL AND METHODS: 27 patients were scanned at two different frame rates at their resting heart rate. From all acquired loops, lower temporal resolution image sequences were generated by dropping frames, decreasing the frame rate by up to 10-fold. RESULTS: Tissue velocities were estimated by automated speckle tracking. Above 40 frames/s the peak velocity was reliably measured. When frame rate was lower, the inter-frame interval containing the instant of highest velocity also contained lower velocities, and therefore the average velocity in that interval was an underestimate of the clinically desired instantaneous maximum velocity. CONCLUSIONS: The higher the frame rate, the more accurately maximum velocities are identified by speckle tracking, until the frame rate drops below 40 frames/s, beyond which there is little increase in peak velocity. We provide in an online supplement the vendor-independent software we used for automatic speckle-tracked velocity assessment to help others working in this field. PMID- 27232909 TI - Determinants of carotid-femoral pulse wave velocity in prepubertal children. AB - BACKGROUND: Pulse wave velocity (PWV) is a noninvasive technique to evaluate arterial stiffness, a dynamic property of the vessels, reflecting their structure and function. Childhood obesity is associated with several cardiovascular comorbidities and to the progression of atherosclerosis. We aimed to compare carotid-femoral PWV between normal weight and overweight/obese prepubertal children and to quantify its association with other cardiovascular risk factors. METHODS: Cross-sectional study of 315 children aged 8-9years. Anthropometrics, 24 h ambulatory blood pressure (BP) and carotid-femoral PWV were measured. Classification of obesity was according to World Health Organization (WHO) body mass index (BMI)-for-age reference values. RESULTS: Compared to normal weight children, overweight and obese children presented significantly higher levels of PWV (4.95 (P25-P75: 4.61-5.23), 5.00 (4.71-5.33), 5.10 (4.82-5.50) m/s, respectively; ptrend<0.001). Significant positive correlations were found between PWV and total cholesterol, LDL cholesterol, triglycerides, fasting insulin and insulin resistance levels (HOMA-IR) and with high-sensitivity C-reactive protein (hs-CRP). In a multivariate linear regression model adjusted for sex, age, height and 24-h systolic blood pressure z-score, the independent determinants of PWV were BMI, HOMA-IR and the absence of dipping. CONCLUSIONS: The association between PWV and the loss of dipping and insulin resistance levels, independently of the BMI, reinforces the contribution of these comorbidities to vascular injury in early life. PMID- 27232911 TI - Adequate muscular strength may help to reduce mortality risk in those with an elevated gamma gap. AB - BACKGROUND: An elevated (>=3.1g/dl) gamma gap (Total Protein (g/dl)-Albumin (g/dl)) is associated with increased heart failure risk and an increased mortality risk. Adequate muscular strength is associated with reduced mortality risk, but the potential protective effects of muscular strength on mortality among those with an elevated gamma gap has yet to be investigated, which was this study's purpose. METHODS: Data from the 1999-2002 NHANES were utilized, with follow-up through 2011. Lower extremity strength was objectively-measured via a knee extensor test. Gamma gap was measured from a blood sample. 2776 participants (50-85yrs) constituted the analytic sample. RESULTS: After adjustments, and among those with an elevated gamma gap, a 50N increase in lower extremity strength was associated with a 27% reduced risk of all-cause mortality (HRadjusted=0.73; 95% CI: 0.65-0.82; P<0.001). CONCLUSIONS: Having adequate lower extremity strength in middle-age and older adult years may be of critical importance in reducing mortality risk, particularly among those with an elevated gamma gap. PMID- 27232910 TI - Heart failure in patients with human immunodeficiency virus infection: Epidemiology and management disparities. AB - BACKGROUND: Persons living with HIV are at a higher risk of cardiovascular disease despite effective antiretroviral therapy and dramatic reductions in AIDS related conditions. We sought to identify the epidemiology of heart failure (HF) among persons living with HIV in the United States in an era of contemporary antiretroviral therapy. METHODS: Explorys is an electronic healthcare database that aggregates medical records from 23 healthcare systems nationwide. Using systemized nomenclature of medicine-clinical terms (SNOMED-CT), we identified adult patients (age>18), who had active records over the past year (September 2014-September 2015). We described the prevalence of HF in HIV patients by demographics and treatment and compared them to HIV-uninfected controls. RESULTS: Overall, there were 36,400 patients with HIV and 12,208,430 controls. The overall prevalence of HF was 7.2% in HIV and 4.4% in controls (RR 1.66 [1.60-1.72], p<0.0001). The relative risk of HF associated with HIV infection was higher among women and younger age groups. Patients receiving antiretroviral therapy had only marginally lower risk (6.4% vs. 7.7%, p<0.0001) of HF compared to those who were untreated. Compared to uninfected patients with HF, HIV patients with HF were less likely to receive antiplatelet drugs, statins, diuretics, and ACE/ARBs (p<0.0001 for all comparisons). For patients with HIV and HF, receiving care from a cardiologist was associated with higher use of antiplatelets, statins, betablockers, ACE/ARBs, and diuretics. CONCLUSIONS: Persons with HIV are at higher risk for HF in this large contemporary sample that includes both men and women. Although the prevalence of heart failure is higher in older HIV patients, the relative risk associated with HIV is highest in young people and in women. HIV patients are less likely to have HF optimally treated, but cardiology referral was associated with higher treatment rates. PMID- 27232912 TI - Left ventricular hypertrophy in adults with previous repair of coarctation of the aorta; association with systolic blood pressure in the high normal range. AB - BACKGROUND: Arterial hypertension is common in adults with repaired coarctation of the aorta (CoA). The associations between the diagnosis of hypertension, actual blood pressure, other factors affecting left ventricular overload, and left ventricular hypertrophy (LVH) are not yet fully explored in this population. MATERIAL AND RESULTS: From the national register for congenital heart disease, 506 adult patients (>=18years old) with previous repair of CoA were identified (37.0% female, mean age 35.7+/-13.8years, with an average of 26.8+/-12.4years post repair). Echocardiographic data were available for all patients, and showed LVH in 114 (22.5%) of these. Systolic blood pressure (SBP) (mmHg) (OR 1.02, CI 1.01-1.04), aortic valve disease, (OR 2.17, CI 1.33-3.53), age (years) (OR 1.03, CI 1.01-1.05), diagnosis of arterial hypertension (OR 3.02, CI 1.81-5.02), and sex (female) (OR 0.41, CI 0.24-0.72) were independently associated with LVH. There was an association with LVH at SBP within the upper reference limits [130, 140] mmHg (OR 2.23, CI 1.05-4.73) that further increased for SBP>140mmHg (OR 8.02, CI 3.76-17.12). CONCLUSIONS: LVH is common post repair of CoA and is associated with SBP even below the currently recommended target level. Lower target levels may therefore become justified in this population. PMID- 27232913 TI - Hypertensive retinopathy and cerebral small vessel disease in Amerindians living in rural Ecuador: The Atahualpa Project. AB - BACKGROUND: Diagnosis of cerebral small vessel disease (SVD) is a challenge in remote areas where MRI is not available. Hypertensive retinopathy (HTRP) has shown to correlate with SVD in different ethnic groups, but there is no information from indigenous Latin American people. We assessed the usefulness of retinal photographs to detect cases with SVD among Amerindians living in rural Ecuador. METHODS: Atahualpa residents aged >=60years with arterial hypertension or prehypertension were identified during a door-to-door survey. A confocal line scanning laser ophthalmoscope was used to identify and grade HTRP (according to the Keith-Wagener-Barker classification). MRIs were read with attention to the presence of white matter hyperintensities (WMH) of presumed vascular origin and lacunar infarcts. Using logistic regression models, we evaluated whether HTRP was independently associated with neuroimaging signatures of SVD. RESULTS: Of 323 eligible candidates, 241 (75%) were enrolled. MRI readings revealed moderate-to severe WMH in 49 (20%) cases and lacunar infarcts in 29 (12%). HTRP Grade 1 was noticed in 90 (37%) individuals and Grade 2-3 in 42 (17%). After adjusting for demographics and cardiovascular risk factors, multivariate analyses showed a significant association between Grades 2-3 HTRP and moderate-to-severe WMH (OR: 3.87, 95% C.I.: 1.64-9.13) but not with lacunar infarcts (OR: 2.22, 95% C.I.: 0.83-5.92). CONCLUSION: Amerindians with HTRP Grades 2-3 are almost four times more likely to have SVD-related subcortical damage than those with no- or only Grade 1-HTRP. Retinal photographs might allow recognition of people who need further investigation and therapy. PMID- 27232914 TI - Surveillance after cardiac arrest in patients with Brugada syndrome without an implantable defibrillator: An alarm effect of the previous syncope. AB - BACKGROUND: Debate regarding the prognosis of asymptomatic patients with Brugada syndrome (BrS) is possibly affected by the selection bias of survivors of sudden cardiac arrest (SCA). We aimed to determine variables influencing surveillance after SCA. METHODS: We analyzed a BrS cohort of 145 patients belonging to 37 families. We compared the clinical data and circumstances surrounding SCA (i.e., place of occurrence and people accompanying the subject) in 10 patients who survived an episode of SCA (Group A) vs. 27 deceased relatives (first or second degree) who suffered sudden cardiac death (SCD; Group B). Information concerning Group B was agreed upon by at least 3 relatives. A sub-analysis was performed considering families carrying a mutation in SCN5A (Group B-Mutant). RESULTS: Syncope was unique in predicting SCA in the BrS cohort. Comparing Groups A vs. B, there were no differences in the mean age at time of SCA/SCD (46.2 [SD 17.1] vs. 39.9 [SD 14.5] years; p=0.271), gender (male 60% vs. 74.1%; p=0.442), prior cardiomyopathy (0%), administration of cardiovascular treatments (anti hypertensive and lipid-lowering drugs; 20% vs. 14.8%; p=0.653) or conventional cardiovascular risk factors. Environmental circumstances surrounding the SCA/SCD were not significantly different between groups. Prior syncope was more frequent in Group A (80% vs. 3.7%; p<0.001) and unique in predicting surveillance (p<0.001). Group B-Mutant displayed equivalent data. CONCLUSIONS: A previous syncope, as an alarm symptom, might contribute to better surveillance of SCA compared with subjects with SCA as the debut of BrS. The latter might behave as a factor of selection bias. PMID- 27232915 TI - Comparison of long-term clinical outcomes of percutaneous coronary intervention in vasospastic angina patients associated with significant coronary artery stenosis. AB - BACKGROUND: Coronary spasm is the major pathophysiology of vasospastic angina (VA). Medical treatment is usually effective in VA patients without significant stenosis. However, there is little information about the percutaneous coronary intervention (PCI) in VA patients with significant coronary artery stenosis (CAS). METHODS: After retrospective screening of all consecutive VA patients from January 2010 to April 2015, we selected significant CAS (>50% of diameter stenosis) after nitrate injection and divided them into two groups according to the presence of PCI. RESULTS: A total of 220 VA patients (41 females, mean age: 58+/-10years old) were screened, and 85 were included in this study. Males were predominant in the VA with significant CAS group (89 vs 76%, p=0.020). PCI was done in 43 patients (51%). The most common culprit coronary artery was the left anterior descending coronary artery (18, 42%), diameter stenosis was significantly higher (66+/-9 vs 61+/-10%, p<0.01), and total number of antianginal medication was significantly lower in the PCI group than in the medical group (1.7+/-0.9 vs 2.1+/-0.8, p=0.039). Moreover, 4 patients underwent PCI to control symptoms in the medical treatment group during the follow-up period (26+/-13months). However, additional antiplatelet therapy was necessary in patients with coronary angioplasty, and there were 2 cases with complication associated with angioplasty (1 restenosis and 1 bleeding complication). CONCLUSION: In VA patients with significant CAS, both treatment modalities showed similar clinical outcomes. Although the PCI can afford symptomatic improvement, it needed additional antiplatelet medications and can be associated with procedural complications. PMID- 27232916 TI - Exercise performance in Ebstein's anomaly in the course of time - Deterioration in native patients and preserved function after tricuspid valve surgery. AB - OBJECTIVE: The purpose of this study was to assess the longitudinal follow-up of exercise performance in patients with native Ebstein anomaly and patients who had received previous tricuspid valve surgery. PATIENTS AND METHODS: We identified 59 patients with Ebstein anomaly who had performed at least two cardiopulmonary exercise tests within a minimum of 6months. 22 patients (15 female, 29.0+/ 13.4years) with native conditions, 37 patients (21 female, 32.1+/-15.3years) had undergone surgery of their tricuspid valve before baseline testing. RESULTS: In the non-operated group peak workload (2.58+/-0.7 to 2.38+/-0.7W/kg, p=.019) declined during a mean follow-up of 4.6+/-2.6years, whereas peak workload remained stable in the surgical group (2.02+/-0.6 to 2.06+/-0.7W/kg, p=.229) throughout the follow-up of 3.4+/-2.3years. In the 18 patients who had their surgery less than one year prior to the first CPET the exercise performance even increased during the follow-up. Peak blood pressure as a marker of cardiac adaption to exercise increased in the follow-up examination only in the surgical group (159+/-23 vs. 171+/-30mmHg, p=.007). In the non-operated group blood pressure remained unchanged at follow-up (161+/-26 vs. 166+/-29, p=.358). CONCLUSION: Exercise performance deteriorates in non-operated patients with Ebstein anomaly in contrast to patients after tricuspid valve surgery where exercise performance remains stable. These facts promote a surgical intervention latest at the time when exercise performance decreases. PMID- 27232917 TI - Lack of control of hypertension in primary cardiovascular disease prevention in Europe: Results from the EURIKA study. AB - BACKGROUND: The prevalence of and factors associated with uncontrolled hypertension and apparent resistant hypertension were assessed in the European Study on Cardiovascular Risk Prevention and Management in Usual Daily Practice (EURIKA; NCT00882336). METHODS: EURIKA was a cross-sectional observational study including patients being treated for the primary prevention of cardiovascular disease in 12 European countries. Patients were assessed if they were being treated for hypertension (N=5220). Blood pressure control was defined according to European guidelines, with sensitivity analysis taking account of patients' age and diabetes status. Associated factors were assessed using multivariate analysis. RESULTS: In the primary analysis, a total of 2691 patients (51.6%) had uncontrolled hypertension. Factors significantly associated with an increased risk of having uncontrolled hypertension included female sex (odds ratio [OR]: 2.29; 95% confidence interval [CI]: 1.93-2.73), body mass index (BMI; OR per kg/m(2): 1.03; 95% CI: 1.01-1.04), and geographic location. A total of 749 patients (14.3%) had apparent resistant hypertension. Factors significantly associated with an increased risk of having apparent resistant hypertension included BMI (OR per kg/m(2): 1.06; 95% CI: 1.04-1.08), diabetes (OR: 1.28; 95% CI: 1.06-1.53), use of statins (OR: 1.36; 95% CI: 1.15-1.62), serum uric acid levels (OR: 1.16; 95% CI: 1.09-1.23), and geographic location. Similar results were seen in sensitivity analyses. CONCLUSIONS: Over 50% of patients treated for hypertension continued to have uncontrolled blood pressure and 14.3% had apparent resistant hypertension. Positive associations were seen with other cardiovascular risk factors. PMID- 27232918 TI - Are BVS suitable for ACS patients? Support from a large single center real live registry. AB - OBJECTIVES: To investigate one-year outcomes after implantation of a bioresorbable vascular scaffold (BVS) in patients presenting with acute coronary syndrome (ACS) compared to stable angina patients. BACKGROUND: Robust data on the outcome of BVS in the setting of ACS is still scarce. METHODS: Two investigator initiated, single-center, single-arm BVS registries have been pooled for the purpose of this study, namely the BVS Expand and BVS STEMI registries. RESULTS: From September 2012-October 2014, 351 patients with a total of 428 lesions were enrolled. 255 (72.6%) were ACS patients and 99 (27.4%) presented with stable angina/silent ischemia. Mean number of scaffold/patient was 1.55+/-0.91 in ACS group versus 1.91+/-1.11 in non-ACS group (P=0.11). Pre- and post-dilatation were performed less frequent in ACS patients, 75.7% and 41.3% versus 89.0% and 62.0% respectively (P=0.05 and P=0.001). Interestingly, post-procedural acute lumen gain and percentage diameter stenosis were superior in ACS patients, 1.62+/ 0.65mm (versus 1.22+/-0.49mm, P<0.001) and 15.51+/-8.47% (versus 18.46+/-9.54%, P=0.04). Major adverse cardiac events (MACE) rate at 12months was 5.5% in the ACS group (versus 5.3% in stable group, P=0.90). One-year definite scaffold thrombosis rate was comparable: 2.0% for ACS population versus 2.1% for stable population (P=0.94), however, early scaffold thromboses occurred only in ACS patients. CONCLUSIONS: One-year clinical outcomes in ACS patients treated with BVS were similar to non-ACS patients. Acute angiographic outcomes were better in ACS than in non-ACS, yet the early thrombotic events require attention and further research. PMID- 27232919 TI - Biphasic response in number of stem cells and endothelial progenitor cells after left ventricular assist device implantation: A 6month follow-up. AB - BACKGROUND: Continuous blood flow could have deleterious effects on endothelium and vascular health. This could have serious consequences in patients with heart failure treated with continuous flow left ventricular assist devices (LVAD). Therefore, we studied effect of LVAD on three circulating vascular biomarkers: stem cells (SC), endothelial progenitor cells (EPC) and microparticles (MP). METHODS: In 23 patients (5 women) with end-stage heart failure, SC, EPC and MP were measured before, and 3 and 6months after implantation of LVAD (HeartMate II). SC were defined using determination of surface antigen expression as mononuclear CD34+/CD45low+ cells and EPC as mononuclear CD34+/CD45low+/KDR+ cells. MP concentrations were determined by ELISA method. RESULTS: Three months after LVAD implantation numbers of SC and EPC significantly decreased (p=0.01 and p=0.001, respectively). On the contrary, between 3rd and 6th month after implantation they significantly increased (p=0.006 and p=0.003, respectively).MP did not change significantly during the study despite exerting similar trend as SC and EPC. CONCLUSIONS: Observed biphasic changes of SC and EPC might reflect two processes. First, shortly after LVAD implantation, improved tissue perfusion could lead to decrease in ischemic stimuli and ensuing decrease of SC and EPC. Second, continuous flow between 3rd and 6th month produced by LVAD could lead to increase of SC and EPC through activation of endothelium. This explanation could be supported also by similar trend in the changes of concentrations of MP. PMID- 27232920 TI - Lung ultrasound and short-term prognosis in heart failure patients. AB - BACKGROUND: Heart failure (HF) is the leading cause of hospitalization for patients older than 65years, with a 30-day readmission rate of 20-25%. Although several markers have been evaluated to stratify timing of follow-up after an acute decompensation is mostly based on clinical judgment. Lung ultrasound (LUS) has been demonstrated to be a valid tool for the assessment and monitoring of pulmonary congestion. Aim of our study was to evaluate if LUS performed in HF patients at discharge could predict 100-day hospital readmission or death. METHODS: One-hundred fifty patients were enrolled. The anterolateral chest was scanned to evaluate the presence of B-lines. A sonographic score was calculated attributing 1 to each positive (>=3 B-lines) sector. Clinical, biochemical and echocardiographic data were recorded. A Cox proportional hazard regression analysis was performed to evaluate the association between variables and 100-day events. RESULTS: Follow-up was obtained in 149 patients. Thirty-four events were recorded. Sonographic score was significantly associated with events (HR 1.19; CI 1.05 to 1.34; p=0.005). On average, the increase of 1 point in the sonographic score was associated with an increase of approximately 24% in the risk of event within 100days. At multivariate analysis NTproBNP remained the only independent prognostic factor. CONCLUSIONS: We confirmed that B-lines at discharge are a prognostic marker for hospital readmission and death at 100days in HF patients. Nevertheless, further randomized clinical studies are needed to definitely support the routine use of LUS in the clinical management of HF patients, in combination or not with NT-proBNP. PMID- 27232921 TI - A meta-analysis of randomized controlled trials assessing the impact of beta blockers on arterial stiffness, peripheral blood pressure and heart rate. AB - BACKGROUND: The recognition of beta-blockers as a preferred initial therapy for hypertension has been a hot topic of debate recently. This meta-analysis was aimed to assess the impact of different beta-blockers on arterial stiffness as indexed by pulse wave velocity (PWV), peripheral blood pressure (BP) and heart rate, relative to the placebo, angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). METHODS: Two authors independently searched articles, appraised eligibility and abstracted information, and the data were analyzed using STATA. RESULTS: Twenty-four articles involving 27 independent trials were eligible. Relative to the placebo, treatment with beta-blockers led to remarkable improvement in PWV (WMD, 95% CI, P: -1.115m/s, -1.561 to -0.669, <0.001), systolic BP (-12.355mmHg, -14.330 to -10.380, <0.001), diastolic BP ( 8.619mmHg, -10.357 to -6.880, <0.001), mean BP (-9.683mmHg, -11.172 to -8.194, <0.001), pulse pressure (-4.448mmHg, -7.386 to -1.510, 0.003) and heart rate ( 12.335, -22.739 to -1.932, 0.020). Beta-blockers were remarkably superior to ACEIs in DBP (-2.540mmHg, -4.463 to -0.617, 0.010) and heart rate (-9.859bpm, 11.752 to -7.969, <0.001). In contrast to ARBs, beta-blocker treatment increased systolic BP (2.042mmHg, 0.639 to 3.444, 0.004) but reduced heart rate (-8.814bpm, -9.756 to -7.873, <0.001) significantly. No publication bias was observed. CONCLUSIONS: Beta-blockers exerted more favorable impact than the placebo on arterial stiffness, peripheral BP and heart rate, but less favorable impact than ACEIs or ARBs on all, except heart rate, characters, especially in trials with longer duration of treatment and higher baseline PWV. PMID- 27232922 TI - A multidisciplinary team-based process improves outpatient anticoagulation quality with continuous-flow left-ventricular assist devices. PMID- 27232923 TI - Extremely elevated BNP in acute heart failure: Patient characteristics and outcomes. AB - BACKGROUND: We explored the clinical characteristics and outcomes of patients with acute systolic heart failure (HF) and extremely elevated admission B-type natriuretic peptide (BNP). METHODS: Extremely elevated BNP was defined if BNP level was >85th percentile of the study cohort (i.e. >1694pg/mL). Our objectives were to find characteristic features that identify patients with extremely elevated BNP, to compare the degree of congestion in both groups and to study post-discharge outcomes. RESULTS: 347 patients (mean age 56years, 74% males) were divided into two groups based on whether BNP was extremely elevated (n=53) or not (n=294). Those with extremely elevated BNP were older (P=0.004), with a lower body mass index (P<0.0001), higher blood urea nitrogen (P=0.01), higher creatinine (P=0.005), lower cardiac output (P<0.0001) and lower cardiac index (P=0.001). With regards to signs of congestion, both groups had no significant difference in the frequency of rales (P=0.454), peripheral edema (P=0.397), jugular venous distension (P=0.396), positive hepatojugular reflux (P=0.083), S3 gallop (P=0.107), mean pulmonary capillary wedge pressure (P=0.351), and right atrial pressure (P=0.310). Both groups had similar frequency of rehospitalization for HF (P=0.939), nonetheless, patients with extremely elevated BNP had longer hospital stay during initial (P=0.014), or subsequent hospitalization (30days: P=0.01, 180days: P=0.008). 6-month all-cause-mortality was higher in patients with extremely elevated BNP (P=0.008), although death due to pump failure was not (P=0.921). Cox proportional hazard analysis revealed that extremely elevated admission BNP is an independent predictor of 6-month all-cause-mortality (hazard ratio 1.857, 95% CI=1.074-3.208, P=0.027) after adjustment for known predictors of post-discharge mortality in HF. CONCLUSION: Extremely elevated admission BNP did not match the degree of congestion nor was a predictor of rehospitalization due to HF. It was associated with decreased COP, prolonged hospital stay, and increased 6-month all-cause-mortality. PMID- 27232924 TI - Comparison of drug-eluting balloon versus drug-eluting stent treatment of drug eluting stent in-stent restenosis: A meta-analysis of available evidence. AB - BACKGROUND: In-stent restenosis (ISR) remains an important concern despite the recent advances in the drug-eluting stent (DES) technology. The introduction of drug-eluting balloons (DEB) offers a good solution to such problem. OBJECTIVES: We performed a meta-analysis to assess the clinical efficiency and safety of DEB compared with DES in patients with DES-ISR. METHODS: A systematic search was conducted and all randomized and observational studies which compared DEB with DES in patients with DES-ISR were included. The primary outcome measure-major adverse cardiovascular events (MACE)-as well as individual events as target lesion revascularization (TLR), stent thrombosis (ST), myocardial infarction (MI), cardiac death (CD) and all-cause mortality, were analyzed. RESULTS: Three randomized and 4 observational studies were included with a total of 2052 patients. MACE (relative risk [RR]=1.00, 95% confidence interval (CI) 0.68 to 1.46, P=0.99), TLR (RR=1.15 [CI 0.79 to 1.68], P=0.44), ST (RR=0.37[0.10 to 1.34], P=0.13), MI (RR=0.97 [0.49 to 1.91], P=0.93) and CD (RR=0.73 [0.22 to 2.45], P=0.61) were not different between patients treated with DEB and with DES. However, all-cause mortality was lower in patients treated with DEB (RR=0.45 [0.23 to 0.87, P=0.019) and in particular when compared to only first generation DES (RR 0.33 [0.15-0.74], P=0.007). There was no statistical evidence for publication bias. CONCLUSIONS: The results of this meta-analysis showed that DEB and DES have similar efficacy and safety for the treatment of DES-ISR. PMID- 27232925 TI - Renal biomarkers and outcomes in outpatients with heart failure: The Atlanta cardiomyopathy consortium. AB - BACKGROUND/OBJECTIVES: Cystatin-C and beta-2-microglobulin may be superior to serum creatinine, blood urea nitrogen (BUN), or estimated glomerular filtration rate (eGFR) in patients hospitalized with heart failure (HF). We compared these renal markers in ambulatory HF patients. METHODS: We prospectively evaluated the association of baseline renal markers and eGFR (by 4 different formulas) with (1) the composite of death or HF-related hospitalization and (2) rates of hospitalizations and emergency department (ED) visits in 166 outpatients with HF (57.3+/-11.6years; 57.2% white, 38.6% black, median left ventricular ejection fraction 27.5% [17.5, 40.0]). RESULTS: After a median of 3.9years, 63 (38.0%) patients met the composite endpoint. There were 458 hospitalizations (177 [38.6%] for HF) and 209 ED visits (51 [24.4%] for HF). Cystatin-based eGFR most consistently predicted (1) the composite endpoint (highest-to-lowest tertile adjusted hazard ratio [HR] 4.92 [95% CI 2.07-11.7; P<0.001]); and (2) hospitalization rates, including HF hospitalizations (highest-to-lowest tertile, adjusted relative rate 5.24 [95% CI 1.61-17.01; P=0.006]). Serum creatinine alone was a strong predictor of the composite endpoint (highest-to-lowest tertile, adjusted HR 3.20 [95% CI, 1.51-6.78; P=0.002]). Only the highest tertile of BUN was associated with rates of ED visits. CONCLUSIONS: In outpatients with HF, cystatin-based eGFR provides consistent prognostication across outcomes, except ED visits. Serum creatinine is an adequate prognosticator of death or HF hospitalization. PMID- 27232926 TI - Congenital heart disease in twins: The contribution of type of conception and chorionicity. AB - BACKGROUND: Increased incidence of congenital heart disease (CHD) has been reported in the offspring of monochorionic twin gestations. Assisted reproductive technology (ART), which is related to increased rates of twinning, has also been associated with higher risk of birth defects. We studied the incidence of CHD in a cohort of twins to clarify the contribution of type of conception and chorionicity. METHODS: Data concerning 874 live-born twins of which at least one was admitted in our Neonatal Unit during 1995-2012 were analysed. Forty-five % (N=197) of the gestations resulted from ART (in vitro fertilisation or intracytoplasmic sperm insertion). RESULTS: In the ART group 32/389 (8.2%) had CHD compared to 21/485 (4.3%) infants conceived naturally (OR 1.90, 95%CI 1.08 3.34, p=0.024). Spontaneous-conception gestations had higher incidence of monochorionic placentation (47/245 versus 4/197, p<0.001), and included younger mothers (29.1+/-5.2 versus 33.9+/-5.5years, p<0.001) who had higher parity (median 2 [range 1-7] versus 1 Pinborg (2005), Blondel and Kaminski (2002), Knopman et al. (2014), Kyvik and Derom (2006) ; p<0.001). Multivariable logistic regression analysis showed that ART (OR 2.60, 95% CI 1.24-5.45) and monochorionicity (OR 3.49, 95% CI 1.57-7.77) were significant determinants of CHD, independently of maternal age, parity, and the gender of the offspring. CONCLUSIONS: We confirmed that monochorionic twins have increased risk of CHD and we documented a higher incidence of CHD in ART twins independently of chorionicity. We suggest improvement of echocardiographic skills of health care professionals involved in prenatal screening and foetal cardiology referral of ART dichorionic twins with suspicious findings at screening, in addition to all monochorionic gestations. PMID- 27232927 TI - The role of levosimendan in acute heart failure complicating acute coronary syndrome: A review and expert consensus opinion. AB - Acute heart failure and/or cardiogenic shock are frequently triggered by ischemic coronary events. Yet, there is a paucity of randomized data on the management of patients with heart failure complicating acute coronary syndrome, as acute coronary syndrome and cardiogenic shock have frequently been defined as exclusion criteria in trials and registries. As a consequence, guideline recommendations are mostly driven by observational studies, even though these patients have a particularly poor prognosis compared to heart failure patients without signs of coronary artery disease. In acute heart failure, and especially in cardiogenic shock related to ischemic conditions, vasopressors and inotropes are used. However, both pathophysiological considerations and available clinical data suggest that these treatments may have disadvantageous effects. The inodilator levosimendan offers potential benefits due to a range of distinct effects including positive inotropy, restoration of ventriculo-arterial coupling, increases in tissue perfusion, and anti-stunning and anti-inflammatory effects. In clinical trials levosimendan improves symptoms, cardiac function, hemodynamics, and end-organ function. Adverse effects are generally less common than with other inotropic and vasoactive therapies, with the notable exception of hypotension. The decision to use levosimendan, in terms of timing and dosing, is influenced by the presence of pulmonary congestion, and blood pressure measurements. Levosimendan should be preferred over adrenergic inotropes as a first line therapy for all ACS-AHF patients who are under beta-blockade and/or when urinary output is insufficient after diuretics. Levosimendan can be used alone or in combination with other inotropic or vasopressor agents, but requires monitoring due to the risk of hypotension. PMID- 27232928 TI - Impact of the origin of the collateral feeding donor artery on short-term mortality in ST-elevation myocardial infarction with comorbid chronic total occlusion. AB - BACKGROUND: Patients with ST-elevation myocardial infarction (STEMI) and multi vessel disease (MVD) have higher mortality, especially with comorbid chronic total occlusion (CTO). The origin of collateral flow to the CTO segment has not been studied in regard to short-term mortality. This study examined the impact of collateral feeding donor arteries from an infarct-related artery (IRA) or non-IRA to the comorbid CTO segment in regard to STEMI short-term mortality. METHODS: Data from 760 consecutive STEMI patients who underwent primary percutaneous coronary intervention were obtained retrospectively from medical records. The number of vessels involved and origin of the collateral feeding donor artery were evaluated using angiograms from the primary percutaneous coronary intervention. The study population was divided into patients with: single-vessel disease (SVD) (n=483), MVD without CTO (n=208), and MVD with CTO (n=64). All CTO segments had collateral flow from an IRA (n=23) or non-IRA (n=46). All-cause mortality (30 day) was analyzed. RESULTS: Compared to SVD and MVD without CTO, MVD with comorbid CTO had a higher mortality (5.4% vs. 15.9% vs. 24.6%, P<0.0001, respectively). Of patients with CTO, those with collateral flow from the IRA had significantly higher mortality than the non-IRA group (52.2% vs. 10.9%, P<0.0001). Collateral flow from the IRA was extracted as an independent predictor associated with 30-day all-cause mortality using a multivariate Cox proportional hazards model (hazard ratio 4.71, 95% confidence interval 1.60-14.2, P=0.0005). CONCLUSIONS: The origin of the collateral donor artery from the IRA had an impact on short-term mortality in STEMI patients with comorbid CTO lesions. PMID- 27232929 TI - Busulfan for the treatment of myeloproliferative neoplasms: the Mayo Clinic experience. PMID- 27232930 TI - Increased circulating VCAM-1 correlates with advanced disease and poor survival in patients with multiple myeloma: reduction by post-bortezomib and lenalidomide treatment. AB - Circulating vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and selectins were prospectively measured in 145 newly diagnosed patients with symptomatic myeloma (NDMM), 61 patients with asymptomatic/smoldering myeloma (SMM), 47 with monoclonal gammopathy of undetermined significance (MGUS) and 87 multiple myeloma (MM) patients at first relapse who received lenalidomide- or bortezomib-based treatment (RD, n=47; or VD, n=40). Patients with NDMM had increased VCAM-1 and ICAM-1 compared with MGUS and SMM patients. Elevated VCAM-1 correlated with ISS-3 and was independently associated with inferior overall survival (OS) (45 months for patients with VCAM 1 >median vs 75 months, P=0.001). MM patients at first relapse had increased levels of ICAM-1 and L-selectin, even compared with NDMM patients and had increased levels of VCAM-1 compared with MGUS and SMM. Both VD and RD reduced dramatically serum VCAM-1 after four cycles of therapy, but only VD reduced serum ICAM-1, irrespective of response to therapy. The reduction of VCAM-1 was more pronounced after RD than after VD. Our study provides evidence for the prognostic value of VCAM-1 in myeloma patients, suggesting that VCAM-1 could be a suitable target for the development of anti-myeloma therapies. Furthermore, the reduction of VCAM-1 and ICAM-1 by RD and VD supports the inhibitory effect of these drugs on the adhesion of MM cells to stromal cells. PMID- 27232932 TI - Anatomic and radiologic review of chronic mesenteric ischemia and its treatment. AB - Chronic mesenteric ischemia (CMI) is a vascular occlusive disease process that generally affects the elderly population. Clinical presentation occurs when two of the three mesenteric arteries are affected and includes non-specific abdominal pain and weight loss. The most common cause of CMI is atherosclerotic arterial occlusion. The aim of this review is to present the vascular anatomy of the mesenteric arterial circulation including the different collateral pathways. The imaging findings and the different treatment options with a brief review of the literature is presented. PMID- 27232931 TI - Malignant pleural mesothelioma: initial experience in integrated (18)F-FDG PET/MR imaging. AB - PURPOSE: This study aims to compare staging results of (18)F-FDG PET/computed tomography (CT) and integrated PET/magnetic resonance (MR) in malignant pleural mesothelioma (MPM) patients and to investigate a potential apparent diffusion coefficient (ADC)/SUV correlation. MATERIALS AND METHODS: Six patients with MPM underwent (18)F-FDG PET/CT and PET/MR including diffusion-weighted imaging. Thoracic TNM staging was performed for both modalities. SUV and ADC were assessed in therapy-naive pleural lesions. RESULTS: In thoracic TNM staging, no differences were found between PET/CT and PET/MR. An inverse correlation was observed between SUVmean and ADCmin (r=-0.63, P=.002). CONCLUSION: MPM can be staged using PET/MR. The inverse correlation ADC/SUV indicates that future research on multiparametric therapy response evaluation may be warranted. PMID- 27232933 TI - Polyomavirus Replication and Smoking Are Independent Risk Factors for Bladder Cancer After Renal Transplantation. AB - BACKGROUND: Solid organ transplant recipients are at increased risk for developing malignancies. Polyomaviruses (PV) have been historically associated with experimental tumor development and recently described in association with renourinary malignancies in transplant patients. The aim of this study was to investigate the relationship between PV replication and smoking, and the development of malignant neoplasms in kidney transplant recipients. METHODS: A retrospective case-control study was conducted for PV replication in all kidney biopsies and urine cytologies performed between 1998 and 2014 from kidney transplant recipients at the University of Maryland Medical Center. Polyomavirus positive patients (n = 943) were defined as having any of the following: a kidney biopsy with PV associated nephropathy, any urine cytology demonstrating "decoy" cells, and/or significant polyomavirus BK viremia. Polyomavirus-negative matched patients (n = 943) were defined as lacking any evidence of PV replication. The incidence of malignancy (excluding nonmelanoma skin tumors) was determined in these 1886 patients and correlated with demographic data and history of smoking. RESULTS: There was a 7.9% incidence of malignant tumors after a mean posttransplant follow-up of 7.9 +/- 5.4 years. Among all cancer subtypes, only bladder carcinoma was significantly associated with PV replication. By multivariate analysis, only PV replication and smoking independently increased the risk of bladder cancer, relative risk, 11.7 (P = 0.0013) and 5.6 (P = 0.0053), respectively. CONCLUSIONS: The findings in the current study indicate that kidney transplant recipients with PV replication and smoking are at particular risk to develop bladder carcinomas and support the need for long-term cancer surveillance in these patients. PMID- 27232935 TI - An Integrative Review of Engaging Clinical Nurses in Nursing Research. AB - PURPOSE: To review the literature for best practices for engaging clinical nurses in nursing research. DESIGN: Review of the research and nonresearch papers published between 2005 and 2015 that answered the evidence-based practice (EBP) question: what are the best practices for engaging clinical nursing staff in nursing research? METHODS: PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Joanna Briggs Institute, and Cochrane were searched using a combination of controlled vocabulary and key words. Nineteen papers that answered the EBP question were selected for review. RESULTS: It can be difficult to involve clinical nurses in research. There are multiple factors to consider when nursing leadership looks to engage clinical nurses in nursing research. CONCLUSIONS: Nurse leaders can take many approaches to engage clinical nurses in research. Each organization must perform its own assessment to identify areas of opportunity. Nursing leadership can take these areas of opportunity to structure a multifaceted approach to support clinical staff in the conduct and dissemination of nursing research. CLINICAL RELEVANCE: The evidence from this review offers EBP recommendations as well as reports on the gaps in the literature related to best practices for engaging clinical nurses in nursing research. PMID- 27232934 TI - Prolonged Survival of Pig Skin on Baboons After Administration of Pig Cells Expressing Human CD47. AB - BACKGROUND: Successful xenotransplantation will likely depend, in part, on the induction of immunological tolerance, because the high levels of immunosuppression otherwise required would likely have unacceptable side effects. Rapid clearance of administered porcine hematopoietic stem cells by primate macrophages has hampered previous attempts to induce tolerance through mixed hematopoietic chimerism across a pig-to-primate barrier. Phagocytosis is normally inhibited by binding of cell surface protein CD47 to macrophage signal regulatory protein alpha receptors. However, pig CD47 has previously been shown to be ineffective in transducing signals through primate signal regulatory protein alpha. METHODS: Mobilized peripheral blood hematopoietic cells from transgenic swine expressing high or low levels of human CD47 were infused into conditioned baboons at 3 time points over a 9-week period. Xenogeneic peripheral blood chimerism was assessed after each infusion. Split thickness skin grafts from the hematopoietic cell donor swine were placed on recipients 5 weeks after the last cell infusion and 7 weeks after the discontinuation of all immunosuppression to test immune response. RESULTS: The level and duration of transient chimerism were substantially greater in baboons receiving hematopoietic cells from a pig expressing high levels of human CD47. Skin graft survival on high CD47 recipients was prolonged as well, in 1 case showing no signs of rejection at least 53 days after placement. CONCLUSIONS: Prolongation of transient porcine chimerism via transgenic expression of human CD47 in a primate model is associated with an immune modulating effect, leading to markedly prolonged survival of donor swine skin xenografts that may be applicable to clinical solid organ xenotransplantation. PMID- 27232936 TI - Mixed Quantum-Classical Liouville Approach for Calculating Proton-Coupled Electron-Transfer Rate Constants. AB - In this work, we derive a general mixed quantum-classical formula for calculating thermal proton-coupled electron-transfer (PCET) rate constants, starting from the time integral of the quantum flux-flux correlation function. This formula allows for the direct simulation of PCET reaction dynamics via the mixed quantum classical Liouville approach. Owing to the general nature of the derivation, this formula does not rely on any prior mechanistic assumptions and can be applied across a wide range of electronic and protonic coupling regimes. To test the validity of this formula, we applied it to a reduced model of a condensed-phase PCET reaction. Good agreement with the numerically exact rate constant is obtained, demonstrating the accuracy of our formalism. We believe that this approach constitutes a solid foundation for future investigations of the rates and mechanisms of a wide range of PCET reactions. PMID- 27232937 TI - Electronic Structure and Dynamics of Higher-Lying Excited States in Light Harvesting Complex 1 from Rhodobacter sphaeroides. AB - Light harvesting in photosynthetic organisms involves efficient transfer of energy from peripheral antenna complexes to core antenna complexes, and ultimately to the reaction center where charge separation drives downstream photosynthetic processes. Antenna complexes contain many strongly coupled chromophores, which complicates analysis of their electronic structure. Two dimensional electronic spectroscopy (2DES) provides information on energetic coupling and ultrafast energy transfer dynamics, making the technique well suited for the study of photosynthetic antennae. Here, we present 2DES results on excited state properties and dynamics of a core antenna complex, light harvesting complex 1 (LH1), embedded in the photosynthetic membrane of Rhodobacter sphaeroides. The experiment reveals weakly allowed higher-lying excited states in LH1 at 770 nm, which transfer energy to the strongly allowed states at 875 nm with a lifetime of 40 fs. The presence of higher-lying excited states is in agreement with effective Hamiltonians constructed using parameters from crystal structures and atomic force microscopy (AFM) studies. The energy transfer dynamics between the higher- and lower-lying excited states agree with Redfield theory calculations. PMID- 27232938 TI - Nucleotide polymorphism affecting FLC expression underpins heading date variation in horticultural brassicas. AB - Variation in flowering time and response to overwintering has been exploited to breed brassica vegetables that can be harvested year-round. Our knowledge of flowering time control now enables the investigation of the molecular basis of this important variation. Here, we show that a major determinant of heading date variation in Brassica oleracea is from variation in vernalization response through allelic variation at FLOWERING LOCUS C.C2 (BoFLC4). We characterize two alleles of BoFLC.C2 that are both functional and confer a requirement for vernalization, but they show distinct expression dynamics in response to cold. Complementation experiments in Arabidopsis thaliana revealed that the allelic variation results from cis polymorphism at BoFLC.C2, which quantitatively influences the degree of cold-induced epigenetic silencing. This results in one allelic variant conferring consistently later heading under both glasshouse and field conditions through reduced environmental sensitivity. Our results suggest that breeding of brassica varieties for commercially valuable variation in heading date has been achieved through the selection of cis polymorphism at FLC, similar to that underpinning natural variation in A. thaliana. This understanding will allow for the selection of alleles with distinct sensitivities to cold and robust heading dates under variable climatic conditions, and will facilitate the breeding of varieties more resistant to climate change. PMID- 27232939 TI - Oximetry for suspected obstructive sleep apnea-Does removal of awake data affect the result? AB - Frequency of dips below 90% on overnight oximetry can be used to estimate severity of obstructive sleep apnea (OSA) in children. Movement can result in artifact on oximetry recordings. Clinicians may therefore be tempted to remove periods of wakefulness from the recording to improve accuracy, but removal of such periods of potential artifact is time consuming. The aim of this study was to determine whether removing periods of wakefulness had a significant impact on analysis of overnight oximetry. Children aged 2-18 years (N = 108) with suspected OSA underwent overnight simultaneous oximetry and actigraphy at home on a single night. Actigraphy defined awake periods were "trimmed" from the oximetry data and oximetry variables compared between full and trimmed analysis. There was a statistically but not clinically significant difference between the full and trimmed data for mean SpO2 , minimum SpO2 , 4% desaturation index, and 3% desaturation index (all P < 0.05). There was no difference between the two analyses for median SpO2 or the frequency of dips below 90%, 85%, or 80%. In conclusion, removal of periods of wakefulness at the start and end of overnight oximetry recordings does not affect the result in the context of testing for suspected OSA in children. Pediatr Pulmonol. 2016;51:1409-1413. (c) 2016 Wiley Periodicals, Inc. PMID- 27232940 TI - Associations between genetic variants located in mature microRNAs and risk of lung cancer. AB - MiRNAs have been focused for their wide range of biological regulatory functions. Previous studies have suggested that individual miRNAs could influence tumorigenesis through their regulation of specific proto-oncogenes and tumor suppressor genes. This study was implemented to investigate the associations between SNPs in mature microRNAs (miRNAs) and development of lung cancer in a two stage, case-control study, followed by some functional validations. First, 11 SNPs were analyzed in a case-control study of lung cancer, and the significant results were validated in an additional population. Our results showed that rs3746444 in mir-499 (allele C vs T: OR = 1.33; 95% CI = 1.15-1.54; P = 1.2 * 10 4) and rs4919510 in mir-608 (allele G vs C: OR = 1.27; 95% CI= 1.13-1.43; P = 5.1 * 10-5) were significantly associated with increased risk of lung cancer. Rs3746444 in mir-499 was also significantly associated with poor survival of lung cancer (HR, 1.35; 95% CI, 1.15-1.58; P = 0.0002). The expression levels of mir 499 and mir-608 were significantly lower than those of adjacent normal tissues (P < 0.0005), and the carriers of minor alleles have lower expression levels of mir 499 and mir-608 than those of major alleles (P < 0.001). These findings indicated that rs3746444 in mir-499 and rs4919510 in mir-608 might play a substantial role in the susceptibility to lung cancer. PMID- 27232941 TI - JMJD2B is required for Helicobacter pylori-induced gastric carcinogenesis via regulating COX-2 expression. AB - Helicobacter pylori (H. pylori) infection is the strongest risk factor for the initiation and progression of gastric cancer. However, the mechanism of H. pylori induced pathogenesis remains unclear. In this study, we investigate the role of H. pylori infection in JMJD2B upregulation and the mechanism underlying gastric carcinogenesis. We find that JMJD2B can be induced by H. pylori infection via beta-catenin pathway. beta-catenin directly binds to JMJD2B promoter and stimulates JMJD2B expression following H. pylori infection. Increased JMJD2B, together with NF-kappaB, binds to COX-2 promoter to enhance its transcription by demethylating H3K9me3 locally. JMJD2B and COX-2 expression is upregulated in H. pylori infected mice in vivo. Furthermore, JMJD2B and COX-2 expression is gradually increased in human gastric tissues from gastritis to gastric cancer. The level of JMJD2B and COX-2 in H. pylori-positive gastritis tissues is significantly higher than that in H. pylori-negative tissues. Moreover, a positive correlation between JMJD2B and COX-2 expression is found in both gastritis and gastric cancer tissues. Therefore, JMJD2B is a crucial factor in triggering H. pylori-induced chronic inflammation and progression of gastric carcinogenesis and it may serve as a novel target for the intervention of gastric cancer. PMID- 27232943 TI - Functional/activity network (FAN) analysis of gene-phenotype connectivity liaised by grape polyphenol resveratrol. AB - Resveratrol is a polyphenol that has witnessed an unprecedented yearly growth in PubMed citations since the late 1990s. Based on the diversity of cellular processes and diseases resveratrol reportedly affects and benefits, it is likely that the interest in resveratrol will continue, although uncertainty regarding its mechanism in different biological systems remains.We hypothesize that insights on disease-modulatory activities of resveratrol might be gleaned by systematically dissecting the publicly available published data on chemicals and drugs. In this study, we tested our hypothesis by querying DTome (Drug-Target Interactome), a web-based tool containing data compiled from open-source databases including DrugBank, PharmGSK, and Protein Interaction Network Analysis (PINA). Four direct protein targets (DPT) and 219 DPT-associated genes were identified for resveratrol. The DPT-associated genes were scrutinized by WebGestalt (WEB-based Gene SeT Analysis Toolkit). This enrichment analysis resulted in 10 identified KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways. Refined analysis of KEGG pathways showed that 2 - one linked to p53 and a second to prostate cancer - have functional connectivity to resveratrol and its four direct protein targets. These results suggest that a functional activity network (FAN) approach may be considered as a new paradigm for guiding future studies of resveratrol. FAN analysis resembles a BioGPS, with capability for mapping a Web-based scientific track that can productively and cost effectively connect resveratrol to its primary and secondary target proteins and to its biological functions. PMID- 27232942 TI - Identification of associations between small molecule drugs and miRNAs based on functional similarity. AB - MicroRNAs (miRNAs) are a class of small non-coding RNA molecules that regulate gene expression at post-transcriptional level. Increasing evidences show aberrant expression of miRNAs in varieties of diseases. Targeting the dysregulated miRNAs with small molecule drugs has become a novel therapy for many human diseases, especially cancer. Here, we proposed a novel computational approach to identify associations between small molecules and miRNAs based on functional similarity of differentially expressed genes. At the significance level of p < 0.01, we constructed the small molecule and miRNA functional similarity network involving 111 small molecules and 20 miRNAs. Moreover, we also predicted associations between drugs and diseases through integrating our identified small molecule miRNA associations with experimentally validated disease related miRNAs. As a result, we identified 2265 associations between FDA approved drugs and diseases, in which ~35% associations have been validated by comprehensive literature reviews. For breast cancer, we identified 19 potential drugs, in which 12 drugs were supported by previous studies. In addition, we performed survival analysis for the patients from TCGA and GEO database, which indicated that the associated miRNAs of 4 drugs might be good prognosis markers in breast cancer. Collectively, this study proposed a novel approach to predict small molecule and miRNA associations based on functional similarity, which may pave a new way for miRNA targeted therapy and drug repositioning. PMID- 27232945 TI - Personality and the Long-Term Outcome of First-Episode Depression: A Prospective 5-Year Follow-Up Study. AB - OBJECTIVE: To determine the impact of the personality traits neuroticism and extraversion as well as comorbid personality disorders on the rate of remission, recurrence, and conversion to bipolar disorder after the first lifetime episode of depression. METHODS: A total of 301 inpatients or outpatients aged 18-70 years with a validated diagnosis of a single depressive episode according to ICD-10 were assessed by the Structured Clinical Interview for DSM-IV Axis II Personality Disorders and the Eysenck Personality Questionnaire from 2005 through 2007. At 5 year follow-up, 262 patients were reassessed by means of the Life Chart Method and diagnostic interviews from 2011 through 2013. Cox regression analyses were used to estimate the effect of personality factors on the rates of remission, recurrence, and conversion to bipolar disorder, respectively. RESULTS: A comorbid cluster C personality disorder decreased the rate of remission by 30% (HR = 0.7; 95% CI, 0.5-0.9; P = .02) and increased the rate of recurrence after remission of the first depression by 80% (HR = 1.8; 95% CI, 1.0-3.0; P = .04). A higher neuroticism score at baseline decreased the rate of remission by 20% for each increase of 1 SD (HR = 0.8; 95% CI, 0.7-0.9; P = .002), and a higher level of extraversion increased the rate of conversion to bipolar disorder by 60% for each increase of 1 SD (HR = 1.6; 95% CI, 1.0-2.5; P = .05). CONCLUSIONS: Comorbidity of cluster C personality disorders and the level of neuroticism and extraversion have significant impact on the long-term prognosis of depression. The identified predictors of the course of illness should guide patients and clinicians for individualized tailored treatment of comorbid conditions in depression. PMID- 27232944 TI - Using lymph node swelling as a potential biomarker for successful vaccination. AB - There is currently a lack of biomarkers to help properly assess novel immunotherapies at both the preclinical and clinical stages of development. Recent work done by our group indicated significant volume changes in the vaccine draining right lymph node (RLN) volumes of mice that had been vaccinated with DepoVaxTM, a lipid-based vaccine platform that was developed to enhance the potency of peptide-based vaccines. These changes in lymph node (LN) volume were unique to vaccinated mice.To better assess the potential of volumetric LN markers for multiple vaccination platforms, we evaluated 100 tumor bearing mice and assessed their response to vaccination with either a DepoVax based vaccine (DPX) or a water-in-oil emulsion (w/o), and compared them to untreated controls. MRI was used to longitudinally monitor LN and tumor volumes weekly over 4 weeks. We then evaluated changes in LN volumes occurring in response to therapy as a potential predictive biomarker for treatment success.We found that for both vaccine types, DPX and w/o, the %RLN volumetric increase over baseline and the ratio of RLN/LLN were strong predictors of successful tumor suppression (LLN is left inguinal LN). The area under the curve (AUC) was greatest, between 0.75 0.85, two (%RLN) or three (RLN/LLN) weeks post-vaccination. For optimized critical thresholds we found these biomarkers consistently had sensitivity >90% and specificity >70% indicating strong prognostic potential. Vaccination with DepoVax had a more pronounced effect on draining lymph nodes than w/o emulsion vaccines, which correlated with a higher anti-tumor activity in DPX-treated mice. PMID- 27232946 TI - Theory versus Practice in the Twentieth-Century Search for the Ideal Anaesthetic Gas. AB - At the beginning of the twentieth century, an anaesthetist could choose between nitrous oxide, chloroform, and ether (diethyl ether) for the induction of painrelieving unconsciousness. By the end of century, the choice was between a small number of fluorinated aliphatic ethers such as Enflurane, Desflurane, and Sevoflurane, and (in some jurisdictions) the rare gas, xenon. Between these endpoints researchers had identified a surprisingly broad range of hydrocarbons, noble gases, organohalogens, and aliphatic ethers that possessed anaesthetic properties. None was entirely satisfactory, but clinicians at various times and in various places employed substances in each of these categories. Behind the search for new anaesthetic gases was a theory of action (Meyer- Overton theory) that was known to be inadequate, but as no alternative was strong enough to displace it the search continued on purely empirical grounds, while lip-service was paid to the theory. By the time a theory couched in more modern terms was proposed, a suite of modern anaesthetic gases was in place, and there have been no attempts to use that theory to drive a new search. PMID- 27232947 TI - The CLE gene family in Populus trichocarpa. AB - The CLE (CLAVATA3/Embryo Surrounding Region-related) peptides are small secreted signaling peptides that are primarily involved in the regulation of stem cell homeostasis in different plant meristems. Particularly, the characterization of the CLE41-PXY/TDR signaling pathway has greatly advanced our understanding on the potential roles of CLE peptides in vascular development and wood formation. Nevertheless, our knowledge on this gene family in a tree species is limited. In a recent study, we reported on a systematically investigation of the CLE gene family in Populus trichocarpa. The potential roles of PtCLE genes were studied by comparative analysis and transcriptional profiling. Among fifty PtCLE members, many PtCLE proteins share identical CLE motifs or contain the same CLE motif as that of AtCLEs, while PtCLE genes exhibited either comparable or distinct expression patterns comparing to their Arabidopsis counterparts. These findings indicate the existence of both functional conservation and functional divergence between PtCLEs and their AtCLE orthologues. Our results provide valuable resources for future functional investigations of these critical signaling molecules in woody plants. PMID- 27232948 TI - Urinary mRNA for the Diagnosis of Renal Allograft Rejection: The Issue of Normalization. AB - Urinary messenger RNA (mRNA) quantification is a promising method for noninvasive diagnosis of renal allograft rejection (AR), but the quantification of mRNAs in urine remains challenging due to degradation. RNA normalization may be warranted to overcome these issues, but the strategies of gene normalization have been poorly evaluated. Herein, we address this issue in a case-control study of 108 urine samples collected at time of allograft biopsy in kidney recipients with (n = 52) or without (n = 56) AR by comparing the diagnostic value of IP-10 and CD3epsilon mRNAs-two biomarkers of AR-after normalization by the total amount of RNA, normalization by one of the three widely used reference RNAs-18S, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Hypoxanthine-guanine phosphoribosyltransferase (HPRT)-or normalization using uroplakin 1A (UPK) mRNA as a possible urine-specific reference mRNA. Our results show that normalization based on the total quantity of RNA is not substantially improved by additional normalization and may even be worsened with some classical reference genes that are overexpressed during rejection. However, considering that normalization by a reference gene is necessary to ensure polymerase chain reaction (PCR) quality and reproducibility and to suppress the effect of RNA degradation, we suggest that GAPDH and UPK1A are preferable to 18S or HPRT RNA. PMID- 27232949 TI - Coulomb blockade based field-effect transistors exploiting stripe-shaped channel geometries of self-assembled metal nanoparticles. AB - Metallic nanoparticles offer possibilities to build basic electric devices with new functionality and improved performance. Due to the small volume and the resulting low self-capacitance, each single nanoparticle exhibits a high charging energy. Thus, a Coulomb-energy gap emerges during transport experiments that can be shifted by electric fields, allowing for charge transport whenever energy levels of neighboring particles match. Hence, the state of the device changes sequentially between conducting and non-conducting instead of just one transition from conducting to pinch-off as in semiconductors. To exploit this behavior for field-effect transistors, it is necessary to use uniform nanoparticles in ordered arrays separated by well-defined tunnel barriers. In this work, CoPt nanoparticles with a narrow size distribution are synthesized by colloidal chemistry. These particles are deposited via the scalable Langmuir-Blodgett technique as ordered, homogeneous monolayers onto Si/SiO2 substrates with pre patterned gold electrodes. The resulting nanoparticle arrays are limited to stripes of adjustable lengths and widths. In such a defined channel with a limited number of conduction paths the current can be controlled precisely by a gate voltage. Clearly pronounced Coulomb oscillations are observed up to temperatures of 150 K. Using such systems as field-effect transistors yields unprecedented oscillating current modulations with on/off-ratios of around 70%. PMID- 27232950 TI - Permeability barriers for generating a unique ciliary protein and lipid composition. AB - Cilia (and flagella) are microtubule-based protrusions that are found in single or multiple copies on the surface of most eukaryotic cells. Defects in cilia formation and/or function have now been correlated with an expanding spectrum of human genetic diseases termed ciliopathies. Recent work indicates that cilia are indeed a bona fide organelle with a unique protein and lipid content that enables specific cellular functions. Despite the physiological and clinical relevance of cilia, our understanding of how a unique protein and lipid composition is generated for this organelle remains poor. Here we review recent work on the mechanisms that determine the protein and lipid content, and thus the functional outputs, of this unique organelle. PMID- 27232951 TI - The effects of bi-hemispheric M1-M1 transcranial direct current stimulation on primary motor cortex neurophysiology and metabolite concentration. AB - PURPOSE: The aim of the present study was to assess, in healthy individuals, the impact of M1-M1 tDCS on primary motor cortex excitability using transcranial magnetic stimulation and sensorimotor metabolite concentration using 1H-MRS. METHODS: For both experiments, each participant received the three following interventions (20 min tDCS, 1 mA): left-anodal/right-cathodal, left cathodal/right-anodal, sham. The effects of tDCS were assessed via motor evoked potentials (experiment 1) and metabolite concentrations (experiment 2) immediately after and 12 minutes following the end of stimulation and compared to baseline measurement. RESULTS: No effect of M1-M1 tDCS on corticospinal excitability was found. Similarly, M1-M1 tDCS did not significantly modulate metabolite concentrations. High inter-subject variability was noted. Response rate analysis showed a tendency towards inhibition following left-anodal/right cathodal tDCS in 50% of participants and increased GABA levels in 45% of participants. CONCLUSION: In line with recent studies showing important inter subject variability following M1-supraorbital tDCS, the present data show that M1 M1 stimulation is also associated with large response variability. The absence of significant effects suggests that current measures may lack sensitivity to assess changes in M1 neurophysiology and metabolism associated with M1-M1 tDCS. PMID- 27232952 TI - Fooling the brain by mirroring the hand: Brain correlates of the perceptual capture of limb ownership. AB - BACKGROUND: Mirror therapy (MT) is an increasingly employed method aimed at reducing phantom pain and other negative sensations following loss of a limb or damage to sensorimotor systems. However, the brain processes associated with the perception of limb ownership, a key correlate of MT, are unknown. OBJECTIVE: To examine whether transient perceptions of limb ownership together with associated neural activity can be elucidated using a purpose-developed mirror reflection task combined with electrophysiological (EEG) measures and cutting-edge analyses. METHODS: Brain activity was measured online using EEG in 20 healthy controls while they produced opening-closing movements of one hand in control conditions or while viewing the mirror reflection of the movements. The key experimental condition required participants to make a foot pedal response whenever a change in perception of ownership (of a mirror-reflected limb) occurred (Mirror condition). Control conditions and a strict epoching regime were employed using standard subtractive logic to isolate the perception of limb ownership (which was further verified by self-reports). RESULTS: Data from 15 participants were suitable for complete analysis; the remaining reported no experience of ownership. Significant spectral power increases were found in central-parietal regions in association with perceptions of ownership, with the most prominent effect specific to the alpha frequency band (8-13 Hz) measured at the right parietal area. Source localization analyses further identified brain networks associated with the mirror reflection condition in the alpha frequency (parietal lobe) and the beta frequency (middle temporal areas). These were distinct from localized networks associated with the foot pedal response. CONCLUSION: Transient perceptions of ownership can be captured experimentally, and are associated with localized sites of neural activation. This is an initial step toward eventual development of therapeutic targets for interventions including brain computer interfaces (BCIs) aimed at ameliorating the negative effects associated with impaired or missing limbs. PMID- 27232954 TI - GM3 synthase deficiency due to ST3GAL5 variants in two Korean female siblings: Masquerading as Rett syndrome-like phenotype. AB - There have been a few reports of GM3 synthase deficiency since the disease of the ganglioside biosynthetic pathway was first reported in 2004. It is characterized by infantile-onset epilepsy with severe intellectual disability, blindness, cutaneous dyspigmentation, and choreoathetosis. Here we report the cases of two Korean female siblings with ST3GAL5 variants, who presented with a Rett-like phenotype. They had delayed speech, hand stereotypies with a loss of purposeful hand movements, and choreoathetosis, but no clinical seizures. One of them had microcephaly, while the other had small head circumference less than 10th centile. There were no abnormal laboratory findings with the exception of a high lactate level. MECP2/CDKL5/FOXG1 genetic tests with an array comparative genomic hybridization revealed no molecular defects. Through whole-exome sequencing of the proband, we found compound heterozygous ST3GAL5 variants (p.Gly201Arg and p.Cys195Ser), both of which were novel. The siblings were the same compound heterozygotes and their unaffected parents were heterozygous carriers of each variant. Liquid chromatography-mass spectrometry analysis confirmed a low level of GM3 and its downstream metabolites, indicating GM3 synthase deficiency. These cases expanded the clinical and genetic spectrum of the ultra-rare disease, GM3 synthase deficiency with ST3GAL5 variants. (c) 2016 Wiley Periodicals, Inc. PMID- 27232953 TI - Cerebellar tDCS as a novel treatment for aphasia? Evidence from behavioral and resting-state functional connectivity data in healthy adults. AB - BACKGROUND: Aphasia is an acquired deficit in the ability to communicate through language. Noninvasive neuromodulation offers the potential to boost neural function and recovery, yet the optimal site of neuromodulation for aphasia has yet to be established. The right posterolateral cerebellum is involved in multiple language functions, interconnects with left-hemisphere language cortices, and is crucial for optimization of function and skill acquisition, suggesting that cerebellar neuromodulation could enhance aphasia rehabilitation. OBJECTIVE: To provide preliminary behavioral and functional connectivity evidence from healthy participants that cerebellar neuromodulation may be useful for rehabilitation of aphasia. METHODS: In Experiment 1, 76 healthy adults performed articulation and verbal fluency tasks before and after anodal, cathodal or sham transcranial direct current stimulation (tDCS) was applied over two cerebellar locations (anterior, right posterolateral). In Experiment 2, we examined whether anodal tDCS over the right posterolateral cerebellum modulated resting-state functional connectivity in language networks in 27 healthy adults. RESULTS: TDCS over the right posterolateral cerebellum significantly improved phonemic fluency. Cerebellar neuromodulation increased functional connectivity between the cerebellum and areas involved in the motor control of speech, and enhanced the correlations between left-hemisphere language and speech-motor regions. CONCLUSION: We provide proof-of-principle evidence that cerebellar neuromodulation improves verbal fluency and impacts resting-state connectivity in language circuits. These findings suggest that the cerebellum is a viable candidate for neuromodulation in people with aphasia. PMID- 27232955 TI - Optimization of a novel series of pyranopyridine RND efflux pump inhibitors. AB - The rise of multidrug resistant (MDR) Gram-negative pathogens complicates our ability to treat bacterial infections with antibiotics. MDR efflux pumps play a major role in the acquisition and expression of the MDR phenotype. The major MDR efflux pumps in Gram-negative pathogens are the resistance-nodulation-division (RND) superfamily pumps. Efflux pump inhibitors (EPIs) that target RND superfamily pumps could play an important role in the clinic as an adjunctive therapy to increase antibiotic efficacy, decrease resistance, and attenuate virulence in Gram-negative pathogens. Here, we review recent advances in the discovery and structurally enabled optimization of a novel series of RND targeting pyranopyridine EPIs currently in the early stages of lead optimization. PMID- 27232956 TI - Treatment of Gram-negative bacterial infections by potentiation of antibiotics. AB - Infections caused by antibiotic-resistant pathogens, particularly Gram-negative bacteria, represent significant treatment challenges for physicians resulting in high rates of morbidity and mortality. The outer membrane of Gram-negative bacteria acts as a permeability barrier to many compounds that would otherwise be effective antibacterial agents, including those effective against Gram-positive pathogens. Potentiator molecules disrupt this barrier allowing entry of otherwise impermeant molecules, thus providing a strategy to render multi-drug resistant pathogens susceptible to a broader range of antibiotics. Potentiator molecules are cationic and the mechanism of disruption involves interaction with the negatively charged outer membrane. This physical attribute, along with an often high degree of lipophilicity typically endears these molecules with unacceptable toxicity. Presented herein are examples of advanced potentiator molecules being evaluated for use in combination therapy for the treatment of resistant Gram negative infections. PMID- 27232957 TI - Finite population analysis of the effect of horizontal gene transfer on the origin of an universal and optimal genetic code. AB - The origin of a universal and optimal genetic code remains a compelling mystery in molecular biology and marks an essential step in the origin of DNA and protein based life. We examine a collective evolution model of genetic code origin that allows for unconstrained horizontal transfer of genetic elements within a finite population of sequences each of which is associated with a genetic code selected from a pool of primordial codes. We find that when horizontal transfer of genetic elements is incorporated in this more realistic model of code-sequence coevolution in a finite population, it can increase the likelihood of emergence of a more optimal code eventually leading to its universality through fixation in the population. The establishment of such an optimal code depends on the probability of HGT events. Only when the probability of HGT events is above a critical threshold, we find that the ten amino acid code having a structure that is most consistent with the standard genetic code (SGC) often gets fixed in the population with the highest probability. We examine how the threshold is determined by factors like the population size, length of the sequences and selection coefficient. Our simulation results reveal the conditions under which sharing of coding innovations through horizontal transfer of genetic elements may have facilitated the emergence of a universal code having a structure similar to that of the SGC. PMID- 27232958 TI - Age-specific metal and accumulation patterns in different tissues of nase (Chodrostoma nasus) from the Medjuvrsje Reservoir. AB - Nase (Chodrostoma nasus L. 1758) specimens of four age classes (1(+) to 4(+)) were caught in July 2013 in the Medjuvrsje Reservoir. Concentrations of 14 metals and elements (Al, B, Ba, Cd, Co, Cr, Cu, Fe, Mn, Mo, Ni, Si, Sr, Zn) in the muscle, gills and liver were analyzed by inductively-coupled plasma optical spectrometry (ICP-OES). The highest concentrations of Al, Ba, Co, Cr, Mn, Si, Sr and Zn were detected in gills, while Cd, Cu, Fe and Mo reached the highest values in the liver. The majority of the analyzed elements were found in minimal concentrations in the muscle. Younger age classes (1(+), 2(+)) were differentiated by higher concentrations of Mn, Sr and Zn in muscle tissue, while the older ones were mainly differentiated by higher concentrations for Ni and Cu. The youngest age class (1(+)) was distinguished by higher concentrations of Zn, while the oldest age class (4(+)) was distinguished by higher concentrations of Ba, Cu, Mo and Sr in gills. Results obtained were likely caused by differences in the physiology and feeding habits between younger (1-2(+)) and older (3-4(+)) age groups of nase. PMID- 27232959 TI - Evaluation of the quality of coastal bathing waters in Spain through fecal bacteria Escherichia coli and Enterococcus. AB - Sun. and beach tourism is very important to the economy of Spain, so the control of the quality of the environment on the beaches is essential. Therefore, the analysis and control of the quality of bathing water is necessary, which is defined by the European Directive 2006/7/EC as excellent, good or sufficient depending on the presence of microbiological contamination or other organisms or waste presenting a risk to bathers' health. For that, 1392 beaches of the Iberian Peninsula and its islands were analysed, taking into account: fecal bacteria (Escherichia coli and Enterococcus), physical characteristics of sediment, level of urbanization, climatic and anthropogenic factors, and maritime climate. Thus, it was observed that urban sand beaches located in seas with fewer hours of sunshine and important tide have higher concentrations of E. coli and Enterococcus. There is also an indirect relationship between these microorganisms with salinity (R(2) 0.746 for E. coli and 0.606 for Enterococcus), temperature (R(2) 0.743 for E. coli and 0.604 for Enterococcus) and hours of sunshine (R(2) 0.781 for E. coli and 0.706 for Enterococcus), while this relationship is direct with rainfall (R(2) 0.640 for E. coli and 0.607 for Enterococcus) or wave height (R(2) 0.769 for E. coli and 0.601 for Enterococcus). From all this, it follows that the Directive 2006/7/EC should define more specific criteria as to the place and time of sampling, and take into account the different environment variables that influence the survival of bacteria, so that the results may reflect reality, and avoid staff responsible for sampling freely choose the place and time of sampling. PMID- 27232960 TI - A microclimate study on hypogea environments of ancient roman building. AB - Roman hypogea, vernacular settlements or crypts, are underground places characterised by specific and unique challenges (RH<90% and almost constant temperature throughout the whole year) related to their relative isolation from the outdoor environment. These sites often require adequate monitoring tools providing complete environmental information in order to carry out appropriate strategies for scheduling routine maintenance and designing suitable layouts for their preservation. In this work we present the results of a carefully planned thermo-hygrometric monitoring campaign conducted in a peculiar Roman building (130CE), the "Casa di Diana" Mithraeum, sited in Ostia Antica (archaeological site, Rome-Italy), with the aim of characterising the indoor environment as the structure suffers of several conservation problems (biocolonisation, efflorescences, evaporating and condensing cycle for wall-building materials). The campaign involving multipoint continuous measurement was carefully planned to better describe this micro-clime. In addition to underground environmental data available in literature, we have also performed, as a checkpoint control, a thermo-hygrometric monitoring campaign in the "Terme di Mitra" Hypogeum, a few meters from the "Casa di Diana". The recorded data was analysed by multivariate statistical and chemometric analyses. The results brought to light the presence of different microclimates (three areas) within a single Mithraeum: a room (pre Mithraeum) and an area (Mithraeum: 2-4m) present a thermo-hygrometric environmental behaviour in accordance with a semi-confined environment, another area (Mithraeum: 1-2m) behaves accordingly with underground environments (although it cannot be described as such), and the last area (Mithraeum: 0-1m) where was recording RH values close to saturation (96-99%), associated with non ventilated areas where the rising damp is "held" and not dispersed, describing an own micro-clime, comparable to a "small greenhouse". This study has allowed to identify some critical areas in view of planning future conservation solutions, without exporting the artefacts kept inside. PMID- 27232961 TI - Toxic airborne S, PAH, and trace element legacy of the superhigh-organic-sulphur Rasa coal combustion: Cytotoxicity and genotoxicity assessment of soil and ash. AB - This paper presents the levels of sulphur, polycyclic aromatic hydrocarbons (PAHs), and potentially toxic trace elements in soils surrounding the Plomin coal fired power plant (Croatia). It used domestic superhigh-organic-sulphur Rasa coal from 1970 until 2000. Rasa coal was characterised by exceptionally high values of S, up to 14%, making the downwind southwest (SW) area surrounding the power plant a significant hotspot. The analytical results show that the SW soil locations are severely polluted with S (up to 4%), and PAHs (up to 13,535ng/g), while moderately with Se (up to 6.8mg/kg), and Cd (up to 4.7mg/kg). The composition and distribution pattern of PAHs in the polluted soils indicate that their main source could be airborne unburnt coal particles. The atmospheric dispersion processes of SO2 and ash particles have influenced the composition and distribution patterns of sulphur and potentially toxic trace elements in studied soils, respectively. A possible adverse impact of analysed soil on the local karstic environment was evaluated by cytotoxic and genotoxic methods. The cytotoxicity effects of soil and ash water extracts on the channel catfish ovary (CCO) cell line were found to be statistically significant in the case of the most polluted soil and ash samples. However, the primary DNA-damaging potential of the most polluted soil samples on the CCO cells was found to be within acceptable boundaries. PMID- 27232962 TI - Potential interactions among disease, pesticides, water quality and adjacent land cover in amphibian habitats in the United States. AB - To investigate interactions among disease, pesticides, water quality, and adjacent land cover, we collected samples of water, sediment, and frog tissue from 21 sites in 7 States in the United States (US) representing a variety of amphibian habitats. All samples were analyzed for >90 pesticides and pesticide degradates, and water and frogs were screened for the amphibian chytrid fungus Batrachochytrium dendrobatidis (Bd) using molecular methods. Pesticides and pesticide degradates were detected frequently in frog breeding habitats (water and sediment) as well as in frog tissue. Fungicides occurred more frequently in water, sediment, and tissue than was expected based upon their limited use relative to herbicides or insecticides. Pesticide occurrence in water or sediment was not a strong predictor of occurrence in tissue, but pesticide concentrations in tissue were correlated positively to agricultural and urban land, and negatively to forested land in 2-km buffers around the sites. Bd was detected in water at 45% of sites, and on 34% of swabbed frogs. Bd detections in water were not associated with differences in land use around sites, but sites with detections had colder water. Frogs that tested positive for Bd were associated with sites that had higher total fungicide concentrations in water and sediment, but lower insecticide concentrations in sediments relative to frogs that were Bd negative. Bd concentrations on frog swabs were positively correlated to dissolved organic carbon, and total nitrogen and phosphorus, and negatively correlated to pH and water temperature. Data were collected from a range of locations and amphibian habitats and represent some of the first field-collected information aimed at understanding the interactions between pesticides, land use, and amphibian disease. These interactions are of particular interest to conservation efforts as many amphibians live in altered habitats and may depend on wetlands embedded in these landscapes to survive. PMID- 27232963 TI - Plastic waste in the marine environment: A review of sources, occurrence and effects. AB - This review article summarises the sources, occurrence, fate and effects of plastic waste in the marine environment. Due to its resistance to degradation, most plastic debris will persist in the environment for centuries and may be transported far from its source, including great distances out to sea. Land- and ocean-based sources are the major sources of plastic entering the environment, with domestic, industrial and fishing activities being the most important contributors. Ocean gyres are particular hotspots of plastic waste accumulation. Both macroplastics and microplastics pose a risk to organisms in the natural environment, for example, through ingestion or entanglement in the plastic. Many studies have investigated the potential uptake of hydrophobic contaminants, which can then bioaccumulate in the food chain, from plastic waste by organisms. To address the issue of plastic pollution in the marine environment, governments should first play an active role in addressing the issue of plastic waste by introducing legislation to control the sources of plastic debris and the use of plastic additives. In addition, plastics industries should take responsibility for the end-of-life of their products by introducing plastic recycling or upgrading programmes. PMID- 27232964 TI - Multilevel modeling of retention and disinfection efficacy of silver nanoparticles on ceramic water filters. AB - This research examined how variations in synthesis methods of silver nanoparticles affect both the release of silver from ceramic water filters (CWFs) and disinfection efficacy. The silver nanoparticles used were stabilized by four different molecules: citrate, polyvinylpyrrolidone, branched polyethylenimine, and casein. A multilevel statistical model was built to quantify if there was a significant difference in: a) extent of silver lost, b) initial amount of silver lost, c) silver lost for water of different quality, and d) total coliform removal. Experiments were performed on location at Pure Home Water, a CWF factory in Tamale, Ghana using stored rainwater and dugout water (a local surface water). The results indicated that using dugout vs. rainwater significantly affects the initial (p-value 0.0015) and sustained (p-value 0.0124) loss of silver, but that silver type does not have a significant effect. On average, dugout water removed 37.5MUg/L more initial silver and had 1.1MUg/L more silver in the filtrate than rainwater. Initially, filters achieved 1.9 log reduction values (LRVs) on average, but among different silver and water types this varied by as much as 2.5 LRV units. Overall, bacterial removal effectiveness was more challenging to evaluate, but some data suggest that the branched polyethylenimine silver nanoparticles provided improved initial bacterial removal over filters which were not painted with silver nanoparticles (p-value 0.038). PMID- 27232965 TI - Nutrient variations and isotopic evidences of particulate organic matter provenance in fringing reefs, South China. AB - Nutrient over-enrichment is considered to be one of the causes of coral decline. Increase in traditional fishing in the Xuwen National Coral Reefs Reserve tract (XW) and tourism around the Sanya National Coral Reefs Reserve tract (SY) are causing this coral decline. This study reviews the current state of knowledge of the nutrient status of coastal fringing reefs in South China and evaluates the primary sources of nutrients using stable isotope method. Surveys of seawater nutrients showed that the seawater remained clean in both the XW and SY coastal coral reef areas. Based on the isotopic differences between anthropogenic sewage and naturally occurring aquatic nutrients, the isotopic values of particulate organic matter (POM) and the C/N ratios were successfully used to identify the presence of anthropogenic nutrients in aquatic environments. The delta(13)C, delta(15)N and C/N compositions of POM from XW and SY (-21.18+/-2.110/00, 10.30+/ 5.540/00, and 5.35+/-0.69 and -20.80+/-1.340/00, 7.06+/-3.950/00, and 5.77+/ 2.15, respectively) showed statistically significant variations with the season. The delta(13)C and delta(15)N values of POM suggest marine and terrestrial derived nutrient sources. Organic carbon is a mixture of marine phytoplankton, marine benthic algae and terrestrial-derived plants. The delta(15)N values suggest terrestrial-derived sewage and upwelling-dominated nitrogen sources. In the presence of natural upwelling and coastal currents, coastal coral reef areas are more vulnerable to the increasing anthropogenic nutrient inputs. Anthropogenic activities might lead to large increases in the nutrient concentrations and could trigger the shift from coral- to macroalgae-dominated ecosystems, which would ultimately result in the degradation of the coastal coral reef ecosystem. These results provide some understanding of the declining coral reef ecosystem and the importance of conservation areas and coastal coral reef resource management. PMID- 27232966 TI - Engineered biochar from microwave-assisted catalytic pyrolysis of switchgrass for increasing water-holding capacity and fertility of sandy soil. AB - Engineered biochars produced from microwave-assisted catalytic pyrolysis of switchgrass have been evaluated in terms of their ability on improving water holding capacity (WHC), cation exchange capacity (CEC) and fertility of loamy sand soil. The addition of K3PO4, clinoptilolite and/or bentonite as catalysts during the pyrolysis process increased biochar surface area and plant nutrient contents. Adding biochar produced with 10wt.% K3PO4+10 wt.% clinoptilolite as catalysts to the soil at 2wt% load increased soil WHC by 98% and 57% compared to the treatments without biochar (control) and with 10wt.% clinoptilolite, respectively. Synergistic effects on increased soil WHC were manifested for biochars produced from combinations of two additives compared to single additive, which may be the result of increased biochar microporosity due to increased microwave heating rate. Biochar produced from microwave catalytic pyrolysis was more efficient in increasing the soil WHC due to its high porosity in comparison with the biochar produced from conventional pyrolysis at the same conditions. The increases in soil CEC varied widely compared to the control soil, ranging from 17 to 220% for the treatments with biochars produced with 10wt% clinoptilolite at 400 degrees C, and 30wt% K3PO4 at 300 degrees C, respectively. Strong positive correlations also exist among soil WHC with CEC and biochar micropore area. Biochar from microwave-assisted catalytic pyrolysis appears to be a novel approach for producing biochar with high sorption affinity and high CEC. These catalysts remaining in the biochar product would provide essential nutrients for the growth of bioenergy and food crops. PMID- 27232967 TI - Coastal groundwater salinization: Focus on the vertical variability in a multi layered aquifer through a multi-isotope fingerprinting (Roussillon Basin, France). AB - The Roussillon sedimentary Basin (South France) is a complex multi-layered aquifer, close to the Mediterranean Sea facing seasonally increases of water abstraction and salinization issues. We report geochemical and isotopic vertical variability in this aquifer using groundwater sampled with a Westbay System(r) at two coastal monitoring sites: Barcares and Canet. The Westbay sampling allows pointing out and explaining the variation of water quality along vertical profiles, both in productive layers and in the less permeable ones where most of the chemical processes are susceptible to take place. The aquifer layers are not equally impacted by salinization, with electrical conductivity ranging from 460 to 43,000MUS.cm(-1). The delta(2)H-delta(18)O signatures show mixing between seawater and freshwater components with long water residence time as evidenced by the lack of contribution from modern water using (3)H, (14)C and CFCs/SF6. S(SO4) isotopes also evidence seawater contribution but some signatures can be related to oxidation of pyrite and/or organically bounded S. In the upper layers (87)Sr/(86)Sr ratios are close to that of seawater and then increase with depth, reflecting water-rock interaction with argillaceous formations while punctual low values reflect interaction with carbonate. Boron isotopes highlight secondary processes such as adsorption/desorption onto clays in addition to mixings. At the Barcares site (120m deep), the high salinity in some layers appear to be related neither to present day seawater intrusion, nor to Salses-Leucate lagoonwater intrusion. Groundwater chemical composition thus highlights binary mixing between fresh groundwater and inherited salty water together with cation exchange processes, water-rock interactions and, locally, sedimentary organic matter mineralisation probably enhanced by pyrite oxidation. Finally, combining the results of this study and those of Caballero and Ladouche (2015), we discuss the possible future evolution of this aquifer system under global change, as well as the potential management strategies needed to preserve quantitatively and qualitatively this water resource. PMID- 27232969 TI - Potential of temperate agricultural soils for carbon sequestration: A meta analysis of land-use effects. AB - Restoring depleted soil organic carbon (SOC) stocks of arable land to remove carbon from the atmosphere and offset fossil fuel emissions is a promising strategy for the mitigation of climate change. In agroecosystems conservational tillage practices and the abandonment of formerly plowed fields (ex-arable land) are shown to have the highest potential to sequester SOC. Nevertheless reported sequestration rates vary and the effects of environmental site conditions remain poorly understood. Our results are based on a meta-analysis of 273 paired SOC estimates from 65 publications which included only mineral soils from the temperate zone. SOC stocks of ex-arable grasslands with an average of 14years since abandonment were 18% larger compared to the SOC of arable land. Likewise, SOC stocks of never-plowed grassland plots were 11% larger than the SOC stocks of abandoned fields. The average sequestration rate was 0.72t Cha(-1)yr(-1). Semi arid and sub-humid climate as well as low initial SOC stocks positively affected proportional SOC gains suggesting that the recovery of carbon stocks is not limited by low primary production. Therefore, the northward shift of cultivation areas in the temperate zone will lead to the abandonment of soils with high SOC recovery potential. However, if native soils are opened up elsewhere to compensate for yield losses due to abandonment the surplus of SOC in ex-arable land can easily be overcompensated by cultivation losses. PMID- 27232968 TI - Microscale traffic simulation and emission estimation in a heavily trafficked roundabout in Madrid (Spain). AB - This paper presents the evaluation of emissions from vehicle operations in a domain of 300m*300m covering a complex urban roundabout with high traffic density in Madrid. Micro-level simulation was successfully applied to estimate the emissions on a scale of meters. Two programs were used: i) VISSIM to simulate the traffic on the square and to compute velocity-time profiles; and ii) VERSIT+micro through ENVIVER that uses VISSIM outputs to compute the related emissions at vehicle level. Data collection was achieved by a measurement campaign obtaining empirical data of vehicle flows and traffic intensities. Twelve simulations of different traffic situations (scenarios) were conducted, representing different hours from several days in a week and the corresponding NOX and PM10 emissions were estimated. The results show a general reduction on average speeds for higher intensities due to braking-acceleration patterns that contribute to increase the average emission factor and, therefore, the total emissions in the domain, especially on weekdays. The emissions are clearly related to traffic volume, although maximum emission scenario does not correspond to the highest traffic intensity due to congestion and variations in fleet composition throughout the day. These results evidence the potential that local measures aimed at alleviating congestion may have in urban areas to reduce emissions. In general, scenario-averaged emission factors estimated with the VISSIM-VERSIT+micro modelling system fitted well those from the average-speed model COPERT, used as a preliminary validation of the results. The largest deviations between these two models occur in those scenarios with more congestion. The design and resolution of the microscale modelling system allow to reflect the impact of actual traffic conditions on driving patterns and related emissions, making it useful for the design of mitigation measures for specific traffic hot-spots. PMID- 27232970 TI - Continuous and event-based time series analysis of observed floodplain groundwater flow under contrasting land-use types. AB - There is an ongoing need to improve quantitative understanding of land-use impacts on floodplain groundwater flow regimes. A study was implemented in Hinkson Creek Watershed, Missouri, USA, including equidistant grids of nine piezometers, equipped with pressure transducers, which were installed at two floodplain study sites: a remnant bottomland hardwood forest (BHF) and a historical agricultural field (Ag). Data were logged at thirty minute intervals for the duration of the 2011, 2012, 2013, and 2014 water years (October 1, 2010 September 30, 2014). Results show significant (p<0.001) differences between Darcy estimated groundwater flow at the two study sites. Although median flow values at the two sites were similar (0.009 and 0.010mday(-1) for the Ag and BHF sites, respectively), the BHF displayed a more dynamic flow regime compared to the Ag site. Maximum flow values were 0.020 and 0.049mday(-1) for the Ag and BHF sites, respectively. Minimum flow values were -0.018 and -0.029mday(-1) for the Ag and BHF sites, respectively. The BHF showed greater magnitude, longer duration, and more frequent negative flows, relative to the Ag site. Event-based analyses indicated a more seasonally responsive flow regime at the BHF, with higher flows than the Ag site during the wet season and lower flows than the Ag site during the dry season. Notably, the seasonal pattern of relative site flow differences was consistent across a wide range of precipitation event magnitudes (i.e. 8 45mm). Results are by majority attributable to greater rates of plant water use by woody vegetation and preferential subsurface flow at the BHF site. Collectively, results suggest greater flood attenuation capacity and streamwater buffering potential by the BHF floodplain, relative to the Ag, and highlight the value of floodplain forests as a land and water resource management tool. PMID- 27232971 TI - Imposex and butyltin contamination still evident in Chile after TBT global ban. AB - Imposex in gastropods (Acanthina monodon, Oliva peruviana and Xanthochorus cassidiformis), butyltin levels in surface sediments (Coquimbo and Concepcion) and tissues (Valparaiso and Concepcion) were assessed in three areas under the influence of maritime activities along the central Chilean coast. The highest TBT concentrations were observed in Sao Vicente Bay (Concepcion), reaching 122.3ngSng(-1) in surface sediments and 59.7ngSng(-1) in gastropods tissue, while in Valparaiso ranged from 7.4 to 15.8ngSng(-1) in biota. The lowest TBT concentrations were detected in sediments from Coquimbo (<2ngSng(-1)), which can be attributed to a much lower ship/boat traffic (probably using TBT free products) in association to local oceanographic conditions. Despite DBT and MBT were the predominant analytes, recent inputs of TBT were evident in some areas. In fact, fishing boats may be a relevant source since they were the predominant maritime activity in the most contaminated sites. In addition, the absence of significant differences within BTs levels between both genders of A. monodon suggests that tissues from distinct sexes can be indistinctly used for future contamination studies. Imposex incidence was detected in 11 out of 15 sampled sites, indicating that environmental levels of TBT have been sufficient to induce deleterious effects on the exposed organisms. Thus, the impacts caused by TBT in Chilean coastal areas were detectable and consistent with other studies performed in South America. This present environmental contamination is probably due to the lack of regulations forbidding the use of TBT-based antifouling paints in Chile. PMID- 27232972 TI - Wastewater-based assessment of regional and temporal consumption patterns of illicit drugs and therapeutic opioids in Croatia. AB - A comprehensive study of spatial and temporal consumption patterns of the selected illicit drugs (heroin, cocaine, amphetamine, MDMA, methamphetamine, cannabis) and therapeutic opioids (codeine, methadone) has been performed in six Croatian cities by applying wastewater-based epidemiology. The investigated cities (Bjelovar, Vinkovci, Varazdin, Karlovac, Zadar and Zagreb) varied widely in the population size (27,000-688,000 inhabitants) as well as in the number of registered drug consumers included in compulsory and voluntary medical treatment and rehabilitation programs (30-513 persons/100,000 inhabitants of age 15-64). The most consumed illicit drugs were cannabis (10-70doses/day/1000 inhabitants), heroin (<0.2-10doses/day/1000 inhabitants) and cocaine (0.2-8.7doses/day/1000 inhabitants), while the consumption of amphetamine-type drugs was much lower (<0.01-4.4doses/day/1000 inhabitants). Enhanced consumption of illegal drugs was generally associated with larger urban centers (Zagreb and Zadar) however comparatively high consumption rate of cocaine, MDMA and methadone was determined in some smaller cities as well. The overall average dose number of 3 major illegal stimulants (cocaine, MDMA, amphetamine) was rather similar to the number of corresponding heroin doses, which is in disagreement with a comparatively much higher proportion of heroin users in the total number of registered drug users in Croatia. Furthermore, the illicit drug consumption pattern in the large continental city (Zagreb) was characterized by a significant enhancement of the consumption of all stimulants during the weekend, which could not be confirmed neither for the coastal city of Zadar nor for the remaining small continental cities. On the other hand, the city of Zadar exhibited a significant increase of stimulant drug usage during summer vacation period, as a result of pronounced seasonal changes of the population composition and lifestyle in coastal tourist centers. The obtained results represent a valuable complementary data source for the optimisation and implementation of strategies to combat drug abuse in Croatia. PMID- 27232973 TI - More than Drought: Precipitation Variance, Excessive Wetness, Pathogens and the Future of the Western Edge of the Eastern Deciduous Forest. AB - For many regions of the Earth, anthropogenic climate change is expected to result in increasingly divergent climate extremes. However, little is known about how increasing climate variance may affect ecosystem productivity. Forest ecosystems may be particularly susceptible to this problem considering the complex organizational structure of specialized species niche adaptations. Forest decline is often attributable to multiple stressors including prolonged heat, wildfire and insect outbreaks. These disturbances, often categorized as megadisturbances, can push temperate forests beyond sustainability thresholds. Absent from much of the contemporary forest health literature, however, is the discussion of excessive precipitation that may affect other disturbances synergistically or that might represent a principal stressor. Here, specific points of evidence are provided including historic climatology, variance predictions from global change modeling, Midwestern paleo climate data, local climate influences on net ecosystem exchange and productivity, and pathogen influences on oak mortality. Data sources reveal potential trends, deserving further investigation, indicating that the western edge of the Eastern Deciduous forest may be impacted by ongoing increased precipitation, precipitation variance and excessive wetness. Data presented, in conjunction with recent regional forest health concerns, suggest that climate variance including drought and excessive wetness should be equally considered for forest ecosystem resilience against increasingly dynamic climate. This communication serves as an alert to the need for studies on potential impacts of increasing climate variance and excessive wetness in forest ecosystem health and productivity in the Midwest US and similar forest ecosystems globally. PMID- 27232974 TI - MRI quantification of human spine cartilage endplate geometry: Comparison with age, degeneration, level, and disc geometry. AB - Geometry is an important indicator of disc mechanical function and degeneration. While the geometry and associated degenerative changes in the nucleus pulposus and the annulus fibrosus are well-defined, the geometry of the cartilage endplate (CEP) and its relationship to disc degeneration are unknown. The objectives of this study were to quantify CEP geometry in three dimensions using an MRI FLASH imaging sequence and evaluate relationships between CEP geometry and age, degeneration, spinal level, and overall disc geometry. To do so, we assessed the MRI-based measurements for accuracy and repeatability. Next, we measured CEP geometry across a larger sample set and correlated CEP geometric parameters to age, disc degeneration, level, and disc geometry. The MRI-based measures resulted in thicknesses (0.3-1 mm) that are comparable to prior measurements of CEP thickness. CEP thickness was greatest at the anterior/posterior (A/P) margins and smallest in the center. The CEP A/P thickness, axial area, and lateral width decreased with age but were not related to disc degeneration. Age-related, but not degeneration-related, changes in geometry suggest that the CEP may not follow the progression of disc degeneration. Ultimately, if the CEP undergoes significant geometric changes with aging and if these can be related to low back pain, a clinically feasible translation of the FLASH MRI-based measurement of CEP geometry presented in this study may prove a useful diagnostic tool. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1410-1417, 2016. PMID- 27232976 TI - Effect of Boundary Edge in DOPC/DPPC/Cholesterol Liposomes on Acceleration of l Histidine Preferential Adsorption. AB - In order to investigate the interaction of hydrophilic molecules with liposomal membranes, we employed 1-(4-(trimethylamino)phenyl)-6-phenyl-1,3,5-hexatriene and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(5-dimethylamino-1 naphthalenesulfonyl) as fluorescent probes to monitor the surface regions of the membrane, and the results for various liposomes were plotted in correlation diagrams. According to the formation of a variety of phase states, different tendencies of decreasing surface hydrophobicity were observed in the liposomes that were modified with high concentrations of cholesterol or in the liposomes that were composed of ternary components. These liposomes, with hydrophobic surfaces, also showed preferential adsorption of l-histidine (l-His), and the hydrophobicity of the liposomal membrane at the surface changed during l-His adsorption regardless of the initial liposomal properties. Furthermore, we revealed that accelerated adsorption of l-His and preferential binding was induced in ternary liposomes forming boundaries between two separate phases. PMID- 27232975 TI - c-Src, Insulin-Like Growth Factor I Receptor, G-Protein-Coupled Receptor Kinases and Focal Adhesion Kinase are Enriched Into Prostate Cancer Cell Exosomes. AB - It is well known that Src tyrosine kinase, insulin-like growth factor 1 receptor (IGF-IR), and focal adhesion kinase (FAK) play important roles in prostate cancer (PrCa) development and progression. Src, which signals through FAK in response to integrin activation, has been implicated in many aspects of tumor biology, such as cell proliferation, metastasis, and angiogenesis. Furthermore, Src signaling is known to crosstalk with IGF-IR, which also promotes angiogenesis. In this study, we demonstrate that c-Src, IGF-IR, and FAK are packaged into exosomes (Exo), c-Src in particular being highly enriched in Exo from the androgen receptor (AR)-positive cell line C4-2B and AR-negative cell lines PC3 and DU145. Furthermore, we show that the active phosphorylated form of Src (SrcpY416 ) is co expressed in Exo with phosphorylated FAK (FAKpY861 ), a known target site of Src, which enhances proliferation and migration. We further demonstrate for the first time exosomal enrichment of G-protein-coupled receptor kinase (GRK) 5 and GRK6, both of which regulate Src and IGF-IR signaling and have been implicated in cancer. Finally, SrcpY416 and c-Src are both expressed in Exo isolated from the plasma of prostate tumor-bearing TRAMP mice, and those same mice have higher levels of exosomal c-Src than their wild-type counterparts. In summary, we provide new evidence that active signaling molecules relevant to PrCa are enriched in Exo, and this suggests that the Src signaling network may provide useful biomarkers detectable by liquid biopsy, and may contribute to PrCa progression via Exo. J. Cell. Biochem. 118: 66-73, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27232977 TI - A substituted sulfonamide and its Co (II), Cu (II), and Zn (II) complexes as potential antifungal agents. AB - A sulfonamide 1-tosyl-1-H-benzo(d)imidazol-2-amine (TBZA) and three new complexes of Co(II), Cu(II), and Zn(II) have been synthesized. The compounds have been characterized by elemental analyses, FTIR, 1H, and 13C-NMR spectroscopy. The structure of the TBZA, and its Co(II) and Cu(II) complexes, was determined by X ray diffraction methods. TBZA and its Co(II) complex crystallize in the triclinic P-1 space group, while the Cu(II) complex crystallizes in the monoclinic P21/c space group. Antifungal activity was screened against eight pathogenic yeasts: Candida albicans (DMic 972576), Candida krusei (DMic 951705), Candida glabrata (DMic 982882), Candida tropicalis (DMic 982884), Candida dubliniensis (DMic 93695), Candida guilliermondii (DMic 021150), Cryptococcus neoformans (ATCC 24067), and Cryptococcus gattii (ATCC MYA-4561). Results on the inhibition of various human (h) CAs, hCA I, II, IV, VII, IX, and XII, and pathogenic beta and gamma CAs are also reported. PMID- 27232978 TI - W5" Test: A simple method for measuring mean power output in the bench press exercise. AB - The aims of the present study were to assess the validity and reliability of a novel simple test [Five Seconds Power Test (W5" Test)] for estimating the mean power output during the bench press exercise at different loads, and its sensitivity to detect training-induced changes. Thirty trained young men completed as many repetitions as possible in a time of ~5 s at 25%, 45%, 65% and 85% of one-repetition maximum (1RM) in two test sessions separated by four days. The number of repetitions, linear displacement of the bar and time needed to complete the test were recorded by two independent testers, and a linear encoder was used as the criterion measure. For each load, the mean power output was calculated in the W5" Test as mechanical work per time unit and compared with that obtained from the linear encoder. Subsequently, 20 additional subjects (10 training group vs. 10 control group) were assessed before and after completing a seven-week training programme designed to improve maximal power. Results showed that both assessment methods correlated highly in estimating mean power output at different loads (r range: 0.86-0.94; p < .01) and detecting training-induced changes (R(2): 0.78). Good to excellent intra-tester (intraclass correlation coefficient (ICC) range: 0.81-0.97) and excellent inter-tester (ICC range: 0.96 0.99; coefficient of variation range: 2.4-4.1%) reliability was found for all loads. The W5" Test was shown to be a valid, reliable and sensitive method for measuring mean power output during the bench press exercise in subjects who have previous resistance training experience. PMID- 27232979 TI - Isolation-hypoxia and re-oxygenation of the pallial cavity of female Crepipatella dilatata during estuarine salinity changes requires increased glyoxylase activity and antioxidant metabolism to avoid oxidative damage to female tissues and developing embryos. AB - The estuarine slipper limpet Crepipatella dilatata is a gastropod that can survive prolonged periods of low salinities (< 24 PSU) caused by tidal changes and/or prolonged periods of rain. During low salinity events, C. dilatata can isolate its body from the outside environment, by sealing its shell against the substrate on which it grows. Prolonged isolation periods from the surrounding environment can greatly lower available oxygen levels inside of the pallial cavity, impacting on the physiology of both females and their incubated encapsulated embryos. When salinity levels return to normal, isolation is terminated and the inflow of seawater results in re-oxygenation. In this study we show that when re-oxygenation of the pallial cavity takes place, oxidative damage, in the form of increased levels of lipid peroxides and protein carbonyls, occurs in both maternal tissues and in incubated embryos. To avoid terminal oxidative damage both females and their embryos increase their levels of the glyoxalase pathway enzymes (GLX-I and GLX-II) and general antioxidant metabolism (SOD, CAT, GR, GPOX and GST). As a result the levels of oxidative damage decline to basal levels within 24 h of reoxygenation. Thus the combination of isolation, a behavioural strategy, combined with encapsulation of embryos and a capacity to up regulate relatively rapidly the glyoxylase pathway and general antioxidant metabolism, play major roles in facilitating the survival of C. dilatata in the small estuaries of Southern Chile. PMID- 27232980 TI - Pharmacokinetics and tissue distribution of five active ingredients of Eucommiae cortex in normal and ovariectomized mice by UHPLC-MS/MS. AB - 1. Pinoresinol di-O-beta-d-glucopyranoside (PDG), geniposide (GE), geniposidic acid (GA), aucubin (AN) and chlorogenic acid (CA) are the representative active ingredients in Eucommiae cortex (EC), which may be estrogenic. 2. The ultra high performance liquid chromatography/tandem mass spectrometry (UHPLC-MS/MS) method for simultaneous determination of the five ingredients showed good linearity, low limits of quantification and high extraction recoveries, as well as acceptable precision, accuracy and stability in mice plasma and tissue samples (liver, spleen, kidney and uterus). It was successfully applied to the comparative study on pharmacokinetics and tissue distribution of PDG, GE, GA, AN and CA between normal and ovariectomized (OVX) mice. 3. The results indicated that except CA, the plasma and tissue concentrations of PDG, GE, GA in OVX mice were all greater than those in normal mice. AN could only be detected in the plasma and liver homogenate of normal mice, which was poorly absorbed in OVX mice and low in other measured tissues. PDG, GE and GA seem to be better absorbed in OVX mice than in normal mice proved by the remarkable increased value of AUC0-infinity and Cmax. It is beneficial that PDG, GE, GA have better plasma absorption and tissue distribution in pathological state. PMID- 27232981 TI - The role of postdeployment social factors in linking deployment experiences and current posttraumatic stress disorder symptomatology among male and female veterans. AB - BACKGROUND AND OBJECTIVES: The postdeployment social context is likely highly salient in explaining mental health symptoms following deployment. The aim of this study was to examine the role of postdeployment social factors (social support and social reintegration difficulty) in linking deployment-related experiences (warfare exposure, sexual harassment, concerns about relationship disruptions, and deployment social support) and posttraumatic stress disorder (PTSD) symptomatology in male and female veterans. DESIGN: A survey was administered to 998 potential participants (after accounting for undeliverable mail) who had returned from deployment to Afghanistan or Iraq. Completed surveys were received from 469 veterans, yielding a response rate of 47%. METHODS: Hypotheses were examined using structural equation modeling. RESULTS: For male and female veterans, deployment factors predicted later PTSD symptoms through postdeployment social support and social reintegration, with lower support and higher social reintegration difficulty both associated with higher PTSD symptomatology. While the final models for women and men indicated similar risk mechanisms, some differences in pathways were observed. Sexual harassment presented more of a risk for women, whereas lower social support was a greater risk factor for men. CONCLUSIONS: Postdeployment social factors appear to represent potentially important targets for interventions aiming to reduce the potential impact of stressful deployment experiences. PMID- 27232983 TI - Structural Characterization of Lecithin-Stabilized Tetracosane Lipid Nanoparticles. Part II: Suspensions. AB - Using photon correlation spectroscopy, transmission electron microscopy, microcalorimetry, wide-angle X-ray scattering (WAXS), and small-angle X-ray and neutron scattering (SAXS, SANS), the structure of 1,2-dimyristoyl-sn-glycero-3 phosphocholine (DMPC)-stabilized colloidal tetracosane suspensions was studied from the molecular level to the microscopic scale as a function of the temperature. The platelike nanocrystals exhibit for tetracosane an unusual orthorhombic low-temperature crystal structure. The corresponding WAXS pattern can be reproduced with a predicted orthorhombic unit cell (space group Pca21), which usually occurs only for much longer even-numbered n-alkanes. Special emphasis was placed on the structure of the DMPC stabilizer layer covering the nanocrystals. Their structure was investigated by SAXS and SANS, using suspensions with different neutron scattering contrasts. As for the emulsions in Part I , the crystallized nanoparticles are covered by a DMPC monolayer. Their significant smaller thickness of 10.5 A (for the emulsions in Part I : 16 A) could be related to a more tilted orientation of the DMPC molecules to cover the expanded surface of the crystallized nanoparticles. PMID- 27232984 TI - Effect of carbon source type on intracellular stored polymers during endogenous denitritation (ED) treating landfill leachate. AB - Glycogen accumulating organisms (GAOs) capable of storing organic compounds as polyhydroxyalkanoate (PHA) have been used for endogenous denitritation (ED), but the effect of carbon sources type on nitrogen removal performance of GAOs treating landfill leachate is unclear. In this study, a successful ED system treating landfill leachate (COD/NH4(+)-N (C/N): 4) without external carbon source addition was applied. The mature leachate with C/N of 1 was used as the feeding base solution, with acetate, propionate, and glucose examined as the carbon sources, and their effects on yields and compositions of PHA produced by GAOs were determined and associated with nitrogen removal performance. In the case of sole carbon source, acetate was much easier to be stored than propionate and glucose, which led to a higher nitrogen removal efficiency. Glucose had the lowest amount of PHA storage and led to the lowest performance. In the case of composite carbon sources (two scenarios: acetate + propionate; acetate + propionate + glucose), GAOs stored sufficient PHA and exhibited similar nitrogen removal efficiencies. Moreover, type of carbon source influenced the compositions of PHA. The polyhydroxybutyrate (PHB) fraction in PHA was far more than polyhydroxyvalerate (PHV) in all tests. PHV was synthesized only when acetate existed in carbon source. The microbial diversity analysis revealed that Proteobacteria was the most abundant phylum. Among the 108 genera detected in this ED system, the genera responsible for denitritation were Thauera, Paracoccus, Ottowia and Comamonadaceae_unclassified, accounting for 46.21% of total bacteria. Especially, Paracoccus and Comamonadaceae_unclassified transformed the carbon source into PHA for denitritation, and carried out endogenous denitritation. PMID- 27232982 TI - Thousands of novel translated open reading frames in humans inferred by ribosome footprint profiling. AB - Accurate annotation of protein coding regions is essential for understanding how genetic information is translated into function. We describe riboHMM, a new method that uses ribosome footprint data to accurately infer translated sequences. Applying riboHMM to human lymphoblastoid cell lines, we identified 7273 novel coding sequences, including 2442 translated upstream open reading frames. We observed an enrichment of footprints at inferred initiation sites after drug-induced arrest of translation initiation, validating many of the novel coding sequences. The novel proteins exhibit significant selective constraint in the inferred reading frames, suggesting that many are functional. Moreover, ~40% of bicistronic transcripts showed negative correlation in the translation levels of their two coding sequences, suggesting a potential regulatory role for these novel regions. Despite known limitations of mass spectrometry to detect protein expressed at low level, we estimated a 14% validation rate. Our work significantly expands the set of known coding regions in humans. PMID- 27232985 TI - Removal of carbamazepine in aqueous solutions through solar photolysis of free available chlorine. AB - Removal of a persistent antiepileptic drug carbamazepine (CBZ) in aqueous solutions was investigated by using solar photolysis combined with free available chlorine (FAC). The combination of chlorination with simulated or natural sunlight markedly enhanced removal of CBZ in 10 mM phosphate buffer solution (pH 7.0) and river water (pH 7.0) compared with sunlight or FAC alone. Further analysis indicated that the observed enhancements in CBZ removal can be attributed to the in situ hydroxyl radical (HO) and ozone (O3) production during FAC photolysis. During 70 min simulated sunlight photolysis combined with FAC treatment, HO reaction contributed to 35.8% removal of CBZ and O3 reaction contributed to 40.6% removal, while only 5.3% of CBZ was removed by HOCl reaction. The oxidation products of CBZ, epoxide CBZ, 10,11-dihydro-10,11 dihydroxy CBZ, 1-(2-benzaldehyde)-4-hydro-(1H,3H)-quinazoline-2-one (BQM), 1-(2 benzaldehyde)-(1H,3H)-quinazoline-2,4-dione (BQD) and 4-aldehyde-9-acridone, were mainly formed from the HO and O3 attack at the double bond on the central heterocyclic ring of CBZ. Formation of these oxidation products did not cause any increase or decrease in toxicity to microbial species tested through Microbial Assay for Toxicity Risk Assessment (MARA). The initial FAC concentration and pH had a major influence on the removal process of CBZ during FAC photolysis, while temperature had a minor effect only. The combination of chlorination with natural sunlight could provide an effective approach for removal of CBZ and other contaminants during water treatment. PMID- 27232986 TI - Indirect sulfur reduction via polysulfide contributes to serious odor problem in a sewer receiving nitrate dosage. AB - Nitrate dosing is commonly used to control hydrogen sulfide production in sewer systems. However, quick rebound of the sulfide concentration after nitrate depletion has been observed and results in more serious odor and corrosion problem. To investigate the mechanism of sulfide regeneration in the nitrate-free period, a laboratory-scale sewer reactor was run for 30 days to simulate sulfide production and oxidation with intermittent nitrate addition. The results show that nitrate addition substantially reduced the sulfide concentration, but the produced elemental sulfur was then quickly reduced back to sulfide in nitrate free periods. This induced more and more sulfide production in the sewer reactor. Elemental sulfur and polysulfide reductions were found in the sewage in nitrate free periods, showing their contributions to the sulfide regeneration. Through batch tests, polysulfide was confirmed as the key intermediate for accelerating sulfur reduction during the nitrate-free period in the sewer. Sulfide production rates significantly increased by 65% and 59% in the presences of tetrasulfide and sulfur with sulfide, respectively, at the beginning of the test. While polysulfide formation was prevented by the ferrous chloride addition, the sulfur reduction rate remarkably decreased from 12.8 mgS/L-h to 1.8 mgS/L-h. This indicates that direct sulfur reduction was significantly slower than the indirect sulfur reduction via polysulfide; the latter process could be the cause for the quick rebound of the sulfide concentration in the sewer with intermittent nitrate dosing. Thus, the pathways of sulfur transformations in a sewer, both in the presence and absence of nitrate, were proposed. Microbial community analysis results reveal that some common sulfate-reducing bacteria (SRB) genera in sewer sediment were possible sulfur reducers. According to this finding, the effect and strategy of nitrate dosing for hydrogen sulfide control in sewers should be re evaluated and re-considered. PMID- 27232987 TI - Superfine powdered activated carbon (S-PAC) coatings on microfiltration membranes: Effects of milling time on contaminant removal and flux. AB - In microfiltration processes for drinking water treatment, one method of removing trace contaminants is to add powdered activated carbon (PAC). Recently, a version of PAC called superfine PAC (S-PAC) has been under development. S-PAC has a smaller particle size and thus faster adsorption kinetics than conventionally sized PAC. Membrane coating performance of various S-PAC samples was evaluated by measuring adsorption of atrazine, a model micropollutant. S-PACs were created in house from PACs of three different materials: coal, wood, and coconut shell. Milling time was varied to produce S-PACs pulverized with different amounts of energy. These had different particles sizes, but other properties (e.g. oxygen content), also differed. In pure water the coal based S-PACs showed superior atrazine adsorption; all milled carbons had over 90% removal while the PAC had only 45% removal. With addition of calcium and/or NOM, removal rates decreased, but milled carbons still removed more atrazine than PAC. Oxygen content and specific external surface area (both of which increased with longer milling times) were the most significant predictors of atrazine removal. S-PAC coatings resulted in loss of filtration flux compared to an uncoated membrane and smaller particles caused more flux decline than larger particles; however, the data suggest that NOM fouling is still more of a concern than S-PAC fouling. The addition of calcium improved the flux, especially for the longer-milled carbons. Overall the data show that when milling S-PAC with different levels of energy there is a tradeoff: smaller particles adsorb contaminants better, but cause greater flux decline. Fortunately, an acceptable balance may be possible; for example, in these experiments the coal-based S-PAC after 30 min of milling achieved a fairly high atrazine removal (overall 80%) with a fairly low flux reduction (under 30%) even in the presence of NOM. This suggests that relatively short duration (low energy) milling is viable for creating useful S-PAC materials applied in tandem with microfiltration. PMID- 27232988 TI - Evolution of phosphorus complexation and mineralogy during (hydro)thermal treatments of activated and anaerobically digested sludge: Insights from sequential extraction and P K-edge XANES. AB - (Hydro)thermal treatments of sewage sludge is a promising option that can simultaneously target safe waste disposal, energy recovery, and nutrient recovery/recycling. The speciation of phosphorus (P) in sludge is of great relevance to P reclamation/recycling and soil application of sludge-derived products, thus it is critical to understand the effects of different treatment techniques and conditions on P speciation. This study systematically characterized P speciation (i.e. complexation and mineral forms) in chars derived from pyrolysis and hydrothermal carbonization (HTC) of municipal sewage sludges. Combined sequential extraction and P K-edge X-ray absorption near edge structure (XANES) spectroscopy analysis revealed the dependence of P transformation on treatment conditions and metal composition in the feedstocks. Pyrolysis of sludges decreased the relative abundance of phytic acid while increased the abundance of Al-associated P. HTC thoroughly homogenized and exposed P for interaction with various metals/minerals, with the final P speciation closely related to the composition/speciation of metals and their affinities to P. Results from this study revealed the mechanisms of P transformation during (hydro)thermal treatments of sewage sludges, and might be applicable to other biosolids. It also provided fundamental knowledge basis for the design and selection of waste management strategies for better P (re)cycling and reclamation. PMID- 27232989 TI - Membrane fouling potentials and cellular properties of bacteria isolated from fouled membranes in a MBR treating municipal wastewater. AB - Membrane fouling remains a major challenge for wider application of membrane bioreactors (MBRs) to wastewater treatment. Membrane fouling is mainly caused by microorganisms and their excreted microbial products. For development of more effective control strategies, it is important to identify and characterize the microorganisms that are responsible for membrane fouling. In this study, 41 bacterial strains were isolated from fouled microfiltration membranes in a pilot scale MBR treating real municipal wastewater, and their membrane fouling potentials were directly measured using bench-scale cross-flow membrane filtration systems (CFMFSs) and related to their cellular properties. It was found that the fouling potential was highly strain dependent, suggesting that bacterial identification at the strain level is essential to identify key fouling causing bacteria (FCB). The FCB showed some common cellular properties. The most prominent feature of FCB was that they formed convex colonies having swollen podgy shape and smooth lustrous surfaces with high water, hydrophilic organic matter and carbohydrate content. However, general and rigid biofilm formation potential as determined by microtiter plates and cell surface properties (i.e., hydrophobicity and surface charge) did not correlate with the fouling potential in this study. These results suggest that the fouling potential should be directly evaluated under filtration conditions, and the colony water content could be a useful indicator to identify the FCB. PMID- 27232990 TI - Long-term natural remediation process in textile dye-polluted river sediment driven by bacterial community changes. AB - The textile and dyeing industries are major sources of environmental water pollution all over the world. The textile wastewater effluents discharged into rivers often appear dark red-purple in color due to azo dyes, which can be transformed into carcinogenic aromatic amines. The chemicals used in dyeing are not readily degraded in nature and thus precipitate in river sediment. However, little is known about how dyeing chemicals affect river sediment and river water or how long they persist because they are difficult to monitor. To assess undetectable dyes and byproducts in river sediments, we evaluated the potential of river sediment bacteria to degrade dyes and aromatic amines. We describe the natural remediation of river sediment long-contaminated by textile dyeing effluent. After cessation of wastewater discharge, the dye-degradation potential decreased, and the aromatic amine-degradation potential increased initially and then declined over time. The changes in degradation potential were consistent with changes in the sediment bacterial community. The transition occurred on the order of years. Our data strongly suggest that dyes remained in the river sediment and that aromatic amines were produced even in transparent- and no longer colored-river water, but these chemicals were degraded by the changing sediment bacteria. Time-course monitoring of the degradation activities of key bacteria thus enables assessment of the fate of dye pollutants in river sediments. PMID- 27232991 TI - Abiotic amidine and guanidine hydrolysis of lamotrigine-N2-glucuronide and related compounds in wastewater: The role of pH and N2-substitution on reaction kinetics. AB - The stability of lamotrigine (LMG) and its principal human metabolite, lamotrigine N2-glucuronide (LMG-N2-G), was studied as a function of pH (4-9). While LMG was stable across the entire pH range, under neutral-basic conditions, LMG-N2-G was converted to three transformation products (TPs) which were identified using high resolution mass spectrometry (HRMS). The MS fragmentation studies indicated that two TPs were the result of the hydrolysis of the amidine and guanidine moieties. The third TP detected was an intermediate in the guanidine hydrolysis reaction. In order to evaluate the transformation kinetics of the LMG-N2-G degradation, another set of pH-dependent experiments was carried out in hospital effluent, wastewater influent and effluent spiked at 20 and 200 nM after pH adjustment (pH 6.5, 7, 8, 8.5 and 9), demonstrating that, at higher pH, LMG-N2-G is degraded at higher rate. Later, the pH-dependent stability of related compounds with different nitrogen N2-substituents (N2-R) on the 1,2,4 triazine ring was studied. This revealed that because of different imino tautomer equilibrium LMG (N2-H) and LMG-N2-oxide ((+)N2-O(-)) were stable at all pHs but N2-methyl-LMG (N2-CH3) as well as LMG-N2-G were susceptible to amidine and guanidine hydrolysis at basic pH. Finally, hospital effluent samples collected over the course of one week were monitored for their presence. LMG, LMG-N2-G and two of its TPs were detected with concentrations ranging between 0.01 and 1 MUgL( 1). PMID- 27232992 TI - Comparison of UV/hydrogen peroxide, potassium ferrate(VI), and ozone in oxidizing the organic fraction of oil sands process-affected water (OSPW). AB - The efficiency of three different oxidation processes, UV/H2O2 oxidation, ferrate(VI) oxidation, and ozonation with and without hydroxyl radical (OH) scavenger tert-butyl alcohol (TBA) on the removal of organic compounds from oil sands process-affected water (OSPW) was investigated and compared. The removal of aromatics and naphthenic acids (NAs) was explored by synchronous fluorescence spectra (SFS), ion mobility spectra (IMS), proton and carbon nuclear magnetic resonance ((1)H and (13)C NMR), and ultra-performance liquid chromatography coupled with time-of-flight mass spectrometry (UPLC TOF-MS). UV/H2O2 oxidation occurred through radical reaction and photolysis, transforming one-ring, two ring, and three-ring fluorescing aromatics simultaneously and achieving 42.4% of classical NAs removal at 2.0 mM H2O2 and 950 mJ/cm(2) UV dose provided with medium pressure mercury lamp. Ferrate(VI) oxidation exhibited high selectivity, preferentially removing two-ring and three-ring fluorescing aromatics, sulfur containing NAs (NAs + S), and NAs with high carbon and high hydrogen deficiency. At 2.0 mM Fe(VI), 46.7% of classical NAs was removed. Ozonation achieved almost complete removal of fluorescing aromatics, NAs + S, and classical NAs (NAs with two oxygen atoms) at the dose of 2.0 mM O3. Both molecular ozone reaction and OH reaction were important pathways in transforming the organics in OSPW as supported by ozonation performance with and without TBA. (1)H NMR analyses further confirmed the removal of aromatics and NAs both qualitatively and quantitatively. All the three oxidation processes reduced the acute toxicity towards Vibrio fischeri and on goldfish primary kidney macrophages (PKMs), with ozonation being the most efficient. PMID- 27232993 TI - Domestic wastewater treatment with purple phototrophic bacteria using a novel continuous photo anaerobic membrane bioreactor. AB - A key future challenge of domestic wastewater treatment is nutrient recovery while still achieving acceptable discharge limits. Nutrient partitioning using purple phototrophic bacteria (PPB) has the potential to biologically concentrate nutrients through growth. This study evaluates the use of PPB in a continuous photo-anaerobic membrane bioreactor (PAnMBR) for simultaneous organics and nutrient removal from domestic wastewater. This process could continuously treat domestic wastewater to discharge limits (<50 mgCOD L(-1), 5 mgN L(-1), 1.0 mgP L( 1)). Approximately 6.4 +/- 1.3 gNH4-N and 1.1 +/- 0.2 gPO4-P for every 100 gSCOD were removed at a hydraulic retention time of 8-24 h and volumetric loading rates of 0.8-2.5 COD kg m(3) d(-1). Thus, a minimum of 200 mg L(-1) of ethanol (to provide soluble COD) was required to achieve these discharge limits. Microbial community through sequencing indicated dominance of >60% of PPB, though the PPB community was highly variable. The outcomes from the current work demonstrate the potential of PPB for continuous domestic (and possibly industrial) wastewater treatment and nutrient recovery. Technical challenges include the in situ COD supply in a continuous reactor system, as well as efficient light delivery. Addition of external (agricultural or fossil) derived organics is not financially nor environmentally justified, and carbon needs to be sourced internally from the biomass itself to enable this technology. Reduced energy consumption for lighting is technically feasible, and needs to be addressed as a key objective in scaleup. PMID- 27232994 TI - Large-scale demonstration of the sulfate reduction autotrophic denitrification nitrification integrated (SANI((r))) process in saline sewage treatment. AB - Recently, the Sulfate reduction Autotrophic denitrification Nitrification Integrated (SANI((r))) process was developed for the removal of organics and nitrogen with sludge minimization in the treatment of saline sewage (with a Sulfate-to-COD ratio > 0.5 mg SO4(2-)-S/mg COD) generated from seawater used for toilet flushing or salt water intrusion. Previously investigated in lab- and pilot-scale, this process has now been scaled up to a 800-1000 m(3)/d full-scale demonstration plant. In this paper, the design and operating parameters of the SANI demo plant built in Hong Kong are analyzed. After a 4-month start-up period, a stable sulfur cycle-based biological nitrogen removal system having a hydraulic retention time (HRT) of 12.5 h was developed, thereby reducing the amount of space needed by 30-40% compared with conventional activated sludge (CAS) plants in Hong Kong. The demo plant satisfactorily met the local effluent discharge limits during both the summer and winter periods. In winter (sewage temperature of 21 +/- 1 degrees C), the maximum volumetric loading rates for organic conversion, nitrification, and denitrification were 2 kg COD/(m(3).d), 0.39 kg N/(m(3).d), and 0.35 kg N/(m(3).d), respectively. The biological sludge production rate of SANI process was 0.35 +/- 0.08 g TSSproduced/g BOD5 (or 0.19 +/- 0.05 g TSS/g COD), which is 60-70% lower than that of the CAS process in Hong Kong. While further process optimization is possible, this study demonstrates the SANI process can be potentially implemented for the treatment of saline sewage. PMID- 27232995 TI - Determination of oxidant exposure during ozonation of secondary effluent to predict contaminant removal. AB - The use of kinetic models to predict oxidation performance in wastewater is limited due to fast ozone depletion during the first milliseconds of the reaction. This paper introduces the Quench Flow Module (QFM), a bench-scale experimental technique developed to measure the first 5-500 milliseconds of ozone depletion for accurate determination of ozone exposure in wastewater-ozonation processes. Calculated ozone exposure in QFM experiments was up to 24% lower than in standard batch experiments, strongly depending on the initial sampling point for measurement in batch experiments. However, oxidation rates of slowly- and moderately-reacting trace organic compounds (TrOCs) were accurately predicted from batch experiments based on integration of ozone depletion and removal of an ozone-resistant probe compound to calculate oxidant exposures. An alternative concept, where ozone and hydroxyl radical exposures are back-calculated from the removal of two probe compounds, was tested as well. Although the QFM was suggested to be an efficient mixing reactor, ozone exposure ranged over three orders of magnitude when different probe compounds reacting moderately with ozone were used for the calculation. These effects were beyond uncertainty ranges for apparent second order rate constants and consistently observed with different ozone-injection techniques, i.e. QFM, batch experiments, bubble columns and venturi injection. This indicates that previously suggested mixing effects are not responsible for the difference and other still unknown factors might be relevant. Results furthermore suggest that ozone exposure calculations from the relative residual concentration of a probe compound are not a promising option for evaluation of ozonation of secondary effluents. PMID- 27232997 TI - Is Working Risky or Protective for Married Adolescent Girls in Urban Slums in Kenya? Understanding the Association between Working Status, Savings and Intimate Partner Violence. AB - INTRODUCTION: Previous studies have shown that women's empowerment, though beneficial in many aspects, can also increase the risk of intimate-partner violence (IPV). This study seeks to examine the association between work and experience of physical violence among married adolescents, and to understand the impact of access to independent financial resources on this risk. Authors draw on the asset-building framework and the ecological model. METHODS: The data is from a baseline survey of girls aged 15-19 residing in urban slums in four cities and towns in Kenya (Nairobi, Thika, Nakuru and Kisumu). The analytic sample is 452 married girls. Logistic regression is used to examine associations between working status, savings and experience of IPV in the previous six months, controlling for other factors. This is complemented by content analysis of in depth interviews with 32 adolescent girls and 16 young men. RESULTS: Compared to girls who did not work, working with no regular savings was significantly associated with greater odds (OR = 1.96, p<0.01) of experiencing IPV. There was no difference between girls who did not work and those who worked but had regular savings. Qualitative findings indicate savings decrease girls' dependency on men and allow them to leave abusive partners. DISCUSSION: Findings imply that in these communities with patriarchal gender norms and high levels of poverty, female employment and financial conflicts can be triggers of violence in marriages. On the other hand, girls' management of and access to independent financial resources through savings can potentially help to reduce this risk. PMID- 27232996 TI - Cryopreservation of Human Mucosal Leukocytes. AB - BACKGROUND: Understanding how leukocytes in the cervicovaginal and colorectal mucosae respond to pathogens, and how medical interventions affect these responses, is important for developing better tools to prevent HIV and other sexually transmitted infections. An effective cryopreservation protocol for these cells following their isolation will make studying them more feasible. METHODS AND FINDINGS: To find an optimal cryopreservation protocol for mucosal mononuclear leukocytes, we compared cryopreservation media and procedures using human vaginal leukocytes and confirmed our results with endocervical and colorectal leukocytes. Specifically, we measured the recovery of viable vaginal T cells and macrophages after cryopreservation with different cryopreservation media and handling procedures. We found several cryopreservation media that led to recoveries above 75%. Limiting the number and volume of washes increased the fraction of cells recovered by 10-15%, possibly due to the small cell numbers in mucosal samples. We confirmed that our cryopreservation protocol also works well for both endocervical and colorectal leukocytes. Cryopreserved leukocytes had slightly increased cytokine responses to antigenic stimulation relative to the same cells tested fresh. Additionally, we tested whether it is better to cryopreserve endocervical cells on the cytobrush or in suspension. CONCLUSIONS: Leukocytes from cervicovaginal and colorectal tissues can be cryopreserved with good recovery of functional, viable cells using several different cryopreservation media. The number and volume of washes has an experimentally meaningful effect on the percentage of cells recovered. We provide a detailed, step-by-step protocol with best practices for cryopreservation of mucosal leukocytes. PMID- 27232998 TI - Case-control study of immediate and delayed vasovagal reactions in blood donors. AB - BACKGROUND AND OBJECTIVE(S): Vasovagal reactions (VVRs) are the most common adverse events associated with blood donations. To assess the relative importance of VVR risk factors, a retrospective case-control study of severe immediate and delayed VVRs was performed. STUDY DESIGN: Vasovagal reactions were defined as immediate when occurring at the transfusion site and as delayed when occurring outside the transfusion site and within 24 h following donation. VVRs with probable or certain imputability and moderate to death severity were considered. One control/case was drawn randomly from among donors without VVR. Explanatory variables (sex, age, body mass index (BMI), donation status, type of phlebotomy) as well as the matching variables (donation region, date) and the interaction term (sex and BMI) were integrated into the multivariate model. RESULTS: In French hemovigilance data collected from 2011 to 2013, 8410 immediate and 833 delayed VVRs occurred among 8 834 214 donations. In multivariate analysis, occurrence of immediate VVR was strongly associated with first-time donation (OR 4.34; 95% CI: 3.93-4.79, P < 0.0001) and the 18-24 age group (OR 2.24; 95% CI: 2.00-2.45, P < 0.0001) and of delayed VVR with women with a normal BMI (OR 7.31; 95% CI: 4.96-10.77, P < 0.0001), overweight BMI (OR 7.89; 95% CI: 4.84-12.87, P < 0.0001) or obese BMI (OR 3.72; 95% CI: 1.42-9.74, P < 0.0001), and in men with an underweight BMI (OR 6.39; 95% CI: 1.56-26.13, P < 0.0001). Apheresis was a risk factor for occurrence of both immediate and delayed VVR. CONCLUSION: Our study highlights that first-time donation by a young person is particularly at risk of immediate VVR while a female donor is at risk of delayed VVR. PMID- 27232999 TI - Omega-3 and Omega-6 Polyunsaturated Fatty Acid Levels and Correlations with Symptoms in Children with Attention Deficit Hyperactivity Disorder, Autistic Spectrum Disorder and Typically Developing Controls. AB - BACKGROUND: There is evidence that children with Attention Deficit Hyperactivity Disorder (ADHD) and Autistic Spectrum Disorder (ASD) have lower omega-3 polyunsaturated fatty acid (n-3 PUFA) levels compared with controls and conflicting evidence regarding omega-6 (n-6) PUFA levels. OBJECTIVES: This study investigated whether erythrocyte n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were lower and n-6 PUFA arachidonic acid (AA) higher in children with ADHD, ASD and controls, and whether lower n-3 and higher n-6 PUFAs correlated with poorer scores on the Australian Twin Behaviour Rating Scale (ATBRS; ADHD symptoms) and Test of Variable Attention (TOVA) in children with ADHD, and Childhood Autism Rating Scale (CARS) in children with ASD. METHODS: Assessments and blood samples of 565 children aged 3-17 years with ADHD (n = 401), ASD (n = 85) or controls (n = 79) were analysed. One-way ANOVAs with Tukey's post-hoc analysis investigated differences in PUFA levels between groups and Pearson's correlations investigated correlations between PUFA levels and ATBRS, TOVA and CARS scores. RESULTS: Children with ADHD and ASD had lower DHA, EPA and AA, higher AA/EPA ratio and lower n-3/n-6 than controls (P<0.001 except AA between ADHD and controls: P = 0.047). Children with ASD had lower DHA, EPA and AA than children with ADHD (P<0.001 for all comparisons). ATBRS scores correlated negatively with EPA (r = -.294, P<0.001), DHA (r = -.424, P<0.001), n 3/n-6 (r = -.477, P<0.001) and positively with AA/EPA (r = .222, P <.01). TOVA scores correlated positively with DHA (r = .610, P<0.001), EPA (r = .418, P<0.001) AA (r = .199, P<0.001), and n-3/n-6 (r = .509, P<0.001) and negatively with AA/EPA (r = -.243, P<0.001). CARS scores correlated significantly with DHA (r = .328, P = 0.002), EPA (r = -.225, P = 0.038) and AA (r = .251, P = 0.021). CONCLUSIONS: Children with ADHD and ASD had low levels of EPA, DHA and AA and high ratio of n-6/n-3 PUFAs and these correlated significantly with symptoms. Future research should further investigate abnormal fatty acid metabolism in these disorders. PMID- 27233000 TI - Curcumin represses the activity of inhibitor-kappaB kinase in dextran sulfate sodium-induced colitis by S-nitrosylation. AB - In this study, we investigated the preventive effects of curcumin using dextran sulfate sodium (DSS)-induced colitis and the potential role of curcumin in regulation of anti-inflammation through S-nitrosylation. After curcumin treatment for 6days, the body weight and disease activity index of DSS-induced mice was alleviated and the colonic length was also rescued. Western blot presented that the protein expression of iNOS can be reduced by curcumin. Consistently, mRNA level of iNOS and pro-inflammatory cytokines, such as TNFalpha, IL-1beta, and IL 6, was also repressed. Moreover, Curcumin reduced the amount of nitrite in DSS induced colitis but not affected total S-nitrosylation level on proteins on day 6, indicating that curcumin inhibited NO oxidation. Furthermore, the protection of S-nitrosylation on IKKbeta in DSS-induced colitis for 6days by curcumin caused the repression of IkappaB phosphorylation and NF-kappaB activation. In conclusion, this study verified that curcumin-mediated S-nitrosylation may be as an important regulator for anti-inflammation in DSS-induced colitis of mice. PMID- 27233001 TI - The association between reduced folate carrier-1 gene 80G/A polymorphism and methotrexate efficacy or methotrexate related-toxicity in rheumatoid arthritis: A meta-analysis. AB - Methotrexate (MTX), the most commonly used anti-rheumatic drug against RA, enters the cell via the action of the reduced folate carrier 1(RFC1). A major polymorphism of the RFC1 gene, 80G/A, has been reported to influence the activity of RFC1, resulting in variable intracellular MTX-polyglutamate (MTX-PG) levels. However, the association studies addressing the RFC1 80G/A polymorphism and MTX efficacy or toxicity in Rheumatoid arthritis (RA) has yielded conflicting results. In the present meta-analysis, we aimed to evaluate the association between the RFC1 80G/A polymorphism and MTX efficacy or toxicity in RA patients. A total 17 studies met our inclusion criteria. Among them, 12 studies with 2049 subjects reported the association between the RFC1 80G/A and MTX response, and 12 studies involving 2627 subjects were on MTX-related toxicity. Meta-analysis revealed significant association between RFC1 80G/A polymorphism and MTX efficacy (odds ratio (OR) for the A allele=1.29, 95% confidence interval (CI) 1.05-1.67, P=0.02; for AA genotype: OR=1.49, 95%CI 1.17-1.907, P=0.001). However, no association could be detected in the analysis of MTX-related toxicity. Stratification by ethnic population also indicated an association between this polymorphism and MTX efficacy in Asian group (P=0.002 for A allele; P=0.003 for AA genotype), but not in the Caucasian group (P=0.15 for A allele; P=0.05 for AA genotype). In both Asian and Caucasian sub-groups, no influence of the RFC1 80G/A polymorphism on MTX toxicity can be detected. In conclusion, the RFC1 G80A polymorphism is associated with responsiveness to MTX therapy, but may not be associated with MTX toxicity in RA patients. PMID- 27233002 TI - Adjuvant effect of docetaxel on HPV16 L2E6E7 fusion protein vaccine in a mouse model. AB - We previously demonstrated that the antineoplastic agent docetaxel enhanced the immune response to an influenza vaccine. This study evaluated the adjuvant effect of docetaxel (DOC) on the therapeutic efficacy of HPV16 L2E6E7 fusion protein (HPV-LFP) in mice inoculated with TC-1 cells. The results demonstrated that docetaxel significantly enhanced the therapeutic effect of HPV-LFP on TC-1 cell induced tumors in mice. The injection of HPV-LFP in combination with docetaxel in TC-1 tumor-bearing mice significantly reduced tumor volume and weight, and a greater percent survival was detected than mice treated with HPV-LFP alone. The inhibition of tumors was associated with significantly increased serum antigen specific IgG and isotypes, activated CTLs, increased IFN-gamma-secreting T cells, and decreased Treg cells and IL-10-secreting cells in spleen. In addition, down regulation of IL-10, VEGF and STAT3, up-regulation of IFN-gamma and decreased Treg cells in the tumor microenvironment may also important contributing factors to the antitumor effect. It may be valuable to use a DOC-containing water to dilute HPV-LFP powder before injection in patients because of its excellent adjuvant effect on HPV-LFP and solubility in water. PMID- 27233003 TI - Interleukin-37 suppresses ICAM-1 expression in parallel with NF-kappaB down regulation following TLR2 activation of human coronary artery endothelial cells. AB - INTRODUCTION: The inflammatory receptor Toll-like receptors (TLRs) activation could induce endothelial inflammatory responses, which plays an important role in the development of many diseases including atherosclerosis. We already found that TLR2 activation of Peptidoglycan (PGN) stimulation could increase intercellular adhesion molecule-1 (ICAM-1) expression in HCAECs. Since anti-inflammatory cytokine interleukin (IL)-37 exhibits intra- and extracellular properties for suppressing innate inflammation, we want to investigate whether IL-37 suppresses ICAM-1 expression and this effect is in parallel with the inhibition of nuclear factor kappa B (NF-kappaB) activation upon PGN stimulation in HCAECs. METHODS: HCAECs were treated with IL-37-transfection plasmid or silent mRNA or nothing for 24h, and we test IL-37 expression by immunoblotting. Same treatments prior to PGN stimulation (10MUg/ml), we analyzed the expression of ICAM-1 and NF-kappaB mRNA at 0, 30min, 1 and 2h by real-time PCR. ICAM-1 protein at 24h and NF-kappaB activation at 0-2h were measured by immunoblotting. RESULTS: IL-37 and silent IL 37 transfection change the expression of IL-37 protein. Stimulation of PGN increased both NF-kappaB activation and ICAM-1 expression at mRNA and protein level, but these inflammatory cytokines' expression was significantly decreased in IL-37-transfection cells. Interestingly, both NF-kappaB activation and ICAM-1 expression were significantly increased when IL-37 was silent. CONCLUSIONS: As an anti-inflammatory cytokine, IL-37 could decrease both NF-kappaB and ICAM-1 expression upon TLR2 activation in HCAECs. The suppressed effect of IL-37 on ICAM 1 may be due to its inhibition on NF-kappaB. PMID- 27233004 TI - Carbon and metal nanotube hybrid structures on graphene as efficient electron field emitters. AB - We report a facile and efficient method for the fabrication of highly-flexible field emission devices by forming tubular hybrid structures based on carbon nanotubes (CNTs) and nickel nanotubes (Ni NTs) on graphene-based flexible substrates. By employing an infiltration process in anodic alumina oxide (AAO) templates followed by Ni electrodeposition, we could fabricate CNT-wrapped Ni NT/graphene hybrid structures. During the electrodeposition process, the CNTs served as Ni nucleation sites, resulting in a large-area array of high aspect ratio field emitters composed of CNT-wrapped Ni NT hybrid structures. As a proof of concepts, we demonstrate that high-quality flexible field emission devices can be simply fabricated using our method. Remarkably, our proto-type field emission devices exhibited a current density higher by two orders of magnitude compared to other devices fabricated by previous methods, while maintaining its structural integrity in various bending deformations. This novel fabrication strategy can be utilized in various applications such as optoelectronic devices, sensors and energy storage devices. PMID- 27233005 TI - Expression of the nirS, hzsA, and hdh Genes in Response to Nitrite Shock and Recovery in Candidatus Kuenenia stuttgartiensis. AB - In this study, Candidatus Kuenenia stuttgartiensis were subjected to distinct nitrite shocks (66 (control), 200, 300, 400, and 500 mg N/L), and the responses of mRNA levels of cytochrome cd1 nitrite/nitric oxide oxidoreductase (nirS), hydrazine synthase (hzsA), and hydrazine dehydrogenase (hdh) were assessed. Changes in the hydrazine dehydrogenase (HDH) protein level were monitored. At 200 mg NO2(-)-N/L, the normalized specific anaerobic ammonium-oxidizing activity (nSAA) slightly increased relative to the control despite a significant decrease in nirS, hzsA, and hdh mRNA levels. When nitrite increased to 300 and 400 mg N/L, increased nirS, hzsA, and hdh mRNA levels were observed, but the nSAA decreased, relative to the 200 mg NO2(-)-N/L exposure. HDH protein detection revealed that Candidatus Kuenenia stuttgartiensis attempted to yield high enzyme levels by stimulating mRNA synthesis to resist the nitrite-induced stress. On 500 mg NO2(-) N/L shock, the nirS, hzsA, and hdh mRNA levels decreased, alongside decreased nSAA and HDH levels. Although the mRNA levels did not always coincide with activities, our findings advance understanding of the mechanisms that anammox bacteria use to cope with nitrite inhibition at the transcriptional and translational levels, which will improve the diagnostic accuracy of bioreactor failures when nitrite accumulation occurs. PMID- 27233006 TI - Making progress. PMID- 27233007 TI - Opioid misuse: containing harms. PMID- 27233008 TI - Community gardens as sites of solace and end-of-life support: a literature review. AB - In a pilot project, members of a community garden explored how they might provide better end-of-life support for their regional community. As part of the project, a literature review was undertaken to investigate the nexus between community gardens and end-of-life experiences (including grief and bereavement) in academic research. This article documents the findings of that review. The authors discovered there is little academic material that focuses specifically on community gardens and end-of-life experiences, but nonetheless the two subjects were seen to intersect. The authors found three points of commonality: both share a need and capacity for a) social/informal support, b) therapeutic space, and c) opportunities for solace. PMID- 27233010 TI - Care home managers' knowledge of palliative care: a Northern Irish study. AB - AIM: The aim of this study was to determine care home managers' knowledge of palliative care using the palliative care quiz for nursing (PCQN). BACKGROUND: Palliative care is strongly advocated for all people living with advancing incurable illness. Within a care home setting there should be a particular emphasis on the importance of palliative care, particularly for those residents who, because of their advancing age, are likely to live with non-malignant diseases such as dementia, chronic obstructive pulmonary disease or heart failure to name a few. METHODS: Before the beginning of a workshop on optimising palliative care for people living in care homes, 56 care home managers (all nurses) completed the PCQN, a validated questionnaire that is used to assess a nurse's knowledge of palliative care, as part of a learning exercise. RESULTS: The quiz consisted of 20 questions for which participants could answer true, false or don't know. The average score was 12.89 correct answers out of a possible 20 (64.45%). CONCLUSION: This study highlights the need to develop the knowledge and competence of care home managers in relation to palliative care. This is particularly important given the increasing number of people who are living with non-malignant disease within a care home setting. PMID- 27233009 TI - Barriers and facilitators to end-of-life communication in advanced chronic organ failure. AB - AIM: The aim of this quantitative, cross-sectional study was to identify barriers and facilitators to end-of-life communication experienced by family caregivers of patients with advanced chronic organ failure and to examine agreement in barriers and facilitators between family caregivers and patients. METHODS: Patients and family caregivers were interviewed using the barriers and facilitators questionnaire. Agreement was determined using intraclass correlation coefficients for continuous variables and Cohen's kappa for categorical variables. RESULTS: A total of 158 patients and family caregiver dyads were included. The most important barriers for family caregivers were related to uncertainty about expected care and focus on staying alive instead of dying. The facilitators were related to trust in and competence of their physician and earlier experiences with death in their (social) environment. For most barriers and facilitators, agreement between patients and family caregivers was fair to moderate. CONCLUSION: Differences in barriers and facilitators between patients and family caregivers ask for an individual approach to facilitate end-of-life communication. PMID- 27233011 TI - The development and evaluation of a holistic needs assessment within children's palliative care. AB - Caring for a child with a life-limiting condition brings a number of challenges and many families require additional support. The need for services to move away from a 'one size fits all' approach to a personalised care planning approach is well recognised, as is the value of establishing a robust way of assessing family members' differing needs. A number of assessment tools that consider individuals' holistic needs already exist. These are predominantly for the adult cancer population and exclude consideration of the child in its system. There was therefore a need to develop a tool that would appropriately meet the needs of children and parents who access services provided by a children's hospice. The tool was evaluated qualitatively. Feedback was positive; the experience of professionals was one of concordance with their ethical stance, improved communication, improved documentation and the wish to embed the tool into daily practice. PMID- 27233012 TI - Cancer-related fatigue in palliative care: a global perspective. AB - Cancer-related fatigue (CRF) in a palliative care setting is a distressing symptom that can have a negative impact on a patient's quality of life. A range of setting- and disease-specific factors, unknown aetiology and absence of unilateral guidelines make CRF treatment a challenge for clinicians. In the absence of high-quality evidence in favour of any pharmacological and nonpharmacological measures, except exercise, cognitive behavioural therapy and psychosocial interventions, a personalised integrative oncology approach can lead to effective management. Findings suggest adoption of a severity-based symptom stage adjusted CRF management care pathway, highlighting best practices to illustrate the lived experience of this symptom. Overcoming barriers by staff training, patient education, facilitating communication and patients' self-care, will increase CRF management effectiveness. Future CRF multisymptom or multidimensional nature investigation trials of its underlying mechanisms and new pharmacological and nonpharmacological strategies applied separately or in combination, will help reveal the best approach to CRF diagnosis, assessment and management. PMID- 27233013 TI - Research Roundup. PMID- 27233014 TI - Politics and palliative care: Egypt. PMID- 27233032 TI - Superior Rim Stability of the Lens Capsule Following Manual Over Femtosecond Laser Capsulotomy. AB - PURPOSE: Cataract surgery requires the removal of a circular segment of the anterior lens capsule (LC) by manual or femtosecond laser (FL) capsulotomy. Tears in the remaining anterior LC may compromise surgical outcome. We investigated whether biophysical differences in the rim properties of the LC remaining in the patient after manual or FL capsulotomy (FLC) lead to different risks with regard to anterior tear formation. METHODS: Lens capsule samples obtained by either continuous curvilinear capsulorhexis (CCC) or FLC were investigated by light microscopy, laser scanning confocal microscopy, and scanning electron microscopy; atomic force microscopy (AFM) was used to test the biomechanical properties of the LC. The mechanical stability of the LC following either of the two capsulotomy techniques was simulated by using finite-element modeling. RESULTS: Continuous curvilinear capsulorhexis produced wedge-shaped, uniform rims, while FLC resulted in nearly perpendicular, frayed rims with numerous notches. The LC is composed of two sublayers: a stiff epithelial layer that is abundant with laminin and a softer anterior chamber layer that is predominantly made from collagen IV. Computer models show that stress is uniformly distributed over the entire rim after CCC, while focal high stress concentrations are observed in the frayed profiles of LC after FLC, making the latter procedure more prone to anterior tear formation. CONCLUSIONS: Finite-element modeling based on three dimensional AFM maps indicated that CCC leads to a capsulotomy rim with higher stress resistance, leading to a lower propensity for anterior radial tears than FLC. PMID- 27233015 TI - Efficient Vaccine Distribution Based on a Hybrid Compartmental Model. AB - To effectively and efficiently reduce the morbidity and mortality that may be caused by outbreaks of emerging infectious diseases, it is very important for public health agencies to make informed decisions for controlling the spread of the disease. Such decisions must incorporate various kinds of intervention strategies, such as vaccinations, school closures and border restrictions. Recently, researchers have paid increased attention to searching for effective vaccine distribution strategies for reducing the effects of pandemic outbreaks when resources are limited. Most of the existing research work has been focused on how to design an effective age-structured epidemic model and to select a suitable vaccine distribution strategy to prevent the propagation of an infectious virus. Models that evaluate age structure effects are common, but models that additionally evaluate geographical effects are less common. In this paper, we propose a new SEIR (susceptible-exposed-infectious sC recovered) model, named the hybrid SEIR-V model (HSEIR-V), which considers not only the dynamics of infection prevalence in several age-specific host populations, but also seeks to characterize the dynamics by which a virus spreads in various geographic districts. Several vaccination strategies such as different kinds of vaccine coverage, different vaccine releasing times and different vaccine deployment methods are incorporated into the HSEIR-V compartmental model. We also design four hybrid vaccination distribution strategies (based on population size, contact pattern matrix, infection rate and infectious risk) for controlling the spread of viral infections. Based on data from the 2009-2010 H1N1 influenza epidemic, we evaluate the effectiveness of our proposed HSEIR-V model and study the effects of different types of human behaviour in responding to epidemics. PMID- 27233033 TI - Capsulorhexis Strength With FLACS Surgery. PMID- 27233034 TI - Protein Disulfide Levels and Lens Elasticity Modulation: Applications for Presbyopia. AB - PURPOSE: The purpose of the experiments described here was to determine the effects of lipoic acid (LA)-dependent disulfide reduction on mouse lens elasticity, to synthesize the choline ester of LA (LACE), and to characterize the effects of topical ocular doses of LACE on mouse lens elasticity. METHODS: Eight month-old mouse lenses (C57BL/6J) were incubated for 12 hours in medium supplemented with selected levels (0-500 MUM) of LA. Lens elasticity was measured using the coverslip method. After the elasticity measurements, P-SH and PSSP levels were determined in homogenates by differential alkylation before and after alkylation. Choline ester of LA was synthesized and characterized by mass spectrometry and HPLC. Eight-month-old C57BL/6J mice were treated with 2.5 MUL of a formulation of 5% LACE three times per day at 8-hour intervals in the right eye (OD) for 5 weeks. After the final treatment, lenses were removed and placed in a cuvette containing buffer. Elasticity was determined with a computer-controlled instrument that provided Z-stage upward movements in 1-MUm increments with concomitant force measurements with a Harvard Apparatus F10 isometric force transducer. The elasticity of lenses from 8-week-old C57BL/6J mice was determined for comparison. RESULTS: Lipoic acid treatment led to a concentration-dependent decrease in lens protein disulfides concurrent with an increase in lens elasticity. The structure and purity of newly synthesized LACE was confirmed. Aqueous humor concentrations of LA were higher in eyes of mice following topical ocular treatment with LACE than in mice following topical ocular treatment with LA. The lenses of the treated eyes of the old mice were more elastic than the lenses of untreated eyes (i.e., the relative force required for similar Z displacements was higher in the lenses of untreated eyes). In most instances, the lenses of the treated eyes were even more elastic than the lenses of the 8-week old mice. CONCLUSIONS: As the elasticity of the human lens decreases with age, humans lose the ability to accommodate. The results, briefly described in this abstract, suggest a topical ocular treatment to increase lens elasticity through reduction of disulfides to restore accommodative amplitude. PMID- 27233036 TI - RACking Up Retinal Oxidative Stress. PMID- 27233035 TI - NADPH Oxidase Contributes to Photoreceptor Degeneration in Constitutively Active RAC1 Mice. AB - PURPOSE: The active form of small GTPase RAC1 is required for activation of NADPH oxidase (NOX), which in turn generates reactive oxygen species (ROS) in nonphagocytic cells. We explored whether NOX-induced oxidative stress contributes to rod degeneration in retinas expressing constitutively active (CA) RAC1. METHODS: Transgenic (Tg)-CA-RAC1 mice were given apocynin (10 mg/kg, intraperitoneal), a NOX inhibitor, or vehicle daily for up to 13 weeks. Superoxide production and oxidative damage were assessed by dihydroethidium staining and by protein carbonyls and malondialdehyde levels, respectively. Outer nuclear layer (ONL) cells were counted and electroretinogram (ERG) amplitudes measured in Tg-CA-RAC1 mice. Outer nuclear layer cells were counted in wild-type (WT) mice after transfer of CA-Rac1 gene by subretinal injection of AAV8-pOpsin CA Rac1-GFP. RESULTS: Transgenic-CA-RAC1 retinas had significantly fewer photoreceptor cells and more apoptotic ONL cells than WT controls from postnatal week (Pw) 3 to Pw13. Superoxide accumulation and protein and lipid oxidation were increased in Tg-CA-RAC1 retinas and were reduced in mice treated with apocynin. Apocynin reduced the loss of photoreceptors and increased the rod ERG a- and b wave amplitudes when compared with vehicle-injected transgenic controls. Photoreceptor loss was also observed in regions of adult WT retina transduced with AAV8-pOpsin-CA Rac1-GFP but not in neighboring regions that were not transduced or in AAV8-pOpsin-GFP-transduced retinas. CONCLUSIONS: Constitutively active RAC1 promotes photoreceptor cell death by oxidative damage that occurs, at least partially, through NOX-induced ROS. Reactive oxygen species are likely involved in multiple forms of retinal degenerations, and our results support investigating RAC1 inhibition as a therapeutic approach that targets this disease pathway. PMID- 27233037 TI - Survival and Functionality of hESC-Derived Retinal Pigment Epithelium Cells Cultured as a Monolayer on Polymer Substrates Transplanted in RCS Rats. AB - PURPOSE: To determine the safety, survival, and functionality of human embryonic stem cell-derived RPE (hESC-RPE) cells seeded on a polymeric substrate (rCPCB RPE1 implant) and implanted into the subretinal (SR) space of Royal College of Surgeons (RCS) rats. METHODS: Monolayers of hESC-RPE cells cultured on parylene membrane were transplanted into the SR space of 4-week-old RCS rats. Group 1 (n = 46) received vitronectin-coated parylene membrane without cells (rMSPM+VN), group 2 (n = 59) received rCPCB-RPE1 implants, and group 3 (n = 13) served as the control group. Animals that are selected based on optical coherence tomography screening were subjected to visual function assays using optokinetic (OKN) testing and superior colliculus (SC) electrophysiology. At approximately 25 weeks of age (21 weeks after surgery), the eyes were examined histologically for cell survival, phagocytosis, and local toxicity. RESULTS: Eighty-seven percent of the rCPCB-RPE1-implanted animals showed hESC-RPE survivability. Significant numbers of outer nuclear layer cells were rescued in both group 1 (rMSPM+VN) and group 2 (rCPCB-RPE1) animals. A significantly higher ratio of rod photoreceptor cells to cone photoreceptor cells was found in the rCPCB-RPE1-implanted group. Animals with rCPCB-RPE1 implant showed hESC-RPE cells containing rhodopsin-positive particles in immunohistochemistry, suggesting phagocytic function. Superior colliculus mapping data demonstrated that a significantly higher number of SC sites responded to light stimulus at a lower luminance threshold level in the rCPCB-RPE1-implanted group. Optokinetic data suggested both implantation groups showed improved visual acuity. CONCLUSIONS: These results demonstrate the safety, survival, and functionality of the hESC-RPE monolayer transplantation in an RPE dysfunction rat model. PMID- 27233039 TI - Correction to A Noninvasive Method for Nanoscale Electrostatic Gating of Pristine Materials. PMID- 27233038 TI - The FBPase Encoding Gene glpX Is Required for Gluconeogenesis, Bacterial Proliferation and Division In Vivo of Mycobacterium marinum. AB - Lipids have been identified as important carbon sources for Mycobacterium tuberculosis (Mtb) to utilize in vivo. Thus gluconeogenesis bears a key role for Mtb to survive and replicate in host. A rate-limiting enzyme of gluconeogenesis, fructose 1, 6-bisphosphatase (FBPase) is encoded by the gene glpX. The functions of glpX were studied in M. marinum, a closely related species to Mtb. The glpX deletion strain (DeltaglpX) displayed altered gluconeogenesis, attenuated virulence, and altered bacterial proliferation. Metabolic profiles indicate an accumulation of the FBPase substrate, fructose 1, 6-bisphosphate (FBP) and altered gluconeogenic flux when DeltaglpX is cultivated in a gluconeogenic carbon substrate, acetate. In both macrophages and zebrafish, the proliferation of DeltaglpX was halted, resulting in dramatically attenuated virulence. Intracellular DeltaglpX exhibited an elongated morphology, which was also observed when DeltaglpX was grown in a gluconeogenic carbon source. This elongated morphology is also supported by the observation of unseparated multi nucleoid cell, indicating that a complete mycobacterial division in vivo is correlated with intact gluconeogenesis. Together, our results indicate that glpX has essential functions in gluconeogenesis, and plays an indispensable role in bacterial proliferation in vivo and virulence of M. marinum. PMID- 27233040 TI - Clinical factors associated with inappropriate prophylaxis of venous thromboembolic disease in critically ill patients. A single day cross-sectional study. AB - PURPOSE: A poor implementation of VTE prophylactic measures recommended for critically ill patients has been observed in several epidemiological studies. The clinical factors associated with this have not been clearly established. The objective of our study was to identify which factors could be related to the inappropriate use of VTE prophylaxis. METHODS: Analytic epidemiological study based on different aspects of VTE prophylaxis performed on Spanish ICU patients. A multiple logistic regression analysis was conducted to identify the risk factors associated with inappropriate prophylaxis, according to the American College of Chest Physicians 2012 guidelines. RESULTS: We enrolled 777 patients. On admission, 62% presented medical, 30% surgical and 8% major trauma pathology. Of all patients, 41% were receiving an inappropriate prophylaxis, including 19% which did not receive any prophylaxis. The presence of a contraindication for pharmacological prophylaxis (OR 3.91, 95% CI 2.50-6.10) and non-medical pathology at ICU admission (OR 11.09; 95% CI 7.63-16.12) were associated with inappropriate prophylaxis. In contrast, mechanical ventilation (OR 0.70, 95% CI 0.45-0.98), bed rest>48h (OR 0.61, 95% CI 0.49-0.98), the use of a protocol for VTE prophylaxis (OR 0.66, 95% CI 0.45-0.98) and a VTE risk scoring system (OR 0.49, 95% CI 0.24 0.98) were associated with adequate prophylaxis. CONCLUSIONS: Our study highlighted a poor compliance with the VTE prophylaxis recommendations proposed for critical patients. The implementation of specific protocols for prophylaxis that include a correct evaluation according to VTE and haemorrhage risk, would allow for optimisation of mechanical and combined prophylaxis, improving adherence to the clinical practice guidelines. PMID- 27233041 TI - The Effectiveness of an Educational Game for Teaching Optometry Students Basic and Applied Science. AB - PURPOSE: To compare the effectiveness of an educational board game with interactive didactic instruction for teaching optometry students elements of the core optometric curriculum. METHODS: Forty-two optometry students were divided into two GPA-matched groups and assigned to either 12 hours of game play (game group) or 12 hours of interactive didactic instruction (lecture group). The same material from the core optometric curriculum was delivered to both groups. Game play was accomplished via an original board game. Written examinations assessed change in knowledge level. A post-intervention opinion survey assessed student attitudes. RESULTS: There was no significant difference in pre- or post intervention test scores between the lecture and game groups (Pre-test: p = 0.9; Post-test: p = 0.5). Post-intervention test scores increased significantly from baseline (Game group: 29.3% gain, Didactic group: 31.5% gain; p<0.001 for each). The score increase difference between groups was not statistically significant (p = 0.6). The post-intervention attitude survey did not reveal any significant between group differences (p = 0.5). CONCLUSIONS: Our results indicate that an educational game and interactive didactic instruction can be equally effective in teaching optometry students basic and applied science. Furthermore, both modes of instruction have the potential to be equally engaging and enjoyable experiences. PMID- 27233042 TI - Correction: Reassimilation of Photorespiratory Ammonium in Lotus japonicus Plants Deficient in Plastidic Glutamine Synthetase. AB - [This corrects the article DOI: 10.1371/journal.pone.0130438.]. PMID- 27233043 TI - Vermicomposting transforms allelopathic parthenium into a benign organic fertilizer. AB - Vermicompost, which had been derived solely by the action of the epigeic earthworm Eisenia fetida on parthenium (Parthenium hysterophorus), was tested for its impact on the germination and early growth of green gram (Vigna radiata), ladies finger (Abelmoschus esculentus) and cucumber (Cucumis sativus). Seedlings were germinated and grown in soil amended with 0 (control), 0.75, 1.5, 2, 4, 8, 20 and 40% (by weight) parthenium vermicompost. Even though parthenium is known to possess strong negative allelopathy, as also plant/animal toxicity in other forms, its vermicompost (VC) manifested none of these attributes. Rather the VC enhanced germination success, introduced plant-friendly physical features in the container media, increased biomass carbon, and was seen to promote early growth as reflected in several morphological and biochemical characteristics in plants which had received parthenium VC in comparison to those which had not. All these effects were statistically significant. Fourier Transform Infrared (FTIR) Spectrometry revealed that the phenols and the sesquiterpene lactones that are responsible for the negative allelopathic impact of parthenium were largely destroyed in the course of vermicomposting. FTIR spectra also indicated that lignin content of parthenium was reduced during its vermicomposting. The findings open up the possibility that several other invasives known for their negative allelopathy and toxicity may also produce vermicompost which may be plant friendly and soil-friendly. It also makes it appear possible that the huge quantities of phytomass that is generated annually by parthenium can be gainfully utilized in producing organic fertilizer via vermicomposting, thereby providing a means of exercising some control over parthenium's rampant growth and invasion. PMID- 27233044 TI - Reduction of CO2 diffuse emissions from the traditional ceramic industry by the addition of Si-Al raw material. AB - The fabrication of ceramics can produce the emission of several gases, denominated exhaust gases, and also vapours resulting from firing processes, which usually contain metals and toxic substances affecting the environment and the health of workers. Especially harmful are the diffuse emissions of CO2, fluorine, chlorine and sulphur from the ceramics industry, which, in highly industrialized areas, can suppose an important emission focus of dangerous effects. Concerning CO2, factories that use carbonate-rich raw materials (>30% carbonates) can emit high concentrations of CO2 to the atmosphere. Thus, carbonate reduction or substitution with other raw materials would reduce the emissions. In this contribution, we propose the addition of Al-shales to the carbonated ceramic materials (marls) for CO2 emission reduction, also improving the quality of the products. The employed shales are inexpensive materials of large reserves in SW-Spain. The ceramic bodies prepared with the addition of selected Al-shale to marls in variable proportions resulted in a 40%-65% CO2 emission reduction. In addition, this research underlines at the same time that the use of a low-price raw material can also contribute to obtaining products with higher added value. PMID- 27233045 TI - The effect of soil type on the bioremediation of petroleum contaminated soils. AB - In this research the bioremediation of four different types of contaminated soils was monitored as a function of time and moisture content. The soils were categorized as sandy soil containing 100% sand (type I), clay soil containing more than 95% clay (type II), coarse grained soil containing 68% gravel and 32% sand (type III), and coarse grained with high clay content containing 40% gravel, 20% sand, and 40% clay (type IV). The initially clean soils were contaminated with gasoil to the concentration of 100 g/kg, and left on the floor for the evaporation of light hydrocarbons. A full factorial experimental design with soil type (four levels), and moisture content (10 and 20%) as the factors was employed. The soils were inoculated with petroleum degrading microorganisms. Soil samples were taken on days 90, 180, and 270, and the residual total petroleum hydrocarbon (TPH) was extracted using soxhlet apparatus. The moisture content of the soils was kept almost constant during the process by intermittent addition of water. The results showed that the efficiency of bioremediation was affected significantly by the soil type (Pvalue < 0.05). The removal percentage was the highest (70%) for the sandy soil with the initial TPH content of 69.62 g/kg, and the lowest for the clay soil (23.5%) with the initial TPH content of 69.70 g/kg. The effect of moisture content on bioremediation was not statistically significant for the investigated levels. The removal percentage in the clay soil was improved to 57% (within a month) in a separate experiment by more frequent mixing of the soil, indicating low availability of oxygen as a reason for low degradation of hydrocarbons in the clay soil. PMID- 27233046 TI - Commitment to and preparedness for sustainable supply chain management in the oil and gas industry. AB - Our current dependency on the oil and gas (O&G) industry for economic development and social activities necessitates research into the sustainability of the industry's supply chains. At present, studies on sustainable supply chain management (SSCM) practices in the industry do not include firm-internal factors that affect the sustainability strategies employed by different functional areas of its supply chains. Our study aims to address this gap by identifying the relevant internal factors and exploring their relationship with SSCM strategies. Specifically, we discuss the commitment to and preparedness for sustainable practices of companies that operate in upstream and downstream O&G supply chain. We study the impact of these factors on their sustainability strategies of four key supply chain functions: supplier management, production management, product stewardship and logistics management. The analyses of data collected through a survey among 81 companies show that management preparedness may enhance sustainable supply chain strategies in the O&G industry more than commitment does. Among the preparedness measures, management of supply chain operational risks is found to be vital to the sustainability of all supply chain functions except for production management practices. The findings also highlight the central importance of supplier and logistics management to the achievement of sustainable O&G supply chains. Companies must also develop an organizational culture that encourages, for example, team collaboration and proactive behaviour to finding innovative sustainability solutions in order to translate commitment to sustainable practices into actions that can produce actual difference to their SSCM practices. PMID- 27233047 TI - A procedure of landscape services assessment based on mosaics of patches and boundaries. AB - We develop a procedure for assessing the environmental value of landscape mosaics that simultaneously considers the values of land use patches and the values of the boundaries between them. These boundaries indicate the ecological interactions between the patches. A landscape mosaic is defined as a set of patches and the boundaries between them and corresponds to a spatial pattern of ecological interactions. The procedure is performed in two steps: (i) an environmental assessment of land use patches by means of a function that integrates values based on the goods and services the patches provide, and (ii) an environmental valuation of mosaics using a function that integrates the environmental values of their patches and the types and frequencies of the boundaries between them. This procedure allows us to measure how changes in land uses or in their spatial arrangement cause variations in the environmental value of landscape mosaics and therefore in that of the whole landscape. The procedure was tested in the Sierra Norte of Madrid (central Spain). The results show that the environmental values of the landscape depend not only on the land use patches but also on the values associated with the pattern of the boundaries within the mosaics. The results also highlight the importance of the boundaries between land use patches as determinants of the goods and services provided by the landscape. PMID- 27233048 TI - Biological removal of pharmaceutical compounds using white-rot fungi with concomitant FAME production of the residual biomass. AB - The efficiency of two white-rot fungi (WRF), Trametes versicolor and Ganoderma lucidum, to eliminate thirteen pharmaceutical pollutants with concomitant biodiesel production from the accumulating lipid content after treatment, was examined. The removal efficiency was studied using both individual and combined strains. The results of individual and combined strains showed a total removal (100%) of diclofenac (DCF), gemfibrozil (GFZ), ibuprofen (IBP), progesterone (PGT) and ranitidine (RNT). Lower removals were achieved for 4-acetamidoantipyrin (AAA), clofibric acid (ACF), atenolol (ATN), caffeine (CFN), carbamazepine (CZP), hydrochlorothiazide (HCT), sulfamethoxazole (SMX) and sulpiride (SPD), although the combination of both strains enhanced the system's efficiency, with removals ranging from 15 to 41%. This increase of the removal efficiency when combining both strains was attributed to the interactions developed between them (i.e., competition). Results from enzymatic and cytochrome P450 examination suggested that both extracellular (laccase, MnP, LiP) and intracellular oxidation mechanisms participate in the biological removal of pharmaceuticals. On the other hand, the "green" potential of the fungal sludge generated during the biological removal process was assessed for biodiesel production by means of one-step direct (in-situ) transformation. This process consists of the simultaneous extraction and conversion of lipids contained in the sludge by catalytic esterification/transesterification using a robust acid heterogeneous Zr-SBA-15 catalyst. This catalytic system provided conversions close to 80% of the saponifiable fraction (including free fatty acids and glycerides) in the presence of high amount of impurities. The overall weight FAME yield, based on the initial dried mass, was close to 30% for both strains. PMID- 27233050 TI - The Paris System for Reporting Urinary Cytology: The Quest to Develop a Standardized Terminology. AB - The main purpose of urine cytology is to detect high-grade urothelial carcinoma. With this principle in mind, The Paris System (TPS) Working Group, composed of cytopathologists, surgical pathologists, and urologists, has proposed and published a standardized reporting system that includes specific diagnostic categories and cytomorphologic criteria for the reliable diagnosis of high-grade urothelial carcinoma. This paper outlines the essential elements of TPS and the process that led to the formation and rationale of the reporting system. TPS Working Group, organized at the 2013 International Congress of Cytology, conceived a standardized platform on which to base cytologic interpretation of urine samples. The widespread dissemination of this approach to cytologic examination and reporting of urologic samples and the scheme's universal acceptance by pathologists and urologists is critical for its success. For urologists, understanding the diagnostic criteria, their clinical implications, and limitations of TPS is essential if they are to utilize urine cytology and noninvasive ancillary tests in a thoughtful and practical manner. This is the first international/inclusive attempt at standardizing urinary cytology. The success of TPS will depend on the pathology and urology communities working collectively to improve this seminal paradigm shift, and optimize the impact on patient care. PMID- 27233049 TI - Heavy metal contamination along the China coastline: A comprehensive study using Artificial Mussels and native mussels. AB - A comprehensive study was carried out to assess metal contamination in five cities spanning from temperate to tropical environment along the coastal line of China with different hydrographical conditions. At each of the five cities, Artificial Mussels (AM) were deployed together with a native species of mussel at a control site and a polluted site. High levels of Cr, Cu and Hg were found in Qingdao, high level of Cd, Hg and Pb was found in Shanghai, and high level of Zn was found in Dalian. Furthermore, level of Cu contamination in all the five cities was consistently much higher than those reported in similar studies in other countries (e.g., Australia, Portugal, Scotland, Iceland, Korea, South Africa and Bangladesh). Levels of individual metal species in the AM showed a highly significant correlation with that in the native mussels (except for Zn in Mytilus edulis and Cd in Perna viridis), while no significant difference can be found between the regression relationships of metal in the AM and each of the two native mussel species. The results demonstrated that AM can provide a reliable time-integrated estimate of metal concentration in contrasting environments over large biogeographic areas and different hydrographic conditions, and overcome the shortcomings of monitoring metals in water, sediment and the use of biomonitors. PMID- 27233052 TI - The Effect of Nurse-Physician Collaboration on Job Satisfaction, Team Commitment, and Turnover Intention in Nurses. AB - Voluntary turnover in nursing can lead to nursing shortages that affect both individuals and the entire hospital unit. We investigated the relationship between group- and individual-level variables by examining the association of nurses' job satisfaction and team commitment at the individual level, and nurse physician collaboration at the group level, with individuals' intention to leave the unit at the individual level. A self-report questionnaire was administered to 1,024 nurses on 72 units in 3 Italian hospitals. At the individual level, affective commitment partially mediated the relationship between job satisfaction and nursing turnover intention. Moreover, a cross-level interaction was found. Nurses with high levels of job satisfaction showed high levels of identification with their team, and this relationship was stronger when the group perception of nurse-physician collaboration was high. Results suggested that managerial strategies to promote nurse-physician collaboration may be important to increase nurses' affective commitment to the team. At the individual level, job satisfaction and team affective commitment are important factors for retaining staff, and at the group level, good work collaboration with physicians is instrumental in developing nurses' affective identification with the team. (c) 2016 Wiley Periodicals, Inc. PMID- 27233053 TI - Designed construction and validation of carbon-free porous MnO spheres with hybrid architecture as anodes for lithium-ion batteries. AB - Porous micro/nanostructures of earth abundant and ecobenign metals are emerging as advanced green materials for use in electrochemical energy storage devices. We present here the custom designed construction of a hybrid architecture containing porous MnO microspheres, formed out of hierarchically assembled nanoparticles using a template-free co-precipitation method, wherein the sacrificial template growth of porous spheres has been obtained by a solution mediated and time dependent oxidation strategy. The nanoporous channels in the MnO microspheres and the nanosized primary particles of MnO anodes in synergy increase the electrolyte percolation, resulting in a discharge capacity of 1200 mA h g(-1) at a current density of 50 mA g(-1) and a capacity as high as 450 mA h g(-1) under the 1000 mA g(-1) condition. The study assumes importance based on the fact that engineering of electrode materials is typically challenging, wherein design, preparation and fabrication of tailor-made electrodes with a desirable micro/nanocrystalline assembly play a critical role, especially when recommended for high capacity and high-rate applications in electrochemical energy storage devices. Further, this communication elaborates the designed construction and validation of porous MnO microspheres engineered through a time dependent process protocol as economically viable and environmentally benign anodes for lithium-ion batteries. PMID- 27233051 TI - Keap1-Independent Regulation of Nrf2 Activity by Protein Acetylation and a BET Bromodomain Protein. AB - Mammalian BET proteins comprise a family of bromodomain-containing epigenetic regulators with complex functions in chromatin organization and gene regulation. We identified the sole member of the BET protein family in Drosophila, Fs(1)h, as an inhibitor of the stress responsive transcription factor CncC, the fly ortholog of Nrf2. Fs(1)h physically interacts with CncC in a manner that requires the function of its bromodomains and the acetylation of CncC. Treatment of cultured Drosophila cells or adult flies with fs(1)h RNAi or with the BET protein inhibitor JQ1 de-represses CncC transcriptional activity and engages protective gene expression programs. The mechanism by which Fs(1)h inhibits CncC function is distinct from the canonical mechanism that stimulates Nrf2 function by abrogating Keap1-dependent proteasomal degradation. Consistent with the independent modes of CncC regulation by Keap1 and Fs(1)h, combinations of drugs that can specifically target these pathways cause a strong synergistic and specific activation of protective CncC- dependent gene expression and boosts oxidative stress resistance. This synergism might be exploitable for the design of combinatorial therapies to target diseases associated with oxidative stress or inflammation. PMID- 27233055 TI - WITHDRAWN: Anticonvulsant drugs for migraine prophylaxis. PMID- 27233054 TI - Interest in initiating an early phase clinical trial: results of a longitudinal study of advanced cancer patients. AB - OBJECTIVE: Enhanced recruitment of patients with advanced cancer (ACP) to early phase (EP) trials is needed. However, selective recruitment may affect the kinds of patients who are recruited. To address whether ACP who initiate EP trial enrollment differ from those who do not, we prospectively surveyed ACP well in advance of potential trial recruitment and followed them over time to identify those who initiated the recruitment process. METHODS: EP trial initiation was defined as a patient being referred for screening to an active EP trial. Depression and anxiety were assessed with the Patient Health Questionnaire (PHQ 9) and Generalized Anxiety Disorder Scale (GAD-7), respectively. Demographic and disease characteristics, functional status, and patient preferences regarding decision making were examined as possible predictors of EP trial initiation. RESULTS: Of the 78 advanced cancer patients in the cohort studied, 21 (27%) initiated EP trial participation, while 57 (73%) did not. Of those who initiated this process, 14 (67%) went on to enroll in an EP study. Level of depression severity was associated with EP trial initiation, with rates of initiation nearly three times higher (35% vs. 12%, p = 0.054) among patients with minimal to mild levels of depression compared to those with moderate or higher levels of depression. EP trial initiation was not associated with demographic or socioeconomic variables, cancer type, functional status, quality of life, or decision-making variables. CONCLUSIONS: The presence of elevated depressive symptoms may be associated with the EP trial recruitment and enrollment processes. This possible relationship warrants further study. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27233056 TI - A Pilot Study of a Peer-Group Lifestyle Intervention Enhanced With mHealth Technology and Social Media for Adults With Serious Mental Illness. AB - This pilot study examined the preliminary effectiveness of a peer-group lifestyle intervention enhanced with mobile health technology and social media for obese individuals with serious mental illness. Thirty-two participants with a body mass index of 30 or higher received a 24-week intervention designed to facilitate peer support for lifestyle change through experiential learning and use of wearable activity tracking devices, smartphone applications, and Facebook to reinforce physical activity, healthy eating, and group participation between sessions. The primary outcome was weight loss. Secondary measures included fitness and participants' perceptions of peer-group support. Most participants (72%) lost weight, including 28% achieving clinically significant weight loss, and 17% of participants showed clinically significant improvements in cardiovascular fitness. Weight loss was associated with perceived peer-group support. This evaluation demonstrated the preliminary effectiveness of a potentially scalable peer-group lifestyle intervention delivered in community mental health settings for obese individuals with serious mental illness. PMID- 27233057 TI - Parental decision making in pediatric otoplasty: The role of shared decision making in parental decisional conflict and decisional regret. AB - OBJECTIVES/HYPOTHESIS: To date, there has been little research on shared decision making and decisional outcomes in pediatric surgery. The objectives of this study were to describe the level of decisional conflict and decisional regret experienced by parents considering otoplasty for their children, and to determine if they are related to perceptions of shared decision making. STUDY DESIGN: Prospective cohort clinical study. METHODS: Sixty-five consecutive parents of children who underwent surgical consultation for otoplasty were prospectively enrolled. Participants completed the Demographic Form, the Decisional Conflict Scale, and the Shared Decision-Making Questionnaire after the consultation visit. The consulting surgeons completed the physician version of the Shared Decision Making Questionnaire. Six months after surgery, parents completed the Decisional Regret Scale. RESULTS: The median decisional conflict was 15.63; 21 (32.8%) parents scored 25 or above, a previously defined cutoff indicating clinically significant decisional conflict. Parent ratings of shared decision making and decisional conflict were significantly negatively correlated (P < 0.001); however, there was no significant correlation between physician ratings of shared decision making and parental decisional conflict. Significant decisional regret was reported in two (3.2%) participants. Decisional regret and parent and physician ratings of shared decision making were both significantly negatively correlated (P = 0.044 and P = 0.001, respectively). Decisional regret and decisional conflict scores were significantly positively correlated (P = 0.001). Parent and physician ratings of shared decision making were correlated (intraclass correlation = 0.625, P < 0.001). CONCLUSION: Many parents experienced significant decisional conflict when making decisions about their child's elective surgical treatment. Fewer parents experienced significant decisional regret after the procedure. Parents who perceived themselves as being more involved in the decision making process reported less decisional conflict and decisional regret. Parents and physicians had varied perceptions of the degree of shared decision making. Future research should develop interventions to increase parents' involvement in decision making and explore the influence of significant decisional conflict and decisional regret on health outcomes. LEVEL OF EVIDENCE: 2b. Laryngoscope, 126:S5-S13, 2016. PMID- 27233068 TI - Editor Introduction. PMID- 27233067 TI - Novel compound heterozygous mutations in inositol polyphosphate phosphatase-like 1 in a family with severe opsismodysplasia. AB - This study aimed to identify the genetic basis of a severe skeletal lethal dysplasia. The main clinical features of two affected fetuses included short limbs with flared metaphyses, bowed radii, femora and tibiae, irregular ossification of hands and feet, and marked platyspondyly. Affected and nonaffected family members were subjected to whole-exome sequencing, followed by immunoblot analysis on amniocytes isolated from one of the affected individuals. Unique compound heterozygous variants in the inositol polyphosphate phosphatase like 1 (INPPL1) gene encoding the SHIP2 protein were identified in both affected individuals. One variant was inherited from each unaffected parent. Both allelic variants, c.(2327-1G>C);(1150_1151delGA), are predicted to result in premature stop codons leading to nonsense-mediated mRNA decay of the mutant alleles and no production of SHIP2. The absence of SHIP2 was confirmed by immunoblot analysis of proband amniocytes. This skeletal disorder is caused by the complete absence of the SHIP2 protein. INPPL1 mutations have been reported in opsismodysplasia, an autosomal recessive skeletal dysplasias with significant delayed bone formation. Our finding highlights the critical role that INPPL1/SHIP2 plays in skeletal development. PMID- 27233069 TI - Elastography Assessment of Liver Fibrosis: Society of Radiologists in Ultrasound Consensus Conference Statement. PMID- 27233070 TI - Contrast-Enhanced Ultrasound: Practical Review for the Assessment of Hepatic and Renal Lesions. AB - The use of microbubble contrast greatly enhances the ability of ultrasound to delineate structures and therefore aid in diagnosis. Ultrasound microbubble contrast agents are composed of low-solubility gas encapsulated in a biomaterial shell. These agents use the physics of ultrasound imaging to effectively identify and characterize focal hepatic and renal lesions. Not only can contrast agents be used to evaluate multiple phases of lesion contrast enhancement, but ultrasound also allows for real-time study of enhancement patterns. The short half-life and intravascular location of the microbubbles allows for multiple, sequential administrations of contrast to observe enhancement of lesions in different sites. Furthermore, the ability to perform imaging without ionizing radiation and the lack of nephrotoxicity make contrast-enhanced ultrasound an ideal evaluation method for patients who need serial surveillance or in whom imaging options are severely limited because of renal insufficiency. These techniques are widely used in many countries for diagnostic radiological purposes; however, the lack of both Food and Drug Administration approval and reimbursement for noncardiac hospital based imaging has delayed widespread use in the United States. Despite these limitations, continued research and innovations in ultrasound contrast make it essential to have a working knowledge of the typical enhancement patterns of frequently seen hepatic and renal lesions as these techniques offer an alternative option for contrast imaging. PMID- 27233071 TI - Recurrence Rates of Benign Phyllodes Tumors After Surgical Excision and Ultrasonography-Guided Vacuum-Assisted Excision. AB - The recurrence rates of benign phyllodes tumors diagnosed through surgery and ultrasound-guided vacuum-assisted excision (US-VAE) were evaluated. A total of 146 benign phyllodes tumors diagnosed by surgery (n = 126) or US-VAE (n = 20) in 144 patients who had further follow-up after surgery or US-VAE were included (median follow-up period, 32.3 months; range, 6.7-142.5 months). Comparisons of recurrence rate, interval to recurrence, patient age, initial tumor size, Breast Imaging Reporting and Data System category, or follow-up interval were performed between the surgery and VAE groups and between groups with and without recurrence. Three cases (2.1%, 3/146) had recurrence and all were in the surgery group (2.4%, 3/126). The surgery group demonstrated larger size than the VAE group (median, 25 vs 16 mm; P < 0.001). The median age of women in the surgery group was older than those in the VAE group (39 vs 33 years, P = 0.509). The median age of women with recurrence (n = 3) was older than those without recurrence (n = 143, 49 vs 38 years, P = 0.023). In conclusion, when benign phyllodes tumor is unexpectedly diagnosed at US-VAE, if there is no residual lesion at US, clinical follow-up rather than further surgery might be recommended. PMID- 27233072 TI - Pitfalls of Sonographic Imaging of Uterine Leiomyoma. AB - Leiomyomas are the most common uterine tumor and the most common cause of uterine enlargement in the nonpregnant patient. Sonography is the imaging modality of choice for the initial diagnosis and imaging workup of uterine leiomyomas and is also extremely helpful in determining the etiology of a broad range of pelvic symptoms in the female patient. Although the classic sonographic appearance of uterine leiomyomas is well established and easily recognizable, other pelvic masses may occasionally be confused with uterine leiomyomas, and the ability to distinguish between these entities is crucial in optimizing appropriate patient care. This article will review pelvic abnormalities that can be confused on ultrasound with uterine leiomyomas and potential methods that can be used to avoid these pitfalls. PMID- 27233073 TI - Ultrasound of Extensor Carpi Ulnaris Tendon Subluxation in a Tennis Player. AB - Wrist pain is common among competitive tennis players. Subluxation of the extensor carpi ulnaris (ECU) tendon has gained recognition as a cause of ulnar side wrist pain in athletes. In tennis, the wrist is forcibly flexed, supinated, and ulnar deviated. These repetitive motions stress the ECU tendon stabilizers allowing tendon subluxation from the ulnar groove, especially in cases of anatomic variations such as a shallow groove. We present the presurgical and postsurgical imaging findings of recurrent ECU tendon subluxation in an elite tennis player. PMID- 27233074 TI - Targeting Notch-1 positive acute leukemia cells by novel fucose-bound liposomes carrying daunorubicin. AB - Complete remission by induction therapy in acute myelogenous leukemia (AML) can be achieved due to improvements in supportive and optimized therapy. However, more than 20% of patients will still need to undergo salvage therapy, and most will have a poor prognosis. Determining the specificity of drugs to leukemia cells is important since this will maximize the dose of chemotherapeutic agents that can be administered to AML patients. In turn, this would be expected to lead to reduced drug toxicity and its increased efficacy. We targeted Notch-1 positive AML cells utilizing fucose-bound liposomes, since activation of Notch-1 is required for O-fucosylation. Herein, we report that intravenously injected, L fucose-bound liposomes containing daunorubicin can be successfully delivered to AML cells that express fucosylated antigens. This resulted in efficient tumor growth inhibition in tumor-bearing mice and decreased proliferation of AML patient-derived leukemia cells. Thus, biological targeting by fucose-bound liposomes that takes advantage of the intrinsic characteristics of AML cells could be a promising new strategy for Notch-1 positive-AML treatment. PMID- 27233075 TI - BKCa promotes growth and metastasis of prostate cancer through facilitating the coupling between alphavbeta3 integrin and FAK. AB - BKCa is a large conductance calcium activated potassium channel promoting prostate cancer cell proliferation, although the mechanism is not fully elucidated. In addition, whether BKCa is involved in metastasis of prostate cancer remains to be explored. Here, we report that BKCa is overexpressed in prostate cancer. BKCa expression positively correlates with Ki67 index and gleason score of prostate cancer. Upregulation of BKCa promoted proliferation, migration and invasion of prostate cancer cells. On the contrary, downregulation of BKCa inhibited growth and metastasis of prostate cancer cells both in vitro and in vivo. Moreover, the ion-conducting function of BKCa contributed moderately to prostate cancer proliferation and migration, although, this was not the primary mechanism. BKCa action was mainly mediated through forming a functional complex with alphavbeta3 integrin. The BKCa/alphavbeta3 integrin complex promoted FAK phosphorylation independent of the channel activity. Overexpression of BKCa enhanced its association with alphavbeta3 integrin and FAK which increased FAK phosphorylation. Conversely, disrupting the complex by downregulation of BKCa reduced FAK phosphorylation. Finally, blocking of alphavbeta3 integrin or p-FAK activity using LM609 or Y15 markedly abrogated BKCa-enhanced cell proliferation and migration. Taken together, these results suggest that targeting BKCa/alphavbeta3/FAK may inaugurate innovative approaches to inhibit prostate cancer growth and metastasis. PMID- 27233076 TI - Selective antitumor activity of roscovitine in head and neck cancer. AB - Radiation and chemotherapy that are commonly used to treat human cancers damage cellular DNA. DNA damage appears to be more toxic to cancer cells than normal cells, most likely due to deregulated checkpoint activation and/or deficiency in DNA repair pathways that are characteristics of many tumors. However, unwanted side effects arise as a result of DNA damage to normal cells during the treatment.Here, we show that roscovitine, a cyclin-dependent kinase (CDK) inhibitor that inhibits CDK-1, CDK-2, CDK-5, CDK-7, and CDK-9 due to competitive binding to the ATP site on the kinases, causes significant DNA damage followed by p53-dependent cell death in human papilloma virus (HPV)-positive, but not in HPV negative, head and neck cancer cells. Since HPV positivity was a molecular marker for increased sensitivity of cells to roscovitine, we reasoned that systemic roscovitine administration would not be toxic to healthy HPV-negative tissue. Indeed, low roscovitine doses significantly inhibited the growth of HPV associated xenografted tumors in mice without causing any detectable side effects.Given that inhibition of CDKs has been shown to inhibit replication of several viruses, we suggest that roscovitine treatment may represent a selective and safe targeted therapeutic option against HPV-positive head and neck cancer. PMID- 27233077 TI - Evaluating L1CAM expression in human endometrial cancer using qRT-PCR. AB - BACKGROUND: Management of endometrial carcinoma (EC) still needs improvement of risk assessment. Recently, L1CAM immunohistochemical (IHC) evaluation showed a unique value to predict the outcome of early EC. However IHC results are often conflicting for lack of inter-laboratory standardisation. METHODS: Here, as a proof of concept and to increase reproducibility we assayed eighty-two EC and 26 normal endometrium samples for L1CAM expression (L1CAMEXP) via qRT-PCR. The IHC evaluation was performed in 50 cancer samples. Moreover, we aimed to substantiate the in-vitro findings of L1CAM regulation through its promoter methylation (L1CAMMET), miR-34a expression and miR-34a promoter methylation. DNA methylation was assessed with MethyLight PCR technique. RESULTS: High overall concordant results between IHC and RT-PCR evaluations were found. L1CAMEXP was detected in 11% of cancer specimens. These positive cancers exhibited a worse DFS (p=0.032) and OS (p=0.016) in a multivariate COX-regression model. L1CAMEXP predicted distant failure (p=0.007) and L1CAMMET predicted risk-reduction of lymph-node involvement (p=0.005). Inverse correlations between L1CAMEXP and L1CAMMET (p=0.004) and between L1CAMEXP and miR-34a expression (p=0.002) were found. CONCLUSIONS: In conclusion qRT-PCR analysis is a reliable approach to evaluate L1CAM status in EC and L1CAMEXP was highly predictive for distant failure and poor outcome, confirming the large IHC-based studies. Interestingly, L1CAMMET was able to assess the risk of pelvic lymph-node involvement. Especially the latter finding has to be confirmed in larger prospective series. PMID- 27233078 TI - The comprehensive summary of surgical versus non-surgical treatment for obesity: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Bariatric surgery has emerged as a competitive strategy for obese patients. However, its comparative efficacy against non-surgical treatments remains ill-defined, especially among nonseverely obese crowds. Therefore, we implemented a systematic review and meta-analysis in order for an academic addition to current literatures. METHODS: Literatures were retrieved from databases of PubMed, Web of Science, EMBASE and Cochrane Library. Randomized trials comparing surgical with non-surgical therapies for obesity were included. A Revised Jadad's Scale and Risk of Bias Summary were employed for methodological assessment. Subgroups analysis, sensitivity analysis and publication bias assessment were respectively performed in order to find out the source of heterogeneity, detect the outcome stability and potential publication bias. RESULTS: 25 randomized trials were eligibly included, totally comprising of 1194 participants. Both groups displayed well comparability concerning baseline parameters (P > 0.05). The pooled results of primary endpoints (weight loss and diabetic remission) revealed a significant advantage among surgical patients rather than those receiving non-surgical treatments (P < 0.05). Furthermore, except for certain cardiovascular indicators, bariatric surgery was superior to conventional arms in terms of metabolic secondary parameters (P < 0.05). Additionally, the pooled outcomes were confirmed to be stable by sensitivity analysis. Although Egger's test (P < 0.01) and Begg's test (P<0.05) had reported the presence of publication bias among included studies, "Trim-and-Fill" method verified that the pooled outcomes remained stable. CONCLUSIONS: Bariatric surgery is a better therapeutic option for weight loss, irrespective of follow-up duration, surgical techniques and obesity levels. PMID- 27233079 TI - Where does current and future pediatric asthma treatment stand? Remodeling and inflammation: Bird's eye view. AB - Airway remodeling is the chronic outcome of inflammation in asthma and a point of intervention between pediatric and adult ages. Pediatric asthma has been of great interest in the efforts to find a valuable time to interrupt remodeling. Various experimental and clinical research have assessed the effect of current therapeutic modalities on airway remodeling in asthma and many new agents are being developed with promising results. The heterogeneity in the results of these studies may lie in the heterogeneity of pathogenesis leading to asthma and remodeling; underlying the need for individualized treatment of the unique pathogenetic characteristics of each child's asthma. The aim of this review is to summarize the evidence about the influence of current and future therapeutic modalities in the concept of inflammation and remodeling in pediatric asthma. Pediatr Pulmonol. 2016;51:1422-1429. (c) 2016 Wiley Periodicals, Inc. PMID- 27233080 TI - The use of educational comics in learning anatomy among multiple student groups. AB - Understanding basic human anatomy can be beneficial for all students, regardless of when, or if, they will later undertake a formal course in the subject. For students who are preparing to undertake a formal anatomy course, educational comics on basic anatomy can serve as a concise and approachable review of the material. For other students, these comics can serve as a helpful and fun introduction to the human body. The objective of the comics in this study was to promote an understanding of fundamental human anatomy through self-learning among students. Based on the authors' previous teaching experience, these anatomy comics were produced in a simple, direct style. The comics were titled after the two main characters, "Anna" (a girl) and "Tommy" (a boy). These comics were then presented to groups of elementary school students, high school students, premedical students, and medical students to assess the comics' ability to enhance student interest and comprehension of basic anatomy. Quiz scores among high school students and premedical students were significantly higher among participants who read the educational comics, indicating a deeper comprehension of the subject. Among medical students, close reading of the comics was associated with improved course grades. These educational anatomy comics may be helpful tools to enrich a broad spectrum of different students in learning basic human anatomy. Anat Sci Educ 10: 79-86. (c) 2016 American Association of Anatomists. PMID- 27233082 TI - Bifidobacterial inulin-type fructan degradation capacity determines cross-feeding interactions between bifidobacteria and Faecalibacterium prausnitzii. AB - Prebiotic inulin-type fructans (ITF) display a bifidogenic and butyrogenic effect. Four bifidobacterial strains (Bifidobacterium breve Yakult, Bifidobacterium adolescentis LMG 10734, Bifidobacterium angulatum LMG 11039(T), and Bifidobacterium longum subsp. longum LMG 11047), displaying different ITF degradation capacities, were each grown in cocultivation with Faecalibacterium prausnitzii DSM 17677(T), an ITF-degrading butyrate-producing colon bacterium, as to unravel their cross-feeding interactions. These coculture fermentations were performed in a medium for colon bacteria, whether or not including acetate (necessary for the growth of F. prausnitzii DSM 17677(T) and whether or not provided through cross-feeding), supplemented with oligofructose or inulin as the sole energy source. Bifidobacterium breve Yakult did not degrade oligofructose, resulting in the production of high concentrations of butyrate by F. prausnitzii DSM 17677(T) through oligofructose degradation. The degradation of oligofructose by B. adolescentis LMG 10734 and of oligofructose and inulin by B. angulatum LMG 11039(T) and B. longum LMG 11047 resulted in the production of acetate, which was cross-fed to F. prausnitzii DSM 17677(T), enabling the latter strain to degrade oligofructose and inulin. Slow preferential degradation of the short chain length fractions of oligofructose (intracellularly) by B. adolescentis LMG 10734 enabled substantial oligofructose degradation by F. prausnitzii DSM 17677(T). However, fast non-preferential degradation of all chain length fractions of oligofructose (extracellularly) and efficient degradation of the short chain length fractions of inulin by B. angulatum LMG 11039(T) and B. longum LMG 11047 made it impossible for F. prausnitzii DSM 17677(T) to compete for the available substrate. These results indicate that cross-feeding interactions between bifidobacteria and acetate-depending, butyrate-producing colon bacteria can be either a pure commensal or beneficial relationship between these bacteria, or can be dominated by competition, depending on the ITF degradation capacities of the bifidobacterial strains involved. PMID- 27233081 TI - A short motif in Arabidopsis CDK inhibitor ICK1 decreases the protein level, probably through a ubiquitin-independent mechanism. AB - The ICK/KRP family of cyclin-dependent kinase (CDK) inhibitors modulates the activity of plant CDKs through protein binding. Previous work has shown that changing the levels of ICK/KRP proteins by overexpression or downregulation affects cell proliferation and plant growth, and also that the ubiquitin proteasome system is involved in degradation of ICK/KRPs. We show in this study that the region encompassing amino acids 21 to 40 is critical for ICK1 levels in both Arabidopsis and yeast. To determine how degradation of ICK1 is controlled, we analyzed the accumulation of hemagglutinin (HA) epitope-tagged ICK1 proteins in yeast mutants defective for two ubiquitin E3 ligases. The highest level of HA ICK1 protein was observed when both the N-terminal 1-40 sequence was removed and the SCF (SKP1-Cullin1-F-box complex) function disrupted, suggesting the involvement of both SCF-dependent and SCF-independent mechanisms in the degradation of ICK1 in yeast. A short motif consisting of residues 21-30 is sufficient to render green fluorescent protein (GFP) unstable in plants and had a similar effect in plants regardless of whether it was fused to the N-terminus or C-terminus of GFP. Furthermore, results from a yeast ubiquitin receptor mutant rpn10Delta indicate that protein ubiquitination is not critical in the degradation of GFP-ICK1(1-40) in yeast. These results thus identify a protein destabilizing sequence motif that does not contain a typical ubiquitination residue, suggesting that it probably functions through an SCF-independent mechanism. PMID- 27233084 TI - The utilization of spirocyclic scaffolds in novel drug discovery. PMID- 27233083 TI - Proline isomerisation as a novel regulatory mechanism for p38MAPK activation and functions. AB - The stress-induced p38 mitogen-activated protein kinase (MAPK) pathway plays an essential role in multiple physiological processes, including cancer. In turn, p38MAPK phosphorylation at Thr180 and Tyr182 is a key regulatory mechanism for its activation and functions. Here we show that this mechanism is actively regulated through isomerisation of Pro224. Different cyclophilins can isomerise this proline residue and modulate the ability of upstream kinases to phosphorylate Thr180 and Tyr182. In vivo mutation of Pro224 to Ile in endogenous p38MAPK significantly reduced its phosphorylation and activity. This resulted in attenuation of p38MAPK signalling, which in turn caused an enhanced apoptosis and sensitivity to a DNA-damaging drug, cisplatin. We further found a reduction in size and number of lesions in homozygous mice carrying the p38MAPK P224I substitution in a K-ras model of lung tumorigenesis. We propose that cyclophilin dependent isomerisation of p38MAPK is an important novel mechanism in regulating p38MAPK phosphorylation and functions. Thus, inhibition of this process, including with drugs that are in clinical trials, may improve the efficacy of current anti-cancer therapeutic regimes. PMID- 27233086 TI - The research on medical image classification algorithm based on PLSA-BOW model. AB - BACKGROUND: With the rapid development of modern medical imaging technology, medical image classification has become more important for medical diagnosis and treatment. OBJECTIVE: To solve the existence of polysemous words and synonyms problem, this study combines the word bag model with PLSA (Probabilistic Latent Semantic Analysis) and proposes the PLSA-BOW (Probabilistic Latent Semantic Analysis-Bag of Words) model. METHODS: In this paper we introduce the bag of words model in text field to image field, and build the model of visual bag of words model. RESULTS: The method enables the word bag model-based classification method to be further improved in accuracy. CONCLUSIONS: The experimental results show that the PLSA-BOW model for medical image classification can lead to a more accurate classification. PMID- 27233085 TI - Staging of Bilateral Lung Transplantation for High-Risk Patients With Interstitial Lung Disease: One Lung at a Time. AB - The choice of a single or bilateral lung transplant for interstitial lung disease (ILD) is controversial, as surgical risk, long-term survival and organ allocation are competing factors. In an effort to balance risk and benefit, our center adopted a staged bilateral lung transplant approach for higher surgical risk ILD patients where the patient has a single lung transplant followed by a second single transplant at a later date. We sought to understand the surgical risk, organ allocation and early outcomes of these staged bilateral recipients as a group and in comparison to matched single and bilateral recipients. Our analysis demonstrates that staged bilateral lung transplant recipients (n = 12) have a higher lung allocation score (LAS), lower pulmonary function tests and a lower glomerular filtration rate prior to the first transplant compared to the second (p < 0.01). There was a shorter length of hospital stay for the second transplant (p = 0.02). The staged bilateral compared to the single and bilateral case matched controls had comparable short-term survival (p = 0.20) and pulmonary function tests at 1 year. There was a higher incidence of renal injury in the conventional bilateral group compared to the single and staged bilateral groups. The staged bilateral procedure is a viable option in select ILD patients. PMID- 27233087 TI - Computational fluid dynamics analysis of tandem carotid artery stenoses: Investigation of neurological complications after carotid artery stenting. AB - BACKGROUND: Combined extra- and intracranial carotid artery stenoses, particularly involving multiple lesions, show complex hemodynamic properties and represent a therapeutic dilemma. We used computational fluid dynamics (CFD) to investigate whether insufficient cerebral blood flow (CBF) in a 70-year-old man with tandem stenoses was the cause of aphasia and right hemiparesis after carotid artery stenting (CAS) of the extracranial stenosis. METHOD: Three-dimensional digital subtraction angiography (3D-DSA) was performed before and after balloon angioplasty and CAS in the patient. The geometrical and rheological conditions of the carotid arteries were determined, and computational meshes were generated from the patient-specific 3D-DSA datasets. CFD analysis was performed, and hemodynamic parameters such as mass flow, pressure, fractional flow reserve, and streamlines were calculated. RESULTS: Post-CAS simulations showed that the percentage of internal carotid artery mass flow from common carotid artery mass flow increased from 9% to 14% and CBF improved by only 5%. CONCLUSIONS: CFD analysis suggested that the neurological complications were caused by insufficient CBF rather than embolic events, and in tandem carotid stenoses, CAS for an extracranial lesion alone may not always sufficiently increase CBF. CFD enabled the noninvasive quantitative estimation of the effects of CAS of each stenotic segment on carotid flow. PMID- 27233088 TI - Endoscopic low-temperature plasma radiofrequency ablation for laryngeal plexiform neurobromatosis-1 in an infant: Case report and review of the literature. AB - To evaluate the feasibility and effectiveness of using endoscopic low-temperature plasma radiofrequency ablation (RFA) for treatment of laryngeal plexiform neurofibromatosis-1 (NF-1). An infant diagnosed as laryngeal plexiform NF-1 based on a detailed medical history, as well as physical, laboratory, and pathological examinations, was treated under general anesthesia with low-temperature plasma RFA in combination with a self-retaining laryngoscope and high definition camera system.The laryngeal plexiform NF-1 tumor was successfully excised using endoscopic low-temperature plasma RFA without complications. Following surgery, the infant displayed an uneventful recovery and no disease recurrence during a 2 year follow-up period. low-temperature plasma RFA is a feasible and effective method for treating laryngeal plexiform NF-1, and has advantages of producing minimal bleeding, providing complete removal of the tumor, and causing only slight degrees of trauma and postoperative tissue reaction. PMID- 27233089 TI - Communication channel modeling of human forearm with muscle fiber tissue characteristics. AB - Human-Body Communication (HBC) is a wireless communication method using the human body tissue as a transmission medium for signals. This paper on the basis of human muscle fiber tissues' characteristics, it is first proposed to establish the analytical model of galvanic coupling human-body communication channel. In this model, the parallel and the transverse electrical characteristics of muscular tissue are fully considered, and the model accurately presents the transmission mechanism of galvanic coupling human-body communication signals in the channel. At last, through compare with the experimental results and calculation results, the maximum error of the model is 22.4% and the average error is 14.2% within the frequency range. PMID- 27233090 TI - Trial of real-time locating and messaging system with Bluetooth low energy. AB - BACKGROUND: Hospital real-time location systems (RTLS) are increasing efficiency and reducing operational costs, but room access tags are necessary. OBJECTVE: We developed three iPhone 5 applications for an RTLS and communications using Bluetooth low energy (BLE). METHODS: The applications were: Peripheral device tags, Central beacons, and a Monitor. A Peripheral communicated with a Central using BLE. The Central communicated with a Monitor using sockets on TCP/IP (Transmission Control Protocol/Internet Protocol) via a WLAN (wireless local area network). To determine a BLE threshold level for the received signal strength indicator (RSSI), relationships between signal strength and distance were measured in our laboratory and on the terrace. RESULTS: The BLE RSSI threshold was set at -70 dB, about 10 m. While an individual with a Peripheral moved around in a concrete building, the Peripheral was captured in a few 10-sec units at about 10 m from a Central. The Central and Monitor showed and saved the approach events, location, and Peripheral's nickname sequentially in real time. Remote Centrals also interactively communicate with Peripherals by intermediating through Monitors that found the nickname in the event database. CONCLUSIONS: Trial applications using BLE on iPhones worked well for patient tracking, and messaging in indoor environments. PMID- 27233091 TI - Remineralization of early enamel caries lesions using different bioactive elements containing toothpastes: An in vitro study. AB - BACKGROUND: Demineralization can be arrested or reversed when remineralization agents are applied to incipient carious or non-cavitated carious lesions. A large number of therapeutic agents including non-fluoridated products have been developed to promote enamel remineralization. OBJECTIVE: This study aims to evaluate the efficacy of different bioactive elements containing toothpastes in remineralization of artificial enamel lesions. METHODS: Artificial carious lesions were created on 40 human enamel slabs, and were randomly divided into four groups: (1) control group (no treatment), (2) casein phosphopeptide amorphous calcium phosphate group (CPP-ACP, GC Tooth Mousse), (3) 8% arginine and calcium carbonate group (ACC, Colgate Sensitive Pro-Relief), (4) calcium sodium phosphosilicate group (CSP, NovaMin(r)). All samples were subjected to 15 days of pH-cycling. Subsequently, a one-hour acid resistance test was carried out. Surface hardness of the samples was assessed using the Knoop hardness test, and surface morphology and roughness were assessed by scanning electron microscopy (SEM) and atomic force microscopy (AFM). Data were analyzed using one-way ANOVA, Tukey's test and paired t test. RESULTS: The three tested toothpastes exhibited a significantly higher remineralization efficacy compared with the control group (P< 0.05 for all). After pH-cycling, the specimens treated with Colgate Sensitive Pro-Relief and NovaMin(r) showed a significant higher surface hardness (P< 0.001 and P= 0.03, respectively) and lower surface roughness (P< 0.05 for both) compared those treated with GC Tooth Mousse. While after the acid resistance test, all groups showed a significant loss of surface hardness (P< 0.001 for all) and significant increase of surface roughness (P< 0.05). The specimens treated with Colgate Sensitive Pro-Relief and NovaMin(r) still showed a significant higher surface hardness and lower surface roughness in comparison with those treated with GC Tooth Mousse (P< 0.05 for all). No significant difference was found in surface hardness and roughness between Colgate Sensitive Pro-Relief and NovaMin(r) during the pH-cycling test and acid resistance test (P= 0.45 and P= 0.83, respectively). CONCLUSIONS: Colgate Sensitive Pro-Relief and NovaMin(r) present an advantage in enhancing remineralization and inhibiting demineralization for early enamel carious lesions in comparison with GC Tooth Mousse. PMID- 27233092 TI - NeuronCyto II: An automatic and quantitative solution for crossover neural cells in high throughput screening. AB - Microscopy is a fundamental technology driving new biological discoveries. Today microscopy allows a large number of images to be acquired using, for example, High Throughput Screening (HTS) and 4D imaging. It is essential to be able to interrogate these images and extract quantitative information in an automated fashion. In the context of neurobiology, it is important to automatically quantify the morphology of neurons in terms of neurite number, length, branching and complexity, etc. One major issue in quantification of neuronal morphology is the "crossover" problem where neurites cross and it is difficult to assign which neurite belongs to which cell body. In the present study, we provide a solution to the "crossover" problem, the software package NeuronCyto II. NeuronCyto II is an interactive and user-friendly software package for automatic neurite quantification. It has a well-designed graphical user interface (GUI) with only a few free parameters allowing users to optimize the software by themselves and extract relevant quantitative information routinely. Users are able to interact with the images and the numerical features through the Result Inspector. The processing of neurites without crossover was presented in our previous work. Our solution for the "crossover" problem is developed based on our recently published work with directed graph theory. Both methods are implemented in NeuronCyto II. The results show that our solution is able to significantly improve the reliability and accuracy of the neurons displaying "crossover." NeuronCyto II is freely available at the website: https://sites.google.com/site/neuroncyto/, which includes user support and where software upgrades will also be placed in the future. (c) 2016 The Authors. Cytometry Part A Published by Wiley Periodicals, Inc. on behalf of ISAC. PMID- 27233094 TI - Influence of fluid dynamic conditions on enzymatic hydrolysis of lignocellulosic biomass: Effect of mass transfer rate. AB - The effect of fluid dynamic conditions on enzymatic hydrolysis of acid pretreated corn stover (PCS) has been assessed. Runs were performed in stirred tanks at several stirrer speed values, under typical conditions of temperature (50 degrees C), pH (4.8) and solid charge (20% w/w). A complex mixture of cellulases, xylanases and mannanases was employed for PCS saccharification. At low stirring speeds (<150rpm), estimated mass transfer coefficients and rates, when compared to chemical hydrolysis rates, lead to results that clearly show low mass transfer rates, being this phenomenon the controlling step of the overall process rate. However, for stirrer speed from 300rpm upwards, the overall process rate is controlled by hydrolysis reactions. The ratio between mass transfer and overall chemical reaction rates changes with time depending on the conditions of each run. PMID- 27233093 TI - Comparative genomic, proteomic and exoproteomic analyses of three Pseudomonas strains reveals novel insights into the phosphorus scavenging capabilities of soil bacteria. AB - Bacteria that inhabit the rhizosphere of agricultural crops can have a beneficial effect on crop growth. One such mechanism is the microbial-driven solubilization and remineralization of complex forms of phosphorus (P). It is known that bacteria secrete various phosphatases in response to low P conditions. However, our understanding of their global proteomic response to P stress is limited. Here, exoproteomic analysis of Pseudomonas putida BIRD-1 (BIRD-1), Pseudomonas fluorescens SBW25 and Pseudomonas stutzeri DSM4166 was performed in unison with whole-cell proteomic analysis of BIRD-1 grown under phosphate (Pi) replete and Pi deplete conditions. Comparative exoproteomics revealed marked heterogeneity in the exoproteomes of each Pseudomonas strain in response to Pi depletion. In addition to well-characterized members of the PHO regulon such as alkaline phosphatases, several proteins, previously not associated with the response to Pi depletion, were also identified. These included putative nucleases, phosphotriesterases, putative phosphonate transporters and outer membrane proteins. Moreover, in BIRD-1, mutagenesis of the master regulator, phoBR, led us to confirm the addition of several novel PHO-dependent proteins. Our data expands knowledge of the Pseudomonas PHO regulon, including species that are frequently used as bioinoculants, opening up the potential for more efficient and complete use of soil complexed P. PMID- 27233095 TI - Determination of kinetic parameters for biomass combustion. AB - The aim of this work is to provide a wide database of kinetic data for the most common biomass by thermogravimetric analysis (TGA) and differential thermogravimetry (DTG). Due to the characteristic parameters of DTG curves, a two stage reaction model is proposed and the kinetic parameters obtained from model based methods with energy activation values for first and second stages in the range 1.75.10(4)-1.55.10(5)J/mol and 1.62.10(4)-2.37.10(5)J/mol, respectively. However, it has been found that Flynn-Wall-Ozawa and Kissinger-Akahira-Sunose model-free methods are not suitable to determine the kinetic parameters of biomass combustion since the assumptions of these two methods were not accomplished in the full range of the combustion process. PMID- 27233096 TI - Deconstruction of lignin linked p-coumarates, ferulates and xylan by NaOH enhances the enzymatic conversion of glucan. AB - Thermo-assisted NaOH pretreatment to deconstruct xylan and lignin in sugar cane bagasse (SCB) is poorly understood. Hence, in this research it is was aimed to study the effect of NaOH pretreatment on the insoluble remaining lignin structures. Hereto, SCB milled fibres were pretreated using different dosages of NaOH at different temperatures and residence times. Of untreated SCB about 63% of the lignin compounds were assigned as p-coumarates and ferulates, analysed by pyrolysis-GC/MS as 4-vinyl phenol and 4-vinyl guaiacol, and designated as non core lignin (NCL) compounds. More severe NaOH pretreatments resulted in lower xylan and lower lignin recoveries in the insoluble residues. Especially, the relative abundance of NCL decreased and this decrease followed a linear trend with the decrease in xylan. Core lignin compounds, analysed as phenol, guaiacol and syringol, accumulated in the residues. The decrease in residual xylan and NCL correlated positively with the enzymatic hydrolysis of the residual glucan. PMID- 27233097 TI - Novel pH control strategy for efficient production of optically active l-lactic acid from kitchen refuse using a mixed culture system. AB - Uninvestigated control factors of meta-fermentation, the fermentative production of pure chemicals and fuels in a mixed culture system, were examined for production of optically pure l-lactic acid (LA) from food waste. In meta fermentations by pH swing control, l-LA production with 100% optical purity (OPl LA) was achieved even using unsterilized model kitchen refuse medium with preferential proliferation of l-LA-producing Bacillus coagulans, a minor member in the seed, whereas agitation decreased OPl-LA drastically. pH constant control shortened the fermentation time but decreased OPl-LA and LA selectivity (SLA) by stimulating growth of heterofermentative Bacillus thermoamylovorans. Deliberately switching from pH swing control to constant control exhibited the best performance for l-LA production: maximum accumulation, 39.2gL(-1); OPl-LA, 100%; SLA, 96.6%; productivity, 1.09gL(-1)h(-1). These results present a novel pH control strategy for efficient l-LA production in meta-fermentation based on a concept different from that of pure culture systems. PMID- 27233098 TI - Comparison of liquid hot water and alkaline pretreatments of giant reed for improved enzymatic digestibility and biogas energy production. AB - Liquid hot water (LHW) and alkaline pretreatments of giant reed biomass were compared in terms of digestibility, methane production, and cost-benefit efficiency for electricity generation via anaerobic digestion with a combined heat and power system. Compared to LHW pretreatment, alkaline pretreatment retained more of the dry matter in giant reed biomass solids due to less severe conditions. Under their optimal conditions, LHW pretreatment (190 degrees C, 15min) and alkaline pretreatment (20g/L of NaOH, 24h) improved glucose yield from giant reed by more than 2-fold, while only the alkaline pretreatment significantly (p<0.05) increased cumulative methane yield (by 63%) over that of untreated biomass (217L/kgVS). LHW pretreatment obtained negative net electrical energy production due to high energy input. Alkaline pretreatment achieved 27% higher net electrical energy production than that of non-pretreatment (3859kJ/kg initial total solids), but alkaline liquor reuse is needed for improved net benefit. PMID- 27233099 TI - Ethanol, feed components and fungal biomass production from field bean (Vicia faba var. equina) seeds in an integrated process. AB - The use of field beans, a non-food leguminous crop, was studied for ethanol, feed components and fungal biomass production. The seeds were hydrolyzed using enzymes or with combination of acid (H3PO4) and alkaline (Ca(OH)2) pretreatment and enzymatic hydrolysis. Fermentation by Saccharomyces cerevisiae, with or without removal of suspended solids, yielded 38.3-42.5gL(-1) ethanol (71.3-79.2% efficiency). The filtration residues contained ca. 247-326gkg(-1) crude protein, 10.6-15.5% acid detergent fiber and 19.9-29.1% neutral detergent fiber. They were enriched in phenolics (by up to 93.4%) and depleted in condensed tannin (by up to 59.3%) in comparison to the raw material. The thin stillages were used for cultivation of edible fungus Neurospora intermedia which produced 8.5-15.9gL(-1) ethanol and 4.8-16.2gL(-1) biomass containing over 62% protein. The mass balances showed that fermentation of unfiltered mashes was more efficient yielding up to 195.9gkg(-1) ethanol and 84.4% of protein recovery. PMID- 27233100 TI - Acclimation strategy to increase phenol tolerance of an anaerobic microbiota. AB - A wide variety of inhibitory substances can induce anaerobic digester upset or failure. In this work the possibility to improve the resistance of an anaerobic microbiota to a common pollutant, the phenol, was evaluated in a lab-scale semi continuous bioreactor. An acclimation strategy, consisting in a regular step-wise adaptation of the microbiota to stressful condition was employed. Degradation performances were monitored and molecular tools (16S sequencing and ARISA fingerprinting technique) were used to track changes in the microbial community. The acclimation strategy progressively minimized the effect of phenol on degradation performances. After 3 successive disturbance episodes, microbiota resistance was considerably developed and total inhibition threshold increased from 895 to 1942mg/L of phenol. Microbiota adaptation was characterized by the selection of the most resistant Archaea OTU from Methanobacterium genus and an important elasticity of Bacteria, especially within Clostridiales and Bacteroidales orders, that probably enabled the adaptation to more and more stressful conditions. PMID- 27233101 TI - Earlier effect of alendronate in mouse metaphyseal versus diaphyseal bone healing. AB - Healing of injured cancellous bone is characterized by a transient stage of rapid bone formation throughout the traumatized bone volume, often followed by similarly rapid resorption. This is different from the slower diaphyseal healing via an external callus. We, therefore, hypothesized that antiresorptive treatment might have an earlier positive effect in cancellous bone healing than in diaphyseal fractures. One hundred and twenty-three male C57bl6 mice received either an internally stabilized diaphyseal osteotomy of the femur or a screw inserted into the tibial metaphysis. The mice were randomized to daily alendronate injections (200 MUg/kg/day), or control injections, and killed for mechanical testing after 14, 21, or 28 days. The hypothesis was tested by a three way Anova (time, site, and drug). The ultimate force was increased by bisphosphonate treatment in both models. There was a significant interaction between time, site, and drug (p < 0.001) so that the full positive effect of alendronate was evident in the metaphysis at 14 days, but first after 28 days in the diaphysis. While the early effect in the metaphysis might be translated into earlier healing, the late effect in the diaphysis was due to delayed remodeling of the callus, which might have less clinical importance. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:793-799, 2017. PMID- 27233102 TI - Effect of propolis in gastric disorders: inhibition studies on the growth of Helicobacter pylori and production of its urease. AB - There is considerable interest in alternative approaches to inhibit Helicobacter pylori (H. pylori) and thus treat many stomach diseases. Propolis is a pharmaceutical mixture containing many natural bioactive substances. The aim of this study was to use propolis samples to treat H. pylori. The anti-H. pylori and anti-urease activities of 15 different ethanolic propolis extracts (EPEs) were tested. The total phenolic contents and total flavonoid contents of the EPE were also measured. The agar-well diffusion assay was carried out on H. pylori strain J99 and the inhibition zones were measured and compared with standards. All propolis extracts showed high inhibition of H. pylori J99, with inhibition diameters ranging from 31.0 to 47.0 mm. Helicobacter pylori urease inhibitory activity was measured using the phenol-hypochlorite assay; all EPEs showed significant inhibition against the enzyme, with inhibition concentrations (IC50; mg/mL) ranging from 0.260 to 1.525 mg/mL. The degree of inhibition was related to the phenolic content of the EPE. In conclusion, propolis extract was found to be a good inhibitor that can be used in H. pylori treatment to improve human health. PMID- 27233103 TI - Stress softening and permanent deformation in human aortas: Continuum and computational modeling with application to arterial clamping. AB - Inelastic phenomena such as stress softening and unrecoverable inelastic deformations induced by supra-physiological loading have been observed experimentally in soft tissues such as arteries. These phenomena need to be accounted for in constitutive models of arterial tissues so that computational models can properly predict the outcome of interventional procedures such as arterial clamping and balloon angioplasty that involve non-physiological tissue loading. Motivated by experimental data, a novel pseudo-elastic damage model is proposed to describe discontinuous softening and permanent deformation in arterial tissues. The model is fitted to experimental data and specific material parameters for 9 abdominal and 14 thoracic aortas are provided. Furthermore, the model was implemented in a finite element code and numerically analyzed with respect to experimental tests, i.e. cyclic uniaxial tension in circumferential and longitudinal directions. Results showed that the model is able to capture specific features including anisotropy, nonlinearity, and damage-induced inelastic phenomena, i.e. stress softening and permanent deformation. Finite element results of a more complex boundary-value problem, i.e. aortic clamping considering the three aortic layers, residual stress, non-symmetric blood pressure after clamping, and patient-specific data are also presented. PMID- 27233104 TI - Synthesis of nanostructured beta-Ni(OH)2 by electrochemical dissolution precipitation and its application as a water oxidation catalyst. AB - A straightforward electrochemical dissolution-precipitation approach has been developed to synthesize nanostructured beta-Ni(OH)2 powders (particle size 10-100 nm, specific surface area ~100 m(2) g(-1)) from Ni metal anodes. The approach differs from existing electrochemical synthesis methods in that it predominantly results in bulk precipitation of nanoparticles, without significant film growth on either of the electrodes. Heat treatment of the as-synthesized beta-Ni(OH)2 afforded NiO with mostly preserved nanostructure and very high specific surface area (<=100 m(2) g(-1), depending on calcination temperature). The as-synthesized beta-Ni(OH)2 was found to be an excellent catalyst for the oxygen evolution reaction (OER) in the technologically important water electrolysis process, apparently contradicting recent reports that the alpha polymorph is required for such high activity. With catalyst loadings <0.1 mg cm(-2), OER current densities of 10 mA cm(-2) were sustained at overpotentials as low as 340 mV, with Tafel slopes of only ~38 mV/decade. The catalyst was highly stable in alkaline media over the course of electrolysis experiments lasting for several hours. This performance surpasses that of many previously reported earth-abundant OER catalysts and is comparable to that obtained with state-of-the-art RuO2 and IrO2 catalysts. PMID- 27233105 TI - Surface Tuning of La0.5Sr0.5CoO3 Perovskite Catalysts by Acetic Acid for NOx Storage and Reduction. AB - Selective dissolution of perovskite A site (A of ABO3 structure) was performed on the La1 - xSrxCoO3 catalysts for the NOx storage and reduction (NSR) reaction. The surface area of the catalysts were enhanced using dilute HNO3 impregnation to dissolve Sr. Inactive SrCO3 was removed effectively within 6 h, and the catalyst preserved the perovskite framework after 24 h of treatment. The tuned catalysts exhibited higher NSR performance (both NOx storage and NO-to-NO2 oxidation) under lean-burn and fuel-rich cycles at 250 degrees C. Large amounts of NOx adsorption were due to the increase of nitrate/nitrite species bonding to the A site and the growth of newly formed monodentate nitrate species. Nitrate species were stored stably on the partial exposed Sr(2+) cations. These exposed Sr(2+) cations played an important role on the NOx reduction by C3H6. High NO-to-NO2 oxidation ability was due to the generation of oxygen defects and Co(2+)-Co(3+) redox couples, which resulted from B-site exsolution induced by A-site dissolution. Hence, our method is facile to modify the surface structures of perovskite catalysts and provides a new strategy to obtain highly active catalysts for the NSR reaction. PMID- 27233106 TI - SENTINEL1: An Observational Study of Respiratory Syncytial Virus Hospitalizations among U.S. Infants Born at 29 to 35 Weeks' Gestational Age Not Receiving Immunoprophylaxis. AB - Objective SENTINEL1 characterized U.S. preterm infants 29 to 35 weeks' gestational age (wGA) < 12 months old hospitalized for laboratory-confirmed respiratory syncytial virus (RSV) disease and not receiving RSV immunoprophylaxis during the 2014 to 2015 RSV season. Study Design This is a noninterventional, observational, cohort study. Results A total of 702 infants were hospitalized with community-acquired RSV disease, of whom an estimated 42% were admitted to the intensive care unit (ICU) and 20% required invasive mechanical ventilation (IMV). Earlier gestational age and younger chronologic age were associated with an increased frequency of RSV-confirmed hospitalization (RSVH), ICU admission, and IMV. Among infants 29 to 32 wGA and < 3 months of age, 68% required ICU admission and 44% required IMV. One death occurred of an infant 29 wGA. Among the 212 infants enrolled for in-depth analysis of health care resource utilization, mean and median RSVH charges were $55,551 and $27,461, respectively, which varied by intensity of care required. Outpatient visits were common, with 63% and 62% of infants requiring visits before and within 1 month following the RSVH, respectively. Conclusion Preterm infants 29 to 35 wGA are at high risk for severe RSV disease, which imposes a substantial health burden, particularly in the first months of life. PMID- 27233107 TI - On RRTs. PMID- 27233108 TI - Exploring eye movements of experienced and novice readers of medical texts concerning the cardiovascular system in making a diagnosis. AB - This study used the eye-tracking method to explore how the level of expertise influences reading, and solving, two written patient cases on cardiac failure and pulmonary embolus. Eye-tracking is a fairly commonly used method in medical education research, but it has been primarily applied to studies analyzing the processing of visualizations, such as medical images or patient video cases. Third-year medical students (n = 39) and residents (n = 13) read two patient case texts in an eye-tracking laboratory. The analysis focused on the diagnosis made, the total visit duration per text slide, and eye-movement indicators regarding task-relevant and task-redundant areas of the patient case text. The results showed that almost all participants (48/52) made the correct diagnosis of the first patient case, whereas all the residents, but only 17 students, correctly diagnosed the second case. The residents were efficient patient-case-solvers: they reached the correct diagnoses, and processed the cases faster and with a lower number of fixations than did the students. Further, the students and residents demonstrated different reading patterns with regard to which slides they proportionally paid most attention. The observed differences could be utilized in medical education to model expert reasoning and to teach the manner in which a good medical text is constructed. Eye-tracking methodology appears to have a great deal of potential in evaluating performance and growing diagnostic expertise in reading medical texts. However, further research using medical texts as stimuli is required. Anat Sci Educ 10: 23-33. (c) 2016 American Association of Anatomists. PMID- 27233109 TI - The synergistic effect of inert oxide and metal fluoride dual coatings on advanced cathode materials for lithium ion battery applications. AB - The effect of Al2O3/LiF dual coatings on the electrochemical performance of over lithiated layered oxide (OLO) has been investigated. A uniform coating of Al2O3 and LiF is obtained on the surface of the layered pristine material. The OLO with a dual Al2O3/LiF coating with a ratio of 1 : 1.5 exhibits excellent electrochemical performance. An initial discharge capacity of 265.66 mA h g(-1) is obtained at a C-rate of 0.1C. This capacity is approximately 15 mA h g(-1) higher than that of pristine OLO. The capacity retention (92.8% at the 50th cycle) is also comparable to that of pristine OLO (91.4% at the 50th cycle). Coating the cathode with a dual layer comprising Al2O3 and LiF leads to improved charging and discharging kinetics, and prevents direct contact between the cathode and the electrolyte. PMID- 27233111 TI - Physical Gelation of alpha-Helical Copolypeptides. AB - Owing to its rod-like alpha-helical secondary structure, the synthetic polypeptide poly(gamma-benzyl-l-glutamate) (PBlG) can form physical and thermoreversible gels in helicogenic solvents such as toluene. The versatility of PBlG can be increased by introducing functionalizable comonomers, such as allylglycine (AG). In this work we examined the secondary structure of PBlG and a series of statistical poly(gamma-benzyl-l-glutamate-co-allylglycine) copolypeptides, varying in composition and chain length, by circular dichroism (CD), Fourier-transform infrared (FTIR) and Raman spectroscopy, and wide-angle X ray scattering (WAXS). The secondary structure of PBlG and the copolypeptides presented dissimilarities that increased with increasing AG molar fraction, especially when racemic AG units were incorporated. The physical gelation behavior of these copolypeptides was analyzed by temperature-sweep (1)H NMR and rheological measurements. The study revealed that both copolypeptide composition and chain length affected secondary structure, gelation temperature, and gel stiffness. PMID- 27233112 TI - Transcription-coupled homologous recombination after oxidative damage. AB - Oxidative DNA damage induces genomic instability and may lead to mutagenesis and carcinogenesis. As severe blockades to RNA polymerase II (RNA POLII) during transcription, oxidative DNA damage and the associated DNA strand breaks have a profoundly deleterious impact on cell survival. To protect the integrity of coding regions, high fidelity DNA repair at a transcriptionally active site in non-dividing somatic cells, (i.e., terminally differentiated and quiescent/G0 cells) is necessary to maintain the sequence integrity of transcribed regions. Recent studies indicate that an RNA-templated, transcription-associated recombination mechanism is important to protect coding regions from DNA damage induced genomic instability. Here, we describe the discovery that G1/G0 cells exhibit Cockayne syndrome (CS) B (CSB)-dependent assembly of homologous recombination (HR) factors at double strand break (DSB) sites within actively transcribed regions. This discovery is a challenge to the current dogma that HR occurs only in S/G2 cells where undamaged sister chromatids are available as donor templates. PMID- 27233110 TI - Fatty acylation of proteins: The long and the short of it. AB - Long, short and medium chain fatty acids are covalently attached to hundreds of proteins. Each fatty acid confers distinct biochemical properties, enabling fatty acylation to regulate intracellular trafficking, subcellular localization, protein-protein and protein-lipid interactions. Myristate and palmitate represent the most common fatty acid modifying groups. New insights into how fatty acylation reactions are catalyzed, and how fatty acylation regulates protein structure and function continue to emerge. Myristate is typically linked to an N terminal glycine, but recent studies reveal that lysines can also be myristoylated. Enzymes that remove N-terminal myristoyl-glycine or myristate from lysines have now been identified. DHHC proteins catalyze S-palmitoylation, but the mechanisms that regulate substrate recognition by individual DHHC family members remain to be determined. New studies continue to reveal thioesterases that remove palmitate from S-acylated proteins. Another area of rapid expansion is fatty acylation of the secreted proteins hedgehog, Wnt and Ghrelin, by Hhat, Porcupine and GOAT, respectively. Understanding how these membrane bound O-acyl transferases recognize their protein and fatty acyl CoA substrates is an active area of investigation, and is punctuated by the finding that these enzymes are potential drug targets in human diseases. PMID- 27233113 TI - DNA damage processing at telomeres: The ends justify the means. AB - Telomeres at chromosome ends are nucleoprotein structures consisting of tandem TTAGGG repeats and a complex of proteins termed shelterin. DNA damage and repair at telomeres is uniquely influenced by the ability of telomeric DNA to form alternate structures including loops and G-quadruplexes, coupled with the ability of shelterin proteins to interact with and regulate enzymes in every known DNA repair pathway. The role of shelterin proteins in preventing telomeric ends from being falsely recognized and processed as DNA double strand breaks is well established. Here we focus instead on recent developments in understanding the roles of shelterin proteins and telomeric DNA sequence and structure in processing genuine damage at telomeres induced by endogenous and exogenous DNA damage agents. We will highlight advances in double strand break repair, base excision repair and nucleotide excision repair at telomeres, and will discuss important questions remaining in the field. PMID- 27233115 TI - Structurally Distinct Cation Channelrhodopsins from Cryptophyte Algae. AB - Microbial rhodopsins are remarkable for the diversity of their functional mechanisms based on the same protein scaffold. A class of rhodopsins from cryptophyte algae show close sequence homology with haloarchaeal rhodopsin proton pumps rather than with previously known channelrhodopsins from chlorophyte (green) algae. In particular, both aspartate residues that occupy the positions of the chromophore Schiff base proton acceptor and donor, a hallmark of rhodopsin proton pumps, are conserved in these cryptophyte proteins. We expressed the corresponding polynucleotides in human embryonic kidney (HEK293) cells and studied electrogenic properties of the encoded proteins with whole-cell patch clamp recording. Despite their lack of residues characteristic of the chlorophyte cation channels, these proteins are cation-conducting channelrhodopsins that carry out light-gated passive transport of Na(+) and H(+). These findings show that channel function in rhodopsins has evolved via multiple routes. PMID- 27233114 TI - Getting it done at the ends: Pif1 family DNA helicases and telomeres. AB - It is widely appreciated that the ends of linear DNA molecules cannot be fully replicated by the conventional replication apparatus. Less well known is that semi-conservative replication of telomeric DNA also presents problems for DNA replication. These problems likely arise from the atypical chromatin structure of telomeres, the GC-richness of telomeric DNA that makes it prone to forming DNA secondary structures, and from RNA-DNA hybrids, formed by transcripts of one or both DNA strands. Given the different aspects of telomeres that complicate their replication, it is not surprising that multiple DNA helicases promote replication of telomeric DNA. This review focuses on one such class of DNA helicases, the Pif1 family of 5'-3' DNA helicases. In budding and fission yeasts, Pif1 family helicases impact both telomerase-mediated and semi-conservative replication of telomeric DNA as well as recombination-mediated telomere lengthening. PMID- 27233116 TI - N-methyl-N-nitrosourea-induced schwannomas in male Sprague-Dawley rats with a literature review of inducible and spontaneous lesions. AB - N-methyl-N-nitrosourea (MNU) possesses peripheral nervous system carcinogenic activity in rats and induces benign and malignant schwannomas in systemic organs. In this retrospective study, we compared the characteristics of various immunohistochemical markers in MNU-induced schwannomas in male Crj:CD(SD)IGS rats including: vimentin (Vim), S100, p75 nerve growth factor receptor (LNGFR), CD57, pancytokeratin (CK), myoglobin, desmin and alpha smooth muscle actin (SMA). Single intraperitoneal exposures of 50 or 75mg/kg MNU in male rats at the age of 4 weeks induced schwannomas in 43 surviving and terminated rats up to 30-weeks old. The incidence rate of neoplastic lesions was 37% (16 of 43 rats). Benign schwannomas (mesentery, pancreas, thymus) and malignant schwannomas (subendocardium, cardiac intramural, thoracic cavity, abdominal cavity, prostate), occurred in nine and seven rats, respectively. All neoplastic lesions were moderately or strongly positive for Vim, S100 and LNGFR proteins. Benign tumors were weakly positive and malignant tumors strongly positive for Ki-67, suggesting a high active proliferation rate of Schwann cell precursors. All lesions were negative for CD57, CK, myoglobin, desmin and SMA. This data may provide useful immunohistochemical information for the investigation of schwannomas in rat chemical carcinogenicity studies. PMID- 27233117 TI - Erratum to "Invasiveness and anchorage independent growth ability augmented by PTEN inactivation through the PI3K/AKT/NFkB pathway in lung cancer cells" [Lung Cancer 73 (3) (2011) 302-309]. PMID- 27233118 TI - Chemotherapy-induced neurotoxicity in pediatric solid non-CNS tumor patients: An update on current state of research and recommended future directions. AB - Neurocognitive sequelae are known to be induced by cranial radiotherapy and central-nervous-system-directed chemotherapy in childhood Acute Lymphoblastic Leukemia (ALL) and brain tumor patients. However, less evidence exists for solid non-CNS-tumor patients. To get a better understanding of the potential neurotoxic mechanisms of non-CNS-directed chemotherapy during childhood, we performed a comprehensive literature review of this topic. Here, we provide an overview of preclinical and clinical studies investigating neurotoxicity associated with chemotherapy in the treatment of pediatric solid non-CNS tumors. Research to date suggests that chemotherapy has deleterious biological and psychological effects, with animal studies demonstrating histological evidence for neurotoxic effects of specific agents and human studies demonstrating acute neurotoxicity. Although the existing literature suggests potential neurotoxicity throughout neurodevelopment, research into the long-term neurocognitive sequelae in survivors of non-CNS cancers remains limited. Therefore, we stress the critical need for neurodevelopmental focused research in children who are treated for solid non-CNS tumors, since they are at risk for potential neurocognitive impairment. PMID- 27233119 TI - Hypofractionated radiotherapy in pancreatic cancer: Lessons from the past in the era of stereotactic body radiation therapy. AB - The role of neoadjuvant and definitive radiotherapy combined or not to chemotherapy in the therapeutic approach to pancreatic cancer has not been yet elucidated. There is some evidence in favour of neoadjuvant local and/or systemic approaches that enable surgical resection in patients initially considered to be "borderline resectable". Nevertheless, most of these studies have been conducted using schedules of radiotherapy (treatment volumes, total doses, dose/fraction) that are nowadays considered not efficient enough and/or too toxic. Recently, stereotactic body radiation therapy (SBRT) has been proposed as a new therapeutic option for pancreatic cancer, both in the neoadjuvant and in the definitive setting. The aim of this study is to review the radiobiological and clinical evidences supporting hypofractionation in pancreatic cancer. Moreover, we performed an extensive review of available clinical and dosimetric data on SBRT in pancreatic cancer. PMID- 27233120 TI - Maternal immunization: Optimizing protection for the mother and infant. AB - Immunizing the pregnant woman to protect both the mother and her infant from infection has been utilized increasingly over the last decade. New outbreaks of pandemic influenza and the resurgence of pertussis have resulted in policy changes and shifts in health authority recommendations for a number of vaccines aimed to protect both pregnant women and their infants in the first months of life. The ability of maternal immunoglobulin IgG antibodies to be transported readily across the healthy intact placenta depends on many different factors including gestational age in the pregnancy, nature and timing of the immunization and presence of maternal HIV or malaria infections. In this paper, the history of maternal immunization is described, and specifically the studies that prompted the recommendations for tetanus, influenza, pertussis, and, when needed, meningococcus vaccines in pregnant women are reviewed. Ongoing research may result in new maternal vaccines against other pathogens including respiratory syncytial virus and group B streptococcus. Both scientific and regulatory considerations remain challenging in licensure of vaccines specifically for maternal immunization. PMID- 27233121 TI - Immunisation of the immunocompromised child. AB - Immunocompromised children have a higher risk of developing infections and associated higher rates of mortality and morbidity. Although this group could benefit the most from vaccine administration, specific considerations regarding immunisations are required. This review is a summary of the vaccines that are relevant to the immunocompromised host, covering both live and non-live vaccines. The burden of disease, safety, immunogenicity/effectiveness and specific recommendations for each vaccine are described as well as specific guidelines from different organisations. PMID- 27233122 TI - Expression of human beta-N-acetylhexosaminidase B in yeast eases the search for selective inhibitors. AB - Human lysosomal beta-N-acetylhexosaminidases from the family 20 of glycoside hydrolases are dimeric enzymes catalysing the cleavage of terminal beta-N acetylglucosamine and beta-N-acetylgalactosamine residues from a broad spectrum of glycoconjugates. Here, we present a facile, robust, and cost-effective extracellular expression of human beta-N-acetylhexosaminidase B in Pichia pastoris KM71H strain. The prepared Hex B was purified in a single step with 33% yield obtaining 10mg of the pure enzyme per 1L of the culture media. The enzyme was used in the inhibition assays with the known mechanism-based inhibitor NAG thiazoline and a wide variety of its derivatives in the search for specific inhibitors of the human GH20 beta-N-acetylhexosaminidases over the human GH84 beta-N-acetylglucosaminidase, which was expressed, purified and used in the inhibition experiments as well. Moreover, enzyme-inhibitor complexes were analysed employing computational tools in order to reveal the structural basis of the results of the inhibition assays, showing the importance of water-mediated interactions between the enzyme and respective ligands. The presented method for the heterologous expression of human Hex B is robust, it significantly reduces the costs and equipment demands in comparison to the expression in mammalian cell lines. This will enhance accessibility of this human enzyme to the broad scientific community and may speed up the research of specific inhibitors of this physiologically important glycosidase family. PMID- 27233123 TI - Heterologous expression of fungal cytochromes P450 (CYP5136A1 and CYP5136A3) from the white-rot basidiomycete Phanerochaete chrysosporium: Functionalization with cytochrome b5 in Escherichia coli. AB - Cytochromes P450 from the white-rot basidiomycete Phanerochaete chrysosporium, CYP5136A1 and CYP5136A3, are capable of catalyzing oxygenation reactions of a wide variety of exogenous compounds, implying their significant roles in the metabolism of xenobiotics by the fungus. It is therefore interesting to explore their biochemistry to better understand fungal biology and to enable the use of fungal enzymes in the biotechnology sector. In the present study, we developed heterologous expression systems for CYP5136A1 and CYP5136A3 using the T7 RNA polymerase/promoter system in Escherichia coli. Expression levels of recombinant P450s were dramatically improved by modifications and optimization of their N terminal amino acid sequences. A CYP5136A1 reaction system was reconstructed in E. coli whole cells by coexpression of CYP5136A1 and a redox partner, NADPH dependent P450 reductase (CPR). The catalytic activity of CYP5136A1 was significantly increased when cytochrome b5 (Cyt-b5) was further coexpressed with CPR, indicating that Cyt-b5 supports electron transfer reactions from NAD(P)H to CYP5136A1. Notably, P450 reaction occurred in E. coli cells that harbored CYP5136A1 and Cyt-b5 but not CPR, implying that the reducing equivalents required for the P450 catalytic cycle were transferred via a CPR-independent pathway. Such an "alternative" electron transfer system in CYP5136A1 reaction was also demonstrated using purified enzymes in vitro. The fungal P450 reaction system may be associated with sophisticated electron transfer pathways. PMID- 27233124 TI - Advances in ovarian cancer diagnosis: A journey from immunoassays to immunosensors. AB - This review focuses on the technological advancements, challenges and trends in immunoassay technologies for ovarian cancer diagnosis. Emphasis is placed on the principles of the technologies, their merits and limitations and on the evolution from laboratory-based methods to point-of-care devices. While the current market is predominantly associated with clinical immunoassay kits, over the last decade a major thrust in development of immunosensors is evident due to their potential in point-of-care devices. Technological advancements in immunosensors, extending from labeled to label-free detection, with and without mediators, for enhancing proficiencies and reliability have been dealt with in detail. Aspects of the utilisation of nanomaterials and immobilization strategies for enhancing sensitivity and altering the detection range have also been addressed. Finally, we have discussed some distinct characteristics and limitations associated with the recently commericalised technologies used for quantitation of relevant ovarian cancer markers. PMID- 27233125 TI - Polyamide 6/chitosan nanofibers as support for the immobilization of Trametes versicolor laccase for the elimination of endocrine disrupting chemicals. AB - In recent years, there has been an increase in efforts to improve wastewater treatment as the concentration of dangerous pollutants, such as endocrine disrupting chemicals, in wastewater increases. These compounds, which mimic the effect of hormones, have a negative impact on human health and are not easily removed from water. One way to effectively eliminate these pollutants is to use enzymatically activated materials. In this study, we report on the use of laccase from the white rot fungus Trametes versicolor immobilized onto polyamide 6/chitosan (PA6/CHIT) nanofibers modified using two different spacers (bovine serum albumin and hexamethylenediamine). We then tested the ability of the PA6/CHIT-laccase biocatalysts to eliminate a mixture containing 50MUM of two endocrine disrupting chemicals: bisphenol A and 17alpha-ethinylestradiol. The PA6/CHIT nanofiber matrix used in this study not only proved to be a suitable carrier for immobilized and modified laccase but was also efficient in the removal of a mixture of endocrine disrupting chemicals in three treatment cycles. PMID- 27233126 TI - Molecular cloning of kman coding for mannanase from Klebsiella oxytoca KUB-CW2-3 and its hybrid mannanase characters. AB - Gene encoding for beta-mannanase (E.C 3.2.1.78) from Klebsiella oxytoca KUB-CW2-3 was cloned and expressed by an E. coli system resulting in 400 times higher mannanase activities than the wild type. A 3314bp DNA fragment obtained revealed an open reading frame of 1164bp, namely kman-2, which encoded for 387 amino acids with an estimated molecular weight of 43.2kDa. It belonged to the glycosyl hydrolase family 26 (GH26) exhibited low similarity of 50-71% to beta-mannanase produced by other microbial sources. Interestingly, the enzyme had a broad range of substrate specificity of homopolymer of ivory nut mannan (6%), carboxymethyl cellulose (30.6%) and avicel (5%), and heteropolymer of konjac glucomannan (100%), locust bean gum (92.6%) and copra meal (non-defatted 5.3% and defatted 7%) which would be necessary for in vivo feed digestion. The optimum temperature and pH were 30-50 degrees C and 4-6, respectively. The enzyme was still highly active over a low temperature range of 10-40 degrees C and over a wide pH range of 4-10. The hydrolysates of konjac glucomannan (H-KGM), locust bean gum (H-LBG) and defatted copra meal (H-DCM) composed of compounds which were different in their molecular weight range from mannobiose to mannohexaose and unknown oligosaccharides indicating the endo action of mannanase. Both H-DCM and H-LBG enhanced the growth of lactic acid bacteria and some pathogens except Escherichia coli E010 with a specific growth rate of 0.36-0.83h(-1). H-LBG was more specific to 3 species of Weissella confusa JCM 1093, Lactobacillus reuteri KUB-AC5, Lb salivarius KL-D4 and E. coli E010 while both H-KGM and H-DCM were to Lb. reuteri KUB-AC5 and Lb. johnsonii KUNN19-2. Based on the nucleotide sequence of kman-2 containing two open reading frames of 1 and 2at 5' end of the +1 and +43, respectively, removal of the first open reading frame provided the recombinant clone E. coli KMAN-3 resulting in the mature protein of mannanase composing of 345 amino acid residues confirmed by 3D structure analysis and amino acid sequence at N-terminal namely KMAN (GenBank accession number KM100456). It exhibited 10 times higher extracellular and periplasmic total activities of 17,600 and 14,800 units than E. coli KMAN-2. With its low similarity to mannanases previously proposed, wide range of homo- and hetero-polysaccharide specificity, negative effect to E. coli and most importance of high production, it would be proposed as a novel mannanase source for application in the future. PMID- 27233127 TI - Effect of changing the nanoscale environment on activity and stability of nitrate reductase. AB - Nitrate reductase (NR) is employed for fabrication of nitrate sensing devices in which the enzyme in immobilized form is used to catalyze the conversion of nitrate to nitrite in the presence of a suitable cofactor. So far, instability of immobilized NR due to the use of inappropriate immobilization matrices has limited the practical applications of these devices. Present study is an attempt to improve the kinetic properties and stability of NR using nanoscale iron oxide (nFe3O4) and zinc oxide (nZnO) particles. The desired nanoparticles were synthesized, surface functionalized, characterized and affixed onto the epoxy resin to yield two nanocomposite supports (epoxy/nFe3O4 and epoxy/nZnO) for immobilizing NR. Epoxy/nFe3O4 and epoxy/nZnO support could load as much as 35.8+/ 0.01 and 33.20+/-0.01MUg/cm(2) of NR with retention of about 93.72+/-0.50 and 84.81+/-0.80% of its initial activity respectively. Changes in surface morphology and chemical bonding structure of both the nanocomposite supports after addition of NR were confirmed by scanning electron microscopy (SEM) and fourier transform infrared spectroscopy (FTIR). Optimum working conditions of pH, temperature and substrate concentration were ascertained for free as well as immobilized NR preparations. Further, storage stability at 4 degrees C and thermal stability between 25-50 degrees C were determined for all the NR preparations. Analytical applications of immobilized NR for determination of soil and water nitrates along with reusability data has been included to make sure the usefulness of the procedure. PMID- 27233128 TI - Improvement of ectoine productivity by using sugar transporter-overexpressing Halomonas elongata. AB - We successfully enhanced the productivity of ectoine with Halomonas elongata by improvement of the transport of sugar. First, we carried out screening for sugar transporters capable of improving glucose and xylose consumption. We found two transporters: b3657 from Escherichia coli, which is capable of improving glucose consumption, and HEO_0208 from H. elongata, which is capable of improving xylose consumption. Using transporter-overexpressing strains, the productivity of ectoine was improved. These results indicate that sugar consumption is important for efficient ectoine production. As result of phenotypic analysis of a HEO_0208 deletion strain, we discovered that HEO_0208 is the major xylose transporter in H. elongata. This is the first report demonstrating improvement of ectoine productivity by enhancing the transport of sugar. PMID- 27233129 TI - Site-directed mutagenesis of porcine pepsin: Possible role of Asp32, Thr33, Asp215 and Gly217 in maintaining the nuclease activity of pepsin. AB - Site-directed mutagenesis of porcine pepsin was performed to identify its active sites that regulate nucleic acid (NA) digestion activity and to analyze the mechanism pepsin-mediated NA digestion. The mutation sites were distributed at the catalytic center of the enzyme (T33A, G34A, Y75H, T77A, Y189H, V214A, G217A and S219A) and at its active site (D32A and D215A) for protein digestion. Mutation of the active site residues Asp32 and Asp215 led to the inactivation of pepsin (both the NA and protein digestion activity), which demonstrated that the active sites of the pepsin protease activity were also important for its nuclease activity. Analysis of the variants revealed that T33A and G217A mutants showed a complete loss of NA digestion activity. In conclusion, residues Asp32, Thr33, Asp215 and Gly217 were related to the pepsin active sites for NA digestion. Moreover, the Y189H and V214A variants showed a loss of digestion activity on double-strand DNA (dsDNA) but only a decrease in digestion activity on single strand DNA (ssDNA). On the contrary, the G34A variant showed a loss of digestion activity on ssDNA but only a decrease in digestion activity on dsDNA. Our findings are the first to identify the active sites of pepsin nuclease activity and lay the framework for further study of the mechanism of pepsin nuclease activity. PMID- 27233130 TI - Screening and identification of five peptides from pinto bean with inhibitory activities against alpha-amylase using phage display technique. AB - The objective of this study was to screen and identify alpha-amylase inhibitor peptides from Pinto bean. Five Pinto bean bioactive peptides were successfully identified: PPHMLP (P1), PLPWGAGF (P3), PPHMGGP (P6), PLPLHMLP (P7) and LSSLEMGSLGALFVCM (P9). Based on ELISA results, their promising optical density values were 1.27; 3.71, 1.67, 3.20 and 1.03, respectively, which indicated the binding interaction between the peptide and alpha-amylase occurred. The highest inhibitory activity (66.72%) of the chemically synthesized peptide was shown in SyP9 followed by SyP1 (48.86%), SyP3 (31.17%), SyP7 (27.88%) and SyP6 (23.96%). The IC50 values were 1.97, 8.96, 14.63, 18.45 and 20.56mgml(-1), respectively. Structure activity relationship study revealed that alpha-amylase was inhibited due to its residues of Ala230, Asp229, Asp326, Tyr54, Met195, Leu194 and His233 were bound. On the other hand, the residues of PBBP (i.e. histidine, proline and methionine) were found to have the highest potency in the binding interaction. PMID- 27233131 TI - Impact of cofactor-binding loop mutations on thermotolerance and activity of E. coli transketolase. AB - Improvement of thermostability in engineered enzymes can allow biocatalysis on substrates with poor aqueous solubility. Denaturation of the cofactor-binding loops of Escherichia coli transketolase (TK) was previously linked to the loss of enzyme activity under conditions of high pH or urea. Incubation at temperatures just below the thermal melting transition, above which the protein aggregates, was also found to anneal the enzyme to give an increased specific activity. The potential role of cofactor-binding loop instability in this process remained unclear. In this work, the two cofactor-binding loops (residues 185-192 and 382 392) were progressively mutated towards the equivalent sequence from the thermostable Thermus thermophilus TK and variants assessed for their impact on both thermostability and activity. Cofactor-binding loop 2 variants had detrimental effects on specific activity at elevated temperatures, whereas the H192P mutation in cofactor-binding loop 1 resulted in a two-fold improved stability to inactivation at elevated temperatures, and increased the critical onset temperature for aggregation. The specific activity of H192P was 3-fold and 19-fold higher than that for wild-type at 60 degrees C and 65 degrees C respectively, and also remained 2.7-4 fold higher after re-cooling from pre incubations at either 55 degrees C or 60 degrees C for 1h. Interestingly, H192P was also 2-times more active than wild-type TK at 25 degrees C. Optimal activity was achieved at 60 degrees C for H192P compared to 55 degrees C for wild type. These results show that cofactor-binding loop 1, plays a pivotal role in partial denaturation and aggregation at elevated temperatures. Furthermore, a single rigidifying mutation within this loop can significantly improve the enzyme specific activity, as well as the stability to thermal denaturation and aggregation, to give an increased temperature optimum for activity. PMID- 27233132 TI - Autonomous osteogenic differentiation of hASCs encapsulated in methacrylated gellan-gum hydrogels. AB - Methacrylated gellan-gum (GG-MA) alone and combined with collagen type I (Coll) is suggested here for the first time as a cell-laden injectable biomaterial for bone regeneration. On-chip high-throughput studies allowed rapidly assessing the suitability of 15 biomaterials/media combinations for the osteodifferentiation of human adipose stem cells (hASCs). Hydrogels composed solely of GG-MA (GG100:0Coll) led hASCs from three different donors into the osteogenic lineage after 21days of cell culture, in the absence of any osteogenic or osteoconductive factors. Hydrogels containing more than 30% of Coll promoted increased cellular proliferation and led hASCs into osteogenic differentiation under basal conditions. Studies using isolated individual hydrogels - excluding eventual on chip crosstalk - and standard biochemical assays corroborated such findings. The formation of focal adhesions of hASCs on GG100:0Coll hydrogels was verified. We hypothesize that the hydrogels osteogenic effect could be guided by mechanotransduction phenomena. Indeed, the hydrogels showed elastic modulus in ranges previously reported as osteoinductive and the inhibition of the actin myosin contractility pathway impaired hASCs' osteodifferentiation. GG-MA hydrogels also did not promote hASCs' adipogenesis while used in basal conditions. Overall, GG-MA showed promising properties as an innovative and off the shelf self-inducing osteogenic injectable biomaterial. STATEMENT OF SIGNIFICANCE: Methacrylated gellan gum (GG-MA) is here suggested for the first time as a widely available polysaccharide to easily prepare hydrogels with cell adhesion properties and capability of inducing the autonomous osteogenic differentiation of human adipose-derived stem cells (hASCs). GG-MA was processed as stand-alone hydrogels or in different combinations with collage type I. All hydrogel formulations elicited the osteogenic differentiation of hASCs, independently of the addition of any osteoconductive or osteogenic stimuli, i.e. in basal/growth medium. Effective cellular adhesion to methacrylated gellan gum hydrogels in the absence of any cell-ligand peptide/protein was here proved for the first time. Moreover, we showed that the encapsulated hASCs underwent osteogenic differentiation due to a mechanotransduction phenomenon dependent on the actin-myosin contractility pathway. PMID- 27233133 TI - SPME as a promising tool in translational medicine and drug discovery: From bench to bedside. AB - Solid phase microextraction (SPME) is a technology where a small amount of an extracting phase dispersed on a solid support is exposed to the sample for a well defined period of time. The open-bed geometry and biocompatibility of the materials used for manufacturing of the devices makes it very convenient tool for direct extraction from complex biological matrices. The flexibility of the formats permits tailoring the method according the needs of the particular application. Number of studies concerning monitoring of drugs and their metabolites, analysis of metabolome of volatile as well as non-volatile compounds, determination of ligand-protein binding, permeability and compound toxicity was already reported. All these applications were performed in different matrices including biological fluids and tissues, cell cultures, and in living animals. The low invasiveness of in vivo SPME, ability of using very small sample volumes and analysis of cell cultures permits to address the rule of 3R, which is currently acknowledged ethical standard in R&D labs. In the current review systematic evaluation of the applicability of SPME to studies required to be conduct at different stages of drug discovery and development and translational medicine is presented. The advantages and challenges are discussed based on the examples directly showing given experimental design or on the studies, which could be translated to the models routinely used in drug development process. PMID- 27233134 TI - Reliability and Validity of the Brief Fatigue Inventory and Dyspnea Inventory in People With Chronic Obstructive Pulmonary Disease. AB - CONTEXT: Dyspnea, fatigue, and pain are common in individuals with chronic obstructive pulmonary disease (COPD). However, questionnaires with a similar format are not available to assess their relative severity and interference. OBJECTIVES: To determine the reliability and validity of the Brief Fatigue Inventory (BFI) and Dyspnea Inventory (DI) in COPD patients who attend pulmonary rehabilitation programs. METHODS: Participants were recruited from four pulmonary rehabilitation programs to complete a survey package containing: the Chronic Respiratory Questionnaire (CRQ), BFI, and DI; and one week later, to complete the BFI and DI. Retrospective data of the CRQ, BFI, and DI were retrieved from one of the programs. RESULTS: For the prospective component, there was an 85% response rate (n = 91) for the first package and 83.5% response rate (n = 76) for the second package. Retrospectively, CRQ, BFI, and DI data were retrieved from 48 charts. The BFI and DI demonstrated excellent internal consistency (Cronbach alpha = 0.96 both), and high test-retest reliability (intraclass correlation3,1 = 0.86 and 0.91, respectively). By comparison to the fatigue and dyspnea domains of the CRQ, the BFI showed high concurrent validity (rho = -0.83), whereas the DI showed moderate (rho = -0.57) to high (rho = -0.78) concurrent validity. Factor analysis provided evidence that the items in the BFI and DI measured the intended constructs. CONCLUSION: The BFI and DI are valid and reliable measures to evaluate fatigue and dyspnea in COPD patients and could be used concurrently with the Brief Pain Inventory to inform the relative severity and interference of these common symptoms in COPD. PMID- 27233135 TI - The Impact of a Novel Tool for Comprehensive Assessment of Palliative Care (MPCAT) on Assessment Outcome at 6- and 12-Month Follow-Up. AB - CONTEXT: Assessment in palliative care settings should be focused, sensitive, specific, and effective to minimize discomfort to vulnerable and often highly morbid patients. This report describes the development of an admission assessment protocol for a Specialist Palliative Care Inpatient Unit and its implementation into clinical practice. OBJECTIVES: The aim of this study was to develop and investigate the impact of the implementation of a Specialist Palliative Care admission assessment tool on documentation of key patient needs. METHODS: The outcome of a systematic literature review was used to develop an admission assessment protocol (the intervention) in a Specialist Palliative Care Inpatient Unit. Mixed methods were used to facilitate a comprehensive evaluation pre- and post-intervention to test the effectiveness, feasibility, and acceptability of the intervention. RESULTS: The documented evidence of pain assessment improved from a baseline rate of 71% to 100% post-intervention. This improvement was maintained 12 months post-introduction of the tool (P < 0.001). The documented evidence of screening for spiritual distress increased from a baseline rate of 23% to 70% at 6 months and to 82% at 12 months (P < 0.001). The number of referrals made in the first 24 hours after assessment increased post-intervention (physiotherapy, P = 0.001; occupational therapy, P = 0.001; social work, P = 0.005; pastoral care, P = 0.005); this was maintained at 12 months. Significantly, more clinicians (88%) agreed that palliative care domains were comprehensively assessed post-intervention in comparison with 59% pre intervention (P = 0.01). CONCLUSION: Introducing the Milford Palliative Care Assessment Tool was associated with significant improvement in assessment of multiple important aspects of patient need. PMID- 27233136 TI - Phase I Cancer Trials and Palliative Care: Antagonism, Irrelevance, or Synergy? AB - This article synthesizes the presentations and conclusions of an international symposium on Phase 1 oncology trials, palliative care, and ethics held in 2014. The purpose of the symposium was to discuss the intersection of three independent trends that unfolded in the past decade. First, large-scale reviews of hundreds of Phase I trials have indicated there is a relatively low risk of serious harm and some prospect of clinical benefit that can be meaningful to patients. Second, changes in the design and analysis of Phase I trials, the introduction of "targeted" investigational agents that are generally less toxic, and an increase in Phase I trials that combine two or more agents in a novel way have changed the conduct of these trials and decreased fears and apprehensions about participation. Third, the field of palliative care in cancer has expanded greatly, offering symptom management to late-stage cancer patients, and demonstrated that it is not mutually exclusive with disease-targeted therapies or clinical research. Opportunities for collaboration and further research at the intersection of Phase 1 oncology trials and palliative care are highlighted. PMID- 27233137 TI - Fatigue in Advanced Cancer Patients: Congruence Between Patients and Their Informal Caregivers About Patients' Fatigue Severity During Cancer Treatment With Palliative Intent and Predictors of Agreement. AB - CONTEXT: Informal caregivers (ICs) are increasingly involved in the monitoring of symptoms during advanced cancer patients' treatment with palliative intent. A common but subjective symptom during this extended treatment phase is fatigue. OBJECTIVES: This exploratory longitudinal study aimed to determine agreement between patients and ICs about patients' fatigue severity. In addition, predictors of agreement over time were studied. METHODS: A sample of 107 patients with advanced cancer (life expectancy >= six months) and their ICs completed the subscale fatigue severity of the Checklist Individual Strength based on the patient's status at baseline and six months later. This eight-item subscale has a validated cutoff to determine the presence of clinically relevant levels of fatigue. ICs' own fatigue severity, strain, self-esteem, and relationship satisfaction were examined as predictors of agreement. RESULTS: A total of 107 dyads completed measures at baseline and 69 dyads six months later. At baseline, ICs' significantly overestimated patients' fatigue severity (P < 0.001) with a moderate amount of bias (Cohen's d = 0.48). In 81 of the 107 dyads (76%), there was congruence about the presence or absence of severe fatigue. On a group level, congruence did not significantly change over time. On a dyad level, there was a tendency to either remain congruent or reach congruence. Next to baseline congruence, ICs' fatigue severity and strain predicted ICs' fatigue ratings (R(2) = 0.22). CONCLUSION: Most ICs accurately predict presence or absence of clinically relevant levels of patients' fatigue. ICs' own fatigue severity and strain should be taken into account as they influence agreement. PMID- 27233139 TI - Association of Descriptors of Breathlessness With Diagnosis and Self-Reported Severity of Breathlessness in Patients With Advanced Chronic Obstructive Pulmonary Disease or Cancer. AB - CONTEXT: Verbal descriptors are important in understanding patients' experience of breathlessness. OBJECTIVES: The aim of this study was to examine the association between selection of breathlessness descriptors, diagnosis, self reported severity of breathlessness and self-reported distress due to breathlessness. METHODS: We studied 132 patients grouped according to their diagnosis of advanced chronic obstructive pulmonary disease (n = 69) or advanced cancer (n = 63), self-reported severity of breathlessness as mild breathlessness (Numerical Rating Scale [NRS] <= 3, n = 53), moderate breathlessness (4 <= NRS >= 6, n = 59) or severe breathlessness (NRS >= 7, n = 20), and distress due to breathlessness as mild distress (NRS <= 3, n = 31), moderate distress (4 <= NRS >= 6, n = 44), or severe distress (NRS >= 7, n = 57). Patients selected three breathlessness descriptors. The relationship between descriptors selected and patient groups was evaluated by cluster analysis. RESULTS: Different combinations of clusters were associated with each diagnostic group; the cluster chest tightness was associated with cancer patients. The association of clusters with patient groups differed depending on their severity of breathlessness and their distress due to breathlessness. The air hunger cluster was associated with patients with moderate or severe breathlessness, and the chest tightness cluster was associated with patients with mild breathlessness. The air hunger cluster was associated with patients with severe distress due to breathlessness. CONCLUSION: The relationship between clusters and diagnosis is not robust enough to use the descriptors to identify the primary cause of breathlessness. Further work exploring how use of breathlessness descriptors reflects the severity of breathlessness and distress due to breathlessness could enable the descriptors to evaluate patient status and target interventions. PMID- 27233138 TI - Predictors of Responses to Corticosteroids for Cancer-Related Fatigue in Advanced Cancer Patients: A Multicenter, Prospective, Observational Study. AB - CONTEXT: Although corticosteroids are widely used to relieve cancer-related fatigue (CRF), information regarding the factors predicting responses to corticosteroids remains limited. OBJECTIVES: The aim of this study was to identify potential factors predicting responses to corticosteroids for CRF in advanced cancer patients. METHODS: Inclusion criteria for this multicenter, prospective, observational study were patients who had metastatic or locally advanced cancer and had a fatigue intensity score of 4 or more on a 0-10 Numerical Rating Scale (NRS). Univariate and multivariate analyses were conducted to identify the factors predicting two-point reduction or more in NRS on day 3. RESULTS: Among 179 patients who received corticosteroids, 86 (48%; 95% CI 41% 56%) had a response with two-point reduction or more. Factors that significantly predicted responses were performance status score of 3 or more, Palliative Performance Scale score more than 40, absence of ascites, absence of drowsiness, absence of depression, serum albumin level greater than 3 mg/dL, serum sodium level greater than 135 mEq/L, and baseline NRS score greater than 5. A multivariate analysis showed that the independent factors predicting responses were baseline NRS score greater than 5 (odds ratio [OR] 6.6, 95% CI 2.8-15.4), Palliative Performance Scale score more than 40 (OR 4.4, 95% CI 2.1-9.3), absence of drowsiness (OR 3.4, 95% CI 1.7-6.9), absence of ascites (OR 2.3, 95% CI 1.1 4.7), and absence of pleural effusion (OR 2.2, 95% CI 1.0-5.0). CONCLUSION: Treatment responses to corticosteroids for CRF may be predicted by baseline symptom intensity, performance status, drowsiness, and severity of fluid retention symptoms. Larger prospective studies are needed to confirm these results. PMID- 27233140 TI - Cost Analysis and Policy Implications of a Pediatric Palliative Care Program. AB - CONTEXT: In 2010, California launched Partners for Children (PFC), a pediatric palliative care pilot program offering hospice-like services for children eligible for full-scope Medicaid delivered concurrently with curative care, regardless of the child's life expectancy. OBJECTIVES: We assessed the change from before PFC enrollment to the enrolled period in 1) health care costs per enrollee per month (PEPM), 2) costs by service type and diagnosis category, and 3) health care utilization (days of inpatient care and length of hospital stay). METHODS: A pre-post analysis compared enrollees' health care costs and utilization up to 24 months before enrollment with their costs during participation in the pilot, from January 2010 through December 2012. Analyses were conducted using paid Medicaid claims and program enrollment data. RESULTS: The average PEPM health care costs of program enrollees decreased by $3331 from before their participation in PFC to the enrolled period, driven by a reduction in inpatient costs of $4897 PEPM. PFC enrollees experienced a nearly 50% reduction in the average number of inpatient days per month, from 4.2 to 2.3. Average length of stay per hospitalization dropped from an average of 16.7 days before enrollment to 6.5 days while in the program. CONCLUSION: Through the provision of home-based therapeutic services, 24/7 access to medical advice, and enhanced, personally tailored care coordination, PFC demonstrated an effective way to reduce costs for children with life-limiting conditions by moving from costly inpatient care to more coordinated and less expensive outpatient care. PFC's home-based care strategy is a cost-effective model for pediatric palliative care elsewhere. PMID- 27233141 TI - Prevalence, Impact, and Correlates of Severe Fatigue in Patients With Gastrointestinal Stromal Tumors. AB - CONTEXT: The introduction of the tyrosine kinase inhibitor (TKI) imatinib in the treatment of gastrointestinal stromal tumor (GIST) in 2000 was the start of a new era of targeted treatment. Since then, the median survival of patients with GIST has substantially increased. Prolonged survival and chronic TKI use are associated with treatment-induced symptoms, such as fatigue, which can compromise quality of life (QoL). OBJECTIVES: This study determined the prevalence of severe fatigue in GIST patients compared to matched healthy controls, the impact of fatigue on daily life, and associations between fatigue and current TKI use. METHODS: One hundred nineteen patients treated with surgery and/or a TKI for GIST were asked to participate. Participants completed questionnaires including the Checklist Individual Strength-Fatigue Severity scale (CIS-fatigue), Short-Form 36 Item Health Survey, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, Fatigue Catastrophizing Scale, Self Efficacy Scale, and the Hospital Anxiety and Depression Scale. RESULTS: Eighty nine GIST patients (75%) completed questionnaires, 61 patients (69%) were on a TKI. Prevalence of severe fatigue measured with CIS-fatigue was significantly higher in GIST patients (30%) than in 234 matched healthy controls (15%). The prevalence of severe fatigue did not differ significantly between patients receiving treatment with curative (29%) or palliative intent (36%). Severely fatigued patients reported lower QoL and more impairment on all functional domains. TKI use, more psychological distress, and lower physical functioning were associated with fatigue. CONCLUSION: Severe fatigue occurs in 30% of GIST patients and in 33% of GIST patients on a TKI. The fatigue is disabling and is not only associated with current TKI use but also with psychological distress and physical functioning. GIST patients should be informed about these associated factors of fatigue that deserve appropriate management. PMID- 27233142 TI - The Experience of Fatigue Across Long-Term Conditions: A Qualitative Meta Synthesis. AB - CONTEXT: Fatigue is a common and debilitating symptom associated with many long term conditions and is reported to cause significant levels of distress for those individuals. There is a substantial body of literature related to the nature of fatigue; however, this has not been drawn together and compared across conditions. OBJECTIVES: The aim of this review was to synthesize data on the nature of fatigue across long-term conditions. METHODS: The review was designed as a qualitative meta-synthesis and followed the Joanna Briggs Institute guidelines for synthesizing qualitative research. The following databases were searched for the period January 1980 to January 2016, Ovid (Medline, Embase, CINAHL, and PsycINFO) and manual searching from the reference lists from articles identified by electronic search. Fifty-seven studies were included in the review, and findings related to the nature of fatigue were extracted and findings meta synthesized. RESULTS: The perceived nature of fatigue across long-term conditions was encompassed in one synthesis; the fatigue experience is without precedent, with four categories: a different fatigue to any experienced before, the intensity of fatigue is overwhelming, the trajectory of fatigue, and impact on sleep and sleep disturbance. Just over half of the participants in the included studies were diagnosed with cancer. Patterns in the experience of fatigue by condition were found for cancer-related fatigue and post-stroke fatigue where data were able to be synthesized. CONCLUSION: Although similarities in the nature of the fatigue experienced were found across conditions, differences were also evident and could be mapped for cancer-related fatigue and post-stroke fatigue. Further qualitative research on the experience of fatigue across a wide range of chronic conditions would further contribute to understanding similarities and differences across conditions and inform both research and practice in relation to assessment and management. PMID- 27233143 TI - Spiritual Needs of Families With Bereavement and Loss of an Infant in the Neonatal Intensive Care Unit: A Qualitative Study. AB - CONTEXT: The hospital is a place full of distress and questions about the meaning of life. The death of a child can cause a spiritual struggle and crisis. Therefore, it is necessary for health care providers in the neonatal intensive care unit (NICU) to assess the spiritual needs of families that have lost a child. OBJECTIVES: The purpose of this study was to explore the spiritual needs of families in Iran at the end of their baby's life and through bereavement in the NICU. METHODS: This study was an exploratory qualitative study performed using purposeful sampling and semi-structured interviews with 24 participants. Inclusion criteria for families, nurses, and physicians included having experienced at least one newborn death in the last six months in the NICU. The research environment was the NICU in Isfahan, one of the largest cities in Iran. RESULTS: Data analysis revealed three main themes: spiritual belief in a supernatural power, the need for comfort of the soul, and human dignity for the newborn. CONCLUSION: The results of this study created a new vision in addressing spiritual needs of Iranian families who experience the death of a newborn. PMID- 27233145 TI - Categorization of Individuals With Burnout Syndrome: A Topic of Controversy. PMID- 27233144 TI - Is It the Difference a Day Makes? Bereaved Caregivers' Perceptions of Short Hospice Enrollment. AB - CONTEXT: Hospice enrollment for less than one month has been considered too late by some caregivers and at the right time for others. Perceptions of the appropriate time for hospice enrollment in cancer are not well understood. OBJECTIVES: The objectives of the study were to identify contributing factors of hospice utilization in cancer for <=7 days, to describe and compare caregivers' perceptions of this as "too late" or at the "right time." METHODS: Semistructured, in-depth, in-person interviews were conducted with a sample subgroup of 45 bereaved caregivers of people who died from cancer within seven days of hospice enrollment. Interviews were transcribed and entered into Atlas.ti for coding. Data were grouped by participants' perceptions of the enrollment as "right time" or "too late." RESULTS: Overall, the mean length of enrollment was MLOE = 3.77 (SD = 1.8) days and ranged from three hours to seven days. The "right time" group (N = 25 [56%]) had a MLOE = 4.28 (SD = 1.7) days. The "too late" group (N = 20 [44%]) had a MLOE = 3.06 (SD = 1.03) days. The difference was statistically significant (P = 0.029). Precipitating factors included: late-stage diagnosis, continuing treatment, avoidance, inadequate preparation, and systems barriers. The "right time" experience was characterized by: perceived comfort, family needs were met, preparedness for death. The "too late" experience was characterized by perceived suffering, unprepared for death, and death was abrupt. CONCLUSION: The findings suggest that one more day of hospice care may increase perceived comfort, symptom management, and decreased suffering and signal the need for rapid response protocols. PMID- 27233146 TI - The Catalonia WHO Demonstration Project of Palliative Care: Results at 25 Years (1990-2015). AB - In 2015, the World Health Organization (WHO) Demonstration Project on Palliative Care in Catalonia (Spain) celebrated its 25th anniversary. The present report describes the achievements and progress made through this project. Numerous innovations have been made with regard to the palliative care (PC) model, organization, and policy. As the concept of PC has expanded to include individuals with advanced chronic conditions, new needs in diverse domains have been identified. The WHO resolution on "Strengthening of palliative care as a component of comprehensive care throughout the life course," together with other related WHO initiatives, support the development of a person-centered integrated care PC model with universal coverage. The Catalan Department of Health, together with key institutions, developed a new program in the year 2011 to promote comprehensive and integrated PC approach strategies for individuals with advanced chronic conditions. The program included epidemiologic research to describe the population with progressive and life-limiting illnesses. One key outcome was the development of a specific tool (NECPAL CCOMS-ICO((c))) to identify individuals in the community in need of PC. Other innovations to emerge from this project to improve PC provision include the development of the essential needs approach and integrated models across care settings. Several educational and research programs have been undertaken to complement the process. These results illustrate how a PC program can respond and adapt to emerging needs and demands. The success of the PC approach described here supports more widespread adoption by other key care programs, particularly chronic care programs. PMID- 27233147 TI - Physiological Plausibility Can Increase Reproducibility in Cognitive Neuroscience. AB - Physiological measurements offer the unique opportunity to assess plausibility along multiple data dimensions, in addition to the significance of statistical tests. Increased emphasis hereon should help increase the reproducibility of research findings by turning what is often considered a threat to reproducibility (a large search space) into part of the solution. PMID- 27233148 TI - Involvement of human primary somatosensory cortex in vibrotactile detection depends on task demand. AB - Detecting and discriminating sensory stimuli are fundamental functions of the nervous system. Electrophysiological and lesion studies suggest that macaque primary somatosensory cortex (SI) is critically involved in discriminating between stimuli, but is not required simply for detecting stimuli. By contrast, transcranial magnetic stimulation (TMS) studies in humans have shown near complete disruption of somatosensory detection when a single pulse of TMS is delivered over SI. To address this discrepancy, we measured the sensitivity and decision criteria of participants detecting vibrotactile stimuli with individually-tailored fMRI-guided TMS over SI, over a control site not activated by vibrotactile stimuli (inferior parietal lobule, IPL), or away from the head (a no TMS condition). In a one-interval detection task, TMS increased participants' likelihood of reporting 'no' target present regardless of site, but TMS over SI also decreased detection sensitivity, and prevented improvement in tactile sensitivity over time. We then measured tactile thresholds in a series of two interval forced-choice (2IFC) detection and discrimination tasks with lower dependence on response criteria and short-term memory load. We found that thresholds for detecting stimuli were comparable with TMS over SI and IPL, but TMS over SI specifically and significantly impaired frequency discrimination. We conclude that, in accordance with macaque studies, human SI is required for discriminating between tactile stimuli and for maintaining stimulus representations over time, or under high task demand, but may not be required for simple tactile detection. SIGNIFICANT STATEMENT: Studies on monkeys have suggested that the primary somatosensory cortex is responsible for discriminating between different vibrations on the fingertips, but not just for detecting these vibrations. However, similar studies in humans suggest that the somatosensory cortex is required both for detecting and discriminating between tactile stimuli. We used magnetic brain stimulation to interfere with human somatosensory cortex while healthy volunteers detected and discriminated between vibrations applied to their fingertips. We found that the somatosensory cortex is required for keeping vibrotactile stimuli in memory for short periods of time and for comparing two vibrotactile stimuli, but is not required merely for detecting vibrotactile stimulation. This suggests that human primary somatosensory cortex is not always needed for vibrotactile detection. PMID- 27233149 TI - Laser ablation-inductively coupled plasma-mass spectrometry imaging of white and gray matter iron distribution in Alzheimer's disease frontal cortex. AB - Iron deposition in the brain is a feature of normal aging, though in several neurodegenerative disorders, including Alzheimer's disease, the rate of iron accumulation is more advanced than in age-matched controls. Using laser ablation inductively coupled plasma-mass spectrometry imaging we present here a pilot study that quantitatively assessed the iron content of white and gray matter in paraffin-embedded sections from the frontal cortex of Alzheimer's and control subjects. Using the phosphorus image as a confirmed proxy for the white/gray matter boundary, we found that increased intrusion of iron into gray matter occurs in the Alzheimer's brain compared to controls, which may be indicative of either a loss of iron homeostasis in this vulnerable brain region, or provide evidence of increased inflammatory processes as a response to chronic neurodegeneration. We also observed a trend of increasing iron within the white matter of the frontal cortex, potentially indicative of disrupted iron metabolism preceding loss of myelin integrity. Considering the known potential toxicity of excessive iron in the brain, our results provide supporting evidence for the continuous development of novel magnetic resonance imaging approaches for assessing white and gray matter iron accumulation in Alzheimer's disease. PMID- 27233150 TI - Allergic skin sensitization promotes eosinophilic esophagitis through the IL-33 basophil axis in mice. AB - BACKGROUND: Eosinophilic esophagitis (EoE) is an allergic inflammatory disorder characterized by accumulation of eosinophils in the esophagus. EoE often coexists with atopic dermatitis, a chronic inflammatory skin disease. The impaired skin barrier in patients with atopic dermatitis has been suggested as an entry point for allergic sensitization that triggers development of EoE. OBJECTIVE: We sought to define the mechanisms whereby epicutaneous sensitization through a disrupted skin barrier induces development of EoE. METHODS: To elicit experimental EoE, mice were epicutaneously sensitized with ovalbumin (OVA), followed by intranasal OVA challenge. Levels of esophageal mRNA for TH2 cytokines and the IL-33 receptor Il1rl1 (St2) were measured by using quantitative PCR. Esophageal eosinophil accumulation was assessed by using flow cytometry and hematoxylin and eosin staining. In vivo basophil depletion was achieved with diphtheria toxin treatment of Mcpt8DTR mice, and animals were repopulated with bone marrow basophils. mRNA analysis of esophageal biopsy specimens from patients with EoE was used to validate our findings in human subjects. RESULTS: Epicutaneous sensitization and intranasal challenge of wild-type mice resulted in accumulation of eosinophils and upregulation of TH2 cytokines and St2 in the esophagus. Disruption of the IL 33-ST2 axis or depletion of basophils reduced these features. Expression of ST2 on basophils was required to accumulate in the esophagus and transfer experimental EoE. Expression of IL1RL1/ST2 mRNA was increased in esophageal biopsy specimens from patients with EoE. Topical OVA application on unstripped skin induced experimental EoE in filaggrin-deficient flaky tail (ft/ft) mice but not in wild-type control or ft/ft.St2-/- mice. CONCLUSION: Epicutaneous allergic sensitization promotes EoE, and this is critically mediated through the IL-33-ST2 basophil axis. PMID- 27233151 TI - Reply. PMID- 27233152 TI - Improvements with sublingual house dust mite immunotherapy in allergic rhinitis. PMID- 27233154 TI - The contribution of different adipose tissue depots to plasma plasminogen activator inhibitor-1 (PAI-1) levels. AB - Increased plasma plasminogen activator inhibitor-1 (PAI-1) level is considered a mechanistic pathway through which obesity contributes to increased cardiovascular disease risk. Abdominal adipose tissue specifically, is a major PAI-1 source with visceral adipose tissue (VAT), an ectopic fat depot, generally considered to produce more PAI-1 than subcutaneous adipose tissue. However, this does not necessarily lead to increased plasma PAI-1 levels. This review provides an overview of studies investigating the association between body fat distribution and plasma PAI-1 levels. It discusses factors that influence this relationship and also considers the contribution of other tissue to plasma PAI-1 levels, placing the relative contribution of adipose tissue into perspective. In conclusion, the relationship between VAT and plasma PAI-1 levels is not fixed but can be modulated by a number of factors such as the size of the subcutaneous adipose tissue depot, ethnicity, possibly genetics and other obesity-related metabolic abnormalities. PMID- 27233153 TI - CD151, a laminin receptor showing increased expression in asthmatic patients, contributes to airway hyperresponsiveness through calcium signaling. AB - BACKGROUND: Airway smooth muscle (ASM) contraction underpins airway constriction; however, underlying mechanisms for airway hyperresponsiveness (AHR) remain incompletely defined. CD151, a 4-transmembrane glycoprotein that associates with laminin-binding integrins, is highly expressed in the human lung. The role of CD151 in ASM function and its relationship to asthma have yet to be elucidated. OBJECTIVE: We sought to ascertain whether CD151 expression is clinically relevant to asthma and whether CD151 expression affects AHR. METHODS: Using immunohistochemical analysis, we determined the expression of CD151 in human bronchial biopsy specimens from patients with varying asthma severities and studied the mechanism of action of CD151 in the regulation of ASM contraction and bronchial caliber in vitro, ex vivo, and in vivo. RESULTS: The number of CD151+ ASM cells is significantly greater in patients with moderate asthma compared with those in healthy nonasthmatic subjects. From loss- and gain-of-function studies, we reveal that CD151 is required for and enhances G protein-coupled receptor (GPCR)-induced peak intracellular calcium release, the primary determinant of excitation-contraction coupling. We show that the localization of CD151 can also be perinuclear/cytoplasmic and offer an explanation for a novel functional role for CD151 in supporting protein kinase C (PKC) translocation to the cell membrane in GPCR-mediated ASM contraction at this site. Importantly, CD151-/- mice are refractory to airway hyperreactivity in response to allergen challenge. CONCLUSIONS: We identify a role for CD151 in human ASM contraction. We implicate CD151 as a determinant of AHR in vivo, likely through regulation of GPCR-induced calcium and PKC signaling. These observations have significant implications in understanding the mechanism for AHR and the efficacy of new and emerging therapeutics. PMID- 27233155 TI - Mass spectrometric imaging of flavonoid glycosides and biflavonoids in Ginkgo biloba L. AB - Ginkgo biloba L. is known to be rich in flavonoids and flavonoid glycosides. However, the distribution within specific plant organs (e.g. within leaves) is not known. By using HPLC-MS and MS/MS we have identified a number of previously known G. biloba flavonoid glycosides and biflavonoids from leaves. Namely, kaempferol, quercetin, isorhamnetin, myricetin, laricitrin/mearnsetin and apigenin glycosides were identified. Furthermore, biflavonoids like ginkgetin/isoginkgetin were also detected. The application of MALDI mass spectrometric imaging, enabled the compilation of concentration profiles of flavonoid glycosides and biflavonoids in G. biloba L. leaves. Both, flavonoid glycosides and biflavonoids show a distinct distribution in leaf thin sections of G. biloba L. PMID- 27233156 TI - Self versus examiner administration of the Ocular Surface Disease Index(c). AB - PURPOSE: To compare the difference in Ocular Surface Disease Index(c) (OSDI) scores when participants were given the OSDI to complete on their own (self guided, SG), versus under the guidance of the examiner (examiner-guided, EG). METHODS: 100 participants enrolled in this prospective two-visit study (fifty under-45 years old, 38F/12M; and fifty 45 years-and-older, 42F/8M). Participants who scored >=1 on the Subjective Evaluation of Symptoms of Dryness (SESoD) were included in this study. Participants completed the OSDI SG during the first visit. Participants returned the next day and repeated the OSDI, but with EG (with standardized instructions). Participants were under deception and believed that they were comparing the OSDI to the SESoD. RESULTS: The mean OSDI score of the SG and EG administration was 32.0+/-17.3 and 33.8+/-19.6 respectively (p>0.05) with 95% limits of agreement between -20.6 and +24.2. The correlation between SG and EG administration was Spearman's r=0.81, p<0.01. The mean difference between SG and EG was not significant (p>0.05) for both the under-45 group, and 45-and-older group. The 95% limits of agreement for the under-45 group were smaller than the 45-and-older group (under-45: [-15.5, +13.1,], 45-and older: [-23.3, +32.2]). A significant difference was found between 8 of the 12 questions items (all p<=0.01). However, the mean difference for each was <0.6 and was not considered to be clinically significant. CONCLUSION: There was no clinically significant difference in OSDI score between SG and EG administration, however having instructions provided with EG administration affected variability of scores in the older group more than the younger group. PMID- 27233157 TI - Real-Time Assessment of Fatigue in Patients With Multiple Sclerosis: How Does It Relate to Commonly Used Self-Report Fatigue Questionnaires? AB - OBJECTIVES: (1) To assess real-time patterns of fatigue; (2) to assess the association between a real-time fatigue score and 3 commonly used questionnaires (Checklist Individual Strength [CIS] fatigue subscale, Modified Fatigue Impact Scale (MFIS), and Fatigue Severity Scale [FSS]); and (3) to establish factors that confound the association between the real-time fatigue score and the conventional fatigue questionnaires in patients with multiple sclerosis (MS). DESIGN: Cross-sectional study. SETTING: MS-specialized outpatient facility. PARTICIPANTS: Ambulant patients with MS (N=165) experiencing severe self-reported fatigue. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: A real-time fatigue score was assessed by sending participants 4 text messages on a particular day (How fatigued do you feel at this moment?; score range, 0-10). Latent class growth mixed modeling was used to determine diurnal patterns of fatigue. Regression analyses were used to assess the association between the mean real-time fatigue score and the CIS fatigue subscale, MFIS, and FSS. Significant associations were tested for candidate confounders (eg, disease severity, work status, sleepiness). RESULTS: Four significantly different fatigue profiles were identified by the real-time fatigue score, namely a stable high (n=79), increasing (n=57), stable low (n=16), and decreasing (n=13). The conventional questionnaires correlated poorly (r<.300) with the real-time fatigue score. The Epworth Sleepiness Scale significantly reduced the regression coefficient between the real-time fatigue score and conventional questionnaires, ranging from 15.4% to 35%. CONCLUSIONS: Perceived fatigue showed 4 different diurnal patterns in patients with MS. Severity of sleepiness is an important confounder to take into account in the assessment of fatigue. PMID- 27233207 TI - Ozonation of indomethacin: Kinetics, mechanisms and toxicity. AB - Ozonation of a commonly used non-steroidal anti-inflammatory drug indomethacin (IM) was studied. Kinetic constants of IM with ozone and hydroxyl radicals were measured at an order of magnitude of 105M-1s-1 and 109M-1s-1, respectively. IM was degraded within 7min under the lowest ozone dose, but TOC removal was only 50% even under the highest ozone dose used in the experiments. Ozone rather than hydroxyl radicals was found to be the main oxidant during reaction, with a contribution rate of 80% under pH 7. Six intermediates were identified by high resolution mass spectrometer. Nitrogen atom, CC double bond and benzene ring were found to be the main reaction sites. Electrophilic attack or Criegee cyclo addition were proved to be the most probable pathways at the first step. The formation mechanism of one of the ozone products was first proposed during the experiment, then confirmed by the density functional theory (DFT) calculation. Acetic acid, formic acid and oxalic acid were detected as small molecule organic products. The toxicity change during ozonation was measured by luminescent bacterium with results showing that the toxicity can be reduced to zero when ozone dose was high enough. PMID- 27233208 TI - Use of fluorescence EEM to monitor the removal of emerging contaminants in full scale wastewater treatment plants. AB - This study investigated the applicability of different techniques for fluorescence excitation/emission matrices data interpretations, including peak picking method, fluorescence regional integration and PARAFAC modelling, to act as surrogates in predicting emerging trace organic compounds (ETOrCs) removal during conventional wastewater treatments that usually comprise primary and secondary treatments. Results showed that fluorescence indexes developed using alternative methodologies but indicative of a same dissolved organic matter component resulted in similar predictions of the removal of the target compounds. The peak index defined by the excitation/emission wavelength positions (lambdaex/lambdaem) 225/290nm and related to aromatic proteins and tyrosine-like fluorescence was determined to be a particularly suitable surrogate for monitoring ETOrCs that had very high removal rates (average removal >70%) (i.e., triclosan, caffeine and ibuprofen). The peak index defined by lambdaex/lambdaem=245/440nm and the PARAFAC component with wavelength of the maxima lambdaex/lambdaem=245, 350/450, both identified as humic-like fluorescence, were found remarkably well correlated with ETOrCs such as atenolol, naproxen and gemfibrozil that were moderately removed (51-70% average removal). Finally, the PARAFAC component with wavelength of the maxima lambdaex/lambdaem=<240, 315/380 identified as microbial humic-like fluorescence was the only index correlated with the removal of the antibiotic trimethoprim (average removal 68%). PMID- 27233209 TI - Identification of non-regulated polycyclic aromatic compounds and other markers of urban pollution in road tunnel particulate matter. AB - A combination of silicone rubber extraction and non-target and suspect screening by gas chromatography coupled to high-resolution time-of flight mass spectrometry was used for the identification of compounds in particulate matter (PM). Tunnel PM is a proxy for local road pollution that constitutes a hazard to the urban environment and human health. The use of silicone rubber for the extraction of PM allowed the pre-concentration of a wide range of compounds for non-target analysis while minimising the effects of the sample matrix. As expected, polycyclic aromatic compounds (PACs) constituted the major group of compounds identified, but only 5 of 50 PACs identified were amongst those regularly monitored and many of them were alkylated or contained a heteroatom. Urban markers of contamination such as organophosphate flame-retardants, phthalates, benzothiazoles, musk compounds and a plasticiser were also identified. The level of confidence for the identifications was high based on accurate mass, the pattern of fragmentation and retention. The unequivocal identification of 16 compounds, from all groups, was confirmed by co-chromatography with standards and the compounds semi-quantified. Most of the PACs identified are not regularly monitored, and the hazards they pose are therefore unknown. Some of these PACs are known to be more persistent and mobile in the environment than the EPA PAH16. PMID- 27233210 TI - Biodegradation of 17beta-estradiol by bacteria isolated from deep sea sediments in aerobic and anaerobic media. AB - Endocrine disrupting compounds (EDCs) are considered as high research priority being a source of potential adverse ecological health effects in environmental waters. 17beta-Estradiol (E2), a recalcitrant natural estrogen, is typically encountered in wastewater treatment plants (WWTPs) at levels ranging 10-30ngL-1 in the influent flow and 1-3ngL-1 in the effluent flow. The exposure to even extremely low concentrations of E2 may interfere with the normal function of the endocrine system of organisms. In this study, five bacteria isolated from enrichment cultures of sediments of mud volcanoes of the Gulf of Cadiz (Moroccan Iberian margin) were identified as aerobic E2 biodegraders, which produce low amounts of biotransformed estrone (E1). Analysis of 16S rDNA gene sequences identified three of them as Virgibacillus halotolerans, Bacillus flexus and Bacillus licheniformis. Among the set of strains, Bacillus licheniformis showed also ability to biodegrade E2 under anaerobic conditions. PMID- 27233211 TI - Postvoidal residual urine is the most significant non-invasive diagnostic test to predict the treatment outcome in children with non-neurogenic lower urinary tract dysfunction. AB - INTRODUCTION: Uroflowmetry (UF) alone is often inadequate or unreliable to diagnose lower urinary tract dysfunction (LUTD). Therefore, other non-invasive tests, such as ultrasound (US), post-voiding residual volume (PVR) assessment and symptom scales, are used as well for objective definition of the problem. OBJECTIVE: The aim of this study was to investigate the possible predictive function of the non-invasive diagnostic tests for the response to treatment. STUDY DESIGN: The prospective registry data of 240 patients with LUTD, from November 2006 to September 2013, were retrospectively analyzed. All patients were aged 5-14 years old. Patients with a previous diagnosis of vesicoureteral reflux (VUR), neurogenic bladder, monosymptomatic nocturnal enuresis (NE) were excluded from the study. Uroflowmetry, US, PVR and the Dysfunctional Voiding and Incontinence Symptom Scale (DVISS) were performed on every patient at their first visit and follow-ups. A DVISS <9 was considered as the DVISS response; parental opinion was based on International Continence Society criteria of clinical response. Time passed until clinical response was the last outcome parameter. RESULTS: Mean age was 8.2 years. Median follow-up was 60.5 months. A total of 62% of patients had complete response, 28.1% had partial response, and 9.7% had no response. Demographic variables were not associated with clinical outcome. Co existing enuresis nocturna, multiple pharmacotherapy, and increased DVISS were associated with longer time until clinical response. Post-voiding residual volume assessment was the only test to have a prognostic value. DISCUSSION: Resolution rates of LUTD ranged from 40 to 90%. High resolution rate could be attributed to the long follow-up period, and the chance of spontaneous resolution. Treatment modalities and co-existing NE were associated with longer time until clinical response. Only PVR was associated with prognosis. This was the first study in literature to report such findings. It was seen that the normalization of pathologic patterns was a good sign for treatment success. The DVISS results showed significantly higher rates of incontinence compared to initial symptoms defined by the patients and/or their parents. This showed the importance of using scoring systems to better define the severity of symptoms. It was hard to establish a standardized cut-off value for bladder wall thickness on US. However, US was a good test for diagnosing additional pathologies. CONCLUSION: Increased PVR was the single tool that was associated with prognosis and, therefore, should always be performed after UF. In addition, DVISS can help parents be counseled about their treatment expectations. PMID- 27233212 TI - Stimuli responsive drug delivery systems based on nano-graphene for cancer therapy. AB - Nano-graphene as a class of two-dimensional sp2 carbon nanomaterial has attracted tremendous attentions in various fields in the past decade. Utilizing its unique physical and chemical properties, nano-graphene has also shown great promises in the area of biomedicine, for application in biosensing, imaging and therapy. In particular, with all atoms exposed on its surface, nano-graphene exhibits ultra high surface area available for efficient binding/loading of various biomolecules of interests, and has been widely used as multifunctional nano-carriers for drug and gene delivery. In this review article, we will summarize the recent advances in the development of nano-graphene as stimuli-responsive nano-carriers for drug delivery, as well as the applications of these smart systems for cancer therapy. PMID- 27233214 TI - Inhibitory effect of extracellular purine nucleotide and nucleoside concentrations on T cell proliferation. AB - The release of nucleic acids and derivatives after tissue-injury may affect cellular immune-response. We studied the impact of extracellular ribo-, desoxyribonucleotides and nucleosides on T-cell immunity. Peripheral-blood mononuclear-cells (PBMCs) or isolated CD3+T-cells obtained from 6 healthy donors were stimulated via CD3/CD28 Dynabeads or dendritic cells (DCs) in the presence or absence of pyrimidine-, purine-nucleotides and -nucleosides (range 2-200uM). Addition of deoxy-, guanosine-triphosphate (dGTP, GTP) and guanosine resulted concentration dependent in a complete, adenosine-triphosphate (ATP) in a partial inhibition of the induced T-cell-proliferation. Deoxyadenosine-triphosphate (dATP), adenosine and the pyrimidine-ribo- and -deoxyribonucleotides displayed no inhibitory capacity. Inhibitory effects of dGTP and GTP, but not of guanosine and ATP were culture-media-dependent and could be almost abrogated by use of the serum-free lymphocyte-culture-media X-Vivo15 instead of RPMI1640 with standard supplementation. In contrast to RPMI1640, X-Vivo15 resulted in a significant down regulation of the cell-surface-located ectonucleotidases CD39 (Ecto-Apyrase) and CD73 (Ecto-5'-Nucleotidase), critical for the extracellular nucleotides hydrolysis to nucleosides, explaining the loss of inhibition mediated by dGTP and GTP, but not Guanosine. In line with previous findings ATP was found to exert immunosuppressive effects on T-cell-proliferation. Purine-nucleotides, dGTP and GTP displayed a higher inhibitory capacity, but seem to be strictly dependent on the microenvironmental conditions modulating the responsiveness of the respective T-lymphocytes. Further evaluation of experimental and respective clinical settings should anticipate these findings. PMID- 27233213 TI - Graphene-based nanomaterials for bioimaging. AB - Graphene-based nanomaterials, due to their unique physicochemical properties, versatile surface functionalization, ultra-high surface area, and good biocompatibility, have attracted considerable interest in biomedical applications such as biosensors, drug delivery, bioimaging, theranostics, and so on. In this review, we will summarize the current advances in bioimaging of graphene-based nanomaterials, including graphene, graphene oxide (GO), reduced graphene oxide (rGO), graphene quantum dots (GQDs), and their derivatives. There are two methods to synthesize graphene-based nanomaterials: in situ synthesis and binding method. We will highlight the molecular imaging modalities including optical imaging (fluorescence (FL), two-photon FL, and Raman imaging), PET/SPECT (positron emission tomography/single photon emission computed tomography), MRI (magnetic resonance imaging), PAI (photoacoustic imaging), CT (computed tomography), and multimodal imaging. In the end, we will elaborate on the prospects and challenges of their future bioimaging applications. PMID- 27233216 TI - Thalamic reticular nucleus in Caiman crocodilus: forebrain connections. AB - Forebrain connections of the thalamic reticular nucleus associated with the lateral forebrain bundle were analyzed in Caiman crocodilus. Both the compact portion, the dorsal peduncular nucleus, and the diffuse part, the perireticular region, associated with the lateral forebrain bundle, were studied. A small tracer injection into the dorsal peduncular nucleus demonstrated reciprocal connections with a restricted portion of the dorsal thalamus. Tracer placements into this nucleus retrogradely labeled cells in a caudal portion of the ventrolateral area of the telencephalon. These results are compared with similar studies in other amniotes. PMID- 27233215 TI - Genetic knockout of the alpha7 nicotinic acetylcholine receptor gene alters hippocampal long-term potentiation in a background strain-dependent manner. AB - Reduced alpha7 nicotinic acetylcholine receptor (nAChR) function is linked to impaired hippocampal-dependent sensory processing and learning and memory in schizophrenia. While knockout of the Chrna7 gene encoding the alpha7nAChR on a C57/Bl6 background results in changes in cognitive measures, prior studies found little impact on hippocampal synaptic plasticity in these mice. However, schizophrenia is a multi-genic disorder where complex interactions between specific genetic mutations and overall genetic background may play a prominent role in determining phenotypic penetrance. Thus, we compared the consequences of knocking out the alpha7nAChR on synaptic plasticity in C57/Bl6 and C3H mice, which differ in their basal alpha7nAChR expression levels. Homozygous alpha7 deletion in C3H mice, which normally express higher alpha7nAChR levels, resulted in impaired long-term potentiation (LTP) at hippocampal CA1 synapses, while C3H alpha7 heterozygous mice maintained robust LTP. In contrast, homozygous alpha7 deletion in C57 mice, which normally express lower alpha7nAChR levels, did not alter LTP, as had been previously reported for this strain. Thus, the threshold of Chrna7 expression required for LTP may be different in the two strains. Measurements of auditory gating, a hippocampal-dependent behavioral paradigm used to identify schizophrenia-associated sensory processing deficits, was abnormal in C3H alpha7 knockout mice confirming that auditory gating also requires alpha7nAChR expression. Our studies highlight the importance of genetic background on the regulation of synaptic plasticity and could be relevant for understanding genetic and cognitive heterogeneity in human studies of alpha7nAChR dysfunction in mental disorders. PMID- 27233217 TI - Aberrant structural and functional connectivity in the salience network and central executive network circuit in schizophrenia. AB - Consistent structural and functional abnormities have been detected in the salience network (SN) and the central-executive network (CEN) in schizophrenia. SN, known for its critical role in switching CEN and default-mode network (DMN) during cognitively demanding tasks, is proved to show aberrant regulation on the interaction between DMN and CEN in schizophrenia. However, it has not been elucidated whether there is a direct alteration of structural and functional connectivity between SN and CEN. 22 schizophrenia patients and 21 healthy controls were recruited for functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) in present study. The results show that schizophrenia patients had lower fractional anisotropy (FA) in right inferior long fasciculus (ILF), left inferior fronto-occipital fasciculus (IFOF) and callosal body than healthy controls. Significantly reduced functional connectivity was also found between right fronto-insular cortex (rFIC) and right posterior parietal cortex (rPPC). FA in right ILF was positively correlated with the functional connectivity of rFIC-rPPC. Therefore, we proposed a disruption of structural and functional connectivity and a positive anatomo-functional relationship in SN-CEN circuit, which might account for a core feature of schizophrenia. PMID- 27233218 TI - Up-regulation of activating transcription factor 4 induces severe loss of dopamine nigral neurons in a rat model of Parkinson's disease. AB - Activating transcription factor 4 (ATF4) is a member of the PERK signaling pathway, which directly binds endoplasmic reticulum stress target genes and plays a crucial role in both adaptations to stress and activation of apoptosis. Previous publications demonstrated conflicting evidence on the role of ATF4 in the pathogenesis of neurodegenerative disorders. In this study, we used recombinant adeno-associate virus (rAAV)-mediated gene transfer to investigate if the sustained up-regulation of ATF4 launches a pro-survival or pro-death trend in the dopamine (DA) cells of the substantia nigra pars compacta in a rat model of Parkinson-like neurodegeneration induced by human alpha-synuclein (alphaS) overexpression. We showed that ATF4 does not protect nigral DA neurons against an alphaS-induced pathology. Moreover, the rAAV-mediated overexpression of ATF4 resulted in severe nigra-striatal degeneration via activation of caspases 3/7. PMID- 27233219 TI - Kisspeptin in the medial amygdala and sexual behavior in male rats. AB - The medial amygdala (MeA) is crucial for sexual behavior; kisspeptin (Kiss1) also plays a role in sexual function. Kisspeptin receptor (Kiss1r) knockout mice display no sexual behavior. Recently Kiss1 and Kiss1r have been discovered in the posterodorsal subnucleus of the medial amygdala (MePD). We hypothesised that Kiss1 in the MePD may have an influence on male sexual behavior. To test this we bilaterally cannulated the MePD and infused kisspeptin-10 in male rats. This caused the rats to have multiple erections, an effect specific to Kiss1 receptor activation, because Kiss1r antagonism blocked the erectile response. When Kiss1 was infused into the lateral cerebroventricle, there were no observed erections. We also measured the plasma levels of LH when Kiss1 is infused into the MePD or lateral cerebroventricle; Kiss1 increased plasma LH to comparable levels when infused into both sites. We conclude that Kiss1 has a role in male sexual behavior, which is specific to the MePD. PMID- 27233221 TI - Assessing Community Participation: Comparing Self-Reported Participation Data with Organizational Attendance Records. AB - How well do self-reported levels of community and organizational participation align with recorded acts of community and organizational participation? This study explores this question among participants in social action community organizing initiatives by comparing responses on a community participation scale designed to retrospectively assess community participation (T1, n = 482; T2, n = 220) with individual participants' attendance records in various social action organizing activities over two 1-year periods. By testing the self-reported measure's overall and item-by-item association with documented participation in various types of organizing activities, we find that the self-report measure is positively, but weakly correlated with actual participation levels in community organizing activities. Moreover, associations between self-report and recorded acts of participation differ by types of activity. Examining this unique source of data raises important questions about how community participation is conceptualized and measured in our field. Implications are explored for theory and measurement of participation in community and organizational contexts. PMID- 27233220 TI - Relatedness-dependent rapid development of brain activity in anterior temporal cortex during pair-association retrieval. AB - Functional MRI studies have revealed that the brain activity in the anterior temporal cortex during memory retrieval increases over months after memory encoding. Behavioral evidence has demonstrated that long-term memory can sometimes be consolidated more rapidly in one or two days. In the present functional MRI study, we manipulated the relatedness between paired faces to be retrieved in a pair-association task. The brain activity in the anterior temporal cortex during retrieval of paired associates increased rapidly in one day, as shown in previous studies. We found that the speed of the brain activity development was dependent on the level of semantic relatedness of paired faces. The results suggest that the semantic relatedness enhances the speed of formation of memory representation in the anterior temporal cortex. PMID- 27233222 TI - Lateral nasal artery perforator V-Y flap for reconstruction of nasal defects. PMID- 27233223 TI - Subcutaneous pedicle V-Y flap for release of incomplete congenital syndactyly. AB - BACKGROUND: Various procedures for correction of congenital syndactyly of hand or foot have been described. For incomplete syndactyly, some of the reported techniques use only local flaps from surrounding tissues. A novel technique for the correction of incomplete syndactyly, using a dorsal triangular flap and two palmar small flaps, is described in this article. METHODS: A triangular flap is first marked on the affected web space. The size of the flap should be the same as the unaffected side or other web space. Then a straight line is marked from the proximal apex of the triangle to the level of the metacarpophalangeal (MP) joint. After full skin incision, minimal peripheral undermining is done, and the triangular flap is transposed proximally, as in the Y-V advancement procedure, and sutured. Then two incisions are made from the distal part of the flap, transposing small flaps as in the five-flap method, and closed primarily. RESULTS: We treated ten cases of congenital syndactyly of the hand or foot. We were able to correct a good web space without skin grafting in all cases. CONCLUSION: The design for our technique is simple, and the technique can be performed easily. The operation can be performed in a short time, the blood supply of the flap is preserved, the flap has a wide range of motion, and a deep and smooth dorsal slope is produced. This technique is an attractive alternative to previously reported methods for syndactyly correction. PMID- 27233224 TI - Improved voice function with anastomosis between somatic and autonomic nerve when ileocolon flap is used for simultaneous reconstruction of esophagus and voice. PMID- 27233225 TI - Commentary on "Blue-blocking glasses as additive treatment for mania: a randomized placebo-controlled trial". PMID- 27233226 TI - A three-tier algorithm for guanidinoacetate methyltransferase (GAMT) deficiency newborn screening. AB - BACKGROUND: Guanidinoacetate methyltransferase (GAMT) deficiency is a rare disorder of creatine biosynthesis presenting with epilepsy and developmental delay in infancy. Excellent developmental outcomes have been reported for infants treated from birth due to a family history. The BC Newborn Screening Program initiated a 3year pilot screening study for GAMT deficiency to evaluate the performance of a novel three-tiered screening approach. METHODS: Over 36months all bloodspots submitted for routine newborn screening were included in the pilot study (de-identified). Initial GAA measurement was integrated into the standard acylcarnitine/amino acid first-tier assay. All samples with elevated GAA were subjected to second-tier GAA analysis by LC-MS/MS integrated into an existing branched-chain amino acid (MSUD) method. GAMT gene sequencing was completed on the original bloodspot for all specimens with elevated GAA on the second-tier test. The protocol allowed for re-identification for treatment of any specimen with one or two likely pathogenic GAMT mutations. RESULTS: Over the study period 135,372 specimens were tested with 259 (0.19%) over the first-tier GAA cut-off. The second-tier assay removed an interference falsely elevating GAA levels, and only 3 samples required genotyping. No mutations were identified in any samples, all were deemed negative screens and no follow-up was initiated. CONCLUSIONS: A three-tier algorithm for GAMT newborn screening showed excellent test performance with zero false positives. No cases were detected, supporting a low incidence for this disorder. Given the low incremental costs and evidence of positive outcomes with early intervention, GAMT deficiency remains an excellent candidate for newborn screening. PMID- 27233227 TI - Evidence of a wide spectrum of cardiac involvement due to ACAD9 mutations: Report on nine patients. AB - Acyl-CoA dehydrogenase 9 (ACAD9) is a mitochondrial protein involved in oxidative phosphorylation complex I biogenesis. This protein also exhibits acyl-CoA dehydrogenase (ACAD) activity. ACAD9-mutated patients have been reported to suffer from primarily heart, muscle, liver, and nervous system disorders. ACAD9 mutation is suspected in cases of elevated lactic acid levels combined with complex I deficiency, and confirmed by ACAD9 gene analysis. At least 18 ACAD9 mutated patients have previously been reported, usually displaying severe cardiac involvement. We retrospectively studied nine additional patients from three unrelated families with a wide spectrum of cardiac involvement between the families as well as the patients from the same families. All patients exhibited elevated lactate levels. Deleterious ACAD9 mutations were identified in all patients except one for whom it was not possible to recover DNA. To our knowledge, this is one of the first reports on isolated mild ventricular hypertrophy due to ACAD9 mutation in a family with moderate symptoms during adolescence. This report also confirms that dilated cardiomyopathy may occur in conjunction with ACAD9 mutation and that some patients may respond clinically to riboflavin treatment. Of note, several patients suffered from patent ductus arteriosus (PDA), with one exhibiting a complex congenital heart defect. It is yet unknown whether these cardiac manifestations were related to ACAD9 mutation. In conclusion, this disorder should be suspected in the presence of lactic acidosis, complex I deficiency, and any cardiac involvement, even mild. PMID- 27233228 TI - Next generation sequencing of patients with mut methylmalonic aciduria: Validation of somatic cell studies and identification of 16 novel mutations. AB - Mutations in the MUT gene, which encodes the mitochondrial enzyme methylmalonyl CoA mutase, are responsible for the mut form of methylmalonic aciduria (MMA). In this study, a next generation sequencing (NGS) based gene panel was used to analyze 53 patients that had been diagnosed with mut MMA by somatic cell complementation analysis. A total of 54 different mutations in MUT were identified in 48 patients; 16 novel mutations were identified, including 1 initiation site mutation (c.2T>C [p.M1?]), 1 missense mutation (c.566A>T [p.N189I]), 2 nonsense mutations (c.129G>A [p.W43*] and c.1975C>T [p.Q659*]), 2 mutations affecting splice sites (c.753+3A>G and c.754-2A>G), 8 small insertions, deletions, and duplications (c.29dupT [p.L10Ffs*39], c.55dupG [p.V19Gfs*30], c.631_633delGAG [p.E211del], c.795_796insT [p.M266Yfs*7], c.1061delCinsGGA [p.S354Wfs*20], c.1065_1068dupATGG [p.S357Mfs*5], c.1181dupT [p.L394Ffs*30], c.1240delG [p.E414Kfs*17]), a large insertion (c.146_147ins279), and a large deletion involving exon 13. Phenotypic rescue and cDNA analysis were used to confirm that the c.146_147ins279 and c.631_633delGAG mutations were associated with the decreased methylmalonyl-CoA mutase function observed in the patient fibroblasts. In five patients, the NGS panel did not confirm the diagnosis made by complementation analysis. One of these patients was found to carry 2 novel mutations (c.433G > A [p.E145K] and c.511A>C [p.N171H]) in the SUCLG1 gene. PMID- 27233229 TI - Web-based information on the treatment of oral leukoplakia - quality and readability. AB - OBJECTIVE: To categorise the content and assess the quality and readability of the online information regarding the treatment for oral leukoplakia. METHODS: An online search using the term 'leukoplakia treatment' was carried out on 8th June 2015 using the Google search engine. The content, quality and readability of the first 100 sites were explored. The quality of the web information was assessed using the following tools, the DISCERN instrument and the Journal of the American Medical Association (JAMA) benchmarks for website analysis and the HON seal. Readability was assessed via the Flesch Reading Ease Score. RESULTS: The search strategy generated 357 000 sites on the Google search engine. Due to duplicate links, non-operating links and irrelevant links, a total of 47 of the first 100 websites were included in this study. The mean overall rating achieved by included websites using the DISCERN instrument was 2.3. With regard to the JAMA benchmarks, the vast majority of examined websites (95.7%) completely fulfilled the disclosure benchmark and less than 50% of included websites met the three remaining criteria. A mean total readability score of 47.5 was recorded with almost 90% of websites having a readability level ranging from fairly difficult to very difficult. CONCLUSION: Based on this study, the online health information regarding oral leukoplakia has challenging readability with content of questionable accuracy. As patients often search for health information online, it would be prudent for clinicians to highlight the caution with which online information should be interpreted. PMID- 27233230 TI - Activity-dependent calcium signalling in oligodendrocyte generation. AB - Throughout postnatal life oligodendrocyte progenitor cells proliferate and differentiate into mature myelinating oligodendrocytes in the central nervous system. Neuronal activity is a major external signal controlling this process. Neurotransmitters, or other signalling molecules released in response to neuronal activity, evoke transient increases in intracellular calcium in oligodendrocyte progenitor cells. As calcium can mediate cellular processes, including the transcription of genes involved in oligodendrocyte progenitor cell division and maturation, a rise in intracellular calcium may be a key signal translating changes in neuronal activity into changes in oligodendrocyte progenitor cell behaviour. Here we review recent advances in our understanding of how neuronal activity can evoke calcium signalling in oligodendrocyte progenitor cells. PMID- 27233231 TI - Long-term population patterns of rodents and associated damage in German forestry. AB - BACKGROUND: Several rodent species can damage forest trees, especially at young tree age in afforestation. Population outbreaks of field voles (Microtus agrestis L.) and bank voles (Myodes glareolus Schreber) in particular can cause losses. RESULTS: Analyses of long-term time series indicate good synchrony of population abundance in rodent species associated with damage in forestry. This synchrony could be related to the effect of beech (Fagus spec.) mast in the previous year on population growth rates of both species. In shorter time series from Eastern Germany, damage in forestry was mostly associated with autumn abundances of rodents. Environmental factors such as beech mast and snow cover did not explain additional variation in rodent damage to trees. CONCLUSIONS: Beech mast is a good indicator of long-term rodent abundance in Northern German afforestation areas. However, rodent damage to forestry in Central Germany did not seem to depend on environmental parameters other than rodent abundance at large scale. As a result, there is still uncertainty about the link between environmental predictors and rodent damage to forestry, and further experimental work is required to identify suitable environmental drivers and their interplay with other potential factors such as the local predator community. (c) 2016 Society of Chemical Industry. PMID- 27233232 TI - Arginine-Glycine Amidinotransferase Deficiency and Functional Characterization of Missense Variants in GATM. AB - Arginine-glycine amidinotransferase (GATM) deficiency is an autosomal-recessive disorder caused by pathogenic variants in GATM. Clinical features include intellectual disability, hypotonia, and myopathy. Due to normal neurodevelopment in asymptomatic individuals on creatine monotherapy, GATM deficiency is a good candidate for newborn screening. To determine the carrier frequency of GATM deficiency, we performed functional characterization of rare missense variants in GATM reported as heterozygous in the Exome Variant Server database. To assess phenotype and genotype correlation, we developed a clinical severity scoring system. Two patients with mild phenotype had a nonsense missense variant. Severe phenotype was present in patients with missense as well as truncating variants. There seems to be no phenotype and genotype correlation. We cloned a novel GATM transcript. We found seven missense variants retaining 0% of wild-type GATM activity indicating putative pathogenicity. Based on our study results, high Genomic Evolutionary Rate Profiling conservation score, conserved amino acid substitution in species, and low allele frequency in exome databases would be the most sensitive in silico analysis tools to predict pathogenicity of missense variants. We present first study of the functional characterization of missense variants in GATM as well as clinical severity score of patients with GATM deficiency. PMID- 27233233 TI - Acidic tumor microenvironment in human melanoma. AB - One characteristic of solid tumors such as malignant melanoma is the acidification of the tumor microenvironment. The deregulation of cancer cell metabolism is considered a main cause of extracellular acidosis. Here, cancer cells utilize aerobic glycolysis instead of oxidative phosphorylation even under normoxic conditions, as originally described by Otto Warburg. These metabolic alterations cause enhanced acid production, especially of lactate and carbon dioxide (CO2 ). The extensive production of acidic metabolites and the enhanced acid export to the extracellular space cause a consistent acidification of the tumor microenvironment, thus promoting the formation of an acid-resistant tumor cell population with increased invasive and metastatic potential. As melanoma is one of the deadliest and most metastatic forms of cancer, understanding the effects of this extracellular acidosis on human melanoma cells with distinct metastatic properties is important. The aim of this review was to summarize recent studies of the acidification of the tumor microenvironment, focusing on the specific effects of the acidic milieu on melanoma cells and to give a short overview of therapeutic approaches. PMID- 27233234 TI - New strategy for the biosorption of atrazine after magnetic solid-phase extraction from water followed by high-performance liquid chromatography analysis. AB - We describe a rapid and simple microextraction of atrazine from water samples. This method is based on the use of magnetic nanoparticles as sorbents and bioaggregates that are applied to the extraction and preconcentration of atrazine. The resulting magnetic nanoparticles possess a fast adsorption kinetics and high adsorption capacity. Bioaggregates made up of rhaminolipid biosurfactant were assessed as a new strategy for the sample treatment. The extractant was obtained from magnetic nanoparticles using the magnetic solid-phase extraction method. Then the target analyte was rapidly transferred from the sorbent surface to bioaggregates, which have a low toxicity and are green and ecofriendly. Finally, the extract is centrifuged and transferred to micro-syringe for analysis by high-performance liquid chromatography. Experimental parameters affecting the extraction efficiency were studied and optimized. Under optimum conditions the enrichment factor was 268. The linear dynamic range and limit of detection were 0.1-50 and 0.033 MUg/L, respectively. The relative standard deviation for six replicate measurements was 5.3%. The results demonstrate good applicability of biosorption-assisted magnetic solid-phase extraction method for the determination of atrazine from water samples. PMID- 27233235 TI - Glaucoma surgery in pseudophakic eyes: Tube shunt first. PMID- 27233236 TI - Trabeculectomy first in pseudophakic eyes requiring surgery for medically uncontrolled glaucoma. PMID- 27233237 TI - Evaluation of an Australian health literacy training program for socially disadvantaged adults attending basic education classes: study protocol for a cluster randomised controlled trial. AB - BACKGROUND: People with low literacy and low health literacy have poorer health outcomes. Literacy and health literacy are distinct but overlapping constructs that impact wellbeing. Interventions that target both could improve health outcomes. METHODS/DESIGN: This is a cluster randomised controlled trial with a qualitative component. Participants are 300 adults enrolled in basic language, literacy and numeracy programs at adult education colleges across New South Wales, Australia. Each adult education institute (regional administrative centre) contributes (at least) two classes matched for student demographics, which may be at the same or different campuses. Classes (clusters) are randomly allocated to receive either the health literacy intervention (an 18-week program with health knowledge and skills embedded in language, literacy, and numeracy training (LLN)), or the standard Language Literacy and Numeracy (LLN) program (usual LLN classes, specifically excluding health content). The primary outcome is functional health literacy skills - knowing how to use a thermometer, and read and interpret food and medicine labels. The secondary outcomes are self-reported confidence, more advanced health literacy skills; shared decision making skills, patient activation, health knowledge and self-reported health behaviour. Data is collected at baseline, and immediately and 6 months post intervention. A sample of participating teachers, students, and community health workers will be interviewed in-depth about their experiences with the program to better understand implementation issues and to strengthen the potential for scaling up the program. DISCUSSION: Outcomes will provide evidence regarding real-world implementation of a health literacy training program with health worker involvement in an Australian adult education setting. The evaluation trial will provide insight into translating and scaling up health literacy education for vulnerable populations with low literacy. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12616000213448 . PMID- 27233238 TI - Outwitting dengue threat and epidemics resurgence in Asia-Pacific countries: strengthening integrated dengue surveillance, monitoring and response systems. AB - Dengue is still a substantial vector-borne viral disease threat and burden of public health importance worldwide. This situation is complicated by dengue virus unprecedented resurgence and persistence of varied serotypes in endemic-prone areas, and man-made and natural activities consequences that promote vector emergence, transmission dynamics and spread across the Asia-Pacific region. There is an urgent need to strengthen operational and contextual surveillance-response research in improving early detection of active reservoir detection, novel drug in case management and quality evidence-based response including the deployment of dengue mass vaccination. Moreover, sustained mapping and watching of dengue risk factors or determinants, performance and outcome indicators of control or elimination programs effectiveness in defining minimum effective data towards community knowledge-based decision-making policy and effective response packages is imperative. Moreover, implementation of a robust, integrated dengue early warning surveillance, monitoring and response systems metrics is required for evidence-based, timely and cost-effective contextual mitigation strategies, and innovative interventions. PMID- 27233239 TI - Safety and efficacy of vernakalant for the conversion of atrial fibrillation to sinus rhythm; a phase 3b randomized controlled trial. AB - BACKGROUND: Atrial fibrillation (AF) is a common cardiac arrhythmia that is associated with significant health risks. One strategy to mitigate the risks associated with long-term AF is to convert AF to sinus rhythm (SR). This study assessed the efficacy and safety of vernakalant hydrochloride for the pharmacological conversion of AF to SR. METHODS: Patients with recent-onset (duration >3 h- <= 7 days) symptomatic AF and no evidence or history of congestive heart failure were randomized in a 2:1 ratio to receive vernakalant or placebo. Patients received an infusion of vernakalant (3 mg/kg) or placebo over 10 min, followed by a second infusion of vernakalant (2 mg/kg) or placebo 15 min later if AF had not been terminated. The primary efficacy endpoint was conversion of AF to SR for at least 1 min within 90 min of the start of drug infusion. The primary safety endpoint was a composite of: occurrence of clinically significant hypotension, clinically significant ventricular arrhythmia (including torsades de pointes, ventricular tachycardia or ventricular fibrillation) or death within 2 h of starting the drug infusion. RESULTS: A total of 217 patients were randomized to receive vernakalant (n = 145) or placebo (n = 72). Of the 129 individuals who received vernakalant, 59 (45.7 %) converted to SR compared with one of the 68 patients (1.5 %) who received placebo (p < 0.0001). Conversion to SR was significantly faster with vernakalant than with placebo (p < 0.0001), and a greater proportion of patients who received vernakalant than those who received placebo reported no AF-related symptoms at 90 min (p = 0.0264). The primary composite safety endpoint was observed in one patient receiving vernakalant and in no patients receiving placebo. In the vernakalant arm, dysgeusia, paraesthesia and sneezing were the most common treatment-emergent adverse events, and three serious adverse events occurred that were considered to be related to study drug. CONCLUSIONS: Vernakalant resulted in rapid cardioversion of recent-onset AF in almost half of the study population and was generally well tolerated. The safety outcomes affirmed the need for careful selection and management of haemodynamically stable candidates for cardioversion. TRIAL REGISTRATION: NCT00989001 . PMID- 27233240 TI - Mineral pitch induces apoptosis and inhibits proliferation via modulating reactive oxygen species in hepatic cancer cells. AB - BACKGROUND: Mineral Pitch (MP) is a dark brown coloured humic matter originating from high altitude rocks. It is an Ayurvedic medicinal food, commonly used by the people of the Himalayan regions of Nepal and India for various body ailments. METHODS: The Huh-7 cells were treated with different concentrations of MP for 24 h, and both apoptosis and proliferation was determined by the TUNEL and MTT assays respectively. The formation of ROS and nitric oxide was analysed by DCFH DA and Griess reagent respectively. The expression of miRNA-21 and miRNA-22 were checked by the real time PCR. Effect of miRNA-22 on proliferation and c-myc was studied by over-expressing miRNA-22 premiRs in Huh-7 cells. RESULTS: We found that MP enhanced anti-cancer effects by inducing apoptosis and inhibiting proliferation. MP induced both ROS and NO, upon neutralizing them, there was a partial recovery of apoptosis and proliferation. MP also induced miRNA-22 expression, while miRNA-21 expression was inhibited. Over-expression of miRNA-22 resulted in a significant inhibition of proliferation. miRNA-22 directly targeted c-myc gene, thereby inhibited proliferation. These results clearly show that MP induces its anti-cancer activity by more than one pathway. CONCLUSION: The data clearly indicate that MP induced apoptosis via the production of ROS, and inhibited proliferation by inducing miRNA-22 and inhibiting miRNA-21 in Huh-7 cells. PMID- 27233242 TI - Cost-effectiveness comparison of prophylactic octreotide and pasireotide for prevention of fistula after pancreatic surgery. AB - PURPOSE: Postoperative pancreatic fistula (POPF) is a major determinant of pancreatic surgery outcome, and prevention of POPF is a relevant clinical challenge. The aim of the present study is to compare the cost-effectiveness of octreotide and pasireotide for POPF prophylaxis. METHODS: A systematic literature review and meta-analysis and a retrospective patient cohort provided the data. Cost-effectiveness was calculated by the incremental cost-effectiveness ratio (ICER) and by decision tree modelling of hospital stay duration. RESULTS: Six randomised trials on octreotide (1255 patients) and one trial on pasireotide (300 patients) were included. The median POPF incidence without prophylaxis was 19.6 %. The relative risks for POPF after octreotide or pasireotide prophylaxis were 0.54 or 0.45. Octreotide prophylaxis (21 * 0.1 mg) costs were 249.69 Euro, compared with 728.84 Euro for pasireotide (14 * 0.9 mg) resulting in an ICER of 266.19 Euro for an additional 1.8 % risk reduction with pasireotide. Decision tree modelling revealed no significant reduction of median hospital stay duration if pasireotide was used instead of octreotide. CONCLUSION: Prophylactic octreotide is almost as effective as pasireotide but incurs significantly fewer drug costs per case. However, the data quality is limited, because the effect of octreotide on clinically relevant POPF is unclear. Together with the lack of multicentric data on pasireotide and its effectiveness, a current off-label use of pasireotide does not appear to be justified. PMID- 27233241 TI - Subtotal parathyroidectomy for secondary renal hyperparathyroidism: a 20-year surgical outcome study. AB - AIM: The aim of this study was to evaluate the outcomes of surgery for patients with secondary renal hyperparathyroidism (rHPT). METHODS: This is a retrospective cohort study. Our institutional database was searched for eligible patients treated in 1995-2014. The inclusion criterion was initial parathyroidectomy for rHPT. Clinical and follow-up data were analyzed to estimate the cure rate (primary outcome), and morbidity (secondary outcome). RESULTS: The study group comprised 297 patients (154 females, age 44.5 +/- 13.7 years, follow-up 24.6 +/- 10.5 months), including 268 (90.2 %) patients who had underwent subtotal parathyroidectomy, and 29 (9.8 %) who had had incomplete parathyroidectomy. Intraoperative iPTH assay was utilized in 207 (69.7 %) explorations. Persistent rHPT occurred in 12/268 (4.5 %) patients after subtotal parathyroidectomy and 5/29 (17.2 %) subjects after incomplete parathyroidectomy (p = 0.005). The patients operated on with intraoperative iPTH assay had a higher cure rate than non-monitored individuals, 201/207 (97.1 %) vs. 79/90 (87.8 %), respectively (p = 0.001). In-hospital mortality occurred in 1/297 (0.3 %) patient. The hungry bone syndrome occurred in 84/268 (31.3 %) patients after subtotal parathyroidectomy and 2/29 (6.9 %) subjects after incomplete parathyroidectomy (p = 0.006). Transient recurrent laryngeal nerve paresis occurred in 14/594 (2.4 %) and permanent in 5/594 (0.8 %) nerves at risk. CONCLUSIONS: Subtotal parathyroidectomy is a safe and efficacious treatment for patients with rHPT. Utilization of intraoperative iPTH assay can guide surgical exploration and improve the cure rate. PMID- 27233243 TI - Strengthening individual capacity in monitoring and evaluation of malaria control programmes to streamline M&E systems and enhance information use in malaria endemic countries. AB - BACKGROUND: Malaria control interventions in most endemic countries have intensified in recent years and so there is a need for a robust monitoring and evaluation (M&E) system to measure progress and achievements. Providing programme and M&E officers with the appropriate skills is a way to strengthen malaria's M&E systems and enhance information use for programmes' implementation. This paper describes a recent effort in capacity strengthening for malaria M&E in sub Saharan Africa (SSA). METHODS: From 2010 to 2014, capacity-strengthening efforts consisted of organizing regional in-person workshops for M&E of malaria programmes for Anglophone and Francophone countries in SSA in collaboration with partners from Ghana and Burkina Faso. Open-sourced online courses were also available in English. A post-workshop assessment was conducted after 5 years to assess the effects of these regional workshops and identify gaps in capacity. RESULTS: The regional workshops trained 181 participants from 28 countries from 2010 to 2014. Trained participants were from ministries of health, national malaria control and elimination programmes, non-governmental organizations, and development partners. The average score (%) for participants' knowledge tests increased from pretest to posttest for Anglophone workshops (2011: 59 vs. 76, 2012: 41 vs. 63, 2013: 51 vs. 73; 2014: 50 vs. 74). Similarly, Francophone workshop posttest scores increased, but were lower than Anglophone due to higher scores at pretest. (2011: 70 vs. 76, 2012: 74 vs. 79, 2013: 61 vs. 68; 2014: 64 vs. 75). Results of the post-workshop assessment revealed that participants retained practical M&E knowledge and skills for malaria programs, but there is a need for a module on malaria surveillance adapted to the pre-elimination context. CONCLUSION: The workshops were successful because of the curriculum content, facilitation quality, and the engagement of partner institutions with training expertise. Results from the post-workshop assessment will guide the curriculum's development and restructuring for the next phase of workshops. Country-specific malaria M&E capacity needs assessments may also inform this process as countries reduce malaria burden. PMID- 27233244 TI - Bedside dressing changes for open abdomen in the intensive care unit is safe and time and staff efficient. AB - BACKGROUND: Patients with an open abdomen (OA) treated with temporary abdominal closure (TAC) need multiple surgical procedures throughout the hospital stay with repeated changes of the vacuum-assisted closure device (VAC changes). The aim of this study was to examine if using the intensive care unit (ICU) for dressing changes in OA patients was safe regarding bloodstream infections (BSI) and survival. Secondary aims were to evaluate saved time, personnel, and costs. METHODS: All patients treated with OA in the ICU from October 2006 to June 2014 were included. Data were retrospectively obtained from registered procedure codes, clinical and administrative patients' records and the OR, ICU, anesthesia and microbiology databases. Outcomes were 30-, 60- and 90-day survival, BSI, time used and saved personnel costs. RESULTS: A total of 113 patients underwent 960 surgical procedures including 443 VAC changes as a single procedure, of which 165 (37 %) were performed in the ICU. Nine patients died before the first scheduled dressing change and six patients were closed at the first scheduled surgery after established OA, leaving 98 patients for further analysis. The mean duration for the surgical team performing a VAC change in the ICU was 63.4 (60.4-66.4) minutes and in the OR 98.2 (94.6-101.8) minutes (p < 0.001). The mean duration for the anesthesia team in the OR was 115.5 minutes, while this team was not used in the ICU. Personnel costs were reduced by ?682 per procedure when using the ICU. Forty two patients had all the VAC changes done in the OR (VAC-OR), 22 in the ICU (VAC ICU) and 34 in both OR and ICU (VAC-OR/ICU). BSI was diagnosed in eight (19 %) of the VAC-OR patients, seven (32 %) of the VAC-ICU and eight (24 %) of the VAC OR/ICU (p = 0.509). Thirty-five patients (83 %) survived 30 days in the VAC-OR group, 17 in the VAC-ICU group (77 %) and 28 (82 %) in the VAC-OR/ICU group (p = 0.844). CONCLUSIONS: VAC change for OA in the ICU saved time for the OR team and the anesthesia team compared to using the OR, and it reduced personnel costs. Importantly, the use of ICU for OA dressing change seemed to be as safe as using the OR. PMID- 27233245 TI - In Vivo Neurochemical Characterization of Developing Guinea Pigs and the Effect of Chronic Fetal Hypoxia. AB - The guinea pig is a frequently used animal model for human pregnancy complications, such as oxygen deprivation or hypoxia, which result in altered brain development. To investigate the impact of in utero chronic hypoxia on brain development, pregnant guinea pigs underwent either normoxic or hypoxic conditions at about 70 % of 65-day term gestation. After delivery, neurochemical profiles consisting of 19 metabolites and macromolecules were obtained from the neonatal cortex, hippocampus, and striatum from birth to 12 weeks postpartum using in vivo (1)H MR spectroscopy at 9.4 T. The effects of chronic fetal hypoxia on the neurochemical profiles were particularly significant at birth. However, the overall developmental trends of neurochemical concentration changes were similar between normoxic and hypoxic animals. Alterations of neurochemicals including N acetylaspartate (NAA), phosphorylethanolamine, creatine, phosphocreatine, and myo inositol indicate neuronal loss, delayed myelination, and altered brain energetics due to chronic fetal hypoxia. These observed neurochemical alterations in the developing brain may provide insights into hypoxia-induced brain pathology, neurodevelopmental compromise, and potential neuroprotective measures. PMID- 27233246 TI - Curcumin Attenuated Bupivacaine-Induced Neurotoxicity in SH-SY5Y Cells Via Activation of the Akt Signaling Pathway. AB - Bupivacaine is widely used for regional anesthesia, spinal anesthesia, and pain management. However, bupivacaine could cause neuronal injury. Curcumin, a low molecular weight polyphenol, has a variety of bioactivities and may exert neuroprotective effects against damage induced by some stimuli. In the present study, we tested whether curcumin could attenuate bupivacaine-induced neurotoxicity in SH-SY5Y cells. Cell injury was evaluated by examining cell viability, mitochondrial damage and apoptosis. We also investigated the levels of activation of the Akt signaling pathway and the effect of Akt inhibition by triciribine on cell injury following bupivacaine and curcumin treatment. Our findings showed that the bupivacaine treatment could induce neurotoxicity. Pretreatment of the SH-SY5Y cells with curcumin significantly attenuated bupivacaine-induced neurotoxicity. Interestingly, the curcumin treatment increased the levels of Akt phosphorylation. More significantly, the pharmacological inhibition of Akt abolished the cytoprotective effect of curcumin against bupivacaine-induced cell injury. Our data suggest that pretreating SH SY5Y cells with curcumin provides a protective effect on bupivacaine-induced neuronal injury via activation of the Akt signaling pathway. PMID- 27233247 TI - Kynurenine metabolic balance is disrupted in the hippocampus following peripheral lipopolysaccharide challenge. AB - BACKGROUND: Inflammation increases the risk of developing depression-related symptoms, and tryptophan metabolism is an important mediator of these behavior changes. Peripheral immune activation results in central up-regulation of pro inflammatory cytokine expression, microglia activation, and the production of neurotoxic kynurenine metabolites. The neuroinflammatory and kynurenine metabolic response to peripheral immune activation has been largely characterized at the whole brain level. It is unknown if this metabolic response exhibits regional specificity even though the unique indoleamine 2,3-dioxygenase (IDO)-dependent depressive-like behaviors are known to be controlled by discrete brain regions. Therefore, regional characterization of neuroinflammation and kynurenine metabolism might allow for better understanding of the potential mechanisms that mediate inflammation-associated behavior changes. METHODS: Following peripheral immune challenge with lipopolysaccharide (LPS), brain tissue from behaviorally relevant regions was analyzed for changes in mRNA of neuroinflammatory targets and kynurenine pathway enzymes. The metabolic balance of the kynurenine pathway was also determined in the peripheral circulation and these brain regions. RESULTS: Peripheral LPS treatment resulted in region-independent up-regulation of brain expression of pro-inflammatory cytokines and glial cellular markers indicative of a neuroinflammatory response. The expression of kynurenine pathway enzymes was also largely region-independent. While the kynurenine/tryptophan ratio was elevated significantly in both the plasma and in each brain regions evaluated, the balance of kynurenine metabolism was skewed toward production of neurotoxic metabolites in the hippocampus. CONCLUSIONS: The upstream neuroinflammatory processes, such as pro-inflammatory cytokine production, glial cell activation, and kynurenine production, may be similar throughout the brain. However, it appears that the balance of downstream kynurenine metabolism is a tightly regulated brain region-dependent process. PMID- 27233248 TI - Online Sex-Seeking Among Men who have Sex with Men in Nigeria: Implications for Online Intervention. AB - The TRUST/RV368 project was undertaken to apply innovative strategies to engage Nigerian MSM into HIV care. In this analysis we evaluate characteristics of online sex-seekers from the TRUST/RV368 cohort of 1370 MSM in Abuja and Lagos. Logistic regression and generalized estimating equation models were used to assess associations with online sex-seeking. Online sex-seeking (n = 843, 61.5 %) was associated with participation in MSM community activities, larger social and sexual networks, and higher levels of sexual behavior stigma. In addition, online sex-seeking was associated with testing positive for HIV at a follow-up visit [adjusted odds ratio (aOR) = 2.02, 95 % confidence interval (CI) = 1.37, 2.98)] among those who were unaware of or not living with HIV at baseline. Across visits, online sex-seekers were marginally more likely to test positive for chlamydia/gonorrhea (aOR 1.28, 95 % CI 0.99, 1.64). Online sex-seekers in Nigeria are at increased risk for HIV/STIs but may not be benefiting from Internet-based risk reduction opportunities. PMID- 27233250 TI - Chromosome Banding in Amphibia. XXXIV. Intrachromosomal Telomeric DNA Sequences in Anura. AB - The mitotic chromosomes of 4 anuran species were examined by various classical banding techniques and by fluorescence in situ hybridization using a (TTAGGG)n repeat. Large intrachromosomal telomeric sequences (ITSs) were demonstrated in differing numbers and chromosome locations. A detailed comparison of the present results with numerous published and unpublished data allowed a consistent classification of the various categories of large ITSs present in the genomes of anurans and other vertebrates. The classification takes into consideration the total numbers of large ITSs in the karyotypes, their chromosomal locations and their specific distribution patterns. A new category of large ITSs was recognized to exist in anuran species. It consists of large clusters of ITSs located in euchromatic chromosome segments, which is in clear contrast to the large ITSs in heterochromatic chromosome regions known in vertebrates. The origin of the different categories of large ITSs in heterochromatic and euchromatic chromosome regions, their mode of distribution in the karyotypes and evolutionary fixation in the genomes, as well as their cytological detection are discussed. PMID- 27233249 TI - Multiple Dimensions of Stigma and Health Related Factors Among Young Black Men Who Have Sex with Men. AB - This study is among the first to examine the association between multiple domains of HIV-related stigma and health-related correlates including viral load and medication adherence among young Black men who have sex with men (N = 92). Individual logistic regressions were done to examine the hypothesized relationships between HIV-related stigma and various health and psychosocial outcomes. In addition to examining total stigma, we also examined four domains of HIV stigma. Findings revealed the various domains of stigma had differential effects on health-related outcomes. Individuals who reported higher levels of total stigma and personalized stigma were less likely to be virally suppressed (OR 0.96, 95 % CI 0.91-1.00 and OR 0.50, 95 % CI 0.25-1.02, respectively). Concerns about public attitudes toward HIV were positively related to medication adherence (OR 2.18, 95 % CI 1.20-3.94) and psychological distress (OR 5.02, 95 % CI 1.54-16.34). The various domains of HIV stigma differentially affected health and psychosocial outcomes, and our findings suggest that some forms of HIV stigma may significantly affect viral load and medication adherence among this population. Stigma-informed approaches to care and treatment are needed, along with incorporated psychological and social supports. PMID- 27233251 TI - Impact of a regimented aminophylline administration protocol on the burden of regadenoson-induced ischemia detected by SPECT myocardial perfusion imaging. AB - BACKGROUND: In patients undergoing regadenoson SPECT myocardial perfusion imaging (MPI), it is unknown how soon and at which dose intravenous aminophylline can be administered to reverse regadenoson-related adverse effects without blunting stress-induced myocardial ischemia. METHODS AND RESULTS: We analyzed the pooled database of the ASSUAGE and ASSUAGE-CKD trials (n = 548). These were double blinded, placebo-controlled, randomized clinical trials in which 75 mg of aminophylline or placebo was administered intravenously 90 seconds following 99mTc-tetrofosmin injection. There were no statistically significant differences in summed difference score (SDS) burden (P = .87) and in the rates of myocardial ischemia (SDS >= 2) (P = .93) between the aminophylline (n = 274) and placebo (n = 274) groups. There was no interaction between aminophylline use and SDS as a determinant of the composite endpoint of cardiac death or MI (P = .32) or the composite endpoint of cardiac death, MI, or coronary revascularization (P = .92). CONCLUSION: In patients undergoing regadenoson-stress SPECT-MPI, the intravenous administration of 75 mg of aminophylline as early as 90 seconds after radioisotope injection does not seem to attenuate the burden of myocardial ischemia. PMID- 27233252 TI - Differences in polar-map patterns using the novel technologies for myocardial perfusion imaging. AB - BACKGROUND: New technologies are available in MPI. Our aim was to evaluate their impact on the uniformity of normal myocardial uptake in the polar-map representation, over different count statistics, with and without the attenuation (AC) and scatter corrections (SC). METHODS: A phantom study was performed using 5 Anger gamma cameras with filtered back projection or iterative reconstruction with resolution recovery (IRR), with or without SCAC; a D530c, with or without AC; and a D-SPECT. Count statistics ranged up to a quarter of the reference for the conventional gamma cameras and up to one half for the advanced scanners. Using polar maps, the segmental uptakes and their uncertainties, the 'global uniformity' of polar maps expressed as the coefficient of variation (COV) among the segmental uptakes and the anterior/inferior (ANT/INF) ratio were calculated. RESULTS: Both segmental uptakes and their uncertainties did not depend on the count statistics in the range studied. An increase in the segmental uptakes was found from IRR to IRR + SCAC (78.0% +/- 13.5% vs 86.1% +/- 9.4%; P < .0001). COV was lower for D-SPECT (10.1% +/- 0.5%) and after SCAC for both conventional (9.9% +/- 3.0%) and advanced systems (8.9% +/- 1.7%). The ANT/INF ratio was above 1 for IRR (1.12 +/- 0.07) and fell slightly below 1 for IRR + SCAC (0.97 +/- 0.05). CONCLUSIONS: To compare data from the analysis of polar maps across different systems will require the adoption of specific normality databases, developed for each system and reconstruction method employed. PMID- 27233253 TI - Sclerosing Microcystic Adenocarcinoma of the Head and Neck Mucosa: A Neoplasm Closely Resembling Microcystic Adnexal Carcinoma. AB - Microcystic adnexal carcinoma (MAC) occurs predominantly in the centrofacial skin and has been only rarely reported in mucosal surfaces. We here present a 5 case series of tumors closely resembling MAC occurring in the mucosal surfaces of the head and neck, which we have termed sclerosing microcystic adenocarcinomas. These tumors showed a predilection for women (4:1) with an average patient age of 52.6 years (range 41-73 years). Location included the tongue (n = 2), the floor of the mouth (n = 2), and the nasopharynx/clivus (n = 1). One occurred after radiation therapy and another occurred in the setting of immune compromise. Immunohistochemistry highlighted a dual cell population with luminal cells showing positivity for high and low-molecular weight keratins and surrounding myoepithelial cells showing S100 and smooth muscle actin staining. No cases had nodal involvement, and the single patient with clinical follow-up was alive and free of disease 34 months after diagnosis and definitive radiochemotherapy. Differential diagnoses for all cases diverged from those provoked by MAC in the skin and included a variety of salivary gland neoplasms such as adenoid cystic carcinoma, polymorphous low grade adenocarcinoma, and mucoepidermoid carcinoma. Recognition of sclerosing microcystic adenocarcinoma in the head and neck mucosa is critical given its bland appearance and subtle infiltration pattern, infrequency of nodal involvement, and behavioral differences from the other entities on the differential. PMID- 27233254 TI - Attachment of Li[Ni0.2Li0.2Mn0.6]O2 Nanoparticles to the Graphene Surface Using Electrostatic Interaction Without Deterioration of Phase Integrity. AB - In this article, we report a facile approach to enhance the electrochemical performance of Li-rich oxides with vulnerable phase stability. The Li-rich oxide nanoparticles were attached to the surface of graphene; the graphene surface acted as a matrix with high electronic conductivity that compensated for the low conductivity and enhanced the rate capability of the oxides. Our novel approach constitutes a direct assembly of two materials via electrostatic interaction, without a high-temperature heat treatment. The inevitable deterioration in phase integrity of previous composites between carbon and Li-rich oxides resulted from the reaction of oxygen in the structure with carbon during the heat-treatment process. However, our new method successfully attached Li-rich nanoparticles to the surface of graphene, without a phase change of the oxides. The resulting graphene/Li-rich oxide composites exhibited superior capacity and rate capability compared to their pristine Li-rich counterparts. PMID- 27233255 TI - Association of gene polymorphisms of FV, FII, MTHFR, SERPINE1, CTLA4, IL10, and TNFalpha with pre-eclampsia in Chinese women. AB - OBJECTIVES: To investigate the association of polymorphisms in genes involved in coagulation, fibrinolysis, and inflammation with pre-eclampsia (PE) in a Chinese population. METHODS: It is a case-control study of patients with PE (n = 117) and controls (n = 286) from the Maternal and Children's Hospital of Shenzhen City carried out between June 2014 and May 2015. The rs6025, rs6020, rs1801133, rs1799963, rs1799889, rs231775, rs1800896, rs1800629, and rs1799724 polymorphisms were analyzed using Snap Shot. Multifactor dimensionality reduction (MDR) and logistic regression analyses were carried out to assess the interactions among these SNPs. RESULTS: The frequencies of polymorphisms in tumor necrosis factor alpha (TNF-alpha) (rs1800629 and rs1799724) and interleukin 10 (IL-10) (rs1800896) were significantly different between patients with PE and controls (P < 0.05). The best interaction model identified a marginally significant interaction between rs1799724 and rs1800896 (P = 0.05). CONCLUSIONS: This study suggests that polymorphisms in the TNF-alpha and IL-10 genes could be associated with PE, but additional studies are necessary to explore the mechanisms involving these polymorphisms and the gene-gene interactions involved in the susceptibility to PE. PMID- 27233256 TI - Evolution and Epidemiology of Chikungunya Virus. AB - Chikungunya is a mosquito-borne Alphavirus that is spreading worldwide in the tropical areas and that has a 11.8 kb RNA genome. The most relevant vectors belong to the genus Aedes and contribute to the diffusion of the three different genotypes of the virus from the original site of first identification in East Africa. Recently, an additional site of origin has been identified in Asia. The epidemiology of Chikungunya has been extensively evaluated from 2004 when the virus initiated its travel eastbound from the coast of Africa to the Indian Ocean. It is noteworthy that this diffusion has been mainly sustained by Ae. albopictus, a new vector to which the virus become adapted due to the mutation E1 Ala226Val. This mutation was also identified during the first, even small, outbreaks of Chikungunya-related disease outside the tropics that occurred in Northern Italy in 2007 and in Southern France in 2010. Three years later the virus appeared for the first time in the Western hemisphere and since then, in less than 24 months spread to North and South America. PMID- 27233257 TI - Molecular Epidemiology of Chikungunya Virus by Sequencing. AB - Molecular surveillance of Chikungunya virus (CHIKV) is important as it provides data on the circulating CHIKV genotypes in endemic countries and enabling activation of measures to be taken in the event of a pending outbreak. Molecular surveillance is carried out by first detecting CHIKV in susceptible humans or among field-caught mosquitoes. This is followed by sequencing a selected region of the virus which will provide evidence on the source of the virus and possible association of the virus to increased cases of Chikungunya infections. PMID- 27233258 TI - Advanced Genetic Methodologies in Tracking Evolution and Spread of Chikungunya Virus. AB - Recent advances in genetic methodologies have substantially expanded our ability to track evolution and spatio-temporal distribution of rapidly evolving pathogens. The information gathered from such analyses can be used to decipher host adaptations that shape disease epidemiology. In this chapter, we demonstrate the utilization of freely available resources to track the evolution and spread of Chikungunya virus. PMID- 27233259 TI - Synthetic Peptide-Based Antibody Detection for Diagnosis of Chikungunya Infection with and without Neurological Complications. AB - Synthetic peptide-based diagnosis of Chikungunya can be an efficient and more accessible approach in immunodiagnostics. Here, we describe the identification of Chikungunya-specific 40 kD protein for development of synthetic peptide-based enzyme-linked immunosorbent assay for the detection of Chikungunya virus-specific antibodies in the patient's sample. The total sodium dodecyl sulfate polyacrylamide gel electrophoresis protein profile of the patient's sample can be done to identify specific protein bands. The identified proteins can be subjected to liquid chromatography-tandem mass spectrometry (LC-MS/MS) for characterization. After characterization, immunogenic peptides can be designed using softwares and subsequently synthesized chemically. The peptides can be used to develop more specific, sensitive, and simpler diagnostic assay. PMID- 27233260 TI - Expression and Purification of E2 Glycoprotein from Insect Cells (Sf9) for Use in Serology. AB - Chikungunya virus (CHIKV) is a mosquito-borne arbovirus which poses a major threat to global public health. Definitive CHIKV diagnosis is crucial, especially in distinguishing the disease from dengue virus, which co-circulates in endemic areas and shares the same mosquito vectors. Laboratory diagnosis is mainly based on serological or molecular approaches. The E2 glycoprotein is a good candidate for serological diagnosis since it is the immunodominant antigen during the course of infection, and reacts with seropositive CHIKV sera. In this chapter, we describe the generation of stable clone Sf9 (Spodoptera frugiperda) cells expressing secreted, soluble, and native recombinant CHIKV E2 glycoprotein. We use direct plasmid expression in insect cells, rather than the traditional technique of generating recombinant baculovirus. This recombinant protein is useful for serological diagnosis of CHIKV infection. PMID- 27233261 TI - Diagnostic Methods for CHIKV Based on Serological Tools. AB - This chapter presents the most commonly used serological methods for the diagnosis of Chikungunya virus (CHIKV) infection in humans. CHIKV is a mosquito borne Alphavirus widely distributed in the tropical and subtropical regions of Africa, Asia, and America. CHIKV infection in human causes acute febrile illness frequently accompanied by severe joint pain. Most of the infected patients may develop chronic arthralgia that may persist for several months or years. Laboratory diagnosis of CHIKV infection is mainly based on molecular and serological tests. The serological tests represent a valuable tool for diagnosis and epidemiological studies. Enzyme-linked immunosorbent assay (ELISA) and immunofluorescence assay (IFA) are simple, rapid, and sensitive techniques widely used for the diagnosis of CHIKV infection. However, these methods represent a screening tool and often require confirmation by a second-line assays. Serum virus neutralization assay is more specific than ELISA and IFA tests and is considered a confirmatory test. Neutralization assay is employed to determine the titer of virus neutralizing antibodies against CHIKV in patients' sera. The basis of microneutralization assay (MNA), results interpretation, and procedures will be illustrated in this chapter. PMID- 27233262 TI - Utilization and Assessment of Throat Swab and Urine Specimens for Diagnosis of Chikungunya Virus Infection. AB - Chikungunya is a mosquito-borne infection with clinical presentation of fever, arthralgia, and rash. The etiological agent Chikungunya virus (CHIKV) is generally transmitted from primates to humans through the bites of infected Aedes aegypti and Aedes albopictus mosquitoes. Outbreaks of Chikungunya occur commonly with varied morbidity, mortality, and sequele according to the epidemiological, ecological, seasonal, and geographical impact. Investigations are required to be conducted as a part of the public health service to understand and report the suspected cases as confirmed by laboratory diagnosis. Holistic sampling at a time of different types would be useful for laboratory testing, result conclusion, and reporting in a valid way. The use of serum samples for virus detection, virus isolation, and serology is routinely practiced, but sometimes serum samples from pediatric and other cases may not be easily available. In such a situation, easily available throat swabs and urine samples could be useful. It is already well reported for measles, rubella, and mumps diseases to have the virus diagnosis from throat swabs and urine. Here, we present the protocols for diagnosis of CHIKV using throat swab and urine specimens. PMID- 27233263 TI - Propagation of Chikungunya Virus Using Mosquito Cells. AB - Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that transmits in between a mosquito host vector to a primate host and then back to the mosquito host vector to complete its life cycle. Hence, CHIKV must be able to replicate in both host cellular systems that are genetically and biochemically distinct. The ability to grow and propagate the virus in high titers in the laboratory is fundamentally crucial in order to understand virus replication in different host cellular systems and many other CHIKV research areas. Here, we describe a method on CHIKV propagation using C6/36, a mosquito cell line derived from Aedes albopictus in both serum-containing and serum-free media. PMID- 27233264 TI - Infectious Viral Quantification of Chikungunya Virus-Virus Plaque Assay. AB - The plaque assay is an essential method for quantification of infectious virus titer. Cells infected with virus particles are overlaid with a viscous substrate. A suitable incubation period results in the formation of plaques, which can be fixed and stained for visualization. Here, we describe a method for measuring Chikungunya virus (CHIKV) titers via virus plaque assays. PMID- 27233265 TI - Detection and Quantification of Chikungunya Virus by Real-Time RT-PCR Assay. AB - Real-time PCR assay has many advantages over conventional PCR methods, including rapidity, quantitative measurement, low risk of contamination, high sensitivity, high specificity, and ease of standardization (Mackay et al., Nucleic Acids Res 30:1292-1305, 2002). The real-time PCR system relies upon the measurement of a fluorescent reporter during PCR, in which the amount of emitted fluorescence is directly proportional to the amount of the PCR product in a reaction (Gibsons et al., Genome Res 6:995-1001, 1996). Here, we describe the use of SYBR Green I based and TaqMan((r)) real-time reverse transcription polymerase chain reaction (RT-PCR) for the detection and quantification of Chikungunya virus (CHIKV). PMID- 27233266 TI - Chikungunya Virus Infection of Aedes Mosquitoes. AB - In vivo infection of mosquitoes is an important method to study and characterize arthropod-borne viruses. Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that is transmitted primarily by Aedes mosquitoes. In this chapter, we describe a protocol for infection of CHIKV in two species of Aedes mosquitoes, Aedes aegypti and Aedes albopictus, together with the isolation of CHIKV in different parts of the infected mosquito such as midgut, legs, wings, salivary gland, head, and saliva. This allows the study of viral infection, replication and dissemination within the mosquito vector. PMID- 27233267 TI - Analysis of CHIKV in Mosquitoes Infected via Artificial Blood Meal. AB - Having a mechanism to assess the transmission dynamics of a vector-borne virus is one critical component of understanding the life cycle of these viruses. Laboratory infection systems using artificial blood meals is one valuable approach for monitoring the progress of virus in its mosquito host and evaluating potential points for interruption of the cycle for control purposes. Here, we describe an artificial blood meal system with Chikungunya virus (CHIKV) and the processing of mosquito tissues and saliva to understand the movement and time course of virus infection in the invertebrate host. PMID- 27233268 TI - Chikungunya Virus Growth and Fluorescent Labeling: Detection of Chikungunya Virus by Immunofluorescence Assay. AB - Immunofluorescence assay (IFA) is a highly versatile and sensitive assay for detection and titration of chikungunya virus (CHIKV). The IFA technique requires virus-infected cells (viral antigen) and antibodies specific to the viral antigens for detection. Suitable antibodies for detection include monoclonal antibodies specific to CHIKV structural and nonstructural proteins, polyclonal antibodies, and convalescent serum samples. Here, the details of virus antigen preparation, detection by IFA method, and applications are described. The described IFA method is potentially useful in a wide range of studies including virus growth kinetics and virus infection mechanism studies. Additionally, the described IFA method can be modified for applications in arbovirus diagnosis, including CHIKV. PMID- 27233269 TI - Virus Isolation and Preparation of Sucrose-Banded Chikungunya Virus Samples for Transmission Electron Microscopy. AB - Virus isolation and purification is an invaluable technique in virology to detect and characterize viruses. This chapter describes a large-scale Chikungunya virus (CHIKV) propagation and purification methods by using discontinuous sucrose gradient, and sample preparation for transmission electron microscopy. Sucrose banding yields large quantities of high-titer (10(10) pfu/ml) CHIKV stocks. Such stocks are stable for years when stored at -70 degrees C. PMID- 27233270 TI - Viral-Host Protein Interaction Studies Using Yeast Two-Hybrid Screening Method. AB - Yeast two-hybrid (Y2H) assay is one of the earliest methods developed to study protein-protein interactions. In the proteomics era, Y2H has created a niche of its own by providing protein interaction maps for various organisms. Owing to limited coding capacities of their genomes, viruses are dependent on their host cellular machinery for successful infection. Identification of the key players orchestrating the survival of virus in their host is essential for understanding viral life cycle and devising strategies to prevent interactions resulting in pathogenesis. In this chapter, Y2H assay will be explained in detail for studying viral-host protein interactions of Chikungunya virus (CHIKV). PMID- 27233271 TI - Application of GelC-MS/MS to Proteomic Profiling of Chikungunya Virus Infection: Preparation of Peptides for Analysis. AB - Gel-enhanced liquid chromatography coupled with tandem mass spectrometry (GeLC MS/MS) is a labor intensive, but relatively straightforward methodology that generates high proteome coverage which can be applied to the proteome analysis of a range of starting materials such as cells or patient specimens. Sample proteins are resolved electrophoretically in one dimension through a sodium dodecyl sulfate (SDS) polyacrylamide gel after which the lanes are sliced into sections. The sections are further diced and the gel cubes generated are subjected to in gel tryptic digestion. The resultant peptides can then be analyzed by tandem mass spectroscopy to identify the proteins by database searching. The methodology can routinely detect several thousand proteins in one analysis. The protocol we describe here has been used with both cells in culture that have been infected with chikungunya virus and specimens from Chikungunya fever patients. This protocol details the process for generating peptides for subsequent mass spectroscopic and bioinformatic analysis. PMID- 27233272 TI - Bioinformatics Based Approaches to Study Virus-Host Interactions During Chikungunya Virus Infection. AB - The limitations of high-throughput genomic methods used for studying virus-host interactions make it difficult to directly obtain insights on virus pathogenesis. In this chapter, the central steps of a protein structure similarity based computational approach used to predict the host interactors of Chikungunya virus are explained by highlighting the important aspects that need to be considered. Identification of such conserved set of putative interactions that allow the virus to take control of the host has the potential to deepen our understanding of the virus-specific remodeling processes of the host cell and illuminate new arenas of disease intervention. PMID- 27233273 TI - T-Cell Epitope Prediction of Chikungunya Virus. AB - There has been a growing demand for vaccines against Chikungunya virus (CHIKV), and epitope-based vaccine is a promising solution. Identification of CHIKV T-cell epitopes is critical to ensure successful trigger of immune response for epitope based vaccine design. Bioinformatics tools are able to significantly reduce time and effort in this process by systematically scanning for immunogenic peptides in CHIKV proteins. This chapter provides the steps in utilizing machine learning algorithms to train on major histocompatibility complex (MHC) class I peptide binding data and build prediction models for the classification of binders and non-binders. The models could then be used in the identification and prediction of CHIKV T-cell epitopes for future vaccine design. PMID- 27233274 TI - Mouse Models of Chikungunya Virus. AB - The majority of medical advances have been made using animals. Studies using mouse models of chikungunya-induced disease have proven invaluable for dissecting the intricate nature of the immune response to this viral infection and identifying potential targets for the development of treatment strategies. Herein we describe the common mouse models used to research the pathobiology of chikungunya virus infection to date. PMID- 27233275 TI - Generation of Mouse Monoclonal Antibodies Specific to Chikungunya Virus Using ClonaCell-HY Hybridoma Cloning Kit. AB - Monoclonal antibodies offer high specificity and this makes it an important tool for molecular biology, biochemistry and medicine. Typically, monoclonal antibodies are generated by fusing mouse spleen cells that have been immunized with the desired antigen with myeloma cells to create immortalized hybridomas. Here, we describe the generation of monoclonal antibodies that are specific to Chikungunya virus using ClonaCell-HY system. PMID- 27233276 TI - Immunohistochemical Detection of Chikungunya Virus Antigens in Formalin-Fixed and Paraffin-Embedded Tissues. AB - Immunohistochemistry is a histological technique that allows detection of one or more proteins of interest within a cell using specific antibody binding, followed by microscopic visualization of a chromogenic substrate catalyzed by peroxidase and/or alkaline phosphatase. Here, we describe a method to localize Chikungunya virus (CHIKV) antigens in formalin-fixed and paraffin-embedded infected mouse brain. PMID- 27233277 TI - Antiviral Strategies Against Chikungunya Virus. AB - In the last few decades the Chikungunya virus (CHIKV) has evolved from a geographically isolated pathogen to a virus that is widespread in many parts of Africa, Asia and recently also in Central- and South-America. Although CHIKV infections are rarely fatal, the disease can evolve into a chronic stage, which is characterized by persisting polyarthralgia and joint stiffness. This chronic CHIKV infection can severely incapacitate patients for weeks up to several years after the initial infection. Despite the burden of CHIKV infections, no vaccine or antivirals are available yet. The current therapy is therefore only symptomatic and consists of the administration of analgesics, antipyretics, and anti-inflammatory agents. Recently several molecules with various viral or host targets have been identified as CHIKV inhibitors. In this chapter, we summarize the current status of the development of antiviral strategies against CHIKV infections. PMID- 27233278 TI - A Real-Time Cell Analyzing Assay for Identification of Novel Antiviral Compounds against Chikungunya Virus. AB - Screening of viral inhibitors through induction of cytopathic effects (CPE) by conventional method has been applied for various viruses including Chikungunya virus (CHIKV), a significant arbovirus. However, it does not provide the information about cytopathic effect from the beginning and throughout the course of virus replication. Conventionally, most of the approaches are constructed on laborious end-point assays which are not capable for detecting minute and rapid changes in cellular morphology. Therefore, we developed a label-free and dynamical method for monitoring the cellular features that comprises cell attachment, proliferation, and viral cytopathogenicity, known as the xCELLigence real-time cell analysis (RTCA). In this chapter, we provide a RTCA protocol for quantitative analysis of CHIKV replication using an infected Vero cell line treated with ribavirin as an in vitro model. PMID- 27233279 TI - Using Bicistronic Baculovirus Expression Vector System to Screen the Compounds That Interfere with the Infection of Chikungunya Virus. AB - Chikungunya virus (CHIKV) is the etiologic agent of Chikungunya fever and has emerged in many countries over the past decade. There are no effective drugs for controlling the disease. A bicistronic baculovirus expression system was utilized to co-express CHIKV structural proteins C (capsid), E2 and E1 and the enhanced green fluorescence protein (EGFP) in Spodoptera frugiperda insect cells (Sf21). The EGFP-positive Sf21 cells fused with each other and with uninfected cells to form a syncytium is mediated by the CHIKV E1 allowing it to identify chemicals that can prevent syncytium formation. The compounds characterized by this method could be anti-CHIKV drugs. PMID- 27233280 TI - Neutralization Assay for Chikungunya Virus Infection: Plaque Reduction Neutralization Test. AB - Neutralization assay is a technique that detects and quantifies neutralizing antibody in serum samples by calculating the percentage of reduction of virus activity, as the concentration of virus used is usually constant. Neutralizing antibody titer is conventionally determined by calculating the percentage reduction in total virus infectivity by counting and comparing number of plaques (localized area of infection due to cytopathic effect) with a standard amount of virus. Conventional neutralizing test uses plaque-reduction neutralization test (PRNT) to determine neutralizing antibody titers against Chikungunya virus (CHIKV). Here we describe the plaque reduction neutralization assay (PRNT) using Vero cell lines to obtain neutralizing antibody titers. PMID- 27233281 TI - Reverse Genetics Approaches for Chikungunya Virus. AB - Reverse genetic systems based on an infectious cDNA clone, a double-stranded copy of the viral genome carried on a plasmid vector, have greatly enhanced the understanding of RNA virus biology by facilitating genetic manipulation of viral RNA genomes. To date, infectious cDNA clones of Chikungunya virus (CHIKV) have been constructed using different combinations of plasmid vectors and/or bacterial host strains. Here, we describe our approaches for the construction of infectious cDNA clones of CHIKV and the protocol for genetic manipulation of the clones by site-directed mutagenesis. PMID- 27233282 TI - Production of Chikungunya Virus-Like Particles and Subunit Vaccines in Insect Cells. AB - Chikungunya virus is a reemerging human pathogen that causes debilitating arthritic disease in humans. Like dengue and Zika virus, CHIKV is transmitted by Aedes mosquitoes in an epidemic urban cycle, and is now rapidly spreading through the Americas since its introduction in the Caribbean in late 2013. There are no licensed vaccines or antiviral drugs available, and only a few vaccine candidates have passed Phase I human clinical trials. Using recombinant baculovirus expression technology, we have generated CHIKV glycoprotein subunit and virus like particle (VLP) vaccines that are amenable to large scale production in insect cells. These vaccines, in particular the VLPs, have shown high immunogenicity and protection against CHIKV infection in different animal models of CHIKV-induced disease. Here, we describe the production, purification, and characterization of these potent CHIKV vaccine candidates. PMID- 27233283 TI - Protocols for Developing Novel Chikungunya Virus DNA Vaccines. AB - To date, there have been several million infections by the Chikungunya virus (CHIKV), a mosquito-transmitted emerging pathogen that is considered to be taxonomically an Old World RNA virus. Although original CHIKV outbreaks were restricted to India, East Asian countries, Northern Italy, and France, a recent sharp rise had been identified in 41 countries or territories in the Caribbean, Central America, South America, and North America. A total of 1,012,347 suspected and 22,579 laboratory-confirmed CHIKV cases have been reported from these areas, which signals an increasing risk to the US mainland. Unlike past epidemics that were usually associated with Ae. aegypti transmission, the Caribbean outbreak was associated with Ae. albopictus transmission as the principal mosquito vector. In addition, the substantial increase in the number of deaths during this epidemic, as well as incidence of neurologic disease, suggests that CHIKV may have become more virulent. Currently, there are no licensed vaccines or therapeutics available for CHIKV or its associated disease pathologies. Therefore, development of new vaccines and therapies that could confer immunity and/or treat clinical symptoms of CHIKV is greatly desired. This chapter describes the use of entirely cutting edge technologies/methodologies developed by our group for the development and evaluation of novel DNA vaccines against CHIKV. PMID- 27233285 TI - Understanding Post-Prandial Hyperglycemia in Patients with Type 1 and Type 2 Diabetes: A Web-based Survey in Germany, the UK, and USA. AB - INTRODUCTION: To explore how patients with diabetes experience post-prandial hyperglycemia (PPH) or elevated blood glucose (BG) following a meal. METHODS: A web-based survey of patients with type 1 or type 2 diabetes using bolus insulin in Germany, the USA, and the UK was conducted. RESULTS: A total of 906 respondents completed the survey. PPH was a frequent occurrence among patients with type 1 and type 2 diabetes; 61.9% of respondents had experienced PPH in the past week, and differences by diabetes type were not significant. More than half of the respondents reported that they knew they were experiencing PPH because they had measured their BG (64.8%) and/or because they "just didn't feel right" (51.9%). The most frequently reported reasons given for PPH were eating more fat/sugar than estimated (31.2%) and over-eating in terms of their calculated bolus insulin dose (30.4%). The most common situations/factors contributing to PPH were stress (27.4%), eating at a restaurant (24.9%), being busy (21.1%), and/or feeling tired (19.2%). The most frequent corrective actions respondents took following PPH were testing BG and taking bolus insulin based on the reading (62.0%), and/or eating less/more carefully at their next meal or snack (18.8%). Additionally, significant differences in the reasons and contributing factors given for PPH and corrective actions following PPH, as well as emotions experienced when taking bolus insulin, were found by diabetes type. CONCLUSION: These findings shed light on how patients with diabetes experience and manage PPH on a day-to-day basis and have implications for improving diabetes self management. Clinicians and diabetes educators should help patients address eating habits and lifestyle issues that may contribute to PPH. FUNDING: This study was sponsored by Novo Nordisk. PMID- 27233284 TI - Target of rapamycin signaling mediates vacuolar fragmentation. AB - In eukaryotic cells, cellular homeostasis requires that different organelles respond to intracellular as well as environmental signals and modulate their behavior as conditions demand. Understanding the molecular mechanisms required for these changes remains an outstanding goal. One such organelle is the lysosome/vacuole, which undergoes alterations in size and number in response to environmental and physiological stimuli. Changes in the morphology of this organelle are mediated in part by the equilibrium between fusion and fission processes. While the fusion of the yeast vacuole has been studied intensively, the regulation of vacuolar fission remains poorly characterized by comparison. In recent years, a number of studies have incorporated genome-wide visual screens and high-throughput microscopy to identify factors required for vacuolar fission in response to diverse cellular insults, including hyperosmotic and endoplasmic reticulum stress. Available evidence now demonstrates that the rapamycin sensitive TOR network, a master regulator of cell growth, is required for vacuolar fragmentation in response to stress. Importantly, many of the genes identified in these studies provide new insights into potential links between the vacuolar fission machinery and TOR signaling. Together these advances both extend our understanding of the regulation of vacuolar fragmentation in yeast as well as underscore the role of analogous events in mammalian cells. PMID- 27233286 TI - Defining filled and empty space: reassessing the filled space illusion for active touch and vision. AB - In the filled space illusion, an extent filled with gratings is estimated as longer than an equivalent extent that is apparently empty. However, researchers do not seem to have carefully considered the terms filled and empty when describing this illusion. Specifically, for active touch, smooth, solid surfaces have typically been used to represent empty space. Thus, it is not known whether comparing gratings to truly empty space (air) during active exploration by touch elicits the same illusionary effect. In Experiments 1 and 2, gratings were estimated as longer if they were compared to smooth, solid surfaces rather than being compared to truly empty space. Consistent with this, Experiment 3 showed that empty space was perceived as longer than solid surfaces when the two were compared directly. Together these results are consistent with the hypothesis that, for touch, the standard filled space illusion only occurs if gratings are compared to smooth, solid surfaces and that it may reverse if gratings are compared to empty space. Finally, Experiment 4 showed that gratings were estimated as longer than both solid and empty extents in vision, so the direction of the filled space illusion in vision was not affected by the nature of the comparator. These results are discussed in relation to the dual nature of active touch. PMID- 27233288 TI - Haldane's Rule: Genetic Bases and Their Empirical Support. AB - There are few patterns in evolution that are as rigidly held as Haldane's rule (HR), which states, "When in the first generation between hybrids between 2 species, 1 sex is absent, rare, or sterile, that sex is always the heterogametic sex." Yet despite considerable attention for almost a century, questions persist as to how many independent examples exist and what is (are) the underlying genetic cause(s). Here, we review recent evidence extending HR to plants, where previously it has only been documented in animals. We also discuss recent comparative analyses that show much more variation in sex-chromosome composition than previously recognized, thus increasing the number of potential independent origins of HR dramatically. Finally, we review the standing of genetic theories proposed to explain HR in light of the new examples and new molecular understanding. PMID- 27233287 TI - Cytochrome P450 Organization and Function Are Modulated by Endoplasmic Reticulum Phospholipid Heterogeneity. AB - Cytochrome P450s (P450s) comprise a superfamily of proteins that catalyze numerous monooxygenase reactions in animals, plants, and bacteria. In eukaryotic organisms, these proteins not only carry out reactions necessary for the metabolism of endogenous compounds, but they are also important in the oxidation of exogenous drugs and other foreign compounds. Eukaryotic P450 system proteins generally reside in membranes, primarily the endoplasmic reticulum or the mitochondrial membrane. These membranes provide a scaffold for the P450 system proteins that facilitate interactions with their redox partners as well as other P450s. This review focuses on the ability of specific lipid components to influence P450 activities, as well as the role of the membrane in P450 function. These studies have shown that P450s and NADPH-cytochrome P450 reductase appear to selectively associate with specific phospholipids and that these lipid-protein interactions influence P450 activities. Finally, because of the heterogeneous nature of the endoplasmic reticulum as well as other biologic membranes, the phospholipids are not arranged randomly but associate to generate lipid microdomains. Together, these characteristics can affect P450 function by 1) altering the conformation of the proteins, 2) influencing the P450 interactions with their redox partners, and 3) affecting the localization of the proteins into specific membrane microdomains. PMID- 27233289 TI - Asperger syndrome in males over two decades: Quality of life in relation to diagnostic stability and psychiatric comorbidity. AB - This study examined objective quality of life (work, academic success, living situation, relationships, support system) and subjective quality of life (Sense of Coherence and Short-Form Health Survey-36) in an adult sample of males ( n = 50, mean age: 30 years) with Asperger syndrome diagnosed in childhood and followed prospectively over two decades. The association between long-term diagnostic stability of an autism spectrum disorder and/or comorbid psychiatric disorders with quality of life was also examined. The results showed great variability as regards quality of life. The subsample that no longer fulfilled an autism spectrum disorder had full-time jobs or studies (10/11), independent living (100%), and reported having two or more friends (100%). In the stable autism spectrum disorder group, 41% had full-time job or studies, 51% lived independently, and 33% reported two or more friends, and a significant minority had specialized employments, lived with support from the government, or had no friends. Academic success was positively correlated with IQ. A majority of the total group scored average Sense of Coherence scores, and the mean for Short-Form Health Survey-36 was above average regarding psychical health and below average regarding mental health. Stability of autism spectrum disorder diagnosis was associated with objective but not subjective quality of life, while psychiatric comorbidity was associated with subjective but not objective quality of life. PMID- 27233290 TI - Cognitive Aging in a Social and Affective Context: Advances Over the Past 50 Years. AB - OBJECTIVE: This review contemplates the recent consideration of social and affective factors within the study of cognitive aging and examines the multiple ways in which these factors intersect. METHODS: The article briefly reviews the models applied to cognitive aging and considers how they can inform the understanding of socioaffective aging. It then discusses the ways in which socioaffective and cognitive abilities intersect. RESULTS: Models of cognitive aging can fruitfully be applied to socioaffective aging, although with some points of divergence. The interactions between cognitive and socioaffective aging are multifaceted and include bidirectional influences. DISCUSSION: Socioaffective domains may preserve function within cognitive domains in part because socioaffective processing provides a rich source of environmental support and links to motivated cognition. The authors outline future directions related to these hypotheses. PMID- 27233292 TI - Johnson and Johnson faces lawsuit over vaginal mesh devices. PMID- 27233291 TI - Assay Establishment and Validation of a High-Throughput Screening Platform for Three-Dimensional Patient-Derived Colon Cancer Organoid Cultures. AB - The application of patient-derived three-dimensional culture systems as disease specific drug sensitivity models has enormous potential to connect compound screening and clinical trials. However, the implementation of complex cell-based assay systems in drug discovery requires reliable and robust screening platforms. Here we describe the establishment of an automated platform in 384-well format for three-dimensional organoid cultures derived from colon cancer patients. Single cells were embedded in an extracellular matrix by an automated workflow and subsequently self-organized into organoid structures within 4 days of culture before being exposed to compound treatment. We performed validation of assay robustness and reproducibility via plate uniformity and replicate-experiment studies. After assay optimization, the patient-derived organoid platform passed all relevant validation criteria. In addition, we introduced a streamlined plate uniformity study to evaluate patient-derived colon cancer samples from different donors. Our results demonstrate the feasibility of using patient-derived tumor samples for high-throughput assays and their integration as disease-specific models in drug discovery. PMID- 27233293 TI - Biliary Elimination of Pemetrexed Is Dependent on Mrp2 in Rats: Potential Mechanism of Variable Response in Nonalcoholic Steatohepatitis. AB - Hepatic multidrug resistance-associated protein 2 (MRP2) provides the biliary elimination pathway for many xenobiotics. Disruption of this pathway contributes to retention of these compounds and may ultimately lead to adverse drug reactions. MRP2 mislocalization from the canalicular membrane has been observed in nonalcoholic steatohepatitis (NASH), the late stage of nonalcoholic fatty liver disease, which is characterized by fat accumulation, oxidative stress, inflammation, and fibrosis. MRP2/Mrp2 mislocalization is observed in both human NASH and the rodent methionine and choline-deficient (MCD) diet model, but the extent to which it impacts overall transport capacity of MRP2 is unknown. Pemetrexed is an antifolate chemotherapeutic indicated for non-small cell lung cancer, yet its hepatobiliary elimination pathway has yet to be determined. The purpose of this study was to quantify the loss of Mrp2 function in NASH using an obligate Mrp2 transport substrate. To determine whether pemetrexed is an obligate Mrp2 substrate, its cumulative biliary elimination was compared between wild-type and Mrp2(-/-) rats. No pemetrexed was detected in the bile of Mrp2(-/-) rats, indicating pemetrexed is completely reliant on Mrp2 function for biliary elimination. Comparing the biliary elimination of pemetrexed between MCD and control animals identified a transporter-dependent decrease in biliary excretion of 60% in NASH. This study identifies Mrp2 as the exclusive biliary elimination mechanism for pemetrexed, making it a useful in vivo probe substrate for Mrp2 function, and quantifying the loss of function in NASH. This mechanistic feature may provide useful insight into the impact of NASH on interindividual variability in response to pemetrexed. PMID- 27233295 TI - The National Science Foundation's science and technology survey and support for science funding, 2006-2014. AB - This study investigates how well the main science and technology focused variables included in the General Social Survey (2006-2014) by the National Science Foundation do in predicting support for science funding. These questions form the primary basis of part of a biannual report to federal lawmakers. It is therefore important to consider whether the most useful variables are included in the survey. The results suggest some bivariate relationships between funding support and demographics, use of science communication channels, science knowledge, and attitudes about science and scientists. However, the overall predictive ability of the available variables appears to be modest when included together as part of multivariate analyses. The results suggest a need for additional discussions aimed at considering revisions to the core survey questions used to track views about science and technology in the United States. PMID- 27233294 TI - Prediction of Altered Bile Acid Disposition Due to Inhibition of Multiple Transporters: An Integrated Approach Using Sandwich-Cultured Hepatocytes, Mechanistic Modeling, and Simulation. AB - Transporter-mediated alterations in bile acid disposition may have significant toxicological implications. Current methods to predict interactions are limited by the interplay of multiple transporters, absence of protein in the experimental system, and inaccurate estimates of inhibitor concentrations. An integrated approach was developed to predict altered bile acid disposition due to inhibition of multiple transporters using the model bile acid taurocholate (TCA). TCA pharmacokinetic parameters were estimated by mechanistic modeling using sandwich cultured human hepatocyte data with protein in the medium. Uptake, basolateral efflux, and biliary clearance estimates were 0.63, 0.034, and 0.074 mL/min/g liver, respectively. Cellular total TCA concentrations (Ct,Cells) were selected as the model output based on sensitivity analysis. Monte Carlo simulations of TCA Ct,Cells in the presence of model inhibitors (telmisartan and bosentan) were performed using inhibition constants for TCA transporters and inhibitor concentrations, including cellular total inhibitor concentrations ([I]t,cell) or unbound concentrations, and cytosolic total or unbound concentrations. For telmisartan, the model prediction was accurate with an average fold error (AFE) of 0.99-1.0 when unbound inhibitor concentration ([I]u) was used; accuracy dropped when total inhibitor concentration ([I]t) was used. For bosentan, AFE was 1.2-1.3 using either [I]u or [I]t This difference was evaluated by sensitivity analysis of the cellular unbound fraction of inhibitor (fu,cell,inhibitor), which revealed higher sensitivity of fu,cell,inhibitor for predicting TCA Ct,Cells when inhibitors exhibited larger ([I]t,cell/IC50) values. In conclusion, this study demonstrated the applicability of a framework to predict hepatocellular bile acid concentrations due to drug-mediated inhibition of transporters using mechanistic modeling and cytosolic or cellular unbound concentrations. PMID- 27233296 TI - Do-it-yourself biology and electronic waste hacking: A politics of demonstration in precarious times. AB - In recent years, there has been an explosion of do it yourself, maker and hacker spaces in Europe. Through makers and do-it-yourself initiatives, 'hacking' is moving into the everyday life of citizens. This article explores the collective and political nature of those hacks by reporting on empirical work on electronic waste and do-it-yourself biology hacking. Using Dewey's experimental approach to politics, we analyse hacks as 'inquiry' to see how they serve to articulate public and political action. We argue that do-it-yourself and makers' hacks are technical and political demonstrations. What do-it-yourself and makers' hacks ultimately demonstrate is that things can be done otherwise and that 'you' can also do it. In this sense, they have a potential viral effect. The final part of the article explores some potential shortcomings of such politics of demonstration. PMID- 27233297 TI - Submaximal Exercise Systolic Blood Pressure and Heart Rate at 20 Years of Follow up: Correlates in the Framingham Heart Study. AB - BACKGROUND: Beyond their resting values, exercise responses in blood pressure (BP) and heart rate (HR) may add prognostic information for cardiovascular disease (CVD). In cross-sectional studies, exercise BP and HR responses correlate with CVD risk factors; however, it is unclear which factors influence longitudinal changes in exercise responses over time, which is important for our understanding of the development of CVD. METHODS AND RESULTS: We assessed BP and HR responses to low-level exercise tests (6-minute Bruce protocol) in 1231 Framingham Offspring participants (55% women) who underwent a routine treadmill test in 1979-1983 (baseline; mean age 39+/-8 years) that was repeated in 1998 2001 (follow-up; mean age 58+/-8 years). Adjusting for baseline exercise responses, we related the follow-up exercise responses to baseline CVD risk factors and to their changes between examinations. Compared with men, women had greater rise in exercise systolic (S)BP and HR at 20-year follow-up (both P<0.005). Baseline blood lipid levels, resting SBP and HR, and smoking status were associated with greater exercise SBP at follow-up (all P<0.05). Weight gain across examinations was associated with higher exercise SBP and HR at follow-up (both P<0.0001). Smoking cessation was associated with a 53% reduced risk of attaining the highest quartile of exercise SBP (>=180 mm Hg) at follow-up (P<0.05). CONCLUSION: An adverse CVD risk factor profile in young adults and its worsening over time were associated with higher SBP and HR responses to low-level exercise in midlife. Maintaining or adopting a healthy risk factor profile may favorably impact the exercise responses over time. PMID- 27233299 TI - Intravenous Hydration and Contrast-Induced Acute Kidney Injury: Too Much of a Good Thing? PMID- 27233298 TI - Excessively High Hydration Volume May Not Be Associated With Decreased Risk of Contrast-Induced Acute Kidney Injury After Percutaneous Coronary Intervention in Patients With Renal Insufficiency. AB - BACKGROUND: No well-defined protocols currently exist regarding the optimal rate and duration of normal saline administration to prevent contrast-induced acute kidney injury (CI-AKI) in patients with renal insufficiency. METHODS AND RESULTS: Hydration volume ratios (hydration volume/weight; HV/W) were calculated in 1406 patients with renal insufficiency (estimated glomerular filtration rate [eGFR], <90 mL/min per 1.73 m(2)) undergoing percutaneous coronary intervention (PCI) with routine speed hydration (1 or 0.5 mL/kg per hour). We investigated the relationship between hydration volume, risk of CI-AKI (increase in serum creatinine >=0.5 mg/dL or 25% within 48-72 hours), and prognosis. Mean follow-up duration was 2.85+/-0.88 years. Individuals with higher HV/W were more likely to develop CI-AKI (quartiles: Q1, Q2, Q3, and Q4: 4.3%, 6.6%, 10.9%, and 15.0%, respectively; P<0.001). After adjusting 12 confounders, including age, sex, eGFR, anemia, emergent PCI, diabetes mellitus, chronic heart failure, diuretics, contrast volume, lesions, smoking status, and number of stents, multivariate analysis showed that a higher HV/W ratio was not associated with a decreased CI AKI risk (Q2 vs Q1: adjusted odds ratio [OR], 1.13; Q3 vs Q1: adjusted OR, 1.51; Q4 vs Q1: adjusted OR, 1.87; all P>0.05) and even increased CI-AKI risk (HV/W >25 mL/kg: adjusted OR, 2.11; 95% CI, 1.24-3.59; P=0.006). Additionally, higher HV/W was significantly associated with an increased risk of death (Q4 vs Q1: adjusted hazard ratio, 3.44; 95% CI, 1.20-9.88; P=0.022). CONCLUSIONS: Excessively high hydration volume at routine speed might be associated with increased risk of CI AKI and death post-PCI in patients with renal insufficiency. PMID- 27233300 TI - Comparison of noninvasive pulse transit time estimates as markers of blood pressure using invasive pulse transit time measurements as a reference. AB - Pulse transit time (PTT) measured as the time delay between invasive proximal and distal blood pressure (BP) or flow waveforms (invasive PTT [I-PTT]) tightly correlates with BP PTT estimated as the time delay between noninvasive proximal and distal arterial waveforms could therefore permit cuff-less BP monitoring. A popular noninvasive PTT estimate for this application is the time delay between ECG and photoplethysmography (PPG) waveforms (pulse arrival time [PAT]). Another estimate is the time delay between proximal and distal PPG waveforms (PPG-PTT). PAT and PPG-PTT were assessed as markers of BP over a wide physiologic range using I-PTT as a reference. Waveforms for determining I-PTT, PAT, and PPG-PTT through central arteries were measured from swine during baseline conditions and infusions of various hemodynamic drugs. Diastolic, mean, and systolic BP varied widely in each subject (group average (mean +/- SE) standard deviation between 25 +/- 2 and 36 +/- 2 mmHg). I-PTT correlated well with all BP levels (group average R(2) values between 0.86 +/- 0.03 and 0.91 +/- 0.03). PPG-PTT also correlated well with all BP levels (group average R(2) values between 0.81 +/- 0.03 and 0.85 +/- 0.02), and its R(2) values were not significantly different from those of I PTT PAT correlated best with systolic BP (group average R(2) value of 0.70 +/- 0.04), but its R(2) values for all BP levels were significantly lower than those of I-PTT (P < 0.005) and PPG-PTT (P < 0.02). The pre-ejection period component of PAT was responsible for its inferior correlation with BP In sum, PPG-PTT was not different from I-PTT and superior to the popular PAT as a marker of BP. PMID- 27233301 TI - Age and hypertension strongly induce aortic stiffening in rats at basal and matched blood pressure levels. AB - Age and hypertension are major causes of large artery remodeling and stiffening, a cardiovascular risk factor for heart and kidney damage. The aged spontaneously hypertensive rat (SHR) model is recognized for human cardiovascular pathology, but discrepancies appeared in studies of arterial stiffness. We performed experiments using a robust analysis via echo tracking in 20-week adult (n = 8) and 80-week-old SHR (n = 7), with age-matched normotensive Wistar Kyoto rats (WKY, n = 6;6) at basal and matched levels of blood pressure (BP). After anesthesia with pentobarbital, abdominal aortic diameter and pressure were recorded and BP was decreased by clonidine i.v. At basal BP, aortic pulse distension, compliance, and distensibility (AD) were reduced and stiffness index increased with age and hypertension and further altered with age + hypertension. When BP was adjusted in SHR to that of normotensive rats (130 mmHg), there was no difference between 20-week-old SHR and WKY Importantly, the age effect was maintained in both WKY and SHR and accentuated by hypertension in old rats. At 130 mmHg, with similar pulse pressure in the four groups, AD (kPa(-3)) = 24.2 +/- 1 in 20 weeks WKY, 19.7 +/- 1.4 in 20 weeks SHR, 12.4 +/- 1.3 in 80 weeks WKY and 6.6 +/- 0.6 in 80 weeks SHR; distension = 7.6 +/- 0.4%, 6.7 +/- 0.6%, 3.7 +/- 0.3%, and 1.8 +/- 0.2% in the same groups. In conclusion, reduced distensibility, that is, stiffening due to age is clearly shown here in both WKY and SHR as well as a synergistic effect of age and hypertension. This technique will allow new studies on the mechanisms responsible and drug intervention. PMID- 27233302 TI - There and back again: insulin, ENaC, and the cortical collecting duct. PMID- 27233303 TI - Aging does not affect soluble guanylate cyclase redox state in mouse aortas. AB - Aging is associated with endothelial dysfunction, defined as a reduction in nitric oxide (NO) bioavailability. Although the redox state of the NO acceptor soluble guanylate cyclase (sGC) is another determinant factor for its bioavailability and is disturbed by reactive oxygen species (ROS) known to be increased with age, it is unclear whether aging actually has an impact on vascular sGC redox equilibrium. Therefore, this study investigated this issue using two different types of compounds, the sGC stimulator BAY 41-2272 and the sGC activator BAY 60-2770. Plasma thiobarbituric acid-reactive substances (TBARS) levels were markedly higher in aged (19-20 months old) mice than in young (2-3 months old) mice, whereas superoxide levels in endothelium-denuded aortas were not different between the groups. The relaxant response of endothelium-denuded aortas to either BAY 41-2272 or BAY 60-2770 was identical in aged and young mice. In addition, the vascular cGMP production stimulated with BAY 41-2272 or BAY 60 2770 in aged mice was the same level as that in young mice. These findings suggest that aging accompanied by an increase in systemic oxidative stress does not affect vascular smooth muscle ROS generation and sGC redox equilibrium. Unless ROS are increased in vascular smooth muscle, the sGC redox equilibrium might remain unchanged. PMID- 27233351 TI - Surface cis Effect: Influence of an Axial Ligand on Molecular Self-Assembly. AB - Adding ligands to molecules can have drastic and unforeseen consequences in the final products of a reaction. Recently a surface trans effect due to the weakening of a molecule-surface bond was reported. Here, we show a surface cis effect where an axial ligand at adsorbed transition-metal complexes enables lateral bonding among the molecules. In the absence of this ligand, the intermolecular interaction is repulsive and supramolecular patterns are not observed. Fe-tetramethyl-tetraazaannulene on Au(111) was investigated using low temperature scanning tunneling microscopy and spectroscopy along with density functional theory calculations. At low coverages, the molecules remain isolated. Exposure to CO leads to axial CO bonding and induces reordering into extended clusters of chiral molecular trimers. The changed self-assembly pattern is due to a CO-induced modification of the molecular structure and the corresponding charge transfer between the molecule and the substrate, which in turn changes the lateral intermolecular forces. PMID- 27233352 TI - Use of transcutaneous ultrasonography to characterize ovarian status, size distribution, and hierarchical status of follicles in Japanese quail (Coturnix coturnix japonica). AB - The present study was undertaken to evaluate the ovarian status of matured breeding female Japanese quail by means of B Mode portable ultrasound scanning. Active ovaries in various stages of hierarchical development and different morphological structure were observed. The large yellow follicles appeared as a cluster of dark circles with various intensity of hyperechoic concentric ring. Sonographically, these follicles were classified into F1, F2, and F3 measuring 16.20 +/- 0.06 mm, 12.48 +/- 0.09 mm, and 7.95 +/- 0.16 mm, respectively. A comparative study on preslaughter and postslaughter ovarian follicular status revealed accuracy of follicles less than 10 mm, 10-15 mm, 15-18 mm, and greater than 18 mm as 26.31%, 78.9%, 93.75%, and 100%, respectively, with an overall accuracy of 71%. This is the first report on the application of transcutaneous ultrasonographic technique to monitor ovarian status on Japanese quail reporting that the ovarian follicular activity and morphological structure can be monitored nonintrusively throughout quail life which can used as model for reproductive and biomedical research. PMID- 27233353 TI - Exploratory study of the role of knowledge brokers in translating knowledge to action following global maternal and newborn health technical meetings. AB - OBJECTIVES: There have been increasing calls for more research on interventions to successfully translate evidence-based knowledge into improved health policy and practices. This paper reports on an exploratory study of knowledge translation interventions conducted with participants of global health meetings held in Bangladesh in 2012 and in South Africa in 2013. We measured stakeholders' uptake of evidence-based knowledge in terms of their translation of this knowledge into actions around public health policy and practice. The research sought to determine whether participants shared and used knowledge from the meetings to improve health policy and practices in their settings and the factors influencing sharing and use. STUDY DESIGN: An exploratory study employed quantitative and qualitative methods of online surveys and in-depth interviews to collect data from all meeting participants. METHODS: All participants in the Bangladesh and South Africa meetings were invited to complete an online survey during the meetings and over the following six weeks. Of 411 participants in the 2012 Bangladesh meeting, 148 participants from 22 countries completed the survey. Eleven of these respondents (from eight countries) were interviewed. Of the 436 participants in the 2013 South Africa meeting, 126 respondents from 33 countries completed an online survey; none of these respondents were interviewed. RESULTS: The analysis revealed that most respondents used new knowledge to advocate for policy change (2012: 65.5%; 2013: 67.5%) or improve service quality (2012: 60.1%; 2013: 70.6%). The type of knowledge that respondents most commonly shared was clinical or scientific information (2012: 79.1%; 2013: 66.7%) and country specific information (2012: 73.0%; 2013: 71.4%). Most 2012 respondents shared knowledge because they thought it would be useful to a co-worker or colleague (79.7%). DISCUSSION: Findings on knowledge use and sharing suggest that most respondents saw themselves as knowledge brokers or intermediaries in a position to influence the translation of knowledge into action in health policy and practices in their countries. Results suggest that supporting knowledge brokers working in a local and regional context to spur change, as described in the paper, has the potential to improve health outcomes. Further research is needed to isolate specific interventions and their knowledge translation outcomes. PMID- 27233354 TI - European patient's cross-border mobility directive. PMID- 27233355 TI - Functional recovery after treatment of extra-articular distal radius fractures in the elderly using the IlluminOss(r) System (IO-Wrist); a multicenter prospective observational study. AB - BACKGROUND: Approximately 17 % of all fractures involve the distal radius. Two thirds require reduction due to displacement. High redislocation rates and functional disability remain a significant problem after non-operative treatment, with up to 30 % of patients suffering long-term functional restrictions. Whether operative correction is superior to non-operative treatment with respect to functional outcome has not unequivocally been confirmed. The IlluminOss(r) System was introduced in 2009 as a novel, patient-specific, and minimally invasive intramedullary fracture fixation. This minimally invasive technique has a much lower risk of iatrogenic soft tissue complications. Because IlluminOss(r) allows for early mobilization, it may theoretically lead to earlier functional recovery and ADL independence than non-operative immobilization. The main aim of this study is to examine outcome in elderly patients who sustained a unilateral, displaced, extra-articular distal radius fracture that was treated with IlluminOss(r). METHODS/DESIGN: The design of the study will be a multicenter, prospective, observational study (case series). The study population comprises elderly (60 years or older; independent in activities of daily living) with a unilateral, displaced, extra-articular distal radius fracture (AO/OTA type 23-A2 and A3) that after successful closed reduction was fixed within 2 weeks after the injury with IlluminOss(r). Critical elements of treatment will be registered, and outcome will be monitored until 1 year after surgery. The Disabilities of the Arm, Shoulder, and Hand score will serve as primary outcome measure. The Patient Rated Wrist Evaluation score, level of pain, health-related quality of life (Short Form-36 and EuroQoL-5D), time to ADL independence, time to activities/work resumption, range of motion of the wrist, radiological outcome, and complications are secondary outcome measures. Health care consumption and lost productivity will be used for a cost analysis. The cost analysis will be performed from a societal perspective. Descriptive data will be reported. DISCUSSION: The results of this study will provide evidence on the effectiveness of operative treatment of patients who sustained an extra-articular distal radius fracture with the IlluminOss(r) System, using clinical, patient-reported, and societal outcomes. TRIAL REGISTRATION: The study is registered at the Netherlands Trial Register ( NTR5457 ; 29-sep-2015). PMID- 27233356 TI - Associations between body composition and nutritional assessments and biochemical markers in patients with chronic radiation enteritis: a case-control study. AB - BACKGROUND: Chronic radiation enteritis (CRE) is defined as loss of absorptive capacity after irradiation due to chronic inflammation and damage of intestinal mucosa, which may lead to varying degrees of malnutrition. The aim of this study was to evaluate the potential correlation between the nutritional status and systemic inflammation in patients with CRE. METHODS: Medical records of 92 patients with CRE and 184 age- and sex-matched controls in a single center from January 2010 to October 2015 were retrospectively reviewed. All enrolled subjects underwent nutritional status analysis, including three different nutritional indices: Nutritional Risk Screening-2002 (NRS-2002), Patient-generated Subjective Global Assessment (PG-SGA) and Controlling Nutritional Status (CONUT), bioelectrical impedance spectroscopy (BIS), and biochemical markers, within 24 h of admission. RESULTS: The results showed that NRS-2002, PG-SGA and CONUT were all positively correlated with neutrophil/lymphocyte ratio (NLR) (r = 0.304, 0.384 and 0.425, all p < 0.001) and C-reactive protein (CRP) (r = 0.357, 0.479 and 0.230, all p < 0.001), while negatively correlated with albumin (r = -0.612, 0.727 and -0.792, all p < 0.001) and total cholesterol (TC) (r = -0.485, -0.545 and -0.473, all p < 0.001) in patients with CRE, respectively. Body cell mass (BCM) has been deemed a key body composition parameter. It was positively correlated with albumin (r = 0.489, p < 0.001) and TC (r = 0.237, p < 0.001), while negatively correlated with NLR (r = -0.140, p = 0.02) and CRP (r = -0.215, p < 0.001). A multivariate linear regression analysis showed that values of intracellular water (beta coefficient = 0.760, p < 0.001), extracellular water (beta coefficient = 0.006, p = 0.011), protein (beta coefficient = 0.235, p < 0.001) and CRP (beta coefficient = 0.001, p = 0.009) were independent determinants of BCM. CONCLUSION: This study revealed that BIS combined with nutritional assessments and biochemical markers were appropriate methods to assess the nutritional and inflammatory status in patients with CRE. Furthermore, the nutritional status was verified to be significantly correlated with systemic inflammation. PMID- 27233357 TI - A retrospective review in the management of T3 laryngeal squamous cell carcinoma: an expanding indication for transoral laser microsurgery. AB - BACKGROUND: The purpose of this study was to evaluate the functional and oncological outcomes of patients treated for T3 laryngeal squamous cell carcinoma. Specifically comparing transoral laser microsurgery and radiotherapy/chemoradiotherapy treatment modalities. METHOD: A retrospective review of patients treated for T3 laryngeal SCC between 2002 and 2010 was undertaken. RESULTS: Forty-nine patients were included. 15 cases were glottic, (9 treated with TLM, 6 with RT/CRT), 33 supraglottic (6 treated with TLM, 27 with RT/CRT) and 1 subglottic subsite (treated with RT/CRT). There was no statistical difference between treatment groups for 24 month locoregional control (72.3 %), overall survival (glottis 86.7 %, supraglottic 70.4 %) and disease specific survival (glottic 93.3 % and supraglottic 74.1 %). Overall laryngeal preservation (84.9 %) was also similar in both groups. CONCLUSION: Our institution is expanding the application of TLM to selected patients with T3 laryngeal carcinoma. Oncological outcomes have not been jeopardized by this approach and the treatment is well tolerated by patients with few complications. PMID- 27233358 TI - Effect of perfluorooctane sulfonate on viability, maturation and gap junctional intercellular communication of porcine oocytes in vitro. AB - Perfluorooctane sulfonate (PFOS) is a broadly used man-made surfactant whose long half-life has led to bioaccumulation. This perfluorinated compound is ubiquitous in human body fluids. PFOS concentrations as high as 26MUM in plasma have been reported in occupationally exposed populations, and high levels of PFOS in human follicular fluid have been associated with subfertility. However, the effect of PFOS on the maturation of oocytes in mammals has not been reported to date. The aim of this study was to determine the effects of PFOS during oocyte maturation. Results indicate that PFOS inhibits oocyte viability (Lethal Concentration50=32MUM) and maturation (inhibition of maturation50=22MUM) at physiologically relevant concentrations. In order to evaluate the mechanisms of oocyte maturation inhibition by PFOS, gap junctional intercellular communication (GJIC) between oocytes and granulosa cells was assessed. GJIC between granulosa cells and the oocyte was significantly affected during the first 8h of maturation. However, the inhibitory effect of PFOS on GJIC was not due to an alteration on the expression of connexin genes Cx43, Cx45 and Cx60. These findings suggest that occupationally exposed populations could be at risk, and that PFOS might affect oocyte maturation by interfering the GJIC in the cumulus oocyte complexes during the first hours of maturation. PMID- 27233360 TI - Proficiencies of Artemisia scoparia against CCl4 induced DNA damages and renal toxicity in rat. AB - BACKGROUND: Artemisia scoparia is traditionally used in the local system of medicine in kidney disorders. This study aimed at scrutinizing the nephroprotective prospective of A. scoparia methanol extract against carbon tetrachloride (CCl4) provoked DNA damages and oxidative stress in kidneys of rat. METHODS: Dried aerial parts of A. scoparia were powdered and extracted with methanol to obtain the viscous material (ASM). Sprague Dawley male rats (42) were grouped (7) having 6 rats in each. Group I remained untreated and Group II treated intraperitoneally (i.p) with DMSO + olive oil (1 ml/kg body weight (bw). Rats of Group III - VI were treated with CCl4 (1 ml/kg bw; i.p 30 % v/v in olive oil). Animals of Group IV were co-administered with 100 mg/kg bw of silymarin whereas rats of Group V and VI with 150 mg/kg bw and 300 mg/kg bw of ASM at an interval of 48 h for four weeks. Animals of Group VII were administered with ASM (300 mg/kg bw) alone. DNA damages were investigated with comet assay in renal tissues while the oxidative injuries were estimated in serum and renal tissues. RESULTS: Co-administration of ASM to rats significantly reduced the DNA damages at 300 mg/kg dose as indicated in comet length (40.80 +/- 2.60 MUm), head length (34.70 +/- 2.21 MUm), tail length (7.43 +/- 1.24 MUm) and DNA content in head (88.03 +/- 2.27 %) to that of CCl4 for comet length (63.16 +/- 2.11 MUm), head length (23.29 +/- 1.50 MUm), tail length (39.21 +/- 2.81 MUm) and DNA content of head (74.81 +/- 2.18 %) in renal cell's nuclei. Increased level of urea, creatinine, bilirubin, blood urea nitrogen whereas decreased concentration of proteins in serum of CCl4 treated animals were restored towards the normal level with co-administration of ASM. CCl4 injection in rats decreased the activity level of CAT, POD, SOD, GST and gamma-GT and GSH contents while elevated levels of TBARS, H2O2 and nitrite contents were observed in renal tissues. A noteworthy retrieval of all these parameters and the altered histopathological observations was notified near to the normal values after treatment with both the doses of ASM. CONCLUSION: Results obtained suggested the therapeutic role of ASM in oxidative stress related disorder of kidneys. PMID- 27233359 TI - Intermittent energy restriction induces changes in breast gene expression and systemic metabolism. AB - BACKGROUND: Observational studies suggest weight loss and energy restriction reduce breast cancer risk. Intermittent energy restriction (IER) reduces weight to the same extent as, or more than equivalent continuous energy restriction (CER) but the effects of IER on normal breast tissue and systemic metabolism as indicators of breast cancer risk are unknown. METHODS: We assessed the effect of IER (two days of 65 % energy restriction per week) for one menstrual cycle on breast tissue gene expression using Affymetrix GeneChips, adipocyte size by morphometry, and systemic metabolism (insulin resistance, lipids, serum and urine metabolites, lymphocyte gene expression) in 23 overweight premenopausal women at high risk of breast cancer. Unsupervised and supervised analyses of matched pre and post IER biopsies in 20 subjects were performed, whilst liquid and gas chromatography mass spectrometry assessed corresponding changes in serum and urine metabolites in all subjects after the two restricted and five unrestricted days of the IER. RESULTS: Women lost 4.8 % (+/-2.0 %) of body weight and 8.0 % (+/-5.0 %) of total body fat. Insulin resistance (homeostatic model assessment (HOMA)) reduced by 29.8 % (+/-17.8 %) on the restricted days and by 11 % (+/-34 %) on the unrestricted days of the IER. Five hundred and twenty-seven metabolites significantly increased or decreased during the two restricted days of IER. Ninety-one percent of these returned to baseline after 5 days of normal eating. Eleven subjects (55 %) displayed reductions in energy restriction-associated metabolic gene pathways including lipid synthesis, gluconeogenesis and glycogen synthesis. Some of these women also had increases in genes associated with breast epithelial cell differentiation (secretoglobulins, milk proteins and mucins) and decreased collagen synthesis (TNMD, PCOLCE2, TIMP4). There was no appreciable effect of IER on breast gene expression in the other nine subjects. These groups did not differ in the degree of changes in weight, total body fat, fat cell size or serum or urine metabolomic markers. Corresponding gene changes were not seen in peripheral blood lymphocytes. CONCLUSION: The transcriptional response to IER is variable in breast tissue, which was not reflected in the systemic response, which occurred in all subjects. The mechanisms of breast responsiveness/non responsiveness require further investigation. TRIAL REGISTRATION: ISRCTN77916487 31/07/2012. PMID- 27233362 TI - Interprofessional collaboration regarding patients' care plans in primary care: a focus group study into influential factors. AB - BACKGROUND: The number of people with multiple chronic conditions demanding primary care services is increasing. To deal with the complex health care demands of these people, professionals from different disciplines collaborate. This study aims to explore influential factors regarding interprofessional collaboration related to care plan development in primary care. METHODS: A qualitative study, including four semi-structured focus group interviews (n = 4). In total, a heterogeneous group of experts (n = 16) and health care professionals (n = 15) participated. Participants discussed viewpoints, barriers, and facilitators regarding interprofessional collaboration related to care plan development. The data were analysed by means of inductive content analysis. RESULTS: The findings show a variety of factors influencing the interprofessional collaboration in developing a care plan. Factors can be divided into 5 key categories: (1) patient related factors: active role, self-management, goals and wishes, membership of the team; (2) professional-related factors: individual competences, domain thinking, motivation; (3) interpersonal factors: language differences, knowing each other, trust and respect, and motivation; (4) organisational factors: structure, composition, time, shared vision, leadership and administrative support; and (5) external factors: education, culture, hierarchy, domain thinking, law and regulations, finance, technology and ICT. CONCLUSIONS: Improving interprofessional collaboration regarding care plan development calls for an integral approach including patient- and professional related factors, interpersonal, organisational, and external factors. Further, the leader of the team seems to play a key role in watching the patient perspective, organising and coordinating interprofessional collaborations, and guiding the team through developments. The results of this study can be used as input for developing tools and interventions targeted at executing and improving interprofessional collaboration related to care plan development. PMID- 27233363 TI - A curvilinear association of body mass index with cardiovascular diseases in Chinese patients with type 2 diabetes mellitus - A population-based retrospective cohort study. AB - AIMS: This epidemiological and longitudinal study aimed to confirm the association between BMI and CVD and determine the optimal BMI range for Chinese patients with T2DM. METHOD: A retrospective cohort study was conducted on 113,194 Chinese adult primary care T2DM patients without prior CVD history at baseline, and had a documented BMI in 2008-2010. Using the average of the annual mean of BMI records (updated BMI) over a median follow-up of 4.2years, the risk of CVD associated with BMI by gender, age group, smoking status and presence of chronic kidney disease group was evaluated using multivariable Cox proportional hazard regression adjusted by socio-demographics and clinical characteristics. RESULTS: The updated BMI value and the incidence of CVD showed a J-shaped curvilinear relationship. Low (<18.5kg/m(2)) or high (>=25kg/m(2)) BMI range was associated with higher risk of CVD and the optimal BMI range associated with the lowest likelihood of CVD was 20-22.9kg/m(2) in overall cohort and all selected groups. CONCLUSIONS: There was no evidence of benefit of underweight or adiposity with regard to the risk of CVD and thus the maintenance of a normal weight should be emphasized as an integral part of preventive intervention in the diabetes management. PMID- 27233364 TI - Multiple immune deviations predictive for IVF failure as possible markers for IVIG therapy. AB - Recently we have shown that immune deviations (ID) may predict IVF failure. Benefit from IVIG therapy was observed in 115 women with repeated IVF failure according to proposed multiple ID that appeared unfavorable for implantation and live birth. Group of 123 women with repeated IVF failure without IVIG therapy was compared with former group. Immune phenotype and NK activity of peripheral blood lymphocytes were studied by flow cytometry. Potentially predictive for IVF failure ID included elevated expression of CD56, CD158a in T lymphocytes, decreased levels of CD4T lymphocytes, up-regulated expression of HLA DR in CD8+ T cells and NK cells, elevated number of NK cells and increased NK cytotoxicity, increased or decreased expression of CD158a and CD8 in NK cells. Three or more ID may predict implantation failure to a greater degree than one or two ID. In women receiving IVIG in subgroups with 0-1 and 2 ID, there was no increase in implantation rate (IR) and live birth rate (LBR) after IVIG in comparison with patients with the same number of ID but without IVIG correction. After IVIG therapy decreased IR and LBR were restored in women with three or more immune deviations. Multiple immune deviations indicate IVF patients who may benefit from IVIG therapy. IVIG seems to convert "unfavorable" immune phenotype to "favorable" one. PMID- 27233361 TI - A glance at subgenomic flavivirus RNAs and microRNAs in flavivirus infections. AB - The family Flaviviridae comprises a wide variety of viruses that are distributed worldwide, some of which are associated with high rates of morbidity and mortality. There are neither vaccines nor antivirals for most flavivirus infections, reinforcing the importance of research on different aspects of the viral life cycle. During infection, cytoplasmic accumulation of RNA fragments mainly originating from the 3' UTRs, which have been designated subgenomic flavivirus RNAs (sfRNAs), has been detected. It has been shown that eukaryotic exoribonucleases are involved in viral sfRNA production. Additionally, viral and human small RNAs (sRNAs) have also been found in flavivirus-infected cells, especially microRNAs (miRNAs). miRNAs were first described in eukaryotic cells and in a mature and functional state present as single-stranded 18-24 nt RNA fragments. Their main function is the repression of translation through base pairing with cellular mRNAs, besides other functions, such as mRNA degradation. Canonical miRNA biogenesis involves Drosha and Dicer, however miRNA can also be generated by alternative pathways. In the case of flaviviruses, alternative pathways have been suggested. Both sfRNAs and miRNAs are involved in viral infection and host cell response modulation, representing interesting targets of antiviral strategies. In this review, we focus on the generation and function of viral sfRNAs, sRNAs and miRNAs in West Nile, dengue, Japanese encephalitis, Murray Valley encephalitis and yellow fever infections, as well as their roles in viral replication, translation and cell immune response evasion. We also give an overview regarding other flaviviruses and the generation of cellular miRNAs during infection. PMID- 27233365 TI - Dengue encephalitis-associated immunopathology in the mouse model: Implications for vaccine developers and antigens inducer of cellular immune response. AB - Despite the many efforts made by the scientific community in the development of vaccine candidates against dengue virus (DENV), no vaccine has been licensed up to date. Although the immunopathogenesis associated to the disease is a key factor to take into account by vaccine developers, the lack of animal models that reproduce the clinical signs of the disease has hampered the vaccine progress. Non-human primates support viral replication, but they are very expensive and do not show signs of disease. Immunocompromised mice develop viremia and some signs of the disease; however, they are not valuable for vaccine testing. Nowadays, immunocompetent mice are the most used model to evaluate the immunogenicity of vaccine candidates. These animals are resistant to DENV infection; therefore, the intracranial inoculation with neuroadapted virus, which provokes viral encephalitis, represents an alternative to evaluate the protective capacity of vaccine candidates. Previous results have demonstrated the crucial role of cellular immune response in the protection induced by the virus and vaccine candidates in this mouse encephalitis model. However, in the present work we are proposing that the magnitude of the cell-mediated immunity and the inflammatory response generated by the vaccine can modulate the survival rate after viral challenge. We observed that the intracranial challenge of naive mice with DENV-2 induces the recruitment of immune cells that contribute to the reduction of viral load, but does not increase the survival rate. On the contrary, animals treated with cyclophosphamide, an immunosuppressive drug that affects proliferating lymphocytes, had a higher viral load but a better survival rate than untreated animals. These results suggest that the immune system is playing an immunopathogenic role in this model and the survival rate may not be a suitable endpoint in the evaluation of vaccine candidates based on antigens that induce a strong cellular immune response. PMID- 27233366 TI - Increased signal intensity in FLAIR sequences in the resection cavity can predict progression and progression-free survival in gliomas. AB - OBJECTIVE: To determine if hyperintense fluid in the postsurgical cavity on follow-up fluid-attenuated inversion recovery (FLAIR) sequences can predict progression in gliomas. MATERIAL AND METHODS: Observational study of magnetic resonance imaging signal of fluid within the post-surgical cavity in patients with glioma (grade II-IV), with surgery and follow-up between 2007 and 2012. Qualitative comparison between the signal of fluid in the cavity and of the ventricular cerebrospinal fluid (CSF) was performed on FLAIR sequences. Fluid in the cavity was classified as isointense or hyperintense compared to CSF. Double blind reading was performed. The signal intensity was correlated with tumour progression, assessed using Response Assessment in Neuro-Oncology criteria. RESULTS: A total of 107 patients were included, of whom 90 had high-grade gliomas. Inter-rater agreement was excellent, and intra-rater complete (k=0.94 and 1, p<.001). Hyperintense fluid in the resection cavity occurred more commonly (58.9% versus 29.4%, p=.025) and earlier (mean 4.5 versus 9.9 months, p<.001) in high-grade than in low-grade gliomas. Hyperintense fluid was associated with progression in high-grade gliomas, with a sensitivity of 65.7% (95%CI, 54.3 75.6%) and a specificity of 70.6% (95%CI, 46.6-87%), and in low-grade gliomas with a sensitivity of 50% (95%CI, 18.7-81.2%), and a specificity of 81.8% (95%CI, 51.1-96%). The positive predictive value of this sign was 90.6% (95%CI, 79.3 96.3%) for high-grade gliomas, and was higher for grade IV (93.2%, 95%CI, 87.3 99.1%) and lower for grade III (77.8%, 95%CI, 59.6-96%), and low-grade gliomas (60%, 95%CI, 22.9-88.4%). False-positives were identified in 7 patients, due to bleeding or infection. Hyperintense fluid in high-grade gliomas preceded progression in 22 patients (30.1%), with a mean of 4.1 months (SD 2.1, 95% CI, 3.2-5), and associated with poorer progression-free survival (mean 6.8 versus 11.7 months, p=.004). CONCLUSIONS: Hyperintense fluid in the resection cavity on follow-up FLAIR sequences occurs more frequently and earlier in high-grade gliomas, and is associated with poorer progression-free survival. Hyperintense fluid is associated with disease progression, and can predict the progression of resected gliomas. False-positives due to bleeding and infection can be observed, and are easily recognizable. PMID- 27233367 TI - [Clinical burden caused by hospitalization for febrile neutropenia in France in 2010-2011: An analysis of the PMSI database]. AB - INTRODUCTION: Febrile neutropenia (FN) is a severe complication of chemotherapy in terms of morbidity and mortality. Using data from the PMSI database, the objective of this work was to estimate the clinical burden caused by hospitalization for FN in France, assessed by number of patients, number of stays and hospital mortality. METHODS: Using the PMSI database (which includes all hospitalizations occurring annually in France), an algorithm was used to select newly-diagnosed patients treated by chemotherapy in 2010/2011 who were hospitalized for FN within the 30 days following each administration of chemotherapy during their first year of treatment. The number, characteristics and comorbidities of patients were described, as well as the number and length of stay and mortality in hospitalized patients. RESULTS: In 2010-11, 10,229 patients were hospitalized for FN, representing a hospitalization rate of 7.4% in newly diagnosed patients receiving chemotherapy. A total of 13,559 stays were identified, with an average duration of 6.3+/-8.7 days (median=4 days). A total of 720 deaths occurred during the hospital stays, corresponding to a mortality rate of 7%. Among patients hospitalized for FN, there were 14% of patients with diabetes, 8 % with heart failure, 34% with hypertension and 41% with at least one of these three comorbidities. DISCUSSION: With 10,299 hospitalized patients and 13,559 stays in 2010-11, the clinical burden induced by febrile neutropenia in cancer patients treated with chemotherapy is considerable. PMID- 27233368 TI - [Systematizing support in cessation smoking to improve care for cancer patients]. AB - Approximately 20% of cancer patients smoke at diagnosis (all localizations included), and over two thirds continue despite the therapeutic management of their cancer, especially when cancer is not associated with tobacco. The impact of smoking on quality of care for patients is actually not enough considered. A literature review conducted by the French National Cancer Institute emphasizes the importance of tobacco cessation to improve the prognosis (decreased mortality from all causes and specific); to reduce the risk of second primary cancers; to reduce per- and post-surgical risks as long as some toxicities related to treatments and to improve the quality of physical and mental life of patients. It is important that a communication with the patient takes place at the beginning of the treatment to impact the smoking behavior. All oncology health professionals should deliver a clearly and personalized cessation advice in the light of scientific data and ensure that smoking cessation help will be offered to the patient. PMID- 27233369 TI - Dietary intake variations from pre-conception to gestational period according to the degree of industrial processing: A Brazilian cohort. AB - OBJECTIVE: To estimate food intake changes from pre-conception to gestational period according to the degree of food processing. METHODS: Prospective cohort conducted in a public health care center in Rio de Janeiro with Brazilian pregnant women (n = 189). A food frequency questionnaire was applied at the first (5(th)-13(th)) and third (30(th)-36(th)) gestational trimesters. The food items were classified according to characteristics of food processing in four groups: unprocessed/minimally processed foods; sugar/fat; processed foods and ultra processed foods. The variation of food intake according to the degree of processing between the pre-conception and gestational period was compared using paired Student's t-test. Linear regression models were performed to estimate the association of mother's characteristics on the variation of food group contribution to the total energy intake between periods. RESULTS: Total energy intake was 2415 (SD = 813) in the pre-conception and 2379 (750) kcal in the gestational period. We excluded women who had implausible total energy intake (<600 and >6000 kcal/day). The contribution of unprocessed/minimally processed food group to total energy intake during pregnancy when compared to the pre conception period was higher [50.5 (14.1) vs. 48.8 (12.4), p-value = 0.048], while the caloric share of ultra-processed food group was lower [41.3 (14.6) vs. 43.1 (12.5), p-value = 0.032]. We observed a negative association of age (p-value = 0.009) and a positive association of pre-pregnancy BMI (p-value = 0.060) with the variation of ultra-processed food intake. CONCLUSIONS: Ultra-processed food intake decreased, while minimally/unprocessed food intake slightly increased from the pre-conception to gestational period. These results indicate potential for a larger improvement in the women's diet quality and that nutritional counseling interventions in pregnant women are still needed. PMID- 27233370 TI - Dysphagia because of unilateral internal jugular vein phlebectasia in an infant. AB - Phlebectasia affecting the internal jugular vein is a rare cause of a benign neck swelling in children. They are mostly asymptomatic and therefore managed conservatively. Ligation of the vein and excision is usually avoided owing to the worry of raised intracranial pressure. We report a case of a large right internal jugular vein phlebectasia, causing dysphagia in a 7month old male child. Contrast enhanced computed tomography with 3-D reconstruction helped in pre-operative anatomical delineation, especially of the lower extent. It was excised through a cervico-thoracic approach with postoperative amelioration of symptoms. Contrary to expectation, the ectasia was not friable and was covered with a pseudocapsule of fibrofatty tissue, making excision easy. PMID- 27233372 TI - Laboratory evaluation for pediatric patients with suspected necrotizing soft tissue infections: A case-control study. AB - BACKGROUND/PURPOSE: Optimal outcomes for necrotizing soft tissue infections (NSTI) depend on rapid diagnosis and management. The Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score is a validated diagnostic tool for adult NSTI, but its value for children remains unknown. We hypothesized that modification of the LRINEC score may increase its diagnostic accuracy for pediatric NSTI. METHODS: We performed a case-control study of pediatric patients (age <18) with NSTI (cases) and patients with severe soft tissue infections prompting surgical consultation (controls). The LRINEC score was calculated for cases and controls and compared to a modified, pediatric LRINEC (P-LRINEC) score. Diagnostic accuracy was analyzed through receiver operating characteristic (ROC) curves. RESULTS: From 2010 to 2014, 20 cases and 20 controls were identified at two children's hospitals. Median LRINEC score was 3.5 (1-8) for cases and 2 (1-7) for controls (p=0.03). The P-LRINEC was comprised of serum CRP >20 (sensitivity=95% (95%CI 79-100%)) and serum sodium <135 (specificity=95% (95%CI 82-100%)). Area under ROC curves was 0.70 (95%CI 0.54-0.87) for the LRINEC score and 0.84 (95%CI 0.72-0.96) for the P-LRINEC score (p=0.06). CONCLUSION: The P LRINEC is a simplified version of the LRINEC score utilizing only CRP and sodium and may provide superior accuracy in predicting pediatric NSTI. PMID- 27233371 TI - Endoplasmic reticulum stress is involved in the colonic epithelium damage induced by maternal separation. AB - BACKGROUND: Maternal separation (MS) leads to intestinal barrier dysfunction in neonatal mice. Endoplasmic reticulum (ER) stress is associated with apoptosis and pro-inflammatory response induction. We hypothesized that MS induced gut damage is associated with ER stress and that administration of an ER stress inhibitor protects gut damage. METHODS: C57BL/6 mice received intraperitoneal PBS (n=10) or Salubrinal (1mg/kg/day, n=10). MS was performed soon after treatment for 3h daily between P5 and P9. Ten untreated neonatal mice served as control. The colon was harvested on P9 and analyzed for ER stress markers (BiP, CHOP), apoptosis (CC3), goblet cell number per crypt and crypt length (Alcian blue, hematoxylin/eosin), and transcellular permeability (Ussing chamber). Groups were compared using one way ANOVA with Bonferroni post-test. RESULTS: Compared to controls, MS mice had higher relative protein expression of ER stress and apoptosis markers (p<0.05) and reduced goblet cell number per crypt and crypt length (p<0.001). In comparison to PBS mice, Salubrinal treated mice had higher goblet cell number (p<0.05), crypt length (p<0.001), and lower transcellular permeability (p<0.05). CONCLUSIONS: Maternal separation induces ER stress and causes colon damage, but ER stress inhibitor protects morphology and permeability. This provides insights on bowel pathogenesis and potential novel treatments for diseases such as necrotizing enterocolitis. PMID- 27233373 TI - Serious sequellae of the hallux valgus surgery: More options for its surgical treatment. AB - OBJECTIVE: The purpose of this study is to present a method for treating the serious consequences that result from failure of corrective techniques used for hallux valgus, which produces severe shortening of the first ray, and makes it difficult to perform the third rocker. MATERIAL AND METHODS: In this study, conducted in 2 hospitals in Madrid and Barcelona, an assessment was made of the clinical and radiological results of 40 cases, of which 97.5% were female. Technically it involves making a metatarsophalangeal arthrodesis after bone distraction with an external mini-fixation, and then inserting an iliac crest bone graft, stabilising it with a plate or the mini-fixator. RESULTS: The pre operative shortening was 2.5cm. and elongation obtained was between 1.5 and 3.0cm. Clinical and radiological bone graft integration was achieved at 2-4 months, although full integration occurred after one year. Falliner and Blauth criteria were used to evaluate the results at 6 and 12 months follow-up, and using Visual Analogue Scale (VAS score/pain, scale 1-10), being favourable in 80%, and not changing over time. The failure rate was 7.5%, which included the non-integration of the graft and infection, requiring additional surgery. DISCUSSION: There are not many publications on the number and type of complication for hallux valgus surgery, or guidelines established, only the treatment by conventional fusion. The problem arises when the patient presents a severe shortening of the ray, and direct fusion would aggravate the insufficiency of the first ray and the transference metatarsalgia. In these cases, these procedures would be indicated. PMID- 27233374 TI - Lengthening of left colon after rectal resection: What all is adequate? A prospective cohort study. AB - BACKGROUND: Adequate mobilization of colon is essential to achieve tension free anastomosis after sphinchter saving surgeries. METHODS: 26 patients undergoing of recto-sigmoid resection underwent low tie of inferior mesenteric artery (IMA), splenic flexure mobilization and descending branch of left colic artery (LCA) ligation in that order. One point at proximal 1/3rd of sigmoid colon (point of partial sigmoid resection) and another at descending-sigmoid colon junction (point of total sigmoid resection) were used for measurements and the distance was measured from pubic symphysis. Mobilization was considered adequate if colon could reach 2 cm beyond the upper border of pubic symphysis. RESULTS: The length gained after each maneuver was 4.2 + 3.6 cm (low tie), 5.8 + 3.7 cm (splenic flexure mobilization) and 4.7 + 4.2 cm (descending branch of LCA ligation). Mobilization was adequate in 19% and 0% (low tie), 56% and 20% (low tie with splenic flexure mobilization) and 100% and 86% (all three manoeuvres) with partial and complete sigmoid resection respectively. In 13 patients undergoing low anterior resection, adequate mobilization for anastomosis was attainable in 15.3% and 0% (low tie), 50% and 0% (low tie with splenic flexure mobilization) and 100% and 83.3% (all three manoeuvres) with partial and complete sigmoid resection respectively. 15.3% had anastomotic leak, however none of the patients undergoing descending branch of LCA ligation had anastomotic insufficiency. CONCLUSIONS: Low tie of IMA, with splenic flexure mobilization as required results in sufficient mobilization only in 50% patients with partial sigmoid resection. Ligation of descending branch of LCA is feasible, safe and enables a tension free anastomosis and is especially beneficial when sigmoid colon is resected completely. PMID- 27233375 TI - Making decisions using radiology in lower GI hemorrhage. AB - Acute lower gastrointestinal bleeding (LGIB) is a common diagnosis in current practice that may warrant hospitalization and invasive management. There is a shift in the paradigm in the management of this condition away from traditional extensive operative intervention to minimally invasive radiological techniques. These newer modalities offer an opportunity to provide more accurate information on location of bleeding and subsequent management. The increased ease of access to interventional radiology units in major teaching hospitals represents an opportunity to adopt its use in the management of gastrointestinal bleeding. Further, with technological improvements, it is becoming an increasingly favoured option. Traditional endoscopic techniques have been fraught with poor vision in the acute setting, requiring the colon to be purged to aide in better visualization. The use of these newer technologies have been the subject of many reviews which highlight their efficacy in providing a road map to the bleeding site and eventual intervention. We aim to review the literature regarding the use of radiology in the management of LGIB, to provide surgeons with a discourse with regards to the approach in synthesizing the data and applying it when deciding its use. PMID- 27233376 TI - Correspondence to: "Tourniquet use during total knee arthroplasty does not offer significant benefit: A retrospective cohort study". PMID- 27233377 TI - Continuous alternating inhaled antibiotics for chronic pseudomonal infection in cystic fibrosis. AB - BACKGROUND: Inhaled antibiotics are standard of care for treating chronic pseudomonal respiratory infections in cystic fibrosis patients, initially approved for intermittent administration. However, use of continuous inhaled antibiotic regimens of differing combinations is growing. METHODS: This double blind trial compared continuous alternating therapy (CAT) to an intermittent treatment regimen. Subjects were treated with 3cycles of 28-days inhaled aztreonam (AZLI) or placebo 3-times daily alternating with 28-days open-label tobramycin inhalation solution (TIS). RESULTS: 90 subjects were randomized over 18months. Study enrollment was limited, in part because of evolving practices by clinicians of adopting a CAT regimen in clinical practice; consequently the study was underpowered. AZLI/TIS treatment reduced exacerbation rates by 25.7% (p=0.25; primary endpoint) and rates of respiratory hospitalizations by 35.8% compared with placebo/TIS (p=0.14). AZLI/TIS CAT therapy was well tolerated. CONCLUSIONS: This trial illustrates challenges with studying treatment regimens in a constantly evolving CF care environment. Nonetheless, the results of this trial indicate that AZLI/TIS CAT is well tolerated and may provide additional clinical benefit in CF patients compared with intermittent use of TIS alone. Clinicaltrials.gov: NCT01641822. PMID- 27233378 TI - Indurated Plaque on the Upper Lip of a Patient With Multiple Myeloma. PMID- 27233379 TI - Endocrine therapy resistance in estrogen receptor (ER)-positive breast cancer. AB - Estrogen receptor (ER)-positive breast cancer represents the majority (~70%) of all breast malignancies. In this subgroup of breast cancers, endocrine therapies are effective both in the adjuvant and recurrent settings, although resistance remains a major issue. Several high-throughput approaches have been used to elucidate mechanisms of resistance and to derive potential predictive markers or alternative therapies. In this review, we cover the state-of-the-art of endocrine resistance biomarker discovery with regard to the latest technological developments, and discuss current opportunities and restrictions for their implementation into a clinical setting. PMID- 27233380 TI - Prevention of Contrast-Associated Acute Kidney Injury: What Should We Do? PMID- 27233382 TI - Corrigendum to "Common variant in PTK2B is associated with late-onset Alzheimer's disease: A replication study and meta-analyses" [Neurosci. Lett. 621 (2016) 83 87]. PMID- 27233424 TI - Hypothyroidism, autoimmunity and systemic characteristics of salivary tumors. PMID- 27233381 TI - Urine Potassium Excretion, Kidney Failure, and Mortality in CKD. AB - BACKGROUND: Low urine potassium excretion, as a surrogate for dietary potassium intake, is associated with higher risk for hypertension and cardiovascular disease in a general population. Few studies have investigated the relationship of urine potassium with clinical outcomes in chronic kidney disease (CKD). STUDY DESIGN: Longitudinal cohort study. SETTING & PARTICIPANTS: The MDRD (Modification of Diet in Renal Disease) Study was a randomized controlled trial (N = 840) conducted in 1989 to 1993 to examine the effects of blood pressure control and dietary protein restriction on kidney disease progression in adults aged 18 to 70 years with CKD stages 2 to 4. This post hoc analysis included 812 participants. PREDICTOR: The primary predictor variable was 24-hour urine potassium excretion, measured at baseline and at multiple time points (presented as time-updated average urine potassium excretion). OUTCOMES: Kidney failure, defined as initiation of dialysis therapy or transplantation, was determined from US Renal Data System data. All-cause mortality was assessed using the National Death Index. RESULTS: Median follow-up for kidney failure was 6.1 (IQR, 3.5-11.7) years, with 9 events/100 patient-years. Median all-cause mortality follow-up was 19.2 (IQR, 10.8-20.6) years, with 3 deaths/100 patient-years. Baseline mean urine potassium excretion was 2.39+/-0.89 (SD) g/d. Each 1-SD higher baseline urine potassium level was associated with an adjusted HR of 0.95 (95% CI, 0.87-1.04) for kidney failure and 0.83 (95% CI, 0.74-0.94) for all-cause mortality. Results were consistent using time-updated average urine potassium measurements. LIMITATIONS: Analyses were performed using urine potassium excretion as a surrogate for dietary potassium intake. Results are obtained from a primarily young, nondiabetic, and advanced CKD population and may not be generalizable to the general CKD population. CONCLUSIONS: Higher urine potassium excretion was associated with lower risk for all-cause mortality, but not kidney failure. PMID- 27233425 TI - Evaluation of Xpert(r) Norovirus Assay performance in comparison with real-time RT-PCR in hospitalized adult patients with acute gastroenteritis. AB - Xpert(r) Norovirus Assay (Cepheid, Sunnyvale, CA) was compared with a laboratory developed real-time RT-PCR assay for the detection of Norovirus GI and GII in hospitalized patients with acute gastroenteritis. The two assays showed a high level of concordance but Xpert(r) Norovirus Assay allowed faster detection of Norovirus and a simpler sample handling. PMID- 27233426 TI - Multi-center and multi-method evaluation of in vitro activities of ceftaroline against S. aureus. AB - This five-site study was performed to assess the reproducibility of ceftaroline MIC and disk results for Staphylococcus aureus. Three commercial broth microdilution, three gradient diffusion and ceftaroline 5MUg disk diffusion methods were compared to a reference broth microdilution method against challenge isolates (n = 41) and isolates collected at four European sites (n = 30/site). For four MIC methods (Sensititre and three gradient diffusion methods), 99.0% of consolidated MIC results were within +/- 1 dilution of the reference MIC. Categorical agreement rates based on EUCAST breakpoints for the challenge isolates were 75.6-100% and for disk testing were 78.0-92.7%. There was no clear distinction between isolates with MIC results of 1 and 2mg/L with regard to variation in MIC or molecular genotyping results. The addition of an intermediate category for isolates with MIC results of 2mg/L would help to identify these isolates as borderline susceptible/non-susceptible isolates. PMID- 27233427 TI - Comparison of Uriswab to alternative methods for urine culture collection and transport: confirmation of standard culture methodology for investigation of urinary tract infections. AB - The ability to isolate and identify causative agents of urinary tract infections relies primarily on the quality of the urine sample that is submitted to the microbiology. The most important factors are the method of collection, the maintenance of viability of the potential pathogens during transport, and standardization of the culturing of the urine sample. This report is a composite of several investigations comparing collection and transport on urine culture paddles, with a preservative urine sponge (Uriswab), and a comparison of Uriswab with the BD preservative transport tube as methods of preservation of urinary pathogens. Primary studies showed that Uriswab maintained significantly more urinary pathogens than the urine culture paddle with fewer mixed or contaminated cultures. The two preservative transport systems were comparable for maintenance of viability of the pathogens, but there were fewer mixed cultures when samples were collected with Uriswab. This study confirms the importance of a standard volume of 1 MUL of urine for culture. PMID- 27233428 TI - What could have caused this weight loss? PMID- 27233429 TI - Rapid hypoglycemia onset associated with antimicrobial use in patients with diabetes: A nationwide population-based case-crossover study. PMID- 27233430 TI - Sensitization patterns in immigrants to Genoa: The relevance of origin. PMID- 27233431 TI - Outcome of mechanically ventilated patients initially denied admission to an intensive care unit and subsequently admitted. AB - The outcome of mechanically ventilated patients initially denied admission to an intensive care unit (ICU) and subsequently admitted is unclear. We compared outcomes of patients denied ICU admission and subsequently admitted, to those of patients admitted to the ICU and to patients refused ICU admission. The medical records of all the patients who were subjected to mechanical ventilation for at least 24h over a 4year period (2010-2014) were reviewed. Of 707 patients (757 admissions), 124 (18%) were initially denied ICU admission and subsequently admitted. Multivariate stepwise logistic regression analysis showed significant association with death of: age, length of stay, nursing home residency, duration of mechanical ventilation, previous admission with mechanical ventilation, cause for mechanical ventilation, rate of failed extubations, associated morbidity (previous cerebrovascular accident, dementia, chronic renal failure), and occurrence of nosocomial bacteremia. The odds for death among patients denied ICU admission and subsequently transferred to the ICU compared to patients admitted directly to the ICU was 3.6 (95% CI: 1.9-6.7) (P<0.0001). The odds for death among patients refused ICU admission compared to those who were initially denied and subsequently admitted were not statistically significant (OR=1.7, 95% CI: 0.8 3.8). In conclusion, patients denied ICU admission and subsequently admitted face a considerable risk of morbidity and mortality. Their odds of death are nearly three times those admitted directly to the ICU. Late admission to the ICU does not appear to provide benefit compared to patients who remain in general medicine wards. PMID- 27233432 TI - Effects of Sesaminol Feeding on Brain Abeta Accumulation in a Senescence Accelerated Mouse-Prone 8. AB - Alzheimer's disease (AD) is characterized by the progressive accumulation of extracellular beta-amyloid (Abeta) aggregates. Recently, the senescence accelerated mouse-prone 8 (SAMP8) model was highlighted as a useful model of age related AD. Therefore, we used the SAMP8 mouse to investigate the preventive effects of sesame lignans on the onset of AD-like pathology. In preliminary in vitro studies, sesaminol showed the greatest inhibitory effect on Abeta oligomerization and fibril formation relative to sesamin, sesamolin, and sesaminol triglucoside. Hence, sesaminol was selected for further evaluation in vivo. In SAMP8 mice, feed-through sesaminol (0.05%, w/w, in standard chow) administered over a 16 week period reduced brain Abeta accumulation and decreased serum 8-hydroxydeoxyguanosine, an indicator of oxidative stress. Furthermore, sesaminol administration increased the gene and protein expression of ADAM10, which is a protease centrally involved in the non-amyloidogenic processing of amyloid precursor protein. Taken together, these data suggest that long-term consumption of sesaminol may inhibit the accumulation of pathogenic Abeta in the brain. PMID- 27233435 TI - Ecological opportunities, habitat, and past climatic fluctuations influenced the diversification of modern turtles. AB - Habitat may be viewed as an important life history component potentially related to diversification patterns. However, differences in diversification rates between aquatic and terrestrial realms are still poorly explored. Testudines is a group distributed worldwide that lives in aquatic and terrestrial environments, but until now no-one has evaluated the diversification history of the group as a whole. We aim here to investigate the diversification history of turtles and to test if habitat influenced speciation rate in these animals. We reconstructed the phylogeny of the modern species of chelonians and estimated node divergence dates using molecular markers and a Bayesian approach. Then, we used Bayesian Analyses of Macroevolutionary Mixtures to evaluate the diversification history of turtles and evaluate the effect of habitat on this pattern. Our reconstructed phylogeny covered 300 species (87% of the total diversity of the group). We found that the emydid subfamily Deirochelyinae, which forms the turtle hotspot in south-eastern United States, had an increase in its speciation rate, and that Galapagos tortoises had similar increases. Current speciation rates are lower in terrestrial turtles, contradicting studies supporting the idea terrestrial animals diversify more than aquatic species. Our results suggest that habitat, ecological opportunities, island invasions, and climatic factors are important drivers of diversification in modern turtles and reinforce the importance of habitat as a diversification driver. PMID- 27233434 TI - A tree of geese: A phylogenomic perspective on the evolutionary history of True Geese. AB - Phylogenetic incongruence can be caused by analytical shortcomings or can be the result of biological processes, such as hybridization, incomplete lineage sorting and gene duplication. Differentiation between these causes of incongruence is essential to unravel complex speciation and diversification events. The phylogeny of the True Geese (tribe Anserini, Anatidae, Anseriformes) was, until now, contentious, i.e., the phylogenetic relationships and the timing of divergence between the different goose species could not be fully resolved. We sequenced nineteen goose genomes (representing seventeen species of which three subspecies of the Brent Goose, Branta bernicla) and used an exon-based phylogenomic approach (41,736 exons, representing 5887 genes) to unravel the evolutionary history of this bird group. We thereby provide general guidance on the combination of whole genome evolutionary analyses and analytical tools for such cases where previous attempts to resolve the phylogenetic history of several taxa could not be unravelled. Identical topologies were obtained using either a concatenation (based upon an alignment of 6,630,626 base pairs) or a coalescent-based consensus method. Two major lineages, corresponding to the genera Anser and Branta, were strongly supported. Within the Branta lineage, the White-cheeked Geese form a well-supported sub-lineage that is sister to the Red-breasted Goose (Branta ruficollis). In addition, two main clades of Anser species could be identified, the White Geese and the Grey Geese. The results from the consensus method suggest that the diversification of the genus Anser is heavily influenced by rapid speciation and by hybridization, which may explain the failure of previous studies to resolve the phylogenetic relationships within this genus. The majority of speciation events took place in the late Pliocene and early Pleistocene (between 4 and 2millionyears ago), conceivably driven by a global cooling trend that led to the establishment of a circumpolar tundra belt and the emergence of temperate grasslands. Our approach will be a fruitful strategy for resolving many other complex evolutionary histories at the level of genera, species, and subspecies. PMID- 27233433 TI - Thermal stability of human plasma electronegative low-density lipoprotein: A paradoxical behavior of low-density lipoprotein aggregation. AB - Low-density lipoprotein (LDL) aggregation is central in triggering atherogenesis. A minor fraction of electronegative plasma LDL, termed LDL(-), plays a special role in atherogenesis. To better understand this role, we analyzed the kinetics of aggregation, fusion and disintegration of human LDL and its fractions, LDL(+) and LDL(-). Thermal denaturation of LDL was monitored by spectroscopy and electron microscopy. Initially, LDL(-) aggregated and fused faster than LDL(+), but later the order reversed. Most LDL(+) disintegrated and precipitated upon prolonged heating. In contrast, LDL(-) partially retained lipoprotein morphology and formed soluble aggregates. Biochemical analysis of all fractions showed no significant degradation of major lipids, mild phospholipid oxidation, and an increase in non-esterified fatty acid (NEFA) upon thermal denaturation. The main baseline difference between LDL subfractions was higher content of NEFA in LDL( ). Since NEFA promote lipoprotein fusion, increased NEFA content can explain rapid initial aggregation and fusion of LDL(-) but not its resistance to extensive disintegration. Partial hydrolysis of apoB upon heating was similar in LDL subfractions, suggesting that minor proteins importantly modulate LDL disintegration. Unlike LDL(+), LDL(-) contains small amounts of apoA-I and apoJ. Addition of exogenous apoA-I to LDL(+) hampered lipoprotein aggregation, fusion and precipitation, while depletion of endogenous apoJ had an opposite effect. Therefore, the initial rapid aggregation of LDL(-) is apparently counterbalanced by the stabilizing effects of minor proteins such as apoA-I and apoJ. These results help identify key determinants for LDL aggregation, fusion and coalescence into lipid droplets in vivo. PMID- 27233436 TI - Genome-wide data help identify an avian species-level lineage that is morphologically and vocally cryptic. AB - Species identification has traditionally relied on morphology. However, morphological conservatism can lead to a high incidence of cryptic species, as characters other than morphological ones can be biologically important. In birds, the combined application of bioacoustic and molecular criteria has led to an avalanche of cryptic species discoveries over the last two decades in which findings of deep vocal differentiation have usually been corroborated by molecular data or vice versa. In this study, we use genome-wide DNA data to uncover an unusual case of cryptic speciation in two species within the South east Asian Streak-eared Bulbul Pycnonotus blanfordi complex, in which both morphology and vocalizations have remained extremely similar. Despite a considerable pre-Pleistocene divergence of these two bulbul species, bioacoustic analysis failed to uncover differences in their main vocalization, but examination of live birds revealed important differences in eye color that had been overlooked in museum material. Our study demonstrates that genome-wide DNA data can be helpful in the detection of cryptic speciation, especially in species that have evolved limited morphological and behavioral differences. PMID- 27233437 TI - Incipient speciation with gene flow on a continental island: Species delimitation of the Hainan Hwamei (Leucodioptron canorum owstoni, Passeriformes, Aves). AB - Because of their isolation, continental islands (e.g., Madagascar) are often thought of as ideal systems to study allopatric speciation. However, many such islands have been connected intermittently to their neighboring continent during recent periods of glaciation, which may cause frequent contact between the diverging populations on the island and continent. As a result, the speciation processes on continental islands may not meet the prerequisites for strictly allopatric speciation. We used multiple lines of evidence to re-evaluate the taxonomic status of the Hainan Hwamei (Leucodioptron canorum owstoni), which is endemic to Hainan, the largest continental island in the South China Sea. Our analysis of mitochondrial DNA and twelve nuclear loci suggests that the Hainan Hwamei can be regarded as an independent species (L. owstoni); the morphological traits of the Hainan Hwamei also showed significant divergence from those of their mainland sister taxon, the Chinese Hwamei (L. canorum). We also inferred the divergence history of the Hainan and Chinese Hwamei to see whether their divergence was consistent with a strictly allopatric model. Our results suggest that the two Hwameis split only 0.2 million years ago with limited asymmetrical post-divergence gene flow. This implies that the Hainan Hwamei is an incipient species and that speciation occurred through ecologically divergent selection and/or assortative mating rather than a strictly allopatric process. PMID- 27233438 TI - Multiple evolutionary units and demographic stability during the last glacial maximum in the Scytalopus speluncae complex (Aves: Rhinocryptidae). AB - The Atlantic Forest (AF) of South America harbors one of the world's highest bird species richness, but to date there is a deficient understanding of the spatial patterns of genetic diversity and the evolutionary history of this biome. Here we estimated the phylogenetic and populational history of the widespread Mouse colored Tapaculo (Scytalopus speluncae) complex across the Brazilian AF, using data from two mitochondrial genes and 12 microsatellite loci. Both markers uncovered several cryptic, mostly allopatric and well-supported lineages that may represent distinct species-level taxa. We investigated whether diversification in S. speluncae is compatible with the Carnaval-Moritz model of Pleistocene refugia. We found that northern lineages have high levels of genetic diversity, agreeing with predictions of more stable forest refugia in these areas. In contrast, southern lineages have lower levels of mtDNA diversity with a signature of population expansion that occurred earlier (~0.2Mya) than the last glacial maximum. This result suggests that the AF may be stable enough to maintain endemic taxa through glacial cycles. Moreover, we propose that the "mid Pleistocene climate transition" between 1.2 and 0.7million years ago, from a warmer to a colder climate, may have played an important but mostly overlooked role in the evolution of AF montane taxa. PMID- 27233439 TI - Mitochondrial phylogeny of the Eurasian/African reed warbler complex (Acrocephalus, Aves). Disagreement between morphological and molecular evidence and cryptic divergence: A case for resurrecting Calamoherpe ambigua Brehm 1857. AB - A tree based on the mitochondrial cyt b gene for 278 samples from throughout the range of the Eurasian Reed Warbler Acrocephalus scirpaceus - African Reed Warbler A. baeticatus complex shows well-supported geographically structured divergence for eight distinct lineages. The phylogenetic structuring together with the clarification of priority, provided by sequence data from seven type specimens, suggests that both taxonomy and distribution boundaries are in need of revision. The Iberian and Moroccan populations form a well-supported clade, and we propose that these are treated as taxonomically distinct, under the name ambiguus (Brehm, 1857). We propose that the names scirpaceus, fuscus, avicenniae, ambiguus, minor, cinnamomeus, hallae and baeticatus are used for the well supported clades in the complex, which we recommend to treat as one polytypic species, A. scirpaceus, pending studies of gene flow and assortative mating in the contact zones. PMID- 27233440 TI - A new amplicon based approach of whole mitogenome sequencing for phylogenetic and phylogeographic analysis: An example of East African white-eyes (Aves, Zosteropidae). AB - Classical Sanger sequencing is still frequently used to generate sequence data for phylogenetic and phylogeographic inference. In this contribution we present a novel approach to genotype whole mitogenomic haplotypes using Illumina MiSeq reads from indexed amplicons. Our new approach reduces preparation time by multiplexing loci within a single or few PCR reactions and by plate format library construction. The use of paired-end reads allows covering amplicons of about 0.5kb and thus no nebulisation and assembly are necessary. We tested the power and effectiveness of this technique by analysing the mitogenomic diversity of East African white-eye bird species (Zosteropidae), a taxonomically highly diverse and complex species flock found in various ecosystems spread across major parts of Africa. We compare the newly generated mitogenomic data set with published data of three mitochondrial genes for a similar set of populations and taxa. The comparison demonstrates that our new procedure represents a cost effective use of NGS for medium throughput phylogenetic analyses. Using this method, we were able to increase the amount of phylogenetic information significantly, while reducing the costs and effort in the laboratory. The mitogenomic data show a higher resolution than previous studies providing higher support and new insights in the relationships of Zosterops species. Our data suggest to split Z. poliogaster into four distinct species, three of which had previously been proposed: Z. silvanus, Z. mbulensis, Z. kikyuensis and Z. kulalensis. Our approach allows the genotyping of whole mitogenomes for a large number of individuals and thus allows more reliable reconstruction of phylogenetic and phylogeographic relationships - also for non-model organisms. PMID- 27233441 TI - Phylogenomics, biogeography and diversification of obligate mealybug-tending ants in the genus Acropyga. AB - Acropyga ants are a widespread clade of small subterranean formicines that live in obligate symbiotic associations with root mealybugs. We generated a data set of 944 loci of ultraconserved elements (UCEs) to reconstruct the phylogeny of 41 representatives of 23 Acropyga species using both concatenation and species-tree approaches. We investigated the biogeographic history of the genus through divergence dating analyses and ancestral range reconstructions. We also explored the evolution of the Acropyga-mealybug mutualism using ancestral state reconstruction methods. We recovered a highly supported species phylogeny for Acropyga with both concatenation and species-tree analyses. The age for crown group Acropyga is estimated to be around 30Ma. The geographic origin of the genus remains uncertain, although phylogenetic affinities within the subfamily Formicinae point to a Paleotropical ancestor. Two main Acropyga lineages are recovered with mutually exclusive distributions in the Old World and New World. Within the Old World clade, a Palearctic and African lineage is suggested as sister to the remaining species. Ancestral state reconstructions indicate that Old World species have diversified mainly in close association with xenococcines from the genus Eumyrmococcus, although present-day associations also involve other mealybug genera. In contrast, New World Acropyga predominantly evolved with Neochavesia until a recent (10-15Ma) switch to rhizoecid mealybug partners (genus Rhizoecus). The striking mandibular variation in Acropyga evolved most likely from a 5-toothed ancestor. Our results provide an initial evolutionary framework for extended investigations of potential co-evolutionary interactions between these ants and their mealybug partners. PMID- 27233442 TI - Species delimitation without prior knowledge: DISSECT reveals extensive cryptic speciation in the Silene aegyptiaca complex (Caryophyllaceae). AB - Species delimitation is a major focus of biosystematics. In recent years, considerable progress has been achieved with the development of the multispecies coalescent (MSC) model, where species constitute the branches of the species tree or network. However, researchers are faced with the limitation that the MSC method of choice often requires a priori assignment of individuals to species. This not only introduces subjectivitiy into the analyses, but may also lead to meaningless species tree hypotheses, if the allele-to-species assignments are inaccurate. DISSECT is a recently introduced method that does not require a priori allele-to-species assignments, but instead examines the posterior probabilities of groupings (clusterings) of individuals under study. Using the DISSECT approach, we analysed genetic data from 75 individual plants belonging to the Silene aegyptiaca species complex that has previously been divided into 3-5 species. Marginal likelihood estimates from (*)BEAST analyses, run with predefined species classifications, strongly favour those compatible with the DISSECT result over those from morphology- and geography-based taxonomy. We found at least nine species, including several cryptic ones, for which no clear geographical or morphological patterns are correlated. However, the limited data and the possibility of unmodelled processes mean there is still much uncertainty about the true number of MSC species, and for taxonomic purposes, other criteria might be relevant. Nevertheless, we argue that the approach signifies an important step towards objective and testable species delimitations in any organismal group. In particular, it makes it possible to avoid biologically irrelevant species classifications. PMID- 27233443 TI - Phylogeography of the Vermilion Flycatcher species complex: Multiple speciation events, shifts in migratory behavior, and an apparent extinction of a Galapagos endemic bird species. AB - The Vermilion Flycatcher (Pyrocephalus rubinus) is a widespread species found in North and South America and the Galapagos. Its 12 recognized subspecies vary in degree of geographic isolation, phenotypic distinctness, and migratory status. Some authors suggest that Galapagos subspecies nanus and dubius constitute one or more separate species. Observational reports of distinct differences in song also suggest separate species status for the austral migrant subspecies rubinus. To evaluate geographical patterns of diversification and taxonomic limits within this species complex, we carried out a molecular phylogenetic analysis encompassing 10 subspecies and three outgroup taxa using mitochondrial (ND2, Cyt b) and nuclear loci (ODC introns 6 through 7, FGB intron 5). We used samples of preserved tissues from museum collections as well as toe pad samples from museum skins. Galapagos and continental clades were recovered as sister groups, with initial divergence at ~1mya. Within the continental clade, North and South American populations were sister groups. Three geographically distinct clades were recovered within South America. We detected no genetic differences between two broadly intergrading North American subspecies, mexicanus and flammeus, suggesting they should not be recognized as separate taxa. Four western South American subspecies were also indistinguishable on the basis of loci that we sampled, but occur in a region with patchy habitat, and may represent recently isolated populations. The austral migrant subspecies, rubinus, comprised a monophyletic mitochondrial clade and had many unique nuclear DNA alleles. In combination with its distinct song, exclusive song recognition behavior, different phenology, and an isolated breeding range, our data suggests that this taxon represents a separate species from other continental populations. Mitochondrial and nuclear genetic data, morphology, and behavior suggest that Galapagos forms should be elevated to two full species corresponding to the two currently recognized subspecies, nanus and dubius. The population of dubius is presumed to be extinct, and thus would represent the first documented extinction of a Galapagos-endemic bird species. Two strongly supported mitochondrial clades divide Galapagos subspecies nanus in a geographic pattern that conflicts with previous hypotheses that were based on plumage color. Several populations of nanus have recently become extinct or are in serious decline. Urgent conservation measures should seek to preserve the deep mitochondrial DNA diversity within nanus, and further work should explore whether additional forms should be recognized within nanus. Ancestral states analysis based on our phylogeny revealed that the most recent common ancestor of extant Vermilion Flycatcher populations was migratory, and that migratory behavior was lost more often than gained within Pyrocephalus and close relatives, as has been shown to be the case within Tyrannidae as a whole. PMID- 27233444 TI - Heterarchies: Reconciling Networks and Hierarchies. AB - Social-ecological systems research suffers from a disconnect between hierarchical (top-down or bottom-up) and network (peer-to-peer) analyses. The concept of the heterarchy unifies these perspectives in a single framework. Here, I review the history and application of 'heterarchy' in neuroscience, ecology, archaeology, multiagent control systems, business and organisational studies, and politics. Recognising complex system architecture as a continuum along vertical and lateral axes ('flat versus hierarchical' and 'individual versus networked') suggests four basic types of heterarchy: reticulated, polycentric, pyramidal, and individualistic. Each has different implications for system functioning and resilience. Systems can also shift predictably and abruptly between architectures. Heterarchies suggest new ways of contextualising and generalising from case studies and new methods for analysing complex structure-function relations. PMID- 27233445 TI - Effects of poly (epsilon-caprolactone) coating on the properties of three dimensional printed porous structures. AB - Powder-based inkjet three-dimensional printing (3DP) to fabricate pre-designed 3D structures has drawn increasing attention. However there are intrinsic limitations associated with 3DP technology due to the weak bonding within the printed structure, which significantly compromises its mechanical integrity. In this study, calcium sulphate ceramic structures demonstrating a porous architecture were manufactured using 3DP technology and subsequently post processed with a poly (epsilon-caprolactone) (PCL) coating. PCL concentration, immersion time, and number of coating layers were the principal parameters investigated and improvement in compressive properties was the measure of success. Interparticle spacing within the 3DP structures were successfully filled with PCL material. Consequently the compressive properties, wettability, morphology, and in vitro resorption behaviour of 3DP components were significantly augmented. The average compressive strength, Young's modulus, and toughness increased 217%, 250%, and 315%, following PCL coating. Addition of a PCL surface coating provided long-term structural support to the host ceramic material, extending the resorption period from less than 7 days to a minimum of 56 days. This study has demonstrated that application of a PCL coating onto a ceramic 3DP structure was a highly effective approach to addressing some of the limitations of 3DP manufacturing and allows this advanced technology to be potentially used in a wider range of applications. PMID- 27233446 TI - Molecular pathophysiology of impaired glucose metabolism, mitochondrial dysfunction, and oxidative DNA damage in Alzheimer's disease brain. AB - In normal brain, neurons in the cortex and hippocampus produce insulin, which modulates glucose metabolism and cognitive functions. It has been shown that insulin resistance impairs glucose metabolism and mitochondrial function, thus increasing production of reactive oxygen species. Recent progress in Alzheimer's disease (AD) research revealed that insulin production and signaling are severely impaired in AD brain, thereby resulting in mitochondrial dysfunction and increased oxidative stress. Among possible oxidative DNA lesions, 8-oxoguanine (8 oxoG) is highly accumulated in the brain of AD patients. Previously we have shown that incorporating 8-oxoG in nuclear and mitochondrial DNA promotes MUTYH (adenine DNA glycosylase) dependent neurodegeneration. Moreover, cortical neurons prepared from MTH1 (8-oxo-dGTPase)/OGG1 (8-oxoG DNA glycosylase)-double deficient adult mouse brains is shown to exhibit significantly poor neuritogenesis in vitro with increased 8-oxoG accumulation in mitochondrial DNA in the absence of antioxidants. Therefore, 8-oxoG can be considered involved in the neurodegenerative process in AD brain. In mild cognitive impairment, mitochondrial dysfunction and oxidative damage may induce synaptic dysfunction due to energy failures in neurons thus resulting in impaired cognitive function. If such abnormality lasts long, it can lead to vicious cycles of oxidative damage, which may then trigger the neurodegenerative process seen in Alzheimer type dementia. PMID- 27233447 TI - A cellular high-throughput screening approach for therapeutic trans-cleaving ribozymes and RNAi against arbitrary mRNA disease targets. AB - Major bottlenecks in development of therapeutic post transcriptional gene silencing (PTGS) agents (e.g. ribozymes, RNA interference, antisense) include the challenge of mapping rare accessible regions of the mRNA target that are open for annealing and cleavage, testing and optimization of agents in human cells to identify lead agents, testing for cellular toxicity, and preclinical evaluation in appropriate animal models of disease. Methods for rapid and reliable cellular testing of PTGS agents are needed to identify potent lead candidates for optimization. Our goal was to develop a means of rapid assessment of many RNA agents to identify a lead candidate for a given mRNA associated with a disease state. We developed a rapid human cell-based screening platform to test efficacy of hammerhead ribozyme (hhRz) or RNA interference (RNAi) constructs, using a model retinal degeneration target, human rod opsin (RHO) mRNA. The focus is on RNA Drug Discovery for diverse retinal degeneration targets. To validate the approach, candidate hhRzs were tested against NUH? cleavage sites (N = G,C,A,U; H = C,A,U) within the target mRNA of secreted alkaline phosphatase (SEAP), a model gene expression reporter, based upon in silico predictions of mRNA accessibility. HhRzs were embedded in a larger stable adenoviral VAI RNA scaffold for high cellular expression, cytoplasmic trafficking, and stability. Most hhRz expression plasmids exerted statistically significant knockdown of extracellular SEAP enzyme activity when readily assayed by a fluorescence enzyme assay intended for high throughput screening (HTS). Kinetics of PTGS knockdown of cellular targets is measureable in live cells with the SEAP reporter. The validated SEAP HTS platform was transposed to identify lead PTGS agents against a model hereditary retinal degeneration target, RHO mRNA. Two approaches were used to physically fuse the model retinal gene target mRNA to the SEAP reporter mRNA. The most expedient way to evaluate a large set of potential VAI-hhRz expression plasmids against diverse NUH? cleavage sites uses cultured human HEK293S cells stably expressing a dicistronic Target-IRES-SEAP target fusion mRNA. Broad utility of this rational RNA drug discovery approach is feasible for any ophthalmological disease-relevant mRNA targets and any disease mRNA targets in general. The approach will permit rank ordering of PTGS agents based on potency to identify a lead therapeutic compound for further optimization. PMID- 27233449 TI - Analysis of neuronal nicotinic acetylcholine receptor alpha4beta2 activation at the single-channel level. AB - The neuronal nicotinic acetylcholine receptor alpha4beta2 forms pentameric proteins with two alternate stoichiometries. The high-sensitivity receptor is related to (alpha4)2(beta2)3 stoichiometry while the low-sensitivity receptor to (alpha4)3(beta2)2 stoichiometry. Both subtypes share two binding sites at the alpha4((+))/beta2((-)) interface with high affinity for agonists. (alpha4)3(beta2)2 has an additional binding site at the alpha4((+))/alpha4((-)) interface with low affinity for agonists. We investigated activation kinetics of both receptor subtypes by patch-clamp recordings of single-channel activity in the presence of several concentrations of acetylcholine (0.5 to 300MUM). We used kinetic software to fit these data with kinetic models. We found that the high sensitivity subtype correlates with the low-conductance channel (g-70=29pS) and does not activate with high efficacy. On the contrary, the low-sensitivity subtype correlated with a high-conductance channel (g-70=44pS) and exhibited higher activation efficacy. Opening events of individual nAChRs at high agonist concentrations occurred in clusters, which allowed us to determine kinetic constants for the activation of the triliganded receptor. Our kinetic modeling identified an intermediate state, between resting and open conformation of the receptor. Binding of the third molecule increases the efficacy of receptor activation by favoring the transition between resting and intermediate state around 18 times. The low rate for this transition in the diliganded receptor explains the action of acetylcholine as partial agonist when it binds to the high affinity sites. The presence of the third binding site emerges as a potent modulator of nicotinic receptor alpha4beta2 activation which may display different functions depending on agonist concentration. PMID- 27233448 TI - Characterisation of the metabolome of ocular tissues and post-mortem changes in the rat retina. AB - Time-dependent post-mortem biochemical changes have been demonstrated in donor cornea and vitreous, but there have been no published studies to date that objectively measure post-mortem changes in the retinal metabolome over time. The aim of the study was firstly, to investigate post-mortem, time-dependent changes in the rat retinal metabolome and secondly, to compare the metabolite composition of healthy rat ocular tissues. To study post-mortem changes in the rat retinal metabolome, globes were enucleated and stored at 4 degrees C and sampled at 0, 2, 4, 8, 24 and 48 h post-mortem. To study the metabolite composition of rat ocular tissues, eyes were dissected immediately after culling to isolate the cornea, lens, vitreous and retina, prior to storing at -80 degrees C. Tissue extracts were subjected to Gas Chromatograph Mass Spectrometry (GC-MS) and Ultra High Performance Liquid Chromatography Mass Spectrometry (UHPLC-MS). Generally, the metabolic composition of the retina was stable for 8 h post-mortem when eyes were stored at 4 degrees C, but showed increasing changes thereafter. However, some more rapid changes were observed such as increases in TCA cycle metabolites after 2 h post-mortem, whereas some metabolites such as fatty acids only showed decreases in concentration from 24 h. A total of 42 metabolites were identified across the ocular tissues by GC-MS (MSI level 1) and 2782 metabolites were annotated by UHPLC-MS (MSI level 2) according to MSI reporting standards. Many of the metabolites detected were common to all of the tissues but some metabolites showed partitioning between different ocular structures with 655, 297, 93 and 13 metabolites being uniquely detected in the retina, lens, cornea and vitreous respectively. Only a small percentage (1.6%) of metabolites found in the vitreous were only detected in the retina and not other tissues. In conclusion, mass spectrometry-based techniques have been used for the first time to compare the metabolic composition of different ocular tissues. The metabolite composition of the retina stored at 4 degrees C post-mortem is mostly stable for at least 8 h. PMID- 27233450 TI - Tat PTD-Endostatin-RGD: A novel protein with anti-angiogenesis effect in retina via eye drops. AB - BACKGROUND: Diabetic retinopathy is a leading cause of blindness. The objective was to design a novel fusion protein, Tat PTD-Endostatin-RGD, to treat retinal neovascularization via eye drops instead of traditional intravitreal injection trepapeutical methods. METHOD: The anti-angiogenesis ability was evaluated in vitro by chick embryo chorioallantoic membrane assay, wound healing assay and tube formation assay. Corneal barrier and blood-retina barrier were constructed in vitro to investigate the penetration ability of Tat PTD-Endostatin-RGD. Western blot was used to detect the integrin alphavbeta3 expression level in rat retina microvascular endothelial cells which was stimulated by S-nitroso-N acetylpenicillamine. The binding affinity of Tat PTD-Endostatin-RGD to integrin alphavbeta3 was investigated by evaluating the penetration ability on blood retina barriers treated with S-nitroso-N-acetylpenicillamine. The pharmacodynamics and efficacy analysis were further carried out in the oxygen induced retinopathy model in vivo. In addition, the pharmacokinetic profile via eye drops was studied on a C57BL/6 mice model. RESULT: Tat PTD-Endostatin-RGD showed high anti-angiogenesis activity and high ability to penetrate these two barriers in vitro. The Western blot results indicated S-nitroso-N acetylpenicillamine upregulated the expression level of integrin alphavbeta3 in a dose-dependent manner. Tat PTD-Endostatin-RGD showed a high affinity to rat retina microvascular endothelial cells treated with S-nitroso-N acetylpenicillamine. The results showed that Tat PTD-Endostatin-RGD could inhibit abnormal angiogenesis in retina via eye drops. CONCLUSION: Tat PTD-Endostatin-RGD showed high penetration ability through ocular barriers, bound specifically to integrin alphavbeta3 and effectively inhibited the abnormal angiogenesis. GENERAL SIGNIFICANCE: Tat PTD-Endostatin-RGD represents a potent novel drug applied via eye drops for fundus oculi neovascularization diseases. PMID- 27233451 TI - Biphasic reduction of histone H3 phosphorylation in response to N-nitroso compounds induced DNA damage. AB - BACKGROUND: N-nitroso compounds (NOC) can cause cancers in a wide variety of animal species, and many of them are also potential human carcinogens. However, their underlying genotoxic mechanisms occurred within the context of chromatin, such as aberrant histone modifications, remained elusive. METHODS: We investigated the dynamic landscapes of histone modifications after N-nitroso compound N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-methyl-N-nitroso-urea (MNU) exposure. Among the altered histone modifications, we also investigated the control mechanisms of histone H3 phosphorylation changes and its possible implications on transcriptional repression. RESULTS: Significantly, we find a specific biphasic reduction of histone H3 phosphorylation at serine 10 (H3S10ph) and serine 28 (H3S28ph), and a rapid decrease of histone H4 acetylation upon MNNG and MNU exposure. Further investigations reveal that the first hypophosphorylation of H3 occurs in a poly(ADP-ribosyl)ation enzyme PARP-1 (Poly(ADP-Ribose) Polymerase 1) dependent manner, whereas the second decline of H3 phosphorylation is at least partially under the control of histone kinase VRK1 (vaccinia-related kinase 1) and dependent on the tumor suppressor protein p53. In addition, DNA damage induced down-regulation of H3S10/S28 phosphorylation also functions in transcriptional repression of genes, such as cell-cycle regulators. CONCLUSIONS: Alkylating damage induced by NOC elicits a biphasic reduction of histone H3 phosphorylation with distinct control mechanisms, which is contributing to DNA damage responses such as the repair-facilitated transcriptional repression. GENERAL SIGNIFICANCE: Identification of the dynamic changes and underlying mechanisms of histone modifications upon NOC exposure would be of great help in understanding the epigenetic regulations of NOC induced DNA damage responses. PMID- 27233452 TI - Limited versus total epithelial debridement ocular surface injury: Live fluorescence imaging of hemangiogenesis and lymphangiogenesis in Prox1 GFP/Flk1::Myr-mCherry mice. AB - BACKGROUND: Immunohistochemical staining experiments have shown that both hemangiogenesis and lymphangiogenesis occur following severe corneal and conjunctival injury and that the neovascularization of the cornea often has severe visual consequences. To better understand how hemangiogenesis and lymphangiogenesis are induced by different degrees of ocular injury, we investigated patterns of injury-induced corneal neovascularization in live Prox1 GFP/Flk1::myr-mCherry mice, in which blood and lymphatic vessels can be imaged simultaneously in vivo. METHODS: The eyes of Prox1-GFP/Flk1::myr-mCherry mice were injured according to four models based on epithelial debridement of the: A) central cornea (a 1.5-mm-diameter circle of tissue over the corneal apex), B) total cornea, C) bulbar conjunctiva, and D) cornea+bulbar conjunctiva. Corneal blood and lymphatic vessels were imaged on days 0, 3, 7, and 10 post-injury, and the percentages of the cornea containing blood and lymphatic vessels were calculated. RESULTS: Neither central corneal nor bulbar conjunctival debridement resulted in significant vessel growth in the mouse cornea, whereas total corneal and corneal+bulbar conjunctival debridement did. On day 10 in the central cornea, total cornea, bulbar conjunctiva, and corneal+bulbar conjunctival epithelial debridement models, the percentage of the corneal surface that was occupied by blood vessels (hemangiogenesis) was 1.9+/-0.8%, 7.14+/-2.4%, 2.29+/-1%, and 15.05+/-2.14%, respectively, and the percentage of the corneal surface that was occupied by lymphatic vessels (lymphangiogenesis) was 2.45+/-1.51%, 4.85+/-0.95%, 2.95+/-1.27%, and 4.15+/-3.85%, respectively. CONCLUSIONS: Substantial corneal debridement was required to induce corneal neovascularization in the mouse cornea, and the corneal epithelium may therefore be partially responsible for maintaining corneal avascularity. GENERAL SIGNIFICANCE: Our study demonstrates that GFP/Flk1::myr-mCherry mice are a useful model for studying coordinated hemangiogenic and lymphangiogenic responses. PMID- 27233453 TI - Thioredoxin (Trx1) regulates CD4 membrane domain localization and is required for efficient CD4-dependent HIV-1 entry. AB - BACKGROUND: CD4 is a glycoprotein expressed on the surfaces of certain immune cells. On lymphocytes, an important function of CD4 is to co-engage Major Histocompatibility Complex (MHC) molecules with the T Cell Receptor (TCR), a process that is essential for antigen-specific activation of T cells. CD4 localizes dynamically into distinct membrane microdomains, an important feature of its immunoregulatory function that has also been shown to influence the efficiency of HIV replication. However, the mechanism by which CD4 localization is regulated and the biological significance of this is incompletely understood. METHODS: In this study, we used confocal microscopy, density-gradient centrifugation and flow cytometry to analyze dynamic redox-dependent effects on CD4 membrane domain localization. RESULTS: Blocking cell surface redox exchanges with both a membrane-impermeable sulfhydryl blocker (DTNB) and specific antibody inhibitors of Thioredoxin-1 (Trx1) induces translocation of CD4 into detergent resistant membrane domains (DRM). In contrast, Trx1 inactivation does not change the localization of the chemokine receptor CCR5, suggesting that this effect is targeted. Moreover, DTNB treatment and Trx1 depletion coincide with strong inhibition of CD4-dependent HIV entry, but only moderate reductions in the infectivity of a CD4-independent HIV pseudovirion. CONCLUSIONS: Changes in the extracellular redox environment, potentially mediated by allosteric consequences of functional disulfide bond oxidoreduction, may represent a signal for translocation of CD4 into DRM clusters, and this sequestration, another potential mechanism by which the anti-HIV effects of cell surface oxidoreductase inhibition are exerted. GENERAL SIGNIFICANCE: Extracellular redox conditions may regulate CD4 function by potentiating changes in its membrane domain localization. PMID- 27233454 TI - Publish and perish. PMID- 27233455 TI - Clinical practice guidelines. PMID- 27233456 TI - Lesion terminology. PMID- 27233457 TI - Authors' response. PMID- 27233458 TI - Authors' response. PMID- 27233459 TI - Author's response. PMID- 27233460 TI - Emergency department visits. PMID- 27233461 TI - Authors' response. PMID- 27233462 TI - Xylitol use and caries prevention. PMID- 27233463 TI - Reach practice potential with new systems. PMID- 27233464 TI - Is it unethical to not present a patient's treatment plan in its entirety? PMID- 27233465 TI - Variance components in confocal scanning laser tomography measurements of neuro retinal rim area and the effect of repeated measurements on the power to detect loss over time. AB - PURPOSE: To estimate the variation in measurements of neuro-retinal rim area (NRA) determined by confocal scanning laser tomography and consequences for clinical follow-up. METHODS: Altogether, 24 healthy subjects were randomized on 320 MUm, Moorfields and Standard NRA plane strategies. Additionally, NRA was measured in 32 glaucoma subjects. Variance components for subjects, visits and measurements were estimated with analysis of variance. Sample sizes required to detect a 6.0 * 10-2 mm2 NRA change were estimated assuming a significance level of 0.05 and a power of 0.8. Consequences for independent group, and paired comparison design, respectively, were analysed. Further, precision in estimates within subjects over time was investigated. RESULTS: The variation of NRA among subjects was considerably larger than the variation among visits and measurements. For glaucoma subjects, the variation among visits and measurements were of the same order but larger than in healthy subjects. It was found that independent group comparisons require inconveniently large sample sizes. Within subject paired comparisons over time require sample sizes of below 15 subjects. The estimated variations for glaucoma subjects imply that 54 months of follow-up is required for detection of change from baseline. CONCLUSIONS: The variance for subjects is substantial in relation to those for visits and measurements. Cross sectional independent group comparisons of levels of NRA are unsuitable, due to considerable subject variation. Levels of NRA differences within subjects between visits can be estimated with acceptable precision. Neuro-retinal rim area (NRA) measurement can be used for long-term follow-up of glaucoma progression. PMID- 27233466 TI - Acute risk factors for suicide attempts and death: prospective findings from the STEP-BD study. AB - OBJECTIVES: Suicide is unfortunately common in psychiatric practice, but difficult to predict. The present study sought to assess which clinical symptoms increase in the months before suicidal behavior in a sample of psychiatric outpatients with bipolar disorder. METHODS: Data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) trial were used. A total of 103 participants who attempted suicide or died by suicide during the trial were included; a 15% random sample of the remaining participants (n = 427) was used as a comparison sample. Linear mixed models in the six months before suicidal behavior were conducted for each of five proposed acute risk factors for suicidal behavior. Participants were assessed using the Clinical Monitoring Form (CMF) at each visit for the following potential acute risk factors for suicidal behavior: suicidal ideation, loss of interest, anxiety, psychomotor agitation, and high risk behavior. RESULTS: Each of the five symptoms was elevated overall in individuals who engaged in suicidal behavior (p < 0.05). The severity of both suicidal ideation and loss of interest significantly increased in the months before suicidal behavior (p < 0.001). Anxiety demonstrated comparable effect sizes across multiple models. Psychomotor agitation and high-risk behavior were not significantly elevated before suicidal behavior. CONCLUSIONS: Suicidal ideation, loss of interest and, to a lesser extent, anxiety may represent acute suicide risk factors up to four months before suicidal behavior in outpatients with bipolar disorder. Further investigation of these potential acute risk factors in prospective analyses is warranted. PMID- 27233467 TI - The frequency of physiologic monitor alarms in a children's hospital. PMID- 27233468 TI - Anesthetic constituents of Zanthoxylum bungeanum Maxim.: A pharmacokinetic study. AB - A sensitive and selective ultra high performance liquid chromatography with tandem mass spectrometry method was established and validated for the simultaneous determination of hydroxy-alpha-sanshool, hydroxy-beta-sanshool, and hydroxy-gamma-sanshool in rat plasma after the subcutaneous and intravenous administration of an extract of the pericarp of Zanthoxylum bungeanum Maxim. Piperine was used as the internal standard. The analytes were extracted from rat plasma by liquid-liquid extraction with ethyl acetate and separated on a Thermo Hypersil GOLD C18 column (2.1 mm * 50 mm, 1.9 MUm) with a gradient elution system at a flow rate of 0.4 mL/min. The mobile phase consisted of acetonitrile/0.05% formic acid in water and the total analysis time was 4 min. Positive electrospray ionization was performed using multiple reaction monitoring mode for the analytes. The calibration curves of the three analytes were linear over the tested concentration range. The intra- and interday precision was no more than 13.6%. Extraction recovery, matrix effect, and stability were satisfactory in rat plasma. The developed and validated method was suitable for the quantification of hydroxy-alpha-sanshool, hydroxy-beta-sanshool, and hydroxy-gamma-sanshool and successfully applied to a pharmacokinetic study of these analytes after subcutaneous and intravenous administration to rats. PMID- 27233470 TI - Functional Analysis of Missense Variants in the Putative Breast Cancer Susceptibility Gene XRCC2. AB - XRCC2 genetic variants have been associated with breast cancer susceptibility. However, association studies have been complicated because XRCC2 variants are extremely rare and consist mainly of amino acid substitutions whose grouping is sensitive to misclassification by the predictive algorithms. We therefore functionally characterized variants in XRCC2 by testing their ability to restore XRCC2-DNA repair deficient phenotypes using a cDNA-based complementation approach. While the protein-truncating variants p.Leu117fs, p.Arg215*, and p.Cys217* were unable to restore XRCC2 deficiency, 19 out of 23 missense variants showed no or just a minor (<25%) reduction in XRCC2 function. The remaining four (p.Cys120Tyr, p.Arg91Trp, p.Leu133Pro, and p.Ile95Leu) had a moderate effect. Overall, measured functional effects correlated poorly with those predicted by in silico analysis. After regrouping variants from published case-control studies based on the functional effect found in this study and reanalysis of the prevalence data, there was no longer evidence for an association with breast cancer. This suggests that if breast cancer susceptibility alleles of XRCC2 exist, they are likely restricted to protein-truncating variants and a minority of missense changes. Our study emphasizes the use of functional analyses of missense variants to support variant classification in association studies. PMID- 27233469 TI - Calcium dynamics predict direction of synaptic plasticity in striatal spiny projection neurons. AB - The striatum is a major site of learning and memory formation for sensorimotor and cognitive association. One of the mechanisms used by the brain for memory storage is synaptic plasticity - the long-lasting, activity-dependent change in synaptic strength. All forms of synaptic plasticity require an elevation in intracellular calcium, and a common hypothesis is that the amplitude and duration of calcium transients can determine the direction of synaptic plasticity. The utility of this hypothesis in the striatum is unclear in part because dopamine is required for striatal plasticity and in part because of the diversity in stimulation protocols. To test whether calcium can predict plasticity direction, we developed a calcium-based plasticity rule using a spiny projection neuron model with sophisticated calcium dynamics including calcium diffusion, buffering and pump extrusion. We utilized three spike timing-dependent plasticity (STDP) induction protocols, in which postsynaptic potentials are paired with precisely timed action potentials and the timing of such pairing determines whether potentiation or depression will occur. Results show that despite the variation in calcium dynamics, a single, calcium-based plasticity rule, which explicitly considers duration of calcium elevations, can explain the direction of synaptic weight change for all three STDP protocols. Additional simulations show that the plasticity rule correctly predicts the NMDA receptor dependence of long-term potentiation and the L-type channel dependence of long-term depression. By utilizing realistic calcium dynamics, the model reveals mechanisms controlling synaptic plasticity direction, and shows that the dynamics of calcium, not just calcium amplitude, are crucial for synaptic plasticity. PMID- 27233471 TI - A case of severe perioperative hypoxia in uncorrected tetralogy of fallot: Anesthetic management. AB - Tetralogy of fallot (TOF) is one of the most common congenital heart disease (CHD) in children. With the development of pediatric surgery and intensive care units, increasing number of grown-up CHD patients are presenting for non-cardiac surgeries. Non-operated TOF patients suffer from chronic hypoxia and decreased pulmonary blood flow resulting in considerable alteration in the physiology. The optimal management of these patients, therefore, require a thorough understanding of the pathophysiology of the uncorrected TOF. We hereby report a case of successful management of a 10-year-old child with an uncorrected TOF posted for tibial external fixation device. PMID- 27233472 TI - Goal directed hemodynamic therapy: The time to implement is now. PMID- 27233473 TI - The first ten years of the Department of Neurosciences Spanish Journal of Anesthesiology and Critical Care. PMID- 27233474 TI - Progesterone receptor activation is required for folic acid-induced anti proliferation in colorectal cancer cell lines. AB - Previously, we demonstrated that folic acid (FA) could inhibit proliferation of colorectal cancer cell lines through activating the folate receptor (FR)alpha/cSrc/ERK1/2/NFkappaB/p53 pathway and anti-COLO-205 tumor growth in vivo. Since we recently also demonstrated that female sex hormones could affect the FA's action in regulating endothelial cell proliferation and migration, the aim of this study was to investigate the effect of progesterone (P4) on the FA induced anti-proliferation in colorectal cancer cells. Treatment with FA significantly reduced the proliferation of the P4 receptor (PR)-positive colon cancer cell lines, COLO-205, HT-29 and LoVo, but did not significantly affect the proliferation of the PR-negative colon cancer cell lines, HCT116 and DLD-1. Pre treatment with Org 31710, a PR specific antagonist, abolished the FA-induced proliferation inhibition and activation in the signaling pathway involved in regulating proliferation inhibition in these PR positive colorectal cancer cell lines. The involvement of PR in the FA-induced activation of cSrc and up regulations in cell cycle inhibitory proteins (p21, p27 and p53) was confirmed by knock-down of PR expression using the siRNA technique. Importantly, we show direct protein interaction between FR and PR in COLO-205. Moreover, treatment with FA induced PR activation in COLO-205. Taken together, these data suggest that FA induced proliferation inhibition in colon cancer cells through activation of PR. This finding might explain some of the controversies of FA's effects on cancer growth and provide valuable reference for clinical applications of FA in treating colorectal cancer. PMID- 27233475 TI - ASC-J9((r)) suppresses castration resistant prostate cancer progression via degrading the enzalutamide-induced androgen receptor mutant AR-F876L. AB - Androgen deprivation therapy (ADT) with the newly developed powerful anti androgen enzalutamide (Enz, also known as MDV3100) has promising therapeutic effects to suppress castration resistant prostate cancer (CRPC) and extending patients' lives an extra 4.8 months. However, most Enz therapy eventually fails with the development of Enz resistance. The detailed mechanisms how CRPC develops Enz resistance remain unclear and may involve multiple mechanisms. Among them, the induction of the androgen receptor (AR) mutant AR-F876L in some CRPC patients may represent one driving force that confers Enz resistance. Here, we demonstrate that the AR degradation enhancer, ASC-J9((r)), not only degrades wild-type AR, but also has the ability to target AR-F876L. The consequence of suppressing AR F876L may then abrogate AR-F876L mediated CRPC cell proliferation and metastasis. Thus, developing ASC-J9((r)) as a new therapeutic approach may represent a novel therapy to better suppress CRPC that has already developed Enz resistance. PMID- 27233477 TI - Examining the Presence of Congregational Programs Focused on Violence Against Women. AB - Religious congregations are uniquely poised to provide programs to support survivors of violence against women; yet little is known regarding the prevalence of such programs. In this study, we used data from three waves of the National Congregation Study (N = 3334) to examine change across time in the presence of a congregational program to support survivors of sexual assault or domestic violence. We also explored results among different Christian religious traditions across time. Given the gendered nature of this violence, we also tested whether the (a) gender of the head clergy (i.e., religious leader), and (b) ability of women to serve in congregational leadership roles predicted the presence of programs. As points of comparison, we also examined the total number of congregational social service programs and food programs in particular. Overall, we found different patterns of change across religious traditions for the different programs. Moreover, clergy gender and the ability of women to serve in leadership roles predicted the presence of different types of programs. Limitations, implications, and directions for future research also are discussed. PMID- 27233476 TI - Regulation of the Nampt-mediated NAD salvage pathway and its therapeutic implications in pancreatic cancer. AB - Nicotinamide adenine dinucleotide (NAD) is a crucial cofactor for the redox reactions in the metabolic pathways of cancer cells that have elevated aerobic glycolysis (Warburg effect). Cancer cells are reported to rely on NAD recycling and inhibition of the NAD salvage pathway causes metabolic collapse and cell death. However, the underlying regulatory mechanisms and clinical implications for the NAD salvage pathway in pancreatic ductal adenocarcinoma (PDAC) remain unclear. This study showed that the expression of Nampt, the rate-limiting enzyme of the NAD salvage pathway, was significantly increased in PDAC cells and PDAC tissues. Additionally, inhibition of Nampt impaired tumor growth in vitro and tumorigenesis in vivo, which was accompanied by a decreased cellular NAD level and glycolytic activity. Mechanistically, the Nampt expression was independent of Kras and p16 status, but it was directly regulated by miR-206, which was inversely correlated with the expression of Nampt in PDAC tissues. Importantly, pharmacological inhibition of Nampt by its inhibitor, FK866, significantly enhanced the antitumor activity of gemcitabine in PDAC cells and in orthotopic xenograft mouse models. In conclusion, the present study revealed a novel regulatory mechanism for Nampt in PDAC and suggested that Nampt inhibition may override gemcitabine resistance by decreasing the NAD level and suppressing glycolytic activity, warranting further clinical investigation for pancreatic cancer treatment. PMID- 27233478 TI - Measuring gender when you don't have a gender measure: constructing a gender index using survey data. AB - BACKGROUND: Disentangling the impacts of sex and gender in understanding male and female differences is increasingly recognised as an important aspect for advancing research and addressing knowledge gaps in the field of work-health. However, achieving this goal in secondary data analyses where direct measures of gender have not been collected is challenging. This study outlines the development of a gender index, focused on gender roles and institutionalised gender, using secondary survey data from the Canadian Labour Force survey. Using this index we then examined the distribution of gender index scores among men and women, and changes in gender roles among male and female labour force participants between 1997 and 2014. METHODS: We created our Labour Force Gender Index (LFGI) using information in four areas: responsibility for caring for children; occupation segregation; hours of work; and level of education. LFGI scores ranged from 0 to 10, with higher scores indicating more feminine gender roles. We examined correlations between each component in our measure and our total LFGI score. Using multivariable linear regression we examined change in LFGI score for male and female labour force participants between 1997 and 2014. RESULTS: Although women had higher LFGI scores, indicating greater feminine gender roles, men and women were represented across the range of LFGI scores in both 1997 and 2014. Correlations indicated no redundancy between measures used to calculate LFGI scores. Between 1997 and 2014 LFGI scores increased marginally for men and decreased marginally for women. However, LFGI scores among women were still more than 1.5 points higher on average than for men in 2014. CONCLUSIONS: We have described and applied a method to create a measure of gender roles using survey data, where no direct measure of gender (masculinity/femininity) was available. This measure showed good variation among both men and women, and was responsive to change over time. The article concludes by outlining an approach to use this measure to examine the relative contribution of gender and sex on differences in health status (or other outcomes) between men and women. PMID- 27233480 TI - Cadmium inhibits mouse sperm motility through inducing tyrosine phosphorylation in a specific subset of proteins. AB - Cadmium (Cd) has been reported to impair male fertility, primarily by disrupting sperm motility, but the underlying molecular mechanism remains unclear. Here we investigated the effects of Cd on sperm motility, tyrosine phosphorylation, AMP activated protein kinase (AMPK) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity, and ATP levels in vitro. Our results demonstrated that Cd inhibited sperm motility, GAPDH activity, AMPK activity and ATP production, and induced tyrosine phosphorylation of 55-57KDa proteins. Importantly, all the parameters affected by Cd were restored to normal levels when incubated with 10MUM Cd in the presence of 30MUM ethylene diamine tetraacetic acid (EDTA). Interestingly, changes of tyrosine phosphorylation levels of 55-57KDa proteins are completely contrary to that of other parameters. These results suggest that Cd-induced tyrosine phosphorylation of 55-57KDa proteins might act as an engine to block intracellular energy metabolism and thus decrease sperm motility. PMID- 27233479 TI - Significant improvements in pain after a six-week physiotherapist-led exercise and education intervention, in patients with osteoarthritis awaiting arthroplasty, in South Africa: a randomised controlled trial. AB - BACKGROUND: A major challenge facing those with late stage osteoarthritis is delayed surgery due to waiting lists. In South Africa patients wait years for a hip/knee arthroplasty. Affected patients require effective management to address their pain, especially while awaiting surgery. Existing literature is mostly available from high income countries exploring effects of interventions during short waiting periods. Research is warranted in low income countries where long waiting periods are common. This study explored the effects of a six-week physiotherapist-led exercise and education intervention on pain in this population. METHODS: A randomised controlled trial was performed at two public hospitals in South Africa. Ethical approval and informed consent was obtained. 74 participants from arthroplasty waiting lists were randomly allocated to an intervention (n = 35) or control group (n = 39). The intervention included six physiotherapist-led group-based sessions (two hours/week of education, exercise and relaxation). The control group received usual care. Data collection was conducted by blinded physiotherapists at baseline, week six, 12 and month six. The primary outcome was pain, measured by the Brief Pain Inventory. Additionally, participants completed an open-ended questionnaire at month six, to gain insight regarding the intervention. Analysis was by intention to treat using two-way analysis of variance and post-hoc Tukey comparisons. Answers to subjective questions were analysed according to common themes that emerged. RESULTS: The intervention group had significant improvements compared with the control group with moderate to large effect sizes (ES) on pain severity [week 6: p < 0.01, ES = 0.94, 95 % CI (0.45,1.41), month 6: p = 0.02. ES = 0.74, 95 % CI (0.26,1.2)] and moderate to large effects on pain interference [week 6: p < 0.01, ES = 1.2, 95 % CI (0.70,1.69), week 12: p = 0.04, ES = 0.68, 95 % CI (0.20,1.14), month 6: p < 0.01, ES = 0.98, 95 % CI (0.49,1.45)]. 53 % of participants reported that the intervention improved their pain. CONCLUSIONS: The intervention resulted in sustained significant improvements in pain severity and interference in patients with hip/knee osteoarthritis, awaiting arthroplasty compared with a control group. Additionally, participants' individual feedback supported observed significant improvements in pain. Such an intervention appears to be effective in managing pain in this population and should be incorporated into practice for appropriate patients. Further research is being conducted to explore long term and postoperative outcomes. CLINICAL TRIAL REGISTRATION: Pan African Clinical Trial Registry, PACTR201409000885765 , PACTR201507001186115 . PMID- 27233481 TI - Thyroid hormone disruption and cognitive impairment in rats exposed to PBDE during postnatal development. AB - Polybrominated diphenyl ether flame-retardants (PBDEs) are thyroid-disrupting environmental chemicals. We investigated the effects of postnatal exposure to DE 71 (a mixture of tetra- and penta-brominated congeners), n-propylthiouracil (PTU) and thyroxine (T4) replacement on open-field (OF) and radial maze (RAM) tests. Wistar rats (5 males/5 females per litter, 32 litters) were treated orally (PND 5 22) with PTU (4mg/kg bw/d), DE-71 (30mg/kg bw/d), with and without co administration of T4 (15MUg/kg bw/d, sc). PTU depressed T4 serum levels and body weight gain and enlarged thyroid gland. Although decreasing T4 levels, DE-71 did not change thyroid and body weights. PTU-treated rats showed hyperactivity (PND 42 and 70), and working and reference memory learning deficits (RAM, PND 100). Although not altering motor activity and working memory, DE-71 caused a reference memory deficit (females only). T4 co-administration averted hypothyroxinemia and long-term cognitive deficits caused by PTU and DE-71. PMID- 27233482 TI - Melatonin delivery by nanocapsules during in vitro bovine oocyte maturation decreased the reactive oxygen species of oocytes and embryos. AB - In this work, a promising approach to increase the advantageous properties of melatonin through its encapsulation into lipid-core nanocapsules (LNC) was examined. Oocytes were treated during in vitro maturation with non-encapsulated melatonin (Mel), melatonin-loaded lipid-core nanocapsules (Mel-LNC), and unloaded LNC. Cytotoxicity, meiotic maturation rate, development to the blastocyst stage, reactive oxygen species (ROS) and glutathione levels, mean cell number and apoptotic cell/blastocyst, and mRNA quantification were evaluated. Both Mel and Mel-LNC enhanced in vitro embryo production, however, Mel-LNC proved to be more effective at decreasing ROS levels and the apoptotic cell number/blastocyst, increasing the cleavage and blastocyst rates, up-regulating the GPX1 and SOD2 genes, and down-regulating the CASP3 and BAX genes. Mel-LNC could penetrate into oocytes and remain inside the cells until they reach the blastocyst stage. In conclusion, when melatonin was encapsulated in LNC and applied during in vitro oocyte maturation, some quality aspects of the blastocysts were improved. PMID- 27233484 TI - Selected anteromedial coronoid fractures can be treated nonoperatively. AB - BACKGROUND: Surgical fixation is currently recommended for unstable anteromedial coronoid fractures, but the role of nonoperative management is not well defined. Our purpose was to report the functional and radiographic outcomes of select patients managed nonoperatively. METHODS: Between 2006 and 2012, 10 patients with anteromedial coronoid fractures underwent nonoperative treatment. Outcomes assessed included elbow range of motion (ROM), stability, strength, radiographs, and 3 functional questionnaires, including the Patient-Rated Elbow Evaluation, Disabilities of Arm, Shoulder and Hand, and Mayo Elbow Performance Index. RESULTS: There were 9 anteromedial subtype 2 coronoid fractures and 1 subtype 3. Mean fragment size was 5 mm, with a mean displacement of 3 mm for the subtype 2 fractures. The subtype 3 fracture was 9 mm in size with 1 mm of maximal gap displacement. At a mean follow-up of 50 months (range, 12-83 months), the average ROM of the affected elbow was 137 degrees +/- 8 degrees of flexion, 2 degrees +/- 5 degrees of extension, 88 degrees +/- 5 degrees of pronation, and 86 degrees +/- 10 degrees of supination. The mean Patient-Rated Elbow Evaluation score was 9 +/- 13, Mayo Elbow Performance Index score was 94 +/- 8, and the Disabilities of Arm, Shoulder and Hand score was 7 +/- 9. All patients had bony union without radiographic arthrosis. There were no cases of recurrent instability or delayed surgical intervention. CONCLUSIONS: Current indications for nonoperative management, based on the results of this study, include fractures that are small, minimally displaced, and most importantly, demonstrate no evidence of elbow subluxation. The elbow joint must be congruent and demonstrate a stable ROM to a minimum of 30 degrees of extension. For selected anteromedial coronoid fractures, nonoperative management is an option that can lead to good clinical and radiographic outcomes. PMID- 27233485 TI - Involvement of the lesser sigmoid notch in elbow fracture dislocations. AB - BACKGROUND: This study addressed the primary null hypothesis that there is no difference in the articular surface area of the lesser sigmoid notch involved among Mayo classes. Secondarily, we analyzed the fracture line location and the pattern of lesser sigmoid notch articular surface involvement among Mayo classes. METHODS: Using quantitative 3-dimensional computed tomography, we reconstructed and analyzed fractures involving the lesser sigmoid notch articular surface in 52 patients. Further, we assessed the surface area involved in the fracture, the number of fracture fragments, and the location and direction of the fracture lines. Coronoid fractures were classified according to Mayo types. RESULTS: There was no significant difference between Mayo types 1 and 2 in any characteristic of the involvement of the lesser sigmoid notch articular surface, whereas Mayo type 3 was significantly different from both Mayo types 1 and 2 in the area involved in the fracture (42% in Mayo type 3 vs. 9% in Mayo types 1 and 2), the number of articular fragments (>3 fragments in type 3 vs. 2 fragments in types 1 and 2), and the direction of fracture line (both horizontal and vertical lines in type 3 vs. only horizontal line in types 1 and 2). CONCLUSION: Mayo type III results in a more complex fracture, which might need to be addressed directly or indirectly during open reduction with internal fixation of olecranon fracture dislocations because changes in the geometry of lesser sigmoid notch may affect the radioulnar joint if it remains incongruent. PMID- 27233486 TI - [Effect size in comparison between two or more groups]. PMID- 27233487 TI - HPV Genotyping from the high risk mRNA Aptima assay- a direct approach using DNA from Aptima sample tubes. AB - The underlying cause of cervical cancer is an infection with the human papilloma virus (HPV) and HPV testing can be used for cervical cancer screening. The Aptima HPV assay from Hologic is an mRNA HPV test used to identify clinically relevant infections but the method does not discriminate between the different high risk genotypes. The aim of the current study was to evaluate if analyzed Aptima sample transfer tubes could be used as a source for HPV genotyping, using sample DNA. Study samples (n=108); were HPV-tested with mRNA Aptima assay and in parallel DNA was extracted and genotyped with Anyplex II HPV28. Analyzed mRNA Aptima tubes were thereafter used as source for a second DNA extraction and genotyping. Using mRNA Aptima result as reference, 90% of the samples (35/39) were high risk positive with the Anyplex II HPV28. Cohen's kappa 0.78 (95% CI: 0.66-0.90), sensitivity 0.90 (95% CI: 0.76-0.97) and specificity 0.90 (95% CI: 0.80-0.96). Two discordant samples carried low-risk genotypes (HPV 82 and HPV 44) and two were negative. DNA-genotyping results, in parallel to and after mRNA testing, were compared and differed significantly (McNemar test: P=0.021) possibly due to sample extraction volume difference. Cohen's kappa 0.81 (95% CI: 0.70-0.92), sensitivity 0.85 (95% CI: 0.74-0.93) and specificity 0.98 (95% CI: 0.88-1.00). In conclusion, analyzed mRNA Aptima sample tubes could be used as a source for DNA HPV genotyping. The sample volume used for extraction needs to be further explored. PMID- 27233488 TI - Functional Decline in Residents Living in Nursing Homes: A Systematic Review of the Literature. AB - OBJECTIVES: To describe the functional dependence progression over time in older people living in nursing homes (NHs). DESIGN: A systematic review of the literature was performed. Studies involving individuals 65 years and older living in NHs, describing their functional decline, improvement or stability in activities of daily living (ADLs), were eligible. The search strategy was applied in MedLine, Cochrane, CINAHL, and SCOPUS databases; aimed at identifying an unbiased and complete list of studies, searching by hand was also performed. The methodological quality of the 27 studies included was assessed. RESULTS: Functional trajectories were documented mainly through multicenter study design including sample size ranging from 2 to 9336 NHs, from 1983 to 2011 throughout a single or multiple follow-ups (>20). The average rate of decline was expressed in different metrics and periods of time: from 3 months with a decline of -0.13 points of 28, to 6 months (-1.78 points of 2829) to 1.85 years (-0.5 points of 6). Eating and toileting were the most documented ADLs and the decline is approximately 0.4 points and 0.2 to 0.4 points of 5 a year, respectively. Among the covariates, individual factors, such as cognitive status, were mainly considered, whereas only 13 studies considered facility-level factors. CONCLUSIONS: Findings report the slow functional decline mainly in women living in US NHs, in years when residents were admitted with a low or medium degree of functional dependence. Considering that in recent years residents have been admitted to NHs with higher-level functional dependence, studies measuring each single ADL, using standardized instruments capable of capturing the signs of decline, stability, or improvement are strongly recommended. Among the covariates, evaluation of both individual and facility-level factors, which may affect functional decline, is also suggested. PMID- 27233489 TI - Antimicrobial Stewardship in Long-Term Care: Metrics and Risk Adjustment. AB - An antimicrobial stewardship program (ASP) has been recommended for long-term care facilities because of the increasing problem of antibiotic resistance in this setting to improve prescribing and decrease adverse events. Recommendations have been made for the components of such a program, but there is little evidence to support any specific methodology at the present time. The recommendations make minimal reference to metrics, an essential component of any ASP, to monitor the results of interventions. This article focuses on the role of antibiotic use metrics as part of an ASP for long-term care. Studies specifically focused on development of antibiotic use metrics for long-term care are reviewed. It is stressed that these metrics should be considered as an integral part of an ASP in long-term care. In order to develop benchmarks for antibiotic use for long-term care, there must be appropriate risk adjustment for interfacility comparisons and quality improvement. Studies that have focused on resident functional status as a risk factor for infection and antibiotic use are reviewed. Recommendations for the potentially most useful and feasible metrics for long-term care are provided along with recommendations for future research. PMID- 27233483 TI - The Philadelphia chromosome in leukemogenesis. AB - The truncated chromosome 22 that results from the reciprocal translocation t(9;22)(q34;q11) is known as the Philadelphia chromosome (Ph) and is a hallmark of chronic myeloid leukemia (CML). In leukemia cells, Ph not only impairs the physiological signaling pathways but also disrupts genomic stability. This aberrant fusion gene encodes the breakpoint cluster region-proto-oncogene tyrosine-protein kinase (BCR-ABL1) oncogenic protein with persistently enhanced tyrosine kinase activity. The kinase activity is responsible for maintaining proliferation, inhibiting differentiation, and conferring resistance to cell death. During the progression of CML from the chronic phase to the accelerated phase and then to the blast phase, the expression patterns of different BCR-ABL1 transcripts vary. Each BCR-ABL1 transcript is present in a distinct leukemia phenotype, which predicts both response to therapy and clinical outcome. Besides CML, the Ph is found in acute lymphoblastic leukemia, acute myeloid leukemia, and mixed-phenotype acute leukemia. Here, we provide an overview of the clinical presentation and cellular biology of different phenotypes of Ph-positive leukemia and highlight key findings regarding leukemogenesis. PMID- 27233490 TI - The Effects of Blood Transfusion on Delirium Incidence. AB - BACKGROUND: Both anemia and blood transfusion could be precipitating factors for delirium; hence in postoperative patients with anemia at high risk for delirium, it is controversial whether transfusion is the best option. The aim of this study is to investigate the association of anemia and delirium and the role of blood transfusion within the multicomponent prevention strategy of delirium. METHODS: We conducted a substudy of a multicenter randomized controlled trial. Four hundred fifteen patients aged 65 to 102 years old admitted for hip fracture surgery were enrolled. Delirium was assessed daily using criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition. Data on hemoglobin values and transfusion were collected from the electronic medical records. RESULTS: One hundred fifteen (32.5%) patients experienced delirium during hospitalization, 238 (57.5%) had a hemoglobin level <= 6.0 mmol/L (9.7 g/dL) at any time during hospitalization, and 140 (33.7%) received a blood transfusion. Anemia (a hemoglobin level <= 6.0 mmol/L [9.7 g/dL]) was associated with delirium (odds ratio, 1.81; 95% confidence interval, 1.15-2.86). Blood transfusion was a protective factor for delirium in patients with the lowest measured hemoglobin level <= 6.0 mmol/L (9.7 g/dL) (odds ratio, 0.26; 95% confidence interval, 0.10-0.70). CONCLUSION: Low hemoglobin level is associated with delirium, and receiving a blood transfusion is associated with a lower delirium incidence. It would be interesting to investigate the effect of blood transfusion as part of the multicomponent treatment of delirium in patients with anemia. PMID- 27233491 TI - Pain Management in the Elderly. PMID- 27233492 TI - Skin Failure: A Practical Concept when Properly Applied. PMID- 27233493 TI - Synthesis of NAM-thiazoline derivatives as novel O-GlcNAcase inhibitors. AB - Human O-GlcNAcase (GH 84) and human beta-N-acetyl-D-hexosaminidase (GH 20) from Homo sapiens are two therapeutic enzyme targets that share the same catalytic mechanism but play different physiological roles in vivo. Selective inhibition toward one of these enzymes is therefore of importance to regulate the corresponding bioprocess. Here ten new NAM-thiazoline derivatives were synthesized and subsequently characterized by NMR and HRMS. A preliminary bioassay showed that most of the synthesized compounds exhibited obvious selective inhibition against human O-GlcNAcase over human beta-N-acetyl-D hexosaminidase. Among the compounds tested, compound 7d (IC50 = 6.4 uM, hOGA; IC50>1 mM, hHex) and 7f (IC50 = 11.9 uM, hOGA; IC50>1 mM, hHex) proved to be a highly selective and potent inhibitor. Structure-activity relationship analysis indicated a correlation between the inhibitory activity and the size of the groups linked to the thiazoline ring. PMID- 27233494 TI - Simulation-based training for burr hole surgery instrument recognition. AB - BACKGROUND: The use of simulation training in postgraduate medical education is an area of rapidly growing popularity and research. This study was designed to assess the impact of simulation training for instrument knowledge and recognition among neurosurgery residents. METHODS: This was a randomized control trial of first year residents from neurosurgery residency training programs across Canada. Eighteen neurosurgery trainees were recruited to test two simulation-based applications: PeriopSimTM Instrument Trainer and PeriopSimTM for Burr Hole Surgery. The intervention was game-based simulation training for learning neurosurgical instruments and applying this knowledge to identify correct instruments during a simulated burr hole surgery procedure. RESULTS: Participants showed significant overall improvement in total score (p < 0.0005), number of errors (p = 0.019) and time saved (p < 0.0005), over three testing sessions when using the PeriopSimTM Instrument Trainer. Participants demonstrated further performance-trained improvements when using PeriopSimTM Burr Hole Surgery. CONCLUSIONS: Training in the recognition and utilization of simulated surgical instruments by neurosurgery residents improved significantly with repetition when using PeriopSimTM Instrument Trainer and PeriopSimTM for Burr Hole Surgery. PMID- 27233495 TI - Germline APOBEC3B deletion is associated with breast cancer risk in an Asian multi-ethnic cohort and with immune cell presentation. AB - BACKGROUND: APOBEC3B is a cytosine deaminase implicated in immune response to viral infection, cancer predisposition and carcinogenesis. Germline APOBEC3B deletion is more common in East Asian women and confers a modest risk to breast cancer in both East Asian and Caucasian women. Analysis of tumour samples from women of European descent has shown that germline APOBEC3B deletion is associated with an increased propensity to develop somatic mutations and with an enrichment for immune response-related gene sets. However, this has not been examined in Asian tumour samples, where population differences in genetic and dietary factors may have an impact on the immune system. METHODS: In this study, we determined the prevalence of germline APOBEC3B deletion and its association with breast cancer risk in a cross-sectional hospital-based Asian multi-ethnic cohort of 1451 cases and 1442 controls from Malaysia. We compared gene expression profiles of breast cancers arising from APOBEC3B deletion carriers and non-carriers using microarray analyses. Finally, we characterised the overall abundance of tumour infiltrating immune cells in breast cancers from TCGA and METABRIC using ESTIMATE and relative frequency of 22 immune cell subsets in breast cancers from METABRIC using CIBERSORT. RESULTS: The minor allelic frequency of APOBEC3B deletion was estimated to be 0.35, 0.42 and 0.16 in female populations of Chinese, Malay and Indian descent, respectively, and that germline APOBEC3B deletion was associated with breast cancer risk with odds ratios of 1.23 (95 % CI: [1.05, 1.44]) for one copy deletion and 1.38 (95 % CI: [1.10, 1.74]) for two-copy deletion compared to women with no deletion. Germline APOBEC3B deletion was not associated with any clinicopathologic features or the expression of any APOBEC family members but was associated with immune response-related gene sets (FDR q values < 0.05). Analysis of breast cancers from METABRIC revealed breast cancers from APOBEC3B deletion carriers to have significantly higher abundance of tumour-infiltrating immune cells (P < 0.001). CONCLUSIONS: Taken together, our data suggests that tumour infiltrating immune cells may be an important feature of breast cancers arising in women with APOBEC3B germline deletion, and that this may be of particular interest in Asian women where the germline deletion is more common. PMID- 27233496 TI - The relationship between housing subsidies and supportive housing on neighborhood distress and housing satisfaction: does drug use make a difference? AB - BACKGROUND: Since the 1970s, the dominant model for U.S. federal housing policy has shifted from unit-based programs to tenant-based vouchers and certificates. Because housing vouchers allow recipients to move to apartments and neighborhoods of their choice, such programs were designed to improve the ability of poor families to move into neighborhoods with less concentrated poverty. However, little research has examined whether housing voucher recipients live in less distressed neighborhoods than those without housing vouchers. There is much reason to believe that drug users may not be able to access or keep federal housing subsidies due to difficulties drug users, many of whom may have criminal histories and poor credit records, may have in obtaining free market rental housing. In response to these difficulties, permanent supportive housing was designed for those who are chronically homeless with one or more disabling condition, including substance use disorders. Little research has examined whether residents of permanent supportive housing units live in more or less economically distressed neighborhoods compared to low-income renters. METHODS: This paper uses survey data from 337 low-income residents of Hartford, CT and geospatial analysis to determine whether low-income residents who receive housing subsidies and supportive housing live in neighborhoods with less concentrated poverty than those who do not. We also examine the relationships between receiving housing subsidies or supportive housing and housing satisfaction. Finally, we look at the moderating effects of drug use and race on level of neighborhood distress and housing satisfaction. RESULTS: Results show that low income residents who receive housing subsidies or supportive housing were not more or less likely to live in neighborhoods with high levels of distress, although Black residents with housing subsidies lived in more distressed neighborhoods. Regarding housing satisfaction, those with housing subsidies perceived significantly more choice in where they were living while those in supportive housing perceived less choice. In addition, those with rental subsidies or supportive housing reported living closer to needed services, unless they also reported heavy drug use. CONCLUSIONS: Housing subsidies and supportive housing have little impact on the level of neighborhood distress in which recipients live, but some effects on housing satisfaction. PMID- 27233498 TI - Trends towards stronger primary care in three western European countries; 2006 2012. AB - BACKGROUND: Strong primary care systems are believed to have an important role in dealing with healthcare challenges. Strengthening primary care systems is therefore a common policy goal for many countries. This study aims to investigate whether the Netherlands, the UK and Germany have strengthened their primary care systems in 2006-2012. METHOD: For this cross-sectional study, data from the International Health Policy surveys of the Commonwealth Fund in 2006, 2009 and 2012 were used. The surveys represent the experiences and perspectives of primary care physicians with their primary care system. The changes over time were researched in three areas: organization of primary care processes, use of IT in primary care and use of benchmarking and financial incentives for performance improvement. RESULTS: Regarding organization of primary care processes, in all countries the use of supporting personnel in general practice increased, but at the same time practice accessibility decreased. IT services were most advanced in the UK. The UK and the Netherlands showed increased use of performance feedback information. German GPs were least satisfied with how their system works across the 2006-2012 timeframe. CONCLUSION: All three countries show trends towards stronger primary care systems, although in different areas. Coordination and comprehensive care through the assignment of assisting personnel and use of disease management programs improved in all countries. In the Netherlands and the UK, informational continuity is in part ensured through better IT services. All countries showed increasing difficulties upholding primary care accessibility. PMID- 27233497 TI - The importance of the excitatory amino acid transporter 3 (EAAT3). AB - The neuronal excitatory amino acid transporter 3 (EAAT3) is fairly ubiquitously expressed in the brain, though it does not necessarily maintain the same function everywhere. It is important in maintaining low local concentrations of glutamate, where its predominant post-synaptic localization can buffer nearby glutamate receptors and modulate excitatory neurotransmission and synaptic plasticity. It is also the main neuronal cysteine uptake system acting as the rate-limiting factor for the synthesis of glutathione, a potent antioxidant, in EAAT3 expressing neurons, while on GABAergic neurons, it is important in supplying glutamate as a precursor for GABA synthesis. Several diseases implicate EAAT3, and modulation of this transporter could prove a useful therapeutic approach. Regulation of EAAT3 could be targeted at several points for functional modulation, including the level of transcription, trafficking and direct pharmacological modulation, and indeed, compounds and experimental treatments have been identified that regulate EAAT3 function at different stages, which together with observations of EAAT3 regulation in patients is giving us insight into the endogenous function of this transporter, as well as the consequences of altered function. This review summarizes work done on elucidating the role and regulation of EAAT3. PMID- 27233499 TI - Post-translational modifications in mitochondria: protein signaling in the powerhouse. AB - There is an intimate interplay between cellular metabolism and the pathophysiology of disease. Mitochondria are essential to maintaining and regulating metabolic function of cells and organs. Mitochondrial dysfunction is implicated in diverse diseases, such as cardiovascular disease, diabetes and metabolic syndrome, neurodegeneration, cancer, and aging. Multiple reversible post-translational protein modifications are located in the mitochondria that are responsive to nutrient availability and redox conditions, and which can act in protein-protein interactions to modify diverse mitochondrial functions. Included in this are physiologic redox signaling via reactive oxygen and nitrogen species, phosphorylation, O-GlcNAcylation, acetylation, and succinylation, among others. With the advent of mass proteomic screening techniques, there has been a vast increase in the array of known mitochondrial post-translational modifications and their protein targets. The functional significance of these processes in disease etiology, and the pathologic response to their disruption, are still under investigation. However, many of these reversible modifications act as regulatory mechanisms in mitochondria and show promise for mitochondrial-targeted therapeutic strategies. This review addresses the current knowledge of post translational processing and signaling mechanisms in mitochondria, and their implications in health and disease. PMID- 27233500 TI - Hes1: the maestro in neurogenesis. AB - The process of neurogenesis is well orchestrated by the harmony of multiple cues in a spatiotemporal manner. In this review, we focus on how a dynamic gene, Hes1, is involved in neurogenesis with the view of its regulation and functional implications. Initially, we have reviewed the immense functional significance drawn by this maestro during neural development in a context-dependent manner. How this indispensable role of Hes1 in conferring the competency for neural differentiation partly relies on the direct/indirect mode of repression mediated by very specific structural and functional arms of this protein has also been outlined here. We also review the detailed molecular mechanisms behind the well tuned oscillatory versus sustained expression of this antineurogenic bHLH repressor, which indeed makes it a master gene to implement the elusive task of neural progenitor propensity. Apart from the functional aspects of Hes1, we also discuss the molecular insights into the endogenous regulatory machinery that regulates its expression. Though Hes1 is a classical target of the Notch signaling pathway, we discuss here its differential expression at the molecular, cellular, and/or regional level. Moreover, we describe how its expression is fine tuned by all possible ways of gene regulation such as epigenetic, transcriptional, post-transcriptional, post-translational, and environmental factors during vertebrate neurogenesis. PMID- 27233502 TI - Oxidative stress markers in type 2 diabetes patients with diabetic nephropathy. AB - BACKGROUND: Epidemiological studies show that 5-40 % of type 2 diabetes (T2DM) patients have diabetic nephropathy, and oxidative stress is one of several underlying mechanisms. We investigated associations between oxidative stress markers and severity of diabetic nephropathy. METHODS: Fifty-nine T2DM patients from the endocrinology outpatient department were included, and their levels of oxidative stress markers were measured. Three groups were determined by their urine albumin-to-creatinine ratio (UACR): group A (UACR < 30 mg/g, n = 22); group B (30 <= UACR < 300 mg/g, n = 22); and group C (UACR >= 300 mg/g, n = 15). RESULTS: Vitamin C levels correlated negatively and moderately with serum creatinine (gamma = -0.459, p < 0.001), urine albumin (gamma s = -0.458, p = 0.001) and UACR (gamma s = -0.408, p = 0.001), but only weakly with hydroxy-2 deoxyguanosine (8-OHdG) and estimated glomerular filtration rate (eGFR). Vitamin C levels decreased as 8-OHdG, serum creatinine, albumin and UACR increased. T2DM patients with more severe diabetic nephropathy had lower vitamin C levels. CONCLUSION: Our results identified several oxidative stress markers that may be clinically important in diabetic nephropathy. Studies with larger sample sizes should be undertaken to confirm these findings. PMID- 27233503 TI - Methylation and Esterification of Magnolol for Ameliorating Cutaneous Targeting and Therapeutic Index by Topical Application. AB - PURPOSE: As a continuing effort to elucidate the impact of structure modification upon cutaneous absorption behavior, we attempted to assess the skin permeation of magnolol by methylation and acetylation. METHODS: Diacetylmagnolol and 2-O-acetyl 2'-O-methylmagnolol (AMM) were designed and synthesized in this study. The anti inflammatory activity against stimulated neutrophils and keratinocytes was evaluated to check the bioactivity of the analogues. In vitro skin absorption was investigated using nude mouse and pig skin models at both equimolar and saturated doses. RESULTS: Magnolol generally showed the strongest anti-inflammatory potential, followed by diacetylmagnolol and AMM. The antibacterial activity was observed for magnolol and diacetylmagnolol but not AMM. Diacetylmagnolol and AMM could be partly hydrolyzed to magnolol and 2-O-methylmagnolol after entering the skin. The hydrolysis rate of diacetylmagnolol was faster than that of AMM. The lipophilicity played a crucial role in cutaneous absorption, with AMM exhibiting the highest skin deposition. AMM accumulation within nude mouse skin was about 2.5-fold greater than that of magnolol and diacetylmagnolol. On the other hand, the transdermal penetration across the skin was lessened by methylation and esterification. This led to a superior skin targeting of AMM. Although the pharmacological activity of AMM was low, the high skin uptake and bioconversion into 2-O-methylmagnolol in the skin contributed to a greater therapeutic index (TI, skin deposition x inflammatory inhibition percentage) compared to the others. The accumulation of AMM in the hair follicles was 77.12 nmol/cm(2), which was significantly greater than that with magnolol (44.84 nmol/cm(2)) and diacetylmagnolol (26.96 nmol/cm(2)). The synthetic analogues were tolerable to the nude mouse skin. CONCLUSIONS: Based on the experimental results, we may suggest topically applied AMM as a potent and safe candidate for the treatment of cutaneous inflammation. PMID- 27233501 TI - Mitochondrial cAMP signaling. AB - Cyclic adenosine 3, 5'-monophosphate (cAMP) is a ubiquitous second messenger regulating many biological processes, such as cell migration, differentiation, proliferation and apoptosis. cAMP signaling functions not only on the plasma membrane, but also in the nucleus and in organelles such as mitochondria. Mitochondrial cAMP signaling is an indispensable part of the cytoplasm mitochondrion crosstalk that maintains mitochondrial homeostasis, regulates mitochondrial dynamics, and modulates cellular stress responses and other signaling pathways. Recently, the compartmentalization of mitochondrial cAMP signaling has attracted great attentions. This new input should be carefully taken into account when we interpret the findings of mitochondrial cAMP signaling. In this review, we summarize previous and recent progress in our understanding of mitochondrial cAMP signaling, including the components of the signaling cascade, and the function and regulation of this signaling pathway in different mitochondrial compartments. PMID- 27233504 TI - Editorial: The Graying of the (Funded) Musculoskeletal Scientist. PMID- 27233505 TI - No Correlation Between Serum Markers and Early Functional Outcome After Contemporary THA. AB - BACKGROUND: Serum markers of inflammation and muscle damage have shown clinical utility in some areas of medicine, but their value in determining the invasiveness or in predicting the early functional outcomes after total hip arthroplasty (THA) has not been demonstrated. QUESTIONS/PURPOSES: (1) Do serum markers of inflammation/muscle damage predict pain or early functional outcomes after contemporary THA performed through a direct anterior or miniposterior approach? (2) Do early functional outcomes as measured by in-hospital outcomes and clinical milestones differ between a contemporary direct anterior and miniposterior approach for THA? METHODS: Between August 31, 2013, and September 1, 2014, all patients presenting as candidates for THA at our institution who had not already had preoperative blood draws (161) were recruited for this study. Forty-two patients failed these exclusion criteria, eight patients declined enrollment, and 11 were consented but did not complete the required preoperative blood tests. Recruitment stopped when 50 patients had been enrolled in both the direct anterior group and the miniposterior group (2n = 100) based on a priori power analysis. One high-volume surgeon performed all of the direct anterior approaches and three high-volume surgeons performed the miniposterior approaches. Groups did not differ with the numbers available in mean age (63 years; SD 10; range, 35-86 years), sex (52% female), or mean body mass index (mean 31 kg/m2; SD 7 kg/m2; range, 20-73 kg/m2). Serum markers measured including hemoglobin, hematocrit, myoglobin, creatine kinase (CK), C-reactive protein, interleukin-6, and tumor necrosis factor-alpha were collected at the preoperative clinic visit and on postoperative days 1 and 2 and compared with operative details, in hospital complications, therapy progress, pain scores, and functional results from a milestone diary. Functional results evaluated included time to discontinue all narcotics and gait aids, independence with activities of daily living, return to driving a motor vehicle, and return to work. RESULTS: Serum markers after contemporary THA were not correlated with early functional outcomes either in hospital or postdischarge. Specifically, no serum marker was predictive of the time to discontinue gait aids or narcotics, return to driving, climb stairs, or independence in activities of daily living (all p > 0.08). The patients receiving the direct anterior approach did have lesser elevations of CK levels than the patients undergoing the miniposterior approach (436 +/- 312 [direct anterior {DA}] versus 1071 +/- 459 [miniposterior {MP}], difference in means: -635; 95% confidence interval [CI], -809 to -462; p < 0.001), myoglobin levels (168 +/- 114 [DA] versus 378 +/- 151 [MP], difference in means: -210, 95% CI, -269 to -151; p < 0.001), C-reactive protein (79 +/- 57 [DA] versus 124 +/- 58 [MP], difference in means: -46, 95% CI, -71 to -21; p < 0.001), and interleukin-6 (45 +/- 34 [DA] versus 80 +/- 53 [MP], difference in means: -35, 95% CI, -54 to -16; p < 0.001), but not in other serum markers. In the hospital, patients undergoing the direct anterior approach ambulated 35 steps farther with physical therapy (178 feet DA versus 142 feet MP, p < 0.01, difference in means: 35, 95% CI, 9-62; p = 0.009) and had visual analog scale pain scores 1.1 less (4.8 DA versus 5.9 MP, difference in means: -1.1, 95% CI, 2.0 to -0.2; p = 0.02) than patients undergoing the miniposterior approach. There were no differences between approaches in other in-hospital outcomes or in posthospital clinical milestones. CONCLUSIONS: Serum markers including CK, myoglobin, C-reactive protein, interleukin-6, and tumor necrosis factor-alpha did not predict early pain/function after contemporary THA approaches. Although lesser elevations in myoglobin, CK, C-reactive protein, and interleukin-6 were found after direct anterior THA, that difference was not clinically meaningful. Further reporting of serum biomarkers as a measure of physiological burden after orthopaedic surgical procedures should be viewed as suspect until clear linear or threshold values are established. LEVEL OF EVIDENCE: Level III, diagnostic study. PMID- 27233506 TI - Prevalence and predictors of vitamin D insufficiency in supplemented and non supplemented women with systemic lupus erythematosus in the Mediterranean region. AB - It has been previously reported that vitamin D deficiency is more prevalent among SLE patients than in the general population. We sought to determine the prevalence of vitamin D insufficiency and deficiency and their related factors, its relationship to SLE symptoms and disease activity on a group of supplemented and non-supplemented female SLE patients from the Mediterranean region. We performed a cross-sectional study including female SLE patients who regularly attended the outpatient Lupus Unit at Parc de Salut Mar-IMAS in Barcelona, from January 2012 to May 2014. Collected data were sociodemographics, vitamin D supplementation, fatigue degree visual analog scale, pharmacological treatment, main SLE serological markers, indexes, scales and plasma levels of 25 hydroxyvitamin D. One hundred and two consecutive female SLE patients were included. Vitamin D overall insufficiency and deficiency were exhibited by 46 and 22.5 % of patients, respectively. Vitamin D insufficiency was found in 50 % of supplemented and 60 % of non-supplemented patients. Among non-supplemented female SLE patients, it was found that patients with vitamin D insufficiency showed more fatigue (p = 0.009) and received more oral corticosteroids (p = 0.02) than those with normal levels. Patients with vitamin D insufficiency (supplemented and non supplemented) received more oral corticosteroids than those without insufficiency (p = 0.008). Vitamin D insufficiency is highly prevalent among female SLE patients, even in southern regions. Non-supplemented female SLE patients showed more fatigue and received more oral corticosteroids than those with normal levels of vitamin D. These data were not found in supplemented patients although having a high prevalence of vitamin D insufficiency (up to 50 %). Further studies with longer follow-up and larger population are needed to confirm our observations. PMID- 27233507 TI - Stomatal closure induced by phytosphingosine-1-phosphate and sphingosine-1 phosphate depends on nitric oxide and pH of guard cells in Pisum sativum. AB - MAIN CONCLUSION: Phyto-S1P and S1P induced stomatal closure in epidermis of pea ( Pisum sativum ) by raising the levels of NO and pH in guard cells. Phosphosphingolipids, such as phytosphingosine-1-phosphate (phyto-S1P) and sphingosine-1-phosphate (S1P), are important signaling components during drought stress. The biosynthesis of phyto-S1P or S1P is mediated by sphingosine kinases (SPHKs). Although phyto-S1P and S1P are known to be signaling components in higher plants, their ability to induce stomatal closure has been ambiguous. We evaluated in detail the effects of phyto-S1P, S1P and SPHK inhibitors on signaling events leading to stomatal closure in the epidermis of Pisum sativum. Phyto-S1P or S1P induced stomatal closure, along with a marked rise in nitric oxide (NO) and cytoplasmic pH of guard cells, as in case of ABA. Two SPHK inhibitors, DL-threo dihydrosphingosine and N',N'-dimethylsphingosine, restricted ABA-induced stomatal closure and prevented the increase of NO or pH by ABA. Modulators of NO or pH impaired both stomatal closure and increase in NO or pH by phyto-S1P/S1P. The stomatal closure by phyto-S1P/S1P was mediated by phospholipase D and phosphatidic acid (PA). When present, PA elevated the levels of pH, but not NO of guard cells. Our results demonstrate that stomatal closure induced by phyto-S1P and S1P depends on rise in pH as well as NO of guard cells. A scheme of signaling events initiated by phyto-S1P/S1P, and converging to cause stomatal closure, is proposed. PMID- 27233508 TI - Child Personality Accounts for Oppositional Defiant Disorder Comorbidity Patterns. PMID- 27233510 TI - Myelomatous meningitis: a case report. PMID- 27233511 TI - Epithelioid haemangioendothelioma infiltrating bone marrow. PMID- 27233509 TI - Gene editing and its application for hematological diseases. AB - The use of precise, rationally designed gene-editing nucleases allows for targeted genome and transcriptome modification, and at present, four major classes of nucleases are being employed: zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), meganucleases (MNs), and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9. Each reagent shares the ability to recognize and bind a target sequence of DNA. Depending on the properties of the reagent, the DNA can be cleaved on one or both strands, or epigenetic changes can be mediated. These novel properties can impact hematological disease by allowing for: (1) direct modification of hematopoietic stem/progenitor cells (HSPCs), (2) gene alteration of hematopoietic lineage committed terminal effectors, (3) genome engineering in non-hematopoietic cells with reprogramming to a hematopoietic phenotype, and (4) transcriptome modulation for gene regulation, modeling, and discovery. PMID- 27233512 TI - Late relapsing mantle cell lymphoma showing preserved sensitivity to single-agent lenalidomide. AB - Mantle cell lymphoma is a hematologic malignancy characterized by poor therapeutic outcomes. Immunomodulatory drugs are a focus of attention in this disease, especially for the elderly and frail patients not able to tolerate the typically intensive therapeutic approaches used in fitter patients. We here present the case of refractory mantle cell lymphoma of the elderly that achieved complete remission following the use of single-agent lenalidomide, and a second complete response to the same regimen on relapse 5 years later. PMID- 27233513 TI - Conversion of glycerol to 1,3-dihydroxyacetone by glycerol dehydrogenase co expressed with an NADH oxidase for cofactor regeneration. AB - OBJECTIVES: To investigate the efficiency of a cofactor regeneration enzyme co expressed with a glycerol dehydrogenase for the production of 1,3 dihydroxyacetone (DHA). RESULTS: In vitro biotransformation of glycerol was achieved with the cell-free extracts containing recombinant GlyDH (glycerol dehydrogenase from Escherichia coli), LDH (lactate dehydrogenase form Bacillus subtilis) or LpNox1 (NADH oxidase from Lactobacillus pentosus), giving DHA at 1.3 g l(-1) (GlyDH/LDH) and 2.2 g l(-1) (GlyDH/LpNox1) with total turnover number (TTN) of NAD(+) recycling of 6039 and 11100, respectively. Whole cells of E. coli (GlyDH-LpNox1) co-expressing both GlyDH and LpNox1 were constructed and converted 10 g glycerol l(-1) to DHA at 0.2-0.5 g l(-1) in the presence of zero to 2 mM exogenous NAD(+). The cell free extract of E. coli (GlyDH-LpNox) converted glycerol (2-50 g l(-1)) to DHA from 0.5 to 4.0 g l(-1) (8-25 % conversion) without exogenous NAD(+). CONCLUSIONS: The disadvantage of the expensive consumption of NAD(+) for the production of DHA has been overcome. PMID- 27233515 TI - Automatic learning of pre-miRNAs from different species. AB - BACKGROUND: Discovery of microRNAs (miRNAs) relies on predictive models for characteristic features from miRNA precursors (pre-miRNAs). The short length of miRNA genes and the lack of pronounced sequence features complicate this task. To accommodate the peculiarities of plant and animal miRNAs systems, tools for both systems have evolved differently. However, these tools are biased towards the species for which they were primarily developed and, consequently, their predictive performance on data sets from other species of the same kingdom might be lower. While these biases are intrinsic to the species, their characterization can lead to computational approaches capable of diminishing their negative effect on the accuracy of pre-miRNAs predictive models. We investigate in this study how 45 predictive models induced for data sets from 45 species, distributed in eight subphyla/classes, perform when applied to a species different from the species used in its induction. RESULTS: Our computational experiments show that the separability of pre-miRNAs and pseudo pre-miRNAs instances is species-dependent and no feature set performs well for all species, even within the same subphylum/class. Mitigating this species dependency, we show that an ensemble of classifiers reduced the classification errors for all 45 species. As the ensemble members were obtained using meaningful, and yet computationally viable feature sets, the ensembles also have a lower computational cost than individual classifiers that rely on energy stability parameters, which are of prohibitive computational cost in large scale applications. CONCLUSION: In this study, the combination of multiple pre-miRNAs feature sets and multiple learning biases enhanced the predictive accuracy of pre-miRNAs classifiers of 45 species. This is certainly a promising approach to be incorporated in miRNA discovery tools towards more accurate and less species-dependent tools. The material to reproduce the results from this paper can be downloaded from http://dx.doi.org/10.5281/zenodo.49754 . PMID- 27233516 TI - The international dimension of drug policy reform in Uruguay. AB - BACKGROUND: In 2013, Uruguay became the first country in the world to legally regulate cannabis from seed to smoke. A growing body of research addresses drug policy reform in Uruguay. However, existing studies have almost completely elided its international dimension, treating the process as exclusively domestic phenomenon. METHODS: To consider the international dimension of drug policy reform in Uruguay, the paper draws on primary and secondary sources such as existing studies, media reports, official documents, parliamentary debates and interviews with stakeholders and policy analysts from Uruguay and elsewhere. RESULTS: The paper shows that, when, and, how international factors and actors contributed to Uruguay's drug policy reform process. Two ways in which the international dimension manifested itself are identified. First, as drug policy debate around the world changed, the context for reforms in Uruguay evolved. This resulted in a rather mixed international reaction to Uruguay's reform proposal. Second, international actors became directly involved in the process. Drug policy experts informed and legitimated cannabis reform and transnational advocates supported campaigning and mobilisation in Uruguay. CONCLUSION: By unearthing the international dimension of Uruguay's drug policy reform, the paper adds a novel perspective to the study of drug policy reform in the Uruguay. PMID- 27233514 TI - The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress. AB - Alterations in the innate inflammatory response may underlie the pathophysiology of psychiatric diseases. Current antipsychotics modulate pro-/anti-inflammatory pathways, but their specific actions on these pathways remain only partly explored. This study was conducted to elucidate the regulatory role of paliperidone (1 mg/kg i.p.) on acute (6 h) and chronic (6 h/day for 21 consecutive days) restraint stress-induced alterations in 2 emerging endogenous anti-inflammatory/antioxidant mechanisms: nuclear factor erythroid-related factor 2 (NRF2)/antioxidant enzymes pathway, and the cytokine milieu regulating M1/M2 polarization in microglia, analyzed at the mRNA and protein levels in prefrontal cortex samples. In acute stress conditions, paliperidone enhanced NRF2 levels, possibly related to phosphoinositide 3-kinase upregulation and reduced kelch-Like ECH-associated protein 1 expression. In chronic conditions, paliperidone tended to normalize NRF2 levels through a phosphoinositide 3-kinase related-mechanism, with no effects on kelch-Like ECH-associated protein 1. Antioxidant response element-dependent antioxidant enzymes were upregulated by paliperidone in acute stress, while in chronic stress, paliperidone tended to prevent stress-induced downregulation of the endogenous antioxidant machinery. However, paliperidone increased transforming growth factor-beta and interleukin-10 in favor of an M2 microglia profile in acute stress conditions, which was also corroborated by paliperidone-induced increased levels of the M2 cellular markers arginase I and folate receptor 2. This latter effect was also produced in chronic conditions. Immunofluorescence studies suggested an increase in the number of microglial cells expressing arginase I and folate receptor 2 in the stressed animals pretreated with paliperidone. In conclusion, the enhancement of endogenous antioxidant/anti-inflammatory pathways by current and new antipsychotics could represent an interesting therapeutic strategy for the future. PMID- 27233517 TI - Active site mapping of Loxosceles phospholipases D: Biochemical and biological features. AB - Brown spider phospholipases D from Loxosceles venoms are among the most widely studied toxins since they induce dermonecrosis, triggering inflammatory responses, increase vascular permeability, cause hemolysis, and renal failure. The catalytic (H12 and H47) and metal-ion binding (E32 and D34) residues in Loxosceles intermedia phospholipase D (LiRecDT1) were mutated to understand their roles in the observed activities. All mutants were identified using whole venom serum antibodies and a specific antibody to wild-type LiRecDT1, they were also analyzed by circular dichroism (CD) and differential scanning calorimetry (DSC). The phospholipase D activities of H12A, H47A, H12A-H47A, E32, D34 and E32A-D34A, such as vascular permeability, dermonecrosis, and hemolytic effects were inhibited. The mutant Y228A was equally detrimental to biochemical and biological effects of phospholipase D, suggesting an essential role of this residue in substrate recognition and binding. On the other hand, the mutant C53A-C201A reduced the enzyme's ability to hydrolyze phospholipids and promote dermonecrosis, hemolytic, and vascular effects. These results provide the basis understanding the importance of specific residues in the observed activities and contribute to the design of synthetic and specific inhibitors for Brown spider venom phospholipases D. PMID- 27233518 TI - Rat Osteosarcoma Cells as a Therapeutic Target Model for Osteoregeneration via Sclerostin Knockdown. AB - There are various conceptually different strategies to improve bone regeneration and to treat osteoporosis, each with distinct inherent advantages and disadvantages. The use of RNA interference strategies to suppress the biological action of catabolic factors or antagonists of osteogenic proteins is promising, and such strategies can be applied locally. They are comparably inexpensive and do not suffer from stability problems as protein-based approaches. In this study, we focus on sclerostin, encoded by the SOST gene, a key regulator of bone formation and remodeling. Sclerostin is expressed by mature osteocytes but also by late osteogenically differentiated cells. Thus, it is difficult and requires long-term cultures to investigate the effects of SOST silencing on the expression of osteogenic markers using primary cells. We, therefore, selected a rat osteosarcoma cell line, UMR-106, that has been shown to express SOST and secrete sclerostin in a comparable fashion as late osteoblasts and osteocytes. We investigated the effects of differentiating supplements on SOST expression and sclerostin secretion in UMR-106 cells and found that addition of 100 ng/ml of bone morphogenetic protein (BMP)-2 strongly induced sclerostin secretion, whereas dexamethasone inhibited secretion. Effects of silencing SOST in UMR-106 cells cultured in various differentiation media including BMP-2 and/or dexamethasone were determined next with the aim to find promising test conditions for a readout system for the evaluation of future small interfering RNA release formulations for local induction of bone formation. We found a direct correlation between attenuated SOST expression and an increase in the osteogenic potential of UMR-106 cells. The combination of SOST silencing and BMP-2 could synergistically improve osteogenic factors. A lowered proliferation rate in silenced groups may indicate a faster switch to differentiation. PMID- 27233519 TI - Voltage-Gated Ion Channels in the PNS: Novel Therapies for Neuropathic Pain? AB - Neuropathic pain arises from injury to the nervous system. Conditions associated with neuropathic pain are diverse, and lesions and/or pathological changes in the central nervous system (CNS) or peripheral nervous system (PNS) can frequently, but not always, be identified. It is difficult to treat, with patients often on multiple, different classes of medications, all with appreciable adverse side effect profiles. Consequently, there is a pressing need for the development of new medications. The development of such therapeutics is predicated on a clear understanding of the relevant molecular and cellular processes that contribute to the development, and maintenance, of the neuropathic pain state. One proposed mechanism thought to contribute to the ontogeny of neuropathic pain is altered expression, trafficking, and functioning of ion channels expressed by primary sensory neurons. Here, we will focus on three voltage-gated ion channel families, CaV, HCN, and NaV, first reviewing the preclinical data and then the human data where it exists. PMID- 27233520 TI - Health Disparities Influence Childhood Melanoma Stage at Diagnosis and Outcome. AB - OBJECTIVE: To identify health disparities in pediatric patients with melanoma that affect disease presentation and outcome. STUDY DESIGN: This was a retrospective cohort study of all persons aged <=18 years diagnosed with melanoma and enrolled in the Texas Cancer Registry between 1995 and 2009. Socioeconomic status (SES) and driving distance to the nearest pediatric cancer treatment center were calculated for each patient. Logistic regression was used to determine factors associated with advanced-stage disease. Life table methods and Cox regression were used to estimate survival probability and hazard ratios. RESULTS: A total of 185 adolescents (age >10 years) and 50 young children (age <=10 years) were identified. Hispanics (n = 27; 12%) were 3 times more likely than non-Hispanic whites (n = 177; 75%) to present with advanced disease (OR, 3.8; 95% CI, 1.7-8.8). Young children were twice as likely as adolescents to present with advanced disease (OR, 2.2; 95% CI, 1.1-4.3). Distance to treatment center and SES did not affect stage of disease at presentation. Hispanics and those in the lowest SES quartile had a significantly higher mortality risk (hazard ratios, 3.0 [95% CI, 1.2-7.8] and 4.3 [95% CI, 1.4-13.9], respectively). In the adjusted survival model, only advanced disease was predictive of mortality (P < .001). CONCLUSION: Hispanics and young children with melanoma are more likely to present with advanced disease, and advanced disease is the single most important predictor of survival. Heightened awareness among physicians is needed to facilitate early detection of melanoma within these groups. PMID- 27233522 TI - Hospitalizations with Lower Respiratory Tract Infections among American Indian and Alaska Native Children Under Age 5 Years: The Use of Non-Federal Hospital Discharge Data to Analyze Rates. PMID- 27233523 TI - Reducing Racial and Ethnic Disparities in Childhood and Adolescent Obesity: Behavior Matters. PMID- 27233524 TI - Cardiac Magnetic Resonance Imaging in Pediatric Turner Syndrome. AB - OBJECTIVE: To compare the detection of cardiac lesions with the use of cardiac magnetic resonance imaging (CMR) and conventional echocardiography in children with Turner syndrome. STUDY DESIGN: Twenty-four girls with Turner syndrome, 8-18 years of age, were recruited through the Pediatric Endocrinology Program. Participants underwent CMR and echocardiography within a 2-year period, and discrepancies between the results of each modality were identified. RESULTS: Fifteen of 24 (63%) girls had a cardiac lesion identified on CMR or echocardiography. Both modalities identified the same lesion in 10 of 15 (67%); however, 6 of 15 (40%) participants had a lesion identified on CMR but not echocardiography. Participants with a missed lesion had a trend towards greater body mass index. Aortic dilation and bicuspid aortic valve were the most commonly missed lesions by echocardiography. CONCLUSIONS: CMR identifies significant cardiac lesions missed by echocardiography in pediatric patients with Turner syndrome, particularly along the aorta. These findings support the current guidelines that recommend screening CMR in addition to echocardiogram. Early identification of cardiac abnormalities in patients with Turner syndrome will allow for a greater understanding of the natural history in these patients and potentially identify candidates for earlier intervention. PMID- 27233525 TI - Self-patterning porous films of giant vesicles of {Mo72Fe30}(DODMA)3 complexes as frameworks. AB - This work describes the preparation and properties of self-patterning porous films consisting of giant vesicles formed by a 2.5-nm-diameter, polyoxometalate (POM) cluster {Mo72Fe30} macroanion, and a double-tailed cationic surfactant dimethyldistearylammonium bromide (DODMABr) in CHCl3-CH3OH mixture solvent (VCHCl3: VCH3OH=3:1). These inverse vesicles with the diameter in the range of 0.45~1.3MUm in organic solution and the porous films consisting of the giant vesicles of the {Mo72Fe30}(DODMA)3 complexes were characterized by SEM, TEM, XPS and AFM observations. Self-patterning of these giant vesicles into porous films that are highly ordered honeycomb films on solid surfaces can survive drying as the frameworks are firstly studied in detail. Water contact angle measurements proved that the porous films of {Mo72Fe30}(DODMA)3 vesicles were endowed hydrophobic property from the hydrophilic surface. This porous film materials consisting of giant vesicles may be promising new options in many fields like photoelectrochemistry, sterilization, template, catalysis, in-situ synthesis. PMID- 27233527 TI - Details of junior doctor contract are published. PMID- 27233526 TI - Fractal-like structures in colloid science. AB - The present work aims at reviewing our current understanding of fractal structures in the frame of colloid aggregation as well as the possibility they offer to produce novel structured materials. In particular, the existing techniques to measure and compute the fractal dimension df are critically discussed based on the cases of organic/inorganic particles and proteins. Then the aggregation conditions affecting df are thoroughly analyzed, pointing out the most recent literature findings and the limitations of our current understanding. Finally, the importance of the fractal dimension in applications is discussed along with possible directions for the production of new structured materials. PMID- 27233528 TI - Association of serum pentraxin 3 concentrations with diabetic nephropathy. AB - Pentraxin 3 (PTX3), a member of a superfamily of conserved proteins, attenuates renal damage in diabetic mice. This study aims to determine whether serum PTX3 concentrations are correlated with the presence of diabetic nephropathy (DN). A total of 160 patients with type 2 diabetes mellitus (T2DM) and 54 healthy subjects were enrolled in this study. Patients with T2DM were divided into three groups in accordance with the levels of urinary albumin excretion (UAE). Serum PTX3 concentrations were determined using an ELISA kit. Serum PTX3 concentrations were significantly higher in patients with T2DM compared with the controls. Patients with T2DM with macroalbuminuria showed higher serum PTX3 concentrations compared with the other three groups. However, there were no significant differences of serum PTX3 concentrations between patients with T2DM with normoalbuminuria and microalbuminuria. Furthermore, a simple regression analysis has shown that serum PTX3 concentrations in patients with T2DM were negatively correlated with body mass index, and positively correlated with blood urea nitrogen, serum creatinine, and UAE. Serum PTX3 concentrations are correlated with DN. PMID- 27233530 TI - Duration of Venodilation for Peripheral Intravenous Cannulation, as Induced by a Thermal Stimulus on the Forearm. AB - BACKGROUND: Application of a thermal stimulus is a common procedure used to promote venodilation for peripheral intravenous cannulation (PIVC); however, the effects of thermal stimulation on the duration of venodilation and skin temperature of the forearm are unclear. AIM: To investigate the duration of venodilation induced by a thermal stimulus on the forearm. METHOD: Healthy female adults ( N = 40) from Japan participated in this study from November to December 2013. A heat pack was warmed to 40 degrees C +/- 2 degrees C and placed over the forearm for 15 min. Vein diameter was measured via ultrasound and skin temperature via temperature sensor at six time points: before application of the thermal stimulus and at 1-min intervals for 5 min upon removal of the thermal stimulus. The main outcomes were vein diameter, proportional change in vein diameter, and skin temperature. We calculated proportional change in vein diameter after application of the thermal stimulus using vein diameter before the thermal stimulus to represent 100%. RESULTS: Compared with vein diameter before thermal stimulus, the diameter at each time point after thermal stimulus was significantly increased ( p < .05) as were proportional change in vein diameter ( p < .05) and skin temperature. CONCLUSION: A thermal stimulus of 40 degrees C +/- 2 degrees C on the forearm dilated veins significantly for PIVC, and the effect persisted for at least 5 min. PMID- 27233529 TI - Endosperm and Nucellus Develop Antagonistically in Arabidopsis Seeds. AB - In angiosperms, seed architecture is shaped by the coordinated development of three genetically different components: embryo, endosperm, and maternal tissues. The relative contribution of these tissues to seed mass and nutrient storage varies considerably among species. The development of embryo, endosperm, or nucellus maternal tissue as primary storage compartments defines three main typologies of seed architecture. It is still debated whether the ancestral angiosperm seed accumulated nutrients in the endosperm or the nucellus. During evolution, plants shifted repeatedly between these two storage strategies through molecular mechanisms that are largely unknown. Here, we characterize the regulatory pathway underlying nucellus and endosperm tissue partitioning in Arabidopsis thaliana We show that Polycomb-group proteins repress nucellus degeneration before fertilization. A signal initiated in the endosperm by the AGAMOUS-LIKE62 MADS box transcription factor relieves this Polycomb-mediated repression and therefore allows nucellus degeneration. Further downstream in the pathway, the TRANSPARENT TESTA16 (TT16) and GORDITA MADS box transcription factors promote nucellus degeneration. Moreover, we demonstrate that TT16 mediates the crosstalk between nucellus and seed coat maternal tissues. Finally, we characterize the nucellus cell death program and its feedback role in timing endosperm development. Altogether, our data reveal the antagonistic development of nucellus and endosperm, in coordination with seed coat differentiation. PMID- 27233531 TI - Creating cellular patterns using genetically engineered, gold- and cell-binding polypeptides. AB - Patterning cells on material surfaces is an important tool for the study of fundamental cell biology, tissue engineering, and cell-based bioassays. Here, the authors report a simple approach to pattern cells on gold patterned silicon substrates with high precision, fidelity, and stability. Cell patterning is achieved by exploiting adsorbed biopolymer orientation to either enhance (gold regions) or impede (silicon oxide regions) cell adhesion at particular locations on the patterned surface. Genetic incorporation of gold binding domains enables C terminal chemisorption of polypeptides onto gold regions with enhanced accessibility of N-terminal cell binding domains. In contrast, the orientation of polypeptides adsorbed on the silicon oxide regions limit the accessibility of the cell binding domains. The dissimilar accessibility of cell binding domains on the gold and silicon oxide regions directs the cell adhesion in a spatially controlled manner in serum-free medium, leading to the formation of well-defined cellular patterns. The cells are confined within the polypeptide-modified gold regions and are viable for eight weeks, suggesting that bioactive polypeptide modified surfaces are suitable for long-term maintenance of patterned cells. This study demonstrates an innovative surface-engineering approach for cell patterning by exploiting distinct ligand accessibility on heterogeneous surfaces. PMID- 27233521 TI - Neonatal Outcomes of Very Low Birth Weight and Very Preterm Neonates: An International Comparison. AB - OBJECTIVE: To compare rates of a composite outcome of mortality or major morbidity in very-preterm/very low birth weight infants between 8 members of the International Network for Evaluating Outcomes. STUDY DESIGN: We included 58 004 infants born weighing <1500 g at 24(0)-31(6) weeks' gestation from databases in Australia/New Zealand, Canada, Israel, Japan, Spain, Sweden, Switzerland, and the United Kingdom. We compared a composite outcome (mortality or any of grade >=3 peri-intraventricular hemorrhage, periventricular echodensity/echolucency, bronchopulmonary dysplasia, or treated retinopathy of prematurity) between each country and all others by using standardized ratios and pairwise using logistic regression analyses. RESULTS: Despite differences in population coverage, included neonates were similar at baseline. Composite outcome rates varied from 26% to 42%. The overall mortality rate before discharge was 10% (range: 5% [Japan]-17% [Spain]). The standardized ratio (99% CIs) estimates for the composite outcome were significantly greater for Spain 1.09 (1.04-1.14) and the United Kingdom 1.16 (1.11-1.21), lower for Australia/New Zealand 0.93 (0.89 0.97), Japan 0.89 (0.86-0.93), Sweden 0.81 (0.73-0.90), and Switzerland 0.77 (0.69-0.87), and nonsignificant for Canada 1.04 (0.99-1.09) and Israel 1.00 (0.93 1.07). The adjusted odds of the composite outcome varied significantly in pairwise comparisons. CONCLUSIONS: We identified marked variations in neonatal outcomes between countries. Further collaboration and exploration is needed to reduce variations in population coverage, data collection, and case definitions. The goal would be to identify care practices and health care organizational factors, which has the potential to improve neonatal outcomes. PMID- 27233532 TI - Perspectives on the use of biomaterials to store platelets for transfusion. AB - Platelets are routinely stored enabling transfusions for a range of conditions. While the current platelet storage bags, composed of either polyvinylchloride or polyolefin, are well-established, the storage of platelets in these bags beyond 7 days reduces platelet viability below clinically usable levels. New materials and coatings that promote platelet respiration while not supporting platelet adhesion or activation have started to emerge, with the potential to enable platelet storage beyond 7 days. This review focuses on the literature describing currently used biomaterials for platelet storage and emerging materials that are showing promise for improving platelet storage. PMID- 27233533 TI - Comprehensive in vitro Proarrhythmia Assay (CiPA): Pending issues for successful validation and implementation. AB - INTRODUCTION: The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a nonclinical Safety Pharmacology paradigm for discovering electrophysiological mechanisms that are likely to confer proarrhythmic liability to drug candidates intended for human use. TOPICS COVERED: Key talks delivered at the 'CiPA on my mind' session, held during the 2015 Annual Meeting of the Safety Pharmacology Society (SPS), are summarized. Issues and potential solutions relating to crucial constituents [e.g., biological materials (ion channels and pluripotent stem cell derived cardiomyocytes), study platforms, drug solutions, and data analysis] of CiPA core assays are critically examined. DISCUSSION: In order to advance the CiPA paradigm from the current testing and validation stages to a research and regulatory drug development strategy, systematic guidance by CiPA stakeholders is necessary to expedite solutions to pending and newly arising issues. Once a study protocol is proved to yield robust and reproducible results within and across laboratories, it can be implemented as qualified regulatory procedure. PMID- 27233534 TI - Application of SV40 T-transformed human corneal epithelial cells to evaluate potential irritant chemicals for in vitro alternative eye toxicity. AB - Assessment of eye irritation potential is important to human safety, and it is necessary for various cosmetics and chemicals that may contact the human eye. Until recently, the Draize test was considered the standard method for estimating eye irritation, despite its disadvantages such as the need to sacrifice many rabbits for subjective scoring. Thus, we investigated the cytotoxicity and inflammatory response to standard eye irritants using SV40 T-transformed human corneal epithelial (SHCE) cells as a step toward development of an animal-free alternative eye irritation test. MTT and NRU assays of cell viability were performed to investigate the optimal experimental conditions for SHCE cell viability when cells were exposed to sodium dodecyl sulfate (SDS) as a standard eye irritant at 6.25*10(-3) to 1*10(-1)%. Additionally, cell viability of SHCE cells was examined in response to six potential eye irritants, benzalkonium chloride, dimethyl sulfoxide, isopropanol, SDS, Triton X-100 and Tween 20 at 5*10(-3) to 1*10(-1)%. Finally, we estimated the secretion level of cytokines in response to stimulation by eye irritants in SHCE cells. SHCE cells showed a good response to potential eye irritants when the cells were exposed to potential irritants for 10min at room temperature (RT), and cytokine production increased in a concentration-dependent manner, indicating that cytotoxicity and cytokine secretion from SHCE cells may be well correlated with the concentrations of irritants. Taken together, these results suggest that SHCE cells could be an excellent alternative in vitro model to replace in vivo animal models for eye irritation tests. PMID- 27233577 TI - Functional roles of the fatty acid desaturases encoded by KlOLE1, FAD2 and FAD3 in the yeast Kluyveromyces lactis. AB - Functional properties of cell membranes depend on their composition, particularly on the relative amount of saturated, unsaturated and polyunsaturated fatty acids present in the phospholipids. The aim of this study was to investigate the effect of cell membrane composition on cell fitness, adaptation and stress response in Kluyveromyces lactis. To this purpose, we have deleted the genes FAD2 and FAD3 encoding Delta12 and omega3 desaturases in Kluyveromyces lactis, thus generating mutant strains with altered fatty acid composition of membranes. These strains were viable and able to grow in stressing conditions like hypoxia and low temperature. Deletion of the Delta9 desaturase-encoding gene KlOLE1 resulted in lethality, suggesting that this enzyme has an essential role in this yeast. Transcription of the desaturase genes KlOLE1, FAD2 and FAD3 and cellular localization of the corresponding enzymes, have been studied under hypoxia and cold stress. Our findings indicate that expression of these desaturase genes and membrane composition were modulated by hypoxia and temperature stress, although the changes induced by these and other assayed conditions did not dramatically affect the general cellular fitness. PMID- 27233578 TI - Analysis of tissue from products of conception and perinatal losses using QF-PCR and microarray: A three-year retrospective study resulting in an efficient protocol. AB - OBJECTIVE: To evaluate the performance of a laboratory protocol for direct genetic analysis performed on tissues obtained from miscarriages, stillbirth and postnatal death. METHODS: Samples were collected between July 1st, 2011 and June 30th, 2014. QF-PCR analysis was the initial test followed by aCGH analysis performed on the normal QF-PCR specimens. RESULTS: Of the 1195 submitted specimens, a total of 1071 samples were confirmed as true fetal. The failure rate was 1.4%. Of those, 30.8% yielded abnormal results. Of the latter, 57.6% had abnormal QF-PCR and 42.4% had abnormal microarray result. Autosomal trisomies were detected in 61.2%, triploidy in 7.6%, monosomy X in 9.1%, sex-chromosome aneuploidy (apart from monosomy X) in 1.5%, molar pregnancies in 5.8% and copy number variants in 14.2% including microdeletions/microduplications and cryptic unbalanced rearrangements. The highest diagnostic yield was observed in the 1st trimester specimens at 67.6%. We confirmed that maternal age correlates with the likelihood of autosomal trisomies but not with triploidy, sex chromosome aneuploidies, molar pregnancy, or CNVs. CONCLUSION: An efficient laboratory protocol, based on QF-PCR and aCGH of uncultured cells has replaced standard cytogenetic analysis in testing of tissue from all pregnancy losses in our center and resulted in reduced test failure rate and increased diagnostic yield. PMID- 27233579 TI - Neurotropin attenuates local inflammatory response and inhibits demyelination induced by chronic constriction injury of the mouse sciatic nerve. AB - Neuropathic pain caused by nerve damage in the central and/or peripheral nervous systems is a refractory disorder and the management of such chronic pain has become a major issue. Neurotropin is a drug widely used in Japan and China to treat chronic pain. Although Neurotropin has been demonstrated to suppress chronic pain through the descending pain inhibitory system, the mechanism of analgesic action in the peripheral nervous system remains to be elucidated. In this study, we investigated the local effects of Neurotropin on peripheral nerve damage in a chronic constriction injury (CCI) model. Neurotropin reduced mRNA expressions of IL-1beta, IL-6, and TNF-alpha in the sciatic nerve 1 day after the injury. Activation of Erk was also inhibited locally in the Neurotropin treatment group. Since Erk activation results in demyelination along with dedifferentiation of Schwann cells, we investigated the expression level of myelin basic protein. Five days after the injury, Neurotropin attenuated the downregulation of myelin basic protein in the sciatic nerve in the CCI model. Local effects of Neurotropin around the injury site may result in discovery of new treatments for not only neuropathic pain but also demyelinating diseases and peripheral nervous system injury. PMID- 27233580 TI - Corrigendum to "Evaluation and comparison of three different separation techniques for analysis of retroamide enantiomers and their biological evaluation against h-P2X7 receptor" [J. Chromatogr. B 986-987 (2015) 35-43]. PMID- 27233581 TI - Development of a rapid RP-UHPLC-MS method for analysis of modifications in therapeutic monoclonal antibodies. AB - Chemical or enzymatic modifications of therapeutic monoclonal antibodies (MAbs) that have high risk to safety and efficacy are defined as critical quality attributes (CQAs). During therapeutic MAbs process development, thorough characterization and quantitative monitoring of CQAs requires a variety of analytical techniques. This paper describes the development of a rapid analytical method to assess modifications in MAbs, based on the analysis of subdomains with molecular weights of ~25kDa. These subdomains were generated by digestion with a highly specific IdeS protease, followed by disulfide bond reduction. A reversed phase UHPLC-MS method was developed that provides efficient separation and identification of the subdomains (Fc, LC, and Fd) and related variants within 10min. Sample preparation and UHPLC instrument parameters were systematically evaluated. The methodology was applied to MAb stress panel characterization to capture the degradations induced by various stress conditions. Among the CQAs monitored by this method, Fc oxidation levels were compared with the values obtained by the more complicated and time-consuming peptide mapping method. The similar trends observed by the two methods demonstrated that the IdeS-UHPLC method is valuable as a higher throughput alternative to peptide mapping for monitoring modifications. In particular, a high-throughput methodology is preferred for analysis of the many samples associated with process development studies. Overall the method has been demonstrated as a fast, convenient and informative platform approach for analysis of therapeutic MAbs modifications including CQAs. PMID- 27233582 TI - Temperature Changes on External Root Surfaces with the Use of Several Thermoplastic Filling Techniques. AB - INTRODUCTION: The purpose of this study was to measure the temperature rise on the external root surface of filled root canals using Touch'n Heat (Analytic Endodontics, Orange, CA), the TC System (TC; Tanaka de Castro & Minatel Ltda, Cascavel, PR, Brazil), and the Tagger technique. METHODS: Forty-five single-canal mandibular premolar human teeth were used in the 3 experimental groups. The root canals were enlarged to accommodate up to an R40 Reciproc file (VDW, Munich, Germany). Next, the specimens were filled according to the technique evaluated. The measurement of the temperature was performed by K chromium-aluminum thermocouples attached to the coronal, middle, and apical root levels. RESULTS: There was a significant difference among the 3 techniques (P < .001) in relation to the temperature variation between the highest temperature and the initial temperature. The highest temperature change was found with the Tagger technique at the middle third root level (11.8 degrees C), and the lowest variation was in TC at the cervical third (2.05 degrees C). CONCLUSIONS: There was a rise of temperature on the external root surface for all of the techniques evaluated. TC showed the lowest temperature rise. PMID- 27233583 TI - Stability of the Effect of a Standardized Meal on QTc. AB - BACKGROUND: The assessment of QTc changes after the intake of a standardized meal has been proposed as an alternative approach to prove assay sensitivity when the proarrhythimic potential of a drug is to be excluded in either TQT or intensive Phase I QT studies. METHODS: In this article, an analysis of the food effect at baseline across periods in two different studies is presented to support the robustness of the method. RESULTS: The results show that the time-effect attributed to food is stable over different study periods demonstrating consistency of the physiological response triggered by food. CONCLUSIONS: Stability and reproducibility of the effect is comparable with moxifloxacin. PMID- 27233584 TI - The role of corneal endothelial morphology in graft assessment and prediction of endothelial cell loss during organ culture of human donor corneas. AB - PURPOSE: Endothelial assessment is crucial in the release of corneas for grafting. We retrospectively analysed the role of endothelial morphology parameters in predicting endothelial cell loss during organ culture. METHODS: Human donor corneas were cultured in minimal essential medium with 2% fetal calf serum and antibiotics. Initial endothelial morphology was assessed microscopically using score parameters polymegethism (POL), pleomorphism (PLE), granulation (GRA), vacuolization (VAC), segmentation of cell membranes (SEG), Descemet's folds (DF), trypan blue-positive cells (TBPC) and endothelial cell free areas (ECFA). Some corneas were primarily rejected based on endothelial assessment. Endothelial cell density (ECD) was assessed at the beginning (I-ECD) and end of culture. Corneas were then placed in dehydration medium (as above + 5% dextran 500). In a subgroup, ECD was reassessed after dehydration. Endothelial cell loss during culture (ECL@Culture) and culture+dehydration (ECL Culture&Dehydration) were calculated. Data were given as mean +/- SD and analysed using multiple linear and logistic regression. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. RESULT: I-ECD was 2812 +/- 360/mm2 (n = 2356). The decision to reject a cornea due to endothelial assessment was associated negatively with I-ECD (OR = 0.77/100 cells, CI 0.7-0.82) and positively with ECFA (OR = 2.7, CI 1.69-4.35), SEG (OR =1.3, CI 1.01-1.68) and donor age (OR = 1.26/decade, CI 1.33-1.41). ECL@Culture was 153 +/- 201/mm2 (n = 1277), ECL@Culture&Dehydration was 169 +/- 183/mm2 (n = 918). ECL@Culture was associated positively with donor age, I-ECD, GRA and TBPC, and negatively with PLE, and DF. ECL@Culture&Dehydration was associated positively with age, sex, initial ECD, POL, PLE, VAC and TBPC. CONCLUSION: Morphological parameters displayed associations with the exclusion of corneas from culture and with endothelial cell loss. Appropriate parameter selection for screening purposes may help improve graft quality. PMID- 27233585 TI - Multicenter Survey of the Effects of Rehabilitation Practices on Pinch Force Strength After Tendon Transfer to Restore Pinch in Tetraplegia. AB - OBJECTIVE: To identify key components of conventional therapy after brachioradialis (BR) to flexor pollicis longus (FPL) transfer, a common procedure to restore pinch strength, and evaluate whether any of the key components of therapy were associated with pinch strength outcomes. DESIGN: Rehabilitation protocols were surveyed in 7 spinal cord injury (SCI) centers after BR to FPL tendon transfer. Key components of therapy, including duration of immobilization, participation, and date of initiating therapy activities (mobilization, strengthening, muscle reeducation, functional activities, and home exercise), were recorded by the patient's therapist. Pinch outcomes were recorded with identical equipment at 1-year follow-up. SETTING: Seven SCI rehabilitation centers where the BR to FPL surgery is performed on a routine basis. PARTICIPANTS: Thirty-eight arms from individuals with C5-7 level SCI injury who underwent BR to FPL transfer surgery (N=34). INTERVENTION: Conventional therapy according to established protocol in each center. MAIN OUTCOME MEASURES: The frequency of specific activities and their time of initiation (relative to surgery) were expressed as means and 95% confidence intervals. Outcome measures included pinch strength and the Canadian Occupational Performance Measure (COPM). Spearman rank-order correlations determined significant relations between pinch strength and components of therapy. RESULTS: There was similarity in the key components of therapy and in the progression of activities. Early cast removal was associated with pinch force (Spearman rho=-.40, P=.0269). Pinch force was associated with improved COPM performance (Spearman rho=.48, P=.0048) and satisfaction (Spearman rho=.45, P=.0083) scores. CONCLUSIONS: Initiating therapy early after surgery is beneficial after BR to FPL surgery. Postoperative therapy protocols have the potential to significantly influence the outcome of tendon transfers after tetraplegia. PMID- 27233586 TI - Early Active Rehabilitation After Grip Reconstructive Surgery in Tetraplegia. AB - OBJECTIVE: To describe and evaluate the concept of early active rehabilitation after tendon transfer to restore grip function in tetraplegia. DESIGN: Retrospective cohort study. SETTING: Two nonprofit rehabilitation units in Sweden and Switzerland. PARTICIPANTS: All patients with tetraplegia who underwent tendon transfer to restore grip ability during 2009 to 2013 (N=49). INTERVENTION: Reconstructive tendon transfer surgery with early active rehabilitation to restore grip ability in tetraplegia. MAIN OUTCOME MEASURES: Grip and pinch strength, grip ability test, and outcome of prioritized activities. RESULTS: In the 49 surgeries performed, postoperative complications included 2 patients with bleeding and 2 infections related to the surgery. There were no reported ruptures or lengthening of transferred tendons. Within 24 hours after surgery, all 47 patients (100%) with finger flexion reconstruction succeeded to activate their finger flexion. All but 1 patient with reconstructed thumb flexion sucessfully activated their thumb flexion (n=40). Three weeks after surgery, all patients (100%) were able to perform basic activities of daily living, and instrumental activities of daily living were achieved by 74%. One year after surgery, the maximum grip strength in restored finger flexion was on average 6.9kg (range, 1.5 15kg; n=29). The maximum pinch strength in restored thumb flexion was on average 3.7kg (range, 1-20; n=29). On average, grip ability improved from 33 to 101 (n=19) according to the COPM. Prioritized activity limitations, as measured with the COPM, equated to an average of 3.5 steps (2.5 steps preoperatively to 6 steps postoperatively). Patients' perceived satisfaction with this improvement was 4 steps (increasing from 2 steps preoperatively to 6 steps postoperatively). CONCLUSIONS: Grip reconstructive surgery followed by early active rehabilitation can be considered a reliable procedure that leads to substantial improvements in grip and pinch strength and activity performance among patients with tetraplegia. PMID- 27233587 TI - Rehabilitation After Posterior Deltoid to Triceps Transfer in Tetraplegia. AB - OBJECTIVE: To describe and evaluate the rehabilitation concept after posterior deltoid to triceps transfer in patients with tetraplegia. DESIGN: Retrospective observational study. SETTING: Rehabilitation units. PARTICIPANTS: Patients with tetraplegia who had posterior deltoid to triceps tendon transfer and had muscle strength measurements 1 year postsurgery from 2009 to 2013 (N=44). INTERVENTIONS: Posterior deltoid to triceps tendon transfer to restore elbow extension and postoperative rehabilitation. MAIN OUTCOME MEASURES: Elbow extension range of motion and muscle strength and the modified Canadian Occupational Performance Measure (COPM). RESULTS: Surgery was performed on 53 arms. No major complications (eg tendon rupture, lengthening) were reported. Muscle strength measured 1 year after surgery was on average grade 3 (out of 5) in the 53 operated arms. The ability to extend the elbow against gravity was achieved in 62% of the arms (muscle strength of grade >=3). In patients with a preoperative elbow extension deficit (n=14), the deficit was reduced on average from 16 degrees to 9 degrees . The performance of the prioritized activities as measured with the COPM improved on average 2.6 scale steps, from 3.3 to 5.9. Satisfaction with the performance improved on average 3.2 scale steps, from 2.8 to 6.0. CONCLUSIONS: The posterior deltoid to triceps tendon transfer with the applied rehabilitation protocol is a safe and effective procedure. There were no tendon ruptures, and all patients were able to complete the rehabilitation protocol. The shorter restriction time after surgery allows the patient to be independent at an earlier stage of the rehabilitation and reduces hospitalization or care burden. PMID- 27233588 TI - Rehabilitation After Spasticity-Correcting Upper Limb Surgery in Tetraplegia. AB - OBJECTIVE: To describe the early active rehabilitation concept developed for spasticity-correcting surgery in tetraplegia and to report the outcomes in grip ability and change of performance and satisfaction in patients' prioritized activities 1 year postoperatively. DESIGN: Retrospective case-control study. SETTING: Nonprofit rehabilitation unit. PARTICIPANTS: All patients who underwent surgeries for correction of spasticity in tetraplegic hands between 2009 and 2013 in the studied unit (N=37). INTERVENTIONS: Spasticity-correcting upper limb surgery with early active rehabilitation to restore grip ability in tetraplegia. MAIN OUTCOME MEASURES: Grasp and release test (GRT) and modified Canadian Occupational Performance Measure (COPM). RESULTS: All patients could accomplish the early active rehabilitation concept. The complication rate related to the treatment was low. Compared with preoperatively, all evaluated individuals experienced improvements in grasp ability and activity performance and satisfaction at 1-year follow-up. The performance in prioritized activities, as measured by the COPM, improved by 2.6 scale steps. Satisfaction with performance improved 3.0 scale steps postoperatively (n=21). The grasp ability, measured by the GRT, improved significantly, from 80 preoperatively to 111 (n=10). CONCLUSIONS: The surgery, combined with the early active rehabilitation protocol, is a reliable and safe procedure. The ability to use the hand improved, and gains were maintained at least 1 year after surgery in all patients with respect to both the objective grasp ability and patients' subjective rating of their performance and satisfaction in their prioritized activities. The procedure should therefore be considered as an adjunct to other treatments of upper limb spasticity in spinal cord injury. PMID- 27233589 TI - Evaluation of a Task-Based Intervention After Tendon Transfer to Restore Lateral Pinch. AB - OBJECTIVE: To quantify changes in pinch force and brachioradialis (BR) activation after a task-based training program designed to improve pinch force after BR to flexor pollicis longus (FPL) transfer. DESIGN: One-group repeated-measures design compared pinch force and BR activation pre- and posttraining. Significant differences were tested with Wilcoxon signed-rank tests for pairwise comparisons at the P<=.05 level. SETTING: Testing occurred in a Veterans Affairs Medical Center research laboratory and training was in a home setting. PARTICIPANTS: Participants with cervical spinal cord injury (SCI) and previous BR to FPL transfer were enrolled in the study (N=8). Six patients completed the training program and posttraining measures. INTERVENTIONS: The 10-week training was a home program that included novel activities to increase BR activation and practice producing pinch force in a variety of upper limb postures. Participants were provided with the task-based training equipment and instructed to practice 3 times per week. MAIN OUTCOME MEASURES: Fine-wire electromyography of the transferred BR was recorded in maximum effort pinch force (N). Secondary measures included the strength and activation of the antagonist elbow extensor. RESULTS: Pinch force increased 3.7N (.38kg) and BR muscle activation increased 10% (P<=.05) after the training. There was no increase in elbow extension strength, but participants with previous posterior deltoid to triceps transfer achieved greater activation of the antagonist elbow extensor. CONCLUSIONS: The findings from this pilot study suggest that outcomes of tendon transfer and conventional therapy can be improved for patients with chronic cervical SCI. PMID- 27233590 TI - Role of Functional Electrical Stimulation in Tetraplegia Hand Surgery. AB - The use of functional electrical stimulation (FES) to improve upper limb function is an established method in the rehabilitation of persons with tetraplegia after spinal cord injury. Surgical reconstruction is another well-established yet underused technique to improve the performance of the upper extremities. Hand surgery plays an essential role in restoring hand function, mobility, and quality of life in the tetraplegic population. The knowledge about the effects of FES on a structural and functional level is fundamental for understanding how and when FES can be used best to support the effect of hand surgery, both pre- and postoperatively. In this article we discuss principles of FES and how FES improves functional outcome after surgical reconstruction. The reported results are based on preliminary clinical observations. PMID- 27233591 TI - Rehabilitation of Supinator Nerve to Posterior Interosseous Nerve Transfer in Individuals With Tetraplegia. AB - Despite being a routine part of the early surgical management of brachial plexus injury, nerve transfers have only recently been used as a reconstructive option for those with tetraplegia. Subsequently, there is limited published literature on the rehabilitation theories and techniques for optimizing outcomes in this population. This article seeks to address this void by presenting our centers' working model for rehabilitation after nerve transfers for individuals with tetraplegia. The model is illustrated with the example of the rehabilitation process after a supinator nerve to posterior interosseous nerve transfer. This nerve transfer reconstructs wrist, finger, and thumb extension. The topics covered in the model include the following: patient selection and presurgical planning/intervention, managing the postoperative healing phase of an individual who is wheelchair dependent, maximizing motor reeducation, increasing muscle strength, and ensuring use in functional tasks. This article provides a platform for further development and collaboration to improve the outcomes of patients who undergo nerve transfers after tetraplegia. PMID- 27233592 TI - Measurement of Outcomes of Upper Limb Reconstructive Surgery for Tetraplegia. AB - Reconstructive arm/hand surgery for tetraplegia is performed to improve arm/hand function and therefore personal well-being for individuals who accept such elective surgeries. However, changes at an impairment level do not always translate into functional or quality of life changes. Therefore, multiple outcome tools should be used that incorporate sufficient responsiveness to detect changes in arm/hand function, activity and participation, and quality of life of the individuals involved. This narrative review aims to assist clinicians to choose the most appropriate tools to assess the need for reconstructive surgery and to evaluate its outcomes. Our specific objectives are (1) to describe aspects to consider when choosing a measure and (2) to describe the measures advised by an international therapist consensus group established in 2007. All advised measures are appraised in terms of the underlying construct, administration, and clinical relevance to arm/hand reconstructions. Essentially there are currently no criterion standard measures to evaluate the consequences of reconstructive arm/hand surgery. However, with judicious use of available measures it is possible to ensure the questions asked or tasks completed are relevant to the surgical reconstruction(s) undertaken. Further work in this field is required. This would be best met by immediate collaboration between 2 outcome's tool developers and by analysis of pre- and postoperative data already held in various international sites, which would allow further evaluation of the measures already in use, or components thereof. PMID- 27233593 TI - Rehabilitation After Surgical Reconstruction to Restore Function to the Upper Limb in Tetraplegia: A Changing Landscape. AB - Upper limb reconstructive surgical procedures for individuals with tetraplegia are performed in many centers internationally. Most recipients of surgery return to local communities and nonsurgical centers for postoperative rehabilitation and long-term follow-up. This supplement focuses on the clinical significance of upper extremity reconstruction, addressing issues related to the availability and choice for surgery, preoperative assessments, postoperative training paradigms, and appropriate outcome measures. Comprehensive intervention protocols are described in terms of dose, timing, specific activities, modalities, and related outcomes. Shared knowledge of current rehabilitation practice, as it relates to reconstructive surgery, can expand treatment options communicated to patients, increase the availability of postoperative muscle reeducation programs, and motivate long-term follow-up assessments. PMID- 27233594 TI - Tendon Transfer Surgery for People With Tetraplegia: An Overview. AB - After cervical spinal cord injury, the loss of upper limb function is common. This affects an individual's ability to perform activities of daily living and participate in previous life roles. There are surgical procedures that can restore some of the upper limb function lost after cervical spinal cord injury. Tendon transfer surgery has been performed in the tetraplegic population since the early 1970s. The goals of surgery are to provide a person with tetraplegia with active elbow extension, wrist extension (if absent), and sufficient pinch and/or grip strength to perform activities of daily living without the need for adaptive equipment or orthoses. These procedures are suitable for a specific group, usually with spinal cord impairment of C4-8, with explicit components of motor and sensory loss. Comprehensive team assessments of current functioning, environment, and personal circumstances are important to ensure success of any procedure. Rehabilitation after tendon transfer surgery involves immobilization for tendon healing followed by specific, targeted therapy based on motor learning and goal-orientated training. Outcomes of tendon transfer surgery are not limited to the improvements in an individual's strength, function, and performance of activities but have much greater life affects, especially with regard to well being, employment, and participation. This article will provide an overview of the aims of surgery, preoperative assessment, common procedures, postoperative rehabilitation strategies, and outcomes based on clinical experience and international published literature. PMID- 27233595 TI - Understanding and Overcoming Barriers to Upper Limb Surgical Reconstruction After Tetraplegia: The Need for Interdisciplinary Collaboration. AB - There are approximately 300,000 persons with spinal cord injury living in the United States, and nearly 60% of these persons have suffered tetraplegia with resultant alterations in body function, activity, and therefore participation. Restoring hand function can improve independence, and various studies have shown that persons with tetraplegia rate restoration of arm and hand function higher than bowel and bladder control, walking, or sexuality. There are conservative options to improve upper limb function in this population (eg, orthoses, neuroprostheses). Surgical interventions are also available, and 70% of surgical patients report satisfaction and improvement in various activities of daily living after surgery to restore arm and hand function. Despite these positive surgical outcomes, <10% of the eligible population of 60% to 70% undergo tendon transfer surgery to restore function. Underutilization of surgical interventions can be explained by population-, provider-, and health care systems-specific barriers. With further education of providers and patients and team building across disciplines these barriers can be overcome, ultimately leading to reduced disability and improved quality of life for persons with tetraplegia. PMID- 27233596 TI - Decision-Making About Upper Limb Tendon Transfer Surgery by People With Tetraplegia for More Than 10 Years. AB - OBJECTIVES: To quantify time from spinal cord injury to upper limb reconstructive surgery for individuals with tetraplegia; to explore influences on decision making about surgery for persons with long-standing (>10y) tetraplegia; and to determine the applicability of our previously developed conceptual framework that described the decision-making processes for people with tetraplegia of <5 years. DESIGN: Quantitative-qualitative mixed-methods study. SETTING: Community based in New Zealand. PARTICIPANTS: People (N=9) living with tetraplegia for >10 years. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: An audit of time frames between injury, assessment, and surgery for people with tetraplegia was undertaken. Interviews of people with tetraplegia were analyzed using constructivist grounded theory. RESULTS: Sixty-two percent of people with tetraplegia assessed for surgery had upper limb reconstructive surgery. Most were assessed within the first 3 years of spinal cord injury. Over half had surgery within 4 years after injury; however, 20% waited >10 years. Changes in prioritized activities, and the identification of tasks possible with surgery, were influential in the decision-making process. Participants were aware of surgery, but required a reoffer from health professionals before proceeding. The influence of peers was prominent in reinforcing the improvement in prioritized activities possible after surgery. CONCLUSIONS: Findings confirmed that the previously developed conceptual framework for decision-making about upper limb reconstructive surgery was applicable for people with tetraplegia of >10 years. Similarities were seen in the influence of goals and priorities (although the nature of these might change) and information from peers (although this influence was greater for those injured longer). Repeat offers for surgery were required to allow for changes in circumstances over time. PMID- 27233597 TI - Upper Extremity Assessment in Tetraplegia: The Importance of Differentiating Between Upper and Lower Motor Neuron Paralysis. AB - Scientific advances are increasing the options for improved upper limb function in people with cervical level spinal cord injury (SCI). Some of these interventions rely on identifying an aspect of paralysis that is not uniformly assessed in SCI: the integrity of the lower motor neuron (LMN). SCI can damage both the upper motor neuron and LMN causing muscle paralysis. Differentiation between these causes of paralysis is not typically believed to be important during SCI rehabilitation because, regardless of the cause, the muscles are no longer under voluntary control by the patient. Emerging treatments designed to restore upper extremity function (eg, rescue microsurgical nerve transfers, motor learning-based interventions, functional electrical stimulation) all require knowledge of LMN status. The LMN is easily evaluated using surface electrical stimulation and does not add significant time to the standard clinical assessment of SCI. This noninvasive evaluation yields information that contributes to the development of a lifetime upper extremity care plan for maximizing function and quality of life. Given the relative simplicity of this assessment and the far reaching implications for treatment and function, we propose that this assessment should be adopted as standard practice for acute cervical SCI. PMID- 27233598 TI - Analytical performance of nano-LC-SRM using nondepleted human plasma over an 18 month period. AB - A standardized procedure for label-free nano-LC-SRM analysis of 32 high-medium abundance proteins from nondepleted human plasma was established and SRM data were acquired on 45 separate days for a control sample that was independently prepared on 39 distinct dates over an 18-month period (542 days). This case study enabled us to assess quantitative variance associated with nano-LC-SRM plasma analysis, mimicking experimental conditions that would be experienced with clinical trial biomarker studies. We assessed sample preparation variability attributed to different technicians and sample storage stability. Instrument performance varied over the 18-month period requiring ion path cleaning, so we assessed the impact of declining performance on specific peptide ion sensitivity and evaluated how various data normalization strategies could compensate for these changes. Our analysis demonstrated that while sample preparation was the main contributor for data variances when MS data were acquired within days, variability in SRM sensitivity was a far greater source of variance when data were acquired over a long period. The overall median multiplexed assay CV was 13% over the 18-month period. This case study is illustrative of large-scale plasma biomarker studies using nano-LC-SRM over extended periods and highlights aspects of bioanalysis that require careful attention to ensure reliable quantitation. PMID- 27233599 TI - Functional and clinical outcomes following anterior hip replacement: a 5-year comparative study versus posterior approach. AB - BACKGROUND: With the evolution of total hip joint replacement techniques, there has been a trend towards minimally invasive surgery. The anterior approach (AA) to total hip arthroplasty has been widely associated with less soft tissue damage. The aim of our study was to compare clinical and 1-year functional outcomes for AA hip arthroplasty versus a posterior approach (PA). METHOD: We retrospectively reviewed 92 (50 anterior and 42 posterior) total hip replacements performed at our centre between 2006 and 2011. Clinical outcomes were recorded from hospital medical records and clinical audit system. Range of motion analysis, Harris hip score (HHS) and Short Form-12 score were recorded pre operatively and at the 12-month follow-up marks. Additionally, we reviewed operative time, length of stay, discharge destination, complications, return to theatre and readmission rates. RESULTS: The results of our study revealed significantly shorter average hospital length of stay for the AA versus PA (4.2 versus 6.0 days, P = 0.004). Interestingly, our study also showed significantly shorter operating time with the AA (83.0 versus 91.8 min, P = 0.048) and lower return to theatre rates (0 versus 9.5%, P = 0.026). Finally, multivariate analysis showed AA to be associated with higher HHS and pre-operative body mass index to be associated with lower HHS at 12-month post-operation (P = 0.02 and <0.001, respectively). CONCLUSIONS: Our study showed improved HHS at 12 months as well as reduced hospital length of stay, operating time and return to theatre with an AA when compared with a PA. PMID- 27233600 TI - Hepcidin inhibition on the effect of osteogenesis in zebrafish. AB - Iron overload, as a risk factor for osteoporosis, can result in the up-regulation of Hepcidin, and Hepcidin knockout mice display defects in their bone microarchitecture. However, the molecular and genetic mechanisms underlying Hepcidin deficiency-derived bone loss remain unclear. Here, we show that hepcidin knockdown in zebrafish using morpholinos leads to iron overload. Furthermore, a mineralization delay is observed in osteoblast cells in hepcidin morphants, and these defects could be partially restored with microinjection of hepcidin mRNA. Quantitative real-time PCR analyses revealed the osteoblast-specific genes alp, runx2a, runx2b, and sp7 in morphants are down-regulated. Furthermore, we confirmed qRT-PCR results by in situ hybridization and found down-regulated genes related to osteoblast function in hepcidin morphants. Most importantly, we revealed that hepcidin was capable of removing whole-body iron which facilitated larval recovery from the reductions in bone formation and osteogenesis induced by iron overload. PMID- 27233601 TI - Central leptin resistance and hypothalamic inflammation are involved in letrozole induced polycystic ovary syndrome rats. AB - Accumulating evidence indicates that leptin acts as an important mediator in energy homeostasis and reproduction. Since dysfunction of reproduction and metabolism are major characteristics of polycystic ovarian syndrome (PCOS), the role of leptin in pathogenesis of PCOS needs further research. Many studies have shown that central leptin resistance existed in obesity rats through leptin intracerebroventricular (icv) injection; however, central leptin resistance in PCOS rats has not been reported. This study aimed to investigate whether there was a state of central leptin resistance in PCOS rats, as well as explore the possible association of hypothalamic inflammation with central leptin resistance. First, letrozole was used to induce the PCOS model, 24 h food intake, 24 h body weight changes and the expression of p-STAT3 were determined following leptin or artificial cerebrospinal fluid (aCSF) icv injection in rats. Second, we further evaluated the expressions of IL-1beta, IL-6, TNF-alpha, p-IKKbeta, NF-kappaB, p NF-kappaB, IkappaBalpha, p-IkappaBalpha and SOCS3 in hypothalamus. The results showed that 24 h food intake and body weight were decreased, while the expression of p-STAT3 was increased in control group rats following leptin icv injection compared with aCSF icv injection; however, both of them showed no significant difference in PCOS rats. Furthermore, inflammatory markers were upregulated in the hypothalami of PCOS rats. Taken together, our data indicated that there was a state of chronic low-grade inflammation in hypothalamus which might be the possible mechanism for central leptin resistance in PCOS rats. PMID- 27233602 TI - The level of nitric oxide regulates lipocalin-2 expression under inflammatory condition in RINm5F beta-cells. AB - We previously reported that proinflammatory cytokines (interleukin-1beta and interferon-gamma) induced the expression of lipocalin-2 (LCN-2) together with inducible nitric oxide synthase (iNOS) in RINm5F beta-cells. Therefore, we examined the effect of nitric oxide (NO) on LCN-2 expression in cytokines-treated RINm5F beta-cells. Additionally, we observed the effect of LCN-2 on cell viability. First, we found the existence of LCN-2 receptor and the internalization of exogenous recombinant LCN-2 peptide in RINm5F and INS-1 beta cells. Next, the effects of NO on LCN-2 expression were evaluated. Aminoguanidine, an iNOS inhibitor and iNOS gene silencing significantly inhibited cytokines-induced LCN-2 expression while sodium nitroprusside (SNP), an NO donor potentiated it. Luciferase reporter assay showed that transcription factor NF kappaB was not involved in LCN-2 expression. Both LCN-2 mRNA and protein stability assays were conducted. SNP did not affect LCN-2 mRNA stability, however, it significantly reduced LCN-2 protein degradation. The LCN-2 protein degradation was significantly attenuated by MG132, a proteasome inhibitor. Finally, the effect of LCN-2 on cell viability was evaluated. LCN-2 peptide treatment and LCN-2 overexpression significantly reduced cell viability. FACS analysis showed that LCN-2 induced the apoptosis of the cells. Collectively, NO level affects LCN-2 expression via regulation of LCN-2 protein stability under inflammatory condition and LCN-2 may reduce beta-cell viability by promoting apoptosis. PMID- 27233603 TI - 14-3-3 proteins: Macro-regulators with great potential for improving abiotic stress tolerance in plants. AB - 14-3-3 proteins (14-3-3s) are highly conserved regulatory proteins that are uniquely eukaryotic, and deeply involved in protein-protein interactions that mediate diverse signaling pathways. In plants, 14-3-3s have been validated to regulate many biological processes, such as metabolism, light and hormone signaling, cell-cycle control and protein trafficking. Recent years we have also witnessed an increasing number of reports describing the functions of 14-3-3s in plant stress responses through interactions with key proteins in both biotic and abiotic stresses. In this review, we highlight the advances that have been made in investigating the roles of 14-3-3s in plant abiotic stress tolerance. These advances provide a framework for our understanding of how signals are integrated to perceive and respond to the abiotic stresses in plants. PMID- 27233604 TI - Molecular dynamics simulation and free energy landscape methods in probing L215H, L217R and L225M betaI-tubulin mutations causing paclitaxel resistance in cancer cells. AB - Drug resistance poses a threatening challenge for mankind, as the development of resistance to already well-established drugs causes serious therapeutic problems. Resistance to paclitaxel (Ptxl), a complex diterpenoid working as microtubule stabilizer, is one such issue in cancer treatment. Microtubule stabilizer drugs, stabilises microtubules upon binding to beta-tubulin subunit of tubulin heterodimer thus causing mitotic arrest leading to death of cancer cell. Leucine point mutations viz. L215H, L217R, and L225M were reported for Ptxl resistance in various cancers. In the current study, molecular mechanism of these resistance causing mutations was explored using molecular docking, molecular dynamics (MD) simulation, binding energy estimation (MMPBSA), free energy decomposition, principle component analysis (PCA) and free energy landscape (FEL) methods. A total of five systems including unbound betaI-tubulin (Apo), docked wild+Ptxl, L215H+Ptxl, L217R+Ptxl and L225M+Ptxl were prepared, and 50 ns MD simulation was performed for each system. Binding energy estimation indicated that leucine mutation reduces the binding affinity of Ptxl in mutant types (MTs) as compared to wild type (WT). Further, in contrast to WT Ptxl interactions with the M-loop (PHE270-VAL286), S6-S7 loop and H9-H10 were significantly altered in MTs. Results showed that in MTs, Ptxl had weak interaction with M-loop residues, while having strong affinity with S6-S7 loop and H6-H7 loop. Moreover, PCA and FEL analysis revealed that M-loop flexible region (THR274-LEU284) was strongly bound with Ptxl in WT preventing its flexible movement and the causing factor for microtubule stabilization. In MTs due to poor interaction with Ptxl, M-loop flexible region retains its flexibility, therefore unable to stabilize microtubule. This study will give an insight into the importance of M-loop flexible region interaction with Ptxl for microtubule stabilization. In addition, it clearly provides the molecular basis of Ptxl resistance mechanism in leucine MTs. This work will help in developing novel microtubule stabilizers molecules active against MTs. PMID- 27233605 TI - PPARalpha activation drives demethylation of the CpG islands of the Gadd45b promoter in the mouse liver. AB - Growth arrest and DNA damage-inducible beta (GADD45b) plays a pivotal role in many intracellular events in both cell survival- and cell death-related signaling. To date, the study of GADD35b has mainly focused on investigation of its function, as well as interacting molecules. However, studies of Gadd45b gene regulation are limited. In this study, we investigated the transcriptional regulation mechanism of Gadd45b. Since Gadd45b mRNA is highly induced by the PPARalpha agonist Wy-14,643 in the mouse liver, we analyzed the Gadd45b promoter using an in vivo reporter assay. Interestingly, the naked Gadd45b-luciferase construct strongly induced luciferase activity without any stimulant in our in vivo system. Therefore, we investigated the epigenetic changes in the Gadd45b promoter region using mouse liver genomic DNA, the methylation-specific restriction enzyme (HpaII), and disulfide conversion. Our results showed that two possible CpG methylation sites were methylated and demethylated by Wy-14,643 treatment. This study indicates that epigenetic change at the Gadd45b promoter is critical for Gadd45b induction. PMID- 27233606 TI - SP600125 enhances the anti-apoptotic capacity and migration of bone marrow mesenchymal stem cells treated with tumor necrosis factor-alpha. AB - Osteoarthritis (OA) and rheumatoid arthritis (RA) are chronic disorders associated with inflammation of joints characterized by damage to the underlying cartilage and bone. Bone marrow mesenchymal stem cells (BMSCs) are candidates for regeneration of bone and cartilage, which is inhibited by inflammatory cytokines in OA and RA, in particular tumor necrosis factor-alpha (TNF-alpha). This study aimed to investigate if the c-Jun N-terminal kinases (JNK)-specific inhibitor SP600125 could enhance the anti-apoptosis and migration of BMSCs treated with TNF alpha. The level of apoptosis was evaluated via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)/4',6-diamidino-2-phenylindole (DAPI) staining, annexin V/propidium iodide (PI) staining and western blotting. Migration of BMSCs was assessed using transwell migration chambers. We showed that the survival capacity and migration of BMSCs was significantly inhibited by TNF-alpha, which was blocked by pretreatment with SP600125. In the presence of SP600125, expression of cleaved caspase-9/-3 and p53 as well as the ratio of Bax to Bcl-2 was significantly decreased compared to treatment with TNF-alpha alone. Our results therefore indicate that SP600125 improves the migration capacity of TNF-alpha-treated BMSCs and exerts a significant effect on the viability of TNF alpha-treated BMSCs through reducing the up-regulation of p53, caspase-9/-3 and the Bcl-2 family induced by TNF-alpha. These findings suggest that SP600125 is of potential use in promoting the regeneration of bone and cartilage in OA and RA. PMID- 27233607 TI - Forced expression of Hnf4a induces hepatic gene activation through directed differentiation. AB - Embryonic stem (ES) cells are capable of unlimited self-renewal and have a diverse differentiation potential. These unique features make ES cells as an attractive source for developmental biology studies. Having the mature hepatocyte in the lab with functional activities is valuable in drug discovery studies. Overexpression of hepatocyte lineage-specific transcription factors (TFs) becomes a promising approach in pluripotent cell differentiation toward liver cells. Many studies generate transgenic ES cell lines to examine the effects of specific TFs overexpression in cell differentiation. In the present report, we have addressed whether a suspension or adherent model of differentiation is an appropriate way to study the role of Hnf4a overexpression. We generated ES cells that carried a doxycycline (Dox)-inducible Hnf4a using lentiviral vectors. The transduced cells were subjected to induced Hnf4a overexpression through both spontaneous and directed differentiation methods. Gene expression analysis showed substantially increased expression of hepatic gene markers, particularly Ttr and endogenous Hnf4a, in transduced cells differentiated by the directed approach. These results demonstrated that forced expression of TFs during directed differentiation would be an appropriate way to study relevant gene activation and the effects of overexpression in the context of hepatic differentiation. PMID- 27233608 TI - A new glycotoxins inhibitor attenuates insulin resistance in liver and fat cells. AB - Glycotoxins/Advanced glycation end products (AGEs) have implications in development of diabetes and related diseases. In the present study we deciphered the mechanisms of action of URM-II-81, a new derivative of isatin, in alleviation of insulin resistance in human hepatocytes and murine adipocytes. URM-II-81 reduced AGEs formation and receptor for advanced glycation end products (RAGE) expression in both cell types. We also observed suppression of methylglyoxal (MGO) mediated ROS production and deactivation of PKC-alpha. URM-II-81 restored proximal insulin signaling by modulating IRS-1 phosphorylation. URM-II-81 also alleviated MGO mediated diminished distal insulin signaling by increasing protein kinase B (PKB) and glycogen synthase kinase 3-beta (GSK-3-beta) phosphorylation. Glycogen synthesis was also increased in hepatocytes after treatment with URM-II 81. In adipocytes URM-II-81 prevented MGO induced reduced glucose uptake. We conclude that URM-II-81 can be a possible treatment target to address glycotoxins induced insulin resistance. PMID- 27233609 TI - Tyrosine binding and promiscuity in the arginine repressor from the pathogenic bacterium Corynebacterium pseudotuberculosis. AB - The arginine repressor (ArgR) regulates arginine biosynthesis in a number of microorganisms and consists of two domains interlinked by a short peptide; the N terminal domain is involved in DNA binding and the C-terminal domain binds arginine and forms a hexamer made-up of a dimer of trimers. The crystal structure of the C-terminal domain of ArgR from the pathogenic Corynebacterium pseudotuberculosis determined at 1.9 A resolution contains a tightly bound tyrosine at the arginine-binding site indicating hitherto unobserved promiscuity. Structural analysis of the binding pocket displays clear molecular adaptations to accommodate tyrosine binding suggesting the possible existence of an alternative regulatory process in this pathogenic bacterium. PMID- 27233610 TI - Phosphatase and tensin homologue (PTEN)-induced putative kinase 1 reduces pancreatic beta-cells apoptosis in glucotoxicity through activation of autophagy. AB - Chronic elevated glucose is harmful to pancreatic beta-cells, resulting in pancreatic beta-cells dysfunction and apoptosis. Understanding the molecular mechanisms associated with beta-cells survival is pivotal for the prevention of beta-cells injury caused by glucotoxicity. The role of Phosphatase and tensin homologue (PTEN)-induced putative kinase 1 (PINK1) in the fate of pancreatic beta cells constantly exposed to high glucose was studied. Sustained high glucose increased PINK1 protein expression both in rat pancreatic beta-cells and INS-1 beta-cells, and that this increase can be inhibited by PINK1 knockdown and further enhanced by PINK1 over-expression. PINK1 deficiency aggravated glucotoxicity-induced pancreatic beta-cells apoptosis and inhibition of autophagy whereas PINK1 could reverse these adverse effects. This study provides fundamental data supporting the potential protective role of PINK1 as a new therapeutic target necessary to preserve beta-cells survival under non physiological hyperglycemia conditions. PMID- 27233612 TI - ELS1, a novel MATE transporter related to leaf senescence and iron homeostasis in Arabidopsis thaliana. AB - The multidrug and toxic compound extrusion (MATE) transporters mediate the coupled exchange of organic substrates and monovalent cations have been recently implicated in various plant biological activities. In this work, we isolated a dominant mutant from an Arabidopsis activation-tagging mutant pool. This mutant exhibits pleiotropic phenotype including early flowering, dwarf and bushy architecture, minified lateral organs and early leaf senescence, and is therefore designated early leaf senescence 1-Dominaint (els1-D). Genotyping assays showed that els1-D is a gain-of-function mutant of a novel MATE transporter gene, ELS1, which encodes a close homolog of the previously reported ADP1, BCD1 and DTX50. Further investigations revealed that the overexpression of ELS1 reduces iron content in els1-D, and the accelerated senescence of the detached els1-D leaves can be recovered by exogenous iron supply. In addition, we also found that ELS1 is an iron responsive gene. Based on these findings, we proposed that ELS1 is related to leaf senescence and iron homeostasis in Arabidopsis. PMID- 27233611 TI - The preclinical evaluation of TIC10/ONC201 as an anti-pancreatic cancer agent. AB - Here we evaluated the potential anti-pancreatic cancer activity by TIC10/ONC201, a first-in-class small-molecule inducer of tumor necrosis (TNF)-related apoptosis inducing ligand (TRAIL). The in vitro results showed that TIC10 induced potent cytotoxic and cytostatic activities in several human pancreatic cancer cell lines (Panc-1, Mia-PaCa2, AsPC-1 or L3.6). TIC10 activated both extrinsic (TRAIL caspase-8-dependent) and endogenous/mitochondrial (caspase-9-dependent) apoptosis pathways in the pancreatic cancer cells. Molecularly, we showed that TIC10 inhibited Akt-Erk activation, yet induced TRAIL expression in pancreatic cancer cells. Significantly, TIC10, at a relatively low concentration, sensitized gemcitabine-induced growth inhibition and apoptosis against pancreatic cancer cells. Further, TIC10 and gemcitabine synergistically inhibited Panc-1 xenograft growth in SCID mice. The combination treatment also significantly improved mice survival. In addition, Akt-Erk in-activation and TRAIL/cleaved-caspase-8 induction were observed in TIC10-treated Panc-1 xenografts. Together, the preclinical results of the study demonstrate the potent anti-pancreatic cancer activity by TIC10, or with gemcitabine. PMID- 27233613 TI - miR-137 suppresses tumor growth of malignant melanoma by targeting aurora kinase A. AB - As an oncogene, aurora kinase A (AURKA) is overexpressed in various types of human cancers. However, the expression and roles of AURKA in malignant melanoma are largely unknown. In this study, a miR-137-AURKA axis was revealed to regulate melanoma growth. We found a significant increase in levels of AURKA in melanoma. Both genetic knockdown and pharmacologic inhibition of AURKA decreased tumor cell growth in vitro and in vivo. Further found that miR-137 reduced AURKA expression through interaction with its 3' untranslated region (3'UTR) and that miR-137 was negatively correlated with AURKA expression in melanoma specimens. Overexpression of miR-137 decreased cell proliferation and colony formation in vitro. Notably, re-expression of AURKA significantly rescued miR-137-mediated suppression of cell growth and clonality. In summary, these results reveal that miR-137 functions as a tumor suppressor by targeting AURKA, providing new insights into investigation of therapeutic strategies against malignant melanoma. PMID- 27233614 TI - Spontaneous nonalcoholic fatty liver disease and ER stress in Sidt2 deficiency mice. AB - Sidt2 is a newly discovered lysosomal membrane protein that is closely related to glucose metabolism. In the present study, we found that Sidt2 is also closely related to lipid metabolism. Gradual increases in serum triglyceride (TG) and free fatty acid, as well as elevated aspartate transaminase and alanine transaminase levels were observed in Sidt2(-/-) mice fed a normal diet from the age of 3 months, suggesting the presence of lipid metabolism disorders and impaired liver function in these mice. In the liver slices of 6-month-old Sidt2( /-) mice, there were obvious fat degeneration and inflammatory changes. Almost all of the liver cells demonstrated different levels of lipid droplet accumulation and cell swelling, and some of the cells demonstrated balloon-like changes. Infiltration of inflammatory cells was observed in the portal area and hepatic lobule. Electron microscopy showed that macrophages tended to be attached to the endothelial cells, and a large number of lipid droplets were present in the liver cells. Oil red O staining showed that there were significantly increased number of deep straining particles in the liver cells of Sidt2(-/-) mice, and the TG content in liver tissue was also significantly increased. Detection of key genes and proteins related to fat synthesis showed that mRNA and protein levels of the SREBP1c in the liver of Sidt2(-/-) mice were significantly elevated, and the downstream genes acetyl-CoA carboxylase, fatty acid synthase, and mitochondrial glycerol 3-phosphate acyltransferase were significantly upregulated. In addition, there was severe endoplasmic reticulum stress (ERS) in the liver of Sidt2(-/-) mice, which had significantly increased levels of markers specific for unfolded protein response activation, Grp78 and CHOP, as well as significant elevation of downstream p-PERK, p-eIF2a, p-IRE1a, along with ER damage. These results suggest that Sidt2(-/-) mice had spontaneous nonalcoholic fatty liver disease (NAFLD) accompanied by ERS. In summary, as a lysosomal membrane protein, Sidt2 plays an important role in the pathogenesis of NAFLD, and ERS may mediate the occurrence and development of this disease in Sdit2 deficiency mice. PMID- 27233615 TI - Contact-dependent abrogation of bone marrow-derived plasmacytoid dendritic cell differentiation by murine mesenchymal stem cells. AB - Plasmacytoid dendritic cells (pDCs) are rare central regulators of antiviral immunity and unsurpassed producers of interferon-alpha (IFN-alpha). Despite their crucial role as a link between innate and adaptive immunity, little is known about the modulation of pDC differentiation by other bone marrow (BM) cells. In this study, we investigated the modulation of pDC differentiation in Flt-3 ligand (Flt3L)-supplemented BM cultures, using highly purified mesenchymal stem cells (MSCs) that were FACS-isolated from murine BM based on surface marker expression and used after in vitro expansion. Initial analysis revealed an almost complete inhibition of BM-derived pDC expansion in the presence of >2% MSC. This inhibition was cell contact-dependent and soluble factor-independent, as indicated by trans-well experiments. The abrogation of functional pDC development by MSCs was confirmed after TLR9 stimulation, revealing a complete, contact dependent suppression of the IFN-a producing capacity of pDCs in Flt3L MSC BM co cultures. MSC selectively inhibited pDC development in contrast to myeloid DC development, as indicated by the significantly increased numbers of myeloid DC in Flt3L-supplemented BM cultures. The absence of significant MSC-mediated inhibitory effects on myeloid DC differentiation was confirmed by additional experiments in GM-CSF/IL-4-supplemented BM cultures. In summary, we describe a novel contact-dependent immunomodulatory mechanism of MSC that targets the BM derived expansion of functional pDCs. PMID- 27233616 TI - All 17 S-locus F-box proteins of the S2 - and S3 -haplotypes of Petunia inflata are assembled into similar SCF complexes with a specific function in self incompatibility. AB - The collaborative non-self-recognition model for S-RNase-based self incompatibility predicts that multiple S-locus F-box proteins (SLFs) produced by pollen of a given S-haplotype collectively mediate ubiquitination and degradation of all non-self S-RNases, but not self S-RNases, in the pollen tube, thereby resulting in cross-compatible pollination but self-incompatible pollination. We had previously used pollen extracts containing GFP-fused S2 -SLF1 (SLF1 with an S2 -haplotype) of Petunia inflata for co-immunoprecipitation (Co-IP) and mass spectrometry (MS), and identified PiCUL1-P (a pollen-specific Cullin1), PiSSK1 (a pollen-specific Skp1-like protein) and PiRBX1 (a conventional Rbx1) as components of the SCF(S) (2-) (SLF) (1) complex. Using pollen extracts containing PiSSK1:FLAG:GFP for Co-IP/MS, we identified two additional SLFs (SLF4 and SLF13) that were assembled into SCF(SLF) complexes. As 17 SLF genes (SLF1 to SLF17) have been identified in S2 and S3 pollen, here we examined whether all 17 SLFs are assembled into similar complexes and, if so, whether these complexes are unique to SLFs. We modified the previous Co-IP/MS procedure, including the addition of style extracts from four different S-genotypes to pollen extracts containing PiSSK1:FLAG:GFP, to perform four separate experiments. The results taken together show that all 17 SLFs and an SLF-like protein, SLFLike1 (encoded by an S-locus linked gene), co-immunoprecipitated with PiSSK1:FLAG:GFP. Moreover, of the 179 other F-box proteins predicted by S2 and S3 pollen transcriptomes, only a pair with 94.9% identity and another pair with 99.7% identity co-immunoprecipitated with PiSSK1:FLAG:GFP. These results suggest that SCF(SLF) complexes have evolved specifically to function in self-incompatibility. PMID- 27233619 TI - Propionibacterium acnes induces an adjuvant effect in B-1 cells and affects their phagocyte differentiation via a TLR2-mediated mechanism. AB - B-1 lymphocytes are present in large numbers in the mouse peritoneal cavity, as are macrophages, and are responsible for natural IgM production. These lymphocytes migrate to inflammatory foci and are also involved in innate immunity. It was also demonstrated that B-1 cells are able to differentiated into phagocytes (B-1CDP), which is characterized by expression of F4/80 and increased phagocytic activity. B-1 cell responses to antigens and adjuvants are poorly characterized. It has been shown that Propionibacterium acnes suspensions induce immunomodulatory effects in both macrophages and B-2 lymphocytes. We recently demonstrated that this bacterium has the ability to increase B-1 cell populations both in vitro and in vivo. P. acnes induces B-1CDP differentiation, increases the expression of TLR2, TLR4 and TLR9 and augments the expression of CD80, CD86 and CD40 in B-1 and B-1CDP cells. Because P. acnes has been shown to modulate TLR expression, in this study, we investigated the role of TLR2 and TLR4 in B-1 cell population, including B-1CDP differentiation and phagocytic activity in vitro and in vivo. Interestingly, we have demonstrated that TLR2 signaling could be involved in the increase in the B-1 cell population induced by P. acnes. Furthermore, the early differentiation of B-1CDP is also dependent of TLR2. It was also observed that TLR signals also interfere in the phagocytic ability of B 1 cells and their phagocytes. According to these data, it is clear that P. acnes promotes an important adjuvant effect in B-1 cells by inducing them to differentiate into B-1CDP cells and modulates their phagocytic functions both in vivo and in vitro. Moreover, most of these effects are mediated primarily via TLR2. These data reinforce the findings that such bacterial suspensions have powerful adjuvant properties. The responses of B-1 cells to exogenous stimulation indicate that these cells are important to the innate immune response. PMID- 27233617 TI - Comparable reduction in Zif268 levels and cytochrome oxidase activity in the retrosplenial cortex following mammillothalamic tract lesions. AB - Damage to the mammillothalamic tract (MTT) produces memory impairments in both humans and rats, yet it is still not clear why this diencephalic pathway is vital for memory. One suggestion is that it is an important route for midbrain inputs to reach a wider cortical and subcortical network that supports memory. Consistent with this idea, MTT lesions produce widespread hypoactivity in distal brain regions as measured by the immediate-early gene, c-fos. To determine whether these findings were selective to c-fos or reflected more general changes in neuronal function, we assessed the effects of MTT lesions on the expression of the immediate-early gene protein, Zif268 and the metabolic marker, cytochrome oxidase, in the retrosplenial cortex and hippocampus. The lesions decreased levels of both activity markers in the superficial and deep layers of the retrosplenial cortex in both its granular and dysgranular subregions. In contrast, no significant changes were observed in the hippocampus, despite the MTT-lesioned animals showing marked impairments on T-maze alternation. These findings are consistent with MTT lesions providing important, indirect inputs for normal retrosplenial cortex functioning. These distal functional changes may contribute to the memory impairments observed after MTT lesions. PMID- 27233620 TI - Protein expression profiling in haemocytes and plasma of the Manila clam Ruditapes philippinarum in response to infection with Perkinsus olseni. AB - The protein expression profiling in clam haemocytes and plasma in response to Perkinsus olseni was addressed. Adult Manila clams from a P. olseni-free bed were experimentally challenged with parasite zoospores to analyse immune response. In another experiment, the effects of longer term infection were assessed in adult clams collected from a P. olseni-affected bed, by comparing moderate to very heavily infected clams with non-infected ones. Haemocyte and plasma proteins were separated by two-dimensional electrophoresis; spot patterns were qualitatively compared between treatments within each experiment and the spots indicating differential protein expression associated with P. olseni challenge or with field infection were processed for protein identification. Fifteen clam proteins (four in haemocytes and eleven in plasma) of which expression was markedly affected by P. olseni were identified. Some of the identified proteins have a well-known role in clam immune response against the parasite, such as lysozyme and lectins. Rho GTPase-activating protein 6 could be a marker of resistance against P. olseni, which should be further studied. PMID- 27233618 TI - Long noncoding RNAs in cancer: mechanisms of action and technological advancements. AB - The previous decade has seen long non-coding RNAs (lncRNAs) rise from obscurity to being defined as a category of genetic elements, leaving its mark on the field of cancer biology. With the current number of curated lncRNAs increasing by 10,000 in the last five years, the field is moving from annotation of lncRNA expression in various tumours to understanding their importance in the key cancer signalling networks and characteristic behaviours. Here, we summarize the previously identified as well as recently discovered mechanisms of lncRNA function and their roles in the hallmarks of cancer. Furthermore, we identify novel technologies for investigation of lncRNA properties and their function in carcinogenesis, which will be important for their translation to the clinic as novel biomarkers and therapeutic targets. PMID- 27233621 TI - The efficacy and safety of silodosin for the treatment of ureteral stones: a systematic review and meta-analysis. AB - BACKGROUND: To evaluate the efficacy and safety of silodosin as a medical expulsive therapy for ureteral stones by means of a systematic review and meta analysis. METHODS: We searched MEDLINE, EMBASE and the Cochrane Controlled Trials Register to identify randomized controlled trials (RCTs) of silodosin in the treatment of ureteral stones. The reference lists of retrieved studies were also investigated. RESULTS: Six RCTs, including 916 participants and comparing silodosin with controls, were used in the meta-analysis. Silodosin was superior to controls in terms of stone expulsion rate, the primary efficacy end point in all six RCTs (odds ratio [OR] for expulsion 2.16, 95 % confidence interval [CI] 1.62 to 2.86, p <0.00001). Silodosin was also more effective for secondary efficacy end points; the stone expulsion time (standardized mean difference [SMD] -3.66, 95 % CI -6.61 to -0.71; p =0.01) and analgesic requirements (SMD -0.89, 95 % CI -1.19 to -0.60; p < 0.00001) were significantly reduced compared with those of controls. Other than the incidence of abnormal ejaculation, which was higher in the silodosin groups (OR 2.84, 95 % CI 1.56 to 5.16, p =0.0006), few adverse effects were observed. CONCLUSION: This meta-analysis indicates silodosin is an effective and safe treatment option for ureteral stones with a low occurrence of side effects. PMID- 27233622 TI - A cognitive prosthesis for memory facilitation by closed-loop functional ensemble stimulation of hippocampal neurons in primate brain. AB - Very productive collaborative investigations characterized how multineuron hippocampal ensembles recorded in nonhuman primates (NHPs) encode short-term memory necessary for successful performance in a delayed match to sample (DMS) task and utilized that information to devise a unique nonlinear multi-input multi output (MIMO) memory prosthesis device to enhance short-term memory in real-time during task performance. Investigations have characterized how the hippocampus in primate brain encodes information in a multi-item, rule-controlled, delayed match to sample (DMS) task. The MIMO model was applied via closed loop feedback micro current stimulation during the task via conformal electrode arrays and enhanced performance of the complex memory requirements. These findings clearly indicate detection of a means by which the hippocampus encodes information and transmits this information to other brain regions involved in memory processing. By employing the nonlinear dynamic multi-input/multi-output (MIMO) model, developed and adapted to hippocampal neural ensemble firing patterns derived from simultaneous recorded multi-neuron CA1 and CA3 activity, it was possible to extract information encoded in the Sample phase of DMS trials that was necessary for successful performance in the subsequent Match phase of the task. The extension of this MIMO model to online delivery of electrical stimulation patterns to the same recording loci that exhibited successful CA1 firing in the DMS Sample Phase provided the means to increase task performance on a trial-by trial basis. Increased utility of the MIMO model as a memory prosthesis was exhibited by the demonstration of cumulative increases in DMS task performance with repeated MIMO stimulation over many sessions. These results, reported below in this article, provide the necessary demonstrations to further the feasibility of the MIMO model as a memory prosthesis to recover and/or enhance encoding of cognitive information in humans with memory disruptions resulting from brain injury, disease or aging. PMID- 27233623 TI - Emerging molecular classifications and therapeutic implications for gastric cancer. AB - Gastric cancer (GC) is a highly aggressive and life-threatening malignancy. Even with radical surgical removal and front-line chemotherapy, more than half of GCs locally relapse and metastasize at a distant site. The dismal outcomes reflect the ineffectiveness of a one-size-fits-all approach for a highly heterogeneous disease with diverse etiological causes and complex molecular underpinnings. The recent comprehensive genomic and molecular profiling has led to our deepened understanding of GC. The emerging molecular classification schemes based on the genetic, epigenetic, and molecular signatures are providing great promise for the development of more effective therapeutic strategies in a more personalized and precise manner. To this end, the Cancer Genome Atlas (TCGA) research network conducted a comprehensive molecular evaluation of primary GCs and proposed a new molecular classification dividing GCs into four subtypes: Epstein-Barr virus associated tumors, microsatellite unstable tumors, genomically stable tumors, and tumors with chromosomal instability. This review primarily focuses on the TCGA molecular classification of GCs and discusses the implications on novel targeted therapy strategies. We believe that these fundamental findings will support the future application of targeted therapies and will guide our efforts to develop more efficacious drugs to treat human GCs. PMID- 27233624 TI - [Updated guidelines for management and monitoring of asthmatic patients: The Societe de pneumologie de langue francaise maintains the control]. PMID- 27233625 TI - Implementing preparatory strategies can help children participate in care. PMID- 27233626 TI - Threats to parents' roles during the process of their child dying in the paediatric intensive care unit. PMID- 27233627 TI - Effective communicating starts with #hellomynameis. PMID- 27233631 TI - Transition to practice: can rural interprofessional education make a difference? A cohort study. AB - BACKGROUND: The transition from student to health practitioner at entry-to practice is complex, requiring critical acquisition of collaborative practice skills. In rural communities where health need is multidimensional, there is potential for multiple intentional collaborative learning objectives to be met concurrently. A five-week, rurally-located, clinically-based interprofessional programme was introduced as a transition-to-practice rotation for final-year, pre registration health professional students in the professions of dentistry, dietetics, medicine, nursing, pharmacy and physiotherapy. The programme integrated learning objectives in four related domains: interprofessional practice; hauora Maori (Maori health); rural health; long-term condition management. This study investigated student learning experiences over the first two complete years of the programme, comparing responses from participating students with those from a cohort of non-participating peers. METHODS: Using a pre and post quasi-experimental design, respondents from two successive student year cohorts completed questionnaires at the start and end of their final year. Additional survey data were collected from participating students at the end of each rotation. RESULTS: 131 students participated in the programme during 2013 2014. Participating student respondents (55/131;42 %) reported being significantly better prepared than a cohort of 56 non-participating colleagues in many aspects of their understanding of and knowledge about each of four key learning domains. 94 % (123/131) of programme participants completed end-of rotation questionnaires. Positive from the outset (mean 5-point Likert scale scores between 3 and 5; 5 = most positive), student satisfaction further increased across all domains in the second year (mean 5-point Likert scale scores between 4 and 5). CONCLUSIONS: At entry-to-practice level, multiple learning objectives, including indigenous health learning, can be met simultaneously in the clinical context within an integrated, rotational programme. Rural settings are highly suitable for delivering such programmes if well supported. PMID- 27233632 TI - A multi-task graph-clustering approach for chromosome conformation capture data sets identifies conserved modules of chromosomal interactions. AB - Chromosome conformation capture methods are being increasingly used to study three-dimensional genome architecture in multiple cell types and species. An important challenge is to examine changes in three-dimensional architecture across cell types and species. We present Arboretum-Hi-C, a multi-task spectral clustering method, to identify common and context-specific aspects of genome architecture. Compared to standard clustering, Arboretum-Hi-C produced more biologically consistent patterns of conservation. Most clusters are conserved and enriched for either high- or low-activity genomic signals. Most genomic regions diverge between clusters with similar chromatin state except for a few that are associated with lamina-associated domains and open chromatin. PMID- 27233633 TI - Cluster randomised trial of a tailored intervention to improve the management of overweight and obesity in primary care in England. AB - BACKGROUND: Tailoring is a frequent component of approaches for implementing clinical practice guidelines, although evidence on how to maximise the effectiveness of tailoring is limited. In England, overweight and obesity are common, and national guidelines have been produced by the National Institute for Health and Care Excellence. However, the guidelines are not routinely followed in primary care. METHODS: A tailored implementation intervention was developed following an analysis of the determinants of practice influencing the implementation of the guidelines on obesity and the selection of strategies to address the determinants. General practices in the East Midlands of England were invited to take part in a cluster randomised controlled trial of the intervention. The primary outcome measure was the proportion of overweight or obese patients offered a weight loss intervention. Secondary outcomes were the proportions of patients with (1) a BMI or waist circumference recorded, (2) record of lifestyle assessment, (3) referred to weight loss services, and (4) any change in weight during the study period. We also assessed the mean weight change over the study period. Follow-up was for 9 months after the intervention. A process evaluation was undertaken, involving interviews of samples of participating health professionals. RESULTS: There were 16 general practices in the control group, and 12 in the intervention group. At follow-up, 15.08 % in the control group and 13.19 % in the intervention group had been offered a weight loss intervention, odds ratio (OR) 1.16, 95 % confidence interval (CI) (0.72, 1.89). BMI/waist circumference measurement 42.71 % control, 39.56 % intervention, OR 1.15 (CI 0.89, 1.48), referral to weight loss services 5.10 % control, 3.67 % intervention, OR 1.45 (CI 0.81, 2.63), weight management in the practice 9.59 % control, 8.73 % intervention, OR 1.09 (CI 0.55, 2.15), lifestyle assessment 23.05 % control, 23.86 % intervention, OR 0.98 (CI 0.76, 1.26), weight loss of at least 1 kg 42.22 % control, 41.65 % intervention, OR 0.98 (CI 0.87, 1.09). Health professionals reported the interventions as increasing their confidence in managing obesity and providing them with practical resources. CONCLUSIONS: The tailored intervention did not improve the implementation of the guidelines on obesity, despite systematic approaches to the identification of the determinants of practice. The methods of tailoring require further development to ensure that interventions target those determinants that most influence implementation. TRIAL REGISTRATION: ISRCTN07457585. PMID- 27233634 TI - General practice variation when initiating long-term prescribing of proton pump inhibitors: a nationwide cohort study. AB - BACKGROUND: Suggestions of overprescribing of proton pump inhibitors (PPIs) for long-term treatment in primary care have been raised. This study aims to analyse associations between general practice characteristics and initiating long-term treatment with PPIs. METHODS: A nationwide register-based cohort study of patients over 18 years redeeming first-time prescription for PPI issued by a general practitioner in Denmark in 2011. Patients redeeming more than 60 defined daily doses (DDDs) of PPI within six months were defined first-time long-term users. Detailed information on diagnoses, concomitant drug use and sociodemography of the cohort was extracted. Practice characteristics such as age and gender of the general practitioner (GP), number of GPs, number of patients per GP, geographical location and training practice status were linked to each PPI user. Logistic regression analysis was used to determine associations between practice characteristics and initiating long-term prescribing of PPIs. RESULTS: We identified 90 556 first-time users of PPI. A total of 30 963 (34.2 %) met criteria for long-term use at six months follow-up. GPs over 65 years had significantly higher odds of long-term prescribing (OR 1.32, CI 1.16-1.50), when compared to younger GPs (<45 years). Furthermore, female GPs were significantly less likely to prescribe long-term treatment with PPIs (OR 0.87, CI 0.81-0.93) compared to male GPs. CONCLUSIONS: Practice characteristics such as GP age and gender could explain some of the observed variation in prescribing patterns for PPIs. This variation may indicate a potential for enhancing rational prescribing of PPIs. PMID- 27233635 TI - Immersion team training in a realistic environment improves team performance in trauma resuscitation. AB - BACKGROUND: In the US military, it is common for health care teams to be formed ad hoc and expected to function cohesively as a unit. Poor team dynamics decreases the effectiveness of trauma care delivery. The US Navy Fleet Surgical Team Three has developed a simulation-based trauma initiative-the Shipboard Surgical Trauma Training (S2T2) Course-that emphasizes team dynamics to improve the delivery of trauma care to the severely injured patient. METHODS: The S2T2 Course combines classroom didactics with hands-on simulation over a period of 6 days, culminating in a daylong, mass casualty scenario. Each resuscitation team was initially evaluated with a simulated trauma resuscitation scenario then retested on the same scenario after completing the course. A written exam was also administered individually both before and after the course. A survey was administered to assess the participants' perceived effectiveness of the course on overall team training. RESULTS: From the evaluation of 20 resuscitation teams made up of 123 medical personnel, there was a decrease in the mean time needed to perform the simulated trauma resuscitation, from a mean of 24.4 minutes to 13.5 minutes (P < .01), a decrease in the mean number of critical events missed, from 5.15 to 1.00 (P < .01), and a mean improvement of 41% in written test scores. More than 90% of participants rated the course as highly effective for improving team dynamics. CONCLUSION: A team-based trauma course with immersion in a realistic environment is an effective tool for improving team performance in trauma training. This approach has high potential to improve trauma care and patient outcomes. The benefits of this team-based course can be adapted to the civilian rural sector, where gaps have been identified in trauma care. PMID- 27233636 TI - Could the immune response in the sentinel lymph nodes of gastric cancer patients be the key to tailored surgery? AB - BACKGROUND: Precise detection of downstream, nonsentinel lymph node metastases is the key to implementation of the sentinel lymph node concept in gastric cancer. To overcome the problem of complex lymphatic drainage, micrometastases, and skip metastases, we investigated the feasibility of tumor cell detection in sentinel lymph nodes, using flow cytometry as well as studied immune suppression in the sentinel lymph node as a potential marker of downstream lymph node metastases. METHODS: In 21 patients with gastric cancer, the sentinel lymph nodes extracted during operation subjected to frozen sections and flow cytometry. The tumor cells were defined with the cell surface markers CEACAM and EpCAM. Simultaneously, the cell densities of different subsets of T cells were determined. RESULTS: The sensitivity and specificity of the determination of nodal status with flow cytometry for tumor cell detection was 100% and 63%, respectively, as seen in frozen sections. Correlations with nonsentinel lymph node metastases were seen for CD127(low)CD25(high) and CD45(neg)CD127(low)CD25(high) cell densities, relative proportion of CD45RA(neg)CD127(low)CD25(high) cells, frozen sections results, lymphangial invasion, and tumor size (P <= .043 each). Multivariate analysis identified the relative proportions of CD45RA(neg)CD127(low)CD25(high) cells as the only significant predictor for downstream nonsentinel lymph node metastases (P = .028; 95% confidence interval, 1.107-5.780). The predictive value of combined detection of flow cytometry tumor cells and the relative proportion of CD45RA(neg)CD127(low)CD25(high) cells for nodal stage determination was 91%. CONCLUSION: Combined detection of tumor cells and CD45RA(neg)CD127(low)CD25(high) cells in sentinel lymph nodes with flow cytometry predicts accurately nonsentinel lymph node metastases. PMID- 27233637 TI - Bacterobilia may trigger the development and severity of pancreatic fistula after pancreatoduodenectomy. AB - BACKGROUND: Although biliary infection (bacterobilia) is considered a risk factor for infectious complications after pancreatoduodenectomy, the association between bacterobilia and postoperative pancreatic fistula has remained unclear. The aim of this study is to investigate the impact of bacterobilia on the development of postoperative pancreatic fistula following pancreatoduodenectomy. METHODS: We conducted a retrospective review of the patients who underwent pancreatoduodenectomy between November 2010 and July 2014. Intraoperative bile cultures and cultures of the peripancreatic drainage fluid on postoperative days 1 and 3 were investigated in all patients. RESULTS: Of 264 patients, 151 (57%) patients had a positive intraoperative bile culture. The incidence of grade B/C postoperative pancreatic fistulas (by the international definition) was greater in patients with a positive intraoperative bile culture than in those with a negative intraoperative bile culture (38% vs 25%, P = .025). A multivariate analysis revealed that a positive intraoperative bile culture (odds ratio, 2.60; P = .002) and a body mass index of >=22 kg/m(2) (odds ratio, 2.18; P = .008) were independent risk factors for grade B/C postoperative pancreatic fistulas. Among the 151 patients with a positive intraoperative bile culture, the microorganism(s) isolated from the bile was detected in the drainage fluid of 100% of the patients on postoperative day 1 and in 88% of patients on postoperative day 3. CONCLUSION: Bacterobilia was found to be a risk factor for grade B/C postoperative pancreatic fistulas, and bacteria from the infected bile may be the source of the grade B/C postoperative pancreatic fistulas. PMID- 27233638 TI - Is lateral pelvic node dissection necessary after preoperative chemoradiotherapy for rectal cancer patients with initially suspected lateral pelvic node? AB - BACKGROUND: Little is known about the effect of lateral pelvic node dissection after preoperative chemoradiotherapy on rectal cancer patients with initially suspected lateral pelvic nodes. The purpose of this study was to identify a subgroup of patients receiving preoperative chemoradiotherapy who can benefit from lateral pelvic node dissection. METHODS: The study included 580 patients who underwent preoperative chemoradiotherapy and total mesorectal excision. The lateral pelvic node responses to preoperative chemoradiotherapy were divided: group I (no suspected lateral pelvic node), lateral pelvic node <5 mm pre- and post-chemoradiotherapy; group II (responsive lateral pelvic node), lateral pelvic node >=5 mm pre-chemoradiotherapy but <5 mm post-chemoradiotherapy; and group III (persistent lateral pelvic node), lateral pelvic node >=5 mm pre- and post chemoradiotherapy. Prognostic factors for lateral pelvic node recurrence-free survival, locoregional recurrence-free survival, relapse-free survival, and overall survival were analyzed. RESULTS: In a multivariate analysis, lateral pelvic node response was an independent factor associated with lateral pelvic node recurrence-free survival, locoregional recurrence-free survival, relapse free survival, and overall survival (P < .05). Group III had significantly poorer lateral pelvic node recurrence-free survival, locoregional recurrence-free survival, relapse-free survival, and overall survival than groups II and I (74.1%, 93.4%, and 98.6%; 71.7%, 89.4%, and 97%; 56.9%, 76.6%, and 81.7%; 74.9%, 85.7%, and 89.1%, respectively; P < .05). Group II tended to have poorer lateral pelvic node recurrence-free survival, locoregional recurrence-free survival, relapse-free survival, and overall survival than group I, and the differences in relapse-free survival and overall survival between the 2 groups were not significant (P > .05). CONCLUSION: Our data suggest that the subgroup with lateral pelvic nodes responsive to preoperative chemoradiotherapy may not benefit from lateral pelvic node dissection, and the subgroup with persistent lateral pelvic node may benefit from lateral pelvic node dissection. PMID- 27233639 TI - Identification and characterization of a novel NAC-like gene in chrysanthemum (Dendranthema lavandulifolium). AB - KEY MESSAGE: A NAC -like gene named DlNAC1 was identified in chrysanthemum and characterized; it may be involved in regulation of response to abiotic stressors, especially in tolerance to drought and salinity. NAC transcription factors in plants play crucial roles in tolerance to abiotic stressors, and overexpression of the NAC gene in Arabidopsis has been demonstrated to lead to improved drought tolerance. Functions of the NAC genes in chrysanthemum, however, remain poorly understood. In this study, a NAC-like gene named DlNAC1 was identified in chrysanthemum (Dendranthema lavandulifolium) and characterized. Phylogenetic analysis indicated that DlNAC1 contains a typical NAC domain and belongs to the ONAC022 subgroup. According to the subcellular localization and yeast one-hybrid assay, the DlNAC1 protein is localized to nuclei and has a transcription activation ability. Moreover, quantitative real-time PCR analyses showed that DlNAC1 was induced by low-temperature, high-salinity, and drought conditions (separately), but not by abscisic acid (ABA) and heat shock. In these experiments, the downstream genes of NAC transcription factors were found to be up-regulated, including stress-responsive genes KIN1 and AMY1. To further explore the effects of DlNAC1 in response to abiotic stressors, DlNAC1 was overexpressed in tobacco, and these transgenic plants showed significantly enhanced tolerance to drought and salinity. This study suggests that in chrysanthemum, the DlNAC1 gene is involved in regulation of the response to abiotic stressors, especially in tolerance to drought and salinity. PMID- 27233640 TI - Clinical and dermoscopic features of lichen planus pigmentosus in 37 patients with frontal fibrosing alopecia. PMID- 27233641 TI - No evidence of morbidity compression in Spain: a time series study based on national hospitalization records. AB - OBJECTIVES: Compression of morbidity postulates that as the populations age, the age of onset of disease is postponed. The objective of this study is to test for evidence of compression of morbidity in Spain. METHODS: We calculated the age and sex-specific incidence of myocardial infarction, heart failure, cerebrovascular disease, as well as bladder, prostate, breast, lung, and colon cancer among hospital discharges covering 99.5 % of the Spanish population, approximately 40 million inhabitants for two non-overlapping periods, 1997-2000 and 2007-2010, and estimated the length of life spent with disease using the Sullivan method. RESULTS: We found that expansion of morbidity due to an earlier age-specific onset of incident disease and increase in life expectancy was the norm in Spain. Notable exceptions were cardiovascular disease in women (-0.2 % time spent with disease) and lung cancer for men (-0.9 % time spent with disease) from 1997-2000 to 2007-2010. CONCLUSIONS: Compression of morbidity is often cited by policy makers when discussing adjustments to the health-care system. If morbidity is measured by age at onset of disease, the burden of morbidity has increased in Spain. PMID- 27233642 TI - HLA-A, -B, -DRB1 allele and haplotype frequencies of 920 cord blood units from Central Chile. AB - We present human leukocyte antigen (HLA) haplotype and allele/antigenic group frequencies derived from a data set of 920 umbilical cord blood units collected in Central Chile. HLA-A and -B genotypes were typed using sequence specific oligonucleotide probe methods while HLA-DRB1 genotypes were obtained from sequencing-based typing. The most frequent haplotype is A*29~B*44~DRB1*07:01 with an estimated frequency of 2.1%. PMID- 27233643 TI - Self-assembly of nanomaterials at fluid interfaces. AB - Recent developments in the field of the self-assembly of nanoscale materials such as nanoparticles, nanorods and nanosheets at liquid/liquid interfaces are reviewed. Self-assembly behavior of both biological and synthetic particles is discussed. For biological nanoparticles, the nanoparticle assembly at fluid interfaces provides a simple route for directing nanoparticles into 2D or 3D constructs with hierarchical ordering. The interfacial assembly of single-walled carbon nanotubes (SWCNTs) at liquid interfaces would play a key role in applications such as nanotube fractionation, flexible electronic thin-film fabrication and synthesis of porous SWCNT/polymer composites foams. Liquids can be structured by the jamming of nanoparticle surfactants at fluid interfaces. By controlling the interfacial packing of nanoparticle surfactants using external triggers, a new class of materials can be generated that combines the desirable characteristics of fluids such as rapid transport of energy carriers with the structural stability of a solid. PMID- 27233644 TI - The regulatory roles of ethylene and reactive oxygen species (ROS) in plant salt stress responses. AB - Soil salinity is one of the most commonly encountered environmental stresses affecting plant growth and crop productivity. Accordingly, plants have evolved a variety of morphological, physiological and biochemical strategies that enable them to adapt to saline growth conditions. For example, it has long been known that salinity-stress increases both the production of the gaseous stress hormone ethylene and the in planta accumulation of reactive oxygen species (ROS). Recently, there has been significant progress in understanding how the fine tuning of ethylene biosynthesis and signaling transduction can promote salinity tolerance, and how salinity-induced ROS accumulation also acts as a signal in the mediation of salinity tolerance. Furthermore, recent advances have indicated that ethylene signaling modulates salinity responses largely via regulation of ROS generating and ROS-scavenging mechanisms. This review focuses on these recent advances in understanding the linked roles of ethylene and ROS in salt tolerance. PMID- 27233645 TI - Effect of Vandetanib on Andes virus survival in the hamster model of Hantavirus pulmonary syndrome. AB - Hantavirus pulmonary syndrome (HPS) is a severe disease caused by hantavirus infection of pulmonary microvascular endothelial cells leading to microvascular leakage, pulmonary edema, pleural effusion and high case fatality. Previously, we demonstrated that Andes virus (ANDV) infection caused up-regulation of vascular endothelial growth factor (VEGF) and concomitant downregulation of the cellular adhesion molecule VE-cadherin leading to increased permeability. Analyses of human HPS-patient sera have further demonstrated increased circulating levels of VEGF. Here we investigate the impact of a small molecule antagonist of the VEGF receptor 2 (VEGFR-2) activation in vitro, and overall impact on survival in the Syrian hamster model of HPS. PMID- 27233647 TI - Structural and electrical properties of oxygen complexes in Cz and FZ silicon crystals implanted with carbon ions. AB - We present a comparative study of thermal donor (TD) center formation mechanisms as a result of carbon ion implantation into float zone (FZ-Si) and Czochralski (Cz-Si) silicon crystals. The kinetics of the TD center formation and transformation of their structure during annealing have been investigated. Also, the TD center formation takes place after additional oxygen implantation into FZ/Cz-Si, and an important role of recoil oxygen atoms (from the screen oxide) has been demonstrated for the FZ-Si case. Their concentration in the Si surface layer depends on the implantation dose and the screen oxide thickness, reaching up to values 10(18) to 10(19) cm(-3), which is comparable with the oxygen concentration in Cz-Si. These oxygen atoms can lead to additional thermal donor centers generation, especially in the FZ-Si. PACS: 34.50.Dy; 61.10.-i; 68.35.Dv. PMID- 27233648 TI - Turning the tide or surfing the wave? Responsible Research and Innovation, fundamental rights and neoliberal virtues. AB - The notion of Responsible Research and Innovation (RRI) has increasingly attracted attention in the academic literature. Up until now, however, the literature has focused on clarifying the principles for which research and innovation are responsible and on examining the conditions that account for managing them responsibly. Little attention has been reserved to exploring the political-economic context in which the notion of RRI has become progressively more prominent. This article tries to address this aspect and suggests some preliminary considerations on the connections between the specific understanding of responsibility in RRI and the framing of responsibility in what has been synthetically defined as 'neoliberalism'. To do so, we try to illustrate how the idea of responsibility has evolved over time so that the specific characteristics of RRI can be better highlighted. These characteristics will then be discussed against the features of neoliberalism and its understanding of responsibility. Eventually, we reaffirm a view of RRI centred on fundamental rights as a possible point of departure between these two perspectives on responsibility. PMID- 27233646 TI - Transposing musical skill: sonification of movement as concurrent augmented feedback enhances learning in a bimanual task. AB - Concurrent feedback provided during acquisition can enhance performance of novel tasks. The 'guidance hypothesis' predicts that feedback provision leads to dependence and poor performance in its absence. However, appropriately structured feedback information provided through sound ('sonification') may not be subject to this effect. We test this directly using a rhythmic bimanual shape-tracing task in which participants learned to move at a 4:3 timing ratio. Sonification of movement and demonstration was compared to two other learning conditions: (1) Sonification of task demonstration alone and (2) completely silent practice (control). Sonification of movement emerged as the most effective form of practice, reaching significantly lower error scores than control. Sonification of solely the demonstration, which was expected to benefit participants by perceptually unifying task requirements, did not lead to better performance than control. Good performance was maintained by participants in the Sonification condition in an immediate retention test without feedback, indicating that the use of this feedback can overcome the guidance effect. On a 24-h retention test, performance had declined and was equal between groups. We argue that this and similar findings in the feedback literature are best explained by an ecological approach to motor skill learning which places available perceptual information at the highest level of importance. PMID- 27233649 TI - Association of a TDRD1 variant with spermatogenic failure susceptibility in the Han Chinese. AB - PURPOSE: Piwi-interacting RNAs (piRNAs) are a broad group of noncoding small RNAs that have important biological functions in germline cells and can maintain genome integrity via silencing of retrotransposons. In this study, we aimed to explore the associations between genetic variants of important genes involved in piRNA biogenesis and male infertility with spermatogenic impairment. METHODS: To this end, five single-nucleotide polymorphisms (SNPs) in the ASZ1, PIWIL1, TDRD1, and TDRD9 genes were genotyped by TaqMan allelic discrimination assays in 342 cases of nonobstructive azoospermia (NOA) and 493 controls. RESULTS: The SNP rs77559927 in TDRD1 was associated with a reduced risk of spermatogenic impairment. The genotypes TC and TC + CC showed odds ratios and 95 % confidence intervals of 0.73 (0.55-0.98, P = 0.034) and 0.73 (0.56-0.97, P = 0.030), respectively, in patients with NOA compared with those in the controls. CONCLUSION: Thus, our results provided the first epidemiological evidence supporting the involvement of TDRD1 genetic polymorphisms in piRNA processing genes in determining the risk of spermatogenic impairment in a Han Chinese population. PMID- 27233650 TI - Closed vitrification of human oocytes and blastocysts: outcomes from a series of clinical cases. AB - PURPOSE: High survival rates and clinical outcomes similar to those from fresh oocytes and blastocysts have been observed with open oocyte vitrification systems. It has been suggested that the extremely fast cooling rates that are only achieved with open systems are necessary for human oocyte and blastocyst vitrification. However, there is a potential risk of introducing contamination with open systems. The aim of this study was to assess whether similar survival and subsequent implantation rates could be achieved using a closed vitrification system for human oocytes and blastocysts. METHODS: Initially, donated immature oocytes that were matured in vitro were vitrified using the cryoprotectants ethylene glycol (EG) + dimethyl sulphoxide (DMSO) + sucrose and either a closed system (Rapid-i(r)) or an open system (Cryolock). The closed system was subsequently introduced clinically for mature oocyte cryopreservation cases and blastocyst vitrification. RESULTS: Using in vitro matured oocytes, a similar survival was achieved with the open system of 92.4 % (73/79) and with the closed system of 89.7 % (35/39). For clinical oocyte closed vitrification, high survival rate of 90.5 % (374/413) and an implantation rate of 32.7 % (18/55) from the transfer of day 2 embryos was achieved, which is similar to fresh day 2 embryo transfers. Blastocysts have also been successfully cryopreserved using the Rapid i closed vitrification system with 94 % of blastocysts having an estimated >=75 % of cells intact and a similar implantation rate (31.5 %) to fresh single blastocyst transfers. CONCLUSION: Closed vitrification can achieve high survival and similar implantation rates to fresh for both oocytes and blastocysts. PMID- 27233651 TI - Does combining magnetic-activated cell sorting with density gradient or swim-up improve sperm selection? AB - PURPOSE: The present study aimed to evaluate whether combining the magnetic activated cell sorting (MACS) with density-gradient (DG) or swim-up (SU) sperm separation techniques can improve sperm selection to obtain higher quality spermatozoa. METHODS: Two commonly used sperm selection techniques, SU and DG, were compared to MACS combined with either SU or DG. Spermatozoa obtained from normozoospermic (n = 10) and oligozoospermic (n = 10) cases were grouped as SU, DG, SU+MACS, and DG+MACS followed by the analysis of sperm morphology, motility, DNA integrity, and the levels of Izumo-1 and PLCZ proteins. RESULTS: Although spermatozoa obtained by SU or DG when combined with MACS have improved aspects when compared to SU or DG alone, results did not reach a statistically significant level. Moreover, separation with MACS caused a significant loss in the numbers of total and rapid progressive spermatozoa. CONCLUSIONS: Considering the cost/benefit ratio, MACS application together with traditional techniques may only be preferred in certain cases having higher concentrations of spermatozoa, but it does not seem to be an ideal and practical sperm selection technique for routine use. PMID- 27233652 TI - [Perseverance time of informal carers: a new concept in dementia care : Validation and exploration]. AB - OBJECTIVE: The aim of this study was to introduce the concept of perseverance time of informal carers of relatives with dementia living at home. METHODS: During 2 years data were collected from 223 informal carers of persons with dementia and the care situation. Convergent validity was assessed by looking at associations of perseverance time with validated instruments for measuring subjective burden and happiness. Content validity was evaluated by performing bi- and multivariate correlations between perseverance time and characteristics of persons with dementia, informal carers and care situations. RESULTS: Correlation coefficients between perseverance time and the validated measures of burden and happiness were significant. Health of the person with dementia, informal carer living apart from the person with dementia, and male gender of informal carer were positively associated with perseverance time; need for supervision, intensity of informal care provision, and reductions in working hours and hobbies in order to be able to provide care negatively. The predictive validity was significant with a perseverance time up to 2 years. CONCLUSIONS: This investigation provides a first indication of the validity of the concept of perseverance time, but replication is necessary. In healthcare practice persevering time provides clues for early detection of overburdening and crises situations. PMID- 27233654 TI - Second operation in low back pain patients. PMID- 27233653 TI - Prefrontal Cortical Opioids and Dysregulated Motivation: A Network Hypothesis. AB - Loss of inhibitory control over appetitively motivated behavior occurs in multiple psychiatric disorders, including drug abuse, behavioral addictions, and eating disorders with binge features. In this opinion article, novel actions of MU-opioid peptides in the prefrontal cortex (PFC) that could contribute to inhibitory control deficits will be discussed. Evidence has accrued to suggest that excessive intra-PFC MU-opioid receptor (MU-OR) signaling alters the PFC response to excitatory drive, resulting in supernormal and incoherent recruitment of multiple PFC output pathways. Affected pathways include functionally opposed PFC->hypothalamus 'appetitive driver' and PFC->striatum 'appetitive limiter' projections. This network perturbation engenders disorganized, impulsive appetitive responses. Evidence supporting this hypothesis from human imaging and animal studies will be discussed, and combinatorial drug treatments targeting MU ORs and specific PFC subcortical targets will be explored. PMID- 27233658 TI - [Not Available]. PMID- 27233656 TI - Arthrolyses in elbow stiffness. PMID- 27233659 TI - S.O.T.EST. PMID- 27233660 TI - The axon as a physical structure in health and acute trauma. AB - The physical structure of neurons - dendrites converging on the soma, with an axon conveying activity to distant locations - is uniquely tied to their function. To perform their role, axons need to maintain structural precision in the soft, gelatinous environment of the central nervous system and the dynamic, flexible paths of nerves in the periphery. This requires close mechanical coupling between axons and the surrounding tissue, as well as an elastic, robust axoplasm resistant to pinching and flattening, and capable of sustaining transport despite physical distortion. These mechanical properties arise primarily from the properties of the internal cytoskeleton, coupled to the axonal membrane and the extracellular matrix. In particular, the two large constituents of the internal cytoskeleton, microtubules and neurofilaments, are braced against each other and flexibly interlinked by specialised proteins. Recent evidence suggests that the primary function of neurofilament sidearms is to structure the axoplasm into a linearly organised, elastic gel. This provides support and structure to the contents of axons in peripheral nerves subject to bending, protecting the relatively brittle microtubule bundles and maintaining them as transport conduits. Furthermore, a substantial proportion of axons are myelinated, and this thick jacket of membrane wrappings alters the form, function and internal composition of the axons to which it is applied. Together these structures determine the physical properties and integrity of neural tissue, both under conditions of normal movement, and in response to physical trauma. The effects of traumatic injury are directly dependent on the physical properties of neural tissue, especially axons, and because of axons' extreme structural specialisation, post-traumatic effects are usually characterised by particular modes of axonal damage. The physical realities of axons in neural tissue are integral to both normal function and their response to injury, and require specific consideration in evaluating research models of neurotrauma. PMID- 27233661 TI - Anti-NGF monoclonal antibody muMab 911 does not deplete neurons in the superior cervical ganglia of young or old adult rats. AB - Nerve growth factor (NGF) blocking therapies are an emerging and effective approach to pain management. However, concerns about the potential for adverse effects on the structure and function of the peripheral nervous system have slowed their development. Early studies using NGF antisera in adult rats reported effects on the size and number of neurons in the sympathetic chain ganglia. In the work described here, both young adult (6-8 week) and fully mature (7-8 month) rats were treated with muMab 911, a selective, murine, anti-NGF monoclonal antibody, to determine if systemic exposures to pharmacologically active levels of antibody for 1 month cause loss of neurons in the sympathetic superior cervical ganglia (SCG). State-of-the-art, unbiased stereology performed by two independent laboratories was used to determine the effects of muMab 911 on SCG neuronal number and size, as well as ganglion size. Following muMab 911 treatment, non-statistically significant trends toward smaller ganglia, and smaller and fewer neurons, were seen when routine, nonspecific stains were used in stereologic assessments. However, when noradrenergic neurons were identified using tyrosine hydroxylase (TH) immunoreactivity, trends toward fewer neurons observed with routine stains were not apparent. The only statistically significant effects detected were lower SCG weights in muMab 911-treated rats, and a smaller volume of TH immunoreactivity in neurons from younger rats treated with muMab 911. These results indicate that therapeutically relevant exposures to the anti-NGF monoclonal antibody muMab 911 for 1 month have no effect on neuron numbers within the SCG from young or old adult rats. PMID- 27233662 TI - Role of a NSAID in the apparent cure of a fungal mycetoma. AB - We report the case of a fungal mycetoma due to Madurella mycetomatis that failed to respond to surgery and antifungal treatment but responded strongly to the addition of a non-steroidal anti-inflammatory drug (NSAID). This African patient was born in Mauritania in 1972. He was a herdsman, living close to the Senegal River. The first nodules appeared on the left foot at the age of 13years (1985). The patient suffered frequent flare-ups with the appearance of black grains and underwent surgery in 1988 and 1992 in Senegal. After remission for several months after surgery, new fistulae occurred. The patient emigrated to France in 1995 and underwent a third surgical intervention in 1996. M. mycetomatis was cultured from the black grains. The patient was otherwise in good health, with no diabetes, and HIV tests were negative. We saw the patient for the first time in 2005, at which time he had flare-ups every two to three months. Imaging disclosed an absence of bone involvement. The patient underwent a fourth operation in October, 2005, and voriconazole treatment was initiated. A new flare-up occurred in February, 2006. CT, MRI, and PET scans revealed calcaneus and tarsal involvement, and posaconazole then replaced voriconazole. Flucytosine was added four months later, due to an absence of improvement. New flares-ups occurred and a fifth surgical intervention was performed in September, 2006. The pain, which had been present for three years, worsened; the patient had to stop working and was no longer able to walk without crutches. Amputation of the foot was considered. Empiric treatment with a NSAID, diclofenac (Voltaren((r)); 100mg/day), was added to the antifungal treatment in November 2006, to treat the patient's pain and inflammation. A major improvement was observed within one week. The patient was able to walk without crutches one month later. After two months, clinical examination was normal: no pain, inflammation, nodules or fistulae. Flucytosine was stopped after six months of treatment, in January 2007, diclofenac after 10months, in October 2007, and posaconazole after 18.5months, also in October 2007. No relapse has occurred during the eight years of follow-up since treatment ended. The patient seems to have been cured and has normal CT, MRI, and PET scans. IN SUMMARY: This eumycetoma, which had progressed over 20years despite surgery and antifungal treatments, seems to have been cured by the addition of a NSAID. This observation suggests that inflammation plays a major role in the pathogenesis of fungal mycetoma. Clinical studies of treatments including an NSAID should be conducted to confirm this finding. PMID- 27233663 TI - Coronary Artery Dilatation in Viral Myocarditis Mimics Coronary Artery Findings in Kawasaki Disease. AB - Coronary artery (CA) dilatations are typical to Kawasaki disease (KD) in the pediatric population. CA involvement is a useful feature to help establish the diagnosis of KD. Since myocarditis is omnipresent in the acute phase of KD, we sought to investigate whether viral myocarditis may cause CA dilatation. This retrospective study reviewed 14 consecutive patients diagnosed with acute myocarditis at CHU Sainte-Justine, Montreal. KD diagnosis was excluded for all patients. All echocardiography studies were reviewed by an independent experienced echocardiographer for CA size and myocardial function parameters. CA involvement was classified under three categories: definite dilatation (Z-score >=2.5 in one or more CA), occult dilatation (Z-score variation >=2 points for the same CA on two different echocardiograms, but maximum Z-score always <2.5), and no dilatation otherwise. Demographics, laboratory values, microbial etiology testing, and diagnostic studies were collected from medical records. Mean age at presentation was 1.67 +/- 3.22 years, where 11/14 (78 %) presented with acute and three with subacute myocarditis. Five (36 %) patients had normal CA measurements, six (43 %) had occult dilatation, and three (21 %) had definite dilatation. Maximal CA Z-score was within the first 8 days of presentation. Patients with viral myocarditis can present CA dilatation during the acute phase of the illness. This finding should be taken into account when KD diagnosis is being based on the CA involvement as the two illnesses may present with similar features. PMID- 27233665 TI - Numerics made easy: solving the Navier-Stokes equation for arbitrary channel cross-sections using Microsoft Excel. AB - The fluid mechanics of microfluidics is distinctively simpler than the fluid mechanics of macroscopic systems. In macroscopic systems effects such as non laminar flow, convection, gravity etc. need to be accounted for all of which can usually be neglected in microfluidic systems. Still, there exists only a very limited selection of channel cross-sections for which the Navier-Stokes equation for pressure-driven Poiseuille flow can be solved analytically. From these equations, velocity profiles as well as flow rates can be calculated. However, whenever a cross-section is not highly symmetric (rectangular, elliptical or circular) the Navier-Stokes equation can usually not be solved analytically. In all of these cases, numerical methods are required. However, in many instances it is not necessary to turn to complex numerical solver packages for deriving, e.g., the velocity profile of a more complex microfluidic channel cross-section. In this paper, a simple spreadsheet analysis tool (here: Microsoft Excel) will be used to implement a simple numerical scheme which allows solving the Navier Stokes equation for arbitrary channel cross-sections. PMID- 27233666 TI - Evidence for common horizontal transmission of Wolbachia among butterflies and moths. AB - BACKGROUND: Wolbachia is one of the most widespread bacteria on Earth. Previous research on Wolbachia-host interactions indicates that the bacterium is typically transferred vertically, from mother to offspring, through the egg cytoplasm. Although horizontal transmission of Wolbachia from one species to another is reported to be common in arthropods, limited direct ecological evidence is available. In this study, we examine horizontal transmission of Wolbachia using a multilocus sequence typing (MLST) strains dataset and used Wolbachia and Lepidoptera genomes to search for evidence for lateral gene transfer (LGT) in Lepidoptera, one of the most diverse cosmopolitan insect orders. We constructed a phylogeny of arthropod-associated MLST Wolbachia strains and calibrated the age of Wolbachia strains associated with lepidopteran species. RESULTS: Our results reveal inter-specific, inter-generic, inter-familial, and inter-ordinal horizontal transmission of Wolbachia strains, without discernible geographic patterns. We found at least seven probable cases of horizontal transmission among 31 species within Lepidoptera and between Lepidoptera and other arthropod hosts. The divergence time analysis revealed that Wolbachia is recently (22.6-4.7 mya, 95 % HPD) introduced in Lepidoptera. Analysis of nine Lepidoptera genomes (Bombyx mori, Danaus plexippus, Heliconius melpomene, Manduca sexta, Melitaea cinxia, Papilio glaucus, P. polytes, P. xuthus and Plutella xylostella) yielded one possible instance of Wolbachia LGT. CONCLUSIONS: Our results provide evidence of high incidence of identical and multiple strains of Wolbachia among butterflies and moths, adding Lepidoptera to the growing body of evidence for common horizontal transmission of Wolbachia. This study demonstrates interesting dynamics of this remarkable and influential microorganism. PMID- 27233667 TI - Long Terminal Repeat Retrotransposon Content in Eight Diploid Sunflower Species Inferred from Next-Generation Sequence Data. AB - The most abundant transposable elements (TEs) in plant genomes are Class I long terminal repeat (LTR) retrotransposons represented by superfamilies gypsy and copia Amplification of these superfamilies directly impacts genome structure and contributes to differential patterns of genome size evolution among plant lineages. Utilizing short-read Illumina data and sequence information from a panel of Helianthus annuus (sunflower) full-length gypsy and copia elements, we explore the contribution of these sequences to genome size variation among eight diploid Helianthus species and an outgroup taxon, Phoebanthus tenuifolius We also explore transcriptional dynamics of these elements in both leaf and bud tissue via RT-PCR. We demonstrate that most LTR retrotransposon sublineages (i.e., families) display patterns of similar genomic abundance across species. A small number of LTR retrotransposon sublineages exhibit lineage-specific amplification, particularly in the genomes of species with larger estimated nuclear DNA content. RT-PCR assays reveal that some LTR retrotransposon sublineages are transcriptionally active across all species and tissue types, whereas others display species-specific and tissue-specific expression. The species with the largest estimated genome size, H. agrestis, has experienced amplification of LTR retrotransposon sublineages, some of which have proliferated independently in other lineages in the Helianthus phylogeny. PMID- 27233668 TI - The Use of Targeted Marker Subsets to Account for Population Structure and Relatedness in Genome-Wide Association Studies of Maize (Zea mays L.). AB - A typical plant genome-wide association study (GWAS) uses a mixed linear model (MLM) that includes a trait as the response variable, a marker as an explanatory variable, and fixed and random effect covariates accounting for population structure and relatedness. Although effective in controlling for false positive signals, this model typically fails to detect signals that are correlated with population structure or are located in high linkage disequilibrium (LD) genomic regions. This result likely arises from each tested marker being used to estimate population structure and relatedness. Previous work has demonstrated that it is possible to increase the power of the MLM by estimating relatedness (i.e., kinship) with markers that are not located on the chromosome where the tested marker resides. To quantify the amount of additional significant signals one can expect using this so-called K_chr model, we reanalyzed Mendelian, polygenic, and complex traits in two maize (Zea mays L.) diversity panels that have been previously assessed using the traditional MLM. We demonstrated that the K_chr model could find more significant associations, especially in high LD regions. This finding is underscored by our identification of novel genomic signals proximal to the tocochromanol biosynthetic pathway gene ZmVTE1 that are associated with a ratio of tocotrienols. We conclude that the K_chr model can detect more intricate sources of allelic variation underlying agronomically important traits, and should therefore become more widely used for GWAS. To facilitate the implementation of the K_chr model, we provide code written in the R programming language. PMID- 27233669 TI - Diversifying Selection Between Pure-Breed and Free-Breeding Dogs Inferred from Genome-Wide SNP Analysis. AB - Domesticated species are often composed of distinct populations differing in the character and strength of artificial and natural selection pressures, providing a valuable model to study adaptation. In contrast to pure-breed dogs that constitute artificially maintained inbred lines, free-ranging dogs are typically free-breeding, i.e., unrestrained in mate choice. Many traits in free-breeding dogs (FBDs) may be under similar natural and sexual selection conditions to wild canids, while relaxation of sexual selection is expected in pure-breed dogs. We used a Bayesian approach with strict false-positive control criteria to identify FST-outlier SNPs between FBDs and either European or East Asian breeds, based on 167,989 autosomal SNPs. By identifying outlier SNPs located within coding genes, we found four candidate genes under diversifying selection shared by these two comparisons. Three of them are associated with the Hedgehog (HH) signaling pathway regulating vertebrate morphogenesis. A comparison between FBDs and East Asian breeds also revealed diversifying selection on the BBS6 gene, which was earlier shown to cause snout shortening and dental crowding via disrupted HH signaling. Our results suggest that relaxation of natural and sexual selection in pure-breed dogs as opposed to FBDs could have led to mild changes in regulation of the HH signaling pathway. HH inhibits adhesion and the migration of neural crest cells from the neural tube, and minor deficits of these cells during embryonic development have been proposed as the underlying cause of "domestication syndrome." This suggests that the process of breed formation involved the same genetic and developmental pathways as the process of domestication. PMID- 27233670 TI - A Genome-Wide Association Study for Regulators of Micronucleus Formation in Mice. AB - In mammals the regulation of genomic instability plays a key role in tumor suppression and also controls genome plasticity, which is important for recombination during the processes of immunity and meiosis. Most studies to identify regulators of genomic instability have been performed in cells in culture or in systems that report on gross rearrangements of the genome, yet subtle differences in the level of genomic instability can contribute to whole organism phenotypes such as tumor predisposition. Here we performed a genome-wide association study in a population of 1379 outbred Crl:CFW(SW)-US_P08 mice to dissect the genetic landscape of micronucleus formation, a biomarker of chromosomal breaks, whole chromosome loss, and extranuclear DNA. Variation in micronucleus levels is a complex trait with a genome-wide heritability of 53.1%. We identify seven loci influencing micronucleus formation (false discovery rate <5%), and define candidate genes at each locus. Intriguingly at several loci we find evidence for sexual dimorphism in micronucleus formation, with a locus on chromosome 11 being specific to males. PMID- 27233672 TI - Characterization of partitioning behaviors of immunoglobulin G in polymer-salt aqueous two-phase systems. AB - The partitioning behavior of immunoglobulin G (IgG) in the aqueous two-phase system (ATPS) composed of poly(ethylene glycol) (PEG) and phosphate was studied. The parameters of ATPS exhibiting the pronounced effects on the partitioning behavior of IgG include phase composition, PEG molecular weight, and the addition of sodium chloride (NaCl). The accumulation of IgG at the interface of the ATPS increased drastically as the tie-line length (TLL) was increased. This trend was correlated with a linear relationship relating the natural logarithm of interfacial partition coefficient (ln G) to the difference of PEG concentration between the top phase and the bottom phase (Delta[PEG]), and a good fit was obtained. An attempt was made to correlate the natural logarithm of partition coefficient (ln K) to the presence of NaCl with the proposed linear relationship, ln K = alpha" ln [Cl-] + beta". The proposed relationship, which serves as a better description of the underlying mechanics of the protein partitioning behavior in the polymer-salt ATPS, provides a good fit (r2 > 0.95) for the data of IgG partitioning. An optimum recovery of 99.97% was achieved in an ATPS (pH 7.5) composed of 14.0% (w/w) PEG 1450, 12.5% (w/w) phosphate and 5.0% (w/w) NaCl. PMID- 27233671 TI - Embryonic Methamphetamine Exposure Inhibits Methamphetamine Cue Conditioning and Reduces Dopamine Concentrations in Adult N2 Caenorhabditis elegans. AB - Methamphetamine (MAP) addiction is substantially prevalent in today's society, resulting in thousands of deaths and costing billions of dollars annually. Despite the potential deleterious consequences, few studies have examined the long-term effects of embryonic MAP exposure. Using the invertebrate nematode Caenorhabditis elegans allows for a controlled analysis of behavioral and neurochemical changes due to early developmental drug exposure. The objective of the current study was to determine the long-term behavioral and neurochemical effects of embryonic exposure to MAP in C. elegans. In addition, we sought to improve our conditioning and testing procedures by utilizing liquid filtration, as opposed to agar, and smaller, 6-well testing plates to increase throughput. Wild-type N2 C. elegans were embryonically exposed to 50 MUM MAP. Using classical conditioning, adult-stage C. elegans were conditioned to MAP (17 and 500 MUM) in the presence of either sodium ions (Na+) or chloride ions (Cl-) as conditioned stimuli (CS+/CS-). Following conditioning, a preference test was performed by placing worms in 6-well test plates spotted with the CS+ and CS- at opposite ends of each well. A preference index was determined by counting the number of worms in the CS+ target zone divided by the total number of worms in the CS+ and CS- target zones. A food conditioning experiment was also performed in order to determine whether embryonic MAP exposure affected food conditioning behavior. For the neurochemical experiments, adult worms that were embryonically exposed to MAP were analyzed for dopamine (DA) content using high-performance liquid chromatography. The liquid filtration conditioning procedure employed here in combination with the use of 6-well test plates significantly decreased the time required to perform these experiments and ultimately increased throughput. The MAP conditioning data found that pairing an ion with MAP at 17 or 500 MUM significantly increased the preference for that ion (CS+) in worms that were not pre-exposed to MAP. However, worms embryonically exposed to MAP did not exhibit significant drug cue conditioning. The inability of MAP-exposed worms to condition to MAP was not associated with deficits in food conditioning, as MAP exposed worms exhibited a significant cue preference associated with food. Furthermore, our results found that embryonic MAP exposure reduced DA levels in adult C. elegans, which could be a key mechanism contributing to the long-term effects of embryonic MAP exposure. It is possible that embryonic MAP exposure may be impairing the ability of C. elegans to learn associations between MAP and the CS+ or inhibiting the reinforcing properties of MAP. However, our food conditioning data suggest that MAP-exposed animals can form associations between cues and food. The depletion of DA levels during embryonic exposure to MAP could be responsible for driving either of these processes during adulthood. PMID- 27233674 TI - Refugee migration and risk of schizophrenia and other non-affective psychoses: cohort study of 1.3 million people in Sweden. PMID- 27233673 TI - Does Warm-Up Training in a Virtual Reality Simulator Improve Surgical Performance? A Prospective Randomized Analysis. AB - INTRODUCTION: Virtual reality surgical simulators (VRSS) have been showing themselves as a valuable tool in laparoscopy training and education. Taking in consideration the effectiveness of the VRSS, new uses for this tool have been purposed. In sports, warming up before exercise clearly shows benefit in performance. It is hypothesized that warming up in the VRSS before going to the operating room may show benefit in surgical performance. OBJECTIVE: Verify whether there is benefit in surgical performance with preoperatory warm-up using a VRSS. MATERIALS AND METHODS: A total of 20 medical students with basic knowledge in laparoscopy were divided in 2 groups (I and II). Group I performed a laparoscopic cholecystectomy in a porcine model. Group II performed preoperative warm-up in a VRSS and then performed a laparoscopic cholecystectomy in a porcine model. The performance between both groups was compared regarding quantitative parameters (time for dissection of the gallbladder pedicle, time for clipping the pedicle, time for cutting the pedicle, time for gallbladder removal, total operative time, and aspirated blood loss) and qualitative parameters (depth perception, bimanual dexterity, efficiency, tissue handling, and autonomy) based on a previously validated score system, in which the higher the score, the better the result. Data were analyzed with level of significance of 5%. RESULTS: The group that underwent preoperative warm-up (group II) showed significantly superior results as to the time for dissection of the gallbladder pedicle (11.91 +/- 9.85 vs. 4.52 +/- 2.89min, p = 0.012), time for clipping the pedicle (5.51 +/ 2.36 vs. 2.89 +/- 2.76min, p = 0.004), time for cutting the pedicle (1.84 +/- 0.7 vs. 1.13 +/- 0.51, p = 0.019), aspirated blood loss (171 +/- 112 vs. 57 +/- 27.8ml, p = 0.006), depth perception (4.5 +/- 0.7 vs. 3.3 +/- 0.67, p = 0.004), bianual dexterity (4.2 +/- 0.78 vs. 3.3 +/- 0.67, p = 0.004), tissue handling (4.2 +/- 0.91 vs. 3.6 +/- 0.66, p = 0.012), and autonomy (4.9 +/- 0.31 vs. 3.6 +/ 0.96, p = 0.028). There was no difference in time for gallbladder removal (11.58 +/- 4.31 vs. 15.08 +/- 4.51min, p = 0.096), total operative time (30.8 +/- 11.07 vs. 25.60 +/- 5.10min, p = 0.188), and efficiency (4 +/- 0.66 vs. 3.6 +/- 0.69, p = 0.320). CONCLUSION: The practice of preoperative warm-up training seems to benefit surgical performance even in subject with mild laparoscopic experience. PMID- 27233675 TI - The Fenix II study: A longitudinal study of psychopathology among burn patients. AB - Psychological symptoms are common among burn survivors. However, knowledge about epidemiology and predictors of psychopathology has shown great heterogeneity in this population. The Fenix-II Project was the first epidemiological study on the psychopathological consequences of burns developed in Spain, providing a detailed analysis of the progression of psychological symptoms during the first six months after injury. Three hundred and thirty-three patients were screened and 183 were included in this study. Posttraumatic, depression and anxiety symptoms showed a general decreasing tendency across time. At 6 months, 34 patients showed clinically significant Posttraumatic Stress Disorder (PTSD) symptoms (20.5% of 166 patients reached at 6 months) as assessed with the MINI Neuropsychiatric Interview. Within this group of patients, anxiety, depression and hyperarousal increased at 30 days, and avoidance 90 days after injury. The most accurate predictors of PTSD were found to be being burned in a Motor Vehicle Crash, risk of social exclusion, low body-image adjustment, anterior trunk location of the burn and life threat perception during the burn-shock period. Considering these factors, clinicians may identify patients at risk of PTSD development, allowing an adequate follow up and preventive interventions which may minimize the psychological consequences of burns. PMID- 27233676 TI - Rehabilitation of a bilateral upper limb amputee in a resource restricted burn service. PMID- 27233677 TI - Transepidermal water loss measured with the Tewameter TM300 in burn scars. AB - Transepidermal water loss (TEWL) is a physiological characteristic to measure the efficiency of the skin barrier. The aim was to investigate the reliability of the Tewameter TM300 for the assessment of TEWL (g/m2/h) in burn scars. Also the relation between TEWL scar values and scar quality parameters was investigated. Three different study areas (scar, healthy adjacent and contralateral skin) were assessed in 55 adult patients. The intra- and inter-observer reliability were tested using the intra-class correlation coefficient (ICC) and the standard error of measurement (SEM). The inter-observer reliability for the three areas was excellent with ICC values between 0.85 and 0.94. SEM values were between 1.76 and 3.97g/m2/h. Bland-Altman plots showed relatively wide LoA values for scar and healthy skin. Mean TEWL scar values were significantly higher than healthy skin (p<0.001). Significant correlations were found between TEWL hypertrophic scar values and erythema (r=0.60, p=0.001) and a negative correlation for weeks after burn (r=-0.61, p=0.001). TEWL values were significantly different between 3 and 6 months and 3 and 12 months old scars (respectively p=0.021 and p=0.002). To evaluate the skin barrier function over time as a measure for scar maturation, Tewameter TM300 measurements have to be performed according to strict and standardized protocols. PMID- 27233678 TI - Suprathel((r)) for severe burns in the elderly: Case report and review of the literature. AB - Large burns in aged patients are common and treatment often reveals challenging. Cardiovascular complications significantly contribute to the unfavorable prognosis in this group of high-risk patients. Pain medication and sedation can negatively influence cardiovascular stability. Suprathel((r)) is well-known for its almost pain free application and reduction of dressing change intervals, and thus lowers the demand for potentially harmful analgesics and sedatives. We present the case of an 81-year-old patient with 51% of total burned body surface area (ABSI=12), who was completely treated with Suprathel((r)). Despite a predicted mortality of more than 80%, the patient survived and was discharged home without significant handicaps 69 days after burn. We hypothesize that Suprathel((r)) beneficially contributed to the favorable clinical course of this critical patient as less frequent wound-dressing changes did not induce additional pain or sedative medication and thus improved cardiovascular stability. PMID- 27233679 TI - Multi drug resistance and Extended Spectrum Beta Lactamases in clinical isolates of Shigella: A study from New Delhi, India. AB - BACKGROUND: Shigella is an important cause of gastroenteritis in local Indian population, as well as of traveler's diarrhea in the international visitors to India. These patients often require appropriate antimicrobial therapy; however, rapid development of antimicrobial resistance poses a major hurdle in achieving this goal. METHOD: A prospective study was conducted during 2009-12 in New Delhi, India, including 6339 stool samples from gastroenteritis patients. 121 Shigella strains were identified on the basis of colony morphology, biochemical reactions, serotyping and ipaH gene based PCR. Antimicrobial susceptibility testing by disc diffusion, MIC determination by Vitek((r)) 2 and phenotypic tests for ESBL/AmpC production were done. RESULTS: Nineteen percent strains (23/121) were found to be resistant to third generation cephalosporins and all were phenotypically confirmed to be ESBL producers; one strain was positive for AmpC. ESBL producing strains were also found to be significantly more resistant (p < 0.05) to several other antimicrobials agents in comparison to ESBL non-producers, [ampicillin (100% vs. 62.2%), ampicillin/sulbactam (100% vs. 30.6%), cotrimoxazole (100% vs. 77.6%), ciprofloxacin (87.0% vs. 49.0%), ofloxacin (87.0% vs. 52.0%) and gentamicin (30.4% vs. 7.1%)]. Multidrug resistance was seen in 76% strains. CONCLUSIONS: Inappropriate use of antimicrobial agents puts high selection pressure on the higher-end antibiotics. Multi-drug resistance and high rates of ESBL production by Shigella is a matter of concern for the local population as well as international travelers. Therefore, better national level antimicrobial management programs are the priority needs. PMID- 27233680 TI - Transmission of blood-borne pathogens in US dental health care settings: 2016 update. AB - BACKGROUND: During the past decade, investigators have reported transmissions of blood-borne pathogens (BBPs) in dental settings. In this article, the authors describe these transmissions and examine the lapses in infection prevention on the basis of available information. METHODS: The authors reviewed the literature from 2003 through 2015 to identify reports of the transmission of BBPs in dental settings and related lapses in infection prevention efforts, as well as to identify reports of known or suspected health care-associated BBP infections submitted by state health departments to the Centers for Disease Control and Prevention. RESULTS: The authors identified 3 published reports whose investigators described the transmission of hepatitis B virus and hepatitis C virus. In 2 of these reports, the investigators described single-transmission events (from 1 patient to another) in outpatient oral surgery practices. The authors of the third report described the possible transmission of hepatitis B virus to 3 patients and 2 dental health care personnel in a large temporary dental clinic. The authors identified lapses in infection prevention practices that occurred during 2 of the investigations; however, the investigators were not always able to link a specific lapse to a transmission event. Examples of lapses included the failure to heat-sterilize handpieces between patients, a lack of training for volunteers on BBPs, and the use of a combination of unsafe injection practices. CONCLUSIONS: The authors found that reports describing the transmission of BBPs in dental settings since 2003 were rare. Failure to adhere to Centers for Disease Control and Prevention recommendations for infection control in dental settings likely led to disease transmission in these cases. PRACTICAL IMPLICATIONS: The existence of these reports emphasizes the need to improve dental health care personnel's understanding of the basic principles and implementation of standard precautions through the use of checklists, policies, and practices. PMID- 27233681 TI - GABAergic Function as a Limiting Factor for Prefrontal Maturation during Adolescence. AB - Adolescence is a vulnerable period for the onset of mental illnesses including schizophrenia and affective disorders, yet the neurodevelopmental processes underlying this vulnerability remain poorly understood. The prefrontal cortex (PFC) and its local GABAergic system are thought to contribute to the core of cognitive deficits associated with such disorders. However, clinical and preclinical end-point analyses performed in adults are likely to give limited insight into the cellular mechanisms that are altered during adolescence but are only manifested in adulthood. This perspective summarizes work regarding the developmental trajectories of the GABAergic system in the PFC during adolescence to provide an insight into the increased susceptibility to psychiatric disorders during this critical developmental period. PMID- 27233683 TI - Supports for medical students during rural clinical placements: factors associated with intention to practise in rural locations. AB - INTRODUCTION: Through rural clinical schools (RCSs), medical students may undertake an extended block of clinical training in rural Australia. The premise of these placements is that meaningful rural exposure will facilitate rural career uptake. RCSs offer a range of supports to facilitate student engagement in the program. This study aims to analyse RCS students' perceptions of these supports and impact on intentions to work rurally. METHODS: Between September 2012 and January 2013 RCS students were invited to complete questions regarding perceptions of student support, as a part of the annual Federation of Australian Medical Educators survey. Multivariable logistic regression was used to identify associations between supports and intentions for rural internship or career. RESULTS: There were 454 participants. A majority of students (n=349, 79.1%) felt well supported by their RCS. Students from a rural background (odds ratio (OR)=1.64 (95% confidence interval (CI):1.13-2.38)), or who indicated that their placement had a positive impact on their wellbeing (OR=1.38 (95%CI:1.07-1.80)), were more likely to intend to complete a rural internship. Those who felt socially isolated were less likely to elect this (OR=0.82 (0.70-0.97)). Outcomes were similar for those indicating a preference for rural or remote practice after completing training. CONCLUSIONS: Student perceptions of supports offered by RCSs were generally very positive. Perceptions of financial support were not predictive of rural career intent. Although this does not negate the importance of providing appropriate financial supports, it does demonstrate that student wellbeing is a more important recruitment factor for rural practice. PMID- 27233682 TI - Microtubules and Growth Cones: Motors Drive the Turn. AB - Navigation of the growth cone at the tip of the developing axon is crucial for the proper wiring of the nervous system. Mechanisms of actin-dependent growth cone steering, via signaling cascades, are well documented. Microtubules are also important in growth cone guidance, because their polarized invasion into the peripheral domain on one side of the growth cone is essential for it to turn in that direction. Classically, microtubules have been considered secondary players, invading the peripheral domain only where the actin cytoskeleton permits them to go. Presented here is evidence for an underappreciated mechanism by which signaling cascades can potentially affect growth cone turning, namely through regulatable forces imposed on the microtubules by molecular motor proteins. PMID- 27233684 TI - Barriers of vaccinations against serious bacterial infections among Australian Hajj pilgrims. AB - OBJECTIVES: Vaccination against serious bacterial infections is recommended for Hajj pilgrims. Although the uptake of mandatory vaccines among Hajj pilgrims is acceptable, the uptake of other recommended vaccines remains suboptimal. In this study, we have explored the barriers to vaccination against serious bacterial infections among Australian Hajj pilgrims. METHODS: Travellers aged 18 years and older planning to attend Hajj in the years 2014 and 2015 were surveyed at the immunization clinic of the Children's Hospital at Westmead, Sydney, Australia. A questionnaire-based survey was conducted to explore pilgrims' vaccination histories for their previous visits to Mecca, the reasons for non-receipt of vaccination, and to assess knowledge about the transmission of infections. RESULTS: A total of 300 participants aged 18-76 (median 41) years completed the survey. Most (233 [77.7%]) were born outside Australia. Overall, 113 (37.7%) had performed pilgrimage in the past; 19 (16.8%) of them reported receiving pneumococcal vaccine and 16 (14.1%) diphtheria, tetanus and pertussis (DTP) vaccine. Lack of awareness about the availability of the vaccines was the main reason for non-receipt of pneumococcal and DTP vaccines (respectively 41.1% and 44.7%). Most pilgrims (266 [88.7%]) believed that travel vaccines are necessary before embarking on a journey; however, some expressed concerns about adverse reactions (156 [52.0%]), cost (114 [38.0%]), and permissibility of the vaccine according to their religion (6 [2.0%]). Respectively, 187 (62.3%), 145 (48.3%) and 86 (28.7%) respondents did not correctly know how meningococcal and pneumococcal diseases and pertussis transmit. Nevertheless, most (256 [85.3%]) indicated that they trust their family doctor for medical information and most (203 [67.7%]) preferred to receive the medical information in English. CONCLUSION: The uptake of recommended vaccines against serious bacterial infections among Australian Hajj pilgrims is low. Lack of awareness about the availability of vaccines, misperceptions surrounding the safety of vaccines and high cost are key barriers of uptake. PMID- 27233685 TI - Aggregation and Particle Formation of Therapeutic Proteins in Contact With a Novel Fluoropolymer Surface Versus Siliconized Surfaces: Effects of Agitation in Vials and in Prefilled Syringes. AB - We examined the effects of an accelerated agitation protocol on 2 protein therapeutics, intravenous immunoglobulin (IVIG) and Avastin (bevacizumab), in contact with a novel fluoropolymer surface and more typical siliconized surfaces. The fluoropolymer surface provides "solid-phase" lubrication for the syringe plunger-obviating the need for silicone oil lubrication in prefilled syringes. We tested the 2 surfaces in a vial system and in prefilled glass syringes. We also examined the effects of 2 buffers, phosphate-buffered saline (PBS) and 0.2-M glycine, with and without the addition of polysorbate 20, on agitation-induced aggregation of IVIG. Aggregation was monitored by measuring subvisible particle formation and soluble protein loss. In both vials and syringes, protein particle formation was much lower during agitation with the fluoropolymer surface than with the siliconized surface. Also, particle formation was greater in PBS than in glycine buffer, an effect attributed to lower colloidal stability of IVIG in PBS. Polysorbate 20 in the formulation greatly inhibited protein particle formation. Overall, the fluoropolymer plunger surface in an unsiliconized glass barrel was demonstrated to be a viable solution for eliminating silicone oil droplets from prefilled syringe formulations and providing a consistent system for rationale formulation development and simplified particle analysis. PMID- 27233686 TI - Transdermal Delivery of Etoposide Phosphate II: In Vitro In Vivo Correlations (IVIVC). AB - A dependable in vitro in vivo correlation (IVIVC) is a vital tool to optimize drug formulation and expedite product development time. Although many IVIVC examples are available for oral delivery systems, IVIVC for transdermal delivery is far less common, especially for electrical-assisted delivery. The objective of this study was to develop an IVIVC for the iontophoretic delivery of the anticancer drug etoposide. Iontophoresis was performed at 4 current densities (100, 200, 300, and 400 MUA/cm(2)) both in vitro using a standard Franz-cell apparatus with excised porcine skin as membrane, and in vivo in a rabbit model. There was strong correlation between the in vitro % permeated across porcine skin and in vivo absorption (AUC, Cmax) in the range 100-300 MUA/cm(2). The correlation between in vitro flux and in vivo input rate (R0) permitted to predict the R0 from a different set of in vitro data (external validation). Convolution of such input rate accurately predicted in vivo plasma profiles (PE% <15) in the absorption phase, whereas the elimination phase was slightly under predicted (PE% >20). In vivo absorption profiles obtained with deconvolution did not overlap directly with the in vitro profiles; however, correction for the lag time and the application of a scaling factor estimated from Levy' s plots resulted in excellent correlation. PMID- 27233687 TI - Thiolated alpha-Cyclodextrin: The Invisible Choice to Prolong Ocular Drug Residence Time. AB - It was the aim of this study to develop cysteamine-conjugated alpha-cyclodextrin (alpha-CD) enabled to form disulfide bonds with cysteine-rich substructures of the ocular mucus layer to provide a prolonged residence time of incorporated drugs at the site of action. Cysteamine was covalently attached to oxidized alpha CD via reductive amination. The resulting alpha-CD-cysteamine conjugates (alpha CD-Cys) were characterized regarding the amount of free thiol groups attached to the oligomer backbone via Ellman's reagent; resazurin assay was conducted for cytotoxicity, and mucoadhesive properties were evaluated on porcine intestinal and ocular mucosal tissues. Furthermore, albino rabbits were used for assessing the irritation-masking effects of alpha-CD-Cys. Free thiol groups attached to the backbone were in the range of 558 +/- 24-1143 +/- 92 MUmol/g. None of these alpha CD-Cys unduly affected the viability of Caco-2 cells in a concentration of 0.5%. Mucoadhesive properties of alpha-CD-Cys were up to 32-fold improved compared to unmodified alpha-CD. Encapsulation of cetirizine into alpha-CD-Cys resulted in significantly reduced local ocular mucosal irritation of this model drug. According to these results, alpha-CD-Cys is a promising new tool to prolong drug residence time on the ocular mucosal surface. PMID- 27233688 TI - Production and Characterization of Chemically Inactivated Genetically Engineered Clostridium difficile Toxoids. AB - A recombinant Clostridium difficile expression system was used to produce genetically engineered toxoids A and B as immunogens for a prophylactic vaccine against C. difficile-associated disease. Although all known enzymatic activities responsible for cytotoxicity were genetically abrogated, the toxoids exhibited residual cytotoxic activity as measured in an in vitro cell-based cytotoxicity assay. The residual cytotoxicity was eliminated by treating the toxoids with 1 ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide. Mass spectrometry and amino acid analysis of the EDC-inactivated toxoids identified crosslinks, glycine adducts, and beta-alanine adducts. Surface plasmon resonance analysis demonstrated that modifications resulting from the chemical treatment did not appreciably affect recognition of epitopes by both toxin A- and B specific neutralizing monoclonal antibodies. Compared to formaldehyde-inactivated toxoids, the EDC/N-hydroxysuccinimide-inactivated toxoids exhibited superior stability in solution with respect to reversion of cytotoxic activity. PMID- 27233689 TI - Transdermal Delivery of Etoposide Phosphate I: In Vitro and In Vivo Evaluation. AB - Cancer chemotherapy frequently requires long periods of multiple intravenous infusions that often results in patients opting out of treatment. The main purpose of this study was to investigate the feasibility of delivering one of these anticancer agents: etoposide phosphate (ETP) transdermally using iontophoresis and a combination of iontophoresis/microporation. The iontophoresis conditions for ETP were first optimized in vitro then tested in vivo in a rabbit model. Both ETP and its active form etoposide (VP) were quantified in dermis (via microdialysis sampling) and in plasma, with a specially developed high performance liquid chromatography method. In vitro, the amount of total etoposide permeated and the steady state flux increased (p < 0.05) with increase in iontophoretic current densities (100-400 MUA/cm(2)). At 300 MUA/cm(2), microporation/iontophoresis further improved both parameters by 2- and 2.8-fold, respectively. In vivo, exposure increased proportionally to current density in plasma, whereas dermal concentration dropped significantly at the highest current density. Microporation led to a 50% increase in Cmax and AUClast values in both skin and plasma. In conclusion, a mild current density (300 MUA/cm(2)) and a small surface area (10.1 cm(2)) achieved and maintained the minimum effective concentration for the entire duration of electrical current delivery; microporation further increased the plasma concentrations at the same current density. PMID- 27233690 TI - Temporal processing and long-latency auditory evoked potential in stutterers. AB - INTRODUCTION: Stuttering is a speech fluency disorder, and may be associated with neuroaudiological factors linked to central auditory processing, including changes in auditory processing skills and temporal resolution. OBJECTIVE: To characterize the temporal processing and long-latency auditory evoked potential in stutterers and to compare them with non-stutterers. METHODS: The study included 41 right-handed subjects, aged 18-46 years, divided into two groups: stutterers (n=20) and non-stutters (n=21), compared according to age, education, and sex. All subjects were submitted to the duration pattern tests, random gap detection test, and long-latency auditory evoked potential. RESULTS: Individuals who stutter showed poorer performance on Duration Pattern and Random Gap Detection tests when compared with fluent individuals. In the long-latency auditory evoked potential, there was a difference in the latency of N2 and P3 components; stutterers had higher latency values. CONCLUSION: Stutterers have poor performance in temporal processing and higher latency values for N2 and P3 components. PMID- 27233691 TI - Ophthalmic complications of endoscopic sinus surgery. AB - INTRODUCTION: The proximity of the paranasal sinuses to the orbit and its contents allows the occurence of injuries in both primary or revision surgery. The majority of orbital complications are minor. The major complications are seen in 0.01-2.25% and some of them can be serious, leading to permanent dysfunction. OBJECTIVE: The aim of this study was to determine the risk and type of ophthalmic complications among patients operated due to a chronic rhinosinusitis. METHODS: This is a retrospective study of 1658 patients who underwent endoscopic sinus surgery for chronic rhinosinusitis with or without polyps or mucocele. Surgeries were performed under general anesthesia in all cases and consisted of polyps' removal, followed by middle metal antrostomy, partial or complete ethmoidectomy, frontal recess surgery and sphenoid surgery if necessary. The ophthalmic complications were classified according to type, frequency and clinical findings. RESULTS: In our material 32.68% of the patients required revision surgery and only 10.1% had been previously operated in our Department. Overall complications occurred in 11 patients (0.66%). Minor complications were observed in 5 patients (0.3%) with the most frequent being periorbital ecchymosis with or without emphysema. Major complications were observed in one patient (0.06%) and were related to a lacrimal duct injury. Severe complications occurred in 5 cases (0.3%), with 2 cases and referred to a retroorbital hematoma, optic nerve injury (2 cases) and one case of extraocular muscle injury. CONCLUSIONS: Orbital complications of endoscopic nasal surgery are rare. The incidence of serious complications, causing permanent disabilities is less than 0.3%. The most important parameters responsible for complications are extension of the disease, previous endoscopic surgery and coexisting anticoagulant treatment. PMID- 27233692 TI - Investigation of force received at the upper teeth by video laryngoscopy. PMID- 27233693 TI - Ulinastatin ameliorates gastrointestinal injury sustained in a 2-hit porcine model of septic shock. AB - BACKGROUND: Ulinastatin is protective against organ dysfunction in severe disease. We investigated the extent of gastrointestinal tract injury and the potential protective effect of ulinastatin in a 2-hit porcine model of septic shock. METHODS: Pigs were randomized to 4 groups, 3 septic shock groups (12 per group)-vancomycin (VAN), vancomycin + ulinastatin (VAN + ULI), and saline (SAL) and a sham-operated group (n = 10). Septic shock was induced by 2 hits: acute lung injury and Staphylococcus aureus challenge. Four hours after the 2 hits, pigs in septic shock received a central venous injection of vancomycin, vancomycin + ulinastatin, or saline. Hemodynamic status and blood samples were obtained. Serum d-lactate, diamine oxidase, and intestinal fatty acid-binding protein were determined, and gastrointestinal ATP enzyme activity was measured. Pathological and ultrastructural tests were performed. RESULTS: Gastrointestinal tract injury after septic shock was significant. Compared with the SAL and VAN groups, the VAN + ULI group had better hemodynamic parameters (improved mean arterial pressure and cardiac output) (P< .05) and improved oxygen metabolism (oxygen delivery and consumption) (P< .05). In VAN + ULI group, serum d-lactate, diamine oxidase, and intestinal fatty acid-binding protein were significantly reduced (P< .05). Moreover, Na(+)-K(+)- and Ca(2+)-ATPase enzyme activity was significantly high (P< .05). Pathological and ultrastructural changes showed that severe gastrointestinal injury was significantly ameliorated in the VAN + ULI group vs the SAL and VAN groups. CONCLUSIONS: Gastrointestinal injury and abnormal energy metabolism are remarkable following septic shock. Ulinastatin can improve energy metabolism and ameliorate injury to the gastrointestinal mucosa in the early stage of septic shock. PMID- 27233694 TI - Treatment of a patient in hemorrhagic shock due to leech bite with tranexamic acid. PMID- 27233695 TI - Stroke prevention for patients with atrial fibrillation: values and preferences of Canadian emergency medicine trainees. PMID- 27233696 TI - Application of LMA Classic for anesthetized, paralyzed children weighing 20 kg: comparison between size 2 and size 2.5. PMID- 27233697 TI - Treatment of ethanol poisoning and associated hypoventilation with doxapram. PMID- 27233698 TI - Dimension reduction: perihematomal edema diameter as a predictive indicator of 30 day mortality of intracranial hematoma. PMID- 27233699 TI - Underuse of information about timing and triggers in diagnosing dizziness in EDs. PMID- 27233700 TI - An overview on catheter-directed option for pulmonary embolism treatment. PMID- 27233741 TI - Hormones and pregnancy: Many players in a very long trip. PMID- 27233742 TI - Maternal alterations in the proteome of the medial prefrontal cortex in rat. AB - : Proteomic differences between rat dams and control mothers deprived of their pups immediately after delivery were investigated in the medial prefrontal cortex (mPFC). A 2-D DIGE minimal dye technique combined with LC-MS/MS identified 32 different proteins that showed significant changes in expression in the mPFC, of which, 25 were upregulated and 7 were downregulated in dams. The identity of one significantly increased protein, the small heat-shock protein alpha-crystallin B chain (Cryab), was confirmed via Western blot analysis. Alpha-crystallin B chain was distributed in scattered cells in the mPFC, as demonstrated by immunohistochemistry. Furthermore, it was found to be localized in parvalbumin containing neurons using double labeling. The elevation of its mRNA level in rat dams was also demonstrated via RT-PCR. The functional classification of the altered proteins was conducted using the UniProt and Gene Ontology protein databases. The identified proteins predominantly participate in synaptic transport and plasticity, neuron development, oxidative stress and apoptosis, and cytoskeleton organization. A common regulator and target analysis of these proteins determined using the Elsevier Pathway Studio Platform suggests that protein level changes associated with pup nursing are driven by growth factors and cytokines, while the MAP kinase pathway was identified as a common target. A high proportion of the proteins that were found to be altered in the mPFC are associated with depression. BIOLOGICAL SIGNIFICANCE: The behavior and emotional state of females change robustly when they become mothers. The brain, which governs these changes, may also undergo molecular alterations in mothers. As no proteomics approaches have been applied regarding maternal changes in the brain, we addressed this issue in the mPFC as this brain area is the uppermost cortical center of maternal control and the associated mood changes. The high number of protein-level alterations found between mothers taking care of their litter and those without pups indicates that pup nursing is associated with cortical protein level changes. Alterations in proteins participating in synaptic transport, plasticity and neuron development suggest neuroplastic changes in the maternal brain. In turn, the relatively high number of altered proteins in the mPFC associated with depression suggests that the physiological effects of the protein level alterations in the maternal mPFC could promote the incidence of postpartum depression. Cryab, a protein confirmed to be increased during maternal behaviors, was selectively found in parvalbumin cells, which, as fast-spiking interneurons, are associated with depression. The function of Cryab should be further investigated to establish whether it can be used to identify drug targets for future drug development. PMID- 27233743 TI - Quantitative proteomics and phosphoproteomics of sugar beet monosomic addition line M14 in response to salt stress. AB - Salinity is a major abiotic stress affecting plant growth, development and agriculture productivity. Understanding the molecular mechanisms of salt stress tolerance will provide valuable information for effective crop engineering and breeding. Sugar beet monosomic addition line M14 obtained from the intercross between Beta vulgaris L. and Beta corolliflora Zoss exhibits tolerance to salt stress. In this study, the changes in the M14 proteome and phosphoproteome induced by salt stress were analyzed. We report the characteristics of the M14 plants under 0, 200, and 400mM NaCl using label-free quantitative proteomics approaches. Protein samples were subjected to total proteome profiling using LC MS/MS and phosphopeptide enrichment to identify phosphopeptides and phosphoproteins. A total of 2182 proteins were identified and 114 proteins showed differential levels under salt stress. Interestingly, 189 phosphoproteins exhibited significant changes at the phosphorylation level under salt stress. Several signaling components associated with salt stress were found, e.g. 14-3-3 and mitogen-activated protein kinases (MAPK). Fifteen differential phosphoproteins and proteins involved in signal transduction were tested at the transcriptional level. The results revealed the short-term salt responsive mechanisms of the special sugar beet M14 line using label-free quantitative phosphoproteomics. BIOLOGICAL SIGNIFICANCE: Sugar beet monosomic addition line M14 is a special germplasm with salt stress tolerance. Analysis of the M14 proteome and phosphoproteome under salt stress has provided insight into specific response mechanisms underlying salt stress tolerance. Reversible protein phosphorylation regulates a wide range of cellular processes such as transmembrane signaling, intracellular amplification of signals, and cell-cycle control. This study has identified significantly changed proteins and phosphoproteins, and determined their potential relevance to salt stress response. The knowledge gained can be potentially applied to improving crop salt tolerance. PMID- 27233744 TI - Air pollution and heart disease. PMID- 27233745 TI - Who should finance WHO's work on emergencies? PMID- 27233747 TI - Interaction of CYP2C19, P2Y12, and GPIIIa Variants Associates With Efficacy of Clopidogrel and Adverse Events on Patients With Ischemic Stroke. AB - OBJECTIVE: Clopidogrel is a clinically important oral antiplatelet agent for the treatment or prevention of cerebrovascular disease. However, different individuals have different sensitivities to clopidogrel. This study assessed variants of different genes for association with response to clopidogrel, clinical outcome, and side effects in patients with ischemic stroke (IS). METHODS: We consecutively enrolled 375 patients with IS after they received clopidogrel therapy, and venous blood samples were subjected to genotyping allelic variants of genes modulating clopidogrel absorption (ATP binding cassette subfamily B1, ABCB1), metabolic activation (cytochrome P450[CYP] 3A and CYP2C19), and biologic activity (platelet membrane receptor [ P2Y12, P2Y1)], and glycoprotein IIIa [ GPIIIa]) and statistically analyzing their interactions with clopidogrel sensitivity (CS) and adverse events, risk of IS recurrence, myocardial infarction, and death during 6 months of follow-up. RESULTS: Adverse events occurred in 37 patients (31 had IS recurrence, 4 died, and 2 had myocardial infarction) during the first 6 months of follow-up. Single locus analysis showed that only the CYP2C19*2(rs4244285) variant was independently associated with CS and risk of adverse events after adjusting covariates. However, there was significant gene-gene interaction among CYP2C19*2(rs4244285), P2Y12(rs16863323), and GPIIIa (rs2317676) analyzed by generalized multifactor dimensionality reduction methods. The rate of adverse events among patients with the 3-loci interaction was 2.82 times the rate among those with no interaction (95% confidence interval: 2.04-8.63). CONCLUSION: Sensitivity of patients with IS to clopidogrel and clopidogrel-induced adverse clinical events may be multifactorial but is not determined by single gene polymorphisms. PMID- 27233748 TI - Evaluation of a New Sonoclot Device for Heparin Management in Cardiac Surgery. AB - BACKGROUND: Sonoclot is used to measure kaolin-based activated clotting time (kACT) for heparin management. Apart from measuring kACT, the device assesses the patient's coagulation status by glass bead-activated tests (gbACTs; measuring also clot rate [CR] and platelet function [PF]). Recently, a new version of the Sonoclot has been released, and the redesign may result in performance changes. The aim of this study was to evaluate and compare the performance of the new (S2) and the previous (S1) Sonoclot. METHODS: The S1 was used in the routine management of 30 patients undergoing elective cardiac surgery. Blood samples were taken at baseline (T1), after heparin administration (200 U/kg, 100 U/kg; T2 and T3), during cardiopulmonary bypass (T4), after protamine infusion (T5), and before intensive care unit transfer (T6). Kaolin-based activated clotting time and gbACTs were measured in duplicate by both the old and the new device and performance compared by Bland-Altman analysis and percentage error calculation. RESULTS: A total of 300 kACT and 180 gbACTs were available. Bland-Altman analysis for kACT revealed that S2 consistently reported results in shorter time compared to S1 (overall = -14.7%). Comparing S2 and S1, the glass bead-activated tests showed mean percentage differences of -18.9% (gbACTs), +37.4% (CR), and -3.7% (PF). CONCLUSION: Since clotting is faster in the new S2 compared to S1, shorter clotting times have to be considered in clinical practice. The use of S2 kACT in heparin management will result in higher heparin and protamine dosing unless heparin kACT target values are adjusted to correct for the differences in results between S1 and S2. PMID- 27233746 TI - Association between air pollution and coronary artery calcification within six metropolitan areas in the USA (the Multi-Ethnic Study of Atherosclerosis and Air Pollution): a longitudinal cohort study. AB - BACKGROUND: Long-term exposure to fine particulate matter less than 2.5 MUm in diameter (PM2.5) and traffic-related air pollutant concentrations are associated with cardiovascular risk. The disease process underlying these associations remains uncertain. We aim to assess association between long-term exposure to ambient air pollution and progression of coronary artery calcium and common carotid artery intima-media thickness. METHODS: In this prospective 10-year cohort study, we repeatedly measured coronary artery calcium by CT in 6795 participants aged 45-84 years enrolled in the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) in six metropolitan areas in the USA. Repeated scans were done for nearly all participants between 2002 and 2005, for a subset of participants between 2005 and 2007, and for half of all participants between 2010 and 2012. Common carotid artery intima-media thickness was measured by ultrasound in all participants at baseline and in 2010-12 for 3459 participants. Residence-specific spatio-temporal pollution concentration models, incorporating community-specific measurements, agency monitoring data, and geographical predictors, estimated concentrations of PM2.5 and nitrogen oxides (NOX) between 1999 and 2012. The primary aim was to examine the association between both progression of coronary artery calcium and mean carotid artery intima-media thickness and long-term exposure to ambient air pollutant concentrations (PM2.5, NOX, and black carbon) between examinations and within the six metropolitan areas, adjusting for baseline age, sex, ethnicity, socioeconomic characteristics, cardiovascular risk factors, site, and CT scanner technology. FINDINGS: In this population, coronary calcium increased on average by 24 Agatston units per year (SD 58), and intima-media thickness by 12 MUm per year (10), before adjusting for risk factors or air pollutant exposures. Participant specific pollutant concentrations averaged over the years 2000-10 ranged from 9.2 22.6 MUg PM2.5/m(3) and 7.2-139.2 parts per billion (ppb) NOX. For each 5 MUg PM2.5/m(3) increase, coronary calcium progressed by 4.1 Agatston units per year (95% CI 1.4-6.8) and for each 40 ppb NOX coronary calcium progressed by 4.8 Agatston units per year (0.9-8.7). Pollutant exposures were not associated with intima-media thickness change. The estimate for the effect of a 5 MUg/m(3) higher long-term exposure to PM2.5 in intima-media thickness was -0.9 MUm per year (95% CI -3.0 to 1.3). For 40 ppb higher NOX, the estimate was 0.2 MUm per year (-1.9 to 2.4). INTERPRETATION: Increased concentrations of PM2.5 and traffic-related air pollution within metropolitan areas, in ranges commonly encountered worldwide, are associated with progression in coronary calcification, consistent with acceleration of atherosclerosis. This study supports the case for global efforts of pollution reduction in prevention of cardiovascular diseases. FUNDING: US Environmental Protection Agency and US National Institutes of Health. PMID- 27233749 TI - A chemiluminescent platform for smartphone monitoring of H2O2 in human exhaled breath condensates. AB - Noninvasive measurement of oxidative markers in clinical samples has the potential to rapidly provide information for disease management, but is limited by the need for expensive analytical instrumentation that precludes home monitoring or point-of-care applications. We have developed a simple to use diagnostic platform for airway hydrogen peroxide (H2O2) that combines optimized reaction-based chemiluminescent designs with an inexpensive home-built darkbox and readily available smartphone cameras. Specialized photography software applications and analysis of pixel intensity enables quantification of sample concentrations. Using this platform, sample H2O2 concentrations as low as 264nM can be detected. The platform has been used to measure H2O2 in the exhaled breath condensates of human subjects, showing good agreement with the standard Amplex Red assay. PMID- 27233751 TI - Global Transcriptome Abnormalities of the Eutopic Endometrium From Women With Adenomyosis. AB - OBJECTIVE: Adenomyosis is a clinical disorder defined by the presence of endometrial glands and stroma within the myometrium, the pathogenesis of which is poorly understood. We postulate that dysregulation of genes and pathways in eutopic endometrium may predispose to ectopic implantation. No study, to our knowledge, has examined the global transcriptome of isolated eutopic endometrium from women with clinically significant adenomyosis. DESIGN: Laboratory-based study with full institutional review board approval and consents. MATERIAL AND METHODS: Endometrial sampling was performed on hysterectomy specimens (proliferative phase) from symptomatic women with pathologically confirmed diffuse adenomyosis (n = 3). Controls (n = 5) were normo-ovulatory patients without adenomyosis. All patients were free from leiomyoma, endometriosis, and hormonal exposures. Isolated purified total RNA was subjected to microarray analysis using the Gene 1.0 ST Affymetrix platform. Data were analyzed with GeneSpring and Ingenuity Pathway analysis. Validation of several genes was undertaken by quantitative real-time reverse transcriptase polymerase chain reaction. RESULTS: Comparison of transcriptomes of proliferative endometrium from women with and without adenomyosis revealed 140 upregulated and 884 downregulated genes in samples from women with adenomyosis compared to controls. Highly differentially expressed genes include those involved in regulation of apoptosis, steroid hormone responsiveness, and proteins involved in extracellular matrix remodeling as well as microRNAs of unknown significance. Affected canonical pathways included eukaryotic initiation factor 2 signaling, oxidative phosphorylation, mitochondrial dysfunction, estrogen receptor signaling, and mammalian target of rapamycin signaling. CONCLUSION: The eutopic endometrium in patients with adenomyosis has fundamental abnormalities that may predispose to invasion and survival beyond the myometrial interface. PMID- 27233752 TI - Association of Endometriosis-Associated Genetic Polymorphisms From Genome-Wide Association Studies With Ovarian Endometriosis in a Chinese Population. AB - Endometriosis is a common multifactorial disease caused by an interaction between multiple gene loci and environment. Four genome-wide association studies (GWASs) of endometriosis have identified several single-nucleotide polymorphisms (SNPs) associated with endometriosis. However, results from independent replication studies with different populations are inconsistent. The present study aims to evaluate whether the GWAS-derived susceptibility loci are correlated with the risk of the development of ovarian endometriosis in North Chinese women. This case-control study comprised 580 patients with ovarian endometriosis and 606 matched control women. Three SNPs were selected for this association study including rs10965235 in CDKN2BAS, rs2235529 located in LINC00339- WNT4, and rs12700667 in an intergenic region on 7p15.2. The results show that the G/A genotype of rs12700667 can significantly increase the risk of developing ovarian endometriosis when compared with the G/G genotype (odds ratio [OR] = 1.57, 95% confidence interval [CI] = 1.23-2.00). Similarly, the carriers with A allele showed a higher risk of ovarian endometriosis than those with G allele (OR = 1.23, 95% CI = 1.12-1.68). The study suggests that the endometriosis-associated genetic polymorphisms (rs12700667) from GWAS be associated with the risk of developing ovarian endometriosis in North Chinese women. PMID- 27233750 TI - Chloroplast Membrane Remodeling during Freezing Stress Is Accompanied by Cytoplasmic Acidification Activating SENSITIVE TO FREEZING2. AB - Low temperature is a seasonal abiotic stress that restricts native plant ranges and crop distributions. Two types of low-temperature stress can be distinguished: chilling and freezing. Much work has been done on the mechanisms by which chilling is sensed, but relatively little is known about how plants sense freezing. Recently, Arabidopsis (Arabidopsis thaliana) SENSITIVE TO FREEZING2 (SFR2) was identified as a protein that responds in a nontranscriptional manner to freezing. Here, we investigate the cellular conditions that allow SFR2 activation. Using a combination of isolated organelle, whole-tissue, and whole plant assays, we provide evidence that SFR2 is activated by changes in cytosolic pH and Mg(2+) Manipulation of pH and Mg(2+) in cold-acclimated plants is shown to cause changes similar to those of freezing. We conclude that pH and Mg(2+) are perceived as intracellular cues as part of the sensing mechanism for freezing conditions. This evidence provides a specific molecular mechanism to combat freezing. PMID- 27233753 TI - Moderate Maternal Energy Restriction During Gestation in Pigs Attenuates Fetal Skeletal Muscle Development Through Changing Myogenic Gene Expression and Myofiber Characteristics. AB - Maternal undernutrition during gestation influences the development of the fetus, thereby increasing the risk of metabolic syndrome in adulthood. Skeletal muscle, one of the key insulin-responsive organs, is susceptible to maternal nutritional programming. This study aimed to evaluate the effect of moderate maternal energy restriction during gestation in pigs on basic events of fetal skeletal myogenesis. Primiparous, purebred Meishan sows were fed a control (normal energy intake) or a low-energy (LE) diet from mating to day 90 of gestation. Biochemical characteristics, myogenic gene expression, and myofiber characteristics were assessed in longissimus dorsi (LD) muscle of fetuses on days 55 and 90 of gestation. Fetal weights, myofiber density, and fetal umbilical vein serum triiodothyronine (T3) concentration decreased in LE group on both days 55 and 90 of gestation. The expression and activity of creatine kinase, the messenger RNA (mRNA) expression of myosin heavy chain ( MYH/ MyHC) genes ( MYH2 and MYH4), concentration of muscular DNA and protein, and protein expression of fast-MyHC isoforms were reduced in LD muscle of LE fetuses on day 55 or 90 of gestation. Meanwhile, myogenic gene expression was reduced in LE fetuses on day 55 or 90 of gestation, indicating the downregulation of myogenesis. Additionally, the exposure to LE diet led to increased isocitrate dehydrogenase activity and slow MyHC (MYH7) mRNA expression on day 90 of gestation, suggesting the elevation of oxidative muscle metabolism. These findings suggest that moderate energy restriction during gestation attenuates fetal skeletal muscle development in pigs, resulting in the delay of skeletal muscle differentiation and maturity. PMID- 27233755 TI - Measurement of Interleukin 8 in Cervicovaginal Fluid in Women With Preterm Premature Rupture of Membranes: A Comparison of Amniotic Fluid Samples. AB - Cervicovaginal fluid (CVF) samples may be a feasible alternative to amniotic fluid (AF) sampling in women with preterm premature rupture of the membranes (PPROMs), because PPROM causes AF to spill into the CVF. We aimed to assess the correlation and limits of agreement of interleukin 8 (IL-8) levels between CVF and AF in women with PPROM and to compare the clinical value of CVF IL-8 to AF IL 8 for the prediction of microbial invasion of amniotic cavity (MIAC). A retrospective cohort observational study was conducted on 85 women with singleton pregnancies (24-34 weeks) presenting with PPROM. The CVF samples were obtained simultaneously with AF samples retrieved by transabdominal amniocentesis. The levels of IL-8 in paired CVF and AF samples were measured with enzyme-linked immunosorbent assay in the same plate in duplicate using the same dilutions. The prevalence of a positive AF culture was 40% (34 of 85). The CVF IL-8 levels were significantly and positively correlated with AF IL-8 levels ( r = 0.778). However, the level of agreement between CVF and AF IL-8 levels yielded a Cohen kappa statistic of 0.276. Paired Student t test revealed that the difference between CVF and AF IL-8 levels was statistically significant. The area under the curve for AF IL-8 was significantly higher than that for CVF IL-8 ( P = .013). In women with PPROM, IL-8 levels in CVF were significantly correlated with, but were significantly different from, those in AF samples. The CVF IL-8 has moderate predictive capability for the risk of MIAC, but this is inferior to AF IL-8. PMID- 27233754 TI - Progesterone Receptor-Mediated Actions Regulate Remodeling of the Cervix in Preparation for Preterm Parturition. AB - This study determined whether a progesterone (P) receptor (PR)-mediated mechanism regulates morphological characteristics associated with prepartum cervix remodeling at term and with preterm birth. With focus on the transition from a soft to ripe cervix, the cervix stroma of untreated controls had reduced cell nuclei density/area and less organized extracellular collagen, while the density of macrophages/area, but not neutrophils, increased just 2 days before birth (day 17 vs day 15 or 16.5 postbreeding). Preterm birth was induced within 24 hours of treatment on day 16 postbreeding with PR antagonist or ovariectomy (Ovx). Pure or mixed PR antagonists increased the density of macrophages in the cervix within 8 hours (day 16.5 postbreeding), in advance of preterm birth. However, neither PR antagonists nor P withdrawal after Ovx affected the densities of cell nuclei and neutrophils or extracellular collagen compared to the same day controls-an indication that the cervix was sufficiently remodeled for birth to occur. To block the effect of systemic P withdrawal, Ovx pregnant mice were given a PR agonist, either pure or mixed. These treatments forestalled preterm birth and prevented further morphological remodeling of the cervix. The resulting increase in macrophage density in cervix stroma following Ovx was only blocked by a pure PR agonist. These findings support the hypothesis that inflammatory processes in the prepartum cervix that include residency of macrophages, cellular hypertrophy, and extracellular collagen structure are regulated by genomic actions of PR in a final common mechanism both at term and with induced preterm birth. PMID- 27233756 TI - Comparison of hospitalization risk before and after changing from risperidone long-acting injection to another long-acting injection or oral antipsychotic in patients with schizophrenia: Mirror-image study. PMID- 27233757 TI - Gebauer SLc Original and Moria One-Use Plus automated microkeratomes for ultrathin Descemet's stripping automated endothelial keratoplasty preparation. AB - PURPOSE: We compared the SLc Original (SLc) and One-Use Plus (OUP) microkeratomes for ultrathin Descemet's stripping automated endothelial keratoplasty (DSAEK) lamella preparation and storage, vis-a-vis accuracy, endothelial cell loss (ECL) and lamellar surface roughness (LSR). METHODS: Twenty-five human corneas were dissected with single-use heads of different sizes aiming for a posterior lamella (PL) thickness of 85 MUm, after which they were incubated for 6 days in a 5% dextran medium. Before preparation (0 hr) and 1, 24, and 144 hr after dissection, ECL and corneal thickness (CCT) were measured by ultrasound pachymetry (USP) and optical coherence tomography (OCT). Lamellar surface roughness (LSR) was assessed by scanning electron microscopy (SEM) and evaluated by two masked observers. RESULTS: Prior to cutting, CCTs did not differ between OCT and USP measurements, with a high correlation between the two modalities (r2 = 0.8; p < 0.0001). Both systems succeeded in UT lamella preparation (CCT 40-130 MUm) in 88% of cases. The OUP heads cut significantly deeper than the according SLc counterparts (p = 0.001), while the variance did not differ. The mean PL thickness increased significantly in the following incubation period (p = 0.01) with no difference between the keratome groups. Endothelial cell density (ECD) decreased significantly from before to 1 hr after preparation (-5.6%; p = 0.04), with no changes in the following 144-hr incubation period and no differences between the OUP and SLc group. Lamellar surface roughness (LSR) did not differ between both systems. CONCLUSIONS: The SLc and the OUP system are both suited for the preparation of UT-DSAEK lamellae. Neither system differed significantly in variability, LSR or ECL, which did not increase during a 6-day incubation period. PMID- 27233759 TI - Preimplantation genetic screening 2.0: an evolving and promising technique. PMID- 27233758 TI - Decreased expression of microRNA-29 family in leiomyoma contributes to increased major fibrillar collagen production. AB - OBJECTIVE: To determine the expression and function of the microRNA-29 family (miRNA-29a, miRNA-29b, miRNA-29c) in human leiomyoma and myometrium. DESIGN: Basic science experimental design. SETTING: Academic medical center. PATIENT(S): Women undergoing surgery for symptomatic uterine fibroids. INTERVENTION(S): Overexpression and knockdown of miRNA-29a, miRNA-29b, and miRNA-29c in primary leiomyoma and myometrial cells. MAIN OUTCOME MEASURE(S): [1] Expression of the miRNA-29 family members in vivo in leiomyoma versus myometrium; [2] Major fibrillar collagen (I, II, III) expression in leiomyoma and myometrial cells with manipulation of miRNA-29 species. RESULT(S): Members of the miRNA-29 family (29a, 29b, 29c) are all down-regulated in leiomyoma versus myometrium in vivo. The expression of the miRNA-29 family can be successfully modulated in primary leiomyoma and myometrial cells. Overexpression of the miRNA-29 family in leiomyoma cells results in down-regulation of the major fibrillar collagens. Down regulation of the miRNA-29 species in myometrium results in an increase in collagen type III deposition. CONCLUSION(S): The miRNA-29 family is consistently down-regulated in leiomyoma compared to matched myometrial tissue. This down regulation contributes to the increased collagen seen in leiomyomas versus myometrium. When miRNA-29 members are overexpressed in leiomyoma cells, protein levels of all of the major fibrillar collagens decrease. The miRNA-29 members are potential therapeutic targets in this highly prevalent condition. PMID- 27233760 TI - Criteria, prevalence, and phenotypes of polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is a highly prevalent disorder effecting reproductive-aged women worldwide. This article addresses the evolution of the criteria used to diagnosis PCOS; reviews recent advances in the phenotypic approach, specifically in the context of the extended Rotterdam criteria; discusses limitations of the current criteria used to diagnosis, particularly when studying adolescents and women in the peri- and postmenopause; and describes significant strides made in understanding the epidemiology of PCOS. This review recognizes that although there is a high prevalence of PCOS, there is increased variability when using Rotterdam 2003 criteria, owing to limitations in population sampling and approaches used to define PCOS phenotypes. Last, we discuss the distribution of PCOS phenotypes, their morbidity, and the role that referral bias plays in the epidemiology of this syndrome. PMID- 27233761 TI - The effects of graded changes in oxygen and carbon dioxide tension on coronary blood velocity independent of myocardial energy demand. AB - In humans, coronary blood flow is tightly regulated by microvessels within the myocardium to match myocardial energy demand. However, evidence regarding inherent sensitivity of the microvessels to changes in arterial partial pressure of carbon dioxide and oxygen is conflicting because of the accompanied changes in myocardial energy requirements. This study aimed to investigate the changes in coronary blood velocity while manipulating partial pressures of end-tidal CO2 (Petco2) and O2 (Peto2). It was hypothesized that an increase in Petco2 (hypercapnia) or decrease in Peto2 (hypoxia) would result in a significant increase in mean blood velocity in the left anterior descending artery (LADVmean) due to an increase in both blood gases and energy demand associated with the concomitant cardiovascular response. Cardiac energy demand was assessed through noninvasive measurement of the total left ventricular mechanical energy. Healthy subjects (n = 13) underwent a euoxic CO2 test (Petco2 = -8, -4, 0, +4, and +8 mmHg from baseline) and an isocapnic hypoxia test (Peto2 = 64, 52, and 45 mmHg). LADVmean was assessed using transthoracic Doppler echocardiography. Hypercapnia evoked a 34.6 +/- 8.5% (mean +/- SE; P < 0.01) increase in mean LADVmean, whereas hypoxia increased LADVmean by 51.4 +/- 8.8% (P < 0.05). Multiple stepwise regressions revealed that both mechanical energy and changes in arterial blood gases are important contributors to the observed changes in LADVmean (P < 0.01). In summary, regulation of the coronary vasculature in humans is mediated by metabolic changes within the heart and an inherent sensitivity to arterial blood gases. PMID- 27233762 TI - R-CEPIA1er as a new tool to directly measure sarcoplasmic reticulum [Ca] in ventricular myocytes. AB - In cardiomyocytes, [Ca] within the sarcoplasmic reticulum (SR; [Ca]SR) partially determines the amplitude of cytosolic Ca transient that, in turn, governs myocardial contraction. Therefore, it is critical to understand the molecular mechanisms that regulate [Ca]SR handling. Until recently, the best approach available to directly measure [Ca]SR was to use low-affinity Ca indicators (e.g., Fluo-5N). However, this approach presents several limitations, including nonspecific cellular localization, dye extrusion, and species limitation. Recently a new genetically encoded family of Ca indicators has been generated, named Ca-measuring organelle-entrapped protein indicators (CEPIA). Here, we tested the red fluorescence SR-targeted Ca sensor (R-CEPIA1er) as a tool to directly measure [Ca]SR dynamics in ventricular myocytes. Infection of rabbit and rat ventricular myocytes with an adenovirus expressing the R-CEPIA1er gene displayed prominent localization in the SR and nuclear envelope. Calibration of R CEPIA1er in myocytes resulted in a Kd of 609 MUM, suggesting that this sensor is sensitive in the whole physiological range of [Ca]SR [Ca]SR dynamics measured with R-CEPIA1er were compared with [Ca]SR measured with Fluo5-N. We found that both the time course of the [Ca]SR depletion and fractional SR Ca release induced by an action potential were similar between these two Ca sensors. R-CEPIA1er fluorescence did not decline during experiments, indicating lack of dye extrusion or photobleaching. Furthermore, measurement of [Ca]SR with R-CEPIA1er can be combined with cytosolic [Ca] measurements (with Fluo-4) to obtain more detailed information regarding Ca handling in cardiac myocytes. In conclusion, R-CEPIA1er is a promising tool that can be used to measure [Ca]SR dynamics in myocytes from different animal species. PMID- 27233764 TI - Symmetry recovery of cell-free layer after bifurcations of small arterioles in reduced flow conditions: effect of RBC aggregation. AB - Heterogeneous distribution of red blood cells (RBCs) in downstream vessels of arteriolar bifurcations can be promoted by an asymmetric formation of cell-free layer (CFL) in upstream vessels. Consequently, the CFL widths in subsequent downstream vessels become an important determinant for tissue oxygenation (O2) and vascular tone change by varying nitric oxide (NO) availability. To extend our previous understanding on the formation of CFL in arteriolar bifurcations, this study investigated the formation of CFL widths from 2 to 6 vessel-diameter (2D 6D) downstream of arteriolar bifurcations in the rat cremaster muscle (D = 51.5 +/- 1.3 MUm). As the CFL widths are highly influenced by RBC aggregation, the degree of aggregation was adjusted to simulate levels seen during physiological and pathological states. Our in vivo experimental results showed that the asymmetry of CFL widths persists along downstream vessels up to 6D from the bifurcating point. Moreover, elevated levels of RBC aggregation appeared to retard the recovery of CFL width symmetry. The required length of complete symmetry recovery was estimated to be greater than 11D under reduced flow conditions, which is relatively longer than interbifurcation distances of arterioles for vessel diameter of ~50 MUm. In addition, our numerical prediction showed that the persistent asymmetry of CFL widths could potentially result in a heterogeneous vasoactivity over the entire arteriolar network in such abnormal flow conditions. PMID- 27233765 TI - Prolonged sitting-induced leg endothelial dysfunction is prevented by fidgeting. AB - Prolonged sitting impairs endothelial function in the leg vasculature, and this impairment is thought to be largely mediated by a sustained reduction in blood flow-induced shear stress. Indeed, preventing the marked reduction of shear stress during sitting with local heating abolishes the impairment in popliteal artery endothelial function. Herein, we tested the hypothesis that sitting induced reductions in shear stress and ensuing endothelial dysfunction would be prevented by periodic leg movement, or "fidgeting." In 11 young, healthy subjects, bilateral measurements of popliteal artery flow-mediated dilation (FMD) were performed before and after a 3-h sitting period during which one leg was subjected to intermittent fidgeting (1 min on/4 min off) while the contralateral leg remained still throughout and served as an internal control. Fidgeting produced a pronounced increase in popliteal artery blood flow and shear rate (prefidgeting, 33.7 +/- 2.6 s(-1) to immediately postfidgeting, 222.7 +/- 28.3 s( 1); mean +/- SE; P < 0.001) that tapered off during the following 60 s. Fidgeting did not alter popliteal artery blood flow and shear rate of the contralateral leg, which was subjected to a reduction in blood flow and shear rate throughout the sitting period (presit, 71.7 +/- 8.0 s(-1) to 3-h sit, 20.2 +/- 2.9 s(-1); P < 0.001). Popliteal artery FMD was impaired after 3 h of sitting in the control leg (presit, 4.5 +/- 0.3% to postsit: 1.6 +/- 1.1%; P = 0.039) but improved in the fidgeting leg (presit, 3.7 +/- 0.6% to postsit, 6.6 +/- 1.2%; P = 0.014). Collectively, the present study provides evidence that prolonged sitting-induced leg endothelial dysfunction is preventable with small amounts of leg movement while sitting, likely through the intermittent increases in vascular shear stress. PMID- 27233766 TI - Uridine adenosine tetraphosphate acts as a proangiogenic factor in vitro through purinergic P2Y receptors. AB - Uridine adenosine tetraphosphate (Up4A), a dinucleotide, exerts vascular influence via purinergic receptors (PR). We investigated the effects of Up4A on angiogenesis and the putative PR involved. Tubule formation assay was performed in a three-dimensional system, in which human endothelial cells were cocultured with pericytes with various Up4A concentrations for 5 days. Expression of PR subtypes and angiogenic factors was assessed in human endothelial cells with and without P2Y6R antagonist. No difference in initial tubule formation was detected between Up4A stimulation and control conditions at day 2 In contrast, a significant increase in vascular density in response to Up4A was observed at day 5 Up4A at an optimal concentration of 5 MUM promoted total tubule length, number of tubules, and number of junctions, all of which were inhibited by the P2Y6R antagonist MRS2578. Higher concentrations of Up4A (10 MUM) had no effects on angiogenesis parameters. Up4A increased mRNA level of P2YRs (P2Y2R, P2Y4R, and P2Y6R) but not P2XR (P2X4R and P2X7R) or P1R (A2AR and A2BR), while Up4A upregulated VEGFA and ANGPT1, but not VEGFR2, ANGPT2, Tie1, and Tie2. In addition, Up4A increased VEGFA protein levels. Transcriptional upregulation of P2YRs by Up4A was inhibited by MRS2578. In conclusion, Up4A is functionally capable of promoting tubule formation in an in vitro coculture system, which is likely mediated by pyrimidine-favored P2YRs but not P2XRs or P1Rs, and involves upregulation of angiogenic factors. PMID- 27233763 TI - Intracrine angiotensin II functions originate from noncanonical pathways in the human heart. AB - Although it is well-known that excess renin angiotensin system (RAS) activity contributes to the pathophysiology of cardiac and vascular disease, tissue-based expression of RAS genes has given rise to the possibility that intracellularly produced angiotensin II (Ang II) may be a critical contributor to disease processes. An extended form of angiotensin I (Ang I), the dodecapeptide angiotensin-(1-12) [Ang-(1-12)], that generates Ang II directly from chymase, particularly in the human heart, reinforces the possibility that an alternative noncanonical renin independent pathway for Ang II formation may be important in explaining the mechanisms by which the hormone contributes to adverse cardiac and vascular remodeling. This review summarizes the work that has been done in evaluating the functional significance of Ang-(1-12) and how this substrate generated from angiotensinogen by a yet to be identified enzyme enhances knowledge about Ang II pathological actions. PMID- 27233768 TI - Chemical Constituents in Hybrids of Ligularia tongolensis and L. cymbulifera: Chemical Introgression in L. tongolensis. AB - Two samples with morphologies intermediate between Ligularia tongolensis and L. cymbulifera were collected in Desha, Sichuan Province, and one, in Pachahai, Yunnan Province, P. R. China. The DNA sequencing confirmed that the samples were hybrids of the two species. Tetradymol (1), the major compound of L. cymbulifera not found in L. tongolensis, was isolated from the hybrid samples collected at both locations, while furanoeremophilan-15-oic acid derivative 4, a compound characteristic to L. tongolensis, was found in the Pachahai hybrid but not in the Desha hybrids. Thus, the chemical consequence of hybridization can be variable. In addition, analysis of L. tongolensis samples at Pachahai indicated that introgression has been a mechanism of generating chemical diversity in the plant. Eleven compounds including three new ones were isolated. PMID- 27233769 TI - Retraction Note: Effects of replacing groundnut cake with rumen content supplemented with or without enzyme in the diet of weaner rabbits. PMID- 27233767 TI - A post-MI power struggle: adaptations in cardiac power occur at the sarcomere level alongside MyBP-C and RLC phosphorylation. AB - Myocardial remodeling in response to chronic myocardial infarction (CMI) progresses through two phases, hypertrophic "compensation" and congestive "decompensation." Nothing is known about the ability of uninfarcted myocardium to produce force, velocity, and power during these clinical phases, even though adaptation in these regions likely drives progression of compensation. We hypothesized that enhanced cross-bridge-level contractility underlies mechanical compensation and is controlled in part by changes in the phosphorylation states of myosin regulatory proteins. We induced CMI in rats by left anterior descending coronary artery ligation. We then measured mechanical performance in permeabilized ventricular trabecula taken distant from the infarct zone and assayed myosin regulatory protein phosphorylation in each individual trabecula. During full activation, the compensated myocardium produced twice as much power and 31% greater isometric force compared with noninfarcted controls. Isometric force during submaximal activations was raised >2.4-fold, while power was 2-fold greater. Electron and confocal microscopy demonstrated that these mechanical changes were not a result of increased density of contractile protein and therefore not an effect of tissue hypertrophy. Hence, sarcomere-level contractile adaptations are key determinants of enhanced trabecular mechanics and of the overall cardiac compensatory response. Phosphorylation of myosin regulatory light chain (RLC) increased and remained elevated post-MI, while phosphorylation of myosin binding protein-C (MyBP-C) was initially depressed but then increased as the hearts became decompensated. These sensitivities to CMI are in accordance with phosphorylation-dependent regulatory roles for RLC and MyBP-C in crossbridge function and with compensatory adaptation in force and power that we observed in post-CMI trabeculae. PMID- 27233770 TI - Intracellular delivery of messenger RNA by recombinant PP7 virus-like particles carrying low molecular weight protamine. AB - BACKGROUND: Cell-penetrating peptides (CPPs) have been widely used as carriers to transport different molecules into living cells, whereas messenger RNAs (mRNAs) have been utilized as target molecules for the prevention and treatment of various diseases. However, the instability of CPPs and mRNAs has limited their application. Bacteriophage PP7 virus-like particles (VLPs) may protect peptides and RNAs from degradation through displaying foreign peptides on their surface and encapsidating RNA linked with the pac site. RESULTS: In this study, the cDNA of the PP7 coat protein single-chain dimer carrying low molecular weight protamine (LMWP) and the cDNA of green fluorescent protein (GFP) were inserted into two multiple cloning sites of pETDuet-1, respectively. PP7 VLPs carrying the LMWP peptide and GFP mRNA were subsequently expressed in Escherichia coli BL21 (DE3) with high yield and thermal stability, and were easily purified. The VLPs were also non-replicative, non-infectious, and non-toxic. Moreover, they penetrated the mouse prostate cancer cells RM-1 after 24 h incubation. Last, PP7 VLPs carrying the LMWP could encapsidate the GFP mRNA, which was translated into mature protein in mammalian cells. CONCLUSIONS: Recombinant PP7 VLPs can be used simultaneously as a targeted delivery vector for both peptides and mRNA due to their abilities to package RNA and display peptides. PMID- 27233771 TI - Enhanced prion detection in biological samples by magnetic particle extraction and real-time quaking-induced conversion. AB - Prions have been demonstrated in body fluids and excreta using bioassay, but at levels too low for detection by conventional direct-detection assays. More rapid and sensitive detection of prions in these clinically accessible specimens would be valuable for diagnosis and investigations of transmission, environmental impact, and interventions. In addition to very low concentrations of prions, in vitro amplification assays are challenged by the presence of inhibitors in these complex sources. Here, we leverage the prion attribute of avid metal binding with the versatile power of real-time quaking-induced conversion (RT-QuIC) to enhance and simplify detection of chronic wasting-disease prions in biological samples. Iron oxide particle binding and magnetic extraction combined with RT-QuIC permitted rapid analysis of the low concentrations of prions in saliva, urine, faeces, and cerebrospinal fluid. These methods are pertinent to ante-mortem detection, monitoring, and surveillance, and could conceivably be applicable to other protein-misfolding disorders. PMID- 27233772 TI - 'It just has to click': Internists' views of: what constitutes productive interactions with chronically ill patients. AB - BACKGROUND: According to the Chronic Care Model, productive interactions are crucial to patient outcomes. Despite productive interactions being at the heart of the Model, however, it is unclear what constitutes such an interaction. The aim of this study was to gain a better understanding of physician views of productive interactions with the chronically ill. METHOD: We conducted a qualitative study and interviewed 20 internists working in an academic hospital. The data were analyzed using a constructivist approach of grounded theory. To categorize the data, a coding process within which a code list was developed and tested with two other coders was conducted. RESULTS: The participants engaged in goal-directed reasoning when reflecting on productive interactions. This resulted in the identification of four goal orientations: (a) health outcome; (b) satisfaction; (c) medical process; and (d) collaboration. Collaboration appeared to be conditional for reaching medical process goals and ultimately health outcome and satisfaction goals. Achieving rapport with the patient ('clicking,' in the term of the participants) was found to be a key condition that catalyzed collaboration goals. Clicking appeared to be seen as a somewhat unpredictable phenomenon that might or might not emerge, which one had to accept and work with. Goal orientations were found to be related to the specific medical context (i.e., a participant's subspecialty and the nature of a patient's complaint). CONCLUSIONS: The participants viewed a productive interaction as essentially goal directed, catalyzed by the two parties clicking, and dependent on the nature of a patient's complaint. Using the findings, we developed a conceptual process model with the four goal orientations as wheels and with clicking in the center as a flywheel. Because clicking was viewed as important, but somewhat unpredictable, teaching physicians how to click, while taking account of the medical context, may warrant greater attention. PMID- 27233773 TI - Clinical evaluation of an allogeneic bone matrix containing viable osteogenic cells in patients undergoing one- and two-level posterolateral lumbar arthrodesis with decompressive laminectomy. AB - BACKGROUND: Trinity Evolution(r) cellular bone allograft (TE) possesses the osteogenic, osteoinductive, and osteoconductive elements essential for bone healing. The purpose of this study is to evaluate the radiographic and clinical outcomes when TE is used as a graft extender in combination with locally derived bone in one- and two-level instrumented lumbar posterolateral arthrodeses. METHODS: In this retrospective evaluation, a consecutive series of subject charts that had posterolateral arthrodesis with TE and a 12-month radiographic follow-up were evaluated. All subjects were diagnosed with degenerative disc disease, radiculopathy, stenosis, and decreased disc height. At 2 weeks and at 3 and 12 months, plain radiographs were performed and the subject's back and leg pain (VAS) was recorded. An evaluation of fusion status was performed at 12 months. RESULTS: The population consisted of 43 subjects and 47 arthrodeses. At 12 months, a fusion rate of 90.7 % of subjects and 89.4 % of surgical levels was observed. High-risk subjects (e.g., diabetes, tobacco use, etc.) had fusion rates comparable to normal patients. Compared with the preoperative leg or back pain level, the postoperative pain levels were significantly (p < 0.0001) improved at every time point. There were no adverse events attributable to TE. CONCLUSIONS: Fusion rates using TE were higher than or comparable to fusion rates with autologous iliac crest bone graft that have been reported in the recent literature for posterolateral fusion procedures, and TE fusion rates were not adversely affected by several high-risk patient factors. The positive results provide confidence that TE can safely replace autologous iliac crest bone graft when used as a bone graft extender in combination with locally derived bone in the setting of posterolateral lumbar arthrodesis in patients with or without risk factors for compromised bone healing. TRIAL REGISTRATION: Because of the retrospective nature of this study, the trial was not registered. PMID- 27233774 TI - Key knowledge and data gaps in modelling the influence of CO2 concentration on the terrestrial carbon sink. AB - Primary productivity of terrestrial vegetation is expected to increase under the influence of increasing atmospheric carbon dioxide concentrations ([CO2]). Depending on the fate of such additionally fixed carbon, this could lead to an increase in terrestrial carbon storage, and thus a net terrestrial sink of atmospheric carbon. Such a mechanism is generally believed to be the primary global driver behind the observed large net uptake of anthropogenic CO2 emissions by the biosphere. Mechanisms driving CO2 uptake in the Terrestrial Biosphere Models (TBMs) used to attribute and project terrestrial carbon sinks, including that from increased [CO2], remain in large parts unchanged since those models were conceived two decades ago. However, there exists a large body of new data and understanding providing an opportunity to update these models, and directing towards important topics for further research. In this review we highlight recent developments in understanding of the effects of elevated [CO2] on photosynthesis, and in particular on the fate of additionally fixed carbon within the plant with its implications for carbon turnover rates, on the regulation of photosynthesis in response to environmental limitations on in-plant carbon sinks, and on emergent ecosystem responses. We recommend possible avenues for model improvement and identify requirements for better data on core processes relevant to the understanding and modelling of the effect of increasing [CO2] on the global terrestrial carbon sink. PMID- 27233775 TI - Bone marrow lesions in hip osteoarthritis are characterized by increased bone turnover and enhanced angiogenesis. AB - OBJECTIVE: Bone marrow lesions (BML), previously denoted bone marrow edema, are detected as water signals by magnetic resonance imaging (MRI). Previous histologic studies were unable to demonstrate any edematous changes at the tissue level. Therefore, our aim was to investigate the underlying biological mechanisms of the water signal in MRI scans of bone affected by BML. METHODS: Tetracycline labeling in addition to water sensitive MRI scans of 30 patients planned for total hip replacement surgery was undertaken. Twenty-one femoral heads revealed BML on MRI, while nine were negative and used as controls (CON). Guided by the MRI images cylindrical biopsies were extracted from areas with BML in the femoral heads. Tissue sections from the biopsies were subjected to histomorphometric image analyses of the cancellous bone envelope. RESULTS: Patients with BML exhibited an average 40- and 18-fold increase of bone formation rate and mineralizing surface, respectively. Additionally, samples with BML demonstrated 2 fold reduction of marrow fat and 28-fold increase of woven bone. Immunohistochemical analysis showed a 4-fold increase of angiogenesis markers CD31 and von Willebrand Factor (vWF) in the BML-group compared to CON. CONCLUSION: This study indicates that BML are characterized by increased bone turnover, vascularity and angiogenesis in keeping with it being a reparatory process. Thus, the water signal, which is the hallmark of BML on MRI, is most probably reflecting increased tissue vascularity accompanying increased remodeling activity. PMID- 27233776 TI - Exome-based proteogenomics of HEK-293 human cell line: Coding genomic variants identified at the level of shotgun proteome. AB - Genomic and proteomic data were integrated into the proteogenomic workflow to identify coding genomic variants of Human Embryonic Kidney 293 (HEK-293) cell line at the proteome level. Shotgun proteome data published by Geiger et al. (2012), Chick et al. (2015), and obtained in this work for HEK-293 were searched against the customized genomic database generated using exome data published by Lin et al. (2014). Overall, 112 unique variants were identified at the proteome level out of ~1200 coding variants annotated in the exome. Seven identified variants were shared between all the three considered proteomic datasets, and 27 variants were found in any two datasets. Some of the found variants belonged to widely known genomic polymorphisms originated from the germline, while the others were more likely resulting from somatic mutations. At least, eight of the proteins bearing amino acid variants were annotated as cancer-related ones, including p53 tumor suppressor. In all the considered shotgun datasets, the variant peptides were at the ratio of 1:2.5 less likely being identified than the wild-type ones compared with the corresponding theoretical peptides. This can be explained by the presence of the so-called "passenger" mutations in the genes, which were never expressed in HEK-293 cells. All MS data have been deposited in the ProteomeXchange with the dataset identifier PXD002613 (http://proteomecentral.proteomexchange.org/dataset/PXD002613). PMID- 27233777 TI - Vision and hearing impairments, cognitive impairment and mortality among long term care recipients: a population-based cohort study. AB - BACKGROUND: Vision and hearing impairments among elders are common, and cognitive impairment is a concern. This study assessed the association of vision and hearing impairments with cognitive impairment and mortality among long-term care recipients. METHODS: Data of 1754 adults aged 65 or older were included in analysis from the Gujo City Long-Term Care Insurance Database in Japan for a mean follow-up period of 4.7 years. Trained and certified investigators assessed sensory impairments and cognitive impairment using a national assessment tool. Five-level scales were used to measure vision and hearing impairments. Cognitive performance was assessed on two dimensions, namely communication/cognition and problem behaviors. We performed logistic regression analysis to estimate odd ratios (ORs) and 95 % confidence intervals (CIs) for the association of vision and hearing impairments with cognitive impairment. Using Cox proportional hazard regression models, we obtained hazard ratios (HRs) for mortality. RESULTS: Of 1754 elders, 773 (44.0 %) had normal sensory function, 252 (14.4 %) vision impairment, 409 (23.3 %) hearing impairment, and 320 (18.2 %) dual sensory impairment. After adjusting for potential cofounders, ORs of cognitive impairment were 1.46 (95 % CI 1.07-1.98) in individuals with vision impairment, 1.47 (95 % CI 1.13-1.92) in those with hearing impairment, and 1.97 (95 % CI 1.46-2.65) in those with dual sensory impairment compared to individuals with normal sensory function. The adjusted HR of overall mortality was 1.29 (95 % CI 1.01-1.65) in individuals with dual sensory impairment and cognitive impairment relative to normal sensory and cognitive functions. CONCLUSIONS: Cognitive impairment was most common in individuals with dual sensory impairment, and those with dual sensory impairment and cognitive impairment had increased mortality. PMID- 27233778 TI - Silencing of six susceptibility genes results in potato late blight resistance. AB - Phytophthora infestans, the causal agent of late blight, is a major threat to commercial potato production worldwide. Significant costs are required for crop protection to secure yield. Many dominant genes for resistance (R-genes) to potato late blight have been identified, and some of these R-genes have been applied in potato breeding. However, the P. infestans population rapidly accumulates new virulent strains that render R-genes ineffective. Here we introduce a new class of resistance which is based on the loss-of-function of a susceptibility gene (S-gene) encoding a product exploited by pathogens during infection and colonization. Impaired S-genes primarily result in recessive resistance traits in contrast to recognition-based resistance that is governed by dominant R-genes. In Arabidopsis thaliana, many S-genes have been detected in screens of mutant populations. In the present study, we selected 11 A. thaliana S genes and silenced orthologous genes in the potato cultivar Desiree, which is highly susceptible to late blight. The silencing of five genes resulted in complete resistance to the P. infestans isolate Pic99189, and the silencing of a sixth S-gene resulted in reduced susceptibility. The application of S-genes to potato breeding for resistance to late blight is further discussed. PMID- 27233779 TI - Stereotactic body radiotherapy in oligometastatic prostate cancer patients with isolated lymph nodes involvement: a two-institution experience. AB - OBJECTIVE: Stereotactic body radiotherapy (SBRT) is emerging as a treatment option in oligometastatic cancer patients. This retrospective study aimed to analyze local control, biochemical progression-free survival (b-PFS), and toxicity in patients affected by isolated prostate cancer lymph node metastases. Finally, we evaluated androgen deprivation therapy-free survival (ADT-FS). METHODS: Forty patients with 47 isolated lymph nodes of recurrent prostate cancer were treated with SBRT. Mostly, two different fractionation schemes were used: 5 * 7 Gy in 23 (48.9 %) lesions and 5 * 8 Gy in 13 (27.7 %) lesions. Response to treatment was assessed with periodical PSA evaluation. Toxicity was registered according to RTOG/EORTC criteria. RESULTS: With a mean follow-up of 30.18 months, local control was achieved in 98 % of the cases, with a median b-PFS of 24 months. We obtained a 2-year b-PFS of 44 % with 40 % of the patients ADT-free at last follow-up (mean value 26.18 months; range 3.96-59.46), whereas 12.5 % had a mean ADT-FS of 13.58 months (range 2.06-37.13). Late toxicity was observed in one (2.5 %) patient who manifested a grade 3 gastrointestinal toxicity 11.76 months after the end of SBRT. CONCLUSION: Our study demonstrates that SBRT is safe, effective, and minimally invasive in the eradication of limited nodal metastases, yielding an important delay in prescribing ADT. PMID- 27233781 TI - Expression patterns of SH3BGR family members in zebrafish development. AB - SH3 domain-binding glutamic acid-rich (SH3BGR) gene family is composed of SH3BGR, SH3BGRL, SH3BGRL2, and SH3BGRL3 which encodes a cluster of small thioredoxin-like proteins and shares a Src homology 3 (SH3) domain. However, biological functions of SH3BGR family members are largely elusive. Given that zebrafish (Danio rerio) sh3bgrl, sh3bgrl2, sh3bgrl3, and sh3bgr are evolutionally identical to their corresponding human orthologues, we analyzed the spatiotemporal expression of SH3BGR family members in zebrafish embryonic development stages by in situ hybridization. Our results revealed that except sh3bgrl, other members are all maternally expressed, especially for sh3bgrl3 that is strongly expressed from one cell stage to juvenile fishes. In situ expression patterns of SH3BGR members are similar in the very early developmental stages, including with commonly strong expression in intestines, olfactory bulbs, and neuromasts for neural system building up. Organ-specific expressions are also demonstrated, of which sh3bgr is uniquely expressed in sarcomere, and sh3bgrl3 in liver. sh3bgrl and sh3bgrl2 are similarly expressed in intestines, notochords, and neuromasts after 12-h post fertilization of embryos. Eventually, messenger RNAs (mRNAs) of all sh3bgr members are mainly constrained into intestines of juvenile fishes. Collectively, our study clarified the expression patterns of sh3bgr family members in diverse organogenesis in embryonic development and indicates that SH3BGR members may play predominant roles in neural system development and in maintenance of normal function of digestive organs, especially for intestine homeostasis. However, their expression patterns are varied with the development stages and organ types, suggesting that the aberrant expression of these members would result in multiple diseases. PMID- 27233780 TI - Update of the ICUD-SIU consultation on upper tract urothelial carcinoma 2016: treatment of low-risk upper tract urothelial carcinoma. AB - INTRODUCTION: The conservative management of upper tract urothelial carcinoma (UTUC) has historically been offered to patients with imperative indications. The recent International Consultation on Urologic Diseases (ICUD) publication on UTUC stratified treatment allocations based on high- and low-risk groups. This report updates the conservative management of the low-risk group. METHODS: The ICUD for low-risk UTUC working group performed a thorough review of the literature with an assessment of the level of evidence and grade of recommendation for a variety of published studies in this disease space. We update these publications and provide a summary of that original report. RESULTS: There are no prospective randomized controlled studies to support surgical management guidelines. A risk-stratified approach based on clinical, endoscopic, and biopsy assessment allows selection of patients who could benefit from kidney-preserving procedures with oncological outcomes potentially similar to radical nephroureterectomy with bladder cuff excision, with the added benefit of renal function preservation. These treatments are aided by the development of high-definition flexible digital URS, multi biopsies with the aid of access sheaths and other tools, and promising developments in the use of adjuvant topical therapy. CONCLUSIONS: Recent developments in imaging, minimally invasive techniques, multimodality approaches, and adjuvant topical regimens and bladder cancer prevention raise the hope for improved risk stratification and may greatly improve the endoscopic treatment for low-risk UTUC. PMID- 27233783 TI - SOCS1 regulates neuropathic pain by inhibiting neuronal sensitization and glial activation in mouse spinal cord. AB - Neuropathic pain is still a basic science and clinical challenge now, the neuronal sensitization and glial activation in the spinal cord (SC) level are more far-reaching for contributing to pain hypersensitivity following chronic constriction injury (CCI). Accumulating evidence indicates that astrocytes and microglia are activated in the spinal cord dorsal horn (SCDH) after CCI. Suppressor of cytokine signaling 1 (SOCS1) plays an important role in regulating of neuronal inflammation. Here, we investigated the role of SOCS1 in SC played in neuropathic pain. We find SOCS1 was persistently downregulated in the spinal neurons after CCI in mice. On the contrary, overexpression of SOCS1 in the SC reversed CCI-induced pain behavioral, activation of neurons, astrocytes, microglia, and the expression of proinflammatory cytokines including tumor necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta) and IL-6. Over all, these results demonstrate that downregulation of SOCS1 contributed to the development and maintenance of neuropathic pain via activating of neurons, astrocytes, microglia, and proinflammatory cytokines. SOCS1 may be developed into a potential target for treating neuropathic pain. PMID- 27233782 TI - Diabetes impairs spatial learning and memory and hippocampal neurogenesis via BDNF in rats with transient global ischemia. AB - Diabetic conditions worsen the prognosis of stroke. The molecular mechanism underlying the impairment of post-stroke recovery is not very clear. Here, we establish a rat model resembling human cerebral infarction with or without diabetes to determine how diabetes impairs cognitive recovery. Our data show that diabetes inhibits hippocampal BDNF expression and impairs the survival and differentiation of the newborn neural cells in rats with ischemia. Consequently, the rats of diabetic ischemia have a significantly lower score in spatial learning and memory in the Morris water maze test than the non-diabetic ischemia model rats. On the other hand, treatment with BDNF effectively improves hippocampal neurogenesis and the spatial learning and memory in rat with diabetic ischemia. All together, our data suggest that diabetes impaired spatial learning and memory and hippocampal neurogenesis in rats with ischemia by inhibition of the BDNF expression in the hippocampus. PMID- 27233785 TI - [Choosing wisely : Primarily the quality of indications]. PMID- 27233784 TI - Neurofeedback of visual food cue reactivity: a potential avenue to alter incentive sensitization and craving. AB - FMRI-based neurofeedback transforms functional brain activation in real-time into sensory stimuli that participants can use to self-regulate brain responses, which can aid the modification of mental states and behavior. Emerging evidence supports the clinical utility of neurofeedback-guided up-regulation of hypoactive networks. In contrast, down-regulation of hyperactive neural circuits appears more difficult to achieve. There are conditions though, in which down-regulation would be clinically useful, including dysfunctional motivational states elicited by salient reward cues, such as food or drug craving. In this proof-of-concept study, 10 healthy females (mean age = 21.40 years, mean BMI = 23.53) who had fasted for 4 h underwent a novel 'motivational neurofeedback' training in which they learned to down-regulate brain activation during exposure to appetitive food pictures. FMRI feedback was given from individually determined target areas and through decreases/increases in food picture size, thus providing salient motivational consequences in terms of cue approach/avoidance. Our preliminary findings suggest that motivational neurofeedback is associated with functionally specific activation decreases in diverse cortical/subcortical regions, including key motivational areas. There was also preliminary evidence for a reduction of hunger after neurofeedback and an association between down-regulation success and the degree of hunger reduction. Decreasing neural cue responses by motivational neurofeedback may provide a useful extension of existing behavioral methods that aim to modulate cue reactivity. Our pilot findings indicate that reduction of neural cue reactivity is not achieved by top-down regulation but arises in a bottom-up manner, possibly through implicit operant shaping of target area activity. PMID- 27233786 TI - [The Choosing Wisely Initiative of the German Society of Internal Medicine : Recommendations of the German Society for Endocrinology and the German Society for Geriatrics]. AB - POSITIVE RECOMMENDATIONS: A. After osteoporotic fractures in the elderly, as a rule specific antiosteoporotic therapy should be initiated. a. Osteoporosis as a disease of the elderly should be diagnosed and treated (recommendation of the German Society for Geriatrics). B. All patients with diabetes mellitus should complete a specific diabetes training program when antidiabetic drug medication is initiated. C. In Germany, all pregnant women should be advised to undertake iodine supplementation. D. Endocrine causes of hypertension should be ruled out in younger patients and in patients on multiple antihypertensive drugs. E. All unclear cases of hypercalcemia should be clarified. NEGATIVE RECOMMENDATIONS: A. Testosterone substitution therapy should not be initiated on the basis of only one measurement of a reduced testosterone level without clinical signs and clarification of the underlying cause. B. Imaging procedures should only be used after the existence of hormonal disease has been confirmed. C. Sonographic screening for thyroid disease is not advised in the elderly. D. Long-term therapy with levothyroxine for nodular goiter should be avoided. E. In relevant stress situations hydrocortisone replacement therapy should not be continued without dose adjustment in patients with adrenal or pituitary insufficiency. PMID- 27233787 TI - Key concepts in MR spectroscopy and practical approaches to gaining biochemical information in children. AB - Magnetic resonance spectroscopy (MRS) provides independent biochemical information and has become an invaluable adjunct to MRI and other imaging modalities. This review introduces key concepts and presents basic methodological steps regarding the acquisition and the interpretation of proton MRS. We review major brain metabolites and discuss MRS dependence on age, location, echo time and field strength. PMID- 27233788 TI - Proton MRS imaging in pediatric brain tumors. AB - Magnetic resonance (MR) techniques offer a noninvasive, non-irradiating yet sensitive approach to diagnosing and monitoring pediatric brain tumors. Proton MR spectroscopy (MRS), as an adjunct to MRI, is being more widely applied to monitor the metabolic aspects of brain cancer. In vivo MRS biomarkers represent a promising advance and may influence treatment choice at both initial diagnosis and follow-up, given the inherent difficulties of sequential biopsies to monitor therapeutic response. When combined with anatomical or other types of imaging, MRS provides unique information regarding biochemistry in inoperable brain tumors and can complement neuropathological data, guide biopsies and enhance insight into therapeutic options. The combination of noninvasively acquired prognostic information and the high-resolution anatomical imaging provided by conventional MRI is expected to surpass molecular analysis and DNA microarray gene profiling, both of which, although promising, depend on invasive biopsy. This review focuses on recent data in the field of MRS in children with brain tumors. PMID- 27233791 TI - Case 4: an adolescent girl with left lower quadrant pain. AB - The imaging management of an adolescent girl with pelvic pain and ovarian pathology is discussed through the details of a specific case. PMID- 27233789 TI - MR spectroscopy in children: protocols and pitfalls in non-tumorous brain pathology. AB - Proton nuclear magnetic resonance spectroscopy (MRS) delivers information about cell content and metabolism in a noninvasive manner. The diagnostic strength of MRS lies in its evaluation of pathologies in combination with conventional magnetic resonance imaging (MRI). MRS in children has been most widely used to evaluate brain conditions like tumors, infections, metabolic diseases or learning disabilities and especially in neonates with hypoxic-ischemic encephalopathy. This article reviews some basic theoretical considerations, routine procedures, protocols and pitfalls and will illustrate the range of spectrum alterations occurring in some non-tumorous pediatric brain pathologies. PMID- 27233793 TI - Identification of a microRNA (miR-663a) induced by ER stress and its target gene PLOD3 by a combined microRNome and proteome approach. AB - INTRODUCTION: MicroRNAs (miRs) regulate gene expression to support important physiological functions. Significant evidences suggest that miRs play a crucial role in many pathological events and in the cell response to various stresses. METHODS: With the aim to identify new miRs induced by perturbation of intracellular calcium homeostasis, we analysed miR expression profiles of thapsigargin (TG)-treated cells by microarray. In order to identify miR-663a regulated genes, we evaluated proteomic changes in miR-663a-overexpressing cells by two-dimensional differential in-gel electrophoresis coupled to mass spectrometric identification of the differentially represented proteins. Microarray and proteomic analyses were supported by biochemical validation. RESULTS: Results of microarray revealed 24 differentially expressed miRs; among them, miR-663a turned out to be by ER stress and under the control of the PERK pathway of the unfolded protein response. Proteomic analysis revealed that PLOD3, which is the gene encoding for collagen-modifying lysyl hydroxylase 3 (LH3), is regulated by miR-663a. Luciferase reporter assays demonstrated that miR-663a indeed reduces LH3 expression by targeting to 3'-UTR of PLOD3 mRNA. Interestingly, miR-663a inhibition of LH3 expression generates reduced extracellular accumulation of type IV collagen, thus suggesting the involvement of miR-663a in modulating collagen 4 secretion in physiological conditions and in response to ER stress. CONCLUSION: The finding of the ER stress-induced PERK-miR 663a pathway may have important implications in the understanding of the molecular mechanisms underlying the function of this miR in normal and/or pathological conditions. PMID- 27233794 TI - Cell-free expression, purification, and membrane reconstitution for NMR studies of the nonstructural protein 4B from hepatitis C virus. AB - We describe the expression of the hepatitis C virus nonstructural protein 4B (NS4B), which is an integral membrane protein, in a wheat germ cell-free system, the subsequent purification and characterization of NS4B and its insertion into proteoliposomes in amounts sufficient for multidimensional solid-state NMR spectroscopy. First spectra of the isotopically [(2)H,(13)C,(15)N]-labeled protein are shown to yield narrow (13)C resonance lines and a proper, predominantly alpha-helical fold. Clean residue-selective leucine, isoleucine and threonine-labeling is demonstrated. These results evidence the suitability of the wheat germ-produced integral membrane protein NS4B for solid-state NMR. Still, the proton linewidth under fast magic angle spinning is broader than expected for a perfect sample and possible causes are discussed. PMID- 27233796 TI - Clinical Trial of Erythropoietin in Young Children With Cerebral Palsy. AB - This study was conducted to assess the safety and efficacy of recombinant human erythropoietin in young children with cerebral palsy aged between 6 months and 3 years. All participants received subcutaneous recombinant human erythropoietin and 8 weeks of rehabilitation therapy. Adverse events, changes of vital signs, and hematologic tests were monitored up to 8 weeks postinjection. Functional measures of development at 4 and 8 weeks postinjection were compared with baseline values, and improvements were compared with those of an age-matched historical control group. Nine participants completed the trial from June 2012 to February 2015. No adverse events were related to recombinant human erythropoietin. Erythropoiesis was noted, although within normal range. Functional improvements were observed in all participants (P < .05) and increases in motor function were higher in recombinant human erythropoietin group than the control group. Accordingly, recombinant human erythropoietin administration was safe without any significant adverse events and improved the functional outcomes in young children with cerebral palsy. PMID- 27233797 TI - Native plasmids restrict growth of Phaeobacter inhibens DSM 17395: Energetic costs of plasmids assessed by quantitative physiological analyses. AB - Plasmid carriage is associated with energetic costs, and thus only those plasmids providing fitness benefits are stably maintained in the host lineage. Marine bacteria of the Roseobacter clade harbor up to 11 extrachromosomal replicons, adding lifestyle-relevant and possibly habitat success-promoting functions to their genomic repertoire. Phaeobacter inhibens DSM 17395 is a nutritionally versatile representative, carrying three stable and functionally distinct plasmids (65, 78, and 262 kb). The present study investigates the physiological and energetic consequences of plasmid carriage in P. inhibens DSM 17395, employing mutants cured from all native plasmids in every possible combination (seven different). Cultivation in process-controlled bioreactors with casamino acids as organic substrate revealed a complex physiological response, suggesting existence of functional interconnections between the replicons. Deletion of the 262 kb plasmid boosted growth rate (>3-fold) and growth efficiency (yields for carbon, O2 and CO2 ), which was not observed for the 65 or 78 kb plasmid. Carriage of the 262 kb plasmid was most costly for the wild type, i.e. contributing ~50% to its energetic (dissimilatory) expenditures. Cost-benefit analysis of plasmid carriage reflects the high value of plasmids for niche specialization of P. inhibens DSM 17395 and most likely also for related Phaeobacter species. PMID- 27233798 TI - Proposing the Use of Partial AUC as an Adjunctive Measure in Establishing Bioequivalence Between Deltoid and Gluteal Administration of Long-Acting Injectable Antipsychotics. AB - The maximum plasma concentration (C max) and the area under the plasma concentration-time curve (AUC) are commonly used to establish bioequivalence between two formulations of the same oral medication. Similarly, these pharmacokinetic parameters have also been used to establish bioequivalence between two sites of administration for the same injectable formulation. However, these conventional methods of establishing bioequivalence are of limited use when comparing modified-release formulations of a drug, particularly those with rates of absorption that are amenable to change with the site of injection. Inherent differences in the rate of absorption can result in clinically significant differences in early exposure and drug response. Here, we propose the use of the partial AUC (pAUC) as a measure of early exposure to aid in the assessment of bioequivalence between the gluteal and the deltoid site of administration for long-acting injectable antipsychotics. PMID- 27233799 TI - Activation of toll-like receptor signaling pathways leading to nitric oxide mediated antiviral responses. AB - Toll-like receptors (TLRs), well-characterized pattern-recognizing receptors of the innate arm of the immune system, are vital in detecting pathogen-associated molecular patterns (PAMPs). The TLR-PAMP interaction initiates an intracellular signaling cascade, predominantly culminating in upregulation of antiviral components, including inducible nitric oxide synthase (iNOS). After activation, various TLR pathways can promote iNOS production via the myeloid differentiation primary response-88 (MyD-88) adapter protein. Subsequently, iNOS facilitates production of nitric oxide (NO), a highly reactive and potent antiviral molecule that can inhibit replication of RNA and DNA viruses. Furthermore, NO can diffuse freely across cell membranes and elicit antiviral mechanisms in various ways, including direct and indirect damage to viral genomes. This review emphasizes current knowledge of NO-mediated antiviral responses elicited after activation of TLR signaling pathways. PMID- 27233801 TI - Partial deletion of stem-loop 2 in the 3' untranslated region of foot-and-mouth disease virus identifies a region that is dispensable for virus replication. AB - The 3' untranslated region (3' UTR) of the foot-and-mouth disease virus (FMDV) genome plays an essential role in virus replication, but the properties of the 3' UTR are not completely defined. In order to determine the role of different regions of the 3' UTR in FMDV replication, we conducted site-directed mutagenesis of the 3' UTR of FMDV serotype O IND R2/1975 using a cDNA clone. Through independent serial deletions in various regions of the 3' UTR, we demonstrated that deletion of nucleotides between the stem-loop (SL) structures and in the beginning and the end regions of the SL2 structure could be lethal for FMDV replication. However, a block deletion of 20 nucleotides (nt 60 to 79) in the middle of SL2 did not affect the viability of FMDV in cultured cells. Characterisation of the deletion mutant virus (O(R2/1975-Delta3'UTR 60-79)) revealed no significant difference in growth kinetics or RNA replication ability compared to the parental virus. However, the mutant virus produced slightly larger plaques when compared to the parental virus. This is the first description of a dispensable 20-nucleotide region in SL2 of the FMDV 3' UTR. PMID- 27233800 TI - Avian reovirus sigmaA and sigmaNS proteins activate the phosphatidylinositol 3 kinase-dependent Akt signalling pathway. AB - The present study was conducted to identify avian reovirus (ARV) proteins that can activate the phosphatidylinositol 3-kinase (PI3K)-dependent Akt pathway. Based on ARV protein amino acid sequence analysis, sigmaA, sigmaNS, MUA, MUB and MUNS were identified as putative proteins capable of mediating PI3K/Akt pathway activation. The recombinant plasmids sigmaA-pcAGEN, sigmaNS-pcAGEN, MUA-pcAGEN, MUB-pcAGEN and MUNS-pcAGEN were constructed and used to transfect Vero cells, and the expression levels of the corresponding genes were quantified by immunofluorescence and Western blot analysis. Phosphorylated Akt (P-Akt) levels in the transfected cells were measured by flow cytometry and Western blot analysis. The results showed that the sigmaA, sigmaNS, MUA, MUB and MUNS genes were expressed in Vero cells. sigmaA-expressing and sigmaNS-expressing cells had higher P-Akt levels than negative control cells, pcAGEN-expressing cells and cells designed to express other proteins (i.e., MUA, MUB and MUNS). Pre-treatment with the PI3K inhibitor LY294002 inhibited Akt phosphorylation in sigmaA- and sigmaNS-expressing cells. These results indicate that the sigmaA and sigmaNS proteins can activate the PI3K/Akt pathway. PMID- 27233802 TI - Clinical Predictors of Venetoclax Pharmacokinetics in Chronic Lymphocytic Leukemia and Non-Hodgkin's Lymphoma Patients: a Pooled Population Pharmacokinetic Analysis. AB - Venetoclax (ABT-199/GDC-0199) is a selective, potent, first-in-class BCL-2 inhibitor that restores apoptosis in cancer cells and has demonstrated clinical efficacy in a variety of hematological malignancies. The objective of this analysis was to characterize the population pharmacokinetics of venetoclax and identify demographic, pathophysiologic, and treatment factors that influence its pharmacokinetics. Plasma concentration samples from 505 subjects enrolled in 8 clinical studies were analyzed using non-linear mixed-effects modeling. Venetoclax plasma concentrations were best described by a two-compartment PK model with first-order absorption and elimination. The terminal half-life in cancer subjects was estimated to be approximately 26 h. Moderate and strong CYP3A inhibitors decreased venetoclax apparent clearance by 19% and 84%, respectively, while weak CYP3A inhibitors and inducers did not affect clearance. Additionally, concomitant rituximab administration was estimated to increase venetoclax apparent clearance by 21%. Gastric acid-reducing agent co-administration had no impact on the rate or extent of venetoclax absorption. Females had 32% lower central volume of distribution when compared to males. Food increased the bioavailability by 2.99- to 4.25-fold when compared to the fasting state. Mild and moderate renal and hepatic impairment, body weight, age, race, weak CYP3A inhibitors and inducers as well as OATP1B1 transporter phenotype and P-gp, BCRP, and OATP1B1/OATP1B3 modulators had no impact on venetoclax pharmacokinetics. Venetoclax showed minimal accumulation with accumulation ratio of 1.30-1.44. In conclusion, the concomitant administration of moderate and strong CYP3A inhibitors and rituximab as well as food were the main factors impacting venetoclax pharmacokinetics, while patient characteristics had only minimal impact. PMID- 27233803 TI - Cell-Based Therapies Formulations: Unintended components. AB - Cell-based therapy is the fastest growing segment of regenerative medicine, a field that promises to cure diseases not treated by other small molecules or biological drugs. The use of living cells as the active medicinal ingredient present great opportunities to deliver treatment that can trigger the body's own capacity to regenerate damaged or diseased tissue. Some of the challenges in controlling the quality of the finished cell-therapy product relate to the use of a variety of raw materials including excipients, process aids, and growth promotion factors. The quality of these materials is critical for ensuring the safety and quality of the finished therapeutic products. This review will discuss some of the challenges and opportunities associated with the qualification of excipients as well as that of the ancillary materials used in manufacturing. PMID- 27233804 TI - Genetic polymorphisms of pharmacogenomic VIP variants in the Mongol of Northwestern China. AB - BACKGROUND: Within a population, the differences of pharmacogenomic variant frequencies may produce diversities in drug efficacy, safety, and the risk associated with adverse drug reactions. With the development of pharmacogenomics, widespread genetic research on drug metabolism has been conducted on major populations, but less is known about minorities. RESULTS: In this study, we recruited 100 unrelated, healthy Mongol adults from Xinjiang and genotyped 85 VIP variants from the PharmGKB database. We compared our data with eleven populations listed in 1000 genomes project and HapMap database. We used chi(2) tests to identify significantly different loci between these populations. We downloaded SNP allele frequencies from the ALlele FREquency Database to observe the global genetic variation distribution for these specific loci. And then we used Structure software to perform the genetic structure analysis of 12 populations. CONCLUSIONS: Our results demonstrated that different polymorphic allele frequencies exist between different nationalities,and indicated Mongol is most similar to Chinese populations, followed by JPT. This information on the Mongol population complements the existing pharmacogenomic data and provides a theoretical basis for screening and therapy in the different ethnic groups within Xinjiang. PMID- 27233805 TI - Base-modified UDP-sugars reduce cell surface levels of P-selectin glycoprotein 1 (PSGL-1) on IL-1beta-stimulated human monocytes. AB - P-selectin glycoprotein ligand-1 (PSGL-1, CD162) is a cell-surface glycoprotein that is expressed, either constitutively or inducibly, on all myeloid and lymphoid cell lineages. PSGL-1 is implicated in cell-cell interactions between platelets, leukocytes and endothelial cells, and a key mediator of inflammatory cell recruitment and transmigration into tissues. Here, we have investigated the effects of the beta-1,4-galactosyltransferase inhibitor 5-(5-formylthien-2-yl) UDP-Gal (5-FT UDP-Gal, compound 1: ) and two close derivatives on the cell surface levels of PSGL-1 on human peripheral blood mononuclear cells (hPBMCs). PSGL-1 levels were studied both under basal conditions, and upon stimulation of hPBMCs with interleukin-1beta (IL-1beta). Between 1 and 24 hours after IL-1beta stimulation, we observed initial PSGL-1 shedding, followed by an increase in PSGL 1 levels on the cell surface, with a maximal window between IL-1beta-induced and basal levels after 72 h. All three inhibitors reduce PSGL-1 levels on IL-1beta stimulated cells in a concentration-dependent manner, but show no such effect in resting cells. Compound 1: also affects the cell surface levels of adhesion molecule CD11b in IL-1beta-stimulated hPBMCs, but not of glycoproteins CD14 and CCR2. This activity profile may be linked to the inhibition of global Sialyl Lewis presentation on hPBMCs by compound 1: , which we have also observed. Although this mechanistic explanation remains hypothetical at present, our results show, for the first time, that small molecules can discriminate between IL-1beta-induced and basal levels of cell surface PSGL-1. These findings open new avenues for intervention with PSGL-1 presentation on the cell surface of primed hPBMCs and may have implications for anti-inflammatory drug development. PMID- 27233806 TI - Control of floral transition in the bioenergy crop switchgrass. AB - Switchgrass (Panicum virgatum L.), a perennial warm season bunchgrass native to North America, has been a target in the U.S. as a renewable bioenergy crop because of its ability to produce moderate to high biomass yield on marginal soils. Delaying flowering can increase vegetative biomass production by allowing prolonged growth before switching to the reproductive phase. Despite the identification of flowering time as a biomass trait in switchgrass, the molecular regulatory factors involved in controlling floral transition are poorly understood. Here we identified PvFT1, PvAPL1-3 and PvSL1, 2 as key flowering regulators required from floral transition initiation to development of floral organs. PvFT1 expression in leaves is developmentally regulated peaking at the time of floral transition, and diurnally regulated with peak at approximately 2 h into the dark period. Ectopic expression of PvFT1 in Arabidopsis, Brachypodium and switchgrass led to extremely early flowering, and activation of FT downstream target genes, confirming that it is a strong activator of flowering in switchgrass. Ectopic expression of PvAPL1-3 and PvSL1, 2 in Arabidopsis also activated early flowering with distinct floral organ phenotypes. Our results suggest that switchgrass has conserved flowering pathway regulators similar to Arabidopsis and rice. PMID- 27233807 TI - Bhasker Kamath. PMID- 27233808 TI - Language effects in second-language learners: A longitudinal electrophysiological study of spanish classroom learning. AB - How do the neural mechanisms involved in word recognition evolve over the course of word learning in adult learners of a new second language? The current study sought to closely track language effects, which are differences in electrophysiological indices of word processing between one's native and second languages, in beginning university learners over the course of a single semester of learning. Monolingual L1 English-speakers enrolled in introductory Spanish were first trained on a list of 228 Spanish words chosen from the vocabulary to be learned in class. Behavioral data from the training session and the following experimental sessions spaced over the course of the semester showed expected learning effects. In the three laboratory sessions participants read words in three lists (English, Spanish and mixed) while performing a go/no-go lexical decision task in which event-related potentials (ERPs) were recorded. As observed in previous studies there were ERP language effects with larger N400s to native than second language words. Importantly, this difference declined over the course of L2 learning with N400 amplitude increasing for new second language words. These results suggest that even over a single semester of learning that new second language words are rapidly incorporated into the word recognition system and begin to take on lexical and semantic properties similar to native language words. Moreover, the results suggest that electrophysiological measures can be used as sensitive measures for tracking the acquisition of new linguistic knowledge. PMID- 27233809 TI - Characterization of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, in rat partial and full nigral 6-hydroxydopamine lesion models of Parkinson's disease. AB - Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, have been demonstrated to promote neuroprotection in the rat 6-hydroxydopamine (6-OHDA) neurotoxin model of Parkinson's disease (PD), a neurodegenerative disorder characterized by progressive nigrostriatal dopaminergic neuron loss. In this report, we characterized the effect of a long-acting GLP-1 receptor agonist, liraglutide (500ug/kg/day, s.c.) in the context of a partial or advanced (full) 6 OHDA induced nigral lesion in the rat. Rats received a low (3ug, partial lesion) or high (13.5ug, full lesion) 6-OHDA dose stereotaxically injected into the right medial forebrain bundle (n=17-20 rats per experimental group). Six weeks after induction of a partial nigral dopaminergic lesion, vehicle or liraglutide was administered for four weeks. In the full lesion model, vehicle dosing or liraglutide treatment was applied for a total of six weeks starting three weeks pre-lesion, or administered for three weeks starting on the lesion day. Quantitative stereology was applied to assess the total number of midbrain tyrosine hydroxylase (TH) positive dopaminergic neurons. As compared to vehicle controls, liraglutide had no effect on the rotational responsiveness to d amphetamine or apomorphine, respectively. In correspondence, while numbers of TH positive nigral neurons were significantly reduced in the lesion side (partial lesion ~55%; full lesion ~90%) liraglutide administration had no influence dopaminergic neuronal loss in either PD model setting. In conclusion, liraglutide showed no neuroprotective effects in the context of moderate or substantial midbrain dopaminergic neuronal loss and associated functional motor deficits in the rat 6-OHDA lesion model of PD. PMID- 27233810 TI - Phylogenetic position of Leishmania isolates from Khyber Pakhtunkhwa province of Pakistan. AB - Several species of the genus Leishmania are causative agents of cutaneous leishmaniasis in Pakistan. This study aimed to determine phylogenetic placement of Leishmania species causing cutaneous leishmaniasis in Khyber Pakhtunkhwa province, Pakistan (34 Leishmania tropica, 3 Leishmania infantum), in-relation to species from other geographical areas using gene sequences encoding cytochrome b (cytb) and internal transcribed spacer 2 (its2). Based on cytochrome b sequence analysis, L. tropica strains from Pakistan and other geographical regions were differentiated into two genotype groups, A and B. Within the province, five distinct L. tropica genotypes were recognized; two in group A, three in group B. Two L. infantum isolates from the province were closely associated with both Afro Eurasian and American species of the Leishmania donovani complex, including Leishmania chagasi, L. infantum and L. donovani from Sudan and Ethiopia; while a third L. infantum isolate could not be differentiated from visceralizing Kenyan and Indian L. donovani. We observed apposite phylogenetic placement of CL-causing L. tropica and L. infantum from Khyber Pakhtunkhwa. Affinities ascribed to Leishmania spp. From the region are valuable in tracing potential importation of leishmaniasis. PMID- 27233811 TI - Beyond awareness of 'difference' and towards social action: 'Solidarity practice' alongside young people. AB - Who I am as a working-class black African woman cannot be disconnected from how I work. It shapes my lens with regard to power, difference and liberation. It is not surprising that I have been drawn to social justice approaches to psychological intervention, such as Narrative Therapy, Coordinated Management of Meaning (CMM), social constructionist systemic therapy and liberation psychology. These practices involve taking up the cause of the oppressed in ways that respect them as agents of their own liberation. In this article, I describe what I term 'solidarity practice' with young people and their families as a counter force resisting the increasingly blaming and individualising discourse of mainstream psychology, psychiatry and social policy. PMID- 27233812 TI - Parallel transverse uterine incisions to control postpartum hemorrhage and preserve fertility during cesarean delivery for placenta previa and accreta. PMID- 27233813 TI - The association between p16 and Ki-67 immunohistostaining and the progression of cervical intraepithelial neoplasia grade 2. AB - OBJECTIVE: To compare the frequency of p16- and Ki-67-positive cells on immunohistostaining among women with progression, persistence, or regression of cervical intraepithelial neoplasia grade 2 (CIN2). METHODS: A retrospective study was conducted of women with CIN2 diagnosed by histology who were treated at a university hospital in Japan during 2004-2011. The immunostaining patterns for p16 and Ki-67 were analyzed and compared between patients with disease progression, persistence, or regression. Kaplan-Meier analysis was used to evaluate the progression rates stratified by immunostaining, and multivariate analysis of risk factors for progression was performed using the Cox proportional hazards model. RESULTS: The analysis included 59 women with progression, 35 women with persistence, and 28 women with regression. Deep p16 expression (staining in more than half of the cervical intraepithelial compartment) and positive Ki-67 staining in more than 50% of cells were significantly more common among women with progression than among those with regression. The risk factors for progression of CIN2 were deep p16 expression (P<0.001) and a Ki-67 ratio of more than 50% (P<0.001). CONCLUSION: Among women with CIN2, positive immunohistostaining for p16 and Ki-67 was strongly associated with disease progression. PMID- 27233814 TI - Prediction of preterm labor by a rapid bedside test detecting phosphorylated insulin-like growth factor-binding protein 1 in cervical secretions. AB - OBJECTIVE: To evaluate the utility of measuring phosphorylated insulin-like growth factor-binding protein 1 (phIGFBP-1) in cervical secretions to predict preterm birth among women with premature uterine contractions. METHODS: A prospective study was conducted between September 27, 2013, and February 28, 2014, at a tertiary center in India. Participants with symptoms of preterm labor at 24-36weeks underwent testing for phIGFBP-1 in cervical secretions. Cervical length was measured by ultrasonography. RESULTS: Cervical swab samples tested positive for phIGFBP-1 among 34 (57%) of the 60 participants. Mean cervical length was 2.15+/-0.63cm among the 46 (77%) women who delivered preterm and 2.54+/-0.47cm among the 14 (23%) women who delivered at term. Of the 46 preterm deliveries, 29 (63%) women tested positive for phIGFBP-1 and 17 (37%) tested negative. Mean length of pregnancy at delivery was 32.11+/-4.09weeks and 35.77+/ 1.68weeks among women who tested positive and negative for phIGFBP-1, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value of phIGFBP-1 to predict preterm birth were 86.96%, 35.29%, 64.52%, and 66.67%, respectively. CONCLUSION: A rapid bedside test measuring phIGFBP-1 identified women at high risk of preterm delivery. PMID- 27233815 TI - Learning curves for laparoscopic hysterectomy after implementation of minimally invasive surgery. AB - OBJECTIVE: To evaluate the learning process for total laparoscopic hysterectomy (TLH) and laparoscopic supracervical hysterectomy (LSH) for benign uterine pathologies among surgeons inexperienced in laparoscopy. METHODS: A retrospective comparative study was conducted of all hysterectomies performed by four attending surgeons and three resident surgeons at a tertiary university center in Homburg/Saar, Germany. Laparoscopic procedures were assessed between October 1, 2009, and October 31, 2010 (period A); November 1, 2010, and March 31, 2012 (period B); and April 1, 2012, and June 30, 2013 (period C). Data were obtained by medical chart review. RESULTS: Overall, 269 patients underwent TLH and 165 underwent LSH. Duration of surgery for all surgeons decreased from 136 +/- 60 minutes in period A to 118 +/- 44 minutes in period B (P=0.013), but increased to 122 +/- 56 minutes in period C (A vs C: P=0.067). Among attending surgeons, the duration of surgery seemed to decrease after 20 TLH procedures and after 10 LSH procedures. Among resident surgeons, duration decreased after 10 LSH procedures; no fall was apparent for TLH. CONCLUSION: Both TLH and LSH were readily adopted among a group of surgeons inexperienced in laparoscopy, although LSH might be easier to learn. Experienced surgeons have a steeper learning curve than do their inexperienced counterparts. PMID- 27233816 TI - Factors predictive of mortality in a cohort of women surgically treated for breast cancer from 1997 to 2014. AB - OBJECTIVE: To determine whether previously reported factors predictive of breast cancer mortality are effectively linked with mortality, particularly breast cancer-specific mortality. METHODS: In a prospective study, clinical, surgical, and follow-up data were assessed for consecutive patients with breast cancer who underwent surgery between 1997 and 2014 at two centers in Barcelona, Spain. Predictors of mortality were assessed by multivariate analysis. RESULTS: Overall, 2134 patients were treated for 2206 breast tumors. Overall mortality was 15.0% (n=319), and breast-cancer-specific mortality was 9.0% (n=191). On multivariate analysis, the most significant factors associated with breast-cancer-specific mortality were clinical stage, inmunohistochemical profile, locoregional relapse, and lymphovascular invasion (all P<0.001). Age at onset, participation in the mass-screening program, histologic grade, and multicentricity were not significant. Patients with three or more positive axillary nodes sustained a specific mortality significantly higher than did node-negative patients or those with fewer than three positive nodes. CONCLUSION: Factors predictive of breast cancer mortality were clinical stage, locoregional relapse, molecular classification, lymphovascular invasion, and neoadjuvant chemotherapy. As a single factor, nodal disease becomes relevant only when three or more lymph nodes are involved. PMID- 27233817 TI - Thyroperoxidase antibodies and polycystic ovarian morphology. AB - OBJECTIVE: To evaluate the association between polycystic ovarian morphology (PCOM) and thyroperoxidase antibody level. METHODS: A cross-sectional study was undertaken of women aged 15-49years living in one of four provinces in Iran recruited between February 2009 and November 2010. Eligible women did not have hirsutism and were eumenorrheic. All participants underwent a comprehensive interview, clinical examination, blood sampling, and ultrasonographic assessment. The serum concentration of thyroperoxidase antibodies was compared between women with and without PCOM. RESULTS: Among 491 participants, 74 (15.1%) had PCOM. In total, 11 (14.9%) women with PCOM and 61 (14.6%) women with normal morphology tested positive for thyroperoxidase antibodies. The serum concentration of thyroperoxidase antibodies was higher among women with PCOM (48.45+/-135.74IU/mL) than among those with normal ovarian morphology (37.99+/-96.49IU/mL), but the difference was not significant (P=0.42). CONCLUSION: Thyroperoxidase antibody levels were higher in Iranian women with PCOM than in women with normal morphology, although the difference was not significant. Larger longitudinal studies are needed to investigate whether the treatment of thyroid disorders can prevent the development of PCOM. PMID- 27233818 TI - Prolonged Intraoperative Cardiac Resuscitation Complicated by Intracardiac Thrombus in a Patient Undergoing Orthotopic Liver Transplantation. AB - We report the case of successful resuscitation after prolonged cardiac arrest during orthotopic liver transplantation. After reperfusion, the patient developed ventricular tachycardia, complicated by intracardiac clot formation and massive hemorrhage. Transesophageal echocardiography demonstrated stunned and nonfunctioning right and left ventricles, with developing intracardiac clots. Treatment with heparin, massive transfusion and prolonged cardiopulmonary resuscitation ensued for 51 minutes. Serial arterial blood gases demonstrated adequate oxygenation and ventilation during cardiopulmonary resuscitation. Cardiothoracic surgery was consulted for potential use of extracorporeal membrane oxygenation, however, the myocardial function improved and the surgery was completed without further intervention. On postoperative day 6, the patient was extubated without neurologic or cardiac impairment. The patient continues to do well 2 years posttransplant, able to perform independent daily activities of living and his previous job. This case underscores the potential for positive outcomes with profoundly prolonged, effective advanced cardiovascular life support in patients who experience postreperfusion syndrome. PMID- 27233819 TI - Validation of the American version of the CareGiver Oncology Quality of Life (CarGOQoL) questionnaire. AB - BACKGROUND: The CareGiver Oncology Quality of Life (CarGOQoL) questionnaire, a 29 item, multidimensional, self-administered questionnaire, was validated using a large French sample. We reported the linguistic validation process and the metric validity of the English version of CarGOQoL in the United- States. METHODS: The translation process consisted of 3 consecutive steps: forward-backward translation, acceptability testing, and cognitive interviews. The psychometric testing was applied to caregivers of consecutive patients with representative cancers who were recruited from the Regional Cancer Center in northwestern Pennsylvania. All individuals completed the CarGOQoL at baseline, day- 30, and day- 90. Internal consistency, reliability, external validity, reproducibility, and sensitivity to change were tested. RESULTS: The translated version was validated on a total of 87 American cancer caregivers. The dimensions of the CarGOQoL generally demonstrated a high internal consistency (Cronbach's alpha > 0.70 for all but four domain scores). External validity testing revealed that the CarGOQoL index score correlated significantly with all SF-36 dimension scores except the physical composite score (Pearson's correlation: 0.28-0.70). Reproducibility was satisfactory at day- 30 (intraclass correlation coefficient: 0.46-0.94) and day- 90 (0.43-0.92). Four specific dimensions of CarGOQoL showed responsiveness: the Psychological well-being, the Relationships with health care system, the Social support and the Finances. CONCLUSIONS: The American version of the CarGOQoL constitutes a useful instrument to measure QoL in caregivers of cancer patients in the United- States. PMID- 27233820 TI - Selection of oleaginous yeasts for fatty acid production. AB - BACKGROUND: Oleaginous yeast species are an alternative for the production of lipids or triacylglycerides (TAGs). These yeasts are usually non-pathogenic and able to store TAGs ranging from 20 % to 70 % of their cell mass depending on culture conditions. TAGs originating from oleaginous yeasts can be used as the so called second generation biofuels, which are based on non-food competing "waste carbon sources". RESULTS: In this study the selection of potentially new interesting oleaginous yeast strains is described. Important selection criteria were: a broad maximum temperature and pH range for growth (robustness of the strain), a broad spectrum of carbon sources that can be metabolized (preferably including C-5 sugars), a high total fatty acid content in combination with a low glycogen content and genetic accessibility. CONCLUSIONS: Based on these selection criteria, among 24 screened species, Schwanniomyces occidentalis (Debaromyces occidentalis) CBS2864 was selected as a promising strain for the production of high amounts of lipids. PMID- 27233821 TI - Multi-level regulation of the chloroplast ATP synthase: the chloroplast NADPH thioredoxin reductase C (NTRC) is required for redox modulation specifically under low irradiance. AB - The chloroplast ATP synthase is known to be regulated by redox modulation of a disulfide bridge on the gamma-subunit through the ferredoxin-thioredoxin regulatory system. We show that a second enzyme, the recently identified chloroplast NADPH thioredoxin reductase C (NTRC), plays a role specifically at low irradiance. Arabidopsis mutants lacking NTRC (ntrc) displayed a striking photosynthetic phenotype in which feedback regulation of the light reactions was strongly activated at low light, but returned to wild-type levels as irradiance was increased. This effect was caused by an altered redox state of the gamma subunit under low, but not high, light. The low light-specific decrease in ATP synthase activity in ntrc resulted in a buildup of the thylakoid proton motive force with subsequent activation of non-photochemical quenching and downregulation of linear electron flow. We conclude that NTRC provides redox modulation at low light using the relatively oxidizing substrate NADPH, whereas the canonical ferredoxin-thioredoxin system can take over at higher light, when reduced ferredoxin can accumulate. Based on these results, we reassess previous models for ATP synthase regulation and propose that NTRC is most likely regulated by light. We also find that ntrc is highly sensitive to rapidly changing light intensities that probably do not involve the chloroplast ATP synthase, implicating this system in multiple photosynthetic processes, particularly under fluctuating environmental conditions. PMID- 27233822 TI - Mice deficient for striatal Vesicular Acetylcholine Transporter (VAChT) display impaired short-term but normal long-term object recognition memory. AB - Substantial evidence implicates Acetylcholine (ACh) in the acquisition of object memories. While most research has focused on the role of the cholinergic basal forebrain and its cortical targets, there are additional cholinergic networks that may contribute to object recognition. The striatum contains an independent cholinergic network comprised of interneurons. In the current study, we investigated the role of this cholinergic signalling in object recognition using mice deficient for Vesicular Acetylcholine Transporter (VAChT) within interneurons of the striatum. We tested whether these striatal VAChT(D2-Cre flox/flox) mice would display normal short-term (5 or 15min retention delay) and long-term (3h retention delay) object recognition memory. In a home cage object recognition task, male and female VAChT(D2-Cre-flox/flox) mice were impaired selectively with a 15min retention delay. When tested on an object location task, VAChT(D2-Cre-flox/flox) mice displayed intact spatial memory. Finally, when object recognition was tested in a Y-shaped apparatus, designed to minimize the influence of spatial and contextual cues, only females displayed impaired recognition with a 5min retention delay, but when males were challenged with a 15min retention delay, they were also impaired; neither males nor females were impaired with the 3h delay. The pattern of results suggests that striatal cholinergic transmission plays a role in the short-term memory for object features, but not spatial location. PMID- 27233823 TI - High-speed video gait analysis reveals early and characteristic locomotor phenotypes in mouse models of neurodegenerative movement disorders. AB - Neurodegenerative diseases of the central nervous system frequently affect the locomotor system resulting in impaired movement and gait. In this study we performed a whole-body high-speed video gait analysis in three different mouse lines of neurodegenerative movement disorders to investigate the motor phenotype. Based on precise computerized motion tracking of all relevant joints and the tail, a custom-developed algorithm generated individual and comprehensive locomotor profiles consisting of 164 spatial and temporal parameters. Gait changes observed in the three models corresponded closely to the classical clinical symptoms described in these disorders: Muscle atrophy due to motor neuron loss in SOD1 G93A transgenic mice led to gait characterized by changes in hind-limb movement and positioning. In contrast, locomotion in huntingtin N171 82Q mice modeling Huntington's disease with basal ganglia damage was defined by hyperkinetic limb movements and rigidity of the trunk. Harlequin mutant mice modeling cerebellar degeneration showed gait instability and extensive changes in limb positioning. Moreover, model specific gait parameters were identified and were shown to be more sensitive than conventional motor tests. Altogether, this technique provides new opportunities to decipher underlying disease mechanisms and test novel therapeutic approaches. PMID- 27233824 TI - Time-dependent effects of repeated THC treatment on dopamine D2/3 receptor mediated signalling in midbrain and striatum. AB - This study examined the time-course of alterations in levels and functional sensitivities of dopamine D2/3 receptors (D2/3R) during the course and up to 6 weeks following cessation of chronic treatment with Delta(9)-Tetrahydrocannabinol (THC) in rats. THC treatment led to an increase in D2/3R levels in striatum, as assessed using [(3)H]-(+)-PHNO, that was readily observable after one week of treatment, remained stably elevated during the subsequent 2 weeks of treatment, but fully reversed within 2 weeks of THC discontinuation. THC-induced D2/3R alterations were more pronounced and longer lasting in the dopamine cell body regions of the midbrain, wherein [(3)H]-(+)-PHNO binding was still elevated at 2 weeks but back to control values at 6 weeks after THC cessation. Parallel analyses of the psychomotor effects of pre- and post-synaptic doses of quinpirole also showed a pattern of D2/3R functional supersensitivity indicative of more rapid subsidence in striatum than in midbrain following drug cessation. These results indicate that chronic THC is associated with a biochemical and functional sensitization of D2/3R signaling, that these responses show a region-specific temporal pattern and are fully reversible following drug discontinuation. These results suggest that an increased post-synaptic D2/3R function and a decreased DA presynaptic signaling, mediated by increased D2/3R autoinhibition, may predominate during distinct phases of withdrawal and may contribute both to the mechanisms leading to relapse and to cannabinoid withdrawal symptoms. The different rates of normalization of D2/3R function in striatum and midbrain may be critical information for the development of new pharmacotherapies for cannabis dependence. PMID- 27233826 TI - An interplay of fusiform gyrus and hippocampus enables prototype- and exemplar based category learning. AB - The aim of the present study was to examine the contributions of different brain structures to prototype- and exemplar-based category learning using functional magnetic resonance imaging (fMRI). Twenty-eight subjects performed a categorization task in which they had to assign prototypes and exceptions to two different families. This test procedure usually produces different learning curves for prototype and exception stimuli. Our behavioral data replicated these previous findings by showing an initially superior performance for prototypes and typical stimuli and a switch from a prototype-based to an exemplar-based categorization for exceptions in the later learning phases. Since performance varied, we divided participants into learners and non-learners. Analysis of the functional imaging data revealed that the interaction of group (learners vs. non learners) and block (Block 5 vs. Block 1) yielded an activation of the left fusiform gyrus for the processing of prototypes, and an activation of the right hippocampus for exceptions after learning the categories. Thus, successful prototype- and exemplar-based category learning is associated with activations of complementary neural substrates that constitute object-based processes of the ventral visual stream and their interaction with unique-cue representations, possibly based on sparse coding within the hippocampus. PMID- 27233825 TI - Working memory contributes to the encoding of object location associations: Support for a 3-part model of object location memory. AB - A recent model by Postma and colleagues posits that the encoding of object location associations (OLAs) requires the coordination of several cognitive processes mediated by ventral (object perception) and dorsal (spatial perception) visual pathways as well as the hippocampus (feature binding) [1]. Within this model, frontoparietal network recruitment is believed to contribute to both the spatial processing and working memory task demands. The current study used functional magnetic resonance imaging (fMRI) to test each step of this model in 15 participants who encoded OLAs and performed standard n-back tasks. As expected, object processing resulted in activation of the ventral visual stream. Object in location processing resulted in activation of both the ventral and dorsal visual streams as well as a lateral frontoparietal network. This condition was also the only one to result in medial temporal lobe activation, supporting its role in associative learning. A conjunction analysis revealed areas of shared activation between the working memory and object in location phase within the lateral frontoparietal network, anterior insula, and basal ganglia; consistent with prior working memory literature. Overall, findings support Postma and colleague's model and provide clear evidence for the role of working memory during OLA encoding. PMID- 27233828 TI - Insulin potentiates the therapeutic effect of memantine against central STZ induced spatial learning and memory deficit. AB - Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. Memantine has been approved for moderate to severe AD, but evidence indicates that it does not modify disease progression. Recently insulin has been found to exert some beneficial effects on cognition. This study aimed to compare the protective effects of memantine and insulin in an animal model of memory deficit. It also evaluated the effects of combination therapy of these drugs. Adult male Sprague-Dawely rats approximately 8-10 weeks old were used. The canules were implanted bilaterally into lateral ventricles. STZ was administered on days 1 and 3 (3mg/kg in divided doses) and Memantine (5 or 10mg/kg/ip) or/and Insulin (3 or 6mU/icv) were started from day 4 and continued till day 13. The animal's learning and memory capability was assessed on days 14-16 using Morris water maze. On day 17 a visible platform test was done to assess the animals' visuomotor ability. After completion of behavioral studies the brain sections were stained with hematoxylin and eosin for routine histological evaluation. The results show that memantine in doses 5 and 10mg/kg improved memory at day 3 of training and memantine 5mg/kg was more potent than memantine 10mg/kg. Insulin in dose 3mU, but not 6 mU, reversed STZ-induced memory deficit from day 2 of training. When insulin was added to memantine, it increased the potency of memantine 5mg/kg in preventing a memory deficit, but surprisingly was not successful in impeding STZ induced amnesia, in combination with memantine 10mg/kg. This research work revealed that insulin act more efficiently than memantine in reversing STZ induced memory impairment. Additionally combination of insulin and memantine seems to act better than memantine alone, providing that a dose adjustment has been done. This study suggests considering the combination therapy of memantine and insulin in dementia and AD. PMID- 27233827 TI - Corticosterone and dopamine D2/D3 receptors mediate the motivation for voluntary wheel running in C57BL/6J mice. AB - Physical exercise can improve cognition but whether this is related to motivation levels is unknown. Voluntary wheel running is a rewarding activity proposed as a model of motivation to exercise. To question the potential effects of exercise motivation on subsequent behaviour, we used a pharmacological approach targeting some reward mechanisms. The stress hormone corticosterone has rewarding effects mediated by activation of low affinity glucocorticoid receptors (GR). To investigate whether corticosterone synthesis motivates exercise via activation of GRs and subsequently, impacts on behaviour, we treated C57BL/6J mice acutely with the inhibitor of corticosterone synthesis metyrapone (35mg/kg) or repeatedly with the GR antagonist mifepristone (30mg/kg) prior to 1-h running wheel sessions. To investigate whether reducing motivation to exercise impacts on behaviour, we antagonised running-induced dopamine D2/D3 receptors activation with sulpiride (25 or 50mg/kg) and assessed locomotor, anxiety-related and memory performance after 20 running sessions over 4 weeks. We found that corticosterone synthesis contributes to running levels, but the maintenance of running behaviour was not mediated by activation of GRs. Intermittent exercise was not associated with changes in behavioural or cognitive performance. The persistent reduction in exercise levels triggered by sulpiride also had limited impact on behavioural performance, although the level of performance for some behaviours was related to the level of exercise. Altogether, these findings indicate that corticosterone and dopamine D2/D3 receptor activation contribute to the motivation for wheel running, but suggest that motivation for exercise is not a sufficient factor to alter behaviour in healthy mice. PMID- 27233829 TI - Blood oxygen level-dependent signals via fMRI in the mood-regulating circuit using two animal models of depression are reversed by chronic escitalopram treatment. AB - BACKGROUND: People exposed to stressful experience are at increased risk of the development of depression. A number of functional imaging studies have found disturbances in the mood-regulating circuit of the stress-exposed depressed patients, although few animal imaging studies have been undertaken addressing the brain functional changes of depression. METHODS: Two rat models of depression: maternal separation (MS) and chronic unpredictable mild stress (CUMS), imitating early life stress and adult stress respectively, were administered with escitalopram. The differences in functional brain changes were determined by blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI). RESULTS: Increased BOLD activation was observed in some brain regions of MS and CUMS animals, such as the bilateral hypothalamus, limbic system, hippocampus and frontal lobe, which were parts of mood-regulating circuit. Furthermore, the MS- and CUMS-induced increases in BOLD activation were partially attenuated by chronic escitalopram treatment. CONCLUSIONS: These results suggested hyperactivation of mood-regulating circuit at baseline in the depressed animals exposed to stressful experience, and escitalopram can at least partially reverse these effects. PMID- 27233830 TI - The flavonoid baicalein rescues synaptic plasticity and memory deficits in a mouse model of Alzheimer's disease. AB - Increasing evidence suggests that disruptions of synaptic functions correlate with the severity of cognitive deficit in Alzheimer's disease (AD). Our previous study demonstrated that baicalein enhances long-term potentiation (LTP) in acute rat hippocampal slices and improves hippocampus-dependent contextual fear conditioning in rats. Given that baicalein possess various biological activities, especially its effects on synaptic plasticity and cognitive function, we examined the effect of baicalein on synaptic function both in vitro and in vivo in AD model. The effect of baicalein on Abeta42 oligomer impaired LTP was investigated by electrophysiological methods. Baicalein was administered orally via drinking water to the APP/PS1 mice and sex- and age-matched wild-type mice. Treatment started at 5 months of age and mice were assessed for cognition and AD-like pathology at 7-month-old. Cognition was analyzed by Morris water maze test, fear conditioning test, and novel object recognition test. Changes in hippocampal 12/15 Lipoxygenase (12/15LO) and glycogen synthase kinase 3beta (GSK3beta) activity, Abeta production, tau phosphorylation, synaptic plasticity, and dendritic spine density were evaluated. Baicalein prevented Abeta-induced impairments in hippocampal LTP through activation of serine threonine Kinase (Akt) phosphorylation. Long-term oral administration of baicalein inhibited 12/15LO and GSK3beta activity, reduced beta-secretase enzyme (BACE1), decreased the concentration of total Abeta, and prevented phosphorylation of tau in APP/PS1 mice. Meanwhile, baicalein restored spine number, synaptic plasticity, and memory deficits. Our results strengthen the potential of the flavonoid baicalein as a novel and promising oral bioactive therapeutic agent that prevents memory deficits in AD. PMID- 27233831 TI - [Metformin - new data for an "old", but efficient, safe and reliable antidiabetic drug]. AB - Metformin is the basic drug of antihyperglycemic therapy in type 2 diabetes: according to actual therapeutic guidelines, it should be given in the absence of contraindications or intolerance during the whole course of the disease even after the initiation of insulin therapy. Recently more and more details have been explored regarding the molecular background of its effects, however, in parallel with the enormous growing knowledge, the number of questions still waiting to be answered has also grown. This review article deals with data already crystallized as well as with details not definitely cleared up. Genetic polymorphisms as well as potential drug interactions influencing the effects of metformin are also briefly summarized. PMID- 27233832 TI - [Hungarian Society for Sleep Medicine guideline for detecting drivers with obstructive sleep apnea syndrome]. AB - Obstructive sleep apnea is the most frequent sleep-disordered breathing. The prevalence of sleep apnea in the general population is 2-4% and the main characteristics of the disease are the intermittent cessation or substantial reduction of airflow during sleep, which is caused by complete, or near complete upper airway obstruction. Decreased airflow is followed by oxygen desaturation and intermittent arousals. Untreated patients are 4-6 times more likely to cause traffic accidents than their healthy counterparts. The aims of the obstructive sleep apnea screening are to prevent and reduce the incidence of serious car accidents, which are often caused by one of the most dangerous sleep disorders. Since April 1, 2015 a modification of the 13/1992 regulation has been in force in Hungary which orders screening of obstructive sleep apnea during medical checkup of drivers. The Hungarian Society for Sleep Medicine made a guideline according to the regulation which was adapted to national circumstances and family doctors, occupational health specialists can more easily screen obstructive sleep apnea in suspected patients. In sleep ambulances the disease can be diagnosed and effective treatment can be started. Patients receiving appropriate treatment and with appropriate compliance can get their driving licence under regular care and control. PMID- 27233833 TI - [The role of mini-sternotomy in aortic valve surgery]. AB - INTRODUCTION: Minimal access aortic valve replacement plays a significant role in modern cardiac surgery. The technical evolution of aortic bioprostheses, particularly sutureless valves, leads to simplify minimal access aortic valve surgery and it allows easier implantation in a narrow work field with the need of less manipulation. AIM: The aim of this study is to summarize the historical and technical aspects of minimal access aortic valve replacement, especially concentrating on sutureless valves, and to present data of own patients of the authors. METHOD: Pre- and post-operative data of 13 minimal access aortic replacement cases who were operated at the Deparment of Cardiac Sugery at the University of Szeged are summarized. RESULTS AND CONCLUSIONS: As compared to full sternotomy, minimal access aortic surgery is safe, and it does not require special instrumentation. It is technically more demanding but it can be learned quickly, and the overall pre- and post-operative results are not worse with the benefit of less pain and superior cosmetics. PMID- 27233834 TI - ["So that each patient may comprehend": measuring health literacy in Hungary]. AB - INRODUCTION: The efficiency of healing is determined by the ability of the patients to comprehend and to apply properly the information provided by the doctors. This ability is influenced by age, intelligence and social background, but above all by health literacy. AIM: The aim of the present study was to translate and adapt the Hungarian version of the Short-Test of Functional Health Literacy, which is a performance based measure and the perception-based Chew screening questions for health literacy in Hungary. METHOD: The sample consisted of 302 people, and it was closely representative for the Hungarian population. RESULTS: The reliability of the reading part of the Short-Test of Functional Health Literacy was excellent, and it was also acceptable regarding the Chew screening questions, but it showed low internal consistency concerning the numeracy part of the Short-Test of Functional Health Literacy. Based on the Short Test of Functional Health Literacy reading scores, participants were categorized into three groups: 8% had inadequate, 6% marginal and 86% adequate health literacy levels. Regarding participants without a chronic illness tended to possess higher health literacy levels based on all the three measurments. CONCLUSIONS: The availability of these measures of health literacy in Hungary can play a crucial role in doctor-patient communication as well as health promotion, that can contribute to develop health literacy policies leading to reduced health care costs in the future. PMID- 27233835 TI - [Rare case of a pregnancy in a woman with paroxysmal nocturnal hemoglobinuria. Case report]. AB - Paroxysmal nocturnal hemoglobinuria is a rare hematological disease. It is associated with increased maternal and fetal complications to such an extent that pregnancy has been considered relatively contraindicated in woman with paroxysmal nocturnal haemoglobinuria. Recently, eculizumab, a monoclonal antibody, has been shown to decrease complications during pregnancies. The highest risk is thromboembolic complication and, therefore, anticoagulant is a standard therapy during pregnancy. In the presented case, a 29-year-old woman with a 5-year history of paroxysmal nocturnal haemoglobinuria had a pregnancy. It was her first pregnancy and was complicated by a sinus thrombosis at the 11th gestational week. After the introduction of eculizumab treatment, the remaining period of pregnancy and delivery were uncomplicated. There are only a few cases in the literature about pregnancy in woman with paroxysmal nocturnal hemoglobinuria who are treated with eculizumab. This monoclonal antibody seems to be safe and it likely prevents many of the complications otherwise observed. PMID- 27233837 TI - Percutaneous fixation of traumatic pubic symphysis diastasis using a TightRope and external fixator versus using a cannulated screw. AB - BACKGROUND: The aim of the study was to introduce a new percutaneous technique for the treatment of traumatic pubic symphysis diastasis using a TightRope and external fixator. A comparison between this technique and percutaneous fixation using a cannulated screw was performed. METHODS: From January 2009 to December 2013, 26 patients with type II traumatic pubic symphysis diastasis were treated at two level 1 regional trauma centers. Among them, 10 patients were treated with a percutaneous TightRope and external fixator and 16 patients were treated with percutaneous cannulated screw fixation. Functional outcomes were evaluated using the Majeed scoring system. Patient satisfaction was evaluated using the modified visual analog scale. Radiological results were assessed based on the width of pubic symphysis preoperatively, immediately postoperatively, and at the final follow-up. Postoperative complications were also recorded. RESULTS: There were no significant differences between the groups in Majeed scores and patient satisfaction (p > 0.05). There were no significant differences in the width of pubic symphysis preoperatively, immediately postoperatively, and at the final follow-up (p > 0.05). No significant differences were found regarding infection, fixation failure, or the need for revision surgery (p > 0.05). CONCLUSIONS: The new percutaneous technique using a TightRope and external fixator is a successful alternative for the treatment of type II traumatic pubic symphysis diastasis, which results in similar outcomes comparing to percutaneous cannulated screw fixation. PMID- 27233838 TI - Comparing the value of bioproducts from different stages of anaerobic membrane bioreactors. AB - The anaerobic digestion process in anaerobic membrane bioreactors is an effective way for waste management, energy sustainability and pollution control in the environment. This digestion process basically involves the production of volatile fatty acids and biohydrogen as intermediate products and methane as a final product. This paper compares the value of bioproducts from different stages of anaerobic membrane bioreactors through a thorough assessment. The value was assessed in terms of technical feasibility, economic assessment, environmental impact and impact on society. Even though the current research objective is more inclined to optimize the production of methane, the intermediate products could also be considered as economically attractive and environment friendly options. Hence, this is the first review study to correlate the idea into an anaerobic membrane bioreactor which is expected to guide future research pathways regarding anaerobic process and its bioproducts. PMID- 27233839 TI - Probing the whole ore chalcopyrite-bacteria interactions and jarosite biosynthesis by Raman and FTIR microspectroscopies. AB - The whole ore chalcopyrite-bacteria interaction and the formation of the extracellular polymeric substances (EPS) during the bioleaching process by microorganisms found in the mine of Hellenic Copper Mines in Cyprus were investigated. Raman and FTIR microspectroscopies have been applied towards establishing a direct method for monitoring the formation of secondary minerals and the newly found vibrational marker bands were used to monitor the time evolution of the formation of covellite, and the K(+) and NH4(+)-jarosites from the chalcopyrite surfaces. The Raman data indicate that the formation of K(+) jarosite is followed by the formation of NH4(+)-jarosite. The variation in color in the FTIR imaging data and the observation of the amide I vibration at 1637cm( 1) indicate that the microorganisms are attached on the mineral surface and the changes in the frequency/intensity of the biofilm marker bands in the 900-1140cm( 1) frequency range with time demonstrate the existence of biofilm conformations. PMID- 27233840 TI - Flexible, dual-form nicotine replacement therapy or varenicline in comparison with nicotine patch for smoking cessation: a randomized controlled trial. AB - BACKGROUND: Extended use of combined pharmacotherapies to treat tobacco dependence may increase smoking abstinence; few studies have examined their effectiveness. The objective of this study was to evaluate smoking abstinence with standard nicotine patch (NRT), extended use of combined formulations of nicotine replacement therapy (NRT+), or varenicline (VR). METHODS: A total of 737 smokers, including those with medical and psychiatric comorbidities, were randomly assigned to one of the above three treatment conditions. The NRT group received 10 weeks of patches (21 mg daily maximum); the NRT+ group received patches (35 mg daily maximum) and gum or inhaler for up to 22 weeks; and the VR group received 1 mg twice daily for up to 24 weeks (22 weeks post target quit date). All participants also received six standardized 15-minute smoking cessation counseling sessions by nurses experienced in tobacco dependence treatment. The primary outcome was carbon monoxide-confirmed continuous abstinence rates (CAR) from weeks 5-52. Secondary outcomes were: CAR from weeks 5 10 and 5-22, and carbon monoxide-confirmed 7-day point prevalence (7PP) at weeks 10, 22, and 52. Adjusted and unadjusted logistic regression analyses were conducted using intention-to-treat procedures. RESULTS: The CARs for weeks 5-52 were 10.0 %, 12.4 %, and 15.3 % in the NRT, NRT+, and VR groups, respectively; no group differences were observed. Results with 7PP showed that VR was superior to NRT at week 52 (odds ratio (OR), 1.84; 97.5 % Confidence Interval (CI), 1.04 3.26) in the adjusted intention-to-treat analysis. Those in the VR group had higher CAR at weeks 5-22 (OR, 2.01; CI, 1.20-3.36) than those in the NRT group. Results with 7PP revealed that both NRT+ (OR, 1.72; CI, 1.04-2.85) and VR (OR, 1.96; CI, 1.20-3.23) were more effective than NRT at 22 weeks. As compared to NRT monotherapy, NRT+ and VR produced significant increases in CAR for weeks 5-10 (OR, 1.52; CI, 1.00-2.30 and OR, 1.58; CI, 1.04-2.39, respectively); results were similar, but somewhat stronger, when 7PP was used at 10 weeks (OR, 1.57; CI, 1.03 2.41 and OR, 1.79; CI, 1.17-2.73, respectively). All medications were well tolerated, but participants in the VR group experienced more fatigue, digestive symptoms (e.g., nausea, diarrhea), and sleep-related concerns (e.g., abnormal dreams, insomnia), but less dermatologic symptoms than those in the NRT or NRT+ groups. The frequency of serious adverse events did not differ between groups. CONCLUSIONS: Flexible and combination NRT and varenicline enhance success in the early phases of quitting. Varenicline improves abstinence in the medium term; however, there is no clear evidence that either varenicline or flexible, dual form NRT increase quit rates in the long-term when compared to NRT monotherapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01623505 ; Retrospectively registered on July 13, 2011. PMID- 27233891 TI - [Epidemiology of urolithiasis in south of France: A retrospective monocentric study]. AB - INTRODUCTION: Incidence of urolithiasis is increasing in industrialized countries. Amendments can be explained among others by dietary changes. More and more young patients have urolithiasis. The objective of this study was to analyze and update the epidemiology of stones in south of France about age and gender. MATERIAL AND METHODS: A retrospective single-center study from 2009 to June 2015 included all urolithiasis analyzed by infrared spectroscopy. Groups were composed according to the mineral content (oxalocalcic with whewellite and weddelite, calcium phosphate stones, uric acid stones...). RESULTS: A total of 749 stones were analyzed. The sex ratio was 1.96 all aged confused. The most common stones were oxalocalcic (51.3 %), followed mixed stones (21.2 %) and calcium phosphate stones (11.9 %). The calcium oxalate stones are mainly composed of whewellite (42 %) and calcium phosphate stones of carbapatite (18.6 %). The stones of whewellite were more frequent in men (P=0.0009), as well as uric acid stones (P=0.01) and mixed stones in women (P=0.00003), as well as calcium phosphate (P=0.0005). CONCLUSIONS: Epidemiology of stones has changed with an increased incidence in women, and nephrolithiasis patients getting older. A change in the type of stones is observed with increasing the proportion of mixed stones especially among women. Nutritional and metabolic studies are needed to find the etiology of the change in the epidemiology of urolithiasis. LEVEL OF EVIDENCE: 4. PMID- 27233892 TI - Canadian Cardiovascular Society/Canadian Society of Cardiac Surgeons/Canadian Society for Vascular Surgery Joint Position Statement on Open and Endovascular Surgery for Thoracic Aortic Disease. AB - In 2014, the Canadian Cardiovascular Society (CCS) published a position statement on the management of thoracic aortic disease addressing size thresholds for surgery, imaging modalities, medical therapy, and genetics. It did not address issues related to surgical intervention. This joint Position Statement on behalf of the CCS, Canadian Society of Cardiac Surgeons, and the Canadian Society for Vascular Surgery provides recommendations about thoracic aortic disease interventions, including: aortic valve repair, perfusion strategies for arch repair, extended arch hybrid reconstruction for acute type A dissection, endovascular management of arch and descending aortic aneurysms, and type B dissection. The position statement is constructed using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, and has been approved by the primary panel, an international secondary panel, and the CCS Guidelines Committee. Advent of endovascular technology has improved aortic surgery safety and extended the indications of minimally invasive thoracic aortic surgery. The combination of safer open surgery with endovascular treatment has improved patient outcomes in this rapidly evolving subspecialty field of cardiovascular surgery. PMID- 27233893 TI - Transradial vs Transfemoral Percutaneous Coronary Intervention in ST-Segment Elevation Myocardial Infarction: A Systemic Review and Meta-analysis. AB - BACKGROUND: The objective of this meta-analysis to evaluate safety and efficacy of transradial vs the transfemoral approach for primary percutaneous coronary intervention (PCI) in ST-segment elevation myocardial infarction (STEMI) patients. METHODS: Randomized controlled trials that compared the transfemoral vs the transradial approach in STEMI patients who underwent PCI were searched in PubMed, Embase, CENTRAL, Cumulative Index to Nursing and Allied Health Literature, and clinicaltrials.gov. Random effect models were used to pool effect sizes. RESULTS: Sixteen trials, comprising data from 9726 patients, were included in the meta-analysis. All-cause mortality (risk ratio [RR], 0.68; 95% confidence interval [CI], 0.54-0.85; relative risk reduction [RRR], 32.8%; I(2) = 0), major bleeding (RR 0.56; 95% CI, 0.42-0.74; RRR, 48.1%; I(2) = 0), access site bleeding (RR, 0.38; 95% CI, 0.29-0.50; RRR, 63.9%; I(2) = 0), major adverse cardiovascular events (RR, 0.80; 95% CI, 0.68-0.94; RRR, 19.3%; I(2) = 0), and length of hospital stay (standardized mean difference, -0.38 days; 95% CI, -0.46 to -0.31 days) were significantly lower with the transradial compared with the transfemoral approach. The greatest reduction in major bleeding was found in the subgroup with trials recruiting only primary PCI participants compared with varying proportions of rescue PCIs. Glycoprotein IIb/IIIa inhibitor use and cross over rates did not have a significant association with outcome measures in the subgroup analysis. Incidence of stroke was numerically greater with the transradial approach but did not achieve statistical significance (RR, 1.22; 95% CI, 0.56-2.66; I(2) = 0). Overall statistical heterogeneity (I(2)) was very low except for length of hospital stay. CONCLUSIONS: The transradial approach for PCI in STEMI patients significantly reduced all-cause mortality, major and access site bleeding, major adverse cardiovascular events, and length of hospital stay. Difference in stroke incidence was not statistically significant with the transradial vs the transfemoral approach. PMID- 27233894 TI - Fecal microbiota transplantation for severe clostridium difficile infection after left ventricular assist device implantation: a case control study and concise review on the local and regional therapies. AB - BACKGROUND: We report herein a case of fecal microbiota transplantation (FMT) used for severe Clostridium difficile infection for a 65-year-old Lebanese man who underwent left ventricular assist device implantation. To the best of our knowledge this is the first case report from Lebanon and the region presenting such technique. CASE PRESENTATION: The patient experienced diarrhea and rectal bleeding and was diagnosed of pseudomembranous colitis (PMC). His condition failed to improve on maximal pharmacological therapy. Protocolectomy, an invasive operation consisting in resection of the entire colon and rectum seemed to be the last resort before the patient responded to FMT given through gastroscopy. CONCLUSION: Despite the increasing experience with FMT for C. difficile infection, published evidence in severe related cases from this region is very limited. Hence, we promote adjunctive FMT, an effective noninvasive method, to be considered as a promising early treatment option in severe C. difficile infection. PMID- 27233896 TI - Gross composition, fatty acid profile and sensory characteristics of Saanen goat milk fed with Cacti varieties. AB - The use of cactus is an alternative for sustainable production systems in Northeast Brazil. The objective of this research was to evaluate the influence of supplying five cacti species from the Brazilian semi-arid northeast region on the physical-chemical sensory characteristics and the profile of fatty acids of Saanen goat milk. Five multiparous goats were used, confined, and distributed in a Latin square 5 * 5 design, with five experimental diets and five periods. Treatments consisted of 473 to 501 g/kg of a cactaceous mix (Pilosocereus gounellei, Cereus jamacaru, Cereus squamosus, Nopalea cochenillifera, or Opuntia stricta) added to 187.8 to 197.9 g/kg of "Sabia" (Mimosa caesalpiniifolia) hay and 311 to 329 g/kg of concentrate. No effects of experimental diets (P > 0.05) were evidenced in the physical and chemical composition of milk for fat, total solids, or salt levels. However, protein, lactose, solids-not-fat levels, and cryoscopy point were influenced by diet (P < 0.05). There was no significant difference (P > 0.05) in the profile of fatty acids between treatments for all acids found, except for butyric acid. Diets also did not (P > 0.05) confer sensory changes in milk characteristics. The use of the native cacti in the dairy goats' diet did not influence the sensory characteristics or lipid profile of milk. PMID- 27233897 TI - Headache: an important factor associated with muscle soreness/pain at the two year follow-up point among patients with major depressive disorder. AB - BACKGROUND: No study has compared the associations of headache, anxiety, and depression at baseline with muscle soreness or pain (MS/P) at baseline and at the two-year follow-up point among outpatients with major depressive disorder (MDD). This study aimed to investigate the above issue. METHODS: This study enrolled 155 outpatients with MDD at baseline, and 131 attended a two-year follow-up appointment. At baseline, migraine was diagnosed based on the International Classification of Headache Disorders, 2(nd) edition. MDD and anxiety disorders were diagnosed using the Structured Clinical Interview for DSM-IV-TR. The visual analog scale was used to evaluate the intensities of headache and MS/P in the neck, shoulder, back, upper limbs, and lower limbs. Depression and anxiety were evaluated using the Hospital Anxiety and Depression Scale. Multiple linear regressions were used to compare the associations of these factors with MS/P. RESULTS: Compared with anxiety disorders, migraine was more strongly associated with MS/P in all areas at baseline and in the upper and lower limbs at follow-up. Headache intensity at baseline was the factor most strongly associated with MS/P in all areas at baseline and follow-up after controlling for depression and anxiety. Headache intensity at baseline predicted MS/P at baseline and follow-up. CONCLUSIONS: Migraine and headache intensity are important factors related to MS/P at baseline and follow-up among patients with MDD. Integrating depression and headache treatment might be indicated to improve MS/P. PMID- 27233898 TI - Is Preoperative Upper Gastrointestinal Endoscopy in Obese Patients Undergoing Bariatric Surgery Mandatory? An Asian Perspective. AB - BACKGROUND: The role of routine preoperative oesopha gogastroduodenoscopy (OGD) for all bariatric surgery candidates is controversial. We aim to investigate the prevalence of clinically significant OGD findings in a primarily Chinese obese population and identify factors that predict a normal screening OGD. METHODS: Medical records of patients who underwent primary bariatric surgery in our centre from August 2002 to December 2014 were reviewed. OGD findings were classified into two groups: group 1 consisted of normal findings and abnormal findings that would not alter the surgical plan; group 2 consisted of lesions that might delay or alter the surgical procedure. RESULTS: We identified 268 patients (169 female), of mean age 39.1 +/- 10.8 years, mean baseline body weight 108.7 +/- 6.1 kg and mean body mass index (BMI) 40.3 +/- 6.1 kg/m2 for analysis. Overall prevalence of abnormal OGD findings was 51.1 %, which included gastritis (32.5 %), hiatus hernia (17.9 %), duodenitis (8.6 %) and erosive oesophagitis (7.5 %); 27.2 % had group 2 lesions. Univariate analysis revealed older age (p = 0.016), use of NSAIDs (p = 0.004) and presence of reflux symptoms (p = 0.029) as significant risk factors of group 2 lesions. On multivariate analysis, use of NSAIDs (p = 0.015) and reflux symptoms (p = 0.039) remained significant predictive factors. In the low-risk subgroup (40 years and younger, without reflux symptoms or use of NSAIDs), the prevalence of group 2 abnormalities was 18.9 %. CONCLUSIONS: Significant endoscopic abnormalities are common among obese Chinese patients which may delay or change the surgical plan. The negative predictive value in low-risk patients was not strong. We therefore recommend routine preoperative endoscopy for all patients. PMID- 27233899 TI - Time-Course Change of Redd1 Expressions in the Hippocampal CA1 Region Following Chronic Cerebral Hypoperfusion. AB - Redd1, also known as RTP801/Dig2/DDIT4, is a stress-induced protein and marked changes of Redd1 expression occurs in response to hypoxia or cerebral ischemia. In the present study, we examined the time-course changes in Redd1 protein expressions in the rat hippocampal CA1 region following chronic cerebral hypoperfusion (CCH) induced by permanent bilateral common carotid arteries occlusion (2VO). Redd1 immunoreactivity in the pyramidal neurons of the hippocampal CA1 region was increased at 7 days after 2VO surgery, and then the immunoreactivity was decreased with time. Especially, very weak Redd1 immunoreactivity was observed in the hippocampal CA1 region at 28 days after 2VO surgery. Western blot analysis showed that Redd1 level in the hippocampal CA1 region was significantly increased at 7 days following CCH and significantly decreased at 28 days after 2VO surgery, compared with that of the sham-operated group. These results indicate that Redd1 expressions is markedly changed in the hippocampal CA1 region following CCH and that change of Redd1 expression may be associated with the CCH-induced neuronal damage in the hippocampal CA1 region. PMID- 27233901 TI - Multiple apocrine hidrocystomas successfully treated with botulinum toxin A. AB - Apocrine hidrocystomas, while rare, present predominantly as solitary papules occurring in the periocular region of the face. Various treatment modalities for these lesions exist depending on their size and location, but the management of multiple hidrocystomas can be more challenging. Recent reports illustrate that multiple eccrine hidrocystomas have been successfully treated with botulinum toxin A. Herein we describe the effective use of botulinum toxin A in a 29-year old man with multiple facial apocrine hidrocystomas, which, to our knowledge, has not yet been reported in the English-language literature. PMID- 27233900 TI - Association of social support during emergency department evaluation for acute coronary syndrome with subsequent posttraumatic stress symptoms. AB - We examined the associations of different aspects of social support during emergency department (ED) evaluation for an acute cardiac event with perceptions of threat in the ED and subsequent posttraumatic stress symptoms (PSS) in 484 patients. Participants were enrolled in the ED where they reported on their perceptions of threat in the ED. Social support in the ED and PSS were assessed at inpatient bedside or by telephone a median of 3 days later. Positive aspects of social support were not associated with subsequent PSS. Anxiety-provoking social support was significantly associated with increased PSS at follow-up. Greater ED threat perception partially mediated that relationship. PMID- 27233902 TI - Removal of simulated biofilm: an evaluation of the effect on root surfaces roughness after scaling. AB - BACKGROUND: Despite the development of less invasive devices, a debate exists about the benefits and risks of hand versus powered root surface instrumentation used in supportive periodontal therapy (SPT). The aim of the in vitro study was to differentially compare plaque removal efficacy and root surface roughening of newly developed sonic, ultrasonic scaler, and curettes in the hands of experienced versus less experienced operators. MATERIALS AND METHODS: Sonic (AIR), ultrasonic devices (TIG), and double-gracey curettes (GRA) were utilized by seven experienced (EO) and four less experienced operators (LO) for root surface instrumentation of standardized plastic teeth on manikins' heads in a randomized sequence. The proportion of residual simulated plaque (RSP area in %) was planimetrically assessed, and the average root surface roughness produced (Ra and ?Ra in MUm) was measured by a precision profilometer. RESULTS: The uninstrumented root surfaces showed a Ra of (median (Q25/Q75)) 1.00 MUm (0.83/1.16). Following instrumentation, EO left significantly less RSP than LO regardless of the used instruments (20.00 % (10.00/34.00) vs. 26.00 % (12.00/44.00) p < 0.001), whereas the ?Ra values (0.29 MUm (-0.04/0.96) vs. 0.35 MUm (-0.04/1.01), p = 0.237) failed to show significant differences. The surface roughness was higher with GRA followed by AIR then TIG regardless of operators' experience (p < 0.001). CONCLUSION: Within the limits of the present study, the sonic device was most efficient in plaque removal, while the ultrasonic device produced the least surface roughness. CLINICAL RELEVANCE: All three tested instruments seem effective in the mechanical root debridement during SPT, whereat the ultrasonic device show the smoothest root surface of all. PMID- 27233903 TI - Treatment of multiple sclerosis by transplantation of neural stem cells derived from induced pluripotent stem cells. AB - Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), with focal T lymphocytic infiltration and damage of myelin and axons. The underlying mechanism of pathogenesis remains unclear and there are currently no effective treatments. The development of neural stem cell (NSC) transplantation provides a promising strategy to treat neurodegenerative disease. However, the limited availability of NSCs prevents their application in neural disease therapy. In this study, we generated NSCs from induced pluripotent stem cells (iPSCs) and transplanted these cells into mice with experimental autoimmune encephalomyelitis (EAE), a model of MS. The results showed that transplantation of iPSC-derived NSCs dramatically reduced T cell infiltration and ameliorated white matter damage in the treated EAE mice. Correspondingly, the disease symptom score was greatly decreased, and motor ability was dramatically rescued in the iPSC-NSC-treated EAE mice, indicating the effectiveness of using iPSC-NSCs to treat MS. Our study provides pre-clinical evidence to support the feasibility of treating MS by transplantation of iPSC-derived NSCs. PMID- 27233905 TI - Ultrasonication processed Panax ginseng berry extract induces apoptosis through an intrinsic apoptosis pathway in HepG2 cells. AB - Ginseng's major active components, ginsenosides, have been known to show anti cancer, neuroprotective, and anti-inflammatory activities. Ultrasonication processed Panax ginseng berry extract (UGB) contains various ginsenosides. The components are different from Panax ginseng berry extract (GBE). This study was aimed to investigate the cytotoxic mechanism of UGB in HepG2 cells, human hepatocellular carcinoma cell line. HepG2 cells were treated with UGB (0, 10, 20 MUg/ml). Cell growth and cellular apoptosis were evaluated by MTT assay and Annexin V/Pi staining, respectively. Intracellular Reactive oxygen species (ROS) levels were also determined by 2', 7'-dichlorofluorescin diacetate (DCFDA) staining. The expressions of Bax, Bcl-2 and caspase-3, the apoptotic markers, were evaluated by Western Blot. UGB dose-dependently inhibited cell growth and induced apoptotic cell death. Intracellular ROS levels were increased. UGB increased the expression of the cleaved form of caspase-3. Furthermore, UGB induced apoptosis of HepG2 cells through Bax activation and Bcl-2 inhibition. In conclusion, UGB induced apoptosis through an intrinsic pathway in HepG2 cells suggesting that UGB might play a role as a novel substance for anti-cancer effect. PMID- 27233906 TI - Molecular Targets in Advanced Therapeutics of Cancers: The Role of Pharmacogenetics. AB - The advent of advanced molecular targeted therapy has resulted in improved prognoses for patients with advanced malignancies. However, despite the significant success and specificity of this advocated targeted therapy, significant on- and off-target adverse effects and inter-individual variability in treatment responses have been reported. The interpatient variability in drug response has been suggested to be partly due to variations in patient genomes. Therefore, the identification of genetic biomarkers by conducting pharmacogenetics studies can help predict patient responses to targeted therapy and may serve as a basis for individualized treatment. In this review, both clinically established and potential molecular targets are highlighted. Overall, current literature suggests that individualization of targeted therapy is promising; however, integrating the clinical benefits of identified biomarkers into clinical practice for personalized medicine remains a major challenge, and further studies to validate these markers and identify novel therapeutic approaches are needed. PMID- 27233907 TI - Challenges and Insights of a Global Radiology Elective in Ecuador. PMID- 27233904 TI - The transcriptome of metamorphosing flatfish. AB - BACKGROUND: Flatfish metamorphosis denotes the extraordinary transformation of a symmetric pelagic larva into an asymmetric benthic juvenile. Metamorphosis in vertebrates is driven by thyroid hormones (THs), but how they orchestrate the cellular, morphological and functional modifications associated with maturation to juvenile/adult states in flatfish is an enigma. Since THs act via thyroid receptors that are ligand activated transcription factors, we hypothesized that the maturation of tissues during metamorphosis should be preceded by significant modifications in the transcriptome. Targeting the unique metamorphosis of flatfish and taking advantage of the large size of Atlantic halibut (Hippoglossus hippoglossus) larvae, we determined the molecular basis of TH action using RNA sequencing. RESULTS: De novo assembly of sequences for larval head, skin and gastrointestinal tract (GI-tract) yielded 90,676, 65,530 and 38,426 contigs, respectively. More than 57 % of the assembled sequences were successfully annotated using a multi-step Blast approach. A unique set of biological processes and candidate genes were identified specifically associated with changes in morphology and function of the head, skin and GI-tract. Transcriptome dynamics during metamorphosis were mapped with SOLiD sequencing of whole larvae and revealed greater than 8,000 differentially expressed (DE) genes significantly (p < 0.05) up- or down-regulated in comparison with the juvenile stage. Candidate transcripts quantified by SOLiD and qPCR analysis were significantly (r = 0.843; p < 0.05) correlated. The majority (98 %) of DE genes during metamorphosis were not TH-responsive. TH-responsive transcripts clustered into 6 groups based on their expression pattern during metamorphosis and the majority of the 145 DE TH responsive genes were down-regulated. CONCLUSIONS: A transcriptome resource has been generated for metamorphosing Atlantic halibut and over 8,000 DE transcripts per stage were identified. Unique sets of biological processes and candidate genes were associated with changes in the head, skin and GI-tract during metamorphosis. A small proportion of DE transcripts were TH-responsive, suggesting that they trigger gene networks, signalling cascades and transcription factors, leading to the overt changes in tissue occurring during metamorphosis. PMID- 27233908 TI - Compliance With Screening Mammography Guidelines After a False-Positive Mammogram. AB - PURPOSE: To assess whether women with a false-positive mammogram who do return for screening are less likely to be compliant with screening mammography guidelines than are women with a negative mammogram. METHODS: This institutional review board-approved, HIPAA-compliant retrospective cohort study includes women >40 years old who received 9,385 consecutive, nonbaseline screening mammograms between December 1, 2012 and December 31, 2013. Using linear regression, we evaluated differences in time between mammograms by prior recall status, after adjusting for location of current mammogram (outpatient office versus mobile unit) and age. Using Fisher's exact test, we evaluated the association between compliance with screening guidelines and the recall status on prior mammogram, and compared by location the proportions of noncompliant women who were recalled from prior mammogram. RESULTS: Time between mammograms does not differ based on prior recall status (P = .83). There is no association between compliance with screening mammography guidelines and recall status on prior mammogram (ACR guidelines P = .398, United States Preventive Services Task Force guidelines P = .416). Noncompliant women recalled on prior mammogram are more likely to undergo mammography at the outpatient office rather than the mobile unit (ACR guidelines P = .0004, United States Preventive Services Task Force guidelines P = .0032). CONCLUSIONS: A prior false-positive mammogram is not a significant deterrent to compliance with screening guidelines in those women who return for screening. PMID- 27233909 TI - 2015 RAD-AID Conference on International Radiology for Developing Countries: The Evolving Global Radiology Landscape. AB - Radiology in low- and middle-income (developing) countries continues to make progress. Research and international outreach projects presented at the 2015 annual RAD-AID conference emphasize important global themes, including (1) recent slowing of emerging market growth that threatens to constrain the advance of radiology, (2) increasing global noncommunicable diseases (such as cancer and cardiovascular disease) needing radiology for detection and management, (3) strategic prioritization for pediatric radiology in global public health initiatives, (4) continuous expansion of global health curricula at radiology residencies and the RAD-AID Chapter Network's participating institutions, and (5) technologic innovation for recently accelerated implementation of PACS in low resource countries. PMID- 27233910 TI - Improving the Transcription of Patient Information From Image Requisitions to the Radiology Information System. AB - PURPOSE: The purpose of this study was to improve the transcription of patient information from imaging study requisitions to the radiology information database at a single institution. METHODS: Five hundred radiology reports from adult outpatient radiographic examinations were chosen randomly from the radiology information system (RIS) and categorized according to their degree of concordance with their corresponding clinical order indications. The number and types of grammatical errors and types of order forms were also recorded. Countermeasures centered on the education of the technical staff and referring physician offices and the implementation of a checklist. Another sample of 500 reports was taken after the implementation of the countermeasures and compared with the baseline data using a chi(2) test. RESULTS: The number of RIS indications perfectly concordant with their corresponding clinical order indications increased from 232 (46.4%) to 314 (62.8%) after the implementation of the countermeasures (P < .0001). The number of partially concordant matches due to inadequate RIS indications dropped from 162 (32.4%) to 114 (22.8%) (P < .001), whereas the number of partially concordant matches due to inadequate clinical order indications increased from 22 (4.4%) to 57 (11.4%) (P < .0001). The number of discordant pairings dropped from 84 (16.8%) to 15 (3%) (P < .0001). Technologists began to input additional patient information obtained from the patients (not present in the image requisitions) in the RIS after the implementation of the countermeasures. CONCLUSIONS: The education of technical staff members and the implementation of a checklist markedly improved the information provided to radiologists on image requisitions from referring providers. PMID- 27233911 TI - Impact of Reimbursement Cuts on the Sustainability and Accessibility of Dopamine Transporter Imaging. AB - PURPOSE: Dopamine transporter single-photon emission computed tomography imaging utilizing iodine-123 ioflupane is accurate for differentiation of Parkinson disease from essential tremor. This study evaluates how reimbursement for I-123 ioflupane imaging changed between 2011 (year of FDA approval) and 2014 (year after loss of pass-through status for hospital-based outpatient imaging from CMS). METHODS: I-123 ioflupane reimbursement data for our institution's hospital based imaging were compared between two periods: (1) July 2011 to October 2012, and (2) 2014. For each time period separately and in combination, averages and ranges of reimbursement for private insurance and CMS were analyzed and compared. A model to ensure recouping of radiopharmaceutical costs was developed. RESULTS: Review yielded 247 studies from July 2011 to October 2012 and 94 studies from 2014. Average reimbursement per study fell from $2,469 (US dollars) in 2011 to 2012 to $1,657 in 2014. CMS reduced average reimbursement by $1,148 in 2014 because of loss of radiopharmaceutical pass-through status. Average reimbursements from CMS versus private payors markedly differed in 2011 to 2012 at $2,266 versus $2,861, respectively, and in 2014 at $1,118 versus $3,470, respectively. Between 2011 to 2012 and 2014, the CMS percentage increased from 54% to 78%. Assuming that I-123 ioflupane cost $2,000, our model based on 2014 data predicts a practice with greater than 60% CMS patients would no longer recover radiopharmaceutical costs. CONCLUSIONS: Reimbursement levels, payor mix, scanner location, and radiopharmaceutical costs are all critical, variable factors for modeling the financial viability of I-123 ioflupane imaging and, by extrapolation, future radiopharmaceuticals. PMID- 27233912 TI - New Cyclohexadepsipeptides from an Entomogenous Fungus Fusarium proliferatum and Their Cytotoxicity and Autophagy-Inducing Activity. AB - Five new cyclohexadepsipeptides termed as enniatins R - V (1 - 5) and seven known cyclohexadepsipeptides (6 - 12) were isolated from the solid culture of Fusarium proliferatum, a fungus isolated from the cadaver of an unidentified insect collected in Tibet. Their structures were elucidated by NMR and MS spectroscopic analysis. The X-ray single-crystal structure of 6 was reported for the first time. Enniatins R and S represented the first enniatins incorporating with an unusual 2,3-dihydroxy-isovaleric acid (Div) residue. The cytotoxicity and autophagy-inducing activities of 1 - 12 were evaluated in vitro. Beauvenniatin F (11) exhibited strong cytotoxicity against K562/A (adriamycin-resistant K562) with IC50 value of 3.78 MUm, and also autophagy-inducing activity at the concentration of 20 MUm in GFP-LC3 stable HeLa cells. PMID- 27233913 TI - Human umbilical cord blood-mesenchymal stem cells transplantation renovates the ovarian surface epithelium in a rat model of premature ovarian failure: Possible direct and indirect effects. AB - This study aimed to isolate mesenchymal stem cells (MSC) from human umbilical cord blood (HCB) and to explore their influence on the ovarian epithelium after paclitaxel-induced ovarian failure. Ninety-five rats were divided into 6 groups: control, paclitaxel, paclitaxel and saline, HCB-MSC-treated for 2 weeks, HCB-MSC treated for 4 weeks, and HCB-MSC-treated for 6 weeks. HCB cells were studied for CD34, CD44, and Oct 3/4 using flow cytometry. Serum levels of FSH and E2 were measured using ELISA, RT-PCR analysis for human gene; beta-actin (ACTB), immunohistochemical analysis for CK 8/18, TGF-beta, PCNA and CASP-3 were performed. We found that ACTB gene was expressed in all rats' ovaries received HCB-MSC. After 4 weeks of transplantation, there was significant reduction in FSH, elevation in E2 levels, stabilization of the surface epithelium morphostasis, an increase in the antral follicle count and increase in integrated densities (ID) of CK 8/18, TGF-beta, and PCNA expressions and decrease in ID of CASP-3 expression. We concluded that HCB-MSC can restore the ovarian function after paclitaxel injection through a direct triggering effect on the ovarian epithelium and/or indirect enrichment of ovarian niche through regulating tissue expression of CK 8/18, TGF-beta and PCNA. These molecules are crucial in regulating folliculogenesis and suppressing CASP-3-induced apoptosis. PMID- 27233914 TI - Characterization of paneth cells in alpacas (Vicugna pacos, Mammalia, Camelidae). AB - Paneth cells are secretory epithelial cells of the innate immune system of the intestine of several mammals, including alpacas. Little is known about the latter; thus, in the present study we described the morphology and histochemical characteristics of Paneth cells in healthy fetuses, and young and adult alpacas. For this purpose, samples of duodenum, jejunum and ileum were taken from 6 fetuses at different days of pregnancy (between days 221-330), 66 offsprings (between 0 and 45-days-old) and 5 adult alpacas (>2-years-old). Samples were fixed in 10% buffered formalin and processed for histological and morphometrical analysis using HE and Masson Trichomics technique. Immunohistochemistry was used to identify Paneth cells using anti-lysozyme antibody. In addition, the lectinhistochemichal binding-pattern of Paneth cells granules was evaluated. Lyzozyme was immunohistochemically detected in the granules of Paneth cells from day 283 of pregnancy in all the small intestinal sections of the studied fetuses. In newborn alpacas Paneth cells were initially found in the duodenum, but the following days (days 18-21 after birth) they were also found in the ileum. Their size gradually increased after birth, but then no significant differences were found. In adult alpacas the number was lower than offsprings. We suggest that Paneth cells early differentiate in the small intestine of alpacas, and the increase in their number during the first two weeks of life strongly support their possible involvement in the intestinal defensive functions against the enteric diseases that occur during the lactancy stage. PMID- 27233915 TI - Histological and lectin histochemical studies of the vomeronasal organ of horses. AB - The morphological characteristics and glycoconjugate composition of the vomeronasal organ (VNO) of the horse was investigated using histological, immunohistochemical, and lectin histochemical methods. The VNO is bilaterally located at the base of the nasal septum, has a tubular structure surrounded by cartilage, and consists of sensory and non-sensory epithelia. Immunohistochemical examination showed that the vomeronasal sensory epithelium (VSE) consisted of receptor cells positive for both olfactory marker protein (OMP) and protein gene product 9.5 (PGP 9.5), supporting cells, and basal cells. VNO receptor cells were positive for G protein Galphai2 (vomeronasal receptor type 1 marker), but not Galphao (vomeronasal receptor type 2 marker). Lectin histochemical studies using 21 biotinylated lectins showed that the free border of the VSE was positive for 20 lectins. The receptor and supporting cells reacted with 16 lectins while the basal cells reacted with 15 lectins, with varying intensities. In the vomeronasal non-sensory epithelium, the free border was positive for 19 lectins. The cilated cells were positive for 17 lectins and the basal cells were positive for 15 lectins. The vomeronasal glands, positioned in the lamina propria, were stained with both periodic acid Schiff (PAS) and alcian blue (pH 2.5). Eighteen lectins stained the acinar cells of the vomeronasal glands with various binding patterns. These findings suggest that horse VNO receptor cells express vomeronasal receptor type 1, and the VNO glands have mucous to seromucous characteristics. Moreover, each lectin differentially binds each cell type in both the VNO sensory and non sensory epithelia. PMID- 27233916 TI - Acquired hearing loss and brain plasticity. AB - Acquired hearing loss results in an imbalance of the cochlear output across frequency. Central auditory system homeostatic processes responding to this result in frequency specific gain changes consequent to the emerging imbalance between excitation and inhibition. Several consequences thereof are increased spontaneous firing rates, increased neural synchrony, and (in adults) potentially restricted to the auditory thalamus and cortex a reorganization of tonotopic areas. It does not seem to matter much whether the hearing loss is acquired neonatally or in adulthood. In humans, no clear evidence of tonotopic map changes with hearing loss has so far been provided, but frequency specific gain changes are well documented. Unilateral hearing loss in addition makes brain activity across hemispheres more symmetrical and more synchronous. Molecular studies indicate that in the brainstem, after 2-5 days post trauma, the glutamatergic activity is reduced, whereas glycinergic and GABAergic activity is largely unchanged. At 2 months post trauma, excitatory activity remains decreased but the inhibitory one is significantly increased. In contrast protein assays related to inhibitory transmission are all decreased or unchanged in the brainstem, midbrain and auditory cortex. Comparison of neurophysiological data with the molecular findings during a time-line of changes following noise trauma suggests that increases in spontaneous firing rates are related to decreases in inhibition, and not to increases in excitation. Because noise-induced hearing loss in cats resulted in a loss of cortical temporal processing capabilities, this may also underlie speech understanding in humans. PMID- 27233917 TI - Functional segregation of monaural and binaural selectivity in the pallid bat auditory cortex. AB - Different fields of the auditory cortex can be distinguished by the extent and level tolerance of spatial selectivity. The mechanisms underlying the range of spatial tuning properties observed across cortical fields are unclear. Here, this issue was addressed in the pallid bat because its auditory cortex contains two segregated regions of response selectivity that serve two different behaviors: echolocation for obstacle avoidance and localization of prey-generated noise. This provides the unique opportunity to examine mechanisms of spatial properties in two functionally distinct regions. Previous studies have shown that spatial selectivity of neurons in the region selective for noise (noise-selective region, NSR) is level tolerant and shaped by interaural level difference (ILD) selectivity. In contrast, spatial selectivity of neurons in the echolocation region ('FM sweep-selective region' or FMSR) is strongly level dependent with many neurons responding to multiple distinct spatial locations for louder sounds. To determine the mechanisms underlying such level dependence, frequency, azimuth, rate-level responses and ILD selectivity were measured from the same FMSR neurons. The majority (~75%) of FMSR neurons were monaural (ILD insensitive). Azimuth tuning curves expanded or split into multiple peaks with increasing sound level in a manner that was predicted by the rate-level response of neurons. These data suggest that azimuth selectivity of FMSR neurons depends more on monaural ear directionality and rate-level responses. The pallid bat cortex utilizes segregated monaural and binaural regions to process echoes and prey-generated noise. Together the pallid bat FMSR/NSR data provide mechanistic explanations for a broad range of spatial tuning properties seen across species. PMID- 27233918 TI - Basal and maximal metabolic rates differ in their response to rapid temperature change among avian species. AB - In birds, acclimation and acclimatization to temperature are associated with changes in basal (BMR), summit (Msum) and maximal (MMR) metabolic rates but little is known about the rate at which species adjust their phenotype to short term temperature variations. Our aims were (1) to determine the pattern of metabolic adjustments following a rapid temperature change, (2) to determine whether performance varies at similar rates during exposure to warm or cold environments, and (3) to determine if BMR, Msum and MMR change at comparable rates during thermal acclimation. We measured these parameters in white-throated sparrows (Zonotrichia albicollis), black-capped chickadees (Poecile atricapillus), and snow buntings (Plectrophenax nivalis) after acclimation to 10 degrees C (day 0) and on the 4th and 8th days of acclimation to either -5 or 28 degrees C. Birds changed their metabolic phenotype within 8 days with patterns differing among species. Sparrows expressed the expected metabolic increases in the cold and decreases at thermoneutrality while performance in chickadees and buntings was not influenced by temperature but changed over time with inverse patterns. Our results suggest that BMR varies at comparable rates in warm and cold environments but changes faster than Msum and MMR, likely due to limitations in the rate of change in organ size and function. They also suggest that maximal metabolic capacity is lost faster in a warm environment than it is gained in a cold environment. With the expected increase in temperature stochasticity at northern latitudes, a loss of thermogenic capacity during warm winter days could, therefore, be detrimental if birds are slow to readjust their phenotype with the return of cold days. PMID- 27233919 TI - [Bone tumors : Radiologic-pathologic correlation]. PMID- 27233920 TI - [Cartilage tumors : Pathology and radiomorphology]. AB - Primary cartilage-forming tumors of the bone are frequent entities in the daily work of skeletal radiologists. This article describes the correlation of pathology and radiology in cartilage-forming skeletal tumors, in particular, enchondroma, osteochondroma, periosteal chondromas, chondroblastoma and various forms of chondrosarcoma. After reading, the radiologist should be able to deduce the different patterns of cartilage tumors on radiographs, CT, and MRI from the pathological aspects. Differentiation of enchondroma and chondrosarcoma is a frequent diagnostic challenge. Some imaging parameters, e. g., deep cortical scalloping (more than two thirds of the cortical thickness), cortical destruction, or a soft-tissue mass, are features of a sarcoma. Osteochondromas are bony protrusions with a continuous extension of bone marrow from the parent bone, the host cortical bone runs continuously from the osseous surface of the tumor into the shaft of the osteochondroma and the osteochondroma has a cartilage cap. Chondromyxoid fibromas are well-defined lytic and eccentric lesions of the metaphysis of the long bones, with nonspecific MRI findings. Chondroblastomas have a strong predilection for the epiphysis of long tubular bones and develop an intense perifocal bone marrow edema. Dedifferentiated chondrosarcomas are bimorphic lesions with a low-grade chondrogenic component and a high-grade noncartilaginous component. Most chondrogenic tumors have a predilection with regard to site and age at manifestation. PMID- 27233921 TI - Clinical safety evaluation of marine oil derived from Calanus finmarchicus. AB - Marine oils are rich in polyunsaturated fatty acids (PUFAs), including docosahexaenoic and eicosapentaenoic acid. These PUFAs are associated with health benefits and additional sustainable sources of marine oils are desirable. One of the source organisms is Calanus finmarchicus, a copepod endemic to the North Atlantic. PUFAs in the lipid fraction of this organism are largely in the form of wax esters. To assess the safety of these wax esters as a source of PUFAs, a randomized, double-blinded, placebo-controlled clinical trial was conducted whereby 64 subjects consumed 2 g Calanus oil in capsule form daily for a period of one year. A group of 53 subjects consumed placebo capsules. At baseline, 6-, and 12-months, series of evaluations were conducted, including: vital signs, clinical chemistry and hematological evaluations, and adverse event reporting. Food intake and physical exercise were controlled by means of a questionnaire. There were no effects on Calanus oil treatment on any of the safety parameters measured. A slight increase in the incidence of eczema was reported in the Calanus oil group, but the response was minor in nature, not statistically significant after controlling for multiple comparisons, and could not be attributed to treatment. PMID- 27233922 TI - Development of linear and threshold no significant risk levels for inhalation exposure to titanium dioxide using systematic review and mode of action considerations. AB - Titanium dioxide (TiO2) has been characterized as a poorly soluble particulate (PSP) with low toxicity. It is well accepted that low toxicity PSPs such as TiO2 induce lung tumors in rats when deposition overwhelms particle clearance mechanisms. Despite the sensitivity of rats to PSPs and questionable relevance of PSP-induced tumors to humans, TiO2 is listed as a possible human carcinogen by some agencies and regulators. Thus, environmental toxicity criteria for TiO2 are needed for stakeholders to evaluate potential risks from environmental exposure and regulatory compliance. A systematic review of the literature was conducted to characterize the available data and identify candidate datasets upon which toxicity values could be derived. Key to this assessment, a survey of mechanistic data relevant for lung cancer was used to support quantitative inhalation risk assessment approaches. A total of 473 human studies were identified, 7 of which were epidemiological studies that met inclusion criteria to quantitatively characterize carcinogenic endpoints in humans. None of these studies supported derivation of toxicity criteria; therefore, animal data were used to derived safety values for TiO2 using different dose-metrics (regional deposited dose ratios, TiO2 particle surface area lung burden, and volumetric overload of alveolar macrophages), benchmark dose modeling, and different low-dose extrapolation approaches. Based on empirical evidence and mechanistic support for nonlinear mode of action involving particle overload, chronic inflammation and cell proliferation, a no significant risk level (NSRL) of 300 MUg/day was derived. By comparison, low-dose linear extrapolation from tumor incidence in the rat lung resulted in an NSRL value of 44 MUg/day. These toxicity values should be useful for stakeholders interested in assessing risks from environmental exposure to respirable TiO2. PMID- 27233923 TI - Issues and approaches for ensuring effective communication on acceptable daily exposure (ADE) values applied to pharmaceutical cleaning. AB - This manuscript centers on communication with key stakeholders of the concepts and program goals involved in the application of health-based pharmaceutical cleaning limits. Implementation of health-based cleaning limits, as distinct from other standards such as 1/1000th of the lowest clinical dose, is a concept recently introduced into regulatory domains. While there is a great deal of technical detail in the written framework underpinning the use of Acceptable Daily Exposures (ADEs) in cleaning (for example ISPE, 2010; Sargent et al., 2013), little is available to explain how to practically create a program which meets regulatory needs while also fulfilling good manufacturing practice (GMP) and other expectations. The lack of a harmonized approach for program implementation and communication across stakeholders can ultimately foster inappropriate application of these concepts. Thus, this period in time (2014 2017) could be considered transitional with respect to influencing best practice related to establishing health-based cleaning limits. Suggestions offered in this manuscript are intended to encourage full and accurate communication regarding both scientific and administrative elements of health-based ADE values used in pharmaceutical cleaning practice. This is a large and complex effort that requires: 1) clearly explaining key terms and definitions, 2) identification of stakeholders, 3) assessment of stakeholders' subject matter knowledge, 4) formulation of key messages fit to stakeholder needs, 5) identification of effective and timely means for communication, and 6) allocation of time, energy, and motivation for initiating and carrying through with communications. PMID- 27233924 TI - Special endpoint and product specific considerations in pharmaceutical acceptable daily exposure derivation. AB - Recently, a guideline has been published by the European Medicines Agency (EMA) on setting safe limits, permitted daily exposures (PDE) [also called acceptable daily exposures (ADE)], for medicines manufactured in multi-product facilities. The ADE provides a safe exposure limit for inadvertent exposure of a drug due to cross-contamination in manufacturing. The ADE determination encompasses a standard risk assessment, requiring an understanding of the toxicological and pharmacological effects, the mechanism of action, drug compound class, and the dose-response as well as the pharmacokinetic properties of the compound. While the ADE concept has broad application in pharmaceutical safety there are also nuances and specific challenges associated with some toxicological endpoints or drug product categories. In this manuscript we discuss considerations for setting ADEs when the following specific adverse health endpoints may constitute the critical effect: genotoxicity, developmental and reproductive toxicity (DART), and immune system modulation (immunostimulation or immunosuppression), and for specific drug classes, including antibody drug conjugates (ADCs), emerging medicinal therapeutic compounds, and compounds with limited datasets. These are challenging toxicological scenarios that require a careful evaluation of all of the available information in order to establish a health-based safe level. PMID- 27233925 TI - Point of departure (PoD) selection for the derivation of acceptable daily exposures (ADEs) for active pharmaceutical ingredients (APIs). AB - The Acceptable Daily Exposure (ADE) derived for pharmaceutical manufacturing is a health-based limit used to ensure that medicines produced in multi-product facilities are safe and are used to validate quality processes. Core to ADE derivation is selecting appropriate point(s) of departure (PoD), i.e., the starting dose of a given dataset that is used in the calculation of the ADE. Selecting the PoD involves (1) data collection and hazard characterization, (2) identification of "critical effects", and (3) a dose-response assessment including the determination of the no-observed-adverse-effect-level (NOAEL) or lowest-observed-adverse-effect-level (LOAEL), or calculating a benchmark dose (BMD) level. Compared to other classes of chemicals, active pharmaceutical ingredients (APIs) are well-characterized and have unique, rich datasets that must be considered when selecting the PoD. Dataset considerations for an API include therapeutic/pharmacological effects, particularities of APIs for different indications and routes of administration, data gaps during drug development, and sensitive subpopulations. Thus, the PoD analysis must be performed by a qualified toxicologist or other expert who also understands the complexities of pharmaceutical datasets. In addition, as the pharmaceutical industry continues to evolve new therapeutic principles, the science behind PoD selection must also evolve to ensure state-of-the-science practices and resulting ADEs. PMID- 27233926 TI - Using default methodologies to derive an acceptable daily exposure (ADE). AB - This manuscript discusses the different historical and more recent default approaches that have been used to derive an acceptable daily exposure (ADE). While it is preferable to derive a health-based ADE based on a complete nonclinical and clinical data package, this is not always possible. For instance, for drug candidates in early development there may be no or limited nonclinical or clinical trial data. Alternative approaches that can support decision making with less complete data packages represent a variety of methods that rely on default assumptions or data inputs where chemical-specific data on health effects are lacking. A variety of default approaches are used including those based on certain toxicity estimates, a fraction of the therapeutic dose, cleaning-based limits, the threshold of toxicological concern (TTC), and application of hazard banding tools such as occupational exposure banding (OEB). Each of these default approaches is discussed in this manuscript, including their derivation, application, strengths, and limitations. In order to ensure patient safety when faced with toxicological and clinical data-gaps, default ADE methods should be purposefully as or more protective than ADEs derived from full data packages. Reliance on the subset of default approaches (e.g., TTC or OEB) that are based on toxicological data is preferred over other methods for establishing ADEs in early development while toxicology and clinical data are still being collected. PMID- 27233927 TI - Why do policies change? Institutions, interests, ideas and networks in three cases of policy reform. AB - Policy researchers have used various categories of variables to explain why policies change, including those related to institutions, interests and ideas. Recent research has paid growing attention to the role of policy networks-the actors involved in policy-making, their relationships with each other, and the structure formed by those relationships-in policy reform across settings and issues; however, this literature has largely ignored the theoretical integration of networks with other policy theories, including the '3Is' of institutions, interests and ideas. This article proposes a conceptual framework integrating these variables and tests it on three cases of policy change in Burkina Faso, addressing the need for theoretical integration with networks as well as the broader aim of theory-driven health policy analysis research in low- and middle income countries. We use historical process tracing, a type of comparative case study, to interpret and compare documents and in-depth interview data within and between cases. We found that while network changes were indeed associated with policy reform, this relationship was mediated by one or more of institutions, interests and ideas. In a context of high donor dependency, new donor rules affected the composition and structure of actors in the networks, which enabled the entry and dissemination of new ideas and shifts in the overall balance of interest power ultimately leading to policy change. The case of strategic networking occurred in only one case, by civil society actors, suggesting that network change is rarely the spark that initiates the process towards policy change. This analysis highlights the important role of changes in institutions and ideas to drive policymaking, but hints that network change is a necessary intermediate step in these processes. PMID- 27233928 TI - Wide Variation in Radiation Exposure During Computerized Tomography. AB - OBJECTIVE: To determine the variance in computeed tomography (CT) radiation measured via dose-length product (DLP) and effective dose (ED) during stone protocol CT scans. METHODS: We retrospectively examined consecutive records of patients receiving stone protocol diagnostic CT scans (n = 1793) in 2010 and 2014 in our health system. Patient age, body mass index (BMI), and gender were recorded, along with the hospital, machine model, year, DLP, and ED of each scan. Multivariate regression was performed to identify predictive factors for increased DLP. We also collected data on head (n = 837) CT scans to serve as a comparison. RESULTS: For stone CT scans, mean patient age was 55.1 +/- 18.4 years with no significant difference in age (P=.2557) or BMI (P=.1794) between 2010 and 2014. Gender, BMI, and machine model were independent predictors of radiation dosage (P < .0001). Within each BMI class, there was an inexplicable 6-fold variation in the ED for the same imaging test when comparing the lowest and highest CT dose patients. There was no significant change in DLP over time for stone CT scans, but head scan patients in 2014 received lower radiation doses than those in 2010 (P < .0001). Low-dose scans for renal colic (defined as <4 mSv) were underutilized. Substantial variation exists for head scan radiation doses. CONCLUSION: Our data demonstrate large variations in diagnostic CT radiation dosage. Such differences within a single institution suggest similar trends elsewhere, warranting more stringent dosage guidelines and regulations for diagnostic CT scans within institutions. PMID- 27233929 TI - Transurethral Bougie-guided Placement of Suprapubic Catheter Over Guide Wire Monorail in Females: A Novel Technique. AB - OBJECTIVE: To assess the safety and effectiveness of a novel transurethral bougie guided monorail technique for suprapubic catheterization in females with vesicovaginal fistula. METHODS: Patients undergoing transvaginal vesicovaginal fistula repair from February 2013 to December 2013 were selected. Suprapubic catheter was placed using this technique and assessment was done in terms of time taken, intraprocedural dislodgement or entanglement of catheter during the procedure, bleeding from the anterior abdominal wall or urethra, or any other intraoperative difficulty. RESULTS: All patients were catheterized smoothly without any intraoperative difficulty, with a mean time of 6 minutes. CONCLUSION: We describe a new technique of performing suprapubic cystostomy in patients, especially where the bladder cannot be distended. It is safe and easy to perform. PMID- 27233930 TI - Functional Restoration of Erectile Function Using End-to-side Autonomic-to somatic Neurorrhaphy in Rats. AB - OBJECTIVE: To investigate the feasibility of erectile function rehabilitation using end-to-side autonomic-to-somatic neurorrhaphy in rats. MATERIALS AND METHODS: Thirty-six adult male Sprague-Dawley rats were divided into 3 groups (n = 12 per group): in the end-to-side coaptation group, the left L6 and S1 spinal nerves were transected, and the distal stump of L6 ventral root was sutured to L4 ventral root through end-to-side neurorrhaphy; in the no-coaptation group, the rats did not undergo coaptation; and in the control group, the left L6 and S1 spinal nerves were transected, but L6 ventral root was preserved. After 4 months, retrograde tracing, histomorphological technique, mating test, and evaluation of functional properties of the regenerated nerve were performed. RESULTS: Mating test showed a significantly higher intromission behavior rate in the end-to-side coaptation group (41.7%) and control group (58.3%) than in the no-coaptation group (0%) (P < .001). Intracavernous pressure in end-to-side coaptation group was 31.6 +/- 12.0 mmHg, significantly higher than in the no-coaptation group (3.1 +/- 1.4 mmHg), but lower than in the control group (67.9 +/- 18.0 mmHg) (P < .0001). Retrograde tracing indicated the establishment of the new neural pathway. Axon counting and ultrastructure observation confirmed axonal regeneration in the end-to-side coaptation group. The bilateral tibialis anterior muscles wet weight in the end-to-side coaptation group were 0.6686 +/- 0.0427 g and 0.6707 +/- 0.0515 g (P = .93). The wet weight and morphology of the tibialis anterior muscles revealed no detrimental effect on the donor nerve. CONCLUSION: Nerve regeneration can be achieved using end-to-side autonomic-to-somatic neurorrhaphy, and erectile function can be restored without the functional impairment of the donor somatic nerve. PMID- 27233931 TI - Survival Comparison Between Endoscopic and Surgical Management for Patients With Upper Tract Urothelial Cancer: A Matched Propensity Score Analysis Using Surveillance, Epidemiology and End Results-Medicare Data. AB - OBJECTIVE: To determine survival differences among patients receiving endoscopic vs surgical management for upper tract urothelial carcinoma (UTUC). MATERIALS AND METHODS: Using Surveillance, Epidemiology and End Results-Medicare data, patients diagnosed with nonmuscle-invasive, low-grade UTUC as their first cancer diagnosis between 2004 and 2009 were identified. Receipts of endoscopic and surgical interventions were assessed, and patients were separated into surgical or endoscopic management cohorts. Two-to-one propensity score analysis was performed to control for baseline characteristics between groups. RESULTS: The endoscopic management (n = 151) and matched surgical management (n = 302) groups demonstrated no significant differences in age, gender, race, marital status, Charlson comorbidity index, or year of diagnosis. Endoscopic management was an independent and significant predictor of all-cause and cancer-specific mortality (hazard ratio 1.6 for overall survival [OS], hazard ratio 2.1 for cancer-specific survival [CSS]). Kaplan-Meier estimated survival was significantly lower for endoscopic management, with both OS and CSS curves diverging at approximately 24 36 months. A subset of patients initially receiving endoscopic management went on to receive surgical intervention (80/151 = 53%) at a median of 8.8 months from diagnosis. For these patients, Kaplan-Meier-estimated CSS was not significantly different from those who continued with only endoscopic management, and remained significantly lower than patients who received upfront surgery. CONCLUSION: Although initial survival outcomes (first 24 months) are similar for endoscopic and surgical management of nonmuscle-invasive, low-grade UTUC, both CSS and OS are significantly inferior for the endoscopic management group in the longer term. Furthermore, transition from initial endoscopic management to surgical intervention appears to have limited impact on survival. PMID- 27233932 TI - Ectopic Vas Deferens Inserting Into Distal Retroiliac Ureter in the Currarino Syndrome. AB - Vas deferens ectopia is a rare congenital anomaly frequently associated with anorectal abnormalities and hypospadias. We present a Currarino syndrome case with an ectopic vas deferens terminating in a distal retroiliac ureter. A left vasectomy, ureteral decussation over the iliac vessels, and a Cohen's-type ureteral reimplantation were performed. The objectives are to preserve renal function, prevent epididymitis, and preserve fertility. There is no evidence in the literature that recommends surgical correction of the vas deferens. Microsurgical epididymal sperm aspiration or testicular sperm extraction combined with intracytoplasmic sperm injection might be a viable strategy for these affected individuals. PMID- 27233933 TI - A Joint Mechanism of Action for Sacral Neuromodulation for Bladder and Bowel Dysfunction? AB - Sacral neuromodulation (SNM) is a clinically effective intervention for treatment of urinary and bowel disorders. The aim is to establish the hypothesis that there is a common mechanism of action for SNM in both systems. Current knowledge includes the following: (1) Therapeutic parameters may be different for the 2 efficacy measures. (2) SNM invokes neural circuits that can be observed as neurochemical changes in specific neuroanatomic structures downstream from the therapy delivery site. (3) There are important central nervous system effects for both therapies. (4) Clinical observations regarding normal continence sensations as well as physiological measures of continence are different for the 2 therapy areas. PMID- 27233934 TI - Perirenal Involvement of Mantle Cell Lymphoma: Imaging Features. AB - Perirenal lymphoma is a rare disease and accounts for less than 10% of all malignant lymphomas. Mantle cell lymphoma (MCL) is the rarest but 1 of the most aggressive non-Hodgkin's lymphoma subtype. The perirenal involvement of MCL has not been reported previously. A 69-year-old male, who had been diagnosed as having MCL 1 year ago, presented with recent-onset right back pain. Herein we present the key imaging findings of perirenal soft tissue manifestation of MCL. PMID- 27233935 TI - Descriptive Technique and Initial Results for Robotic Radical Perineal Prostatectomy. AB - OBJECTIVE: To minimize technical challenges of radical perineal prostatectomy (RPP), we conceived and applied the robotic approach to this technique in an aim to improve surgical applicability of RPP. Radical prostatectomy via the perineal route, avoiding the intra-abdominal cavity, has been shown to be oncologically safe, with excellent functional outcomes and a short hospital stay. We report our initial results with this novel approach. MATERIALS AND METHODS: We performed the procedure in 4 patients. With the patient in the exaggerated lithotomy position, following a 3 cm perineal incision, the initial perineal dissection using Belt's approach is performed, followed by single port placement and docking of the robot. RESULTS: The median age for patients was 64 years (60-69). Two patients had no rectum because of the abdominoperineal resection due to inflammatory bowel diseases. One of the other 2 patients had a surgical history of aborted robotic assisted laparoscopic radical prostatectomy and 1 patient had no surgical history. There were no perioperative complications and the patients were discharged within 16-48 hours. Urethral catheter was removed within 10 days in 3 patients, and 3 weeks in 1 patient. Two patients were immediately continent when Foley was removed. The final pathology revealed focally positive margin in those 3 patients who had surgical histories and it was margin negative in the patient with native anatomy. All patients had undetectable prostate-specific antigen postoperatively. CONCLUSION: RPP was successfully completed in 4 cases, applying a single port robotic perineal approach. Initial results are encouraging, with short hospital stay and minimal postoperative pain. PMID- 27233936 TI - Topological surface states interacting with bulk excitations in the Kondo insulator SmB6 revealed via planar tunneling spectroscopy. AB - Samarium hexaboride (SmB6), a well-known Kondo insulator in which the insulating bulk arises from strong electron correlations, has recently attracted great attention owing to increasing evidence for its topological nature, thereby harboring protected surface states. However, corroborative spectroscopic evidence is still lacking, unlike in the weakly correlated counterparts, including Bi2Se3 Here, we report results from planar tunneling that unveil the detailed spectroscopic properties of SmB6 The tunneling conductance obtained on the (001) and (011) single crystal surfaces reveals linear density of states as expected for two and one Dirac cone(s), respectively. Quite remarkably, it is found that these topological states are not protected completely within the bulk hybridization gap. A phenomenological model of the tunneling process invoking interaction of the surface states with bulk excitations (spin excitons), as predicted by a recent theory, provides a consistent explanation for all of the observed features. Our spectroscopic study supports and explains the proposed picture of the incompletely protected surface states in this topological Kondo insulator SmB6. PMID- 27233937 TI - Free-energy landscape of a hyperstable RNA tetraloop. AB - We report the characterization of the energy landscape and the folding/unfolding thermodynamics of a hyperstable RNA tetraloop obtained through high-performance molecular dynamics simulations at microsecond timescales. Sampling of the configurational landscape is conducted using temperature replica exchange molecular dynamics over three isochores at high, ambient, and negative pressures to determine the thermodynamic stability and the free-energy landscape of the tetraloop. The simulations reveal reversible folding/unfolding transitions of the tetraloop into the canonical A-RNA conformation and the presence of two alternative configurations, including a left-handed Z-RNA conformation and a compact purine Triplet. Increasing hydrostatic pressure shows a stabilizing effect on the A-RNA conformation and a destabilization of the left-handed Z-RNA. Our results provide a comprehensive description of the folded free-energy landscape of a hyperstable RNA tetraloop and highlight the significant advances of all-atom molecular dynamics in describing the unbiased folding of a simple RNA secondary structure motif. PMID- 27233939 TI - Contactin-associated protein-like (CNTNAP) 2 gene mutation in a patient with bilateral schizencephaly. PMID- 27233938 TI - Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons. AB - Fragile X syndrome (FXS) is caused by the absence of the Fragile X Mental Retardation Protein (FMRP) in neurons. In the mouse, the lack of FMRP is associated with an excessive translation of hundreds of neuronal proteins, notably including postsynaptic proteins. This local protein synthesis deregulation is proposed to underlie the observed defects of glutamatergic synapse maturation and function and to affect preferentially the hundreds of mRNA species that were reported to bind to FMRP. How FMRP impacts synaptic protein translation and which mRNAs are most important for the pathology remain unclear. Here we show by cross-linking immunoprecipitation in cortical neurons that FMRP is mostly associated with one unique mRNA: diacylglycerol kinase kappa (Dgkkappa), a master regulator that controls the switch between diacylglycerol and phosphatidic acid signaling pathways. The absence of FMRP in neurons abolishes group 1 metabotropic glutamate receptor-dependent DGK activity combined with a loss of Dgkkappa expression. The reduction of Dgkkappa in neurons is sufficient to cause dendritic spine abnormalities, synaptic plasticity alterations, and behavior disorders similar to those observed in the FXS mouse model. Overexpression of Dgkkappa in neurons is able to rescue the dendritic spine defects of the Fragile X Mental Retardation 1 gene KO neurons. Together, these data suggest that Dgkkappa deregulation contributes to FXS pathology and support a model where FMRP, by controlling the translation of Dgkkappa, indirectly controls synaptic proteins translation and membrane properties by impacting lipid signaling in dendritic spine. PMID- 27233941 TI - John Cockrill. PMID- 27233940 TI - Lobular breast cancer: Clinical, molecular and morphological characteristics. AB - Infiltrating lobular breast cancer (ILBC) is the most common special breast cancer subtype. This review provides a comprehensive description of ILBC characteristics, including epidemiology, clinical features, molecular genetics and histomorphology. Twenty detailed supplemental data tables guide through primary data of more than 200 original studies. Meta-analyses indicate that ILBC is at least twice as common in the Western world as it is in other geographic regions. ILBC is over-represented in so-called interval carcinomas and in primary metastatic breast cancer. ILBC is also associated higher age, higher pT stage and hormone receptor (ER/PR) positivity. Pathological complete response rates after neoadjuvant chemotherapy are low, ranging between 0% and 11%. Positive resection margins after breast-conserving surgery are comparatively frequent and 17% to 65% of patients undergo a second surgical intervention. Depending on the morphological stringency in the diagnosis of ILBC, lack of E-cadherin expression is observed in 55% to 100% of cases. CDH1/E-cadherin mutation detection rates vary between 12% and 83%. Various additional molecular factors, including PIK3CA, TP53, FOXA1, FGFR1, ZNF703 and BCAR4, have been implicated in ILBC or progression of lobular carcinoma in situ (LCIS) to invasive cancer and are discussed in detail. Eight instructive figure plates recapitulate the histomorphology of ILBC and its variants. Furthermore, we draw attention to rarely addressed histological details, such as two-sided nuclear compression and fat-avoiding growth at the invasion front. Last but not least, we discuss future translational research directions and emphasize the concept of synthetic lethality, which promises new options for targeted ILBC therapy. PMID- 27233942 TI - Designing piperlongumine-directed anticancer agents by an electrophilicity-based prooxidant strategy: A mechanistic investigation. AB - Piperlongumine (PL), a natural electrophilic alkaloid bearing two alpha, beta unsaturated imides, is a promising anticancer molecule by targeting the stress response to reactive oxygen species (ROS). Considering that ROS generation depends on electrophilicity of PL, PL-CL was designed as its analog by introducing the alpha-substituent chlorine on the lactam ring to increase moderately its electrophilicity. In comparison with the parent molecule, this molecule was identified as a stronger ROS (O2(?-) and H2O2) inducer and cytotoxic agent, and manifested more than 15-fold selectivity toward A549 cells over normal WI-38 cells. Mechanistic study uncovers for the first time that the selenoprotein thioredoxin reductase (TrxR) is one of the targets by which PL-CL promotes the ROS generation. Stronger intracellular TrxR inhibition and higher accumulation of ROS (O2(?-) and H2O2) are responsible for more effective S-phase arrest and mitochondria-mediated apoptotic induction of A549 cells by PL-CL than PLvia p53 p21-cyclinA/CDK2 and ASK1-JNK/p38 signaling cascade pathways, respectively. This work provides an example of successfully designing PL-directed anticancer agent by an electrophilicity-based prooxidant (ROS-generating agent) strategy and gives added confidence for extending this strategy to other natural products. PMID- 27233945 TI - Association between childbirth attitudes and fear on birth preferences of a future generation of Australian parents. AB - BACKGROUND: The reality of childbirth fear is recognised for expectant parents but we lack knowledge about the childbirth attitudes of the next generation of Australian parents. AIM: Examination of adults' attitudes toward childbirth including influencing contributing factors, fear scores, birth preferences and reasons for this preference. METHODS: A cross-sectional online study was conducted with 654 Western Australian students attending one tertiary institution. Students (male and female) were eligible to participate if they were less than 40 years of age and did not currently have children but confirmed their intention to become parents. To assess associations or comparison of means, bi variable analyses (Chi square test, Fisher's Exact test, Independent Student's t test or one way ANOVA) were used. Factors associated with childbirth fear and birth preferences were assessed with binary logistic regression analysis. FINDINGS: Childbirth attitudes were shaped by family members' (82.0%) and friends' experiences (64.4%) plus media (TV, YouTube, and movies) (63.5%). Furthermore, 15.6% of adults indicated a preference for a caesarean birth, even without obstetric complications. Likewise, 26.1% reported elevated fear; students with elevated fear scores had 2.6 times greater odds of wanting a caesarean birth. Only 23.4% of students felt confident about their childbirth knowledge. CONCLUSION: Adults reported fear levels that warrant attention prior to a future pregnancy. Although the majority would choose a vaginal birth, they require awareness of benefits and risks for both vaginal and caesarean births to ensure their decisions reflect informed choice rather than influences of inadequate knowledge or fear. PMID- 27233947 TI - Near-catastrophic event from a benign cause. PMID- 27233944 TI - Hsp90-binding immunophilin FKBP51 forms complexes with hTERT enhancing telomerase activity. AB - FK506-binding proteins are members of the immunophilin family of proteins. Those immunophilins associated to the 90-kDa-heat-shock protein, Hsp90, have been proposed as potential modulators of signalling cascade factors chaperoned by Hsp90. FKBP51 and FKBP52 are the best characterized Hsp90-bound immunophilins first described associated to steroid-receptors. The reverse transcriptase subunit of telomerase, hTERT, is also an Hsp90 client-protein and is highly expressed in cancer cells, where it is required to compensate the loss of telomeric DNA after each successive cell division. Because FKBP51 is also a highly expressed protein in cancer tissues, we analyzed its potential association with hTERT.Hsp90 complexes and its possible biological role. In this study it is demonstrated that both immunophilins, FKBP51 and FKBP52, co-immunoprecipitate with hTERT. The Hsp90 inhibitor radicicol disrupts the heterocomplex and favors the partial cytoplasmic relocalization of hTERT in similar manner as the overexpression of the TPR-domain peptide of the immunophilin. While confocal microscopy images show that FKBP51 is primarily localized in mitochondria and hTERT is totally nuclear, upon the onset of oxidative stress, FKBP51 (but not FKBP52) becomes mostly nuclear colocalizing with hTERT, and longer exposure times to peroxide favors hTERT export to mitochondria. Importantly, telomerase activity of hTERT is significantly enhanced by FKBP51. These observations support the emerging role assigned to FKBP51 as antiapoptotic factor in cancer development and progression, and describe for the first time the potential role of this immunophilin favoring the clonal expansion by enhancing telomerase activity. PMID- 27233943 TI - Mifepristone increases mRNA translation rate, triggers the unfolded protein response, increases autophagic flux, and kills ovarian cancer cells in combination with proteasome or lysosome inhibitors. AB - The synthetic steroid mifepristone blocks the growth of ovarian cancer cells, yet the mechanism driving such effect is not entirely understood. Unbiased genomic and proteomic screenings using ovarian cancer cell lines of different genetic backgrounds and sensitivities to platinum led to the identification of two key genes upregulated by mifepristone and involved in the unfolded protein response (UPR): the master chaperone of the endoplasmic reticulum (ER), glucose regulated protein (GRP) of 78 kDa, and the CCAAT/enhancer binding protein homologous transcription factor (CHOP). GRP78 and CHOP were upregulated by mifepristone in ovarian cancer cells regardless of p53 status and platinum sensitivity. Further studies revealed that the three UPR-associated pathways, PERK, IRE1alpha, and ATF6, were activated by mifepristone. Also, the synthetic steroid acutely increased mRNA translation rate, which, if prevented, abrogated the splicing of XBP1 mRNA, a non-translatable readout of IRE1alpha activation. Moreover, mifepristone increased LC3-II levels due to increased autophagic flux. When the autophagic-lysosomal pathway was inhibited with chloroquine, mifepristone was lethal to the cells. Lastly, doses of proteasome inhibitors that are inadequate to block the activity of the proteasomes, caused cell death when combined with mifepristone; this phenotype was accompanied by accumulation of poly ubiquitinated proteins denoting proteasome inhibition. The stimulation by mifepristone of ER stress and autophagic flux offers a therapeutic opportunity for utilizing this compound to sensitize ovarian cancer cells to proteasome or lysosome inhibitors. PMID- 27233948 TI - Off limits: highly sensitive troponin in the general population. PMID- 27233949 TI - [Autologous fat grafting in children]. AB - Lipofilling or fat grafting transfer is defined as a technique of filling soft tissue by autologous fat grafting. The basic principle of lipofilling is based on a harvest of adipose tissue, followed by a reinjection after treatment. Lipofilling main objective is a volume defect filling, but also improving cutaneous trophicity. Lipofilling specificities among children is mainly based on these indications. Complications of autologous fat grafting among children are the same as those in adults: we distinguish short-term complications (intraoperative and perioperative) and the medium and long-term complications. The harvesting of fat tissue is the main limiting factor of the technique, due to low percentage of body fat of children. Indications of lipofilling among children may be specific or similar to those in adults. There are two types of indications: cosmetic, in which the aim of lipofilling is correcting a defect density, acquired (iatrogenic, post-traumatic scar) or malformation (otomandibular dysplasia, craniosynostosis, Parry Romberg syndrom, Poland syndrom, pectus excavatum...). The aim of functional indications is correcting a velar insufficiency or lagophthalmos. In the paediatric sector, lipofilling has become an alternative to the conventional techniques, by its reliability, safety, reproducibility, and good results. PMID- 27233950 TI - [Introduction]. PMID- 27233951 TI - Are Guidelines Mantra? Musings About Uncertainty in Medicine. PMID- 27233952 TI - Electrical Stimulation of the Vagus Nerve for Chronic Heart Failure: Is It Time to Pull the Plug? PMID- 27233953 TI - HLA class I molecular variation and peptide-binding properties suggest a model of joint divergent asymmetric selection. AB - The main function of HLA class I molecules is to present pathogen-derived peptides to cytotoxic T lymphocytes. This function is assumed to drive the maintenance of an extraordinary amount of polymorphism at each HLA locus, providing an immune advantage to heterozygote individuals capable to present larger repertories of peptides than homozygotes. This seems contradictory, however, with a reduced diversity at individual HLA loci exhibited by some isolated populations. This study shows that the level of functional diversity predicted for the two HLA-A and HLA-B genes considered simultaneously is similar (almost invariant) between 46 human populations, even when a reduced diversity exists at each locus. We thus propose that HLA-A and HLA-B evolved through a model of joint divergent asymmetric selection conferring all populations an equivalent immune potential. The distinct pattern observed for HLA-C is explained by its functional evolution towards killer cell immunoglobulin-like receptor (KIR) activity regulation rather than peptide presentation. PMID- 27233954 TI - Molecular characterization of MHC class II in the Australian invasive cane toad reveals multiple splice variants. AB - The cane toad has gained notoriety for its invasion across the Australian landscape, with significant impacts on the native Australian fauna. The invasion has accelerated over time, with invading cane toads adapted for highly dispersive traits. This, however, has come at the cost of the immune system, with lower investment in some immune functions. To investigate the cane toad's immunogenetics, we characterized four major histocompatibility complex (MHC) class IIA and three MHC class IIB loci. Preliminary observations suggest very low allelic diversity at all loci. We also observed various splice isoforms. One isoform seen at one class IIA and two class IIB loci was missing exon 2, which is essential to peptide binding and presentation. The other isoform, observed at a class IIA locus, is likely to be a soluble MHC product. These results may suggest a significant role of alternative splicing of MHC loci in the Australian cane toad. PMID- 27233956 TI - Does your reinforced tube have a Murphy EYE? PMID- 27233955 TI - Cynomolgus macaque (Macaca fascicularis) immunoglobulin heavy chain locus description. AB - Cynomolgus macaques (Macaca fascicularis) have become an important animal model for biomedical research. In particular, it is the animal model of choice for the development of vaccine candidates associated with emerging dangerous pathogens. Despite their increasing importance as animal models, the cynomolgus macaque genome is not fully characterized, hindering molecular studies for this model. More importantly, the lack of knowledge about the immunoglobulin (IG) locus organization directly impacts the analysis of the humoral response in cynomolgus macaques. Recent advances in next generation sequencing (NGS) technologies to analyze IG repertoires open the opportunity to deeply characterize the humoral immune response. However, the IG locus organization for the animal is required to completely dissect IG repertoires. Here, we describe the localization and organization of the rearranging IG heavy (IGH) genes on chromosome 7 of the cynomolgus macaque draft genome. Our annotation comprises 108 functional genes which include 63 variable (IGHV), 38 diversity (IGHD), and 7 joining (IGHJ) genes. For validation, we provide RNA transcript data for most of the IGHV genes and all of the annotated IGHJ genes, as well as proteomic data to validate IGH constant genes. The description and annotation of the rearranging IGH genes for the cynomolgus macaques will significantly facilitate scientific research. This is particularly relevant to dissect the immune response during vaccination or infection with dangerous pathogens such as Ebola, Marburg and other emerging pathogens where non-human primate models play a significant role for countermeasure development. PMID- 27233957 TI - Gender Differences in Concussion Reporting Among High School Athletes. AB - BACKGROUND: An athlete's lack of concussion knowledge could lead to significant underreporting and injury mismanagement. To provide more effective management strategies of concussions in adolescent athletes, further examination of reporting behaviors is of critical importance. HYPOTHESIS: The hypotheses for this study were as follows: (1) Girls are more likely to report concussion, (2) girls are more likely to report future concussions after an educational intervention, and (3) a difference in rationale for not reporting concussion will be found between sexes. STUDY DESIGN: Cross-sectional, cohort design. LEVEL OF EVIDENCE: Level 3. METHODS: Survey answers were collected on 454 high school athletes (212 girls, 242 boys; mean age, 15.7 +/- 1.15 years). Individual team meetings lasting approximately 30 minutes were held to collect data and provide an educational lecture. Participants were randomly provided an iClicker to submit a response to questions asked. RESULTS: Girls were more likely to report a concussion (chi(2) = 8.32, df = 3, N = 454, P = 0.040) and more likely to report future concussions after educational intervention (chi(2) = 8.54, df = 2, N = 454, P = 0.014). There were no differences between sexes regarding rationale for not reporting a concussion (chi(2) = 6.42, df = 4, N = 454, P = 0.170). CONCLUSION: There is concern these athletes still fail to understand the severity and potential sequelae of concussion injury. Both sexes cited that concussion is not a serious enough injury to warrant reporting to a medical professional. CLINICAL RELEVANCE: High school athletes recover more slowly from concussions compared with college athletes; therefore, educating this population and promoting the importance of being knowledgeable regarding concussion recognition may increase reporting prevalence. PMID- 27233958 TI - Influenza Vaccination Generates Cytokine-Induced Memory-like NK Cells: Impact of Human Cytomegalovirus Infection. AB - Human NK cells are activated by cytokines, immune complexes, and signals transduced via activating ligands on other host cells. After vaccination, or during secondary infection, adaptive immune responses can enhance both cytokine driven and Ab-dependent NK cell responses. However, induction of NK cells for enhanced function after in vitro exposure to innate inflammatory cytokines has also been reported and may synergize with adaptive signals to potentiate NK cell activity during infection or vaccination. To test this hypothesis, we examined the effect of seasonal influenza vaccination on NK cell function and phenotype in 52 previously unvaccinated individuals. Enhanced, IL-2-dependent, NK cell IFN gamma responses to Influenza A/California/7/2009 virus were detected up to 4 wk postvaccination and higher in human CMV (HCMV)-seronegative (HCMV(-)) individuals than in HCMV-seropositive (HCMV(+)) individuals. By comparison, robust NK cell degranulation responses were observed both before and after vaccination, due to high titers of naturally occurring anti-influenza Abs in human plasma, and did not differ between HCMV(+) and HCMV(-) subjects. In addition to these IL-2 dependent and Ab-dependent responses, NK cell responses to innate cytokines were also enhanced after influenza vaccination; this was associated with proliferation of CD57(-) NK cells and was most evident in HCMV(+) subjects. Similar enhancement of cytokine responsiveness was observed when NK cells were cocultured in vitro with Influenza A/California/7/2009 virus, and this was at least partially dependent upon IFN-alphabetaR2. In summary, our data indicate that attenuated or live viral vaccines promote cytokine-induced memory-like NK cells and that this process is influenced by HCMV infection. PMID- 27233959 TI - Ly49C Impairs NK Cell Memory in Mouse Cytomegalovirus Infection. AB - NK cells possess inhibitory receptors that are responsible for self-MHC class I recognition; beyond their inhibitory function, accumulating evidence indicates that such receptors confer NK cell functional competence through an unclear process termed "licensing." Ly49C is the main self-specific inhibitory Ly49 receptor in H-2(b) C57BL/6 (B6) mice. We used B6 Ly49C-transgenic and B6 beta2 microglobulin (beta2m)-knockout Ly49C-transgenic mice to investigate the impact of licensing through this inhibitory receptor in precursor and mature NK cells. We found that self-specific inhibitory receptors affected NK cell precursor survival and proliferation at particular developmental stages in an MHC class I dependent manner. The presence of Ly49C impacted the NK cell repertoire in a beta2m-dependent manner, with reduced Ly49A(+), Ly49G2(+), and Ly49D(+) subsets, an increased DNAM-1(+) subset, and higher NKG2D expression. Licensed NK cells displayed a skewed distribution of the maturation stages, which was characterized by differential CD27 and CD11b expression, toward the mature phenotypes. We found that Ly49C-mediated licensing induced a split effect on NK cell functions, with increased cytokine-production capabilities following engagement of various activating receptors while cytotoxicity remained unchanged. Analysis of licensed NK cell functions in vivo, in a system of mouse CMV infection, indicated that licensing did not play a major role in the NK cell antiviral response during acute infection, but it strongly impaired the generation and/or persistence of memory NK cells. This study unravels multifaceted effects of licensing on NK cell populations and their functions. PMID- 27233960 TI - Progesterone Levels Associate with a Novel Population of CCR5+CD38+ CD4 T Cells Resident in the Genital Mucosa with Lymphoid Trafficking Potential. AB - The female genital tract (FGT) provides a means of entry to pathogens, including HIV, yet immune cell populations at this barrier between host and environment are not well defined. We initiated a study of healthy women to characterize resident T cell populations in the lower FGT from lavage and patient-matched peripheral blood to investigate potential mechanisms of HIV sexual transmission. Surprisingly, we observed FGT CD4 T cell populations were primarily CCR7(hi), consistent with a central memory or recirculating memory T cell phenotype. In addition, roughly half of these CCR7(hi) CD4 T cells expressed CD69, consistent with resident memory T cells, whereas the remaining CCR7(hi) CD4 T cells lacked CD69 expression, consistent with recirculating memory CD4 T cells that traffic between peripheral tissues and lymphoid sites. HIV susceptibility markers CCR5 and CD38 were increased on FGT CCR7(hi) CD4 T cells compared with blood, yet migration to the lymphoid homing chemokines CCL19 and CCL21 was maintained. Infection with GFP-HIV showed that FGT CCR7(hi) memory CD4 T cells are susceptible HIV targets, and productive infection of CCR7(hi) memory T cells did not alter chemotaxis to CCL19 and CCL21. Variations of resident CCR7(hi) FGT CD4 T cell populations were detected during the luteal phase of the menstrual cycle, and longitudinal analysis showed the frequency of this population positively correlated to progesterone levels. These data provide evidence women may acquire HIV through local infection of migratory CCR7(hi) CD4 T cells, and progesterone levels predict opportunities for HIV to access these novel target cells. PMID- 27233961 TI - mTORC2 in Thymic Epithelial Cells Controls Thymopoiesis and T Cell Development. AB - Thymic epithelial cells (TECs) play important roles in T cell generation. Mechanisms that control TEC development and function are still not well defined. The mammalian or mechanistic target of rapamycin complex (mTORC)2 signals to regulate cell survival, nutrient uptake, and metabolism. We report in the present study that mice with TEC-specific ablation of Rictor, a critical and unique adaptor molecule in mTORC2, display thymic atrophy, which accompanies decreased TEC numbers in the medulla. Moreover, generation of multiple T cell lineages, including conventional TCRalphabeta T cells, regulatory T cells, invariant NKT cells, and TCRgammadelta T cells, was reduced in TEC-specific Rictor-deficient mice. Our data demonstrate that mTORC2 in TECs is important for normal thymopoiesis and efficient T cell generation. PMID- 27233963 TI - Human Xenobiotic Nuclear Receptor PXR Augments Mycobacterium tuberculosis Survival. AB - Mycobacterium tuberculosis can evade host defense processes, thereby ensuring its survival and pathogenesis. In this study, we investigated the role of nuclear receptor, pregnane X receptor (PXR), in M. tuberculosis infection in human monocyte-derived macrophages. In this study, we demonstrate that PXR augments M. tuberculosis survival inside the host macrophages by promoting the foamy macrophage formation and abrogating phagolysosomal fusion, inflammation, and apoptosis. Additionally, M. tuberculosis cell wall lipids, particularly mycolic acids, crosstalk with human PXR (hPXR) by interacting with its promiscuous ligand binding domain. To confirm our in vitro findings and to avoid the reported species barrier in PXR function, we adopted an in vivo mouse model expressing hPXR, wherein expression of hPXR in mice promotes M. tuberculosis survival. Therefore, pharmacological intervention and designing antagonists to hPXR may prove to be a promising adjunct therapy for tuberculosis. PMID- 27233962 TI - STAT2 Is Required for TLR-Induced Murine Dendritic Cell Activation and Cross Presentation. AB - TLR-stimulated cross-presentation by conventional dendritic cells (cDCs) is important in host defense and antitumor immunity. We recently reported that cDCs lacking the type I IFN signaling molecule STAT2 are impaired in cross-presenting tumor Ags to CD8(+) T cells. To investigate how STAT2 affects cross-presentation, we determined its requirements for dendritic cell activation. In this study, we report that STAT2 is essential for the activation of murine female cDCs upon TLR3, -4, -7, and -9 stimulation. In response to various TLR ligands, Stat2(-/-) cDCs displayed reduced expression of costimulatory molecules and type I IFN stimulated genes. The cDC responses to exogenous IFN-alpha that we evaluated required STAT2 activation, indicating that the canonical STAT1-STAT2 heterodimers are the primary signaling transducers of type I IFNs in cDCs. Interestingly, LPS induced production of IL-12 was STAT2 and type I IFN receptor (IFNAR) dependent, whereas LPS-induced production of TNF-alpha and IL-6 was STAT2 and IFNAR independent, suggesting a specific role of the IFNAR-STAT2 axis in the stimulation of proinflammatory cytokines by LPS in cDCs. In contrast, R848- and CpG-induced cytokine production was less influenced by the IFNAR-STAT2 axis. Short kinetics and IFNAR blockade studies showed that STAT2 main function is to transduce signals triggered by autocrine type I IFNs. Importantly, Stat2(-/-) cDCs were deficient in cross-presenting to CD8(+) T cells in vitro upon IFN alpha, CpG, and LPS stimulation, and also in cross-priming and licensing cytotoxic T cell killers in vivo. We conclude that STAT2 plays a critical role in TLR-induced dendritic cell activation and cross-presentation, and thus is vital in host defense. PMID- 27233965 TI - The Ron Receptor Tyrosine Kinase Regulates Macrophage Heterogeneity and Plays a Protective Role in Diet-Induced Obesity, Atherosclerosis, and Hepatosteatosis. AB - Obesity is a chronic inflammatory disease mediated in large part by the activation of inflammatory macrophages. This chronic inflammation underlies a whole host of diseases including atherosclerosis, hepatic steatosis, insulin resistance, type 2 diabetes, and cancer, among others. Macrophages are generally classified as either inflammatory or alternatively activated. Some tissue resident macrophages are derived from yolk sac erythromyeloid progenitors and fetal liver progenitors that seed tissues during embryogenesis and have the ability to repopulate through local proliferation. These macrophages tend to be anti-inflammatory in nature and are generally involved in tissue remodeling, repair, and homeostasis. Alternatively, during chronic inflammation induced by obesity, bone marrow monocyte-derived macrophages are recruited to inflamed tissues, where they produce proinflammatory cytokines and exacerbate inflammation. The extent to which these two populations of macrophages are plastic in their phenotype remains controversial. We have demonstrated previously that the Ron receptor tyrosine kinase is expressed on tissue-resident macrophages, where it limits inflammatory macrophage activation and promotes a repair phenotype. In this study, we demonstrate that Ron is expressed in a subpopulation of macrophages during chronic inflammation induced by obesity that exhibit a repair phenotype as determined by the expression of arginase 1. In addition, we demonstrate that the Ron receptor plays a protective role in the progression of diet-induced obesity, hepatosteatosis, and atherosclerosis. These results suggest that altering macrophage heterogeneity in vivo could have the potential to alleviate obesity-associated diseases. PMID- 27233966 TI - Cutting Edge: A Cullin-5-TRAF6 Interaction Promotes TRAF6 Polyubiquitination and Lipopolysaccharide Signaling. AB - TNFR-associated factor (TRAF)6 integrates signals from multiple cell surface receptors for the activation of NF-kappaB. However, the mechanism underlying LPS induced TRAF6 signaling remains unclear. We report that cullin-5 (Cul-5), a cullin family scaffold protein, binds to TRAF6 and promotes TRAF6 polyubiquitination at Lys(63) in response to LPS stimulation. A direct interaction between the C-terminal domain of Cul-5 and the TRAF-C domain of TRAF6 facilitates polyubiquitination of TRAF6. Hemizygous Cul-5 knockout is associated with improved survival of mice following LPS challenge and significant delays in the phosphorylation of p65/RelA, ERK, JNK, and p38 MAPKs in LPS-stimulated macrophages, along with a marked decrease in NF-kappaB activation. These findings identify Cul-5 as a signaling component that connects an LPS-activated TLR4-MyD88 complex to TRAF6 for efficient activation of NF-kappaB. PMID- 27233964 TI - A Novel Role for TL1A/DR3 in Protection against Intestinal Injury and Infection. AB - TNF-like cytokine 1A (TL1A) is expressed on APCs and provides costimulatory signals to activated lymphocytes that bear its functional receptor, death receptor 3 (DR3). TL1A/DR3 signaling is involved in the pathogenesis of human and experimental inflammatory bowel disease. In the current study, we investigated the role of this cytokine/receptor pair in acute intestinal injury/repair pathways. We demonstrate that intact DR3 signaling protected mice from acute dextran sodium sulfate colitis because DR3(-/-) mice showed more severe mucosal inflammation and increased mortality. DR3(-/-) mice were compromised in their ability to maintain adequate numbers of CD4(+)CD25(+)Foxp3(+) regulatory T cells in response to acute mucosal damage. This defect in immune regulation led to a nonspecific upregulation of effector proinflammatory pathways, which was most prominent for the Th17 immunophenotype. TL1A(-/-) mice were similarly more susceptible to dextran sodium sulfate colitis, although without mortality and with delayed kinetics compared with DR3(-/-) mice, and also displayed significantly reduced numbers of regulatory T cells. Infection of DR3(-/-) mice with Salmonella typhimurium was associated with defective microbial clearance and elevated bacterial load. Taken together, our findings indicate a novel protective role for the TL1A/DR3 axis in the regulation of mucosal homeostasis during acute intestinal injury/repair, which contrasts with its known pathogenic function during chronic intestinal inflammation. PMID- 27233967 TI - IL-21-Induced MHC Class II+ NK Cells Promote the Expansion of Human Uncommitted CD4+ Central Memory T Cells in a Macrophage Migration Inhibitory Factor-Dependent Manner. AB - NK cells are critical for innate immunity-mediated protection. The main roles of NK cells rely on their cytotoxic functions or depend on the tuning of Th1 adaptive immunity by IFN-gamma. However, the precise influence of inflammatory cytokines on NK cell and CD4 T lymphocyte interactions was never investigated. In this study, we provide evidence that IL-21, a cytokine produced during chronic inflammation or infectious diseases, promotes the differentiation of a specific subset of NK cells coexpressing CD86 and HLA-DR and lacking NKp44. More importantly, IL-21-propagated HLA-DR(+) NK cells produce macrophage migration inhibitory factor and provide costimulatory signaling during naive CD4(+) T cell priming inducing the differentiation of uncommitted central memory T cells. Central memory T cells expanded in the presence of HLA-DR(+) NK cells are CXCR3(+)CCR6(-)CCR4(-)CXCR5(-) and produce IL-2, as well as low levels of TNF alpha. Costimulation of CD4(+) T cells by HLA-DR(+) NK cells prevents the acquisition of effector memory phenotype induced by IL-2. Moreover, we identified this population of NK HLA-DR(+) macrophage migration inhibitory factor(+) cells in inflammatory human appendix. Collectively, these results demonstrate a novel function for IL-21 in tuning NK and CD4(+) T cell interactions promoting a specific expansion of central memory lymphocytes. PMID- 27233969 TI - Differences in cognitive impairment between schizophrenia and bipolar disorder: Considering the role of heterogeneity. AB - Schizophrenia is associated with significant cognitive impairment. Bipolar disorder (BD) also presents with cognitive deficits that are similar to, albeit less severe, than those reported in schizophrenia. There has been controversy over whether selective deficits in social cognition or developmental trajectory of cognitive deficits can distinguish schizophrenia from BD. Also, available studies have not generally considered the potential effect of cognitive heterogeneity within the two disorders on between-group differences. The current review examines the evidence on the specificity of social cognitive deficits and early neurocognitive impairment to schizophrenia and explores the overall outcome of studies investigating within and cross-diagnosis cognitive heterogeneity in schizophrenia and BD. Current evidence does not support the specificity of social cognitive impairment to schizophrenia. Available studies also suggest that cognitive impairment in premorbid and early stages is evident not only in schizophrenia but also in many BD patients. Both schizophrenia and BD have a number of cognitive subgroups, including severe impairment, good functioning, and one or more selective or modest impairment clusters. While both disorders are represented in each cognitive subgroup, there are significant cross-diagnostic differences regarding prevalences of individuals belonging to the severe impairment and good functioning subgroups. Individuals with schizophrenia are much more likely to exhibit severe cognitive impairment than individuals with BD and good cognitive functioning is more often observed in BD patients than schizophrenia patients. Further identification of the neurobiological and genetic characteristics of the cognitive subgroups in major psychoses can improve the validity of diagnostic systems and can advance the development of personalized management approaches, including cognitive remediation. PMID- 27233970 TI - She's Back Again. PMID- 27233971 TI - Reply. PMID- 27233968 TI - Imatinib Triggers Phagolysosome Acidification and Antimicrobial Activity against Mycobacterium bovis Bacille Calmette-Guerin in Glucocorticoid-Treated Human Macrophages. AB - Glucocorticoids are extensively used to treat inflammatory diseases; however, their chronic intake increases the risk for mycobacterial infections. Meanwhile, the effects of glucocorticoids on innate host responses are incompletely understood. In this study, we investigated the direct effects of glucocorticoids on antimycobacterial host defense in primary human macrophages. We found that glucocorticoids triggered the expression of cathelicidin, an antimicrobial critical for antimycobacterial responses, independent of the intracellular vitamin D metabolism. Despite upregulating cathelicidin, glucocorticoids failed to promote macrophage antimycobacterial activity. Gene expression profiles of human macrophages treated with glucocorticoids and/or IFN-gamma, which promotes induction of cathelicidin, as well as antimycobacterial activity, were investigated. Using weighted gene coexpression network analysis, we identified a module of highly connected genes that was strongly inversely correlated with glucocorticoid treatment and associated with IFN-gamma stimulation. This module was linked to the biological functions autophagy, phagosome maturation, and lytic vacuole/lysosome, and contained the vacuolar H(+)-ATPase subunit a3, alias TCIRG1, a known antimycobacterial host defense gene, as a top hub gene. We next found that glucocorticoids, in contrast with IFN-gamma, failed to trigger expression and phagolysosome recruitment of TCIRG1, as well as to promote lysosome acidification. Finally, we demonstrated that the tyrosine kinase inhibitor imatinib induces lysosome acidification and antimicrobial activity in glucocorticoid-treated macrophages without reversing the anti-inflammatory effects of glucocorticoids. Taken together, we provide evidence that the induction of cathelicidin by glucocorticoids is not sufficient for macrophage antimicrobial activity, and identify the vacuolar H(+)-ATPase as a potential target for host-directed therapy in the context of glucocorticoid therapy. PMID- 27233972 TI - Ultrasound Visualization of Atypical Abscess Ultimately Containing Bot Fly Larva. AB - BACKGROUND: Because of the rise in community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), presentations to the emergency department for the evaluation of cutaneous abscesses have risen dramatically over the past 2 decades. Soft tissue point of care ultrasound (POCUS) differentiates abscess from cellulitis, determines the size and shape, and characterizes the contents of the abscess. It has been shown to improve medical decision-making and therefore the emergency management of cutaneous abscesses over physical examination alone. CASE REPORT: We report a case of an unusual nonhealing abscess in an 18-year-old woman with a recent history of foreign travel where soft tissue POCUS identified motion within the abscess pocket. This changed the management of the case, leading to the diagnosis of bot fly myiasis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Clinicians should entertain a broader differential for an apparent abscess and consider liberal use of soft tissue POCUS in these cases. PMID- 27233973 TI - Bone remodeling during pregnancy and post-partum assessed by metal lead levels and isotopic concentrations. AB - Bone remodeling is normally evaluated using bone turnover markers/indices as indicators of bone resorption and formation. However, during pregnancy and post partum, there have been inconsistent results between and within biomarkers for bone formation and resorption. These differences may relate to pregnancy-related changes in metabolism and/or hemodilution altering measured marker levels. An alternative approach to evaluating bone remodeling is to use the metal lead (Pb) concentrations and Pb isotopic compositions in blood. These measurements can also provide information on the amount of Pb that is mobilized from the maternal skeleton. Despite some similarities with accepted bone turnover markers, the Pb data demonstrate increased bone resorption throughout pregnancy that further continues post-partum independent of length of breast-feeding, dietary intake and resumption of menses. Furthermore the isotopic measurements are not affected by hemodilution. These data confirm calcium balance studies that indicate increased bone resorption throughout pregnancy and lactation. They also indicate potentially major public health implications of the transfer of maternal Pb burden to the fetus and new born. PMID- 27233983 TI - Alteration of the cytokine signature by various TLR ligands in different T cell populations in MOG37-50 and MOG35-55-induced EAE in C57BL/6 mice. AB - Interleukin 17 (IL-17), produced by T cells, plays an important role in Multiple Sclerosis (MS) and its animal model, Experimental Autoimmune Encephalomyelitis (EAE). In contrast to IL-17-producing CD4+ T cells, the contribution of IL-17 producing CD8+ T cells (Tc17) in CNS autoimmunity has been investigated less intensively. Here we investigate the role of TC17 in EAE. We compare different T cell populations and their cytokine pattern in the MOG35-55- and MOG37-50-induced EAE. We detected a similar cytokine phenotype for both EAE models in the autoimmune process assessed at different stages. Regarding the migratory activity, an involvement of IL-17 and IFN-gamma in disease onset was suggested. Furthermore, we show that PAMPs have the ability to drive autoimmune process. To modify the cytokine pattern of different T cell populations, a combination of distinct factors is required (the activation of MyD88 or Syk, the genetic background, the presence of APCs and CD4+ T cells). PMID- 27233984 TI - Single chest tube drainage is superior to double chest tube drainage after lobectomy: a meta-analysis. AB - BACKGROUND: In this meta-analysis, we conducted a pooled analysis of clinical studies comparing the efficacy of single chest tube versus double chest tube after a lobectomy. METHODS: According to the recommendations of the Cochrane Collaboration, we established a rigorous study protocol. We performed a systematic electronic search of the PubMed, Embase, Cochrane Library and Web of Science databases to identify articles to include in our meta-analysis. A literature search was performed using relevant keywords. A meta-analysis was performed using RevMan(c) software. RESULTS: Five studies, published between 2003 and 2014, including 630 patients (314 patients with a single chest tube and 316 patients with a double chest tube), met the selection criteria. From the available data, the patients using a single tube demonstrated significantly decreased postoperative pain [weighted mean difference [WMD] -0.60; 95 % confidence intervals [CIs] -0.68-- 0.52; P < 0.00001], duration of drainage [WMD 0.70; 95 % CIs -0.90-- 0.49; P < 0.00001] and hospital stay [WMD -0.51; 95 % CIs 0.91-- 0.12; P = 0.01] compared to patients using a double tube after a pulmonary lobectomy. However, there were no significant differences in postoperative complications [OR 0.91; 95 % CIs 0.57-1.44; P = 0.67] and re-drainage rates [OR 0.81; 95 % CIs 0.42-1.58; P = 0.54]. CONCLUSION: Our results showed that a single drain method is effective, reducing postoperative pain, hospitalization times and duration of drainage in patients who undergo a lobectomy. Moreover, the single drain method does not increase the occurrence of postoperative complications and re-drainage rates. PMID- 27233985 TI - Plastics and microplastics in the oceans: From emerging pollutants to emerged threat. AB - Plastic production has increased dramatically worldwide over the last 60 years and it is nowadays recognized as a serious threat to the marine environment. Plastic pollution is ubiquitous, but quantitative estimates on the global abundance and weight of floating plastics are still limited, particularly for the Southern Hemisphere and the more remote regions. Some large-scale convergence zones of plastic debris have been identified, but there is the urgency to standardize common methodologies to measure and quantify plastics in seawater and sediments. Investigations on temporal trends, geographical distribution and global cycle of plastics have management implications when defining the origin, possible drifting tracks and ecological consequences of such pollution. An elevated number of marine species is known to be affected by plastic contamination, and a more integrated ecological risk assessment of these materials has become a research priority. Beside entanglement and ingestion of macro debris by large vertebrates, microplastics are accumulated by planktonic and invertebrate organisms, being transferred along food chains. Negative consequences include loss of nutritional value of diet, physical damages, exposure to pathogens and transport of alien species. In addition, plastics contain chemical additives and efficiently adsorb several environmental contaminants, thus representing a potential source of exposure to such compounds after ingestion. Complex ecotoxicological effects are increasingly reported, but the fate and impact of microplastics in the marine environment are still far to be fully clarified. PMID- 27233986 TI - Antiviral anthraquinones and azaphilones produced by an endophytic fungus Nigrospora sp. from Aconitum carmichaeli. AB - A new hydroanthraquinone derivative, 6-O-demethyl-4-dehydroxyaltersolanol A (1), and two new azaphilones, 8,11-didehydrochermesinone B (6) and (7S)-7-hydroxy-3,7 dimethyl-isochromene-6,8-dione (8), along with five known analogues (2-5 and 7), were isolated from the culture broth of Nigrospora sp. YE3033, an endophytic fungus obtained from Aconitum carmichaeli. Their structures were elucidated on the basis of spectroscopic analyses. Biological activity test indicated that compounds 1-3, and 7 exhibited the inhibitory effects on influenza viral strain of A/Puerto Rico/8/34 (H1N1) with the IC50 values of 2.59, 8.35, 7.82, and 0.80MUg/mL, respectively, while the low cytotoxicity of 7 with the CC50 value of 184.75MUg/mL, displaying a promising potential of 7 in the development of anti influenza A virus drugs. PMID- 27233987 TI - Isolation, modification, and aldose reductase inhibitory activity of rosmarinic acid derivatives from the roots of Salvia grandifolia. AB - To find aldose reductase inhibitors, two previously unreported compounds, grandifolias H and I, and five known compounds, including rosmarinic acid and rosmarinic acid derivatives, were isolated from the roots of Salvia grandifolia. A series of rosmarinic acid derivatives was obtained from rosmarinic acid using simple synthetic methods. The aldose reductase inhibitory activity of the isolated and synthesized compounds was assessed. Seven of the tested compounds showed moderate aldose reductase inhibition (IC50=0.06-0.30MUM). The structure activity relationship of aldose reductase inhibitory activity of rosmarinic acid derivatives was discussed for the first time. This study provided useful information that will facilitate the development of aldose reductase inhibitors. PMID- 27233988 TI - Silybum marianum pericarp yields enhanced silymarin products. AB - An improved method for the purification of silymarin, the flavonolignan complex from the fruits of milk thistle, Silybum marianum, is reported. The method enables a more efficient extraction of silymarin from the pericarp after it has been separated mechanically from the rest of the fruits. Accelerated solvent extraction (ASE) was employed for each extraction procedure. Quantitation of the eight major silymarin components in the pericarp extract was compared to that of the whole fruit extract using two orthogonal analytical methods. The pericarp extract showed higher silymarin content (2.24-fold by HPLC and 2.12-fold by qHNMR) than whole fruit extract using acetone as an extraction solvent following defatting with hexane. Furthermore, the mg/g recovery of silymarin major components was not diminished by eliminating the hexane defatting step from the pericarp extraction procedure. The efficiencies of acetone, ethanol, and methanol as extraction solvents were compared. Methanol pericarp extract showed the highest content of the silymarin major components, 2.72-fold higher than an extract prepared from the whole fruits using acetone. Finally, all of the major silymarin components showed a higher w/w content in the pericarp extract than in a commercial extract. PMID- 27233990 TI - Cardiovascular Health Benefits of Exercise in People With Spinal Cord Injury: More Complex Than a Prescribed Exercise Intervention? PMID- 27233989 TI - Effect of nerve growth factor on sperm quality in asthenozoosprmic men during cryopreservation. AB - BACKGROUND: Although routinely used in assisted reproductive technology, human sperm cryopreservation is not an entirely successful procedure. This study determined the effect of nerve growth factor (NGF) supplementation of cryopreservation medium on post-thaw viability, motility, intracellular nitric oxide (NO) concentration, and DNA fragmentation of human spermatozoa in asthenozoospermic men. METHODS: Semen samples were collected from 25 asthenozoosprmic men and divided into the following groups (n = 5/group): fresh semen (control); frozen-thawed semen without treatment; frozen-thawed semen with NGF treatment (0.5, 1, and 5 ng/ml). Prior to dividing the asthenozoospermic samples, 200 MUl of each sample was collected for NGF content assessment by ELISA and then compared with normozoospermic semen samples (25 normozoospermic men). Sperm motility and viability were assessed according to WHO criteria. Furthermore, intracellular nitric oxide and DNA fragmentation were evaluated by Flow Cytometry. RESULTS: NGF content was significantly higher in normozoospermic compared with asthenozoospermic men. Cryopreservation of asthenozoospermic semen samples significantly decreased sperm viability and motility, and increased intracellular nitric oxide concentration and DNA damage (p < 0.01). In asthenozoospermic frozen-thawed samples treated with 0.5 ng/ml exogenous NGF, we observed a significantly increased viability, motility, and decreased DNA fragmentation (p < 0.05), but intracellular nitric oxide concentration was not reduced. The other high doses (1 and 5 ng/ml) had no significant effect on the variables. CONCLUSION: Supplementation with exogenous NGF could have partial and limited protective effect during cryopreservation of human spermatozoa but further research is needed to evaluate the possible clinical applications. PMID- 27233991 TI - The Authors Respond. PMID- 27233992 TI - Correction. PMID- 27233993 TI - Correction. PMID- 27233994 TI - Physical Activity Recommendations for the Aging Brain: A Clinician-Patient Guide. PMID- 27233995 TI - Biosynthesis of oxidized lipid mediators via lipoprotein-associated phospholipase A2 hydrolysis of extracellular cardiolipin induces endothelial toxicity. AB - We (66) have previously described an NSAID-insensitive intramitochondrial biosynthetic pathway involving oxidation of the polyunsaturated mitochondrial phospholipid, cardiolipin (CL), followed by hydrolysis [by calcium-independent mitochondrial calcium-independent phospholipase A2-gamma (iPLA2gamma)] of oxidized CL (CLox), leading to the formation of lysoCL and oxygenated octadecadienoic metabolites. We now describe a model system utilizing oxidative lipidomics/mass spectrometry and bioassays on cultured bovine pulmonary artery endothelial cells (BPAECs) to assess the impact of CLox that we show, in vivo, can be released to the extracellular space and may be hydrolyzed by lipoprotein associated PLA2 (Lp-PLA2). Chemically oxidized liposomes containing bovine heart CL produced multiple oxygenated species. Addition of Lp-PLA2 hydrolyzed CLox and produced (oxygenated) monolysoCL and dilysoCL and oxidized octadecadienoic metabolites including 9- and 13-hydroxyoctadecadienoic (HODE) acids. CLox caused BPAEC necrosis that was exacerbated by Lp-PLA2 Lower doses of nonlethal CLox increased permeability of BPAEC monolayers. This effect was exacerbated by Lp PLA2 and partially mimicked by authentic monolysoCL or 9- or 13-HODE. Control mice plasma contained virtually no detectable CLox; in contrast, 4 h after Pseudomonas aeruginosa (P. aeruginosa) infection, 34 +/- 8 mol% (n = 6; P < 0.02) of circulating CL was oxidized. In addition, molar percentage of monolysoCL increased twofold after P. aeruginosa in a subgroup analyzed for these changes. Collectively, these studies suggest an important role for 1) oxidation of CL in proinflammatory environments and 2) possible hydrolysis of CLox in extracellular spaces producing lysoCL and oxidized octadecadienoic acid metabolites that may lead to impairment of pulmonary endothelial barrier function and necrosis. PMID- 27233996 TI - Alveolar epithelial disintegrity in pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by progressive decline in lung function, resulting in significant morbidity and mortality. Current concepts of the pathogenesis of IPF primarily center on dysregulated epithelial cell repair and altered epithelial-mesenchymal communication and extracellular matrix deposition following chronic exposure to cigarette smoke or environmental toxins. In recent years, increasing attention has been directed toward the role of the intercellular junctional complex in determining the specific properties of epithelia in pulmonary diseases. Additionally, recent genomewide association studies suggest that specific genetic variants predictive of epithelial cell dysfunction may confer susceptibility to the development of sporadic idiopathic pulmonary fibrosis. A number of genetic disorders linked to pulmonary fibrosis and familial interstitial pneumonias are associated with loss of epithelial integrity. However, the potential links between extrapulmonary clinical syndromes associated with defects in epithelial cells and the development of pulmonary fibrosis are not well understood. Here, we report a case of hereditary mucoepithelial dysplasia that presented with pulmonary fibrosis and emphysema on high-resolution computed tomography. This case illustrates a more generalizable concept of epithelial disintegrity in the development of fibrotic lung diseases, which is explored in greater detail in this review article. PMID- 27233997 TI - Vascular endothelial-cadherin downregulation as a feature of endothelial transdifferentiation in monocrotaline-induced pulmonary hypertension. AB - Increased pulmonary vascular resistance in pulmonary hypertension (PH) is caused by vasoconstriction and obstruction of small pulmonary arteries by proliferating vascular cells. In analogy to cancer, subsets of proliferating cells may be derived from endothelial cells transitioning into a mesenchymal phenotype. To understand phenotypic shifts transpiring within endothelial cells in PH, we injected rats with alkaloid monocrotaline to induce PH and measured lung tissue levels of endothelial-specific protein and critical differentiation marker vascular endothelial (VE)-cadherin. VE-cadherin expression by immonoblotting declined significantly 24 h and 15 days postinjection to rebound to baseline at 30 days. There was a concomitant increase in transcriptional repressors Snail and Slug, along with a reduction in VE-cadherin mRNA. Mesenchymal markers alpha smooth muscle actin and vimentin were upregulated by immunohistochemistry and immunoblotting, and alpha-smooth muscle actin was colocalized with endothelial marker platelet endothelial cell adhesion molecule-1 by confocal microscopy. Apoptosis was limited in this model, especially in the 24-h time point. In addition, monocrotaline resulted in activation of protein kinase B/Akt, endothelial nitric oxide synthase (eNOS), nuclear factor (NF)-kappaB, and increased lung tissue nitrotyrosine staining. To understand the etiological relationship between nitrosative stress and VE-cadherin suppression, we incubated cultured rat lung endothelial cells with endothelin-1, a vasoconstrictor and pro proliferative agent in pulmonary arterial hypertension. This resulted in activation of eNOS, NF-kappaB, and Akt, in addition to induction of Snail, downregulation of VE-cadherin, and synthesis of vimentin. These effects were blocked by eNOS inhibitor N(omega)-nitro-l-arginine methyl ester. We propose that transcriptional repression of VE-cadherin by nitrosative stress is involved in endothelial-mesenchymal transdifferentiation in experimental PH. PMID- 27233998 TI - Histone deacetylation contributes to low extracellular superoxide dismutase expression in human idiopathic pulmonary arterial hypertension. AB - Epigenetic mechanisms, including DNA methylation and histone acetylation, regulate gene expression in idiopathic pulmonary arterial hypertension (IPAH). These mechanisms can modulate expression of extracellular superoxide dismutase (SOD3 or EC-SOD), a key vascular antioxidant enzyme, and loss of vascular SOD3 worsens outcomes in animal models of pulmonary arterial hypertension. We hypothesized that SOD3 gene expression is decreased in patients with IPAH due to aberrant DNA methylation and/or histone deacetylation. We used lung tissue and pulmonary artery smooth muscle cells (PASMC) from subjects with IPAH at transplantation and from failed donors (FD). Lung SOD3 mRNA expression and activity was decreased in IPAH vs. FD. In contrast, mitochondrial SOD (Mn-SOD or SOD2) protein expression was unchanged and intracellular SOD activity was unchanged. Using bisulfite sequencing in genomic lung or PASMC DNA, we found the methylation status of the SOD3 promoter was similar between FD and IPAH. Furthermore, treatment with 5-aza-2'-deoxycytidine did not increase PASMC SOD3 mRNA, suggesting DNA methylation was not responsible for PASMC SOD3 expression. Though total histone deacetylase (HDAC) activity, histone acetyltransferase (HAT) activity, acetylated histones, and acetylated SP1 were similar between IPAH and FD, treatment with two selective class I HDAC inhibitors increased SOD3 only in IPAH PASMC. Class I HDAC3 siRNA also increased SOD3 expression. Trichostatin A, a pan-HDAC inhibitor, decreased proliferation in IPAH, but not in FD PASMC. These data indicate that histone deacetylation, specifically via class I HDAC3, decreases SOD3 expression in PASMC and HDAC inhibitors may protect IPAH in part by increasing PASMC SOD3 expression. PMID- 27234000 TI - Haemosporidian parasite prevalence, parasitemia, and diversity in three resident bird species at a shrubland dominated landscape of the Mexican highland plateau. AB - BACKGROUND: Studies of avian haemosporidians allow understanding how these parasites affect wild bird populations, and if their presence is related to factors such as habitat loss, degradation and fragmentation, and climate change. Considering the importance of the highland Plateau of Mexico as part of the North American bird migratory route and as a region containing important habitat for numerous bird species, the purpose of this study was to document haemosporidian species richness and how habitat degradation, bird body condition, and distance from water sources correlate with bird parasitemia. METHODS: We assessed the presence of avian haemosporidians in three resident bird species through microscopy and PCR amplification of a fragment of the haemosporidian cytochrome b gene. Average parasitemia was estimated in each species, and its relationship with habitat degradation through grazing, bird body condition and distance from water bodies was assessed. RESULTS: High levels of parasitemia were recorded in two of the three bird species included in this study. Four lineages of haemosporidians were identified in the study area with nearly 50 % prevalence. Areas with highly degraded shrublands and villages showed higher parasitemia relative to areas with moderately degraded shrublands. No strong relationship between parasitemia and distance from water bodies was observed. There were no significant differences in prevalence and parasitemia between the two bird species infected with the parasites. Two of the sequences obtained from the fragments of the parasite's cytochrome b gene represent a lineage that had not been previously reported. CONCLUSIONS: Haemosporidian diversity in arid zones of the Mexican highland plateau is high. Shrubland habitat degradation associated to the establishment of small villages, as well as tree extraction and overgrazing in the surroundings of these villages, significantly enhances parasitemia of birds by haemosporidians. PMID- 27234001 TI - An intensive social cognitive program (can do treatment) in people with relapsing remitting multiple sclerosis and low disability: a randomized controlled trial protocol. AB - BACKGROUND: In people with multiple sclerosis (MS) disabilities and limitations may negatively affect self-efficacy. Lowered self-efficacy has been associated with decreases in health-related quality of life, physical activity and cognitive performance. In an explorative observational study we found that a 3-day intensive social cognitive program (Can Do Treatment [CDT]) with the participation of support partners was followed by substantial increases in self efficacy control and health-related quality of life 6 months after treatment in those people with MS who had relapsing remitting disease and low disability. METHODS/DESIGN: CDT is a sociologically oriented approach, its goal is to uncover and promote existing capabilities, and the notion "stressor" is the central concept. CDT's components are plenary group sessions, small group sessions, consultations, a theatre evening, and start of the day with a joint activity. The small group sessions form the actual training. Depending on their individual goals the participants join the training groups 'Body', 'Feeling' or 'Life', to work out their aims and to reduce their stressors. The multidisciplinary team includes a psychiatrist, psychiatric nurse, neurologist, specialized MS nurse, physiotherapist, dance therapist, and a person with MS. To evaluate the (cost)effectiveness of CDT in persons with relapsing remitting MS and low disability we perform a single-centre, randomized controlled trial in 140 patients, with or without support partners. The primary outcome is self-efficacy control. The secondary outcomes are self-efficacy function, health-related quality of life, autonomy and participation, anxiety, depression, cost effectiveness and cost utility. The tertiary outcome is care-related strain to support partners. Outcomes are assessed at baseline and at 1, 3 and 6 months after CDT. DISCUSSION: This randomized controlled trial will adequately evaluate the clinical and cost effectiveness of a 3-day intensive social cognitive program in people with relapsing remitting MS and low disability, with self-efficacy control as primary outcome. DUTCH TRIAL REGISTRY: Application number: 22444. PMID- 27233999 TI - Metabolic syndrome and osteoporotic fracture: a population-based study in China. AB - BACKGROUND: Associations between metabolic syndrome (MetS) and osteoporotic fracture have been reported. However, the epidemiological studies are not conclusive. The objective of the study was to determine whether metabolic syndrome associates with osteoporotic fracture. METHODS: This was a cross sectional study of 9930 Chinese adults aged 40 year or older in the Chongming District, Shanghai, China. A questionnaire, anthropometric measurements and laboratory tests were conducted. MetS was defined according to the updated National Cholesterol Education Program Adult Treatment Panel III criteria for Asian-Americans. A history of fractures was collected with an interviewer assisted questionnaire. Osteoporotic fractures were defined as fractures that occurred due to low-trauma in 2 years prior to the study. RESULTS: Among women, the prevalence of osteoporotic fractures was significantly higher in those with MetS (3.5 vs. 2.6 %, P =0.028). However, the difference was not found in men (2.6 vs. 2.4 %, P =0.737). The presence of Mets was significantly associated with increased odds of osteoporotic fracture among women (odds ratio 1.22; 95 % confidence interval 1.12-1.54; P = 0.039) after controlling for potential confounders. The significant associations were not detected in men. CONCLUSIONS: The presence of MetS was significantly associated with a recent history of osteoporotic fracture in middle-aged and elderly Chinese women. PMID- 27234002 TI - Purification and characterization of a novel cell-penetrating carrier similar to cholera toxin chimeric protein. AB - Developing a recombinant vector for noninvasively delivering biological macromolecules into the brain is important. This study constructed and purified a protein complex based on the cholera toxin (CT) molecular structure. Enhanced green fluorescent protein (EGFP)-modified A2 subunits of CT (CTA2) were used as tracer molecules for introduction of transactivator of transcription (TAT) through the A subunit into cells. The protein complex EGFP-CTA2-TAT/(CTB)5 (CTB: B subunit of CT) was obtained using an in vitro recombination method and verified by monosialoganglioside-enzyme-linked immunosorbent assay and high performance liquid chromatography assay. The protein complexes bound more strongly to monosialoganglioside (GM1) than (CTB)5 at low concentrations (0.625-1.25 MUg/mL). In vitro assays revealed that the transmembrane function of TAT was also maintained. The GM1-binding activity and cell membrane-penetrating ability suggested that a CT structure-based protein complexes could be used to design a delivery carrier for intranasal administration through GM1 binding. The expression vector introduced in this study provides a feasible expression frame for constructing several new macromolecular protein drugs for effective cell penetration. PMID- 27234003 TI - Microbial dinitrogen fixation in coral holobionts exposed to thermal stress and bleaching. AB - Coral holobionts (i.e., coral-algal-prokaryote symbioses) exhibit dissimilar thermal sensitivities that may determine which coral species will adapt to global warming. Nonetheless, studies simultaneously investigating the effects of warming on all holobiont members are lacking. Here we show that exposure to increased temperature affects key physiological traits of all members (herein: animal host, zooxanthellae and diazotrophs) of both Stylophora pistillata and Acropora hemprichii during and after thermal stress. S. pistillata experienced severe loss of zooxanthellae (i.e., bleaching) with no net photosynthesis at the end of the experiment. Conversely, A. hemprichii was more resilient to thermal stress. Exposure to increased temperature (+ 6 degrees C) resulted in a drastic increase in daylight dinitrogen (N2 ) fixation, particularly in A. hemprichii (threefold compared with controls). After the temperature was reduced again to in situ levels, diazotrophs exhibited a reversed diel pattern of activity, with increased N2 fixation rates recorded only in the dark, particularly in bleached S. pistillata (twofold compared to controls). Concurrently, both animal hosts, but particularly bleached S. pistillata, reduced both organic matter release and heterotrophic feeding on picoplankton. Our findings indicate that physiological plasticity by coral-associated diazotrophs may play an important role in determining the response of coral holobionts to ocean warming. PMID- 27234005 TI - "You can also save a life!": children's drawings as a non-verbal assessment of the impact of cardiopulmonary resuscitation training. AB - Drawings made by training children into cardiopulmonary resuscitation (CPR) during the special education week called "School otherwise" can be used as non verbal means of expression and communication to assess the impact of such training. We analyzed the questionnaires and drawings completed by 327 schoolchildren in different stages of education. After a brief overview of the basic life support (BLS) steps and after watching a video presenting the dynamic performance of the BLS sequence, subjects were asked to complete a questionnaire and make a drawing to express main CPR messages. Questionnaires were filled completely in 97.6 % and drawings were done in 90.2 % cases. Half of the subjects had already witnessed a kind of medical emergency and 96.94 % knew the correct "112" emergency phone number. The drawings were single images (83.81 %) and less cartoon strips (16.18 %). Main themes of the slogans were "Save a life!", "Help!", "Call 112!", "Do not be indifferent/insensible/apathic!" through the use of drawings interpretation, CPR trainers can use art as a way to build a better relation with schoolchildren, to connect to their thoughts and feelings and obtain the highest quality education. PMID- 27234004 TI - Factors preventing kneeling in a group of pre-educated patients post total knee arthroplasty. AB - BACKGROUND: Difficulties in kneeling, one of the poorest scoring functional outcomes post total knee arthroplasty (TKA),have been attributed to a lack of patient education. This is the first study to investigate specific factors affecting a patient's perceived ability to kneel post TKA, following exposure to a preoperative kneeling education session. MATERIALS AND METHODS: A cross sectional study was conducted following TKA with patients who had been educated about kneeling prior to the operation. Patients completed kneeling questionnaires at 6 (n = 115) and 12 (n = 82) months post TKA. In addition to the 12-month kneeling questionnaire, patients also completed the Oxford knee score (OKS) survey. RESULTS: Seventy-two percent of patients perceived they could kneel at 12 months post TKA. Overall, pain and discomfort were the most common factors deterring patients from kneeling. Perceived kneeling ability was the poorest scored outcome on the OKS with patients reporting mild to moderate difficulty with this task. Kneeling scores were strongly correlated with overall knee function scores (R = 0.70), strongly correlated with pain scores (R = 0.45) and weakly correlated with knee stability scores (R = 0.29). When asked about other factors preventing kneeling other than pain or discomfort, 75 % had reasons unrelated to the knee or TKA. The most common reason was 'problems with the other knee' (n = 19). CONCLUSIONS: Patients in this study were provided with education regarding their kneeling ability post TKA, yet still experienced limitations in perceived kneeling ability postoperatively. Contrary to previous research, our study suggests that factors other than patient education affect a patient's perceived kneeling ability post TKA. PMID- 27234006 TI - Interaction of Visual and Chemical CUES in Promoting Attraction of Agrilus planipennis. AB - Female emerald ash borers, Agrilus planipennis (Coleoptera: Buprestidae), emit a macrocyclic lactone, (Z)-3-dodecen-12-olide, that increases field trap captures on large-panel prism traps when co-emitted with the green leaf volatile (Z)-3 hexenol. We assessed attraction to these compounds by using visual decoy-baited branch traps, which attract males by mimicking a living female resting upon a leaf. Pairs of branch traps, with and without visual decoy beetles, were placed on green ash, Fraxinus pennsylvanica, trees, which were assigned different odor treatments: 1) no odor, 2) (Z)-3-hexenol alone, and 3) (Z)-3-hexenol-plus lactone. Male captures were positively affected by the presence of decoys and the emission of either (Z)-3-hexenol or (Z)-3-hexenol plus lactone. The decoy-baited traps with the combination of (Z)-3-hexenol plus lactone caught more males than any other treatment. Greater male captures were associated with continuing captures later in the season, suggesting that decoy and odor attractants remain attractive throughout the flight period. Female captures were not affected by the visual decoys, but odors did influence captures, with the (Z)-3-hexenol plus lactone treatment catching the greatest number of females. The rare female trap captures were negatively correlated with the more common male captures on the odorless and (Z)-3-hexenol-baited traps, but were not correlated with male captures when the lactone was added. Thus, in the absence of the lactone, the visual signal of other conspecifics can inhibit female attraction. However, the pheromone attracts both sexes independently of the visual signal on the trap. PMID- 27234009 TI - A Model of Engagement Promotion in a Professionally Facilitated Online Intervention for Couples Affected by Breast Cancer. AB - Professionally facilitated web-based interventions for couples affected by an illness such as cancer are growing in popularity. Attrition rates for such online programs, however, are substantially higher than what is observed in face-to-face therapeutic contexts, and lower levels of participant engagement are associated with poorer outcomes. In the present investigation, a task analysis was employed to develop a model of engagement promotion in an online intervention for couples affected by breast cancer called "Couplelinks." Results indicated that facilitators utilized a variety of meta-processes, such as humanizing the technology, and associated "eBehaviors," to maintain three relationships involved in promoting online engagement: (a) between the facilitator and couple; (b) between the intervention and couple; and (c) between the partners within the couple. PMID- 27234008 TI - The Effect of Menstrual Cycle on Singing Voice: A Systematic Review. AB - OBJECTIVE: Research has reported the difference in a woman's voice across the different stages of the menstrual cycle. A review of the studies in singers on the influence of menstruation on the singing voice will enable a better understanding of these changes. METHODS/DESIGN: A systematic literature search was carried out on PubMed, CINAHL, Scopus, Cochrane, and regional electronic databases. The keywords "menstrual cycle," "voice change," and "singer" were used in different combinations. Only those articles that discussed the effect of menstrual cycle on the singing voice were included in the final review. RESULTS: Six studies in the English language were identified and included in the review. Hormonal variations occur to a great extent during menstrual cycle, and these variations can influence the voice of singers. A great variability was found in the included studies. There are limited studies that have been carried out exploring the relationship between menstrual cycle and the singing voice. CONCLUSION: Even though the studies included in the review point out toward the changes in the singing voice associated with menstrual cycle, there is a need for more studies to be carried out in diverse singing populations and in different outcome measures. PMID- 27234010 TI - Ophthalmologic involvement in Leigh syndrome. PMID- 27234007 TI - The role of tissue factor and autophagy in pulmonary vascular remodeling in a rat model for chronic thromboembolic pulmonary hypertension. AB - BACKGROUND: Few reports have examined tissue factor (TF) and autophagy expression in chronic pulmonary thromboembolic hypertension (CTEPH) animal models. OBJECTIVES: To investigate the role of tissue factor (TF), autophagy and their interactions during chronic thromboembolic pulmonary hypertension (CTEPH) pathogenesis in a rat model. METHODS: Autologous blood clots were repeatedly injected into the left jugular vein of rats with injecting endogenous fibrinolysis inhibitor tranexamic acid (TXA). Mean pulmonary arterial pressure (mPAP), histopathology and TF, Beclin-1 and microtubule-associated protein 1 light chain (LC3) expression levels were detected. RESULTS: The mPAP and vessel wall area/total area (WA/TA) ratio in the experiment group increased significantly (P < 0.05). TF mRNA and protein expression levels in the experiment group increased significantly (P < 0.05). Beclin-1 and LC3B mRNA and protein expression levels were lower in the experiment group (P < 0.05). The mPAP had a positive correlation with WA/TA ratio (r = 0.955, P < 0.05). Beclin-1 and LC3B protein expression had a negative correlation with the WA/TA ratio (r = -0.963, P < 0.05, r = -0.965, P < 0.05, respectively). TF protein expression had a negative correlation with both Beclin-1 and LC3B protein expression (r = -0.995, P <0.05, r = -0972, P < 0.05, respectively). CONCLUSIONS: A rat model of CTEPH can be established by repeatedly introducing autologous blood clots into the pulmonary artery with injecting TXA. TF and autophagy may play a key role during CTEPH pathogenesis, especially in vascular remodeling. PMID- 27234011 TI - Safety and tolerability of chlorhexidine gluconate (2%) as a vaginal operative preparation in patients undergoing gynecologic surgery. AB - BACKGROUND: The use of chlorhexidine gluconate (CHG) as an intraoperative vaginal preparation has been shown to be more effective than vaginal povidone-iodine (PI) in decreasing vaginal bacterial colony counts. However, PI remains the standard vaginal preparation because of concerns of CHG's potential for vaginal irritation. The primary outcome of this study is a comparison of the rate of patient-reported vaginal irritation between 2% CHG and PI. METHODS: Consecutive patients were enrolled in a pre-post study. Group 1 consisted of consecutive patients who received PI as a vaginal preparation. Group 2 consisted of consecutive patients who received 2% CHG as a vaginal preparation. Patients used a standardized instrument to report irritation to trained nurse practitioners 1 day after surgery. RESULTS: A total of 117 patients received vaginal operative preparation during the course of the study, with 64 patients in group 1 and 53 patients in group 2. Of the patients in group 1, 60 (93.7%) reported no vaginal irritation, 3 (4.69%) reported mild irritation, and 1 (1.56%) reported moderate irritation. In group 2 (2% CHG vaginal preparation), all of the patients (100%) reported no vaginal irritation (P = .38). CONCLUSIONS: The use of 2% CHG as a vaginal operative preparation is not associated with increased vaginal irritation compared with PI in gynecologic surgery. It can safely be used, taking advantage of its efficacy in reducing vaginal bacterial colony counts. PMID- 27234012 TI - Evaluation of the ability of different detergents and disinfectants to remove and kill organisms in traditional biofilm. AB - BACKGROUND: The objective of this study was to assess the ability of different detergent and disinfectant combinations to eradicate bacteria in traditional biofilm. METHODS: Enterococcus faecalis and Pseudomonas aeruginosa were used to develop biofilm over 8 days. The biofilm on each minimum biofilm eradication concentration peg contained 8 log10 colony forming units (CFU)/cm2 of both bacteria. The detergents evaluated were as follows: Prolystica Enzymatic 2X, Prolystica Neutral 2X, Neodisher, and Endozime Bio-Clean. The disinfectants evaluated were as follows: glutaraldehyde, accelerated hydrogen peroxide, and ortho-phthalaldehyde. Biofilm removal was evaluated using viable count, protein and carbohydrate quantitation, and scanning electron microscopy. RESULTS: Only Prolystica Enzymatic 2X and Endozime Bio-Clean killed both E faecalis (3.90 log10 CFU/mL reduction) and P aeruginosa (3.96 log10 CFU/mL reduction) in suspension. None of the detergents tested could provide >1 log10 CFU/cm2 reduction for bacteria within biofilm. Any combination of detergent and high-level disinfectant reduced the level of both E faecalis and P aeruginosa within biofilm by 3-5 log10 CFU/cm2. Although the combination of Endozime Bio-Clean and glutaraldehyde provided a 6 log10 reduction, it could not eliminate both bacteria within biofilm. CONCLUSIONS: Our data indicate that if biofilm accumulates in flexible endoscope channels during repeated rounds of reprocessing, then neither the detergent nor high-level disinfectant will provide the expected level of bacterial removal or killing. PMID- 27234014 TI - Discussion. PMID- 27234013 TI - Threat captures attention, but not automatically: Top-down goals modulate attentional orienting to threat distractors. AB - The rapid orienting of attention to potential threats has been proposed to proceed outside of top-down control. However, paradigms that have been used to investigate this have struggled to separate the rapid orienting of attention (i.e. capture) from the later disengagement of focal attention that may be subject to top-down control. Consequently, it remains unclear whether and to what extent orienting to threat is contingent on top-down goals. The current study manipulated the goal-relevance of threat distractors (spiders), whilst a strict top-down attentional set was encouraged by presenting the saliently colored target and the threat distracter simultaneously for a limited time. The goal relevance of threatening distractors was manipulated by including a spider amongst the possible target stimuli (Experiment 1: spider/cat targets) or excluding it (Experiment 2: bird/fish targets). Orienting and disengagement were disentangled by cueing attention away from or towards the threat prior to its onset. The results indicated that the threatening spider distractors elicited rapid orienting of attention when spiders were potentially goal-relevant (Experiment 1) but did so much less when they were irrelevant to the task goal (Experiment 2). Delayed disengagement from the threat distractors was even more strongly contingent on the task goal and occurred only when a spider was a possible target. These results highlight the role of top-down goals in attentional orienting to and disengagement from threat. PMID- 27234015 TI - Ode to the mitral valve: "The times are a changin'". PMID- 27234016 TI - Finally, Cinderella goes to the party. PMID- 27234017 TI - Capitalizing on the mathematical foundation of cardiovascular physiology and the image processing capabilities of the human mind. PMID- 27234018 TI - Redosing antibiotics during cardiopulmonary bypass: The time is now. PMID- 27234019 TI - Transcatheter mitral regurgitation treatment: Let's learn from surgeons. PMID- 27234020 TI - Atrial arrhythmias after lung transplantation: Incidence and risk factors in 652 lung transplant recipients. AB - OBJECTIVES: Atrial arrhythmia (AA) after lung transplantation (LTx) is a potentially morbid event often associated with increased length of hospital stay. Predictors of postsurgical AA, however, are incompletely understood. We characterized the incidence and predisposing risk factors for AA in patients undergoing LTx. METHODS: A retrospective analysis of prospectively collected data was conducted to identify LTx recipients between January 2008 and October 2013. Patients were divided into 2 groups on the basis of postoperative AA development. Univariable and multivariable analyses were performed to define differences between groups and identify factors associated with AA. Survival differences were assessed by the use of competing risks methodology. RESULTS: A total of 198 of 652 (30.4%) patients developed AA at a median onset of 5 days after transplant. Increasing age (hazard ratio [HR] 1.03 per additional year, P < .001) and previous coronary artery bypass grafting (HR 2.77, P = .002) were found to be independent risk factors. Counterintuitively, patients with a medical history of AA before LTx had a lower incidence of postoperative AA. Preoperative beta blocker usage was not a significant predictor of postoperative AA. Postoperative AA was a significant predictor of long-term mortality (HR 1.63, P = .007) when we adjusted for other risk factors. CONCLUSIONS: AA is a common occurrence after LTx, occurring with greatest frequency in the first postoperative week, and results in a significant reduction in long-term survival. Increasing age and before coronary artery bypass grafting were identified as independent risk factors for AA development. Better understanding of these risk factors may improve identification of patients at heightened risk after transplantation. PMID- 27234021 TI - Ensuring compliance in hemodynamic outcomes. PMID- 27234022 TI - Single transversus abdominis muscle flap: Another possibility for large congenital diaphragmatic hernia repair. PMID- 27234023 TI - Bioprosthetic valve thrombosis: What we know and what we need to know. AB - Bioprosthetic valve thrombosis account for 11% of all reoperations for bioprosthetic valve dysfunction, and preoperative diagnosis can be made based on echocardiographic features. Early reoperation can be prevented if BPVT is identified and treated preoperatively. PMID- 27234024 TI - Outcomes of limited proximal aortic replacement for type A aortic dissection in octogenarians: What does "age" mean? PMID- 27234025 TI - Multiple arterial conduits for bypass grafting: How many are enough? PMID- 27234026 TI - Hemangioma of the cervical esophagus: A rare case of dysphagia mimicking a large esophageal polyp on endoscopy. PMID- 27234027 TI - The use of extended criteria donors decreases one-year survival in high-risk lung recipients: A review of the United Network of Organ Sharing Database. AB - OBJECTIVE: The study objective was to investigate the impact of matching donor quality to recipient severity on survival after lung transplant. METHODS: By using the Organ Procurement and Transplantation Network/United Network for Organ Sharing dataset, we analyzed lung transplant recipients from May 4, 2005, to December 31, 2012. By using adjusted Cox regressions, we identified extended criteria donors as those who had 1 or more of the following: age 65 years or more, smoking history of 20 pack-years or more, diabetes mellitus, or African American race. All other donors were considered standard donors. Recipients were categorized by lung allocation score: lung allocation score less than 70 and lung allocation score 70 or greater. Our primary outcome was 1-year survival after lung transplantation. RESULTS: Of the 10,995 lung recipients, 3792 (34%) received extended criteria donor organs. Extended criteria donors were associated with an increased hazard of death (hazard ratio [HR], 1.41; 95% confidence interval [CI], 1.26-1.56; P < .001). One-year survival was 87% and 82% (P < .001) for recipients with a lung allocation score less than 70 and 80% and 72% (P = .017) for recipients with a lung allocation score 70 or greater who received standard donor and extended criteria donor organs, respectively. In Cox regression models, the hazard of death was increased for recipients with a lung allocation score less than 70 + extended criteria donor (HR, 1.42; 95% CI, 1.27-1.60; P < .001), recipients with a lung allocation score 70 or greater + standard donor (HR, 1.37; 95% CI, 1.10-1.71; P = .005), and was the highest for recipients with a lung allocation score 70 or greater + extended criteria donor (HR, 1.81; 95% CI, 1.40 2.33; P < .001) compared with recipients with a lung allocation score less than 70 + standard donor. CONCLUSIONS: Extended criteria donors are associated with reduced 1-year survival, and recipients with a lung allocation score 70 or greater who receive extended criteria donor organs have the lowest survival. PMID- 27234028 TI - Alzheimer's disease risk genes in wild-type adult zebrafish exhibit gender specific expression changes during aging. PMID- 27234030 TI - Assessment of left ventricular diastolic function during trastuzumab treatment in patients with HER2-positive breast cancer. AB - BACKGROUND: The ratio of mitral peak velocity of early filling (E) to early diastolic mitral annular velocity (e', E/e' ratio) as estimated by tissue Doppler imaging is a noninvasive surrogate for the left ventricular diastolic function. Because diastolic dysfunction usually precedes systolic dysfunction in cardiovascular diseases, we investigated whether monitoring the E/e' ratio can help to predict the risk of trastuzumab-induced cardiotoxicity. METHODS: E/e' ratio on tissue Doppler imaging was retrospectively reviewed to assess its value for early detection of the left ventricular ejection fraction (LVEF) decline in women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer who received trastuzumab with or without cytotoxic chemotherapy. Echocardiography was performed at baseline and every 3 months after treatment began. RESULTS: Among 129 patients, LVEF declined in 25 (19 %) during trastuzumab treatment; the decline was grade 2 in 23 patients and grade 3 in 2. Elevation of the E/e' ratio to more than 15 was detected in 17 patients (13 %), 7 of whom (5.4 % of total) concurrently had LVEF decline. A weak negative correlation was observed between E/e' elevation and the worst LVEF decline (P = 0.0077), which was confirmed by multiple regression analysis (P = 0.023). E/e' ratio at baseline or 3 months after beginning trastuzumab treatment was not significantly associated with the subsequent LVEF decline. CONCLUSION: Monitoring of the left ventricular diastolic function on the basis of the E/e' ratio at baseline or 3 months after is unlikely to predict LVEF decline in patients who receive trastuzumab. However, there is a potential chronological relation between E/e' elevation and LVEF decline, implying that the degree of E/e' elevation could have a role as a surrogate marker for predicting the LVEF decline characteristic of trastuzumab-induced cardiotoxicity. PMID- 27234029 TI - Cogena, a novel tool for co-expressed gene-set enrichment analysis, applied to drug repositioning and drug mode of action discovery. AB - BACKGROUND: Drug repositioning, finding new indications for existing drugs, has gained much recent attention as a potentially efficient and economical strategy for accelerating new therapies into the clinic. Although improvement in the sensitivity of computational drug repositioning methods has identified numerous credible repositioning opportunities, few have been progressed. Arguably the "black box" nature of drug action in a new indication is one of the main blocks to progression, highlighting the need for methods that inform on the broader target mechanism in the disease context. RESULTS: We demonstrate that the analysis of co-expressed genes may be a critical first step towards illumination of both disease pathology and mode of drug action. We achieve this using a novel framework, co-expressed gene-set enrichment analysis (cogena) for co-expression analysis of gene expression signatures and gene set enrichment analysis of co expressed genes. The cogena framework enables simultaneous, pathway driven, disease and drug repositioning analysis. Cogena can be used to illuminate coordinated changes within disease transcriptomes and identify drugs acting mechanistically within this framework. We illustrate this using a psoriatic skin transcriptome, as an exemplar, and recover two widely used Psoriasis drugs (Methotrexate and Ciclosporin) with distinct modes of action. Cogena out-performs the results of Connectivity Map and NFFinder webservers in similar disease transcriptome analyses. Furthermore, we investigated the literature support for the other top-ranked compounds to treat psoriasis and showed how the outputs of cogena analysis can contribute new insight to support the progression of drugs into the clinic. We have made cogena freely available within Bioconductor or https://github.com/zhilongjia/cogena . CONCLUSIONS: In conclusion, by targeting co-expressed genes within disease transcriptomes, cogena offers novel biological insight, which can be effectively harnessed for drug discovery and repositioning, allowing the grouping and prioritisation of drug repositioning candidates on the basis of putative mode of action. PMID- 27234031 TI - Improved diagnostic yield of neuromuscular disorders applying clinical exome sequencing in patients arising from a consanguineous population. AB - Neuromuscular diseases (NMDs) include a broad range of disorders affecting muscles, nerves and neuromuscular junctions. Their overlapping phenotypes and heterogeneous genetic nature have created challenges in diagnosis which calls for the implementation of massive parallel sequencing as a candidate strategy to increase the diagnostic yield. In this study, total of 45 patients, mostly offspring of consanguineous marriages were examined using whole exome sequencing. Data analysis was performed to identify the most probable pathogenic rare variants in known NMD genes which led to identification of causal variants for 33 out of 45 patients (73.3%) in the following known genes: CAPN3, Col6A1, Col6A3, DMD, DYSF, FHL1, GJB1, ISPD, LAMA2, LMNA, PLEC1, RYR1, SGCA, SGCB, SYNE1, TNNT1 and 22 novel pathogenic variants were detected. Today, the advantage of whole exome sequencing in clinical diagnostic strategies of heterogeneous disorders is clear. In this cohort, a diagnostic yield of 73.3% was achieved which is quite high compared to the overall reported diagnostic yield of 25% to 50%. This could be explained by the consanguineous background of these patients and is another strong advantage of offering clinical exome sequencing in diagnostic laboratories, especially in populations with high rate of consanguinity. PMID- 27234032 TI - Bio-therapeutic Potential and Cytotoxicity Assessment of Pectin-Mediated Synthesized Nanostructured Cerium Oxide. AB - In the present studies, renewable and nontoxic biopolymer, pectin, was extracted from Indian red pomelo fruit peels and used for the synthesis of cerium oxide nanoparticles (CeO2-NPs) having bio-therapeutic potential. The structural information of extracted pectin was investigated by FTIR and NMR spectroscopic techniques. Physicochemical characteristics of this pectin suggested its application in the synthesis of metal oxide nanoparticles. Using this pectin as a template, CeO2-NPs were synthesized by simple, one step and eco-friendly approach. The UV-Vis spectrum of synthesized CeO2-NPs exhibited a characteristic absorption peak at wavelength 345 nm, which can be assigned to its intrinsic band gap (3.59 eV) absorption. Photoluminescence measurements of CeO2-NPs revealed that the broad emission was composed of seven different bands. FTIR analysis ensured involvement of pectin in the formation and stabilization of CeO2-NPs. FT Raman spectra showed a sharp Raman active mode peak at 461.8 cm-1 due to a symmetrical stretching mode of Ce-O vibration. DLS, FESEM, EDX, and XRD analysis showed that the CeO2-NPs prepared were polydispersed, spherical shaped with a cubic fluorite structure and average particle size <=40 nm. These CeO2-NPs displayed broad spectrum antimicrobial activity, antioxidant potential, and non cytotoxic nature. PMID- 27234033 TI - Smoking History as a Predictor of Pemetrexed Monotherapy in Patients with Non Squamous Non-Small Cell Lung Cancer. AB - BACKGROUND: Pemetrexed monotherapy has come to be recognized as the standard of care for second-line therapy of non-squamous non-small cell lung cancer (NSCLC). Thymidylate synthase (TS) expression is recognized as a potential predictor of the response to pemetrexed-based chemotherapy in patients with advanced NSCLC. The purpose of this study was to identify useful predictors of the response to pemetrexed other than TS expression. METHODS: The records of non-squamous NSCLC patients without driver mutations who received pemetrexed monotherapy as a second or later line of chemotherapy at Kitasato University Hospital between March 2009 and October 2015 were retrospectively reviewed, and the treatment outcomes were evaluated. RESULTS: In the 116 patients with non-squamous NSCLC, the overall response rate and progression-free survival (PFS) were 10.3% and 2.1 months, respectively. The disease control rate and PFS differed significantly among current smokers and never-smokers/former light smokers (44.9 vs. 65.8%, and 1.8 vs. 4.0 months, respectively). Furthermore, multivariate analysis identified Eastern Cooperative Oncology Group Performance Status and smoking status as independent predictors of the PFS. CONCLUSION: The clinical data obtained in this study may provide a valuable basis for the use of smoking status as a predictor of pemetrexed monotherapy in wild-type NSCLC patients. PMID- 27234034 TI - Seroepidemiology of human Toxocara and Ascaris infections in the Netherlands. AB - Toxocara canis, Toxocara cati and Ascaris suum are worldwide-distributed zoonotic roundworms of dogs, cats and pigs, respectively. The epidemiology of these parasites in developed countries is largely unclear. Two countrywide cross sectional serosurveys were therefore conducted in the Netherlands in 1995/1996 and 2006/2007 to investigate the prevalence, trends and risk factors for human Toxocara and Ascaris infections in the general population. The Netherlands is characterized by high pig production, freedom from stray dogs and virtual absence of autochthonous infections with the human-adapted roundworm Ascaris lumbricoides. Over the 10 years between the two serosurveys, Toxocara seroprevalence decreased significantly from 10.7 % (n = 1159) to 8.0 % (n = 3683), whereas Ascaris seroprevalence increased significantly from 30.4 % (n = 1159) to 41.6 % (n = 3675), possibly reflecting concomitant improvements in pet hygiene management and increased exposure to pig manure-contaminated soil. Increased anti-Toxocara IgGs were associated with increasing age, male gender, contact with soil, ownership of cats, cattle or pigs, hay fever, low education, high income and non-Western ethnic origin. Increased anti-Ascaris IgGs were associated with increasing age, owning pigs, low education, childhood geophagia and non-Dutch ethnic origin. Besides identifying specific groups at highest risk of Toxocara and Ascaris infections, our results suggest that these infections mainly occur through environmental, rather than foodborne, routes, with direct contact with soil or cat and pig ownership being potentially modifiable exposures. PMID- 27234035 TI - Impact of experimental flooding on larvae and pupae of dung-breeding Culicoides. AB - Culicoides biting midges (Diptera: Ceratopogonidae) spend the greatest part of their life in the larval stage. However, knowledge on the immature stages and the impact of abiotic factors on their development is still poor. Therefore, we investigated the effect of flooding on the larvae and pupae of Culicoides chiopterus (Meigen, 1830) and C. dewulfi Goetghebuer, 1936. In water, the larvae of both species showed head-to-tail flexions and sinuous flexions, at slow rates, but were not able to swim. Flooding of larvae for 24 h did not affect the number of emerging adults; flooding of pupae significantly reduced the emergence rate of C. chiopterus, compared to the control group, while C. dewulfi was not affected. Pupae were not able to float and no pupae survived flooding for 10 days. After flooding of larvae for 10 days, 50 % of C. chiopterus and 4 % of C. dewulfi completed the pre-adult development. During this treatment, 84 % of C. chiopterus and 48 % of C. dewulfi larvae pupated in water. PMID- 27234036 TI - Integrated Dual Disorder Treatment Implementation in a Large State Sample. AB - Individuals with co-occurring illnesses are at risk for poor outcomes related to criminal justice, hospitalization, housing, and employment. High fidelity evidence-based models, including integrated dual disorder treatment (IDDT), are associated with significant outcome improvements. A descriptive analysis of secondary datasets including the full sample of IDDT fidelity reviews completed from 2006 to 2012 in one state was completed. Total IDDT fidelity significantly improved from baseline fidelity review (68) to second review (40) [t(38) = 35.00, p < .001], and from second review to third review (13) [t(12) = 22.60, p < .001], with adequate inner-rater reliability by the second review. Individual items that were lower across reviews included practice penetration and family interventions, and higher individual items included multi-disciplinary team, integrated treatment specialist, and time-unlimited services, and treatment measures are higher than organizational measures in baseline and subsequent reviews. In this large state-wide sample, IDDT took time to implement, and improved fidelity occurred from baseline to third review, and variance between components of the practice was significant. PMID- 27234037 TI - Impact of malnutrition on cardiac autonomic modulation in children. AB - OBJECTIVE: To compare the autonomic behavior between malnourished children and a control group using analysis of heart rate variability (HRV). METHOD: Data were analyzed from 70 children who were divided into two groups: malnourished and eutrophic, according to the Z-score nutritional status for height and age. For analysis of HRV indices, heart rate was recorded beat to beat with the child in the supine position for 20min. The analysis of these indices was performed using linear methods, analyzed in the time and frequency domains. Student's t-test for unpaired data and the Mann-Whitney test were used to compare variables between groups, with a significance level of 5%. RESULTS: A reduction in systolic and diastolic blood pressure and an increase in heart rate were found in malnourished children compared to eutrophic children. The HRV indices suggested that malnourished children present reductions in both sympathetic and parasympathetic autonomic nervous system activity. The SDNN, rMSSD, NN50, pNN50, SD1, SD2, TINN, LF (ms2), and HF (ms2) indices were lower in malnourished children. CONCLUSION: Malnourished children present changes in cardiac autonomic modulation, characterized by reductions in both sympathetic and parasympathetic activity, as well as increased heart rate and decreased blood pressure. PMID- 27234039 TI - Computational fluid dynamics-based study of possibility of generating pulsatile blood flow via a continuous-flow VAD. AB - Until recent years, it was almost beyond remedy to save the life of end-stage heart failure patients without considering a heart transplant. This is while the need for healthy organs has always far exceeded donations. However, the evolution of VAD technology has certainly changed the management of these patients. Today, blood pumps are designed either pulsatile flow or continuous flow, each of which has its own concerns and limitations. For instance, pulsatile pumps are mostly voluminous and hardly can be used for children. On the other hand, the flow generated by continuous-flow pumps is in contrast with pulsatile flow of the natural heart. In this project, having used computational fluid dynamics, we studied the possibility of generating pulsatile blood flow via a continuous-flow blood pump by adjusting the rotational speed of the pump with two distinct patterns (sinusoidal and trapezoidal), both of which have been proposed and set based on physiological needs and blood flow waveform of the natural heart. An important feature of this study is setting the outlet pressure of the pump similar to the physiological conditions of a patient with heart failure, and since these axial pumps are sensitive to outlet pressures, more secure and reliable results of their performance are achieved. Our results show a slight superiority of a sinusoidal pattern compared to a trapezoidal one with the potential to achieve an adequate pulsatile flow by precisely controlling the rotational speed. PMID- 27234038 TI - Temporal and spatial evolution of maternal and neonatal mortality rates in Brazil, 1997-2012. AB - OBJECTIVE: Maternal and neonatal mortality are important public health issues in low-income countries. This study evaluated spatial and temporal maternal and neonatal mortality trends in Brazil between 1997 and 2012. METHODS: This study employed spatial analysis techniques using death records from the mortality information system. Maternal mortality rates per 100,000 and neonatal mortality rates (early and late) per 1000 live births were calculated by state, region, and period (1997-2000, 2001-2004, 2005-2008, and 2009-2012). Multivariate negative binomial models were used to explain the risk of death. RESULTS: The mean Brazilian maternal mortality rate was 55.63/100,000 for the entire 1997-2012 period. The rate fell 10% from 1997-2000 (58.92/100,000) to 2001-2004 (52.77/100,000), but later increased 11% during 2009-2012 (58.69/100,000). Early and late neonatal mortality rates fell 33% (to 7.36/1000) and 21% (to 2.29/1000), respectively, during the 1997-2012 period. Every Brazilian region witnessed a drop in neonatal mortality rates. However, maternal mortality increased in the Northeast, North, and Southeast regions. CONCLUSION: Brazil's neonatal mortality rate has improved in recent times, but maternal mortality rates have stagnated, failing to meet the Millennium Development Goals. Public policies and intersectoral efforts may contribute to improvements in these health indicators. PMID- 27234040 TI - Right hemicolectomy using ileocecal pedicel flap-a new technique for ileocecal sphincter preservation in complex Crohn's disease with right sided colon cancer. PMID- 27234041 TI - Impact of age on the prognostic value of number of lymph nodes retrieved in patients with stage II colorectal cancer. AB - PURPOSE: A small number of lymph nodes retrieved (NLNR) is a known risk factor in stage II colorectal cancer. NLNR is influenced by age, but little is known about whether the impact of small NLNR on survival differs with age. This retrospective study sought to determine such impact in elderly patients with stage II colorectal cancer. METHODS: We reviewed data for 2100 patients with stage II colorectal cancer who underwent surgery without adjuvant chemotherapy between January 1997 and December 2003. The optimal cutoff value of NLNR for survival was determined, and the impact of small NLNR on survival was analyzed. The association between age and NLNR was evaluated. The relation between age and risk of small NLNR with respect to survival was then assessed to determine the impact of small NLNR on elderly patients' survival. RESULTS: The optimal cutoff value of NLNR was determined as 6. The small NLNR group (SNG) showed significantly worse prognosis than the large NLNR group (LNG) (p < 0.001). Age, surgical method, and scope of lymph node dissection were significantly associated with NLNR. A potential interaction was noted between age and risk of small NLNR in relation to relapse-free survival (RFS). Five-year RFS was significantly worse in SNG than in LNG for elderly patients (41.7 and 76.4 %, respectively; p < 0.001) but not for non-elderly patients (75.9 and 84.6 %, respectively; p = 0.083). CONCLUSIONS: NLNR <6 was identified to be an important prognostic factor for elderly patients with stage II colorectal cancer. PMID- 27234042 TI - Literature review of the role of lateral internal sphincterotomy (LIS) when combined with excisional hemorrhoidectomy. AB - BACKGROUND AND AIM: Pain following hemorrhoidectomy is a distressing sequel to the procedure. Various methods have been used to alleviate post-hemorrhoidectomy pain; among these methods is the lateral internal sphincterotomy (LIS). This review aimed to analyze all studies that evaluated the impact of LIS on the outcome of excisional hemorrhoidectomy. PATIENTS AND METHODS: Seventeen studies were included after organized search of the literature using electronic databases including PubMed/Medline and EMBASE. The studies included comprised 2180 patients with median age of 44 years. Variables selected for the review comprised patients' characteristics, postoperative pain assessment, analgesic consumption, and complications as fecal incontinence (FI), urinary retention, and anal stenosis. RESULTS: Overall, 933 (42.7 %) patients underwent LIS. Almost all studies assessing postoperative pain reported lower pain scores and less need for postoperative analgesia among patients who underwent LIS in comparison with patients who did not have LIS. Eleven of 13 studies that assessed continence state postoperatively reported higher rates of FI among patients who had LIS with a median rate of 7.7 % versus 1.25 % for patients who did not have LIS. Incidence of urinary retention after LIS ranged from 0 to 60 %. Anal stenosis occurred in 0 14.5 % of patients who had LIS versus 0-36.4 % in patients without LIS. CONCLUSION: LIS effectively reduced postoperative pain and need for analgesics following excisional hemorrhoidectomy. LIS also managed to decrease incidence of postoperative urinary retention and anal stenosis significantly. The negative aspect of adding LIS to excisional hemorrhoidectomy was developing minor FI after surgery which was temporary in duration. PMID- 27234046 TI - Hepatitis B virus enhances cisplatin-induced hepatotoxicity via a mechanism involving suppression of glucose-regulated protein of 78 Kda. AB - Cisplatin is a classical platinum-based chemotherapeutic drug used in the treatment of many cancer types, including hepatocellular carcinoma (HCC). The application of cisplatin is significantly limited by its toxicity, which may be affected by various biological factors. Persistence of Hepatitis B virus (HBV) infection leads to HCC development and may be associated with higher incidence of severe hepatitis during chemotherapy. However, whether HBV alters the susceptibility of hepatocytes to cisplatin remains poorly understood. Here, we demonstrate that HBV transfection enhanced cisplatin-induced hepatotoxicity via a mechanism involving suppression of glucose-regulated protein of 78 KDa (Grp78), a major stress-induced chaperone that localizes to the endoplasmic reticulum. Silencing Grp78 gene increased the susceptibility of HepG2 to cisplatin by activating caspase-3. Grp78 expression was down-regulated by HBV infection both in vitro and in liver tissues of patients. We compared the cisplatin sensitivity of hepatoma cells either expressing (HepG2.2.15 cells) or not expressing the entire Hepatitis B Virus genome (HepG2). HepG2.2.15 cells showed increased sensitivity to cisplatin and a higher apoptosis rate. Overexpression of Grp78 counteracted the increase of sensitivity of HepG2.215 cells to cisplatin. Furthermore, we found that HBV disrupted Grp78 synthesis in response to cisplatin stimulation, which may trigger severe and prolonged endoplasmic reticulum (ER) stress that can induce cellular apoptosis. Our findings provide new information into the effect of HBV in the modulation of Grp78 expression, and, consequently on cisplatin-induced hepatotoxicity during viral infection. PMID- 27234045 TI - Incidence of urinary tract infections and antibiotic resistance in the outpatient setting: a cross-sectional study. AB - PURPOSE: In 2012-2013, a cross-sectional survey was conducted in women visiting a general practitioner for urinary tract infection (UTI), to estimate the annual incidence of UTIs due to antibiotic-resistant Escherichia coli (E. coli). METHODS: A sampling design (stratification, stages and sampling weights) was taken into account in all analyses. Urine analyses were performed for each woman and centralised in one laboratory. RESULTS: Among 538 included women, urine culture confirmed UTI in 75.2 % of cases. E. coli represented 82.8 % of species. Among E. coli, resistance (I + R) was most common to amoxicillin [38 % (95 % confidence interval 31.1-44.5)] and to trimethoprim/sulfamethoxazole [18.1 % (12.0-24.1)]. Resistance to ciprofloxacin and cefotaxime was lower [1.9 % in both cases, (0.3-3.5)], as it was for nitrofurantoin [0.4 (0-1.0)] and fosfomycin (0). Extended-spectrum beta-lactamase (ESBL) represented 1.6 % of E. coli (0.2-2.9). Annual incidence rate of confirmed UTI was estimated at 2400 per 100,000 women (1800-3000). Incidence rates of UTI due to fluoroquinolone-resistant and ESBL producing E. coli were estimated at 102 per 100,000 women (75-129) and at 32 (24 41), respectively. CONCLUSIONS: ESBL had been found in a community population, and even though the rate was low, it represents a warning and confirms that surveillance should continue. PMID- 27234044 TI - Environmental Health and Long Non-coding RNAs. AB - An individual's risk of developing a common disease typically depends on an interaction of genetic and environmental factors. Epigenetic research is uncovering novel ways through which environmental factors such as diet, air pollution, and chemical exposure can affect our genes. DNA methylation and histone modifications are the most commonly studied epigenetic mechanisms. The role of long non-coding RNAs (lncRNAs) in epigenetic processes has been more recently highlighted. LncRNAs are defined as transcribed RNA molecules greater than 200 nucleotides in length with little or no protein-coding capability. While few functional lncRNAs have been well characterized to date, they have been demonstrated to control gene regulation at every level, including transcriptional gene silencing via regulation of the chromatin structure and DNA methylation. This review aims to provide a general overview of lncRNA function with a focus on their role as key regulators of health and disease and as biomarkers of environmental exposure. PMID- 27234048 TI - Blockade of store-operated calcium entry alleviates high glucose-induced neurotoxicity via inhibiting apoptosis in rat neurons. AB - Altered store-operated calcium entry (SOCE) has been suggested to be involved in many diabetic complications. However, the association of altered SOCE and diabetic neuronal damage remains unclear. This study aimed to investigate the effects of altered SOCE on primary cultured rat neuron injury induced by high glucose. Our data demonstrated that high glucose increased rat neuron injury and upregulated the expression of store-operated calcium channel (SOC). Inhibition of SOCE by a pharmacological inhibitor and siRNA knockdown of stromal interaction molecule 1 weakened the intracellular calcium overload, restored mitochondrial membrane potential, downregulated cytochrome C release and inhibited cell apoptosis. As well, treatment with the calcium chelator BAPTA-AM prevented cell apoptosis by ameliorating the high glucose-increased intracellular calcium level. These findings suggest that SOCE blockade may alleviate high glucose-induced neuronal damage by inhibiting apoptosis. SOCE might be a promising therapeutic target in diabetic neurotoxicity. PMID- 27234047 TI - Penetration and decontamination of americium-241 ex vivo using fresh and frozen pig skin. AB - Skin contamination is one of the most probable risks following major nuclear or radiological incidents. However, accidents involving skin contamination with radionuclides may occur in the nuclear industry, in research laboratories and in nuclear medicine departments. This work aims to measure the penetration of the radiological contaminant Americium (241Am) in fresh and frozen skin and to evaluate the distribution of the contamination in the skin. Decontamination tests were performed using water, Fuller's earth and diethylene triamine pentaacetic acid (DTPA), which is the recommended treatment in case of skin contamination with actinides such as plutonium or americium. To assess these parameters, we used the Franz cell diffusion system with full-thickness skin obtained from pigs' ears, representative of human skin. Solutions of 241Am were deposited on the skin samples. The radioactivity content in each compartment and skin layers was measured after 24 h by liquid scintillation counting and alpha spectrophotometry. The Am cutaneous penetration to the receiver compartment is almost negligible in fresh and frozen skin. Multiple washings with water and DTPA recovered about 90% of the initial activity. The rest remains fixed mainly in the stratum corneum. Traces of activity were detected within the epidermis and dermis which is fixed and not accessible to the decontamination. PMID- 27234049 TI - In vitro - In vivo metabolism and pharmacokinetics of picroside I and II using LC ESI-MS method. AB - Picroside I and II, iridoid glycosides, are the major active markers of roots and rhizomes of Picrorhiza kurroa (family: Scrophulariaceae). The rhizomes of P. kurroa have been traditionally used to treat worms, constipation, low fever, scorpion sting, asthma and ailments affecting the liver. Various Ayurvedic and herbal preparations are available in the market which contains P. kurroa e.g. Arogyavadhini vati, Tiktadi kwath, Picrolax capsules and suspension. These preparations are used without any significant pharmacokinetics data. Previously, we have reported that oral bioavailability of picroside I and II is low. Most of the iridoid glycosides are primarily metabolized by intestinal microbial flora. So, it is necessary to determine the metabolic profile of picroside I and II and check the correlation with lower bioavailability. Therefore, this study was designed to check metabolic (in vitro and in vivo) profile along with pharmacokinetic profile of picroside I and II. For this, a sensitive and selective LC-ESI-MS method was developed and validated for simultaneous determination of picroside I and II in rat plasma. Chromatographic separations were performed on C18 column. The mobile phase consisted of acetonitrile: 10 mM ammonium acetate buffer [90:10 v/v], pH 3.5. In-vitro Metabolic study was performed on rat liver microsomes and primary hepatocytes. In-vivo pharmacokinetic and metabolic profile of picroside I and II was generated after oral administration of Kutkin (mixture of picroside I and II) to Sprague-Dawley rats. Various pharmacokinetic parameters viz. Cmax, Tmax, AUC(0-t) were determined. In metabolic study, eight metabolites of picroside I and six metabolites of picroside II were identified in vitro, out of which four metabolites for each picroside I and picroside II were identified in vivo. PMID- 27234050 TI - Extracorporeal shock wave lithotripsy and ERCP to remove a fractured guidewire in the pancreatic duct in a patient with chronic pancreatitis and pancreatic duct stones. PMID- 27234051 TI - Balloon enteroscopy-assisted ERCP and cholangioscopy. PMID- 27234052 TI - Treatment of gastrocutaneous fistula after percutaneous gastrostomy placement. PMID- 27234053 TI - Endoscopic closure of spontaneous idiopathic esophagobronchial fistula. PMID- 27234054 TI - A modified EUS-guided rendezvous technique with needle-knife sphincterotomy over a transpapillary bile duct wire. PMID- 27234055 TI - Ramakant Maganlal Rash. PMID- 27234058 TI - Editorial. PMID- 27234059 TI - Neuronal endocytosis of anti-ganglioside antibodies: implications for Guillain Barre syndrome. PMID- 27234057 TI - Working memory performance is related to intrinsic resting state functional connectivity changes in community-dwelling elderly cohort. AB - Characterization of normal age-related changes in resting state brain networks associated with working memory performance is a major prerequisite for studying neurodegenerative diseases. The aim of this study was to investigate the relationship between performing a working memory task (under MRI) and resting state brain networks in a large cohort of healthy elderly subjects (n=337). Functional connectivity and interactions between networks were assessed within the default mode (DMN), salience (SN), and right and left central executive (CEN) networks in two groups of subjects classed by their performance (low and high). The low performance group showed lower functional connectivity in both the DMN and SN, and higher functional connectivity in the right and left CEN compared to the high performance group. Overall the functional connectivity within the DMN and the CEN were correlated. The lower functional connectivity within the DMN and SN in the low performance group is suggestive of altered attentional and memory processes and/or altered motivation. The higher functional connectivity within the CEN could be related to compensatory mechanisms, without which the subjects would have even lower performances. The correlation between the DMN and CEN suggests a modulation between the lower functional connectivity within the DMN and the higher functional connectivity within the CEN when performance is reduced. Finally, this study suggests that performance modifications in healthy elderly subjects are associated with reorganization of functional connectivity within the DMN, SN, and CEN. PMID- 27234056 TI - Fine-Tuning of CD8(+) T Cell Mitochondrial Metabolism by the Respiratory Chain Repressor MCJ Dictates Protection to Influenza Virus. AB - Mitochondrial respiration is regulated in CD8(+) T cells during the transition from naive to effector and memory cells, but mechanisms controlling this process have not been defined. Here we show that MCJ (methylation-controlled J protein) acted as an endogenous break for mitochondrial respiration in CD8(+) T cells by interfering with the formation of electron transport chain respiratory supercomplexes. Metabolic profiling revealed enhanced mitochondrial metabolism in MCJ-deficient CD8(+) T cells. Increased oxidative phosphorylation and subcellular ATP accumulation caused by MCJ deficiency selectively increased the secretion, but not expression, of interferon-gamma. MCJ also adapted effector CD8(+) T cell metabolism during the contraction phase. Consequently, memory CD8(+) T cells lacking MCJ provided superior protection against influenza virus infection. Thus, MCJ offers a mechanism for fine-tuning CD8(+) T cell mitochondrial metabolism as an alternative to modulating mitochondrial mass, an energetically expensive process. MCJ could be a therapeutic target to enhance CD8(+) T cell responses. PMID- 27234060 TI - Seizure prediction: making mileage on the long and winding road. PMID- 27234061 TI - Riddle is to conundrum as the frontal pole is to...? PMID- 27234062 TI - Multiple cues support speech perception. PMID- 27234064 TI - A phase I dose escalation trial of AXP107-11, a novel multi-component crystalline form of genistein, in combination with gemcitabine in chemotherapy-naive patients with unresectable pancreatic cancer. AB - BACKGROUND: AXP107-11 is a novel, multi-component crystalline form of the naturally occurring compound genistein. AXP107-11 has improved physiochemical properties and oral bioavailability compared to the natural form of genistein, and it is possible that combining AXP107-11 with chemotherapy may increase the effect and reduce chemoresistance. The purpose of this dose escalation phase Ib study was to assess the safety, maximum tolerated dose (MTD) and pharmacokinetics (PK) of AXP107-11 in combination with gemcitabine in treatment-naive patients with inoperable pancreatic carcinoma. PATIENTS AND METHODS: AXP107-11 was given orally in escalating doses (400 mg-1600 mg daily) in combination with standard gemcitabine treatment (1000 mg/m(2)/week) for the first seven of eight weeks and thereafter for a maximum of four * four-week treatment cycles. PK, safety, MTD and efficacy of AXP107-11 in combination with gemcitabine were evaluated. RESULTS: Sixteen patients were enrolled and received AXP107-11. The maximum concentration in serum of unconjugated (free) genistein was 1 MUM. Neither dose limiting toxicities (DLTs) nor signs of hematological or non-hematological toxicities related to AXP107-11 were observed over a period ranging from 0.7 to 13.2 months. The median overall survival time was 4.9 months (range 1.5-19.5 months). Seven patients (44%) survived longer than six months and 19% were alive at the one-year follow-up. CONCLUSION: Treatment of pancreatic cancer patients with AXP107-11 in combination with gemcitabine resulted in a favorable PK-profile with high serum levels without signs of either hematological or non-hematological toxicity. Accordingly, we suggest further studies with AXP107-11 in pancreatic cancer patients. PMID- 27234063 TI - Genetic structure of phenotypic robustness in the collaborative cross mouse diallel panel. AB - Developmental stability and canalization describe the ability of developmental systems to minimize phenotypic variation in the face of stochastic micro environmental effects, genetic variation and environmental influences. Canalization is the ability to minimize the effects of genetic or environmental effects, whereas developmental stability is the ability to minimize the effects of micro-environmental effects within individuals. Despite much attention, the mechanisms that underlie these two components of phenotypic robustness remain unknown. We investigated the genetic structure of phenotypic robustness in the collaborative cross (CC) mouse reference population. We analysed the magnitude of fluctuating asymmetry (FA) and among-individual variation of cranial shape in reciprocal crosses among the eight parental strains, using geometric morphometrics and a diallel analysis based on a Bayesian approach. Significant differences among genotypes were found for both measures, although they were poorly correlated at the level of individuals. An overall positive effect of inbreeding was found for both components of variation. The strain CAST/EiJ exerted a positive additive effect on FA and, to a lesser extent, among individual variance. Sex- and other strain-specific effects were not significant. Neither FA nor among-individual variation was associated with phenotypic extremeness. Our results support the existence of genetic variation for both developmental stability and canalization. This finding is important because robustness is a key feature of developmental systems. Our finding that robustness is not related to phenotypic extremeness is consistent with theoretical work that suggests that its relationship to stabilizing selection is not straightforward. PMID- 27234065 TI - Morus alba extract modulates blood pressure homeostasis through eNOS signaling. AB - SCOPE: Morus alba is a promising phytomedicine cultivated in oriental countries that is extensively used to prevent and treat various cardiovascular problems. To date, despite its beneficial effects, the molecular mechanisms involved remain unclear. Thus, we investigate the vascular and haemodynamic effects of Morus alba extract in an experimental model focusing our attention on the molecular mechanisms involved. METHODS AND RESULTS: Through vascular reactivity studies, we demonstrate that Morus alba extract evokes endothelial vasorelaxation through a nitric oxide-dependent pathway. Our molecular analysis highlights an increase in endothelial nitric oxide synthase (eNOS) phosphorylation. In vivo administration of Morus alba extract reduces blood pressure levels exclusively in wild-type mice, whereas it fails to evoke any haemodynamic effects in eNOS-deficient mice. Molecular analyses revealed that its beneficial action on vasculature is mediated by the activation of two important proteins that act as stress sensors and chaperones: PERK and heat shock protein 90. Finally, Morus alba extract exerts antihypertensive action in an experimental model of arterial hypertension. CONCLUSION: Through its action on eNOS signaling, Morus alba extract could act as a food supplement for the regulation of cardiovascular system, mainly in clinical conditions characterized by eNOS dysfunction, such as arterial hypertension. PMID- 27234126 TI - Massive hemoperitoneum due to a ruptured umbilical vein in a cirrhotic patient. PMID- 27234127 TI - Intraluminal leiomyosarcoma of the common femoral vein. PMID- 27234128 TI - Spontaneous rupture of a splenic aneurysm in classic Ehlers-Danlos syndrome. PMID- 27234129 TI - Acute pancreatitis secondary to periampullary duodenal diverticulitis. PMID- 27234130 TI - Follistatin-like 1 promotes osteoclast formation via RANKL-mediated NF-kappaB activation and M-CSF-induced precursor proliferation. AB - Follistatin-like 1 (FSTL1) functions as a pivotal modulator of inflammation and is implicated in many inflammatory diseases such as rheumatoid arthritis. Here, we report that FSTL1 is strongly upregulated and secreted during osteoclast differentiation of bone marrow-derived macrophages (BMMs) and that FSTL1 positively regulates osteoclast formation induced by RANKL and M-CSF. The overexpression of FSTL1 or treatment with recombinant FSTL1 (rFSTL1) in BMMs enhances the formation of multinuclear osteoclasts and the induction of c-Fos and NFATc1, transcription factors important for osteoclastogenesis. Conversely, knockdown of FSTL1 using a small hairpin RNA suppresses osteoclast formation and the expression of these transcription factors. While FSTL1 does not affect RANKL stimulated activation of p38 MAPK, phosphorylation of IkappaBalpha, JNK, and ERK were increased by overexpression or addition of rFSTL1. Furthermore, rFSTL1 increased RANKL-induced NF-kappaB transcriptional activity in a dose-dependent manner. In addition to its role in osteoclastogenesis, FSTL1 promotes proliferation of osteoclast precursors by increasing M-CSF-induced ERK activation, which in turn leads to accelerated osteoclast formation. Together, our findings demonstrate that FSTL1 is a secreted osteoclastogenic factor that plays a critical role in osteoclast formation via the NF-kappaB and MAPKs signaling pathways. PMID- 27234131 TI - Porphyromonas gingivalis infected macrophages upregulate CD36 expression via ERK/NF-kappaB pathway. AB - CD36, a scavenger receptor, plays an important role in the progression of atherosclerosis through its interaction with oxidized low-density lipoprotein (ox LDL). Porphyromonas gingivalis (P. gingivalis, Pg) has been shown to promote macrophage-derived foam cell formation by affecting the expression of CD36. However, the regulatory role of CD36 in macrophages infected with Pg remains largely unknown. Therefore, the aim of the present study was to explore the molecular mechanism of Pg induced CD36 expression in macrophages. Our results showed that Pg promoted ox-LDL uptake by macrophages and the formation of foam cells. Pg infection increased CD36 mRNA and protein levels in ox-LDL-untreated macrophages. Moreover, small interferon RNA (siRNA) targeting CD36 significantly reduced foam cell formation induced by Pg. Additionally, Pg stimulated nuclear translocation of p65, which directly bound to the promoters of CD36 to facilitate its transcription. Inhibition of p65, NF-kappaB or ERK1/2 blocked Pg-induced CD36 production; whereas, overexpression of NF-kappaB subunits p65 and p50 upregulated CD36. Furthermore, Ras inhibitors significantly attenuated ERK1/2 activation and CD36 expression. Taken together, the data indicated that stimulation of the ERK/NF-kappaB pathway by Pg led to transactivation of the CD36 promoters, thereby upregulating CD36 expression in the infected macrophages. These findings may help design new treatment strategies in atherosclerosis. PMID- 27234132 TI - Surface area-volume ratios in insects. AB - Body mass, volume and surface area are important for many aspects of the physiology and performance of species. Whereas body mass scaling received a lot of attention in the literature, surface areas of animals have not been measured explicitly in this context. We quantified surface area-volume (SA/V) ratios for the first time using 3D surface models based on a structured light scanning method for 126 species of pollinating insects from 4 orders (Diptera, Hymenoptera, Lepidoptera, and Coleoptera). Water loss of 67 species was measured gravimetrically at very dry conditions for 2 h at 15 and 30 degrees C to demonstrate the applicability of the new 3D surface measurements and relevance for predicting the performance of insects. Quantified SA/V ratios significantly explained the variation in water loss across species, both directly or after accounting for isometric scaling (residuals of the SA/V ~ mass2/3 relationship). Small insects with a proportionally larger surface area had the highest water loss rates. Surface scans of insects to quantify allometric SA/V ratios thus provide a promising method to predict physiological responses, improving the potential of body mass isometry alone that assume geometric similarity. PMID- 27234133 TI - Prophylactic neuroprotective efficiency of co-administration of Ginkgo biloba and Trifolium pretense against sodium arsenite-induced neurotoxicity and dementia in different regions of brain and spinal cord of rats. AB - The present study was carried out to evaluate the potential protective role of co administration of Ginkgo biloba, Trifolium pretenseagainst sodium arsenite induced neurotoxicity in different parts of brain (Cerebral cortex, Hippocampus, striatum and Hind brain) and in the spinal cord of rats. Sodium arsenite caused impairment in the acquisition and learning in all the behavioral tasks and caused significant increase in tumor necrosis factor-alpha,thiobarbituric acid-reactive substances andlipid profile, while caused significant decrease in glutathione, total thiol content, total antioxidant capacity, acetylcholinesterase, monoamine oxidase and ATPases activities. These results were confirmed by histopathological, fluorescence and scanning electron microscopy examination of different regions of brain. From these results sodium arsenite-induced neurodegenerative disorder in different regions of brain and spinal cord and this could be mediated through modifying the intracellular brain ions homeostasis, cholinergic dysfunction and oxidative damage. The presence of Ginkgo biloba and/orTrifolium pretense with sodium arsenite minimized its neurological damages. It was pronounced that using Ginkgo biloba and Trifolium pretense in combination was more effective as protective agents compared to use eachone of them alone. PMID- 27234135 TI - In vitro assays in natural products research - a matter of concentration and relevance to in vivo administration using resveratrol, alpha-mangostin/gamma mangostin and xanthohumol as examples. AB - Herbal or botanical dietary supplements are an ever increasingly popular category of products in the United States and around the world. In vitro data can provide meaningful insight into the potential target and mechanism of action for a proposed active compound but may also be misused to promote a supplement to consumers with unverified health claims. In vitro data need to be considered alongside pharmacokinetic and pharmacodynamic data in preclinical animal and clinical human trials. While considerable activity of compounds and extracts in vitro may lead to further testing in vivo, in many instances, concentrations tested in cell lines or isolated targets are not achievable at the target site in vivo. Thus, whether the in vitro data are relevant to humans after oral administration is questionable. This review will discuss this discrepancy using in vitro and in vivo data of resveratrol, xanthones (alpha-mangostin and gamma mangostin) and xanthohumol. PMID- 27234136 TI - Pathogenesis of thyroid autoimmune disease: the role of cellular mechanisms. AB - Hashimoto's thyroiditis (HT) and Graves' disease (GD) are two very common organ specific autoimmune diseases which are characterized by circulating antibodies and lymphocyte infiltration. Although humoral and cellular mechanisms have been classically considered separately in the pathogenesis of autoimmune thyroid diseases (AITD), recent research suggests a close reciprocal relationship between these two immune pathways. Several B- and T-cell activation pathways through antigen-presenting cells (APCs) and cytokine production lead to specific differentiation of T helper (Th) and T regulatory (Treg) cells. This review will focus on the cellular mechanisms involved in the pathogenesis of AITD. Specifically, it will provide reasons for discarding the traditional simplistic dichotomous view of the T helper type 1 and 2 pathways (Th1/Th2) and will focus on the role of the recently characterized T cells, Treg and Th17 lymphocytes, as well as B lymphocytes and APCs, especially dendritic cells (DCs). PMID- 27234137 TI - The value of surgeon-specific outcome data: results of a questionnaire. AB - OBJECTIVES: The publication of surgeon-specific data has been controversial. To assess the profession's opinion, a forum was organized at the 2015 EACTS meeting followed by a questionnaire of the value of surgeon-specific outcome and its impact. METHODS: A series of presentations were made including assessments of quality and safety in one major European country, the relationship between volume and outcome, the role of guidelines, the effect of publication of results on training, and discussion for and against publication of surgeon-specific data. A questionnaire was given to all attendees at the forum on the value of surgeon specific data and their impact on the specialty. RESULTS: The questionnaire was completed by 118 attendees. Of the total, 69% felt that mortality is a surrogate for quality and that it should be reported at the hospital and unit level as opposed to the individual surgeon level, but 81% wished there were different criteria for quality outcome. Of the total, 91% felt that the individual surgeons' data should be collected but not published in public portals, and that publication produces risk-averse behaviour; 65% felt that it hinders innovation; 86% felt that EuroSCORE II is not reliable in identifying high-risk patients and the same number felt that it has affected entry into the specialty. CONCLUSIONS: The information that is collectable will be published, but we can control the way in which it is published and presented. PMID- 27234134 TI - Comparison of endpoints relevant to toxicity assessments in 3 generations of CD-1 mice fed irradiated natural and purified ingredient diets with varying soy protein and isoflavone contents. AB - Diet is an important variable in toxicology. There are mixed reports on the impact of soy components on energy utilization, fat deposition, and reproductive parameters. Three generations of CD-1 mice were fed irradiated natural ingredient diets with varying levels of soy (NIH-41, 5K96, or 5008/5001), purified irradiated AIN-93 diet, or the AIN-93 formulation modified with ethanol-washed soy protein concentrate (SPC) or SPC with isoflavones (SPC-IF). NIH-41 was the control for pairwise comparisons. Minimal differences were observed among natural ingredient diet groups. F0 males fed AIN-93, SPC, and SPC-IF diets had elevated glucose levels and lower insulin levels compared with the NIH-41 group. In both sexes of the F1 and F2 generations, the SPC and SPC-IF groups had lower body weight gains than the NIH-41 controls and the AIN-93 group had an increased percent body fat at postnatal day 21. AIN-93 F1 pups had higher baseline glucose than NIH-41 controls, but diet did not significantly affect breeding performance or responses to glucose or uterotrophic challenges. Reduced testes weight and sperm in the AIN-93 group may be related to low thiamine levels. Our observations underline the importance of careful selection, manufacturing procedures, and nutritional characterization of diets used in toxicological studies. PMID- 27234138 TI - Semi-rational engineering of cytochrome CYP153A from Marinobacter aquaeolei for improved omega-hydroxylation activity towards oleic acid. AB - omega-Hydroxy oleic acid is an important intermediate for the synthesis of certain polyesters and polyamides. In this study, a functional CYP153A/putidaredoxin (Pdx)/putidaredoxin reductase (Pdr) hybrid system was engineered for improved omega-hydroxylation activity towards oleic acid. By the combination of site-directed saturation mutagenesis (SDSM) and iterative saturation mutagenesis (ISM), a best mutant (Variant II) was obtained with mutations at two sites (S120 and P165) at the Pdx interaction interface with CYP153A, and one site (S453) in the substrate binding pocket. The in vitro reconstituted activity of Variant II with purified Pdx and Pdr was 2.7-fold that of the template, while the whole cell transformation activity was 2.0-fold that of the template. A 96-well format-based screening scheme for CYP153A was also developed, which should be useful for engineering of other P450s with low activity. Kinetic analyses indicated that the activity improvement for CYP153A variants largely resulted from enhanced electron transfer. This further demonstrates the importance of the electron transfer between P450s and the non native redox partners for the overall performance of hybrid P450 systems. PMID- 27234139 TI - Phenotypic and genotypic screening of human-originated lactobacilli for vitamin B12 production potential: process validation by micro-assay and UFLC. AB - Vitamin B12 (B12) production is a strain specific, rare and hidden functional attribute of lactobacilli and a cogent protocol for selection of such isolates from the herd of lactobacilli is required. The present study included isolation of lactobacilli from human samples (milk and fecal), screening them by a polyphasic (three-phase) methodology for probable B12 production potential and validating the screening protocol by exploring selected strains for in vitro vitamin production (two-phase fermentation) and quantification [micro-assay and ultra fast liquid chromatography (UFLC)]. Fifty-nine Lactobacillus strains were recovered from tested biological samples. Contrary to screening inapplicabilities of first [growth potential (GP) in B12-free medium] and second phases (GP in B12 free and cobalt chloride-supplemented conditions), third phase (cbiK gene detection on genomic DNA) alone was revealed as a validated strategy for selection of two probable B12-producing lactobacilli. Microbiological assay confirmed production and bioavailability of produced vitamin, while UFLC testing validated the results by precisely quantifying the cyanocobalamin (industrially produced bio-available form of B12) in cell extracts of both possible B12 producers [BHM10 (10.91 +/- 1.55 MUg/l) and BCF20 (23.90 +/- 1.73 MUg/l)] and positive standard [Lactobacillus reuteri DSM20016 (20.03 +/- 4.17 MUg/l)]. Moreover, this study generates a novel report for genomic detection, partial amplification and sequencing of cbiK gene in Lactobacillus plantarum species (both BHM10 and BCF20). In conclusion, contrary to first two phases, cbiK gene detection strategy successfully selects B12-producing strains from a group of human-originated lactobacilli and can be used in the future for similar screening studies. PMID- 27234140 TI - Removal of pharmaceuticals from synthetic wastewater in an aerobic granular sludge membrane bioreactor and determination of the bioreactor microbial diversity. AB - Five types of pharmaceuticals and personal care products (PPCPs) substances were selected as pollutants in this study. The effects of the removal of these pollutants and the microbial succession process in a granular sludge membrane bioreactor (GMBR) were investigated. Results showed that wastewater containing PPCPs influenced the performance of granular sludge. The removal of the five PPCPs from the GMBR had different effects. The removal rates of prednisolone, norfloxacin and naproxen reached 98.5, 87.8 and 84 %, respectively. The degradation effect in the GMBR system was relatively lower for sulphamethoxazole and ibuprofen, with removal efficiency rates of 79.8 and 63.3 %, respectively. Furthermore, the microbial community structure and diversity variation of the GMBR were analysed via high-throughput sequencing technology. The results indicated the structural and functional succession of the microbial community based on the GMBR process. The results indicate the key features of bacteria with an important role in drug degradation. PMID- 27234141 TI - Implementing a VATS Lobectomy Program in Spain. The Wet Lab, a Necessary Tool. PMID- 27234142 TI - Strength-Duration Relationship in Paired-pulse Transcranial Magnetic Stimulation (TMS) and Its Implications for Repetitive TMS. AB - BACKGROUND: Paired-pulse protocols have played a pivotal role in neuroscience research using transcranial magnetic stimulation (TMS). Stimulus parameters have been optimized over the years. More recently, pulse width (PW) has been introduced to this field as a new parameter, which may further fine-tune paired pulse protocols. The relationship between the PW and effectiveness of a stimulus is known as the "strength-duration relationship". OBJECTIVE: To test the "strength-duration relationship", so as to improve paired-pulse TMS protocols, and to apply the results to develop new repetitive TMS (rTMS) methods. METHODS: Four protocols were investigated separately: short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), short-interval intracortical facilitation (SICF) and long-interval intracortical inhibition (LICI). First, various stimulus parameters were tested to identify those yielding the largest facilitation or inhibition of the motor evoked potential (MEP) in each participant. Using these parameters, paired-pulse stimulations were repeated every five seconds for 30 minutes (repetitive paired-pulse stimulation, rPPS). The after-effects of rPPS were measured using MEP amplitude as an index of motor cortical excitability. RESULTS: Altogether, the effect of changing PW was similar to that of changing the stimulus intensity in the conventional settings. The best parameters were different for each participant. When these parameters were used, rPPS based on either SICF or ICF induced an increase in MEP amplitude. CONCLUSIONS: PW was introduced as a new parameter in paired-pulse TMS. Modulation of PW influenced the results of paired-pulse protocols. rPPS using facilitatory protocols can be a good candidate to induce enhancement of motor-cortical excitability. PMID- 27234143 TI - Incidental injury and repair of obturator nerve during laparoscopic pelvic lymphadenectomy. AB - OBJECTIVE: To demonstrate a surgical video wherein left obturator nerve was iatrogenically injured during pelvic lymphadenectomy and repaired immediately with laparoscopic epineural end-to-end tension free anastomosis. METHODS: This is a step-by-step demonstration of an incidental injury and laparoscopic repair of left obturator nerve during pelvic lymphadenectomy. The patient was a 59year-old Hispanic female who was found to have endometrial adenocarcinoma. She was referred to our division for laparoscopic staging during which left obturator nerve was iatrogenically injured. After completion of left pelvic lymphadenectomy, proximal and distal cut ends of the obturator nerve were identified. Careful inspection revealed that the nerve was transected cleanly without any fraying of the edges. Tension-free reattachment of the edges seemed possible without further mobilization of the nerve since the resected part was approximately 5mm. The obturator nerve edges were oriented and stay sutures were placed in order to perform tension-free anastomosis. Epineural end-to-end coaptation was completed with 5-0 polypropylene sutures [1,2]. RESULTS: Postoperatively, the patient did not exhibit any clinically apparent loss of adductor function or any other neurologic deficiency and was discharged home on postoperative day one. Over 6months of follow-up, the patient experienced no residual neuropathy or deficit in the left thigh. CONCLUSION: Laparoscopic repair of a transected obturator nerve during gynecologic surgery is feasible. In this case, immediate repair of the damaged nerve by an experienced laparoscopic gynecologic surgeon did not result in any neurologic deficit postoperatively. PMID- 27234144 TI - Variation in care in concurrent chemotherapy administration during radiation for locally advanced cervical cancer. AB - BACKGROUND: To evaluate the usage of concurrent chemo-radiotherapy (C-CRT) for the treatment of locally advanced cervical cancer. METHODS: Patients with locally invasive cervical carcinoma diagnosed between January 1, 2004 and December 31, 2012 from the National Cancer Database (NCDB) were included. Outcomes for patients undergoing radiation therapy only, 'RT alone' group were compared to those receiving chemotherapy concurrent with radiation 'C-CRT group'. Trends in utilization of C-CRT and factors associated with the deviation from standard of care were explored. Lastly, the effect of hospital volume on utilization of C-CRT was investigated. RESULTS: A total of 18,164 patients undergoing definitive radiation therapy were available for analysis. Utilization of C-CRT increased from 72.4% in 2004 to 84.3% in 2012 (p-trend<0.001). After adjusting for patient, tumor, and treatment factors, a multivariable logistic regression model revealed increasing age, African-American race, Charlson-comorbidity index of >=2, Medicaid insurance status, uninsured status, and Stage I disease were each independently associated with the lack of C-CRT. After adjusting for patient characteristics, low volume hospitals were noted to have overall significantly lower rates and greater variation in C-CRT administration. Patients in 'RT alone' group had an overall worse survival rate (adjusted-HR 1.47, 95%CI 1.4-1.56). CONCLUSION: Rates of C-CRT administration varied significantly across hospitals in the United States. Hospitals with a high case volume had higher rates and more consistent patterns of C-CRT administration. Furthermore, we identified independent factors, all of which represent noteworthy health disparities, associated with lower rates of C-CRT administration. PMID- 27234145 TI - A Serious Game for Clinical Assessment of Cognitive Status: Validation Study. AB - BACKGROUND: We propose the use of serious games to screen for abnormal cognitive status in situations where it may be too costly or impractical to use standard cognitive assessments (eg, emergency departments). If validated, serious games in health care could enable broader availability of efficient and engaging cognitive screening. OBJECTIVE: The objective of this work is to demonstrate the feasibility of a game-based cognitive assessment delivered on tablet technology to a clinical sample and to conduct preliminary validation against standard mental status tools commonly used in elderly populations. METHODS: We carried out a feasibility study in a hospital emergency department to evaluate the use of a serious game by elderly adults (N=146; age: mean 80.59, SD 6.00, range 70-94 years). We correlated game performance against a number of standard assessments, including the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and the Confusion Assessment Method (CAM). RESULTS: After a series of modifications, the game could be used by a wide range of elderly patients in the emergency department demonstrating its feasibility for use with these users. Of 146 patients, 141 (96.6%) consented to participate and played our serious game. Refusals to play the game were typically due to concerns of family members rather than unwillingness of the patient to play the game. Performance on the serious game correlated significantly with the MoCA (r=-.339, P <.001) and MMSE (r=-.558, P <.001), and correlated (point-biserial correlation) with the CAM (r=.565, P <.001) and with other cognitive assessments. CONCLUSIONS: This research demonstrates the feasibility of using serious games in a clinical setting. Further research is required to demonstrate the validity and reliability of game based assessments for clinical decision making. PMID- 27234146 TI - Discovery and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole picolinamides as positive allosteric modulators of the metabotropic glutamate receptor 4 (mGlu4). AB - Herein we report the synthesis and characterization of a novel series of N phenylsulfonyl-1H-pyrrole picolinamides as novel positive allosteric modulators of mGlu4. We detail our work towards finding phenyl replacements for the core scaffold of previously reported phenyl sulfonamides and phenyl sulfone compounds. Our efforts culminated in the identification of N-(1-((3,4 dimethylphenyl)sulfonyl)-1H-pyrrol-3-yl)picolinamide as a potent PAM of mGlu4. PMID- 27234147 TI - Quantitative relationships between structure and cytotoxic activity of flavonoid derivatives. An application of Hirshfeld surface derived descriptors. AB - Quantitative relationships between the structure and cytotoxic activity of series flavonoid derivatives were examined. The first regression-based model, developed for 18 flavanone-2-pyrazoline hybrids, involved two interpretable descriptors: a Mor04v and partial atomic charge. The second model, developed for structurally diverse set of compounds, was based on descriptors derived from Hirshfeld surface analysis. This model suggests that cytotoxic activity of compounds can be successfully predicted based on a fraction of H?H contacts and a fraction of interactions involving a halogen atom. For non-halogen derivatives, the data reveal that cytotoxic activity is inversely proportional to the percentage of O?H and N?H close contacts to Hirshfeld surface, while directly proportional to the percentage of H?H interactions. Chlorine (1k) and bromine (1l) derivatives of compounds, containing flavanone fused with N-methyl-2-pyrazoline, exhibited high cytotoxic potential against HL-60 cancer cell line (IC50<10MUM). The cytotoxicity of 1k and 1l towards normal cells (HUVEC) was 10 and 25-fold lower, respectively. PMID- 27234148 TI - Design, synthesis, and biological evaluation of anti-EV71 agents. AB - Enterovirus 71 (EV71) is a major causative agent of hand, foot and mouth disease (HFMD), which can spread its infections to the central nervous and other systems with severe consequences. In this article, design, chemical synthesis, and biological evaluation of various anti-EV71 agents which incorporate Michael acceptors are described. Further SAR study demonstrated that lactone type of Michael acceptor provided a new lead of anti-EV71 drug candidates with high anti EV71 activity in cell-based assay and enhanced mouse plasma stability. One of the most potent compounds (2K, cell-based anti-EV71 EC50=0.028MUM), showed acceptable stability profile towards mouse plasma, which resulted into promising pharmacokinetics in mouse via IP administration. PMID- 27234149 TI - Recall of indoor tanning salon warnings and safety guidelines among a national sample of tanners. AB - Indoor tanning (IT) is a known carcinogen, and regulation has increased across the USA. However, there is minimal point-of-sale regulation for adult users. The purpose of the present study is to explore whether IT users recall being provided with warnings or safety guidelines at tanning salons. A national sample of 273 young adult, female IT users (mean age = 22.26, SD = 2.38) was surveyed regarding the frequency that they recalled being provided with six different warnings and safety guidelines when at tanning salons. Between 65 and 90.1 % of participants reported recalling the various warnings and guidelines. Having very fair skin was reported by 16.8 % of participants, and these high-risk individuals were less likely to recall having read and signed a consent form than other IT users (p = .002). The current level of regulation is insufficient to provide IT users with consistent warnings and safety guidelines at tanning salons. PMID- 27234151 TI - Erratum to: Mapping training needs for dissemination and implementation research: lessons from a synthesis of existing D&I research training programs. PMID- 27234150 TI - Development and refinement of a clinician intervention to facilitate primary care patient use of the PTSD Coach app. AB - Posttraumatic stress disorder (PTSD) is common and undertreated among Veterans Affairs (VA) primary care patients. A brief primary care intervention combining clinician support with a self-management mobile app (Clinician-Supported PTSD Coach, CS-PTSD Coach) may improve patient outcomes. This study developed and refined an intervention to provide clinician support to facilitate use of the PTSD Coach app and gathered VA provider and patient qualitative and quantitative feedback on CS-PTSD Coach to investigate preliminary acceptability and implementation barriers/facilitators. VA primary care providers and mental health leadership (N = 9) completed a survey and interview regarding implementation barriers and facilitators structured according to the Consolidated Framework for Implementation Research (CFIR). Clinicians who delivered CS-PTSD Coach (N = 3) and patients (N = 9) who received it provided feedback on the intervention and implementation process. CS-PTSD Coach has high provider and patient acceptability. Important implementation factors included that CS-PTSD Coach be compatible with the clinics' current practices, have low complexity to implement, be perceived to address patient needs, and have strong support from leadership. Diverse factors related to CS-PTSD Coach delivery facilitate implementation, provide an opportunity to problem-solve barriers, and improve integration of the intervention into primary care. PMID- 27234152 TI - Erratum to: Development and refinement of a clinician intervention to facilitate primary care patient use of the PTSD Coach app. PMID- 27234153 TI - Erratum to: Recall of indoor tanning salon warnings and safety guidelines among a national sample of tanners. PMID- 27234154 TI - Continued Intimate Partner Violence During Pregnancy and After Birth and Its Effect on Child Functioning. AB - OBJECTIVE: To investigate the effect of intimate partner violence (IPV) during pregnancy with continued IPV up to 6 months after birth and its effect on child functioning. DESIGN: Nonexperimental descriptive design. SETTING: Safe shelters and the District Attorney's office in a large urban community in the United States. PARTICIPANTS: Abused women (N = 284) who reported IPV and reached out for services. METHODS: Abused women who reported IPV answered a questionnaire on the effects of abuse during pregnancy and continued abuse after birth and child behaviors. Women who continued to experience abuse during pregnancy were compared with women who did not report abuse during pregnancy and after birth. The Achenback Child Behavior Checklist was used to evaluate child behavior. Research questions were analyzed through the use of nonparametric analyses. RESULTS: Between the two groups, the relationship between IPV during pregnancy and IPV during the first 6 months after birth was significant (p < .001). The relation between women who reported abuse during pregnancy and conception rape was significant (p < .001). Most abused women (76%) were not screened for IPV during pregnancy (p = .025). Significant findings related to child behaviors and IPV during pregnancy were found for internalizing behaviors (p < .009), externalizing behaviors (p < .001), and total behavioral problems (p < .001). CONCLUSION: Intimate partner violence during pregnancy increases the risk of IPV 6 months after birth. These findings also indicated a negative intergenerational effect of IPV during pregnancy on child behavior. Screening for IPV during pregnancy is vital to interrupt ongoing IPV and possible negative outcomes for mother and child. PMID- 27234155 TI - Consequences of Inadequate Staffing Include Missed Care, Potential Failure to Rescue, and Job Stress and Dissatisfaction. AB - OBJECTIVE: To evaluate responses of registered nurse members of the Association of Women's Health, Obstetric and Neonatal Nurses (AWHONN) to a survey that sought their recommendations for staffing guidelines and their perceptions of the consequences of inadequate nurse staffing. The goal was to use these member data to inform the work of the AWHONN nurse staffing research team. DESIGN: Secondary analysis of responses to the 2010 AWHONN nurse staffing survey. SETTING: Online. PARTICIPANTS: AWHONN members (N = 884). METHODS: Review of data from an online survey of AWHONN members through the use of thematic analysis for descriptions of the consequences of inadequate nurse staffing during the childbirth process. RESULTS: Three main themes emerged as consequences of inadequate staffing or being short-staffed: Missed Care, Potential for Failure to Rescue, and Job Related Stress and Dissatisfaction. These themes are consistent with those previously identified in the literature related to inadequate nurse staffing. CONCLUSION: Based on the responses from participants in the 2010 AWHONN nurse staffing survey, consequences of inadequate staffing can be quite serious and may put patients at risk for preventable harm. PMID- 27234156 TI - Intimate Partner Violence During the Childbearing Years. PMID- 27234157 TI - Interrupting Intimate Partner Violence During Pregnancy With an Effective Screening and Assessment Program. AB - Intimate partner violence is a public health problem that affects many women during pregnancy and can compromise the health and safety of mothers and infants. Identification and routine assessment of intimate partner violence during pregnancy is essential, and health care providers must be afforded training and resources that support an effective screening and assessment program. The essential components of an intimate partner violence assessment program for women who are abused during pregnancy are explored. PMID- 27234158 TI - Effect of menopausal hormone therapy on components of the metabolic syndrome. AB - The world population is aging, and women will spend an increasing share of their lives in a postmenopausal state that predisposes to metabolic dysfunction. Thus, the prevalence of metabolic syndrome (MetS) in women is likely to increase dramatically. This article summarizes the effects of menopause in predisposing to components of MetS including visceral obesity, dyslipidemia, type 2 diabetes (T2D) and hypertension (HTN). We also summarize the effects of menopausal hormone therapy (MHT) in reversing these metabolic alterations and discuss therapeutic advances of novel menopausal treatment on metabolic function. PMID- 27234159 TI - Notch4+ cancer stem-like cells promote the metastatic and invasive ability of melanoma. AB - Sphere formation in conditioned serum-free culture medium supplemented with epidermal growth factor and basic fibroblast growth factor (tumorospheres) is considered useful for the enrichment of cancer stem-like cells, also known as tumor-initiating cells. We used a gene expression microarray to investigate the gene expression profile of melanoma cancer stem-like cells (MCSLCs). The results showed that MCSLCs highly expressed the following Notch signaling pathway molecules: Notch3 (NM_008716), Notch4 (NM_010929), Dtx4 (NM_172442), and JAG2 (NM_010588). Immunofluorescence staining showed tumorosphere cells highly expressed Notch4. Notch4(high) B16F10 cells were isolated by FACS, and Western blotting showed that high Notch4 expression is related to the expression of epithelial-mesenchymal transition (EMT)-associated proteins. Reduced invasive and migratory properties concomitant with the downregulation of the EMT markers Twist1, vimentin, and VE-cadherin and the overexpression of E-cadherin was observed in human melanoma A375 and MUM-2B cells. In these cells, Notch4 was also downregulated, both by Notch4 gene knockdown and by application of the gamma secretase inhibitor, DAPT. Mechanistically, the re-overexpression of Twist1 by the transfection of cells with a Twist1 expression plasmid led to an increase in VE-cadherin expression and a decrease in E-cadherin expression. Immunohistochemical analysis of 120 human melanoma tissues revealed a significant correlation between the high expression of Notch4 and the metastasis of melanoma. Taken together, our findings indicate that Notch4+ MCSLCs trigger EMT and promote the metastasis of melanoma cells. PMID- 27234160 TI - Catheter ablation for atrial fibrillation in hypertrophic cardiomyopathy: a systematic review and meta-analysis. AB - OBJECTIVE: Atrial fibrillation (AF) is common in hypertrophic cardiomyopathy (HCM) and is associated with a high risk of stroke. The efficacy and safety of catheter ablation in this setting is poorly characterised. We aimed to systematically review the existing literature and to perform a meta-analysis to determine the efficacy and safety of catheter ablation of AF in patients with HCM. METHODS: Random-effects meta-analysis of studies comparing HCM versus non HCM controls. The outcomes of freedom from AF/atrial tachycardia, and acute procedure-related complications were assessed. Studies were searched on MEDLINE, EMBASE, COCHRANE and clinicaltrials.gov. RESULTS: Fourteen studies were considered eligible for the systematic review, of which five were included in the meta-analysis. Freedom from AF/atrial tachycardia relapse was higher in patients without HCM (after a single procedure: 38.7% HCM vs 49.8% controls, OR=2.25, 95% CI 1.09 to 4.64, p=0.03; after >=1 procedure: 51.8% HCM vs 71.2% controls, OR=2.62, 95% CI 1.52 to 4.51, p=0.0006; I(2)=33% and 26%, respectively). Risk of procedure-related adverse events was low. Repeat procedures (mean difference=0.16, 95% CI 0.0 to 0.32, p=0.05, I(2)=53%) and antiarrhythmic drugs (OR=4.70, 95% CI 2.31 to 9.55, p<0.0001, I(2)=0%) are more frequently needed in patients with HCM to prevent arrhythmia relapse. Sensitivity analyses suggested that the outcome in patients with HCM with less dilated atria and paroxysmal AF may be more comparable to the general population. CONCLUSIONS: The observed complication rate of catheter ablation of AF in patients with HCM was low. Even though the risk of relapse is twofold higher, catheter ablation can be effective in patients with HCM and AF, particularly in patients with paroxysmal AF and smaller atria. PMID- 27234170 TI - Blood pressure variability provokes vascular beta-adrenoceptor desensitization in rats. AB - Spontaneous variation in blood pressure is defined as 'blood pressure variability' (BPV). Sinoaortic denervation (SAD) is characterized by BPV without sustained hypertension. In the present study, we investigated whether BPV could be related to vascular beta-adrenoceptor desensitization in rats. Three days after surgery (SAD and control), aortic rings were placed in an organ chamber and the relaxation stimulated by beta-adrenoceptor agonists, isoprenaline, terbutaline, BRL37344 and cyanopindolol was verified. The participation of intracellular nucleotides signaling pathways was also verified using forskolin, sodium nitroprusside and acetylcholine to induce relaxation. The effects of BPV on the increase in endothelial cytosolic Ca(2+) concentration stimulated by the beta2-adrenoceptor agonist was examined by confocal microscopy. In addition, the vascular expression of the beta2-adrenoceptor was also examined by immunohistochemistry. The results show that isoprenaline and terbutaline-induced relaxation was lower in the aortas of rats with BPV. Relaxation responses to other vasorelaxant compounds were similar in both groups of rats. Histological analysis revealed a lower level of beta2-adrenoceptor and confocal microscopy showed minor cytosolic Ca(2+) concentration in endothelial cells stimulated by the beta2-adrenoceptor agonist in rats with BPV. In conclusion, BPV leads to desensitization of the beta2-adrenoceptor, which could contribute to worse beta adrenoceptor agonist-induced relaxation in isolated aortas. PMID- 27234171 TI - Targeting endoplasmic reticulum stress in hypoxia-induced cardiac injury. PMID- 27234172 TI - To breathe or fight? Siamese fighting fish differ when facing a real opponent or mirror image. AB - Displays are a feature of animal contest behaviour and have been interpreted as a means of gathering information on opponent fighting ability, as well as signalling aggressive motivation. In fish, contest displays often include frontal and lateral elements, which in the latter involves contestants showing their flanks to an opponent. Previous work in a range of fish species has demonstrated population-level lateralization of these displays, preferentially showing one side to their opponent. Mirrors are commonly used in place of a real opponent to study aggression in fish, yet they may disrupt the normal pattern of display behaviour. Here, using Siamese fighting fish, Betta splendens, we compare the aggressive behaviour of males to a mirror image and real opponent behind a transparent barrier. As this species is a facultative air-breather, we also quantify surface breathing, providing insights into underlying fight motivation. Consistent with previous work, we found evidence of population-level lateralization, with a bias to present the left side and use the left eye when facing a real opponent. Contrary to expectations, there were no differences in the aggressive displays to a mirror and real opponent, with positive correlations between the behaviour in the two scenarios. However, there were important differences in surface breathing, which was more frequent and of longer duration in the mirror treatment. The reasons for these differences are discussed in relation to the repertoire of contest behaviour and motivation when facing a real opponent. PMID- 27234173 TI - Watering holes: The use of arboreal sources of drinking water by Old World monkeys and apes. AB - Water is one of the most important components of an animal's diet, as it is essential for life. Primates, as do most animals, procure water directly from standing or free-flowing sources such as pools, ponds and rivers, or indirectly by the ingestion of certain plant parts. The latter is frequently described as the main source of water for predominantly arboreal species. However, in addition to these, many species are known to drink water accumulated in tree-holes. This has been commonly observed in several arboreal New World primate species, but rarely reported systematically from Old World primates. Here, we report observations of this behaviour from eight great ape and Old World monkey species, namely chimpanzee, orangutan, siamang, western hoolock gibbon, northern pig tailed macaque, bonnet macaque, rhesus macaque and the central Himalayan langur. We hypothesise three possible reasons why these primates drink water from tree holes: (1) coping with seasonal or habitat-specific water shortages, (2) predator/human conflict avoidance, and (3) potential medicinal benefits. We also suggest some alternative hypotheses that should be tested in future studies. This behaviour is likely to be more prevalent than currently thought, and may have significant, previously unknown, influences on primate survival and health, warranting further detailed studies. PMID- 27234174 TI - Having cancer in a foreign country. AB - OBJECTIVES: Although immigration and cancer care are two frequently discussed topics in healthcare, the combination of both has seldom been done. Little is known about how immigrant patients experience having cancer in a foreign country. The aim of the study is to gain deeper insight into the meaning of having cancer, in a foreign country and to identify the expectations and experiences of immigrant patients confronted with this disease. METHODS: Thirty adult non western immigrant cancer patients were interviewed by means of an in-depth interview technique. The technique of constant comparison, derived from the constructivist grounded theory, was used to analyze the data from the interviews. RESULTS: Having cancer is a human experience, regardless of one's country of origin. Patients show universal reactions and reaction patterns when confronted with cancer and dealing with cancer treatment. Immigrant patients experience specific obstacles when dealing with cancer, of which the language barrier is the most important. A general lack of accurate basic knowledge about health and disease was found, making certain patients more vulnerable. CONCLUSIONS AND PRACTICE IMPLICATIONS: When dealing with cancer, immigrant patients are confronted with two major obstacles: a language barrier and a lack of knowledge about health and disease. The implications for a better practice occur on three levels: empowering patients, training healthcare professionals and adapting policy. PMID- 27234175 TI - The importance of review articles in making the voice of rare diseases heard: OJRD's 10th anniversary. PMID- 27234176 TI - Compulsive buying disorder clustering based on sex, age, onset and personality traits. AB - In spite of the revived interest in compulsive buying disorder (CBD), its classification into the contemporary nosologic systems continues to be debated, and scarce studies have addressed heterogeneity in the clinical phenotype through methodologies based on a person-centered approach. OBJECTIVES: To identify empirical clusters of CBD employing personality traits, as well as patients' sex, age and the age of CBD onset as indicators. METHODS: An agglomerative hierarchical clustering method defining a combination of the Schwarz Bayesian Information Criterion and log-likelihood was used. RESULTS: Three clusters were identified in a sample of n=110 patients attending a specialized CBD unit a) "male compulsive buyers" reported the highest prevalence of comorbid gambling disorder and the lowest levels of reward dependence; b) "female low dysfunctional" mainly included employed women, with the highest level of education, the oldest age of onset, the lowest scores in harm avoidance and the highest levels of persistence, self-directedness and cooperativeness; and c) "female highly-dysfunctional" with the youngest age of onset, the highest levels of comorbid psychopathology and harm avoidance, and the lowest score in self directedness. CONCLUSION: Sociodemographic characteristics and personality traits can be used to determine CBD clusters which represent different clinical subtypes. These subtypes should be considered when developing assessment instruments, preventive programs and treatment interventions. PMID- 27234177 TI - Quality of life of adult daughters of women with schizophrenia: Associations with psychological resource losses and gains. AB - OBJECTIVE: This study examined the relationship between perceived losses and gains of psychological resources and quality of life of adult daughters of women with schizophrenia. METHOD: Thirty one adult daughters of mothers with schizophrenia (age range 30 to 50years) and thirty women of similar socio demographic characteristics whose mothers were mentally healthy (the control group) participated in this study. RESULTS: (a) Resource loss was higher and resource gains were lower among daughters of women with schizophrenia, compared to the control group; (b) despite resource gains total score of quality of life was significantly lower among daughters of mothers with schizophrenia compared to the controls; (c) daughters of mothers with schizophrenia had lower levels of family functioning, a higher level of negative emotions and a lower level of positive emotions; (d) resource gains moderated the negative relationship between resource loss and quality of life; (e) the most significant predictor of quality of life was the group (i.e. daughters of women with schizophrenia compared with controls); (f) quality of life was more strongly associated with resource loss than with resource gain. DISCUSSION: The findings of this research underscore the importance of raising awareness of caregivers and healthcare authorities to the needs of the unique population of daughters of women diagnosed with schizophrenia for support and even treatment. PMID- 27234178 TI - Facial emotion recognition in euthymic patients with bipolar disorder and their unaffected first-degree relatives. AB - BACKGROUND: Facial emotion recognition (FER) is an important task associated with social cognition because facial expression is a significant source of non-verbal information that guides interpersonal relationships. Increasing evidence suggests that bipolar disorder (BD) patients present deficits in FER and these deficits may be present in individuals at high genetic risk for BD. The aim of this study was to evaluate the occurrence of FER deficits in euthymic BD patients, their first-degree relatives, and healthy controls (HC) and to consider if these deficits might be regarded as an endophenotype candidate for BD. METHODS: We studied 23 patients with DSM-IV BD type I, 22 first-degree relatives of these patients, and 27 HC. We used the Penn Emotion Recognition Tests to evaluate tasks of FER, emotion discrimination, and emotional acuity. Patients were recruited from outpatient facilities at the Institute of Psychiatry of the University of Sao Paulo Medical School, or from the community through media advertisements, had to be euthymic, with age above 18years old and a diagnosis of DSM-IV BD type I. RESULTS: Euthymic BD patients presented significantly fewer correct responses for fear, and significantly increased time to response to recognize happy faces when compared with HC, but not when compared with first-degree relatives. First-degree relatives did not significantly differ from HC on any of the emotion recognition tasks. CONCLUSION: Our results suggest that deficits in FER are present in euthymic patients, but not in subjects at high genetic risk for BD. Thus, we have not found evidence to consider FER as an endophenotype candidate for BD. PMID- 27234179 TI - Predictors of neurocognitive impairment at 2years after a first-episode major depressive disorder. AB - BACKGROUND: Neurocognitive impairment is a contributor to major depressive disorder (MDD). However, MDD patients show great variability in the level and course of deficits. The present longitudinal study was to identify predictors of neurocognitive impairment in first-episode MDD patients. METHODS: Neurocognitive performance was analyzed in a cohort of 100 patients at 2years after a first episode MDD. Subgroups, deficit type vs. non-deficit type, were compared on baseline clinical, neuropsychological, premorbid and sociodemographic characteristics. The analysis was performed using the multivariate logistic regression to obtain a model for neurocognitive impairment determination. The predicted probabilities of multivariate logistic regression were analyzed using receiver operating characteristic (ROC) curve. RESULTS: Fifty-two percent of MDD participants presented general neurocognitive impairment. The regression analyses demonstrated that clinical and sociodemographic characteristics were not predictive variables. A model composed of processing speed, executive function, and attention, dexterity correctly classified 85.8% of the MDD patients with deficit type. ROC curve indicated that the changes of these three cognitions could identify MDD with deficit type from MDD with non-deficit type. In addition, ROC curve also indicated that processing speed and executive function could identify MDD from CN subjects. Finally, processing speed performance was negatively correlated with Hamilton Depression Scale scores in both MDD with deficit and non-deficit type. CONCLUSION: The present study provides novel insights on frequency and neurocognitive profile of subtypes of patients showing impairment. Our results suggest that processing speed impairment is a trait dimension of the disorder related to specific cognitive dysfunctions and the severity of depression. PMID- 27234180 TI - Differential melatonin alterations in cerebrospinal fluid and serum of patients with major depressive disorder and bipolar disorder. AB - BACKGROUND: Melatonin, which plays an important role for regulation of circadian rhythms and the sleep/wake cycle has been linked to the pathophysiology of major depressive and bipolar disorder. Here we investigated melatonin levels in cerebrospinal fluid (CSF) and serum of depression and bipolar patients to elucidate potential differences and commonalities in melatonin alterations across the two disorders. METHODS: Using enzyme-linked immunosorbent assays, CSF and serum melatonin levels were measured in 108 subjects (27 healthy volunteers, 44 depressed and 37 bipolar patients). Covariate adjusted multiple regression analysis was used to investigate group differences in melatonin levels. RESULTS: In CSF, melatonin levels were significantly decreased in bipolar (P<0.001), but not major depressive disorder. In serum, we observed a significant melatonin decrease in major depressive (P=0.003), but not bipolar disorder. No associations were found between serum and CSF melatonin levels or between melatonin and measures of symptom severity or sleep disruptions in either condition. CONCLUSION: This study suggests the presence of differential, body fluid specific alterations of melatonin levels in bipolar and major depressive disorder. Further, longitudinal studies are required to explore the disease phase dependency of melatonin alterations and to mechanistically explore the causes and consequences of site-specific alterations. PMID- 27234181 TI - Additional support for the cognitive model of schizophrenia: evidence of elevated defeatist beliefs in schizotypy. AB - OBJECTIVES: The cognitive model of poor functioning in schizophrenia posits that defeatist performance beliefs-overgeneralized negative beliefs about one's ability to perform tasks-develop prior to the onset of psychosis and contribute to the development and maintenance of negative symptoms and poor functioning. Although several studies with schizophrenia samples have provided support for the model, there is a paucity of research investigating these beliefs in individuals with schizotypy-those exhibiting traits reflecting a putative genetic liability for schizophrenia. This study had two aims: to examine whether defeatist performance beliefs (1) are elevated in schizotypy compared to controls and (2) are associated with decreased quality of life and working memory and increased negative but not positive schizotypy traits in the schizotypy group. METHODS: Schizotypy (n=48) and control (n=53) groups completed measures of schizotypy traits, defeatist performance beliefs, quality of life, and working memory. RESULTS: Analyses revealed that the schizotypy group reported significantly more defeatist performance beliefs than the control group. Within the schizotypy group, increased defeatist performance beliefs were significantly associated with greater negative schizotypy traits and lower quality of life. No significant associations were observed between defeatist performance beliefs and positive schizotypy traits and working memory. CONCLUSIONS: Results generally support the theoretical validity of the cognitive model of poor functioning in schizophrenia and suggest that elevated defeatist performance beliefs may contribute to the manifestation of subclinical negative symptom traits and reduced quality of life among those with a latent vulnerability for schizophrenia. PMID- 27234182 TI - Relating DSM-5 section II and section III personality disorder diagnostic classification systems to treatment planning. AB - BACKGROUND: Beginning with DSM-III, the inclusion of a "personality" axis was designed to encourage awareness of personality disorders and the treatment related implications of individual differences, but since that time there is little accumulated evidence that the personality disorder categories provide substantial treatment-related guidance. The DSM-5 Personality and Personality Disorders Work Group sought to develop an Alternative Model for personality disorder, and this study examined whether this model is more closely related to clinicians' decision-making processes than the traditional categorical personality disorder diagnoses. PROCEDURES: A national sample of 337 clinicians provided complete personality disorder diagnostic information and several treatment-related clinical judgments about one of their patients. FINDINGS: The dimensional concepts of the DSM-5 Alternative Model for personality disorders demonstrated stronger relationships than categorical DSM-IV/DSM-5 Section II diagnoses to 10 of 11 clinical judgments regarding differential treatment planning, optimal treatment intensity, and long-term prognosis. CONCLUSIONS: The constructs of the DSM-5 Alternative Model for personality disorders may provide more clinically useful information for treatment planning than the official categorical personality disorder diagnostic system retained in DSM-5 Section II. PMID- 27234183 TI - New DSM-5 criteria for ADHD - Does it matter? AB - OBJECTIVE: The new Diagnostic Statistical Manual (DSM) requires the presence of fewer symptoms to make a diagnosis of adult ADHD while the criteria for diagnosis in childhood are unchanged as compared to previous editions. This study examines the prevalence of adults meeting the revised DSM-5 symptoms cutoff as compared to the previous DSM-IV symptoms cutoff. METHOD: This study is part of a larger nationwide study that evaluated the use of, and the attitudes toward, ADHD medications by university students. 445 students from four major university faculties were surveyed and filled out questionnaires for our study. RESULTS: The proportion of participants that met the minimum threshold of six out of nine current symptoms in either of the two DSM-IV symptom domains (inattentive presentation and hyperactive/impulsive presentation) for ADHD was 12.7% while the proportion that met the minimum threshold of five symptoms in either of the DSM-5 symptom domains was 21%. CONCLUSION: Since the new DSM requires fewer current symptoms for a diagnosis of ADHD, a significant increase (65%) was observed in the number of participants meeting the new cutoff as compared to the old DSM-IV symptoms cutoff. This increase in the number of adults meeting symptoms cutoff may affect the rates of adults diagnosed with ADHD. Using the new criteria may identify more adults with ADHD and fewer diagnoses will be missed. However, meeting the new symptoms cutoff should be considered within the overall clinical context to prevent over-diagnosis. PMID- 27234184 TI - Prevalence of personality disorders in patients with chronic migraine. AB - BACKGROUND: The present study aimed to investigate the prevalence of personality disorders (PDs) in patients with chronic migraine (CM). METHODS: This study included 105 CM patients who were diagnosed according to the criteria of the International Headache Society (IHS) and 100 healthy volunteers. PDs were diagnosed with the Structured Clinical Interview for DSM, Revised Third Edition Personality Disorders, and pain severity and level of disability were assessed with the Migraine Disability Assessment (MIDAS) test. RESULTS: Of the 105 CM patients, 85 (81%) had at least one PD. PDs were more prevalent in the patient group than in the healthy control group, and the most common PDs were obsessive compulsive (n=53, 50.5%), dependent (n=20, 19%), avoidant (n=20, 19%), and passive-aggressive (n=14, 13.3%) PDs. The MIDAS scores of the CM patients with PDs were higher than those of the CM patients without PDs. CONCLUSION: PDs, particularly obsessive-compulsive, dependent, avoidant, and passive-aggressive PDs, were frequently observed in CM patients in the present study. PMID- 27234185 TI - Compulsive buying and hoarding as identity substitutes: The role of materialistic value endorsement and depression. AB - PURPOSE: In the present study, we investigated whether the relationship between identity confusion and compulsive buying (offline/online) and hoarding is mediated by materialistic value endorsement and depression. PROCEDURES: The community sample consisted of 254 Flemish adults who completed self-report questionnaires to assess identity confusion (Erikson Psychosocial Stage Inventory), compulsive buying tendencies (Compulsive Buying Scale/short-Internet Addiction Scale, adapted for shopping), hoarding tendencies (Saving-Inventory Revised), materialistic value endorsement (Materialistic Value Scale), and depression (Patient Health Questionnaire-9). FINDINGS: We found significant positive associations between identity confusion, compulsive buying, and hoarding. The association between identity confusion and compulsive buying was fully mediated by materialistic value endorsement; whereas depression mediated the association between identity confusion and hoarding. CONCLUSIONS: The results suggest that the collection or buying of material goods can be considered as identity substitutes. PMID- 27234186 TI - Anxious temperament as a risk factor of suicide attempt. AB - OBJECTIVE: Suicide has been reported to be associated with cyclothymic, irritable, depressive and anxious temperaments. In contrast, hyperthymic temperament has been reported to be protective against suicide. In the present study, we hypothesized that Japanese patients with suicide attempt may have higher scores of cyclothymic, irritable, depressive, and anxious temperaments but lower scores of hyperthymic temperament than non-suicidal patients. In order to examine this hypothesis, we investigated Japanese patients of a university emergency center. METHODS: The association of temperament and suicide attempt was investigated in 116 patients referred to a university emergency center for intoxication or injury. Of them, 35 patients of suspected suicide attempt were categorized as 18 patients who intended to die with attempted suicide and suffered from self-inflicted but not fatal injury (Suicide Attempt II), 4 patients whose intention to die were undetermined although they suffered from self-inflicted injury (Undetermined Suicide-Related Behavior II), and 13 patients who had no intention to die although they suffered from self-inflicted injury (Self-Harm II). Logistic regression analyses and multiple regression analyses were used to identify factors associated with the present suicide attempt and the number of suicide attempts, respectively. RESULTS: Anxious temperament scores were significantly and directly associated with Suicide Attempt II group whereas irritable temperament scores were associated with Self-Harm II group. CONCLUSION: The present findings suggest that those with anxious temperament may have more suicide attempts than those with other temperaments, indicating anxious temperament as a risk factor of suicide attempt. PMID- 27234187 TI - Prevalence of depression in Syrian refugees and the influence of religiosity. AB - BACKGROUND: Many surveys have underlined the high levels of distress Syrian refugees have endured since the conflict aroused in their country, yet few have used reliable diagnostic tools for the clinical assessment of resulting mental disorders. The aim of our study is to assess for the onset of new depressive disorders following the Syrian war, and to investigate the correlation of religiosity with depression. METHODS: Single individual interviews were used, in a sample of 310 Syrian forced migrants, retrospectively assessing for depressive disorders with onset at different timelines of the conflict outbreak. Religiosity was assessed in a cross-sectional design using a reliable, recently developed and tested tool. Bivariate analysis and logistic regression analysis were used with a level of significance at 0.05. RESULTS: The prevalence of current depression was 43.9% (95% Confidence Interval (CI): 38.5-49.4%) with no difference across all socio-demographic factors, including gender. The overall mean for religiosity for the current sample was moderate (mean=9.76; standard deviation SD=2.34). No substantial correlation was found with religiosity. The prevalence rate for pre war depression was 6.5% (95% CI: 4.2-9.8%) following the global pattern of socio demographic epidemiological characteristics. Prevalence for past depression was 27.1% (95% CI: 22.5-32.3%); for current dysthymia: 4.5% (95% CI: 2.7-7.4%); for prewar and past dysthymia: 1% (95% CI: 0.3-2.8%), all with no significant differences detected across all demographic variables. CONCLUSION: In this retrospective study on a sample of Syrian refugees who fled their country after the war, we found a substantial emergence of depressive disorders with no meaningful correlation with the level of religiosity. PMID- 27234188 TI - Sex differences in the effect of childhood trauma on the clinical expression of early psychosis. AB - Childhood trauma, a risk factor of psychosis, is associated the clinical expression of the illness (greater severity of psychotic symptoms; poorer cognitive performance). We aimed to explore whether there are sex differences in this relationship. We studied 79 individuals with a psychotic disorder (PD) with <3years of illness and 59 healthy subjects (HS). All participants were administered the MATRICS Cognitive Consensus Cognitive Battery (MCCB) to assess cognition. Depressive, positive and negative psychotic symptoms, and global functioning were also assessed. History of childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ). Patients reported a greater history of childhood trauma on all CTQ domains (emotional, physical and sexual abuse, and physical and emotional neglect). A poorer cognitive performance was also observed in PD when compared to HS. No sex differences were found in the CTQ scores. In the relationship between childhood trauma and psychopathological symptoms, significant correlations were found between CTQ scores and positive and negative psychotic symptoms, depressive symptoms and poorer functionality, but only in women. Childhood trauma was associated with poorer social cognition in both men and women. Of all CTQ dimensions, emotional neglect and physical neglect were more clearly associated with a more severe psychopathological and cognitive profile. Our results suggest that childhood trauma, particularly emotional and physical neglect, is associated with the clinical expression of psychosis and that there are sex differences in this relationship. PMID- 27234189 TI - Five-year follow-up of people diagnosed with compulsive shopping disorder. AB - BACKGROUND: The authors assessed clinical symptoms and self-reported shopping and spending behavior in people diagnosed with compulsive shopping (CS) at a 5-year follow-up interview. METHODS: All met the criteria of McElroy et al. for lifetime CS and had the disorder for >1year. Structured and semistructured instruments and self-report questionnaires were used to collect data. RESULTS: Of the original 26 subjects, 17 (65%) were interviewed and are the focus of this report. At follow up, their ages ranged from 23 to 67years (mean=44years). Lifetime psychiatric comorbidity was common, but few had current psychiatric disorders at follow-up. Interest in shopping and spending decreased for eight (47%), stayed the same for five (29%), and increased for four (24%) subjects. Eleven subjects (65%) reported having attempted to quit their CS and three (18%) reported successfully doing so. Triggers for returning to CS included feelings of pressure/excitement/tension to shop; boredom; negative feelings such as sadness, depression, frustration, or anger; and the desire for positive feelings like happiness, power, or elation. Mean scores on the Compulsive Buying Scale (CBS) and the shopping version of the Yale-Brown Obsessive-Compulsive Scale showed overall improvement in CS symptoms (d=1.16 and d=-1.19, respectively); subjects were also less impulsive (d=-0.48). At baseline and follow-up, those with a lifetime mood disorder tended to have greater CS severity. CONCLUSIONS: While the subjects showed overall improvement, most had ongoing symptoms of CS. The implications of the findings are discussed. PMID- 27234190 TI - Examining Dark Triad traits in relation to sleep disturbances, anxiety sensitivity and intolerance of uncertainty in young adults. AB - BACKGROUND: The Dark Triad (DT) describes a set of three closely related personality traits, Machiavellianism, narcissism, and psychopathy. The aim of this study was to examine the associations between DT traits, sleep disturbances, anxiety sensitivity and intolerance of uncertainty. METHOD: A total of 341 adults (M=29years) completed a series of questionnaires related to the DT traits, sleep disturbances, anxiety sensitivity, and intolerance of uncertainty. RESULTS: A higher DT total score was associated with increased sleep disturbances, and higher scores for anxiety sensitivity and intolerance of uncertainty. In regression analyses Machiavellianism and psychopathy were predictors of sleep disturbances, anxiety sensitivity, and intolerance of uncertainty. CONCLUSIONS: Results indicate that specific DT traits, namely Machiavellianism and psychopathy, are associated with sleep disturbances, anxiety sensitivity and intolerance of uncertainty in young adults. PMID- 27234191 TI - Are obsessive-compulsive symptoms impulsive, compulsive or both? AB - BACKGROUND: The relationships between obsessive-compulsive symptoms and distinct forms of impulsivity and compulsivity are unclear. Such examination would be relevant in terms of how best to classify psychiatric disorders and in understanding candidate 'traits' that extend across a continuum between normalcy and clinical disorders. METHOD: 515 young adults (aged 18-29years) completed the Padua Inventory and undertook detailed clinical and neurocognitive assessments. Relationships between obsessive-compulsive symptoms and distinct types of impulsivity and compulsivity were evaluated using linear regression modeling. RESULTS: Obsessive-Compulsive symptoms were significantly predicted by female gender, lower quality of life, psychiatric disorders in general (but not impulse control disorders), and worse extra-dimensional set-shifting. Obsessive Compulsive symptoms were not significantly predicted by alcohol/nicotine consumption, stop-signal reaction times, or decision-making abilities. CONCLUSION: These data indicate that obsessive-compulsive symptoms are more related to certain forms of compulsivity than to impulsivity. These findings have important implications for diagnostic conceptualizations and neurobiological models. PMID- 27234192 TI - Study of positive and negative feedback sensitivity in psychosis using the Wisconsin Card Sorting Test. AB - BACKGROUND: Schizophrenia involves marked motivational and learning deficits that may reflect abnormalities in reward processing. The purpose of this study was to examine positive and negative feedback sensitivity in schizophrenia using computational modeling derived from the Wisconsin Card Sorting Test (WCST). We also aimed to explore feedback sensitivity in a sample with bipolar disorder. METHODS: Eighty-three individuals with schizophrenia and 27 with bipolar disorder were included. Demographic, clinical and cognitive outcomes, together with the WCST, were considered in both samples. Computational modeling was performed using the R syntax to calculate 3 parameters based on trial-by-trial execution on the WCST: reward sensitivity (R), punishment sensitivity (P), and choice consistency (D). The associations between outcome variables and the parameters were investigated. RESULTS: Positive and negative sensitivity showed deficits, but P parameter was clearly diminished in schizophrenia. Cognitive variables, age, and symptoms were associated with R, P, and D parameters in schizophrenia. The sample with bipolar disorder would show cognitive deficits and feedback abnormalities to a lesser extent than individuals with schizophrenia. CONCLUSION: Negative feedback sensitivity demonstrated greater deficit in both samples. Idiosyncratic cognitive requirements in the WCST might introduce confusion when supposing model free reinforcement learning. Negative symptoms of schizophrenia were related to lower feedback sensitivity and less goal-directed patterns of choice. PMID- 27234193 TI - The risk of male adult alcohol dependence: The role of the adverse childhood experiences and ecological executive function. AB - OBJECTIVE: To explore the association between male adult alcohol dependence and their adverse childhood experiences as well as ecological executive function. METHODS: The questionnaires of Adverse Childhood Experiences (ACEs) and Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) were adopted for the assessments of 102 alcohol dependent patients who were diagnosed according to the criteria defined by the International Classification of diseases and related health problems (ICD-10) and 106 healthy volunteers, and the differences between patients and healthy volunteers were analyzed. RESULTS: The percentage of adverse childhood experiences in alcohol dependent patients was significantly higher than that in healthy volunteers (chi(2)=17.28, P<0.01); and the incidences of emotional abuse, physical neglect, violence witness, and substance abuse were significantly higher in alcohol dependent patients than those in healthy volunteers (chi(2)=4.59, 4.46, 10.51, and 44.09 respectively; P<0.05). The ecological executive function analysis showed that the BRIEF total score and scores for each item were all significantly higher in alcohol dependent patients than those of healthy volunteers (P<0.01). CONCLUSIONS: The adult alcohol dependence was associated with their adverse childhood experiences and ecological executive function. Then physical neglect and substance abuse of parents in childhood, and emotional control defect in the ecological executive function showed strong association with adult alcohol dependence. PMID- 27234194 TI - Examining weight and eating behavior by sexual orientation in a sample of male veterans. AB - OBJECTIVE: Eating disorders are understudied in men and in sexual minority populations; however, extant evidence suggests that gay men have higher rates of disordered eating than heterosexual men. The present study examined the associations between sexual orientation, body mass index (BMI), disordered eating behaviors, and food addiction in a sample of male veterans. METHOD: Participants included 642 male veterans from the Knowledge Networks-GfK Research Panel. They were randomly selected from a larger study based on previously reported trauma exposure; 96% identified as heterosexual. Measures included the Eating Disorder Diagnostic Scale, the Yale Food Addiction Scale, and self-reported height and weight. RESULTS: Heterosexual and sexual minority men did not differ significantly in terms of BMI. However, gay and bisexual men (n=24) endorsed significantly greater eating disorder symptoms and food addiction compared to heterosexual men. CONCLUSIONS: Our findings that sexual minority male veterans may be more likely to experience eating disorder and food addiction symptoms compared to heterosexual male veterans highlight the importance of prevention, assessment, and treatment efforts targeted to this population. PMID- 27234195 TI - Well-being in clozapine-treated schizophrenia patients: The significance of positive symptoms. AB - OBJECTIVES: Well-being perception is seldom explored in schizophrenia patients. Recurrent limitations, such as the questionable applicability of gold standard definitions of health and well-being, and fewer tools available to assess well being, are pronounced in this subpopulation. This cross-sectional study sought to explore potential clinical factors that may predict subjective well-being scores in chronic schizophrenia patients (N=142) receiving clozapine treatment. METHODS: The Short Warwick-Edinburgh Mental Well-being Scale (SWEMWBS) was used to measure well-being. We correlated SWEMWBS scores and 27 clinically recognized factors, spanning socio-demographics, symptom severity scores, physical health diagnosis, clozapine side effects, habits and prescribed medication. Factors with a p<0.2 correlation were included as a predictors in a linear regression model. RESULTS: Ten factors were included in the linear regression model, however only positive symptom severity was a significant predictor of SWEMWBS score (p<0.0001). CONCLUSIONS: We suggest that greater levels of clinical attention given to positive symptoms compared with other symptoms and aspects of well-being, during biomedical treatment for chronic schizophrenia, may partially explain the finding that only positive symptoms significantly predicted patient perceptions of low well-being. PMID- 27234196 TI - Validation of the French Autism Spectrum Quotient scale and its relationships with schizotypy and Eysenckian personality traits. AB - BACKGROUND: Autism and schizophrenia spectra were long considered distinct entities. Yet, recent studies emphasized overlapping clinical and personality features suggesting common mechanisms and liabilities. Independent notions, however, highlight that the two spectra oppose each other socially (positive schizotypal hyper-mentalism versus autistic hypo-mentalism). METHODS: To clarify these relationships, we used data from 921 French-speaking Swiss undergraduates to firstly validate the French Autism Spectrum Questionnaire (AQ) identifying an optimal factor structure. Secondly, we assessed relationships between this AQ structure and schizotypic personality traits. RESULTS: Results from correlational and principal component analyses replicated both overlapping and opposing relationships. CONCLUSIONS: We conjecture that autistic traits opposing positive schizotypy represent autistic mentalizing deficits. We discuss implications of our findings relative to theories of autism and schizophrenia spectrum relationships. PMID- 27234197 TI - Validation of the Spanish version of the Dimensional Yale-Brown Obsessive Compulsive Scale (DYBOCS) in children and adolescents. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) is best understood as a complex overlap of obsessive-compulsive (OC) symptom dimensions with specific clinical and etiological characteristics. The Dimensional Yale-Brown Obsessive-Compulsive Scale (DYBOCS) was developed to assess the presence and severity of each of these OC symptom dimensions. Despite showing excellent psychometric properties in adults, the psychometric properties of the DYBOCS have not been widely investigated in children and adolescents. METHODS: We examined the psychometric properties of the DYBOCS Spanish version in a sample of 97 OCD children and adolescents. RESULTS: The results of the psychometric analyses were excellent overall. The internal consistency for each OC symptom dimension was high, although somewhat lower than in previous studies with adult samples. The DYBOCS showed overall good convergent and divergent validity. Factors obtained from a principal component analysis corresponded with the five DYBOCS dimensions (aggressive; sexual/religious; contamination; symmetry; and hoarding) and each one accounted for approximately 20% of the variance. CONCLUSIONS: The DYBOCS is a valid instrument for assessing the frequency and severity of OC symptom dimensions in children and adolescents with OCD. The principal component analysis supported the division of OC symptoms into five dimensions. OCD is a heterogeneous disorder, and a dimensional approach can help to understand its clinical, etiological and treatment response characteristics. PMID- 27234198 TI - The role of interpersonal personality traits and reassurance seeking in eating disorder symptoms and depressive symptoms among women with bulimia nervosa. AB - INTRODUCTION: The role of interpersonal factors has been proposed in various models of eating disorder (ED) psychopathology and treatment. We examined the independent and interactive contributions of two interpersonal-focused personality traits (i.e., social avoidance and insecure attachment) and reassurance seeking in relation to global ED psychopathology and depressive symptoms among women with bulimia nervosa (BN). METHOD: Participants were 204 adult women with full or subclinical BN who completed a battery of self-report questionnaires. Hierarchical multiple OLS regressions including main effects and interaction terms were used to analyze the data. RESULTS: Main effects were found for social avoidance and insecure attachment in association with global ED psychopathology and depressive symptoms. In addition, two-way interactions between social avoidance and reassurance seeking were observed for both global ED psychopathology and depressive symptoms. In general, reassurance seeking strengthened the association between social avoidance and global ED psychopathology and depressive symptoms. CONCLUSION: These results demonstrate the importance of reassurance seeking in psychopathology among women with BN who display personality features characterized by social avoidance. PMID- 27234200 TI - Psychiatric morbidity and its correlates among informal caregivers of older adults. AB - OBJECTIVE: This present study estimated the psychiatric morbidity among informal caregivers of older adults and investigated its association with their socio demographic factors and older adult's health status, including dementia, depression and physical health conditions. METHODS: Data from a national cross sectional survey were used. For each participating older adult, an informal caregiver who 'knew the older adult best' and was aware of their health condition, was also interviewed to collect information on the older adults' care needs, and behavioral and psychological symptoms of dementia (BPSD). Data from 693 pairs was used. Informal caregivers were administered the Self Reporting Questionnaire (SRQ)-20 and psychiatric morbidity was defined as those with a total SRQ score of >=8. Measures included informal caregivers' socio-demographic characteristics, assessment of dementia and depression in the older adults and self-report on their lifetime and current physical conditions. The association of socio-demographic characteristics, health conditions, care assistance and BPSD was investigated using backward stepwise logistic regression analysis where psychiatric morbidity (total SRQ score=8) was used as a dependent variable and all other variables served as independent covariates. RESULTS: Among informal caregivers, 8.8% exhibited psychiatric morbidity. Higher proportions of spousal caregivers and caregivers of older adults having more care needs and BPSD exhibited psychiatric morbidity. After adjusting for all covariates, caregivers' marital status, and the presence of BPSD and dementia in the older adults were identified as the strongest correlates of caregivers' psychiatric morbidity. The prevalence of psychiatric morbidity was 10%, 13.9% and 12.7% respectively in these groups. Married caregivers had higher odds of psychiatric morbidity (OR 2.50, 95% CI: 1.13-5.52). In addition, caregivers of older adults' with any BPSD (OR 5.87, 95% CI: 2.60-13.24) and dementia (OR 2.28, 95% CI: 1.23-4.20) were also associated with higher odds of psychiatric morbidity. CONCLUSION: Informal caregivers' marital status and presence of any BPSD and dementia in the older adults in their care were identified as the strongest correlates of caregivers' psychiatric morbidity. Clinicians should be cognizant of the risk in this group of caregivers and assess and intervene to alleviate caregivers' psychological problems. PMID- 27234199 TI - Insight among people with severe mental illness, co-occurring PTSD and elevated psychotic symptoms: Correlates and relationship to treatment participation. AB - BACKGROUND: There is a dearth of research on what factors are predictive of insight among people with severe mental illness and co-occurring PTSD. METHOD: Data were drawn from 146 participants with severe mental illness, co-occurring PTSD and elevated psychotic symptoms participating in a randomized controlled trial comparing two interventions for PTSD among people with severe mental illness. We examined the clinical and demographic correlates of insight at baseline, the relationship between baseline insight and treatment participation, the relationship between treatment participation and post-treatment insight, and the relationship between change in insight and change in other clinical variables. RESULTS: Impaired insight was relatively common, with roughly half the sample demonstrating mild or moderate impairment at baseline. Baseline insight was associated with fewer psychotic and disorganized symptoms, and greater emotional discomfort and PTSD knowledge, but was not associated with negative symptoms, PTSD symptoms, depression/anxiety, or treatment participation. Participation in PTSD treatment was associated with increased insight at post treatment. Improved insight was associated with improvements in disorganization and negative symptoms, but not with knowledge of PTSD or positive symptoms. DISCUSSION: The findings suggest that engagement in treatment that includes educating people about PTSD may lead to improvements in insight and related improvements in other psychiatric symptoms. PMID- 27234201 TI - Disturbed self concept mediates the relationship between childhood maltreatment and adult personality pathology. AB - BACKGROUND: Despite a robust literature documenting the relationship between childhood maltreatment and personality pathology in adulthood, there is far less clarity about the mechanism underlying this relationship. One promising candidate for such a linking mechanism is disturbance in the sense of self. This paper tests the hypothesis that disturbances in the sense of self mediate the relationship between childhood maltreatment and adult personality pathology. Specifically, we assess the self-related traits of stable self-image, self reflective functioning, self-respect and feeling recognized. METHODS: The sample included 113 non-psychotic psychiatric inpatients. Participants completed the Child Trauma Questionnaire (CTQ), the Personality Diagnostic Questionnaire-4 (PDQ 4+), and the self-reflexive functioning, stable self image, self-respect, and feeling recognized scales from the Severity Indices of Personality Problems (SIPP 118). A series of linear regressions was then performed to assess the direct and indirect effects of childhood trauma on personality disorder traits (PDQ-4+ total score), as mediated by self concept (SIPP-118 scales). Aroian tests assessed the statistical significance of each mediating effect. RESULTS: There was a significant mediating effect for all SIPP self concept variables, with a full mediating effect for the SIPP composite score and for SIPP feeling recognized and self-reflexive functioning, such that the direct effect of childhood trauma on personality did not retain significance after accounting for the effect of these variables. There was a partial mediating effect for SIPP stable self image and self-respect, such that the direct effect of the CTQ retained significance after accounting for these variables. SIPP feeling recognized had the strongest mediating effect. CONCLUSIONS: Multiple facets of self concept, particularly the degree to which an individual feels understood by other people, may mediate the relationship between childhood maltreatment and adult personality pathology. This underscores the importance of attending to disturbances in the sense of self in patients with personality pathology and a history of childhood maltreatment. These findings also support the centrality of disturbed self concept to the general construct of personality pathology. PMID- 27234202 TI - Word processing during reading sentences in patients with schizophrenia: evidences from the eyetracking technique. AB - PURPOSE: The current study analyze the effect of word properties (i.e., word length, word frequency and word predictability) on the eye movement behavior of patients with schizophrenia (SZ) compared to age-matched controls. METHOD: 18 SZ patients and 40 age matched controls participated in the study. Eye movements were recorded during reading regular sentences by using the eyetracking technique. Eye movement analyses were performed using linear mixed models. FINDINGS: Analysis of eye movements revealed that patients with SZ decreased the amount of single fixations, increased their total number of second pass fixations compared with healthy individuals (Controls). In addition, SZ patients showed an increase in gaze duration, compared to Controls. Interestingly, the effects of current word frequency and current word length processing were similar in Controls and SZ patients. The high rate of second pass fixations and its low rate in single fixation might reveal impairments in working memory when integrating neighbor words. In contrast, word frequency and length processing might require less complex mechanisms, which were functioning in SZ patients. CONCLUSION: To the best of our knowledge, this is the first study measuring how patients with SZ process dynamically well-defined words embedded in regular sentences. The findings suggest that evaluation of the resulting changes in eye movement behavior may supplement current symptom-based diagnosis. PMID- 27234203 TI - Dissociation in patients with schizophrenia spectrum disorders: What is the role of different types of childhood adversity? AB - AIMS: Our study aimed to explore the effects of different types of adverse childhood experiences (e.g. domestic violence, early loss, parental dysfunction, sexual and physical abuse) as well as experiences of sexual and physical abuse in adulthood on dissociative symptoms in adult patients with schizophrenia-spectrum disorders. METHODS: 145 patients were examined for psychotic symptoms with the Positive and Negative Syndrome Scale (PANSS), for dissociative symptoms with the German version of the Dissociative Experiences Scale (DES) and for adverse experiences in childhood and adulthood with the Structured Trauma Interview (STI). RESULTS: Childhood physical abuse was reported by 32%, childhood sexual abuse by 17% of the patients. Other forms of childhood adversity were also quite common; 18% had witnessed domestic violence, 26% reported early loss, and nearly half of patients reported at least one condition potentially related to parental dysfunction. The DES total score was significantly associated with childhood sexual abuse, witnessing of domestic violence and paternal dysfunction, as well as with physical violence in adulthood. In the final regression model, reports of paternal dysfunction and sexual abuse in childhood were independently associated with adult dissociation. Variance in dissociative symptoms was mainly explained by paternal dysfunction (18%). CONCLUSION: Substantial rates of childhood adversity were found and specific associations were evident with adult dissociation amongst psychosis patients who reported sexual abuse or paternal dysfunction in childhood. Therefore, it is important that patients with schizophrenia-spectrum disorders are routinely asked about a broad range of possible adverse childhood experiences in order to provide appropriate interventions. PMID- 27234204 TI - Experiential pleasure deficits in the prodrome: A study of emotional experiences in individuals at ultra-high risk for psychosis and recent-onset schizophrenia. AB - BACKGROUND: Previous studies report deficits in noncurrent but not current pleasure experience in schizophrenia, but little is known about pleasure experiences of the prodrome. This study investigated noncurrent and current pleasure experiences and its relationship with neurocognitive function and self esteem in ultra-high risk (UHR) for psychosis and recent-onset schizophrenia (ROSPR). METHODS: Twenty-four UHR, 25 ROSPR and 42 normal controls completed the physical and social anhedonia scales for noncurrent emotional experience and the laboratory-based assessment of valence and arousal evoked by positive, neutral and negative emotional stimuli for current emotional experience. Relationships of current and noncurrent emotional experience, episodic memory and self-esteem were investigated. RESULTS: For ROSPR, noncurrent pleasure, but not current pleasure evoked by positive stimuli, was diminished. Noncurrent anhedonia in ROSPR was related to episodic memory deficits and low self-esteem. In UHR subjects, both noncurrent pleasure and current pleasure to positive and neutral stimuli were diminished. Noncurrent anhedonia in UHR was not associated with episodic memory nor self-esteem. For arousal, ROSPR patients showed higher arousal than UHR subjects to positive stimuli. CONCLUSIONS: Findings indicate the presence of experiential hedonic deficits during the prodrome phase. Diminished noncurrent pleasure reports exist in ROSPR, which seems to be associated with cognitive deficits and low self-concept. Future research is needed to probe into further underlying mechanisms. PMID- 27234205 TI - The Internship Preparation Camp at the University of Maryland. AB - BACKGROUND: Specialty-specific 'boot camps' boost the competence and confidence of medical school graduates as they prepare to enter a residency programme. OBJECTIVE: We sought to evaluate the efficacy of a specialty-neutral Internship Preparation Camp (IPC) that we developed and made available to senior medical students at our medical school. The primary goal of the IPC is to educate students in the cognitive and procedural skills that are applicable to postgraduate year 1 trainees in all fields of specialisation. METHODS: The curriculum was developed through input from senior medical students and faculty from multiple specialties. The course used small-group sessions and skills labs led by distinguished speakers from various professions (medicine, nursing and pharmacy) to teach senior medical students the information and skills common to the needs of all new physicians, regardless of the specialty they have chosen. The course was presented across 3 half-days and was offered just prior to graduation. RESULTS: Of 166 possible participants, 65 attended the course; 39 (60%) of them completed evaluations immediately following the course and 29 (45%) of participants completed a follow-up evaluation 3 months later. All respondents reported increased confidence in caring for patients in all subject areas taught. In the follow-up survey, 82% of respondents reported using information learned during the course on an hourly, daily or weekly basis in their care of patients. CONCLUSIONS: A specialty-neutral IPC is of benefit to its attendees, regardless of the medical specialty in which they train. PMID- 27234206 TI - Patient-centred mountain medicine. AB - Venturing into the mountains, doctors have accompanied expeditions to provide routine care to the teams, undertake research and occasionally take on a rescue role. The role of doctors practicing mountain medicine is evolving. Public health issues involving concepts of health and safety have become necessary with the coming of commercial and youth expeditions. Increasingly individuals with a disability or a medical diagnosis choose to ascend to high altitudes. Doctors become involved in assessment of risk and providing advice for such individuals. The field of mountain medicine is perhaps unique in that acceptance of risk is part of the ethos of climbing and adventure. The pursuit of mountaineering goals may represent the ultimate conquest of a disability. Knowledge of mountain environment is essential in facilitating mountain ascents for those who choose to undertake them, in spite of a disability or medical condition. PMID- 27234207 TI - Erdheim-Chester disease with vascular involvement mimics large vessel vasculitis. PMID- 27234208 TI - An Entamoeba histolytica ADP-ribosyl transferase from the diphtheria toxin family modifies the bacterial elongation factor Tu. AB - ADP-ribosyl transferases are enzymes involved in the post-translational modification of proteins; they participate in multiple physiological processes, pathogenesis and host-pathogen interactions. Several reports have characterized the functions of these enzymes in viruses, prokaryotes and higher eukaryotes, but few studies have reported ADP-ribosyl transferases in lower eukaryotes, such as parasites. The locus EHI_155600 from Entamoeba histolytica encodes a hypothetical protein that possesses a domain from the ADP-ribosylation superfamily; this protein belongs to the diphtheria toxin family according to a homology model using poly-ADP-ribosyl polymerase 12 (PARP12 or ARTD12) as a template. The recombinant protein expressed in Escherichia coli exhibited in vitro ADP ribosylation activity that was dependent on the time and temperature. Unlabeled betaNAD(+), but not ADP-ribose, competed in the enzymatic reaction using biotin betaNAD(+) as the ADP-ribose donor. The recombinant enzyme, denominated EhToxin like, auto-ADP-ribosylated and modified an acceptor from E. coli that was identified by MS/MS as the elongation factor Tu (EF-Tu). To the best of our knowledge, this is the first report to identify an ADP-ribosyl transferase from the diphtheria toxin family in a protozoan parasite. The known toxins from this family (i.e., the diphtheria toxin, the Pseudomonas aeruginosa toxin Exo-A, and Cholix from Vibrio cholerae) modify eukaryotic elongation factor two (eEF-2), whereas the amoeba EhToxin-like modified EF-Tu, which is another elongation factor involved in protein synthesis in bacteria and mitochondria. PMID- 27234209 TI - In vitro effect of sodium arsenite on Echinococcus granulosus protoscoleces. AB - Cystic echinococcosis (CE) caused by the metacestodes of Echinococcus granulosus is an important cosmopolitan zoonosis. Surgery is the main treatment option for CE. Meanwhile, chemotherapy is used as an significant adjunct to surgery. However, the benzimidazole carbamate group and the existing scolicidal agents may not be as effective as hoped. In this study, we aimed to explore the in vitro effect of sodium arsenite (NaAsO2) on Echinococcus granulosus protoscoleces, the causative agents of CE. Protoscoleces of E. granulosus were incubated in vitro with 4, 8, 12, 16, and 20MUM NaAsO2. Viability and changes in morphology were investigated by 0.1% eosin staining. The ultrastructural alterations were observed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Additionally, caspase-3 activity was measured by colorimetric assay. Obvious protoscolicidal effect was seen with NaAsO2 at concentrations of 16MUM and 20MUM. Protoscolex mortality was 83.24% (16MUM) and 100% (20MUM) after 6 days post-incubation. SEM showed that the primary site of drug damage was the tegument of the protoscoleces. TEM analysis demonstrated that the internal tissues were severely affected and revealed an increase in the number of lipid droplets and vacuoles after treatment with 16MUM NaAsO2. Meanwhile, the caspase-3 activity significantly increased in protoscoleces after 24h of NaAsO2 incubation compared to the untreated controls. Our study demonstrated the clear in vitro scolicidal effect of NaAsO2 against E. granulosus protoscoleces. However, the in vivo efficacy, specific mechanism, and any possible side effects of NaAsO2 remain to be investigated. PMID- 27234210 TI - Role of porcine serum haptoglobin in the host-parasite relationship of Taenia solium cysticercosis. AB - Human and porcine cysticercosis is a parasitic disease caused by the larval stage (cysts) of the tapeworm Taenia solium. Cysts may live in several host tissues such as skeletal muscle or brain. We have previously described the presence of host haptoglobin (Hp) and hemoglobin (Hb) in different protein extracts of the T. solium cysts. Here, we report the binding of host Hp and Hb to a number of cyst proteins, evaluated through measuring electrophoretic and light absorbance changes. In the sera obtained from 18 cysticercotic pigs, Hp-Hb complexes were abundant, whereas free Hp was undetectable. In contrast, in the sera from non 18 cysticercotic pigs, Hp-Hb and free Hp were found. In the soluble protein fraction of cysts tissue, free Hp was detected showing a considerable Hb-binding ability, whereas in the vesicular fluid, Hp is mainly bound to Hb. Interestingly, assays carried out with the insoluble fraction of T. solium cysts tissue, showed binding of Hp and Hp-Hb in a saturable way, suggesting the existence of specific interactions. Our results suggested that the parasite can take advantage of the uptaken host Hp and Hb, either free or in complexes, as a source of iron or as a way to modulate the inflammatory response surrounding the T. solium cysts. PMID- 27234211 TI - CNS tau efflux via exosomes is likely increased in Parkinson's disease but not in Alzheimer's disease. AB - INTRODUCTION: Alzheimer's disease (AD) and Parkinson's disease (PD) involve tau pathology. Tau is detectable in blood, but its clearance from neuronal cells and the brain is poorly understood. METHODS: Tau efflux from the brain to the blood was evaluated by administering radioactively labeled and unlabeled tau intracerebroventricularly in wild-type and tau knock-out mice, respectively. Central nervous system (CNS)-derived tau in L1CAM-containing exosomes was further characterized extensively in human plasma, including by single molecule array technology with 303 subjects. RESULTS: The efflux of Tau, including a fraction via CNS-derived L1CAM exosomes, was observed in mice. In human plasma, tau was explicitly identified within L1CAM exosomes. In contrast to AD patients, L1CAM exosomal tau was significantly higher in PD patients than controls and correlated with cerebrospinal fluid tau. CONCLUSIONS: Tau is readily transported from the brain to the blood. The mechanisms of CNS tau efflux are likely different between AD and PD. PMID- 27234213 TI - For Medication Abortion, Science Should Guide Policy. PMID- 27234212 TI - Public/community engagement in health research with men who have sex with men in sub-Saharan Africa: challenges and opportunities. AB - BACKGROUND: Community engagement, incorporating elements of the broader concepts of public and stakeholder engagement, is increasingly promoted globally, including for health research conducted in developing countries. In sub-Saharan Africa, community engagement needs and challenges are arguably intensified for studies involving gay, bisexual and other men who have sex with men, where male same-sex sexual interactions are often highly stigmatised and even illegal. This paper contextualises, describes and interprets the discussions and outcomes of an international meeting held at the Kenya Medical Research Institute-Wellcome Trust in Kilifi, Kenya, in November 2013, to critically examine the experiences with community engagement for studies involving men who have sex with men. DISCUSSION: We discuss the ethically charged nature of the language used for men who have sex with men, and of working with 'representatives' of these communities, as well as the complementarity and tensions between a broadly public health approach to community engagement, and a more rights based approach. We highlight the importance of researchers carefully considering which communities to engage with, and the goals, activities, and indicators of success and potential challenges for each. We suggest that, given the unintended harms that can emerge from community engagement (including through labelling, breaches in confidentiality, increased visibility and stigma, and threats to safety), representatives of same-sex populations should be consulted from the earliest possible stage, and that engagement activities should be continuously revised in response to unfolding realities. Engagement should also include less vocal and visible men who have sex with men, and members of other communities with influence on the research, and on research participants and their families and friends. Broader ethics support, advice and research into studies involving men who have sex with men is needed to ensure that ethical challenges - including but not limited to those related to community engagement - are identified and addressed. Underlying challenges and dilemmas linked to stigma and discrimination of men who have sex with men in Africa raise special responsibilities for researchers. Community engagement is an important way of identifying responses to these challenges and responsibilities but itself presents important ethical challenges. PMID- 27234214 TI - Oral manifestations in vitamin B12 deficiency patients with or without history of gastrectomy. AB - BACKGROUND: The purpose of this study was to compare clinical features of vitamin B12 deficiency patients with a history of gastrectomy to those without a history of gastrectomy. METHODS: Twenty-two patients with vitamin B12 deficiency were included. Patients' chief complaints, oral manifestations, blood examination results, and past medical histories were reviewed. RESULTS: Eleven patients had a history of gastrectomy and 11 did not. The chief complaint was glossodynia in all patients. No significant differences were observed between the two groups regarding age, sex, symptom duration, or plasma vitamin B12 level. Erythema and depapillation of the tongue were the most common findings, however less common among patients without a history of gastrectomy. Two patients with a history of gastrectomy and 5 patients without a history of gastrectomy had normal oral mucosa. Patients with a history of gastrectomy were more anemic. Oral symptoms of the majority of patients responded to antifungals and vitamin B12 replacement. The suggested etiologies for vitamin B12 deficiency in the patients without a history of gastrectomy were gastritis, medications, diet, autoimmunity, and early gastric cancer. CONCLUSIONS: Vitamin B12 deficiency and its associated etiological factors should be considered in patients with glossodynia, even those whose oral mucosa appears normal and who lack a history of gastrectomy. PMID- 27234216 TI - [Assessment of sentinel lymph node biopsy in patients receiving neoadjuvant chemotherapy in breast cancer: before or after?]. AB - The main goal of preoperative chemotherapy is to reduce the size of the tumor and allow conservative treatment. Neoadjuvant treatment can affect axillary status with a downstaging in one third of the cases. For these patients, the benefit of axillary node dissection is questioned and the sentinel node biopsy (SLNB) seems to be a relevant option. However, the timing of performing SLNB is still debated especially for clinical negative patients with negative axillary ultrasound before preoperative chemotherapy. For axillary positive nodes proved by biopsy/cytology before preoperative chemotherapy, SLNB can be an option if there is a good clinical and radiological response. PMID- 27234215 TI - Environmental factors influencing tick densities over seven years in a French suburban forest. AB - BACKGROUND: Worldwide changes in socio-economic and environmental factors and the global climate are recognised causes of variation in tick distribution and density. Thus it is of great importance that new studies address the changing risk of infection for exposed populations. In Europe, Ixodes ricinus ticks are the most common vectors of several pathogens impacting veterinary and public health that have colonised suburban habitats. METHODS: This study aimed to evaluate longitudinal I. ricinus questing densities and infection rates over 7 years in a French suburban forested area with high human population density. Ticks were collected in spring yearly between 2008 and 2014 and, out of a total of 8594 collected I. ricinus, a representative subset of adult females (n = 259) were individually examined for the presence of several pathogens via PCR. RESULTS: Nymph densities peaked in 2009-2011, and then declined in 2012-2014. Changes in monthly temperature only had a modest impact on this variation. In contrast, analysis revealed a complex intra-annual relationship between mean nymph density and both concurrent and lagged mean monthly temperatures. The following pathogens were detected in the studied area: Anaplasma phagocytophilum, Rickettsia helvetica, Babesia venatorum and B. divergens, Francisella tularensis, Borrelia miyamotoi, B. afzelii/valaisiana, B. garinii/lusitaniae and Bartonella spp. CONCLUSION: Our findings reinforce the conclusion that ticks are important vectors of pathogenic microorganisms in suburban forests and suggest that despite complex intra-annual relationships between tick densities and temperature, there is no evidence for a climate-associated increase in infection risk over the 7 year period. Rather, tick densities are likely to be strongly influenced by population density fluctuations in vertebrate host species and wildlife management. Further detailed studies on the impact of climate change on tick population densities are required. PMID- 27234218 TI - Effects of nutritional supplementation with selenium and zinc on natural killer cell activity in hemodialysis patients: a single-arm study. PMID- 27234217 TI - SLCO1B1*5 polymorphism (rs4149056) is associated with chemotherapy-induced amenorrhea in premenopausal women with breast cancer: a prospective cohort study. AB - BACKGROUND: Because inheritance is recognized as playing a role in age at menarche and natural menopause, the development of chemotherapy-induced amenorrhea (CIA) might depend on inherited genetic factors; however, studies that explore such a correlation are few and have received scant attention. Given the importance of this topic we conducted a comprehensive genotype study in young women (<=45 years) with early-stage breast cancer. METHODS: Our approach tested the effect of variant polymorphisms in drug metabolism enzymes (DMEs) using a predesigned pharmacogenomics panel (TaqMan(r) OpenArray(r), Life Technologies GmbH, Darmstadt, Germany) in premenopausal women (n = 50). Patients received contemporary chemotherapy; in all cases a cyclophosphamide-based regimen with a dose of at least 500 mg/m(2) for six cycles. CIA was considered to be present in women with no resumption of menstrual bleeding within 12 months after completion of chemotherapy or goserelin. RESULTS: Twenty-six patients (52 %) showed CIA during follow-up whereas 24 women (48 %) remained premenopausal. Of all the DMEs studied, only the SLCO1B1*5 (rs4149056) genotype was associated with the development of CIA (P = 0.017). Of the 26 patients who were homozygous for the T/T allele SLCO1B1*5, 18 (69.2 %) developed CIA compared with 8 (30.8 %) of the 22 patients who were heterozygous (C/T allele). The association of heterozygous SLCO1B1*5 allele (OR 0.038; 95%CI: 0.05-0.92) with a lower risk of developing CIA remained significant in a binary logistic regression analysis that include age, SLCO1B1*5 allele variants, and goserelin therapy. CONCLUSIONS: Patient age and SLCO1B1*5 allele variants predict the likelihood of young women with breast cancer developing CIA. PMID- 27234219 TI - Overview of complications during pharmacological spasm provocation tests. AB - Pharmacological spasm provocation tests are invasive methods and we always have the potential to encounter complications when performing these tests. In 1980, Buxton et al. reported three deaths when they performed intravenous ergonovine testing. However, we now employ the intracoronary ergonovine test instead of the intravenous injection of ergonovine from a safety procedure point of view. Past serious major complications of intravenous ergonovine tests, intracoronary ergonovine tests, and intracoronary acetylcholine tests were 0.31% (26/8419), 0.51% (11/2173), and 0.95% (148/15,527), respectively. Selective intracoronary testing had the serious major complications in 0.89% of patients including just one death (0.006%) and two acute myocardial infarctions (0.01%). Selective spasm provocation tests had no additional risks compared with performing diagnostic coronary angiography alone. In the Western countries, the pharmacological spasm provocation tests are not familiar in the clinic except for some specialized institutions. We need international clinical studies using the same protocol of spasm provocation tests to compare the frequency, clinical features, and prognosis of acetylcholine- or ergonovine-provoked coronary spasm between Western and Asian countries. And we hope that Western guidelines give spasm provocation testing a class I indication similar to Japanese Circulation Society guidelines because coronary artery spasm may have fewer racial differences and borders. PMID- 27234220 TI - Safety of transradial diagnostic cardiac catheterization in patients under oral anticoagulant therapy. AB - BACKGROUND: Cardiac catheterization in anticoagulated patients is usually performed after the anticoagulation has been withdrawn, at least in the previous 48h, and sometimes bridging therapy with heparin is used. METHODS: A prospective observational study including 489 patients undergoing transradial catheterization was conducted. A total of 140 patients were under acenocoumarol (group A) and they were compared with the remainder (group B) for complications after the procedure (bleeding and vascular access complications). RESULTS: Patients in group A were older (74+/-12 years vs. 68+/-17 years, p<0.01) and the main indication for anticoagulation was atrial fibrillation (58.6%). No complications occurred during the procedures. There were no acute bleedings just after the bandage removal. During the first 24h, only 3 (2.1%) radial occlusions in group A and 2 (0.6%) in group B (p=0.14) were recorded. Hematomas between 5 and 10cm appeared in 5% of the group A vs. 4.6% in group B. During the 1-month follow-up period, one more radial occlusion in each group was recorded and there were 4 (1.1%) additional mild hematomas in group B and none in group A (p=0.48). CONCLUSIONS: Performing a transradial diagnostic cardiac catheterization without removal of the oral chronic anticoagulation appears safe in patients under acenocumarol therapy. PMID- 27234221 TI - Genome sequence of Candida versatilis and comparative analysis with other yeast. AB - The genome of Candida versatilis was sequenced to understand its characteristics in soy sauce fermentation. The genome size of C. versatilis was 9.7 Mb, the content of G + C was 39.74 %, scaffolds of N50 were 1,229,640 bp in length, containing 4711 gene. There were predicted 269 tRNA genes and 2201 proteins with clear function. Moreover, the genome information of C. versatilis was compared with another salt-tolerant yeast Zygosaccharomyces rouxii and the model organism Saccharomyces cerevisiae. C. versatilis and Z. rouxii genome size was close and both smaller than 12.1 for the Mb of S. cerevisiae. Using the OrthoMCL protein, three genomes were divided into 4663 groups. There were about 3326 homologous proteins in C. versatilis, Z. rouxii and S. cerevisiae. PMID- 27234222 TI - Reconstruction after esophagectomy for esophageal cancer patients with a history of gastrectomy. AB - Pedicled jejunal flap and colon graft interposition are choices for esophageal reconstruction in patients with a history of gastrectomy or those who have undergone synchronous esophagogastrectomy. However, the optimal conduit in this situation is still being debated. We reviewed the literature concerning esophageal reconstruction using a conduit other than the stomach. Approximately 10 % of esophagectomized patients undergo esophageal reconstruction using pedicled jejunum or colon interposition in Japan. The jejunal graft and colon graft are selected evenly, although the percentage of jejunal graft use is gradually increasing. Microvascular supercharge was performed in most of the reports of pedicled jejunal graft reconstruction, whereas vascular enhancement was not popularly used in the reports of colon graft interposition. Although the incidences of graft loss and anastomotic leakage were comparable between grafts, mortality rates seem to be higher in patients who undergo colon graft reconstruction than in those who undergo reconstruction with a jejunal graft. Prospective comparisons of short-term outcomes as well as long-term quality of life are needed to identify the best method of reconstruction. PMID- 27234223 TI - Aortic valve replacement and prosthesis-patient mismatch in the era of trans catheter aortic valve implantation. AB - OBJECTIVE: The treatment strategy for aortic stenosis (AS) has been changing due to newly developed valvular prostheses and trans-catheter aortic valve implantation (TAVI). To determine the role of new modalities for AS with a small aortic root, papers using the concept of prosthesis-patient mismatch (PPM) were reviewed. METHODS: First, to determine the cut-off value of the indexed effective orifice area (IEOA) for defining PPM, the studies of surgical aortic valve replacement (SAVR) with a follow-up longer than 5 years and a patient number larger than 500 were reviewed. Second, the papers comparing TAVI and SAVR were reviewed. Furthermore, the prevalence of PPM was reviewed, with the addition of papers on aortic root enlargement, sutureless AVR, and aortic valve reconstruction with autologous pericardium. RESULTS AND CONCLUSION: The results of the long-term survival after aortic valve replacement (AVR) have indicated that an IEOA less than 0.65 cm(2)/m(2) should be avoided in all cases, whereas the indications for patients with an IEOA between 065 and 0.85 cm(2)/m(2) should be determined by considering multiple factors. A large body size and younger age have a significantly negative influence on the long-term survival. In Asian population, the prevalence of PPM was low, despite the fact that the size of the aortic annulus was small. The IEOA after TAVI was larger than after surgical AVR in population-matched studies. To evaluate the role of TAVI and other modalities for a small aortic root, studies with a longer follow-up and larger volume are thus warranted. PMID- 27234224 TI - Multicenter prospective study of sublobar resection for c-stage I non-small cell lung cancer patients unable to undergo lobectomy (KLSG-0801): complete republication. AB - BACKGROUND: Local therapy for stage I non-small cell lung cancer (NSCLC) is divided into surgical and radiation treatment, and given to patients unable to tolerate a lobectomy. A prospective phase II study of cases that received stereotactic body radio therapy (SBRT) (JCOG0403) revealed an overall 3-year survival rate (3-YSR) of 76.0 %, 3-year relapse free survival rate (3-YRFS) of 69.0 %, and rate of morbidity of grade 3 or greater of 9 %. However, few prospective multicenter studies have reported regarding surgery for high-risk stage I NSCLC patients. METHODS: We investigated this issue in the setting of a prospective multicenter observational study. Thirty-two high-risk NSCLC patients (30 males, 2 females; median age 74 years, 61-85 years) were analyzed. RESULTS: Two (6.3 %) showed morbidity of grade 3 or greater, though there were no postoperative deaths. The margin local control rate was 97.0 % (surgical margin recurrence, 1) and local recurrence control rate was 75.0 % (ipsilateral thorax recurrence, 8), while the 3-YSR and 3-YRFS was 79.0 and 75.9 %, respectively. CONCLUSION: A sublobar pulmonary resection for patients unable to tolerate a lobectomy with stage I NSCLC was shown to be safe and provided results comparable with those of SBRT. PMID- 27234225 TI - Percutaneous transapical closure of cardiac apex and mitral prosthetic paravalvular leak is feasible and alternative approach to the septal approach. PMID- 27234226 TI - Engineering Escherichia coli for production of 4-hydroxymandelic acid using glucose-xylose mixture. AB - BACKGROUND: 4-Hydroxymandelic acid (4-HMA) is a valuable aromatic fine chemical and widely used for production of pharmaceuticals and food additives. 4-HMA is conventionally synthesized by chemical condensation of glyoxylic acid with excessive phenol, and the process is environmentally unfriendly. Microbial cell factory would be an attractive approach for 4-HMA production from renewable and sustainable resources. RESULTS: In this study, a biosynthetic pathway for 4-HMA production was constructed by heterologously expressing the fully synthetic 4 hydroxymandelic acid synthase (shmaS) in our L-tyrosine-overproducing Escherichia coli BKT5. The expression level of shmaS was optimized to improve 4-HMA production by fine tuning of four promoters of different strength combined with three plasmids of different copy number. Furthermore, two genes aspC and tyrB in the competitive pathway were deleted to block the formation of byproduct to enhance 4-HMA biosynthesis. The final engineered E. coli strain HMA15 utilized glucose and xylose simultaneously and produced 15.8 g/L of 4-HMA by fed-batch fermentation in 60 h. CONCLUSIONS: Metabolically engineered E. coli strain for 4 HMA production was designed and constructed, and efficiently co-fermented glucose and xylose, the major components in the hydrolysate mixture of agricultural biomass. Our research provided a promising biomanufacturing route to produce 4 HMA from lignocellulosic biomass. PMID- 27234227 TI - Chromosome number reduction in the sister clade of Carica papaya with concomitant genome size doubling. AB - PREMISE OF THE STUDY: Caricaceae include six genera and 34 species, among them papaya, a model species in plant sex chromosome research. The family was held to have a conserved karyotype with 2n = 18 chromosomes, an assumption based on few counts. We examined the karyotypes and genome size of species from all genera to test for possible cytogenetic variation. METHODS: We used fluorescent in situ hybridization using standard telomere, 5S, and 45S rDNA probes. New and published data were combined with a phylogeny, molecular clock dating, and C values (available for ~50% of the species) to reconstruct genome evolution. KEY RESULTS: The African genus Cylicomorpha, which is sister to the remaining Caricaceae (all neotropical), has 2n = 18, as do the species in two other genera. A Mexican clade of five species that includes papaya, however, has 2n = 18 (papaya), 2n = 16 (Horovitzia cnidoscoloides), and 2n = 14 (Jarilla caudata and J. heterophylla; third Jarilla not counted), with the phylogeny indicating that the dysploidy events occurred ~16.6 and ~5.5 million years ago and that Jarilla underwent genome size doubling (~450 to 830-920 Mbp/haploid genome). Pericentromeric interstitial telomere repeats occur in both Jarilla adjacent to 5S rDNA sites, and the variability of 5S rDNA sites across all genera is high. CONCLUSIONS: On the basis of outgroup comparison, 2n = 18 is the ancestral number, and repeated chromosomal fusions with simultaneous genome size increase as a result of repetitive elements accumulating near centromeres characterize the papaya clade. These results have implications for ongoing genome assemblies in Caricaceae. PMID- 27234228 TI - Polyploidy: Pitfalls and paths to a paradigm. AB - Investigators have long searched for a polyploidy paradigm-rules or principles that might be common following polyploidization (whole-genome duplication, WGD). Here we attempt to integrate what is known across the more thoroughly investigated polyploid systems on topics ranging from genetics to ecology. We found that while certain rules may govern gene retention and loss, systems vary in the prevalence of gene silencing vs. homeolog loss, chromosomal change, the presence of a dominant genome (in allopolyploids), and the relative importance of hybridization vs. genome doubling per se. In some lineages, aspects of polyploidization are repeated across multiple origins, but in other species multiple origins behave more stochastically in terms of genetic and phenotypic change. Our investigation also reveals that the path to synthesis is hindered by numerous gaps in our knowledge of even the best-known systems. Particularly concerning is the absence of linkage between genotype and phenotype. Moreover, most recent studies have focused on the genetic and genomic attributes of polyploidy, but rarely is there an ecological or physiological context. To promote a path to a polyploidy paradigm (or paradigms), we propose a major community goal over the next 10-20 yr to fill the gaps in our knowledge of well studied polyploids. Before a meaningful synthesis is possible, more complete data sets are needed for comparison-systems that include comparable genetic, genomic, chromosomal, proteomic, as well as morphological, physiological, and ecological data. Also needed are more natural evolutionary model systems, as most of what we know about polyploidy continues to come from a few crop and genetic models, systems that often lack the ecological context inherent in natural systems and necessary for understanding the drivers of biodiversity. PMID- 27234229 TI - A transposon present in specific strains of Bacillus subtilis negatively affects nutrient- and dodecylamine-induced spore germination. AB - Spore germination shows a large inter-strain variability. Spores of certain Bacillus subtilis strains, including isolates from spoiled food products, exhibit different germination behavior from spores of the well-studied model organism Bacillus subtilis 168, often for unknown reasons. In this study, we analyzed spore germination efficiencies and kinetics of seventeen B. subtilis strains with previously sequenced genomes. A subsequent gene-trait matching analysis revealed a correlation between a slow germination phenotype and the presence of a mobile genetic element, i.e., a Tn1546-like transposon. A detailed investigation of the transposon elements showed an essential role of a specific operon (spoVA2mob ) in inhibiting spore germination with nutrients and with the cationic surfactant dodecylamine. Our results indicate that this operon negatively influences release of Ca-DPA by the SpoVA channel and may additionally alter earlier germination events, potentially by affecting proteins in the spore inner membrane. The spoVA2mob operon is an important factor that contributes to inter-strain differences in spore germination. Screening for its genomic presence can be applied for identification of spores that exhibit specific properties that impede spore eradication by industrial processes. PMID- 27234230 TI - Long-term efficacy and safety of interferon alpha-2a therapy in severe refractory ophthalmic Behcet's disease. AB - Ophthalmic involvement is the most debilitating complication of Behcet's disease (BD). The aim of the current study is to report on the efficacy and safety of a long-term use of interferon alpha-2a (IFNalpha-2a) in the treatment of refractory ophthalmic BD in the Azari population of Iran. We retrospectively analyzed the clinical data of 12 patients with ophthalmic BD who were under IFNalpha-2a therapy. All these patients had previously been treated unsuccessfully with corticosteroid and at least one conventional immunosuppressive drug. IFNalpha-2a was administered at a daily dose of 6 million IU (MIU). After controlling the symptoms, a dose of 6 MIU three times per week was applied for 8-12 weeks, and then, a dose of 3 MIU was administered three times per week as a subcutaneous injection. Visual acuity and total inflammatory activity index (TIAI) were used in order to assess the response to the treatment. Response to the treatment and complete eye remission were obtained in 10 (83.3 %) and 7 (58.3 %) patients, irrespectively. Improvement or stabilization of visual acuity was observed in 18 (81.8 %) out of 22 eyes. After a mean period of 29.6 months, the use of IFNa-2a was discontinued in eight (66.7 %) patients. Unaltered vision for 2 years after IFNa-2a discontinuation happened in eight (100 %) patients. IFNa-2a is probably effective and safe in the treatment of refractory sight-threatening ophthalmic BD in the Azari population of Iran. PMID- 27234231 TI - STAT4 rs7574865 G/T polymorphism is associated with rheumatoid arthritis and disease activity, but not with anti-CCP antibody levels in a Mexican population. AB - Rheumatoid arthritis (RA) is a systemic autoimmune disease in whose etiology genetic factors are known to play an important role. Among the genes associated with RA, STAT4 could be an important factor in conducting helper T cells toward the pro-inflammatory Th1 and Th17 lineages. The aim of this study is to determine the association of the STAT4 polymorphism rs7574865 with RA, disease activity, and anti-cyclic citrullinated peptide (CCP) antibody levels in a Mexican population. Genotyping was carried out using the Taqman(r) system from Applied Biosystems in 140 patients with RA and 150 healthy subjects. Disease activity was evaluated by a rheumatologist using the DAS28 and Spanish-HAQ-DI instruments. Anti-CCP levels were determined by ELISA. Associations of the genotypes of rs7574865 with DAS28, HAQ, and anti-CCP antibody levels with RA were determined. Findings showed that the GT and TT genotypes and the T allele from rs7574865 were all associated as risk factors for RA, independently of their anti-CCP status. An association with moderate-to-high disease activity (DAS28 >= 3.2) was also found. Additionally, patients with the GT or TT genotypes showed lower HAQ values than those who carried the GG genotype. No differences in anti-CCP antibody levels or DAS28 and genotypes were found. This work supports the association of the STAT4 rs7574865 polymorphism with RA and disease activity, but not with anti-CCP antibody levels in a Mexican population. PMID- 27234233 TI - Intersection of mitochondrial fission and fusion machinery with apoptotic pathways: Role of Mcl-1. AB - Mitochondria actively contribute to apoptotic cell death through mechanisms including the loss of integrity of the outer mitochondrial membrane, the release of intermembrane space proteins, such as cytochrome c, in the cytosol and the caspase cascade activation. This process is the result of careful cooperation not only among members of the Bcl-2 family but also dynamin-related proteins. These events are often accompanied by fission of the organelle, thus linking mitochondrial dynamics to apoptosis. Emerging evidences are suggesting a fine regulation of mitochondrial morphology by Bcl-2 family members and active participation of fission-fusion proteins in apoptosis. The debate whether in mitochondrial morphogenesis the role of Bcl-2 family members is functionally distinct from their role in apoptosis is still open and, above all, which morphological changes are associated with cell death sensitisation. This review will cover the findings on how the mitochondrial fission and fusion machinery may intersect apoptotic pathways focusing on recent advances on the key role played by Mcl-1. PMID- 27234234 TI - Differential gene expression in gall midge susceptible rice genotypes revealed by suppressive subtraction hybridization (SSH) cDNA libraries and microarray analysis. AB - BACKGROUND: A major pest of rice, the Asian rice gall midge (Orseolia oryzae Wood Mason), causes significant yield losses in the rice growing regions throughout Asia. Feeding by the larvae induces susceptible plants to produce nutritive tissue to support growth and development. In order to identify molecular signatures during compatible interactions, genome wide transcriptional profiling was performed using SSH library and microarray technology. RESULTS: Results revealed up-regulation of genes related to primary metabolism, nutrient relocation, cell organization and DNA synthesis. Concomitantly, defense, secondary metabolism and signaling genes were suppressed. Further, real-time PCR validation of a selected set of 20 genes, in three susceptible rice varieties (TN1, Kavya and Suraksha) during the interaction with the respective virulent gall midge biotypes, also revealed variation in gene expression in Kavya as compared to TN1 and Suraksha. CONCLUSIONS: These studies showed that virulent insects induced the plants to step up metabolism and transport nutrients to their feeding site and suppressed defense responses. But Kavya rice mounted an elevated defense response during early hours of virulent gall midge infestation, which was over-powered later, resulting in host plant susceptibility. PMID- 27234232 TI - Fluorescence activated cell sorting followed by small RNA sequencing reveals stable microRNA expression during cell cycle progression. AB - BACKGROUND: Previously, drug-based synchronization procedures were used for characterizing the cell cycle dependent transcriptional program. However, these synchronization methods result in growth imbalance and alteration of the cell cycle machinery. DNA content-based fluorescence activated cell sorting (FACS) is able to sort the different cell cycle phases without perturbing the cell cycle. MiRNAs are key transcriptional regulators of the cell cycle, however, their expression dynamics during cell cycle has not been explored. METHODS: Following an optimized FACS, a complex initiative of high throughput platforms (microarray, Taqman Low Density Array, small RNA sequencing) were performed to study gene and miRNA expression profiles of cell cycle sorted human cells originating from different tissues. Validation of high throughput data was performed using quantitative real time PCR. Protein expression was detected by Western blot. Complex statistics and pathway analysis were also applied. RESULTS: Beyond confirming the previously described cell cycle transcriptional program, cell cycle dependently expressed genes showed a higher expression independently from the cell cycle phase and a lower amplitude of dynamic changes in cancer cells as compared to untransformed fibroblasts. Contrary to mRNA changes, miRNA expression was stable throughout the cell cycle. CONCLUSIONS: Cell cycle sorting is a synchronization-free method for the proper analysis of cell cycle dynamics. Altered dynamic expression of universal cell cycle genes in cancer cells reflects the transformed cell cycle machinery. Stable miRNA expression during cell cycle progression may suggest that dynamical miRNA-dependent regulation may be of less importance in short term regulations during the cell cycle. PMID- 27234235 TI - Accumulation of starch in Zn-deficient rice. AB - Zinc (Zn) is an essential micronutrient for living organisms, and understanding the molecular mechanisms of Zn deficiency may help to develop strategies to mitigate this problem. Microarray analysis of Zn deficient rice revealed the up regulation of several genes involved in Zn transport. Moreover many genes involved in starch synthesis/transport were up-regulated by Zn deficiency in rice roots and shoots. Furthermore, starch granules were detected mainly in the cortical cells of these tissues. The gene encoding inactive RNase was much more highly transcribed than those encoding active RNases. Although the level of RNA degradation in a crude extract of Zn-deficient shoots was higher than that of Zn sufficient shoots, addition of Zn significantly reduced the level of degradation. These results indicate that RNA degradation could be regulated by the amount of Zn in the cell, and that the tolerance of rice plants to low levels of Zn is promoted by the accumulation of starch and inactive RNase. PMID- 27234236 TI - Application of temperature, water stress, CO2 in rice growth models. AB - In recent decades, numerous studies have attempted to project the impact of hypothesised anthropogenic climate change on rice production. In this study, we offer a comprehensive review of our current understanding related to temperature, CO2, and water-demand parameters in rice growth models. As to future rice yield, night time temperature should be focused in the models as well as day time temperature owing to the contribution of temperature on the night time respiration. Furthermore, although CO2-enhanced photosynthesis is critical for the accurate prediction of rice production in a higher CO2 atmosphere, we found that recent well-developed photosynthesis-stomatal model cannot realize the variation of CO2 stomatal sensitivity with humidity conditions. To estimate water stress under projected climate-change conditions, rice growth model should be required to link with water resource model, which includes natural processes and anthropogenic regulations. The understanding of abilities and limitations in the models is important not only to improve the schemes that models employ, but to also critically review the simulated results. PMID- 27234238 TI - Evolutionary expansion and functional diversification of oligopeptide transporter gene family in rice. AB - BACKGROUND: Oligopeptide transporters (OPTs) play important roles in the mobilization of organic nitrogenous compounds and usually associate with tissues that show signs of rapid protein hydrolysis, such as germinating seeds and senescing leaves. This study is to investigate rice OPT genes. RESULTS: A total of sixteen OsOPT genes (Os for Oryza sative L.) were identified in the rice genome, which were then classified into six sections that belong to two subfamilies (the PT and YSL subfamily). The major mechanisms for evolutionary expansion of the sixteen genes during the rice genome evolution include segmental and tandem duplication. Calculation of the duplication event dates indicated that the sixteen genes originated from nine original OsOPT genes, and the duplication events could be classified into three evolutionary stages. The first evolutionary stage occurred approximately 50 million years ago (Mya) and involved the evolution of four new genes. The second evolutionary stage was approximately 20 Mya and was marked by the appearance of two new genes, and the third evolutionary stage was approximately 9 Mya when two new genes evolved. Mining of the expression database and RT-PCR analysis indicated that the expression of most duplicated OsOPT genes showed high tissue specificities. Diverse expression patterns for the sixteen genes were evaluated using both semi-quantitative RT-PCR and the MPSS data. Expression levels of some OsOPT genes were regulated by abiotic and biotic stresses suggesting the potential involvement of these gene products in rice stress adaptation. Five OsOPT gene mutants showed abnormal development and growth, the primary analysis of five OsOPT gene mutants suggested that they may be necessary for rice development. CONCLUSIONS: These results suggested that rice-specific OsOPT genes might be potentially useful in improving rice. PMID- 27234237 TI - Salinity tolerance mechanisms in glycophytes: An overview with the central focus on rice plants. AB - Elevated Na(+) levels in agricultural lands are increasingly becoming a serious threat to the world agriculture. Plants suffer osmotic and ionic stress under high salinity due to the salts accumulated at the outside of roots and those accumulated at the inside of the plant cells, respectively. Mechanisms of salinity tolerance in plants have been extensively studied and in the recent years these studies focus on the function of key enzymes and plant morphological traits. Here, we provide an updated overview of salt tolerant mechanisms in glycophytes with a particular interest in rice (Oryza sativa) plants. Protective mechanisms that prevent water loss due to the increased osmotic pressure, the development of Na(+) toxicity on essential cellular metabolisms, and the movement of ions via the apoplastic pathway (i.e. apoplastic barriers) are described here in detail. PMID- 27234239 TI - Mapping and characterization of quantitative trait loci for mesocotyl elongation in rice (Oryza sativa L.). AB - Mesocotyl elongation is an important trait for seedling emergence in direct seeding cultivation in rice. In this study, a backcross inbred line (BIL) population from a cross between Kasalath and Nipponbare was employed to map quantitative trait loci (QTLs) for mesocotyl elongation. A total of 5 QTLs for mesocotyl length were identified on chromosomes 1, 3, 7, 9, and 12 in 2 independent experiments. At all QTL, the Kasalath alleles contributed to an increase in mesocotyl length. Two QTLs (qMel-1 and qMel-3) on chromosomes 1 and 3 were consistently detected in both experiments. To fine map the QTLs, a cross was made between 2 chromosome segment substitution lines (CSSL-6 and CSSL-15), each harboring the Kasalath allele across the qMel-1 and qMel-3 regions, and an F2:3 population was developed. A two-way ANOVA indicated that no epistatic interaction was detected between the 2 QTLs in the F2 population (P = 0.31). Moreover, analysis of two F3 near-isogenic lines (NILs) derived from the same cross, indicated that the 2 QTLs act additively in distinct or complementary pathways in controlling mesocotyl elongation. Substitution mapping indicated that the qMel-1 QTL was located between the 2 SSR markers RM5448 and RM5310, which are 3,799-kb apart, and that the qMel-3 QTL was located between the 2 SSR markers RM3513 and RM1238, which are 6,964-kb apart. To our knowledge, this is the first report to fine-map QTLs for mesocotyl elongation and to analyze their interaction. PMID- 27234240 TI - Re-sequencing and genetic variation identification of a rice line with ideal plant architecture. AB - BACKGROUND: The ideal plant architecture (IPA) includes several important characteristics such as low tiller numbers, few or no unproductive tillers, more grains per panicle, and thick and sturdy stems. We have developed an indica restorer line 7302R that displays the IPA phenotype in terms of tiller number, grain number, and stem strength. However, its mechanism had to be clarified. FINDINGS: We performed re-sequencing and genome-wide variation analysis of 7302R using the Solexa sequencing technology. With the genomic sequence of the indica cultivar 9311 as reference, 307 627 SNPs, 57 372 InDels, and 3 096 SVs were identified in the 7302R genome. The 7302R-specific variations were investigated via the synteny analysis of all the SNPs of 7302R with those of the previous sequenced none-IPA-type lines IR24, MH63, and SH527. Moreover, we found 178 168 7302R-specific SNPs across the whole genome and 30 239 SNPs in the predicted mRNA regions, among which 8 517 were Non-syn CDS. In addition, 263 large-effect SNPs that were expected to affect the integrity of encoded proteins were identified from the 7302R-specific SNPs. SNPs of several important previously cloned rice genes were also identified by aligning the 7302R sequence with other sequence lines. CONCLUSIONS: Our results provided several candidates account for the IPA phenotype of 7302R. These results therefore lay the groundwork for long-term efforts to uncover important genes and alleles for rice plant architecture construction, also offer useful data resources for future genetic and genomic studies in rice. PMID- 27234241 TI - Genetic structure of Thai rice and rice accessions obtained from the International Rice Research Institute. AB - BACKGROUND: Although the genetic structure of rice germplasm has been characterized worldwide, few studies investigated germplasm from Thailand, the world's largest exporter of rice. Thailand and the International Rice Research Institute (IRRI) have diverse collections of rice germplasm, which could be used to develop breeding lines with desirable traits. This study aimed to investigate the level of genetic diversity and structures of Thai and selected IRRI germplasm. Understanding the genetic structure and relationships among these germplasm will be useful for parent selection used in rice breeding programs. RESULTS: From the 98 InDel markers tested for single copy and polymorphism, 19 markers were used to evaluate 43 Thai and 57 IRRI germplasm, including improved cultivars, breeding lines, landraces, and 5 other Oryza species. The Thai accessions were selected from all rice ecologies such as irrigated, deep water, upland, and rainfed lowland ecosystems. The IRRI accessions were groups of germplasm having agronomic desirable traits, including temperature-sensitive genetic male sterility (TGMS), new plant type, early flowering, and biotic and abiotic stress resistances. Most of the InDel markers were genes with diverse functions. These markers produced the total of 127 alleles for all loci, with a mean of 6.68 alleles per locus, and a mean Polymorphic Information Content (PIC) of 0.440. Genetic diversity of Thai rice were 0.3665, 0.4479 and 0.3972 for improved cultivars, breeding lines, and landraces, respectively, while genetic diversity of IRRI improved and breeding lines were 0.3272 and 0.2970, respectively. Cluster, structure, and differentiation analyses showed six distinct groups: japonica, TGMS, deep-water, IRRI germplasm, Thai landraces and breeding lines, and other Oryza species. CONCLUSIONS: Thai and IRRI germplasm were significantly different. Thus, they can be used to broaden the genetic base and trait improvements. Cluster, structure, and differentiation analyses showed concordant results having six distinct groups, in agreement with their development, and ecologies. PMID- 27234242 TI - Specific patterns of genetic diversity among aromatic rice varieties in Myanmar. AB - BACKGROUND: After observing peculiar rice varieties in Myanmar, in terms of classification in varietal groups and of grain quality, we focused on Myanmar varieties and analyzed variations at 19 microsatellite loci as well as sequences of the aroma gene BADH2. RESULTS: Microsatellites were able to retrieve the well established classification into Indica (isozyme group 1), Japonica (group 6, comprising temperate and tropical forms) and specific groups from the Himalayan foothills including some Aus varieties (group 2) and some aromatic varieties (group 5). They revealed a new cluster of accessions close to, but distinct from, non-Myanmar varieties in group 5. With reference to earlier terminology, we propose to distinguish a group "5A" including group 5 varieties from the Indian subcontinent (South and West Asia) and a group "5B" including most group 5 varieties from Myanmar. In Myanmar varieties, aroma was distributed in group 1 (Indica) and in group 5B. New BADH2 variants were found. Some accessions carried a 43 bp deletion in the 3' UTR that was not completely associated with aroma. Other accessions, all of group 5B, displayed a particular BADH2 allele with a 3 bp insertion and 100% association with aroma. CONCLUSION: With the new group and the new alleles found in Myanmar varieties, our study shows that the Himalayan foothills contain series of non-Indica and non-Japonica varietal types with novel variations for useful traits. PMID- 27234243 TI - Seed wintering and deterioration characteristics between weedy and cultivated rice. AB - BACKGROUND: Incidences of weedy rice continuously occurred in paddy fields because its shattering seeds were able to over-winter. In this research, the seed deterioration of weedy rice was investigated compared with cultivated rice, and the wintering characteristics of these two types of rice were investigated with the field wintering test, freezing resistance test, and accelerated aging test. RESULTS: For the wintering test, the seeds of weedy rice were placed on the soil surface of a paddy with cultivated rice seeds during the 2008/2009 and 2009/2010 winter seasons from November to April. The viability of seeds after wintering was 4.3% for cultivated rice, but 92.7% for weedy rice in 2008/2009. In the second wintering test, the seeds were placed under flooded and dry paddy conditions. The seed viability of cultivated rice was 5% in dry paddy and 0.5% in flooded paddy, but weedy rice maintained a high viability during winter of 90% in the dry paddy and 61% in the flooded paddy. Following freezing treatment of the imbibed seeds, the seed viability was 78% for weedy rice and 16% for cultivated rice. The deterioration of seed tissue induced by freezing treatment was observed by the tetrazolium test. In an accelerated aging test at low temperature and soaking conditions, the seed viability of the weedy rice was 40% higher than the cultivated rice 90 days after treatment. During accelerated aging of seeds, the protein content remained higher in the weedy rice compared to the cultivated rice, and fat acidity remained lower in the weedy rice compared to the cultivated rice. Catalase and superoxide dismutase activity of the weedy rice was 4 times higher than that of the cultivated rice, and DPPH radical scavenging activity of the weedy rice was also much higher than for the cultivated rice. CONCLUSION: In conclusion, the superior ability of seed wintering in weedy rice was based on freezing resistibility of embryo cellular tissue and higher antioxidant activity to protect seed deterioration during the winter season. PMID- 27234245 TI - OGRO: The Overview of functionally characterized Genes in Rice online database. AB - BACKGROUND: The high-quality sequence information and rich bioinformatics tools available for rice have contributed to remarkable advances in functional genomics. To facilitate the application of gene function information to the study of natural variation in rice, we comprehensively searched for articles related to rice functional genomics and extracted information on functionally characterized genes. RESULTS: As of 31 March 2012, 702 functionally characterized genes were annotated. This number represents about 1.6% of the predicted loci in the Rice Annotation Project Database. The compiled gene information is organized to facilitate direct comparisons with quantitative trait locus (QTL) information in the Q-TARO database. Comparison of genomic locations between functionally characterized genes and the QTLs revealed that QTL clusters were often co localized with high-density gene regions, and that the genes associated with the QTLs in these clusters were different genes, suggesting that these QTL clusters are likely to be explained by tightly linked but distinct genes. Information on the functionally characterized genes compiled during this study is now available in the O verview of Functionally Characterized G enes in R ice O nline database (OGRO) on the Q-TARO website ( http://qtaro.abr.affrc.go.jp/ogro ). The database has two interfaces: a table containing gene information, and a genome viewer that allows users to compare the locations of QTLs and functionally characterized genes. CONCLUSIONS: OGRO on Q-TARO will facilitate a candidate-gene approach to identifying the genes responsible for QTLs. Because the QTL descriptions in Q TARO contain information on agronomic traits, such comparisons will also facilitate the annotation of functionally characterized genes in terms of their effects on traits important for rice breeding. The increasing amount of information on rice gene function being generated from mutant panels and other types of studies will make the OGRO database even more valuable in the future. PMID- 27234244 TI - Rice UBC13, a candidate housekeeping gene, is required for K63-linked polyubiquitination and tolerance to DNA damage. AB - While plant growth and reproduction is dependent on sunlight, UV irradiation from sunlight is one of the major genotoxic stresses that threaten plant survival and genome stability. In addition, many environmental chemicals can also damage the plant genome. In yeast and mammalian cells protection against the above genome instability is provided by an error-free DNA-damage tolerance (DDT) pathway, which is dependent on Ubc13-mediated K63-linked polyubiquitination of the proliferating cell nuclear antigen (PCNA). In this study, we isolated the UBC13 gene from rice and characterized its functions. Expression of OsUBC13 can protect a yeast ubc13 null mutant against spontaneous and environmental DNA damage. Furthermore, OsUbc13 physically interacts with human Ubc13 partners Mms2 and Uev1A, and catalyzes K63 polyubiquitination in vitro. These observations collectively suggest that the K63 polyubiquitination is conserved in rice, and that OsUBC13 may be involved in DDT and other cellular processes. In addition, OsUBC13 is constitutively expressed at a high level even under various stress conditions, suggesting that it is a housekeeping gene. PMID- 27234246 TI - A WUSCHEL-related homeobox 3B gene, depilous (dep), confers glabrousness of rice leaves and glumes. AB - BACKGROUND: Glabrousness is an important agricultural trait for the practical breeding of rice. In this study, depilous (dep), the gene responsible for glabrous leaves and glumes of rice was identified by map-based cloning. RESULTS: The dep gene encodes a WUSCHEL-related homeobox 3B that was fine-mapped to a 22 kb region on the short arm of chromosome 5 using progenies derived from crosses between Koshihikari (pubescent) and GLSL15, an Oryza glaberrima chromosome segment substitution line (glabrous). Complementation tests confirmed the conditioning of the glabrous phenotype by the dep gene. Phylogenetic analysis showed that dep groups with the WOX3 family of plant-specific homeobox transcription factors that are involved in regulating lateral organ development. Localization of dep in the nucleus indicates the function of the gene as a transcription factor. Spatial expression of the gene was observed in the base of young shoots, the leaf sheath, midrib, young roots and nodal structures. CONCLUSION: The identification and cloning of dep will not only provide basis for future research on the elucidation of the molecular mechanisms underlying trichome formation in rice but will also aid in breeding programs for the development of glabrous varieties. PMID- 27234247 TI - Molecular mapping of the Pi2/9 allelic gene Pi2-2 conferring broad-spectrum resistance to Magnaporthe oryzae in the rice cultivar Jefferson. AB - BACKGROUND: Utilization of broad-spectrum resistance (R) genes is an effective and economical strategy to control the fungal pathogen Magnaporthe oryzae, the causal agent of the rice blast disease. Among the cloned blast resistance genes, Pi9, Pi2 and Piz-t confer broad-spectrum resistance to diverse M. oryzae isolates and were isolated from the Pi2/9 locus on chromosome 6. Identification and isolation of additional R genes with different resistance spectra from this locus will provide novel genetic resources for better control of this important rice disease. RESULTS: In this study, we identified a dominant R gene, Pi2-2, at the Pi2/9 locus from Jefferson, an elite U.S. rice cultivar, through genetic and physical mapping. Inoculation tests showed that Jefferson has different resistant specificities to M. oryzae isolates compared rice lines with the Pi9, Pi2 and Piz t genes. Fine mapping delimited Pi2-2 to a 270-kb interval between the markers AP5659-3 and RM19817, and this interval contains three nucleotide-binding site leucine-rich repeat (NBS-LRR) genes in the Nipponbare genome. Five bacterial artificial chromosome (BAC) clones spanning the region were identified, and a BAC contig covering the Pi2-2 locus was constructed. CONCLUSIONS: We identified a new allelic gene at the Pi2/9 locus and fine-mapped the gene within a 270-kb region. Our results provide essential information for the isolation of the Pi2-2 gene and tightly linked DNA markers for rice blast resistance breeding. PMID- 27234248 TI - A WUSCHEL-like homeobox gene, OsWOX3B responses to NUDA/GL-1 locus in rice. AB - BACKGROUND: Most of the rice varieties are pubescent. However, the presence of trichomes is an undesirable characteristic in rice production because trichomes can cause atmospheric pollution. The use of glabrous rice varieties represents a solution to this problem. Yunnan Nuda Rice, a glabrous cultivar that constitutes approximately 20% of rice germplasms in Yunnan can provide important recourse for breeding of glabrous rice varieties. RESULTS: The "Nuda" phenotype in Yunnan Nuda Rice was found to be controlled by a single recessive allelic gene within the well-characterized GL-1 locus. A high-resolution genetic and physical map was constructed using 1,192 Nuda individuals from the F2 population that was delivered from the cross between the Yunnan Nuda variety HMK and the pubescent TN1 variety. The NUDA/GL-1 gene was mapped to a 28.5 kb region containing six annotated genes based on the Nipponbare genomic sequence. By comparing the sequences and expression patterns of different pubescent and glabrous varieties, LOC_Os05g02730, a WUSCHEL-like homeobox gene (OsWOX3B) was identified as the candidate gene. This hypothesis was confirmed by RNA interference (RNAi) and transgenic complementation. Trichome deficiency in RNAi lines was associated with increased efficiency of grain packaging but did not affect the main agronomic traits. CONCLUSION: NUDA/GL-1 locus encodes OsWOX3B gene. PMID- 27234249 TI - Drought yield index to select high yielding rice lines under different drought stress severities. AB - BACKGROUND: Drought is the most severe abiotic stress reducing rice yield in rainfed drought prone ecosystems. Variation in intensity and severity of drought from season to season and place to place requires cultivation of rice varieties with different level of drought tolerance in different areas. Multi environment evaluation of breeding lines helps breeder to identify appropriate genotypes for areas prone to similar level of drought stress. From a set of 129 advanced rice (Oryza sativa L.) breeding lines evaluated under rainfed drought-prone situations at three locations in eastern India from 2005 to 2007, a subset of 39 genotypes that were tested for two or more years was selected to develop a drought yield index (DYI) and mean yield index (MYI) based on yield under irrigated, moderate and severe reproductive-stage drought stress to help breeders select appropriate genotypes for different environments. RESULTS: ARB 8 and IR55419-04 recorded the highest drought yield index (DYI) and are identified as the best drought-tolerant lines. The proposed DYI provides a more effective assessment as it is calculated after accounting for a significant genotype x stress-level interaction across environments. For rainfed areas with variable frequency of drought occurrence, Mean yield index (MYI) along with deviation in performance of genotypes from currently cultivated popular varieties in all situations helps to select genotypes with a superior performance across irrigated, moderate and severe reproductive-stage drought situations. IR74371-70-1-1 and DGI 75 are the two genotypes identified to have shown a superior performance over IR64 and MTU1010 under all situations. CONCLUSION: For highly drought-prone areas, a combination of DYI with deviation in performance of genotypes under irrigated situations can enable breeders to select genotypes with no reduction in yield under favorable environments compared with currently cultivated varieties. For rainfed areas with variable frequency of drought stress, use of MYI together with deviation in performance of genotypes under different situations as compared to presently cultivated varieties will help breeders to select genotypes with superior performance under all situations. PMID- 27234250 TI - Functional Improvement in Rats' Pancreatic Islets Using Magnesium Oxide Nanoparticles Through Antiapoptotic and Antioxidant Pathways. AB - According to undiscovered toxicity and safety of magnesium oxide nanoparticles (MgO NPs) in isolated pancreatic islet cells, this study was designed to examine the effects of its various concentrations on a time-course basis on the oxidative stress, viability, and function of isolated islets of rat's pancreas. Pancreatic islets were isolated and exposed to different MgO NP (<100 nm) concentrations within three different time points. After that, oxidative stress biomarkers were investigated and the best exposure time was selected. Then, safety of MgO NPs was investigated by flow cytometry and fluorescent staining, and levels of insulin secretion and caspase activity were measured. The results illustrated a considerable decrease in oxidative stress markers such as reactive oxygen species (ROS) and lipid peroxidation (LPO) levels of pancreatic islets which were treated by MgO NPs for 24 h. Also, in that time of exposure, cell apoptosis investigation by flow cytometry and insulin test showed that MgO NPs, in a concentration of 100 MUg/ml, decreased the rate of apoptotic cells via inhibiting caspase-9 activity and made a significant increase in the level of insulin secretion. Data of function and apoptosis biomarkers correlated with each other. It is concluded that the use of MgO NPs in concentration of as low as 100 MUg/ml can induce antiapoptotic, antioxidative, and antidiabetic effects in rat pancreatic islets, which support its possible benefit in islet transplantation procedures. PMID- 27234251 TI - Effects of Fluoride on Expression of P450, CREM and ACT Proteins in Rat Testes. AB - Fluoride (F) is an essential trace element that humans and animals ingest from water, air, and fluoride-containing products; however, excessive fluoride absorption can damage a variety of organs and tissues, including the male reproductive system. Our previous studies found that fluoride exposure lowered sperm quality and interfered with spermatogenesis; however, the exact mechanism remained unclear. Proteins cytochrome P450 (P450), cAMP-responsive element modulator (CREM), and activator of CREM in testis (ACT) play the key roles in spermatogenesis and sperm motility. To investigate whether fluoride affects the expression of P450, CREM, and ACT, we used immunohistochemical techniques to determine expression levels of these proteins in testes of rats administered 100 mg NaF/L for 2 weeks via drinking water. The results showed that P450 expression was decreased while CREM and ACT expression was increased in the fluoride group, compared to the control. These data suggest that fluoride can impair male reproduction by affecting expression of P450, CREM, and ACT in the testes. PMID- 27234252 TI - Biological Response of Broiler Chickens to Decreasing Dietary Inclusion Levels of Zinc Glycine Chelate. AB - The study was carried out to evaluate the effect of Zn-Gly supplementation on the selected antioxidative enzymes and on the mineral composition in the liver and faeces as well as the biochemical and haematological parameters of chicken blood. Two hundred and fifty-one-day-old Ross 308 male broiler chicks were randomly allotted to five dietary treatments, each of which was replicated five times (10 birds in each cage). Five experimental groups were formed: control negative (CN) without Zn, control positive supplemented with 100 mg ZnO, and three groups supplemented with 100, 50, and 25 mg Zn-Gly. An increase (P < 0.05) was recorded in the concentration of Cu and Zn in chicken livers after Zn-Gly supplementation, irrespective of the level of supply with the diet. The addition of 100 mg.Zn-Gly improved the activity of SODCuZn (P < 0.05) and reduced the MDA value (P < 0.05) in chicken livers. The addition of 100, 50, and 25 mg Zn-Gly reduced the concentration of zinc in the birds' droppings, compared to the CN and 100 mg ZnO group. Zn-Gly at the level of 50 mg increased the concentration of Cu and Ca in chicken blood. The results indicate that the addition of Zn-Gly increased the antioxidative capacity of the body and storage of Zn and Cu in the liver; it also reduced the amount of Zn excreted with faeces. Zn-Gly can be an alternative to ZnO in providing a good source of Zn to enrich feed mixtures for broilers. PMID- 27234253 TI - Fluoride-Induced Oxidative and Inflammatory Stress in Osteosarcoma Cells: Does It Affect Bone Development Pathway? AB - Oxidative stress is reported to negatively affect osteoblast cells. Present study reports oxidative and inflammatory signatures in fluoride-exposed human osteosarcoma (HOS) cells, and their possible association with the genes involved in osteoblastic differentiation and bone development pathways. HOS cells were challenged with sublethal concentration (8 mg/L) of sodium fluoride for 30 days and analyzed for transcriptomic expression. In total, 2632 transcripts associated with several biological processes were found to be differentially expressed. Specifically, genes involved in oxidative stress, inflammation, osteoblastic differentiation, and bone development pathways were found to be significantly altered. Variation in expression of key genes involved in the abovementioned pathways was validated through qPCR. Expression of serum amyloid A1 protein, a key regulator of stress and inflammatory pathways, was validated through western blot analysis. This study provides evidence that chronic oxidative and inflammatory stress may be associated with the fluoride-induced impediment in osteoblast differentiation and bone development. PMID- 27234254 TI - 'Liquid-Tumor Biopsies' and the Future of Solid Tumor Oncology. PMID- 27234255 TI - A Dual-Channel Sensor for Hg(2+) Based on a Diarylethene with a Rhodamine B Unit. AB - A novel diarylethene derivative with a Rhodamine B unit was synthesized successfully. It displayed favorable photochromism upon irradiation with UV/vis light. Upon addition of Hg(2+), distinct changes were observed in the absorption and fluorescent spectra due to the formation of a 1:1 ligand/metal complex. As a result, the diarylethene can serve as a fluorescence / colorimetric dual-channel sensor for highly selective and sensitive recognition of Hg(2+) in acetonitrile. Moreover, a complicated logic circuit was constructed with the combinational stimuli of UV/vis, Hg(2+)/ EDTA as input signals and the fluorescence intensity at 605 nm as output signal. PMID- 27234256 TI - Variations on a theme: ET-14 notes from mentor and trainees. PMID- 27234257 TI - Characterizing Local Optima for Maximum Parsimony. AB - Finding the best phylogenetic tree under the maximum parsimony optimality criterion is computationally difficult. We quantify the occurrence of such optima for well-behaved sets of data. When nearest neighbor interchange operations are used, multiple local optima can occur even for "perfect" sequence data, which results in hill-climbing searches that never reach a global optimum. In contrast, we show that when neighbors are defined via the subtree prune and regraft metric, there is a single local optimum for perfect sequence data, and thus, every such search finds a global optimum quickly. We further characterize conditions for which sequences simulated under the Cavender-Farris-Neyman and Jukes-Cantor models of evolution yield well-behaved search spaces. PMID- 27234259 TI - Levels of Contamination by Perfluoroalkyl Substances in Honey from Selected European Countries. AB - Perfluoroalkyl substances (PFASs) are man-made chemicals manufactured for numerous applications. The aim of this study was to assess the levels of 10 PFASs in selected types of honey samples from selected eastern, northern and southern European countries. A total of 26 samples of honey were analyzed. PFCAs (perfluoroalkyl carboxylic acids) were detected in almost all (92 %) analyzed samples in the range of 0.124-0.798 ng g(-1) ww (wet weight). The average concentrations of particular PFCAs (ng g(-1) ww) in honey samples increased in the following order: perfluorononanoic acid (0.164) < perfluorooctanoic acid (0.189) < perfluoroheptanoic acid (0.271) < perfluorodecanoic acid (0.278). Amongst perfluoroalkane sulfonates, only perfluorohexane sulfonate (PFHxS) was identified in four of 26 analyzed samples, and its concentrations ranged from 0.080 to 0.191 ng g(-1) ww. Italian eucalyptus honey contained the highest total content of PFASs (0.878 ng g(-1) ww). Samples originating from an industrial region of Poland showed 20 % higher concentrations of PFCAs compared to those from non-industrial regions. PMID- 27234258 TI - Obesity alters molecular and functional cardiac responses to ischemia/reperfusion and glucagon-like peptide-1 receptor agonism. AB - This study tested the hypothesis that obesity alters the cardiac response to ischemia/reperfusion and/or glucagon like peptide-1 (GLP-1) receptor activation, and that these differences are associated with alterations in the obese cardiac proteome and microRNA (miRNA) transcriptome. Ossabaw swine were fed normal chow or obesogenic diet for 6 months. Cardiac function was assessed at baseline, during a 30-minutes coronary occlusion, and during 2 hours of reperfusion in anesthetized swine treated with saline or exendin-4 for 24 hours. Cardiac biopsies were obtained from normal and ischemia/reperfusion territories. Fat-fed animals were heavier, and exhibited hyperinsulinemia, hyperglycemia, and hypertriglyceridemia. Plasma troponin-I concentration (index of myocardial injury) was increased following ischemia/reperfusion and decreased by exendin-4 treatment in both groups. Ischemia/reperfusion produced reductions in systolic pressure and stroke volume in lean swine. These indices were higher in obese hearts at baseline and relatively maintained throughout ischemia/reperfusion. Exendin-4 administration increased systolic pressure in lean swine but did not affect the blood pressure in obese swine. End-diastolic volume was reduced by exendin-4 following ischemia/reperfusion in obese swine. These divergent physiologic responses were associated with obesity-related differences in proteins related to myocardial structure/function (e.g. titin) and calcium handling (e.g. SERCA2a, histidine-rich Ca(2+) binding protein). Alterations in expression of cardiac miRs in obese hearts included miR-15, miR-27, miR-130, miR 181, and let-7. Taken together, these observations validate this discovery approach and reveal novel associations that suggest previously undiscovered mechanisms contributing to the effects of obesity on the heart and contributing to the actions of GLP-1 following ischemia/reperfusion. PMID- 27234260 TI - Special-"T" Training: Extended Follow-up Results from a Residency-Wide Professionalism Workshop on Transgender Health. AB - OBJECTIVE: Transgender people face unique challenges when accessing health care, including stigma and discrimination. Most residency programs devote little time to this marginalized population. METHODS: The authors developed a 90-min workshop to enhance residents' ability to empathize with and professionally treat transgender patients. Attendees completed pre-, post, and 90-day follow-up surveys to assess perceived empathy, knowledge, comfort, interview skill, and motivation for future learning. RESULTS: Twenty-two residents (64.7 %) completed pre- and post-workshop surveys; 90.9 % of these completed the 90-day follow-up. Compared to baseline, there were statistically significant post-workshop increases in perceived empathy, knowledge, comfort, and motivation for future learning. However on 90-day follow-up, there were no statistically significant differences across any of the five domains, compared to baseline. CONCLUSIONS: This workshop produced significant short-term increases in resident professionalism toward transgender patients. However, extended follow-up results highlight the limitations of one-time interventions and call for recurrent programming to yield durable improvements. PMID- 27234262 TI - Co-corresponding Authorship: Institutional Glorification or Ethical Confusion? PMID- 27234261 TI - Effects of contrastive accents on children's discourse comprehension. AB - What role do contrastive accents play in children's discourse comprehension? By 6 years of age, children use contrastive accents during online comprehension to predict upcoming referents (Ito et al., 2014; Sekerina & Trueswell, 2012). But, at this age, children's performance on offline tasks of accent comprehension is poor (e.g., Wells et al., 2004). To examine whether the asymmetry could reflect a developmental stage in which the processing system uses contrastive accents to make local predictions, but fails to incorporate this information into discourse representations, we tested the effect of contrastive accents on children's memory of the content of a discourse. Five-year-olds heard 12 different stories consecutively, one after another, and the critical words were manipulated so that they were produced either with a contrastive L+H* accent or with a presentational H* accent. We found that children remembered facts about the contrast set better when the target word had an appropriate contrastive accent earlier than when it had a presentational accent. The results show that by 5 years, children are able to use contrastive accents for encoding a discourse, as well as for making local predictions during online comprehension. PMID- 27234263 TI - A roadmap for gene system development in Clostridium. AB - Clostridium species are both heroes and villains. Some cause serious human and animal diseases, those present in the gut microbiota generally contribute to health and wellbeing, while others represent useful industrial chassis for the production of chemicals and fuels. To understand, counter or exploit, there is a fundamental requirement for effective systems that may be used for directed or random genome modifications. We have formulated a simple roadmap whereby the necessary gene systems maybe developed and deployed. At its heart is the use of 'pseudo-suicide' vectors and the creation of a pyrE mutant (a uracil auxotroph), initially aided by ClosTron technology, but ultimately made using a special form of allelic exchange termed ACE (Allele-Coupled Exchange). All mutants, regardless of the mutagen employed, are made in this host. This is because through the use of ACE vectors, mutants can be rapidly complemented concomitant with correction of the pyrE allele and restoration of uracil prototrophy. This avoids the phenotypic effects frequently observed with high copy number plasmids and dispenses with the need to add antibiotic to ensure plasmid retention. Once available, the pyrE host may be used to stably insert all manner of application specific modules. Examples include, a sigma factor to allow deployment of a mariner transposon, hydrolases involved in biomass deconstruction and therapeutic genes in cancer delivery vehicles. To date, provided DNA transfer is obtained, we have not encountered any clostridial species where this technology cannot be applied. These include, Clostridium difficile, Clostridium acetobutylicum, Clostridium beijerinckii, Clostridium botulinum, Clostridium perfringens, Clostridium sporogenes, Clostridium pasteurianum, Clostridium ljungdahlii, Clostridium autoethanogenum and even Geobacillus thermoglucosidasius. PMID- 27234264 TI - Hypomyelinating leukodystrophies - a molecular insight into the white matter pathology. AB - Hypomyelinating leukodystrophies (HLDs) are a group of neurodevelopmental disorders that affect proper formation of the myelin sheath in the central nervous system. They are characterized by developmental delay, hypotonia, spasticity, and variable intellectual disability. In the past various classification systems for HLDs have been used, based on imaging findings, clinical manifestation, and organelle-specific disorders. Here we present a molecular insight into HLDs based on a defect in specific gene engaged in myelination. We discuss recent findings on pathogenesis, clinical presentation, and imaging related to these disorders. We focus on HLDs that are in use in differential diagnostics of Pelizaeus-Merzbacher disease (PMD), with a special emphasis on Allan-Herndon-Dudley syndrome (AHDS), an X-linked condition with delayed myelination due to thyroid transport disturbances. On the background of previously published patients we describe a proband initially considered as presenting with a severe PMD, whose diagnosis of AHDS due to a novel nonsense SLC16A2 mutation unraveled two previously undiagnosed generations of affected males who died in infancy from unexplained reasons. Since AHDS is found to be a relatively frequent cause of X-linked intellectual disability, we emphasize the need for determining the whole thyroid profile especially in hypotonic males with a delay of psychomotor development. PMID- 27234265 TI - Lumbar spondylolysis in the adolescent athlete. AB - INTRODUCTION: Spondylolysis is a common occurrence for adolescent athletes who have low back pain. The injury involves a defect in the pars interarticularis, occurring as a result of repeated hyperextension and rotation. CLINICAL PRESENTATION: Clinical findings might include tightness of the hip flexors and hamstrings, weakness of the abdominals and gluteals, and an excessive lordotic posture. The validity of several clinical tests were compared alongside magnetic resonance imaging, but were not able to distinguish spondylolysis from other causes of low back pain. Medical referral should be arranged so that medical imaging and diagnostic testing can be completed to insure a proper diagnosis. INTERVENTIONS: Initial intervention includes rest from sport, which may vary from 2 weeks to 6 months. Bracing is also used to help minimize lumbar lordosis and lumbar extension. Exercises that focus on stabilization and spine neutral position should be incorporated in physical therapy intervention. Avoiding end ranges is important while performing exercises to minimize the translational and rotational stresses on the spine. Surgical interventions have also been recommended for athletes who have had persistent low back pain for more than six months with no relief from rest and bracing. PMID- 27234266 TI - Alan Wilfrid Gough Goolden. PMID- 27234267 TI - Established atherosclerosis might be a prerequisite for chicory and its constituent protocatechuic acid to promote endothelium-dependent vasodilation in mice. AB - SCOPE: Chicory (Cichorium intybus L. var. foliosum, Belgian endive), a typical Mediterranean vegetable, and its constituent protocatechuic acid (PCA) can inhibit established atherosclerosis progression. We thus investigated whether chicory can improve vascular relaxation, a critical pathway for combating atherosclerosis, and whether PCA is a contributor to a chicory-induced effect. METHODS AND RESULTS: Apolipoprotein E-deficient (ApoE-/- ) mice with established atherosclerosis and C57BL/6J mice without atherosclerosis were fed an AIN-93G diet, or AIN-93G plus 0.5% freeze-dried chicory or 0.003% PCA for 1 wk. In ApoE-/ mice, both chicory and PCA consumption increased endothelium-dependent vasodilation and endothelial nitric oxide synthase (eNOS) activity independent of eNOS and phospho-eNOS Ser1177 and Thr495 protein expression. Chicory- or PCA induced eNOS activities were associated with increased vascular tetrahydrobiopterin (BH4 ) levels that result from reduced BH4 oxidation partially through preventing eNOS uncoupling. In C57BL/6J mice, neither chicory nor PCA consumption affected endothelium-dependent vasodilation and eNOS activity. Notably, in vitro studies showed that PCA increases eNOS activity in mouse aortic endothelial cells in co-culture with macrophage foam cells, but not in aortic endothelial cells alone. CONCLUSIONS: Chicory improves eNOS-mediated endothelium-dependent vasodilation by increasing BH4 levels in mice with established atherosclerosis, which might be partially ascribed to its constituent PCA. PMID- 27234268 TI - Ictal lack of binding to brain parenchyma suggests integrity of the blood-brain barrier for 11C-dihydroergotamine during glyceryl trinitrate-induced migraine. AB - SEE DREIER DOI 101093/AWW112 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: For many decades a breakdown of the blood-brain barrier has been postulated to occur in migraine. Hypothetically this would facilitate access of medications, such as dihydroergotamine or triptans, to the brain despite physical properties otherwise restricting their entry. We studied the permeability of the blood-brain barrier in six migraineurs and six control subjects at rest and during acute glyceryl trinitrate-induced migraine attacks using positron emission tomography with the novel radioligand (11)C-dihydroergotamine, which is chemically identical to pharmacologically active dihydroergotamine. The influx rate constant Ki, average dynamic image and time activity curve were assessed using arterial blood sampling and served as measures for receptor binding and thus blood-brain barrier penetration. At rest, there was binding of (11)C-dihydroergotamine in the choroid plexus, pituitary gland, and venous sinuses as expected from the pharmacology of dihydroergotamine. However, there was no binding to the brain parenchyma, including the hippocampus, the area with the highest density of the highest affinity dihydroergotamine receptors, and the raphe nuclei, a postulated brainstem site of action during migraine, suggesting that dihydroergotamine is not able to cross the blood-brain barrier. This binding pattern was identical in migraineurs during glyceryl trinitrate-induced migraine attacks as well as in matched control subjects. We conclude that (11)C-dihydroergotamine is unable to cross the blood-brain barrier interictally or ictally demonstrating that the blood-brain barrier remains tight for dihydroergotamine during acute glyceryl trinitrate-induced migraine attacks. PMID- 27234269 TI - Improving Healthcare Systems to Reduce Healthcare Disparities in Viral Hepatitis. AB - Chronic hepatitis B (CHB) and C (CHC) represent significant public health problems worldwide. Combined, over 7 million persons in the USA are chronically infected with either the hepatitis B or the hepatitis C virus. Although the populations affected by the viruses differ, both CHB and CHC are ideal conditions for preventive screening because of a high prevalence and low rate of diagnosis; an early asymptomatic period; highly sensitive and specific test; and treatments which have been shown to result in improved clinical outcomes including liver related mortality and hepatocellular carcinoma. Improving healthcare delivery for CHB and CHC requires interventions that will increase screening for the infections, expanded capacity for evaluation and monitoring of the infection, and ultimately improved access to treatment. Many of these interventions may leverage opportunities within electronic health records, but must also address unique social, cultural, and language barriers that may prevent effective implementation of novel interventions. Herein, we will review current knowledge related to strategies employed to improve healthcare systems to reduce disparities in viral hepatitis. PMID- 27234271 TI - Helicobacter pylori Gastritis: Susceptible to Further Testing? PMID- 27234270 TI - Eosinophilic Gastroenteritis: An Underdiagnosed Condition. AB - BACKGROUND: Eosinophilic gastroenteritis (EOGE) is a rare idiopathic disease characterized by eosinophil-predominant inflammation of the stomach and/or intestines. Our aims are to determine the epidemiology, clinical features and outcomes of EOGE cases in a tertiary-care hospital. METHODS: Retrospective cohort study of patients with gastrointestinal eosinophilic infiltration from 2004 through 2014. All relevant specimens were reviewed by an expert pathologist. Significant eosinophilic infiltrate was defined as >25 eosinophils/HPF in the stomach or small intestine and >50 eosinophils/HPF in the colon. RESULTS: Three hundred and sixty-one charts were reviewed and 13 EOGE cases were identified, including nine adults and four pediatric cases. The majority (78 %) of adult cases were females. Clinical presentation was variable; most patients (62 %) had abdominal pain, followed by diarrhea (31 %) and nausea/vomiting (31 %). Atopy and food allergies were present in 54 and 38 % of patients, respectively. Weight loss and failure to thrive were present only in pediatric cases (50 vs 0 %; P = .01). Most EOGE cases (69 %) had peripheral eosinophilia, which was more prominent in patients with ascites compared to patients without ascites (37.3 +/- 25.4 vs 9.3 +/- 5.4 %; P = .01). Among patients who had long-term follow-up; 30 % had spontaneous remission, 60 % responded to steroids and/or restriction diet, and 10 % had refractory disease. CONCLUSION: EOGE is an underdiagnosed condition. In contrast to eosinophilic esophagitis; the disease might be female-predominant in adults. High index of clinical suspicion is required for diagnosis. Further studies about the long-term outcomes and the efficacy of restriction diet in adult patients are required. PMID- 27234273 TI - Thyroid screening in trisomy 21. PMID- 27234272 TI - Encapsulation of biophenolic phytochemical EGCG within lipid nanoparticles enhances its stability and cytotoxicity against cancer. AB - Epigallocatechin gallate (EGCG), a green tea polyphenolic catechin, has been known to possess a variety of beneficial biological activities. The in-vitro anti cancer activity of EGCG is well documented. However, the use of EGCG in modern therapeutics is limited due to its poor bioavailability and limited stability at physiological pH. In this study, we have investigated the stability profiles of EGCG in aqueous solutions using UV-vis spectroscopy. Stability results showed very low stability profile of EGCG at physiological pH with rapid degradation under alkaline conditions. Therefore, we have encapsulated EGCG in solid lipid nanoparticles to increase its stability and evaluated for anticancer activity. The lipid core of nanoparticles not only provides an additional structural reinforcement to the nanoparticle assembly, but also makes it biologically compatible, thereby enabling a stealth vehicle for efficient drug delivery. EGCG loaded nanoparticles (EGCG-SLN) were characterized using dynamic light scattering, Fourier transform infrared spectroscopy and differential scanning calorimetry. EGCG and EGCG-SLN were evaluated for their anticancer activities by cellular proliferation. The cytotoxicity of EGCG-SLN was found to be 8.1 times higher against MDA-MB 231 human breast cancer cells and 3.8 times higher against DU-145 human prostate cancer cells than that of the pure EGCG. PMID- 27234274 TI - Multiplex PCR testing during respiratory infections: good for the patient, good for infection prevention and antimicrobial stewardship. PMID- 27234275 TI - Are neonatal stroke and hypoxic-ischemic encephalopathy related? PMID- 27234276 TI - When should we predict outcomes for extreme prematurity? PMID- 27234277 TI - The Barker hypothesis revisited. PMID- 27234278 TI - Math at work: a new neonatal calculator to predict weight loss. PMID- 27234279 TI - Aerobic fitness and academic achievement. PMID- 27234280 TI - The Pediatric Subspecialty Match: Past, Present, and Future. PMID- 27234281 TI - 50 Years Ago in TheJournal ofPediatrics: Hepatolenticular Degeneration: The Comparative Effectiveness of D-Penicillamine, Potassium Sulfide, and Diethyldithiocarbamate as Decoppering Agents. PMID- 27234282 TI - 50 Years Ago in TheJournal ofPediatrics: Induction of Remission in Acute Leukemia of Childhood by Combination of Prednisone and Either 6-Mercaptopurine or Methotrexate. PMID- 27234283 TI - 50 Years Ago in TheJournal ofPediatrics: Idiopathic Thrombocytopenic Purpura in Childhood. PMID- 27234284 TI - 50 Years Ago in TheJournal ofPediatrics: Vitamin B12 Studies in Myelogenous Leukemia of Childhood. PMID- 27234285 TI - 50 Years Ago in TheJournal ofPediatrics: Early versus Delayed Feeding of Low Birth Weight Infants: Effects on Physiologic Jaundice. PMID- 27234286 TI - Correction. PMID- 27234287 TI - Correction. PMID- 27234288 TI - Correction. PMID- 27234289 TI - Foster Care: A Fragile Reality Needing Social Attention, and Economic Investments. PMID- 27234290 TI - Methylmercury degradation and exposure pathways in streams and wetlands impacted by historical mining. AB - Monomethyl mercury (MMHg) and total mercury (THg) concentrations and Hg stable isotope ratios (delta(202)Hg and Delta(199)Hg) were measured in sediment and aquatic organisms from Cache Creek (California Coast Range) and Yolo Bypass (Sacramento Valley). Cache Creek sediment had a large range in THg (87 to 3870ng/g) and delta(202)Hg (-1.69 to -0.200/00) reflecting the heterogeneity of Hg mining sources in sediment. The delta(202)Hg of Yolo Bypass wetland sediment suggests a mixture of high and low THg sediment sources. Relationships between %MMHg (the percent ratio of MMHg to THg) and Hg isotope values (delta(202)Hg and Delta(199)Hg) in fish and macroinvertebrates were used to identify and estimate the isotopic composition of MMHg. Deviation from linear relationships was found between %MMHg and Hg isotope values, which is indicative of the bioaccumulation of isotopically distinct pools of MMHg. The isotopic composition of pre photodegraded MMHg (i.e., subtracting fractionation from photochemical reactions) was estimated and contrasting relationships were observed between the estimated delta(202)Hg of pre-photodegraded MMHg and sediment IHg. Cache Creek had mass dependent fractionation (MDF; delta(202)Hg) of at least -0.40/00 whereas Yolo Bypass had MDF of +0.2 to +0.50/00. This result supports the hypothesis that Hg isotope fractionation between IHg and MMHg observed in rivers (-MDF) is unique compared to +MDF observed in non-flowing water environments such as wetlands, lakes, and the coastal ocean. PMID- 27234291 TI - Gene Expression Profile in Major Depressive Disorder Shows Reduced Mitochondrial Biogenesis. PMID- 27234292 TI - [Quality in diabetes mellitus control in Primary Care Units in Mexico. A study of the perspectives of the patient's family]. AB - OBJECTIVE: To identify the perspectives of the patient's family in the quality of diabetes mellitus control. DESIGN: Qualitative methodology of exploratory design, oriented towards health services research, conducted in 2014 using non probability sampling. LOCATION: Primary Care Units mainly situated in the state of Tabasco, Mexico. PARTICIPANTS AND/OR CONTEXTS: 42 family members were selected, who agreed to participate voluntarily in the study. METHOD: Six focus groups were set up; interview guides and group dynamics were employed. The information was documented, saturated and categorised; the most representative discourses were used, and conclusions reached. RESULTS: The results show a highly critical position of the families as regards the patient, some of which appear justified, and others have a cultural, historical, and to some extent, an ignorance connotation. They have also commented on the health care and the role that patients and families can play, in both cases, also expressed critically. CONCLUSIONS: The family perspectives reveal what they think and feel about diabetes mellitus. It is important to note their lack of support and the content of their expressions due to lack of knowledge of the disease. Their discourses are critical, mythical, and with false beliefs of the fear of being future carriers of the disease. They feel sorry for the patient but they resist taking care of them, and do not want a life with diabetes. The family is the closest support for patients and an invaluable human resource for health services. PMID- 27234293 TI - Horizontal transfers of transposable elements in eukaryotes: The flying genes. AB - Transposable elements (TEs) are the major components of eukaryotic genomes. Their propensity to densely populate and in some cases invade the genomes of plants and animals is in contradiction with the fact that transposition is strictly controlled by several molecular pathways acting at either transcriptional or post transcriptional levels. Horizontal transfers, defined as the transmission of genetic material between sexually isolated species, have long been considered as rare phenomena. Here, we show that the horizontal transfers of transposable elements (HTTs) are very frequent in ecosystems. The exact mechanisms of such transfers are not well understood, but species involved in close biotic interactions, like parasitism, show a propensity to exchange genetic material horizontally. We propose that HTTs allow TEs to escape the silencing machinery of their host genome and may therefore be an important mechanism for their survival and their dissemination in eukaryotes. PMID- 27234295 TI - Occupational Snake Bites: a Prospective Case Series of Patients Reported to the ToxIC North American Snakebite Registry. AB - INTRODUCTION: In the developing world, occupation has been identified as a risk factor for snake bite. Such an association has not been described in the USA. The objective of this study was to describe the epidemiology and clinical manifestations of occupational snake bite in patients reported to the ToxIC North American Snakebite Registry (NASBR). METHODS: This was a prospective case series of patients reported to the ToxIC NASBR between January 1, 2014 and November 5, 2015. Variables collected included snake species, patient demographics, date and location of exposure, occupation, bite location, clinical manifestations, and management. RESULTS: Of 180 adult snake bites reported, 25 (13.9 %; 95 % CI 9.2 19.8 %) were occupational in nature. Rattlesnake envenomations were common (80 %). Most snake bites (96 %) occurred in men. Occupations most associated with snake bite were landscaping (28 %) and working directly with snakes (24 %). Fifty six percent of bites occurred in an outdoor work environment. Seventy-six percent of envenomations were to the upper extremities. Intentional interaction occurred in 40 % of cases, all of which sustained finger envenomations. No cases presented with apparent acute ethanol intoxication. CONCLUSIONS: The majority of occupational snake bites occurred in men working outdoors and were unintentional injuries. Bites involving the upper extremity tended to result from intentional interactions. Acute ethanol intoxication did not appear to be involved with occupational envenomations. PMID- 27234294 TI - Altered DNA base excision repair profile in brain tissue and blood in Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease (AD) is a progressive, multifactorial neurodegenerative disorder that is the main cause of dementia globally. AD is associated with increased oxidative stress, resulting from imbalance in production and clearance of reactive oxygen species (ROS). ROS can damage DNA and other macromolecules, leading to genome instability and disrupted cellular functions. Base excision repair (BER) plays a major role in repairing oxidative DNA lesions. Here, we compared the expression of BER components APE1, OGG1, PARP1 and Polbeta in blood and postmortem brain tissue from patients with AD, mild cognitive impairment (MCI) and healthy controls (HC). RESULTS: BER mRNA levels were correlated to clinical signs and cerebrospinal fluid biomarkers for AD. Notably, the expression of BER genes was higher in brain tissue than in blood samples. Polbeta mRNA and protein levels were significantly higher in the cerebellum than in the other brain regions, more so in AD patients than in HC. Blood mRNA levels of OGG1 was low and PARP1 high in MCI and AD. CONCLUSIONS: These findings reflect the oxidative stress-generating energy-consumption in the brain and the importance of BER in repairing these damage events. The data suggest that alteration in BER gene expression is an event preceding AD. The results link DNA repair in brain and blood to the etiology of AD at the molecular level and can potentially serve in establishing novel biomarkers, particularly in the AD prodromal phase. PMID- 27234296 TI - Baclofen Toxicity Causing Acute, Reversible Dyskinesia. AB - The following unique case demonstrates an episode of acute dyskinesia secondary to oral baclofen toxicity. We discuss an 80-year-old man with a history of Stage III chronic kidney disease, coronary artery disease, diabetes and stroke who presented to the Emergency Department with new onset of behavioral changes and irregular jerking movements. The patient had been recently prescribed baclofen 10mg twice daily for a back strain he suffered; he subsequently was admitted to the hospital, and his symptoms resolved within 48 hours of admission and discontinuance of baclofen. PMID- 27234297 TI - Ubiquitin-like domains can target to the proteasome but proteolysis requires a disordered region. AB - Ubiquitin and some of its homologues target proteins to the proteasome for degradation. Other ubiquitin-like domains are involved in cellular processes unrelated to the proteasome, and proteins containing these domains remain stable in the cell. We find that the 10 yeast ubiquitin-like domains tested bind to the proteasome, and that all 11 identified domains can target proteins for degradation. Their apparent proteasome affinities are not directly related to their stabilities or functions. That is, ubiquitin-like domains in proteins not part of the ubiquitin proteasome system may bind the proteasome more tightly than domains in proteins that are bona fide components. We propose that proteins with ubiquitin-like domains have properties other than proteasome binding that confer stability. We show that one of these properties is the absence of accessible disordered regions that allow the proteasome to initiate degradation. In support of this model, we find that Mdy2 is degraded in yeast when a disordered region in the protein becomes exposed and that the attachment of a disordered region to Ubp6 leads to its degradation. PMID- 27234300 TI - Regulation of vernal migration in Gambel's white-crowned sparrows: Role of thyroxine and triiodothyronine. AB - Appropriate timing of migratory behavior is critical for migrant species. For many temperate zone birds in the spring, lengthening photoperiod is the initial cue leading to morphological, physiological and behavior changes that are necessary for vernal migration and breeding. Strong evidence has emerged in recent years linking thyroid hormone signaling to the photoinduction of breeding in birds while more limited information suggest a potential role in the regulation of vernal migration in photoperiodic songbirds. Here we investigate the development and expression of the vernal migratory life history stage in captive Gambel's white-crowned sparrows (Zonotrichia leucophrys gambelii) in a hypothyroidic state, induced by chemical inhibition of thyroid hormone production. To explore possible variations in the effects of the two thyroid hormones, triiodothyronine and thyroxine, we subsequently performed a thyroid inhibition coupled with replacement therapy. We found that chemical inhibition of thyroid hormones resulted in complete abolishment of mass gain, fattening, and muscle hypertrophy associated with migratory preparation as well as resulting in failure to display nocturnal restlessness behavior. Replacement of thyroxine rescued all of these elements to near control levels while triiodothyronine replacement displayed partial or delayed rescue. Our findings support thyroid hormones as being necessary for the expression of changes in morphology and physiology associated with migration as well as migratory behavior itself. PMID- 27234298 TI - SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development. AB - Skp1-Cul1-F-box protein (SCF) ubiquitin ligases direct cell survival decisions by controlling protein ubiquitylation and degradation. Sufu (Suppressor of fused) is a central regulator of Hh (Hedgehog) signaling and acts as a tumor suppressor by maintaining the Gli (Glioma-associated oncogene homolog) transcription factors inactive. Although Sufu has a pivotal role in Hh signaling, the players involved in controlling Sufu levels and their role in tumor growth are unknown. Here, we show that Fbxl17 (F-box and leucine-rich repeat protein 17) targets Sufu for proteolysis in the nucleus. The ubiquitylation of Sufu, mediated by Fbxl17, allows the release of Gli1 from Sufu for proper Hh signal transduction. Depletion of Fbxl17 leads to defective Hh signaling associated with an impaired cancer cell proliferation and medulloblastoma tumor growth. Furthermore, we identify a mutation in Sufu, occurring in medulloblastoma of patients with Gorlin syndrome, which increases Sufu turnover through Fbxl17-mediated polyubiquitylation and leads to a sustained Hh signaling activation. In summary, our findings reveal Fbxl17 as a novel regulator of Hh pathway and highlight the perturbation of the Fbxl17-Sufu axis in the pathogenesis of medulloblastoma. PMID- 27234301 TI - Scientific Opinion on Risk Assessment of Synthetic Biology. AB - In 2013, three Scientific Committees of the European Commission (EC) drafted Scientific Opinions on synthetic biology that provide an operational definition and address risk assessment methodology, safety aspects, environmental risks, knowledge gaps, and research priorities. These Opinions contribute to the international discussions on the risk governance for synthetic biology developments. PMID- 27234299 TI - HSV-1 ICP27 targets the TBK1-activated STING signalsome to inhibit virus-induced type I IFN expression. AB - Herpes simplex virus (HSV) 1 stimulates type I IFN expression through the cGAS STING-TBK1 signaling axis. Macrophages have recently been proposed to be an essential source of IFN during viral infection. However, it is not known how HSV 1 inhibits IFN expression in this cell type. Here, we show that HSV-1 inhibits type I IFN induction through the cGAS-STING-TBK1 pathway in human macrophages, in a manner dependent on the conserved herpesvirus protein ICP27. This viral protein was expressed de novo in macrophages with early nuclear localization followed by later translocation to the cytoplasm where ICP27 prevented activation of IRF3. ICP27 interacted with TBK1 and STING in a manner that was dependent on TBK1 activity and the RGG motif in ICP27. Thus, HSV-1 inhibits expression of type I IFN in human macrophages through ICP27-dependent targeting of the TBK1-activated STING signalsome. PMID- 27234302 TI - Pasos Hacia La Salud: a randomized controlled trial of an internet-delivered physical activity intervention for Latinas. AB - BACKGROUND: Internet access has grown markedly in Latinos during the past decade. However, there have been no Internet-based physical activity interventions designed for Latinos, despite large disparities in lifestyle-related conditions, such as obesity and diabetes, particularly in Latina women. The current study tested the efficacy of a 6-month culturally adapted, individually tailored, Spanish-language Internet-based physical activity intervention. METHODS: Inactive Latinas (N = 205) were randomly assigned to the Tailored Physical Activity Internet Intervention or the Wellness Contact Control Internet Group. Participants in both groups received emails on a tapered schedule over 6 months to alert them to new content on the website. The primary outcome was minutes/week of moderate to vigorous physical activity (MVPA) at 6 months as measured by the 7 Day Physical Activity Recall; activity was also measured by accelerometers. Data were collected between 2011 and 2014 and analyzed in 2015 at the University of California, San Diego. RESULTS: Increases in minutes/week of MVPA were significantly greater in the Intervention Group compared to the Control Group (mean difference = 50.00, SE = 9.5, p < 0.01). Increases in objectively measured MVPA were also significantly larger in the Intervention Group (mean differences = 31.0, SE = 10.7, p < .01). The Intervention Group was also significantly more likely to meet national physical activity guidelines at 6 months (OR = 3.12, 95% CI 1.46-6.66, p < .05). CONCLUSION: Findings from the current study suggest that this Internet-delivered individually tailored intervention successfully increased MVPA in Latinas compared to a Wellness Contact Control Internet Group. TRIAL REGISTRATION: NCT01834287. PMID- 27234303 TI - High Frequency Electrical Stimulation of Lateral Habenula Reduces Voluntary Ethanol Consumption in Rats. AB - BACKGROUND: Development of new strategies that can effectively prevent and/or treat alcohol use disorders is of paramount importance, because the currently available treatments are inadequate. Increasing evidence indicates that the lateral habenula (LHb) plays an important role in aversion, drug abuse, and depression. In light of the success of high-frequency stimulation (HFS) of the LHb in improving helplessness behavior in rodents, we assessed the effects of LHb HFS on ethanol-drinking behavior in rats. METHODS: We trained rats to drink ethanol under an intermittent access two-bottle choice procedure. We used c-Fos immunohistochemistry and electrophysiological approaches to examine LHb activity. We applied a HFS protocol that has proven effective for reducing helplessness behavior in rats via a bipolar electrode implanted into the LHb. RESULTS: c-Fos protein expression and the frequency of both spontaneous action potential firings and spontaneous excitatory postsynaptic currents were higher in LHb neurons of ethanol-withdrawn rats compared to their ethanol-naive counterparts. HFS to the LHb produced long-term reduction of intake and preference for ethanol, without altering locomotor activity. Conversely, low-frequency electrical stimulation to the LHb or HFS applied to the nearby nucleus did not affect drinking behavior. CONCLUSIONS: Our results suggest that withdrawal from chronic ethanol exposure increases glutamate release and the activity of LHb neurons, and that functional inhibition of the LHb via HFS reduces ethanol consumption. Thus, LHb HFS could be a potential new therapeutic option for alcoholics. PMID- 27234304 TI - Influence of the lateral pterygoid muscle on traumatic temporomandibular joint bony ankylosis. AB - BACKGROUND: The pathogenesis of traumatic TMJ ankylosis remains unclear. This study aimed to verify the role of the lateral pterygoid muscle in the pathogenesis of traumatic temporomandibular joint (TMJ) bony ankylosis. METHODS: Eight 6-month-old male sheep were used in this study. Bilateral TMJ osteotomies were performed to induce sagittal fractures of the mandibular condyle. The lateral one-fourth segment of the disc was removed to establish a model of TMJ bony ankylosis. Subsequently, the function of the left and right lateral pterygoid muscles was blocked (experimental group) or maintained (control group), respectively. At 12 weeks postoperatively, animals were sacrificed and TMJ complex samples were evaluated by gross observation, spiral computed tomography (CT), micro-CT, and histological examinations. RESULTS: Gross observation revealed bony ankylosis in the control TMJs and fibrous adhesions in the experimental TMJs. Spiral CT and micro-CT demonstrated that, compared to the experimental group, the control group showed calcified callus formation in the joint space and roughened articular surfaces after new bone formation, which protruded into the joint space. Maximum mediolateral and anteroposterior condylar diameters were significantly larger in the control group than in the experimental group. Micro-CT also showed that the primary growth orientation of new trabeculae was consistent with the direction of lateral pterygoid traction in the control group, but not in the experimental group. Histological examination showed fibro osseous ankylosis in the control group, but not in the experimental group. CONCLUSIONS: The lateral pterygoid simulates the effects of distraction osteogenesis, which is an important factor in the pathogenesis of TMJ bony ankylosis during the healing of sagittal condylar fractures. PMID- 27234305 TI - Erratum to: Apoptosis mediated leishmanicidal activity of Azadirachta indica bioactive fractions is accompanied by Th1 immunostimulatory potential and therapeutic cure in vivo. PMID- 27234306 TI - The ligand (s) anchored lipobrid nanoconstruct mediated delivery of methotrexate: an effective approach in breast cancer therapeutics. AB - The present study was designed to engineer surface-anchored and methotrexate loaded lipobrid nano-constructs for targeting breast cancer. Ligands (fucose, galactose and mannose) anchored lipobrid nano-constructs were used to compare and assess delivery efficiency in breast cancer cell lines as well as in DMBA induced breast cancer animal model. The developed and characterized formulations were used to comparatively assess cellular uptake, cell-viability, apoptosis, lysosomal membrane permeability, bioavailability, bio-distribution, changes in tumor volume and animal survival. Our results show greater cellular uptake, cytotoxicity at low IC50, apoptosis with altered lysosomal membrane permeability and greater rate of degradation of lysosomal membrane. We saw better bioavailability and tumor targeting efficiency with minimum secondary organ drug distribution. The significant reduction was seen in tumor burden with ligand anchored lipobrids in comparison to plain and MTX-lipobrid formulations. In conclusion, fucose anchored MTX-lipobrid formulation showed promising results, and warrants to explore the development of therapeutic interventions for breast cancer. PMID- 27234307 TI - Laminin alpha5 in the keratinocyte basement membrane is required for epidermal dermal intercommunication. AB - Laminin alpha5 is broadly expressed in the epidermal basement membrane (BM) of mature mice and its elimination at this site (Lama5Ker5 mouse) results in hyperproliferation of basal keratinocytes and a delay in hair follicle development, which correlated with upregulation of the dermally-derived laminin alpha2 and laminin alpha4 chains in the epidermal BM and of tenascin-C subjacent to the BM. In vitro studies revealed laminin 511 to be strongly adhesive for primary keratinocytes and that loss of laminin alpha5 does not result in cell autonomous defects in proliferation. Flow cytometry reveals that the loss of laminin alpha5 resulted in increased numbers of CD45+, CD4+ and CD11b+ immune cells in the skin, which temporo-spatial analyses revealed were detectable only subsequent to the loss of laminin alpha5 and the appearance of the hyperproliferative keratinocyte phenotype. These findings indicate that immune cell changes are the consequence and not the cause of keratinocyte hyperproliferation. Loss of laminin alpha5 in the epidermal BM was also associated with changes in the expression of several dermally-derived growth factors involved in keratinocyte proliferation and hair follicle development in adult but not new born Lama5Ker5 skin, including KGF, EGF and KGF-2. In situ binding of FGF-receptor-2alpha (IIIb)-Fc chimera (FGFR2IIIb) to mouse skin sections revealed decoration of several BMs, including the epidermal BM, which was absent in Lama5Ker5 skin. This indicates reduced levels of FGFR2IIIb ligands, which include KGF and KGF-2, in the epidermal BM of adult Lama5Ker5 skin. Our data suggest an initial inhibitory effect of laminin alpha5 on basal keratinocyte proliferation and migration, which is exacerbated by subsequent changes in growth factor expression by epidermal and dermal cells, implicating laminin alpha5 in epidermal-dermal intercommunication. PMID- 27234308 TI - Deletion of the epidermis derived laminin gamma1 chain leads to defects in the regulation of late hair morphogenesis. AB - Laminins are the most abundant non-collagenous basement membrane (BM) components, composed of an alpha, beta and gamma chain. The laminin gamma1 chain, encoded by LAMC1, is the most abundant gamma chain. The main laminin isoforms in the dermo epidermal junction (DEJ) are laminin-332, laminin-511 and laminin-211, the latter being restricted to the lower part of hair follicles (HFs). Complete deletion of LAMC1 results in lethality around embryonic day 5.5. To study the function of laminin gamma1 containing isoforms in skin development and maturation after birth, we generated mice lacking LAMC1 expression in basal keratinocytes (LAMC1EKO) using the keratin 14 (K14) Cre/loxP system. This deletion resulted in loss of keratinocyte derived laminin-511 and in deposition of fibroblast derived laminin-211 throughout the whole DEJ. The DEJ in areas between hemidesmosomes was thickened, whereas hemidesmosome morphology was normal. Most strikingly, LAMC1EKO mice showed delayed HF morphogenesis accompanied by reduced proliferation of hair matrix cells and impaired differentiation of hair shafts (HS). However, this deletion did not interfere with early HF development, since placode numbers and embryonic hair germ formation were not affected. Microarray analysis of skin revealed down regulation of mainly different hair keratins. This is due to reduced expression of transcription factors such as HoxC13, FoxN1, FoxQ1 and Msx2, known to regulate expression of hair keratins. While the role of laminin 511 in signaling during early hair germ formation and elongation phase has been described, we here demonstrate that epidermal laminin-511 is also a key regulator for later hair development and HS differentiation. PMID- 27234309 TI - The quality of life in boys with Duchenne muscular dystrophy. AB - We conducted a study to evaluate the quality of life in boys with Duchenne muscular dystrophy aged 8-18 years, compared with that in matched healthy controls. A total of 85 boys with Duchenne muscular dystrophy aged 8-18 years and 136 age, sex and living place matched healthy controls were included in this study. Patients and one of their parents separately completed the 27-item Persian version of KIDSCREEN questionnaire (child and adolescent version and parent version). From the children's perspective, the quality of life in patients was found to be lower in two subclasses: "physical activities and health" (p < 0.001) and "friends" (p = 0.005). Parental estimation of their sick child's quality of life was significantly lower than children's own assessment in two subclasses: "physical activities and health" (p < 0.001) and "general mood and feelings" (p < 0.001). Our results indicate that boys with Duchenne muscular dystrophy have quite a satisfactory quality of life. A happier and more hopeful life can be promoted through increasing social support and improving the parental knowledge regarding their child's more positive life perspective. PMID- 27234310 TI - Relationship between muscle impairments, postural stability, and gait parameters assessed with lower-trunk accelerometry in myotonic dystrophy type 1. AB - This study evaluated gait using lower-trunk accelerometry and investigated relationships between gait abnormalities, postural instability, handgrip myotonia, and weakness in lower-limb and axial muscle groups commonly affected in myotonic dystrophy type 1 (DM1). Twenty-two patients (11 men, 11 women; age = 42 years (range: 26-51)) with DM1 and twenty healthy controls (9 men, 11 women; age = 44 years (range: 24-50)) participated in this study. Gait analysis using lower trunk accelerometry was performed at self-selected walking pace. Postural stability was measured via center of pressure displacement analysis using a force platform during eyes-closed normal stance. Handgrip myotonia was quantified using force-relaxation curve modeling. Patients displayed lower walking speed, stride frequency, stride length, gait regularity, and gait symmetry. Strength of ankle plantar flexors, ankle dorsal flexors and neck flexors correlated with interstride regularity in the vertical direction (rho = 0.57, rho = 0.59, and rho = 0.44, respectively; all P < 0.05). Knee extension strength correlated with gait symmetry in the anteroposterior direction (rho = 0.45, P < 0.05). Center of pressure velocity was greater in patients and correlated with neck flexion and ankle plantar flexion weakness (rho = -0.51 and rho = -0.62, respectively; both P < 0.05), and with interstride regularity in the vertical direction (rho = -0.58, P < 0.05). No correlation was found between handgrip myotonia and any other variable studied. Lower-trunk accelerometry allows the characterization of gait pattern abnormalities in patients with DM1. Further studies are required to determine the relevance of systematic gait analysis using lower-trunk accelerometry for patient follow-up and intervention planning. PMID- 27234311 TI - Different alpha crystallin expression in human age-related and congenital cataract lens epithelium. AB - BACKGROUND: The purpose of this study was to investigate the different expressions of alphaA-crystallin and alphaB-crystallin in human lens epithelium of age-related and congenital cataracts. METHODS: The central part of the human anterior lens capsule approximately 5 mm in diameter together with the adhering epithelial cells, were harvested and processed within 6 hours after cataract surgery from age-related and congenital cataract patients or from normal eyes of fresh cadavers. The mRNA and soluble protein levels of alphaA-crystallin and alphaB-crystallin in the human lens epithelium were detected by real-time PCR and western blots, respectively. RESULTS: The mRNA and soluble protein expressions of alphaA-crystallin and alphaB-crystallin in the lens epithelium were both reduced in age-related and congenital cataract groups when compared with the normal control group. However, the degree of alpha-crystallin loss in the lens epithelium was highly correlated with different cataract types. The alpha crystallin expression of the lens epithelium was greatly reduced in the congenital cataract group but only moderately decreased in the age-related cataract group. The reduction of alphaA-crystallin soluble protein levels in the congenital cataract group was approximately 2.4 fold decrease compared with that of the age-related cataract group, while an mRNA fold change of 1.67 decrease was observed for the age-related cataract group. Similarly, the reduction of soluble protein levels of alphaB-crystallin in the congenital cataract group was approximately a 1.57 fold change compared with that of the age-related cataract group. A 1.75 fold change for mRNA levels compared with that of the age-related cataract group was observed. CONCLUSIONS: The results suggest that the differential loss of alpha-crystallin in the human lens epithelium could be associated with the different mechanisms of cataractogenesis in age-related versus congenital cataracts, subsequently resulting in different clinical presentations. PMID- 27234312 TI - Characterization of virus-like particles derived from a GII.3 norovirus strain distantly related with current dominating strains. AB - Genogroup II, genotype 3 noroviruses (GII.3 NoVs) are secondary to GII.4 NoVs in causing acute non-bacterial gastroenteritis worldwide. In our previous study, we found that virus-like particles (VLPs) derived from a GII.3 NoV strain exhibited no binding activity to any salivary and synthetic histo-blood group antigens (HBGAs) tested. In this study, the nucleotide sequence encoding the major capsid protein of another documented GII.3 NoV strain was codon-optimized and synthesized, and the major capsid protein was expressed using recombinant baculovirus virus expression system. The assembly of VLPs was verified by electron microscopy, and the binding profiles of the assembled VLPs to salivary HBGAs were determined, and in vitro VLP-salivary HBGAs binding blockade assay was used to test the cross-blocking effects of hyperimmune sera produced against different genotypes (GI.2, GII.3, and GII.4). The expression of the major capsid proteins led to the successful assembly of VLPs, and in vitro VLP-salivary HBGAs binding assay indicated that the assembled VLPs bound to salivary HBGAs from blood type A, B, AB, and O individuals, with the highest binding capacity to type A salivary HBGAs. In vitro VLP-salivary HBGAs binding blockade assay demonstrated the absence of blocking activities for hyperimmune sera produced against GI.2and GII.4 VLPs and the presence of blocking activity for that against GII.3 VLPs. Our results suggest the absence of cross-blocking activities among different genotypes and the presence of blocking activities between GII.3 NoVs from different clusters, which might have implications for the design of multivalent NoV vaccines. PMID- 27234313 TI - Combination effects of azole fungicides in male rats in a broad dose range. AB - Two 28-day feeding studies were performed in male rats to investigate combination effects of azole fungicides in a broad dose range. Following separate administration of cyproconazole, epoxiconazole, prochloraz, propiconazole, and tebuconazole at five dose levels, the first three compounds were selected to be administered in two different mixtures at three dose levels including very low doses. Here we present the data obtained by clinical observations, pathology, histopathology, clinical chemistry and haematology. The liver was the common main target organ of all compounds and their mixtures. In addition, epoxiconazole exhibited an effect on the adrenals. Furthermore, food consumption and efficiency and body weight (gain) were affected. Adverse effects of the combinations were observed at dose levels at which the individual substances caused similar effects. No evidence of adverse effects was found at dose levels below the previously established NOAELs. Our findings indicate that the concept of dose additivity appears sufficiently protective for risk assessment of the fungicides examined. Besides toxicological testing, tissue residues of the azole compounds in liver, testis and kidney were determined revealing remarkable differences following administration of the single substances and of the mixtures. PMID- 27234314 TI - Recreational use of marijuana during pregnancy and negative gestational and fetal outcomes: An experimental study in mice. AB - The prevalence of marijuana use among pregnant women is high. However, the effects on gestation and fetal development are not well known. Epidemiological and experimental studies present conflicting results because of the route of administration, dose, time of exposure, species used, and how Cannabis toxicity is tested (prepared extracts, specific components, or by pyrolysis). In this study, we experimentally investigated the effects of maternal inhalation of Cannabis sativa smoke representing as nearly as possible real world conditions of human marijuana use. Pregnant mice (n=20) were exposed (nose-only) daily for 5min to marijuana smoke (0.2g of Cannabis) from gestational day (GD) 5.5 to GD17.5 or filtered air. Food intake and maternal weight gain were recorded. Ultrasound biomicroscopy was performed on 10.5 and 16.5dpc.On GD18.5, half of the dams were euthanized for the evaluation of term fetus, placenta, and resorptions. Gestation length, parturition, and neonatal outcomes were evaluated in the other half. Five minutes of daily (low dose) exposure during pregnancy resulted in reduced birthweight, and litter size was not altered; however, the number of male pups per litter was higher. Besides, placental wet weight was increased and fetal to placental weight ratio was decreased in male fetuses, showing a sex-specific effect. At the end of gestation, females from the Cannabis group presented reduced maternal net body weight gain, despite a slight increase in their daily food intake compared to the control group. In conclusion, our results indicate that smoking marijuana during pregnancy even at low doses can be embryotoxic and fetotoxic. PMID- 27234315 TI - Understanding alterations on blood and biochemical parameters in athletes that use dietary supplements, steroids and illicit drugs. AB - In recent years it was verified there are an alarming growing number of teenagers and young adults using a combination of dietary supplements (DS) anabolic androgenic steroids (AAS) and drugs of abuse. This practice is used to improve physical fitness and appearance, may cause serious side effects. This article shows the alterations in the hematological and renal function parameters associate with these substances in 40 athletes. This research involved three steps: 1-the administration of a self-completion questionnaire ; 2-the assessment of hematological and biochemical parameters of renal function and; 3 toxicological urinalysis. Hematological and biochemical tests were conducted in an accredited laboratory and the toxicological urinalysis was validated in our laboratory using liquid-liquid extraction (LLE) and gas chromatography-mass spectrometry (GC-MS). The testosterone levels in the participants who consumed steroids increased 20-60% and alterations in serum creatinine, urea and uric reached values of up to 1.9; 60.6 and 7.5mg/dL, respectively. The toxicological urinalysis supports self-reports confirming the use of AAS and recreational drugs, putting at risk the health of those athletes increasing the chances of kidney diseases. PMID- 27234316 TI - Biochemical responses induced by co-exposition to arsenic and titanium dioxide nanoparticles in the estuarine polychaete Laeonereis acuta. AB - The production and use of nanoparticles, as titanium dioxide (nanoTiO2) is growing exponentially in the last years and their release into aquatic environment seem be inevitable. Once into environment, this nanomaterial can interact with other contaminant, as arsenic, and to exert toxic effect in living organisms. So, the objective of present study was to evaluate if the co-exposure to nanoTiO2 (1mg/L) can alter the As effect (nominal concentration of 50MUg/L) in the estuarine polychaeta Laeonereis acuta after 48h of exposure. Were performed biochemical analyses such ROS production, enzymatic activities (GST, GR and GSTOmega), total antioxidant capacity against peroxyl radicals and damage to macromolecules (lipid and DNA), besides also were determined the accumulation of total arsenic and arsenic speciation in the worms. The results showed that co exposure induced an increase in the ROS levels, decrease in total antioxidant capacity, increase in GR activity, and damage in lipid and DNA. Also, the co exposure showed to affect the metabolization capacity of arsenic characterized by increase in dimethylated arsenic forms, a compound moderately toxic. So, these results suggest that the co-exposure to both contaminants is harmful to this species and the use of nanoTiO2 to treatment of contaminated water by arsenic should be considered of a toxicological point of view. PMID- 27234317 TI - An autophagic process is activated in HepG2 cells to mediate BDE-100-induced toxicity. AB - To reduce flammability and meet regulatory requirements, Brominated Flame Retardants (BFRs) are added to a wide variety of consumer products including furniture, textiles, electronics, and construction materials. Exposure to polybrominated phenyl ethers (PBDEs) adversely affects the human health. Bearing in mind that (i) PBDEs are potentially toxic, (ii) the mechanism of PBDE toxicity is unclear, and (iii) the importance of the autophagy to the field of toxicology is overlooked, this study investigates whether an autophagic process is activated in HepG2 cells (human hepatoblastoma cell line) to mediate BDE-100-induced toxicity. HepG2 cells were exposed with BDE-100 at three concentrations (0.1, 5, and 25MUM), selected from preliminary toxicity tests, for 24 and 48h. To assess autophagy, immunocytochemistry was performed after exposure of HepG2 cells to BDE 100. Labeling of HepG2 cells with 100nM LysoTracker Red DND-99 aided examination of lysosome distribution. Proteins that are key to the autophagic process (p62 and LC3) were evaluated by western blotting. DNA was isolated and quantified to assess mitochondrial DNA copy number by qPCR on the basis of the number of DNA copies of a mitochondrial encoded gene normalized against a nuclear encoded gene. Conversion of LC3-I to LC3-II increased in HepG2 cells. Pre-addition of 100nM wortmannin decreased the amount of LC3 in the punctuate form and increased nuclear fragmentation (apoptotic feature). HepG2 cells exposed to BDE-100 presented increased staining with the lysosomal dye and had larger LC3 and p62 content after pre-treatment with ammonium chloride. The mitochondrial DNA copy number decreased, which probably constituted an attempt of the cell to manage mitochondrial damage by selective mitochondrial degradation (mitophagy). In conclusion, an autophagic process is activated in HepG2 cells to mediate BDE-100 induced toxicity. PMID- 27234318 TI - Protection against UV-induced toxicity and lack of mutagenicity of Antarctic Sanionia uncinata. AB - Antarctica moss Sanionia uncinata (Hedw.) Loeske is exposed in situ to damaging levels of ultraviolet (UV) radiation. This moss has the ability to respond to UV radiation exposure producing secondary metabolites such as flavonoids, and has been recommended as a potential source of photoprotective compounds and antioxidants. The aim of the present paper was to investigate the free-radical scavenging activity and mutagenic and photomutagenic properties of methanolic (ME), hydroethanolic (HE) and ethanolic (EE) extracts of S. uncinata. The phenolic contents were evaluated by high-performance liquid chromatography (HPLC) and spectrophotometry. The findings showed that ME and EE presented the highest phenolic contents and inhibited free radical-scavenging activity against 2,2' diphenyl-1 picrylhydrazyl (DPPH) and the HPLC analysis indicated several classes of phenolic acids and flavonoids. The sun protection factors (SPF) were determined by an in vitro method and the results showed significant values. The SPF values of BZ-3 at 50MUg/mL increased significantly in association with ME, HE and EE. The extracts did not induce mutagenicity in auxotrophic Salmonella typhimurium histidine and photomutagenicity was not detected in the TA102 and TA104 strains after exposure to UV-A at doses of up to 6.5J/cm2 for the TA102 strain and up to 0.24J/cm2 for the TA104 strain. In addition, with the exception of ME, all the extracts induced photoprotective effects in the presence of the TA104 strain at 0.04J/cm2. The present results suggest that S. uncinata extracts did not induce photomutation and showed promise for photoprotection against the photobiological and ROS-inducing effects of the UV-A radiation. PMID- 27234319 TI - Penile Traumatic Neuroma: A Late Complication of Penile Dorsal Neurotomy to Treat Premature Ejaculation. AB - INTRODUCTION: Traumatic neuroma is a reactive process caused by the regeneration of an injured nerve that usually forms a nodular proliferation of small nerve bundles. Penile traumatic neuroma is rare; only a few cases related to circumcision have been reported. AIM: To report on a case of traumatic neuroma in the penis after selective dorsal neurotomy (SDN) to treat premature ejaculation. METHODS: The penile traumatic neuroma was successfully removed by excision and confirmed by histopathology. RESULTS: A 55-year-old man who had had several painless, slow-growing nodules on his penis for 2 years presented to our hospital. He had no history of genital trauma, urinary tract infection, or penile surgery, except SDN to treat premature ejaculation. The nodules were excised and the final diagnosis was traumatic neuroma. No recurrence has been detected during 1 year of follow-up. CONCLUSION: The main complications of SDN are recurrence of premature ejaculation, pain or paresthesia on the glans penis, and erectile dysfunction. However, no traumatic neuroma has been reported as a complication. We report that a traumatic neuroma can occur after SDN. PMID- 27234321 TI - Metastatic melanoma: Pathologic characterization, current treatment, and complications of therapy. AB - Metastatic melanoma (MM) has the potential to involve virtually any anatomical site, and it also has a wide spectrum of histological appearances. General clinicopathologic data pertaining to MM are presented in this review, together with a discussion of its differential diagnosis and therapy. "Biological" agents used in the treatment of melanoma are considered, along with the pathological features of the complications that they may cause. PMID- 27234322 TI - Mucosal melanomas: Site-specific information, comparisons with cutaneous tumors, and differential diagnosis. AB - Melanoma of the skin is the fifth leading new cancer diagnosis, having accounted for almost 77,000 cases and more than 9000 deaths in the United States in 2013. Although cutaneous neoplasms of this type are relatively common, their mucosal counterparts are not. Mucosal melanomas comprise approximately 1.3% of all melanocytic malignancies. Although they are rare, these lesions present at an advanced stage with more adverse prognoses. In addition, at a molecular level, they have proven to be distinct entities because they possess genetic mutations not usually seen in their cutaneous counterparts. Conversely, a sizable proportion of mucosal melanomas lack the gene aberrations seen in cutaneous melanomas. Such findings indicate different pathways in tumorigenesis for the two subtypes. Because melanomas arising from the mucosae are not often encountered, very little has been published on staging guidelines and prognostic factors. This causes dilemmas for both patients and physicians. Further work is necessary to define staging systems for all mucosal locations, so that accurate prognoses can be assigned to such lesions. PMID- 27234320 TI - Detection of Plasmodium using filter paper and nested PCR for patients with malaria in Sanliurfa, in Turkey. AB - BACKGROUND: The objective of this study to detect Plasmodium and a subspecies of Plasmodium using filter paper in malaria endemic province, Sanliurfa, in Turkey, compare the results of nested PCR (nPCR) with microscopy for the diagnosis of malaria and present the epidemiological data of malaria. METHODS: This study was carried out in malaria-endemic Sanliurfa between 2008 and 2011. Finger prick blood samples, thick and thin Giemsa-stained blood smears, were collected from 153 malaria-suspected farmworkers. The Giemsa-stained blood smears were examined microscopically. The obtained DNA products, extracted from blood-spotted filter papers or from the thick blood smears, were analysed by nPCR to amplify the 18S ssrRNA Plasmodium gene with genus and specific primers. The results of the microscopy were compared to the nPCR results. RESULTS: Of the specimens, 7.2 % were determined as Plasmodium-positive by microscopy, whereas 9.8 % were determined as Plasmodium-positive by nPCR. Of the positive Plasmodium specimens, 93.33 % were identified as P. vivax. Four out of the 15 specimens that were microscopically diagnosed as negative were Plasmodium-positive with nPCR. When compared to the microscopy, the sensitivity, specificity, and positive predictive values of the nPCR were determined as 100, 97.2 and 73.3 %, respectively. nPCR was determined to be more sensitive and specific than microscopy. CONCLUSIONS: This study revealed that the accurate diagnosis of malaria by nPCR was compulsory in malaria-endemic Sanliurfa and nPCR should be applied routinely in laboratory studies. PMID- 27234323 TI - A novel regulatory role for tissue transglutaminase in epithelial-mesenchymal transition in cystic fibrosis. AB - Cystic fibrosis (CF) is a genetic disorder caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) for which there is no overall effective treatment. Recent work indicates tissue transglutaminase (TG2) plays a pivotal intracellular role in proteostasis in CF epithelia and that the pan TG inhibitor cysteamine improves CFTR stability. Here we show TG2 has another role in CF pathology linked with TGFbeta1 activation and signalling, induction of epithelial-mesenchymal transition (EMT), CFTR stability and induction of matrix deposition. We show that increased TG2 expression in normal and CF bronchial epithelial cells increases TGFbeta1 levels, promoting EMT progression, and impairs tight junctions as measured by Transepithelial Electric Resistance (TEER) which can be reversed by selective inhibition of TG2 with an observed increase in CFTR stability. Our data indicate that selective inhibition of TG2 provides a potential therapeutic avenue for reducing fibrosis and increasing CFTR stability in CF. PMID- 27234324 TI - Quality Measures Need Measures of Quality. PMID- 27234325 TI - Erratum. PMID- 27234326 TI - Erratum to: Acoustic behavior associated with cooperative task success in bottlenose dolphins (Tursiops truncatus). PMID- 27234334 TI - The correlation between coloration and exploration behaviour varies across hierarchical levels in a wild passerine bird. AB - In vertebrates, darker individuals are often found to be more active and willing to take risks (representing characteristics of a 'proactive' coping style), whereas lighter individuals are instead more cautious and less active (representing characteristics of a 'reactive' coping style). It is thus generally expected that melanin-based coloration and proactivity form a suite of positively integrated traits at the among-individual level. Here, we use a multigenerational pedigree of free-living great tits (Parus major) to partition variation in, and the correlation between, melanin-based breast stripe ('tie') size and exploration behaviour (a proxy for coping style) into its among- and within-individual components. We show that both traits harbour heritable variation. Against predictions, tie size and speed of exploration were negatively correlated at the among-individual level due to the combined influences of permanent environmental and additive genetic effects. By contrast, the two traits were weakly positively correlated within individuals (i.e. individuals increasing in tie size after moult tended to become more explorative). The patterns of among-individual covariance were not caused by correlational selection as we found additive and opposite selection pressures acting on the two traits. These findings imply that testing hypotheses regarding the existence of a 'syndrome' at the among individual level strictly requires variance partitioning to avoid inappropriate interpretations as the negative 'unpartitioned' phenotypic correlation between exploration and tie size resulted from counteracting effects of within- and among individual correlations. Identifying sources and levels of (co)variation in phenotypic traits is thus critical to our understanding of biological patterns and evolutionary processes. PMID- 27234335 TI - [Arterial hypertension at the time of diagnosis of type 2 diabetes in adults]. AB - AIM OF STUDY: Our aim was to determine the prevalence of arterial hypertension and evaluate its association with vascular chronic complications in newly diagnosed type 2 diabetes patients, in an observational, prospective study. MATERIAL AND METHODS: We have recruited 327 newly diagnosed type 2 diabetics aged from 40 to 70 years, in general practice units. Arterial blood pressure has been measured according to WHO guidelines. All data on clinical examination, diabetes's chronic complications were collected during 6 months and statistically analyzed with Epi-Info 6.04 database program. RESULTS: Among the patients, 66.7% had arterial hypertension at diagnosis of diabetes, 28% were known as hypertensive. They were 54.3+/-8.4years old and have metabolic syndrome in 88.4%. Men have more frequently a higher cardiovascular risk, higher glycaemia and albuminuria; women were more likely to have a metabolic syndrome and a higher BMI. Blood pressure increases with cardiovascular risk and metabolic syndrome components. Microangiopathy is present in 65.7%, atherosclerosis in 59.4 and 71.2% of hypertensive patients who have atherosclerosis have also microvascular complications. CONCLUSION: The prevalence of arterial hypertension in newly diagnosed type 2 diabetes is high. This association is linked with an alarming level of vascular morbidity. Early detection and treatment of these two diseases need a better implication and motivation of patients and health care providers. Clinicaltrials.gov ID: NCT02002091. PMID- 27234336 TI - [Impact of the ExSel((r)) test administration on the excessive salt consumption in hypertensive patients followed in general practice]. AB - OBJECTIVE: To evaluate the impact of the Exsel((r)) test administration on salt intake in hypertensive subjects followed in general practice. METHOD: In a group practice of general practitioners in the Ile-de-France, the ExSel((r)) test http://www.comitehta.org/testez-vous/consommez-vous-du-sel-en-exces-test-exsel/ was administered to 329 outpatients. The questionnaire was filled in the waiting room and then commented by the doctor. In patients treated for hypertension, 24hours urinary Na was prescribed after the consultation. Excessive salt consumption (ESC) was defined as a urinary Na>=200mmol/day. RESULTS: The population included subjects aged on average 57 years with 43 % of hypertensive patients. According Exsel((r)), an ESC was suspected in 36 % of patients and was more common in treated hypertensive patients (44 %; [36-52]) in hypertensive men (57 %; [46-68]) than among non-hypertensive (31 %; [24-38]) and non hypertensive women (18 % [11-25]). Urinary Na has been finally performed by 63 % of subjects and 24hours excretion was 157+/-56mmol in men and 123+/-39mmol in women. After this 24hours urinary sodium evaluation, subsequent to ExSel((r)) test, ESC frequency was lower among men (19 %) and very low among women (5 %). CONCLUSION: To estimate the ESC, the ExSel((r)) test is easily performed in general practice while 24hours urinary sodium is more difficult to obtain. Achieving an ExSel((r)) test was accompanied by a decrease in the frequency of excessive salt consumers with a greater effect in women. PMID- 27234337 TI - Metatranscriptome of the protistan community in Reticulitermes flaviceps. AB - The hindgut of lower termites harbors various symbiotic protists, which perform varied functions in lignocellulose decomposition. As termites are social insects, the species and numbers of these flagellated protists in the termite gut vary among the different castes. Juvenile hormones (JHs) can regulate caste differentiation in termites. In this study, we used the juvenile hormone analog fenoxycarb to induce termite workers (Reticulitermes flaviceps) to differentiate into pre-soldiers. A metatranscriptomic investigation of the protistan community was then performed by 454 pyrosequencing. From a thorough analysis based on 597 312 generated reads, we found that the starch and sucrose metabolism pathway was the most abundant pathway across the metatranscriptome. The current study demonstrates that the metatranscriptome of the protistan community in termites contains an abundance of lignocellulase, which plays a vital role in termite nutrition. PMID- 27234338 TI - POEM Procedure: What the Radiologist Needs to Know for This New Surgical Intervention for Achalasia. AB - Achalasia is a debilitating condition resulting from the failure of appropriate lower esophageal sphincter relaxation. Traditionally, the treatment of choice for achalasia has been a Heller myotomy, performed either via laparotomy or laparoscopically. The latter method has gained wide popularity in its documented lower postoperative morbidity. Recently, however, a new technique has been developed that can be performed by both thoracic surgeons and endoscopists-Per Oral Endoscopic Myotomy. This procedure offers an alternative to invasive surgery and provides excellent outcomes with minimal recovery time.1 This article would help familiarize radiologists with this new technique, as well as both normal and abnormal postoperative appearances. PMID- 27234339 TI - Molecular epidemiology of Rhodococcus equi in slaughtered swine, cattle and horses in Poland. AB - BACKGROUND: Rhodococcus equi is an emerging zoonotic presumably foodborne pathogen. Since the data on the worldwide prevalence of R. equi in meat animals are scarce, the present study aimed to investigate the molecular epidemiology of R. equi in swine, cattle and horse carcasses intended for human consumption in Poland. RESULTS: Totally 1028 lymph node samples were examined. R. equi was isolated from 26.6 % (105/395) swine and 1.3 % (3/234) bovine healthy submaxillary lymph nodes. In horses, R. equi was isolated only from 0.5 % (1/198) samples of middle tracheo-branchiales lymph node while no lymphocentrum retropharyngeum sample was positive (0/198). The purulent lesions were observed only in 0.8 % swine submaxillary lymph nodes samples (3/398) and in two of them R. equi was detected. All bovine and most of swine isolates (98.1 %) were vapB positive. 87.9 % of swine isolates carried 95-kb type 5 plasmid, 3.7 % type 1 and plasmid types: 4, 7, 10, 11, 21, 31 were carried by a single isolate (0.9 %). All bovine isolates carried VAPB type 26. Single horse isolate was vapA-positive and carried plasmid VAPA 85-kb type I. CONCLUSIONS: The prevalence of vapB-positive R. equi in investigated healthy swine intended for human consumption was very high. Not only swine, but also even apparently healthy cattle or horse carcasses should be considered as a potential source of R. equi for humans, especially in countries where undercooked or raw beef or horsemeat is traditionally consumed. PMID- 27234340 TI - Nissen Sleeve (N-Sleeve) operation: preliminary results of a pilot study. AB - BACKGROUND: Sleeve gastrectomy (SG) is one of the most frequently performed bariatric procedures worldwide. Despite its impressive results, there is a growing concern about the relationship between SG and gastroesophageal reflux disease (GERD). OBJECTIVES: We present our pilot study of patients operated with a Nissen anti-reflux valve added to a standard SG. SETTING: University hospital in Montpellier, France. METHODS: A prospective monocentric study including 25 consecutive patients operated with a laparoscopic Nissen-Sleeve (N-Sleeve) gastrectomy was carried out between September 2013 and March 2014. Inclusion criteria were indication for bariatric surgery for patients with GERD (Montreal's definition and classification). All patients were followed postoperatively for 1 year. RESULTS: There were 13 (54%) females and 12 (46%) males with mean age of 41+/-12 (20-65) years. Mean body mass index was 42+/-4.8 (35-53) kg/m2. Preoperatively, all patients had esophageal syndromes. Twenty-three (92%) patients had typical symptoms of GERD, but 2 were asymptomatic; however, they had esophageal injury. Esophagitis grade I-III presented in 10 (40%) patients and Barrett's esophagus in 8 (32%) cases. Two (8%) patients also had extraesophageal syndrome represented by asthma. Nineteen (76%) patients previously took proton pump inhibitors, regularly and 22 (88%) had experienced a hiatal hernia. There was no conversion to the open technique. Operative time was 84+/-13 (54-106) minutes. There were no deaths. Complications included one case of staple line bleeding and one Nissen valve perforation without recognized ischemia. No staple line failure was observed. Three months after N-Sleeve, 19 (76%) patients remained asymptomatic without proton pump inhibitor use. At 6 months and 1 year, 3 (12%) patients were still experiencing reflux. Excess weight loss at 1 year was 58+/-23%, total weight loss was 27+/-10%, and body mass index change was -11+/-4 kg/m2. CONCLUSION: The N-Sleeve seems to be a safe procedure that provides an adequate reflux control with no clear interference on the expected bariatric results of a standard SG. PMID- 27234341 TI - Bariatric surgery patient perceptions and willingness to consent to resident participation. AB - BACKGROUND: Many bariatric surgery programs are located at teaching hospitals, where they are integral to the training of surgical residents. OBJECTIVES: The purpose of this study was to examine preexisting bariatric patient perceptions and willingness to allow resident participation in their surgery. SETTING: Madigan Army Medical Center, Tacoma, Washington, USA. METHODS: Anonymous questionnaire was given to bariatric patients at their preoperative appointment at an academic teaching hospital. The survey captured demographic characteristics, overall opinions of teaching programs, and willingness to consent to various scenarios of trainee participation. Univariate and multivariate analyses were performed. RESULTS: One hundred eight patients (93% female) completed the questionnaire. Most patients (92.4%) expressed overall support for their procedure being performed at a teaching hospital. When presented with several realistic scenarios, most patients would consent to having a staff surgeon operate and residents/students observe (86%). However, only 56% of patients would consent to a resident assisting staff during a procedure and barely 14% of patients would consent to staff surgeon observing. An independent factor associated with increased willingness to consent to resident participation included patients whose first choice would be to undergo surgery at a teaching hospital (P< .05). CONCLUSION: Overall, patients expressed support for the teaching hospital model and resident education and participation. However, their willingness to consent to specific realistic scenarios involving various levels of resident participation in their surgery ranged widely. Although patients prefer detailed informed consent, it has the potential to negatively affect resident participation and training. PMID- 27234342 TI - Persistent moderate or severe obstructive sleep apnea after laparoscopic Roux-en Y gastric bypass: which patients? AB - BACKGROUND: Patients with severe obesity and obstructive sleep apnea (OSA) might decide to undergo bariatric surgery to improve this disease or, more specifically, to become independent of continuous positive airway pressure (CPAP) therapy, which is generally indicated in case of moderate and severe OSA. Knowledge of this topic is important for patient education on expectations of surgical outcome. OBJECTIVES: To evaluate the prevalence and phenotypes of patients with persistent moderate to severe OSA after bariatric surgery. SETTING: Obesity Center Amsterdam, Amsterdam, the Netherlands. METHODS: Patients who underwent a laparoscopic Roux-en-Y gastric bypass, had a preoperative apnea hypopnea index (AHI)>=15/hr, and of whom a follow-up AHI/hr was available were included. RESULTS: Out of 437 patients, 205 underwent pre- and postoperative polysomnography; 232 (53.1%) were lost to follow-up. Median AHI was 32.3/hr (range, 15-138) and mean body mass index was 46 (standard deviation 7.2) kg/m2. A postoperative AHI<15/hr was achieved in 152 patients (74.1%), whereas 53 (25.9%) still had moderate or severe disease 8.6 (standard deviation 4.8) months postoperatively. Predictive factors for persistent moderate to severe disease were age>=50 years, preoperative AHI>=30/hr, excess weight loss (EWL)<60%, and hypertension (area under the curve: .772). CONCLUSION: After bariatric surgery, around three quarters of the moderate to severe OSA patients had no or mild OSA, whereas one quarter (25.9%) still had moderate to severe OSA. Age>=50 years, preoperative AHI>=30/hr, EWL<60%, and hypertension were predictive factors for this persistent postoperative AHI>=15/hr. PMID- 27234343 TI - Activity Theory as a Theoretical Framework for Health Self-Quantification: A Systematic Review of Empirical Studies. AB - BACKGROUND: Self-quantification (SQ) is a way of working in which, by using tracking tools, people aim to collect, manage, and reflect on personal health data to gain a better understanding of their own body, health behavior, and interaction with the world around them. However, health SQ lacks a formal framework for describing the self-quantifiers' activities and their contextual components or constructs to pursue these health related goals. Establishing such framework is important because it is the first step to operationalize health SQ fully. This may in turn help to achieve the aims of health professionals and researchers who seek to make or study changes in the self-quantifiers' health systematically. OBJECTIVE: The aim of this study was to review studies on health SQ in order to answer the following questions: What are the general features of the work and the particular activities that self-quantifiers perform to achieve their health objectives? What constructs of health SQ have been identified in the scientific literature? How have these studies described such constructs? How would it be possible to model these constructs theoretically to characterize the work of health SQ? METHODS: A systematic review of peer-reviewed literature was conducted. A total of 26 empirical studies were included. The content of these studies was thematically analyzed using Activity Theory as an organizing framework. RESULTS: The literature provided varying descriptions of health SQ as data-driven and objective-oriented work mediated by SQ tools. From the literature, we identified two types of SQ work: work on data (ie, data management activities) and work with data (ie, health management activities). Using Activity Theory, these activities could be characterized into 6 constructs: users, tracking tools, health objectives, division of work, community or group setting, and SQ plan and rules. We could not find a reference to any single study that accounted for all these activities and constructs of health SQ activity. CONCLUSIONS: A Health Self-Quantification Activity Framework is presented, which shows SQ tool use in context, in relation to the goals, plans, and competence of the user. This makes it easier to analyze issues affecting SQ activity, and thereby makes it more feasible to address them. This review makes two significant contributions to research in this field: it explores health SQ work and its constructs thoroughly and it adapts Activity Theory to describe health SQ activity systematically. PMID- 27234345 TI - Correction for Shin et al., Histone Deacetylase Classes I and II Regulate Kaposi's Sarcoma-Associated Herpesvirus Reactivation. PMID- 27234344 TI - Impaired error processing in late-phase psychosis: Four-year stability and relationships with negative symptoms. AB - Error processing is impaired in psychosis, and numerous event-related potential studies have found reductions in the error-related negativity (ERN) and, more recently, the error positivity (Pe). The stability of reduced ERN/Pe in psychosis, however, is unknown. In a previous cross-sectional report, reduced ERN was associated with negative symptom severity and reduced Pe with a diagnosis of schizophrenia versus other psychosis. Here, we test the stability of impaired error processing over a four-year follow-up and relationships with subdimensions of negative symptoms. The ERN and Pe were recorded from individuals with psychotic disorders twice: 79 individuals were assessed 15years after first hospitalization, and 69 were assessed at 19years; 59 (26 with schizophrenia, 33 with other psychotic disorders) had data at both assessments. At 19years the Pe was blunted in schizophrenia. The ERN and Pe exhibited temporal stability over the four years (r=0.59 and 0.60, respectively). Reduced ERN and Pe correlated with the negative symptom subdimensions of inexpressivity and avolition, respectively, and not with psychotic or disorganized symptoms. Moreover, 15-year ERN predicted an increase in inexpressivity by year 19. No evidence was found for the reverse: negative symptoms did not predict change in ERN/Pe. Similar to non clinical samples, the ERN and Pe show impressive four-year stability in late phase psychosis. The ERN and Pe are promising neural measures for capturing individual differences in psychotic disorders, particularly with regard to negative symptomatology. They may prove to be useful clinically for forecasting illness course and as treatment targets. PMID- 27234346 TI - Correction for Colman et al., Genome-Wide Analysis of Host mRNA Translation during Hepatitis C Virus Infection. PMID- 27234347 TI - Correction for Soh and Whelan, Tracking the Fate of Genetically Distinct Vesicular Stomatitis Virus Matrix Proteins Highlights the Role for Late Domains in Assembly. PMID- 27234349 TI - Meniere's Disease and Underlying Medical and Mental Conditions: Towards Factors Contributing to the Disease. AB - PURPOSE OF THE STUDY: To investigate the relation of Meniere's disease (MD) with medical comorbidity or mental conditions. PROCEDURES: Demographic data, medical and mental comorbidities were retrospectively collected and compared from 3 groups of 30 patients each: a group with patients with definite MD, a second one with patients with vestibulopathies other than MD (non-Meniere's vertigo, NMV) and a third one with patients without any vestibular symptoms (control). The level of significance was set at 0.05. RESULTS: The prevalence of mental conditions was 26.7, 23.3 and 6.7% for the MD, the NMV and the control group, respectively. Medical comorbidity was found in 80% of patients in the MD, 63% in the NMV and 20% in the control group. Arthritis was encountered in 8 patients with MD, 3 with NMV and none from the control group. The differences in prevalence of mental disease, comorbidities and arthritis between the MD and the control group were statistically significant (p = 0.02, p < 0.001 and p = 0.008, respectively). CONCLUSION: Psychological conditions play an important role in patients with MD. The significantly increased prevalence of arthritis in the MD group suggests an inflammatory/autoimmune background as a contributing factor to the disease. PMID- 27234351 TI - Editorial Commentary: Are statins a solution to reduce the risk of cognitive decline or lower the risk of dementia? PMID- 27234350 TI - Circadian and ultradian glucocorticoid rhythmicity: Implications for the effects of glucocorticoids on neural stem cells and adult hippocampal neurogenesis. AB - Psychosocial stress, and within the neuroendocrine reaction to stress specifically the glucocorticoid hormones, are well-characterized inhibitors of neural stem/progenitor cell proliferation in the adult hippocampus, resulting in a marked reduction in the production of new neurons in this brain area relevant for learning and memory. However, the mechanisms by which stress, and particularly glucocorticoids, inhibit neural stem/progenitor cell proliferation remain unclear and under debate. Here we review the literature on the topic and discuss the evidence for direct and indirect effects of glucocorticoids on neural stem/progenitor cell proliferation and adult neurogenesis. Further, we discuss the hypothesis that glucocorticoid rhythmicity and oscillations originating from the activity of the hypothalamus-pituitary-adrenal axis, may be crucial for the regulation of neural stem/progenitor cells in the hippocampus, as well as the implications of this hypothesis for pathophysiological conditions in which glucocorticoid oscillations are affected. PMID- 27234352 TI - Intrauterine therapy for structural congenital heart disease: Contemporary results and Canadian experience. AB - Percutaneous, ultrasound-guided fetal cardiac intervention (FCI) is increasingly used to alter the prognosis of specific forms of congenital heart disease. Careful patient selection and postnatal management strategy are essential for optimal outcomes. This article discusses the rationale, patient selection criteria, procedural techniques, and contemporary results of FCI. Sources of information included published patient series, the International Fetal Cardiac Intervention Registry, and the Toronto experience as the Canadian referral center. PMID- 27234353 TI - Chronic obstructive pulmonary disease and sudden cardiac death: A systematic review. AB - Both chronic obstructive pulmonary disease (COPD) and sudden cardiac death (SCD) are major health burdens. A number of studies have addressed their interrelationship, but currently no systematic review has been published. Our objective is to give an overview of the literature of the association between COPD and SCD. A search on PubMed with both MeSH headings and free-text keywords was performed. We selected all original articles of studies in humans that assessed COPD on the one hand and SCD, electrocardiographic markers for SCD, ventricular arrhythmias, or asystole on the other. The electronic search yielded 251 articles, from which 27 full publications were selected after careful evaluation of the full-text articles. In these studies, COPD was associated with a prolonged and shortened QT interval. In patients with a myocardial infarction (MI), COPD was associated with an increased risk of ventricular arrhythmias and decreased survival. COPD was a risk factor for SCD both in cardiovascular patient groups and in community-based studies, independent from cardiovascular risk profile. Studies of the potential impact of respiratory treatment on the occurrence of SCD showed conflicting results. In conclusion, cumulating evidence associates COPD with an increased risk of SCD. Asystole and pulseless electric activity could be more common than VT/VF in deaths associated with COPD. Underlying mechanisms explaining this association require further investigation. PMID- 27234354 TI - Extra-cardiac manifestations of adult congenital heart disease. AB - Advancement in correction or palliation of congenital cardiac lesions has greatly improved the lifespan of congenital heart disease patients, resulting in a rapidly growing adult congenital heart disease (ACHD) population. As this group has increased in number and age, emerging science has highlighted the systemic nature of ACHD. Providers caring for these patients are tasked with long-term management of multiple neurologic, pulmonary, hepatic, renal, and endocrine manifestations that arise as syndromic associations with congenital heart defects or as sequelae of primary structural or hemodynamic abnormalities. In this review, we outline the current understanding and recent research into these extra cardiac manifestations. PMID- 27234355 TI - Editorial Commentary: Whither antiarrhythmic drug therapy? PMID- 27234356 TI - Mycoplasma hominis vertebral spine infection: Case report and a review of infections of bone and joints. AB - BACKGROUND: Mycoplasma hominis (M. hominis) is a common commensal that colonizes the human urogenital tract, wherein it is also known to cause genito-urinary infections. It has rarely been reported to cause spinal infections. CASE DESCRIPTION: We describe the case of a 53-year old diabetic woman who developed spontaneous, culture-negative L3-4 osteomyelitis that progressed clinically and radiographically despite debridement, stabilization, and empiric broad-spectrum antimicrobial therapy. After her third debridement procedure, cultures of the multiple intraoperative specimens yielded M. hominis. LITERATURE REVIEW: A PubMed search identified a total of 4 reports of M. hominis causing spinal osteomyelitis and 22 other cases involving bones and joints. CLINICAL RELEVANCE: M. hominis is a rare cause of bone and joint infections. Because of low clinical suspicion for this pathogen, combined with its fastidious nature and the difficult growth characteristics of this organism, M. hominis infections may be unrecognized and untreated, resulting in high morbidity. In addition to bacterial culture, molecular tests are available to detect M. hominis in clinical samples. This case report and review of the literature suggest that, in some cases of purulent culture-negative osteomyelitis, especially if not responding to standard empiric antibacterial therapy, M. hominis should be considered as a potential pathogen. PMID- 27234357 TI - Acute pyelonephritis and renal vein thrombosis: A case report and review of the literature. AB - A 68-year-old female presented with a week history of fever and generalized weakness. Clinical examination, blood work and urinalysis were compatible with sepsis due to acute pyelonephritis. Urine cultures were positive for Escherichia coli and blood cultures were negative. After 5 days of antibiotic therapy with cefuroxime, inflammatory parameters (CRP level and white blood cell count) remained highly elevated. Abdominal CT scan showed right kidney pyelonephritis with renal and perirenal abscess and right renal vein thrombosis. The patient improved after percutaneous drainage of the perirenal abscess and anticoagulation treatment. She was discharged on hospital day 14. PMID- 27234359 TI - Evidence for Good Cardiovascular Outcomes among Patients with Type 2 Diabetes, and Promising Treatment for Patients with Type 1 Diabetes. PMID- 27234358 TI - Clinical and microbiological characterization of serotype 6D pneumococcal infections in South Korea. AB - BACKGROUND: The prevalence of Serotype 6D Streptococcus pneumoniae was reported relatively high in South Korea. Since the introduction of 7-valent pneumococcal conjugate vaccine (PCV7), serotype replacement was observed. This study was designed to better clarify genetic diversity of pneumococcal serotype 6D and its clinical characteristics after introduction of PCV7 in 2000. METHODS: We performed serotyping analysis with 1298 pneumococcal isolates from clinical specimens in South Korea from 2004 to 2011. Multilocus sequence typing was performed, and minimal inhibitory concentration was determined for the available serotype 6D and nontypeable (NT) pneumococcal isolates during the 2006-2007 period. RESULTS: The proportion of serotype 6D pneumococci increased from 0.8% (2004-2007) to 2.9% (2008-2011) of all clinical pneumococcal isolates, accounting for 14.9% of serogroup 6 pneumococci in South Korea. NT pneumococci markedly increased to 13.3% during 2006-2007 in advance of the increase in serotype 6D. Among the 26 available serotype 6D pneumococcal isolates, ST282 was predominant (23 isolates, 88.5%). The STs of NT pneumococci (26 isolates) were diverse, but clonal complex 271 was the dominant clone. The oral penicillin non-susceptibility rate was 92.3% (24 among 26 isolates) for both serotype 6D and NT pneumococci. The ceftriaxone non-susceptibility rates of serotype 6D and NT pneumococci were 7.7% and 3.8%, respectively. CONCLUSION: ST228(6D) strain expanded, particularly among old adults with comorbidities in South Korea. Both antibiotic and PCV7 pressure might have contributed to the selective increase of NT and serotype 6D pneumococci. PMID- 27234360 TI - Pathogen Prevalence and Antimicrobial Susceptibility Among Enterobacteriaceae Causing Hospital-associated Intra-abdominal Infections in Adults in the United States (2012-2013). AB - PURPOSE: Selection and prompt initiation of the appropriate empiric antimicrobial therapy are critical to decrease morbidity and mortality and shorten the length of hospitalization among patients with hospital-associated intra-abdominal infections (HA-IAIs). Therapeutic choices for the treatment of patients with HA IAI require careful consideration. This study was conducted to evaluate the antimicrobial susceptibility of common pathogens collected from adult patients with HA-IAI in the United States. METHODS: Gram-negative bacilli (N = 1285) were collected during 2012-2013 from SMART (Study for Monitoring Antimicrobial Resistance Trends). Isolates were tested at a central laboratory by using Clinical and Laboratory Standards Institute methods and interpretation of susceptibility to 12 antimicrobial agents. FINDINGS: Most of the isolates (80.8%) were Enterobacteriaceae, and Escherichia coli was the most common species. Susceptibility to frequently used antimicrobial agents for treating IAI showed that ertapenem, imipenem, and amikacin were more active than other agents against Enterobacteriaceae, including multidrug-resistant isolates. More than 92% of E coli, including extended-spectrum beta-lactamase (ESBL) producers, and Klebsiella pneumoniae isolates were susceptible to ertapenem, imipenem, and amikacin. Cefepime was the most active (>90% susceptibility) cephalosporin against all species except K pneumoniae (86.6%) but with much reduced activity against isolates with ESBLs. Piperacillin/tazobactam had reduced activity against Enterobacter species (70.4%-76.4% susceptible) and ESBL-producing K pneumoniae (22.5% susceptible). Fluoroquinolones exhibited poor activity against E coli (overall susceptibility <70%). IMPLICATIONS: Proper empiric antimicrobial treatment, including combining appropriate agents, of HA-IAI requires detailed understanding of the epidemiology of common pathogens and antimicrobial resistance patterns. In light of rising rates of antimicrobial resistance, ongoing surveillance is critical for clinical decision-making. PMID- 27234361 TI - Molecular Docking and Molecular Dynamics Studies to Identify Potential OXA-10 Extended Spectrum beta-Lactamase Non-hydrolysing Inhibitors for Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic bacterium that frequently causes nosocomial infections. New generation cephalosporins and beta lactams along with inhibitors are used for the treatment of opportunistic bacterial infections. The indiscriminate use of antibiotics has led to the emergence of bacterial resistance. Carbapenem class of antibiotics like imipenem and meropenem are currently the final line of antibiotics for the treatment of infections caused by multidrug-resistant P. aeruginosa. Recent reports indicate that P. aeruginosa has acquired resistance to imipenem through a class D oxacillinase-OXA-10 extended spectrum beta-lactamase (ESBL). OXA-10 ESBL is encoded by the gene blaOXA-10. There is an urgent need to develop OXA-10 ESBL non hydrolysing inhibitors. We have attempted to locate OXA-10 ESBL inhibitors by performing molecular docking and molecular dynamics studies on OXA-10 ESBL with imipenem analogues from ZINC database as well as employing imipenem to understand the mechanism of resistance at the structural level. Our in-silico analysis of imipenem analogues reveals that ZINC44672480 has ideal characteristics for a potent OXA-10 ESBL non-hydrolysing inhibitor. We believe that the results from our study will provide valuable insights into the mechanism of drug resistance and aid in designing potent inhibitors against OXA-10 ESBL producing P. aeruginosa. PMID- 27234362 TI - Predictors of Heart Disease Knowledge Among Older and Younger Asian Indian Adults. AB - Coronary heart disease (CHD) has been estimated to be the leading cause of mortality in developing countries in 2010, particularly among Asian Indians. When compared to other populations globally, Asian Indians less than 40 years of age are at an increased risk of myocardial infarction. The objective of this study was to identify the predictors of knowledge of heart disease among younger and older Asian Indians adults. A cross-sectional survey was undertaken in Sydney Australia. One hundred and forty-four participants of Asian Indian descent who attended the health promotion stall at the Australia India Friendship Fair in Sydney participated in the study. All participants completed a self-administered questionnaire. The Primary outcome of the survey was knowledge of heart disease as measured by the 25 item Heart Disease Facts Questionnaire. All six modifiable risk factors for heart disease namely smoking, high blood pressure, diabetes, high cholesterol, physical inactivity and overweight were identified by 45.2 % of those aged below 40 and 53.5 % of those aged above 40 years of age respectively. For younger adults, only smoking status was significant and was an independently predictor of knowledge related to CHD (b = -10.6, p = 0.001, sr2 = 0.16). For older adults, smoking status and duration of residence were significant predictors of knowledge related to CHD (b = -7.4, p = 0.000, sr2 = 0.24; b = 0.13, p = 0.001, sr2 = 0.069 respectively). Although suboptimal, there were no statistically significant differences in the level of knowledge among older and younger Asian Indians. Nevertheless, strategies to improve the knowledge of heart disease among this cohort are warranted. PMID- 27234363 TI - A global synthesis of the rate and temperature sensitivity of soil nitrogen mineralization: latitudinal patterns and mechanisms. AB - Soil net nitrogen (N) mineralization (Nmin ) is a pivotal process in the global N cycle regulating the N availability of plant growth. Understanding the spatial patterns of Nmin, its temperature sensitivity (Q10 ) and regulatory mechanisms is critical for improving the management of soil nutrients. In this study, we evaluated 379 peer-reviewed scientific papers to explore how Nmin and the Q10 of Nmin varied among different ecosystems and regions at the global scale. The results showed that Nmin varied significantly among different ecosystems with a global average of 2.41 mg N soil kg-1 day-1 . Furthermore, Nmin significantly decreased with increasing latitude and altitude. The Q10 varied significantly among different ecosystems with a global average of 2.21, ranging from the highest found in forest soils (2.43) and the lowest found for grassland soils (1.67) and significantly increased with increasing latitude. Path analyses indicated that Nmin was primarily affected by the content of soil organic carbon (C), soil C:N ratio, and clay content, where Q10 was primarily influenced by the soil C:N ratio and soil pH. Furthermore, the activation energy (Ea ) of soil N mineralization was significantly and negative correlated with the substrate quality index among all ecosystems, indicating the applicability of the carbon quality temperature hypothesis to soil N mineralization at a global scale. These findings provided empirical evidence supporting that soil N availability, under global warming scenarios, is expected to increase stronger in colder regions as compared with that low-latitude regions due to the higher Q10 . This may alleviate the restriction of N supply for increased primary productivity at higher latitudes. PMID- 27234364 TI - Occurrence and distribution of antifouling biocide Irgarol-1051 in coral reef ecosystems, Zanzibar. AB - 2-methythiol-4-tert-butylamino-6-cyclopropylamino-s-triazine (Irgarol-1051) has been widely used as effective alternative antifouling paint in marine structures including ships. However, it has been causing deleterious effects to marine organisms including reef building corals. The main objective of this study was to establish baseline levels of Irgarol-1051 around coral reefs and nearby ecosystems along coastline of Zanzibar Island. The levels of Irgarol-1051 ranged from 1.35ng/L around coral reefs to 15.44ng/L around harbor with average concentration of 4.11 (mean)+/-0.57 (SD) ng/L. This is below Environmental Risk Limit of 24ng/L as proposed by Dutch Authorities which suggests that the contamination is not alarming especially for coral reef ecosystem health. The main possible sources of the contamination are from shipping activities. This paper provides important baseline information of Irgarol-1051 around the coral reef ecosystems within the Western Indian Ocean (WIO) region and may be useful for formulation of marine conservation strategies and policies. PMID- 27234365 TI - Effects of sedimentary sulfide on community structure, population dynamics, and colonization depth of macrozoobenthos in organic-rich estuarine sediments. AB - An annual field survey and in situ recolonization experiment revealed the effects of sedimentary sulfide (H2S) on macrozoobenthos in a eutrophic brackish lagoon. Species diversity was much lower throughout the year in muddy opportunist dominant sulfidic areas. Mass mortality occurred during warmer months under elevated H2S levels. An enclosure experiment demonstrated that sedimentary H2S modified community composition, size structure, and colonization depth of macrozoobenthos. Species-specific responses to each sediment type (sand, sulfidic mud, and mud with H2S removed) resulted in changes in the established community structure. Dominant polychaetes (Hediste spp., Pseudopolydora spp., and Capitella teleta) occurred predominantly in a thin surface layer in the presence of H2S. On the other hand, organic-rich mud facilitated settlement of polychaete larvae if it does not contain H2S. These results demonstrate that sediment characteristics, including H2S level and organic content, were key structuring factors for the macrozoobenthic assemblage in organically polluted estuarine sediments. PMID- 27234366 TI - Spatial distribution and seasonal variation of the trace hazardous element contamination in Jakarta Bay, Indonesia. AB - The Jakarta Bay Ecosystem is located in the vicinity of the megacity Jakarta, the capital city of Indonesia. Surrounding rivers and canals, carrying solid and fluid waste from households and several industrial areas, flow into the bay. Therefore, the levels of selected trace hazardous elements in water, surface sediments and animal tissues were determined. Samples were collected from two different seasons. The spatial distribution pattern of trace elements in sediment and water as well as the seasonal variation of the contamination were assessed. Quality assessment of sediment using the effects range median (ERM) showed that the concentrations of Hg, Cu and Cr at some stations exceeded the recommended values. Moreover, the concentrations of several trace hazardous elements in the sediments exceeded previously reported toxicity thresholds for benthic species. PMID- 27234367 TI - Organochlorine compounds in surface sediments from the northern coast of Cyprus, Eastern Mediterranean: Levels, possible sources and potential risk. AB - Organochlorines (OCs) were determined in sediments collected from different regions of northern coast of Cyprus. The OCPs and Aroclors had a wide range from 2.78 to 306 and 15 to 325ngg(-1), respectively. The highest level was found at Yedi Dalga site. DDE was the most abundant compound. The ratios of metabolites to parent DDT showed that DDTs were derived mostly from the aged and weathered inputs. Comparing our results with the previous studies showed that POPs in sediments were found to be lower than those in samples for Mediterranean and Black Sea coasts. The SQG implied that, Aroclor1254 exceeded the TEL values, showing that adverse biological effects are expected occasionally at some of the sediment samples. DDTs were dominant and more ecotoxicological concern in the northern Cyprus. Altogether, it may be summarized that DDTs will impose ecologically hazardous impacts in the sedimentary environment at the present. PMID- 27234369 TI - Effects of oil and oil burn residues on seabird feathers. AB - It is well known, that in case of oil spill, seabirds are among the groups of animals most vulnerable. Even small amounts of oil can have lethal effects by destroying the waterproofing of their plumage, leading to loss of insulation and buoyancy. In the Arctic these impacts are intensified. To protect seabirds, a rapid removal of oil is crucial and in situ burning could be an efficient method. In the present work exposure effects of oil and burn residue in different doses was studied on seabird feathers from legally hunted Common eider (Somateria mollissima) by examining changes in total weight of the feather and damages on the microstructure (Amalgamation Index) of the feathers before and after exposure. The results of the experiments indicate that burn residues from in situ burning of an oil spill have similar or larger fouling and damaging effects on seabird feathers, as compared to fresh oil. PMID- 27234368 TI - Phylogenetic analysis of bacterial community composition in sediments with organic contaminants from the Jiaojiang estuary in China. AB - The aim of this study was to investigate the bacterial community composition, the concentration of organic contaminants, and their relationship in the sediments of Jiaojiang estuary. Sediments were collected from seven stations and the environmental parameters were analyzed. The results showed that the site closest to the chemical industry zone was the most polluted. Bacterial communities were determined using 16S rRNA clone libraries and phylogenetic analysis. These results revealed that there were 13 known bacterial phyla in the sediments and that Proteobacteria were the dominant group. Using these data, we assessed the correlation between bacterial communities and organic contaminants using cluster, multidimensional scaling, and redundancy analyses. These showed that there was no simple relationship between organic contaminants and bacterial community diversity in the sediments, but polycyclic aromatic hydrocarbons were more influential than the other pollutants and negatively affected Chloroflexi. PMID- 27234370 TI - Complete mitochondrial genome sequences of Atlantic representatives of the invasive Pacific coral species Tubastraea coccinea and T. tagusensis (Scleractinia, Dendrophylliidae): Implications for species identification. AB - Members of the azooxanthellate coral genus Tubastraea are invasive species with particular concern because they have become established and are fierce competitors in the invaded areas in many parts of the world. Pacific Tubastraea species are spreading fast throughout the Atlantic Ocean, occupying over 95% of the available substrate in some areas and out-competing native endemic species. Approximately half of all known coral species are azooxanthellate but these are seriously under-represented compared to zooxanthellate corals in terms of the availability of mitochondrial (mt) genome data. In the present study, the complete mt DNA sequences of Atlantic individuals of the invasive scleractinian species Tubastraea coccinea and Tubastraea tagusensis were determined and compared to the GenBank reference sequence available for a Pacific "T. coccinea" individual. At 19,094bp (compared to 19,070bp for the GenBank specimen), the mt genomes assembled for the Atlantic T. coccinea and T. tagusensis were among the longest sequence determined to date for "Complex" scleractinians. Comparisons of genomes data showed that the "T. coccinea" sequence deposited on GenBank was more closely related to that from Dendrophyllia arbuscula than to the Atlantic Tubastraea spp., in terms of genome length and base pair similarities. This was confirmed by phylogenetic analysis, suggesting that the former was misidentified and might actually be a member from the genus Dendrophyllia. In addition, although in general the COX1 locus has a slow evolutionary rate in Scleractinia, it was the most variable region of the Tubastraea mt genome and can be used as markers for genus or species identification. Given the limited data available for azooxanthellate corals, the results presented here represent an important contribution to our understanding of phylogenetic relationships and the evolutionary history of the Scleractinia. PMID- 27234371 TI - Anaerobic microbial Fe(II) oxidation and Fe(III) reduction in coastal marine sediments controlled by organic carbon content. AB - Coastal marine sediments contain varying concentrations of iron, oxygen, nitrate and organic carbon. It is unknown how organic carbon content influences the activity of nitrate-reducing and phototrophic Fe(II)-oxidizers and microbial Fe redox cycling in such sediments. Therefore, microcosms were prepared with two coastal marine sediments (Kalo Vig and Norsminde Fjord at Aarhus Bay, Denmark) varying in TOC from 0.4 to 3.0 wt%. The microcosms were incubated under light/dark conditions with/without addition of nitrate and/or Fe(II). Although most probable number (MPN) counts of phototrophic Fe(II)-oxidizers were five times lower in the low-TOC sediment, phototrophic Fe(II) oxidation rates were higher compared with the high-TOC sediment. Fe(III)-amended microcosms showed that this lower net Fe(II) oxidation in the high-TOC sediment is caused by concurrent bacterial Fe(III) reduction. In contrast, MPN counts of nitrate reducing Fe(II)-oxidizers and net rates of nitrate-reducing Fe(II) oxidation were comparable in low- and high-TOC sediments. However, the ratio of nitratereduced :iron(II)oxidized was higher in the high-TOC sediment, suggesting that a part of the nitrate was reduced by mixotrophic nitrate-reducing Fe(II)-oxidizers and chemoorganoheterotrophic nitrate-reducers. Our results demonstrate that dynamic microbial Fe cycling occurs in these sediments and that the extent of Fe cycling is dependent on organic carbon content. PMID- 27234372 TI - Transcriptional responses in Lactococcus lactis subsp. cremoris to the changes in oxygen and redox potential during milk acidification. AB - Milk acidification and metabolic activity of the starter cultures are affected by oxygen; however, molecular factors related to the redox changes are poorly defined. The objective of the study was to investigate transcriptional responses in Lactococcus lactis subsp. cremoris CHCCO2 grown in milk to the shifts of oxygen and redox potential (Eh7 ). Transcriptomic studies were performed with the use of Illumina HiSeq 2000 mRNA sequencing and validated by the real-time quantitative PCR. In total 105 differentially expressed genes were assigned functional gene names. Most of the differentially expressed genes were detected during aerobic reduction phase. Upregulated genes were implicated in lactose utilization, glycogen biosynthesis, amino sugar metabolism, oxidation-reduction, pyrimidine biosynthesis and DNA integration processes. Genes of purine nucleotide biosynthesis and genes encoding amino acid, multidrug resistance and ion ABC transporters were mostly downregulated, while oligopeptide transporter genes were reduced during oxygen depletion and induced at minimum Eh7 . SIGNIFICANCE AND IMPACT OF THE STUDY: Understanding of gene responses in starter cultures to the changes of oxidation-reduction state is important for the better control and reproducibility of dairy fermentations. We applied mRNA sequencing by Illumina HiSeq 2000 to investigate gene expression profile in a dairy strain of Lactococcus lactis subsp. cremoris during milk acidification. Novelty of this study lies in linking transcriptional responses to oxygen depletion and the changes of redox potential with the fermentation kinetics and clarification of molecular factors specifically expressed in milk which might be essential for bacterial performance and the final quality of cheeses. PMID- 27234373 TI - De novo RRAGC mutation activates mTORC1 signaling in syndromic fetal dilated cardiomyopathy. AB - Idiopathic dilated cardiomyopathy (DCM) is a heritable, genetically heterogeneous disorder with variable age-dependent penetrance. We sought to identify the genetic underpinnings of syndromic, sporadic DCM in a newborn female diagnosed in utero. Postnatal evaluation revealed ventricular dilation and systolic dysfunction, bilateral cataracts, and mild facial dysmorphisms. Comprehensive metabolic and genetic testing, including chromosomal microarray, mitochondrial DNA and targeted RASopathy gene sequencing, and clinical whole exome sequencing for known cardiomyopathy genes was non-diagnostic. Following exclusion of asymptomatic DCM in the parents, trio-based whole exome sequencing was carried out on a research basis, filtering for rare, predicted deleterious de novo and recessive variants. An unreported de novo S75Y mutation was discovered in RRAGC, encoding Ras-related GTP binding C, an essential GTPase in nutrient-activated mechanistic target of rapamycin complex 1 (mTORC1) signaling. In silico protein modeling and molecular dynamics simulation predicted the mutation to disrupt ligand interactions and increase the GDP-bound state. Overexpression of RagC(S75Y) rendered AD293 cells partially insensitive to amino acid deprivation, resulting in increased mTORC1 signaling compared to wild-type RagC. These findings implicate mTORC1 dysregulation through a gain-of-function mutation in RagC as a novel molecular basis for syndromic forms of pediatric heart failure, and expand genotype-phenotype correlation in RASopathy-related syndromes. PMID- 27234374 TI - Feasibility of stereotactic MRI-based image guidance for the treatment of vascular malformations: a phantom study. AB - PURPOSE: Treatment of vascular malformations requires the placement of a needle within vessels which may be as small as 1 mm, with the current state of the art relying exclusively on two-dimensional fluoroscopy images for guidance. We hypothesize that the combination of stereotactic image guidance with existing targeting methods will result in faster and more reproducible needle placements, as well as reduced radiationexposure, when compared to standard methods based on fluoroscopy alone. METHODS: The proposed navigation approach was evaluated in a phantom experiment designed to allow direct comparison with the conventional method. An anatomical phantom of the left forearm was constructed, including an independent control mechanism to indicate the attainment of the target position. Three interventionalists (one inexperienced, two of them frequently practice the conventional fluoroscopic technique) performed 45 targeting attempts utilizing the combined and 45 targeting attempts utilizing the standard approaches. RESULTS: In all 45 attempts, the users were able to reach the target when utilizing the combined approach. In two cases, targeting was stopped after 15 min without reaching the target when utilizing only the C-arm. The inexperienced user was faster when utilizing the combined approach and applied significantly less radiation than when utilizing the conventional approach. Conversely, both experienced users were faster when using the conventional approach, in one case significantly so, with no significant difference in radiation dose when compared to the combined approach. CONCLUSIONS: This work presents an initial evaluation of a combined navigation fluoroscopy targeting technique in a phantom study. The results suggest that, especially for inexperienced interventionalists, navigation may help to reduce the time and the radiation dose. Future work will focus on the improvement and clinical evaluation of the proposed method. PMID- 27234375 TI - A novel navigation system to guide metallic foreign body extraction. AB - PURPOSE: Metallic foreign bodies (MFBs) retained in soft tissue may pose potential threats to patient health. Interventional procedures using conventional navigation systems are associated with high rate of radiation exposure. We postulated that the surgical approach visualization and navigation system would offer precise percutaneous localization and linear guidance with reduced radiation dosage and system complexity. METHODS: In total, 76 patients underwent percutaneous MFB extraction with the technique, which consists of: (A) displaying the target spot (here the MFB) on the screen; (B) projecting the laser beam onto the skin surface; (C) indicating the optimal direction and angle of the needle; and (D) guiding the surgical approach until the MFB was extracted. RESULTS: A total of 76 MFBs were successfully extracted with a single operation. No systemic complications were observed. The procedure took between 2 and 11 min, with an average of [Formula: see text] min, demonstrating the characteristics of a normal distribution. The mean size of wound was [Formula: see text] mm. The mean amount of bleeding was [Formula: see text] ml. The number of times the intra-operative fluoroscopy was used ranged from one to four times for a single procedure, with an average of 1.89 +/- 0.74. CONCLUSION: The proposed navigation system which combines the laser positioning and navigation techniques seems to be a novel surgical approach of high accuracy and efficiency. PMID- 27234376 TI - Factors Associated With Non-compliance of Asbestos Occupational Standards in Brake Repair Workers. AB - Asbestos and non-asbestos containing brake products are currently used in low- and middle-income countries like Colombia. Because brake products are distributed detached from their supports, they require manipulation before installation, which release fibers and expose workers. Previous studies of our research group have documented exposures in excess of the widely accepted 0.1 f/cm(3) exposure guideline. The aim of this study is to identify factors associated with non compliance of the 8-h time weighted average (TWA) 0.1 f/cm(3) asbestos occupational limit among brake mechanics (i.e. riveters). Eighteen brake repair shops (BRS) located in Bogota (Colombia) were sampled during 3 to 6 consecutive days for the entire work-shift. Personal and short-term personal samples were collected following NIOSH methods 7400 and 7402. Longitudinal based logistic regression models were used to determine the association between the odds of exceeding the 8-h TWA 0.1 f/cm(3) asbestos occupational limit and variables such as type of tasks performed by workers, workload (number of products manipulated daily), years of experience as riveters, and shop characteristics. These models can be used to estimate the odds of being currently or historically overexposed when sampling data do not exist. Since the information required to run the models can vary for both retrospective and current asbestos occupational exposure studies, three models were constructed with different information requirements. The first model evaluated the association between the odds of non-compliance with variables related to the workload, the second model evaluated the association between the odds of non-compliance with variables related to the manipulation tasks, and the third model evaluated the association between the odds of non compliance with variables related with both the type of tasks performed by workers and the workload. Variables associated with the odds of non-compliance included conducting at least one manipulation activity with beveling and grinding of asbestos and non-asbestos containing brake products during the work shift, the location of the worker in the shop during non-manipulation activities, cleaning activities of the manipulation area, the years of experience working as riveters, and the number of asbestos and non-asbestos containing brake products manipulated daily. These models could be useful for current and retrospective occupational studies, in determining the odds of non-compliance of the asbestos occupational limit among brake mechanics. PMID- 27234377 TI - Potential Release of Manufactured Nano Objects During Sanding of Nano-Coated Wood Surfaces. AB - Increasing production and applications of manufactured nano objects (MNOs) have become a source for human exposure and therefore raise concerns and questions about the possible health effects. In this study, the potential release of nano objects, their agglomerates, and aggregates (NOAA) as a result of sanding of hardwood treated with MNOs-containing coating was examined. Two types of MNO containing coating were compared with untreated hardwood that allowed the evaluation of the influence of the chemical composition on the release of particles. Furthermore, the rotation speed of the sander and the grit size of the sanding paper were varied in order to assess their influence on the release of particles.Measurements were conducted in a gas-tight chamber with a volume of 19.5 m(3) in which ventilation was minimized during experiments. Particle size distributions were assessed by scanning mobility particle sizer , aerodynamic particle sizer, and electrical low pressure impactor. Furthermore, aerosol number concentrations (Nanotracer), active surface area (LQ1), and fractionated mass (Cascade Impactor) were measured before, during, and after sanding. Scanning electron microscope/energy dispersive X-ray (SEM/EDX) analysis was performed to adequately characterize the morphology, size, and chemical composition of released particles.SEM/EDX analysis indicated that sanding surfaces treated with MNO-containing coating did not release the designated MNO as free primary particles. In both coatings, clusters of MNO were perceived embedded in and attached to micro-sized wood and/or coating particles created by sanding the coated surface. Real-time measurements indicated a lower release of micro-sized particles from sanding of surfaces treated with Coating I than from sanding untreated surfaces or surfaces treated with Coating II. A substantial increase in nanosized and a slight increase in micro-sized particles was perceived as the rotation speed of the sander increased. However, most nanosized particles were most likely emitted by the sanding machine. No effect of the grit size on the release of particles was detected. PMID- 27234378 TI - Association of 3' nearby gene BTLA polymorphisms with the risk of renal cell carcinoma in the Polish population. AB - OBJECTIVE: T cells play an important role in antitumor immunity, and molecules regulating T-cell activity could influence cancer susceptibility. The distinct role of coinhibitory receptors in immunosurveillance has been considered. B- and T-lymphocyte attenuator (BTLA) is one of these receptors, which negatively regulate immune responses. The aim of this study was to investigate the association between BTLA gene polymorphisms and susceptibility to renal cell carcinoma (RCC) in the Polish population. METHODS: Altogether 282 patients with RCC and 480 healthy subjects were genotyped for the following polymorphisms: rs2705511, rs1982809, rs9288952, rs16859633, rs9288953, rs2705535, and rs1844089 using the TaqManSNP Genotyping Assays. RESULTS: Here, we found that the presence of rs1982809G allele (genotype GG+AG) is associated with increased risk of RCC (odds ratio = 1.38; 95% CI: 1.03-1.86; P = 0.03). In patients with clear-cell RCC (ccRCC) with high-grade (3 and 4) tumors, the frequency of rs1982809[GG] genotype was significantly higher as compared to those with low-grade (1 and 2) tumors and to the controls (0.14 vs. 0.06, P = 0.05 and 0.14 vs. 0.06, P = 0.04, respectively). Moreover, we have noticed the trend for overrepresentation of carriers of rs2705511C allele in patients with RCC as compared with the controls (0.51 vs. 0.44, P = 0.08) Haplotype rs2705511C/rs1982809G/rs9288952A/rs9288953T/rs2705535C/rs1844089G (CGATCG) increased the risk of RCC of 46% (odds ratio = 1.46; 95% CI: 1.08-1.96; Pcorrected = 0.05). CONCLUSION: Our results indicate that polymorphisms rs1982809 situated in 3' UTR nearby region of BTLA gene might be considered as low penetrating risk factor for RCC, but results have to be confirmed in further studies. PMID- 27234379 TI - Prognostic serum markers in patients with high-grade upper tract urothelial carcinoma. AB - INTRODUCTION: The role of preoperative serum-based markers in predicting survival outcomes of patients has been reported for several cancer types; however, their association with upper tract urothelial carcinoma (UTUC) prognosis is unclear. We evaluated the role of systemic serum-based markers in predicting adverse pathological features and survival outcomes in patients surgically treated for high-grade (HG) UTUC. METHODS: We retrospectively reviewed all patients undergoing surgery for HG UTUC between June 2006 and July 2013 at our institution. Comprehensive clinicopathologic data and preoperative serum-based markers including hemoglobin, white blood cell count, platelet count, serum albumin, calcium, and liver function tests were recorded. Associations of serum markers with pathologic features and recurrence-free survival (RFS) were determined by logistic and Cox regression analyses, respectively. The concordance index for the oncologic outcomes model was determined. RESULTS: In total, 101 patients were identified with a median follow-up of 18.5 months (range: 1-74mo). In all, 60% of patients had pT2 or less and 11% had nodal metastases. Preoperative elevated alkaline phosphatase (ALP) (>=116IU/l) was associated with multiple adverse pathologic features including advanced T stage, lymphovascular invasion, and histologic necrosis. On univariate analysis, serum markers independently associated with RFS included hemoglobin<=12.9 (hazards ratio [HR] = 2.51; 95% CI: 1.17-5.36, P = 0.018), albumin<=4g/dl (HR = 4.4; 95% CI: 2.04-9.30; P<0.0001), ALP>=116U/l (HR = 13.3; 95% CI: 5.3-33.52, P<0.0001), alanine transaminase>=27 (HR = 2.63, 95% CI: 1.11-6.21, P = 0.028), serum aspartate transaminase>=20 (HR = 2.21, 95% CI: 1.04-4.69, P = 0.038), and corrected calcium>=9.3 (HR = 2.45, 95% CI: 1.01-5.93, P = 0.047). The 2 strongest predictors, albumin and ALP, were combined to form an AA score (range: 0-2), which improved the baseline preoperative clinical model concordance index for prediction of RFS from 0.626 to 0.799. CONCLUSION: In HG UTUC, elevated preoperative ALP was associated with adverse pathologic features. Additionally, elevated ALP and low albumin were independently associated with worse RFS and overall survival. These serum-based markers are often measured in the preoperative workup of UTUC, and thus they can be included in future prognostic models to risk stratify patients. PMID- 27234382 TI - Activating KRAS mutations are characteristic of oncocytic sinonasal papilloma and associated sinonasal squamous cell carcinoma. AB - Oncocytic sinonasal papillomas (OSPs) are benign tumours of the sinonasal tract, a subset of which are associated with synchronous or metachronous sinonasal squamous cell carcinoma (SNSCC). Activating EGFR mutations were recently identified in nearly 90% of inverted sinonasal papillomas (ISPs) - a related tumour with distinct morphology. EGFR mutations were, however, not found in OSP, suggesting that different molecular alterations drive the oncogenesis of these tumours. In this study, tissue from 51 cases of OSP and five cases of OSP associated SNSCC was obtained retrospectively from six institutions. Tissue was also obtained from 50 cases of ISP, 22 cases of ISP-associated SNSCC, ten cases of exophytic sinonasal papilloma (ESP), and 19 cases of SNSCC with no known papilloma association. Using targeted next-generation and conventional Sanger sequencing, we identified KRAS mutations in 51/51 (100%) OSPs and 5/5 (100%) OSP associated SNSCCs. The somatic nature of KRAS mutations was confirmed in a subset of cases with matched germline DNA, and four matched pairs of OSP and concurrent associated SNSCC had concordant KRAS genotypes. In contrast, KRAS mutations were present in only one (5%) SNSCC with no known papilloma association and none of the ISPs, ISP-associated SNSCCs, or ESPs. This is the first report of somatic KRAS mutations in OSP and OSP-associated SNSCC. The presence of identical mutations in OSP and concurrent associated SNSCC supports the putative role of OSP as a precursor to SNSCC, and the high frequency and specificity of KRAS mutations suggest that OSP and OSP-associated SNSCC are biologically distinct from other similar sinonasal tumours. The identification of KRAS mutations in all studied OSP cases represents an important development in our understanding of the pathogenesis of this disease and may have implications for diagnosis and therapy. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 27234383 TI - Respiratory diseases call for special attention from clinical and translational science. AB - Respiratory diseases will become one of the top 3 leading causes of estimated mortality in 2020 and become about one third of total causes of estimated mortality. The journal of Translational Respiratory Medicine is a truly international, peer-reviewed journal devoted to the publication of articles on outstanding work with translational potentials between basic research and clinical application to understanding respiratory disease. Translational respiratory medicine will more focus on biomarker identification and validation in pulmonary diseases in combination with clinical informatics, targeted proteomics, bioinformatics, systems medicine, or mathematical science; on different translational strategies of cell-based therapy to clinical application to treat lung diseases; on targeted therapies in combination with personalized medicine; and on distant electronic medicine to monitor a large population of people's health. Translational Respiratory Medicine is an additional but unique opportunity for scientists and clinicians who work on pulmonary diseases to publish their outstanding findings, initiative results, and critical and perceptive opinions in the journal. PMID- 27234381 TI - Meniscal injuries in children and adolescents undergoing surgical treatment for tibial eminence fractures. AB - PURPOSE: To prospectively evaluate the prevalence and characteristics of meniscal injuries in children and adolescents undergoing surgical treatment for tibial eminence fractures and to test for possible relationships between associated meniscal lesions and patient demographics or injury characteristics. METHODS: A prospective multicenter study was conducted to arthroscopically assess the prevalence and characteristics of meniscal injuries in children and adolescents undergoing surgical treatment for tibial eminence fractures between 04/2014 and 10/2015. Patient demographics and injury characteristics were assessed preoperatively. The presence of a meniscal injury was evaluated arthroscopically and characterized according to tear type and location (Cooper classification). Patients with and without meniscal injuries were compared with regard to sex, age, height, weight, BMI, type of injury, mechanism of injury, time to surgery, Tanner stage, sexual maturity (prepubescent vs. pubescent), and modified Meyers and McKeever classification. RESULTS: A total of 54 consecutive patients (65 % males, mean age: 12.5 +/- 3.2 years) were enrolled. Meniscal injury were found in 20 patients (37 %). The lateral meniscus was involved in 18 patients (90 % of all meniscus injuries) and the medial meniscus in 2 patients (10 % of all meniscus injuries). The most common tear pattern was a longitudinal tear of the posterior horn of the lateral meniscus (30 % of all meniscus injuries) and the second most common tear was a root detachment of the anterior horn of the lateral meniscus (20 % of all meniscus injuries). Higher age, advanced Tanner stage, and pubescence were significantly associated with an accompanying meniscal injury. CONCLUSION: Meniscal injuries in children and adolescents undergoing surgical treatment for tibial eminence fractures must be expected in almost 40 %, with a higher prevalence with increasing age and sexual maturity. With regard to the clinical relevance, the results of the present study argue in favor for magnetic resonance imaging prior to surgery in every patient with a suspected tibial eminence fracture and for an arthroscopic approach to adequately diagnose and treat meniscal injuries. LEVEL OF EVIDENCE: II. PMID- 27234384 TI - A linear polyethylenimine mediated siRNA-based therapy targeting human epidermal growth factor receptor in SPC-A1 xenograft mice. AB - BACKGROUND: Linear polyethylenimine (LPEI) is considered as a desirable gene in vivo delivery system, but whether it could deliver the specific siRNA targeted EGFR to the tumor site to inhibit the growth of NSCLC xenograft in nude mice still needs to be examined. METHODS: In this study, LPEI/siRNA was made into a complex and SPC-A1-xenografted mice model was established. Then, stable LPEI/siRNA-EGFR complexes were intraperitoneally administrated. Afterwards, tumor growth was measured every 3 days. At the end of the experiment, tumor volume was calculated, and tumors were weighed, and examined for EGFR expression, proliferation, and apoptosis evaluations. By using blood samples, toxicity tests including aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea and creatinine (Cr) were measured for liver and renal function evaluation. Serum concentrations of TNF-alpha and IFN-gamma were also examined. RESULTS: Our results demonstrated that LPEI/siRNA-EGFR complexes could downregulate EGFR expression in SPC-A1 xenografted tumor upon single i.p. injection. LPEI/siRNA EGFR complexes inhibited tumor growth and did not induce organ toxicity in SPC-A1 xenografted mice. At the end of the experiment no significant IFN-alpha increase was detected in LPEI/siRNA complexes or glucose-treated groups. CONCLUSIONS: The novel modality of siRNA-based therapy targeting EGFR may be of great potential in NSCLC treatment. PMID- 27234385 TI - Blood viscosity as a forgotten factor and its effect on pulmonary flow. AB - BACKGROUND: The effect of smoking on blood viscosity is widely known. There are, however, few studies on the effect of blood viscosity on pulmonary circulation. METHODS: We aimed to observe the relationship between blood viscosity and pulmonary circulation among smokers and non-smokers. The study comprised 114 subjects in three groups: group 1, ex-smokers; group 2, smoked at least 10 packs/year and still smoking; group 3, never smoked. Blood viscosity (BV), pulmonary blood flow (PBF), and right ventricular systolic pressure (RVSP) were measured in all subjects. RESULTS: PBF was significantly lower in group 1 compared with group 3 (p < 0.05). BV in group 1 was significantly higher than group 3 (p < 0.05) while BV in group 2 was significantly higher than group 3 (p < 0.05). PBF in group 2 was significantly lower than group 3 (p = 0.01). CONCLUSIONS: We believe that BV is a significant and forgotten factor that plays an important role in pulmonary and cardiovascular diseases. BV may affect PF even during the course of smoking, and before the clinical onset of chronic obstructive pulmonary disease (COPD). Therefore, individuals at risk of pulmonary hypertension could be detected earlier with a simple blood test. PMID- 27234386 TI - A half doubling dose change in bronchial hyperresponsiveness in a population represents an important difference. AB - BACKGROUND: The prevalence of asthma has increased over recent decades and the reasons for this are poorly understood. A sensitive tool that can evaluate potential risk factors for asthma is bronchial hyperresponsiveness (BHR), a key physiological characteristic of asthma. However, although the minimum clinically important difference in BHR for an individual is accepted to be around one doubling dose, the minimum important change in a population is not defined. As with surrogate measures of cardiovascular disease risk such as blood pressure and cholesterol, a change that is not clinically important in an individual may be extremely important in public health terms. FINDINGS: To assess the potential impact of a small absolute change in BHR across a population, we modelled the effect of different changes in BHR on the prevalence rates of moderate and severe BHR in an asthmatic population. We calculate that a one half doubling dose increase in BHR increases the prevalence of moderate and severe BHR by 30%. If this was accompanied by an equivalent increase in the population prevalence of moderate and severe asthma, this would be highly significant in public health terms. CONCLUSIONS: We propose that a one half doubling dose worsening in BHR across a population may represent an important change. PMID- 27234387 TI - Self-aggregating TIAF1 in lung cancer progression. AB - Recent studies have demonstrated that transforming growth factor beta (TGF-beta1) induced antiapoptotic factor (TIAF1) is able to form aggregates in the hippocampi of middle-aged normal individuals. The aggregating TIAF1 induces generation of amyloid beta (Abeta) for causing neurodegeneration. Intriguingly, TIAF1 aggregates are shown, together with Smad4 and Abeta, in the cancer stroma and peritumor capsules of many solid tumors. During lung cancer progression, for example, TIAF1 and amyloid fibrils are significantly upregulated in the cancer stroma. Aggregates of TIAF1 and Abeta are shown on the interface between metastatic lung cancer cells and the brain tissues. Conceivably, these peritumor materials are needed for cancer cells to survive. In vitro experiments revealed that TIAF1 is a crucial component for tumor suppressors p53 and WWOX-mediated tumor suppression and apoptosis. While metastatic lung cancer cells are frequently devoid of WWOX and p53, we provide new perspectives regarding the role of TIAF1 in the pathogenesis of lung cancer development, and propose a therapeutic approach for targeting TIAF1. PMID- 27234380 TI - Can heart function lost to disease be regenerated by therapeutic targeting of cardiac scar tissue? AB - Myocardial infarction results in scar tissue that cannot actively contribute to heart mechanical function and frequently causes lethal arrhythmias. The healing response after infarction involves inflammation, biochemical signaling, changes in cellular phenotype, activity, and organization, and alterations in electrical conduction due to variations in cell and tissue geometry and alterations in protein expression, organization, and function - particularly in membrane channels. The intensive research focus on regeneration of myocardial tissues has, as of yet, only met with modest success, with no near-term prospect of improving standard-of-care for patients with heart disease. An alternative concept for novel therapeutic approach is the rejuvenation of cardiac electrical and mechanical properties through the modification of scar tissue. Several peptide therapeutics, locally applied genetic therapies, or delivery of genetically modified cells have shown promise in improving the characteristics of the fibrous scar and post-myocardial infarction prognosis in experimental models. This review highlights several factors that contribute to arrhythmogenesis in scar formation and how these might be targeted to regenerate some of the electrical and mechanical function of the post-MI scar. PMID- 27234388 TI - Oncogenic driver mutations in lung cancer. AB - Lung cancer is a heterogeneous and complex disease. Genomic and transcriptomic profiling of lung cancer not only further our knowledge about cancer initiation and progression, but could also provide guidance on treatment decisions. The fact that targeted treatment is most successful in a subset of tumors indicates the need for better classification of clinically related molecular tumor phenotypes based on better understanding of the mutations in relevant genes, especially in those oncogenic driver mutations. EGFR gene mutations, KRAS gene mutations, EML4 ALK rearrangements and altered MET signaling are widely recognized alterations that play important roles in both the biological mechanisms and the clinical sensitivity to treatment in lung cancer. In this article, we reviewed the discovery of the clinical values of these oncogenic driver mutations and the clinical studies revealing the prognostic and predictive values of these biomarkers for clinical sensitivity and resistance to anti-EGFR therapy or other targeted therapies. These form the basis of personalized treatment in lung cancer based on biomarker profiles of individual tumor, leading to therapeutic advancement and betterment. PMID- 27234389 TI - Inhaled corticosteroid influence toll like receptor 2 expression in induced sputum from patients with COPD. AB - BACKGROUND: The link between long-term ICS therapy and respiratory infection in COPD patients is controversial. We investigated the effect of long-term use of inhaled corticosteroid on Toll like receptor 2 (TLR2) expression in induced sputum from COPD patients. METHODS: 51 patients were divided into two groups according to their treatment history: long-term ICS treatment group (patients who have used ICS (equivalent to Fluticasone Propionate (FP) >= 500 ug/day for more than 1 year) (n = 21) and ICS naive group (who have never routinely used ICS before, n = 29). In their induced sputum, we tested TLR2 extracellular and intracellular expression on macrophages using flowcytometry. TLR2 and tumor necrosis factor alphamRNA expression were also evaluated by real-time PCR. RESULTS: TLR2 extracellular expression on the macrophages from induced sputum in long-term ICS treatment group was lower than the ICS naive group (13.69% +/- 1.17% vs 20.12% +/- 4.37%, p = 0.019). TLR2 intracellular expression in the macrophages, the TLR2 and TNFalphamRNA in the induced sputum also showed a trend towards decreased endpoint in ICS long-term treatment group compare to ICS naive group but did not reach significance. TLR2 extracellular and TLR2 intracellular expression were strongly related (r = 0.645, p = P = 0.017) as well as TNFalphamRNA and TLR2 mRNA expression (r = 0.894, p = 0.0001). CONCLUSION: Long term use of ICS may have negative influence on TLR2 expression in the airway of severe COPD patient. PMID- 27234390 TI - The effect of high concentration oxygen therapy on PaCO2 in acute and chronic respiratory disorders. AB - There is evidence that the potential for high concentration oxygen therapy to increase PaCO2 is not limited to stable and acute exacerbations of COPD, but also to other acute respiratory disorders with abnormal gas exchange such as asthma and pneumonia, and chronic respiratory conditions with hypercapnia such as obesity hypoventilation syndrome. This evidence forms the basis of consensus guidelines which recommend that oxygen therapy is titrated in COPD and other respiratory conditions, to ensure the maximal benefits of oxygen therapy are achieved while reducing the potential for harm due to hyperoxia. PMID- 27234391 TI - The need for translational research in respiratory medicine. AB - Medical advances have failed to arrest the growing morbidity and mortality from lung diseases. COPD, lung cancer and pulmonary infections remain leading causes of death. More than any other time in human history, we need high quality, translatable, patient-focussed respiratory research that will improve clinical practice. Close teamwork of scientists and clinicians are essential. The results of these work need to be disseminated quickly and widely. The creation of an open access journal, such as Translational Respiratory Medicine, dedicated to translational respiratory research can help foster progress. PMID- 27234392 TI - The acute respiratory distress syndrome in 2013. AB - Acute lung injury and the acute respiratory distress syndrome are major causes of morbidity and mortality in critically ill patients. This review focuses on new developments in definitions, epidemiology, clinical and basic research, and promising new directions in treatment. There is new information about the potential contribution of environmental factors, especially exposure to cigarette smoke. Pathologic findings in ARDS have been limited to case reports of open lung biopsies and post-mortem studies but there is some new information from a recent pathology study relative to the frequency of diffuse alveolar damage and the severity of arterial hypoxemia. Further, therapy with lung-protective ventilation and fluid conservative protocol has improved outcomes, but several new trials are in progress to test several promising strategies. PMID- 27234393 TI - Sputum matrix metalloproteinase-9 is associated with the degree of emphysema on computed tomography in COPD. AB - BACKGROUND: Matrix-metalloproteinase (MMP)-9 has been implicated in the pathogenesis of COPD, although its link to disease severity is unclear. The purpose of the study was to examine the relationship between disease severity assessed by lung function and computed tomography (CT) and sputum MMP-9 expression, concentration and activity in patients with COPD. FINDINGS: In 53 COPD subjects, smokers and ex-smokers; 46 healthy controls, smokers and never smokers, we measured sputum MMP-9 concentrations (ELISA) and enzyme activity (FRET), sputum MMP-9 mRNA expression, spirometry, diffusing capacity for carbon monoxide (DLco) and CT assessment of emphysema (% low attenuation areas below-950 Hounsfield units). Sputum MMP-9 concentrations and mRNA expression in COPD subjects were significantly greater than in healthy never-smokers (p = 0.007 and p = 0.001 respectively) and similar to those in healthy smokers. Disease severity when assessed by the extent of emphysema measured by CT, but not by spirometry or DLco values, was directly associated with sputum MMP-9 concentrations [r = 0.442 (0.171, 0.634), p = 0.020], and MMP-9 activity [r = 0.447 (0.219, 0.643), p = 0.010]. In moderate to severe COPD, increased MMP-9 mRNA expression levels were associated with reduced post-bronchodilator FEV1 [r = -0.530 (-0.686, -0.327), p < 0.001], FEV1/FVC ratio [r = -0.551 (-0.701, -0.354), p < 0.001] and reduced DLco [r = -0.399 (-539, -0.102), p = 0.048]. CONCLUSIONS: Sputum MMP-9 concentrations in COPD are directly associated with the extent of emphysema measured by CT and MMP-9 expression levels are inversely associated with DLco. These findings support a role for MMP-9 in the pathogenesis of COPD. PMID- 27234394 TI - Bacteria in COPD; their potential role and treatment. AB - The role of bacterial infection in chronic obstructive pulmonary disease (COPD) and how it should be treated has been an ongoing source of controversy. For many years bacterial infection has not been thought to have an important effect in the pathology of this condition. Recent advances in diagnostic techniques, particularly the use 16S sequencing has demonstrated that there are a large range of bacteria present in the lower respiratory tract, both in terms of exacerbations and chronic colonization. A proportion of the bacteria present in the lower respiratory have also been shown to produce inflammation and hence are likely to be relevant for the pathogenesis of COPD. The accurate diagnosis of bacterial infection in individual patients remains a major challenge. The trials that have assessed the effect of antibiotics in COPD have generally been of low quality and have not been placebo controlled. Recent studies of macrolides for long-term treatment in COPD have found significantly reduced rates of exacerbations. Major challenges remain in accurately defining the potential role of bacteria in the inflammatory process and how best to optimize the use of antibiotics without the overuse of this limited resource. Alternative strategies to treat infection in COPD remain very limited. PMID- 27234395 TI - Standardization developments for large scale biobanks in smoking related diseases - a model system for blood sample processing and storage. AB - BACKGROUND: Biobank samples stored in biobanks give researchers and respiratory healthcare institutions access to datasets of analytes valuable for both diagnostic and research practices. The usefulness of these samples in clinical decision-making is highly dependent on their quality and integrity. New procedures that better preserve sample integrity and reduce degradation are being developed to meet the needs of both present and future biobanking. Hereby we present an automatic sample workflow scheme that is designed to handle high numbers of blood samples. METHODS: Blood fractions are aliquoted, heat sealed using novel technology, and stored in 384 tube high-density sample arrays. RESULTS: The newly developed 384 biobank rack system is especially suited for preserving identical small aliquots. We provide data on robotic processing of clinical samples at -80 degrees C, following initial processing, analysis and shipping between laboratories throughout Europe. Subsequent to unpacking, re sorting, and storage at these sites, the samples have been returned for analysis. Biomarker analysis of 13 common tests in the clinical chemistry unit of the hospital provides evidence of qualitative and stable logistics using the 384 sample tube system. CONCLUSIONS: This technology development allows rapid access to a given sample in the frozen archive while maintaining individual sample integrity with sample tube confinement and quality management. PMID- 27234398 TI - Food incentives to improve completion of tuberculosis treatment: randomised controlled trial in Dili, Timor-Leste. PMID- 27234397 TI - Pulmonary vascular remodeling and right heart failure in pulmonary hypertension: future role of positron emission tomography in decoding the enigma. AB - Whereas the insights into the cellular and molecular mechanisms of pulmonary arterial hypertension (PAH) and associated right heart failure have increased in recent years, there is a lack of clinical tools to assess the pathobiological mechanisms in patients. Positron emission tomography (PET) provides an array of new possibilities to image and quantify relevant disease processes, including proliferation, angiogenesis, matrix remodeling, shifts in metabolism and neurohormonal signaling. Here we describe the first studies which were conducted to image pulmonary vascular remodeling and right heart failure in vivo and discuss additional targets for imaging which hold great promise for future use in PAH patients. PMID- 27234396 TI - Role of WWOX and NF-kappaB in lung cancer progression. AB - It is generally agreed that the pro-inflammatory, pro-survival transcription factor NF-kappaB is a tumor promoter. Tumor necrosis factor alpha (TNF-alpha or TNF) mediates NF-kappaB activation. Tumor suppressor WWOX (FOR or WOX1) is a downstream effector of the TNF signaling. Thus, activation of both WWOX (FOR or WOX1) and NF-kappaB may occur during TNF signaling and/or under stress conditions. Indeed, the first WW domain of WWOX induces the activation of NF kappaB-responsive promoter without TNF participation. It appears that WWOX counteracts with NF-kappaB in regulating cell survival and death. For example, WWOX becomes activated with Tyr33 phosphorylation and relocates together with NF kappaB and many transcription factors to the nucleus to cause neuronal death in sciatic nerve-transected rats. While WWOX is frequently lost in lung cancer and many other cancers, NF-kappaB activation-induced cancer promotion probably requires WWOX-independent signaling networks to induce expression of pro-survival factors. The antagonistic role of WWOX and NF-kappaB in the regulation of lung cancer progression is discussed. PMID- 27234403 TI - Selective screening of Niemann-Pick type C Brazilian patients by cholestane 3beta,5alpha,6beta-triol and chitotriosidase measurements followed by filipin staining and NPC1/NPC2 gene analysis. PMID- 27234399 TI - Obese ZDF rats fermented resistant starch with effects on gut microbiota but no reduction in abdominal fat. AB - SCOPE: To determine if whole-grain (WG) flour with resistant starch (RS) will produce greater fermentation than isolated RS in obese Zucker Diabetic Fatty (ZDF) rats, and whether greater fermentation results in different microbiota, reduced abdominal fat, and increased insulin sensitivity. METHODS AND RESULTS: This study utilized four groups fed diets made with either isolated digestible control starch, WG control flour (6.9% RS), isolated RS-rich corn starch (25% RS), or WG corn flour (25% RS). ZDF rats fermented RS and RS-rich WG flour to greatest extent among groups. High-RS groups had increased serum glucagon-like peptide 1 (GLP-1) active. Feeding isolated RS showed greater Bacteroidetes to Firmicutes phyla among groups, and rats consuming low RS diets possessed more bacteria in Lactobacillus genus. However, no differences in abdominal fat were observed, but rats with isolated RS had greatest insulin sensitivity among groups. CONCLUSIONS: Data demonstrated ZDF rats (i) possess a microbiota that fermented RS, and (ii) WG high-RS fermented better than purified RS. However, fermentation and microbiota changes did not translate into reduced abdominal fat. The defective leptin receptor may limit ZDF rats from responding to increased GLP 1 and different microbiota for reducing abdominal fat, but did not prevent improved insulin sensitivity. PMID- 27234405 TI - Introduction: Emerging Roles of Bioactive Components in Pediatric Nutrition. PMID- 27234404 TI - Genetic testing of the FBN1 gene in Chinese patients with Marfan/Marfan-like syndrome. AB - Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder typically involving the ocular, skeletal and cardiovascular systems, and aortic aneurysms/dissection mainly contributes to its mortality. Here, we performed genetic testing of the FBN1 gene in 39 Chinese probands with Marfan/Marfan-like syndrome and their related family members by Sanger sequencing. In total, 29 pathogenic/likely pathogenic FBN1 mutations, including 17 novel ones, were identified. In addition, most MFS patients with aortic disease (62%) had a truncating or splicing mutation. These results expand the FBN1 mutation spectrum and enrich our knowledge of genotype-phenotype correlations. Genetic testing for MFS and its related aortic diseases is increasingly important for early intervention and treatment. PMID- 27234406 TI - Overview of Lactoferrin as a Natural Immune Modulator. AB - Lactoferrin is thought to be the most polyvalent protein present in host defense against tissue injuries and infections in vertebrates. Owing to the propensity of its basic N-terminal domain to interact with various microbial and host targets, lactoferrin not only has antimicrobial properties, but also modulates the innate and adaptive immune responses. Lactoferrin may indeed up- and downregulate immune cell activation, migration, and growth. Whereas the immunomodulatory properties of lactoferrin are evidenced from in vivo studies using either lactoferrin knockout, lactoferrin-overexpressing transgenic models, and dietary lactoferrin, few mechanisms from in vitro studies have been proposed to explain these properties. The best characterized lactoferrin targets are negatively charged molecules. They encompass pro-inflammatory microbial molecules, such as pathogen associated molecular patterns (eg, lipopolysaccharide), but also host components such as DNA, the glycosaminoglycan chains of proteoglycans, and surface cell receptors. Signaling through these receptors is thought to be the main lever used by lactoferrin to influence immune cells and cytokine-balance-controlling cell activity. This article aims to review our current understanding, though incomplete, of the many ways lactoferrin influences the complex immune machinery and the known and putative mechanisms that may explain its properties. PMID- 27234407 TI - The Role of Lactoferrin in Gastrointestinal and Immune Development and Function: A Preclinical Perspective. AB - The early postnatal period is a critical time for gastrointestinal (GI) and immune development. Neonates fed mother's milk have more rapid GI and immune development than fed-formula infants. In addition, clinical and epidemiologic data provide strong evidence that breastfeeding reduces the incidence and/or severity of infectious diseases. Lactoferrin is a 77 kDa, iron-binding glycoprotein that is present at high concentration in human milk compared with bovine milk and infant formula. It is a multifunctional protein that mediates many of the physiological processes in which breastfed infants have advantages over their formula-fed peers, including promoting GI and immune development, protection from infections, and improved cognitive development. Feeding bovine lactoferrin or recombinant human lactoferrin was well tolerated and stimulated intestinal cell proliferation and increased villus length and crypt depth in piglets. Lactoferrin also influenced both systemic and GI immune development by stimulating a balanced T-helper-1/T-helper-2 cytokine immune response. Further, there was a tendency for immune cells to secrete more anti-inflammatory cytokines in an unstimulated state, while being primed for a robust pro-inflammatory response when presented with a bacterial trigger in piglets fed lactoferrin. These findings support clinical studies demonstrating benefits of dietary lactoferrin in the prevention of infections, late onset sepsis, and necrotizing enterocolitis. PMID- 27234408 TI - Molecular Determinants of Milk Lactoferrin as a Bioactive Compound in Early Neurodevelopment and Cognition. AB - Lactoferrin is a sialic acid-rich, iron-binding milk glycoprotein, known to have multifunctional health benefits, including its ability to modulate immune function and facilitate iron absorption, as well as its antibacterial and antiinflammatory actions. Human milk contains significantly higher lactoferrin levels than bovine milk at the same stages of lactation. The purpose of this review is to discuss the current state of knowledge of lactoferrin as a conditional nutrient for neurodevelopment, neuroprotection, and cognitive function during the period of rapid brain growth. PMID- 27234409 TI - Randomized Control Trial of Human Recombinant Lactoferrin: A Substudy Reveals Effects on the Fecal Microbiome of Very Low Birth Weight Infants. AB - The purpose of this study is to evaluate the effects of enteral lactoferrin on the fecal microbiome and contrast those influences with the neonatal intensive care unit (NICU) environment. We theorized that lactoferrin and the NICU habitat shape the fecal microbial composition of very preterm infants. Although functions attributed to lactoferrin include intestinal immune system development and emergence of a healthy gut microbiota, evidence is limited. Twenty-one very low birth weight (VLBW <1500 g) infants received twice-daily talactoferrin (TLf, a drug designation for recombinant human lactoferrin) or its excipient by gastric gavage from day 1-28 of life. Twenty-four-hour fecal samples were collected on day 21 of life and compared with fecal operational taxonomy units (OTUs) in treated and control infants in 2 NICUs. Workflow included fecal DNA isolation, generation of amplicons for the V1-V3 region of bacterial 16S ribosomal RNA, and sequencing of a gel-purified multiplex amplicon library using a Roche 454 GS FLX Titanium (Roche, Branford, Connecticut) platform and protocols. Fecal OTUs per infant were higher in NICU 1 vs NICU 2 (P < .001), consistent with fewer antibiotic days (P < .02) and a shorter duration of parenteral nutrition (P < .007) in NICU 1. Proteobacteria and Firmicutes were the major phyla in infants treated with TLf and placebo. Among Enterobacteriaceae, TLf prophylaxis reduced Enterobacter and Klebsiella, but increased Citrobacter in feces of VLBW infants. Citrobacter caused no neonatal infections in the study population. OTUs for Clostridiaceae increased in NICU 1 among infants treated with TLf. Importantly, OTUs of staphylococci were barely detectable in both NICUs among infants fed TLf. Fewer hospital-acquired infections occurred in infants treated with TLf vs controls, although the reduction was seen mostly in coagulase-negative staphylococci-related bloodstream and central line infections (P = .06). TLf modified the fecal microbiome in VLBW infants, but care practices in the NICU habitat also contributed. Future research must establish whether elimination vs enrichment of gut-related microbiota reduces clinically significant hospital acquired infections and promotes a healthy commensal microflora in the intestines of VLBW infants. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00854633. PMID- 27234410 TI - Bioactive Proteins in Human Milk: Health, Nutrition, and Implications for Infant Formulas. AB - Breast milk confers many benefits to the newborn and developing infant. There is substantial support for better long-term outcomes, such as less obesity, diabetes, and cardiovascular disease, in breastfed compared with formula-fed infants. More short-term outcomes, such as incidence and duration of illness, nutrient status, and cognitive development during the first year of life also demonstrate benefits of breastfeeding. Several proteins in breast milk, including lactoferrin, alpha-lactalbumin, milk fat globule membrane proteins, and osteopontin, have been shown to have bioactivities that range from involvement in the protection against infection to the acquisition of nutrients from breast milk. In some cases, bovine counterparts of these proteins exert similar bioactivities. It is possible by dairy technology to add protein fractions highly enriched in these proteins to infant formula. PMID- 27234411 TI - Clinical Benefits of Lactoferrin for Infants and Children. AB - To discuss the potential clinical benefits of lactoferrin in preterm and term infants, as well as in young children and to review information on the burden of neonatal sepsis. Current evidence on the mechanisms that explain the role of human milk in the neonatal and infant anti-infective responses will be briefly reviewed and preclinical research data on the potential mechanisms of action by which lactoferrin may impact infant gut health, gut immune development and functions, including the lactoferrin effects on the neonatal microbiome, will be examined. Finally, updated translational research on lactoferrin will be presented and discussed and the current evidence from prospective randomized controlled trials in neonates, infants, and toddlers will be analyzed. These randomized controlled trials demonstrate that lactoferrin has a clinically significant impact on feeding, the microbiome, and clinical outcomes in neonates and infants. PMID- 27234412 TI - Role of Sphingolipids in Infant Gut Health and Immunity. AB - Sphingomyelin (SM), glycosphingolipids, and gangliosides are important polar lipids in the milk fat globule membrane but are not found in standard milk replacement formulas. Because digestion and absorption of SM and glycosphingolipids generate the bioactive metabolites ceramide, sphingosine, and sphingosine-1-phosphate (S1P), and because intact gangliosides may have beneficial effects in the gut, this may be important for gut integrity and immune maturation in the neonate. The brush border enzymes that hydrolyze milk SM, alkaline sphingomyelinase (nucleotide phosphodiesterase pyrophosphatase 7), and neutral ceramidase are expressed at birth in both term and preterm infants. Released sphingosine is absorbed, phosphorylated to S1P, and converted to palmitic acid via S1P-lyase in the gut mucosa. Hypothetically, S1P also may be released from absorptive cells and exert important paracrine actions favoring epithelial integrity and renewal, as well as immune function, including secretory IgA production and migration of T lymphocyte subpopulations. Gluco-, galacto-, and lactosylceramide are hydrolyzed to ceramide by lactase-phlorizin hydrolase, which also hydrolyzes lactose. Gangliosides may adhere to the brush border and is internalized, modified, and possibly transported into blood, and may exert protective functions by their interactions with bacteria, bacterial toxins, and the brush border. PMID- 27234413 TI - Clinical Benefits of Milk Fat Globule Membranes for Infants and Children. AB - The milk fat globule membrane (MFGM) in breast milk contains many bioactive components. Infant formulas traditionally have been devoid of the MFGM fraction, but dairy technology now has made the addition of bovine MFGM technically feasible. We identified 6 double-blinded randomized controlled trials exploring the effects of MFGM supplementation on the diets of infants or children. Results suggest that supplementation is safe and indicate positive effects on both neurodevelopment and defense against infections. MFGM supplementation of infant formula may narrow the gap in cognitive performance and infection rates between breastfed and formula-fed infants. Because of the small number of studies and the heterogeneity of interventions, more high-quality double-blinded randomized controlled trials are needed, with well characterized and clearly defined MFGM fractions, before firm conclusions on the effects of MFGM supplementation on the health and development of infants can be drawn. PMID- 27234414 TI - High-Level Ciprofloxacin-Resistant Campylobacter jejuni Isolates Circulating in Humans and Animals in Incheon, Republic of Korea. AB - Campylobacter jejuni is one of the major causative pathogens of outbreaks or sporadic cases of diarrhoeal diseases worldwide. In this study, we compared the phenotypic and genetic characteristics of C. jejuni isolates of human and food producing animal origins in Korea and examined the genetic relatedness between these two groups of isolates. Regardless of isolation source, all C. jejuni isolates harboured four virulence genes, cadF, cdtB, ciaB and racR, whereas the wlaN and virB11 genes were more frequently observed in human isolates. Antimicrobial susceptibility testing showed that the majority of C. jejuni isolates displayed high-level resistance to fluoroquinolone (95.2%) or tetracycline (76.2%) antibiotics, and 12.4% of isolates exhibited multidrug resistance (more than three classes of antibiotics tested). Pulsed-field gel electrophoresis (PFGE) of all Campylobacter isolates revealed 51 different SmaI PFGE patterns and six major clusters containing both human and animal isolates. These results indicate that genetically diverse strains of C. jejuni with antimicrobial drug-resistance and virulence properties have prevailed in Incheon. Nevertheless, some particular populations continue to circulate within the community, providing the evidence for an epidemiological link of C. jejuni infections between humans and food-producing animals. Therefore, the continued monitoring and surveillance of C. jejuni isolates of human and food-producing animal origins are required for public health and food safety. PMID- 27234415 TI - [Traveller's diarrhoea]. AB - Traveller's diarrhoea (TD) is acquired primarily through ingestion of food and drinks contaminated with pathogens that cause diarrhoea. They can be bacteria, protozoa, helminths, and viruses. Globally, the most common causes of TD are two pathotypes of Escherichia coli (enterotoxigenic and enteroaggregative) and Campylobacter, although there are significant variations by geographic area visited. Most TD occurs in individuals traveling to low-middle income countries. The type of travel, length of stay, traveller's age, and the presence of certain underlying conditions are important risk factors to consider for the acquisition of TD. While TD is usually a mild and self-limiting disease, half of travellers with TD experience some limitation of activities during their trip, while up to 10% will experience persistent diarrhoea or other complications. The purpose of this article is to provide an updated microbiological, epidemiological, and clinical profile of traveller's diarrhoea, including known risk factors, as well as to make recommendations on the prevention and treatment of TD. PMID- 27234416 TI - Comparison of 2-Dose and 3-Dose 9-Valent Human Papillomavirus Vaccine Schedules in the United States: A Cost-effectiveness Analysis. AB - A recent clinical trial using the 9-valent human papillomavirus virus (HPV) vaccine has shown that antibody responses after 2 doses are noninferior to those after 3 doses, suggesting that 2 and 3 doses may have comparable vaccine efficacy. We used an individual-based transmission-dynamic model to compare the population-level effectiveness and cost-effectiveness of 2- and 3-dose schedules of 9-valent HPV vaccine in the United States. Our model predicts that if 2 doses of 9-valent vaccine protect for >=20 years, the additional benefits of a 3-dose schedule are small as compared to those of 2-dose schedules, and 2-dose schedules are likely much more cost-efficient than 3-dose schedules. PMID- 27234417 TI - Nucleoside Inhibitors of Zika Virus. AB - There is growing evidence that Zika virus (ZIKV) can cause devastating infant brain defects and other neurological disorders in humans. However, no specific antiviral therapy is available at present. We tested a series of 2'-C- or 2'-O methyl-substituted nucleosides, 2'-C-fluoro-2'-C-methyl-substituted nucleosides, 3'-O-methyl-substituted nucleosides, 3'-deoxynucleosides, derivatives with 4'-C azido substitution, heterobase-modified nucleosides, and neplanocins for their ability to inhibit ZIKV replication in cell culture. Antiviral activity was identified when 2'-C-methylated nucleosides were tested, suggesting that these compounds might represent promising lead candidates for further development of specific antivirals against ZIKV. PMID- 27234418 TI - Hepatitis E Virus (HEV) ORF2 Antigen Levels Differentiate Between Acute and Chronic HEV Infection. AB - BACKGROUND: Hepatitis E virus (HEV) genotype 3 infections are frequent in Europe and North America, with acute and chronic courses described in the literature. HEV RNA detection by real-time polymerase chain reaction (PCR) is the gold standard for diagnosis. Recently, an anti-HEV antigen (Ag)-specific enzyme-linked immunosorbent assay (ELISA) directed against the HEV capsid became commercially available. The effectiveness of anti-HEV Ag-specific ELISA at detecting HEV genotype 3 infections remains undefined. METHODS: The performance of anti-HEV Ag ELISA was compared with that of real-time PCR, using sera from a cohort of acutely infected individuals, in addition to a cohort of chronically infected patients undergoing ribavirin therapy. Furthermore, virion properties were evaluated by density fractionation. RESULTS: Anti-HEV Ag-specific ELISA was less sensitive than real-time PCR at detection of HEV infection. Anti-HEV Ag-specific ELISA revealed significantly higher HEV Ag in chronically infected individuals as compared to acutely infected patients, with high sensitivity and specificity to distinguish acute from chronic HEV infection. Of note, HEV Ag remained detectable for >100 days after HEV RNA clearance in ribavirin-treated patients with chronic HEV. Density gradients revealed the presence of membrane-associated virions in the sera, with a different distribution as compared to HEV RNA. CONCLUSIONS: The anti-HEV Ag-specific ELISA is less sensitive than HEV RNA real-time PCR but represents a useful tool to discriminate chronic from acute infection. PMID- 27234420 TI - Congenital Tuberculosis after in-vitro Fertilization in a Woman Previously Undiagnosed with Tuberculosis Salpingitis. PMID- 27234419 TI - The Type of Growth Medium Affects the Presence of a Mycobacterial Capsule and Is Associated With Differences in Protective Efficacy of BCG Vaccination Against Mycobacterium tuberculosis. AB - BACKGROUND: Bacillus Calmette-Guerin (BCG) vaccine is widely used for the prevention of tuberculosis, despite limited efficacy. Most immunological studies of BCG or Mycobacterium tuberculosis strains grow bacteria in the presence of detergent, which also strips the mycobacterial capsule. The impact of the capsule on vaccine efficacy has not been explored. METHODS: We tested the influence of detergent in cultures of BCG and M. tuberculosis strains on the outcome of vaccination experiments on mice and transcriptional responses on M. tuberculosis RESULTS: Vaccination of mice with encapsulated BCG promoted a more potent immune response relative to vaccination with unencapsulated BCG, including higher polysaccharide-specific capsule antibody titers, higher interferon gamma and interleukin 17 splenic responses, and more multifunctional CD4(+) T cells. These differences correlated with variability in the bacterial burden in lung and spleen of mice infected with encapsulated or unencapsulated M. tuberculosis The combination of vaccination and challenge with encapsulated strains resulted in the greatest protection efficacy. The transcriptome of encapsulated M. tuberculosis was similar to that of starvation, hypoxia, stationary phase, or nonreplicating persistence. CONCLUSIONS: The presence of detergent in growth media and a capsule on BCG were associated with differences in the outcome of vaccination, implying that these are important variables in immunological studies. PMID- 27234421 TI - Interlocking intramedullary nail fixation with additional bone grafting from trochanter via a femoral hollow trephine in the treatment of femoral shaft fractures: design and clinical application. AB - PURPOSE: The purpose of this study was to describe and evaluate the clinical application of the technique of interlocking intramedullary (IM) nailing via an entry point at the tip of greater trochanter using a specially designed femoral hollow trephine to stabilize diaphyseal fractures of the femur. METHODS: From February 2010 to April 2014, 35 consecutive patients with femoral shaft fractures were treated by the therapy of bone grafting from trochanter region with interlocking IM nail. The average age of these 23 male and 12 female patients was 37.5 years (range, 22-67 years). Fractures were classified according to AO classification system (15 type A, 17 type B, 3 type C). Femoral canal reaming and the collection of cancellous bone were simultaneously performed in a single step with the specially designed femoral hollow trephine, followed by regular IM nailing procedure. RESULTS: Of the 35 cases, the mean volume of spongy bone obtained was 5.63 cm3 (range, 3.0-7.0 cm3). Thirty-five patients with femoral shaft fractures had a mean follow-up period of 16.2 months (range, 12-22 months). All patients achieved bony union, at a mean of 5.4 months (range, 4-6 months). No patient developed a delayed union or a nonunion. There were no complications such as infections, injury of vascular and nerve, or heterotopic ossification in hip. CONCLUSIONS: These results indicate that the technique of use of IM nailing with the femoral hollow trephine significantly decreases the occurrence of nonunion in femoral shaft fractures. PMID- 27234422 TI - Lymantria mathura nucleopolyhedrovirus: Identification, occurrence and genetic diversity in Iwate Prefecture, Japan. AB - A high prevalence of nuclear polyhedrosis has been observed in larval outbreaks of Lymantria mathura in Iwate Prefecture, Japan. However, the virus responsible has not been identified. Here the virus was designated Lymantria mathura nucleopolyhedrovirus (LymaNPV), based on partial sequence results of the lef-8, lef-9, and polh genes and transmission electron microscopic observations. Diagnosis by polymerase chain reaction targeting of the partial polh gene and a subsequent restriction fragment length polymorphism (RFLP) analysis indicated that LymaNPV was an exclusive causative agent for the nuclear polyhedrosis of the L. mathura larvae. LymaNPV was also detected from a very small fraction of L. dispar larvae that co-occurred with L. mathura larvae where the prevalence of LymaNPV-caused disease was high. A bioassay using LymaNPV against L. dispar larvae produced infection with the inoculated virus. This finding was consistent with the results of the field sample analysis. LymaNPV contained six genome types in the L. mathura populations sampled, as determined by RFLP of LymaNPV genomic DNA and southern blot hybridization analyses. None of the genome types was unique to any sampling site, indicating that some flow had occurred among sites. However, genome-type composition seemed to differ among sites. This study provides basic information about the interaction between L. mathura and LymaNPV. PMID- 27234423 TI - Metarhizium anisopliae infection alters feeding and trophallactic behavior in the ant Solenopsis invicta. AB - In social insects, social behavior may be changed in a way that preventing the spread of pathogens. We infected workers of the ant Solenopsis invicta with an entomopathogenic fungus Metarhizium anisopliae and then videotaped and/or measured worker feeding and trophallactic behavior. Results showed that fungal infected S. invicta enhanced their preference for bitter alkaloid chemical quinine on 3days after inoculation, which might be self-medication of S. invicta by ingesting more alkaloid substances in response to pathogenic infection. Furthermore, infected ants devoted more time to trophallactic behavior with their nestmates on 3days post inoculation, in return receiving more food. Increased interactions between exposed ants and their naive nestmates suggest the existence of social immunity in S. invicta. Overall, our study indicates that S. invicta may use behavioral defenses such as self-medication and social immunity in response to a M. anisopliae infection. PMID- 27234424 TI - Ostreid herpesvirus type 1 genomic diversity in wild populations of Pacific oyster Crassostrea gigas from Italian coasts. AB - Ostreid herpesvirus 1 (OsHV-1) is a significant pathogen affecting the young Pacific oyster Crassostrea gigas, worldwide. A new variant, OsHV-1 MUVar, has been associated with recurrent mortality events in Europe since 2008. Epidemiological data collection is key for global risk assessment; however little is known about health status and genotypes present in European wild oyster beds. Most studies to date have involved only cultivated individuals during mortality events, and reported low genotype diversity. With this study, conducted along the Italian coasts, we investigated for the first time the presence of OsHV-1 in European natural oyster beds. Analysis of three genomic regions revealed the presence of at least nine different genotypes, including two variants close to the OsHV-1 reference, known since the early 1990s but with no European record reported since 2010, and highlights relevant genotype diversity in natural environment. Phylogenetic analysis distinguished two distinct clusters and geographical distribution of genotypes, with the exception of a variant very closely related to the MUVar, which appeared the single genotype present in all the Adriatic sites. Interestingly, these wild symptom free populations could represent, in Europe, an accessible alternative to the import of OsHV-1-resistant oyster strains from the East Pacific, the native area of C. gigas, avoiding the high-risk of non-native marine species and new pathogen introductions. PMID- 27234425 TI - Calcium activated adenylyl cyclase AC8 but not AC1 is required for prolonged behavioral anxiety. AB - BACKGROUND: Anxiety disorder is a state of mental discomfort while acute anxiety induces an enhancement of vigilance/arousal or increased anxious responses. Most of the previous studies investigated basic mechanisms for acute anxiety, while less information is available for prolonged or repetitive anxiety. RESULTS: In the present study, we wanted to examine possible molecular mechanisms for behavioral anxiety after repeated exposures. Performing a paradigm of five sessions of the elevated plus-maze (EPM), we show that the repeated exposure to the EPM induces a long-lasting anxiety causing a gradual increase of anxiolytic activity, which is maintained for at least 21 days. Genetic deletion of AC8 (adenylyl cyclase 8) but not AC1 abolished long-lasting anxiety. CONCLUSIONS: Our results suggest that calcium-stimulated AC8 is required to sustain the long lasting anxiety caused by repeated EPM testing, and we can identify in AC8 a novel target for treating anxiety-related mood disorders. PMID- 27234427 TI - Proteomic analysis of short-term preload-induced eccentric cardiac hypertrophy. AB - BACKGROUND: Hemodynamic load leads to cardiac hypertrophy and heart failure. While afterload (pressure overload) induces concentric hypertrophy, elevation of preload (volume overload) yields eccentric hypertrophy and is associated with a better outcome. Here we analysed the proteomic pattern of mice subjected to short term preload. METHODS AND RESULTS: Female FVB/N mice were subjected to aortocaval shunt-induced volume overload that leads to an eccentric hypertrophy (left ventricular weight/tibia length +31 %) with sustained systolic heart function at 1 week after operation. Two-dimensional gel electrophoresis (2-DE) followed by mass spectrometric analysis showed alteration in the expression of 25 protein spots representing 21 different proteins. 64 % of these protein spots were up regulated and 36 % of the protein spots were consistently down-regulated. Interestingly, alpha-1-antitrypsin was down-regulated, indicating higher elastin degradation and possibly contributing to the early dilatation. In addition to contractile and mitochondrial proteins, polymerase I and transcript release factor protein (PTRF) was also up-regulated, possibly contributing to the preload induced signal transduction. CONCLUSIONS: Our findings reveal the proteomic changes of early-stage eccentric myocardial remodeling after volume overload. Induced expression of some of the respiratory chain enzymes suggests a metabolic shift towards an oxidative phosphorylation that might contribute to the favorable remodeling seen in early VO. Down-regulation of alpha-1-antitrypsin might contribute to extracellular matrix remodeling and left ventricular dilatation. We also identified PTRF as a potential signaling regulator of volume overload induced cardiac hypertrophy. PMID- 27234428 TI - Long-Term Survival in a Patient With Abdominal Sarcomatosis From Uterine Leiomyosarcoma: Role of Repeated Laparoscopic Surgery in Treatment and Follow-Up. AB - Uterine leiomyosarcoma (LMS) in some cases may disseminate through the abdominal cavity, without extra-abdominal spreading, determining a condition of abdominal sarcomatosis, which represents a peculiar situation. Only radical surgical removal offers a chance of long-term survival in such cases of LMS. Here we describe a case of diffuse abdominal sarcomatosis from uterine LMS in a 51-year old perimenopausal woman who underwent laparoscopic radical hysterectomy, bilateral salpingo-oophorectomy, total pelvic peritonectomy, pelvic lymphadenectomy to the mesenteric inferior artery, and omentectomy. Then, given the high probability of disease recurrence, the patient underwent a close follow up consisting of positron emission tomography (PET)/computed tomography every 3 months and diagnostic (and if necessary operative) laparoscopy every 6 months. To date, the patient had 11 laparoscopies; 5 of them were preceded by a PET indicative of the presence of disease with high metabolic activity, which was confirmed at surgery and each time completely removed laparoscopically with no evidence of residual disease. To date, 5 years from diagnosis the patient is alive and continues her follow-up. Our report brings to light the ability of laparoscopic surgery to obtain disease control in a case of LMS with abdominal dissemination. Moreover, laparoscopic surgery, as demonstrated in our case, may have an important role in the close follow-up of the disease and allow a timely and early radical surgical approach of relapses before they become extremely large and difficult to remove radically. PMID- 27234429 TI - Office Hysteroscopic Findings of Congested Endometrial Spiral Arterioles. PMID- 27234430 TI - Postpartum Permanent Sterilization: Could Bilateral Salpingectomy Replace Bilateral Tubal Ligation? AB - STUDY OBJECTIVE: There has recently been an expansion in the use of bilateral salpingectomy at the time of sterilization to theoretically decrease ovarian cancer risk. We sought to determine if postpartum salpingectomy is equivalent to postpartum bilateral tubal ligation (BTL) in terms of duration, estimated blood loss (EBL), and complication rate. DESIGN: A retrospective case series (Canadian Task Force Classification II-2). SETTING: An academic inner-city hospital. PATIENTS: All patients admitted for delivery of full-term intrauterine pregnancy desiring permanent sterilization between March 2014 and March 2015 were included. Excluded patients included those who had sterilization at the time of the cesarean section or other surgical procedure. Two cohorts were identified, those who had a planned postpartum tubal ligation and those having a postpartum salpingectomy. INTERVENTIONS: Postpartum sterilization. MEASUREMENTS AND MAIN RESULTS: Researchers of this study recorded demographics, medical histories, and abdominal surgical histories for all patients who met the inclusion criteria. Surgical times, EBL, and complication rates were reviewed. Unpaired t test calculations were used to identify differences between age, body mass index, parity, and surgical time between the 2 cohorts. Chi-square tests were used to determine the statistical significance between complication rates, history of abdominal surgery, and past medical history of tubal disease between the 2 cohorts. Eighty women were identified, 64 in the BTL group and 16 in the salpingectomy cohort. The demographics of each cohort were equivocal. The average surgical time was 59.13 and 71.44 minutes in the BTL and salpingectomy cohorts, respectively. Of the 80 patients, only 1 had an EBL greater than 50 mL; this patient was in the BTL group. Four complications were noted in the BTL cohort, but none were evident in the salpingectomy group. There were no documented sterilization failures in the follow-up period (median = 9 months). CONCLUSION: Postpartum salpingectomy is slightly longer in duration but with similar blood loss and complication rates. Salpingectomy could be considered in particularly high-risk patients at risk for ovarian cancer when consenting for a postpartum sterilization procedure. PMID- 27234431 TI - Increased levels of CD4(+) and CD8(+) T cells expressing CCR1 in patients developing allograft dysfunction; a cohort study. AB - BACKGROUND: Leukocyte infiltration into the graft has pivotal effects on kidney transplantation outcome. The present study sought to determine whether the expression of sequential chemokine receptors on CD4(+) and CD8(+) T cells in human renal allograft can predict clinical episodes. METHODS: Blood samples from 52 consecutive renal transplant patients were evaluated at the time of transplantation and at three times (2, 90 and 180days) after transplantation to analyze the expression of CCR1 and CXCR3 on CD4(+) and CD8(+) T cells by flowcytometry. A total of 30 biopsies, including protocol biopsy (n=24) and cause biopsy (n=6), were investigated according to the Banff criteria. RESULTS: The mean percentage of CD4(+) and CD8(+) T cells expressing CCR1 was significantly increased in patients with allograft dysfunction (n=25) (p=0.006, p=0.004). The mean fluorescence intensity of CXCR3 on CD4(+) and CD8(+) T cells were found to be significantly higher in graft dysfunction than that in well-functioning grafts. (p<0.001, p=0.007). Receiver Operating Characteristic (ROC) Curve Analysis showed that the calculated AUC was 0.86 at the third month for CD4(+)CCR1(+) and CD8(+)CCR1(+) (p<0.001). Multiple logistic regression analysis showed that an increase in CD4(+) expressing CXCR3 leads to a lower risk of graft dysfunction (OR=0.37), while an increase in CD8(+) expressing CCR1 results in a higher risk of graft dysfunction (OR=3.66). CONCLUSION: During renal transplantation, CD4(+) and CD8(+) T cells expressing CCR1 were increased in patients who developed graft dysfunction. These findings may prospectively predict allograft dysfunction, and help elucidate the underlying pathogenic mechanisms. PMID- 27234432 TI - Pain levels and typical symptoms of acute endodontic infections: a prospective, observational study. AB - BACKGROUND: This study aimed to identify key symptoms that could be associated with the diagnosis of acute forms of symptomatic apical periodontitis (SAP) and symptomatic irreversible pulpitis (SIP), and to identify a diagnostic algorithm based on these symptoms. METHODS: In this prospective, observational study 173 emergency patients diagnosed with acute pain of endodontic origin and no swelling or fistula were included. Patients were asked 11 specific questions from a checklist with a possible discerning value between acute SAP and acute SIP. Pain levels were recorded using the numeric rating scale (NRS-11). Subsequently, the painful tooth was diagnosed. Logistic regression was used to evaluate the checklist regarding its differentiation between SAP (N = 103) and SIP (N = 70). Moreover, a decision tree was constructed based on recursive partitioning to identify a hierarchy in differentiating symptoms. RESULTS: With identical median NRS-11 scores of 8, the teeth diagnosed with acute SAP and SIP were severely painful. The decision tree analysis resulted in a tree with splits according to pain on cold, perceived tooth extrusion, and pain duration. The overall sensitivity of the tree to detect SAP based on key symptoms was 95 %, its specificity was 31 %. CONCLUSIONS: The best indicator for SAP was a reported absence of pain to cold stimuli. In teeth that did have a history of pain triggered by cold stimuli, the decision tree correctly identified SAP in 72 % of the teeth that felt too high and had hurt for less than one week. PMID- 27234433 TI - New radiological clues in the diagnosis of spindle cell oncocytoma of the adenohypophysis. AB - AIM: To present three new cases of spindle cell oncocytoma (SCO) from a single centre and to identify new radiological clues in the diagnosis of SCO according to the information obtained from the cases presented. MATERIALS AND METHODS: Three adults with SCO confirmed at histopathology were retrospectively reviewed. The medical records, imaging findings, operative notes, and histopathology findings for each patient were recorded. Magnetic resonance imaging (MRI) findings were evaluated, including tumour localisation, tumour size, signal intensity, imaging features on T1-weighted and T2-weighted images, and contrast enhancement characteristics. The study protocol was approved by the institutional review board. Informed consent was obtained from each patient. RESULTS: T1 weighted imaging (WI) and T2WI demonstrated millimetric hypointense foci and linear signal void areas in all lesions. Consistent with the hypervascular features of the tumour, intense contrast enhancement was observed during the early stages of dynamic contrast enhanced (DCE) MRI. Linear signal void areas showed contrast enhancement, but some of the hypointense millimetric foci remained without contrast enhancement. CONCLUSIONS: Although the radiological findings and preoperative diagnosis of SCO have been reported to be non-specific and impossible, respectively, in the literature, the characteristics of MRI and different patterns of contrast enhancement can help in recognising this rare entity. This article represents a single institution case series of SCOs and also includes the first description of a correlation of the histopathological findings with radiological findings and new clues in the differential diagnosis of SCOs. We described these new radiological clues as "Hasiloglu's Signs". PMID- 27234434 TI - Automatic radiation dose monitoring for CT of trauma patients with different protocols: feasibility and accuracy. AB - AIM: To demonstrate the feasibility and accuracy of automatic radiation dose monitoring software for computed tomography (CT) of trauma patients in a clinical setting over time, and to evaluate the potential of radiation dose reduction using iterative reconstruction (IR). MATERIALS AND METHODS: In a time period of 18 months, data from 378 consecutive thoraco-abdominal CT examinations of trauma patients were extracted using automatic radiation dose monitoring software, and patients were split into three cohorts: cohort 1, 64-section CT with filtered back projection, 200 mAs tube current-time product; cohort 2, 128-section CT with IR and identical imaging protocol; cohort 3, 128-section CT with IR, 150 mAs tube current-time product. Radiation dose parameters from the software were compared with the individual patient protocols. Image noise was measured and image quality was semi-quantitatively determined. RESULTS: Automatic extraction of radiation dose metrics was feasible and accurate in all (100%) patients. All CT examinations were of diagnostic quality. There were no differences between cohorts 1 and 2 regarding volume CT dose index (CTDIvol; p=0.62), dose-length product (DLP), and effective dose (ED, both p=0.95), while noise was significantly lower (chest and abdomen, both -38%, p<0.017). Compared to cohort 1, CTDIvol, DLP, and ED in cohort 3 were significantly lower (all -25%, p<0.017), similar to the noise in the chest (-32%) and abdomen (-27%, both p<0.017). Compared to cohort 2, CTDIvol (-28%), DLP, and ED (both -26%) in cohort 3 was significantly lower (all, p<0.017), while noise in the chest (+9%) and abdomen (+18%) was significantly higher (all, p<0.017). CONCLUSION: Automatic radiation dose monitoring software is feasible and accurate, and can be implemented in a clinical setting for evaluating the effects of lowering radiation doses of CT protocols over time. PMID- 27234435 TI - Radiological assessment of paediatric cervical spine injury in blunt trauma: the potential impact of new NICE guidelines on the use of CT. AB - AIM: To determine the potential effect of changes to the National Institute for Health and Care Excellence (NICE) guidelines to the use of computed tomography (CT) in the assessment of suspected paediatric cervical spine (c-spine) injury. MATERIAL AND METHODS: A 5 year retrospective study was conducted of c-spine imaging in paediatric (<10 years) patients presenting following blunt trauma at a Level 1 trauma centre in London. All patients under the age of 10 years who underwent any imaging of the c-spine following blunt trauma were included. Clinical data relating to the presenting signs and symptoms were obtained from the retrospective review of electronic records and paper notes. This was then applied to the previous NICE guideline (CG56) and to the new NICE guideline (CG176). Patients with incomplete data were excluded. RESULTS: Two hundred and seventy-eight patients <10 years underwent imaging of the c-spine following blunt trauma. Two hundred and seventy (97.12%) examinations had complete data and were included in further analysis. One hundred and forty-nine (55.19%) met the criteria for a CT of the c-spine under NICE CG56, whereas 252 (93.33%) met the updated NICE CG176 criteria for c-spine CT. Five (1.85%) patients had a c-spine injury and met the criteria under both CG56 and CG176 NICE guidelines. CONCLUSION: Recent changes to NICE Head Injury Guidelines relating to radiological assessment of paediatric c-spine following blunt trauma are likely to result in an increased usage of CT as the initial radiological investigation over plain radiographs, without an apparent increase in specificity in the present series. PMID- 27234436 TI - Susac syndrome with prominent dermatological findings and a prompt response to intravenous immunoglobulin, steroids, and rituximab: a case report. AB - BACKGROUND: Susac syndrome (retinocochleocerebral vasculopathy) is an autoimmune endotheliopathy affecting the precapillary arterioles of the brain, retina, and inner ear. It presents with encephalopathy, branch retinal artery occlusions, and hearing loss. The condition is often under recognized because the clinical symptoms may present at different times and physicians may be unfamiliar with the syndrome. Peripheral findings would be helpful in early diagnosis. There are numerous treatment regimens proposed with varying effectiveness. CASE PRESENTATION: We report the case of a 22-year-old Caucasian man in whom there were prominent skin findings, including livedo reticularis and a micropapular eruption which responded promptly to treatment suggesting that skin involvement may facilitate earlier diagnosis. Rituximab has occasionally been used in more refractory disease. We observed a prompt response to the combination of intravenous immunoglobulin, corticosteroids, and rituximab instituted immediately after diagnosis. CONCLUSIONS: A careful search for dermatological manifestations may help with earlier diagnosis. Skin findings may be another marker of endothelial cell involvement. Early use of rituximab as part of the therapeutic regimen may be warranted. PMID- 27234437 TI - Bonding resin thixotropy and viscosity influence on dentine bond strength. AB - OBJECTIVES: To investigate the influence of bonding resin thixotropy and viscosity on dentine tubule penetration, blister formation and consequently on dentine bond strength as a function of air-blowing pressure (air-bp) intensity. METHODS: Two HEMA-free, acetone-based, one-bottle self-etch adhesives with similar composition except disparate silica filler contents and different bonding resin viscosities were investigated. The high-filler-containing adhesive (G-Bond) featured a lower viscous bonding resin with inherent thixotropic resin (TR) properties compared to the low-filler-containing adhesive (iBond) exhibiting a higher viscous bonding resin with non-thixotropic resin (NTR) properties. Shear bond strength tests for each adhesive with low (1.5bar; 0.15MPa; n=16) and high (3.0bar; 0.30MPa; n=16) air-bp application were performed after specimen storage in distilled water (24h; 37.0+/-1.0 degrees C). Results were analysed using a Student's t-test to identify statistically significant differences (p<0.05). Fracture surfaces of TR adhesive specimens were morphologically characterised by SEM. RESULTS: Statistically significant bond strength differences were obtained for the thixotropic resin adhesive (high-pressure: 24.6MPa, low-pressure: 9.6MPa). While high air-bp specimens provided SEM images revealing resin-plugged dentine tubules, resin tags and only marginally blister structures, low air-bp left copious droplets and open dentine tubules. In contrast, the non-thixotropic resin adhesive showed no significant bond strength differences (high-pressure: 9.3MPa, low-pressure: 7.6MPa). CONCLUSIONS: A pressure-dependent distinct influence of bonding resin thixotropy and viscosity on dentine bond strength has been demonstrated. Stronger adhesion with high air-bp application is explained by improved resin fluidity and facilitated resin penetration into dentine tubules. CLINICAL SIGNIFICANCE: Filler particles used in adhesive systems may induce thixotropic effects in bonding resin layers, accounting for improved free-flowing resin properties. In combination with high air-bp this effect allows an easy plugging of dentine tubules and elimination of blister structures, both resulting in superior dentine bond strength. PMID- 27234438 TI - Human Herpesvirus Type 8-associated Large B-cell Lymphoma: A Nonserous Extracavitary Variant of Primary Effusion Lymphoma in an HIV-infected Man: A Case Report and Review of the Literature. AB - BACKGROUND: Primary effusion lymphoma (PEL) is a rare non-Hodgkin lymphoma subtype primarily seen in human immunodeficiency virus (HIV)-infected individuals with low CD4(+) cell counts and elevated HIV viral loads. It has always been associated with human herpesvirus type 8 (HHV-8) and in 80% of cases has also been associated with Epstein-Barr virus (EBV). Less commonly, PEL has presented in patients with advanced age and other conditions associated with an altered immunity, including malignancy, liver cirrhosis, and immunosuppressive medications. It is a tumor of B-cell lineage; however, it shows a "null" phenotype, rarely expressing pan-B cell surface antigens. It will usually express CD45, CD30, CD38, CD138, and MUM1 and is characterized by lymphomatous effusions in body cavities but not lymphadenopathy. It is an aggressive lymphoma, with an average median survival of < 1 year. HHV-8-associated large B-cell lymphoma (HHV 8-LBL) is a second variant of PEL that is both solid and extracavitary. It has immunoblastic and/or anaplastic morphologic features and a distinct immunohistochemical staining pattern. It could also have a different clinical presentation than that of classic PEL. MATERIALS AND METHODS: We describe the case of a 57-year-old HIV-infected man who presented with a slow-growing and asymptomatic abdominal mass. Examination of an excisional biopsy specimen showed malignant large cells with prominent cytoplasm that were positive for pan-B cell antigen CD20, HHV-8, and EBV and negative for CD138, CD10, BCL-6, CD3, and CD30. The Ki-67 labeling index was 90%. The diagnosis was stage IIIA HHV-8-LBL, and he was treated with 6 cycles of R-EPOCH (rituximab, etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone) infusion chemotherapy. At 12 months after treatment, he was in complete remission. We also performed a Medline and Embase search to better understand the clinical findings of our patient and the unique attributes of HHV-8-LBL. Focusing our search on English language studies, we identified 83 cases of HHV-8-LBL without an effusion component. We compared these 83 cases with 118 reported cases of classic PEL. RESULTS: The median age of the patients with HHV-8-LBL was 41 years (range, 24-77), and 96% of the cases were associated with HIV. The median age of the patients with classic PEL was 41 years (range, 26-86), and 96% of the cases were associated with HIV. Of those with HHV-8-LBL, 31 of 61 (51%) had a pre-existing diagnosis of acquired immunodeficiency syndrome (AIDS) and 47 of 63 (75%) were coinfected with EBV. In contrast, 69 of 96 patients (72%) with classic PEL had a pre-existing AIDS diagnosis and 40 of 49 (82%) were coinfected with EBV. The mean CD4(+) count of the HHV-8-LBL patients was 256 cells/MUL (range, 18-1126 cells/MUL) compared with 139 cells/MUL (range, 2-557 cells/MUL) in the classic PEL patients. The median survival time for both groups was similar at 5.5 months (range, 25 days to >= 25 months) for patients with HHV-8-LBL and 4 months (range, 2 days to >= 113 months) for those with classic PEL. More patients with HHV-8-LBL were alive at the last follow-up point (59% vs. 18%). The percentage of patients achieving complete remission was 54% (30 of 56) and 36% (32 of 89) for HHV-8-LBL and classic PEL, respectively. CONCLUSION: Our patient's high CD4(+) cell count, the lack of a pre existing AIDS diagnosis, and the excellent response to chemotherapy highlights that HHV-8-LBL might have distinct clinical features and possibly a better response to chemotherapy than classic PEL. HHV-8-LBL should be included in the differential diagnosis of HIV patients with solid lesions. It is essential that patients' Centers for Disease Control and Prevention HIV clinical status and HIV viral load at the diagnosis of PEL and HHV-8-LBL be reported and that the reported clinical results include longer term follow-up data. Only then will a more complete clinical picture of this little-appreciated and little-understood PEL variant be defined. PMID- 27234439 TI - The decision-making process and criteria in selecting candidate drugs for progeria clinical trials. PMID- 27234441 TI - The composition of collagen in the aneurysm wall of men and women. AB - BACKGROUND: Loss of vessel wall integrity by degradation is essential for the development of abdominal aortic aneurysm (AAA) and ultimately its rupture. The observed greater rupture rate in women with AAA might be related to gender differences in the biomechanical properties of the aneurysm wall. The aim of the study was to compare the biomechanically important structure of collagen between men and women with AAA. METHODS: Biopsies of the aneurysm walls were obtained during elective open repair of men (n = 14) and women (n = 14) treated for AAA. High-performance liquid chromatography (HPLC), Western blot, messenger RNA expression, and histochemical analyses were performed to assess the cross-linking and the amount and the composition of collagen. RESULTS: There was neither a difference in the thickness of the aneurysm wall, nor in the histological evaluation of the collagen composition between the sexes. Relative collagen content in the aneurysm wall was similar in men and women, as assessed by messenger RNA expression and HPLC. Collagen cross-linking differed between the sexes; women had more lysyl pyridinoline (LP) than men (0.140 vs 0.07; P = .005), resulting in a lower hydroxyl pyridinoline (HP):LP ratio (3.28 vs 8.41; P = .003). There was no difference in messenger RNA and protein expressions of lysyl hydroxylase and lysyl oxidase to associate with the lower HP:LP ratio in women. CONCLUSIONS: The composition of collagen in the aneurysm wall of men and women are in several aspects similar, with the exception of collagen cross-linking, suggesting that the difference in rupture rate between the sexes rather depend on the composition of other vessel wall structures. PMID- 27234440 TI - Follistatin-like 1 promotes cardiac fibroblast activation and protects the heart from rupture. AB - Follistatin-like 1 (Fstl1) is a secreted protein that is acutely induced in heart following myocardial infarction (MI). In this study, we investigated cell type specific regulation of Fstl1 and its function in a murine model of MI Fstl1 was robustly expressed in fibroblasts and myofibroblasts in the infarcted area compared to cardiac myocytes. The conditional ablation of Fstl1 in S100a4 expressing fibroblast lineage cells (Fstl1-cfKO mice) led to a reduction in injury-induced Fstl1 expression and increased mortality due to cardiac rupture during the acute phase. Cardiac rupture was associated with a diminished number of myofibroblasts and decreased expression of extracellular matrix proteins. The infarcts of Fstl1-cfKO mice displayed weaker birefringence, indicative of thin and loosely packed collagen. Mechanistically, the migratory and proliferative capabilities of cardiac fibroblasts were attenuated by endogenous Fstl1 ablation. The activation of cardiac fibroblasts by Fstl1 was mediated by ERK1/2 but not Smad2/3 signaling. This study reveals that Fstl1 is essential for the acute repair of the infarcted myocardium and that stimulation of early fibroblast activation is a novel function of Fstl1. PMID- 27234442 TI - A male infant had subdural effusion and paroxysmal supraventricular tachycardia during the febrile episode of Kawasaki disease: a case report and literature review. AB - BACKGROUND: Kawasaki disease is an acute, febrile, self-limiting, inflammatory systemic vasculitis seen in early childhood, most commonly in those below 5 years of age. In Kawasaki disease, the coronary arteries are most commonly affected, which may lead to asymptomatic coronary artery ectasia or formation of an aneurysm. Paroxysmal supraventricular tachycardia(PSVT) is a severe and rare cardiovascular complication of Kawasaki disease. A case of Kawasaki disease presenting with unusual findings, including subdural effusion and PSVT is reported. CASE PRESENTATION: This is a 4-month-10-day-old boy presents with anterior fontanelle bulging and moderate bilateral subdural effusion at the acute stage of Kawasaki disease and PSVT at the subacute stage of Kawasaki disease. The subdural effusion was resolution after intravenous immunoglobulin(IVIG) administration. And the PSVT was subsided after administered 3 doses of adenosine, 1 dose of amiodarone loading and Propranolol twice per day use. At 1 year follow-up has made a complete recovery with no arrhythmia episodes, developmental effects or abnormal neurologic findings. CONCLUSION: Subdural effusion in the acute stage of Kawasaki disease may be an inflammatory response. It may resolves spontaneously after anti-inflammatory treatment such as IVIG infusion. PSVT is a severe cardiovascular complication of Kawasaki disease. In those who taking aspirin, we need to carefully observe the heart rhythm and PSVT side effects, especially in the first month. PMID- 27234443 TI - A rapid, highly sensitive and culture-free detection of pathogens from whole blood by removal of white blood cells using immuno-magnetic beads. AB - Using anti-human CD45 antibody coated beads, we show a 98% reduction of WBCs from spiked blood samples in 1h, thereby enriching it for pathogens. This enrichment allowed the detection of <10CFU of Escherichia coli in 1mL blood using quantitative PCR; something not observed in unenriched samples. PMID- 27234444 TI - Femoral locking plate failure salvaged with hexapod circular external fixation: a report of two cases. AB - Femoral non-unions are difficult to treat even for the experienced orthopaedic trauma surgeon. If the non-union follows failure of modern stable internal fixation, the complexity of the management is further increased. We report two cases of stiff hypertrophic femoral non-unions after failed locking plate fixation that were successfully treated with a new hexapod circular external fixator. In addition to providing the necessary stability for functional rehabilitation and union, the hexapod circular fixator software allows gradual correction of deformities in order to restore the normal mechanical alignment of the limb. PMID- 27234445 TI - Synthesis and In Vivo Imaging of N-(3-[11C]Methoxybenzyl)-2-(3 Methoxyphenyl)ethylaniline as a Potential Targeting Agent for P-glycoprotein. AB - PURPOSE: The plasma membrane P-glycoprotein (Pgp) is an efflux transporter involved in multidrug resistance and in the onset of neurodegenerative disease. Its function and most mechanisms of action are still under investigation. We developed a C-11-labeled 2-arylethylphenylamine-([11C]AEPH) derivative for positron emission tomography (PET), as a novel probe to better understand the activity and the function of Pgp in vivo. PROCEDURES: The synthetic procedure and the quality control of the selected lead compound, [11C]AEPH-1, were set up and optimized. The biodistribution and the dynamic extraction in target organs of [11C]AEPH-1 were studied in vivo by PET in healthy rats at baseline and after pre treatment with a Pgp inhibitor (tariquidar). RESULTS: In vivo dynamic imaging was consistent with the results of ex vivo extraction on explanted organs. An adequate stability for in vivo studies, as well as a high activity of [11C]AEPH-1 in intestine and barrier tissues, has been demonstrated. Results of the blockade study showed a decrease of uptake after the pre-treatment, indicating a behavior attributable to a Pgp ligand. CONCLUSIONS: The suitable pharmacokinetics and the specificity tested in the pre-treated animals have indicated the potentiality of this AEPH derivative to act as Pgp ligand, providing new opportunities for further studies on expression and function of this important efflux transporter in the fields of neurology and oncology. PMID- 27234454 TI - Ornament size and colour as alternative strategies for effective communication in gliding lizards. AB - Sexual ornamentation needs to be conspicuous to be effective in attracting potential mates and defending territories and indeed, a multitude of ways exists to achieve this. Two principal mechanisms for increasing conspicuousness are to increase the ornament's colour or brightness contrast against the background and to increase the size of the ornament. We assessed the relationship between the colour and size of the dewlap, a large extendible throat-fan, across a range of species of gliding lizards (Agamidae; genus Draco) from Malaysia and the Philippines. We found a negative relationship across species between colour contrast against the background and dewlap size in males, but not in females, suggesting that males of different species use increasing colour contrast and dewlap size as alternative strategies for effective communication. Male dewlap size also increases with increasing sexual size dimorphism, and dewlap colour and brightness contrast increase with increasing sexual dichromatism in colour and brightness, respectively, suggesting that sexual selection may act on both dewlap size and colour. We further found evidence that relative predation intensity, as measured from predator attacks on models placed in the field, may play a role in the choice of strategy (high chromatic contrast or large dewlap area) a species employs. More broadly, these results highlight that each component in a signal (such as colour or size) may be influenced by different selection pressures and that by assessing components individually, we can gain a greater understanding of the evolution of signal diversity. PMID- 27234446 TI - Asymptomatic Plasmodium infections in 18 villages of southern Savannakhet Province, Lao PDR (Laos). AB - BACKGROUND: A large fraction of Plasmodium infections do not cause clinical signs and symptoms of disease and persist at densities in blood that are not detectable by microscopy or rapid diagnostic tests. These infections may be critical as a transmission reservoir in areas of low malaria endemicity. Understanding the epidemiology of these infections would be helpful for malaria elimination. METHODS: A cross-sectional survey was conducted in Thapangthong and Nong Districts of Savannakhet Province, Lao PDR, to determine the prevalence of parasitaemia. A total of 888 blood samples were collected from afebrile volunteers aged >=15 years in 18 villages during March and July 2015. Plasmodium infections were diagnosed by rapid diagnostic tests (RDT) and high volume, ultra sensitive quantitative polymerase chain reaction (uPCR). RESULTS: uPCR detected Plasmodium infections in 175 of 888 samples (20 %). The species distribution was Plasmodium falciparum 3.6 % (32/888), Plasmodium vivax 11.1 % (99/888), mixed infections with P. falciparum and P. vivax 1.6 % (14/888) and Plasmodium of undetermined species 3.4 % (30/888). RDT identified only 2 % (18/888) positive cases. Using uPCR as reference, the sensitivity and specificity of RDTs were 28 and 100 %, respectively, in detecting P. falciparum infections, and 3 and 99 % in detecting asymptomatic P. vivax infections. The K13 kelch propeller domain C580Y mutation, associated with reduced susceptibility to artemisinin derivatives, was found in 75 % (12/18) of P. falciparum isolates from Thapangthong and in 7 % (2/28) from Nong (p < 0.001). In a multivariate analysis, males were more likely to have P. vivax infections [adjusted odds ratio (aOR) 4.76 (95 % CI 2.84-8.00)] while older villagers were at lower risk for parasitaemia [aOR for increasing age 0.98 (95 % CI 0.96-0.99)]. CONCLUSION: There is a high prevalence of asymptomatic Plasmodium infections in southern Savannakhet. Artemisinin-resistant P. falciparum strains form an increasing proportion of the parasite population in Thapangthong District and are already present in the more remote Nong District. This worrying trend has wider implications for Laos and could reverse the gains achieved by the successful control of malaria in Laos and the Greater Mekong Sub region (GMS). Rapid elimination of P. falciparum has to be a top priority in Laos as well as in the wider GMS. PMID- 27234455 TI - [Follow-up of patients treated by VKA: Interest of a pharmaceutical link between the hospital and the retail pharmacies]. AB - Vitamin K antagonists (VKA) are used by 1,7% of the French population. Patient education and monitoring can decrease the number of iatrogenic hospitalizations due to VKA. We assessed the impact of a communication between hospital and retail pharmacists about patient's knowledge on VKA. The aim of our study has been to evaluate the value added by the link between the hospital pharmacist and the community pharmacist on the follow-up of patients treated by vitamin K antagonist. Patient information about VKA treatment is offered to inpatients in our hospital. An information form is filled for each patient treated by VKA. Patient's knowledge is assessed on the document (Name of VKA, cause of treatment, monitoring, risks of overdose, compliance...). This form is sent to the community pharmacist after the training when the patient leaves the hospital (by fax or by email). The form is sent back by the community pharmacist after the second training. Sixty-eight patients received the training, 48 forms have been sent to the retail pharmacists and 43 forms have been sent back to the hospital. Seven retail pharmacists replied spontaneously. Twenty-eight patients increased their knowledge (in average+21%) and 12 patients stabilized their knowledge. The best known concepts were the INR target, the time of drug intake, the risks of overdose and the information of the family. The improvement of knowledge is significant for the name of VKA, the cause of treatment, efficacy assessment and signs of overdose. The implementation of a communication between the hospital and the retail pharmacies is time-consuming but the follow-up of those patients seems essential to keep a good knowledge. PMID- 27234456 TI - Which Parasites Should We be Most Concerned About in Wildlife Translocations? PMID- 27234457 TI - Evaluation of Yersinia pestis Transmission Pathways for Sylvatic Plague in Prairie Dog Populations in the Western U.S. AB - Sylvatic plague, caused by the bacterium Yersinia pestis, is periodically responsible for large die-offs in rodent populations that can spillover and cause human mortalities. In the western US, prairie dog populations experience nearly 100% mortality during plague outbreaks, suggesting that multiple transmission pathways combine to amplify plague dynamics. Several alternate pathways in addition to flea vectors have been proposed, such as transmission via direct contact with bodily fluids or inhalation of infectious droplets, consumption of carcasses, and environmental sources of plague bacteria, such as contaminated soil. However, evidence supporting the ability of these proposed alternate pathways to trigger large-scale epizootics remains elusive. Here we present a short review of potential plague transmission pathways and use an ordinary differential equation model to assess the contribution of each pathway to resulting plague dynamics in black-tailed prairie dogs (Cynomys ludovicianus) and their fleas (Oropsylla hirsuta). Using our model, we found little evidence to suggest that soil contamination was capable of producing plague epizootics in prairie dogs. However, in the absence of flea transmission, direct transmission, i.e., contact with bodily fluids or inhalation of infectious droplets, could produce enzootic dynamics, and transmission via contact with or consumption of carcasses could produce epizootics. This suggests that these pathways warrant further investigation. PMID- 27234458 TI - The discovery of CRISPR in archaea and bacteria. AB - CRISPR-Cas are self-/nonself-discriminating systems found in prokaryotic cells. They represent a remarkable example of molecular memory that is hereditarily transmitted. Their discovery can be considered as one of the first fruits of the systematic exploration of prokaryotic genomes. Although this genomic feature was serendipitously discovered in molecular biology studies, it was the availability of multiple complete genomes that shed light about their role as a genetic immune system. Here we tell the story of how this discovery originated and was slowly and painstakingly advanced to the point of understating the biological role of what initially was just an odd genomic feature. PMID- 27234459 TI - Validation study of the Italian version of the Insomnia Severity Index (ISI). AB - To test the factorial structure of the Italian version of the Insomnia Severity Index (ISI) using a confirmatory approach and to assess its psychometric properties. ISI questionnaire was completed by 272 patients (average age 41.28, range 18-73) with insomnia diagnosis performed by a sleep medicine physician and retrospectively enrolled in the study. All patients underwent Cognitive Behavioral Treatment for Insomnia (CBT-I) and completed sleep diaries before starting the treatment. Data from sleep diaries were analyzed for assessing concurrent validity of the ISI. Confirmatory factor analysis (CFA) for ordinal Likert-type items was applied to compare four competing models proposed in the literature. 244 patients, out of the 272, completed the ISI at the end of CBT-I. A comparison of ISI score before and after treatment was performed. The CFA analysis confirmed the presence of three main factors conceptualized as severity and impact of the disease along with sleep satisfaction. Significant correlations of the first three items of the questionnaire, investigating three different subtypes of insomnia, and the subjective measures from the sleep diaries were found, thus supporting the concurrent validity of the test. Sleep efficiency (SE) had a significant inverse correlation with the severity and satisfaction factors and with ISI's total score. After CBT-I treatment, a significant reduction of ISI's scores was observed, thus confirming the effectiveness of the CBT-I treatment. The internal reliability coefficient was 0.75. The ISI questionnaire maintains good psychometric properties in the Italian version, thus confirming that this instrument is reliable for detecting insomnia severity and identifying patients' symptoms. PMID- 27234460 TI - Polyunsaturated fats, carbohydrates and carotid disease: The Atherosclerosis Risk in Communities (ARIC) Carotid MRI study. AB - BACKGROUND AND AIMS: Carbohydrates and fat intake have both been linked to development of atherosclerosis. We examined associations between glycemic index (GI) and fat intake with carotid atherosclerosis. METHODS: The Atherosclerosis Risk in Communities (ARIC) cohort enrolled participants during the period 1987 1989 and the Carotid MRI sub-study occurred between 2004 and 2006 (1672 participants attending both visits). Measures of carbohydrate quality (usual GI), fat intake (total, polyunsaturated and saturated) and overall dietary quality index (DASH Diet Score) were derived from a 66-item food frequency questionnaire administered at baseline. Trained readers measured lipid core presence and maximum wall thickness. Using multivariate logistic regression, we determined the odds of lipid core presence by quintile (Q) of energy-adjusted dietary components. Restricted cubic spline models were used to examine non-linear associations between dietary components and maximum wall thickness. RESULTS: Mean daily polyunsaturated fat intake was 5 g (SD 1.4). GI and polyunsaturated fat intake had a nonlinear relationship with maximum wall thickness. Low (1-4 g) and high (6-12 g) polyunsaturated fat intake were associated with a statistically significant decreased odds of lipid core presence compared to intake in a majority of participants (OR Q5 vs. Q2-4: 0.64, 95% CI 0.42 to 0.98; OR Q1 vs. Q2 4: 0.64, 95% CI 0.42, 0.96), however, the association with lipid core was attenuated by adjustment for maximum wall thickness, hypertension, hyperlipidemia, and diabetes. CONCLUSIONS: GI and polyunsaturated fat intake were not associated with high-risk plaque features, such as lipid core presence, independent of traditional vascular risk factors. PMID- 27234461 TI - Description of compensatory gyrA mutations restoring fluoroquinolone susceptibility in Mycobacterium tuberculosis. AB - OBJECTIVES: Resistance to fluoroquinolones (FQs) in Mycobacterium tuberculosis (Mtb) is mainly due to mutations in DNA gyrase (GyrA2B2), with the most common substitutions located at positions 90 and 94 in GyrA. Two clinical MDR Mtb (MDR TB) strains harbouring an A90E or D94N substitution in GyrA were found to be surprisingly susceptible to FQs (ofloxacin MIC <=2 mg/L). We studied the impact of the additional GyrA substitutions found in these strains (T80A and T80A + A90G, respectively) on FQ susceptibility. METHODS: Mutants of interest were generated by site-specific mutagenesis of GyrA alleles. WT and mutant TB DNA gyrase subunits were overexpressed in Escherichia coli and purified, and the in vitro susceptibility to FQs of their DNA supercoiling reaction was studied. RESULTS: IC50s of mutant gyrase complexes bearing GyrA D94N and A90E were 3- to 36-fold higher than WT IC50s, whereas IC50s of gyrase bearing T80A + A90G + D94N and T80A + A90E were close to the WT IC50s. CONCLUSIONS: We demonstrated that substitutions T80A and A90G restore FQ susceptibility when associated with a substitution implicated in high-level FQ resistance. Line probe assay misclassification of MDR-TB strains as pre-XDR or XDR can be corrected by sequence analysis of gyrA. PMID- 27234462 TI - An observational study of the universal use of octenidine to decrease nosocomial bloodstream infections and MDR organisms. AB - OBJECTIVES: To investigate the effect of universal decolonization with octenidine on the incidence of ICU-acquired bloodstream infections (BSI) and MDR organisms (MDRO). METHODS: A system-wide change in practice was performed in the ICUs of a university hospital with three campuses (eight medical ICUs and nine surgical ICUs). All ICUs had a general admission screening strategy for MRSA with subsequent isolation in the 12 month baseline period, which was stopped. After a wash-in period of 1 month, decolonization of the nose with octenidine nasal gel and octenidine wash cloths was introduced. The endpoints were ICU-acquired BSI and ICU-acquired MDRO isolates from clinical cultures. Segmented regression analysis of interrupted time series was used to assess the effect of intervention. RESULTS: A total of 29 532 ICU patients (16 677 surgical and 12 855 medical) were included in the study. The baseline incidence density of ICU acquired BSI was 5.1 per 1000 patient days and the baseline ICU-acquired MRSA rate was 0.97 per 1000 patient days. Whereas no significant effect on either outcome was found in surgical ICUs, we identified a significant effect on ICU acquired BSI for the intervention in medical ICUs by means of multivariate analysis (incidence rate ratio 0.78; 95% CI 0.65-0.94). In addition, the intervention was also effective in decreasing ICU-acquired MRSA in medical ICUs (incidence rate ratio 0.58; 95% CI 0.41-0.82). No effect on ICU-acquired VRE and Gram-negative MDRO was found. CONCLUSIONS: System change was successful by decreasing infection rates in medical ICUs and improving the management in all ICUs. PMID- 27234463 TI - Factors associated with virological response to a switch regimen containing maraviroc for antiretroviral-experienced HIV-1-infected patients. AB - OBJECTIVES: There are few data on clinical and virological factors associated with maraviroc virological response (VR) in clinical practice. This study aimed to identify factors associated with VR in 94 treatment-experienced, but CCR5 inhibitor-naive, HIV-1 patients switched to maraviroc-containing regimens. METHODS: Patients with HIV-1 RNA viral load (VL) <50 copies/mL switching to an antiretroviral treatment containing maraviroc were followed. VR was defined at month 3 as VL <50 copies/mL. The impact of age, baseline tropism, zenith VL, nadir CD4 cell count and CD4 cell count, HIV subtype (B versus non-B), genotypic susceptibility score of treatment, once- or twice-daily treatment and presence of raltegravir in optimized background therapy on VR was investigated. RESULTS: Baseline characteristics were: median age 49 years (range 25-73 years), median CD4 cell count 481 cells/mm(3) (range 57-1830 cells/mm(3)) and median nadir CD4 cell count 99 cells/mm(3) (range 3-585). Maraviroc was administered twice daily in 88 of 94 patients and once daily in 6 of 94 patients (300 mg/day for 4 of 6 and 150 mg/day for 2 of 6). At month 3, 89.4% of patients were responders. A better VR to a switch regimen containing maraviroc was associated with the B subtype (P = 0.0216) and a lower zenith VL (median of 5.24 and 5.70 log10 copies/mL for patients in success or in failure, respectively) in univariate analysis. Only B subtype was associated with a better VR in multivariate analysis. CONCLUSIONS: This study evidenced the efficacy of a switch regimen containing maraviroc in clinical practice. VR was better for patients with a lower zenith VL and B subtype. PMID- 27234465 TI - Neurotherapy As a Catalyst in the Treatment of Fatigue in Breast Cancer Survivorship. AB - Pharmacologic and non-pharmacologic treatments for cancer-related fatigue (CRF) have produced mixed and often disappointing results. Treatment using the Flexyx Neurotherapy System (FNS), a novel variant of electroencephalograph biofeedback that involves minutely pulsed electromagnetic (EM) stimulation of brainwave functioning, was explored to determine utility for alleviating CRF in a 45-year old woman who had debilitating fatigue with onset during chemotherapy for stage II infiltrating right breast cancer, who had been free of signs of disease for over five years, and who had been struggling to increase her activity level and engage in regular exercise without benefit. FNS was administered in 10 weekly sessions. Alleviation of fatigue and other potentially interrelated symptoms (cognitive clouding, sleep disturbance, pain, and negative mood/emotions) and overall greater activity level was sustained at six-month follow-up. Very low energy EM brainwave stimulation therapies such as FNS may contribute to an enlivening of drive to engage in greater energized activity. PMID- 27234464 TI - Identification and characterization of miRNAs and targets in flax (Linum usitatissimum) under saline, alkaline, and saline-alkaline stresses. AB - BACKGROUND: MicroRNAs (miRNAs) play a critical role in responses to biotic and abiotic stress and have been characterized in a large number of plant species. Although flax (Linum usitatissimum L.) is one of the most important fiber and oil crops worldwide, no reports have been published describing flax miRNAs (Lus miRNAs) induced in response to saline, alkaline, and saline-alkaline stresses. RESULTS: In this work, combined small RNA and degradome deep sequencing was used to analyze flax libraries constructed after alkaline-salt stress (AS2), neutral salt stress (NSS), alkaline stress (AS), and the non-stressed control (CK). From the CK, AS, AS2, and NSS libraries, a total of 118, 119, 122, and 120 known Lus miRNAs and 233, 213, 211, and 212 novel Lus-miRNAs were isolated, respectively. After assessment of differential expression profiles, 17 known Lus-miRNAs and 36 novel Lus-miRNAs were selected and used to predict putative target genes. Gene ontology term enrichment analysis revealed target genes that were involved in responses to stimuli, including signaling and catalytic activity. Eight Lus miRNAs were selected for analysis using qRT-PCR to confirm the accuracy and reliability of the miRNA-seq results. The qRT-PCR results showed that changes in stress-induced expression profiles of these miRNAs mirrored expression trends observed using miRNA-seq. Degradome sequencing and transcriptome profiling showed that expression of 29 miRNA-target pairs displayed inverse expression patterns under saline, alkaline, and saline-alkaline stresses. From the target prediction analysis, the miR398a-targeted gene codes for a copper/zinc superoxide dismutase, and the miR530 has been shown to explicitly target WRKY family transcription factors, which suggesting that these two micRNAs and their targets may significant involve in the saline, alkaline, and saline-alkaline stress response in flax. CONCLUSIONS: Identification and characterization of flax miRNAs, their target genes, functional annotations, and gene expression patterns are reported in this work. These findings will enhance our understanding of flax miRNA regulatory mechanisms under saline, alkaline, and saline-alkaline stresses and provide a foundation for future elucidation of the specific functions of these miRNAs. PMID- 27234466 TI - Three Cases of Cutaneous Warts Treated With Moxibustion. AB - Moxibustion is a treatment that uses thermal stimulation generated when herbal materials are burned, indirectly or directly, on the affected area or acupoint. Three cases are presented to report the efficacy of direct moxibustion on cutaneous warts. Three patients with chronic cutaneous warts received direct moxibustion made of Artemisia argyi (Dongbang Inc., Chungnam, Korea). Moxa burning was performed using moxa cones. Approximately 80% of a cone was burned, until patients reported feeling a burning sensation, at which time the cone was removed and another one burned. As part of this approach, patients underwent 5-19 moxibustion procedures during and after wart removal. After warts were completely eliminated, moxa burning was performed on each patient until approximately 60% of a cone was burned or the patient felt heat sensitization but no pain. In these cases, moxibustion seemed to have an effect on cutaneous warts. A possible mechanism is that direct moxibustion likely induces tissue damage from burning and, subsequently, a wound healing effect at a different temperature level. Our reports suggest that it would be worthwhile to conduct further studies on the safety and efficacy of moxibustion on warts or to develop a medical device that uses modified moxibustion. PMID- 27234467 TI - Homeopathy for Depression, Music for Postoperative Recovery, Red Yeast Rice for High Cholesterol, Acupuncture for Seasonal Allergic Rhinitis, and Ginger for Osteoarthritis. PMID- 27234469 TI - [Congenital anomalies of poor prognosis. Genetics Consensus Committee]. AB - INTRODUCTION: The Genetic Branch of the Chilean Society of Paediatrics, given the draft Law governing the decriminalisation of abortion on three grounds, focusing on the second ground, which considers the "embryo or foetus suffering from a congenital structural anomaly or a genetic disorder incompatible with life outside the womb", met to discuss the scientific evidence according to which congenital anomalies (CA) may be included in this draft law. METHODOLOGY: Experts in clinical genetics focused on 10 CA, reviewed the literature evidence, and met to discuss it. RESULTS: It was agreed not to use the term "incompatible with life outside the womb", as there are exceptions and longer survivals, and change to "congenital anomaly of poor prognosis (CAPP)". Ten CA were evaluated: serious defects of neural tube closure: anencephaly, iniencephaly and craniorachischisis, pulmonary hypoplasia, acardiac foetus, ectopia cordis, non-mosaic triploidy, "limb body wall" complex, "body stalk" anomaly, trisomy 13, trisomy 18, and bilateral renal agenesis. Findings on the prevalence, natural history, prenatal diagnostic methods, survival, and reported cases of prolonged survival were analysed. Post-natal survival, existence of treatments, and outcomes, as well as natural history without intervention, were taken into account in classifying a CA as a CAPP. CONCLUSION: A CAPP would be: anencephaly, severe pulmonary hypoplasia, acardiac foetus, cervical ectopia cordis, non-mosaic triploidy, limb body wall complex, body stalk anomaly, non-mosaic trisomy 13, non-mosaic trisomy 18, and bilateral renal agenesis. For their diagnosis, it is required that all pregnant women have access to assessments by foetal anatomy ultrasound and occasionally MRI, and cytogenetic and molecular testing. PMID- 27234470 TI - Nicotinic Acetylcholine Receptors in Head and Neck Cancer and Their Correlation to Tumor Site and Progression. AB - BACKGROUND: Nicotine contributes to tumorigenesis through stimulation of nicotinic acetylcholine receptors (nAChRs) in head and neck squamous cell carcinoma (SCC). Although many factors have been found to be involved in the pathogenesis of head and neck cancer, the effect of nAChRs is still unclear. The study provides information on different subtypes in SCC and normal mucosa (NM) and their clinicopathological correlation to tumor progression. METHODS: SCC (n = 34) of oropharynx, hypopharynx, larynx and corresponding NM (n = 38) were analyzed by quantitative real-time polymerase chain reaction, immunoblotting and immunohistochemistry and correlated to tumor grading and Union for International Cancer Control (UICC) stage. RESULTS: nAChR subtypes alpha1, alpha3, alpha5 and alpha7 were found in NM and SCC of the upper aerodigestive tract with high rates of alpha1 and alpha5 in SCC. An overexpression of alpha1 was found in laryngeal and hypopharyngeal SCC, while alpha3 and alpha7 subunits were downregulated. The expression of alpha1 and alpha5 subunits increased with tumor progression. CONCLUSION: The nAChR subunit pattern shows a difference between NM and SCC and changes in the process of tumor progression. Therefore, it is conceivable that it contributes to tumorigenesis. The findings provide a basis for further studies in prognostic assessment and identifying carcinogenic changes from NM to SCC. PMID- 27234476 TI - FDA Announces Limits on Electronic Cigarettes. AB - Under new rules set to go into effect in August, the FDA will stop sales of electronic cigarettes to minors and regulate all tobacco products, including pipe tobacco and cigars. PMID- 27234477 TI - Ethical Assessment of Human Embryonic Stem Cell Research According to Turkish Muslim Scholars: First Critical Analysis and Some Reflections. AB - BACKGROUND: Turkey, with a Muslim population of officially over 99 %, is one of the few secular states in the Muslim world. Although state institutions are not based on Islamic juridical and ethical norms, the latter play a significant role in defining people's attitudes towards controversial issues in the modern world, especially when backed by opinions of Muslim scholars living in Turkey. Accordingly, opinions of Muslim scholars undoubtedly have an important effect on bioethical decisions made by institutions and individuals. OBJECTIVE(S): To explore the ethical positions of Muslim scholars living in Turkey and their arguments used in the ethical assessment of embryonic stem cell research; to discuss the biological-moral tensions arising in medical research on human embryos. DESIGN: Qualitative study. SETTING: Muslim scholars located in different parts of Turkey. METHODS: Qualitative method, involving the collection of opinions of various scholars, by means of 15 individual semi-structured interviews, evaluated using thematic qualitative analysis. RESULTS: Positions regarding embryonic stem cell research differ among Muslim scholars in Turkey. On the other hand, even where positions are similar, they are often supported by different arguments. CONCLUSION: Despite the heterogeneity of the arguments presented, the dominant position considers embryonic stem cell research as morally acceptable. PMID- 27234479 TI - Efficient Fine Arrhythmia Detection Based on DCG P-T Features. AB - Due to the high mortality associated with heart disease, there is an urgent demand for advanced detection of abnormal heart beats. The use of dynamic electrocardiogram (DCG) provides a useful indicator of heart condition from long term monitoring techniques commonly used in the clinic. However, accurately distinguishing sparse abnormal heart beats from large DCG data sets remains difficult. Herein, we propose an efficient fine solution based on 11 geometrical features of the DCG PQRST(P-T) waves and an improved hierarchical clustering method for arrhythmia detection. Data sets selected from MIT-BIH are used to validate the effectiveness of this approach. Experimental results show that the detection procedure of arrhythmia is fast and with accurate clustering. PMID- 27234478 TI - Identification of Major Adverse Kidney Events Within the Electronic Health Record. AB - Acute kidney injury is common among critically ill adults and is associated with increased mortality and morbidity. The Major Adverse Kidney Events by 30 days (MAKE30) composite of death, new renal replacement therapy, or persistent renal dysfunction is recommended as a patient-centered outcome for pragmatic trials involving acute kidney injury. Accurate electronic detection of the MAKE30 endpoint using data within the electronic health record (EHR) could facilitate the use of the EHR in large-scale kidney injury research. In an observational study using prospectively collected data from 200 admissions to a single medical intensive care unit, we tested the performance of electronically-extracted data in identifying the MAKE30 composite compared to the reference standard of two physician manual chart review. The incidence of MAKE30 on manual-review was 16 %, which included 8.5 % for in-hospital mortality, 3.5 % for new renal replacement therapy, and 8.5 % for persistent renal dysfunction. There was strong agreement between the electronic and manual assessment of MAKE30 (98.5 % agreement [95 % CI 96.5-100.0 %]; kappa 0.95 [95 % CI 0.87-1.00]; P < 0.001), with only three patients misclassified by electronic assessment. Performance of the electronic MAKE30 assessment was similar among patients with and without CKD and with and without a measured serum creatinine in the 12 months prior to hospital admission. In summary, accurately identifying the MAKE30 composite outcome using EHR data collected as a part of routine care appears feasible. PMID- 27234481 TI - Medical Marijuana in Patients Prescribed Opioids: A Cloud of Uncertainty. PMID- 27234480 TI - The Electronic CardioMetabolic Program (eCMP) for Patients With Cardiometabolic Risk: A Randomized Controlled Trial. AB - BACKGROUND: Effective lifestyle interventions targeting high-risk adults that are both practical for use in ambulatory care settings and scalable at a population management level are needed. OBJECTIVE: Our aim was to examine the potential effectiveness, feasibility, and acceptability of delivering an evidence-based Electronic Cardio-Metabolic Program (eCMP) for improving health-related quality of life, improving health behaviors, and reducing cardiometabolic risk factors in ambulatory care high-risk adults. METHODS: We conducted a randomized, wait-list controlled trial with 74 adults aged >=18 years recruited from a large multispecialty health care organization. Inclusion criteria were (1) BMI >=35 kg/m(2) and prediabetes, previous gestational diabetes and/or metabolic syndrome, or (2) BMI >=30 kg/m(2) and type 2 diabetes and/or cardiovascular disease. Participants had a mean age of 59.7 years (SD 11.2), BMI 37.1 kg/m(2) (SD 5.4) and were 59.5% female, 82.4% white. Participants were randomized to participate in eCMP immediately (n=37) or 3 months later (n=37). eCMP is a 6-month program utilizing video conferencing, online tools, and pre-recorded didactic videos to deliver evidence-based curricula. Blinded outcome assessments were conducted at 3 and 6 months postbaseline. Data were collected and analyzed between 2014 and 2015. The primary outcome was health-related quality of life. Secondary outcomes included biometric cardiometabolic risk factors (eg, body weight), self-reported diet and physical activity, mental health status, retention, session attendance, and participant satisfaction. RESULTS: Change in quality of life was not significant in both immediate and delayed participants. Both groups significantly lost weight and reduced waist circumference at 6 months, with some cardiometabolic factors trending accordingly. Significant reduction in self reported anxiety and perceived stress was seen in the immediate intervention group at 6 months. Retention rate was 93% at 3 months and 86% at 6 months post baseline. Overall eCMP attendance was high with 59.5-83.8% of immediate and delayed intervention participants attending 50% of the virtual stress management and behavioral lifestyle sessions and 37.8-62.2% attending at least 4 out of 7 in person physical activity sessions. The intervention received high ratings for satisfaction. CONCLUSIONS: The technology-assisted eCMP is a feasible and well accepted intervention and may significantly decrease cardiometabolic risk among high-risk individuals. TRIAL REGISTRATION: Clinicaltrials.gov NCT02246400; https://clinicaltrials.gov/ct2/show/NCT02246400 (Archived by WebCite at http://www.webcitation.org/6h6mWWokP). PMID- 27234482 TI - Prophylactic Intraoperative Embolization of Abdominal Aortic Aneurysm Sacs Using N-Butyl Cyanoacrylate/Lipiodol/Ethanol Mixture with Proximal Neck Aortic Balloon Occlusion during Endovascular Abdominal Aortic Repair. AB - PURPOSE: To determine the feasibility of prophylactic intraoperative abdominal aortic aneurysm (AAA) sac embolization using a mixture of N-butyl cyanoacrylate/Lipiodol/ethanol (NLE) with proximal neck aortic balloon occlusion during endovascular aneurysm repair (EVAR) to prevent the occurrence of endoleak and aneurysm sac expansion. MATERIALS AND METHODS: Prophylactic intraoperative AAA sac embolization was performed in 24 patients with an infrarenal neck angulation > 60 degrees (n = 16) or AAA sac diameter > 60 mm (n = 17). AAA sac pressure was continuously measured with a 3-F catheter inserted into the AAA sac. The systolic sac pressure index (SPI) was calculated as the ratio of systolic AAA sac pressure to the simultaneously measured systolic aortic pressure, and was measured with and without proximal neck aortic balloon occlusion. The aneurysm sac was embolized with NLE during proximal neck aortic balloon occlusion immediately after EVAR. Endoleak and AAA sac diameter were evaluated by enhanced computed tomography and subtraction magnetic resonance imaging at 6 months and yearly after EVAR. RESULTS: Mean SPIs after EVAR with and without proximal neck aortic balloon occlusion were 0.36 and 0.57, respectively. There were no adverse events related to intraoperative sac embolization. Follow-up imaging (mean, 12.1 mo) revealed three minor endoleaks (12.5%) and no aneurysm sac expansion. CONCLUSIONS: Prophylactic intraoperative sac embolization with NLE during proximal neck aortic balloon occlusion was safe and feasible and may reduce endoleaks and prevent sac expansion after EVAR in patients with unfavorable anatomic factors. PMID- 27234483 TI - Transcatheter Arterial Embolization of Angiographically Visible and Occult Renal Capsular Artery Hemorrhage in 28 Patients. AB - PURPOSE: To evaluate the effectiveness and safety of transcatheter arterial embolization to control bleeding from the renal capsular artery (RCA). MATERIALS AND METHODS: Embolization was performed in 28 patients (14 men; mean age, 49.7 y). Presence and type of previous invasive procedures, initial presentation, and coagulation profile were reviewed. Any preceding abdominal computed tomography (CT) findings were analyzed. Angiographic findings were categorized as active bleeding, suspicious for bleeding, or no bleeding. Technical and clinical success and clinical outcomes were evaluated. Changes in hemoglobin level and transfusion volume of packed red blood cells (pBRCs) before and after embolization were evaluated with the paired t test and Wilcoxon signed-rank test, respectively. RESULTS: Technical and clinical success rates of therapeutic embolization for active bleeding (n = 11) were 90.9% and 80%, respectively. One case of technical failure (5.9%) and 3 cases of postembolization bleeding (18.7%) were noted in the prophylactic embolization group in patients with suspicion of bleeding (n = 13) or no bleeding (n = 4). Transient renal insufficiency occurred in 4 patients (14.3%). The average hemoglobin level and volume of transfused pBRCs changed from 8.1 g/dL to 9.9 g/dL and from 871 mL to 543 mL, respectively (P < .05). Extravasation of contrast media or acute hematoma in the right subhepatic or perirenal space on CT was noted in 21 patients (78%). CONCLUSIONS: Embolization can provide an effective and safe method to control RCA bleeding. Perirenal invasive procedures and signs of active or recent right subhepatic or perirenal hemorrhage should raise the suspicion of an RCA source. PMID- 27234485 TI - Tumor Growth Kinetics and Oncologic Outcomes of Patients Undergoing Active Surveillance for Residual Renal Tumor following Percutaneous Thermal Ablation. AB - PURPOSE: To evaluate growth kinetics and oncologic outcomes of patients with renal tumors undergoing active surveillance (AS) for residual viable tumor following percutaneous ablation. MATERIALS AND METHODS: Following percutaneous thermal ablation, residual tumor was detected in 21/133 (16%) patients on initial follow-up imaging, and AS was undertaken in 17/21 (81%) patients. Initial tumor volumes and volumes after ablation were assessed from cross-sectional imaging to calculate volumetric growth rate (VGR) and volume doubling time (VDT) of residual tumor. The rate of metastasis, overall survival, and renal cell carcinoma (RCC) specific survival were compared between patients in the AS group and in the routine follow up group of patients who did not have residual tumor. RESULTS: Median tumor volume prior to ablation, after first ablation, and at final follow up were 25 cm(3), 6 cm(3), and 6 cm(3), respectively, in patients with residual tumor. Stable, mild, and moderate VGR occurred in 8/17 (47%), 4/17 (24%), and 5/17 (29%) cases, respectively. The 4 cases with fastest VDT underwent delayed intervention with ablation (n = 1) and nephrectomy (n = 3) without subsequent residual, recurrence, or metastasis. There was no significant difference in the rates of RCC metastasis, overall survival, or RCC-specific survival between AS and routine follow-up groups. Metastatic RCC and subsequent death occurred in 1 patient in the AS group, after the patient had refused offers for retreatment for local progression over 60.7 months of follow-up. CONCLUSIONS: In cases when patients are not amenable to further intervention, AS of residual tumor may be an acceptable alternative and allows for successful delayed intervention when needed. PMID- 27234484 TI - Portal Vein Embolization via Percutaneous Transsplenic Access prior to Major Hepatectomy for Patients with Insufficient Future Liver Remnant. AB - PURPOSE: To evaluate the feasibility and safety of percutaneous transsplenic portal vein embolization (PVE) before major hepatectomy for patients with insufficient future liver remnant. MATERIALS AND METHODS: From May 2014 to June 2015, 27 transsplenic PVEs were attempted in 26 patients. In 16 patients, transsplenic PVE was indicated because of huge or multiple tumors in the trajectory of the puncture (n = 15) or a high-positioned liver (n = 1), which prevented safe ipsilateral transhepatic access. In the remaining 10 patients, transsplenic access was planned. A perihilar splenic vein was punctured using a 21-gauge Chiba needle under ultrasound and fluoroscopic guidance. Embolization of portal venous branches was performed using gelatin sponge particles followed by application of coils, an AMPLATZER Vascular Plug (AGA Medical Corporation, Golden Valley, Minnesota), or glue to prevent recanalization. Embolization of transsplenic routes was performed using coils followed by glue. RESULTS: Transsplenic PVE was successful in 24 (88.9%) of 27 sessions; 3 procedures failed because of splenic vein dissection (n = 1) and failed splenic vein puncture (n = 2). Major complications occurred in 1 patient (3.8%) with splenic vein dissection. Minor complications occurred in 2 patients: a small amount of fluid collection in the splenic hilar area in 1 patient and glue migration along the splenic vein in 1 patient. Planned liver resection was performed in 24 of 26 patients at 4.9 weeks +/- 3.5 after PVE. CONCLUSIONS: Transsplenic PVE is safe and feasible and can be an effective alternative treatment for patients with a challenging ipsilateral, transhepatic route. PMID- 27234486 TI - Prediction for Improvement of Liver Function after Balloon-Occluded Retrograde Transvenous Obliteration for Gastric Varices to Manage Portosystemic Shunt Syndrome. AB - PURPOSE: To investigate predictive factors and cutoff value of transient elastography (TE) measurements for assessing improvement in liver function after balloon-occluded retrograde transvenous obliteration (BRTO) for gastric varices (GV). MATERIALS AND METHODS: Retrospective analysis was performed of 50 consecutive patients followed for > 3 months after BRTO, who had undergone TE before BRTO between January 2011 and February 2015. The correlation between change in liver function (total bilirubin, albumin, and prothrombin time) and baseline liver function values and liver stiffness measurement (LSM) by TE was evaluated by Pearson correlation test. Receiver operating characteristic curves were used to determine cutoff values for discriminating between patients who had improved liver function and patients who did not. The time interval from BRTO to aggravation of esophageal varices (EV) (worsening morphology, development of new varices, or variceal rupture) grouped by cutoff values was also analyzed. RESULTS: Serum albumin was significantly improved at 3 months after BRTO (3.57 g/dL vs 3.74 g/dL, P < .001). There was a significant negative correlation between change in albumin and baseline LSM (r = -0.50, P < .001). The best cutoff point for LSM was <= 22.9 kPa, with sensitivity and specificity of 78.4% and 69.2%, respectively, for predicting which patients would have improved albumin after BRTO. Among 33 patients, 29 (88%) patients had improved albumin. The 1-year progression rate of EV after BRTO was 13.6% in patients with LSM <= 22.9 kPa. CONCLUSIONS: The predictive factor for improvement in albumin after BRTO was lower LSM (<= 22.9 kPa) using TE. PMID- 27234487 TI - Implications of oncocytic change in papillary thyroid cancer. AB - OBJECTIVE: Although the presence of oncocytic change in less than 75% of a tumour is not considered to indicate oncocytic variants of papillary thyroid carcinoma (PTC), we frequently observe partial oncocytic change, especially in obese PTC patients. Thus, we sought to investigate the relationship between the presence of oncocytic change of PTC and its prognosis. DESIGN, SETTING AND PARTICIPANTS: We retrospectively studied 142 patients with PTC who had undergone surgery between 2000 and 2005, and re-evaluated their PTC slides to record the proportion of oncocytic change in 10% increments from 0% to 100%. MAJOR OUTCOME MEASURE: We analysed the relationship between the proportion of oncocytic change and clinicopathological prognostic factors. RESULTS: Oncocytic change was found in 45.8% (65/142) of PTC patients. The proportion of patients with oncocytic change was higher in obese patients than in lean patients and showed a significant correlation with the BMI (r = 0.195, P = 0.020). The PTC patients with oncocytic change showed a higher recurrence rate than PTC patients without oncocytic change (30.8% vs 11.7%, respectively; P = 0.005). The presence of oncocytic change in PTC patients was associated with a shorter disease-free survival in a Kaplan Meier analysis after a mean follow-up of 8.9 years. CONCLUSION: The patients with PTC with oncocytic change presented with a higher recurrence rate and were more likely to be obese. These findings suggest that presence of oncocytic change is a poor prognostic factor in PTC patients, even if the oncocytic change involves less than 75% of a tumour. PMID- 27234488 TI - Impact of pollen resources drift on common bumblebees in NW Europe. AB - Several bee species are experiencing significant population declines. As bees exclusively rely on pollen for development and survival, such declines could be partly related to changes in their host plant abundance and quality. Here, we investigate whether generalist bumblebee species, with stable population trends over the past years, adapted their diets in response to changes in the distribution and chemical quality of their pollen resources. We selected five common species of bumblebee in NW Europe for which we had a precise description of their pollen diet through two time periods ('prior to 1950' and '2004-2005'). For each species, we assessed whether the shift in their pollen diet was related with the changes in the suitable area of their pollen resources. Concurrently, we evaluated whether the chemical composition of pollen resources changed over time and experimentally tested the impact of new major pollen species on the development of B. terrestris microcolonies. Only one species (i.e. B. lapidarius) significantly included more pollen from resources whose suitable area expanded. This opportunist pattern could partly explain the expansion of B. lapidarius in Europe. Regarding the temporal variation in the chemical composition of the pollen diet, total and essential amino acid contents did not differ significantly between the two time periods while we found significant differences among plant species. This result is driven by the great diversity of resources used by bumblebee species in both periods. Our bioassay revealed that the shift to new major pollen resources allowed microcolonies to develop, bringing new evidence on the opportunist feature of bumblebee in their diets. Overall, this study shows that the response to pollen resource drift varies among closely related pollinators, and a species-rich plant community ensures generalist species to select a nutrient-rich pollen diet. PMID- 27234489 TI - A model analysis for dose-response relationship of warfarin in Japanese children: An introduction of the SIZE parameter. AB - The objective of the present study was to develop an optimal equation for the pediatric dose-response relationship of warfarin using a size parameter with an exponent of body weight (SIZE) which has been proposed for scaling drug clearance. Twenty patients with stable anticoagulation by warfarin were enrolled in the present study. During a mean follow-up period of 7.36 years, 857 data points were obtained. The average patient age and body weight were 8.49 years and 24.5 kg, respectively. The relative response index to warfarin with PT-INR values normalized by daily-dose per SIZE showed fewer systematic changes than those per body weight. The anticoagulant effect of warfarin in patients with the VKORC1 1173CT or 1173CC genotype was 47.3% of that with the 1173TT genotype. Concomitant use of bosentan attenuated the anticoagulant effect of warfarin to 84.1%. In conclusion, the SIZE parameter appeared to be an effective way to describe the pediatric dose-response relationship of warfarin, and consequently, a longitudinal follow-up study design with multiple measurements was useful to detect changes within individual subjects. PMID- 27234490 TI - Prediction of bacterial associations with plants using a supervised machine learning approach. AB - Recent scenarios of fresh produce contamination by human enteric pathogens have resulted in severe food-borne outbreaks, and a new paradigm has emerged stating that some human-associated bacteria can use plants as secondary hosts. As a consequence, there has been growing concern in the scientific community about these interactions that have not yet been elucidated. Since this is a relatively new area, there is a lack of strategies to address the problem of food-borne illnesses due to the ingestion of fruits and vegetables. In the present study, we performed specific genome annotations to train a supervised machine-learning model that allows for the identification of plant-associated bacteria with a precision of ~93%. The application of our method to approximately 9500 genomes predicted several unknown interactions between well-known human pathogens and plants, and it also confirmed several cases for which evidence has been reported. We observed that factors involved in adhesion, the deconstruction of the plant cell wall and detoxifying activities were highlighted as the most predictive features. The application of our strategy to sequenced strains that are involved in food poisoning can be used as a primary screening tool to determine the possible causes of contaminations. PMID- 27234491 TI - Low molecular weight fucoidan modulates P-selectin and alleviates diabetic nephropathy. AB - Diabetic nephropathy (DN) is a serious microvascular complication that can lead to chronic and end-stage renal failure. It is understood that inflammation is associated with the onset and process of DN. Low molecular weight fucoidan (LMWF) isolated from Saccharina japonica has anti-inflammatory properties. Therefore, this study aimed to explore the mechanism of LMWF in DN model induced by streptozotocin. The biochemical indices levels showed LMWF reduced the DN diagnostic indices to protect renal function. The HE stained sections exhibited LMWF protected normal morphological structures and reduced inflammatory cell infiltration in the kidneys of DN rats. Furthermore, the levels of P-selectin and selectin-dependent inflammatory cytokines resulting from LMWF were obviously decreased at both the transcriptional and protein levels. Thus, our results found that LMWF protected the renal function in DN rats and alleviated inflammation through the modulation of P-selectin and inflammatory cytokines. LMWF may have therapeutic potential against DN. PMID- 27234492 TI - Release properties of tannic acid from hydrogen bond driven antioxidative cellulose nanofibrous films. AB - Layer-by-layer (LBL) assembled films have been exploited for surface-mediated bioactive compound delivery. Here, an antioxidative hydrogen-bonded multilayer electrospun nanofibrous film was fabricated from tannic acid (TA), acting as a polyphenolic antioxidant, and poly(ethylene glycol) (PEG) via layer-by-layer assembly. It overcame the burst release behavior of nanofibrous carrier, due to the reversible/dynamic nature of hydrogen bond, which was responded to external stimuli. The PEG/TA nanofibrous films disassembled gradually and released TA to the media, when soaked in aqueous solutions. The release rate of TA increased with increasing bilayer number, pH and temperature, but decreased with enhancing ionic strength. The surface morphology of the nanofibrous mats was observed by scanning electron microscopy (SEM). The following antioxidant activity assay revealed that it could scavenge DPPH free radicals and ABTS(+) cation radicals, a major biological activity of polyphenols. This technology can be used to fabricate other phenolic-containing slowly releasing antioxidative nanofibrous films. PMID- 27234493 TI - A low-temperature polygalacturonase from P. occitanis: characterization and application in juice clarification. AB - An extracellular endo-polygalacturonase (PGase) was purified, after a single purification step, from the constitutive and hyperpectinolytic CT1 mutant of Penicillium occitanis. This enzyme named PG2 has a molecular weight of 42kDa. It was optimally active at 35 degrees C and pH6 with more than 85% of activity at pH7 in contrast to the majority of fungal PGase, generally acting at 50 degrees C and pH5. The specific activity obtained was among the highest ones, 31397.26U/mg. The PGase activity increased with the decrease of the degree of methylation (DM) of pectin, but it was also able to degrade the highly methyl-esterified substrates, 70% (DM) and 90% (DM), with almost 80% and 40% of residual activity respectively. Interestingly, PG2 is completely inhibited by DEPC, suggesting the implication of a Histidine residue in the active site. The sequencing of P. occitanis whole genome allowed us to identify the pga2 gene encoding PG2 and to localize the His residue, target of DEPC, while it was absent in the PG1 that resisted to DEPC. Besides that, the potentialities of PG2 have been put in use in juice clarification of pear, banana and citrus juice. PMID- 27234494 TI - Physicochemical properties and antioxidant activities of polysaccharides sequentially extracted from peony seed dreg. AB - The sequential extraction of peony seed dreg polysaccharides (PSDP) with hot buffer (HBSS), chelating agent (CHSS), dilute alkaline (DASS) and concentrated alkaline (CASS) yielded four different polysaccharide fractions. Based on their absorptions at 3600-3200cm(-1) and 1200-800cm(-1), these fractions were confirmed to be polysaccharides. The properties of four PSDPs displayed some slight differences. The CASS showed the highest peak temperature and endothermic enthalpy. The emulsifying activity and emulsifying stability of four PSDPs exhibited a dose-dependent pattern; HBSS showed the highest emulsifying activity, and CHSS displayed the longest emulsifying stability. The four PSDPs also exhibited wide variations in their antioxidant activities. For example, i) CASS showed the highest DPPH radical scavenging activity, reducing power and ABTS radical scavenging activity; ii) HBSS exhibited the highest hydroxyl radical scavenging activity, and iii) CHSS displayed the higher ferrous ions chelating ability than others. PMID- 27234495 TI - Anti-aggregation activity of small heat shock proteins under crowded conditions. AB - It is becoming evident that small heat shock proteins (sHsps) are important players of protein homeostasis system. Their ability to bind misfolded proteins may play a crucial role in preventing protein aggregation in cells. The remarkable structural plasticity of sHsps is considered to underlie the mechanism of their activity. However, all our knowledge of the anti-aggregation functioning of sHsps is based on data obtained in vitro in media greatly different from the cellular highly crowded milieu. The present review highlights available data on the effect of crowding on the anti-aggregation activity of sHsps. There is some evidence that crowding affects conformation and dynamics of sHsps oligomers as well as their anti-aggregation properties. Crowding stimulates association of sHsp-client protein complexes into large-sized aggregates thus diminishing the apparent anti-aggregation activity of sHsps. Nevertheless, it is also shown that complexes between suboligomers (dissociated forms) of sHsps and client proteins may be stabilized and exist for longer period of time under crowded conditions. Moreover, crowding may retard the initial stages of aggregation which correspond to the formation of sHsp-containing nuclei and their clusters. Thus, dissociation of sHsps into suboligomers appears to be an important feature for the anti aggregation activity of sHsps in crowded media. PMID- 27234496 TI - Effect of counter ions of arginine as an additive for the solubilization of protein and aromatic compounds. AB - Arginine is widely used in biotechnological application, but mostly with chloride counter ion. Here, we examined the effects of various anions on solubilization of aromatic compounds and reduced lysozyme and on refolding of the lysozyme. All arginine salts tested increased the solubility of propyl gallate with acetate much more effectively than chloride. The effects of arginine salts were compared with those of sodium or guanidine salts, indicating that the ability of anions to modulate the propyl gallate solubility is independent of the cation. Comparison of transfer free energy of propyl gallate between sodium and arginine salts indicates that the interaction of propyl gallate is more favorable with arginine than sodium. On the contrary, the solubility of aromatic amino acids is only slightly modulated by anions, implying that there is specific interaction between acetic acid and propyl gallate. Unlike their effects on the solubility of small aromatic compounds, the solubility of reduced lysozyme was much higher in arginine chloride than in arginine acetate or sulfate. Consistent with high solubility, refolding of reduced lysozyme was most effective in arginine chloride. These results suggest potential broader applications of arginine modulated by different anions. PMID- 27234497 TI - Anti-inflammatory effects of sodium alginate/gelatine porous scaffolds merged with fucoidan in murine microglial BV2 cells. AB - Microglia are the immune cells of the central nervous system (CNS). Overexpression of inflammatory mediators by microglia can induce several neurological diseases. Thus, the underlying basic requirement for neural tissue engineering is to develop materials that exhibit little or no neuro-inflammatory effects. In this study, we have developed a method to create porous scaffolds by adding fucoidan (Fu) into porous sodium alginate (Sa)/gelatine (G) (SaGFu). For mechanical characterization, in vitro degradation, stress/strain, swelling, and pore size were measured. Furthermore, the biocompatibility was evaluated by assessing the adhesion and proliferation of BV2 microglial cells on the SaGFu porous scaffolds using scanning electron microscopy (SEM) and lactate dehydrogenase (LDH) assay, respectively. Moreover, we studied the neuro inflammatory effects of SaGFu on BV2 microglial cells. The effect of gelatine and fucoidan content on the various properties of the scaffold was investigated and the results showed that mechanical properties increased porosity and swelling ratio with an increase in the gelatine and fucoidan, while the in vitro biodegradability decreased. The average SaGFu diameter attained by fabrication of SaGFu ranged from 60 to 120MUm with high porosity (74.44%-88.30%). Cell culture using gelatine 2.0% (SaG2Fu) and 4.0% (SaG4Fu), showed good cell proliferation; more than 60-80% that with Sa alone. Following stimulation with 0.5MUg/mL LPS, microglia cultured in porous SaGFu decreased their expression of nitric oxide (NO), prostaglandin E2 (PGE2), and reactive oxygen species (ROS). SaG2Fu and SaG4Fu also inhibited the activation and translocation of p65 NF-kappaB protein levels, resulting in reduction of NO, ROS, and PGE2 production. These results provide insights into the diverse biological effects and opens new avenues for the applications of SaGFu in neuroscience. PMID- 27234498 TI - Strain differences of cadmium-induced toxicity in rats: Insight from spleen and lung immune responses. AB - The impact of genetic background on effects of acute i.p. cadmium administration (0.5mg/kg and 1mg/kg) on basic immune activity of spleen and lungs was examined in two rat strains, Albino Oxford (AO) and Dark Agouti (DA), known to react differently to chemicals. More pronounced inhibition of Concanavalin A (ConA) induced and Interleukin (IL)-2 stimulated spleen cell proliferation as well as higher levels of nitric oxide (known to decrease cell's proliferative ability) in DA rats at 1mg/kg, along with greater inhibition of ConA-induced Interferon (IFN gamma)-production by total and mononuclear (MNC) spleen cells and IL-17 production by spleen MNC in DA vs. AO rats at this dose show greater susceptibility of this strain to Cd effects on spleen cells response. More pronounced infiltration of neutrophils/CD11b(+) cells to lungs of DA rats treated with 1mg/kg of Cd and decreased IL-17 lung cell responses noted solely in DA rats speaks in favor of their higher susceptibility to this metal. However, lack of strain disparity in lung cells IFN-gamma responses show that there are regional differences as well. Novel data from this study depict complexity of the influence of genetic background on the effects of cadmium on host immune reactivity. PMID- 27234499 TI - Benzo[ghi]perylene activates the AHR pathway to exert biological effects on the NL-20 human bronchial cell line. AB - Polycyclic aromatic hydrocarbons (PAH) are produced by incomplete combustion of organic material. In the Mexico City atmosphere, the most abundant PAH is benzo[ghi]perylene (BghiP), a gasoline combustion marker. At present, there are no reports of the effects of BghiP on human bronchial cells, so the aim of the study was to evaluate the effects in vitro of BghiP on the NL-20 cell line. Results showed that BghiP induced the formation of small vesicles throughout the cytoplasm, with absence of nuclear fragmentation. At 48h exposition, damage in cell membrane increased significantly at 1.24MUg/mL of BghiP (p<0.05). Immunocytochemistry revealed that BghiP provokes nuclear translocation of AhR receptor, which indicates that this compound can induce transcription of genes via receptor binding (AhR pathway activation). BghiP induced a two-fold increase (p<0.05) in the expression of AhR and CYP4B1 (a lung-specific pathway effector). In the presence of the receptor antagonist CH-223191, the loss of viability, the nuclear translocation and the overexpression of genes decreased, though this did not prevent the formation of vesicles. BghiP induced oxidative stress and in presence of the receptor antagonist this increased significantly. In conclusion, BghiP can activate the overexpression of AhR and CYP4B1, and the effects are abated by the AhR receptor antagonist. This is the first report to prove that BghiP utilizes the AhR pathway to exert its toxic effects on the NL-20 human bronchial cell line . PMID- 27234500 TI - An in vitro investigation on the cytotoxic and nuclear receptor transcriptional activity of the mycotoxins fumonisin B1 and beauvericin. AB - Fumonisin B1 (FB1) and beauvericin (BEA) are secondary metabolites of filamentous fungi, which under appropriate temperature and humidity conditions may develop on various foods and feeds. To date few studies have been performed to evaluate the toxicological and endocrine disrupting effects of FB1 and BEA. The present study makes use of various in vitro bioassays including; oestrogen, androgen, progestagen and glucocorticoid reporter gene assays (RGAs) for the study of nuclear receptor transcriptional activity, the thiazolyl blue tetrazolium bromide (MTT) assay to monitor cytotoxicity and high content analysis (HCA) for the detection of pre-lethal toxicity in the RGA and Caco-2 human colon adenocarcinoma cells. At the receptor level, 0.001-10MUM BEA or FB1 did not induce any agonist responses in the RGAs. However at non-cytotoxic concentrations, an antagonistic effect was exhibited by FB1 on the androgen nuclear receptor transcriptional activity at 10MUM and BEA on the progestagen and glucocorticoid receptors at 1MUM. MTT analysis showed no decrease in cell viability at any concentration of FB1, whereas BEA showed a significant decrease in viability at 10MUM. HCA analysis confirmed that the reduction in the progestagen receptor transcriptional activity at 1MUM BEA was not due to pre-lethal toxicity. In addition, BEA (10MUM) induced significant toxicity in both the TM-Luc (progestagen responsive) and Caco 2 cells. PMID- 27234501 TI - Role of stem cell factor in the placental niche. AB - Stem cell factor (SCF) is a cytokine found in hematopoietic stem cells (HSCs) and causes proliferation and differentiation of cells by binding to its receptor (c kit). It is produced in the yolk sac, fetal liver and bone marrow during the development of the fetus and, together with its signaling pathway, plays an important role in the development of these cells. The placenta, an important hematopoiesis site before the entry of cells into the liver, is rich in HSCs, with definitive hematopoiesis in a variety of HSC types and embryonic stem cells. Chorionic-plate-derived mesenchymal stem cells (CP-MSCs) isolated from the placenta show stem cell markers such as CD41 and cause the self-renewal of cells under hypoxic conditions. In contrast, hypoxia can result in apoptosis and autophagy via oxidative stress in stem cells. As a hypoxia-induced factor, SCF causes a balance between cell survival and death by autophagy in CP-MSCs. Stromal cells and MSCs have a crucial function in the development of HSCs in the placenta via SCF expression in the placental vascular niche. Defects in hematopoietic growth factors (such as SCF and its signaling pathways) lead to impaired hematopoiesis, resulting in fetal death and abortion. Therefore, an awareness of the role of the SCF/c-kit pathway in the survival, apoptosis and development of stem cells can significantly contribute to the exploration of stem cell production pathways during the embryonic period and in malignancies and in the further generation of these cells to facilitate therapeutic approaches. In this review, we discuss the role of SCF in the placental niche. PMID- 27234502 TI - Periostin as a multifunctional modulator of the wound healing response. AB - During tissue healing, the dynamic and temporal alterations required for effective repair occur in the structure and composition of the extracellular matrix (ECM). Matricellular proteins (MPs) are a group of diverse non-structural ECM components that bind cell surface receptors mediating interactions between the cell and its microenviroment, effectively regulating adhesion, migration, proliferation, signaling, and cell phenotype. Periostin (Postn), a pro-fibrogenic secreted glycoprotein, is defined as an MP based on its expression pattern and regulatory roles during development and healing and in disease processes. Postn consists of a typical signal sequence, an EMI domain responsible for binding to fibronectin, four tandem fasciclin-like domains that are responsible for integrin binding, and a C-terminal region in which multiple splice variants originate. This review focuses specifically on the role of Postn in wound healing and remodeling, an area of intense research during the last 10 years, particularly as related to skin healing and myocardium post-infarction. Postn interacts with cells through various integrin pairs and is an essential downstream effector of transforming growth factor-beta superfamily signaling. Across various tissues, Postn is associated with the pro-fibrogenic process: specifically, the transition of fibroblasts to myofibroblasts, collagen fibrillogenesis, and ECM synthesis. Although the complexity of Postn as a modulator of cell behavior in tissue healing is only beginning to be elucidated, its expression is clearly a defining event in moving wound healing through the proliferative and remodeling phases. PMID- 27234503 TI - Prognostic relevance of estrogen receptor alpha, beta and aromatase expression in non-small cell lung cancer. AB - Sex steroids and their receptors are important in the fetal development of normal lung tissue. In addition emerging evidence reveals their significance in lung cancer pathogenesis. This encourages the exploitation of hormone receptors as treatment targets in lung cancer, as it has been successfully used in breast cancer. This study investigates the prognostic impact of estrogen receptor (ER) alpha and beta and the aromatase (AR) enzyme in non-small cell lung cancer (NSCLC) patients. Tumor tissue from 335 NSCLC patients was collected and tissue microarrays (TMAs) were constructed. Immunohistochemical analyses were performed to evaluate the expression of ERalpha, ERbeta and AR in the cytoplasme and nuclei of cells in the tumor epithelial and stromal compartment. By use of survival statistics we investigated the markers impact on disease-specific survival (DSS). Nuclear ERbeta expression in tumor epithelial cells in female patients (HR 3.03; 95% CI 1.39-6.61) and tumor cell AR expression in all patients (HR 1.55; 95% CI 1.08-2.23) were significant negative prognostic markers of disease-specific survival in our cohort. High ERbeta expression correlates with worse outcome in female patients. Further, patients with high AR expression had an unfavorable prognostic outcome compared with patients expressing low AR levels. These results emphasize the importance of sex steroids role in NSCLC, and, as anti-hormonal drugs are widely available, could lead to the development of novel palliative or even adjuvant treatment strategies in this patient population. PMID- 27234504 TI - Anti-inflammatory steroids from the rhizomes of Dioscorea septemloba Thunb. AB - Seven new steroid glycosides, dioscorosides A1 (1), A2 (2), B1 (3), B2 (4), C1 (5), C2 (6), and D (7), together with 22 known ones (8-29) were isolated from the rhizomes of Dioscorea septemloba, their structures were elucidated by chemical and spectroscopic methods. All isolates were evaluated for in vitro anti inflammatory potential using LPS-stimulated RAW 264.7 murine macrophages. Among them, spirostane glycosides 18 and 21-24 exhibited significant inhibition of nitrite production. Moreover, the structure-activity relationship was summarized. PMID- 27234506 TI - Peptide Biosynthesis with Stable Isotope Labeling from a Cell-free Expression System for Targeted Proteomics with Absolute Quantification. AB - Because of its specificity and sensitivity, targeted proteomics using mass spectrometry for multiple reaction monitoring is a powerful tool to detect and quantify pre-selected peptides from a complex background and facilitates the absolute quantification of peptides using isotope-labeled forms as internal standards. How to generate isotope-labeled peptides remains an urgent challenge for accurately quantitative targeted proteomics on a large scale. Herein, we propose that isotope-labeled peptides fused with a quantitative tag could be synthesized through an expression system in vitro, and the homemade peptides could be enriched by magnetic beads with tag-affinity and globally quantified based on the corresponding multiple reaction monitoring signals provided by the fused tag. An Escherichia coli cell-free protein expression system, protein synthesis using recombinant elements, was adopted for the synthesis of isotope labeled peptides fused with Strep-tag. Through a series of optimizations, we enabled efficient expression of the labeled peptides such that, after Strep Tactin affinity enrichment, the peptide yield was acceptable in scale for quantification, and the peptides could be completely digested by trypsin to release the Strep-tag for quantification. Moreover, these recombinant peptides could be employed in the same way as synthetic peptides for multiple reaction monitoring applications and are likely more economical and useful in a laboratory for the scale of targeted proteomics. As an application, we synthesized four isotope-labeled glutathione S-transferase (GST) peptides and added them to mouse sera pre-treated with GST affinity resin as internal standards. A quantitative assay of the synthesized GST peptides confirmed the absolute GST quantification in mouse sera to be measurable and reproducible. PMID- 27234507 TI - Perinatal outcome in women with prolonged premature rupture of membranes at term undergoing labor induction. AB - PURPOSE: We aimed to evaluate perinatal outcome in women with prolonged (>24 h) premature rupture of membranes (PROM) undergoing induction of labor (IoL). METHODS: We retrospectively assessed all women presenting with term (>=37 weeks) PROM and Bishop-score <7 in a tertiary hospital (2012-14). Women without spontaneous onset of labor <24 h from PROM underwent Prostaglandin E2 (PGE2) IoL and were compared to women with low Bishop-score who developed spontaneous onset of labor <24 h. Women with IoL at <24 h from PROM, women presenting in active labor at admission or women who did not attempt vaginal delivery were excluded. RESULTS: Among 15,563 deliveries 1,171 (8.2 %) admitted with term PROM. Of them, 625 (53 %) were eligible; 155 (24.8 %) in the induction group and 470 (75.2 %) served as comparison group. No significant difference was found between the groups regarding maternal age, parity and obstetrical complications. Women in the induction group were at increased risk for Cesarean section (CS) (OR 8.27, CI 1.30-52.36, p = 0.025) and especially CS due to labor dystocia (2.97, 1.20-7.36, p = 0.018). The rate of neonatal complications was comparable between the groups. CONCLUSION: Women undergoing IoL for prolonged term PROM were at increased risk for CS compared to those with spontaneous onset of labor. However, neonatal outcome was comparable between the groups. PMID- 27234505 TI - Plasma-derived Extracellular Vesicles Contain Predictive Biomarkers and Potential Therapeutic Targets for Myocardial Ischemic (MI) Injury. AB - Myocardial infarction (MI) triggers a potent inflammatory response via the release of circulatory mediators, including extracellular vesicles (EVs) by damaged cardiac cells, necessary for myocardial healing. Timely repression of inflammatory response are critical to prevent and minimize cardiac tissue injuries, nonetheless, progression in this aspect remains challenging. The ability of EVs to trigger a functional response upon delivery of carried bioactive cargos, have made them clinically attractive diagnostic biomarkers and vectors for therapeutic interventions. Using label-free quantitative proteomics approach, we compared the protein cargo of plasma EVs between patients with MI and from patients with stable angina (NMI). We report, for the first time, the proteomics profiling on 252 EV proteins that were modulated with >1.2-fold after MI. We identified six up-regulated biomarkers with potential for clinical applications; these reflected post-infarct pathways of complement activation (Complement C1q subcomponent subunit A (C1QA), 3.23-fold change, p = 0.012; Complement C5 (C5), 1.27-fold change, p = 0.087), lipoprotein metabolism (Apoliporotein D (APOD), 1.86-fold change, p = 0.033; Apolipoprotein C-III (APOCC3), 2.63-fold change, p = 0.029) and platelet activation (Platelet glycoprotein Ib alpha chain (GP1BA), 9.18-fold change, p < 0.0001; Platelet basic protein (PPBP), 4.72-fold change, p = 0.027). The data have been deposited to the ProteomeXchange with identifier PXD002950. This novel biomarker panel was validated in 43 patients using antibody-based assays (C1QA (p = 0.005); C5 (p = 0.0047), APOD (p = 0.0267); APOC3 (p = 0.0064); GP1BA (p = 0.0031); PPBP (p = 0.0465)). We further present that EV-derived fibrinogen components were paradoxically down-regulated in MI, suggesting that a compensatory mechanism may suppress post-infarct coagulation pathways, indicating potential for therapeutic targeting of this mechanism in MI. Taken together, these data demonstrated that plasma EVs contain novel diagnostic biomarkers and therapeutic targets that can be further developed for clinical use to benefit patients with coronary artery diseases (CADs). PMID- 27234508 TI - Peritoneal dialysis impairs nitric oxide homeostasis and may predispose infants with low systolic blood pressure to cerebral ischemia. AB - BACKGROUND & PURPOSE: Infants on chronic peritoneal dialysis (PD) have an increased risk of developing neurological morbidities; however, the underlying biological mechanisms are poorly understood. In this clinical study, we investigated whether PD-mediated impairment of nitric oxide (NO) bioavailability and signaling, in patients with persistently low systolic blood pressure (SBP), can explain the occurrence of cerebral ischemia. METHODS & RESULTS: Repeated blood pressure measurements, serial neuroimaging studies, and investigations of systemic nitrate and nitrite levels, as well as NO signaling, were performed in ten pediatric patients on PD. We consistently observed the loss of both inorganic nitrate (-17 +/- 3%, P < 0.05) and nitrite (-34 +/- 4%, P < 0.05) during PD, which may result in impairment of the nitrate-nitrite-NO pathway. Indeed, PD was associated with significant reduction of cyclic guanosine monophosphate levels ( 59.4 +/- 15%, P < 0.05). This reduction in NO signaling was partly prevented by using a commercially available PD solution supplemented with l-arginine. Although PD compromised nitrate-nitrite-NO signaling in all cases, only infants with persistently low SBP developed ischemic cerebral complications. CONCLUSIONS: Our data suggests that PD impairs NO homeostasis and predisposes infants with persistently low SBP to cerebral ischemia. These findings improve current understanding of the pathogenesis of infantile cerebral ischemia induced by PD and may lead to the new treatment strategies to reduce neurological morbidities. PMID- 27234509 TI - Evaluation of pulmonary perfusion by SPECT imaging using an endothelial cell tracer in supine humans and dogs. AB - BACKGROUND: Pulmonary perfusion is not spatially homogeneously distributed, and its variations could be of diagnostic value in lung vascular disease. PulmoBind is a ligand of the adrenomedullin receptor densely expressed in endothelial cells of lung capillaries. The aim of this study was to evaluate spatial distribution of human lung perfusion by using this novel molecular tracer of the pulmonary vascular endothelium. METHODS: Normal humans (n = 19) enrolled into the PulmoBind phase I trial were studied (Clinicaltrials.gov. NCT01539889 ). They were injected with (99m)Tc-PulmoBind for SPECT imaging. Results were compared with (99m)Tc PulmoBind in quadruped mammals (dogs, n = 5). Imaging was performed in the supine position and distribution of activity was determined as a function of cumulative voxels along the different anatomical planes. RESULTS: PulmoBind uptake in humans was 58 +/- 1 % (mean +/- SEM) of the injected dose. Dorsal activity was 18.1 +/- 2.1 % greater than ventral, and caudal activity was 25.7 +/- 1.6 % greater than cranial. Lateral activity was only mildly higher than medial by 7.0 +/- 1.0 %. In supine dogs, similar but higher PulmoBind gradients were present: dorsal 28.6 +/- 2.5 %, caudal 34.1 +/- 5.0 % and lateral 18.1 +/- 2.0 %. CONCLUSIONS: The perfused pulmonary circulation of supine humans, assessed by an adrenomedullin receptor ligand, is not homogeneously distributed with more prominent distribution in dorsal and caudal regions. It is qualitatively similar to a supine quadruped mammal confirming the presence of a microcirculatory gravitational perfusion gradient detectable with this tracer. Future studies are needed to determine if this novel endothelial cell tracer could be used to detect physiologic and pathologic variations of lung perfusion such as in pulmonary hypertension. CLINICAL TRIAL: ClinicalTrial.gov, NCT01539889. PMID- 27234510 TI - Comparison of LDPI to SPECT perfusion imaging using (99m)Tc-sestamibi and (99m)Tc pyrophosphate in a murine ischemic hind limb model of neovascularization. AB - BACKGROUND: We aimed to determine the accuracy of laser Doppler perfusion imaging (LDPI) in an animal model for hind limb ischemia. METHODS: We used a murine (C57Bl/6 mice) ischemic hind limb model in which we compared LDPI with the clinically used (99m)Tc-sestamibi SPECT perfusion imaging (n = 7). In addition, we used the SPECT tracer (99m)Tc-pyrophosphate ((99m)Tc-PyP) to image muscular damage (n = 6). RESULTS: LDPI indicated a quick and prominent decrease in perfusion immediately after ligation, subsequently recovering to 21.9 and 25.2 % 14 days later in the (99m)Tc-sestamibi and (99m)Tc-PyP group, respectively. (99m)Tc-sestamibi SPECT scans also showed a quick decrease in perfusion. However, nearly full recovery was reached 7 days post ligation. Muscular damage, indicated by the uptake of (99m)Tc-PyP, was highest at day 3 and recovered to baseline levels at day 14 post ligation. Postmortem histology supported these findings, as a significantly increased collateral diameter was found 7 and 14 days after ligation and peak macrophage infiltration and TUNEL positivity was found on day 3 after ligation. CONCLUSIONS: Here, we indicate that LDPI strongly underestimates perfusion recovery in a hind limb model for profound ischemia. PMID- 27234511 TI - Anthony David Barnes. PMID- 27234512 TI - Analysis of the dust emissions from a naturally ventilated turkey house using tracer gas method. AB - Particulate matter (PM) emissions are becoming increasingly important in licensing procedures for the construction of new livestock houses or for the modernization of existing ones. Emission predictions require reliable data about emission rates. On this account, it is necessary to obtain information about the emission development and the relevant influencing factors in naturally ventilated turkey houses. The primary objective of the present research was to describe different aspects of PM emissions from a naturally ventilated turkey house. This includes the quantification of PM emissions and descriptions of the relevant influencing factors. Moreover, the tracer gas decay (TGD) method for ventilation rate estimation had to be used. To determine the emission mass flow from livestock buildings, it was necessary to measure the concentration of the target substance in the exhaust air and the airflow volume. The PM concentration measurements were carried out with a light scattering aerosol spectrometer in the exhaust air. The airflow volume was determined using the TGD method. To this purpose, tracer gas was injected into the supply air before the concentration decay was measured in the exhaust air of the building. The main influences on the PM concentration and the PM size distribution were shown to be animal activity and air volume flow. For the turkey barn, the PM emission factor averaged 0.027 g h(-1) animal(-1) over the entire year. If service times were to be included in the calculation, the emission factor 0.021 g h(-1) animal(-1), again averaged over the entire year, is well below the regulatory limit. PMID- 27234513 TI - The relative abundance and seasonal distribution correspond with the sources of polycyclic aromatic hydrocarbons (PAHs) in the surface sediments of Chenab River, Pakistan. AB - Chenab River is one of the most important rivers of Punjab Province (Pakistan) that receives huge input of industrial effluents and municipal sewage from major cities in the Central Punjab, Pakistan. The current study was designed to evaluate the concentration levels and associated ecological risks of USEPA priority polycyclic aromatic hydrocarbons (PAHs) in the surface sediments of Chenab River. Sampling was performed from eight (n = 24) sampling stations of Chenab River and its tributaries. We observed a relatively high abundance of ?16PAHs during the summer season (i.e. 554 ng g(-1)) versus that in the winter season (i.e. 361 ng g(-1)), with an overall abundance of two-, five- and six-ring PAH congeners. Results also revealed that the nitrate and phosphate contents in the sediments were closely associated with low molecular weight (LMW) and high molecular weight (HMW) PAHs, respectively. Source apportionment results showed that the combustion of fossil fuels appears to be the key source of PAHs in the study area. The risk quotient (RQ) values indicated that seven PAH congeners (i.e. phenanthrene, anthracene, fluoranthene, pyrene, benzo(a)pyrene, chrysene and benzo(a)anthracene) could pose serious threats to the aquatic life of the riverine ecosystem in Pakistan. PMID- 27234515 TI - Content Validation and Evaluation of an Endovascular Teamwork Assessment Tool. AB - OBJECTIVE/BACKGROUND: To modify, content validate, and evaluate a teamwork assessment tool for use in endovascular surgery. METHODS: A multistage, multimethod study was conducted. Stage 1 included expert review and modification of the existing Observational Teamwork Assessment for Surgery (OTAS) tool. Stage 2 included identification of additional exemplar behaviours contributing to effective teamwork and enhanced patient safety in endovascular surgery (using real-time observation, focus groups, and semistructured interviews of multidisciplinary teams). Stage 3 included content validation of exemplar behaviours using expert consensus according to established psychometric recommendations and evaluation of structure, content, feasibility, and usability of the Endovascular Observational Teamwork Assessment Tool (Endo-OTAS) by an expert multidisciplinary panel. Stage 4 included final team expert review of exemplars. RESULTS: OTAS core team behaviours were maintained (communication, coordination, cooperation, leadership team monitoring). Of the 114 OTAS behavioural exemplars, 19 were modified, four removed, and 39 additional endovascular-specific behaviours identified. Content validation of these 153 exemplar behaviours showed that 113/153 (73.9%) reached the predetermined Item Content Validity Index rating for teamwork and/or patient safety. After expert team review, 140/153 (91.5%) exemplars were deemed to warrant inclusion in the tool. More than 90% of the expert panel agreed that Endo-OTAS is an appropriate teamwork assessment tool with observable behaviours. Some concerns were noted about the time required to conduct observations and provide performance feedback. CONCLUSION: Endo-OTAS is a novel teamwork assessment tool, with evidence for content validity and relevance to endovascular teams. Endo-OTAS enables systematic objective assessment of the quality of team performance during endovascular procedures. PMID- 27234516 TI - [Glandular lesions of the uterine cervix: Case 4]. PMID- 27234517 TI - [Glandular lesions of the uterine cervix: Case 1]. PMID- 27234514 TI - Risk screening of pharmaceutical compounds in Romanian aquatic environment. AB - The aquatic environment is under increased pressure by pharmaceutically active compounds (PhACs) due to anthropogenic activities. In spite of being found at very low concentrations (ng/L to MUg/L) in the environment, PhACs represent a real danger to aquatic ecosystems due to their bioaccumulation and long-term effects. In this study, the presence in the aquatic environment of six non steroidal anti-inflammatory drugs (ibuprofen, diclofenac, acetaminophen, naproxen, indomethacin, and ketoprofen), caffeine, and carbamazepine were monitored. Moreover, their aquatic risk and ecotoxicity by three biological models were evaluated. The monitoring studies performed in Romania showed that all studied PhACs were naturally present at concentrations >0.01 MUg/L, pointing out the necessity to perform further toxicity tests for environmental risk assessment. The toxicity studies were carried out on aquatic organisms or bacteria and they indicated, for most of the tested PhACs, an insignificant or low toxicity effects: lethal concentrations (LC50) on fish Cyprinus carpio ranged from 42.60 mg/L to more than 100 mg/L; effective concentrations (EC50) on planktonic crustacean Daphnia magna ranged from 11.02 mg/L to more than 100 mg/L; inhibitory concentrations (IC50)/microbial toxic concentrations (MTC) on Vibrio fischeri and other bacterial strains ranged from 7.02 mg/L to more than 100 mg/L. The PhAC aquatic risk was assessed by using the ratio between measured environmental concentration (MEC) and predicted no effect concentration (PNEC) calculated for each type of organism. The average of quotient risks (RQs) revealed that the presence of these compounds in Romania's aquatic environment induced a lower or moderate aquatic risk. PMID- 27234518 TI - [About a case of a recurrent glandular cardiac myxoma in a child]. AB - Primary cardiac tumors are extremely rare and mainly benign. The majority of these are myxomas (40%). Myxoma are generally sporadic tumors which occur most commonly in adult females between 30 and 40 years, and are seldom found in the paediatric population (5%). Seven percent are associated with igenetic diseases. We report the case of an eight-year-old boy presenting a recurrent glandular cardiac myxoma. In 2011, he presented a deterioration of the general state. An echocardiography highlighted a left atrial mass on the interatrial septum, with a pedicular insertion. On the microscope, it consisted of a proliferation of stellate cells isolated or clustered in rudimentary vessels in a myxoid stroma presenting haemorrhage changes. These cells expressed CD34 and calretinine. Glandular elements without atypia were clustered within the myxomatous proliferation. They expressed cytokeratin (CK) 7. Surgical resection was macroscopically complete. In 2014, the boy had a sudden neurological deficit during a football match. An echocardiography revealed a recurrence at the same location. The lesion was excised and addressed in several fragments. Classical myxoma was associated with glands without atypia. This last component expressed CKAE1/AE3 and CK7. Ki67 index of proliferation was low. The surgical reintervention was macroscopically complete. The final diagnosis was glandular cardiac myxoma. A genetic survey was conducted, showing the presence of Carney complex. This is the first description in the litterature of a recurrent glandular cardiac myxoma occuring in a child. PMID- 27234519 TI - [Glandular lesions of the uterine cervix: Case 2]. PMID- 27234520 TI - Familial Influences on Recantation in Substantiated Child Sexual Abuse Cases. AB - The underlying reasons for recantation in children's disclosure of child sexual abuse (CSA) have been debated in recent years. In the present study, we examined the largest sample of substantiated CSA cases involving recantations to date (n = 58 cases). We specifically matched those cases to 58 nonrecanters on key variables found to predict recantation in prior research (i.e., child age, alleged parent figure perpetrator, and caregiver unsupportiveness). Bivariate analyses revealed that children were less likely to recant when they were (1) initially removed from home postdisclosure and (2) initially separated from siblings postdisclosure. Multivariate analyses revealed that children were less likely to recant when family members (other than the nonoffending caregiver) expressed belief in the children's allegations and more likely to recant when family members (other than the nonoffending caregiver) expressed disbelief in the allegations and when visitations with the alleged perpetrator were recommended at their first hearing. Results have implications for understanding the complex ways in which social processes may motivate some children to retract previous reports of sexual abuse. PMID- 27234521 TI - Incidence rate for stomach cancer in Japanese in Japan and in the USA from Cancer Incidence in Five Continents. PMID- 27234523 TI - Plant-growth regulators alter phytochemical constituents and pharmaceutical quality in Sweet potato (Ipomoea batatas L.). AB - BACKGROUND: Sweet potato (Ipomoea batatas L.) is one of the most important consumed crops in many parts of the world because of its economic importance and content of health-promoting phytochemicals. METHODS: With the sweet potato (Ipomoea batatas L.) as our model, we investigated the exogenous effects of three plant-growth regulators methyl jasmonate (MeJA), salicylic acid (SA), and abscisic acid (ABA) on major phytochemicals in relation to phenylalanine ammonia lyase (PAL) activity. Specifically, we investigated the total phenolic content (TPC), total flavonoid content (TFC), total anthocyanin content (TAC), and total beta-carotene content (TCC). Individual phenolic and flavonoid compounds were identified using ultra-high performance liquid chromatography (UHPLC). Antioxidant activities of treated plants were evaluated using a 1,1-diphenyl-2 picrylhydrazyl (DPPH) assay and a beta-carotene bleaching assay. Anticancer activity of extracts was evaluated against breast cancer cell lines (MCF-7 and MDA-MB-231) using MTT assay. RESULTS: TPC, TFC, TAC, and TCC and antioxidant activities were substantially increased in MeJA-, SA-, and ABA-treated plants. Among the secondary metabolites identified in this study, MeJA application significantly induced production of quercetin, kaempferol, myricetin, gallic acid, chlorogenic acid, 3,5-dicaffeoylquinic acid, and 4,5-dicaffeoylquinic acid. Luteolin synthesis was significantly induced by SA application. Compared with control plants, MeJA-treated sweet potato exhibited the highest PAL activity, followed by SA and ABA treatment. The high DPPH activity was observed in MeJA followed by SA and ABA, with half-maximal inhibitory concentration (IC50) values of 2.40, 3.0, and 3.40 mg/mL compared with alpha-tocopherol (1.1 mg/mL). Additionally, MeJA-treated sweet potato showed the highest beta-carotene bleaching activity, with an IC50 value of 2.90 mg/mL, followed by SA (3.30 mg/mL), ABA (3.70 mg/mL), and control plants (4.5 mg/mL). Extracts of sweet potato root treated with MeJA exhibited potent anticancer activity with IC50 of 0.66 and 0.62 mg/mL against MDA-MB-231 and MCF-7 cell lines respectively, compared to that of extracts of sweet potato treated with SA (MDA-MB-231 = 0.78 mg/mL; MCF-7 = 0.90 mg/mL) and ABA (MDA-MB-231 = 0.94 mg/mL; MCF-7 = 1.40 mg/mL). The results of correlation analysis showed that anthocyanins and flavooids are corresponding compounds in sweet potato root extracts for anticancer activity against breast cancer cell lines. CONCLUSIONS: MeJA has great potential to enhance the production of important health-promoting phytochemicals in sweet potato. PMID- 27234524 TI - Autoaugmentation Mastopexy Modification Prevents Bottoming-Out Deformity and Areola Distortion: A Preliminary Report. AB - BACKGROUND: Ptotic breast deformity results from involution of breast parenchyma and leads to a loss of volume, along with a converse laxity of the skin envelope. As the breast tissue descends inferiorly with gravity, there is an apparent volume loss in the upper pole and the central breast, and the lower pole becomes fuller and often wider. This study presents modifications for a well-known mastopexy technique which provides not only autoaugmentation for the breast but also suspension for the breast parenchyma and reduces bottoming-out deformity, and also obtains a regular areola shape in all types of breasts. PATIENTS AND METHODS: The modifications involve 2-4 cm subareolar crescentic incisions for regular areolas and cylindrical excision of the recipient area in the superior medial and lateral pillars for wide flaps in medium and large-size breasts. RESULTS: The present study included 63 female patients, with an average body mass index of 25.5 +/- 2.0 kg/m(2), aged 26-47 years (average 35 years). The author performed vertical scar mastopexy and augmented the breasts with a distal-based flap of deepithelialized dermoglandular tissue inserted beneath the breast parenchyma of a superior-based nipple-areolar complex pedicle. CONCLUSIONS: In this study, modifications included subareolar crescentic incisions and cylindrical excisions in the superior medial and lateral pillar regions. This technique produced satisfactory results for all types of breasts in terms of good breast shape, natural image at the upper pole of the breast, good projection, and reduced bottoming-out deformity. This simple modified technique maintained the size of the breasts and avoided augmentation by breast implants. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 27234525 TI - Factors That May Enhance Longevity: A Literature Review and a Comprehensive Update for Aesthetic Surgeons. AB - INTRODUCTION: After surgery, the plastic surgeon is very often questioned about how to maintain the result and more frequently how to slow down the aging process. However, this type of knowledge is not commonly delivered during medical education or at least needs an update. This review could be used as a guide to help plastic surgeons to manage these frequent postoperative consultations. The aim of this literature review was to focus discussion on specific positive factors, identified to have a significant impact on human longevity. MATERIALS AND METHODS: A literature review was performed using the automated computerized PubMed search, with the keywords "human longevity." Only papers written in the English language were included. References were screened to identify further relevant articles. Experimental studies based on microorganisms and animals, works published in non-indexed journals, case reports, letters, and viewpoints were excluded. RESULTS: One hundred and twenty-four articles reporting factors influencing human longevity were analyzed for data extraction. A total of 59 articles reporting only positive factors were included. Fourteen factors seemed to have a positive impact on longevity: caloric restriction, active effort and sports, happiness, vitamins, vegetarian or Mediterranean diet, oriental practices, socioeconomic status, genetics, sexual activity, sleep, moderate wine consumption, religion, and education. CONCLUSION: While some factors with a positive impact on longevity are clearly identified and should be integrated in the postoperative process, further studies are still needed to be able to slow down the aging process. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 27234522 TI - Current status and perspectives in translational biomarker research for PD-1/PD L1 immune checkpoint blockade therapy. AB - Modulating immune inhibitory pathways has been a major recent breakthrough in cancer treatment. Checkpoint blockade antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programed cell-death protein 1 (PD-1) have demonstrated acceptable toxicity, promising clinical responses, durable disease control, and improved survival in some patients with advanced melanoma, non-small cell lung cancer (NSCLC), and other tumor types. About 20 % of advanced NSCLC patients and 30 % of advanced melanoma patients experience tumor responses from checkpoint blockade monotherapy, with better clinical responses seen with the combination of anti-PD-1 and anti-CTLA-4 antibodies. Given the power of these new therapies, it is important to understand the complex and dynamic nature of host immune responses and the regulation of additional molecules in the tumor microenvironment and normal organs in response to the checkpoint blockade therapies. In this era of precision oncology, there remains a largely unmet need to identify the patients who are most likely to benefit from immunotherapy, to optimize the monitoring assays for tumor-specific immune responses, to develop strategies to improve clinical efficacy, and to identify biomarkers so that immune-related adverse events can be avoided. At this time, PD-L1 immunohistochemistry (IHC) staining using 22C3 antibody is the only FDA-approved companion diagnostic for patients with NSCLC-treated pembrolizumab, but more are expected to come to market. We here summarize the current knowledge, clinical efficacy, potential immune biomarkers, and associated assays for immune checkpoint blockade therapies in advanced solid tumors. PMID- 27234526 TI - The Impact of Resident Participation in Outpatient Plastic Surgical Procedures. AB - INTRODUCTION: Ensuring patient safety along with a complete surgical experience for residents is of utmost importance in plastic surgical training. The effect of resident participation on the outcomes of outpatient plastic surgery procedures remains largely unknown. We assess the impact of resident participation on surgical outcomes using a prospective, validated, national database. METHODS: We identified all outpatient procedures performed by plastic surgeons between 2007 and 2012 in the American College of Surgeons National Surgical Quality Improvement Program database. Multivariate regression models assessed the impact of resident participation when compared to attendings alone on 30-day wound complications, overall complications, and return to the operating room (OR). RESULTS: A total of 18,641 patients were identified: 12,414 patients with an attending alone and 6227 with residents participating. The incidence of overall complications, wound complications, and return to OR was increased with resident participation. When confounding variables were controlled for in multivariate analysis, resident participation was no longer associated with increased risk of wound complications. When stratified by year, incidence of overall complications, wound complications, and return to OR in the resident participation group are trending down and fail to be significantly different in 2011 and 2012. Multivariate analysis shows a similar trend. CONCLUSIONS: Resident participation is no longer independently associated with increased complications in outpatient plastic surgery in recent years, suggesting that plastic surgical training is successfully continuing to improve in both outcomes and safety. Additional prospective studies that characterize patient outcomes with resident seniority and the degree of resident participation are warranted. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 27234527 TI - Epigallocatechin gallate inhibits urate crystals-induced peritoneal inflammation in C57BL/6 mice. AB - Gouty arthritis is a type of monosodium urate (MSU) crystals-induced inflammation in the articular tissue and shows the increased levels of neutrophil infiltration and IL-1beta secretion. MSU is capable of activating IL-1beta through a nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome. Epigallocatechin gallate (EGCG), a bioactive polyphenol in green tea with potent antioxidant activity, is effective to prevent rheumatoid arthritis and osteoarthritis. However, it remains unclear whether EGCG improves gouty inflammation. This study aimed to investigate the effect of EGCG on MSU induced inflammation and NLRP3 inflammasome activation. C57BL/6 mice were received subcutaneous injection or oral gavage of EGCG before the intraperitoneal injection of MSU. The results demonstrated that EGCG inhibited MSU-induced neutrophil infiltration and IL-1beta secretion. Furthermore, EGCG decreased MSU triggered neutrophil cytosolic factor 1 and NLRP3 protein expression, limiting pro-inflammatory mediator secretion such as IL-1beta, IL-6, monocyte chemoattractant protein-1, and serum amyloid A. In addition, EGCG treatment suppressed NLRP3 inflammasome activation in MSU-challenged THP-1 monocytes. These findings indicate that EGCG treatment ameliorates MSU-induced inflammation, suggesting that EGCG exerts anti-inflammatory effect against MSU-induced acute gout attack. PMID- 27234528 TI - Acaricidal activity of leaf extracts of Dalbergia sissoo Roxb. (Fabaceae) against synthetic pyrethroid resistant Rhipicephalus (Boophilus) microplus. AB - Resistance status of Rhipicephalus (Boophilus) microplus against synthetic pyrethroids was assessed by larval packet test which revealed level I and II resistance against cypermethrin and deltamethrin, respectively. Adult immersion test was employed to study the acaricidal activity of leaf extracts of Dalbergia sissoo (sheesham) against these ticks. Mortality and fecundity of ticks exposed to sheesham leaf aqueous (SLA) and ethanolic (SLE) extracts were evaluated at concentrations of 0.625, 1.25, 2.5, 5.0 and 10.0% and controls (distilled water and 10% ethanol). Higher acaricidal activity was recorded in SLA with a lower LC50 (95% CL) value of 1.58% (0.92-2.71%) than SLE [5.25% (4.91-5.63%)]. A significant decrease in egg mass weight and reproductive index was recorded in treated ticks along with an increase in percent inhibition of oviposition. A complete inhibition of hatching was recorded in eggs laid by ticks treated with higher concentrations of SLA, whereas, SLE exhibited no effect on hatching percentage. PMID- 27234530 TI - In vivo and in vitro effectiveness of Azadirachta indica-synthesized silver nanocrystals against Plasmodium berghei and Plasmodium falciparum, and their potential against malaria mosquitoes. AB - Malaria transmission is a serious emergence in urban and semiurban areas worldwide, becoming a major international public health concern. Malaria is transmitted through the bites of Anopheles mosquitoes. The extensive employ of synthetic pesticides leads to negative effects on human health and the environment. Recently, plant-synthesized nanoparticles have been proposed as highly effective mosquitocides. In this research, we synthesized silver nanoparticles (AgNP) using the Azadirachta indica seed kernel extract as reducing and stabilizing agent. AgNP were characterized by UV-vis spectrophotometry, SEM, EDX, XRD and FTIR spectroscopy. The A. indica seed kernel extract was toxic against Anopheles stephensi larvae and pupae, LC50 were 232.8ppm (larva I), 260.6ppm (II), 290.3ppm (III), 323.4ppm (IV), and 348.4ppm (pupa). AgNP LC50 were 3.9ppm (I), 4.9ppm (II), 5.6ppm (III), 6.5ppm (IV), and 8.2ppm (pupa). The antiplasmodial activity of A. indica seed kernel extract and AgNP was evaluated against CQ-resistant (CQ-r) and CQ-sensitive (CQ-s) strains of Plasmodium falciparum. IC50 of A. indica seed kernel extract were 63.18MUg/ml (CQ-s) and 69.24MUg/ml (CQ-r). A. indica seed kernel-synthesized AgNP achieved IC50, of 82.41MUg/ml (CQ-s) and 86.12MUg/ml (CQ-r). However, in vivo anti-plasmodial experiments conducted on Plasmodium berghei infecting albino mice showed moderate activity of the A. indica extract and AgNP. Overall, this study showed that the A. indica-mediated fabrication of AgNP is of interest for a wide array of purposes, ranging from IPM of mosquito vectors to the development of novel and cheap antimalarial drugs. PMID- 27234529 TI - Epidemiological investigation reveals genetic diversity and high co-infection rate of canine bocavirus strains circulating in Heilongjiang province, Northeast China. AB - To trace evolution of CBoV in Northeast China, 201 fecal samples from rectal swabs of diarrheic dogs collected from May 2014 to April 2015 were investigated using PCR targeting partial NS1 gene (440bp). Furthermore, phylogenetic analysis of the identified CBoV strains was conducted using nucleotide sequences of the partial NS1 gene. The results indicated that 15 of 201 fecal samples (7.5%) were positive for CBoV; the partial NS1 genes of the 15 CBoV strains exhibited 83.1% 100% nucleotide identity, and 75.8%-100% amino acid identity; the entire VP2 gene of five selected CBoV strains exhibited 82.9%-96.8% nucleotide identity, and 90.4%-99.1% amino acid identity. The 15 CBoV strains exhibited high co-infection rates with CPV-2 (40%), CCoV (20%), and CaKV (26.67%). Phylogenetic analysis of the partial NS1 gene revealed that the 15 CBoV strains were divided into different subgroups of CBoV-2 when compared with CBoV-2 strains from South Korea, USA, Germany, and Hong Kong in China. Moreover, phylogenetic analysis of the VP2 gene indicated that five selected CBoV strains were divided into three different genetic groups of CBoV-2, involving in CBoV-2HK group, CBoV-2C group, and CBoV-2B group. The recombination analysis using the entire VP2 gene revealed three potential recombination events that occurred among five selected strains in our study. These data demonstrated that the CBoV strains circulating in Heilongjiang province, Northeast China showed genetic diversities, potential recombination events, and high co-infection rate. Further studies will be required to address the potential pathogenic role of these diverse CBoV strains. PMID- 27234531 TI - Cholinesterase in porcine saliva: Analytical characterization and behavior after experimental stress. AB - The purpose of this study was to measure and characterize the enzyme cholinesterase (ChE) in porcine saliva, as well as to evaluate its behavior in experimental stressful conditions. The results of ChE characterization by using different substrates and the selective inhibitors ethopropazine and physostigmine showed that the main enzyme existing in porcine saliva was butyrylcholinesterase (BChE). An automated assay using butyrylthiocholine iodide as substrate was validated providing adequate reproducibility, linearity results and limit of detection. Salivary ChE was measured using the validated assay in two models of acute stress: twenty pigs stressed for 2min with a nasal snare and other twenty pigs subjected to a short-term road transport. Salivary ChE significantly increased after restraint and transport stress in pigs, as well as the ChE to total protein ratio. In conclusion, BChE is the predominant isoenzyme in porcine saliva, it can be measured by the fast, simple and automated method described in this paper and it increases in the models of stress used in this study. PMID- 27234532 TI - White snakeroot poisoning in goats: Variations in toxicity with different plant chemotypes. AB - Tremetone and possibly other benzofuran ketones are believed to be the toxic compounds in white snakeroot. However, disease has not been reproduced with purified toxins and the concentrations of the benzofuran ketones in white snakeroot populations that cause toxicosis have not been documented. The objectives of this study were to compare the toxicity of seven plant populations, better characterize the clinical and pathologic changes of poisoning, and correlate intoxication with benzofuran ketone content. Four of the seven white snakeroot collections were toxic at the dose and duration used in the study. Affected goats became exercise intolerant, had significant serum enzyme changes and histological lesions in the large appendicular muscles. The incidence and severity of poisoning was not correlated with total doses of tremetone or total benzofuran ketone concentrations suggesting they may not be closely involved in producing toxicity and the possible involvement of an unidentified toxin. The results also demonstrate that white snakeroot populations vary chemically and toxicologically. PMID- 27234533 TI - Establishment and characterization of an MDCK cell line stably-transfected with chicken Abcb1 encoding P-glycoprotein. AB - Chicken P-glycoprotein (chP-gp), encoded by Abcb1, determines the bioavailability because of its effect on pharmacokinetics of various drugs. However, comprehensive studies on chP-gp are still limited. In this study, the chicken full-length cDNA was first successfully cloned and then stably expressed in MDCK cell line. The open reading frame of chicken Abcb1 consists of 3864 nucleotides, encoding for a 1287-amino acid protein. Sequence alignments analysis showed that chicken P-gp had high identities with the homologues of turkey (95%), human (72%), pig (72%), rat (71%) and cattle (68%). The efflux ratio of rhodamine123 (Rho123, a human P-gp substrate) in chAbcb1 transfected MDCK cells was significantly higher than that in the wild type MDCK cell (6.24 vs 1.64, P<0.05), suggesting a good transporting function of chicken P-gp overexpressed in the transfected cell. Importantly, MDCK-chAbcb1 cells, unlike Caco-2 cells, exhibited biphasic saturation kinetics in transporting Rho123. In conclusion, an MDCK cell line stably expressing chAbcb1 was successfully established, which could provide a new cell model to screen its substrates and inhibitors and study the drug-drug interaction medicated via chicken P-gp. PMID- 27234534 TI - Attitudes of Danish pig farmers towards requirements for hospital pens. AB - According to Danish legislation, sick or injured pigs must be housed in hospital pens with specific requirements. During recent years the majority of cases of non compliance with legislation have been related to management of these animals. Hence, we hypothesized that 1) pig farmers generally find a requirement for hospital pens reasonable, but do not know the specific requirements; 2) pig farmers do not find the specific requirements for hospital pens meaningful compared with their perception of what sick pigs need; and 3) pig farmers often omit to move sick pigs to hospital pens due to lack of time or labour. An on-line questionnaire regarding farmers' attitudes towards and knowledge about legal requirements for hospital pens was constructed and e-mailed to 2348 pig farmers. In total, 508 farmers answered the questionnaire. Overall, 66% of the respondents found that the requirements for hospital pens made good sense, and more than 90% found that it made at least partial sense. Even though almost all respondents thought they knew the legal requirements for specific facilities in hospital pens, in fact 20% of them did not. The majority of respondents found all specific requirements in accordance with the needs of sick pigs, with the exception of cooling (only 17% agreed that cooling was needed). Unexpectedly, lack of time or labour wasn't reported to be a major obstacle to the use of hospital pens. Possibly, different thresholds for defining a pig as 'sick enough' to need housing in a hospital pen may exist between farmers and authorities. PMID- 27234535 TI - Differentiation at necropsy between in vivo gas embolism and putrefaction using a gas score. AB - Gas bubble lesions consistent with decompression sickness in marine mammals were described for the first time in beaked whales stranded in temporal and spatial association with military exercises. Putrefaction gas is a post-mortem artifact, which hinders the interpretation of gas found at necropsy. Gas analyses have been proven to help differentiating putrefaction gases from gases formed after hyperbaric exposures. Unfortunately, chemical analysis cannot always be performed. Post-mortem computed tomography is used to study gas collections, but many different logistical obstacles and obvious challenges, like the size of the animal or the transport of the animal from the stranding location to the scanner, limit its use in stranded marine mammals. In this study, we tested the diagnostic value of an index-based method for characterizing the amount and topography of gas found grossly during necropsies. For this purpose, putrefaction gases, intravenously infused atmospheric air, and gases produced by decompression were evaluated at necropsy with increased post-mortem time in New Zealand White Rabbits using a gas score index. Statistical differences (P<0.001) were found between the three experimental models immediately after death. Differences in gas score between in vivo gas embolism and putrefaction gases were found significant (P<0.05) throughout the 67h post-mortem. The gas score-index is a new and simple method that can be used by all stranding networks, which has been shown through this study to be a valid diagnostic tool to distinguish between fatal decompression, iatrogenic air embolism and putrefaction gases at autopsies. PMID- 27234536 TI - Alterations in PTEN, MDM2, TP53 and AR protein and gene expression are associated with canine prostate carcinogenesis. AB - The PTEN, AR, MDM2 and p53 protein network plays a central role in the development of many human cancers, thus eliciting the development of targeted cancer therapeutics. Dogs spontaneously develop tumours, and they are considered a good model for comparative oncology initiatives. Due to the limited information on these proteins in canine tumours, this study aimed to investigate gene and protein alterations in PTEN, AR, MDM2 and p53 in canine prostate cancer (PC). Protein expression was evaluated by immunohistochemistry (15 normal, 22 proliferative inflammatory atrophy (PIA) and 19 PC samples) and Western blotting (2 normal prostate tissue, 2 BPH, 2 PIA samples and 2 PC samples) and gene expression by RT-qPCR (10 normal, 10 PIA and 15 PC samples) of formalin-fixed tissue. We identified nuclear and cytoplasmic expression of PTEN and p53 in all samples, with only nuclear staining found for MDM2 and AR. Our results revealed high expression of MDM2 in PC and PIA samples compared to normal samples, whereas PTEN, P53 and AR expression was down-regulated in PC compared to normal tissue. All tumour samples (n=19) showed loss of nuclear PTEN expression, and all cancer mimickers showed positive nuclear staining. Therefore, nuclear PTEN staining could be a good diagnostic marker for differentiating between malignant lesions and mimickers. Canine prostate carcinogenesis involves increased expression of MDM2 in association with decreased expression of PTEN, p53 and AR, such as occurs in hormone refractory PC in men. Thus, dogs may be an important model for studying advanced stage PC. PMID- 27234537 TI - Agreement of manual cell counts and automated counts of the scil Vet abc Plus(+) hematology analyzer for analysis of equine synovial fluid. AB - The purpose of this study was to determine whether the scil Vet abc Plus(+) (SCIL Animal Care Company, Altorf, France), an impedance hematology analyzer, can accurately quantify and differentiate nucleated blood cells (NBCs) in equine synovial fluid. Synovial fluid samples (n=242) in different stages of experimentally induced inflammation were analyzed with and without hyaluronidase pretreatment and compared to manual hemocytometer counts and smear reviews. No significant effect of hyaluronidase pretreatment was observed. Total nucleated cell counts of the scil Vet abc Plus(+) were significantly higher compared to the manual method (P=0.02), yet the difference was small and clinically irrelevant (ratio manual/automated count equal to 0.97 with 95% CI [0.95, 1.00]). Differential cell counts of the scil Vet abc Plus(+) were not accurate. In conclusion, the scil Vet abc Plus(+) hematology analyzer is highly accurate for quantification, but not accurate for differentiation of NBCs in equine synovial fluid. PMID- 27234538 TI - Effect of equilibration time on the motility and functional integrity of canine spermatozoa frozen in three different extenders. AB - The present work aimed to assess the effect of equilibration time on post-thaw motility parameters of canine sperm frozen in three extenders: 6% low-density lipoproteins (LDL), 6% liposomes (LIPO), and 40% egg yolk plasma (EYP). A second experiment is aimed at evaluating the functional integrity of canine spermatozoa frozen in the three extenders at the best equilibration time found in the experiment one. In the first experiment, 20 ejaculates harvested from 7 dogs, were frozen in three extenders (LDL, LIPO, and EYP) after four equilibration times (30min, 1h, 3h, and 6h). The semen was evaluated after thawing using an image analyser (HT-IVOS 14.0). The 6h equilibration time gave better results of motility and progressive motility in the three studied extenders. (LDL: 58.9% vs. 42.7%; LIPO: 54.4% vs. 31.9%; EYP: 55.4% vs 40.5% for motility 6 vs. 1h). In the second experiment, 10 ejaculates taken from 6 dogs were frozen under the same conditions as the previous experiment, after 6h equilibration time. The integrity parameters of the spermatozoal membrane (hypo-osmotic swelling test, and SYBR14/propidium Iodide staining), acrosome (FITC-Pisium sativum Aglutinin staining), and DNA (acridine orange staining) were evaluated at three different stages: post-dilution (T0), post-equilibration, and post-thawing. Post-thaw results were as follows: membrane integrity (HOSt: 62;6% vs 58% vs 64.4%; SYBR14/IP: 63.6% vs 57.9% vs 64.8%); acrosome integrity (FITC-PSA: 79.4% vs 74% vs 76.2%) and DNA integrity (Acridine-orange: 98.9% vs 98.5% vs 98.7%) respectively for LDL vs. LIPO vs. EYP. No significant difference existed between the extenders tested; thus 6%LIPO and 40%EYP could be good candidates for replacement of 6%LDL in the protection of canine sperm during the freeze-thaw process without altering motility and integrity parameters. PMID- 27234539 TI - Studies on pathology, cytokine gene expression and molecular typing of Mycobacterium avium subsp. paratuberculosis of naturally occurring Johne's disease in bullocks. AB - Pathology of Johne's disease (JD) in bullocks (castrated, adult male cattle) is rarely studied. Here, we report the pathology and cytokine gene expression of naturally occurring JD in bullocks. The small intestine and mesenteric lymph nodes collected from 404 bullocks, aged between 5 and 10years, were examined for JD lesions and detection of Mycobacterium avium subsp. paratuberculosis (Map). A total of 8.7% bullocks exhibited JD lesions, which were classified into multibacillary-diffuse granulomatous (n=2), paucibacillary-focal granulomatous (n=18) and paucibacillary-diffuse lymphocytic (n=15) lesions. The tissue cytokine gene expression profiles in all three forms of lesions corroborated with different immuno-pathological processes of JD in bullocks. The molecular typing and gene sequencing identified Map isolates from bullocks as bison type. PMID- 27234540 TI - Determination of minimum alveolar concentration of isoflurane in dogs and cats using the up-and-down method. A preliminary study. AB - Minimum alveolar concentration (MAC) is a reliable measurement of the potency of inhaled anesthetic agents. The determination of MAC in different species has followed a fairly consistent methodology. In people, MAC is determined with the up-and-down method, whereas in animal the bracketing technique is commonly used. The objectives of this study were to determine the MAC value of isoflurane in dogs and cats using the up-and-down method and to determine the MAC value of isoflurane at extubation (MACex). General anesthesia was induced in 13 dogs and 5 cats with 5% isoflurane in oxygen. An initial end-tidal isoflurane concentration of 1.3% was used for the first dog and of 1.6% for the first cat and maintained constant for >=20min. A noxious stimulus in the form of Carmalt forceps was applied to the base of the tail for no more than one minute or until movement was noticed. After stimulation, the response was recorded as positive (movement) or negative (no movement) and the animal was recovered. The end-tidal isoflurane concentration of the following animal was increased or decreased by 0.1% if the response of the previous animal to the stimulus was negative or positive, respectively. Isoflurane MAC values in dogs were 1.27% and 1.23%. Isoflurane MAC value in cats was 1.58%. MACex value was 0.45% in dogs and in cats. The up-and down method for MAC determination achieved similar results when compared to MAC values of isoflurane in dogs and cats reported in the literature using the bracketing technique. PMID- 27234541 TI - Reduction of liver function delays resumption of postpartum ovarian activity and alters the synthesis of acute phase proteins in dairy cows. AB - The aim of this study was to evaluate the concentration of acute phase proteins, milk production, and resumption of postpartum ovarian activity of clinically healthy dairy cows in a semi-extensive system with different Liver Functionality Index (LFI) values. The animals were divided into two groups: Low LFI (LLFI: -7 to -12; n: 10) and High LFI (HLFI: -7 to -4; n: 10). Animals with LLFI had lower paraoxonase activity and lower albumin concentration in the pre- and postpartum periods (P<0.05), higher non-esterified fatty acids prepartum (P<0.005), and higher haptoglobin concentration postpartum (P<0.01). The LLFI group showed lower resumption of ovarian activity until 44days postpartum (29%; P<0.05) than HLFI (86%). Milk production did not differ between groups. Therefore, this study suggests that the LFI is an important biomarker of synthesis of acute phase proteins and the first ovulation interval, and it can be used to improve the production and reproductive performance. PMID- 27234542 TI - The prevalence of ABCB1:c.227_230delATAG mutation in affected dog breeds from European countries. AB - Deletion of 4-base pairs in the canine ABCB1 (MDR1) gene, responsible for encoding P-glycoprotein, leads to nonsense frame-shift mutation, which causes hypersensitivity to macrocyclic lactones drugs (e.g. ivermectin). To date, at least 12 purebred dog breeds have been found to be affected by this mutation. The aim of this study was to update information about the prevalence of ABCB1 mutation (c.227_230delATAG) in predisposed breeds in multiple European countries. This large scale survey also includes countries which were not involved in previous studies. The samples were collected in the period from 2012 to 2014. The overview is based on genotyping data of 4729 individuals. The observed mutant allele frequencies were 58.5% (Smooth Collie), 48.3% (Rough Collie), 35% (Australian Shepherd), 30.3% (Shetland Sheepdog), 28.1% (Silken Windhound), 26.1% (Miniature Australian Shepherd), 24.3% (Longhaired Whippet), 16.2% (White Swiss Shepherd) and 0% (Border Collie). The possible presence of an ABCB1 mutant allele in Akita-Inu breed has been investigated with negative results. This information could be helpful for breeders in optimization of their breeding strategy and for veterinarians when prescribing drug therapy for dogs of predisposed breeds. PMID- 27234543 TI - In vitro protective efficacy of Lithium chloride against Mycoplasma hyopneumoniae infection. AB - Mycoplasma hyopneumoniae (M. hyopneumoniae) infection affects the swine industry. Lithium chloride (LiCl), is a drug used to treat bipolar disorder and has also shown activity against bacterial and viral infections. Herein, we evaluated the antibacterial activity of LiCl on PK-15 cells infected with M. hyopneumoniae. Incubation of LiCl (40mM) with cells for 24h, did not significantly affect the cell viability. The qRT-PCR showed ~80% reduction in M. hyopneumoniae genome when LiCl added post-infection. A direct effect of LiCl on bacteria was also observed. However, treatment of cells with LiCl prior infection, does not protect against the infection. Anti-bacterial activity of LiCl was further confirmed by IFA, which demonstrated a reduction in the bacterial protein. With 40mM LiCI, the apoptotic cell death, production of nitric oxide and superoxide anion induced by M. hyopneumoniae, were prevented by ~80%, 60% and 58% respectively. Moreover, caspase-3 activity was also reduced (82%) in cells treated with 40mM LiCl. LiCl showed activity against various strains of M. hyopneumoniae examined in our study. Collectively, our data showed that LiCl inhibited the infection of M. hyopneumoniae through anti-apoptotic mechanism. PMID- 27234544 TI - Investigation of the potential immunomodulatory effects of resveratrol on equine whole blood: An in vitro investigation. AB - Horses affected with gastrointestinal conditions such as colic or colitis are at substantial risk for translocation of bacterial components such as lipopolysaccharide (LPS, endotoxin) from the gastrointestinal tract into circulation resulting in systemic inflammation and subsequent morbidity and mortality. Therefore, there is a need for effective preventive and treatment strategies aimed at minimizing the host's inflammatory reaction to these pathogen associated molecular patterns (PAMPs) from gastrointestinal disease. Resveratrol (RES, trans-3,5,4'-trihydroxystilbene) is a phytoalexin commonly found in fruits and beverages, including red wine. Health benefits associated with the consumption of red wine have been attributed to RES. Resveratrol has been significantly shown to exert a powerful anti-inflammatory effect in laboratory animals subjected to experimental endotoxemia/sepsis. Therefore, the objective of this study was to determine in vitro whether RES had an inhibitory effect on the production of tumor necrosis factor (TNF) in cultivated whole blood (Cwb) following stimulation by PAMPs. We hypothesized that RES would inhibit TNF production in Cwb following stimulation by LPS or lipoteichoic acid (LTA). Production of TNF bioactivity in Cwb was measured in the presence of phosphate buffered saline (control), ethanol (solvent control), dexamethasone (anti inflammatory control), LPS, LTA, and three different concentrations of RES. Both LPS and LTA stimulated TNF production, and addition of dexamethasone was inhibitory to this effect. An anti-inflammatory effect for RES was not demonstrated under the current experimental conditions. Further studies are required to characterize the effect of RES on the equine innate immune system during systemic inflammation. PMID- 27234545 TI - Expression analysis of Sox9 genes during annual reproductive cycles in gonads and after nanodelivery of LHRH in Clarias batrachus. AB - Transcription factor Sox9 plays a crucial role in determining the fate of several cell types and is a primary factor in regulation of gonadal development. Present study reports full-length cDNA sequence of Sox9a gene and partial coding sequence (cds) of Sox9b (two duplicate orthologs of Sox9 gene) from Clarias batrachus. The coding region of Sox9a gene encoded a peptide of 460 amino acids. The partial cds of Sox9b with the length of 558bp was amplified that codes for 186 amino acids. Quantitative Real-time PCR (qRT-PCR) analysis revealed that Sox9a and Sox9b mRNA expression was significantly higher in gonads and brain tissues. Furthermore Sox9a and Sox9b mRNA expression levels were high during preparatory and pre spawning phases and decreased gradually with onset of spawning and post-spawning phases of reproductive cycles in gonads. Chitosan nanoconjugated sLHRH (CsLHRH) of particle size 133.0nm and zeta potential of 34.3mV were synthesized and evaluated against naked sLHRH (salmon luteinizing hormone-releasing hormone). The entrapment efficiency of CsLHRH was 63%. CsLHRH nanoparticles increased the expression level of Sox9 transcripts in gonads and steroid hormonal levels in blood of male and female. Thus, our findings clearly indicate that Sox9 genes play essential role during seasonal variation of gonads. Besides, the current study reports that sustained release delivery-system will be helpful for proper gonadal development of fish. To the best of our knowledge, till date no study has been reported on nanodelivery of sLHRH and their effect on reproductive gene expression in fish. PMID- 27234546 TI - Topical distribution of acyclovir in normal equine skin and equine sarcoids: An in vitro study. AB - Topical acyclovir application is an owner-friendly treatment for occult equine sarcoids, without the caustic side-effects other topical treatments have. Variable clinical success rates have been described, but it is not known to what rate and extent acyclovir penetrates in and through equine skin from a topical formulation. In the current study, an in vitro Franz diffusion model was used to determine the permeation parameters for a generic 5% acyclovir cetomacrogol cream for both healthy and sarcoid equine skin. The distribution of acyclovir between different layers of both skin types was also evaluated. While acyclovir penetrated through both skin types, significantly less acyclovir permeated to the deep dermis of sarcoid skin (197.62ng/mm(3)) compared to normal skin (459.41ng/mm(3)). Within sarcoid skin samples, significantly higher acyclovir concentrations were found in the epidermis (983.59ng/mm(3)) compared to the superficial dermis (450.02ng/mm(3)) and the deep dermis. At each sample point, significantly more acyclovir permeated to the receptor fluid through normal skin compared to sarcoid skin, which is reflected in the significantly higher permeation parameters of normal skin. Normal skin was found to be more permissive for acyclovir, but even in sarcoid skin, enough acyclovir reached the deep dermis to treat a Herpes simplex virus infection. In the case of equine sarcoids, the treatment is aimed at the Bovine papillomavirus and no information is available on the susceptibility of the DNA polymerase of this virus for acyclovir. Therefore, further research is needed to determine the efficacy of acyclovir to treat equine sarcoids. PMID- 27234547 TI - Neck Kaposiform haemangioendothelioma in a Fischer's lovebird (Agapornis fischeri). AB - A six-year-old female Fischer's lovebird (Agapornis fischeri) presented at necropsy with a cutaneous mass on the neck, 3.5cm in diameter, yielding and with blood content. Histopathological findings showed a neoplasm characterized by proliferation of vascular endothelial cells. The histology of the mass revealed a multinodular, focally infiltrating tumor. Deeper dermal nodules were made of spindle cells forming vascular slits reminiscent of the histology seen in Kaposi's sarcoma (KS). More superficially located dermal nodules consisted of small blood vessels, with histology resembling capillary hemangioma. The spindle cells and capillaries were strongly positive for Vimentin, endothelial cell marker CD31, and negative for sarcomeric alpha-smooth muscle actin (alpha-SMA). Intravascular platelet trapping and Periodic acid-Schiff (PAS)-positive hyaline globules were also observed. Differential diagnosis included Kaposi's sarcoma, capillary haemangioma, spindle cell haemangioendothelioma, and epithelioid haemangioendothelioma. Based on morphological and immunohistochemical findings, the tumor was diagnosed as a cutaneous Kaposiform haemangioendothelioma (KHE), a rare, low-grade malignant vascular neoplasm. Other organs showed no abnormalities. PCR amplifications, conducted using Kaposi's sarcoma-associated herpesvirus (KSHV)-specific primers and degenerate sets of primers designed to detect and characterize members of the Herpesviridae, on DNA extracted from tumor tissue and from whole blood failed to amplify any KSHV-related sequence. Moreover, no specific signal was obtained using primers for detection of psittacine herpesvirus, known to be linked to Pacheco's disease in parrots. To the best of our knowledge, this unusual case is the third report of KHE in a non human animal species, the first described in a bird. PMID- 27234548 TI - An outbreak of bovine tuberculosis in a fallow deer herd (Dama dama) in Sicily. AB - Wild ruminants have an important role in the epidemiology of bovine tuberculosis (bTB). This study describes an outbreak of bovine tuberculosis occurring in a fallow deer herd in Sicily. In 2012 a Sicilian herd of 47 animals was referred for cachexia. Pathological examination of 2 dead animals revealed disseminated granulomas predominantly involving the skin and subcutaneous tissues. Tissue samples were submitted for histological analysis, bacteriological culture, and biomolecular assay. PCR analysis identified Mycobacterium strains. Genotyping by spoligotyping and MIRU-VNTR profiles identified Mycobacterium bovis spoligotype SB0120 in both animals. In 2014, bTB skin testing of 28 fallow deer from the same group was positive in 4 and inconclusive in another 4. All 8 positive/inconclusive reactors were euthanized. Disseminated granulomatous lesions were noted in 6 of these animals, 3 of which (2 positive and 1 negative to skin tests) also presented cutaneous lesions. M. bovis spoligotype SB0120 was identified from all animals in which tuberculous-like lesions were observed, including 2 negative reactors. Many of the animals involved in this outbreak presented diffuse skin lesions, a potential route of transmission of M. bovis infection. Given the epidemiological role wildlife play in the maintenance of bTB infection and its potential risk for humans, a comprehensive monitoring plan for this zoonosis in wildlife species in Sicily is needed. PMID- 27234549 TI - HER-2, EGFR, Cox-2 and Ki67 expression in lymph node metastasis of canine mammary carcinomas: Association with clinical-pathological parameters and overall survival. AB - Studies about canine mammary tumors based on single molecular markers probably cannot accurately account for the heterogeneity of this disease, and the investigation of multiple molecular alterations in primary tumors and their metastases, in conjunction, has assumed great importance for the understanding of mammary tumor progression. In the present study, we selected 54 primary mammary carcinomas with lymph node metastasis (T1,2,3N1M0), 29 primary mammary carcinomas without metastasis (T1,2,3N0M0), and 25 canine lymph nodes metastasis to evaluate the immunohistochemical expression of HER-2, EGFR, Cox-2 and Ki67 and its association with clinical-pathological parameters and overall survival. Our results found a concordance between the expression of HER-2 (K coefficient: 0.250), Cox-2 (K coefficient: 0.571), and Ki67 (K coefficient: 0.397) and a discordance between EGFR expression (K coefficient: -0.195) in primary mammary carcinomas and paired lymph node metastasis. Furthermore, a high Ki67 index (>24%), large tumor size and the presence of angiolymphatic invasion in canine primary mammary carcinoma with lymph node metastasis plus the presence of extracapsular extension in lymph nodes metastasis were also related to worse prognoses and shorter overall survival (P<0.05). In conclusion, our study demonstrates that primary mammary carcinomas with high expression of HER-2, Cox-2 and Ki67 also show high expression of these markers in paired lymph node metastasis. Moreover, the expression of these molecular markers in lymph nodes metastasis did not demonstrate a prognostic relevance. PMID- 27234550 TI - Effect of Acarbose, Sitagliptin and combination therapy on blood glucose, insulin, and incretin hormone concentrations in experimentally induced postprandial hyperglycemia of healthy cats. AB - Acarbose (AC) and Sitagliptin (STGP) are oral hypoglycemic agents currently used either alone or in conjunction with human diabetic (Type 2) patients. AC has been used with diabetic cats, but not STGP thus far. Therefore, the objective of this study was to determine the potential use of AC or STGP alone and in combination for diabetic cats, by observing their effect on short-term post-prandial serum glucose, insulin, and incretin hormone (active glucagon-like peptide-1 (GLP-1) and total glucose dependent insulinotropic polypeptide (GIP)) concentrations in five healthy cats, following ingestion of a meal with maltose. All treatments tended (p<0.10; 5-7.5% reduction) to reduce postprandial glucose area under the curve (AUC), with an accompanying significant reduction (p<0.05, 35-45%) in postprandial insulin AUC as compared to no treatment. Meanwhile, a significant increase (p<0.05) in postprandial active GLP-1 AUC was observed with STGP (100% higher) and combined treatment (130% greater), as compared to either AC or no treatment. Lastly, a significant reduction (p<0.05) in postprandial total GIP AUC was observed with STGP (21% reduction) and combined treatment (7% reduction) as compared to control. Overall, AC, STGP, or combined treatment can significantly induce positive post-prandial changes to insulin and incretin hormone levels of healthy cats. Increasing active GLP-1 and reducing postprandial hyperglycemia appear to be the principal mechanisms of combined treatment. Considering the different, but complementary mechanisms of action by which AC and STGP induce lower glucose and insulin levels, combination therapy with both these agents offers great potential for treating diabetic cats in the future. PMID- 27234551 TI - Circulating immune complexes of calves with bronchopneumonia modulate the function of peripheral blood leukocytes: In vitro evaluation. AB - In this work we studied if circulating immune complexes (CIC) of calves with bronchopneumonia have the capacity to modulate function of peripheral blood leukocytes of healthy cattle. CIC of three month old calves (6 healthy and 6 diseased) were isolated by PEG precipitation. Peripheral blood mononuclear cells (MNCs) and granulocytes from healthy calves and cows were the CIC responder cells in in vitro tests. The most remarkable increase of adhesiveness to polystyrene and ROS synthesis (assessed by NBT test) was detected in cows' granulocytes stimulated with CIC of diseased calves. Results of MTT test showed that CIC of both healthy and diseased calves reduced granulocytes' viability. The strongest effect of inhibition of cows' granulocytes resulted from CIC of diseased calves. CIC only moderately reduced spontaneous viability of calves' MNCs. Again, the strongest effect of CIC isolated from diseased calves was observed. In contrast to the low impact of CIC on non-stimulated cells, their inhibitory effect on viability of mitogen stimulated MNCs was very strong. With CFSE assay we showed that both types of CIC stimulated spontaneous, but inhibited mitogen induced proliferation of calves' MNCs. Propidium iodide staining reviled that CIC increased apoptosis/necrosis of both non-stimulated and mitogen stimulated MNCs. CIC of both healthy and diseased calves modulated the function of peripheral blood MNCs and granulocytes, but a stronger effect of CIC of diseased calves was shown. The age of the donors (calves or cows) of the responder cells, and the activation state of these cells, were also of influence. PMID- 27234552 TI - Intraosseous stress distribution and bone interaction during load application across the canine elbow joint: A preliminary finite element analysis for determination of condylar fracture pathogenesis in immature and mature dogs. AB - Distal humeral fractures are common fractures especially in immature small breed dogs. The pathogenesis is still unknown. For this study, a three- dimensional bone model of the canine elbow was created and finite element analysis performed in order to determine the relationship between fracture type and bone interactions. Fused and non-fused humeral condyles were considered. A failure criterion was implemented to simulate the pathogenesis until fracture. Our study results confirm the clinical observation that lateral condylar fracture is the most common fracture type, implying interaction with the radius. Medial and Y fractures are less common and occur always in interaction with the ulna whereas the radius causes lateral condylar fracture. Additionally, the fracture type is sensitive to bone positioning during trauma. The pathogenesis of distal humeral fractures is more complex than generally reported in the literature. PMID- 27234553 TI - Effects of inactivated porcine epidemic diarrhea virus on porcine monocyte derived dendritic cells and intestinal dendritic cells. AB - Porcine epidemic diarrhea (PED) is a serious infection in neonatal piglets. As the causative agent of PED, porcine epidemic diarrhea virus (PEDV) results in acute diarrhea and dehydration with high mortality rates in swine. Dendritic cells (DCs) are highly effective antigen-presenting cells to uptake and present viral antigens to T cells, which then initiate a distinct immune response. In this study, our results show that the expression of Mo-DCs surface markers such as SWC3a(+)CD1a(+), SWC3a(+)CD80/86(+) and SWC3a(+)SLA-II-DR(+) is increased after incubation with UV-PEDV for 24h. Mo-DCs incubated with UV-PEDV produce higher levels of IL-12 and INF-gamma compared to mock-infected Mo-DCs. Interactions between Mo-DCs and UV-PEDV significantly stimulate T-cell proliferation in vitro. Consistent with these results, there is an enhancement in the ability of porcine intestinal DCs to activate T-cell proliferation in vivo. We conclude that UV-PEDV may be a useful and safe vaccine to trigger adaptive immunity. PMID- 27234554 TI - The antiviral activity of arctigenin in traditional Chinese medicine on porcine circovirus type 2. AB - Arctigenin (ACT) is a phenylpropanoid dibenzylbutyrolactone lignan extracted from the traditional herb Arctium lappa L. (Compositae) with anti-viral and anti inflammatory effects. Here, we investigated the antiviral activity of ACT found in traditional Chinese medicine on porcine circovirus type 2 (PCV2) in vitro and in vivo. Results showed that dosing of 15.6-62.5MUg/mL ACT could significantly inhibit the PCV2 proliferation in PK-15 cells (P<0.01). Dosing of 62.5MUg/mL ACT 0, 4 or 8h after challenge inoculation significantly inhibited the proliferation of 1MOI and 10MOI in PK-15 cells (P<0.01), and the inhibitory effect of ACT dosing 4h or 8h post-inoculation was greater than 0h after dosing (P<0.01). In vivo test with mice challenge against PCV2 infection demonstrated that intraperitoneal injection of 200MUg/kg ACT significantly inhibited PCV2 proliferation in the lungs, spleens and inguinal lymph nodes, with an effect similar to ribavirin, demonstrating the effectiveness of ACT as an antiviral agent against PCV2 in vitro and in vivo. This compound, therefore, may have the potential to serve as a drug for protection of pigs against the infection of PCV2. PMID- 27234555 TI - Construction and characterization of a full-length infectious cDNA clone of foot and-mouth disease virus strain O/JPN/2010 isolated in Japan in 2010. AB - A full-length infectious cDNA clone of the genome of a foot-and-mouth disease virus isolated from the 2010 epidemic in Japan was constructed and designated pSVL-f02. Transfection of Cos-7 or IBRS-2 cells with this clone allowed the recovery of infectious virus. The recovered virus had the same in vitro characterization as the parental virus with regard to antigenicity in neutralization and indirect immunofluorescence tests, plaque size and one-step growth. Pigs were experimentally infected with the parental virus or the recombinant virus recovered from pSVL-f02 transfected cells. There were no significant differences in clinical signs or antibody responses between the two groups, and virus isolation and viral RNA detection from clinical samples were similar. Virus recovered from transfected cells therefore retained the in vitro characteristics and the in vivo pathogenicity of their parental strain. This cDNA clone should be a valuable tool to analyze determinants of pathogenicity and mechanisms of virus replication, and to develop genetically engineered vaccines against foot-and-mouth disease virus. PMID- 27234556 TI - Cloning and characterization of giant panda (Ailuropoda melanoleuca) IL-18 binding protein. AB - The giant panda (Ailuropoda melanoleuca) is an endangered species. Interleukin-18 (IL-18) plays an important role in the innate and adaptive immune responses by inducing IFN-gamma. IL-18 has been implicated in the pathogenesis of various diseases. IL-18 binding protein (IL-18BP) is an intrinsic inhibitor of IL-18 that possesses higher affinity to IL-18. In this study, we cloned and characterized IL 18BP in giant panda (AmIL-18BP) from the spleen. The amino acid sequence of giant panda IL-18BP ORF shared about 65% identities with other species. To evaluate the effects of AmIL-18BP on the immune responses, we expressed the recombinant AmIL 18BP in Escherichia coli BL21 (DE3).The fusing protein PET-AmIL-18BP was purified by nickel affinity column chromatography. The biological function of purified PET AmIL-18BP was determined on mice splenocyte by qRT-PCR. The results showed that AmIL-18BP was functional and could significantly reduce IFN-gamma production in murine splenocytes. These results will facilitate the study of protecting giant panda on etiology and immunology. PMID- 27234557 TI - Paratuberculosis in sheep: Histochemical, immunohistochemical and in situ hybridization evidence of in utero and milk transmission. AB - To investigate in utero and milk transmission of Mycobacterium avium subsp. paratuberculosis (MAP), tissues from thirteen pregnant sheep, naturally infected and serologically positive to MAP, were examined by means of histochemistry, immunohistochemistry and in situ hybridization. Soon after parturition, ewes were euthanized and tissues samples were collected and prepared. The offspring (18 lambs) were divided into three groups to investigate different routes of MAP transmission. Lambs were sacrificed at three months old and the tissue samples collected, formalin-fixed and paraffin embedded. Hematoxylin and eosin and Ziehl Neelsen staining methods were performed on fixed tissues for general examination and for detection of acid-fast bacteria. Additionally, immunohistochemical and in situ hybridization techniques were used to detect MAP antigen and MAP DNA respectively. This study of a flock of MAP-infected sheep indicates both in utero and milk transmission of MAP from dams to their offspring. Importantly, this study detected the presence of MAP in the mammary gland and mammary lymph nodes of adult ewes therefore indicating a significant route for the potential exposure to humans from this bacterial infection. PMID- 27234558 TI - Antibodies reacting to carbonic anhydrase isozymes (I and II) and albumin in sera from dogs. AB - IgGs to carbonic anhydrase isozymes (CA-I and CA-II) and albumin were identified in dog serum. IgG titers were determined in the sera of asymptomatic dogs, and in dogs with atopic dermatitis, diarrhea and/or vomiting, diabetes and/or pancreatitis, kidney disease, hepatic disease, and thyroid gland disease, using ELISA. Low titres of IgG-reactive CA-I, CA-II, BSA, and CSA were found in the sera of healthy beagles. Compared with healthy beagles, there was a significant difference in the titers of antibodies against CA-I in asymptomatic dogs, dogs with diabetes and/or pancreatitis, or thyroid gland disease, or hepatic disease. Compared with healthy beagles, there was a significant difference in the antibody titer of anti-CA-II IgG in asymptomatic dogs and in those with hepatic disease. There was a significant difference in the antibody titer of anti-BSA IgG between healthy beagles and dogs with hepatic disease. PMID- 27234559 TI - Molecular genetics of the COL2A1-related disorders. AB - Type II collagen, comprised of three identical alpha-1(II) chains, is the major collagen synthesized by chondrocytes, and is found in articular cartilage, vitreous humour, inner ear and nucleus pulposus. Mutations in the collagen type II alpha-1 gene (COL2A1) have been reported to be responsible for a series of abnormalities, known as type II collagenopathies. To date, 16 definite disorders, inherited in an autosomal dominant or recessive pattern, have been described to be associated with the COL2A1 mutations, and at least 405 mutations ranging from point mutations to complex rearrangements have been reported, though the underlying pathogenesis remains unclear. Significant clinical heterogeneity has been reported in COL2A1-associated type II collagenopathies. In this review, we highlight current knowledge of known mutations in the COL2A1 gene for these disorders, as well as genetic animal models related to the COL2A1 gene, which may help us understand the nature of complex phenotypes and underlying pathogenesis of these conditions. PMID- 27234560 TI - Biomonitoring of genotoxic effects for human exposure to nanomaterials: The challenge ahead. AB - Exposures to nanomaterials (NMs), with their specific physico-chemical characteristics, are likely to increase over the next years, as their production for industrial, consumer and medical applications is steadily rising. Therefore, there is an urgent need for the implementation of human biomonitoring studies of genotoxic effects after NM exposures in order to monitor and assure safety for workers and the general population. In this review, most commonly used biomarkers of early genetic effects were analyzed for their adequacy after NM exposures. A more in depth analysis of the ex vivo/in vitro lymphocyte MN assay was performed, although, in literature no studies are available using this assay for NM exposures. Therefore, the known factors determining the NMs tissue/cellular targets and the multiplicity of modes of action of NMs were summarized. The main pending questions are whether (1) lymphocytes are a NM target or an adequate surrogate tissue, (2) whether the buccal MN assay might be more suitable for NM exposures via inhalation or ingestion, as buccal cells might be exposed more directly. While the current state-of-the-art does not allow for drawing firm conclusions, major research gaps are identified and some cautious recommendations can be formulated. Therefore in vitro and in vivo studies should be conducted comparing methodologies side-by-side in the same subjects and for different types of NMs. The ex vivo/in vitro MN assay in its automated version, allowing objective analysis of large cohorts and detection of direct and indirect genotoxic effects, remains a valuable candidate for human biomonitoring to NM exposure. Considering the potential cancer risk from exposure to NMs and previous dramatic experiences with too late surveillance of occupational exposures to similar substances (e.g. to asbestos), there is an urgent need to define and implement adequate scientifically sound biomonitoring methods and programme for exposure to NMs. PMID- 27234562 TI - The many faces of histone H3K79 methylation. AB - Dot1/DOT1L (disruptor of telomeric silencing-1) is an evolutionarily conserved histone methyltransferase that methylates lysine 79 located within the globular domain of histone H3. Dot1 was initially identified by a genetic screen as a disruptor of telomeric silencing in Saccharomyces cerevisiae; further, it is the only known non-SET domain containing histone methyltransferase. Methylation of H3K79 is involved in the regulation of telomeric silencing, cellular development, cell-cycle checkpoint, DNA repair, and regulation of transcription. hDot1L mediated H3K79 methylation appears to have a crucial role in transformation as well as disease progression in leukemias involving several oncogenic fusion proteins. This review summarizes the multiple functions of Dot1/hDOT1L in a range of cellular processes. PMID- 27234561 TI - Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: A systematic literature review. AB - Accumulating evidence suggests that epigenetic alterations play an important role in chemically-induced carcinogenesis. Although the epigenome and genome may be equally important in carcinogenicity, the genotoxicity of chemical agents and exposure-related transcriptomic responses have been more thoroughly studied and characterized. To better understand the evidence for epigenetic alterations of human carcinogens, and the potential association with genotoxic endpoints, we conducted a systematic review of published studies of genotoxic carcinogens that reported epigenetic endpoints. Specifically, we searched for publications reporting epigenetic effects for the 28 agents and occupations included in Monograph Volume 100F of the International Agency for the Research on Cancer (IARC) that were classified as "carcinogenic to humans" (Group 1) with strong evidence of genotoxic mechanisms of carcinogenesis. We identified a total of 158 studies that evaluated epigenetic alterations for 12 of these 28 carcinogenic agents and occupations (1,3-butadiene, 4-aminobiphenyl, aflatoxins, benzene, benzidine, benzo[a]pyrene, coke production, formaldehyde, occupational exposure as a painter, sulfur mustard, and vinyl chloride). Aberrant DNA methylation was most commonly studied, followed by altered expression of non-coding RNAs and histone changes (totaling 85, 59 and 25 studies, respectively). For 3 carcinogens (aflatoxins, benzene and benzo[a]pyrene), 10 or more studies reported epigenetic effects. However, epigenetic studies were sparse for the remaining 9 carcinogens; for 4 agents, only 1 or 2 published reports were identified. While further research is needed to better identify carcinogenesis-associated epigenetic perturbations for many potential carcinogens, published reports on specific epigenetic endpoints can be systematically identified and increasingly incorporated in cancer hazard assessments. PMID- 27234563 TI - Mechanisms of mutagenesis: DNA replication in the presence of DNA damage. AB - Environmental mutagens cause DNA damage that disturbs replication and produces mutations, leading to cancer and other diseases. We discuss mechanisms of mutagenesis resulting from DNA damage, from the level of DNA replication by a single polymerase to the complex DNA replisome of some typical model organisms (including bacteriophage T7, T4, Sulfolobus solfataricus, Escherichia coli, yeast and human). For a single DNA polymerase, DNA damage can affect replication in three major ways: reducing replication fidelity, causing frameshift mutations, and blocking replication. For the DNA replisome, protein interactions and the functions of accessory proteins can yield rather different results even with a single DNA polymerase. The mechanism of mutation during replication performed by the DNA replisome is a long-standing question. Using new methods and techniques, the replisomes of certain organisms and human cell extracts can now be investigated with regard to the bypass of DNA damage. In this review, we consider the molecular mechanism of mutagenesis resulting from DNA damage in replication at the levels of single DNA polymerases and complex DNA replisomes, including translesion DNA synthesis. PMID- 27234565 TI - Y chromosome b2/b3 deletions and male infertility: A comprehensive meta-analysis, trial sequential analysis and systematic review. AB - The correlation of Y-chromosome b2/b3 partial deletions with spermatogenic failure remains dubious. We undertook a systematic review of the literature followed by meta-analyses and trial sequential analyses in order to compare the frequency of b2/b3 deletions between oligo/azoospermic infertile and normozoospermicmen. Out of twenty-four studies reviewed for meta-analysis, twenty reported no correlation between this deletion and male infertility and two studies each reported a direct and inverse correlation. In the collective analysis, 241 out of 8892 (2.71%) oligo/azoospermic individuals and 118 out of 5842 (2.02%) normozoospermic controls had a b2/b3 deletion, suggesting a relatively higher frequency of deletions in the cases. Eventually, meta-analysis showed a significant correlation between b2/b3 deletions and the risk of spermatogenic loss/infertility (Fixed model: OR=1.313, 95% CI=1.04-1.65, p=0.02; Random model: OR=1.315, 95% CI=1.02-1.70, p=0.037). Further meta-analysis on studies grouped by ethnicity and geographic regions showed that the b2/b3 deletions are significantly associated with spermatogenic loss/infertility in Mongolians, Nigro-Caucasians, East Asians and Africans, but not in Caucasians, Europeans, South Asians and Dravidians. In summary, the Y-chromosome b2/b3 deletions increase infertility risk; however, it may be significant only in the Mongolian populations and the East Asian region. PMID- 27234564 TI - Role of nucleotide excision repair proteins in response to DNA damage induced by topoisomerase II inhibitors. AB - In cancer treatment, chemotherapy is one of the main strategies used. The knowledge of the cellular and molecular characteristics of tumors allows the use of more specific drugs, making the removal of tumors more efficient. Among the drugs of choice in these treatments, topoisomerase inhibitors are widely used against different types of tumors. Topoisomerases are enzymes responsible for maintaining the structure of DNA, altering its topological state temporarily during the processes of replication and transcription, in order to avoid supercoiling and entanglements at the double helix. The DNA damage formed as a result of topoisomerase inhibition can be repaired by DNA repair mechanisms. Thus, DNA repair pathways can modulate the effectiveness of chemotherapy. Homologous recombination (HR) and non-homologous end joining (NHEJ) are the main pathways involved in the removal of double strand breaks (DSBs); while nucleotide excision repair (NER) is mainly characterized by the removal of lesions that lead to significant structural distortions in the DNA double helix. Evidence has shown that DSBs are the main type of damage resulting from the inhibition of the DNA topoisomerase II enzyme, and therefore the involvement of HR and NHEJ pathways in the repair process is well established. However, some topoisomerase II inhibitors induce other types of lesions, like DNA adducts, interstrand crosslinks and reactive oxygen species, and studies have shown that other DNA repair pathways might be participating in removing injury induced by these drugs. This review aims to correlate the involvement of proteins from different DNA repair pathways in response to these drugs, with an emphasis on NER. PMID- 27234566 TI - Prognostic impact of high levels of circulating plasmacytoid dendritic cells in breast cancer. AB - BACKGROUND: Identifying immune markers in blood that are informative for breast cancer patient survival would not only be useful for prognosis but might also provide mechanistic insights into processes facilitating survival. METHODS: We phenotyped circulating plasmacytoid dendritic cells (pDCs), myeloid-derived suppressor cells (MDSCs) and regulatory T-cells in relation to T-cell responses to Her-2 in vitro in 75 untreated breast cancer patients 28-87 years of age at diagnosis. RESULTS: Patients with later stage tumors had lower levels of circulating pDCs (p = 0.008). There was a positive association between 5-year survival and higher than median levels of circulating pDCs (p = 0.03). We confirmed that 5-year survival correlated with CD8+ but not CD4+ T-cell responsiveness to Her-2 peptides in this cohort of younger and older patients (p = 0.04). Including pDCs in the analysis of previously-established parameters revealed that patients who had a CD8+ T-cell response to Her-2 together with a low ratio of MDSCs:pDCs had 100 % 5-year survival. High levels of pDCs and the presence of a CD8+ T-cell response to Her-2 were independent positive survival indicators according to multivariate Cox analysis. CONCLUSIONS: Our new results suggest that circulating pDCs could be a positive prognostic indicator in breast cancer patients of all ages, together with the previously established CD8+ T-cell reactivity to Her-2 antigens in older patients only. These two prognostic indicators were independent and emphasize the important role of immunity in ensuring breast cancer patient survival, even in those not undergoing immunotherapy. PMID- 27234568 TI - Regenerative medicine in kidney disease. AB - The treatment of renal failure has changed little in decades. Organ transplantation and dialysis continue to represent the only therapeutic options available. However, decades of fundamental research into the response of the kidney to acute injury and the processes driving progression to chronic kidney disease are beginning to open doors to new options. Similarly, continued investigations into the cellular and molecular basis of normal kidney development, together with major advances in stem cell biology, are now delivering options in regenerative medicine not possible as recently as a decade ago. In this review, we will discuss advances in regenerative medicine as it may be applied to the kidney. This will cover cellular therapies focused on ameliorating injury and improving repair as well as advancements in the generation of new renal tissue from stem/progenitor cells. PMID- 27234567 TI - Chromosome 17q12 microdeletions but not intragenic HNF1B mutations link developmental kidney disease and psychiatric disorder. AB - Heterozygous mutations of the HNF1B gene are the commonest known monogenic cause of developmental kidney disease. Half of patients have a deletion (approximately 1.3 Mb) of chromosome 17q12, encompassing HNF1B plus 14 additional genes. This 17q12 deletion has been linked with an increased risk of neurodevelopmental disorders, such as autism. Here we compared the neurodevelopmental phenotype of 38 patients with HNF1B-associated renal disease due to an intragenic mutation in 18 patients or due to 17q12 deletion in 20 patients to determine whether haploinsufficiency of HNF1B is responsible for the neurodevelopmental phenotype. Significantly, brief behavioral screening in children with the deletion showed high levels of psychopathology and its impact. Eight individuals (40%) with a deletion had a clinical diagnosis of a neurodevelopmental disorder compared to none with an intragenic mutation. The 17q12 deletions were also associated with more autistic traits. Two independent clinical geneticists were able to predict the presence of a deletion with a sensitivity of 83% and specificity of 79% when assessing facial dysmorphic features as a whole. Thus, the 17q12 deletions but not HNF1B intragenic mutations are associated with neurodevelopmental disorders. Hence, the HNF1B gene is not involved in the neurodevelopmental phenotype of these patients. Nephrologists need to be aware of this association to ensure appropriate referral to psychiatric services. PMID- 27234570 TI - The subtle art of compromise and reconciliation: a tale from Lower Dir. PMID- 27234569 TI - Take A Breath: study protocol for a randomized controlled trial of an online group intervention to reduce traumatic stress in parents of children with a life threatening illness or injury. AB - BACKGROUND: A substantial proportion of parents whose child is diagnosed with a life-threatening illness, experience high levels of distress that can lead to long-term difficulties in mental health, family functioning and child adjustment. This study evaluates the efficacy of an Acceptance Commitment Therapy-based group intervention designed to reduce distress symptoms in these parents. The program is delivered using videoconferencing to overcome factors that prevent participation in traditional face-to-face therapy. METHOD/DESIGN: The study is a randomized control trial of the Take A Breath group intervention for parents demonstrating elevated symptoms of acute stress, delivered via videoconferencing in six 90 min group sessions. Participants are the primary caregivers of children aged 0 to 18 years admitted for a life threatening illness or injury to the Oncology, Cardiology, Neurology or Intensive Care Departments of a tertiary pediatric hospital. Parents will be randomized to intervention or waitlist control 4-10 months after their child's diagnosis. Measures will be collected prior to and immediately post intervention for intervention and waitlist parents to assess program efficacy. Intervention parents will be followed up at 6 months to assess the maintenance of program effects. We predict that intervention parents will show fewer symptoms post intervention than waitlist parents (primary outcomes: traumatic stress, depression, anxiety, stress symptoms), reflecting improvements in the psychological skills addressed in the intervention (mediating factors). It is anticipated that reductions in mental health difficulties for intervention parents will be maintained up to 6 months post-intervention and will be associated with broader improvements in parents' adjustment, child adjustment and child wellbeing (secondary outcomes). DISCUSSION: This study is unique in evaluating a group intervention delivered to parents of children affected by of a diverse range life-threatening illness or injury. Online communication technology is employed to reduce participation barriers. If proven efficacious, this trans diagnostic approach offers the potential for broad use as part of the suite of psychosocial services provided to families through tertiary pediatric settings. TRIAL REGISTRATION: ACTRN12611000090910 . Trial Registration Date: 14/09/2011 Protocol Date/version: September 2015, version M Study Status: Ongoing. PMID- 27234571 TI - Correction of ankle valgus by hemiepiphysiodesis using the tension band principle in patients with multiple hereditary exostosis. AB - BACKGROUND: Ankle valgus is a common deformity in patients with multiple hereditary exostoses (MHE) and a potential risk factor for early degenerative arthritis. In children, medial hemiepiphysiodesis of the distal tibia is a relatively simple surgical technique used to correct this deformity. We present here the first results of applying this procedure using the eight-Plate guided growth system (eight-Plate) for growth guidance. METHODS: Between 2006 and 2011 we performed hemiepiphysiodesis of the distal medial tibia in 30 ankles of 18 children with MHE using the eight-Plate. Weight-bearing total leg radiographs were obtained preoperatively, during follow-up and at the time of implant removal or when the distal tibial physis had closed. The lateral distal tibia angle (LDTA) was measured and fibular shortening assessed using the Malhotra classification. To evaluate the effect of hemiepiphysiodesis, we correlated the LDTA with age. RESULTS: The mean age at time of surgery was 12.6 (range 9.5-15.0) years, and the mean preoperative LDTA was 76.9 degrees (range 68.5 degrees -83.5 degrees ). During follow-up, the implant was removed in 12 extremities and the physis had closed in 18 extremities. The mean LDTA at the time of implant removal or at closure of the physis was 83.6 degrees (range 76.5 degrees -90.0 degrees ). Mean correction of LDTA was 6.9 degrees after a mean follow-up period of 22 (range 3-43) months. During follow-up, no changes in the Malhotra classification were found in any of the patients. Correction of the valgus deformity of the ankle was significantly correlated (r = -0.506) (p = 0.004) with age in all patients. CONCLUSION: Temporary medial hemiepiphyseodesis of the distal tibia seems to be an effective strategy for correcting ankle valgus in children with MHE. Timing of the intervention is, however, of importance. Hemiepiphyseodesis alone has no effect on the Malhotra classification. LEVEL OF EVIDENCE: IV, retrospective review. PMID- 27234572 TI - Delineating pathological pathways in a chemically induced mouse model of Gaucher disease. AB - Great interest has been shown in understanding the pathology of Gaucher disease (GD) due to the recently discovered genetic relationship with Parkinson's disease. For such studies, suitable animal models of GD are required. Chemical induction of GD by inhibition of acid beta-glucosidase (GCase) using the irreversible inhibitor conduritol B-epoxide (CBE) is particularly attractive, although few systematic studies examining the effect of CBE on the development of symptoms associated with neurological forms of GD have been performed. We now demonstrate a correlation between the amount of CBE injected into mice and levels of accumulation of the GD substrates, glucosylceramide and glucosylsphingosine, and show that disease pathology, indicated by altered levels of pathological markers, depends on both the levels of accumulated lipids and the time at which their accumulation begins. Gene array analysis shows a remarkable similarity in the gene expression profiles of CBE-treated mice and a genetic GD mouse model, the Gba(flox/flox) ;nestin-Cre mouse, with 120 of the 144 genes up-regulated in CBE-treated mice also up-regulated in Gba(flox/flox) ;nestin-Cre mice. We also demonstrate that various aspects of neuropathology and some behavioural abnormalities can be arrested upon cessation of CBE treatment during a specific time window. Together, our data demonstrate that injection of mice with CBE provides a rapid and relatively easy way to induce symptoms typical of neuronal forms of GD. This is particularly useful when examining the role of specific biochemical pathways in GD pathology, since CBE can be injected into mice defective in components of putative pathological pathways, alleviating the need for time-consuming crossing of mice. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 27234573 TI - Digital Drainage System Reduces Hospitalization After Video-Assisted Thoracoscopic Surgery Lung Resection. AB - BACKGROUND: The purpose of this study was to assess the efficacy of a digital versus traditional drainage system on hospitalization for patients undergoing video-assisted thoracoscopic surgery (VATS) anatomic lung resection. METHODS: Consecutive patients who underwent VATS anatomic lung resection (July 2014 through January 2015) for lung cancer were analyzed. Patients were managed with overnight suction (-20 cm H2O) followed by gravity drainage (water seal or -8 cm H2O) in both the traditional and digital drainage systems, respectively; the digital system also allowed for continuous monitoring of air leaks. Chest tubes were removed when the air leak was absent for 12 hours and pleural drainage was less than 300 mL/24 h; patient outcomes selected by propensity matching were compared. RESULTS: The VATS lung resections (lobectomy or segmentectomy) were performed in 108 patients during the 7-month study period. The pleural cavity was drained with the traditional system in 75 patients and with the digital system in 33 patients. By propensity score matching at a 2:1 ratio, 40 patients were placed in the traditional group and 20 patients, in the digital group for analysis. Demographics, percent predicted forced expiratory volume in 1 second, tumor size, stage, and type of resection were similar between the groups. The majority of patients (85%) underwent a lobectomy. There were no operative deaths. Overall complications were fewer in the digital system group (22%) compared with the traditional system group (35%; p = 0.01). Median air leak days (-1.1), chest tube days (-1.6), and total hospital stay (-1.5) were significantly reduced in the digital drainage system group. CONCLUSIONS: Patients undergoing VATS lung resections who were managed postoperatively with a digital drainage system experienced less morbidity and decreased hospitalization. A digital drainage system appears to be a safe alternative for management of the pleural cavity after VATS anatomic lung resection. PMID- 27234574 TI - Incidence and Predictors for Postoperative Thrombotic Complications in Children With Surgical and Nonsurgical Heart Disease. AB - BACKGROUND: Children with congenital heart disease are at increased risk of thrombotic complications (thrombosis and thromboembolism). This study sought to assess the incidence and predictors of thrombotic complications in children with surgical and nonsurgical heart diseases. METHODS: We performed a retrospective analysis of the Health Care Cost and Use Project Kid's Inpatient Database. Children with surgical and nonsurgical heart diseases were categorized into the following four subgroups: (1) septal defects, (2) single ventricle physiology, (3) right ventricle outflow tract obstruction, and (4) left ventricle outflow tract obstruction. Demographic information, comorbidities, and outcomes, such as mortality, acute kidney injury, sepsis, neurologic complications, thrombotic complications, extracorporeal membrane oxygenation, and ventricular assist device use, were identified. We used propensity-matched analysis and multivariate logistic regression analysis to determine the variables associated with thrombotic complications. RESULTS: After propensity-matched analysis, the incidence of thrombotic complications was 3.90% (947/24,251) in children with surgical and 2.13% (516/24,251) in children with nonsurgical heart disease (p < 0.001). Multivariate logistic regression analysis revealed that single ventricle physiology or right ventricle outflow tract obstruction, extracorporeal membrane oxygenation, ventricular assist device, acute kidney injury, sepsis, and the presence of a coagulopathy increased the risk of thrombotic complications in children with surgical or nonsurgical heart disease. Age younger than 1 year increased the risk of thrombotic complications in the surgical population, whereas age older than 12 years increased the risk in the nonsurgical population. CONCLUSIONS: Children with both surgical and nonsurgical heart disease have increased risk of thrombotic complications. The risk is increased in patients with cyanotic heart disease and is highest in the presence of single ventricle physiology. PMID- 27234575 TI - Cost Analysis of Physician Assistant Home Visit Program to Reduce Readmissions After Cardiac Surgery. AB - BACKGROUND: A physician assistant home care (PAHC) program providing house calls was initiated to reduce hospital readmissions after adult cardiac surgery. The purpose of our study was to compare 30-day PAHC and pre-PAHC readmission rate, length of stay, and cost. METHODS: Patients who underwent adult cardiac surgery in the 48 months from September 2008 through August 2012 were retrospectively reviewed using pre-PAHC patients as the control group. Readmission rate, length of stay, and health care cost, as measured by hospital billing, were compared between groups matched with propensity score. RESULTS: Of the 1,185 patients who were discharged directly home, 155 (13%) were readmitted. Total readmissions for the control group (n = 648) was 101 patients (16%) compared with the PAHC group (n = 537) total readmissions of 54 (10%), a 38% reduction in the rate of readmission (p = 0.0049). Propensity score matched groups showed a rate reduction of 41% with 17% (62 of 363) for the control compared with 10% (37 of 363) for the PAHC group (p = 0.0061). The average hospital bill per readmission was $39,100 for the control group and $56,600 for the PAHC group (p = 0.0547). The cost of providing home visits was $25,300 for 363 propensity score matched patients. CONCLUSIONS: The PAHC program reduced the 30-day readmission rate by 41% for propensity score matched patients. Analysis demonstrated a savings of $977,500 at a cost of $25,300 over 2 years, or $39 in health care saved, in terms of hospital billing, for every $1 spent. Therefore, a home visit by a cardiac surgical physician assistant is a cost-effective strategy to reduce readmissions after cardiac surgery. PMID- 27234576 TI - Unbiased Profile of MicroRNA Expression in Ascending Aortic Aneurysm Tissue Appoints Molecular Pathways Contributing to the Pathology. AB - BACKGROUND: Complex etiopathogenesis of ascending aortic aneurysm suggests contribution of epigenetic mechanisms in its development. Several studies appointed microRNAs (miRs) as essential epigenetic factors in various human diseases; however, little is known about their role in ascending aortic aneurysm. Therefore, the aim of this study was to perform unbiased molecular screening of miRs expression in aneurysmal tissue and establish their functions on a transcriptional level. METHODS: Samples of ascending aortic tissue were obtained from 15 patients, and total RNA was isolated separately from aneurysmal and unaffected aortic tissue obtained from the same patient. Expression of the complete panel of human miRs was assessed by quantitative real-time polymerase chain reaction. Using bioinformatic tools, 13 genes were selected that were putatively regulated by overexpressed miRs. Expression level of transcripts were evaluated by quantitative real-time polymerase chain reaction and correlated with their targeting miRs. RESULTS: Overexpression of 10 miRs distinguished aneurysmal tissue from the unchanged one. These miRs were involved in cell senescence (miR 191-5p), maintenance of vascular integrity (miR-126-3p and miR-374-5p), nitric oxide-dependent vascular relaxation (miR-21-5p), smooth muscle differentiation, and contractility (miR-145- 3p, miR-29c-3p, miR-133a-3p, miR-186-5p, miR-143-3p, and miR-24-3p), and correlated with abundance of its miR targets. CONCLUSIONS: Altered expression of particular miRs selectively in the affected tissue indicate their role as factors that trigger pathways of aneurysmal transformation. Limited reparative properties due to overexpression of miR-191 may play a crucial role for aneurysm enlargement, whereas nitric oxide-dependent relaxation of vascular smooth muscle mediated by miR-21 offers an attractive explanation of the aneurysm's initiation, and is confirmed in experimental conditions. PMID- 27234577 TI - Early and Late Outcomes of Thoracic Aortic Surgery in Hemodialysis Patients. AB - BACKGROUND: The number of cardiovascular surgeries among hemodialysis patients is increasing according to the growing population of hemodialysis patients; however, the clinical outcome has not yet been clarified, especially in thoracic aortic surgery. The purpose of this study was to assess the early and late outcomes of thoracic aortic surgery in hemodialysis patients. METHODS: We retrospectively analyzed the outcomes of 700 consecutive open thoracic aortic surgeries from 2002 to 2014. We identified 21 patients receiving preoperative hemodialysis (group HD) and 679 patients not receiving preoperative hemodialysis (group N). The patients were predominantly male, had diabetes mellitus and cardiogenic shock, and had less hyperlipidemia and elective surgery in group HD. The early and late outcomes were compared between 21 patients in each group using a propensity-score matched analysis. RESULTS: The hospital stay and intensive care unit stay were significantly longer in group HD even after matching. The 30-day mortality and inhospital mortality showed no significant differences, whereas the rate of postoperative pneumonia was significantly higher in group HD compared with the matched group N (p = 0.0067). The 1-year, 3-year, and 7-year survival rates in group HD were 73.4%, 45.7%, and 30.5%, respectively, which were significantly poorer than that of group N both in the prematched (p < 0.001) and matched analyses (p = 0.0027). CONCLUSIONS: Considering the various operative risks associated with hemodialysis patients, the early mortality rate is acceptable, even after the association with many respiratory complications. Although hemodialysis patients have a compromised prognosis after surgery, excessive hesitation to perform thoracic aortic surgery may be avoided. PMID- 27234578 TI - Undersized Rigid Nonplanar Annuloplasty: The Key to Effective and Durable Repair of Functional Tricuspid Regurgitation. AB - BACKGROUND: Previous clinical experiences have demonstrated high early and late recurrence rates after repair of functional tricuspid regurgitation (TR). We investigated the results of functional TR repair with undersized rigid nonplanar annuloplasty rings. METHODS: From January 2007 to December 2013, 216 consecutive patients with moderate or greater functional TR were treated with undersized (size 26 mm or 28 mm) rigid nonplanar annuloplasty rings. RESULTS: The mean age was 69 +/- 13 years. There was a previous history of cardiac operation in 25% (54 of 216 patients). Tricuspid regurgitation was graded as severe in 47% (102 of 216) and moderate in 53% (114 of 216). Concomitant operations included mitral valve procedures in 92% (198 of 216), coronary artery bypass grafting in 21% (45 of 216), aortic valve procedures in 9% (20 of 216), and cryomaze procedures in 35% (76 of 216). Size 26 mm rings were used in 38% of patients (81 of 216), and size 28 mm in 62% (135 of 216). The perioperative mortality rate was 6% (14 of 216). On predischarge echocardiography, TR grade was none or mild in 94% (176 of 187 patients), moderate in 4% (7 of 187), and severe in 2% (4 of 187). At a mean follow-up of 33.0 +/- 24.0 months, TR grade was none or mild in 81% of patients (130 of 160), moderate in 16% (26 of 160), and severe in 2% (4 of 160). There were no reoperations for recurrent TR, and no patients have had tricuspid stenosis or annuloplasty ring dehiscence. CONCLUSIONS: Treatment of functional TR with undersized (26 mm or 28 mm) nonplanar rigid annuloplasty rings is safe and highly effective, with a near absence of recurrent severe TR at midterm follow up. PMID- 27234579 TI - Outcomes of Major Lung Resection After Induction Therapy for Non-Small Cell Lung Cancer in Elderly Patients. AB - BACKGROUND: This study analyzes the impact of age on perioperative outcomes and long-term survival of patients undergoing surgery after induction chemotherapy for non-small cell lung cancer. METHODS: Short- and long-term outcomes of patients with non-small cell lung cancer who were at least 70 years and received induction chemotherapy followed by major lung resection (lobectomy or pneumonectomy) from 1996 to 2012 were assessed using multivariable logistic regression, Kaplan-Meier, and Cox proportional hazard analysis. The outcomes of these elderly patients were compared with those of patients younger than 70 years who underwent the same treatment from 1996 to 2012. RESULTS: Of the 317 patients who met the study criteria, 53 patients were at least 70 years. The median age was 74 years (range, 70 to 82 years) in the elderly group, and induction chemoradiation was used in 24 (45%) patients. Thirty-day mortality was similar between the younger (n = 12) and elderly (n = 3) patients (5% versus 6%; p = 0.52). There were no significant differences in the incidence of postoperative complications between younger and elderly patients (49% versus 57%; p = 0.30). Patients younger than 70 years had a median overall survival (30 months; 95% confidence interval [CI], 24 to 43) and a 5-year survival (39%; 95% CI, 33 to 45) that was not significantly different from patients at least 70 years (median overall survival, 30 months; 95% CI, 18 to 68; and 5-year overall survival, 36%; 95% CI, 21 to 51). However, there was a trend toward worse survival in the elderly group after multivariable adjustment (hazard ratio, 1.43; 95% CI, 0.97 to 2.12; p = 0.071). CONCLUSIONS: Major lung resection after induction chemotherapy can be performed with acceptable short- and long-term results in appropriately selected patients at least 70 years, with outcomes that are comparable to those of younger patients. PMID- 27234580 TI - Robotic Thymectomy in Anterior Mediastinal Mass: Propensity Score Matching Study With Transsternal Thymectomy. AB - BACKGROUND: Robot-assisted thymectomy (RT) has been increasingly performed for treating anterior mediastinal masses. The aim of this study was to compare the early and long-term outcomes between RT and transsternal thymectomy (ST). METHODS: A total of 429 patients who underwent surgical resection of anterior mediastinal masses were included in this study. RT was performed in 117 patients (27%). Propensity score matching was performed between RT and ST, and 100 patients were selected for each group. RESULTS: RT and ST were performed for anterior mediastinal masses, including thymic epithelial tumor and mediastinal cysts. Thymic epithelial tumor was the most common type of tumor, and distribution of pathologic stages was not significantly different between RT and ST (41% versus 39% in stage I, 46% versus 50% in stage II, 9% versus 5% in stage III, and 4% versus 5% in stage IV, p = 0.96). The RT group had significantly less intraoperative blood loss (100.9 +/- 105.4 mL versus 354.5 +/- 412.4 mL, p < 0.001), lower incidence of postoperative complication (1% versus 12%, p = 0.002), and shorter length of postoperative hospital stay (2.5 +/- 1.2 days versus 6.4 +/ 6.6 days, p < 0.001) compared with the ST group. Three-year overall survival rates and freedom from recurrence were not significantly different (100% versus 100%; p = 0.88 and 92% versus 99%, p = 0.12) between RT and ST. CONCLUSIONS: RT demonstrated excellent early outcomes compared with ST, and RT could also achieve comparable long-term oncologic outcomes with ST in thymic epithelial tumor. Therefore, RT should be considered as an alternative surgical option for treating anterior mediastinal masses. PMID- 27234581 TI - Is the Risk of Wound Infection Related to Bilateral Internal Thoracic Artery Graft Potentiated by Age? AB - BACKGROUND: Older age and the use of bilateral internal thoracic artery (ITA) grafting are both considered risk factors for surgical wound infection (SWI) after coronary artery bypass grafting (CABG). The 2014 European Guidelines recommend that bilateral ITA grafting should be considered in patients aged younger than 70 years. Our aim was to investigate interaction between age and the number of ITA grafts. METHODS: All patients aged 18 years and older who had undergone CABG with at least 1 ITA at Rouen University Hospital between 2001 and 2012 were selected. Data regarding surgical procedure (single/bilateral ITA grafting) were extracted from the medical information system. SWI was identified from prospective surveillance of patients according to Centers for Disease Control and Prevention criteria. Independent factors associated with SWI were assessed by logistic regression, and an interaction test between age (<=69 or >=70 years) and the number of ITA grafts was performed. RESULTS: SWI occurred in 71 of 2,726 patients (2.6%). Bilateral ITA grafting was associated with SWI (adjusted odds ratio [aOR], 2.55; 95% confidence interval, 1.51 to 4.30). After fitting an interaction term between age and number of ITA grafts, the aORs for SWI after bilateral ITA grafting substantially differed between patients aged 69 years and younger (aOR, 1.88; 95% confidence interval, 0.94 to 3.75) and 70 years and older (aOR, 3.52; 95% confidence interval, 1.69 to 7.33). However, this interaction failed to reach statistical significance (p = 0.2213), possibly because of insufficient statistical power (23.5%) despite the large sample size. CONCLUSIONS: Age 70 years and older compared with age 69 years and younger was associated with higher occurrence of SWI after bilateral ITA grafting, but this interaction was not statistically significant. Larger studies are needed to test this interaction. PMID- 27234582 TI - Hepatocellular carcinoma incidentally detected at second hepatectomy for repeated colorectal liver metastasis in a patient with hepatitis C virus-related cirrhosis: a case report. AB - BACKGROUND: It has been reported that liver metastasis rarely occurs in a cirrhotic/hepatitic liver. Thus, coexistence of liver metastasis and hepatocellular carcinoma has been scarcely reported. To the best of our knowledge, there are no cases with hepatocellular carcinoma, which developed during an observational period after hepatectomy for colorectal liver metastasis, in the worldwide English literature. Here we present a case of hepatocellular carcinoma which occurred during a period between the first and second hepatectomy for repeated colorectal liver metastasis. CASE PRESENTATION: A 65-year-old Japanese woman underwent rectal resection for advanced rectal cancer. Hepatitis C cirrhosis was diagnosed at that time and antiviral therapy was offered but rejected because of socioeconomic reasons. At the age of 68, she developed two colorectal liver metastases originating from the rectal cancer, which were treated by local ablation and partial hepatectomy. At the age of 71, solitary recurrent colorectal liver metastasis was observed adjacent to the previously ablated lesion in segment 4, and thus segmentectomy 4 was performed. During surgery, a small tumor in segment 8 was incidentally identified. Taking into account her history, the tumor was considered to be recurrent colorectal liver metastasis and it was extirpated by partial hepatectomy. However, the segment 4 tumor was diagnosed as recurrent colorectal liver metastasis on the basis of histological findings and the segment 8 tumor was diagnosed as hepatocellular carcinoma. Although she had a cut surface abscess postoperatively, she was discharged from hospital 21 days after the surgery and is currently doing well 18 months after the second hepatectomy. She is currently receiving interferon and ribavirin therapy to eliminate hepatitis C virus. CONCLUSIONS: If antiviral therapy was performed earlier for the present case and viral elimination was achieved, hepatocellular carcinoma might not have developed. This case reemphasizes the importance of antiviral therapy for preventing carcinogenesis of hepatocellular carcinoma in patients with viral hepatitis even if they have other cancers. PMID- 27234583 TI - Cabazitaxel for metastatic hormone-relapsed prostate cancer treated with docetaxel. PMID- 27234584 TI - Glycosylation of matrix metalloproteases and tissue inhibitors: present state, challenges and opportunities. AB - Matrix metalloproteases (MMPs) are crucial components of a complex and dynamic network of proteases. With a wide range of potential substrates, their production and activity are tightly controlled by a combination of signalling events, zymogen activation, post-translational modifications and extracellular inhibition. Slight imbalances may result in the initiation or progression of specific disease states, such as cancer and pathological inflammation. As glycosylation modifies the structures and functions of glycoproteins and many MMPs contain N- or O-linked oligosaccharides, we examine, compare and evaluate the evidence for whether glycosylation affects MMP catalytic activity and other functions. It is interesting that the catalytic sites of MMPs do not contain O linked glycans, but instead possess a conserved N-linked glycosylation site. Both N- and O-linked oligosaccharides, attached to specific protein domains, endow these domains with novel functions such as the binding to lectins, cell-surface receptors and tissue inhibitors of metalloproteases (TIMPs). Validated glycobiological data on N- and O-linked oligosaccharides of gelatinase B/MMP-9 and on O-linked structures of membrane-type 1 MMP/MMP-14 indicate that in-depth research of other MMPs may yield important insights, e.g. about subcellular localizations and functions within macromolecular complexes. PMID- 27234586 TI - Re-programming tumour cell metabolism to treat cancer: no lone target for lonidamine. AB - Tumour cell metabolism is very different from normal cell metabolism; cancer cells re-programme the metabolic pathways that occur in normal cells in such a manner that it optimizes their proliferation, growth and survival. Although this metabolic re-programming obviously operates to the advantage of the tumour, it also offers unique opportunities for effective cancer therapy. Molecules that target the tumour cell-specific metabolic pathways have potential as novel anti cancer drugs. Lonidamine belongs to this group of molecules and is already in use in some countries for cancer treatment. It has been known for a long time that lonidamine interferes with energy production in tumour cells by inhibiting hexokinase II (HKII), a glycolytic enzyme. However, subsequent studies have uncovered additional pharmacological targets for the drug, which include the electron transport chain and the mitochondrial permeability transition pore, thus expanding the pharmacological effects of the drug on tumour cell metabolism. A study by Nancolas et al. in a recent issue of the Biochemical Journal identifies two additional new targets for lonidamine: the pyruvate transporter in the mitochondria and the H(+)-coupled monocarboxylate transporters in the plasma membrane (PM). It is thus becoming increasingly apparent that the anti-cancer effects of lonidamine do not occur through a single target; the drug works at multiple sites. Irrespective of the molecular targets, what lonidamine does in the end is to undo what the tumour cells have done in terms of re-programming cellular metabolism and mitochondrial function. PMID- 27234587 TI - Sustained efficacy of artesunate-sulfadoxine-pyrimethamine against Plasmodium falciparum in Yemen and a renewed call for an adjunct single dose primaquine to clear gametocytes. AB - BACKGROUND: In Yemen, artesunate plus sulfadoxine-pyrimethamine (AS + SP) has been used as first-line treatment for uncomplicated falciparum malaria, which accounts for about 99 % of malaria cases. There is evidence that resistance to SP is increasing, with potential negative impact on efficacy, and in particular on curbing transmission. This study aims: (a) to evaluate the therapeutic efficacy of AS + SP treatment for uncomplicated falciparum malaria in Yemen; (b) to investigate the frequency of mutations in Plasmodium falciparum genes associated with resistance to AS (Kelch 13 propeller domain, pfK13) and SP (dihydrofolate reductase, pfdhfr, and dihydropteroate synthase, pfdhps); and (c) to assess the adequacy of this ACT to clear gametocytes. METHODS: A 28-day in vivo evaluation of the clinical and parasitological response to three-day course of AS + SP was carried out in two areas of high endemicity (Hodeidah and Al-Mahwit provinces, Tehama region) in Yemen according to standard WHO protocol 2009. Clinical and parasitological indices were monitored over a 28-day follow-up, and the outcome was PCR-corrected. The frequencies of mutations in the pfdhfr, pfdhps, and pfK13 genes were obtained by sequencing following amplification. RESULTS: Eighty-six patients completed the study, with a cure rate of 96.5 % (94.2 % PCR uncorrected). Whereas four (4.7 %) patients still showed parasitaemia on day 2 post-treatment, all were found negative for asexual malaria stages on days 3 and 7. The efficacy of gametocyte clearance was poor (14.5, 42.5 and 86.0 % on days 7, 14 and 28, respectively), with gametocytes persisting throughout the study in some patients. All the isolates sequenced had the pfk13 propeller domain wild type allele, and mutations associated with SP failure were observed only for pfdhfr with the double mutation (S108N + N51I) found in 65.4 % of the isolates sequenced. CONCLUSION: In Yemen, AS + SP therapy remains effective for the treatment of uncomplicated falciparum malaria. Mutations were not detected in pfk13 or pfdhps, though double mutations were observed for pfdhfr. The observed persistent gametocytaemia re-enforces calls to add a single dose primaquine to this ACT in order to minimizes the potential for transmission and enhance regional efforts to eliminate malaria. PMID- 27234588 TI - Endoscopic ultrasonography-guided drainage of intra-abdominal fluid collection after liver transplantation: a case series of six patients. AB - Intra-abdominal fluid collection associated with infection is a major complication after liver transplantation (LT). However, post-LT recipients are at high risk for requiring various interventions and surgeries, due to their poor, immunosuppressed conditions. We herein describe six patients with symptomatic or growing intra-abdominal fluid collection after LT who underwent endoscopic ultrasonography (EUS)-guided drainage. There were five males and one female, and the median age was 47 years (24-60 years). All procedures were technically and clinically successful in all patients. The median number of endoscopic sessions was 2.5 (1-4 sessions) until resolution. Procedure-related adverse events occurred in two patients and included peritonitis, bleeding, and stent migration, which improved conservatively or endoscopically. During the median follow-up period of 63 months (17-110 months), recurrence occurred in one patient. EUS guided drainage is an effective and safe treatment for intra-abdominal fluid collection even in post-LT recipients. PMID- 27234589 TI - Corrigendum to "effect of progestins on immunity: medroxyprogesterone but not norethisterone or levonorgestrel suppresses the function of T cells and pDCs" [contraception 90 (2014) 123-129]. PMID- 27234585 TI - Insulin signalling and glucose transport in the ovary and ovarian function during the ovarian cycle. AB - Data derived principally from peripheral tissues (fat, muscle and liver) show that insulin signals via diverse interconnecting intracellular pathways and that some of the major intersecting points (known as critical nodes) are the IRSs (insulin receptor substrates), PI3K (phosphoinositide kinase)/Akt and MAPK (mitogen-activated protein kinase). Most of these insulin pathways are probably also active in the ovary and their ability to interact with each other and also with follicle-stimulating hormone (FSH) and luteinizing hormone (LH) signalling pathways enables insulin to exert direct modulating influences on ovarian function. The present paper reviews the intracellular actions of insulin and the uptake of glucose by ovarian tissues (granulosa, theca and oocyte) during the oestrous/menstrual cycle of some rodent, primate and ruminant species. Insulin signals through diverse pathways and these are discussed with specific reference to follicular cell types (granulosa, theca and oocyte). The signalling pathways for FSH in granulosa cells and LH in granulosa and theca cells are summarized. The roles of glucose and of insulin-mediated uptake of glucose in folliculogenesis are discussed. It is suggested that glucose in addition to its well-established role of providing energy for cellular function may also have insulin-mediated signalling functions in ovarian cells, involving AMPK (AMP dependent protein kinase) and/or hexosamine. Potential interactions of insulin signalling with FSH or LH signalling at critical nodes are identified and the available evidence for such interactions in ovarian cells is discussed. Finally the action of the insulin-sensitizing drugs metformin and the thiazolidinedione rosiglitazone on follicular cells is reviewed. PMID- 27234590 TI - Exploring the metabolic heterogeneity of coagulase-negative staphylococci to improve the quality and safety of fermented meats: a review. AB - The production of fermented meats, such as fermented sausage, relies on the metabolic activities of lactic acid bacteria and catalase-positive cocci, in particular the group of coagulase-negative staphylococci (CNS). Conventional use of CNS as meat starter cultures usually leads to an appropriate cured colour development based on their nitrate reductase activity, whereas their catalase activity reduces oxidative damage. In addition, CNS metabolism contributes to flavour, although the precise effects are difficult to estimate. There are reasons to believe that these basic technological features of CNS can be further enlarged by exploring their full metabolic potential. Non-negligible differences in metabolism among and within different species of CNS indicate that a rational selection of strains may lead to the development of novel starter cultures with enhanced functionality. Firstly, the use of CNS strains with a superior ability to use alternative energy sources, such as nucleosides or arginine, may improve culture competitiveness and survival. Secondly, cured colour generation could be optimised to lower the amounts of curing salts needed, either by selecting for efficient nitrate-reducing CNS strains or by exploring the potential alternative based on nitric oxide synthase activity. Thirdly, CNS with specific aroma producing abilities may help to accentuate specific flavours, whereby the selection of wild-type strains from artisan-type fermented sausages seems attractive in the framework of innovation-through-tradition. Finally, bacteriocin producing CNS strains may offer solutions for bioprotection towards meat pathogens such as Clostridium botulinum and Staphylococcus aureus. Overall, making use of the metabolic inter- and intraspecies heterogeneity of CNS is promising for the elaboration of healthier, tastier, and safer fermented meats. Yet, the proposed strategies are sometimes still overly theoretical and speculative, requiring further proof-of-principle. PMID- 27234591 TI - Schmallenberg Virus Infection Diagnosis: Results of a German Proficiency Trial. AB - Since Schmallenberg virus (SBV), an orthobunyavirus of the Simbu serogroup, was detected in Central Europe in 2011 for the first time, numerous diagnostic test systems for genome or antibody detection have been established. Therefore, a laboratory proficiency trial with 28 veterinary laboratories was initiated to allow performance evaluations of the different veterinary diagnostic laboratories and the performance of the used assays. A panel of selected sera and bovine semen samples for the analysis by real-time PCR and an additional set of serum samples for serological analysis were provided. All participants were asked to investigate the samples with the test systems routinely used in their laboratory. While SBV-genome was reliably detected in serum samples, the sensitivity in semen samples seems to depend on the application of the recommended optimized nucleic acid extraction method (TRIzol(r) LS Reagent-based, Hoffmann et al., 2013, Vet. Microbiol., 167, 289). SBV-antibody-positive samples and sera negative for antibodies against Simbu serogroup viruses were in most cases correctly classified by the participants with the used commercial ELISA kits. However, a serum of the panel which contained antibodies against Akabane and Aino viruses, which are closely related to SBV, was repeatedly tested positive by two of four used ELISA kits. However, an excellent diagnostic sensitivity and specificity was achieved using a serum neutralization test. In conclusion, the here described German SBV proficiency test demonstrated that the available test systems allowed reliable SBV diagnostics in standard veterinary laboratories when recommended and approved assays are used. PMID- 27234592 TI - Effects of vancomycin versus nafcillin in enhancing killing of methicillin susceptible Staphylococcus aureus causing bacteremia by human cathelicidin LL-37. AB - Recent studies have demonstrated that anti-staphylococcal beta-lactam antibiotics, like nafcillin, render methicillin-resistant Staphylococcus aureus (MRSA) more susceptible to killing by innate host defense peptides (HDPs), such as cathelicidin LL-37. We compared the effects of growth in 1/4 minimum inhibitory concentration (MIC) of nafcillin or vancomycin on the LL-37 killing of 92 methicillin-susceptible S. aureus (MSSA) isolates. For three randomly selected strains among these, we examined the effects of nafcillin, vancomycin, daptomycin, or linezolid on LL-37 killing and autolysis. Growth in the presence of subinhibitory nafcillin significantly enhanced LL-37 killing of MSSA compared to vancomycin and antibiotic-free controls. Nafcillin also reduced MSSA production of the golden staphylococcal pigment staphyloxanthin in 39 % of pigmented strains vs. 14 % for vancomycin. Among the antibiotics tested, only nafcillin resulted in significantly increased MSSA autolysis. These studies point to additional mechanisms of anti-staphylococcal activity of nafcillin beyond direct bactericidal activity, properties that vancomycin and other antibiotic classes do not exhibit. The ability of nafcillin to enhance sensitivity to innate HDPs may contribute to its superior effectiveness against MSSA, as suggested by studies comparing clinical outcomes to vancomycin treatment. PMID- 27234594 TI - Generation of a Double KO Mouse by Simultaneous Targeting of the Neighboring Genes Tmem176a and Tmem176b Using CRISPR/Cas9: Key Steps from Design to Genotyping. AB - The CRISPR/Cas9 system has been tailored to a revolutionary genetic tool because of its remarkable simplicity and efficacy. While complex genome editing in the mouse since the 1990s has been dominated by the use of embryonic stem (ES) cells, CRISPR/Cas9 now offers a versatile and fast approach to precisely modify virtually any DNA regions directly in mouse zygotes. Yet, this relative simplicity does not preclude a conscientious preparatory work that is often neglected when initiating a project. Here, we describe the key steps leading to successful generation of a double knockout (KO) mouse by simultaneously targeting two homolog genes, Tmem176a and Tmem176b, which are located in the same genomic locus. Additionally, we show that similar efficiency can be obtained in a mixed genetic background or directly in the C57BL/6 inbred strain. Thus, presented as a detailed case study that should be helpful to the non-specialists, we focus on the genotyping strategy to anticipate the various possibilities. PMID- 27234593 TI - Survey of laboratory-acquired infections around the world in biosafety level 3 and 4 laboratories. AB - Laboratory-acquired infections due to a variety of bacteria, viruses, parasites, and fungi have been described over the last century, and laboratory workers are at risk of exposure to these infectious agents. However, reporting laboratory associated infections has been largely voluntary, and there is no way to determine the real number of people involved or to know the precise risks for workers. In this study, an international survey based on volunteering was conducted in biosafety level 3 and 4 laboratories to determine the number of laboratory-acquired infections and the possible underlying causes of these contaminations. The analysis of the survey reveals that laboratory-acquired infections have been infrequent and even rare in recent years, and human errors represent a very high percentage of the cases. Today, most risks from biological hazards can be reduced through the use of appropriate procedures and techniques, containment devices and facilities, and the training of personnel. PMID- 27234595 TI - Normative values of the Epworth Sleepiness Scale (ESS), derived from a large German sample. AB - PURPOSE: Daytime sleepiness is associated with several medical problems. The aim of this paper is to provide normative values for one of the most often used questionnaires measuring daytime sleepiness, the Epworth Sleepiness Scale (ESS). METHODS: A large sample of 9711 people from the German general population took part in this study. In addition to the ESS, several other questionnaires were used, and sociodemographic and behavioral factors were recorded. RESULTS: Normative values for the ESS are given. According to the generally accepted criterion ESS > 10, 23 % of the sample showed excessive daytime sleepiness. Males reported significantly more daytime sleepiness than females (effect size d = 0.19). In the age range of 40-80 years, a continuous decline of daytime sleepiness was observed. Psychometric properties of the ESS were good. Alcohol intake and nicotine consumption were marginally associated with daytime sleepiness, and obese people reported significantly more sleepiness than people of normal weight (OR = 1.39). CONCLUSIONS: The normative tables allow clinicians and researchers to assess the degree of their patients' daytime sleepiness, especially in the upper range of scores. PMID- 27234598 TI - A single value of high-sensitive troponin T below the limit of detection is not enough for ruling out non ST elevation myocardial infarction in the emergency department. AB - BACKGROUND: Recent 2015 ESC recommendations for the management of patients with suspected acute myocardial infarction (AMI) support that a single value of high sensitivity cardiac troponin (HS-cTn) measured at presentation could rule out AMI if below the limit of blank (LoB) or detection (LoD). OBJECTIVES: We aimed to evaluate whether an undetectable HS-cTnT at presentation safely rules out NSTEMI in unselected patients with chest pain. PATIENTS AND METHODS: This is a post hoc analysis of two prospective cohorts with similar design that included patients suspected of AMI at three French university hospitals. Patients were followed-up during one month, before the adjudication of a final diagnosis. RESULTS: 413 patients (mean age 58+/-17years) were analyzed; 45 (11%) had a final diagnosis of NSTEMI, and 26 (6%) had STEMI. The sensitivity of HS-cTnT value at 3ng/L (LoB) for NSTEMI was 97.8% [95% CI: 86.8-99.9], yielding a negative predictive value (NPV) of 99.3% [95% CI: 95.4-100.0]. Proportion of patients ruled out for NSTEMI was 32% when applying the LoB. The sensitivity of HS-cTnT value at 5ng/L (LoD) was 97.8% [95% CI: 86.8-99.9] yielding a NPV of 99.5% [95% CI: 96.5-100.0]. Proportion of patients ruled out for NSTEMI was 43% when applying the LoD. One patient (delay between onset of chest pain and presentation <3h) had NSTEMI and HS-cTnT 0.05). In male CAD patients, polymorphisms at TGF beta1 rs1800470 (+T29C) were, however, associated with the severity of CAD. The T allele frequency was significantly and positively correlated with the number of narrowed coronary arteries (three or more vessels: 49.3%, two vessels: 44.1%, one vessel: 36.9%) (P=0.039). Gensini scores in patients with the TT, CT, and CC genotype were 34.33+/-2.23, 32.06+/-4.79, and 26.90+/-3.83, respectively (P<0.05). In multiple linear regression analysis, the T allele of TGF-beta1 polymorphism was independently correlated with the Gensini score (beta=0.131). CONCLUSION: TGF-beta1 T29C gene polymorphism may be associated with severity of CAD in male patients. TGFBR2 polymorphisms may not determine the genetic susceptibility to CAD. PMID- 27234601 TI - Automated pictographic illustration of discharge instructions with Glyph: impact on patient recall and satisfaction. AB - OBJECTIVES: First, to evaluate the effect of standard vs pictograph-enhanced discharge instructions on patients' immediate and delayed recall of and satisfaction with their discharge instructions. Second, to evaluate the effect of automated pictograph enhancement on patient satisfaction with their discharge instructions. MATERIALS AND METHODS: Glyph, an automated healthcare informatics system, was used to automatically enhance patient discharge instructions with pictographs. Glyph was developed at the University of Utah by our research team. Patients in a cardiovascular medical unit were randomized to receive pictograph enhanced or standard discharge instructions. Measures of immediate and delayed recall and satisfaction with discharge instructions were compared between two randomized groups: pictograph (n = 71) and standard (n = 73). RESULTS: Study participants who received pictograph-enhanced discharge instructions recalled 35% more of their instructions at discharge than those who received standard discharge instructions. The ratio of instructions at discharge was: standard = 0.04 +/- 0.03 and pictograph-enhanced = 0.06 +/- 0.03. The ratio of instructions at 1 week post discharge was: standard = 0.04 +/- 0.02 and pictograph-enhanced 0.04 +/- 0.02. Additionally, study participants who received pictograph-enhanced discharge instructions were more satisfied with the understandability of their instructions at 1 week post-discharge than those who received standard discharge instructions. DISCUSSION: Pictograph-enhanced discharge instructions have the potential to increase patient understanding of and satisfaction with discharge instructions. CONCLUSION: It is feasible to automatically illustrate discharge instructions and provide them to patients in a timely manner without interfering with clinical work. Illustrations in discharge instructions were found to improve patients' short-term recall of discharge instructions and delayed satisfaction (1 week post hospitalization) with the instructions. Therefore, it is likely that patients' understanding of and interaction with their discharge instructions is improved by the addition of illustrations. PMID- 27234602 TI - ITPKA Gene Body Methylation Regulates Gene Expression and Serves as an Early Diagnostic Marker in Lung and Other Cancers. AB - INTRODUCTION: Despite recent advances in cancer therapy, the overall 5-year survival rate of patients with lung cancer remains low. The aim of our study was to search for novel markers for early diagnosis in patients with lung cancer. METHODS: Complementary DNA microarray analysis was performed in primary lung adenocarcinomas and cell lines to search for differentially expressed genes, followed by in vivo and in vitro tumorigenic assays to characterize the oncogenic potential of the candidate genes. Gene body methylation was analyzed by 450K methylation array, bisulfite sequencing, and quantitative methylation-specific polymerase chain reaction assays. In silico analysis of The Cancer Genome Atlas data set was also performed. RESULTS: Inositol-trisphosphate 3-kinase A gene (ITPKA), a kinase with limited tissue distribution, was identified as a potential oncogene. We showed that ITPKA expression is up-regulated in many forms of cancers, including lung and breast cancers, and that overexpressed ITPKA contributes to tumorigenesis. We also demonstrated that ITPKA expression is regulated by epigenetic DNA methylation of ITPKA gene body through modulation of the binding of SP1 transcription factor to the ITPKA promoter. ITPKA gene body displayed low or absent levels of methylation in most normal tissue but was significantly methylated in malignant tumors. In lung cancer, ITPKA gene body methylation first appeared at the in situ carcinoma stage and progressively increased after invasion. CONCLUSIONS: ITPKA is a potential oncogene that it is overexpressed in most tumors, and its overexpression promotes tumorigenesis. ITPKA gene body methylation regulates its expression and thus serves as a novel and potential biomarker for early cancer detection. PMID- 27234603 TI - Value of the Glasgow Prognostic Score as a Prognostic Factor in Resectable Non Small Cell Lung Cancer. AB - BACKGROUND: Over the past decade, the Glasgow prognostic score (GPS), which is based on serum C-reactive protein and albumin levels, has been reported to be associated with the prognosis of patients with several types of inoperable and operable cancers. However, its applicability to operable non-small cell lung cancer (NSCLC) has not yet been established. METHODS: We retrospectively collected data from patients with pathological stage I or II NSCLC who underwent complete resection. A total of 1048 patients were categorized as either GPS-0 (n = 817 [78.0%]), GPS-1 (184 [17.6%]), or GPS-2 (47 [4.5%]). Survival curves were estimated using the Kaplan-Meier method, and the Cox proportional hazard model was used to analyze the relationship between prognosis and GPS status. RESULTS: The 5-year overall survival (OS) rates were 91.2%, 78.3%, and 75.8% for GPS-0, GPS-1, and GPS-2, respectively. There were significant differences in OS between GPS-0 and GPS-1 (p < 0.001) and between GPS-0 and GPS-2 (p < 0.001). Ten variables demonstrated to be associated with OS in a univariate analysis were subjected to a multivariate analysis. The results showed that male sex (p = 0.031), vascular invasion (p < 0.001), lymph node metastasis (p < 0.001), and GPS (p = 0.025) were significantly associated with OS. CONCLUSIONS: A high GPS is significantly associated with poor OS. Although the biological mechanism that underlies this association is not clear, this inflammation-based score may be a useful indicator of the prognosis in patients with resectable NSCLC. PMID- 27234604 TI - Pretreatment Anemia Portends Poor Survival and Nonlocal Disease Progression in Patients with Stage I Non-Small Cell Lung Cancer Treated with Stereotactic Body Radiation Therapy. AB - INTRODUCTION: We determined whether pretreatment anemia predicted for poor outcomes in the setting of early-stage NSCLC treated with stereotactic body radiation therapy (SBRT). METHODS: Pretreatment hemoglobin levels were evaluated to determine the association with local, regional, and distant control; disease free survival; and overall survival. Survival rates were estimated with Kaplan Meier analysis, and multivariate analysis was completed with adjustment for age, T stage, and radiation dose using the Cox proportional hazards model. Receiver operating characteristic curve analysis was used to determine the optimal pretreatment hemoglobin level that would predict for poor outcomes. RESULTS: A total of 147 cases of cases of early-stage NSCLC treated with SBRT were evaluated with a median follow-up of 28.9 months. The 3-year local, regional and distant control rates were 95%, 87%, and 89%, respectively. The 3-year overall survival and disease-free survival rates were 75% and 83%, respectively. On multivariate analysis, a lower pretreatment hemoglobin level predicted for poor regional control, poor disease-free survival, and overall survival (p = 0.02, p = 0.03, p = 0.05, respectively). Pretreatment hemoglobin levels did not predict poor local control. Receiver operating characteristic (ROC) analysis found that pretreatment hemoglobin values less than 12.2 g/dL optimally predicted for poor disease-free survival and regional control. The 3-year disease-free survival for patients with a hemoglobin level of at least 12.2 g/dL was 94% versus 70% in patients with a hemoglobin level less than 12.2 g/dL (p = 0.008). CONCLUSIONS: In the setting of SBRT for early-stage NSCLC, we found pretreatment anemia to be predictive of aggressive disease with poor overall survival and nonlocal disease progression. PMID- 27234605 TI - The effect of rubber dam on atmospheric bacterial aerosols during restorative dentistry. AB - Rotatory dental instruments generate atmospheric aerosols that settle on various surfaces, including the dentist's head. The aim of this study was to quantitatively assess bacterial contamination of the dentist's head and to evaluate whether it is affected by using a rubber dam. Senior dental students (n=52) were asked to wear autoclaved headscarves as collection media while performing restorative dental treatment with and without a rubber dam. Four points from each headscarf were swabbed for bacterial culture after 30min of operative work. Bacterial contamination was quantified by counting the colony forming units. Regardless of the collection point, using a rubber dam was associated with more bacterial colony-forming units than not using a rubber dam (P=0.009). Despite its clinical value, the rubber dam seems to result in significantly higher aerosol levels on various areas of the dentist's head, requiring that dentists cover their heads with suitable protective wear. PMID- 27234606 TI - Percutaneous bipolar radiofrequency thermocoagulation for the treatment of lumbar disc herniation. AB - Lumbar disc herniation is usually managed with conservative treatment or surgery. However, conservative therapy seldom yields good results, and surgery is associated with multiple complications. This study aimed to assess bipolar radiofrequency thermocoagulation for the treatment of lumbar disc herniation. A total of 168 patients with lumbar disc herniation suitable for radiofrequency thermocoagulation were enrolled and randomized to monopolar radiofrequency thermocoagulation (control group, n=84) or bipolar radiofrequency thermocoagulation (experimental group, n=84) treatment groups. Ablation sites were targeted under CT scan guidance, and consecutive radiofrequency therapy was used. One and two probes were used for monopolar and bipolar thermocoagulation, respectively. Thermocoagulation was achieved at 50 degrees C, 60 degrees C, and 70 degrees C for 60s each, 80 degrees C for 90s, and 92 degrees C for 100s. Symptoms and complications were evaluated using the modified Macnab criteria and Visual Analog Scale at 7, 30, and 180days postoperatively. At 180days, a significantly higher efficacy rate was obtained in the experimental group compared with control patients (91.6% versus 79.7%, P<0.05). No severe complications were occurred in either group. Targeted ablation via bipolar radiofrequency thermocoagulation is efficient for lumbar disc herniation treatment, and should be further explored for broad clinical application. PMID- 27234607 TI - Staged laser interstitial thermal therapy and topectomy for complete obliteration of complex focal cortical dysplasias. AB - Anatomically complex focal cortical dysplasias may present significant challenges to safe and complete surgical resection via standard operative corridors. Laser interstitial thermal therapy (LITT) is an emerging minimally invasive technique that may address some of these challenges, enabling stereotactic ablation of deep and/or surgically inaccessible regions. However, complete ablation may not be feasible in all cases. To address this dilemma, we have designed a protocol utilizing staged LITT followed by topectomy to effect complete obliteration of a complex focal cortical dysplasia. The approach presented demonstrates the feasibility, safety, and clinical utility of combining laser ablation and open surgery for the definitive management of this lesion. PMID- 27234608 TI - Atraumatic multifocal intracerebral hemorrhage. AB - This article describes a patient with atraumatic multifocal intracerebral, subarachnoid, and bilateral frontal convexity acute subdural hematomas. The patient is a 46-year-old Caucasian man who presented with a spontaneous severe progressive headache. Following a description of the case, this article reviews the reported incidence, proposed etiology, and current management strategies for multifocal spontaneous intracerebral hemorrhage. PMID- 27234609 TI - Difference in canal encroachment by the fusion mass between anterior cervical discectomy and fusion with bone autograft and anterior plating, and stand-alone cage. AB - We conducted a prospective randomized study comparing stand-alone cage and bone autograft and plate implants in anterior cervical discectomy and fusion (www.clinicaltrials.gov, NCT01011569). Our interim analysis showed autologous bone graft with plating was superior to a stand-alone cage for segmental lordosis. During this analysis, we noted a difference in canal encroachment by the fusion mass between the two fusion groups. A narrow cervical spinal canal is an important factor in the development of cervical spondylotic myelopathy, therefore this unexpected potential risk of spinal cord compression necessitated another interim analysis to investigate whether there was a difference in canal encroachment by the fusion mass between the two groups. Patients had a minimum 1year of follow-up. The Neck Disability Index, neck and arm pain Visual Analog Scales and lateral radiographs, including bone fusion patterns, were evaluated. Twenty-seven (16 males, 11 females, mean age 54.8years) and 31 (24 males, seven females, mean age 54.5years) patients were in the cage and plate group, respectively. Both groups improved after surgery. Fusion began at 2.6months and 1.3months and finished at 6.7months and 4.0months in 24 (88.9%) and 28 (90.3%) patients in the cage and plate group, respectively. Encroachment into the spinal canal by the fusion mass was significantly different between the fusion types, occuring in 21 (77.8%) patients in the cage group versus six (19.4%) in the plate group (p=0.003). There was a high incidence of spinal canal encroachment by the fusion mass in the stand-alone cage group, possibly limiting use in narrow spinal canals. PMID- 27234610 TI - A novel mutation in NF1 is associated with diverse intra-familial phenotypic variation and astrocytoma in a Chinese family. AB - Neurofibromatosis type 1 (NF1) is a dysregulated neurocutaneous disorder, characterized by neurofibromas and cafe-au-lait spots. NF1 is caused by mutations in the NF1 gene, encoding neurofibromin. Here, we present a clinical molecular study of a three-generation Chinese family with NF1. The proband was a male patient who showed cafe-au-lait spots and multiple subcutaneous neurofibromas over the whole body, but his siblings only had regional lesions. The man's daughter presented with severe headache and vomiting. Neurological examination revealed an intracranial space occupying lesion. Surgery was undertaken and the histopathological examination showed a grade I-II astrocytoma. Next-Generation sequencing (Illumina HiSeq2500 Analyzers; Illumina, San Diego, CA, USA) and Sanger sequencing (ABI PRISM 3730 automated sequencer; Applied Biosystems, Foster City, CA, USA) identified the c.227delA mutation in the NF1 gene in the man. The mutation is co-segregated with the disease phenotypes among the affected members of this family and was absent in 100 healthy controls. This novel mutation results in a frameshift (p.Asn78IlefsX7) as well as truncation of neurofibromin by formation of a premature stop codon. Our results not only extended the mutational and phenotypic spectra of the gene and the disease, but also highlight the importance of the other genetic or environmental factors in the development and severity of the disease. PMID- 27234611 TI - The Clinical Neurosciences: Evolution, Opportunities and a Forum for Communication. PMID- 27234612 TI - Postoperative dysphagia correlates with increased morbidity, mortality, and costs in anterior cervical fusion. AB - Anterior cervical fusion (ACF) after discectomy and/or corpectomy is a common procedure with traditionally good patient outcomes. Though typically mild, postoperative dysphagia can result in significant patient morbidity. In this study, we examine the relationship between postoperative dysphagia and in hospital outcomes, readmissions, and overall costs. The University HealthSystem Consortium (UHC) database was utilized to perform a retrospective cohort study of all adults who underwent a principal procedure of ACF of the anterior column (International Classification of Diseases, Ninth Revision [ICD-9] procedure code 81.02) between 2013 and 2015. Patients with a diagnosis of dysphagia (ICD-9 78720 78729) were compared to those without. Patient demographics, length of stay, in hospital mortality, 30-day readmissions, and direct costs were recorded. A total of 49,300 patients who underwent ACF were identified. Mean age was 54.5years and 50.2% were male. Dysphagia was documented in 3,137 patients (6.4%) during their hospital stay. Patients with dysphagia had an average 2.1 comorbidities, while patients without dysphagia had 1.5 (p<0.01). Mean length of stay was 6.38days in patients with dysphagia, and 2.13days in those without (p<0.01). In-hospital mortality was 0.10% in patients without dysphagia, and 0.61% in those with dysphagia (p<0.01). Direct costs were $13,099 in patients without dysphagia, and $21,245 in those with dysphagia (p<0.01). Thirty-day readmission rate was 2.9% in patients without dysphagia, and 5.3% in those with dysphagia (p=0.01). In summary, dysphagia in patients who undergo ACF correlates with significantly increased length of stay, 30-day readmissions, and in-hospital mortality. Direct costs are similarly increased as a result. PMID- 27234613 TI - Short-Term Dynamic Observation of the Color Change and Enhancement Effect of Polyethylenimine-Entrapped Gold Nanoparticles Used for Indirect Lymphography. AB - AIMS: To dynamically observe the color change and enhancement effect of gadolinium-loaded polyethylenimine-entrapped gold nanoparticles (Gd-Au PENPs) as a dual-mode CT/MRI contrast agent for sentinel lymph node (SLN) identification. METHODS: In 6 rabbits, Gd-Au PENPs were injected into the right side tongue submucosa, after which the color change of cervical draining lymph nodes was observed. Then the draining lymph nodes were examined by CT/MRI scan. Another 6 rabbits were randomly divided into a CT lymphography (CT-LG) and a MRI lymphography (MRI-LG) group and examined by CT/MRI scan 1 and 30 min after injection. Then SLNs were identified under the guidance of CT/MRI-LG. RESULTS: The ipsilateral afferent lymphatic vessels, cervical draining lymph nodes and efferent lymphatic vessels were stained black orderly and constantly after Gd-Au PENPs injection. Thirty minutes after injection, all cervical lymph nodes were excised to be examined by CT/MRI scan, and only the black-stained draining lymph nodes were enhanced. The 6 rabbits with CT/MRI-LG showed clear enhancement of SLNs. With indirect lymphography, the black-stained SLNs were easily visualized at autopsy. In all rabbits, the identification rate of lingual SLNs was 100%. CONCLUSIONS: Rabbit lingual SLNs could be identified with indirect lymphography using Gd-Au PENPs as a dual-mode contrast agent. PMID- 27234614 TI - l-carnosine dipeptide overcomes acquired resistance to 5-fluorouracil in HT29 human colon cancer cells via downregulation of HIF1-alpha and induction of apoptosis. AB - Hypoxia-inducible factor (HIF-1alpha) protein is over-expressed in many human cancers and is a major cause of resistance to drugs. HIF-1alpha up-regulation decreases the effectiveness of several anticancer agents, including 5 fluorouracil (5-FU), because it induces the expression of drug efflux transporters, alters DNA repair mechanisms and modifies the balance between pro- and antiapoptotic factors. These findings suggest that inhibition of HIF-1alpha activity may sensitize cancer cells to cytotoxic drugs. We previously reported that l-carnosine reduces HIF-1alpha expression by inhibiting the proliferation of colon cancer cells. In the present study we investigated the effect of l carnosine on HT29 colon cancer cells with acquired resistance to 5-FU. We found that l-carnosine reduces colon cancer cell viability, decreases HIF-1alpha and multi-drug resistant protein MDR1-pg expression, and induces apoptosis. Moreover, the l-carnosine/5-FU combination lowers the expression of some chemoresistance markers. The combination index evaluated in vitro on the HT29-5FU cell line by median drug effect analysis reveals a significant synergistic effect. PMID- 27234615 TI - Characterization of recombinase DMC1B and its functional role as Rad51 in DNA damage repair in Giardia duodenalis trophozoites. AB - Homologous recombination (HR) is a highly conserved pathway for the repair of chromosomes that harbor DNA double-stranded breaks (DSBs). The recombinase RAD51 plays a key role by catalyzing the pairing of homologous DNA molecules and the exchange of information between them. Two putative DMC1 homologs (DMC1A and DMC1B) have been identified in Giardia duodenalis. In terms of sequences, GdDMC1A and GdDMC1B bear all of the characteristic recombinase domains: DNA binding domains (helix-turn-helix motif, loops 1 and 2), an ATPcap and Walker A and B motifs associated with ATP binding and hydrolysis. Because GdDMC1B is expressed at the trophozoite stage and GdDMC1A is expressed in the cyst stage, we cloned the giardial dmc1B gene and expressed and purified its protein to determine its activities, including DNA binding, ATP hydrolysis, and DNA strand exchange. Our results revealed that it possessed these activities, and they were modulated by divalent metal ions in different manners. GdDMC1B expression at the protein and transcript levels, as well as its subcellular localization in trophozoites upon DNA damage, was assessed. We found a significant increase in GdDMC1B transcript and protein levels after ionizing radiation treatment. Additionally, GdDMC1B protein was mostly located in the nucleus of trophozoites after DNA damage. These results indicate that GdDMC1B is the recombinase responsible for DSBs repair in the trophozoite; therefore, a functional Rad51 role is proposed for GdDMC1B. PMID- 27234616 TI - Antifungal peptides: To be or not to be membrane active. AB - Most antifungal peptides (AFPs), if not all, have membrane activity, while some also have alternative targets. Fungal membranes share many characteristics with mammalian membranes with only a few differences, such as differences in sphingolipids, phosphatidylinositol (PI) content and the main sterol is ergosterol. Fungal membranes are also more negative and a better target for cationic AFPs. Targeting just the fungal membrane lipids such as phosphatidylinositol and/or ergosterol by AFPs often translates into mammalian cell toxicity. Conversely, a specific AFP target in the fungal pathogen, such as glucosylceramide, mannosyldiinositol phosphorylceramide or a fungal protein target translates into high pathogen selectivity. However, a lower target concentration, absence or change in the specific fungal target can naturally lead to resistance, although such resistance in turn could result in reduced pathogen virulence. The question is then to be or not to be membrane active - what is the best choice for a successful AFP? In this review we deliberate on this question by focusing on the recent advances in our knowledge on how natural AFPs target fungi. PMID- 27234617 TI - Emotional contexts modulate intentional memory suppression of neutral faces: Insights from ERPs. AB - The main goal of present work is to gain new insight into the temporal dynamics underlying the voluntary memory control for neutral faces associated with neutral, positive and negative contexts. A directed forgetting (DF) procedure was used during the recording of EEG to answer the question whether is it possible to forget a face that has been encoded within a particular emotional context. A face scene phase in which a neutral face was showed in a neutral or emotional scene (positive, negative) was followed by the voluntary memory cue (cue phase) indicating whether the face had to-be remember or to-be-forgotten (TBR and TBF). Memory for faces was then assessed with an old/new recognition task. Behaviorally, we found that it is harder to suppress faces-in-positive-scenes compared to faces-in-negative and neutral-scenes. The temporal information obtained by the ERPs showed: 1) during the face-scene phase, the Late Positive Potential (LPP), which indexes motivated emotional attention, was larger for faces-in-negative-scenes compared to faces-in-neutral-scenes. 2) Remarkably, during the cue phase, ERPs were significantly modulated by the emotional contexts. Faces-in-neutral scenes showed an ERP pattern that has been typically associated to DF effect whereas faces-in-positive-scenes elicited the reverse ERP pattern. Faces-in-negative scenes did not show differences in the DF-related neural activities but larger N1 amplitude for TBF vs. TBR faces may index early attentional deployment. These results support the hypothesis that the pleasantness or unpleasantness of the contexts (through attentional broadening and narrowing mechanisms, respectively) may modulate the effectiveness of intentional memory suppression for neutral information. PMID- 27234618 TI - Plasma Amyloid Beta 1-42 and DNA Methylation Pattern Predict Accelerated Aging in Young Subjects with Down Syndrome. AB - Gene methylation is an age-related dynamic process that influences diseases. Premature aging and disturbed methylation are components of Down syndrome (DS). We studied blood biomarkers and DNA methylation (DNAm) of three CpG sites (ASPA, ITGA2B, and PDE4C) in 60 elderly subjects (mean age = 68 years), 31 subjects with DS (12.1 years) and 44 controls (12.8 years). Plasma concentrations of amyloid beta (Abeta) 1-42 and biomarkers of methylation were measured in the young groups. Subjects with DS had significantly higher concentrations of plasma S adenosylhomocysteine (SAH) and Abeta and reduced S-adenosylmethionine/SAH ratio compared with the controls. Methylations (%) of ASPA and ITGA2B were lower in DS [mean difference; 95 % confidence intervals = -2.2 (-4.5, 0.1) for ASPA and -5.0 (-8.9, -1.1) for ITGA2B]. Methylation of PDE4C did not differ between the groups. The sum of z-scores for methylations of ASPA and ITGA2B, both of which declined with age, was significantly lower in DS [-1.01 (-1.93, -0.20), p = 0.017]. Subjects with DS were found to be 3.1 (1.5-4.6) years older than their predicted age based on a regression model of the controls. Elevated SAH levels predicted lower DNAm of ASPA and ITGA2B in stepwise regression analysis. Therefore, methylation of three CpGs combined with plasma Abeta has shown a 3-year accelerated aging in subjects with DS at the age of 12 years. Disorders in the methylation cycle explained pathoepigenetic modifications in subjects with DS. The influence of modifications in the methylation cycle on epigenetic markers of aging warrants further investigations. PMID- 27234619 TI - Evaluation of a Theory-Based Intervention Aimed at Improving Coaches' Recommendations on Sports Nutrition to Their Athletes. AB - BACKGROUND: Coaches are a major source of nutrition information and influence for young athletes. Yet, most coaches do not have training in nutrition to properly guide their athletes. OBJECTIVE: The aim of this study was to evaluate the effectiveness of an intervention aimed at improving the accuracy of coaches' recommendations on sports nutrition. DESIGN: This was a quasi-experimental study with a comparison group and an intervention group. Measurements were made at baseline, post-intervention, and after a 2-month follow-up period. Coaches' recommendations on sports nutrition during the follow-up period were recorded in a diary. PARTICIPANTS/SETTING: High school coaches from various sports (n=41) were randomly assigned to a comparison group or an intervention group. INTERVENTION: Both groups attended two 90-minute sessions of a theory-based intervention targeting determinants of coaches' intention to provide recommendations on sports nutrition. The intervention group further received an algorithm that summarizes sports nutrition guidelines to help promote decision making on sports nutrition recommendations. MAIN OUTCOME MEASURES: Nutrition knowledge and accuracy of coaches' recommendations on sports nutrition. STATISTICAL ANALYSIS PERFORMED: chi(2) analyses and t-tests were used to compare baseline characteristics; mixed and general linear model analyses were used to assess the change in response to the intervention and differences in behaviors, respectively. RESULTS: Coaches in the intervention vs comparison group provided more nutrition recommendations during the 2-month post-intervention period (mean number of recommendations per coach 25.7+/-22.0 vs 9.4+/-6.5, respectively; P=0.004) and recommendations had a greater accuracy (mean number of accurate recommendations per coach 22.4+/-19.9 [87.1%] vs 4.3+/-3.2 [46.1%], respectively; P<0.001). Knowledge was significantly increased post-intervention in both groups, but was maintained only in the intervention group during the 2-month follow-up (Pgroup*time=0.04). CONCLUSIONS: A theory-based intervention combined with a decision-making algorithm maintained coaches' sports nutrition knowledge level over time and helped them to provide more accurate recommendations on sports nutrition. PMID- 27234620 TI - Does weightlifting increase residual force enhancement? AB - The force maintained following stretching of an active muscle exceeds the isometric force at the same muscle length. This residual force enhancement (RFE) is different for various muscles. It is currently unknown whether training induces changes in RFE. Weightlifters perform a large number of eccentric contractions during training, and RFE might be functionally relevant. The aim of this study was to examine whether there is increased RFE in weightlifters versus a reference group. Therefore, we measured external reaction forces during a multi joint leg extension in weightlifters (n=10) and a reference group (n=11) using a motor driven leg press dynamometer (ISOMED 2000). Steady state isometric forces after stretching were compared to the corresponding forces obtained during isometric reference contractions. Statistical analyses yielded a significant RFE for both groups (p<0.001), but there were no RFE differences between the groups (p=0.320). However, RFE tends to decrease slower in the weightlifting group versus the reference group. We conclude that long-term weightlifting has only a minor influence on RFE. We speculate that the specific training including a combination of eccentric and concentric exercises induced almost no changes in titin-isoform expression which may be responsible for generation of RFE after active muscle stretching. PMID- 27234621 TI - Invited Commentary. PMID- 27234622 TI - Invited Commentary. PMID- 27234623 TI - Invited Commentary. PMID- 27234624 TI - Invited Commentary. PMID- 27234625 TI - Invited Commentary. PMID- 27234626 TI - Invited Commentary. PMID- 27234627 TI - The Truth about Double Adenomas: Incidence, Localization, and Intraoperative Parathyroid Hormone. AB - BACKGROUND: Double adenoma is reported in 3% to 12% of patients with primary hyperparathyroidism. The aim of this study was to determine the true incidence of double adenoma and analyze the use of localization studies and intraoperative parathyroid hormone (IOTPH) assay in these cases. STUDY DESIGN: We conducted a retrospective review of a series of consecutive parathyroid surgical operations from 2010 to 2013. According to the surgical findings, the series was divided into single-gland disease (SGD), double-gland disease (DGD), and multi-gland disease (MGD, more than 2 glands). The sensitivity of ultrasound, technetium 99m sestamibi, and 4-dimensional CT to correctly lateralize each gland in the DGD group was calculated. Results of the IOPTH assay and how they impacted the extent of surgery were analyzed. RESULTS: Three hundred and forty-seven patients had SGD (69%), 68 patients had DGD (13.5%), and 86 had MGD (17%). In the DGD group, sensitivity of ultrasound, technetium 99m-sestamibi, and 4-dimensional CT to lateralize each adenoma was 42%, 34.5%, and 64%, respectively. Initially, 27 patients (40%) with DGD had been planned for a focal exploration. The conversion to bilateral neck exploration was due to the IOPTH assay in 18 cases (two-thirds of the initially planned focal explorations). At 6-month follow-up, all DGD patients were normocalcemic. CONCLUSIONS: Localization studies in DGD can be misleading by reporting SGD. Four-dimensional CT seems to have the highest sensitivity. In focal explorations, the excision of all hyperfunctioning parathyroid tissue should be verified by IOPTH measurement. PMID- 27234628 TI - Invited Commentary. PMID- 27234629 TI - Invited Commentary. PMID- 27234630 TI - Invited Commentary. PMID- 27234631 TI - Invited Commentary. PMID- 27234632 TI - Program Director Perceptions of Surgical Resident Training and Patient Care under Flexible Duty Hour Requirements. AB - BACKGROUND: The Flexibility in Duty Hour Requirements for Surgical Trainees (FIRST) trial was a national, cluster-randomized, pragmatic, noninferiority trial of 117 general surgery programs, comparing standard ACGME resident duty hour requirements ("Standard Policy") to flexible, less-restrictive policies ("Flexible Policy"). Participating program directors (PDs) were surveyed to assess their perceptions of patient care, resident education, and resident well being during the study period. STUDY DESIGN: A survey was sent to all PDs of the general surgery residency programs participating in the FIRST trial (N = 117 [100% response rate]) in June and July 2015. The survey compared PDs' perceptions of the duty hour requirements in their arm of the FIRST trial during the study period from July 1, 2014 to June 30, 2015. RESULTS: One hundred percent of PDs in the Flexible Policy arm indicated that residents used their additional flexibility in duty hours to complete operations they started or to stabilize a critically ill patient. Compared with the Standard Policy arm, PDs in the Flexible Policy arm perceived a more positive effect of duty hours on the safety of patient care (68.9% vs 0%; p < 0.001), continuity of care (98.3% vs 0%; p < 0.001), and resident ability to attend educational activities (74.1% vs 3.4%; p < 0.001). Most PDs in both arms reported that safety of patient care (71.8%), continuity of care (94.0%), quality of resident education (83.8%), and resident well-being (55.6%) would be improved with a hypothetical permanent adoption of more flexible duty hours. CONCLUSIONS: Program directors involved in the FIRST trial perceived improvements in patient safety, continuity of care, and multiple aspects of resident education and well-being with flexible duty hours. PMID- 27234633 TI - Portal Hypertension Over the Last 25 Years: Where Did It Go? AB - BACKGROUND: Portal hypertension has seemingly vanished from surgery; this study was undertaken to determine where it has gone. STUDY DESIGN: Data from the Agency for Health Care Administration for 33,166,201 hospital inpatients in Florida for the periods 1988 to 1992, 1998 to 2002, and 2008 to 2012 were analyzed. RESULTS: Admissions with a diagnosis of portal hypertension dramatically increased: 5,473 patients from 1988 to 1992, 7,366 patients from 1998 to 2002, and 36,554 patients from 2008 to 2012. Endoscopic treatment of esophageal varices also dramatically increased. The number of decompressive shunts placed nominally increased, but application of endoscopic therapy increased significantly faster than the application of decompressive shunts (p < 0.0001). The percentage of patients who underwent shunting dramatically and significantly decreased (p < 0.0001), and surgeons undertook proportionally fewer shunts (42% in 1992 to 4% in 2012; p < 0.0001). For patients with a diagnosis of portal hypertension, in-hospital mortality progressively decreased, from 9% in 1988 to 1992 to 3% in 2008 to 2012 (p < 0.0001). CONCLUSIONS: In the state of Florida, over 25 years, there has been a 7-fold increase in the number of patients admitted with a diagnosis of portal hypertension, with a 65% reduction of in-hospital mortality. Application of endoscopic treatment of varices has increased dramatically. Decompressive shunts are applied to an ever-decreasing percentage of patients, and when applied, are now routinely undertaken by nonsurgeons. Therefore, portal hypertension has disappeared from the purview of surgery and has migrated toward the world of medical and endoscopic therapy, probably never to return. PMID- 27234634 TI - A Shared Ethos: The Military Health System Strategic Partnership with the American College of Surgeons. PMID- 27234635 TI - Invited Commentary. PMID- 27234636 TI - Does Resident Involvement Equate with Development of Independent Surgical Practitioners? PMID- 27234637 TI - Safety of Resident Involvement in Surgery: A Starting Point for Improvement of Surgical Residency Training: In Reply to D'Souza and Aggarwal. PMID- 27234639 TI - The Ancient-Turned-New Concept of "Spiritual Hygiene": An Investigation of Media Coverage of Meditation from 1979 to 2014. AB - A spiritual-yet not religious-practice, meditation has been touted as beneficial to boosting the immune system, lowering blood pressure, alleviating migraines, and increasing gray matter in parts of the brain. While scientific research on meditation is beginning to quantify its benefits, there is increasing concern among the scientific community that news outlets glorify the potential benefits of meditation. This paper considers coverage of meditation in mainstream print media by analyzing 764 articles printed in English from worldwide media outlets from 1979 to 2014. Frame theory analysis is employed to better understand how meditation is presented in print media and how the perception of the practice is interpreted by readers. Results indicate that articles reflect the health and wellness challenges present in contemporary culture, together with a desire for personal relief from such issues. The paper suggests that the practice of meditation as "spiritual hygiene" is indicative of a sociocultural shift in which meditative techniques are becoming increasingly recognized, encouraged, and practiced. PMID- 27234640 TI - CEA response is associated with tumor response and survival in patients with KRAS exon 2 wild-type and extended RAS wild-type metastatic colorectal cancer receiving first-line FOLFIRI plus cetuximab or bevacizumab (FIRE-3 trial). AB - BACKGROUND: To examine the relation of carcinoembryonic antigen (CEA) response with tumor response and survival in patients with (K)RAS wild-type metastatic colorectal cancer receiving first-line chemotherapy in the FIRE-3 trial comparing FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab. PATIENTS AND METHODS: CEA response assessed as the percentage of CEA decrease from baseline to nadir was evaluated for its association with tumor response and survival. Receiver operating characteristic analysis revealed an optimal cut-off value of 75% using the maximum of sensitivity and specificity for CEA response to discriminate CEA responders from non-responders. In addition, the time to CEA nadir was calculated. RESULTS: Of 592 patients in the intent-to-treat population, 472 were eligible for analysis of CEA (cetuximab arm: 230 and bevacizumab arm: 242). Maximal relative CEA decrease (%) significantly (P = 0.003) differed between the cetuximab arm (median 83.0%; IQR 40.9%-94.7%) and the bevacizumab arm (median 72.3%; IQR 26.3%-91.0%). In a longitudinal analysis, the CEA decrease occurred faster in the cetuximab arm and was greater than in the bevacizumab arm at all evaluated time points until 56 weeks after treatment start. CEA nadir occurred after 3.3 months (cetuximab arm) and 3.5 months (bevacizumab arm), (P = 0.49). In the cetuximab arm, CEA responders showed a significantly longer progression-free survival [11.8 versus 7.4 months; hazard ratio (HR) 1.53; 95% Cl, 1.15-2.04; P = 0.004] and longer overall survival (36.6 versus 21.3 months; HR 1.73; 95% Cl, 1.24-2.43; P = 0.001) than CEA non-responders. Analysis of extended RAS wild-type patients revealed similar results. CONCLUSION: In the FIRE-3 trial, CEA decrease was significantly faster and greater in the cetuximab arm than in the bevacizumab arm and correlated with the prolonged survival observed in patients receiving FOLFIRI plus cetuximab. CLINICAL TRIALS NUMBER: NCT00433927 (ClinicalTrials.gov); AIO KRK0306 FIRE-3. PMID- 27234643 TI - Estimation of a transient response from steady-state responses by deconvolution with built-in constraints. AB - Evidence suggests that the steady-state response (SSR) elicited by a periodic train of auditory stimuli can largely be understood as a superposition of transient responses. This study is devoted to the problem of how to estimate that transient response from measured SSRs. The proposed method differs from previous approaches in that the solution can be constrained to be consistent with physiology-based prior knowledge or educated guesses. To achieve this goal, the transient response is not represented by a time series, but by a linear combination of auxiliary functions, called components. Constraints are introduced by assigning certain properties to the components. Only few parameters are required for that purpose, because the individual components are derived from a suitably designed mother component. After adjusting the components to the problem at hand, the component amplitudes are determined by optimizing the match between predicted and measured SSRs. This requires solving a linear inverse problem. A model simulation as well as an analysis of exemplary experimental data (auditory SSRs elicited by periodically presented clicks) prove the workability of the method. Since part of the theory is quite general, it would be relatively easy to refine and extend the method. Not only could responses other than SSRs be dealt with, it could also be realized that certain key parameters of the transient response, such as amplitude and delay, depend on stimulus repetition rate. PMID- 27234642 TI - The time to progression ratio: a new individualized volumetric parameter for the early detection of clinical benefit of targeted therapies. AB - BACKGROUND: Early signs of efficacy are critical in drug development. Response Evaluation Criteria in Solid Tumors (RECIST) are commonly used to determine the efficacy of anti-cancer therapy in clinical trials. RECIST, however, emphasizes the value of tumor shrinkage, while many targeted agents induce prolonged tumor growth arrest. This limits its use for the detection of treatment efficacy for these more cytostatic regimens. Therefore, we designed an individualized variant of a time to progression (TTP) end point based on prospective volumetric measurements and an intra-patient control, the TTP ratio. PATIENTS AND METHODS: Patients with any metastatic malignancy, without regular treatment options, were treated with the mTOR inhibitor everolimus. Treatment response was determined using both RECIST and the TTP ratio. The TTP ratio was defined as the volumetric pretreatment TTP divided by the volumetric on-treatment TTP. A patient was classified as a responder if the TTP ratio was <0.7. Consistency and reproducibility of volumetric measurements were determined. RESULTS: Seventy three patients were included of whom 59 started treatment. A TTP ratio could be established in 73% (n = 43) of the treated patients. The inter-observer agreement for volumetric progression was 0.78 (95% confidence interval 0.70-0.87) (Krippendorff's alpha-coefficient). According to RECIST, 35 patients (59%) had stable disease (SD) and 1 patient demonstrated a partial response (PR), whereas only 21 patients (36%) met the prespecified criteria for treatment efficacy according to the TTP ratio. Treatment response according to both the TTP ratio and RECIST (SD + PR) correlated with overall survival (OS) [P(log-rank) < 0.001]. The TTP ratio, however, was also able to differentiate which patients had a better OS within the RECIST SD group [P(log-rank) = 0.0496]. CONCLUSION: The TTP ratio had a high inter-observer agreement, correlated with OS and identified which patients within the RECIST SD group had a longer OS. CLINICALTRIALSGOV IDENTIFIER: NCT01566279. PMID- 27234644 TI - A comparison of ancestral state reconstruction methods for quantitative characters. AB - Choosing an ancestral state reconstruction method among the alternatives available for quantitative characters may be puzzling. We present here a comparison of seven of them, namely the maximum likelihood, restricted maximum likelihood, generalized least squares under Brownian, Brownian-with-trend and Ornstein-Uhlenbeck models, phylogenetic independent contrasts and squared parsimony methods. A review of the relations between these methods shows that the maximum likelihood, the restricted maximum likelihood and the generalized least squares under Brownian model infer the same ancestral states and can only be distinguished by the distributions accounting for the reconstruction uncertainty which they provide. The respective accuracy of the methods is assessed over character evolution simulated under a Brownian motion with (and without) directional or stabilizing selection. We give the general form of ancestral state distributions conditioned on leaf states under the simulation models. Ancestral distributions are used first, to give a theoretical lower bound of the expected reconstruction error, and second, to develop an original evaluation scheme which is more efficient than comparing the reconstructed and the simulated states. Our simulations show that: (i) the distributions of the reconstruction uncertainty provided by the methods generally make sense (some more than others); (ii) it is essential to detect the presence of an evolutionary trend and to choose a reconstruction method accordingly; (iii) all the methods show good performances on characters under stabilizing selection; (iv) without trend or stabilizing selection, the maximum likelihood method is generally the most accurate. PMID- 27234641 TI - The role of oral hygiene in head and neck cancer: results from International Head and Neck Cancer Epidemiology (INHANCE) consortium. AB - BACKGROUND: Poor oral hygiene has been proposed to contribute to head and neck cancer (HNC) risk, although causality and independency of some indicators are uncertain. This study investigates the relationship of five oral hygiene indicators with incident HNCs. METHODS: In a pooled analysis of 8925 HNC cases and 12 527 controls from 13 studies participating in the International Head and Neck Cancer Epidemiology Consortium, comparable data on good oral hygiene indicators were harmonized. These included: no denture wear, no gum disease (or bleeding), <5 missing teeth, tooth brushing at least daily, and visiting a dentist >=once a year. Logistic regression was used to estimate the effects of each oral hygiene indicator and cumulative score on HNC risk, adjusting for tobacco smoking and alcohol consumption. RESULTS: Inverse associations with any HNC, in the hypothesized direction, were observed for <5 missing teeth [odds ratio (OR) = 0.78; 95% confidence interval (CI) 0.74, 0.82], annual dentist visit (OR = 0.82; 95% CI 0.78, 0.87), daily tooth brushing (OR = 0.83, 95% CI 0.79, 0.88), and no gum disease (OR = 0.94; 95% CI 0.89, 0.99), and no association was observed for wearing dentures. These associations were relatively consistent across specific cancer sites, especially for tooth brushing and dentist visits. The population attributable fraction for <= 2 out of 5 good oral hygiene indicators was 8.9% (95% CI 3.3%, 14%) for oral cavity cancer. CONCLUSION: Good oral hygiene, as characterized by few missing teeth, annual dentist visits, and daily tooth brushing, may modestly reduce the risk of HNC. PMID- 27234645 TI - Mathematical model for cell competition: Predator-prey interactions at the interface between two groups of cells in monolayer tissue. AB - The phenomenon of 'cell competition' has been implicated in the normal development and maintenance of organs, such as in the regulation of organ size and suppression of neoplastic development. In cell competition, one group of cells competes with another group through an interaction at their interface. Which cell group "wins" is governed by a certain relative fitness within the cells. However, this idea of cellular fitness has not been clearly defined. We construct two types of mathematical models to describe this phenomenon of cell competition by considering the interaction at the interface as a predator-prey type interaction in a monolayer tissue such as epithelium. Both of these models can reproduce several typical experimental observations involving systems of mutant cells (losers) and normal cells (winners). By analyzing one of the model and defining an index for the degree of fitness in groups of cells, we show that the fate of each group mainly depends on the relative carrying capacities of certain resources and the strength of the predator-prey interaction at the interface. This contradicts the classical hypothesis in which the relative proliferation rate determines the winner. PMID- 27234646 TI - Cyclophosphamide-induced Down-Regulation of Uroplakin II in the Mouse Urinary Bladder Epithelium is Prevented by S-Allyl Cysteine. AB - The alkylating anticancer drug, cyclophosphamide (CP), induces a number of toxic effects including haemorrhagic cystitis (HC) in the urinary bladder. Uroplakins are unique urinary transmembrane proteins of urothelium, which may become potential targets of CP metabolites and reactive free radicals. Natural compounds, especially those rich in thiols, have shown protective effects against CP-induced HC. In this study, we studied the modulatory effect of the thiol-rich compound S-allyl cysteine (SAC) on the mRNA level of uroplakin II by real-time polymerase chain reaction and expression of uroplakin II protein by immunoblotting. SAC (150 mg/kg) showed significant (p < 0.001) protective effects against CP (200 mg/kg)-induced alteration in mRNA level and protein expression of uroplakin II. SAC also protected animals from CP-induced HC as assessed by gross morphological examination of urinary bladder. When compared with mercaptoethane sulphonic acid (mesna) (40 mg/kg), a known thiol-rich drug used in clinical application, SAC was found to be more efficacious in affording protection in urinary bladder tissues. Role of uroplakins in CP-induced urinary bladder toxicity has not been well investigated. This study demonstrated that uroplakins may be the potential target of toxic metabolites of CP and natural compounds such as SAC have the capacity to modulate their expression leading to reduced toxicity burden on the urinary bladder epithelium. PMID- 27234647 TI - Comprehensive Medication Management programs: 2015 status in Southern California. PMID- 27234648 TI - Histories of host shifts and cospeciation among free-living parasitoids of Rhagoletis flies. AB - Host shifts by specialist insects can lead to reproductive isolation between insect populations that use different hosts, promoting diversification. When both a phytophagous insect and its ancestrally associated parasitoid shift to the same novel host plant, they may cospeciate. However, because adult parasitoids are free living, they can also colonize novel host insects and diversify independent of their ancestral host insect. Although shifts of parasitoids to new insect hosts have been documented in ecological time, the long-term importance of such shifts to parasitoid diversity has not been evaluated. We used a genus of flies with a history of speciation via host shifting (Rhagoletis [Diptera: Tephritidae]) and three associated hymenopteran parasitoid genera (Diachasma, Coptera and Utetes) to examine cophylogenetic relationships between parasitoids and their host insects. We inferred phylogenies of Rhagoletis, Diachasma, Coptera and Utetes and used distance-based cophylogenetic methods (ParaFit and PACo) to assess congruence between fly and parasitoid trees. We used an event-based method with a free-living parasitoid cost model to reconstruct cophylogenetic histories of each parasitoid genus and Rhagoletis. We found that the current species diversity and host-parasitoid associations between the Rhagoletis flies and parasitoids are the primary result of ancient cospeciation events. Parasitoid shifts to ancestrally unrelated hosts primarily occur near the branch tips, suggesting that host shifts contribute to recent parasitoid species diversity but that these lineages may not persist over longer time periods. Our analyses also stress the importance of biologically informed cost models when investigating the coevolutionary histories of hosts and free-living parasitoids. PMID- 27234649 TI - Assessment of Quality and Content of Online Information About Hip Arthroscopy. AB - PURPOSE: The purpose of this study was to assess the quality of information available to patients on the Internet when using popular search engines to search the term "hip arthroscopy." METHODS: We analyzed the quality and content of information about hip arthroscopy (HA) on the first 50 websites returned by the search engines Google and Bing for the search term "hip arthroscopy." The sites were categorized by type, and quality and content were measured using the DISCERN score, along with an HA-specific content score. The HA-specific content score was used to assess each website for the presence or absence of 19 topics about HA determined to be important for a patient seeking information about the procedure. The Health on the Net Code (HONcode) status of each website was also noted. RESULTS: The mean DISCERN score for all websites analyzed was 39.5, considered "poor," while only 44.6% of sites were considered "fair" or "good." Governmental and nonprofit organization (NPO) websites had the highest average DISCERN score. The mean HA-specific content score was 8.6 (range, 2 to 16). The commercial website category had the highest average HA-specific content score, followed by the governmental and NPO category. Sites that bore the HONcode certification obtained significantly higher DISCERN scores than those without the certification (P = .0032) but did not obtain significantly higher HA-specific content scores. CONCLUSIONS: "Hip arthroscopy" is a fairly general term, and there is significant variability in the quality of HA information available online. The HONcode is useful to identify quality patient information websites; however, it is not commonly used in HA-specific websites and does not encompass all quality websites about HA. CLINICAL RELEVANCE: This study increases awareness of the quality of information on HA available online. PMID- 27234650 TI - The Effect of Different Bone Marrow Stimulation Techniques on Human Talar Subchondral Bone: A Micro-Computed Tomography Evaluation. AB - PURPOSE: To evaluate morphological alterations, microarchitectural disturbances, and the extent of bone marrow access to the subchondral bone marrow compartment using micro-computed tomography analysis in different bone marrow stimulation (BMS) techniques. METHODS: Nine zones in a 3 * 3 grid pattern were assigned to 5 cadaveric talar dome articular surfaces. A 1.00-mm microfracture awl (s.MFX), a 2.00-mm standard microfracture awl (l.MFX), or a 1.25-mm Kirschner wire (K-wire) drill hole was used to penetrate the subchondral bone in each grid zone. Subchondral bone holes and adjacent tissue areas were assessed by micro-computed tomography to analyze adjacent bone area destruction and communicating channels to the bone marrow. Grades 1 to 3 were assigned, where 1 = minimal compression/sclerosis; 2 = moderate compression/sclerosis; 3 = severe compression/sclerosis. Bone volume/total tissue volume, bone surface area/bone volume, trabecular thickness, and trabecular number were calculated in the region of interest. RESULTS: Visual assessment revealed that the s.MFX had significantly more grade 1 holes (P < .001) and that the l.MFX had significantly more poor/grade 3 holes (P = .002). Bone marrow channel assessment showed a statistically significant increase in the number of channels in the s.MFX when compared with both K-wire and l.MFX holes (P < .001). Bone volume fraction for the s.MFX was significantly less than that of the l.MFX (P = .029). CONCLUSIONS: BMS techniques using instruments with larger diameters resulted in increased trabecular compaction and sclerosis in areas adjacent to the defect. K-wire and l.MFX techniques resulted in less open communicating bone marrow channels, denoting a reduction in bone marrow access. The results of this study indicate that BMS using larger diameter devices results in greater microarchitecture disturbances. CLINICAL RELEVANCE: The current study suggests that the choice of a BMS technique should be carefully considered as the results indicate that smaller diameter hole sizes may diminish the amount of microarchitectural disturbances in the subchondral bone. PMID- 27234651 TI - Tibial Tubercle Osteotomy for Patellar Chondral Pathology in an Active United States Military Population. AB - PURPOSE: To quantify rates of perioperative complications, secondary surgery, subjective pain relief, and knee-related medical separation in an active military population after a tibial tubercle osteotomy (TTO) for the primary indication of chondral pathology. METHODS: All active-duty service members undergoing TTO with a minimum of 2 years' follow-up were isolated from the Military Health System database. The exclusion criteria were patients with patellar instability, other periarticular osteotomy, and insufficient follow-up. Demographic information and surgical characteristics were abstracted from the electronic health record and correlated with improvement in pain and medical discharge from the military. RESULTS: A total of 76 patients (86 knees) who underwent TTO for patellofemoral chondromalacia were identified with a mean age of 32.3 years. Major and minor complications occurred in four patients (4.7%) and three patients (3.5%), respectively, and the overall improvement in the visual analog scale score after TTO was 1.5 (P < .0001). At a mean follow-up of 3.4 years (range, 2.0 to 7.3 years), 37% of patients were unable to return to modified military activity because of knee-related limitations. Junior military rank group (P = .0084), age younger than 35 years (P = .0031), bilateral TTO procedures (P = .0294), and tobacco use (P = .0218; odds ratio, 3.29; 95% confidence interval, 1.19 to 9.12) were risk factors for medical separation, whereas absence of concomitant chondral repair (P = .5408), previous knee procedures (P = .9674), and greater occupational demands (P = .7062) were not. CONCLUSIONS: At short-term to midterm follow-up, 63% of patients successfully returned to military function with a low rate of perioperative complications (8%). The postoperative decrease in pain after TTO is of unknown clinical significance. Age younger than 35 years, junior military rank, bilateral TTO procedures, and tobacco use were significant risk factors for medical separation, whereas absence of concomitant cartilage repair, previous knee procedures, and lower occupational demands were not associated with improved visual analog scale scores or prevention of knee-related medical discharge. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 27234652 TI - Arthroscopic Training Courses Improve Trainee Arthroscopy Skills: A Simulation Based Prospective Trial. AB - PURPOSE: To evaluate the correlation between timed task performance on an arthroscopy shoulder simulator and participation in a standardized expert shoulder arthroscopy educational course. METHODS: Orthopaedic trainees were voluntarily recruited from over 25 residency programs throughout the United States and Canada. Each trainee was tested on arrival at the Arthroscopy Association of North America orthopaedic learning center on a virtual reality arthroscopy shoulder simulator, and his or her performance was objectively scored. Each trainee's postgraduate year level was recorded, as was his or her experience in residency with shoulder arthroscopy as measured by Accreditation Council for Graduate Medical Education case-log totals. After the focused 4-day training curriculum consisting of didactics and cadaveric experience, each trainee was re-evaluated on the same simulator. Statistical analysis was performed to determine if participation in the course was associated with changes in simulation performance from before to after assessment. RESULTS: Forty-eight trainees completed the testing. On completion of the course, trainees showed significant improvements in all objective measures recorded by the simulator. Total probe distance needed to complete the task decreased by 42% (from 420.4 mm to 245.3 mm, P < .001), arthroscope tip distance traveled decreased by 59% (from 194.1 mm to 80.2 mm, P < .001), and time to completion decreased by 38% (from 66.8 seconds to 41.6 seconds, P < .001). Highly significant improvements in all 3 measures suggest improved instrument handling, anatomic recognition, and arthroscopy-related visual-spatial ability. CONCLUSIONS: This study shows objective improvement in orthopaedic trainee basic arthroscopy skill and proficiency after a standardized 4-day arthroscopy training curriculum. The results validate the Arthroscopy Association of North America resident training course and its curriculum with objective evidence of benefit. LEVEL OF EVIDENCE: Level III, prospective study of nonconsecutive participants. PMID- 27234653 TI - Surgical Techniques and Outcomes of Repairing Meniscal Radial Tears: A Systematic Review. AB - PURPOSE: To systematically review meniscal radial tear repair procedures and compare the techniques, outcomes, and complications. METHODS: Studies were identified through a systematic review of the literature using the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, PubMed (1980-2014), Medline (1980-2014), and Embase. Inclusion criteria included a minimum follow-up of 24 months, English language, and publications from 1980 or later. Exclusion criteria were surgical techniques not reporting follow-up, biomechanical studies, cadaver/anatomic studies, and non-radial tear meniscal repair procedures. Meniscal radial repair, meniscal radial tear, meniscal radial tear repair, radial repair and radial tear were used as search terms. RESULTS: A total of 6 studies (55 patients) met the inclusion criteria. The mean duration of follow-up ranged from 24 to 71 months. Of the 6 studies, 5 reported radial tears to the lateral meniscus and 1 study reported cases of both medial and lateral meniscal radial tears. Two studies reported different inside out repair techniques, 2 studies reported the use of an all-inside anchor-based repair system, 1 study reported an all-inside repair technique with absorbable sutures, and 1 study reported an inside-out repair with fibrin clots. Average postoperative Lysholm scores were reported in all 6 studies and ranged from 86.9 to 95.6. Average postoperative Tegner activity scores were reported in 4 studies and ranged from 1 to 6.7. The majority of studies concluded that their techniques produced satisfactory healing of the radial tear, without serious subsequent complications. CONCLUSIONS: Radial repair techniques differed among studies; however, postoperative subjective outcomes revealed patient improvement with repairing radial tears. With the increasing concern of long-term osteoarthritis after meniscectomy, meniscal preservation with repair of radial tears results in improved short-term clinical outcomes; however, long-term outcomes remain unknown. LEVEL OF EVIDENCE: Level IV, systematic review of level IV studies. PMID- 27234655 TI - Keratin 8-deletion induced colitis predisposes to murine colorectal cancer enforced by the inflammasome and IL-22 pathway. AB - Keratins (K) are intermediate filament proteins important in protection from cellular stress. K8, K18 and K19 are the main components of keratin filaments in colonic epithelia but their role in intestinal diseases remains ambiguous. A function for keratins in intestinal health is supported by the K8-knock-out (K8( /-)) mouse which manifests an early chronic ulcerative colitis-like inflammatory bowel disease and epithelial hyperproliferation. We tested whether K8(-/-) mice are more susceptible to colorectal cancer (CRC) compared to K8 wild type (K8(+/+)), and K8 heterozygote (K8(+/-)) mice showing increased proliferation but no inflammation. K8(-/-) mice did not develop CRC spontaneously, but had dramatically increased numbers of tumors in the distal colon in the azoxymethane (AOM) and Apc(Min/+) CRC models while neither K8(+/+) nor K8(+/-) mice were susceptible. Upregulation of IL-22 in combination with a complete loss of its negative regulator IL-22BP, and increased downstream STAT3-signaling in K8(-/-) and K8(-/-)Apc(Min/+) colonic epithelia confirmed that the IL-22 pathway, important in inflammation, proliferation and tissue regeneration, was activated. The nearly total loss of IL-22BP correlated with an activated inflammasome leading to increased cleaved caspase-1, and the putative IL-22BP inhibitor, IL 18, as well as a decrease in ALDH1/2. Ablation of K8 in a colorectal cancer cell line similarly resulted in increased IL-18 and decreased ALDH1/2. K8/K18 co immunoprecipitated with pro-caspase-1, a component of the inflammasome in the colon, which suggests that keratins modulate inflammasome activity and protect the colon from inflammation and tumorigenesis. The K8-null mouse models also provide novel epithelial-derived robust colon-specific CRC models. PMID- 27234654 TI - Association of a let-7 miRNA binding region of TGFBR1 with hereditary mismatch repair proficient colorectal cancer (MSS HNPCC). AB - The purpose of this study was to identify novel colorectal cancer (CRC)-causing alleles in unexplained familial CRC cases. In order to do so, coding regions in five candidate genes (MGMT, AXIN2, CTNNB1, TGFBR1 and TGFBR2) were sequenced in 11 unrelated microsatellite-stable hereditary non-polyposis CRC (MSS HNPCC) cases. Selected genetic variants were genotyped in a discovery set of 27 MSS HNPCC cases and 85 controls. One genetic variant, rs67687202, in TGFBR1 emerged as significant (P = 0.002), and it was genotyped in a replication set of 87 additional MSS HNPCC-like cases and 338 controls where it was also significantly associated with MSS HNPCC cases (P = 0.041). In the combined genotype data, rs67687202 was associated with a moderate increase in CRC risk (OR = 1.68; 95% CI = 1.13-2.50; P = 0.010). We tested a highly correlated SNP rs868 in 723 non familial CRC cases compared with 629 controls, and it was not significantly associated with CRC risk (P = 0.370). rs868 is contained in a let-7 miRNA binding site in the 3'UTR of TGFBR1, which might provide a functional basis for the association in MSS HNPCC. In luciferase assays, the risk-associated allele for rs868 was associated with half the luciferase expression in the presence of miRNA let-7b-5p compared with protective allele, suggesting more binding of let-7b-5p and less TGFBR1 expression. Thus, rs868 potentially is a CRC risk-causing allele. Our results support the concept that rs868 is associated with lower TGFBR1 expression thereby increasing CRC risk. PMID- 27234656 TI - Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease. AB - Glymphatic transport, defined as cerebrospinal fluid (CSF) peri-arterial inflow into brain, and interstitial fluid (ISF) clearance, is reduced in the aging brain. However, it is unclear whether glymphatic transport affects the distribution of soluble Abeta in Alzheimer's disease (AD). In wild type mice, we show that Abeta40 (fluorescently labeled Abeta40 or unlabeled Abeta40), was distributed from CSF to brain, via the peri-arterial space, and associated with neurons. In contrast, Abeta42 was mostly restricted to the peri-arterial space due mainly to its greater propensity to oligomerize when compared to Abeta40. Interestingly, pretreatment with Abeta40 in the CSF, but not Abeta42, reduced CSF transport into brain. In APP/PS1 mice, a model of AD, with and without extensive amyloid-beta deposits, glymphatic transport was reduced, due to the accumulation of toxic Abeta species, such as soluble oligomers. CSF-derived Abeta40 co localizes with existing endogenous vascular and parenchymal amyloid-beta plaques, and thus, may contribute to the progression of both cerebral amyloid angiopathy and parenchymal Abeta accumulation. Importantly, glymphatic failure preceded significant amyloid-beta deposits, and thus, may be an early biomarker of AD. By extension, restoring glymphatic inflow and ISF clearance are potential therapeutic targets to slow the onset and progression of AD. PMID- 27234657 TI - Clinical features of registry-ascertained alcohol use disorders that reflect familial risk. AB - BACKGROUND: Alcohol Use Disorder (AUD) is clinically heterogeneous. Using a large epidemiological sample ascertained via public registries, is it possible to identify clinical and historical features of AUD that reflect familial risk? METHODS: Using registration in national medical, legal or pharmacy registries, we identified four kinds of relative pairs (n=683,223) starting with a proband with AUD: cousins, half-siblings, full-siblings and monozygotic cotwins. Using linear hazard regression, we examined the interaction between five clinical/historical features of AUD in the proband and risk for AUD in these relatives. RESULTS: Increased risk for AUD in relatives was predicted by the proband's early age at first registration, total number of registrations, recurrence, history of drug abuse and ascertainment in the medical versus the legal or pharmacy registry. In multivariate models, age at first registration, number of registrations, recurrence and history of drug abuse remained significant and in aggregate strongly predicted the risk for AUD in relatives. The risk for AUD in siblings of AUD probands in the highest decile of genetic risk predicted by these four indices was more than twice as great as that predicted in siblings of probands in the lowest risk decile. CONCLUSIONS: In an epidemiological sample, familial risk for AUD can be assessed by simple clinical and historical variables. PMID- 27234658 TI - Opioid withdrawal suppression efficacy of oral dronabinol in opioid dependent humans. AB - BACKGROUND: The cannabinoid (CB) system is a rational novel target for treating opioid dependence, a significant public health problem around the world. This proof-of-concept study examined the potential efficacy of a CB1 receptor partial agonist, dronabinol, in relieving signs and symptoms of opioid withdrawal. METHODS: Twelve opioid dependent adults participated in this 5-week, inpatient, double-blind, randomized, placebo-controlled study. Volunteers were maintained on double-blind oxycodone (30mg oral, four times/day) and participated in a training session followed by 7 experimental sessions, each testing a single oral test dose (placebo, oxycodone 30 and 60mg, dronabinol 5, 10, 20, and 30mg [decreased from 40mg]). Placebo was substituted for oxycodone maintenance doses for 21h before each session in order to produce measurable opioid withdrawal. Outcomes included observer- and participant-ratings of opioid agonist, opioid withdrawal and psychomotor/cognitive performance. RESULTS: Oxycodone produced prototypic opioid agonist effects (i.e. suppressing withdrawal and increasing subjective effects indicative of abuse liability). Dronabinol 5 and 10mg produced effects most similar to placebo, while the 20 and 30mg doses produced modest signals of withdrawal suppression that were accompanied by dose-related increases in high, sedation, bad effects, feelings of heart racing, and tachycardia. Dronabinol was not liked more than placebo, showed some impairment in cognitive performance, and was identified as marijuana with increasing dose. CONCLUSION: CB1 receptor activation is a reasonable strategy to pursue for the treatment of opioid withdrawal; however, dronabinol is not a likely candidate given its modest withdrawal suppression effects of limited duration and previously reported tachycardia during opioid withdrawal. PMID- 27234659 TI - The role of pain intensity and smoking expectancies on smoking urge and behavior following experimental pain induction. AB - INTRODUCTION: Contemporary models of pain and smoking posit a cyclical relationship wherein smoking reduces pain in the short term but, ultimately, serves to exacerbate it in the long term. Such models were influenced by initial experimental findings suggesting situational pain is sufficient to increase smoking-urge and behavior. The initial experimental findings have not yet been replicated and potential mediating smoking motives and anxiety variables have not been explored. METHODS: The current investigation was designed with the aims of exploring whether (a) electrical heat-pain is sufficient to increase smoking urge, (b) pain intensity, anxiety sensitivity, and smoking expectancies for pain relief account for variance in post-pain smoking-urge, and (c) individuals are more likely to smoke following a pain experience. RESULTS: Participants in the heat-pain condition (n=16) reported greater smoking-urge than those in the no pain control condition (n=16). In the heat-pain condition, approximately 31% of variance in smoking-urge was accounted for by the belief that smoking would help with pain coping or relief. Anxiety sensitivity and pain intensity ratings were not significant predictors of smoking-urge. Significantly more individuals in the heat-pain condition attempted to smoke (100%) after the pain manipulation than those in the no-pain control condition (62.5%). CONCLUSIONS: Acute heat-pain increases smoking-urge and behavior, especially for individuals with expectancies that smoking will help with pain coping. Pain and pain-related smoking expectancies may serve as barriers to smoking cessation for those experiencing pain. Findings provide support for smoking cessation interventions strategies aimed at pain management and challenging smoking expectancies for pain coping/relief. PMID- 27234660 TI - Diagnostic accuracy of a two-item screen for drug use developed from the alcohol, smoking and substance involvement screening test (ASSIST). AB - AIMS: The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) is a screening instrument to detect substance use in primary care (PC). To screen for illicit substances (excluding tobacco and alcohol), the ASSIST consists of 8-57 questions and requires complicated scoring. To improve the efficiency of screening of drug misuse in PC, this study constructed and validated a two-item screen for drug use from the ASSIST. METHODS: Guided by previous reviews, the ASSIST was revised. Patients were recruited in VA primary care clinics (N=1283). Half of the sample was used to develop the ASSIST-Drug; the other half was used to validate it. The Mini International Neuropsychiatric Interview (MINI) and the Inventory of Drug Use Consequences were the criterion measures. RESULTS: A brief, two-item ASSIST-Drug was constructed. Based on the development sample, the ASSIST Drug was 94.1% sensitive and 89.6% specific for drug use disorders. Based on the validation sample, it was 95.4% sensitive and 87.8% specific. The ASSIST-Drug also had comparable sensitivity and specificity to identify drug use negative consequences, as well as for diverse subgroups of patients in terms of gender, age, race/ethnicity, marital status, educational levels, and post traumatic stress disorder status. CONCLUSIONS: The ASSIST-Drug may be a useful screening tool for PC settings. It is reliable, brief, and easy to remember, administer and score. It is sensitive and specific for drug use disorders and drug use negative consequences, and the predictive properties are consistent across subgroup of patients. PMID- 27234662 TI - Kinetics of batch anaerobic co-digestion of poultry litter and wheat straw including a novel strategy of estimation of endogenous decay and yield coefficients using numerical integration. AB - The kinetics of anaerobic co-digestion of poultry litter and wheat straw has not been widely reported in the literature. Since endogenous decay and yield coefficients are two basic parameters for the design of anaerobic digesters, they are currently estimated only by continues experiments. In this study, numerical integration was employed to develop a novel strategy to estimate endogenous decay and yield coefficients using initial and final liquid data combined with methane volumes produced over time in batch experiments. To verify this method, the kinetics of batch anaerobic co-digestion of poultry litter and wheat straw at different TS and VS levels was investigated, with the corresponding endogenous decay and (non-observed) yield coefficients in the exponential periods determined to be between 0.74 * 10(-3) and 6.1 * 10(-3) d(-1), and between 0.0259 and 0.108 g VSS (g VS)(-1), respectively. A general Gompertz model developed early for bio product could be used to simulate the methane volume profile in the co-digestion. The same model parameters obtained from the methane model combined with the corresponding yield coefficients could also be used to describe the VSS generation and VS destruction. PMID- 27234661 TI - Childhood weight status and timing of first substance use in an ethnically diverse sample. AB - BACKGROUND: We examined associations between weight status during childhood and timing of first cigarette, alcohol, and marijuana use in an ethnically diverse sample. METHODS: Data were drawn from child respondents of the 1979 National Longitudinal Survey of Youth, including 1448 Hispanic, 2126 non-Hispanic Black, and 3304 non-Hispanic, non-Black (White) respondents aged 10 years and older as of last assessment. Cox proportional hazards regression was conducted predicting age at first use from weight status (obese, overweight, and underweight relative to healthy weight) assessed at ages 7/8, separately by substance class, sex, and race/ethnicity. Tests of interactions between weight status and respondent sex and race/ethnicity were also conducted. RESULTS: Compared to healthy-weight females of the same race/ethnicity, overweight Hispanic females were at increased likelihood of alcohol and marijuana use and overweight White females were at increased likelihood of cigarette and marijuana use. Compared to healthy-weight males of the same race/ethnicity, obese White males were at decreased likelihood of cigarette and alcohol use and underweight Hispanic and Black males were at decreased likelihood of alcohol and marijuana use. Significant differences in associations by sex and race/ethnicity were observed in tests of interactions. CONCLUSIONS: Findings highlight childhood weight status as a predictor of timing of first substance use among Hispanic and Non-Hispanic Black and White female and male youth. Results suggest that collapsing across sex and race/ethnicity, a common practice in prior research, may obscure important within-group patterns of associations and thus may be of limited utility for informing preventive and early intervention efforts. PMID- 27234664 TI - Management of recalcitrant osteomyelitis and segmental bone loss of the forearm with the Masquelet technique. PMID- 27234663 TI - At-Home Versus In-Clinic INR Monitoring: A Cost-Utility Analysis from The Home INR Study (THINRS). AB - BACKGROUND: Effective management of patients using warfarin is resource intensive, requiring frequent in-clinic testing of the international normalized ratio (INR). Patient self-testing (PST) using portable at-home INR monitoring devices has emerged as a convenient alternative. As revealed by The Home INR Study (THINRS), event rates for PST were not significantly different from those for in-clinic high-quality anticoagulation management (HQACM), and a cumulative gain in quality of life was observed for patients undergoing PST. OBJECTIVE: To perform a cost-utility analysis of weekly PST versus monthly HQACM and to examine the sensitivity of these results to testing frequency. PATIENTS/INTERVENTIONS: In this study, 2922 patients taking warfarin for atrial fibrillation or mechanical heart valve, and who demonstrated PST competence, were randomized to either weekly PST (n = 1465) or monthly in-clinic testing (n = 1457). In a sub-study, 234 additional patients were randomized to PST once every 4 weeks (n = 116) or PST twice weekly (n = 118). The endpoints were quality of life (measured by the Health Utilities Index), health care utilization, and costs over 2 years of follow-up. RESULTS: PST and HQACM participants were similar with regard to gender, age, and CHADS2 score. The total cost per patient over 2 years of follow up was $32,484 for HQACM and $33,460 for weekly PST, representing a difference of $976. The incremental cost per quality-adjusted life year gained with PST once weekly was $5566 (95 % CI, -$11,490 to $25,142). The incremental cost effectiveness ratio (ICER) was sensitive to testing frequency: weekly PST dominated PST twice weekly and once every 4 weeks. Compared to HQACM, weekly PST was associated with statistically significant and clinically meaningful improvements in quality of life. The ICER for weekly PST versus HQACM was well within accepted standards for cost-effectiveness, and was preferred over more or less frequent PST. These results were robust to sensitivity analyses of key assumptions. CONCLUSION: Weekly PST is a cost-effective alternative to monthly HQACM and a preferred testing frequency compared to twice weekly or monthly PST. PMID- 27234665 TI - Role of bacterial biofilm in development of middle ear effusion. AB - Biofilms have been implicated in the development of several chronic upper respiratory tract infections. Role of bacterial biofilms has been well studied in the pathogenesis of chronic rhinosinusitis. However, its impact on development of middle ear effusion is still a matter of debate. To study the extent of surface adenoid biofilm and evaluate its role in the pathogenesis of chronic otitis media with effusion in children. The study was carried out on 40 children in Alexandria Main University Hospital between 1 and 16 years of age without sex predilection, who were divided into two groups. The first group (20 children) had otitis media with effusion associated with adenoid hypertrophy, whereas the second group (20 children) had adenoid hypertrophy without middle ear effusion. Adenoidectomy with ventilation tube insertion was done for group 1 cases, whereas, only Adenoidectomy was done for group 2 cases. The samples were processed for the detection of biofilms by scanning electron microscopy. The biofilm formation was graded according to extension. Biofilm formation was detected on all samples for group 1. Adenoids removed from patients with otitis media with effusion had higher-grade biofilm formation than the other group (P 0.0001). No correlation was found between adenoid size and biofilm formation. In pediatric population, adenoid surface biofilm formation may be involved in the pathogenesis otitis media with effusion. PMID- 27234666 TI - Clinical and audiologic characteristics of patients with sensorineural tinnitus and its association with psychological aspects: an analytic retrospective study. AB - This study was performed to analyze clinical and audiologic characteristics of sensorineural tinnitus and to investigate the associating factors reflecting psychological aspects of stress and depression of the patients. This is a retrospective analytical study conducted in a tinnitus clinic of a tertiary referral center of a university hospital. The medical records of 216 patients suffering from sensorineural tinnitus were thoroughly evaluated to determine correlations between clinical and audiological characteristics, including age, sex, predisposing or etiologic factors, hearing levels up to extended high frequencies, and tinnitus severity. Psychological aspects of stress and depression were also evaluated and analyzed to seek the associations with tinnitus severity. All data were stored in our database bank and were statistically analyzed. Our study subjects showed a slight male predominance. The highest percentage of tinnitus was found in patients of 60-80 years old. Only 32.5 % of tinnitus patients were subjectively aware of their hearing loss, whereas 73 % of subjects had hearing deficits in some frequencies in their audiogram. Hearing impairments were of the low-frequency sensorineural type in 18.2 % of patients and were limited to the high frequencies in 77.9 % of patients. Tinnitus was unilateral in 51 % of patients and had a tonal nature in 45 % of patients. In total, 45.8 % of patients with high-frequency sensorineural hearing loss had high-pitched tinnitus. There were significant correlations between tinnitus severity, loudness and annoyance. Correlations with THI (Tinnitus Handicap Inventory) and Beck depression index scores were also found. Sensorineural tinnitus was related with hearing loss in some frequencies nevertheless of patients' own awareness of hearing loss. Loudness and annoyance of tinnitus seems to be two important factors reflecting psychological problems of patients' stress and depression. PMID- 27234667 TI - Liquid biopsy as a novel tool to monitor the carcinogenesis of Barrett's esophagus. AB - Barrett's esophagus (BE) is associated with an increased risk of developing esophageal adenocarcinoma. For this reason, endoscopic-based surveillance protocols have been developed. This prevention program is, however, burdensome for the patients and expensive for the national health systems. Thus, diagnostic strategies with a low invasiveness and a reduced economic impact are required. This study investigated the power of plasma circulating free DNA (cfDNA) in predicting neoplastic transformation in the natural history of two BE patients who progressed to esophageal adenocarcinoma. Longitudinally collected DNAs from plasma and paired formalin fixed paraffin embedded samples were examined for both loss of heterozygosity (LOH) in areas proximal to TP53, FHIT and BRCA2 genes, and mutations in TP53 gene. Results showed that: (i) early BE molecular alterations are mainly localized proximal to, or within, TP53 gene; (ii) LOH events present in cfDNA not only retrace the time-matched biopsy profile but better represent the total alterations of the BE epithelium. In conclusion, our findings suggested that LOH analysis in plasma cfDNA could represent an additional, less invasive, diagnostic tool to monitor neoplastic progression of BE epithelium. PMID- 27234668 TI - The association between glucose metabolism status, diabetes severity and a history of fractures and recent falls in participants of 50 years and older-the Maastricht Study. AB - : In this cohort of relatively young and well-treated participants with type 2 diabetes, we found no association between diabetes status and a history of previous fractures and recent falls. Furthermore, no association between diabetes severity and previous fractures or recent falls was found. INTRODUCTION: In this study, we examined the association between glucose metabolism status and historical fractures or recent falls and the effect of diabetes severity (glucose control, insulin use, and diabetes duration) on falls and fractures in the participants with type 2 diabetes. METHODS: Cross-sectional data from 2005 participants of the Maastricht Study. Falls in the past 6 months and fractures >=age 50 were assessed by questionnaire. Glucose metabolism status (normal glucose metabolism, impaired glucose metabolism, or type 2 diabetes) was based on the oral glucose tolerance test and medication use. RESULTS: In the completely adjusted model, the odds for a fall were not significantly higher in those with impaired glucose metabolism status (OR (95%CI) 1.28 (0.93-1.77)) or with type 2 diabetes (OR (95%CI) 1.21 (0.80-1.81)) compared with the group with normal glucose metabolism. Within the group with type 2 diabetes, there were no significant differences with regard to reported falls between participants with HbA1c >7 % (53 mmol/mol) versus HbA1c <=7 % (OR (95%CI) 1.05 (0.58-1.90)), insulin users versus non-insulin users (OR (95%CI) 1.51 (0.79-2.89)), and with a diabetes duration >5 versus <=5 years (OR (95%CI) 0.52 (0.46-1.47)). Similarly, neither glucose metabolism status nor diabetes severity was associated with prior fractures. CONCLUSIONS: Glucose metabolism status was not significantly associated with previous fractures and recent falls. In addition, in this cohort of relatively young and well-treated participants with type 2 diabetes, diabetes severity was not associated with previous fractures and recent falls. PMID- 27234669 TI - Men's health-seeking behaviours regarding bone health after a fragility fracture: a secondary analysis of qualitative data. AB - In our qualitative study, men with fragility fractures described their spouses as playing an integral role in their health behaviours. Men also described taking risks, preferring not to dwell on the meaning of the fracture and/or their bone health. Communication strategies specific to men about bone health should be developed. INTRODUCTION: We examined men's experiences and behaviours regarding bone health after a fragility fracture. METHODS: We conducted a secondary analysis of five qualitative studies. In each primary study, male and female participants were interviewed for 1-2 h and asked to describe recommendations they had received for bone health and what they were doing about those recommendations. Maintaining the phenomenological approach of the primary studies, the transcripts of all male participants were re-analyzed to highlight experiences and behaviours particular to men. RESULTS: Twenty-two men (50-88 years old) were identified. Sixteen lived with a wife, male partner, or family member and the remaining participants lived alone. Participants had sustained hip fractures (n = 7), wrist fractures (n = 5), vertebral fractures (n = 2) and fractures at other locations (n = 8). Fourteen were taking antiresorptive medication at the time of the interview. In general, men with a wife/female partner described these women as playing an integral role in their health behaviours, such as removing tripping hazards and organizing their medication regimen. While participants described giving up activities due to their bone health, they also described taking risks such as drinking too much alcohol and climbing ladders or deliberately refusing to adhere to bone health recommendations. Finally, men did not dwell on the meaning of the fracture and/or their bone health. CONCLUSIONS: Behaviours consistent with those shown in other studies on men were described by our sample. We recommend that future research address these findings in more detail so that communication strategies specific to men about bone health be developed. PMID- 27234670 TI - The effect of single-task and dual-task balance exercise programs on balance performance in adults with osteoporosis: a randomized controlled preliminary trial. AB - : Osteoporosis is a serious disease characterized by muscle weakness in the lower extremities, shortened length of trunk, and increased dorsal kyphosis leading to poor balance performance. Although balance impairment increases in adults with osteoporosis, falls and fall-related injuries have been shown to occur mainly during the dual-task performance. Several studies have shown that dual-task performance was improved with specific repetitive dual-task exercises. INTRODUCTION: The aims of this study were to compare the effect of single- and dual-task balance exercise programs on static balance, dynamic balance, and activity-specific balance confidence in adults with osteoporosis and to assess the effectiveness of dual-task balance training on gait speed under dual-task conditions. METHODS: Older adults (N = 42) (age range, 45-88 years) with osteoporosis were randomly assigned into two groups. Single-task balance training group was given single-task balance exercises for 4 weeks, whereas dual-task balance training group received dual-task balance exercises. Participants received 45-min individualized training session, three times a week. Static balance was evaluated by one-leg stance (OLS) and a kinesthetic ability trainer (KAT) device. Dynamic balance was measured by the Berg Balance Scale (BBS), Time Up and Go (TUG) test, and gait speed. Self-confidence was assessed with the Activities-specific Balance Confidence (ABC-6) scale. Assessments were performed at baseline and after the 4-week program. RESULTS: At the end of the treatment periods, KAT score, BBS score, time in OLS and TUG, gait speeds under single- and dual-task conditions, and ABC-6 scale scores improved significantly in all patients (p < 0.05). However, BBS and gait speeds under single- and dual-task conditions showed significantly greater improvement in the dual-task balance training group than in the single-task balance training group (p < 0.05). ABC-6 scale scores improved more in the single-task balance training group than in the dual-task balance training group (p < 0.05). CONCLUSIONS: A 4-week single- and dual-task balance exercise programs are effective in improving static balance, dynamic balance, and balance confidence during daily activities in older adults with osteoporosis. However, single- and dual-task gait speeds showed greater improvement following the application of a specific type of dual-task exercise programs. CLINICAL TRIAL REGISTRATION NUMBER: 24102014-2. PMID- 27234671 TI - Treatment responses with once-weekly teriparatide therapy for osteoporosis. AB - Monitoring bone mineral density is useful to assess treatment response for osteoporosis, but it does not always reflect fracture prevention. Two types of bone mineral density thresholds were used to analyze data from a once-weekly teriparatide trial, and they appear to be useful indicators of treatment success for osteoporosis. INTRODUCTION: This study aimed to clarify whether the criteria of treatment response could be used to evaluate treatment success with once weekly teriparatide. METHODS: The data of subjects whose lumbar or femoral neck bone mineral density (BMD) was measured in the TOWER study were included. The least significant change (LSC) and the absolute change were used as the criteria for judgment of treatment success. The correlation between the incidence of fractures and the treatment response was also assessed. RESULTS: There was no significant difference in baseline characteristics between the placebo and teriparatide groups. Once-weekly teriparatide therapy for 72 weeks showed treatment success in 79.2 % of the subjects for lumbar BMD and 44.1 % for femoral neck BMD by LSC and in 50.5 and 39.6 % by absolute change, respectively. A lower incidence of vertebral fracture was observed in patients who achieved treatment success for lumbar BMD. With the LSC, some treatment success was observed in the early phase of treatment, and it increased with treatment duration. CONCLUSIONS: It appears that the LSC could be used as a surrogate efficacy indicator at an earlier stage of treatment, and the absolute criterion of -2.5SD was confirmed as a useful marker of long-term treatment success. PMID- 27234672 TI - An uncommon cause of dysphagia. PMID- 27234673 TI - Comparison of fosfomycin to ertapenem for outpatient or step-down therapy of extended-spectrum beta-lactamase urinary tract infections. AB - Extended-spectrum beta-lactamase (ESBL) enzymes cause resistance to common beta lactam antibiotics and are associated with poor outcomes. Management of ESBL urinary tract infections (UTIs) is challenging given the limited treatment options available outside the hospital setting. In this study, the primary endpoint of UTI-related 30-day hospital re-admission or emergency department/clinic revisit rates was compared for fosfomycin and ertapenem outpatient ESBL UTI treatments. A retrospective cohort study was performed on patients with ESBL UTIs treated with outpatient fosfomycin or ertapenem from January 2010 to February 2015. Inclusion criteria were age >=18 years, outpatient treatment with fosfomycin or ertapenem for symptomatic ESBL UTI, and positive urine cultures with microbiologically proven ESBL-producing bacteria. A non inferiority margin of 0.15 was selected to detect a difference in the primary endpoint. Patient and infection characteristics were compared. A sensitivity analysis with propensity score matching was performed. In total, 178 patients were included (89 fosfomycin-treated and 89 ertapenem-treated). Ertapenem-treated patients received longer outpatient antibiotic treatment (10 days vs. 6 days; P <0.001). ESBL isolates identified were 149 Escherichia coli (83.7%), 26 Klebsiella spp. (14.6%) and 3 other (1.7%). Common dosage regimens were oral dose of 3 g fosfomycin every 72 h (62%), oral dose of 3 g fosfomycin every 48 h (23%) and intravenous dose of 1 g ertapenem daily (76%). The thirty-day re admission/revisit rates for fosfomycin and ertapenem were 14.6% vs. 13.5% (1.1% difference; 97.5% CI, -0.11 to 0.13). Fosfomycin was non-inferior to ertapenem for treating outpatient ESBL UTIs and should be considered as appropriate step down therapy for these infections. PMID- 27234674 TI - Effectiveness of increasing the frequency of posaconazole syrup administration to achieve optimal plasma concentrations in patients with haematological malignancy. AB - Few data are available on whether adjusting the dose of posaconazole syrup is effective in patients receiving anti-cancer chemotherapy. The aim of this prospective study was to analyse the impact of increasing the frequency of posaconazole administration on optimal plasma concentrations in adult patients with haematological malignancy. A total of 133 adult patients receiving chemotherapy for acute myeloid leukaemia or myelodysplastic syndrome who received posaconazole syrup 200 mg three times daily for fungal prophylaxis were enrolled in this study. Drug trough levels were measured by liquid chromatography-tandem mass spectrometry. In 20.2% of patients (23/114) the steady-state concentration of posaconazole was suboptimal (<500 ng/mL) on Day 8. In these patients, the frequency of posaconazole administration was increased to 200 mg four times daily. On Day 15, the median posaconazole concentration was significantly increased from 368 ng/mL [interquartile range (IQR), 247-403 ng/mL] to 548 ng/mL (IQR, 424-887 ng/mL) (P = 0.0003). The median increase in posaconazole concentration was 251 ng/mL (IQR, 93-517 ng/mL). Among the patients with initially suboptimal levels, 79% achieved the optimal level unless the steady state level was <200 ng/mL. This study shows that increasing the administration frequency of posaconazole syrup is effective for achieving optimal levels in patients with haematological malignancy undergoing chemotherapy. PMID- 27234675 TI - Resistance to colistin: what is the fate for this antibiotic in pig production? AB - Colistin, a cationic polypeptide antibiotic, has reappeared in human medicine as a last-line treatment option for multidrug-resistant Gram-negative bacteria (MDR GNB). Colistin is widely used in veterinary medicine for the treatment of gastrointestinal infections caused by Enterobacteriaceae. GNB resistant to colistin owing to chromosomal mutations have already been reported both in human and veterinary medicine, however several recent studies have just identified a plasmid-mediated mcr-1 gene encoding for colistin resistance in Escherichia coli colistin resistance. The discovery of a non-chromosomal mechanism of colistin resistance in E. coli has led to strong reactions in the scientific community and to concern among physicians and veterinarians. Colistin use in food animals and particularly in pig production has been singled out as responsible for the emergence of colistin resistance. The present review will focus mainly on the possible link between colistin use in pigs and the spread of colistin resistance in Enterobacteriaceae. First we demonstrate a possible link between Enterobacteriaceae resistance emergence and oral colistin pharmacokinetics/pharmacodynamics and its administration modalities in pigs. We then discuss the potential impact of colistin use in pigs on public health with respect to resistance. We believe that colistin use in pig production should be re-evaluated and its dosing and usage optimised. Moreover, the search for competitive alternatives to using colistin with swine is of paramount importance to preserve the effectiveness of this antibiotic for the treatment of MDR-GNB infections in human medicine. PMID- 27234676 TI - Response to: 'Continuous versus intermittent infusion of vancomycin in adult patients: a systematic review and meta-analysis'. PMID- 27234677 TI - Misuse of antibiotics reserved for hospital settings in outpatients: a prospective clinical audit in a university hospital in Southern France. AB - Some antibiotics are reserved essentially for hospital settings owing to cost effectiveness and in order to fight the emerging antibiotic resistance crisis. In some cases, antibiotics reserved exclusively for use in hospitals may be prescribed in outpatients for serious infections or in the absence of a therapeutic alternative. A 30-day prospective audit of outpatient prescriptions of antibiotics reserved exclusively for use in hospitals was performed. The objective of this study was to evaluate the relevance of outpatient antibiotic prescriptions by measuring appropriateness according to guidelines. During the study period, 53 prescriptions were included, only 40% of which were appropriate. Among the 32 inappropriate prescriptions, 4 cases lacked microbial arguments, 1 case was not adequate for the infection type, 1 case involved an incorrect antibiotic dosage, 1 case involved an incorrect interval of dose administration, 3 cases had a therapeutic alternative and 22 cases were not recommended. Of the 53 prescriptions, 66% were started in hospital and 34% in outpatients. Only 25% of cases were prescribed with infectious diseases specialist (IDS) advice, 64% were based on microbiological documentation and 13% had a negative bacterial culture. Inappropriate prescriptions were usually observed in antibiotic lock therapy, skin infections, Clostridium difficile colitis, intra-abdominal infections and intravascular catheter-related infections. Outpatient prescriptions of antimicrobial drugs reserved exclusively for use in hospitals are frequently inappropriate. We recommend a real-time analysis algorithm with the involvement of an IDS for monitoring prescriptions to improve the quality of these prescriptions and possibly to prevent antibiotic resistance. PMID- 27234678 TI - Hepatic encephalopathy in the course of anti-HCV therapy with paritaprevir/ritonavir, ombitasvir, dasabuvir and ribavirin. PMID- 27234679 TI - Can we guarantee less nephrotoxicity when vancomycin is administered by continuous infusion? PMID- 27234680 TI - Developing and Validating a Renal Nutrition Screening Tool to Effectively Identify Undernutrition Risk Among Renal Inpatients. AB - OBJECTIVE: To develop and validate a nutrition screening tool that is effective to recognize renal inpatients at risk of undernutrition. DESIGN: A prospective, criterion validation. SUBJECTS: Adults admitted to a hospital ward with acute kidney injury, chronic kidney disease, and dialysis regardless of gender or ethnicity (n = 122) were recruited. INTERVENTION: The renal nutrition screening tool (R-NST) was developed from the Malnutrition Screening Tool and renal specific risk variables such as biochemical measures to identify renal inpatients who are at undernutrition risk. MAIN OUTCOME MEASURE: The undernutrition risk of each participant was independently assessed using the R-NST and the 7-point Subjective Global Assessment (SGA). The R-NST was autonomously used by nursing staff to determine its feasibility as a routine screening method at ward level. RESULTS: The SGA and R-NST tools classified 53.3% and 68.0% of participants as malnourished or at undernutrition risk, respectively. The R-NST was determined to be valid to detect undernutrition risk (sensitivity = 97.3%, specificity = 74.4%, positive predictive value = 88.0%, and negative predictive value = 93.6%) compared with the SGA. The R-NST also showed ability to recognize timely dietetic intervention required due to renal conditions. The compliance rate in the R-NST screening by the nursing staff was low (22.6%). CONCLUSION: The R-NST is a good screening tool for identifying renal inpatients at undernutrition risk. Further research is warranted to explore innovative yet effective strategies to establish undernutrition screening as standard renal ward practice. PMID- 27234690 TI - Ribosomes Structure and Mechanisms in Regulation of Protein Synthesis Part I. PMID- 27234691 TI - Facilitating Secure Sharing of Personal Health Data in the Cloud. AB - BACKGROUND: Internet-based applications are providing new ways of promoting health and reducing the cost of care. Although data can be kept encrypted in servers, the user does not have the ability to decide whom the data are shared with. Technically this is linked to the problem of who owns the data encryption keys required to decrypt the data. Currently, cloud service providers, rather than users, have full rights to the key. In practical terms this makes the users lose full control over their data. Trust and uptake of these applications can be increased by allowing patients to feel in control of their data, generally stored in cloud-based services. OBJECTIVE: This paper addresses this security challenge by providing the user a way of controlling encryption keys independently of the cloud service provider. We provide a secure and usable system that enables a patient to share health information with doctors and specialists. METHODS: We contribute a secure protocol for patients to share their data with doctors and others on the cloud while keeping complete ownership. We developed a simple, stereotypical health application and carried out security tests, performance tests, and usability tests with both students and doctors (N=15). RESULTS: We developed the health application as an app for Android mobile phones. We carried out the usability tests on potential participants and medical professionals. Of 20 participants, 14 (70%) either agreed or strongly agreed that they felt safer using our system. Using mixed methods, we show that participants agreed that privacy and security of health data are important and that our system addresses these issues. CONCLUSIONS: We presented a security protocol that enables patients to securely share their eHealth data with doctors and nurses and developed a secure and usable system that enables patients to share mental health information with doctors. PMID- 27234692 TI - A novel dominant negative mutation in the intracellular domain of GHR is associated with growth hormone insensitivity. PMID- 27234694 TI - [Role of reflectance confocal microscopy and optical coherence tomography as aids in the diagnosis of pemphigoid gestationis]. PMID- 27234695 TI - Doxorubicin loaded large-pore mesoporous hydroxyapatite coated superparamagnetic Fe3O4 nanoparticles for cancer treatment. AB - In the present study, a series of multifunctional drug delivery systems based on mesostructured hydroxyapatite coating and superparamagnetic nanoparticles with pH responsive characters was prepared. The structure of each new synthesized nanoscale composite was fully characterized by XRD, FTIR, TEM, VSM and BET. The results showed a good ordered mesostructure having large pores, high pore volume, high surface area, and varied super paramagnetic properties. The mesoporous hydroxyapatite coated super paramagnetic Fe3O4 nanoparticles were applied as a drug delivery carrier loaded with doxorubicin (DOX) as a model drug. The storage/release properties of the developed nonocarriers in phosphate buffer saline (PBS) were studied in two certain pHs: pH=7.4 (the human blood pH) and pH=5.5 (pH of cancer cells). The large pores in the synthesized mesoporous acted as an excellent carrier for DOX molecules with a loading efficiency of ~93% which is much higher than that of the conventional hydroxyapatite particles. When the pH of the release medium (PBS) was changed from 7.4 to 5.5, the drug release increased significantly from 10% of the adsorbed drug to about 70%. DOX-loaded mesostructure hydroxyapatite reduced the viability of SKBR3 and T47D cells by 54.7 and 57.3%, respectively, which were very similar to 56.8 and 60.4% reduction resulted from free DOX incubation. This new drug delivery system which benefits from both super paramagnetic properties and pH-responsive performances may serve as a suitable platform for developing new biocompatible drug carriers and could have a good potential use in targeted cancer therapy. PMID- 27234693 TI - Randomized double-blind clinical trial comparing basal insulin peglispro and insulin glargine, in combination with prandial insulin lispro, in patients with type 2 diabetes: IMAGINE 4. AB - AIMS: To evaluate the efficacy and safety of basal insulin peglispro (BIL) with those of insulin glargine, both in combination with prandial insulin lispro, in patients with type 2 diabetes (T2D). METHODS: In this phase III, multicentre, double-blind, 26-week study, we randomized patients with T2D [glycated haemoglobin (HbA1c) >=7 and <12%, on >=1 insulin injections daily) to BIL (n = 691) or glargine (n = 678), in combination with lispro. RESULTS: At week 26, the primary objective of non-inferiority of BIL versus glargine for HbA1c reduction was achieved (least squares mean difference -0.21%; 95% confidence interval -0.31 to -0.11%), with statistical superiority of BIL with multiplicity adjustment (p < 0.001). HbA1c at baseline was 8.4% versus 8.5% for BIL versus glargine and at 26 weeks it was 6.8% versus 7.0%. At 26 weeks, more patients reached HbA1c <7% with BIL than with glargine (63.3% vs 53.3%; p < 0.001), the nocturnal hypoglycaemia rate (<=3.9 mmol/l) was lower with BIL (0.51 vs 0.92 events/30 days; p < 0.001), but the daytime hypoglycaemia rate was higher with BIL (5.47 vs 4.53 events/30 days; p < 0.001). The total hypoglycaemia relative rate was 1.10 (p = 0.053). At 26 weeks, patients in the BIL group had lower fasting serum glucose levels, higher basal insulin dosing, with no statistically significant difference in prandial or total insulin dosing, reduced glucose variability and less weight gain (1.3 kg vs 2.2 kg) compared with the glargine group. The BIL group had higher mean triglyceride and aminotransferase levels. CONCLUSIONS: In patients with T2D, BIL with insulin lispro provided greater improvement in glycaemic control with less nocturnal hypoglycaemia, lower glucose variability and less weight gain compared with glargine. The daytime hypoglycaemia rate and mean triglyceride and aminotransferase levels were higher with BIL. PMID- 27234696 TI - In vitro and in vivo evaluation of stimuli-responsive vesicle from PEGylated hyperbranched PAMAM-doxorubicin conjugate for gastric cancer therapy. AB - Gastric Cancer is one of the major leading causes of death by cancer worldwide, but the chemotherapeutics, one of the preferred approaches, bring about extensive side effects when systemically injected. In our work, doxorubicin-loaded pH and redox responsive hyperbranched poly(amidoamine)(h-PAMAM)-based vesicle was prepared to enhance anti-tumor efficacy of chemotherapeutic compounds. The doxorubicin (DOX) molecules were attached to PEGylated h-PAMAM by acid sensitive cis-aconityl linkage to form pH sensitive conjugate (PPCD), which self-assembled in THF into micelles. The resulted micelles were then crosslinked by disulfide bonds and transferred from THF into water to form vesicles, which could be disassembled into small-sized conjugates under the redox condition. The drug release profiles showed that the PPCD vesicle presented stimuli-triggered drug release in acidic and reducing environment, and lower DOX leakage under neutral condition. The in vitro cell assay reflected the rapid DOX release and significant tumor-cytotoxic effect of the PPCD vesicle. The in vivo anticancer activity and systematic toxicity studies showed that the PPCD vesicles had lower tissue toxicity with good antitumor effect. In brief, h-PAMAM-based PPCD vesicle provides a safe and effective drug delivery system for the therapy of gastric cancer. PMID- 27234697 TI - Dendrosomal curcumin nanoformulation modulate apoptosis-related genes and protein expression in hepatocarcinoma cell lines. AB - The side-effects observed in conventional therapies have made them unpromising in curing Hepatocellular carcinoma; therefore, developing novel treatments can be an overwhelming significance. One of such novel agents is curcumin which can induce apoptosis in various cancerous cells, however, its poor solubility is restricted its application. To overcome this issue, this paper employed dendrosomal curcumin (DNC) was employed to in prevent hepatocarcinoma in both RNA and protein levels. Hepatocarcinoma cells, p53 wild-type HepG2 and p53 mutant Huh7, were treated with DNC and investigated for toxicity study using MTT assay. Cell cycle distribution and apoptosis were analyzed using Flow-cytometry and Annexin-V-FLUOS/PI staining. Real-time PCR and Western blot were employed to analyze p53, BAX, Bcl-2, p21 and Noxa in DNC-treated cells. DNC inhibited the growth in the form of time-dependent manner, while the carrier alone was not toxic to the cell. Flow-cytometry data showed the constant concentration of 20MUM DNC during the time significantly increases cell population in SubG1 phase. Annexin-V-PI test showed curcumin induced apoptosis was enhanced in Huh7 as well as HepG2, compared to untreated cells. Followed by treatment, mRNA expression of p21, BAX, and Noxa increased, while the expression of Bcl-2 decreased, and unlike HepG2, Huh7 showed down regulation of p53. In summary, DNC-treated hepatocellular carcinoma cells undergo apoptosis by changing the expression of genes involved in the apoptosis and proliferation processes. These findings suggest that DNC, as a plant-originated therapeutic agent, could be applied in cancer treatment. PMID- 27234698 TI - Novel polymeric micelles for drug delivery: Material characterization and formulation screening. AB - A rising number of new chemical entities that exhibit only poor aqueous solubility are identified in drug discovery processes. Polymeric micelles composed of block copolymers (BP) facilitate the delivery of such lipophilic molecules in drug therapy. Consequently, a rational screening and selection procedure for novel BP was established. Further, the interplay of polymer structure, micelle formation and drug binding was studied. Therefore seven polymers (BP001 to BP007) were synthesized from different monomer compositions resulting in nanocarriers varying in surface decoration and lipophilicity. These polymers were characterized by H(1)-NMR and SEC. The molecular weight was ranging between 13 and 37kDa. The critical micelle concentration and micellar integrity in presence of human plasma were determined. Micelles were loaded with dexamethasone and characterized with regards to their size, morphology and surface charge. Polymeric micelles with a size of 49.21-236.37nm were obtained. A half-life of 11h was determined for five of the copolymers in presence of human plasma. Two nanocarrier formulations (BP006 and BP007) were exhibiting optimal micellar integrity in vitro and a modified release profile under biorelevant conditions. Strongest drug-polymer interaction was observed for nanocarrier compositions providing benzyl and carboxylic groups and were composed of BP006 and BP007. PMID- 27234699 TI - Argpyrimidine-tagged rutin-encapsulated biocompatible (ethylene glycol dimers) nanoparticles: Synthesis, characterization and evaluation for targeted drug delivery. AB - Diabetes mellitus represents a major metabolic disorder affecting millions of people all over the world. Currently available therapeutic treatments are not good enough to control the long-term complications of diabetes. Active targeting via inclusion of a specific ligand on the nanoparticles provides effective therapeutic approach in different diseases. However, such specific drug delivery systems have not been explored much in diabetes due to lack of suitable biological targets in this disorder. Our objective is to synthesize a ligand tagged drug-loaded nanoparticle for delivery of the drug at specific sites to enhance its therapeutic efficiency in diabetic condition. The nanoparticles have been prepared by using biocompatible ethylene glycol-bis (succinic acid N hydroxysuccinimide ester) dimers. Although advanced glycation end products (AGEs) are the root causes of diabetic complications, argpyrimidine, an AGE, possesses antioxidant and reducing activities. AGE interacts selectively with its cell surface receptors (RAGE), which are significantly increased in diabetic condition. We have selected RAGE as the target of argpyrimidine, which is tagged on the nanoparticles as a ligand. Rutin, having anti-hyperglycemic and anti glycating activities, has been used for nanoencapsulation. Rutin-loaded argpyrimidine-tagged nanoparticles have been synthesized and characterized. We have demonstrated the drug releasing capacity and target specificity of the synthesised drug delivery system under ex vivo and in vivo conditions. PMID- 27234700 TI - Anti-tumor effect via passive anti-angiogenesis of PEGylated liposomes encapsulating doxorubicin in drug resistant tumors. AB - The PEGylated liposomal (PEG-LP) Doxorubicin, PEG-LP (DOX), with a diameter of around 100nm, accumulates in tumors via the enhanced permeability and retention (EPR) effect, and is used clinically for the treatment of several types of cancer. However, there are a number of tumor types that are resistant to DOX. We report herein on a unique anti-tumor effect of PEG-LP (DOX) in a DOX-resistant tumor xenograft model. PEG-LP (DOX) failed to suppress the growth of the DOX resistant tumors (ex. non-small cell lung cancer, H69AR; renal cell carcinoma, OSRC-2) as observed in the xenograft model. Unexpectedly, tumor growth was suppressed in a DOX-resistant breast cancer (MDA-MB-231) xenograft model. We investigated the mechanism by which PEG-LP (DOX) responses differ in different drug resistant tumors. In hyperpermeable OSRC-2 tumors, PEG-LP was distributed to deep tumor tissues, where it delivers DOX to drug-resistant tumor cells. In contrast, extracellular matrix (ECM) molecules such as collagen, pericytes, cancer-associated fibroblasts render MDA-MB-231 tumors hypopermeable, which limits the extent of the penetration and distribution of PEG-LP, thereby enhancing the delivery of DOX to the vicinity of the tumor vasculature. Therefore, a remarkable anti-angiogenic effect with a preferential suppression in tumor growth is achieved. Based on the above findings, it appears that the response of PEG-LP (DOX) to drug-resistant tumors results from differences in the tumor microenvironment. PMID- 27234701 TI - Role of moisture on the physical stability of polymorphic olanzapine. AB - The focus of this study was the understanding of the hydrate transformations of anhydrous olanzapine Forms I and II (the most common polymorphs) upon exposure to different moisture conditions (11, 53, 75, 93% RH) and direct contact with water (e.g. aqueous slurry) and the impact of hydration on the aqueous dissolution rates of the polymorphs. The kinetics of reversible transformations (anhydrate hydrate phases) and the identification of polymorphs were evaluated by differential scanning calorimetry, thermogravimetry, infrared (DRIFT) and X-ray powder diffraction. The results showed that anhydrous Forms I and II have undergone water vapor phase induced transformations at 93% and 75% RH, respectively. At 93% RH Forms I and II showed to hydrate into dihydrates D and B, respectively, the latter with a higher hydration rate. The conversion of Form I into the dihydrate D showed to affect the dissolution rate of olanzapine (f2<50). As slurries both forms showed to hydrate into a mixture of two different Forms - dihydrate B and higher hydrate. The study provided an understanding of the conversion pathways of the different forms when they were exposed to humid air or aqueous environments, resembling the transformations that might occur during processing, storage or during the persecution of dissolution tests to assess the quality of dosage forms delivering olanzapine. PMID- 27234702 TI - Platelet lysate and chondroitin sulfate loaded contact lenses to heal corneal lesions. AB - Hemoderivative tear substitutes contain various ephiteliotrophic factors, such as growth factors (GF), involved in ocular surface homeostasis without immunogenic properties. The aim of the present work was the loading of platelet lysate into contact lenses to improve the precorneal permanence of platelet lysate growth factors on the ocular surface to enhance the treatment of corneal lesions. To this purpose, chondroitin sulfate, a sulfated glycosaminoglycan, which is normally present in the extracellular matrix, was associated with platelet lysate. In fact, chondroitin sulfate is capable of electrostatic interaction with positively charged growth factors, in particular, with bFGF, IGF, VEGF, PDGF and TGF-beta, resulting in their stabilization and reduced degradation in solution. In the present work, various types of commercially available contact lenses have been loaded with chondroitin sulfate or chondroitin sulfate in association with platelet lysate to achieve a release of growth factors directly onto the corneal surface lesions. One type of contact lenses (PureVision((r))) showed in vitro good proliferation properties towards corneal cells and were able to enhance cut closure in cornea constructs. PMID- 27234703 TI - Effects of temperature variability on community structure in a natural microbial food web. AB - Climate change research has demonstrated that changing temperatures will have an effect on community-level dynamics by altering species survival rates, shifting species distributions, and ultimately, creating mismatches in community interactions. However, most of this work has focused on increasing temperature, and still little is known about how the variation in temperature extremes will affect community dynamics. We used the model aquatic community held within the leaves of the carnivorous plant, Sarracenia purpurea, to test how food web dynamics will be affected by high temperature variation. We tested the community response of the first (bacterial density), second (protist diversity and composition), and third trophic level (predator mortality), and measured community respiration. We collected early and late successional stage inquiline communities from S. purpurea from two North American and two European sites with similar average July temperature. We then created a common garden experiment in which replicates of these communities underwent either high or normal daily temperature variation, with the average temperature equal among treatments. We found an impact of temperature variation on the first two, but not on the third trophic level. For bacteria in the high-variation treatment, density experienced an initial boost in growth but then decreased quickly through time. For protists in the high-variation treatment, alpha-diversity decreased faster than in the normal-variation treatment, beta-diversity increased only in the European sites, and protist community composition tended to diverge more in the late successional stage. The mortality of the predatory mosquito larvae was unaffected by temperature variation. Community respiration was lower in the high-variation treatment, indicating a lower ecosystem functioning. Our results highlight clear impacts of temperature variation. A more mechanistic understanding of the effects that temperature, and especially temperature variation, will have on community dynamics is still greatly needed. PMID- 27234704 TI - Constipation and risk of Parkinson's disease: A Danish population-based cohort study. AB - OBJECTIVES: To examine long-term associations between constipation and Parkinson's disease (PD) in men and women, we conducted a population-based cohort study using prospectively collected registry data on hospital contacts for constipation and PD, stratified by follow-up time and sex. METHODS: We linked Danish registries to construct a cohort of all patients in Denmark with an outpatient hospital diagnosis of constipation 1995-2012 and a matched general population comparison cohort. Using Cox regression, we computed hazard ratios (HRs) for PD and corresponding 95% confidence intervals (CIs), adjusting for potential confounders, stratified by sex and follow-up time. RESULTS: The 31,905 patients with constipation had a higher risk of PD than 159,092 comparison cohort members (adjusted (a) HR = 3.03, 95% CI 2.50-3.66), which was sustained to 11-15 years follow-up (aHR = 3.65, 95% CI 1.67-7.95). Increased risk was apparent in both sexes but stronger in men [aHR = 3.52 (2.67-4.64] than women [aHR = 2.64 (95% CI 2.02-3.44]. CONCLUSION: In this large population-based cohort study, constipation was associated with sustained increased risk of a PD diagnosis, and the relative risk was higher for men than for women. PMID- 27234705 TI - The unique myelopoiesis strategy of the amphibian Xenopus laevis. AB - Myeloid progenitors reside within specific hematopoietic organs and commit to progenitor lineages bearing megakaryocyte/erythrocyte (MEP) or granulocyte/macrophage potentials (GMP) within these sites. Unlike other vertebrates, the amphibian Xenopus laevis committed macrophage precursors are absent from the hematopoietic subcapsular liver and instead reside within their bone marrow. Presently, we demonstrate that while these frogs' liver-derived cells are unresponsive to recombinant forms of principal X. laevis macrophage (colony-stimulating factor-1; CSF-1) and granulocyte (CSF-3) growth factors, bone marrow cells cultured with CSF-1 and CSF-3 exhibit respectively archetypal macrophage and granulocyte morphology, gene expression and functionalities. Moreover, we demonstrate that liver, but not bone marrow cells possess erythropoietic capacities when stimulated with a X. laevis erythropoietin. Together, our findings indicate that X. laevis retain their MEP within the hematopoietic liver while sequestering their GMP to the bone marrow, thus marking a very novel myelopoietic strategy as compared to those seen in other jawed vertebrate species. PMID- 27234706 TI - Inflammatory markers as exacerbation risk factors after asthma therapy switch from inhaled steroids to montelukast. AB - BACKGROUND: Asthma guidelines allow anti-leukotriene medications to be used as an alternative to inhaled corticosteroids (ICS) in second-step intensity therapy. The aim of the study was to analyze the risk factors of exacerbations, particularly inflammatory markers, during the 12-month period following therapy reduction from an ICS to montelukast in young patients with mild asthma. METHODS: A total of 84 patients (aged 7-18 years old) with mild asthma controlled by low dose ICS, had their treatment switched to montelukast. Exhaled nitric oxide (eNO), sputum eosinophils (sEos), and bronchial hyperreactivity (BHR) were assessed at the beginning and then every three months throughout the one-year period. The patients with asthma exacerbations (first severe or third mild) were discontinued from the study. RESULTS: Over the study period, 22 patients (26%) discontinued montelukast due to asthma exacerbations. An increased risk of exacerbations was noted among patients with initial sEos above 2.5% (relative risk, RR 36.6; 95% CI: 7.1-189.3; p < 0.001), as well as those with augmented BHR (RR 9.5; 2.8-31.6; p < 0.001), or eNO greater than 20 ppb (RR 3.7; 95% CI: 1.3 10.7; p = 0.013). An increase in BHR and eNO was observed during the last visit before exclusion. CONCLUSIONS: After switching treatment from a low-dose ICS, montelukast maintained control of asthma symptoms in 75% of patients. High sEos before the treatment change was the strongest exacerbation risk factor. In patients with asthma controlled by low-dose ICS and low inflammatory markers, treatment could be safely switched to montelukast. PMID- 27234707 TI - [Disseminated masses]. PMID- 27234708 TI - A forgotten or minimized head trauma, rather than a mild FVII deficiency, is the most likely cause of a subdural hematoma. PMID- 27234709 TI - Prophylactic antibiotics to prevent pneumonia and other complications after measles: community based randomised double blind placebo controlled trial in Guinea-Bissau. PMID- 27234711 TI - Autologous Platelet-Rich Plasma for the Treatment of Pattern Hair Loss. AB - Platelet-rich plasma (PRP) is a solution derived from whole blood that is enriched in the platelet fraction. Platelets serve as a reservoir of growth factors and cytokines. When platelets are activated in vivo, signaling molecules are released into the immediate microenvironment and activate receptors for various pathways. Historically, PRP has been applied to wound beds to promote healing of complex wounds. Over the last decade, it has served as a valuable therapeutic tool in various specialties such as maxillofacial surgery, plastic surgery, orthopedics and sports medicine. Only recently has PRP been utilized for dermatologic purposes, more specifically, for the treatment of male and female pattern hair loss. In this review, we discuss molecular and cellular pathways upregulated by PRP important in hair folliculogenesis, and examine clinical evidence from all previously published studies involving the use of PRP for pattern hair loss. PMID- 27234710 TI - Site-specific characterization of N-linked glycosylation in human urinary glycoproteins and endogenous glycopeptides. AB - Glycosylation is a very important post-translational modification involved in various cellular processes, such as cell adhesion, signal transduction and immune response. Urine is a rich source of glycoproteins and attractive biological fluid for biomarker discovery, owing to its availability, ease of collection, and correlation with pathophysiology of diseases. Although the urinary proteomics have been explored previously, the urinary glycoproteome characterization remains challenging requiring the development and optimization of analytical and bioinformatics methods for protein glycoprofiling. This study describes the high confident identification of 472 unique N-glycosylation sites covering 256 urinary glycoproteins. Besides, 202 unique N-glycosylation sites were identified in low molecular weight endogenous glycopeptides, which belong to 90 glycoproteins. Global site-specific characterization of the N-linked glycan heterogeneity was achieved by intact glycopeptide analysis, revealing 303 unique glycopeptides most of them displaying complex/hybrid glycans composed by sialic acid and fucose. These datasets consist in a valuable resource of glycoproteins and N glycosylation sites found in healthy human urine that can be further explored in different disorders, in which the N-linked glycosylation may be aberrant. PMID- 27234713 TI - Preface. PMID- 27234712 TI - beta-Caryophyllene attenuates palmitate-induced lipid accumulation through AMPK signaling by activating CB2 receptor in human HepG2 hepatocytes. AB - SCOPE: Nonalcoholic fatty liver disease is currently the most common chronic liver disease worldwide, characterized by excessive hepatic lipid accumulation without significant ethanol consumption. We have performed a screening for medicinal foods that inhibit hepatocytic lipid accumulation through activation of AMP-activated protein kinase (AMPK), which is a critical regulator of the hepatic lipid metabolism. METHODS AND RESULTS: We found that clove (Syzygium aromaticum), which is commonly used as a spice, markedly inhibits palmitate-inducible lipid accumulation in human HepG2 hepatocytes. Analyses of the clove extracts found that beta-caryophyllene, an orally-active cannabinoid, is the principal suppressor of the lipid accumulation, and stimulates the phosphorylation of AMPK and acetyl-CoA carboxylase 1 (ACC1). Our data also showed that beta-caryophyllene prevents the translocation of sterol regulatory element-binding protein-1c (SREBP 1c) into the nucleus and forkhead box protein O1 (FoxO1) into the cytoplasm through AMPK signaling, and consequently, induces a significant downregulation of fatty acid synthase (FAS) and upregulation of adipose triglyceride lipase, respectively. Moreover, we demonstrated that the beta-caryophyllene-induced activation of AMPK could be mediated by the cannabinoid type 2 receptor-dependent Ca2+ signaling pathway. CONCLUSION: Our results suggest that beta-caryophyllene has the potential efficacy in preventing and ameliorating nonalcoholic fatty liver disease and its associated metabolic disorders. PMID- 27234714 TI - The Potential Role of Social Capital in the Willingness to be a Deceased Organ Donor: A Case Study of UK Polish Migrants. AB - BACKGROUND: In the United Kingdom, the demand for transplantable organs exceeds supply, leaving many patients on the active transplant waiting list with the majority on dialysis as the kidney is the most commonly transplanted organ. This is a marked issue across black, Asian, and minority ethnic communities. This article uses the Polish migrant community as a case study for making new theoretical insights into the willingness to become an organ donor in a host country using social capital theory. METHODS: There were 31 participants who took part in interviews and small group discussions. Grounded theory methodology was used as the study explored the relationships between deceased organ donation, religion, and Mauss's gift-exchange theory and the notion of social capital arose as an emergent theme from the study. RESULTS: Elements of social capital were explored with participants such as social networks, civil engagement, trust, and reciprocity. Polish social networks were found to be small and the formation of networks to be influenced by English language skills. Participants were willing to donate organs to others inside and outside of their social networks in the United Kingdom and wanted to help a patient in need and influenced by the overall migrant experience in the United Kingdom and whether they felt a sense of belonging. Overall, participants had mixed experiences and views about trust in the National Health Service. CONCLUSIONS: Through a discussion of the results using a communitarian social capital, cognitive and structural social capital lens, and collective-action theory, it is concluded that an interplay of these social capital theories can reframe debates within organ donation such as reciprocity policies, the relevancy of altruism, and the role of migration experiences and networks in the willingness to donate organs posthumously in a host country. PMID- 27234715 TI - Role of Religion in Organ Donation-Development of the United Kingdom Faith and Organ Donation Action Plan. AB - At a national policy level, the United Kingdom is at the forefront of recognizing the role of faith and its impact on organ donation. This is demonstrated by the recommendations of the Organ Donation Taskforce, National Institute for Clinical Excellence guidelines on organ donation, All-Party Parliamentary Kidney Group, and National Black, Asian and Minority Ethnic Taskforce Alliance. Evidence to date shows that further thought is required to ensure the active engagement of faith communities with organ donation in the UK. The "Taking Organ Transplantation to 2020" strategy was launched in July 2013 by National Health Service Blood and Transplant (NHSBT) in collaboration with the Department of Health and Welsh, Scottish, and Northern Irish governments and seeks to increase the number of people, from all sections of the UK's multiethnic and multifaith population, who consent to and authorize organ donation in their life. NHSBT seeks to work in partnership with faith leaders and this culminated in a Faith and Organ Donation Summit. Faith leaders highlight that there is a need for engagement at both national and local levels concerning organ donation as well as diagnosis and definition of death. PMID- 27234716 TI - Decision Making by Young Transplant Surgeons Regarding Expanded-Criteria Donors With Acute Kidney Injury or Allocation Failure. AB - BACKGROUND: The utilization of expanded-criteria donors (ECDs) has increased to overcome donor shortages. Unfortunately, the discard rate has also increased, especially in ECDs with acute kidney injury (AKI). We evaluated the outcomes of kidney transplantation in ECDs and standard-criteria donors (SCDs) with and without AKI. METHODS: We reviewed the medical records of patients who underwent kidney transplantation. We used the AKI definition published by the Kidney Disease: Improving Global Outcomes group and reviewed the demographic characteristics of donors and recipients. We analyzed transplantation outcomes. RESULTS: Twenty-seven patients underwent kidney transplantation from ECDs with AKI (n = 6) or without AKI (n = 5) and SCDs with AKI (n = 6) or without AKI (n = 10). Initial creatinine and estimated glomerular filtration rate (eGFR) were not significantly different between the groups. The incidence of delayed graft function was highest in ECDs with AKI (n = 3; 36.4%), but this was not a significantly difference. There was no difference in the last creatinine and eGFR in ECDs with AKI (1.32 mg/dL, 58.7 mL/min/1.73 m(2)), ECDs without AKI (1.67 mg/dL, 44.2 mL/min/1.73 m(2)), SCDs with AKI (0.94 mg/dL, 81.5 mL/min/1.73 m(2)) and SCDs without AKI (0.97 mg/dL, 81.8 mL/min/1.73 m(2)). CONCLUSIONS: As the donor pool is extended to ECDs, young transplant surgeons may increasingly face decisions regarding ECDs with AKI or allocation failure. There is no consensus regarding discard criteria. However, if the donor showed initially normal creatinine levels or if dual-kidney transplantation can be performed, young transplant surgeons should not hesitate to use ECDs with AKI or allocation failure. PMID- 27234717 TI - Safety and Effectiveness of Marginal Donor in Living Kidney Transplantation. AB - BACKGROUND: We evaluated the safety and feasibility of living kidney transplantation from marginal donors. PATIENTS AND METHODS: Between June 2006 and March 2015, we performed 61 living related renal transplantations at two renal transplantation centers. Marginal donors were defined as those who were older than 70 years or who had hypertension, reduced renal function, body mass index greater than 30 kg/m(2), or mildly impaired glucose tolerance. We retrospectively compared renal function and graft survival between marginal and standard living donor kidney transplantations. To evaluate renal function, creatinine clearance (CCr) was preoperatively used for donors, and estimated glomerular filtration rate (eGFR) was postoperatively used for donors and recipients. RESULTS: Among 61 donors, 14 (23%) met the marginal criteria, the major reason being hypertension (91%). The mean age tended to be higher in the marginal group. Preoperative eGFR was significantly lower in the marginal group, whereas postoperative renal function decline ratio at two years was not significantly different between the groups (67% vs 67%, P = .960). Five-year graft survival rates were not significantly different between the two groups. However, recipient eGFR 1 year after kidney transplantation was lower in the marginal group than in the standard group (44 +/- 8 vs 55 +/- 9 in eGFR, P = .003). CONCLUSIONS: No significant differences were observed between the groups regarding donor renal function. Careful marginal donor selection can be safe and feasible for donors and recipients of living kidney transplantation; however, it may have a negative impact on recipient renal function. PMID- 27234718 TI - Postoperative Compensatory Changes and Blood Flow Parameter of the Preserved Kidney in Elderly Living Related Donors Evaluated by Doppler Ultrasonography. AB - INTRODUCTION: Elderly kidney donors have recently become more common in living related kidney transplantation in Japan. Therefore, it is important to evaluate whether kidney function in elderly donors after nephrectomy is preserved over long periods of time. Doppler ultrasonography measurement is practical for donors after nephrectomy because it involves simple and noninvasive examinations. Doppler ultrasonography can detect compensatory hypertrophy and blood flow parameters, namely resistive index (RI) and pulsatility index (PI), of the preserved kidney in living donors. PATIENTS AND METHODS: Our study included 58 donors, divided into 2 groups according to age; the elderly donor group was comprised of those 65 years old or older. We measured length, width, and short diameter of the preserved kidney using Doppler ultrasonography, and calculated kidney volume. RESULTS: The elderly group was comprised of 13 patients. In this group, the median preserved kidney volume was 145.0 cm(3) (101.8-193.5) before nephrectomy, and 127.6 cm(3) (99.0-183.4) and 145.5 cm(3) (141.3-148.6) at 1 and 12 months after nephrectomy, respectively. We did not observe significant compensatory hypertrophy in the preserved kidneys of elderly donors postoperatively. Both the mean PI and RI values of elderly donors increased progressively after nephrectomy. No compensatory hypertrophy occurred in the preserved kidneys of elderly donors, although the PI and RI did increase in these donors. CONCLUSION: Our results indicate that nephrectomy caused nephrosclerosis in the preserved kidneys of elderly donors and that prevention of hypertension may be important after nephrectomy in elderly donors. PMID- 27234720 TI - Compensatory Hypertrophy After Living Donor Nephrectomy. AB - BACKGROUND: Previous studies have shown that kidney volume enhances the estimation of glomerular filtration rate (eGFR) in kidney donors. This study aimed to describe the phenomenon of compensatory hypertrophy after donor nephrectomy as measured on computerized tomographic (CT) scans. METHODS: An institutional Domain Specific Review Board (DSRB)-approved study involved approaching kidney donors to have a follow up CT scan from 6 months to 1 year after surgery; 29 patients participated; 55% were female. Clinical chart review was performed, and the patient's remaining kidney volume was measured before and after surgery based on CT scans. eGFR was determined with the use of the Modification of Diet in Renal Disease equation. RESULTS: Mean parenchymal volume of the remaining kidney for this population (mean age, 44.3 +/- 8.5 y) was 204.7 +/- 82.5 cc before surgery and 250.5 +/- 113.3 cc after donor nephrectomy. Compensatory hypertrophy occurred in 79.3% of patients (n = 23). Mean increase in remaining kidney volume was 22.4 +/- 23.2% after donor nephrectomy in healthy individuals. Over a median follow-up of 52.9 +/- 19.8 months, mean eGFR was 68.9 +/- 12.4 mL/min/1.73 m(2), with 24.1% of patients (n = 7) in chronic kidney disease grade 3. Absolute and relative change in kidney volume was not associated with sex, race, surgical approach, or background of hypertension (P = NS). There was a trend of decreased hypertrophy with increasing age (P = .5; Spearman correlation, -0.12). CONCLUSIONS: In healthy kidney donors, compensatory hypertrophy of the remaining kidney occurs in 79.3% of the patients, with an average increment of about 22.4%. Older patients may have a blunted compensatory hypertrophy response after surgery. PMID- 27234719 TI - A Novel Assessment of Vascular Regions Using an Intraoperative Near-Infrared Fluorescence. AB - INTRODUCTION: The risk of complications and transplant renal function increases in multiple arterial renal transplantations compared with single arterial renal transplantations. Even when multiple arteries are involved, with the introduction of laparoscopic nephrectomy, I mainly choose the left side kidney. Therefore, the number of renal artery reconstructions is increasing, and simultaneous imaging of arterial rebuilding during the donor nephrectomy is important. MATERIAL: Between 2006 and 2015, we performed 132 living donor kidney transplantations at our center and analyzed 32 cases that were diagnosed pre- and intraoperatively. METHOD: We compared the single renal artery (SRA) and multiple renal arteries (MRA) groups and analyzed the number of renal arteries, reconstruction methods, donor and recipient ages, sex, total ischemic times, and 1-month serum creatinine values. RESULT: In the MRA and SRA groups, the average recipient age was 52.3 and 47.0 years, respectively, while the average donor age was 52.9 and 53.1 years, respectively. In SRA and MRA groups, total ischemic time (TIT) was 96.1 and 143.6 min (P < .01). Serum creatinine level 1 month post-transplantation was 1.54 and 1.25, respectively (P < .001). Here we experienced 12 cases of living renal donor nephrectomy with multiple vessels in which the vascular supply territory was first assessed in April 2013 using an intraoperative near-infrared fluorescence camera system. In addition, regarding TIT, it is possible to shorten surgery by using individual anastomosis and ligation. CONCLUSION: By managing multiple donors; arteries by nephrectomy, it is possible to improve kidney transplantation results. PMID- 27234721 TI - Abdominal Aortic Calcification in Living Kidney Donors. AB - OBJECTIVE: This study assesses the association between abdominal aortic calcification (AAC) and renal function of living kidney donors and evaluate AAC as a surrogate marker for nephrosclerosis. METHODS: Between January 2010 and March 2013, 287 donors who underwent living donor nephrectomy were enrolled. We analyzed computed tomography angiographies and quantified AAC scores by calculating the Agatston score for the abdominal aorta. The donors were stratified into the non-AAC group (AAC score = 0; n = 238) and the AAC group (AAC score >0; n = 49). The relationship between AAC and perioperative estimated glomerular filtration rate was analyzed. For the 180 donors consenting to implantation biopsy, the nephrosclerosis score was defined as the sum of abnormalities, including glomerulosclerosis, tubular atrophy, interstitial fibrosis, and arteriosclerosis. RESULTS: The mean AAC score was 185.5 +/- 263.3 in the AAC group. The AAC group was older than the non-AAC group (51.1 +/- 6.1 vs 37.9 +/- 11 years; P < .001). Perioperative renal function was not different between the 2 groups. However, among the AAC group, donors with an AAC score of >100 were associated with delayed renal function recovery (P = .035). Donors with AAC were more likely to have glomerulosclerosis (50.0% vs 29.1%; P = .022), tubular atrophy (62.5% vs 33.1%; P = .002), and a higher nephrosclerosis score (P = .002). CONCLUSIONS: Living donors with an AAC score of >100 require close observation because they have a higher probability of delayed renal function recovery after donation. AAC is associated with nephrosclerosis in healthy adults. PMID- 27234722 TI - Study of Cadaveric Kidney Transplantation: A Single Center Experience. AB - BACKGROUND: To increase the number of cadaveric kidney transplants in Japan, it is necessary to proactively perform transplantation from marginal donors. We had the opportunity to frequently perform kidney transplantation from expanded criteria donors (ECDs), and it is anticipated that there will be increases in the number of ECD kidney transplants. METHODS: In our institution, 18 patients underwent cadaveric kidney transplantation from January 2001 to December 2011. Sixteen of those patients were classified into 2 groups according to donation after brain death (BD) or after cardiac death (CD). We also classified donors as ECDs or standard-criteria donors (SCDs). RESULTS: Kidney graft survival and engraftment were observed in all of the patients. Renal function at 1 year after transplantation was significantly better in the BD group than in the CD group. However, there was no significant difference between the groups in renal function at 3 and 5 years. Renal function at 1 and 3 years after transplantation was significantly better in the SCD group than in the ECD group, but there was no difference in renal function between the SDC and ECD groups at 5 years. CONCLUSIONS: The results were good for all of the patients. There are many reports that graft survival rate at 3-5 years after transplantation from ECDs is poorer than from SCDs. However, no statistically significant difference was found in kidney function at >=5 years between the ECD and SCD groups in our patients. PMID- 27234723 TI - Comparison of Cosmesis and Body Image After Laparoendoscopic Single-Site Versus Conventional Laparoscopic Donor Nephrectomy. AB - BACKGROUND: This study used a questionnaire to objectively assess the body image of donors who underwent conventional laparoscopic donor nephrectomy (L-DN) or laparoscopic single-site donor nephrectomy (LESS-DN). Surgical outcomes were compared between the two groups. METHODS: Twenty patients underwent L-DN and 20 underwent LESS-DN. The postoperative outcomes of the two approaches were retrospectively compared and evaluated for differences in cosmesis and body image. The questionnaire comprised a body image questionnaire, including a body image scale (BIS) and cosmetic scale (CS), and a photo-series questionnaire (PSQ). A higher score indicated a more favorable assessment. Pain was assessed by comparing the number of times an analgesic was administered during hospitalization. RESULTS: There were no significant differences in operative outcomes between L-DN and LESS-DN. The average BIS score (maximum possible, 20 points) was 18.5 points for patients who underwent L-DN and 19.5 points for patients who underwent LESS-DN (P = .025). Patients who underwent L-DN had a median CS score (maximum possible, 24 points) of 17.5 points, whereas patients who underwent LESS-DN had a median CS score of 19.0 points (P = .113). The average PSQ score was 7.1 points for patients who underwent L-DN and 8.8 points for patients who underwent LESS-DN (P = .01). Patients who underwent LESS-DN were administered an analgesic was significantly number of times less than patients who underwent DN (P = .01). CONCLUSIONS: LESS-DN results in a better body image and better cosmetic appearance than does L-DN, indicating the clinical usefulness of LESS-DN. PMID- 27234724 TI - Utility of the Japanese Glomerular Filtration Rate Equation in Estimating Glomerular Filtration Rate of Donor Kidney. AB - BACKGROUND: An equation for the estimated glomerular filtration rate (eGFR) is generally used for evaluating renal function in Japan. OBJECTIVE: To assess the accuracy of the preoperative eGFR for estimating kidney donors' measured glomerular filtration rate (mGFR). METHODS: Between April 2009 and August 2014, 91 Japanese living kidney donors were included in this study. The eGFR was calculated as follows: eGFR = 194 * serum creatinine(-1.094) * Age(-0.287) (and * 0.739 for women), and the mGFR was evaluated using inulin clearance. The preoperative eGFR was then compared with the mGFR. RESULTS: Patients included 27 men and 64 women with a mean age of 56.8 +/- 9.5 years (range, 36-79 years), mean body surface area of 1.56 +/- 0.14 m(2) (range 1.27-1.92 m(2)), mean body mass index of 22.3 +/- 2.3 kg/m(2) (range 14.0-27.0 kg/m(2)), and mean serum creatinine level of 0.66 +/- 0.14 mg/dL (range 0.39-0.97 mg/dL). The mean eGFR was 81.3 +/- 14.2 mL/min/1.73 m(2) (range 45.5-125.9 mL/min/1.73 m(2)), and the mean mGFR was 89.0 +/- 15.5 mL/min/1.73 m(2) (range 45.4-130.7 mL/min/1.73 m(2)). The eGFR was significantly lower than the mGFR (P < .001). The correlation coefficient for the relationship between the eGFR and mGFR values was 0.503, and the mean difference between the 2 values was -7.8 (8.7%). CONCLUSIONS: Although the eGFR correlated with the mGFR, the eGFR values did not accurately estimate the mGFR in living kidney donors. Therefore, it is necessary to evaluate the mGFR, especially in marginal kidney donors. PMID- 27234725 TI - Plasma Neutrophil Gelatinase-associated Lipoprotein in Living Kidney Donors. AB - BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker for acute kidney injury. This study was conducted to determine the clinical implications of perioperative plasma NGAL levels for renal function after living donor nephrectomy. METHODS: Between July 2013 and May 2014, 112 donors underwent live donor nephrectomy at our institution. Donor plasma NGAL levels were measured perioperatively for 6 months. The relationship between perioperative plasma NGAL and recovery of renal function was analyzed. Renal function was estimated with the Modification of Diet in Renal Disease formula. RESULTS: Mean preoperative NGAL was 62.1 +/- 29.5 ng/mL. Plasma NGAL was most elevated 1 week postoperatively (218 +/- 95.5 ng/mL), and stabilized after 1 month (122.9 +/- 45.3 ng/mL). Preoperative plasma NGAL was not correlated with donor age or preoperative estimated glomerular filtration rates (eGFR), but was negatively correlated with 6-month eGFR (r = -0.458, P < .001). During the observation period, plasma NGAL at 1 week was most correlated with 6-month eGFR (r = -0.554, P < .001). An ROC curve analysis showed that age, preoperative eGFR, and 1-week postoperative plasma NGAL were highly predictive of developing of chronic kidney disease (CKD), defined as eGFR <60 mL/min/1.73 m(2), 6 months postoperatively (AUC = 0.91, P < .001). One-week postoperative plasma NGAL was also independently associated with CKD risk at 6 months (odds ratio: 1.13 for each 10 ng/mL increase, P = .013). CONCLUSION: Plasma NGAL becomes elevated after kidney donation and can provide information about acute kidney injury during the compensatory hyperfiltration period. Donors with increased perioperative plasma NGAL require close observation because their possibility of developing CKD after donation may be greater. PMID- 27234726 TI - Ethical Issues in Live-Donor Reimbursement Program. AB - Reimbursement of expenses and costs incurred by live organ donation is permitted in many countries to encourage donation and to protect the welfare of live donors. Potential ethical issues may arise with reimbursement programs and their implementation, which vary across countries. This paper discusses some ethical issues with live donor reimbursement to stimulate discussion on how to ethically enhance its implementation to improve outcomes for both donors and recipients. In addition, we will consider whether reimbursement should be supplemented with compensation for nonfinancial losses, such as pain and suffering, to encourage live donation. PMID- 27234727 TI - Factors Determining Physical and Mental Quality of Life of Living Kidney Donors in Taiwan. AB - BACKGROUND: Living-donor kidney transplantation has a positive influence on recipients' life expectancy and improves quality of life for patients with end stage renal disease compared with dialysis patients. Evaluation of the physical and mental quality of life for donors can promote positive perceptions about donation and help potential donors in their decision-making process. The aim of this study was to explore the predictive factors of quality of life for living kidney donors. METHODS: A cross-sectional and descriptive design was used, and the study was conducted from January to July 2013. The donors were a convenience sample of 34 participants who had undergone kidney transplant surgery >1 year earlier. RESULTS: The results showed that kidney donors had a low to moderate physical and mental quality of life. Multiple regression analysis revealed that financial concerns and anxiety explained 27.8% of the total variance of quality of life in the physical component. Anxiety and paid work explained 61.4% of the total variance of quality of life in the mental component. CONCLUSIONS: After renal transplantation, living kidney donors experienced low to moderate quality of life. Because donors are family members (siblings, sons or daughters, spouses, or parents), monthly family income is a significant issue that influences both the decision to donate and quality of life after transplantation. Our findings suggest that pre-transplantation assessment must include social workers as part of the health care team to evaluate the impact of a donor's financial status on post-transplantation quality of life. PMID- 27234728 TI - Gene Polymorphisms of CD207 (Langerin) Are Associated With End-Stage Renal Disease. AB - BACKGROUND: The CD207 molecule, also known as langerin, is known to be the first immunologic barrier expressed on Langerhans cells, which are the immature dendritic cells of the epidermis and mucosa. Inflammation could be a causal factor in the progression of chronic kidney disease. To date, convincing experimental and clinical evidence indicates that langerin plays a role in antigen uptake and processing, which is the primary function of Langerhans cells. In this study, we hypothesized that polymorphisms of the CD207 (Langerin) gene may be associated with end-stage renal disease (ESRD). METHODS: To evaluate whether an association exists between CD207 and ESRD susceptibility, we assessed the relation between 10 exonic single-nucleotide polymorphisms (SNPs) in the CD207 gene and ESRD in 90 kidney transplant patients and 545 control subjects. RESULTS: Compared with the control participants, the frequencies of the CD207 rs13421115*T and rs17718987*C alleles were significantly higher in the patients with ESRD. Genotyping analysis demonstrated that 2 SNPs (rs13421115 and rs17718987) included in the study were significantly associated with ESRD in the codominant1 (rs13421115; Fisher exact P = .027), dominant (rs13421115; Fisher exact P = .004; and rs17718987; Fisher exact P = .004), and log-additive (rs13421115; Fisher exact P = .004; and rs17718987; Fisher exact P = .004) models after adjusting for age and sex. CONCLUSIONS: We suggest that CD207 gene polymorphisms rs13421115 and rs17718987 increase the risk of development of ESRD. PMID- 27234729 TI - Role of Pretransplant Complement-fixing Donor-specific Antibodies Identified by C1q Assay in Kidney Transplantation. AB - BACKGROUND: Kidney transplant recipients who have pretransplant donor-specific human leukocyte antigen (HLA) antibodies have greater risk for developing allograft rejection and allograft loss. However, there is a varied effect of graft injury among patients with pretransplantation donor-specific antibodies (DSA). The difference of complement activating ability may be the reason why some DSA are detrimental to kidney allograft. This study aimed to investigate the association between pretransplantation C1q-binding DSA and clinical outcomes. METHODS: This retrospective study included 48 pretransplant sera from kidney transplant recipients who had pretransplant DSA with negative complement dependent cytotoxic (CDC) crossmatches. The IgG DSA testing and C1q testing were performed on a Luminex platform with single antigen bead assay. The clinical outcomes between C1q-positive and C1q-negative groups were compared. RESULTS: C1q positive DSA were detected in 12 out of 48 patients (25%). The incidences of antibody-mediated rejection (AMR) were higher among patients with C1q-positive DSA than patients with C1q-negative DSA (66.7% vs 41.7%). Nevertheless, there were no statistically significant associations between C1q-DSA and AMR (odds ratio 2.8, 95% CI 0.68-11.6, P = .13) and between C1q-DSA and graft loss (odds ratio 0.52, 95% CI 0.09-2.89, P = .44). The C1q-positive DSA group had significantly higher IgG DSA MFI than the C1q-negative DSA group (P < .001). CONCLUSION: C1q-binding ability of DSA in pretransplant sera of kidney recipients was not associated with antibody-mediated rejection and graft loss post transplantation. In contrast with the clinical relevance of C1q testing in the post-transplantation setting, C1q testing in pretransplant sera has limited use for immunological risk assessment. PMID- 27234730 TI - Significance of HLA Antibody Detected by PRA-Bead Method in Kidney Transplant Outcomes. AB - BACKGROUND: The impact of specific HLA antibodies on the allograft function in the Luminex era is not clearly known. This study aimed to investigate kidney transplantation outcomes in patients with different anti-HLA antibody status as detected by Luminex PRA. METHODS: This retrospective study included 106 deceased donor kidney transplantation (DDKT) patients divided into 3 groups by PRA status as detected by PRA-bead: (1) PRA = 0; (2) positive PRA but with negative antibody against donor's HLA antigens; and (3) positive PRA with positive anti-HLA antibody specificity against donor's HLA antigens. RESULTS: There were 65, 23, and 18 patients in groups 1, 2, and 3, respectively. Early allograft rejections were highest in group 3 (22.2%) (P = .02). In multivariate analysis, delayed graft function was the only factor that was associated with allograft rejection (hazard ratio, 8.9; 95% confidence interval, 1.9-39.8; P = .004). Estimated glomerular filtration rates at 1 year of the 3 groups were 54.6, 55.8, and 60.0 mL/min (P = .71). One-year allograft failure and death were not different among the 3 groups. Expanded-criteria deceased donors were associated with both allograft failure (P = .003) and patient death (P = .02). CONCLUSIONS: Anti-HLA antibody as detected by Luminex PRA was associated with early allograft rejection but not graft or patient survival. The effect of newer treatment modalities can improve the outcomes of PRA-positive patients to be similar to nonsensitized patients at 1 year. PMID- 27234731 TI - Evaluation of Changes in New Calculated Panel Reactive Antibody Adopting HLA-Cw, DR51/52/53, and DQ Antigens in Koreans. AB - BACKGROUND: Calculated panel reactive antibody (cPRA) (%) is percentage of donors that would be incompatible with the candidate, based on the candidate's unacceptable HLA antigens. cPRA based on antigen frequencies of HLA-A, B, and DR has been used in Korea. We developed new cPRA including HLA-Cw, DR51/52/53, and DQ. Changes in new-cPRA were evaluated. METHODS: We analyzed the differences between cPRA based on HLA-A, -B, and -DR antigens (old-cPRA) from cPRA based on HLA-A, -B, -Cw, -DR, -DR51/52/53, and -DQ antigens (new-cPRA) on 125 waitlisted candidates for renal transplantation in Seoul National University Hospital. cPRA for unacceptable antigens was calculated according to 3 different cut-off values (MFI <1000, 3000, and 10000 for cPRAw, cPRAm, and cPRAs, respectively). RESULTS: For HLA class I, cPRAw and cPRAm were significantly increased in new-cPRA compared to old-cPRA (median 78.3% vs 71.7%, P < .001; 34.0% vs 23.5%, P = .029, respectively). For HLA class II, cPRAw, cPRAm, and cPRAs were significantly increased in new-cPRA compared to old-cPRA (median 86.8% vs 42.6%; 58.0% vs 0.0%; 0.0% vs 0.0%, P < .001 for all). CONCLUSIONS: cPRA (%) including HLA-Cw, DR51/52/53, and -DQ showed remarkable increase, especially in HLA class II antigens. The meaning of this should be carefully interpreted through further studies considering clinical outcomes. PMID- 27234732 TI - Impact of Pretransplant Panel-Reactive Antibody Level on Renal Graft Survival in Patients With a Negative Crossmatch and No Donor-Specific Antibody. AB - BACKGROUND: Patients with high panel-reactive antibody (PRA) levels before transplantation tend to remain on the waiting list longer when considering cadaveric donor transplantation and have worse outcomes than those with lower PRA levels. This study investigated the impact of the pretransplantation PRA level on rejection and graft survival after kidney transplantation in patients with a negative crossmatch (CXM(-)) and no donor-specific antibody (DSA(-)). METHODS: We retrospectively analyzed 513 recipients of kidney allograft treated from January 2009 to April 2013. Those who tested positive on crossmatching, had donor specific antibodies, were ABO incompatible, or had no PRA level data were excluded (n = 130). The remaining patients were stratified into 3 groups according to their PRA levels: group I, PRA = 0 (314 [80.1%]); group II, PRA <=50% (27 [7.2%]); and group III, PRA >50% (27 [7.2%]). Graft failure was defined as a return to dialysis, transplant nephrectomy, or death with a functioning kidney. RESULTS: The mean patient follow-up was 30.4 +/- 4.6 months. The rejection rate was 20.1% (group I, 18.5% [n = 58] vs group II, 23.8% [n = 10] vs group III, 33.3% [n = 9] [P = .053]). The graft failure rate was 21.7% (group I, 6.4% [n = 20] vs group II. 7.1% [n = 3] vs group III, 7.4% [n = 7] [P = .792]), and the 3-year graft survival rates were 96.3, 92.4, and 92.5%, respectively (P = .851). CONCLUSIONS: The pretransplant PRA level was not significantly associated with graft survival in patients with CXM(-) and DSA(-). However, the rejection rate tended toward significance as the PRA level increased (P = .053). PMID- 27234733 TI - Effectiveness of Multimedia for Transplant Preparation for Kidney Transplant Waiting List Patients. AB - BACKGROUND: A multimedia program could effectively advise patients about preparing for transplantation while on the waiting list for a kidney transplant. This study aimed to compare knowledge about transplant preparation for patients on a kidney transplant waiting list before and after participating in a multimedia program, and to evaluate patient satisfaction with the multimedia program. METHODS: Research design was quasiexperimental with the use of 1 group. Subjects were 186 patients on the kidney transplant waiting list after HLA matching in Ramathibodi Hospital. The questionnaires were developed by the researchers. The statistical tools used were basic statistics, percentage, average, standard deviation, and the difference of score between before and after participation in the multimedia program (t test). RESULTS: The evaluation knowledge for transplant preparation for kidney transplant waiting list patients after participating in the multimedia program averaged 85.40%, and there was an increased improvement of score by an average 3.27 out of a possible full score of 20 (P < .05). The result of patient satisfaction for the multimedia program had good average, 4.58. PMID- 27234734 TI - Clinical Experience of Late Conversion From Antimetabolites With Standard Exposure Calcineurin Inhibitors to Everolimus With Calcineurin Inhibitor Minimization in Stable Kidney Transplant Recipients With Good Renal Function. AB - INTRODUCTION: This study describes our clinical experience of late conversion from antimetabolites with standard exposure calcineurin inhibitors (CNIs) to everolimus with CNI minimization in stable kidney transplant recipients with good graft function. PATIENTS AND METHODS: A 1-year retrospective pilot study of 26 kidney recipients converted from antimetabolites with standard exposure CNIs to everolimus with CNI minimization was performed. The recipients enrolled in this study had normal or slightly impaired renal function defined as a serum creatinine value <2.0 mg/dL, and normal or slightly increased albuminuria defined as a urinary albumin excretion rate <100 mg/g creatinine. RESULTS: The median time from transplant to conversion was 39.5 months posttransplant (range, 3-275). Treatment with everolimus was stopped owing to adverse events in 11 patients (42.3%). In the analysis of the patients in whom everolimus was maintained, the mean estimated glomerular filtration rate (eGFR) significantly increased from 50.7 +/- 11.9 mL/min/1.73 m(2) at baseline to 53.6 +/- 13.9 mL/min/1.73 m(2) at 1 year after conversion. In the patients in whom everolimus was stopped during the observation period, there was no difference in eGFR between baseline and 1 year after conversion. CONCLUSIONS: This study demonstrated that, among the patients converted to everolimus at a late stage, there was no deterioration in renal function whether everolimus was maintained or stopped within 1 year after conversion. PMID- 27234735 TI - Induction Immunosuppressive Therapy With Everolimus and Low-Dose Tacrolimus Extended-Release Preserves Good Renal Function at 1 Year After Kidney Transplantation. AB - BACKGROUND: Utilization of everolimus (EVR) has been increasing in recent years for patients undergoing renal transplantation to reduce calcineurin inhibitor (CNI) levels. However, an optimum regimen has yet to be established. METHODS: We retrospectively examined 12 renal transplant recipients who underwent an induction immunosuppressive protocol; the protocol comprises 5 agents, including EVR plus low-dose tacrolimus extended-release (TAC-ER) treatment. We compared those findings from those of 14 patients who underwent a conventional protocol without EVR. Clinical outcome and pathologic changes were assessed by using protocol graft biopsy findings obtained at 3 months and 1 year after transplantation. RESULTS: The estimated glomerular filtration rate was significantly higher for the EVR group at both 3 months and 1 year compared with the conventional group (P < .01 and P = .03, respectively). TAC-ER trough levels were also significantly lower at 3 months and 1 year (both, P < .01). Histologic findings of the 3-month protocol biopsy samples in the EVR group revealed 4 cases of borderline change and 2 of acute cellular-mediated rejection. The findings from the 1-year biopsy samples revealed 10 cases with normal findings with no evidence of CNI toxicity. Patients in the EVR group developed subclinical borderline change and acute cellular-mediated rejection after 3 months at a significantly higher rate than the conventional group (P = .02). CONCLUSIONS: Use of the present therapeutic strategy successfully maintained the trough of each drug at a lower level, and it also kept renal function stable up to 1 year after transplantation. PMID- 27234736 TI - Effectiveness of the Combination of Everolimus and Tacrolimus With High Dosage of Mizoribine for Living Donor-Related Kidney Transplantation. AB - BACKGROUND: Everolimus (EVR) has been used widely for the purpose of reducing the dosage of calcineurin inhibitor (CNI), leading to decreasing CNI nephrotoxicity. In Japan, high-dose mizoribine (MZR) (6 mg/kg/day) has been increasingly used because of incidences of virus infection and gastrointestinal disorder in kidney transplant recipients. However, the efficacy and safety of EVR and MZR combination therapy is still uncertain. METHODS: A total of 29 living kidney transplant recipients from October 2012 to June 2014 were analyzed. Tacrolimus (TAC), MZR, basiliximab, and prednisolone were administered to all recipients. EVR was added to the regimen for 10 recipients from postoperative day 10 to 14; TAC trough levels were minimized simultaneously (EVR group). The remaining 19 recipients were defined as the control group. We evaluated the outcomes between the 2 groups. RESULTS: The mean TAC trough level was 5.17 ng/mL at 1 month after transplantation in the EVR group, and 7.89 ng/mL in the control group (P = .007), respectively. The mean TAC trough level was 4.0 ng/mL at 18 months after transplantation in the EVR group, and 6.97 ng/mL in the control group (P = .003) respectively. There were no differences in the rate of acute rejection and serum creatinine level. There was no significant difference in the incidence of histological nephrotoxicity between the 2 groups in the 1-year biopsy results. CONCLUSIONS: We succeeded in reducing TAC trough level immediately after transplantation by adding EVR. Our study results suggest that this combination therapy is effective for kidney transplantation recipients. PMID- 27234737 TI - Risk Factors Associated With Mammalian Target of Rapamycin Inhibitor Withdrawal in Kidney Transplant Recipients. AB - BACKGROUND: Mammalian target of rapamycin inhibitors (mTORi) play an essential role as novel immunosuppressive agents in kidney transplantation (KT). Treatment cessation usually occurs after adverse effects occur. We investigated the risk factors associated with withdrawal of mTORi in KT recipients and evaluated the outcomes related to the withdrawal. METHODS: The study enrolled KT recipients being followed up in a medical center in southern Taiwan from January 1999 through December 2014. RESULTS: Risk factors associated with mTORi withdrawal were initial proteinuria level, higher initial serum creatinine level posttransplantation, and history of glomerulonephritis as the primary etiology of renal failure. mTORi withdrawal was associated with increased risk of graft failure (hazard ratio [HR], 9.97 [95% confidence interval (CI), 1.03-96.8]; P = .047). Higher body mass index (HR, 11.2 [95% CI, 1.63-76.6]; P = .01) and tacrolimus usage (HR, 8.30 [95% CI, 1.14-60.7]; P = .037) were associated with increased risk of new-onset diabetes after transplantation in mTORi withdrawal groups. CONCLUSIONS: Proteinuria, poor graft function, and primary glomerulonephritis were associated with cessation of mTORi treatment. Earlier identification of these risk factors may prevent further adverse events and optimize transplantation outcomes after mTORi conversion. PMID- 27234738 TI - Efficacy and Safety of High-Dose Mizoribine Combined With Cyclosporine, Basiliximab, and Corticosteroids in Renal Transplantation: A Japanese Multicenter Study. AB - Mizoribine (MZR) is an immunosuppressive agent that exhibits a less potent immunosuppressive effect at doses up to 3 mg/kg/d. We investigated whether high dose MZR is effective and safe for renal transplant patients in conjunction with cyclosporine (CsA), basiliximab, and corticosteroids. Ninety Japanese renal transplant patients were administered MZR (6 mg/kg/d), CsA (7 mg/kg/d), prednisolone (maintenance dose, 10 mg/d), and basiliximab (20 mg/body). They were compared with a control group of 81 renal transplant patients who received mycophenolate mofetil (MMF; 1500 mg/d), CsA, prednisolone, and basiliximab. The 2 year patient and graft survival rates were 98.9% and 97.8% in the MZR group and 98.8% and 97.5% in the MMF group, respectively. The rejection rate within 2 years after transplantation was 21.1% in the MZR group and 16.0% in the MMF group; the difference was nonsignificant. None of the MZR group developed cytomegalovirus (CMV) disease, whereas 12.3% of the MMF group contracted CMV (P < .0001). CMV viremia developed in 28.9% of the MZR group vs 46.9% of the MMF group (P < .0001); their peak antigen levels were 20.4 +/- 44.1 and 252.8 +/- 527.0 (P < .01). Furthermore, the incidence of gastrointestinal disorder, hyperlipidemia, and blood disorder was significantly lower in the MZR group than in the MMF group. The combination of high-dose MZR with CsA, basiliximab, and corticosteroids not only provides satisfactory immunosuppression but is also associated with a low incidence of CMV infection and gastrointestinal and blood disorders. PMID- 27234740 TI - Progress in Desensitization of the Highly HLA Sensitized Patient. AB - The presence of HLA antibodies remains a significant and often impenetrable barrier to kidney transplantation, leading to increased morbidity and mortality for patients remaining on long-term dialysis. In recent years, a number of new approaches have been developed to overcome these barriers. Intravenous immunoglobulin (IVIG) remains the lynchpin of HLA desensitization therapy and has been shown in a prospective, randomized, placebo-controlled trial to improve transplantation rates. In addition, IVIG used in low doses with plasma exchange is a reliable protocol for desensitization. Another significant advancement was the addition of rituximab (anti-B-cell therapy) to IVIG and plasma exchange-based desensitization. This approach has significantly improved rates of transplantation and outcomes. There is limited experience with bortezomib (anti plasma cell therapy) and eculizumab (complement inhibition) for desensitization. However, recent data from a completed trial of eculizumab failed to show a significant benefit for prevention of antibody-mediated rejection compared with standard therapy plus placebo, and bortezomib produced inconsistent results. There is a growing interest in developing new therapeutic agents for desensitization. Newer approaches that address antibody reduction with B-cell depletion are discussed. PMID- 27234739 TI - Immunosuppressive Therapy for Elderly Kidney Transplant Recipients. AB - OBJECTIVES: In elderly kidney transplant (KT) recipients, the incidence of acute rejection is decreased, while that of fatal infections is increased. There are currently no guidelines for an upper age limit for KT, which is very difficult to determine. Here we examined several cases of elderly KT recipients. METHODS: We evaluated 127 KT patients treated at our department between 2003 and 2012 and followed them for 3 years post-transplant. The subjects were divided into two groups by age: >=60 years (elderly group; n = 24); and <59 years (non-elderly group; n = 103). The presence or absence of acute rejection and infection, dose of immunosuppressive drugs, trough calcineurin inhibitor level, renal function, and graft and patient survival rates were retrospectively examined. RESULTS: Our basic immunosuppressive regimen was a combination of calcineurin inhibitor, methylprednisolone, mycophenolate mofetil, and basiliximab. At 1 year post transplantation, the average tacrolimus and cyclosporine dose and trough levels were not significantly different. The mean dose of mycophenolate mofetil in the elderly group at 1 year post-transplantation was significantly lower than that of the non-elderly group. The incidences of cytomegalovirus infection and acute rejection during follow-up did not differ significantly between groups. There were no significant differences in creatinine level between the two groups. In the elderly group, the graft survival rates at 1 and 5 years were 100% and 95.4%, respectively, while those in the non-elderly group were 98.1% and 92.5%, respectively. CONCLUSION: Using our current immunosuppressive protocol, the outcomes of patients in the elderly group were considered acceptable. PMID- 27234741 TI - Complement Inhibition for Prevention and Treatment of Antibody-Mediated Rejection in Renal Allograft Recipients. AB - Therapeutic interventions aimed at the human complement system are recognized as potentially important strategies for the treatment of inflammatory and autoimmune diseases because there is often evidence of complement-mediated injury according to pathologic assessments. In addition, there are a large number of potential targets, both soluble and cell bound, that might offer potential for new drug development, but progress in this area has met with significant challenges. Currently, 2 drugs are approved aimed at inhibition of complement activation. The first option is eculizumab (anti-C5), which is approved for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Eculizumab has also been studied in human transplantation for the treatment and prevention of antibody-mediated rejection (ABMR). Initial data from uncontrolled studies suggested a significant benefit of eculizumab for the prevention of ABMR in highly HLA-sensitized patients, but a subsequent randomized, placebo controlled trial failed to meet its primary endpoint. Anecdotal data, primarily from case studies, showed benefits in treating complement-mediated ABMR. A second approved complement-inhibiting therapy is C1 esterase inhibitor (C1-INH), which is approved for use in patients with hereditary angioedema, a condition caused by mutations in the gene that codes for C1-INH. A recent placebo-controlled trial of C1-INH for prevention of ABMR in HLA-sensitized patients found that the drug was safe, with evidence for inhibition of systemic complement activation and complement-activating donor-specific antibodies. Other drugs are now under development. PMID- 27234742 TI - A Promoter Polymorphism in the CD46 Complement Regulatory Protein Gene Is Associated With Acute Renal Allograft Rejection. AB - OBJECTIVES: CD46 molecule (complement regulatory protein [CD46]), known as a human cell surface receptor, plays an important role in complement and T-cell regulation for organ transplantation. This study was performed to evaluate the association of promoter polymorphism (rs2796267, -496 A/G) of the CD46 gene with acute renal allograft rejection (AR), late acute rejection (LAR), and graft loss (GL) in Korean patients. METHODS: A total of 334 patients with kidney transplants were recruited. Transplantation outcomes were determined in terms of AR, LAR, and GL criteria. The promoter single nucleotide polymorphism (SNP) of CD46 was genotyped by direct sequencing. RESULTS: The rs2796267 SNP exhibited significant differences between the AR group and non-AR group (codominant1 model, P = .012; odds ratio [OR], 0.47 [95% confidence interval, 0.26-0.84]; dominant model, P = .012; OR, 0.50 [95% CI, 0.29-0.86]; and allele distribution, P = .034; OR, 0.64 [95% CI, 0.43-0.94]). In addition, the SNP also exhibited significant associations with LAR (codominant2 model, P = .041; OR, 0.12 [95% CI, 0.02-0.92]; recessive model, P = .005; OR, 0.13 [95% CI, 0.02-0.94]; and allele distribution, P = .038; OR, 0.58 [95% CI, 0.35-0.97]). CONCLUSIONS: This study suggests that the promoter polymorphism (rs2796267, -496 A/G) CD46 gene may be related to susceptibility of AR in Korean kidney transplantation recipients. PMID- 27234743 TI - Association Interleukin-4 and Interleukin-4 Receptor Gene Polymorphism and Acute Rejection and Graft Dysfunction After Kidney Transplantation. AB - BACKGROUND: Cytokine genotypes have previously been studied in patients undergoing solid organ transplantation; certain polymorphisms have been implicated in the development of acute rejection (AR) and graft dysfunction (GD). Allograft outcomes determined, in part, by alloimmune responses is mainly mediated by T-cell responses, activated and driven by cytokines. Interleukin-4 (IL-4) is one such cytokine, which exerts its biological effects through binding to the IL-4 receptor (IL-4R) complex on target cells. In the present study, we investigated whether polymorphisms of the IL-4 and/or IL-4R gene were associated with susceptibility to acute AR and GD after kidney transplantation. METHODS: We analyzed 2 single nucleotide polymorphism (SNPs) of IL-4 (rs2243250 and rs2070874) and 3 SNPs of IL-4R (rs1801275, rs2107356, and rs1805010) in 344 kidney transplant recipients. These patients included 62 of whom had developed AR and 215 of whom had GD in 1 year after kidney transplantation. RESULTS: The AR group included 62 patients (45 men and 17 women). There was a statistically significant difference in the male-to-female ratio and the use of tacrolimus in the AR group. The GD group included 215 patients. Patients who developed GD were more likely to be older and have an underlying cause of end-stage renal disease that was unknown compared with patients who did not have GD, the cause of which was typically known. Among the SNPs examined, 1 of the SNPs in the IL-4R gene (ie, rs1801275) showed a statistical association with AR (co-dominant model, P = .061; dominant model, P = .019; and log-addictive model, P = .029). In addition, 1 of the IL-4R SNPs (ie, rs2107356) was statistically associated with GD (dominant model, P = .034). No significant difference in the IL-4 genotype was observed between the AR/GD and non-AR/non-GD subjects. CONCLUSIONS: One IL-4R gene polymorphism (rs1801275) was associated with AR. In addition, a separate IL 4R SNP (rs2107356) was statistically associated with GD after kidney transplantation. PMID- 27234744 TI - Short-Term Outcomes of ABO-Incompatible Living Donor Kidney Transplantation With Uniform Protocol: Significance of Baseline Anti-ABO Titer. AB - Antibody-mediated rejection (AMR) is one of the major causes of poor outcomes in ABO-incompatible kidney transplantation (ABOi KT). Studies investigating AMR risk factors found that anti-ABO titer is a major issue. However, the significance of antibody titer has been debated. This retrospective study analyzed AMR risk factors in 59 patients who underwent ABOi KT between August 2010 and January 2015. We also analyzed AMR risk factors in recipients with high anti-ABO baseline titers (>=1:64 on dithiothreitol at 37 degrees C phase or >=1:256 on antihuman globulin phase). The 2-year patient survival rate was 95.8%, and the 2-year graft survival rate was 94.9%. Nine patients (15.3%) experienced clinical (6 of 59 [10.2%]) or subclinical (3 of 59 [5.1%]) AMR. One patient experienced graft loss from hyperacute rejection. AMR risk factor analysis revealed that baseline antibody titer was associated with incidence of AMR. In patients with high baseline titers, low doses of rituximab (200-mg single-dose), an antibody against CD20, was predictive for AMR. Six patients who received pretransplant intravenous immunoglobulin did not experience AMR even when they had high baseline antibody titers. Our results indicate that a high baseline antibody titer affected the incidence of AMR. ABOi KT candidates with high baseline titers need to undergo an intensified preconditioning protocol, including high-dose rituximab (375 mg/m(2)) and intravenous immunoglobulin. PMID- 27234745 TI - Preemptive Living Donor Kidney Transplantation and Kidney Function at the Initial Hospital Visit: A Single-Center Case-Control Study. AB - BACKGROUND: Studies have revealed that patients who undergo preemptive kidney transplantation (PKT) have favorable prognoses compared with those who undergo kidney transplantation after the initiation of dialysis. The number of PKT cases performed worldwide has been increasing. The goal of this study was to determine the clinical characteristics of patients who may successfully receive PKT. METHODS: A single-center, case-control study was conducted to determine the clinical factors that lead to referral for PKT. RESULTS: Between April 1, 2009, and August 1, 2015, a total of 118 patients underwent living donor kidney transplantation. Thirty of these patients had not undergone dialysis before their initial visit to the study hospital. Of these, 20 received kidney transplantation before and after dialysis initiation, respectively (group PKT+, successful PKT; group PKT-, failed PKT). The baseline characteristics at the primary visit were compared between groups. The median duration from the first visit to the study institution to PKT was 5.6 +/- 0.7 months. Serum creatinine (Cr) levels differed significantly between groups (PKT+ vs PKT-, 6.0 +/- 0.3 mg/dL vs 7.5 +/- 0.5 mg/dL; P = .03). The receiver-operating characteristic curves revealed that a serum Cr level >5.7 mg/dL at the initial visit to the unit was a cutoff point for predicting the success of PKT (area under the curve, 0.721; P = .02). CONCLUSIONS: Our results indicate that PKT should be performed within ~6 months of the initial visit to the transplant center. Serum Cr levels <5.7 mg/dL predict successful PKT. PMID- 27234746 TI - Clinical Outcomes and Results of Pathological Findings of 1-year Protocol Biopsy in Recipients of ABO-Incompatible Living Donor Kidney Transplantants. AB - OBJECTIVES: ABO-incompatible kidney transplantation has increased the possibility of finding suitable living donors for patients with renal failure. However, there are inevitable immunological risks, including a high risk of early post transplantation complications. The purpose of this study was to evaluate recipient outcomes following ABO-incompatible kidney transplantation. METHODS: Seventy-one patients who had undergone living-donor kidney transplantation (LDKT) at our center between January 2008 and December 2013 were divided into ABO incompatible (ABOi; n = 21) and ABO-compatible (ABOc; n = 50) groups. Baseline data, graft function, immunosuppressant use, and the results of biopsy 1 year after LDKT were compared between the groups. RESULTS: Recipient preemptive LDKT rates were significantly different between groups (P = .017). Graft function, incidence of infection, and rates of T-cell-mediated rejection and borderline changes requiring medication were not significantly different. There was no acute antibody-mediated rejection. Selectivity of the immunosuppressant, tacrolimus, was significantly different between groups (P < .01); however, steroid withdrawal rates, mycophenolate mofetil doses, and calcineurin inhibitor trough levels were not different. Regarding biopsy data, interstitial fibrosis scores were significantly different between groups (P = .011), as were interstitial fibrosis and tubular atrophy scores (P = .045) and arteriolar hyalinosis score (P = .022). CONCLUSION: ABOi LDKT was relatively safe, with no significant difference in the incidence of rejection compared to ABOc LDKT. Managing chronic pathological changes and arteriolar hyalinosis prophylaxis after ABOi LDKT may result in more successful outcomes. PMID- 27234747 TI - Outcomes of Renal Allograft Recipients With Hepatitis C. AB - BACKGROUND: Studies on the effect of hepatitis C virus (HCV) infection showed decreased graft survival compared to HCV-negative matched patients. It was also identified as an independent risk factor for graft loss and mortality in kidney transplantation patients. OBJECTIVE: This study was designed to evaluate the 10 year graft and patient outcomes of renal allograft recipients with HCV infection at the National Kidney and Transplant Institute. METHODS: This is a retrospective study of patients who underwent renal transplantation with HCV infection and a group who were HCV-negative in the same post-transplantation period. Data were gathered from the in-patient and out-patient clinic records. RESULTS: Patient survival was significantly lower in the HCV-positive than in the HCV-negative group. The mean duration of patient survival was 154.95 (+4.95) months (12 years and 10 months) in HCV-negative patients compared to 141 (+6.52) months (11 years and 9 months) in the HCV-positive group (P = .05). Graft survival did not differ significantly between HCV-positive and HCV-negative recipients (P = .734). The mean duration of graft survival was 137 (+7.68) months (11 years and 5 months) in HCV-negative patients compared to 130 (+6.84) months (10 years and 10 months) in HCV-positive patients. Short- and long-term outcomes including biopsy-proven acute rejection, transplant glomerulopathy, chronic allograft nephropathy, renal function, and proteinuria were similar in both groups. CONCLUSION: Rejection, glomerulopathy, and renal function were similar in both groups. HCV progression was also observed in patients with detectable HCV-RNA 6 months before transplantation. PMID- 27234748 TI - Clinical Outcome of Simultaneous Native Nephrectomy and Kidney Transplantation in Patients With Autosomal Dominant Polycystic Kidney Disease. AB - BACKGROUND: End-stage renal disease patients with autosomal dominant polycystic kidney disease may require native nephrectomy for various indications. However, the appropriate timing for nephrectomy in kidney transplantation and its effect on allograft survival have not been fully investigated. METHODS: We retrospectively analyzed 41 kidney transplant recipients with autosomal dominant polycystic kidney disease in whom transplantation was done simultaneously, after, or without native nephrectomy at Seoul St. Mary's hospital between January 1987 and February 2014. We divided patients into 2 groups based on when native nephrectomy was performed: simultaneously (group A, n = 13) and after or without nephrectomy (group B, n = 28), and compared perioperative outcomes, posttransplantation complications, and allograft survival rates. RESULTS: The mean operative time was significantly longer in group A than in group B (6.48 +/- 1.84 vs 5.27 +/- 0.84 hours; P = .048). The mean numbers of units required for intraoperative blood transfusions were also significantly higher in group A than in group B (3.66 +/- 3.43 vs 0.75 +/- 0.26 units; P = .018). However, there were no differences between groups in the incidence of acute rejection and other complications such as postoperative bleeding and infectious complications (P > .05, for all). The allograft survival rate also did not differ between groups (P > .05). CONCLUSIONS: Our study showed that patients undergoing simultaneous nephrectomy and kidney transplantations had clinical outcomes, in terms of complications and allograft survival, that were comparable to those in patients undergoing kidney transplantations with or without previous nephrectomy. PMID- 27234749 TI - Health-Related Quality of Life of Kidney Transplantation Patients: Results from the KoreaN Cohort Study for Outcome in Patients With Kidney Transplantation (KNOW KT) Study. AB - BACKGROUND: As patient and graft survival rates have been improving after kidney transplantation, health-related quality of life (HR-QOL) has become an important indicator of effective treatment. This study aimed to evaluate changes in HR-QOL after kidney transplantation. MATERIALS AND METHODS: The KoreaN cohort study for Outcome in patients With Kidney Transplantation (KNOW-KT) is a multicenter, observational, 9-year, cohort study. The HR-QOL of patients in the KNOW-KT study was assessed before transplantation and 2 years after transplantation using the Kidney Disease Quality of Life Short Form (KDQOL-SF) including chronic kidney disease targeted area and the Medical Outcome Study 36-item Short Form Health Survey (SF-36). Multivariate linear regression was used to identify significant factors associated with follow-up QOL scores. RESULTS: A total of 175 patients from 8 centers were analyzed. All QOL scores including the total QOL score, chronic kidney disease targeted score, and SF-36 at the 2-year follow-up were significantly increased compared to baseline values. Both physical and mental scale scores were improved after transplantation. CONCLUSION: The QOL scores for both the mental and physical scales were improved at 2 years after kidney transplantation. High glomerular filtration rate at 2 years, high baseline QOL score, and low body mass index were associated with good follow-up QOL scores. Kidney transplantation for an Asian population with end-stage renal disease can result in better QOL as well as better patient and graft survival. PMID- 27234750 TI - Outcome of Living Donor Transplant Kidneys With Multiple Arteries. AB - BACKGROUND: Living donor transplantation (LDT) using kidneys with multiple arteries (MA) has previously been reported to be associated with increased complications and poorer outcomes in recipients. The objective of this study was to investigate outcomes of LDT with MA at the National University Hospital of Singapore, an institution with modest kidney transplant volumes. METHODS: From 2007 to 2014, a total of 109 consecutive living donor kidney transplantations were performed. Of the nephrectomies, 91% were left sided. A total of 19 cases involved MA, of which 7 with small polar vessels (<2 mm) were ligated and 12 were revascularized. Baseline characteristics and outcomes were comparable between donor-recipient pairs with MA and single artery (SA). Both groups had equivalent induction and maintenance immunosuppressive regimens. RESULTS: Mean warm ischemia time (minutes) was similar for kidneys with MA and SA (4.3 +/- 3.2 vs 3.9 +/- 3.2, P = .38). Operative time (minutes) in the recipients was also equivalent (P > .05) for MA and SA (158 +/- 39.2 and 145 +/- 57.2, respectively). The MA kidney recipients had a lower estimated glomerular filtration rate (eGFR) on postoperative day 5 compared to SA (56.6 +/- 24.2 vs 74.1 +/- 35.9 mL/min/1.73 m(2), P = .058). However, eGFR at 1 year was the similar for both groups (64.9 +/ 16.2 vs 66.4 +/- 18.1 mL/min/1.73 m(2), respectively, P = .76). Delayed graft function rates were 5.6% and 6.6% for MA and SA, respectively (P = .9). There were no surgical complications for LDT recipients within the MA group. Patient and graft survival was 100% in the MA group compared with 98% in the SA group (P > .05). CONCLUSIONS: With current surgical techniques, LDT with MA can achieve equally good functional outcomes at 1 year as SA kidneys, with minimal surgical complications. PMID- 27234751 TI - Outcomes of Kidney Transplantations Under the Philippine Health Insurance Corporation's Type Z Benefit Package at the National Kidney and Transplant Institute, Philippines. AB - BACKGROUND: Under the Universal Health Care Program of the Department of Health, the Philippine Health Insurance Corporation (PHIC) launched the Case Type Z benefit package for kidney transplantation, providing the largest amount (USD $13,300.00) for any single medical procedure. The objective of this study was to describe under the PHIC Case Type Z Benefit Package for kidney transplantation at the National Kidney and Transplant Institute and kidney transplantation outcomes under this package. METHODS: Included in the benefit were standard risk recipients between 10 and 70 years of age with at least 1 human leukocyte antigen (HLA) DR match with the donor, panel-reactive antibody (PRA) less than 20%, and absence of donor-specific antibody (DSA). Previous transplantations, malignancy, hepatitis B and C, human immunodeficiency virus (HIV) positivity, cytomegalovirus (CMV) R-/D+, congestive heart failure, and liver cirrhosis were exclusion criteria. Patients were evaluated by a medical social worker according to their family's financial status. RESULTS: Since June 2012, a total of 261 patients have received the benefit, with 44 under service, 37 with fixed co-pay and 180 with variable co-pay. Of the living donor kidney transplants, 98% had immediate graft function, with 2.3% (6/261) acute rejection rates at 1 year. The total cost of hospitalization was within the benefit for living donor kidney transplants (less than USD 8000.00) but exceeded it in all cases of deceased donor kidney transplants. CONCLUSIONS: The successful use of and excellent outcomes under the Case Type Z benefit demonstrated how collaboration among government agencies, health care providers, and pharmaceutical companies could result in a program that improved the access to health care for Filipino patients with end-stage renal disease. PMID- 27234752 TI - Health-Related Quality of Life and Psychologic Distress in Korean Kidney Transplant Recipients. AB - BACKGROUND: Little is known about the extent to which transplant recipients face psychologic distress with the receipt of a transplanted organ. The purpose of this study was to investigate health-related quality of life (HRQoL) and psychologic distress in 105 adults who had undergone kidney transplantation (KT). METHODS: HRQoL was measured with the use of the Korean version of Medical Outcome Study Short Form 36 version 2, and psychologic distress with the use of the Transplant Effects Questionnaire (TEQ). Clinical and demographic data were collected from questionnaires. The data were collected from August 2014 to November 2014 at 2 medical centers in Korea. RESULTS: Of the 105 patients, 53.3% were male and the overall mean age was 46.99 years. The mean score of each of the TEQ subscales ranged from 2.45 to 4.62. In the subscales of HRQoL, the mean score of physical component summary (PCS) was 50.23, and the mean score of mental component summary (MCS) was 46.19. MCS was negatively correlated with worry (P = .001) and guilt (P = .037) and positively correlated with adherence (P = .006) in the TEQ subscales, whereas there was no significant correlation between PCS and the TEQ subscales. CONCLUSIONS: The study indicates that mental HRQoL is correlated with psychologic distress. Therefore, to increase the HRQoL, continuous attention is needed in kidney transplant recipients who experience psychologic distress and adherence problem. In addition, further empirical studies should be conducted to explain the mechanisms underlying this relationship. PMID- 27234753 TI - Matrix Metalloproteinase Gene Polymorphisms and New-Onset Diabetes After Kidney Transplantation in Korean Renal Transplant Subjects. AB - BACKGROUND: New-onset diabetes after transplantation (NODAT) is a serious metabolic complication that may follow renal transplantation. Matrix metalloproteinases (MMPs) contribute to insulin insufficiency and beta-cell dysfunction in a rat model. The MMP-2 concentrations were lower in patients with type 2 diabetes mellitus, and the plasma MMPs levels were related to diabetes. Similar to the pathogenesis of type 2 diabetes mellitus, insulin resistance and insulin secretion dysfunction occur in patients with the development of NODAT. Therefore, we examined the association between NODAT and 11 single-nucleotide polymorphisms (SNPs) located within the 3 genes of MMPs that might be related to NODAT. METHODS: A total of 309 renal transplant recipients without a history of diabetes were included in this study. DNA was extracted from the blood samples of recipients, and we analyzed the association between the development of NODAT and a panel of 11 SNPs within 3 MMP genes (MMP-1, MMP-2, and MMP-3). RESULTS: In terms of allele frequencies, rs243849*C (MMP-2) was significantly higher in patients with NODAT. Two of the 11 (18.1%) SNPs were significantly associated with NODAT development after adjusting for age, sex, and tacrolimus usage: MMP-2 (rs1132896) and MMP-2 (rs243849). In the multiple logistic regression analysis, these 2 SNPs were significantly associated with the development of NODAT in the codominant and recessive or codominant and dominant models. CONCLUSIONS: MMP-2 gene rs1132896 and rs243849 polymorphisms may serve as genetic markers for the development of NODAT. The exact molecular mechanisms still must be clarified. PMID- 27234755 TI - Effect of Prolonged Diarrhea in Renal Transplant Recipients at a Single Center in Taiwan. AB - OBJECTIVE: Post-renal transplantation diarrhea is a common complication; however, it is easily ignored. This study aimed to determine the factors influencing graft function for renal transplant recipients with diarrhea. METHODS: A single-center retrospective study with the use of the Hyperion data warehouse was conducted to search and evaluate for renal transplant recipients who came for medical care for diarrhea at our transplant center from January 2009 to August 2015. The clinical features of patients with diarrhea were compared with the features of recipients without diarrhea. The causes and risk factors of post-transplantation diarrhea were also evaluated. RESULTS: For the 67 patients collected for the study, infectious diarrhea (ID) was confirmed in 27 patients (40.3%), and the most common causes were cytomegalovirus and Clostridium difficile infection. A significant difference was found between ID and noninfectious (NID) groups for serum creatinine change (0.31 +/- 0.51 vs 0.1 +/- 0.27 mg/dL; P = .0319), revealing that the impact of diarrhea on renal function was greater for ID patients. When diarrhea of >=10 days was used as a cutoff for serum creatinine change, the change of serum creatinine became greater when the diarrhea period was longer (<7 d vs >14 d: 0.07 +/- 0.22 vs 0.55 +/- 0.6 mg/mL; P = .0001). CONCLUSIONS: Infectious diarrhea does more damage to the kidney graft than NID in transplant recipients. If the period of diarrhea is lengthened to >10 days, the renal function of the graft would be impaired and irreversible graft loss would be expected. PMID- 27234754 TI - Inverse Association Between Serum Osteoprotegerin and Bone Mineral Density in Renal Transplant Recipients. AB - BACKGROUND: Osteoprotegerin (OPG) has pleiotropic effects on bone metabolism as well as endocrine function. Our aim was to evaluate the relationship between bone mineral density (BMD) and serum OPG concentration in renal transplant recipients. METHODS: Fasting blood samples were obtained from 69 renal transplant recipients. BMD was measured in lumbar vertebrae (L2-L4) by dual-energy X-ray absorptiometry. Eight patients (11.6%) had BMD values indicative of osteoporosis, 28 patients (40.6%) had BMD values indicative of osteopenia, and 33 patients had normal BMD values. Increased serum OPG levels (P < .001), decreased body mass index (BMI) (P = .033), and decreased body weight (P = .010) were significantly correlated with low lumbar T-score cut-off points between groups (normal, osteopenia, and osteoporosis). RESULTS: Women had significantly lower lumbar BMD values than men (P = .013). Menopause (P = .005), use of tacrolimus (P = .020), and use of cyclosporine (P = .046) were associated with lower lumbar BMD in renal transplant recipients. Univariate linear regression analysis revealed that lumbar BMD was positively correlated with height (P = .016), body weight (P = .001), and BMI (P = .015) and negatively correlated with age (P = .039) and log-OPG (P = .001). Multivariate linear regression analysis revealed that log-OPG (beta: -0.275, R(2) change = 0.154, P = .014), body weight (beta: 0.334, R(2) change = 0.073, P = .004), and age (beta: -0.285, R(2) change = 0.079, P = .008) were independent predictors of lumbar BMD values in renal transplant recipients. CONCLUSIONS: Serum OPG concentration correlated negatively with lumbar BMD values in renal transplant recipients. PMID- 27234756 TI - Pathologic Features of Parathyroid Glands Associated With the Pathogenesis of Long-lasting Persistent Hyperparathyroidism After Kidney Transplantation in Long term Dialysis Patients. AB - BACKGROUND: Persistent hyperparathyroidism in kidney transplant recipients may be prolonged for a few years, and in these cases, parathyroidectomy is indicated even if graft function is satisfactory. The aim of this study was to characterize the parathyroid glands in long-term dialysis recipients and determine the pathogenesis of persistent hyperparathyroidism. METHODS: We analyzed 44 parathyroid glands resected from 11 patients who underwent parathyroidectomy after kidney transplantation. The histopathologic types and weights of all the parathyroid glands were evaluated. RESULTS: The mean dialysis period was 15.8 years, and the time from kidney transplantation to parathyroidectomy ranged from 3.5 to 89 months. Nodular hyperplasia was present in parathyroid glands in all cases. The mean glandular weight was 396.0 +/- 299.0 mg, and the maximum glandular weight was 3200 mg. Seven patients who underwent parathyroidectomy >1 year after kidney transplantation (late PT) were compared with 4 patients who underwent parathyroidectomy within 10 months after transplantation (early PT). The maximum (442.9 vs 1503 mg; P = .018) and mean (312.5 +/- 177.4 mg vs 1135.6 +/- 977.7 mg; P = .001) glandular weights were significantly lower in patients who underwent late PT compared with those who received early PT. Based on the histopathologic type and glandular weight of each parathyroid gland, nodular hyperplasia in glands <=150 mg was common in patients who underwent late PT. CONCLUSIONS: The presence of nodular hyperplasia in parathyroid glands with a low weight may be involved in long-lasting persistent hyperparathyroidism in patients undergoing long-term dialysis. PMID- 27234757 TI - Post-Transplant Anemia Has Strong Influences on Renal and Patient Outcomes in Living Kidney Transplant Patients. AB - BACKGROUND: Post-transplant anemia (PTA) is a risk factor for mortality and graft loss in kidney transplant patients. METHODS: In all, 172 patients were included in this study. PTA was defined as hemoglobin <13.0 g/dL in men and 12.0 g/dL in women. The primary outcome of interest was the renal outcome, defined as a 50% increase in serum levels of creatinine, a return to chronic dialysis, and subsequent kidney transplantation (KTx). The secondary outcome was a composite of the primary outcome and death. RESULTS: At baseline, 75 patients (43.6%) had PTA. During follow-up of a median of 7.3 years, 52 patients (30.2%) had 2-fold higher creatinine levels than at baseline, 24 patients (14.0%) had to return to chronic dialysis or subsequent KTx, and 11 patients (6.4%) died; 8 (4.7%) of the deceased patients had functioning allografts. Univariate regression analyses showed that a lower hemoglobin level and positive proteinuria were significantly associated with both outcomes. After adjusting for important clinical variables, a lower hemoglobin level remained a strong predictor for both outcomes. Restricted cubic splines showed an almost linear inverse association with a hemoglobin level >=12 g/dL. The risk of the outcomes increased with decreasing tertiles of the baseline hemoglobin level for both men and women, but the associations in women were much weaker than those in men, suggesting a different prognostic value of the hemoglobin level between men and women. CONCLUSIONS: PTA strongly influenced the renal and patient outcomes in living kidney transplant patients. PMID- 27234758 TI - Can Kidney Transplantation Improve Arterial Stiffness in End-Stage Renal Patients? AB - BACKGROUND: Arterial stiffness is associated with cardiovascular disease in end stage renal disease (ESRD) and after kidney transplantation. We examined how kidney transplantation influences brachial-ankle pulse-wave velocity (baPWV) in ESRD patients. METHODS: The prospective observational study enrolled 67 patients who underwent successful kidney transplantation. Serial baPWV and biochemical parameters were measured before surgery and 6 months, 1 year, and 2 years after transplantation. RESULTS: baPWV prior to kidney transplantation and 6 months, 1 year, and 2 years after transplantation was 1533 +/- 261 cm/s, 1417 +/- 254 cm/s, 1414 +/- 285 cm/s, and 1384 +/- 233 cm/s, respectively. baPWV and biochemical parameters including alkaline phosphatase, intact parathyroid hormone, and 1,25 hydroxyvitamin D improved significantly at 6 months (P < .05), but there were no changes between 6 months and 2 years after transplantation. The majority of patients (73%) improved, whereas the remainder showed progression of baPWV after transplantation. Sixty-three percent of all kidney transplantation patients displayed higher baPWV than the healthy control subjects at 6 months after transplant. CONCLUSIONS: In the majority of patients, baPWV improved soon after kidney transplantation but overall remained higher than in the generally healthy population. PMID- 27234760 TI - Adherence to Dietary Recommendations in Maintenance Phase Kidney Transplant Patients. AB - OBJECTIVES: Current adherence to dietary recommendations for chronic kidney disease was evaluated in kidney transplant patients in the maintenance phase. METHODS: A total of 268 maintenance phase kidney transplant patients were included in the study. Estimated daily intakes of oral protein and salt were calculated from 24-h urinary excretion of nitrogen and sodium, respectively. Dietary recommendations for chronic kidney disease, as issued in 2014 by the Japanese Society of Nephrology, were used as the basis for assessing diet. RESULTS: The study included 114 female patients and 154 male patients. The mean age, posttransplantation years, body mass index, estimated glomerular filtration rate, and 24-h urinary excretion of protein were 56.3 years, 11.2 years, 22.0 kg/m(2), 42.6 mL/min/1.73 m(2), and 321 mg/d, respectively. Estimated daily protein and salt intakes were 0.98 +/- 0.26 g/kg/d and 9.3 +/- 3.9 g/d. Only 47 patients (17.5%) in the case of salt intake and 105 patients (39.2%) in the case of protein intake were within reference values. The 24-h urinary protein excretion of the daily salt intake-adherent group (<6 g) was significantly less than that of the nonadherent group (>=6 g) (P = .021). CONCLUSIONS: The adherence rate to dietary recommendations for chronic kidney disease in kidney transplant patients was low. The 24-h urinary protein excretion of the daily salt intake adherent group was significantly less than that of the nonadherent group. Dietary therapy for these patients may have the potential to improve kidney graft function and survival. PMID- 27234759 TI - Concurrent Post-Transplantation Diabetes Mellitus in Renal Allograft Recipients With Immunoglobulin A Nephropathy. AB - BACKGROUND: The prevalence of post-transplantation immunoglobulin A nephropathy (PTIgAN) and diabetes mellitus (PTDM) increases with time after transplantation, and recognition and management of these conditions is becoming more important in renal allograft recipients as graft survival increases. METHODS: We explored the influence of concurrent PTDM on renal allograft histology and function in 111 cases with PTIgAN diagnosed from 2000 to 2010 at our institution. RESULTS: Sixteen patients (14.4%) had PTDM at the time of diagnosis of PTIgAN, which increased to 28 patients (25.2%) at the last follow-up (10.4 years after transplantation). Donor ages were younger in PTIgAN patients with concurrent PTDM. However, other clinical and demographic data were not significantly different between PTIgAN patients with and without PTDM. Histologically, Banff "mm" scores were higher and "M1" of the Oxford classification was more frequent in PTIgAN patients with concurrent PTDM than in patients without PTDM, but the difference did not reach statistical significance. Serum creatinine levels and proteinuria at the time of biopsy and overall graft survival did not vary according to the presence of PTDM both at biopsy and at the last follow-up. CONCLUSIONS: Concurrent PTDM does not significantly influence graft function or outcome for 10 years after transplantation in PTIgAN patients. PMID- 27234761 TI - Early Weight Gain After Transplantation Can Cause Adverse Effect on Transplant Kidney Function. AB - BACKGROUND: The outcomes of kidney transplant recipients with increased body mass index (BMI) remain controversial. We studied the relationship between changes in BMI and kidney transplant function, especially during the first year after transplantation. METHODS: We performed an observational cohort study of all kidney transplant recipients at our center from March 2009 to June 2014 to determine whether changes in BMI were associated with kidney transplant function, as measured by estimated glomerular filtration rate (eGFR). Recipient BMI and eGFR were calculated pre-transplant and at 1, 3, 6, 9, and 12 postoperative months (POM) after transplantation. The correlation between changes in BMI and eGFR was then evaluated. RESULTS: Eighty-one patients were studied. There was a strong negative correlation between changes in BMI and eGFR from pre-transplant to POM 1 (correlation coefficient, -0.406; P < .0001) and from POM 1 to POM 3 (r = -0.324, P = .004). CONCLUSIONS: We found that increased BMI caused a significant decline in renal function as measured by eGFR, especially in the initial 3 months after kidney transplantation. PMID- 27234762 TI - Sequential Changes of Vitamin D Level and Parathyroid Hormone After Kidney Transplantation. AB - BACKGROUND: Numerous studies have shown that vitamin D deficiency is common in end stage renal disease patients. However, change of the vitamin D deficiency after kidney transplantation is not fully understood. METHODS: Twenty-five kidney transplant (KT) recipients with serum 25-hydroxyvitamin D (25D) level, 1,25 dihydroxyvitamin D (1,25D) level, parathyroid hormone (PTH) level before and 6, 12, and 24 months after transplantation were reviewed. RESULTS: Serum PTH level and 1,25D level showed significant changes at 6 months after transplantation, but did not show further change at 12 months. 25D level did not increase within 6 months after transplantation. However, 25D level showed gradual increase after 6 months. The proportion of recipients with 25D deficiency (<10 ng/mL) was 68%, 40%, and 28% before, 12 months after, and 24 months after transplantation, respectively. Patients with vitamin D deficiency at 24 month were younger at transplantation (37.7 +/- 9.6 y vs 48.2 +/- 8.0 y; P = .029) and had lower 25D level before transplantation (7.96 +/- 1.74 ng/mL vs 10.59 +/- 4.35 ng/mL; P = .041). CONCLUSIONS: 25D deficiency is persistent in almost kidney transplant recipients even 12 months after transplantation, although serum PTH levels decrease and serum 25D levels increase after transplantation. PMID- 27234763 TI - Impact of mTOR Inhibitors on Cancer Development in Kidney Transplantation Recipients: A Population-Based Study. AB - BACKGROUND: The mammalian target of rapamycin (mTOR) inhibitor is an immunosuppressive drug used in kidney transplantation. Whether the mTOR inhibitor is associated with reduced risk of cancer development and mortality after kidney transplantation is controversial. METHODS: We conducted a nationwide population based study. Patients who did not have malignancy history and received kidney transplantation between 2010 and 2013 were enrolled. Recipients who had mTOR inhibitors (n = 430) for more than 30 days comprised the study group; 1720 recipients who did not have mTOR inhibitors comprised the control group. The primary outcome is the development of cancer after kidney transplantation. These patients were followed until the first-time admission with diagnosis of cancer, death, or the end of 2014. A Cox proportional-hazard model was used to determine the risk of cancer development and all-cause mortality. RESULTS: During the 35 month median duration of observation, there were 16 and 61 patients with cancer development in the study group and the control group, respectively. The cancer incidence was 12.8 and 12.4 per 1000 person-years. There were 10 and 135 mortality cases, with the incidence rate of 7.8 and 26.9 per 1000 person-years. After multivariable adjustment, the mTOR inhibitors users were not associated with reduced risk of new cancer development as compared with control (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.46-1.60; P = .63), nor risk of all-cause mortality (HR, 0.70; 95% CI, 0.33-1.46; P = .34). CONCLUSIONS: The use of mTOR inhibitors was not associated with a reduction in the risk of cancer development and all-cause mortality in kidney transplantation recipients. PMID- 27234764 TI - Robot-Assisted Radical Prostatectomy for Localized Prostate Cancer in Asian Renal Transplant Recipients. AB - BACKGROUND: The purpose of this study was to present our experience with robot assisted radical prostatectomy (RARP) for localized prostate cancer in renal transplant recipients (RTRs) and to determine the feasibility and efficacy of RARP in these patients. METHODS: We retrospectively reviewed the medical records of 236 patients who underwent RARP for localized prostate cancer at our institution between August 2011 and July 2015 and identified 3 patients who were RTRs. We reviewed the available clinical data of the 3 patients. RESULTS: All patients underwent RARP successfully without any major complications. The mean operation time was 162 minutes (range, 127-195 minutes). The mean estimated blood loss was 52 mL (range, 30-75 mL); therefore, the patients did not need any perioperative blood transfusion. In all cases, graft function, as determined according to the serum creatinine level, was stable during and after the operation. Pathological examination showed negative surgical margins with organ confined disease in all patients. CONCLUSIONS: We reported 3 RTRs with localized prostate cancer who were treated with RARP. RARP might be a feasible and effective minimally invasive technique for the treatment of localized prostate cancer in carefully selected RTRs. PMID- 27234765 TI - Efficacy and Feasibility of Low-Dose Rate Brachytherapy for Prostate Cancer in Renal Transplant Recipients. AB - BACKGROUND: In young patients with localized prostate cancer, radical prostatectomy is the treatment of choice in the general population. Radiotherapy, such as low-dose rate (LDR) brachytherapy or intensity-modulated radiotherapy, is a viable alternative as well. However, in transplant patients, irradiation is not proposed as often as it is in healthy adults because of the risk of post radiation ureteral stenosis and gastrointestinal toxicity as the result of fragile tissue. The objective of the study was to assess the efficacy and feasibility of LDR brachytherapy for prostate cancer in renal transplant recipients (RTRs). METHODS: Between May 2007 and December 2014, all patients who had undergone LDR brachytherapy for clinically localized prostate cancer at our institution were retrospectively identified (n = 203). Of these patients, 2 had a history of renal transplantation. We reviewed all available clinical data retrospectively. One patient had a functioning graft and the other had re-started hemodialysis 7 years after the transplantation. RESULTS: The mean time from renal transplantation to prostate cancer diagnosis was 16 years. The mean follow-up after seed implantation was 45 months. There were no peri-operative complications after seed implantation. The 2 patients remained free of prostate-specific antigen progression during the follow-up period. The renal function of the patient with a functioning graft, as measured by serum creatinine, was stable during and after the operation. CONCLUSIONS: LDR brachytherapy is technically feasible and acceptable as a minimally invasive treatment in carefully selected RTRs with localized prostate cancer. This treatment should be considered a suitable option for RTRs with localized prostate cancer. PMID- 27234766 TI - Efficacy and Feasibility of Intensity-Modulated Radiation Therapy for Prostate Cancer in Renal Transplant Recipients. AB - BACKGROUND: In transplant patients with localized prostate cancer, irradiation is not proposed as often as it is in healthy adults because of the post-radiation risks, such as ureteral stenosis and gastrointestinal toxicity as the result of fragile tissue. The objective of the study was to analyze the efficacy and feasibility of intensity-modulated radiation therapy (IMRT) for prostate cancer in renal transplant recipients (RTRs). METHODS: Between May 2005 and December 2014, all patients who had undergone IMRT for clinically localized prostate cancer at our institution were retrospectively identified (n = 365). Of these patients, 2 had a history of renal transplantation. We reviewed all available clinical data. One patient had a functioning graft and the other had restarted hemodialysis 7 years after the transplantation. RESULTS: The mean time from renal transplantation to prostate cancer diagnosis was 11 years. The mean follow-up after irradiation was 43 months. The 2 patients remain free of prostate-specific antigen progression. There was no severe acute and chronic genitourinary and gastrointestinal toxicity. Renal function of the patient with a functioning graft as measured by serum creatinine was stable during and after the irradiation. CONCLUSIONS: IMRT is feasible and acceptable as a minimally invasive treatment in the carefully selected RTRs with localized prostate cancer. This treatment should be considered a good option for RTRs with localized prostate cancer. PMID- 27234767 TI - Prognosis of Kidney Transplant Recipients With Pretransplantation Malignancy: A Nationwide Population-Based Cohort Study in Taiwan. AB - OBJECTIVE: The objective of this study was to evaluate the prognosis of kidney transplant recipients with pretransplantation malignancy and the incidence of recurrent malignancy in kidney transplant recipients using claims data from Taiwan's universal health insurance program. METHOD: A total of 4350 transplant recipients were retrospectively analyzed. The rates of pretransplantation or recurrent malignancy, which was defined by their inclusion in the catastrophic illness patient registry using the International Classification of Diseases, 9th Revision, were evaluated. Cox proportional hazard regression and Kaplan-Meier curves were used for the analyses. RESULTS: In total, there were 4350 kidney transplant recipients, 52.1% of patients were male, the mean age at transplantation was 45.8 years old, and the percentages of diabetes mellitus, hypertension, hepatitis B viral infection, and hepatitis C viral infection were 14%, 63.2%, 4.2%, and 2.4%, respectively. There were 95 patients (2.2%) with pretransplantation malignancy. The top 3 pretransplantation malignancies, in decreasing order, were urinary tract, kidney, and breast cancers. After kidney transplantation, 10 recipients had recurrent cancer. The overall cancer recurrence rate was 10.5%. These 10 cancers included urothelial carcinoma (n = 5), renal cell carcinoma (n = 3), breast cancer (n = 1), and thyroid cancer (n = 1). Eleven recipients had a secondary cancer. Patients without pretransplantation and post-transplantation malignancy had the best survival. Patients with pretransplantation malignancy had a greater occurrence of cancers and increased mortality regardless of whether or not they had recurrence of cancer. CONCLUSION: Our results suggest the higher risk of cancer, recurrent or secondary, and mortality after kidney transplantation. Adequate waiting time before transplantation and preventive strategies are strongly suggested in kidney transplant recipients with cancer history. PMID- 27234768 TI - Association Between the Polyomaviruses Titers and Decoy Cell Positivity Rates After Renal Transplantation. AB - BACKGROUND: Urinary decoy cells develop after renal transplantation and their appearance is attributable primarily to the proliferation of polyomavirus types BK and JC. We measured the levels of these 2 viruses that cause decoy cells to appear in the urine. PATIENTS AND METHODS: BK and JC virus levels were quantified in 1182 urine samples from 335 renal transplant patients using a multiplex Taqman real-time polymerase chain reaction assay. Forty-four samples were excluded from analyses because both viruses were present at >=10(4) copies/mL. We analyzed the relationship between viral load and the presence of urinary decoy cells. RESULTS: Decoy cells were observed in 237 of 1138 urine samples (21%) and the BK and JC viruses were positive in 205 (18%) and 455 (40%) samples, respectively. Decoy cells were observed in 0%, 21%, 67%, 87%, 100%, and 96% of urine samples when the BK viral load was <10(4), 10(4)-10(5), 10(5)-10(6), 10(6)-10(7), 10(7)-10(8), and >=10(8) copies/mL, respectively; and in 1%, 13%, 41%, 59%, 87%, and 97% of urine samples when the JC viral load was <10(4), 10(4)-10(5), 10(5)-10(6), 10(6)-10(7), 10(7)-10(8), and >=10(8) copies/mL, respectively. CONCLUSIONS: BK virus more frequently triggered the appearance of decoy cells than did JC virus at equivalent viral titers. PMID- 27234769 TI - How to Improve the Positive Predictive Value of Urinary Decoy Cell Surveillance for Polyomavirus BK-Associated Nephropathy in Kidney Transplant Patients. AB - BACKGROUND: Polyomavirus BK-associated nephropathy (BKVN) has been a serious problem after kidney transplantation. Detection of urinary decoy cells (UDCs) and assessment of polyomavirus BK nucleic acids by polymerase chain reactions (PCRs) are currently used, noninvasive tests. PCRs have better positive predictive value (PPV) but higher cost and lower accessibility. This study investigated ways to improve the PPV of UDCs for BKVN prediction. METHODS: From 2000 to 2013, kidney transplant recipients with sustained UDCs for more than half a month and who had received allograft biopsies were enrolled. We analyzed the PPV of UDCs for BKVN with 2 variables: (i) the percentage changes in serum creatinine (SCr) levels and (ii) the duration of sustained UDCs by receiver operating characteristic (ROC) curve analysis; we predicted the percentage changes in SCr levels with the corresponding PPV using a linear regression model. RESULTS: BKVN was diagnosed in 26 of 68 enrolled patients. The percentage changes in SCr levels significantly deteriorated in the BKVN group during 1-2 months of UDC positivity. According to ROC curve analysis, percentage changes in SCr levels had a significant discriminating power for BKVN during 1-1.5 month, and if the percentage changes in SCr levels were >19%, the PPV of UDCs for BKVN was 50%. CONCLUSIONS: An UDC surveillance program is a judicious strategy to predict BKVN in kidney transplant patients, particularly when graft renal function shows deterioration after 1 month of UDC positivity. PMID- 27234770 TI - Effects of Granulocyte and Monocyte Adsorptive Apheresis in Renal Transplantation Recipients With Concomitant Cytomegalovirus Infection. AB - BACKGROUND: Granulocyte and monocyte adsorptive apheresis (GMAA) is widely used as a treatment for active ulcerative colitis (UC) in Japan. Much attention has been paid to the possibility of GMAA for the treatment and control of cytomegalovirus (CMV) reactivation in patients with refractory UC and concomitant CMV infection. In this study, the effects of the combination of GMAA and antiviral therapy were examined in renal transplant recipients with concomitant CMV infection. METHODS: Combination therapy of GMAA and antiviral drugs was performed 9 times in 7 renal transplant recipients with concomitant CMV infection. Four of the cases were positive for CMV-IgG, and 3 were negative. The clinical presentation of CMV infection was viremia in 6 cases and disease (CMV retinitis) in 1 case. CMV infection was diagnosed by using an antigenemia assay (C7-HRP). GMAA session was performed once, and the duration of the session was 120 min. Immediately after the GMAA session, ganciclovir was administered at 5 mg/kg/body weight. CMV infection was monitored based on C7-HRP and CMV-DNA in the peripheral blood samples. RESULTS: All cases became negative for C7-HRP and CMV DNA within 21 days (median, 14 days; range, 3-21 days) and 17 days (median, 6 days; range, 3-17 days), respectively, after starting the combination therapy. No side effects of GMAA were observed. CONCLUSIONS: This case series found that GMAA in combination with antiviral drugs may shorten the duration of treatment against CMV infection in renal transplant recipients. Further studies in a larger number of patients are required to confirm these results. PMID- 27234772 TI - Successful Management of New-Onset Diabetes Mellitus and Obesity With the Use of Laparoscopic Sleeve Gastrectomy After Kidney Transplantation-A Case Report. AB - In kidney transplantation, obesity is associated with poorer graft survival and patient survival. Bariatric surgery may provide benefit for these patients, not only by inducing weight loss, but also via reduction of diabetes. We report a case of morbid obesity, poorly controlled new-onset diabetes mellitus, and gout after kidney transplantation that was treated with laparoscopic sleeve gastrectomy 3 years after kidney transplantation. After 1 year of follow-up, 76% excessive body weight loss was attained. No complications were noted. The operation also provided total remission of diabetes and gout as well as good graft survival. Based on our experience, laparoscopic sleeve gastrectomy may be a feasible treatment for obese patients after renal transplantation to help resolve obesity and control new-onset diabetes. However, the timing of operation and the long-term potential for graft and patient survivals with this operation require further study. PMID- 27234771 TI - Characteristics of Femoral Motor Neuropathies Induced After Kidney Transplantation: A Case Series. AB - BACKGROUND: Femoral motor neuropathy (FMN) induced after kidney transplantation (KT) can injure the patient and graft, and it sometimes can leave sequelae on gait. Nevertheless, the cause of FMN has not been determined. We assessed 5 cases of FMN in an attempt to determine the traits induced after KT. METHODS: Patient data about general characteristics, immunologic characteristics, operative findings, post-operative status, and FMN characteristics were assessed. A Bookwalter self-retaining retractor was used and quadruple immunosuppression was implemented in all cases. RESULTS: Five patients had FMN. Four of the 5 patients were women. The mean body mass index (BMI) was 20.38 +/- 1.99 kg/m(2) prior to KT and 19.08 +/- 1.98 kg/m(2) after KT. The mean graft-recipient weight ratio was 3.46 +/- 0.99 g/kg. There was no case of psoas muscle abscess or hematoma. Motor function recovery was obtained 3 to 313 days after rehabilitation. Immediate graft function was favorable in all patients with no rejection or significant complications. CONCLUSIONS: FMN after KT may occur in patients with a lower BMI and higher graft-recipient weight ratio. This study was based on only 5 patients, and therefore further studies with a larger population size are necessary. PMID- 27234773 TI - Immunoglobulin A Nephropathy in a Living Kidney Donor Diagnosed and Treated After Transplantation: A Case Report. AB - OBJECTIVE: We report the clinical course and pathologic findings of a kidney transplant donor who was diagnosed with immunoglobulin A (IgA) nephropathy by means of preimplantation biopsy and was later treated with methylprednisolone and tonsillectomy. CASE REPORT: The patient was a 57-year-old woman who met the criteria for kidney donation and was accepted as a donor. Donor nephrectomy was performed, and the preimplantation biopsy revealed that the donor had IgA nephropathy. One month after the nephrectomy, the donor's laboratory findings indicated proteinuria and hematuria. Because these findings indicated active IgA nephropathy, we decided to perform tonsillectomy and methylprednisolone pulse therapy. Soon after these treatments, the patient's proteinuria and hematuria were no longer observed. CONCLUSIONS: Subclinical IgA nephropathy can be incidentally found on preimplantation biopsies of living kidney donors. As demonstrated in this case, IgA nephropathy can become exacerbated and requires therapeutic intervention after kidney donation. Informed consent and careful observation should be used before and after transplantation, even for donors who have been determined to be eligible for kidney donation. PMID- 27234774 TI - A Rare HLA-DRB1*14:22-DQB1*04:01 Haplotype in a Kidney Donor: Implication in the Interpretation of Donor-Specific Antibody in Kidney Transplantation-A Case Report. AB - BACKGROUND: The presence of donor-specific human leukocyte antigen antibodies (HLA-DSA) can be determined by performing Luminex assay with single-antigen beads. The single-antigen beads' panels cover the most frequent HLA alleles of the HLA-A, B, C, DRB1, DRB3/4/5, DQB, and DP loci, although the HLA typing for deceased donors often includes only HLA-A, B, and DR. Therefore, the information of haplotypic association between DRB1 and DQB1 is essential for the analysis of HLA-DSA, especially when HLA-DQ antibodies are identified in the patient's serum. CASE REPORT: We report the finding of a rare HLA-DRB1*14:22-DQB1*04:01 haplotype in a Thai potential kidney donor. HLA class I and class II high-resolution typing were performed by a method of polymerase chain reaction with the use of sequence specific primers. The HLA-A*24:02-C*04:06-B*13:01-DRB3*02:02-DRB1*14:22 DQA1*05:05-DQB1*04:01 haplotype in the kidney donor was confirmed by segregation analysis in the kidney donor's family. This rare haplotype was also identified in her father and the 2 of her offspring. CONCLUSIONS: To our knowledge, this is the 1st report of the rare HLA-DRB1*14:22-DQB1*04:01 haplotype in Thai individuals. The information of the rare HLA-DR-DQ haplotypic association provides a caution for HLA laboratory personnel when analyzing HLA-DSA in a patient with HLA-DQ antibodies and the HLA-DQ typing of a deceased donor is unavailable. PMID- 27234775 TI - Effective Treatment With Everolimus for Recurrent Granulomatous Interstitial Nephritis in a Renal Transplant Recipient: A Case Report. AB - BACKGROUND: Granulomatous interstitial nephritis (GIN) is a rare renal disease, and its etiology remains unknown. We report recurrent GIN in renal allograft successfully treated with everolimus (EVR). CASE REPORT: A 22-year-old man with GIN received a kidney from his mother. On follow-up 8 months later, his serum creatinine level was increased, from 1.3 mg/dL to 1.7 mg/dL, and he had microhematuria and proteinuria. A protocol graft biopsy at 1 year after transplantation showed epithelioid granuloma with multinucleated giant cells. He received steroid pulse therapy for recurrent GIN twice, but he developed allograft dysfunction, hematuria, and proteinuria. EVR was started in combination with maintenance immunosuppressants at 28 months after transplantation. Thereafter, the serum creatinine level decreased, from 2.1 mg/dL to 1.6 mg/dL, and microhematuria and proteinuria were stable despite reduction of steroid dose. CONCLUSIONS: Maintenance immunosuppressive therapy combined with EVR may be effective for the recurrence of idiopathic GIN in renal allograft. PMID- 27234776 TI - Abscess of Native Kidney Caused by Carbapenem-Resistant Acinetobacter baumannii (CRAB) in Renal Transplantation: A Case Report. AB - BACKGROUND: Abscess of native kidney is a rare postoperative event after renal transplantation. This report describes a case of back pain, fever and pyuria caused by carbapenem-resistant Acinetobacter baumannii (CRAB) in a patient who underwent renal-transplantation. CASE REPORT: A 40-year-old man, presenting with hypertension and renal failure, underwent renal transplantation 1 month previously. He developed sudden intense back pain and fever (39 degrees C). There was normal blood flow in graft kidney but there were the swelling and cyst of right native kidney. We aspirated the pus in native kidney and performed the native nephrectomy. The carbapenem-resistant Acinetobacter baumannii (CRAB) was isolated as in pus and native kidney. We performed the tigecyline monotherapy during 3 weeks. He recovered without complication after treatment. CONCLUSIONS: To our knowledge, no report in the literature to date describes abscess in native kidney secondary to CRAB in a renal transplant. Infections caused by CRAB have become critical for immunosuppressed patients. The presence of complication greater risk, by an organism whose pathogenicity and virulence are not yet elucidated should determine an aggressive empirical antimicrobial therapy. PMID- 27234777 TI - Heart Transplantation Under Mechanical Circulatory Support for Acute Fulminant Myocarditis With Cardiogenic Shock: 10 Years' Experience of a Single Center. AB - BACKGROUND: Acute fulminant myocarditis with intractable cardiogenic shock is a fatal condition; its only therapeutic option is mechanical circulatory support. The use of mechanical circulatory support, either extracorporeal membrane oxygenation (ECMO) or a ventricular assist device (VAD), serves as a bridge to recovery or as a bridge to transplantation. OBJECTIVES: The aim of this research was to advance our understanding of the outcome of heart transplantation under mechanical support for acute myocarditis. Two groups of patients were compared: those recovered without undergoing transplantation and those who underwent transplantation. METHODS: We reviewed 134 patients experiencing acute myocarditis who required mechanical circulatory support (including ECMO and/or VAD) in our institute between 1994 and 2014. Demographic data, clinical characteristics, support duration, and outcome of individuals were retrospectively analyzed. RESULTS: Patients taking part in this study were aged from 1 month to 70 years, with an average age of 28 years. The transplantation-free survival rate in adults was 54%. A total of 6 adult patients receive a heart transplant under ECMO/left VAD; 2 of these patients died of uncontrolled sepsis after the heart transplantation. The duration of mechanical support ranged from 10 to 130 days (average, 41 days). CONCLUSIONS: Mechanical circulatory support in patients with acute myocarditis proved to be effective. Approximately one half of all adult patients in this study experienced myocardium recovery under mechanical support, with only 5% undergoing a successful heart transplantation. In terms of patients who survived after heart transplantation, the mid-term and long-term outcomes are favorable. PMID- 27234778 TI - Oxygen Uptake Efficiency Slope Predicts Major Cardiac Events in Patients With End Stage Heart Failure. AB - INTRODUCTION: Oxygen uptake efficiency slope (OUES) has been shown as a predictor of stable heart failure (HF) survival. However, there is a lack of evidence for end-stage HF. OBJECTIVES: We aimed to investigate the prognostic value of OUES in end-stage HF patients. METHODS: The study design was a retrospective cohort. End staged HF patients who had cardiopulmonary exercise testing (CPET) for evaluation between 2004 and 2009 were included. The primary outcomes were cardiac death and heart transplantation. The independent survival predictors were determined using Cox regression hazard model adjusted for demographics, New York Heart Association (NYHA) classification, medication, and left ventricular ejection fraction (LVEF). The Kaplan-Meier survival curves and log-rank test were used. Probability values less than .05 were considered significant. RESULTS: Mean age of the 128 patients was 50 +/- 12 years and 93 were male. Mean LVEF was 23% +/- 9%. Forty-three subjects suffered cardiac events (5 cardiac deaths and 38 urgent heart transplantations) during the 2-year follow-up period. Cox regression indicated that OUES and diuretics were significant predictors of 2-year survival, although peak oxygen uptake and ventilatory equivalent of carbon dioxide were not. Patients with high OUES (>=1.6) had a higher survival rate (P < .001; odds ratio [OR], 13.10; 95% confidence interval [CI], 3.30-58.63). The Kaplan-Meier curves show survival was significantly higher in those with OUES >=1.6. CONCLUSIONS: OUES might be an aid in prognosis of patients with end-stage HF and useful in the assessment of patients unable to perform maximal exercise testing. PMID- 27234779 TI - Case Series: Heart Transplantation After Fontan Operation-Single-Center Experience. AB - BACKGROUND: Fontan failure (FF) occurs rarely. In patients with Fontan failure, heart transplantation is believed to be the most effective therapy. We review our experience in heart transplantations after the Fontan operation. METHODS: From July 1987 to December 2014, 4 of 513 patients underwent orthotopic heart transplantation (OHT). Among them, 4 were due to FF. We reviewed these 4 cases via retrospective chart review. Clinical history, laboratory data, surgical technique, perioperative variables, and outcomes of long-term follow-up are presented herein. The primary outcomes were hospital mortality, 1-year-survival rate, and 4-year-survival rate. The secondary outcome is the improvement in patients with protein-losing enteropathy. RESULTS: The hospital mortality rate was 0% in the 4 FF patients receiving OHT. No surgically related hemorrhage or infection was observed. The 1-year-survival rate was 100% (n = 4) and the 4-year survival rate 50% (n = 2). One patient died of posttransplantation lymphoproliferative disorder. Hypoalbuminemia improved in 1 of 3 patients 4 months after OHT. CONCLUSIONS: Despite technical challenges, heart transplantation can be performed successfully in patients with Fontan operation. However, protein-losing enteropathy might not be resolved quickly after heart transplantation. PMID- 27234780 TI - Caring Difficulties and Coping Strategies for Pediatric Organ Transplant Recipients and Their Families During Dark Recovery Experiences in the Hospital: Perspective of Health Professionals in Taiwan. AB - BACKGROUND: This study explored caring difficulties and the reliable coping strategies for pediatric organ transplant recipients (POTR) and their families during their dark recovery experiences (DRE) in the hospital from the perspectives of Taiwan organ transplant health professionals (OTHP) in Taiwan. METHODS: A qualitative design was used with a purposive sample of OT surgeons (OTS) and nurses. Data were collected by face-to-face in-depth interviews and analyzed by content analysis. RESULTS: Fifty-five subjects (39 females, 16 males) participated in this project. They included 15 OTS and 40 nurses. The nurses included registered nurses (n = 27), nurse practitioners (n = 5), and assistant or head nurses (n = 8). Their ages ranged from 25 to 66 (M = 38.4) years old. Thirty-eight (69%) had a college education and 17 (31%) had a graduate education. Their OT careers ranged from between 3 to 40 (M = 23.8) years for OTS, and 0.5 to 15 (M = 4.10) years for the OT nursing group. Six types of coping strategies for caring difficulties were reported: (a) implementing humanistic care training programs, (b) developing clinical paths for complex multiple OT cases, (c) holding case conferences for successful and failed cases, (d) developing OT expert training programs for interdisciplinary team members, (e) integrating acute and long-term care teams for difficult OT cases and families, and (f) inviting assistance from social workers. CONCLUSIONS: This research identifies important care difficulties and provides coping strategies that help to empower OTHP to care for POTR and their families during DRE, including increasing the manpower of experienced OT staff, conducting systematic in-service training, building teamwork between OTHP, and establishing a good pediatric OTHP team with consensus and good communication channels so as to effectively deal with the difficulties faced when caring for the POTR, and further to effectively enhance the overall quality of clinical care of POTR. PMID- 27234781 TI - Malignancy After Heart Transplantation Under Everolimus Versus Mycophenolate Mofetil Immunosuppression. AB - BACKGROUND: With advances in immunosuppressive therapy, heart transplantation is currently recommended as the only established surgical treatment for refractory heart failure. However, chronic immunosuppression increases the risk for malignancy. Everolimus (EVR) is a potent mammalian target of rapamycin inhibitor that is used after transplantation and to treat advanced malignancies, as we have done in Taiwan after heart transplantation since 2004. Mycophenolate mofetil (MMF) and EVR are frequently used as cell-cycle inhibitors to optimize post transplantation outcomes. METHODS: We retrospectively analyzed the characteristics and outcomes of 454 patients who received either MMF (n = 232) or EVR (n = 222) after heart transplantation at the National Taiwan University Hospital from March 1, 1990, to March 1, 2015. Patient characteristics and Kaplan Meier survival curves were compared between groups. RESULTS: During a median follow-up of 69.2 months, malignancy was diagnosed in 27 patients receiving MMF (n = 23) or EVR (n = 4). There was a significant difference in malignancy risk between groups (9.91% vs 1.80%, P = .001). The most common malignancies were non Hodgkin lymphoma, skin cancers, and lung squamous cell carcinoma. The 2-year overall survival after malignancy was 50% in the EVR group and 47% in the MMF group (P = .745). CONCLUSIONS: EVR treatment after heart transplant is associated with a lower risk of malignancy than is MMF treatment. The 2-year survival rate after malignancy was similar between EVR and MMF groups. PMID- 27234782 TI - Low Incidence of Malignancy After Heart Transplantation in Taiwan. AB - BACKGROUND: Malignancy is the leading cause of death in Taiwan. The risk of malignancy is higher in heart transplant recipients than in the general population. We reviewed the malignancy incidence among the patients who underwent heart transplantation (HT) at the National Taiwan University Hospital (NTUH) during the past 28 years. We found that the incidence of malignancy is low in Taiwan and that the pattern of malignancy is different from that in the Western population. METHODS: From July 1987 to March 2015, 518 patients underwent HT at NTUH. Forty-four patients who died within 1 month after transplantation were excluded from this study. Thus, a total of 476 patients were enrolled in this study. There were 393 male and 83 female patients, with a mean age of 45 years at transplantation. The major indications for HT were dilated cardiomyopathy (52%) and ischemic cardiomyopathy (33%). After HT, all patients received triple immunosuppressive therapy, including a calcineurin inhibitor (cyclosporine or tacrolimus), cell-cycle inhibitor (azathioprine, mycophenolate mofetil, or everolimus), and steroid. After 1995, induction with rabbit anti-human thymocyte globulin was routinely performed. Survival was estimated by means of the Kaplan Meier method. RESULTS: Twenty-seven patients without pre-transplantation malignancy developed malignancies after HT. The median survival time (MST) of these 27 HT patients was 76.8 months. After malignancy was diagnosed, the overall MST was 20.7 months. The 3- and 5-year overall survival rates were 44% and 27%, respectively. Twenty-one patients (77.8%) died, 10 of them because of cancer. The most common malignancy was non-Hodgkin lymphoma (n = 6), followed by skin cancer (including 2 keratoacanthomas, 2 squamous cell carcinomas, and 1 basal cell carcinoma; n = 5) and lung squamous cell carcinoma (n = 3). The univariate analysis identified cancer stage (P = .044) and comorbidity (P = .002) as factors associated with poor malignancy survival. In the multivariate analysis, comorbidity was an independent prognostic factor for greater risk of death because of post-transplantation malignancy (P = .002). CONCLUSIONS: In Taiwan, the risk of malignancy after HT is low (5.7%), as is the incidence of skin cancer. The most common malignancy was non-Hodgkin lymphoma, followed by skin cancer and lung cancer. Comorbidity was an independent factor for overall survival in cancer patients who previously underwent HT. PMID- 27234783 TI - Surveillance of Immunosuppression During Pregnancy After Heart Transplantation: Case Report. AB - BACKGROUND: Transplantation and immunosuppressive drugs are major limitations to the success of pregnancy. In 1988, the first pregnancy after a heart transplant was reported, which has given female recipients the hope to give birth. During pregnancy, physiologic changes with increased blood volume and hemodilution may influence blood drug level. CASE REPORT: We reported our experience in monitoring on immunosuppressive drugs for 2 cases. Both of them underwent heart transplantation in 2006 and were 34 and 37 years old at time of pregnancy. For both cases, we frequently monitored the blood level and increased the dosage of immunosuppressive drugs accordingly. Both cases had uneventful pregnancy and delivery to healthy babies at the National Taiwan University Hospital in Taiwan. Their postpartum courses were uneventful as well. CONCLUSIONS: We advocate adjusting the immunosuppressive dosage according to the blood level before pregnancy. PMID- 27234784 TI - Prolonged Negative Pressure Wound Therapy Followed by Split-Thickness Skin Graft Placement for Wide Dehiscence of Clamshell Incision After Bilateral Lung Transplantation: A Case Report. AB - Clamshell incision is a standard approach for bilateral lung transplantation, providing a good operative field; however, once wide dehiscence occurs, its management is sometimes difficult because of intense immunosuppression and malnutrition of the recipient. A 22-year-old man with idiopathic pulmonary arterial hypertension underwent cadaveric bilateral lung transplantation through a clamshell incision using standard cardiopulmonary bypass. He developed wound dehiscence on postoperative day (POD) 20 that resulted in exposure of the bilateral fifth ribs and open pneumothorax. Considering the extreme malnutrition and emaciation of the recipient, we avoided initial closure of the dehiscence. After the debridement of necrotic tissue, negative pressure wound therapy was initiated on POD 25 and was continued for approximately 6 months with trafermin spray application. Eventually, the wound, including the fifth ribs, was completely covered with granulation tissue except for the wire tying the sternum. On POD 217, the patient underwent removal of the sternal wire followed by split thickness skin grafting. His wound was successfully closed and he was discharged without activity limitation on POD 265. PMID- 27234785 TI - Successful Case of Somatostatin Analog Stopping Gastrointestinal Bleeding, One of the Most Frequent Complications After Simultaneous Pancreas-kidney Transplantation: A Case Report. AB - OBJECT: Pancreas transplantation has the highest surgical complication rate of all routinely performed organ transplantation procedures. The complications are not only caused by the pancreas itself but also occur due to issues with the transplant recipient. We report the case of a patient who experienced massive gastrointestinal bleeding after simultaneous pancreas-kidney transplantation (SPK), which was stopped successfully using somatostatin analog. PATIENTS AND METHODS: The patient was a 45-year-old woman with diabetes mellitus type 1 who underwent SPK with enteric drainage. She had melena 5 days after SPK. RESULTS: At first, we suspected that the melena was caused by the transplanted duodenum because of rejection and ischemic changes. The patient experienced severe bleeding 9 days after SPK. We quickly performed open surgery and inserted an endoscope from the recipient's ileum to investigate the transplanted duodenum. However, no bleeding source was found, including in the transplanted duodenum and the recipient's ileum end. We determined that the bleeding source was the recipient's ascending colon. We attempted to perform endovascular treatment but could not detect the source of the bleeding; therefore, we used somatostatin analog to let the blood vessels shrink and reduce pancreatic output. Thereafter, the function of the transplanted pancreas and kidney gradually recovered, and the recipient was discharged 154 days after SPK. CONCLUSION: Gastrointestinal bleeding is a lethal complication and has several different causes, such as mucosal rejection, ischemic changes, and exocrine output of the pancreas graft. Somatostatin analog is one of the most acceptable treatments for patients who have gastrointestinal bleeding after SPK. PMID- 27234786 TI - Six-Year Graft Survival After Partial Pancreas Heterotopic Auto-Transplantation: A Case Report. AB - BACKGROUND: Long-term graft survival of partial pancreas auto-transplantation after total pancreatectomy has not been clarified. The clinical implications of repeat completion pancreatectomy for locally recurrent pancreatic carcinoma in the remnant pancreas after initial pancreatectomy also have not been clarified. METHODS: We have previously reported a 61-year-old woman presenting with re sectable carcinoma of the remnant pancreas at 3 years after undergoing a pylorus preserving pancreaticoduodenectomy for invasive ductal carcinoma of the pancreas head. We also performed distal pancreas auto-transplantation with the use of a part of the resected pancreas to preserve endocrine function. RESULTS: The patient was discharged at 20 days after surgery without any complications. She had been followed regularly in our outpatient clinic. She had been treated with S 1 as adjuvant chemotherapy; 72 months after the completion total pancreatectomy with distal partial pancreas auto-transplantation, the patient was alive without any evidence of the pancreatic carcinoma recurrence. The pancreas graft was still functioning with a blood glucose level of 112 mg/dL, HbA1C of 6.7%, and serum C peptide of 1.2 ng/mL; and urinary C-peptide was 11.6 MUg/d. CONCLUSIONS: Our patient demonstrated that repeated pancreatectomies can provide a chance for survival after a locally recurrent pancreatic carcinoma if the disease is limited to the remnant pancreas. An additional partial pancreas auto-transplantation was successfully performed to preserve endocrine function. However, the indications for pancreas auto-transplantation should be decided carefully in the context of pancreatic carcinoma recurrence. PMID- 27234788 TI - The Power of Checklists. PMID- 27234787 TI - Regulation of plasma lipid homeostasis by hepatic lipoprotein lipase in adult mice. AB - LPL is a pivotal rate-limiting enzyme to catalyze the hydrolysis of TG in circulation, and plays a critical role in regulating lipid metabolism. However, little attention has been paid to LPL in the adult liver due to its relatively low expression. Here we show that endogenous hepatic LPL plays an important physiological role in plasma lipid homeostasis in adult mice. We generated a mouse model with the Lpl gene specifically ablated in hepatocytes with the Cre/LoxP approach, and found that specific deletion of hepatic Lpl resulted in a significant decrease in plasma LPL contents and activity. As a result, the postprandial TG clearance was markedly impaired, and plasma TG and cholesterol levels were significantly elevated. However, deficiency of hepatic Lpl did not change the liver TG and cholesterol contents or glucose homeostasis. Taken together, our study reveals that hepatic LPL is involved in the regulation of plasma LPL activity and lipid homeostasis. PMID- 27234790 TI - AORN Surgical Conference & Expo Highlights. PMID- 27234789 TI - Aging and Ageism in Perioperative Nursing. PMID- 27234791 TI - Research, Evidence-Based Practice, and Clinical Improvement/Innovation Posters. PMID- 27234792 TI - Aorn Surgical Conference & Expo Awards. PMID- 27234793 TI - Caring for Surgical Patients With Piercings. AB - Body piercing, a type of body modification that is practiced in many cultures, creates an unnatural tract through tissue that is then held open by artificial means. Today, professional body piercing is often performed in piercing establishments that are subject to dissimilar forms of regulation. The most frequently reported medical complication of body piercing and similar body modifications, such as dermal implantation, is infection. Patients with piercings who undergo surgery may have additional risks for infection, electrical burns, trauma, or airway obstruction. The published research literature on piercing prevalence, complications, regulations, education, and nursing care is outdated. The purpose of this article is to educate nurses on topics related to nursing care for patients with piercings and similar body modifications, including the history, prevalence, motivations for, and perceptions of body piercings as well as possible complications, devices used, locations, healing times, regulations, patient education, and other health concerns. PMID- 27234794 TI - Integrating Perioperative Content in Nursing Curricula: A Case Study Approach. AB - Perioperative nursing care requires unique specialty knowledge, skills, and abilities. National initiatives in nursing education and health care support integrating perioperative nursing content into curricular offerings in nursing schools and health care institutions. We provide an overview of the initiatives affecting nursing education, followed by a case study example and a guide to assist educators with incorporating perioperative case studies into their education plans. These resources may enhance the integration of perioperative nursing concepts in undergraduate curricula, internships, and continuing education offerings. The purpose of this article is to provide resources for nurse educators to systematically create case studies and to encourage increased exposure to perioperative concepts and competencies in a myriad of educational environments. PMID- 27234795 TI - Pain Management After Total Joint Arthroplasty. AB - Controlling pain after total joint arthroplasty (TJA) is critical to minimizing complications, decreasing costs, and expediting patients' return to function. We implemented a TJA multimodal pain management protocol at a Level III trauma center in a small, rural community in New York. We retrospectively reviewed 266 patient charts and collected patient demographics, pain management information, and discharge data. Our primary goals were to quantify the total number of narcotic medication doses used and length of hospital stay. The multimodal pain management protocol significantly reduced the number of narcotic doses used (P < .01). Hospital length of stay decreased slightly; although not statistically significant (P = .25), this may be clinically significant. Gender, age, and type of arthroplasty (ie, knee, hip) were not significant factors. A multimodal approach to pain management after TJA can reduce narcotic use and hospital length of stay, thereby also reducing the incidence of side effects from narcotics. PMID- 27234796 TI - An Innovative Approach to the Surgical Time Out: A Patient-Focused Model. AB - The surgical time out is an integral component of patient safety in OR settings. At The Center for Outpatient Surgery (TCOPS), a team of nurses and plastic and breast surgeons evaluated discrepancies, wrong-site surgeries, near misses, team communication, and patient satisfaction to develop and implement a surgical checklist that would help improve efficiency and patient safety and reduce near misses. This checklist involves the surgical team and patient, and it includes preoperative, preincision, and postoperative time outs. Since 2011, 4,453 procedures have used the preoperative and preincision timeouts. Of those, 998 have used all three when we added the postoperative component. Since the implementation of the checklist, there have been zero discrepancies and zero wrong-site surgeries. Patients have expressed satisfaction with their inclusion in the preoperative time out. Staff members at TCOPS have noted excellent results, and the checklist can be adopted by other specialties. PMID- 27234797 TI - Innovative Programs Promoting Careers in OR Nursing. AB - Much of the baby boomer workforce is approaching retirement, and nurses who are part of this generation will need to be replaced. The strain is especially notable in the perioperative nursing environment. To assist in recruiting new perioperative nurses, three programs were introduced at a rural academic medical center. Leaders at this facility developed a perioperative nursing course to train new graduate nurses and nurses without OR experience, an introduction to perioperative nursing course for junior and senior undergraduate nursing students, and an intraoperative learning experience for high school students interested in a career in nursing. These three programs provide an opportunity to expose new nurses, nursing students, and high school students to an OR nursing career path. The programs and their successful outcomes are shared as exemplars for enhancing the education of new OR nurses and generating interest in OR nursing as a career path. PMID- 27234798 TI - Setting a Quality Improvement and Research Agenda for Patient Safety in a Tertiary Hospital in Australia. PMID- 27234799 TI - The WakeWings Journey: Creating a Patient Safety Program. PMID- 27234800 TI - Clinical Issues-June 2016. AB - Use of alcohol (ethanol)-based hand rubs (ABHRs) during pregnancy Key words: alcohol, ethanol, hand rub, ABHR, hand sanitizer. Working when experiencing a shingles infection Key words: shingles, varicella, zoster, employee health. Cleaning rigid containers Key words: rigid container, container, instrument pan. PMID- 27234801 TI - Anchoring Bias With Critical Implications. PMID- 27234802 TI - San Huang Shel Shin Tang beta-cyclodextrin complex augmented the hepatoprotective effects against carbon tetrachloride-induced acute hepatotoxicity in rats. AB - BACKGROUND: San Huang Shel Shin Tang (SHSST) is a traditional herbal decoction used as a hepato-protective agent and is composed of Rheum officinale Baill, Scutellaria baicalnsis Geprgi and Coptis chinensis Franch (2:1:1 w/w). Beta cyclodextrin (beta-CD) modification may potentially increase the solubility and spectral properties of SHSST. METHODS: In this research, the hepato-protective effects of unmodified SHSST, beta-CD modified SHSST complex (SHSSTc) and silymarin were evaluated in carbon tetrachloride (CCl4) induced acute hepatotoxicity in rats. RESULTS: SHHSTc (40 mg/kg/day) and silymarin (100 mg/kg/day) both decreased the CCl4-induced cirrhosis pathway-related transforming growth factor beta (TGF-beta) and apoptosis pathway-related caspase-8 protein expressions, but SHSST (40 mg/kg/day) did not reduce TGF-beta and caspase-8 significantly . Moreover, SHHSTc (40 mg/kg/day) enhanced the activation of insulin-like growth factor 1 receptor (IGF1R) mediated survival pathway than the silymarin (100 mg/kg/day) to protect the liver from damage induced by CCl4. CONCLUSIONS: beta-CD modification promotes hepato-protective effects of SHSST and reduces the required-dosage of the SHSST. PMID- 27234804 TI - Editorial Comment. PMID- 27234803 TI - Environmental Behavior's Dirty Secret: The Prevalence of Waste Management in Discussions of Environmental Concern and Action. AB - Humankind and the planet face many thorny environmentally related challenges that require a range of responses, including changing behaviors related to transportation, eating habits, purchasing, and myriad other aspects of life. Using data from a 1201-person survey and 14 Community Listening Sessions (CLSs), we explore people's perceptions of and actions taken to protect the environment. Our data indicate a striking prevalence of waste management-related actions. Survey respondents described actions and concerns related to trash, recycling, and composting as the most common environmental behaviors; similarly, participants in CLSs discussed waste-related topics, for which we did not prompt, as frequently as those topics for which we specifically prompted. Explanations for this prevalence emerging from the data include (1) the nature of waste related behaviors (concrete, supported by infrastructure, simple, compatible with lifestyle); (2) norms and social dynamics (family interactions, feelings of belonging/participation, government policy); and (3) internal psychological processes (internalized norms and environmental concern). We also found that many waste-related discussions were relatively superficial, focusing on immediate waste-related issues (e.g., litter or recycling) rather than larger issues such as consumption. Our results may provide insight into future efforts to encourage pro-environmental behavior. Given that most pro-environmental behavior involves tasks more complex and lifestyle-changing than those related to simple aspects of waste management, we suggest focusing on the latter two intertwined categories that our data suggest are important: encouraging social dynamics and related development of norms concerning environmental behavior (category 2), and fostering internalized norms and environmental concern (category 3). PMID- 27234806 TI - Human factors for a sustainable future. AB - Current human activities are seriously eroding the ability of natural and social systems to cope. Clearly we cannot continue along our current path without seriously damaging our own ability to survive as a species. This problem is usually framed as one of sustainability. As concerned professionals, citizens, and humans there is a strong collective will to address what we see as a failure to protect the natural and social environments that supports us. While acknowledging that we cannot do this alone, human factors and ergonomics needs to apply its relevant skills and knowledge to assist where it can in addressing the commonly identified problem areas. These problems include pollution, climate change, renewable energy, land transformation, and social unrest amongst numerous other emerging global problems. The issue of sustainability raises two fundamental questions for human factors and ergonomics: which system requires sustaining and what length of time is considered sustainable? In this paper we apply Wilson (2014) parent-sibling-child model to understanding what is required of an HFE sustainability response. This model is used to frame the papers that appear in this Special Issue. PMID- 27234805 TI - Genomic and transcriptomic predictors of response levels to endurance exercise training. AB - Predicting the responsiveness to regular exercise is a topic of great relevance due to its potential role in personalized exercise medicine applications. The present review focuses on cardiorespiratory fitness (commonly measured by maximal oxygen uptake, VO2 max ), a trait with wide-ranging impact on health and performance indicators. Gains in VO2 max demonstrate large inter-individual variation even in response to standardized exercise training programmes. The estimated DeltaVO2 max heritability of 47% suggests that genomic-based predictors alone are insufficient to account for the total trainability variance. Candidate gene and genome-wide linkage studies have not significantly contributed to our understanding of the molecular basis of trainability. A genome-wide association study suggested that VO2 max trainability is influenced by multiple genes of small effects, but these findings still await rigorous replication. Valuable evidence, however, has been obtained by combining skeletal muscle transcript abundance profiles with common DNA variants for the prediction of the VO2 max response to exercise training. Although the physiological determinants of VO2 max measured at a given time are largely enunciated, what is poorly understood are the details of tissue-specific molecular mechanisms that limit VO2 max and related signalling pathways in response to exercise training. Bioinformatics explorations based on thousands of variants have been used to interrogate pathways and systems instead of single variants and genes, and the main findings, along with those from exercise experimental studies, have been summarized here in a working model of VO2 max trainability. PMID- 27234807 TI - Centrosome associated genes pattern for risk sub-stratification in multiple myeloma. AB - BACKGROUND: The genome of multiple myeloma (MM) cells is extremely unstable, characterized by a complex combination of structure and numerical abnormalities. It seems that there are several "myeloma subgroups" which differ in expression profile, clinical manifestations, prognoses and treatment response. In our previous work, the list of 35 candidate genes with a known role in carcinogenesis and associated with centrosome structure/function was used as a display of molecular heterogeneity with an impact in myeloma pathogenesis. The current study was devoted to establish a risk stratification model based on the aforementioned candidate genes. METHODS: A total of 151 patients were included in this study. CD138+ cells were separated by magnetic-activated cell sorting (MACS). Gene expression profiling (GEP) and Interphase FISH with cytoplasmic immunoglobulin light chain staining (cIg FISH) were performed on plasma cells (PCs). All statistical analyses were performed using freeware R and its additional packages. Training and validation cohort includes 73 and 78 patients, respectively. RESULTS: We have finally established a model that includes 12 selected genes (centrosome associated gene pattern, CAGP) which appears to be an independent prognostic factor for MM stratification. We have shown that the new CAGP model can sub-stratify prognosis in patients without TP53 loss as well as in IMWG high risk patients' group. CONCLUSIONS: We assume that newly established risk stratification model complements the current prognostic panel used in multiple myeloma and refines the classification of patients in relation to the disease risks. This approach can be used independently as well as in combination with other factors. PMID- 27234808 TI - Psychosocial Aspects of Continuous Glucose Monitoring: Connecting to the Patients' Experience. AB - Continuous glucose monitoring (CGM) systems provide people with diabetes with valuable real-time information on glucose trajectories and trends, thus offering opportunities for improving diabetes self-management. Ample evidence from clinical trials underscores CGM effectiveness for biomedical outcomes including HbA1C and hypoglycemia. However, interindividual variability in CGM uptake seems to be substantial: Neither do all individuals with diabetes adopt CGM readily in their diabetes self-management, nor do all of them benefit from CGM. In this article, we focus on CGM effects on quality of life and the potential role of psychosocial patient characteristics for determining the uptake and outcomes of CGM. After providing a brief overview on existing evidence on psychosocial factors in CGM use, gaps in existing research are identified and directions for future research are proposed that could answer key research questions and offer guidance for clinical diabetes care. PMID- 27234809 TI - Diabetes Technology: Uptake, Outcomes, Barriers, and the Intersection With Distress. AB - Patients managing type 1 diabetes have access to new technologies to assist in management. This manuscript has two aims: 1) to briefly review the literature on diabetes technology use and how this relates to psychological factors and 2) to present an example of human factors research using our data to examine psychological factors associated with technology use. Device/technology uptake and use has increased over the years and at present day is a common clinical practice. There are mixed results in terms of health and psychosocial outcomes, with specific subgroups doing better than others with technology. Our data demonstrated that patients have moderately elevated diabetes distress across differing types of technology used, from low-tech to high-tech options, possibly meaning that technology does not add or take away distress. In addition, users on multiple daily injections compared to all other technology groups have less positive attitudes about technology. Finally, we discuss implications for clinical practice and future research. PMID- 27234810 TI - Crime and victimisation in people with intellectual disability: a case linkage study. AB - BACKGROUND: Studies have suggested that people with intellectual disability are disproportionately involved in crime both as perpetrators and victims. METHOD: A case linkage design used three Australian contact-level databases, from disability services, public mental health services and police records. Rates of contact, and official records of victimisation and criminal charges were compared to those in a community sample without intellectual disability. RESULTS: Although people with intellectual disability were significantly less likely to have an official record of victimisation and offending overall, their rates of violent and sexual victimisation and offending were significantly higher. The presence of comorbid mental illness considerably increased the likelihood of victimisation and offending; several sex differences were also noted. CONCLUSIONS: People with intellectual disability are at increased risk for both violent and sexual victimisation and offending. The presence of comorbid mental illness aggravates the risk of offending and victimisation. Future research should focus on a more nuanced exploration of the risks associated with intellectual disability and specific mental disorders and related indices of complexity. PMID- 27234811 TI - Helminths and Intestinal Flora Team Up to Improve Gut Health. AB - Inflammatory bowel diseases (IBD) are associated with impaired intestinal barrier function, chronic inflammation, and microbial dysbiosis. In a recent publication in Science, Ramanan et al. used murine and human studies to demonstrate that infections with gastrointestinal helminths can protect against IBD by provoking immune responses that alter the balance of commensal and pathogenic bacteria in the intestine. PMID- 27234812 TI - Metabolic Crosstalk between Leishmania and the Macrophage Host. AB - Goldman-Pinkovich et al. have shown that intracellular stages of Leishmania actively sense arginine levels within the phagolysosome of the host macrophage and activate a MAP kinase-dependent response when arginine is reduced. This response may impact macrophages responses as well as being required for parasite intracellular replication. PMID- 27234813 TI - Outcomes of Catheter Ablation of Ventricular Tachycardia in the Setting of Structural Heart Disease. AB - Sustained ventricular tachycardias are common in the setting of structural heart disease, either due to prior myocardial infarction or a variety of non-ischemic etiologies, including idiopathic dilated cardiomyopathy, hypertrophic cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy. Over the past two decades, percutaneous catheter ablation has evolved dramatically and has become an effective tool for the control of ventricular arrhythmias. Single and multicenter observational studies as well as several prospective randomized trials have begun to investigate long-term outcomes after catheter ablation procedures. These studies encompass a wide range of mapping and ablation techniques, including conventional activation mapping/entrainment criteria, substrate modification guided by pacemapping, late potential and abnormal electrogram ablation, scar de-channeling, and core isolation. While large-scale, multicenter prospective randomized clinical trials are somewhat limited, the published data demonstrate favorable outcomes with respect to a reduction in overall ventricular tachycardia (VT) burden, reduction of implantable cardioverter defibrillator (ICD) shocks, and discontinuation of anti-arrhythmic medications across varying disease subtypes and convincingly support the use of catheter ablation as the standard of care for many patients with VT in the setting of structural heart disease. PMID- 27234814 TI - Effect of deoxyribonuclease I treatment for dementia in end-stage Alzheimer's disease: a case report. AB - BACKGROUND: Alzheimer's disease is the most common cause of dementia and is characterized by a progressive loss of brain tissue leading to amyloid-beta accumulation and severe decline in cognitive function. The cause of Alzheimer's disease is poorly understood, and available treatments are limited in their efficacy, particularly for patients with more severe symptoms. CASE PRESENTATION: We report the case of a 77-year-old Caucasian man with severe dementia and behavioral disturbance secondary to Alzheimer's disease treated with memantine who began adjunct treatment with deoxyribonuclease I. Prior to initiation of deoxyribonuclease I treatment, our patient appeared to be in a stuporous state, with a Mini-Mental State Examination score of 3 and a Functional Assessment Staging Test score of 7. After obtaining informed consent from family members, we started administration of 120 mg of deoxyribonuclease I per day (1500 KU/mg) for treatment of severe cognitive impairment. CONCLUSIONS: Our patient began to demonstrate rapid, considerable improvement in cognitive function 2 days following initiation of deoxyribonuclease I treatment. After 2 months of continued treatment, Mini-Mental State Examination and Functional Assessment Staging Test scores were 18 and 4, respectively. PMID- 27234815 TI - Erratum to: K13 mutations and pfmdr1 copy number variation in Plasmodium falciparum malaria in Myanmar. PMID- 27234817 TI - Near Infrared Spectroscopic Mapping of Functional Properties of Equine Articular Cartilage. AB - Mechanical properties of articular cartilage are vital for normal joint function, which can be severely compromised by injuries. Quantitative characterization of cartilage injuries, and evaluation of cartilage stiffness and thickness by means of conventional arthroscopy is poorly reproducible or impossible. In this study, we demonstrate the potential of near infrared (NIR) spectroscopy for predicting and mapping the functional properties of equine articular cartilage at and around lesion sites. Lesion and non-lesion areas of interests (AI, N = 44) of equine joints (N = 5) were divided into grids and NIR spectra were acquired from all grid points (N = 869). Partial least squares (PLS) regression was used to investigate the correlation between the absorbance spectra and thickness, equilibrium modulus, dynamic modulus, and instantaneous modulus at the grid points of 41 AIs. Subsequently, the developed PLS models were validated with spectral data from the grid points of 3 independent AIs. Significant correlations were obtained between spectral data and cartilage thickness (R 2 = 70.3%, p < 0.0001), equilibrium modulus (R 2 = 67.8%, p < 0.0001), dynamic modulus (R 2 = 68.9%, p < 0.0001) and instantaneous modulus (R 2 = 41.8%, p < 0.0001). Relatively low errors were observed in the predicted thickness (5.9%) and instantaneous modulus (9.0%) maps. Thus, if well implemented, NIR spectroscopy could enable arthroscopic evaluation and mapping of cartilage functional properties at and around lesion sites. PMID- 27234816 TI - Controlled and Sequential Delivery of Fluorophores from 3D Printed Alginate-PLGA Tubes. AB - Controlled drug delivery systems, that include sequential and/or sustained drug delivery, have been utilized to enhance the therapeutic effects of many current drugs by effectively delivering drugs in a time-dependent and repeatable manner. In this study, with the aid of 3D printing technology, a novel drug delivery device was fabricated and tested to evaluate sequential delivery functionality. With an alginate shell and a poly(lactic-co-glycolic acid) (PLGA) core, the fabricated tubes displayed sequential release of distinct fluorescent dyes and showed no cytotoxicity when incubated with the human embryonic kidney (HEK293) cell line or bone marrow stromal stem cells (BMSC). The controlled differential release of drugs or proteins through such a delivery system has the potential to be used in a wide variety of biomedical applications from treating cancer to regenerative medicine. PMID- 27234818 TI - Transcatheter Mitral Valve Repair Therapies: Evolution, Status and Challenges. AB - Mitral regurgitation is a common cardiac valve lesion, developing from primary lesions of the mitral valve or secondary to cardiomyopathies. Moderate or higher severity of mitral regurgitation imposes significant volume overload on the left ventricle, causing permanent structural and functional deterioration of the myocardium and heart failure. Timely correction of regurgitation is essential to preserve cardiac function, but surgical mitral valve repair is often delayed due to the risks of open heart surgery. Since correction of mitral regurgitation can provide symptomatic relief and halt progressive cardiac dysfunction, transcatheter mitral valve repair technologies are emerging as alternative therapies. In this approach, the mitral valve is repaired either with sutures or implants that are delivered to the native valve on catheters introduced into the cardiovascular system under image guidance, through small vascular or ventricular ports. Several transcatheter mitral valve technologies are in development, but limited clinical success has been achieved. In this review, we present a historical perspective of mitral valve repair, review the transcatheter technologies emerging from surgical concepts, the challenges they face in achieving successful clinical application, and the increasing rigor of safety and durability standards for new transcatheter valve technologies. PMID- 27234819 TI - Transcriptome Sequencing and Comparative Analysis of Ovary and Testis Identifies Potential Key Sex-Related Genes and Pathways in Scallop Patinopecten yessoensis. AB - Bivalve mollusks have fascinatingly diverse modes of reproduction. However, research investigating sex determination and reproductive regulation in this group of animals is still in its infancy. In this study, transcriptomes of three ovaries and three testes of Yesso scallop were sequenced and analyzed. Transcriptome comparison revealed that 4394 genes were significantly different between ovaries and testes, of which 1973 were ovary-biased (upregulated in the ovaries) and 2421 were testis-biased. Crucial sex-determining genes that were previously reported in vertebrates and putatively present in bivalves, namely FOXL2, DMRT, SOXH, and SOXE, were investigated. The genes all possessed conserved functional domains and were detected in the gonads. Except for PySOXE, the other three genes were significantly differentially expressed between the ovaries and testes. PyFOXL2 was ovary-biased, and PyDMRT and PySOXH were testis-biased, suggesting that these three genes are likely to be key candidates for scallop sex determination/differentiation. Furthermore, GO and KEGG enrichment analyses were conducted for both ovary- and testis-biased genes. Interestingly, both neurotransmitter transporters and GABAergic synapse genes were overrepresented in the ovary-biased genes, suggesting that neurotransmitters, such as GABA and glycine, are likely to participate in scallop ovary development. Our study will assist in better understanding of the molecular mechanisms underlying bivalve sex determination and reproductive regulation. PMID- 27234820 TI - [Spanish funded paediatric research: Contribution of Anales de Pediatria to its dissemination]. AB - OBJECTIVE: To identify Spanish funded paediatric research published in general paediatric journals included in the Web of Science (WoS) from 2010 to 2014) and those published in the Anales de Pediatria. To examine the relationship between funding and the prestige of the journals. To describe the journal conditions to meet the open access criteria. MATERIAL AND METHOD: Spanish funded paediatric articles (FA) were identified by using the WoS Funding Agency field, and by reviewing the original documents for the Anales de Pediatria (AP). For the FA published in AP the number and kind of funding agencies were identified. The possible differences in citations between FA and non-funded was assessed for articles published in this journal using the Kruskal-Wallis non-parametric test. For general journals, the patterns of distribution of FA and non-FA were investigated according to the quartile of the journal. The journal's self archiving conditions were described using Sherpa/romeo database. RESULTS: Funding was received for 27.5%, being 16.6% for those published in AP. In these, 105 funding agencies were identified, with 80% being national. The FA published in AP did not receive significantly more citations. In general journals, the presence of FA is greater in Q1 and Q2 journals. More than half (56%) of articles were published in subscription journals. All journals that publish FA allow self archiving in repositories, but with embargos of at least 12 months. CONCLUSIONS: The role of AP in the dissemination of FA is still limited. Embargos in self archiving permits compliance of Spanish open access mandate, but may hinder compliance in Europe. PMID- 27234821 TI - [Hemiplegic migraine and arterial spin labelling sequence]. PMID- 27234822 TI - [Recommendations for the prevention of foreign body aspiration]. AB - The aspiration of a foreign body remains a common paediatric problem, with serious consequences that can produce both acute and chronic disease. Aspiration usually causes a medical emergency that requires a prompt diagnosis and an urgent therapeutic approach as it may result in the death of the child or severe brain injury. It typically involves organic foreign bodies (mainly food or nuts) aspirated by children under 5 years old, and usually at home. In this statement, the Committee on Safety and Prevention of Non-Intentional Injury in Childhood of the Spanish Paediatrics Association provides a series of recommendations, both educational (while eating and playing), as well as legal, to prevent such episodes. PMID- 27234823 TI - Impact of metal pollution, food availability, and excessive fishing on Rhabdosargus haffara stock (family: Sparidae) in Timsah lake. AB - The lakes' fisheries play an important role in Egyptian economy. In 1980s, they provided more than 50 % of harvested fish in Egypt but now their contribution to the Egypt fish production decreased to only 12.5 % in 2012. Lake Timsah, one of the Suez Canal lakes, faced many challenges that lead to serious changes in its water and fish quality, fish production, as well as the catch composition. The present work investigated the impact of pollution, food availability, and excessive fishing mortality on the haffara production in lake Timsah. The distribution of four heavy metals (Pb, Zn, Ni, and Fe) was detected seasonally in water and in muscles, gills, and livers of Rhabdosargus haffara, during 2012 through 2013. Fe and Zn were presented by high values in liver, while Pb and Ni in gills. Generally, the lowest concentrations of all metals were found in muscles. The recorded crustacean organisms (the main food of haffara) decreased from 12 species and 32,079 organisms/m(2) in 2012 to only 7 species and 7290 organisms/m(2) in 2013 while the amphipods completely disappeared. This serious change was due to the severe pollution in the lake. A logistic surplus production model was fitted to the catch per unit effort indices, to estimate the maximum sustainable yield and the optimum level of fishing effort. The results revealed that haffara stock at lake Timsah is overfished, and the estimated precautionary target reference points advised the reduction of fishing effort by about 30-50 %. PMID- 27234824 TI - A multi-analytical approach for the assessment of the provenience of geological amber: the collection of the Earth Sciences Museum of Bari (Italy). AB - The Earth Sciences Museum of the University of Bari Aldo Moro (Italy) exhibits a wide collection of amber samples. These have been catalogued as Baltic amber (succinite), Sicilian amber (simetite), amber from New Jersey, Apennine amber and New Zealand copaline. However, some samples revealed to be erroneously classified as a consequence of incorrect information on the labels or in the museum catalogue. This may be due to historical forgeries, as is often the case of simetite, or to a possible exchange of samples that probably occurred during the displacement of the museum collection from the Central University Building to the Geo-environmental and Earth Sciences Department. In this study, all amber samples were systematically investigated with long wave UV rays, attenuated total reflectance (ATR), Fourier transform infrared (FTIR) spectroscopy and pyrolysis gas chromatography-mass spectrometry (Py-GC-MS) using on-line thermally assisted hydrolysis and methylation. The combined use of the latter two analytical techniques allowed for a complete characterisation of the ambers, whereas UV fluorescence showed to be of little value. The compositional data could be used for a better classification and valorisation of the amber samples of the museum collection. Two of the purported amber samples were shown to be copal, while four others are ambers but had been wrongly classified. Moreover, for some samples, it could be established that they had been subjected to treatment with a drying oil. PMID- 27234825 TI - Effects of oxygenated polycyclic aromatic hydrocarbons on the early life stages of Japanese medaka. AB - Oxygenated polycyclic aromatic hydrocarbons (oxyPAHs) are directly discharged into the atmosphere with exhaust gas from diesel engine automobiles and industry and are also generated by photo-oxidation and/or microbial metabolism of parent polycyclic aromatic hydrocarbons (PAHs). They are widely distributed in environment, especially around urban areas. We evaluated the effects of exposure to oxyPAHs as acenaphthenequinone (ANQ), 7,12-benz(a)anthracenequinone (BAQ), 1,4 naphthoquinone (NAQ), and 9,10-phenanethrenequinone (PHQ) in Japanese medaka (Oryzias latipes) embryos. ANQ (>2720 MUg/L) caused caving in the yolk sac, and BAQ (>22.4 MUg/L) caused tanning of the oil droplet. Additionally, NAQ (>314 MUg/L) and PHQ (>734 MUg/L) stopped development of medaka embryos beginning 2 days after the start of exposure. The hatched larvae from embryos exposed to ANQ, BAQ, NAQ, or PHQ at 518, 9.86, 36.5, or 80.7 MUg/L, respectively, exhibited incomplete development of the cephalic region, incomplete palate, unabsorbed and hypertrophied yolk sac, tubular heart, altered axial curvature, and poor swimming ability. These symptoms were similar to those observed in blue sac disease, which is caused by exposure to PAHs. PMID- 27234826 TI - Synthesis process and photocatalytic properties of BiOBr nanosheets for gaseous benzene. AB - A series of nano-BiOBr were prepared by an effective hydrothermal method in the presence of cetyltrimethyl ammonium bromide (CTAB) and ethanol at different calcination temperatures. The as-prepared nano-BiOBr samples were characterized by measuring the specific area (S BET), UV-Vis diffuse reflectance spectrum, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and X ray diffraction (XRD). The results show that the calcination temperature has an important impact on the morphology and microstructure of BiOBr. The nano-BiOBr calcined at 120 degrees C showed excellent photocatalytic degradation properties for benzene, with photocatalytic degradation rate of 75 % for benzene under UV irradiation for 90 min, and removal efficiency of benzene was significantly enhanced by using nano-BiOBr catalyst compared to UV irradiation alone. BiOBr catalyst possessed good photocatalytic activity even after three consecutive photocatalytic reaction cycles, illustrating its excellent stability. The photocatalytic degradation of benzene followed the first-order kinetics, and the good catalytic capability of nano-BiOBr catalyst can be attributed to its crystalline, hierarchical nanostructure and nanosheet thickness. PMID- 27234827 TI - Column-integrated aerosol optical properties and direct radiative forcing over the urban-industrial megacity Nanjing in the Yangtze River Delta, China. AB - Aerosol optical properties were measured and analyzed through the ground-based remote sensing Aerosol Robotic Network (AERONET) over an urban-industrial site, Nanjing (32.21 degrees N, 118.72 degrees E, and 62 m above sea level), in the Yangtze River Delta, China, during September 2007-August 2008. The annual averaged values of aerosol optical depth (AOD500) and the Angstrom exponent (AE440-870) were measured to be 0.94 +/- 0.52 and 1.10 +/- 0.21, respectively. The seasonal averaged values of AOD500 (AE440-870) were noticed to be high in summer (autumn) and low in autumn (spring). The characterization of aerosol types showed the dominance of mixed type followed by the biomass burning and urban industrial type of aerosol at Nanjing. Subsequently, the curvature (a 2) obtained from the second-order polynomial fit and the second derivative of AE (alpha') were also analyzed to understand the dominant aerosol type. The single scattering albedo at 440 nm (SSA440) varied from 0.88 to 0.93 with relatively lower (higher) values during the summer (spring), suggesting an increase in black carbon and mineral dust (desert dust) aerosols of absorbing (scattering) nature. The averaged monthly and seasonal evolutions of shortwave (0.3-4.0 MUm) direct aerosol radiative forcing (DARF) values were computed from the Santa Barbara DISORT Atmospheric Radiative Transfer (SBDART) model both at the top of atmosphere (TOA) and bottom of atmosphere (SUR) during the study period. Further, the aerosol forcing efficiency (AFE) and the corresponding atmospheric heating rates (AHR) were also estimated from the forcing within the atmosphere (ATM). The derived DARF values, therefore, produced a warming effect within the atmosphere due to strong absorption of solar radiation. PMID- 27234828 TI - Bacterial host and reporter gene optimization for genetically encoded whole cell biosensors. AB - Whole-cell biosensors based on reporter genes allow detection of toxic metals in water with high selectivity and sensitivity under laboratory conditions; nevertheless, their transfer to a commercial inline water analyzer requires specific adaptation and optimization to field conditions as well as economical considerations. We focused here on both the influence of the bacterial host and the choice of the reporter gene by following the responses of global toxicity biosensors based on constitutive bacterial promoters as well as arsenite biosensors based on the arsenite-inducible Pars promoter. We observed important variations of the bioluminescence emission levels in five different Escherichia coli strains harboring two different lux-based biosensors, suggesting that the best host strain has to be empirically selected for each new biosensor under construction. We also investigated the bioluminescence reporter gene system transferred into Deinococcus deserti, an environmental, desiccation- and radiation-tolerant bacterium that would reduce the manufacturing costs of bacterial biosensors for commercial water analyzers and open the field of biodetection in radioactive environments. We thus successfully obtained a cell survival biosensor and a metal biosensor able to detect a concentration as low as 100 nM of arsenite in D. deserti. We demonstrated that the arsenite biosensor resisted desiccation and remained functional after 7 days stored in air-dried D. deserti cells. We also report here the use of a new near-infrared (NIR) fluorescent reporter candidate, a bacteriophytochrome from the magnetotactic bacterium Magnetospirillum magneticum AMB-1, which showed a NIR fluorescent signal that remained optimal despite increasing sample turbidity, while in similar conditions, a drastic loss of the lux-based biosensors signal was observed. PMID- 27234830 TI - Low temperature destruction of PCDD/Fs over V2O5-CeO2/TiO2 catalyst with ozone. AB - Catalytic destruction of PCDD/Fs (polychlorinated dibenzo-p-dioxins and furans) over V2O5-CeO2/TiO2 catalyst was investigated at a low temperature range of 140 180 degrees C, in the absence and presence of ozone (200 ppm). Nano-TiO2 support was used to prepare the catalyst by step impregnation method. A stable PCDD/Fs generating system was established to support the catalytic destruction tests. In the presence of ozone alone, destruction efficiencies of PCDD/Fs are between 32.2 and 43.1 % with temperature increasing from 140 to 180 degrees C. The activity of V2O5-CeO2/TiO2 catalyst alone on PCDD/Fs destruction is also studied. The increase of temperature from 140 to 180 degrees C enhances the activity of catalyst with destruction efficiencies increasing from 54.7 to 73.4 %. However, ozone addition greatly enhances the catalytic activity of V2O5-CeO2/TiO2 catalyst on PCDD/Fs decomposition. At 180 degrees C, the destruction efficiency of PCDD/Fs achieved with V2O5-CeO2/TiO2 catalyst and ozone is above 86.0 %. It indicates that the combined use of ozone and catalyst reduces the reaction temperature of PCDD/Fs oxidation and offers a new method to destroy PCDD/Fs with high destruction efficiency at a low temperature. Furthermore, the destruction efficiencies of 17 toxic PCDD/F congeners, achieved with ozone alone, catalyst alone, and catalyst/ozone are analyzed. PMID- 27234829 TI - Molecular characterization and phylogeny of Shiga toxin-producing E. coli (STEC) from imported beef meat in Malaysia. AB - This study aimed at determining the presence and characterization of Escherichia coli and Shiga toxin-producing E. coli (STEC) from imported frozen beef meats. Seventy-four (74) frozen imported beef meat samples from two countries, India (42 samples) and Australia (32 samples), were collected and tested for E. coli. These samples were purchased from the frozen meat sections of five different supermarkets in different locations in Selangor, Malaysia, from April 2012 to October 2014. A total of 222 E. coli strains were isolated from the meat samples; 126 strains were isolated from country A (India), and 96 E. coli strains were from country of origin B (Australia), respectively. A total of 70 E. coli strains were identified and characterized. All E. coli strains were isolated into Fluorocult medium and identified using API 20E kit. All selected E. coli strains were characterized for Shiga toxin genes (stx1 and stx2). All biochemically identified E. coli in this study were further subjected to molecular detection through polymerase chain reaction (PCR) amplification and characterization using 16S ribosomal RNA (rRNA) gene of Shiga toxin-producing E. coli. Of the 70 E. coli strains, 11 strains were positive for both Shiga toxin genes (stx1 and stx2) and 11 (11/70) strains were positive for stx1 gene, while 25 (25/70) strains were positive for stx2 gene. The analysis of 16S rRNA gene of all the E. coli isolates in this study was successfully sequenced and analyzed, and based on sequence data obtained, a phylogenetic tree of the 16S rRNA gene was performed using Clustal W programme in MEGA 6.06 software. Phylogenetic tree showed that the E. coli isolates in our study cluster with the strain of E. coli isolated in other countries, which further confirm that the isolates of E. coli in this study are similar to those obtained in other studies. As a result, all the strains obtained in this study proved to be a strain of pathogenic E. coli, which may cause a serious outbreak of food-borne disease. The isolation of pathogenic E. coli strains from the imported meat samples calls for prudent management of imported meats by the relevant authorities. PMID- 27234831 TI - Evaluation of soil amendments as a remediation alternative for cadmium contaminated soils under cacao plantations. AB - Elevated plant-available cadmium (Cd) in soils results in contamination to cacao (Theobroma cacao L) beans. Effectiveness of vermicompost and zeolite in reducing available Cd in three cacao-growing soils was studied under laboratory conditions. Sorption-desorption experiments were conducted in soils and amendments. Cadmium was added at 0 or 5 mg kg(-1) (spiked), then, amendments were incorporated at 0, 0.5, or 2 %. Amended soils were incubated at room temperature for 28 days. Plant-available Cd was determined using 0.01 M CaCl2 (WSE) and Mehlich 3 (M3) extraction procedures in subsamples taken from individual bags at six time intervals. Soils and amendments displayed different sorption characteristics and a better fit was attained with Freundlich model (R (2) > 0.82). Amendments were ineffective in reducing extractable Cd in non-spiked soils. In Cd-spiked soils, vermicompost at 2 % significantly reduced WSE-Cd (P < 0.01) from 3.36, 0.54, and 0.38 mg kg(-1) to values lower that instrument's detection in all the three soils and significantly diminished M3-extractable Cd (P < 0.05) from 4.62 to 4.11 mg kg(-1) in only one soil. Vermicompost at 0.5 % significantly decreased WSE-Cd (P < 0.01) from 3.04 and 0.31 to 1.69 and 0.20 mg kg(-1), respectively, in two soils with low sorption capacity for Cd. In contrast, zeolite failed to reduce WSE- or M3-extractable Cd in all studied soils. A negative correlation occurred between soil pH and WSE-Cd (r > -0.89, P < 0.01). The decrease in WSE-Cd appears to be associated with the increase in pH of the vermicompost-amended soils. PMID- 27234832 TI - Aquatic bioaccumulation and trophic transfer of tetrabromobisphenol-A flame retardant introduced from a typical e-waste recycling site. AB - While the flame retardant chemical, tetrabromobisphenol-A (TBBP-A), has been frequently detected in the environment, knowledge regarding its species-specific bioaccumulation and trophic transfer is limited, especially in the highly contaminated sites. In this study, the components of an aquatic food web, including two invertebrates, two prey fish, and one predator fish, collected from a natural pond at an electronic waste (e-waste) recycling site in South China were analyzed for TBBP-A, using liquid chromatography-tandem mass spectrometry. The aquatic species had TBBP-A concentrations ranging from 350 to 1970 pg/g wet weight, with higher concentrations in the invertebrates relative to the fish species. Field-determined bioaccumulation factors of TBBP-A in the two aquatic invertebrates were nearly or greater than 5000, suggesting that TBBP-A is highly bioaccumulative in the two species. The lipid-normalized concentrations of TBBP-A in the aquatic species were negatively correlated with the trophic levels determined from stable nitrogen isotope (delta(15)N) (r = -0.82, p = 0.09), indicating that this compound experienced trophic dilution in the current food web. PMID- 27234833 TI - Textile wastewater reuse after additional treatment by Fenton's reagent. AB - This study verifies textile wastewater reuse treated by the conventional activated sludge process and subjected to further treatment by advanced oxidation processes. Three alternative processes are discussed: Fenton, photo-Fenton, and UV/H2O2. Evaluation of treatments effects was based on factorial experiment design in which the response variables were the maximum removal of COD and the minimum concentration of residual H2O2 in treated wastewater. Results indicated Fenton's reagent, COD/[H2O2]/[Fe2+] mass ratio of 1:2:2, as the best alternative. The selected technique was applied to real wastewater collected from a conventional treatment plant of a textile mill. The quality of the wastewater before and after the additional treatment was monitored in terms of 16 physicochemical parameters defined as suitable for the characterization of waters subjected to industrial textile use. The degradation of the wastewater was also evaluated by determining the distribution of its molecular weight along with the organic matter fractionation by ultrafiltration, measured in terms of COD. Finally, a sample of the wastewater after additional treatment was tested for reuse at pilot scale in order to evaluate the impact on the quality of dyed fabrics. Results show partial compliance of treated wastewater with the physicochemical quality guidelines for reuse. Removal and conversion of high and medium molecular weight substances into low molecular weight substances was observed, as well as the degradation of most of the organic matter originally present in the wastewater. Reuse tests indicated positive results, confirming the applicability of wastewater reuse after the suggested additional treatment. Graphical abstract Textile wastewater samples after additional treatment by Fenton's reagent, photo-Fenton and H2O2/UV tested in different conditions. PMID- 27234834 TI - Crop residue management and fertilization effects on soil organic matter and associated biological properties. AB - Returning crop residue may result in nutrient reduction in soil in the first few years. A two-year field experiment was conducted to assess whether this negative effect is alleviated by improved crop residue management (CRM). Nine treatments (3 CRM and 3 N fertilizer rates) were used. The CRM treatments were (1) R0: 100 % of the N using mineral fertilizer with no crop residues return; (2) R: crop residue plus mineral fertilizer as for the R0; and (3) Rc: crop residue plus 83 % of the N using mineral and 17 % manure fertilizer. Each CRM received N fertilizer rates at 270, 360, and 450 kg N ha(-1) year(-1). At the end of the experiment, soil NO3-N was reduced by 33 % from the R relative to the R0 treatment, while the Rc treatment resulted in a 21 to 44 % increase in occluded particulate organic C and N, and 80 degrees C extracted dissolved organic N, 19 to 32 % increase in microbial biomass C and protease activity, and higher monounsaturated phospholipid fatty acid (PLFA):saturated PLFA ratio from stimulating growth of indigenous bacteria when compared with the R treatment. Principal component analysis showed that the Biolog and PLFA profiles in the three CRM treatments were different from each other. Overall, these properties were not influenced by the used N fertilizer rates. Our results indicated that application of 17 % of the total N using manure in a field with crop residues return was effective for improving potential plant N availability and labile soil organic matter, primarily due to a shift in the dominant microorganisms. PMID- 27234835 TI - Evaluating the ready biodegradability of two poorly water-soluble substances: comparative approach of bioavailability improvement methods (BIMs). AB - Difficulties encountered in estimating the biodegradation of poorly water-soluble substances are often linked to their limited bioavailability to microorganisms. Many original bioavailability improvement methods (BIMs) have been described, but no global approach was proposed for a standardized comparison of these. The latter would be a valuable tool as part of a wider strategy for evaluating poorly water-soluble substances. The purpose of this study was to define an evaluation strategy following the assessment of different BIMs adapted to poorly water soluble substances with ready biodegradability tests. The study was performed with two poorly water-soluble chemicals-a solid, anthraquinone, and a liquid, isodecyl neopentanoate-and five BIMs were compared to the direct addition method (reference method), i.e., (i) ultrasonic dispersion, (ii) adsorption onto silica gel, (iii) dispersion using an emulsifier, (iv) dispersion with silicone oil, and (v) dispersion with emulsifier and silicone oil. A two-phase evaluation strategy of solid and liquid chemicals was developed involving the selection of the most relevant BIMs for enhancing the biodegradability of tested substances. A description is given of a BIM classification ratio (R BIM), which enables a comparison to be made between the different test chemical sample preparation methods used in the various tests. Thereby, using this comparison, the BIMs giving rise to the greatest biodegradability were ultrasonic dispersion and dispersion with silicone oil or with silicone oil and emulsifier for the tested solid chemical, adsorption onto silica gel, and ultrasonic dispersion for the liquid one. PMID- 27234836 TI - Hazard posed by metals and As in PM2.5 in air of five megacities in the Beijing Tianjin-Hebei region of China during APEC. AB - Airborne fine particulate matter (PM2.5) from five megacities including Beijing, Tianjin, Shijiazhuang, Baoding, and Jinan were collected during November 2014 and compared with similar periods in 2012 and 2013. The November 2014 period coincided with the Asia Pacific Economic Cooperation (APEC) Leaders Meeting during which measures to control pollution of the air were introduced. Concentrations of 11 elements in PM2.5 were quantified by inductively coupled plasma-mass spectrometry (ICP-MS) after microwave-assisted digestion. Potential effects of five toxic trace metals including Mn, Ni, Cu, Zn, Pb, and the metalloid As on health were assessed. In 2014, concentrations of PM2.5 were significantly less than during the same period in 2012 and 2013. Mean concentrations of six elements ranked in decreasing order, Zn > Pb > Cu ~ Mn > As > Ni, and spatial concentrations ranked in decreasing order, Shijiazhuang > Baoding > Tianjin > Jinan > Beijing. Risks of the five metals and the metalloid As to health of humans were small, except for Mn in Shijiazhuang. Risks to health posed by other elements were less during the period of study. Risks posed by the five metals and As in Beijing were greater to varying degrees after the APEC meeting. Risks to health of humans during the APEC were overall lesser than the same period in 2012 and 2013, mostly due to lesser emissions due to the short term control measures. PMID- 27234837 TI - Indoor and outdoor particulate matter in primary school classrooms with fan assisted natural ventilation in Singapore. AB - We conducted multiday continuous monitoring of indoor and outdoor particulate matter (PM) in classrooms with fan-assisted natural ventilation (NV) at five primary schools in Singapore. We monitored size-resolved number concentration of PM with diameter 0.3-10 MUm at all schools and alveolar deposited surface area concentrations of PM with diameter 0.01-1.0 MUm (SA0.01-1.0) at two schools. Results show that, during the monitoring period, schools closer to expressways and in the downtown area had 2-3 times higher outdoor PM0.3-1.0 number concentrations than schools located in suburban areas. Average indoor SA0.01-1.0 was 115-118 MUm(2) cm(-3) during periods of occupancy and 72-87 MUm(2) cm(-3) during unoccupied periods. There were close indoor and outdoor correlations for fine PM during both occupied and unoccupied periods (Pearson's r = 0.84-1.0) while the correlations for coarse PM were weak during the occupied periods (r = 0.13-0.74). Across all the schools, the size-resolved indoor/outdoor PM ratios (I/O ratios) were 0.81 to 1.58 and 0.61 to 0.95 during occupied and unoccupied periods, respectively, and average infiltration factors were 0.64 to 0.94. Average PM net emission rates, calculated during periods of occupancy in the classrooms, were lower than or in the lower range of emission rates reported in the literature. This study also reveals that indoor fine and submicron PM predominantly come from outdoor sources, while indoor sources associated with occupancy may be important for coarse PM even when the classrooms have high air exchange rates. PMID- 27234839 TI - Treatment of hospital laundry wastewater by UV/H2O2 process. AB - Hospitals consume a large volume of water to carry out their activities and, hence, generate a large volume of effluent that is commonly discharged into the local sewage system without any treatment. Among the various sectors of healthcare facilities, the laundry is responsible for the majority of water consumption and generates a highly complex effluent. Although several advanced oxidation processes (AOPs) are currently under investigation on the degradation of a variety of contaminants, few of them are based on real wastewater samples. In this paper, the UV/H2O2 AOP was evaluated on the treatment of a hospital laundry wastewater, after the application of a physicochemical pretreatment composed of coagulation-flocculation and anthracite filtration. For the UV/H2O2 process, a photoreactor equipped with a low-pressure UV-C lamp was used and the effects of initial pH and [H2O2]/chemical oxygen demand (COD) ratio on COD removal were investigated through a randomized factorial block design that considered the batches of effluent as blocks. The results indicated that the initial pH had no significant effect on the COD removal, and the process was favored by the increase in [H2O2]/COD ratio. Color and turbidity were satisfactorily reduced after the application of the physicochemical pretreatment, and COD was completely removed by the UV/H2O2 process under suitable conditions. The results of this study show that the UV/H2O2 AOP is a promising candidate for hospital laundry wastewater treatment and should be explored to enable wastewater reuse in the washing process. PMID- 27234840 TI - Geometrical and functional changes of left heart in adults with prehypertension and hypertension: a cross-sectional study from China. AB - BACKGROUND: Studies regarding the association between prehypertension and the structual changes of left heart are scanty. However, which type of the geometrical change of left heart is predominated one in prehypertension and hypertension is controversial. It is therefore important to investigate geometrical and functional changes of left heart in adults with prehypertension and hypertension because of their prognostic significance. METHODS: The study was based on a cross-sectional design, a total of 10547 participants were classified into normotension group, prehypertension group and hypertension group. We analyzed clinical characteristics, echocardiographic parameters and distribution of left ventricular (LV) geometrical patterns in different groups. RESULTS: Participants with prehypertension had higher values of most of echocardiographic parameters than those with normotension. The prevalence of left ventricular hypertrophy(LVH) was statistically different among three groups (P <0.001), and the rates of LVH in the three groups were 5.9, 8.6, 28.4 % by indexation to height(2.7) and 4.9, 5.3, 19.3 % by indexation to BSA, respectively. The prevalence rates of eccentric hypertrophy, concentric remodeling and concentric hypertrophy were 7.3 %, 5.3 % and 1.4 % in prehypertension group, and 17.8 %, 8.8 % and 10.6 % in hypertension group. Logistic regression analysis showed that systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean artery pressure (MAP) were all independent risk factors for left cardiac structural changes, and pulse pressure (PP) was independent risk factor for concentric and eccentric hypertrophy. Among four indices, DBP levels with OR values of 1.192, 1.759 and 1.278 were the strongest indicator for concentric remodeling, concentric hypertrophy and eccentric hypertrophy, respectively (P <0.001). CONCLUSIONS: There exists LV geometrical change in adults with prehypertension and hypertension in rural Chinese population, and the eccentric hypertrophy was the highest proportion of geometric alterations. SBP, DBP, MAP and PP were all positively associated with left cardiac structural changes, and the association of DBP was the strongest. PMID- 27234838 TI - Molecular perspectives and recent advances in microbial remediation of persistent organic pollutants. AB - Nutrition and pollution stress stimulate genetic adaptation in microorganisms and assist in evolution of diverse metabolic pathways for their survival on several complex organic compounds. Persistent organic pollutants (POPs) are highly lipophilic in nature and cause adverse effects to the environment and human health by biomagnification through the food chain. Diverse microorganisms, harboring numerous plasmids and catabolic genes, acclimatize to these environmentally unfavorable conditions by gene duplication, mutational drift, hypermutation, and recombination. Genetic aspects of some major POP catabolic genes such as biphenyl dioxygenase (bph), DDT 2,3-dioxygenase, and angular dioxygenase assist in degradation of biphenyl, organochlorine pesticides, and dioxins/furans, respectively. Microbial metagenome constitutes the largest genetic reservoir with miscellaneous enzymatic activities implicated in degradation. To tap the metabolic potential of microorganisms, recent techniques like sequence and function-based screening and substrate-induced gene expression are proficient in tracing out novel catabolic genes from the entire metagenome for utilization in enhanced biodegradation. The major endeavor of today's scientific world is to characterize the exact genetic mechanisms of microbes for bioremediation of these toxic compounds by excavating into the uncultured plethora. This review entails the effect of POPs on the environment and involvement of microbial catabolic genes for their removal with the advanced techniques of bioremediation. PMID- 27234841 TI - Evolution of hepatitis C virus in HIV coinfected patients under antiretroviral therapy. AB - Five patients (P) were followed-up for an average of 7.73years after highly active antiretroviral therapy (HAART) initiation. Patients' immune and virological status were determined by periodical CD4+T-cell counts and HIV and HCV viral load. HCV populations were studied using longitudinal high throughput sequence data obtained in parallel by virological and immunological parameters. Two patients (P7, P28) with sub-optimal responses to HAART presented HCV viral loads significantly higher than those recorded for two patients (P1, P18) that achieved good responses to HAART. Interestingly, HCV populations from P7 and P28 displayed a stable phylogenetic structure, whereas HCV populations from P1 and P18showeda significant increase in their phylogenetic structure, followed by a decrease after achieving acceptable CD4+T-cell counts (>500 cell/MUl). The fifth patient (P25) presented high HCV viral loads, preserved CD4+T-cell counts from baseline and all along the follow-up, and displayed a constant viral phylogenetic structure. These results strongly suggest that HAART-induced immune recovery induces a decrease in HCV viral load and an increase in the HCV population phylogenetic structure likely reflecting the virus diversification in response to the afresh immune response. The relatively low HCV viral load observed in the HAART responder patients suggests that once HCV is adapted it reaches a maximum number of haplotypes higher than that achieved during the initial stages of the immune response as inferred from the two recovering patients. Future studies using larger number of patients are needed to corroborate these hypotheses. PMID- 27234842 TI - Combinatorial effects of the configuration of the cationic and the anionic chiral subunits of four zwitterionic chiral stationary phases leading to reversal of elution order of cyclic beta3-amino acid enantiomers as ampholytic model compounds. AB - In a systematic way enantioseparations of non-methylated and the corresponding N monomethylated ampholytic cyclic beta3-amino acids were carried out on four zwitterionic chiral stationary phases (CSPs; ZWIX(+)TM, ZWIX(-)TM, ZWIX(+A), ZWIX(-A)). CSPs were based on the combinations of quinine and quinidine as the cationic and of (R,R)- and (S,S)-aminocyclohexane sulfonic acid as the anionic sites. In polar-ionic mobile phase systems, the effects of the composition of the bulk solvents, the additives, the concentration of the co- and counter-ions, the temperature, and the structures of the ampholytic analytes were investigated. The changes in standard enthalpy, Delta(DeltaH degrees ), entropy, Delta(DeltaS degrees ), and free energy, Delta(DeltaG degrees ), were calculated from the linear van't Hoff plots derived from the ln alpha vs 1/T curves in the studied temperature range (5-40 degrees C). Unusual temperature behavior was observed on the ZWIX(-)TM column: decreased retention times were accompanied by increased separation factors with increasing temperature, and separation was entropically driven. For the other three CSPs, enthalpically-driven enantioseparations were observed. Via the consequent determination of the elution order of the resolved enantiomers, the effects of the absolute configuration of the chiral anionic and cationic subunits of the zwitterionic CSPs could be elucidated. N-methylation of the amino acids led unexpectedly to a reversal of the elution sequence, which can be interpreted by a subtle shift of the hierarchical order of the sterically most important driving interaction sites from the cationic to the anionic units, and vice versa. PMID- 27234843 TI - Separation, isolation and stereochemical assignment of imazalil enantiomers and their quantitation in an in vitro toxicity test. AB - A simple method for the separation of the enantiomers of the fungicide imazalil was developed. Racemic imazalil was separated into its enantiomers with an enantiomeric purity of 99% using HPLC-UV with an enantioselective column (permethylated cyclodextrin) operated in reversed phase mode (water with 0.2% trimethylamine and 0.08% acetic acid and methanol). The absolute configuration of the separated enantiomers was assigned and unequivocally confirmed by optical rotation as well as by vibrational circular dichroism (VCD) and electronic circular dichroism (ECD) combined with ab-initio calculations. The same enantioselective column was also used to develop an HPLC-MS/MS method for the quantification of imazalil enantiomers. The HPLC-MS/MS method reached limits of quantification (LOQs) of 0.025mg/mL with 5MUL injections. This method was used to verify imazalil concentrations and enantiomeric fractions in samples from an in vitro test on effects on human steroidogenesis (H295R steroidogenesis assay). The quantification verified the stability of the enantiomers of imazalil during the in vitro tests. PMID- 27234844 TI - On-line solid phase extraction-ultra high performance liquid chromatography tandem mass spectrometry as a powerful technique for the determination of sulfonamide residues in soils. AB - Sulfonamides are antimicrobials used widely as veterinary drugs, and their residues have been detected in environmental matrices. An analytical method for determining sulfadiazine, sulfathiazole, sulfamethazine, sulfamethoxazole, sulfadimethoxine and sulfaquinoxaline residues in soils employing a solid phase extraction on-line technique coupled with ultra-high performance liquid chromatography and tandem mass spectrometry (SPE-UHPLC-MS/MS) was developed and validated in this study. SPE and chromatographic separation were performed using an Oasis HLB column and an Acquity UPLC BEH C18 analytical column, respectively, at 40 degrees C. Samples were prepared by extracting sulfonamides from soil using a solid-liquid extraction method with water:acetonitrile, 1:1v/v (recovery of 70.2-99.9%). The following parameters were evaluated to optimize the on-line SPE process: sorbent type (Oasis and C8), sample volume (100-400MUL), loading solvent (water and different proportions of water:methanol) and washing volume (0.19 0.66mL). The method produced linear results for all sulfonamides from 0.5 to 12.5ngg(-1) with a linearity greater than 0.99. The precision of the method was less than 15%, and the matrix effect was -27% to -87%. The accuracy was in the range of 77-112% for all sulfonamides. The limit of quantitation in the two soils (clay and sand) was 0.5ngg(-1). The SPE column allowed for the analysis of many (more than 2000) samples without decreasing the efficiency. PMID- 27234845 TI - A single-step pesticide extraction and clean-up multi-residue analytical method by selective pressurized liquid extraction followed by on-line solid phase extraction and ultra-high-performance liquid chromatography-tandem mass spectrometry for complex matrices. AB - Pesticides, a group of compounds linked to human activity, may, when in toxic levels, have a profound effect on water quality, and hence result in adverse consequences to aquatic life and ultimately to human health. Analytical challenges arise when successfully trying to determine these levels in environmental complex matrices. Therefore, fast, simple, sensitive and selective analytical methodologies for multi-residue determination of pesticides (atrazine, azoxystrobin, bentazon, lambda-cyhalothrin, penoxsulam and terbuthylazine) in sediment, macrophytes (algae and aquatic plants) and aquatic animals were developed and validated. The established methods were matrix-dependent and were based on Selective Pressurized Liquid Extraction (SPLE) followed by on-line Solid Phase Extraction and Ultra Performance Liquid Chromatography-tandem Mass Spectrometry (on-line SPE-UPLC-ESI-MS/MS). This cutting-edge research methodology uses a small amount of sample, is time saving and reduces the use of organic solvents in compliance with Green Chemistry principles. The analytical features were adequate for all compounds in all studied matrices. The established methodology was applied on real marine samples and no pesticide concentrations above their respective method quantification limits were measured in sediments or aquatic plants. However, terbuthylazine was found in the macroalgae Ulva spp. (108ngg(-1)dw) and all the prospected pesticides were measured above their respective method quantification limits in the bivalve Scrobicularia plana (atrazine: 48ngg(-1)dw, azoxystrobin: 64ngg(-1)dw, bentazon: 33ngg(-1)dw, lambda cyhalothrin: 2531ngg(-1)dw, penoxsulam: 50ngg(-1)dw, and terbuthylazine: 44ngg( 1)dw). PMID- 27234846 TI - Experimental evidence of the kinetic performance achievable with columns packed with new 1.9MUm fully porous particles of narrow particle size distribution. AB - Fully porous particles of narrow particle size distribution (nPSD) are now commercially available. In this paper, the kinetic performance of columns packed with these particles (1.9MUm, 80A pore size) has been investigated under typical reversed phase conditions by using a mixture of benzene derivatives as probes. The columns exhibited remarkably high efficiency (in the order of 300,000 theoretical plates per meter) and the possibility to be used at relatively high flow rates without loss of performance. These results contrast with previous studies on the same columns. Indeed we have found column efficiency comparable to that reported in previous work but, on the other hand, we could not observe the same dramatic loss of performance when columns were operated at high flow rates. The results presented in this paper, based on a set of six columns with different geometries (2.1 and 3.0 internal diameter*50, 75 and 100mm length), are not consistent with the previously proposed hypothesis that the unusually low intraparticle diffusion, which would characterize these particles, is the origin of the high efficiency of the columns. In a companion paper [1], a detailed investigation of the different terms leading to band broadening will be performed to point out the major contribution to plate height on nPSD columns. PMID- 27234847 TI - Chiral separation of 2-hydroxyglutaric acid on cinchonan carbamate based weak chiral anion exchangers by high-performance liquid chromatography. AB - d- and l-2-Hydroxyglutaric acid (d- and l-2-HG, respectively) are metabolites related to some diseases (2-hydroxyglutaric aciduria, cancer), which make their identification and analysis crucially important for diagnostic purposes. Chiral stationary phases (CSP) based on tert-butylcarbamoyl-quinine and -quinidine (Chiralpak QN-AX and QD-AX), and the corresponding zwitterionic derivatives (Chiralpak ZWIX(+) and Chiralpak ZWIX(-)) were employed in a weak anion-exchange mechanism to perform the enantiomer separation of d- and l-2-HG without derivatization. QD-AX CSP showed the most promising separation and therefore optimization of eluent, additives, and temperature, required for the baseline separation of solutes was carried out. Depending on experimental conditions resolution values ranged up to 2.0 with run times <20min and MS-compatible conditions. Inversion on the elution order of d- and l-2-HG was possible by using the pseudo-enantiomeric QN-AX CSP. PMID- 27234848 TI - Polydopamine-reinforced magnetization of zeolitic imidazolate framework ZIF-7 for magnetic solid-phase extraction of polycyclic aromatic hydrocarbons from the air water environment. AB - Zeolitic imidazolate frameworks (ZIFs) consist of metal nodes connected to imidazolate linkers, having both the properties of metal-organic frameworks (MOFs) and inorganic zeolites, such as controllable pore sizes, high porosity and surface areas, as well as exceptional thermal and chemical stability, thereby making them a class of attractive materials for diverse analytical applications. In this study, we reported a facile magnetization process of ZIF-7 (zinc benzimidazolate) for simultaneous magnetic extraction of polycyclic aromatic hydrocarbons (PAHs) by simply mixing ZIF-7 and polydopamine (PDA)-coated Fe3O4 nanoparticles (PDA@Fe3O4) in solutions. Functional groups (-OH and -NH2), provided by PDA as a highly efficient molecular linker, could attract and anchor ZIF-7 through noncovalent adsorption and covalent cross-link interactions, thereby promoting the complete magnetization of ZIFs and enhancing their stability and reusability. The bridging ligand benzimidazolate, could be bonded with PAHs because of its high surface area, large pores, accessible coordinative unsaturated sites (pi-complexation), and pi-pi stacking action. This ZIF-based magnetic solid-phase extraction (SPE), coupled with gas chromatography/tandem mass spectrometry (GC/MS), was further evaluated for analysis of PAHs from rainwater and air samples of particulate matter less than 2.5MUm in diameter (PM2.5). The main effective parameters, including ionic strength, solution pH, extraction time, desorption solvent and desorption time, were investigated, respectively. Under optimized conditions, the developed method based on Fe3O4@PDA/ZIF-7 gave detection limits of 0.71-5.79ng/L, and quantification limits of 2.50-19.2ng/L for PAHs, respectively. The relative standard deviations for intra-day and inter-day analyses were in the range of 3.1-9.1% and 6.1-12.7%, respectively. The PAHs founded in PM2.5 were in the range of 0.40-6.79ng/m(3). Good recoveries (>82%) with low relative standard deviations (<=9.2%) were achieved. This method was demonstrated to be an accurate, convenient and sensitive pretreatment procedure for trace analysis of environmental water and air samples. PMID- 27234849 TI - Neurology letter from Guyana. PMID- 27234850 TI - Functional foreign accent syndrome. AB - Foreign accent syndrome (FAS) is a rare disorder where the affected person speaks in an accent that the listener perceives as foreign. Although most cases have left hemisphere lesions, some may be functional. We describe a case of functional FAS and present a video of her speech. We identify characteristics that help to distinguish functional from structural cases. These include preceding motor disturbances causing the maladaptive speech response, inconsistencies in accent production, the adoption of unusual mannerisms in speech and the speech disturbances being transient and reversible. We conclude that FAS is a complex disorder encompassing both functional and structural causes. PMID- 27234851 TI - A call for the proper action on drowning resuscitation. PMID- 27234852 TI - Adenoid cystic carcinoma of the head and neck: a single-institution's analysis of 45 consecutive cases over a 29-year period. AB - OBJECTIVE: A series of patients with head and neck adenoid cystic carcinoma (ACC) was studied with respect to treatment modalities, recurrence, survival and prognostic factors. STUDY DESIGN: Between August 1984 and December 2013, 45 patients with ACC of the head and neck who were primary surgically treated at our institution were retrospectively reviewed. RESULTS: Disease-specific survival (DSS) rates at 5, 10, and 15 years were 85%, 79.4%, and 65.7%, respectively. Tumors of the major salivary glands had a better DSS. Patients with ACC of the paranasal sinuses or nasal cavity had poorer survival compared with other head and neck subsites, although this correlation did not reach statistically significant level. DSS rates were 81.5% at 5 years, 70.5% at 10 years, and 31.3% at 15 years for patients with perineural invasion (PNI) compared with 88.9% for those patients who did not have PNI (P = .01). Follow-up ranged from 7 to 337 months (mean 129.4 months). CONCLUSIONS: ACC is a unique malignant salivary gland tumor associated with prolonged survival even in metastatic settings, which emphasizes the necessity for lifetime follow-up as well as more active oncologic treatment. In our study, survival was adversely affected by the primary tumor site and PNI. PMID- 27234853 TI - Mucosal leishmaniasis in Brazilian patients: two case reports with similar clinical presentation and different approaches. AB - Mucosal leishmaniasis is a chronic infection that affects the upper respiratory tract and/or the oral mucosa caused by Leishmania protozoan parasites. We present two cases of oral leishmaniasis and discuss the different diagnostic strategies and treatment. In both cases, the patients were male, 60 and 94 years of age, and presented with lesions on the soft palate. In the first patient, the final diagnosis was made on the basis of histopathologic examination. In the second case, polymerase chain reaction and Montenegro skin test were necessary to confirm the diagnosis. The first patient was treated with meglumine antimoniate (Glucantime), and the lesions healed after 2 months. In the second case, the patient received treatment with liposomal amphotericin B but later died as a result of generalized infection. Mucosal leishmaniasis is a highly disfiguring disease. Early diagnosis is important to prevent a lethal outcome. PMID- 27234854 TI - Evaluation of a surgical treatment of denosumab-related osteonecrosis of the jaws. AB - OBJECTIVE: Denosumab, a monoclonal antibody, is a relatively new antiresorptive agent that has recently shown a serious adverse effect: denosumab-related osteonecrosis of the jaws (DRONJ). The purpose of this study was to retrospectively observe the efficacy of the combined surgical and antimicrobial treatment of DRONJ. STUDY DESIGN: In this case series, all patients with osteonecrosis that occurred after starting treatment with denosumab, were treated with surgery and antimicrobial treatment and followed up. The primary outcome was healing of the jaw. For patient characterization, secondary variables, such as clinical features, denosumab use, dental history (including luxation), and duration of complaints, were studied. RESULTS: Eleven patients met the criteria to be included in this study. Nine patients experienced healing within 4 weeks after surgery. Two patients were not cured and died as a result of their underlying disease. In all patients, a dental focus was found. Six patients had been treated only with denosumab, and five had also been treated with bisphosphonates. CONCLUSIONS: We were able to achieve healing in 9 of the 11 patients with DRONJ. Our treatment protocol showed promising results; however, further research is needed. PMID- 27234855 TI - [Mechanisms of signaling associated with reactive nitrogen and oxygen in apoptosis]. AB - The knowledge of apoptotic mechanisms is essential in many biologic aspects related to both normal and neoplastic cells. Cell death by apoptosis is a very desirable way to eliminate unwanted cells: prevents release of the cellular content, which, in contrast to necrosis, provides no activation of inflammatory reactions. Apoptosis is a multistep process in where an extremely important role is played by caspases. Functions of caspases and their modifications are fundamental to understanding the signaling pathways responsible for regulation of apoptosis. These enzymes belong to a family of cysteine proteases that have the potential to destroy the enzymatic and structural proteins, and in the final stages of apoptosis, to lead to the disintegration of the cell. Apoptosis can be modulated by certain signaling pathway. PMID- 27234856 TI - Value of D-dimer and HDL cholesterol concentrations in predicting the occurrence of acute pulmonary embolism. AB - Pulmonary embolism (PE) usually is a clinical manifestation of venous thromboembolism. The lack of simple and safe laboratory test to confirm or exclude PE is a problem that slows down the diagnosis. AIM: The aim of the study was the assessment the usefulness of D-dimer and HDL cholesterol concentration in predicting the occurrence of acute pulmonary embolism. MATERIALS AND METHODS: The study group comprised 86 patients. High-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels were measured by catalase HDL-C and LDLC assay. The D-dimer level was assessed using immunoenzymatic method with high sensitivity test (VIDAS D-Dimer Exclusion). Pulmonary embolism was diagnosed using contrast-enhanced multidetector computer tomography (16-row GE Light Speed Pro and 64-row Toshiba Aquilion Systems). RESULTS: In all patients with PE, higher D-dimer concentration was found. Odds ratio (OR) calculated for the D-dimer indicates that the concentration of D-dimer >=859,5 ng/ml increases the risk of PE 612 times, compared with those with levels below 859,5 ng/ml. HDL cholesterol level in patients with PE was significantly lower compared with the control group (p < 0,05). Odds ratio (OR) calculated for the HDL cholesterol indicates that the risk of PE in subjects with the concentration of HDL-C <=44 mg/dl is 26,89 times higher, compared with individuals with HDL-C >44 mg/dl. CONCLUSIONS: According the studies, increase D-dimer and decrease HDL levels are an independent risk factors for occurrence of acute pulmonary embolism. PMID- 27234857 TI - [Estimation of plasma 25(OH)D vitamin deficiency in patients with metabolic syndrome]. AB - Cardiovascular diseases have been the main cause of mortality in Poland for many years, including premature death and the incidence is systematically growing. These diseases contribute to an increase in the number of disabled people and the cost of medical care. The problem of the so called metabolic syndrome (MS), which includes metabolic risks of atherosclerosis, has been known by doctors for a long time. Results of studies which have been conducted for some years confirm that vitamin D deficiency is a risk factor of MS disorders, including obesity, arterial hypertension, diabetes. AIM: The aim of the study was to assess plasma 25(OH)D vitamin deficiency in patients with MS. MATERIALS AND METHODS: The study included 268 patients with MS, 136 men and 132 women, aged 30-65 years (mean 59,62+/-9,21 years). The study group was divided according to the age and season. The plasma level of 25(OH)D above 30 ng/ml was considered normal, between 21 ng/ml and 30 ng/ml - suboptimal (hypovitaminosis) and below 20 ng/ml - insufficient (deficiency). RESULTS: Plasma 25(OH)D vitamin deficiency was observed in 80,97% patients with MS, hipovitaminosis - in 17,16%. The recommended 25(OH)D concentration in the plasma was confirmed only in 1,87%. Plasma 25(OH)D vitamin deficiency was detected more often in men than women (93,38% vs. 68,18%, p<0,05);the lowest percentage of patients with 25(OH)D vitamin deficiency was observed during summer months (47,14%). CONCLUSIONS: Plasma 25(OH)D vitamin deficiency was very high in patients with metabolic syndrome, especially in men, people over 55 years and during winter months. PMID- 27234858 TI - [The correlation between testosterone levels and C-reactive protein in acute bacterial epididymo-orchitis]. AB - Acute bacterial epididymo-orchitis is common urological condition that usually originates from ascending infection of lower urinary tract. It is characterized by infection of testis combined with spermatogenesis and steroidogenesis impairment. There is also a component of local and systemic inflammation. AIM: The aim of this study was to assess the effect of systemic inflammation associated with acute epididymo-orchitis on testis steroidogenesis. MATERIALS AND METHODS: 30 patients with acute bacterial epididymoorchitis treated in our ward without any oncologic involvement or other systemic inflammatory conditions were considered for the study. Total serum levels of testosterone and C-reactive protein measured within 12 hours of admission. RESULTS: Low total testosterone levels regarding to random laboratory population norms were noticed in 11 patients. Diminished serum total testosterone levels regarding to medium age levels were identified in 24 patients (80%). 29 patients had serum CRP levels elevated what gives average 22x fold. There is a statistically significant negative correlation between serum total testosterone levels and CRP serum levels were found (R - 0.75; p<0.000002 Spearman's correlation). CONCLUSIONS: There is a strong influence of ongoing systemic inflammation caused by bacterial infection on steroidogenesis in testis in acute epididymo-orchitis patients. PMID- 27234859 TI - [Changes of chosen physiological parameters in young healthy persons after sauna bathing procedures]. AB - The profitable influence of sauna bathing interventions on functional human organism has been known for many years. However, range of argumentation wakes up the influence of sauna bathing procedures on heart action. This questions concerns the frequency of heart action, minute heart volume as well as the parameters of arterial blood pressure. AIM: The aim of the study was to evaluate a changes of some cardiac parameters after sauna bathing. MATERIALS AND METHODS: The study group was changes of physiological parameters pulse, arterial blood pressure as well as the temperature of body at 44 young the healthy persons (22 men and 22 women) in age 20-25 years (the average age 22,3+/-1,2 years) executed. None of studied persons was ill in past on illness of respiratory and circulation system arrangement the single bathing intervention were subjected. The temperature in cabin of sauna on level 3 bench carried out 110 degrees C and moisture achieved 15% maximally. Applied the temperature of water refreshing the body near use the shower 16-18 degrees C carried out. According with methodology of bath in sauna near next entry to cabin of sauna studied it was commanded was to occupy on laid bench the place higher in relation to floor of sauna. Before and after intervention of sauna bathing was at all studied the measurement of arterial blood pressure, frequency of pulse as well as the temperature of body was executed. It the measurements of above mentioned parameters were after end of bath in chamber of sauna directly, and then after chilling body and 20-one-minute rest beginning. RESULTS: The statistical significant characteristic growth of value of arterial blood pressure after single cycle of bathing sauna at all studied persons was showed (cramp and diastolic) as well as the frequency of pulse and the temperature the whole body, which however he did not cross the border of physiological norms (the p<0,05), near what these higher values of all analyzed parameters be comprised in borders of physiological norms for human organism. After chilling of body and 20 minutes did not differ one-minute rest of values all of estimated parameters from exit values significant. CONCLUSIONS: The single intervention in sauna causes the growth of value of arterial blood pressure, the frequency of pulse and the temperature of young body healthy persons, be comprising in borders of physiological norms for human organism near what these higher values of all they be comprised in borders of physiological norms the analyzed parameters for human organism. PMID- 27234860 TI - [The effect of high-frequency current and ultrasonic wave on selected parameters of fat tissue]. AB - Obesity and struggle with its consequences, also aesthetic type resulted in the growing development of methods of body shaping, contouring shapes, increasing skin firmness and skin tightening. The reason is the increasing in recent years, public demand, especially in developed countries. Development of aesthetic dermatology is driven by the search for therapeutic options with minimal invasiveness, enabling the reduction of excess body fat, to obtain a slim figure and reduce the laxity of the skin without the need for surgery. Current high frequency sound wave is an alternative method of treatment for patients with less severe defects. The continuous development of new technologies in the future will improve treatments for increasing the effectiveness and consistency of the results, while maintaining a favorable profile of the associated side effects. AIM: The aim of the study was to evaluate the behavior of the selected parameters of fat tissue in patients undergoing fat reduction BTL Exilis device. MATERIALS AND METHODS: The study included a 50-member group of women who are patients of the Specialist Clinic Al-Med in Kolobrzeg. Test was performed twice blood biochemical parameters before the first day of treatment and ten days after the fourth treatment. RESULTS: The results showed no statistical significance of the blood biochemical parameters in all subjects such as total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and the activity of enzymes AST and ALT. CONCLUSIONS: No changes in biochemical parameters of lipid organism in the group of patients indicate the safety of therapy carried out by means of a device emitting high-frequency power and ultrasound. The treatment was evaluated by respondents as effective. PMID- 27234861 TI - Personality traits and styles of coping with stress in physicians. AB - The stress of being a doctor and being responsible for own decisions is one of the most intense feelings the doctors have to cope with. The stress coping styles are determined by the factors dependent on psychological variables such as personality. AIM: The aim of study was to assess the relation between personality traits and stress coping among physicians. MATERIALS AND METHODS: The study group consisted of 50 physicians (males n=25; 50%) employed in Norbert Barlicki Memorial Medical University Teaching Hospital No 1 in Lodz. The stress coping styles were assessed using Coping Inventory for Stressful Situations, whereas the tool used for personality assessment was NEO Five Factor Inventory of Personality. RESULTS: Task-oriented coping (TOC) was the predominant stress coping style among physicians (mean sten value 6.7+/-2.0; high sten scores - 8-10 in 38%). Among all dimensions of the doctors' personality, extraversion predominated significantly (mean sten value 9.7+/-0.7). Neuroticism correlated positively with emotional oriented coping (EOC) (r=0.43). Extraversion influenced more infrequent adoption of EOC by males (r=-0.43) and older subjects (>=44years) (r=-0.52). Conscientiousness influenced more frequent adoption of TOC by females (r=0.46). Both the doctors' age (r=-0.49 p<0.05)), and duration of employment (r= 0.49 p<0.05)) significantly correlated negatively with AOC. The doctors' gender did not affect their stress coping styles. CONCLUSIONS: Task oriented coping was the dominant stress coping style among physicians. High levels of neuroticism correlated positively, and those of extraversion negatively with the adoption of emotional oriented coping with stress. The tendency to choose the avoidance oriented coping decreases with the physicians' age and duration of employment. PMID- 27234862 TI - [Epidemiological study of prevalence and risk factors for dental erosions among Polish young adults]. AB - Dental erosion for many years has been a pathology of secondary interest to dental public health authorities, but this point of view is changing. In recent years the occurrence and severity of erosive tooth wear seems to have increased. Various studies have shown that the prevalence of erosive tooth wear has particularly increased among younger population. AIM: Across-sectional oral health survey of randomly selected sample of 1886, 18-year old adults was carried out in Poland. Tooth wear was diagnosed according to BEWE index. Information about general health, oral hygiene habits, dietary habits, were gathered in a questionnaire. MATERIALS AND METHODS: Across-sectional oral health survey of randomly selected sample of 1886, 18-year old adults was carried out in Poland. Tooth wear was diagnosed according to BEWE index. Information about general health, oral hygiene habits, dietary habits, were gathered in a questionnaire. RESULTS: Out of 1886 young adults 42% had signs of dental erosion. Early damage to the enamel (BEWE 1) was diagnosed in 28.9% patients. More advanced lesions (BEWE 2) were observed in 12% of patients and the highest score (BEWE 3) was diagnosed in 1.4% of the examined population. About 85,7% of the population answered "I feel healthy", 2,7% had gastroesophageal reflux disease, 8,5% allergy, 2,7% asthma, 2,7% eating disorders. CONCLUSIONS: The present study indicate that the dental erosion is common oral disease in 18-year old population in Poland with prevalence of frequency and intensity in males. Acidic diet, hygienic habits and medical conditions such as asthma, eating disorders and esophageal reflux showed statistical significance, as associated with erosive in examined population. In this young adult sample 13,4% had signs of advanced tooth wear which may increase clinical problems in the future. PMID- 27234863 TI - [The difficulties with the diagnosis of cerebral sinus thrombosis of a young woman - a case report]. AB - Cerebral venous stroke is disfunction of brain cause by thrombosis of cerebral veins or thrombosis of sinus of the dura mater. This disease represents about 0,5 1% of all strokes. Women are ill more often. There are over 100 factors which cause this disease. The most often symptoms are headache, epileptic fit, oedema of optic nerve, loss of visual acuity, speech defects. Magnetic resonance proves the diagnosis. MRI with contrast is recommended. A CASE REPORT: We show the case of a young woman taking the oral contraceptive pill whose only symptom of venous thrombosis for a few days was a strong headache. When the woman was admitted to hospital, she didn't have any other symptoms ( in neurology examine, tomography and blood tests). The severity of headache after lumbar puncture (because of suspected subarachnoid bleeding) suggested presented of post-dural-puncture headache, which delayed the correct diagnosis. It was not until after the symptoms of the focal brain damage appeared on the fifth day that we finally made the correct diagnosis confirmed by some additional tests/examinations. Thus we started causal and symptomatic treatment. The difficulties we had with making the correct diagnosis indicate that the recognition of cerebral thrombosis should be taken into account when treating every young woman taking contraceptive pills and suffering from strong headaches. Headaches can be the only symptom of venous stroke in 90% of cases. PMID- 27234864 TI - [Treatment methods of atypical gunshot wounds to the head--case reports]. AB - Due to a high mortality rate, headshot injuries pose serious diagnostic and clinical problems. In this work, we wanted to describe four atypical headshot injuries. The first patient with a headshot injury using a nail gun mishap; the second one after a headshot injury, as a result of attempted murder (the bullet came to a parasagittal halt in the left parietal area); the third victim, after a suicide attempt (the bullet was removed from clivus area, below the pituitary gland); in the case of the fourth patient, after shooting himself with a self constructed weapon in the chin, the metal body was surgically removed - a bearing pellet from the corpus callosum. Males dominate among victims of headshot injuries. Alcohol is one of the elements that facilitate suicidal behaviour. Anti spasm, antibacterial, anti-tetanus prophylaxes are incredibly important. In some cases, the metallic body does not have to be removed from the brain. Pulmonary embolism can be a cause of death after 7 days from injury. PMID- 27234865 TI - [Autoimmune pancreatitis as an element of autoimmune polyglandular syndrome]. AB - Autoimmune pancreatitis constantly belongs to diseases which often causes significant diagnostic problem and often runs out with surgical intervention as considered to be a pancreatic cancer. Important although usually underestimated problems are polyglandular syndromes, which may consist of autoimmune pancreatitis (AIP) problem as well. This case report is an example of autoimmune polyglandular syndrome (APS), which was connected with the surgical treatment with biliary bypass anastomosis because of the unresectable lesion in the head of pancreas. The definite remission of the pancreatic lesion finally came after a steroid therapy. Differentiation between neoplastic and inflammatory pancreatic tumors very often remains a serious clinical problem. On grounds of imaging and cytopathology exams it is often difficult to decide about the nature of a lesion. The negative result of cytopathological biopsy examination does not finally settle straightforward diagnosis. Diagnostic problems affect also autoimmune pancreatitis. It is worth to undertake attempts to differentiate pancreatic lesions especially in cases of concomitance with other autoimmune polyglandular syndromes. That is because it is connected with completely different treatment and outcome. We should remember about diagnostic criteria of autoimmune pancreatitis. Appropriate diagnosis for patients with AIP gives them a chance to avoid serious surgical resection and possible complications. PMID- 27234866 TI - [New orally anticoagulants and brain stroke]. AB - Brain stroke is a grave society problem. About 20% ischemic strokes are cardiac related problems. Atrial fibrillation (AF) is the most common cause of ischemic strokes. Decision to deploy anticoagulant treatment with AF patient depends on bleeding and thrombo-embolic risk which summerise scale CHA(2)DS(2)VASc and HAS BLED. Past recent years in AF treatment anticoagulants from the group of vitamin K antagonist were used. At present in brain stroke prevention and systemic emboilment, new oral anticoagulants (NOA) which weren't worst than vitamin K antagonists, and they are recomendet in most cases of AF unrelated with heart valve defets. Useing NOA causes lower risk of bleeding, including intracranial heamorrhage. It is believed that this is related to the selective inhibition of specific coagulation factors, and respect other hemostatic mechanisms. Results from clinical studies NOA are encouraging, but still lacks clear answers regarding, among other things: long-term safety of treatment and economically viable in everyday clinical practice. In addition, to date there is no specific antidote for this group of drugs. PMID- 27234867 TI - [White adipose tissue dysfunction observed in obesity]. AB - Obesity is a disease with continuingly increasing prevalence. It occurs worldwide independently of age group, material status or country of origin. At these times the most common reasons for obesity are bad eating habits and dramatic reduction of physical activity, which cause the energy imbalance of organism. Fundamental alteration observed in obese subjects is white adipose tissue overgrowth, which is linked to increased incidence of obesity-related comorbidities, such as: cardiovascular diseases, type 2 diabetes or digestive tract diseases. What is more, obesity is also a risk factor for some cancers. Special risk for diseases linked to excessive weight is associated with overgrowth of visceral type of adipose tissue. Adipose tissue, which is the main energy storehouse in body and acts also as an endocrine organ, undergoes both the morphological and the functional changes in obesity, having a negative impact on whole body function. In this article we summarize the most important alterations in morphology and function of white adipose tissue, observed in obese subjects. PMID- 27234868 TI - Long-term follow-up of implantable cardioverter-defibrillators in adult congenital heart disease patients: indications and outcomes. AB - Aims: Ventricular arrhythmias are a major cause of mortality in adult congenital heart disease (ACHD) patients. The European Society of Cardiology guidelines state that implantable cardioverter-defibrillators (ICD) should be considered in patients with congenital heart disease following spontaneous sustained ventricular tachycardia (VT) or cardiac arrest and in patients at presumed high risk. This study sought to analyse the circumstances in which ACHD patients received ICD and to assess outcomes of ICD implantation, including therapies delivered and the rate of complications. Methods and results: A retrospective review was performed of all adult patients with congenital heart disease undergoing ICD implant between 2000 and 2014, in a large quaternary referral centre with over 4000 adults with congenital heart disease under active follow up. Demographics: 42 patients with congenital heart disease had ICD implants: 55% male; age range 21-71 years and mean age 45 years. Mean age at implantation of ICD was 41 years. Mean follow-up was 5 years. Diagnosis: 50% of patients had repaired tetralogy of Fallot (TOF). Twelve per cent of patients had repaired transposition of the great arteries. Reason for ICD: 15 patients (35.7%) received ICD after sustained VT. Eleven patients (26.2%) received ICD after cardiac arrest. Sixteen (38%) had ICD implanted as primary prophylaxis. Outcome: Since implantation, six patients received an appropriate full-output shock for VT from ICD. Nineteen (45%) patients suffered significant complications (inappropriate shocks 11, inappropriate anti-tachycardia pacing resulting in VF 1, infection requiring extraction 3, lead abnormalities 3, and pneumothorax 1). Equal proportions of primary and secondary prevention patients received appropriate shocks. Conclusions: Most patients had ICD for secondary prevention (62%), and the majority had repaired TOF. There was a 2.9% annual appropriate shock rate. However, there was a high incidence of complications with more than a third suffering a major complication (9% per annum). The risks and benefits of ICD implantation are patient and disease specific, and must be clearly discussed prior to implantation. Further research is warranted into the use of primary prevention ICD in ACHD and in alternatives to ICD such as ablation in specific patient groups. PMID- 27234869 TI - Current and future developments in the field of central sleep apnoea. AB - Central sleep apnoea (CSA) occurs in ~30-50% of patients with heart failure (HF) with reduced left ventricular ejection fraction (LVEF) and in as much as in 18 30% of patients with preserved LVEF. In HF patients, it is characterized by periodic breathing also known as the Cheyne-Stokes respiration followed by pauses of breathing. Central sleep apnoea remains often unrecognized due to its chronic and insidious incidences. Patients may report excessive daytime somnolence, poor sleep quality, nocturnal angina, recurrent arrhythmias, refractory HF symptoms, or demonstrate abnormal respiratory pattern or apnoeas. The pathogenesis of CSA remains incompletely understood, but changes in CO2 above and below the apnoea threshold play a major role in its pathogenesis. The presence of CSA in patients with HF is associated with some neurohumoral and haemodynamic responses that are detrimental to the failing heart including increased morbidity and mortality. The development of successful therapies targeting CSA and its harmful downstream effects is therefore important. Several different therapies from medications to implantable devices have been tested with varying effects and primarily in small non-randomized and/or single-centre studies. Large studies to date have been disappointing, but therapeutic options targeting the physiology of the disease may herald a new era in understanding and treating CSA. PMID- 27234870 TI - Extra-cardiac stimulators: what do cardiologists need to know? AB - For several decades, treating patients with pacemakers has been the privilege of cardiologists. However, in the last 30 years, researchers have found new targets for electrical stimulation in different clinical subspecialities, such as deep brain stimulation (for the treatment of Parkinson's disease, essential tremor, dystonia, and some psychiatric illnesses); spinal cord stimulation (for refractory angina, chronic pain, and peripheral artery disease); and sacral (for diverse urologic and proctologic conditions), vagal (for epilepsy), and phrenic nerve stimulation (for sleep apnoea). The purpose of this article is to familiarize cardiologists with these 'extra-cardiac pacemakers' and to discuss potential issues that must be addressed when these patients undergo cardiac procedures. PMID- 27234871 TI - Unstable intertrochanteric versus displaced femoral neck fractures treated with cementless bipolar hemiarthroplasty in elderly patients; a comparison of 80 matched patients. AB - BACKGROUND: While hemiarthroplasty (HA) is considered the treatment of choice for displaced femoral neck (FN) fractures in elderly patients, HA has been partly performed as an alternative treatment option for unstable intertrochanteric (IT) fractures. However, there is a paucity of data regarding the risk and availability of HA for unstable IT fractures compared to HA for displaced FN fractures in elderly patients. Therefore, we performed this case-control study to determine whether HA for unstable IT fractures provides clinical results and survival comparable to HA for displaced FN fractures in elderly patients. HYPOTHESIS: HA for unstable IT fractures in elderly patients provides clinical results and 1-year survival comparable to HA for displaced FN fractures in the same aging group. MATERIALS AND METHODS: We identified 80 patients aged 75years or older, who underwent cementless bipolar HA for unstable IT fracture (AO/OTA type 31-A2.2/3 and A3.3). Their clinical results and 1-year survival were compared to the matched control group of 80 patients with displaced FN fractures (Garden type 3 and 4) treated with the same procedure. Perioperative results, postoperative complications, and 1-year survival were investigated between the two groups. Functional outcome was assessed by walking status and Harris hip score (HHS) 6months after surgery. RESULTS: Operating time was significantly longer in the IT group than the FN group (97.3min [50 to 255] vs. 79.3min [40 to 175], P=0.016). However, the two groups did not significantly differ regarding perioperative results, such as total blood loss, transfusion, intraoperative fracture, length of hospital stay, and postoperative complication. No statistically significant differences in walking status and HHS were observed between the groups. No significant difference in cumulative survival was observed between the two groups (P=0.836), with a 1-year survival rate of 80% (95% confidence interval [CI], 71.8 to 87.5) in the IT group and 82% (95% CI, 73.1 to 89.4) in the FN group. CONCLUSION: HA for unstable IT fractures in elderly patients showed clinical results and 1-year survival comparable to HA as the treatment of choice for displaced FN fractures in the same aging group. LEVEL OF EVIDENCE: Level III, case-control study. PMID- 27234872 TI - Bracing can partially limit tibial rotation during stressful activities after anterior crucial ligament reconstruction with a hamstring graft. AB - BACKGROUND: Hamstring graft has substantial differences with BPTB graft regarding initial mechanical strength, healing sequence, and vascularization, which may imply that a different approach during rehabilitation period is required. The purpose of this study was to investigate the influence of knee bracing on tibial rotation in ACL-reconstructed patients with a hamstring autograft during high loading activities. The hypothesis was that there would be a decrease in tibial rotation in the ACL-reconstructed braced knee as compared to the unbraced knee. METHODS: Twenty male patients having undergone unilateral ACL reconstruction with a semitendinosus/gracilis autograft were assessed. Kinematic data were collected with an eight-camera optoelectronic system during two stressful tasks: (1) descending from a stair and subsequent pivoting; and (2) landing from a platform and subsequent pivoting. In each patient, three different experimental conditions were evaluated: (A) wearing a prophylactic brace (braced condition); (B) wearing a patellofemoral brace (sleeved condition); (C) without brace (unbraced condition). The intact knee without brace served as a control. RESULTS: Tibial rotation was significantly lower in the intact knee compared to all three conditions of the ACL-reconstructed knee (P<=0.01 for both tasks). Presence of a brace or sleeve resulted in lower tibial rotation than in the unbraced condition (p=0.003 for descending/pivot and P=0.0004 for landing/pivot). The braced condition resulted in lower rotation than the sleeved condition for descending/pivoting (P=0.031) while no differences were found for landing/pivoting (P=0.230). CONCLUSION: Knee bracing limited the excessive tibial rotation during pivoting under high loading activities in ACL-reconstructed knees with a hamstring graft. This partial restoration of normal kinematics may have a potential beneficial effect in patients recovering from ACL reconstruction with a hamstring autograft. LEVEL OF EVIDENCE: Level III, case-control therapeutic study. PMID- 27234873 TI - Elucidation of the hepatoprotective moiety of 5beta-scymnol that suppresses paracetamol toxicity in mice. AB - The shark bile alcohol, 5beta-scymnol, protects mice from the hepatotoxic effects of paracetamol (APAP) overdose. To elucidate the hepatoprotective structural moiety of scymnol, we compared its effect with that of its analogue and natural bile salt, sodium scymnol sulfate, in a clinically relevant model of APAP-induced toxicity. Exposure of healthy male Swiss mice to a toxic overdose of APAP (350 mg/kg, ip) significantly increased serum hepatocellular enzyme activities, decreased hepatocellular glutathione (GSH) levels, and induced severe centrilobular hepatocellular necrosis. Repeated low-dose scymnol (5 mg/kg/day for 7 days, ip) significantly reduced the extent of APAP-induced hepatotoxicity without preventing GSH depletion. Sodium scymnol sulfate, which lacks the tri hydroxyl-substituted aliphatic side chain of scymnol, failed to reduce the APAP hepatotoxicity or prevent GSH depletion when tested under the same experimental conditions. We conclude that the tri-hydroxyl-substituted aliphatic side chain is the hepatoprotective structural moiety of 5beta-scymnol that suppresses APAP induced cytotoxicity in mice. PMID- 27234874 TI - Safety and effectiveness data for emergency contraceptive pills among women with obesity: a systematic review. AB - OBJECTIVE: This study aims to determine whether emergency contraceptive pills (ECPs) are less safe and effective for women with obesity compared with those without obesity. STUDY DESIGN: We searched PubMed for articles through November 2015 regarding the safety and effectiveness of ECPs [ulipristal acetate (UPA), levonorgestrel (LNG) and combined estrogen and progestin] among obese users. We assessed study quality using the United States Preventive Services Task Force evidence grading system. RESULTS: We identified four pooled secondary analyses (quality: poor to fair), two of which examined UPA and three examined LNG formulations. Three analyses pooled overlapping data from a total of three primary studies and demonstrated significant associations between obesity and risk of pregnancy after ECP use. One analysis reported a 4-fold increased risk of pregnancy among women with obesity (BMI>=30kg/m2) compared with women within normal/underweight categories (BMI<25kg/m2) after use of LNG ECPs [odds ratio (OR) 4.4; 95% confidence interval (CI) 2.0-9.4]. Further analysis of the same LNG data found that, at an approximate weight of 80 kg, the rate of pregnancy rose above 6%, which is the estimated pregnancy probability without contraception; at weights less than 75 kg, the rate of pregnancy was less than 2%. Two analyses examining UPA suggested an approximate 2-fold increased risk of pregnancy among women with obesity compared with either normal/underweight women or nonobese (BMI<30kg/m2) women (OR 2.6; 95% CI 0.9-7.0 and OR 2.1; 95% CI 1.0-4.3, respectively), but CIs were wide. Finally, the fourth secondary analysis pooled data from three separate randomized controlled trials on LNG ECPs and found no increase in pregnancy risk with increasing weight or BMI and found no consistent association between pregnancy and both factors when adjusted for other covariates. CONCLUSION: While data are limited and poor to fair quality, findings suggest that women with obesity experience an increased risk of pregnancy after use of LNG ECP compared with those normal/underweight. Women with obesity may also experience an increased risk of pregnancy compared with women without obesity after use of UPA ECP, though differences did not reach statistical significance. Providers should counsel all women at risk for unintended pregnancy, including those with obesity, about the effectiveness of the full range of emergency contraception options in order for them to understand their options, to receive advanced supplies of emergency contraception as needed and to understand how to access an emergency copper intrauterine device if desired. PMID- 27234875 TI - Reply to: "mifepristone by prescription: not quite a reality in Australia". PMID- 27234877 TI - Corrigendum to "Poultry and human infections" [Clin Microbiol Infect 22 (2016) 101-102]. PMID- 27234876 TI - T-shaped macular buckling combined with 25G pars plana vitrectomy for macular hole, macular schisis, and macular detachment in highly myopic eyes. AB - OBJECTIVE: To report our experience using the T-shaped macular buckle (MB) with or without pars plana vitrectomy (PPV) as primary surgery or with a previous failed surgical approach in patients affected by high myopia and macular hole (MH) with or without macular detachment and with or without macular schisis. The primary goal was to evaluate complete closure of the MH and reattachment of the retina. DESIGN: Retrospective case series of 21 consecutive patients who underwent T-shaped MB implant alone or combined with PPV at the Academic Medical Center in Amsterdam, The Netherlands, between January 2013 and November 2014. The mean axial length was 31.22 mm. The mean follow-up period was 7 months. RESULTS: Retinal reattachment was achieved in 100% of cases while MH closure was achieved in 90.5%. No major perioperative complications were observed. Best corrected visual acuity improved in 71.4% of patients. CONCLUSIONS: MB combined with PPV should be considered as the preferred surgical approach both in primary and recurrent retinal detachment secondary to MH in high myopic eyes. PMID- 27234878 TI - Expression of nattokinase in Escherichia coli and renaturation of its inclusion body. AB - Nattokinase is an important fibrinolytic enzyme with therapeutic applications for cardiovascular diseases. The full-length and mature nattokinase genes were cloned from Bacillus subtilis var. natto and expressed in pQE30 vector in Escherichia coli. The full-length gene expressed low nattokinase activity in the intracellular soluble and the medium fractions. The mature gene expressed low soluble nattokinase activity and large amount insoluble protein in inclusion bodies without enzyme activity. Large amount of refolding solutions (RSs) at different pH values were screening and RS-10 and RS-11 at pH 9 were selected to refold nattokinase inclusion bodies. The recombinant cells were lysed with 0.1mg/mL lysozyme and ultrasonic treatment. After centrifugation, the pellete was washed twice with 20mM Tris-HCl buffer (pH 7.5) containing 1% Triton X-100 to purify the inclusion bodies. The inclusion bodies were dissolved in water at pH 12.0 and refolded with RS-10. The refolded proteins showed 42.8IU/mg and 79.3IU/mg fibrinolytic activity by the traditional dilution method (20-fold dilution into RS-10) and the directly mixing the protein solution with equal volume RS-10, respectively, compared to the 52.0IU/mg of total water-soluble proteins from B. subtilis var. natto. This work demonstrated that the inclusion body of recombinant nattokinase expressed in E. coli could be simply refolded to the natural enzyme activity level by directly mixing the protein solution with equal volume refolding solution. PMID- 27234879 TI - Directed evolution of adenylosuccinate synthetase from Bacillus subtilis and its application in metabolic engineering. AB - Adenylosuccinate synthetase (EC. 6.3.4.4) encoded by purA in Bacillus subtilis, catalyzing the first step of the conversion of IMP to AMP, plays an important role in flux distribution in the purine biosynthetic pathway. In this study, we described the use of site saturation mutagenesis to obtain a desired enzyme activity of adenylosuccinate synthetase and its application in flux regulation. Based on sequence alignment and structural modeling, a library of enzyme variants was created by a semi-rational evolution strategy in position Thr238 and Pro242. Other than purA deletion, the leaky mutation purA(P242N) partially reduced the flux towards AMP derived from IMP and increased the riboflavin synthesis precursor GTP, while also kept the requirement of ATP synthesis for cell growth. PurA(P242N) was introduced into an inosine-producing strain and resulted in an approximately 4.66-fold increase in inosine production, from 0.088+/-0.009g/L to 0.41+/-0.051g/L, in minimal medium without hypoxanthine accumulation. These results underline that the directed evolution of adenylosuccinate synthetase could tailor its activities and adjust metabolic flux. This mutation may provide a promising application in purine-based product accumulation, like inosine, guanosine and folate which are directly stemming from purine pathway in B. subtilis. PMID- 27234880 TI - Aptamer-nanobody based ELASA for specific detection of Acinetobacter baumannii isolates. AB - Acinetobacter baumannii has turned into an important threat in nosocomial outbreak infections and multidrug resistance leading to high mortality rates in the 21st century. In recent years its mortality has increased by 15% which in part could be due to lack of a rapid and sensitive diagnostic test. In this work we introduced a new detection test for A. baumannii with two highly specific aptamer and nanobody molecules. High binding affinity DNA oligonucleotide aptamers toward A. baumannii were selected through 12 rounds of whole cell System Evolution of Ligands by EXponential enrichment process (SELEX). The SELEX procedures was monitored by flow cytometry. The dissociation constant and binding efficiency of the selected aptamer Aci49 was 7.547+/-1:353pM and 47.50%, respectively. A sandwich enzyme linked aptamer sorbent assay (ELASA) was designed with the biotinylated Aci49 aptamer and our previously developed nanobody against biofilm associated protein (Bap). The assay system was optimized with A. baumannii (ATCC 19606) and 47 clinical isolates of A. baumannii were tested. The threshold of detection in sandwich ELASA process was10(3) CFU/ml. The sensitivity of test toward the clinical isolates was 95.47%. Our results reveal that the sandwich ELASA is sensitive and specific enough for the rapid detection of A. baumannii from clinical isolates. PMID- 27234881 TI - Citric acid production from partly deproteinized whey under non-sterile culture conditions using immobilized cells of lactose-positive and cold-adapted Yarrowia lipolytica B9. AB - The present study was performed to produce citric acid (CA) from partly deproteinized cheese whey (DPCW) under non-sterile culture conditions using immobilized cells of the cold-adapted and lactose-positive yeast Yarrowia lipolytica B9. DPCW was prepared using the temperature treatment of 90 degrees C for 15min. Sodium alginate was used as entrapping agent for cell immobilization. Optimum conditions for the maximum CA production (33.3g/L) in non-sterile DPCW medium were the temperature of 20 degrees C, pH 5.5, additional lactose concentration of 20g/L, sodium alginate concentration of 2%, number of 150 beads/100mL and incubation time of 120h. Similarly, maximum citric acid/isocitric acid (CA/ICA) ratio (6.79) could be reached under these optimal conditions. Additional nitrogen and phosphorus sources decreased CA concentration and CA/ICA ratio. Immobilized cells were reused in three continuous reaction cycles without any loss in the maximum CA concentration. The unique combination of low pH and temperature values as well as cell immobilization procedure could prevent undesired microbial contaminants during CA production. This is the first work on CA production by cold-adapted microorganisms under non-sterile culture conditions. Besides, CA production using a lactose-positive strain of the yeast Y. lipolytica was investigated for the first time in the present study. PMID- 27234882 TI - Mating type and ploidy effect on the beta-glucosidase activity and ethanol producing performance of Saccharomyces cerevisiae with multiple delta-integrated bgl1 gene. AB - In order to investigate the effect of mating type and ploidy on enzymatic activity and fermentation performance in yeast with multiple delta-integrated foreign genes, eight ploidy series strains were constructed. The initial haploid strain BGL-a was shown to contain about 19 copies of the bgl1 gene. In rich media containing 2% (w/v) sugar the specific activities of BGL-aalpha were lower than those of BGL-aa or BGL-alphaalpha, which indicates the existence of mating type effects. While the maximum OD660 decreased with rising ploidy, the biomass yield showed no significant difference between the eight strains and the specific activities (expressed as U/mL or U/mg DCW) showed little to no variation. When cellobiose was used as the carbon source and beta-glucosidase substrate, beta glucosidase was expressed more quickly and at higher levels than in glucose containing media. The maximum specific activitiy values obtained were 19.07U/mL and 19.39U/mL for BGL-alphaalpha and BGL-aa, repsectively. The anaerobic biomass and ethanol-producing performance in rich media containing 10% cellobiose showed no significant difference among the eight strains. Their maximal ethanol concentrations and corresponding yields ranged from 40.27 to 43.46g/L and 77.56 to 83.71%, respectively. When the acid- and alkali-pretreated corncob (10% solids content) was used, the diploid BGL-aalpha fermented the best. When urea was used as the only supplemented nutrient, the ethanol titer and yield were 35.65g/L and 83.69%, respectively, while a control experiment using industrial Angel yeast with exogenous beta-glucosidase addition gave values of 37.93g/L and 89.04%. The combined effects of delta-integration of bgl1, ploidy and mating type result in BGL-aa or BGL-alphaalpha being the optimal choice for enzyme production and BGL aalpha being more suitable for cellulosic ethanol fermentation. These results provide valuable information for future yeast breeding and utilization efforts. PMID- 27234883 TI - Laparoscopic Management of Uterine Rupture After Early Second-Trimester Medical Abortion in a Patient With a Prior Cesarean Section. AB - STUDY OBJECTIVE: To show the possibility of laparoscopic management of uterine rupture. DESIGN: Video with explanations. SETTING: In the medical management with misoprostol for termination of pregnancy at any time the risk of uterine rupture may be possible. The risk is likely higher in women with a previous uterus surgery. In a systematic review of available studies, the risk of rupture was .28% among women with a prior cesarean delivery who were undergoing second trimester misoprostol-induced abortion, meaning if 414 women with a history of cesarean delivery were given misoprostol for second-trimester abortion, 1 would experience uterine rupture. Uterine rupture has only been reported 3 times in first-trimester abortion and only once managed via laparoscopy: a missed abortion reported in 2005, a case of a ruptured unscarred uterus in a women undergoing medical abortion, and a case of a delayed miscarriage at 8 weeks' gestation after misoprostol managed by laparotomy and sharp curettage. INTERVENTIONS: Total laparoscopic management in a patient with uterine tear after misoprostol treatment. CONCLUSION: Early second-trimester medical abortions with misoprostol can cause uterine rupture. In hemodynamically stable cases, total laparoscopic management is possible approach. PMID- 27234884 TI - Blood Pressure Responses to Endovascular Stimulation: A Potential Therapy for Autonomic Disorders With Vasodilatation. AB - BACKGROUND: We have previously shown that sympathetic ganglia stimulation via the renal vein rapidly increases blood pressure. This study further investigated the optimal target sites and effective energy levels for stimulation of the renal vasculatures and nearby sympathetic ganglia for rapid increase in blood pressure. METHODS: The pre-study protocol for endovascular stimulations included 2 minutes of stimulation (1-150 V and 10 pulses per second) and at least 2 minutes of rest during poststimulation. If blood pressure and/or heart rate were changed during the stimulation, time to return to baseline was allowed prior to the next stimulation. RESULTS: In 11 acute canine studies, we performed 85 renal artery, 30 renal vein, and 8 hepatic vasculature stimulations. The mean arterial pressure (MAP) rapidly increased during stimulation of renal artery (95 +/- 18 mmHg vs. 103 +/- 15 mmHg; P < 0.0001), renal vein (90 +/- 16 mmHg vs. 102 +/- 20 mmHg; P = 0.001), and hepatic vasculatures (74 +/- 8 mmHg vs. 82 +/- 11 mmHg; P = 0.04). Predictors of a significant increase in MAP were energy >10 V focused on the left renal artery, bilateral renal arteries, and bilateral renal veins (especially the mid segment). Overall, heart rate was unchanged, but muscle fasciculation was observed in 22.0% with an output >10 V (range 15-150 V). Analysis after excluding the stimulations that resulted in fasciculation yielded similar results to the main findings. CONCLUSIONS: Stimulation of intra-abdominal vasculatures promptly increased the MAP and thus may be a potential treatment option for hypotension in autonomic disorders. Predictors of optimal stimulation include energy delivery and the site of stimulation (for the renal vasculatures), which informs the design of subsequent research. PMID- 27234885 TI - Evaluation of N-substituent structural variations in opioid receptor profile of LP1. AB - The benzomorphan scaffold has great potential as lead structure and the nature of the N-substituent is able to influence affinity, potency, and efficacy at all three opioid receptors. Building upon these considerations, we synthesized a new series of LP1 analogues by introducing naphthyl or heteroaromatic rings in propanamide side chain of its N-substituent (9-15). In vitro competition-binding assays in HEK293 cells stably expressing MOR, DOR or KOR showed that in compound 9 the 1-naphthyl ring led to the retention of MOR affinity (Ki(MOR)=38+/-4nM) displaying good selectivity versus DOR and KOR. In the electrically stimulated GPI, compound 9 was inactive as agonist but produced an antagonist potency value (pA2) of 8.6 in presence of MOR agonist DAMGO. Moreover, subcutaneously administered it antagonized the antinociceptive effects of morphine with an AD50=2.0mg/kg in mouse-tail flick test. Modeling studies on MOR revealed that compound 9 fit very well in the binding pocket but in a different way in respect to the agonist LP1. Probably the replacement of its N-substituent on the III, IV and V TM domains reflects an antagonist behavior. Therefore, compound 9 could represent a potential lead to further develop antagonists as valid therapeutic agents and useful pharmacological tools to study opioid receptor function. PMID- 27234887 TI - Discovery of new [1,4]dioxino[2,3-f]quinazoline-based inhibitors of EGFR including the T790M/L858R mutant. AB - A novel series of 2,3-dihydro-[1,4]dioxino[2,3-f]quinazoline derivatives were designed, synthesized and evaluated as reversible and noncovalent epidermal growth factor receptor (EGFR) inhibitors. Most of the compounds exhibited good potency against EGFR(wt) and some showed moderate to excellent potency against EGFR(T790M/L858R) mutant. The half-maximal inhibitory concentration (IC50) values of twenty-one compounds against EGFR(wt) were less than 50nM, and those of six compounds were less than 10nM. The IC50 values of eleven compounds against EGFR(T790M/L858R) were less than 100nM. Among these, compound b1 displayed the most potent inhibitory activity against EGFR(wt) (IC50=2.0nM) and EGFR(T790M/L858R) (IC50=6.9nM). Compounds with excellent inhibitory activities against EGFR(wt) and EGFR(T790M/L858R) kinase inhibitory activities showed good antiproliferative activities against H358 and A549 cells. Docking study was performed to position compound b1 into the EGFR active pocket to determine the probable binding conformation. PMID- 27234888 TI - Dihydrochelerythrine and its derivatives: Synthesis and their application as potential G-quadruplex DNA stabilizing agents. AB - A convenient route was envisaged toward the synthesis of dihydrochelerythrine (DHCHL), 4 by intramolecular Suzuki coupling of 2-bromo-N-(2-bromobenzyl) naphthalen-1-amine derivative 5 via in situ generated arylborane. This compound was converted to (+/-)-6-acetonyldihydrochelerythrine (ADC), 3 which was then resolved by chiral prep-HPLC. Efficiency of DHCHL for the stabilization of promoter quadruplex DNA structures and a comparison study with the parent natural alkaloid chelerythrine (CHL), 1 was performed. A thorough investigation was carried out to assess the quadruplex binding affinity by using various biophysical and biochemical studies and the binding mode was explained by using molecular modeling and dynamics studies. Results clearly indicate that DHCHL is a strong G-quadruplex stabilizer with affinity similar to that of the parent alkaloid CHL. Compounds ADC and DHCHL were also screened against different human cancer cell lines. Among the cancer cells, (+/-)-ADC and its enantiomers showed varied (15-48%) inhibition against human colorectal cell line HCT116 and breast cancer cell line MDA-MB-231 albeit low enantio-specificity in the inhibitory effect; whereas DHCHL showed 30% inhibition against A431 cell line only, suggesting the compounds are indeed cancer tissue specific. PMID- 27234886 TI - Biological characterization of the hygrobafilomycin antibiotic JBIR-100 and bioinformatic insights into the hygrolide family of natural products. AB - The hygrolides, a family of 16-member-ring-containing plecomacrolides produced by Actinobacteria, exhibit numerous reported bioactivities. Using HR-MS/MS, nucleophilic 1,4-addition-based labeling, NMR, and bioinformatic analysis, we identified Streptomyces varsoviensis as a novel producer of JBIR-100, a fumarate containing hygrolide, and elucidated the previously unknown stereochemistry of the natural product. We investigated the antimicrobial activity of JBIR-100, with preliminary insight into mode of action indicating that it perturbs the membrane of Bacillus subtilis. S. varsoviensis is known to produce compounds from multiple hygrolide sub-families, namely hygrobafilomycins (JBIR-100 and hygrobafilomycin) and bafilomycins (bafilomycin C1 and D). In light of this, we identified the biosynthetic gene cluster for JBIR-100, which, to our knowledge, represents the first reported for a hygrobafilomycin. Finally, we performed a bioinformatic analysis of the hygrolide family, describing clusters from known and predicted producers. Our results indicate that potential remains for the Actinobacteria to yield novel hygrolide congeners, perhaps with differing biological activities. PMID- 27234889 TI - Systematic evaluation of methyl ester bioisosteres in the context of developing alkenyldiarylmethanes (ADAMs) as non-nucleoside reverse transcriptase inhibitors (NNRTIs) for anti-HIV-1 chemotherapy. AB - The alkenyldiarylmethanes (ADAMs) are a class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) targeting HIV-1. Four chemically and metabolically stabilized ADAMs incorporating N-methoxyimidoyl halide replacements of the methyl esters of the lead compound were previously reported. In this study, twenty-five new ADAMs were synthesized in order to investigate the biological consequences of installing nine different methyl ester bioisosteres at three different locations. Attempts to define a universal rank order of methyl ester bioisosteres and discover the 'best' one in terms of inhibitory activity versus HIV-1 reverse transcriptase (RT) led to the realization that the potencies are critically dependent on the surrounding structure at each location, and therefore the definition of universal rank order is impossible. This investigation produced several new non-nucleoside reverse transcriptase inhibitors in which all three of the three methyl esters of the lead compound were replaced by methyl ester bioisosteres, resulting in compounds that are more potent as HIV-1 RT inhibitors and antiviral agents than the lead compound itself and are expected to also be more metabolically stable than the lead compound. PMID- 27234890 TI - Comparing the efficacy of photodynamic and sonodynamic therapy in non-melanoma and melanoma skin cancer. AB - Sonodynamic therapy (SDT) involves the activation of a non-toxic sensitiser drug using low-intensity ultrasound to produce cytotoxic reactive oxygen species (ROS). Given the low tissue attenuation of ultrasound, SDT provides a significant benefit over the more established photodynamic therapy (PDT) as it enables activation of sensitisers at a greater depth within human tissue. In this manuscript, we compare the efficacy of aminolevulinic acid (ALA) mediated PDT and SDT in a squamous cell carcinoma (A431) cell line as well as the ability of these treatments to reduce the size of A431 ectopic tumours in mice. Similarly, the relative cytotoxic ability of Rose Bengal mediated PDT and SDT was investigated in a B16-melanoma cell line and also in a B16 ectopic tumour model. The results reveal no statistically significant difference in efficacy between ALA mediated PDT or SDT in the non-melanoma model while Rose Bengal mediated SDT was significantly more efficacious than PDT in the melanoma model. This difference in efficacy was, at least in part, attributed to the dark pigmentation of the melanoma cells that effectively filtered the excitation light preventing it from activating the sensitiser while the use of ultrasound circumvented this problem. These results suggest SDT may provide a better outcome than PDT when treating highly pigmented cancerous skin lesions. PMID- 27234891 TI - Inhibitors of secreted phospholipase A2 suppress the release of PGE2 in renal mesangial cells. AB - The upregulation of PGE2 by mesangial cells has been observed under chronic inflammation condition. In the present work, renal mesangial cells were stimulated to trigger a huge increase of PGE2 synthesis and were treated in the absence or presence of known PLA2 inhibitors. A variety of synthetic inhibitors, mainly developed in our labs, which are known to selectively inhibit each of GIVA cPLA2, GVIA iPLA2, and GIIA/GV sPLA2, were used as tools in this study. Synthetic sPLA2 inhibitors, such as GK115 (an amide derivative based on the non-natural amino acid (R)-gamma-norleucine) as well as GK126 and GK241 (2-oxoamides based on the natural (S)-alpha-amino acid leucine and valine, respectively) presented an interesting effect on the suppression of PGE2 formation. PMID- 27234892 TI - Corrigendum to "Purinylpyridinylamino-based DFG-in/alphaC-helix-out B-Raf inhibitors: Applying mutant versus wild-type B-Raf selectivity indices for compound profiling" [Bioorg. Med. Chem. 24 (2016) 2215-2234]. PMID- 27234893 TI - Synthesis of 4-(thiazol-2-ylamino)-benzenesulfonamides with carbonic anhydrase I, II and IX inhibitory activity and cytotoxic effects against breast cancer cell lines. AB - A series of 4-(thiazol-2-ylamino)-benzenesulfonamides was synthesized and screened for their carbonic anhydrase (CA, EC 4.2.1.1) inhibitory and cytotoxic activity on human breast cancer cell line MCF-7. Human (h) CA isoforms I, II and IX were included in the study. The new sulfonamides showed excellent inhibition of all three isoforms, with KIs in the range of 0.84-702nM against hCA I, of 0.41 288nM against hCA II and of 5.6-29.2 against the tumor-associated hCA IX, a validated anti-tumor target, with a sulfonamide (SLC-0111) in Phase I clinical trials for the treatment of hypoxic, metastatic solid tumors overexpressing CA IX. The new compounds showed micromolar inhibition of growth efficacy against breast cancer MCF-7 cell lines. PMID- 27234894 TI - The defensive effect of phellodendrine against AAPH-induced oxidative stress through regulating the AKT/NF-kappaB pathway in zebrafish embryos. AB - AIMS: This study is to investigate the effect of phellodendrine (PHE) against AAPH-induced oxidative stress and find out the biological mechanism of PHE by using the zebrafish embryo model. MAIN METHODS: After treatments by AAPH or PHE, the mortality and heartbeat of zebrafish embryos were recorded and the production of reactive oxygen species (ROS), lipid-peroxidation and the rate of cell death were detected by fluorescence spectrophotometry respectively. Whereafter, the pathways of PHE against AAPH-induced oxidative stress were screened by inhibitors to explore its biological mechanism. The related genes and proteins expressions were analyzed by real-time quantitative reverse-transcription polymerase-chain reaction (qRT-PCR) and western blotting. KEY FINDINGS: The PHE obviously improved the decreased survival rate and abnormally elevated heart-beating rate of zebrafish embryos caused by AAPH. Especially 200MUg/mL of PHE make the survival rate increased to 90.26+/-1.40% at 72hfp and the heartbeat back to normal. Besides, AAPH caused a significant increase in the production of reactive oxygen species (ROS), lipid-peroxidation and cell death rate, all of which could be decreased after PHE treatment dose-dependently. And PHE exerted the protective activity against AAPH-induced oxidative stress through down-regulating AKT phosphorylation and NF-kB3 expression, which associate with modulation of IKK phosphorylation in zebrafish embryos. SIGNIFICANCE: The PHE showed a good antioxidant effect in vivo, and the mechanism has been stated that the PHE can down-regulating AKT, IKK, NF-kB phosphorylation and COX-2 expression induced by AAPH. Moreover, the PHE also ameliorated the ROS-mediated inflammatory response. PMID- 27234895 TI - Mechanism of dihydroartemisinin-induced apoptosis in prostate cancer PC3 cells: An iTRAQ-based proteomic analysis. AB - AIMS: Prostate cancer (PCa) is one of the most common cancers in men in the world. Advanced PCa, especially castration-resistant PCa (CRPC), is difficult to cure. There is an urgent need to develop novel agents for CPRC. Dihydroartemisinin (DHA) is a semisynthetic derivative of artemisinin and is a well-known antimalarial drug. DHA has been documented to be a potential anticancer agent for PCa. However, the mechanisms underlying the anticancer activity of DHA are still unknown. MAIN METHODS: Proteomics analysis based on iTRAQ technology was performed to determine the protein profile changes in human prostate cancer PC3 cells treated by DHA, and apoptosis was detected by flow cytometry and transmission electron microscopy. KEY FINDINGS: DHA induced obvious apoptosis in PC3 cells. Using iTRAQ technology, we found 86 differentially expressed proteins linked to the cytotoxicity of DHA in PC3 cells. Gene ontology analysis showed the differentially expressed proteins were mainly associated with the protein synthesis and translation. Protein interaction network analysis and KEGG pathway analysis revealed altered aminoacyl-tRNA biosynthesis and metabolic pathways. Moreover, one candidate protein, heat shock protein HSP70 (HSPA1A), was identified by western blot analysis. SIGNIFICANCE: Our results indicate that multiple mechanisms involved in the anticancer activity of DHA in PC3 cells. Decreased HSP70 expression may have an important role in DHA-induced apoptosis in PC3 cells. Our data also provide novel insights into the anticancer mechanisms of DHA. PMID- 27234896 TI - Effects of endurance, resistance, and concurrent exercise on learning and memory after morphine withdrawal in rats. AB - AIMS: Continuous morphine consumption contributes to the development of cognitive disorders. This work investigates the impacts of different types of exercise on learning and memory in morphine-dependent rats. MAIN METHODS: Forty morphine dependent rats were randomly divided into five groups: sedentary-dependent (Sed D), endurance exercise-dependent (En-D), strength exercise-dependent (St-D), and combined (concurrent) exercise-dependent (Co-D). Healthy rats were used as controls (Con). After 10weeks of regular exercise (endurance, strength, and concurrent; each five days per week), spatial and aversive learning and memory were assessed using the Morris water maze and shuttle box tests. KEY FINDINGS: The results showed that morphine addiction contributes to deficits in spatial learning and memory. Furthermore, each form of exercise training restored spatial learning and memory performance in morphine-dependent rats to levels similar to those of healthy controls. Aversive learning and memory during the acquisition phase were not affected by morphine addiction or exercise, but were significantly decreased by morphine dependence. Only concurrent training returned the time spent in the dark compartment in the shuttle box test to control levels. SIGNIFICANCE: These findings show that different types of exercise exert similar effects on spatial learning and memory, but show distinct effects on aversive learning and memory. Further, morphine dependence-induced deficits in cognitive function were blocked by exercise. Therefore, different exercise regimens may represent practical treatment methods for cognitive and behavioral impairments associated with morphine-related disease. PMID- 27234897 TI - Neuromuscular Effects of Rocuronium Bromide in Patients in Statin Therapy for at least Three Months. AB - Statins cause skeletal muscle myopathy. However, the neuromuscular effects of non depolarizing neuromuscular-blocking agent in patients in long-term statin therapy remain unclear. Hence, we investigated the neuromuscular effects of rocuronium and muscle injury in patients in long-term statin therapy. Eighteen statin users using statins for at least 3 months were included in the statin group and 18 non statin users were included in the non-statin group. General anaesthesia was induced with intravenous midazolam, etomidate, sufentanil and rocuronium 0.9 mg/kg (3ED95 ) for intubation. Anaesthesia was maintained with 1% propofol and remifentanil. The onset time and duration 10% T1 and 25% T1 of rocuronium were recorded. Blood samples were obtained before induction and 5 min., 1 hr, 2 hr, 4 hr, 12 hr and 24 hr after rocuronium administration to measure creatine kinase (CK), myoglobin and potassium. Myalgia was determined at 2 and 24 hr after surgery. There were no significant differences in the basic clinical characteristics between the two groups. The onset time of the statin group was significantly shorter than that of the non-statin group (p = 0.02), while the duration 10% T1 and duration 25% T1 of the statin group were significantly longer than those of the non-statin group (p = 0.006; p = 0.045). The myoglobin and CK concentrations increased after rocuronium administration as compared to baseline in both groups. CK concentration in the statin group was significantly higher than in the non-statin group just at 24 hr (p = 0.000003). However, myoglobin showed no significant difference between the two groups. The onset time of rocuronium decreases and its duration time increases in patients in long-term statin therapy. PMID- 27234899 TI - Atypical 1,4-dihydropyridine derivatives, an approach to neuroprotection and memory enhancement. AB - This mini review is devoted to the design and pharmacological studies of novel atypical 1,4-dihydropyridine (DHP) derivatives which differ to a great extent from the traditional DHPs either by lack of neuronal calcium channel blocking activity and/or inability to protect mitochondrial processes. About 100 new DHP derivatives were screened and the mostly active were selected for detailed studies. The compounds of the series of the amino acid ("free" plus "crypto") containing DHPs and lipophilic di-cyclic DHPs demonstrated long-lasting neuroprotective and/or memory-enhancing action, particularly at low doses (0.005 0.05mg/kg) in different neurodeficiency rat or mice models, and exerted neurotransmitter-modulating effects. The studies have shown an ability of these atypical DHPs to normalize the expression of neuronal proteins, which participate in the regulation of neurotransmission (particularly of the GABAergic system) and synaptic plasticity that has been impaired in animal models, including Alzheimer's disease transgenic mice. The obtained results indicate that the tested DHP compounds can be considered as candidate molecules either for their further chemical modifications or for the more detailed studies to identify cell targets essential for neuroprotection and memory enhancing. PMID- 27234898 TI - A historical summary of the Brazilian Society of Pharmacology and Experimental Therapeutics (SBFTE). PMID- 27234900 TI - [French shift workers seen at health centres have an increased risk of lipid disorders]. AB - AIMS: To describe cardiovascular risk factors and metabolic disturbances in a French population including shift workers and study whether possible changes were noticeable after non-shift to shift work transition within the last five years. METHODS: The study population included 4764 attendees of two health examinations (5 years apart), between January 1996 and October 2008, in 11 health examination centres. Clinical, biological and metabolic factors together with their changes over a five-year period were compared between attendees who kept a non-shift daytime job, those who kept working shift and those who switched from non-shift daytime to shift work over the last 5 years. RESULTS: At baseline, working shift was, independently of lifestyle or BMI, significantly related to more elevated plasma triglycerides (beta=0.04, P=0.05) and rate of hypertriglyceridemia (beta=0.27, P=0.01), lower plasma HDL-C levels (beta=-2.03, P=0.006) and less hypertension (beta=-0.25, P=0.01) compared to non-shift daytime work. In men, a slightly more elevated yet non significant proportion of hypertriglyceridemia was observed with the transition from non-shift daytime to shift work within the last 5 years in comparison to men who kept a non-shift daytime job (13.9% vs. 11.0% P=0.17). CONCLUSION: Our results are in agreement with previous studies showing a deleterious effect of shift work on lipid metabolism. In our population, triglycerides and HDL-C levels were the main parameters negatively influenced by shift work. Consequently, a regular biological monitoring together with the promotion of healthy behaviours should be provided to shift workers before negative consequences of working shift become noticeable. PMID- 27234901 TI - [Severe genotype 4 acute autochthonous hepatitis E]. PMID- 27234902 TI - [Erdheim-Chester disease (ECD), an inflammatory myeloid neoplasia]. AB - In a compatible clinico-radiological setting, the diagnosis of Erdheim-Chester disease (ECD) involves the analysis of histiocytes in tissue biopsies: they are typically foamy and CD68+ CD1a, whereas in Langerhans cell histiocytosis (LCH) they are CD68+ CD1a+. Overlap forms of histiocytoses are frequent. Technetium bone scintigraphy showing nearly constant tracer uptake by the long bones is highly suggestive of ECD and a 'hairy kidney' appearance on abdominal CT scan is observed in more than half ECD cases. CNS involvement is a strong prognostic factor and an independent predictor of death in cases of ECD. Optimal initial therapy for ECD appears to be administration of IFN-alpha (and/or pegylated IFN alpha) and prolonged treatment significantly improves survival; however, tolerance may be poor. Best alternative therapies are anakinra, mainly effective for mild forms of the disease, infliximab, and sirolimus. Cases of ECD present with strong systemic immune activation, involving IFN-alpha, IL-1/IL1-RA, IL-6, IL-12, and MCP-1, consistent with the systemic immune Th-1-oriented disturbance associated with the disease. Between 57 and 75 % of ECD patients carry the BRAFV600E mutation, an activating mutation of the proto-oncogene BRAF. More than 50 cases harboring BRAF mutation and with severe multisystemic and refractory ECD (sometimes associated with LCH) have been treated worldwide with vemurafenib, a BRAF inhibitor that proved to be very beneficial. Other recurrent mutations of the MAPK (NRAS, MAP2K1) and PIK3 pathways (PIK3CA) have been found among ECD patients. As recurrent mutations in the MAPK pathway are found in ECD and LCH on a background of chronic inflammation, we believe that both conditions should be redefined as an inflammatory myeloid neoplasia. PMID- 27234903 TI - [Persistent median nerve artery and carpal tunnel syndrome. Usefulness of duplex echography]. PMID- 27234904 TI - [Medical approaches for managing preeclampsia]. AB - Preecalmpsia is an hypertensive disease of pregnancy complicating 1-5 % of all pregnancies. Although symptomatic management has improved, there is currently no curative treatment, and only childbirth and delivery of the placenta, usually prematurely, alleviate the mother's symptoms. When preeclampsia occurs before 37 weeks of gestation expectant management is often possible in order to reduce post natal complications related to prematurity. The management depends on the severity of the disease and gestational age. The modalities of this management are reviewed in this article. PMID- 27234905 TI - [Allergy to neuromuscular blocking agents]. AB - Allergy to neuromuscular blocking agents (NMBAs) has been the first cause of perioperative anaphylaxis for decades, in most countries. The most frequently involved agents are suxamethonium and rocuronium. The allergy work-up is compulsory to demonstrate or rule out allergy to NMBAs, if there is a compatible clinical history. Doing otherwise exposes the patient to death if the same or related NMBA is re-injected. In cases of true allergy, assessing cross-reactivity to other NMBAs is mandatory. The cross-sensitization hypothesis is presently being investigated and if confirmed, it could allow primary prevention measures to be implemented. PMID- 27234906 TI - [Risk stratification of sudden death in hypertrophic cardiomyopathy in 2016]. AB - Patients with hypertrophic cardiomyopathy (HCM) are at an increased risk of death from many causes and sudden cardiac death is one of them. The study of the sudden cardiac death of patients with HCM has allowed the identification of risk factors and among them major risk factor are: family history of sudden cardiac death, the occurrence of syncope/dizziness, the existence of non-sustained ventricular tachycardia an abnormal blood pressure response during stress test, presence of severe left ventricular hypertrophy>=30mm. Risk stratification for sudden cardiac death is essential, for symptomatic or asymptomatic HCM patients. Two approaches are possible: the classical approach or risk stratification methods with major risk factors and the new approach using the risk-calculator recommended by the ESC. Both methods are not in opposition but complementary. The risk stratification in hypertrophic cardiomyopathy should be still improved to be sure that only the most high-risk patients receive an implantable cardiac defibrillator. PMID- 27234907 TI - Spread and persistence of VIM-1 Carbapenemase-producing Enterobacteriaceae in three German swine farms in 2011 and 2012. AB - The occurrence of carbapenemase-producing Enterobacteriaceae in livestock is considered as a threat for public health. In Germany, VIM-1-producing Escherichia (E.) coli sequence type (ST) 88 and Salmonella Infantis isolates harbouring blaVIM-1IncHI2 plasmids have been isolated from swine and poultry farms. A retrospective study was performed to determine if there was a broader distribution of VIM-1-positive isolates in any of the carbapenemase-positive swine farms. Selective incubation (carbapenem-containing broth) of 249 conserved cultures collected in three farms (2011-2012), allowed the detection of 40 blaVIM 1-positive isolates. Apart from the already known non-motile Salmonella Infantis isolate R25 (farm S1) and R27 (S2), a third isolate was recovered from farm S3. For E. coli, additional to isolates R29 and R178 (S2), 35 new isolates were identified in the same farm during all the sampling periods (three dates, 2011) and in samples from different animals, farm environment, manure and flies. The newly identified E. coli and Salmonella isolates showed similar genetic and phenotypic characteristics (XbaI-PFGE profiles, antimicrobial resistance patterns, plasmid content, phylogroups, antigenic formula) to those in the previously described strains, suggesting microevolution within the clonal lines within one fattening period. The study shows that persistence of carbapenemase producing clonal lines in livestock farms is possible, and underlines the need for harmonised monitoring and surveillance studies to follow up the occurrence of such bacteria in European livestock. PMID- 27234908 TI - CD11b+Gr-1+ myeloid-derived suppressor cells reduce atherosclerotic lesion development in LDLr deficient mice. AB - AIMS: Myeloid-derived suppressor cells (MDSCs) form a heterogeneous population of cells composed of early myeloid progenitor cells and immature myeloid cells, which strongly suppress pro-inflammatory immune cells in inflammatory diseases. Currently, it is unknown whether MDSCs contribute to atherosclerosis, a chronic inflammatory disease in which accumulation of lipoproteins in the arterial wall activates the immune system causing abnormal vascular remodelling and vessel occlusion. Here, we investigated whether and how MDSCs contribute to the development of atherosclerosis. METHODS AND RESULTS: We show that MDSCs arise in the bone marrow of LDLr(-/-) mice during atherosclerosis and strongly suppress proliferation of T cells. Adoptive transfer of MDSCs into both female and male LDLr(-/-) mice fed a Western-type diet (WTD) ameliorates atherosclerosis with 35%. We observed a 54% reduction in adventitial T cells, and more specifically, MDSCs suppress Th1 and Th17 cells. In addition, treatment with MDSCs reduces circulating pro-atherogenic B2 cells. We found two subsets of MDSCs in the bone marrow of hypercholesterolemic mice, monocytic and granulocytic MDSCs (mo- and gr MDSCs, respectively), of which the percentage of mo-MDSCs significantly increased during WTD feeding. Moreover, mo-MDSCs completely abolished splenocyte proliferation, whereas gr-MDSCs were unable to suppress proliferation. Mechanistically, we show that MDSCs from atherosclerotic mice suppress T cells in an IFN-gamma- and nitric oxide-dependent manner, which is associated with the action of mo-MDSCs. CONCLUSION: This study demonstrates that MDSCs develop during atherosclerosis and reduce atherosclerosis via suppression of pro-inflammatory immune responses. PMID- 27234909 TI - Longitudinal assessment of renal size and function in extremely low birth weight children at 7 and 11 years of age. AB - BACKGROUND: There are a lack of studies describing a longitudinal association between preterm delivery and renal complications later in life. We assessed renal size and function in preterm infants born with extremely low birth weight (ELBW) during 4 years of follow-up, comparing these parameters to age-matched children born full term (term controls). METHODS: The results of selected renal laboratory tests [levels of cystatin C, creatinine, blood urea nitrogen (BUN)] and of renal ultrasound evaluations were compared between the ELBW group and the term control group at age 7 and 11 years. RESULTS: The study population consisted of 64 children born with ELBW (ELBW children) who had been recruited at birth and 36 children born at term (term children) who took part in both follow-up assessments. Renal ultrasound examination revealed a significantly smaller renal volume in the 7- and 11-year-old ELBW children compared to the term controls [right kidney volume: 50.8 vs. 61.2 ml/m(2), respectively, at 7 years (p <0.01) and 51.4 vs. 58.2 ml/m(2), respectively, at 11 years (p <0.01); left kidney volume: 51.4 vs. 60.3 ml/m(2), respectively, at 7 years (p <0.01) and 55.2 vs. 60.7 ml/m(2), respectively, at 11 years (p = 0.02)]. Renal function in ELBW children was also affected. Serum cystatin C levels were significantly higher in ELBW children than in the controls at 7 years of age, and this difference remained statistically significant at 11 years of age [0.63 vs. 0.59 mg/l, respectively, at 7 years (p = 0.02) and 0.72 vs. 0.61 mg/l, respectively, at 11 years (p = 0.01)]. Six ELBW children also had elevated cystatin C levels (0.97 1.11 mg/l) at 11 years of age. Cystatin C levels were within normal range in the ELBW children at age 7 years and in term children in both follow-up studies. BUN levels were higher in ELBW children at the age of 11 years (4.49 vs. 4.15 mmol/l; p = 0.028). CONCLUSION: Continued follow-up of these patients will reveal whether the observed worsening in renal function will persist into adulthood. PMID- 27234910 TI - The significance of tubulointerstitial lesions in childhood Henoch-Schonlein nephritis. AB - BACKGROUND: Little information is currently available on the development of tubulointerstitial lesions in children with Henoch-Schonlein nephritis (HSN). To identify the impact of the development of tubulointerstitial changes in HSN, we retrospectively analyzed renal biopsies obtained from children with HSN. METHODS: Twenty-eight children with HSN from whom serial renal biopsies had been obtained before and after immunosuppressive therapy were enrolled in the study. The patients were divided into two groups according to the observed change in tubulointerstitial lesion development: group I (n = 15), with stable or improved tubulointerstitial lesions, and group II (n = 13), with worsened tubulointerstitial lesions. Group II patients had longer duration of proteinuria than group I patients (3.7 +/- 3.7 years vs. 1.7 +/- 1.7 years, p = 0.052). RESULTS: The change in serum albumin level was negatively correlated with the change in tubulointerstitial scores before and after treatment (gamma = -0.444, p = 0.018). Group II patients showed a significant decrease in immunoglobulin G (IgG) and IgA deposits after treatment (p = 0.039 and 0.003, respectively), while group II patients did not (p = 0.458 and 0.506, respectively). CONCLUSIONS: Although the International Study of Kidney Disease in Children classification of HSN does not include tubulointerstitial lesions, they can progress during treatment and could have significant clinical implications in association with the duration of proteinuria. PMID- 27234912 TI - [The origins of the French neurosurgery]. AB - Modern French neurosurgery starts at the beginning of the XXth century under the motivation of Joseph Babinski. He submitted his patients to Thierry de Martel who had learned this new specialized area of medicine with H. Cushing in the Etats Unis and V. Horsey in Great Britain. His first successfully treated case of an intracranial tumor was published in 1909. But the true founding father was Clovis Vincent, initially a neurologist and collaborator of de Martel, who became the first chairman in 1933 of the neurosurgical department at the Pitie hospital of Paris and the first professor of neurosurgery in 1938. After the Second World War, many departments were created outside of Paris. Neurosurgery was definitively recognized as a specialized area in medicine in 1948. Currently, more than 400 neurosurgeons work in France. Because I had the very great privilege to be present at the birth of this society in 1970 and to still be in contact with some of the second and third generation of French neurosurgeons who led it to its high international recognition, the Chairman of the French Neurosurgical Society asked me to write this short historical vignette. PMID- 27234911 TI - Genetic causes of hypomagnesemia, a clinical overview. AB - Magnesium is essential to the proper functioning of numerous cellular processes. Magnesium ion (Mg2+) deficits, as reflected in hypomagnesemia, can cause neuromuscular irritability, seizures and cardiac arrhythmias. With normal Mg2+ intake, homeostasis is maintained primarily through the regulated reabsorption of Mg2+ by the thick ascending limb of Henle's loop and distal convoluted tubule of the kidney. Inadequate reabsorption results in renal Mg2+ wasting, as evidenced by an inappropriately high fractional Mg2+ excretion. Familial renal Mg2+ wasting is suggestive of a genetic cause, and subsequent studies in these hypomagnesemic families have revealed over a dozen genes directly or indirectly involved in Mg2+ transport. Those can be classified into four groups: hypercalciuric hypomagnesemias (encompassing mutations in CLDN16, CLDN19, CASR, CLCNKB), Gitelman-like hypomagnesemias (CLCNKB, SLC12A3, BSND, KCNJ10, FYXD2, HNF1B, PCBD1), mitochondrial hypomagnesemias (SARS2, MT-TI, Kearns-Sayre syndrome) and other hypomagnesemias (TRPM6, CNMM2, EGF, EGFR, KCNA1, FAM111A). Although identification of these genes has not yet changed treatment, which remains Mg2+ supplementation, it has contributed enormously to our understanding of Mg2+ transport and renal function. In this review, we discuss general mechanisms and symptoms of genetic causes of hypomagnesemia as well as the specific molecular mechanisms and clinical phenotypes associated with each syndrome. PMID- 27234913 TI - [Multiple meningiomas]. AB - Multiple meningiomas (MMs) or meningiomatosis are defined by the presence of at least 2 lesions that appear simultaneously or not, at different intracranial locations, without the association of neurofibromatosis. They present 1-9 % of meningiomas with a female predominance. The occurrence of multiple meningiomas is not clear. There are 2 main hypotheses for their development, one that supports the independent evolution of these tumors and the other, completely opposite, that suggests the propagation of tumor cells of a unique clone transformation, through cerebrospinal fluid. NF2 gene mutation is an important intrinsic risk factor in the etiology of multiple meningiomas and some exogenous risk factors have been suspected but only ionizing radiation exposure has been proven. These tumors can grow anywhere in the skull but they are more frequently observed in supratentorial locations. Their histologic types are similar to unique meningiomas of psammomatous, fibroblastic, meningothelial or transitional type and in most cases are benign tumors. The prognosis of these tumors is eventually good and does not differ from the unique tumors except for the cases of radiation induced multiple meningiomas, in the context of NF2 or when diagnosed in children where the outcome is less favorable. Each meningioma lesion should be dealt with individually and their multiple character should not justify their resection at all costs. PMID- 27234914 TI - [Management of spinal metastasis by minimal invasive surgery technique: Surgical principles, indications: A literature review]. AB - INTRODUCTION: Spinal metastasis are getting more frequent. This raises the question of pain and neurological complications, which worsen the functional and survival prognosis of this oncological population patients. The surgical treatment must be the most complete as possible: to decompress and stabilize without delaying the management of the oncological disease. Minimal invasive surgery techniques are by definition, less harmful on musculocutaneous plan than opened ones, with a comparable efficiency demonstrated in degenerative and traumatic surgery. So they seem to be applicable and appropriate to this patient population. MATERIAL AND METHODS: We detailed different minimal invasive techniques proposed in the management of spinal metastasis. For this, we used our experience developed in degenerative and traumatic pathologies, and we also referred to many authors, establishing a literature review thanks to Pubmed, Embase. RESULTS: Thirty eight articles were selected and allowed us to describe different techniques: percutaneous methods such as vertebro-/kyphoplasty and osteosynthesis, as well as mini-opened surgery, through a posterior or anterior way. DISCUSSION: We propose a surgical approach using these minimal invasive techniques, first according to the predominant symptom (pain or neurologic failure), then characteristics of the lesions (number, topography, type...) and the deformity degree. Whatever the technique, the main goal is to stabilize and decompress, in order to maintain a good quality of life for these fragile patients, without delaying the medical management of the oncological disease. PMID- 27234915 TI - [A new human machine interface in neurosurgery: The Leap Motion((r)). Technical note regarding a new touchless interface]. AB - Currently, cross-sectional imaging viewing is used in routine practice whereas the surgical procedure requires physical contact with an interface (mouse or touch-sensitive screen). This type of contact results in a risk of lack of aseptic control and causes loss of time. The recent appearance of devices such as the Leap Motion((r)) (Leap Motion society, San Francisco, USA) a sensor which enables to interact with the computer without any physical contact is of major interest in the field of surgery. However, its configuration and ergonomics produce key challenges in order to adapt to the practitioner's requirements, the imaging software as well as the surgical environment. This article aims to suggest an easy configuration of the Leap Motion((r)) in neurosurgery on a PC for an optimized utilization with Carestream((r)) Vue PACS v11.3.4 (Carestream Health, Inc., Rochester, USA) using a plug-in (to download at: https://drive.google.com/?usp=chrome_app#folders/0B_F4eBeBQc3ybElEeEhqME5DQkU) and a video tutorial (https://www.youtube.com/watch?v=yVPTgxg-SIk). PMID- 27234916 TI - [Vagus nerve stimulation for intractable epilepsy: A retrospective bicentric cohort study of 101 patients operated on between 1999 and 2010]. AB - BACKGROUND: Vagus nerve stimulation is an adjunctive palliative therapy for refractory epilepsy. MATERIAL AND METHODS: We reviewed the clinical and surgical records of patients who had a VNS implantation for intractable epilepsy between the years 1999 and 2010 at two institutions, Bordeaux and Toulouse University Hospitals. RESULTS: A total of 101 patients were included of whom 57 were male. Median age at epilepsy onset was 7.5 years, inter quartile range (IQR) [2.5-12.5] and the median time between epilepsy onset and VNS implantation was 21.1 years, IQR [11.9-29.5]. At the end of the study, 85 patients were alive with a functional VNS. Survival probability of having a functional VNS at 1, 2 and 5 years were respectively: 99%, IC95% [97.1,100]; 96.49%, IC95% [92.7,100] and, 88.2%, IC95% [79.9,97.4]. Among the patients, 41.6% demonstrated a seizure decrease of more than 50%. The mean number of seizures was reduced by 5.7 per week. We failed to demonstrate any factor affecting the outcome. CONCLUSION: The VNS can decrease the seizure frequency but, also reduce their intensity and had a favourable effect on the patients mood. Morbidity is low and the therapeutic effect of the stimulation is sustainable. The indication of the VNS should be discussed earlier in the evolution of a nonsurgical and severe epilepsy. PMID- 27234917 TI - L-DOPA elicits non-vesicular releases of serotonin and dopamine in hemiparkinsonian rats in vivo. AB - The control of the secretory activity of serotonergic neurons has been pointed out to reduce motor and non-motor side effects of the antiparkinsonian drug L DOPA. This strategy deserves further investigation because it is presently unclear whether L-DOPA promotes a non-vesicular release of dopamine and serotonin from serotonergic neurons. To get a full neurochemical picture compatible with the existence of such a mechanism, we combined multisite intracerebral microdialysis, post mortem tissue measurement and single unit extracellular recordings in the dorsal raphe nucleus from hemiparkinsonian rats. L-DOPA (3 100mg/kg, ip.) non-homogeneously decreased extracellular serotonin levels in the striatum, substantia nigra pars reticulata, hippocampus and prefrontal cortex and homogenously serotonin tissue content in the striatum, cortex and cerebellum. L DOPA (12mg/kg) did not modify the firing rate or pattern of serotonergic-like neurons recorded in the dorsal raphe nucleus. When focusing on serotonin release in the prefrontal cortex and the hippocampus, we found that L-DOPA (12 or 100mg/kg) enhanced serotonin extracellular levels in both regions upon Ca(2+) removal. Concomitantly, L-DOPA-stimulated dopamine release partly persisted in the absence of Ca(2+) in a region-dependent manner. Local application of the serotonin reuptake inhibitor citalopram (1uM) blunted the responses to L-DOPA (3 12mg/kg), measured as extracellular dopamine levels, most prominently in the hippocampus. These data stress that L-DOPA, already at low to moderate doses, promotes non-vesicular releases of serotonin and dopamine in a region-dependent manner. PMID- 27234918 TI - Citicoline for Acute Ischemic Stroke: A Systematic Review and Formal Meta analysis of Randomized, Double-Blind, and Placebo-Controlled Trials. AB - BACKGROUND: Citicoline is a drug approved for the treatment of acute ischemic stroke. Although evidence of its efficacy has been reported, recently published results of a large placebo-controlled clinical trial did not show differences. This study aims to assess whether starting citicoline treatment within 14 days after stroke onset improves the outcome in patients with acute ischemic stroke, as compared with placebo. METHODS: A systematic search was performed to identify all published, unconfounded, randomized, double-blind, and placebo-controlled clinical trials of citicoline in acute ischemic stroke. RESULTS: Ten randomized clinical trials met our inclusion criteria. The administration of citicoline was associated with a significant higher rate of independence, independently of the method of evaluation used (odds ratio [OR] 1.56, 95% confidence interval [CI] = 1.12-2.16 under random effects; OR 1.20, 95% CI = 1.06-1.36 under fixed effects). After studying the cumulative meta-analysis, and with the results obtained with the subgroup of patients who were not treated with recombinant tissue plasminogen activator (rtPA) (OR 1.63, 95% CI = 1.18-2.24 under random effects; OR 1.42, 95% CI = 1.22-1.66 under fixed effects), our hypothesis of dilution of the effect of citicoline was confirmed. When we analyzed the effect of citicoline in patients who were not treated with rtPA and were receiving the highest dose of citicoline started in the first 24 hours after onset, based on more recent trials, there was no heterogeneity, and the size of the effect has an OR of 1.27 (95% CI = 1.05 1.53). CONCLUSIONS: This systematic review supports some benefits of citicoline in the treatment of acute ischemic stroke. But, on top of the best treatment available (rtPA), citicoline offers a limited benefit. PMID- 27234919 TI - Semiautomated Magnetic Resonance Imaging Assessment of Carotid Plaque Lipid Content. AB - BACKGROUND: The composition of a carotid plaque is important for plaque vulnerability and stroke risk. The main aim of this study was to assess the potential of semiautomated segmentation of carotid plaque magnetic resonance imaging (MRI) in the assessment of the size of the lipid-rich necrotic core (LRNC). METHODS: Thirty-four consecutive patients with carotid stenosis of 70% or higher, who were scheduled for carotid endarterectomy, underwent a clinical neurological examination, Color duplex ultrasound, 3-T MRI with an 8-channel carotid coil, and blood tests. All examinations were performed less than 24 hours prior to surgery and plaques were assessed histologically immediately following endarterectomy. Plaques were defined as symptomatic when associated with ipsilateral cerebral ischemic symptoms within 30 days prior to inclusion. The level of agreement between the size of the LRNC and calcification on MRI to the histological estimation of the same tissue components, plaque echolucency on ultrasound, and symptoms was assessed. RESULTS: The size of the LRNC on MRI was significantly correlated to the percentage amount of lipid per plaque on histological assessment (P = .010, r = .5), and to echogenicity on ultrasound with echolucent plaques having larger LRNC than echogenic plaques (P = .001, r = .7). CONCLUSIONS: In this study, we found that semiautomated MRI assessments of the percentage LRNC in carotid plaques were significantly correlated to the percentage LRNC per plaque on histological assessment, and to echogenicity on ultrasound with echolucent plaques having larger LRNC than echogenic plaques. PMID- 27234920 TI - Subarachnoid Hemorrhage due to Spinal Cord Schwannoma Presenting Findings Mimicking Meningitis. AB - BACKGROUND: Subarachnoid hemorrhage (SAH) of spinal origin is uncommon in clinical practice, and spinal schwannomas associated with SAH are even more rarely reported. We report an unusual case of spinal SAH mimicking meningitis with normal brain computed tomography (CT)/magnetic resonance imaging (MRI) and negative CT angiography. Cerebrospinal fluid examination results were consistent with the manifestation of SAH. Spinal MRI performed subsequently showed an intradural extramedullary mass. The patient received surgery and was finally diagnosed with spinal cord schwannoma. METHOD: A retrospective chart review of the patient was performed. RESULTS: We describe a case of SAH due to spinal cord schwannoma. Our case highlights the importance of careful history taking and complete evaluation. CONCLUSION: We emphasize that spinal causes should always be ruled out in patients with angionegative SAH and that schwannoma should be considered in the differential diagnosis of SAH etiologies even though rare. PMID- 27234921 TI - Plasma D-dimer Level, the Promising Prognostic Biomarker for the Acute Cerebral Infarction Patients. AB - BACKGROUND: Despite being an important cause of death and functional disability, acute cerebral infarction (ACI) lacks accurate and easy tools to predict the outcome of patients beyond clinical variables such as age and stroke severity. METHODS: To investigate if plasma D-dimer level can be used as such a prognostic biomarker for ACI, so as to better guide patients' management, we studied the association between plasma D-dimer and the functional recovery of 1173 ACI patients. The patients were divided into 2 groups according to modified Rankin Scale (mRS) scores or National Institutes of Health Stroke Scale (NIHSS) scores evaluated on the 30th day after onset. RESULTS: We observed that plasma D-dimer level correlated significantly with the prognosis of ACI evaluated based on both mRS scores (389.68 +/- 32.06 ug/L for poor prognosis versus 377.70 +/- 32.68 ug/L for good prognosis, P < .001) and NIHSS scores (387.01 +/- 30.60 ug/L for poor prognosis versus 375.23 +/- 30.66 ug/L for good prognosis, P < .01). Logistic analysis confirmed that higher D-dimer level was a risk factor for poor prognosis (mRS: odds ratio [OR], 1.604; 95% confidence interval [CI], 1.360-1.892; P < .001; NIHSS: OR, 1.733; 95% CI, 1.461-2.056; P < .01), after adjusted for age, gender, hypertension, diabetes, smoking, and hyperlipidemia. CONCLUSION: Our results show that plasma D-dimer level is a promising prognosis biomarker for ACI. PMID- 27234922 TI - Bilateral Vein of Trolard Thrombosis. AB - Isolated cortical vein thrombosis without dural sinus involvement is not common. The vein of Trolard is an important cortical vein as it drains eloquent cortex. We report 2 cases of bilateral vein of Trolard thrombosis; one with and the other without dural sinus involvement. To our knowledge, there have been no cases of bilateral vein of Trolard thrombosis reported in literature. The clinical presentation of cerebral venous thrombosis is variable; patients can present with isolated intracranial hypertension, focal neurological abnormalities, seizures, or encephalopathy. PMID- 27234923 TI - Intravitreal Bevacizumab as an adjunct to laser in the management of adult onset Coats' disease. PMID- 27234924 TI - Similarity among tasks is the key to show generalization of cognitive training effects in Alzheimer's disease: a case study. AB - Cognitive training can allow patients with Alzheimer's disease (AD) to reinforce individual cognitive abilities. In the present case study, we investigated the generalizability of trained cognitive skills to novel tasks, and their stability over time. One AD patient underwent a structured cognitive training using the GEO (Geographical Exercise for cognitive Optimization) task, whereas eight AD patients underwent a control cognitive intervention. Participants' performances on the GEO task, on a similar untrained cognitive task, and on a different untrained cognitive task were recorded before and after the intervention, and at the follow-up. On both the trained and the similar untrained tasks patients' and controls' performance significantly differed from one another. Our preliminary evidence shows that a cognitive training could allow patients to improve and maintain their performance not only on the trained task, but also on a similar task. PMID- 27234926 TI - Impact of an mHealth Platform for Pregnancy on Nutrition and Lifestyle of the Reproductive Population: A Survey. AB - BACKGROUND: Poor nutrition and lifestyle behaviors exert detrimental effects on reproduction and health during the life course. Therefore, lifestyle interventions during the periconceptional period can improve fertility, pregnancy outcome, and health of subsequent generations. OBJECTIVE: This survey investigates the compliance, usability, and initial effectiveness of the Web based mHealth platform, Smarter Pregnancy. METHODS: A free subscription to the mHealth platform, Smarter Pregnancy, was provided to couples contemplating pregnancy (n=1275) or already pregnant (n=603). After baseline identification of inadequate nutrition and lifestyle behaviors, a personal online coaching program of 6 months was generated. Using multiple imputation and the generalized estimating equation model with independent correlations, we estimated the changes from inadequate to adequate nutrition and lifestyle behaviors over time. Subgroup analyses were performed for (1) overweight and obese women (body mass index [BMI] >=25 kg/m(2)), (2) pregnant women at the start of the program, and (3) couples. RESULTS: A 64.86% (1218/1878) compliance rate was observed and 54.7% (range 39.2 73.4%) of participants rated the program usability as positive or very positive. Adequate nutrition and lifestyle behaviors at baseline were 21.57% (405/1878) for vegetable intake, 52.61% (988/1878) for fruit intake, 85.44% (1303/1525) for folic acid use, 86.79% (1630/1878) for no tobacco use, and 64.43% (1210/1878) for no alcohol consumption. After 6 months of coaching, these lifestyle behaviors improved by 26.3% (95% CI 23.0-29.9) for vegetable intake, 38.4% (95% CI 34.5 42.5) for fruit intake, 56.3% (95% CI 48.8-63.6) for folic acid use, 35.1% (95% CI 29.1-41.6) for no tobacco use, and 41.9% (95% CI 35.2-48.9) for no alcohol consumption. The program showed the strongest effectiveness for participating couples. CONCLUSIONS: This novel Web-based mHealth platform shows high compliance and usability, and users demonstrate improvements in nutrition and lifestyle behaviors. The next step will be further validation in randomized controlled trials and implementation. PMID- 27234925 TI - The signaling of amitriptyline-induced inhibitory effect on electrical field stimulation response in colon smooth muscle. AB - Amitriptyline, a well-known antidepressant, exerts inhibitory effect on electrically stimulated rat colon smooth muscle contraction. In this study, we investigated the signaling pathway of amitriptyline-induced inhibitory effect. Changes in isometric force of colon muscle were recorded on polygraph, and data were analyzed by measuring the inhibitory extent induced by amitriptyline. Firstly, muscles were contracted by stimulation with electric field stimulation (EFS), and then, amitriptyline was added cumulatively to determine its influence effect on EFS. Amitriptyline significantly inhibited EFS-induced contraction dose dependently. Then, the mechanism of inhibitory effect of amitriptyline was evaluated by pretreating with various antagonists such as L-NAME, methylene blue, atropine, 5-HT receptors blockers, guanethidine, prazosin, guanabenz, isoprenaline, Y27632 (Rho-kinase inhibitor), ML9 (myosin light chain kinase (MLCK) inhibitor), U73122 (PLC inhibitor), and chelerythrine (PKC inhibitor). Then, Ca(2+) channel blocker (nifedipine) and K(+)channel blockers, tetraethylammonium (TEA), 4-aminopyridine (4-AP), and glybenclamide, were used to determine the involvement of ion channels. L-NAME, guanabenz, 5HT4 receptor blocker, ML9, and Y27632 enhanced the effect of amitriptyline. Meanwhile, methylene blue, atropine, guanethidine, prazosin, methylsergide, ondansetron, U73122, and chelerythrine blocked its effect. It was also shown that nifedipine enhanced but TEA and glybenclamide blocked amitriptyline-induced inhibitory effect on EFS. Our results indicated that amitriptyline may exert inhibitory effect in response to EFS by inhibiting muscarinic receptors and then PLC mediated PKC pathway leading to opening of ATP-sensitive potassium channel. PMID- 27234927 TI - Epidermotropic metastasis of primary lung adenocarcinoma. AB - Cutaneous metastasis of lung cancer is a rare event and usually portends a grim prognosis. Several cases of lung cancer with cutaneous metastasis have been reported, but these have been largely limited to the dermis. Here we describe a unique case of cutaneous metastatic lung adenocarcinoma largely limited to the epidermis, mimicking Paget's disease or a cutaneous adnexal tumor. PMID- 27234928 TI - Impact of surgeon laparoscopic training and case volume of laparoscopic surgery on conversion during elective laparoscopic colorectal surgery. AB - AIM: The study aimed to determine whether laparoscopic volume and type of training influence conversion during elective laparoscopic colorectal surgery. METHOD: An Institutional Review Board-approved prospective database was reviewed for patients who underwent colorectal resection, performed by six colorectal surgeons, for all diagnoses from 2009 to 2014. Surgeons were designated as laparoscopic- or open-trained based on formal laparoscopic colorectal surgery training, and were classified as low laparoscopic volume (LLV) (i.e. had performed < 100 laparoscopic procedures) or high laparoscopic volume (HLV) (i.e. had performed >= 100 laparoscopic procedures). Technique was laparoscopic, open or converted (pre-emptive or reactive). Conversion was compared among three groups: LLV, laparoscopic trained (group A); LLV, open trained (group B); and HLV, open trained (group C). RESULTS: In total, 159/567 procedures were open and 408 laparoscopic procedures were attempted. Of the 408 laparoscopic procedures, 73 were converted. Among the 567 patients [mean age: 56 +/- 17 years (44% male)], the overall conversion rate was 13% (73/567), including 75% pre-emptive and 25% reactive. Conversion rates for groups A, B and C were 17.9%, 42.6% and 14.3%, respectively. Significantly higher conversion was seen in group B compared with group C (P = 0.01), but not between group A and group C (P = 0.85) or between group B and group A (P = 0.11). Converted patients were older (P < 0.001), with lower rates of proctectomy (P = 0.007), higher rates of anastomosis (P < 0.001) and higher body mass index (BMI) (P < 0.001). After adjusting for patient and surgeon factors, training type was not associated with conversion (P = 0.15). Compared with successful laparoscopy, converted patients had a significantly higher incidence of ileus (P < 0.001), length of stay (P = 0.002), time to flatus (OR = 3.21, P < 0.001) and time to solids (P < 0.001). Converted patients experienced increased morbidity. CONCLUSION: Training is not associated with conversion. Rather, HLV surgeons, regardless of training, convert less frequently than do LLV surgeons. PMID- 27234929 TI - Intraocular Pressure Reduction after Phacoemulsification versus Manual Small Incision Cataract Surgery: A Randomized Controlled Trial. AB - PURPOSE: To compare reduction in intraocular pressure (IOP) and change in anterior chamber angle configuration between eyes undergoing phacoemulsification versus those undergoing manual small-incision cataract surgery (MSICS). DESIGN: Prospective, randomized, double-masked, parallel assignment clinical trial. PARTICIPANTS: Five hundred eyes of 500 participants 40 to 70 years of age with normal IOP, gonioscopically open angles, and age-related cataract. METHODS: Eyes underwent phacoemulsification or MSICS after a 1:1 randomization and allocation code. Best-corrected vision, IOP, comprehensive slit-lamp evaluation, and anterior segment (AS) optical coherence tomography (OCT) were performed at baseline and at 1, 3, and 6 months follow-up. MAIN OUTCOME MEASURES: Change in IOP (DeltaIOP) and AS OCT parameters between baseline and 6 months after surgery. RESULTS: Six months, similar IOP reduction was observed in eyes undergoing phacoemulsification (DeltaIOP = 2.7+/-2.9 mmHg) and MSICS (DeltaIOP = 2.6+/-2.6 mmHg; P = 0.70). Widening of the angle opening distance (AOD) 500 MUm from the scleral spur (median DeltaAOD500 = 103 MUm; interquartile range = 39-179 MUm) was also similar in both groups (P = 0.28). Multivariate linear regression analysis showed that eyes with higher baseline IOP experienced significantly greater reduction in IOP at 6 months (DeltaIOP = 0.46-mmHg reduction for every 1-mmHg increment in baseline IOP; 95% confidence interval [CI], 0.4-0.5 mmHg; P < 0.001). After adjusting for covariates, the magnitude of widening of AOD500 was not associated significantly with reduction in IOP (1.33-mmHg reduction for every 1-mm increment in AOD500; P = 0.07). Baseline AOD500 (beta = -0.60-mm change/1-mm increment of baseline AOD; 95% CI, -0.67 to -0.53 mm) and anterior chamber depth (beta = 0.07-mm change/1-mm increment of baseline anterior chamber depth; 95% CI, 0.04-0.1 mm) were significant predictors of AOD500 widening at 6 months. CONCLUSIONS: Both phacoemulsification and MSICS led to significant and similar IOP reductions 6 months after surgery, and both surgeries produced similar changes in anterior chamber and angle parameters. Higher baseline IOP was associated with greater IOP reduction; IOP reduction also can be attributed partly to changes in angle and anterior chamber configuration, although these parameters were unable to predict significantly predict IOP drop at 6 months. PMID- 27234930 TI - The Impact of Systemic Factors on Clinical Response to Ranibizumab for Diabetic Macular Edema. AB - PURPOSE: To evaluate the effect of systemic factors on best-corrected visual acuity (BCVA) achieved with ranibizumab (Lucentis; Genentech, Inc, South San Francisco, CA) for treatment of diabetic macular edema (DME) in the RIDE and RISE phase 3 studies. DESIGN: Exploratory, post hoc analysis of 2 randomized, double masked, sham-injection controlled studies. PARTICIPANTS: Adults with DME, BCVA of 20/40 to 20/320 Snellen equivalent, and central foveal thickness of 275 MUm or more. METHODS: Analysis of RIDE (clinicaltrials.gov identifier, NCT00473382) and RISE (clinicaltrials.gov identifier, NCT00473330) pooled ranibizumab data through month 24. Change in BCVA was assessed for association with the following covariates: age, body mass index (BMI), blood pressure, serum glucose, glycosylated hemoglobin (HbA1c), blood urea nitrogen, serum creatinine, estimated glomerular filtration rate, and blood chemistry variables. Change in BCVA at month 24 was assessed according to the following categories of diabetes medication use history: insulin only (n = 193), insulin plus other medications (n = 221), or other noninsulin medications (n = 331). MAIN OUTCOME MEASURES: Change in BCVA from baseline assessed by randomized treatment group in pooled 0.3- and 0.5-mg monthly ranibizumab groups. RESULTS: In patients with DME, vision improvement with ranibizumab was not influenced by systemic factors such as diabetes medication history, serum glucose, HbA1c, renal function, BMI, and blood pressure. Patients taking insulin with or without other medications at baseline had longer diabetes disease duration (mean, 17.4 and 20.9 years, respectively) compared with those taking other noninsulin medications (mean, 11.9 years). At month 24, among ranibizumab-treated patients, the mean BCVA change from baseline (Early Treatment Diabetic Retinopathy Study letters +/- standard deviation) was not different between patients taking only insulin (12.6+/-11.2 letters), insulin plus other medications (12.2+/-12.4 letters), or other noninsulin medications (14.0+/-13.7 letters). Mean BCVA change also was comparable among patients taking thiazolidinediones (12.9+/-9.7 letters) and those not taking thiazolidinediones (13.2+/-13.3 letters). CONCLUSIONS: There were no associations between systemic factors (baseline values or change from baseline) and mean change of BCVA at month 24. These results suggest that visual response to ranibizumab therapy in DME was not influenced by nonocular factors related to systemic management of diabetes in the RIDE and RISE studies. PMID- 27234931 TI - The learning environment in professional doctorate and postgraduate dental education: a qualitative study. AB - INTRODUCTION: Currently, there is a lack of studies focusing on professional doctoral students' and graduates' perceptions of their learning environment, in particular, using a qualitative approach to elicit in-depth information. This article aims to contribute to the existing body of knowledge by systematically exploring, critically analysing and getting a deeper understanding of professional doctorate dental students' and graduates' insights into effective and ineffective clinical and physical learning environment characteristics. METHODS: The study included a total of 20 participants. Participants included 16 final-year Doctor of Clinical Dentistry (DClinDent) students and four dental specialists (graduates of the DClinDent programme). Semi-structured, individual interviews were used. Participants were asked to reflect upon and describe in detail their effective and ineffective learning environment experiences. The critical incident technique was used to guide the data collection. Data were analysed using a general inductive qualitative approach. RESULTS: Learning environment characteristics which participants associated with effective learning included the following: sufficient opportunities for comprehensive treatment planning; introduction to a number of patient treatment philosophies; a sufficient number of complex cases; clinically oriented research and assignment topics; a focus on clinical training in the programme generally; a research topic of a realistic depth and breadth, suitable for their 'specialist training' degree; and a well-resourced and updated physical infrastructure. On the other hand, most participants indicated that the absence of an adequate number of clinical cases, an overemphasis on research (as opposed to clinical practice) in the DClinDent programme and an 'outdated' physical infrastructure in the dental school clinics could hamper effective clinical learning. CONCLUSION: These findings contribute to the meaningful advancement of the literature on learning environment strategies through the exploration of (and in-depth qualitative insights into) what facilitated effective learning by New Zealand professional doctorate candidates and graduates. These findings provide a starting point for reflection by international academic directors, educational developers, curriculum planners, programme managers and clinical teachers in respect of the further development of the learning environment. Although the findings from this study may not be directly transferable to all international contexts, they have the potential to contribute to the further development of theory in this area. PMID- 27234932 TI - The TIDieR (Template for Intervention, descriptor and replication) checklist will benefit the physiotherapy profession. PMID- 27234933 TI - New high-cloning-efficiency vectors for complementation studies and recombinant protein overproduction in Escherichia coli and Salmonella enterica. AB - Galloway et al. recently described a method to alter vectors to include Type IIS restriction enzymes for high efficiency cloning. Utilizing this method, the multiple cloning sites of complementation and overexpression vectors commonly used in our laboratory were altered to contain recognition sequences of the Type IIS restriction enzyme, BspQI. Use of this enzyme increased the rate of cloning success to >97% efficiency. L(+)-Arabinose-inducible complementation vectors and overexpression vectors encoding N-terminal recombinant tobacco etch virus protease (rTEV)-cleavable H6-tags were altered to contain BspQI sites that allowed for cloning into all vectors using identical primer overhangs. Additionally, a vector used for directing the synthesis of proteins with a C terminal, rTEV-cleavable H6-tag was engineered to contain BspQI sites, albeit with different overhangs from that of the previously mentioned vectors. Here we apply a method used to engineer cloning vectors to contain BspQI sites and the use of each vector in either in vivo complementation studies or in vitro protein purifications. PMID- 27234934 TI - Development of a national EUCAST challenge panel for antimicrobial susceptibility testing. AB - A challenge panel of bacterial strains useful for clinical laboratories to validate their European Committee on Antimicrobial Susceptibility Testing (EUCAST) antimicrobial susceptibility test (AST) system was established. A total of 117 strains, obtained from Belgian Reference Centres (n = 57) and from routine clinical samples (n = 60) was selected based on resistance pattern. These strains were analysed in seven different laboratories by three different automated AST systems (Vitek (n = 2), Phoenix (n = 2) and Microscan (n = 2)) and by disc diffusion from five different manufacturers (Rosco (n = 2), Becton-Dickinson (n = 2), Biomerieux (n = 1), Bio-rad (n = 1) and i2a (n = 1)). To select the challenge panel, selection criteria were set for categorical agreement between the different systems and the number of very major errors, major errors and minor errors. Very major and major errors for at least two antibiotics were observed in 43% of all strains, leading to the exclusion of these strains from the selected panel. In only 10% of all tested strains was there 100% categorical agreement for all antibiotics. Finally, 28 strains (14 Gram-positive and 14 Gram-negative) covering a wide spectrum of resistance mechanisms were selected. Pilot-testing of this challenge panel in 20 laboratories mainly confirmed the results of the validation study. Only six strains withheld for the pilot study could not be used as challenge strain due to an overall (very) major error rate of >5% for a particular antibiotic (n = 5) or for two antibiotics (n = 1). To conclude, this challenge panel should facilitate the implementation and use of EUCAST breakpoints in laboratories. PMID- 27234935 TI - Low vitamin K1 intake in haemodialysis patients. AB - BACKGROUND & AIMS: Vitamin K acts as a coenzyme in the gamma-carboxylation of vitamin K-dependent proteins, including coagulation factors, osteocalcin, matrix Gla protein (MGP), and the growth arrest-specific 6 (GAS6) protein. Osteocalcin is a key factor for bone matrix formation. MGP is a local inhibitor of soft tissue calcification. GAS6 activity prevents the apoptosis of vascular smooth muscle cells. Few data on vitamin K intake in chronic kidney disease patients and no data in patients on a Mediterranean diet are available. In the present study, we evaluate the dietary intake of vitamin K1 in a cohort of patients undergoing haemodialysis. METHODS: In this multi-centre controlled observational study, data were collected from 91 patients aged >18 years on dialysis treatment for at least 12 months and from 85 age-matched control subjects with normal renal function. Participants completed a food journal of seven consecutive days for the estimation of dietary intakes of macro- and micro-nutrients (minerals and vitamins). RESULTS: Compared to controls, dialysis patients had a significant lower total energy intake, along with a lower dietary intake of proteins, fats, carbohydrates, fibres, and of all the examined minerals (Ca, P, Fe, Na, K, Zn, Cu, and Mg). With the exception of vitamin B12, vitamins intake followed a similar pattern, with a lower intake in vitamin A, B1, B2, C, D, E, folates, K1 and PP. These finding were confirmed also when normalized for total energy intake or for body weight. In respect to the adequate intakes recommended in the literature, the prevalence of a deficient vitamin K intake was very high (70-90%) and roughly double than in controls. Multivariate logistic model identified vitamin A and iron intake as predictors of vitamin K deficiency. CONCLUSIONS: Haemodialysis patients had a significantly low intake in vitamin K1, which could contribute to increase the risk of bone fractures and vascular calcifications. Since the deficiency of vitamin K intake seems to be remarkable, dietary counselling to HD patients should also address the adequacy of vitamin K dietary intake and bioavailability. Whether diets with higher amounts of vitamin K1 or vitamin K supplementation can improve clinical outcomes in dialysis patients remains to be demonstrated. PMID- 27234936 TI - Assessing the association of obesity and asthma morbidity in older adults. AB - BACKGROUND: Obesity is a robust predictor of poor asthma control in younger adults. Given the high prevalence of asthma and obesity in older Americans, weight reduction could benefit asthma management in this population. OBJECTIVE: To assess the association between obesity and asthma outcomes among older adults. METHODS: We recruited from urban primary care clinics a prospective cohort of nonsmoking individuals with asthma who were 60 years or older without a history of other respiratory diseases. At baseline, body mass index (BMI) measurements were classified as normal (BMI, 18-25), overweight (BMI, 25-30), or obese (BMI, >30). Measures of asthma morbidity (Asthma Control Questionnaire [ACQ], and Mini Asthma Quality of Life Questionnaire [Mini-AQLQ]) and asthma-related resource utilization (inpatient or outpatient) were taken at baseline and at 3- and 12 month interviews. We used generalized estimating equation models to assess associations between obesity and asthma outcomes after controlling for potential confounders. RESULTS: Of the 437 older adults with asthma in the study, 17% had a normal BMI, 32% were overweight, and 51% were obese. Unadjusted analyses revealed that obesity was associated with lower ACQ scores (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.09-1.31) and poorer Mini-AQLQ scores (OR, 1.21; 95% CI, 1.11-1.33). Adjusted analyses revealed no significant association between obesity and ACQ (OR, 1.05; 95% CI, 0.96-1.15) and Mini-AQLQ (OR, 1.08; 95% CI, 0.99-1.19). CONCLUSION: Our study suggests that obesity is not independently associated with worse asthma outcomes in older adults, reflecting potential differences in the mechanisms that link obesity with asthma control in older vs younger populations. PMID- 27234938 TI - Joseph A. Bellanti, MD, FAAP, FACAAI, FAAAAI. PMID- 27234937 TI - An unusual case of immediate hypersensitivity reaction to a common medication. PMID- 27234939 TI - Effect of sitting vs standing posture on spirometry in children. PMID- 27234940 TI - Coexisting atopic conditions influence the likelihood of allergic bronchopulmonary aspergillosis in asthma. AB - BACKGROUND: The diagnosis of allergic bronchopulmonary aspergillosis (ABPA) in asthma is often made in patients with total serum IgE levels greater than 1,000 IU/mL in conjunction with evidence of Aspergillus sensitization. The specificity of total serum IgE for the diagnosis of ABPA is low even when combined with serum Aspergillus specific IgE. OBJECTIVE: To determine the prevalence of ABPA and to identify alternative clinical predictors for ABPA among asthmatic patients with a total serum IgE level greater than 1,000 IU/ml. METHODS: This study was conducted in a tertiary hospital in Melbourne, Australia, with a large asthma and allergy service. Patients with asthma and total serum IgE levels greater than 1,000 IU/ml from January 1, 2005, through December 31, 2014, were included. Patients were considered to have concomitant allergic conditions if they had atopic eczema, allergic rhinitis, or both. The diagnosis of ABPA was based on the managing physician's documented diagnosis and referenced to criteria proposed by the International Society for Human and Fungal Mycology. RESULTS: The prevalence of ABPA in our cohort was 15.8%. Older age, elevated total serum IgE level, reduced lung function, and the absence of other concomitant allergic conditions increased the risk of ABPA. After multivariate logistic regression, patients without concomitant allergic conditions had an odds ratio of 4.4 (95% confidence interval, 1.9-10.1; P = .001) for ABPA when compared with patients with allergic conditions. CONCLUSION: The absence of atopic eczema and allergic rhinitis in these patients increases the likelihood of ABPA. Eliciting an accurate allergy history may be a useful bedside clinical tool when considering the diagnosis of ABPA. PMID- 27234942 TI - Gregory Anthony Hugh Cookson. PMID- 27234941 TI - Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) expression and possible function in mouse tooth germ development. AB - Abnormal expression of Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) is involved in the pathogenesis of FSHD. FRG1 is also important for the normal muscular and vascular development. Our previous study showed that FRG1 is one of the highly expressed genes in the mandible on embryonic day 10.5 (E10.5) than on E12.0. In this study, we investigated the temporospatial expression pattern of FRG1 mRNA and protein during the development of the mouse lower first molar, and also evaluated the subcellular localization of the FRG1 protein in mouse dental epithelial (mDE6) cells. The FRG1 expression was identified in the dental epithelial and mesenchymal cells at the initiation and bud stages. It was detected in the inner enamel epithelium at the cap and early bell stages. At the late bell and root formation stages, these signals were detected in ameloblasts and odontoblasts during the formation of enamel and dentin matrices, respectively. The FRG1 protein was localized in the cytoplasm in the mouse tooth germ in vivo, while FRG1 was detected predominantly in the nucleus and faintly in the cytoplasm in mDE6 cells in vitro. In mDE6 cells treated with bone morphogenetic protein 4 (BMP4), the protein expression of FRG1 increased in cytoplasm, suggesting that FRG1 may translocate to the cytoplasm. These findings suggest that FRG1 is involved in the morphogenesis of the tooth germ, as well as in the formation of enamel and dentin matrices and that FRG1 may play a role in the odontogenesis in the mouse following BMP4 stimulation. PMID- 27234943 TI - Early Treatment in HCV: Is it a Cost-Utility Option from the Italian Perspective? AB - BACKGROUND AND OBJECTIVE: In Italy, the Italian Pharmaceutical Agency (AIFA) criteria used F3-F4 fibrosis stages as the threshold to prioritise the treatment with interferon (IFN)-free regimens, while in genotype 1 chronic hepatitis C (G1 CHC) patients with fibrosis of liver stage 2, an approach with pegylated interferon (PEG-IFN)-based triple therapy with simeprevir was suggested. The key clinical question is whether, in an era of financial constraints, the application of a universal IFN-free strategy in naive G1 CHC patients is feasible within a short time horizon. The aim of this study is to perform an economic analysis to estimate the cost-utility of the early innovative therapy in Italy for managing hepatitis C virus (HCV)-infected patients. METHODS: The incremental cost-utility analysis was carried out to quantify the benefits of the early treatment approach in HCV subjects. A Markov simulation model including direct and indirect costs and health outcomes was developed from an Italian National Healthcare Service and societal perspective. A total of 5000 Monte Carlo simulations were performed on two distinct scenarios: standard of care (SoC) which includes 14,000 genotype 1 patients in Italy treated with innovative interferon-free regimens in the fibrosis of liver stages 3 and 4 (F3-F4) versus early-treatment scenario (ETS) where 2000 patients were additionally treated with simeprevir plus PEG-IFN and ribavirin in the fibrosis stage 2 (F2) (based on Italian Medicines Agency AIFA reimbursement criteria). A systematic literature review was carried out to identify epidemiological and economic data, which were subsequently used to inform the model. Furthermore, a one-way probabilistic sensitivity was performed to measure the relationship between the main parameters of the model and the cost utility results. RESULTS: The model shows that, in terms of incremental cost effectiveness ratio (ICER) per quality adjusted life year (QALY) gained, ETS appeared to be the most cost-utility option compared with both perspective societal (ICER = EUR11,396) and NHS (ICER = EUR14,733) over a time period of 10 years. The cost-utility of ETS is more sustainable as it extends the time period analysis [ICER = EUR 6778 per QALY to 20 years and EUR4474 per QALY to 30 years]. From the societal perspective, the ETS represents the dominant option at a time horizon of 30 years. If we consider the sub-group population of treated patients [16,000 patients of which 2000 not treated in the SoC, the ETS scenario was dominant after only 5 years and the cost-utility at 2 years of simulation. The one-way sensitivity analysis on the main variables confirmed the robustness of the model for the early-treatment approach. CONCLUSION: Our model represents a tool for policy makers and health-care professionals, and provided information on the cost-utility of the early-treatment approach in HCV-infected patients in Italy. Starting innovative treatment regimens earlier keeps HCV-infected patients in better health and reduces the incidence of HCV-related events; generating a gain both in terms of health of the patients and correct resource allocation. PMID- 27234945 TI - Reuma.pt - case study. PMID- 27234944 TI - Vascular catheter colonization: surveillance based on culture of needleless connectors. AB - BACKGROUND: Superficial culture has a high negative predictive value in the assessment of catheter tip colonization (CC) and catheter-related bloodstream infection (C-RBSI). However, the process of hub culture requires the hubs to be swabbed, and this carries a risk of dislodging the biofilm. At present, most catheter hubs are closed by needleless connectors (NCs) that are periodically replaced. Our objective was to compare the yield of SC (skin + hub culture) with that of skin + NC culture in the assessment of CC and C-RBSI. METHODS: During 5 months, we included the patients on the Major Heart Surgery ICU when a central venous catheter (CVC) remained in place >=7 days after insertion. SCs were taken simultaneously when the NC was withdrawn and processed by the semi-quantitative method, even when the catheter was not removed. All catheter tips were cultured. All NCs belonging to a single catheter lumen were individually flushed with 100 MUl of brain-heart infusion (BHI) broth. We considered the lumen to be colonized when >=1 NC culture from the lumen flush was positive. We collected a total of 60 catheters. RESULTS: The overall CC rate was 15.0 %, and we confirmed two episodes of C-RBSI. The validity values after the comparison of SCs with skin + NC culture for prediction of CC were the following: sensitivity 66.7 % vs. 77.8 %, and negative predictive value 93.6 % vs. 93.1 %. The sensitivity and negative predictive value for prediction of C-RBSI was 100 % for both SC and skin + NC culture. CONCLUSION: The combination of skin and flushed NC culture can be an alternative to conventional SC for ruling out CC and C-RBSI. PMID- 27234946 TI - [Is it Fabry Disease? Diagnostic and Follow-Up Approach]. PMID- 27234947 TI - Impact of Compliance with a Sepsis Resuscitation Bundle in a Portuguese Emergency Department. AB - INTRODUCTION: Severe sepsis and septic shock are common conditions with high levels of morbi-mortality surpassing those of coronary heart disease or stroke. The reality of hospital treated sepsis is largely unknown outside of the intensive care unit. We therefore aimed to evaluate the level of compliance with the Surviving Sepsis Campaign 6-hour bundle in a Portuguese emergency department and to relate it to the patient clinical outcomes. MATERIAL AND METHODS: We conducted a retrospective, observational cohort study with 178 severe sepsis/septic shock patients admitted to the intensive and intermediate care unit between January 1st 2012 and December 31st 2012. RESULTS: In the study, period septic shock was diagnosed in 100 patients (56.2%) and severe sepsis in 78 patients (43.8%). Compliance with the sepsis bundle was: (1) 62.9% for lactate measurement; (2) 62.9% for blood cultures before antibiotics; (3) 41.6% for antibiotics in the first 3 hours; (4) 76.4% for fluid administration; (5) 25% for vasopressor administration; (6) 37% for central venous pressure measurement and (7) 39% for central venous oxygen saturation measurement. Full compliance was observed in 22% of the patients. The individual bundle measure - Blood cultures before antibiotics - was significantly associated with a decreased risk of both intensive care unit mortality and 28-day mortality. There was also a trend for an inverse correlation between increased compliance with the full bundle and the intensive care unit and 28-days hospital mortality. DISCUSSION: There was a low compliance with the Surviving Sepsis Campaign 6-hour bundle, a result that replicates the findings in similar international studies. The explanation is complex but it may include the lack of institutional quality monitoring in the emergency department. CONCLUSIONS: The compliance with a sepsis resuscitation bundle starting in the emergency department was positively associated with the outcomes of the septic patients. Nonetheless the bundle was unreliably performed. PMID- 27234948 TI - Relation between QT Variables and Left Ventricular Geometry in Athletes and Obese Children. AB - INTRODUCTION: We aimed to evaluate the relation between QT variables and left ventricular geometry in athletes and obese children. MATERIAL AND METHODS: This study included 209 children and adolescents. Thirty-eight of them were obese, 140 were athletes and 31 were normal weighted. Children with history of functional and structural cardiovascular diseases (acquired and congenital), chronic systemic diseases, hypertension, sleep apnea, endocrinological disorders were excluded. All subjects underwent detailed electrocardiographic and echocardiographic examination. RESULTS: QT dispersion was significantly higher in obese children, basketball players, football players and swimmers compared to control group (p < 0.05, p < 0.001, < 0.001 and < 0.01 respectively). Basketball players had the highest QT dispersion. Left ventricular endsystolic diameter (mm/m2) was higher in footballers, swimmers, wrestlers and tennis players compared to obese subjects. Interventricular septal thickness at diastole was highest in swimmers compared to control group (p < 0.001) and left ventricular posterior wall thickness was significantly higher in footballers and swimmers compared to healthy subjects (p < 0.01 and p < 0.001 respectively). Left ventricular geometry was normal in 84 patients (47.1%), but 34 patients (19.1%) had concentric remodelling, 20 (22.4%) had concentric hypertrophy and 40 (28.6%) had eccentric hypertrophy. No concentric and eccentric hypertrophy was observed in obese subjects. Left ventricle hypertrophy was prominent in dynamic and combined groups but it was not statistically significant (p = 0.204). QT dispersion was statistically higher in obese, dynamic sports and combined sports compared to control group (p < 0.05, p < 0.001 and p < 0.001 respectively). DISCUSSION: In this study we determined that QT dispersion is elevated in dynamic and combined sports types and obese children. CONCLUSION: QT dispersion is prolonged in obese and athletes who participate dynamic and combined sports. PMID- 27234949 TI - [Anogenital Warts in a Major Venereology Clinic: Centro de Saude da Lapa - Lisbon, 2008 to 2014]. AB - INTRODUCTION: Human papillomavirus infection is the most common sexual transmitted infection in the world, being associated with different diseases, namely anogenital warts, recurrent respiratory papillomatosis and anal, cervical, and oropharyngeal cancers. Among sexually active people, approximately 1% has anogenital warts, 90% of cases resulting from genotypes 6 and 11. MATERIAL AND METHODS: Patients diagnosed with first episode of anogenital warts from 2008 to 2014 in Lisbon's major venereology clinic were identified, and characterized according to sex, sexual orientation, age, warts location, and number of sexual partners. RESULTS: We observed a statistically significant decrease in first anogenital warts diagnosis among < 19 year old females (r = -0.848;p = 0.016) and a non-statistically significant decrease among < 19 ' year-old males and among 20 ' 24 year old females. DISCUSSION: In October 2008, the quadrivalent vaccine (genotypes 6, 11, 16, 18) was introduced in the Portuguese national vaccination program, targeting 13-year-old females, with a catch-up for 17 year old females. In the women''s group, decrease in first anogenital warts diagnosis is probably related to human papillomavirus vaccination before onset of sexual activity. CONCLUSION: This study reinforces the importance of national human papillomavirus vaccination program. PMID- 27234950 TI - Post-Surgical Quality of Life, Psychological State and what Patients Think about the Effectiveness of Heller Myotomy in the Treatment of Achalasia. AB - INTRODUCTION: The disruption of esophageal motility that characterizes achalasia typically provokes dysphagia, pain, loss of weight and malnutrition. Therefore, patients frequently report a reduction in quality of life and negative emotional states. Laparoscopic Heller myotomy proved to be an effective therapy, enabling the resumption of good quality of life. MATERIAL AND METHODS: The authors studied 45 patients previously submitted to laparoscopic Heller myotomy. Postoperative evaluation was performed using a customized version of the achalasia disease specific quality of life questionnaire. Quality of life and the presence of depressive and anxiety symptoms were assessed using the Portuguese versions of the Medical Outcomes Study SF-36 and the Hospital Anxiety and Depression Scale. RESULTS: Thirty-one patients responded to the survey. Dysphagia was the main clinical symptom before surgery. A clear improvement in dysphagia, regurgitation, pain and weight loss was found after surgery (p < 0.001). The Mental Health domain of SF-36 presented a Pearson correlation coefficient of -0.689 with HADS-D and of -0.557 with HADS-A (p < 0.001 and p = 0.002, respectively). CONCLUSION: This study demonstrates that the Heller myotomy is associated with a good quality of life in patients with achalasia and strengthens the evidence that this is a safe and reliable procedure. PMID- 27234951 TI - [Development and Validation of the National Functionality Table for Chronic Diseases]. AB - INTRODUCTION: Systematic evaluation and registration of adults functionality with chronic diseases is relevant, because it allows: 'flattening' health, social and employment policies, according to the person's functionality with chronic diseases, providing health and social professionals with a data collection, which complements disease records, and finally, measuring functionality gains. The objective of the study was to develop a National Functionality Table for active age adults with chronic disease, according to the International Classification of Functioning, Disability and Health of the World Health Organization. MATERIAL AND METHODS: Quantitative and qualitative methods were used; literature review (17 articles), focal group (nine experts), Delphi panel (16 experts) and exploratory study (309 persons with chronic diseases). RESULTS: The literature review identified 67 limited activities in the study population, from which 40 activities were selected by the focal group and 38 activities were validated by the Delphi panel. DISCUSSION: In order to test the psychometric properties we have compared the average value of all possible coefficients of internal consistency type (split-half). When analyzing the discrimination of functional levels in different samples, equality of variances was verified, using the Levene test as well as the 't' test. According to the observation and analysis of alpha Cronbach coefficient we have found that the National Functionality Table shows good reliability levels. From the main component analysis, five dimensions were identified. CONCLUSION: the National Functionality Table has appropriate psychometric characteristics in respect to its consistency, reliability and internal validity. PMID- 27234952 TI - Parcial Nephrectomies - results of 12 years from an Oncology Institution. AB - INTRODUCTION: The diagnosis of renal cell carcinoma has been increasing in recent years, especially due to incidental cases, and thus indication for nephron preserving surgery has also risen. OBJECTIVES: To review a series of partial nephrectomies from an oncology institution namely technique features, survival and change in renal function. MATERIAL AND METHODS: A retrospective analysis of all patients with renal tumors that were submitted to partial nephrectomy at our institution between January 2000 and December 2012. RESULTS: A total 156 partial nephrectomies were performed, 85 in men and 71 in women, with mean overall age of 62 '+/- 15 years. Surgical approach was transperitoneal laparoscopic in 23 cases with the remainder 133 through lumbotomy. Mean ischemic time was < 25 min in all patients and complication rate was 10.9 %, mostly corresponding grade 2 and 3 of the Clavien-Dindo scale. Mean tumor size was 2.9 '+/- 1.4 cm and the surgical margin was focally affected by tumor in 9.6% of cases. Histologically, 26.2% of cases corresponded to clear cell renal cell carcinoma, with oncocytomas being the most common benign neoplasm with 14.7% of the total. There were 4 cases of recurrence and one case death at follow-up. The mean change in estimated glomerular filtration rate was -5.3 mL/min per 1.73 m2 (p < 0.001). There was no association between warm ischemia time, body mass index, age, ASA score, presence of complications with this decrease in glomerular filtration rate. DISCUSSION: Our positive surgical margins cases were slightly above what is described in literature, however we didn't find any predictive factor for such finding and ultimately there was no evidence of tumor recurrence or influence in survival in all these cases. Even though there was a significant decrease in estimated glomerular filtration rate, warm ischemia time was very low and only five patients presented with de novo eGFR < 60 mL/min per 1.73 m2, and two patients started hemodialysis. A high volume center seems to be critical for technique optimization and complication management. CONCLUSION: Our series of partial nephrectomies presents oncological results and preservation of renal function similar to those published in literature. This is a safe technique with good results, justifying its growth. PMID- 27234953 TI - Recent surgical advances in Peyronie's Disease. AB - INTRODUCTION: Peyronie's disease, a fibrotic disorder of the tunica albuginea of the penis, has been associated with penile shortening and some degree of erectile dysfunction. It affects patient's quality of life, leading to severe psychological, mental, and physical stress. Penile deformation hampers sexual life leading to depression, lack of sexual confidence, loss of sexual function and performance anxiety. Peyronie's disease etiology is yet to be known. MATERIAL AND METHODS: Literature search was conducted in Medline, Embase, and Cochrane databases in January 2015 in order to identify papers related to Peyronie's disease, concerning evolving surgical management, technique, outcomes as well as ancillary treatments. Publications not concerning humans were not considered. We identified original articles, review articles, and editorials addressing the subject. All articles published in the English language were selected for screening. The eligibility criteria for inclusion were based on relevance concerning the subject. RESULTS: The variety of penile deformities associated with Peyronie's disease still doesn't have an effective and reliable non-surgical therapy. We summarize the updated surgical techniques and management algorithm described for Peyronie's disease. DISCUSSION: Surgical management shares similar goals: correcting the curvature, preserving erectile function and penile length, and minimizing morbidity. CONCLUSION: To date there is no high level of evidence based data to determine the best surgical treatment of Peyronie's disease. After proper diagnosis, surgical reconstruction should be based on giving a functional penis, that is, rectifying the penis with rigidity enough to enable sexual intercourse. PMID- 27234954 TI - Advanced Stage Hepatocellular Carcinoma with Multiple Metastasis and Vascular Thrombosis: A Case of Complete Response to Sorafenib. AB - Sorafenib is a multi-targeted tyrosine kinase inhibitor, with antiangiogenic and antiproliferative properties, approved for the treatment of advanced hepatocellular carcinoma. It induces a significant increase in the median overall survival, despite a complete response to treatment being rare. We report a clinical case of a 60-year-old male with hepatic cirrhosis, Child-Pugh class A and performance status 0, and advanced hepatocellular carcinoma. The primary tumor measured 17 x 8 cm and had diffuse intrahepatic metastization, extensive lung and left adrenal invasion, as well as thrombosis of inferior vena cava, with projection to the right atrium. This patient showed a rapid and complete response to sorafenib, evaluated by mRECIST (modified Response Evaluation Criteria in Solid Tumors), that remains after three years of treatment. PMID- 27234955 TI - [Encephalomeningocele: Inside the Picture]. PMID- 27234956 TI - [Portuguese Consensus on the Diagnosis, Prevention and Treatment of Anaemia in Inflammatory Bowel Disease]. AB - INTRODUCTION: Anaemia can be considered the most common extra-intestinal manifestation in inflammatory bowel disease. Nevertheless, anaemia is often under diagnosed and under-treated both in adults and children with inflammatory bowel disease. Herein, we report the consensus statements on the management of anaemia in inflammatory bowel disease developed by the Portuguese Working Group on Inflammatory Bowel Disease (known as Grupo de Estudo da Doenca Inflamatoria Intestinal - GEDII) to aid clinicians in daily management of inflammatory bowel disease patients. MATERIAL AND METHODS: A comprehensive literature review was conducted in order to prepare consensus statements on the following topics: (1) prevalence and diagnosis of anaemia in inflammatory bowel disease, (2) iron supplementation for the prevention of anaemia in inflammatory bowel disease and (3) treatment of anaemia in inflammatory bowel disease. The final statements for each topic were discussed at a consensus meeting and rated according to the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence. CONSENSUS: It was concluded that anaemia has a high incidence and prevalence in inflammatory bowel disease, particularly in those with active disease and hospitalised. Patients with anaemia had decreased quality of life and frequently complained of fatigue. Absolute indications for intravenous therapy should be considered: (1) moderate to severe anaemia (haemoglobin < 10.5 g/dL) or clearly symptomatic anaemia; (2) previous intolerance to oral iron supplements; (3) inappropriate response to oral iron; (4) active severe intestinal disease; (5) need for a quick therapeutic response (e.g. surgery in the short term); (6) concomitant therapy with erythropoiesis-stimulating agent; and (7) patient's preference. PMID- 27234957 TI - Association of Ward Acquired, On-admission, Progressive and Non-progressive AKI with Death among Dengue Patients: A Hidden Relationship. PMID- 27234958 TI - Selective adsorption of protein by a high-efficiency Cu(2+) -cooperated magnetic imprinted nanomaterial. AB - We report a core-shell magnetic molecularly imprinted polymer with high affinity through a facile sol-gel method for the selective adsorption of bovine hemoglobin from real bovine blood. Copper ions grafted on the surface of the matrix could immobilize template protein through chelation, which greatly enhances the orderliness of imprinted cavities and affinity of polymers. The obtained products exhibit a desired level of magnetic susceptibility, resulting in the highly efficient adsorption process. The results of adsorption experiments show that the saturation adsorption capacity of imprinted products could reach 116.3 mg/g within 30 min. Meanwhile, the specific binding experiment demonstrates the high selectivity of polymers for bovine hemoglobin. Furthermore, satisfactory reusability is demonstrated by ten adsorption-desorption cycles with no obvious deterioration in binding capacity. Electrophoretic analysis suggests the polymer could be used successfully in separation and enrichment of bovine hemoglobin from the bovine blood sample, which exhibits potential application in pretreatment of proteomics. PMID- 27234959 TI - Transcatheter Arterial Embolization for Life-Long Urinary Incontinence Associated with Bilateral Ureteral Duplication with Ectopia. PMID- 27234960 TI - Erratum to "PI3K-Akt signaling pathway upregulates hepatitis C virus RNA translation through the activation of SREBPs" [Virology 490 (2016) 99-108]. PMID- 27234961 TI - A Fucus vesiculosus extract inhibits estrogen receptor activation and induces cell death in female cancer cell lines. AB - BACKGROUND: We previously reported the anti-estrogenic activity of the brown seaweed, Fucus vesiculosus. The present study aimed to further investigate its anti-estrogenic modes of action and to assess other potentially biologically relevant anti-tumorigenic effects in estrogen receptor (ER)-dependent and independent female cancer cell lines. METHODS: The CALUX(r) assay was used to determine the effect of a F. vesiculosus extract (FVE) on activation of the ER. Aromatase enzymatic activity was measured to determine the potential effect of FVE on estradiol (E2) biosynthesis. Transcriptional activity profiling of 248 genes involved in cancer, immunity, hormonal regulation, protein phosphorylation, transcription, metabolism, and cellular structure was conducted using the NanoString nCounter(r) analysis system in FVE-treated breast, ovarian and endometrial cancer cell lines. The effects of FVE on cell viability, morphology, membrane integrity, mitochondrial toxicity, induction of apoptotic and autophagic markers, and cell signaling were also analyzed. RESULTS: In co-treatments with 12.5 pM (EC50) E2, FVE (2 %) reduced ER activation by 50 %, exhibiting potent ER antagonistic effects. FVE inhibited aromatase activity in an in vitro assay (IC50 2.0 %). ER-dependent and -independent cancer cell lines showed significantly decreased viability that correlated with increasing FVE concentrations and altered morphological features suggestive of apoptosis and autophagy. Expression of genes that were significantly altered by FVE (p < 0.05) revealed predominantly apoptotic, autophagic and kinase signaling pathways. FVE also effectively inhibited the phosphorylation of Akt, resulting in reduced mTORC1 activities to stimulate autophagy in cells. Concentration-dependent cleavage of PARP and induction of caspase-3 and -7 activities were observed in MDA-MB-231 cells supporting a role for FVE in the promotion of apoptosis. CONCLUSIONS: Our study provides new insights into the anti-estrogenic activity of F. vesiculosus. Moreover, the induction of autophagy and apoptosis on breast, endometrial and ovarian cancer cell lines suggests additional anti-tumorigenic actions of FVE that are independent of ER status in female cancers. PMID- 27234962 TI - Pro-inflammatory signaling by 24,25-dihydroxyvitamin D3 in HepG2 cells. AB - The vitamin D metabolite 24,25-dihydroxyvitamin D3 (24, 25[OH]2D3) was shown to induce nongenomic signaling pathways in resting zone chondrocytes and other cells involved in bone remodeling. Recently, our laboratory demonstrated that 24,25 [OH]2D3 but not 25-hydroxyvitamin D3, suppresses apolipoprotein A-I (apo A-I) gene expression and high-density lipoprotein (HDL) secretion in hepatocytes. Since 24,25-[OH]2D3 has low affinity for the vitamin D receptor (VDR) and little is known with regard to how 24,25-[OH]2D3 modulates nongenomic signaling in hepatocytes, we investigated the capacity of 24,25-[OH]2D3 to activate various signaling pathways relevant to apo A-I synthesis in HepG2 cells. Treatment with 24,25-[OH]2D3 resulted in decreased peroxisome proliferator-activated receptor alpha (PPARalpha) expression and retinoid-X-receptor alpha (RXRalpha) expression. Similarly, treatment of hepatocytes with 50 nM 24,25-[OH]2D3 for 1-3 h induced PKCalpha activation as well as c-jun-N-terminal kinase 1 (JNK1) activity and extracellular-regulated kinase 1/2 (ERK1/2) activity. These changes in kinase activity correlated with changes in c-jun phosphorylation, an increase in AP-1 dependent transcriptional activity, as well as repression of apo A-I promoter activity. Furthermore, treatment with 24,25-[OH]2D3 increased IL-1beta, IL-6, and IL-8 expression by HepG2 cells. These observations suggest that 24,25-[OH]2D3 elicits several novel rapid nongenomic-mediated pro-inflammatory protein kinases targeting AP1 activity, increasing pro-inflammatory cytokine expression, potentially impacting lipid metabolism and hepatic function. PMID- 27234963 TI - Impact of postharvest drying conditions on in vitro starch digestibility and estimated glycemic index of cooked non-waxy long-grain rice (Oryza sativa L.). AB - BACKGROUND: Wet paddy needs to be dried to reduce its moisture content after harvesting. In this study, effects of postharvest drying condition on in vitro starch digestibility and estimated glycemic index of cooked rice (Oryza sativa L.) were investigated. Varying drying conditions, i.e. hot-air drying at 40, 65, 90 and 115 degrees C, and sun drying were applied to raw paddy. After husking and polishing, polished grains were cooked using an electric rice cooker. Cooked samples were analyzed for their moisture content and amount of resistant and total starch. Five samples in both intact grain and slurry were digested under simulated in vitro gastrointestinal digestion process. The in vitro starch digestion rate was measured and the hydrolysis index (HI) and estimated glycemic index (eGI) were calculated. RESULTS: Cooked rice obtained from hot-air drying showed relatively lower HI and eGI than that obtained from sun-drying. Among samples from hot-air drying treatment, eGI of cooked rice decreased with increasing drying temperature, except for the drying temperature of 115 degrees C. As a result, cooked rice from the hot-air drying at 90 degrees C showed lowest eGI. CONCLUSION: The results indicated that cooked rice digestibility was affected by postharvest drying conditions. (c) 2016 Society of Chemical Industry. PMID- 27234964 TI - A review of the literature to inform a best-practice clinical supervision model for midwifery students in Australia. AB - Effective clinical supervision in midwifery programs leading to registration is essential to ensure that students can provide safe and competent woman centred care by the completion of their program. A number of different clinical supervision models exist in Australia and internationally, with varying levels of support and facilitation of student learning opportunities. In Australia, midwifery students must achieve specified learning outcomes and midwifery practice requirements to be eligible to register as a midwife. Identifying a best practice clinical supervision model for Australian midwifery students is therefore a priority for all key stakeholders, particularly education and maternity care providers. The aim of this literature review was to explore different types of clinical supervision models in order to develop and implement a best practice model in midwifery education programs. PMID- 27234965 TI - Benzodiazepine prescription for patients in treatment for drug use disorders: a nationwide cohort study in Denmark, 2000-2010. AB - BACKGROUND: Benzodiazepines are frequently prescribed to patients with drug use disorders. However, it has previously been difficult to distinguish whether this frequent prescribing was due to underlying psychiatric disorders or inappropriate prescribing. In a nationwide cohort study, we investigated the prescribing of benzodiazepines to patients with drug use disorders in connection with treatment admission. METHODS: Benzodiazepine prescriptions to patients (N = 33203) aged 18 to 67 years admitting for outpatient treatment for drug use disorders in Denmark, 2000 to 2010, were studied by using linked data from nationwide health registries. Factors associated with increasing amounts of benzodiazepine use within the first year after admission were assessed by multinomial logistic regression. Proportions of very long-term benzodiazepine prescription were calculated. RESULTS: During the first year after admission to treatment, 26.2 % of patients were prescribed benzodiazepines. Of these, 35.5 % were prescribed benzodiazepines at dose levels that might indicate inappropriate use (>365 Defined Daily Dose per year), and 34.6 % were prescribed more than one type of benzodiazepines. Diazepam was the most commonly prescribed type. Among patients with opioid use, 43.2 % were prescribed benzodiazepines which were three times higher than for patients with cannabis (12.2 %) or central stimulating drugs (13.8 %) as their primary drug use. Admitting to treatment for a drug use disorder did not increase the specialized psychiatric treatment coverage of this patient group, disregarding use of prescribed benzodiazepines. 29.5 % were new users of prescribed benzodiazepines, and of these, 27.5 % continued into very long-term use (>=4 years after admission) during the study period. CONCLUSIONS: Benzodiazepines were commonly prescribed to patients admitting to treatment for drug use disorders, and included prescription of multiple and non-optimal types, high doses, and very long-term prescriptions. These findings point towards inappropriate prescribing of benzodiazepines in many cases more than treatment for psychiatric disorders. PMID- 27234966 TI - Ultrasound in juvenile idiopathic arthritis. AB - BACKGROUND: In the recent years, musculoskeletal ultrasound (MSUS) has been regarded as especially promising in the assessment of juvenile idiopathic arthritis (JIA), as a reliable method to precisely document and monitor the synovial inflammation process. MAIN CONTENT: MSUS is particularly suited for examination of joints in children due to several advantages over other imaging modalities. Some challenges should be considered for correct interpretation of MSUS findings in children, due to the peculiar features of the growing skeleton. MSUS in JIA is considered particularly useful for its ability to detect subclinical synovitis, to improve the classification of patients in JIA subtypes, for the definition of remission, as guidance to intraarticular corticosteroid injections and for capturing early articular damage. Current evidence and applications of MSUS in JIA are documented by several authors. Recent advances and insights into further investigations on MSUS in healthy children and in JIA patients are presented and discussed in the present review. CONCLUSIONS: MSUS shows great promise in the assessment and management of children with JIA. Nonetheless, anatomical knowledge of sonographic changes over time, underlying immunopathophysiology, standardization and validation of MSUS in healthy children and in patients with JIA are still under investigation. Further research and educational efforts are required for expanding this imaging modality to more clinicians in their daily practice. PMID- 27234967 TI - Public-private sector interactions and the demand for supplementary health insurance in the United Kingdom. AB - We examine the demand for private health insurance (PHI) in the United Kingdom and relate this to changes in the supply of public and private healthcare. Using a novel collection of administrative, private sector and survey data, we re assess the relationships between the quality and availability of public and private sector inpatient care, and the demand for PHI. We find that PHI coverage in the United Kingdom is positively related to the median of the region- and year specific public sector waiting times. We find that PHI prevalence ceteris paribus increases with being self-employed and employed, while it decreases with having financial difficulties. In addition, we highlight the complexities of inter sectoral relations and their impact on PHI demand. Within a region, we find that an increase in private healthcare supply is associated with a decrease in public sector waiting times, implying lower PHI demand. This may be explained by the usage of private facilities by NHS commissioners. These results have important implications for policymakers interested in the role of private healthcare supply in enhancing the availability of and equitable access to acute inpatient care. PMID- 27234968 TI - The long-term reform in the Netherlands: what is the scientific rational for the WMO? PMID- 27234969 TI - Association between reduction in copayment and gastric cancer patient concentration to the capital area in South Korea: NHI cohort 2003-2013. AB - Since 2004, the South Korean government has introduced a policy that decreases copayment for cancer patients by strengthening public coverage in the National Health Insurance (NHI) system (first phase=copayment for outpatient care from 30% to 20%; second phase=copayment for total medical expenditures from 20% to 10%; third phase=copayment for total medical expenditures from 10% to 5%). We aimed to investigate the relationship between the policy introduction and patient visits to hospitals in the capital area. We used data from the NHI Cohort 2003-2013, which included all medical claims (7193 cases) filed for 2124 patients who visited the hospital due to stomach cancer, and performed a segmented Poisson regression analysis. Of all hospital visits, 40.6% of patients were from the capital area. After the introduction of the second phase of the policy, there was an increase in patient concentration in the capital area, although there were no significant effects on patient concentration during the first and third phases of the policy. In conclusion, our findings suggest that the introduction of a policy that reduces copayment for cancer patients had a substantial impact on patient concentration in the capital area. Therefore, health policymakers should consider effective alternatives including efficient allocation of medical resources or support for the more vulnerable population as flexible benefit plans to aid healthcare utilization by cancer patients. PMID- 27234970 TI - Complications of Treatment in Youth with HIV. AB - While combination antiretroviral therapy allows HIV-infected patients to have life expectancies similar to that of the general population, it may also contribute to the development of co-morbidities, such as cardiovascular disease and osteoporosis. Such complications could compromise long-term quality of life, especially in HIV-infected youth whose lifetime cumulative exposure to antiretrovirals is likely to be many decades. Recent studies continue to demonstrate abnormalities associated with antiretroviral therapy, although clinical manifestations are rare in this younger population, especially with modern antiretrovirals. The purpose of this paper is to review the most recent literature on complications of treatment in youth with HIV. PMID- 27234971 TI - In vivo therapeutic efficacy and pharmacokinetics of colistin sulfate in an experimental model of enterotoxigenic Escherichia coli infection in weaned pigs. AB - Enterotoxigenic Escherichia coli (ETEC: F4) associated with post-weaning diarrhea (PWD) in pigs has developed resistance against several antimicrobial families, leading to increased use of colistin sulfate (CS) for the treatment of this disease. The objective of this study was to determine the efficacy of oral CS treatment in experimental PWD due to ETEC: F4 challenge and determine the effect of this challenge on CS intestinal absorption. In this study, 96 pigs were divided into two trials based on CS dose (100 000 or 50 000 IU/kg). Fecal shedding of ETEC: F4, total E. coli, and CS-resistant E. coli, diarrhea scores, and weight changes were evaluated. Colistin sulfate plasma concentrations were determined by HPLC-MS/MS. Regardless of the dose, CS treatment resulted in a reduction of fecal ETEC: F4 and total E. coli shedding, and in diarrhea scores but only during the treatment period. However, CS treatment resulted in a slight increase in fecal shedding of CS resistant E. coli and did not prevent weight loss in challenged pigs. In addition, challenge with ETEC: F4 resulted in an increase of CS intestinal absorption. Our study is among the first to demonstrate that under controlled conditions, CS was effective in reducing fecal shedding of ETEC: F4 and total E. coli in experimental PWD. However, CS treatment was associated with a slight selection pressure on E. coli and did not prevent pig weight loss. Further studies are needed in field conditions, to better characterize CS therapeutic regimen efficacy and bacterial resistance dissemination. PMID- 27234972 TI - Encouraging impact following 2.5 years of reinforced malaria control interventions in a hyperendemic region of the Republic of Guinea. AB - BACKGROUND: Malaria is one of the principal causes of morbidity and mortality in the Republic of Guinea, particularly in the highly endemic regions. To assist in malaria control efforts, a multi-component malaria control intervention was implemented in the hyperendemic region of Gueckedou Prefecture. The coverage of the intervention and its impact on malaria parasite prevalence were assessed. METHODS: Five cross-sectional surveys using cluster-based sampling and stratified by area were conducted from 2011 to 2013 in three sous-prefectures of Gueckedou Prefecture that received the intervention: Gueckedou City, Tekoulo and Guendembou in addition to one comparison sous-prefecture that did not receive the intervention, Koundou. Surveys were repeated every 6 months, corresponding with the dry and rainy seasons. Rapid diagnostic tests (RDT) were used to diagnose malaria infection. In each selected household, bed net use and ownership were assessed. RESULTS: A total of 35,123 individuals participated in the surveys. Malaria parasite prevalence declined in all intervention sous-prefectures from 2011 to 2013 (56.4-45.9 % in Gueckedou City, 64.9-54.1 % in Tekoulo and 69.4-56.9 % in Guendembou) while increasing in the comparison sous-prefecture (64.5-69 %). It was consistently higher in children 5-14 years of age followed by those 1-59 months and >=15 years. Indicators of intervention coverage, the proportion of households reporting ownership of at least one bed net and the proportion of survey participants with fever who received treatment from a health facility or community health worker also increased significantly in the intervention areas. CONCLUSIONS: Implementation of the multi-component malaria control intervention significantly reduced the prevalence of malaria in the sous-prefectures of intervention while also increasing the coverage of bed nets. However, malaria prevalence remains unacceptably high and disproportionately affects children <15 years of age. In such situations additional vector control interventions and age specific interventions should be considered. PMID- 27234974 TI - Prediction of vascular dementia and Alzheimer's disease in patients with atrial fibrillation or atrial flutter using CHADS2 score. AB - BACKGROUND: Atrial fibrillation (AF) is associated with an increased risk of dementia. However, limited data are available on the predictors of dementia in patients with AF. This study aimed to evaluate whether the CHADS2 score could be a useful tool for risk stratification with regard to dementia occurrence among patients with AF. METHODS: AF patients were identified from the National Health Insurance sampling database, which has accumulated a total of 1,000,000 participants since 2000. After excluding patients diagnosed with dementia prior to the index day of enrollment, CHADS2 score was measured to investigate its association with the occurrence of dementia, including vascular dementia and Alzheimer's disease. RESULTS: During the mean follow-up period of 3.71 +/- 2.78 years, 1135 dementia cases (7.36%) were identified, including 241 cases of vascular dementia and 894 cases of Alzheimer's disease. In multivariate analysis, an increase of 1 point in the CHADS2 score was independently associated with a 54% increase in the risk of vascular dementia (hazard ratio = 1.54; 95% confidence interval, 1.41-1.69; p < 0.001) and a 40% increase in Alzheimer's disease (hazard ratio = 1.40; 95% confidence interval, 1.34-1.46; p < 0.001). CONCLUSION: CHADS2 score is a useful predictor for the development of vascular dementia as well as Alzheimer's disease in patients with AF. PMID- 27234973 TI - Aflibercept exhibits VEGF binding stoichiometry distinct from bevacizumab and does not support formation of immune-like complexes. AB - Anti-vascular endothelial growth factor (VEGF) therapies have improved clinical outcomes for patients with cancers and retinal vascular diseases. Three anti-VEGF agents, pegaptanib, ranibizumab, and aflibercept, are approved for ophthalmic indications, while bevacizumab is approved to treat colorectal, lung, and renal cancers, but is also used off-label to treat ocular vascular diseases. The efficacy of bevacizumab relative to ranibizumab in treating neovascular age related macular degeneration has been assessed in several trials. However, questions persist regarding its safety, as bevacizumab can form large complexes with dimeric VEGF165, resulting in multimerization of the Fc domain and platelet activation. Here, we compare binding stoichiometry, Fcgamma receptor affinity, platelet activation, and binding to epithelial and endothelial cells in vitro for bevacizumab and aflibercept, in the absence or presence of VEGF. In contrast to bevacizumab, aflibercept forms a homogenous 1:1 complex with each VEGF dimer. Unlike multimeric bevacizumab:VEGF complexes, the monomeric aflibercept:VEGF complex does not exhibit increased affinity for low-affinity Fcgamma receptors, does not activate platelets, nor does it bind to the surface of epithelial or endothelial cells to a greater degree than unbound aflibercept or control Fc. The latter finding reflects the fact that aflibercept binds VEGF in a unique manner, distinct from antibodies not only blocking the amino acids necessary for VEGFR1/R2 binding but also occluding the heparin-binding site on VEGF165. PMID- 27234975 TI - Predictive value of plasma neutrophil gelatinase-associated lipocalin for acute renal failure in patients with severe sepsis. AB - BACKGROUND: Predicting acute renal failure in patients with severe sepsis is important, because patients may need renal replacement therapy (RRT). Neutrophil gelatinase-associated lipocalin (NGAL) has been evaluated for its ability to detect and predict acute kidney injury (AKI) in critically ill patients. This study aimed to assess the predictive value of plasma NGAL for acute renal failure in adult severely septic patients. METHODS: Thirty healthy adults and 85 adult patients admitted to the medical intensive care unit (ICU) were enrolled. Serum creatinine, plasma NGAL, and interleukin (IL)-6, IL-10, and IL-17 levels were evaluated. AKI was classified as Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (RIFLE). RESULTS: RIFLE-Failure (RIFLE-F) developed in 30 of 76 (39.5%) patients with severe sepsis without chronic kidney disease within 7 days after ICU admission. Serum creatinine, plasma NGAL, IL-6, and IL-10 could predict RIFLE-F within 7 days after ICU admission. The discriminatory power of plasma NGAL was not significant for predicting hospital mortality. The area under the receiver operating characteristic curve of plasma NGAL was not higher than that of serum creatinine in predicting RIFLE-F within 7 days. CONCLUSION: Plasma NGAL is a useful tool for predicting acute renal failure in adult patients with severe sepsis. Serum creatinine has a similar ability to detect RIFLE-F occurrence. PMID- 27234976 TI - Experimental strategies towards increasing intracellular mitochondrial activity in oocytes: A systematic review. AB - PURPOSE: The mitochondrial complement is critical in sustaining the earliest stages of life. To improve the Assisted Reproductive Technology (ART), current methods of interest were evaluated for increasing the activity and copy number of mitochondria in the oocyte cell. METHODS: This covered the researches from 1966 to September 2015. RESULTS: The results provided ten methods that can be studied individually or simultaneously. CONCLUSION: Though the use of these techniques generated great concern about heteroplasmy observation in humans, it seems that with study on these suggested methods there is real hope for effective treatments of old oocyte or oocytes containing mitochondrial problems in the near future. PMID- 27234977 TI - Tendon entrapments and dislocations in ankle and hindfoot fractures: evaluation with multidetector computed tomography. AB - The purpose of this study was to assess the incidence of tendon entrapments and tendon dislocations associated with ankle and hindfoot fractures in patients studied by multidetector computed tomography (MDCT). Additionally, we describe particular tendon injuries associated with specific fractures. This was a retrospective review of all individuals with a trauma-protocol CT for suspected ankle and/or hindfoot fractures during a consecutive 41-month time period at a single Level I Trauma Center. Each patient's images were evaluated by two radiologists and an orthopedic surgeon for tendon entrapment, tendon dislocation, and bone(s) fractured or dislocated. There were 398 patients with ankle and/or hindfoot fractures that showed tendon entrapment or dislocation in 64 (16.1 %) patients. There were 30 (46.9 %) patients with 40 tendon entrapments, 31 (48.4 %) patients with 59 tendon dislocations, and three (4.7 %) patients with both tendon entrapment and dislocation. All patients with tendon entrapments were seen with either pilon fractures and/or a combination of posterior, medial, or lateral malleolar fractures. The most frequently entrapped tendon was the posterior tibialis tendon (PTT) in 27 patients (27/30, 90.0 %). The peroneal tendons were the most frequently dislocated, representing 27 (87.1 %) of patients with tendon dislocation; all resulted from a talar or calcaneal fracture or subluxation. This study demonstrates that tendon entrapments and tendon dislocations are commonly seen in complex fractures of the ankle and hindfoot. Pilon fractures were associated with the majority of tendon entrapments, whereas calcaneus fractures were associated with the majority of tendon dislocations. PMID- 27234979 TI - WITHDRAWN: Corrigendum to 'sensitivity of epicardial electrical markers to acute ischemia detection'. PMID- 27234978 TI - A report on the Academic Emergency Medicine 2015 consensus conference "Diagnostic imaging in the emergency department: a research agenda to optimize utilization". AB - In May 2015, the Academic Emergency Medicine consensus conference "Diagnostic imaging in the emergency department: a research agenda to optimize utilization" was held. The goal of the conference was to develop a high-priority research agenda regarding emergency diagnostic imaging on which to base future research. In addition to representatives from the Society of Academic Emergency Medicine, the multidisciplinary conference included members of several radiology organizations: American Society for Emergency Radiology, Radiological Society of North America, the American College of Radiology, and the American Association of Physicists in Medicine. The specific aims of the conference were to (1) understand the current state of evidence regarding emergency department (ED) diagnostic imaging utilization and identify key opportunities, limitations, and gaps in knowledge; (2) develop a consensus-driven research agenda emphasizing priorities and opportunities for research in ED diagnostic imaging; and (3) explore specific funding mechanisms available to facilitate research in ED diagnostic imaging. Through a multistep consensus process, participants developed targeted research questions for future research in six content areas within emergency diagnostic imaging: clinical decision rules; use of administrative data; patient-centered outcomes research; training, education, and competency; knowledge translation and barriers to imaging optimization; and comparative effectiveness research in alternatives to traditional computed tomography use. PMID- 27234980 TI - Polypharmacology of dopamine receptor ligands. AB - Most neurological diseases have a multifactorial nature and the number of molecular mechanisms discovered as underpinning these diseases is continuously evolving. The old concept of developing selective agents for a single target does not fit with the medical need of most neurological diseases. The development of designed multiple ligands holds great promises and appears as the next step in drug development for the treatment of these multifactorial diseases. Dopamine and its five receptor subtypes are intimately involved in numerous neurological disorders. Dopamine receptor ligands display a high degree of cross interactions with many other targets including G-protein coupled receptors, transporters, enzymes and ion channels. For brain disorders like Parkinsons disease, schizophrenia and depression the dopaminergic system, being intertwined with many other signaling systems, plays a key role in pathogenesis and therapy. The concept of designed multiple ligands and polypharmacology, which perfectly meets the therapeutic needs for these brain disorders, is herein discussed as a general ligand-based concept while focusing on dopaminergic agents and receptor subtypes in particular. PMID- 27234981 TI - A hair on the tongue. AB - INTRODUCTION: Human hairs are generally localized on the cutaneous part of the head, neck, torso, armpits, pubis and limbs. Sometimes it can be found in an unusual localization and is then called heterotopic. OBSERVATION: A 30-year-old man presented with a hair in the middle of the dorsum of the tongue. It was decided to perform an excision under local anesthesia. DISCUSSION: Few reports exist that describe hair growing on mucosa. Only one other case has been published concerning the tongue. PMID- 27234982 TI - Biofilm-Related Genes: Analyses in Multi-Antibiotic Resistant Acinetobacter Baumannii Isolates From Mainland China. AB - BACKGROUND Acinetobacter baumannii is an important nosocomial pathogen which shows a high level of mortality risk. Several papers have reported biofilm formation as a well-known pathogenic mechanism in A. baumannii infections and exceptional antibiotic resistance. The study aims to explore the potential relationships between biofilm-related genes and antimicrobial resistance. MATERIAL AND METHODS Samples from 122 patients with lower respiratory tract infections of A. baumannii were collected at Fujian Longyan First Hospital from January 2013 to September 2014. A. baumannii was isolated from sputum specimens. Biofilm-related genes including abaI, csuE, ompA, and bla-PER1 were analyzed by PCR. The minimum inhibitory concentration method was used to determine the sensitivity of each strain to antibiotics. RESULTS The clinical manifestations of A. baumannii-induced lower respiratory tract infections lacked specificity. Infected patients were most commonly admitted to intensive care units (54.9%) and frequently had chronic obstructive pulmonary disease (27.0%). The detection rates of abaI and csuE were both 59.8%, and those of ompA and bla-PER1 were 100% and 0%, respectively. After genetic testing, antimicrobial resistance to amikacin, ampicillin/sulbactam, and 14 other types of antimicrobials was higher in abaI- and csuE-positive strains than in abaI- and csuE-negative strains (P<0.05). CONCLUSIONS The findings of our study suggest that abaI- and csuE-positive Acinetobacter baumannii strains are associated with a higher incidence of antibiotic resistance in 14 types of antimicrobials. PMID- 27234983 TI - Corrigendum to "Technical Description of the Medial and Lateral Anterior Temporal Approach for the Treatment of Complex Proximal Posterior Cerebral Artery Aneurysms" [World Neurosurg. 86 (2016) 490-496]. PMID- 27234984 TI - Social Media Self-Efficacy of Health Education Specialists: Training and Organizational Development Implications. AB - A growing number of public health organizations are applying the power of social media (SM) for health promotion and behavior change. This cross-sectional study of health education specialists (n = 353) examined which demographic and occupational factors were associated with SM self-efficacy, and evaluated SM self efficacy related to each of the Seven Areas of Responsibility. A series of one way analyses of variance were conducted to determine whether differences in SM self-efficacy existed by sex, age, years of work experience, and SM access at work. A multiple linear regression examined the relationship between SM self efficacy and SM experience when controlling for demographic and occupational factors. Statistically significant differences in SM self-efficacy existed by age, F(2, 289) = 6.54, p = .002. SM experience (beta = 1.43, t = 11.35, p < .001) was a statistically significant predictor of SM self-efficacy, even after controlling for age, sex, years of work experience, and level of SM access, F(5, 290) = 30.88, p < .001, R2 = .35. Results revealed statistically significant differences in mean SM self-efficacy scores by the Areas of Responsibility, F(4.69, 1425.46) = 22.46, p < .001. Professional health organizations should have policies in place and trainings that are conducive to learning and applying SM for health education research and practice. PMID- 27234985 TI - Examination of Teacher Knowledge, Dissemination Preferences, and Classroom Management of Student Concussions: Implications for Return-to-Learn Protocols. AB - OBJECTIVES: To determine teacher knowledge of (1) concussion symptomatology, (2) dissemination preferences, and (3) classroom management practices of student concussions. STUDY DESIGN: A cross-sectional survey assessing concussion-related information was completed by teachers/instructors in the state of Alabama. RESULTS: One-hundred and thirty participants completed the survey. Only a quarter perceived they were "very" or "extremely" confident enough to recognize signs related to a concussion (22.3%), and only 12.4% reported they were "very knowledgeable" about concussions. The majority were able to recognize more common concussion symptoms/challenges: headaches (95.4%), trouble concentrating (86.2%), memory (82.3%), balance problems/dizziness (82.3%), changes vision/hearing (76.2%), difficulty completing tasks (70.8%), difficulty making decisions (66.2%), changes in sleep (61.5%), and fatigue (60.8%); only half recognized emotional symptoms (e.g., mood) or symptoms associated with more prolonged recovery. Concussion informants were school nurses (74.4%), followed by parents (46.2%), students (46.2%), and coaches/athletic trainers (45.4%). A little under half of participants received concussion information as part of their job (41.9%). About 14.1% of teachers reported that someone had come to their school to talk with them as a group about concussions, and 82% felt they needed more information. Of the 37% who taught a concussed student, 83% reported they altered the classroom management strategies. CONCLUSIONS: In general, teachers were able to recognize the more commonly experienced concussion symptoms as well as management strategies. However, they appear to want greater concussion information and training. Given the daily influence of teachers on student tasks involving cognitive exertion, incorporation of formal concussion education for teachers is warranted. PMID- 27234986 TI - Primary Hepatic Lymphoma: the Importance of Liver Biopsy. PMID- 27234987 TI - Modification of trout sperm membranes associated with activation and cryopreservation. Implications for fertilizing potential. AB - We investigated the effects of two trout sperm activation solutions on sperm physiology and membrane organization prior to and following cryopreservation using flow cytometry and investigated their impact on in vitro fertility. Overall, frozen-thawed samples had greater phospholipid disorder when compared with fresh samples (high plasma membrane fluidity; P < 0.0001) and sperm activated with water also had high plasma membrane fluidity when compared to sperm activated with Lahnsteiner solution (LAS; P < 0.0001). Following cryopreservation water activated samples had membranes with greater membrane protein disorganization compared with LAS but the membrane protein organization of LAS samples was similar to samples prior to freezing (P < 0.0001). Post-thaw water activation resulted in significant increases in intracellular calcium compared to LAS (P < 0.002). In vitro fertility trials with frozen-thawed milt and LAS activation resulted in greater fertility (45%) compared to water activated samples (10%; P < 0.0001). Higher fertility rates correlated with lower intracellular calcium with water (R(2) = -0.9; P = 0.01) and LAS (R(2) = -0.85; P = 0.03) activation. Greater plasma membrane phospholipid (R(2) = -0.89; P = 0.02) and protein (R(2) = -0.84; P = 0.04) disorder correlated with lower water activation fertility rates. These membrane organization characteristics only approached significance with LAS activation in vitro fertility (P = 0.09, P = 0.06, respectively). Potentially the understanding of sperm membrane reorganizations and the physiology associated with activation following cryopreservation may enable users in a repository or hatchery setting to estimate the fertilizing potential of a sample and determine its value. PMID- 27234988 TI - Effectiveness of a clinician intervention to improve physical activity discussions in underserved adults. AB - BACKGROUND: Physical activity (PA) counselling is challenging in primary care. It is unknown whether clinician training on the 5As (Ask, Advise, Agree, Assist, Arrange) improves PA counselling skills. OBJECTIVE: To evaluate the effect of a clinician training intervention on PA counselling for underserved adults using the 5As framework. METHODS: Pragmatic pilot clinical trial was used in the study. Clinicians (n = 13) were randomly assigned to two groups. Each group received the intervention consisting of four 1-hour training sessions to teach the 5As for PA counselling. Patient-clinician visits (n = 325) were audio recorded at baseline, immediately post-intervention, and at 6 months. Outcomes were the frequency and quality of PA discussions using the 5As, assessed by blinded coders. RESULTS: Patients' mean age was 44 years; 75% were African American. PA was discussed in 37% (n = 119) of visits overall and did not change from baseline to follow-up. When PA discussions occurred, the frequency of 5As increased from baseline to follow-up for Advise (51-54%), Agree (11-26%), and Assist (11-17%); however, none of the 5As had a statistically significant increase. For Agree, exploration of patient willingness to engage in PA increased from 23% at baseline to 50% at follow-up. CONCLUSION: A clinician-directed intervention to improve PA counselling increased the frequency of Advise, Agree and Assist, and the quality of Ask and Agree statements, though the absolute numbers were small and only Agree reached statistical significance. Future research is needed to understand the factors that affect the optimal uptake and approach to 5As counselling. PMID- 27234989 TI - Trabectedin for Soft Tissue Sarcoma: Current Status and Future Perspectives. AB - Trabectedin (ET743, Yondelis((r)), manufactured by Baxter Oncology GmbH, Halle/Westfalen, Germany, for Janssen Products, LP, Horsham, PA), derived from the marine ascidian, Ecteinascidia turbinata, is a natural alkaloid with multiple complex mechanisms of action. On 23 October 2015, 15 years after the results of the first Phase 1 clinical trial using trabectedin for chemotherapy-resistant solid malignancies was reported, and 8 years after its approval in Europe, the United States Food and Drug Administration (USFDA) finally approved trabectedin for the treatment of unresectable or metastatic liposarcoma or leiomyosarcoma that has failed a prior anthracycline-containing regimen. Approval was based on the results of a pivotal Phase 3 trial involving a 2:1 randomization of 518 patients (who were further stratified by soft tissue sarcoma subtype), in which a significant improvement in progression-free survival was reported in the trabectedin-treated group vs. the dacarbazine-treated group (p < 0.001). In this trial, the most common adverse reactions were nausea, fatigue, vomiting, constipation, anorexia, diarrhea, peripheral edema, dyspnea, and headache, while the most serious were neutropenic sepsis, rhabdomyolysis, cardiomyopathy, hepatotoxicity, and extravasation leading to tissue necrosis. The most common grade 3-4 adverse events were laboratory abnormalities of myelosuppression in both arms and transient transaminitis in the trabectedin arm. In a recent Phase 2 trial, trabectedin had a similar outcome as doxorubicin when given as a single agent in the first-line setting. Studies are also being conducted to expand the use of trabectedin not only as a first-line cancer drug, but also for a number of other clinical indications, for example, in the case of mesenchymal chondrosarcoma, for which trabectedin has been reported to be exceptionally active. The possibility of combining trabectedin with targeted therapies, immune checkpoint inhibitors or virotherapy would also be an interesting concept. In short, trabectedin is an old new drug with proven potential to impact the lives of patients with soft tissue sarcoma and other solid malignancies. FUNDING: Sarcoma Oncology Center, Santa Monica, CA 90405. PMID- 27234991 TI - Erratum to: Behavioural effects of basal ganglia rho-kinase inhibition in the unilateral 6-hydroxydopamine rat model of Parkinson's disease. PMID- 27234990 TI - Aberrantly expressed long noncoding RNAs are involved in sevoflurane-induced developing hippocampal neuronal apoptosis: a microarray related study. AB - The commonly used volatile anesthetic sevoflurane has been shown to induce widespread apoptosis in the developing brain, yet the underlying molecular mechanisms are not fully understood. Accumulating research has demonstrated that long noncoding RNAs (lncRNAs) regulate multiple biological processes, including neural development, differentiation and apoptosis. They are aberrantly expressed in multiple neurodegenerative diseases. In this study, we employed a lncRNA-mRNA microarray analysis to determine whether and how lncRNAs are involved in sevoflurane-induced hippocampal neuronal apoptosis in neonatal mice. Our data showed that a single 6-h sevoflurane exposure of P7 mice resulted in significant morphological changes and apoptosis in the hippocampus. Moreover, the microarray simultaneously revealed 817 lncRNAs and 856 of their potential coding targets that related to apoptosis, of which 31 lncRNAs (19 up and 12 down) and 25 mRNAs were significantly differentially expressed (P < 0.05) after sevoflurane exposure. Importantly, we found that Bcl2l11 (BIM), which potentiates mitochondria-dependent apoptosis and its nearby enhancer-like lncRNA ENSMUST00000136025, were both more highly expressed in sevoflurane-treated samples compared with control samples. Subsequent qRT-PCR results confirmed the changes. Further CNC network indicated that lncRNA ENSMUST00000136025 was positively correlated with Bim. Moreover, sevoflurane induced a significant increase of pro-apoptotic protein BIM and Bax but a reduction of anti-apoptotic proteins Bcl-2 in the hippocampus. Our study first demonstrates that aberrantly expressed lncRNAs play a role in sevoflurane-induced hippocampal apoptosis. We noted that up-regulated ENSMUST00000136025 highly likely induced the over expression of BIM, which eventually promoted mitochondria-mediated apoptosis. Such findings further broaden the understanding of molecular mechanisms responsible for sevoflurane-induced neurotoxicity. PMID- 27234992 TI - The model homologue of the partially defective human 5,10 methylenetetrahydrofolate reductase, considered as a risk factor for stroke due to increased homocysteine level, can be protected and reactivated by heat shock proteins. AB - The A222 V substitution in the human MTHFR gene product (5,10 methylenetetrahydrofolate reductase) is responsible for a decreased activity of this enzyme. This may cause an increased homocysteine level, considered as a risk factor for arteriosclerosis and stroke. The bacterial homologue of the human enzyme, MetF, has been found to be a useful model in genetic and biochemical studies. The similarity of Escherichia coli MetF and human MTHFR proteins is so high that particular mutations in the corresponding human gene can be reflected by the bacterial mutants. For example, the A222 V substitution in MTHFR (caused by the C667T substitution in the MTHFR gene) can be ascribed to the A117 V substitution in MetF. Here, it is reported that a temperature-sensitive MetF117 (A117 V) protein can be partially protected from a thermal inactivation by the heat shock proteins from the Hsp70/100 systems. Moreover, activity of the thermally denatured enzyme can be partially restored by the same heat shock proteins. High temperature protein G (HtpG) had no effect on MetF117 activity in both experimental systems. The presented results indicate that functions of heat shock proteins may be required for maintenance of the MetF117 function. This may have implications for the mechanisms of arteriosclerosis and stroke, especially in the light of previous findings that the A222 V MTHFR polymorphism may be a risk factor for stroke, as well as recently published results which demonstrated the increased levels of antibodies against heat shock proteins in stroke patients. PMID- 27234994 TI - Corrigendum to "Avian haemosporidians from Neotropical highlands: evidence from morphological and molecular data" [Parasitol. Int. 64 (2015) 48-59]. PMID- 27234993 TI - Hemoglobins as new players in multiple sclerosis: metabolic and immune aspects. AB - Basic science investigations and clinical observations in recent years indicate that hemoglobins (Hbs) may have important roles in the pathogenesis of multiple sclerosis (MS). These findings can be summarized as follows: 1- Erythrocyte fragility is higher in MS patients, the released free Hb damages blood-brain barrier, myelin basic protein and also triggers iron overload and inflammation. 2 Free Hb may further activate the inflammatory responses through Toll-like receptor 4 (TLR4), present on microglia and other innate immunocytes. 3- Hbs are expressed in neural cells including dopaminergic neurons. Also, several studies have demonstrated that Hbs are expressed in astrocytes and oligodendroglia. 4- Hb overexpression in neural cells upregulate mitochondrial complex I-V subunits. The comparison of the mitochondrial proteome between healthy and patients with MS revealed only four differentially expressed proteins including Hb beta-chain. 5- Microarray analysis of 8300 genes in monocytes of twins with and without MS showed a difference in 25 genes that include genes encoding alpha- and beta globins as well. 6- beta- and alpha-globin gene clusters reside at chromosomal regions 11p15.5 and 16p13.3, respectively. Whole genome screen (WGS) in Sardinian MS families using 327 markers revealed linkage in 3 regions including 11p15.5 loci. Further, 11p15.5 and 16p13.3 were part of the 17 regions identified in the WGS study of 136 sibling-pairs in Nordic countries analyzing 399 microsatellite markers. In the light of these findings, we propose that free Hb released from dying erythrocytes is detrimental. On the contrary, intracellular Hbs in neural cells are protective in MS. The genomic linkage findings can be explained by common haematologically-silent Hb variants that may lower the protective function of intracellular Hbs, and therefore, enhance the risk for MS. In the absence of such variants, aberrations in the translational and post-translational mechanisms controlling synthesis of neural Hbs may also enhance the vulnerability to MS. Alternatively, such genetic variants may perturb the metabolism of anti inflammatory hemorphins produced via cleavage of Hbs. PMID- 27234995 TI - Properties and genomic analysis of Lactococcus garvieae lysogenic bacteriophage PLgT-1, a new member of Siphoviridae, with homology to Lactococcus lactis phages. AB - The lysogenic phage PLgT-1 is highly prevalent in Lactococcus garvieae, which is a serious bacterial pathogen in marine fish. Therefore, information regarding this phage is one of the key factors to predict the evolution of this bacterium. However, many properties of this phage, its complete genome sequence, and its relationship with other viral communities has not been investigated to date. Here, we demonstrated that the phage PLgT-1 was not only induced by an induction agent (Mitomycin C), but could be released frequently during cell division in a nutrient-rich environment or in natural seawater. Integration of PLgT-1 into non lysogenic bacteria via transduction changed the genotype, resulting in the diversification of L. garvieae. The complete DNA sequence of PLgT-1 was also determined. This phage has a dsDNA genome of 40,273bp with 66 open reading frames (ORFs). Of these, the biological functions of 24 ORFs could be predicted but those of 42 ORFs are unknown. Thus, PLgT-1 is a novel phage with several novel proteins encoded in its genome. The strict MegaBLAST search program for the PLgT 1 genome revealed that this phage had no similarities with other previously investigated phages specific to L. garvieae (WP-2 and GE1). Notably, PLgT-1 was relatively homologous with several phages of Lactococcus lactis and 17 of the 24 predicted proteins encoded in PLgT-1 were homologous with the deduced proteins of various phages from these dairy bacteria. Comparative genome analysis revealed that the L. garvieae phage PLgT-1 was most closely related to the L. lactis phage TP712. However, they differed from each other in genome size and gene arrangement. The results obtained in this study suggest that the lysogenic phage PLgT-1 is a new member of the family Siphoviridae and has been involved in horizontal gene exchange with microbial communities, especially with L. lactis and its phages. PMID- 27234996 TI - Integrating Molecular Profiling of Liquid Biopsy Samples with a Calculator Algorithm To Detect High-risk Prostate Cancer. PMID- 27234998 TI - Safety and Early Oncologic Effectiveness of Primary Robotic Retroperitoneal Lymph Node Dissection for Nonseminomatous Germ Cell Testicular Cancer. AB - BACKGROUND: Primary robot-assisted retroperitoneal lymph node dissection (R RPLND) has been studied as an alternative to open RPLND in single-institution series for patients with low-stage nonseminomatous germ cell tumors (NSGCT). OBJECTIVE: To evaluate a multicenter series of primary R-RPLND for low-stage NSGCT. DESIGN, SETTING, AND PARTICIPANTS: Between 2011 and 2015, 47 patients underwent primary R-RPLND at four centers for Clinical Stage (CS) I-IIA NSGCT. SURGICAL PROCEDURE: R-RPLND was performed using the da Vinci surgical system (Intuitive Surgical Inc., Sunnyvale, CA, USA). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Data were collected regarding patient demographics, primary tumor characteristics, pathologic findings, and clinical outcomes. RESULTS AND LIMITATIONS: Forty-two patients (89%) were CS I and five (11%) were CS IIA. The median operative time was 235min (interquartile range [IQR]: 214-258min), estimated blood loss was 50ml (IQR: 50-100ml), node count was 26 (IQR: 18-32), and length of stay was 1 d. There were two intraoperative complications (4%), four early postoperative complications (9%), no late complications, and the rate of antegrade ejaculation was 100%. Of the eight patients (17%) with positive nodes (seven pN1and one pN2), five (62%) received adjuvant chemotherapy. The one recurrence was out of template in the pelvis after adjuvant chemotherapy (resected teratoma). The median follow-up was 16 mo and the 2-yr recurrence-free survival rate was 97% (95% confidence interval: 82-100%). Limitations include retrospective design and limited follow-up. CONCLUSIONS: Our multicenter experience supports R-RPLND as a potential option at experienced centers in select patients with low-stage NSGCT. Informal comparison to open and laparoscopic series suggests R-RPLND has an acceptably low morbidity profile, but oncologic efficacy evaluation requires further evaluation. PATIENT SUMMARY: We examined outcomes after robot-assisted retroperitoneal lymph node dissection for patients with low-stage nonseminomatous testicular cancer with our data suggesting the robotic approach has acceptable morbidity and early oncologic outcomes. PMID- 27234997 TI - Enhanced Recovery After Robot-assisted Radical Cystectomy: EAU Robotic Urology Section Scientific Working Group Consensus View. AB - CONTEXT: Radical cystectomy (RC) is associated with frequent morbidity and prolonged length of stay (LOS) irrespective of surgical approach. Increasing evidence from colorectal surgery indicates that minimally invasive surgery and enhanced recovery programmes (ERPs) can reduce surgical morbidity and LOS. ERPs are now recognised as an important component of surgical management for RC. However, there is comparatively little evidence for ERPs after robot-assisted radical cystectomy (RARC). Due to the multimodal nature of ERPs, they are not easily validated through randomised controlled trials. OBJECTIVE: To provide a European Association of Urology (EAU) Robotic Urology Section (ERUS) policy on ERPs to guide standardised perioperative management of RARC patients. EVIDENCE ACQUISITION: The guidance was formulated in four phases: (1) systematic literature review of evidence for ERPs in robotic, laparoscopic, and open RC; (2) an online questionnaire survey formulated and sent to ERUS Scientific Working Group members; (3) achievement of consensus from an expert panel using the Delphi process; and (4) a standardised reporting template to audit compliance and outcome designed and approved by the committee. EVIDENCE SYNTHESIS: Consensus was reached in multiple areas of an ERP for RARC. The key principles include patient education, optimisation of nutrition, RARC approach, standardised anaesthetic, analgesic, and antiemetic regimens, and early mobilisation. CONCLUSIONS: This consensus represents the views of an expert panel established to advise ERUS on ERPs for RARC. The ERUS Scientific Working Group recognises the role of ERPs and endorses them as standardised perioperative care for patients undergoing RARC. ERPs in robotic surgery will continue to evolve with technological and pharmaceutical advances and increasing understanding of the role of surgery specific ERPs. PATIENT SUMMARY: There is currently a lack of high-level evidence exploring the benefits of enhanced recovery programmes (ERPs) in patients undergoing robot-assisted radical cystectomy (RARC). We reported a consensus view on a standardised ERP specific to patients undergoing RARC. It was formulated by experts from high-volume RARC hospitals in Europe, combining current evidence for ERPs with experts' knowledge of perioperative care for robotic surgery. PMID- 27234999 TI - Expanding the Armamentarium for Castrate-resistant Prostate Cancer. PMID- 27235000 TI - Efficacy of Left Atrial Voltage-Based Catheter Ablation of Persistent Atrial Fibrillation. AB - BACKGROUND: Low-voltage zones (LVZs) represent fibrotic tissue and are substrates for atrial fibrillation (AF). We hypothesized that LVZ-based substrate modification along with pulmonary vein isolation (PVI) would improve outcomes in persistent AF (PeAF) patients with LVZs, whereas PVI alone would work in patients without LVZs. METHODS AND RESULTS: Voltage mapping of the left atrium (LA) was performed during sinus rhythm in 101 PeAF patients in whom LVZ was defined as an area with bipolar electrograms <0.5 mV. Thirty-nine patients had LVZs and underwent ablation of the entire LVZ area after PVI (LVZabl group). In the remaining 62 patients without LVZs, PVI alone was performed with no further substrate modifications (PVI group). An additional group of 16 consecutive PeAF patients with LVZ did not undergo any substrate modification after PVI and were used as a comparison group (LVZnon-abl group) despite having similar size of LVZs to that in the LVZabl group. After a single session, 28 (72%) patients in the LVZabl group had no recurrence, whereas 49 (79%) patients in the PVI group had no recurrence during 18 +/- 7 months of follow-up (log-rank, P = 0.400). In the LVZnon-abl group, only 6 patients (38%) had no recurrence during 32 +/- 7 months of follow-up, even after a mean number of sessions of 1.8 (log-rank, P < 0.001, compared with the LVZabl group). CONCLUSIONS: Additional LVZ-based substrate modification after PVI improved the outcome in PeAF patients with LVZs, whereas PVI alone worked in patients without LVZs, even in those with PeAF. PMID- 27235001 TI - Reprint of "Hypomyelinating disorders: An MRI approach. AB - In recent years, the concept of hypomyelinating disorders has been proposed as a group of disorders with varying systemic manifestations that are identified by MR findings of absence or near absence of the T2 hypointensity that develops in white matter as a result of myelination. Initially proposed as a separate group because they were the largest single category of undiagnosed leukodystrophies, their separation as a distinct group that can be recognized by looking for a specific MRI feature has resulted in a marked increase in their diagnosis and a better understanding of the different causes of hypomyelination. This review will discuss the clinical presentations, imaging findings on standard MRI, and new MRI related techniques that allow a better understanding of these disorders and proposed methods for quantifying the myelination as a potential means of assessing disease course and the effects of proposed treatments. Disorders with hypomyelination of white matter, or hypomyelinating disorders (HMDs), represent the single largest category among undiagnosed genetic leukoencephalopathies (Schiffmann and van der Knaap, 2009; Steenweg et al., 2010). This group of inborn errors of metabolism is characterized by a magnetic resonance imaging (MRI) appearance of reduced or absent myelin development: delay in the development of T2 hypointensity and, often, T1 hyperintensity in the white matter of the brain. The concept of hypomyelination was first conceptualized by (Schiffmann and van der Knaap, 2009; Steenweg et al., 2010; Schiffmann et al., 1994) in a series of papers that showed that these MRI characteristics were easily recognized, were different from the MRI characteristics of dysmyelinating and demyelinating disorders, and that the combination of these imaging findings with specific other clinical and imaging features could be used to make diagnoses with some confidence. In this manuscript, we will discuss the physiologic and genetic bases of hypomyelinating disorders, as well as their classification, clinical manifestations and imaging characteristics. PMID- 27235002 TI - Validation of Dynamic optical coherence tomography for non-invasive, in vivo microcirculation imaging of the skin. AB - OBJECTIVES: Dynamic optical coherence tomography (D-OCT) is an angiographic variation of OCT that non-invasively provides images of the in vivo microvasculature of the skin by combining conventional OCT images with flow data. The objective of this study was to investigate and report on the D-OCT technique for imaging of the vascular networks in skin as well as to validate the method by comparing the results against already accepted blood flow measuring tools. METHODS: 35 healthy subjects were recruited for the multicentre study, consisting of three experiments set up to examine the vascular blood perfusion during different induced physiologic changes in the blood flow. In order to validate the D-OCT images against existing techniques for blood flow measuring we performed consecutive D-OCT, chromametry and laser speckle contrast imager (LSCI) measurements on identical skin sites in all of the experiments. Blinded observer evaluations were performed in order to evaluate the vascular morphology in the D OCT images. RESULTS: The results showed a statistically significant positive correlation between the D-OCT measurements and the LCSI flux measurements (rs=0.494; 95% CI [0.357, 0.615]; p<0.001), and also the redness a* measurements were positively correlated with the D-OCT measurements (r=0.48; 95% CI [0.406, 0.55]). D-OCT was able to reliably image and identify morphologic changes in the vascular network consistent with the induced physiological changes of blood flow. CONCLUSION: This study has initiated validation of the use of D-OCT for imaging of skin blood flow. Our results showed that D-OCT was able to reliably image and identify changes in the skin vasculature consistent with the induced physiological blood flow changes. These basic findings support the use of D-OCT imaging for in vivo microcirculation imaging of the skin. PMID- 27235003 TI - PXD101 analogs with L-phenylglycine-containing branched cap as histone deacetylase inhibitors. AB - Histone deacetylases (HDACs) allow histones to wrap DNA more tightly and finally lead to the repression of some tumor suppressor genes. Histone deacetylase inhibitors (HDACIs) have been proved to have effects on tumorigenesis and tumor progression. In this study, we reported the design, synthesis, and in vitro activity evaluation of novel PXD101 analogs with L-phenylglycine-containing cap as HDACIs. Our results showed that HDACs inhibitory activities of compounds 10k, 10r, and 10s were not only superior to the first approved HDACI SAHA, but also comparable to their parent compound PXD101, a recently approved HDACI in 2014. However, all 6 selected PXD101 analogs exhibited moderate in vitro antiproliferative activities, less potent than PXD101 and SAHA. Representative compound 10s showed similar HDACs isoform selective profile to PXD101, which demonstrated that introduction of L-phenylglycine-containing branched cap group could not change the isoform selectivity of PXD101 dramatically. PMID- 27235004 TI - Periprocedural Anticoagulation Management of Patients with Thrombophilia. AB - BACKGROUND: Appropriate periprocedural management of the chronically anticoagulated patient with an inherited or acquired thrombophilia is uncertain. The objective of this study was to test "thrombophilia" as a potential predictor of the 3-month cumulative incidence of thromboembolism and major bleeding among chronically anticoagulated patients undergoing an invasive procedure. METHODS: In a prospective cohort study, consecutive chronically anticoagulated patients referred to the Mayo Thrombophilia Center for standardized periprocedural anticoagulation management who had venous thromboembolism and complete thrombophilia testing were categorized as "severe," "non-severe," or "no identifiable" thrombophilia. The 3-month cumulative incidence rates of thromboembolism, bleeding, and death were estimated using the Kaplan-Meier product limit method. RESULTS: Among 362 patients with complete thrombophilia testing, 165 (46%) had a defined thrombophilia; 76 patients had severe thrombophilia, mainly due to antiphospholipid syndrome (66%). Half of the patients in each of the 3 groups received pre- and postprocedure heparin. During follow-up, there were no thromboembolic events, rare major bleeding events (1% for each group), and 4 deaths. Due to the very low event rates for each of these outcomes, Cox proportional hazard modeling could not be performed. CONCLUSIONS: Periprocedural event rates were low irrespective of thrombophilia status. Inherited or acquired thrombophilia was not a predictor of thromboembolism, major bleeding, or mortality after temporary interruption of chronic anticoagulation for an invasive procedure. PMID- 27235005 TI - Presumptive Lupus Enteritis. PMID- 27235006 TI - Mitral Valve Prolapse, Psychoemotional Status, and Quality of Life: Prospective Investigation in the Current Era. AB - OBJECTIVE: The purpose of this study is to investigate whether mitral valve prolapse is associated with the patient's psychoemotional status and health related quality of life. METHODS: Mitral valve prolapse and mitral regurgitation were prospectively and comprehensively assessed in 281 patients (age 61 +/- 13 years; 63% men); 216 patients with mitral valve prolapse were compared with 65 without mitral valve prolapse (of similar age and sex). Simultaneously, we assessed the patient's psychoemotional status (anxiety, depression, posttraumatic stress symptoms), health-related quality of life, and perceived severity of illness using validated questionnaires. RESULTS: Twenty-nine percent of the patients had either no or mild mitral regurgitation (area of effective regurgitant orifice <=0.2), and 71% had clinically significant mitral regurgitation (moderate/severe). Stratifying patients into no/mild vs moderate/severe mitral regurgitation revealed no differences in psychoemotional status or mental health-related quality of life between patients with mitral valve prolapse vs those without mitral valve prolapse within each subgroup; no/mild mitral regurgitation and moderate/severe mitral regurgitation (all P >= .5). In multivariate analysis, mitral valve prolapse was not independently associated with psychoemotional status or health-related quality of life (all P >= .4). In addition, while objective severity of the illness was not related to psychoemotional status or health-related quality of life (all P >= .2), the patient's perceived severity of illness predicted in and of itself all psychoemotional (all P < .03) and quality-of-life outcomes (all P < .003). CONCLUSION: Mitral valve prolapse is not a determinant of the patient's psychoemotional status or quality of life. Psychoemotional status and health related quality of life are determined by the patient's perception of the severity of the mitral valve disease, rather than by the presence of mitral valve prolapse. PMID- 27235007 TI - The Call for a Physical Activity Vital Sign in Clinical Practice. PMID- 27235008 TI - Patients Have a Right to All Their Medical Test Results. PMID- 27235009 TI - Active pulmonary tuberculosis: Role for amikacin in early treatment. AB - OBJECTIVE: To evaluate the efficacy of amikacin on sputum conversion during initial sputum smear positive tuberculosis treatment. MATERIAL AND METHODS: Single-center observational cohort study (2012-2013) evaluating time to sputum smear conversion with standard treatment (ST) versus standard treatment+amikacin (IV 15mg/kg/day) for seven days (STamK). RESULTS: Forty-five patients were included. Median time to smear negative samples was 26.5 days (14-56) for the 30 (66.7%) patients included in the ST group and 48 days (19.5-69.5) for the 15 patients (33.3%) included in the STamK group (P=0.76). Time to negative culture was only known for 27 patients (61.4%): 47.5 days (26-58) for 18 patients in the ST group and 40 days (14-77) for nine patients in the STamK group. CONCLUSION: Despite our small sample size, the addition of amikacin in active tuberculosis treatment did not seem to impact time to smear conversion or period of contagiousness. PMID- 27235014 TI - Effects of drug discontinuation after short-term daily alendronate administration on osteoblasts and osteocytes in mice. AB - In order to determine whether osteoclastic bone resorption is restarted after withdrawn of bisphosphonates, we conducted histological examinations on murine osteoclasts, osteoblasts and osteocytes after discontinuation of a daily regimen of alendronate (ALN) with a dosage of 1 mg/kg/day for 10 days. After drug discontinuation, metaphyseal trabecular number and bone volume remained unaltered for the first 4 days. Osteoclast number did not increase, while the number of apoptotic osteoclasts was elevated. On the other hand, tissue non-specific alkaline phosphatase-immunoreactive area was markedly reduced after ALN discontinuation. In addition, osteocytes showed an atrophic profile with empty lacunar areas during and after ALN treatment. Interestingly, as early as 36 h after a single ALN injection, osteocytes show signs of atrophy despite the presence of active osteoblasts. Structured illumination microscopy system showed shortening of osteocytic cytoplasmic processes after drug cessation, suggesting a possible morphological and functional disconnection between osteocytes and osteoblasts. Taken together, it appears that osteoclastic bone resorption is not resumed after ALN discontinuation; also, osteoblasts and osteocytes hardly seem to recover once they are inactivated and atrophied by ALN. In summary, it seems that one must pay more attention to the responses of osteoblasts and osteocytes, rather focusing on the resuming of osteoclastic bone resorption after the ALN discontinuation. PMID- 27235015 TI - The effects of morphine on the temporal structure of Wistar rat behavioral response to pain in hot-plate. AB - RATIONALE: The largest amount of researches on the hot-plate test was carried out using quantitative assessments. However, the evaluation of the relationships among the different elements that compose the behavioral response to pain requires different approaches. Although previous studies have provided clear information on the behavioral structure of the response, no data are available on its temporal structure. OBJECTIVES: The objective of this study was to investigate the temporal structure of the behavioral response to pain in Wistar rat tested in hot-plate and how this structure was influenced by morphine-induced analgesia. METHODS: The behavior of four groups of subjects tested in hot-plate, one administered saline and three with different doses (3, 6, 12 mg/kg) of morphine IP, was analyzed by means of quantitative and t-pattern analyses. The latter is a multivariate technique able to detect the existence of statistically significant temporal relationships among the behavioral events in time. RESULTS: A clear-cut influence of morphine on quantitative parameters of the response to the noxious stimulation was observed. T-pattern analysis evidenced profound structural changes of behavior. Twenty-four different t-patterns were identified following saline, whereas a dose-dependent reduction was observed following morphine. Such a reduction was accompanied by a decrease of the total amount of t patterns detected. CONCLUSIONS: Morphine, by reducing the effects of the noxious stimulation, orients animal behavior prevalently toward exploratory t-patterns. In addition, it is suggested that the temporal structure of the response is very quickly organized and adapted to environmental noxious cues. PMID- 27235016 TI - Self-titration by experienced e-cigarette users: blood nicotine delivery and subjective effects. AB - RATIONALE: Self-titration is well documented in the tobacco literature. The extent to which e-cigarette users (vapers) self-titrate is unknown. OBJECTIVE: This study explored the effects of high and low nicotine strength liquid on puffing topography, nicotine delivery and subjective effects in experienced vapers. METHODS: Eleven experienced male vapers completed 60 min of ad libitum vaping under low (6 mg/mL) and high (24 mg/mL) nicotine liquid conditions in two separate sessions. Measurements included puffing topography (puff number, puff duration, volume of liquid consumed) and changes in plasma nicotine levels, craving, withdrawal symptoms, self-reported hit, satisfaction and adverse effects. RESULTS: Liquid consumption and puff number were higher and puff duration longer, in the low nicotine strength condition (all ps < 0.01). The mean difference in nicotine boost from baseline in the low condition was 8.59 (7.52) ng/mL, 16.99 (11.72) ng/mL and 22.03 (16.19) ng/mL at 10, 30 and 60 min, respectively. Corresponding values for the high condition were 33.77 (34.88) ng/mL, 35.48 (28.31) ng/mL and 43.57 (34.78) ng/mL (ps < 0.05). There were no statistically significant differences between conditions in self-reported craving, withdrawal symptoms, satisfaction, hit or adverse effects. CONCLUSIONS: Vapers engaged in compensatory puffing with lower nicotine strength liquid, doubling their consumption. Whilst compensatory puffing was sufficient to reduce craving and withdrawal discomfort, self-titration was incomplete with significantly higher plasma nicotine levels in the high condition. PMID- 27235017 TI - Neuropeptide S differently modulates alcohol-related behaviors in alcohol preferring and non-preferring rats. AB - RATIONALE: Neuropeptide S (NPS) displays unique pharmacological properties and induces both anxiolytic and pro-stress/arousal activities. Previous studies performed using Wistar rats demonstrated that NPS facilitated alcohol and cocaine seeking but did not affect alcohol or cocaine consumption. OBJECTIVES: Here, we investigated the effects of NPS in Marchigian Sardinian alcohol-preferring (msP) rats, a rat strain characterized by excessive alcohol consumption comorbid with heightened anxiety and depressive-like phenotypes. Specifically, we evaluated the effect of NPS on operant alcohol self-administration by msP rats compared to Wistar rats. The effect of NPS on cue-induced reinstatement of alcohol seeking in msP rats was also evaluated. Finally, using the open field test (OFT) and the elevated plus maze (EPM), we evaluated the effects of NPS on locomotor activity and anxiety. RESULTS: NPS reduced alcohol self-administration but did not affect cue-induced reinstatement in the msP rat. In addition, NPS induced reinstatement of extinguished alcohol seeking in Wistar rats without affecting alcohol intake. In the EPM task, NPS, in accordance with its anxiolytic activity, increased the time spent in the open arm of the arena by msP rats, although this effect was not observed in Wistar rats. CONCLUSIONS: These data suggest that the effect of NPS is strongly influenced by the genetic background of the animal. In Wistar rats, NPS acts as a pro-arousal agent to promote the reinstatement of alcohol seeking. However, when alcohol drinking is motivated by or associated with a state of pathological anxiety, NPS attenuates alcohol consumption and seeking due to its anxiolytic activity. PMID- 27235018 TI - The Effects of Ferulic Acid Against Oxidative Stress and Inflammation in Formaldehyde-Induced Hepatotoxicity. AB - This study was designed to elucidate the protective effects of ferulic acid (FA) on formaldehyde-induced hepatotoxicity by measuring some routine biochemical parameters, cytokine levels, and oxidative stress-related parameters in addition to YKL-40 in male Wistar albino rats. Tissue superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) activities, and tissue malondialdehyde (MDA) levels were measured. Also, serum YKL-40, TNF-alpha, IL-6, IL-1beta, IL-8, total protein, albumin, total bilirubin concentrations, and AST, ALT, ALP, and LDH activities were measured. Histological specimens were examined in light microscopy. Formaldehyde significantly increased tissue MDA, and serum cytokine levels and also decreased activities of antioxidant enzymes. FA treatment decreased MDA and cytokine levels and increased activities of antioxidant enzymes. FA also alleviated degeneration due to formaldehyde toxicity. We suggested that FA can be used as a promising hepatoprotective agent against formaldehyde toxicity because of the obvious beneficial effects on oxidative stress parameters. PMID- 27235019 TI - The combination effects of Shen-Ling-Bai-Zhu on promoting apoptosis of transplanted H22 hepatocellular carcinoma in mice receiving chemotherapy. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Shen-Ling-Bai-Zhu Powder (SLBZP) is a classic traditional Chinese medical formula that has been used for several decades in the treatment of patients with gastrointestinal malignancies. Whether SLBZP is best employed as single agent or adjunctive therapy has yet to be determined as does the mechanism whereby SLBZP exerts its anti-tumor effects. AIM OF THE STUDY: To investigate the effects of SLBZP alone and in combination with Cytoxan (CTX) on tumor growth, malignant cell apoptosis and Akt/Nuclear Factor kappa B (NF-KB) signaling in a murine model of hepatocellular carcinoma (HCC) receiving chemotherapy. MATERIALS AND METHODS: Sixty-four adult mice developed HCC following subcutaneous inoculation with H22 hepatocellular carcinoma cells. Seven days later, all received chemotherapy with CTX (200mg/kg) once. Mice were then randomized into eight study groups (N=8/group). Three groups were treated with different concentrations of SLBZP alone (6.00, 3.00, 1.5g/kg), three with SLBZP (6.00, 3.00, 1.5g/kg) plus CTX (20mg/kg), one with CTX (20mg/kg) alone (positive control), and one with physiologic saline (untreated, negative control). All groups were treated for 14 days. Tumor size, histology and serum or tissue levels and/or mRNA expression of PDGF-BB, VEGF, Ang-1, Ang-2, NF-KB, B-cell lymphoma-2 (Bcl-2); B-cell lymphoma-extra large (Bcl-xL); X-linked inhibitor of apoptosis (XIAP), Survivin, Caspase-3, Caspase-9, Caspase-7, Akt and phosphorylated Akt expression were documented at the end of treatment. RESULTS: Compared to untreated negative controls, tumor sizes were decreased in the CTX alone, SLBZP (M)+CTX and SLBZP (H)+CTX groups (-52%,-53% and -58% respectively). Tumor cell density was decreased in all treated groups but most apparent in the SLBZP (H)+CTX group. Electron microscopic evidence of apoptosis was also most apparent in this group. Serum and/or tissue levels and expression of PDGF-BB, VEGF, Ang-1, Ang-2, their downstream signaling proteins and anti-apoptotic markers were lowest and pro-apoptotic markers highest in SLBZP (H)+CTX treated mice. CONCLUSIONS: In this chemotherapy-induced animal model of HCC, SLBZP was most efficacious as adjunctive therapy and appears to act by inhibiting tumor growth promoters and anti-apoptotic proteins while enhancing pro-apoptotic proteins. PMID- 27235021 TI - Multimodal Brain Monitoring in Congenital Cardiac Surgery: The Importance of Processed Electroencephalogram Monitor, NeuroSENSE, in Addition to Cerebral Near Infrared Spectroscopy. PMID- 27235020 TI - Amelioration of testosterone induced benign prostatic hyperplasia by Prunus species. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Benign prostatic hyperplasia (BPH) is a common urological disorder of men. The ethnomedicinal use of an African plant Prunus africana (Hook.f.) Kalkman (Pygeum) in treating men's problems made it a popular remedy all over the globe for the treatment of BPH and related disorders. However, rampant collections made from the wild in Africa have pushed the plant to Appendix II of CITES demanding conservation of the species. AIM OF THE STUDY: In the present study, the aim was to unearth the protective effect of bark of different species of Prunus against BPH. The five selected Indian plants of family Rosaceae viz. Prunus amygdalus Stokes, Prunus armeniaca L., Prunus cerasoides Buch.-Ham. ex D. Don, Prunus domestica L. and Prunus persica (L.) Batsch were evaluated against P. africana (Hook.f.) Kalkman for a suitable comparison of efficacy as antiBPH agents. MATERIALS AND METHODS: The antiBPH activity was evaluated in testosterone (2mg/kg/day, s.c, 21 days) induced BPH in Wistar rats. The parameters studied were body weights; histopathological examination, immunohistochemistry (PCNA) and biochemical estimations of the prostate; supported by prostatic index, testicular index, creatinine, testosterone levels; antioxidant and anti-inflammatory evaluation. The study also included chemical profiling using three markers (beta-sitosterol, docosyl ferulate and ursolic acid) and estimation of beta-sitosterol content through GC. RESULTS: The Prunus species showed the presence of all the three markers in their TLC fingerprint profile and maximum amount of beta-sitosterol by GC was observed in P. domestica. Interestingly, all the species exhibited significant amelioration in testosterone induced parameters with P. domestica showing the most encouraging effect as indicated from histopathological examination, immunohistochemistry and biochemical studies. The Prunus species further showed remarkable anti-inflammatory and antioxidant activity signifying their role in interfering with various possible factors involved in BPH. CONCLUSIONS: These findings are suggestive of a meaningful inhibitory effect of testosterone induced BPH by the bark of different species of Prunus in the order of P. domestica, P. persica, P. amygdalus, P. cerasoides and P. armeniaca with an efficacy of P. domestica comparable to P. africana and can be used as the potential backup of Pygeum for the management of BPH. PMID- 27235022 TI - Benefits of a Paleolithic diet with and without supervised exercise on fat mass, insulin sensitivity, and glycemic control: a randomized controlled trial in individuals with type 2 diabetes. AB - BACKGROUND: Means to reduce future risk for cardiovascular disease in subjects with type 2 diabetes are urgently needed. METHODS: Thirty-two patients with type 2 diabetes (age 59 +/- 8 years) followed a Paleolithic diet for 12 weeks. Participants were randomized to either standard care exercise recommendations (PD) or 1-h supervised exercise sessions (aerobic exercise and resistance training) three times per week (PD-EX). RESULTS: For the within group analyses, fat mass decreased by 5.7 kg (IQR: -6.6, -4.1; p < 0.001) in the PD group and by 6.7 kg (-8.2, -5.3; p < 0.001) in the PD-EX group. Insulin sensitivity (HOMA-IR) improved by 45% in the PD (p < 0.001) and PD-EX (p < 0.001) groups. HbA1c decreased by 0.9% (-1.2, -0.6; p < 0.001) in the PD group and 1.1% (-1.7, -0.7; p < 0.01) in the PD-EX group. Leptin decreased by 62% (p < 0.001) in the PD group and 42% (p < 0.001) in the PD-EX group. Maximum oxygen uptake increased by 0.2 L/min (0.0, 0.3) in the PD-EX group, and remained unchanged in the PD group (p < 0.01 for the difference between intervention groups). Male participants decreased lean mass by 2.6 kg (-3.6, -1.3) in the PD group and by 1.2 kg (-1.3, 1.0) in the PD-EX group (p < 0.05 for the difference between intervention groups). CONCLUSIONS: A Paleolithic diet improves fat mass and metabolic balance including insulin sensitivity, glycemic control, and leptin in subjects with type 2 diabetes. Supervised exercise training may not enhance the effects on these outcomes, but preserves lean mass in men and increases cardiovascular fitness. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27235075 TI - An Evaluation of Web- and Print-Based Methods to Attract People to a Physical Activity Intervention. AB - BACKGROUND: Cost-effective and efficient methods to attract people to Web-based health behavior interventions need to be identified. Traditional print methods including leaflets, posters, and newspaper advertisements remain popular despite the expanding range of Web-based advertising options that have the potential to reach larger numbers at lower cost. OBJECTIVE: This study evaluated the effectiveness of multiple Web-based and print-based methods to attract people to a Web-based physical activity intervention. METHODS: A range of print-based (newspaper advertisements, newspaper articles, letterboxing, leaflets, and posters) and Web-based (Facebook advertisements, Google AdWords, and community calendars) methods were applied to attract participants to a Web-based physical activity intervention in Australia. The time investment, cost, number of first time website visits, the number of completed sign-up questionnaires, and the demographics of participants were recorded for each advertising method. RESULTS: A total of 278 people signed up to participate in the physical activity program. Of the print-based methods, newspaper advertisements totaled AUD $145, letterboxing AUD $135, leaflets AUD $66, posters AUD $52, and newspaper article AUD $3 per sign-up. Of the Web-based methods, Google AdWords totaled AUD $495, non-targeted Facebook advertisements AUD $68, targeted Facebook advertisements AUD $42, and community calendars AUD $12 per sign-up. Although the newspaper article and community calendars cost the least per sign-up, they resulted in only 17 and 6 sign-ups respectively. The targeted Facebook advertisements were the next most cost-effective method and reached a large number of sign-ups (n=184). The newspaper article and the targeted Facebook advertisements required the lowest time investment per sign-up (5 and 7 minutes respectively). People reached through the targeted Facebook advertisements were on average older (60 years vs 50 years, P<.001) and had a higher body mass index (32 vs 30, P<.05) than people reached through the other methods. CONCLUSIONS: Overall, our results demonstrate that targeted Facebook advertising is the most cost-effective and efficient method at attracting moderate numbers to physical activity interventions in comparison to the other methods tested. Newspaper advertisements, letterboxing, and Google AdWords were not effective. The community calendars and newspaper articles may be effective for small community interventions. CLINICALTRIAL: Australian New Zealand Clinical Trials Registry: ACTRN12614000339651; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363570&isReview= rue (Archived by WebCite at http://www.webcitation.org/6hMnFTvBt). PMID- 27235077 TI - Impaired fear extinction in adolescent rodents: Behavioural and neural analyses. AB - Despite adolescence being a developmental window of vulnerability, up until very recently there were surprisingly few studies on fear extinction during this period. Here we summarise the recent work in this area, focusing on the unique behavioural and neural characteristics of fear extinction in adolescent rodents, and humans where relevant. A prominent hypothesis posits that anxiety disorders peak during late childhood/adolescence due to the non-linear maturation of the fear inhibition neural circuitry. We discuss evidence that impaired extinction retention in adolescence is due to subregions of the medial prefrontal cortex and amygdala mediating fear inhibition being underactive while other subregions that mediate fear expression are overactive. We also review work on various interventions and surprising circumstances which enhance fear extinction in adolescence. This latter work revealed that the neural correlates of extinction in adolescence are different to that in younger and older animals even when extinction retention is not impaired. This growing body of work highlights that adolescence is a unique period of development for fear inhibition. PMID- 27235076 TI - Mechanisms contributing to prefrontal cortex maturation during adolescence. AB - Adolescence is defined as a transitional period between childhood and adulthood characterized by changes in social interaction and acquisition of mature cognitive abilities. These changes have been associated with the maturation of brain regions involved in the control of motivation, emotion, and cognition. Among these regions, the protracted development of the human prefrontal cortex during adolescence has been proposed to underlie the maturation of cognitive functions and the regulation of affective responses. Studies in animal models allow us to test the causal contribution of specific neural processes in the development of the prefrontal cortex and the acquisition of adult behavior. This review summarizes the cellular and synaptic mechanisms occurring in the rodent prefrontal cortex during adolescence as a model for understanding the changes underlying human prefrontal development. PMID- 27235078 TI - Reappraising striatal D1- and D2-neurons in reward and aversion. AB - The striatum has been involved in complex behaviors such as motor control, learning, decision-making, reward and aversion. The striatum is mainly composed of medium spiny neurons (MSNs), typically divided into those expressing dopamine receptor D1, forming the so-called direct pathway, and those expressing D2 receptor (indirect pathway). For decades it has been proposed that these two populations exhibit opposing control over motor output, and recently, the same dichotomy has been proposed for valenced behaviors. Whereas D1-MSNs mediate reinforcement and reward, D2-MSNs have been associated with punishment and aversion. In this review we will discuss pharmacological, genetic and optogenetic studies that indicate that there is still controversy to what concerns the role of striatal D1- and D2-MSNs in this type of behaviors, highlighting the need to reconsider the early view that they mediate solely opposing aspects of valenced behaviour. PMID- 27235080 TI - What's in the name 'alexithymia'? A commentary on "Affective agnosia: Expansion of the alexithymia construct and a new opportunity to integrate and extend Freud's legacy.". AB - The recent proposal of a new type of agnosia termed 'affective agnosia' extends Freud's legacy and captures the concept of not knowing one's own emotions. This concept links well with the theory of levels of emotional awareness and maps onto a hierarchical model of neural substrates of emotional experience, but does not encompass the pensee operatoire component of the alexithymia construct. Moreover, identifying agnosia and anomia subtypes, which connotes a categorical conceptualization of alexithymia, is inconsistent with the dimensional nature of the construct. We describe a more widely accepted definition of alexithymia, and argue that although aptly descriptive, the concept of affective agnosia does not advance the theory, measurement, and treatment of alexithymia. A review of alexithymia literature indicates that impairment in the mental representation of emotions has been a central aspect of alexithymia theory since the concept was introduced, and guided the development of the Toronto Alexithymia Scale and other measures of the construct. Moreover, techniques to enhance mentalization of emotions have been used by psychotherapists for several decades. PMID- 27235079 TI - Adolescence and the ontogeny of the hormonal stress response in male and female rats and mice. AB - Adolescent development is marked by many changes in neuroendocrine function, resulting in both immediate and long-term influences on an individual's physiology and behavior. Stress-induced hormonal responses are one such change, with adolescent animals often showing different patterns of hormonal reactivity following a stressor compared with adults. This review will describe the unique ways in which adolescent animals respond to a variety of stressors and how these adolescent-related changes in hormonal responsiveness can be further modified by the sex and previous experience of the individual. Potential central and peripheral mechanisms that contribute to these developmental shifts in stress reactivity are also discussed. Finally, the short- and long-term programming effects of chronic stress exposure during adolescence on later adult hormonal responsiveness are also examined. Though far from a clear understanding of the neurobehavioral consequences of these adolescent-related shifts in stress reactivity, continued study of developmental changes in stress-induced hormonal responses may shed light on the increased vulnerability to physical and psychological dysfunctions that often accompany a stressful adolescence. PMID- 27235083 TI - Self, cortical midline structures and the resting state: Implications for Alzheimer's disease. AB - Different aspects of the self have been reported to be affected in many neurological or psychiatric diseases such as Alzheimer's disease (AD), including mainly higher-level cognitive self-unawareness. This higher sense of self awareness is most likely related to and dependent on episodic memory, due to the proper integration of ourselves in time, with a permanent conservation of ourselves (i.e., sense of continuity across time). Reviewing studies in this field, our objective is thus to raise possible explanations, especially with the help of neuroimaging studies, for where such self-awareness deficits originate in AD patients. We describe not only episodic (and autobiographical memory) impairment in patients, but also the important role of cortical midline structures, the Default Mode Network, and the resting state (intrinsic brain activity) for the processing of self-related information. PMID- 27235084 TI - Measles immunity among pregnant women aged 15-44 years in Namibia, 2008 and 2010. AB - BACKGROUND: Namibia experienced a large measles outbreak starting in 2009, with 38% of reported cases in adults, including women of reproductive age. Population immunity was assessed among pregnant women to determine whether immunization activities were needed in adults to achieve measles elimination in Namibia. METHODS: A total of 1708 and 2040 specimens sampled from Namibian pregnant women aged 15-44 years who were included in the 2008 and 2010 National HIV Sentinel Survey, respectively, were tested for measles immunoglobulin G antibody. The proportion of women seropositive overall and by 5-year age strata was determined, and factors associated with seropositivity were analyzed by logistic regression, including age, facility type, gravidity, HIV status, and urban/rural setting. Seropositivity in 2008 versus 2010 was compared. RESULTS: In both analysis years, measles seropositivity was lower in 15-19-year-olds (77%) and 20-24-year-olds (85 87%) and higher in 25-44-year-olds (90-94%) (2008, p<0.001; 2010, p<0.001). Overall measles seropositivity did not differ between 2008 (87%) and 2010 (87%) (p=0.7). HIV status did not affect seropositivity. CONCLUSIONS: Late in a large measles outbreak, 13% of pregnant women in Namibia, and almost one in four 15-19 year-old pregnant women, remained susceptible to measles. In Namibia, immunization campaigns with measles-containing vaccine should be considered for adults. PMID- 27235082 TI - Adolescence as a period of vulnerability and intervention in schizophrenia: Insights from the MAM model. AB - Adolescence is a time of extensive neuroanatomical, functional and chemical reorganization of the brain, which parallels substantial maturational changes in behavior and cognition. Environmental factors that impinge on the timing of these developmental factors, including stress and drug exposure, increase the risk for psychiatric disorders. Indeed, antecedents to affective and psychotic disorders, which have clinical and pathophysiological overlap, are commonly associated with risk factors during adolescence that predispose to these disorders. In the context of schizophrenia, psychosis typically begins in late adolescence/early adulthood, which has been replicated by animal models. Rats exposed during gestational day (GD) 17 to the mitotoxin methylazoxymethanol acetate (MAM) exhibit behavioral, pharmacological, and anatomical characteristics consistent with an animal model of schizophrenia. Here we provide an overview of adolescent changes within the dopamine system and the PFC and review recent findings regarding the effects of stress and cannabis exposure during the peripubertal period as risk factors for the emergence of schizophrenia-like deficits. Finally, we discuss peripubertal interventions appearing to circumvent the emergence of adult schizophrenia-like deficits. PMID- 27235086 TI - A screening system for smear-negative pulmonary tuberculosis using artificial neural networks. AB - OBJECTIVES: Molecular tests show low sensitivity for smear-negative pulmonary tuberculosis (PTB). A screening and risk assessment system for smear-negative PTB using artificial neural networks (ANNs) based on patient signs and symptoms is proposed. METHODS: The prognostic and risk assessment models exploit a multilayer perceptron (MLP) and inspired adaptive resonance theory (iART) network. Model development considered data from 136 patients with suspected smear-negative PTB in a general hospital. RESULTS: MLP showed higher sensitivity (100%, 95% confidence interval (CI) 78-100%) than the other techniques, such as support vector machine (SVM) linear (86%; 95% CI 60-96%), multivariate logistic regression (MLR) (79%; 95% CI 53-93%), and classification and regression tree (CART) (71%; 95% CI 45-88%). MLR showed a slightly higher specificity (85%; 95% CI 59-96%) than MLP (80%; 95% CI 54-93%), SVM linear (75%, 95% CI 49-90%), and CART (65%; 95% CI 39-84%). In terms of the area under the receiver operating characteristic curve (AUC), the MLP model exhibited a higher value (0.918, 95% CI 0.824-1.000) than the SVM linear (0.796, 95% CI 0.651-0.970) and MLR (0.782, 95% CI 0.663-0.960) models. The significant signs and symptoms identified in risk groups are coherent with clinical practice. CONCLUSIONS: In settings with a high prevalence of smear-negative PTB, the system can be useful for screening and also to aid clinical practice in expediting complementary tests for higher risk patients. PMID- 27235085 TI - Assessing the burden of pneumonia using administrative data from Malaysia, Indonesia, and the Philippines. AB - OBJECTIVES: To describe the incidence, mortality, cost, and length of stay (LOS) of hospitalized community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP) in three Southeast Asian countries: Malaysia, Indonesia, and the Philippines. METHODS: Using Casemix system data from contributing hospitals, patients with International Classification of Diseases 10(th) revision (ICD-10) codes identifying pneumonia were categorized into CAP or HAP using a logical algorithm. The incidence among hospitalized patients, case fatality rates (CFR), mean LOS, and cost of admission were calculated. The population incidence was calculated based on Malaysian data. RESULTS: For every 100000 discharges, CAP and HAP incidences were 14245 and 5615 cases, respectively, in the Philippines, 4205 and 2187, respectively, in Malaysia, and 988 and 538, respectively, in Indonesia. The impact was greatest in the young and the elderly. The CFR varied from 1.4% to 4.2% for CAP and from 9.1% and 25.5% for HAP. The mean LOS was 6.1-8.6 days for CAP and 6.9-10.2 days for HAP. The cost of hospitalization was between USD 254 and USD 1208 for CAP and between USD 275 and USD 1482 for HAP. CONCLUSIONS: The burden of CAP and HAP is high. Results varied between the three countries, likely due to differences in socio-economic conditions, health system differences, and ICD-coding practices. PMID- 27235087 TI - Epidemiological and virological differences in human clustered and sporadic infections with avian influenza A H7N9. AB - BACKGROUND: Previous research has suggested that avian influenza A H7N9 has a greater potential pandemic risk than influenza A H5N1. This research investigated the difference in human clustered and sporadic cases of H7N9 virus and estimated the relative risk of clustered infections. METHODS: Comparative epidemiology and virology studies were performed among 72 sporadic confirmed cases, 17 family clusters (FCs) caused by human-to-human transmission, and eight live bird market clusters (LCs) caused by co-exposure to the poultry environment. RESULTS: The case fatality of FCs, LCs and sporadic cases (36%, 26%, and 29%, respectively) did not differ among the three groups (p>0.05). The average age (36 years, 60 years, and 58 years), co-morbidities (31%, 60%, and 54%), exposure to birds (72%, 100%, and 83%), and H7N9-positive rate (20%, 64%, and 35%) in FCs, LCs, and sporadic cases, respectively, differed significantly (p<0.05). These higher risks were associated with increased mortality. There was no difference between primary and secondary cases in LCs (p>0.05). However, exposure to a person with confirmed avian influenza A H7N9 (primary 12% vs. secondary 95%), history of visiting a live bird market (100% vs. 59%), multiple exposures (live bird exposure and human to-human transmission history) (12% vs. 55%), and median days from onset to antiviral treatment (6 days vs. 3 days) differed significantly between primary and secondary cases in FCs (p<0.05). Mild cases were found in 6% of primary cases vs. 32% of secondary cases in FCs (p<0.05). Twenty-five isolates from the three groups showed 99.1-99.9% homology and increased human adaptation. CONCLUSIONS: There was no statistical difference in the case fatality rate and limited transmission between FCs and LCs. However, the severity of the primary cases in FCs was much higher than that of the secondary cases due to the older age and greater underlying disease of the latter patients. PMID- 27235081 TI - Sensory processing in autism spectrum disorders and Fragile X syndrome-From the clinic to animal models. AB - Brains are constantly flooded with sensory information that needs to be filtered at the pre-attentional level and integrated into endogenous activity in order to allow for detection of salient information and an appropriate behavioral response. People with Autism Spectrum Disorder (ASD) or Fragile X Syndrome (FXS) are often over- or under-reactive to stimulation, leading to a wide range of behavioral symptoms. This altered sensitivity may be caused by disrupted sensory processing, signal integration and/or gating, and is often being neglected. Here, we review translational experimental approaches that are used to investigate sensory processing in humans with ASD and FXS, and in relevant rodent models. This includes electroencephalographic measurement of event related potentials, neural oscillations and mismatch negativity, as well as habituation and pre-pulse inhibition of startle. We outline robust evidence of disrupted sensory processing in individuals with ASD and FXS, and in respective animal models, focusing on the auditory sensory domain. Animal models provide an excellent opportunity to examine common mechanisms of sensory pathophysiology in order to develop therapeutics. PMID- 27235088 TI - Simultaneous detection of 13 viruses involved in meningoencephalitis using a newly developed multiplex PCR Mag-array system. AB - BACKGROUND: The early detection and identification of pathogens in central nervous system viral infections associated with neurological disease increases the survival rate. However, the limitations of current diagnostic methods contribute to a lack of proper diagnosis in 62% of patients. Therefore, a robust method for detecting multiple viruses in a single reaction with high specificity, throughput, and speed is required. METHODS: A multiplex PCR Mag-Array (MPMA) system was developed that integrates three strategies: chimeric primer design, temperature switch PCR, and MagPlex-TAG techniques. The MPMA was used to amplify 13 target viral sequences simultaneously, with plasmids containing specific viral sequences as standard samples. To evaluate its clinical performance, 177 cerebrospinal fluid (CSF) samples were tested. RESULTS: The MPMA system presented high specificity and efficiency in detecting a control panel of 13 plasmids. Among 177 CSF samples, consistent results were achieved for 19 samples pre-tested using a commercial kit. Viral pathogens were found in 28/138 undiagnosed samples, with herpes simplex viruses (HSV-1 and HSV-2) being predominant. The 20 non infectious samples revealed negative results. Compared to sequencing methods, sensitivity for detecting HSV-1 and HSV-2 was 100% and 98.78%, respectively, and specificity was 100% and 98.22%, respectively. CONCLUSIONS: A robust MPMA system that can simultaneously and reliably detect 13 meningoencephalitis-associated viruses with high specificity, throughput, and speed has been developed. PMID- 27235089 TI - Comparison of dental students' performances and perceptions in preclinical and clinical pharmacology in an Irish Dental School. AB - INTRODUCTION: Knowledge of pharmacology is essential for dental students and for its safe application in the clinical environment. AIMS: The goals of our study were to assess dental students' performances in pharmacology with and without shared instruction, to investigate correlations between students' final grades in pre-clinical and clinical pharmacology, to determine if gender affects test performance and to explore characteristics of effective dental student learning. METHODS: A 9 year mixed method study was undertaken comprising (i) quantitative analysis of undergraduate performances in basic and clinical pharmacology (n = 320) and (ii) quantitative and qualitative exploration of student perceptions on teaching and learning in pharmacology. RESULTS: Mean basic pharmacology scores were not significantly different when dental students were co-taught with medical and pharmacy students. Regression analysis showed a statistically significant correlation (r = 0.582, P < 0.01) between basic and clinical pharmacology dental student scores. Interestingly, correlation was independent of gender with female student scores demonstrating a correlation of r = 0.480, P < 0.01 and males a correlation of 0.684, P < 0.01. Quantitative and qualitative feedback highlighted four thematic areas of effective dental student learning namely: (i) quality of instructors, (ii) lecture content, (iii) assessment type and (iv) learning environment. CONCLUSIONS: Teaching basic pharmacology in a multidisciplinary environment did not adversely affect dental students' examination performances. Dental students who perform well in basic pharmacology perform similarly well in clinical pharmacology. However, whether students' understanding and the application of pharmacology affects the quality of patient care in the clinical environment awaits further investigation. PMID- 27235090 TI - New polyprenyl phosphate based preparation Fortepren((r)) as promising cytokine regulationg antiviral remedy. AB - Fortepren((r)), a product of the phosphorylation of polyprenols from fir needles (with sodium polyprenyl phosphate being the main active ingredient), belongs to the class of antiviral drugs with immunomodulating activity. Fortepren((r)) may be used as the drug of choice in the treatment of herpes diseases. It was shown that treatment with Fortepren((r)) of patients with a chronic recurrent herpes infection after acute phase termination with acyclovir decreased the recurrence rate, as well as the severity of local symptoms. Fortepren((r)) treatment of patients with a high incidence of recurrent herpes infection led to an increase in the interferon-producing ability of leucocytes stimulated with NDV, as well as in the production of key cytokines (IL-1beta, IL-15, MIP-1alpha, IFN-gamma, IL-12 (p40), TNF-alpha, IFN-alpha2, IL-12 (p70), IL-6) taking part in the protection against viral infection. Data suggest that the action of the drug is directed, first of all, to the cells responsible for the natural resistance of the organism (macrophages, dendritic cells, etc.). The activation of natural immunity appears to be a leading mechanism of protection from herpesviral infection under the influence of polyprenyl phosphate. PMID- 27235093 TI - Determination of hexabromocyclododecane enantiomers in chicken whole blood by a modified quick, easy, cheap, effective, rugged, and safe method with liquid chromatography and tandem mass spectrometry. AB - A rapid and simple analytical method has been developed for the determination of hexabromocyclododecane enantiomers in chicken whole blood, based on a modified quick, easy, cheap, effective, rugged, and safe approach before liquid chromatography coupled with tandem mass spectrometry. The factors influencing performance of method were investigated by single factor experiment, and further optimized by the response surface methodology based on Box-Behnken design. The matrix effects were also evaluated by the isotopic dilution method. Under the optimal conditions, the proposed method showed good linearity within the range of 1-500 MUg/L and good repeatability with relative standard deviation less than 9.5% (n = 5). The limits of detection (S/N = 3) were 0.03-0.19 MUg/L. The developed method was successfully applied for the analysis of hexabromocyclododecane enantiomers in real chicken blood samples. The satisfactory recoveries ranging of 83.6-115.0% were obtained (at spiked levels of 5, 20, and 100 MUg/L). The results demonstrated that the proposed method would be a practical value method for the determination of hexabromocyclododecane enantiomers in animal blood. It would be further developed with confidence to analyze other lipophilic organic pollutants in blood sample. PMID- 27235091 TI - A gradient of glucocorticoid sensitivity among helper T cell cytokines. AB - Helper T (Th) cells secret specific cytokines that promote immune responses whereas glucocorticoids limit the extent of immune responses by inhibiting cytokine secretion and other functions of Th cells. However, glucocorticoid resistance develops in subgroups of patients with Th cell-driven diseases such as asthma and Crohn's disease. Recent evidence supports that Th1, Th2, and Th17 cells have distinct glucocorticoid sensitivity. Th1 cells are sensitive to glucocorticoid-induced apoptosis and cytokine suppression while Th2 cells are sensitive to the latter but not the former and Th17 cells are resistant to both. This gradient of glucocorticoid sensitivity of Th cells corresponds to the glucocorticoid sensitivity of the diseases they underlie. We identify the mechanisms contributing to distinct glucocorticoid sensitivity of Th cells and their cytokines in the literature, as this information is useful to improve treatment strategies for glucocorticoid resistant immunological disorders. PMID- 27235092 TI - Facial nerve palsy including Bell's palsy: Case definitions and guidelines for collection, analysis, and presentation of immunisation safety data. PMID- 27235094 TI - Association Between Non-Steroidal Anti-Inflammatory Drug Use and Cognitive Decline: A Systematic Review and Meta-Analysis of Prospective Cohort Studies. AB - BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly used medications in the elderly. They have been widely studied as possible preventive agents against cognitive decline because of the properties of anti-inflammatories, which sustain cerebral blood flow and mitigate the neurotoxicity of microglial cells. However, the results remain controversial. OBJECTIVE: Our objective was to assess the effects of NSAID use on the risk of cognitive decline. We reviewed and quantitatively synthesized the evidence from prospective cohort studies via a meta-analysis. METHODS: We identified pertinent studies by searching the PubMed, EMBASE, and China National Knowledge Infrastructure databases through to December 2015 and by reviewing the reference lists of retrieved articles. We used fixed- or random-effects models to pool relative risks (RRs) with 95 % confidence intervals (CIs) and performed sensitivity analyses to evaluate the robustness of the results. Small-study effect was evaluated using Egger's test and funnel plots. RESULTS: Of the 2171 articles identified through searching the databases, ten articles including 11 prospective cohort studies were eligible. Overall, NSAID use was associated with a 13 % decreased risk of cognitive decline (pooled RR 0.87; 95 % CI 0.81-0.94). In subgroup analysis, the pooled RRs were 0.89 (95 % CI 0.81-0.98) for follow-up time >=5 years, 0.85 (95 % CI 0.75-0.96) for follow-up time <5 years, and 0.85 (95 % CI 0.78-0.93) for studies conducted in North America, respectively. Sensitivity analyses found results to be robust. No evidence of significant small study effect was identified. CONCLUSIONS: This meta-analysis of prospective cohort studies indicates that NSAID use may be associated with a decreased risk of cognitive decline. Larger, high-quality randomized controlled trials are needed to verify the effects of NSAID use on the risk of cognitive decline. PMID- 27235095 TI - All together now: how and why scientific communities should develop best practice guidelines. PMID- 27235096 TI - Frizzled to finance: one PhD's path from a Drosophila lab to Wall Street. AB - An equity research analyst's job is to determine whether the price of a stock is likely to go up or down. For science-based businesses, particularly biotechnology companies, a PhD in the life sciences can be very helpful in making this determination. I transitioned from a postdoc position to working in equity research. Here I present information on how I made the transition, an overview of the day-to-day activities of an analyst, and thoughts on how to prepare to look for a job in finance. There are significant positives to working on Wall Street, including exposure to cutting-edge clinical/translational research, access to some of the best scientists in the world, a dynamic work environment, and compensation that generally exceeds academic salaries. This comes at the cost of some independence and the satisfaction of being able to call oneself a scientist. PMID- 27235098 TI - Probiotic lactic acid bacteria - the fledgling cuckoos of the gut? AB - It is tempting to look at bacteria from our human egocentric point of view and label them as either 'good' or 'bad'. However, a microbial society has its own system of government - 'microcracy' - and its own rules of play. Lactic acid bacteria are often referred to as representatives of the good ones, and there is little doubt that those belonging to the normal intestinal flora are beneficial for human health. But we should stop thinking of lactic acid bacteria as always being 'friendly' - they may instead behave like fledgling cuckoos. PMID- 27235099 TI - Similarity-Based Fusion of MEG and fMRI Reveals Spatio-Temporal Dynamics in Human Cortex During Visual Object Recognition. AB - Every human cognitive function, such as visual object recognition, is realized in a complex spatio-temporal activity pattern in the brain. Current brain imaging techniques in isolation cannot resolve the brain's spatio-temporal dynamics, because they provide either high spatial or temporal resolution but not both. To overcome this limitation, we developed an integration approach that uses representational similarities to combine measurements of magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) to yield a spatially and temporally integrated characterization of neuronal activation. Applying this approach to 2 independent MEG-fMRI data sets, we observed that neural activity first emerged in the occipital pole at 50-80 ms, before spreading rapidly and progressively in the anterior direction along the ventral and dorsal visual streams. Further region-of-interest analyses established that dorsal and ventral regions showed MEG-fMRI correspondence in representations later than early visual cortex. Together, these results provide a novel and comprehensive, spatio temporally resolved view of the rapid neural dynamics during the first few hundred milliseconds of object vision. They further demonstrate the feasibility of spatially unbiased representational similarity-based fusion of MEG and fMRI, promising new insights into how the brain computes complex cognitive functions. PMID- 27235100 TI - Effects of Hypocretin/Orexin and Major Transmitters of Arousal on Fast Spiking Neurons in Mouse Cortical Layer 6B. AB - Fast spiking (FS) GABAergic neurons are thought to be involved in the generation of high-frequency cortical rhythms during the waking state. We previously showed that cortical layer 6b (L6b) was a specific target for the wake-promoting transmitter, hypocretin/orexin (hcrt/orx). Here, we have investigated whether L6b FS cells were sensitive to hcrt/orx and other transmitters associated with cortical activation. Recordings were thus made from L6b FS cells in either wild type mice or in transgenic mice in which GFP-positive GABAergic cells are parvalbumin positive. Whereas in a control condition hcrt/orx induced a strong increase in the frequency, but not amplitude, of spontaneous synaptic currents, in the presence of TTX, it had no effect at all on miniature synaptic currents. Hcrt/orx effect was thus presynaptic although not by an action on glutamatergic terminals but rather on neighboring cells. In contrast, noradrenaline and acetylcholine depolarized and excited these cells through a direct postsynaptic action. Neurotensin, which is colocalized in hcrt/orx neurons, also depolarized and excited these cells but the effect was indirect. Morphologically, these cells exhibited basket-like features. These results suggest that hcrt/orx, noradrenaline, acetylcholine, and neurotensin could contribute to high-frequency cortical activity through an action on L6b GABAergic FS cells. PMID- 27235102 TI - Optimization of the process of aromatic and medicinal plant maceration in grape marc distillates to obtain herbal liqueurs and spirits. AB - BACKGROUND: Herbal liqueurs are alcoholic beverages produced by the maceration or distillation of aromatic and medicinal plants in alcohol, and are also highly valued for their medicinal properties. The process conditions, as well as the number and quantity of the plants employed, will have a great influence on the quality of the liqueur obtained. The aim of this research was to optimize these important variables. RESULTS: A Box-Benhken experimental design was used to evaluate the independent variables: alcohol content, amount of plant and time during the experimental maceration of plants in grape marc distillate. Four plants were assessed, with the main compound of each plant representing the dependent variable evaluated with respect to following the evolution of the maceration process. Bisabolol oxide A in Matricaria recutita L., linalool in Coriander sativum L. and eucalyptol in Eucalyptus globulus Labill. were quantified using a gas chromatography-flame ionization detector. Glycyrrhizic acid in Glycyrrhiza glabra L was determined using a high-performance liquid chromatography-diode array detector. Other dependent variables were also evaluated: total phenolic content, color parameters and consumer preference (i.e. appearance). CONCLUSION: The experimental designs allowed the selection of the optimal maceration conditions for each parameter, including the preference score of consumers: 70% (v/v) of ethanol, 40 g L-1 plant concentration and a maceration process of 3 weeks. (c) 2016 Society of Chemical Industry. PMID- 27235101 TI - Opposing Effects of Maternal Hypo- and Hyperthyroidism on the Stability of Thalamocortical Synapses in the Visual Cortex of Adult Offspring. AB - Insufficient or excessive thyroid hormone (TH) levels during fetal development can cause long-term neurological and cognitive problems. Studies in animal models of perinatal hypo- and hyperthyroidism suggest that these problems may be a consequence of the formation of maladaptive circuitry in the cerebral cortex, which can persist into adulthood. Here we used mouse models of maternal hypo- and hyperthyroidism to investigate the long-term effects of altering thyroxine (T4) levels during pregnancy (corresponding to embryonic days 6.5-18.5) on thalamocortical (TC) axon dynamics in adult offspring. Because perinatal hypothyroidism has been linked to visual processing deficits in humans, we performed chronic two-photon imaging of TC axons and boutons in primary visual cortex (V1). We found that a decrease or increase in maternal serum T4 levels was associated with atypical steady-state dynamics of TC axons and boutons in V1 of adult offspring. Hypothyroid offspring exhibited axonal branch and bouton dynamics indicative of an abnormal increase in TC connectivity, whereas changes in hyperthyroid offspring were indicative of an abnormal decrease in TC connectivity. Collectively, our data suggest that alterations to prenatal T4 levels can cause long-term synaptic instability in TC circuits, which could impair early stages of visual processing. PMID- 27235103 TI - Guidelines for risk reduction when handling gametes from infectious patients seeking assisted reproductive technologies. AB - According to the Americans with Disabilities Act (1990), couples with blood-borne viruses that lead to infectious disease cannot be denied fertility treatment as long as the direct threat to the health and safety of others can be reduced or eliminated by a modification of policies or procedures. Three types of infectious patients are commonly discussed in the context of fertility treatment: those with human immunodeficiency virus (HIV), hepatitis C or hepatitis B. Seventy-five per cent of hepatitis C or HIV positive men and women are in their reproductive years, and these couples look to assisted reproductive techniques for risk reduction in conceiving a pregnancy. In many cases, only one partner is infected. Legal and ethical questions about treatment of infectious patients aside, the question most asked by clinical embryologists and andrologists is: "What are the laboratory protocols for working with gametes and embryos from patients with infectious disease?" The serostatus of each patient is the key that informs appropriate treatments. This guidance document describes protocols for handling gametes from seroconcordant and serodiscordant couples with infectious disease. With minor modifications, infectious patients with stable disease status and undetectable or low viral load can be accommodated in the IVF laboratory. PMID- 27235104 TI - Classic Spotlight: Identifying the Core of the Flagellar Motor. PMID- 27235105 TI - Classic Spotlight: Studies of the Stringent Response. PMID- 27235108 TI - Protein palmitoylation activate zygotic gene expression during the maternal-to zygotic transition. AB - Upon fertilization, maternal factors direct development and trigger zygotic genome activation at the maternal-to-zygotic transition (MZT). However, the factors that activate the zygotic program in vertebrates are not well defined. Here, we found that protein palmitoylation played an important role in acquiring transcriptional competency and orchestrating the clearance of the maternal program in zebrafish. After inhibition of protein palmitoylation, zebrafish embryos developed normally before the Mid-Blastula Transition (MBT); however, they did not initiate epiboly. Moreover, our results showed that protein palmitoylation is required to initiate the zygotic developmental program and induce clearance of the maternal program by activating miR-430 expression. PMID- 27235109 TI - Letter to the Editor, "Assessment of mercury exposure in human populations: A status report from Augusta Bay (southern Italy)". PMID- 27235110 TI - Letter to the Editor-Assessment of mercury exposure in human populations: A status report from Augusta Bay (southern Italy). PMID- 27235111 TI - Life without plastic: A family experiment and biomonitoring study. AB - Exposure to bisphenol-A (BPA) and phthalates has been associated with negative health outcomes in animal and human studies, and human bio-monitoring studies demonstrate widespread exposure in the US and Europe. Out of concern for the environment and health, individuals may attempt to modify their environment, diet, and consumer choices to avoid such exposures, but these natural experiments are rarely if ever quantitatively evaluated. The aim of the study was to evaluate the difference in urinary concentrations of BPA and phthalate metabolites following an exposure reduction intervention among an Austrian family of five. Urine samples were taken shortly after the family had removed all plastic kitchenware, toys, and bathroom products, and started a concerted effort to eat less food packaged in plastic. Two-months later, urine samples were collected at a follow-up visit, and concentrations of BPA and phthalate metabolites were compared. Shortly after removal of plastic urinary concentrations of BPA were below limit of quantification in all samples. Phthalate concentrations were low, however, 10 of 14 investigated metabolites could be found above limit of quantification. After the two-month intervention, phthalate urinary concentrations had declined in some but not all family members. In the mother most phthalate metabolites increased. The low levels might be partly due to the environmentally conscious lifestyle of the family and partly due to the fact that body levels had dropped already because of the delay of four days between finishing removal and first measurement. Further two months avoidance of dietary exposure and exposure to environmental plastics reduced urinary concentrations for all but one metabolite in the oldest son only, but decreased somewhat in all family members except the mother. PMID- 27235112 TI - Broadening Our Portfolio in the Genetic Improvement of Maize Chemical Composition. AB - The adoption of recombinant inbred line and introgression line populations, as well as the study of association mapping panels, has greatly accelerated our ability to identify the genes underlying plant phenotypic variance. In tandem, the development of metabolomics approaches has greatly enhanced our ability to comprehensively define cellular chemical composition. As a consequence, breeding for chemical composition is being extended beyond our traditional targets of oil and protein to include components such as essential amino acids, vitamins, and antioxidant secondary metabolites with considerable purported consequences for human health. Here, we review the above-mentioned developments paying particular attention to the genetic architecture of metabolic traits as well as updating the perspective for utilizing metabolomics in maize improvement. PMID- 27235113 TI - Causes and Consequences of Multi-Locus Imprinting Disturbances in Humans. AB - Eight syndromes are associated with the loss of methylation at specific imprinted loci. There has been increasing evidence that these methylation defects in patients are not isolated events occurring at a given disease-associated locus but that some of these patients may have multi-locus imprinting disturbances (MLID) affecting additional imprinted regions. With the recent advances in technology, methylation profiling has revealed that imprinted loci represent only a small fraction of the methylation differences observed between the gametes. To figure out how imprinting anomalies occur at multiple imprinted domains, we have to understand the interplay between DNA methylation and histone modifications in the process of selective imprint protection during pre-implantation reprogramming, which, if disrupted, leads to these complex imprinting disorders (IDs). PMID- 27235114 TI - Training Endogenous Task Shifting Using Music Therapy: A Feasibility Study. AB - BACKGROUND: People with acquired brain injury (ABI) are highly susceptible to disturbances in executive functioning (EF), and these effects are pervasive. Research studies using music therapy for cognitive improvement in this population are limited. OBJECTIVE: The purpose of this study was to determine the feasibility of a Musical Executive Function Training (MEFT) intervention to address task-shifting skills in adults with ABI and to obtain preliminary evidence of intervention effect on task shifting. METHODS: Fourteen participants were randomly assigned to one of three groups: a music therapy intervention group (MTG), a singing group (SG), or the no-intervention control group (CG). The SG and MTG met for one hour a day for five days. Feasibility measures included participant completion rates and intervention fidelity. Potential benefits were measured using the Trail Making Test and the Paced Auditory Serial Addition Task as a pre- and posttest measure. RESULTS: Participant completion rates and interventionist fidelity to the protocol supported feasibility. One-way ANOVA of the pre- and posttest group differences revealed a trend toward improvement in the MTG over the SG. CONCLUSIONS: Feasibility and effect size data support a larger trial of the MEFT protocol. PMID- 27235115 TI - Association of Pneumonia With Short- and Long-Term Mortality After Cardiac Surgery. PMID- 27235116 TI - Authors' Response. PMID- 27235117 TI - Silencing of ST6GalNAc I suppresses the proliferation, migration and invasion of hepatocarcinoma cells through PI3K/AKT/NF-kappaB pathway. AB - ST6GalNAc I is the major Sialyl-Tn antigen (STn) synthase that is highly correlated with tumor invasion and metastasis. However, the roles and molecular mechanisms by which ST6GalNAc I mediates the malignant phenotypes of hepatocarcinoma cells still remain poorly unknown. In this study, we investigated the expression of STn and ST6GalNAc I in mouse hepatocarcinoma cell lines Hca-F, Hca-P, and Hepa1-6, which have different metastatic potential, as compared with normal mouse liver cell line IAR-20. The results showed that the expression of ST6GalNAc I and STn in Hca-F and Hca-P cells was much higher than that in Hepa1-6 and IAR20 cells. Knockdown of ST6GalNAc I by shRNA in Hca-F cells significantly decreased the expression of STn and inhibited the growth of tumor cells in vitro and in vivo. This reduction of ST6GalNAc I expression also led to the decreased migration and invasion of Hca-F cells. Furthermore, we found that ST6GalNAc I knockdown inhibited the expression levels of PI3k, p-Akt473, p-Akt308, NF-kappaB, and their downstream molecules. Together, our results suggest a role of ST6GalNAc I in promoting the growth and invasion of hepatocarcinoma cells through regulating PI3K/AKT signaling, and ST6GalNAc I might be a promising marker for the prognosis and therapy of hepatocarcinoma. PMID- 27235119 TI - Erratum to: Spheroid-plug model as a tool to study tumor development, angiogenesis, and heterogeneity in vivo. PMID- 27235120 TI - Feedback mechanisms between M2 macrophages and Th17 cells in colorectal cancer patients. AB - IL-17 and IL-22 are linked to the development of intestinal inflammation and colorectal cancer (CRC). However, the maintenance of IL-17 and IL-22 production, as well as the cell type (Th17) that mediates these cytokines in CRC patients, remains unknown. To examine this, untreated CRC patients and healthy controls were recruited in this study. We first observed that CRC patients contained significantly elevated levels of IL-17- and IL-22-producing CD4+ T cells. The vast majority of IL-22-expressing CD4+ T cells also expressed IL-17. We then found that the production of both IL-17 and IL-22 required support from autologous monocytes, since the depletion of monocytes significantly downregulated IL-17 and IL-22 secretion. Naive T cells from CRC patients did not secrete IL-17 or IL-22 initially, but long-term coculture with autologous monocytes significantly upregulated IL-17 and IL-22 production in an IL-6 dependent manner. Blockade of IL-6 significantly reduced the levels of both IL-17 and IL-22. We then observed that CD163+ M2 macrophages were the main contributor of IL-6. Interestingly, incubation of monocytes with CCR4+CCR6+ Th17 cells resulted in significantly higher levels of CD163+ macrophages as well as higher IL-6 secretion, than incubation with non-Th17 CD4+ T cells. Together, our study discovered a positive feedback mechanism between Th17 and M2 macrophages in CRC patients. PMID- 27235121 TI - Interstitial cystitis: Another rotation of the kaleidoscope of autoimmunity? PMID- 27235118 TI - mTOR inhibitors in urinary bladder cancer. AB - Despite the great scientific advances that have been made in cancer treatment, there is still much to do, particularly with regard to urinary bladder cancer. Some of the drugs used in urinary bladder cancer treatment have been in use for more than 30 years and show reduced effectiveness and high recurrence rates. There have been several attempts to find new and more effective drugs, to be used alone or in combination with the drugs already in use, in order to overcome this situation.The biologically important mammalian target of rapamycin (mTOR) pathway is altered in cancer and mTOR inhibitors have raised many expectations as potentially important anticancer drugs. In this article, the authors will review the mTOR pathway and present their experiences of the use of some mTOR inhibitors, sirolimus, everolimus and temsirolimus, in isolation and in conjunction with non-mTOR inhibitors cisplatin and gemcitabine, on urinary bladder tumour cell lines. The non-muscle-invasive cell line, 5637, is the only one that exhibits a small alteration in the mTOR and AKT phosphorylation after rapalogs exposure. Also, there was a small inhibition of cell proliferation. With gemcitabine plus everolimus or temsirolimus, the results were encouraging as a more effective response was noticed with both combinations, especially in the 5637 and T24 cell lines. Cisplatin associated with everolimus or temsirolimus also gave promising results, as an antiproliferative effect was observed when the drugs were associated, in particular on the 5637 and HT1376 cell lines. Everolimus or temsirolimus in conjunction with gemcitabine or cisplatin could have an important role to play in urinary bladder cancer treatment, depending on the tumour grading. PMID- 27235122 TI - Comment on "Polyarteritis nodosa: A contemporary overview". PMID- 27235123 TI - Patterns in clinical students' self-regulated learning behavior: a Q-methodology study. AB - Students feel insufficiently supported in clinical environments to engage in active learning and achieve a high level of self-regulation. As a result clinical learning is highly demanding for students. Because of large differences between students, supervisors may not know how to support them in their learning process. We explored patterns in undergraduate students' self-regulated learning behavior in the clinical environment, to improve tailored supervision, using Q methodology. Q-methodology uses features of both qualitative and quantitative methods for the systematic investigation of subjective issues by having participants sort statements along a continuum to represent their opinion. We enrolled 74 students between December 2014 and April 2015 and had them characterize their learning behavior by sorting 52 statements about self regulated learning behavior and explaining their response. The statements used for the sorting were extracted from a previous study. The data was analyzed using by-person factor analysis to identify clusters of individuals with similar sorts of the statements. The resulting factors and qualitative data were used to interpret and describe the patterns that emerged. Five resulting patterns were identified in students' self-regulated learning behavior in the clinical environment, which we labelled: Engaged, Critically opportunistic, Uncertain, Restrained and Effortful. The five patterns varied mostly regarding goals, metacognition, communication, effort, and dependence on external regulation for learning. These discrete patterns in students' self-regulated learning behavior in the clinical environment are part of a complex interaction between student and learning context. The results suggest that developing self-regulated learning behavior might best be supported regarding individual students' needs. PMID- 27235124 TI - Medical student stories of participation in patient care-related activities: the construction of relational identity. AB - Professional identity formation is acknowledged as one of the fundamental tasks of contemporary medical education. Identity is a social phenomenon, constructed through participation in everyday activities and an integral part of every learning interaction. In this paper we report from an Australian ethnographic study into how medical students and patients use narrative to construct their identities. The dialogic narrative analysis employed focused on the production of meaning through the use of language devices in a given context, and the juxtaposition of multiple perspectives. Two stories told by students about their participation in patient care-related activities reveal how identities are constructed in this context through depictions of the relationships between medical students, patients and clinical teachers. These students use the rhetorical functions of stories to characterise doctors and patients in certain ways, and position themselves in relation to them. They defend common practices that circumvent valid consent processes, justified by the imperative to maximise students' participation in patient care-related activities. In doing so, they identify patients as their adversaries, and doctors as allies. Both students are influenced by others' expectations but one reveals the active nature of identity work, describing subtle acts of resistance. These stories illustrate how practices for securing students' access to patients can influence students' emerging identities, with implications for their future disclosure and consent practices. We argue that more collaborative ways of involving medical students in patient care-related activities will be facilitated if students and clinical teachers develop insight into the relational nature of identity work. PMID- 27235125 TI - Decreased LPP for sexual images in problematic pornography users may be consistent with addiction models. Everything depends on the model. (Commentary on Prause, Steele, Staley, Sabatinelli, & Hajcak, 2015). PMID- 27235126 TI - Optical measures of changes in cerebral vascular tone during voluntary breath holding and a Sternberg memory task. AB - The human cerebral vasculature responds to changes in blood pressure and demands for oxygenation via cerebral autoregulation. Changes in cerebrovascular tone (vasoconstriction and vasodilation) also mediate the changes in blood flow measured by the BOLD fMRI signal. This cerebrovascular reactivity is known to vary with age. In two experiments, we demonstrate that cerebral pulse parameters measured using optical imaging can quantify changes in cerebral vascular tone, both globally and locally. In experiment 1, 51 older adults (age range=55-87) performed a voluntary breath-holding task while cerebral pulse amplitude measures were taken. We found significant pulse amplitude variations across breath-holding periods, indicating vasodilation during, and vasoconstriction after breath holding. The breath-holding index (BHI), a measure of cerebrovascular reactivity (CVR) was derived and found to correlate with age. BHI was also correlated with performance in the Modified Mini-Mental Status Examination, even after controlling for age and education. In experiment 2, the same participants performed a Sternberg task, and changes in regional pulse amplitude between high (set-size 6) and low (set-size 2) task loads were compared. Only task-related areas in the fronto-parietal network (FPN) showed significant reduction in pulse amplitude, indicating vasodilation. Non-task-related areas such as the somatosensory and auditory cortices did not show such reductions. Taken together, these experiments suggest that optical pulse parameters can index changes in brain vascular tone both globally and locally, using both physiological and cognitive load manipulations. PMID- 27235127 TI - The role of steroid administration in the management of dysphagia in anterior cervical procedures. AB - Dysphagia is a common postoperative symptom for patients undergoing anterior cervical spine procedures. The purpose of this study is to present the current literature regarding the effect of steroid administration in dysphagia after anterior cervical spine procedures. We performed a literature search in the PubMed database, using the following terms: "dysphagia," "ACDF," "cervical," "surgery," "anterior," "spine," "steroids," "treatment," and "complications." We included in our review any study correlating postoperative dysphagia and steroid administration in anterior cervical spine surgery. Studies, which did not evaluate, pre- and postoperatively, dysphagia with a specific clinical or laboratory methodology were excluded from our literature review. Five studies were included in our results. All were randomized, prospective studies, with one being double blinded. Steroid administration protocol was different in every study. In two studies, dexamethasone was used. Methylprednisolone was administrated in three studies. In four studies, steroids were applied intravenously, while in one study, locally in the retropharyngeal space. Short term dysphagia and prevertebral soft tissue edema were diminished by steroid administration, according to the results of two studies. In one study, prevertebral soft tissue edema was not affected by the steroid usage. Furthermore, short-term osseous fusion rate was impaired by the steroid administration, according to the findings of one study. The usage of steroids in patients undergoing anterior cervical spine procedures remains controversial. Multicenter, large-scale, randomized, prospective studies applying the same protocol of steroid administration and universal outcome criteria should be performed for extracting statistically powerful and clinically meaningful results. PMID- 27235129 TI - A significant correlation between delayed cure after microvascular decompression and positive response to preoperative anticonvulsant therapy in patients with hemifacial spasm. AB - Although microvascular decompression (MVD) is a reliable treatment for hemifacial spasm (HFS), the postoperative course is varied. We retrospectively analyzed the resolution pattern of the spasm and specified predictors for delayed cure after MVD. This study included 114 consecutive patients with typical HFS. All of them were followed up for at least 1 year after operation. Patients were divided into three groups depending on the postoperative course: immediate cure, delayed cure, and failure. To identify the predictive factors for delayed cure after MVD, logistic regression analyses were applied using candidate clinical factors, such as duration of symptom, the tendency of the spasm, preoperative medical treatment, and offending vessels. Among the 114 patients, 107 patients were cured. For those cured, 65 patients were classified as immediate cure and 42 patients were classified as delayed cure. Cumulative spasm-free rates after 1 week, 1 month, and 3 months after MVD were 70, 88, and 97 %, respectively. No predictive factors between the cured and failure groups were observed. According to multivariate analysis, preoperative anticonvulsant therapy was found to be the sole significant predictive factor for delayed cure after MVD (p = 0.025). A significant correlation between delayed cure and preoperative anticonvulsant therapy was found in our study, which suggests that hyperexcitation of the facial nucleus plays an important role in pathogenesis of delayed cure. Therefore, if a patient demonstrating a positive response to preoperative anticonvulsant therapy showed a persistent spasm after MVD, reoperation should be delayed for at least 3 months after the initial operation. PMID- 27235128 TI - Decompressive craniectomy and expansive duraplasty with evacuation of hypertensive intracerebral hematoma, a randomized controlled trial. AB - Hypertensive intracerebral hemorrhage (ICH) has high morbidity and mortality rates. Decompressive craniectomy (DC) is generally used for the treatment of cases associated with refractory increased intracranial pressure (ICP). In this study, we investigated the beneficial effects of adding DC and expansive duraplasty (ED) to hematoma evacuation in patients who underwent surgery for large hypertensive ICH. A prospective randomized controlled clinical trial where 40 patients diagnosed having large hypertensive ICH was randomly allocated to either group A or B, each comprised 20 patients. Group A patients, the treatment group, were submitted to hematoma evacuation together with DC and ED, whereas group B patients, the control group, were submitted only to hematoma evacuation. Twenty-three (57.5 %) of the patients were males, with an overall age range of 34 79 years (mean 59.3 years). Preoperative Glasgow Coma Scale (GCS) scores in group A ranged from 4 to 13 (mean 7.1), while in group B it ranged from 4 to 12 (mean 6.8). Postoperative hydrocephalus occurred in 3 (15 %) patients in group A and in 4 (20 %) patients in group B, whereas meningitis occurred in one patient (5 %) in group A. The mortality rate was 2 (10 %) patients in group A as compared to 5 (25 %) patients in group B (p = 0.407). High admission GCS (p = 0.0032), younger age (p = 0.0023), smaller hematoma volume (p = 0.044), subcortical hematoma location (p = 0.041), absent or minimal preoperative (p = 0.0068), and postoperative (p = 0.0031) midline shift as well as absent intraventricular extension of the hematoma (p = 0.036) contributed significantly to a better outcome. Selected patients' subgroups who benefited from adding DC and ED to ICH evacuation were age category of 30 to less than 50 (p = 0.0015) and from 50 to less than 70 (p = 0.00619) as well as immediate preoperative GCS from 6 to 8 (p = 0.000436) and from 9 to 12 (p = 0.00774). At 6 months' follow-up, 14 (70 %) patients of group A had favorable outcome as compared to 4 (20 %) patients of group B (p = 0.0015). Adding DC with ED to evacuation of a large hypertensive hemispheric ICH might improve the outcome in selected group of patients. PMID- 27235130 TI - Vascularized pericranial flap for the reconstruction of dural defect in a watertight fashion in patients with history cranial radiation exposure: technical note. PMID- 27235131 TI - Evidence-based medicine in neurosurgery: an academic publication view. AB - Although evidence-based medicine (EBM) has been progressively developing for decades in neurosurgery, there remains a lack of data to fully understand this topic. This study was aimed to evaluate extensively EBM related to neurosurgery through the analysis of neurosurgical EBM publications. We searched the Web of Science (WoS) Core Collection database for all EBM publications related to neurosurgery. The number of publications and other information were obtained. Data were extracted from the search results to obtain the following information: document type, countries/territories, funding agencies, organizations, publication year, source of titles, and research area. From among all of the publications, we extracted randomized controlled trials (RCTs) for further analysis at RCT characteristic and funding agencies. According to the search strategy, 6907 publications were related to EBM in neurosurgery. A total of 91 countries/territories participated in neurosurgical EBM publications. English speaking countries (USA, England, and Canada) contributed most of the publications. "University of Toronto" is the organization which published the most EBM publications. In total, 1654 neurosurgical RCTs were found. We summarize their characteristics and record the highest cited (more than 400) RCTs, which we descript the distribution in different neurosurgical fields and stages. We also found that more than half of the RCTs were directly funded by industrial companies, and government-funded agencies accounted for no more than one fifth of the RCTs. EBM in neurosurgery has a good foundation but also needs to be constantly revised and improved to synchronize with evidence-based medicine development. PMID- 27235132 TI - Teratoid cyst of the tongue: A rare variant of dermoid cyst. PMID- 27235133 TI - New drug treatments versus structured education programmes for type 2 diabetes: comparing cost-effectiveness. PMID- 27235134 TI - A Special Connection between gammadelta T Cells and Natural Antibodies? AB - Natural antibodies (NAbs) play an important role in early host defense, autophagy and tissue remodeling, and in immune regulation. They arise spontaneously (without specific immunization), and are already present at birth. NAbs are produced by B1 B cells, MZ B cells and other B cell types. They include all major Ig subclasses but IgM antibodies are prevalent, especially early in development. NAbs may be poly-specific, recognize particular auto-antigens, or detect neo determinants such as those exposed during apoptosis or generated by oxidation. NAbs do not require cognate T cell help but depend on soluble mediators produced by T cells. Our recent studies suggest that gammadelta T cells may have a special relationship with NAbs, and play a prominent role in their regulation, in part through the fine-tuning of IL-4 levels. The spontaneously activated state of these cells likely enables their cytokine production and other functions in the absence of external stimulation. Ontogenetically, the earlier arising gammadelta T cells are better positioned than alphabeta T cells to shape the developing repertoire of NAbs. Intriguingly, ligand specificities of NAbs and gammadelta T cell receptors appear to be overlapping, perhaps allowing gammadelta cognate help for certain NAb specificities. Via NAbs, gammadelta T cells could exert a regulatory influence on numerous processes in health and disease. PMID- 27235135 TI - Novel mutations in RASGRP2, which encodes CalDAG-GEFI, abrogate Rap1 activation, causing platelet dysfunction. AB - In addition to mutations in ITG2B or ITGB3 genes that cause defective alphaIIbbeta3 expression and/or function in Glanzmann's thrombasthenia patients, platelet dysfunction can be a result of genetic variability in proteins that mediate inside-out activation of alphaIIbbeta3 The RASGRP2 gene is strongly expressed in platelets and neutrophils, where its encoded protein CalDAG-GEFI facilitates the activation of Rap1 and subsequent activation of integrins. We used next-generation sequencing (NGS) and whole-exome sequencing (WES) to identify 2 novel function-disrupting mutations in RASGRP2 that account for bleeding diathesis and platelet dysfunction in 2 unrelated families. By using a panel of 71 genes, we identified a homozygous change (c.1142C>T) in exon 10 of RASGRP2 in a 9-year-old child of Chinese origin (family 1). This variant led to a p.Ser381Phe substitution in the CDC25 catalytic domain of CalDAG-GEFI. In 2 Spanish siblings from family 2, WES identified a nonsense homozygous variation (c.337C>T) (p.Arg113X) in exon 5 of RASGRP2 CalDAG-GEFI expression was markedly reduced in platelets from all patients, and by using a novel in vitro assay, we found that the nucleotide exchange activity was dramatically reduced in CalDAG GEFI p.Ser381Phe. Platelets from homozygous patients exhibited agonist-specific defects in alphaIIbbeta3 integrin activation and aggregation. In contrast, alpha- and delta-granule secretion, platelet spreading, and clot retraction were not markedly affected. Integrin activation in the patients' neutrophils was also impaired. These patients are the first cases of a CalDAG-GEFI deficiency due to homozygous RASGRP2 mutations that are linked to defects in both leukocyte and platelet integrin activation. PMID- 27235136 TI - How I treat acute myeloid leukemia presenting with preexisting comorbidities. AB - Acute myeloid leukemia (AML) is a devastating disease with an incidence that progressively increases with advancing age. Currently, only ~40% of younger and 10% of older adults are long-term survivors. If untreated, the overall prognosis of AML remains dismal. Initiation of therapy at diagnosis is usually urgent. Barriers to successful therapy for AML are the attendant toxicities directly related to chemotherapy or those associated with inevitable aplasia. Organ dysfunction often further complicates such toxicities and may even be prohibitive. There are few guidelines to manage such patients and the fear of crossing the medico-legal abyss may dominate. Such clinical scenarios provide particular challenges and require experience for optimal management. Herein, we discuss select examples of common pretreatment comorbidities, including cardiomyopathy, ischemic heart disease; chronic renal failure, with and without dialysis; hepatitis and cirrhosis; chronic pulmonary insufficiency; and cerebral vascular disease. These comorbidities usually render patients ineligible for clinical trials and enormous uncertainty regarding management reigns, often to the point of withholding definitive therapy. The scenarios described herein emphasize that with appropriate subspecialty support, many AML patients with comorbidities can undergo therapy with curative intent and achieve successful long-term outcome. PMID- 27235137 TI - Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia. AB - Inhibition of B-cell receptor (BCR) signaling pathways in chronic lymphocytic leukemia (CLL) provides significant clinical benefit to patients, mainly by blocking adhesion of CLL cells in the lymph node microenvironment. The currently applied inhibitors ibrutinib and idelalisib have limited capacity however to induce cell death as monotherapy and are unlikely to eradicate the disease. Acquired resistance to therapy in CLL is often caused by mutations in the response network being targeted, both for DNA damage or BCR signaling pathways. Thus, drugs with dual targeting capacity could offer improved therapeutic value. Here, the potency of CC-115, a novel inhibitor of mammalian target of rapamycin kinase (TORK) and DNA-dependent protein kinase (DNA-PK), was evaluated in primary CLL cells in vitro and in CLL patients. Combined TORK and DNA-PK inhibition in vitro resulted in caspase-dependent cell killing irrespective of p53, ATM, NOTCH1, or SF3B1 status. Proliferation induced by CD40(+) interleukin-21 stimulation was completely blocked by CC-115, and CD40-mediated resistance to fludarabine and venetoclax could be reverted by CC-115. BCR-mediated signaling was inhibited by CC-115 and also in CLL samples obtained from patients with acquired resistance to idelalisib treatment. Clinical efficacy of CC-115 was demonstrated in 8 patients with relapsed/refractory CLL/small lymphocytic lymphoma harboring ATM deletions/mutations; all but 1 patient had a decrease in lymphadenopathy, resulting in 1 IWCLL partial response (PR) and 3 PRs with lymphocytosis. In conclusion, these preclinical results, along with early promising clinical activity, suggest that CC-115 may be developed further for treatment of CLL. The trial was registered at www.clinicaltrials.gov as #NCT01353625. PMID- 27235138 TI - Impact of complete molecular response on survival in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. AB - The impact of achieving complete molecular response (CMR) in Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL) remains undefined. We evaluated the impact of CMR on outcomes among 85 patients with Ph(+) ALL who received first-line hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and high-dose cytarabine plus a tyrosine kinase inhibitor, had minimal residual disease (MRD) assessments for BCR ABL1 by quantitative polymerase chain reaction at complete remission (CR) and at 3-month time points, and did not undergo allogeneic stem cell transplantation (SCT). MRD status at 3 months had better discrimination for overall survival (OS; P = .005) and relapse-free survival (RFS; P = .002) than did MRD status at CR (P = .11 and P = .04, respectively). At 3 months, achievement of CMR vs response less than CMR was associated with longer median OS (127 vs 38 months, respectively; P = .009) and RFS (126 vs 18 months, respectively; P = .007). By multivariate analysis, only CMR at 3 months was prognostic for OS (hazard ratio, 0.42; 95% confidence interval, 0.21-0.82; P = .01). Patients with Ph(+) ALL who achieve CMR at 3 months have superior survival compared with those with lesser molecular responses and have excellent long-term outcomes even without SCT. PMID- 27235139 TI - GDF-15 inhibits integrin activation and mouse neutrophil recruitment through the ALK-5/TGF-betaRII heterodimer. AB - Growth differentiation factor 15 (GDF-15) is the first cytokine known to counteract chemokine-induced activation of leukocyte integrins. We showed recently that this activity dampens neutrophil recruitment into inflamed tissue and is required for survival of myocardial infarction in mice. The receptor responsible for this GDF-15-triggered anti-inflammatory mechanism on myeloid cells is not known. Here, we identify this receptor as transforming growth factor beta receptor I (TGF-betaRI) (activin receptor-like kinase 5 [ALK-5]) and TGF beta receptor II (TGF-betaRII). We show that interference with these receptors by small-molecule inhibitors, antibodies, or small interfering RNA, blocked the GDF 15 effect on leukocyte integrin activation. Likewise, gene inactivation of each of the 2 receptors in neutrophils isolated from conditional gene-deficient mice abolished the inhibitory effect of GDF-15 on CXCL1-induced beta2-integrin activation and neutrophil diapedesis. Rapid neutrophil arrest induced by CXCL1 in vivo was inhibited by GDF-15 in an ALK-5 and TGF-betaRII dependent way. As for GDF-15 gene-deficient mice, we found that extravasation of neutrophils deficient for ALK-5 or TGF-betaRII was strongly increased in the interleukin-1beta inflamed cremaster. The inhibitory effects of GDF-15 on neutrophil integrin activation and in vivo neutrophil arrest were also found for TGF-beta1. Mechanistically, GDF-15 and TGF-beta1 interfered with integrin activation by inhibiting the activation of Ras-related protein 1 (Rap-1), an effect that depended on CalDAG- guanine nucleotide exchange factor 1 (GEF1) and cell division control protein 42 homolog. We conclude that both GDF-15 and TGF-beta1 counteract chemokine-induced integrin activation on neutrophils via the ALK-5/TGF-betaRII heterodimer. This represents a novel, rapid anti-inflammatory activity of the 2 TGF-beta receptors and of TGF beta1. PMID- 27235142 TI - What motivates individuals with sickle cell disease to talk with others about their illness? Reasons for and against sickle cell disease disclosure. AB - This interview study documented how individuals with sickle cell disease make decisions about who to talk with concerning their illness based on psychological and interpersonal issues that are important to them. Reasons for sickle cell disease disclosure to specific persons were self-related (receiving support, venting feelings), other-related (educating others about sickle cell disease, forewarning others about sickle cell disease-related problems, someone asked for information about the disease), or situational (mostly focusing on another person being physically close or available to talk to). Reasons for sickle cell disease nondisclosure to specific persons were self-related (fear of rejection, being stereotyped, maintaining privacy) or other-related (lack of support, not worrying someone). PMID- 27235140 TI - Letrozole-induced functional changes in carcinoma-associated fibroblasts and their influence on breast cancer cell biology. AB - Accumulating evidence suggests that carcinoma-associated fibroblasts (CAFs) influence the efficacy of endocrine therapy. Aromatase inhibitors inhibit the growth of breast tumors by inhibiting the synthesis of estrogen. However, it remains unknown whether the aromatase inhibitor letrozole has an additional impact on CAFs, which further influence the efficacy of endocrine therapy. Primary CAFs were isolated from primary estrogen receptor-positive human breast tumors. Estrogen-deprived culture medium was used to exclude the influence of steroids. In co-culture, primary cultured CAFs increased MCF7 cell adhesion, invasion, migration and proliferation, and letrozole treatment inhibited these increases, except for the increase in proliferation. In total, 258 up-regulated genes and 47 down-regulated genes with an absolute fold change >2 were identified in CAFs co-cultured with MCF7 cell after letrozole treatment. One up-regulated genes (POSTN) and seven down-regulated genes (CCL2, CCL5, CXCL1, IL-8, CXCL5, LEP and NGF) were further validated by real-time PCR. The changes in CCL2 and CXCL1 expression were further confirmed using an automated microscopic imaging-based, high content analysis platform. Although the results need further functional validation, this study is the first to describe the differential tumor-promoting phenotype of CAFs induced by letrozole and the associated gene expression alterations. Most importantly, our data revealed that down-regulation of several secreted factors (CCL2, CCL5, CXCL1 etc.) in CAFs might be partially responsible for the efficacy of letrozole. PMID- 27235141 TI - Sequential addition of aprepitant in patients receiving carboplatin-based chemotherapy. AB - Chemotherapy-induced nausea and vomiting is a challenging issue. Although aprepitant is sometimes used as a therapeutic option in patients receiving moderately emetogenic chemotherapy, the potential benefit of sequential addition of aprepitant to dexamethasone and a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist during the second cycle of carboplatin-based chemotherapy remains unclear. Chemo-naive patients with advanced non-small cell lung cancer (NSCLC) who received carboplatin-based chemotherapy were treated with doublet antiemetic therapy with dexamethasone and a 5-HT3 receptor antagonist during the first cycle of chemotherapy. Aprepitant was then added during the second cycle of chemotherapy. The primary endpoint was overall complete response rate, defined as no vomiting and no rescue therapy during the 120 h after administration of chemotherapy. Sixty-seven patients were enrolled, 63 of whom were eligible after two cycles of chemotherapy. The overall complete response rate was significantly improved in the second cycle [87.3 %, 95 % confidence interval (CI) 76.5-94.4 %] compared with the first cycle (65.1 %, 95 % CI 52.0-76.7 %; p < 0.001). Improvement was observed in the delayed phase, but not in the acute phase. Subsequent addition of aprepitant significantly improved the overall complete response rate in NSCLC patients receiving a second cycle of carboplatin-based chemotherapy. PMID- 27235143 TI - Maternal perception of emotional difficulties of preschool children in rural Niger. AB - Mental health care for infants and young children is often greatly limited in low resource settings. The purpose of this study was to describe maternal perception of emotional difficulties of preschool children in a rural area of Niger (Maradi). In this context, both mental health awareness and services were scarce. This research was part of a larger cross-cultural validation study of a screening tool for psychological difficulties in children aged 3 to 6 years old. Data collection included group discussion and individual interviews. A total of 10 group interviews and 83 individual interviews were conducted. The results highlight mothers' perceptions concerning their children's psychological difficulties. Sleep difficulties were considered significant by the mothers and were used often as an entry point for further discussion of concerns. Peer and sibling relationships, separation anxiety, and reactions to difficult events were also described. Identification of mothers' perceptions of children's main difficulties through a mixed-method approach shows promise as a way to inform interventions to provide culturally appropriate care for children in need. PMID- 27235144 TI - On the history of cultural psychiatry: Georges Devereux, Henri Ellenberger, and the psychological treatment of Native Americans in the 1950s. AB - Henri Ellenberger (1905-1993) wrote the first French-language synthesis of transcultural psychiatry ("Ethno-psychiatrie") for the French Encyclopedie Medico Chirurgicale in 1965. His work casts new light on the early development of transcultural psychiatry in relation to scientific communities and networks, particularly on the role of Georges Devereux (1908-1985). The Ellenberger archives offer the possibility of comparing published texts with archival ones to create a more nuanced account of the history of transcultural psychiatry, and notably of the psychological treatment of Native Americans. This paper examines some key moments in the intellectual trajectories of Devereux and Ellenberger, including Devereux's dispute with Ackerknecht, the careers of Devereux and Ellenberger as therapists at the Menninger Foundation (Topeka, Kansas) in the 1950s, and their respective positions in the research network developed by McGill University (Montreal, Quebec) with the newsletter Transcultural Research in Mental Health Problems Finally, I consider their ties to other important figures in this field as it transitioned from colonial medicine to academic medicine, including Roger Bastide (France), Henri Collomb and the Ortigues (France and Africa), as well as Eric Wittkower and Brian Murphy (Canada) and Alexander Leighton (United States and Canada). PMID- 27235145 TI - Microsurgical resection of tumors of the lateral and third ventricles: operative corridors for difficult-to-reach lesions. AB - Tumors of the lateral and third ventricles are cradled on all sides by vital vascular and eloquent neural structures. Microsurgical resection, which always requires attentive planning, plays a critical role in the contemporary management of these lesions. This article provides an overview of the open microsurgical approaches to the region highlighting key clinical perspectives. PMID- 27235146 TI - Syndecan4 coordinates Wnt/JNK and BMP signaling to regulate foregut progenitor development. AB - Temporally and spatially dynamic Wnt and BMP signals are essential to pattern foregut endoderm progenitors that give rise to the liver, pancreas and lungs, but how these two signaling pathways are coordinated in the extracellular space is unknown. Here we identify the transmembrane heparan sulphate proteoglycan Syndecan-4 (Sdc4), as a key regulator of both non-canonical Wnt and BMP signaling in the Xenopus foregut. Foregut-specific Sdc4 depletion results in a disrupted Fibronectin (Fn1) matrix, reduced cell adhesion, and failure to maintain foregut gene expression ultimately leading to foregut organ hypoplasia. Sdc4 is required to maintain robust Wnt/JNK and BMP/Smad1 signaling in the hhex+ foregut progenitors. Pathway analysis suggests that Sdc4 functionally interacts with Fzd7 to promote Wnt/JNK signaling, which maintains foregut identity and cell adhesion. In addition, the Sdc4 ectodomain is required to support Fn1 matrix assembly, which is essential for the robust BMP signaling that promotes foregut gene expression. This work sheds lights on how the extracellular matrix can coordinate different signaling pathways during organogenesis. PMID- 27235148 TI - Endothelial FoxO proteins impair insulin sensitivity and restrain muscle angiogenesis in response to a high-fat diet. AB - Skeletal muscle microvascular dysfunction contributes to disease severity in type 2 diabetes. Recent studies indicate a role for Forkhead box O (FoxO) transcription factors in modulating endothelial cell phenotype. We hypothesized that a high-fat (HF) diet generates a dysfunctional vascular niche through an increased expression of endothelial FoxO. FoxO1 protein increased (+130%) in the skeletal muscle capillaries from HF compared to normal chow-fed mice. FoxO1 protein was significantly elevated in cultured endothelial cells exposed to the saturated fatty acid palmitate or the proinflammatory cytokine TNF-alpha. In HF fed mice, endothelium-directed depletion of FoxO1/3/4 (FoxO(Delta)) improved insulin sensitivity (+110%) compared to that of the controls (FoxO(L/L)). The number of skeletal muscle capillaries increased significantly in the HF FoxO(Delta) mice. Transcript profiling of skeletal muscle identified significant increases in genes associated with angiogenesis and lipid metabolism in HF FoxO(Delta) vs. HF-FoxO(L/L) mice. HF-FoxO(Delta) muscle also was characterized by a decrease in inflammation-related genes and an enriched M2 macrophage signature. We conclude that endothelial FoxO proteins promote insulin resistance in HF diet, which may in part result from FoxO proteins establishing an antiangiogenic and proinflammatory microenvironment within skeletal muscle. These findings provide mechanistic insight into the development of microvascular dysfunction in the progression of type 2 diabetes.-Nwadozi, E., Roudier, E., Rullman, E., Tharmalingam, S., Liu, H.-Y., Gustafsson, T., Haas, T. L. Endothelial FoxO proteins impair insulin sensitivity and restrain muscle angiogenesis in response to a high-fat diet. PMID- 27235149 TI - Corrigendum to Genetic identities and local inbreeding in pure diploid clones with homoplasic markers: SNPs may be misleading [Infect. Genet. Evol. 33 (2015) 227-232]. PMID- 27235150 TI - Synergistic active targeting of dually integrin alphavbeta3/CD44-targeted nanoparticles to B16F10 tumors located at different sites of mouse bodies. AB - Conventional enhanced permeation and retention (EPR) mediates the effects of many drugs, including the accumulation of nanocarriers at tumor sites, but its efficiency remains low. In this study, this limitation was overcome by developing a dual-targeting delivery system based on hyaluronan (HA, a major ligand of CD44) and tetraiodothyroacetic acid (tetrac, a specific ligand of alphavbeta3), which was exploited to carry docetaxel (DTX) for the synergistic active targeting to tumors. First, a tetrac-HA (TeHA) conjugate was synthesized and grafted onto the surfaces of solid lipid nanoparticles (SLNs) (TeHA-SLNs/DTX), with a high encapsulation efficiency of >91.6%. The resulting SLNs exhibited an approximately toroid morphology revealed using TEM. The cellular uptake and cytotoxicity of various formulations on CD44/alphavbeta3-enriched B16F10 cells were then assessed, and both results confirmed the selective uptake and high cytotoxicity of the TeHA-SLNs/DTX in a TeHA-dependent manner. In vivo imaging and vessel distribution tests revealed the efficiency of synergistic active targeting was higher than that of EPR-mediated passive targeting by the TeHA-SLNs to alphavbeta3-expressing tumor blood vessels and CD44-expressing tumor cells via selective targeting. Finally, in both xenograft tumor mice and in situ lung metastasis tumor mice, tumor growth was significantly inhibited by TeHA-SLNs/DTX. Therefore, TeHA-SLNs are an efficient system for the dual-targeted delivery of drugs to treat cancer in vivo. PMID- 27235147 TI - An Elk transcription factor is required for Runx-dependent survival signaling in the sea urchin embryo. AB - Elk proteins are Ets family transcription factors that regulate cell proliferation, survival, and differentiation in response to ERK (extracellular signal regulated kinase)-mediated phosphorylation. Here we report the embryonic expression and function of Sp-Elk, the single Elk gene of the sea urchin Strongylocentrotus purpuratus. Sp-Elk is zygotically expressed throughout the embryo beginning at late cleavage stage, with peak expression occurring at blastula stage. Morpholino antisense-mediated knockdown of Sp-Elk causes blastula stage developmental arrest and embryo disintegration due to apoptosis, a phenotype that is rescued by wild-type Elk mRNA. Development is also rescued by Elk mRNA encoding a serine to aspartic acid substitution (S402D) that mimics ERK mediated phosphorylation of a conserved site that enhances DNA binding, but not by Elk mRNA encoding an alanine substitution at the same site (S402A). This demonstrates both that the apoptotic phenotype of the morphants is specifically caused by Elk depletion, and that phosphorylation of serine 402 of Sp-Elk is critical for its anti-apoptotic function. Knockdown of Sp-Elk results in under expression of several regulatory genes involved in cell fate specification, cell cycle control, and survival signaling, including the transcriptional regulator Sp Runt-1 and its target Sp-PKC1, both of which were shown previously to be required for cell survival during embryogenesis. Both Sp-Runt-1 and Sp-PKC1 have sequences upstream of their transcription start sites that specifically bind Sp-Elk. These results indicate that Sp-Elk is the signal-dependent activator of a feed-forward gene regulatory circuit, consisting also of Sp-Runt-1 and Sp-PKC1, which actively suppresses apoptosis in the early embryo. PMID- 27235151 TI - Incidence and risk factors for postoperative delirium after major head and neck cancer surgery. AB - BACKGROUND: Postoperative delirium is a common and serious complication after extensive surgery. This study aimed to investigate the incidence and risk factors for postoperative delirium after major head and neck cancer surgery. METHODS: A retrospective analysis was performed for 293 patients who underwent major head and neck cancer surgery lasting >6 h at our institution between January 2012 and November 2015. All data were assessed by two psychiatrists. Univariate and multivariate analyses were performed. RESULTS: Postoperative delirium developed in 50 (17.1%) patients; most cases (84.0%) of postoperative delirium were observed between postoperative day (POD) 1 and POD 3. Multivariate analysis revealed that an age >70 years was the significant risk factor for postoperative delirium incidence after major head and neck cancer surgery; the multivariate hazard ratio was 3.935 (95% confidence interval 1.873-8.265, p < 0.001). CONCLUSIONS: Most cases of postoperative delirium after major head and neck cancer surgery were observed between POD 1 and POD 3, and a multivariate analysis revealed that an age >70 years was a significant risk factor for postoperative delirium incidence. Clinicians should pay particular attention to the possibility of delirium incidence during the first 3 days after surgery for patients aged >70 years. PMID- 27235152 TI - Bilamina cortical tenting grafting technique for three-dimensional reconstruction of severely atrophic alveolar ridges in anterior maxillae: A 6-year prospective study. AB - OBJECTIVE: To evaluate the efficacy and long-term outcome of the bilaminar cortical tenting grafting technique for reconstruction of vertical and horizontal alveolar ridge defects. MATERIAL AND METHODS: A bone block harvested from the lateral aspect of the mandibular ramus was bisected into two cortical laminae, which were then used to reconstruct the buccal and palatal walls of an alveolar ridge defect. The inter-laminar space was filled with particulate autogenous bone and the whole graft was covered with anorganic bone graft and collagen membrane. After 4-6 months, the width and height of the augmentation were recorded. The study sample consisted of 21 patients who were followed up for 6.09 +/- 1.18 years. RESULTS: Vertical and horizontal bone gain was 5.70 +/- 1.09 and 8.45 +/- 0.87 mm, respectively, and respective resorption rates were 10.20% and 6.15%. One patient showed soft-tissue dehiscence, while all others healed without complication. After an average follow-up of 6-years, the block grafts were well integrated into the recipient sites and there was only a small reduction in the peri-implant bone level (0.77 +/- 0.50 mm). CONCLUSION: This technique was effective and reliable for three-dimensional reconstruction of severely atrophic alveolar ridges in anterior maxillae. PMID- 27235153 TI - A CAD-CAM-prototyped temporomandibular condyle connected to a bony plate to support a free fibula flap in patients undergoing mandiblectomy: A pilot study with 5 years of follow up. AB - Reconstruction of the condyle after an ablative procedure with the aim of cancer elimination remains surgically challenging. This pilot study focused on mandibular condylar replacement using CAD-CAM temporomandibular prostheses connected to customized reconstructive plates to support free fibula flaps in oncological patients. Five patients underwent mandibular disarticulation resection, and two of them completed their 5-year follow ups. The condylar anatomy, the position of the condyle within the glenoid fossa, and glenoid anatomy were measured by superimposing pre- and postoperative CT images (obtained after 6 months and 5 years of follow up). When comparing condyle anatomy, the shift was no more than 0.19 mm; when calculating condyle downward displacement the values were inferior to 2.92 mm; when analyzing glenoid fossa thickness, in case #1, glenoid fossa thickness increased by 0.62 and 0.48 mm at the 6-month and 5-year follow ups, respectively, and in case #2 were 0.50 and -0.11 mm, respectively. The hypothesis that the absence of anatomical change would prevent biodynamic alteration of tissues of the articulation chamber (the glenoid fossa, the synovial liquid, and the disc) was confirmed by the preliminary findings of this study. PMID- 27235154 TI - Market approval processes for new types of spinal devices: challenges and recommendations for improvement. AB - BACKGROUND: Spinal pathology and related symptoms are among the most common health problems and are associated with high health care costs and productivity losses. Due to the aging population, these costs are further increasing every year. Another important reason for the increasing costs is the market approval of new technologies, such as spinal devices that are usually more expensive than the existing technologies. Previous cases of medical device failure led to concern about possible deficiencies in the market approval process. OBJECTIVE: The objective is to provide an overview of U.S. Food and Drug Administration (FDA) regulation regarding spinal implants to delineate the challenges and opportunities that spine surgery currently faces. METHODS: In this paper, two cases of market entries of spinal devices are presented and evaluated to illustrate these deficiencies. RESULTS: Spinal implant regulation is facing several challenges. New spinal devices should increase patient outcomes and safety at reasonable societal costs. The main challenge is to have a rigorous evaluation before dissemination, while still leaving room for innovative behavior that thrusts the healthcare practice forward. CONCLUSION: We have provided recommendations to enhance spinal implant regulation and improve and ensure the patient's safety and the future of spine surgery. PMID- 27235156 TI - Announcements for issue 7, 2016. PMID- 27235155 TI - Halo-gravity traction combined with assisted ventilation: an effective pre operative management for severe adult scoliosis complicated with respiratory dysfunction. AB - PURPOSE: To investigate the change of pulmonary function in adult scoliosis patients with respiratory dysfunction undergoing HGT combined with assisted ventilation. METHODS: 21 adult patients were retrospectively reviewed with a mean age of 26.2 years. Inclusion criteria were as follows: age over 18 years old; coronal Cobb angle greater than 100 degrees ; with respiratory failure; and duration of HGT more than 1 month. All patients underwent respiratory training. RESULTS: The Cobb angle averaged 131.21 degrees and was reduced to 107.68 degrees after HGT. Significantly increased mean forced vital capacity (FVC) was found after HGT (P = 0.003) with significantly improved percent-predicted values for FVC (P < 0.001). Meanwhile, significantly increased forced expiratory volume in 1 s (FEV1) was also observed (P < 0.001) with significantly improved percent predicted values for FEV1 (P = 0.003) after HGT. CONCLUSION: The results of our study revealed that combined HGT and assisted ventilation would be beneficial to pulmonary function improvement in severe adult scoliosis cases, most of which were young adults. PMID- 27235158 TI - Cross-validation of a mass spectrometric-based method for the therapeutic drug monitoring of irinotecan: implementation of matrix-assisted laser desorption/ionization mass spectrometry in pharmacokinetic measurements. AB - Irinotecan is a widely used antineoplastic drug, mostly employed for the treatment of colorectal cancer. This drug is a feasible candidate for therapeutic drug monitoring due to the presence of a wide inter-individual variability in the pharmacokinetic and pharmacodynamic parameters. In order to determine the drug concentration during the administration protocol, we developed a quantitative MALDI-MS method using CHCA as MALDI matrix. Here, we demonstrate that MALDI-TOF can be applied in a routine setting for therapeutic drug monitoring in humans offering quick and accurate results. To reach this aim, we cross validated, according to FDA and EMA guidelines, the MALDI-TOF method in comparison with a standard LC-MS/MS method, applying it for the quantification of 108 patients' plasma samples from a clinical trial. Standard curves for irinotecan were linear (R (2) >= 0.9842) over the concentration ranges between 300 and 10,000 ng/mL and showed good back-calculated accuracy and precision. Intra- and inter-day precision and accuracy, determined on three quality control levels were always <12.8 % and between 90.1 and 106.9 %, respectively. The cross-validation procedure showed a good reproducibility between the two methods, the percentage differences within 20 % in more than 70 % of the total amount of clinical samples analysed. PMID- 27235157 TI - The influence of participant characteristics on the relationship between cuff pressure and level of blood flow restriction. AB - PURPOSE: Previous investigations to establish factors influencing the blood flow restriction (BFR) stimulus have determined cuff pressures required for complete arterial occlusion, which does not reflect the partial restriction prescribed for this training technique. This study aimed to establish characteristics that should be accounted for when prescribing cuff pressures required for partial BFR. METHODS: Fifty participants were subjected to incremental blood flow restriction of the upper and lower limbs by proximal pneumatic cuff inflation. Popliteal and brachial artery diameter, blood velocity and blood flow was assessed with Doppler ultrasound. Height, body mass, limb circumference, muscle-bone cross-sectional area, adipose thickness (AT) and arterial blood pressure were measured and used in different models of hierarchical linear regression to predict the pressure at which 60 % BFR (partial occlusion) occurred. RESULTS: Combined analysis revealed a difference in cuff pressures required to elicit 60 % BFR in the popliteal (111 +/- 12 mmHg) and brachial arteries (101 +/- 12 mmHg). MAP (r = 0.58) and AT (r = 0.45) were the largest independent determinants of lower and upper body partial occlusion pressures. However, greater variance was explained by upper and lower limb regression models composed of DBP and BMI (48 %), and arm AT and DBP (30 %), respectively. CONCLUSION: Limb circumference has limited impact on the cuff pressure required for partial blood flow restriction which is in contrast to its recognised relationship with complete arterial occlusion. The majority of the variance in partial occlusion pressure remains unexplained by the predictor variables assessed in the present study. PMID- 27235159 TI - The detection method for small molecules coupled with a molecularly imprinted polymer/quantum dot chip using a home-built optical system. AB - A method to detect small molecules with a molecularly imprinted polymer/quantum dot (MIP-QD) chip using a home-built optical fluidic system was first proposed in this study. Ractopamine (RAC) was used as the model molecule to demonstrate its feasibility. The sensing of the target molecule is based on the quenching amount of the quantum dots. The method is facile, cost-saving, easy for miniaturization and avoids the cumbersome steps that are needed to get the fluorescent quenching curve using a spectrofluorometer. Most importantly, more details and accurate response time can be obtained by use of this method. The experimental results show that the prepared chips with low cost are highly selective and the home built detection system allows the fast binding kinetics. The recorded quenching process was used to study the kinetic uptake of RAC onto the MIP-QD chip and the specificity towards RAC. The system can further be utilized to study the effect of the solvent, pH and temperature on the selectivity of the prepared MIP. The methodology could be extended to other similar studies with different molecules. Graphical abstract Schematic illustration of the molecularly imprinted polymer/quantum dot chip capturing the target molecule. PMID- 27235160 TI - Rapid determination of sulfonamide residues in pork by surface-modified hydrophilic electrospun nanofibrous membrane solid-phase extraction combined with ultra-performance liquid chromatography. AB - This study aimed to rapidly determine 13 representative sulfonamide (SA) residues in pork by using a surface-modified hydrophilic polystyrene sulfonic acid (PSSA) electrospun nanofibrous membrane as the solid-phase extraction (SPE) pretreatment sorbent, followed by ultra-performance liquid chromatography (UPLC) analysis. The highly hydrophilic nature of PSSA nanofibrous membrane created by vacuum plasma treatment was characterized using Fourier transform infrared spectroscopy (FT IR), field emission scanning electron microscopy (FE-SEM), water contact angle, and X-ray photoelectron spectroscopy (XPS) measurements. In the pretreatment procedures, 13 SA standards, which were spiked in the fatty pork samples, were extracted, enriched, and purified by the SPE procedure based on the principle of ion exchange with the sulfonic groups on the PSSA chains. Under the optimized conditions, the calibration curves of 13 SA compounds showed good linearities with correlation coefficients (r) of more than 0.99 in the range of 50.0-200 MUg kg(-1). The mean recoveries of 13 SAs at the spiked concentrations of 50, 100, and 200 MUg kg(-1) were in the range of 70.3-92.5 % with average RSDs (n = 6) of less than 15 % (except for sulfacetamide, 56.9-61.6 %). Compared with other pretreatment methods reported previously, less organic solvent (especially without degreasing the extract with n-hexane) was used in this time-saving SPE procedure, which avoids the possibility of emulsification and therefore enhances the recoveries. The developed and validated analysis method was sensitive, accurate, rapid, convenient, environmentally friendly, and was successfully applied for the detection of 13 SA residues in commercially available pork samples. PMID- 27235161 TI - Adult with Middle Interhemispheric Variant of Holoprosencephaly: Neuropsychological, Clinical, and Radiological Findings. AB - OBJECTIVE: The middle interhemispheric variant of holoprosencephaly (MIHV) is a mild, rare variant of holoprosencephaly. Only a few cases of children with MIHV have been reported. Here we report in detail an adult case. METHOD: The patient is a female in her 30s. The patient underwent an extensive neuropsychological examination, a neurological examination and a magnetic resonance imaging. RESULTS: Neuroradiologically, the patient had a typical finding of MIHV, with the absence of the central corpus callosum and union of posterior frontal and anterior parietal gyri. In neuropsychological examination, the patient had average or above average performance in verbal comprehension, naming, reading and writing, and below average performance in perceptual reasoning, visuospatial abilities, processing speed and memory. Also difficulties in mathematical abilities, psychomotor skills, and executive functions were found. No gross neurological involvement was noted. She was diagnosed with atypical depression, post-traumatic stress disorder and a dissociative disorder in early adulthood. Despite cognitive deficits, she was able to achieve a tertiary level education. CONCLUSIONS: This is the first adult case of MIHV described in detail. Our case emphasizes the possibility of a missed diagnosis of marked brain malformations in patients with craniofacial abnormalities. More cases and prospective follow-up studies are needed to understand the evolvement of both neuropsychological and psychiatric symptoms in these patients. PMID- 27235162 TI - The Role of the 21-Gene Recurrence Score in Breast Cancer Treatment. AB - Several multi-gene assays have been developed to predict the risk of recurrence in patients with estrogen receptor-positive early breast cancer and in whom endocrine therapy is planned. The 21-gene assay is widely used and its prognostic value has been retrospectively validated, showing significant differences in the risk of distant recurrence for patients at high versus low risk. Its role in predicting chemotherapy benefit has also been established, showing a clear benefit for high-risk patients and minimal benefit in those at low risk. These findings have been prospectively investigated in TAILORx (Trial Assigning Individualized Options for Treatment), where available data from the low-risk cohort confirms the prognostic value of this diagnostic test. The prognostic utility of the 21-gene assay increases when combined with clinicopathologic variables, and data from integrated models suggest that its use should be limited to patients with tumor characteristics suggestive of potential chemotherapy benefit. Furthermore, the 21-gene assay has been shown to impact clinical decision making in a cost-effective manner, although direct evidence of benefit from modified treatment recommendations is yet to be proven. The prognostic value of this test has also been shown in populations with node-positive or locally advanced disease treated with neoadjuvant chemotherapy, and ongoing trials aim to prospectively validate these findings. PMID- 27235163 TI - Corticotropin-releasing factor in ventromedial prefrontal cortex mediates avoidance of a traumatic stress-paired context. AB - Post-traumatic stress disorder (PTSD) affects 7.7 million Americans. One diagnostic criterion for PTSD is avoidance of stimuli that are related to the traumatic stress. Using a predator odor stress conditioned place aversion (CPA) model, rats can be divided into groups based on stress reactivity, as measured by avoidance of the odor-paired context. Avoider rats, which show high stress reactivity, exhibit persistent avoidance of stress-paired context and escalated alcohol drinking. Here, we examined the potential role of corticotropin-releasing factor (CRF), a neuropeptide that promotes anxiety-like behavior in mediating avoidance and escalated alcohol drinking after stress. CRF is expressed in the medial prefrontal cortex (mPFC). The dorsal and ventral sub-regions of the mPFC (dmPFC and vmPFC) have opposing roles in stress reactivity and alcohol drinking. We hypothesized that vmPFC CRF-CRFR1 signaling contributes functionally to stress induced avoidance and escalated alcohol self-administration. In Experiment 1, adult male Wistar rats were exposed to predator odor stress in a CPA paradigm, indexed for avoidance of odor-paired context, and brains processed for CRF immunoreactive cell density in vmPFC and dmPFC. Post-stress, Avoiders exhibited higher CRF cell density in vmPFC, but not the dmPFC. In Experiment 2, rats were tested for avoidance of a context repeatedly paired with intra-vmPFC CRF infusions. In Experiment 3, rats were stressed and indexed, then tested for the effects of intra-vmPFC CRFR1 antagonism on avoidance and alcohol self administration. Intra-vmPFC CRF infusion produced avoidance of a paired context, and intra-vmPFC CRFR1 antagonism reversed avoidance of a stress-paired context, but did not alter post-stress alcohol self-administration. These findings suggest that vmPFC CRF-CRFR1 signaling mediates avoidance of stimuli paired with traumatic stress. PMID- 27235165 TI - Pathogens Causing Upper Respiratory Tract Infections in Outpatients. AB - The aim of the present study was to determine the results of typical and atypical bacteria microbiological tests in patients with symptoms of chronic cough. We investigated 230 outpatients aged from 1 to 83 years (112 female, 72 male, and 46 children) who were free of any respiratory tract infection at the time of study. The material for the investigation consisted of pharyngeal swabs. Two hundred and thirty pharyngeal swabs were examined for Chlamydia pneumoniae antigen and for typical pathogens each. Chlamydia pneumoniae antigen was detected using an indirect immunofluorescence test and classical microbiological culture was used for the detection of typical bacteria. The antigen was found in 44/230 (19.1 %) patients with chronic cough (23 women, 13 men, and 8 children). Positive culture for typical pathogens was observed in 65/230 (28.3 %) patients (37 women, 14 men, and 14 children). Simultaneous occurrence of Chlamydia pneumoniae and typical pathogens such as Staphylococcus aureus, Streptococcus pyogenes, Moraxella catarrhalis, and Haemophilus influenzae, was observed in 11/230 (4.8 %) patients. The results show that in patients with chronic cough Chlamydia pneumoniae is detected less frequently than the typical pathogens are. A search for atypical bacteria in patients with chronic cough is needed to be able to conduct effective and sufficiently long therapy. PMID- 27235164 TI - Combination of Eribulin and Aurora A Inhibitor MLN8237 Prevents Metastatic Colonization and Induces Cytotoxic Autophagy in Breast Cancer. AB - Recent findings suggest that the inhibition of Aurora A (AURKA) kinase may offer a novel treatment strategy against metastatic cancers. In the current study, we determined the effects of AURKA inhibition by the small molecule inhibitor MLN8237 both as a monotherapy and in combination with the microtubule-targeting drug eribulin on different stages of metastasis in triple-negative breast cancer (TNBC) and defined the potential mechanism of its action. MLN8237 as a single agent and in combination with eribulin affected multiple steps in the metastatic process, including migration, attachment, and proliferation in distant organs, resulting in suppression of metastatic colonization and recurrence of cancer. Eribulin application induces accumulation of active AURKA in TNBC cells, providing foundation for the combination therapy. Mechanistically, AURKA inhibition induces cytotoxic autophagy via activation of the LC3B/p62 axis and inhibition of pAKT, leading to eradication of metastases, but has no effect on growth of mammary tumor. Combination of MLN8237 with eribulin leads to a synergistic increase in apoptosis in mammary tumors, as well as cytotoxic autophagy in metastases. These preclinical data provide a new understanding of the mechanisms by which MLN8237 mediates its antimetastatic effects and advocates for its combination with eribulin in future clinical trials for metastatic breast cancer and early-stage solid tumors. Mol Cancer Ther; 15(8); 1809-22. (c)2016 AACR. PMID- 27235167 TI - Lessons from genome skimming of arthropod-preserving ethanol. AB - Field-collected specimens of invertebrates are regularly killed and preserved in ethanol, prior to DNA extraction from the specimens, while the ethanol fraction is usually discarded. However, DNA may be released from the specimens into the ethanol, which can potentially be exploited to study species diversity in the sample without the need for DNA extraction from tissue. We used shallow shotgun sequencing of the total DNA to characterize the preservative ethanol from two pools of insects (from a freshwater habitat and terrestrial habitat) to evaluate the efficiency of DNA transfer from the specimens to the ethanol. In parallel, the specimens themselves were subjected to bulk DNA extraction and shotgun sequencing, followed by assembly of mitochondrial genomes for 39 of 40 species in the two pools. Shotgun sequencing from the ethanol fraction and read-matching to the mitogenomes detected ~40% of the arthropod species in the ethanol, confirming the transfer of DNA whose quantity was correlated to the biomass of specimens. The comparison of diversity profiles of microbiota in specimen and ethanol samples showed that 'closed association' (internal tissue) bacterial species tend to be more abundant in DNA extracted from the specimens, while 'open association' symbionts were enriched in the preservative fluid. The vomiting reflex of many insects also ensures that gut content is released into the ethanol, which provides easy access to DNA from prey items. Shotgun sequencing of DNA from preservative ethanol provides novel opportunities for characterizing the functional or ecological components of an ecosystem and their trophic interactions. PMID- 27235166 TI - Genotyping of EGFR Mutations from Bronchial Cytological Specimens in Slovakian Lung Cancer Patients. AB - Non-small cell lung cancer (NSCLC) is a histologically and molecularly heterogeneous disease predominating in Slovakia among newly diagnosed oncological disorders and leading in the number of associated deaths. NSCLC diagnostics has advanced especially in molecular typing of epidermal growth factor receptor (EGFR) and subsequent targeted molecular therapy using tyrosine-kinase inhibitor(s) (TKI). The selection of patients for targeted therapy, we describe in this study, is mostly guided through bronchial smears rather than more invasive biopsies. We identified 32 adenocarcinomas, 40 squamous-cell carcinomas, 12 large-cell carcinomas, along with two unspecified carcinomas, in the NSCLC group who had bronchial smears taken. The assessment of tumor cell number, and genomic DNA allowed for screening of clinically relevant somatic EGFR mutations in 86 patients. Using quantitative PCR, 12 patients (14 %) were recommended for EGFR-TKI therapy. The most prevalent EGFR HIT-a in the somatosome, terms introduced and defined in this study, were exon 19 deletions, which were found in combination with the TKI-resistant p.T790M mutation in exon 20 in one patient. The study describes a method that is minimally invasive, reliable, and meets all criteria of routine molecular diagnostics. A multidisciplinary approach of EGFR genotyping from bronchial smears implemented in the study allows expanding targeted molecular therapy in NSCLC patients. PMID- 27235169 TI - An esophageal lymphoma discovered by echocardiography. PMID- 27235170 TI - A model system using confocal fluorescence microscopy for examining real-time intracellular sodium ion regulation. AB - The gills of euryhaline fish are the ultimate ionoregulatory tissue, achieving ion homeostasis despite rapid and significant changes in external salinity. Cellular handling of sodium is not only critical for salt and water balance but is also directly linked to other essential functions such as acid-base homeostasis and nitrogen excretion. However, although measurement of intracellular sodium ([Na(+)]i) is important for an understanding of gill transport function, it is challenging and subject to methodological artifacts. Using gill filaments from a model euryhaline fish, inanga (Galaxias maculatus), the suitability of the fluorescent dye CoroNa Green as a probe for measuring [Na(+)]i in intact ionocytes was confirmed via confocal microscopy. Cell viability was verified, optimal dye loading parameters were determined, and the dye-ion dissociation constant was measured. Application of the technique to freshwater- and 100% seawater-acclimated inanga showed salinity-dependent changes in branchial [Na(+)]i, whereas no significant differences in branchial [Na(+)]i were determined in 50% seawater-acclimated fish. This technique facilitates the examination of real-time changes in gill [Na(+)]i in response to environmental factors and may offer significant insight into key homeostatic functions associated with the fish gill and the principles of sodium ion transport in other tissues and organisms. PMID- 27235171 TI - A continuous spectrophotometric assay and nonlinear kinetic analysis of methionine gamma-lyase catalysis. AB - In this article, we present a new, easy-to-implement assay for methionine gamma lyase (MGL)-catalyzed gamma-elimination reactions of l-methionine and its analogues that produce alpha-ketobutyrate (alpha-KB) as product. The assay employs ultraviolet-visible (UV-Vis) spectrophotometry to continuously monitor the rate of formation of alpha-KB by its absorbance at 315 nm. We also employ a nonlinear data analysis method that obviates the need for an "initial slope" determination, which can introduce errors when the progress curves are nonlinear. The spectrophotometric assay is validated through product analysis by (1)H NMR (nuclear magnetic resonance), which showed that under the conditions of study l methionine (l-met) and l-methionine sulfone (l-met sulfone) substrates were converted to alpha-KB product with greater than 99% yield. Using this assay method, we determined for the first time the Michaelis-Menten parameters for a recombinant form of MGL from Porphyromonas gingivalis, obtaining respective kcat and Km values of 328 +/- 8 min(-1) and 1.2 +/- 0.1 mM for l-met gamma-elimination and 2048 +/- 59 min(-1) and 38 +/- 2 mM for l-met sulfone gamma-elimination reactions. We envisage that this assay method will be useful for determining the activity of MGL gamma-elimination reactions that produce alpha-KB as the end product. PMID- 27235172 TI - A novel cell-based duplex high-throughput screening assay combining fluorescent Ca(2+) measurement with homogeneous time-resolved fluorescence technology. AB - Cell-based assays for G-protein-coupled receptor (GPCR) activation applied in high-throughput screening (HTS) monitor various readouts for second messengers or intracellular effectors. Recently, our understanding of diverging signaling pathways downstream of receptor activation and the capability of small molecules to selectively modulate signaling routes has increased substantially, underlining the importance of selecting appropriate readouts in cellular functional screens. To minimize the rate of false negatives in large-scale screening campaigns, it is crucial to maximize the chance of a ligand being detected, and generally applicable methods for detecting multiple analytes from a single well might serve this purpose. The few assays developed so far based on multiplexed GPCR readouts are limited to only certain applications and usually rely on genetic manipulations hindering screening in native or native-like cellular systems. Here we describe a more generally applicable and HTS-compatible homogeneous assay based on the combination of fluorometric detection of [Ca(2+)] with subsequent homogeneous time-resolved fluorescence (HTRF) cAMP readout in the same well. Besides describing development and validation of the assay, using a cell line recombinantly expressing the human PTH1 receptor screening of a small library is also presented, demonstrating the robustness and HTS compatibility of the novel paradigm. PMID- 27235173 TI - Sequential development of chronic myelogenous leukemia and primary myelofibrosis in a patient with history of large B-cell lymphoma treated with radiotherapy and chemotherapy: two myeloid neoplasms with distinct genotypic profiles suggestive of biclonality in a single individual. PMID- 27235174 TI - Mutual relationship between serum ferroxidase activity and hemoglobin levels in elderly individuals. AB - The identification of hemoglobin (Hb) biological determinants is of primary clinical interest, in particular in the elderly because of the well-documented relationship between anemia and cognitive and functional decline. Ceruloplasmin (Cp) and non-Cp ferroxidase activity might influence Hb production because of its role in modulating iron mobilization. This potential connection has never been explored so far. Therefore, in the present study, we evaluated the possible association between serum ferroxidase activity (sFeOx) and Hb in a sample of 136 apparently healthy older individuals. The results revealed that nonlinear (quadratic) regression explained the relationship between the two variables of interest better than did the linear one (R (2) = 0.09 vs. R (2) = 0.03). The same analysis highlighted a linear behavior for the relationship between Hb and sFeOx, for two separate subsamples stratified on the basis of the Hb value (141 g/L) corresponding to the parabola vertex. In the subset with higher Hb (high Hb), sFeOx was positively associated (r = 0.44, p = 0.003) while in the low Hb subset, the association was negative (r = -0.26, p = 0.01). Notably, we found that the concentration of Cp was significantly higher in Low Hb compared to High Hb subsample (p < 0.05), with this multicopper oxidase selectively contributing to sFeOx in the former group (r = 0.348, p = 0.001). Collectively, this exploratory study suggests that ferroxidases might play a role in dispatching the body's iron toward erythropoietic tissues, with Cp contribution that might become more important in stress-like conditions. PMID- 27235175 TI - Expression, purification, and buffer solubility optimization of the putative human peptidyl-tRNA hydrolase PTRHD1. AB - Performing the essential function of recycling peptidyl-tRNAs, peptidyl-tRNA hydrolases are ubiquitous in all domains of life. The multicomponent eukaryotic Pth system differs greatly from the bacterial system composed predominantly of a single Pth1 enzyme. While bacterial Pth1s are structurally well characterized and promising new targets for antibiotic development, eukaryotic Pths are largely understudied. From amino acid sequence alignment and secondary structure predictions, the human gene product PTRHD1 was classified as a eukaryotic Pth. Herein, we report cloning, recombinant bacterial expression, and weak binding to peptidyl-tRNA for PTRHD1. Additionally, we report binding to tRNA but absence of peptidyl-tRNA hydrolase activity. Thus, PTRHD1 is not a Pth and the functional consequence of nucleotide binding remains undefined. PMID- 27235176 TI - Optimization of purification method and characterization of recombinant human Centrin-1. AB - Centrins are acidic proteins, present in all eukaryotes to perform imperative roles in centrosome positioning and segregation. Existing methods for the purification of centrins for biophysical studies involves either multiple steps or yields protein with an affinity tag, which pins additional tag-cleavage step. Therefore, we have made an attempt to develop a simple and single step method for protein purification. We have performed categorical evaluation of existing methods, and describe a one-step procedure based on cleavable Intein-tag, which can be utilized for routine preparation of any isoform of centrins. Since human Centrin-1 and Centrin-2 are devoid of Trp, we exploit this feature to assess the purity of the protein using Tyr fluorescence; an essential point ignored generally. In addition, we report important spectral and hydrodynamic characteristics of human Centrin-1, accounting that HsCentrin-1 has moderate affinity for Ca(2+). Centrin-1 does not gain structure as seen by far- and near UV circular dichroism, rather there is a loss of ellipticity, though inconsiderable upon binding Ca(2+). PMID- 27235177 TI - Recurrent Malignancy in Osteoradionecrosis Specimen. AB - PURPOSE: Osteoradionecrosis (ORN) is a well-known complication of head and neck radiation therapy. Statistically, the mandible is the most commonly affected site. The incidental finding of malignancy in the resection specimen has been documented but is somewhat rare. The aim of this review is to investigate the presence of recurrent carcinoma and sarcoma or new primary malignancies in resection specimens previously diagnosed and treated as ORN. PATIENTS AND METHODS: This study is a retrospective case series. We conducted a chart review of all cases managed at the University of Miami Miller School of Medicine/Jackson Memorial Hospital. The inclusion criteria included a history of head and neck carcinoma treated with radiation of at least 6,000 cGy; clinical diagnosis of ORN; and surgical intervention with osseous resection for treatment of ORN. The study endpoint measured included microscopic evidence of malignancy in the resected ORN specimen. Additional data collected included gender, age, and type of primary pathology. RESULTS: A total of 564 patients met the inclusion criteria. Of these patients, 14 had microscopic evidence of cancer in the specimen (2.48%) and 5 had a proven second primary malignancy in the foregut (1 in the lung, 0.18%, and 4 in the oropharynx, 0.70%). In 1 of the 14 patients, a high-grade sarcoma was diagnosed and the patient died within 1 year of diagnosis. In the treatment of our ORN patient population, a total of 19 malignancies were found collectively (3.37%). Of the 564 patients, 352 were men and 212 were women. The median age was 46 years (range, 33 to 97 years). Head and neck squamous cell carcinoma represented 531 cases in our sample, followed by 28 cases of salivary gland carcinoma and only 5 cases of sarcoma. CONCLUSIONS: Although the finding of malignancy in ORN patients is relatively rare (3.37% in this study), oral and maxillofacial surgeons should be cognizant of its potential presence. The treatment of malignant disease is different than that of ORN, and a multidisciplinary treatment approach is recommended if a malignancy is diagnosed in an ORN patient. PMID- 27235178 TI - Dental Care Professionals Should Avoid the Administration of Amoxicillin in Healthy Patients During Third Molar Surgery: Is Antibiotic Resistence the Only Problem? PMID- 27235179 TI - Use of Fibrin Glue as an Adjunct in the Repair of Lingual Nerve Injury: Case Report. AB - This report describes a case of lingual nerve injury repair using a novel technique in which Tisseel fibrin glue was used to stabilize an Axoguard nerve conduit placed around the site of primary neurorrhaphy to decrease the number of sutures required for stabilization. Five months postoperatively, the patient subjectively had increased sensation and improved taste in the left lingual nerve distribution. At neurosensory examination, the patient exhibited functional neurosensory recovery (S3+ on the Medical Research Council Scale). PMID- 27235180 TI - Clinical Outcomes of Infants With Periorbital Hemangiomas Treated With Oral Propranolol. AB - PURPOSE: Periorbital infantile hemangiomas (IHs) require early intervention because they have the potential risk of causing visual disturbances. In recent years, propranolol has shown promise in the effective management of periocular and periorbital IHs. The objective of our study was to assess the clinical outcomes, efficacy, and safety of propranolol in the management of infants with high-risk periorbital IHs. PATIENTS AND METHODS: This retrospective study was conducted at the Stomatological Hospital affiliated with China Medical University. The medical records of infants with periorbital hemangiomas who were treated with systemic propranolol at a dose of 1.0 to 1.5 mg/kg per day between January 2014 and June 2015 were reviewed. We excluded infants who did not qualify for propranolol treatment and infants who received previous therapy or other treatments. The records were reviewed for treatment response, adverse events during treatment, length of treatment, and recurrences. Treatment response was classified using a 4-point scale system based on reduction in volume as poor (<25%), moderate (25 to 50%), good (50 to 75%), or excellent (>75 to 100%) and change in color, as well as surface texture, by a panel of 3 plastic surgeons using 2-dimensional photographs, clinical examination, and Doppler ultrasonography measurements taken before and after treatment. RESULTS: Of 38 infants with periorbital hemangiomas, 26 were treated with systemic propranolol at a dose of 1.0 to 1.5 mg/kg administered once daily. A total of 11 male and 15 female infants with a mean age of 5.2 months (range, 2 to 12 months) were treated. The mean length of treatment was 22 weeks (range, 4 to 41 weeks). Adverse events of diarrhea (n = 3) and sleep changes (n = 1) were encountered during treatment in 4 patients. The overall treatment response was scored as excellent in 17 patients, good in 7, moderate in 2, and poor in 0. No patients required discontinuation of treatment because of adverse events, and there were no cases of recurrence or tumor regrowth noted during the mean follow-up period of 6.5 months (range, 3 to 10 months). CONCLUSIONS: Oral propranolol at a dose of 1.0 to 1.5 mg/kg per day (age <=3 months, 1.0 mg/kg; age >3 months, 1.5 mg/kg) was effective and well tolerated for the management of 26 Chinese infants with high-risk periorbital IHs. Early intervention should be considered to reduce risk of visual impairment and improve esthetic outcomes. PMID- 27235182 TI - Primary Ectopic Meningioma of the Tongue: Case Report and Review of the Literature. AB - Primary ectopic (extracranial) meningiomas (PEMs) are very rare and have been reported only sporadically. Histologically speaking, PEMs are similar to their intracranial counterparts in being composed of neoplastic arachnoidal (meningothelial) cells. In addition, several types of microscopic cellular morphologies have been observed in intracranial meningiomas: meningothelial (syncytial), psammomatous, atypical, anaplastic, fibrous, and angioblastic. To the best of the authors' knowledge, PEM presenting as a mass in the tongue has not been reported previously. This report describes a case of lingual PEM in a 17 year-old boy. Special attention is given to the unique clinical presentation and management. The literature was reviewed to provide valuable knowledge to clinicians. PMID- 27235181 TI - Accuracy of Different Modalities to Record Natural Head Position in 3 Dimensions: A Systematic Review. AB - PURPOSE: Three-dimensional (3D) images are taken with positioning devices to ensure a patient's stability, which, however, place the patient's head into a random orientation. Reorientation of images to the natural head position (NHP) is necessary for appropriate assessment of dentofacial deformities before any surgical planning. The aim of this study was to review the literature systematically to identify and evaluate the various modalities available to record the NHP in 3 dimensions and to compare their accuracy. MATERIALS AND METHODS: A systematic literature search of the PubMed, Cochrane Library and Embase databases, with no limitations on publication time or language, was performed in July 2015. The search and evaluations of articles were performed in 4 rounds. The methodologies, accuracies, advantages, and limitations of various modalities to record NHP were examined. RESULTS: Eight articles were included in the final review. Six modalities to record NHP were identified, namely 1) stereophotogrammetry, 2) facial markings along laser lines, 3) clinical photographs and the pose from orthography and scaling with iterations (POSIT) algorithm, 4) digital orientation sensing, 5) handheld 3D camera measuring system, and 6) laser scanning. Digital orientation sensing had good accuracy, with mean angular differences from the reference within 1 degrees (0.07 +/- 0.49 degrees and 0.12 +/- 0.54 degrees , respectively). Laser scanning was shown to be comparable to digital orientation sensing. The method involving clinical photographs and the POSIT algorithm was reported to have good accuracy, with mean angular differences for pitch, roll, and yaw within 1 degrees (-0.17 +/- 0.50 degrees ). Stereophotogrammetry was reported to have the highest reliability, with mean angular deviations in pitch, roll, and yaw for active and passive stereophotogrammetric devices within 0.1 degrees (0.004771 +/- 0.045645 degrees and 0.007572 +/- 0.079088 degrees , respectively). CONCLUSIONS: This systematic review showed that recording the NHP in 3 dimensions with a digital orientation sensor has good accuracy. Laser scanning was found to have comparable accuracy to digital orientation sensing, but routine clinical use was limited by its high cost and low portability. Stereophotogrammetry and the method using a single clinical photograph and the POSIT algorithm were potential alternatives. Nevertheless, clinical trials are needed to verify their applications in patients. Preferably, digital orientation sensor should be used as a reference for comparison with new proposed methods of recording the NHP in future research. PMID- 27235183 TI - Efficacy of Ethanolamine Oleate Sclerotherapy in Treatment of Peripheral Giant Cell Granuloma. AB - PURPOSE: The aim of this study was to evaluate the efficacy of ethanolamine oleate (EO) sclerotherapy in the treatment of peripheral giant cell granuloma. PATIENTS AND METHODS: This study included 24 patients presenting with PGCGs greater than 2 cm in diameter. Definitive diagnosis was confirmed after histopathologic examination of incisional biopsy specimens. EO sclerotherapy at a concentration of 2.5% was injected into each lesion once a week. Repeated injections were performed if needed. The treatment response was recorded as complete remission, moderate response, or no change. RESULTS: This study involved 11 male and 13 female patients, ranging in age from 9 to 70 years; the average age was 45.3 years. The mandible (75%) was involved more than the maxilla. PGCGs occurred posteriorly (62.5%) more than anteriorly. The number of injection sessions was 57, with an average of 2.4 sessions per lesion. Clinical improvement was seen in 23 patients: complete remission in 20 (83.3%) and moderate improvement in 3 (12.5%). No clinical improvement occurred in 1 patient (4.2%). CONCLUSIONS: EO injection offers an alternative to conventional methods for the treatment of PGCG. The technique is straightforward, safe, and cost-effective with a high success rate. PMID- 27235184 TI - Regarding "Central Giant Cell Granuloma of the Mandible Requiring Multiple Treatment Modalities: A Case Report". PMID- 27235185 TI - Pilot study on the feasibility of limited focused real-time echocardiography during pediatric renal transplantation. AB - Pediatric renal transplantation protocols describe supraphysiological blood pressure and CVP to optimize graft perfusion. Ideal CVP and blood pressure targets in children are uncertain and difficult to achieve and/or sustain without incurring morbidity. We correlated intra-operative ECHO with standard monitoring to assess intravascular volume at critical intra-operative stages. A feasibility pilot study of real-time limited ECHO images during four critical stages of pediatric renal transplantation (baseline; venous and arterial clamps on; clamps off; 5-10 min post-clamp release) was conducted. Simultaneous CVP, SBP and DBP measurements were obtained with ECHO images. A surgeon blinded to the ECHO study assessed the quality of graft perfusion. Thirteen patients (nine TTE and four TEE) were enrolled. The CI increased in all patients at vascular clamp removal and the post-resuscitation period (average increase in CI 20%, range 8-49%). SBP, DBP and CVP were inconsistent. ECHO data confirmed an appropriate CI increase even when the targeted CVP and BP values described in protocols were not achieved. The surgeons were satisfied with graft perfusion in 12 of 13 cases, with one locally obstructed vessel. We suggested that aiming for fixed targets in CVP and BP is not necessary to augment CI and encourage good renal perfusion. PMID- 27235186 TI - Using International Videoconferencing to Extend the Global Reach of Community Health Nursing Education. AB - Travel abroad provides college students with a unique learning experience. When plans to take undergraduate community health nursing students from the United States to Haiti were cancelled due to health and safety concerns, faculty piloted international videoconferencing with a nursing program in Haiti as an alternative. During this semester-long course, students in both countries assessed a local community using the Community as Partner framework and compared findings during videoconferences with their international peers. Despite communication challenges such as language barriers and limited internet access in Haiti, evaluative data suggests that all students valued learning with their nursing student peers in another country. For future international videoconferencing endeavors, especially with under-resourced communities, we provide recommendations in the following categories: 1) Building relationships with a partner school, 2) Technology, 3) Pedagogy, and 4) Facilitating interactions between students. PMID- 27235187 TI - Preference for Sucrose Solutions Modulates Taste Cortical Activity in Humans. AB - High time resolution is required to reliably measure neuronal activity in the gustatory cortex in response to taste stimuli. Hedonic aspects of gustatory processing have never been explored using gustatory evoked potentials (GEPs), a high-time-resolution technique. Our aim was to study cerebral processing of hedonic taste in humans using GEPs in response to sucrose solutions in subjects with different ratings of pleasantness regarding sucrose. In this exploratory study, 30 healthy volunteers were randomly stimulated with 3 sucrose solutions. The sucrose stimulus was presented to the tongue for 1s 20 times. GEPs were recorded from 9 cortical sites with EEG sensors at Cz, Fz, Pz, C3, C4, F3, F4, Fp1, and Fp2 (10/20 system). The main result was that subjects who preferred the high-concentration (20g/100mL) sucrose solution had higher GEP amplitudes on the Pz, Cz, and Fz electrodes than did subjects who preferred the low-concentration (5g/100mL) or the moderate-concentration (10g/100mL) solutions regardless of stimulus intensity. The difference in P1N1 amplitude on the Pz, Cz, and Fz electrodes according to sucrose preference of the subjects was described with stronger significance with stimulation by the 20 g-sucrose solution than by the 5 and 10g sucrose solutions. Using the reliable and safe GEP technique, we provide an original demonstration of variability of the gustatory response on the Pz, Cz, and Fz electrodes according to a sweet preference in humans. Further studies are needed to correlate the electric signal recorded by surface electrodes to the neural generator. PMID- 27235188 TI - Voltammetric aptasensors for protein disease biomarkers detection: A review. AB - An electrochemical aptasensor is a compact analytical device where the bioreceptor (aptamer) is coupled to a transducer surface to convert a biological interaction into a measurable signal (current) that can be easily processed, recorded and displayed. Since the discovery of the Systematic Evolution of Ligands by Enrichment (SELEX) methodology, the selection of aptamers and their application as bioreceptors has become a promising tool in the design of electrochemical aptasensors. Aptamers present several advantages that highlight their usefulness as bioreceptors such as chemical stability, cost effectiveness and ease of modification towards detection and immobilization at different transducer surfaces. In this review, a special emphasis is given to the potential use of electrochemical aptasensors for the detection of protein disease biomarkers using voltammetry techniques. Methods for the immobilization of aptamers onto electrode surfaces are discussed, as well as different electrochemical strategies that can be used for the design of aptasensors. PMID- 27235189 TI - Antimicrobial peptides as novel anti-tuberculosis therapeutics. AB - Tuberculosis (TB), a disease caused by the human pathogen Mycobacterium tuberculosis, has recently joined HIV/AIDS as the world's deadliest infectious disease, affecting around 9.6 million people worldwide in 2014. Of those, about 1.2 million died from the disease. Resistance acquisition to existing antibiotics, with the subsequent emergence of Multi-Drug Resistant mycobacteria strains, together with an increasing economic burden, has urged the development of new anti-TB drugs. In this scope, antimicrobial peptides (AMPs), which are small, cationic and amphipathic peptides that make part of the innate immune system, now arise as promising candidates for TB treatment. In this review, we analyze the potential of AMPs for this application. We address the mechanisms of action, advantages and disadvantages over conventional antibiotics and how problems associated with its use may be overcome to boost their therapeutic potential. Additionally, we address the challenges of translational development from benchside to bedside, evaluate the current development pipeline and analyze the expected global impact from a socio-economic standpoint. The quest for more efficient and more compliant anti-TB drugs, associated with the great therapeutic potential of emerging AMPs and the rising peptide market, provide an optimal environment for the emergence of AMPs as promising therapies. Still, their pharmacological properties need to be enhanced and manufacturing-associated issues need to be addressed. PMID- 27235190 TI - Selenium: environmental significance, pollution, and biological treatment technologies. AB - Selenium is an essential trace element needed for all living organisms. Despite its essentiality, selenium is a potential toxic element to natural ecosystems due to its bioaccumulation potential. Though selenium is found naturally in the earth's crust, especially in carbonate rocks and volcanic and sedimentary soils, about 40% of the selenium emissions to atmospheric and aquatic environments are caused by various industrial activities such as mining-related operations. In recent years, advances in water quality and pollution monitoring have shown that selenium is a contaminant of potential environmental concern. This has practical implications on industry to achieve the stringent selenium regulatory discharge limit of 5MUgSeL(-1) for selenium containing wastewaters set by the United States Environmental Protection Agency. Over the last few decades, various technologies have been developed for the treatment of selenium-containing wastewaters. Biological selenium reduction has emerged as the leading technology for removing selenium from wastewaters since it offers a cheaper alternative compared to physico-chemical treatments and is suitable for treating dilute and variable selenium-laden wastewaters. Moreover, biological treatment has the advantage of forming elemental selenium nanospheres which exhibit unique optical and spectral properties for various industrial applications, i.e. medical, electrical, and manufacturing processes. However, despite the advances in biotechnology employing selenium reduction, there are still several challenges, particularly in achieving stringent discharge limits, the long-term stability of biogenic selenium and predicting the fate of bioreduced selenium in the environment. This review highlights the significance of selenium in the environment, health, and industry and biotechnological advances made in the treatment of selenium contaminated wastewaters. The challenges and future perspectives are overviewed considering recent biotechnological advances in the management of these selenium-laden wastewaters. PMID- 27235191 TI - Effect of manganese and manganese plus noise on auditory function and cochlear structures. AB - The degenerative actions of Mn caused by persistent exposure to high atmospheric levels not only provokes irreversible damage to the CNS with symptoms comparable to that of Parkinson's disease but also may have deleterious consequences to other organs including the auditory system. The putative deleterious consequences of prolonged Mn overexposure on hearing, however, is confounded by the fact that chronically-exposed individuals often work in high noise environments where noise by itself is known to cause hearing loss. Thus, the question as to whether Mn alone is actually ototoxic and whether exposure to Mn when combined with noise increases the risk of hearing loss and cochlear pathology has never been examined. To examine whether noise effects Mn ototoxicity, we exposed rats to a moderate dose of Mn (10mg MnCl2/liter water) alone, a high level of noise (octave band noise, 8-16kHz, presented at 90dB SPL for 8h/d) alone or the combination of Mn plus noise and measured the changes in auditory function and the cochlear histopathologies. Results of these studies, based on various measures of hearing including histological examination of cochlear tissue suggest that noise alone produced significant hearing deficits whereas semi-chronic exposure to moderate levels of Mn in drinking water for 90days either in the presence or absence of noise had, at best, only a minor effect on hearing. PMID- 27235192 TI - Organic solvent-induced changes in membrane geometry in human SH-SY5Y neuroblastoma cells - a common narcotic effect? AB - Exposure to organic solvents may cause narcotic effects. At the cellular level, these narcotic effects have been associated with a reduction in neuronal excitability caused by changes in membrane structure and function. In order to critically test whether changes in membrane geometry contribute to these narcotic effects, cultured human SH-SY5Y neuroblastoma cells have been exposed to selected organic solvents. The solvent-induced changes in cell membrane capacitance were investigated using the whole-cell patch clamp technique for real-time capacitance measurements. Exposure of SH-SY5Y cells to the cyclic hydrocarbons m-xylene, toluene, and cyclohexane caused a rapid and reversible increase of membrane capacitance. The aliphatic, nonpolar n-hexane did not cause a detectable change of whole-cell membrane capacitance, whereas the amphiphiles n-hexanol and n hexylamine caused an increase of membrane capacitance and a concomitant reduction in membrane resistance. Despite a large difference in dielectric properties, the chlorinated hydrocarbons 1,1,2,2-tetrachoroethane and tetrachloroethylene caused a similar magnitude increase in membrane capacitance. The theory on membrane capacitance has been applied to deduce changes in membrane geometry caused by solvent partitioning. Although classical observations have shown that solvents increase the membrane capacitance per unit area of membrane, i.e., increase membrane thickness, the present results demonstrate that solvent partitioning predominantly leads to an increase in membrane surface area and to a lesser degree to an increase in membrane thickness. Moreover, the present results indicate that the physicochemical properties of each solvent are important determinants for its specific effects on membrane geometry. This implies that the hypothesis that solvent partitioning is associated with a common perturbation of membrane structure needs to be revisited and cannot account for the commonly observed narcotic effects of different organic solvents. PMID- 27235193 TI - Paediatric neurothrombectomy: Time is (childhood) brain or First, do no harm? PMID- 27235194 TI - Natural Leishmania (Viannia) spp. infections in phlebotomine sand flies (Diptera: Psychodidae) from the Brazilian Amazon region reveal new putative transmission cycles of American cutaneous leishmaniasis. AB - In Amazonian Brazil the etiological agents of American cutaneous leishmaniasis (ACL) belong to at least seven Leishmania species but little is known about the putative phlebotomine sand fly vectors in different biomes. In 2002-2003 a survey of the phlebotomine fauna was undertaken in the "Floresta Nacional do Tapajos", Belterra municipality, in the lower Amazon region, western Para State, Brazil, where we recently confirmed the presence of a putative hybrid parasite, L. (V.) guyanensis * L. (V.) shawi shawi. Sand flies were collected from Centers for Disease Control (CDC) light traps, Shannon traps and by aspiration on tree bases. Females were dissected and attempts to isolate any flagellate infections were made by inoculating homogenized midguts into Difco B(45) medium. Isolates were characterized by monoclonal antibodies and isoenzyme electrophoresis. A total of 9,704 sand flies, belonging to 68 species or subspecies, were collected. Infections were found in the following sand flies: L. (V.) naiffi with Psychodopygus hirsutus hirsutus (1) and Ps. davisi (2); and L. (V.) shawi shawi with Nyssomyia whitmani (3) and Lutzomyia gomezi (1). These results provide strong evidence of new putative transmission cycles for L. (V.) naiffi and L. (V.) s. shawi. PMID- 27235196 TI - Global health is our health. PMID- 27235195 TI - MicroRNA profiling of the intestinal tissue of Kazakh sheep after experimental Echinococcus granulosus infection, using a high-throughput approach. AB - Cystic echinococcosis (CE), caused by infection with the larval stage of the cestode Echinococcus granulosus, is a chronic zoonosis, to which sheep are highly susceptible. Previously, we found that Kazakh sheep with different MHC haplotypes differed in CE infection. Sheep with haplotype MHCMvaIbc-SacIIab-Hin1Iab were resistant to CE infection, while their counterparts without this haplotype were not. MicroRNAs (miRNAs), a class of small non-coding RNAs, are key regulators of gene expression at the post-transcriptional level and play essential roles in fundamental biological processes such as development and metabolism. To identify microRNA controlling resistance to CE in the early stage of infection, microRNA profiling was conducted in the intestinal tissue of sheep with resistant and non resistant MHC haplotypes after peroral infection with E. granulosus eggs. A total of 351 known and 186 novel miRNAs were detected in the resistant group, against 353 known and 129 novel miRNAs in the non-resistant group. Among these miRNAs, 83 known miRNAs were significantly differentially expressed, including 75 up regulated and 8 down-regulated miRNAs. Among these known microRNAs, miR-21-3p, miR-542-5p, miR-671, miR-134-5p, miR-26b, and miR-27a showed a significantly higher expression in CE-resistant sheep compared to the CE-non-resistant library, with the FC > 3. Functional analysis showed that they were NF-kB pathway responsive miRNAs, which are involved in the inflammation process. The results suggest that these microRNAs may play important roles in the response of intestinal tissue to E. granulosus. PMID- 27235198 TI - Acinetobacter baumannii and A. pittii clinical isolates lack adherence and cytotoxicity to lung epithelial cells in vitro. AB - The molecular and genetic basis of Acinetobacter baumannii and Acinetobacter pittii virulence remains poorly understood, and there is still lack of knowledge in host cell response to these bacteria. In this study, we have used eleven clinical Acinetobacter strains (A. baumannii n = 5; A. pittii n = 6) to unravel bacterial adherence, invasion and cytotoxicity to human lung epithelial cells. Our results showed that adherence to epithelial cells by Acinetobacter strains is scarce and cellular invasion was not truly detected. In addition, all Acinetobacter strains failed to induce any cytotoxic effect on A549 cells. PMID- 27235197 TI - High fecal IgA is associated with reduced Clostridium difficile colonization in infants. AB - Colonization of infants with Clostridium difficile is on the rise. Although better tolerated by infants than adults, it is a risk factor for future allergic disease. The present study describes associations between infant fecal immunoglobulin A (IgA) and colonization with C. difficile in 47 infants enrolled in the Canadian Healthy Infant Longitudinal Development (CHILD) study. C. difficile colonization was observed in over half (53%) of the infants. Median IgA was lower in infants colonized with C. difficile (10.9 MUg versus 25.5 MUg per g protein; p = 0.18). A smaller proportion of infants with IgA in the highest tertile were colonized with C. difficile compared to the other tertiles (31.3% versus 64.5%, p = 0.03). In unadjusted analysis, odds of colonization with C. difficile was reduced by 75% (OR 0.25 95% CI 0.07, 0.91 p = 0.04) among infants with IgA in the highest tertile compared to those in the other tertiles. Following adjustment for parity, birth mode and breastfeeding, this association was even stronger (aOR 0.17, 95% CI 0.03, 0.94, p = 0.04). Our study provides evidence that high fecal IgA, independent of breastfeeding, is associated with reduced likelihood of C. difficile colonization in infancy. PMID- 27235199 TI - Receptor specific binding regions of Plasmodium vivax tryptophan rich antigens and parasite growth inhibition activity of PvTRAg35.2. AB - Plasmodium tryptophan rich proteins play important role in host-parasite interaction. Earlier, we have described that one of the merozoite expressed Plasmodium vivax tryptophan-rich antigen PvTRAg35.2 binds to the host erythrocytes, have conserved sequences in parasite population, and generates humoral as well as cellular immune responses in humans during this parasitic infection. Here, we show that PvTRAg35.2 interferes with the parasite growth in a heterologous Plasmodium falciparum culture system. This probably suggests the recognition of the common erythrocyte receptor(s) by certain merozoite ligands of these two parasite species. We have mapped the erythrocyte binding activity of PvTRAg35.2 to its two different regions positioned at amino acid residues 155-190 and 263-283. Binding of these peptide domains to the erythrocytes was inhibited by anti-PvTRAg35.2 antibodies either raised in rabbit or produced by the P. vivax patients. The cross-competition between peptides of PvTRAg35.2 and PvTRAg33.5 or PvTRAg38 during erythrocyte binding assay suggested sharing of host cell receptors by these PvTRAgs. Further studies on these receptor-ligand interactions may lead to the development of therapeutic agents for P. vivax malaria. PMID- 27235201 TI - Effect of elicitors on the evolution of grape phenolic compounds during the ripening period. AB - BACKGROUND: The effect of the application of benzothiadiazole (BTH) and methyl jasmonate (MeJ) at veraison on the phenolic composition of grapes from three varieties (Monastrell, Syrah and Merlot) was studied during the ripening period, using HPLC techniques to measure flavonols, anthocyanins and tannins. RESULTS: The effects of the treatments differed in the three varieties, and the maximum concentration of phenolic compounds was not always reached at the end of the ripening period but some days before harvest. At the end of ripening both treated Syrah grapes only differed from control grapes in the flavonol concentration, whereas MeJ-treated Merlot grapes presented higher anthocyanin and skin tannin contents than the control and BTH-treated grapes. Only the anthocyanin content was significantly higher in treated Monastrell grapes at the moment of harvest. CONCLUSION: The results indicate that the moment of elicitor treatment should be more studied since differences between treated and control grapes were, in general greater several days before harvest in all three varieties. (c) 2016 Society of Chemical Industry. PMID- 27235200 TI - Oestradiol levels may differ between premenopausal women, ages 18-50, with type 1 diabetes and matched controls. AB - BACKGROUND: This study aimed to investigate whether oestradiol differs between premenopausal women with and without type 1 diabetes and whether levels are associated with such factors as age, reproductive history or diabetes management. METHODS: Oestradiol in premenopausal women with type 1 diabetes (n = 89; age = 18 50 years; duration = 13-18 years) and age-matched/race-matched controls without diabetes (n = 76) was collected during a cross-sectional ancillary study of the Wisconsin Diabetes Registry Study, a population-based incident cohort. Total and bioavailable oestradiol and sex hormone-binding globulin were compared using multivariable regression (e.g. adjusting for reproductive history). RESULTS: Adjusted mean total and bioavailable oestradiol did not differ overall by diabetes status (p >= 0.74), while adjusted mean sex hormone-binding globulin was higher in type 1 diabetes women (p = 0.02). However, only in women with type 1 diabetes and not controls (interaction p = 0.0005) was total oestradiol positively associated with the duration of reproductive years with unsuppressed ovarian function (UnsuppOvFx = years since menarche minus years on hormonal contraceptives/pregnant/breastfeeding). When stratified into less than/equal to or greater than the median 9 years' duration of UnsuppOvFx, compared with controls, women with type 1 diabetes had significantly lower total oestradiol in the <=9 years group [beta = -43.2 pg mL-1 (-158.6 pmol L-1 ), p = 0.04] and significantly higher total oestradiol in the >9 years group [beta = 53.9 pg mL-1 (197.9 pmol L-1 ), p = 0.04]. Results remained consistent during additional statistical adjustments and sensitivity analyses. CONCLUSIONS: Compared with controls, women with type 1 diabetes may have lower oestradiol when they have a shorter duration of UnsuppOvFx and higher oestradiol when they have a longer duration of UnsuppOvFx. Given the potential effects of insulin on ovarian function, oestradiol production may vary across the lifespan for women with type 1 diabetes. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27235202 TI - Ultra-trace analysis of furanic compounds in transformer/rectifier oils with water extraction and high-performance liquid chromatography. AB - A novel approach for the determination of parts-per-billion level of 5 hydroxymethyl-2-furaldehyde, furfuryl alcohol, furfural, 2-furyl methyl ketone, and 5-methylfurfural in transformer or rectifier oils has been successfully innovated and implemented. Various extraction methods including solid-phase extraction, liquid-liquid extraction using methanol, acetonitrile, and water were studied. Water was by far the most efficient solvent for use as an extraction medium. Separation of the analytes was conducted using a 4.6 mm * 250 mm * 3.5 MUm Agilent Zorbax column while detection and quantitation were conducted with a variable wavelength UV detector. Detection limits of all furans were at 1 ppb v/v with linear ranges range from 5 to 1000 ppb v/v with correlation coefficients of 0.997 or better. A relative standard deviation of at most 2.4% at 1000 ppb v/v and 7.3% at 5 ppb v/v and a recovery from 43% to 90% depending on the analyte monitored were obtained. The method was purposely designed to be environmental friendly with water as an extraction medium. Also, the method uses 80% water and 20% acetonitrile with a mere 0.2 mL/min of acetonitrile in an acetonitrile/water mixture as mobile phase. The analytical technique has been demonstrated to be highly reliable with low cost of ownership, suitable for deployment in quality control labs or in regions where available analytical resources and solvents are difficult to procure. PMID- 27235203 TI - Hyperbilirubinemia in Preterm Neonates. AB - Preterm neonates with increased bilirubin production loads are more likely to sustain adverse outcomes due to either neurotoxicity or overtreatment with phototherapy and/or exchange transfusion. Clinicians should rely on expert consensus opinions to guide timely and effective interventions until there is better evidence to refine bilirubin-induced neurologic dysfunction or benefits of bilirubin. In this article, we review the evolving evidence for bilirubin-induced brain injury in preterm infants and highlight the clinical approaches that minimize the risk of bilirubin neurotoxicity. PMID- 27235204 TI - Hemolysis in Preterm Neonates. AB - Hemolysis can be an important cause of hyperbilirubinemia in premature and term neonates. It can result from genetic abnormalities intrinsic to or factors exogenous to normal to red blood cells (RBCs). Hemolysis can lead to a relatively rapid increase in total serum/plasma bilirubin, hyperbilirubinemia that is somewhat slow to fall with phototherapy, or hyperbilirubinemia that is likely to rebound after phototherapy. Laboratory methods for diagnosing hemolysis are more difficult to apply, or less conclusive, in preterm infants. Transfusion of donor RBCs can present a bilirubin load that must be metabolized. Genetic causes can be identified by next-generation sequencing panels. PMID- 27235206 TI - A Pharmacologic View of Phototherapy. AB - A pharmacologic view of phototherapy for neonatal jaundice is presented. By considering the photons of therapy light as molecules of a drug, this view connects therapeutic efficacy with photon wavelength, photon dose, dose rate and regimen, efficiency of photon absorption by bilirubin, quantum yields of photoproducts, and their metabolic courses. Based on this view, recommendations to ultimately improve efficacy and safety are presented. Special attention is given to phototherapy regimens for low gestational age, low birthweight infants. PMID- 27235207 TI - Biology of Bilirubin Photoisomers. AB - Phototherapy is the main treatment for neonatal hyperbilirubinemia. In acute treatment of extreme hyperbilirubinemia, intensive phototherapy may have a role in 'detoxifying' the bilirubin molecule to more polar photoisomers, which should be less prone to crossing the blood-brain barrier, providing a 'brain-sparing' effect. This article reviews the biology of bilirubin isomers. Although there is evidence supporting the lower toxicity of bilirubin photoisomers, there are studies showing the opposite. There are methodologic weaknesses in most studies and better-designed experiments are needed. In an infant acutely threatened by bilirubin-induced brain damage, intensified phototherapy should be used expediently and aggressively. PMID- 27235205 TI - Bilirubin Binding Capacity in the Preterm Neonate. AB - Total serum/plasma bilirubin (TB), the biochemical measure currently used to evaluate and manage hyperbilirubinemia, is not a useful predictor of bilirubin induced neurotoxicity in premature infants. Altered bilirubin-albumin binding in premature infants limits the usefulness of TB in premature infants. In this article, bilirubin-albumin binding, a modifying factor for bilirubin-induced neurotoxicity, in premature infants is reviewed. PMID- 27235208 TI - Phototherapy and the Risk of Photo-Oxidative Injury in Extremely Low Birth Weight Infants. AB - Phototherapy has been used to treat newborns with jaundice for more than 50 years with the presumption that it is safe and effective for all infants. In fact, this presumption may not be true for all infants, especially the smallest and most immature. The safety and efficacy of phototherapy have never really been questioned or adequately tested in the latter, yet clinical applications of phototherapy have been further refined as its mechanisms of action have been better understood and alternative light sources have become available. This article addresses what is known about the possible risks of photo-oxidative injury in extremely low birth weight infants. PMID- 27235209 TI - Bilirubin-Induced Neurotoxicity in the Preterm Neonate. AB - Bilirubin-induced neurotoxicity in preterm neonates remains a clinical concern. Multiple cellular and molecular cascades likely underlie bilirubin-induced neuronal injury, including plasma membrane perturbations, excitotoxicity, neuroinflammation, oxidative stress, and cell cycle arrest. Preterm newborns are particularly vulnerable secondary to central nervous system immaturity and concurrent adverse clinical conditions that may potentiate bilirubin toxicity. Acute bilirubin encephalopathy in preterm neonates may be subtle and manifest primarily as recurrent symptomatic apneic events. Low-bilirubin kernicterus continues to be reported in preterm neonates, and although multifactorial in nature, is often associated with marked hypoalbuminemia. PMID- 27235211 TI - The Preterm Infant: A High-Risk Situation for Neonatal Hyperbilirubinemia Due to Glucose-6-Phosphate Dehydrogenase Deficiency. AB - Prematurity and glucose-6-phosphate dehydrogenase (G6PD) deficiency are risk factors for neonatal hyperbilirubinemia. The 2 conditions may interact additively or synergistically, contributing to extreme hyperbilirubinemia, with the potential for bilirubin neurotoxicity. This hyperbilirubinemia is the result of sudden, unpredictable, and acute episodes of hemolysis in combination with immaturity of bilirubin elimination, primarily of conjugation. Avoidance of contact with known triggers of hemolysis in G6PD-deficient individuals will prevent some, but not all, episodes of hemolysis. All preterm infants with G6PD deficiency should be vigilantly observed for the development of jaundice both in hospital and after discharge home. PMID- 27235212 TI - Glucose-6-Phosphate Dehydrogenase Deficiency and the Need for a Novel Treatment to Prevent Kernicterus. AB - Hyperbilirubinemia occurs frequently in newborns, and in severe cases can progress to kernicterus and permanent developmental disorders. Glucose-6 phosphate dehydrogenase (G6PD) deficiency, one of the most common human enzymopathies, is a major risk factor for hyperbilirubinemia and greatly increases the risk of kernicterus even in the developed world. Therefore, a novel treatment for kernicterus is needed, especially for G6PD-deficient newborns. Oxidative stress is a hallmark of bilirubin toxicity in the brain. We propose that the activation of G6PD via a small molecule chaperone is a potential strategy to increase endogenous defense against bilirubin-induced oxidative stress and prevent kernicterus. PMID- 27235210 TI - Bilirubin-Induced Audiologic Injury in Preterm Infants. AB - Although hyperbilirubinemia is extremely common among neonates and is usually mild and transient, it sometimes leads to bilirubin-induced neurologic damage (BIND). The auditory pathway is highly sensitive to the effects of elevated total serum/plasma bilirubin (TB) levels, with damage manifesting clinically as auditory neuropathy spectrum disorder. Compared to full-term neonates, preterm neonates are more susceptible to BIND and suffer adverse effects at lower TB levels with worse long-term outcomes. Furthermore, although standardized guidelines for management of hyperbilirubinemia exist for term and late preterm neonates, similar guidelines for neonates less than 35 weeks gestational age are limited. PMID- 27235213 TI - Cholestasis in Preterm Infants. AB - Cholestasis in preterm infants has a multifactorial etiology. Risk factors include degree of prematurity, lack of enteral feeding, intestinal injury, prolonged use of parenteral nutrition (PN), and sepsis. Soy-based parenteral lipid emulsions have been implicated in the pathophysiology of PN-associated liver injury. Inflammation plays an important role. Medical therapies are used; however, their effects have not consistently proven effective. Evaluation of cholestasis involves laboratory work; direct bilirubin levels are used for diagnosis and trending. Adverse outcomes include risk for hepatobiliary dysfunction, irreversible liver failure, and death. Early enteral feedings as tolerated is the best way to prevent and manage cholestasis. PMID- 27235214 TI - Development of a Web-Based Decision Support Tool to Operationalize and Optimize Management of Hyperbilirubinemia in Preterm Infants. AB - Premie BiliRecs is a novel electronic clinical decision support tool for the management of hyperbilirubinemia in moderately preterm infants less than 35 weeks gestational age. It serves to operationalize and automate current expert consensus-based guidelines, and to aid in the generation of new practice-based evidence to inform future guidelines. PMID- 27235215 TI - Why the Premature Brain Is More Prone to Bilirubin-induced Injury. PMID- 27235216 TI - Preterm Neonates: Beyond the Guidelines for Neonatal Hyperbilirubinemia. PMID- 27235267 TI - Therapeutic anticoagulation-free extracorporeal membrane oxygenation as a bridge to lung transplantation. PMID- 27235268 TI - Respiratory virus infections and chronic lung allograft dysfunction: Assessment of virology determinants. PMID- 27235269 TI - Risk scores and biomarkers in heart failure: A journey to predictive accuracy and clinical utility. PMID- 27235270 TI - Small-volume potentiometric titrations: EPR investigations of Fe-S cluster N2 in mitochondrial complex I. AB - EPR-based potentiometric titrations are a well-established method for determining the reduction potentials of cofactors in large and complex proteins with at least one EPR-active state. However, such titrations require large amounts of protein. Here, we report a new method that requires an order of magnitude less protein than previously described methods, and that provides EPR samples suitable for measurements at both X- and Q-band microwave frequencies. We demonstrate our method by determining the reduction potential of the terminal [4Fe-4S] cluster (N2) in the intramolecular electron-transfer relay in mammalian respiratory complex I. The value determined by our method, Em7=-158mV, is precise, reproducible, and consistent with previously reported values. Our small-volume potentiometric titration method will facilitate detailed investigations of EPR active centres in non-abundant and refractory proteins that can only be prepared in small quantities. PMID- 27235271 TI - A combined crystallographic analysis and ab initio calculations to interpret the reactivity of functionalized hexavanadates and their inhibitor potency toward Na(+)/K(+)-ATPase. AB - In vitro influence of five synthesized functionalized hexavanadates (V6) on commercial porcine cerebral cortex Na(+)/K(+)-ATPase activity has been studied. Dose dependent Na(+)/K(+)-ATPase inhibition was obtained for all investigated compounds. Calculated half maximal inhibitory concentration IC50 values, in mol/L, for Na(+)/K(+)-ATPase were 7.6*10(-5), 1.8*10(-5), 2.9*10(-5), 5.5*10(-5) for functionalized hexavanadates (V6) with tetrabutylammonium (TBA) [V6 CH3][TBA]2, [V6-NO2][TBA]2, [V6-OH][TBA]2 and [V6-C3][TBA]2 respectively. [V6 OH][Na]2 inhibited Na(+)/K(+)-ATPase activity up to 30% at maximal investigated concentration 1*10(-3)mol/L. This reactivity has been interpreted using a study of the non-covalent interactions of functionalized hexavanadate hybrids through Cambridge Structural Database (CSD) analysis. Bibliographic searching has led to 18 different structures and 99 contacts. We have observed that C-H?O contacts consolidate the structures. We have also performed density functional theory (DFT) calculations and have determined electrostatic potential values at the molecular surface on a series of functionalized V6. These results enlightened their chemical reactivity and their potential biological applications such as the inhibition of the ATPase. PMID- 27235272 TI - A comparative study on the interactions of human copper chaperone Cox17 with anticancer organoruthenium(II) complexes and cisplatin by mass spectrometry. AB - Herein we report investigation of the interactions between anticancer organoruthenium complexes, [(eta(6)-arene)Ru(en)(Cl)]PF6 (en=ethylenediamine, arene=p-cymene (1) or biphenyl (2)), and the human copper chaperone protein Cox17 by mass spectrometry with cisplatin as a reference. The electrospray ionization mass spectrometry (ESI-MS) results indicate much weaker binding of the ruthenium complexes than that of cisplatin to apo-Cox172s-s, the functional state of Cox17. Up to tetra-platinated Cox17 adducts were identified while only mono-ruthenated and a little amount of di-ruthenated Cox17 adducts were detected even for the reactions with 10-fold excess of the Ru complexes. However, ESI-MS analysis coupled with liquid chromatography of tryptic digests of metalated proteins identified only three platination sites as Met4, Cys27 and His47 residues, possibly due to the lower abundance or facile dissociation of Pt bindings at other sites. Complexes 1 and 2 were found to bind to the same three residues with Met4 as the major site. Inductively coupled plasma mass spectrometry results revealed that ~7mol Pt binding to 1mol apo-Cox172s-s molecules, compared to only 0.17 (1) and 0.10 (2) mol Ru to 1mol apo-Cox172s-s. This is in line with the circular dichroism results that much larger unfolding extent of alpha-helix of apo-Cox172s-s was observed upon cisplatin binding than that upon organoruthenium bindings. These results collectively indicate that Cox17 might not participate in the action of these anticancer organoruthenium complexes, and further verify the distinct anticancer mechanism of the organoruthenium(II) complexes from cisplatin. PMID- 27235273 TI - Tacrine-(hydroxybenzoyl-pyridone) hybrids as potential multifunctional anti Alzheimer's agents: AChE inhibition, antioxidant activity and metal chelating capacity. AB - Three novel potentially site-activated multitarget tacrine-(hydroxybenzoyl pyridone) (TAC-HBP) hybrids were designed, synthesized and evaluated as acetylcholinesterase (AChE) inhibitors, antioxidants and biometal chelators. All of them are dual-binding site AChE inhibitors with activity in sub-micromolar range (IC50=0.57-0.78MUM), which is comparable to the parent tacrine, and have good 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging capacity (EC50=204 249MUM) conferred by the hydroxybenzoyl-pyridone (HBP) moiety. Their chelating capacity towards redox-active and/or amyloid-beta-binding metal ions (Fe(III), Cu(II)), Zn(II)) was evaluated by using 2'-hydroxy-4'-methoxybenzoyl-2-pyridone derivative as a model compound in 30% w/w DMSO/water medium. It was proved that the HBP moiety acts as a moderate/good chelator of these biometals (pFe=13.9, pCu=6.0 and pZn=6.0 at pH6.0, CL/CM=10, CM=10-6M), being able to form complexes with beta-phenol-keto coordination mode, and that this chelating ability is preserved in the TAC-HBP hybrids. PMID- 27235274 TI - High kinetic stability of Zn(II) coordinated by the tris(histidine) unit of carbonic anhydrase towards solvolytic dissociation studied by affinity capillary electrophoresis. AB - Solvolytic dissociation rate constants (kd) of bovine carbonic anhydrase II (CA) and its metallovariants (M-CAs, M=Co(II), Ni(II), Cu(II), Zn(II), and Cd(II)) were estimated by a ligand substitution reaction, which was monitored by affinity capillary electrophoresis to selectively detect the undissociated CAs in the reaction mixture. Using EDTA as the competing ligand for Zn-CA, the dissociation followed the unimolecular nucleophilic substitution (SN1) mechanism with kd=1.0*10(-7)s(-1) (pH7.4, 25 degrees C). The corresponding solvolysis half-life (t1/2) was 80days, showing the exceptionally high kinetic stability of t Zn-CA, in contrast to the highly labile [Zn(II)(H2O)6](2+), where the water exchange rate (kex) is high. This behavior is attributed to the tetrahedral coordination geometry supported by the tris(histidine) unit (His3) of CA. In the case of Co CA, it showed a somewhat larger kd value (5.7*10(-7)s(-1), pH7.4, 25 degrees C) even though it shares the same tetrahedral coordination environment with Zn-CA, suggesting that the d(7) electronic configuration of Co(II) in the transition state of the dissociation is stabilized by the ligand field. Among M-CAs, only Ni CA showed a bimolecular nucleophilic substitution (SN2) reaction path in its reaction with EDTA, implying that the large coordination number (6) of Ni(II) in Ni-CA allows EDTA to form an EDTA-Ni-CA intermediate. Overall, kd values roughly correlated with kex values among M-CAs, with the kd value of Zn-CA deviating strongly from the trend and highlighting the exceptionally high kinetic stabilization of Zn-CA by the His3 unit. PMID- 27235275 TI - Perceptions and Experiences of Intrusive Behavior and Stalking: Comparing LGBTIQ and Heterosexual Groups. AB - The present research employed a mixed-methods approach and quasi-experimental design to examine perceptions and experiences of intrusive behavior (comprising 47 individual intrusive activities) within individuals identifying as lesbian, gay, bisexual, transgender, intersex, or queer (LGBTIQ) with a matched (in terms of age, sex, and income) sample of individuals identifying as heterosexual (N = 214). Despite only minor differences between the LGBTIQ and heterosexual groups concerning perceptions of the acceptability of intrusive behavior, the LGBTIQ group was more likely to report experiencing a range of individual intrusive activities and to report experiencing stalking victimization (self-reported rates of 35.5% vs. 15.0%). Participant sex and personal experience of being stalked were minimally associated with perceptions of the acceptability of intrusive behavior. Sexual orientation significantly predicted whether a person had experienced stalking victimization, whereas participant sex did not. The qualitative analysis revealed that the two groups shared some experiences of intrusive behavior, whereas others represented a unique subset of intrusions that related to sexual orientation. PMID- 27235276 TI - Low-Level But Not High-Level Baroreceptor Stimulation Inhibits Atrial Fibrillation in a Pig Model of Sleep Apnea. AB - BACKGROUND: Obstructive sleep apnea (OSA) increases susceptibility to atrial fibrillation (AF) by a combined sympatho-vagal hyperactivation. The purpose of this study was to investigate the effect of autonomic nervous system modulation by low-level baroreceptor stimulation (LL-BRS) compared to high-level BRS (HL BRS) on atrial arrhythmogenic changes in a pig model of OSA. METHODS AND RESULTS: Sixteen pigs received tracheotomy under general urethane/chloralose anesthesia. Group 1 pigs (n = 8) received LL-BRS (at 80% of that slowing sinus rate) for 3 hours and group 2 pigs (n = 8) received HL-BRS (slowing sinus rate). Changes in atrial effective refractory period (AERP) and AF-inducibility were determined during applied negative thoracic pressure (NTP) for 2 minutes before and at the end of the 3-hour stimulation protocol. Group 1: LL-BRS prolonged AERP from 150 +/- 5 to 172 +/- 19 milliseconds (P < 0.001). After 3 hours of LL-BRS, NTP induced AERP-shortening was diminished from -51 +/- 10 milliseconds (-34%) to -22 +/- 4 milliseconds (-13%) (P < 0.01). AF-inducibility during NTP maneuvers decreased from 90% at baseline to 15% (P < 0.01). Group 2: HL-BRS shortened AERP from 150 +/- 17 to 132 +/- 8 milliseconds (P = 0.024). After 3 hours of HL-BRS, NTP-induced AERP-shortening was increased from -55 +/- 7 milliseconds (-36%) to 72 +/- 11 milliseconds (-54%) (P < 0.05) and AF-inducibility was not affected. NTP-induced changes in blood gases and blood pressure were not different between the groups. CONCLUSION: LL-BRS suppressed NTP-induced AERP-shortening and AF inducibility. By contrast HL-BRS further perpetuated NTP-induced AERP-shortening and increased AF-inducibility. These findings support only the use of LL-BRS as a novel therapeutic modality to treat AF in OSA. PMID- 27235277 TI - Antigen negative red blood cell inventory of Indian blood donors. AB - BACKGROUND: Screening the donor population for clinically important antigens and creating a database of phenotyped donors will eliminate the tedious task of large scale screening for antigen negative units. The aim of the present study is to identify donors lacking common antigens and a combination of common antigens to establish an antigen negative inventory. MATERIALS AND METHODS: Blood samples of 1221 regular blood donors were phenotyped for the clinically important common antigens of the Rh, Duffy, Kell, Kidd and MNS blood group systems using standard tube technique. RESULTS: Out of 1221 total donors tested, we observed that 261 donors lacked a combination of clinically important common antigens (C, D, e, Fya, Jka, s). After excluding the RhD negative donors in this study 15.56% lacked a combination of two or three common antigens. Of all donors, 3.2% lacked Fya and Jka antigens, 1.96% Fya and s, 1.88% Jka and s antigens and 0.57% lacked three common antigens. DISCUSSION: An antigen negative inventory of donors who lack a single common antigen or a combination of common antigens was prepared from regular donors which will prove useful for efficient management of transfusion therapy in patients with multiple antibodies against common antigens. PMID- 27235278 TI - ALA-induced fluorescence image guided surgery of meningiomas: A meta-analyses. AB - BACKGROUND: Though meningiomas are often benign and well circumscribed in nature, many are associated with recurrences and poor outcome because of their attachment to neurovascular nearby structures or invasion of adjacent venous sinuses or bone, forcing incomplete excision and deployment of further salvage therapy. Recently, ALA-FIGS has been reported as an aid to increase the chances of complete resection and minimizing collateral damage. METHODS: Critical review and meta-analyses of the literature published to date. All studies reporting ALA-FIGS in meningiomas were critically reviewed. Nineteen studies fulfilled the inclusion criteria with a total of 222 patients, of which 206 were included in the meta analyses. RESULTS: ALA-FIGS was highly specific, and highly sensitive (95%, range 91.8-97.7%). There was no correlation between WHO grading (WHO grade I versus WHO grades II & III) and fluorescence (odds ratio 1.2, p>0.05). ALA-FIGS altered the surgical plan intraoperatively in 75% of high-grade and 19% of low-grade meningiomas, improving the extent of surgical excision. ALA-FIGS was also highly sensitive and specific in differentiating hypertrophy and tumor invasion of adjacent dura and bone. CONCLUSIONS: ALA-FIGS in meningiomas is very selective, highly sensitive, and improves the extent of surgical resection in meningiomas. Long-term outcome of these tumors in the future should be categorized into those with and without residual fluorescent tissue. A new surgical resection grading system based on ALA-FIGS is proposed. PMID- 27235279 TI - ALA-PDT combined with antibiotics for the treatment of multiple skin abscesses caused by Mycobacterium fortuitum. AB - BACKGROUND: Atypical mycobacterial skin infection is rare in clinical practice. Because atypical mycobacteria are highly hydrophobic, the permeability of the outer membrane of the bacterial wall is very low, which makes it difficult for drugs to cross the barrier. Additionally, atypical mycobacteria are resistant to many drugs, and thus, infection tends to last for a long time and become recurrent and difficult to treat. Thus, it is very important to find new, more effective treatment methods. Mycobacterium fortuitum is a type of fast-growing atypical mycobacterium that is resistant to all of the primary anti-TB drugs and thus is very difficult to treat. Recently, in vivo and in vitro experiments have shown that singlet oxygen generated by photodynamic therapy can kill various microorganisms, including atypical mycobacteria. Herein, we report one case of 5 aminolevulinic acid photodynamic therapy (ALA-PDT) combined with antibiotics for the treatment of multiple skin abscesses in the hands caused by M. fortuitum. The results showed that ALA-PDT combined with antibiotics was very effective for treating multiple skin abscesses caused by M. fortuitum and significantly shortened the treatment time. PMID- 27235280 TI - Patient-Reported Outcomes and Clinical Trials. PMID- 27235281 TI - Testosterone and Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Propensity Score-Matched Analysis. AB - INTRODUCTION: A recent study investigated the role of testosterone (T) in chronic prostatitis or chronic pelvic pain syndrome (CP/CPPS). However, only a small amount of data is available to date, and the results are inconsistent. AIMS: To evaluate the relation between total T (TT) and CP/CPPS. METHODS: We conducted a propensity-matched study by identifying men with a TT level lower than 3.5 ng/mL among 8,336 men in their 40s and 50s. A control group of men with a TT level of at least 3.5 ng/mL matched for age, metabolic syndrome, and body mass index at a 5:1 ratio was selected for comparison. Using the same cohort and methods, another case group (TT < 3.0 ng/mL) and control group (TT >= 3.0 ng/mL) were selected. The National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI) was administered. A chi(2) test, a t-test and logistic regression analyses were used to evaluate the relation between TT and prostatitis-like symptoms. MAIN OUTCOME MEASURES: Association of TT with NIH-CPSI score. RESULTS: After propensity score matching, 948 cases (TT < 3.5 ng/mL) and 4,740 controls (TT >= 3.5 ng/mL) were included. The ratio of mild and moderate to severe prostatitis like symptoms was higher in the case group than in the control group (24.0% vs 27.4%, P = .001). The ratio of moderate to severe prostatitis-like symptoms also was higher in the case group than in the control group (6.2% vs 9.2%, P = .028). The pain domain of the NIH-CPSI, quality of life, and total NIH-CPSI scores also were higher in the case group. Ratios of severe lower urinary tract symptoms (12.6% vs 15.1%, P = .044) to maximal flow rate no higher than 10 mL/sec (3.8% vs 5.3%, P = .044) and postvoid residual urine volume of at least 100 mL (4.0% vs 5.6%, P = .035), which suggest high pressure in the prostate urethra, were higher in the case group. After adjusting for voided volume during uroflowmetry and total prostate volume, the relations of a TT level lower than 3.5 ng/mL to a maximal flow rate no higher than 10 mL/sec (odds ratio = 1.402, 95% CI = 1.017 1.934, P = .039) and to a postvoid residual urine volume of at least 100 mL (odds ratio = 1.410, 95% CI = 1.031-1.927, P = .031) were maintained. Using the cutoff TT value of 3.0 ng/mL, 437 cases (TT < 3.0 ng/mL) and 2,185 controls (TT >= 3.0 ng/mL) were included. The result of the 3.0-ng/mL cutoff value for TT showed a higher incidence of prostatitis-like symptoms in the group with a TT level lower than 3.0 ng/mL, but this was not statistically significant. CONCLUSION: Low TT level (<3.5 ng/mL) was significantly correlated with prostatitis-like symptoms in this study. PMID- 27235282 TI - Perceived Discrimination, Social Support, and Quality of Life in Gender Dysphoria. AB - INTRODUCTION: Transgender individuals experience discrimination in all domains of their personal and social life. Discrimination is believed to be associated with worse quality of life (QoL). AIM: To investigate the relation between QoL and perceived levels of discrimination and social support in individuals with gender dysphoria (GD). METHODS: Individuals with GD who attended a psychiatry clinic from January 2012 through December 2014 were recruited. Demographic, social, and medical transition features were collected with standardized forms. MAIN OUTCOME MEASURES: Self-report measurements of QoL (Turkish version of the World Health Organization's Quality of Life-BREF) that included physical, psychological, social, and environmental domains, perceived discrimination with personal and group subscales (Perceived Discrimination Scale [PDS]), and social support (Multidimensional Scale of Perceived Social Support) were completed. RESULTS: Ninety-four participants (76.6% trans men) adequately completed the study measurements. Regression models with each QoL domain score as a dependent variable indicated a significant predictor value of personal PDS in social and environmental QoL. Social support from family was associated with better QoL in psychological QoL, whereas perceived support from friends significantly predicted all other domains of QoL. There was a tendency for group PDS to be rated higher than personal PDS, suggesting personal vs group discrimination discrepancy. However, group PDS was not found to be a predictor of QoL in the multivariate model. CONCLUSION: Perceived personal discrimination and social support from different sources predicted domains of QoL with a non-uniform pattern in individuals with GD. Social support and discrimination were found to have opposing contributions to QoL in GD. The present findings emphasize the necessity of addressing discrimination and social support in clinical work with GD. Moreover, strategies to improve and strengthen friend and family support for individuals with GD should be explored by clinicians. Further research with larger and community-based samples is required. PMID- 27235283 TI - Is Bondage and Discipline, Dominance and Submission, and Sadomasochism Recreational Leisure? A Descriptive Exploratory Investigation. AB - INTRODUCTION: Recent studies have suggested that, in contrast to traditional psychopathologic explanations, bondage and discipline, dominance and submission, and sadomasochism (BDSM) could be understood as recreational leisure. However, the theoretical framing of BDSM as potential leisure has not been empirically explored. AIM: To conduct an initial empirical exploration to determine whether BDSM experience fits established characteristics of recreational leisure. METHODS: A convenience sample of BDSM participants (N = 935) completed an online survey (9 demographic questions and 17 leisure questions) that assessed BDSM experience according to important attributes of leisure. Responses also were assessed and statistically compared as being primarily casual or serious leisure according to general BDSM identities (ie, dominants vs submissives vs switches). MAIN OUTCOME MEASURES: BDSM experiences were assessed as a form of potential leisure. RESULTS: Most BDSM experiences met leisure criteria. Participants reported that "most of the time or nearly always" BDSM was associated with a sense of personal freedom (89.7% of participants), pleasure or enjoyment (98.5%), sense of adventure (90.7%), use of personal skills (90.8%), relaxation or decreased stress (91.4%), self-expression or exploration (90.6%), and positive emotions (96.6%). BDSM seemed to function as primarily serious, rather than casual, leisure, but important statistical differences were observed based on specific BDSM identities. CONCLUSION: A leisure science perspective could be valuable to researchers and clinicians in reinterpreting the wide range of diverse BDSM motivations and practices. PMID- 27235284 TI - PDE5A Polymorphisms Influence on Sildenafil Treatment Success. AB - INTRODUCTION: Diabetes and cardiovascular disease are risk factors for erectile dysfunction (ED). Selective inhibitors of the type 5 phosphodiesterase are the first option for treating ED. However, it is unknown why there are patients with low response to this treatment. Polymorphisms in the PDE5A gene may influence the response to PDE5 inhibitors treatment. AIM: The aim of this study is to analyze the relationship between PDE5A polymorphisms, diabetes, and the efficacy of sildenafil treatment. METHODS: A Spanish prospective cohort of 170 Caucasian male patients diagnosed with ED and ischemic heart disease treated with angioplasty was studied. MAIN OUTCOME MEASURES: ED was evaluated according to the 5-item version of the International Index for Erectile Function before and after treatment with sildenafil 50 mg. The gene sequence of the PDE5A gene was analyzed for the presence of rs12646525 and rs3806808 polymorphisms. Glucose and glycosylated hemoglobin levels were measured in blood serum samples. The relationship between treatment response, genotype, and glycemic status was analyzed. RESULTS: Patients with G-allele of rs3806808 polymorphism showed a worse response to the treatment compared to TT-homozygote patients. Nondiabetic G allele carriers showed a worse treatment response than TT-homozygotes patients. These differences were not seen in diabetic patients. There were no significant differences in treatment response according to the rs12646525 polymorphism in total population or according to the glycemic status. Logistic regression analysis showed that nondiabetic carriers of the major allele of both the rs12646525 and rs3806808 polymorphism had a significantly higher likelihood to respond to the treatment than diabetic patients carriers of the minor allele (P < .05). CONCLUSION: The response to sildenafil treatment depends on polymorphisms in the PDE5A gene and the glycemic status of the patients. PMID- 27235285 TI - Aortic Subannular Rupture. Complication After TAVI Implantation. PMID- 27235286 TI - Health Promotion to Reduce Delays in Seeking Medical Attention in Patients With Acute Coronary Syndrome. Response. PMID- 27235287 TI - Health Promotion to Reduce Delays in Seeking Medical Attention in Patients With Acute Coronary Syndrome. PMID- 27235288 TI - Octogenarians: Too Old for Surgical Myocardial Revascularization? Response. PMID- 27235289 TI - Echocardiography Outside the Cardiology Setting. Position Paper and Recommendations of the Spanish Society of Cardiology. PMID- 27235290 TI - The Usefulness of Vernakalant in Maintaining Sinus Rhythm During Ablation Procedures. PMID- 27235291 TI - Kommerell Diverticulum and Aberrant Right Subclavian Artery. PMID- 27235294 TI - Curcumin in depressive disorders: An overview of potential mechanisms, preclinical and clinical findings. AB - Considering the high prevalence of psychiatric disorders, its social burden and the limitations of currently available treatments, alternative therapeutic approaches targeting different biological pathways have been investigated. Curcumin is a natural compound with multi-faceted pharmacological properties, interacting with several neurotransmitter systems and intracellular signaling pathways involved in mood regulation. Also, curcumin has anti-inflammatory, antioxidant and neurotrophic effects, suggesting a strong potential to manage conditions associated with neurodegeneration, such as psychiatric disorders. Most literature data focused on the potential of curcumin to counteract behavioral and neurochemical alterations in preclinical models of depression. The findings still need to be further explored and clinical reports share some controversial results that might be associated with its low systemic bioavailability following oral administration. Other psychiatric disorders also have neurochemical alterations similar to those found in depression, including neurotoxicity, oxidative stress and neuroinflammation. Despite the limited number of reports, preclinical models investigated the potential role for curcumin in anxiety, bipolar disorder, post traumatic stress disorder and autism spectrum disorders. Here, we will summarize the cellular targets of curcumin relevant to psychiatric disorders and its effects in preclinical and clinical studies with depression, anxiety disorders and other psychiatric related conditions. PMID- 27235292 TI - Acute kidney injury in the perioperative period and in intensive care units (excluding renal replacement therapies). PMID- 27235295 TI - Effects of genistein on cognitive dysfunction and hippocampal synaptic plasticity impairment in an ovariectomized rat kainic acid model of seizure. AB - The major objective of this study was to investigate the probable effects of genistein (one of the most important soy phytoestrogens-SPEs) on seizure-induced cognitive dysfunction, hippocampal early long-term potentiation (E-LTP) impairment and morphological damage to CA1 neurons in ovariectomized (OVX) rats. Three weeks after ovariectomy, cannulae were implanted over the left lateral ventricle. After a 7-day recovery period, animals were injected by genistein (0.5 or 5mg/kg) or vehicle during four consecutive days, each 24h. One h after the last treatment, kainic acid (KA) or vehicle was perfused into the left lateral ventricle to induce generalized tonic-clonic seizures. Finally, 7 days later, spatial learning and memory of animals were examined using the Morris water maze (MWM) task, hippocampal E-LTP was assessed using in-vivo field potential recordings and the morphology of hippocampal CA1 area was examined using Fluoro Jade C staining. KA-induced generalized seizures resulted in spatial learning and memory impairment, E-LTP deficit and CA1 cell injury. Seizure-induced abnormalities improved partially only by the lower dose of genistein (0.5mg/kg). However, genistein at the higher dose (5mg/kg) did not have any beneficial effects. Also, genistein did not affect seizure activity. It is concluded that genistein may have partially preventive effects against seizure-induced cognitive impairment in OVX rats. Also, it seems that such effects of genistein are correlated with its beneficial effects on hippocampal synaptic plasticity and morphology. PMID- 27235296 TI - The role of financial hardship, mastery and social support in the association between employment status and depression: results from an Australian longitudinal cohort study. AB - OBJECTIVE: There is robust epidemiological and clinical evidence of the harmful effects of unemployment on psychological well-being, but the mechanisms through which this occurs is still strongly debated. In addition, there is even less evidence on the impact of underemployment on mental health. Using longitudinal data collected from a cohort of 20-24 years old, the present study examines a range of employed states and investigates the role of mastery, financial hardship and social support in the relationship between labour status and depression. METHOD: Responses were from the Personality and Total Health (PATH) Through Life Project: A representative, community-based survey conducted in Canberra and Queanbeyan (NSW) in Australia, where respondents (n=2404) in their early twenties were followed for 8 years. Depression was measured using the self-report Goldberg Depression Scale, with the likely presence of depression being indicated by scores 7 or greater. RESULTS: The analyses identified unemployment and underemployment as significant predictors of depression, compared to their employed counterparts. Both unemployment and underemployment remained significantly correlated with depression even after accounting for sociodemographic, economic and psychological variables. Social support, financial hardship and a sense of personal control (mastery) all emerged as important mediators between unemployment and depression. CONCLUSIONS: Both unemployment and underemployment were associated with increased risk of depression. The strength of this relationship was attenuated but remained significant after accounting for key variables (mastery, financial hardship and social support), and extensive sociodemographic and health covariates, indicating that no or inade-quate employment contributes to poorer mental health over and above these factors. PMID- 27235297 TI - Protocol for a pragmatic cluster randomised controlled trial for reducing irrational antibiotic prescribing among children with upper respiratory infections in rural China. AB - INTRODUCTION: Irrational use of antibiotics is a serious issue within China and internationally. In 2012, the Chinese Ministry of Health issued a regulation for antibiotic prescriptions limiting them to <20% of all prescriptions for outpatients, but no operational details have been issued regarding policy implementation. This study aims to test the effectiveness of a multidimensional intervention designed to reduce the use of antibiotics among children (aged 2-14 years old) with acute upper respiratory infections in rural primary care settings in China, through changing doctors' prescribing behaviours and educating parents/caregivers. METHODS AND ANALYSIS: This is a pragmatic, parallel-group, controlled, cluster-randomised superiority trial, with blinded evaluation of outcomes and data analysis, and un-blinded treatment. From two counties in Guangxi Province, 12 township hospitals will be randomised to the intervention arm and 13 to the control arm. In the control arm, the management of antibiotics prescriptions will continue through usual care via clinical consultations. In the intervention arm, a provider and patient/caregiver focused intervention will be embedded within routine primary care practice. The provider intervention includes operational guidelines, systematic training, peer review of antibiotic prescribing and provision of health education to patient caregivers. We will also provide printed educational materials and educational videos to patients' caregivers. The primary outcome is the proportion of all prescriptions issued by providers for upper respiratory infections in children aged 2-14 years old, which include at least one antibiotic. ETHICS AND DISSEMINATION: The trial has received ethical approval from the Ethics Committee of Guangxi Provincial Centre for Disease Control and Prevention, China. The results will be disseminated through workshops, policy briefs, peer-reviewed publications, local and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN14340536; Pre-results. PMID- 27235298 TI - Longitudinal trends in use of targeted therapies for treatment of malignant neoplasms of the eye: a population-based study in Taiwan. AB - OBJECTIVES: This study examined the recent trend in use and costs of antineoplastic agents for treatment of eye malignancies in Taiwan from 2009 to 2012. We also forecasted use and costs of targeted therapies up to and including year 2016 based on the current patterns. DESIGN: Retrospective observational study focusing on the usage of targeted therapies for treatment of eye malignancy. SETTING: The monthly claims data for eye malignancy-related antineoplastic agents were retrieved from Taiwan's National Health Insurance Research Database (2009-2012). MAIN OUTCOME MEASURES: We calculated the number of prescriptions and costs for each class of medications, and analysed their time trends. In addition, using a time series design with ARIMA models, we estimated the market share by prescription volume and the proportion of costs for targeted therapies for year 2016. RESULTS: The market share by prescription volume of targeted therapies grew from 1.56% in 2009 to 9.98% in 2012 among all antineoplastic agents, and the proportion of costs for targeted therapies rose from 15.12% in 2009 to 58.88% in 2012. Especially, the proportion of costs for protein kinase inhibitors grew from 25.62% to 45.28% among all antineoplastic agents between 2010 and 2012. The market share by prescription volume and the proportion of costs for targeted therapies for treatment of eye malignancies were predicted to reach 27.33% and 91.39% by the fourth quarter in 2016, respectively. CONCLUSIONS: This is the first study that examined and forecasted use and costs of targeted therapies for treatment of eye malignancies in Taiwan. Our findings indicate that, compared with other classes of drugs, targeted therapies are having a more and more relevant share among all treatment strategies for eye malignancies in Taiwan, and due to their high costs they are likely to cause great economic burden. PMID- 27235299 TI - A cross-sectional study of the effect of health literacy on diabetes prevention and control among elderly individuals with prediabetes in rural China. AB - OBJECTIVES: This study was designed to examine the effect of health literacy on diabetes prevention and control and risk factors for low diabetes health literacy among elderly individuals with prediabetes in rural areas in China. DESIGN SETTING AND PARTICIPATES: A cross-sectional survey was conducted among elderly individuals in rural communities in Yiyang City in China. Multi-staged cluster random sampling was used to select 42 areas and 434 individuals with prediabetes who were interviewed using a questionnaire on diabetes health literacy in China. MAIN OUTCOME MEASURES: Participants were asked for general information (age, gender, marital status, history of hyperglycaemia, family history of diabetes mellitus, presence of other diseases and level of education). Binary logistic regression analysis was used to identify risk factors for poor health literacy concerning diabetes prevention and control among elderly subjects with prediabetes. RESULTS: The median health literacy score for diabetes prevention and prediabetes control was 10.0 (IQR 7.0-13.0). The level of diabetes health literacy among men was lower than among women (OR 2.831, 95% CI 1.818 to 4.408), and lower among respondents with 1-6 years of education than among those with 6 years or more of education (OR 14.274, 95% CI 5.927 to 34.375). Those with less than 1 year of education had the lowest literacy (OR 31.148, 95% CI 11.661 to 83.204). The level of diabetes health literacy among elderly individuals with prediabetes but no history of hyperglycaemia was lower than among those with a history of hyperglycaemia (OR 2.676, 95% CI 1.101 to 6.504). CONCLUSIONS: Health literacy concerning diabetes prevention and control among elderly individuals with prediabetes was very low in rural China. Appropriate health education for elderly individuals with low educational levels should be incorporated into diabetes prevention efforts. TRIAL REGISTRATION NUMBER: ChiCTR-IOR-15007033; Results. PMID- 27235300 TI - Quality assessment of patient leaflets on misoprostol-induced labour: does written information adhere to international standards for patient involvement and informed consent? AB - OBJECTIVES: The need for thorough patient information is increasing as maternity care becomes more medicalised. The aim was to assess the quality of written patient information on labour induction. In most Danish hospitals, misoprostol is the first-choice drug for induction in low-risk pregnancies. Misoprostol has been associated with adverse side effects and severe outcomes for mother and child and is not registered for obstetric use in Denmark. SETTING: Secondary care hospitals in Denmark. DATA: Patient information leaflets from all hospitals that used misoprostol as an induction agent by June 2015 (N=13). DESIGN: Patient leaflets were evaluated according to a validated scoring tool (International Patient Decision Aid Standards instrument, IPDAS), core elements in the Danish Health Act, and items regarding off-label use and non-registered medication. Two of the authors scored all leaflets independently. OUTCOME MEASURES: Women's involvement in decision-making, information on benefits and harms associated with the treatment, other justifiable treatment options, and non-registered treatment. RESULTS: Generally, the hospitals scored low on the IPDAS checklist. No hospitals encouraged women to consider their preferences. Information on side effects and adverse outcomes was poorly covered and varied substantially between hospitals. Few hospitals informed about precautions regarding outpatient inductions, and none informed about the lack of evidence on the safety of this procedure. None informed that misoprostol is not registered for induction or explained the meaning of off-label use or use of non-registered medication. Elements such as interprofessional consensus, long-term experience, and health authorities' approval were used to add credibility to the use of misoprostol. CONCLUSIONS: Central criteria for patient involvement and informed consent were not met, and the patient leaflets did not inform according to current evidence on misoprostol induced labour. Our findings indicate that patients receive very different, sometimes contradictory, information with potential ethical implications. Concerns should be given to outpatient inductions, where precise written information is of particular importance. PMID- 27235301 TI - Patterns of electronic cigarette use in current and ever users among college students in France: a cross-sectional study. AB - OBJECTIVE: There is sparse information on electronic cigarette use and health behaviours among college student populations. Our objectives were to identify the patterns of electronic cigarette use in current and ever users among college students in France. DESIGN: Cross-sectional study. SETTINGS: A multicentre cross sectional study was conducted on two major campuses in France. Students filled in an anonymous questionnaire on their use of electronic cigarettes and on targeted behaviours such as smoking, alcohol consumption, binge drinking, use of cannabis, practice of sport and eating disorders. Ever use of electronic cigarettes was defined as use but not during the previous 30 days, and current use of electronic cigarettes as any use in the previous 30 days. The opinions and motivations of electronic cigarette users were also sought and collected. PARTICIPANTS: 1134 college students between October 2014 and February 2015. RESULTS: The 1134 students included had a mean age of 20.8 years. The prevalence of ever use and current use of electronic cigarettes was 23.0% (95% CI (20.5% to 25.3%)) and 5.7% (95% CI (4.4% to 7.1%)), respectively. The prevalence of the combined use of conventional cigarettes and electronic cigarettes was 14.5%. Almost half (45.8%) of the ever users of electronic cigarettes had never smoked conventional cigarettes. Behaviours associated with ever use of electronic cigarettes were current cigarette smoking (adjusted OR (AOR)=3.97, 95% CI 2.71 to 5.83), former smoking (AOR=2.56, 95% CI 1.42 to 4.61), cannabis use (AOR=2.44, 95% CI 1.70 to 3.51) and occasional binge drinking (AOR=1.83, 95% CI 1.28 to 2.64). The only behaviour associated with current use of electronic cigarettes was conventional smoking, either previously (AOR=4.85, 95% CI 1.53 to 15.34) or currently (AOR=14.53, 95% CI 6.81 to 31.02). CONCLUSIONS: The ever users have an experimenter's profile with sensation-seeking while the current users are mostly smokers with intention to quit smoking. Our findings are crucial for the accurate targeting of student populations at risk and to implement appropriate awareness campaigns and health education programmes. PMID- 27235302 TI - Social and behavioural factors associated with frailty trajectories in a population-based cohort of older adults. AB - OBJECTIVE: The goal of this study was to identify distinct frailty trajectories (clusters of individuals following a similar progression of frailty over time) in an ageing population and to determine social and behavioural factors associated with frailty trajectories. DESIGN: Population-based cohort study. SETTING: Olmsted County, Minnesota. PARTICIPANTS: Olmsted County, Minnesota residents aged 60-89 in 2005. PRIMARY OUTCOME MEASURE: Changes in frailty over an 8-year period from 2005 to 2012, measured by constructing a yearly frailty index. Frailty trajectories by decade of age were determined using k-means cluster modelling for longitudinal data. RESULTS: After adjustment for age and sex, all social and behavioural factors (education, marital status, living arrangements, smoking status and alcohol use) were significantly associated with frailty trajectories in those aged 60-69 and 70-79 years. After further adjustment for baseline frailty, the likelihood of being in the high frailty trajectory was greatest among those reporting concerns from relatives/friends about alcohol consumption (OR (95% CI) 2.26 (1.19 to 4.29)) and those with less than a high school education (OR (95% CI) 1.98 (1.32 to 2.96)) in the 60-69 year olds. In the 70-79 year olds, the largest associations were observed among those with concerns from oneself about alcohol consumption (OR (95% CI) 1.92 (1.23 to 3.00)), those with less than a high school education (OR (95% CI) 1.57 (1.12 to 2.22)), and those living with family (vs spouse; OR (95% CI) 1.76 (1.05 to 2.94)). No factors remained associated with frailty trajectories in the 80-89 year olds after adjustment for baseline frailty. CONCLUSIONS: Social and behavioural factors are associated with frailty, with stronger associations observed in younger ages. Recognition of social and behavioural factors associated with increasing frailty may inform interventions for individuals at risk of worsening frailty, specifically when targeted at younger individuals. PMID- 27235303 TI - Barriers and enablers in primary care clinicians' management of osteoarthritis: protocol for a systematic review and qualitative evidence synthesis. AB - INTRODUCTION: Osteoarthritis is a highly prevalent and disabling condition. Primary care management of osteoarthritis is generally suboptimal despite evidence for several modestly effective interventions and the availability of high-quality clinical practice guidelines. This report describes a planned study to synthesise the views of primary care clinicians on the barriers and enablers to following recommended management of osteoarthritis, with the aim of providing new interpretations that may facilitate the uptake of recommended treatments, and in turn improve patient care. METHODS AND ANALYSIS: A systematic review and meta synthesis of qualitative studies. 5 databases will be searched using key search terms for qualitative research, evidence-based practice, clinical practice guidelines, osteoarthritis, beliefs, perceptions, barriers, enablers and adherence. A priori inclusion/exclusion criteria include availability of data from primary care clinicians, reports on views regarding management of osteoarthritis, and studies using qualitative methods for both data collection and analysis. At least 2 independent reviewers will identify eligible reports, conduct a critical appraisal of study conduct, extract data and synthesise reported findings and interpretations. Synthesis will follow thematic analysis within a grounded theory framework of inductive coding and iterative theme identification. The reviewers plus co-authors will contribute to the meta synthesis to find new themes and theories. The Confidence in the Evidence from Reviews of Qualitative research (CERQual) approach will be used to determine a confidence profile of each finding from the meta-synthesis. The protocol has been registered on PROSPERO and is reported using the Preferred Reporting Items for Systematic Review and Meta-Analyses Protocols (PRISMA-P) guidelines. ETHICS AND DISSEMINATION: Ethical approval is not required. The systematic review will be published in a peer-reviewed journal. The results will help to inform policy and practice and assist in the optimisation of management for people with osteoarthritis. PROSPERO REGISTRATION NUMBER: CRD42015027543. PMID- 27235305 TI - Rural-to-Urban Migration, Strain, and Juvenile Delinquency: A Study of Eighth Grade Students in Guangzhou, China. AB - This examination of minor and serious delinquency among eighth graders in a large southern Chinese city, Guangzhou, also compared groups of these students, observing differences between the delinquency of migrants and that of urban natives. Data used were originally collected for the study "Stuck in the City: Migration and Delinquency Among Migrant Adolescents in Guangzhou." The present study asked whether and how various sources of strain and social control factors explained students' delinquency, questioning how meaningfully migration status moderated several of the observed delinquency relationships. Of students in the sample, 741 reported being natives of Guangzhou, and 497 reported migrating to Guangzhou from a rural area. The study conceptualized internal migration as a strain factor leading to delinquency, but the analyses did not suggest direct association between internal migration and delinquency. Results generally supported Agnew's theory, and, what's more, they tended to confirm that migration status moderated juvenile delinquency. PMID- 27235306 TI - Safety of tubeless or totally tubeless drainage and nephrostomy tube as a drainage following percutaneous nephrolithotomy: A comprehensive review. AB - Percutaneous nephrolithotomy (PCNL) using a nephrostomy tube as a drainage has been considered the standard procedure. However, recently many literatures have reported the use of tubeless and totally tubeless drainage following PCNL with excellent results. A literature search was conducted using MEDLINE databases to review each drainage technique following PCNL (tubeless, totally tubeless, or nephrostomy tube) and also to assess the most recent evidence that compare the safety of these drainage procedures with a clear-cut clinical parameter imposed. Tubeless or totally tubeless PCNL is significantly superior to standard PCNL in terms of length of hospital stay, postoperative pain (visual analog scale) score, demands or dosage of analgesics required, as well as faster return to activity for the patients. However, despite the many advantages of tubeless or totally tubeless PCNL over standard PCNL, there are a number of situations requiring the consideration of nephrostomy tube placement. Nonetheless, decision to use or not to use nephrostomy tube after PCNL depends on the surgeon's experience and clinical judgment. PMID- 27235304 TI - Non-specific mechanisms in orthodox and CAM management of low back pain (MOCAM): theoretical framework and protocol for a prospective cohort study. AB - INTRODUCTION: Components other than the active ingredients of treatment can have substantial effects on pain and disability. Such 'non-specific' components include: the therapeutic relationship, the healthcare environment, incidental treatment characteristics, patients' beliefs and practitioners' beliefs. This study aims to: identify the most powerful non-specific treatment components for low back pain (LBP), compare their effects on patient outcomes across orthodox (physiotherapy) and complementary (osteopathy, acupuncture) therapies, test which theoretically derived mechanistic pathways explain the effects of non-specific components and identify similarities and differences between the therapies on patient-practitioner interactions. METHODS AND ANALYSIS: This research comprises a prospective questionnaire-based cohort study with a nested mixed-methods study. A minimum of 144 practitioners will be recruited from public and private sector settings (48 physiotherapists, 48 osteopaths and 48 acupuncturists). Practitioners are asked to recruit 10-30 patients each, by handing out invitation packs to adult patients presenting with a new episode of LBP. The planned multilevel analysis requires a final sample size of 690 patients to detect correlations between predictors, hypothesised mediators and the primary outcome (self-reported back-related disability on the Roland-Morris Disability Questionnaire). Practitioners and patients complete questionnaires measuring non specific treatment components, mediators and outcomes at: baseline (time 1: after the first consultation for a new episode of LBP), during treatment (time 2: 2 weeks post-baseline) and short-term outcome (time 3: 3 months post-baseline). A randomly selected subsample of participants in the questionnaire study will be invited to take part in a nested mixed-methods study of patient-practitioner interactions. In the nested study, 63 consultations (21/therapy) will be audio recorded and analysed quantitatively and qualitatively, to identify communication practices associated with patient outcomes. ETHICS AND DISSEMINATION: The protocol is approved by the host institution's ethics committee and the NHS Health Research Authority Research Ethics Committee. Results will be disseminated via peer-reviewed journal articles, conferences and a stakeholder workshop. PMID- 27235307 TI - Childhood predictors of adult fatty liver. The Cardiovascular Risk in Young Finns Study. AB - BACKGROUND & AIMS: Fatty liver is a potentially preventable cause of serious liver diseases. This longitudinal study aimed to identify childhood risk factors of fatty liver in adulthood in a population-based group of Finnish adults. METHODS: Study cohort included 2,042 individuals from the Cardiovascular Risk in Young Finns Study aged 3-18years at baseline in 1980. During the latest follow-up in 2011, the liver was scanned by ultrasound. In addition to physical and environmental factors related to fatty liver, we examined whether the genetic risk posed by a single nucleotide polymorphism in the patatin-like phospholipase domain-containing protein 3 gene (PNPLA3) (rs738409) strengthens prediction of adult fatty liver. RESULTS: Independent childhood predictors of adult fatty liver were small for gestational age, (odds ratio=1.71, 95% confidence interval=1.07 2.72), variant in PNPLA3 (1.63, 1.29-2.07 per one risk allele), variant in the transmembrane 6 superfamily 2 gene (TM6SF2) (1.57, 1.08-2.30), BMI (1.30, 1.07 1.59 per standard deviation) and insulin (1.25, 1.05-1.49 per standard deviation). Childhood blood pressure, physical activity, C-reactive protein, smoking, serum lipid levels or parental lifestyle factors did not predict fatty liver. Risk assessment based on childhood age, sex, BMI, insulin levels, birth weight, TM6SF2 and PNPLA3 was superior in predicting fatty liver compared with the approach using only age, sex, BMI and insulin levels (C statistics, 0.725 vs. 0.749; p=0.002). CONCLUSIONS: Childhood risk factors on the development of fatty liver were small for gestational age, high insulin and high BMI. Prediction of adult fatty liver was enhanced by taking into account genetic variants in PNPLA3 and TM6SF2 genes. LAY SUMMARY: The increase in pediatric obesity emphasizes the importance of identification of children and adolescents at high risk of fatty liver in adulthood. We used data from the longitudinal Cardiovascular Risk in Young Finns Study to examine the associations of childhood (3-18years) risk variables with fatty liver assessed in adulthood at the age of 34-49years. The findings suggest that a multifactorial approach with both lifestyle and genetic factors included would improve early identification of children with a high risk of adult fatty liver. PMID- 27235309 TI - Should Ventilator-Associated Events become a Quality Indicator for ICUs? AB - The United States Centers for Disease Control and Prevention replaced their longstanding ventilator-associated pneumonia (VAP) definitions with ventilator associated event (VAE) definitions in 2013. Controversy abounds as to whether VAE definitions are potentially suitable to serve as quality indicators for ICUs. On the pro side, VAE definitions overcome many of the weaknesses of traditional VAP surveillance. VAE definitions are objective, reproducible, electronically computable, and strongly predict poor outcomes for patients. There is an increasing amount of data on clinical correlates, risk factors, and approaches to prevent VAEs. Potential strategies to prevent VAEs are highly aligned with accepted best practices in critical care. VAE surveillance therefore has the potential to catalyze better care and to help hospitals track outcomes in ventilated patients more rigorously and more efficiently. On the con side, the complete VAE definition set with subtiers is complicated, neither sensitive nor specific for VAP, non-physiological compared with other ICU metrics, susceptible to gaming, and may bring about changes in clinician behavior that could paradoxically end up harming patients. PMID- 27235308 TI - Genomic Prediction for Quantitative Traits Is Improved by Mapping Variants to Gene Ontology Categories in Drosophila melanogaster. AB - Predicting individual quantitative trait phenotypes from high-resolution genomic polymorphism data is important for personalized medicine in humans, plant and animal breeding, and adaptive evolution. However, this is difficult for populations of unrelated individuals when the number of causal variants is low relative to the total number of polymorphisms and causal variants individually have small effects on the traits. We hypothesized that mapping molecular polymorphisms to genomic features such as genes and their gene ontology categories could increase the accuracy of genomic prediction models. We developed a genomic feature best linear unbiased prediction (GFBLUP) model that implements this strategy and applied it to three quantitative traits (startle response, starvation resistance, and chill coma recovery) in the unrelated, sequenced inbred lines of the Drosophila melanogaster Genetic Reference Panel. Our results indicate that subsetting markers based on genomic features increases the predictive ability relative to the standard genomic best linear unbiased prediction (GBLUP) model. Both models use all markers, but GFBLUP allows differential weighting of the individual genetic marker relationships, whereas GBLUP weighs the genetic marker relationships equally. Simulation studies show that it is possible to further increase the accuracy of genomic prediction for complex traits using this model, provided the genomic features are enriched for causal variants. Our GFBLUP model using prior information on genomic features enriched for causal variants can increase the accuracy of genomic predictions in populations of unrelated individuals and provides a formal statistical framework for leveraging and evaluating information across multiple experimental studies to provide novel insights into the genetic architecture of complex traits. PMID- 27235310 TI - Should Aerosolized Antibiotics Be Used to Treat Ventilator-Associated Pneumonia? AB - In patients with ventilator-associated pneumonia, systemic use of antibiotics is the cornerstone of medical management. Supplemental use of aerosolized antibiotics with intravenous antibiotics in both experimental and clinical studies has been shown to have the following pharmacologic benefits: (1) aerosolized antibiotics reach the infected lung parenchyma without crossing the pulmonary alveolar capillary barrier; (2) aerosolized antibiotics increase anti bacterial efficacy through increased local antibiotic concentration; and (3) aerosolized antibiotics decrease systemic toxicity. These benefits may be particularly beneficial to treat pneumonia caused by multidrug-resistant pathogens. Clinical data on the benefits of aerosolized antibiotics are more limited. Studies to date have not clearly shown improvements in time to extubation, mortality, or other patient-centered outcomes. At present, amikacin, colistin, and ceftazidime are the most frequently used and studied aerosolized antibiotics. This review summarizes the characteristics of aerosolized antibiotics, reviews the advantages and disadvantages of using aerosolized antibiotics, and calls for future investigations based on animal study data. PMID- 27235311 TI - Is Automated Weaning Superior to Manual Spontaneous Breathing Trials? AB - Weaning from mechanical ventilation involves the reduction or withdrawal of ventilatory support in proportion to the patient's ability to sustain spontaneous ventilation. Protocolized weaning has been shown to reduce weaning duration; however, its weakness lies in the reliance on human intervention. Automated weaning is theoretically superior to manual weaning because of its ability to rapidly recognize deviations from desired behavior and enforce compliance with a standardized weaning strategy unencumbered by external influences. Whether currently available methods for automated weaning fulfill that potential to achieve superiority depends on patient type, care environment, and cause of ventilator dependence. PMID- 27235312 TI - Should Airway Pressure Release Ventilation Be the Primary Mode in ARDS? AB - Airway pressure release ventilation (APRV) was originally described as a mode to treat lung-injured patients with the goal to maintain a level of airway pressure that would not depress the cardiac function, deliver mechanical breaths without excessive airway pressure, and to allow unrestricted spontaneous ventilation. Indeed, based on its design, APRV has technological features that serve the goals of safety and comfort. Animal studies suggest that APRV leads to alveolar stability and recruitment which result in less lung injury. These features are sought in patients at risk for lung injury or with ARDS. APRV allows unrestricted spontaneous ventilation, which is welcome in the era of less sedation and increased patient mobility (the effects in terms of lung injury remain to be explored). However, we must highlight that the performance of APRV is dependent on the operator-selected settings and the ventilator's performance. The clinician must select the appropriate settings in order to make effective the imputed benefits. This is a challenge when the ventilator's performance is not uniform, and the outcomes depend on high precision settings (very short expiratory time), where small variations can lead to undesired outcomes (de-recruitment or large tidal volumes leading to lung injury). Finally, we do not have evidence that APRV (as originally described) improves relevant clinical outcomes of patients with ARDS. For APRV to become the primary mode of ventilation for ARDS, it will require development of sound protocols and technological enhancements to ensure its performance and safety. For now, APRV does have a greater potential for adversely affecting patient outcome than improving it; unless definitive data are forthcoming demonstrating outcome benefits from the use of APRV in ARDS, there is no reason to consider this approach to ventilatory support. PMID- 27235313 TI - Should A Tidal Volume of 6 mL/kg Be Used in All Patients? AB - It has been shown that mechanical ventilation by itself can cause lung injury and affect outcomes. Ventilator-induced lung injury is associated with high tidal volumes in lungs afflicted with ARDS. However, the question is: Do high tidal volumes have this same effect in normal lungs or lungs that have respiratory compromise stemming from something other than ARDS? Many clinicians believe that a tidal volume strategy of 6 mL/kg predicted body weight should be standard practice in all patients receiving mechanical ventilation. There is a growing body of evidence related to this issue, and this is the debate that will be tackled in this paper from both pro and con perspectives. PMID- 27235314 TI - Should High-Frequency Ventilation in the Adult Be Abandoned? AB - High-frequency oscillatory ventilation (HFOV) can improve ventilation-perfusion matching without excessive alveolar tidal stretching or collapse-reopening phenomenon. This is an attractive feature in the ventilation of patients with ARDS. However, two recent large multi-center trials of HFOV failed to show benefits in this patient population. The following review addresses whether, in view of these trails, HFOV should be abandoned in the adult population? PMID- 27235315 TI - Should Oxygen Therapy Be Tightly Regulated to Minimize Hyperoxia in Critically Ill Patients? AB - Oxygen is both lifesaving and toxic. Appropriate use of oxygen aims to provide a balance between the two effects. Although local oxygen toxicity to the lung is well accepted, recent evidence has called into question the negative consequences of hyperoxemia in other organ beds. Hyperoxia following cardiac arrest, traumatic brain injury, and stroke has been shown to worsen outcomes. The role of hyperoxemia in mechanically ventilated patients, in the face of non-toxic inspired oxygen concentrations, is less clear. This paper will review the data for and against the use of conservative oxygen targets and the avoidance of hyperoxemia in mechanically ventilated patients. PMID- 27235316 TI - Should Early Prone Positioning Be a Standard of Care in ARDS With Refractory Hypoxemia? AB - For the past 4 decades, the prone position has been employed as an occasional rescue option for patients with severe hypoxemia unresponsive to conventional measures applied in the supine orientation. Proning offers a high likelihood of significantly improved arterial oxygenation to well selected patients, but until the results of a convincing randomized trial were published, its potential to reduce mortality risk remained in serious doubt. Proning does not benefit patients of all disease severities and stages but may be life-saving for others. Because it requires advanced nursing skills and escalation of monitoring surveillance to deploy safely, its place as an early stage standard of care depends on the definition of that label. PMID- 27235317 TI - Should a Portable Ventilator Be Used in All In-Hospital Transports? AB - Movement of the mechanically ventilated patient may be for a routine procedure or medical emergency. The risks of transport seem manageable, but the memory of a respiratory-related catastrophe still gives many practitioners pause. The risk/benefit ratio of transport must be assessed before movement. During transport of the ventilated patients, should we always use a transport ventilator? What is the risk of using manual ventilation? How are PEEP and FIO2 altered? Is there an impact on the ability to trigger during manual ventilation? Is hyperventilation and hypoventilation a common problem? Does hyperventilation or hypoventilation result in complications? Are portable ventilators worth the cost? What about the function of portable ventilators? Can these devices faithfully reproduce ICU ventilator function? The following pro and con discussion will attempt to address many of these issues by reviewing the current evidence on transport ventilation. PMID- 27235318 TI - Should Intermittent Mandatory Ventilation Be Abolished? AB - Intermittent mandatory ventilation (IMV) was introduced nearly 50 years ago. Despite the initial fanfare and early adoption by many, the role of IMV continues to be questioned. The use of small tidal volumes complicates the application of IMV, and issues with work of breathing, weaning and lack of clear advantages have many calling for a moratorium on its use. Spontaneous breathing, however, has a number of salutatory effects on gas exchange, the distribution of ventilation, and hemodynamics. These issues will be explored in light of a growing body of evidence. PMID- 27235319 TI - Should Early Mobilization Be Routine in Mechanically Ventilated Patients? AB - ICU-acquired weakness is a major complication of critical illness requiring mechanical ventilation. Early mobilization has been shown to decrease the negative consequences of ICU-acquired weakness. However, early mobilization might entail risks to the patient. Additional staffing needs might have a negative financial impact. This review examines whether early mobilization should be routinely performed in mechanically ventilated patients. PMID- 27235321 TI - Editor's Commentary. PMID- 27235320 TI - Should PEEP Titration Be Based on Chest Mechanics in Patients With ARDS? AB - Functional residual capacity (FRC) is essentially the alveolar volume and a determinant of both oxygenation and respiratory system compliance (CRS). ARDS decreases FRC, and sufficient PEEP restores FRC; thus, assessments of PEEP by its impact on oxygenation and CRS are intimately linked. PEEP also can ameliorate or aggravate ventilator-induced lung injury. Therefore, it can be argued that PEEP should be titrated primarily by its impact on CRS The pro position argues that the heterogeneous nature of lung injury and its unique presentation in individual patients results in an uncoupling between oxygenation and CRS Therefore, relying upon oxygenation alone may enhance lung injury and mortality risk, particularly in those with severe ARDS. The con argument is that the preponderance of preclinical and clinical evidence suggests that a relatively narrow range of PEEP is required to manage all but the most severe cases of ARDS. In addition, pathological alterations in chest wall compliance confuse the interpretation of chest mechanics. Moreover, ambiguities and technical limitations in advanced techniques, such as esophageal manometry and pressure-volume curves, add a layer of complexity that renders its broader application in all ARDS patients both impractical and unnecessary. Whether sophisticated monitoring of chest mechanics in severe ARDS might improve outcomes further is open to question and should be studied further. However, it is highly improbable that we will ever discover a PEEP strategy that optimizes all aspects of cardiorespiratory function and chest mechanics for individual patients suffering from ARDS. PMID- 27235323 TI - In Memoriam. PMID- 27235322 TI - Scientific and Regulatory Policy Committee Points to Consider Review: Inclusion of Reproductive and Pathology End Points for Assessment of Reproductive and Developmental Toxicity in Pharmaceutical Drug Development. AB - Standard components of nonclinical toxicity testing for novel pharmaceuticals include clinical and anatomic pathology, as well as separate evaluation of effects on reproduction and development to inform clinical development and labeling. General study designs in regulatory guidances do not specifically mandate use of pathology or reproductive end points across all study types; thus, inclusion and use of these end points are variable. The Scientific and Regulatory Policy Committee of the Society of Toxicologic Pathology (STP) formed a Working Group to assess the current guidelines and practices on the use of reproductive, anatomic pathology, and clinical pathology end points in general, reproductive, and developmental toxicology studies. The Working Group constructed a survey sent to pathologists and reproductive toxicologists, and responses from participating organizations were collected through the STP for evaluation by the Working Group. The regulatory context, relevant survey results, and collective experience of the Working Group are discussed and provide the basis of each assessment by study type. Overall, the current practice of including specific end points on a case-by case basis is considered appropriate. Points to consider are summarized for inclusion of reproductive end points in general toxicity studies and for the informed use of pathology end points in reproductive and developmental toxicity studies. PMID- 27235324 TI - Tracking Epidermal Nerve Fiber Changes in Asian Macaques: Tools and Techniques for Quantitative Assessment. AB - Quantitative assessment of epidermal nerve fibers (ENFs) has become a widely used clinical tool for the diagnosis of small fiber neuropathies such as diabetic neuropathy and human immunodeficiency virus-associated sensory neuropathy (HIV SN). To model and investigate the pathogenesis of HIV-SN using simian immunodeficiency virus (SIV)-infected Asian macaques, we adapted the skin biopsy and immunostaining techniques currently employed in human patients and then developed two unbiased image analysis techniques for quantifying ENF in macaque footpad skin. This report provides detailed descriptions of these tools and techniques for ENF assessment in macaques and outlines important experimental considerations that we have identified in the course of our long-term studies. Although initially developed for studies of HIV-SN in the SIV-infected macaque model, these methods could be readily translated to a range of studies involving peripheral nerve degeneration and neurotoxicity in nonhuman primates as well as preclinical investigations of agents aimed at neuroprotection and regeneration. PMID- 27235325 TI - The study of progesterone action in human myometrial explants. AB - STUDY HYPOTHESIS: Myometrial explants represent a superior model compared with cell culture models for the study of human myometrial progesterone (P4) signalling in parturition. STUDY FINDING: Gene expression analysis showed myometrial explants closely resemble the in vivo condition and the anti inflammatory action of P4 is not lost with labour onset. WHAT IS KNOWN ALREADY: Circulating P4 levels decline before the onset of parturition in most animals, but not in humans. This has led to the suggestion that there is a functional withdrawal of P4 action at the myometrial level prior to labour onset. However, to date, no evidence of a loss of P4 function has been provided, with studies hampered by a lack of a physiologically relevant model. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: Myometrial biopsies obtained at Caesarean section were dissected into explants after a portion was immediately snap frozen (t = 0). Microarray analysis was used to compare gene expression of t = 0 with paired (i) explants, (ii) passage 4 myometrial cell cultures or (iii) the hTERT myometrial cell line. Western blotting and chemokine/cytokine assays were used to study P4 signalling in myometrial explants. MAIN RESULTS AND THE ROLE OF CHANCE: Gene expression comparison of t = 0 to the three models demonstrated that explants more closely resemble the in vivo status. At the protein level, explants maintain both P4 receptor (PR) and glucocorticoid receptor (GR) levels versus t = 0 whereas cells only maintain GR levels. Additionally, treatment with 1 uM P4 led to a reduction in interleukin-1 (IL-1) beta-driven cyclooxygenase-2 in explants but not in cells. P4 signalling in explants was PR-mediated and associated with a repression of p65 and c-Jun phosphorylation. Furthermore, the anti-inflammatory action of P4 was maintained after labour onset. LIMITATIONS/REASONS FOR CAUTION: There is evidence of basal inflammation in the myometrial explant model. WIDER IMPLICATIONS OF THE FINDINGS: Myometrial explants constitute a novel model to study P4 signalling in the myometrium and can be used to further elucidate the mechanisms of P4 action in human labour. LARGE SCALE DATA: Data deposited at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=gvmpggkurbgxfqf&acc=GSE77830. STUDY FUNDING AND COMPETING INTEREST: This work was supported by grants from the Joint Research Committee of the Westminster Medical School Research Trust, Borne (No. 1067412-7; a sub-charity of the Chelsea and Westminster Health Charity) and the Imperial NIHR Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS or the Department of Health. The authors have no conflict of interest. PMID- 27235326 TI - Semimembranosus Release for Medial Soft Tissue Balancing Does Not Weaken Knee Flexion Strength in Patients Undergoing Varus Total Knee Arthroplasty. AB - BACKGROUND: The sequential medial release technique including semimembranosus (semiM) release is effective and safe during varus total knee arthroplasty (TKA). However, there are concerns about weakening of knee flexion strength after semiM release. We determined whether semiM release to balance the medial soft tissue decreased knee flexion strength after TKA. METHODS: Fifty-nine consecutive varus knees undergoing TKA were prospectively enrolled. A 3-step sequential release protocol which consisted of release of (1) the deep medial collateral ligament (dMCL), (2) the semiM, and (3) the superficial medial collateral ligament based on medial tightness. Gap balancing was obtained after dMCL release in 31 knees. However, 28 knees required semiM release or more after dMCL release. Isometric muscle strength of the knee was compared 6 months postoperatively between the semiM release and semiM nonrelease groups. Knee stability and clinical outcomes were also compared. RESULTS: No differences in knee flexor or extensor peak torque were observed between the groups 6 months postoperatively (P = .322 and P = .383, respectively). No group difference was observed in medial joint opening angle on valgus stress radiographs (P = .327). No differences in the Knee Society or Western Ontario and McMaster Universities Osteoarthritis Index scores were detected between the groups (P = .840 and P = .682, respectively). CONCLUSION: These results demonstrate that semiM release as a sequential step to balance medial soft tissue in varus knees did not affect knee flexion strength after TKA. PMID- 27235327 TI - Can the Visibility of Both Prosthetic Posterior Femoral Condyles on a Postoperative Radiograph Assure that Limb Rotation Is Appropriate to Allow Accurate Measurement of the Anatomic Knee Axis? AB - BACKGROUND: To better define radiographic parameters for a true anterior posterior (AP) knee radiograph after total knee arthroplasty, we cataloged the radiographic appearance of 7 different designs of commercially available femoral components at various points of rotation to correlate the visibility of the prosthetic posterior femoral condyles (PPFCs) with the amount of rotation of the femoral component, and hence, the limb. METHODS: AP radiographs of 7 left-sided, cruciate-retaining femoral trial components were obtained at 5 degrees increments of rotation from 20 degrees internal rotation (IR) to 20 degrees external rotation (ER). Rotational profiles were cataloged based on the visibility of either or both of the PPFCs. RESULTS: Three categories of femoral component rotation profiles were noted, based on the visibility of the PPFC: overt ER with only the medial PFC visible at greater than 10 degrees ER, overt IR with only the lateral PFC visible at greater than 20 degrees IR, and near neutral rotation with both medial and lateral PPFCs visible between 5 degrees ER and 15 degrees IR. CONCLUSION: An acceptable AP radiograph to measure the anatomic knee axis after total knee arthroplasty is one where both the medial and lateral PPFCs are visible on either side of the trochlear flange. PMID- 27235328 TI - The Diagnosis of Infection in Metal-on-Metal Hip Arthroplasties. AB - BACKGROUND: Distinction of aseptic from septic hip arthroplasty failure can be challenging. Some studies report an increased incidence of septic failure with metal-on-metal (MoM) hip arthroplasties. The Musculoskeletal Infection Society (MSIS) have formulated criteria to facilitate the diagnosis of periprosthetic joint infection (PJI). In this study, we determined the prevalence and histologic features of septic MoM hip failure. METHODS: Overall, 104 cases of failed MoM hip arthroplasty, classified as septic or aseptic by MSIS microbiological criteria, were analyzed. The overall prevalence of septic failure was determined and the nature of the causative organisms noted. The extent of the neutrophil polymorph (NP) infiltrate in periprosthetic tissue in all cases was analyzed by hematoxylin eosin and chloroacetate esterase staining. RESULTS: The prevalence of septic MoM hip arthroplasty failure was 6.7%. Infective organisms were coagulase-negative Staphylococcus in 4 cases; Staphylococcus aureus, Streptococcus, and Propionibacterium species were isolated in the remaining cases. Chloroacetate esterase staining facilitated identification of NPs. All cases of PJI contained more than 5 NPs per high-power field (HPF) on average. Four cases of aseptic MoM implant failure contained scanty or scattered NPs (less than 5 per HPF on average). CONCLUSION: The prevalence of PJI as a cause of MoM hip arthroplasty failure was relatively high compared to other hip bearing combinations; however, the organisms responsible were similar. Histologically, a minority of aseptic MoM implant failures contained some NPs, but the MSIS criteria for the histologic diagnosis of PJI (>5 NPs/HPF) correctly identified all microbiologically confirmed cases of septic failure. PMID- 27235329 TI - Do Patients' Perceptions of Leg Length Correlate With Standing 2- and 3 Dimensional Radiographic Imaging? AB - BACKGROUND: This study compared 2- and 3-dimensional (2D and 3D) radiographic measurements of anatomical and functional leg length and knee coronal and sagittal alignments and correlated these measurements with patients' leg-length perceptions. METHODS: Patients without symptomatic spinal pathology, previous surgery of the spine, and lower extremities (140 lower extremities) were evaluated on EOS images obtained in standing position. Numerous measurements of each limb were compared to the contralateral limb. All 2D/3D measures were evaluated and compared for repeatability and reproducibility. RESULTS: Mean 2D functional and anatomical lengths were 78.7 cm (64.7-88.4, confidence interval [CI] 95%: 77.4-80) and 78.3 cm (64.9-87.9, CI 95%: 77-79.6), respectively. Mean 3D functional and anatomical lengths were 78.9 cm (65.1-88.7, CI 95%: 77.6-80.2) and 78.9 cm (65.6-88.3, CI 95%: 77.8-80.5), respectively (P < .001). Mean 2D and 3D knee varus/valgus angles were -1.9 degrees (-26.4 to 9.1, CI 95%: -3.5 to 0.7) and -0.9 degrees (-19.2 to 11.8, CI 95%: -2.4 to 0.2), respectively (P = .004). Multiple regression analysis found that patients with >10 degrees of flexum/recurvatum were 2.1* more likely to perceive unequal length (P < .1). Patients with irreducible varus/valgus knee deformity were 4* more likely to perceive unequal length (P < .04). CONCLUSION: EOS imaging allows more accurate assessment of anatomical and functional lengths. Patients' perceptions of lower extremity length may correlate more closely with coronal and sagittal alignments of the knee than with femoral or tibial length. This study highlights the importance of physical examination of all the joints and 3D measurements in functional standing position. PMID- 27235330 TI - The Use of a Supra-Acetabular Antibiotic-Loaded Cement Shelf to Improve Hip Stability in First-Stage Infected Total Hip Arthroplasty. AB - BACKGROUND: Antibiotic-loaded cement spacers in first-stage revision total hip arthroplasty (THA) for managing infection are associated with high dislocation and fracture rates. The aim of this study was to report the use of an antibiotic loaded cemented supra-acetabular roof augmentation to reinforce hip stability after cement spacer insertion for first-stage total hip revision in the treatment of infected THA. METHODS: We retrospectively reviewed a consecutive series of 50 THAs involving 47 patients with an infected hip requiring staged revisions of THA. We documented dislocation, reinfection, and time for revision and outcome. RESULTS: There were no cases of hip dislocation, cement fractures, or any other technical complications associated with the use of the roof augmentation lip. Thirteen cases (26%) had a cemented spacer for longer than 120 days. Seven (14%) cases had recurrent infection after staged revision THA. CONCLUSION: The antibiotic-loaded cemented supra-acetabular roof augment improved femoral head spacer coverage for patients requiring a staged revision THA for infection. PMID- 27235331 TI - The problem of estimating recent genetic connectivity in a changing world. AB - Accurate understanding of population connectivity is important to conservation because dispersal can play an important role in population dynamics, microevolution, and assessments of extirpation risk and population rescue. Genetic methods are increasingly used to infer population connectivity because advances in technology have made them more advantageous (e.g., cost effective) relative to ecological methods. Given the reductions in wildlife population connectivity since the Industrial Revolution and more recent drastic reductions from habitat loss, it is important to know the accuracy of and biases in genetic connectivity estimators when connectivity has declined recently. Using simulated data, we investigated the accuracy and bias of 2 common estimators of migration (movement of individuals among populations) rate. We focused on the timing of the connectivity change and the magnitude of that change on the estimates of migration by using a coalescent-based method (Migrate-n) and a disequilibrium based method (BayesAss). Contrary to expectations, when historically high connectivity had declined recently: (i) both methods over-estimated recent migration rates; (ii) the coalescent-based method (Migrate-n) provided better estimates of recent migration rate than the disequilibrium-based method (BayesAss); (iii) the coalescent-based method did not accurately reflect long term genetic connectivity. Overall, our results highlight the problems with comparing coalescent and disequilibrium estimates to make inferences about the effects of recent landscape change on genetic connectivity among populations. We found that contrasting these 2 estimates to make inferences about genetic connectivity changes over time could lead to inaccurate conclusions. PMID- 27235332 TI - Biphasic effects of l-ascorbate on the tumoricidal activity of non-thermal plasma against malignant mesothelioma cells. AB - Non-thermal plasma (NTP) is a recently developed technology that elicits a variety of biological effects. This includes cancer cell-specific cytotoxicity, which is mainly attributed to the regional generation of reactive oxygen species (ROS). We studied the effects of NTP on malignant mesothelioma (MM) and its modulation by l-ascorbate. l-ascorbate is a major water-soluble anti-oxidant in vivo, but its pro-oxidant activity in vitro has been well recognized. Thus, the effects of ascorbate on the efficacy of NTP is important to examine. NTP exposure dose-dependently killed MM cells, whereas MM cells tolerated 1 mM l-ascorbate. However, brief pre-treatment with a pharmacological dose (250-750 MUM) of l ascorbate immediately prior to NTP exposure significantly increased its cytotoxicity in a dose-dependent manner, which was inhibited by the iron chelator, deferoxamine. However, paradoxically, this potentiating effect of l ascorbate was completely abolished by a prolonged 4 h pre-incubation with l ascorbate (500 MUM). MM cytotoxicity induced by NTP was associated with immediate oxidative stress evaluated by 2',7'-dichlorodihydrofluorecein diacetate, which was followed by an increase in the expression of the autophagosome marker, LC3B II. In conclusion, MM can be a target for NTP treatment and l-ascorbate can increase or decrease its efficacy depending on the length of the pre-incubation period. PMID- 27235333 TI - Sex determination in the wild: a field application of loop-mediated isothermal amplification successfully determines sex across three raptor species. AB - PCR-based methods are the most common technique for sex determination of birds. Although these methods are fast, easy and accurate, they still require special facilities that preclude their application outdoors. Consequently, there is a time lag between sampling and obtaining results that impedes researchers to take decisions in situ and in real time considering individuals' sex. We present an outdoor technique for sex determination of birds based on the amplification of the duplicated sex-chromosome-specific gene Chromo-Helicase-DNA binding protein using a loop-mediated isothermal amplification (LAMP). We tested our method on Griffon Vulture (Gyps fulvus), Egyptian Vulture (Neophron percnopterus) and Black Kite (Milvus migrans) (family Accipitridae). We introduce the first fieldwork procedure for sex determination of animals in the wild, successfully applied to raptor species of three different subfamilies using the same specific LAMP primers. This molecular technique can be deployed directly in sampling areas because it only needs a voltage inverter to adapt a thermo-block to a car lighter and results can be obtained by the unaided eye based on colour change within the reaction tubes. Primers and reagents are prepared in advance to facilitate their storage at room temperature. We provide detailed guidelines how to implement this procedure, which is simpler (no electrophoresis required), cheaper and faster (results in c. 90 min) than PCR-based laboratory methods. Our successful cross species application across three different raptor subfamilies posits our set of markers as a promising tool for molecular sexing of other raptor families and our field protocol extensible to all bird species. PMID- 27235334 TI - Skin autofluorescence and peripheral neuropathy four years later in type 1 diabetes. AB - OBJECTIVE: Advanced glycation end products (AGEs) are involved in diabetes complications. We aimed to investigate whether the accumulation of AGEs measured by skin autofluorescence (sAF) was associated with signs of diabetic peripheral neuropathy and to sensitivity, pain, motor and autonomic function 4 years later in patients with type 1 diabetes. METHODS: At baseline, 188 patients (age 51 years, diabetes duration 22 years) underwent skin autofluorescence measurement using the AGE Reader. Four years later, signs of diabetic peripheral neuropathy were defined as the presence of neuropathic pain and/or feet sensory loss or foot ulceration. Neurological tests were systematically performed: vibration perception threshold by neuroesthesiometry, neuropathic pain by the Douleur Neuropathique en 4 Questions score, muscle strength by dynamometry and electrochemical skin conductance. Multivariate analyses were adjusted by age, sex, height, body mass index, tobacco, HbA1c , diabetes duration, estimated glomerular filtration rate and albumin excretion rate. RESULTS: At the 4-year follow-up, 13.8% of patients had signs of diabetic peripheral neuropathy. The baseline sAF was higher in those with signs of diabetic peripheral neuropathy (2.5 +/- 0.7 vs 2.1 +/- 0.5 arbitrary units (AU), p < 0.0005). In the multivariate analysis, a 1 SD higher skin autofluorescence at baseline was associated with an increased risk of signs of neuropathy (OR = 2.68, p = 0.01). All of the neurological tests were significantly altered in the highest quartile of the baseline sAF (>2.4 AU) compared with the lowest quartiles after multivariate adjustment. CONCLUSION: This non-invasive measurement of skin autofluorescence may have a value for diabetic peripheral neuropathy in type 1 diabetes and a potential clinical utility for detection of diabetic peripheral neuropathy. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27235335 TI - Immunization against HTLV-I with chitosan and tri-methylchitosan nanoparticles loaded with recombinant env23 and env13 antigens of envelope protein gp46. AB - To prevent the spread of HTLV-I (Human T-lymphotropic virus type 1), a safe and effective vaccine is required. To increase immune responses against the peptide antigens can be potentiated with polymer-based nanoparticles, like chitosan (CHT) and trimethylchitosan (TMC), as delivery system/adjuvant. CHT and TMC nanoparticles loaded with recombinant proteins (env23 & env13) of gp46 were prepared by direct coating of antigens with positively charged polymers. The size of CHT and TMC nanoparticles (NPs) loaded with each antigen was about 400 nm. The physical stability of NPs was followed for 4 weeks. Both formulations showed to be stable for about 15 days. The immunogenicity of NPs loaded with antigens was studied after nasal and subcutaneous immunization in mice. Three immunizations (7.5 MUg antigen) were performed with 2 weeks intervals. Two weeks after the last booster dose, sera IgG subtypes were measured. After subcutaneous administration, for both nanoparticulate antigens, serum IgG1 and IgGtotal levels were higher than antigen solution (P < 0.001). After nasal administration, for env23, IgG2a levels and IgG2a/IgG1 ratio was significantly higher than groups with subcutaneous administration (P < 0.001). Both nanoparticles showed good immunoadjuvant potential. Env23 antigen was a better candidate for vaccination against HTLV-I, as it induced higher cellular immune responses, compared with env13. PMID- 27235336 TI - Survival of high-risk pediatric neuroblastoma patients in a developing country. AB - Little information is available about survival of high-risk pediatric neuroblastoma patients in developing countries. We aimed to assess survival among high-risk pediatric neuroblastoma patients in La Plata, Argentina. Individuals eligible for our cohort were aged <20 yr when diagnosed with high-risk neuroblastoma and received cancer-directed therapy including stem cell transplantation at Hospital de Ninos Sor Maria Ludovica between February 1999 and February 2015. We estimated overall survival probabilities using an extended Kaplan-Meier approach. Our study population comprised 39 high-risk neuroblastoma patients, of whom 39% were aged >4 yr at diagnosis, 54% were male, and 62% had adrenal neuroblastoma. We observed 18 deaths, and the median survival time of our study population was 1.7 yr. The five-yr overall survival probability was 24% (95% CL: 10%, 41%). In contrast, five-yr survival of high-risk neuroblastoma patients ranges between 23% and 76% in developed countries. Survival among high risk neuroblastoma patients is generally poor regardless of geographic location, but our results illustrate dramatically worse survival for patients in a developing country. We speculate that the observed survival differences could be attenuated or eliminated with improvements in treatment and supportive care, but addressing these issues will require creative solutions because of resource limitations. PMID- 27235337 TI - Driving time modulates accommodative response and intraocular pressure. AB - Driving is a task mainly reliant on the visual system. Most of the time, while driving, our eyes are constantly focusing and refocusing between the road and the dashboard or near and far traffic. Thus, prolonged driving time should produce visual fatigue. Here, for the first time, we investigated the effects of driving time, a common inducer of driver fatigue, on two ocular parameters: the accommodative response (AR) and the intraocular pressure (IOP). A pre/post-test design has been used to assess the impact of driving time on both indices. Twelve participants (out of 17 recruited) completed the study (5 women, 24.42+/ 2.84years old). The participants were healthy and active drivers with no visual impairment or pathology. They drove for 2h in a virtual driving environment. We assessed AR and IOP before and after the driving session, and also collected subjective measures of arousal and fatigue. We found that IOP and AR decreased (i.e., the accommodative lag increased) after the driving session (p=0.03 and p<0.001, respectively). Moreover, the nearest distances tested (20cm, 25cm, and 33cm) induced the highest decreases in AR (corrected p-values<0.05). Consistent with these findings, the subjective levels of arousal decreased and levels of fatigue increased after the driving session (all p-values<0.001). These results represent an innovative step towards an objective, valid, and reliable assessment of fatigue-impaired driving based on visual fatigue signs. PMID- 27235338 TI - Altered diurnal pattern of steroid hormones in relation to various behaviors, external factors and pathologies: A review. AB - The adrenal and gonadal stress steroids [i.e., cortisol, testosterone and dehydroepiandrosterone (DHEA)] have gathered considerable attention in the last few decades due to their very broad physiological and psychological actions. Their diurnal patterns have become a particular focus following new data implicating altered diurnal hormone patterns in various endocrine, behavioral and cardiovascular risk profiles. In this review of the current literature, we present a brief overview of the altered diurnal patterns of these hormones that may occur in relation to chronic stress, nutritional behaviors, physical exercise, drugs and sleep deprivation/shift. We also present data on the altered diurnal hormone patterns implicated in cardiometabolic and psychiatric/neurologic diseases, cancer and other complex pathologies. We consider the occasionally discrepant results of the studies, and summarize the current knowledge in this new field of interest, underlining the potential effects on both biological and psychological functioning, and assess the implications of these effects. Last, we conclude with some practical considerations and perspectives. PMID- 27235339 TI - Paired-housing selectively facilitates within-session extinction of avoidance behavior, and increases c-Fos expression in the medial prefrontal cortex, in anxiety vulnerable Wistar-Kyoto rats. AB - OBJECTIVE: The perseveration of avoidance behavior, even in the absence of once threatening stimuli, is a key feature of anxiety and related psychiatric conditions. This phenomenon can be observed in the Wistar-Kyoto (WKY) rat which, in comparison to outbred controls, demonstrates impaired extinction of avoidance behavior. Also characteristic of the WKY rat is abnormalities of the neurocircuitry and neuroplasticity of the medial prefrontal cortex (mPFC). One means of reducing physiological responses to anxiety, and conditioned fear, in social species is the presence of a conspecific animal. The current study investigates whether or not pair-housed WKY rats would show facilitated extinction of avoidance in comparison to individual-housed WKY rats, and whether or not pair-housing influences mPFC activation during lever-press avoidance. METHODS: Male WKY rats were assigned to individual-housed and pair-housed conditions. Rats were trained in lever-press avoidance. Each session of lever press avoidance consisted of 20 trials, where pressing a lever in response to a warning tone prevented foot-shocks. Rats received 12 acquisition sessions over 4weeks; followed by 6 extinction sessions over 2weeks, where foot-shocks ceased to be delivered. Brains were harvested 90min after trials 1 and 10 of extinction sessions 1 and 6, and mPFC sections underwent c-Fos staining as a measure of activation. RESULTS: Pair-housed rats showed facilitated lever-press avoidance extinction rates, but the main cause for this overall difference was a selective facilitation of within-session extinction. Similar to individual-housed rats, pair-housed rats continued to avoid during trial 1 of extinction even when the avoidance responding had been significantly reduced by the end of the previous session. Pair-housed rats sacrificed on trial 1 showed greater c-Fos expression in the anterior cingulate cortex and prelimbic cortex subregions of the mPFC compared individual-housed rats sacrificed on trial 1. CONCLUSION: This data shows pair-housing to facilitate the extinction of avoidance, and to influence activity of the mPFC, in WKY rats. Despite this environmental manipulation, the pair-housed WKY rats continued to show avoidance responding on trial 1 of extinction sessions. This demonstrates that within-session extinction can be dissociated from between-session extinction-resistance in WKY rats. Furthermore, it suggests the individual-housing of WKY rats selectively slows within-session extinction, possibly by reducing neuronal activity of the mPFC during the testing situation. PMID- 27235340 TI - Ultrasound: Which role in body composition? AB - Ultrasound is a non-invasive, fast, relatively inexpensive and available tool for estimating adiposity in clinical practice, and in several research settings. It does not expose patients to ionizing radiation risks, making the method ideal for the evaluation, and for follow-up studies. Several parameters and indexes based on adipose tissue thickness have been introduced and tested, and these have been correlated with clinical and laboratoristic parameters. Moreover, ultrasound can also be directed to the estimation of adipose tissue and intracellular fat indirectly, at cellular-molecular level: an opportunity for many radiologists who already and sometimes unconsciously perform "body composition" assessment when looking at the liver, at muscle as well as at other organs. However, standardized procedure and parameters are needing to improve accuracy and reproducibility. The purposes of this review are: 1) to provide a complete overview of the most used and shared measurements of adiposity; 2) to analyze technical conditions, accuracy, and clinical meaning of ultrasound in the study of body composition; 3) to provide some elements for the use of ultrasound in the evaluation of intra cellular lipids accumulation, in two hot spots: liver and skeletal muscle. PMID- 27235341 TI - Autoimmune encephalitis mimicking sporadic Creutzfeldt-Jakob disease: A retrospective study. AB - Autoimmune encephalitis associated with anti-voltage-gated potassium channel antibodies are most likely to be misdiagnosed as sporadic Creutzfeldt-Jakob disease (sCJD). Our goal was to delineate patients who were initially suspected to have CJD but were later found to have AE. We performed a retrospective clinical review of cases of individuals and made a comparison between groups of patients diagnosed with sCJD and AE. Patients who had rapidly progressing dementia and focal neurological impairment, such as aphasia, gait disturbance, visual disturbance, and depression, at onset were diagnosed with sCJD, whereas epilepsy, hyponatremia and dysautonomia were strong hints for AE. Fluoroscope positron emission tomography (PET) of patients with AE revealed variable metabolism and normative and long-term immunosuppression were less likely to relapse. PMID- 27235342 TI - Antibodies to myelin basic protein are associated with cognitive decline after stroke. AB - B lymphocytes cause post-stroke cognitive decline in mice. We therefore evaluated the association between autoantibodies and post-stroke cognitive decline in a prospectively collected human cohort. The mini-mental state exam (MMSE) was administered 30, 90, 180, and 365days after stroke. Antibody titers to myelin basic protein (MBP), proteolipid protein, and several non-specific proteins were determined. Among 58 subjects with initial MMSE>=20 and at least 2 MMSE examinations in the year after stroke, cognitive decline (MMSE decrease >=2) occurred in 10 (17%) subjects. In multivariate analysis, MBP antibody titers were the only independent predictor of cognitive decline (OR=9.02 [1.18, 68.90]; P=0.03). PMID- 27235343 TI - TLR4 induces CCR7-dependent monocytes transmigration through the blood-brain barrier. AB - In this study, we examined whether bacterial pathogen-associated molecular patterns recognized by toll-like receptors (TLRs) can modify the CCR7-dependent migration of human monocytes. MonoMac-1 (MM-1) cells and freshly isolated human monocytes were cultivated in the presence of agonists for TLR4 (which senses lipopolysaccharides from gram-negative bacteria), TLR1/2 (which senses peptidoglycan from gram-positive bacteria), and TLR9 (which recognizes bacterial DNA rich in unmethylated CpG DNA). CCR7 mRNA transcription was measured using quantitative reverse transcription polymerase chain reaction and protein expression was examined using flow cytometry. CCR7 function was monitored using migration and transmigration assays in response to CCL19/CCL21, which are natural ligands for CCR7. Our results show that TLR4 strongly increases monocyte migratory capacity in response to CCL19 in chemotaxis and transmigration assays in a model that mimics the human blood-brain barrier, whereas TLR1/2 and 9 have no effect. Examination of monocyte migration in response to TLRs that are activated by bacterial components would contribute to understanding the excessive monocyte migration that characterizes the pathogenesis of bacterial infections and/or neuroinflammatory diseases. PMID- 27235344 TI - Screening for anti-titin antibodies in patients with various paraneoplastic neurological syndromes. AB - Anti-titin antibodies indicate a paraneoplastic etiology pointing towards a thymoma in myasthenia gravis (MG), but their seroprevalence and potential diagnostic value in patients with other paraneoplastic neurological syndromes (PNS) is unknown. Therefore, we screened the sera of 44 PNS patients with well characterized onconeural antibodies (anti-Hu, Yo, Ri, CV2/CRMP5, Ma1, Ma2/Ta, or amphiphysin) for anti-titin reactivity. Two patients (4.5%) were positive for anti-titin antibodies: both patients differed regarding the PNS (sensorimotor neuropathy and subacute cerebellar degeneration vs. chorea), well-characterized onconeural antibodies (CV2/CRMP5 vs. Ri), and malignoma (small cell lung cancer vs. breast cancer). However, retrospectively, the patients neither showed any symptoms of MG nor a thymoma on a computed tomographic (CT) scan. The results of this study indicate that anti-titin antibodies without a predictive relevance for MG or thymoma may be present in a small proportion of patients with PNS. PMID- 27235345 TI - Inflammatory signals induce the expression of tonicity-responsive enhancer binding protein (TonEBP) in microglia. AB - Tonicity-responsive enhancer (TonE) binding protein (TonEBP) is known as an osmosensitive transcription factor that regulates cellular homeostasis during states of hypo- and hypertonic stress. In addition to its role in osmoadaptation, growing lines of evidence suggest that TonEBP might have tonicity-independent functions. In particular, a number of studies suggest that inflammatory stimuli induce the expression and activation of TonEBP in peripheral immune cells. However, whether TonEBP is expressed in microglia, resident immune cells of the central nervous system, is unknown. Here we show that inflammatory signals induce the expression of TonEBP in microglia both in vitro and in vitro. In cultured primary microglia, treatment with lipopolysaccharide (LPS), interferon-gamma, and interleukin 4 increased the expression of TonEBP. Moreover, we found that stereotaxic injection of LPS into the substantia nigra region of rat brain increased TonEBP expression in OX-42-positive cells. Furthermore, expression of TonEBP was induced in OX-42-positive cells in a rat model of transient middle cerebral artery occlusion. Together these results show that the expression of TonEBP is regulated by inflammatory signals in mammalian brain, suggesting that TonEBP might play a part during neuroinflammation. PMID- 27235347 TI - Quantitative profiling of neurotransmitter abnormalities in the hippocampus of rats treated with lipopolysaccharide: Focusing on kynurenine pathway and implications for depression. AB - Peripheral administration of lipopolysaccharide (LPS) can induce the rodents to a depression-like state accompanied with remarkable changes of neurotransmitter systems. In this study, the effect of an intraperitoneal LPS injection (3mg/kg) on the concentrations of neurotransmitters was investigated by in vivo microdialysis in rat hippocampus. To further explore dysregulation pattern of the neurotransmitters following continuous inflammatory process, we then analyzed the neurotransmitters in the hippocampus of rats after 2-week LPS exposure (500MUg/kg every other day). Acute treatment of LPS quickly enhanced glutamate release and increased the extracellular levels of dopamine, serotonin and their metabolites. Elevated glutamate status was also found in the chronic inflamed hippocampus, whereas dopamine and serotonin was decreased following prolonged LPS exposure. Interestingly, both acute and chronic treatment of LPS significantly elevated hippocampal kynurenine concentrations and altered the balance between the serotonin and kynurenine branches of tryptophan metabolism-increasing kynurenine/tryptophan ratio, but decreasing serotonin/tryptophan ratio. Additionally, kynurenic acid, the endogenous NMDA receptor antagonist, and the ratio of kynurenic acid/kynurenine were significantly decreased by acute treatment of LPS, which may further strengthen NMDA receptor activation. Since that NMDA activation can exacerbate inflammatory and neurodegenerative process, the enhanced glutamate release and dysregulated kynurenine pathway might constitute a vicious cycle playing a pivotal role in the neuropsychiatric disorders associated with inflammation, such as depression. PMID- 27235346 TI - Effect of chronic morphine administration on circulating dendritic cells in SIV infected rhesus macaques. AB - We studied the effect of chronic morphine administration on the circulating dendritic cell population dynamics associated with SIV infection using rhesus macaques. Animals were either first infected with SIV and then given chronic morphine, or visa versa. SIV infection increased the numbers of myeloid DCs (mDCs), but morphine treatment attenuated this mDC expansion. In contrast, morphine increased the numbers of plasmacytoid DCs (pDCs) in SIV-infected animals. Finally, chronic morphine administration (no SIV) transiently increased the numbers of circulating pDCs. These results show that chronic morphine induces a significant alteration in the available circulating levels of critical antigen presenting cells. PMID- 27235348 TI - Anti-inflammatory role of sesamin in STZ induced mice model of diabetic retinopathy. AB - Diabetic retinopathy (DR) is the common cause of diabetic vascular complications that leads to the blindness in the working age population throughout the world. Free radicals mediated oxidative stress and inflammation play a significant role in pathophysiology of DR. To find a new and safe drug to treat DR is still challenging and for that purpose the natural compounds may be therapeutic agents. Here we show that sesamin (SES), which is the main component of sesame seed and its oil, and has been reported as potent antioxidant and neuroprotective, could be a therapeutic agent in DR. In the present study, we investigated protective effect of SES in Streptozotocin (STZ) induced DR in mice. The mice were divided into three groups (Control, DR and DR+SES) for the study. After two weeks post diabetic establishment, mice were treated with SES (30mg/kg BW, i.p, alternate day) for four weeks. Mice body weight and blood glucose level were measured from each group. The microglial activation of retina was determined by immunohistochemistry analysis by using Iba-1 as a microglia marker. Retinal mRNA levels of Iba-1, tumor necrosis factor-alpha (TNF-alpha), inducible nitric oxide synthase (iNOS) and Intercellular Adhesion Molecule 1 (ICAM-1) were examined by qRT-PCR. The level of iNOS protein expression was examined by immunoblotting. Together these data demonstrate that SES treatment lowered the progression of diabetic retinal injury by: 1) decreasing blood glucose level, 2) suppressing microglia activation, 3) reducing retinal TNF-alpha and ICAM-1 levels and 4) quenching iNOS expression. In conclusion, the results suggest that SES treatment may be of therapeutic benefit in reducing the progression of DR by ameliorating hyperglycemia and inflammation in diabetic retina. PMID- 27235349 TI - Ganglionic acetylcholine receptor autoantibodies in patients with Guillain-Barre syndrome. AB - OBJECTIVES: Although standardized autonomic tests are useful for diagnosing autonomic failure in patients with Guillain-Barre syndrome (GBS), they cannot be used as predictive markers. Thus, serological markers may correctly identify patients with GBS who are at risk for autonomic dysfunction. METHODS: We validated a luciferase immunoprecipitation system that detects IgG antibodies in patient serum that specifically bind to the alpha3 or beta4 subunits of ganglionic neuronal nicotinic acetylcholine receptors (gAChR). We then used luciferase-conjugated ligands specific to antibodies against two gAChR subunits to test 79 sera samples from patients with GBS, 34 from subjects with other neurological diseases (OND), and 73 from healthy controls (HC). 1) In the first analysis, patients were classified into two groups according to the presence or absence of autonomic symptoms (AS). We compared the frequency of the anti-gAChR antibodies between these two groups (AS+ and AS-). 2) In the second analysis, furthermore, patients were classified depending on the presence or absence of anti-glycolipid antibodies (AGA). We compared the frequency of the anti-gAChR antibodies between the four categories of GBS (AS+/AGA+, AS+/AGA-, AS-/AGA+, and AS-/AGA-), OND, and HC. RESULTS: Eight subjects with GBS were positive for alpha3 subunits, while one was positive for beta4 subunits. Anti-alpha3 and -beta4 gAChR antibodies were also detected in 13.6% of AS+ GBS group in the first analysis. Two of 35 patients in AS-GBS group were seropositive for the anti-gAChR antibodies and AGA in the second analysis. Patients with GBS that were positive for serum antibodies to the alpha3 and/or beta4 subunits of gAChRs showed a range of clinical features including AS and AGA. CONCLUSIONS: Patients with GBS may have circulating antibodies against gAChR, which may contribute to the autonomic dysfunction associated with this disease. PMID- 27235350 TI - T cell-derived interleukin-10 is an important regulator of the Th17 response during lethal alphavirus encephalomyelitis. AB - Neuroadapted Sindbis virus infection of mice causes T cell-mediated fatal encephalomyelitis. In the absence of IL-10, pathogenic Th17 cells are increased and disease is accelerated. Lymphoid and myeloid cell contributions to IL-10 production were determined using VertX IL-10 transcriptional eGFP reporter mice. Effector and regulatory CD4(+) and CD8(+) T cells in the brain, but not the cervical lymph nodes, were the primary producers of IL-10. Th17 and Th1/Th17 cells were increased in mice that lacked T cell IL-10 production, although less than in the absence of IL-10. Morbidity and mortality were not affected suggesting an IL-10 threshold for disease exacerbation. PMID- 27235352 TI - Vitamin D level status in Thai neuromyelitis optica patients. AB - Vitamin D status of Thai clinically isolated syndrome (CIS), multiple sclerosis (MS) and NMO/neuromyelitis optica spectrum disorders (NMOSD) patients were prospectively collected (N=130). Its associations with disability score, and disease activity were sought. Mean vitamin D levels were not significantly different (CIS, 22.18+/-8.2; MS, 23.41+/-11.9; NMO/NMOSD, 23.54+/-9.3ng/mL; p=0.857). Prevalence of vitamin D insufficiency and deficiency (<=30ng/mL) was 73 80%. Neither disability score nor disease activity was associated with vitamin D level. Vitamin D insufficiency was common in Thai CIS, MS, and NMO/NMOSD patients without association with disability or disease activity. PMID- 27235351 TI - The contribution of antibiotics, pneumonia and the immune response to stroke outcome. AB - BACKGROUND: Infections are common following stroke and associated with worse outcome. Using an animal model of pneumonia, we assessed the effect of infection and its treatment on the immune response and stroke outcome. METHODS: Lewis rats were subjected to transient cerebral ischemia and survived for 4weeks. One day after stroke animals were exposed to aerosolized Staphylococcus aureus, Pseudomonas aeruginosa or saline. Antibiotics (ceftiofur or enrofloxacin) were started immediately after exposure or delayed for 3days. Behavioral tests were performed weekly. ELISPOT assays were done on lymphocytes from spleen and brain to assess autoimmune responses to myelin basic protein (MBP). RESULTS: Among animals that received immediate antibiotic therapy, infection was associated with worse outcome in ceftiofur but not enrofloxacin treated animals. (The outcome with immediate enrofloxacin therapy was so impaired that further worsening may have been difficult to detect.) A delay in antibiotic therapy was associated with better outcomes in both ceftiofur and enrofloxacin treated animals. Infection was associated with an increased likelihood of developing Th1(+) responses to MBP in non-infarcted brain (OR=2.94 [1.07, 8.12]; P=0.04), and Th1(+) responses to MBP in spleen and non-infarcted brain were independently associated with a decreased likelihood of stroke recovery (OR=0.16 [0.05, 0.51; P=0.002 and OR=0.32 [0.12, 0.84]; P=0.02, respectively). CONCLUSIONS: Infection worsens stroke outcome in ceftiofur treated animals and increases Th1 responses to MBP. These data may help explain how infection worsens stroke outcome and suggest that treatment of infection may contribute to this outcome. PMID- 27235353 TI - Enteric glial cells have specific immunosuppressive properties. AB - Enteric glial cells (EGC) have trophic and neuroregulatory functions in the enteric nervous system, but whether they exert a direct effect on immune cells is unknown. Here, we used co-cultures to show that human EGC can inhibit the proliferation of activated T lymphocytes. Interestingly, EGC from Crohn's patients were effective at one EGC for two T cells whereas EGC from control patients required a ratio of 1:1. These data suggest that EGC contribute to local immune homeostasis in the gastrointestinal wall. They also raise the possibility that EGC have particular immunosuppressive properties in inflammatory bowel diseases such as Crohn's disease. PMID- 27235355 TI - Schwann cell differentiation inhibits interferon-gamma induction of expression of major histocompatibility complex class II and intercellular adhesion molecule-1. AB - Interferon-gamma (IFN-gamma) upregulates major histocompatibility complex class II (MHC class II) antigens and intercellular adhesion molecule-1 (ICAM-1) on Schwann cells (SC) in vitro, but in nerves of animals and patients MHC class II is primarily expressed on inflammatory cells. We investigated whether SC maturation influences their expression. IFN-gamma induced MHC class II and upregulated ICAM-1; the axolemma-like signal 8-bromo cyclic adenosine monophosphate (8 Br cAMP) with IFN-gamma inhibited expression. Delaying addition of 8 Br cAMP to SC already exposed to IFN-gamma inhibited ongoing expression; addition of IFN-gamma to SC already exposed to 8 Br cAMP resulted in minimal expression. Variability of cytokine-induced MHC class II and ICAM-1 expression by SC in vivo may represent the variability of signals from axolemma. PMID- 27235354 TI - MuSK induced experimental autoimmune myasthenia gravis does not require IgG1 antibody to MuSK. AB - Sera of myasthenia gravis (MG) patients with muscle-specific receptor kinase antibody (MuSK-Ab) predominantly display the non-complement fixing IgG4 isotype. Similarly, mouse IgG1, which is the analog of human IgG4, is the predominant isotype in mice with experimental autoimmune myasthenia gravis (EAMG) induced by MuSK immunization. The present study was performed to determine whether IgG1 anti MuSK antibody is required for immunized mice to develop EAMG. Results demonstrated a significant correlation between clinical severity of EAMG and levels of MuSK-binding IgG1+, IgG2+ and IgG3+ peripheral blood B cells in MuSK immunized wild-type (WT) mice. Moreover, MuSK-immunized IgG1 knockout (KO) and WT mice showed similar EAMG severity, serum MuSK-Ab levels, muscle acetylcholine receptor concentrations, neuromuscular junction immunoglobulin and complement deposit ratios. IgG1 and IgG3 were the predominant anti-MuSK isotypes in WT and IgG1 KO mice, respectively. These observations demonstrate that non-IgG1 isotypes can mediate MuSK-EAMG pathogenesis. PMID- 27235356 TI - Bioinformatics evaluation of the possibility of heat shock proteins as autoantigens in multiple sclerosis based on molecular mimicry hypothesis. AB - Molecular mimicry is the explanatory link between the heat shock proteins (HSPs) of infectious agents and triggering multiple sclerosis. Considering that there are many similarities between self- and bacterial-HSPs, the goal was to investigate a panel of 60- and 70kDa HSPs from a variety of bacteria in order to predict the role of each microorganism in triggering or progression of the disease under the molecular mimicry hypothesis. By clarifying the peptides meeting criteria for cross-reactivity and elucidating the role of each microorganism in MS pathogenesis, it would be easier to suggest more effective treatment and preventive strategies for this disease. PMID- 27235357 TI - Immune markers in the RASopathy neurofibromatosis type 1. AB - Neurofibromatosis type 1 (NF1) is a genetic disorder with an early mortality determined mostly by malignancy. Little is known about the immunosurveillance factors in NF1 patients. In this study we evaluated inflammatory markers and their cellular sources in NF1 patients to try understanding the relation of immune factors and the tumorigenesis that characterizes the disease. Using flow cytometry and ELISA, we assayed cytokines, co-stimulatory molecules, the functional state of circulating blood cells and cytokine plasma levels in a case control transversal study. The frequency of CD4+ T cells seems reduced. In addition, a shift towards an anti-inflammatory profile was observed in cells expressing cytokines, except for a small subpopulation of CD8+ T cells that displayed an increased frequency of cells expressing the pro-inflammatory cytokine Tumor necrosis factor (TNF-alpha), while plasma soluble levels of Transforming growth factor-beta (TGF-beta) and interleukin-6 (IL-6) were increased in NF1 patients. Knowledge of the regulation of NF1 and the role of TGF beta signaling pathway in malignant peripheral nerve sheath tumor pathogenesis might shed light on molecular carcinogenesis mechanisms and lead to putative interventions both in prevention and treatment of malignant tumors. PMID- 27235359 TI - Proteinase-activated receptor 2 is involved in the behavioural changes associated with sickness behaviour. AB - Proteinase-activated receptor-2 (PAR2) is widely expressed in the CNS but whether it plays a key role in inflammation-related behavioural changes remains unknown. Hence, in the present study we have examined whether PAR2 contributes to behaviour associated with systemic inflammation using PAR2 transgenic mice. The onset of sickness behaviour was delayed and the recovery accelerated in PAR2(-/-) mice in the LPS-induced model of sickness behaviour. In contrast, PAR2 does not contribute to behaviour under normal conditions. In conclusion, these data suggest that PAR2 does not contribute to behaviour in the normal healthy brain but it plays a role in inflammation-related behavioural changes. PMID- 27235358 TI - Acute and prolonged complement activation in the central nervous system during herpes simplex encephalitis. AB - Herpes simplex encephalitis (HSE) is characterized by a pronounced inflammatory activity in the central nervous system (CNS). Here, we investigated the acute and prolonged complement system activity in HSE patients, by using enzyme-linked immunosorbent assays (ELISAs) for numerous complement components (C). We found increased cerebrospinal fluid concentrations of C3a, C3b, C5 and C5a in HSE patients compared with healthy controls. C3a and C5a concentrations remained increased also compared with patient controls. Our results conclude that the complement system is activated in CNS during HSE in the acute phase, and interestingly also in later stages supporting previous reports of prolonged inflammation. PMID- 27235360 TI - MicroRNAs associated with the pathogenesis of multiple sclerosis. AB - Multiple sclerosis (MS) is not only an autoimmune disease in which autoreactive immune cells against myelin damage axons and nerves in the central nervous system, but also a neurodegenerative disease, in which progressive loss of structure and function of neurons occurs. The mechanisms of MS pathogenesis have not been fully understood. It has been reported that miRNAs may play a critical role in MS pathogenesis. In this review, we have extensively discussed the alterations in the expression of miRNAs detected in patients with MS. The dysregulated miRNAs have been shown to be associated with the pathogenesis of MS. We suggest that such dysregulated miRNAs may potentially be used as biomarkers in the diagnosis of MS, to discover new therapeutic targets for MS treatment, and to predict prognostic markers in responses to MS treatment. PMID- 27235361 TI - Corrigendum to "Characterization of MCAM contribution to neuroinflammation using a new murine knockout model" [J. Neuroimmunol., 275 (1-2) (2014) 143]. PMID- 27235362 TI - Corrigendum to "Expression of DNA methylation genes in secondary progressive multiple sclerosis" [J. Neuroimmunol. 290 (2016 Jan. 15) 66-9]. PMID- 27235363 TI - Corrigendum to "An investigation into the association between HLA-G 14bp insertion/deletion polymorphism and multiple sclerosis susceptibility" [Journal of Neuroimmunology 290 (2016) 115-118]. PMID- 27235364 TI - Genome-based study of a spatio-temporal cluster of invasive meningococcal disease due to Neisseria meningitidis serogroup C, clonal complex 11. AB - OBJECTIVES: To describe a spatio-temporal cluster of invasive meningococcal disease (IMD) due to serogroup C meningococci, occurred in a restricted area of Tuscany between January and October 2015, and the results of whole genome sequencing (WGS). METHODS: Surveillance activities and public health measures were implemented in the Region. Bacterial isolates from IMD cases were characterized by the National Reference Laboratory of the Istituto Superiore di Sanita (ISS), and WGS was performed on available strains. The kSNP software was used to identify core genome SNPs. RESULTS: Overall, 28 IMD cases due to meningococcus C were identified up to 31st October, 2015. Of them, 26 were due to meningococcus C:P1.5-1,10-8: F3-6:ST-11 (cc11) and 2 to C:P1.5-1,10-8: F3-6:ST 2780 (cc11). WGS of 13 meningococci isolated during the outbreak occurred in Tuscany in 2015 showed higher similarity when compared with those of 47 C: P1.5 1,10-8: F3-6:ST-11 (cc11) invasive strains from sporadic cases previously detected in Italy. CONCLUSIONS: A highly aggressive meningococcal C strain was involved in the cluster of severe IMD occurred in Tuscany, a Region with high vaccine coverage among children. Whether this was due to low herd immunity related to the short duration of vaccine protection needs further investigation. PMID- 27235365 TI - Characterization of immune-related genes in the yellow catfish Pelteobagrus fulvidraco in response to LPS challenge. AB - Fish are considered an excellent model for studies in comparative immunology as they are a representative population of lower vertebrates linked to invertebrate evolution. To gain a better understanding of the immune response in fish, we constructed a subtractive cDNA library from the head kidney of lipopolysaccharide stimulated yellow catfish (Pelteobagrus fulvidraco) using suppression subtractive hybridization (SSH). A total of 300 putative EST clones were identified which contained 95 genes, including 27 immune-related genes, 7 cytoskeleton-related genes, 3 genes involved in the cell cycle and apoptosis, 9 respiration and energy metabolism-related genes, 7 genes related to transport, 24 metabolism-related genes, 10 genes involved in stress responses, seven genes involved in regulation of transcription and translation and 59 unknown genes. Using real-time quantitative reverse transcription PCR, a subset of randomly selected genes involved in the immune response to lipopolysaccharide challenge were investigated to verify the reliability of the SSH data which identified 16 up-regulated genes. The genes identified in this study provide novel insight into the immune response in fish. PMID- 27235366 TI - Stress and immune responses in skin of turbot (Scophthalmus maximus) under different stocking densities. AB - Fish skin and its mucus provide the first line of defense against chemical, physical and biological stressors, but little is known about the role of skin and its mucus in immune response to crowding stress. In the present study, we investigated the stress and immune responses in skin of turbot (Scophthalmus maximus) under different stocking densities. Turbot (average weight 185.4 g) were reared for 120 days under three densities: low density (LD), medium density (MD), and high density (HD). After 120 days, fish were weighed and sampled to obtain blood, mucus and skin tissues which were used for analyses of biochemical parameters and genes expression. The results showed HD treatment significantly suppressed growth and enhanced plasma cortisol and glucose levels (P < 0.05). In mucus, the activities of lysozyme (LZM), alkaline phosphatase (ALP) and esterase in HD treatment were lower than LD and MD treatments (P < 0.05) In skin, HD treatment resulted in up-regulation in malondialdehyde (MDA) formation and heat shock protein 70 (HSP 70) mRNA level, and down-regulation in activity of superoxide dismutase (SOD) and the transcriptions of glutathione-s-transferase (GST), interleukin-1beta (IL-1beta), tumor necrosis factor -alpha (TNF-alpha), insulin-like growth factor- (IGF-) and LZM (P < 0.05). Overall, the data suggested that overly high stocking density was a stressor which caused an immunosuppression in skin of turbot. Moreover, this information would help to understand the skin immunity and their relation with stress and disease in fish. PMID- 27235367 TI - Grouper TRIM13 exerts negative regulation of antiviral immune response against nodavirus. AB - The tripartite motif (TRIM)-containing proteins have attracted particular attention to their multiple functions in different biological processes. TRIM13, a member of the TRIM family, is a RING domain-containing E3 ubiquitin ligase which plays critical roles in diverse cellular processes including cell death, cancer and antiviral immunity. In this study, a TRIM13 homolog from orange spotted grouper, Epinephelus coioides (EcTRIM13) was cloned and characterized. The full-length of EcTRIM13 cDNA encoded a polypeptide of 399 amino acids which shared 81% identity with TRIM13 homolog from large yellow croaker (Larimichthys crocea). Amino acid alignment analysis showed that EcTRIM13 contained conserved RING finger and B-box domain. Expression patterns analysis indicated that EcTRIM13 was abundant in liver, spleen, kidney, intestine and gill. Moreover, the transcript of EcTRIM13 in grouper spleen was differently regulated after injection with Singapore grouper iridovirus (SGIV) or polyinosin-polycytidylic acid (poly I:C). Under fluorescence microscopy, we observed the tubular structure in wild type EcTRIM13 transfected cells, but the RING domain mutant resulted in the fluorescence distribution was changed and the bright punctate fluorescence was evenly situated throughout the cytoplasm, suggesting that the RING domain was essential for its accurate localization. Overexpression of EcTRIM13 in vitro obviously increased the replication of red spotted grouper nervous necrosis virus (RGNNV), and the enhancing effect of EcTRIM13 on virus replication was affected by the RING domain. Furthermore, the ectopic expression of EcTRIM13 not only negatively regulated the interferon promoter activity induced by interferon regulator factor (IRF) 3, IRF7, and melanoma differentiation-associated protein 5 (MDA5), but also decreased the expression of several interferon related factors. In addition, the overexpression of EcTRIM13 also differently regulated the transcription of pro-inflammatory factors. Together, our results firstly demonstrated that fish TRIM13 exerted negative regulation of antiviral response against nodavirus infection. PMID- 27235368 TI - NOD2 in zebrafish functions in antibacterial and also antiviral responses via NF kappaB, and also MDA5, RIG-I and MAVS. AB - NOD2/RIPK2 signalling plays essential role in the modulation of innate and adaptive immunity in mammals. In this study, NOD2 was functionally characterized in zebrafish (Danio rerio), and its interaction with a receptor-interaction protein, RIPK2, and RLRs such as MDA5 and RIG-I, as well as the adaptor, MAVS was revealed in fish innate immunity. The expression of NOD2 and RIPK2 in ZF4 cells has been constitutive and can be induced by the infection of Edwardsiella tarda and SVCV. The NOD2 can sense MDP in PGN from Gram-negative and -positive bacteria. It is further revealed that the NOD2 and RIPK2 can activate NF-kappaB and IFN promoters, inducing significantly antiviral defense against SVCV infection. As observed in the reduced bacterial burden in RIPK2 overexpressed cells, RIPK2 also has a role in inhibiting the bacterial replication. The overexpression of NOD2 in zebrafish embryos resulted in the increase of immune gene expression, especially those encoding PRRs and cytokines involved in antiviral response such as MDA5, RIG-I, and type I IFNs, etc. Luciferase reporter assays and co-immunoprecipitation assays demonstrated that zebrafish NOD2 is associated with MDA5 and RIG-I in signalling pathway. In addition, it is further demonstrated that RIPK2 and MAVS in combination with NOD2 have an enhanced role in NOD2-mediated NF-kappaB and type I IFN activation. It is concluded that teleost fish NOD2 can not only sense MDP for activating innate immunity as reported in mammals, but can also interact with other PRRs to form a network in antiviral innate response. PMID- 27235369 TI - Molecular and functional characterization of a novel CD302 gene from ayu (Plecoglossus altivelis). AB - Recognizing the presence of invading pathogens by pattern recognition receptors (PRRs) is key to mounting an effective innate immune response. Mammalian CD302 is an unconventional C-type lectin like receptor (CTLR) involved in the functional regulation of immune cells. However, the role of CD302 in fish remains unclear. In this study, we characterized a novel CD302 gene from ayu (Plecoglossus altivelis), which was tentatively named PaCD302. The cDNA sequence of PaCD302 is 1893 nucleotides in length, and encodes a polypeptide of 241 amino acids with molecular weight 27.1 kDa and pI 4.69. Sequence comparison and phylogenetic tree analysis showed that PaCD302 is a type I transmembrane CTLR devoid of the known amino acid residues essential for Ca(2+)-dependent sugar binding. PaCD302 mRNA expression was detected in all tissues and cells tested, with the highest level in the liver. Following Vibrio anguillarum infection, PaCD302 mRNA expression was significantly upregulated in all tissues tested. For further functional analysis, we generated a recombinant protein for PaCD302 (rPaCD302) by prokaryotic expression and raised a specific antibody against rPaCD302. Western blot analysis revealed that the native PaCD302 is glycosylated. Refolded rPaCD302 was unable to bind to five monosaccharides (l-fucose, d-galactose, d-glucose, d-mannose and N acetyl glucosamine) or two other polysaccharides (lipopolysaccharide and peptidoglycan). It was able to bind to three Gram-positive and seven Gram negative bacteria, but show no bacterial agglutinating activity. PaCD302 function blocking using anti-PaCD302 IgG resulted in inhibition of phagocytosis and bactericidal activity of ayu monocytes/macrophages (MO/MPhi), suggesting that PaCD302 regulates the function of ayu MO/MPhi. In summary, our study demonstrates that PaCD302 may participate in the immune response of ayu against bacterial infection via modulation of MO/MPhi function. PMID- 27235370 TI - Coagulation profile, gene expression and bioinformatics characterization of coagulation factor X of striped murrel Channa striatus. AB - A transcriptome wide analysis of the constructed cDNA library of snakehead murrel Channa striatus revealed a full length cDNA sequence of coagulation factor X. Sequence analysis of C. striatus coagulation factor X (CsFX) showed that the cDNA contained 1232 base pairs (bp) comprising 1209 bp open reading frame (ORF). The ORF region encodes 424 amino acids with a molecular mass of 59 kDa. The polypeptide contains gamma-carboxyglutamic acid (GLA) rich domain and two epidermal growth factor (EGF) like domains including EGF-CA domain and serine proteases trypsin signature profile. CsFX exhibited the maximum similarity with fish species such as Stegastes partitus (78%), Poecilia formosa (76%) and Cynoglossus semilaevis (74%). Phylogenetically, CsFX is clustered together with the fish group belonging to Actinopterygii. Secondary structure of factor X includes alpha helix 28.54%, extended strand 20.75%, beta turn 7.78% and random coil 42.92%. A predicted 3D model of CsFX revealed a short alpha-helix and a Ca(2+) (Gla domain) binding site in the coil. Four disulfide bridges were found in serine protease trypsin profile. Obviously, the highest gene expression (P < 0.05) was noticed in blood. Further, the changes in expression of CsFX was observed after inducing with bacterial (Aeromonas hydrophila) and fungal (Aphanomyces invadans) infections and other synthetic immune stimulants. Variation in blood clotting time (CT), prothrombin time (PT) and activated prothromboplastin time (APTT) was analyzed and compared between healthy and bacterial infected fishes. During infection, PT and APTT showed a declined clotting time due to the raised level of thrombocytes. PMID- 27235372 TI - Nighttime evaporative demand induces plasticity in leaf and root hydraulic traits. AB - Increasing evidence suggests that nocturnal transpiration rate (TRN ) is a non negligible contributor to global water cycles. Short-term variation in nocturnal vapor pressure deficit (VPDN ) has been suggested to be a key environmental variable influencing TRN . However, the long-term effects of VPDN on plant growth and development remain unknown, despite recent evidence documenting long-term effects of daytime VPD on plant anatomy, growth and productivity. Here we hypothesized that plant anatomical and functional traits influencing leaf and root hydraulics could be influenced by long-term exposure to VPDN . A total of 23 leaf and root traits were examined on four wheat (Triticum aestivum) genotypes, which were subjected to two long-term (30 day long) growth experiments where daytime VPD and daytime/nighttime temperature regimes were kept identical, with variation only stemming from VPDN , imposed at two levels (0.4 and 1.4 kPa). The VPDN treatment did not influence phenology, leaf areas, dry weights, number of tillers or their dry weights, consistently with a drought and temperature independent treatment. In contrast, vein densities, adaxial stomata densities, TRN and cuticular TR, were strongly increased following exposure to high VPDN . Simultaneously, whole-root system xylem sap exudation and seminal root endodermis thickness were decreased, hypothetically indicating a change in root hydraulic properties. Overall these results suggest that plants 'sense' and adapt to variations in VPDN conditions over developmental scales by optimizing both leaf and root hydraulics. PMID- 27235371 TI - Effects of berberine on the growth and immune performance in response to ammonia stress and high-fat dietary in blunt snout bream Megalobrama amblycephala. AB - This study aimed to figure out the effects of berberine on growth performance, immunity, oxidative stress and hepatocyte apoptosis of blunt snout bream (Megalobrama amblycephala) fed with high-fat diet. 320 fish (80.00 +/- 0.90 g) were divided randomly into four trial groups (each with four replicates) and fed with 4 diets (normal diet, normal diet with 50 mg/kg berberine, high-fat diet, high-fat diet with 50 mg/kg berberine), respectively. At the end of the feeding trial, ammonia stress test was carried out for 5 days. The result showed the growth performance, immune parameters including plasm acid phosphatase (ACP) activities, lysozyme (LYZ) activities and alternative complement C3 and C4 contents were suppressed in fish fed with high-fat diets but improved in berberine diets compared with control (normal diet). Hepatopancreas oxidative status, the malondialdehyde (MDA), protein carbonyl (PC) and lipid peroxide (LPO) were increased significantly (P < 0.05) when fish were fed with high-fat diets. Berberine could slow the progression of the oxidative stress induced by high-fat through increasing superoxide dismutase (SOD) activities and total sulfydryl (T SH) levels of fish. And the hepatocyte apoptosis in the high-fat group could also be alleviated by berberine. After the ammonia stress test, the accumulative mortality was extremely (P < 0.05) low in fish fed high-fat diet with berberine compared to other groups. It was concluded berberine as a functional feed additive significantly inhibited the progression of oxidative stress, reduced the apoptosis and enhanced the immunity of fish fed with high-fat diet. PMID- 27235373 TI - Implementing the United Kingdom Government's 10-Year Teenage Pregnancy Strategy for England (1999-2010): Applicable Lessons for Other Countries. AB - PURPOSE: Teenage pregnancy is an issue of inequality affecting the health, well being, and life chances of young women, young men, and their children. Consequently, high levels of teenage pregnancy are of concern to an increasing number of developing and developed countries. The UK Labour Government's Teenage Pregnancy Strategy for England was one of the very few examples of a nationally led, locally implemented evidence-based strategy, resourced over a long duration, with an associated reduction of 51% in the under-18 conception rate. This article seeks to identify the lessons applicable to other countries. METHODS: The article focuses on the prevention program. Drawing on the detailed documentation of the 10-year strategy, it analyzes the factors that helped and hindered implementation against the World Health Organization (WHO) ExpandNet Framework. The Framework strives to improve the planning and management of the process of scaling-up of successful pilot programs with a focus on sexual and reproductive health, making it particularly suited for an analysis of England's teenage pregnancy strategy. RESULTS: The development and implementation of the strategy matches the Framework's key attributes for successful planning and scaling up of sexual and reproductive health programs. It also matched the attributes identified by the Centre for Global Development for scaled up approaches to complex public health issues. CONCLUSIONS: Although the strategy was implemented in a high-income country, analysis against the WHO-ExpandNet Framework identifies many lessons which are transferable to low- and medium-income countries seeking to address high teenage pregnancy rates. PMID- 27235374 TI - Youth and Caregiver Perspectives on Barriers to Gender-Affirming Health Care for Transgender Youth. AB - PURPOSE: Few transgender youth eligible for gender-affirming treatments actually receive them. Multidisciplinary gender clinics improve access and care coordination but are rare. Although experts support use of pubertal blockers and cross-sex hormones for youth who meet criteria, these are uncommonly offered. This study's aim was to understand barriers that transgender youth and their caregivers face in accessing gender-affirming health care. METHODS: Transgender youth (age 14-22 years) and caregivers of transgender youth were recruited from Seattle-based clinics, and readerships from a blog and support group listserv. Through individual interviews, focus groups, or an online survey, participants described their experiences accessing gender-affirming health care. We then used theoretical thematic analysis to analyze data. RESULTS: Sixty-five participants (15 youth, 50 caregivers) described barriers spanning six themes: (1) few accessible pediatric providers are trained in gender-affirming health care; (2) lack of consistently applied protocols; (3) inconsistent use of chosen name/pronoun; (4) uncoordinated care and gatekeeping; (5) limited/delayed access to pubertal blockers and cross-sex hormones; and (6) insurance exclusions. CONCLUSIONS: This is the first study aimed at understanding perceived barriers to care among transgender youth and their caregivers. Themed barriers to care led to the following recommendations: (1) mandatory training on gender-affirming health care and cultural humility for providers/staff; (2) development of protocols for the care of young transgender patients, as well as roadmaps for families; (3) asking and recording of chosen name/pronoun; (4) increased number of multidisciplinary gender clinics; (5) providing cross-sex hormones at an age that permits peer-congruent development; and (6) designating a navigator for transgender patients in clinics. PMID- 27235375 TI - Research Priorities for Eight Areas of Adolescent Health in Low- and Middle Income Countries. AB - PURPOSE: To conduct an expert-led process for identifying research priorities for eight areas of adolescent health in low- and middle-income countries. Specific adolescent health areas included communicable diseases prevention and management, injuries and violence, mental health, noncommunicable diseases management, nutrition, physical activity, substance use, and health policy. METHODS: We used a modified version of the Child Health and Nutrition Research Initiative methodology for reaching consensus on research priorities. In a three phase process, we (1) identified research and program experts with wide-ranging backgrounds and experiences from all geographic regions through systematic searches and key informants; (2) invited these experts to propose research questions related to descriptive epidemiology, interventions (discovery, development/testing, and delivery/implementation), and health policy/systems; and (3) asked the experts to prioritize the research questions based on five criteria: clarity, answerability, importance or impact, implementation, and equity. RESULTS: A total of 142 experts submitted 512 questions which were edited and reduced to 303 for scoring. Overall, the types of the top 10 research questions in each of the eight health areas included descriptive epidemiology (26%), interventions: discovery (11%), development/testing (25%), delivery (33%), and policy, health and social systems (5%). Across health areas, the top questions highlighted integration of health services, vulnerable populations, and different health platforms (such as primary care, schools, families/parents, and interactive media). CONCLUSIONS: Priority questions have been identified for research in eight key areas of adolescent health in low- and middle-income countries. These expert-generated questions may be used by donors, program managers, and researchers to prioritize and stimulate research in adolescent health. PMID- 27235376 TI - Limited School Drinking Water Access for Youth. AB - PURPOSE: Providing children and youth with safe, adequate drinking water access during school is essential for health. This study used objectively measured data to investigate the extent to which schools provide drinking water access that meets state and federal policies. METHODS: We visited 59 middle and high schools in Massachusetts during spring 2012. Trained research assistants documented the type, location, and working condition of all water access points throughout each school building using a standard protocol. School food service directors (FSDs) completed surveys reporting water access in cafeterias. We evaluated school compliance with state plumbing codes and federal regulations and compared FSD self-reports of water access with direct observation; data were analyzed in 2014. RESULTS: On average, each school had 1.5 (standard deviation: .6) water sources per 75 students; 82% (standard deviation: 20) were functioning and fewer (70%) were both clean and functioning. Less than half of the schools met the federal Healthy Hunger-Free Kids Act requirement for free water access during lunch; 18 schools (31%) provided bottled water for purchase but no free water. Slightly over half (59%) met the Massachusetts state plumbing code. FSDs overestimated free drinking water access compared to direct observation (96% FSD reported vs. 48% observed, kappa = .07, p = .17). CONCLUSIONS: School drinking water access may be limited. In this study, many schools did not meet state or federal policies for minimum student drinking water access. School administrative staff may not accurately report water access. Public health action is needed to increase school drinking water access. PMID- 27235378 TI - Change in the Grade of Preexcitation and Progressive Prolongation of S-Delta Interval. PMID- 27235377 TI - A Multimodal Counseling-Based Adolescent Physical Activity Intervention. AB - PURPOSE: National guidelines recommend adolescents achieve 60 minutes of moderate to-vigorous physical activity (MVPA)/day, yet few adolescents meet these guidelines. METHODS: We piloted a novel quasi-randomized physical activity intervention to promote adolescent's use of their surrounding built environment among 30 intervention and 30 control overweight/obese adolescents aged 10-16 years living in greater Boston from 2013 to 2015. Location-specific MPVA was measured by accelerometry and global positioning system for three one-week periods (Time 1 [T1], Time 2 [T2], and Time 3 [T3]). One month after T1, intervention participants received individualized counseling on how to use their surrounding built environment to increase MVPA, and control participants received standard-of-care lifestyle modification counseling; both groups received their T1 physical activity data. T2 assessment occurred the week after the counseling visit and T3 assessment 3-4 months later. The main outcome was change in average daily minutes of MVPA; the secondary outcome was meeting national MVPA guidelines. Multivariable modeling accounted for covariates (baseline MVPA, body mass index, age, sex, race/ethnicity) and clustering by study group and town. RESULTS: Among the 60 adolescents recruited, 55 (92%) completed data collection. Short-term (T2) intervention effects included increased average MVPA of +13.9 minutes intervention versus -.6 minutes control (p < .0001). Differential increase in mean daily MVPA was sustained at T3 (9.3 minutes more in intervention group; p = .0006). The proportion of adolescents in the intervention group who achieved 60 minutes/day of MVPA increased from 11% (T1) to 21% (T2), whereas declining (7%-0%) among controls. CONCLUSIONS: Individualized counseling about the built environment can help increase MVPA among overweight and obese adolescents. PMID- 27235379 TI - Dosimetric Predictors of Hypothyroidism After Radical Intensity-modulated Radiation Therapy for Non-metastatic Nasopharyngeal Carcinoma. AB - AIMS: To investigate dosimetric predictors of hypothyroidism after radical intensity-modulated radiation therapy (IMRT) for non-metastatic nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: Patients with non-metastatic NPC treated with radical IMRT from 2008 to 2013 were reviewed. Serum thyroid function tests before and after IMRT were regularly monitored. Univariable and multivariable analyses were carried out for predictors of biochemical and clinical hypothyroidism. RESULTS: In total, 149 patients were recruited. After a median follow-up duration of 3.1 years, 33 (22.1%) and 21 (14.1%) patients developed biochemical and clinical hypothyroidism, respectively. Eight (24.2%) patients who had biochemical hypothyroidism developed clinical hypothyroidism later. Univariable and multivariable analyses revealed that the volume of the thyroid (P=0.002, multivariable), VS60 (the absolute thyroid volume spared from 60 Gy or less) (P<0.001, multivariable) and VS45 (P<0.001, multivariable) of the thyroid were significant predictors of biochemical hypothyroidism. The freedom from biochemical hypothyroidism was longer for those whose VS60 >= 10 cm(3) (mean 90.9 versus 62.6 months; P<0.001) and VS45 >= 5 cm(3) (mean 91.9 versus 65.2 months; P=0.001). Similarly multivariable analyses revealed that VS60 (P=0.001) and VS45 (P=0.003) were significant predictors of clinical hypothyroidism. The freedom from clinical hypothyroidism was longer for those whose VS60 >= 10 cm(3) (91.5 versus 73.3 months; P=0.002) and VS45 >= 5 cm(3) (91.5 versus 75.9 months; P=0.007). CONCLUSIONS: VS60 and VS45 of the thyroid should be considered important dose constraints against hypothyroidism without compromising target coverage during IMRT optimisation for NPC. PMID- 27235380 TI - Multidisciplinary Influence on Care of Lung Cancer Patients at the Time of Diagnosis: a Patient Survey. PMID- 27235382 TI - A comprehensive clinical review of maxillary sinus floor elevation: anatomy, techniques, biomaterials and complications. AB - Several systematic reviews have shown that maxillary sinus augmentation is a predictable and effective procedure for augmentation of an atrophic posterior maxilla. However, we know of no reviews that have covered all the clinical aspects. We searched the PubMed, EMBASE, Cinhal, and Cochrane databases up to January 2015 to select relevant studies that cover the different objectives of this review, including the anatomy of the maxillary sinus, surgical techniques, biomaterials used in the sinus augmentation, and potential complications. PMID- 27235381 TI - Effects of d-amphetamine upon psychosocial stress responses. AB - Psychostimulant drugs alter the salience of stimuli in both laboratory animals and humans. In animals, stimulants increase rates of responding to conditioned incentive stimuli, and in humans, amphetamine increases positive ratings of emotional images. However, the effects of stimulants on real-life emotional events have not been studied in humans. In this study, we examined the effect of d-amphetamine on responses to acute psychosocial stress using a public speaking task. Healthy volunteers (N=56) participated in two experimental sessions, one with a psychosocial stressor (the Trier Social Stress Test) and one with a non stressful control task. They were randomly assigned to receive d-amphetamine (5 mg n=18, 10 mg n=20) or placebo (n=18) on both sessions under double blind conditions. Salivary cortisol, subjective mood, and vital signs were measured at regular intervals during the session. Subjects also provided cognitive appraisals of the tasks before and after their performances. Amphetamine produced its expected mood and physiological effects, and the Trier Social Stress Test produced its expected effects on cortisol and mood. Although neither dose of amphetamine altered cardiovascular or hormonal responses to stress, amphetamine (10 mg) increased participants' pre-task appraisals of how challenging the task would be, and it increased post-task ratings of self-efficacy. Paradoxically, it also increased ratings of how stressful the task was, and prolonged aversive emotional responses. These findings suggest that amphetamine differentially affects stress response components: it may increase participants' appraisals of self-efficacy without dampening the direct emotional or physiological responses to the stress. PMID- 27235383 TI - Exosomal formulation enhances therapeutic response of celastrol against lung cancer. AB - Celastrol (CEL), a plant-derived triterpenoid, is a known inhibitor of Hsp90 and NF-kappaB activation pathways and has recently been suggested to be of therapeutic importance in various cancers. However, the molecular mechanisms of celastrol-mediated effects in lung cancer are not systematically studied. Moreover, it suffers from poor bioavailability and off-site toxicity issues. This study aims to study the effect of celastrol loaded into exosomes against two non small cell-lung carcinoma (NSCLC) cell lines and explore the molecular mechanisms to determine the proteins governing the cellular responses. We observed that celastrol inhibited the proliferation of A549 and H1299 NSCLC cells in a time- and concentration-dependent manner as indexed by MTT assay. Mechanistically, CEL pre-treatment of H1299 cells completely abrogated TNFalpha-induced NF-kappaB activation and upregulated the expression of ER-stress chaperones Grp 94, Grp78, and pPERK. These changes in ER-stress mediators were paralleled by an increase in apoptotic response as evidenced by higher annexin-V/PI positive cells evaluated by FACS and immunoblotting which showed upregulation of the ER stress specific pro-apoptotic transcription factor, GADD153/CHOP and alteration of Bax/Bcl2 levels. Exosomes loaded with CEL exhibited enhanced anti-tumor efficacy as compared to free CEL against lung cancer cell xenograft. CEL did not exhibit any gross or systemic toxicity in wild-type C57BL6 mice as determined by hematological and liver and kidney function test. Together, our data demonstrate the chemotherapeutic potential of CEL in lung cancer and that exosomal formulation enhances its efficacy and reduces dose related toxicity. PMID- 27235385 TI - Metastatic Basosquamous Carcinoma: Report of Two Cases and Clinicopathological Considerations. AB - Basosquamous carcinoma is a rare cutaneous tumor considered by some authors as an aggressive type of basal cell carcinoma having a propensity for local recurrence and a potential risk for regional and distant metastatic spread. Herein we present 2 cases of basosquamous carcinoma of head and neck region, with metastatic spread to parotid gland (case 1) and to cervical nodes (case 2). Both patients had recurrence 2 years after initial treatment of the primary lesion (first patient: surgery; second patient: radiotherapy) and at the same time developed regional metastases. We conclude that basosquamous carcinoma must be considered as an aggressive variant of basal cell carcinoma having a great propensity to metastasize even at an early tumor stage. The clinical features, the morphologic aspects, and the treatment of this rare entity are discussed in this article. PMID- 27235386 TI - A high-throughput detection method for invasive fruit fly (Diptera: Tephritidae) species based on microfluidic dynamic array. AB - Invasive species can be detrimental to a nation's ecology, economy and human health. Rapid and accurate diagnostics are critical to limit the establishment and spread of exotic organisms. The increasing rate of biological invasions relative to the taxonomic expertise available generates a demand for high throughput, DNA-based diagnostics methods for identification. We designed species specific qPCR primer and probe combinations for 27 economically important tephritidae species in six genera (Anastrepha, Bactrocera, Carpomya, Ceratitis, Dacus and Rhagoletis) based on 935 COI DNA barcode haplotypes from 181 fruit fly species publically available in BOLD, and then tested the specificity for each primer pair and probe through qPCR of 35 of those species. We then developed a standardization reaction system for detecting the 27 target species based on a microfluidic dynamic array and also applied the method to identify unknown immature samples from port interceptions and field monitoring. This method led to a specific and simultaneous detection for all 27 species in 7.5 h, using only 0.2 MUL of reaction system in each reaction chamber. The approach successfully discriminated among species within complexes that had genetic similarities of up to 98.48%, while it also identified all immature samples consistent with the subsequent results of morphological examination of adults which were reared from larvae of cohorts from the same samples. We present an accurate, rapid and high throughput innovative approach for detecting fruit flies of quarantine concern. This is a new method which has broad potential to be one of international standards for plant quarantine and invasive species detection. PMID- 27235387 TI - De Novo vs Nevus-Associated Melanomas: Differences in Associations With Prognostic Indicators and Survival. AB - BACKGROUND: Although 20% to 30% of melanomas are histopathologically 'nevus associated,' the majority of melanomas arise de novo, ie, in clinically normal skin with no associated nevus. We examined whether these forms of melanoma differed in their associations with clinical and histopathologic features and patient survival. METHODS: We analyzed two prospective cohorts from our institution with protocol-driven follow-up information (NYU1, n = 1024; NYU2, n = 1125). We used univariate and multivariable analyses to examine associations between de novo vs nevus-associated melanoma classification and age, anatomic site, tumor thickness, tumor ulceration, mitotic index, histological subtype, clinical stage, and survival. We tested the associations identified in NYU1 using NYU2 as a replication cohort. All tests of statistical significance were two sided. RESULTS: In NYU1, de novo melanomas were associated with tumor thickness greater than 1.0 mm (odds ratio [OR] = 1.96, 95% confidence interval [CI] = 1.43 to 2.70, P < .001), ulceration (OR = 1.65, 95% CI = 1.10 to 2.54, P = .02), nodular subtype (OR = 3.26, 95% CI = 1.70 to 7.11, P = .001), greater than stage I (OR = 2.35, 95% CI = 1.65 to 3.40, P < .001), older age (OR = 1.64, 95% CI = 1.18 to 2.30, P = .004), and shorter overall survival (HR = 1.63, 95% CI = 1.22 to 2.18, P < .001). In NYU2, de novo melanoma was again statistically significantly associated with thickness greater than 1.0 mm (OR = 2.24, 95% CI = 1.72 to 2.93, P < .001), ulceration (OR = 2.88, 95% CI = 1.95 to 4.37, P < .001), nodular subtype (OR = 2.41, 95% CI = 1.75 to 3.37, P < .001), greater than stage I (OR = 2.42, 95% CI = 1.80 to 3.29, P < .001), older age (OR = 1.68, 95% CI = 1.31 to 2.17, P < .001), and shorter overall survival (HR = 2.52, 95% CI = 1.78 to 3.56, P < .001). In multivariable analysis, de novo classification was an independent, poor prognostic indicator in NYU2 (HR = 1.70, 95% CI = 1.19 to 2.44, P = .004). Male patients had a statistically significantly worse survival than female patients if their melanoma was de novo (NYU1, P < .001; NYU2, P < .001); unexpectedly, there was no sex difference in survival among patients with nevus associated tumors. CONCLUSIONS: These data suggest that de novo melanomas are more aggressive than nevus-associated melanomas. This classification scheme may also provide a useful framework for investigations into sex differences in melanoma outcomes. PMID- 27235388 TI - Identification of IL-7 as a candidate disease mediator in osteoarthritis in Chinese Han population: a case-control study. AB - OBJECTIVES: Little is known about the biochemical mediators IL-7 that correlate with the initiation and progression of OA. We performed this study to assess the role of variants of IL-7 in OA susceptibility in the Chinese Han population. METHODS: We performed a retrospective, case-control study in the Chinese Han population from 2013 to 2015. Four single nucleotide polymorphisms were genotyped (using a ligase detection reaction) in 602 patients and 454 controls. Differences between groups were analysed, and association was assessed by the odds ratio (OR) and 95% CI. RESULTS: Among these polymorphisms, rs2583764, rs2583760 and rs6993386 showed no significant association with OA in the Chinese Han population {rs2583764 [P-allele = 0.98651, P-genotype = 0.40392, OR (95% CI): 1.00162 (0.83066, 1.20775)]; rs2583760 [P-allele = 0.384500, P-genotype = 0.58752, OR (95% CI): 0.69859 (0.30996, 1.57449)]; rs6993386 [P-allele = 0.69525, P-genotype = 0.50712, OR (95% CI): 0.96432 (0.80406, 1.15653)]}. However, the results showed that the rs2583759 polymorphism was significantly associated with OA [P-allele = 0.00 P-genotype = 3.86 * 10(-30), OR (95% CI): 0.27794 (0.22407, 0.34476)], even when the 10 000 times permutation was performed (P-allele-permutation < 0.00010, P-genotype-permutation = 0.00010). Haplotype analyses showed A-G-A-C, A-G-A-T and G-G-G-C of rs2583764-rs2583760-rs6993386-rs2583759 were risk factors for OA, both before or after the 10 000 times permutation, indicating IL-7 to be associated with OA. CONCLUSION: There was a significant association between IL-7, especially rs2583759, and OA in the Chinese Han population. PMID- 27235389 TI - Endovascular treatment of complex abdominal aortic aneurysms by combining different types of endoprostheses. AB - PURPOSE: To describe an off-the-shelf method for the treatment of abdominal aortic aneurysms with hostile (large, >30 mm) neck and/or small (<20 mm) aortic bifurcation. CASE REPORT: We describe five patients with large aortic necks and/or small aortic bifurcations, which were treated by combining an AFX endoprosthesis with a Valiant Captiva endograft, and additional proximal endoanchors when deemed necessary. Initial technical success was 100%. Follow-up ranged from 228 to 875 days. One patient suffered a type 1A and 1B endoleak at 446 days follow-up, which were successfully treated by endovascular means. CONCLUSION: Combining the AFX and Valiant Captiva endografts is an off-the-shelf solution for treatment of large diameter aortic necks and small aortic bifurcations in patients deemed unfit for open repair or declined for fenestrated endografts. Longer follow-up is required to assess the long-term safety with special focus on aortic neck dilation. PMID- 27235390 TI - K201 (JTV519) is a Ca2+-Dependent Blocker of SERCA and a Partial Agonist of Ryanodine Receptors in Striated Muscle. AB - K201 (JTV-519) may prevent abnormal Ca(2+) leak from the sarcoplasmic reticulum (SR) in the ischemic heart and skeletal muscle (SkM) by stabilizing the ryanodine receptors (RyRs; RyR1 and RyR2, respectively). We tested direct modulation of the SR Ca(2+)-stimulated ATPase (SERCA) and RyRs by K201. In isolated cardiac and SkM SR microsomes, K201 slowed the rate of SR Ca(2+) loading, suggesting potential SERCA block and/or RyR agonism. K201 displayed Ca(2+)-dependent inhibition of SERCA-dependent ATPase activity, which was measured in microsomes incubated with 200, 2, and 0.25 uM Ca(2+) and with the half-maximal K201 inhibitory doses (IC50) estimated at 130, 19, and 9 uM (cardiac muscle) and 104, 13, and 5 uM (SkM SR). K201 (>=5 uM) increased RyR1-mediated Ca(2+) release from SkM microsomes. Maximal K201 doses at 80 uM produced ~37% of the increase in SkM SR Ca(2+) release observed with the RyR agonist caffeine. K201 (>=5 uM) increased the open probability (Po) of very active ("high-activity") RyR1 of SkM reconstituted into bilayers, but it had no effect on "low-activity" channels. Likewise, K201 activated cardiac RyR2 under systolic Ca(2+) conditions (~5 uM; channels at Po ~0.3) but not under diastolic Ca(2+) conditions (~100 nM; Po < 0.01). Thus, K201 induced the inhibition of SR Ca(2+) leak found in cell-system studies may relate to potentially potent SERCA block under resting Ca(2+) conditions. SERCA block likely produces mild SR depletion in normal conditions but could prevent SR Ca(2+) overload under pathologic conditions, thus precluding abnormal RyR mediated Ca(2+) release. PMID- 27235391 TI - DNA vaccines to attack cancer: Strategies for improving immunogenicity and efficacy. AB - DNA vaccination represents a smart and promising approach to cancer immunotherapy. DNA vaccines for cancer immunotherapy are designed to deliver one or several genes encoding tumor antigens, thereby eliciting or augmenting antigen specific immune responses against antigens that play a central role in tumor initiation, progression and metastasis. Vaccine efficacy can be significantly improved by implementing strategies for enhancing antigen presentation and immunogenicity, such as new delivery systems, addition of molecular adjuvants and immunostimulatory signals, optimized prime-boost strategies or blockade of immune checkpoints. Taken into consideration that innate immune responses are important in the induction and enhancement of antigen-specific adaptive responses, manipulations that integrate these approaches in the vaccine design can achieve activation of protective adaptive immune responses, thereby overcoming the self tolerance towards many tumor antigens. Such approaches are employed in a number of clinical trials for DNA cancer immunotherapy and hold promise for prophylactic and therapeutic vaccine development. In this context, strategies that improve immunogenicity and enhance the efficacy of DNA vaccines for cancer immunotherapy are discussed. PMID- 27235392 TI - Palliative medicine and the diagnostic process: who is prematurely closing the door on whom? PMID- 27235393 TI - Development, implementation and evaluation of a terminal and hospice care educational online module for preclinical students. AB - OBJECTIVES: To explore the application of an online learning tool to teach preclinical medical students terminal and hospice care in a blended curricula. METHODS: We created and evaluated a 30 min interactive online module at the Yale School of Medicine. Second-year medical students were randomly assigned to complete the online module or not (control group) prior to attending a required half-day hospice clinical experience. We assessed the students' knowledge and attitudes with a 23-item survey. RESULTS: 152 students (response rate 51%) participated in this study from 2012 to 2014. 56% (n=85) completed the online module, 37% (n=56) did not and 7% (n=11) did not indicate whether they had completed the module or not. Students who completed the online module prior to the hospice experience scored higher (p<0.05, two-way analysis of variance) on 5 out of 8 of the multiple choice questions pertaining to hospice and palliative care, but their attitudes were similar to those who did not complete the online module. Overall, the students felt somewhat uncomfortable caring for dying patients although they regarded it as a physician's duty and felt that palliative/hospice care education is important in medical school. CONCLUSIONS: When combined with a mentored clinical hospice experience, an online module appears to enhance the teaching of the dying process and terminal care for preclinical medical students. This online module may prove useful for other institutions. PMID- 27235394 TI - Immunostimulatory role of mitochondrial DAMPs: alarming for pre-eclampsia? AB - Mitochondria are critical signaling organelles that play an integral cellular role in the activation of diverse physiological responses to perturbation. Mitochondrial damage-associated molecular patterns (DAMPs) act as redox signaling nodes synchronizing mitochondrial metabolism with triggering of inflammation. Oxidative stress and inflammation are implicated in the pathogenesis of pre eclampsia; however, the mechanisms involved in the novel crosstalk between these two pathogenic pathways are less well elucidated. In this review, we show that mitochondrial redox signals are paramount for regulating and maintaining the inflammatory response to danger signals. Mitochondrial DNA (mtDNA) represents a mitochondrial DAMP and is often liberated as signal of mitochondrial dysfunction. This review will explore the mechanistic role of mitochondrial DNA in directly coordinating adaptive changes in the maternal inflammatory status in pre eclampsia through recruitment of innate immune cells and subsequent cytokine production. Finally, we provide emerging evidence of elevated circulating mitochondrial DAMPs in pre-eclampsia. PMID- 27235395 TI - Distal Hydrogen-bonding Interactions in Ligand Sensing and Signaling by Mycobacterium tuberculosis DosS. AB - Mycobacterium tuberculosis DosS is critical for the induction of M. tuberculosis dormancy genes in response to nitric oxide (NO), carbon monoxide (CO), or hypoxia. These environmental stimuli, which are sensed by the DosS heme group, result in autophosphorylation of a DosS His residue, followed by phosphotransfer to an Asp residue of the response regulator DosR. To clarify the mechanism of gaseous ligand recognition and signaling, we investigated the hydrogen-bonding interactions of the iron-bound CO and NO ligands by site-directed mutagenesis of Glu-87 and His-89. Autophosphorylation assays and molecular dynamics simulations suggest that Glu-87 has an important role in ligand recognition, whereas His-89 is essential for signal transduction to the kinase domain, a process for which Arg-204 is important. Mutation of Glu-87 to Ala or Gly rendered the protein constitutively active as a kinase, but with lower autophosphorylation activity than the wild-type in the Fe(II) and the Fe(II)-CO states, whereas the E87D mutant had little kinase activity except for the Fe(II)-NO complex. The H89R mutant exhibited attenuated autophosphorylation activity, although the H89A and R204A mutants were inactive as kinases, emphasizing the importance of these residues in communication to the kinase core. Resonance Raman spectroscopy of the wild-type and H89A mutant indicates the mutation does not alter the heme coordination number, spin state, or porphyrin deformation state, but it suggests that interdomain interactions are disrupted by the mutation. Overall, these results confirm the importance of the distal hydrogen-bonding network in ligand recognition and communication to the kinase domain and reveal the sensitivity of the system to subtle differences in the binding of gaseous ligands. PMID- 27235396 TI - The HIV-1 Tat Protein Is Monomethylated at Lysine 71 by the Lysine Methyltransferase KMT7. AB - The HIV-1 transactivator protein Tat is a critical regulator of HIV transcription primarily enabling efficient elongation of viral transcripts. Its interactions with RNA and various host factors are regulated by ordered, transient post translational modifications. Here, we report a novel Tat modification, monomethylation at lysine 71 (K71). We found that Lys-71 monomethylation (K71me) is catalyzed by KMT7, a methyltransferase that also targets lysine 51 (K51) in Tat. Using mass spectrometry, in vitro enzymology, and modification-specific antibodies, we found that KMT7 monomethylates both Lys-71 and Lys-51 in Tat. K71me is important for full Tat transactivation, as KMT7 knockdown impaired the transcriptional activity of wild type (WT) Tat but not a Tat K71R mutant. These findings underscore the role of KMT7 as an important monomethyltransferase regulating HIV transcription through Tat. PMID- 27235397 TI - CHD4 Is a Peripheral Component of the Nucleosome Remodeling and Deacetylase Complex. AB - Chromatin remodeling enzymes act to dynamically regulate gene accessibility. In many cases, these enzymes function as large multicomponent complexes that in general comprise a central ATP-dependent Snf2 family helicase that is decorated with a variable number of regulatory subunits. The nucleosome remodeling and deacetylase (NuRD) complex, which is essential for normal development in higher organisms, is one such macromolecular machine. The NuRD complex comprises ~10 subunits, including the histone deacetylases 1 and 2 (HDAC1 and HDAC2), and is defined by the presence of a CHD family remodeling enzyme, most commonly CHD4 (chromodomain helicase DNA-binding protein 4). The existing paradigm holds that CHD4 acts as the central hub upon which the complex is built. We show here that this paradigm does not, in fact, hold and that CHD4 is a peripheral component of the NuRD complex. A complex lacking CHD4 that has HDAC activity can exist as a stable species. The addition of recombinant CHD4 to this nucleosome deacetylase complex reconstitutes a NuRD complex with nucleosome remodeling activity. These data contribute to our understanding of the architecture of the NuRD complex. PMID- 27235398 TI - Direct Modulation of Heterotrimeric G Protein-coupled Signaling by a Receptor Kinase Complex. AB - Plants and some protists have heterotrimeric G protein complexes that activate spontaneously without canonical G protein-coupled receptors (GPCRs). In Arabidopsis, the sole 7-transmembrane regulator of G protein signaling 1 (AtRGS1) modulates the G protein complex by keeping it in the resting state (GDP-bound). However, it remains unknown how a myriad of biological responses is achieved with a single G protein modulator. We propose that in complete contrast to G protein activation in animals, plant leucine-rich repeat receptor-like kinases (LRR RLKs), not GPCRs, provide this discrimination through phosphorylation of AtRGS1 in a ligand-dependent manner. G protein signaling is directly activated by the pathogen-associated molecular pattern flagellin peptide 22 through its LRR RLK, FLS2, and co-receptor BAK1. PMID- 27235399 TI - Regulation of Connexin43 Function and Expression by Tyrosine Kinase 2. AB - Connexin43 (Cx43) assembly and degradation, the regulation of electrical and metabolic coupling, as well as modulating the interaction with other proteins, involve phosphorylation. Here, we identified and characterized the biological significance of a novel tyrosine kinase that phosphorylates Cx43, tyrosine kinase 2 (Tyk2). Activation of Tyk2 led to a decrease in Cx43 gap junction communication by increasing the turnover rate of Cx43 from the plasma membrane. Tyk2 directly phosphorylated Cx43 residues Tyr-247 and Tyr-265, leading to indirect phosphorylation on residues Ser-279/Ser-282 (MAPK) and Ser-368 (PKC). Although this phosphorylation pattern is similar to what has been observed following Src activation, the response caused by Tyk2 occurred when Src was inactive in NRK cells. Knockdown of Tyk2 at the permissive temperature (active v-Src) in LA-25 cells decreased Cx43 phosphorylation, indicating that although activation of Tyk2 and v-Src leads to phosphorylation of the same Cx43CT residues, they are not identical in level at each site. Additionally, angiotensin II activation of Tyk2 increased the intracellular protein level of Cx43 via STAT3. These findings indicate that, like Src, Tyk2 can also inhibit gap junction communication by phosphorylating Cx43. PMID- 27235400 TI - The Essential Neo1 Protein from Budding Yeast Plays a Role in Establishing Aminophospholipid Asymmetry of the Plasma Membrane. AB - Eukaryotic organisms typically express multiple type IV P-type ATPases (P4 ATPases), which establish plasma membrane asymmetry by flipping specific phospholipids from the exofacial to the cytosolic leaflet. Saccharomyces cerevisiae, for example, expresses five P4-ATPases, including Neo1, Drs2, Dnf1, Dnf2, and Dnf3. Neo1 is thought to be a phospholipid flippase, although there is currently no experimental evidence that Neo1 catalyzes this activity or helps establish membrane asymmetry. Here, we use temperature-conditional alleles (neo1(ts)) to test whether Neo1 deficiency leads to loss of plasma membrane asymmetry. Wild-type (WT) yeast normally restrict most of the phosphatidylserine (PS) and phosphatidylethanolamine (PE) to the inner cytosolic leaflet of the plasma membrane. However, the neo1-1(ts) and neo1-2(ts) mutants display a loss of PS and PE asymmetry at permissive growth temperatures as measured by hypersensitivity to pore-forming toxins that target PS (papuamide A) or PE (duramycin) exposed in the extracellular leaflet. When shifted to a semi permissive growth temperature, the neo1-1(ts) mutant became extremely hypersensitive to duramycin, although the sensitivity to papuamide A was unchanged, indicating preferential exposure of PE. This loss of asymmetry occurs despite the presence of other flippases that flip PS and/or PE. Even when overexpressed, Drs2 and Dnf1 were unable to correct the loss of asymmetry caused by neo1(ts) However, modest overexpression of Neo1 weakly suppressed loss of membrane asymmetry caused by drs2Delta with a more significant correction of PE asymmetry than PS. These results indicate that Neo1 plays an important role in establishing PS and PE plasma membrane asymmetry in budding yeast. PMID- 27235401 TI - The Role of Active Site Flexible Loops in Catalysis and of Zinc in Conformational Stability of Bacillus cereus 569/H/9 beta-Lactamase. AB - Metallo-beta-lactamases catalyze the hydrolysis of most beta-lactam antibiotics and hence represent a major clinical concern. The development of inhibitors for these enzymes is complicated by the diversity and flexibility of their substrate binding sites, motivating research into their structure and function. In this study, we examined the conformational properties of the Bacillus cereus beta lactamase II in the presence of chemical denaturants using a variety of biochemical and biophysical techniques. The apoenzyme was found to unfold cooperatively, with a Gibbs free energy of stabilization (DeltaG(0)) of 32 +/- 2 kJ.mol(-1) For holoBcII, a first non-cooperative transition leads to multiple interconverting native-like states, in which both zinc atoms remain bound in an apparently unaltered active site, and the protein displays a well organized compact hydrophobic core with structural changes confined to the enzyme surface, but with no catalytic activity. Two-dimensional NMR data revealed that the loss of activity occurs concomitantly with perturbations in two loops that border the enzyme active site. A second cooperative transition, corresponding to global unfolding, is observed at higher denaturant concentrations, with DeltaG(0) value of 65 +/- 1.4 kJ.mol(-1) These combined data highlight the importance of the two zinc ions in maintaining structure as well as a relatively well defined conformation for both active site loops to maintain enzymatic activity. PMID- 27235403 TI - Corrigendum. PMID- 27235402 TI - Identification of the High-affinity Substrate-binding Site of the Multidrug and Toxic Compound Extrusion (MATE) Family Transporter from Pseudomonas stutzeri. AB - Multidrug and toxic compound extrusion (MATE) transporters exist in all three domains of life. They confer multidrug resistance by utilizing H(+) or Na(+) electrochemical gradients to extrude various drugs across the cell membranes. The substrate binding and the transport mechanism of MATE transporters is a fundamental process but so far not fully understood. Here we report a detailed substrate binding study of NorM_PS, a representative MATE transporter from Pseudomonas stutzeri Our results indicate that NorM_PS is a proton-dependent multidrug efflux transporter. Detailed binding studies between NorM_PS and 4',6 diamidino-2-phenylindole (DAPI) were performed by isothermal titration calorimetry (ITC), differential scanning calorimetry (DSC), and spectrofluorometry. Two exothermic binding events were observed from ITC data, and the high-affinity event was directly correlated with the extrusion of DAPI. The affinities are about 1 MUm and 0.1 mm for the high and low affinity binding, respectively. Based on our homology model of NorM_PS, variants with mutations of amino acids that are potentially involved in substrate binding, were constructed. By carrying out the functional characterization of these variants, the critical amino acid residues (Glu-257 and Asp-373) for high-affinity DAPI binding were determined. Taken together, our results suggest a new substrate-binding site for MATE transporters. PMID- 27235404 TI - Effect on falls of providing single lens distance vision glasses to multifocal glasses wearers: VISIBLE randomised controlled trial. PMID- 27235406 TI - Cutaneous lupus erythematosus and systemic lupus erythematosus are associated with clinically significant cardiovascular risk: a Danish nationwide cohort study. AB - Systemic lupus erythematosus (SLE) is a well-known cardiovascular risk factor. Less is known about cutaneous lupus erythematosus (CLE) and the risk of developing cardiovascular disease (CVD). Therefore, we investigated the risk of mortality and adverse cardiovascular events in patients diagnosed with SLE and CLE. We conducted a cohort study of the entire Danish population aged >= 18 and <= 100 years, followed from 1997 to 2011 by individual-level linkage of nationwide registries. Multivariable adjusted Cox regression models were used to estimate the hazard ratios (HRs) for a composite cardiovascular endpoint and all cause mortality, for patients with SLE and CLE. A total of 3282 patients with CLE and 3747 patients with SLE were identified and compared with 5,513,739 controls. The overall HR for the composite CVD endpoint was 1.31 (95% CI 1.16-1.49) for CLE and 2.05 (95% CI 1.15-3.44) for SLE. The corresponding HRs for all-cause mortality were 1.32 (95% CI 1.20-1.45) for CLE and 2.21 (95% CI 2.03-2.41) for SLE. CLE and SLE were associated with a significantly increased risk of CVD and all-cause mortality. Local and chronic inflammation may be the driver of low grade systemic inflammation. PMID- 27235405 TI - Decreased Coenzyme Q10 Levels in Multiple System Atrophy Cerebellum. AB - In familial and sporadic multiple system atrophy (MSA) patients, deficiency of coenzyme Q10 (CoQ10) has been associated with mutations in COQ2, which encodes the second enzyme in the CoQ10 biosynthetic pathway. Cerebellar ataxia is the most common presentation of CoQ10 deficiency, suggesting that the cerebellum might be selectively vulnerable to low levels of CoQ10 To investigate whether CoQ10 deficiency represents a common feature in the brains of MSA patients independent of the presence of COQ2 mutations, we studied CoQ10 levels in postmortem brains of 12 MSA, 9 Parkinson disease (PD), 9 essential tremor (ET) patients, and 12 controls. We also assessed mitochondrial respiratory chain enzyme activities, oxidative stress, mitochondrial mass, and levels of enzymes involved in CoQ biosynthesis. Our studies revealed CoQ10 deficiency in MSA cerebellum, which was associated with impaired CoQ biosynthesis and increased oxidative stress in the absence of COQ2 mutations. The levels of CoQ10 in the cerebella of ET and PD patients were comparable or higher than in controls. These findings suggest that CoQ10 deficiency may contribute to the pathogenesis of MSA. Because no disease modifying therapies are currently available, increasing CoQ10 levels by supplementation or upregulation of its biosynthesis may represent a novel treatment strategy for MSA patients. PMID- 27235408 TI - Pedicle screw placement in patients with variant atlas pedicle. AB - OBJECTIVE: To investigate how the anatomy of variant atlas vertebra impacts on the strategy used to place pedicle screws used to treat atlantoaxial instability. METHODS: The study enrolled patients with cervical instability who had a posterior arch pedicle height <3.5 mm at the anchor point, a vertebral artery groove height <3.5 mm, or both. Pedicle screws were fitted according to the anatomy of the variant atlas vertebra. Patients were followed-up to evaluate accuracy of the screw placement and maintenance of cervical stability. RESULTS: A total of 28 patients were enrolled. The mean height of the atlas pedicle proximal section was >5.0 mm. For the vertebral artery groove, the height of the lateral region was significantly greater than that of the medial region. Approximately 60% of atlas vertebrae had lateral heights >3.5 mm (34 of 56). The majority of the posterior arch heights were <3.0 mm. There were no perioperative or postoperative complications observed. CONCLUSIONS: Pedicle screw placement in the lateral pedicle region is the safest and most reliable strategy to treat variant atlas pedicles. PMID- 27235407 TI - Incidence and age and gender profiles of hyperplasia in individual cervical vertebrae. AB - OBJECTIVE: To analyze the incidence and age and gender profiles of hyperplasia in individual cervical vertebrae. METHODS: In this retrospective study, computed tomography three-dimensional reconstruction images of cervical vertebrae from patients with neck discomfort were analyzed for the presence of hyperplasia and compared with age and gender data. RESULTS: Scans from a total of 580 patients (352 males, 228 females) were analyzed. The highest incidence of hyperplasia was seen in C2 (25%), followed by C1 (23%), C6 (16%), C5 (15%), C7 (9%), C4 (8%) and C3 (4%). Patients with C2 hyperplasia were the youngest and those with C1 hyperplasia were the second youngest, while patients with C7 hyperplasia were the oldest. Of those with C2, C1 and C7 hyperplasia, males were significantly younger than females, whereas of those with C3, C4, C5 and C6 hyperplasia, females were significantly younger than males. CONCLUSIONS: Hyperplasia of the cervical spine shows different age and gender profiles among the seven vertebrae. These findings may be helpful for the early recognition of cervical hyperplasia and highlight the importance of protecting the atlanto-axial joint in daily life. PMID- 27235409 TI - Health insurer extinguishes tobacco investment. PMID- 27235410 TI - First report on violent attacks on healthcare shows 959 deaths over two years. PMID- 27235411 TI - Fear of an HIV positive test result: an exploration of the low uptake of couples HIV counselling and testing (CHCT) in a rural setting in Mukono district, Uganda. AB - BACKGROUND: Couples HIV counselling and testing (CHCT) is a key preventive strategy used to reduce the spread of HIV. In Uganda, HIV prevalence among married or cohabiting couples is 5.6%, compared to 2.2% among those never married. CHCT can help ease disclosure of HIV positive status, which in turn may help increase opportunities to obtain social supports and reduce new infections. The purpose of this study was aimed at exploring the possible reasons for the low uptake of CHCT in Mukono district, a rural in setting in Uganda. METHODS: The study was conducted in two sub-counties in a rural district (Mukono district) using a descriptive qualitative research design. Specifically, we conducted four focus group discussions and 10 key informant interviews. We also interviewed 53 individuals in couple relationships. Data were collected mainly in the local language Luganda and English, all data were transcribed into English and coded for emergent themes. Ethical clearance for this study was obtained from the Mengo Hospital Research Review Board and from the Uganda National Council of Science and Technology. RESULTS: Fear of a positive HIV test result emerged strongly as the most significant barrier to CHCT. To a lesser extent, perceptions and knowledge of CHCT, mistrust in marriages and culture were also noted by participants as important barriers to the uptake of CHCT among couples. Participants offered suggestions on ways to overcome these barriers, including peer couple counselling, offering incentives to couples that test together and door-to-door CHCT testing. CONCLUSION: In an effort to improve the uptake of CHCT, it is crucial to involve both females and males in the planning and implementation of CHCT, as well as to address the misconceptions about CHCT and to prioritise CHCT within health care systems management. PMID- 27235412 TI - Comprendre les mecanismes qui sous-tendent les inegalites de sante : lecons tirees de l'economie. PMID- 27235413 TI - Assessment of arterial stiffness in patients with venous thromboembolism: Separate or continuous circuits? AB - Objectives The aim of this study is to evaluate the association of venous thromboembolism with arterial stiffness by cardio-ankle vascular index method. Method We included 52 patients with a documented lower extremity venous thromboembolism within the last six months and 52 healthy subjects to this cross sectional observational study. Results Cardio-ankle vascular index (8.58 +/- 1.60 versus 7.05 +/- 1.44, p < 0.001, respectively) and systolic blood pressure (128.02 +/- 7.13 mmHg versus 123.94 +/- 8.12 mmHg, p = 0.008, respectively) were significantly higher among patients with venous thromboembolism than controls. Cardio-ankle vascular index was an independent predictor of venous thromboembolism in multivariate logistic regression analysis (p < 0.001, odds ratio = 1.864, 95% confidence interval = 1.370-2.536). Cardio-ankle vascular index value > 7.8 had a sensitivity of 82.7% and a specificity of 80.8% for predicting venous thromboembolism (area under curve = 0.789, 95% confidence interval = 0.698-0.863, p < 0.001) in receiver operating characteristic curve analysis. Conclusion We found that arterial stiffness was increased in patients with venous thromboembolism which highlights the fact that arterial and venous circulation is in continuum and an insult may affect both of these circuits. PMID- 27235414 TI - An atlas of gene expression and gene co-regulation in the human retina. AB - The human retina is a specialized tissue involved in light stimulus transduction. Despite its unique biology, an accurate reference transcriptome is still missing. Here, we performed gene expression analysis (RNA-seq) of 50 retinal samples from non-visually impaired post-mortem donors. We identified novel transcripts with high confidence (Observed Transcriptome (ObsT)) and quantified the expression level of known transcripts (Reference Transcriptome (RefT)). The ObsT included 77 623 transcripts (23 960 genes) covering 137 Mb (35 Mb new transcribed genome). Most of the transcripts (92%) were multi-exonic: 81% with known isoforms, 16% with new isoforms and 3% belonging to new genes. The RefT included 13 792 genes across 94 521 known transcripts. Mitochondrial genes were among the most highly expressed, accounting for about 10% of the reads. Of all the protein-coding genes in Gencode, 65% are expressed in the retina. We exploited inter-individual variability in gene expression to infer a gene co-expression network and to identify genes specifically expressed in photoreceptor cells. We experimentally validated the photoreceptors localization of three genes in human retina that had not been previously reported. RNA-seq data and the gene co-expression network are available online (http://retina.tigem.it). PMID- 27235415 TI - Systematic analysis of plant mitochondrial and chloroplast small RNAs suggests organelle-specific mRNA stabilization mechanisms. AB - Land plant organellar genomes encode a small number of genes, many of which are essential for respiration and photosynthesis. Organellar gene expression is characterized by a multitude of RNA processing events that lead to stable, translatable transcripts. RNA binding proteins (RBPs), have been shown to generate and protect transcript termini and eventually induce the accumulation of short RNA footprints. We applied knowledge of such RBP-derived footprints to develop software (sRNA miner) that enables identification of RBP footprints, or other clusters of small RNAs, in organelles. We used this tool to determine mitochondrial and chloroplast cosRNAs (clustered organellar sRNAs) in Arabidopsis. We found that in mitochondria, cosRNAs coincide with transcript 3' ends, but are largely absent from 5'-ends. In chloroplasts this bias is absent, suggesting a different mode of 5' processing, possibly owing to different sets of RNases. Furthermore, we identified a large number of cosRNAs that represent silenced insertions of mitochondrial DNA in the nuclear genome of Arabidopsis. Steady-state RNA analyses demonstrate that cosRNAs display differential accumulation during development. Finally, we demonstrate that the chloroplast RBP PPR10 associates in vivo with its cognate cosRNA. A hypothetical role of cosRNAs as competitors of mRNAs for PPR proteins is discussed. PMID- 27235416 TI - Antagonistic control of the turnover pathway for the global regulatory sRNA CsrB by the CsrA and CsrD proteins. AB - The widely conserved protein CsrA (carbon storage regulator A) globally regulates bacterial gene expression at the post-transcriptional level. In many species, CsrA activity is governed by untranslated sRNAs, CsrB and CsrC in Escherichia coli, which bind to multiple CsrA dimers, sequestering them from lower affinity mRNA targets. Both the synthesis and turnover of CsrB/C are regulated. Their turnover requires the housekeeping endonuclease RNase E and is activated by the presence of a preferred carbon source via the binding of EIIA(Glc) of the glucose transport system to the GGDEF-EAL domain protein CsrD. We demonstrate that the CsrB 3' segment contains the features necessary for CsrD-mediated decay. RNase E cleavage in an unstructured segment located immediately upstream from the intrinsic terminator is necessary for subsequent degradation to occur. CsrA stabilizes CsrB against RNase E cleavage by binding to two canonical sites adjacent to the necessary cleavage site, while CsrD acts by overcoming CsrA mediated protection. Our genetic, biochemical and structural studies establish a molecular framework for sRNA turnover by the CsrD-RNase E pathway. We propose that CsrD evolution was driven by the selective advantage of decoupling Csr sRNA decay from CsrA binding, connecting it instead to the availability of a preferred carbon source. PMID- 27235417 TI - JAR3D Webserver: Scoring and aligning RNA loop sequences to known 3D motifs. AB - Many non-coding RNAs have been identified and may function by forming 2D and 3D structures. RNA hairpin and internal loops are often represented as unstructured on secondary structure diagrams, but RNA 3D structures show that most such loops are structured by non-Watson-Crick basepairs and base stacking. Moreover, different RNA sequences can form the same RNA 3D motif. JAR3D finds possible 3D geometries for hairpin and internal loops by matching loop sequences to motif groups from the RNA 3D Motif Atlas, by exact sequence match when possible, and by probabilistic scoring and edit distance for novel sequences. The scoring gauges the ability of the sequences to form the same pattern of interactions observed in 3D structures of the motif. The JAR3D webserver at http://rna.bgsu.edu/jar3d/ takes one or many sequences of a single loop as input, or else one or many sequences of longer RNAs with multiple loops. Each sequence is scored against all current motif groups. The output shows the ten best-matching motif groups. Users can align input sequences to each of the motif groups found by JAR3D. JAR3D will be updated with every release of the RNA 3D Motif Atlas, and so its performance is expected to improve over time. PMID- 27235418 TI - The effect of leaving groups on binding and reactivity in enzyme-free copying of DNA and RNA. AB - The template-directed incorporation of nucleotides at the terminus of a growing primer is the basis of the transmission of genetic information. Nature uses polymerases-catalyzed reactions, but enzyme-free versions exist that employ nucleotides with organic leaving groups. The leaving group affects yields, but it was not clear whether inefficient extensions are due to poor binding, low reactivity toward the primer, or rapid hydrolysis. We have measured the binding of a total of 15 different activated nucleotides to DNA or RNA sequences. Further, we determined rate constants for the chemical step of primer extension involving methylimidazolides or oxyazabenzotriazolides of deoxynucleotides or ribonucleotides. Binding constants range from 10 to >500 mM and rate constants from 0.1 to 370 M(-1) h(-1) For aminoterminal primers, a fast covalent step and slow hydrolysis are the main factors leading to high yields. For monomers with weakly pairing bases, the leaving group can improve binding significantly. A detailed mechanistic picture emerges that explains why some enzyme-free primer extensions occur in high yield, while others remain recalcitrant to copying without enzymatic catalysis. A combination of tight binding and rapid extension, coupled with slow hydrolysis induces efficient enzyme-free copying. PMID- 27235419 TI - Does Unc-GFP uncover ciliary structures in the rhabdomeric eye of Drosophila? AB - The uncoordinated (unc) gene product, a potential ortholog of mammalian orofaciodigital syndrome 1 (Ofd1), is involved in the assembly of the ciliary axoneme in Drosophila and it is, therefore, constrained to cell types that have ciliary structures, namely type 1 sensory neurons and male germ cells. Here, we show that evenly spaced Unc-GFP spots are present in the eye imaginal discs of third-instar larvae. These spots are restricted to the R8 photoreceptor cell of each ommatidium in association with mother centrioles. This finding is unexpected because the Drosophila eye is of the rhabdomeric type and would be expected to lack ciliary structures. PMID- 27235422 TI - Does depth of the frontal sinus affect near-infrared spectroscopy measurement? AB - Near-infrared spectroscopy (NIRS) is a non-invasive method that reflects real time cerebral oxygenation (rSO2) by the use of two adhesive optodes placed on the forehead of the patient. Frontal sinuses vary anatomically and a large frontal sinus might compromise the NIRS signal since the NIRS optodes are placed at the skin surface superficial to the underlying frontal sinus. The aim of this case series was to elucidate whether there is a difference in the obligate changes in rSO2 during cardiac surgery between patients with a small as opposed to a large anterior-posterior distance of the frontal sinus based on magnetic resonance imaging. Two matched groups with small (n = 5) vs. large (n = 5) frontal sinus (3.2 vs. 18.1 millimeters) in this case-series showed no difference in obligate changes of rSO2 (p = 0.54). PMID- 27235420 TI - Deleterious assembly of the lamin A/C mutant p.S143P causes ER stress in familial dilated cardiomyopathy. AB - Mutation of the LMNA gene, encoding nuclear lamin A and lamin C (hereafter lamin A/C), is a common cause of familial dilated cardiomyopathy (DCM). Among Finnish DCM patients, the founder mutation c.427T>C (p.S143P) is the most frequently reported genetic variant. Here, we show that p.S143P lamin A/C is more nucleoplasmic and soluble than wild-type lamin A/C and accumulates into large intranuclear aggregates in a fraction of cultured patient fibroblasts as well as in cells ectopically expressing either FLAG- or GFP-tagged p.S143P lamin A. In fluorescence loss in photobleaching (FLIP) experiments, non-aggregated EGFP tagged p.S143P lamin A was significantly more dynamic. In in vitro association studies, p.S143P lamin A failed to form appropriate filament structures but instead assembled into disorganized aggregates similar to those observed in patient cell nuclei. A whole-genome expression analysis revealed an elevated unfolded protein response (UPR) in cells expressing p.S143P lamin A/C. Additional endoplasmic reticulum (ER) stress induced by tunicamycin reduced the viability of cells expressing mutant lamin further. In summary, p.S143P lamin A/C affects normal lamina structure and influences the cellular stress response, homeostasis and viability. PMID- 27235421 TI - Ccndbp1 is a new positive regulator of skeletal myogenesis. AB - Skeletal myogenesis is a multistep process in which basic helix-loop-helix (bHLH) transcription factors, such as MyoD (also known as MyoD1), bind to E-boxes and activate downstream genes. Ccndbp1 is a HLH protein that lacks a DNA-binding region, and its function in skeletal myogenesis is currently unknown. We generated Ccndbp1-null mice by using CRISPR-Cas9. Notably, in Ccndbp1-null mice, the cross sectional area of the skeletal tibialis anterior muscle was smaller, and muscle regeneration ability and grip strength were impaired, compared with those of wild type. This phenotype resembled that of myofiber hypotrophy in some human myopathies or amyoplasia. Ccndbp1 expression was upregulated during C2C12 myogenesis. Ccndbp1 overexpression promoted myogenesis, whereas knockdown of Ccndbp1 inhibited myogenic differentiation. Co-transfection of Ccndbp1 with MyoD and/or E47 (encoded by TCF3) significantly enhanced E-box-dependent transcription. Furthermore, Ccndbp1 physically associated with MyoD but not E47. These data suggest that Ccndbp1 regulates muscle differentiation by interacting with MyoD and enhancing its binding to target genes. Our study newly identifies Ccndbp1 as a positive modulator of skeletal myogenic differentiation in vivo and in vitro, providing new insights in order to decipher the complex network involved in skeletal myogenic development and related diseases. PMID- 27235423 TI - Intermittent smoking and chronic kidney disease. PMID- 27235424 TI - Comparison of oral versus intravenous vitamin D receptor activator in reducing infection-related mortality in hemodialysis patients: the Q-Cohort Study. AB - BACKGROUND: Hemodialysis patients who receive vitamin D receptor activator (VDRA) reportedly have better survival after infection than those who do not. However, the optimal route of its administration for minimizing death from infection remains unclear. METHODS: This prospective cohort study aimed to compare the effectiveness of oral versus intravenous VDRA regarding infection-related mortality in 3372 hemodialysis patients. Eligible subjects were divided into the following three groups by route of administration of VDRA: oral (n = 1868), intravenous (n = 492) and not administered (n = 1012). The effect of VDRA on infection-related mortality was examined using a Cox regression model with propensity score-based adjustments. RESULTS: During follow-up (median, 4.0 years), 118 study patients died of infection. There was a significantly lower incidence of death from infection in subjects who received intravenous VDRA than in those who did not receive VDRA; however, oral VDRA did not significantly reduce the risk of mortality from infection compared with those who did not receive VDRA [hazard ratio (HR) for intravenous VDRA, 0.16; 95% confidence interval (CI), 0.10-0.25, and HR for oral VDRA, 0.78; 95% CI, 0.60-1.01]. Direct comparison between the oral and intravenous VDRA groups showed that the intravenous group had significantly better survival than the oral group (HR, 0.39; 95% CI, 0.27-0.62). CONCLUSIONS: Treatment with intravenous VDRA more effectively reduces the incidence of mortality from infection than oral VDRA in hemodialysis patients. PMID- 27235426 TI - Transformed occupational prospects for HIV-associated brain syndromes. AB - We report a case of a full-time worker with late undiagnosed HIV disease presenting as encephalopathy with motor features and a manic-like picture. HIV encephalopathy was a terminal condition before the advent of combination highly active anti-retroviral therapy (HAART). Treatment with HAART, with follow-up in a neuropsychiatric service and rehabilitation involving the occupational health department of his employer, produced a successful return to work. This case demonstrates a remarkable transformation in occupational and other outcomes of HIV-related brain disease in the era of HAART. PMID- 27235425 TI - The Spectrum and Clinical Impact of Epigenetic Modifier Mutations in Myeloma. AB - PURPOSE: Epigenetic dysregulation is known to be an important contributor to myeloma pathogenesis but, unlike other B-cell malignancies, the full spectrum of somatic mutations in epigenetic modifiers has not been reported previously. We sought to address this using the results from whole-exome sequencing in the context of a large prospective clinical trial of newly diagnosed patients and targeted sequencing in a cohort of previously treated patients for comparison. EXPERIMENTAL DESIGN: Whole-exome sequencing analysis of 463 presenting myeloma cases entered in the UK NCRI Myeloma XI study and targeted sequencing analysis of 156 previously treated cases from the University of Arkansas for Medical Sciences (Little Rock, AR). We correlated the presence of mutations with clinical outcome from diagnosis and compared the mutations found at diagnosis with later stages of disease. RESULTS: In diagnostic myeloma patient samples, we identify significant mutations in genes encoding the histone 1 linker protein, previously identified in other B-cell malignancies. Our data suggest an adverse prognostic impact from the presence of lesions in genes encoding DNA methylation modifiers and the histone demethylase KDM6A/UTX The frequency of mutations in epigenetic modifiers appears to increase following treatment most notably in genes encoding histone methyltransferases and DNA methylation modifiers. CONCLUSIONS: Numerous mutations identified raise the possibility of targeted treatment strategies for patients either at diagnosis or relapse supporting the use of sequencing-based diagnostics in myeloma to help guide therapy as more epigenetic targeted agents become available. Clin Cancer Res; 22(23); 5783-94. (c)2016 AACR. PMID- 27235427 TI - Shape Changes and Interaction Mechanism of Escherichia coli Cells Treated with Sericin and Use of a Sericin-Based Hydrogel for Wound Healing. AB - To verify the interaction mechanism between sericin and Escherichia coli, especially the morphological and structural changes in the bacterial cells, the antimicrobial activity of sericin against E. coli as a model for Gram-negative bacteria was investigated. The antibacterial activity of sericin on E. coli and the interaction mechanism were investigated in this study by analyzing the growth, integrity, and morphology of the bacterial cells following treatment with sericin. The changes in morphology and cellular compositions of bacterial cells treated with sericin were observed by an inverted fluorescence microscope, scanning electron microscopy, and transmission electron microscopy. Changes in electrical conductivity, total sugar concentration of the broth for the bacteria, and protein expression of the bacteria were determined to investigate the permeability of the cell membrane. A sericin-based hydrogel was prepared for an in vivo study of wound dressing. The results showed that the antibacterial activity of the hydrogel increased with the increase in the concentration of sericin from 10 g/liter to 40 g/liter. The introduction of sericin induces membrane blebbing of E. coli cells caused by antibiotic action on the cell membrane. The cytoplasm shrinkage phenomenon was accompanied by blurring of the membrane wall boundaries. When E. coli cells were treated with sericin, release of intracellular components quickly increased. The electrical conductivity assay indicated that the charged ions are reduced after exposure to sericin so that the integrity of the cell membrane is weakened and metabolism is blocked. In addition, sodium dodecyl sulfate-polyacrylamide gel electrophoresis demonstrated that sericin hinders the expression of bacterial protein. Sericin may damage the integrity of the bacterial cell membrane, thereby eventually inhibiting the growth and reproduction of E. coli Compared to sterile gauze, the sericin-based hydrogel promoted fibroblast cell proliferation and accelerated the formation of granulation tissues and neovessels. IMPORTANCE: The specific relationship and interaction mechanism between sericin and E. coli cells were investigated and elucidated. The results show that after 12 h of treatment, sericin molecules induce membrane blebbing of E. coli cells, and the bacteria show decreases in liquidity and permeability of biological membrane, resulting in alterations in the conductivity of the culture medium and the integrity of the outer membrane. The subsequent in vivo results demonstrate that the sericin-poly(N isopropylacrylamide-N,N'-methylene-bis-acrylamide [NIPAm-MBA]) hydrogel accelerated wound healing compared to that with sterile gauze, which is a beneficial result for future applications in clinical medicine and the textile, food, and coating industries. PMID- 27235428 TI - Anaplasma marginale Actively Modulates Vacuolar Maturation during Intracellular Infection of Its Tick Vector, Dermacentor andersoni. AB - Tick-borne transmission of bacterial pathogens in the order Rickettsiales is responsible for diverse infectious diseases, many of them severe, in humans and animals. Transmission dynamics differ among these pathogens and are reflected in the pathogen-vector interaction. Anaplasma marginale has been shown to establish and maintain infectivity within Dermacentor spp. for weeks to months while escaping the complex network of vacuolar peptidases that are responsible for digestion of the tick blood meal. How this prolonged maintenance of infectivity in a potentially hostile environment is achieved has been unknown. Using the natural vector Dermacentor andersoni, we demonstrated that A. marginale-infected tick vacuoles (AmVs) concurrently recruit markers of the early endosome (Rab5), recycling endosome (Rab4 and Rab11), and late endosome (Rab7), are maintained near neutral pH, do not fuse with lysosomes, exclude the protease cathepsin L, and engage the endoplasmic reticulum and Golgi apparatus for up to 21 days postinfection. Maintenance of this safe vacuolar niche requires active A. marginale protein synthesis; in its absence, the AmVs mature into acidic, protease-active phagolysosomes. Identification of this bacterially directed modeling of the tick midgut endosome provides a mechanistic basis for examination of the differences in transmission efficiency observed among A. marginale strains and among vector populations. IMPORTANCE: Ticks transmit a variety of intracellular bacterial pathogens that cause significant diseases in humans and animals. For successful transmission, these bacterial pathogens must first gain entry into the tick midgut digestive cells, avoid digestion, and establish a replicative niche without harming the tick vector. Little is known about how this replicative niche is established and maintained. Using the ruminant pathogen A. marginale and its natural tick vector, D. andersoni, this study characterized the features of the A. marginale niche in the tick midgut and demonstrates that A. marginale protein synthesis is required for the maintenance of this niche. This work opens a new line of inquiry about the pathogen effectors and their targets within the tick that mediate tick-pathogen interactions and ultimately serve as the determinants of pathogen success. PMID- 27235429 TI - The General Stress Response Is Conserved in Long-Term Soil-Persistent Strains of Escherichia coli. AB - Although Escherichia coli is generally considered to be predominantly a commensal of the gastrointestinal tract, a number of recent studies suggest that it is also capable of long-term survival and growth in environments outside the host. As the extraintestinal physical and chemical conditions are often different from those within the host, it is possible that distinct genetic adaptations may be required to enable this transition. Several studies have shown a trade-off between growth and stress resistance in nutrient-poor environments, with lesions in the rpoS locus, which encodes the stress sigma factor RpoS (sigma(S)). In this study, we investigated a unique collection of long-term soil-persistent E. coli isolates to determine whether the RpoS-controlled general stress response is altered during adaptation to a nutrient-poor extraintestinal environment. The sequence of the rpoS locus was found to be highly conserved in these isolates, and no nonsense or frameshift mutations were detected. Known RpoS-dependent phenotypes, including glycogen synthesis and gamma-aminobutyrate production, were found to be conserved in all strains. All strains expressed the full-length RpoS protein, which was fully functional using the RpoS-dependent promoter reporter fusion PgadX::gfp RpoS was shown to be essential for long-term soil survival of E. coli, since mutants lacking rpoS lost viability rapidly in soil survival assays. Thus, despite some phenotypic heterogeneity, the soil-persistent strains all retained a fully functional RpoS-regulated general stress response, which we interpret to indicate that the stresses encountered in soil provide a strong selective pressure for maintaining stress resistance, despite limited nutrient availability. IMPORTANCE: Escherichia coli has been, and continues to be, used as an important indicator species reflecting potential fecal contamination events in the environment. However, recent studies have questioned the validity of this, since E. coli has been found to be capable of long-term colonization of soils. This study investigated whether long-term soil-persistent E. coli strains have evolved altered stress resistance characteristics. In particular, the study investigated whether the main regulator of genes involved in stress protection, the sigma factor RpoS, has been altered in the soil-persistent strains. The results show that RpoS stress protection is fully conserved in soil-persistent strains of E. coli They also show that loss of the rpoS gene dramatically reduces the ability of this organism to survive in a soil environment. Overall, the results indicate that soil represents a stressful environment for E. coli, and their survival in it requires that they deploy a full stress protection response. PMID- 27235430 TI - Genome Evolution and Nitrogen Fixation in Bacterial Ectosymbionts of a Protist Inhabiting Wood-Feeding Cockroaches. AB - By combining genomics and isotope imaging analysis using high-resolution secondary ion mass spectrometry (NanoSIMS), we examined the function and evolution of Bacteroidales ectosymbionts of the protist Barbulanympha from the hindguts of the wood-eating cockroach Cryptocercus punctulatus In particular, we investigated the structure of ectosymbiont genomes, which, in contrast to those of endosymbionts, has been little studied to date, and tested the hypothesis that these ectosymbionts fix nitrogen. Unlike with most obligate endosymbionts, genome reduction has not played a major role in the evolution of the Barbulanympha ectosymbionts. Instead, interaction with the external environment has remained important for this symbiont as genes for synthesis of transporters, outer membrane proteins, lipopolysaccharides, and lipoproteins have been retained. The ectosymbiont genome carried two complete operons for nitrogen fixation, a urea transporter, and a urease, indicating the availability of nitrogen as a driving force behind the symbiosis. NanoSIMS analysis of C. punctulatus hindgut symbionts exposed in vivo to (15)N2 supports the hypothesis that Barbulanympha ectosymbionts are capable of nitrogen fixation. This genomic and in vivo functional investigation of protist ectosymbionts highlights the diversity of evolutionary forces and trajectories that shape symbiotic interactions. IMPORTANCE: The ecological and evolutionary importance of symbioses is increasingly clear, but the overall diversity of symbiotic interactions remains poorly explored. In this study, we investigated the evolution and nitrogen fixation capabilities of ectosymbionts attached to the protist Barbulanympha from the hindgut of the wood-eating cockroach Cryptocercus punctulatus In addressing genome evolution of protist ectosymbionts, our data suggest that the ecological pressures influencing the evolution of extracellular symbionts clearly differ from intracellular symbionts and organelles. Using NanoSIMS analysis, we also obtained direct imaging evidence of a specific hindgut microbe playing a role in nitrogen fixation. These results demonstrate the power of combining NanoSIMS and genomics tools for investigating the biology of uncultivable microbes. This investigation paves the way for a more precise understanding of microbial interactions in the hindguts of wood-eating insects and further exploration of the diversity and ecological significance of symbiosis between microbes. PMID- 27235431 TI - Host-Specific Patterns of Genetic Diversity among IncI1-Igamma and IncK Plasmids Encoding CMY-2 beta-Lactamase in Escherichia coli Isolates from Humans, Poultry Meat, Poultry, and Dogs in Denmark. AB - CMY-2 is the most common plasmid-mediated AmpC beta-lactamase in Escherichia coli isolates of human and animal origin. The aim of this study was to elucidate the epidemiology of CMY-2-producing E. coli in Denmark. Strain and plasmid relatedness was studied in 93 CMY-2-producing clinical and commensal E. coli isolates collected from 2006 to 2012 from humans, retail poultry meat, broilers, and dogs. Multilocus sequence typing (MLST), antimicrobial susceptibility testing, and conjugation were performed in conjunction with plasmid replicon typing, plasmid multilocus sequence typing (pMLST), restriction fragment length polymorphism (RFLP), and sequencing of selected blaCMY-2-harboring plasmids. MLST revealed high strain diversity, with few E. coli lineages occurring in multiple host species and sample types. blaCMY-2 was detected on plasmids in 83 (89%) isolates. Most (75%) of the plasmids were conjugative and did not (96%) cotransfer resistance to antimicrobials other than cephalosporins. The main replicon types identified were IncI1-Igamma (55%) and IncK (39%). Isolates from different host species mainly carried distinct plasmid subtypes. Seven of the 18 human isolates harbored IncI1-Igamma/sequence type 2 (ST2), IncI1-Igamma/ST12, or IncK plasmids highly similar to those found among animal isolates, even though highly related human and animal plasmids differed by nonsynonymous single nucleotide polymorphisms (SNPs) or insertion sequence elements. This study clearly demonstrates that the epidemiology of CMY-2 can be understood only by thorough plasmid characterization. To date, the spread of this beta-lactam resistance determinant in Denmark is mainly associated with IncK and IncI1-Igamma plasmids that are generally distributed according to host-specific patterns. These baseline data will be useful to assess the consequences of the increasing human exposure to CMY-2-producing E. coli via animal sources. IMPORTANCE: CMY-2 is the most common plasmid-mediated AmpC beta-lactamase in Escherichia coli This beta-lactamase is poorly inhibited by clavulanic acid and confers resistance to cephamycins, third-generation cephalosporins, and aztreonam. Furthermore, resistance to carbapenems has been reported in E. coli as a result of production of plasmid-encoded CMY-2 beta-lactamase in combination with decreased outer membrane permeability. The gene encoding CMY-2 generally resides on transferable plasmids belonging to different incompatibility groups. The prevalence of CMY-2 mediated cephalosporin resistance in E. coli varies significantly depending on the geographical region and host. This study demonstrates that the epidemiology of CMY-2 can be understood only by thorough plasmid characterization. To date, the spread of this beta-lactam resistance determinant in Denmark is mainly associated with IncK and IncI1-Igamma plasmids, which are generally distributed according to host-specific patterns. These data will be useful to assess the consequences of the increasing human exposure to CMY-2-producing E. coli via animal sources. PMID- 27235432 TI - Effects of Oxygen Availability on Acetic Acid Tolerance and Intracellular pH in Dekkera bruxellensis. AB - The yeast Dekkera bruxellensis, associated with wine and beer production, has recently received attention, because its high ethanol and acid tolerance enables it to compete with Saccharomyces cerevisiae in distilleries that produce fuel ethanol. We investigated how different cultivation conditions affect the acetic acid tolerance of D. bruxellensis We analyzed the ability of two strains (CBS 98 and CBS 4482) exhibiting different degrees of tolerance to grow in the presence of acetic acid under aerobic and oxygen-limited conditions. We found that the concomitant presence of acetic acid and oxygen had a negative effect on D. bruxellensis growth. In contrast, incubation under oxygen-limited conditions resulted in reproducible growth kinetics that exhibited a shorter adaptive phase and higher growth rates than those with cultivation under aerobic conditions. This positive effect was more pronounced in CBS 98, the more-sensitive strain. Cultivation of CBS 98 cells under oxygen-limited conditions improved their ability to restore their intracellular pH upon acetic acid exposure and to reduce the oxidative damage to intracellular macromolecules caused by the presence of acetic acid. This study reveals an important role of oxidative stress in acetic acid tolerance in D. bruxellensis, indicating that reduced oxygen availability can protect against the damage caused by the presence of acetic acid. This aspect is important for optimizing industrial processes performed in the presence of acetic acid. IMPORTANCE: This study reveals an important role of oxidative stress in acetic acid tolerance in D. bruxellensis, indicating that reduced oxygen availability can have a protective role against the damage caused by the presence of acetic acid. This aspect is important for the optimization of industrial processes performed in the presence of acetic acid. PMID- 27235433 TI - Hyperconcentrated Sweet Whey, a New Culture Medium That Enhances Propionibacterium freudenreichii Stress Tolerance. AB - Propionibacterium freudenreichii is used as a cheese-ripening starter and as a probiotic. Its reported physiological effects at the gut level, including modulation of bifidobacteria, colon epithelial cell proliferation and apoptosis, and intestinal inflammation, rely on active metabolism in situ Survival and activity are thus key factors determining its efficacy, creating stress adaptation and tolerance bottlenecks for probiotic applications. Growth media and growth conditions determine tolerance acquisition. We investigated the possibility of using sweet whey, a dairy by-product, to sustain P. freudenreichii growth. It was used at different concentrations (dry matter) as a culture medium. Using hyperconcentrated sweet whey led to enhanced multistress tolerance acquisition, overexpression of key stress proteins, and accumulation of intracellular storage molecules and compatible solutes, as well as enhanced survival upon spray drying. A simplified process from growth to spray drying of propionibacteria was developed using sweet whey as a 2-in-1 medium to both culture P. freudenreichii and protect it from heat and osmotic injury without harvesting and washing steps. As spray drying is far cheaper and more energy efficient than freeze-drying, this work opens new perspectives for the sustainable development of new starter and probiotic preparations with enhanced robustness. IMPORTANCE: In this study, we demonstrate that sweet whey, a dairy industry by-product, not only allows the growth of probiotic dairy propionibacteria, but also triggers a multitolerance response through osmoadaptation and general stress response. We also show that propionibacteria accumulate compatible solutes under these culture conditions, which might account for the limited loss of viability after spray drying. This work opens new perspectives for more energy-efficient production of dairy starters and probiotics. PMID- 27235434 TI - Evaluation of Various Campylobacter-Specific Quantitative PCR (qPCR) Assays for Detection and Enumeration of Campylobacteraceae in Irrigation Water and Wastewater via a Miniaturized Most-Probable-Number-qPCR Assay. AB - Campylobacter spp. are the leading cause of bacterial gastroenteritis worldwide, and water is increasingly seen as a risk factor in transmission. Here we describe a most-probable-number (MPN)-quantitative PCR (qPCR) assay in which water samples are centrifuged and aliquoted into microtiter plates and the bacteria are enumerated by qPCR. We observed that commonly used Campylobacter molecular assays produced vastly different detection rates. In irrigation water samples, detection rates varied depending upon the PCR assay and culture method used, as follows: 0% by the de Boer Lv1-16S qPCR assay, 2.5% by the Van Dyke 16S and Jensen glyA qPCR assays, and 75% by the Linton 16S endpoint PCR when cultured at 37 degrees C. Primer/probe specificity was the major confounder, with Arcobacter spp. routinely yielding false-positive results. The primers and PCR conditions described by Van Dyke et al. (M. I. Van Dyke, V. K. Morton, N. L. McLellan, and P. M. Huck, J Appl Microbiol 109:1053-1066, 2010, http://dx.doi.org/10.1111/j.1365 2672.2010.04730.x) proved to be the most sensitive and specific for Campylobacter detection in water. Campylobacter occurrence in irrigation water was found to be very low (<2 MPN/300 ml) when this Campylobacter-specific qPCR was used, with the most commonly detected species being C. jejuni, C. coli, and C. lari Campylobacters in raw sewage were present at ~10(2)/100 ml, with incubation at 42 degrees C required for reducing microbial growth competition from arcobacters. Overall, when Campylobacter prevalence and/or concentration in water is reported using molecular methods, considerable validation is recommended when adapting methods largely developed for clinical applications. Furthermore, combining MPN methods with molecular biology-based detection algorithms allows for the detection and quantification of Campylobacter spp. in environmental samples and is potentially suited to quantitative microbial risk assessment for improved public health disease prevention related to food and water exposures. IMPORTANCE: The results of this study demonstrate the importance of assay validation upon data interpretation of environmental monitoring for Campylobacter when using molecular biology-based assays. Previous studies describing Campylobacter prevalence in Canada utilized primers that we have determined to be nonspecific due to their cross-amplification of Arcobacter spp. As such, Campylobacter prevalence may have been vastly overestimated in other studies. Additionally, the development of a quantitative assay described in this study will allow accurate determination of Campylobacter concentrations in environmental water samples, allowing more informed decisions to be made about water usage based on quantitative microbial risk assessment. PMID- 27235435 TI - Phytophthora Species in Rivers and Streams of the Southwestern United States. AB - Phytophthora species were isolated from rivers and streams in the southwestern United States by leaf baiting and identified by sequence analysis of internal transcribed spacer (ITS) ribosomal DNA (rDNA). The major waterways examined included the Rio Grande River, Gila River, Colorado River, and San Juan River. The most prevalent species identified in rivers and streams were Phytophthora lacustris and P. riparia, both members of Phytophthora ITS clade 6. P. gonapodyides, P. cinnamomi, and an uncharacterized Phytophthora species in clade 9 were also recovered. In addition, six isolates recovered from the Rio Grande River were shown to be hybrids of P. lacustris * P. riparia Pathogenicity assays using P. riparia and P. lacustris failed to produce any disease symptoms on commonly grown crops in the southwestern United States. Inoculation of Capsicum annuum with P. riparia was shown to inhibit disease symptom development when subsequently challenged with P. capsici, a pathogenic Phytophthora species. IMPORTANCE: Many Phytophthora species are significant plant pathogens causing disease on a large variety of crops worldwide. Closer examinations of streams, rivers, and forest soils have also identified numerous Phytophthora species that do not appear to be phytopathogens and likely act as early saprophytes in aquatic and saturated environments. To date, the Phytophthora species composition in rivers and streams of the southwestern United States has not been evaluated. This article details a study to determine the identity and prevalence of Phytophthora species in rivers and streams located in New Mexico, Arizona, Colorado, Utah, and Texas. Isolated species were evaluated for pathogenicity on crop plants and for their potential to act as biological control agents. PMID- 27235436 TI - Detection of Antibiotic Resistance Genes in Source and Drinking Water Samples from a First Nations Community in Canada. AB - Access to safe drinking water is now recognized as a human right by the United Nations. In developed countries like Canada, access to clean water is generally not a matter of concern. However, one in every five First Nations reserves is under a drinking water advisory, often due to unacceptable microbiological quality. In this study, we analyzed source and potable water from a First Nations community for the presence of coliform bacteria as well as various antibiotic resistance genes. Samples, including those from drinking water sources, were found to be positive for various antibiotic resistance genes, namely, ampC, tet(A), mecA, beta-lactamase genes (SHV-type, TEM-type, CTX-M-type, OXA-1, and CMY-2-type), and carbapenemase genes (KPC, IMP, VIM, NDM, GES, and OXA-48 genes). Not surprisingly, substantial numbers of total coliforms, including Escherichia coli, were recovered from these samples, and this result was also confirmed using Illumina sequencing of the 16S rRNA gene. These findings deserve further attention, as the presence of coliforms and antibiotic resistance genes potentially puts the health of the community members at risk. IMPORTANCE: In this study, we highlight the poor microbiological quality of drinking water in a First Nations community in Canada. We examined the coliform load as well as the presence of antibiotic resistance genes in these samples. This study examined the presence of antibiotic-resistant genes in drinking water samples from a First Nations Community in Canada. We believe that our findings are of considerable significance, since the issue of poor water quality in First Nations communities in Canada is often ignored, and our findings will help shed some light on this important issue. PMID- 27235437 TI - How To Live with Phosphorus Scarcity in Soil and Sediment: Lessons from Bacteria. AB - Phosphorus (P) plays a fundamental role in the physiology and biochemistry of all living things. Recent evidence indicates that organisms in the oceans can break down and use P forms in different oxidation states (e.g., +5, +3, +1, and -3); however, information is lacking for organisms from soil and sediment. The Cuatro Cienegas Basin (CCB), Mexico, is an oligotrophic ecosystem with acute P limitation, providing a great opportunity to assess the various strategies that bacteria from soil and sediment use to obtain P. We measured the activities in sediment and soil of different exoenzymes involved in P recycling and evaluated 1,163 bacterial isolates (mainly Bacillus spp.) for their ability to use six different P substrates. DNA turned out to be a preferred substrate, comparable to a more bioavailable P source, potassium phosphate. Phosphodiesterase activity, required for DNA degradation, was observed consistently in the sampled-soil and sediment communities. A capability to use phosphite (PO3 (3-)) and calcium phosphate was observed mainly in sediment isolates. Phosphonates were used at a lower frequency by both soil and sediment isolates, and phosphonatase activity was detected only in soil communities. Our results revealed that soil and sediment bacteria are able to break down and use P forms in different oxidation states and contribute to ecosystem P cycling. Different strategies for P utilization were distributed between and within the different taxonomic lineages analyzed, suggesting a dynamic movement of P utilization traits among bacteria in microbial communities. IMPORTANCE: Phosphorus (P) is an essential element for life found in molecules, such as DNA, cell walls, and in molecules for energy transfer, such as ATP. The Valley of Cuatro Cienegas, Coahuila (Mexico), is a unique desert characterized by an extreme limitation of P and a great diversity of microbial life. How do bacteria in this valley manage to obtain P? We measured the availability of P and the enzymatic activity associated with P release in soil and sediment. Our results revealed that soil and sediment bacteria can break down and use P forms in different oxidation states and contribute to ecosystem P cycling. Even genetically related bacterial isolates exhibited different preferences for molecules, such as DNA, calcium phosphate, phosphite, and phosphonates, as substrates to obtain P, evidencing a distribution of roles for P utilization and suggesting a dynamic movement of P utilization traits among bacteria in microbial communities. PMID- 27235438 TI - Regulation of the Cobalt/Nickel Efflux Operon dmeRF in Agrobacterium tumefaciens and a Link between the Iron-Sensing Regulator RirA and Cobalt/Nickel Resistance. AB - The Agrobacterium tumefaciens C58 genome harbors an operon containing the dmeR (Atu0890) and dmeF (Atu0891) genes, which encode a transcriptional regulatory protein belonging to the RcnR/CsoR family and a metal efflux protein belonging to the cation diffusion facilitator (CDF) family, respectively. The dmeRF operon is specifically induced by cobalt and nickel, with cobalt being the more potent inducer. Promoter-lacZ transcriptional fusion, an electrophoretic mobility shift assay, and DNase I footprinting assays revealed that DmeR represses dmeRF transcription through direct binding to the promoter region upstream of dmeR A strain lacking dmeF showed increased accumulation of intracellular cobalt and nickel and exhibited hypersensitivity to these metals; however, this strain displayed full virulence, comparable to that of the wild-type strain, when infecting a Nicotiana benthamiana plant model under the tested conditions. Cobalt, but not nickel, increased the expression of many iron-responsive genes and reduced the induction of the SoxR-regulated gene sodBII Furthermore, control of iron homeostasis via RirA is important for the ability of A. tumefaciens to cope with cobalt and nickel toxicity. IMPORTANCE: The molecular mechanism of the regulation of dmeRF transcription by DmeR was demonstrated. This work provides evidence of a direct interaction of apo-DmeR with the corresponding DNA operator site in vitro The recognition site for apo-DmeR consists of 10-bp AT-rich inverted repeats separated by six C bases (5'-ATATAGTATACCCCCCTATAGTATAT-3'). Cobalt and nickel cause DmeR to dissociate from the dmeRF promoter, which leads to expression of the metal efflux gene dmeF This work also revealed a connection between iron homeostasis and cobalt/nickel resistance in A. tumefaciens. PMID- 27235439 TI - Evidence for a Role for the Plasma Membrane in the Nanomechanical Properties of the Cell Wall as Revealed by an Atomic Force Microscopy Study of the Response of Saccharomyces cerevisiae to Ethanol Stress. AB - A wealth of biochemical and molecular data have been reported regarding ethanol toxicity in the yeast Saccharomyces cerevisiae However, direct physical data on the effects of ethanol stress on yeast cells are almost nonexistent. This lack of information can now be addressed by using atomic force microscopy (AFM) technology. In this report, we show that the stiffness of glucose-grown yeast cells challenged with 9% (vol/vol) ethanol for 5 h was dramatically reduced, as shown by a 5-fold drop of Young's modulus. Quite unexpectedly, a mutant deficient in the Msn2/Msn4 transcription factor, which is known to mediate the ethanol stress response, exhibited a low level of stiffness similar to that of ethanol treated wild-type cells. Reciprocally, the stiffness of yeast cells overexpressing MSN2 was about 35% higher than that of the wild type but was nevertheless reduced 3- to 4-fold upon exposure to ethanol. Based on these and other data presented herein, we postulated that the effect of ethanol on cell stiffness may not be mediated through Msn2/Msn4, even though this transcription factor appears to be a determinant in the nanomechanical properties of the cell wall. On the other hand, we found that as with ethanol, the treatment of yeast with the antifungal amphotericin B caused a significant reduction of cell wall stiffness. Since both this drug and ethanol are known to alter, albeit by different means, the fluidity and structure of the plasma membrane, these data led to the proposition that the cell membrane contributes to the biophysical properties of yeast cells. IMPORTANCE: Ethanol is the main product of yeast fermentation but is also a toxic compound for this process. Understanding the mechanism of this toxicity is of great importance for industrial applications. While most research has focused on genomic studies of ethanol tolerance, we investigated the effects of ethanol at the biophysical level and found that ethanol causes a strong reduction of the cell wall rigidity (or stiffness). We ascribed this effect to the action of ethanol perturbing the cell membrane integrity and hence proposed that the cell membrane contributes to the cell wall nanomechanical properties. PMID- 27235440 TI - Environmental Sequencing Provides Reasonable Estimates of the Relative Abundance of Specific Picoeukaryotes. AB - High-throughput sequencing (HTS) is revolutionizing environmental surveys of microbial diversity in the three domains of life by providing detailed information on which taxa are present in microbial assemblages. However, it is still unclear how the relative abundance of specific taxa gathered by HTS correlates with cell abundances. Here, we quantified the relative cell abundance of 6 picoeukaryotic taxa in 13 planktonic samples from 6 European coastal sites using epifluorescence microscopy on tyramide signal amplification-fluorescence in situ hybridization preparations. These relative abundance values were then compared with HTS data obtained in three separate molecular surveys: 454 sequencing of the V4 region of the 18S ribosomal DNA (rDNA) using DNA and RNA extracts (DNA-V4 and cDNA-V4) and Illumina sequencing of the V9 region (cDNA-V9). The microscopic and molecular signals were generally correlated, indicating that a relative increase in specific 18S rDNA was the result of a large proportion of cells in the given taxa. Despite these positive correlations, the slopes often deviated from 1, precluding a direct translation of sequences to cells. Our data highlighted clear differences depending on the nucleic acid template or the 18S rDNA region targeted. Thus, the molecular signal obtained using cDNA templates was always closer to relative cell abundances, while the V4 and V9 regions gave better results depending on the taxa. Our data support the quantitative use of HTS data but warn about considering it as a direct proxy of cell abundances. IMPORTANCE: Direct studies on marine picoeukaryotes by epifluorescence microscopy are problematic due to the lack of morphological features and due to the limited number and poor resolution of specific phylogenetic probes used in fluorescence in situ hybridization (FISH) routines. As a consequence, there is an increasing use of molecular methods, including high-throughput sequencing (HTS), to study marine microbial diversity. HTS can provide a detailed picture of the taxa present in a community and can reveal diversity not evident using other methods, but it is still unclear what the meaning of the sequence abundance in a given taxon is. Our aim is to investigate the correspondence between the relative HTS signal and relative cell abundances in selected picoeukaryotic taxa. Environmental sequencing provides reasonable estimates of the relative abundance of specific taxa. Better results are obtained when using RNA extracts as the templates, while the region of 18S ribosomal DNA had different influences depending on the taxa assayed. PMID- 27235441 TI - Vibrio anguillarum Is Genetically and Phenotypically Unaffected by Long-Term Continuous Exposure to the Antibacterial Compound Tropodithietic Acid. AB - Minimizing the use of antibiotics in the food production chain is essential for limiting the development and spread of antibiotic-resistant bacteria. One alternative intervention strategy is the use of probiotic bacteria, and bacteria of the marine Roseobacter clade are capable of antagonizing fish-pathogenic vibrios in fish larvae and live feed cultures for fish larvae. The antibacterial compound tropodithietic acid (TDA), an antiporter that disrupts the proton motive force, is key in the antibacterial activity of several roseobacters. Introducing probiotics on a larger scale requires understanding of any potential side effects of long-term exposure of the pathogen to the probionts or any compounds they produce. Here we exposed the fish pathogen Vibrio anguillarum to TDA for several hundred generations in an adaptive evolution experiment. No tolerance or resistance arose during the 90 days of exposure, and whole-genome sequencing of TDA-exposed lineages and clones revealed few mutational changes, compared to lineages grown without TDA. Amino acid-changing mutations were found in two to six different genes per clone; however, no mutations appeared unique to the TDA exposed lineages or clones. None of the virulence genes of V. anguillarum was affected, and infectivity assays using fish cell lines indicated that the TDA exposed lineages and clones were less invasive than the wild-type strain. Thus, long-term TDA exposure does not appear to result in TDA resistance and the physiology of V. anguillarum appears unaffected, supporting the application of TDA-producing roseobacters as probiotics in aquaculture. IMPORTANCE: It is important to limit the use of antibiotics in our food production, to reduce the risk of bacteria developing antibiotic resistance. We showed previously that marine bacteria of the Roseobacter clade can prevent or reduce bacterial diseases in fish larvae, acting as probiotics. Roseobacters produce the antimicrobial compound tropodithietic acid (TDA), and we were concerned regarding whether long term exposure to this compound could induce resistance or affect the disease causing ability of the fish pathogen. Therefore, we exposed the fish pathogen Vibrio anguillarum to increasing TDA concentrations over 3 months. We did not see the development of any resistance to TDA, and subsequent infection assays revealed that none of the TDA-exposed clones had increased virulence toward fish cells. Hence, this study supports the use of roseobacters as a non-risk-based disease control measure in aquaculture. PMID- 27235442 TI - Effects of Bacterial Community Members on the Proteome of the Ammonia-Oxidizing Bacterium Nitrosomonas sp. Strain Is79. AB - Microorganisms in the environment do not exist as the often-studied pure cultures but as members of complex microbial communities. Characterizing the interactions within microbial communities is essential to understand their function in both natural and engineered environments. In this study, we investigated how the presence of a nitrite-oxidizing bacterium (NOB) and heterotrophic bacteria affect the growth and proteome of the chemolithoautotrophic ammonia-oxidizing bacterium (AOB) Nitrosomonas sp. strain Is79. We investigated Nitrosomonas sp. Is79 in co culture with Nitrobacter winogradskyi, in co-cultures with selected heterotrophic bacteria, and as a member of the nitrifying enrichment culture G5-7. In batch culture, N. winogradskyi and heterotrophic bacteria had positive effects on the growth of Nitrosomonas sp. Is79. An isobaric tag for relative and absolute quantification (iTRAQ) liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomics approach was used to investigate the effect of N. winogradskyi and the co-cultured heterotrophic bacteria from G5-7 on the proteome of Nitrosomonas sp. Is79. In co-culture with N. winogradskyi, several Nitrosomonas sp. Is79 oxidative stress response proteins changed in abundance, with periplasmic proteins increasing and cytoplasmic proteins decreasing in abundance. In the presence of heterotrophic bacteria, the abundance of proteins directly related to the ammonia oxidation pathway increased, while the abundance of proteins related to amino acid synthesis and metabolism decreased. In summary, the proteome of Nitrosomonas sp. Is79 was differentially influenced by the presence of either N. winogradskyi or heterotrophic bacteria. Together, N. winogradskyi and heterotrophic bacteria reduced the oxidative stress for Nitrosomonas sp. Is79, which resulted in more efficient metabolism. IMPORTANCE: Aerobic ammonia-oxidizing microorganisms play an important role in the global nitrogen cycle, converting ammonia to nitrite. In their natural environment, they coexist and interact with nitrite oxidizers, which convert nitrite to nitrate, and with heterotrophic microorganisms. The presence of nitrite oxidizers and heterotrophic bacteria has a positive influence on the growth of the ammonia oxidizers. Here, we present a study investigating the effect of nitrite oxidizers and heterotrophic bacteria on the proteome of a selected ammonia oxidizer in a defined culture to elucidate how these two groups improve the performance of the ammonia oxidizer. The results show that the presence of a nitrite oxidizer and heterotrophic bacteria reduced the stress for the ammonia oxidizer and resulted in more efficient energy generation. This study contributes to our understanding of microbe-microbe interactions, in particular between ammonia oxidizers and their neighboring microbial community. PMID- 27235443 TI - Population Genetic Structure of Listeria monocytogenes Strains as Determined by Pulsed-Field Gel Electrophoresis and Multilocus Sequence Typing. AB - Listeria monocytogenes is a ubiquitous bacterium that may cause the foodborne illness listeriosis. Only a small amount of data about the population genetic structure of strains isolated from food is available. This study aimed to provide an accurate view of the L. monocytogenes food strain population in France. From 1999 to 2014, 1,894 L. monocytogenes strains were isolated from food at the French National Reference Laboratory for L. monocytogenes and classified according to the five risk food matrices defined by the European Food Safety Authority (EFSA). A total of 396 strains were selected on the basis of different pulsed-field gel electrophoresis (PFGE) clusters, serotypes, and strain origins and typed by multilocus sequence typing (MLST), and the MLST results were supplemented with MLST data available from Institut Pasteur, representing human and additional food strains from France. The distribution of sequence types (STs) was compared between food and clinical strains on a panel of 675 strains. High congruence between PFGE and MLST was found. Out of 73 PFGE clusters, the two most prevalent corresponded to ST9 and ST121. Using original statistical analysis, we demonstrated that (i) there was not a clear association between ST9 and ST121 and the food matrices, (ii) serotype IIc, ST8, and ST4 were associated with meat products, and (iii) ST13 was associated with dairy products. Of the two major STs, ST121 was the ST that included the fewest clinical strains, which might indicate lower virulence. This observation may be directly relevant for refining risk analysis models for the better management of food safety. IMPORTANCE: This study showed a very useful backward compatibility between PFGE and MLST for surveillance. The results enabled better understanding of the population structure of L. monocytogenes strains isolated from food and management of the health risks associated with L. monocytogenes food strains. Moreover, this work provided an accurate view of L. monocytogenes strain populations associated with specific food matrices. We clearly showed that some STs were associated with food matrices, such as meat, meat products, and dairy products. We opened the way to source attribution modeling in order to quantify the relative importance of the main food matrices. PMID- 27235444 TI - Distance-Decay Relationship for Biological Wastewater Treatment Plants. AB - Patterns in the spatial distribution of organisms provide important information about mechanisms underlying biodiversity and the complexity of ecosystems. One of the most well-documented spatial patterns is the distance-decay relationship, which is a universal biogeographic pattern observed repeatedly for plant and animal communities, particularly for microorganisms in natural ecosystems such as soil, ocean, and salt marsh sediment. However, it is uncertain whether the microorganisms exhibit a distance-decay pattern in engineered ecosystems. Therefore, we measured the distance-decay relationship across various microbial functional and phylogenetic groups in 26 biological wastewater treatment plants (WWTPs) in China using a functional gene array (GeoChip 4.2). We found that microbial communities of activated sludge in WWTPs exhibited a significant but very weak distance-decay relationship. The taxon-area z values for different functional and phylogenetic groups were <0.0065, which is about 1 to 2 orders of magnitude lower than those observed in microbial communities elsewhere. Variation partitioning analysis (VPA) showed that the relationships were driven by both environmental heterogeneity and geographic distance. Collectively, these results provided new insights into the spatial scaling of microbial communities in engineering ecosystems and highlighted the importance of environmental heterogeneity and geographic distance in shaping biogeographic patterns. IMPORTANCE: Determining the distance-decay relationship of microbial biodiversity is important but challenging in microbial ecology. All studies to date are based on natural environments; thus, it remains unclear whether there is such a relationship in an engineered ecosystem. The present study shows that there is a very weak distance-decay relationship in an engineered ecosystem (WWTPs) at the regional-to-continental scale. This study makes fundamental contributions to a mechanistic, predictive understanding of microbial biogeography. PMID- 27235445 TI - Fasting Is Not Routinely Required for Determination of a Lipid Profile: Clinical and Laboratory Implications Including Flagging at Desirable Concentration Cutpoints-A Joint Consensus Statement from the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine. AB - AIMS: To critically evaluate the clinical implications of the use of non-fasting rather than fasting lipid profiles and to provide guidance for the laboratory reporting of abnormal non-fasting or fasting lipid profiles. METHODS AND RESULTS: Extensive observational data, in which random non-fasting lipid profiles have been compared with those determined under fasting conditions, indicate that the maximal mean changes at 1-6 h after habitual meals are not clinically significant [+0.3 mmol/L (26 mg/dL) for triglycerides; -0.2 mmol/L (8 mg/dL) for total cholesterol; -0.2 mmol/L (8 mg/dL) for LDL cholesterol; +0.2 mmol/L (8 mg/dL) for calculated remnant cholesterol; -0.2 mmol/L (8 mg/dL) for calculated non-HDL cholesterol]; concentrations of HDL cholesterol, apolipoprotein A1, apolipoprotein B, and lipoprotein(a) are not affected by fasting/non-fasting status. In addition, non-fasting and fasting concentrations vary similarly over time and are comparable in the prediction of cardiovascular disease. To improve patient compliance with lipid testing, we therefore recommend the routine use of non-fasting lipid profiles, whereas fasting sampling may be considered when non fasting triglycerides are >5 mmol/L (440 mg/dL). For non-fasting samples, laboratory reports should flag abnormal concentrations as triglycerides >=2 mmol/L (175 mg/dL), total cholesterol >=5 mmol/L (190 mg/dL), LDL cholesterol >=3 mmol/L (115 mg/dL), calculated remnant cholesterol >=0.9 mmol/L (35 mg/dL), calculated non-HDL cholesterol >=3.9 mmol/L (150 mg/dL), HDL cholesterol <=1 mmol/L (40 mg/dL), apolipoprotein A1 <=1.25 g/L (125 mg/dL), apolipoprotein B >=1.0 g/L (100 mg/dL), and lipoprotein(a) >=50 mg/dL (80th percentile); for fasting samples, abnormal concentrations correspond to triglycerides >=1.7 mmol/L (150 mg/dL). Life-threatening concentrations require separate referral for the risk of pancreatitis when triglycerides are >10 mmol/L (880 mg/dL), for homozygous familial hypercholesterolemia when LDL cholesterol is >13 mmol/L (500 mg/dL), for heterozygous familial hypercholesterolemia when LDL cholesterol is >5 mmol/L (190 mg/dL), and for very high cardiovascular risk when lipoprotein(a) >150 mg/dL (99th percentile). CONCLUSIONS: We recommend that non-fasting blood samples be routinely used for the assessment of plasma lipid profiles. Laboratory reports should flag abnormal values on the basis of desirable concentration cutpoints. Non-fasting and fasting measurements should be complementary but not mutually exclusive. PMID- 27235446 TI - Asphyxia, Neurologic Morbidity, and Perinatal Mortality in Early-Term and Postterm Birth. AB - BACKGROUND AND OBJECTIVES: Neonatal outcomes vary by gestational age. We evaluated the association of early-term, full-term, and postterm birth with asphyxia, neurologic morbidity, and perinatal mortality. METHODS: Our register based study used retrospective data on 214 465 early-term (37(+0)-38(+6) gestational weeks), 859 827 full-term (39(+0)-41(+6)), and 55 189 postterm (>=42(+0)) live-born singletons during 1989-2008 in Finland. Asphyxia parameters were umbilical cord pH and Apgar score at 1 and 5 minutes. Neurologic morbidity outcome measures were cerebral palsy (CP), epilepsy, intellectual disability, and sensorineural defects diagnosed by the age of 4 years. Newborns with major congenital anomalies were excluded from perinatal deaths. RESULTS: Multivariate analysis showed that, compared with full-term pregnancies, early-term birth increased the risk for low Apgar score (<4) at 1 and 5 minutes (odds ratio 1.03, 95% confidence interval 1.03-1.04 and 1.24, 1.04-1.49, respectively), CP (1.40, 1.27-1.55), epilepsy (1.14, 1.06-1.23), intellectual disability (1.39, 1.27 1.53), sensorineural defects (1.24, 1.17-1.31), and perinatal mortality (2.40, 2.14-2.69), but risk for low umbilical artery pH <=7.10 was decreased (0.83, 0.79 0.87). Postterm birth increased the risk for low Apgar score (<4) at 1 minute (1.26, 1.26-1.26) and 5 minutes (1.80, 1.43-2.34), low umbilical artery pH <=7.10 (1.26, 1.19-1.34), and intellectual disability (1.19, 1.00-1.43), whereas risks for CP (1.03, 0.84-1.26), epilepsy (1.00, 0.87-1.15), sensorineural defects (0.96, 0.86-1.07), and perinatal mortality (0.91, 0.69-1.22) were not increased. CONCLUSIONS: Early-term birth was associated with low Apgar score, increased neurologic morbidity, and perinatal mortality. Asphyxia and intellectual disability were more common among postterm births, but general neurologic morbidity and perinatal mortality were not increased. PMID- 27235447 TI - Childhood Infections, Socioeconomic Status, and Adult Cardiometabolic Risk. AB - BACKGROUND AND OBJECTIVES: Socioeconomic disadvantage throughout the life course is associated with increased risk of cardiometabolic diseases, but traditional risk factors do not fully account for the social gradient. We investigated the interactions between low socioeconomic status (SES) and infection in childhood and adverse cardiometabolic parameters in adulthood. METHODS: Participants from the Cardiovascular Risk in Young Finns Study, a cohort well phenotyped for childhood and adulthood cardiometabolic risk factors and socioeconomic parameters, were linked to lifetime hospitalization data from birth onward available from the Finnish National Hospital Registry. In those with complete data, we investigated relationships between infection-related hospitalization in childhood, SES, and childhood and adult cardiometabolic parameters. RESULTS: The study cohort consisted of 1015 participants (age range 3-18 years at baseline and 30-45 years at follow-up). In adults who were raised in below-median income families, childhood infection-related hospitalizations (at age 0-5 years) were significantly associated with higher adult BMI (beta +/- SE comparing those with 0 vs >=1 hospitalizations 2.4 +/- 0.8 kg/m(2), P = .008), waist circumference (7.4 +/- 2.3 cm, P = .004), and reduced brachial flow-mediated dilatation (-2.7 +/- 0.9%, P = .002). No equivalent associations were observed in participants from higher-SES families. CONCLUSIONS: Infection was associated with worse cardiovascular risk factor profiles only in those from lower-SES families. Childhood infection may contribute to social gradients observed in adult cardiometabolic disease risk factors. These findings suggest reducing childhood infections, especially in socioeconomic disadvantaged children, may reduce the cardiometabolic disease burden in adults. PMID- 27235448 TI - Haplotype and diplotype analyses of variation in ERCC5 transcription cis regulation in normal bronchial epithelial cells. AB - Excision repair cross-complementation group 5 (ERCC5) gene plays an important role in nucleotide excision repair, and dysregulation of ERCC5 is associated with increased lung cancer risk. Haplotype and diplotype analyses were conducted in normal bronchial epithelial cells (NBEC) to better understand mechanisms responsible for interindividual variation in transcript abundance regulation of ERCC5 We determined genotypes at putative ERCC5 cis-regulatory SNPs (cis-rSNP) rs751402 and rs2296147, and marker SNPs rs1047768 and rs17655. ERCC5 allele specific transcript abundance was assessed by a recently developed targeted sequencing method. Syntenic relationships among alleles at rs751402, rs2296147, and rs1047768 were assessed by allele-specific PCR followed by Sanger sequencing. We then assessed association of ERCC5 allele-specific expression at rs1047768 with haplotype and diplotype structure at cis-rSNPs rs751402 and rs2296147. Genotype analysis revealed significantly (P < 0.005) higher interindividual variation in allelic ratios in cDNA samples relative to matched gDNA samples at both rs1047768 and rs17655. By diplotype analysis, mean expression was higher at the rs1047768 alleles syntenic with rs2296147 T allele compared with rs2296147 C allele. Furthermore, mean expression was lower at rs17655 C allele, which is syntenic with G allele at a linked SNP rs873601 (D' = 0.95). These data support the conclusions that in NBEC, T allele at SNP rs2296147 upregulates ERCC5, variation at rs751402 does not alter ERCC5 regulation, and that C allele at SNP rs17655 downregulates ERCC5 Variation in ERCC5 transcript abundance associated with allelic variation at these SNPs could result in variation in NER function in NBEC and lung cancer risk. PMID- 27235449 TI - Coronary artery disease susceptibility gene ADTRP regulates cell cycle progression, proliferation, and apoptosis by global gene expression regulation. AB - The ADTRP gene encodes the androgen-dependent TFPI-regulating protein and is a susceptibility gene for contrary artery disease (CAD). We performed global gene expression profiling for ADTRP knock-down using microarrays in human HepG2 cells. Follow-up real-time RT-PCR analysis demonstrated that ADTRP knock-down regulates a diverse set of genes, including upregulation of seven histone genes, downregulation of multiple cell cycle genes (CCND1, CDK4, and CDKN1A), and upregulation of apoptosis genes (CASP7 and PDCD2) in HepG2 cells and endothelial cells. Consistently, ADTRP increases the number of S phase cells during cell cycle, promotes cell proliferation, and inhibits apoptosis. Our study provides novel insights into the function of ADTRP and biological pathways involving ADTRP, which may be involved in the pathogenesis of CAD. PMID- 27235450 TI - Loss of bone marrow adrenergic beta 1 and 2 receptors modifies transcriptional networks, reduces circulating inflammatory factors, and regulates blood pressure. AB - Hypertension (HTN) is a prevalent condition with complex etiology and pathophysiology. Evidence exists of significant communication between the nervous system and the immune system (IS), and there appears to be a direct role for inflammatory bone marrow (BM) cells in the pathophysiology of hypertension. However, the molecular and neural mechanisms underlying this interaction have not been characterized. Here, we transplanted whole BM cells from the beta 1 and 2 adrenergic receptor (AdrB1(tm1Bkk)AdrB2(tm1Bkk)/J) knockout (KO) mice into near lethally irradiated C57BL/6J mice to generate a BM AdrB1.B2 KO chimera. This allowed us to evaluate the role of the BM beta 1 and beta 2 adrenergic receptors in mediating BM IS homeostasis and regulating blood pressure (BP) in an otherwise intact physiological setting. Fluorescence-activated cell sorting demonstrated that a decrease in systolic and mean BP in the AdrB1.B2 KO chimera is associated with a decrease in circulating inflammatory T cells, macrophage/monocytes, and neutrophils. Transcriptomics in the BM identified 7,419 differentially expressed transcripts between the C57 and AdrB1.B2 KO chimera. Pathway analysis revealed differentially expressed transcripts related to several cell processes in the BM of C57 compared with AdrB1.B2 KO chimera, including processes related to immunity (e.g., T-cell activation, T-cell recruitment, cytokine production, leukocyte migration and function), the cardiovascular system (e.g., blood vessel development, peripheral nerve blood flow), and the brain (e.g., central nervous system development, neurite development) among others. This study generates new insight into the molecular events that underlie the interaction between the sympathetic drive and IS in modulation of BP. PMID- 27235452 TI - Letter to the Editor. PMID- 27235451 TI - Correlation of CT imaging features and tumor size with Fuhrman grade of clear cell renal cell carcinoma. AB - Background Identification of clinical features to determine the aggressive potential of tumors is highly warranted to stratify patients for adequate treatment. Computed tomography (CT) imaging features of clear cell renal cell carcinoma (ccRCC) may contribute to personalized risk assessment. Purpose To assess the correlation between CT imaging features and Fuhrman grade of ccRCC, and to identify the predictors of high Fuhrman grade in conjunction with tumor size. Material and Methods CT scans of 169 patients with 173 pathologically proven ccRCCs were retrospectively reviewed in consensus by two radiologists for the presence of intratumoral necrosis and intratumoral cyst and tumor size. Histologic grade was classified as either low (Fuhrman grade I or II) or high (Fuhrman grade III or IV). Statistical significance was evaluated by using univariate, multivariate regression, receiver operating characteristic (ROC) curve, and Spearman correlation analyses. Results On CT, 20 of the 173 tumors had intratumoral cysts, 60 had intratumoral necrosis, and 93 showed entirely solid tumors. The odds of high grade were higher with intratumoral necrosis and entirely solid tumor than with intratumoral cyst ( P < 0.03). Intratumoral necrosis showed a significantly high odds ratio of 25.73 for high Fuhrman grade. The ROC curve showed a threshold tumor size of 36 mm to predict high Fuhrman grade for overall tumors (area under the ROC curve, 0.70). In ccRCCs with intratumoral necrosis or cyst, tumor size did not significantly correlate with Fuhrman grade. Conclusion Intratumoral necrosis on CT was a strong and independent predictor of biologically aggressive ccRCCs, irrespective of tumor size. PMID- 27235453 TI - Influence of fractional anisotropy thresholds on diffusion tensor imaging tractography of the periprostatic neurovascular bundle and selected pelvic tissues: do visualized tracts really represent nerves? AB - Background Diffusion tensor imaging (DTI) tractography has recently been shown to successfully visualize periprostatic tracts allegedly representing the neurovascular bundle. Purpose To examine the impact of different fractional anisotropy (FA) thresholds on the results of DTI tractography in the male pelvis as well as to evaluate the resulting specificity for nerve tracts. Material and Methods Ten healthy male volunteers were examined at 3 Tesla. DTI tractography was performed based on seed points placed circularly around the prostate, in the rectoprostatic angle, the peripheral zone of the prostate, the sciatic nerve, and in addition the urinary bladder using FA thresholds of 0.20, 0.05, and 0.01. DTI tract number and DTI tract length measured with different FA thresholds were compared. ANOVA with repeated measures was used for statistics. Results DTI tract number and tract length were significantly dependent on FA thresholds. While a FA threshold of 0.20 visualized the typical distribution of DTI tracts in the sciatic nerve, a FA threshold of <=0.05 was necessary to yield results visually mimicking the distribution of nerve tracts in the NVB. However, with such low FA thresholds even in the filled urinary bladder DTI tracts could be visualized. With FA thresholds of 0.20, the number and length of periprostatic DTI tracts did not differ from those measured within the prostate. Conclusion DTI tractography can be used to visualize DTI tracts periprostatically. However, one may doubt that these DTI tracts represent nerve tracts and that the periprostatic neurovascular bundle can be evaluated in a meaningful way with the current methods available. PMID- 27235454 TI - Effects of nodule characteristics on sampling number and duration of thyroid fine needle aspiration biopsy: size does not matter, but cystic degeneration ratio does. AB - Background Ultrasound-guided fine needle aspiration biopsy (FNAB) of thyroid nodules, though the most accurate method to rule out malignancy, still has an inherent risk of yielding non-diagnostic specimens despite immediate assessment of specimen adequacy by an on-site cytopathologist. Purpose To evaluate the effects of nodule volume and extent of cystic degeneration on total biopsy time and number of aspirations required for obtaining an adequate specimen. Material and Methods A total of 510 patients underwent FNAB by a single radiologist accompanied by a cytopathologist who immediately assessed each sample for specimen adequacy. All sampled nodules were single and had one maximum diameter > 10 mm. Nodule volumes and cystic degeneration ratios were calculated prior to the intervention. Aspirations were repeated until the cytological material was deemed adequate by the cytopathologist; the number of aspirations and total biopsy time were then recorded. Results Nodule volumes did not have significant effect on neither number of aspirations necessary for achieving specimen adequacy ( P > 0.05) nor total biopsy time (r = -0.148 with P = 0.001). Predominantly cystic nodules, compared to predominantly solid nodules, required more sampling per nodule (4.58 +/- 1.11 vs. 3.44 +/- 1.19 aspirations, P = 0.001) and longer total biopsy time (16.40 +/- 6.19 vs. 11.15 +/- 6.18 min, P = 0.001). Conclusion Predominantly cystic nodules require allocation of more time for biopsy. To ensure specimen adequacy when immediate specimen evaluation by an on-site cytopathologist is not possible, four samples from predominantly solid nodules and five passes through predominantly cystic nodules are required. PMID- 27235455 TI - Functional and morphological alterations associated with working memory dysfunction in patients with generalized anxiety disorder. AB - Background Generalized anxiety disorder (GAD) has been related to functional brain activities and structural brain abnormalities. Purpose To investigate the neural mechanism on working memory dysfunction in patients with GAD in terms of the combined functional and morphological brain abnormalities. Material and Methods Patients with GAD and healthy controls matched for age, sex, and education level underwent high-resolution T1-weighted (T1W) magnetic resonance imaging (MRI) and functional MRI (fMRI). In this study, fMRI and voxel-based morphometry (VBM) were used for assessing the differential brain activation patterns, as well as for comparing the morphological alterations between the two groups. Results In response to the neutral distractors, the patients showed significantly lower activities in the regions of the fusiform gyrus (FuG), superior parietal gyrus (SPG), precuneus (PCu), superior occipital gyrus (SOG), lingual gyrus (LiG), cuneus (Cun), calcarine cortex (CaC), parahippocampal gyrus (PHG) and cerebellar cortex (Cb) compared to the controls. In response to the anxiety-inducing distractors, the patients showed significantly higher activity in the hippocampus and lower activities in the regions of the dorsolateral prefrontal cortex (DLPFC), FuG, SPG, PCu, SOG, and Cb. Also, the patients showed a significant reduction of the white matter volumes in the DLPFC, anterior limb of the internal capsule (ALIC) and midbrain. Conclusion This study provides the first evidence for the association between the morphometric alterations and functional deficit in the working memory processing with the neutral and anxiety inducing distractors in GAD patients. These findings would be helpful to understand the neural mechanisms on working memory impairment in connection with GAD symptoms. PMID- 27235456 TI - Preclinical Medical Students' Diverse Educational and Emotional Responses to a Required Hospice Experience. AB - BACKGROUND: Physicians' lack of comfort and skill in communicating about hospice care results in deficits and delays in hospice referrals. Preclinical exposure to hospice may lay a foundation to improve medical students' knowledge and comfort with hospice care. OBJECTIVE: To understand how preclinical medical student (MS) 2s respond both educationally and emotionally to a required hospice care experience (HCE). DESIGN: Accompanied by hospice clinicians, MS-2s spent 3 hours seeing inpatient or home hospice patients followed by a 1-hour debriefing. Students submitted written reflections to e-mailed educational and emotional prompts. SETTING/PATIENTS: Two hundred and two MS-2s from 2 academic cohorts completed the HCE at 1 of 2 hospice sites. MEASUREMENTS: Written reflective responses were analyzed qualitatively, where salient themes extracted and responses were coded. RESULTS: Ninety-two students submitted 175 responses to Prompt #1 (educational impact) and 85 students entered 85 responses to prompt #2 (emotional impact) of the HCE. Eleven themes were identified for prompt #1, most frequently focusing on hospice services and goals and hospice providers' attitudes and skills. Prompt #2 elicited a diverse spectrum of emotional responses, spanning positive and negative emotions. Most often, students reported "no specified emotional reaction," "sad/depressed," "difficult /challenging," "heartened/encouraged," and "mixed emotions." CONCLUSION: In an HCE, preclinical students reported learning core aspects of hospice care and experiencing a broad spectrum of emotional responses. These findings may assist educators in the planning of HCEs for preclinical students, including debriefing sessions with skilled clinicians and opportunities for triggered reflection. PMID- 27235458 TI - Erratum. PMID- 27235457 TI - Femoral Artery Ultrasound Examination. AB - We compared intima-media thickness (IMT) and the prevalence of plaques in the common carotid artery (CCA) and common femoral artery (CFA) in apparently healthy participants. This multicenter study included 322 participants (59.9% female; age 20-78 years, mean 52.1 +/- 15.3 years) who underwent Echo-color Doppler examination of the CCA and CFA bilaterally. Prevalence and composition of plaque were recorded. A significant ( P < .01) difference between mean CCA-IMT and mean CFA-IMT was detected (0.70 vs 0.73 mm). Plaque prevalence was significantly higher in the CFA compared to the CCA (40.7% vs 30.4%). Atherosclerotic plaques were found in both CFA and CCA in 46% of the cases, solely in CFA in 38%, and in CCA alone in 17%. The observed difference in plaque prevalence was even greater when only fibrolipid isolated plaques were considered (CFA 39.4% vs CCA 22.1%). In a healthy general population, atherosclerotic plaques were present in the CFA but not in the CCA in over one-third of the cases. Further studies must confirm whether ultrasonography of the CFA might be introduced in the screening protocols for cardiovascular risk assessment. PMID- 27235459 TI - A Case of Prenatal Neurocytoma Associated With ATR-16 Syndrome. PMID- 27235460 TI - All Tied Up and Nowhere to Go: Report of a Figure-eight Umbilical Cord Complex True Knot and Triple Nuchal Cord Detected on Antenatal Sonography. PMID- 27235461 TI - Diagnosis of a Radiographically Occult Calcaneus Fracture With Bedside Sonography. PMID- 27235462 TI - Peripheral Nerve Ultrasound and Short-Segment Nerve Conduction Studies Before and After Ulnar Nerve Decompression. PMID- 27235463 TI - A 30-Year-Old Patient Who Refuses to Be Drug Tested. PMID- 27235464 TI - Commentary. PMID- 27235466 TI - Correction. PMID- 27235465 TI - Commentary. PMID- 27235467 TI - Persistently High Cardiac Troponin T with a Negative Cardiac Workup. PMID- 27235468 TI - Hyponatremia, Hypokalemia, Hypochloremia, and Other Abnormalities. PMID- 27235469 TI - Severe Hypercholesterolemia and Cutaneous Xanthomas in a 3-Year-Old Boy. PMID- 27235472 TI - Emotions: From Jackson Pollock to Contemporary Science. PMID- 27235470 TI - Systematic Review of Calcineurin Inhibitor Monitoring and Dosing Strategies in Renal Transplantation: Notice of a New Report Funded by the Agency for Healthcare Research and Quality. PMID- 27235473 TI - Lower Extremity Permanent Dialysis Vascular Access. AB - Hemodialysis remains the most commonly used RRT option around the world. Technological advances, superior access to care, and better quality of care have led to overall improvement in survival of patients on long-term hemodialysis. Maintaining a functioning upper extremity vascular access for a prolonged duration continues to remain a challenge for dialysis providers. Frequently encountered difficulties in clinical practice include (1) a high incidence of central venous catheter-related central vein stenosis and (2) limited options for creating a functioning upper extremity permanent arteriovenous access. Lack of surgical skills, fear of complications, and limited involvement of the treating nephrologists in the decision-making process are some of the reasons why lower extremity permanent dialysis access remains an infrequently used option. Similar to upper extremity vascular access options, lower extremity arteriovenous fistula remains a preferred access over arteriovenous synthetic graft. The use of femoral tunneled catheter as a long-term access should be avoided as far as possible, especially with the availability of newer graft-catheter hybrid devices. Our review provides a summary of clinical evidence published in surgical, radiology, and nephrology literature highlighting the pros and cons of different types of lower extremity permanent dialysis access. PMID- 27235474 TI - Adult Olfactory Bulb Neurogenesis. AB - Most organisms use their olfactory system to detect and analyze chemical cues from the external world to guide essential behaviors. From worms to vertebrates, chemicals are detected by odorant receptors expressed by olfactory sensory neurons, which in vertebrates send an axon to the primary processing center called the olfactory bulb (OB). Within the OB, sensory neurons form excitatory synapses with projection neurons and with inhibitory interneurons. Thus, because of complex synaptic interactions, the output of a given projection neuron is determined not only by the sensory input, but also by the activity of local inhibitory interneurons that are regenerated throughout life in the process of adult neurogenesis. Herein, we discuss how it is optimized and why. PMID- 27235491 TI - Balancing ethical decisions and financial constraints in practice. AB - Some vets find charging properly for their services to be a stressful and challenging aspect of practice. However, as James Yeates argued during a session at the BSAVA congress in Birmingham last month, charging correctly can be justified both economically and ethically. Laura Honey reports. PMID- 27235477 TI - Antibacterial Drug Discovery Targeting the Lipopolysaccharide Biosynthetic Enzyme LpxC. AB - The enzyme LpxC (UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase) is broadly conserved across Gram-negative bacteria and is essential for synthesis of lipid A, the membrane anchor of the lipopolysaccharides (LPSs), which are a major component of the outer membrane in nearly all Gram-negative bacteria. LpxC has been the focus of target-directed antibiotic discovery projects in numerous pharmaceutical and academic groups for more than 20 years. Despite intense effort, no LpxC inhibitor has been approved for therapeutic use, and only one has yet reached human studies. This article will summarize the history of LpxC as a drug target and the parallel history of research on LpxC biology. Both academic and industrial researchers have used LpxC inhibitors as tool compounds, leading to increased understanding of the differing mechanisms for regulation of LPS synthesis in Escherichia coli and Pseudomonas aeruginosa. PMID- 27235490 TI - Raw food diets for dogs and cats: do we know enough? AB - Feeding pets a raw food diet has long been contentious. A debate at this year's BSAVA congress explored the increasing trend among pet owners to feed raw and how vets can respond appropriately and advise their clients. Lee-Mey Goh reports. PMID- 27235475 TI - Neurogenesis in the Developing and Adult Brain-Similarities and Key Differences. AB - Adult neurogenesis in the mammalian brain is often viewed as a continuation of neurogenesis at earlier, developmental stages. Here, we will critically review the extent to which this is the case highlighting similarities as well as key differences. Although many transcriptional regulators are shared in neurogenesis at embryonic and adult stages, recent findings on the molecular mechanisms by which these neuronal fate determinants control fate acquisition and maintenance have revealed profound differences between development and adulthood. Importantly, adult neurogenesis occurs in a gliogenic environment, hence requiring adult-specific additional and unique mechanisms of neuronal fate specification and maintenance. Thus, a better understanding of the molecular logic for continuous adult neurogenesis provides important clues to develop strategies to manipulate endogenous stem cells for the purpose of repair. PMID- 27235494 TI - Disease surveillance in England and Wales, May 2016. AB - ? Current and emerging issues? Highlights from the scanning surveillance network? Update on international disease threats? Health issues in young gamebirdsThese are among matters discussed in the Animal and Plant Health Agency's (APHA's) May disease surveillance report. PMID- 27235495 TI - Health issues in young gamebirds. AB - This article, prepared by the APHA Avian Expert Group, summarises some of the health issues affecting young gamebirds during the first few weeks of the rearing season. PMID- 27235476 TI - Oncogenic Mutant p53 Gain of Function Nourishes the Vicious Cycle of Tumor Development and Cancer Stem-Cell Formation. AB - More than half of human tumors harbor an inactivated p53 tumor-suppressor gene. It is well accepted that mutant p53 shows an oncogenic gain-of-function (GOF) activity that facilitates the transformed phenotype of cancer cells. In addition, a growing body of evidence supports the notion that cancer stem cells comprise a seminal constituent in the initiation and progression of cancer development. Here, we elaborate on the mutant p53 oncogenic GOF leading toward the acquisition of a transformed phenotype, as well as placing mutant p53 as a major component in the establishment of cancer stem cell entity. Therefore, therapy targeted toward cancer stem cells harboring mutant p53 is expected to pave the way to eradicate tumor growth and recurrence. PMID- 27235496 TI - Lumpy skin disease: a direct threat to Europe. PMID- 27235498 TI - Use of antibiotics in animals and people. PMID- 27235497 TI - Government's U-turn on welfare codes. PMID- 27235499 TI - Taking pets abroad. PMID- 27235500 TI - Continuity of care. PMID- 27235501 TI - Brachycephalic dog breeds. PMID- 27235508 TI - Achieving perspective in work and leisure. AB - With a passion for beautiful landscapes, Richard Fox balances his working life as a diagnostic veterinary histopathologist with photography. PMID- 27235510 TI - How critical is body mass index, and who decides? PMID- 27235509 TI - Development of interleukin-17-producing Vgamma2+ gammadelta T cells is reduced by ICOS signaling in the thymus. AB - Co-stimulation is an integral part of T cell signaling involved in almost all facets of T cell biology. While much is known about co-stimulation in differentiation and function of conventional alphabeta T cells, less is known about how co-stimulation affects the development and programming of gammadelta T cells. In this study, we have investigated the role of inducible T cell co stimulator (ICOS) on the development of gammadelta T cells. We show that ICOS is expressed by a population of immature Vgamma2+CD45RBlow gammadelta T cells predisposed to interleukin-17 (IL-17) production. We found that treatment with ICOS specific antibodies drastically reduces fetal development of IL-17-producing gammadelta T cells by agonistic actions, and that ICOS deficient mice have a significant increase in the population of IL-17-producing Vgamma2+ gammadelta T cells in the thymus, spleen, lymph nodes and skin and exhibit exacerbated sensitization responses to 2,4-dinitrofluorobenzene. In conclusion, this study demonstrates that development of IL-17-producing Vgamma2+ gammadelta T cells is reduced by ICOS signaling in the thymus. PMID- 27235511 TI - Osteochondritis dissecans of the knee: a practical guide for surgeons. AB - Osteochondritis Dissecans (OCD) is a condition for which the aetiology remains unknown. It affects subchondral bone and secondarily its overlying cartilage and is mostly found in the knee. It can occur in adults, but is generally identified when growth remains, when it is referred to as juvenile OCD. As the condition progresses, the affected subchondral bone separates from adjacent healthy bone, and can lead to demarcation and separation of its associated articular cartilage. Any symptoms which arise relate to the stage of the disease. Early disease without separation of the lesion results in pain. Separation of the lesion leads to mechanical symptoms and swelling and, in advanced cases, the formation of loose bodies. Early identification of OCD is essential as untreated OCD can lead to the premature degeneration of the joint, whereas appropriate treatment can halt the disease process and lead to healing. Establishing the stability of the lesion is a key part of providing the correct treatment. Stable lesions, particularly in juvenile patients, have greater propensity to heal with non surgical treatment, whereas unstable or displaced lesions usually require surgical management. This article discusses the aetiology, clinical presentation and prognosis of OCD in the knee. It presents an algorithm for treatment, which aims to promote healing of native hyaline cartilage and to ensure joint congruity. TAKE HOME MESSAGE: Although there is no clear consensus as to the best treatment of OCD, every attempt should be made to retain the osteochondral fragment when possible as, with a careful surgical technique, there is potential for healing even in chronic lesions Cite this article: Bone Joint J 2016;98-B:723 9. PMID- 27235512 TI - The acetabular labrum: a review of its function. AB - The acetabular labrum is a soft-tissue structure which lines the acetabular rim of the hip joint. Its role in hip joint biomechanics and joint health has been of particular interest over the past decade. In normal hip joint biomechanics, the labrum is crucial in retaining a layer of pressurised intra-articular fluid for joint lubrication and load support/distribution. Its seal around the femoral head is further regarded as a contributing to hip stability through its suction effect. The labrum itself is also important in increasing contact area thereby reducing contact stress. Given the labrum's role in normal hip joint biomechanics, surgical techniques for managing labral damage are continuously evolving as our understanding of its anatomy and function continue to progress. The current paper aims to review the anatomy and biomechanical function of the labrum and how they are affected by differing surgical techniques. TAKE HOME MESSAGE: The acetabular labrum plays a critical role in hip function and maintaining and restoring its function during surgical intervention remain an essential goal. Cite this article: Bone Joint J 2016;98-B:730-5. PMID- 27235513 TI - Pseudotumour formation and subsequent resolution in metal-on-metal total hip arthroplasty following revision: Instructional review and an illustrative case report with revision using a dual mobility design. AB - The use of large-diameter metal-on-metal (MoM) components in total hip arthroplasty (THA) is associated with an increased risk of early failure due to adverse local tissue reaction to metal debris (ARMD) in response to the release of metal ions from the bearing couple and/or head-neck taper corrosion. The aim of this paper was to present a review of the incidence and natural history of ARMD and the forms of treatment, with a focus on the need for and extent of resection or debulking of the pseudotumour. An illustrative case report is presented of a patient with an intra-pelvic pseudotumour associated with a large diameter MoM THA, which was treated successfully with revision of the bearing surface to a dual mobility couple and retention of the well-fixed acetabular and femoral components. The pseudotumour was left in situ Resolution of the intra pelvic mass and normalisation of metal ion levels was observed seven months post operatively. Cite this article: Bone Joint J 2016;98-B:736-40. PMID- 27235514 TI - Do labral tears influence poor outcomes after periacetabular osteotomy for acetabular dysplasia? AB - AIMS: Acetabular dysplasia is frequently associated with intra-articular pathology such as labral tears, but whether labral tears should be treated at the time of periacetabular osteotomy (PAO) remains controversial. The purpose of this study was to compare the clinical outcomes and radiographic corrections of PAO for acetabular dysplasia between patients with and without labral tears pre operatively. PATIENTS AND METHODS: We retrospectively reviewed 70 hips in 67 patients with acetabular dysplasia who underwent PAO. Of 47 hips (45 patients) with labral tears pre-operatively, 27 (25 patients) underwent PAO alone, and were classified as the labral tear alone (LT) group, and 20 (20 patients) underwent combined PAO and osteochondroplasty, and were classified as the labral tear osteochondroplasty (LTO) group. The non-labral tear (NLT) group included 23 hips in 22 patients. RESULTS: There were no significant differences between groups for post-operative Harris hip scores, degree of progression of osteoarthritis or rate of reoperation. The pre-operative alpha angle was significantly larger in the LTO group compared with the other groups (p < 0.0001). CONCLUSION: PAO provides equivalent short-term relief of pain and functional outcome in patients with or without labral tears. The rate of progression of osteoarthritis and reoperation was not significantly increased in patients with labral tears. TAKE HOME MESSAGE: PAO provides equivalent short-term pain relief and functional outcomes in patients with acetabular dysplasia with and without labral tears. We did not find significantly increased risks of progression of osteoarthritis or re-operation in those with labral tears. Cite this article: Bone Joint J 2016;98-B:741-6. PMID- 27235515 TI - Tranexamic acid reduces blood loss in patients with extracapsular fractures of the hip: results of a randomised controlled trial. AB - AIMS: We chose unstable extra-capsular hip fractures as our study group because these types of fractures suffer the largest blood loss. We hypothesised that tranexamic acid (TXA) would reduce total blood loss (TBL) in extra-capsular fractures of the hip. PATIENTS AND METHODS: A single-centre placebo-controlled double-blinded randomised clinical trial was performed to test the hypothesis on patients undergoing surgery for extra-capsular hip fractures. For reasons outside the control of the investigators, the trial was stopped before reaching the 120 included patients as planned in the protocol. RESULTS: In all 72 patients (51 women, 21 men; 33 patients in the TXA group, 39 in the placebo group) were included in the final analysis, with a significant mean reduction of 570.8 ml (p = 0.029) in TBL from 2100.4 ml (standard deviation (sd) = 1152.6) in the placebo group to 1529.6 ml (sd = 1012.7) in the TXA group. The 90-day mortality was 27.2% (n = 9) in the TXA group and 10.2% (n = 4) in the placebo group (p = 0.07). We were not able to ascertain a reliable cause of death in these patients. DISCUSSION: TXA significantly reduced TBL in extra-capsular hip fractures, but concerns regarding its safety in this patient group must be investigated further before the use of TXA can be recommended. TAKE HOME MESSAGE: We present a randomised clinical trial that is unique in the literature. We evaluate the effect of TXA in very homogenous population - extra-capsular fractures operated with short intramedullary nails. Cite this article: Bone Joint J 2016;98-B:747 53. PMID- 27235516 TI - A comparison between the direct anterior and posterior approaches for total hip arthroplasty: the role of an 'Enhanced Recovery' pathway. AB - AIMS: We assessed the difference in hospital based and early clinical outcomes between the direct anterior approach and the posterior approach in patients who undergo total hip arthroplasty (THA). PATIENTS AND METHODS: The outcome was assessed in 448 (203 males, 245 females) consecutive patients undergoing unilateral primary THA after the implementation of an 'Enhanced Recovery' pathway. In all, 265 patients (mean age: 71 years (49 to 89); 117 males and 148 females) had surgery using the direct anterior approach (DAA) and 183 patients (mean age: 70 years (26 to 100); 86 males and 97 females) using a posterior approach. The groups were compared for age, gender, American Society of Anesthesiologists grade, body mass index, the side of the operation, pre operative Oxford Hip Score (OHS) and attendance at 'Joint school'. Mean follow-up was 18.1 months (one to 50). RESULTS: There was no significant difference in mean length of stay (p = 0.07), pain scores on the day of surgery, the first, second and third post-operative days (p = 0.36, 0.23, 0.25 and 0.59, respectively), the day of mobilisation (p = 0.12), the mean OHS at six and 24 months (p = 0.08, and 0.29, respectively), the incidence of infection (p = 1.0), dislocation (p = 1.0), re-operation (p = 0.21) or 28 days' re-admission (p = 0.06). Significantly more patients in the DAA group achieved a planned discharge target of three days post operatively (68% vs 56%, p = 0.007). The rate of periprosthetic femoral fractures was significantly higher in the DAA group (p = 0.04). CONCLUSION: We conclude that there is no difference in clinical outcomes between the DAA and the posterior approach in patients undergoing THA when an 'Enhanced Recovery' pathway is used. However, a significantly higher rate of periprosthetic femoral fractures remains a concern with the DAA, even in experienced hands. TAKE HOME MESSAGE: Our results show that the DAA for THA is not superior to posterior approach when 'Enhanced Recovery' pathway is used. Cite this article: Bone Joint J 2016;98 B:754-60. PMID- 27235517 TI - Ethnic differences in heterotopic ossification following total hip arthroplasty. AB - AIMS: We aimed to assess the influence of ethnicity on the incidence of heterotopic ossification (HO) after total hip arthroplasty (THA). PATIENTS AND METHODS: We studied the six-month post-operative anteroposterior radiographs of 1449 consecutive primary THAs (1324 patients) and retrospectively graded them for the presence of HO, using the Brooker Classification. RESULTS: Based on multivariate analysis, African-American ethnicity was an independent risk factor for HO formation following THA with an adjusted odds ratio (OR) of 2.6 (95% confidence interval (CI) 1.3 to 5.2, p = 0.007) for severe HO and 1.9 (95% CI 1.3 to 2.7, p < 0.001) for any grade of HO. CONCLUSION: Given the increased risk of HO formation, particularly high grade HO, and the potentially poorer outcomes associated with HO, it is important to consider using prophylaxis against HO in patients of African-American ethnicity undergoing THA. TAKE HOME MESSAGE: African Americans are at an increased risk for developing heterotopic ossification and thus may benefit from HO prophylaxis. Cite this article: Bone Joint J 2016;98 B:761-6. PMID- 27235518 TI - Porous tantalum uncemented acetabular components in revision total hip arthroplasty: a minimum ten-year clinical, radiological and quality of life outcome study. AB - AIMS: Reconstruction of the acetabulum after failed total hip arthroplasty (THA) can be a surgical challenge in the presence of severe bone loss. We report the long-term survival of a porous tantalum revision acetabular component, its radiological appearance and quality of life outcomes. PATIENTS AND METHODS: We reviewed the results of 46 patients who had undergone revision of a failed acetabular component with a Paprosky II or III bone defect and reconstruction with a hemispherical, tantalum acetabular component, supplementary screws and a cemented polyethylene liner. RESULTS: After a minimum follow-up of ten years (ten to 12), the survivorship of the porous tantalum acetabular component was 96%, with further revision of the acetabular component as the end point. The ten-year survivorship, with hip revision for any reason as the end point, was 92%. We noted excellent pain relief (mean Western Ontario and McMaster Universities Arthritis Index (WOMAC) score pain 92.6, (40 to 100)) and good functional outcomes (mean WOMAC function 90.3 (30.9 to 100), mean University of California Los Angeles activity scale 5 (2 to 10)) and generic quality of life measures (mean Short Form-12 (SF-12) physical component 48.3 (18.1 to 56.8), mean SF-12 mental component 56.7 (32.9 to 70.3)). Patient satisfaction with pain relief, function and return to recreational activities were excellent. TAKE HOME MESSAGE: Uncemented acetabular reconstruction using a tantalum acetabular component gives excellent clinical and quality of life outcomes at a minimum follow-up of ten years. Cite this article: Bone Joint J 2016;98-B:767-71. PMID- 27235519 TI - Review of the outcomes of complex acetabular reconstructions using a stemmed acetabular pedestal component. AB - AIM: Until now, there has been no consensus as to whether stemmed acetabular components are appropriate for use in patients undergoing revision total hip arthroplasty (THA) who have major acetabular defects or pelvic discontinuity. We wished to address this deficiency in the literature. PATIENTS AND METHODS: We carried out a retrospective study of 35 patients (six men and 29 women) with a mean age of 68 years (37 to 87), with major acetabular defects who underwent revision THA between 2000 and 2012. RESULTS: At a mean follow-up of 63 months (24 to 141), a total of 15 patients (43%) had required at least one further operation. Six implants (17%) loosened aseptically, four (11%) were further revised for infection and two (6%) for technical failure. By taking revision for any reason as the endpoint, the rate of survival of the implant was 61% after five years; by taking revision for aseptic loosening as the end point, it was 78%. The cumulative five-year survival for aseptic loosening was 94% in patients without pelvic discontinuity, and 56% in those with pelvic discontinuity. CONCLUSION: These results indicate a significantly worse survival in patients with pelvic discontinuity (p = 0.020) and we advise caution in the use of the pedestal component in patients with major acetabular defects and pelvic discontinuity who require revision THA. As a result of these findings we have stopped using this implant and prefer to use particulate bone grafts protected with an anti-protrusion cage and posterior column plate fixation, if necessary. TAKE HOME MESSAGE: Based on these poor results, we advise caution if using the pedestal component in patients with major acetabular defects with the presence of a pelvic discontinuity. Cite this article: Bone Joint J 2016;98-B:772-9. PMID- 27235520 TI - The influence of body mass index on functional outcome and quality of life after total knee arthroplasty. AB - AIMS: This study investigated the influence of body mass index (BMI) on the post operative fall in the level of haemoglobin (Hb), length of hospital stay (LOS), 30-day re-admission rate, functional outcome and quality of life, two years after total knee arthroplasty (TKA). PATIENTS AND METHODS: A total of 7733 patients who underwent unilateral primary TKA between 2001 and 2010 were included. The mean age was 67 years (30 to 90). There were 1421 males and 6312 females. The patients were categorised into three groups: BMI < 25.0 kg/m(2) (normal); BMI between 25.0 and 39.9 kg/m(2) (obese); and BMI >= 40.0 kg/m(2) (morbidly obese). RESULTS: Compared with the normal and obese groups, the mean LOS was longer by one day (95% confidence interval (CI) 0 to 2) in the morbidly obese group (p = 0.003 and p = 0.001 respectively). The 30-day re-admisison rate was also higher in the morbidly obese group compared to the obese group (OR 2.323, 95% CI 1.101 to 4.900, p = 0.024); and showed a higher trend compared to the normal group (OR 1.850, 95% CI 0.893 to 3.831, p = 0.100). However, the morbidly obese group had a smaller drop in post-operative Hb level by a mean of 0.5 g/dl (0.3 to 0.6) and 0.3 g/dl (0.1 to 0.5), when compared with the normal and obese groups respectively (both p < 0.001). Furthermore, the mean improvement in Oxford Knee Score (OKS) and Knee Society Knee Score (KSKS) at two years follow-up was three points (two to four) and five points (two to seven) more in the morbidly obese group than in the normal group (both p < 0.001). The mean improvement in Knee Society Function Score, and Physical and Mental Component Scores of Short Form-36 were comparable between the three BMI groups (p = 0.736, p = 0.739 and p = 0.731 respectively). The ten-year rate of survival was 98.8% (98.0 to 99.3), 98.9% (98.5 to 99.2) and 98.0% (95.8 to 100), for the normal, obese and morbidly obese groups, respectively (p = 0.703). CONCLUSION: Although morbidly obese patients have a longer LOS and higher 30-day re-admission rate after TKA, they have a smaller drop in post-operative Hb level and larger improvement in OKS and KSKS at two years follow-up. The ten-year rate of survival of TKA was also comparable with those with a normal BMI. TAKE HOME MESSAGE: Morbidly obese patients should not be excluded from the benefits of TKA. Cite this article: Bone Joint J 2016;98 B:780-5. PMID- 27235521 TI - A radiological analysis of the difference between MRI- and CT-based patient specific matched guides for total knee arthroplasty from the same manufacturer: a randomised controlled trial. AB - AIMS: This prospective randomised controlled trial was designed to evaluate the outcome of both the MRI- and CT-based patient-specific matched guides (PSG) from the same manufacturer. PATIENTS AND METHODS: A total of 137 knees in 137 patients (50 men, 87 women) were included, 67 in the MRI- and 70 in the CT-based PSG group. Their mean age was 68.4 years (47.0 to 88.9). Outcome was expressed as the biomechanical limb alignment (centre hip-knee-ankle: HKA-axis) achieved post operatively, the position of the individual components within 3 degrees of the pre-operatively planned alignment, correct planned implant size and operative data (e.g. operating time and blood loss). RESULTS: The patient demographics (e.g. age, body mass index), correct planned implant size and operative data were not significantly different between the two groups. The proportion of outliers in the coronal and sagittal plane ranged from 0% to 21% in both groups. Only the number of outliers for the posterior slope of the tibial component showed a significant difference (p = 0.004) with more outliers in the CT group (n = 9, 13%) than in the MRI group (0%). CONCLUSION: The post-operative HKA-axis was comparable in the MRI- and CT-based PSGs, but there were significantly more outliers for the posterior slope in the CT-based PSGs. TAKE HOME MESSAGE: Alignment with MRI-based PSG is at least as good as, if not better, than that of the CT-based PSG, and is the preferred imaging modality when performing TKA with use of PSG. Cite this article: Bone Joint J 2016;98-B:786-92. PMID- 27235522 TI - Dynamic intraligamentary stabilisation: initial experience with treatment of acute ACL ruptures. AB - AIMS: The purpose of this study was to report the experience of dynamic intraligamentary stabilisation (DIS) using the Ligamys device for the treatment of acute ruptures of the anterior cruciate ligament (ACL). PATIENTS AND METHODS: Between March 2011 and April 2012, 50 patients (34 men and 16 women) with an acute rupture of the ACL underwent primary repair using this device. The mean age of the patients was 30 years (18 to 50). Patients were evaluated for laxity, stability, range of movement (ROM), Tegner, Lysholm, International Knee Documentation Committee (IKDC) and visual analogue scale (VAS) scores over a follow-up period of two years. RESULTS: At final follow-up, anteroposterior translation differed from the normal knee by a mean of 0.96 mm (-2 mm to 6 mm). Median (interquartile range) IKDC, Tegner, Lysholm and VAS scores were 98 (95 to 100), 6 (5 to 7), 100 (98 to 100) and 10 (9 to 10), respectively. Pre-injury Tegner activity levels were reached one year post-operatively. A total of nine patients (18%) required a secondary intervention; five developed instability, of whom four underwent secondary hamstring reconstructive surgery, and five required arthroscopic treatment for intra-articular impingement due to scar tissue which caused a fixed flexion deformity. In addition, 30 patients (60%) required removal of the tibial screw. CONCLUSION: While there was a high rate of secondary interventions, 45 patients (90%) retained their repaired ACL two years post operatively, with good clinical scores and stability of the knee. TAKE HOME MESSAGE: Dynamic intraligamentary stabilisation presents a promising treatment option for acute ACL ruptures, eliminating the need for ACL reconstruction. Cite this article: Bone Joint J 2016;98-B:793-8. PMID- 27235523 TI - The impact of frailty on outcomes and healthcare resource usage after total joint arthroplasty: a population-based cohort study. AB - AIMS: Total joint arthroplasty (TJA) is commonly performed in elderly patients. Frailty, an aggregate expression of vulnerability, becomes increasingly common with advanced age, and independently predicts adverse outcomes and the use of resources after a variety of non-cardiac surgical procedures. Our aim was to assess the impact of frailty on outcomes after TJA. PATIENTS AND METHODS: We analysed the impact of pre-operative frailty on death and the use of resources after elective TJA in a population-based cohort study using linked administrative data from Ontario, Canada. RESULTS: Of 125 163 patients aged > 65 years having elective TJA, 3023 (2.4%) were frail according to the Johns Hopkins ACG frailty defining diagnoses indicator. One year follow-up was complete for all patients. Frail patients had a higher adjusted one year risk of mortality (hazard ratio 3.03, 95% confidence interval (CI) 2.62 to 3.51), a higher rate of admission to intensive care (odds ratio (OR) 2.52, 95% CI 2.21 to 2.89), increased length of stay (incidence rate ratio 1.62, 95% CI 1.59 to 1.65), a higher rate of discharge to institutional care (OR 2.09, 95% CI 1.93 to 2.25), a higher rate of re admission (OR 1.33, 95% CI 1.07 to 1.66) and increased costs at 30, 90 and 365 days post-operatively. Frailty affected outcomes after total hip arthroplasty more than after total knee arthroplasty. TAKE HOME MESSAGE: Frailty is an important risk factor for death after elective TJA, and increases post-operative resource utilisation across many metrics. Processes to optimise the outcomes and efficiency of TJA in frail patients are needed. Cite this article: Bone Joint J 2016;98-B:799-805. PMID- 27235524 TI - Symptomatic treatment or cast immobilisation for avulsion fractures of the base of the fifth metatarsal: a prospective, randomised, single-blinded non inferiority controlled trial. AB - AIMS: The purpose of this study was to compare symptomatic treatment of a fracture of the base of the fifth metatarsal with immobilisation in a cast. Our null hypothesis was that immobilisation gave better patient reported outcome measures (PROMs). The alternative hypothesis was that symptomatic treatment was not inferior. PATIENTS AND METHODS: A total of 60 patients were randomised to receive four weeks of treatment, 36 in a double elasticated bandage (symptomatic treatment group) and 24 in a below-knee walking cast (immobilisation group). The primary outcome measure used was the validated Visual Analogue Scale Foot and Ankle (VAS-FA) Score. Data were analysed by a clinician, blinded to the form of treatment, at presentation and at four weeks, three months and six months after injury. Loss to follow-up was 43% at six months. Multiple imputations missing data analysis was performed. RESULTS: At four weeks and six months, symptomatic treatment proved non-inferior in terms of primary outcome. TAKE HOME MESSAGE: Immobilisation is no better than symptomatic treatment in the management of a fracture of the base of the fifth metatarsal when judged by PROMs. Significant loss to follow-up with this injury could be expected in longer term. Cite this article: Bone Joint J 2016;98-B:806-11. PMID- 27235525 TI - Open reduction and internal fixation of posterior malleolar fractures using the posterolateral approach. AB - AIMS: Involvement of the posterior malleolus in fractures of the ankle probably adversely affects the functional outcome and may be associated with the development of post-traumatic osteoarthritis. Anatomical reduction is a predictor of a successful outcome. The purpose of this study was to describe the technique and short-term outcome of patients with trimalleolar fractures, who were treated surgically using a posterolateral approach in our hospital between 2010 and 2014. PATIENTS AND METHODS: The study involved 52 patients. Their mean age was 49 years (22 to 79). There were 41 (79%) AO 44B-type and 11 (21%) 44C-type fractures. The mean size of the posterior fragment was 27% (10% to 52%) of the tibiotalar joint surface. RESULTS: Reduction was anatomical in all patients with a residual step in the articular surface of <= 1 mm. In nine of the C-type fractures (82%), the syndesmosis was stable after fixation of the posterior fragment and a syndesmosis screw was not required. Apart from one superficial wound infection, there were no wound healing problems. At a mean radiological follow-up of 34 weeks (seven to 131), one patient with a 44C-type fracture had widening of the syndesmosis which required further surgery. CONCLUSION: We conclude that the posterolateral surgical approach to the ankle gives adequate access to the posterior malleolus, allowing its anatomical reduction and stable fixation: it has few complications. TAKE HOME MESSAGE: Fixation of the posterior malleolus in trimalleolar fractures can be easily done via the posterolateral approach whereby anatomical reduction and stable fixation can be reached due to adequate visualisation of the fracture. Cite this article: Bone Joint J 2016;98-B:812-17. PMID- 27235526 TI - The influence of a history of clinical depression on peri-operative outcomes in elective total shoulder arthroplasty: a ten-year national analysis. AB - AIMS: Depression can significantly affect quality of life and is associated with higher rates of medical comorbidities and increased mortality following surgery. Although depression has been linked to poorer outcomes following orthopaedic trauma, total joint arthroplasty and spinal surgery, we wished to examine the impact of depression in elective total shoulder arthroplasty (TSA) as this has not been previously explored. PATIENTS AND METHODS: The United States Nationwide Inpatient Sample (NIS) was used to identify patients undergoing elective TSA over a ten-year period. Between 2002 and 2012, 224 060 patients underwent elective TSA. RESULTS: Among the identified patients who had undergone TSA, 12.4% had a diagnosis of a history of depression. A diagnosis of depression was twice as common in women compared with men (16.0% vs 8.0%, p < 0.001), and more frequent in those with low income and Medicaid insurance (p < 0.001). A diagnosis of depression was an independent risk factor for post-operative delirium (odds ratio (OR) 2.29, p < 0.001), anaemia (OR 1.65, p < 0.001), infection (2.09, p = 0.045) and hospital discharge to a placement other than home (OR 1.52, p < 0.001) CONCLUSION: A history of clinical depression is present in 12.4% of patients undergoing elective TSA and the disease burden is projected to increase further in the future. Depression is often underdiagnosed and pre-operative screening and appropriate peri-operative management of patients is encouraged. TAKE HOME MESSAGE: The awareness that clinical depression is associated with increased complications following total shoulder arthroplasty provides physicians an opportunity for early intervention in this at-risk population. Cite this article: Bone Joint J 2016;98-B:818-24. PMID- 27235527 TI - Missed cervical spine injuries: a national survey of the practice of evaluation of the cervical spine in confused and comatose patients. AB - AIM: Identifying cervical spine injuries in confused or comatose patients with multiple injuries provides a diagnostic challenge. Our aim was to investigate the protocols which are used for the clearance of the cervical spine in these patients in English hospitals. PATIENTS AND METHODS: All hospitals in England with an Emergency Department were asked about the protocols which they use for assessing the cervical spine. All 22 Major Trauma Centres (MTCs) and 141 of 156 non-MTCs responded (response rate 91.5%). RESULTS: Written guidelines were used in 138 hospitals (85%). CT scanning was the first-line investigation in 122 (75%). A normal CT scan was sufficient to clear the cervical spine in 73 (45%). However, 40 (25%) would continue precautions until the patient regained full consciousness. MRI was performed in all confused or comatose patients with a possible cervical spinal injury in 15 (9%). There were variations in the grade and speciality of the clinician who had responsibility for deciding when to discontinue precautions. A total of 31 (19%) reported at least one missed cervical spinal injury following discontinuation of spinal precautions within the last five years. Only 93 (57%) had a formal mechanism for reviewing missed injuries. TAKE HOME MESSAGE: There are significant variations in protocols and practices for the clearance of the cervical spine in multiply injured patients in acute hospitals in England. The establishment of trauma networks should be taken as an opportunity to further standardise trauma care. Cite this article: Bone Joint J 2016;98-B:825-8. PMID- 27235528 TI - Effectiveness and safety of Mobi-C for treatment of single-level cervical disc spondylosis: a randomised control trial with a minimum of five years of follow up. AB - AIMS: In order to evaluate the effectiveness of the Mobi-C implant in cervical disc degeneration, a randomised study was conducted, comparing the Mobi-C prosthesis arthroplasty with anterior cervical disc fusion (ACDF) in patients with single level cervical spondylosis. PATIENTS AND METHODS: From January 2008 to July 2009, 99 patients were enrolled and randomly divided into two groups, those having a Mobi-C implant (n = 51; 30 men, 21 women) and those undergoing ACDF (n = 48; 28 men, 20 women).The patients were followed up for five years, with the primary outcomes being the Japanese Orthopaedic Association score, visual analogue scale for pain and the incidence of further surgery. The secondary outcomes were the Neck Disability Index and range of movement (ROM) of the treated segment. RESULTS: The incidence of further surgery was found to be statistically significant between the two groups (p = 0.49), with seven ACDF patients requiring further surgery and only one Mobi-C patient requiring re operation. There were significant differences (p < 0.001) between the two groups in the ROM of the treated segment. However, both Mobi-C surgery and ACDF surgery were effective in improving the patient's clinical symptoms. TAKE HOME MESSAGE: Mobi-C implant surgery is a safe alternative to ACDF surgery in cervical disc degeneration. Cite this article: Bone Joint J 2016;98-B:829-3. PMID- 27235529 TI - Anterior debridement may not be necessary in the treatment of tuberculous spondylitis of the thoracic and lumbar spine in adults: a retrospective study. AB - AIM: Many aspects of the surgical treatment of patients with tuberculosis (TB) of the spine, including the use of instrumentation and the types of graft, remain controversial. Our aim was to report the outcome of a single-stage posterior procedure, with or without posterior decompression, in this group of patients. PATIENTS AND METHODS: Between 2001 and 2010, 51 patients with a mean age of 62.5 years (39 to 86) underwent long posterior instrumentation and short posterior or posterolateral fusion for TB of the thoracic and lumbar spines, followed by anti TB chemotherapy for 12 months. No anterior debridement of the necrotic tissue was undertaken. Posterior decompression with laminectomy was carried out for the 30 patients with a neurological deficit. RESULTS: The mean kyphotic angle improved from 26.1 degrees (- 1.8 degrees to 62 degrees ) to 15.2 degrees (-25 degrees to 51 degrees ) immediately after the operation. At a mean follow-up of 68.8 months (30 to 144) the mean kyphotic angle was 16.9 degrees (-22 degrees to 54 degrees ), with a mean loss of correction of 1.6 degrees (0 degrees to 10 degrees ). There was a mean improvement in neurological status of 1.2 Frankel grades in those with a neurological deficit. Bony union was achieved in all patients, without recurrent infection. CONCLUSIONS: Long posterior instrumentation with short posterior or posterolateral fusion is effective in the treatment of TB spine. It controls infection, corrects the kyphosis, and maintains correction and neurological improvement over time. TAKE HOME MESSAGE: With effective anti-TB chemotherapy, a posterior only procedure without debridement of anterior lesion is effective in the treatment of TB spondylitis, and an anterior procedure can be reserved for those patients who have not improved after posterior surgery. Cite this article: Bone Joint J 2016;98-B:834 9. PMID- 27235530 TI - The administration of intermittent parathyroid hormone affects functional recovery from trochanteric fractured neck of femur: a randomised prospective mixed method pilot study. AB - AIMS: We wished to assess the feasibility of a future randomised controlled trial of parathyroid hormone (PTH) supplements to aid healing of trochanteric fractures of the hip, by an open label prospective feasibility and pilot study with a nested qualitative sub study. This aimed to inform the design of a future powered study comparing the functional recovery after trochanteric hip fracture in patients undergoing standard care, versus those who undergo administration of subcutaneous injection of PTH for six weeks. PATIENTS AND METHODS: We undertook a pilot study comparing the functional recovery after trochanteric hip fracture in patients 60 years or older, admitted with a trochanteric hip fracture, and potentially eligible to be randomised to either standard care or the administration of subcutaneous PTH for six weeks. Our desired outcomes were functional testing and measures to assess the feasibility and acceptability of the study. RESULTS: A total of 724 patients were screened, of whom 143 (20%) were eligible for recruitment. Of these, 123 were approached and 29 (4%) elected to take part. However, seven patients did not complete the study. Compliance with the injections was 11 out of 15 (73%) showing the intervention to be acceptable and feasible in this patient population. TAKE HOME MESSAGE: Only 4% of patients who met the inclusion criteria were both eligible and willing to consent to a study involving injections of PTH, so delivering this study on a large scale would carry challenges in recruitment and retention. Methodological and sample size planning would have to take this into account. PTH administration to patients to enhance fracture healing should still be considered experimental. Cite this article: Bone Joint J 2016;98-B:840-5. PMID- 27235532 TI - Nerve injuries associated with supracondylar fractures of the humerus in children: our experience in a specialist peripheral nerve injury unit. AB - AIMS: We aimed to identify the pattern of nerve injury associated with paediatric supracondylar fractures of the humerus. PATIENTS AND METHODS: Over a 17 year period, between 1996 and 2012, 166 children were referred to our specialist peripheral nerve injury unit. From examination of the medical records and radiographs were recorded the nature of the fracture, associated vascular and neurological injury, treatment provided and clinical course. RESULTS: Of the 166 patients (111 male, 55 female; mean age at time of injury was seven years (standard deviation 2.2)), 26 (15.7%) had neurological dysfunction in two or more nerves. The injury pattern in the 196 affected nerves showed that the most commonly affected nerve was the ulnar nerve (43.4%), followed by the median (36.7%) and radial (19.9%) nerves. A non-degenerative injury was seen in 27.5%, whilst 67.9% were degenerative in nature. Surgical exploration of the nerves was undertaken in 94 (56.6%) children. The mean follow-up time was 12.8 months and 156 (94%) patients had an excellent or good clinical outcome according to the grading of Birch, Bonney and Parry. CONCLUSION: Following paediatric supracondylar fractures we recommend prompt referral to a specialist unit in the presence of complete nerve palsy, a positive Tinel's sign, neuropathic pain or vascular compromise, for consideration of nerve exploration. TAKE HOME MESSAGE: When managed appropriately, nerve recovery and clinical outcomes for this paediatric population are extremely favourable. Cite this article: Bone Joint J 2016;98-B:851-6. PMID- 27235531 TI - Nails or plates for fracture of the distal femur? data from the Victoria Orthopaedic Trauma Outcomes Registry. AB - AIMS: Fractures of the distal femur are an important cause of morbidity. Their optimal management remains controversial. Contemporary implants include angular stable anatomical locking plates and locked intramedullary nails (IMNs). We compared the long-term patient-reported functional outcome of fixation of fractures of the distal femur using these two methods of treatment. PATIENTS AND METHODS: A total of 297 patients were retrospectively identified from a State wide trauma registry in Australia: 195 had been treated with a locking plate and 102 with an IMN. Baseline characteristics of the patients and their fractures were recorded. Health-related quality-of-life, functional and radiographic outcomes were compared using mixed effects regression models at six months and one year. RESULTS: There was a clinically relevant and significant difference in quality-of-life at six months in favour of fixation with an IMN (mean difference in EuroQol-5 Dimensions Score (EQ-5D) = 0.12; 95% CI 0.02 to 0.22; p = 0.025). There was weak evidence that this trend continued to one year (mean difference EQ 5D = 0.09; 95% CI -0.01 to 0.19; p = 0.073). There was a significant although very small reduction in angular deformity using an IMN (mean difference -1.02; 95% CI -1.99 to -0.06; p = 0.073). There was no evidence that there was a difference in any other outcomes at any time point. TAKE HOME MESSAGE: IMN may be a superior treatment compared with anatomical locking plates for fractures of the distal femur. These findings are concordant with other data from pilot randomised studies which favour treatment of these fractures with an IMN. This study strongly supports the need for a definitive randomised trial. Cite this article: Bone Joint J 2016;98-B:846-50. PMID- 27235533 TI - Very long-term outcomes after endoprosthetic replacement for malignant tumours of bone. AB - AIMS: The aim of this study was to establish what happens to patients in the long term after endoprosthetic replacement for a primary malignant tumour of bone. PATIENTS AND METHODS: We conducted a retrospective analysis of a prospectively maintained database to identify all patients who had undergone an endoprosthetic replacement more than 25 years ago and who were still alive. Their outcomes were investigated with reference to their complications and need for further surgery. A total of 230 patients were identified. Their mean age at diagnosis was 20.7 years (five to 62). The most common diagnosis was osteosarcoma (132). The most common site was the distal femur (102). RESULTS: The mean follow-up was 29.4 years (25 to 43). A total of 610 further operations were undertaken, an average of 2.7 further operations per patient. A total of 42 patients (18%) still had the original prosthesis in place. The risk of amputation was 16% at 30 years (31 patients). Those without infection had a mean of 2.1 further operations (one to nine) while those with infection had a mean of 4.6 further operations (two to 11). The risk of infection persisted throughout the life of the prosthesis with a mean of 1% per year becoming infected. Of the 60 patients who developed an infection, 21 (35%) developed this following the primary procedure at a mean of 50 months, but another 19 developed this within a year of another surgical procedure. The risk of infection after any further surgery was 2.7%. The site with the highest risk of infection was the proximal tibia (43.3%). TAKE HOME MESSAGE: This study highlights the inevitable need for further surgery following first-generation endoprosthetic reconstruction, although in most cases, limb salvage is maintained. Late complications, especially infection, continue for the lifetime of the implant. Cite this article: Bone Joint J 2016;98-B:857-64. PMID- 27235534 TI - A giant inguinoscrotal hernia associated with other abdominal wall defects A case report. AB - INTRODUCTION: Giant inguinoscrotal hernias are unusual in developed countries and rarely associated with other wall hernias, such as controlateral inguinal hernia, umbilical hernia. The presence of more parietal defects can facilitate reinstatement of giant hernia content without respiratory and circulatory compromise, but the risk of occlusion and bowel strangulation results increased. CASE REPORT: Here, we report an unusual case of an asymptomatic giant inguinal hernia associated with controlateral inguinal and umbilical hernia in a 60 years old Caucasian male treated with sequential surgical approach. In particular, the Lichtenstein's technique under spinal anesthesia was performed and it could be considered the gold standard for this disease. CONCLUSION: Giant inguinal hernia and abdomen wall defects should not be repaired at the same time. It is more useful to be less aggressive, monitoring the progressive and natural adaptation of the viscera into the abdomen. Anyway, thereby literature results very poor and additional reports are required. KEY WORDS: Giant inguinoscrotal hernia, Hernia, Hernia treatment, Wall defects. PMID- 27235535 TI - Expression of proliferation genes in formalin-fixed paraffin-embedded (FFPE) tissue from breast carcinomas. Feasibility and relevance for a routine histopathology laboratory. AB - AIM: Breast carcinoma proliferative activity, histological grade and commercial molecular tests are all important in prognostication and treatment. There is a particular need for improved, standardised techniques for subclassification of grade 2 breast cancers into low-risk and high-risk prognostic groups. In this study we investigated whether gene expression profiling of five proliferation genes was feasible using breast cancer tissue in a clinical setting and whether these profiles could enhance pathological assessment. METHODS: Expression of five proliferation gene mRNAs; Ki-67, STK 15, CCNB1, CCND1 and MYBL2, was quantified in 27 breast carcinomas and compared with Ki-67 proliferation index (PI) and Nottingham mitotic score. RESULTS: Expression of Ki-67, STK15 and MYBL2 mRNA showed moderate Spearman's correlation with Ki-67 PI (p<0.01), but CCND1 and CCNB1 showed weak, non-significant correlation. Individual gene expression did not associate with mitotic score but combined mRNA expression correlated with both Ki-67 PI (p=0.018) and mitotic score (p=0.03; 0.007). CONCLUSIONS: This study confirms mRNA analysis in breast carcinoma formalin-fixed, paraffin embedded samples is feasible and suggests gene expression profiling, using a small set of five proliferation genes, has potential in aiding histological grading or assessment of proliferative activity of breast cancers. To fully evaluate the clinical applicability of this approach, a larger cohort study with long-term follow-up data is required. PMID- 27235536 TI - Gene of the month: BAP1. AB - The BAP1 gene (BRCA1-associated protein 1) is a tumour suppressor gene that encodes a deubiquitinating enzyme (DUB), regulating key cellular pathways, including cell cycle, cellular differentiation, transcription and DNA damage response. Germline BAP1 mutations cause a novel cancer syndrome characterised by early onset of multiple atypical Spitz tumours and increased risk of uveal and cutaneous melanoma, mesothelioma, renal cell carcinoma and various other malignancies. Recognising the clinicopathological features of specific BAP1 deficient tumours is crucial for early screening/tumour detection, with significant impact on patient outcome. PMID- 27235537 TI - The effect of long-term -80 degrees C storage of thyroid biospecimens on RNA quality and ensuring fitness for purpose. AB - AIMS: To establish whether RNA degrades in long-term storage at -80 degrees C and whether RNA integrity numbers (RINs) determine 'fitness for purpose' in severely degraded RNA. METHODS: RNA was extracted from 549 thyroid biospecimens stored at 80 degrees C for 0.1-10.9 years then their RINs correlated with storage time. RT PCR for 65, 265, 534 and 942 base pair amplicons of hydroxymethylbilane synthase was used to measure amplicon length in RNA from cryopreserved and FFPE biospecimens that were equally degraded according to RIN. RESULTS: Storage time did not correlate with RIN. Longer amplicons were obtained from cryopreserved samples than FFPE samples with equal RINs. CONCLUSIONS: RNA does not degrade in thyroid biospecimens stored for long periods of time at -80 degrees C. Although RINs are known to predict amenability to analytical platforms in good quality samples, this prediction is unreliable in severely degraded samples. PMID- 27235539 TI - Environment and development. PMID- 27235540 TI - Transposable element influences on gene expression in plants. AB - Transposable elements (TEs) comprise a major portion of many plant genomes and bursts of TE movements cause novel genomic variation within species. In order to maintain proper gene function, plant genomes have evolved a variety of mechanisms to tolerate the presence of TEs within or near genes. Here, we review our understanding of the interactions between TEs and gene expression in plants by assessing three ways that transposons can influence gene expression. First, there is growing evidence that TE insertions within introns or untranslated regions of genes are often tolerated and have minimal impact on expression level or splicing. However, there are examples in which TE insertions within genes can result in aberrant or novel transcripts. Second, TEs can provide novel alternative promoters, which can lead to new expression patterns or original coding potential of an alternate transcript. Third, TE insertions near genes can influence regulation of gene expression through a variety of mechanisms. For example, TEs may provide novel cis-acting regulatory sites behaving as enhancers or insert within existing enhancers to influence transcript production. Alternatively, TEs may change chromatin modifications in regions near genes, which in turn can influence gene expression levels. Together, the interactions of genes and TEs provide abundant evidence for the role of TEs in changing basic functions within plant genomes beyond acting as latent genomic elements or as simple insertional mutagens. This article is part of a Special Issue entitled: Plant Gene Regulatory Mechanisms and Networks, edited by Dr. Erich Grotewold and Dr. Nathan Springer. PMID- 27235541 TI - Development of a lateral-flow assay (LFA) for rapid detection of Soybean mosaic virus. AB - Soybean mosaic virus (SMV) is the most common virus in soybean and poses a serious threat to crop production and germplasm recession in many countries worldwide. In this study, a highly practical and rapid lateral-flow assay (LFA) was developed for the detection of SMV. The SMV coat protein (CP) was prokaryotically expressed and purified to immunize mice. After generation of hybridoma cell lines, four anti-SMV monoclonal antibodies were selected. The LFA strip was then assembled using a double-antibody sandwich strategy. When the SMV infected leaf sample was assayed using the assembled LFA-strip, the positive pink color appeared in the test line within 5-10min. The strip only gave positive results with SMV and not other viruses tested and could be used to detect 800 fold dilutions of infected leaf samples. The LFA could be used to detect SMV in infected leaf tissue as well as soybean seeds. To our knowledge, this is the first report of the development of a LFA for the detection of SMV. The practical, rapid and specific assay that was developed in this study can be widely applied to the diagnosis and surveillance of SMV in the laboratory and the field. PMID- 27235542 TI - beta3 integrin promotes chemoresistance to epirubicin in MDA-MB-231 through repression of the pro-apoptotic protein, BAD. AB - Resistance to anthracycline based chemotherapy is a major limitation in the treatment of breast cancer, particularly of the triple negative sub-type that lacks targeted therapies. Resistance that arises from tumor-stromal interaction facilitated by integrins provides the possibility of targeted disruption. In the present study, we demonstrate that integrin beta3 signaling inhibits apoptosis induced by a DNA-damaging chemotherapeutic agent, epirubicin, in MDA-MB-231 breast cancer cells. Drug efflux based mechanisms do not contribute to this effect. We show that integrin beta3 employs the PI3K-Akt and the MAPK pathway for enabling cell survival and proliferation. Further, our results indicate that integrin beta3 helps inhibit epirubicin induced cytotoxicity by repression of the pro-apoptotic protein BAD, thus promoting an anti-apoptotic response. Myristoylated RGT peptide and a monoclonal antibody against integrin beta3 brought about a reversal of this effect and chemosensitized the cells. These results identify beta3 integrin signaling via repression of BAD as an important survival pathway used by breast cancer cells to evade chemotherapy induced stress. PMID- 27235544 TI - A multiproxy approach to evaluate biocidal treatments on biodeteriorated majolica glazed tiles. AB - The Fishing House located on the grounds of the Marquis of Pombal Palace, Oeiras, Portugal, was built in the 18th century. During this epoch, Portuguese gardens, such as the one surrounding the Fishing House, were commonly ornamented with glazed wall tile claddings. Currently, some of these outdoor tile panels are covered with dark colored biofilms, contributing to undesirable aesthetic changes and eventually inducing chemical and physical damage to the tile surfaces. Phylogenetic analyses revealed that the investigated biofilms are mainly composed of green algae, cyanobacteria and dematiaceous fungi. With the aim of mitigating biodeterioration, four different biocides (TiO2 nanoparticles, Biotin(r) T, Preventol(r) RI 80 and Albilex Biostat(r) ) were applied in situ to the glazed wall tiles. Their efficacy was monitored by visual examination, epifluorescence microscopy and DNA-based analysis. Significant changes in the microbial community composition were observed 4 months after treatment with Preventol(r) RI 80 and Biotin(r) T. Although the original community was inactivated after these treatments, an early stage of re-colonization was detected 6 months after the biocide application. TiO2 nanoparticles showed promising results due to their self-cleaning effect, causing the detachment of the biofilm from the tile surface, which remained clean 6 and even 24 months after biocide application. (c) 2013 Society for Applied Microbiology and John Wiley & Sons Ltd. PMID- 27235538 TI - DNA damage in the oligodendrocyte lineage and its role in brain aging. AB - Myelination is a recent evolutionary addition that significantly enhances the speed of transmission in the neural network. Even slight defects in myelin integrity impair performance and enhance the risk of neurological disorders. Indeed, myelin degeneration is an early and well-recognized neuropathology that is age associated, but appears before cognitive decline. Myelin is only formed by fully differentiated oligodendrocytes, but the entire oligodendrocyte lineage are clear targets of the altered chemistry of the aging brain. As in neurons, unrepaired DNA damage accumulates in the postmitotic oligodendrocyte genome during normal aging, and indeed may be one of the upstream causes of cellular aging - a fact well illustrated by myelin co-morbidity in premature aging syndromes arising from deficits in DNA repair enzymes. The clinical and experimental evidence from Alzheimer's disease, progeroid syndromes, ataxia telangiectasia and other conditions strongly suggest that oligodendrocytes may in fact be uniquely vulnerable to oxidative DNA damage. If this damage remains unrepaired, as is increasingly true in the aging brain, myelin gene transcription and oligodendrocyte differentiation is impaired. Delineating the relationships between early myelin loss and DNA damage in brain aging will offer an additional dimension outside the neurocentric view of neurodegenerative disease. PMID- 27235543 TI - Exercise preconditioning reduces neonatal incision surgery-induced enhanced hyperalgesia via inhibition of P38 mitogen-activated protein kinase and IL-1beta, TNF-alpha release. AB - Neonatal surgery leads to enhanced hyperalgesia to noxious stimulation in adulthood via a mechanism caused by enhanced phosphorylated (p)-p38 expression in microglia. We tested the effect of exercise on reducing enhanced hypersensitivity primed by neonatal incision surgery. Adult female Wistar rats, with or without neonatal incision surgery at postnatal day (P) 3, received right hind paw plantar incision surgery under anesthesia at P44. The rats performed wheel-running exercise from P22 to P41. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were measured and ipsilateral spinal cords were collected for protein quantification. For PWT and PWL, exercise reduced the pain index after incision surgery at P44 in rats with neonatal surgery (P<0.01). Western blots showed that exercise suppressed P-p38 expression relative to adult rats without neonatal surgery (P<0.05). Results of ELISA showed that exercise reduced IL-1beta and TNF-alpha (P<0.05) concentration in the ipsilateral spinal cord. Exercise preconditioning is an effective approach to reducing enhanced adult hyperalgesia primed by neonatal surgery. The mechanism may be explained by exercise-induced inhibition of P-p38 activation and IL-1beta, TNF-alpha release. PMID- 27235545 TI - Protein Co-localization Studies: Issues and Considerations. PMID- 27235546 TI - Discrimination and Quantification of True Biological Signals in Metabolomics Analysis Based on Liquid Chromatography-Mass Spectrometry. PMID- 27235548 TI - A Specific Class of Short Treadmilling Microtubules Enhances Cortical Microtubule Alignment. PMID- 27235547 TI - Soybean miR172a Improves Salt Tolerance and Can Function as a Long-Distance Signal. PMID- 27235549 TI - Phylogenetic relationships within the Callicebus cupreus species group (Pitheciidae: Primates): Biogeographic and taxonomic implications. AB - The genus Callicebus (Thomas, 1903) is one of the most diverse of Neotropical primate genera and the only extant member of the Callicebinae subfamily. It has a widespread distribution from Colombia to Brazil, Bolivia, Peru and northern Paraguay. Coat colouring and colour pattern vary substantially within the genus, and this has led to the description of numerous species and subspecies, as well as numerous species groups. However, a lack of molecular phylogenetic analyses on the genus means that phylogenetic relationships and biogeographic history of species are poorly understood. Here, we examined phylogenetic relationships and patterns of diversification within the Callicebus cupreus species Group (sensu Kobayashi, 1995) using complete mitochondrial DNA cytochrome b gene sequence. Analyses indicate that the Callicebus cupreus Group underwent recent and extensive diversification. The common ancestor appears to have emerged some 2.3 million years ago (Ma) from a centre of origin in the western Amazon region, followed by diversification of the group between about 1.5 and 1.2Ma. Phylogenetic analyses were able to recover most previously described species (including the recently described Colombian endemic Callicebus caquetensis). However, there are some notable inconsistences between the obtained phylogeny and current taxonomy. Some previously recognized taxa were not separated by our data (e.g., Callicebus caligatus and Callicebus dubius), while currently unrecognized species diversity was uncovered within C. cupreus in the form of two divergent lineages: one of which exhibited greater phylogenetic similarity to species from the C. moloch Group. Based on the present study, we challenge current taxonomic arrangements for the C. cupreus species Group and call for a thorough taxonomic revision within the genus Callicebus. PMID- 27235550 TI - Multiple instances of paraphyletic species and cryptic taxa revealed by mitochondrial and nuclear RAD data for Calandrella larks (Aves: Alaudidae). AB - The avian genus Calandrella (larks) was recently suggested to be non monophyletic, and was divided into two genera, of which Calandrella sensu stricto comprises 4-5 species in Eurasia and Africa. We analysed mitochondrial cytochrome b (cytb) and nuclear Restriction-site Associated DNA (RAD) sequences from all species, and for cytb we studied 21 of the 22 recognised subspecies, with the aim to clarify the phylogenetic relationships within the genus and to compare large scale nuclear sequence patterns with a widely used mitochondrial marker. Cytb indicated deep splits among the currently recognised species, although it failed to support the interrelationships among most of these. It also revealed unexpected deep divergences within C. brachydactyla, C. blanfordi/C. erlangeri, C. cinerea, and C. acutirostris. It also suggested that both C. brachydactyla and C. blanfordi, as presently circumscribed, are paraphyletic. In contrast, most of the many subspecies of C. brachydactyla and C. cinerea were unsupported by cytb, although two populations of C. cinerea were found to be genetically distinct. The RAD data corroborated the cytb tree (for the smaller number of taxa analysed) and recovered strongly supported interspecific relationships. However, coalescence analyses of the RAD data, analysed in SNAPP both with and without an outgroup, received equally strong support for two conflicting topologies. We suggest that the tree rooted with an outgroup - which is not recommended for SNAPP - is more trustworthy, and suggest that the reliability of analyses performed without any outgroup species should be thoroughly evaluated. We also demonstrate that degraded museum samples can be phylogenetically informative in RAD analyses following careful bioinformatic treatment. We note that the genus Calandrella is in need of taxonomic revision. PMID- 27235551 TI - mTOR remains unchanged in diet-resistant (DR) rats despite impaired LKB1/AMPK cascade in adipose tissue. AB - Liver kinase B1 (LKB1) plays an important role in adipogenesis, but the underlying molecular mechanism is poorly understood. Here, we explored the functional relationship between LKB1 and the mammalian target of rapamycin (mTOR) in regulating adipogenesis in rats and preadipocytes. We found that LKB1 and the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) cascade are impaired in the white adipose tissue (WAT) of diet-induced obesity (DIO) and diet resistant (DR) rats when compared with chow-fed (CF) rats. While DIO activated the mTOR pathway in WAT and led to a more fat mass gain, DR maintained the normal activity of the mTOR pathway and normal weight and percentage of fat mass. We further constructed overexpressed LKB1 (OE) and silenced LKB1 (Si) 3T3-L1 preadipocytes monoclonal cell lines. In the OE cell line, the mTOR pathway was inactivated, and intracellular lipid content was reduced during differentiation. This effect could be reversed by AMPK inhibition. Conversely, in the Si cell line, the mTOR pathway was activated and intracellular lipid content increased. This effect could be reversed by rapamycin, an inhibitor of mTOR. Our results suggest that mTOR mediates the effect of LKB1 on adipogenesis, and normal activity of mTOR in DR rats interferes with the effect of LKB1 in WAT. PMID- 27235552 TI - Hypoxic stress up-regulates Kir2.1 expression and facilitates cell proliferation in brain capillary endothelial cells. AB - The blood-brain barrier (BBB) is mainly composed of brain capillary endothelial cells (BCECs), astrocytes and pericytes. Brain ischemia causes hypoxic encephalopathy and damages BBB. However, it remains still unclear how hypoxia affects BCECs. In the present study, t-BBEC117 cells, an immortalized bovine brain endothelial cell line, were cultured under hypoxic conditions at 4-5% oxygen for 72 h. This hypoxic stress caused hyperpolarization of resting membrane potential. Patch-clamp recordings revealed a marked increase in Ba(2+)-sensitive inward rectifier K(+) current in t-BBEC117 cells after hypoxic culture. Western blot and real-time PCR analyses showed that Kir2.1 expression was significantly up-regulated at protein level but not at mRNA level after the hypoxic culture. Ca(2+) imaging study revealed that the hypoxic stress enhanced store-operated Ca(2+) (SOC) entry, which was significantly reduced in the presence of 100 MUM Ba(2+). On the other hand, the expression of SOC channels such as Orai1, Orai2, and transient receptor potential channels was not affected by hypoxic stress. MTT assay showed that the hypoxic stress significantly enhanced t-BBEC117 cell proliferation, which was inhibited by approximately 60% in the presence of 100 MUM Ba(2+). We first show here that moderate cellular stress by cultivation under hypoxic conditions hyperpolarizes membrane potential via the up-regulation of functional Kir2.1 expression and presumably enhances Ca(2+) entry, resulting in the facilitation of BCEC proliferation. These findings suggest potential roles of Kir2.1 expression in functional changes of BCECs in BBB following ischemia. PMID- 27235553 TI - Novel glyceryl glucoside is a low toxic alternative for cryopreservation agent. AB - Glyceryl glucoside (GG, alpha-d-glucosyglycerol) is a natural glycerol derivative found in alcoholic drinks. Recently GG has been used as an alternative for glycerol in cosmetic products. However, the safety of using GG is still unclear. Currently, dimethyl sulfoxide (DMSO) and glycerol are wildly used in cryopreservation. Despite GG being a derivative of glycerol, the ability of GG in cryopreservation is still unknown. By using a system of Chinese Hamster Ovary cells (CHO), A549 cells and AG1522 cells, the study examined the cryoprotective effects of DMSO, glycerol and GG. Cytotoxic and genotoxic responses induced by the three chemicals were also investigated with CHO to determine the safety of GG for cosmetic products. Our data suggests that GG has great cryopresearvation ability in the concentration of 30%-40% (v/v). For cytotoxic studies, DMSO showed the highest cytotoxicity above 3% (v/v) in cell doubling time delay among three chemicals. For the acute cytotoxicity with trypan blue dye exclusion assay, GG showed stronger cell killing effect within 24 h above 4% (v/v). For the continuous cytotoxicity with colony formation assay for 7 days, DMSO showed significantly reduced clonogenic ability above 2%. In genotoxicity studies, CHO treated with glycerol at 2% concentration induced three times higher frequencies of sister chromatid exchange (SCE) than background levels. GG did not induce significant amounts of SCE compared to background. Micronuclei formation was equally observed in the 2% and above concentrations of glycerol and GG. Our data showed that GG has significant effects on cryopreservation compared to DMSO. Glycerol and GG have similar cytotoxicity effects to CHO, but glycerol induced genotoxic responses in the same concentration. Therefore, we conclude that GG may be a safer alternative compound to glycerol in cosmetic products and safer alternative to DMSO in cryopreservation. PMID- 27235554 TI - RETRACTED: Ghrelin protects infarcted myocardium by induction of autophagy and AMP-activated protein kinase pathway. 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 Editor-in-Chief. It contains LM images in figure 2E, which were originally published in Nat. Comm. 6/2015, p. 1-14 (http://doi:10.1038/ncomms8388). Permission to reproduce this figure was not requested nor granted by the authors of the original article for its re-use.The authors of this article would like to apologize to all affected parties. PMID- 27235555 TI - Mechanistic role of cytochrome P450 (CYP)1B1 in oxygen-mediated toxicity in pulmonary cells: A novel target for prevention of hyperoxic lung injury. AB - Supplemental oxygen, which is routinely administered to preterm infants with pulmonary insufficiency, contributes to bronchopulmonary dysplasia (BPD) in these infants. Hyperoxia also contributes to the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in adults. The mechanisms of oxygen-mediated pulmonary toxicity are not completely understood. Recent studies have suggested an important role for cytochrome P450 (CYP)1A1/1A2 in the protection against hyperoxic lung injury. The role of CYP1B1 in oxygen-mediated pulmonary toxicity has not been studied. In this investigation, we tested the hypothesis that CYP1B1 plays a mechanistic role in oxygen toxicity in pulmonary cells in vitro. In human bronchial epithelial cell line BEAS-2B, hyperoxic treatment for 1-3 days led to decreased cell viability by about 50-80%. Hyperoxic cytotoxicity was accompanied by an increase in levels of reactive oxygen species (ROS) by up to 110%, and an increase of TUNEL-positive cells by up to 4.8-fold. Western blot analysis showed hyperoxia to significantly down-regulate CYP1B1 protein level. Also, there was a decrease of CYP1B1 mRNA by up to 38% and Cyp1b1 promoter activity by up to 65%. On the other hand, CYP1B1 siRNA appeared to rescue the cell viability under hyperoxia stress, and overexpression of CYP1B1 significantly attenuated hyperoxic cytotoxicity after 48 h of incubation. In immortalized lung endothelial cells derived from Cyp1b1-null and wild-type mice, hyperoxia increased caspase 3/7 activities in a time-dependent manner, but endothelial cells lacking the Cyp1b1 gene showed significantly decreased caspase 3/7 activities after 48 and 72 h of incubation, implying that CYP1B1 might promote apoptosis in wild type lung endothelial cells under hyperoxic stress. In conclusion, our results support the hypothesis that CYP1B1 plays a mechanistic role in pulmonary oxygen toxicity, and CYP1B1-mediated apoptosis could be one of the mechanisms of oxygen toxicity. Thus, CYP1B1 could be a novel target for preventative and/or therapeutic interventions against BPD in infants and ALI/ARDS in adults. PMID- 27235556 TI - Biocompatible Zr-based nanoscale MOFs coated with modified poly(epsilon caprolactone) as anticancer drug carriers. AB - Nanoscale Zr-based metal organic frameworks (MOFs) UiO-66 and UiO-67 were studied as potential anticancer drug delivery vehicles. Two model drugs were used, hydrophobic paclitaxel and hydrophilic cisplatin, and were adsorbed onto/into the nano MOFs (NMOFs). The drug loaded MOFs were further encapsulated inside a modified poly(epsilon-caprolactone) with d-alpha-tocopheryl polyethylene glycol succinate polymeric matrix, in the form of microparticles, in order to prepare sustained release formulations and to reduce the drug toxicity. The drugs physical state and release rate was studied at 37 degrees C using Simulated Body Fluid. It was found that the drug release depends on the interaction between the MOFs and the drugs while the controlled release rates can be attributed to the microencapsulated formulations. The in vitro antitumor activity was assessed using HSC-3 (human oral squamous carcinoma; head and neck) and U-87 MG (human glioblastoma grade IV; astrocytoma) cancer cells. Cytotoxicity studies for both cell lines showed that the polymer coated, drug loaded MOFs exhibited better anticancer activity compared to free paclitaxel and cisplatin solutions at different concentrations. PMID- 27235557 TI - The utility of QSARs in predicting acute fish toxicity of pesticide metabolites: A retrospective validation approach. AB - The European Plant Protection Products Regulation 1107/2009 requires that registrants establish whether pesticide metabolites pose a risk to the environment. Fish acute toxicity assessments may be carried out to this end. Considering the total number of pesticide (re-) registrations, the number of metabolites can be considerable, and therefore this testing could use many vertebrates. EFSA's recent "Guidance on tiered risk assessment for plant protection products for aquatic organisms in edge-of-field surface waters" outlines opportunities to apply non-testing methods, such as Quantitative Structure Activity Relationship (QSAR) models. However, a scientific evidence base is necessary to support the use of QSARs in predicting acute fish toxicity of pesticide metabolites. Widespread application and subsequent regulatory acceptance of such an approach would reduce the numbers of animals used. The work presented here intends to provide this evidence base, by means of retrospective data analysis. Experimental fish LC50 values for 150 metabolites were extracted from the Pesticide Properties Database (http://sitem.herts.ac.uk/aeru/ppdb/en/atoz.htm). QSAR calculations were performed to predict fish acute toxicity values for these metabolites using the US EPA's ECOSAR software. The most conservative predicted LC50 values generated by ECOSAR were compared with experimental LC50 values. There was a significant correlation between predicted and experimental fish LC50 values (Spearman rs = 0.6304, p < 0.0001). For 62% of metabolites assessed, the QSAR predicted values are equal to or lower than their respective experimental values. Refined analysis, taking into account data quality and experimental variation considerations increases the proportion of sufficiently predictive estimates to 91%. For eight of the nine outliers, there are plausible explanation(s) for the disparity between measured and predicted LC50 values. Following detailed consideration of the robustness of this non-testing approach, it can be concluded there is a strong data driven rationale for the applicability of QSAR models in the metabolite assessment scheme recommended by EFSA. As such there is value in further refining this approach, to improve the method and enable its future incorporation into regulatory guidance and practice. PMID- 27235558 TI - Comment on "Exposure-response modeling of non-cancer effects in humans exposed to Libby Amphibole Asbestos; update" by Benson et al. (2015). PMID- 27235559 TI - Does infrared visualization improve selection of venipuncture sites for indwelling needle at the forearm in second-year nursing students? AB - OBJECTIVES: To evaluate the effectiveness of a vein visualization display system using near-infrared light ("Vein Display") for the safe and proper selection of venipuncture sites for indwelling needle placement in the forearm. METHODS: Ten second year nursing students were recruited to apply an indwelling needle line with and without Vein Display. Another ten participants were recruited from various faculty to serve as patients. The quality of the venipuncture procedure at various selected sites was evaluated according to a scale developed by the authors. Time, scores and patterns of puncture-site selection were compared with respect to three different methods: [1] attempt 1 (tourniquet only), [2] attempt 2 (Vein Display only) and [3] attempt 3 (both). To validate the effectiveness of Vein Display, 52 trials were conducted in total. RESULTS: We found that venipuncture site selection time was significantly improved with the Vein Display, particularly in the case of difficult to administer venipuncture sites. Overall, we found no significant difference with respect to venipuncture quality, as determined by our scale. CONCLUSION: These results suggest that equipment such as the Vein Display can contribute immensely to the improvement of practical skills, such as venipuncture, especially in the context of elderly patients. PMID- 27235560 TI - Professional culture brokers: Nursing faculty perceptions of nursing culture and their role in student formation. AB - Socialization, or formation of students to the professional nurse role, is an expectation of nursing education. This process is complex and challenging for students, who continue to experience culture shock moving from academe to practice settings. Viewing formation as enculturation is one way to address culture shock. Nursing faculty are key figures in this process, yet their views are not known. This focused ethnography study explored nursing faculty's perceptions about the culture of nursing and how they bring students into that culture. Data collected at two accredited, undergraduate pre-licensure baccalaureate nursing programs were analyzed using Leininger's four phases of data analysis. Four themes emerged: 1. The culture of nursing is multifaceted, multivalent and at times contradictory 2. Many factors interact and have influence on the culture of nursing 3. Navigating the subcultures (academia, service and organizational culture) is challenging for faculty, and 4. Nursing faculty believe that the right conditions facilitate the enculturation of students. Nursing faculty believe nursing has a professional culture and they bring students into that culture. Viewing the faculty role in enculturation to professional nursing as a culture broker can facilitate the process for students and mitigate the culture shock new graduate nurses experience. PMID- 27235561 TI - Australian nursing and midwifery educators delivering evidence-based education in Tanzania: A qualitative study. AB - Since 2011, Western Australian nursing and midwifery educators have been providing evidence-based continuing education to Tanzanian health professionals. Despite thorough preparation before departure, differences in local resource levels and available facilities have necessitated impromptu adaptation of curriculum content and delivery methods to ensure an effective program was delivered. This study explored the personal, cultural and teaching strategies utilised by Western Australian nursing and midwifery educators in Tanzania and examined if the transferability of education packages was influenced by the educators' cultural competence. Using a qualitative exploratory approach, data was collected from 15 Western Australian nursing and midwifery educators using a demographic survey and in-depth individual semi-structured interviews. The core themes identified from the analysis were Determination to learn, Assessing needs, Communication skills and Greater understanding. These findings are described using the conceptual framework of Campinha-Bacote's The Process of Cultural Competence in the Delivery of Healthcare Services. With appropriate levels of cultural competence, international health professionals can be effective at providing ongoing professional development to colleagues in developing country contexts, which may help address difficulties with retention and motivation of staff. It is essential that prior to departure cultural competence training is provided to educators to enhance their teaching capacity and effectiveness in international settings. PMID- 27235562 TI - A qualitative study of freshmen's and academic advisors' perspectives on academic advising in nursing. AB - Many universities have established academic advisor schemes so that academic advisors play a proactive role in supporting freshmen, helping them to achieve both academic goals and personal and professional aspirations. This research aimed to explore freshmen's and academic advisors' perspectives on the academic advisor scheme of a nursing school. A total of 79 participants (74 freshmen and five academic advisors) were recruited to participate in this qualitative research. The freshmen participated in a focus group interview, with 6-10 freshmen per group, and the academic advisors participated in an individual in depth interview. Both expressed their perspectives on academic advising in four domains: (i) relationship building, (ii) academic development, (iii) personal growth, and (iv) professional goals. Most of the freshmen were satisfied and indicated that they had benefited from the academic advisor scheme, suggesting that academic advisors played a significant role in advising and supporting them. However, the results showed that relationships between freshmen and academic advisors should be further strengthened. PMID- 27235563 TI - Embedding evidence-based practice among nursing undergraduates: Results from a pilot study. AB - Evidence-based practice is currently one of the most important developments in health care. Research in nursing science is rapidly growing; however, translating the knowledge based on this research into clinical practice is often hampered, and may be dependent on reflective skills. The aim of this study was to see how undergraduate nursing students in nursing should increase their skills and knowledge related to evidence-based practice through participation in clinical research projects. A qualitative approach was used in collecting and analyzing the data. Students participated in a pilot clinical research project and a received guidance related to their bachelor thesis. After the project was completed, all students filled in a questionnaire. The students' motivation to participate in this study was reported to be high, but they reported low knowledge related to evidence-based practice. All students reported that their attitude towards evidence-based practice changed in a positive direction during their participation in the project. Evidence-based practice influenced nursing practices by putting more focus on critical thinking, increasing pride and giving a sense of ownership in the clinical field. The curricula and the pedagogical perspectives in nursing education can influence the attitude towards evidence based practice and skills among nursing bachelor students. PMID- 27235564 TI - The nurse match instrument: Exploring professional nursing identity and professional nursing values for future nurse recruitment. AB - From April 1st 2015 it will be mandatory for Higher Education Institutions (HEI) in the United Kingdom (UK) providing pre-qualifying health care higher education to use a Values Based Recruitment (VBR) tool, to ensure only the candidates with the "right" personal identity and values commensurate with the Professional Identity of Nursing (PIN) are accepted for nurse education. "Nurse Match" instrument was developed to enhance the recruitment and selection of candidates for pre-qualifying nursing. Action Research into PIN commenced with voluntary, purposive, convenience samples of qualified nurses (n = 30), Service Users (N = 10), postgraduate diploma nurses in mental health (N = 25), third year mental health branch students (N = 20) and adult and child student nurses in years 2 and 3 (N = 20) in Focus Groups. Data collection and analysis occurred concomitantly between July 2013 and October 2014, aided by NVivo 10 software and revealed Key Quality Indicators (KQIs) of the social construction of PIN. Construct development included a literature review spanning the last fifteen years, which identified four main themes; 1. Nursing's ethics and values. 2. Nursing's professional identity and caring. 3. Nursing's emotional intelligence. 4. Nursing's professionalism. Nurse Match offers an evidence-based enhancement to VBR, for future nurse recruitment locally, nationally and internationally. PMID- 27235565 TI - Students' perceptions of the use of eportfolios in nursing and midwifery education. AB - ePortfolios have been introduced into many higher education degrees in the past decade in an effort to help students to link theory, practice and personal experiences. This pilot study used a survey to examine ePortfolio use from the perspective of undergraduate nursing and postgraduate midwifery students. Fifty seven students from a regional Australian university completed an online questionnaire which contained questions about the following areas of ePortfolio use: understanding of the tool; psychological perceptions; challenges around use; assessment; outcomes of use; benefits; maintenance of the ePortfolio; and enhanced learning. The majority of respondents were female, undergraduate students, aged 21-30 years. Results indicated that many students found ePortfolio use frustrating; in particular, technological and logistical challenges in using ePortfolios were highlighted. Most students, however, noted ePortfolios could be useful repositories for documents, reflections and learning experiences. Undergraduate students were more likely than postgraduate students to see the positive potential of ePortfolio use. The findings, coupled with the literature, raise questions about the effectiveness of ePortfolio use in nursing and midwifery education and, particularly, whether ePortfolios have been implemented with misguided and misinformed good intention. Further research is required to better understand the logistical and technological aspects of successful implementation of ePortfolios and fully capitalise on their benefits for nursing and midwifery education. PMID- 27235566 TI - Measuring third year undergraduate nursing students' reflective thinking skills and critical reflection self-efficacy following high fidelity simulation: A pilot study. AB - Critical reflection underpins critical thinking, a highly desirable generic nursing graduate capability. To improve the likelihood of critical thinking transferring to clinical practice, reflective thinking needs to be measured within the learning space of simulation. This study was divided into two phases to address the reliability and validity measures of previously untested surveys. Phase One data was collected from individuals (n = 6) using a 'think aloud' approach and an expert panel to review content validity, and verbatim comment analysis was undertaken. The Reflective Thinking Instrument and Critical Reflection Self-Efficacy Visual Analogue Scale items were contextualised to simulation. The expert review confirmed these instruments exhibited content validity. Phase Two data was collected through an online survey (n = 58). Cronbach's alpha measured internal consistency and was demonstrated by all subscales and the Instrument as a whole (.849). There was a small to medium positive correlation between critical reflection self-efficacy and general self efficacy (r = .324, n = 56, p = .048). Participant responses were positive regarding the simulation experience. The research findings demonstrated that the Reflective Thinking and Simulation Satisfaction survey is reliable. Further development of this survey to establish validity is recommended to make it viable. PMID- 27235567 TI - The operating room as a clinical learning environment: An exploratory study. AB - Students undertake their clinical placement in various clinical settings for the exposure to and acquisition of skills related to that particular context. The operating room is a context that offers the opportunity to develop critical skills related to the perioperative care of the patient. Despite numerous studies that have been undertaken in this field, few have investigated the operating room as a clinical learning environment in the South African private healthcare context. The aim of this study was to determine nursing students' perceptions of the operating room as a clinical learning environment. An exploratory, interpretive and descriptive design generating qualitative data was utilized. Eight nursing students completed an open-ended questionnaire, and twelve nursing students participated in the focus group discussion. Four themes emerged, namely, 'interpersonal factors', 'educational factors', 'private operating room context', and 'recommendations'. The opinion that the operating room offers an opportunity to gain skills unique to this context was expressed. However, despite the potential learning opportunities, the key findings of this study reveal negative perceptions of nursing students regarding learning experiences in the operating room. Exploration into the preparatory needs of students specific to learning outcomes before operating room placement should be considered. It will also be necessary to improve collaboration between lecturers, mentors and theatre managers. PMID- 27235568 TI - Clinical reasoning of nursing students on clinical placement: Clinical educators' perceptions. AB - Graduate nurses may have knowledge and adequate clinical psychomotor skills however they have been identified as lacking the clinical reasoning skills to deliver safe, effective care suggesting contemporary educational approaches do not always facilitate the development of nursing students' clinical reasoning. While nursing literature explicates the concept of clinical reasoning and develops models that demonstrate clinical reasoning, there is very little published about nursing students and clinical reasoning during clinical placements. Semi-structured interviews were conducted with ten clinical educators to gain an understanding of how they recognised, developed and appraised nursing students' clinical reasoning while on clinical placement. This study found variability in the clinical educators' conceptualisation, recognition, and facilitation of students' clinical reasoning. Although most of the clinical educators conceptualised clinical reasoning as a process those who did not demonstrated the greatest variability in the recognition and facilitation of students' clinical reasoning. The clinical educators in this study also described being unable to adequately appraise a student's clinical reasoning during clinical placement with the use of the current performance assessment tool. PMID- 27235569 TI - The unitary zROC slope in amnesics does not reflect the absence of recollection: critical simulations in healthy participants of the zROC slope. AB - The functional deficit underlying amnesia has been argued to be in recollective processing. This idea is based on the DPSD model, wherein recognition comprises a mixture of recollection and familiarity signals, with familiarity conforming to an equal-variance signal-detection mechanism while recollection is binary. This model interprets the greater variance for targets than for lures revealed in sub unit zROC slopes, to be a consequence of the mixture of two signals. Importantly, equal variance between targets and lures is found in amnesic, and is consequently interpreted by DPSD to reflect impairment to recollection alongside the sparing of familiarity. Here, we pointed to a logical fallacy in this interpretation. We then asked participants, in two experiments, to make remember-know (RK) and confidence judgments. Simulating equal variance in healthy participants, we either excluded from the analysis 'remember' responses, reflecting recollection, or the most accurate memories, reflecting strength. We found that only the exclusion of the strongest responses led to equal-variance distributions. In addition, we found that accuracy was associated with an interlaced ordering of RK response groups nested under confidence, a pattern hard to reconcile with classic recognition models (DPSD, UVSD). This pattern can, however, be accommodated by the Continuous Dual Process (CDP) model (Wixted and Mickes, 2010), wherein both familiarity and recollection are continuous signals. Amnesia may thus be characterized as the inability to form strong memories, recollection as well as familiarity. PMID- 27235570 TI - Characterizing cerebellar activity during autobiographical memory retrieval: ALE and functional connectivity investigations. AB - Previous neuroimaging research has shown that the cerebellum is often activated during autobiographical memory (AM) retrieval. However, the reliability of that activation, its localization within the cerebellum, and its relationship to other areas of the AM network remains unknown. The current study used Activation Likelihood Estimation meta-analysis (ALE) as well as resting-state and task related functional connectivity analyses to better characterize cerebellar activation in relation to AM. The ALE meta-analysis was run on 32 neuroimaging studies of AM retrieval. The results revealed a cluster of reliable AM-related activity within the Crus I lobule of the right posterior cerebellum. Using the peak ALE coordinate within Crus I as a seed region, both task-related and resting state functional connectivity analyses were run on fMRI data from 38 healthy participants. To determine the specificity of connectivity patterns to Crus I, we also included a cerebellar seed region in right Lobule VI previously identified in an ALE meta-analysis as associated with working memory. Resting-state functional connectivity analyses indicated that Crus I was intrinsically connected with other areas of the AM network as well as surrounding and contralateral cerebellar regions. In contrast, the Lobule VI seed was functionally connected with cerebral and cerebellar regions typically associated with working memory. The task-related connectivity analyses revealed a similar pattern, where the Crus I seed exhibited significant connectivity with key nodes of the AM network while the Lobule IV seed did not. During a semantic control task, both Crus I and Lobule VI showed significant correlations with a network of regions that was largely distinct from the AM network. Together these results indicate that right Crus I lobule is reliably engaged during AM retrieval and is functionally connected to the AM network both during rest, and more importantly, during AM retrieval. PMID- 27235571 TI - Polycyclic aromatic hydrocarbons exposure and lung function decline among coke oven workers: A four-year follow-up study. AB - OBJECTIVES: This study aimed to investigate quantitative relationships of urinary PAH metabolites with lung function declines among coke-oven workers. METHODS: We performed a prospective investigation involving 1243 workers with follow-up periods from 2010 to 2014. Their lung function measurements, including forced vital capacity (FVC), forced expiratory volume in one second (FEV1), the percentage of predicted FVC (FVC%) and FEV1 (FEV1%), FEV1/FVC ratio, and forced expiratory flow between 25% and 75% of vital capacity (FEF25-75), were detected in both baseline (2010) and follow-up study (2014). We also detected the urinary concentrations of 12 PAH metabolites in the baseline study. The relationships between the baseline urinary PAH metabolites and 4-year lung function declines were analyzed by multivariate linear regressions, with adjustment for potential confounders. RESULTS: We found that the baseline concentrations of urinary 1 hydroxynaphthalene (1-OHNa), 2-OHNa, 2-hydroxyfluorene (2-OHFlu), 9-OHFlu, 1 hydroxyphenanthrene (1-OHPh), 2-OHPh, and SigmaOH-PAHs were significantly associated with accelerated decline in FEV1/FVC [all beta>0 and false discovery rate (FDR) P<0.05]. Additionally, the baseline levels of urinary 1-OHNa, 1-OHPh, 2-OHPh, 9-OHPh, 1-hydroxypyrene (1-OHP), and SigmaOH-PAHs were associated with significantly deeper decline in FEF25-75 (all beta>0 and FDR P<0.10). When using backward selection to adjustment for 10 urinary PAH metabolites, the most significant determiner for FEV1/FVC decline was 1-OHNa among nonsmokers and 9 OHFlu among smokers, and the significant determiner for FEF25-75 decline was 9 OHPh among nonsmokers and 1-OHP among smokers. CONCLUSIONS: This longitudinal study revealed that higher baseline exposure levels of PAHs could lead to greater decline in lung function over a 4-year follow-up. PMID- 27235573 TI - First description of an in vitro culture system for Eimeria ovinoidalis macromeront formation in primary host endothelial cells. AB - The apicomplexan parasite Eimeria ovinoidalis is distributed worldwide and causes clinical ovine coccidiosis. As one of the most pathogenic species in sheep, the principal clinical sign is profuse diarrhoea in young animals, which leads to important economic losses in the ovine industry. We here aimed to establish an in vitro culture system for the development of E. ovinoidalis macromeronts, as no suitable systems are currently available for any ovine Eimeria species. Faecal samples containing more than 90% of E. ovinoidalis oocysts were collected from naturally infected lambs and ewes in Murcia Region (Spain). E. ovinoidalis oocysts were collected, left to sporulate in potassium dichromate and stored at 4 degrees C until further studies were conducted. Moreover, a suitable excystation protocol was effectively established, resulting in the release of viable sporozoites, which were allowed to infect primary bovine umbilical vein endothelial cells (BUVEC) and permanent bovine colonic epithelial cells (BCEC). In vitro first merogony was successfully accomplished exclusively in BUVEC leading to macromeront formation (up to 100MUm) and the release of fully developed and viable merozoites I stages. Given that we were able to establish a suitable in vitro system for the first merogony of such pathogenic Eimeria species in sheep, advances might be further made not only on studies regarding the control of ovine coccidiosis, such as drug screenings, but also on the better understanding of molecular parasite-host cell interactions as already demonstrated for other ruminant Eimeria species. PMID- 27235572 TI - Molecular identification of Spirometra spp. (Cestoda: Diphyllobothriidae) in some wild animals from Brazil. AB - Species of the genus Spirometra are diphyllobothriid tapeworms with complex life cycles and are involved in human sparganosis, a neglected disease that affects individuals worldwide. Although some species were reported in wild felids and human cases of sparganosis were described in Brazil, the biology and taxonomy of these parasites are poorly understood. In the present study, samples of diphyllobothriids (eggs and/or proglottids) obtained from the stools of wild carnivores (Leopardus pardalis and Lycalopex vetulus) and plerocercoid larvae found in a snake (Crotalus durissus) from Brazil were analysed by amplifying a fragment of the gene cytochrome c oxidase subunit 1 (cox 1). The DNA sequences obtained here for the first time from the Spirometra spp. from Brazil were used to evaluate the phylogenetic relationships with other species. Molecular data identified two species in the Brazilian samples (evolutionary divergence of 17.8 19.2%). The species were identified as Spirometra sp. 1, found in Le. pardalis, and Spirometra sp. 2 found in Ly. vetulus and C. durissus, and they differed from Asian isolates of Spirometra erinaceieuropaei (17.5-20.2% and 12.2-15.6%, respectively), a species previously considered to be distributed worldwide. Moreover, Spirometra sp. 1 is genetically distinct from Sparganum proliferum from Venezuela (19.6-20.4%), while Spirometra sp. 2 is more closely related with the Venezuelan species (6.1-7.0%). Sequences of Spirometra sp. 2 revealed that it is conspecific with the Argentinean isolate of Spirometra found in Lycalopex gymnocercus (1.9-2.2%). Taxonomic and phylogenetic aspects related to New World species of Spirometra are briefly discussed. PMID- 27235574 TI - Protein extraction from Ca-alginate encapsulated plant material for comparative proteomic analysis. AB - The extensive use of encapsulation material in biotechnology drove the need to develop analytical techniques for this type of material. This study focuses on the specific problems of protein extraction from Ca-alginate encapsulated plant material. Proteomics is one of the fast-developing analysis categories, specifically for stress resistance and developmental changes in plant material. Sample preparation is a critical step in a two-dimensional gel electrophoresis proteome approach and is essential for good results. The aim was to avoid preliminary manipulations and get good quality material for comparative proteome analysis technique 2DE. The phenol extraction method and the complex method with preliminary TCA precipitation, SDS buffer and phenol phase were compared with respect to the efficiency and quality of the resulting 2DE gel. The most appropriate method turned out to be the TCA/phenol method with the phenol fractioning technique adapted to the gentian cell suspension. It resulted in a high protein concentration and good quality sample that could be analyzed using the standard separation procedures of 2DE and spectrometric identification with high efficiency. The work presented here confirms the possibility of obtaining a sufficient protein sample for effective proteomic analysis from a small number of capsules. PMID- 27235575 TI - Heparin-binding peptide as a novel affinity tag for purification of recombinant proteins. AB - Purification of recombinant proteins constitutes a significant part of the downstream processing in biopharmaceutical industries. Major costs involved in the production of bio-therapeutics mainly depend on the number of purification steps used during the downstream process. Affinity chromatography is a widely used method for the purification of recombinant proteins expressed in different expression host platforms. Recombinant protein purification is achieved by fusing appropriate affinity tags to either N- or C- terminus of the target recombinant proteins. Currently available protein/peptide affinity tags have proved quite useful in the purification of recombinant proteins. However, these affinity tags suffer from specific limitations in their use under different conditions of purification. In this study, we have designed a novel 34-amino acid heparin binding affinity tag (HB-tag) for the purification of recombinant proteins expressed in Escherichia coli (E. coli) cells. HB-tag fused recombinant proteins were overexpressed in E. coli in high yields. A one-step heparin-Sepharose-based affinity chromatography protocol was developed to purify HB-fused recombinant proteins to homogeneity using a simple sodium chloride step gradient elution. The HB-tag has also been shown to facilitate the purification of target recombinant proteins from their 8 M urea denatured state(s). The HB-tag has been demonstrated to be successfully released from the fusion protein by an appropriate protease treatment to obtain the recombinant target protein(s) in high yields. Results of the two-dimensional NMR spectroscopy experiments indicate that the purified recombinant target protein(s) exist in the native conformation. Polyclonal antibodies raised against the HB-peptide sequence, exhibited high binding specificity and sensitivity to the HB-fused recombinant proteins (~10 ng) in different crude cell extracts obtained from diverse expression hosts. In our opinion, the HB-tag provides a cost-effective, rapid, and reliable avenue for the purification of recombinant proteins in heterologous hosts. PMID- 27235576 TI - Effects of movement-related afferent inputs on spinal reflexes evoked by transcutaneous spinal cord stimulation during robot-assisted passive stepping. AB - Studies of robot-assisted passive stepping paradigms have reported that movement related afferent inputs strongly inhibit the excitability of the Hoffmann (H) reflex in the soleus (Sol) during walking. However, it is unknown if movement related afferent inputs have the same effect on the excitability of spinal reflexes in the other lower-limb muscles that are involved in normal walking in healthy subjects. The aim of this study was to examine the effects of movement related afferent inputs on the spinal reflexes in lower-limb muscles during walking. Spinal reflexes that were elicited by transcutaneous spinal cord stimulation (tSCS) were recorded during passive air standing and air stepping at three stepping velocities (stride frequencies: 14, 25, and 36 strides/min). The amplitude of the spinal reflexes was reduced in most of the recorded muscles during passive air stepping compared with air standing. Furthermore, in the Sol and lateral gastrocnemius, the amplitude of the reflexes during air stepping significantly decreased as stride frequency increased. These results demonstrate that movement-related afferent inputs inhibit spinal reflexes in the Sol and other lower-limb muscles during walking. PMID- 27235577 TI - Electrophysiological properties of brain-natriuretic peptide- and gastrin releasing peptide-responsive dorsal horn neurons in spinal itch transmission. AB - Spinal itch transmission has been reported to be mediated by at least two neuronal populations in spinal dorsal horn, neurons expressing brain-natriuretic peptide (BNP) receptor (Npra) and gastrin-releasing peptide (GRP) receptor (GRPR). Although Npra-expressing neurons were shown to be upstream of GRPR- expressing neurons in spinal itch transmission, the roles of BNP and GRP in the spinal neurotransmission of histamine-dependent and -independent itch remains unclear. Using in vivo electrophysiology and behavior analysis, this study examined the responses of chloroquine (histamine-independent pruritogen) responsive and histamine-responsive dorsal horn neurons to spinal applications of BNP and GRP. Electrophysiologically, 9.5% of chloroquine-responsive neurons responded to BNP, 33.3% to GRP, and 4.8% to both, indicating that almost half of chloroquine-responsive neurons were unresponsive to both BNP and GRP. In contrast, histamine-responsive neurons did not respond to spinal BNP application, whereas 30% responded to spinal GRP application, indicating that 70% of histamine responsive neurons were unresponsive to both BNP and GRP. Behavioral analyses showed differences in the time-course and frequency of scratching responses evoked by intrathecal BNP and GRP. These findings provide evidence that most BNP Npra and GRP-GRPR signaling involve different pathways of spinal itch transmission, and that multiple neurotransmitters, in addition to BNP and GRP, are involved in spinal itch transmission. The electrophysiological results also suggest that spinal BNP contributes little to histaminergic itch directly. PMID- 27235578 TI - Elevation of Ser9 phosphorylation of GSK3beta is required for HERV-W env-mediated BDNF signaling in human U251 cells. AB - Human endogenous retrovirus W family (HERV-W) envelope (env) is known to be associated with neurological and psychiatric disorders, such as multiple sclerosis and schizophrenia. Previous studies showed that overexpression of HERV W env could induce brain-derived neurotrophic factor (BDNF) gene expression. In human and rat cells, BDNF-mediated signal transduction might be modulated by glycogen synthase kinase 3beta (GSK3beta). Both BDNF and GSK3beta are schizophrenia-related genes. In this paper, we investigated whether GSK3beta was involved in the HERV-W env-induced expression of BDNF. We found that HERV-W env increased phosphorylation of GSK3beta at Ser9 (p-GSK3beta (Ser9)) and the ratio of p-GSK3beta (Ser9) to total GSK3beta (p<0.05) in U251 cells. Overexpression of HERV-W env led to a 36.2% reduction in GSK3beta activity compared to control (p<0.05). The levels of beta-catenin, cyclin D1 and TSC2 mRNAs were upregulated (p<0.05). These data suggested that overexpression of HERV-W env might activate the GSK3beta signaling pathway in U251 cells. Further, knockdown of GSK3beta reduced the expression of total GSK3beta, p-GSK3beta (Ser9), and the ratio of p GSK3beta (Ser9) to total GSK3beta by 28.6%, 50.4%, and 30.2%, respectively (p<0.05). Levels of beta-catenin, cyclin D1 and TSC2 mRNAs were also reduced (p<0.05). Interestingly, GSK3beta activity increased (p<0.05). Knockdown of GSK3beta also decreased mRNA and protein expression of BDNF by 49.9% and 48.5% respectively (p<0.05). These results indicated that phosphorylation of GSK3beta at Ser9 might be involved in HERV-W env-induced BDNF expression, and will hopefully improve our understanding of the role of HERV-W env in neurological and psychiatric diseases (schizophrenia, etc). PMID- 27235579 TI - c-Jun-N-terminal kinase 1 is necessary for nicotine-induced enhancement of contextual fear conditioning. AB - Acute nicotine enhances hippocampus-dependent learning. Identifying how acute nicotine improves learning will aid in understanding how nicotine facilitates the development of maladaptive memories that contribute to drug-seeking behaviors, help development of medications to treat disorders associated with cognitive decline, and advance understanding of the neurobiology of learning and memory. The effects of nicotine on learning may involve recruitment of signaling through the c-Jun N-terminal kinase family (JNK 1-3). Learning in the presence of acute nicotine increases the transcription of mitogen-activated protein kinase 8 (MAPK8, also known as JNK1), likely through a CREB-dependent mechanism. The functional significance of JNK1 in the effects of acute nicotine on learning, however, is unknown. The current studies undertook a backward genetic approach to determine the functional contribution JNK1 protein makes to nicotine-enhanced contextual fear conditioning. JNK1 wildtype (WT) and knockout (KO) mice were administered acute nicotine prior to contextual and cued fear conditioning. 24h later, mice were evaluated for hippocampus-dependent (contextual fear conditioning) and hippocampus-independent (cued fear conditioning) memory. Nicotine selectively enhanced contextual conditioning in WT mice, but not in KO mice. Nicotine had no effect on hippocampus-independent learning in either genotype. JNK1 KO and WT mice given saline showed similar levels of learning. These data suggest that JNK1 may be recruited by nicotine and is functionally necessary for the acute effects of nicotine on learning and memory. PMID- 27235580 TI - Regulation of proapoptotic proteins Bak1 and p53 by miR-125b in an experimental model of Alzheimer's disease: Protective role of 17beta-estradiol. AB - Alzheimer's disease has become one of the most impacting disorders since world population is rapidly aging. MicroRNA-125b plays a crucial role in many cellular processes and pathologies, but, to date, its role in Alzheimer's disease is controversial. In this study, we demonstrated, for the first time, that the down regulation of miR-125b is a key event for the neurotoxic effect of Abeta treatment in cortical neurons. Moreover, we found that 17beta-estradiol treatment protects neurons from the Abeta-peptide induced neurotoxicity by increasing miR 125b expression that, in turn, decreased the expression, both at gene and protein levels, of the pro-apoptopic proteins Bak1 and p53. Overall, our data reveal miR 125b as a novel neuro-protector miRNA in Alzheimer's disease. PMID- 27235581 TI - Pharmacokinetics/pharmacodynamic correlations of fluconazole in murine model of cryptococcosis. AB - The emergence of fluconazole-resistant Cryptococcus gattii is a global concern, since this azole is the main antifungal used worldwide to treat patients with cryptococcosis. Although pharmacokinetic (PK) and pharmacodynamic (PD) indices are useful predictive factors for therapeutic outcomes, there is a scarcity of data regarding PK/PD analysis of antifungals in cryptococcosis caused by resistant strains. In this study, PK/PD parameters were determined in a murine model of cryptococcosis caused by resistant C. gattii. We developed and validated a suitable liquid chromatography-electrospray ionization tandem mass spectrometry method for PK studies of fluconazole in the serum, lungs, and brain of uninfected mice. Mice were infected with susceptible or resistant C. gattii, and the effects of different doses of fluconazole on the pulmonary and central nervous system fungal burden were determined. The peak levels in the serum, lungs, and brain were achieved within 0.5h. The AUC/MIC index (area under the curve/minimum inhibitory concentration) was associated with the outcome of anti-cryptococcal therapy. Interestingly, the maximum concentration of fluconazole in the brain was lower than the MIC for both strains. In addition, the treatment of mice infected with the resistant strain was ineffective even when high doses of fluconazole were used or when amphotericin B was tested, confirming the cross-resistance between these drugs. Altogether, our novel data provide the correlation of PK/PD parameters with antifungal therapy during cryptococcosis caused by resistant C. gattii. PMID- 27235582 TI - Flexible dropped head deformity following laminectomy for cervical spondylotic myelopathy: a case series and review of literature. AB - BACKGROUND CONTEXT: Flexible dropped head deformity (FDHD) following laminectomy for cervical spondylotic myelopathy (CSM) is a debilitating entity. Patients need to support their head manually to look forward in standing or sitting position. Flexible dropped head deformity is different from rigid dropped head deformity in patients with post-laminectomy kyphosis or ankylosing spondylitis and has only once been described after surgery to the cervical spine. PURPOSE: This case report aimed to report a rare, but severe complication of cervical posterior decompressive surgery, to describe its possible etiology, and to review the literature on the management of FDHD in order to provide recommendations for its treatment. STUDY DESIGN: This is a retrospective clinical case series. PATIENT SAMPLE: This sample comprises four patients with FDHD. METHODS: We retrospectively reviewed the charts with clinical follow-up data of all patients who underwent posteriorly directed spinal interventions and concomitantly developed FDHD and were admitted between January 1998 and September 2015. RESULTS: Cervical decompressive laminectomy is regularly performed in our institution. Four patients with FDHD were identified (3 men and 1 woman). The overall prevalence was less than 1% (=4 of 460 total estimated CSM surgeries). Flexible dropped head deformity developed within weeks or months after surgery. One patient was treated conservatively, whereas the other three received surgery to reconstruct stability of the cervical spine. Two of the surgically corrected patients eventually required revision surgery as a result of failure of the hardware and because of skin erosion. CONCLUSIONS: Flexible dropped head deformity is a rare, but serious complication of posterior decompressive surgery. Its etiology appears multifactorial. Its management needs to be directed toward early surgical intervention. PMID- 27235583 TI - Age-dependent characteristics of feedback evaluation related to monetary gains and losses. AB - Monitoring the consequences of actions is of crucial importance in order to optimize behavior to the challenges of the environment. Recently the age-related aspects of this fundamentally important cognitive processing have been brought into the focus of investigation since behavioral monitoring and related control mechanisms are widely known to be affected by aging. Processing of feedback stimuli is a core mechanism for rapid evaluation of the functionally significant aspects of outcome, guiding behavior towards avoidance or approach. The aim of the present study was to analyze the age-related alterations in the most prominent electrophysiological correlates of feedback processing, the feedback related negativity (FRN) and the P3 event-related potential components, using a two-choice-single-outcome gambling task with two amounts of monetary stakes. In terms of behavioral indices higher proportion of risky choices was observed after loss than after gain events in both groups. In the young the FRN component was found to be an indicator of the goodness of outcome (loss or gain), and the P3 showed a complex picture of feedback evaluation with selective sensitivity to large amount of gain. In contrast, in the elderly group outcome valence had no effect on the amplitude of the FRN, and the P3 was also insensitive of the complex outcome properties. As the ERP-correlates of feedback processing are not as pronounced in the elderly, it is suggested that normal aging is accompanied by an alteration of the neural mechanisms signaling the most salient feedback stimulus properties. PMID- 27235584 TI - Phospholipid-related signaling in physiology and pathology. PMID- 27235585 TI - The effect of glycosylation on the transferrin structure: A molecular dynamic simulation analysis. AB - Transferrins have been defined by the highly cooperative binding of iron and a carbonate anion to form a Fe-CO3-Tf ternary complex. As such, the layout of the binding site residues affects transferrin function significantly; In contrast to N-lobe, C-lobe binding site of the transferrin structure has been less characterized and little research which surveyed the interaction of carbonate with transferrin in the C-lobe binding site has been found. In the present work, molecular dynamic simulation was employed to gain access into the molecular level understanding of carbonate binding site and their interactions in each lobe. Residues responsible for carbonate binding of transferrin structure were pointed out. In addition, native human transferrin is a glycoprotein that two N-linked complex glycan chains located in the C-lobe. Usually, in the molecular dynamic simulation for simplifying, glycan is removed from the protein structure. Here, we explore the effect of glycosylation on the transferrin structure. Glycosylation appears to have an effect on the layout of the binding site residue and transferrin structure. On the other hand, sometimes the entire transferrin formed by separated lobes that it allows the results to be interpreted in a straightforward manner rather than more parameters required for full length protein. But, it should be noted that there are differences between the separated lobe and full length transferrin, hence, a comparative analysis by the molecular dynamic simulation was performed to investigate such structural variations. Results revealed that separation in C-lobe caused a significant structural variation in comparison to N-lobe. Consequently, the separated lobes and the full length one are different, showing the importance of the interlobe communication and the impact of the lobes on each other in the transferrin structure. PMID- 27235586 TI - Identifying functional cancer-specific miRNA-mRNA interactions in testicular germ cell tumor. AB - Testicular cancer is the most common cancer in men aged between 15 and 35 and more than 90% of testicular neoplasms are originated at germ cells. Recent research has shown the impact of microRNAs (miRNAs) in different types of cancer, including testicular germ cell tumor (TGCT). MicroRNAs are small non-coding RNAs which affect the development and progression of cancer cells by binding to mRNAs and regulating their expressions. The identification of functional miRNA-mRNA interactions in cancers, i.e. those that alter the expression of genes in cancer cells, can help delineate post-regulatory mechanisms and may lead to new treatments to control the progression of cancer. A number of sequence-based methods have been developed to predict miRNA-mRNA interactions based on the complementarity of sequences. While necessary, sequence complementarity is, however, not sufficient for presence of functional interactions. Alternative methods have thus been developed to refine the sequence-based interactions using concurrent expression profiles of miRNAs and mRNAs. This study aims to find functional cancer-specific miRNA-mRNA interactions in TGCT. To this end, the sequence-based predicted interactions are first refined using an ensemble learning method, based on two well-known methods of learning miRNA-mRNA interactions, namely, TaLasso and GenMiR++. Additional functional analyses were then used to identify a subset of interactions to be most likely functional and specific to TGCT. The final list of 13 miRNA-mRNA interactions can be potential targets for identifying TGCT-specific interactions and future laboratory experiments to develop new therapies. PMID- 27235587 TI - Flavonoids from Radix Tetrastigmae inhibit TLR4/MD-2 mediated JNK and NF-kappaB pathway with anti-inflammatory properties. AB - Radix Tetrastigmae (RT) has immunomodulatory activity, particularly on inflammation and the flavonoids from RT (RTFs) are one of the main components. In this study, we detected the anti-inflammation potential of RTFs in LPS-induced RAW264.7 cells and tried to uncover the underlying mechanism. Results demonstrated that RTFs (10-160MUg/ml) treatment significantly decreased LPS induced production of pro-inflammatory mediators, including NO, IL-1beta, TNF alpha, IL-6, IL-12p40, sTNF-R1 and increased anti-inflammatory cytokine IL-10 expression in macrophages in a dose-dependent manner. Molecular research showed the up-regulated expression of TLR4, MD-2, MyD88 and TLR4/MD-2 complex induced by LPS were attenuated after RTFs treatment. Furthermore, phosphorylation and activity of JNK and NF-kappaB, two important downstream signaling molecules of TLR4/MD-2 pathway, were also changed along with TLR4/MD-2 complex. But no significant phosphorylation was observed on p38 and ERK. In conclusion, RTFs contribute to the regulation of LPS-induced inflammatory response in RAW264.7 cells through TLR4/MD-2 mediated NF-kappaB and JNK pathway. It may be a potential choice for the treatment of inflammation diseases. PMID- 27235589 TI - A gas-filled abdominal cyst in an elderly woman: A giant colonic diverticulum case report. AB - INTRODUCTION: Giant colonic diverticulum (GCD), a rare complication of the diverticular disease, can present with a wide range of nonspecific symptoms as abdominal pain and bowel obstruction. Its diagnosis represents a challenge that mainly depends on imaging findings. PRESENTATION OF CASE: We report the case of a 79 year-old female patient that came to our emergency department complaining of 5 day history of hypogastric pain and constipation. Physical examination reveled a 15cm hypogastric round, tender and tympanic mass. Enhanced abdominal CT scan showed a large air-filled cyst adjacent to a diverticular sigmoid colon without evidence of intra-abdominal free air or fluid. Based on the radiological features, GCD was suspected and surgical treatment performed. The mass and the sigmoid colon were resected. The postoperative course was uneventful. Histopathology confirmed the preoperative diagnosis. DISCUSSION: GCD, defined as a diverticulum larger than 4cm, represents a rare complication of the diverticular disease. Usually abdominal X-ray and computed tomography (CT) scan show a gas-filled structure, sometimes communicating with the adjacent colon. GCD resection and segmental colectomy are strongly recommended even in asymptomatic cases due to the high incidence and severity of complications. CONCLUSION: Because of its rarity and variable and non-specific clinical presentation, the diagnosis of GCD depends mainly on imaging findings. The gold standard treatment is surgical resection of the GCD and the compromised colon with primary anastomosis when possible. PMID- 27235588 TI - IL-2, IL-4, IFN-gamma or TNF-alpha enhances BAFF-stimulated cell viability and survival by activating Erk1/2 and S6K1 pathways in neoplastic B-lymphoid cells. AB - B-cell activating factor of the TNF family (BAFF) has been documented to act as a critical factor in the development of aggressive B lymphocytes and autoimmune diseases. However, the effect of various cytokines on BAFF-elicited neoplastic B lymphoid cells is not known. In this study, we exhibited that administration of human soluble BAFF (hsBAFF), IL-2, IL-4, IFN-gamma, or TNF-alpha alone increased cell viability and survival in Raji cells concentration-dependently, yet a more robust viability/survival was seen in the cells co-treatment of IL-2, IL-4, IFN gamma, or TNF-alpha with hsBAFF, respectively. Further research revealed that both Erk1/2 and S6K1 signaling pathways were essential for IL-2, IL-4, IFN-gamma, or TNF-alpha enhancement of the viability/survival in the hsBAFF-stimulated cells, as inhibition of Erk1/2 with U0126 or down-regulation of Erk1/2, or blockage of S6K1 with rapamycin or silencing S6K1, or silencing S6K1/Erk1/2, respectively, reduced the cell viability/survival in the cells treated with/without hsBAFF+/-IL-2, IL-4, IFN-gamma, or TNF-alpha. These findings indicate that IL-2, IL-4, IFN-gamma or TNF-alpha enhances BAFF-stimulated cell viability/survival by activating Erk1/2 and S6K1 signaling in neoplastic B lymphoid cells. Our data suggest that modulation of IL-2, IL-4, IFN-gamma and/or TNF-alpha levels, or inhibitors of Erk1/2 or S6K1 may be a new approach to prevent BAFF-induced aggressive B-cell malignancies. PMID- 27235590 TI - Bilateral primitive cholesteatoma of external auditory canal with congenital stenosis. PMID- 27235591 TI - A case of acute intoxication due to combined use of fentanyl and 3,4-dichloro-N [2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700). AB - A 30-year old man was found dead in his home after inhaling fumes of a powder burned on aluminum foil. Blood and urine were taken by the medical examiner during the external body examination and submitted to the laboratory for a comprehensive systematic toxicological analysis. A toxic fentanyl level of 10.9MUg/L was measured in the subclavian blood. Police investigation revealed that the man searched the internet for information on new psychotropic substances, among others including U-47700. A powder found in the victims' home was transferred to the laboratory for analysis, in which trace amounts of fentanyl (0.0035%, m/m) and U-47700 (0.0012%, m/m) were identified by gas chromatography mass spectrometry. U-47700 is an opioid analgesic drug, considered to have a potency of approximately 7.5 times that of morphine. A target analysis on U-47700 was performed using liquid-liquid extraction and ultra performance liquid chromatography tandem mass spectrometry operating in multiple reaction monitoring mode. The method validation was based on the Scientific Working Group of Forensic Toxicology document 'Standard Practices of Method Validation in Forensic Toxicology'. In blood and urine the U-47700 concentration was 13.8 and 71.0MUg/L, respectively. To the author's knowledge, this is the first case report of a fatal intoxication involving U-47700 abused as a new psychotropic substance. PMID- 27235592 TI - Characterizing and classifying water-based lubricants using direct analysis in real time((r))-time of flight mass spectrometry. AB - Lubricant analysis is a relatively recent addition to the examination protocol in sexual assault cases by the forensic science community. Currently, lubricants cannot be unequivocally identified, although their presence can be determined based on the detection of a few chemical components, i.e. polydimethylsiloxane, polyethylene glycol, glycerol or nonoxynol-9. Confirmation of their presence typically requires that an authentic reference sample be submitted and compared to the unknown sample to determine if they potentially came from the same source. In this study, 33 individual personal water-based lubricants were characterized by direct analysis in real time-time of flight mass spectroscopy (DART-TOFMS). The resultant mass spectral data were evaluated using well-established multivariate statistical techniques, such as principal component and linear discriminant analysis. Statistical analysis revealed six different groupings within the data that could be correlated to sub-categories of water-based lubricants that contain additives in the form of anesthetics, sensation enhancers and flavorings. This variability in the personal lubricant sources can be utilized to aid in identifying the specific type of lubricant when only a questioned sample is available. PMID- 27235593 TI - Adult femicide victims in forensic autopsy in Taiwan: A 10-year retrospective study. AB - BACKGROUND: Violence against women and adult femicides are critical medico-legal issues worldwide. Intimate partner violence is one of the leading contributory risk factors. This study aimed to describe the characteristics of femicides in Taiwan. METHODS: A retrospective analysis of forensic autopsy records of adult femicide victims in Taiwan during a 10-year period was carried out. The age, victim-offender relationship, injury patterns and causes of death were analyzed. RESULTS: Among the 220 adult femicide victims recruited, 114 were killed by intimate partners and 106 were killed by non-intimate partner offenders. The average age of victims killed by intimate partners (40.0 y/o) were younger than those killed by non-intimate partner perpetrators (48.6 y/o). The most common site of injuries in the intimate partner group and the non-intimate partner group was the neck and the upper limbs, respectively. The rates of bruise and intracranial injury of non-intimate partner group were significantly higher than that of the intimate partner group. The most common causes of death in both groups were strangulation and sharp force injury. The heart injury was significantly more frequent in victims offended by intimate partners than by other assailants. CONCLUSIONS: The characteristics of adult femicides, and the patterns of injury in victims killed by intimate partners and non-intimate partner offenders were different. This data is helpful for corpus inspection in forensic casework and for strategic planning of femicides prevention. PMID- 27235594 TI - Development of fingermark on the surface of fired cartridge casing using amino acid sensitive reagents: Change of viewpoint. AB - Four amino acid sensitive fingermark enhancement reagents (ninhydrin, 5 methylthioninhydrin (5-MTN), 1,8-diazafloren-9-one (DFO), 1,2-indandione (1,2 IND) were used for the development of fingermark on the surface of brass. The reagents were used for the detection of a trace amount of metallic ion on the surface of cartridge casings to develop latent fingermarks. Ninhydrin-l-alanine (NIN-ALA), 5-MTN-l-alanine (MTN-ALA), DFO-l-alanine (DFO-ALA), 1,2-IND-l-alanine (IND-ALA) complexes were prepared and applied to the fired cartridge casings, for the further enhancement of fingermarks developed by corrosion on the surface of brass. Of the four complexes, NIN-ALA and MTN-ALA complexes induced color changes to enhance fingermarks on fired cartridge casings, but photoluminescence was not observed. About 31% of cartridge casings treated with MTN-ALA showed enhanced fingermarks. DFO-ALA and IND-ALA did not show any enhancement of fingermarks. PMID- 27235595 TI - CD4(+)B220(+)TCRgammadelta(+) T cells produce IL-17 in lupus-prone MRL/lpr mice. AB - Systemic lupus erythematosus is an autoimmune disease with comprehensive immune cell disorders. Recent studies suggested that pro-inflammatory cytokine IL-17 plays important role in lupus, leaving the cellular sources and their pathogenic and physiologic characters largely unknown. In the current study, by using lupus prone MRL/lpr mice, we demonstrated that Th17 response prevails in lupus disease regarding significantly accumulated serum IL-17, increased IL-17-producing splenocytes, and elevated phospho-STAT3 in CD4(+) T cells. Intracellular staining revealed that unusual CD4(+)B220(+) T cells are major IL-17-producing cells, whereas conventional CD4(+)B220(-) T cells are major IFN-gamma-producing cells. Subsequent studies showed that CD4(+)B220(+) cells contains both alphabeta and gammadelta T cells in the spleen and thymus of MRL/lpr mice. Further study showed that around 60% of gammadelta T cells in MRL/lpr mice co-express both B220 and CD4 on their surface, and are the major RORgammat(+) cells in MRL/lpr mice. Finally, CD4(+)B220(+) T cells alone do not proliferate, but could enhance the proliferation and IFN-gamma-production of conventional CD4(+)B220(-) T cells. Our findings suggest the pathogenic role of unusual CD4(+)B220(+) T cells in lupus disease in MRL/lpr mice according to their IL-17-producing ability and stimulatory function for conventional CD4(+)B220(-) T cells. PMID- 27235596 TI - RhIL-11 treatment normalized Th1/Th2 and T-bet/GATA-3 imbalance in in human immune thrombocytopenic purpura (ITP). AB - Immune thrombocytopenia (ITP) is an autoimmune hemorrhagic disorder characterized by reduction in platelet counts. T helper 1 (Th1) cells polarization with an increased shift of Th1/Th2 ratio has been reported in ITP. This shift is associated with transcription factor T-box expressed in T cells (T-bet) upregulation and GATA-binding protein 3 (GATA-3) downregulation, leading to an increased T-bet/GATA-3 ratio. Our previous in vitro study showed that recombinant human interleukin-11 (rhIL-11) could normalize Th1/Th2 imbalance in the peripheral blood mononuclear cells (PBMCs) isolated from adult ITP patients, which co-occurred with T-bet/GATA-3 ratio restoration. In this report, we investigated whether rhIL-11 had therapeutic effect in clinical ITP patients and whether rhIL-11 treatment could normalize Th1/Th2 and T-bet/GATA-3 levels in vivo. We found rhIL-11 treatment had a response rate of 67.7% and significantly decreased Th1 and T-bet levels but increased Th2 and GATA-3 levels in ITP patients who showed good response, normalizing Th1/Th2 and T-bet/GATA-3 ratios similar to that in healthy controls. Thus our study suggested rhIL-11 was effective with tolerable adverse effects in ITP. The treatment strategy warrants further clinical investigation. PMID- 27235597 TI - Genetic diversity and transmission networks of HIV-1 strains among men having sex with men (MSM) in Lome, Togo. AB - Understanding the HIV epidemic in key populations is important. Today only scarce information is available on HIV-1 strains that circulate in men having sex with men (MSM) in sub-Saharan Africa. Here, we studied for the first time the genetic diversity of HIV-1 strains circulating in the MSM population in Lome, the capital city from Togo. The overall subtype/CRF distribution in pol (protease and/or partial reverse transcriptase (RT)) among the 79 HIV-1 strains from MSM was as follows: CRF02_AG (72%, n=57), subtype G (2.5%, n=2), sub-subtype A3 (1.3%, n=1), and unique recombinant forms (URF) (24%, n=19). Among the 19 URFs four different mosaic structures were observed, annotated as URF1 to URF4. Fifteen sequences (URF1) had the same mosaic structure in pol (G/CRF02_AG) and could represent a new circulating recombinant form (CRF). Phylogenetic analysis of the RT sequences showed that there were several introductions of CRF02_AG strains in the MSM population, however half of the CRF02_AG and all URF1 strains formed a separate, well-supported cluster suggesting one major introduction of CRF02_AG in the MSM population followed by efficient transmission and emergence of a possible new CRF. At least 40% of the strains fell into recent transmission chains involving two to seven MSM. Comparison with >950 HIV-1 sequences from previous studies in Togo showed intermixing of the HIV-1 epidemics between MSM and the general population. Moreover, an HIV-1 strain from a recently HIV-1 infected male patient from Germany, fell within a cluster of HIV-1 strains from MSM from Togo, illustrating recent exchange between MSM from Africa and people from other geographic regions. With growing evidence of the importance of MSM in the dynamic of the HIV epidemic in Africa there is an urgent need for appropriate interventions to limit HIV transmission in this population group. PMID- 27235598 TI - Mechanism of action of endosulfan as disruptor of gonadal steroidogenesis in the cichlid fish Cichlasoma dimerus. AB - The organochlorine pesticide endosulfan (ES) is used in several countries as a wide spectrum insecticide on crops with high commercial value. Due to its high toxicity to non-target animals, its persistence in the environment and its ability to act as an endocrine disrupting compound in fish, ES use is currently banned or restricted in many other countries. Previous studies on the cichlid fish Cichlasoma dimerus have shown that waterborne exposure to ES can lead to both decreased pituitary FSH content and histological alterations of testes. As gonadotropin-stimulated sex steroids release from gonads was inhibited by ES in vitro, the aim of the present study was to elucidate possible mechanisms of disruption of ES on gonadal steroidogenesis in C. dimerus, as well as compare the action of the active ingredient (AI) with that of currently used commercial formulations (CF). Testis and ovary fragments were incubated with ES (AI or CF) and/or steroidogenesis activators or precursors. Testosterone and estradiol levels were measured in the incubation media. By itself, ES did not affect hormone levels. Co-incubation with LH and the adenylate cyclase activator forskolin caused a decrease of the stimulated sex steroids release. When co incubated with precursors dehydroandrostenedione and 17alphahydroxyprogesterone, ES did not affect the increase caused by their addition alone. No differences were observed between the AI and CFs, suggesting that the effect on steroidogenesis disruption is mainly caused by the AI. Results indicate that action of ES takes place downstream of LH-receptor activation and upstream of the studied steroidogenic enzymes. PMID- 27235599 TI - In vitro nuclear receptor activity and in vivo gene expression analysis in Murray Darling rainbowfish (Melanotaenia fluviatilis) after short-term exposure to fluoxetine. AB - Fluoxetine (FLX) is one of numerous pharmaceuticals found in treated municipal wastewater discharged to the environment. In the present study, we investigated the effects of short-term (96h) waterborne FLX exposure (1MUg/L or 100MUg/L) on the expression of selected genes in brain, liver, and gonads of female Murray Darling rainbowfish (Melanotaenia fluviatilis), a small-bodied teleost of ecotoxicological relevance in the Australasia region. Plasma 17beta-estradiol (E2) levels were also determined. In the brain, no significant changes in mRNA levels were observed for the selected genes. In ovaries, 100MUg/L FLX caused a 10 fold downregulation of aromatase A (cyp19a1a) mRNA and a 4-fold upregulation of estrogen receptor alpha (esr1) mRNA levels. In liver, mRNA levels for vitellogenin A (vtga) and choriogenin L (chgl) were downregulated by 50-fold and 18-fold compared with controls, respectively, in response to 100MUg/L FLX. Concentrations of E2 in plasma were significantly lower than controls in response to 100MUg/L FLX. This could be attributable to a decrease in estrogen biosynthesis as a result of the observed downregulation of cyp19a1a mRNA. To establish whether the observed changes in gene expression could be explained by the modulation of selected nuclear receptors by FLX, we employed panel of reporter gene assays in agonistic and antagonistic modes. Apart from minor activation of ERalpha after exposure to high concentrations (5MUM), FLX did not activate or inhibit the nuclear receptors tested. Further study is required to determine whether the observed downregulation of ovarian aromatase expression and liver estrogen-regulated genes also occurs at environmentally relevant FLX concentrations over longer exposure periods. PMID- 27235600 TI - Social participation and the onset of functional disability by socioeconomic status and activity type: The JAGES cohort study. AB - The impact of social participation on older adults' health may differ by individual socioeconomic status (SES). Consequently, we examined SES effect modification on the associations between types of social activity participation and incident functional disability. Cohort data from the 2003 Japan Gerontological Evaluation Study (JAGES) was utilized. This included individuals who were aged 65 or older and functionally independent at baseline. Analysis was carried out on 12,991 respondents after acquisition of information about their long-term care (LTC) status in Japan. Incident functional disability was defined based on medical certification and LTC information was obtained from municipal insurance databases. Cox proportional hazard regression was conducted for analysis. Results indicated that participants in a sport (hazard ratio [HR]: 0.66; 95% confidence interval [CI]: 0.51, 0.85) or hobby group (HR: 0.69; 95% CI: 0.55, 0.87), or who had a group facilitator role (HR: 0.82; 95% CI: 0.66, 1.02) were less likely to be disabled. While men with 13 or more years of education were less likely to become disabled if they held facilitator roles, this association was weak among men with 0-5years of education (HR of interaction term between 0 and 5years of education and facilitator role dummy variable=3.95; 95% CI: 1.30, 12.05). In conclusion, the association between group participation and smaller risk of the functional disability was stronger among highly educated older adults. Intervention programs promoting social participation should consider participants' socioeconomic backgrounds. PMID- 27235601 TI - Impact of Affordable Care Act coverage expansion on women's reproductive preventive services in the United States. AB - INTRODUCTION: The Affordable Care Act (ACA) expansion mandated the private health plans to cover women's preventive services starting August 2012. With limited and contradictory evidence, this study intends to assess the impact of ACA on the utilization rates and the cost burden of women's reproductive preventive service. METHODS: A pre-post analysis was conducted using a nationally representative sample of females (aged 15-44years, n=4397) participating in the 2011-2013 National Survey of Family Growth. The utilization rates and cost burdens were compared for six services using bivariate and multivariable logistic regression models. RESULTS: After the ACA expansion, there wasn't a significant increase in the utilization rates of birth control/prescription (33.7% vs. 30.7%), birth control counseling (17.7% vs. 16.9%), sterilization counseling (3.3% vs. 3.5%), STI counsel/test/treat (15% vs. 14.6%) and HIV screening (24.1% vs. 23.1%). Respondents paying through insurance increased after ACA, but out-of-pocket spending (cost-sharing) didn't decrease for respondents. Type of insurance was an important predictor of utilization rates with publicly insured having significantly higher Odds Ratio (OR) or likelihood of receiving birth control counseling (OR:1.71), sterilization counseling (OR:2.67), STI counsel/test/treat (OR:1.54) and HIV screening (OR:1.69) compared to privately insured. CONCLUSIONS: The early-on impact of ACA expansion on utilization rates of women's reproductive preventive services didn't appear to be significant. Private health plans, however, might have expanded their coverage but burden of cost sharing still existed. Future research should evaluate the long term impact of ACA expansion on women's health and the economic gains. PMID- 27235602 TI - Physically active vs. sedentary academic lessons: A dose response study for elementary student time on task. AB - BACKGROUND: Physically active academic lessons are an effective intervention to reduce sedentary time and increase student physical activity. They have also been shown to enhance task engagement, as indicated by observations of attention and behavior control, time on task (TOT). However, it is not clear if the improved TOT stems from the physical activity or if it is the result of an enjoyable break from traditional instruction. If it is due to physical activity, what dose of intensity is required for the effect? This study was designed to test these questions. METHODS: Participants were 320 children (7-9years) recruited from school districts in Central Texas in 2012. They were assigned by classroom (n=20) to one of four conditions: 1) sedentary, standard lesson (n=72); 2) sedentary academic game (n=87); 3) low to moderate intensity PA (LMPA), academic game (n=81); and 4) moderate to vigorous intensity PA (MVPA), academic game (n=76). Measures included PA via accelerometer and TOT. RESULTS: Mixed-method RMANOVA indicated TOT decreased following the standard lesson (p<0.001), showed no change following the sedentary academic game (p=0.68), and increased following the LMPA (p<0.01) and MVPA (p<0.001) academic games. CONCLUSIONS: While the sedentary, academic game prevented the reduction in TOT observed in the standard lesson, PA resulted in increased TOT. Future research should be designed to examine the potential academic benefits of the change in TOT. PMID- 27235603 TI - A potential role of anti-poverty programs in health promotion. AB - Poverty is one of the most pervasive risk factors underlying poor health, but is rarely targeted to improve health. Research on the effects of anti-poverty interventions on health has been limited, at least in part because funding for that research has been limited. Anti-poverty programs have been applied on a large scale, frequently by governments, but without systematic development and cumulative programmatic experimental studies. Anti-poverty programs that produce lasting effects on poverty have not been developed. Before evaluating the effect of anti-poverty programs on health, programs must be developed that can reduce poverty consistently. Anti-poverty programs require systematic development and cumulative programmatic scientific evaluation. Research on the therapeutic workplace could provide a model for that research and an adaptation of the therapeutic workplace could serve as a foundation of a comprehensive anti-poverty program. Once effective anti-poverty programs are developed, future research could determine if those programs improve health in addition to increasing income. The potential personal, health and economic benefits of effective anti poverty programs could be substantial, and could justify the major efforts and expenses that would be required to support systematic research to develop such programs. PMID- 27235604 TI - Correlates of children's objectively measured physical activity and sedentary behavior in early childhood education and care services: A systematic review. AB - OBJECTIVE: To systematically review the correlates of physical activity and sedentary behavior among children in Early Childhood Education and Care (ECEC) services. Appropriate levels of physical activity and sedentary behavior are important to promote in ECEC services. METHODS: A systematic search of 8 databases identified 27 studies published between 1992 and 2015 that met the inclusion criteria. The data were collected and analyzed in 2014 and 2015, and variables were categorized using a Social Ecological Framework. RESULTS: Sixty six variables were identified. The domains of child characteristics (18 studies) and physical environmental factors (17 studies) were most consistently studied, and, for physical activity had the most positive associations. The strongest associations of physical activity were: child's sex and age, children's gross motor coordination, provision of active opportunities for physical activity, and features of outdoor environments (size, use of and presence). The only strong association for sedentary behavior was the presence of outdoor environments. CONCLUSION: The correlates of physical activity and sedentary behavior in ECEC services vary. It appears that the most significant influence from within these settings is the physical environments for both physical activity and sedentary behavior. There was an absence of consistent evidence at the educator and organizational levels. Further research in this area should focus on effective use of space, intentional teaching opportunities and well as professional development for educators with an emphasis on their role as a facilitator of quality experiences. This review has been registered with Prospero, #CRD42014013660. PMID- 27235605 TI - Increasing the intent to receive a pandemic influenza vaccination: Testing the impact of theory-based messages. AB - OBJECTIVE: Vaccination is an effective preventive measure to reduce influenza transmission, especially important in a pandemic. Despite the messages encouraging vaccination during the last pandemic, uptake remained low (37.6% in clinical risk groups). This study investigated the effect of different types of messages regarding length, content type, and framing on vaccination intention. METHOD: An online experiment was conducted in February 2015. A representative sample of 1424 people living in England read a mock newspaper article about a novel influenza pandemic before being randomised to one of four conditions: standard Department of Health (DoH) (long message) and three brief theory-based messages - an abridged version of the standard DoH and two messages additionally targeting pandemic influenza severity and vaccination benefits (framed as risk reducing or health-enhancing, respectively). Intention to be vaccinated and potential mediators were measured. RESULTS: The shortened DoH message increased vaccination intention more than the longer one, by increasing perceived susceptibility, anticipated regret and perceived message personal relevance while lowering perceived costs, despite the longer one being rated as slightly more credible. Intention to be vaccinated was not improved by adding information on severity and benefits, and the health-enhancing message was not more effective than the risk-reducing. CONCLUSION: A briefer message resulted in greater intention to be vaccinated, whereas emphasising the severity of pandemic influenza and the benefits of vaccination did not. Future campaigns should consider using brief theoretically-based messages, targeting knowledge about influenza and precautionary measures, perceived susceptibility to pandemic influenza, and the perceived efficacy and reduced costs of vaccination. PMID- 27235606 TI - The effect of a school-centered multicomponent intervention on daily physical activity and sedentary behavior in primary school children: The Active Living study. AB - The aim of the current study was to examine the effectiveness of a school centered multicomponent PA intervention, called 'Active Living', on children's daily PA levels. A quasi-experimental design was used including 9 intervention schools and 9 matched control schools located in the Netherlands. The baseline measurement took place between March-June 2013, and follow-up measurements were conducted 12months afterwards. Accelerometer (ActiGraph, GT3X+) data of 520 children aged 8-11years were collected and supplemented with demographics and weather conditions data. Implementation magnitude of the interventions was measured by keeping logbooks on the number of implemented physical environmental interventions (PEIs) and social environmental interventions (SEIs). Multilevel multivariate linear regression analyses were used to study changes in sedentary behavior (SB), light physical activity (LPA) and moderate-to-vigorous physical activity (MVPA) between baseline and follow-up. Finally, effect sizes (ESs) were calculated using Cohen's d. No pooled effects on PA and SB were found between children exposed and not exposed to Active Living after 12months. However, children attending Active Living schools that implemented larger numbers of both PEIs and SEIs engaged in 15 more minutes of LPA per weekday at follow-up than children in the control condition (ES=0.41; p<.05). Moreover, children attending these schools spent less time in SB at follow-up (ES=0.33), although this effect was non-significant. No significant effects were found on MVPA. A school-centered multicomponent PA intervention holds the potential to activate children, but a comprehensive set of intervention elements with a sufficient magnitude is necessary to achieve at least moderate effect sizes. PMID- 27235607 TI - Nanoscale drug delivery for targeted chemotherapy. AB - Despite significant improvements in diagnostic methods and innovations in therapies for specific cancers, effective treatments for neoplastic diseases still represent major challenges. Nanotechnology as an emerging technology has been widely used in many fields and also provides a new opportunity for the targeted delivery of cancer drugs. Nanoscale delivery of chemotherapy drugs to the tumor site is highly desirable. Recent studies have shown that nanoscale drug delivery systems not only have the ability to destroy cancer cells but may also be carriers for chemotherapy drugs. Some studies have demonstrated that delivery of chemotherapy via nanoscale carriers has greater therapeutic benefit than either treatment modality alone. In this review, novel approaches to nanoscale delivery of chemotherapy are described and recent progress in this field is discussed. PMID- 27235608 TI - Exploiting in situ antigen generation and immune modulation to enhance chemotherapy response in advanced melanoma: A combination nanomedicine approach. AB - Therapeutic anticancer vaccine development must address a number of barriers to achieve successful tumor specific killing, including effective antigen presentation and antigen-specific T-cell activation to mediate cytotoxic cellular effects, inhibition of an immune-suppressive tumor microenvironment in order to facilitate and enhance CTL activity, and induction of memory T-cells to prolong tumor rejection. While traditional as well as modern vaccines rely upon delivery of both antigen and adjuvant, a variety of clinically relevant cancers lack ideal immunogenic antigens. Building upon recent efforts, we instead chose to exploit chemotherapy-induced apoptosis to allow for in situ antigen generation in a combination, nanomedicine-based approach. Specifically, lipid-coated cisplatin nanoparticles (LPC) and CpG-encapsulated liposomes (CpG-Lipo) were prepared for the temporally-controlled and multifaceted treatment of an advanced in vivo model of melanoma. Such combination therapy established strong synergistic effects, both in apoptotic extent and subsequent abrogation of tumor growth, which were due largely to both an enhanced cytotoxic T-cell recruitment and a reduction of immune-suppressive mediators in the microenvironments of both spleens and tumor. These results underlie a prolonged host lifespan in the combination approach (45 days) as compared with control (25 days, p < 0.02), providing promise toward a personalized approach to nanomedicine by establishing effect synergy in host specific immunotherapy following chemotherapy. PMID- 27235609 TI - Pharmacologic Therapy of Type 2 Diabetes. AB - Type 2 diabetes (T2DM) is a common condition. Treatment of diabetes and related complications can be complex. In addition to lifestyle changes, medications play an important role in controlling patients' blood glucose levels and preventing complications. From an individual and societal standpoint, it is also an expensive disease. Medical spending attributed to diabetes per individual is significant. With appropriate therapy, patients can lead full, healthy lives with the disease, so making informed decisions regarding pharmacotherapy for T2DM is clearly of great importance. PMID- 27235610 TI - Update in Hypertension Therapy. AB - Hypertension is the leading cause of early mortality in the world, and reduction of blood pressure can help to reduce that burden. There is an enormous and ever expanding body of literature on hypertension, with a 2016 Medline search for hypertension retrieving more than 113,000 publications. Recent guidelines from major societies have been published, and often present conflicting recommendations based on the same data. Using a question-and-answer format, this article reviews some of the recent developments and opinions on management of blood pressure and provides practical suggestions for management in the clinical arena. PMID- 27235611 TI - Pharmacologic Therapies in Anticoagulation. AB - Anticoagulants are beneficial for prevention and treatment of venous thromboembolism and stroke prevention in atrial fibrillation. The development of target-specific oral anticoagulants is changing the landscape of anticoagulation therapy and created growing interest on this subject. Understanding the pharmacology of different anticoagulants is the first step to adequately treat patients with best available therapy while avoiding serious bleeding complications. This article reviews the pharmacology of the main anticoagulant classes (vitamin K antagonists, direct oral anticoagulants, and heparins) and their clinical indications based on evidence-based data currently available in the literature. PMID- 27235612 TI - Pharmacologic Therapies for Rheumatologic and Autoimmune Conditions. AB - Disease-modifying antirheumatic drugs (DMARDs) are commonly prescribed by rheumatologists to reduce disease activity and induce remission in autoimmune conditions such as systemic lupus erythematosus and rheumatoid arthritis. Steroids are sometimes used in combination with DMARD therapy and should be used at the lowest effective dose for the least amount of time. There are many biologic agents available for use for inflammatory arthritis and other autoimmune conditions. Care should be taken when prescribing and managing DMARDS, steroids and biologic agents medications with a careful eye towards screening for infectious disease, vaccination, bone heath and lab monitoring. PMID- 27235613 TI - Movement Disorders: A Brief Guide in Medication Management. AB - Movement disorders can be challenging to manage and often use a specific set of medications. Because it is a complex and broad field within neurology, many providers are unfamiliar with the classes of medications. This paper details medications used for specific conditions, explains why these medications are helpful, and shares pearls and pitfalls related to each agent, focusing on parameters such as dose titration, side effect profiles, and specific drug-drug interactions and challenges. We focus on the most commonly encountered movement disorders, including essential tremor, Parkinson's disease, rapid eye movement sleep behavior disorder, and restless leg syndrome. PMID- 27235614 TI - Pharmacologic Therapies in Women's Health: Contraception and Menopause Treatment. AB - Female hormones play a significant role in the etiology and treatment of many women's health conditions. This article focuses on the common uses of hormonal therapy. When prescribing estrogen-containing regimens throughout the span of a woman's life, the risks are similar (ie, cardiovascular risk and venous thromboembolism), but the degree of risk varies significantly depending on a woman's particular set of risk factors and the details of the hormone regimen. In addition to estrogens and progestogens, this article also touches on the use of selective steroid receptor modulators in emergency contraception and in treatment of menopause symptoms. PMID- 27235615 TI - Pharmacologic Therapy in Men's Health: Hypogonadism, Erectile Dysfunction, and Benign Prostatic Hyperplasia. AB - This article reviews current pharmacologic treatment options for 3 common men's health concerns: hypogonadism, erectile dysfunction (ED), and benign prostatic hyperplasia (BPH). Specific topics addressed include: management of male hypogonadism using testosterone replacement therapy, use of oral phosphodiesterase inhibitors as first-line therapy for men with ED and the utility of intraurethral and intrapenile alprostadil injections for patients who do not respond to oral medications, and the role of alpha1-adrenergic antagonists, 5-alpha-reductase inhibitors, anticholinergic agents, and herbal therapies in the management of BPH. PMID- 27235616 TI - Evaluation and Treatment of Osteoporosis. AB - As the population ages, the rates of osteoporotic fractures will increase, with postmenopausal women incurring most of these fractures. Diagnosis and treatment of osteoporosis are extremely important. Dual-energy x-ray absorptiometry scan screening is recommended in all women more than 65 years of age or in women aged 50 to 64 years with certain risk factors. Treatment should be considered if osteoporosis is present, there is a history of fragility fracture, or in the setting of osteopenia plus high risk for fracture. PMID- 27235617 TI - Pharmacologic Therapies in Gastrointestinal Diseases. AB - Several key areas in gastroenterology pharmacotherapy are rapidly evolving, including the treatment of hepatitis C virus (HCV), irritable bowel syndrome, gastroesophageal reflux disease (GERD) and peptic ulcer disease. HCV treatment has radically changed in the past 2 years and now most patients are treatment candidates and have a high likelihood of permanent cure. Pharmacotherapy is now first-line treatment for patients with moderate to severe symptoms of irritable bowel syndrome. Proton pump inhibitors (PPIs) are the mainstay of therapy in gastric and duodenal ulcers and GERD, although long-term use carries the risk of several side effects that should be considered. PMID- 27235618 TI - Pharmacologic Therapies in Pulmonology and Allergy. AB - Conditions such as chronic rhinitis, urticaria, angioedema, and asthma are frequently seen in clinics and hospitals, and there are a core group of medications that are often used to treat these conditions. Knowing the indications, optimal dosing, and side-effect profile of these medications can improve outcomes. Chronic rhinitis due to various causes is one of the most common reasons for primary care physician visits. Knowing the indications for use, forms of administration, and side-effect profiles of these medications can help improve patient outcomes in these common conditions. This review focuses on the medications used to treat these conditions. PMID- 27235619 TI - Pharmacologic Therapies in Musculoskeletal Conditions. AB - Musculoskeletal conditions are common, and there are many options for pharmacologic therapy. Unfortunately, there is not strong evidence for the use of many of these medications. Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) are generally first-line medications for most musculoskeletal pain, but there is more evidence these medications are not as safe as once thought. Other analgesic and antispasmodic medications can be effective for acute pain but generally are not as effective for chronic pain. Antidepressants and anticonvulsants can be more effective for chronic or neuropathic pain. Topical formulations of NSAIDs can be effective for pain with fewer side effects. PMID- 27235620 TI - Pharmacotherapy for Substance Use Disorders. AB - This article reviews the current pharmacotherapy options available for the treatment of patients with substance use disorders. In the United States there are medications available to treat tobacco use disorders (nicotine replacement, bupropion, and varenicline), alcohol use disorders (naltrexone and acamprosate), and opioid use disorders (methadone and buprenorphine). These medications are likely underused and physicians should more readily prescribe for eligible patients. PMID- 27235621 TI - New Approaches to Antibiotic Use and Review of Recently Approved Antimicrobial Agents. AB - Antimicrobial drug-resistance continues to force adaptation in our clinical practice. We explore new evidence regarding adjunctive antibiotic therapy for skin and soft tissue abscesses as well as duration of therapy for intra-abdominal abscesses. As new evidence refines optimal practice, it is essential to support clinicians in adopting practice patterns concordant with evidence-based guidelines. We review a simple approach that can 'nudge' clinicians towards concordant practices. Finally, the use of novel antimicrobials will play an increasingly important role in contemporary therapy. We review five new antimicrobials recently FDA-approved for use in drug-resistant infections: dalbavancin, oritavancin, ceftaroline, ceftolozane-tazobactam, and ceftazidime avibactam. PMID- 27235622 TI - Antiretroviral Therapy for Prevention of Human Immunodeficiency Virus Infection. AB - Human immunodeficiency virus (HIV) infection is considered a chronic medical condition. Several new drugs are available, including fixed-dose combination tablets, that have greatly simplified combination antiretroviral therapy (ART) regimens to treat HIV, while increasing the life-expectancy of infected individuals. In the last decade, multiple well-regarded studies have established the benefits of using ART in high-risk, HIV-negative persons to prevent HIV acquisition. The primary care provider must not only understand commonly encountered issues pertaining to ART, such as toxicities and drug interactions, but also needs to be aware of using ART for HIV prevention. PMID- 27235623 TI - Pharmacologic Therapy. PMID- 27235624 TI - Pharmacologic Therapies: Updates and Clinical Pearls. PMID- 27235625 TI - Human DNA polymerase epsilon is phosphorylated at serine-1940 after DNA damage and interacts with the iron-sulfur complex chaperones CIAO1 and MMS19. AB - We describe a dynamic phosphorylation on serine-1940 of the catalytic subunit of human Pol epsilon, POLE1, following DNA damage. We also describe novel interactions between POLE1 and the iron-sulfur cluster assembly complex CIA proteins CIAO1 and MMS19. We show that serine-1940 is essential for the interaction between POLE1 and MMS19, but not POLE1 and CIAO1. No defect in either proliferation or survival was identified when POLE1 serine-1940 was mutated to alanine in human cells, even following treatment with DNA damaging agents. We conclude that serine-1940 phosphorylation and the interaction between serine-1940 and MMS19 are not essential functions in the C terminal domain of the catalytic subunit of DNA polymerase epsilon. PMID- 27235626 TI - SCR7 is neither a selective nor a potent inhibitor of human DNA ligase IV. AB - DNA ligases are attractive therapeutics because of their involvement in completing the repair of almost all types of DNA damage. A series of DNA ligase inhibitors with differing selectivity for the three human DNA ligases were identified using a structure-based approach with one of these inhibitors being used to inhibit abnormal DNA ligase IIIalpha-dependent repair of DNA double strand breaks (DSB)s in breast cancer, neuroblastoma and leukemia cell lines. Raghavan and colleagues reported the characterization of a derivative of one of the previously identified DNA ligase inhibitors, which they called SCR7 (designated SCR7-R in our experiments using SCR7). SCR7 appeared to show increased selectivity for DNA ligase IV, inhibit the repair of DSBs by the DNA ligase IV-dependent non-homologous end-joining (NHEJ) pathway, reduce tumor growth, and increase the efficacy of DSB-inducing therapeutic modalities in mouse xenografts. In attempting to synthesize SCR7, we encountered problems with the synthesis procedures and discovered discrepancies in its reported structure. We determined the structure of a sample of SCR7 and a related compound, SCR7-G, that is the major product generated by the published synthesis procedure for SCR7. We also found that SCR7-G has the same structure as the compound (SCR7-X) available from a commercial vendor (XcessBio). The various SCR7 preparations had similar activity in DNA ligation assay assays, exhibiting greater activity against DNA ligases I and III than DNA ligase IV. Furthermore, SCR7-R failed to inhibit DNA ligase IV-dependent V(D)J recombination in a cell-based assay. Based on our results, we conclude that SCR7 and the SCR7 derivatives are neither selective nor potent inhibitors of DNA ligase IV. PMID- 27235627 TI - Divalent ions attenuate DNA synthesis by human DNA polymerase alpha by changing the structure of the template/primer or by perturbing the polymerase reaction. AB - DNA polymerases (pols) are sophisticated protein machines operating in the replication, repair and recombination of genetic material in the complex environment of the cell. DNA pol reactions require at least two divalent metal ions for the phosphodiester bond formation. We explore two understudied roles of metals in pol transactions with emphasis on polalpha, a crucial enzyme in the initiation of DNA synthesis. We present evidence that the combination of many factors, including the structure of the template/primer, the identity of the metal, the metal turnover in the pol active site, and the influence of the concentration of nucleoside triphosphates, affect DNA pol synthesis. On the poly dT70 template, the increase of Mg(2+) concentration within the range typically used for pol reactions led to the severe loss of the ability of pol to extend DNA primers and led to a decline in DNA product sizes when extending RNA primers, simulating the effect of "counting" of the number of nucleotides in nascent primers by polalpha. We suggest that a high Mg(2+) concentration promotes the dynamic formation of unconventional DNA structure(s), thus limiting the apparent processivity of the enzyme. Next, we found that Zn(2+) supported robust polalpha reactions when the concentration of nucleotides was above the concentration of ions; however, there was only one nucleotide incorporation by the Klenow fragment of DNA pol I. Zn(2+) drastically inhibited polalpha, but had no effect on Klenow, when Mg(2+) was also present. It is possible that Zn(2+) perturbs metal-mediated transactions in pol active site, for example affecting the step of pyrophosphate removal at the end of each pol cycle necessary for continuation of polymerization. PMID- 27235629 TI - Depletion of tyrosyl DNA phosphodiesterase 2 activity enhances etoposide-mediated double-strand break formation and cell killing. AB - DNA topoisomerase 2 (Top2) poisons, including common anticancer drugs etoposide and doxorubicin kill cancer cells by stabilizing covalent Top2-tyrosyl-DNA 5' phosphodiester adducts and DNA double-strand breaks (DSBs). Proteolytic degradation of the covalently attached Top2 leaves a 5'-tyrosylated blocked termini which is removed by tyrosyl DNA phosphodiesterase 2 (TDP2), prior to DSB repair through non-homologous end joining (NHEJ). Thus, TDP2 confers resistance of tumor cells to Top2-poisons by repairing such covalent DNA-protein adducts, and its pharmacological inhibition could enhance the efficacy of Top2-poisons. We discovered NSC111041, a selective inhibitor of TDP2, by optimizing a high throughput screening (HTS) assay for TDP2's 5'-tyrosyl phosphodiesterase activity and subsequent validation studies. We found that NSC111041 inhibits TDP2's binding to DNA without getting intercalated into DNA and enhanced etoposide's cytotoxicity synergistically in TDP2-expressing cells but not in TDP2 depleted cells. Furthermore, NSC111041 enhanced formation of etoposide-induced gamma-H2AX foci presumably by affecting DSB repair. Immuno-histochemical analysis showed higher TDP2 expression in a sub-set of different type of tumor tissues. These findings underscore the feasibility of clinical use of suitable TDP2 inhibitors in adjuvant therapy with Top2-poisons for a sub-set of cancer patients with high TDP2 expression. PMID- 27235630 TI - Identification and description of controlled clinical trials published in Spanish Gynaecology and Obstetrics journals and risk of bias assessment of trials on assisted reproductive techniques. AB - OBJECTIVES: To identify and describe controlled clinical trials (CCTs) published in Spanish Gynaecology and Obstetrics journals. In addition, to assess the quality of the CCTs on Assisted Reproduction Techniques (ART) identified in this project. STUDY DESIGN: In order to identify eligible CCTs, all Spanish Gynaecology and Obstetrics journals were handsearched. Handsearching was conducted following the guidelines provided by the Cochrane Collaboration, which state that each journal article must be carefully reviewed, including original articles and other types of studies, letters to the editor, abstracts, and conference presentations. The results of the handsearching process were compared with an electronic search conducted in MEDLINE (PubMed). A descriptive analysis of the main characteristics of the identified CCTs was performed, as well as a methodological assessment of CCTs on ART. RESULTS: Sixteen Gynaecology and Obstetrics journals were identified, four of which have been indexed in MEDLINE at some point, although not currently. The journal with the most CCTs was "Progresos de Obstetricia y Ginecologia". A total of 235 CCTs were published in these journals, of which 29 were on ART. Most CCTs (216, 91.9%) were carried out in a hospital setting; 201 (89.4%) were unicentric. Obstetrics was the most studied subspecialty (46.4%). Among CCTs on ART, the risk of bias was predominantly high. CONCLUSIONS: The number of CCTs published in Spanish Gynaecology and Obstetrics journals is limited. CCTs on ART present deficiencies in the report of results and low methodological quality. It is advised that authors and journals adhere to the CONSORT statement and to the Cochrane Collaboration recommendations to reduce risk of bias when designing and disseminating research projects. PMID- 27235631 TI - Pregnancy in sickle cell-haemoglobin C (SC) disease. A retrospective study of birth size and maternal weight gain. AB - OBJECTIVE: To assess pregnancy and fetal outcomes in Jamaican subjects with sickle cell-haemoglobin C (SC) disease. STUDY DESIGN: A retrospective chart review over 21 years (1992-2012) of all pregnancies in SC disease and a comparison group matched by gender and date of delivery in mothers with a normal haemoglobin (AA) phenotype at the University Hospital of the West Indies, Jamaica. There were 118 pregnancies in 81 patients with SC disease and 110 pregnancies in 110 in the normal comparison group. Corrections were made for repeat pregnancies from the same mother. Outcome measures included maternal weight at 20, 25, 30, 35 and 38 weeks gestation, maternal pregnancy complications, birth weight, head circumference and crown heel length and were used to analyse possible predictors of birth weight. RESULTS: First antenatal visits occurred later in women with SC disease, who also had lower haemoglobin level and lower systolic blood pressure. The prevalence of pregnancy-induced hypertension, pre-eclampsia, ante-partum or postpartum haemorrhage did not differ between genotypes. Maternal weight gain was significantly lower in SC disease and there was a significantly lower birth weight, head circumference, and gestational age. CONCLUSIONS: Pregnancy in SC disease is generally benign but mothers had lower weight gain and lower birth weight babies, the difference persisting after correction for gestational age. PMID- 27235632 TI - STAT4 single nucleotide gene polymorphisms and susceptibility to endometriosis related infertility. AB - INTRODUCTION: Endometriosis is a multifactorial benign gynecologic disorder, characterized by the ectopic growth of misplaced endometrial cells with complex genetic inheritance and changing of some immune based factors and also shares some autoimmune characteristics. However, it is not clear yet that how and when these immunological factors affect the initiation or progression of the disease. It has been shown that STAT4 is a predisposing gene in the development of some autoimmune diseases. METHOD: The study group comprised 114 patients with endometriosis and 92 sex-, age-, and ethnicity-matched healthy controls of Iranian ancestry. Four SNPs (rs7574865, rs7601754, rs7582694 and rs11889341) were genotyped using the MGB TaqMan. RESULTS: A significant association in rs7582694 between C allele (P=0.002, OR=1.986, 95% CI: 1.262-3.126) and endometriosis was found in our study, while the G allele (P=0.002, OR=0.0503, 95% CI: 0.319-0.792) was significantly decreased in the patients population. The GC genotype (P=0.004, OR=2.234, 95% CI: 1.301-4.150) was also significantly overrepresented in the patients with endometriosis, while the frequency of GG genotype was significantly lower in the patient group, compared to the controls (P=0.007, OR=0.457, 95% CI: 0.256-0.813). CONCLUSIONS: Our results for the first time showed a significant association between rs7582694 alleles and genotypes and susceptibility to endometriosis in a population. PMID- 27235633 TI - Uranium removal by novel graphene oxide-immobilized Saccharomyces cerevisiae gel beads. AB - To evaluate its ability to absorb dissolved uranium (VI), the waste biomass of Saccharomyces cerevisiae was immobilized using different agents, including Ca alginate (Ca-SA), Ca-alginate with graphene oxide (GO), polyvinyl alcohol (PVA, 5% or 10%, w/v)-SA-GO in CaCl2-boric acid solution. The experimental results showed that graphene oxide at 0.01% (w/v) could enhance the performance of the immobilized cells. The yeast gel beads prepared with 5% PVA-1% SA-2% yeast-0.01% GO-2% CaCl2-saturated boric acid (4#) generally showed the better physical chemical properties such as higher tolerance to the unfavorable environmental conditions. Moreover, the 4# gel beads exhibited more stable capacity for U(VI) sorption and desorption at various conditions, such as pH in the range of 3-9. A pseudo second-order kinetic model could describe the kinetics of U(VI) sorption onto the 4# gel beads (R2 = 0.96). The Langmuir, Freundlich, Tempkin and Sips models could be used to describe U(VI) sorption by the 4# gel beads, with the R2 being 0.90, 0.83, 0.96, 0.97, respectively. The Sips maximum capacity of 4# gel beads was 24.4 mg U/g dry weight. The desorption efficiency of U(VI) adsorbed onto the 4# gel beads was 91%, 73% and 40% by 0.1 M HNO3, 0.1 M HCl and 0.1 M NaOH, respectively. However, the 4# gel beads exhibited lower U(VI) sorption capacity than the raw yeast cell (Sips maximum capacity of 35.6 mg U/g). The immobilized Saccharomyces cerevisiae using SA, PVA and/or GO showed obvious changes in the molecular vibration of functional groups such as carboxyl, amide and hydroxyl groups compared with the raw yeast cells, according to FTIR analysis. The SEM-EDX analysis showed that U(VI) was adsorbed unevenly on the cellular surface. Carboxyl and hydroxyl groups may be involved in U(VI) binding by yeast cells. PMID- 27235634 TI - Role of oxidative stress in disrupting the function of negative glucocorticoid response element in daily amphetamine-treated rats. AB - Amphetamine (AMPH)-induced appetite suppression is associated with changes in hypothalamic reactive oxygen species (ROS), antioxidants, neuropeptides, and plasma glucocorticoid. This study explored whether ROS and glucocorticoid response element (GRE), which is the promoter site of corticotropin-releasing hormone (CRH) gene, participated in neuropeptides-mediated appetite control. Rats were treated daily with AMPH for four days, and changes in food intake, plasma glucocorticoid and expression levels of hypothalamic neuropeptide Y (NPY), proopiomelanocortin (POMC), superoxide dismutase (SOD), CRH, and glucocorticoid receptor (GR) were examined and compared. Results showed that food intake decreased and NPY gene down-regulated, while POMC, SOD, and CRH gene up-regulated during AMPH treatment. GR and GRE-DNA bindings were disrupted on Day 1 and Day 2 when glucocorticoid levels were still high. Pretreatment with GR inhibitor or ROS scavenger modulated mRNA levels in NPY, POMC, SOD and CRH in AMPH-treated rats. We suggest that disruptions of negative GRE (nGRE) on Day 1 and Day 2 are associated with an increase in oxidative stress during the regulation of NPY/POMC mediated appetite control in AMPH-treated rats. These results advance the understanding of molecular mechanism in regulating AMPH-mediated appetite suppression. PMID- 27235635 TI - Correspondence between hair cortisol concentrations and 30-day integrated daily salivary and weekly urinary cortisol measures. AB - Characterization of cortisol production, regulation and function is of considerable interest and relevance given its ubiquitous role in virtually all aspects of physiology, health and disease risk. The quantification of cortisol concentration in hair has been proposed as a promising approach for the retrospective assessment of integrated, long-term cortisol production. However, human research is still needed to directly test and validate current assumptions about which aspects of cortisol production and regulation are reflected in hair cortisol concentrations (HCC). Here, we report findings from a validation study in a sample of 17 healthy adults (mean+/-SD age: 34+/-8.6 yrs). To determine the extent to which HCC captures cumulative cortisol production, we examined the correspondence of HCC, obtained from the first 1cm scalp-near hair segment, assumed to retrospectively reflect 1-month integrated cortisol secretion, with 30 day average salivary cortisol area-under-the curve (AUC) based on 3 samples collected per day (on awakening, +30min, at bedtime) and the average of 4 weekly 24-h urinary free cortisol (UFC) assessments. To further address which aspects of cortisol production and regulation are best reflected in the HCC measure, we also examined components of the salivary measures that represent: (1) production in response to the challenge of awakening (using the cortisol awakening response [CAR]), and (2) chronobiological regulation of cortisol production (using diurnal slope). Finally, we evaluated the test-retest stability of each cortisol measure. Results indicate that HCC was most strongly associated with the prior 30-day integrated cortisol production measure (average salivary cortisol AUC) (r=0.61, p=0.01). There were no significant associations between HCC and the 30-day summary measures using CAR or diurnal slope. The relationship between 1-month integrated 24-h UFC and HCC did not reach statistical significance (r=0.30, p=0.28). Lastly, of all cortisol measures, test-retest correlations of serial measures were highest for HCC (month-to-month: r=0.84, p<0.001), followed by 24-h UFC (week-to-week: r's between 0.59 and 0.68, ps<0.05) and then integrated salivary cortisol concentrations (week-to-week: r's between 0.38 and 0.61, p's between 0.13 and 0.01). These findings support the contention that HCC provides a reliable estimate of long-term integrated free cortisol production that is aligned with integrated salivary cortisol production measured over a corresponding one-month period. PMID- 27235637 TI - Leptin serum concentrations are associated with weight gain during lithium augmentation. AB - BACKGROUND: Meta-analytical data show lithium augmentation (LA) as an effective treatment strategy in major depression. Weight-gain is a common side effect of LA. The proteohormone leptin is discussed to be involved in the pathophysiology of weight gain induced by psychopharmacological treatment. The purpose of our study was to investigate the association of leptin and body mass index (BMI) during LA in a prospective cohort study. METHODS: Leptin serum concentrations and body mass index (BMI) were measured in a total of 89 acute depressive patients before and then after four weeks of LA. RESULTS: In a linear mixed model analysis the following variables had a significant positive effect on BMI: time (equal with "treatment effect of LA"; F1.83=6.05; p=0.016) and leptin (F1.111=13.83; p=0.0003) as well as the covariates male gender (F1.89=5.08; p=0.027) and adiposity (F1.85=105.13; p<0.0001). LIMITATIONS: If the reported effect of leptin on BMI is specific to LA remains unclear without a control group. CONCLUSION: Leptin signalling might be involved in lithium-induced weight-gain. PMID- 27235636 TI - Cognitive impairment effects of early life stress in adolescents can be predicted with early biomarkers: Impacts of sex, experience, and cytokines. AB - Childhood adversity increases vulnerability to psychiatric disorders that emerge in adolescence, in a sex-dependent manner. Early adversity modeled in rodents with maternal separation (MS) affects cognition and medial prefrontal cortex (mPFC) circuitry. Humans and animals exposed to early life adversity also display heightened circulating inflammatory cytokines, however the predictive relationship of these early measures with later behavioral deficits is unknown. Here, male and female rats were exposed to MS or control rearing during the postnatal period (P2-21). Blood samples were taken at distinct developmental time points for analysis of the pro-inflammatory cytokine IL-1beta and the anti inflammatory cytokines IL-4, and IL-10, followed by win-shift cognitive testing and analysis of mPFC parvalbumin (PVB) immunofluorescent interneurons in adolescence. Regression analyses were conducted to explore the relationship between early cytokines and adolescent behavioral measures. We observed sex- and age-dependent effects of MS on circulating cytokines. MS also yielded adolescent decreases in mPFC PVB and cognitive deficits, which were predicted by early cytokine expression in a sex- and experience-dependent manner. Taken together, the present data reveals that circulating cytokines and PVB levels are predictive of adolescent cognitive deficits, and therefore provide compelling evidence for a putative role of early biomarkers in mediating MS-induced behavioral dysfunction. Importantly, predictive relationships often depended on sex and on MS history, suggesting that early life experiences may yield individualistic mechanisms of vulnerability compared to the general population. PMID- 27235640 TI - Introducing the Academy's 2016-2017 President: Lucille Beseler, MS, RDN, LDN, CDE. PMID- 27235638 TI - Stressing over anxiety: A novel interaction of 5-HTTPLR genotype and anxiety related phenotypes in older adults. AB - Variation within the serotonin transporter gene-linked polymorphic region (5 HTTPLR) contributes to individual differences in trait neuroticism and increases risk for the development of psychopathology in the context of stressful life events. The underlying mechanisms may involve dysregulation of the hypothalamic pituitary-adrenal (HPA) axis and the release of stress-related hormones. Yet, observed effects are small, possibly because they occur against the background of many other, mostly unknown, genetic and environmental variables. In this study, we removed much of the variance contributed by such background factors by including complex trait and behavioral measures in our analyses, to isolate the unique contributions of 5-HTTLPR genotype to cortisol baseline, reactivity, and recovery during the Trier Social Stress Test. We recruited 82 community-dwelling older adults (55 and older), an under-studied population, and measured salivary cortisol levels at baseline and following the TSST. As a comparison group we also recruited 88 younger adults (males only, 18-51 years old). Neuroticism, trait anxiety, perceived stress levels, and early childhood trauma experiences were measured using self-report questionnaires. An exploratory factor analysis revealed a latent anxiety trait. Cortisol baseline levels were significantly elevated in older adult S-allele carriers (but not in LL-homozygotes) who scored higher on the latent anxiety trait, relative to S-allele carriers. No such differences were found among younger adults, nor amongst measures obtained during the reactivity or recovery periods. These results highlight the utility of taking into account background variables that may otherwise obscure associations between genetic variables and endophenotypes. PMID- 27235642 TI - Erratum. PMID- 27235639 TI - Daily family stress and HPA axis functioning during adolescence: The moderating role of sleep. AB - The present study examined the moderating role of sleep in the association between family demands and conflict and hypothalamic-pituitary-adrenal (HPA) axis functioning in a sample of ethnically diverse adolescents (n=316). Adolescents completed daily diary reports of family demands and conflict for 15 days, and wore actigraph watches during the first 8 nights to assess sleep. Participants also provided five saliva samples for 3 consecutive days to assess diurnal cortisol rhythms. Regression analyses indicated that sleep latency and efficiency moderated the link between family demands and the cortisol awakening response. Specifically, family demands were related to a smaller cortisol awakening response only among adolescents with longer sleep latency and lower sleep efficiency. These results suggest that certain aspects of HPA axis functioning may be sensitive to family demands primarily in the context of longer sleep latency and lower sleep efficiency. PMID- 27235641 TI - Summer Meal Programs Provide an Opportunity for Nutrition Education and Physical Activity. PMID- 27235643 TI - What's the Latest on Acrylamide? PMID- 27235644 TI - Detection of phenolic endocrine disrupting chemicals (EDCs) from maternal blood plasma and amniotic fluid in Indian population. AB - There is a widespread exposure of general population, including pregnant women and developing fetuses, to the endocrine disrupting chemicals (EDCs). These chemicals have been reported to be present in urine, blood serum, breast milk and amniotic fluid. We aimed to investigate the association between the maternal exposure and in utero fetal exposure levels of these chemicals to study their transfer from maternal to fetal unit indicating prenatal exposure. Samples of maternal blood and amniotic fluid were collected as set from 53 pregnant women at full term. Nine phenolic EDCs, methyl paraben (MP; 20.92ng/mL and 18.92ng/mL), ethyl paraben (EP; 1.97ng/ mL and 1.89ng/mL), propyl paraben (PP; 19.22ng/mL and 18.82ng/mL), butyl paraben (BP; 1.11ng/mL and 1.37ng/mL), p-hydroxybenzoic acid (PHBA; 29.99ng/mL and 26.15ng/mL), bisphenol A (BPA; 7.43ng/mL and 7.75ng/mL), triclosan (TCS; 7.17ng/mL and 7.04ng/mL), octyl phenol (OP; 5.46ng/mL and 5.72ng/mL) and nonyl phenol (NP; 9.38ng/mL and 8.44ng/mL), were simultaneously detected in samples of maternal blood plasma and amniotic fluid respectively using Gas Chromatography-Mass Spectrometry (GC-MS). Highest positive correlation was found for total concentration of 4-nonyl phenol, NP (r=0.575, p<0.001), whereas the lowest positive correlation was found for free form of bisphenol A, BPA (r=0.343, p<0.05), when compared between the two matrices. Our results suggest that maternal exposure to several EDCs is positively associated with in utero exposure to the developing fetus. Future studies should focus on collection of amniotic fluid at different trimesters and the corresponding maternal samples to better characterize the pharmacokinetics and the associated disease etiologies of these EDCs during fetal development. PMID- 27235645 TI - Prediction and prevention of Gestational Diabetes: an update of recent literature. AB - A diagnosis of Gestational Diabetes (GDM) confers adverse risk to the health of the mother and fetus both in pregnancy and later life. The background rate in pregnancy varies between 2 and 14% with incidences reported to be as high as 40% in obese populations. GDM diagnoses are escalating because of rising numbers of overweight and obesity in the reproductive age group but also because of different screening and diagnostic criteria. Lifestyle modification in those diagnosed with GDM has been proven to be an effective treatment in attenuating the metabolic dysregulation associated with this and potentially avoiding the need for medical therapy with either metformin or insulin. Emerging evidence in previous years suggests lifestyle interventions (dietary+/-physical activity and behavior modification) either pre-pregnancy or antenatally may reduce the incidence of GDM. The first trimester is also becoming an important interrogation period for the prediction of many adverse obstetric outcomes including abnormal glucose metabolism. This review outlines the most contemporary evidence on the prediction and non-pharmacological antenatal prevention strategies used for Gestational Diabetes. PMID- 27235646 TI - Regulation of biosynthesis and emission of volatile phenylpropanoids/benzenoids in petunia* hybrida flowers by multi-factors of circadian clock, light, and temperature. AB - Floral volatile phenylpropanoids and benzenoids (VPBs) play important ecological functions and have potential economic applications. Little is known about how multi-factors in integration regulate the formation and emission of floral VPBs. In the present study, we investigated effects of multi factors including endogenous circadian clock, light, and temperature on the formation and emission of VPBs, which are major volatiles in flowers of Petunia* hybrida cv. 'Mitchell Diploid'. Endogenous circadian clock was proposed as the most important factor regulating rhythmic emission of VPBs and expressions of structural genes involved in the upstream biosynthetic pathway of VPBs, but did not affect expression levels of structural genes involved in the downstream pathway and VPBs-related regulators. In contrast to light, temperature was a more constant factor affecting emission of VPBs. VPBs emission could be inhibited within a short time by increasing temperature. The information will contribute to our understanding of emission mechanism of floral volatiles. PMID- 27235647 TI - Cloning and biochemical characterization of indole-3-acetic acid-amino acid synthetase PsGH3 from pea. AB - Phytohormone conjugation is one of the mechanisms that maintains a proper hormonal homeostasis and that is necessary for the realization of physiological responses. Gretchen Hagen 3 (GH3) acyl acid amido synthetases convert indole-3 acetic acid (IAA) to IAA-amino acid conjugates by ATP-dependent reactions. IAA aspartate (IAA-Asp) exists as a predominant amide conjugate of auxin in pea tissues and acts as an intermediate during IAA catabolism. Here we report a novel recombinant indole-3-acetic acid-amido synthetase in Pisum sativum. In silico analysis shows that amino acid sequence of PsGH3 has the highest homology to Medicago truncatula GH3.3. The recombinant His-tag-PsGH3 fusion protein has been obtained in E. coli cells and is a soluble monomeric polypeptide with molecular mass of 69.18 kDa. The PsGH3 was purified using Ni(2+)-affinity chromatography and native PAGE. Kinetic analysis indicates that the enzyme strongly prefers IAA and L-aspartate as substrates for conjugation revealing Km(ATP) = 0.49 mM, Km(L Asp) = 2.2 mM, and Km(IAA) = 0.28 mM. Diadenosine pentaphosphate (Ap5A) competes with ATP for catalytic site and diminishes the PsGH3 affinity toward ATP approximately 1.11-fold indicating Ki = 8.5 MUM. L-Tryptophan acts as an inhibitor of IAA-amido synthesizing activity by competition with L-aspartate. Inorganic pyrophosphatase (PPase) hydrolyzing pyrophosphate to two phosphate ions, potentiates IAA-Asp synthetase activity of PsGH3. Our results demonstrate that PsGH3 is a novel enzyme that is involved in auxin metabolism in pea seeds. PMID- 27235648 TI - Phenotyping two tomato genotypes with different nitrogen use efficiency. AB - Nitrogen (N) supply usually limits crop production and optimizing N-use efficiency (NUE) to minimize fertilizer loss is important. NUE is a complex trait that can be dissected into crop N uptake from the soil (NUpE) and N utilization (NUtE). We compared NUE in 14 genotypes of three week old tomatoes grown in sand or hydroponic culture supplied with nitrate (NO3(-)). Culture method influenced measured NUE for some cultivars, but Regina Ostuni (RO) and UC82 were consistently identified as high and low NUE genotypes. To identify why these genotypes had contrasting NUE some traits were compared growing under 0.1 and 5 mM NO3(-) supply. UC82 showed greater root (15)NO3(-) influx at low and high supply, and stronger SlNRT2.1/NAR2.1 transporter expression under low supply when compared with RO. Conversely, RO showed a higher total root length and thickness compared to UC82. Compared with UC82, RO showed higher shoot SlNRT2.3 expression and NO3(-) storage at high supply, but similar NO3(-) reductase activity. After N starvation, root cell electrical potentials of RO were significantly more negative than UC82, but nitrate elicited similar responses in both root types. Overall for UC82 and RO, NUtE may play a greater role than NUpE for improved NUE. PMID- 27235649 TI - [Perception of adverse reactions of chemotherapy and hormone therapy by women treated for breast cancer]. AB - INTRODUCTION: In Europe, breast cancer is the most common cancer among women. His treatment (TTT) can have a significant impact on daily life. AIMS: Explore the experienced short-term side effects (SE) of chemotherapy and hormonal therapy by women themselves, the information delivered and the place of the general practitioner (GP). METHOD: Qualitative study by individual interview, conducted from January to May 2015, with 14 women followed for no metastatic breast cancer after chemotherapy and possible initiation of hormone therapy, at the Cancer Institute of the Loire (France). RESULTS: The SE of chemotherapy, except vomiting, have appeared very trying (fatigue, pains oral and cutaneous involvement), punctuated and accentuated by the cures. They were resounding on daily life, requiring family or professional assistance. Falling dander, considered stigmatizing, violated the person and femininity. The women have estimated to be well informed. They had appreciated the initial response of the pivot nurse. The least expected SE of hormone therapy, hot flashes and articular pains might limit activities. To counteract these side effects, mostly accepted to prevent recidivism, a remedy for complementary therapies was frequent. The GP was solicited for some SE, sometimes for complementary medicine (CM). CONCLUSION: Over the cures, women suggested support meetings, a more sustainable action of the pivot nurse, a better attention to their complaints and a more personalized information. The development of TTT less EI provider was desired. The effect of CM on SE should be explored. PMID- 27235650 TI - [Medicines and frailty in older people. Towards a new nosological entity: A pharmacological frailty?]. AB - Frailty is a complex geriatric syndrome linked to the overall decrease of physiological reserves. It could lead to disability and to an increase in mortality. Frailty could have an impact on the effect and on the use of medications. Drugs could also affect the frailty process. Currently, no specific guidelines exist for appropriately prescribing medications to frail older people. The aim of this paper is to explore the body of current knowledge about the relationship between drugs and frailty in older people and to introduce a new nosological entity: pharmacological frailty. PMID- 27235651 TI - [Efficacy and safety of ustekinumab in psoriatic arthritis after anti-TNFalpha failure in routine practice]. AB - PURPOSE: Evaluation of effectiveness and safety of ustekinumab in psoriatic arthritis after anti-TNFalpha failure. METHODS: We conducted a retrospective and monocentric study. The evaluation of articular and cutaneous effectiveness by the patient was made with numeric scale and satisfaction scale and by the physician during a rhumatological-dermatological consultation. The safety was analyzed by collecting the adverse effects. RESULTS: Nine patients with anti-TNF failure were included. Five of them stopped the treatment because of severe adverse effects. The mean duration treatment of ustekinumab was 24 months. Articular and cutaneous effectiveness were respectively 4.4/10 and 6.7/10. Two thirds of the patients were "satisfied" and one third could stop any analgesic treatment. The mean PASI score decreased from 8.4 to 1.7 after 3 months treatment. Only minor adverse effects were collected and there were no recidivism of the adverse effects observed with anti-TNFalpha. CONCLUSION: Ustekinumab is an effective and safe alternative for patients with anti-TNFalpha failure in psoriatic arthritis. PMID- 27235652 TI - [Good use and knowledge of paracetamol (acetaminophen) among self-medicated patients: Prospective study in community pharmacies]. AB - Acetaminophen (paracetamol), the highest over-the-counter (OTC) selling drug in France, is also the first cause of acute hepatic failure. We aimed to assess the good use and the knowledge of acetaminophen in a setting of urban self-medicated patients. We conducted a prospective observational study in randomly selected community pharmacies of Metz (France) agglomeration. Patients coming to buy OTC acetaminophen for themselves or their family had to answer to an anonymous autoquestionnaire. Responses were individually and concomitantly analyzed through 3 scores: good use, knowledge and overdosage. Twenty-four community pharmacies participated and 302 patients were interviewed by mean of a dedicated questionnaire. Most of patients (84.4%) could be considered as "good users" and independent factors of good use were (i) a good knowledge of acetaminophen (OR=5.3; P<0.0001) and more surprisingly; (ii) the fact of having no children (parentality: OR=0.1; P=0.006). Responses corresponding to involuntary overdosage were mostly due to a too short interval between drug intakes (3hours). Only 30.8% of patients were aware of liver toxicity of acetaminophen and only 40.7% knew the risk of the association with alcohol. Both good use and knowledge were significantly higher in patients looking for information from their pharmacist, physician and package leaflet. Patients should definitely be better informed about acetaminophen to warrant a better safety of its consumption. Pharmacists and physicians have to remind patients the risk factors of unintentional overdose and liver toxicity. Package leaflets have also to be more informative. PMID- 27235653 TI - [Comparisons outpatient drug prescriptions: France, Denmark, Norway, Sweden]. AB - Comparisons outpatient drug prescriptions: France, Denmark, Norway, Sweden. OBJECTIVE: Project compares quantitatively outpatient drug prescriptions in France, Denmark, Norway and Sweden. METHODS: Data were obtained from national databases; the unit of measurement was defined daily dose per 1000 inhabitants. The five most prescribed drug classes were compared in each country in 2009, then benzodiazepines and antibiotics from 2006 to 2012. A literature review was focused on the context of prescriptions for each country. RESULTS: In 2009, the five most prescribed drug classes in the four countries represented seven classes in total. France was not the biggest prescriber of drugs, but from 2006 to 2012 benzodiazepines and antibiotics were prescribed much more in France than in the other countries. The evolution of prescriptions was different for each country, and very stable in France. CONCLUSION: In 2009, France was not the biggest drugs consumer of all classes, but was characterized by high prescriptions in some classes. PMID- 27235655 TI - [Co-occurrent cannabis and tobacco uses: Clinical knowledge and therapeutic prospects]. AB - Cannabis and tobacco are two of the most prevalent addictive drugs used worldwide. Concurrent use of cannabis and tobacco is common, whether simultaneous in joints or not. In France, cannabis is mainly used in joints also containing tobacco. According to the current literature, combined use of cannabis and tobacco exacerbates on additive or multiplicative mode the somatic, psychological and social consequences of each drug. In addition, concurrent use of cannabis and tobacco potentiates tobacco and cannabis dependence, which maintains the use of both drugs, increases the risk of relapse and reduces motivation to care. Combined use thus leads to a reduced likelihood of therapeutic success. We discuss the usefulness of simultaneous cessation treatment together with the use of currently available pharmacological and psychological help as valuable therapeutic tools. PMID- 27235654 TI - [Characteristics of subjects under opiate maintenance treatment in primary care using the OPEMA data 2013]. AB - AIM: The objective of the study is to describe the characteristics of subjects under opiate maintenance treatment by general practionners (GPs). METHOD: Data analysis from observatory for pharmacodependency in ambulatory medicine survey (observation des pharmacodependances en medecine ambulatoire [OPEMA]) program in 2013 of the subjects under high dosage buprenorphine (HDB) and methadone prescribed or obtained illegally reported by GPs in France. RESULTS: Survey concerned consumers with 862, 433 and 429 of high dosage buprenorphine and respectively methadone. The average age is 39+/-9 years respectively, and 36+/-8 years; over 70% are male; 55% have paid employment and over 30% report social benefits; 9% are in temporary housing. In both groups, more than 50% have anxiety and depression; over 25% have associated somatic disorders and digestive diseases, respiratory, pain is the most common. Almost 99% use oral route; nearly 100% have a daily consumption and about 20% of the alcohol concomitantly; 24% of HDB use benzodiazepines and 18% of the methadone group (P=0.06); 33% of the population using methadone consume illicit psychoactive substances and 21% for HDB population (P<0.0001), in particular cannabis (P<0.0001). Heroin and cocaine are also consumed. CONCLUSION: The population consuming opiate maintenance treatments shows social, somatic and psychiatric vulnerability. Misuse associated forms and consumption of other psychoactive substances and illegal drugs are observed. Despite the complexity of management of these patients, general practitioners have a major role to play. PMID- 27235656 TI - [Benzodiazepine or non-benzodiazepine hypnotics withdrawal syndrome during hospitalization: A series of 22 cases]. AB - Twenty-two cases related to benzodiazepine (BZD) withdrawal syndrome were identified and reported to Amiens's regional pharmacovigilance center between January 1st, 1995 and March 25th, 2014, all with a favourable outcome after reintroduction of a BZD. Despite being a very classical well-known side effect, physicians may underestimate this risk. Our series also confirms that the patient is misinformed about the consequences of an abrupt BZD discontinuation especially when the BZD has been consumed for many years. Interviewing patient and his family on the nature of the current medical treatments should be systematic and an early diagnostic step taken by physicians faced with a recent behavioral disorder. Moreover, this would prevent unnecessary, sometimes invasive, expensive investigations and a prolonged hospitalization. PMID- 27235657 TI - [Evaluation of the website of the Nord-Pas-de-Calais regional pharmacovigilance center]. AB - We posted the Nord-Pas-de-Calais regional pharmacovigilance center website and distributed a survey to its potential users between August 2014 and October 2014 (135 general practitioners, 45 pharmacists, 14 patients). Satisfaction was 7.3+/ 1.6 out of 10 points for the visual aspect, 7.8+/-1.5 out of 10 points for navigation and 7.6+/-1.4 out of 10 points for content. The website was declared useful by 98% respondents, particularly for the reporting of adverse drugs reactions (89%). PMID- 27235658 TI - [Shoulder bilateral senile hemorrhagic associated with the use of fluoroquinolones]. PMID- 27235659 TI - [Esomeprazole-induced resistance to fluindione: An unrecognized interaction]. PMID- 27235660 TI - [Occurrence of peripheral edema in a switch from buprenorphine alone to the buprenorphine-naloxone combination: About one case]. PMID- 27235661 TI - [Immediate hypersensitivity reaction to phloroglucinol (Spasfon((r)))]. PMID- 27235662 TI - Sulfasalazine-induced Sweet's syndrome. PMID- 27235663 TI - Acute withdrawal syndrome after discontinuation of a short analgesic treatment with tramadol. PMID- 27235664 TI - Fatal methotrexate toxicity in a patient treated for an ectopic pregnancy. PMID- 27235665 TI - Graphene and the immune system: Challenges and potentiality. AB - In the growing area of nanomedicine, graphene-based materials (GBMs) are some of the most recent explored nanomaterials. For the majority of GBM applications in nanomedicine, the immune system plays a fundamental role. It is necessary to well understand the complexity of the interactions between GBMs, the immune cells, and the immune components and how they could be of advantage for novel effective diagnostic and therapeutic approaches. In this review, we aimed at painting the current picture of GBMs in the background of the immune system. The picture we have drawn looks like a cubist image, a sort of Picasso-like portrait looking at the topic from all perspectives: the challenges (due to the potential toxicity) and the potentiality like the conjugation of GBMs to biomolecules to develop advanced nanomedicine tools. In this context, we have described and discussed i) the impact of graphene on immune cells, ii) graphene as immunobiosensor, and iii) antibodies conjugated to graphene for tumor targeting. Thanks to the huge advances on graphene research, it seems realistic to hypothesize in the near future that some graphene immunoconjugates, endowed of defined immune properties, can go through preclinical test and be successfully used in nanomedicine. PMID- 27235666 TI - Effect of DHA supplements during pregnancy on the concentration of PUFA in breast milk of Chinese lactating mothers. AB - OBJECTIVE: To determine whether there is an effect of prenatal supplementation with docosahexaenoic acid (DHA) on the concentration of polyunsaturated fatty acids (PUFAs) in the breast milk of Chinese lactating women. METHODS: A total of 409 participants were recruited at the postpartum care center during their 1 month postpartum care. They were assigned to the supplement group or the control group according to whether or not DHA supplements were taken during pregnancy. Dietary intake was assessed with a food frequency questionnaire (FFQ). Breast milk samples were collected on 1 day between the 22nd and 25th day postpartum and levels of eight kinds of fatty acids in the breast milk were measured by gas chromatography. RESULTS: DHA intake was divided into three levels (<57 mg/day, 57 185 mg/day and >185 mg/day). The concentration of DHA postpartum in the breast milk of the group receiving a DHA supplement >185 mg/day was significantly higher (P=0.003) compared to the control group. CONCLUSIONS: DHA intake >185 mg/day resulted in increased DHA concentrations in breast milk. This finding suggests that mothers with inadequate dietary intake of DHA should change their dietary habits to consume a diet rich in DHA or take sufficient DHA supplements to meet the average nutritional needs of infants. PMID- 27235667 TI - Risk factors of uterine rupture with a special interest to uterine fundal pressure. AB - PURPOSE: Uterine rupture is a rare but serious event with a median incidence of 0.09%. Previous uterine surgery is the most common risk factor. The aim of our study was to analyze retrospectively women with uterine rupture during labor and to evaluate postulated risk factors such as uterine fundal pressure (UFP). METHODS: Twenty thousand one hundred and fifty-two deliveries were analyzed retrospectively. Inclusion criteria were 22 weeks and 0 days-42 weeks and 0 days of gestation, singleton pregnancy and cephalic presentation. Women with primary cesarean section were excluded. A logistic regression analysis adjusting for possible risk factors was conducted and a subgroup analysis of women with unscarred uterus was performed. RESULTS: Twenty-eight cases of uterine rupture were identified (incidence: 0.14%). Uterine rupture was noticed in multipara patients only. In the multivariate analysis among all study patients, only previous cesarean section remained a statistically significant risk factor [adjusted odds ration (adj. OR) 12.52 confidence interval (CI) 95% 5.21-30.09]. In the subgroup analysis among women with unscarred uterus (n=19,415) three risk factors were associated with uterine rupture: UFP (adj. OR 5.22 CI 95% 1.07 25.55), abnormal placentation (adj. OR 20.82 CI 95% 2.48-175.16) and age at delivery >40 years (adj. OR 4.77 CI 95% 1.44-15.85). CONCLUSIONS: The main risk factor for uterine rupture in the whole study population is previous uterine surgery. Risk factors in women with unscarred uterus were UFP, abnormal placentation, and age at delivery >40 years. The only factor which can be modified is UFP. We suggest that UFP should be used with caution at least in presence of other supposed risk factors. PMID- 27235668 TI - Zoledronate for Osteogenesis imperfecta: evaluation of safety profile in children. AB - BACKGROUND: The advent of bisphosphonates (BPs) has revolutionised the outcome of Osteogenesis imperfecta (OI) in the last few years. There has always been a safety concern regarding zoledronate's use due to a paucity of studies. The current study is a retrospective evaluation of children with OI on the short- and long-term side effects of zoledronate and the frequency of fractures per year after the drug was introduced. METHODS: A total of 26 children diagnosed with OI, with a median age of 84 (45-121) months were enrolled in the study. They received cyclical zoledronate for a median duration of 36 (11-61) months at quarterly intervals between January 2008 and December 2014. Safety evaluation involved assessment of its short- and long-term effects in addition to the frequency of fractures after its usage. RESULTS: One (3%) neonate had symptomatic hypocalcemia 15 days after the infusion. Three children (11%) had acute phase reactions. None had long-term side effects, including osteonecrosis of the jaw, in our 7-year experience. OI of types III and IV (total of 22) had significant reductions in the number of fractures (p<0.05). CONCLUSIONS: Further long-duration studies are necessary to evaluate the longterm safety of zoledronate. PMID- 27235669 TI - Evaluation of left and right ventricular functions using conventional and tissue Doppler echocardiography in children with type 1 diabetes mellitus. AB - BACKGROUND: The aim of the study was the evaluation of the effects of glycemic control in children and adolescents with type 1 diabetes on cardiac functions. METHODS: Diabetic patients were divided into two groups as well-controlled and poorly controlled patients. All patients underwent M-mode, two-dimensions (2D), pulsed wave (PW) Doppler, and tissue Doppler (TDI) echocardiography to evaluate systolic and diastolic functions. RESULTS: Early diastolic mitral flow velocity (Em) and the ratio of early to late diastolic mitral flow velocity (Em/Am) obtained with TDI were found to be significantly lower in the well-controlled then the control group and significantly lower in the poorly-controlled group than the well-controlled group. Am, isovolumetric relaxation time (IVRT) and myocardial performance index (MPI) were significantly higher in the poorly controlled group. The ratio of early mitral diastolic flow velocity obtained with PW Doppler (E) to Em (E/Em) was significantly higher in the diabetic group. According to the mitral valve PW Doppler results, 13.6% of the well-controlled group and 31% of the poorly-controlled group had type 1 diastolic dysfunction. According to the mitral TDI results, 18% of the well-controlled group and 40.4% of poorly-controlled group had type 1 diastolic dysfunction. CONCLUSIONS: Conventional and TDI echocardiography revealed impairment in left ventricular functions in some patients. Tissue Doppler echocardiography also revealed diastolic impairment in some patients who appeared normal with PW Doppler echocardiography. The present study found that impairment in left ventricular diastolic functions is directly related to glycemic control and the rate of diabetic cardiomyopathy was higher in children with poor metabolic control. PMID- 27235670 TI - Central precocious puberty in a boy with 22q13 deletion syndrome and NOTCH-1 gene duplication. AB - The 22q13 deletion syndrome or Phelan-McDermid syndrome is a neurodevelopmental disorder associated with developmental delay, hypotonia, delayed or absent speech, autistic-like behavior, normal to accelerated growth and dysmorphic faces. We report the occurrence of central precocious puberty in a boy diagnosed with Phelan-McDermid syndrome. At the age of 1 year, our patient presented with increased testicular volume for his age, bone age advancement and growth acceleration. Stimulated gonadotropin levels demonstrated a premature activation of the hypothalamic-pituitary-gonadal (HPG) axis. Central precocious puberty was treated with gonadotropin-releasing hormone (GnRH) analog. Molecular diagnosis with array-comparative genomic hybridization (CGH) revealed a major deletion of 5.8 Mb at the 22q13 chromosomal region and a 25 kb duplication at the 9q34.3 region that included the NOTCH-1 gene. On the background of 22q13 deletion syndrome and data from animals on the effect of abnormal NOTCH-1 gene expression on kisspeptin neuron formation, we discuss the probable role of Notch signaling in the premature activation of the HPG axis. PMID- 27235671 TI - Elevated serum adiponectin is related to elevated serum ferritin and interleukin 6 in beta-thalassaemia major children. AB - BACKGROUND: There is evidence that iron affects lipid metabolism and adipocyte biology. Given the effects of iron on adiponectin, the role of iron in lipid oxidation, and the potential additive effects of oxidative stress from excess iron and lipid metabolism. We aimed to investigate serum adiponectin in relation to clinical and laboratory parameters including the inflammation markers [C reacitve protein (CRP) and interleukin-6 (IL-6)] in beta-thalassaemia major children. METHODS: We investigated 58 beta-thalassaemia major children under scheduled blood transfusion and 30 controls. Routine clinical evaluation, laboratory investigations including serum ferritin as well as CRP measured by immunoturbidimetry, IL-6 and serum adiponectin measured by ELISA are performed. RESULTS: CRP, IL-6 and serum adiponectin levels were higher in patients than controls (p<0.001, p=0.04 and p<0.001, respectively). Patients received desferoxamine showed significantly lower levels of adiponectin than those did not receive it (mean+/-SD=4.50+/-3.37 vs. 9.96+/-9.68, p=0.006). Serum adiponectin was significantly negatively correlated with hemoglobin (Hb) concentration (r= 0.36, p=0.005). It was significantly positively correlated with platelets count, serum ferritin, CRP and IL-6 (r=0.27, r=0.26, r=0.30, r=0.35, respectively and p=0.04, p=0.04, p=0.01, p=0.008, respectively). Serum ferritin and IL-6 were the significant predictors of serum adiponectin level (p<0.001 and p=0.003, respectively). CONCLUSIONS: Serum adiponectin was increased in beta-thalassaemia major as were pro-inflammatory markers (CRP and IL-6). Its level is directly associated with ferritin and IL-6 levels. PMID- 27235672 TI - Non-diabetic clinical applications of insulin. AB - BACKGROUND: Introducing a new drug to the market is a time-consuming process, is complex, and involves consumption of a lot of resources. Therefore, discovering new uses for the old drugs (i.e. drug repurposing) benefits the patients by providing them time-tested drugs. With developments in insulin therapy still happening, it is worth keeping up to date on trends in the use of this powerful glucose-lowering agent. The aim of this article is to explore the potential non diabetic clinical applications of insulin. METHODS: Literature survey was carried out through the various scientific journals publishing experimental and clinical research papers regarding the diverse applications of insulin other than in diabetes mellitus. These applications include both therapeutic as well as diagnostic uses of insulin. The relevant information collected from these publications was paraphrased in the present paper. RESULTS: On studying the literature, the non-diabetic uses of insulin include the following: wound healing, parenteral nutrition, antiaging, body building, cardioprotection in acute coronary syndromes, insulin tolerance test to test the hypothalamo pituitary-adrenal axis functioning, cell culture, cancer treatment, organ preservation, and management of septic shock, calcium channel, beta-blocker overdose and other critical illnesses in intensive care units. CONCLUSIONS: This review attempts to survey some interesting new applications of insulin other than in diabetes mellitus. PMID- 27235673 TI - Hemolysis rates in blood samples: differences between blood collected by clinicians and nurses and the effect of phlebotomy training. AB - BACKGROUND: Hemolytic samples are one of the most challenging preanalytical issues in laboratory medicine. Even causes leading to hemolytic specimen are various, including phlebotomy practices. Respective educational interventions as well as the reduction of the number of people involved in blood collections are claimed to influence the sample quality for the better. In our hospital 70 junior doctors were in charge of routine phlebotomy until 2012, when this task was shifted to 874 nurses, including a preceding training in phlebotomy and preanalytics. Our aim was to evaluate the impact of this training effect and the increase of people involved on sample quality. METHODS: The hemolysis index (HI) of 43,875 samples was measured before (n=21,512) and after (n=22,363) the switch of blood collection responsibilities. Differences in overall hemolysis rates and the amount of plasma samples with a concentration of free hemoglobin (fHb) above 0.5 g/L and 1 g/L were calculated. RESULTS: Overall HI as well as the percentage of samples with an fHb concentration >0.5 g/L decreased after the responsibility for phlebotomy changed. The rate of samples with an fHb concentration >1 g/L remained unchanged. CONCLUSIONS: Hemolysis rates were reduced upon passing phlebotomy tasks from untrained physicians on to a trained nursing staff. We therefore conclude that the number of people performing phlebotomy seems to play a minor role, compared to the effect of a standardized training. However, whether a reduction in the number of people involved in blood collection could lead to further improvement of sample quality, remains to be investigated in future studies. PMID- 27235674 TI - The role of ghrelin in the regulation of glucose homeostasis. AB - Ghrelin is a 28-amino acid (aa) stomach-derived peptide discovered in 1999 as the endogenous ligand for growth hormone secretagogue-receptor (GHS-R). Ghrelin producing cells constitute a distinct group of endocrine cells dispersed throughout the gastric mucosa and to a lesser extent in the small intestine and the endocrine pancreas. Ghrelin plasma levels rise during fasting and chronic caloric restriction to stimulate food intake and fat storage and to prevent life threatening falls in blood glucose. Plasma ghrelin levels decrease after a meal is consumed and in conditions of energy surplus (such as obesity). Ghrelin has emerged as a key player in the regulation of appetite and energy homeostasis. Ghrelin achieves these functions through binding the ghrelin receptor GHS-R in appetite-regulating neurons and in peripheral metabolic organs including the endocrine pancreas. Ghrelin levels are negatively correlated with body mass index (BMI) and insulin resistance. In addition, ghrelin secretion is impaired in obesity and insulin resistance. Several studies highlight an important role for ghrelin in glucose homeostasis. Genetic, immunological, and pharmacological blockade of ghrelin signaling resulted in improved glucose tolerance and insulin sensitivity. Furthermore, exogenous ghrelin administration was shown to decrease glucose-induced insulin release and increase glucose level in both humans and rodents. GHS-R was shown to be expressed in pancreatic beta-cells and ghrelin suppressed insulin release via a Ca2+-mediated pathway. In this review, we provide a detailed summary of recent advances in the field that focuses on the role of insulin and insulin resistance in the regulation of ghrelin secretion and on the role of ghrelin in glucose-stimulated insulin secretion (GSIS). PMID- 27235676 TI - Why Argonaute is needed to make microRNA target search fast and reliable. AB - MicroRNA (miRNA) interferes with the translation of cognate messenger RNA (mRNA) by finding, preferentially binding, and marking it for degradation. To facilitate the search process, Argonaute (Ago) proteins come together with miRNA, forming a dynamic search complex. In this review we use the language of free-energy landscapes to discuss recent single-molecule and high-resolution structural data in the light of theoretical work appropriated from the study of transcription factor search. We suggest that experimentally observed internal states of the Ago miRNA search complex may have the explicit biological function of speeding up search while maintaining specificity. PMID- 27235675 TI - Up-regulation of miR-455-5p by the TGF-beta-SMAD signalling axis promotes the proliferation of oral squamous cancer cells by targeting UBE2B. AB - MicroRNAs (miRNAs) are involved in the tumourigenesis of various cancers by regulating their downstream targets. To identify the changes of miRNAs in oral squamous cell carcinoma (OSCC), we investigated the expression profiles of miRNAs in 40 pairs of OSCC specimens and their matched non-tumour epithelial tissues. Our data revealed higher miR-455-5p expression in the tumour tissues than in the normal tissues; the expression was also higher in oral cancer cell lines than in normal keratinocyte cell lines. MiR-455-5p knockdown reduced both the anchorage independent growth and the proliferative ability of oral cancer cells, and these factors increased in miR-455-5p-overexpressing cells. Furthermore, by analysing the array data of patients with cancer and cell lines, we identified ubiquitin conjugating enzyme E2B (UBE2B) as a target of miR-455-5p, and further validated this using 3'-untranslated region luciferase reporter assays and western blot analysis. We also demonstrated that UBE2B suppression rescued the impaired growth ability of miR-455-5p-knockdown cells. Furthermore, we observed that miR-455-5p expression was regulated, at least in part, by the transforming growth factor beta (TGF-beta) pathway through the binding of SMAD3 to specific promoter regions. Notably, miR-455-5p expression was associated with the nodal status, stage, and overall survival in our patients, suggesting that miR-455-5p is a potential marker for predicting the prognosis of patients with oral cancer. In conclusion, we reveal that miR-455-5p expression is regulated by the TGF-beta dependent pathway, which subsequently leads to UBE2B down-regulation and contributes to oral cancer tumourigenesis. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 27235678 TI - Nurses' Own Birth Experiences Influence Labor Support Attitudes and Behaviors. AB - OBJECTIVE: To describe the attitudes of intrapartum nurses about the importance of and intent to provide professional labor support (PLS); barriers to PLS, such as perceived subjective norms and perceived behavioral control; and relationships among attitudes, behaviors, and nurse and site characteristics. DESIGN: A cross sectional, mixed-methods, descriptive design was guided by the Theory of Planned Behavior. SETTING: Three hospital sites in one region of a single Midwestern state. PARTICIPANTS: Sixty intrapartum nurses participated. METHODS: The Labor Support Questionnaire and demographic questionnaire were administered online. The Labor Support Questionnaire is used to measure attitudes about the importance of and intended behaviors associated with labor support. RESULTS: Nurse Caring Behaviors was the highest rated PLS dimension. Participants' own personal birth experiences and length of current intrapartum experience were positively correlated with attitudes about and intent to provide PLS. Barriers to PLS included staffing, documentation, physicians, use of epidural analgesia, doulas, and birth plans. CONCLUSION: Personal birth and work experience influenced attitudes about and intent to provide PLS and demonstrated the relationships described in the Theory of Planned Behavior. Intrapartum nurses may benefit from an examination of their personal experiences to see how they might influence attitudes about PLS. Enhanced training and expanded labor and birth experience for novice nurses or students may improve attitudes and intended behavior with regard to PLS. Further investigations of the factors that affect integration of PLS into care are important to promote healthy birth outcomes. PMID- 27235677 TI - Refining paracervical block techniques for pain control in first trimester surgical abortion: a randomized controlled noninferiority trial. AB - OBJECTIVES: Our objective was to evaluate two different aspects of the paracervical block (PCB) technique for first trimester surgical abortion, to compare a 3-min wait prior to cervical dilation to no wait and to compare four site with two-site injection. STUDY DESIGN: We conducted two consecutive randomized, single-blinded noninferiority trials. In the first trial, women <11 weeks gestational age received a 20-mL 1% buffered lidocaine four-site PCB with either a 3-min wait between PCB injection and dilation or no wait. In the second trial, we compared a four-site with a two-site PCB. We evaluated dilation pain [100-mm visual analogue scale (VAS)] as the primary outcome. Secondary outcomes included pain at additional time points, anxiety, satisfaction and adverse events. RESULTS: Both trials fully enrolled (total n=332). Results were inconclusive as to whether no wait was noninferior to waiting 3-min prior to cervical dilation for dilation pain [VAS: 63 mm (SD, 24 mm) vs. 56 mm (SD, 32mm)] and as to whether a two-site PCB was noninferior to a four-site block [VAS: 68 mm (SD, 21 mm) vs. 60 mm (SD, 30 mm)]. Noninferiority analysis was inconclusive because the confidence interval of the mean pain score difference between groups included the predefined inferiority margin of 13-mm pain difference. Superiority analysis showed the four-site PCB to be superior to the two-site PCB. CONCLUSION: It remained inconclusive whether a 3-min wait time between PCB and cervical dilation provides noninferior pain control for first trimester surgical abortion. However, a four-site PCB appeared to be superior to a two-site PCB. IMPLICATIONS: It remained inconclusive whether a 3-min wait time between PCB and cervical dilation or using a two-site instead of a four-site PCB provided noninferior pain control for first trimester surgical abortion. This study did not assess whether the combination of the two separate factors provides additive benefit. PMID- 27235679 TI - Use of the Cranial Cup to Correct Positional Head Shape Deformities in Hospitalized Premature Infants. AB - OBJECTIVE: To examine the feasibility, effectiveness, and safety of the cranial cup for the correction of visible head shape deformities in premature infants. DESIGN: A prospective descriptive research design. SETTING: Two study sites, an urban Level 4 NICU and a suburban Level 2 special care nursery. PARTICIPANTS: The study sample consisted of 23 neonates and infants with deformational plagiocephaly who were born at less than or equal to 35 weeks gestation, weighed greater than 1 kg, and were in the convalescent phase (stable) of their hospitalizations. METHODS: All participants received the experimental treatment with the cranial cup. Infants were positioned on the cranial cup for a minimum of 12 hours per day. They also received routine position changes at least every 3 to 4 hours. Demographic data and baseline and discharge cranial measurements were obtained for each infant. RESULTS: All participants (N = 23) had visible deformational plagiocephaly on study entry, and 86% (n = 19) had corresponding abnormal cranial measurements. The median hours per day on the cranial cup was 12.7 (range = 6.3 to 18.0). At hospital discharge, 83% (n = 19) of participants had normal cranial measurements. Furthermore, there were no reported safety concerns associated with use of the cranial cup. CONCLUSION: Use of the cranial cup during the convalescent phase of hospitalization is feasible and safe, and it provides effective correction of DP for premature neonates and infants. PMID- 27235681 TI - Factors That Regulate the Generation of Antibody-Secreting Plasma Cells. AB - The generation of antigen-specific neutralizing antibodies and memory B cells is one of the most important immune protections of the host and is the basis for successful vaccination strategies. The protective antibodies, secreted by preexisting long-lived plasma cells and reactivated antigen-experienced memory B cells, constitute the main humoral immune defense. Distinct from the primary antibody response, the humoral memory response is generated much faster and with greater magnitude, and it produces antibodies with higher affinity and variable isotypes. Humoral immunity is critically dependent on the germinal center where high-affinity memory B cells and plasma cells are generated. In this chapter, we focus on recent advances in our understanding of the molecular mechanisms that govern fate decision for memory B cells and plasma cells and the mechanisms that maintain the long-lived plasma-cell pool, with emphasis on how the transcription factor Blimp-1 (B lymphocyte-induced maturation protein-1) helps regulate the above-mentioned immunoregulatory steps to ensure the production and maintenance of antibody-secreting plasma cells as well as how it directs memory cell vs plasma-cell fate. We also discuss the molecular basis of Blimp-1 action and how its expression is regulated. PMID- 27235682 TI - Deep Profiling Human T Cell Heterogeneity by Mass Cytometry. AB - Advances of mass cytometry and high-dimensional single-cell data analysis have brought cellular immunological research into a new generation. By coupling these two powerful technology platforms, immunologists now have more tools to resolve the tremendous diversity of immune cell subsets, and their heterogeneous functionality. Since the first introduction of mass cytometry, many reports have been published using this novel technology to study a range of cell types. At the outset, studies of human hematopoietic stem cell and peripheral CD8(+) T cells using mass cytometry have shad the light of future experimental approach in interrogating immune cell phenotypic and functional diversity. Here, we briefly revisit the past and present understanding of T cell heterogeneity, and the technologies that facilitate this knowledge. In addition, we review the current progress of mass cytometry and high-dimensional cytometric analysis, including the methodology, panel design, experimental procedure, and choice of computational algorithms with a special focus on their utility in exploration of human T cell immunology. PMID- 27235680 TI - Malondialdehyde Epitopes as Targets of Immunity and the Implications for Atherosclerosis. AB - Accumulating evidence suggests that oxidation-specific epitopes (OSEs) constitute a novel class of damage-associated molecular patterns (DAMPs) generated during high oxidative stress but also in the physiological process of apoptosis. To deal with the potentially harmful consequences of such epitopes, the immune system has developed several mechanisms to protect from OSEs and to orchestrate their clearance, including IgM natural antibodies and both cellular- and membrane-bound receptors. Here, we focus on malondialdehyde (MDA) epitopes as prominent examples of OSEs that trigger both innate and adaptive immune responses. First, we review the mechanisms of MDA generation, the different types of adducts on various biomolecules and provide relevant examples for physiological carriers of MDA such as apoptotic cells, microvesicles, or oxidized low-density lipoproteins. Based on recent insights, we argue that MDA epitopes contribute to the maintenance of homeostatic functions by acting as markers of elevated oxidative stress and tissue damage. We discuss multiple lines of evidence that MDA epitopes are proinflammatory and thus important targets of innate and adaptive immune responses. Finally, we illustrate the relevance of MDA epitopes in human pathologies by describing their capacity to drive inflammatory processes in atherosclerosis and highlighting protective mechanisms of immunity that could be exploited for therapeutic purposes. PMID- 27235683 TI - Germinal Center B-Cell-Associated Nuclear Protein (GANP) Involved in RNA Metabolism for B Cell Maturation. AB - Germinal center B-cell-associated nuclear protein (GANP) is upregulated in germinal center B cells against T-cell-dependent antigens in mice and humans. In mice, GANP depletion in B cells impairs antibody affinity maturation. Conversely, its transgenic overexpression augments the generation of high-affinity antigen specific B cells. GANP associates with AID in the cytoplasm, shepherds AID into the nucleus, and augments its access to the rearranged immunoglobulin (Ig) variable (V) region of the genome in B cells, thereby precipitating the somatic hypermutation of V region genes. GANP is also upregulated in human CD4(+) T cells and is associated with APOBEC3G (A3G). GANP interacts with A3G and escorts it to the virion cores to potentiate its antiretroviral activity by inactivating HIV-1 genomic cDNA. Thus, GANP is characterized as a cofactor associated with AID/APOBEC cytidine deaminase family molecules in generating diversity of the IgV region of the genome and genetic alterations of exogenously introduced viral targets. GANP, encoded by human chromosome 21, as well as its mouse equivalent on chromosome 10, contains a region homologous to Saccharomyces Sac3 that was characterized as a component of the transcription/export 2 (TREX-2) complex and was predicted to be involved in RNA export and metabolism in mammalian cells. The metabolism of RNA during its maturation, from the transcription site at the chromosome within the nucleus to the cytoplasmic translation apparatus, needs to be elaborated with regard to acquired and innate immunity. In this review, we summarize the current knowledge on GANP as a component of TREX-2 in mammalian cells. PMID- 27235686 TI - Retinotopic mapping of visual event-related potentials. AB - Visual stimulation is frequently employed in electroencephalographic (EEG) research. However, despite its widespread use, no studies have thoroughly evaluated how the morphology of the visual event-related potentials (ERPs) varies according to the spatial location of stimuli. Hence, the purpose of this study was to perform a detailed retinotopic mapping of visual ERPs. We recorded EEG activity while participants were visually stimulated with 60 pattern-reversing checkerboards placed at different polar angles and eccentricities. Our results show five pattern-reversal ERP components. C1 and C2 components inverted polarity between the upper and lower hemifields. P1 and N1 showed higher amplitudes and shorter latencies to stimuli located in the contralateral lower quadrant. In contrast, P2 amplitude was enhanced and its latency was reduced by stimuli presented in the periphery of the upper hemifield. The retinotopic maps presented here could serve as a guide for selecting optimal visuo-spatial locations in future ERP studies. PMID- 27235684 TI - Advances in PET Detection of the Antitumor T Cell Response. AB - Positron emission tomography (PET) is a powerful noninvasive imaging technique able to measure distinct biological processes in vivo by administration of a radiolabeled probe. Whole-body measurements track the probe accumulation providing a means to measure biological changes such as metabolism, cell location, or tumor burden. PET can also be applied to both preclinical and clinical studies providing three-dimensional information. For immunotherapies (in particular understanding T cell responses), PET can be utilized for spatial and longitudinal tracking of T lymphocytes. Although PET has been utilized clinically for over 30 years, the recent development of additional PET radiotracers have dramatically expanded the use of PET to detect endogenous or adoptively transferred T cells in vivo. Novel probes have identified changes in T cell quantity, location, and function. This has enabled investigators to track T cells outside of the circulation and in hematopoietic organs such as spleen, lymph nodes, and bone marrow, or within tumors. In this review, we cover advances in PET detection of the antitumor T cell response and areas of focus for future studies. PMID- 27235685 TI - Adolescent's respiratory sinus arrhythmia is associated with smoking rate five years later. AB - INTRODUCTION: Vulnerability factors like respiratory sinus arrhythmia (RSA) may help identify adolescents at risk for nicotine dependence. We examined if resting RSA and the acute effects of smoking on RSA was associated with cigarette smoking five years later among adolescents at high risk for smoking escalation and nicotine dependence. METHODS: Sixty-nine adolescents participated in a baseline laboratory session- RSA was collected before and after smoking a single cigarette ad libitum. Participants were then followed for five years. RESULTS: Lower pre smoke resting RSA was related to higher past month smoking rate five years later, even after controlling for baseline smoking rate and other relevant covariates including gender, race/ethnicity, age of initiated use, and frequency of exercise at baseline (p=0.018). Exploratory analyses suggested resting RSA is an independent predictor of increased cigarette rate beyond other baseline predictors. CONCLUSIONS: Low resting RSA may be a vulnerability factor, helping to identify adolescents at risk for cigarette escalation. PMID- 27235687 TI - Comparison of oral bioavailability of benzo[a]pyrene in soils using rat and swine and the implications for human health risk assessment. AB - BACKGROUND: There are many uncertainties concerning variations in benzo[a]pyrene (B[a]P) soil guidelines protecting human health based on carcinogenic data obtained in animal studies. Although swine is recognised as being much more representative of the human child in terms of body size, gut physiology and genetic profile the rat/mice model is commonly used in practice. OBJECTIVES: We compare B[a]P bioavailability using a rat model to that estimated in a swine model, to investigate the correlation between these two animal models. This may help reduce uncertainty in applying bioavailability to human health risk assessment. METHODS: Twelve spiked soil samples and a spiked silica sand (reference material) were dosed to rats in parallel with a swine study. B[a]P bioavailability was estimated by the area under the plasma B[a]P concentration time curve (AUC) and faecal excretion as well in the rats. Direct comparison between the two animal models was made for: firstly, relative bioavailability (RB) using AUC assay; and secondly, the two assays in the rat model. RESULTS: Both AUC and faecal excretion assays showed linear dose-response for the reference material. However, absolute bioavailability was significantly higher when using faecal excretion assay (p<0.001). In aged soils faecal excretion estimated based on solvent extraction was not accurate due to the form of non extractable fraction through ageing. A significant correlation existed between the two models using RB for soil samples (RBrat=0.26RBswine+17.3, R(2)=0.70, p<0.001), despite the regression slope coefficient revealing that the rat model would underestimate RB by about one quarter compared to using swine. CONCLUSIONS: In the comparison employed in this study, an interspecies difference of four in RB using AUC assay was identified between the rat and swine models regarding pharmacokinetic differences, which supported the body weight scaling method recommended by US EPA. Future research should focus on the carcinogenic competency (pharmacodynamics) used in experiment animals and humans. PMID- 27235688 TI - A developmental perspective on early-life exposure to neurotoxicants. AB - BACKGROUND: Studies of early-life neurotoxicant exposure have not been designed, analyzed, or interpreted in the context of a fully developmental perspective. OBJECTIVES: The goal of this paper is to describe the key principles of a developmental perspective and to use examples from the literature to illustrate the relevance of these principles to early-life neurotoxicant exposures. METHODS: Four principles are discussed: 1) the effects of early-life neurotoxicant exposure depend on a child's developmental context; 2) deficits caused by early life exposure initiate developmental cascades that can lead to pathologies that differ from those observed initially; 3) early-life neurotoxicant exposure has intra-familial and intergenerational impacts; 4) the impacts of early-life neurotoxicant exposure influence a child's ability to respond to future insults. The first principle is supported by considerable evidence, but the other three have received much less attention. DISCUSSION: Incorporating a developmental perspective in studies of early-life neurotoxicant exposures requires prospective collection of data on a larger array of covariates than usually considered, using analytical approaches that acknowledge the transactional processes between a child and the environment and the phenomenon of developmental cascades. CONCLUSION: Consideration of early-life neurotoxicant exposure within a developmental perspective reveals that many issues remain to be explicated if we are to achieve a deep understanding of the societal health burden associated with early-life neurotoxicant exposures. PMID- 27235689 TI - Compulsivity-A new trans-diagnostic research domain for the Roadmap for Mental Health Research in Europe (ROAMER) and Research Domain Criteria (RDoC) initiatives. PMID- 27235690 TI - The cost and impact of compulsivity: A research perspective. AB - Compulsivity is the defining feature of various psychiatric disorders including Obsessive Compulsive Related Disorders (OCRDs), and other compulsive, impulsive, and addictive disorders. These disorders are disabling, chronic conditions with an early onset and high rates of comorbidity, misdiagnoses, and delay in treatment onset. Disorders of compulsivity are responsible for considerable socioeconomic burden to society. We review the costs and impacts of compulsivity. In order to facilitate earlier diagnosis and targeted treatments, we examine the overlapping mechanisms that underlie compulsivity. We reconceptualize psychiatric disorders based on core features of compulsivity, highlight challenges in harmonizing research in children and adults, describe newer research methodologies, and point to future directions that can impact the costs and impact of disorders of compulsivity. PMID- 27235691 TI - Dying younger in Scotland: Trends in mortality and deprivation relative to England and Wales, 1981-2011. AB - Given previous evidence that not all Scotland's higher mortality compared to England & Wales (E&W) can be explained by deprivation, the aim was to enhance understanding of this excess by analysing changes in deprivation and mortality in Scotland and E&W between 1981 and 2011. Mortality was compared by means of direct standardisation and log-linear Poisson regression models, adjusting for age, sex and deprivation. Different measures of deprivation were employed, calculated at different spatial scales. Results show that Scotland became less deprived compared to E&W between 1981 and 2011. However, the Scottish excess (the difference in mortality rates relative to E&W after adjustment for deprivation) increased from 4% higher (c.1981) to 10% higher in 2010-12. The latter figure equates to c. 5000 extra deaths per year. The increase was driven by higher mortality from cancer, suicide, alcohol related causes and drugs-related poisonings. The size and increase in Scottish excess mortality are major concerns. Investigations into its underlying causes continue, the findings of which will be relevant to other populations, given that similar excesses have been observed elsewhere in Britain. PMID- 27235692 TI - Fate and action of ricin in rat liver in vivo: translocation of endocytosed ricin into cytosol and induction of intrinsic apoptosis by ricin B-chain. AB - Cytotoxicity of many plant and bacterial toxins requires their endocytosis and retrograde transport from endosomes to the endoplasmic reticulum. Using cell fractionation and immunoblotting procedures, we have assessed the fate and action of the plant toxin ricin in rat liver in vivo, focusing on endosome-associated events and induction of apoptosis. Injected ricin rapidly accumulated in endosomes as an intact A/B heterodimer (5-90 min) and was later (15-90 min) partially translocated to cytosol as A- and B-chains. Unlike cholera and diphtheria toxins, which also undergo endocytosis in liver, neither in cell-free endosomes loaded by ricin in vivo nor upon incubation with endosomal lysates did ricin undergo degradation in vitro. A time-dependent translocation of ricin across the endosomal membrane occurred in cell-free endosomes. Endosome-located thioredoxin reductase-1 was required for translocation as shown by its physical association with ricin chains and effects of its removal and inhibition. Ricin induced in vivo intrinsic apoptosis as judged by increased cytochrome c content, activation of caspase-9 and caspase-3, and enrichment of DNA fragments in cytosol. Furthermore, reduced ricin and ricin B-chain caused cytochrome c release from mitochondria in vivo and in vitro, suggesting that the interaction of ricin B-chain with mitochondria is involved in ricin-induced apoptosis. PMID- 27235693 TI - PUMA and survivin are involved in the apoptosis of HepG2 cells induced by microcystin-LR via mitochondria-mediated pathway. AB - The present study aimed to determine the cytotoxicity of microcystin-LR (MC-LR) on the human hepatocellular carcinoma (HepG2) cells in order to elucidate the mechanism of apoptosis induced by MC-LR. Morphological evaluation results showed that MC-LR induced time- and concentration-dependent apoptosis in HepG2 cells. The biochemical assays revealed that MC-LR-exposure caused overproduction of reactive oxygen species (ROS), cyclooxygenase-2 activity alteration, cytochrome c release, and remarkable activation of caspase-3 and caspase-9 in HepG2 cells, indicating that MC-LR-induced apoptosis is mediated by mitochondrial pathway. Moreover, we also found that p53 and Bax might play an important role in MC-LR induced apoptosis in HepG2 cells in which PUMA and survivin were involved. However, further studies are necessary to elucidate the possible functions of PUMA and survivin in MC-LR-induced apoptosis in HepG2 cells. PMID- 27235694 TI - The present status and future prospects of peptide-based cancer vaccines. AB - Tumor cells commonly express several antigens, such as tumor-associated antigens (TAAs) or mutation-derived antigens (neoantigens), that can be regarded as foreign antigens and elicit anti-tumor immune responses in cancer patients. Various TAAs or neoantigens expressed in cancer cells have been identified and utilized as targets for cancer vaccines. One approach to elicit tumor-specific immune responses is termed peptide-based cancer vaccination; it involves administrating TAAs or neoantigen-derived peptide for treatment of cancers. There have been several forms of peptide-based cancer vaccines depending on which effector cells, such as CTLs or CD4(+) T-helper cells, are targeted to be activated. Many phase I and II clinical trials of peptide-based cancer vaccines using TAA-derived CTL epitopes, T-helper cell epitopes or dendritic cells loaded with TAA-derived peptides for various malignant tumors have been conducted and provide clinical benefits in a small fraction of patients. Nowadays, to improve the efficiency of peptide-based cancer vaccines, combination immunotherapy of peptide-based cancer vaccines with the immune-checkpoint blockade therapies using mAbs specific for CTLA-4, programmed cell death 1 (PD-1), or PD-1 ligand 1 (PD L1) have been developed for clinical application. Furthermore, along with the recent technological progress in genetic and bioinformatic analysis, it has become easier to identify neoantigens from individual cancer patients. It is expected that peptide-based cancer vaccines targeting neoantigens as a personalized cancer immunotherapy will be developed. PMID- 27235696 TI - Rectal chlamydia - should screening be recommended in women? AB - Chlamydia trachomatis is the most common bacterial sexually transmitted infection in Europe and has large impacts on patients' physical and emotional health. Unidentified asymptomatic rectal Chlamydia trachomatis could be a partial explanation for the high Chlamydia trachomatis prevalence. In this study, we evaluated rectal Chlamydia trachomatis testing in relation to symptoms and sexual habits in women and men who have sex with men. Rectal Chlamydia trachomatis prevalence was 9.1% in women and 0.9% in men who have sex with men. None of the patients reported any rectal symptoms; 59.0% of the women with a rectal Chlamydia trachomatis infection denied anal intercourse and 18.8% did not have a urogenital infection; 9.4% did neither have a urogenital infection nor reported anal sex. We suggest that rectal sampling should be considered in women visiting sexually transmitted infection clinics regardless of rectal symptoms and irrespective of anal intercourse, since our data suggest that several cases of rectal Chlamydia trachomatis otherwise would be missed, thus enabling further disease transmission. PMID- 27235695 TI - Association Between Markers of Inflammation and Total Stroke by Hypertensive Status Among Women. AB - BACKGROUND: Markers of systemic inflammation (high-sensitivity C-reactive protein [hsCRP], soluble intercellular adhesion molecule 1 [sICAM-1], and fibrinogen) have been associated with a greater risk of total and ischemic stroke, in addition to elevated blood pressure. However, the role of these inflammatory markers on stroke pathophysiology by hypertension status is uncertain. METHODS: Blood samples were collected and assayed for hsCRP, sICAM-1, and fibrinogen among 27,330 initially healthy women from the Women's Health Study, and women were followed up from 1992 to 2013. Prior to randomization, the baseline questionnaire collected self-reported hypertension status, cardiovascular risk factors, and lifestyle factors. New cases of total, ischemic, and hemorrhagic stroke were updated annually through questionnaires and confirmed by medical records according to the National Survey of Stroke criteria. Multivariable Cox models estimated overall associations between each inflammatory marker and stroke and separately stratified by hypertension status. RESULTS: We observed 629 incident total strokes over 477,278 person-years. In adjusted analyses, extreme quartiles of hsCRP and sICAM-1 were each associated with a significantly greater risk of total stroke (hsCRP: hazard ratios [HR] = 1.77, 95% confidence interval [CI]: 1.39-2.26; sICAM-1: HR = 1.28, 95% CI: 1.00-1.63). Fibrinogen was not associated with a significantly greater stroke risk. In analyses stratified by hypertension status, elevated hsCRP was associated with a nonstatistically significant greater risk of total stroke among prehypertensive and hypertensive women. CONCLUSIONS: These data indicate that hsCRP and sICAM-1 are associated with hypertension status and stroke risk among women. Further work should examine the role of inflammatory markers on ischemic stroke subtypes and clarify mechanisms. PMID- 27235698 TI - The Effects of Theory of Mind Training on the False Belief Understanding of Deaf and Hard-of-Hearing Students in Prekindergarten and Kindergarten. AB - Data from a growing number of research studies indicate that children with hearing loss are delayed in Theory of Mind (ToM) development when compared to their typically developing, hearing peers. While other researchers have studied the developmental trajectories of ToM in school-age students who are deaf, a limited number have addressed the need for interventions for this population. The present study extends the current research on ToM interventions to the Prekindergarten and Kindergarten levels. This study used a single-case multiple baseline design to examine the effects of a ToM intervention on participants' false belief understanding as well as outcomes on a near generalization measure and a far generalization measure. A ToM thought bubble intervention (i.e., a visual representation of what people are thinking) developed by Wellman and Peterson (2013 Deafness, thought bubbles, and theory-of-mind development. Developmental Psychology, 49, 2357-2367) was modified in key areas. Results from the Single-Case Design portion of the study indicate a functional, or causal, relation between the ToM intervention and the participants' acquisition of the targeted skills in each stage although progress was not uniform. Results from the pre-post assessments indicate that the children did make progress up the scale. These results inform the field in regard to the efficacy and feasibility of a ToM intervention for young deaf children. PMID- 27235699 TI - Level of Educational Attainment Among Deaf Adults Who Attended Bilingual Bicultural Programs. AB - In Scandinavia and some other countries, a bilingual-bicultural approach to deaf education was celebrated in national programs from the mid-1980s until the broad popularity of cochlear implantation in middle 2000s created a shift back to an emphasis on spoken language for many deaf children. At the same time, only a few studies evaluated the long-term outcomes of bilingual-bicultural education, and several of their findings have raised questions about benefits of the approach. This study examined the level of educational attainment of 408 deaf individuals who attended primary school either before or during the period of bilingual bicultural education in Denmark, both relative to a comparable hearing cohort. Beyond group comparisons, three logistic regression models were created to evaluate the prediction of educational attainment by a number of relevant variables. Compared to the hearing population, the deaf population had a significantly lower level of educational attainment both before and after the introduction of bilingual-bicultural education. Signed language and spoken language abilities, the kind of school attended, degree of hearing loss, parental hearing loss, and gender were found significantly to explain levels of educational attainment in the deaf population. PMID- 27235697 TI - RevBayes: Bayesian Phylogenetic Inference Using Graphical Models and an Interactive Model-Specification Language. AB - Programs for Bayesian inference of phylogeny currently implement a unique and fixed suite of models. Consequently, users of these software packages are simultaneously forced to use a number of programs for a given study, while also lacking the freedom to explore models that have not been implemented by the developers of those programs. We developed a new open-source software package, RevBayes, to address these problems. RevBayes is entirely based on probabilistic graphical models, a powerful generic framework for specifying and analyzing statistical models. Phylogenetic-graphical models can be specified interactively in RevBayes, piece by piece, using a new succinct and intuitive language called Rev. Rev is similar to the R language and the BUGS model-specification language, and should be easy to learn for most users. The strength of RevBayes is the simplicity with which one can design, specify, and implement new and complex models. Fortunately, this tremendous flexibility does not come at the cost of slower computation; as we demonstrate, RevBayes outperforms competing software for several standard analyses. Compared with other programs, RevBayes has fewer black-box elements. Users need to explicitly specify each part of the model and analysis. Although this explicitness may initially be unfamiliar, we are convinced that this transparency will improve understanding of phylogenetic models in our field. Moreover, it will motivate the search for improvements to existing methods by brazenly exposing the model choices that we make to critical scrutiny. RevBayes is freely available at http://www.RevBayes.com [Bayesian inference; Graphical models; MCMC; statistical phylogenetics.]. PMID- 27235700 TI - Ethnic differences in the epidemiology of cutaneous lupus erythematosus in New Zealand. AB - Background The prevalence and variation by ethnicity of cutaneous lupus in New Zealand is not known. Therefore, a cross-sectional study to determine the prevalence and variation by ethnicity of cutaneous lupus in the ethnically diverse community of South Auckland, New Zealand, was undertaken. Methods Multiple sources were examined to determine the prevalence of acute cutaneous lupus erythematosus, subacute cutaneous erythematosus and discoid lupus erythematosus. Ethnicities examined were European, Maori/Pacific and Indian/Asian. Capture-recapture was used to determine the overall population prevalence of cutaneous lupus. Results A total of 145 cases of cutaneous lupus were identified. There were 22 men and 123 women, with an average age (standard deviation), respectively, of 46.4 (+/-21.5) and 43.1 (+/-14.8) years. There were 53 cases of acute cutaneous lupus erythematosus, 19 cases of subacute cutaneous erythematosus and 66 cases of discoid lupus erythematosus. The age and sex adjusted relative risk (95% confidence interval; CI) of Maori/Pacific compared to the European population was 2.47 (95% CI 1.67-3.67) for all types of cutaneous lupus, 1.60 (95% CI 0.84-3.18) for acute cutaneous lupus erythematosus, 0.09 (95% CI 0.01-1.1) for subacute cutaneous erythematosus and 5.96 (95% CI 3.06-11.6) for discoid lupus erythematosus. The overall prevalence of cutaneous lupus was 30.1 (95% CI 25.5-35.4) per 100,000. However, capture-recapture estimated the unadjusted prevalence of cutaneous lupus to be 86.0 (95% CI 78.1-94.7) per 100,000. Conclusion Maori and Pacific people in Auckland, New Zealand, have a greater relative risk of all types of cutaneous lupus compared to the European population and a particularly high risk of discoid lupus erythematosus. PMID- 27235701 TI - The caregiver burden in lupus: findings from UNVEIL, a national online lupus survey in the United States. AB - OBJECTIVES: Lupus imposes a substantial burden on patients; however, little is known about its impact on those caring for patients with the disease. In this study, we examined the impact 'caring for patients with lupus' has on caregivers from their own perspective. METHODS: UNVEIL was a one-time online national cross sectional survey developed in partnership with the Lupus Foundation of America and fielded targeting the US Lupus Foundation of America constituents in 2014. Eligible caregivers were adults who self-identified as unpaid caregivers of patients with lupus. Eligible caregivers had to complete a series of sociodemographic questions as well as a series of well established outcome measures, such as the Short Form 12v2 Health Survey, the Work Productivity and Activity Index, the Caregiver Burden Inventory, and the Perceived Benefits of Caregiving Scale. RESULTS: A total of 253 caregivers completed the survey. The majority of caregivers (90.1%) were aged 60 years or younger, more than half (54.2%) were men, and more than half (59.7%) identified themselves as either a spouse or a partner to the patient with lupus they were caring for. Overall health-related quality of life was close to the norm mean of the general US population. Caregivers who were employed missed an average of 12.8% of paid work time due to caregiving responsibilities and reported a 33.5% reduction in on-the job effectiveness. Nearly half of the caregivers surveyed (49.4%) indicated that their caregiving responsibilities impacted their ability to socialize with friends, and almost all caregivers (97.6%) reported experiencing increased anxiety and stress in relation to their caregiving role. CONCLUSIONS: Caregiving for patients with lupus has a substantial impact on the work productivity and the social and emotional functioning of caregivers. Healthcare professionals and policymakers should continually assess the impact of healthcare decisions on the well-being of those caring for patients with lupus. PMID- 27235702 TI - Understanding the Role of Additives in Tobacco Products. PMID- 27235703 TI - Delivering "Just-In-Time" Smoking Cessation Support Via Mobile Phones: Current Knowledge and Future Directions. AB - : Smoking lapses early on during a quit attempt are highly predictive of failing to quit. A large proportion of these lapses are driven by cravings brought about by situational and environmental cues. Use of cognitive-behavioral lapse prevention strategies to combat cue-induced cravings is associated with a reduced risk of lapse, but evidence is lacking in how these strategies can be effectively promoted. Unlike most traditional methods of delivering behavioral support, mobile phones can in principle deliver automated support, including lapse prevention strategy recommendations, Just-In-Time (JIT) for when a smoker is most vulnerable, and prevent early lapse. JIT support can be activated by smokers themselves (user-triggered), by prespecified rules (server-triggered) or through sensors that dynamically monitor a smoker's context and trigger support when a high risk environment is sensed (context-triggered), also known as a Just-In-Time Adaptive Intervention (JITAI). However, research suggests that user-triggered JIT cessation support is seldom used and existing server-triggered JIT support is likely to lack sufficient accuracy to effectively target high-risk situations in real time. Evaluations of mobile phone cessation interventions that include user and/or server-triggered JIT support have yet to adequately assess whether this improves management of high risk situations. While context-triggered systems have the greatest potential to deliver JIT support, there are, as yet, no impact evaluations of such systems. Although it may soon be feasible to learn about and monitor a smoker's context unobtrusively using their smartphone without burdensome data entry, there are several potential advantages to involving the smoker in data collection. IMPLICATIONS: This commentary describes the current knowledge on the potential for mobile phones to deliver automated support to help smokers manage or cope with high risk environments or situations for smoking, known as JIT support. The article categorizes JIT support into three main types: user-triggered, server-triggered, and context-triggered. For each type of JIT support, a description of the evidence and their potential to effectively target specific high risk environments or situations is described. The concept of unobtrusive sensing without user data entry to inform the delivery of JIT support is finally discussed in relation to potential advantages and disadvantages for behavior change. PMID- 27235704 TI - Clinical validation of urine 3-methoxytyramine as a biomarker of neuroblastoma and comparison with other catecholamine-related biomarkers. AB - Background Urinary dopamine, homovanillic acid and 4-hydroxy-3-methoxymandelic acid are established tests for diagnosis and monitoring of neuroblastic disease. We compared the diagnostic performance of total urinary 3-methoxytyramine, the O methylated product of dopamine, to these three established tumour markers. Methods Urinary 3-methoxytyramine, dopamine, homovanillic acid and 4-hydroxy-3 methoxymandelic acid were measured by high-performance liquid chromatography with electrochemical detection on consecutive urine samples from histologically proven neuroblastic patients and controls. Patients with neuroblastic disease were further classified as untreated, advancing, residual or absent disease based on clinical and radiological criteria. Receiver operating characteristic curve analysis was used to compare the diagnostic performance of the four tumour markers. Results Urinary 3-methoxytyramine was well correlated with established tumour markers and its concentration correlated with disease activity. It was the most commonly elevated tumour marker in neuroblastic disease and showed similar sensitivity to dopamine and homovanillic acid. The diagnostic utility of urinary 3-methoxytyramine as measured by area under the receiver operating characteristic curve was similar to dopamine and homovanillic acid. Conclusion Our results support the use of urinary 3-methoxytyramine as a tumour marker in the diagnosis and the monitoring of neuroblastoma disease. PMID- 27235705 TI - Concentrations of prealbumin and some appetite-controlling hormones in pregnancies associated with hyperemesis gravidarium. AB - Background Hyperemesis gravidarum, which affects 0.3-2.3% of pregnancies, is defined as excessive vomiting during pregnancy and usually starts in week 4 or 5 of gestation. Symptoms include weight loss, dehydration, ketonaemia, ketonuria, fasting acidosis, alkalosis due to hydrochloric acid loss and hypokalaemia and its exact cause is unknown. The present study was undertaken to investigate the relationship between prealbumin, ghrelin, nesfatin-1 and obestatin concentrations in pregnancies associated with hyperemesis gravidarum. Methods A total of 40 pregnant females with hyperemesis gravidarum and 38 pregnant females without hyperemesis gravidarum as controls were included in this study. Serum concentrations of prealbumin, ghrelin, obestatin and nesfatin-1 were measured. Results There were no significant differences in age, gestational week, gravidity and parity between the two groups. Body mass index was significantly lower in cases than in controls. Serum ghrelin and prealbumin concentrations were significantly lower in cases than in controls ( P <0.05 and P < 0.001, respectively). There was no significant difference in serum concentrations of obestatin and nesfatin-1 between the two groups. There was no significant association between body mass index and serum ghrelin, nesfatin-1, obestatin or prealbumin concentrations in patients with hyperemesis gravidarum. Conclusions Decreased serum concentrations of ghrelin and prealbumin in patients with hyperemesis gravidarum are independent of body mass index. Based on our results, we believe that ghrelin may be considered to play a role in the aetiopathogenesis of hyperemesis gravidarum and that hyperemesis gravidarum may result in disruption of the relationship between nesfatin-1 and ghrelin. In addition, we believe that the measurement of serum prealbumin may be used for assessing nutritional status in pregnancy. PMID- 27235706 TI - Carnosic acid induces proteasomal degradation of Cyclin B1, RB and SOX2 along with cell growth arrest and apoptosis in GBM cells. AB - BACKGROUND: Carnosic acid (CA) is a diterpenoid found in Rosmarinus officinalis L. and Salvia officinalis L. as well as in many other Lamiaceae. This compound is reported to have antioxidant and antimicrobial properties. In addition, a number of reports showed that CA has a cytotoxic activity toward several cancer cell lines. PURPOSE: The aim of this study was to establish whether CA has any specific antiproliferative effect toward human glioblastoma (GBM) cells and to analyze the molecular mechanisms involved. METHODS: We evaluated cell survival by MTT assay, apoptosis and DNA content by flow cytometry, protein expression and phosphorylation by immunoblot analyses. RESULTS: Our results showed that CA inhibited cell survival on both normal astrocytes and GBM cells. In GBM cells, in particular, CA caused an early G2 block, a reduction in the percentage of cells expressing Ki67, an enhanced expression of p21(WAF) and induced apoptosis. Furthermore, we showed that CA promoted proteasomal degradation of several substrate proteins, including Cyclin B1, retinoblastoma (RB), SOX2, and glial fibrillary acid protein (GFAP), whereas MYC levels were not modified. In addition, CA dramatically reduced the activity of CDKs. CONCLUSION: In conclusion, our findings strongly suggest that CA promotes a profound deregulation of cell cycle control and reduces the survival of GBM cells via proteasome-mediated degradation of Cyclin B1, RB and SOX2. PMID- 27235707 TI - Farrerol inhibited angiogenesis through Akt/mTOR, Erk and Jak2/Stat3 signal pathway. AB - BACKGROUND: Farrerol is one of traditional Chinese medicines, isolated from Rhododendron dauricum L. It has been reported that Farrerol exerts multiple biological activities. Angiogenesis is an important drug target for cancer and inflammation therapy, the effect of Farrerol on angiogenesis is unknown. HYPOTHESIS/PURPOSE: We aimed to investigate whether Farrerol may have inhibitory effects against angiogenesis. STUDY DESIGN/METHODS: Two kinds of endothelial cells, named human umbilical vein endothelia cell and human micro vessel endothelial cells, were used to examine the effect and mechanism of Farrerol on angiogenesis. MTT assay was used to detect cell proliferation, wound healing assay and boyden's chamber assay were used to examine cell migration, Matrigel was used as basement membrane substratum in tube formation assay, Annexin V FITC/PI dual staining assay and trypan blue staining were used to detect cell apoptosis, mouse aortic rings assay was performed as ex vivo assay, the expression of proteins involved in angiogenesis was tested using western blot, the binding of Farrerol to Stat3 was monitored by docking assay, molecular dynamics simulations and MM-GBSA method. RESULTS: Farrerol showed an inhibitory effect on proliferation, migration and tube formation of human umbilical vein endothelia cell and human micro vessel endothelial cells in a concentration dependent manner. Farrerol induced cell cycle arrest and increased the apoptotic percentage of endothelial cells. Farrerol also suppressed the formation of new micro vessels from mouse aortic rings. Moreover, Farrerol reduced the phosphorylation levels of Erk, Akt, mTOR, Jak2 and Stat3 as well as protein expression of Bcl-2 and Bcl-xl. Docking assay, molecular dynamics simulations and MM-GBSA method showed that Farrerol bound to domain of Stat3, Ser613,Gln635, Glu638 and Thr714 are the main residues in Farrerol binding sites with the binding free energy -7.3 ~ -9.0kcal/mol. CONCLUSIONS: In this study, we demonstrated that Farrerol inhibited angiogenesis through down regulation of Akt/mTOR, Erk and Jak2/Stat3 signal pathway. The inhibitory effect of Farrerol on angiogenesis suggested that this compound may be helpful to the angiogenesis related diseases treatment, such as cancer and inflammations. PMID- 27235708 TI - The effect of ethyl acetate extract from persimmon leaves on Alzheimer's disease and its underlying mechanism. AB - BACKGROUND: Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders characterized by neuronal loss in the brain and cognitive impairment. AD is now considered to be the third major cause of death in developed countries, after cardiovascular disease and cancer. Persimmon leaves are used as a popular folk medicine to treat hypertension, angina and internal haemorrhage in Cyangbhina, and it has been reported that ethyl acetate extract of persimmon leaves (EAPL) displays a potential therapeutic effect on neurodegenerative diseases. HYPOTHESIS/PURPOSE: This study was designed to investigate the effects of EAPL on AD, to clarify the possible mechanism by which EAPL exerts its beneficial effects and prevents AD, and to determine the major constituents involved. STUDY DESIGN: AD model was established by bilateral injection of Abeta1-42 into the hippocampus of rats. The cognitive performance was determined by the Morris water maze and step-down tests. Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), apoptosis, total and phosphorylated c-Jun NH2-terminal kinase (JNK/p-JNK), caspase-3, Bax and Bcl 2 were determined. In addition, a sensitive and reliable LC-QTOF-MS method was applied to identify the major compounds present in EAPL. RESULTS: EAPL at doses of 200mg/kg, 400mg/kg could markedly reduce the latency, significantly increase the time in the first quadrant and number of the target crossing times in Morris water maze test, markedly increase the latency and reduce the number of errors in the step-down test, significantly inhibit the reductions in SOD and GSH-Px activities, and increase the level of MDA. In addition, EAPL treatment attenuated neuronal apoptosis in the hippocampus, reduced the expression of p-JNK, caspase 3, and the relative ratio of Bax/Bcl-2. Meanwhile, 32 constituents were identified by LC-QTOF-MS/MS assays. CONCLUSION: The results indicate that EAPL has a potent protective effect on cognitive deficits induced by Abeta in rats and this effect appears to be associated with the regulation of the antioxidative defense system and the mechanism of mitochondrial-mediated apoptosis. Furthermore, analysis of the LC-MS data suggests that flavonoids and triterpenoids may be responsible for the potential biological effects of EAPL. PMID- 27235709 TI - Curcumin hampers the antitumor effect of vinblastine via the inhibition of microtubule dynamics and mitochondrial membrane potential in HeLa cervical cancer cells. AB - BACKGROUND: Curcumin, a major component of curry powder, which is a natural polyphenol product extracted from rhizoma curcumae longae, interacts with a specific binding site on microtubules. Vinblastine is an antitumor drug that induces microtubule depolymerization. PURPOSE: We investigated whether curcumin influences the antitumor effect of vinblastine in HeLa human cervical cancer cells. STUDY DESIGN: Changes in microtubule filaments were visualized by immuno staining. Cell death was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide(MTT) or water-soluble tetrazolium(WST) assay. Apoptotic cell formation was assessed by flow cytometry after staining cells with propidium iodide(PI) and/or Annexin V or with 6-diamidino-2-phenylindole(DAPI). Reactive oxygen species(ROS) were also measured by flow cytometry using dichloro dihydro-fluorescein diacetate(DCF-DA). JC-1 was used to determine mitochondrial membrane potential (MMP). RESULTS: When cells were pretreated with curcumin, microtubule filaments were disordered. Vinblastine-induced microtubule depolymerization and cell death were reduced in HeLa human cervical cancer cells pretreated with curcumin compared to the control. The decrease in cell death was much greater in cells pretreated with curcumin compared to cotreatment or post treatment. DNA condensation by vinblastine was also decreased in curcumin pretreated cells. Curcumin reduced ROS production by vinblastine. However, no changes in vinblastine-mediated microtubule depolymerization were detected upon N acetylcysteine(NAC) treatment. In contrast, vinblastine-induced MMP collapse was inhibited by pretreatment with curcumin or NAC. These findings suggest that vinblastine-induced tumor cell death might be inhibited by curcumin via ROS independent microtubule dynamics and ROS-dependent MMP collapse. It also suggests that microtubule dynamics could be necessary for the optimal antitumor activity of vinblastine. Our results suggest that patients treated with vinblastine should not consume curcumin. PMID- 27235710 TI - Protective effects of lupeol against mancozeb-induced genotoxicity in cultured human lymphocytes. AB - BACKGROUND: Lup-20(29)-en-3H-ol (Lupeol), a dietary pentacyclic triterpenoid has been shown to possess multiple medicinal activities including anti-inflammatory, anti-oxidant and anti-carcinogenic effects. Mancozeb is a widely used broad spectrum fungicide with well-known carcinogenic hazards in rodents. PURPOSE: The present study has been designed to investigate the protective effects of lupeol against mancozeb-induced genotoxicity and apoptosis in cultured human lymphocytes (CHLs). METHODS: The genotoxic effect of mancozeb was evaluated by chromosomal aberration and micronucleus assays. The cell cycle kinetics and intracellular reactive oxygen species (ROS) generation was measured by flow cytometry. The levels of anti-oxidant enzymes and lipid peroxidation (LPO) were estimated by enzymatic assays. The localization of p65NF-kappaB was measured by immunocytochemical analysis. The differential expression of genes associated with genotoxicity was measured by qRT-PCR. RESULTS: Mancozeb exposure (5ug/ml) for 24h caused significant induction of chromosomal aberrations (CAs) and micronuclei (MN) formation in CHLs. Pre-and post-treatment (25 and 50ug/ml) of lupeol for 24h significantly (p<0.05) reduced the frequency of CAs and MN induction, in a dose dependent manner in mancozeb treated CHLs. Concomitantly, lupeol pre-treatment for 24h significantly increased the levels of anti-oxidant enzymes, superoxide dismutase (SOD) and catalase and decreased ROS generation and LPO. Additionally, lupeol pre-treatment significantly reduced mancozeb-induced apoptosis as shown by Sub-G1 peak analysis and annexin V-PI assay, in a dose dependent manner. Moreover, pre-treatment with lupeol attenuated mancozeb-induced NF-kappaB activation in CHLs. Furthermore, the results of qRT-PCR showed that lupeol pre treatment significantly (p<0.05) decreased mancozeb-induced expression of DNA damage (p53, MDM2, COX-2, GADD45alpha and p21) and increased expression of DNA repair responsive genes (hOGG1 and XRCC1) in CHLs. CONCLUSION: Taken together, our findings suggest that lupeol could attenuate mancozeb-induced oxidative stress, which in turn could inhibit NF-kappaB activation and thus provide protection against mancozeb-induced genotoxicity and apoptosis. So, lupeol could be used as a potent anti-oxidant regimen against pesticide induced genotoxicity in agricultural farm workers. PMID- 27235712 TI - Berberine induces neuronal differentiation through inhibition of cancer stemness and epithelial-mesenchymal transition in neuroblastoma cells. AB - BACKGROUND: Berberine, a plant alkaloid, has been used since many years for treatment of gastrointestinal disorders. It also shows promising medicinal use against metabolic disorders, neurodegenerative disorders and cancer; however its efficacy in neuroblastoma (NB) is poorly explored. HYPOTHESIS: EMT is important in cancer stemness and metastasis resulting in failure to differentiate; thus targeting EMT and related pathways can have clinical benefits. STUDY DESIGN: Potential of berberine was investigated for (i) neuronal differentiation and cancer stemness inhibition, (ii) underlying molecular mechanisms regulating cancer-stemness and (iii) EMT reversal. METHODS: Using neuro2a (N2a) neuroblastoma cells (NB); we investigated effect of berberine on neuronal differentiation, cancer-stemness, EMT and underlying signalling by immunofluorescence, RT-PCR, Western blot. High glucose-induced TGF-beta mediated EMT model was used to test EMT reversal potential by Western blot and RT-PCR. STRING analysis was done to determine and validate functional protein-interaction networks. RESULTS: We demonstrate berberine induces neuronal differentiation accompanying increased neuronal differentiation markers like MAP2, beta-III tubulin and NCAM; generated neurons were viable. Berberine attenuated cancer stemness markers CD133, beta-catenin, n-myc, sox2, notch2 and nestin. Berberine potentiated G0/G1 cell cycle arrest by inhibiting proliferation, cyclin dependent kinases and cyclins resulting in apoptosis through increased bax/bcl-2 ratio. Restoration of tumor suppressor proteins, p27 and p53, indicate promising anti cancer property. The induction of NCAM and reduction in its polysialylation indicates anti-migratory potential which is supported by down regulation of MMP 2/9. It increased epithelial marker laminin and smad and increased Hsp70 levels also suggest its protective role. Molecular insights revealed that berberine regulates EMT via downregulation of PI3/Akt and Ras-Raf-ERK signalling and subsequent upregulation of p38-MAPK. TGF-beta secretion from N2a cells was potentiated by high glucose and negatively regulated by berberine through modulation of TGF-beta receptors II and III. Berberine reverted mesenchymal markers, vimentin and fibronectin, with restoration of epithelial marker E cadherin, highlighting the role of berberine in reversal of EMT. CONCLUSION: Collectively, the study demonstrates prospective use of berberine against neuroblastoma as elucidated through inhibition of fundamental characteristics of cancer stem cells: tumorigenicity and failure to differentiation and instigates reversal in the EMT. PMID- 27235711 TI - Apoptotic effect of eugenol envolves G2/M phase abrogation accompanied by mitochondrial damage and clastogenic effect on cancer cell in vitro. AB - BACKGROUND: Eugenol (EUG) is a major phenolic compound present in clove whose anti-cancer properties have been demonstrated previously. These anti-cancer properties may involves the modulation of different mechanisms, including alpha estrogen receptor (alphaER) in luminal breast cancer cells, COX-2 inhibition in melanoma cells or p53 and caspase-3 activation in colon cancer cells. HYPOTHESIS: EUG promotes a burst in ROS production causing cell-cycle perturbations, mitochondria toxicity and clastogenesis triggering apoptosis in melanoma breast- and cervix-cancer cells in vitro. METHODS: Morphological changes were evaluated through the light- and electronic- microscopy. Cell-cycle, ROS, PCNA and Apoptosis was detected by flow cytometry and clastogenicity was evaluated by Comet-assay. RESULTS: The results obtained herein pointed out that EUG promotes, increasing ROS production leading to abrogation of G2/M of phase of cell-cycle, and consecutively, clastogenesis in vitro. In addition, EUG induces Proliferation Cell Nuclear Antigen (PCNA) downregulation and decreasing in mitochondria potential (DeltaPsim). Of note, a Bax up-regulation was also observed on cells treated with EUG. All of these findings cooperate in order to induce apoptosis in cancer cells. CONCLUSION: These promising results presented herein shed new light on the mechanisms of action of EUG suggesting a possible applicability of this phenylpropanoid as adjuvant in anti-cancer therapy. PMID- 27235713 TI - Latex protein extracts from Calotropis procera with immunomodulatory properties protect against experimental infections with Listeria monocytogenes. AB - BACKGROUND: The latex from the medicinal plant Calotropis procera is often used in folk medicine against infectious and inflammatory diseases. PURPOSE: In this study, we investigate a protein fraction with immunomodulatory properties, named LPPI, against experimental infections, in vitro and in vivo, with a virulent strain of Listeria monocytogenes. STUDY DESIGN: LPPI was exposed to cultured macrophages or Swiss mice and then challenged with L. monocytogenes. METHODS: Peritoneal macrophages were obtained from Swiss mice, and cultured in 96-well microplates. Soluble latex proteins (LP) were subjected to fractionation by ion exchange chromatography. The major peak (LPPI) was added into wells at 10 or 100ug/ml. Albumin (100ug/ml) was used for comparison between protein treatments. After incubation for 1h at 5% CO2/ 37 degrees C, the supernatant was discarded and 0.2ml of L. monocytogenes overnight culture was added in the wells. Following 4h and 24h infection, the cytokine mRNA expression was evaluated as well as the number of intracellular colony forming units. Swiss mice (n=16) were injected intraperitoneally (i.p.) with LPPI (5 and 10mg/kg) while the control mice received albumin (10mg/kg) or LP (10mg/kg). After 24h, all animal groups were challenged with L. monocytogenes (10(6) CFU/ ml), also by i.p. route. RESULTS: LPPI was not toxic to uninfected macrophages (pMO) and significantly increased mRNA expression of TNF-alpha, IL-6, IL-1beta and iNOS. Following infection, cell viability was reduced by 50% in albumin-treated pMO (control); but only 17% in pMO treated with LPPI at 100ug/ml. In this case, LPPI increased expression of TNF alpha and IL-6 whereas the number of bacterial colony-forming units was reduced 100-fold in comparison to control groups. Swiss mice pretreated with LPPI showed dose-dependent survival rates that reached 80%, while mice that received albumin died 1-3 days after infection. After 24h infection, leukocyte migration to the infectious foci was high in LPPI-treated mice whereas the number of viable bacteria in the peritoneal fluid, liver and bloodstream were significantly reduced. CONCLUSION: We conclude that LPPI present immunomodulatory properties that are beneficial for prevention of systemic bacterial infections caused by the intracellular bacteria L. monocytogenes. PMID- 27235715 TI - Postischemic fish oil treatment restores long-term retrograde memory and dendritic density: An analysis of the time window of efficacy. AB - We reported that fish oil (FO) prevented the loss of spatial memory caused by transient, global cerebral ischemia (TGCI), provided the treatment covered the first days prior to and after ischemia. Continuing these studies, trained rats were subjected to TGCI, and FO was administered for 10days, with a time window of efficacy (TWE) of 4, 8 or 12h post-ischemia. Retrograde memory was assessed up to 43days after TGCI. In another experiment, ischemic rats received FO with a 4- or 12-h TWE, and dendritic density was assessed in the hippocampus and cerebral cortex. The brain lipid profile was evaluated in sham-operated and ischemic rats that were treated with FO or vehicle with a 4-h TWE. Ischemia-induced retrograde amnesia was prevented by FO administration that was initiated with either a 4- or 8-h TWE. Fish oil was ineffective after a 12-h TWE. Independent of the TWE, FO did not prevent ischemic neuronal death. In the hippocampus, but not cerebral cortex, TGCI-induced dendritic loss was prevented by FO with a 4-h TWE but not 12 h TWE. The level of docosahexaenoic acid almost doubled in the hippocampus in ischemic, FO-treated rats (4-h TWE). The data indicate that (i) the anti-amnesic effect of FO can be observed with a TWE of up to 8h, (ii) the stimulation of dendritic neuroplasticity may have contributed to this effect, and (iii) DHA in FO may be the main active constituent in FO that mediates the cognitive and neuroplasticity effects on TGCI. PMID- 27235714 TI - The anatomy of empathy: Vicarious experience and disorders of social cognition. AB - Empathy, the ability to vicariously experience and to understand the affect of other people, is fundamental for successful social-cognitive ability and behaviour. Empathy is thought to be a critical facilitator of prosocial behaviour and is disrupted in a number of psychiatric and neurological disorders. Research has begun to uncover the neural basis of such 'vicarious experience', which has been studied as a proxy measure of empathy. Together, these studies have identified portions of the insula and anterior cingulate cortex as critically involved. A key debate is whether overlapping or non-overlapping brain areas respond to personal and vicarious experience. This review will highlight emerging evidence for both types of brain response. Importantly, animal models have suggested that there are central divisions between the anterior cingulate gyrus and anterior cingulate sulcus that may be crucial for understanding social behaviour. Attention to this specific anatomy of vicarious processing could therefore help shed light on the functional profile of empathy. Studies in individuals with psychopathy and autism spectrum disorders have found that vicarious experience is atypical. However, the precise nature of these atypicalities is mixed. Understanding the mechanisms of vicarious experience can enhance our knowledge of the neural basis of empathy and, ultimately, help those with disorders of social cognition and behaviour. PMID- 27235716 TI - Subdural hematoma decompression model: A model of traumatic brain injury with ischemic-reperfusional pathophysiology: A review of the literature. AB - The prognosis for patients with traumatic brain injury (TBI) with subdural hematoma (SDH) remains poor. In accordance with an increasing elderly population, the incidence of geriatric TBI with SDH is rising. An important contributor to the neurological injury associated with SDH is the ischemic damage which is caused by raised intracranial pressure (ICP) producing impaired cerebral perfusion. To control intracranial hypertension, the current management consists of hematoma evacuation with or without decompressive craniotomy. This removal of the SDH results in the immediate reversal of global ischemia accompanied by an abrupt reduction of mass lesion and an ensuing reperfusion injury. Experimental models can play a critical role in improving our understanding of the underlying pathophysiology and in exploring potential treatments for patients with SDH. In this review, we describe the epidemiology, pathophysiology and clinical background of SDH. PMID- 27235717 TI - The ibrutinib B-cell proliferation inhibition is potentiated in vitro by dexamethasone: Application to chronic lymphocytic leukemia. AB - New B-cell receptor-targeted therapies such as ibrutinib, a Bruton tyrosine kinase inhibitor, are now proposed for lymphoid pathologies. The putative benefits of its combination with glucocorticoids were evaluated here. We compared the effects of dexamethasone (DXM), ibrutinib and their in vitro combination on proliferation and metabolic stress markers in stimulated normal B-lymphocytes and in malignant lymphocytes from chronic lymphocytic leukemia (CLL) patients. In both cellular models, cell cycle progression was globally inhibited by DXM and/or ibrutinib. This inhibition was significantly amplified by DXM addition to ibrutinib and was related to a significant decrease in the expression of the cell cycle regulatory proteins CDK4 and cyclin E. Apoptosis increased especially with DXM/ibrutinib combination and was associated with a significant decrease in Mcl-1 expression. Treatment effects on metabolic stress were evaluated by DNA damage recognition after 53BP1 foci labeling. The percentage of cells with more than five 53BP1 foci decreased significantly with ibrutinib in normal and CLL lymphocytes. This decrease was strongly reinforced, in CLL, by DXM addition. Our data indicated that, in vitro, DXM potentiated antiproliferative effects of ibrutinib and decreased DNA damage in lymphoid B-cells. Thus their combination may be proposed for CLL treatment. PMID- 27235718 TI - Prenatal screening for fetal aneuploidy: time to examine where we are and where we are going. PMID- 27235719 TI - Inflammatory intracellular pathways activated by electronegative LDL in monocytes. AB - AIMS: Electronegative LDL (LDL(-)) is a plasma LDL subfraction that induces cytokine release in monocytes through toll-like receptor 4 (TLR4) activation. However, the intracellular pathways induced by LDL(-) downstream TLR4 activation are unknown. We aimed to identify the pathways activated by LDL(-) leading to cytokine release in monocytes. METHODS AND RESULTS: We determined LDL(-)-induced activation of several intracellular kinases in protein extracts from monocytes using a multikinase ELISA array. LDL(-) induced higher p38 mitogen-activated protein kinase (MAPK) phosphorylation than native LDL. This was corroborated by a specific cell-based assay and it was dependent on TLR4 and phosphoinositide 3 kinase (PI3k)/Akt pathway. P38 MAPK activation was involved in cytokine release promoted by LDL(-). A specific ELISA showed that LDL(-) activated cAMP response element binding (CREB) in a p38 MAPK dependent manner. P38 MAPK was also involved in the nuclear factor kappa-B (NF-kB) and activating protein-1 (AP-1) activation by LDL(-). We found that NF-kB, AP-1 and CREB inhibitors decreased LDL(-)-induced cytokine release, mainly on MCP1, IL6 and IL10 release, respectively. CONCLUSIONS: LDL(-) promotes p38 MAPK phosphorylation through TLR4 and PI3k/Akt pathways. Phosphorylation of p38 MAPK is involved in NF-kB, AP-1 and CREB activation, leading to LDL(-)-induced cytokine release in monocytes. PMID- 27235720 TI - Is computational modeling adding value for understanding the Heart? PMID- 27235721 TI - Hidden heterogeneity of transcription factor binding sites: A case study of SF-1. AB - Steroidogenic factor 1 (SF-1) belongs to a small group of the transcription factors that bind DNA only as a monomer. Three different approaches-Sitecon, SiteGA, and oPWM-constructed using the same training sample of experimentally confirmed SF-1 binding sites have been used to recognize these sites. The appropriate prediction thresholds for recognition models have been selected. Namely, the thresholds concordant by false positive or negative rates for various methods were used to optimize the discrimination of steroidogenic gene promoters from the datasets of non-specific promoters. After experimental verification, the models were used to analyze the ChIP-seq data for SF-1. It has been shown that the sets of sites recognized by different models overlap only partially and that an integration of these models allows for identification of SF-1 sites in up to 80% of the ChIP-seq loci. The structures of the sites detected using the three recognition models in the ChIP-seq peaks falling within the [-5000, +5000] region relative to the transcription start sites (TSS) extracted from the FANTOM5 project have been analyzed. The MATLIGN classified the frequency matrices for the sites predicted by oPWM, Sitecon, and SiteGA into two groups. The first group is described by oPWM/Sitecon and the second, by SiteGA. Gene ontology (GO) analysis has been used to clarify the differences between the sets of genes carrying different variants of SF-1 binding sites. Although this analysis in general revealed a considerable overlap in GO terms for the genes carrying the binding sites predicted by oPWM, Sitecon, or SiteGA, only the last method elicited notable trend to terms related to negative regulation and apoptosis. The results suggest that the SF-1 binding sites are different in both their structure and the functional annotation of the set of target genes correspond to the predictions by oPWM+Sitecon and SiteGA. Further application of Homer software for de novo identification of enriched motifs in ChIP-Seq data for SF-1ChIP-seq dataset gave the data similar to oPWM+Sitecon. PMID- 27235722 TI - Cancer cell specific cytotoxic effect of Rhoeo discolor extracts and solvent fractions. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Traditional or folk medicine has led to the discovery of important bioactive substances used in several health-related areas. Phytochemicals in Rhoeo discolor (R. discolor) extracts have proven to have important cancer cell specific cytotoxic activity. In the present research, we determined the cytotoxic effect of extracts of R. discolor, a plant commonly used in Mexico for both medicinal and ornamental purposes. AIM OF THE STUDY: We evaluated the cytotoxic effects against three representative human cancer cell lines: HT-29 colon cancer, Hep-G2 liver cancer and PC-3 prostate cancer cell lines, as well as a control fibroblast cell line NIH 3T3. MATERIALS AND METHODS: Ten different crude extracts were tested along with fractions derived from the five most bioactive crude extracts. Analytical data, HPLC-MS-TOF, revealed a high content of phenolic compounds such as anthocyanins, ferulic, vanillic, chlorogenic and p-coumaric acid in the extracts. Phenolic compounds have previously been reported as health beneficial with antioxidant and potential cancer specific cytotoxic effects. RESULTS: Studies revealed that low concentrations of these crude bioactive extracts (10ug/ml) and their fractions (50ug/ml) were effective as cancer specific cytotoxic agents, since they caused a significant proliferation inhibition on cancer cell lines (up to 94.2% in HT-29, 92.9% in Hep-G2 and 61.8% in PC-3 of apoptosis induction) with little harm to the control cell line (no higher than 28.3% apoptosis induction), and, importantly, the most effective extracts were mainly water, methanol and ethanol based. CONCLUSIONS: These results suggest that a diet containing these compounds may function as a medical aid or chemoprotective. PMID- 27235723 TI - Proteome of Plasmopara viticola-infected Vitis vinifera provides insights into grapevine Rpv1/Rpv3 pyramided resistance to downy mildew. AB - : Grapevine is one of the major fruit crops worldwide and requires phytochemical use due to susceptibility to numerous pests, including downy mildew. The pyramiding of previous identified QTL resistance regions allows selection of genotypes with combined resistance loci in order to build up sustainable resistance. This study investigates resistance response of pyramided plants containing Rpv1 and Rpv3 loci to Plasmopara viticola infection process. Phenotypic characterization showed complete resistance and lack of necrotic hypersensitive response spots. Principal Component Analysis revealed infected 96hpi (hours post-inoculation) samples with the most distant proteomes of the entire dataset, followed by the proteome of infected 48hpi samples. Quantitative and qualitative protein differences observed using 2-DE gels coupled to nanoHPLC ESI-MS/MS analysis showed a lack of transient breakdown in defense responses (biphasic modulation) accompanying the onset of disease. Forty-one proteins were identified, which were mainly included into functional categories of redox and energy metabolism. l-ascorbate degradation pathway was the major altered pathway and suggests up-regulation of anti-oxidant metabolism in response to apoplastic oxidative burst after infection. Overall, these data provide new insights into molecular basis of this incompatible interaction and suggests several targets that could potentially be exploited to develop new protection strategies against this pathogen. BIOLOGICAL SIGNIFICANCE: This study provide new insights into the molecular basis of incompatible interaction between Plasmopara viticola and pyramided Rpv1/Rpv3 grapevine and suggests several targets that could potentially be exploited to develop new protection strategies against this pathogen. This is the first proteomic characterization of resistant grapevine available in the literature and it presents contrasting proteomic profiles of that of susceptible plants. The resistance against downy mildew in grapevine has been a long sought and the availability of resistance loci is of major importance. This is the first molecular characterization of resistance provided by Rpv1 and Rpv3 genes. PMID- 27235724 TI - Proteomics offers insight to the mechanism behind Pisum sativum L. response to pea seed-borne mosaic virus (PSbMV). AB - : Pea seed-borne mosaic virus (PSbMV) significantly reduces yields in a broad spectra of legumes. The eukaryotic translation initiation factor has been shown to confer resistance to this pathogen, thus implying that translation and proteome dynamics play a role in resistance. This study presents the results of a proteome-wide analysis of Pisum sativum L. response to PSbMV infection. LC-MS profiling of two contrasting pea cultivars, resistant (B99) and susceptible (Raman) to PSbMV infection, detected >2300 proteins, 116 of which responded to PSbMV ten and/or twenty days post-inoculation. These differentially abundant proteins are involved in number of processes that have previously been reported in the plant-pathogen response, including protein and amino acid metabolism, stress signaling, redox homeostasis, carbohydrate metabolism, and lipid metabolism. We complemented our proteome-wide analysis work with targeted analyses of free amino acids and selected small molecules, fatty acid profiling, and enzyme activity assays. Data from these additional experiments support our findings and validate the biological relevance of the observed proteome changes. We found surprising similarities in the resistant and susceptible cultivars, which implies that a seemingly unaffected plant, with no detectable levels of PSbMV, actively suppresses viral replication. BIOLOGICAL SIGNIFICANCE: Plant resistance to PSbMV is connected to translation initiation factors, yet the processes involved are still poorly understood at the proteome level. To the best of our knowledge, this is the first survey of the global proteomic response to PSbMV in plants. The combination of label-free LC-MS profiling and two contrasting cultivars (resistant and susceptible) provided highly sensitive snapshots of protein abundance in response to PSbMV infection. PSbMV is a member of the largest family of plant viruses and our results are in accordance with previously characterized potyvirus-responsive proteomes. Hence, the results of this study can further extend our knowledge about these pathogens. We also show that even though no viral replication is detected in the PSbMV-resistant cultivar B99, it is still significantly affected by PSbMV inoculation. PMID- 27235725 TI - Utility of C-peptide for a reliable estimate of insulin secretion in children with growth hormone deficiency. AB - OBJECTIVE: GH treatment (GHT) can lead to glucose metabolism impairment through decreased insulin sensitivity and impaired pancreatic beta-cell function, which are the two key components of the pathogenesis of diabetes. Therefore, in addition to insulin sensitivity, during GHT it is very important to perform a reliable evaluation of insulin secretion. However, conflicting data exist regarding the insulin secretion in children during GHT. C-peptide provides a more reliable estimate of beta-cell function than insulin, but few studies evaluated it during GHT. Our aim was to assess the usefulness of C-peptide in the evaluation of insulin secretion in GH deficiency (GHD) children. DESIGN: In 48 GHD children, at baseline and after 12 and 24months of GHT, and in 56 healthy subjects we evaluated fasting and glucagon-stimulated (AUCCpep) C-peptide levels in addition to other commonly used secretion indexes, such as fasting and oral glucose tolerance test-stimulated insulin levels (AUCINS), Homa-beta, and insulinogenic index. The main outcomes were the change in C-peptide during GHT and its correlation with the auxological and hormonal parameters. RESULTS: At baseline GHD children showed a significant lower AUCCpep (p=0.006), while no difference was found for the other indexes. Both fasting C-peptide (beta 0.307, p=0.016) and AUCCpep (beta 0.379, p=0.002) were independently correlated with IGF I SDS, while no correlation was found for all other indexes. After 12months an increase in Homa-beta (p<0.001), fasting C-peptide (p=0.002) and AUCCpep (p<0.001) was found. At multivariate analysis, only fasting C-peptide (beta 0.783, p=0.001) and AUCCpep (beta 0.880, p<0.001) were independently correlated with IGF-I SDS. CONCLUSIONS: C-peptide, rather than the insulin-derived indexes, has proved to be the most useful marker of insulin secretion correlated to IGF-I levels in GHD children. Therefore, we suggest the use of glucagon test both as diagnostic test for the GH assessment and as a useful tool for the evaluation of insulin secretion during GHT in children. PMID- 27235726 TI - Overexpression of RANKL in osteoblasts: a possible mechanism of susceptibility to bone disease in cystic fibrosis. AB - Bone fragility and loss are a significant cause of morbidity in patients with cystic fibrosis (CF), and the lack of effective therapeutic options means that treatment is more often palliative rather than curative. A deeper understanding of the pathogenesis of CF-related bone disease (CFBD) is necessary to develop new therapies. Defective CF transmembrane conductance regulator (CFTR) protein and chronic inflammation in bone are important components of the CFBD development. The receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) drive the regulation of bone turnover. To investigate their roles in CFBD, we evaluated the involvement of defective CFTR in their production level in CF primary human osteoblasts with and without inflammatory stimulation, in the presence or not of pharmacological correctors of the CFTR. No major difference in cell ultrastructure was noted between cultured CF and non-CF osteoblasts, but a delayed bone matrix mineralization was observed in CF osteoblasts. Strikingly, resting CF osteoblasts exhibited strong production of RANKL protein, which was highly localized at the cell membrane and was enhanced in TNF (TNF-alpha) or IL-17-stimulated conditions. Under TNF stimulation, a defective response in OPG production was observed in CF osteoblasts in contrast to the elevated OPG production of non-CF osteoblasts, leading to an elevated RANKL-to-OPG protein ratio in CF osteoblasts. Pharmacological inhibition of CFTR chloride channel conductance in non-CF osteoblasts replicated both the decreased OPG production and the enhanced RANKL-to-OPG ratio. Interestingly, using CFTR correctors such as C18, we significantly reduced the production of RANKL by CF osteoblasts, in both resting and TNF-stimulated conditions. In conclusion, the overexpression of RANKL and high membranous RANKL localization in osteoblasts are related to defective CFTR, and may worsen bone resorption, leading to bone loss in patients with CF. Targeting osteoblasts with CFTR correctors may represent an effective strategy to treat CFBD. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 27235728 TI - Protective effect of mesoporous silica particles on encapsulated folates. AB - Mesoporous silica particles (MSPs) are considered suitable supports to design gated materials for the encapsulation of bioactive molecules. Folates are essential micronutrients which are sensitive to external agents that provoke nutritional deficiencies. Folates encapsulation in MSPs to prevent degradation and to allow their controlled delivery is a promising strategy. Nevertheless, no information exists about the protective effect of MSPs encapsulation to prevent their degradation. In this work, 5-formyltetrahydrofolate (FO) and folic acid (FA) were entrapped in MSPs functionalized with polyamines, which acted as pH dependent molecular gates. The stability of free and entrapped vitamins after acidic pH, high temperature and light exposure was studied. The results showed the degradation of FO after high temperature and acidic pH, whereas entrapped FO displayed enhanced stability. Free FA was degraded by light, but MSPs stabilized the vitamin. The obtained results point toward the potential use of MSPs as candidates to enhance stability and to improve the bioavailability of functional biomolecules. PMID- 27235727 TI - PLGA nanoparticles modified with a TNFalpha mimicking peptide, soluble Leishmania antigens and MPLA induce T cell priming in vitro via dendritic cell functional differentiation. AB - Poly(lactide-co-glycolide) nanoparticles (PLGA NPs) represent a new approach for vaccine delivery due to their ability to be taken up by phagocytes and to activate immune responses. In the present study PLGA NPs were surface-modified with a TNFalpha mimicking peptide, and encapsulated soluble Leishmania antigens (sLiAg) and MPLA adjuvant. The synthesized PLGA NPs exhibited low cytotoxicity levels, while surface-modified NPs were more efficiently taken up by dendritic cells (DCs). The prepared nanoformulations induced maturation and functional differentiation of DCs by elevating co-stimulatory molecule levels and stimulating IL-12 and IL-10 production. Sensitized DCs promoted T cell priming, characterized by the development of mixed T cell subsets differentiation expressing Th lineage-specific transcriptional factors and cytokine genes. Moreover, PLGA NPs were biocompatible, while they were located in lymphoid organs and taken up by phagocytic cells. Our results suggest that surface-modified PLGA NPs encapsulating sLiAg and MPLA could be considered as an effective vaccine candidate against leishmaniasis. PMID- 27235729 TI - Acid-labile pHPMA modification of four-arm oligoaminoamide pDNA polyplexes balances shielding and gene transfer activity in vitro and in vivo. AB - We report novel pH-reversibly surface-shielded polyplexes with enhanced gene transfer activity upon systemic administration. A four-arm-structured sequence defined cationic oligomer KK[HK[(H-Sph-K)3HC]2]2 was designed and synthesized on solid-phase, containing additional lysine residues not only for improved pDNA polyplex stability, but also providing attachment points for subsequent polyplex functionalization with amine-reactive shielding polymers. Herein, the surface of polyplexes was shielded with hydrophilic polymers, monovalent PEG or monovalent and multivalent pHPMA, optionally attached to the polyplex via the acid-labile linker AzMMMan. Overall, surface modification with PEG or pHPMA resulted in a decrease in the zeta potential of polyplexes, consistent with the degree of surface shielding. At pH 6.0, only polyplexes modified via the acid-labile linkage showed an increase in zeta potential, consistent with a "deshielding" in acidic environment, expected as beneficial for endosomal escape. Shielding was more efficient for multivalent pHPMA (20kDa, 30kDa) as compared to monovalent pHPMA (10kDa, 20kDa, 30kDa) or PEG (5kDa). In vitro transfection studies revealed higher gene expression by the polyplexes with the acid-labile shield as compared to their irreversibly shielded counterparts. Intravenous administration of AzMMMan-pHPMA modified polyplexes in an in vivo tumor mouse model mediated enhanced gene expression in the subcutaneous tumor and reduced undesirable expression in the liver. PMID- 27235730 TI - Antioxidant activities of polysaccharides obtained from Chlorella pyrenoidosa via different ethanol concentrations. AB - An ultrasonic-assisted extraction of Chlorella pyrenoidosa polysaccharides (CPP) was carried out using different concentrations of ethanol for precipitation, and named as CPP60, CPP70 and CPP85, respectively. The monosaccharide composition of each polysaccharide (CPP) was determined using gas chromatography (GC) and the antioxidant activity of each was investigated via the reducing power and scavenging activity of hydroxyl radicals, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals and superoxide anion radicals, respectively. All of the polysaccharides examined possessed antioxidant activity in vitro. CPP70 exhibited stronger scavenging activity against superoxide, DPPH and hydroxyl radicals, when compared with CPP60 and CPP85. This suggests that polysaccharides from C. pyrenoidosa precipitated by a final ethanol concentration of 70%, have the potential to be developed as natural antioxidants for use in food and pharmaceuticals. PMID- 27235731 TI - Characterization and biotechnological application of recombinant xylanases from Aspergillus nidulans. AB - Two xylanases from Aspergillus nidulans, XlnB and XlnC, were expressed in Pichia pastoris, purified and characterized. XlnB and XlnC achieved maximal activities at 60 degrees C and pH 7.5 and at 50 degrees C and pH 6.0, respectively. XlnB showed to be very thermostable by maintaining 50% of its original activity after 49h incubated at 50 degrees C. XlnB had its highest activity against wheat arabinoxylan while XlnC had the best activity against beechwood xylan. Both enzymes were completely inhibited by SDS and HgCl2. Xylotriose at 1mg/ml also totally inibited XlnB activity. TLC analysis showed that the main product of beechwood xylan hydrolysis by XlnB and XlnC was xylotetraose. An additive effect was shown between XlnB and XlnC and the xylanases of two tested commercial cocktails. Sugarcane bagasse saccharification results showed that these two commercial enzymatic cocktails were able to release more glucose and xylose after supplementation with XlnB and XlnC. PMID- 27235732 TI - A bimetallic nanocomposite modified genosensor for recognition and determination of thalassemia gene. AB - The main roles of DNA in the cells are to maintain and properly express genetic information. It is important to have analytical methods capable of fast and sensitive detection of DNA damage. DNA hybridization sensors are well suited for diagnostics and other purposes, including determination of bacteria and viruses. Beta thalassemias (betath) are due to mutations in the beta-globin gene. In this study, an electrochemical biosensor which detects the sequences related to the beta-globin gene issued from real samples amplified by polymerase chain reaction (PCR) is described for the first time. The biosensor relies on the immobilization of 20-mer single stranded oligonucleotide (probe) related to betath sequence on the carbon paste electrode (CPE) modified by 15% silver (Ag) and platinum (Pt) nanoparticles to prepare the bimetallic nanocomposite electrode and hybridization of this oligonucleotide with its complementary sequence (target). The extent of hybridization between the probe and target sequences was shown by using linear sweep voltammetry (LSV) with methylene blue (MB) as hybridization indicator. The selectivity of sensor was investigated using PCR samples containing non complementary oligonucleotides. The detection limit of biosensor was calculated about 470.0pg/MUL. PMID- 27235734 TI - Alzheimer's disease: Is this a brain specific diabetic condition? AB - Alzheimer's disease (AD) and type 2 diabetes (T2DM) are the two major health issues affecting millions of elderly people worldwide, with major impacts in the patient's daily life. Numerous studies have demonstrated that patients with diabetes have an increased risk of developing AD compared with healthy individuals. The principal biological mechanisms that associate with the progression of diabetes and AD are not completely understood. Impaired insulin signaling, uncontrolled glucose metabolism, oxidative stress, abnormal protein processing, and the stimulation of inflammatory pathways are common features to both AD and T2DM. In recent years brain specific abnormalities in insulin and insulin like growth factor (IGF) signaling considered as a major trigger involved in the etiopathogenesis of AD, showing T2DM like milieu. This review summarizes the pathways that might link diabetes and AD and the effect of diminished insulin. PMID- 27235733 TI - Methylglyoxal can mediate behavioral and neurochemical alterations in rat brain. AB - Diabetes is associated with loss of cognitive function and increased risk for Alzheimer's disease (AD). Advanced glycation end products (AGEs) are elevated in diabetes and AD and have been suggested to act as mediators of the cognitive decline observed in these pathologies. Methylglyoxal (MG) is an extremely reactive carbonyl compound that propagates glycation reactions and is, therefore, able to generate AGEs. Herein, we evaluated persistent behavioral and biochemical parameters to explore the hypothesis that elevated exogenous MG concentrations, induced by intracerebroventricular (ICV) infusion, lead to cognitive decline in Wistar rats. A high and sustained administration of MG (3MUmol/MUL; subdivided into 6days) was found to decrease the recognition index of rats, as evaluated by the object-recognition test. However, MG was unable to impair learning-memory processes, as shown by the habituation in the open field (OF) and Y-maze tasks. Moreover, a single high dose of MG induced persistent alterations in anxiety related behavior, diminishing the anxiety-like parameters evaluated in the OF test. Importantly, MG did not alter locomotion behavior in the different tasks performed. Our biochemical findings support the hypothesis that MG induces persistent alterations in the hippocampus, but not in the cortex, related to glyoxalase 1 activity, AGEs content and glutamate uptake. Glial fibrillary acidic protein and S100B content, as well as S100B secretion (astroglial-related parameters of brain injury), were not altered by ICV MG administration. Taken together, our data suggest that MG interferes directly in brain function and that the time and the levels of exogenous MG determine the different features that can be seen in diabetic patients. PMID- 27235735 TI - Coconut and sunflower oil ratios in ice cream influence subsequent food selection and intake. AB - The effect of coconut oil (CO, containing mainly medium chain triglycerides - MCTs) and sunflower oil (SO, containing mainly long chain triglycerides - LCTs) used as fat source (10% fat ice cream) in different ratios (25% CO and 75% SO - 25CO:75SO, 50% CO and 50% SO - 50CO:50SO, 75% CO and 25% SO - 75CO:25SO) was investigated to assess differences in appetite and ad-libitum (evening and snack) food intake using a single blind design. 36 healthy female participants consumed a fixed portion (150g) of ice cream 45min before an ad-libitum dinner and snacks. Appetite sensations were tracked across the day. Participants ate significantly less fat after 75CO:25SO than 25CO:75SO (p=0.007) and there was also a trend for lower fat intake in this condition as compared to 50CO:50SO (p=0.068). High fat savoury snack intake significantly decreased after 75CO:25SO in comparison with both 25CO:75SO (p=0.038) and 50CO:50SO (p=0.008). Calorie intake from snacks was also found to be significantly lower after 25CO:75SO and 50CO:50SO than 75CO:25SO (p=0.021 and 0.030 respectively). There was no effect of condition on appetite or desire ratings over the day. Eating a standard portion of ice cream containing different ratios of MCTs and LCTs can modestly influence acute food selection and intake, with MCTs manifesting their effect earlier and LCTs later due to differences in the absorption and metabolism of these lipids. However, the differences evident in the present study were small, and require further research before firm conclusions can be drawn. PMID- 27235736 TI - Color perception influences microhabitat selection of refugia and affects monitoring success for a cryptic anuran species. AB - Perceptual-biases are important for understanding an animal's natural history, identifying potential ecological traps, and for developing effective means to monitor individuals and populations. Despite research demonstrating anurans having a positive phototactic response towards blue colors, we do not yet understand if color cues are used functionally beyond sexual selection. The aim of our study was to determine if color cues are used in selecting microhabitat, and if anuran's blue-positive phototactic response could increase selection of artificial PVC refugia used to monitor cryptic camouflaging anuran species. We captured 32 Cope's Gray Treefrogs and placed them in mesh enclosures with three PVC tubes painted blue, brown, and white. Concurrently, we placed blue, brown, or unpainted white PVC tubes in stratified arrays around a treefrog breeding pond, and counted the number of occasions treefrogs occupied different colored PVC tubes. In the confined choice experiment, treefrogs selected blue tubes (48.3%) significantly more often than brown (28.5%) or white (23.2%) tubes. Our field experiment mirrored these findings (52.0% of capture events in blue, 29.0% in brown, and 19.0% in unpainted white tubes). Our results suggest color influences Cope's Gray Treefrog microhabitat selection, and they utilize color vision when choosing refugia. We demonstrate simple, small changes based on perceptual-biases can induce behaviors that may in turn have large impacts on sampling techniques used in monitoring and inventorying. Incorporating non-traditional physiological measures into animal inventorying and monitoring programs can be used in the future to improve conservation efforts. PMID- 27235737 TI - Components of Motor Deficiencies in ADHD and Possible Interventions. AB - There is a growing body of evidence pointing at several types of motor abnormalities found in attention-deficit/hyperactivity disorder (ADHD). In this article we review findings stemming from different paradigms, and suggest an interweaving approach to the different stages involved in the motor regulation process. We start by reviewing various aspects of motor abnormalities found in ADHD and related brain mechanisms. Then, we classify reported motor impairments associated with ADHD, into four classes of motor stages: Attention to the task, motion preparation, motion execution and motion monitoring. Motor abnormalities and corresponding neural activations are analyzed in the context of each of the four identified motor patterns, along with the interactions among them and with other systems. Given the specifications and models of the role of the four motor impairments in ADHD, we ask what treatments correspond to the identified motor impairments. We analyze therapeutic interventions targeting motor difficulties most commonly experienced among individuals with ADHD; first, Neurofeedback training and EMG-biofeedback. As some of the identified components of attention, planning and monitoring have been shown to be linked to abnormal oscillation patterns in the brain, we examine neurofeedback interventions aimed to address these types of oscillations: Theta/beta frequency training and SCP neurofeedback targeted at elevating the CNV component. Additionally we discuss EMG-Biofeedback interventions targeted at feedback on motor activity. Further we review physical activity and motor interventions aimed at improving motor difficulties, associated with ADHD. These kinds of interventions are shown to be helpful not only in aspects of physical ability, but also in enhancing cognition and executive functioning. PMID- 27235738 TI - Role of the oxytocin system in amygdala subregions in the regulation of social interest in male and female rats. AB - We previously found that oxytocin (OT) receptor (OTR) binding density in the medial amygdala (MeA) correlated positively with social interest (i.e., the motivation to investigate a conspecific) in male rats, while OTR binding density in the central amygdala (CeA) correlated negatively with social interest in female rats. Here, we determined the causal involvement of OTR in the MeA and CeA in the sex-specific regulation of social interest in adult rats by injecting an OTR antagonist (5ng/0.5MUl/side) or OT (100pg/0.5MUl/side) before the social interest test (4-min same-sex juvenile exposure). OTR blockade in the CeA decreased social interest in males but not females, while all other treatments had no behavioral effect. To further explore the sex-specific involvement of the OT system in the CeA in social interest, we used in vivo microdialysis to determine possible sex differences in endogenous OT release in the CeA during social interest. Interestingly, males and females showed similar levels of extracellular OT release at baseline and during social interest, suggesting that factors other than local OT release mediate the sex-specific role of CeA-OTR in social interest. Moreover, we found a positive correlation between CeA-OT release and social investigation time in females. This was further reflected by reduced CeA-OT release during social interest in females that expressed low compared to high social interest. We discuss the possibility that this reduction in OT release may be a consequence, rather than a cause, of exposure to a social stimulus. Overall, our findings show for the first time that extracellular OT release in the CeA is similar between males and females and that OTR in the CeA plays a causal role in the regulation of social interest toward juvenile conspecifics in males. PMID- 27235739 TI - The impact of biological sex and sex hormones on cognition in a rat model of early, pre-motor Parkinson's disease. AB - Parkinson's disease (PD) is well known for motor deficits such as bradykinesia. However, patients often experience additional deficits in working memory, behavioral selection, decision-making and other executive functions. Like other features of PD, the incidence and severity of these cognitive symptoms differ in males and females. However, preclinical models have not been used to systematically investigate the roles that sex or sex hormones may play in these complex signs. To address this, we used a Barnes maze spatial memory paradigm to compare the effects of a bilateral nigrostriatal dopamine lesion model of early PD on cognitive behaviors in adult male and female rats and in adult male rats that were gonadectomized or gonadectomized and supplemented with testosterone or estradiol. We found that dopamine lesions produced deficits in working memory and other executive operations, albeit only in male rats where circulating androgen levels were physiological. In males where androgen levels were depleted, lesions produced no additional Barnes maze deficits and attenuated those previously linked to androgen deprivation. We also found that while most measures of Barnes maze performance were unaffected by dopamine lesions in the females, lesions did induce dramatic shifts from their preferred use of thigmotactic navigation to the use of spatially guided place strategies similar to those normally preferred by males. These and other sex- and sex hormone-specific differences in the effects of nigrostriatal dopamine lesions on executive function highlight the potential of gonadal steroids as protective and/or therapeutic for the cognitive symptoms of PD. However, their complexity also indicates the need for a more thorough understanding of androgen and estrogen effects in guiding the development of hormone therapies that might effectively address these non-motor signs. PMID- 27235740 TI - Endogenous opioids regulate glucocorticoid-dependent stress-coping strategies in mice. AB - Coping skills are essential in determining the outcomes of aversive life events. Our research was aimed to elucidate the molecular underpinnings of different coping styles in two inbred mouse strains, C57BL/6J and SWR/J. We compared the influence of a preceding stressor (0.5h of restraint) on behavioral and gene expression profiles between these two strains. The C57BL/6J strain exhibited increased conditioned fear and high immobility (passive coping). Oppositely, the SWR/J mice demonstrated low freezing and immobility, low post-restraint anxiety and considerable struggling during the forced swim test (active coping). Gene profiling in the amygdala revealed transcriptional patterns that were related to the differential stress reactivity, such as the activation of glucocorticoid dependent genes specifically in the C57BL/6J mice. Post-restraint blood sampling for corticosterone levels confirmed the association of hypothalamic-pituitary adrenal (HPA) activation with a passive coping style. Pharmacological tools were used to modulate the stress-coping strategies. The blockade of opioid receptors (ORs) before the aversive event caused transcriptional and neuroendocrine changes in the SWR/J mice that were characteristic of the passive coping strategy. We found that treatment with a glucocorticoid receptor (GR) agonist (dexamethasone (DEX), 4mg/kg) impaired the consolidation of fear memory in the C57BL/6J mice and that this effect was reversed by OR blockade (naltrexone (NTX), 2mg/kg). In parallel, a glucocorticoid receptor antagonist (mifepristone (MIF), 20mg/kg) reversed the effect of morphine (20mg/kg) on conditioned fear in the C57BL/6J mice. Our results suggest that in mice, stress-coping strategies are determined by opioid-dependent mechanisms that modulate activity of the HPA axis. PMID- 27235741 TI - Bexarotene protects against traumatic brain injury in mice partially through apolipoprotein E. AB - Bexarotene has been proved to have neuroprotective effects in many animal models of neurological diseases. However, its neuroprotection in traumatic brain injury (TBI) is still unknown. This study aims to explore the neuroprotective effects of bexarotene on TBI and its possible mechanism. Controlled cortical impact (CCI) model was used to simulate TBI in C57BL/6 mice as well as APOE gene knockout (APOE-KO) mice. After CCI, mice were daily dosed with bexarotene or vehicle solution intraperitoneally. The motor function, learning and memory, inflammatory factors, microglia amount, apoptosis condition around injury site and main side effects were all measured. The results showed that, after CCI, bexarotene treatment markedly improved the motor function and spatial memory in C57BL/6 compare to APOE-KO mice which showed no improvement. The inflammatory cytokines, microglia amount, cell apoptosis rate, and protein of cleaved caspase-3 around the injury site were markedly upregulated after TBI in both C57BL/6 and APOE-KO mice, and all these upregulation were significantly mitigated by bexarotene treatment in C57BL/6 mice, but not in APOE-KO mice. No side-effects were detected after consecutive administration. Taken together, bexarotene inhibits the inflammatory response as well as cell apoptosis and improves the neurological function of mice after TBI partially through apolipoprotein E. This may make it a promising candidate for the therapeutic treatment after TBI. PMID- 27235742 TI - Environmental enrichment as a therapeutic avenue for anxiety in aged Wistar rats: Effect on cat odor exposition and GABAergic interneurons. AB - The use of more ethological animal models to study the neurobiology of anxiety has increased in recent years. We assessed the effect of an environmental enrichment (EE) protocol (24h/day over a period of two months) on anxiety-related behaviors when aged Wistar rats (21months old) were confronted with cat odor stimuli. Owing to the relationship between GABAergic interneurons and the anxiety related neuronal network, we examined changes in the expression of Parvalbumin (PV) and 67kDa form of glutamic acid decarboxylase (GAD-67) immunoreactive cells in different brain regions involved in stress response. Behavioral results revealed that enriched rats traveled further and made more grooming behaviors during the habituation session. In the cat odor session, they traveled longer distances and they showed more active interaction with the odor stimuli and less time in freezing behavior. Zone analysis revealed that the enriched group spent more time in the intermediate zone according to the proximity of the predator odor. Regarding the neurobiological data, the EE increased the expression of PV positive cells in some medial prefrontal regions (cingulate (Cg) and prelimbic (PL) cortices), whereas the GAD-67 expression in the basolateral amygdala was reduced in the enriched group. Our results suggest that EE is able to reduce anxiety-like behaviors in aged animals even when ethologically relevant stimuli are used. Moreover, GABAergic interneurons could be involved in mediating this resilient behavior. PMID- 27235743 TI - Prenatal stress alters diazepam withdrawal syndrome and 5HT1A receptor expression in the raphe nuclei of adult rats. AB - Early-life events have long-term effects on brain structures and cause behavioral alterations that persist into adulthood. The present experiments were designed to investigate the effects of prenatal stress on diazepam-induced withdrawal syndrome and serotonin-1A (5HT1A) receptor expression in the raphe nuclei of adult offspring. The results of the present study reveal that maternal exposure to chronic footshock stress increased the anxiety-like behavior in the prenatally stressed (PS) animals withdrawn from chronic diazepam (2.5mg/kg/day i.p for 1week). Moreover, prenatal stress induced a down-regulation of 5HT1A mRNA in the raphe nuclei of adult offspring. To our knowledge, this study is the first to demonstrate that maternal exposure to chronic footshock stress enhances diazepam withdrawal symptoms and alters 5HT1A receptor gene expression in the raphe nuclei of adult offspring. Thus, more studies are needed to clarify the mechanisms underlying the decrease of 5HT1A receptors expression in the raphe nuclei of PS rats. PMID- 27235744 TI - Dynamics of population coding for object views following object discrimination training. AB - We have previously demonstrated that inferotemporal neurons respond to objects viewed from a range of angles, even without any prior experience in learning the associations among the views. Several models have been proposed to explain object recognition across disparate views. However, direct neuronal evidence is rare. In the present study, we focused on the response similarity of a population of inferotemporal cells to object views, following different prior experiences. Two monkeys were subjected to a task in which object discrimination across views was required. We found significantly higher neural response similarity to 30 degrees separated views, 190ms after object image presentation, than without any prior discrimination experience across views. The time period over which the similarity was significant began and endured similarly for 60 degrees separated views at 190-850ms. For 90 degrees separated views, the time period over which the similarity was significant was shorter and started later, at 230-550ms. The results demonstrate the dynamics of cell population activity and suggest a possible explanation for object recognition across disparate views. PMID- 27235745 TI - Early-life experiences and the development of adult diseases with a focus on mental illness: The Human Birth Theory. AB - In mammals, early adverse experiences, including mother-pup interactions, shape the response of an individual to chronic stress or to stress-related diseases during adult life. This has led to the elaboration of the theory of the developmental origins of health and disease, in particular adult diseases such as cardiovascular and metabolic disorders. In addition, in humans, as stated by Massimo Fagioli's Human Birth Theory, birth is healthy and equal for all individuals, so that mental illness develop exclusively in the postnatal period because of the quality of the relationship in the first year of life. Thus, this review focuses on the importance of programming during the early developmental period on the manifestation of adult diseases in both animal models and humans. Considering the obvious differences between animals and humans we cannot systematically move from animal models to humans. Consequently, in the first part of this review, we will discuss how animal models can be used to dissect the influence of adverse events occurring during the prenatal and postnatal periods on the developmental trajectories of the offspring, and in the second part, we will discuss the role of postnatal critical periods on the development of mental diseases in humans. Epigenetic mechanisms that cause reversible modifications in gene expression, driving the development of a pathological phenotype in response to a negative early postnatal environment, may lie at the core of this programming, thereby providing potential new therapeutic targets. The concept of the Human Birth Theory leads to a comprehension of the mental illness as a pathology of the human relationship immediately after birth and during the first year of life. PMID- 27235746 TI - Low-frequency electrical stimulation enhances the effectiveness of phenobarbital on GABAergic currents in hippocampal slices of kindled rats. AB - Low frequency stimulation (LFS) has been proposed as a new approach in the treatment of epilepsy. The anticonvulsant mechanism of LFS may be through its effect on GABAA receptors, which are the main target of phenobarbital anticonvulsant action. We supposed that co-application of LFS and phenobarbital may increase the efficacy of phenobarbital. Therefore, the interaction of LFS and phenobarbital on GABAergic inhibitory post-synaptic currents (IPSCs) in kindled and control rats was investigated. Animals were kindled by electrical stimulation of basolateral amygdala in a semi rapid manner (12 stimulations/day). The effect of phenobarbital, LFS and phenobarbital+LFS was investigated on GABAA-mediated evoked and miniature IPSCs in the hippocampal brain slices in control and fully kindled animals. Phenobarbital and LFS had positive interaction on GABAergic currents. In vitro co-application of an ineffective pattern of LFS (100 pulses at afterdischarge threshold intensity) and a sub-threshold dose of phenobarbital (100MUM) which had no significant effect on GABAergic currents alone, increased the amplitude and area under curve of GABAergic currents in CA1 pyramidal neurons of hippocampal slices significantly. Interestingly, the sub-threshold dose of phenobarbital potentiated the GABAergic currents when applied on the hippocampal slices of kindled animals which received LFS in vivo. Post-synaptic mechanisms may be involved in observed interactions. Obtained results implied a positive interaction between LFS and phenobarbital through GABAA currents. It may be suggested that a combined therapy of phenobarbital and LFS may be a useful manner for reinforcing the anticonvulsant action of phenobarbital. PMID- 27235747 TI - The pathogenesis of systemic lupus erythematosus - From the viewpoint of oxidative stress and mitochondrial dysfunction. AB - SLE is characterized by an increased production of detrimental autoantigens, exaggerated effects of pro-inflammatory cytokines, dysregulated functioning of immunocompetent cells including lymphocytes and leukocytes, and devastating tissue and organ damage. All of these derangements can be potentiated or attenuated by the abnormal energy expenditure and overproduction of reactive oxygen species (ROS). Mitochondrial heteroplasmy or dysfunction has been recognized to play a role in these abnormalities. Abnormal redox reaction, decreased functioning of biogenesis-related enzymes, increased NETosis, harmful cytokine effects, and aberrant lymphocyte behavior have been shown to be associated with the pathological state of mitochondria. There is accumulating data which support the importance of abnormal oxygen metabolism and mitochondrial disorders in the immunopathogenesis of SLE. Further laboratory as well as clinical data are required to expand our understanding of SLE pathogenesis. PMID- 27235748 TI - Nitric oxide up-regulates endothelial expression of angiotensin II type 2 receptors. AB - Increasing vascular NO levels following up-regulation of endothelial nitric oxide synthase (eNOS) is considered beneficial in cardiovascular disease. Whether such beneficial effects exerted by increased NO-levels include the vascular renin angiotensin system remains elucidated. Exposure of endothelial cells originated from porcine aorta, mouse brain and human umbilical veins to different NO-donors showed that expression of the angiotensin-II-type-2-receptor (AT2) mRNA and protein is up-regulated by activation of soluble guanylyl cyclase, protein kinase G and p38 mitogen-activated protein kinase without changing AT2 mRNA stability. In mice, endothelial-specific overexpression of eNOS stimulated, while chronic treatment with the NOS-blocker l-nitroarginine inhibited AT2 expression. The NO induced AT2 up-regulation was associated with a profound inhibition of angiotensin-converting enzyme (ACE)-activity. In endothelial cells this reduction of ACE-activity was reversed by either the AT2 antagonist PD 123119 or by inhibition of transcription with actinomycin D. Furthermore, in C57Bl/6 mice an acute i.v. bolus of l-nitroarginine did not change AT2-expression and ACE activity suggesting that inhibition of ACE-activity by endogenous NO is crucially dependent on AT2 protein level. Likewise, three weeks of either voluntary or forced exercise training increased AT2 expression and reduced ACE-activity in C57Bl/6 but not in mice lacking eNOS suggesting significance of this signaling interaction for vascular physiology. Finally, aortic AT2 expression is about 5 times greater in female as compared to male C57Bl/6 and at the same time aortic ACE activity is reduced in females by more than 50%. Together these findings imply that endothelial NO regulates AT2 expression and that AT2 may regulate ACE activity. PMID- 27235749 TI - The Near-future Impact of Retirement on the Urologic Workforce: Results From the American Urological Association Census. AB - OBJECTIVE: To assess self-perceived planned retirement patterns among urologists by using the American Urological Association Census Data. With an expanding elderly population and an aging urologic workforce, concerns regarding increased demand and decreased supply of urologists have been raised. MATERIALS AND METHODS: We analyzed data from the 2014 American Urological Association Census, which is a specialty representative survey distributed to the urologists who practice in the United States. A total of 2204 census samples were weighted to represent 11,703 urologists who practiced in the United States in 2014. We compared urologists who are nearing retirement (within 5 years of their planned retirement) with the rest of urologists on their demographic, geographic, and practice characteristics. RESULTS: Of the 11,703 practicing urologists in the United States, 3181 (95% confidence interval: 2884-3479) or 27% (95% confidence interval: 25%-30%) are nearing planned retirement. The mean age (standard deviation [SD]) of urologists nearing retirement (69, SD = 8.2) was older than nonretiring urologists (48, SD = 10.3), P < .01. Nearly double the proportion of nearing retirement urologists is found in nonmetropolitan compared to nonretiring urologists, 534 (17%) vs 782 (9%), P < .01, respectively. Urologists nearing retirement are more likely to practice general urology compared to nonretiring urologists, 2341 (74%) vs 5072 (60%), P < .01. Among urologists nearing retirement, 2155 (68%) of them still perform inpatient operations. CONCLUSION: More than one-fourth of existing practicing urologists plan to retire in the next 5 years. General urology and urology practices outside of metropolitan areas will be impacted the most by the planned retiring workforce. PMID- 27235750 TI - Wideband Doppler Ultrasound-guided Mini-endoscopic Combined Intrarenal Surgery as an Effective and Safe Procedure for Management of Large Renal Stones: A Preliminary Report. AB - OBJECTIVE: To evaluate the efficacy and safety of wideband Doppler ultrasound guided mini-endoscopic combined intrarenal surgery (mini-ECIRS) for large renal stones. MATERIALS AND METHODS: This study included 41 patients with large renal stones (>30 mm) treated by mini-ECIRS using a retrograde flexible ureteroscope and miniature nephroscope by wideband Doppler ultrasound guidance in the modified Valdivia position from January 2013 to September 2015. Surgical parameters, including the stone-free rate, operative time, complications (especially hemorrhagic complications), and hemoglobin drop were recorded and analyzed. Univariate analysis was performed to identify risk factors for a hemoglobin drop of >=1 g/dL. RESULTS: The mean stone size, including staghorn calculi in 41.4% of cases, was 45.5 +/- 14.7 mm. Percutaneous access into the calices using wideband Doppler ultrasound was successful in all cases. The mean total operative time was 158.4 +/- 51.3 minutes. The mean mini-ECIRS time (from first percutaneous puncture to end of procedure) was 106.2 +/- 36.0 minutes. The initial stone-free rate was 73.2% (n = 30). The final stone-free rate after auxiliary treatment was 97.5% (n = 40). The mean hemoglobin drop was 0.54 +/- 0.65 g/dL. Three (7.3%) postoperative modified Clavien grade II complications occurred. Univariate analysis revealed no significant risk factors for a hemoglobin drop of >=1 g/dL. CONCLUSION: Wideband Doppler ultrasound-guided renal puncture is safe and feasible. Wideband Doppler ultrasound-guided mini-ECIRS is a beneficial, versatile, and safe treatment option for management of large renal stones of >30 mm. PMID- 27235752 TI - Unique Imaging Features of Renal Arteriopelvic Fistula on Contrast-enhanced Multidetector Computed Tomography. AB - The development of renal arteriopelvic fistula after percutaneous renal interventions is an extremely rare complication. We report a case of iatrogenic left renal arteriopelvic fistula in a 78-year-old man with unique imaging features on contrast-enhanced multidetector computed tomography. PMID- 27235751 TI - Pelvic Lymph Node Dissection in Patients Treated for Testis Cancer: The Memorial Sloan Kettering Cancer Center Experience. AB - OBJECTIVE: To describe the pathologic findings and clinical outcome data for patients undergoing pelvic lymph node dissection (PLND) in the course of management of testicular germ cell tumors at Memorial Sloan Kettering Cancer Center (MSKCC). PATIENTS AND METHODS: Following institutional review board approval, data on 2186 patients who underwent retroperitoneal lymph node dissection (RPLND) at MSKCC between 1989 and 2011 were retrospectively reviewed. Of these 2186 patients, we analyzed data for 44 patients (2%) who underwent PLND at the time of RPLND. RESULTS: PLND was performed in 14/44 (31%) patients at time of primary RPLND (P-RPLND), and in 21/44(48%) patients at time of postchemotherapy RPLND (PC-RPLND), usually for suspicious radiologic or intraoperative findings, whereas 9/44 (21%) underwent PLND for treatment of relapse. Positive pelvic findings on imaging included pelvic disease <=5 cm in 17/44 (39%) patients and >5 cm in 11/44 (25%) patients (median size = 4 cm). At the time of PC-RPLND, alpha-fetoprotein and beta human chorionic gonadotropin were elevated in 6/21 (29%) and 4/21 (19%) patients, respectively. Histology revealed teratoma in 15/44 (34%) and viable tumor in 5/44 (11%) patients. At a median follow-up of 46 months, 40/44 (91%) patients were living without disease, 3/44 (7%) were living with disease (1 after PC-RPLND and 2 after relapse), and 1/44 (2%) died of other causes. CONCLUSION: PLND was performed infrequently in our series of patients who underwent RPLND for testis cancer. Teratoma was the dominant tumor histology in the resected tissue. PMID- 27235753 TI - Combinatorial effect of genistein and female sex-steroids on uterine fluid volume and secretion rate and aquaporin (AQP)-1, 2, 5, and 7 expression in the uterus in rats. AB - : We hypothesized that genistein can interfere with the regulation of uterine fluid volume, secretion rate and expression of aquaporin in the uterus by female sex-steroids, i.e., estrogen and progesterone. Therefore, the aims of this study were to investigate changes in these parameters in the presence of genistein and female sex-steroids. METHODS: Female Sprague-Dawley rats were ovariectomized and received 3-days estradiol-17beta benzoate (E2) plus genistein (25, 50, or 100 mg kg-1 day-1 ) or 3-days E2 followed by 3-days E2 plus progesterone with genistein (25, 50, or 100 mg kg-1 day-1 ). A day after last treatment, uterine fluid secretion rate was determined by in vivo uterine perfusion with rats under anesthesia. Animals were sacrificed and uteri were harvested and subjected for histological analyses. Luminal/outer uterine circumference was determined and distribution of AQP-1, 2, 5, and 7 in endometrium was visualized by immunofluorescence. Expression of AQP-1, 2, 5, and 7 proteins and mRNAs were determined by Western blotting and Real-time PCR respectively. RESULTS: Combined treatment of E2 with high dose genistein (50 and 100 mg kg-1 day-1 ) resulted in significant decrease in uterine fluid volume, secretion rate and expression of AQP-1, 2, 5, and 7 proteins and mRNAs in uterus (p < 0.05). No significant changes in these parameters were observed when 25 mg kg-1 day-1 genistein was given with E2 or when genistein was given with E2 followed by E2 plus progesterone Conclusions: Decreased in uterine fluid volume, secretion rate and AQP-1, 2, 5, and 7 expression in the uterus by high dose genistein in the presence of E2 could potentially affect female fertility. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 832-844, 2017. PMID- 27235754 TI - Observed bodies generate object-based spatial codes. AB - Contemporary studies of spatial and social cognition frequently use human figures as stimuli. The interpretation of such studies may be complicated by spatial compatibility effects that emerge when researchers employ spatial responses, and participants spontaneously code spatial relationships about an observed body. Yet, the nature of these spatial codes - whether they are location- or object based, and coded from the perspective of the observer or the figure - has not been determined. Here, we investigated this issue by exploring spatial compatibility effects arising for objects held by a visually presented whole bodied schematic human figure. In three experiments, participants responded to the colour of the object held in the figure's left or right hand, using left or right key presses. Left-right compatibility effects were found relative to the participant's egocentric perspective, rather than the figure's. These effects occurred even when the figure was rotated by 90 degrees to the left or to the right, and the coloured objects were aligned with the participant's midline. These findings are consistent with spontaneous spatial coding from the participant's perspective and relative to the normal upright orientation of the body. This evidence for object-based spatial coding implies that the domain general cognitive mechanisms that result in spatial compatibility effects may contribute to certain spatial perspective-taking and social cognition phenomena. PMID- 27235755 TI - Hematopoiesis during development, aging, and disease. AB - Hematopoietic stem cells were once considered identical. However, in the mid 1990s, it became apparent that stem cells from a person's early developmental phases are superior to those from adults, and aged stem cells are defective compared with young stem cells. It has since become clear that polycomb group proteins are important regulators of stem cell functioning. Polycomb group proteins are chromatin-associated proteins involved in writing or reading epigenetic histone modifications. Polycomb group proteins are involved in normal blood cell formation, in cancer, and possibly in aging. In this review, we describe how the different phases of hematopoietic stem cells-birth, maintenance, functional decline, derailment, and death-are continuous processes that may be controlled by polycomb group proteins. PMID- 27235756 TI - GATA-related hematologic disorders. AB - The transcription factors GATA1 and GATA2 are fundamental regulators of hematopoiesis and have overlapping expression profiles. GATA2 is expressed in hematopoietic stem cells and early erythroid-megakaryocytic progenitors and activates a certain set of early-phase genes, including the GATA2 gene itself. GATA2 also initiates GATA1 gene expression. In contrast, GATA1 is expressed in relatively mature erythroid progenitors and facilitates the expression of genes associated with differentiation, including the GATA1 gene itself; however, GATA1 represses the expression of GATA2. Switching the GATA factors from GATA2 to GATA1 appears to be one of the key regulatory mechanisms underlying erythroid differentiation. Loss-of-function analyses using mice in vivo have indicated that GATA2 and GATA1 are functionally nonredundant and that neither can compensate for the absence of the other. However, transgenic expression of GATA2 under the transcriptional regulation of the Gata1 gene rescues lethal dyserythropoiesis in GATA1-deficient mice, illustrating that the dynamic expression profiles of these GATA factors are critically important for the maintenance of hematopoietic homeostasis. Analysis of naturally occurring leukemias in GATA1-knockdown mice revealed that leukemic stem cells undergo functional alterations in response to exposure to chemotherapeutic agents. This mechanism may also underlie the aggravating features of relapsing leukemias. Recent hematologic analyses have suggested that disturbances in the balance of the GATA factors are associated with specific types of hematopoietic disorders. Here, we describe GATA1- and GATA2-related hematologic diseases, focusing on the regulation of GATA factor gene expression. PMID- 27235759 TI - Gait, Falls, and Dementia. PMID- 27235757 TI - Clonal hematopoiesis as determined by the HUMARA assay is a marker for acquired mutations in epigenetic regulators in older women. AB - Recent large cohort studies revealed that healthy older individuals harbor somatic mutations that increase their risk for hematologic malignancy and all cause cardiovascular deaths. The majority of these mutations are in chromatin and epigenetic regulatory genes (CERGs). CERGs play a key role in regulation of DNA methylation (DNMT3A and TET2) and histone function (ASXL1) and in clonal proliferation of hematopoietic stem cells. We hypothesize that older women manifesting clonal hematopoiesis, defined here as a functional phenomenon in which a hematopoietic stem cell has acquired a survival and proliferative advantage, harbor a higher frequency of somatic mutations in CERGs. The human androgen receptor gene (HUMARA) assay was used in our study to detect the presence of nonrandom X inactivation in women, a marker for clonal hematopoiesis. In our pilot study, we tested 127 blood samples from women >=65 years old without a history of invasive cancer or hematologic malignancies. Applying stringent qualitative criteria, we found that 26% displayed clonal hematopoiesis; 52.8% displayed polyclonal hematopoiesis; and 21.3% had indeterminate patterns (too close to call by qualitative assessment). Using Illumina MiSeq next-generation sequencing, we identified somatic mutations in CERGs in 15.2% of subjects displaying clonal hematopoiesis (three ASXL1 and two DNMT3A mutations with an average variant allele frequency of 15.7%, range: 6.3%-23.3%). In a more limited sequencing analysis, we evaluated the frequency of ASXL1 mutations by Sanger sequencing and found mutations in 9.7% of the clonal samples and 0% of the polyclonal samples. By comparing several recent studies (with some caveats as described), we determined the fold enrichment of detecting CERG mutations by using the HUMARA assay as a functional screen for clonal hematopoiesis. We conclude that a functional assay of clonal hematopoiesis is enriching for older women with somatic mutations in CERGs, particularly for ASXL1 and TET2 mutations and less so for DNMT3A mutations. PMID- 27235758 TI - History of graft-versus-host disease. AB - Nuclear warfare at the end of World War II inspired Dick W. van Bekkum to study total-body irradiation (TBI) in animal models. After high-dose TBI, mice died from "primary disease" or bone marrow (BM) aplasia. Intravenous administration of allogeneic BM cells delayed mortality but did not prevent it. Initially the delayed deaths were said to be caused by "secondary disease," which was later renamed graft-versus-host disease (GvHD). GvHD is caused by donor T lymphocytes that destroy recipient cells in skin, intestinal mucosa, bile ducts, and lymph nodes. GvHD is opposed by host-versus-graft disease (HvGD), in which host T lymphocytes destroy the administered allogeneic BM cells, including the administered T lymphocytes of the BM donor. In 1960, van Bekkum became the director of the Radiobiological Institute of the Dutch Organization for Applied Scientific Research TNO, Rijswijk, The Netherlands, where he built a multidisciplinary team that defined the variables controlling the outcome of a BM transplant. The team published their early results in the Journal of Experimental Hematology [1981;9:904-916 and 1956;4:482-488]. Later, protocols were established for BM transplantation (BMT) in patients with severe combined immunodeficiency disease, leukemia, lymphoma, and other diseases of the hematopoietic system. This review honors the scientific contributions made by Dick van Bekkum and his team in defining the four dominant variables for improving the therapeutic ratio of allogeneic BMT and in fostering the international collaboration necessary to translate this knowledge into current clinical practice. PMID- 27235760 TI - Defining Safety in the Nursing Home Setting: Implications for Future Research. AB - Currently, the Agency for Healthcare Research and Quality (AHRQ) Common Format for nursing homes (NHs) accommodates voluntary reporting for 4 adverse events: falls with injury, pressure ulcers, medication errors, and infections. In 2015, AHRQ funded a technical brief to describe the state of the science related to safety in the NH setting to inform a research agenda. Thirty-six recent systematic reviews evaluated NH safety-related interventions to address these 4 adverse events and reported mostly mixed evidence about effective approaches to ameliorate them. Furthermore, these 4 events are likely inadequate to capture safety issues that are unique to the NH setting and encompass other domains related to residents' quality of care and quality of life. Future research needs include expanding our definition of safety in the NH setting, which differs considerably from that of hospitals, to include contributing factors to adverse events as well as more resident-centered care measures. Second, future research should reflect more rigorous implementation science to include objective measures of care processes related to adverse events, intervention fidelity, and staffing resources for intervention implementation to inform broader uptake of efficacious interventions. Weaknesses in implementation contribute to the current inconclusive and mixed evidence base as well as remaining questions about what outcomes are even achievable in the NH setting, given the complexity of most resident populations. Also related to implementation, future research should determine the effects of specific staffing models on care processes related to safety outcomes. Last, future efforts should explore the potential for safety issues in other care settings for older adults, most notably dementia care within assisted living. PMID- 27235761 TI - The Group Reminiscence Approach Can Increase Self-Awareness of Memory Deficits and Evoke a Life Review in People With Mild Cognitive Impairment: The Kurihara Project Data. AB - OBJECTIVES: The group reminiscence approach (GRA) and reality orientation (RO) are common psychosocial interventions for patients with dementia. As a qualitative evaluation of the reminiscence approach in patients with dementia, the Patient Report Outcome (PRO) is useful. The purpose of this study was to investigate the effects of GRA-RO for participants with mild cognitive impairment (MCI) using the PRO. DESIGN: A cluster randomized controlled trial. SETTING: Community-based study. PARTICIPANTS: Ninety-four patients with MCI (39 GRA-RO, 23 physical activity, and 32 cognitive training) described their impressions. INTERVENTION: Based on the database of the Kurihara Project, we retrospectively analyzed the participants' descriptions of their impressions as a PRO in the nonpharmacological interventions: GRA-RO, physical activity, and cognitive training. We categorized the descriptions according to the following 2 types: impression with content and reminiscence with life review. We assessed what they wrote regarding memory loss. The content on their life reviews was also a particular focus for the GRA-RO group. MEASUREMENTS: PRO. RESULTS: Compared with the physical activity and the clinical training groups, the GRA-RO patients described their reminiscence with life review and their own memory problems. There was no confusion of the order of events of their autobiographical memories. There was a significant time effect between the 2 family involvement groups in quality-of-life (QOL) scores, and the postintervention QOL scores were significantly better than preintervention. CONCLUSION: This study suggests that the GRA-RO in participants with MCI not only stimulates life review but also increases self-awareness of memory deficits without confusion of the order of events. Thus, the GRA-RO may improve self-esteem and develop self-awareness. PMID- 27235762 TI - Sarcopenia Is a Possible Independent Risk Factor of Cognitive Decline in Community-Dwelling Older People. PMID- 27235763 TI - Comment on Modifying Effect of Body Mass Index on Survival in Elderly Type 2 Diabetic Patients: Hong Kong Diabetes Registry and Reverse Epidemiology of Traditional Cardiovascular Risk Factors in the Geriatric Population. PMID- 27235764 TI - How to Implement Multidomain Interventions for the Prevention of Alzheimer Disease in China? PMID- 27235765 TI - Do Clinicians Recommend Multivitamin and Mineral Supplements to Long-Term Care Residents According to Nutritional Status? PMID- 27235766 TI - Uterine septum: a guideline. AB - The purpose of this guideline is to review the literature regarding septate uterus and determine optimal indications and methods of treatment for it. Septate uterus has been associated with an increase in the risk of miscarriage, premature delivery, and malpresentation; however, there is insufficient evidence that a uterine septum is associated with infertility. Several studies indicate that treating a uterine septum is associated with an improvement in live-birth rates in women with a history of prior pregnancy loss, recurrent pregnancy loss, or infertility. In a patient without infertility or prior pregnancy loss, it may be reasonable to consider septum incision following counseling regarding potential risks and benefits of the procedure. Many techniques are available to surgically treat a uterine septum, but there is insufficient evidence to recommend one specific method over another. PMID- 27235767 TI - S-nitrosothiols dilate the mesenteric artery more potently than the femoral artery by a cGMP and L-type calcium channel-dependent mechanism. AB - S-nitrosothiols (SNOs) are metabolites of NO with potent vasodilatory activity. Our previous studies in sheep indicated that intra-arterially infused SNOs dilate the mesenteric vasculature more than the femoral vasculature. We hypothesized that the mesenteric artery is more responsive to SNO-mediated vasodilation, and investigated various steps along the NO/cGMP pathway to determine the mechanism for this difference. In anesthetized adult sheep, we monitored the conductance of mesenteric and femoral arteries during infusion of S-nitroso-l-cysteine (L cysNO), and found mesenteric vascular conductance increased (137 +/- 3%) significantly more than femoral conductance (26 +/- 25%). Similar results were found in wire myography studies of isolated sheep mesenteric and femoral arteries. Vasodilation by SNOs was attenuated in both vessel types by the presence of ODQ (sGC inhibitor), and both YC-1 (sGC agonist) and 8-Br-cGMP (cGMP analog) mediated more potent relaxation in mesenteric arteries than femoral arteries. The vasodilatory difference between mesenteric and femoral arteries was eliminated by antagonists of either protein kinase G or L-type Ca(2+) channels. Western immunoblots showed a larger L-type Ca(2+)/sGC abundance ratio in mesenteric arteries than in femoral arteries. Fetal sheep mesenteric arteries were more responsive to SNOs than adult mesenteric arteries, and had a greater L Ca(2+)/sGC ratio (p = 0.047 and r = -0.906 for correlation between Emax and L Ca(2+)/sGC). These results suggest that mesenteric arteries, especially those in fetus, are more responsive to SNO-mediated vasodilation than femoral arteries due to a greater role of the L-type calcium channel in the NO/cGMP pathway. PMID- 27235768 TI - Feelings of loss and grief in parents of children diagnosed with autism spectrum disorder (ASD). AB - BACKGROUND: Various authors have reported feelings of loss and grief in parents of children with autism spectrum disorder. However, no previous studies have investigated the structure of these feelings. AIMS: To analyze in depth the feelings of loss in parents of children diagnosed with autism spectrum disorder. METHOD: A qualitative study was conducted based on grounded theory. Twenty parents participated through purposive sampling. PROCEDURE: Semi-structured interviews were conducted, asking about different emotional aspects of the upbringing of a child with autism spectrum disorder. Atlas.ti 6.2 program was used for open, axial, and selective coding. RESULTS: The core category that explained the feelings of these parents was unexpected child loss, associated with shock, negation, fear, guilt, anger, and/or sadness. Two processes were identified, one associated with the resolution of grief and the other with obstacles to overcoming it. IMPLICATIONS: Feelings of loss play an important role in explaining the complex emotions experienced by these parents. Different intervention strategies are proposed. PMID- 27235769 TI - Differences in speech and language abilities between children with 22q11.2 deletion syndrome and children with phenotypic features of 22q11.2 deletion syndrome but without microdeletion. AB - BACKGROUND: 22q11.2DS is the most common microdeletion syndrome in humans, usually associated with speech and language delay (SLD). Approximately 75% of children with 22q11.2 microdeletion have congenital heart malformations (CHM) which after infant open-heart surgery might lead to SLD. AIMS: The purpose of this study was to determine whether factors associated with microdeletion contribute to SLD in children with 22q11.2DS. METHODS AND PROCEDURES: We compared speech and language abilities of two groups of school-aged children: those with 22q11.2 microdeletion (E1) and those with the phenotype resembling 22q11.2DS but without the microdeletion (E2). An age-matched group of typically developing children was also tested. OUTCOMES AND RESULTS: The obtained results revealed that children from group E1 have lower level of speech and language abilities compared to children from group E2 and control group. Additionally, mild to moderate SLD was detected in children from group E2 compared to children from the control group. CONCLUSIONS AND IMPLICATIONS: The obtained results imply that both CHM after infant open-heart surgery and other factors associated with 22q11.2 microdeletion, contribute to SLD in patients with 22q11.2 microdeletion. Based on this, we could postulate that there is/are some potential candidate gene(s), located in the 22q11.2 region, whose function could be important for speech and language development. PMID- 27235770 TI - Collaboration between teachers and parents of children with ASD on issues of education. AB - This study examines the views of teachers and parents on critical issues concerning their collaboration in the education of children with ASD. For the purposes of this study, a total of 171 teachers and 50 parents of children with ASD, attending mainstream or special primary school units, were randomly selected in Greece in order to respond to a structured questionnaire. The majority of teachers and parents were found to be of the opinion that communication and collaboration between teachers and parents are rendered as critical [n=165 teachers (96.5%), n=50 parents (100%)]. Postgraduate academic studies and working experience with children with ASD are seen to be the most important factors shaping the attitudes of teachers towards collaboration with parents. On the other hand, the types of working unit teachers were employed in are seen to rank in lower importance. PMID- 27235771 TI - Thinking styles of university deaf or hard of hearing students and hearing students. AB - BACKGROUND AND AIMS: Although their university enrollment has increased dramatically over the past two decades, deaf or hard of hearing (DHH) students face great challenges and a tremendous environmental adjustment when entering a mainstream university. This study aims to facilitate DHH students' university success through exploring differences in thinking styles between DHH and hearing students from Art and Design academic disciplines in two universities in China. METHODS AND PROCEDURES: The Thinking Styles Inventory-Revised II (TSI-R2) and its accommodated version were administered to 286 hearing and 256 DHH students, respectively. A demographic sheet was administered to all 542 participants. OUTCOMES AND RESULTS: Results show that DHH students tended to score significantly lower on Type I thinking styles (legislative and global), Type II executive style, and Type III external style than hearing students. In addition, differences in Type I styles (liberal and hierarchical) and Type II executive style between DHH and hearing students were significantly influenced by institution. CONCLUSIONS AND IMPLICATIONS: The present research indicates that DHH and hearing students have significant differences in their thinking styles. This yields implications for the higher education of DHH students, and for deaf schools preparing DHH students for university entry. PMID- 27235772 TI - Comparison between mixed liquors of two side-stream membrane bioreactors treating wastewaters from waste management plants with high and low solids anaerobic digestion. AB - In the last years, biological treatment plants for the previously separated organic fraction from municipal solid wastes (OFMSW) have gained importance. In these processes a liquid effluent (liquid fraction from the digestate and leachate from composting piles), which has to be treated previously to its discharge, is produced. In this paper, the characteristics of the mixed liquor from two full-scale membrane bioreactors treating the effluents of two OFMSW treatment plants have been evaluated in view to study their influence on membrane fouling in terms of filterability. For that, the mixed liquor samples have been ultrafiltrated in an UF laboratory plant. Besides, the effect of the influent characteristics to MBRs and the values of the chemical and physical parameters of the mixed liquors on the filterability have been studied. Results showed that the filterability of the mixed liquor was strongly influenced by the soluble microbial products in the mixed liquors and the influent characteristics to MBR. Permeate flux of MBR mixed liquor treating the most polluted wastewater was considerable the lowest (around 20 L/m(2) h for some samples), what was explained by viscosity and soluble microbial products concentration higher than those measured in other MBR mixed liquor. PMID- 27235773 TI - Molecular characterization of low molecular weight dissolved organic matter in water reclamation processes using Orbitrap mass spectrometry. AB - Reclaimed water has recently become an important water source for urban use, but the composition of dissolved organic matter (DOM) in reclaimed water has rarely been characterized at the compound level because of its complexity. In this study, the transformation and changes in composition of low molecular weight DOM in water reclamation processes, where secondary effluent of the municipal wastewater treatment plant was further treated by biofiltration, ozonation and chlorination, were investigated by "unknown" screening analysis using Orbitrap mass spectrometry (Orbitrap MS). The intense ions were detected over an m/z range from 100 to 450. In total, 2412 formulae with various heteroatoms were assigned, and formulae with carbon (C), hydrogen (H) and oxygen (O) only and C, H, O and sulfur (S) were the most abundant species. During biofiltration, CHO-only compounds with relatively high hydrogen to carbon (H/C) ratio or with saturated structure were preferentially removed, while CHOS compounds were mostly removed. Ozonation induced the greatest changes in DOM composition. CHOS compounds were mostly decreased after ozonation while ozone selectively removed CHO compounds with relatively unsaturated structure and produced compounds that were more saturated and with a higher degree of oxidation. After chlorination, 168 chlorine containing formulae, chlorinated disinfection by-products (DBPs), were additionally detected. Candidate DBP precursors were determined by tracking chlorinated DBPs formed via electrophilic substitution, half of which were generated during the ozonation. PMID- 27235774 TI - Low temperature treatment of domestic wastewater by purple phototrophic bacteria: Performance, activity, and community. AB - Low wastewater temperatures affect microbial growth rates and microbial populations, as well as physical chemical characteristics of the wastewater. Wastewater treatment plant design needs to accommodate changing temperatures, and somewhat limited capacity is a key criticism of low strength anaerobic treatment such as Anaerobic Membrane Bioreactors (AnMBR). This study evaluates the applicability of an alternative platform utilizing purple phototrophic bacteria for low temperature domestic wastewater treatment. Two photo-anaerobic membrane bioreactors (PAnMBR) at ambient (22 degrees C) and low temperatures (10 degrees C) were compared to fully evaluate temperature response of critical processes. The results show good functionality at 10 degrees C in comparison with ambient operation. This enabled operation at 10 degrees C to discharge limits (TCOD < 100 mg L(-1); TN < 10 mg L(-1) and TP < 1 mg L(-1)) at a HRT < 1 d. While capacity of the system was not limited, microbial community showed a strong shift to a far narrower diversity, almost complete dominance by PPB, and of a single Rhodobacter spp. compared to a more diverse community in the ambient reactor. The outcomes of the current work enable applicability of PPB for domestic wastewater treatment to a broad range of regions. PMID- 27235775 TI - Chronic impact of sulfamethoxazole on the metabolic activity and composition of enriched nitrifying microbial culture. AB - This study investigated the chronic impact of sulfamethoxazole (SMX) on activated sludge sustaining an enriched nitrifying biomass. For this purpose, a laboratory scale fill and draw reactor was operated with 100 mg COD/L of peptone mixture and 50 mg N/L of ammonia at a sludge age of 15 days. Additionally, the biomass was exposed to a daily SMX dose of 50 mg/L once the reactor reached steady-state conditions. The reactor performance and microbial composition were monitored for 37 days with conventional parameters and molecular techniques based on the gene for ammonia monooxygenase subunit A (amoA) and the prokaryotic 16S rRNA gene. Denaturing gradient gel electrophoresis (DGGE) and 16S rRNA gene cloning analyses suggested a microbial community change concurrent with the addition of SMX. Specifically, quantitative polymerase chain reaction analyses (qPCR/RT-qPCR) revealed a significant reduction in the levels and activity of ammonia oxidizing bacteria (AOB). However, the acclimation period ended with high amoA mRNA levels and improved nitrification efficiency. Partial degradation of SMX by heterotrophic bacteria was also observed. PMID- 27235777 TI - Attenuation of laser generated ultrasound in steel at high temperatures; comparison of theory and experimental measurements. AB - This article reexamines some recently published laser ultrasound measurements of the longitudinal attenuation coefficient obtained during annealing of two steel samples (DP600 and S550). Theoretical attenuation models based on perturbation theory are compared to these experimental measurements. It is observed that the Rayleigh attenuation formulas provide the correct qualitative agreement, but overestimate the experimental values. The more general theoretical attenuation model considered here demonstrates strong quantitative agreement, which highlights the applicability of the model during real-time metal processing. PMID- 27235776 TI - 3D analysis is superior to 2D analysis for contrast-enhanced ultrasound in revealing vascularity in focal liver lesions - A retrospective analysis of 83 cases. AB - OBJECTIVE: To examine whether dynamic 3D contrast-enhanced ultrasound (CEUS) is superior to 2D imaging in revealing vascularization of focal liver lesions (FLLs). METHODS: Dynamic 2D and 3D CEUS were used to assess the vascularity of FLLs in 83 patients. The two analyses were carried out sequentially following a bolus intravenous injection of SonoVue contrast agent, one injection of 1.5-2mL was given for each part of the study (one for the 2D and another for the 3D). Due to the large data volume for 3D analysis, only the arterial phase (20-25s) was recorded and analyzed. The data were analyzed by two independent analysts. RESULTS: The current study included a total of 83 patients with FLL. The diagnosis was established based on histopathology, Computed Tomography (CT), and magnetic resonance imaging (MRI). Among the 83 cases, 61 were hepatocellular carcinomas (include 10 metastasis, 51 HCCs), and the remaining 22 were benign lesions: hemangiomas (n=15), focal nodular hyperplasias (n=4), and inflammatory lesions (n=3). The overall analysis showed similar patterns of enhancement between the 2D and 3D CEUS in the following features: morphological characteristics, and spatial relationships. In comparison to 2D imaging, 3D CEUS reveal more details of the boundary and feeding arteries of the lesions, as well as distorted features of supply vessels of hepatocellular carcinomas. CONCLUSIONS: Dynamic 3D-CEUS is superior to 2D-CEUS in displaying the spatial relationship of FLLs and their vascularity patterns, and simultaneous imaging of FLL perfusion and anatomic features. PMID- 27235778 TI - Full-matrix capture with phased shift migration for flaw detection in layered objects with complex geometry. AB - This paper introduces a method for an ultrasonic imaging with a phased array based on a wave migration algorithm. The method allows for imaging layered objects with lateral velocity variations such as objects with a complex geometry or layers that are not perpendicular to the array's axis. The full-matrix capture ensures that there is enough information to reconstruct an image even when the wave indication angle is large. The method is implemented in a omega-k domain. The proposed algorithm is first tested in a single simulation of a concave object with side drilled holes under the concave surface. For evaluating the algorithm's performance three experiments are presented: one with a tilted object (surface not perpendicular with respect to the array axis) with side drilled holes and two experiments of an object with concave surface and two artificial defects under it. The results presented in the paper verify that the proposed method reconstructs images from the data gathered with the phased array. PMID- 27235779 TI - Large-scale maps of variable infection efficiencies in aquatic Bacteroidetes phage-host model systems. AB - Microbes drive ecosystem functioning and their viruses modulate these impacts through mortality, gene transfer and metabolic reprogramming. Despite the importance of virus-host interactions and likely variable infection efficiencies of individual phages across hosts, such variability is seldom quantified. Here, we quantify infection efficiencies of 38 phages against 19 host strains in aquatic Cellulophaga (Bacteroidetes) phage-host model systems. Binary data revealed that some phages infected only one strain while others infected 17, whereas quantitative data revealed that efficiency of infection could vary 10 orders of magnitude, even among phages within one population. This provides a baseline for understanding and modeling intrapopulation host range variation. Genera specific host ranges were also informative. For example, the Cellulophaga Microviridae, showed a markedly broader intra-species host range than previously observed in Escherichia coli systems. Further, one phage genus, Cba41, was examined to investigate nonheritable changes in plating efficiency and burst size that depended on which host strain it most recently infected. While consistent with host modification of phage DNA, no differences in nucleotide sequence or DNA modifications were detected, leaving the observation repeatable, but the mechanism unresolved. Overall, this study highlights the importance of quantitatively considering replication variations in studies of phage-host interactions. PMID- 27235780 TI - Detection of degradation in polyester implants by analysing mode shapes of structure vibration. AB - This paper presents a numerical study on using vibration analysis to detect degradation in degrading polyesters. A numerical model of a degrading plate sample is considered. The plate is assumed to degrade following the typical behaviour of amorphous copolymers of polylactide and polyglycolide. Due to the well-known autocatalytic effect in the degradation of these polyesters, the inner core of the plate degrades faster than outer surface region, forming layers of materials with varying Young's modulus. Firstly the change in molecular weight and corresponding change in Young's modulus at different times are calculated using the mathematical models developed in our previous work. Secondly the first four mode shapes of transverse vibration of the plate are calculated using the finite element method. Finally the curvature of the mode shapes are calculated and related to the spatial distribution of the polymer degradation. It is shown that the curvature of the mode shapes can be used to detect the onset and distribution of polymer degradation. The level of measurement accuracy required in an experiment is presented to guide practical applications of the method. At the end of this paper a demonstration case of coronary stent is presented showing how the method can be used to detect degradation in an implant of sophisticated structure. PMID- 27235781 TI - Study of low-modulus biomedical beta Ti-Nb-Zr alloys based on single-crystal elastic constants modeling. AB - CALPHAD-type modeling was used to describe the single-crystal elastic constants of the bcc solution phase in the ternary Ti-Nb-Zr system. The parameters in the model were evaluated based on the available experimental data and first-principle calculations. The composition-elastic properties of the full compositions were predicted and the results were in good agreement with the experimental data. It is found that the beta phase can be divided into two regions which are separated by a critical dynamical stability composition line. The corresponding valence electron number per atom and the polycrystalline Young's modulus of the critical compositions are 4.04-4.17 and 30-40GPa respectively. Orientation dependencies of single-crystal Young's modulus show strong elastic anisotropy on the Ti-rich side. Alloys compositions with a Young's modulus along the <100> direction matching that of bone were found. The current results present an effective strategy for designing low modulus biomedical alloys using computational modeling. PMID- 27235782 TI - Taking stock and looking ahead: Behavioural science lessons for implementing the nonavalent human papillomavirus vaccine. AB - The development and licensing of a nonavalent human papillomavirus (HPV) vaccine has the potential to reduce morbidity and mortality from HPV-related cancers beyond that of first generation HPV vaccines. However, this benefit can only be realised if the offer of vaccination is accepted. Uptake of first generation HPV vaccines is not complete and shows huge global variation. In addition to practical and financial challenges to optimising coverage, behavioural issues explain a large proportion of the variance in vaccine receipt. This commentary draws on the findings of over a decade of behavioural science research seeking to understand uptake of first generation HPV vaccines, in order to anticipate challenges to implement the nonavalent HPV vaccine. Challenges include distrust of combination vaccines, uncertainty about long-term efficacy, distrust of a new and (perceived to be) untested vaccine, cost and uncertainty regarding interchanging doses of first generation and nonavalent vaccines and the appropriateness of revaccination. We use behavioural science theory and existing evaluations of interventions to increase uptake of vaccines to identify evidence based approaches that can be implemented by vaccine stakeholders to address parents' concerns and maximise uptake of the nonavalent HPV vaccine. PMID- 27235783 TI - Subtomogram analysis using the Volta phase plate. AB - Cryo-electron tomography (CET) and subtomogram analysis allow studying the structures of macromolecular complexes in their natural context. The radiation sensitivity of vitrified biological specimens and the resulting low signal-to noise ratio (SNR) in CET limit the amount of structural information that can be mined from tomographic data. The Volta phase plate (VPP) has emerged as an effective means to increase the SNR and hence contrast compared to 'conventional' defocus-based phase contrast transmission electron microscopy (CTEM). Here, we assess the performance of the VPP compared to CTEM in subtomogram analysis, using the mammalian 80S ribosome as a test case. Accurate focusing is the major factor for achieving high resolution with the VPP, as highlighted by a comparison of slightly different focusing strategies. From only 1400 subtomograms, the VPP yields a subtomogram average of the mammalian 80S ribosome at 9.6A resolution without laborious contrast transfer function (CTF) correction. The subtomogram averages obtained using CTEM approaches are comparable, but suffer from lower signal transfer in certain frequency bands due to the oscillations of the CTF. Our study demonstrates that the VPP is a valuable tool for subtomogram analysis, because it enables improved performance and efficiency in terms of structure localization and number of subtomograms required for a given resolution. PMID- 27235784 TI - Organic cation rhodamines for screening organic cation transporters in early stages of drug development. AB - The aim of this study was to investigate the suitability of rhodamine-123, rhodamine-6G and rhodamine B as non-radioactive probes for characterizing organic cation transporters in respiratory cells. Fluorescent characteristics of the compounds were validated under standard in vitro drug transport conditions (buffers, pH, and light). Uptake/transport kinetics and intracellular accumulation of the compounds were investigated. Uptake/transport mechanisms were investigated by comparing the effect of pH, temperature, concentration, polarity, OCTs/OCTNs inhibitors/substrates, and metabolic inhibitors on the cationic dyes uptake in Calu-3 cells. Fluorescence stability and intensity of the compounds were altered by buffer composition, light, and pH. Uptake of the dyes was concentration-, temperature- and pH-dependent. OCTs/OCTNs inhibitors significantly reduced intracellular accumulation of the compounds. Whereas rhodamine-B uptake was sodium-dependent, pH had no effect on rhodamine-123 and rhodamine-6G uptake. Transport of the dyes across the cells was polarized: (AP >BL>BL->AP transport) and saturable: {Vmax=14.08+/-2.074, Km=1821+/-380.4 (rhodamine-B); Vmax=6.555+/-0.4106, Km=1353+/-130.4 (rhodamine-123) and Vmax=0.3056+/-0.01402, Km=702.9+/-60.97 (rhodamine-6G)}. The dyes were co localized with MitoTracker(r), the mitochondrial marker. Cationic rhodamines, especially rhodamine-B and rhodamine- 6G can be used as organic cation transporter substrates in respiratory cells. During such studies, buffer selection, pH and light exposure should be taken into consideration. PMID- 27235785 TI - Comparative study of CYP2B1/2 induction and the transport of bilirubin and taurocholate in rat hepatocyte-mono- and hepatocyte-Kupffer cell co-cultures. AB - INTRODUCTION: Hepatocyte-Kupffer cell (KC) co-cultures represent a promising approach for in vitro modeling of complex interactions between parenchymal and non-parenchymal cells in the liver, responsible for drug-induced liver injury (DILI). In this study we aimed to compare hepatocyte monocultures with hepatocyte KC co-cultures regarding some basic liver functions associated with the chemical defense system. These pathways involve transporters and enzymes the function of which is highly sensitive towards hepatotoxic events. METHODS: CYP2B1/2 induction and the biliary and sinusoidal elimination of bilirubin (B) and taurocholate (TC) were studied in rat hepatocyte sandwich cultures compared with rat hepatocyte-KC sandwich co-cultures of 1:0, 6:1, 2:1 and 1:1 cell combinations representing the physiologic and pathologic conditions of the liver. RESULTS: KCs decreased phenobarbital inducibility of CYP2B1/2 in a cell ratio dependent manner and activation of KCs by lipopolisacharide (LPS) amplified this effect. Similarly, KCs decreased the transport of B and its glucuronides (BG) in both sinusoidal and canalicular directions resulting in its intracellular accumulation. In contrast, the uptake and the efflux of TC were greater in the co-cultures than in the hepatocyte monocultures. Immuno-labelling of sodium-dependent taurocholate transporter (Ntcp) revealed increased expression of the transporter in the presence of KCs. DISCUSSION: Here we presented that KCs have a direct impact on some hepatocyte functions suggesting that the co-culture model may be more suitable for drug related hepatotoxicity studies than hepatocyte monocultures. PMID- 27235786 TI - Drug discrimination: A versatile tool for characterization of CNS safety pharmacology and potential for drug abuse. AB - Drug discrimination studies for assessment of psychoactive properties of drugs in safety pharmacology and drug abuse and drug dependence potential evaluation have traditionally been focused on testing novel compounds against standard drugs for which drug abuse has been documented, e.g. opioids, CNS stimulants, cannabinoids etc. (e.g. Swedberg & Giarola, 2015), and results are interpreted such that the extent to which the test drug causes discriminative effects similar to those of the standard training drug, the test drug would be further characterized as a potential drug of abuse. Regulatory guidance for preclinical assessment of abuse liability by the European Medicines Agency (EMA, 2006), the U.S. Food and Drug Administration (FDA, 2010), the International Conference of Harmonization (ICH, 2009), and the Japanese Ministry of Health Education and Welfare (MHLW, 1994) detail that compounds with central nervous system (CNS) activity, whether by design or not, need abuse and dependence liability assessment. Therefore, drugs with peripheral targets and a potential to enter the CNS, as parent or metabolite, are also within scope (see Swedberg, 2013, for a recent review and strategy). Compounds with novel mechanisms of action present a special challenge due to unknown abuse potential, and should be carefully assessed against defined risk criteria. Apart from compounds sharing mechanisms of action with known drugs of abuse, compounds intended for indications currently treated with drugs with potential for abuse and or dependence are also within scope, regardless of mechanism of action. Examples of such compounds are analgesics, anxiolytics, cognition enhancers, appetite control drugs, sleep control drugs and drugs for psychiatric indications. Recent results (Swedberg et al., 2014; Swedberg & Raboisson, 2014; Swedberg, 2015) on the metabotropic glutamate receptor type 5 (mGluR5) antagonists demonstrate that compounds causing hallucinatory effects in humans did not exhibit clear discriminative effects when tested against classical drugs of abuse in drug discrimination studies, and were not self-administered by rats. However, these compounds did cause salient discriminative effects of their own in animals trained to discriminate them from no drug. Therefore, from a safety pharmacology perspective, novel compounds that do not cause discriminative effects similar to classical drugs of abuse, may still cause psychoactive effects in humans and carry the potential to maintain drug abuse, suggesting that proactive investigation of drug abuse potential is warranted (Swedberg, 2013). These and other findings will be discussed, and the application of drug discrimination procedures beyond the typical standard application of testing novel compounds against known and well characterized reference drugs will be addressed. PMID- 27235787 TI - Human ex-vivo action potential model for pro-arrhythmia risk assessment. AB - While current S7B/E14 guidelines have succeeded in protecting patients from QT prolonging drugs, the absence of a predictive paradigm identifying pro-arrhythmic risks has limited the development of valuable drug programs. We investigated if a human ex-vivo action potential (AP)-based model could provide a more predictive approach for assessing pro-arrhythmic risk in man. Human ventricular trabeculae from ethically consented organ donors were used to evaluate the effects of dofetilide, d,l-sotalol, quinidine, paracetamol and verapamil on AP duration (APD) and recognized pro-arrhythmia predictors (short-term variability of APD at 90% repolarization (STV(APD90)), triangulation (ADP90-APD30) and incidence of early afterdepolarizations at 1 and 2Hz to quantitatively identify the pro arrhythmic risk. Each drug was blinded and tested separately with 3 concentrations in triplicate trabeculae from 5 hearts, with one vehicle time control per heart. Electrophysiological stability of the model was not affected by sequential applications of vehicle (0.1% dimethyl sulfoxide). Paracetamol and verapamil did not significantly alter anyone of the AP parameters and were classified as devoid of pro-arrhythmic risk. Dofetilide, d,l-sotalol and quinidine exhibited an increase in the manifestation of pro-arrhythmia markers. The model provided quantitative and actionable activity flags and the relatively low total variability in tissue response allowed for the identification of pro arrhythmic signals. Power analysis indicated that a total of 6 trabeculae derived from 2 hearts are sufficient to identify drug-induced pro-arrhythmia. Thus, the human ex-vivo AP-based model provides an integrative translational assay assisting in shaping clinical development plans that could be used in conjunction with the new CiPA-proposed approach. PMID- 27235788 TI - Indocyanine Green Guided Pelvic Lymph Node Dissection: An Efficient Technique to Classify the Lymph Node Status of Patients with Prostate Cancer Who Underwent Radical Prostatectomy. AB - PURPOSE: We evaluated the effectiveness of indocyanine green guided pelvic lymph node dissection for the optimal staging of prostate cancer and analyzed whether the technique could replace extended pelvic lymph node dissection. MATERIALS AND METHODS: A solution of 25 mg indocyanine green in 5 ml sterile water was transperineally injected. Pelvic lymph node dissection was started with the indocyanine green stained nodes followed by extended pelvic lymph node dissection. Primary outcome measures were sensitivity, specificity, predictive value and likelihood ratio of a negative test of indocyanine green guided pelvic lymph node dissection. RESULTS: A total of 84 patients with a median age of 63.55 years and a median prostate specific antigen of 8.48 ng/ml were included in the study. Of these patients 60.7% had intermediate risk disease and 25% had high or very high risk disease. A median of 7 indocyanine green stained nodes per patient was detected (range 2 to 18) with a median of 22 nodes excised during extended pelvic lymph node dissection. Lymph node metastasis was identified in 25 patients, 23 of whom had disease properly classified by indocyanine green guided pelvic lymph node dissection. The most frequent location of indocyanine green stained nodes was the proximal internal iliac artery followed by the fossa of Marcille. The negative predictive value was 96.7% and the likelihood ratio of a negative test was 8%. Overall 1,856 nodes were removed and 603 were stained indocyanine green. Pathological examination revealed 82 metastatic nodes, of which 60% were indocyanine green stained. The negative predictive value was 97.4% but the likelihood ratio of a negative test was 58.5%. CONCLUSIONS: Indocyanine green guided pelvic lymph node dissection correctly staged 97% of cases. However, according to our data it cannot replace extended pelvic lymph node dissection. Nevertheless, its high negative predictive value could allow us to avoid extended pelvic lymph node dissection if we had an accurate intraoperative lymph fluorescent analysis. PMID- 27235789 TI - Elective Nephron Sparing Surgery Decreases Other Cause Mortality Relative to Radical Nephrectomy Only in Specific Subgroups of Patients with Renal Cell Carcinoma. AB - PURPOSE: There is no consensus regarding a protective effect on mortality due to a cause other than cancer in patients treated with elective nephron sparing surgery relative to their radical nephrectomy counterparts. We test whether the protective effect of nephron sparing surgery relative to radical nephrectomy is universal or present in specific subgroups of patients. MATERIALS AND METHODS: A collaborative database of 5 institutions was queried to evaluate 1,783 patients without chronic kidney disease diagnosed with a clinical T1 renal mass that was treated with nephron sparing surgery or radical nephrectomy. Multivariable Cox regression analysis was done to assess the impact of surgery type (nephron sparing surgery vs radical nephrectomy) on other cause mortality after adjustment for patient and cancer characteristics. Interaction terms were used to test the hypothesis that the impact of surgery type varies according to specific subcohorts of patients. RESULTS: Ten-year other cause mortality-free survival rates were 90% and 88% after nephron sparing surgery and radical nephrectomy, respectively. In the overall population radical nephrectomy was not associated with an increased risk of other cause mortality on multivariable analysis compared to nephron sparing surgery (HR 0.91, 95% CI 0.6-1.38, p = 0.6). However, radical nephrectomy increased the risk of other cause mortality according to the increasing baseline Charlson comorbidity index (interaction test p = 0.0008). For example, in a patient with a Charlson comorbidity index of 4 the probability of 10-year other cause mortality-free survival was 86% after nephron sparing surgery and 60% after radical nephrectomy. CONCLUSIONS: Elective nephron sparing surgery does not improve other cause survival relative to radical nephrectomy consistently in all patients with kidney cancer. Patients who are more ill with relevant comorbidities are those who benefit the most from nephron sparing surgery in terms of other cause mortality. PMID- 27235790 TI - Branch number matters: Promoting catalytic reduction of 4-nitrophenol over gold nanostars by raising the number of branches and coating with mesoporous SiO2. AB - In this study, we demonstrate for the first time that highly branched gold nanostars (AuNSs) and silica-coated AuNSs (AuNSs@mSiO2) could potentially serve as efficient hydrogenation catalysts. The catalytic activity could be promoted by raising the number of tipped-branches of AuNSs, which reveals that the tips play an important role as active sites. The fabricated sharply-pointed AuNSs benefit the electron transfer from BH4 anions to 4-nitrophenol. Coating AuNSs with mesoporous silica (AuNSs@mSiO2) further enhanced the reduction rate and recyclability, and also contributed to reducing the induction period. The AuNSs@mSiO2 (50-100nm in diameter) are large enough to be catalytically inactive, but they consist of sharply-pointed tips with the radius of 2.6-3.6nm, which are rich in coordinately unsaturated sites similar to those of nanoparticles and clusters. Such features in structure and activity would also extend their application range in heterogeneous catalysis. PMID- 27235792 TI - Sam68 modulates apoptosis of intestinal epithelial cells via mediating NF-kappaB activation in ulcerative colitis. AB - Sam68 (Src-associated substrate during mitosis of 68 KDa), also known as KHDRBS1 (KH domain containing, RNA binding, signal transduction associated 1), belongs to the prototypic member of the signal transduction activator of RNA (STAR) family of RNA-binding proteins. Sam68 is implicated in various cellular processes including RNA metabolism, apoptosis, signal transduction. Previous researches demonstrated that Sam68 regulated nuclear transcription factor kappa B (NF kappaB) to induce inflammation. However, the expression and biological functions of Sam68 in ulcerative colitis (UC) are not clear. In this study, we reported for the first time that Sam68 was up-regulated in intestinal epithelial cells (IECs) of patients with UC. In DSS-induced mouse colitis model, we observed the overexpression of Sam68 accompanied with increased levels of IEC apoptotic markers (active caspase-3 and cleaved PARP) and NF-kappaB activation indicators (p-p65 and p-IkappaB) in colitis IECs. Co-localization of Sam68 with active caspase-3 (and p-p65) in IECs of the DSS-induced colitis group further indicated the possible involvement of NF-kappaB-mediated IEC apoptosis. Applying TNF-alpha treated HT-29 cells as an in vitro IEC inflammation model, we confirmed the positive correlation amomg Sam68, NF-kappaB activation and caspase-dependent apoptosis. Immunofluorescence and immunoprecipitation assay identified nuclear translocation and physical interaction of Sam68 and NF-kappaB subunits in TNF alpha-treated HT-29 cells. Besides, depletion of Sam68 by RNA interference greatly alleviated NF-kappaB activation and apoptosis in TNF-alpha-treated HT-29 cells. Taken together, our results indicated that Sam68 modulates apoptosis of intestinal epithelial cells via mediating NF-kappaB activation in UC. PMID- 27235791 TI - Human precision-cut liver slices as a model to test antifibrotic drugs in the early onset of liver fibrosis. AB - Liver fibrosis is the progressive accumulation of connective tissue ultimately resulting in loss of organ function. Currently, no effective antifibrotics are available due to a lack of reliable human models. Here we investigated the fibrotic process in human precision-cut liver slices (PCLS) and studied the efficacy of multiple putative antifibrotic compounds. Our results demonstrated that human PCLS remained viable for 48h and the early onset of fibrosis was observed during culture, as demonstrated by an increased gene expression of Heat Shock Protein 47 (HSP47) and Pro-Collagen 1A1 (PCOL1A1) as well as increased collagen 1 protein levels. SB203580, a specific inhibitor of p38 mitogen activated protein kinase (MAPK) showed a marked decrease in HSP47 and PCOL1A1 gene expression, whereas specific inhibitors of Smad 3 and Rac-1 showed no or only minor effects. Regarding the studied antifibrotics, gene levels of HSP47 and PCOL1A1 could be down-regulated with sunitinib and valproic acid, while PCOL1A1 expression was reduced following treatment with rosmarinic acid, tetrandrine and pirfenidone. These results are in contrast with prior data obtained in rat PCLS, indicating that antifibrotic drug efficacy is clearly species-specific. Thus, human PCLS is a promising model for liver fibrosis. Moreover, MAPK signaling plays an important role in the onset of fibrosis in this model and transforming growth factor beta pathway inhibitors appear to be more effective than platelet derived growth factor pathway inhibitors in halting fibrogenesis in PCLS. PMID- 27235793 TI - Treatment of human and livestock helminth infections in a mobile pastoralist setting at Lake Chad: Attitudes to health and analysis of active pharmaceutical ingredients of locally available anthelminthic drugs. AB - Mobile pastoralists face challenges in accessing quality health care and medication for managing human and animal diseases. We determined livestock disease priorities, health seeking behaviour of people bearing helminthiases and placing particular emphasis on trematode infections - treatment strategies and outcome satisfaction among mobile pastoralists of four ethnic groups in the Lake Chad area using focus group discussions. People suffering from schistosomiasis were interviewed about symptoms, health seeking behaviour and their satisfaction with respect to the provided treatment. Anthelminthic drugs for human and veterinary use obtained from various health care structures were analysed for active pharmaceutical ingredients (API) and quantity, using high pressure liquid chromatography-UV and liquid chromatography combined with tandem mass spectrometry. Most people suffering from schistosomiasis sought treatment at health care centres. Yet, they also consulted informal providers without medical training. Regarding animal health, self-mediated therapy was common to manage suspected livestock fascioliasis. Self-reported treatment satisfaction for human schistosomiasis and trematodiasis treatment outcome in livestock were low. Mobile pastoralists perceived the purchased drugs to be of low quality. Among 33 products locally sold as anthelminthic drugs for human or veterinary use, 27 contained albendazole or mebendazole, varying between 91% and 159% of the labelled amount. Six products were sold loosely with incomplete information and their API could not be identified. No counterfeit anthelminthic drugs were detected. None of the samples contained praziquantel or triclabendazole, the drugs of choice against schistosomiasis and fascioliasis, respectively. The perceived unsatisfactory treatment outcomes in humans and animals infected with trematodes are most likely due to empiric diagnosis and the resulting use of inadequate therapy for human schistosomiasis and the lack of efficacious drugs against livestock fascioliasis. PMID- 27235794 TI - Abnormal corneal epithelial maintenance in mice heterozygous for the micropinna microphthalmia mutation Mp. AB - We investigated the corneal morphology of adult Mp/+ mice, which are heterozygous for the micropinna microphthalmia mutation, and identified several abnormalities, which implied that corneal epithelial maintenance was abnormal. The Mp/+ corneal epithelium was thin, loosely packed and contained goblet cells in older mice. Evidence also suggested that the barrier function was compromised. However, there was no major effect on corneal epithelial cell turnover and mosaic patterns of radial stripes indicated that radial cell movement was normal. Limbal blood vessels formed an abnormally wide limbal vasculature ring, K19-positive cells were distributed more widely than normal and K12 was weakly expressed in the peripheral cornea. This raises the possibilities that the limbal-corneal boundary was poorly defined or the limbus was wider than normal. BrdU label-retaining cell numbers and quantitative clonal analysis suggested that limbal epithelial stem cell numbers were not depleted and might be higher than normal. However, as corneal epithelial homeostasis was abnormal, it is possible that Mp/+ stem cell function was impaired. It has been shown recently that the Mp mutation involves a chromosome 18 inversion that disrupts the Fbn2 and Isoc1 genes and produces an abnormal, truncated fibrillin-2(MP) protein. This abnormal protein accumulates in the endoplasmic reticulum (ER) of cells that normally express Fbn2 and causes ER stress. It was also shown that Fbn2 is expressed in the corneal stroma but not the corneal epithelium, suggesting that the presence of truncated fibrillin-2(MP) protein in the corneal stroma disrupts corneal epithelial homeostasis in Mp/+ mice. PMID- 27235795 TI - A novel explanation of corneal clouding in a bone marrow transplant-treated patient with Hurler syndrome. AB - One common complication of mucopolysaccharidosis I-Hurler (MPS1-H) is corneal clouding, which occurs despite current treatments, including bone marrow transplantation. Human corneas were obtained from a 14 year old subject with MPS1 H and visual disability from progressive corneal clouding despite a prior bone marrow transplant at age 2. This was compared to a cornea from a 17 year old donated to our eye bank after his accidental death. The corneas were analyzed microscopically after staining with Alcian blue, antibodies to collagen I, IV, VI, and alpha-smooth muscle actin. Differences in levels of expression of the indicated molecules were assessed. Corneas from Hurler and control mice were examined similarly to determine potential mechanistic overlap. The MPS1-H subject cornea showed elevations in mucopolysaccharide deposition. The MPS1-H and Hurler mice corneas showed increased and disorganized expression of collagen I and IV relative to the control corneas. The MPS1-H corneas also showed increased and disordered expression of collagen VI. Positive expression of alpha-smooth muscle actin indicated myofibroblast conversion within the MPS1-H cornea in both the patient and mutant mouse material compared to normal human and control mouse cornea. Increased deposition of collagens and smooth muscle actin correlate with corneal clouding, providing a potential mechanism for corneal clouding despite bone marrow transplantation in MPS1-H patients. It might be possible to prevent or slow the onset of corneal clouding by treating the cornea with drugs known to prevent myofibroblast conversion. PMID- 27235796 TI - The effect of forced swim stress on morphine sensitization: Involvement of D1/D2 like dopamine receptors within the nucleus accumbens. AB - Nucleus accumbens (NAc) plays an essential role in morphine sensitization and suppression of pain. Repeated exposure to stress and morphine increases dopamine release in the NAc and may lead to morphine sensitization. This study was carried out in order to investigate the effect of forced swim stress (FSS), as a predominantly physical stressor and morphine on the development of morphine sensitization; focusing on the function of D1/D2-like dopamine receptors in the NAc in morphine sensitization. Eighty-five adult male Wistar rats were bilaterally implanted with cannulae in the NAc and various doses of SCH-23390 (0.125, 0.25, 1 and 4MUg/0.5MUl/NAc) as a D1 receptor antagonist and sulpiride (0.25, 1 and 4MUg/0.5MUl/NAc) as a D2 receptor antagonist were microinjected into the NAc, during a sensitization period of 3days, 5min before the induction of FSS. After 10min, animals received subcutaneous morphine injection (1mg/kg). The procedure was followed by 5days free of antagonist, morphine and stress; thereafter on the 9th day, the nociceptive response was evaluated by tail-flick test. The results revealed that the microinjection of sulpiride (at 1 and 4MUg/0.5MUl/NAc) or SCH-23390 (at 0.25, 1 and 4MUg/0.5MUl/NAc) prior to FSS and morphine disrupts the antinociceptive effects of morphine and morphine sensitization. Our findings suggest that FSS can potentiate the effect of morphine and causes morphine sensitization which induces antinociception. PMID- 27235797 TI - Developmental validation of STRmixTM, expert software for the interpretation of forensic DNA profiles. AB - In 2015 the Scientific Working Group on DNA Analysis Methods published the SWGDAM Guidelines for the Validation of Probabilistic Genotyping Systems [1]. STRmixTM is probabilistic genotyping software that employs a continuous model of DNA profile interpretation. This paper describes the developmental validation activities of STRmixTM following the SWGDAM guidelines. It addresses the underlying scientific principles, and the performance of the models with respect to sensitivity, specificity and precision and results of interpretation of casework type samples. This work demonstrates that STRmixTM is suitable for its intended use for the interpretation of single source and mixed DNA profiles. PMID- 27235798 TI - Characteristic manifestations of acute paint thinner-intoxicated children. AB - In this study, we evaluated the acute clinical and para-clinical abnormalities arising from paint thinner (PT) poisoning in children. Data were collected from 2008 to 2013, and sourced from the medical records of PT-intoxicated children and through questionnaires. A total of 42 children were enrolled in the study. The mean age was 37.2+/-2.4 months. The participants ranged from10 to 96 months of age; with a median age of 3 months; and a modal age of 24 months. The sex ratio in the study was 22 males (64.9%) to 20 females (35.1%). Clinical biochemistry results of participants revealed the significant presence of alkaline phosphatase (ALP, 569.25+/-151.58U/L), and lactate dehydrogenase (LDH, 576.14+/-164.97 IU/L). Arterial blood gas (ABG) analysis was also carried out. Chest X-ray predominantly revealed right side alveolar air space consolidation. These results confirmed hepatotoxicity and pneumonia in PT-intoxicated children. The study also revealed that positive outcomes were achieved in patients with early treatment and management. In addition, the current finding confirmed the timely transfer of the victim to the poisoning center. PMID- 27235799 TI - Human exposure to acrolein: Time-dependence and individual variation in eye irritation. AB - The aim of the study was to examine the time dependence on sensory irritation detection following exposure to threshold levels of acrolein, in humans. The exposures occurred in an exposure chamber and the subjects were breathing fresh air through a mask that covered the nose and mouth. All participants participated in four exposure conditions, of which three consisted of a mixture of acrolein and heptane and one of only heptane. Exposure to acrolein at a concentration half of the TLV-C lead to sensory irritation. The perceived sensory irritation resulted in both increased detectability and sensory irritation after about 6.8min of exposure in 58% of the participants. The study confirm the previously suggested LOAEL of about 0.34mg/m(3) for eye irritation due to acrolein exposure. The sensory irritation was still significant 10min after exposure. These results have implications for risk assessment and limit setting in occupational hygiene. PMID- 27235800 TI - A novel method to use fuzzy soft sets in decision making based on ambiguity measure and Dempster-Shafer theory of evidence: An application in medical diagnosis. AB - OBJECTIVE: Recently, fuzzy soft sets-based decision making has attracted more and more interest. Although plenty of works have been done, they cannot provide the uncertainty or certainty of their results. To manage uncertainty is one of the most important and toughest tasks of decision making especially in medicine. In this study, we improve the performance of reducing uncertainty and raising the choice decision level in fuzzy soft set-based decision making. METHODS AND MATERIAL: We make use of two appropriate tools (ambiguity measure and Dempster Shafer theory of evidence) to improve fuzzy soft set-based decision making. Our proposed approach consists of three procedures: primarily, the uncertainty degree of each parameter is obtained by using ambiguity measure; next, the suitable basic probability assignment with respect to each parameter (or evidence) is constructed based on the uncertainty degree of each parameter obtained in the first step; in the end, the classical Dempster's combination rule is applied to aggregate independent evidences into the collective evidence, by which the candidate alternatives are ranked and the best alternative will be obtained. RESULTS: We compare the results of our proposed method with the recent relative works. Through employing our presented approach, in Example 5, the belief measure of the uncertainty falls to 0.0051 from 0.0751; in Example 6, the belief measure of the uncertainty drops to 0.0086 from 0.0547; in Example 7, the belief measure of the uncertainty falls to 0.0847 from 0.1647; in application, the belief measure of the uncertainty drops 0.0001 from 0.0069. CONCLUSION: Three numerical examples and an application in medical diagnosis are provided to demonstrate adequately that, on the one hand, our proposed method is feasible and efficient; on the other hand, our proposed method can reduce uncertainty caused by people's subjective cognition and raise the choice decision level with the best performance. PMID- 27235801 TI - From frames to OWL2: Converting the Foundational Model of Anatomy. AB - OBJECTIVE: The Foundational Model of Anatomy (FMA) [Rosse C, Mejino JLV. A reference ontology for bioinformatics: the Foundational Model of Anatomy. J. Biomed. Inform. 2003;36:478-500] is an ontology that represents canonical anatomy at levels ranging from the entire body to biological macromolecules, and has rapidly become the primary reference ontology for human anatomy, and a template for model organisms. Prior to this work, the FMA was developed in a knowledge modeling language known as Protege Frames. Frames is an intuitive representational language, but is no longer the industry standard. Recognizing the need for an official version of the FMA in the more modern semantic web language OWL2 (hereafter referred to as OWL), the objective of this work was to create a generalizable Frames-to-OWL conversion tool, to use the tool to convert the FMA to OWL, to "clean up" the converted FMA so that it classifies under an EL reasoner, and then to do all further development in OWL. METHODS: The conversion tool is a Java application that uses the Protege knowledge representation API for interacting with the initial Frames ontology, and uses the OWL-API for producing new statements (axioms, etc.) in OWL. The converter is relation centric. The conversion is configurable, on a property-by-property basis, via user-specifiable XML configuration files. The best conversion, for each property, was determined in conjunction with the FMA knowledge author. The convertor is potentially generalizable, which we partially demonstrate by using it to convert our Ontology of Craniofacial Development and Malformation as well as the FMA. Post-conversion cleanup involved using the Explain feature of Protege to trace classification errors under the ELK reasoner in Protege, fixing the errors, then re-running the reasoner. RESULTS: We are currently doing all our development in the converted and cleaned-up version of the FMA. The FMA (updated every 3 months) is available via our FMA web page http://si.washington.edu/projects/fma, which also provides access to mailing lists, an issue tracker, a SPARQL endpoint (updated every week), and an online browser. The converted OCDM is available at http://www.si.washington.edu/projects/ocdm. The conversion code is open source, and available at http://purl.org/sig/software/frames2owl. Prior to the post conversion cleanup 73% of the more than 100,000 classes were unsatisfiable. After correction of six types of errors no classes remained unsatisfiable. CONCLUSION: Because our FMA conversion captures all or most of the information in the Frames version, is the only complete OWL version that classifies under an EL reasoner, and is maintained by the FMA authors themselves, we propose that this version should be the only official release version of the FMA in OWL, supplanting all other versions. Although several issues remain to be resolved post-conversion, release of a single, standardized version of the FMA in OWL will greatly facilitate its use in informatics research and in the development of a global knowledge base within the semantic web. Because of the fundamental nature of anatomy in both understanding and organizing biomedical information, and because of the importance of the FMA in particular in representing human anatomy, the FMA in OWL should greatly accelerate the development of an anatomically based structural information framework for organizing and linking a large amount of biomedical information. PMID- 27235803 TI - A physics-based intravascular ultrasound image reconstruction method for lumen segmentation. AB - Intravascular ultrasound (IVUS) refers to the medical imaging technique consisting of a miniaturized ultrasound transducer located at the tip of a catheter that can be introduced in the blood vessels providing high-resolution, cross-sectional images of their interior. Current methods for the generation of an IVUS image reconstruction from radio frequency (RF) data do not account for the physics involved in the interaction between the IVUS ultrasound signal and the tissues of the vessel. In this paper, we present a novel method to generate an IVUS image reconstruction based on the use of a scattering model that considers the tissues of the vessel as a distribution of three-dimensional point scatterers. We evaluated the impact of employing the proposed IVUS image reconstruction method in the segmentation of the lumen/wall interface on 40MHz IVUS data using an existing automatic lumen segmentation method. We compared the results with those obtained using the B-mode reconstruction on 600 randomly selected frames from twelve pullback sequences acquired from rabbit aortas and different arteries of swine. Our results indicate the feasibility of employing the proposed IVUS image reconstruction for the segmentation of the lumen. PMID- 27235802 TI - Evolving classification of intensive care patients from event data. AB - OBJECTIVE: This work aims at predicting the patient discharge outcome on each hospitalization day by introducing a new paradigm-evolving classification of event data streams. Most classification algorithms implicitly assume the values of all predictive features to be available at the time of making the prediction. This assumption does not necessarily hold in the evolving classification setting (such as intensive care patient monitoring), where we may be interested in classifying the monitored entities as early as possible, based on the attributes initially available to the classifier, and then keep refining our classification model at each time step (e.g., on daily basis) with the arrival of additional attributes. MATERIALS AND METHODS: An oblivious read-once decision-tree algorithm, called information network (IN), is extended to deal with evolving classification. The new algorithm, named incremental information network (IIN), restricts the order of selected features by the temporal order of feature arrival. The IIN algorithm is compared to six other evolving classification approaches on an 8-year dataset of adult patients admitted to two Intensive Care Units (ICUs) in the United Kingdom. RESULTS: Retrospective study of 3452 episodes of adult patients (>=16years of age) admitted to the ICUs of Guy's and St. Thomas' hospitals in London between 2002 and 2009. Random partition (66:34) into a development (training) set n=2287 and validation set n=1165. Episode-related time steps: Day 0-time of ICU admission, Day x-end of the x-th day at ICU. The most accurate decision-tree models, based on the area under curve (AUC): Day 0: IN (AUC=0.652), Day 1: IIN (AUC=0.660), Day 2: J48 decision-tree algorithm (AUC=0.678), Days 3-7: regenerative IN (AUC=0.717-0.772). Logistic regression AUC: 0.582 (Day 0)-0.827 (Day 7). CONCLUSIONS: Our experimental results have not identified a single optimal approach for evolving classification of ICU episodes. On Days 0 and 1, the IIN algorithm has produced the simplest and the most accurate models, which incorporate the temporal order of feature arrival. However, starting with Day 2, regenerative approaches have reached better performance in terms of predictive accuracy. PMID- 27235804 TI - Strategic analysis of a water rights conflict in the south western United States. AB - A strategic analysis of the ongoing conflict between Nevada and Utah, over groundwater allocation at Snake Valley, is carried out in order to investigate ways on how to resolve this dispute. More specifically, the Graph Model for Conflict Resolution is employed to formally model and analyze this conflict using the decision support system called GMCR+. The conflict analysis findings indicate that the dispute is enduring because of a lack of incentive and opportunity for any party to move beyond the present circumstances. Continued negotiations are not likely to resolve this conflict. A substantial change in the preferences or options of the disputants, or new governance tools will be required to move this conflict forward. This may hold lessons for future groundwater conflicts. It is, however, increasingly likely that the parties will require a third party intervention, such as equal apportionment by the US Supreme Court. PMID- 27235805 TI - Identification, quantification and treatment of fecal odors released into the air at two wastewater treatment plants. AB - Odorous emissions from wastewater treatment plants (WWTPs) are an annoyance for neighboring communities. This article, for the first time, quantitatively reports on an evaluation of the presence of fecal odorants identified in air samples from two exemplary WWTPs by the odor profile method (OPM) and chemical analysis. The fecal odorants indole and skatole were identified by Gas Chromatography-Mass Spectrometry. The odor threshold concentration of skatole was determined to be 0.327 ng/L (60 pptV) in Teflon Bags by an expert panel. Skatole was found to be the primary chemical leading to fecal odor, due to its odor concentration to odor threshold concentration ratio that ranged from 2.8 to 22.5. The Weber-Fechner law was followed by pure skatole, but was not applicable when there was a mixture of fecal odorants and other odorant types present in WWTP air emission samples. This is probably caused by antagonism with other odorant types. Several existing odor control treatment methods for fecal odorants were evaluated at different wastewater treatment operations at two WWTPs by the OPM and chemical analysis for indole and skatole. Chemical scrubbing and biofiltration performed best in removing fecal odors among current control technologies. PMID- 27235806 TI - Linking mitochondrial dynamics to mitochondrial protein quality control. AB - Over the last decade, countless discoveries have been made that have expanded our knowledge of mitochondrial biology, and more often than not, these discoveries provided fascinating new insights into the etiology of human disease. For example, advances in mitochondrial genetics exposed the role of mitochondrial mutations in cancer progression, and the discovery of mitophagy highlighted the role of mitochondrial quality control in Parkinson's disease. Additional discoveries underscored the importance of the mTor pathway in aging and disease, and more recently, the mitochondrial unfolded protein response was implicated in the regulation of mammalian lifespan. Some of the most fundamental discoveries though, were made in the context of mitochondrial fusion and fission. The balance between these two opposing forces shapes the mitochondrial population in our cells, and influences mitochondrial function at every level. Here, we highlight the basic biology that underlies mitochondrial fusion and fission, explain how these processes promote human health by solving a problem that is innate to multifarious organelles, and make a novel prediction: that fusion and fission are intimately linked to mitochondrial protein quality control. PMID- 27235808 TI - Intercellular mitochondrial transfer: bioenergetic crosstalk between cells. AB - Mitochondrial transfer from donor cells to cells of injured tissues is a promising cell-based therapy for effectively bringing about recovery of tissue bioenergetics. Here, we review recent studies on intercellular mitochondrial transfer in organs and cells. We also review studies that shed light on our current understanding of the known mechanisms and conditions that lead to intercellular mitochondrial transfer. PMID- 27235807 TI - Mitochondria-associated ER membranes and Alzheimer disease. AB - The series of events underlying the pathogenesis of Alzheimer disease (AD) in unknown. The most widely accepted hypothesis is called the amyloid cascade, based on the observation that the brains of AD patients contain high levels of extracellular plaques, composed mainly of beta-amyloid (Abeta), and intracellular tangles, composed of hyperphosphorylated forms of the microtubule-associated protein tau. However, AD is also characterized by other features, including aberrant cholesterol, phospholipid, and calcium metabolism, and mitochondrial dysfunction, all ostensibly unrelated to plaque and tangle formation. Notably, these 'other' aspects of AD pathology are functions related to mitochondria associated ER membranes (MAM), a subdomain of the endoplasmic reticulum (ER) that is apposed to, and communicates with, mitochondria. Given the potential relationship between MAM and AD, we explored the possibility that perturbed MAM function might play a role in AD pathogenesis. We found that gamma-secretase activity, which processes the amyloid precursor protein to generate Abeta, is located predominantly in the MAM, and that ER-mitochondrial apposition and MAM function are increased significantly in cells from AD patients. These observations may help explain not only the aberrant Abeta production, but also many of the 'other' biochemical and morphological features of the disease. Based on these, and other, data we propose that AD is fundamentally a disorder of ER mitochondrial hyperconnectivity. PMID- 27235809 TI - Bay laurel (Laurus nobilis) as potential antiviral treatment in naturally BQCV infected honeybees. AB - Viral diseases are one of the multiple factors associated with honeybee colony losses. Apart from their innate immune system, including the RNAi machinery, honeybees can use secondary plant metabolites to reduce or fully cure pathogen infections. Here, we tested the antiviral potential of Laurus nobilis leaf ethanolic extracts on forager honeybees naturally infected with BQCV (Black queen cell virus). Total viral loads were reduced even at the lowest concentration tested (1mg/ml). Higher extract concentrations (>=5mg/ml) significantly reduced virus replication. Measuring vitellogenin gene expression as an indicator for transcript homeostasis revealed constant RNA levels before and after treatment, suggesting that its expression was not impacted by the L. nobilis treatment. In conclusion, plant secondary metabolites can reduce virus loads and virus replication in naturally infected honeybees. PMID- 27235810 TI - Enhanced immune responses against Japanese encephalitis virus using recombinant adenoviruses coexpressing Japanese encephalitis virus envelope and porcine interleukin-6 proteins in mice. AB - Japanese encephalitis is a reproductive disorder caused by Japanese encephalitis virus (JEV) in swine. Previous studies have demonstrated that recombinant adenovirus serotype 5 (Ad5) may be a potential vaccine candidate because it can express JEV envelope epitopes and induce immune responses against JEV. Still, it will be necessary to develop an adjuvant that can enhance both humoral and cellular immune responses to the recombinant antigen delivered by non-replicating Ad5. In this study, we investigated the systemic immune responses of BALB/c mice immunized with recombinant adenovirus expressing JEV envelope epitopes in combination with porcine interleukin-6 (rAdE-IL-6).The rAdE-IL-6 immunized group had the highest titers of anti-JEV antibody as detected by an enzyme-linked immunosorbent assay (ELISA), as well as the highest levels of neutralizing antibody (1:75) as detected by a serum neutralization test. Similarly, higher concentrations of interferon-gamma (834.7pg/ml) and interleukin-6 (IL-6) (229.7pg/ml) were detected in the rAdE-IL-6 group using an ELISA assay. These data indicate that immunized BALB/c induce a strong cellular response against rAdE-IL-6. Furthermore, after challenge with the virulent JEV SCYA201201 strain, the rAdE-IL-6 group generated an immune protective response 70% greater than that of the control group, indicating that rAdE-IL-6 induced a protective immune response against JEV challenge in mice. The results from this study demonstrated that IL-6 is a strong adjuvant that can enhance both humoral and cellular immune responses in mice. Furthermore, a recombinant adenovirus coexpressing JEV envelope epitopes and porcine IL-6 protein may be an effective vaccine in animals. PMID- 27235811 TI - Agonistic interactions elicit rapid changes in brain nonapeptide levels in zebrafish. AB - The teleost fish nonapeptides, arginine vasotocin (AVT) and isotocin (IT), have been implicated in the regulation of social behavior. These peptides are expected to be involved in acute and transient changes in social context, in order to be efficient in modulating the expression of social behavior according to changes in the social environment. Here we tested the hypothesis that short-term social interactions are related to changes in the level of both nonapeptides across different brain regions. For this purpose we exposed male zebrafish to two types of social interactions: (1) real opponent interactions, from which a Winner and a Loser emerged; and (2) mirror-elicited interactions, that produced individuals that did not experience a change in social status despite expressing similar levels of aggressive behavior to those of participants in real-opponent fights. Non-interacting individuals were used as a reference group. Each social phenotype (i.e. Winners, Losers, Mirror-fighters) presented a specific brain profile of nonapeptides when compared to the reference group. Moreover, the comparison between the different social phenotypes allowed to address the specific aspects of the interaction (e.g. assessment of opponent aggressive behavior vs. self assessment of expressed aggressive behavior) that are linked with neuropeptide responses. Overall, agonistic interactions seem to be more associated with the changes in brain AVT than IT, which highlights the preferential role of AVT in the regulation of aggressive behavior already described for other species. PMID- 27235812 TI - Comparison of clear and narrow outcomes on testosterone levels in social competition. AB - A contribution to a special issue on Hormones and Human Competition. Social competition is associated with marked emotional, behavioral and hormonal responses, including changes in testosterone levels. The strength and direction of these responses is often modulated by levels of other hormones (e.g. cortisol) and depends on psychological factors - classically, the objective outcome of a competition (win vs. loss) but also, hypothetically, the closeness of that outcome (e.g. decisive victory vs. close victory). We manipulated these two aspects of a social contest among male participants (N=166), to investigate how testosterone and affect fluctuated as a function of clear vs. narrow wins and clear vs. narrow losses. We found that losing a competition by a small margin (a narrow loss) was experienced as more pleasant than a clear loss. Among individuals with higher levels of basal cortisol, winning the competition by a narrow margin was associated with a decrease in testosterone levels. These findings are discussed within the framework of the status instability hypothesis and the growing literature on how situational and physiological factors modulate testosterone reactivity to social contests. PMID- 27235813 TI - Subregional localization and characterization of Ly6aGFP-expressing hematopoietic cells in the mouse embryonic head. AB - Hematopoietic cell generation in the midgestation mouse embryo occurs through the natural transdifferentiation of temporally and spatially restricted set of hemogenic endothelial cells. These cells take on hematopoietic fate in the aorta, vitelline and umbilical arteries and appear as hematopoietic cell clusters that emerge from the vascular wall. Genetic and live imaging data have supported this. Recently, the embryonic head has been shown to contain fully functional hematopoietic stem cells (HSC). By lineage tracing, cerebrovascular specific endothelial cells were shown to contribute to the postnatal mouse hematopoietic system. Since Ly6aGFP is a marker of all HSCs, some hematopoietic cluster cells and hemogenic endothelial cells in the midgestation mouse aorta, we examine here whether embryonic head HSCs and vascular endothelial cells are positive for this marker. Whereas some head vasculature, single hematopoietic cells and all HSCs are Ly6aGFP expressing, we do not find clusters of hematopoietic cells emerging from the cerebrovasculature that are characteristic of endothelial-to hematopoietic transition. PMID- 27235814 TI - Enteric nervous system development in avian and zebrafish models. AB - Our current understanding of the developmental biology of the enteric nervous system (ENS) and the genesis of ENS diseases is founded almost entirely on studies using model systems. Although genetic studies in the mouse have been at the forefront of this field over the last 20 years or so, historically it was the easy accessibility of the chick embryo for experimental manipulations that allowed the first descriptions of the neural crest origins of the ENS in the 1950s. More recently, studies in the chick and other non-mammalian model systems, notably zebrafish, have continued to advance our understanding of the basic biology of ENS development, with each animal model providing unique experimental advantages. Here we review the basic biology of ENS development in chick and zebrafish, highlighting conserved and unique features, and emphasising novel contributions to our general understanding of ENS development due to technical or biological features. PMID- 27235815 TI - Multi-sample Arabidopsis Growth and Imaging Chamber (MAGIC) for long term imaging in the ZEISS Lightsheet Z.1. AB - Time-course imaging experiments on live organisms are critical for understanding the dynamics of growth and development. Light-sheet microscopy has advanced the field of long-term imaging of live specimens by significantly reducing photo toxicity and allowing fast acquisition of three-dimensional data over time. However, current light-sheet technology does not allow the imaging of multiple plant specimens in parallel. To achieve higher throughput, we have developed a Multi-sample Arabidopsis Growth and Imaging Chamber (MAGIC) that provides near physiological imaging conditions and allows high-throughput time-course imaging experiments in the ZEISS Lightsheet Z.1. Here, we illustrate MAGIC's imaging capabilities by following cell divisions, as an indicator of plant growth and development, over prolonged time periods. To automatically quantify the number of cell divisions in long-term experiments, we present a FIJI-based image processing pipeline. We demonstrate that plants imaged with our chamber undergo cell divisions for >16 times longer than those with the glass capillary system supplied by the ZEISS Z1. PMID- 27235816 TI - Enteric nervous system assembly: Functional integration within the developing gut. AB - Co-ordinated gastrointestinal function is the result of integrated communication between the enteric nervous system (ENS) and "effector" cells in the gastrointestinal tract. Unlike smooth muscle cells, interstitial cells, and the vast majority of cell types residing in the mucosa, enteric neurons and glia are not generated within the gut. Instead, they arise from neural crest cells that migrate into and colonise the developing gastrointestinal tract. Although they are "later" arrivals into the developing gut, enteric neural crest-derived cells (ENCCs) respond to many of the same secreted signalling molecules as the "resident" epithelial and mesenchymal cells, and several factors that control the development of smooth muscle cells, interstitial cells and epithelial cells also regulate ENCCs. Much progress has been made towards understanding the migration of ENCCs along the gastrointestinal tract and their differentiation into neurons and glia. However, our understanding of how enteric neurons begin to communicate with each other and extend their neurites out of the developing plexus layers to innervate the various cell types lining the concentric layers of the gastrointestinal tract is only beginning. It is critical for postpartum survival that the gastrointestinal tract and its enteric circuitry are sufficiently mature to cope with the influx of nutrients and their absorption that occurs shortly after birth. Subsequently, colonisation of the gut by immune cells and microbiota during postnatal development has an important impact that determines the ultimate outline of the intrinsic neural networks of the gut. In this review, we describe the integrated development of the ENS and its target cells. PMID- 27235817 TI - Physical activity and sedentary behavior in people with bipolar disorder: A systematic review and meta-analysis. AB - BACKGROUND: Mortality rates are approximately two to three times higher in people with bipolar disorder (BD) than in general population. Lack of physical activity (PA) and sedentary behavior (SB) are independent risk factors for cardiovascular disease and premature mortality. AIMS: We conducted a meta-analysis to investigate PA and SB levels and its predictors in BD. METHODS: Major electronic databases were searched from inception till 02/2016 for articles measuring PA and SB with a self-report questionnaire (SRQ) or objective measure (e.g. accelerometer) in BD. A random effects meta-analysis and meta-regression analysis were conducted. RESULTS: Six studies were eligible including 279 (129?) people with BD (mean age=43.9 years; range: 32.0-51.5 years). The trim and fill analysis demonstrated people with BD spent in total 210.1min (95%CI=146.3-273.9min) per day being physically active and 613.3min (95%CI=389.9-836.6min) during waking hours being sedentary. No significant difference in total PA per day was observed between people with BD and controls (g=-0.62, 95% CI=-1.55 to 0.31, I(2)=88.5%, n BD =82, n controls =86). Objective measures of PA recorded significantly lower levels (P=0.03) compared to self-report PA. Meta-regression demonstrated that older age and a higher body mass index predicted lower PA levels. LIMITATIONS: Only a limited number of studies were identified assessing SB in people with BD. CONCLUSIONS: Adults with BD engage in high levels of sedentary behavior during waking hours. Given that sedentary behavior is an independent predictor of cardiovascular disease, future lifestyle interventions specifically targeting the prevention of sedentary behavior are warranted. PMID- 27235818 TI - Altered neuronal spontaneous activity correlates with glutamate concentration in medial prefrontal cortex of major depressed females: An fMRI-MRS study. AB - BACKGROUND: Major depressive disorder (MDD) is twice more prevalent in females than in males. Yet, there have only been a few studies on the functional brain activity in female MDD patients and the detailed mechanisms underlying their neurobiology merit further investigations. In the present work, we used combined fMRI-MRS methods to investigate the altered intrinsic neuronal activity and its association with neurotransmitter concentration in female MDD patients. METHODS: The whole brain amplitude of low frequency fluctuation (ALFF) analysis using resting state functional magnetic resonance imaging (fMRI) was performed to explore the alteration of intrinsic neuronal signals in MDD females (n=11) compared with female healthy controls (n=11). With a specific interest in the medial prefrontal cortex (mPFC) area, we quantified the concentration of amino acid neurotransmitters including GABA ((r-aminobutyric acid)), Glu (Glutamate), and Glx (Glutamate + Glutamine) using (1)H-MRS technology. Moreover, we conducted Pearson correlation analysis between the ALFF value and neurotransmitter concentration to find out the functional-biochemical relation in mPFC area. The relationship between the metabolites concentration and MDD symptomatology was also examined through Spearman correlation analysis. RESULTS: We found that the female MDD patients showed increased neuronal spontaneous activity in left medial prefrontal cortex (mPFC) and left middle frontal cortex, with decreased ALFF level in right putamen and right middle temporal cortex (p<0.01, Alphasim corrected). The ALFF in mPFC was shown positively correlated with Glu concentration in female MDD patients (r=0.67, p=0.023). The Glu concentration in mPFC was positively correlated with patients HAMA scores (r=0.641, p=0.033). LIMITATIONS: The relatively small sample size, metabolite information acquired only in mPFC and not all patients were unmedicated are the major limitations of our study. CONCLUSIONS: Using combined fMRI-MRS methods, we found increased spontaneous neuronal activity was correlated with Glu concentration in mPFC of female MDD patients. Other regions including left middle frontal gyrus, right putamen and middle temporal gyrus also showed altered spontaneous neuronal activities. The abnormal intrinsic neuronal activities in fronto-cortical regions shed light on the pathogenesis underlying MDD females. The multimodal resting state neuroimaging technique served as a useful tool for functional-biochemical investigation of MDD pathophysiology. PMID- 27235819 TI - Depression predicts mortality and hospitalization in heart failure: A six-years follow-up study. AB - BACKGROUND: The aim of this study is to evaluate the prevalence of depressive symptoms (DS) and its relation on hospitalization for cardiovascular (CV) causes and all-cause mortality risk among outpatients with HF. METHODS: A prospective study was conducted on 130 adult outpatients with HF. The Beck Depression Inventory Scale-second edition (BDI-II) was used to screen for DS. All-cause mortality and hospitalization for CV causes were registered over 6 years. Logistic regression and multinomial logistic regression analysis were used to evaluate the independent prognostic value of DS on mortality and hospitalization for CV causes after adjustment for clinical risk factors. RESULTS: During a mean follow-up of 6 years, 44% of patients were classified as having DS. Sixty-two participants died for all causes, representing 61% of those with DS and 37% of those without (p=0.006); Forty-nine participants (38%) were hospitalized for CV causes, representing 49% of those with DS and 29% of those without (p=0.027). Logistic regression analysis indicated that DS predicted all-cause mortality (OR: 2.905; 95% CI:1.228-6.870; p=0.006) and multinomial logistic regression indicated that DS were predictive of hospitalization for CV causes (OR: 3.169; 95% CI: 1.230-8.164; p=0.027). These associations were independent of conventional risk factors. LIMITATIONS: Only outpatient sample; measure of DS only at baseline; cause of death was not known. CONCLUSION: This study, first held in a portuguese population, showed that DS are independent predictors of death and hospitalization for CV causes among HF patients and its impact persists over 6 years. PMID- 27235820 TI - Late-life depression symptom dimensions and cognitive functioning in the Longitudinal Aging Study Amsterdam (LASA). AB - BACKGROUND: Depression often co-occurs in late-life in the context of declining cognitive functions, but it is not clear whether specific depression symptom dimensions are differentially associated with cognitive abilities. METHODS: The study sample comprised 3107 community-dwelling older adults from the Longitudinal Aging Study Amsterdam (LASA). We applied a Multiple Indicators Multiple Causes (MIMIC) model to examine the association between cognitive abilities and latent dimensions of the Center for Epidemiologic Studies Depression Scale (CES-D), while accounting for differential item functioning (DIF) due to age, gender and cognitive function levels. RESULTS: A factor structure consisting of somatic symptoms, positive affect, depressed affect, and interpersonal difficulties fitted the data well. Higher levels of inductive reasoning were significantly associated with lower levels of depressed affect and somatic symptoms, whereas faster processing speed was significantly associated with lower levels of somatic symptoms. DIF due to age and gender was found, but the magnitude of the effects was small and did not alter substantive conclusions. LIMITATIONS: Due to the cross-sectional context of this investigation, the direction of influence between depression symptom levels and cognitive function levels cannot be established. Furthermore, findings are relevant to non-clinical populations, and they do not clarify whether certain DIF effects may be found only at high or low levels of depression. CONCLUSIONS: Our findings suggest differential associations between late-life depression dimensions and cognitive abilities in old age, and point towards potential etiological mechanisms that may underline these associations. These findings carry implications for the prognosis of cognitive outcomes in depressed older adults. PMID- 27235821 TI - Potential antidepressant-like properties of the TC G-1008, a GPR39 (zinc receptor) agonist. AB - Some forms of depression appear to be more related to the glutamatergic system. G coupled protein receptor 39 (GPR39) is the metabotropic zinc receptor, which may be involved in the pathophysiology of depression and in the antidepressant response. Its deficiency abolishes the antidepressant response, which means that GPR39 is required to obtain a therapeutic effect in depression. This raises the possibility that agonists of the zinc receptor may have a role in antidepressant treatment. To explore this possibility we investigated animal behaviour in the forced swim test, the tail suspension test (to assess antidepressant-like properties), the light/dark test and the elevated plus maze test (to assess anxiolytic-like properties), following acute administration of a GPR39 agonist (TC G-1008). We found an antidepressant response (as measured by the forced swim test but not by the tail suspension test) in mice following the GPR39 agonist treatment. Additionally, we observed the opposite results in the light/dark box (decreased overall distance; increased time spent in the lit compartment; decreased time spent in the dark compartment; increased freezing time) and elevated plus maze (no significant changes), which may be a consequence of the sedative effect of TC G-1008. We also found hippocampal GPR39 and brain-derived neurotrophic factor (BDNF) up-regulation following administration of the GPR39 agonist, which may be undiscovered so far as a possible novel agent in the treatment of mood disorders. PMID- 27235822 TI - Motivations for choosing various food groups based on individual foods. AB - Understanding "why people eat what they eat" is important for improving the lives of people around the world by helping provide industrial and social solutions for people to have greater pleasure and health from the foods they choose. The objective of this study was to investigate the motivations behind everyday choices of different food groups using a bottom-up approach that targeted the specific choices of foods and beverages people consumed at various times of a day. This study was conducted using an online survey included questions related to demographics, the most recent meal including specific food choices, and a slightly modified Eating Motivation Surveys (2 motivations were added, and Check All-That-Apply procedure was used), which contained 50 sub-scales to measure 17 motivations including such topics as Liking, Pleasure, Convenience, Health, Price, Variety Seeking etc. A total of 198 participants have completed the surveys. Data were analyzed by Correspondence Analysis. Liking was found to be the strongest motivation that drove people to select all sorts of foods. Need and Hunger and Convenience were the main motivations for baked products, "fast" foods, sausages and meats, and snack foods while Health and Weight Control were found to be the main driving factors for vegetables, fruits & fruit juices, nuts, seeds, dairy & egg, and poultry products. Sweets were linked to Pleasure. For beverages, people were motivated most by Heath and Weight Control to choose water and tea. Coffee was used due to Habits; soda was because of Pleasure and alcoholic was for socialization purposes. This study provided developers, marketers, health educators, etc. With a new method to understand food choice in order to promote better eating. PMID- 27235823 TI - Increased textural complexity in food enhances satiation. AB - For the first time this study has shown a direct effect of food textural complexity on satiation. Independent of oral processing time, increasing the textural complexity of a food significantly decreased food intake. Foods with complex textures stimulate many sensory perceptions during oral processing, with a succession of textures perceived between first bite and swallow. Previously the impact of texture on satiation (commonly tested by increasing viscosities of semi solids) has been explained by texture's influence on oral processing time; a long oral processing time enhances satiation. The results of the current study show that subjects in a randomised cross-over trial who consumed a "starter" (preload) model food with high textural complexity went on to eat significantly less of a two course ad libitum meal. Subjects who consumed a "starter" model food with low textural complexity, but with the same flavour, energy density and oral processing time, ate significantly more of the same ad libitum meal. The results show that increasing the number of textures perceived during chewing of a solid food triggers the satiation response earlier than when chewing a less texturally complex food. Increasing textural complexity of manufactured foods, to allow for greater sensory stimulation per bite, could potentially be used as a tool to enhance the satiation response and decrease food intake. PMID- 27235824 TI - A prime a day keeps calories away: The effects of supraliminal priming on food consumption and the moderating role of gender and eating restraint. AB - The link between intentions and action in weight control is weaker than previously thought, so recent research has called for further investigation of ways to improve weight control that bypass conscious intentions. Priming has been shown to have effects on individual behavior in a variety of contexts by influencing subconscious cognition. This paper investigates the effects of semantic priming using healthy body image, goal-oriented words on food consumption. The moderating role of both restrained eating and gender is investigated. 161 participants were involved in an experiment using a novel version of a scrambled sentence priming game. The outcome measure was the number of kilocalories consumed, examined using a between subjects ANCOVA with priming, gender, restrained eating index, self-reported BMI, and two interaction terms (primingxgender, and primingxrestrained eating index). There was no main effect of priming but there was an interaction of priming with gender. Females consumed significantly fewer kilocalories after being exposed to priming words related to a healthy body image (i.e. "slim", "fit,") compared to females receiving the neutral prime, with a medium effect size (d = 0.58). The body image prime did not significantly affect food intake for males, nor did it have a differential effect on restrained eaters. This study shows that priming can be an effective method for influencing females to reduce food intake, regardless of whether they are restrained or unrestrained eaters. Future studies could investigate whether different priming words related to a male's healthy body image goal (i.e. "buff," "muscles," etc.) would similarly reduce food intake for males. PMID- 27235825 TI - Determinants of meal satisfaction in a workplace environment. AB - Workplace lunches are recurrent meal occasions that can contribute to the general well-being of employees. The objective of our research was to study which factors influence consumers' satisfaction with these meals by exploring the relative role of food-related, personal, situational factors. Using a longitudinal approach, we monitored a total of 71 participants compiled and experienced 519 meals from their workplace canteen buffet during a three-month period; in addition the composed lunches were photographed. Before and after the lunch choice period respondents filled in a questionnaire on several meal-related variables. A mixed modelling approach was used to analyse the data. Meal satisfaction was directly associated with a positive ambience and a positive evaluation of both the quality of the food eaten and the buffet assortment, whereas the meal's energy content did not contribute to meal satisfaction. Additionally, meal satisfaction was associated with a more positive mood, lower hunger level as well as feeling less busy and stressed after lunch. The buffet assortment, a more positive mood before lunch and mindful eating contributed to the perceived food quality, but not associated with the hunger level before lunch. Time available, mindful eating and eating with close colleagues were positively associated with perceived ambience. The results indicate that consumers' satisfaction with workplace meals can be increased by putting emphasis on the quality of food served, but equally important is the ambience in the lunch situation. Most of the ambience factors were related to available time and mental resources of the participants and the possibility to share the meal with close colleagues. These are factors that can be facilitated by the service provider, but not directly influenced. PMID- 27235826 TI - Simultaneous removal of Cr(VI) and phenol by persulfate activated with bentonite supported nanoscale zero-valent iron: Reactivity and mechanism. AB - The applicability of bentonite-supported nanoscale zero-valent iron (B-nZVI) as a catalyst to activate persulfate (PS) for the simultaneous removal of Cr(VI) and phenol was systematically investigated in this study. Experimental results demonstrated that phenol degradation was significantly enhanced under acidic condition and with oxygen supply, whereas the Cr(VI) reduction was not obviously declined. The removal efficiencies of Cr(VI) and phenol in B-nZVI/PS combined system were 99.8 and 72.3%, respectively. Cr(VI) reduction and phenol oxidation was simultaneously achieved in B-nZVI/PS combined system, which provided a promising environmental treatment for industrial wastewater containing metal ions and organic compounds. An acidic condition was more favorable to the decomposition of persulfate for the production of sulfate radicals. Radical scavenging tests revealed that the predominant reactive oxygen species for phenol degradation was SO4(-), neither HO nor O2(-). A reaction mechanism, which involves the Cr(VI) removal mainly by the reduction of nZVI and the degradation of phenol mainly by the SO4(-) from the decomposition of persulfate, was proposed. These findings revealed that B-nZVI/PS combined system has a potential in the environmental remediation polluted jointly by organic compounds and/or heavy metals. PMID- 27235827 TI - Increased photocatalytic activity of Zn(II)/Cu(II) oxides and sulfides by coupling and supporting them onto clinoptilolite nanoparticles in the degradation of benzophenone aqueous solution. AB - Photocatalytic activity of the coupled ZnO-CuO and ZnS-CuS semiconductors supported onto clinoptilolite nanoparticles (CNP) and micronized one (CMP) was studied in photodegradation of benzophenone (BP) aqueous solution. The ZnO CuO/CNP (or MCP) and ZnS-CuS/CNP (or MCP) catalysts were prepared via calcination and sulfiding of their Zn(II)-Cu(II) ion-exchanged samples, respectively. XRD patterns confirmed loading of the mentioned semiconductors onto the zeolite, and nano dimension of the catalysts was confirmed by XRD and TEM results. Typical Tauc plots obtained from UV-vis DRS spectra showed red shifts for the band gap energies of the supported coupled semiconductors with respect to the supported monocomponent ones especially for ZnO/NCP and ZnS/NCP catalysts. Also, in both indirect and direct transitions, these red shifts were more considerable in the oxidic systems with respect to the sulfidic systems. Accordingly, the supported oxidic systems showed better photocatalytic activity than the sulfidic one. In the oxidic systems changing the dose of CuO played important role while in the sulfidic systems ZnS played considerable role in the degradation of BP. In the used systems, CuO and ZnS played the main e/h generators in the oxidic and sulfidic systems, respectively, while ZnO and CuS played the preventer e/h recombination. Based on the results, production of e/h is the rate limiting step in the used systems. The maximum degradation activity of the catalysts was obtained at: 0.12gL(-1) of ZnO0.80-CuO3.18/NCP and 0.10gL(-1) of ZnS1.39 CuS2.88/NCP catalysts, initial BP concentration of 30mgL(-1) at pH 7.5. PMID- 27235828 TI - Enhancing prediction power of chemometric models through manipulation of the fed spectrophotometric data: A comparative study. AB - Effect of data manipulation in preprocessing step proceeding construction of chemometric models was assessed. The same set of UV spectral data was used for construction of PLS and PCR models directly and after mathematically manipulation as per well known first and second derivatives of the absorption spectra, ratio spectra and first and second derivatives of the ratio spectra spectrophotometric methods, meanwhile the optimal working wavelength ranges were carefully selected for each model and the models were constructed. Unexpectedly, number of latent variables used for models' construction varied among the different methods. The prediction power of the different models was compared using a validation set of 8 mixtures prepared as per the multilevel multifactor design and results were statistically compared using two-way ANOVA test. Root mean squares error of prediction (RMSEP) was used for further comparison of the predictability among different constructed models. Although no significant difference was found between results obtained using Partial Least Squares (PLS) and Principal Component Regression (PCR) models, however, discrepancies among results was found to be attributed to the variation in the discrimination power of adopted spectrophotometric methods on spectral data. PMID- 27235829 TI - In-situ formation of ion-association nanoparticles induced enhancements of resonance Rayleigh scattering intensities for quantitative analysis of trace Hg(2+) ions in environmental samples. AB - In this paper, Hg(2+) ions are demonstrated to form anionic [HgI4](2-) complexes after interacting with massive amount of I(-) ions. Subsequently, the addition of tetradecyl pyridyl bromide (TPB) can make [HgI4](2-) anionic complexes react with univalent tetradecyl pyridyl cationic ions (TP(+)), forming dispersed ion association complexes (TP)2(HgI4). Due to the extrusion action of water and Van der Waals force, the hydrophobic ion-association complexes aggregate together, forming dispersed nanoparticles with an average size of about 8.5nm. Meanwhile, resonance Rayleigh scattering (RRS) intensity is apparently enhanced due to the formation of (TP)2(HgI4) ion-association nanoparticles, contributing to a novel technique for Hg(2+) detection. The wavelength of 365nm is chosen as a detection wavelength and several conditions affecting the RRS responses of Hg(2+) are optimized. Under the optimum condition, the developed method is used for the determination of Hg(2+) in aqueous solution and the detection limit is estimated to be 0.8ngmL(-1). Finally, the practical application of the developed method can be confirmed through the detections of Hg(2+) in waste and river water samples with satisfactory results. PMID- 27235830 TI - Inhibitors in Severe Hemophilia A: 25-Year Experience in Slovakia. AB - We present 25-year experience with inhibitors in previously untreated patients (PUPs) with severe hemophilia A in Slovakia, where safe factor VIII (FVIII) concentrates have been used since 1990. A prospective study focused on inhibitor incidence in PUPs was established in 1997. Out of a total 61 PUPs born between January 1997 and October 2015, 59 were eligible for evaluation; 50 and 9 were treated with > 20 exposure days (ED) of plasma-derived FVIII (pdFVIII) and recombinant FVIII (rFVIII) products, respectively. In the entire group 13/59 (22%) PUPs developed inhibitors; i.e. 7/50 (14%) and 6/9 (67%) treated with pdFVIII and rFVIII, respectively. Univariate analysis of inhibitor risk factors in patient groups with and without inhibitors showed the rFVIII and serious/recurrent infections within the first 50 EDs to be associated with inhibitor development (OR of 12.3 [95% CI 2.48-60.83; p = 0.002] and 5.0; [95% CI 1.16-21.9; p = 0.03), respectively]). Also, in multivariate Cox regression analysis, peak treatment >= 5 EDs reached statistical significance. The hazard ratio (HR) was 7.15 (95% CI 1.65-31.36) p = 0.0086 for rFVIII and 4.38 (95% CI 1.02-18.67) p = 0.046 for intensive treatment. Between 1993 and 2015, 21 immune tolerance inductions (ITIs) in 19 inhibitor patients were performed in the two largest hemophilia centers in Slovakia. In all but one ITI courses pdFVIII containing von Willebrand factor (FVIII/VWF) was used with preferred use of high dose ITI (HD ITI) in high responders (HRs). Complete or partial success was achieved in 17/19 (89.5%) patients. Evaluating only the patients who already completed ITI, the success rate was even higher (15/16; 94%), including 7/7 low responders and 8/9 HR. CONCLUSION: Our national prospective study comprising entire group of PUPs with severe hemophilia A showed higher incidence of inhibitors in patients treated with rFVIII and those with intensive therapy within first 50 EDs. However, our experience is limited to small numbers of patients; thus, our results must be interpreted cautiously. High success rate of the ITI in our inhibitor patients has been achieved with FVIII/VWF concentrates and preferred use of HD ITI in HR patients. PMID- 27235831 TI - Triple Oral Antithrombotic Therapy in Atrial Fibrillation and Coronary Artery Stenting: Searching for the Best Combination. AB - Patients with atrial fibrillation (AF) who are treated with oral anticoagulants often have concurrent coronary artery disease. Triple oral antithrombotic therapy (TOAT) is often necessity to prevent stent thrombosis or myocardial infarction associated with percutaneous coronary intervention or acute coronary syndrome in patients with comorbid coronary artery disease and AF. Although the use of TOAT (aspirin, clopidogrel, and warfarin) has excellent efficacy against thrombotic complications, this comes on the expense of increased bleeding risk. This review discusses potential strategies to improve TOAT benefit-risk ratio evidence from the literature. These strategies include: (1) dropping aspirin; (2) reducing the duration of TOAT; (3) switching warfarin to a direct oral anticoagulant (DOAC); (4) the use of DOAC in combination with a single antiplatelet agent; and (5) switching clopidogrel to a novel antiplatelet agent. Although dropping aspirin and reducing TOAT duration should be considered in selected AF patients at low risk of thrombosis, the role of DOACs and novel antiplatelets in TOAT has not been thoroughly studied, and there is limited evidence to support their use currently. Ongoing studies will provide safety and efficacy data to guide clinicians who frequently face the challenge of determining the best TOAT combination for their patients. PMID- 27235832 TI - A hemagglutinin isolated from Northeast China black beans induced mitochondrial dysfunction and apoptosis in colorectal cancer cells. AB - Incidence of colorectal cancer is closely related with the lifestyle, especially the dietary habits of patients. Epidemiological researches have demonstrated a negative correlation between legume consumption and colorectal cancer incidence. Lectins/hemagglutinins are a type of carbohydrate binding proteins which are abundantly stored in legumes. Their eminent pH-stability allows them to survive digestion and remain active in the intestine where they may have direct contact with colorectal tumors. It is therefore interesting to explore the direct interaction between lectins/hemagglutinins and colorectal cancer. In the present research, we reported a detailed research on the interaction between a hemagglutinin isolated from an edible legume with two colorectal cancer cell lines. This hemagglutinin (NCBBH) was found to first bind to tumor cell membrane as early as 30min post treatment and was gradually transported inside the cytoplasm within 3h, with some of it localized in the Golgi apparatus and some in the lysosomes. After its entrance, the hemagglutinin induced aggregation of the Golgi apparatus, which in turn adversely affected the transportation of protein from endoplasmic reticulum (ER) to the Golgi apparatus, resulting in protein accumulation in ER and ER stress. The hemagglutinin-treated cells also manifested severe mitochondrial malformation and membrane depolarization, accompanied by obvious apoptosis characteristics, like chromatin condensation, phosphatidylserine exposure and caspase activation. Collectively, our results indicate that the hemaggltuinin could successfully enter the cytoplasm of colorectal cancer cells and adversely affect their growth, providing a mechanism in support of the application of edible legumes to the prevention and treatment of colorectal cancer. PMID- 27235834 TI - Acartia tonsa eggs as a biomonitor to evaluate bioavailability/toxicity of persistent contaminants in anoxic/sulfidic conditions: The case of cadmium and nickel. AB - The evaluation of toxicity due to persistent pollutants in anoxic aquatic environments has met with various problems, as most test organisms can not withstand oxygen lack and exposure to free sulfide. We evaluated the suitability of the eggs of the brackish copepod Acartia tonsa for bioassays in anoxic/sulfidic conditions: when exposed to deep hypoxia and free sulfide, the eggs become quiescent and are able to resume hatching after restoring normoxic conditions. Tests with cadmium and nickel were performed in normoxic and deeply hypoxic conditions and in anoxic water containing H2S or H2S+FeSO4 on an equimolar basis. Active and quiescent eggs showed equivalent sensitivity to the metals, both suffering significant reductions in hatching success at 89MUM Cd and 17MUM Ni. As expected on the basis of the SEM/AVS model, Cd toxicity was almost completely suppressed in presence of sulfides. Dissolved Cd concentration drastically dropped and hatching success was generally >80%, as against values <6% observed in sulfide-free water, indicating that the applied experimental procedure can simulate metal-sulfide interaction. Ni toxicity was only slightly reduced by the presence of sulfides. High dissolved Ni concentrations were detected and mean hatching percentages were <=32%, suggesting that Ni bioavailability/toxicity was only partially controlled by excess reactive sulfides. The results suggest that A. tonsa eggs could be a useful biomonitor to evaluate toxicity due persistent contaminants in anoxic conditions and the role of sulfides in reducing metal bioavailability/toxicity. PMID- 27235833 TI - Integrin-mediated transactivation of P2X7R via hemichannel-dependent ATP release stimulates astrocyte migration. AB - Our previous reports indicate that ligand-induced alphaVbeta3 integrin and Syndecan-4 engagement increases focal adhesion formation and migration of astrocytes. Additionally, ligated integrins trigger ATP release through unknown mechanisms, activating P2X7 receptors (P2X7R), and the uptake of Ca(2+) to promote cell adhesion. However, whether the activation of P2X7R and ATP release are required for astrocyte migration and whether alphaVbeta3 integrin and Syndecan-4 receptors communicate with P2X7R via ATP remains unknown. Here, cells were stimulated with Thy-1, a reported alphaVbeta3 integrin and Syndecan-4 ligand. Results obtained indicate that ATP was released by Thy-1 upon integrin engagement and required the participation of phosphatidylinositol-3-kinase (PI3K), phospholipase-C gamma (PLCgamma) and inositol trisphosphate (IP3) receptors (IP3R). IP3R activation leads to increased intracellular Ca(2+), hemichannel (Connexin-43 and Pannexin-1) opening, and ATP release. Moreover, silencing of the P2X7R or addition of hemichannel blockers precluded Thy-1 induced astrocyte migration. Finally, Thy-1 lacking the integrin-binding site did not stimulate ATP release, whereas Thy-1 mutated in the Syndecan-4-binding domain increased ATP release, albeit to a lesser extent and with delayed kinetics compared to wild-type Thy-1. Thus, hemichannels activated downstream of an alphaVbeta3 integrin-PI3K-PLCgamma-IP3R pathway are responsible for Thy-1 induced, hemichannel-mediated and Syndecan-4-modulated ATP release that transactivates P2X7Rs to induce Ca(2+) entry. These findings uncover a hitherto unrecognized role for hemichannels in the regulation of astrocyte migration via P2X7R transactivation induced by integrin-mediated ATP release. PMID- 27235836 TI - The role of treatment delivery factors in exposure-based cognitive behavioral therapy for panic disorder with agoraphobia. AB - Treatment delivery factors (i.e., therapist adherence, therapist competence, and therapeutic alliance) are considered to be important for cognitive behavioral therapy (CBT) for panic disorder and agoraphobia (PD/AG). In the current study, four independent raters conducted process evaluations based on 168 two-hour videotapes of 84 patients with PD/AG treated with exposure-based CBT. Two raters evaluated patients' interpersonal behavior in Session 1. Two raters evaluated treatment delivery factors in Session 6, in which therapists provided the rationale for conducting exposure exercises. At the 6-month follow-up, therapists' adherence (r=0.54) and therapeutic alliance (r=0.31) were significant predictors of changes in agoraphobic avoidance behavior; therapist competence was not associated with treatment outcomes. Patients' interpersonal behavior in Session 1 was a significant predictor of the therapeutic alliance in Session 6 (r=0.17). The findings demonstrate that treatment delivery factors, particularly therapist adherence, are relevant to the long-term success of CBT for PD/AG. PMID- 27235835 TI - Personality and trajectories of posttraumatic psychopathology: A latent change modelling approach. AB - BACKGROUND: Survivors of traumatic events may develop a range of psychopathology, across the internalizing and externalizing dimensions of disorder and associated personality traits. However, research into personality-based internalizing and externalizing trauma responses has been limited to cross-sectional investigations of PTSD comorbidity. Personality typologies may present an opportunity to identify and selectively intervene with survivors at risk of posttraumatic disorder. Therefore this study examined whether personality prospectively influences the trajectory of disorder in a broader trauma-exposed sample. METHODS: During hospitalization for a physical injury, 323 Australian adults completed the Multidimensional Personality Questionnaire-Brief Form and Structured Clinical Interview for DSM-IV, with the latter readministered 3 and 12 months later. Latent profile analysis conducted on baseline personality scores identified subgroups of participants, while latent change modelling examined differences in disorder trajectories. RESULTS: Three classes (internalizing, externalizing, and normal personality) were identified. The internalizing class showed a high risk of developing all disorders. Unexpectedly, however, the normal personality class was not always at lowest risk of disorder. Rather, the externalizing class, while more likely than the normal personality class to develop substance use disorders, were less likely to develop PTSD and depression. CONCLUSIONS: Results suggest that personality is an important mechanism in influencing the development and form of psychopathology after trauma, with internalizing and externalizing subtypes identifiable in the early aftermath of injury. These findings suggest that early intervention using a personality-based transdiagnostic approach may be an effective method of predicting and ultimately preventing much of the burden of posttraumatic disorder. PMID- 27235837 TI - How does social capital matter to the health status of older adults? Evidence from the China Health and Retirement Longitudinal Survey. AB - This paper uses longitudinal data from China to examine the causal relationship between structural social capital and health among Chinese older adults. We employ various econometric strategies to control for the potential endogeneity of social capital and account for the possible contextual confounding effects by including community-level social capital. We use three indicators to measure individuals' general, physical, and mental health. Results indicate that social capital has a significant and positive effect on general and physical health. Based on our primary IV findings, a one standard-deviation increase in social capital leads to a 4.9 standard-deviation decrease in the probability of having bad health and a 2.2 standard-deviation decrease in physical activity limitations. Our results are robust to a series of sensitivity checks. Further analysis suggests heterogeneous effects by age but not by gender or area of residence. PMID- 27235838 TI - HIV drug interaction resources from the University of Liverpool. PMID- 27235839 TI - Imported infections: What information should be collected by surveillance systems to inform public health policy? AB - BACKGROUND: International travel carries the risk of imported diseases, which are an increasingly significant public health problem. There is little guidance about which variables should be collected by surveillance systems for strategy-based surveillance. METHODS: Surveillance forms for dengue, malaria, hepatitis A, typhoid and measles were collected from Australia and New Zealand and information on these compared with national surveillance forms from the UK and Canada by travel health experts. Variables were categorised by information relating to recent travel, demographics and disease severity. RESULTS: Travel-related information most commonly requested included country of travel, vaccination status and travel dates. In Australia, ethnicity information requested related to indigenous status, whilst in New Zealand it could be linked to census categories. Severity of disease information most frequently collected were hospitalisation and death. CONCLUSIONS: Reviewing the usefulness of variables collected resulted in the recommendation that those included should be: overseas travel, reason for travel, entry and departure dates during the incubation period, vaccination details, traveller's and/or parents' country of birth, country of usual residence, time resident in current country, postcode, hospitalisation and death details. There was no agreement about whether ethnicity details should be collected. The inclusion of these variables on surveillance forms could enable imported infection-related policy to be formulated nationally and internationally. PMID- 27235840 TI - Benefits of Invasive Species. PMID- 27235841 TI - Chiral 6-aryl-furo[2,3-d]pyrimidin-4-amines as EGFR inhibitors. AB - Epidermal growth factor receptor inhibitors are of importance in cancer therapy and possibly in the management of pain. Herein, we report a structure-activity relationship study with 29 new 6-aryl-furo[2,3-d]pyrimidin-4-amines, involving modification of the 4-amino group and 6-aryl function. The EGFR activity was especially dependent on having a chiral 4-benzylamino group with correct stereochemistry. Molecular dynamics indicate this to be due to favourable cation pi interactions. The most active inhibitor identified, equipotent to Erlotinib, was substituted with (R)-1-phenylethylamine at C-4 and a N(1), N(1)-dimethyl-1,2 diamine group in para position of the 6-aryl moiety. These new furopyrimidines had a different off-target kinase profile when compared to Erlotinib, and also possessed high activity towards Ba/F3 EGFR(L858R) reporter cells. Further, comparing the EGFR data of the furo[2,3-d]pyrimidin-4-amines with that of the corresponding thieno- and pyrrolopyrimidines concludes the furopyrimidine scaffold to be highly useful for development of new epidermal growth factor receptor antagonists. PMID- 27235842 TI - Structure-based design and synthesis of triazole-based macrocyclic inhibitors of norovirus protease: Structural, biochemical, spectroscopic, and antiviral studies. AB - Outbreaks of acute gastroenteritis caused by noroviruses constitute a public health concern worldwide. To date, there are no approved drugs or vaccines for the management and prophylaxis of norovirus infections. A potentially effective strategy for the development of norovirus therapeutics entails the discovery of inhibitors of norovirus 3CL protease, an enzyme essential for noroviral replication. We describe herein the structure-based design of the first class of permeable, triazole-based macrocyclic inhibitors of norovirus 3C-like protease, as well as pertinent X-ray crystallographic, biochemical, spectroscopic, and antiviral studies. PMID- 27235843 TI - Are inflammatory parameters predictors of amputation in acute arterial occlusions? AB - Background The aim of the present study was to investigate the role of inflammatory markers to predict amputation following embolectomy in acute arterial occlusion. Methods A total of 123 patients operated for arterial thromboembolectomy due to acute embolism were included in the study. The patients without an extremity amputation following thromboembolectomy were classified as Group 1 ( n = 91) and the rest were classified as Group 2 ( n = 32). These groups were compared in terms of clinical and demographic characteristics, C-reactive protein, complete blood count parameters, neutrophil-lymphocyte ratio, platelet lymphocyte ratio and red cell distribution width. Results The average age was 68.0 +/- 11.7 years. The most common thromboembolism localization was femoral artery. When preoperative mean C-reactive protein ( p = 0.0001), mean platelet volume ( p = 0.0001), platelet-lymphocyte ratio ( p = 0.0001), neutrophil lymphocyte ratio ( p = 0.0001) and red cell distribution width ( p = 0.0001) were compared, a statistically significant difference was observed between groups. In univariate and multivariate regression analysis, higher levels of preoperative C reactive protein ( p = 0.009) and mean platelet volume ( p = 0.04) were detected as independent risk factors of early extremity amputation. Conclusion We observed that preoperative mean platelet volume and C-reactive protein were predictors of amputation after thromboembolectomy in acute arterial occlusion. PMID- 27235844 TI - Offering self-sampling to cervical screening non-attenders in primary care. AB - Objectives To assess the feasibility and acceptability of offering self-sampling for Human Papillomavirus (HPV) testing to cervical screening non-attenders when they consult primary care for any reason. Methods In a pilot implementation study, six general practices in London, UK, offered self-sampling kits during consultation to women aged 25-64 who were at least six months overdue for cervical screening (no cytology test recorded in the past 3.5 years if aged 25 49, or 5.5 years if aged 50-64). Eligible women were identified using an automated real-time search (during consultation) of the general practice electronic medical record system. Women collected samples either in clinic or at home (dry flocked swabs analysed using Roche Cobas(r)4800). Results Of approximately 5000 eligible women, 3131 consulted primary care between January and December 2014 (mean recruitment period 9.5 months). Of these, 21% (652) were offered kits, 14% (443) accepted, and 9% (292) returned a self-sample. The proportion of eligible women offered kits varied considerably among practices (11 36%). Sample return rates increased with kit offered rates ( r = 0.8, p = 0.04). Of 39 HPV positive women 85% (33) attended follow-up, including two with invasive cancers (stage 2A1 and 1A1). Conclusions Offering self-sampling to cervical screening non-attenders opportunistically in primary care is feasible. Return rates could be increased if more women were offered kits. A large trial is needed to identify how self-sampling is best integrated into the national screening programme, and to identify determinants of uptake. PMID- 27235845 TI - Medical students' views about person-centred communication in dementia care. AB - Adopting principles of person-centred communication has been highlighted as one strategy to improve care of people living with dementia (PLWD) in health and social care settings. However, person-centred communication is interpreted and applied variably in different settings, and healthcare professionals' views about communicating with PLWD are under-explored. This study aimed to investigate medical students' views about the principles and applicability of a model of person centred communication - the Dementia Model of Effective Communication (DeMEC) - to clinical practice. Quantitative and qualitative data was collected using questionnaires ( n = 531), focus groups ( n = 21) and interviews ( n = 10). Students generally endorsed the person-centred approach to communication, but two aspects were highlighted as complex and divisive - the acceptability or otherwise of lying, and of communicating with family in advance of the PLWD. We discuss the nature of these communicative dilemmas, implications for the education and training of medical students, and future directions for research. PMID- 27235846 TI - The Role of Rainfall in Sternechus subsignatus (Coleoptera: Curculionidae) Adult Emergence From the Soil After Its Winter Dormant Period. AB - In this work, we report the effect of rainfall on Sternechus subsignatus Boheman, 1836, adult emergence after winter dormancy. This weevil is a univoltine soybean pest found in northwestern Argentina, a subtropical region with dry winters and rainy summers. Before harvest, fully grown larvae burrow into the soil where they overwinter. In the spring, they emerge as adults and recolonize the crop during its planting and early vegetative stages. Our study examines the seasonal timing of adult emergence with the aim of improving chemical control strategies and avoiding unnecessary pesticide applications. To do so, we developed a regression model to predict adult emergence onset as a function of cumulated rainfall after 1st November. The regression with the highest coefficient of determination between cumulated rainfall and adult emergence onset was Emergence onset (Julian day) = -7.98 Ln(cumulative rainfall) + 65.7. The negative relationship showed that adults emerged earlier in wet years than in dry years. Also it was observed that adults emerged from late November to mid-March, in pulses following periods of rainfall. Males were more abundant than females at first, but then the reverse was true toward the end of the period. In most cases, there was a suggestion of relationship (though not significantly) between peaks of adult emergence with peaks of rainfall 15 d before adult emergence. These results reveal that rainfall has a significant impact on the beginning and dynamics of adult emergence from the soil. PMID- 27235847 TI - Occupational Exposure to Bioaerosols in Norwegian Crab Processing Plants. AB - INTRODUCTION: Aerosolization of components when processing king crab (Paralithodes camtschaticus) and edible crab (Cancer pagurus) may cause occupational health problems when inhaled by workers. METHODS: A cross-sectional study was carried out in three king crab plants and one edible crab plant. Personal exposure measurements were performed throughout work shifts. Air was collected for measurement of tropomyosin, total protein, endotoxin, trypsin, and N-acetyl-beta-d-glucosaminidase (NAGase). T-tests and ANOVAs were used to compare the levels of exposure in the different plants and areas in the plants. RESULTS: Total protein and tropomyosin levels were highest in the edible crab plant, endotoxin levels were highest in king crab plants. King crab exposure levels were highest during raw processing. Tropomyosin levels were highest during raw king crab processing with geometric mean (GM) 9.6 versus 2.5ng m(-3) during cooked processing. Conversely, edible crab tropomyosin levels were highest during cooked processing with GM 45.4 versus 8.7ng m(-3) during raw processing. Endotoxin levels were higher in king crab plants than in the edible crab plant with GM = 6285.5 endotoxin units (EU) m(-3) versus 72 EU m(-3). In the edible crab plant, NAGase levels were highest during raw processing with GM = 853 pmol4 methylumbelliferone (MU) m(-3) versus 422 pmol4-MU m(-3) during cooked processing. Trypsin activity was found in both king crab and edible crab plants and levels were higher in raw than cooked processing. Differences in exposure levels between plants and worker groups (raw and cooked processing) were identified. CONCLUSIONS: Norwegian crab processing workers are exposed to airborne proteins, tropomyosin, endotoxins, trypsin, and NAGase in their breathing zone. Levels vary between worker groups and factories. PMID- 27235849 TI - Skeletal muscle adaptation to immobilization and subsequent retraining in elderly men: No effect of anti-inflammatory medication. AB - BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) may enhance resistance training induced gain in skeletal muscle mass and strength, but it is unknown if NSAIDs affects muscle loss during periods of inactivity in elderly individuals. Thus, we studied the influence of NSAID treatment on human skeletal muscle during immobilization and rehabilitation resistance training (retraining). METHODS: 19 men (60-80yrs, range) were randomly assigned to ibuprofen (1200mg/d, Ibu) or placebo (Plc). One lower limb was immobilized in a cast for 2weeks and retrained for 6weeks. Moreover, whey protein isolate was ingested (2*20g/d) throughout the whole study period. Plasma inflammatory markers, quadriceps muscle mass and strength, and muscle gene expression were investigated. RESULTS: Muscle mass and strength decreased after 2weeks of immobilization (P<0.001), but returned to baseline levels after 2weeks of retraining combined with whey protein supplementation (P<0.001). Furthermore, muscle mass and strength reached beyond baseline levels after 6weeks of retraining (p<0.05), and NSAID did not significantly affect this (p>0.05). No group-differences, but differences over time, were observed for muscle gene expression of proteolytic and anabolic factors. Plasma inflammatory markers were unaffected by the study intervention and NSAID treatment. CONCLUSION: Two weeks of lower limb immobilization lead to a reduction in muscle mass and strength, but these parameters were restored already after2 weeks of retraining and whey protein supplementation. After 6weeks of retraining and whey protein supplementation, muscle mass and strength increased beyond baseline levels, and NSAID treatment did not significantly influence this in elderly. PMID- 27235848 TI - Aging-related 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurochemial and behavioral deficits and redox dysfunction: improvement by AK-7. AB - Aging is a prominent risk factor for the occurrence and progression of Parkinson disease (PD). Aging animals are more significant for PD research than young ones. It is promising to develop effective treatments for PD through modulation of aging-related molecules. Sirtuin 2 (SIRT2), a strong deacetylase highly expressed in the brain, has been implicated in the aging process. In our present study, 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 12mg/kg once daily) was observed to bring about significant behavioral deficits and striatal dopamine depletion in aging male and female mice, while it did not do so in young animals. MPTP did not cause significant reduction in striatal 5-hydroxytryptamine content in aging male and female mice. Furthermore, we observed that MPTP treatment resulted in significant reduction in GSH content and significant increase in MDA content and SIRT2 expression in the substantia nigra (SN) of aging mice, while it did not do so in young animals. Importantly, we observed that AK-7 (a selective SIRT2 inhibitor) significantly improved behavior abnormality and neurochemical deficits in aging male and female mice treated with MPTP. Significant increase in GSH content and significant decrease in MDA content were also observed in the SN of aging male and female mice co-treated with MPTP and AK-7 compared with the MPTP-treated animals. Our results indicated that MPTP induce aging-related neurochemical and behavioural deficits and dysfunction of redox network in male and female mice and AK-7 may be neuroprotective in PD through modulating redox network. PMID- 27235850 TI - What physical performance measures predict incident cognitive decline among intact older adults? A 4.4year follow up study. AB - Reductions in physical performance, cognitive impairment (CI) and decline (CD), are common in older age, but few prospective cohort studies have considered the relationship between these domains. In this study we investigated whether reduced physical performance and low handgrip/lower limbs strength, could predict a higher incidence of CI/CD during a 4-year follow-up among a cohort of elderly individuals. From 3099 older community-dwelling individuals initially enrolled in the Progetto Veneto Anziani (PRO.V.A.) study, 1249 participants without CI at the baseline were included (mean age 72.2years, 59.5% females). Physical performance measures included the Short Physical Performance Battery (SPPB), 4m gait speed, chair stands time, leg extension and flexion, handgrip strength, and 6-Minute Walking Test (6MWT), categorized in gender-specific tertiles. CI was defined as a Mini-Mental State Examination (MMSE) score below 24; CD a decline of 3 or more points in the MMSE without CI. At baseline, participants developing CI during follow-up scored significantly worse across all physical performance measures compared to those that retained normal cognitive status. After adjusting for potential confounders, a significant trend for MMSE changes was noted for all physical performance tests, except for the SPPB and chair stands time. Multinomial logistic regression revealed that slow gait speed at baseline significantly predicted CD at follow up. Poor SPPB performance and slower gait speed predicted the onset of CI at the follow-up. In conclusion, slow walking speed appears to be the best independent predictor of poor cognitive status over a 4.4-year follow-up, while other items of SPPB were also significantly associated with CI. PMID- 27235851 TI - Keeping the senescence secretome under control: Molecular reins on the senescence associated secretory phenotype. AB - Cellular senescence is historically associated with cancer suppression and aging. Recently, the reach of the senescence genetic program has been extended to include the ability of senescent cells to actively participate in tissue remodelling during many physiological processes, including placental biology, embryonic patterning, wound healing, and tissue stress responses caused by cancer therapy. Besides growth arrest, a significant feature of senescent cells is their ability to modify their immediate microenvironment using a senescence-associated (SA) secretome, commonly termed the SA secretory phenotype (SASP). Among others, the SASP contains growth factors, cytokines, and extracellular proteases that modulate the majority of both the beneficial and detrimental microenvironmental phenotypes caused by senescent cells. The SASP is thus becoming an obvious pharmaceutical target to manipulate SA effects. Herein, we review known signalling pathways underlying the SASP, including the DNA damage response (DDR), stress kinases, inflammasome, alarmin, inflammation- and cell survival-related transcription factors, miRNAs, RNA stability, autophagy, chromatin components, and metabolic regulators. We also describe the SASP as a temporally regulated dynamic sub-program of senescence that can be divided into a rapid DDR-associated phase, an early self-amplification phase, and a late "mature" phase, the late phase currently being the most widely studied SASP signature. Finally, we discuss how deciphering the signalling pathways regulating the SASP reveal targets that can be manipulated to harness the SA effects to benefit therapies for cancer and other age-related pathologies. PMID- 27235852 TI - William Whewell's philosophy of architecture and the historicization of biology. AB - William Whewell's work on historical science has received some attention from historians and philosophers of science. Whewell's own work on the history of German Gothic church architecture has been touched on within the context of the history of architecture. To a large extent these discussions have been conducted separately. I argue that Whewell intended his work on Gothic architecture as an attempt to (help) found a science of historical architecture, as an exemplar of historical science. I proceed by analyzing the key features of Whewell's philosophy of historical science. I then show how his architectural history exemplifies this philosophy. Finally, I show how Whewell's philosophy of historical science matches some developments in a science (biological systematics) that, in the mid-to late-nineteenth century, came to be reinterpreted as a historical science. I comment briefly on Whewell as a potential influence on nineteenth century biology and in particular on Darwin. PMID- 27235853 TI - "Triple negative breast cancer": Translational research and the (re)assembling of diseases in post-genomic medicine. AB - The paper examines the debate about the nature and status of "Triple-negative breast cancer", a controversial biomedical entity whose existence illustrates a number of features of post-genomic translational research. The emergence of TNBC is intimately linked to the rise of molecular oncology, and, more generally, to the changing configuration of the life sciences at the turn of the new century. An unprecedented degree of integration of biological and clinical practices has led to the proliferation of bio-clinical entities emerging from translational research. These translations take place between platforms rather than between clinical and laboratory settings. The complexity and heterogeneity of TNBC, its epistemic and technical, biological and clinical dualities, result from its multiple instantiations via different platforms, and from the uneven distribution of biological materials, techniques, and objects across clinical research settings. The fact that TNBC comes in multiple forms, some of which seem to be incompatible or, at least, only partially overlapping, appears to be less a threat to the whole endeavor, than an aspect of an ongoing translational research project. Discussions of translational research that rest on a distinction between basic research and its applications fail to capture the dynamics of this new domain of activity, insofar as application is built-in from the very beginning in the bio-clinical entities that emerge from the translational research domain. PMID- 27235855 TI - Senescent endothelial cells: Potential modulators of immunosenescence and ageing. AB - Recent studies have demonstrated that the accumulation of senescent endothelial cells may be the primary cause of cardiovascular diseases. Because of their multifunctional properties, endothelial cells actively take part in stimulating the immune system and inflammation. In addition, ageing is characterized by the progressive deterioration of immune cells and a decline in the activation of the immune response. This results in a loss of the primary function of the immune system, which is eliminating damaged/senescent cells and neutralizing potential sources of harmful inflammatory reactions. In this review, we discuss cellular senescence and the senescence-associated secretory phenotype (SASP) of endothelial cells and summarize the link between endothelial cells and immunosenescence. We describe the possibility that age-related changes in Toll like receptors (TLRs) and microRNAs can affect the phenotypes of senescent endothelial cells and immune cells via a negative feedback loop aimed at restraining the excessive pro-inflammatory response. This review also addresses the following questions: how do senescent endothelial cells influence ageing or age-related changes in the inflammatory burden; what is the connection between ECs and immunosenescence, and what are the crucial hypothetical pathways linking endothelial cells and the immune system during ageing. PMID- 27235854 TI - Experimentally-induced anti-myeloperoxidase vasculitis does not require properdin, MASP-2 or bone marrow-derived C5. AB - Anti-neutrophil cytoplasmic antibody vasculitis is a systemic autoimmune disease with glomerulonephritis and pulmonary haemorrhage as major clinical manifestations. The name reflects the presence of autoantibodies to myeloperoxidase and proteinase-3, which bind to both neutrophils and monocytes. Evidence of the pathogenicity of these autoantibodies is provided by the observation that injection of anti-myeloperoxidase antibodies into mice causes a pauci-immune focal segmental necrotizing glomerulonephritis which is histologically similar to the changes seen on renal biopsy in patients. Previous studies in this model have implicated the alternative pathway of complement activation and the anaphylatoxin C5a. Despite this progress, the factors that initiate complement activation have not been defined. In addition, the relative importance of bone marrow-derived and circulating C5 is not known. This is of interest given the recently identified roles for complement within leukocytes. We induced anti-myeloperoxidase vasculitis in mice and confirmed a role for complement activation by demonstrating protection in C3-deficient mice. We showed that neither MASP-2- nor properdin-deficient mice were protected, suggesting that alternative pathway activation does not require properdin or the lectin pathway. We induced disease in bone marrow chimaeric mice and found that circulating and not bone marrow-derived C5 was required for disease. We have therefore excluded properdin and the lectin pathway as initiators of complement activation and this means that future work should be directed at other potential factors within diseased tissue. In addition, in view of our finding that circulating and not bone marrow-derived C5 mediates disease, therapies that decrease hepatic C5 secretion may be considered as an alternative to those that target C5 and C5a. (c) 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 27235856 TI - C(16)-C(22) oxygen-bridged analogues of ceDAF-12 and LXR ligands. AB - The DAF-12 receptor in nematodes and the Liver X Receptor (LXR) in mammals are structurally related transcription factors that play key roles in determining the life span of the organism. Both types of receptors are activated by oxysterols, cholesterol metabolites with oxidized side chains. Restricting the movement of the oxysterol side chain to certain orientations may have profound effects in the activity profile, however this has not been explored so far. In a first attempt to obtain analogues of natural ligands of DAF-12 and LXR with restricted side chain mobility we introduced a 16,22-oxygen bridge in 26-hydroxycholesterol, a cholestenoic acid and a dafachronic acid (5-7). Diosgenin was used as starting material, the key step to obtain the 16,22 epoxy functionality was the one pot formation and reduction of a cyclic hemiketal via the oxocarbenium ion using sodium cyanoborohydride. All new compounds were characterized by NMR and mass spectrometry and assayed as ceDAF-12 or LXR ligands in transactivation cell-based assays. The dafachronic acid analogue 7 behaved as a ceDAF-12 agonist. PMID- 27235857 TI - Muscle composition measured by CT scan is a measurable predictor of overall survival in advanced ovarian cancer. AB - OBJECTIVES: To assess the impact of muscle composition and sarcopenia on overall survival in advanced epithelial ovarian cancer (EOC) after primary debulking surgery (PDS). METHODS: Women with stage IIIC/IV EOC who underwent PDS with curative intent between 1/1/2006 and 12/31/2012 were included. Patient variables and vital status were abstracted. Body composition was evaluated in a semi automated process using Slice-O-Matic software v4.3 (TomoVision). Skeletal muscle area and mean skeletal muscle attenuation were recorded. Associations with overall survival were evaluated using Cox proportional hazards models and recursive partitioning. RESULTS: We identified 296 patients and 132 (44.6%) were classified as sarcopenic. The average mean skeletal muscle attenuation of the entire cohort was 33.4 Hounsfield units (HU). A multivariate model of overall risk of death included histology, residual disease, and mean skeletal attenuation. Among patients without residual disease, overall survival, but not progression free survival was significantly different between patients with low versus high mean skeletal attenuation (median survival, 2.8 vs. 3.3years). Among patients with residual disease, overall survival was significantly different between patients with low versus high mean skeletal attenuation >=36.40 vs. <36.40 HU (median survival, 2.0 vs. 3.3years). CONCLUSIONS: Sarcopenia and low mean skeletal muscle attenuation are common in women undergoing PDS for advanced EOC. These factors are associated with poorer outcomes, and can be used in preoperative risk stratification and patient counseling. Further research into body composition and whether this risk factor can be altered via nutrition or fitness in this population is warranted. PMID- 27235858 TI - Characterization of ovarian cancer cell lines as in vivo models for preclinical studies. AB - OBJECTIVE: The value of cell lines for pre-clinical work lies in choosing those with similar characteristics. Selection of cell lines is typically based on patient history, histological subtype at diagnosis, mutation patterns, or signaling pathways. Although recent studies established consensus regarding molecular characteristics of ovarian cancer cell lines, data on in vivo tumorigenicity remains only sporadically available, impeding translation of in vitro work to xenograft models. METHODS: We introduced 18 ovarian cancer cell lines into athymic nude mice through subcutaneous, intraperitoneal, and ovary intrabursal routes, and observed tumor development over 6weeks. We also profiled cell line gene expression and identified differentially expressed gene sets based on their ability to form tumors in the subcutaneous or intraperitoneal locations. Representative cell lines were further subjected to proteomic analyses. RESULTS: Ovarian cancer cell lines showed variable ability to grow in mice when implanted subcutaneous, intraperitoneal, or intrabursal. While some cell lines grew well in both SC and IP locations, others showed a strong propensity to grow in one location only. Gene expression profiles suggested that cell lines showing preference for IP growth had gene expression patterns more similar to primary tumors. CONCLUSIONS: We report the tumorigenicity of 17 human ovarian cancer cell lines and one mouse cell line in three distinct anatomical locations, and associated gene networks. Growth patterns and histopathology, linked to molecular characteristics, provide a valuable resource to the research community, and better guide the choice of cell lines for in vitro studies to translate efficiently into xenograft testing. PMID- 27235859 TI - Intra-cellular mechanism of Anti-Mullerian hormone (AMH) in regulation of follicular development. AB - Anti-Mullerian hormone (AMH) is a member of the transforming growth factor-beta superfamily and plays a crucial role in testicular and ovarian functions. In clinical practice, AMH is used as a diagnostic and/or prognostic marker in women in association with ovulation induction and in various pathophysiological conditions. Despite widespread clinical use of AMH, our mechanistic understanding of AMH actions in regulating follicular development is limited. Using a mouse model, we in this study report that in vivo AMH treatment while stalls follicular development and inhibits ovulation, also prevents follicular atresia. We further show that these AMH actions are mediated through induction of two miRNAs, miR 181a and miR-181b, which regulate various aspects of FSH signaling and follicular growth, ultimately affecting downstream gene expression and folliculogenesis. We also report that in this mouse model AMH pre-treatment prior to superovulation improves oocyte yield. These studies, therefore, offer new mechanistic insight into AMH actions in folliculogenesis and point toward potential utilization of AMH as a therapeutic agent. PMID- 27235860 TI - PGC-1alpha ameliorates AngiotensinII-induced eNOS dysfunction in human aortic endothelial cells. AB - Increasing evidences support that PGC-1alpha participates in regulating endothelial homeostasis, in part by mediating endothelial nitric oxide (NO) synthase (eNOS) activity and NO production. However, the molecular mechanisms by which PGC-1alpha regulates eNOS activity are not completely understood. In the present study, we investigated the effects of PGC-1alpha on eNOS dysfunction and further explore the underlying mechanisms. The results showed that PGC-1alpha expression was downregulated after AngiotensinII (AngII) treatment and paralleled with the decreased NO generation in human aortic endothelial cells. Overexpression of PGC-1alpha with adenovirus or pharmacological agonist ameliorated AngII-induced the decrease of NO generation, evidenced by the restoration of cGMP and nitrite concentration. Rather than affecting eNOS expression and uncoupling, PGC-1alpha inhibited AngII-induced decrease of eNOS serine 1177 phosphorylation through activation of PI3K/Akt signaling. In addition, PGC-1alpha overexpression suppressed AngII-induced the increase of PP2A A/eNOS interaction and PP2A phosphatase activity, with a concomitant decrease in PP2A phosphorylation, leading to eNOS serine 1177 phosphorylation. However, pharmacological inhibition of PI3K/Akt signaling blunted the observed effect of PGC-1alpha on PP2A activity. Taken together, our findings suggest that PGC-1alpha overexpression improves AngII-induced eNOS dysfunction and that improved eNOS dysfunction is associated with activated PI3K/Akt pathway, impaired PP2A activity and reduced PP2A-A/eNOS association. These date indicate that forced PGC-1alpha expression may be a novel therapeutic approach for endothelial dysfunction. PMID- 27235862 TI - The evaluation of new psychoactive drugs. PMID- 27235861 TI - Vascular disrupting activity of combretastatin analogues. AB - Tubulin binding agents (TBAs) are drugs commonly used in cancer therapy as antimitotics. In the last years it has been described that TBAs, like combretastatin A-4 (CA-4), present also vascular disrupting activity and among its derivatives we identified three analogues endowed with potent microtubule depolymerizing activity, higher than that of the lead compound. In this paper we have investigated the anti-vascular activity of these derivatives. We tested the anti-angiogenic effects in human umbilical endothelial cells (HUVEC) and in vivo in chick chorioallantoic membrane assay (CAM), and in a syngeneic tumor mouse model. The three molecules, compound 1: 1-(3,4,5-trimethoxyphenyl)-5-(4 ethoxyphenyl)-1H-1,2,4-triazole; compound 2: (1-(3,4,5-trimethoxyphenyl)-5-(4 ethoxyphenyl)-1H-tetrazole, compound-3 (4-amino-2-p-tolylaminothiazol-5-yl) (3,4,5-trimethoxyphenyl)-methanone) showed a moderate effect on the growth of HUVEC cells at concentrations below 200nM. At lower concentrations (5-20nM), in particular compound 2, they induced inhibition of capillary tube formation, inhibition of endothelial cell migration and affected endothelial cell morphology as demonstrated by the alteration of the microfilaments network. Moreover, they also increased permeability of HUVEC cells in a time dependent manner. In addition, compounds 1 and 3, as well as the reference compound CA-4, inhibited VEGF-induced phosphorylation of VE-cadherin and in addition compound 3 prevented the VEGF-induced phosphorylation of FAK. In CAM assay, both compounds 2 and 3 efficiently counteracted the strong angiogenic response induced by bFGF, even at the lowest concentration used (1pmol/egg). Moreover in a syngenic mouse model, compounds 1-3 after a single i.p. injection (30mg/kg), showed a stronger reduction of microvascular density. Altogether our results identified these derivatives as potential new vascular disrupting agents candidates. PMID- 27235863 TI - Survival analysis of veteran patients with pancreatic cancer. AB - OBJECTIVE: For patients with pancreatic cancer, the identification of reliable predictors of their outcomes could be invaluable for directing the managements. This study aimed to identify clinical and laboratory factors that could be used to predict early (<=6 months) or late (>6 months) mortality. METHODS: Medical records of patients diagnosed with pancreatic cancer in the VA North Texas Health Care System from 2005 to 2010 were retrospectively reviewed. Univariate and multivariate analyses (MVA) were performed and the utility of cancer antigen 19-9 (CA19-9) test was explored. RESULTS: Altogether 109 patients with pancreatic cancer, 89.0% of whom were with adenocarcinoma, were divided into early (n = 62) and late (n = 47) mortality groups. Kaplan-Meier analysis revealed a median survival of 154 days [95% confidence interval (CI) 93-194 days]. On MVA, abdominal pain (OR = 10.6, P = 0.009) and large tumor size (OR = 2.4, P = 0.028) were significantly associated with early mortality, while palliative chemotherapy (OR = 0.048, P = 0.001) and neuroendocrine tumor (OR = 0.009, P = 0.024) were significantly associated with late mortality. Subgroup analyses of adenocarcinoma and late-stage patients revealed similar results. Serum CA19-9 performed poorly as a prognostic indicator in both groups (P = 0.43), in metastatic disease at diagnosis (P = 0.32) and after treatment (P = 0.65). CONCLUSIONS: Abdominal pain and large tumor size portends a poor prognosis in patients with pancreatic cancer. Palliative chemotherapy and surgical intervention may prolong the patient's survival. CA19-9 is not universally reliable for predicting metastasis, survival, or the responses to chemotherapy. PMID- 27235864 TI - Tracing short connections of the temporo-parieto-occipital region in the human brain using diffusion spectrum imaging and fiber dissection. AB - The temporo-parieto-occipital (TPO) junction plays a unique role in human high level neurological functions. Long-range fibers from and to this area have been described in detail but little is known about short TPO tracts mediating local connectivity. In this study, we performed high angular diffusion spectrum imaging (DSI) analyses to visualize the short TPO connections in the human brain. Fiber tracking was conducted on a subject-specific approach (10 subjects) and a template of 90 subjects (NTU-90 Atlas). Three tracts were identified: posterior segment of the superior longitudinal fasciculus (SLF-V), connecting the posterior part of the middle and inferior temporal gyri with the angular gyrus and supramarginal gyrus, vertical occipital fasciculus (VOF), connecting the inferior parietal with the lower temporal and occipital lobe, and a novel temporo-parietal (TP) connection, interconnecting the inferior temporal gyrus, middle temporal gyrus and fusiform gyrus, and inferior occipital lobe with the superior parietal lobe. These studies were complemented by fiber dissection techniques. It is the first study that demonstrated the trajectory and connectivity of the VOF using fiber dissection, as well as displayed the spatial relationship of the SLF-V with the cortex and the adjacent fiber bundles on one dissecting hemisphere. By providing a more accurate and detailed description of the local connectivity of the TPO junction, our findings help to develop new insights into its functional role in the human brain. PMID- 27235865 TI - Hippocampal neurogenesis response: What can we expect from two different models of hypertension? AB - Hypertension is associated with cerebrovascular disease, white matter lesion and cognitive deficit, both in experimental models and clinical observations. Furthermore, in non-clinical models it is shown that hippocampus is affected by hypertension and hypoxia. Herein, two distinct hypertension models were used to study neurogenic response in hippocampus. Dahl salt sensitive (DSS) rat model is a genetic based idiopathic model, while chronic intermittent hypoxia (CIH) mimics the hypertension observed in patients with obstructive sleep apnea (OSA). Both models are chronic and trigger hypertension. No macroscopic alterations based on histological analysis were found in hippocampus derived from DSS and CIH exposure rats. Nevertheless, in hippocampus derived from CIH-induced hypertensive rats, there was a decrease on neuronal population (MAP2 and NeuN positive cells) and an increase on astrocytic marker GFAP. Accordingly, a higher increase on Ki67 expressing cells was found in dentate gyrus (DG) region, suggesting an enhancement of cell proliferation, concomitantly with an increase of Nestin staining, which indicates the presence of immature neurons under differentiation. While, in hippocampus of DSS rats with or without high salt diet, there was no remarkable difference indicating potential neuronal loss, astrocytic activation or neurogenesis. Furthermore, in both models hypertension did not alter the levels of expression of the stress response enzyme heme oxygenase-1 in DG. These data indicate that intermittent hypoxia might be the key factor involved in neurogenesis modulation in hippocampus. Furthermore, two hypotheses can be explored: (i) activation of neurogenesis is a response against neuronal loss induced by hypertension and/or hypoxia or (ii) neurogenesis can be directly stimulated by hypoxia as a neuroprotective mechanism. PMID- 27235867 TI - The role of orexin type-1 receptors in the development of morphine tolerance in locus coeruleus neurons: An electrophysiological perspective. AB - Long-term exposure to opioid agonists results in tolerance to their analgesic effects, so the effectiveness of opioid agonists in the management of pain becomes limited. The locus coeruleus (LC) nucleus has been involved in the development of tolerance to opiates. Orexin type-1 receptors (OX1Rs) are highly expressed in LC nucleus. Orexin plays a noteworthy role in the occurrence of morphine tolerance. The purpose of the present study is to investigate the role of orexin type-1 receptors in the development of morphine tolerance in LC neurons. In this study, adult male Wistar rats weighing 250-300g were utilized. Induction of morphine tolerance was obtained by single injection of morphine per day for 6 successive days. An orexin type-1 receptor antagonist (SB-334867) was injected into the lateral ventricle instantly prior to morphine injection. On day 7, the effect of morphine on the electrical activity of LC neurons was studied using in vivo extracellular single unit recording. The results demonstrate that morphine injection for 6 consecutive days led to the development of morphine induced tolerance in LC neurons. In other words, there was a significant decrease in LC neuronal responsiveness to morphine injection. Inhibitory responses of LC neurons to intraperitoneally applied morphine can be observed with the treatment of the SB-334867 prior to morphine injection. This study showed that OX1R blockade by SB-334867 prevents the development of morphine tolerance in LC neurons. We hope that further studies will lead to considerable progress in understanding the molecular adaptations that contribute to morphine tolerance. PMID- 27235866 TI - Expression of microRNA-34a in Alzheimer's disease brain targets genes linked to synaptic plasticity, energy metabolism, and resting state network activity. AB - Polygenetic risk factors and reduced expression of many genes in late-onset Alzheimer's disease (AD) impedes identification of a target(s) for disease modifying therapies. We identified a single microRNA, miR-34a that is over expressed in specific brain regions of AD patients as well as in the 3xTg-AD mouse model. Specifically, increased miR-34a expression in the temporal cortex region compared to age matched healthy control correlates with severity of AD pathology. miR-34a over expression in patient's tissue and forced expression in primary neuronal culture correlates with concurrent repression of its target genes involved in synaptic plasticity, oxidative phosphorylation and glycolysis. The repression of oxidative phosphorylation and glycolysis related proteins correlates with reduced ATP production and glycolytic capacity, respectively. We also found that miR-34a overexpressed neurons secrete miR-34a containing exosomes that are taken up by neighboring neurons. Furthermore, miR-34a targets dozens of genes whose expressions are known to be correlated with synchronous activity in resting state functional networks. Our analysis of human genomic sequences from the tentative promoter of miR-34a gene shows the presence of NFkappaB, STAT1, c Fos, CREB and p53 response elements. Together, our results raise the possibilities that pathophysiology-induced activation of specific transcription factor may lead to increased expression of miR-34a gene and miR-34a mediated concurrent repression of its target genes in neural networks may result in dysfunction of synaptic plasticity, energy metabolism, and resting state network activity. Thus, our results provide insights into polygenetic AD mechanisms and disclose miR-34a as a potential therapeutic target for AD. PMID- 27235869 TI - Different contributions of visual and motor brain areas during liking judgments of same- and different-gender bodies. AB - Previous neuroimaging studies have shown that body aesthetic appreciation involves the activation of both visual and motor areas, supporting a role of sensorimotor embodiment in aesthetic processing. Causative evidence, however, that neural activity in these areas is crucial for reliable aesthetic body appreciation has so far provided only for extrastriate body area (EBA), while the functional role played by premotor regions remained less clear. Here, we applied short trains of repetitive transcranial magnetic stimulation (rTMS) over bilateral dorsal premotor cortex (dPMC) and EBA during liking judgments of female and male bodies varying in weight and implied motion. We found that both dPMC and EBA are necessary for aesthetic body appreciation, but their relative contribution depends on the model's gender. While dPMC-rTMS decreased the liking judgments of same-, but not of different-gender models, EBA-rTMS increased the liking judgments of different-, but not of same-gender models. Relative contributions of motor and visual areas may reflect processing of diverse aesthetic properties, respectively implied motion vs. body form, and/or greater sensorimotor embodiment of same- vs. different-gender bodies. Results suggest that aesthetic body processing is subserved by a network of motor and visual areas, whose relative contribution may depend on the specific stimulus and task. PMID- 27235868 TI - Hypothermia-induced ischemic tolerance is associated with Drp1 inhibition in cerebral ischemia-reperfusion injury of mice. AB - Excessive mitochondrial fission activation has been implicated in cerebral ischemia-reperfusion (IR) injury. Hypothermia is effective in preventing cerebral ischemic damage. However, effects of hypothermia on ischemia-induced mitochondrial fission activation is not well known. Therefore, the aim of this study was to investigate whether hypothermia protect the brain by inhibiting mitochondrial fission-related proteins activation following cerebral IR injury. Adult male C57BL/6 mice were subjected to transient forebrain ischemia induced by 15min of bilateral common carotid artery occlusion (BCCAO). Mice were divided into three groups (n=48 each): Hypothermia (HT) group, with mild hypothermia (32 34 degrees C) for 4h; Normothermia (NT) group, similarly as HT group except for cooling; Sham group, with vessels exposed but without occlusion or cooling. Hematoxylin and eosin (HE), Nissl staining, Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) staining and behavioral testing (n=6 each) demonstrated that hypothermia significantly decreased ischemia-induced neuronal injury. The expressions of Dynamin related protein 1 (Drp1) and Cytochrome C (Cyto C) (n=6 each) in mice hippocampus were measured at 3, 6, 24, and 72h of reperfusion. IR injury significantly increased expressions of total Drp1, phosphorylated Drp1 (P-Drp1 S616) and Cyto C under normothermia. However, mild hypothermia inhibited Drp1 activation and Cyto C cytosolic release, preserved neural cells integrity and reduced neuronal necrosis and apoptosis. These findings indicated that mild hypothermia-induced neuroprotective effects against ischemia-reperfusion injury is associated with suppressing mitochondrial fission-related proteins activation and apoptosis execution. PMID- 27235870 TI - WITHDRAWN: Neurotrophins and specific receptors in the oviduct tracts of Japanese quail (Coturnix coturnix japonica). AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published in Ann. Anat., 210 (2017) 112 - 120>, http://dx.doi.org/10.1016/j.aanat.2016.04.034. The duplicate article has therefore been withdrawn.The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal. PMID- 27235871 TI - Fluid collection in the retropharyngeal space: A wide spectrum of various emergency diseases. AB - Fluid collections in the retropharyngeal space (RPS) result from a wide spectrum of diseases, including retropharyngeal abscess, cervical osteomyelitis, and calcific tendinitis of the longus colli muscle. These conditions should be managed by different specialties; beginning with care in the emergency room, physicians from orthopedics, pediatrics, otolaryngology, and oncology are in charge of the treatment. Since these diseases demonstrate similar fluid collections in the RPS on computed tomography (CT) and magnetic resonance imaging (MRI), the radiologist's diagnosis based on the characteristic imaging findings is very important to identify the primary disease. Also, since some of the diseases require immediate surgical intervention to avoid life-threatening mediastinitis or airway obstruction, radiologists must distinguish these diseases correctly and provide recommendations for their management to physicians. Understanding clinical features and imaging findings of these fluid collections in the RPS is crucial for the best care. PMID- 27235872 TI - Virtual unenhanced imaging of the liver with third-generation dual-source dual energy CT and advanced modeled iterative reconstruction. AB - OBJECTIVES: To compare image quality and diagnostic accuracy for the detection of liver lesions of virtual unenhanced (VU) images based on third-generation dual source dual- energy computed tomography (DECT) compared to conventional unenhanced (CU) images. METHODS: Thirty patients underwent triphasic abdominal CT consisting of single-energy CU (120kV, 147 ref.mAs) and dual-energy CT arterial and portal-venous phase acquisitions (100/Sn150kV, 180/90 ref.mAs). VU images were generated from arterial (AVU) and portal venous (PVU) phases. CU, AVU and PVU datasets were reconstructed. Quantitative image quality analysis was performed and two abdominal radiologists independently analyzed all datasets to evaluate image quality and identify liver lesions. Radiation dose was recorded and potential radiation dose reduction was estimated. RESULTS: Image quality was rated diagnostic in 100% of the VU datasets. The mean subjective image quality of the CU datasets was higher than that of VU images (p<0.0001). No significant difference was observed in the mean attenuation values of the liver parenchyma (p>0.99) and hypoattenuating liver lesions (p>=0.21) between CU, AVU and PVU. However, a significant reduction in the attenuation values of calcified lesions (p<0.0001), metallic clips (p<0.0001) and gallstones (p<=0.047) was observed in the AVU and PVU images compared with CU images. A total of 122 liver lesions were found in 25 patients. VU images were more sensitive than CU images for detection of small hypoattenuating liver lesions (<=1cm). However, CU images were more sensitive than VU for calcified liver lesions. The mean radiation dose reduction achievable by avoiding the unenhanced acquisition was 32.9%+/-1.1% (p<0.01). CONCLUSIONS: Third-generation DSCT VU images of the liver provide diagnostic image quality and improve small (<=1cm) liver lesion detection; however calcified liver lesions can be missed due to complete subtraction. PMID- 27235873 TI - Differentiating locally recurrent rectal cancer from scar tissue: Value of diffusion-weighted MRI. AB - OBJECTIVES: To determine a cut-off apparent diffusion coefficient (ADC) value distinguishing local recurrence from scar tissue in patients with rectal cancer treated with complete surgical tumour removal. METHODS: 72 patients were retrospectively included. Patients underwent 1.5T MRI including multiplanar T2 weighted turbo-spin-echo sequences (TSE) and axial single-shot epi-diffusion weighted sequences (EPSE). Two independent observers measured mean tumour and scar tissue ADCs by manually drawing regions of interest (ROIs). The t-test and ROC analysis were used for comparison and determining an optimal discrimination threshold. As reference standard histopathological results were used in 23 patients (32%) and clinical follow-up in 49 patients (68%). RESULTS: Recurrent rectal cancer was found in 30 patients (4 female, 26 male, median age 63.13 years) and treatment related changes such as scar tissue in 42 patients (11 female, 31 male, median age 63.67 years). The mean ADC value of tumour recurrence was 1.02*10(-3)mm(2)/s (0.63-1.44*10(-3)mm(2)/s) and of scar tissue 1.77*10( 3)mm(2)/s (1.11-2.41*10(-3)mm(2)/s) showing a statistically significant difference (p<0.001). The cut-off ADC value was 1.34*10(-3)mm(2)/s with a sensitivity, specificity, and accuracy of 93%, 91%, and 92% respectively. CONCLUSIONS: Diffusion weighted MRI allows for the differentiation of tumour recurrence from scar tissue after surgical resection of rectal cancer. PMID- 27235874 TI - Graft complications following orthotopic liver transplantation: Role of non invasive cross-sectional imaging techniques. AB - Orthotopic liver transplantation is the treatment of choice in adult patients with endstage liver disease. Survival of both graft and patient has progressively improved over time due to improvements in surgical and medical treatment. However, post-transplant complications still have a significant impact on morbidity and mortality associated with transplant surgery. The most common adverse events of the graft include vascular (arterial and venous stenosis and thrombosis), biliary (leakage, strictures, stones) and parenchymal complications (hepatitis virus C infection, HCC recurrence, liver abscesses). The diagnosis of these adverse events is often challenging because of the low specificity of clinical and biologic findings. Different diagnostic algorithms have been proposed for the detection of graft complications and, in this setting, radiological evaluation plays a key role in differential diagnosis of graft complications and the exclusion of other adverse events. Ultrasound examination is established the first-line method of identifying adverse events in liver transplant recipients but a normal or a technically unsatisfactory study cannot exclude the presence of biliary, vascular and/or parenchymal complications. In these circumstances, before planning any treatment, multi-detector CT and/or MR imaging and MR cholangiography should be performed for the evaluation of vascular structures, biliary system, liver parenchyma and fluid collections. The aim of this review is to illustrate the role and state-of-the-art of non-invasive cross sectional imaging techniques in the diagnosis and management of complications which primarily affect the graft in patients after liver transplantation. PMID- 27235875 TI - Diffusion weighted MRI of osteoid osteomas: Higher ADC values after radiofrequency ablation. AB - PURPOSE: Feasibility of diffusion weighted MRI (DWI) pre- and post-radiofrequency ablation (RFA) in patients with osteoid osteoma (OO). MATERIAL AND METHODS: Ten patients (1 female, 24+/-9years) received RFA of OO (mean size 8.7+/-3.2mm). Two OO recurred, in one of these a second RFA was performed. A 1.5T DWI (b=50, 400, and 800s/mm(2)) and a fat saturated DCE MRI were obtained the day before and after RFA. In DWI, the mean apparent diffusion coefficient (ADC) was recorded. With DCE MRI, signal-to-noise ratio, contrast-to-noise ratio, absolute signal intensity (SI), relative SI, and SI ratio were documented. All parameters were compared pre- and post-RFA using paired Wilcoxon rank test. RESULTS: ADC values were significantly higher post-ablation, 1.6+/-0.5MUm(2)/ms versus 1.3+/ 0.6MUm(2)/ms (p<0.05). Perfusion was significantly reduced after ablation [SNR, CNR, SI, %SI, and SI OO/SI muscle]; post-RFA: 55+/-13, 27+/-20, 757+/-534, 102+/ 16, and 1.6+/-0.2; pre-RFA: 88+/-37, 65+/-22, 1038+/-755, 226+/-51, and 2.0+/-0.5 (p<0.05). DISCUSSION: DWI is feasible in OO. ADC values increased and contrast enhancement decreased after RFA of OO. This may be explained by RFA-induced necrosis and devascularization. PMID- 27235876 TI - IVIM-diffusion-MRI for the differentiation of solid benign and malign hypervascular liver lesions-Evaluation with two different MR scanners. AB - PURPOSE: Hepatocellular carcinoma (HCC) and focal nodular hyperplasia (FNH) as the most common malign and benign liver tumors are both hypervascularized and potentially difficult to differentiate. DWI in liver MRI has been shown to be helpful in the classification of liver lesions, although with a substantial ADC values-overlap. First results suggest that IVIM allows for improved characterization of liver lesions. In this study we evaluated IVIM-derived parameters in HCC and FNH with two different MR-scanners. MATERIAL AND METHODS: 72 patients (29 FNH, 43HCC) were examined prospectively using two 1.5 T-MRI scanners (Aera/MagnetomAvanto, Siemens, Germany). Quantitative analysis of IVIM derived parameters and ADC800-values was performed independently by two radiologists. The concordance between the reviewers was tested using a Pearson /Spearman-correlation. The mean values for significant differences between FNHs and HCCs and between the two MR scanners were compared using a two-tailed t test/Mann-Whitney-U test. An ROC analysis assessing the diagnostic performance of the parameters was performed. RESULTS: The concordance between the two f-, D- and D*-measurements were r=0.81, 0.81 and 0.84, and r=0.58 for ADC-values. D-values and ADC800-values were significantly lower in HCC compared to FNH (p<0.001), there was no significant difference for f and D*. D had the largest AUC (0.76) for the differentiation between the two entities. Most parameters were not significantly different between the two MRIs. CONCLUSION: IVIM-derived D and ADC are comparable for the differentiation between HCC and FNH. Since ADC-measurement means less effort than IVIM, ADC should be used for the differentiation between the two entities. Furthermore, quantitative results obtained from different scanners match closely. PMID- 27235877 TI - Capability of arterial spin labeling MR imaging in localizing seizure focus in clinical seizure activity. AB - PURPOSE: The purpose of this study was to evaluate cerebral blood flow using arterial spin labeling (ASL) perfusion magnetic resonance (MR) imaging in patients with clinical seizure activity and determine its diagnostic performance in identifying seizure focus. MATERIALS AND METHODS: Institutional Review Board of our hospital approved this retrospective study. Informed consent was waived. Clinical seizure focus was determined by a neurologist based on seizure semiology, electroencephalography, and conventional imaging modalities. The diagnostic performance of ASL perfusion MR imaging to identifying seizure focus compared to clinical seizure focus was analyzed. RESULTS: Clinical seizure focus was localized in 95% (42/44) of patients. The sensitivity and specificity of ASL perfusion MR imaging for identifying seizure focus were 74% (95% CI: 58%, 86%) (clinical seizure focus was localizable in 31 of 42 patients, including complete concordance in 10 patients and partial concordance in 21 patients) and 0% (95% CI: 0%, 84%) (for the two patients whose clinical seizure foci were not localizable, they were identified by ASL perfusion MR imaging), respectively. Thus, the overall accuracy of ASL perfusion MR imaging for localizing seizure focus was 70% (33/44). For 4 patients who had abnormal perfusion on ASL, their seizure foci based on ASL perfusion MR imaging were discordant with clinical seizure foci. CONCLUSION: ASL perfusion MR imaging can provide information about perfusion status and important diagnostic clue in localizing seizure focus in patients with clinical seizure activity. It has the potential as a non-invasive complementary diagnostic tool for patients with clinical seizure activity. PMID- 27235878 TI - Differentiation of prostatitis and prostate cancer using the Prostate Imaging Reporting and Data System (PI-RADS). AB - PURPOSE: To determine if prostate cancer (PCa) and prostatitis can be differentiated by using PI-RADS. MATERIALS AND METHODS: 3T MR images of 68 patients with 85 cancer suspicious lesions were analyzed. The findings were correlated with histopathology. T2w imaging (T2WI), diffusion weighted imaging (DWI), dynamic contrast enhancement (DCE), and MR-Spectroscopy (MRS) were acquired. Every lesion was given a single PI-RADS score for each parameter, as well as a sum score and a PI-RADS v2 score. Furthermore, T2-morphology, ADC value, perfusion type, citrate/choline-level, and localization were evaluated. RESULTS: 44 of 85 lesions showed PCa (51.8%), 21 chronic prostatitis (24.7%), and 20 other benign tissue such as hyperplasia or fibromuscular tissue (23.5%). The single PI-RADS score for T2WI, DWI, DCE, as well as the aggregated score including and not including MRS, and the PI-RADS v2-score were all significantly higher for PCa than for prostatitis or other tissue (p<0.001). The single PI-RADS score for MRS and the PI-RADS sum score including MRS were significantly higher for prostatitis than for other tissue (p=0.029 and p=0.020), whereas the other parameters were not different. Prostatitis usually presented borderline pathological PI-RADS scores, showed restricted diffusion with ADC>=900mm(2)/s in 100% of cases, was more often indistinctly hypointense on T2WI (66.7%), and localized in the transitional zone (57.1%). An ADC>=900mm(2)/s achieved the highest predictive value for prostatitis (AUC=0.859). CONCLUSION: Prostatitis can be differentiated from PCa using PI-RADS, since all available parameters are more distinct in cases of cancer. However, there is significant overlap between prostatitis and other benign findings, thus PI-RADS is only suitable to a limited extent for the primary assessment of prostatitis. Restricted diffusion with ADC>=900mm(2)/s is believed to be a good indicator for prostatitis. MRS can help to distinguish between prostatitis and other tissue. PMID- 27235879 TI - Evaluation of C-arm CT metal artifact reduction algorithm during intra-aneurysmal coil embolization: Assessment of brain parenchyma, stents and flow-diverters. AB - PURPOSE: Flat panel C-arm CT images acquired in the interventional suite provide valuable information regarding brain parenchyma, vasculature, and device status during the procedure. However, these images often suffer from severe streak artifacts due to the presence of metallic objects such as coils. These artifacts limit the capability to make diagnostic inferences and thus need to be reduced for better image interpretation. The main purpose of this paper is to systematically evaluate the accuracy of one such C-arm CT based metal artifact reduction (MAR) algorithm and to demonstrate its usage in both stent and flow diverter assisted coil embolization procedures. METHODS: C-arm CT images routinely acquired in 24 patients during coil embolization procedure (stent assisted (12) and flow-diverter assisted (12)) were included in this study in a retrospective fashion. These images were reconstructed without and with MAR algorithm on an offline workstation and compared using quantitative image analysis metrics. This analysis was carried out to assess the improvements in both brain parenchyma and device visibility with MAR algorithm. Further, ground truth reference images from phantom experiments and clinical data were used for accurate assessment. RESULTS: Quantitative image analysis of brain parenchyma showed uniform distribution of grayscale values and reduced image noise after MAR correction. The line profile plot analysis of device profile in both phantom and clinical data demonstrated improved device visibility with MAR correction. CONCLUSIONS: MAR algorithm successfully reduced streak artifacts from coil embolization in all cases, thus allowing more accurate assessment of devices and adjacent brain parenchyma. PMID- 27235880 TI - Right ventricular long axis strain-validation of a novel parameter in non ischemic dilated cardiomyopathy using standard cardiac magnetic resonance imaging. AB - PURPOSE: Right ventricular longitudinal axis strain (RV-LAS) is a simple measure of RV longitudinal function. The purpose of this study was the evaluation of its diagnostic performance in non-ischemic dilated cardiomyopathy (NIDCM) and the determination of reference values in controls. METHODS: 217 NIDCM patients and 200 healthy controls were analysed retrospectively regarding the diagnostic performance of RV-LAS using receiver operating characteristic curves in comparison with RV ejection fraction (RVEF), tricuspid annular plane systolic excursion (TAPSE) and global longitudinal strain (RV-GLS). Hereby, four different approaches were evaluated to assess RV-LAS based on different reference points. RV-LAS LVapex/mid was defined as the change in distance between the LV apex and the middle of a line connecting the origins of the tricuspidal valve leaflets in systole and diastole. The ethical approval was obtained in all participants. RESULTS: NIDCM and controls were 48 years in mean. Controls were equally gender distributed, while the proportion of men with NIDCM was higher with 77%. Among the four approaches RV-LAS LVapex/mid provided the highest diagnostic performance for discrimination between NIDCM and controls (AUC=0.94). Of all RV functional parameters RV-LAS LVapex/mid preformed significantly better than RVEF (delta AUC=0.05; p=0.003), TAPSE (delta AUC=0.23; p<0.0001) and RV-GLS (delta AUC=0.31; p<0.0001). A significant correlation was found between RV-LAS LVapex/mid and RVEF (r=-0.65; p<0.0001). The reference mean values for RV-LAS LVapex/mid were -17.4+/ 3.5 for men and -18.5+/-3.7 for women. CONCLUSION: RV-LAS showed better diagnostic accuracy for RV dysfunction than RVEF, TAPSE and RV-GLS. Furthermore, it has a rapid accessibility and low intra- and interobserver variability. PMID- 27235882 TI - Current utilities of imaging in grading musculoskeletal soft tissue sarcomas. AB - The care of patients with musculoskeletal malignancies has increasingly become a multidisciplinary function. Radiologists play an important role in many areas of these patients' care including initial diagnosis, staging, in many cases guiding therapy, and monitoring treatment response. However, the gold standard for the final diagnosis of these diseases remains the histopathologic proof. Intense efforts have been made to develop non-invasive methods of determining the tumor grade, or a surrogate, in order to predict biologic behavior, aid early treatment decisions, and provide prognostic information. Multiple imaging modalities have been employed in this domain-including computed tomography (CT); anatomic magnetic resonance (MR) imaging techniques; functional MR imaging sequences such as dynamic contrast enhancement (DCE), diffusion weighted imaging (DWI), MR spectroscopy (MRS); and positron emission tomography (PET). This article reviews current available literature in this realm and highlights future directions towards the potential of non-invasive imaging in grading of soft tissue sarcomas. PMID- 27235881 TI - MR angiography findings in infants with neonatal arterial ischemic stroke in the middle cerebral artery territory: A prospective study using circle of Willis MR angiography. AB - AIM: Neonatal arterial ischemic stroke (NAIS) results from a focal disruption of the blood flow in a cerebral artery by a not well understood mechanism. Our objective is to describe the acute MRangiography (MRA) findings in infants with an NAIS in the middle cerebral artery (MCA) territory and correlate them with early parenchymal infarcts and motor outcome. METHODS: Among one hundred prospectively followed neonates with NAIS, we studied thirty-seven patients with an MCA infarct explored with circle of Willis MRA. MCA flow characteristics were documented, along with infarct location/extent and motor outcome at age 7 years. RESULTS: Twenty-three (62%) of the children showed arterial changes, all ipsilateral to the NAIS, with occlusion in six, thrombus-type flow defect in nine, and unilateral increased flow in enlarged insular arteries in the remaining eight. There was a statistically significant correlation between parenchymal and arterial MR findings (p=0.0002). A normal MRA had a negative predictive value of 100% (95% CI: 76.8-100) in ruling out a main branch infarct. Patients with abnormal MRA tended to be at increased risk for cerebral palsy (OR=3.1). Occlusion was associated with a worse outcome (p=0.04). INTERPRETATION: MRangiography shows arterial abnormalities suggesting that embolism is a frequent cause of NAIS. PMID- 27235883 TI - Antimicrobial activity of mosquito cecropin peptides against Francisella. AB - Francisella tularensis is the cause of the zoonotic disease tularemia. In Sweden and Scandinavia, epidemiological studies have implicated mosquitoes as a vector. Prior research has demonstrated the presence of Francisella DNA in infected mosquitoes but has not shown definitive transmission of tularemia from a mosquito to a mammalian host. We hypothesized that antimicrobial peptides, an important component of the innate immune system of higher organisms, may play a role in mosquito host-defense to Francisella. We established that Francisella sp. are susceptible to two cecropin antimicrobial peptides derived from the mosquito Aedes albopictus as well as Culex pipiens. We also demonstrated induced expression of Aedes albopictus antimicrobial peptide genes by Francisella infection C6/36 mosquito cell line. We demonstrate that mosquito antimicrobial peptides act against Francisella by disrupting the cellular membrane of the bacteria. Thus, it is possible that antimicrobial peptides may play a role in the inability of mosquitoes to establish an effective natural transmission of tularemia. PMID- 27235884 TI - Avian biological clock - Immune system relationship. AB - Biological rhythms in birds are driven by the master clock, which includes the suprachiasmatic nucleus, the pineal gland and the retina. Light/dark cycles are the cues that synchronize the rhythmic changes in physiological processes, including immunity. This review summarizes our investigations on the bidirectional relationships between the chicken pineal gland and the immune system. We demonstrated that, in the chicken, the main pineal hormone, melatonin, regulates innate immunity, maintains the rhythmicity of immune reactions and is involved in the seasonal changes in immunity. Using thioglycollate-induced peritonitis as a model, we showed that the activated immune system regulates the pineal gland by inhibition of melatonin production at the level of the key enzyme in its biosynthetic pathway, arylalkylamine-N-acetyltransferase (AANAT). Interleukin 6 and interleukin 18 seem to be the immune mediators influencing the pineal gland, directly inhibiting Aanat gene transcription and modulating expression of the clock genes Bmal1 and Per3, which in turn regulate Aanat. PMID- 27235885 TI - Optical spectroscopy of the Ce-doped multicomponent garnets. AB - Here, we report our results referring to the preparation of Ce doped Y2.22MgGa2Al2SiO12, Y1.93MgAl4SiO12 and Y2.22Gd0.75Ga2Al3O12 using solid state reaction at high temperature. Several complementary methods (i.e. powder x-ray diffraction (XRPD), energy dispersive analysis of X-rays (EDX), scanning electron microscopy (SEM) and Fourier transforms infrared spectroscopy (FTIR)) were studied to examine the effects of the synthesis procedure on the morphology and structure. XRD analyses revealed that all compounds include yttrium aluminate phase with garnet structure. Cathodoluminescence (CL), radioluminescence (RL) and photoluminescence (PL) measurements were carried out for clarification of relationship between host lattice defects and the spectral luminescence emissions. Luminescence emission of phosphors is peaked at 530nm assigned to 5d 4f transitions of the dopant Ce(3+) ions with a broad emission band in 400-700nm range. Under electron irradiation, the emission spectrum of Ce doped (YGd)3Ga2Al3O12 is well defined and has a characteristic fairly narrow and sharp emission band peaking at 312nm and 624nm corresponding to transition of (6)P7/2 >(8)S7/2 and (6)GJ->(6)PJ (Gd(3+)), respectively. We suggest some of phosphors might be excellent phototherapy phosphor materials under electron excitation. PMID- 27235886 TI - Elemental characterization of Hazm El-Jalamid phosphorite by instrumental neutron activation analysis. AB - Instrumental neutron activation analyses (INAA) have been used to achieve accurate knowledge about the elemental analysis of phosphate ore deposits collected from Hazm El-Jalamid Northeast of Saudi Arabia. The samples were prepared for irradiation by thermal neutrons using a thermal neutron flux of 7*10(12)ncm(-2)s(-1) at ACT Lab Canada. The concentrations of 19 elements were determined. These included 12 major, minor and trace elements (Au, As, Ba, Br, Cr, Mo, Sb, Sc, Sr, Th, U and Zn) and 7 rare earth elements (REEs) (La, Ce, Nd, Sm, Eu, Yb and Lu). Major elements (Si, Al, Fe, Ca, Mg, Na, K, Cr, Ti, Mn, P, Sr and Ba) were determined using an inductively coupled plasma-mass spectrometer (ICP-MS). The comparison of the concentration of U and the REEs in the Hazm El Jalamid phosphate samples with those of the Umm Wu'al phosphate from Saudi Arabia and El-Sibayia and El Hamrawein phosphate from Egypt shows that the contents of U and REEs are clearly higher in the Umm Wu'al, El-Sibayia and El Hamrawein phosphates than in the Hazm El-Jalamid phosphate samples. The results of major, trace elements, uranium and rare earth elements (REE) from El Jalamid phosphate have been compared with the global values of these elements. The concentrations for most of the elements studied are lower than the concentrations reported in the literature. The acquired data will serve as a reference for the follow-up studies to assess the agronomic effectiveness of the Hazm El-Jalamid phosphate rocks. PMID- 27235887 TI - Activation cross sections of proton induced nuclear reactions on palladium up to 80MeV. AB - Activation cross sections of proton induced nuclear reactions on palladium were measured up to 80MeV by using the stacked foil irradiation technique and gamma ray spectrometry. The beam intensity, the incident energy and the energy degradation were controlled by a method based on flux constancy via normalization to the excitation functions of monitor reactions measured in parallel. Excitation functions for direct and cumulative cross-sections were measured for the production of (104m,104g,105g,106m,110m)Ag, (100,101)Pd, (99m,99g,100,101m,101g,102m,102g,105)Rh and (103,97)Ru radioisotopes. The cross section data were compared with the theoretical predictions of TENDL-2014 and 2015 libraries. For practical applications thick target yields were derived from the measured excitation functions. Application in the field of medical radionuclide production is shortly discussed. PMID- 27235888 TI - Robustness of plastic scintillation microspheres in the continuous measurement of different river waters. AB - Plastic scintillation microspheres (PSm) represent one of the most promising options for monitoring alpha and beta radioactivity in river water. For that reason, a study of the stability of PSm packed into a cell against the continuous flow of river water with different degrees of turbidity was performed over a period of 100h. The results showed that the volume of the cell became stable after 15h of pumping and continued to be stable throughout the 100h of the experiment. During this period of time, the detection efficiency of the PSm, in terms of efficiency*volume, presented mean values of 0.75(3)% for (3)H and 272(11)% for (90)Sr/(90)Y. No dependence on flow time or river water type was observed. The background was also constant for 100h and for the different water types, although (222)Rn should be removed from the water beforehand to prevent its accumulation in the PSm. Since PSm did not present any degradation throughout the whole experiment, PSm can undoubtedly be used for monitoring radioactivity with low reagent consumption, low waste generation and low maintenance costs. PMID- 27235889 TI - Neutron spectra around a tandem linear accelerator in the generation of (18)F with a bonner sphere spectrometer. AB - A Bonner sphere spectrometer was used to measure the neutron spectra produced at the collision of protons with an H2(18)O target at different angles. A unique H2(18)O target to produce (18)F was designed and placed in a Tandem linear particle accelerator which produces 8.5MeV protons. The neutron count rates measured with the Bonner spheres were unfolded with the MAXED code. With the GEANT4 Monte Carlo code the neutron spectrum induced in the (p, n) reaction was estimated, this spectrum was used as initial guess during unfolding. Although the cross section of the reaction (18)O(p,n)(18)F is well known, the neutron energy spectra is not correctly defined and it is necessary to verify the simulation with measurements. For this reason, the sensitivity of the unfolding method to the initial spectrum was analyzed applying small variation to the fast neutron peak. PMID- 27235890 TI - Organization and mode of action of two component system signaling circuits from the various kingdoms of life. AB - Two-component system (TCS) signaling circuits regulate numerous cellular processes in response to environmental cues in both prokaryotic and eukaryotic cells. These signaling circuits are all based on phosphoryl-group transfers between histidine and aspartate containing modules of sensor kinase and response regulator proteins. Curiously, the architecture and organization of prokaryotic and eukaryotic two-component systems reveal notable variations, raising the question of whether the input-response specificity that governs the majority of prokaryotic TCSs also governs the eukaryotic ones. In this review, we contrast the TCS architecture and signaling circuits of prokaryotes and eukaryotes, and discuss their possible consequences on signaling specificity. PMID- 27235891 TI - Reply. PMID- 27235892 TI - Risks of probable SUDEP among people with convulsive epilepsy in rural West China. AB - PURPOSE: This study aimed to examine the risk factors of probable sudden unexpected death in epilepsy (SUDEP) among patients with convulsive epilepsy in rural communities. METHOD: A total of 35 cases with identified probable SUDEP were recruited in the study and compared with three survival controls that were sex and age matched from the same cohort for each case. Three healthy controls per case were chosen as a control group. Risk factors were analyzed using the logistic regression model. The odds ratio (OR) was calculated to determine the risk or protective effect. RESULTS: The following three factors significantly increased the risk of probable SUDEP: early-onset age of seizures (<=10 years vs. >10 years) with an OR of 6.8 (95% CI: 1.5-32.6), high seizure frequency at baseline (>10 years vs. <=10 years) before regular phenobarbital treatment with an OR of 5.9 (95% CI: 2.2-16.6), and experiencing one or more seizures (vs. seizure-free) in the month prior to probable SUDEP with an OR of 9.5 (95% CI: 3.0 30.1). CONCLUSION: Lack of seizure freedom before and during regular antiepileptic drug treatment increase the risk of probable SUDEP. Special attention should be given to patients with early convulsive epilepsy-onset, and the proper control of convulsive seizures is critical for the prevention of probable SUDEP. PMID- 27235893 TI - The temporal relation between seizure onset and arousal-awakening in temporal lobe seizures. AB - PURPOSE: Our main aim was to determine the time interval between the seizure onsets and arousal-awakening related to these seizures in patients with temporal lobe epilepsy (TLE) and to discuss the role of lateralization on arousal awakening mechanisms. METHODS: Thirty-three TLE patients who underwent video-EEG monitoring with simultaneous polysomnography (PSG) and had recorded nocturnal seizures were retrospectively examined. These TLE patients had 64 seizures during sleep. The onsets of seizures and arousal-awakening related to these seizures were marked according to clinical and electrophysiological features. The time interval between the seizure onset and arousal-awakening related to the seizure was compared in patients with right- or left-sided temporal lobe seizures. RESULTS: In our TLE patients nocturnal seizures mostly followed arousal-awakening (64%). The time interval between the seizure onset and arousal-awakening related to the seizure was significantly shorter in patients with left-sided temporal lobe seizures (p=0.01). CONCLUSION: Video-EEG monitoring and PSG with scalp electrodes in our TLE patients showed that nocturnal seizures mostly followed arousal-awakening, and it was more pronounced in those with left-sided seizures. Arousal-awakening might be a signal for subsequent seizures in patients with TLE. PMID- 27235894 TI - A dynamic tree-based registration could handle possible large deformations among MR brain images. AB - Multi-atlas segmentation is a powerful approach to automated anatomy delineation via fusing label information from a set of spatially normalized atlases. For simplicity, many existing methods perform pairwise image registration, leading to inaccurate segmentation especially when shape variation is large. In this paper, we propose a dynamic tree-based strategy for effective large-deformation registration and multi-atlas segmentation. To deal with local minima caused by large shape variation, coarse estimates of deformations are first obtained via alignment of automatically localized landmark points. The dynamic tree capturing the structural relationships between images is then employed to further reduce misalignment errors. Evaluation based on two real human brain datasets, ADNI and LPBA40, shows that our method significantly improves registration and segmentation accuracy. PMID- 27235895 TI - Determination of post-burial interval using entomology: A review. AB - Insects and other arthropods are used in different matters pertinent to the criminal justice system as they play very important role in the decomposition of cadavers. They are used as evidence in a criminal investigation to determine post mortem interval (PMI). Various researches and review articles are available on forensic entomology to determine PMI in the terrestrial environment but very less work has been reported in context to buried bodies. Burring the carcass, is one of the methods used by criminals to conceal the crime. So, to drive the attention of researchers toward this growing field and to help various investigating agencies, the present paper reviews the studies done on determination of post burial interval (PBI), its importance and future prospective. PMID- 27235896 TI - The Relationship Between 25-hydroxy Vitamin D, Parathyroid Hormone and Glycemia During Pregnancy and Postpartum. PMID- 27235897 TI - Benchmarking wastewater treatment plants under an eco-efficiency perspective. AB - The new ISO 14045 framework is expected to slowly start shifting the definition of eco-efficiency toward a life-cycle perspective, using Life Cycle Assessment (LCA) as the environmental impact assessment method together with a system value assessment method for the economic analysis. In the present study, a set of 22 wastewater treatment plants (WWTPs) in Spain were analyzed on the basis of eco efficiency criteria, using LCA and Life Cycle Costing (LCC) as a system value assessment method. The study is intended to be useful to decision-makers in the wastewater treatment sector, since the combined method provides an alternative scheme for analyzing the relationship between environmental impacts and costs. Two midpoint impact categories, global warming and eutrophication potential, as well as an endpoint single score indicator were used for the environmental assessment, while LCC was used for value assessment. Results demonstrated that substantial differences can be observed between different WWTPs depending on a wide range of factors such as plant configuration, plant size or even legal discharge limits. Based on these results the benchmarking of wastewater treatment facilities was performed by creating a specific classification and certification scheme. The proposed eco-label for the WWTPs rating is based on the integration of the three environmental indicators and an economic indicator calculated within the study under the eco-efficiency new framework. PMID- 27235898 TI - Fate of iron and polycyclic aromatic hydrocarbons during the remediation of a contaminated soil using iron-activated persulfate: A column study. AB - Remediation of contaminated soils under flow-through conditions is an issue of great interest since it provides a better approach to real case applications than batch experiments. In this work, a column filled with soil, artificially spiked and aged for three months with Phenanthrene (PHE), Anthracene (ANT), Pyrene (PYR) and Benzo(a)pyrene (BaP), was treated for 25days with persulfate (PS) activated by Fe(3+) and nanoparticles of zerovalent iron (nZVI). Effects of type of iron fed into the column (Fe(3+) or nZVI) and nZVI concentration were studied. PS inlet concentration was 0.2mmolcm(-3) and residence time in the column was close to 1.72days. Iron, PS and polycyclic aromatic hydrocarbons (PAHs) concentration, as well as pH, were monitored during treatment. Concentration profiles of iron and PAHs were observed along the column, with higher iron concentrations and higher PAHs removal efficiencies in the closest sections to the column entrance. BaP and ANT were completely depleted regardless the conditions used, but PHE and PYR showed higher resistance to oxidation, achieving near a 90% removal in the closest sections to the injection source in all runs, but decreasing significantly with column length. Besides, natural degradation of ANT resulted in the formation 9.10-anthraquinone (ATQ), an oxy-PAH which showed higher resistance than PHE and PYR. Although higher PAHs removal efficiencies were achieved when nZVI was used as activator, only a moderate improvement was noticed when the highest concentration of nZVI was used as a consequence of radical scavenging by an excess of Fe(2+). Finally, a kinetic model based on runs performed in batch, from a previous work, was able to predict the experimental average concentrations of PAHs in the column when Fe(3+) was used as activator. PMID- 27235899 TI - Environmental occurrence and ecological risk assessment of organic UV filters in marine organisms from Hong Kong coastal waters. AB - Organic UV filters, now considered to be emerging contaminants in aquatic ecosystems, are being intensively tracked in environmental waters worldwide. However, their environmental fate and impact of these contaminants on marine organisms remains largely unknown, especially in Asia. This work elucidates the occurrence and the ecological risks of seven UV filters detected in farmed fish, wild mussels and some other wild organisms collected from local mariculture farms in Hong Kong. For all of the organisms, ethylhexyl methoxycinnamate (EHMC) and octyl dimethyl p-aminobenzoic acid (OD-PABA) were the predominant contaminants with the highest concentrations up to 51.3 and 24.1ng/g (dw), respectively; lower levels were found for benzophenone-8 (BP-8), octocrylene (OC) and benzophenone-3 (BP-3) from 3weeks hospitalization or which resulted in death). Using EAD data, this study has shown the adverse health effects of ambient air pollution. This highlights the importance of reducing the level of air pollution in order to maintain population health and well-being. PMID- 27235904 TI - A novel rat model for subchondral microdamage in acute knee injury: a potential mechanism in post-traumatic osteoarthritis. AB - OBJECTIVE: Subchondral microdamage may play an important role in post-traumatic osteoarthritis (PTOA) development following anterior cruciate ligament (ACL) rupture. It remains unknown whether this injury mechanism causes subchondral microdamage, or whether its repair occurs by targeted osteoclast-mediated remodeling. If so these events may represent a mechanism by which subchondral bone is involved in PTOA. Our objective was to test the hypothesis that subchondral microdamage occurs, and is co-localized with remodeling, in a novel rat model of ACL rupture. DESIGN: We developed a novel non-invasive rat animal model for ACL rupture and subchondral microdamage generation. By inducing ACL rupture noninvasively rather than surgically, this more closely mimics the clinical injury. MicroCT, MRI and histological methods were used to measure microstructural changes, ligament damage, and cellular/matrix degeneration, respectively. RESULTS: We reproducibly generated ACL rupture without damage to other soft joint tissues. Immediately after injury, increased microdamage was found in the postero-medial aspect of the tibia. Microstructural parameters showed increased resorption at 2 weeks, which returned to baseline. Dynamic histomorphometry showed increased calcein label uptake in the same region at 4 and 8 weeks. Chondrocyte death and protease activity in cartilage was also noted, however whether this was directly linked to subchondral changes is not yet known. Similarly, cartilage scoring showed degradation at 4 and 8 weeks post-injury. CONCLUSIONS: This study shows that our novel model can be used to study subchondral microdamage after ACL-rupture, and its association with localized remodeling. Cartilage degeneration, on a similar time-scale to other models, is also a feature of this system. PMID- 27235905 TI - Effect of N-acetyl cysteine and glycine supplementation on growth performance, glutathione synthesis, anti-oxidative and immune ability of Nile tilapia, Oreochromis niloticus. AB - An 8-week feeding trial was conducted to evaluate the effect of N-acetyl cysteine (NAC) and glycine supplementation on growth performance, glutathione (GSH) synthesis, anti-oxidative and immune ability of Nile tilapia, Oreochromis niloticus. Four practical diets were formulated, control, control +0.2% NAC, control +0.5% glycine, control +0.2% NAC +0.5% glycine. Each diet was randomly assigned to quadruplicate groups of 30 fish (approximately 9.5 g). The weight gain and specific growth rate were significantly increased with the supplementation of NAC and glycine. While they had no effect on feed efficiency feed intake and survival. Glutathion peroxidase (GPx) was increased by NAC and gamma-glutamine cysteine synthase (gamma-GCS) in plasma were increased by glycine. After the feeding trail, fish were challenged by Streptococcus iniae, fish fed the diet supplemented with NAC obtained significantly higher survival rate after 72 h challenge test. NAC also decreased malonaldehyde (MDA) in liver, increased glutathione S-transferase (GST) activity in plasma, up-regulated mRNA expression of Superoxide dismutase (SOD) and GPx in liver and headkidney. Dietary supplementation of glycine increased the anti-oxidative ability of tilapia through increase anti-oxidative enzyme activity (SOD, glutathione reductase, myeloperoxidase) and up-regulate anti-oxidative gene expression (SOD). Immune ability only enhanced by the supplementation of NAC through increased interleukin 1beta (IL-1beta) mRNA expression. These results clearly indicated that the supplementation of NAC and glycine can significantly improve the growth performance of tilapia, and NAC also enhance the anti-oxidative and immune capacity of tilapia, glycine could only enhance the anti-oxidative ability. PMID- 27235906 TI - Cell-free DNA: Comparison of Technologies. AB - Cell-free fetal DNA screening for Down syndrome has gained rapid acceptance over the past few years with increasing market penetration. Three main laboratory methodologies are currently used: a massive parallel shotgun sequencing (MPSS), a targeted massive parallel sequencing (t-MPS) and a single nucleotide polymorphism (SNP) based approach. Although each of these technologies has its own advantages and disadvantages, the performance of all was shown to be comparable and superior to that of traditional first-trimester screening for the detection of trisomy 21 in a routine prenatal population. Differences in performance were predominantly shown for chromosomal anomalies other than trisomy 21. Understanding the limitations and benefits of each technology is essential for proper counseling to patients. These technologies, as well as few investigational technologies described in this review, carry a great potential beyond screening for the common aneuploidies. PMID- 27235907 TI - Strategies for Implementing Cell-Free DNA Testing. AB - Maternal plasma cell-free (cf) DNA testing has higher discriminatory power for aneuploidy than any conventional multi-marker screening test. Several strategies have been suggested for introducing it into clinical practice. Secondary cfDNA, restricted only to women with positive conventional screening test, is generally cost saving and minimizes the need for invasive prenatal diagnosis but leads to a small loss in detection. Primary cfDNA, replacing conventional screening or retaining the nuchal translucency scan, is not currently cost-effective for third party payers. Contingent cfDNA, testing about 20% of women with the highest risks based on a conventional test, is the preferred approach. PMID- 27235908 TI - Genetic Counseling for Patients Considering Screening and Diagnosis for Chromosomal Abnormalities. AB - With the introduction of cell-free DNA screening for fetal aneuploidy and chromosomal microarray for prenatal diagnostic testing, options for pregnant women have become increasingly complex. Discussions regarding options for prenatal testing for aneuploidy should occur prior to any testing and should include pertinent risks and benefits of each alternative test. There is no single screening or diagnostic test option that is the right choice for all patients; patient decisions should be based on each individual woman's values and preferences after a discussion of all options. PMID- 27235909 TI - Cost-Effectiveness of Old and New Technologies for Aneuploidy Screening. AB - Cost-effectiveness analyses allow assessment of whether marginal gains from new technology are worth increased costs. Several studies have examined cost effectiveness of Down syndrome (DS) screening and found it to be cost-effective. Noninvasive prenatal screening also appears to be cost-effective among high-risk women with respect to DS screening, but not for the general population. Chromosomal microarray (CMA) is a genetic sequencing method superior to but more expensive than karyotype. In light of CMAs greater ability to detect genetic abnormalities, it is cost-effective when used for prenatal diagnosis of an anomalous fetus. This article covers methodology and salient issues of cost effectiveness. PMID- 27235910 TI - Modifying Risk of Aneuploidy with a Positive Cell-Free Fetal DNA Result. AB - Noninvasive genomic assessments of the fetus while in utero have been made possible by the analysis of cell-free fetal DNA fragments from the serum of pregnant women, as part of a noninvasive prenatal testing screening strategy. Between 7% and 10% of total cell-free DNA in the maternal blood comes from placental trophoblasts, allowing for identification of the DNA associated with the fetal component of the placenta. Using simple venipuncture in the outpatient setting, this cell-free, extracellular fetal DNA can be isolated in the maternal serum from a single blood draw as early as the seventh week of gestation. PMID- 27235911 TI - Chromosomal Microarrays for the Prenatal Detection of Microdeletions and Microduplications. AB - Chromosomal microarray analysis has replaced conventional G-banded karyotype in prenatal diagnosis as the first-tier test for the cytogenetic detection of copy number imbalances in fetuses with/without major structural abnormalities. This article reviews the basic technology of microarray; the value and clinical significance of the detection of microdeletions, microduplications, and other copy number variants; as well as the importance of genetic counseling for prenatal diagnosis. It also discusses the current status of noninvasive screening for some of these microdeletion and microduplication syndromes. PMID- 27235912 TI - Genetic Carrier Screening in the Twenty-first Century. AB - Historically, carrier screening for a small number of autosomal recessive disorders has been offered to targeted populations based on ethnicity and family history. These chosen disorders are associated with severe morbidity or mortality, have a well-established carrier frequency in the targeted population, and have an acceptably high detection rate to make screening efficient. With advancing genetic technology, expanded panels rapidly are being designed and offered to the panethnic general population. This article reviews current recommendations for ethnicity-specific carrier screening for common disorders as well as the limitations and counseling complexities associated with expanded panels. PMID- 27235913 TI - Screening and Testing in Multiples. AB - The choice of screening or invasive procedure in twin pregnancies is a personal choice of whether the patient wishes to take a small risk of having a baby with a serious disorder versus a small risk of having a complication because she wishes to avoid that. How to interpret such risks has profound effects on the perceived value of techniques, either leading to a decision to screening or going directly to chorionic villus sampling. There are profound issues surrounding the data and the interpretation of the data. No single short review can exhaustively examine all of the issues. PMID- 27235914 TI - Inverted Pyramid of Care. AB - First-trimester pregnancy evaluation using fetal and maternal parameters not only allows for diagnoses to be made early in gestation but can also assess the risk of complications that become clinically evident later in pregnancy. This evaluation makes it possible for pregnancy care to be individualized. In select cases, treatment that reduces the risk of complications can be started early in pregnancy. Even though cell free DNA is a significant advance in diagnosing fetal aneuploidy, the combination of first-trimester ultrasound and maternal serum biochemistries casts a much wider diagnostic net; therefore, the 2 technologies are best used in combination. PMID- 27235915 TI - Aspirin for the Prevention of Preeclampsia and Intrauterine Growth Restriction. AB - Low-dose aspirin (LDA) has been used for several years for the prevention of preeclampsia (PE). LDA started in early pregnancy is associated with improvement of placental implantation. The best evidence suggest that LDA can prevent more than half of PE cases in high-risk women when started before 16 weeks of gestation. Moreover, LDA started in early pregnancy reduces the risk of other placenta-mediated complications such as intrauterine growth restriction (IUGR) and perinatal death. The efficacy of LDA has been demonstrated in women with abnormal first-trimester uterine artery Doppler or with prior history of chronic hypertension or preeclampsia. PMID- 27235916 TI - First-, Second-, and Third-Trimester Screening for Preeclampsia and Intrauterine Growth Restriction. AB - Preeclampsia and intrauterine growth restriction are major contributors to perinatal mortality and morbidity. Accurate prediction is important for identifying those who require more intensive monitoring, permitting earlier recognition and intervention and targeting of potential preventive measures. Although measures of placental dysfunction have been associated with increased risk adverse pregnancy outcomes, the ability of any single measure to predict these outcomes is poor. Predictive models combining analytes and measurements of placental structure and blood flow have produced mixed results. Biochemical markers plus uterine artery Doppler screening throughout gestation show promise as screening tools. Published studies, however, suggest limited clinical applicability. PMID- 27235917 TI - Maternal Serum Analytes as Predictors of Fetal Growth Restriction with Different Degrees of Placental Vascular Dysfunction. AB - Abnormal levels of maternal serum analytes have been associated with fetal growth restriction (FGR) and preeclampsia secondary to placental vascular dysfunction. Accurately identifying the FGR fetuses at highest risk for adverse outcomes remains challenging. Placental function can be assessed by Doppler analysis of the maternal and fetal circulation. Although the combination of multiple abnormal maternal serum analytes and abnormal Doppler findings is strongly associated with adverse outcomes, the predictive value remains too low to be used as a screening test in a low-risk population. Stratification of cases based on the severity of Doppler abnormalities may improve predictive models. PMID- 27235918 TI - Biophysical and Biochemical Screening for the Risk of Preterm Labor: An Update. AB - The heterogeneous causes of spontaneous preterm birth make prediction and prevention difficult. Recently developed biochemical and biophysical tests add significantly to clinicians' ability to evaluate and treat women at risk for spontaneous preterm birth. The primary importance of transvaginal cervical sonography and cervicovaginal fetal fibronectin lies in the high negative predictive values of the tests for preterm delivery risk. Cervical length may be useful in identifying women who are candidates for cervical cerclage or progesterone therapy for preterm birth prevention. Together, cervical length and fibronectin can be used in the triaging of women symptomatic for preterm labor. PMID- 27235919 TI - The Past, Present, and Future of Preimplantation Genetic Testing. AB - Preimplantation genetic testing (PGT) of oocytes and embryos is the earliest form of prenatal testing. PGT requires in vitro fertilization for embryo creation. In the past 25 years, the use of PGT has increased dramatically. The indications of PGT include identification of embryos harboring single-gene disorders, chromosomal structural abnormalities, chromosomal numeric abnormalities, and mitochondrial disorders; gender selection; and identifying unaffected, HLA matched embryos to permit the creation of a savior sibling. PGT is not without risks, limitations, or ethical controversies. This review discusses the techniques and clinical applications of different forms of PGT and the debate surrounding its associated uncertainty and expanded use. PMID- 27235920 TI - Screening for Open Neural Tube Defects. AB - Biochemical prenatal screening was initiated with the use of maternal serum alpha fetoprotein to screen for open neural tube defects. Screening now includes multiple marker and sequential screening protocols involving serum and ultrasound markers to screen for aneuploidy. Recently cell-free DNA screening for aneuploidy has been initiated, but does not screen for neural tube defects. Although ultrasound is highly effective in identifying neural tube defects in high-risk populations, in decentralized health systems maternal serum screening still plays a significant role. Abnormal maternal serum alpha fetoprotein alone or in combination with other markers may indicate adverse pregnancy outcome in the absence of open neural tube defects. PMID- 27235921 TI - Toxoplasmosis, Parvovirus, and Cytomegalovirus in Pregnancy. AB - There are several infections in adults that warrant special consideration in pregnant women given the potential fetal consequences. Among these are toxoplasmosis, parvovirus B19, and cytomegalovirus. These infections have an important impact on the developing fetus, depending on the timing of infection. This article reviews the modes of transmission as well as maternal and neonatal effects of each of these infections. In addition, the article outlines recommended testing, fetal surveillance, and treatment where indicated. PMID- 27235922 TI - Prenatal Screening for Thrombophilias: Indications and Controversies, an Update. AB - Pregnancy is associated with increased clotting potential and decreased fibrinolysis. Women with thrombophilias have an increased risk of venous thromboembolism during pregnancy. At least 50% of cases of venous thromboembolism in pregnant women are associated with an inherited or acquired thrombophilia. Acquired thrombophilias have also been linked with adverse pregnancy outcomes such as recurrent pregnancy loss, intrauterine fetal demise, early onset severe preeclampsia, placental abruption, and fetal growth restriction. This article addresses indications for thrombophilia testing, the appropriate laboratory tests, and timing of testing to ensure reliability of results. PMID- 27235923 TI - Sleep Disordered Breathing and Adverse Pregnancy Outcomes. AB - Sleep disordered breathing (SDB) occurs in 0.6% to 15% of reproductive-aged women. Because of an overlap in symptoms of SDB and normal pregnancy findings, the diagnosis of SDB in pregnancy is challenging. The repetitive arousals, sleep fragmentation, and hypoxias experienced by patients with SDB lead to an increase in oxidative stress and inflammation. In the nonpregnant population SDB is associated with an increased risk of diabetes mellitus, heart disease, and stroke. Increasing evidence identifies an association between SDB in pregnancy and gestational diabetes, preeclampsia, and fetal growth abnormalities. PMID- 27235924 TI - Prenatal Screening: The Birth of a New Era. PMID- 27235925 TI - Mathematical model for blood flow through a bifurcated artery using couple stress fluid. AB - In this article, the blood flow through a bifurcated artery with mild stenosis is investigated taking blood as couple stress fluid. The artery configuring bifurcation is assumed to be symmetric about the axis of the artery and straight cylinders of finite length. The governing equations are non-dimensionalized and coordinate transformation is used to convert the irregular boundary to a regular boundary. The resulting system of equations is solved numerically using the finite difference method. The variation of shear stress, flow rate and impedance near the apex with pertinent parameters are studied graphically. It has been noticed that shear stress, flow rate and impedance have been changing suddenly with all the parameters on both sides of the apex. This occurs because of the backflow of the streaming blood at the onset of the lateral junction and secondary flow near the apex in the daughter artery. PMID- 27235926 TI - Effects of 4-nitrophenol on expression of the ER-alpha and AhR signaling pathway associated genes in the small intestine of rats. AB - 4-Nitrophenol (PNP) is a persistent organic pollutant that was proven to be an environmental endocrine disruptor. The aim of this study was to evaluate the role of the estrogen receptor-alpha (ER-alpha) and aryl hydrocarbon receptor (AhR) signaling pathway in regulating the damage response to PNP in the small intestine of rats. Wistar-Imamichi male rats (21 d) were randomly divided into two groups: the control group and PNP group. Each group had three processes that were gavaged with PNP or vehicle daily: single dose (1 d), repeated dose (3 consecutive days) (3 d), and repeated dose with recovery (3 consecutive days and 3 recovery days) (6 d). The weight of the body, the related viscera, and small intestine were examined. Histological parameters of the small intestine and the quantity of mucus proteins secreted by small goblet cells were determined using HE staining and PAS staining. The mRNA expression of AhR, ER-alpha, CYP1A1, and GST was measured by real-time qPCR. In addition, we also analyzed the AhR, ER-alpha, and CYP1A1 expression in the small intestine by immunohistochemical staining. The small intestines histologically changed in the PNP-treated rat and the expression of AhR, CYP1A1, and GST was increased. While ER-alpha was significantly decreased in the small intestine, simultaneously, when rats were exposed to a longer PNP treatment, the damages disappeared. Our results demonstrate that PNP has an effect on the expression of AhR signaling pathway genes, AhR, CYP1A1, and GST, and ER-alpha in the rat small intestine. PMID- 27235928 TI - Subordinate clause comprehension and tense/agreement inconsistency in children with specific language impairment. AB - Several recent studies have suggested that the production errors of children with specific language impairment (SLI) such as The girl singing may be explained by a misinterpretation of grammatical adult input containing a similar structure (e.g., The boy hears the girl singing). Thirteen children with SLI and 13 younger typically developing children with comparable sentence comprehension test scores (TD-COMP) completed a comprehension task to assess their understanding of sentences involving a nonfinite subject-verb sequence in a subordinate clause such as The dad sees the boy running. TD-COMP children were more accurate on subordinate clause items than children with SLI despite similar performance on simple transitive (e.g., The horse sees the cow) and simple progressive (e.g., The cow is eating) items. However, no relationship was found between the SLI group's specific subordinate clause comprehension level and their specific level of auxiliary is production, casting some doubt on this type of structure as a source for inconsistent use of auxiliary is. LEARNING OUTCOMES: The reader will learn that children with specific language impairment (SLI): (1) have difficulty understanding complex sentences that include nonfinite subject-verb sequences; (2) that this difficulty is apparent in comparison to younger typically developing peers who have similar scores not only on a sentence comprehension test, but also on simple sentences that correspond to the component parts of the complex sentences; and (3) that this weakness is concurrent with these children's inconsistent use of auxiliary is in production. Although novel verb studies show a clear connection between how children with SLI hear new verbs and how they use them, we do not yet have evidence that this connection is tied to a poor understanding of the input sentences that house the verbs. PMID- 27235927 TI - Persistent organic pollutants in blood samples of Southern Giant Petrels (Macronectes giganteus) from the South Shetland Islands, Antarctica. AB - Seabirds play an important role as top consumers in the food web and can be used as biomonitors of exposure to pollutants. Contamination studies involving non destructive sampling methods are of considerable importance, allowing better evaluation of the levels of pollutants and their toxic effects. In the present study, organohalogen contaminants were analyzed in 113 blood samples from Southern Giant Petrel (Macronectes giganteus) adults and chicks collected in the austral summer of 2011/2012 and 2012/2013 from colonies on Elephant and Livingston Islands, South Shetland, Antarctica. Polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB), pentachlorobenzene (PeCB), mirex, dichlorodiphenyltrichloroetane and derivatives (DDTs) and chlordanes were detected in all birds, whereas polybrominated diphenyl ethers (PBDEs) were not detected in any blood samples. No significant differences were found in organochlorine levels between sampling events. Adults exhibited significantly higher levels than chicks, except for PeCB. PCBs, HCB, mirex and DDTs were statistically similar in males and females from Elephant Island. Females on Livingston Island exhibited higher HCB values than males, but no sex differences were found regarding other organochlorines. The similarity in organochlorine levels between sexes in birds with very marked sexual segregation in feeding habits during the breeding season may indicate that significant amounts of contaminants are acquired during migration to lower latitudes, when the diets of males and females are similar. Birds sampled on Livingston Island exhibited significantly lower levels of PCBs, HCB, DDTs, mirex and chlordanes in comparison to those on Elephant Island, which could be the result of distinct foraging patterns between the two colonies. Organochlorine levels were similar between years in birds captured in two consecutive breeding seasons. Blood samples from Southern Giant Petrels adults and chicks proved to be useful for the comparison of intraspecific contamination levels and appear to be adequate for the long-term assessment of organohalogen contaminants in antarctic top predators. Organochlorine contaminants in blood samples of Southern Giant Petrels reflected intra-specific differences and suggested distinct foraging patterns between colonies. PMID- 27235929 TI - C57BL/6J bone marrow transplant increases sociability in BTBR T+ Itpr3tf/J mice. AB - Associative studies across a range of neurodevelopmental disorders have revealed a relationship between immune system function and behavioral deficits. These correlations are particularly evident in individuals with autism spectrum disorders (ASD), a developmental disorder characterized by social behavior deficits and noted for its high instances of immune system dysfunction. Mouse models provide a unique opportunity to explore causal links between immune and nervous system function and reveal how changes in these systems alter behavioral profiles. The BTBR T+ Itpr3tf/J (BTBR) mouse strain is characterized by both social behavior impairments and aberrant immune responses, affording the unique opportunity to investigate the causal relationship between behavior and immunity through direct manipulation of these systems. Using bone marrow from the highly social C57BL/6J (C57) mouse strain, BTBR mice were tested for changes in social approach behavior and repetitive grooming following irradiation and bone marrow transplant. BTBR recipient mice treated with allogeneic bone marrow from C57 donor mice, but not syngeneic BTBR bone marrow, displayed increased sociability as measured by the three-chamber social approach task and total time spent social sniffing. In addition, C57 recipient mice given allogeneic bone marrow from BTBR donors showed a significant increase in repetitive grooming behavior. These data provide evidence for a causal relationship between peripheral immune phenotype and social behavior in the BTBR mouse strain and further strengthen and expand on our existing understanding of the role of immune function in behavior. PMID- 27235930 TI - Schizophrenia associated sensory gating deficits develop after adolescent microglia activation. AB - Maternal infection during pregnancy is a well-established risk factor for schizophrenia in the adult offspring. Consistently, prenatal Poly(I:C) treatment in mice has been validated to model behavioral and neurodevelopmental abnormalities associated with schizophrenia. By using the Poly(I:C) BALB/c mouse model, we investigated the functional profile of microglia by flow cytometry in relation to progressive behavioral changes from adolescence to adulthood. Prenatal Poly(I:C) treatment induced the expected sensory gating deficits (pre pulse inhibition (PPI) of the acoustic startle response) in 100day-old adult offspring, but only in female not in male descendants. No PPI-deficits were present in 30day-old adolescent mice. Sensory gating deficits in adult females were preceded by a strong M1-type microglia polarization pattern during puberty as determined by flow cytometric analysis of multiple pro- and anti-inflammatory surface markers. Microglia activation in females did not persist until adulthood and was absent in behaviorally unaffected male descendants. Further, the specific activation pattern of microglia was not mirrored by a similar activation of peripheral immune cells. We conclude that prenatal Poly(I:C) treatment induces post pubertal deficits in sensory gating which are specifically preceded by a pro inflammatory activation pattern of microglia during puberty. PMID- 27235931 TI - Reducing liver metastases of colon cancer in the context of extensive and minor surgeries through beta-adrenoceptors blockade and COX2 inhibition. AB - Liver metastases are a major cause of colorectal cancer death, and the perioperative period is believed to critically affect the metastatic process. Here we tested whether blocking excess release of catecholamines and prostaglandins during surgical procedures of different extent can reduce experimental liver metastasis of the syngeneic CT26 colon cancer in female and male BALB/c mice. Animals were either treated with the beta-blocker, propranolol, the COX-2 inhibitor, etodolac, both drugs, or vehicle. The role of NK cells in controlling CT26 hepatic metastasis and in mediating the effect of the drugs was assessed by in vivo depletion or stimulation of NK cells, using anti-asialo GM1 or CpG-C, respectively. Surgical extent was manipulated by adding laparotomy to small incision, extending surgical duration, and enabling hypothermia. The results indicated that combined administration of propranolol and etodolac, but neither drug alone, significantly improved host resistance to metastasis. These beneficial effects occurred in both minor and extensive surgeries, in both sexes, and in two tumor inoculation approaches. NK cell-mediated anti-CT26 activity is involved in mediating the beneficial effects of the drugs. Specifically, CpG-C treatment, known to profoundly activate mice marginating-hepatic NK cytotoxicity, reduced CT26 hepatic metastases; and NK-depletion increased metastases and prevented the beneficial effects of the drugs. Overall, given prevalent perioperative psychological and physiological stress responses in patients, and ample prostaglandin release by colorectal tumors and injured tissue, propranolol and etodolac could be tested clinically in laparoscopic and open colorectal surgeries, attempting to reduce patients' metastatic disease. PMID- 27235932 TI - hESC-derived neural progenitors prevent xenograft rejection through neonatal desensitisation. AB - Stem cell therapies for neurological disorders are rapidly moving towards use in clinical trials. Before initiation of clinical trials, extensive pre-clinical validation in appropriate animal models is essential. However, grafts of human cells into the rodent brain are rejected within weeks after transplantation and the standard methods of immune-suppression for the purpose of studying human xenografts are not always sufficient for the long-term studies needed for transplanted human neurons to maturate, integrate and provide functional benefits in the host brain. Neonatal injections in rat pups using human fetal brain cells have been shown to desensitise the host to accept human tissue grafts as adults, whilst not compromising their immune system. Here, we show that differentiated human embryonic stem cells (hESCs) can be used for desensitisation to achieve long-term graft survival of human stem cell-derived neurons in a xenograft setting, surpassing the time of conventional pharmacological immune-suppressive treatments. The use of hESCs for desensitisation opens up for a widespread use of the technique, which will be of great value when performing pre-clinical evaluation of stem cell-derived neurons in animal models. PMID- 27235934 TI - Phasic activation of the external urethral sphincter increases voiding efficiency in the rat and the cat. AB - OBJECTIVE: Electrical stimulation of the pudendal nerve (PN) is a potential therapy for bladder dysfunction, but voiding efficiency (VE) produced by PN stimulation appears limited to 60-70%. We conducted experiments in rats and cats to investigate the hypothesis that introduction of artificial phasic bursting activity of the external urethral sphincter (EUS) would enhance VE under conditions where such activity was absent. MATERIALS AND METHODS: Cystometry experiments were conducted in 17 urethane anesthetized female Sprague-Dawley rats and 4 alpha-chloralose anesthetized male cats. The effects of phasic stimulation of the pudendal motor branch on VE were quantified in intact conditions, following bilateral transection of the motor branch of the PN, and following subsequent bilateral transection of the sensory branch of the PN. RESULTS: Artificial phasic bursting activity in the EUS generated by electrical stimulation of the motor branch of the PN increased VE in both rats and cats. Subsequent transection of the sensory branch of the PN abolished the increased VE elicited by phasic stimulation in both rats and cats. CONCLUSIONS: Artificial phasic EUS bursting restored efficient voiding in rats. Introduction of artificial phasic bursting in cats, which normally exhibit EUS relaxation while voiding, was also effective in promoting efficient voiding. In both species phasic EUS activity increased voiding efficiency via activation of pudendal sensory pathways. These results provide further insight into the function of phasic EUS activity in efficient voiding and highlight a novel approach to increase VE generated by pudendal afferent nerve stimulation. PMID- 27235933 TI - Conditional Sox9 ablation improves locomotor recovery after spinal cord injury by increasing reactive sprouting. AB - The absence of axonal regeneration after spinal cord injury (SCI) has been attributed to the up-regulation of axon-repelling molecules, such as chondroitin sulfate proteoglycans (CSPGs) present in the glial scar that forms post-SCI. We previously identified the transcription factor SOX9 as a key up-regulator of CSPG production and also demonstrated that conditional Sox9 ablation leads to decreased CSPG levels and improved recovery of hind limb function after SCI. We herein demonstrate increased neural input onto spinal neurons caudal to the lesion in spinal cord injured Sox9 conditional knock out mice as indicated by increased levels of the presynaptic markers synaptophysin and vesicular glutamate transporter 1 (VGLUT1) compared to controls. Axonal sparing, long-range axonal regeneration and reactive sprouting were investigated as possible explanations for the increase in neural inputs caudal to the lesion and for the improved locomotor outcomes in spinal cord-injured Sox9 conditional knock out mice. Whereas retrograde tract-tracing studies failed to reveal any evidence for increased axonal sparing or for long-range regeneration in the Sox9 conditional knock out mice, anterograde tract-tracing experiments demonstrated increased reactive sprouting caudal to the lesion after SCI. Finally we demonstrate that application of a broad spectrum MMP inhibitor to reduce CSPG degradation in Sox9 conditional knock out mice prevents the improvements in locomotor recovery observed in untreated Sox9 conditional knock out mice. These results suggest that improved recovery of locomotor function in Sox9 conditional knock out mice after SCI is due to increased reactive sprouting secondary to reduced CSPG levels distal to the lesion. PMID- 27235935 TI - Impairment of sensory afferents by intrathecal administration of botulinum toxin A improves neurogenic detrusor overactivity in chronic spinal cord injured rats. AB - Spinal cord injury (SCI) often leads to neurogenic detrusor overactivity (NDO) due to sprouting of sensory afferents on the lumbosacral spinal cord. NDO is characterized by high frequency of voiding contractions and increased intravesical pressure that may lead to urinary incontinence. The latter has been described as one of the consequences of SCI that mostly decreases quality of life. Bladder wall injections of botulinum toxin A (Onabot/A) are an effective option to manage NDO. The toxin strongly impairs parasympathetic and sensory fibres coursing the bladder wall. However the robust parasympathetic inhibition may inhibit voiding contractions and cause urinary retention in patients that retain voluntary voiding. Here, we hypothesised that by restricting the toxin activity to sensory fibres we can improve NDO without impairing voiding contractions. In the present work, we assessed the effect of Onabot/A on sensory neurons in chronic (4weeks) SCI rats by injecting the toxin intrathecally (IT), at lumbosacral spinal cord level. This route of administration was shown before to have an effect on bladder pain and contractility in an animal model of bladder inflammation. We found that IT Onabot/A led to a significant reduction in the frequency of expulsive contractions and a normalization of bladder basal pressure while maintaining voiding contractions of normal amplitude. Cleavage of SNAP-25 protein occurred mainly at the dorsal horn regions where most of the bladder afferents end. Cleaved SNAP-25 was not detected in motor or preganglionic parasympathetic neurons. A significant decrease in CGRP expression, a peptide exclusively present in sensory fibres in the spinal cord, occurred at the L5/L6 segments and associated dorsal root ganglia (DRG) after Onabot/A injection in SCI animals. Onabot/A strongly increased the expression of ATF3, a marker of neuronal stress, in L5/L6 DRG neurons. Taken together, our results suggest that IT Onabot/A has a predominant effect on bladder sensory fibres, and that such effect is enough to control NDO following chronic SCI. The mechanism of action of Onabot/A includes not only the cleavage of SNAP-25 in sensory terminals but also impairment of basic cellular machinery in the cell body of sensory neurons. PMID- 27235936 TI - Time to think about pathways to TB care from a different perspective. PMID- 27235937 TI - Scaling up of HIV-TB collaborative activities: Achievements and challenges in India. AB - India has been implementing HIV/TB collaborative activities since 2001 with rapid scale-up of infrastructure across the country during past decade in National AIDS Control Programme and Revised National TB Control Programme. India has shown over 50% reduction in new infections and around 35% reduction in AIDS-related deaths, thereby being one of the success stories globally. Substantial progress in the implementation of collaborative TB/HIV activities has occurred in India and it is marching towards target set out in the Global Plan to Stop TB and endorsed by the UN General Assembly to halve HIV associated TB deaths by 2015. While the successful approaches have led to impressive gains in HIV/TB control in India, there are emerging challenges including newer pockets with rising HIV trends in North India, increasing drug resistance, high mortality among co-infected patients, low HIV testing rates among TB patients in northern and eastern states in India, treatment delays and drop-outs, stigma and discrimination, etc. In spite of these difficulties, established HIV/TB coordination mechanisms at different levels, rapid scale-up of facilities with decentralisation of treatment services, regular joint supervision and monitoring, newer initiatives like use of rapid diagnostics for early diagnosis of TB among people living with HIV, TB notification, etc. have led to success in combating the threat of HIV/TB in India. This article highlights the steps taken by India, one of the largest HIV/TB programmes in world, in scaling up of the joint HIV-TB collaborative activities, the achievements so far and discusses the emerging challenges which could provide important lessons for other countries in scaling up their programmes. PMID- 27235938 TI - Accelerating TB notification from the private health sector in Delhi, India. AB - INTRODUCTION: In India, almost half of all patients with tuberculosis (TB) seek care in the private sector as the first point of care. The national programme is unable to support such TB patients and facilitate effective treatment, as there is no information on TB and Multi or Extensively Drug Resistant TB (M/XDR-TB) diagnosis and treatment in private sector. OBJECTIVE: To improve this situation, Government of India declared TB a notifiable disease for establishing TB surveillance system, to extend supportive mechanism for TB treatment adherence and standardised practices in the private sector. But TB notification from the private sector is a challenge and still a lot needs to be done to accelerate TB notification. METHODS: Delhi State TB Control Programme had taken initiatives for improving notification of TB cases from the private sector in 2014. Key steps taken were to constitute a state level TB notification committee to oversee the progress of TB notification efforts in the state and direct 'one to one' sensitisation of private practitioners (PPs) (in single PP's clinic, corporate hospitals and laboratories) by the state notification teams with the help of available tools for sensitising the PP on TB notification - TB Notification Government Order, Guidance Tool for TB Notification and Standards of TB Care in India. RESULTS: As a result of focussed state level interventions, without much external support, there was an accelerated notification of TB cases from the private sector. TB notification cases from the private sector rose from 341 (in 2013) to 4049 (by the end of March 2015). CONCLUSION: Active state level initiatives have led to increase in TB case notification. PMID- 27235939 TI - Vaccines against tuberculosis: A review. AB - Tuberculosis (TB) has taken toll of many lives, therefore a need of effective TB vaccine, which can provide sufficient immunity to prevent developing of disease has been felt for a longer time. BCG, the only available vaccine, though prevents against severe form of primary tuberculosis in paediatric population, failed to have its efficacy in pulmonary patients. Few candidates are in the pipeline undergoing clinical trial. An extensive research is needed to ensure their safety and efficacy before their acceptance as a TB vaccine to be incorporated in national immunization programmes. PMID- 27235940 TI - Cost analysis of different diagnostic algorithms for pulmonary tuberculosis varying in placement of Xpert MTB/RIF. AB - BACKGROUND: We undertook cost analysis for diagnosis of pulmonary tuberculosis (PTB) using present algorithm under Revised National Tuberculosis Control programme and using Xpert MTB/RIF (Xpert) as frontline test or in conjunction with smear microscopy and/or chest radiography. METHODS: Costs were estimated for different strategies: (A) present algorithm involving sputum smear examination followed by antibiotic trial in smear negative patients, repeat smear examination (RE) if symptoms continue and chest radiography if RE negative; (B) direct Xpert; (C) smear microscopy followed by Xpert in smear negative patients; (D) radiography followed by Xpert in those having abnormal pulmonary shadows; and (E) smear examination followed by radiography among smear negative patients and Xpert in presence of abnormal pulmonary shadow. RESULTS: Cost to program was estimated lowest with Strategy A and highest with Strategy B. Compared to the latter, program cost reduces by 7%, 4.5%, and 17.4% by strategies C, D, and E, respectively. Cost to the group of individuals with presumptive PTB and their attendants is significantly higher for Strategy A compared to other four strategies. Among the latter, the patients' cost was minimum with Strategy B and maximum with Strategy C. Program cost per case diagnosed was lowest by Strategy A and highest by Strategy B. Patient cost per case diagnosed was highest by Strategy A and lowest by Strategy B. Using Xpert, Strategy E had the lowest program as well as overall cost per case diagnosed. CONCLUSION: Strategy E may be chosen for diagnosis of PTB. When resources would no longer be a constraint, direct Xpert would reduce costs incurred by the patients. PMID- 27235941 TI - General and tuberculosis mortality in two states of India: A population-based survey. AB - BACKGROUND: General and cause-specific mortality data for causes of death are not available for the states of Andhra Pradesh (AP) and Orissa in India. OBJECTIVES: To estimate general mortality rate (GMR) and the tuberculosis mortality rate (TMR) among the general population in the two states. METHODS: All permanent residents in households of selected districts of AP and Orissa states were registered in the survey in 2005-2006. A sample size of 380,000 persons was selected from each state. Health workers carried out house-to-house enumeration. Demographic and occurrence of death data were collected. The cause of death was determined using the instrument of verbal autopsy. RESULTS: The GMR for AP and Orissa was 636 (95% CI: 610-662) and 616 (95% CI: 588-643) per 100,000 person years (p-ys) respectively. The TMR for AP and Orissa was 76 (95% CI: 67-85) and 41 (95% CI: 34-48) per 100,000 p-ys respectively. The difference in TMR between the states was statistically significant (P<0.0001). CONCLUSION: The GMRs are similar in AP and Orissa states. Tuberculosis accounted for 12% and 7% of deaths in AP and Orissa respectively. Focused strategies are needed to reduce mortality due to tuberculosis. PMID- 27235942 TI - Risk factors associated with development of pulmonary impairment after tuberculosis. AB - BACKGROUND: Treatment of pulmonary tuberculosis (PTB) focuses on microbiological cure and radiological improvement. However, many patients develop pulmonary impairment after the completion of anti-tubercular therapy (ATT), which affects their quality of life (QoL). AIM AND OBJECTIVE: To study the occurrence and severity of pulmonary impairment after tuberculosis (PIAT), risk factors associated with development of PIAT and QoL after development of PIAT. METHODOLOGY: 146 eligible PTB patients, who completed their ATT during January 2013 to December 2013 at National Institute of TB and Respiratory Diseases (NITRD), New Delhi and peripheral centres were enrolled after informed consent and evaluated. PIAT was graded using spirometric parameters. Severity of dyspnoea was assessed using Borg scale and Medical Research Council (MRC) scale. QoL was assessed using Seattle's Obstructive Lung Diseases Questionnaire (SOLDQ). RESULTS: 74% (108) had PIAT. On univariate analysis, smoking, education, body mass index (BMI), duration of illness prior to diagnosis of TB and number of prior ATT courses taken were the significant risk factors associated with the development of PIAT. On multiple logistic regression, patients who had taken ATT more than once was the independent risk factor associated with PIAT. Severity of dyspnoea was increased on both Borg scale and MRC scale with the increase in impairment of lung function. QoL was lower in patients with severe impairment. CONCLUSION: After bacteriological cure of TB after treatment, significant numbers of patients have poor lung function and poor QoL. There is need for prevention and management of such sequelae under national programme. PMID- 27235943 TI - Universal access to DOTS in Delhi Prisons: Where do we stand? AB - BACKGROUND: Universal access implies that all tuberculosis (TB) patients in the community should have access to early, good quality diagnosis and treatment services that are affordable and convenient to the patient in time, place, and person. To achieve universal access, all affected vulnerable and marginalized population like prison inmates should have access to TB diagnostic and treatment services. OBJECTIVES: To assess the TB control activities in prisons of Delhi, the capital of India, and to suggest interventions for strengthening the program based on the observations. MATERIALS AND METHODS: Study was conducted at Tihar Prison, Delhi. TB case notification data from the Revised National TB Control Program (RNTCP) between 2008 and 2012 and log process framework were used to assess various parameters. RESULTS: Mean number of patients initiated on TB treatment was 120.6 annually between 2008 and 2012. The RNTCP has been implemented in Delhi Prisons since 2002; however, gaps were identified in human resource, training needs, case finding, diagnostic and treatment services, and supervision on situational analysis. Coordination between prison authorities and RNTCP authorities in relation to initial screening and discharge process appeared to be weak. CONCLUSION AND RECOMMENDATIONS: Because of the restricted access, vulnerability of the prison population, increase in drug-resistant TB, the TB control activities in the prison require restructuring. Initial screening for early diagnosis and treatment and "Discharge planning" needs to be devised so that there is sufficient time before release or transfer of individuals from prison. This needs strong commitment from the prison health authorities and RNTCP staff. PMID- 27235944 TI - Etiology of hemoptysis: A retrospective study from a tertiary care hospital from northern Madhya Pradesh, India. AB - OBJECTIVE: To evaluate the various etiologies of hemoptysis and outcome in an Indian cohort. MATERIAL AND METHODS: Retrospective analysis of patients admitted with complaints of hemoptysis in the department of Pulmonary Medicine between April 2010 and March 2013. We categorized the patients according to various etiologies and according to the grades of hemoptysis. RESULTS: Three hundred and forty-six patients were included in the study. Of these, 214 (67%) were men and 142 (33%) were women. Tuberculosis (79.2%) accounted for majority of cases of hemoptysis. Other causes of hemoptysis were lung cancer (7.2%), bronchitis (4.6%), and bronchiectasis (3.5%). Moderate grade (73.4%) of hemoptysis was the frequent mode of presentation. CONCLUSION: Hemoptysis is the most frequent presentation of tuberculosis in India. It may be the presentation of healed pulmonary tuberculosis. Moderate amount of hemoptysis is commonly seen in the general population. PMID- 27235945 TI - Innovatively addressing the challenge of maintaining binocular microscopes under Tuberculosis Programme in India - Is this feasible? AB - BACKGROUND: India is a high TB burden country. The preferred first line diagnostic tool under National TB Programme is sputum smear microscopy through binocular microscopes (BMs) from 13,000 designated microscopy centres across the country. The programme had devised innovative strategy for maintenance of BMs. A study was conducted to look into the operational feasibility of an external agency to provide maintenance services for BMs engaged through newer strategy. METHODS: A cross-sectional study was conducted in the states of Uttar Pradesh, Bihar and Rajasthan during 2010-2013. RESULTS: A total of 9314 BMs were serviced during the period 2011-2013, of which 1104 (11.8%) had major repairs, 2204 (23.6%) had minor repairs, 1054 (11.3%) were provided emergency breakdown services and 223 (2.4%) were condemned. CONCLUSION: The bold initiative and newer strategy of the programme to engage agencies for BMs maintenance services is worthwhile and should be continued and could be considered for replication across the country. PMID- 27235946 TI - A case-control study identifying the characteristics of patients providing incorrect contact information at registration for DOTS in Pune, India. AB - BACKGROUND: Provision of incorrect contact information by the patient at the time of registration for treatment is a deterrent to treatment adherence. OBJECTIVE: To determine the characteristics of patients providing incomplete contact information at the time of registration for Directly Observed Treatment Short course (DOTS) at the tuberculosis units (TUs) in Pune, India. METHODS: A nested case-control study was conducted where the characteristics of patients who had provided incorrect contact information (cases) were compared with the characteristics of patients who could be traced (controls). Cases and controls were identified from a cohort of 3802 tuberculosis patients registered at the DOTS centres in Pune. Correct or incorrect contact information was ascertained by visiting each address provided at the time of registration. Characteristics associated with providing incorrect contact information were determined through multinomial regression analysis. RESULTS: There were 406 (10.7%) patients who could not be traced due to incorrect address provided at the time of registration at the DOTS centres. Registration at the TUs in the peripheral areas of the city (odds ratio (OR)=3.57, 95% confidence interval (CI)=2.64-4.84) and engagement in migration prone occupation (OR=1.83, 95% CI=1.47-2.26) were associated with odds of providing incorrect information at the time of registration. CONCLUSION: Untraceable patients were more likely to be engaged in occupations with a potential for migration. DOTS centres located in developing areas of cities should reinforce validation of contact information of patients. PMID- 27235947 TI - Successful removal of self-expanding metallic stent after deployment for tubercular bronchostenosis. AB - The use of metallic stents is traditionally not recommended for benign tracheobronchial conditions. With advances in the field of interventional bronchoscopy, metal tracheobronchial stents have occasionally been used to treat benign disease. However, the removal of these stents from the airway is technically difficult. We are reporting the case of a young female subject who received a self-expanding metallic stent for alleviation of post-tubercular bronchostenosis, which was successfully removed after two months without complications. Metal stents can be used in benign tracheobronchial conditions but require meticulous follow-up to monitor complications. Experienced operators can remove them without major complications and this may be life-saving in emergencies. We are reporting this case for the rarity of such procedures in India. PMID- 27235948 TI - Hematemesis: Unusual presentation of isolated gastric tuberculosis. AB - A 25-year-old male presented with hematemesis, epigastric pain, and melena. He had dyspepsia with significant weight loss for 3 months period. On clinical examination, he was pale with no organomegaly or lymphadenopathy. The X-ray chest was normal, and ultrasound abdomen was normal. Upper GI endoscopy revealed nodularity and ulceration along proximal part of lesser curvature of the stomach. CT scan abdomen showed thickening of lesser curvature just below gastro esophageal junction. The biopsies were negative for malignancy. Repeat upper GI endoscopy showed a nonhealing ulcer, on repeat well biopsies taken from the base of ulcer primary gastric tuberculosis was diagnosed. It showed many epithelioid cell granulomas and multinucleated giant cells with caseous necrosis on histology. Acid-fast bacilli on Zeil Neelsen staining and TB PCR were positive for Mycobacterium tuberculosis. He was put on four-drug anti-tuberculous treatment. On follow-up, the patient gradually improved and regained weight. Repeat upper GI endoscopy done after 8 weeks showed healing of the ulcer with decrease in nodularity. PMID- 27235949 TI - Answer to letter sent by Dr. M.D. Rogers (Chairman of the International Glutamate Technical Committee (IGTC), Belgium) related to Ataseven et al. article published in Food and Chemical Toxicology 2016; 91:8-18. PMID- 27235951 TI - Welcome to Singapore! PMID- 27235950 TI - Polycyclic aromatic hydrocarbons in Haliotis tuberculata (Linnaeus, 1758) (Mollusca, Gastropoda): Considerations on food safety and source investigation. AB - Polycyclic aromatic hydrocarbons were analyzed in wild specimens of Haliotis tuberculata from three sites of the Sothern Ionian Sea. The species Ht is commonly found at these sites and has significant commercial value. Main results revealed mean values of benzo(a)pyrene higher than the threshold set by Regulation No. 835/2011/EU in all sampling sites and the sum of selected PAHs, expressed as SigmaPAH4 by EC Regulation, were below the limit set by the same Regulation in ME and VSG. We found generally higher concentrations than literature finding, especially for low molecular weight PAHs, and results of diagnostic ratios highlighted both pyrolytic and petrogenic sources. The potential human health risks due consumption of Ht by local inhabitants have been assessed by exposure daily intake (EDI), target hazard quotient (THQ) and lifetime cancer risk (CR). EDI values were below the intake range reviewed by EFSA for each class of contaminant. BaP daily intake was below the value of 10 ng/Kg/day, suggested by JFCFA, and CRBaP was slightly higher than the acceptable risk level (ARL) of 1*10(-5). Conversely, target hazard quotient (THQ) resulted always below 1, thus the risk to develop chronic systemic effects due naphthalene, acenaphthene, fluorene, anthracene, fluoranthene and pyrene was low. PMID- 27235952 TI - Patterns and trends in the incidence of paediatric and adult germ cell tumours in Australia, 1982-2011. AB - PURPOSE: Germ cell tumour (GCT) aetiology is uncertain and comprehensive epidemiological studies of GCT incidence are few. METHODS: Nationwide data on all malignant GCTs notified to Australian population-based cancer registries during 1982-2011 were obtained. Age- and sex-specific, and World age-standardised incidence rates were calculated for paediatric (0-14) and adult (15+) cases using the latest WHO subtype classification scheme. Temporal trends were examined using Joinpoint regression. RESULTS: There were 17,279 GCTs (552 paediatric, 16,727 adult). Age-specific incidence in males (all histologies combined) was bimodal, with peaks during infancy for most sites, and second, larger, peaks during young adulthood. Incidence of ovarian tumours peaked at age 15-19. Around half of paediatric tumours were extragonadal, whereas adult tumours were mostly gonadal. Yolk sac tumours and teratomas predominated in infants, whereas germinomas became more frequent towards adulthood. Increasing incidence trends for some adult gonadal tumours have stabilised; the trend for male extragonadal tumours is also declining. CONCLUSION: Broad similarities in the shape of age-specific incidence curves, particularly for gonadal, central nervous system, and mediastinal tumours provide epidemiological support for commonalities in aetiology among clinically disparate GCT subtypes. Differences in peak ages reflect underlying subtype specific biological differences. Declining incidence trends for some adult gonadal tumours accords with the global transition in GCT incidence, and supports the possibility of a reduction in prevalence of shared aetiological exposures. PMID- 27235954 TI - Moving Forward in Love and Acceptance. PMID- 27235953 TI - Affective responses to dance. AB - The objective of the present work was the characterization of mechanisms by which affective experiences are elicited in observers when watching dance movements. A total of 203 dance stimuli from a normed stimuli library were used in a series of independent experiments. The following measures were obtained: (i) subjective measures of 97 dance-naive participants' affective responses (Likert scale ratings, interviews); and (ii) objective measures of the physical parameters of the stimuli (motion energy, luminance), and of the movements represented in the stimuli (roundedness, impressiveness). Results showed that (i) participants' ratings of felt and perceived affect differed, (ii) felt and perceived valence but not arousal ratings correlated with physical parameters of the stimuli (motion energy and luminance), (iii) roundedness in posture shape was related to the experience of more positive emotion than edgy shapes (1 of 3 assessed rounded shapes showed a clear effect on positiveness ratings while a second reached trend level significance), (iv) more impressive movements resulted in more positive affective responses, (v) dance triggered affective experiences through the imagery and autobiographical memories it elicited in some people, and (vi) the physical parameters of the video stimuli correlated only weakly and negatively with the aesthetics ratings of beauty, liking and interest. The novelty of the present approach was twofold; (i) the assessment of multiple affect-inducing mechanisms, and (ii) the use of one single normed stimulus set. The results from this approach lend support to both previous and present findings. Results are discussed with regards to current literature in the field of empirical aesthetics and affective neuroscience. PMID- 27235955 TI - Energizing Generations: The Race to Distinction! PMID- 27235956 TI - The Duration of Self-Selected Music Needed to Reduce Preoperative Anxiety. AB - PURPOSE: Preoperative anxiety affects patients both physically and psychologically. It may also influence the patient's perioperative experience and result in reduced patient satisfaction with care and potentially delayed recovery. Previous research indicates that patients who listen to music in the perioperative setting experience less anxiety than patients who do not listen to music. Research does not address the duration of music required to effectively reduce anxiety in this population. DESIGN: A randomized control trial was used. METHODS: Two intervention groups (15-minute music and 30-minute music) and one control group (no music) were compared. FINDINGS: Patients (n = 133) demonstrated less anxiety after listening to either 15 or 30 minutes of music (P < .0001). Patients (n = 47) who listened to 15 minutes of music demonstrated less anxiety than those who did not listen to music (P = .005), whereas patients (n = 41) who listened to 30 minutes of music demonstrated less anxiety than those who did not listen to music (P < .001). CONCLUSIONS: Listening to as little as 15 minutes of music preoperatively is an effective method to reduce anxiety in patients who are about to have surgery. PMID- 27235957 TI - Background Music Playback in the Preoperative Setting: Does It Reduce the Level of Preoperative Anxiety Among Candidates for Elective Surgery? AB - BACKGROUND: Contemporary medicine and nursing use music to stabilize mood, relieve tension and anxiety, and achieve higher treatment efficiency. Preoperative anxiety may be responsible for cognitive and behavioral changes affecting treatment efficiency. PURPOSE: To evaluate the effect of background music on preoperative anxiety in elective surgery patients and on noise levels in the surgery waiting room. DESIGN: One hundred fifty-nine elective surgery patients were divided into an intervention group (n = 82) and a control group (n = 77). Data were collected and evaluated on the evening before surgery in the department, on entering the waiting room, and 30 minutes later in the preoperative setting. Data were gathered using the State-Trait Anxiety Inventory scale and by measuring vital signs. Daily noise levels in the preoperative waiting room were recorded as well. FINDINGS: Exposure to background music was associated with decreased levels of state anxiety irrespective of age, sex, and previous exposure to surgery or anesthesia (P < .001). Background music was also related to environmental noise reduction in the surgery waiting room (P < .0001). CONCLUSIONS: Background music can be useful as a means of decreasing preoperative anxiety. PMID- 27235958 TI - Factors Influencing Intraoperative Waiting Time According to the Experience of Iranian Families. AB - PURPOSE: The purpose of this study was to explore factors influencing family members' experience of waiting for patients' surgery. DESIGN: A qualitative design using content analysis approach was used. METHODS: The study took place at a university medical center hospital in an urban area of Iran. After using a purposive sampling method for the selection of participants, semistructured interviews and field notes were held for data collection. FINDINGS: The experience of 16 Iranian family members who were waiting for their patient's surgery to be finished was analyzed. Data analysis led to the development of three main themes: "family member-related factors," "patient-related factors," and "organization-related factors." CONCLUSIONS: The results revealed some factors in real context that can help health care professionals, especially nurses, to get a better understanding of the situation and improve quality of care. In addition, understanding these factors will contribute to the body of knowledge in nursing. PMID- 27235959 TI - A Review of the Effects of Sedation on Thermoregulation: Insights for the Cardiac Catheterization Laboratory. AB - PURPOSE: To examine the effects that the sedative and analgesic medications commonly used in the cardiac catheterization laboratory have on thermoregulation. DESIGN: A structured review strategy was used. METHODS: MEDLINE and CINAHL were searched for published studies, and reference lists of retrieved studies were scrutinized for further studies. Data were extracted using a standardized extraction tool. FINDINGS: A total of nine studies examined the effect that sedative and analgesic medications have on thermoregulation. Midazolam has minimal impact on thermoregulation, whereas opioids, dexmedetomidine, and propofol markedly decrease vasoconstriction and shivering thresholds. CONCLUSIONS: Patients who receive sedation in the cardiac catheterization laboratory may be at risk of hypothermia because of the use of medications that impair thermoregulation. Further research is required to identify the prevalence of unplanned hypothermia during sedation in the cardiac catheterization laboratory. PMID- 27235960 TI - Analysis of Cricoid Pressure Force and Technique Among Anesthesiologists, Nurse Anesthetists, and Registered Nurses. AB - PURPOSE: The purpose of this project was to assess the ability of anesthesiologists, nurse anesthetists, and registered nurses to correctly identify anatomic landmarks of cricoid pressure and apply the correct amount of force. DESIGN: The project included an educational intervention with one group pretest-post-test design. METHODS: Participants demonstrated cricoid pressure on a laryngotracheal model. After an educational intervention video, participants were asked to repeat cricoid pressure on the model. FINDINGS: Participants with a nurse anesthesia background applied more appropriate force pretest than other participants; however, post-test results, while improved, showed no significant difference among providers. Participant identification of the correct anatomy of the cricoid cartilage and application of correct force were significantly improved after education. CONCLUSION: This study revealed that participants lacked prior knowledge of correct cricoid anatomy and pressure as well as the ability to apply correct force to the laryngotracheal model before an educational intervention. The intervention used in this study proved successful in educating health care providers. PMID- 27235961 TI - Promoting Patient Safety With Perioperative Hand-off Communication. AB - Effective perioperative hand-off communication is essential for patient safety. The purpose of this quality improvement project was to demonstrate how a structured hand-off tool and standardized process could increase effective perioperative communication of essential elements of care and assist in the timely recognition of patients at risk for clinical deterioration in the initial postoperative period. A team-based pilot project used the Iowa Model of Evidence Based Practice and the principles of Lean Six Sigma to implement Perioperative PEARLS, a perioperative specific hand-off communication tool and a standardized framework for hand-off communication. The implementation of a structured hand-off tool and standardized process supports compliance with regulatory standards of care and eliminates waste from the hand-off process. A review of pre implementation and post-implementation data revealed evidence of safer patient care. Evidence-based perioperative hand-off communication facilitates expedited patient evaluation, rapid interventions, reduction in adverse events, and a safer perioperative environment. PMID- 27235962 TI - Ensuring a Smooth Discharge Home After Ambulatory Surgery. PMID- 27235963 TI - Pharmacological Interventions for Prevention or Treatment of Postoperative Pain in People Undergoing Laparoscopic Cholecystectomy. PMID- 27235964 TI - Evidence Into Practice: Leading New Graduate Nurses to Evidence-Based Practice Through a Nurse Residency Program. PMID- 27235965 TI - Technology Failures. PMID- 27235966 TI - Optimizing Acute Pain Management in the Obese Patient: Treatment and Monitoring Considerations. PMID- 27235967 TI - Research News: Emergency Surgery in Ambulatory Settings. PMID- 27235968 TI - "Show Me Your Stethoscope" - Social Media Response. PMID- 27235969 TI - Plasma ferritin concentrations are not associated with abdominal aortic aneurysm diagnosis, size or growth. AB - BACKGROUND AND AIMS: Experimental studies using a rodent model have suggested that iron overload may contribute to abdominal aortic aneurysm (AAA) pathogenesis. METHODS: We assessed the association of total body iron, as measured by plasma ferritin, with AAA diagnosis, size and growth in 4024 community-dwelling older men screened for AAA, using logistic regression and linear mixed effects models. RESULTS: Plasma ferritin concentrations were similar in men who did (n = 293) and did not (n = 3731) have an AAA (median [inter quartile range] concentrations 115.4 [63.0-203.1] and 128.5 [66.1-229.1] ng/mL respectively, p = 0.124). There was no association between plasma ferritin concentration and AAA diagnosis in unadjusted logistic regression (odds ratio (OR) for a 1 standard deviation increase: 0.880 [95%CI: 0.764-1.015]; p = 0.078), or when adjusting for AAA risk factors and factors known to influence circulating ferritin (OR for a 1 standard deviation increase: 0.898 [95% CI: 0.778-1.035]; p = 0.138). Iron overload prevalence (plasma ferritin concentrations >200 ng/mL) was lower in men with an AAA (25.3%) than those without (30.8%; p = 0.048), but was not associated with AAA diagnosis after adjusting as above (OR: 0.781 [95% CI:0.589-1.035]; p = 0.086). The association of iron overload with AAA growth was investigated in 265 men with small AAAs who received at least 1 repeat ultrasound scan in the 3 years following screening. We saw no difference in AAA growth between men who did and did not have iron overload (n = 65 and 185 respectively, p = 0.164). CONCLUSIONS: Our data suggest that iron overload is unlikely to be important in AAA pathogenesis. PMID- 27235970 TI - Evolution of microbial community along with increasing solid concentration during high-solids anaerobic digestion of sewage sludge. AB - High-solids anaerobic digestion (HSAD), a promising method with smaller reactor and less heating energy consumption, showed relatively lower digestion efficiency sometimes and higher tolerance to some inhibitors. To investigate the phenomena, the archaeal and bacterial communities in four anaerobic digesters treating sewage sludge with total solids (TS) of 10-19% were investigated. Although acetoclastic methanogenesis conducted mainly by genus Methanosarcina was still the main pathway producing methane, the total ratio of acetoclastic methanogens decreased along with the increased TS. In contrary, the relative abundance of hydrogenotrophic methanogens increased from 6.8% at TS 10% to 22.3% at TS 19%, and methylotrophic methanogens from 10.4% to 20.9%. The bacterial community was dominated by five phyla. Acidogenic and acetogenic bacteria affiliated to Firmicutes decreased following the increase of TS; while the proteolysis phylum Bacteroidetes increased, with a tolerant family ST-12K33 notably existing in the digesters at TS 17% and 19%. PMID- 27235971 TI - Kinetics and thermodynamics of biodegradation of hydrolyzed polyacrylamide under anaerobic and aerobic conditions. AB - Kinetics and thermodynamics of hydrolyzed polyacrylamide (HPAM) biodegradation in anaerobic and aerobic activated sludge biochemical treatment systems were explored to determine the maximum rate and feasibility of HPAM biodegradation. The optimal nutrient proportions for HPAM biodegradation were determined to be 0.08g.L(-1) C6H12O6, 1.00g.L(-1) NH4Cl, 0.36g.L(-1) NaH2PO4 and 3.00g.L(-1) K2HPO4 using response surface methodology (RSM). Based on the kinetics, the maximum HPAM biodegradation rates were 16.43385mg.L(-1).d(-1) and 2.463mg.L( 1).d(-1) in aerobic and anaerobic conditions, respectively. The activation energy (Ea) of the aerobic biodegradation was 48.9897kJ.mol(-1). Entropy changes (DeltaS) of biochemical treatment system decreased from 216.21J.K(-1) to 2.39J.K( 1). Thermodynamic windows of opportunity for HPAM biodegradation were drawn. And it demonstrated HPAM was biodegraded into acetic acid and CO2 under laboratory conditions. Growth-process equations for functional bacteria anaerobically grown on polyacrylic acid were constructed and it confirmed electron equivalence between substrate and product. PMID- 27235972 TI - Cathodes enhance Corynebacterium glutamicum growth with nitrate and promote acetate and formate production. AB - The industrially important Corynebacterium glutamicum can only incompletely reduce nitrate into nitrite which then accumulates and inhibits growth. Herein we report that cathodes can resolve this problem and enhance glucose fermentation and growth by promoting nitrite reduction. Cell growth was inhibited at relatively high potentials but was significant when potentials were more reductive (-1.20V with anthraquinone-2-sulfonate as redox mediator or -1.25V vs. Ag/AgCl). Under these conditions, glucose was consumed up to 6 times faster and acetate was produced at up to 11 times higher yields (up to 1.1mol/mol-glucose). Acetate concentrations are the highest reported so far for C. glutamicum under anaerobic conditions, reaching values up to 5.3+/-0.3g/L. Herein we also demonstrate for the first time formate production (up to 3.4+/-0.3g/L) by C. glutamicum under strongly reducing conditions, and we attribute this to a possible mechanism of CO2 bioreduction that was electrochemically triggered. PMID- 27235973 TI - A comparative study of the growth of Tetraselmis sp. in large scale fixed depth and decreasing depth raceway ponds. AB - In this study, an alternative approach was proposed where excess seawater would be added only during inoculation (DD) rather than daily addition (FD). Growth and metabolite contents of Tetraselmis sp. weren't affected for daily increase of 2% NaCl salinity. Tetraselmis sp. was then cultured in DD and FD pond. In DD pond, initial culture depth was 23.5cm and its depth reduced as no water was added; for FD pond, everyday sterilized seawater was added to maintain 20cm depth. DD pond had higher biomass productivity compared to FD pond, until DD pond was deeper than FD pond; metabolite content and FAME profile of Tetraselmis sp. were also similar in both cultures. Therefore, considering the simplicity in operation, halo tolerant microalgae can be grown in DD pond method. PMID- 27235974 TI - Improved operational stability of d-psicose 3-epimerase by a novel protein engineering strategy, and d-psicose production from fruit and vegetable residues. AB - The aim of the present work was to improve stability of d-psicose 3-epimerase and biotransformation of fruit and vegetable residues for d-psicose production. The study established that N-terminal fusion of a yeast homolog of SUMO protein - Smt3 - can confer elevated optimal temperature and improved operational stability to d-psicose 3-epimerase. The Smt3-d-psicose 3-epimerase conjugate system exhibited relatively better catalytic efficiency, and improved productivity in terms of space-time yields of about 8.5kgL(-1)day(-1). It could serve as a promising catalytic tool for the pilot scale production of the functional sugar, d-psicose. Furthermore, a novel approach for economical production of d-psicose was developed by enzymatic and microbial bioprocessing of fruit and vegetable residues, aimed at epimerization of in situd-fructose to d-psicose. The bioprocessing led to achievement of d-psicose production to the extent of 25-35% conversion (w/w) of d-fructose contained in the sample. PMID- 27235975 TI - Efficient performance and the microbial community changes of submerged anaerobic membrane bioreactor in treatment of sewage containing cellulose suspended solid at 25 degrees C. AB - Influence of cellulose as suspended solid (SS) on the performance of submerged anaerobic membrane bioreactor (SAnMBR) was evaluated at 25 degrees C using two types of synthetic sewage (SS contained or not). During the 110days operation, COD and BOD removal, CH4 gas recovery and cellulose accumulation were investigated in detail. The influence of cellulose as SS in sewage on the SAnMBR performance was not significant at HRT longer than12h and 65-72% of the influent COD was recovered as methane gas at HRT of 12h. At HRT of 6h, the quality of effluent got worse and the accumulation of cellulose was found in reactor. 16S rRNA analysis revealed that the microbial diversity distribution including Archaea and Bacteria changed due to the addition of SS in sewage and specific microbe for cellulose degradation such as Proteobacteria was detected. Sludge in SAnMBR could acclimate to characteristics of sewage by self-adaptation. PMID- 27235976 TI - Pulmonary administration of small interfering RNA: The route to go? AB - Ever since the discovery of RNA interference (RNAi), which is a post transcriptional gene silencing mechanism, researchers have been studying the therapeutic potential of using small interfering RNA (siRNA) to treat diseases that are characterized by excessive gene expression. Excessive gene expression can be particularly harmful if it occurs in a vulnerable organ such as the lungs as they are essential for physiological respiration. Consequently, RNAi could offer an approach to treat such lung diseases. Parenteral administration of siRNA has been shown to be difficult due to degradation by nucleases in the systemic circulation and excretion by the kidneys. To avoid these issues and to achieve local delivery and local effects, pulmonary administration has been proposed as an alternative administration route. Regarding this application, various animal studies have been conducted over the past few years. Therefore, this review presents a critical analysis of publications where pulmonary administration of siRNA in animals has been reported. Such an analysis is necessary to determine the feasibility of this administration route and to define directions for future research. First, we provide background information on lungs, pulmonary administration, and delivery vectors. Thereafter, we present and discuss relevant animal studies. Though nearly all publications reported positive outcomes, several reoccurring challenges were identified. They relate to 1) the necessity, efficacy, and safety of delivery vectors, 2) the biodistribution of siRNA in tissues other than the lungs, 3) the poor correlation between in vitro and in vivo models, and 4) the long-term effects upon (repeated) administration of siRNA. Finally, we present recommendations for future research to define the route to go: towards safer and more effective pulmonary administration of siRNA. PMID- 27235977 TI - Laser-facilitated epicutaneous immunotherapy to IgE-mediated allergy. AB - Allergen specific immunotherapy has been shown to be the only effective treatment for long-lasting clinical benefit to IgE-mediated allergic diseases, but a fewer than 5% of patients choose the treatment because of inconvenience and a high risk of anaphylaxis. Recently, epicutaneous allergen-specific immunotherapy (EPIT) has proven effective, yet with limitations owing to strong skin reactions. We demonstrate here safer and faster EPIT, named MUEPIT, by delivering powdered allergen and adjuvants into many micropores in the epidermis. We fabricated a microarray patch fractionally coated with a powder mixture of ovalbumin (OVA) model allergen, CpG, and 1,25-dihydroxyvitamin D3 (VD3). Topical application of the patch onto laser-microperforated skin resulted in a high level of epidermal delivery while greatly minimizing allergen leakage into circulation system as compared to current subcutaneous immunotherapy (SCIT). Moreover, only three times of MUEPIT over two weeks could sufficiently inhibit allergen-specific IgE responses in mice suffering OVA-induced airway hyperresponsivness (AHR), which was unattainable by eight times of SCIT over three weeks. Mechanistically, MUEPIT preferably enhanced IgG2a production suggesting TH1-biased immune responses and induced a high level of T-regulatory (Treg) cells against repeated allergen sensitization. The immune tolerance was confirmed by marked reduction in airway wall thickness as well as eosinophil and neutrophil infiltration into the respiratory airway. The MUEPIT represents a novel and painless technology to treat IgE-mediated allergic diseases with little local skin reaction and a minimal risk of anaphylaxis. PMID- 27235978 TI - Sustained delivery by a cyclodextrin material-based nanocarrier potentiates antiatherosclerotic activity of rapamycin via selectively inhibiting mTORC1 in mice. AB - Increasing evidence has demonstrated special advantages of the nanomedicinal approach for the management of cardiovascular disease. We hypothesize that sustained delivery of rapamycin (RAP) may provide more desirable therapeutic effects than traditional oral administration by selectively inhibiting mammalian target of rapamycin complex 1 (mTORC1) signaling. To evidence this assumption and develop an effective, safe, and translational nanotherapy for atherosclerosis, this study was designed to examine antiatherosclerotic efficacy of a RAP nanotherapy based on an acetalated beta-cyclodextrin (Ac-bCD) material in apolipoprotein E-deficient (ApoE(-/-)) mice. First, biodegradable and biocompatible materials of Ac-bCDs were synthesized by kinetically controlled acetalation, giving rise to carrier materials that may not generate acidic byproducts after hydrolysis. Then RAP-loaded nanoparticles base on various Ac bCDs were prepared by a nanoemulsion technique, which can sustain drug release for different periods of time, depending on the composition of Ac-bCDs. For a RAP/Ac-bCD180-derived nanotherapy (RAP-NP) that may continue RAP release for up to 20days in vitro, it afforded constant drug levels in both the blood and aortic tissue after subcutaneous injection, while orally administered free RAP showed typical peak-valley profiles with remarkably high peak concentrations. Therapeutic studies conducted in an experimental model of atherosclerosis established in ApoE(-/-) mice revealed that RAP-NP significantly reduced the formation of atherosclerotic lesions and dramatically enhanced the stability of plaques, which was more efficacious than orally delivered free RAP. Moreover, rupture-prone proinflammatory factors in both serum and aortas were significantly decreased after treatment. Whereas oral administration of RAP simultaneously inhibited mTORC1 and mTORC2 in the aorta, sustained delivery by RAP-NP selectively suppressed mTORC1, agreeing with in vitro results in smooth muscle cells. These findings demonstrated that antiatherosclerotic activity of RAP may be considerably improved by sustained release via the Ac-bCD material-derived nanocarrier, which was achieved through selectively inhibiting mTORC1. PMID- 27235979 TI - MUPET imaging of the pharmacokinetic behavior of medium and high molar mass (89)Zr-labeled poly(2-ethyl-2-oxazoline) in comparison to poly(ethylene glycol). AB - Poly(2-oxazoline)s are a promising class of polymers for biomedical applications and a versatile alternative to poly(ethylene glycol)s (PEG). In this work, the pharmacokinetic behavior of well defined (89)Zr-labeled poly(2-ethyl-2 oxazoline)s (PEtOx) was evaluated and compared to that of (89)Zr-labeled PEG, both with varying molar mass. Amine-terminated PEtOx of low dispersity in a molar mass range of 20 to 110kDa and PEG of 20 and 40kDa were functionalized with a desferrioxamine chelator and radiolabeled with (89)Zr. The tissue distribution of both radiolabeled PEtOx and PEG polymers was studied by means of micro Positron Emission Tomography (MUPET) molecular imaging in mice longitudinally up to 1week post injection, followed by ex vivo biodistribution. As previously described for other classes of non-ionic polymers, the blood clearance of PEtOx decreased with molar mass. The cut off for glomerular filtration of PEtOx is likely to be around 40kDa. The head to head comparison of PEG and PEtOx revealed that the biodistribution is mostly dominated by polymer chain length and not polymer molar mass. This study constitutes an important addition to further establishing PEtOx as a promising polymer in biomedical applications. PMID- 27235980 TI - Non-invasive, neuron-specific gene therapy by focused ultrasound-induced blood brain barrier opening in Parkinson's disease mouse model. AB - Focused ultrasound (FUS)-induced with microbubbles (MBs) is a promising technique for noninvasive opening of the blood-brain barrier (BBB) to allow targeted delivery of therapeutic substances into the brain and thus the noninvasive delivery of gene vectors for CNS treatment. We have previously demonstrated that a separated gene-carrying liposome and MBs administration plus FUS exposure can deliver genes into the brain, with the successful expression of the reporter gene and glial cell line-derived neurotrophic factor (GDNF) gene. In this study, we further modify the delivery system by conjugating gene-carrying liposomes with MBs to improve the GDNF gene-delivery efficiency, and to verify the possibility of using this system to perform treatment in the 1-Methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-induced animal disease model. FUS-BBB opening was verified by contrast-enhanced MRI, and GFP gene expression was verified via in vivo imaging system (IVIS). Western blots as well as enzyme-linked immunosorbent assay (ELISA) were conducted to measure protein expression, and immunohistochemistry (IHC) was conducted to test the Tyrosine hydroxylase (TH) neuron distribution. Dopamine (DA) and its metabolites as well as dopamine active transporter (DAT) were quantitatively analyzed to show dopaminergic neuronal dopamine secretion/activity/metabolism. Motor performance was evaluated by rotarod test weekly. Results demonstrated that the LpDNA-MBs (gene-liposome-MBs) complexes successfully serve as gene carrier and BBB-opening catalyst, and outperformed the separated LpDNA/MBs administration both in terms of gene delivery and expression. TH-positive IHC and measurement of DA and its metabolites DOPAC and HVA confirmed improved neuronal function, and the proposed system also provided the best neuroprotective effect to retard the progression of motor-related behavioral abnormalities. Immunoblotting and histological staining further confirmed the expression of reporter genes in neuronal cells. This study suggests that FUS exposures with the administration of LpDNA-MBs complexes synergistically can serve as an effective gene therapy strategy for MPTP-animal treatment, and may have potential for further application to perform gene therapy for neurodegenerative disease. PMID- 27235981 TI - Tunable phosphatase-sensitive stable prodrugs of 5-aminolevulinic acid for tumor fluorescence photodetection. AB - 5-Aminolevulinic acid (5-ALA) has been at the forefront of small molecule based fluorescence-guided tumor resection and photodynamic therapy. 5-ALA and two of its esters received marketing authorization but suffer from several major limitations, namely low stability and poor pharmacokinetic profile. Here, we present a new class of 5-ALA derivatives aiming at the stabilization of 5-ALA by incorporating a phosphatase sensitive group, with or without self-cleavable linker. Compared to 5-ALA hexyl ester (5-ALA-Hex), these compounds display an excellent stability under acidic, basic and physiological conditions. The activation and conversion into the 5-ALA is controlled and can be structure tailored. The prodrugs display reduced acute toxicity compared to 5-ALA-Hex with superior dose response profiles of protoporphyrin IX synthesis and fluorescence intensity in human glioblastoma cells in vitro. Clinically relevant fluorescence kinetics in vivo shown in U87MG glioblastoma spheroid tumor model in chick embryos provide a solid basis for their further development and translation to clinical fluorescence guided tumor resection and photodynamic therapy. PMID- 27235982 TI - Fusarium spp infections in a pediatric burn unit: nine years of experience. AB - INTRODUCTION: Fusarium spp are ubiquitous fungi recognized as opportunistic agents of human infections, and can produce severe infections in burn patients. The literature on Fusarium spp infections in pediatric burn patients is scarce. OBJECTIVES: To describe the clinical and epidemiological features as well as outcome of Fusarium spp infections in pediatric burn patients. PATIENTS AND METHODS: Retrospective, descriptive study of Fusarium spp infections in a specialized intensive care burn unit. RESULTS: In 15 patients Fusarium spp infections were diagnosed. Median age was 48 months. Direct fire injury was observed in ten patients. The median affected burn surface area was 45%. Twelve patients had a full thickness burn. Fourteen patients had a Garces Index >=3. Fungal infection developed at a median of 11 days after burn injury. Fungi were isolated from burn wound in 14 patients and from the bone in one patient. Amphotericin B was the drug of choice for treatment followed by voriconazole. Median time of treatment completion was 23 days. One patient (7%) died of fungal infection-related causes. CONCLUSION: In our series Fusarium spp was an uncommon pathogen in severely burnt patients. The burn wound was the most common site of infection and mortality was low. PMID- 27235983 TI - The sequence, structural, and functional diversity within a protein family and implications for specificity and safety: The case for ETX_MTX2 insecticidal proteins. AB - The need for sustainable insect pest control is driving the investigation and discovery of insecticidal proteins outside of the typical 3-domain Cry protein family from Bacillus thuringiensis (Bt). Examples include Cry35 and Cry51 that belong to protein families (Toxin_10, ETX_MTX2) sharing a common beta-pore forming structure and function with known mammalian toxins such as epsilon toxin (ETX). Although beta-pore forming proteins are related to mammalian toxins, there are key differences in sequence and structure that lead to organism specificity that is useful in the weight-of-evidence approach for safety assessment. Despite low overall amino acid sequence identity among ETX_MTX2 proteins, sequence and structural similarities are found in the tail region responsible for the shared oligomerization and pore formation functions (causing the "relatedness"). Conversely, most of the sequence and structural diversity is located in the head region that is likely responsible for differential receptor binding and target species specificity (e.g., insecticidal vs. mammalian). Therefore, inclusion of a domain-based protein characterization approach that includes bioinformatic and functional comparisons of conserved and diverse domains will enhance the overall weight of evidence safety assessment of proteins including recently reported Cry51 protein variants (Cry51Aa1, Cry51Aa2, and Cry51Aa2.834_16). PMID- 27235984 TI - A single dose of vortioxetine, but not ketamine or fluoxetine, increases plasticity-related gene expression in the rat frontal cortex. AB - Ketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist that has been shown to induce a rapid antidepressant effect in treatment resistant patients. Vortioxetine is a multimodal-acting antidepressant that exert its therapeutic activity through serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibition and modulation of several 5-HT receptors. In clinical trials, vortioxetine improves depression symptoms and cognitive dysfunction. Neuroplasticity as well as serotonergic and glutamatergic signaling attain significant roles in depression pathophysiology and antidepressant responses. Here, we investigate the effects of ketamine and vortioxetine on gene expression related to serotonergic and glutamatergic neurotransmission as well as neuroplasticity and compare them to those of the selective serotonin reuptake inhibitor fluoxetine. Rats were injected with fluoxetine (10mg/kg), ketamine (15mg/kg), or vortioxetine (10mg/kg) at 2, 8, 12, or 27h prior to harvesting of the frontal cortex and hippocampus. mRNA levels were measured by real-time quantitative polymerase chain reaction (qPCR). The main finding was that vortioxetine enhanced plasticity-related gene expression (Mtor, Mglur1, Pkcalpha, Homer3, Spinophilin, and Synapsin3) in the frontal cortex at 8h after a single dose. Ingenuity pathway analysis of this subset of data identified a biological network that was engaged by vortioxetine and is plausibly associated with neuroplasticity. Transcript levels had returned to baseline levels 12h after injection. Only minor effects on gene expression were found for ketamine or fluoxetine. In conclusion, acute vortioxetine, but not fluoxetine or ketamine, transiently increased plasticity-related gene expression in the frontal cortex. These effects may be ascribed to the direct 5-HT receptor activities of vortioxetine. PMID- 27235985 TI - Predicting real-world functional milestones in schizophrenia. AB - Schizophrenia is a severe disorder that often causes impairments in major areas of functioning, and most patients do not achieve expected real-world functional milestones. The aim of this study was to identify which variables of demography, illness activity, and functional capacity predict patients' ability to attain real-world functional milestones. Participants were 235 outpatients, 149 men and 86 women, diagnosed with schizophrenia spectrum disorder. Our results showed that younger patients managed to achieve a higher level of functioning in educational level, marital status, and social contacts. Patients' functional capacity was primarily associated with educational level and housing situation. We also found that women needed less support regarding housing and obtained a higher level of marital status as compared with men. Our findings demonstrate the importance of considering current symptoms, especially negative symptoms, and remission stability over time, together with age, duration of illness, gender, educational level, and current functional capacity, when predicting patients' future real world functioning. We also conclude that there is an advantage in exploring symptoms divided into positive, negative, and general domains considering their probable impact on functional achievements. PMID- 27235986 TI - Sitting time, physical fitness impairments and metabolic abnormalities in people with bipolar disorder: An exploratory study. AB - A sedentary lifestyle is an independent risk factor for cardiovascular disease and mortality. Little is known however about sedentary behavior in people with bipolar disorder (BD). The primary aim of this study was to explore associations between sitting time (as a proxy for a sedentary lifestyle) and physical fitness and metabolic parameters in BD. A secondary aim was to investigate associations between psychiatric symptoms, psychotropic medication use and sitting time. Thirty-nine (21?) participants (43.7+/-12.4 years) completed a full metabolic screening, the sitting time item of the International Physical Activity Questionnaire, the Quick Inventory of Depressive Symptomatology self-report and the Hypomania Checklist-32. Additionally participants performed the Eurofit-test battery and 6-min walk test. The mean time spent sitting per day for the entire sample was 7.0+/-3.0h. A higher body mass index, worse physical fitness and higher antipsychotic medication dose were identified as independent predictors of higher levels of sitting behavior. The model explained 76.5% of the variability in the sitting time. Given that a sedentary lifestyle is an independent predictor of cardiovascular disease, future interventions specifically targeting time spend sitting are warranted in BD, with a particular emphasis on those with high body mass index and low fitness levels. PMID- 27235987 TI - Neuronal vs glial glutamate uptake: Resolving the conundrum. AB - Neither normal brain function nor the pathological processes involved in neurological diseases can be adequately understood without knowledge of the release, uptake and metabolism of glutamate. The reason for this is that glutamate (a) is the most abundant amino acid in the brain, (b) is at the cross roads between several metabolic pathways, and (c) serves as the major excitatory neurotransmitter. In fact most brain cells express glutamate receptors and are thereby influenced by extracellular glutamate. In agreement, brain cells have powerful uptake systems that constantly remove glutamate from the extracellular fluid and thereby limit receptor activation. It has been clear since the 1970s that both astrocytes and neurons express glutamate transporters. However the relative contribution of neuronal and glial transporters to the total glutamate uptake activity, however, as well as their functional importance, has been hotly debated ever since. The present short review provides (a) an overview of what we know about neuronal glutamate uptake as well as an historical description of how we got there, and (b) a hypothesis reconciling apparently contradicting observations thereby possibly resolving the paradox. PMID- 27235988 TI - Three-month effects of Project EX: A smoking intervention pilot program with Thai adolescents. AB - Adolescent smoking is a major public health problem around the world, including Thailand. The current study provides a three-month follow-up evaluation of the Project EX tobacco use cessation program among Thai adolescents. The intervention was tested involving a quasi-experimental trial with 185 smokers, with two program and two control condition schools (within each condition, one school in Bangkok Province and one school in Nakhon Pathom Province). At 3-month follow-up, the intent-to-treat (ITT) quit rate was 23% in the program group and 11% in the standard care control group (p<0.02). The intervention also lowered the level of last 30-day smoking at follow-up among persons who did not quit in the program condition, while no change in level of smoking was reported in the control condition. These results are promising for teen tobacco use cessation programming in Thailand. PMID- 27235989 TI - Association between adherence to free nicotine replacement therapy and successful quitting. AB - INTRODUCTION: Providing free nicotine replacement therapy (NRT) can be a cost effective strategy for increasing quit attempts and cessation rates at a population level. However, the optimal amount of NRT to provide is unknown. Associations between duration of NRT use and abstinence may be overestimated as a result of reverse causality due to discontinuation following relapse. We examined the association between adherence to 10weeks of cost-free NRT and quit success at 6-month follow-up, after controlling for reverse causation by excluding participants who reported nonadherence due to relapse. METHODS: Individuals 18years or older who smoked at least 10 cigarettes daily and intended to quit within 30days received 10weeks of NRT at a smoking cessation workshop. There were 3922 participants who attended one of 114 workshops in 70 different localities in Ontario, Canada from 2007 to 2008. RESULTS: At end of treatment participants were asked whether they had used "all" of the NRT (20%), "most" of it (28%), "some" of it (47%), or whether they "did not use any" of it (5%). After controlling for reverse causation and adjusting for potential confounding variables, poorer quit success was reported by those who used either some (AOR=0.43, 95% CI=0.26-0.69, p=0.001) or none (AOR=0.30, 95% CI=0.09-0.95, p=0.041) of the NRT versus all 10weeks. Post-estimation contrasts revealed using some versus most of the NRT was also associated with poorer quit success (p=0.026). CONCLUSIONS: After controlling for reverse causation, adherence to 10weeks of cost-free NRT was associated with successful abstinence at six months post-treatment. PMID- 27235991 TI - Academic physicians' and medical students' perceived barriers toward bystander administered naloxone as an overdose prevention strategy. AB - AIMS: To identify perceived barriers to the prescription of naloxone to third party contacts of opiate users. DESIGN: Qualitative descriptive study. SETTING: Two academic hospitals in Baltimore, MD, USA. PARTICIPANTS: Thirty medical providers, including both physicians and medical students. MEASUREMENTS: Qualitative; in-depth interviews and focus groups analyzed using line-by-line, focused, and axial coding based on methods adapted from grounded theory. FINDINGS: Academic physicians and medical students cited three categories of barriers to naloxone prescription related to drug, provider, and patient characteristics. Concerns about naloxone itself included inability to prevent addictive behaviors, duration of action, medical risks, expiration date, and route of administration. Concerns about medical providers included lack of knowledge or experience, medical community common practices and norms, insufficient provision of third-party education, physician and clinic scheduling practices, worry about insulting patients, and fear of being viewed as enabling drug abuse. Concerns about patients included increased risk-taking behaviors, opiate withdrawal symptoms, potential repeat overdose related to withdrawal discomfort, decreased contact with medical providers, and stigma. CONCLUSIONS: Minimizing barriers to naloxone provision may increase acceptability and prescription practice in the medical community. Addressing these barriers from multiple provider perspectives is critical to advance naloxone prescription as a harm reduction strategy, which has the potential to prevent opiate overdoses. PMID- 27235990 TI - Panic attacks and smoking cessation among cancer patients receiving smoking cessation treatment. AB - OBJECTIVE: Little is known about factors associated with smoking cessation in cancer patients. This study examined the impact of panic attacks on smoking abstinence likelihood among cancer patients receiving tobacco cessation treatment. METHOD: The relationship of panic attacks to 7-day point-prevalence abstinence at mid-treatment, end of treatment, and 6-month post-end of treatment were examined among cancer patients (N=2255 patients; 50.1% female; Mage=54.9, SD=11.0) who received counseling and pharmacotherapy for smoking cessation. Panic attack history indexed by two questions from the Patient Health Questionnaire (PHQ). Point-prevalence abstinence was assessed via the Timeline Follow-Back. RESULTS: Cancer patients with a history of panic attacks, (n=493, 21.9%) relative to those without, were less likely to be abstinent at mid-treatment (OR=0.79, CI95%=0.64-0.98) and end of treatment (OR=0.72, CI95%=0.58-0.89). After adjusting for significant covariates, panic attack history remained predictive of decreased abstinence likelihood at end of treatment (OR =0.78, CI95%=0.62-0.99). CONCLUSIONS: Panic attacks may be related to poorer cessation outcome during smoking treatment among cancer patients, and may be usefully assessed and targeted for intervention. PMID- 27235992 TI - The use of pre-existing CT imaging in screening for abdominal aortic aneurysms. AB - Ultrasound screening for abdominal aortic aneurysm (AAA) is recommended for male smokers >65 years of age, but screening rates remain low. If computed tomography (CT) performed for other indications could be considered adequate for screening, one-third of ultrasounds would potentially be unnecessary, and overall screening rates would be substantially higher. The objective of this study was to evaluate the sensitivity of CT imaging of the abdomen for the detection of AAA when performed for other clinical indications. We performed a retrospective study of patients eligible for AAA screening who had undergone an abdominal ultrasound as well as an abdominal CT scan for other indications within 3 years prior to that study. The primary outcome was identification of an AAA, recorded in the findings narrative or impression of the CT scan report. Of 142 patients with both a CT scan and an AAA on ultrasound, 127 (89.4%) were noted to have an AAA in the report of a CT scan performed within the 3 years prior to the ultrasound. An additional 10 films demonstrated an AAA that was not mentioned in the report. The sensitivity of pre-existing CT scans for AAA screening was 97.2% (137/141) [95% CI: 93.4-99.0%]; 123 (86.6%) of these positive findings were reported in the findings narrative and 120 (84.5%) were reported in the radiologist's final impression. The sensitivity for AAA identification in the report of a pre existing CT scan of the abdomen performed for alternate indications appears high enough to use as a screening test. When radiologists note an AAA, they should be sure to include it in the final impression. PMID- 27235993 TI - Microbiology of cooked and dried edible Mediterranean field crickets (Gryllus bimaculatus) and superworms (Zophobas atratus) submitted to four different heating treatments. AB - To increase the shelf life of edible insects, modern techniques (e.g. freeze drying) add to the traditional methods (degutting, boiling, sun-drying or roasting). However, microorganisms become inactivated rather than being killed, and when rehydrated, many return to vegetative stadia. Crickets (Gryllus bimaculatus) and superworms (Zophobas atratus) were submitted to four different drying techniques (T1 = 10' cooking, 24 h drying at 60C; T2 = 10' cooking, 24 h drying at 80C; T3 = 30' cooking, 12 h drying at 80C, and 12 h drying at 100C; T4 = boiling T3-treated insects after five days) and analysed for total bacteria counts, Enterobacteriaceae, staphylococci, bacilli, yeasts and moulds counts, E. coli, salmonellae, and Listeria monocytogenes (the latter three being negative throughout). The microbial counts varied strongly displaying species- and treatment-specific patterns. T3 was the most effective of the drying treatments tested to decrease all counts but bacilli, for which T2 was more efficient. Still, total bacteria counts remained high (G. bimaculatus > Z. atratus). Other opportunistically pathogenic microorganisms (Bacillus thuringiensis, B. licheniformis, B. pumilis, Pseudomonas aeruginosa, and Cryptococcus neoformans) were also encountered. The tyndallisation-like T4 reduced all counts to below detection limit, but nutrients leakage should be considered regarding food quality. In conclusion, species-specific drying procedures should be devised to ensure food safety. PMID- 27235994 TI - Substrate stiffness and matrix composition coordinately control the differentiation of liver progenitor cells. AB - Recent approaches have utilized microfabricated platforms to examine combinations of microenvironmental signals that regulate stem and progenitor cell differentiation. However, the majority of these efforts have focused on the biochemical properties of extracellular matrix (ECM) or soluble factors without simultaneously exploring the biomechanical effects of cell-substrate interactions. To address this need, we combined a high-throughput approach for the analysis of combinatorial ECM cues with substrates of modular stiffness and traction force microscopy. This integrated approach enabled the characterization of cell-generated traction stress and phenotypic expression in response to ECM cues. We investigated the impact of substrate stiffness and ECM composition on the differentiation of bipotential mouse embryonic liver (BMEL) progenitor cells. We observed that hepatocyte differentiation was primarily regulated by ECM composition, and cholangiocyte differentiation was cooperatively influenced by ECM proteins and stiffness properties. In particular, stiffness-mediated cholangiocyte differentiation was observed for cells cultured on fibronectin, while collagen IV promoted differentiation independent of substrate stiffness. We demonstrated the influence of cell contractility and traction stress in early cholangiocyte specification and further uncovered the roles of ERK and ROCK in this differentiation process. Overall, these findings illustrate the involvement of biomechanical signals in liver progenitor differentiation. Further, this approach could enable investigations for a broad range of cell types and ECM proteins, providing an integrated platform for evaluating the combinatorial effects of biochemical and biophysical signals in cell differentiation. PMID- 27235995 TI - Synthetic niche to modulate regenerative potential of MSCs and enhance skeletal muscle regeneration. AB - Severe injury to the skeletal muscle often results in the formation of scar tissue, leading to a decline in functional performance. Traditionally, tissue engineering strategies for muscle repair have focused on substrates that promote myogenic differentiation of transplanted cells. In the current study, the reported data indicates that mesenchymal stromal cells (MSCs) transplanted via porous alginate cryogels promote muscle regeneration by secreting bioactive factors that profoundly influence the function of muscle progenitor cells. These cellular functions, which include heightened resistance of muscle progenitor cells to apoptosis, migration to site of injury, and prevention of premature differentiation are highly desirable in the healing cascade after acute muscle trauma. Furthermore, stimulation of MSCs with recombinant growth factors IGF-1 and VEGF165 was found to significantly enhance their paracrine effects on muscle progenitor cells. Multifunctional alginate cryogels were then utilized as synthetic niches that facilitate local stimulation of seeded MSCs by providing a sustained release of growth factors. In a clinically relevant injury model, the modulation of MSC paracrine signaling via engineered niches significantly improved muscle function by remodeling scar tissue and promoting the formation of new myofibers, outperforming standalone cell or growth factor delivery. PMID- 27235996 TI - Redox nanoparticle increases the chemotherapeutic efficiency of pioglitazone and suppresses its toxic side effects. AB - Pioglitazone is a widely used anti-diabetic drug that induces cytotoxicity in cancer cells; however, its clinical use is questioned due to its associated liver toxicity caused by increased oxidative stress. We therefore employed nitroxide radical containing nanoparticle, termed redox nanoparticle (RNP(N)) which is an effective scavenger of reactive oxygen species (ROS) as a drug carrier. RNP(N) encapsulation increased pioglitazone solubility, thus increasing cellular uptake of encapsulated pioglitazone which reduced the dose required to induce toxicity in prostate cancer cell lines. Investigation of in vitro molecular mechanism of pioglitazone revealed that both apoptosis and cell cycle arrest were involved in tumor cell death. In addition, intravenously administered pioglitazone-loaded RNP(N) produced significant tumor volume reduction in vivo due to enhanced permeation and retention effect. Most importantly, oxidative damage caused by pioglitazone in the liver was significantly suppressed by pioglitazone-loaded RNP(N) due to the presence of nitroxide radicals. It is interesting to note that oral administration of encapsulated pioglitazone, and co-administration of RNP(N) and pioglitazone, i.e., no encapsulation of pioglitazone in RNP(N) also significantly contributed to suppression of the liver injury. Therefore, use of RNP(N) either as an adjuvant or as a carrier for drugs with severe side effects is a promising chemotherapeutic strategy. PMID- 27235997 TI - Pesticide Vendors in the Informal Sector: Trading Health for Income. AB - South African low-income communities face many challenges (e.g., insufficient housing, poor service delivery, and abject poverty); additionally, a silent challenge of pest infestation plagues these areas resulting in disease risks, nuisances, and stigma. Consequently, an enterprising urban informal sector business has emerged providing residents with highly toxic, effective, cheap, and illegal "street pesticides." These pesticides pose acute and chronic health risks for vendors and residents. The economic opportunity provided by the high demand for effective and cheap pest control results in the high risk of health effects being traded for income. Current measures to control and "regulate" the massive street pesticide sales result in toxic stockpiles and government's "turning a blind eye." Solutions will only be achieved through open dialog identifying and developing non-toxic pest control strategies while ensuring vendors' income; and relevant stakeholder recognition that pest infestation is a social and environmental health determinant needing acknowledgement in different government policies. PMID- 27235998 TI - Gathering Occupational Health Data from Informal Workers: The Brazilian Experience. AB - This study describes how occupational health data have been gathered by the Brazilian Unified Health System (SUS) to provide morbidity and mortality estimates for formal and informal workers. In 2007, data on work-related diseases and injuries was incorporated into the compulsory notification system (SINAN) and analyzed by the SUS occupational health service network, which covers all Brazilian states. However, this work has not been fully implemented, resulting in the large-scale undercounting and underreporting of cases, particularly in relation to informal workers. This is suggestive of barriers that prevent access to services and good quality health care. The inclusion of work-related diseases and injuries in SINANs appears to be a feasible strategy for the collection of useful data for the surveillance of the entire universe of workers, particularly in countries where informal workers prevail within the labor force. Attention needs to be paid to the disparities in access and quality that affect low-paid, informal workers. PMID- 27235999 TI - Simultaneous determination of three azo dyes in food product by ion mobility spectrometry. AB - Color is an important property for food evaluation. Synthetic azo dyes are usually used in food product to obtain better appearance because of their stability and low cost. However, such dyes should be strictly controlled because of their potential threat to human health. A simple, rapid and sensitive method has been developed to determine orange II, allura red, and para red simultaneously by ion mobility spectrometry. The three dyes could be separated at the same time and the migration time of orange II, allura red, and para red are 12.070+/-0.010, 8.180+/-0.015, and 11.037+/-0.016ms, respectively. The effects of different parameters, such as pH, solvent, percentage of water, were investigated to establish the optimal condition. The detection limits were 0.1, 0.05, and 0.2MUg/mL for orange II, allura red, and para red, respectively. The recoveries of the three azo dyes from jellies were all higher than 81%. The developed method is fast and accurate for the detection of the three synthetic dyes. PMID- 27236000 TI - Simultaneous measurement of etravirine, maraviroc and raltegravir in pigtail macaque plasma, vaginal secretions and vaginal tissue using a LC-MS/MS assay. AB - Etravirine (ETR), maraviroc (MVC) and raltegravir (RAL) are promising antiretroviral drugs being used in HIV treatment and may be interesting for prevention applications such as oral or topical pre-exposure prophylaxis. Here we describe a sensitive and accurate method for the simultaneous detection of ETR, MVC and RAL from pigtail macaque plasma, vaginal secretions, and vaginal tissue. This method is characterized by a straightforward precipitation extraction method, a limit of quantification <0.5ngmL(-1) for all three antiretrovirals bolstered by a corresponding internal standard for each drug analyte, and short run time. Quantification is performed using positive ion electrospray triple quadrupole mass spectrometry. This method was validated over clinically relevant ranges for the three ARV drugs in all three matrices: 0.1-100ngmL(-1) for ETR, 0.05-100ngmL(-1) for MVC and 1-100ngmL(-1) for RAL. Our method is accurate and precise, with measured mean inter-assay precision (%CV) and accuracy (% bias) of 5.08% and 1.96%, respectively, while the mean intra-assay precision and accuracy were 3.44% and 1.08%. The overall post-extraction recovery for ETR, MVC and RAL was >94% in all cases. We also show that extracted biological samples are stable after storage at room temperature or 4 degrees C and after three freeze/thaw cycles. This is the first analytical method capable of quantifying ETR, MVC and RAL in biological matrices relevant for pre-clinical testing of oral or topical HIV prevention methods in pigtailed macaques. PMID- 27236001 TI - Impact of adjuvants on CD4(+) T cell and B cell responses to a protein antigen vaccine: Results from a phase II, randomized, multicenter trial. AB - Immunogenicity and safety of different adjuvants combined with a model antigen (HBsAg) were compared. Healthy HBV-naive adults were randomized to receive HBs adjuvanted with alum or Adjuvant Systems AS01B, AS01E, AS03A or AS04 at Days 0 and 30. Different frequencies of HBs-specific CD4+ T cells 14days post dose 2 but similar polyfunctionality profiles were induced by the different adjuvants with frequencies significantly higher in the AS01B and AS01E groups than in the other groups. Antibody concentrations 30days post-dose 2 were significantly higher in AS01B, AS01E and AS03A than in other groups. Limited correlations were observed between HBs-specific CD4+ T cell and antibody responses. Injection site pain was the most common solicited local symptom and was more frequent in AS groups than in alum group. Different adjuvants formulated with the same antigen induced different adaptive immune responses and reactogenicity patterns in healthy naive adults. The results summary for this study (GSK study number 112115 - NCT# NCT00805389) is available on the GSK Clinical Study Register and can be accessed at www.gsk-clinicalstudyregister.com. PMID- 27236002 TI - Multicenter study for the evaluation of the antibody response against salmonella typhi Vi vaccination (EMPATHY) for the diagnosis of Anti-polysaccharide antibody production deficiency in patients with primary immunodeficiency. PMID- 27236003 TI - Honokiol induces autophagic cell death in malignant glioma through reactive oxygen species-mediated regulation of the p53/PI3K/Akt/mTOR signaling pathway. AB - Honokiol, an active constituent extracted from the bark of Magnolia officinalis, possesses anticancer effects. Apoptosis is classified as type I programmed cell death, while autophagy is type II programmed cell death. We previously proved that honokiol induces cell cycle arrest and apoptosis of U87 MG glioma cells. Subsequently in this study, we evaluated the effect of honokiol on autophagy of glioma cells and examined the molecular mechanisms. Administration of honokiol to mice with an intracranial glioma increased expressions of cleaved caspase 3 and light chain 3 (LC3)-II. Exposure of U87 MG cells to honokiol also induced autophagy in concentration- and time-dependent manners. Results from the addition of 3-methyladenine, an autophagy inhibitor, and rapamycin, an autophagy inducer confirmed that honokiol-induced autophagy contributed to cell death. Honokiol decreased protein levels of PI3K, phosphorylated (p)-Akt, and p-mammalian target of rapamycin (mTOR) in vitro and in vivo. Pretreatment with a p53 inhibitor or transfection with p53 small interfering (si)RNA suppressed honokiol-induced autophagy by reversing downregulation of p-Akt and p-mTOR expressions. In addition, honokiol caused generation of reactive oxygen species (ROS), which was suppressed by the antioxidant, vitamin C. Vitamin C also inhibited honokiol induced autophagic and apoptotic cell death. Concurrently, honokiol-induced alterations in levels of p-p53, p53, p-Akt, and p-mTOR were attenuated following vitamin C administration. Taken together, our data indicated that honokiol induced ROS-mediated autophagic cell death through regulating the p53/PI3K/Akt/mTOR signaling pathway. PMID- 27236005 TI - Use of Saphenous Vein Bypass Grafts for Retrograde Recanalization of Coronary Chronic Total Occlusions: Insights From a Multicenter Registry. AB - BACKGROUND: The use of saphenous vein grafts (SVGs) for retrograde native-vessel chronic total occlusion (CTO) percutaneous coronary intervention (PCI) has received limited study. METHODS: We retrospectively reviewed the medical records and coronary angiograms of retrograde CTO-PCI performed through an SVG at four United States institutions between 2012 and 2013. RESULTS: During the study period, retrograde CTO-PCI was performed in 144 of 572 cases (25.2%) and retrograde CTO-PCI via SVG in 21 patients (14.6% of all retrograde cases). Mean age was 71 +/- 7 years and 95.2% of the patients were men. The CTO target vessel was the right coronary (38%), circumflex (38%), and left anterior descending (24%) artery. Mean J-CTO score was 3.5 +/- 1.0. The most common reentry technique was reverse controlled antegrade dissection and reentry. Technical and procedural success rates were 86% and 81%, respectively, with retrograde SVG-PCI attempts being successful in 67%. A major adverse cardiac event occurred in 2 patients (1 periprocedural myocardial infarction and 1 tamponade resulting in death). Median contrast volume, fluoroscopy time, and procedure time were 250 mL, 91.6 minutes, and 214 minutes, respectively. Two SVGs were coiled due to competitive flow after CTO recanalization. CONCLUSION: Retrograde native-vessel CTO-PCI via SVG represents a small proportion of retrograde CTO-PCIs and was associated with high technical success rates, but may carry increased risk for complications. PMID- 27236004 TI - Integrated pathway analysis of nasopharyngeal carcinoma implicates the axonemal dynein complex in the Malaysian cohort. AB - Nasopharyngeal carcinoma (NPC) is an epithelial squamous cell carcinoma on the mucosal lining of the nasopharynx. The etiology of NPC remains elusive despite many reported studies. Most studies employ a single platform approach, neglecting the cumulative influence of both the genome and transcriptome toward NPC development. We aim to employ an integrated pathway approach to identify dysregulated pathways linked to NPC. Our approach combines imputation NPC GWAS data from a Malaysian cohort as well as published expression data GSE12452 from both NPC and non-NPC nasopharynx tissues. Pathway association for GWAS data was performed using MAGENTA while for expression data, GSA-SNP was used with gene p values derived from differential expression values from GEO2R. Our study identified NPC association in the gene ontology (GO) axonemal dynein complex pathway (pGWAS-GSEA = 1.98 * 10(-2) ; pExpr-GSEA = 1.27 * 10(-24) ; pBonf Combined = 4.15 * 10(-21) ). This association was replicated in a separate cohort using gene expression data from NPC and non-NPC nasopharynx tissues (pAmpliSeq-GSEA = 6.56 * 10(-4) ). Loss of function in the axonemal dynein complex causes impaired cilia function, leading to poor mucociliary clearance and subsequently upper or lower respiratory tract infection, the former of which includes the nasopharynx. Our approach illustrates the potential use of integrated pathway analysis in detecting gene sets involved in the development of NPC in the Malaysian cohort. PMID- 27236006 TI - Retrograde CTO-PCI Through Vein Grafts: Come on Down! PMID- 27236007 TI - PCI in Patients Supported With CF-LVADs: Indications, Safety, and Outcomes. AB - PURPOSE: Patients with heart failure supported with left ventricular assist devices (LVADs) may require coronary intervention during their support. This case series seeks to explore the indications, safety, and outcomes of percutaneous coronary intervention (PCI) in this population. METHODS: Electronic medical records of patients with LVADs undergoing PCI at a large academic medical center were reviewed. Demographics, reason for PCI, procedural success, complications, and outcomes were collected. RESULTS: From 2010-2014, a total of 6 patients underwent PCI post LVAD implantation. Three patients had PCI in the early postimplantation period (1-3 days post LVAD implantation) while the other three received it later in the LVAD support period. Three indications for PCI were found in the reviewed cases: right ventricular failure (right coronary artery stenting), bridge to left ventricular recovery, and ventricular tachycardia (VT) storm. All patients were maintained on triple blood thinning therapy (aspirin, clopidogrel, and warfarin). There were no acute complications during the interventions; however, 2 patients died in the early intervention period and 2 died much later. The 2 deaths in the early intervention period were related to fatal gastrointestinal bleeding while on dual-antiplatelet therapy and warfarin, and intractable VT that PCI did not correct. The 2 deaths in the late postintervention period occurred due to unknown causes nearly 1 and 2 years post intervention, respectively. CONCLUSIONS: PCI was performed in patients with continuous-flow LVAD with several possible indications and without acute complications. The utility of PCI in this patient population, however, is likely limited by the risk of bleeding related to combined antiplatelet and anticoagulation therapies as well as lack of immediate apparent benefit. Further studies are necessary to better characterize this risk as well as quantify any potential long-term benefits. PMID- 27236008 TI - Mechanical Circulatory Support in Percutaneous Coronary Interventions: Expanding the Possibilities. PMID- 27236009 TI - Numbers, Numbers, Numbers...So Many Details Hide in Plain Sight! Insights From HEAT-PPCI and HEAT-SEALED. PMID- 27236010 TI - Ultrasound-Guided Arterial Access: Outcomes Among Patients With Peripheral Artery Disease and Critical Limb Ischemia Undergoing Peripheral Interventions. AB - OBJECTIVE: Arterial cannulation is a vital component of endovascular interventions and often unconventional access approaches are required due to disease complexity. Historically, varying maneuvers have been utilized to obtain arterial access. Lack of consensus exists regarding the safest and most effective method. This study examined the feasibility and immediate outcomes of ultrasound guided access in traditional and advanced access approaches. METHODS: Data were analyzed from a cohort of 407 patients enrolled in the Peripheral RegIstry of Endovascular Clinical OutcoMEs (PRIME). The 407 patients underwent 649 procedures with 896 access sites utilized. Access success, immediate outcomes, complications, and length of hospital stay were analyzed. RESULTS: Mean age was 70 years, and 67% were male. The majority of patients had critical limb ischemia (58%), 39% were Rutherford classification III. Most commonly utilized access sites were common femoral retrograde, common femoral antegrade, posterior tibial, and anterior tibial arteries (34.6%, 33.0%, 12.1%, and 12.1%, respectively). Mean number of attempts was 1.2, 1.2, 1.5, and 1.4, respectively; median time to access was 39, 45, 41, and 59 seconds, respectively; and access success rate was 99.4%, 97.3%, 90.7%, and 92.6%; respectively. Access-site combinations utilized were femoral antegrade (n = 188), femoral retrograde (n = 185), dual femoral/ tibio-pedal (n = 130), dual femoral retrograde (n = 44), retrograde tibio-pedal (n = 73), and other (n = 29). Access-related complications were low overall: hematoma (1.2%), bleeding requiring transfusion/intervention (1.7%), pseudoaneurysm (1.7%), arteriovenous fistula (0.3%), aneurysm (0%), compartment syndrome (0%), and death (0%). CONCLUSION: Utilization of ultrasound-guided arterial access in this complex cohort was shown to be safe and effective regardless of arterial bed and approach. PMID- 27236011 TI - Catheter Entrapment During Posterior Mitral Leaflet Pushing Maneuver for MitraClip Implantation. AB - MitraClip (Abbott Vascular) therapy has been reported to be an effective procedure for mitral regurgitation, especially in high-risk patients. Recently, the novel pushing maneuver technique has been described for approaching restricted and short posterior leaflets with a pigtail catheter in order to facilitate grasping of the clip. However, complications or unexpected situations may occur. We report the case of an 84-year-old patient who underwent MitraClip implantation wherein the pushing maneuver was complicated by the clip accidentally gripping the pigtail catheter along with the two leaflets. PMID- 27236012 TI - Coronary Embolism After Iatrogenic Radial Endarterectomy. AB - A 55-year-old man with double-vessel coronary artery disease was revascularized by percutaneous coronary intervention three years ago. Elective coronary angiography was indicated for angina with positive stress test. During the procedure, severe radial spasm occurred; after the first injection, we detected loss in pressure trace in the diagnostic catheter and acute distal circumflex occlusion. Suspecting catheter thrombosis with coronary embolization, the entire system was exchanged and inspected; inside, we discovered a 2 x 50 mm white biological cylinder. Histological study of this material was compatible with endarterectomy. We present a rare complication of severe radial artery spasm and endarterectomy, with occlusion of the diagnostic catheter and coronary embolization. PMID- 27236013 TI - Prehospital Clopidogrel Administration in Patients With ST-Segment Elevation Myocardial Infarction Treated With Primary PCI: Real-Life Experience From the Multicenter NRDES Registry. PMID- 27236014 TI - Synthesis, characterization and in vitro evaluation of amphiphilic ion pairs of erythromycin and kanamycin antibiotics with liposaccharides. AB - The hydrophilic ion paring strategy (HIP) is a method explored to improve the cell/tissue uptake of poorly adsorbed drugs and to optimize their physico chemical characteristics. In this context, we here describe the synthesis of some ion pairs of two model cationic antibiotics, erythromycin (ERY) and kanamycin A (KAN), with liposaccharides having different levels of lipophilicity and charge. The formation of drug-liposaccharide complexes was confirmed by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) analysis. The effect of the amphiphilic liposaccharide moieties on the antimicrobial activity of ERY and KAN was assessed by measuring the minimal inhibitory concentration (MIC) of the compounds against a panel of bacterial strains that were susceptible or resistant to the parent antibiotics. The ion pairing did not depress the in vitro antibiotic activity, although no lowering of MIC values was registered. The experimental findings would motivate the future investigation of this ion pairing strategy in drug design, for instance allowing improvement of the encapsulation efficiency of hydrophilic antibiotics in lipid-based nanocarriers, or changing their in vivo biodistribution and pharmacokinetic profile. PMID- 27236015 TI - Synthesis and biological evaluation of novel 4-hydroxytamoxifen analogs as estrogen-related receptor gamma inverse agonists. AB - Estrogen-related receptor gamma (ERRgamma) has recently been recognized as an attractive target for treating inflammation, cancer, and metabolic disorders. Herein, we discovered and demonstrated the in vitro pharmacology as well as the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of chemical entities that could act as highly selective inverse agonists for ERRgamma. The results were comparable to those for GSK5182 (4), a leading ERRgamma inverse agonist ligand. Briefly, the half-maximal inhibitory concentration (IC50) range of the synthesized compounds for ERRgamma was 0.1-10 MUM. Impressively, compound 24e exhibited potency comparable to 4 but was more selective for ERRgamma over three other subtypes: ERRalpha, ERRbeta, and estrogen receptor alpha. Furthermore, compound 24e exhibited a superior in vitro ADMET profile compared to the other compounds. Thus, the newly synthesized class of ERRgamma inverse agonists could be lead candidates for developing clinical therapies for ERRgamma-related disorders. PMID- 27236017 TI - Risk factors, complications and outcome of cholelithiasis in children: A retrospective, single-centre review. AB - AIM: The aim of this study was to evaluate the clinical presentation, risk factors, complications, treatment and outcomes of cholelithiasis in children. METHODS: Children with cholelithiasis were reviewed for demographic information, predisposing factors, presenting symptoms, laboratory findings, complications, treatment and outcome, retrospectively. RESULTS: A total of 254 children with cholelithiasis (mean age: 8.9 +/- 5.2 years) were recruited to the study. Girls (52.8%) were significantly older than boys (P < 0.001). Symptomatic patients (59%) were significantly older than asymptomatic patients (P = 0.002). Abdominal pain was the most frequent symptom. No risk factors were identified in 56.6% of the patients. Ceftriaxone (20%) was the most commonly associated risk factor. At presentation, at least one of the following complications was seen in 14.1% of patients: cholecystitis (10.9%), obstructive jaundice (2.7%), pancreatitis (1.96%) and cholangitis (1.2%). There was no relationship between gallstone size and symptoms, aetiological factors and complications. The cholelithiasis dissolution rate was higher in younger children (P = 0.032), in those with biliary sludge (P < 0.0001) and ceftriaxone-related cholelithiasis (P < 0.001). Haemolytic anaemia (P = 0.001) and older age (P = 0.002) were associated with stable stones. Ursodeoxycholic acid was administered to 94.4% of patients at presentation. Twenty-nine patients underwent cholecystectomy, and seven patients underwent endoscopic retrograde cholangiopancreotography. Patients who were symptomatic at presentation had significantly more frequent symptoms at follow-up (P < 0.001) CONCLUSIONS: Dissolution rate of cholelithiasis was higher in younger children, biliary sludge formation and ceftriaxone-related cholelithiasis but lower in older children and haemolytic anaemia-related cholelithiasis. PMID- 27236016 TI - Nitroimidazole carboxamides as antiparasitic agents targeting Giardia lamblia, Entamoeba histolytica and Trichomonas vaginalis. AB - Diarrhoeal diseases caused by the intestinal parasites Giardia lamblia and Entamoeba histolytica constitute a major global health burden. Nitroimidazoles are first-line drugs for the treatment of giardiasis and amebiasis, with metronidazole 1 being the most commonly used drug worldwide. However, treatment failures in giardiasis occur in up to 20% of cases and development of resistance to metronidazole is of concern. We have re-examined 'old' nitroimidazoles as a foundation for the systematic development of next-generation derivatives. Using this approach, derivatisation of the nitroimidazole carboxamide scaffold provided improved antiparasitic agents. Thirty-three novel nitroimidazole carboxamides were synthesised and evaluated for activity against G. lamblia and E. histolytica. Several of the new compounds exhibited potent activity against G. lamblia strains, including metronidazole-resistant strains of G. lamblia (EC50 = 0.1-2.5 MUM cf. metronidazole EC50 = 6.1-18 MUM). Other compounds showed improved activity against E. histolytica (EC50 = 1.7-5.1 MUM cf. metronidazole EC50 = 5.0 MUM), potent activity against Trichomonas vaginalis (EC50 = 0.6-1.4 MUM cf. metronidazole EC50 = 0.8 MUM) and moderate activity against the intestinal bacterial pathogen Clostridium difficile (0.5-2 MUg/mL, cf. metronidazole = 0.5 MUg/mL). The new compounds had low toxicity against mammalian kidney and liver cells (CC50 > 100 MUM), and selected antiparasitic hits were assessed for human plasma protein binding and metabolic stability in liver microsomes to demonstrate their therapeutic potential. PMID- 27236018 TI - Recommendations From Parents to Improve Health Services for Managing Pediatric Obesity in Canada. AB - OBJECTIVE: Although parents are uniquely positioned to offer first-hand insights that can be used to improve health services for managing pediatric obesity, their perspective is underexplored. Our objective was to characterize parents' recommendations for enhancing tertiary-level health services for managing pediatric obesity in Canada. METHODS: Semistructured, one-on-one interviews were conducted with parents of children who initiated treatment at 1 of 4 Canadian tertiary-level, multidisciplinary weight management clinics. Parent perspectives were elicited regarding the strengths and weaknesses of the health services they received as well as areas for potential improvement. Interviews were audio recorded and transcribed verbatim. We used qualitative description as the methodological framework and manifest content analysis as the analytical strategy. RESULTS: Parents (n = 65; 88% female; 72% Caucasian; 74% with at least some postsecondary education; 52% >$50,000 CDN household income) provided a range of recommendations that were organized according to health care: 1) accessibility, 2) content, and 3) delivery. The most common recommendations included increasing scheduling options (44%; n = 29), tailoring services to families' needs and circumstances (29%; n = 19), placing greater emphasis on physical activity (29%; n = 19), altering program duration (29%; n = 19), incorporating interactive elements (25%; n = 16), information provision (25%; n = 16), and providing services at sites closer to participants' homes (24%; n = 15). CONCLUSIONS: Parents' recommendations to enhance health services for managing pediatric obesity concerned modifiable factors related to accessibility, content, and delivery of care. Further research is needed to evaluate whether implementing suggested recommendations improves clinically relevant outcomes including attrition, quality of care, and success in weight management. PMID- 27236019 TI - Trehalose rescues glial cell dysfunction in striatal cultures from HD R6/1 mice at early postnatal development. AB - The pathological hallmark of Huntington disease (HD) is the intracellular aggregation of mutant huntingtin (mHTT) in striatal neurons and glia associated with the selective loss of striatal medium-sized spiny neurons. Up to the present, the role of glia in HD is poorly understood and has been classically considered secondary to neuronal disorder. Trehalose is a disaccharide known to possess many pharmacological properties, acting as an antioxidant, a chemical chaperone, and an inducer of autophagy. In this study, we analyzed at an early postnatal development stage the abnormalities observed in striatal glial cell cultures of postnatal R6/1 mice (HD glia), under baseline and stressing conditions and the protective effects of trehalose. Our data demonstrate that glial HD alterations already occur at early stages of postnatal development. After 20 postnatal days in vitro, striatal HD glia cultures showed more reactive astrocytes with increased expression of glial fibrillary acidic protein (GFAP) but with less replication capacity, less A2B5(+) glial progenitors and more microglia than wild-type (WT) cultures. HD glia had lower levels of intracellular glutathione (GSH) and was more susceptible to H2O2 and epoxomicin insults. The amount of expressed GDNF and secreted mature-BDNF by HD astrocytes were much lower than by WT astrocytes. In addition, HD glial cultures showed a deregulation of the major proteolytic systems, the ubiquitin-proteasomal system (UPS), and the autophagic pathway. This produces a defective protein quality control, indicated by the elevated levels of ubiquitination and p62 protein. Interestingly, we show that trehalose, through its capacity to induce autophagy, inhibited p62/SQSTM1 accumulation and facilitated the degradation of cytoplasmic aggregates from mHTT and alpha-synuclein proteins. Trehalose also reduced microglia activation and reversed the disrupted cytoskeleton of astrocytes accompanied with an increase in the replication capacity. In addition, trehalose up-regulated mature-BDNF neurotrophic factor expression and secretion, probably mediating cytoskeletal organization and helping in vesicular BDNF transport. Together, these findings indicate that glia suffers functional early changes in the disease process, changes that may contribute to HD neurodegeneration. Trehalose could be a very promising compound for treatment of HD and other diseases with abnormal protein aggregates. Furthermore our study identifies glial cells as a novel target for trehalose to induce neurotrophic and neuroprotective actions in HD. PMID- 27236020 TI - Polysialic acid enters the cell nucleus attached to a fragment of the neural cell adhesion molecule NCAM to regulate the circadian rhythm in mouse brain. AB - In the mammalian nervous system, the neural cell adhesion molecule NCAM is the major carrier of the glycan polymer polysialic acid (PSA) which confers important functions to NCAM's protein backbone. PSA attached to NCAM contributes not only to cell migration, neuritogenesis, synaptic plasticity, and behavior, but also to regulation of the circadian rhythm by yet unknown molecular mechanisms. Here, we show that a PSA-carrying transmembrane NCAM fragment enters the nucleus after stimulation of cultured neurons with surrogate NCAM ligands, a phenomenon that depends on the circadian rhythm. Enhanced nuclear import of the PSA-carrying NCAM fragment is associated with altered expression of clock-related genes, as shown by analysis of cultured neuronal cells deprived of PSA by specific enzymatic removal. In vivo, levels of nuclear PSA in different mouse brain regions depend on the circadian rhythm and clock-related gene expression in suprachiasmatic nucleus and cerebellum is affected by the presence of PSA-carrying NCAM in the cell nucleus. Our conceptually novel observations reveal that PSA attached to a transmembrane proteolytic NCAM fragment containing part of the extracellular domain enters the cell nucleus, where PSA-carrying NCAM contributes to the regulation of clock-related gene expression and of the circadian rhythm. PMID- 27236021 TI - Quantitative PCR for detection of DNA damage in mitochondrial DNA of the fission yeast Schizosaccharomyces pombe. AB - Quantitative polymerase chain reaction (QPCR) has been employed to detect DNA damage and repair in mitochondrial DNA (mtDNA) of human and several model organisms. The assay also permits the quantitation of relative mtDNA copy number in cells. Here, we developed the QPCR assay primers and reaction conditions for the fission yeast Schizosaccharomyces pombe, an important model of eukaryote biology, not previously described. Under these conditions, long targets (approximately 10kb) in mtDNA were quantitatively amplified using 0.1ng of crude DNA templates without isolation of mitochondria and mtDNA. Quantitative detection of oxidative DNA damage in mtDNA was illustrated by using a DNA template irradiated with UVA in the presence of riboflavin. The damage to mtDNA in S. pombe cells treated with hydrogen peroxide and paraquat was also quantitatively measured. Finally, we found that mtDNA copy number in S. pombe cells increased after transition into a stationary phase and that the damage to mtDNA due to endogenous cellular processes accumulated during chronological aging. PMID- 27236022 TI - Skeletal stem cell isolation: A review on the state-of-the-art microfluidic label free sorting techniques. AB - Skeletal stem cells (SSC) are a sub-population of bone marrow stromal cells that reside in postnatal bone marrow with osteogenic, chondrogenic and adipogenic differentiation potential. SSCs reside only in the bone marrow and have organisational and regulatory functions in the bone marrow microenvironment and give rise to the haematopoiesis-supportive stroma. Their differentiation capacity is restricted to skeletal lineages and therefore the term SSC should be clearly distinguished from mesenchymal stem cells which are reported to exist in extra skeletal tissues and, critically, do not contribute to skeletal development. SSCs are responsible for the unique regeneration capacity of bone and offer unlimited potential for application in bone regenerative therapies. A current unmet challenge is the isolation of homogeneous populations of SSCs, in vitro, with homogeneous regeneration and differentiation capacities. Challenges that limit SSC isolation include a) the scarcity of SSCs in bone marrow aspirates, estimated at between 1 in 10-100,000 mononuclear cells; b) the absence of specific markers and thus the phenotypic ambiguity of the SSC and c) the complexity of bone marrow tissue. Microfluidics provides innovative approaches for cell separation based on bio-physical features of single cells. Here we review the physical principles underlying label-free microfluidic sorting techniques and review their capacity for stem cell selection/sorting from complex (heterogeneous) samples. PMID- 27236023 TI - Correlation between headaches and affective symptoms in patients with epilepsy. AB - Headaches are a neglected entity in patients with epilepsy (PWE), although PWE have a high chance of suffering from seizure-related as well as seizure-unrelated headaches. We aimed to identify the prevalence and characteristics of headaches and investigate the correlation between headaches and affective symptoms in PWE. Consecutive PWE who visited our tertiary outpatient clinic were interviewed about headaches and epilepsy. Affective symptoms were evaluated using the Korean version of the Beck Depression Inventory-II (BDI-II), Beck Anxiety Inventory (BAI), and suicidality portion of the Mini-International Neuropsychiatric Interview. We classified headaches as interictal or seizure-related headaches (SRHs; pre- and postictal). Tension-type headache and migraine were defined based on International Classification of Headache Disorders criteria. From the initial cohort of 177 patients (92 men, mean age: 37.1years), 73 (41.2%) reported suffering from interictal (N=34, 19.2%), preictal (N=3, 1.7%), and postictal (N=48, 27.1%) headaches. Univariate analysis revealed significantly higher BDI and BAI scores in the headache group. Tension-type headaches were the most frequent, and half of the interictal headaches and most of the SRHs were untreated. Spearman's partial correlation analyses showed that headaches overall were significantly related with depression and anxiety. Interictal headaches were correlated with depression only, and postictal headaches were correlated with depression as well as suicidality, separately. These results show that investigating and controlling headaches may relieve affective symptoms and ultimately improve the quality of life of PWE. PMID- 27236024 TI - SUDEP in female patients: Yesterday's news or tomorrow's headlines? PMID- 27236025 TI - Prognostic importance of postoperative QRS widening in patients with heart failure receiving cardiac resynchronization therapy. AB - BACKGROUND: Landmark reports have suggested that patients with QRS widening immediately after cardiac resynchronization therapy (CRT) experienced less frequently reverse left ventricular remodeling during follow-up. OBJECTIVE: We sought to investigate the relationship between postoperative QRS widening relative to baseline and mortality in a prospective cohort of heart failure patients receiving CRT. METHODS: A 12-lead electrocardiogram was recorded for 237 heart failure patients (New York Heart Association class II to IV, left ventricular ejection fraction <=35%, and QRS width >=120 ms) before and immediately after CRT device implantation. The relationships between QRS widening, all-cause and cardiovascular mortality, and echocardiographic response to CRT were studied. RESULTS: During a median follow-up of 24 months, 39 patients died. Fifty patients (21%) experienced QRS widening after CRT [QRS(+) group]. During follow-up, all-cause mortality was higher in QRS(+) patients than in QRS( ) patients (36-month survival free from death 81% +/- 7% vs 64% +/- 16%; log rank, P = .029). After adjustment for important prognostic confounders, QRS(+) patients remained associated with an excess overall mortality (adjusted hazard ratio [HR] 2.67; 95% confidence interval 1.07-6.65; P = .035) and cardiovascular mortality (adjusted hazard ratio 3.63; 95% confidence interval 1.13-11.65; P = .03). QRS(+) patients were less frequent responders to CRT than were QRS(-) patients (20 [47%] vs 136 [83%]; P < .0001). CONCLUSION: Postoperative QRS widening relative to baseline after CRT is associated with a considerable increased mortality risk during follow-up. Whether QRS narrowing should be achieved to optimize CRT placement, and thereby increase the rate of CRT responders and improve outcome, deserves further research. PMID- 27236027 TI - Trials and tribulations: Antiarrhythmic drugs for the acute conversion of atrial fibrillation. PMID- 27236026 TI - Periesophageal vagal plexus injury is a favorable outcome predictor after catheter ablation of atrial fibrillation. AB - BACKGROUND: Collateral damage to periesophageal vagal plexus associated with symptomatic gastric hypomotility and associated symptoms are not uncommon after catheter ablation of atrial fibrillation (AF). The injury may indicate transmural ablation lesions. OBJECTIVE: The purpose of this study was to evaluate the periesophageal vagal plexus injury (PNI) and long-term outcome after catheter ablation of AF. METHODS: A total of 441 consecutive patients with AF (mean age 54.71 +/- 10.52 years; 134 women) who underwent catheter ablation (paroxysmal AF, n = 312; persistent AF, n = 129) were retrospectively enrolled from 2011 to 2013; group 1 was defined as patients with PNI and associated symptoms (n = 88), and group 2 was defined as patients without PNI or associated symptoms (n = 353). Baseline characteristics and electrophysiological properties were collected to analyze the relationship between PNI and clinical outcome. The association of AF recurrence after catheter ablation and PNI symptoms was also investigated. RESULTS: During a mean follow-up period of 37.3 +/- 0.94 months, group 1 had longer AF-freedom days in sinus rhythm after AF ablation and had less recurrence after the blanking period compared with group 2 (mean recurrence days, 1254.22 +/ 45.26 days vs 1065.21 +/- 33.35 days; P < .01). Multivariate analysis also revealed that PNI was an independently protective predictor of AF recurrence (hazard ratio 0.527; 95% confidence interval 0.289-0.959; P = .036). There was no difference in baseline characteristics, CHA2DS2-VASc score, or echocardiography follow-up duration. CONCLUSION: PNI and associated symptoms are not uncommon after catheter ablation of AF. A better long-term outcome is thereby independently predicted, suggesting transmural ablation lesions during pulmonary vein isolation. PMID- 27236028 TI - Catheter ablation of supraventricular tachyarrhythmia after extracardiac Fontan surgery. AB - BACKGROUND: Extracardiac total cavopulmonary connection (E-TCPC) is widely performed for single ventricle palliation, yet there is little experience with catheter ablation in this population. OBJECTIVES: We hypothesized that atrial tachycardia substrates after primary E-TCPC would be similar to those in other forms of congenital heart disease and that catheter ablation could be performed effectively using a primarily transconduit approach. METHODS: Catheter ablation characteristics of patients with E-TCPC from 9 centers were collected. Acute procedural success was defined as elimination of all sustained supraventricular tachyarrhythmias. Procedural complications, acute success, and recurrences were assessed. RESULTS: Forty-six catheter ablation procedures were performed in 36 patients. Access to the atrium was by transconduit puncture in 29 procedures (63%). The most common supraventricular tachyarrhythmia mechanism was intra atrial reentrant tachycardia (IART) in 21 patients (58%); and for all patients with primary E-TCPC and IART, an isthmus between the atrioventricular valve annulus and the oversewn inferior vena cava was critical for maintenance of tachycardia. Overall, acute success was achieved in 38 procedures (83%). There were 8 complications, with only 1 requiring intervention (epicardial pacemaker) and none related to conduit puncture. Recurrence after the final procedure occurred in 6 patients (17%) over a median follow-up duration of 0.4 years (interquartile range 0.1-1.5 years). CONCLUSION: Catheter ablation could be performed effectively in this group of patients with E-TCPC, and the underlying IART substrate after primary E-TCPC appears to be reproducible. Catheter ablation may be a reasonable alternative to long-term antiarrhythmic therapy in this patient group. PMID- 27236029 TI - CXCL12 impairs the acquisition and extinction of auditory fear conditioning in rats via crosstalk with GABAergic system. AB - OBJECTIVE: Chemokines, such as CXCL12, are signaling molecules playing an important role in immune regulations. Chemokine upsurge has also been associated with neuroinflammatory conditions characterized with cognitive impairments. Recently, some in-vitro data suggests that CXCL12 is a potential neuromodulator and interacts with GABAergic system, but, so far, whether these effects translate into alterations in neural and behavioral functions has not been investigated. METHODS: In the present study, we used auditory fear conditioning as a model to define the contribution of CXCL12/CXCR4 on fear-related cognitive disorders. We microinjected different dosages of CXCL12 into the bilateral amygdala of rats to investigate their behavioral effects on the acquisition and extinction of conditioned fear memory. Moreover, we pretreated the rats with the selective CXCR4 receptor antagonist (AMD3100), GABAA antagonist (bicuculline) and GABAB antagonist (CGP55845) to examine whether the CXCL12 induced changes could be reversed. RESULTS: We found that intra-amygdala infusion of CXCL12 impaired the acquisition and extinction of conditioned fear response. Pretreatment with AMD3100, rescued the CXCL12 induced impairments, indicating that CXCL12 produced the effects by activating CXCR4 receptors. Furthermore, both bicuculline and CGP55845 prevented CXCL12 from impairing the rat's ability of conditioned learning, indicating a crosstalk between CXCL12/CXCR4 and GABAergic system. CONCLUSION: Our data suggest that the chemokine CXCL12 is able to regulate neurotransmitter mechanisms involved in associative learning functions, and the effect of GABAergic agents on CXCL12/CXCR4 may be new therapeutic potentials for neuroinflammatory diseases. PMID- 27236031 TI - Association of the DISC1 and NRG1 genetic polymorphisms with schizophrenia in a Chinese population. AB - Polymorphisms in Disrupted-in-Schizophrenia 1 (DISC1) and Neuregulin 1 (NRG1) might be associated with schizophrenia; however, the conclusions of relevant studies were inconsistent across different ethnic populations. This population based case-control study was carried out to determine whether polymorphisms in these two genes could be associated with schizophrenia in the Chinese population. A case-control study of 248 schizophrenia patients and 236 controls was performed with the Sequenom MassARRAY platform. The results revealed that the DISC1 rs821616 heterozygous (AT vs. AA: adjusted OR, 1.98, 95%CI: 1.30-3.02) and co dominant (AT/TT vs. AA: adjusted OR=1.94; 95%CI: 1.29-2.92) patterns were associated with increased risk for developing schizophrenia in all participants and subgroups (stratified by sex and age at onset), respectively. Moreover, in the male subgroup, the DISC1 rs821597 genotype GA or GA/AA exhibited increased risk of schizophrenia. For NRG1 polymorphisms, in the early onset subgroup (<=25years), the rs3924999 G/G genotype was susceptible to schizophrenia. The interaction of DISC1 rs821616 T allele with the NRG1 rs3924999 A allele or that of DISC1 rs821597 A allele with NRG1 rs3924999 A allele had synergic effects on the development of schizophrenia. This study concluded that carriers of the DISC1 rs821616 T allele have increased risk for developing schizophrenia, and that the DISC1 rs821597 A allele was susceptible to schizophrenia for the male, and that there are marked interactions between the DISC1 rs821616 T and/or rs821597 A alleles and the NRG1 rs3924999 A allele for the development of schizophrenia. PMID- 27236032 TI - Expression and clinical significance of miRNAs that may be associated with the FHIT gene in breast cancer. AB - The dysregulation of miRNA expression has frequently been observed in breast cancer. Therefore, we investigated the expression profile of miRNAs that may be associated with expression of the FHIT gene in breast cancer and assessed their clinicopathological significance. The expression levels of miR-143, miR-663a, miR 668, miR-922 and FHIT were analyzed in normal and malignant breast tissues from 65 patients with breast cancer. We studied the correlation between the expression of miR-143, miR-663a, miR-668, miR-922 and FHIT and the clinicopathological features presented by the patients. The expression levels of the miRNAs and FHIT were downregulated in breast cancer tissue. The expression levels of miR-143, miR 663a and miR-668 were significantly reduced in FHIT downregulated tumors. miR-668 expression was also significantly altered relative to FHIT down- and up- regulated tumor tissues. Reduced miR-663a expression was statistically associated with high-grade ER/PR (+) status, benign reactive hyperplasia, lymph-node metastasis, in-situ component >25% and Ki 67>15% compared with non-tumor tissues. Additionally, reduced miR-668 expression was significantly different between tumors with and without lymph-node metastasis. miR-668 may play an important role in breast cancer development and progression by regulating the expression of FHIT. Furthermore, miR-668 and miR-663a may be potential prognostic biomarkers for breast cancer. PMID- 27236030 TI - Effects of the psychotomimetic benzomorphan N-allylnormetazocine (SKF 10,047) on prepulse inhibition of startle in mice. AB - N-allylnormetazocine (NANM; SKF 10,047) is a benzomorphan opioid that produces psychotomimetic effects. (+)-NANM is the prototypical agonist for the sigma-1 (sigma1) receptor, and there is a widespread belief that the hallucinogenic effects of NANM and other benzomorphan derivatives are mediated by interactions with sigma1 sites. However, NANM is also an agonist at the kappa opioid receptor (KOR) and binds to the PCP site located within the channel pore of the NMDA receptor, interactions that could potentially contribute to the effects of NANM. NMDA receptor antagonists such as phencyclidine (PCP) and ketamine are known to disrupt prepulse inhibition (PPI) of acoustic startle, a measure of sensorimotor gating, in rodents. We recently found that racemic NANM disrupts PPI in rats, but it is not clear whether the effect is mediated by blockade of the NMDA receptor, or alternatively whether interactions with KOR and sigma1 receptors are involved. The present studies examined whether NANM and its stereoisomers alter PPI in C57BL/6J mice, and tested whether the effects on PPI are mediated by KOR or sigma1 receptors. Racemic NANM produced a dose-dependent disruption of PPI (3 30mg/kg SC). (+)-NANM also disrupted PPI, whereas (-)-NANM was ineffective. Pretreatment with the selective KOR antagonist nor-binaltorphimine (10mg/kg SC) or the selective sigma1 antagonist NE-100 (1mg/kg IP) failed to attenuate the reduction in PPI produced by racemic NANM. We also found that the selective KOR agonist (-)-U-50,488H (10-40mg/kg SC) had no effect on PPI. These findings confirm that NANM reduces sensorimotor gating in rodents, and indicate that the effect is mediated by interactions with the PCP receptor and not by activation of KOR or sigma1 receptors. This observation is consistent with evidence indicating that the sigma1 receptor is not linked to hallucinogenic or psychotomimetic effects. PMID- 27236033 TI - LDLR, ApoB and ApoE genes polymorphisms and classical risk factors in premature coronary artery disease. AB - Lipoproteins play a central role in the development of atherosclerotic disease. So, with their ability to affect lipid levels, the LDLR, ApoB and ApoE polymorphisms could be one of the factors influencing development of atherosclerosis. This hypothesis has been tested in different populations with conflicting results. The purpose of the present study was to investigate the association between the LDLR, ApoB and ApoE genes polymorphisms with premature CAD (PCAD) in Egyptians. One hundred thirty-five patients of PCAD and one hundred thirty-two ages and sex matched control subjects were included in the study. LDLR and ApoB genes polymorphisms were analyzed by polymerase chain reaction (PCR). The ApoE genotypes were identified by multiplex amplification refractory mutation system (multi-AMRS). We found that LDLR A(+)A(+) genotype, ApoB X(+) allele and ApoE E4 allele increased the risk of PCAD by 1.8, 2.1 and 12.1 respectively. The present study proved that smoking, metabolic syndrome, ApoB X(+)X(+) genotype and ApoE E4 allele were independent risk factors for the development of PCAD. This is the first study investigate the association between low density lipoprotein receptor, apolipoprotein B and apolipoprotein E genes polymorphisms with PCAD and lipid levels in Egyptians and we concluded that the LDLR A(+)A(+) genotype, ApoB X(+) allele and ApoE E4 allele may be associated with an increased risk for development of PCAD by elevated levels of total cholesterol (TC) and low density lipoprotein (LDLc). The coexistence of CAD risk factors with LDLR A(+)A(+) genotype, ApoB X(+) allele and ApoE E4 allele may increase the risk of the development of PCAD in Egyptian patients. PMID- 27236034 TI - A method for quantification of serum tenascin-X by nano-LC/MS/MS. AB - BACKGROUND: Complete deficiency of an extracellular matrix tenascin-X (TNX) leads to a classical type of Ehlers-Danlos syndrome (EDS). TNX haploinsufficiency is a cause of hypermobility type of EDS. Human TNX is also present in a serum form (sTNX) with a molecular size of 140kDa. In this study, we established a method for quantification of sTNX using nano-liquid chromatography tandem mass spectrometry (LC/MS/MS) with selected/multiple reaction monitoring. METHODS: Twelve abundant protein-depleted sera were reduced, alkylated, and digested with Lys-C and trypsin. Subsequently, the digests were fractionated by strong cation exchange chromatography. Optimal and validated transitions of precursor and product ions of the peptides from sTNX were developed on a triple quadrupole mass spectrometer. RESULTS: Serum concentrations of sTNX of healthy individuals were quantified as an average of 144ng/ml. However, sTNX was not detected by this method in serum from a patient with a classical type of EDS in whom sTNX was not found by Western blot analysis. The limit of quantification (LOQ) of sTNX by nano LC/MS/MS method was 2.8pg whereas the detection sensitivity of sTNX by Western blot analysis was 19pg. The nano-LC/MS/MS method is more sensitive than Western blot analysis. CONCLUSIONS: The quantification method will be useful for diagnosis and risk stratification of EDS caused by TNX deficiency and haploinsufficiency. PMID- 27236035 TI - Prediction of stemless humeral implant micromotion during upper limb activities. AB - BACKGROUND: Adequate primary stability is essential for the long term success of uncemented stemless shoulder implants. The goal of this study was to evaluate the micromotion of a stemless humeral implant during various upper limb activities. METHODS: A finite element model was validated by reproducing experimental primary stability testing. Loading from an instrumented prosthesis representing a set of 29 upper limb activities were applied within the validated FE model. Peak micromotion and percentage area for different micromotion thresholds were considered. FINDINGS: In all simulated activities, at least 99% of the implant surface experienced micromotion below 150MUm. Micromotion depended strongly on loading with large discrepancies between upper limb activities. Carrying no external weight and keeping the arm at lower angles induced lower micromotion. Activities representative of demanding manual labor generally led to higher micromotion. Axilla crutches led to lower micromotion than forearm crutches. Micromotion increased when a wheelchair was used on slopes above 2% inclination. INTERPRETATION: Micromotions below the 150MUm threshold below which bone ingrowth occurs were measured over at least 99% of the implant surface for all simulated activities. Peak micromotion dependence on activity type demonstrates the need to consider physiologic in vivo loading and the full contact interface in primary stability evaluations. Focusing on activities with no hand weight and low arm motions during the rehabilitation period may enhance primary stability. For patients unable to walk without aids, axilla crutches and motorized wheelchairs might be more beneficial than forearm crutches and manual drive wheelchairs respectively. PMID- 27236036 TI - The interplay between sleep behavior and affect in elementary school children's daily life. AB - Recent reviews raised the idea of a bidirectional relation between sleep behavior and affect in adults, but little is known about this interplay in general and especially regarding children. In this micro-longitudinal study, the interplay of sleep and affect was captured directly in children's daily life context in and out of school through ambulatory assessment. For 31 consecutive days, 110 elementary school children (8-11 years old) provided information about their last night's sleep and reported their current affect at four daily occasions in school and at home on smartphones. A multilevel approach was used to analyze the relation between sleep and affect the next day (morning, noon, and afternoon) and the relation between evening affect and subsequent sleep. At the within-person level, sleep quality was related to all observed facets of affect the next day and the strongest effects were found in the morning. The effect of sleep quality on positive affect was particularly pronounced for children who on average went to bed early and slept long. There were, however, no direct within-person effects of sleep quantity on affect. Furthermore, evening affect was related to subsequent sleep. The findings support the idea of a bidirectional relation between affect and sleep in children's daily life (including school). They suggest that good sleep provides a basis and resource for children's affective well-being the next day and demonstrate the importance of analyzing within-person variations of children's sleep. Micro-longitudinal findings can contribute to explain how macro-longitudinal relations between sleep and affect develop over time. PMID- 27236037 TI - Children's evaluation of public and private generosity and its relation to behavior: Evidence from China. AB - This research examined children's evaluation of public and private prosocial giving and whether such evaluation would predict actual behavior. We tested children between 6 and 12 years old (N=192) in China, where children are socialized not to call positive attention to themselves. In Study 1, a significant age-related change was found; younger children evaluated public acts of prosocial giving more favorably than private acts, whereas older children showed the opposite pattern. Study 2 not only replicated the findings of Study 1 but also showed that children's evaluation of public versus private giving predicted their actual behavior in communicating about their own prosocial giving. These findings are the first to show that age-related changes in children's understanding of generosity predict reputation management behavior. PMID- 27236039 TI - Clamping end-tidal carbon dioxide during graded exercise with control of inspired oxygen. AB - Exercise- and hypoxia-induced hyperventilation decreases the partial pressure of end-tidal carbon dioxide (PETCO2), which in turn exerts many physiological effects. Several breathing circuits that control PETCO2 have been previously described, but their designs are not satisfactory for exercise studies where changes in inspired oxygen (FIO2) may be desired. This study is the first report of a breathing system that can maintain PETCO2 constant within a single session of graded submaximal exercise and graded hypoxia. Thirteen fit and healthy subjects completed two bouts of exercise consisting of three 3min stages on a cycle ergometer with increasing exercise intensity in normoxia (Part A; 142+/-14, 167+/-14, 192+/-14W) or with decreasing FIO2 at a constant exercise intensity (Part B; 21, 18, and 14%). One bout was a control (CON) where PETCO2 was not manipulated, while during the other bout the investigator clamped PETCO2 within 2mmHg (CO2Clamp) using sequential gas delivery (SGD). During the final 30s of each exercise stage during CO2Clamp, PETCO2 was successfully maintained in Part A (43+/-4, 44+/-4, 44+/-3mmHg; P=0.44) and Part B (45+/-3, 46+/-3, 45+/-3mmHg; P=0.68) despite the increases in ventilation due to exercise. These findings demonstrate that this SGD circuit can be used to maintain isocapania in exercising humans during progressively increasing exercise intensities and changing FIO2. PMID- 27236038 TI - Kindergartners' fluent processing of symbolic numerical magnitude is predicted by their cardinal knowledge and implicit understanding of arithmetic 2years earlier. AB - Fluency in first graders' processing of the magnitudes associated with Arabic numerals, collections of objects, and mixtures of objects and numerals predicts current and future mathematics achievement. The quantitative competencies that support the development of fluent processing of magnitude, however, are not fully understood. At the beginning and end of preschool (M=3years 9months at first assessment, range=3years 3months to 4years 3months), 112 children (51 boys) completed tasks measuring numeral recognition and comparison, acuity of the approximate number system, and knowledge of counting principles, cardinality, and implicit arithmetic and also completed a magnitude processing task (number sets test) in kindergarten. Use of Bayesian and linear regression techniques revealed that two measures of preschoolers' cardinal knowledge and their competence at implicit arithmetic predicted later fluency of magnitude processing, controlling domain-general factors, preliteracy skills, and parental education. The results help to narrow the search for the early foundation of children's emerging competence with symbolic mathematics and provide direction for early interventions. PMID- 27236040 TI - Short-term cardiovascular and autonomic effects of inhaled salbutamol. AB - Asthma independently increases the risk of developing cardiovascular disease. As inhaled beta-agonists have systemic cardiovascular effects, and elevations in arterial stiffness and sympathetic nerve activity are associated with increased cardiovascular morbidity/mortality, this study examines the effect of salbutamol use on pulse wave velocity (PWV) and muscle sympathetic nervous activity (MSNA). Healthy men and women (26.2+/-1.5years) were recruited for: Day 1: 4 inhalations of placebo followed by 4 inhalations of salbutamol (4*100MUg); Day 2: placebo only; Day 3: carotid-femoral PWV measurements before/after placebo/salbutamol. Heart rate (HR), mean arterial pressure (MAP), and carotid-radial PWV were obtained on Day 1 and 2. MSNA was obtained on Day 1. Salbutamol increased HR and total MSNA (Baseline1: 2.8+/-2.8au; Placebo: 2.4+/-2.1au; Baseline2: 2.7+/-3.0au; Salbutamol: 3.3+/-2.9au; p=0.05), with no changes in MAP or PWV. There were no effects of placebo on HR, MSNA, or PWV. Acute salbutamol use increases sympathetic activity suggesting that salbutamol could contribute to cardiovascular morbidity/mortality in individuals using inhaled beta-agonists. PMID- 27236041 TI - Cognitive training for substance use disorders: Neuroscientific mechanisms. AB - This article reviews the emerging research on cognitive training for substance use disorders, and discusses the neuroscientific mechanisms that underlie cognitive training effects in addiction. Four cognitive training interventions are reviewed: cognitive bias modification (CBM), response inhibition, working memory (including specific and multi-component approaches), and goal-directed interventions. Based on the knowledge of the mechanisms involved in these trainings they can be clustered in two classes: (1) CBM and response inhibition, which have shown to operate via reorientation of stimulus-action approach biases and rewiring of the medial prefrontal cortex and the amygdala; (2) Working memory and goal-oriented interventions, which have been associated with improvements in stimulus-outcome representations e.g. increased future-based delay-discounting and decision-making, and rewiring of the dorsolateral and ventrolateral prefrontal cortices. The cognitive trainings are generally efficacious in improving the trained cognitive processes. The transfer to clinical outcomes is notable and theoretically coherent, although evidence is still preliminary. Replication studies and randomised controlled trials that incorporate neuroscience-based mechanistic accounts are needed to gauge the significance of this line of research. PMID- 27236042 TI - Estimating functional cognition in older adults using observational assessments of task performance in complex everyday activities: A systematic review and evaluation of measurement properties. AB - Functional cognition is a relatively new concept in assessment of older adults with mild cognitive impairment or dementia. Instruments need to be reliable and valid, hence we conducted a systematic review of observational assessments of task performance used to estimate functional cognition in this population. Two separate database searches were conducted: firstly to identify instruments; and secondly to identify studies reporting on the psychometric properties of the instruments. Studies were analysed using a published checklist and their quality reviewed according to specific published criteria. Clinical utility was reviewed and the information formulated into a best evidence synthesis. We found 21 instruments and included 58 studies reporting on measurement properties. The majority of studies were rated as being of fair methodological quality and the range of properties investigated was restricted. Most instruments had studies reporting on construct validity (hypothesis testing), none on content validity and there were few studies reporting on reliability. Overall the evidence on psychometric properties is lacking and there is an urgent need for further evaluation of instruments. PMID- 27236043 TI - BDNF Val66Met polymorphism and bipolar disorder in European populations: A risk association in case-control, family-based and GWAS studies. AB - Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has antidepressant-like effects in animal models and may be implicated in the etiology of mood-related phenotypes. A functional polymorphism (Val66Met) in the BDNF gene was demonstrated to influence BDNF's secretion and function, as well as mood and cognitive related phenotypes. However, previous genetic association studies of Val66Met polymorphism in the clinical risk of mood disorders have been complicated, possibly due to phenotypic diversity, underpowered statistical association or ancestry-specific effects. Here, we collected mood phenotypic and genetic data in over 90,000 individuals from diverse ethnic groups and conducted a systematic meta-analysis. The results showed that the Val66Met polymorphism was significantly associated with BPD in Europeans (Pmeta=0.0029, OR=1.136), but not in Asians (Pmeta=0.443). Also, it appears that the risk for MDD conferred by BDNF is waning, as the Val66Met variant was not associated with MDD in either European or Asian samples (Pmeta>0.5). PMID- 27236044 TI - Factors influencing cancer specialists' decision to collaborate with geriatricians in treating older cancer patients. AB - BACKGROUND: the collaboration between geriatricians and cancer specialists holds significant potential for improving care outcomes for older cancer patients. The realisation of this collaboration partly depends on cancer specialists involving geriatricians in caring for their older patients. Yet only a few studies have focused on understanding the reasons for cancer specialists' choice to involve or not involve geriatricians in this care. OBJECTIVE: this study shed some light on the challenges of collaboration between geriatricians and cancer specialists. It describes the case of a hospital that established a clinic staffed by geriatricians to assist cancer treatment teams. The focus of this article is to identify and explain the patterns of referrals of cancer specialists to this clinic. RESULTS: our study suggests that the referral practices of cancer specialists are considerably influenced by their specialty. The cancer specialists who find more applied value from geriatric assessments tend to refer their patients to geriatricians. Medical oncology is the sub-specialty that struggles the most in practically using information from the assessments to adjust their treatment. Cancer specialists who regularly referred to the clinic were the ones who thought that geriatricians had a unique contribution to patient care with their assessments and also with their intervention in palliative and psychosocial care. These specialists were usually from surgery and radiation oncology. CONCLUSIONS: ageing confers an increased risk of developing cancer. Providing adequate care to older cancer patients is still a challenge. Our study opens the 'black box' of collaboration between two important groups of professionals who may intervene in this care. PMID- 27236045 TI - Sex differences in jaw muscle duty factors during exercise in two environments: A pilot study. AB - It is unknown if females and males use jaw muscles similarly during exercise. This pilot study assessed jaw elevator muscle duty factors (DFs=time of muscle activity/total recording time) at repeated sessions to test if DFs are reliable and different between sexes during exercises in two environments. Ten female and seven male subjects recruited from university soccer teams provided informed consent. Surface electromyography was recorded from masseter and temporalis muscles during biting and leg-extension laboratory exercises. Average activities to produce 20N bite-forces for each muscle and subject determined thresholds (5 80%.T20N) for subject-specific DF calculations during exercises performed in laboratory and natural environments. Subjects self-recorded via portable electromyography equipment during in-field leg-extension and weight-lifting exercises. Effects of variables on DFs were assessed via ANOVA (alpha=0.05) and simple effects testing (Bonferroni-adjusted p?0.012). All subjects used jaw muscles during exercises in both environments. DFs between laboratory sessions were reliable (R=0.84). During laboratory exercises, male temporalis DFs were significantly higher than female DFs from both muscles (p?0.001). During in-field exercises females had higher DFs during weight-lifting while males had higher DFs during leg-extensions. In-field sex differences were significant at most thresholds and showed larger effect sizes for leg-extension compared to weight lifting exercises. PMID- 27236046 TI - Studies on some metal complexes of quinoxaline based unsymmetric ligand: Synthesis, spectral characterization, in vitro biological and molecular modeling studies. AB - Mononuclear Co(II), Ni(II), Cu(II) and Zn(II) complexes of an unsymmetric Schiff base ligand, 3-(-(3-(-3,5-dichloro-2 hydroxybenzylideneamino)propylimino)methyl)quinoxalin-2(1H) -one (L) were synthesized and characterized by various analytical and spectral techniques. The molar conductance values of metal complexes indicate non-electrolytic behavior of the metal complexes. The Schiff base act as tetra dentate ONNO donor ligand in Co(II), Ni(II), Zn(II) complexes and tridentate NNO donor in Cu(II) complex. Thermal stabilities of the newly synthesized compounds were determined by thermal analysis. Crystallinity, average grain size and unit cell parameters were determined from powder X-ray diffraction study. Electrochemical behaviors of the compounds were examined by cyclic voltammetry technique. The Schiff base and its complexes have been screened for their in vitro antimicrobial activities against some bacterial and fungal strains by disc diffusion method. The interaction of the compounds with calf thymus DNA (CT DNA) has been investigated by electronic absorption spectral titration and viscosity measurement (hydrodynamic) methods. Furthermore, the pUC18 DNA cleavage activities of the complexes have been explored. The compounds were also subjected to in vitro antioxidant, anticancer activity screening, druglikeness and bioactivity predictions using Molinspiration software. Molecular docking studies of the present compounds were carried out against B-DNA dodecamer d(CGCGAATTCGCG)2 and vascular endothelial growth factor receptor (VEGFR-2) kinase. Quantum chemical calculations were done with DFT method to determine the optimum geometry of the ligand and its metal complexes. From the quantum chemical parameters, the reactivity parameters of the compounds were established. PMID- 27236047 TI - Photocatalytic and antibacterial properties of phytosynthesized CeO2 NPs using Moringa oleifera peel extract. AB - Biosynthetic methods are alternative approaches which are much safer than the normal techniques (physical and chemical) used for the methods for synthesis of metal nanoparticles. The benefits are sample as it is economic and environment friendly. Herein present investigation, we have reported a microwave mediated eco friendly synthetic approach for preparing cerium oxide (CeO2) nanoparticles. Here, we used Moringa oleifera peel as the stabilizing and reducing agent towards synthesize of Ce2O NPs via microwave irradiation. The NPs were further characterized using UV-Vis, FT-IR, XRD and HR-TEM techniques. The FTIR analysis confirmed the phytochemical involvement in NPs stabilization. The crystallinity of CeO2 nanoparticles are well demonstrated through X-ray Diffraction and HR-TEM. The TEM images reveal the spherical shape of the CeO2 NPs having an average size of 45nm. Additionally, these CeO2 NPs were used successfully as a catalyst in the degradation of the dye, crystal violet. Also the antibacterial activity of the synthesized CeO2 NPs was evaluated using Staphylococcus aureus (Gram positive bacteria) and Escherichia coli (Gram negative bacteria). CeO2 NPs showed better activity on E. coli than S. aureus. We have demonstrated an eco-friendly preparation of CeO2 nanoparticles, a good photocatalyst and having better antibacterial properties. PMID- 27236048 TI - Spectroscopic and calorimetric investigations on the binding of phenazinium dyes safranine-O and phenosafranine to double stranded RNA polynucleotides. AB - RNA targeting through small molecules that can selectively bind specific RNA structures is an important current strategy in therapeutic drug development. Towards this strategy a comparative study on the interaction of two phenazinium dyes, safranine-O and phenosafranine to double stranded RNAs, poly(I).poly(C), poly(A).poly(U) and poly(C).poly(G) was performed. Spectrophotometric and spectrofluorimetric studies revealed non-cooperative binding of the dyes to the duplex RNA with binding constants of the order 10(5)M(-1) with a higher affinity of safranine-O to poly(I).poly(C) followed by poly(A).poly(U) and poly(C).poly(G). Anisotropy and fluorescence quenching results confirmed an intercalation mode of binding for the dyes on these RNAs. Binding induced conformational changes in the RNA polynucleotides were revealed from circular dichroism data. Thermal melting study and DSC experiments demonstrated stabilization of dye-RNA complexes. Calorimetric studies revealed that the binding was accompanied by a large positive entropy term with a small negative enthalpy contributions. Significant hydrophobic forces in the complexation of the double stranded RNAs with the dyes were confirmed from the negative heat capacity changes. Enthalpy-entropy compensation was also observed in the binding. Parsing of the Gibbs energy suggested a larger non-electrostatic contribution in all the cases. The results presented here may be helpful to design new types of RNA-based therapeutic agents. PMID- 27236049 TI - Biosynthesis of gold nanoparticles: A green approach. AB - Nanotechnology is an immensely developing field due to its extensive range of applications in different areas of technology and science. Different types of methods are employed for synthesis of nanoparticles due to their wide applications. The conventional chemical methods have certain limitations with them either in the form of chemical contaminations during their syntheses procedures or in later applications and use of higher energy. During the last decade research have been focussed on developing simple, clean, non-toxic, cost effective and eco-friendly protocols for synthesis of nanoparticles. In order to get this objective, biosynthesis methods have been developed in order to fill this gap. The biosynthesis of nanoparticles is simple, single step, eco-friendly and a green approach. The biochemical processes in biological agents reduce the dissolved metal ions into nano metals. The various biological agents like plant tissues, fungi, bacteria, etc. are used for biosynthesis for metal nanoparticles. In this review article, we summarised recent literature on biosynthesis of gold nanoparticles which have revolutionised technique of synthesis for their applications in different fields. Due to biocompatibility of gold nanoparticles, it has find its applications in biomedical applications. The protocol and mechanism of biosynthesis of gold nanoparticles along with various applications have also been discussed. PMID- 27236050 TI - ALS: A bucket of genes, environment, metabolism and unknown ingredients. AB - The scientific scenario of amyotrophic lateral sclerosis (ALS) has dramatically changed since TDP-43 aggregates were discovered in 2006 as the main component of the neuronal inclusions seen in the disease, and more recently, when the implication of C9ORF72 expansion in familial and sporadic cases of ALS and frontotemporal dementia was confirmed. These discoveries have enlarged an extense list of genes implicated in different cellular processes such as RNA processing or autophagia among others and have broaden the putative molecular targets of the disease. Some of ALS-related genes such as TARDBP or SOD1 among others have important roles in the regulation of glucose and fatty acids metabolism, so that an impairment of fatty acids (FA) consumption and ketogenic deficits during exercise in ALS patients would connect the physiopathology with some of the more intriguing epidemiological traits of the disease. The current understanding of ALS as part of a continuum with other neurodegenerative diseases and a crossroads between genetic, neurometabolic and environmental factors represent a fascinating model of interaction that could be translated to other neurodegenerative diseases. In this review we summarize the most relevant data obtained in the ten last years and the key lines for future research in ALS. PMID- 27236051 TI - Long-term consequences of prenatal stress and neurotoxicants exposure on neurodevelopment. AB - There is a large consensus that the prenatal environment determines the susceptibility to pathological conditions later in life. The hypothesis most widely accepted is that exposure to insults inducing adverse conditions in-utero may have negative effects on the development of target organs, disrupting homeostasis and increasing the risk of diseases at adulthood. Several models have been proposed to investigate the fetal origins of adult diseases, but although these approaches hold true for almost all diseases, particular attention has been focused on disorders related to the central nervous system, since the brain is particularly sensitive to alterations of the microenvironment during early development. Neurobiological disorders can be broadly divided into developmental, neurodegenerative and neuropsychiatric disorders. Even though most of these diseases share genetic risk factors, the onset of the disorders cannot be explained solely by inheritance. Therefore, current understanding presumes that the interactions of environmental input, may lead to different disorders. Among the insults that can play a direct or indirect role in the development of neurobiological disorders are stress, infections, drug abuse, and environmental contaminants. Our laboratories have been involved in the study of the neurobiological impact of gestational stress on the offspring (Dr. Antonelli's lab) and on the effect of gestational exposure to toxicants, mainly methyl mercury (MeHg) and perfluorinated compounds (PFCs) (Dr. Ceccatelli's lab). In this focused review, we will review the specialized literature but we will concentrate mostly on our own work on the long term neurodevelopmental consequences of gestational exposure to stress and neurotoxicants. PMID- 27236053 TI - New Approaches to Positive Airway Pressure Treatment in Obstructive Sleep Apnea. AB - Continuous positive airway pressure (CPAP) is a mainstay of therapy in patients with obstructive sleep apnea (OSA). This technology has gone through tremendous changes that resulted in devices that can recognize and differentiate sleep disordered breathing events, adjust their output to these events, monitor usage, and communicate with the treatment team. This article discusses recent developments in treatment of OSA with PAP. PMID- 27236052 TI - New Approaches to Diagnosing Sleep-Disordered Breathing. AB - Novel concepts and technological advances have the potential to change the landscape on which clinical sleep medicine is practiced. Screening for sleep apnea will take advantage of readily available mobile telephone technology (sound, accelerometers) to enable widespread recognition of sleep-disordered breathing. Advanced computer-assisted scoring algorithms will improve efficiency and reliability of sleep apnea diagnoses. As the field adopts a personalized approach to therapies, methods to determine the mechanisms of sleep apnea in individuals will be developed-utilizing simplified tests and available recordings with the promise of predicting outcomes of novel therapies. PMID- 27236054 TI - Monitoring Progress and Adherence with Positive Airway Pressure Therapy for Obstructive Sleep Apnea: The Roles of Telemedicine and Mobile Health Applications. AB - Technology is changing the way health care is delivered and how patients are approaching their own health. Given the challenge within sleep medicine of optimizing adherence to continuous positive airway pressure (CPAP) therapy in patients with obstructive sleep apnea (OSA), implementation of telemedicine-based mechanisms is a critical component toward developing a comprehensive and cost effective solution for OSA management. Key elements include the use of electronic messaging, remote monitoring, automated care mechanisms, and patient self management platforms. Current practical sleep-related telemedicine platforms include Web-based educational programs, automated CPAP follow-up platforms that promote self-management, and peer-based patient-driven Internet support forums. PMID- 27236055 TI - Novel Approaches to the Management of Sleep-Disordered Breathing. AB - In the last several years, a variety of novel approaches to the treatment of sleep-disordered breathing have emerged. This new technology holds promise in serving to re-engage with patients who have previously been lost to follow-up due to continuous positive airway pressure intolerance. With more tools at our disposal, in turn more options can be offered to patients' growing demand for alternatives that are tailored to their individual needs. The key to proper deployment of alternative therapies will often depend on identification of certain phenotypic traits that trend toward a reasonable response to a given therapy. PMID- 27236056 TI - Novel Surgical Approaches for the Treatment of Obstructive Sleep Apnea. AB - Novel approaches to upper airway anatomic phenotyping, more reconstructive upper airway surgical techniques, and new implantable hypoglossal neurostimulation technology have very favorable potential to improve symptoms and quality-of-life measures, to reduce obstructive sleep apnea (OSA) disease severity and associated cardiovascular risk, and to serve as an adjunct to continuous positive airway pressure, oral appliances, and other forms of OSA medical therapy. Successful surgical therapy depends critically on accurate diagnosis, skillful knowledge and examination of the upper airway anatomy, proper procedure selection, and proficient technical application. PMID- 27236057 TI - Pharmacologic Approaches to the Treatment of Obstructive Sleep Apnea. AB - The concept of pharmacologic therapy for obstructive sleep apnea (OSA) treatment has always been considered but no agent has had a large enough effect size to drive substantial adoption. A new construct of the pathophysiology of OSA is that there are 4 primary physiologic traits that dictate who develops OSA. These traits vary substantially between patients, meaning OSA may develop for quite different reasons. This encourages new thinking regarding pharmacologic therapy and continued attempts to find the ideal or acceptable drug. PMID- 27236058 TI - The Challenges of Precision Medicine in Obstructive Sleep Apnea. AB - Obstructive sleep apnea (OSA) is a highly prevalent condition that remains underdiagnosed and undertreated. The onerous and labor-intensive nature of polysomnography or similar diagnostic multichannel-based approaches paves the way for exploration of biomarkers aimed at diagnosis, morbidity detection, and monitoring of therapy and its outcomes. To this effect, "Omics" technologies coupled with appropriate bioinformatic approaches should enable discovery of unique biomarker-based signatures, enabling simplified and highly precise algorithms for the evaluation and treatment of symptomatic individuals. Such approaches are likely to not only lead to improved outcomes but also permit personalized medicine to become reality in the context of OSA. PMID- 27236059 TI - Novel Therapies for the Treatment of Central Sleep Apnea. AB - Neurophysiologically, central apnea is due to a temporary cessation of respiratory rhythmogenesis in medullary respiratory networks. Central apneas occur in several disorders and result in pathophysiological consequences, including arousals and desaturation. The 2 most common causes in adults are congestive heart failure and chronic use of opioids to treat pain. Under such circumstances, diagnosis and treatment of central sleep apnea may improve quality of life, morbidity, and mortality. This article discusses recent developments in the treatment of central sleep apnea in heart failure and opioids use. PMID- 27236061 TI - Advances and New Approaches to Managing Sleep-Disordered Breathing Related to Chronic Pulmonary Disease. AB - Chronic obstructive pulmonary disease (COPD) is a common disease affecting about 20 million US adults. Sleep-disordered breathing (SDB) problems are frequent and poorly characterized for patients with COPD. Both the well-known success of noninvasive ventilation (NIV) in the acute COPD exacerbation in the hospital setting and that NIV is the cornerstone of chronic therapy for SDBs have urged the attention of the medical community to determine the impact of NIV on chronic COPD management with and without coexisting SDBs. Early observational studies showed decreased long-term survival rates on patients with COPD with concomitant chronic hypercapnia when compared with normocapnic patients. PMID- 27236060 TI - The Role of Big Data in the Management of Sleep-Disordered Breathing. AB - Analysis of large-volume data holds promise for improving the application of precision medicine to sleep, including improving identification of patient subgroups who may benefit from alternative therapies. Big data used within the health care system also promises to facilitate end-to-end screening, diagnosis, and management of sleep disorders; improve the recognition of differences in presentation and susceptibility to sleep apnea; and lead to improved management and outcomes. To meet the vision of personalized, precision therapeutics and diagnostics and improving the efficiency and quality of sleep medicine will require ongoing efforts, investments, and change in our current medical and research cultures. PMID- 27236062 TI - Novel Approaches to the Management of Sleep-Disordered Breathing: Reviewing the Past and Looking Into the Future. PMID- 27236063 TI - Physiological adjustments and transcriptome reprogramming are involved in the acclimation to salinity gradients in diatoms. AB - Salinity regimes in estuaries and coastal areas vary with river discharge patterns, seawater evaporation, the morphology of the coastal waterways and the dynamics of marine water mixing. Therefore, microalgae have to respond to salinity variations at time scales ranging from daily to annual cycles. Microalgae may also have to adapt to physical alterations that induce the loss of connectivity between habitats and the enclosure of bodies of water. Here, we integrated physiological assays and measurements of morphological plasticity with a functional genomics approach to examine the regulatory changes that occur during the acclimation to salinity in the estuarine diatom Thalassiosira weissflogii. We found that cells exposed to different salinity regimes for a short or long period presented adjustments in their carbon fractions, silicon pools, pigment concentrations and/or photosynthetic parameters. Salinity-induced alterations in frustule symmetry were observed only in the long-term (LT) cultures. Whole transcriptome analyses revealed a down-regulation of nuclear and plastid encoded genes during the LT response and identified only a few regulated genes that were in common between the ST and LT responses. We propose that in diatoms, one strategy for acclimating to salinity gradients and maintaining optimal cellular fitness could be a reduction in the cost of transcription. PMID- 27236064 TI - Anti-mycobacterial activity of thymine derivatives bearing boron clusters. AB - A series of novel thymine derivatives bearing lipophilic, electron-neutral 1,2 dicarba-closo-dodecaborane, 1,12-dicarba-closo-dodecaborane or hydrophilic 7,8 dicarba-nido-undecaborate anions were synthesized. Synthesis was performed via copper(I)-catalysed Huisgen-Meldal-Sharpless 1,3-dipolar cycloaddition of N(1) propargylthymine or N(1),N(3)-bispropargylthymine to 1-(3-azidopropyl)-1,2 dicarba-closo-dodecaborane. The obtained compounds were tested in vitro against Mycobacterium tuberculosis thymidylate kinase (TMPKmt) and as inhibitors of mycobacteria growth in culture using both saprophytic Mycobacterium smegmatis (M. smegmatis) and pathogenic Mycobacterium tuberculosis (M. tuberculosis) strains. The most potent TMPKmt inhibitor in the series contained two negatively charged 7,8-dicarba-nido-undecaborate modifications at positions 1 and 3 of thymine (9) and exhibited a Ki value of 1.5 MUM. The most potent inhibitors of mycobacteria growth was compound 5 with one electron-neutral 1,2-dicarba-closo-dodecaborane modification at position 1 of thymine, and compound 8 with two modifications, at position 1 and 3. Both compounds completely inhibited M. smegmatis proliferation at a concentration of 100 MUg/mL (0.25 mM and 0.15 mM, respectively). PMID- 27236065 TI - Differentiation of skeletal osteogenic progenitor cells to osteoblasts with 3,4 diarylbenzopyran based amide derivatives: Novel osteogenic agents. AB - A series of 3,4-diarylbenzopyran based amide derivatives was synthesized and evaluated for osteogenic activity in in vitro and in vivo models of osteoporosis. Compounds 17a, 21b-c and 22a-b showed significant osteogenic activity in osteoblast differentiation assay. Among the synthesized compounds, 22b was identified as lead molecule which showed significant osteogenic activity at 1 pM concentration in osteoblast differentiation assay and at 1 mg kg(-1) body weight dose in estrogen deficient balb/c mice model. In vitro bone mineralization and expression of osteogenic marker genes viz BMP-2, RUNX-2, OCN, and collagen type 1 further confirmed the osteogenic potential of 22b. Gene expression study for estrogen receptor alpha and beta (ER-alpha and ER-beta) in mouse calvarial osteoblasts (MCOs) unveiled that possibly 22b exerted osteogenic efficacy via activation of Estrogen receptor-beta preferentially. In vivo pharmacokinetic, estrogenicity and acute toxicity studies of 22b showed that it had good bioavailability and was devoid of uterine estrogenicity at 1 mg kg(-1) and inherent toxicity up to 1000 mg kg(-1) body weight dose respectively. PMID- 27236066 TI - Kinetic, thermodynamic and structural analysis of tamiphosphor binding to neuraminidase of H1N1 (2009) pandemic influenza. AB - Influenza virus causes severe respiratory infections that are responsible for up to half a million deaths worldwide each year. Two inhibitors targeting viral neuraminidase have been approved to date (oseltamivir, zanamivir). However, the rapid development of antiviral drug resistance and the efficient transmission of resistant viruses among humans represent serious threats to public health. The approved influenza neuraminidase inhibitors have (oxa)cyclohexene scaffolds designed to mimic the oxonium transition state during enzymatic cleavage of sialic acid. Their active forms contain a carboxylate that interacts with three arginine residues in the enzyme active site. Recently, the phosphonate group was successfully used as an isostere of the carboxylate in oseltamivir, and the resulting compound, tamiphosphor, was identified as a highly active neuraminidase inhibitor. However, the structure of the complex of this promising inhibitor with neuraminidase has not yet been reported. Here, we analyzed the interaction of a set of oseltamivir and tamiphosphor derivatives with neuraminidase from the A/California/07/2009 (H1N1) influenza virus. We thermodynamically characterized the binding of oseltamivir carboxylate or tamiphosphor to the neuraminidase catalytic domain by protein microcalorimetry, and we determined crystal structure of the catalytic domain in complex with tamiphosphor at 1.8 A resolution. This structural information should aid rational design of the next generation of neuraminidase inhibitors. PMID- 27236067 TI - Synthesis and biological properties of polyamine modified flavonoids as hepatocellular carcinoma inhibitors. AB - A series of polyamine conjugates of flavonoids with a naphthalene motif were synthesized and evaluated for their anti-hepatocellular carcinoma properties using in vitro and in vivo assays. Compound 8a displayed favorable selectivity between hepatocellular carcinoma cells and normal hepatocyte cells, and the combination of 8a with aspirin resulted in additive inhibition of in vitro tumor cell growth and migration. The 8a-aspirin combination also inhibited H22 liver tumor growth and pulmonary metastasis and improved body weight index in animal models. Preliminary mechanistic studies indicated that 8a increased the expression of apoptosis-related proteins such as p-p38, p-JNK, p53 and Bcl-2, an effect that was further amplified by aspirin. Therefore, a cocktail therapy of flavonoid-polyamine conjugates with aspirin has potential use as an antitumor therapy. PMID- 27236068 TI - Lupane and 18alpha-oleanane derivatives substituted in the position 2, their cytotoxicity and influence on cancer cells. AB - Lupane derivatives containing an electronegative substituent in the position 2 of the skeleton are often cytotoxic, however, the most active compounds are not selective enough. To further study the influence of a substituent in the position 2 in lupane and 18alpha-oleanane derivatives on their biological properties, we prepared a set of 38 triterpenoid compounds, 19 of them new, most of them substituted in the position 2. From betulin, we obtained 2-bromo dihydrobetulonic acid and 2-bromo allobetulon and their substitutions yielded derivatives with various substituents in the position 2 such as amines, amides, thiols, and thioethers. Nitration of allobetulon and dihydrobetulonic acid gave 2-nitro and 2,2-dinitro derivatives. Fifteen derivatives had IC50 < 50 MUM on a chemosensitive CCRF-CEM (acute lymphoblastic leukemia) cell line and were tested on another seven cancer cell lines including resistant and two non-cancer lines. 2-Amino allobetulin had IC50 4.6 MUM and caused significant block of the tumor cells in S and slightly in G2/M transition and caused strong inhibition of DNA and RNA synthesis at 5 * IC50. 2-Amino allobetulin is the most active derivative of 18alpha-oleanane skeletal type prepared in our research group to date. PMID- 27236069 TI - Fragment-based solid-phase assembly of oligonucleotide conjugates with peptide and polyethylene glycol ligands. AB - Ligand conjugation to oligonucleotides is an attractive strategy for enhancing the therapeutic potential of antisense and siRNA agents by inferring properties such as improved cellular uptake or better pharmacokinetic properties. Disulfide linkages enable dissociation of ligands and oligonucleotides in reducing environments found in endosomal compartments after cellular uptake. Solution phase fragment coupling procedures for producing oligonucleotide conjugates are often tedious, produce moderate yields and reaction byproducts are frequently difficult to remove. We have developed an improved method for solid-phase coupling of ligands to oligonucleotides via disulfides directly after solid-phase synthesis. A 2'-thiol introduced using a modified nucleotide building block was orthogonally deprotected on the controlled pore glass solid support with N butylphosphine. Oligolysine peptides and a short monodisperse ethylene glycol chain were successfully coupled to the deprotected thiol. Cleavage from the resin and full removal of oligonucleotide protection groups were achieved using methanolic ammonia. After standard desalting, and without further purification, homogenous conjugates were obtained as demonstrated by HPLC, gel electrophoresis, and mass spectrometry. The attachment of both amphiphilic and cationic ligands proves the versatility of the conjugation procedure. An antisense oligonucleotide conjugate with hexalysine showed pronounced gene silencing in a cell culture tumor model in the absence of a transfection reagent and the corresponding ethylene glycol conjugate resulted in down regulation of the target gene to nearly 50% after naked application. PMID- 27236070 TI - Comparison of 1- Versus 3-Minute Stage Duration During Arm Ergometry in Individuals With Spinal Cord Injury. AB - OBJECTIVE: To investigate the effect of stage duration on peak physiological response to arm ergometry incremental exercise testing in individuals with spinal cord injury or disease (SCI/D) in support of developing a more individualized approach to testing. DESIGN: Parallel reliability study. SETTING: University research laboratory. PARTICIPANTS: Individuals with SCI/D (N=38) performed 2 peak oxygen consumption assessments comprised of 1-minute or 3-minute stages on 1 day. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Heart rate and oxygen consumption were recorded continuously from baseline through recovery. Every 1 minute or 3 minutes, resistance increased at an individualized level, and participants continued until volitional fatigue. The highest 30-second average was selected as peak oxygen consumption (Vo2peak) and peak heart rate. The highest workload achieved for >=30 seconds was recorded as peak power output (PO). RESULTS: Intraclass correlation coefficients (ICCs) were >.95 for the following variables: absolute Vo2peak (mean +/- SD, 1min: 1.2+/-0.7, 3min: 1.2+/ .62L/min; 95% CI, .91-.98), relative Vo2peak (mean +/- SD, 1min: 16.6+/-9.4, 3min: 15.8+/-8.0mL/kg/min; 95% CI, .90-.98), absolute peak PO (mean +/- SD, 1min: 61+/-41, 3min: 66+/-41W; 95% CI, .92-.98), and relative peak PO (mean +/- SD, 1min: .80+/-56, 3min: .90+/-.55W/kg; 95% CI, .91-.98). There was no significant difference in peak heart rate between 3 minutes (132+/-27 beats per minute [bpm]) and 1 minute (130+/-28 bpm); however, the ICC lower limit was <.75 (0.67-0.90). Total test time was significantly longer in the 3-minute (8:17+/-2:52min:s) than in the 1-minute (6:29+/-2:21min:s) protocol. CONCLUSIONS: For measuring peak physiological values in an incremental arm ergometry test, stage duration is of little consequence because similar values were obtained for the main outcome measures in both protocols. PMID- 27236071 TI - Transgastric hybrid surgery for the flexible endoscopist: early experience with the TAGSS system. PMID- 27236072 TI - Beyond the scope: using the single-operator digital cholangioscope to access an afferent loop obstruction. PMID- 27236073 TI - Effects of brief mindful acceptance induction on implicit dysfunctional attitudes and concordance between implicit and explicit dysfunctional attitudes. AB - Mindfulness-based interventions have been shown to be effective in alleviating depressive symptoms. While much work has examined the effects of mindfulness training on subjective symptoms and experiences, and less is known regarding whether mindfulness training may alter relatively uncontrollable cognitive processes associated with depressed mood, particularly implicit dysfunctional attitudes. The present study examined the effects of a brief mindful acceptance induction on implicit dysfunctional attitudes and degree of concordance between implicit and explicit dysfunctional attitudes in the context of sad mood. A total of 79 adult participants with elevated depressive symptoms underwent an autobiographical mood induction procedure before being randomly assigned to mindful acceptance or thought wandering inductions. Results showed that the effect of mindful acceptance on implicit dysfunctional attitude was significantly moderated by trait mindfulness. Participants high on trait mindfulness demonstrated significant improvements in implicit dysfunctional attitudes following the mindful acceptance induction. Those low on trait mindfulness demonstrated significantly worse implicit dysfunctional attitudes following the induction. Significantly greater levels of concordance between implicit and explicit dysfunctional attitudes were observed in the mindful acceptance condition versus the thought wandering condition. The findings highlight changes in implicit dysfunctional attitudes and improvements in self-concordance as two potential mechanisms underlying the effects of mindfulness-based interventions. PMID- 27236074 TI - Positive extreme responding after cognitive therapy for depression: Correlates and potential mechanisms. AB - "Extreme responding" is the tendency to endorse extreme responses on self-report measures (e.g., 1s and 7s on a 7-point scale). It has been linked to depressive relapse after cognitive therapy (CT), but the mechanisms are unknown. Moreover, findings of positive extreme responding (PER) predicting depressive relapse do not support the original hypothesis of "extreme" negative thinking leading to extreme negative emotional reactions. We assessed the relationships between post treatment PER on the Dysfunctional Attitudes Scale (DAS) and Attributional Style Questionnaire (ASQ) and these constructs: coping skills, in-session performance of cognitive therapy skills, age, and estimated IQ. Significant correlates were entered into a model predicting rate of relapse to determine whether these constructs explained the relationship between PER and relapse. The sample consisted of 60 individuals who participated in CT for moderate to severe depression. Results indicated the following relationships: a negative correlation between ASQ PER and IQ, negative correlations between DAS PER and performance of CT skills and planning coping, and a positive correlation between DAS PER and behavioral disengagement coping. IQ scores fully accounted for the relationship between ASQ PER and relapse. These results suggest two potential mechanisms linking PER to relapse: cognitive limitations and coping deficits/cognitive avoidance. PMID- 27236075 TI - Take a look at the bright side: Effects of positive body exposure on selective visual attention in women with high body dissatisfaction. AB - Women with high body dissatisfaction look less at their 'beautiful' body parts than their 'ugly' body parts. This study tested the robustness of this selective viewing pattern and examined the influence of positive body exposure on body dissatisfied women's attention for 'ugly' and 'beautiful' body parts. In women with high body dissatisfaction (N = 28) and women with low body dissatisfaction (N = 14) eye-tracking was used to assess visual attention towards pictures of their own and other women's bodies. Participants with high body dissatisfaction were randomly assigned to 5 weeks positive body exposure (n = 15) or a no treatment condition (n = 13). Attention bias was assessed again after 5 weeks. Body-dissatisfied women looked longer at 'ugly' than 'beautiful' body parts of themselves and others, while participants with low body dissatisfaction attended equally long to own/others' 'beautiful' and 'ugly' body parts. Although positive body exposure was very effective in improving participants' body satisfaction, it did not systematically change participants' viewing pattern. The tendency to preferentially allocate attention towards one's 'ugly' body parts seems a robust phenomenon in women with body dissatisfaction. Yet, modifying this selective viewing pattern seems not a prerequisite for successfully improving body satisfaction via positive body exposure. PMID- 27236076 TI - Prevalence and characteristics of verotoxigenic Escherichia coli strains isolated from pigs and pork products in Umbria and Marche regions of Italy. AB - In total 1095 samples from 675 pork products, 210 swine colon contents, and 210 swine carcass sponge swabs were collected in Umbria and Marche regions of Italy and examined for the presence of Shiga toxin-producing Escherichia coli (STEC), also known as Verotoxin-producing E. coli (VTEC). After an enrichment step, each sample was analysed by real-time PCR to detect the stx1, stx2, and eae genes. stx Positive samples were further tested for the "top five" serogroup markers (O157, O26, O103, O111, O145) and cultured onto selective media. The isolates were assigned to stx subtypes and tested for the presence of aaiC and aggR genes. Out of 420 swine samples, 38.6% faecal samples and 13.8% carcass sponge swabs were stx-positive. In total, 33 E. coli STEC isolates were obtained from 30 samples (4 carcasses and 26 colon contents) indicating a culture-positive rate of 7.1%. A higher culture-positive rate was observed in faecal samples (12.4%) than in carcass sponge swabs (1.9%). Out of 675 pork samples, 19 (2.8%) were stx positive. No STEC strains were isolated from stx-positive pork products. We concluded that STEC isolation from foodstuffs remains difficult, despite the application of ISO/TS 13136:2012. Furthermore, in accordance with the results of studies conducted in other countries, we observed that most of swine STEC strains carried stx2e gene and lacked of virulence genes, such as eae, aaiC and aggR, indicative of potential pathogenic characteristics for humans. Although the majority of STEC isolates did not express virulence factors correlating with severe human diseases, the association between swine STEC strains and human illness requires further investigations. PMID- 27236077 TI - The role of PGC-1alpha and MRP1 in lead-induced mitochondrial toxicity in testicular Sertoli cells. AB - The lead-induced toxic effect on mitochondria in Sertoli cells is not well studied and the underlying mechanism is poorly understood. Here we reported the potential role of peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) and multidrug resistance protein 1 (MRP1) in lead acetate induced mitochondrial toxicity in mouse testicular Sertoli cells TM4 line. We found that lead acetate treatment significantly reduced the expression level of PGC-1alpha, but increased the level of MRP1 in mitochondria of TM4 cells. To determine the role of PGC-1alpha and MRP1 in lead acetate-induced mitochondrial toxicity, we then generated PGC-1alpha stable overexpression and MRP1 stable knockdown TM4 cells, respectively. The lead acetate treatment caused TM4 cell mitochondrial ultrastructure damages, a decrease in ATP synthesis, an increase in ROS levels, and apoptotic cell death. In contrast, stably overexpressing PGC 1alpha significantly ameliorated the lead acetate treatment-caused mitochondrial toxicity and apoptosis. Moreover, it was also found that stably knocking down the level of MRP1 increased the TM4 cell mitochondrial lead-accumulation by 4-6 folds. Together, the findings from this study suggest that PGC-1alpha and MRP1 plays important roles in protecting TM4 cells against lead-induced mitochondrial toxicity, providing a better understanding of lead-induced mitochondrial toxicity. PMID- 27236078 TI - Protective potential of recombinant non-purified botulinum neurotoxin serotypes C and D. AB - Botulinum neurotoxin (BoNT) serotypes C and D are responsible for cattle botulism, a fatal paralytic disease that results in great economic losses in livestock production. Vaccination is the main approach to prevent cattle botulism. However, production of commercially available vaccines (toxoids) involves high risk and presents variation of BoNT production between batches. Such limitations can be attenuated by the development of novel nontoxic recombinant vaccines through a simple and reproducible process. The aim of this study was to evaluate the protective potential of recombinant non-purified botulinum neurotoxin serotypes C and D. Bivalent vaccines containing 200 MUg rHCC and rHCD each were formulated in three different ways: (1) purified antigens; (2) recombinant Escherichia coli bacterins; (3) recombinant E. coli cell lysates (supernatant and inclusion bodies). Guinea pigs immunized subcutaneously with recombinant formulations developed a protective immune response against the respective BoNTs as determined by a mouse neutralization bioassay with pooled sera. Purified recombinant antigens were capable of inducing 13 IU/mL antitoxin C and 21 IU/mL antitoxin D. Similarly, both the recombinant bacterins and the cell lysate formulations were capable of inducing 12 IU/mL antitoxin C and 20 IU/mL antitoxin D. These values are two times as high as compared to values induced by the commercial toxoid used as control, and two to ten times as high as the minimum amount required by the Brazilian Ministry of Agriculture, Livestock and Food Supply (MAPA), respectively. Therefore, we used a practical, industry friendly, and efficient vaccine production process that resulted in formulations capable of inducing protective immune response (neutralizing antitoxins) against botulism serotypes C and D. PMID- 27236079 TI - Lessons from crystal structures of kainate receptors. AB - Kainate receptors belong to the family of ionotropic glutamate receptors. These receptors assemble from five subunits (GluK1-5) into tetrameric ion channels. Kainate receptors are located at both pre- and postsynaptic membranes in the central nervous system where they contribute to excitatory synaptic transmission and modulate network excitability by regulating neurotransmitter release. Dysfunction of kainate receptors has been implicated in several neurological disorders such as epilepsy, schizophrenia and depression. Here we provide a review on the current understanding of kainate receptor structure and how they bind agonists, antagonists and ions. The first structure of the ligand-binding domain of the GluK1 subunit was reported in 2005, seven years after publication of the crystal structure of a soluble construct of the ligand-binding domain of the AMPA-type subunit GluA2. Today, a full-length structure has been determined of GluK2 by cryo electron microscopy to 7.6 A resolution as well as 84 high resolution crystal structures of N-terminal domains and ligand-binding domains, including agonist and antagonist bound structures, modulatory ions and mutations. However, there are still many unanswered questions and challenges in front of us. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'. PMID- 27236080 TI - Isolation of proflavine as a blocker of G protein-gated inward rectifier potassium channels by a cell growth-based screening system. AB - The overexpression of Kir3.2, a subunit of the G protein-gated inwardly rectifying K(+) channel, is implicated in some of the neurological phenotypes of Down syndrome (DS). Chemical compounds that block Kir3.2 are expected to improve the symptoms of DS. The purpose of this study is to develop a cell-based screening system to identify Kir3.2 blockers and then investigate the mode of action of the blocker. Chemical screening was carried out using a K(+) transporter-deficient yeast strain that expressed a constitutively active Kir3.2 mutant. The mode of action of an effective blocker was electrophysiologically analyzed using Kir channels expressed in Xenopus oocytes. Proflavine was identified to inhibit the growth of Kir3.2-transformant cells and Kir3.2 activity in a concentration-dependent manner. The current inhibition was strong when membrane potentials (Vm) was above equilibrium potential of K(+) (EK). When Vm was below EK, the blockage apparently depended on the difference between Vm and [K(+)]. Furthermore, the inhibition became stronger by lowering extracellular [K(+)]. These results indicated that the yeast strain serves as a screening system to isolate Kir3.2 blockers and proflavine is a prototype of a pore blocker of Kir3.2. PMID- 27236081 TI - Hemodynamic correlates of spontaneous neural activity measured by human whole head resting state EEG+fNIRS. AB - The brains of awake, resting human subjects display spontaneously occurring neural activity patterns whose magnitude is typically many times greater than those triggered by cognitive or perceptual performance. Evoked and resting state activations affect local cerebral hemodynamic properties through processes collectively referred to as neurovascular coupling. Its investigation calls for an ability to track both the neural and vascular aspects of brain function. We used scalp electroencephalography (EEG), which provided a measure of the electrical potentials generated by cortical postsynaptic currents. Simultaneously we utilized functional near-infrared spectroscopy (NIRS) to continuously monitor hemoglobin concentration changes in superficial cortical layers. The multi-modal signal from 18 healthy adult subjects allowed us to investigate the association of neural activity in a range of frequencies over the whole-head to local changes in hemoglobin concentrations. Our results verified the delayed alpha (8-16Hz) modulation of hemodynamics in posterior areas known from the literature. They also indicated strong beta (16-32Hz) modulation of hemodynamics. Analysis revealed, however, that beta modulation was likely generated by the alpha-beta coupling in EEG. Signals from the inferior electrode sites were dominated by scalp muscle related activity. Our study aimed to characterize the phenomena related to neurovascular coupling observable by practical, cost-effective, and non-invasive multi-modal techniques. PMID- 27236082 TI - Gender transition affects neural correlates of empathy: A resting state functional connectivity study with ultra high-field 7T MR imaging. AB - Sex-steroid hormones have repeatedly been shown to influence empathy, which is in turn reflected in resting state functional connectivity (rsFC). Cross-sex hormone treatment in transgender individuals provides the opportunity to examine changes to rsFC over gender transition. We aimed to investigate whether sex-steroid hormones influence rsFC patterns related to unique aspects of empathy, namely emotion recognition and description as well as emotional contagion. RsFC data was acquired with 7Tesla magnetic resonance imaging in 24 male-to-female (MtF) and 33 female-to-male (FtM) transgender individuals before treatment, in addition to 33 male- and 44 female controls. Of the transgender participants, 15 MtF and 20 FtM were additionally assessed after 4 weeks and 4 months of treatment. Empathy scores were acquired at the same time-points. MtF differed at baseline from all other groups and assimilated over the course of gender transition in a rsFC network around the supramarginal gyrus, a region central to interpersonal emotion processing. While changes to sex-steroid hormones did not correlate with rsFC in this network, a sex hormone independent association between empathy scores and rsFC was found. Our results underline that 1) MtF transgender persons demonstrate unique rsFC patterns in a network related to empathy and 2) changes within this network over gender transition are likely related to changes in emotion recognition, -description, and -contagion, and are sex-steroid hormone independent. PMID- 27236084 TI - Neural representation of object orientation: A dissociation between MVPA and Repetition Suppression. AB - How is object orientation represented in the brain? Behavioral error patterns reveal systematic tendencies to confuse certain orientations with one another. Using fMRI, we asked whether more confusable orientations are represented more similarly in object selective cortex (LOC). We compared two widely-used measures of neural similarity: multi-voxel pattern similarity (MVP-similarity) and Repetition Suppression. In LO, we found that multi-voxel pattern similarity was predicted by the confusability of two orientations. By contrast, Repetition Suppression effects in LO were unrelated to the confusability of orientations. To account for these differences between MVP-similarity and Repetition Suppression, we propose that MVP-similarity reflects the topographical distribution of neural populations, whereas Repetition Suppression depends on repeated activation of particular groups of neurons. This hypothesis leads to a unified interpretation of our results and may explain other dissociations between MVPA and Repetition Suppression observed in the literature. PMID- 27236083 TI - Exploring the role of the posterior middle temporal gyrus in semantic cognition: Integration of anterior temporal lobe with executive processes. AB - Making sense of the world around us depends upon selectively retrieving information relevant to our current goal or context. However, it is unclear whether selective semantic retrieval relies exclusively on general control mechanisms recruited in demanding non-semantic tasks, or instead on systems specialised for the control of meaning. One hypothesis is that the left posterior middle temporal gyrus (pMTG) is important in the controlled retrieval of semantic (not non-semantic) information; however this view remains controversial since a parallel literature links this site to event and relational semantics. In a functional neuroimaging study, we demonstrated that an area of pMTG implicated in semantic control by a recent meta-analysis was activated in a conjunction of (i) semantic association over size judgements and (ii) action over colour feature matching. Under these circumstances the same region showed functional coupling with the inferior frontal gyrus - another crucial site for semantic control. Structural and functional connectivity analyses demonstrated that this site is at the nexus of networks recruited in automatic semantic processing (the default mode network) and executively demanding tasks (the multiple-demand network). Moreover, in both task and task-free contexts, pMTG exhibited functional properties that were more similar to ventral parts of inferior frontal cortex, implicated in controlled semantic retrieval, than more dorsal inferior frontal sulcus, implicated in domain-general control. Finally, the pMTG region was functionally correlated at rest with other regions implicated in control demanding semantic tasks, including inferior frontal gyrus and intraparietal sulcus. We suggest that pMTG may play a crucial role within a large-scale network that allows the integration of automatic retrieval in the default mode network with executively-demanding goal-oriented cognition, and that this could support our ability to understand actions and non-dominant semantic associations, allowing semantic retrieval to be 'shaped' to suit a task or context. PMID- 27236085 TI - Improved spatial accuracy of functional maps in the rat olfactory bulb using supervised machine learning approach. AB - Functional MRI (fMRI) is a popular and important tool for noninvasive mapping of neural activity. As fMRI measures the hemodynamic response, the resulting activation maps do not perfectly reflect the underlying neural activity. The purpose of this work was to design a data-driven model to improve the spatial accuracy of fMRI maps in the rat olfactory bulb. This system is an ideal choice for this investigation since the bulb circuit is well characterized, allowing for an accurate definition of activity patterns in order to train the model. We generated models for both cerebral blood volume weighted (CBVw) and blood oxygen level dependent (BOLD) fMRI data. The results indicate that the spatial accuracy of the activation maps is either significantly improved or at worst not significantly different when using the learned models compared to a conventional general linear model approach, particularly for BOLD images and activity patterns involving deep layers of the bulb. Furthermore, the activation maps computed by CBVw and BOLD data show increased agreement when using the learned models, lending more confidence to their accuracy. The models presented here could have an immediate impact on studies of the olfactory bulb, but perhaps more importantly, demonstrate the potential for similar flexible, data-driven models to improve the quality of activation maps calculated using fMRI data. PMID- 27236086 TI - Direct measurement of actual levels of nitric oxide (NO) in cell culture conditions using soluble NO donors. AB - Applying soluble nitric oxide (NO) donors is the most widely used method to expose cells of interest to exogenous NO. Because of the complex equilibria that exist between components in culture media, the donor compound and NO itself, it is very challenging to predict the dose and duration of NO cells actually experience. To determine the actual level of NO experienced by cells exposed to soluble NO donors, we developed the CellNO Trap, a device that allows continuous, real-time monitoring of the level of NO adherent cells produce and/or experience in culture without the need to alter cell culturing procedures. Herein, we directly measured the level of NO that cells grown in the CellNO Trap experienced when soluble NO donors were added to solutions in culture wells and we characterized environmental conditions that effected the level of NO in in vitro culture conditions. Specifically, the dose and duration of NO generated by the soluble donors S-nitroso-N-acetylpenicillamine (SNAP), S-nitrosoglutathione (GSNO), S-nitrosocysteine (CysNO) and the diazeniumdiolate diethyltriamine (DETA/NO) were investigated in both phosphate buffered saline (PBS) and cell culture media. Other factors that were studied that potentially affect the ultimate NO level achieved with these donors included pH, presence of transition metals (ion species), redox level, presence of free thiol and relative volume of media. Then murine smooth muscle cell (MOVAS) with different NO donors but with the same effective concentration of available NO were examined and it was demonstrated that the cell proliferation ratio observed does not correlate with the half-lives of NO donors characterized in PBS, but does correlate well with the real-time NO profiles measured under the actual culture conditions. This data demonstrates the dynamic characteristic of the NO and NO donor in different biological systems and clearly illustrates the importance of tracking individual NO profiles under the actual biological conditions. PMID- 27236087 TI - Contextual predictability enhances reading performance in patients with schizophrenia. AB - In the present work we analyzed fixation duration in 40 healthy individuals and 18 patients with chronic, stable SZ during reading of regular sentences and proverbs. While they read, their eye movements were recorded. We used lineal mixed models to analyze fixation durations. The predictability of words N-1, N, and N+1 exerted a strong influence on controls and SZ patients. The influence of the predictabilities of preceding, current, and upcoming words on SZ was clearly reduced for proverbs in comparison to regular sentences. Both controls and SZ readers were able to use highly predictable fixated words for an easier reading. Our results suggest that SZ readers might compensate attentional and working memory deficiencies by using stored information of familiar texts for enhancing their reading performance. The predictabilities of words in proverbs serve as task-appropriate cues that are used by SZ readers. To the best of our knowledge, this is the first study using eyetracking for measuring how patients with SZ process well-defined words embedded in regular sentences and proverbs. Evaluation of the resulting changes in fixation durations might provide a useful tool for understanding how SZ patients could enhance their reading performance. PMID- 27236088 TI - Complete Immediate Paraplegia Reversal after Performing Aorto-Lumbar Bypass on the Patient who Underwent Aortoiliac Reconstruction. AB - Although both internal iliac arteries were saved during operation, the patient developed paraplegia immediately after aortoiliac reconstruction due to the spinal cord ischemia. We report a successfully treated immediate postoperative paraplegia by performing second operation and creating bypass from the bifurcated Dacron graft to the previously detected nonpaired huge lumbar artery. PMID- 27236089 TI - Endovascular Repair of Ruptured Abdominal Aortic Aneurysm Is Associated with Lower Incidence of Post-operative Acute Renal Failure. AB - BACKGROUND: Acute renal failure (ARF) after surgical treatment of ruptured abdominal aortic aneurysm (AAA) is an independent predictor of post-operative mortality. Open repair for ruptured AAA has been the gold standard treatment; however, there has been a recent trend in increased utilization of endovascular repair (EVAR) for treatment of ruptured AAA. The purpose of this study was to retrospectively review and compare the incidence of ARF among patients treated with open versus endovascular repair of ruptured AAA. METHODS: American College of Surgeons National Surgical Quality Improvement Program database was searched for surgeries performed for AAA during 2005-2010. Patients' demographics and co morbidities (diabetes mellitus, hypertension, chronic obstructive pulmonary disease, congestive heart failure, myocardial infarction, peripheral arterial disease) were collected. Incidence of ARF after surgery was reviewed. We also collected American Society for Anesthesiologists scores, operating times, functional status, post-operative complications, and mortality. RESULTS: Of total 2179 operations for ruptured AAA, incidence of mortality within first 30 days after operation was 17% after EVAR for ruptured AAA and 33.2% after open repair of ruptured AAA. Incidence of ARF was 6.9% after EVAR for ruptured AAA and 13.5% after open repair of ruptured AAA. Odds ratio for mortality after open repair was 1.94 (confidence interval [CI] 1.51-2.49) when compared with EVAR (P < 0.001), and odds ratio for developing ARF after EVAR was 1.62 (CI 1.14-2.29) as compared with open AAA repair (P < 0.05) in multivariable logistic regression models. Open repair of ruptured AAA and totally dependent functional status were associated with post-operative mortality and ARF. CONCLUSIONS: Incidence of mortality and post-operative ARF for ruptured AAA is significantly higher when treated with open repair, as compared to EVAR. Totally dependent functional status was associated with post-operative mortality and ARF. PMID- 27236090 TI - Relationships between 2-Year Survival, Costs, and Outcomes following Carotid Endarterectomy in Asymptomatic Patients in the Vascular Quality Initiative. AB - BACKGROUND: Carotid endarterectomy (CEA) for asymptomatic patients with limited life expectancy may not be beneficial or cost-effective. The purpose of this study was to examine relationships among survival, outcomes, and costs within 2 years following CEA among asymptomatic patients. METHODS: Prospectively collected data from 3097 patients undergoing CEA for asymptomatic disease from Vascular Quality Initiative VQI registry were linked to Medicare. Models were used to identify predictors of 2-year mortality following CEA. Patients were classified as low, medium, or high risk of death based on this model. Next, we examined costs related to cerebrovascular care, occurrence of stroke, rehospitalization, and reintervention within 2 years following CEA across risk strata. RESULTS: Overall, 2-year mortality was 6.7%. Age, diabetes, smoking, congestive heart failure (CHF), chronic obstructive pulmonary disease, renal insufficiency, absence of statin use, and contralateral internal carotid artery (ICA) stenosis were independently associated with a higher risk of death following CEA. In hospital costs averaged $7500 among patients defined as low risk for death, and exceeded $10,800 among high risk patients. Although long-term costs related to cerebrovascular disease were 2 times higher in patients deemed high risk for death compared with low risk patents ($17,800 vs. $8800, P = 0.001), high risk of death was not independently associated with a high probability of high cost. Predictors of high cost at 2 years were severe contralateral ICA stenosis, dialysis dependence, and American Society for Anesthesia Class 4. Both statin use and CHF were protective of high cost. CONCLUSIONS: Greater than 90% of patients undergoing CEA live long enough to realize the benefits of their procedure. Moreover, the long-term costs are supported by the effectiveness of this procedure at all levels of patient risk. PMID- 27236091 TI - Sternum-Sparing Hybrid Repair of a Symptomatic Innominate Artery Aneurysm in a Frail Patient with Bovine Aortic Arch. AB - We present the case of a 65-year-old man with a bovine aortic arch variation, who presented a symptomatic aneurysm of the innominate artery. Standard open repair was contraindicated and an hybrid approach was performed, regarding general status (Organisation Mondiale de la Sante (OMS) Performance Status score 3 and American Society of Anesthesiologists Physical Status classification system score 3). Right common carotid artery and right subclavian artery were revascularized surgically from the left common carotid artery. Proximal aneurysm exclusion was performed with a vascular plug. Follow-up computed tomography angiography confirmed the exclusion of the innominate artery aneurysm. Vascular plugs can be used safely through a sternum-sparing hybrid approach to treat symptomatic innominate artery aneurysms in frail patients. PMID- 27236092 TI - The Effect of Age on Post-EVAR Outcomes. AB - BACKGROUND: This study aims to investigate the relationship of increased age on post-endovascular aneurysm repair (EVAR) outcomes. METHODS: A total of 1,380 of 1,853 consecutive patients who underwent EVAR between 1992 and 2012 met our inclusion criteria and were reviewed. Five hundred of the 1,380 patients had computed tomography angiography data to characterize anatomic differences. Age <70 years and >=70 years were compared. RESULTS: Older patients had higher Glasgow Aneurysm Scores (85.8 +/- 8.2 vs. 70.9 +/- 8.5, P < 0.0001), indicating higher preoperative risk in patients >=70 years of age. Patients >=70 years had increased tortuosity indices, angulation, and iliac calcification. Older patients required higher transfusion volumes (101.1 +/- 266.8 vs. 57.6 +/- 202.6 mL, P = 0.018). Overall comorbidities, blood loss, and procedure times were similar between groups. The older cohort had higher major and minor perioperative complication rates (10.7% vs. 7.0%, P = 0.007), with a trend toward more major perioperative complications (7.5% vs. 4.8%, P = 0.077). AAA-related perioperative mortality, all-cause perioperative mortality, and intraoperative complication rates were similar between the 2 cohorts. Patients <70 years were more likely to be discharged on postoperative day 1 (76.1% vs. 67.6%, P < 0.0001). Older patients were more likely to develop endoleaks (21.9% vs. 12.8%, P < 0.0001) and required more reinterventions (7.2% vs. 4.7%, P = 0.003). Freedom from AAA related mortality was similar between the 2 groups (P = nonsignificant); however, patients <70 years had improved overall survival (P < 0.001). CONCLUSIONS: Older age is associated with more complex aneurysm morphology. These features likely resulted in more endoleaks, reinterventions, and complications observed in patients >=70 years following EVAR. PMID- 27236093 TI - Endovascular Repair of an Iliac Ureteroarterial Fistula with Late Stent Thrombosis and Migration into the Bladder. AB - BACKGROUND: Ureteroarterial fistulas are rare. We describe a case of ureteral arterial fistulas (UAF) repaired with an endovascular stent graft and examine late complications associated with the procedure. CASE REPORT: A 37-year-old woman with a history of complicated locally invasive cervical cancer treated with chemoradiation presented initially with right leg rest pain and chronic intermittent gross hematuria. She was found to have an ureteroarterial fistula and underwent successful endovascular exclusion with a covered stent with resolution of her symptoms. She returned 1 year later with stent-graft thrombosis manifesting as lower extremity rest pain, requiring a femoral-femoral bypass. She then returned 6 months later with imaging evidence of extravascular migration of the stent graft into the bladder. Because of a poor prognosis of recurrent gynecologic cancer, extraction was not attempted, and she underwent complete urinary diversion. CONCLUSIONS: UAFs are a rare occurrence but may be treated successfully with endovascular stent grafting. Despite technical success, late complications such as stent thrombosis may occur even with anticoagulation. Extravascular stent migration may occur in the presence of a chronically dilated ureter. PMID- 27236094 TI - Ruptured Mycotic Abdominal Aortic Pseudoaneurysm in a Patient on Hemodialysis Complicated with Oxacillin-Resistant Staphylococcus aureus Bacteremia. AB - Despite a high incidence of Staphylococcus aureus bacteremia in hemodialysis patients, bacterial invasion with aortic wall infection resulting in a pseudoaneurysm rarely occurs. This report describes a case of mycotic pseudoaneurysm of the abdominal aorta that grew rapidly and ruptured into the distal vena cava causing persistent bacteremia in a patient undergoing hemodialysis complicated with oxacillin-resistant S. aureus bacteremia. PMID- 27236095 TI - Successful Endovascular Repair of a Penetrating Aortic Ulcer in Bacterial Aortitis. AB - Infective aortitis (IA) and penetrating aortic ulcer (PAU) impending for rupture represent 2 hostile life-threatening conditions. Simultaneous presentations of these rare entities can be considered an exception. The pleomorphic clinical presentation and the multifactorial etiology require a multidisciplinary approach to reach a correct diagnosis and an urgent treatment. We report the case of a 65 year-old patient presented with acute abdominal pain and septic shock secondary to a bacterial aortitis and penetrating ulcer of abdominal aorta. Unfit for surgery due to severe comorbidities, he was treated by means of a tubular endograft and long-term antibiotic therapy. A rapid improvement of clinical conditions was observed during the subsequent hospital stay. Complete regression of aortic involvement was demonstrated after 1 year. In conclusion, for selected patients affected by IA and PAU an endovascular approach associated to long-term antibiotic therapy may be safe and effective. PMID- 27236096 TI - Retrograde Stent Placement for Symptomatic Spontaneous Isolated Dissection of the Superior Mesenteric Artery. AB - Various treatment options are currently available for spontaneous isolated dissection of the superior mesenteric artery (SIDSMA) including conservative management, anticoagulation therapy, endovascular stenting, and surgical repair. We report an experience with retrograde open mesenteric stenting for SIDSMA. A 45 year-old man presented to the emergency department with acute onset of severe abdominal and back pain. Computed tomography angiography revealed a long occlusion of the SMA trunk. Initially, an endovascular solution was attempted, but this was unsuccessful as the guidewire failed to cross the lesion. Four hours after the onset of symptoms, because of aggravation of abdominal pain, the patient underwent an exploratory laparotomy under general anesthesia. The small intestine looked pale, and the arterial pulsation was not recognized in the mesentery. A 5-cm mesenteric portion of the SMA trunk was exposed. The SIDSMA diagnosis was confirmed after arteriotomy because a freshly formed thrombus and a severely stenosed true lumen (TL) were detected beneath the adventitia. From the proximal stump of the TL, a 6-French sheath introducer was inserted in a retrograde fashion. The occlusion was traversed with a 0.035-in guidewire. After predilatation, self-expandable stents were placed inside the occluded SMA. The patient was discharged from the hospital 3 weeks after the operation. Stent patency has been confirmed for 6 months. Retrograde stenting performed under laparotomy could be a rescue procedure after the failure of percutaneous stenting for SIDSMA. PMID- 27236097 TI - The influence of liposomal formulation on the incorporation and retention of PNA oligomers. AB - Liposomal formulations composed of phospholipids with different unsaturation degrees, head groups and at different cholesterol content have been tested for the encapsulation of Peptide Nucleic Acid (PNA) oligomers. The best loading capability (177MUg, ER%=87.2) was obtained for pure liposomes of phosphatidylglycerol (DOPG) with negatively charged head group. The insertion of a 10-20% of cholesterol in DOPG based liposomes provides a slight decrease (~160MUg) of the PNA loading. On the other hand, the cholesterol addition (20 30%) slows down the PNA's release (~27%) in fetal bovine serum from the liposomal formulation. Based on the encapsulation and the release properties, PEGylated DOPG liposomes with a percentage of cholesterol of 10-20% are the optimal formulation for the loading of PNA-a210. PMID- 27236098 TI - Investigation of human cell response to covalently attached RADA16-I peptide on silicon surfaces. AB - We described a modification of the ionic (RADARADARADARADA)(1) peptide or RADA16 I with 4-azidophenyl isothiocyanate via a specific and gentle reaction. The azidated peptide was covalently immobilized on an alkyne-terminated monolayer on Si(111) via the Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction. Detailed characterization using Impedance spectroscopy (IS), X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared (FTIR) spectroscopy demonstrated high coverage of the RADA 16-I peptide on silicon surfaces. Scanning electron microscopy (SEM) and methyl tetrazole sulfate (MTS) assay were used to characterize the morphology and proliferation ability of human fibroblast cells on surfaces. Cell adhesion assay was performed to examine cell-substrate interactions. Significant differences in fibroblast cell morphology, adhesion, and viability were observed on the RADA16-I peptide modified surfaces compared to the control surfaces. These results may suggest a potential application of RADA16 I peptide modified surfaces in biomedical applications. PMID- 27236099 TI - Ecological momentary assessment and beyond: The rising interest in e-mental health research. PMID- 27236100 TI - Mixed-mode chromatography in pharmaceutical and biopharmaceutical applications. AB - Mixed-mode chromatography (MMC) is a fast growing area in recent years, thanks to the new generation of mixed-mode stationary phases and better understanding of multimode interactions. MMC has superior applications in the separation of compounds that are not retained or not well resolved by typical reversed-phase LC methods, especially for polar and charged molecules. Due to the multiple retention modes that a single MMC column can offer, often MMC provides additional dimension to a separation method by adjusting the mobile phase conditions. Mixed mode media is also an effective way to clean up complex sample matrices for purification purposes or for sensitive detection of trace amounts of analytes. In this article, we discuss mixed-mode stationary phases and separation mechanisms and review recent advances in pharmaceutical and biopharmaceutical applications including the analysis and/or purification of counterions, small molecule drugs, impurities, formulation excipients, peptides and proteins. PMID- 27236101 TI - Near infrared spectroscopy for counterfeit detection using a large database of pharmaceutical tablets. AB - Medicine counterfeiting is one of the current burdens of the pharmaceutical world. Reliable technologies have become available for the chemical analysis of suspect medicines. Near infrared spectroscopy (NIRS) allows for instance fast, specific and non-destructive authentication of pharmaceutical products. In this paper, a NIRS method is presented for the identification of 29 different pharmaceutical product families of tablets, one family containing one or more formulation (s), e.g. different dosages. This selection represents the whole tablet portfolio of our firm. The high number of product families constituted a challenge, given that the measurement of the samples, made on two similar instruments, generated a dataset of 7120 spectra. Several chemometric tools proved efficient for the identification of these medicines. The dataset was first investigated with a Principal Component Analysis (PCA) in order to provide an overview of the distribution of the samples. The K-Nearest Neighbors (KNN), the Support Vector Machines (SVM) and the Discriminant Analysis (DA) supervised classification tools were successfully applied and generated an outstanding classification rate of 100% of correct answer. The methods were then fully validated with an independent set of spectra. The DA was selected as the method for the routine analysis of suspect tablets with the Mahalanobis distance as acceptance criterion for identification. Counterfeits, generics and placebos samples, constituting a second validation set, were tested and rejected by the method. NIRS has thus been demonstrated as an efficient tool for the quick identification of a large dataset of pharmaceutical tablets and the detection of counterfeit medicines. PMID- 27236102 TI - Next-Generation Proficiency Testing. AB - This commentary highlights the article by Davies et al that demonstrates the feasibility of applying proficiency testing directly to the postsequencing analysis of next-generation sequencing data. PMID- 27236104 TI - The Relentless Rise in the Incidence of Melanoma in Susceptible Australians. PMID- 27236103 TI - Myeloid-Derived Suppressor Cells in Psoriasis Are an Expanded Population Exhibiting Diverse T-Cell-Suppressor Mechanisms. AB - Psoriasis vulgaris is an inflammatory skin disease caused by hyperactivated T cells regulated by positive and negative mechanisms; although the former have been much studied, the latter have not. We studied the regulatory mechanism mediated by myeloid-derived suppressor cells (MDSCs) and showed that MDSCs expanded in melanoma patients express dendritic cell-associated heparan sulfate proteoglycan-dependent integrin ligand, a critical mediator of T-cell suppressor function. We examined expansion of DC-HIL(+) MDSCs in psoriasis and characterized their functional properties. Frequency of DC-HIL(+) monocytic MDSCs (CD14(+)HLA DR(no/low)) in blood and skin was markedly increased in psoriatic patients versus healthy control subjects, but there was no statistically significant relationship with disease severity (based on Psoriasis Area and Severity Index score). Blood DC-HIL(+) MDSC levels in untreated patients were significantly higher than in treated patients. Compared with melanoma-derived MDSCs, psoriatic MDSCs exhibited significantly reduced suppressor function and were less dependent on DC-HIL, but they were capable of inhibiting proliferation and IFN-gamma and IL-17 responses of autologous T cells. Psoriatic MDSCs were functionally diverse among patients in their ability to suppress allogeneic T cells and in the use of either IL 17/arginase I or IFN-gamma/inducible nitric oxide synthase axis as suppressor mechanisms. Thus, DC-HIL(+) MDSCs are expanded in psoriasis patients, and their mechanistic heterogeneity and relative functional deficiency may contribute to the development of psoriasis. PMID- 27236106 TI - Response to Czarnecki. PMID- 27236105 TI - RASopathy Gene Mutations in Melanoma. AB - Next-generation sequencing of melanomas has unraveled critical driver genes and genomic abnormalities, mostly defined as occurring at high frequency. In addition, less abundant mutations are present that link melanoma to a set of disorders, commonly called RASopathies. These disorders, which include neurofibromatosis and Noonan and Legius syndromes, harbor germline mutations in various RAS/mitogen-activated protein kinase signaling pathway genes. We highlight shared amino acid substitutions between this set of RASopathy mutations and those observed in large-scale melanoma sequencing data, uncovering a significant overlap. We review the evidence that these mutations activate the RAS/mitogen-activated protein kinase pathway in melanoma and are involved in melanomagenesis. Furthermore, we discuss the observations that two or more RASopathy mutations often co-occur in melanoma and may act synergistically on activating the pathway. PMID- 27236107 TI - The suppressor of cytokine signaling SOCS1 promotes apoptosis of intestinal epithelial cells via p53 signaling in Crohn's disease. AB - The suppressor of cytokine signaling SOCS1 is a member of the cytokine signaling pathway inhibitor family, which is induced by the IFN-gamma induced JAK signaling pathway. The expression of SOCS1 has been found to increase in Crohn's disease (CD) patients, but the role of SOCS1 in intestinal epithelium is unclear. This study was designed to investigate whether SOCS1 has a role in the death of intestinal epithelial cells and intestinal injury. The results showed that the expression of SOCS1 increased in CD patients, and the expression of SOCS1, p-p53 and PUMA increased in the mouse TNBS induced colitis model. Using IFN-gamma treated HT-29 cells as an apoptotic model of intestinal epithelial cells in vitro, we confirmed that SOCS1 promoted apoptosis of intestinal epithelial cells by activating p53. In HT-29 cells which were treated with IFN-gamma, the interaction between p53 and SOCS1 and phosphorylation of p53 were significantly higher than untreated cells. When knocking SOCS1 down by using SOCS1 siRNA, phosphorylation of p53 and apoptosis of intestinal epithelial cells which was induced by IFN-gamma were significantly inhibited. In summary, our findings suggest that SOCS1 may promote apoptosis of intestinal epithelial cells at least partly through mediating p53 signaling. PMID- 27236108 TI - Effects of intensive glucose lowering in treatment of type 2 diabetes mellitus on cardiovascular outcomes: A meta-analysis of data from 58,160 patients in 13 randomized controlled trials. AB - BACKGROUND: Previous trials indicated that intensive glucose lowering in treatment of patients with type 2 diabetes mellitus (T2DM) was associated with a higher incidence of mortality. We therefore conducted a meta-analysis to evaluate the benefits and harms of intensive glucose lowering therapy in treatment of T2DM patients on major cardiovascular outcomes. METHODS: Randomized controlled trials (RCTs) were obtained from searches of PubMed, EmBase, and the Cochrane Library electronic databases until Feb. 2016. Relative risk (RR) was used to measure the treatment effect by random-effect model. Meta-regression, sensitivity analyses, subgroup analyses, and publication biases were also conducted. RESULTS: Thirteen RCTs were included with 58,160 T2DM patients and reported 5719 major cardiovascular events (MACEs), 6569 deaths, 2057 cardiac death cases, 3201 myocardial infarction (MI) cases, 1835 stroke cases, and 1778 congestive heart failure cases. Intensive glucose lowering therapy significantly reduced risk of MACEs (RR: 0.92; 95%CI: 0.85-1.00; P=0.042), and MI (RR: 0.90; 95%CI: 0.82-0.98; P=0.020) compared with conventional glucose control therapy. Furthermore, intensive glucose lowering therapy has no significant effect on the incidence of total mortality (RR: 0.98; 95%CI: 0.91-1.07; P=0.693), cardiac death (RR: 1.00; 95%CI: 0.87-1.04; P=0.999), stroke (RR: 0.94; 95%CI: 0.84-1.06; P=0.333), and congestive heart failure (RR: 1.19; 95%CI: 0.96-1.48; P=0.108). CONCLUSION: T2DM patients who received intensive glucose lowering therapy are associated with a reduced risk of MACEs and MI, whereas it has no significant effect on the risk of total mortality, cardiac death, stroke, and congestive heart failure. These effects might differ when stratified by baseline characteristics in T2DM patients. PMID- 27236109 TI - The utility of a CHA2DS2-VASc score in predicting the presence of significant stenosis and occlusion of veins with indwelling endocardial leads. AB - BACKGROUND: Currently, there are no studies in which a CHA2DS2-VASc score has been used to predict the risk of venous stenosis and occlusion (VSO) in patients after the implantation of a cardiac implantable electronic device (CIED). METHODS: The material consists of the records of 223 consecutive patients qualified for transvenous lead extraction, generator change and system revisions or upgrades in whom we assessed the utility of a CHA2DS2-VASc score in the prediction of VSO. The CHA2DS2-VASc score was calculated retrospectively based on the clinical data. The whole study population was divided into two groups, based on the presence (group I) or absence (group II) of VSO. Using the receiver operating characteristic (ROC) curve, we identified the optimal cut-off point for the CHA2DS2-VASc score that allowed the prediction of the absence of VSO. RESULTS: The venography was performed in 223 consecutive patients aged on average 68.2years (25.7-95.3), 77 females (34.5%). The presence of VSO was detected in 79 (35.4%) patients aged 68.3+/-14.1years, 30 female (40%) patients-group I. The level of the cut-off point for the CHA2DS2-VASc score that allowed the prediction of the absence of VSO was 3.0. CONCLUSION: In the whole population the incidence of VSO amounted to 35.4%. The result of the CHA2DS2-VASc score was a destimulant of VSO occurrence and was characterized by moderate sensitivity (73.4%) and specificity (42.4%) in predicting the absence of VSO. The most significant factor, which prevented VSO development was diabetes. PMID- 27236110 TI - Effects of DPP-4 inhibitors on cardiovascular outcomes in patients with type 2 diabetes and end-stage renal disease. AB - BACKGROUND: Recent clinical trials have evaluated the cardiovascular outcomes of dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes mellitus (T2DM), but those with end-stage renal disease (ESRD) were ineligible for participation in these trials. We aimed to characterize the impact of DPP-4 inhibitors on major adverse cardiovascular events (MACEs) in patients with T2DM and ESRD undergoing chronic dialysis. METHODS: This nationwide observational study utilized data from 3556 patients aged >=20years with T2DM and ESRD who initiated treatment with DPP-4 inhibitors between 1 March 2009 and 31 June 2013, retrieved from Taiwan's National Health Insurance Research Database. Each DPP-4 inhibitor user was matched to a non-user control subject using propensity scores. The primary outcomes were all-cause mortality and MACEs (ischemic stroke and myocardial infarction). The secondary outcomes were hospitalization for heart failure and hypoglycemia. All subjects were followed until death or 31 December 2013. RESULTS: Compared with non-users, DPP-4 inhibitor users had lower risks of all-cause mortality (hazard ratio [HR] 0.43, 95% confidence interval [CI] 0.39 0.47), MACEs (HR 0.76, 95% CI 0.65-0.90), and ischemic stroke (HR 0.77, 95% CI 0.61-0.97); the risks of myocardial infarction and hospitalization for heart failure and hypoglycemia did not differ. This treatment effect remained consistent in subgroup analyses according to age, sex, comorbidities, dialysis modality, and insulin use. CONCLUSIONS: In this nationwide ESRD cohort, DPP-4 inhibitor use was associated with reduced risks of all-cause mortality and ischemic stroke. PMID- 27236111 TI - Digoxin and short term mortality after acute STEMI: Results from the MAGIC trial. AB - BACKGROUND: The safety of digoxin has been a subject of debate for decades, most recently among patients with atrial fibrillation (AF). Digoxin has been used during the acute phase of ST elevation myocardial infarction (STEMI) complicated with AF or heart failure. Data about digoxin in this setting are scarce. HYPOTHESIS: We hypothesize that digoxin maybe associated with increased mortality when used during the acute phase of ST segment myocardial infarction. METHODS: We investigated the association between digoxin and mortality in patients enrolled in the MAGnesium In Coronaries (MAGIC) study, which evaluated the efficacy of early magnesium administration in STEMI. Multiple Cox proportional hazards models were examined to assess the aforementioned association after correction for clinical characteristics and comorbidities. RESULTS: After excluding 639 (10.3%) patients for missing data, we analyzed the remaining 5574 patients. There were 852 (15.3%) deaths during the one month follow-up and 170 (3.0%) patients on digoxin concomitantly, among which 42 patients (24.7%) died. There was a statistically significant association between digoxin and increased mortality in the unadjusted statistical analysis; however, this association disappeared after correction for clinical characteristics and comorbidities in the primary multivariable analysis (estimated hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.62-1.19, p=0.372) and in three additional multivariable analyses. CONCLUSION: Digoxin use as a new or preexisting medication during the acute phase of STEMI in the MAGIC trial was not associated with a significant increase in mortality after correcting for clinical characteristics and comorbidities. PMID- 27236112 TI - Circulating regulatory T cells in patients with aortic valve stenosis: Association with disease progression and aortic valve intervention. AB - BACKGROUND: Severe aortic valve stenosis (AS) accounts for considerable morbidity and death, especially in older patients. There is increasing evidence to suggest a role for immune modulating cells in aortic valve (AV) degeneration. Regulatory T cells (Tregs) tune down inflammation. We aimed to study the levels of circulating Tregs in patients with AS and to assess their association with disease progression. METHOD AND RESULTS: The number of Tregs (CD4+CD25+Foxp3+) was determined by flow cytometry in 229 patients with AS and a control group of 69 patients. Tregs were significantly higher in patients with AS compared to the control group (1.64+/- .61% vs 1.13+/-0.97%, p=0.04). In the logistic regression analysis, adjusted for baseline characteristics, only the hemoglobin level and Treg percent correlated with the presence of AS (OR 0.642 95% CI 0.512-0.805, p<0.001 and OR 1.411, 95% CI 1.080-1.844, p=0.011, respectively). One hundred patients underwent 2 echocardiographic studies during follow-up. The median decrease in AV area (AVA) was 0.1cm(2)/year. A borderline association was observed between Tregs and AVA progression (r=0.19, p=0.054). In a subgroup of 68 patients with severe AS, the association between Tregs and AVA progression was significant (r=0.374, p=0.0017). In addition, a drop in Treg levels was observed 3-6months after AV-intervention (1.86+/-1.6% vs 1.04+/-1.8%, p=0.0005). CONCLUSIONS: Circulating Tregs are elevated in patients with AS. The levels of Tregs are higher in patients with severe AS and accelerated progression of valve narrowing. These results may help to identify AS patients with accelerated disease progression and possibly in need for earlier intervention. PMID- 27236113 TI - Expression of functional tissue factor in activated T-lymphocytes in vitro and in vivo: A possible contribution of immunity to thrombosis? AB - OBJECTIVE: T-lymphocyte activation plays an important role in the pathophysiology of acute coronary syndromes (ACS). Plaques from ACS patients show a selective oligoclonal expansion of T-cells, indicating a specific, antigen-driven recruitment of T-lymphocytes within the unstable lesions. At present, however, it is not known whether T-cells may contribute directly to thrombosis by expressing functional tissue factor (TF). Accordingly, the aim of the present study was to investigate whether T-cells are able to express functional TF in their activated status. METHODS: In vitro, CD3(+)-cells, isolated from buffy coats, were stimulated with anti-CD3/CD28 beads, IL-6, TNF-alpha, IL-17, INF-gamma or PMA/ionomycin. Following stimulation, TF expression on cell-surface, at gene and protein levels, as well as its procoagulant activity in whole cells and microparticles was measured. In vivo, TF expression was evaluated in CD3(+)-cells isolated from the aorta and the coronary sinus of ACS-NSTEMI and stable coronary artery disease (SCAD) patients. The presence of CD3(+)-TF(+)cells was also evaluated by immunohistochemistry in thrombi aspirated from ACS-STEMI patients. RESULTS: PMA/ionomycin and IL-17 plus INF-gamma stimulation resulted in a significant TF increase at gene and protein levels as well as at cell-surface expression. This was accompanied by a parallel increase in FXa generation, both in whole cells and in microparticles, indicating that the induced membrane-bound TF was active. Furthermore, transcardiac TF gradient was significantly higher in CD3(+)-cells obtained from ACS-patients compared to SCAD-patients. Interestingly, thrombi from ACS-STEMI patients resulted enriched in CD3(+)-cells, most of them expressing TF. CONCLUSIONS: Our data demonstrate that activated T-lymphocytes in vitro express functional TF on their membranes, suggesting a direct pathophysiological role of these cells in the thrombotic process; this hypothesis is further supported by the observations in vivo that CD3(+)-cells from coronary circulation of ACS-NSTEMI patients show increased TF levels and that coronary thrombi from ACS-STEMI patients are enriched in CD3(+)-cells expressing TF. PMID- 27236115 TI - Influence of radial anatomy on pain experienced during transradial coronary angiography. AB - BACKGROUND: The transradial route has become the primary approach for coronary angiography with the presence of radial artery anomalies found to be 10-20%. There has been limited study on the influence of these anomalies on procedural pain. Our aims were to determine local prevalence of the high radial origin (HRO) anatomical variant; to investigate factors influencing transradial procedural pain; and to determine if HRO specifically was associated with increased pain. METHODS: Radial artery anatomy was characterized by arteriography in sequential patients undergoing angiography. Patients were asked to mark their perceived procedural pain on a visual analog scale, which was converted to a pain score. RESULTS: 382 patients were enrolled, 5 were excluded. There were 259 males (68.7%) and 118 females (31.3%). HRO was present in 51 patients (13.5%). Overall mean pain score was 2.6 (SD 2.5). HRO was associated with a higher mean pain score than normal anatomy (3.3 (SD 2.9) vs. 2.4 (SD 2.4) p=0.027). HRO was not associated with increased procedural failure, screening time or procedure time. When pain score was dichotomized into mild pain (<4.0) and moderate-to-severe pain (>=4.0), HRO was associated with almost double the frequency of moderate-to severe pain (37.2% vs. 21.1%, p=0.012). Using a logistic regression model, only female gender, younger age and HRO remained significant predictors of moderate-to severe pain. CONCLUSIONS: There was significantly increased pain in patients with HRO without increased procedure/screening time or procedural failure. Female gender and younger age were also found to be significant predictors of increased pain. PMID- 27236114 TI - Provoking conditions, management and outcomes of type 2 myocardial infarction and myocardial necrosis. AB - BACKGROUND: Type 2 myocardial infarction (MI) is defined as myocardial necrosis (myonecrosis) due to an imbalance in supply and demand with clinical evidence of ischemia. Some clinical scenarios of supply-demand mismatch predispose to myonecrosis but limit the identification of symptoms and ECG changes referable to ischemia; therefore, the MI definition may not be met. Factors that predispose to type 2 MI and myonecrosis without definite MI, approaches to treatment, and outcomes remain poorly characterized. METHODS: Patients admitted to an academic medical center with an ICD-9 diagnosis of secondary myocardial ischemia or non primary diagnosis of non-ST-elevation MI were retrospectively reviewed. Cases were classified as either MI (n=255) or myonecrosis without definite MI (n=220) based on reported symptoms, ischemic ECG changes, and new wall motion abnormalities. RESULTS: Conditions associated with type 2 MI or myonecrosis included non-cardiac surgery (38%), anemia or bleeding requiring transfusion (32%), sepsis (31%), tachyarrhythmia (23%), hypotension (22%), respiratory failure (23%), and severe hypertension (8%). Inpatient mortality was 5%, with no difference between patients with MI and those with myonecrosis (6% vs. 5%, p=0.41). At discharge, only 43% of patients received aspirin and statin therapy. CONCLUSIONS: Type 2 MI and myonecrosis occur frequently in the setting of supply demand mismatch due to non-cardiac surgery, sepsis, or anemia. Myonecrosis without definite MI is associated with similar in-hospital mortality as type 2 MI; both groups warrant further workup for cardiovascular disease. Antiplatelet and statin prescriptions were infrequent at discharge, reflecting physician uncertainty about the role of secondary prevention in these patients. PMID- 27236116 TI - Imaging right ventricular function to predict outcome in pulmonary arterial hypertension. AB - BACKGROUND: Right ventricular (RV) function is a major determinant of outcome in pulmonary arterial hypertension (PAH). However, uncertainty persists about the optimal method of evaluation. METHODS: We measured RV end-systolic and end diastolic volumes (ESV and EDV) using cardiac magnetic resonance imaging and RV pressures during right heart catheterization in 140 incident PAH patients and 22 controls. A maximum RV pressure (Pmax) was calculated from the nonlinear extrapolations of early and late systolic portions of the RV pressure curve. The gold standard measure of RV function adaptation to afterload, or RV-arterial coupling (Ees/Ea) was estimated by the stroke volume (SV)/ESV ratio (volume method) or as Pmax/mean pulmonary artery pressure (mPAP) minus 1 (pressure method) (n=84). RV function was also assessed by ejection fraction (EF), right atrial pressure (RAP) and SV. RESULTS: Higher Ea and RAP, and lower compliance, SV and EF predicted outcome at univariate analysis. Ees/Ea estimated by the pressure method did not predict outcome but Ees/Ea estimated by the volume method (SV/ESV) did. At multivariate analysis, only SV/ESV and EF were independent predictors of outcome. Survival was poorer in patients with a fall in EF or SV/ESV during follow-up (n=44, p=0.008). CONCLUSION: RV function to predict outcome in PAH is best evaluated by imaging derived SV/ESV or EF. In this study, there was no added value of invasive measurements or simplified pressure-derived estimates of RV-arterial coupling. PMID- 27236117 TI - Mapping clinical journeys of Asian patients presenting to the Emergency Department with syncope: Strict adoption of international guidelines does not reduce hospitalisations. AB - BACKGROUND: Limited data exists about management of syncope in Asia. The American College of Emergency Physicians (ACEP) and European Society of Cardiology (ESC) guidelines have defined the high-risk syncope patient. This study aims to determine the effectiveness of managing syncope in an Asian healthcare system and whether strict adherence of international guidelines would reduce hospitalizations. METHODS: Patients attending the Emergency Department of a Singaporean tertiary hospital with syncope were identified. Clinical journeys of all patients were meticulously mapped by interrogation of a comprehensive electronic medical record system and linkages with national datasets. Primary endpoint was hospitalization. Secondary endpoints were recurrent syncope within 1year and all-cause mortality. Expected admission rates based on application of ACEP/ESC guidelines were calculated. RESULTS: 638 patients (43.8+/-22.4years, 49.0% male) presented with syncope. 48.9% were hospitalized for 2.9+/-3.2days. Yields of common investigations ranged from 0 to 11.5% and no diagnosis was reached in 51.5% of patients. Diuretics use (HR 5.1, p=0.01) and prior hospitalization for syncope (HR 6.9, p<0.01) predicted recurrent syncope. Over 2.8 SD 0.3years of follow-up, 40 deaths occurred. 24 patients who died within 12months of presentation were admitted or had a firm diagnosis upon discharge. Application of guidelines did not significantly reduce hospitalisations, with limited agreement which patients warrant admission. (Actual 376, ACEP 354, ESC 391 admissions, p=NS). CONCLUSIONS: Unstructured management of syncope results in nearly half of patients being admitted and substantial healthcare expenditures, yet with limited diagnostic yield. Strict adoption of ACEP or ESC guidelines does not reduce admissions. PMID- 27236118 TI - Comparison of the risk of de novo cardiovascular disease between hemodialysis and peritoneal dialysis in patients with end-stage renal disease. AB - BACKGROUND: The purpose of the study was to compare the risk of de novo cardiovascular disease (CVD) between hemodialysis (HD) and peritoneal dialysis (PD) in patients with incident end-stage renal disease (ESRD). METHODS: From a Taiwanese universal insurance claims database, we identified 45309 incident ESRD patients without preexisting CVD from 2000 to 2010. Using the propensity score matching method, we included 6516 patients in HD and PD groups, respectively. All patients were followed up until the end of 2011. The Cox proportional hazards regression model was employed to calculate the impact of dialysis modality on the risk of new onset cardiovascular events including ischemic heart disease, and congestive heart failure (CHF). RESULTS: No difference was observed in the overall risk of de novo ischemic heart disease between the propensity score matched HD and PD groups (HD versus PD, adjusted hazard ratio [HR]: 1.03, 95% confidence interval [CI]: 0.86-1.22). However, HD was associated with a higher risk of de novo CHF (adjusted HR: 1.29, 95% CI: 1.13-1.47) than PD was. The risk of de novo CHF was particularly high in the first year under dialysis treatment for propensity score-matched HD patients, compared to PD patients. CONCLUSIONS: No difference was observed in the overall risk of de novo major ischemic heart events between HD and PD patients. However, HD was associated with a higher risk of de novo CHF than PD in the first year under dialysis treatment. PMID- 27236119 TI - The prognostic value of exercise-induced ventricular arrhythmias in patients with and without coronary artery disease: A meta-analysis. AB - BACKGROUND: Significance of exercise-induced ventricular arrhythmias (EIVAs) is controversial. This meta-analysis aimed to determine the prognostic value of EIVAs in patients with and without coronary artery disease (CAD). METHODS: Relevant studies were searched on Pubmed though December, 2015. Pooled odds ratio (OR) of endpoints (all-cause death, cardiac death or cardiac events) for all included studies was calculated at first to explore the significance of EVIAs in unselected population. Then, sensitivity analysis based on CAD status of population was performed to determine ORs of endpoints in CAD population, non-CAD population and mixed population, respectively. RESULTS: A total of 14 studies examining 23,002 patients were included, with 5 studies involved CAD population, 4 involved non-CAD population, and 5 involved mixed population (%CAD ranged from 51.2% to 76.8%). EIVAs in unselected population were associated with a pooled OR of 1.626 (95%CI 1.334 to 1.983, p<0.001) of endpoints when compared with those without EIVAs. Sensitivity analysis further indicated that pooled ORs of endpoints were 1.395 (95%CI 1.061 to 1.833, p=0.017) in CAD population, 1.933 (95%CI 1.567 to 2.384, p<0.001) in non-CAD population, and 1.402 (95%CI 1.198 to 1.640, p<0.001) in mixed population. Heterogeneous among studies was identified. Meta-regression analysis found that study quality, mean follow-up period, percentage of lost, percentage of diabetes were associated with ORs of endpoints. CONCLUSIONS: EIVAs were associated with increased risk of worse outcomes, no matter the patients had CAD or not. However, more studies are required to confirm this finding due to the variation of current evidences. PMID- 27236120 TI - Coronary microvascular dysfunction in patients with cardiac syndrome X: Ongoing debate. PMID- 27236121 TI - Safety and efficacy of oral factor-Xa inhibitors versus Vitamin K antagonist in patients with non-valvular atrial fibrillation: Meta-analysis of phase II and III randomized controlled trials. AB - BACKGROUND: Aim of our study was to assess the safety and efficacy on factor-Xa inhibitors (FXIs) in patients with non-valvular atrial fibrillation (NVAF) as compared to Vitamin K antagonist (VKA). METHODS: Phase II and III randomized controlled trials that reported clinical safety and efficacy of FXI in patients with NVAF were identified from MEDLINE, Embase, and Cochrane Central Register of Controlled Trials through December 10, 2015. The primary safety outcome of our study was composite of stroke and systemic embolic event. Secondary outcomes studied were individual endpoints of primary safety outcome, major bleeding, clinically relevant non-major bleed (CRNMB), and all-cause mortality. RESULTS: We included 11 RCTs with a total of 59,164 participants, of which 34,231 patients received oral FXI and 24,933 patients were on VKA with a mean follow-up of 369days. There was a significant reduction in primary outcome with FXI compared to VKA, 1,112 (3.4%) versus 816 (3.6%) events, respectively (OR 0.82; 95% CI 0.68 0.99). Use of FXI significantly reduced major bleeding events compared to VKA, OR 0.74, 95% CI 0.58-0.96, test for heterogeneity (I(2)=74%). Incidence of CRNMB was not different between FXI and VKA groups, OR 0.84, 95% CI 0.68-1.04. There was a significant reduction in all-cause mortality in FXI group compared to VKA group, OR 0.88, 95% CI 0.83-0.94 with no significant heterogeneity. CONCLUSION: Use of FXI was associated with a significant reduction in major bleeding events and all cause mortality without increased risk of stroke or SEE compared to VKA. PMID- 27236123 TI - The relationship between plasma hyaluronan levels and anthracycline-related cardiotoxicity in breast cancer patients. AB - AIM: Anthracycline-derived antineoplastic agents are used as the main form of treatment in many malignant diseases, including breast cancer and childhood cancers. Cardiotoxicity is one of the most feared life-threatening complications of cancer therapy. In the present study, we aimed to investigate the relationship between plasma hyaluronan (HA) levels and anthracycline-induced cardiotoxicity. MATERIALS AND METHODS: Fifty eight of 73 female patients who were diagnosed with breast cancer and treated with a chemotherapy regimen including anthracycline were enrolled in this study. Anamneses were taken from each patient before and after chemotherapy. Further, physical examinations, electrocardiography, and transthoracic echocardiography were performed, and plasma hyaluronan levels were determined by using ELISA assay for each patient before and after treatment. RESULTS: Following anthracycline-based chemotherapy, the average left ventricular ejection fraction decreased (62.6+/-3.7% vs. 58.6+/-4.4%, p<0.001), and diastolic functions significantly deteriorated (p<0.001). However, troponin and hyaluronan levels significantly increased following chemotherapy [Troponin (ng/ml, mean+/ SD): before 0.01+/-0.002, after 0.037+/-0.02, p<0.001], [Plasma HA (ng/ml, mean+/ SD): before 41.3+/-5.4, after 70+/-8.5, p<0.001]. The increase in troponin values correlated with systolic dysfunction (p=0.002), but did not correlate with diastolic dysfunction (p=0.661). Significant correlations were found between systolic/diastolic dysfunction and plasma HA levels (r=0.417, p=0.001; r=0.339, p=0.009, respectively). CONCLUSIONS: Both systolic and diastolic functions were significantly deteriorated after chemotherapy. In addition, plasma levels of HA and troponin increased after treatment. Further, both systolic and diastolic dysfunctions were found to correlate with serum HA levels. All these data suggest that HA might have a function on anthracycline-induced cardiotoxicity. PMID- 27236122 TI - Screening pulmonary arteriovenous malformations in a large cohort of Spanish patients with hemorrhagic hereditary telangiectasia. AB - BACKGROUND AND OBJECTIVES: Because of the serious nature of potential complications, screening for pulmonary arteriovenous malformations is required in patients with hereditary hemorrhagic telangiectasia. The aim of this study was to evaluate the utility of contrast echocardiography and compare the performance of two contrast agents: agitated saline and Gelofusine. MATERIAL AND METHODS: Two hundred and five patients screened for PAVMs using TTCE and computed tomography (CT) performed with an interval of less than 180days. Contrast echocardiography studies were graded on a 4-point semiquantitative scale based on the amount of microbubbles seen in left heart chambers. RESULTS: Positive TTCE findings were seen in 137 (66.8%) patients, whereas CT confirmed PAVMs in 59 (43.1%). Two of 67 grade 1 patients; 18 of 42 grade 2; 17 of 22 grade 3 and all grade 4 had PAVMs on CT. Embolotherapy was feasible in 38.9% patients in grade 2 and 82.3% and 95.2% in grades 3-4. No patients in grade 1 were embolized. The mean cardiac cycle in which bubbles were first seen in the left heart in patients without and with PAVMs on CT was 6.1 and 3.9 (p<0.0001). Compared to saline, Gelofusine produced an overall increase in grade. CONCLUSIONS: No grade 1 patients had treatable PAVMs. There is a need for improvement in the selection of patients for CT in grade 2, where less than half have PAVMs on CT. The cardiac cycle may help to differentiate between patients with and without PAVMs. Gelofusine was not better than saline for PAVM screening. PMID- 27236124 TI - Clinical utility of natriuretic peptides and troponins in hypertrophic cardiomyopathy. AB - The diagnosis of hypertrophic cardiomyopathy (HCM) is based on clinical, echocardiographic and in some cases genetic findings. However, prognostication remains limited except in the subset of patients with high-risk indicators for sudden cardiac death. Additional methods are needed for risk stratification and to guide clinical management in HCM. We reviewed the available data regarding natriuretic peptides and troponins in HCM. Plasma levels of natriuretic peptides, and to a lesser extent serum levels of troponins, correlate with established disease markers, including left ventricular thickness, symptom status, and left ventricular hemodynamics by Doppler measurements. As a reflection of left ventricular filling pressure, natriuretic peptides may provide an objective measure of the efficacy of a specific therapy. Both natriuretic peptides and troponins predict clinical risk in HCM independently of established risk factors, and their prognostic power is additive. Routine measurement of biomarker levels therefore may be useful in the clinical evaluation and management of patients with HCM. PMID- 27236125 TI - Association of smoking with the risk of incident atrial fibrillation: A meta analysis of prospective studies. AB - BACKGROUND: Several studies have investigated the role of smoking in incident atrial fibrillation (AF) but have reported contradictory results. Identifying the quantitative association between smoking and AF risk is important for AF management and prevention; therefore, we aimed to estimate the association of smoking with incident AF. METHODS: We systematically retrieved relevant studies reporting on the association between smoking and AF using the Cochrane Library, PubMed, and Embase databases. The data were extracted from applicable articles, and we used a random effects model to pool the effect estimates. RESULTS: Sixteen prospective studies with an overall number of 286,217 participants and 11,878 AF cases met the inclusion criteria. A higher prevalence of AF was confirmed among smokers (risk ratio [RR]=1.23, 95% confidence interval [CI] 1.08-1.39; P=0.001). These results were stable in the sensitivity analysis. The pooled RRs showed consistent positive associations in most subgroups. Specifically, 8 articles compared both current smokers (RR=1.39, 95% CI 1.11-1.75) and former smokers (RR=1.16, 95% CI: 1.00-1.36) with never smokers. Four articles compared ever smokers (pooled RR=1.21, 95% CI 0.93-1.57) with never smokers, and 7 articles compared current smokers (pooled RR=1.21, 95% CI 1.03-1.42) with non-current smokers. Additionally, we estimated that 6.7% of the total risk of AF in men and 1.4% of the risk in women were attributable to smoking worldwide. CONCLUSIONS: Based on the published literature, smoking is associated with a modest increased risk of incident AF. Smoking cessation seemed to reduce but not entirely eliminate the excess risk of AF. PMID- 27236126 TI - Kounis syndrome, a coronary hypersensitivity disorder: A rare case of amiodarone induced coronary vasospasm and simultaneous peripheral vasodilation intraoperatively. PMID- 27236127 TI - Introduction: Iron Management in Chronic Kidney Disease. PMID- 27236129 TI - Diagnosis of Iron-Deficiency Anemia in Chronic Kidney Disease. AB - Anemia is a common and clinically important consequence of chronic kidney disease (CKD). It is most commonly a result of decreased erythropoietin production by the kidneys and/or iron deficiency. Deciding on the appropriate treatment for anemia associated with CKD with iron replacement and erythropoietic-stimulating agents requires an ability to accurately diagnose iron-deficiency anemia. However, the diagnosis of iron-deficiency anemia in CKD patients is complicated by the relatively poor predictive ability of easily obtained routine serum iron indices (eg, ferritin and transferrin saturation) and more invasive gold standard measures of iron deficiency (eg, bone marrow iron stores) or erythropoietic response to supplemental iron. In this review, we discuss the diagnostic utility of currently used serum iron indices and emerging alternative markers of iron stores. PMID- 27236128 TI - Iron Balance and the Role of Hepcidin in Chronic Kidney Disease. AB - The hepatic iron-regulatory hormone hepcidin and its receptor, the cellular iron exporter ferroportin, constitute a feedback-regulated mechanism that maintains adequate plasma concentrations of iron-transferrin for erythropoiesis and other functions, ensures sufficient iron stores, and avoids iron toxicity and iron dependent microbial pathogenesis. In chronic kidney disease, inflammation and impaired renal clearance increase plasma hepcidin, inhibiting duodenal iron absorption and sequestering iron in macrophages. These effects of hepcidin can cause systemic iron deficiency, decreased availability of iron for erythropoiesis, and resistance to endogenous and exogenous erythropoietin. Together with impaired renal production of erythropoietin, hepcidin-mediated iron restriction contributes to anemia of chronic kidney disease. PMID- 27236131 TI - Iron Treatment Strategies in Dialysis-Dependent CKD. AB - Iron deficiency is common in patients on chronic dialysis, and most require iron replacement therapy. In addition to absolute iron deficiency, many patients have functional iron deficiency as shown by a suboptimal response to the use of erythropoietin-stimulating agents. Both absolute and functional iron-deficiency anemia have been shown to respond to intravenous (IV) iron replacement. Although parenteral iron is an efficacious method and superior to standard doses of oral iron in patients on hemodialysis, there are ongoing safety concerns about repeated exposure potentially enhancing infection risk and cardiovascular disease. Each IV iron product is composed of an iron core with a carbohydrate shell. The avidity of iron binding and the type of carbohydrate shell play roles in the safe maximal dose and the frequency and severity of acute infusion reactions. All IV iron products are taken up into the reticuloendothelial system where the shell is metabolized and the iron is stored within tissue ferritin or exported to circulating transferrin. IV iron can be given as large intermittent doses (loading therapy) or in smaller doses at frequent intervals (maintenance dosing regimen). Limited trial data and observational data suggest that a maintenance dosing regimen is more efficacious and possibly safer than loading therapy. There is no consensus regarding the preferred method of iron repletion in patients on peritoneal dialysis, although small studies comparing oral and parenteral iron regimens in these patients have shown the latter to be more efficacious. Use of IV iron in virtually all hemodialysis and many peritoneal dialysis patients remains the standard of care. PMID- 27236130 TI - Iron Treatment Strategies in Nondialysis CKD. AB - In contrast to managing patients on hemodialysis in whom iron strategies are more focused on intravenous iron, nondialysis chronic kidney disease (CKD) patients may receive either oral or intravenous iron. There are advantages and disadvantages for both strategies. Oral iron is simple and cheap to administer and does not require hospital visits, but is poorly absorbed in advanced CKD and is associated with unpleasant gastrointestinal side effects. Intravenous iron, on the other hand, guarantees iron bioavailability and avoids problems of variable absorption of iron from the gastrointestinal tract, but requires specialist clinic services. Intravenous iron also is associated with hypersensitivity reactions, albeit very rarely. The efficacy of intravenous iron in improving hemoglobin, ferritin, and transferrin saturation is well established, and superior to oral iron, but the long-term safety of this route of administration has not been established and there are theoretical concerns that patients may be exposed to increased oxidative stress and exacerbation of infections. The final choice of iron management strategy will depend on individual physician preference, as well as the facilities that are available. PMID- 27236132 TI - Safety Issues in Iron Treatment in CKD. AB - Intravenous iron products are essential for the treatment of anemia in end-stage renal disease patients maintained on hemodialysis. Although proper use of these compounds is necessary for the prevention of iron deficiency, their indiscriminate use could potentially cause insidious adverse consequences. Iron overload can intensify the chronic kidney disease-associated oxidative stress, inflammation, and cardiovascular disease; increase the risk of infections; worsen the severity of type 2 diabetes; and exacerbate neurologic and cognitive dysfunction. These and other adverse effects largely are mediated by iron catalyzed generation of reactive oxygen species. Unlike conventional oral iron products, the newly released iron-containing phosphate binder ferric citrate has been shown to increase iron stores in end-stage renal disease patients. Therefore, iron indices should be monitored in patients receiving this product. Two published studies have shown a high prevalence of hepatic iron loading among hemodialysis patients treated with erythropoiesis-stimulating agents and intravenous iron compounds. Given the potential risks related to iron treatment in this vulnerable population, studies to better understand safety are needed. PMID- 27236133 TI - Balance of Benefit and Risk in Intravenous Iron Treatment in Chronic Kidney Disease. AB - Iron supplementation is an important aspect of treatment for hemodialysis patients, with most administration by an intravenous route. As with any drug, decisions as to treatment are most meaningful when benefits and risks are weighed in the context of the individual patient's clinical characteristics. In this article, knowledge of benefits and risks of intravenous iron are reviewed. PMID- 27236135 TI - Ferric Citrate in Patients With Chronic Kidney Disease. AB - Ferric citrate (FC) is an iron-containing phosphate binder that has been shown to effectively decrease serum phosphate, increase hemoglobin, and replete iron stores in patients with chronic kidney disease. Intestinal absorption of iron from FC results in increases in serum iron, ferritin, and transferrin saturation, effects that occur over 12 to 24 weeks and subsequently appear to plateau. As a result, use of erythropoiesis-stimulating agents and intravenous iron is reduced significantly and in clinical trials in patients receiving hemodialysis, the majority of subjects were able to discontinue intravenous iron use completely. One-year safety data have indicated that FC-treated subjects have reduced rates of hospitalization and reduced serious adverse events related to gastrointestinal, infectious, and cardiovascular causes, although the mechanism for this finding is unclear. The large doses of oral iron administered and lack of precise information on relative absorption over time or on the potential effect of FC on intestinal epithelial function should prompt continued clinical investigation. Although not yet approved for use in the United States for patients with non-dialysis-dependent chronic kidney disease, FC is a welcome addition to the available treatment options for decreasing phosphate concentrations. The multifaceted favorable effects on anemia and phosphate in combination with the erythropoiesis-stimulating agent and intravenous iron sparing data support the use of FC as a first-line treatment option when phosphate-decreasing therapy is indicated. PMID- 27236134 TI - Ferric Pyrophosphate Citrate: A Novel Iron Replacement Agent in Patients Undergoing Hemodialysis. AB - Management of anemia remains an integral component in the care of patients with chronic kidney disease undergoing hemodialysis. In addition to erythropoiesis stimulating agents, iron-replacement agents remain a key strategy for anemia treatment in this patient population. Ferric pyrophosphate citrate (FPC), a novel iron-replacement agent, was approved by the US Food and Drug Administration in January 2015 for use in adult patients receiving chronic hemodialysis (HD). This iron product is administered to patients on HD via the dialysate. The recently published, multicenter, randomized, placebo-controlled, phase 3 clinical trials found FPC to maintain hemoglobin level and iron balance in patients undergoing chronic HD. The mean hemoglobin level in these phase 3 clinical studies was maintained from baseline to the end of the treatment in the dialysate iron (FPC treated) group, however, it decreased by 0.4 g/dL in the control group (P < 0.001). Adverse and serious adverse events were similar in both groups. Another recent study showed a significant reduction in the prescribed ESA dose at the end of treatment in the FPC-treated group compared with placebo. These studies have shown that FPC administered via the dialysate is efficacious and apparently well tolerated. In this article, in addition to reviewing the clinical studies evaluating the efficacy and safety of FPC, we propose a protocol for iron management in HD centers where FPC is to be used. PMID- 27236136 TI - A high-resolution mitochondria-targeting ratiometric fluorescent probe for detection of the endogenous hypochlorous acid. AB - Hypochlorite anion, one of the biologically important reactive oxygen species, plays an essential role in diverse normal biochemical functions and abnormal pathological processes. Herein, an efficient high-resolution mitochondria targeting ratiometric fluorescent probe for hypochlorous acid detection has been designed, synthesized and characterized. It is easily synthesized by the condensation reaction (CC) of a 2-(2-hydroxyphenyl) quinazolin-4(3H)-one fluorophore and a cyanine group (mitochondria-targeting), which made the whole molecular a large Stokes shift (210nm) and the two well-resolved emission peaks separated by 140nm. As a result, it is considered as a good candidate for high resolution hypochlorous acid imaging in live cells. The ratiometric fluorescent probe exhibited outstanding features of high sensitivity, high selectivity, rapid response time (within 50s), and excellent mitochondria-targeting ability. Moreover, the probe can also be successfully applied to imaging endogenously hypochlorous acid in the mitochondria of living cells with low cytotoxicity, and high resolution. PMID- 27236137 TI - Establishing the reference intervals of NK cell functions in healthy adults. AB - Natural killer (NK) cells play a key role in host defense against microbial pathogens. Establishing the reference intervals (RIs) of NK cell functions would be valuable in assessing the immune status of hosts. We evaluated the NK cell activity in healthy adults. We further established and validated the RIs of representative NK cell functions. Flow cytometry was used to evaluate the cytokine production and CD107a degranulation of NK cells. Levels of soluble IFN gamma in the culture supernatants were evaluated by ELISA. Our results demonstrated that the intracellular IFN-gamma production of NK cells was positively correlated with CD107a expression and soluble IFN-gamma levels. There were no significant differences in NK cell functions between different age and gender groups. The mean values and RIs of representative NK cell functions are as following: IFN-gamma(+) NK cells (%): 28.09 (11.3-51.95); CD107a(+) NK cells (%): 17.90 (9.852-27.56); soluble IFN-gamma (pg/ml): 330.4 (41.38-717.8). In addition, the intracellular IFN-gamma production and degranulation activity of NK cells in patients with colorectal cancer were significantly lower than that in healthy adults. Our study has established the RIs of NK cell functions in healthy adults, which might be used for monitoring the immune status of the hosts. PMID- 27236138 TI - The nanocrystalline coordination polymer of AMT-Ag for an effective detection of ciprofloxacin hydrochloride in pharmaceutical formulation and biological fluid. AB - The present report highlights a cost effective and portable AMT-Ag nanocrystalline coordination polymer (NCCP) based electrochemical sensor for an efficient sensing of biologically active drug molecule ciprofloxacin hydrochloride (CFX). The AMT-Ag NCCP, is synthesized using an easily accessible organic ligand 2-amino-5-mercapto-1,3,4-thiadiazole (AMT) with silver nitrate. In the infinite polymer array of AMT-Ag, silver (I) centers are bridged by tecton AMT through the exocyclic thiol and amino linkage. A successful ultra-trace detection of CFX has been achieved due to the prominent electron channeling through the pores of polymeric nano-crystallites. The efficient charge transfer arises at the interface of electrolyte and AMT-Ag nano-crystals anchored electrode through hydrophobic interaction and pi-pi electron coupling. The voltammogram reveals the critical redox features of CFX and provides a clear representation about the steps involved in the AMT-Ag assisted oxidation of CFX. This specific signature further applied in the voltammetric assay of CFX in pharmaceutical formulation (eye drops) and biological fluid (urine) by a significantly high sensitivity (0.002uA/uM and 0.007uA/uM) and detection limit (22nM and 60nM) respectively without any interference. Therefore, the developed AMT-Ag NCCP could serve as a highly valuable platform for the fabrication of high performance electrochemical sensors for the detection of biologically important drug molecules. PMID- 27236139 TI - Indirect electrochemical detection for total bile acids in human serum. AB - Bile acids level in serum is a useful index for screening and diagnosis of hepatobiliary diseases. As bile acids concentration is closely related to the degree of hepatobiliary diseases, detecting it is a vital factor to understand the stage of the diseases. The prevalent determination for bile acids is the enzymatic cycling method which has low sensitivity while reagent-consuming. It is desirable to develop a new method with lower cost and higher sensitivity. An indirect electrochemical detection (IED) for bile acids in human serum was established using the screen printed carbon electrode (SPCE). Since bile acids do not show electrochemical signals, they were converted to 3-ketosteroids by 3 alpha-hydroxysteroid dehydrogenase (3alpha-HSD) in the presence of nicotinamide adenine dinucleotide (NAD(+)), which was reduced to NADH. NADH could then be oxidized on the surface of SPCE, generating a signal that was used to calculate the total bile acids (TBA) concentration. A good linear calibration for TBA was obtained at the concentration range from 5.00MUM to 400MUM in human serum. Both the precisions and recoveries were sufficient to be used in a clinical setting. The TBA concentrations in 35 human serum samples by our IED method didn't show significant difference with the result by enzymatic cycling method, using the paired t-test. Moreover, our IED method is reagent-saving, sensitive and cost effective. PMID- 27236140 TI - Performance enhanced UV/vis spectroscopic microfluidic sensor for ascorbic acid quantification in human blood. AB - Quantitative analysis of antioxidants in a fast, simple and accurate manner is of great importance in the view of real-time monitoring the health of individuals. Recently, we have developed a UV/vis spectroscopic microfluidic sensor to specifically quantify ascorbic acid based on the immobilization of ascorbate oxidase, a relatively unstable enzyme. In this work, three different strategies for the immobilization of the unstable enzyme, including alumina sol-gel encapsulation, physisorption to PDMS channels with, and without alumina xerogel modification, were compared to build a microsensor. We found that the loading amount of the enzyme is not the determinative factor for the performance of the microfluidic biosensor but the retained activity of the enzyme and diffusion in the microfluidic channel. Taking into account of the two factors, the protocol of adsorbing enzymes to alumina (Al2O3) xerogel modified PDMS surface was demonstrated to be the best for preparing the microfluidic sensor among the utilized protocols. The microsensor prepared under the optimized protocol was further used to quantify ascorbic acid in human blood, where only dozens of microliters of blood (few drops) was required, demonstrating its potential application in clinical diagnosis. The developed strategy is featured with optimized enzymatic activity, simple process of microfluidic platform, low sample consumption, and straightforward spectrophotometry based detection. PMID- 27236141 TI - Embryonated pigeon eggs as a model to investigate Neospora caninum infection. AB - It has been shown that embryonated chicken eggs can be used as animal models for experimental infections. The aim of the present study was to investigate pigeon embryonated eggs as animal models for experimental neosporosis. An infection with Neospora caninum Nc1 isolate was conducted in chicken and pigeon embryonated eggs to evaluate LD50. After calculation of LD50, 2LD50 of tachyzoites were injected into the eggs. Macroscopic changes of each embryo were observed, and immunohistochemistry (IHC) and molecular methods were used to investigate the parasitic distribution in the tissues. In the present study, histopathological changes were considered, and sections of those used for histopathological examination including the heart, liver, brain and chorioallantoic (CA) membrane were also subjected to IHC. Pigeon embryos showed more macroscopic changes than chicken embryos. A hemorrhage of the CA membrane was the main gross lesion. Microscopic examination of tissues revealed acute neosporosis due to hemorrhage, necrosis and infiltration of mononuclear inflammatory cells. Based on IHC and molecular results, the parasite DNA was detected in the liver, heart and CA membrane. As with chicken embryonated eggs, these results reinforce the susceptibility of pigeon embryonated eggs to N. caninum, and provide new insights into using an inexpensive and available animal model for N. caninum research. The results of the present study suggest that pigeon embryos may be a good choice for studying the biology of N. caninum in living organisms. PMID- 27236142 TI - Drugs of abuse and alcohol consumption among different groups of population on the Greek Island of Lesvos through sewage-based epidemiology. AB - The occurrence of 22 drugs of abuse, their metabolites, and the alcohol metabolite ethyl sulphate was investigated in raw sewage samples collected during the non-touristic season from three sewage treatment plants (STPs), which serve different sizes and types of population in the Greek island of Lesvos. Using the sewage-based epidemiology approach, the consumption of these substances was estimated. Five target analytes, cocaine (COC), benzoylecgonine (BE), 3,4 methylenedioxymethamphetamine (MDMA), 11-nor-9-carboxy-delta-9 tetrahydrocannabinol (THC-COOH) and ethyl sulphate (EtS) were detected at concentrations above their limit of quantification, whereas the rest eighteen target compounds were not detected. THC-COOH was detected in most of the samples with concentrations ranging between <20 and 90ngL(-1), followed by EtS (range <1700-12,243ngL(-1)). COC, BE, and MDMA were present only in the STP that serves Mytilene (the main city of the island), at mean concentrations of 3.9ngL(-1) for COC (95% CI: 1.7-6.1), 9.4ngL(-1) for BE (95% CI: -1.6-23) and 3.2ngL(-1) for MDMA (95% CI: 1.2-5.1). Back-calculations to an amount of used substance indicated more intense use of drugs among city population than rural and University population with average values of 9.5 and 1.2mgday(-1) per 1000 inhabitants for COC (95% CI: -1.43-20.4) and MDMA (95% CI: 0.52-1.85), respectively, and 2.8gday(-1) per 1000 inhabitants for tetrahydrocannabinol (THC) (95% CI: 2.4-3.1), the active ingredient of cannabis. Alcohol consumption was observed to be higher in the city population (5.4mL pure alcohol per day per inhabitant) than in the rural population (3.4mL pure alcohol per day per inhabitant), but the difference was not statistically significant. Consumption of THC differed significantly among the three STPs. PMID- 27236143 TI - Screening accuracy of brief alcohol screening instruments in a general hospital setting. AB - AIM: The aim of this study was to examine the screening accuracy of four brief alcohol screening instruments in a general hospital setting. METHODS: Ten outpatient clinics were recruited to ensure a representative mix of demographics (e.g. sex, age and diagnosis). The staff at the reception desk handed out pre sorted envelopes with questionnaires and information letters to the visitors. The questionnaires consisted of the 10-item Alcohol Use Disorders Identification Test (AUDIT), the Weekly Consumption Question (WCQ), the Heavy Episodic Drinking (HED) question and two questions on sex and age. Sensitivity and specificity were calculated for the AUDIT-C, AUDIT-3, WCQ and HED using the full 10-item AUDIT for comparison, with cut-off points of ?6 for women and ?8 for men. RESULTS: In all, 898 questionnaires were included (52% women). According to the full AUDIT, 12.0% of the women and 14.8% of the men were drinking above the hazardous level. Corresponding percentages for the brief screening instruments for women and men, respectively, were as follows: AUDIT-C: 17.2% and 27.4%; the AUDIT-3: 6% and 16.2%; the WCQ: 2% and 1.6%; and the HED screener: 12.9% and 21.2%. CONCLUSIONS THE AUDIT-C MAY BE USED AS A BRIEF SCREENER IN A GENERAL HOSPITAL SETTING THE WCQ, AS A STAND-ALONE SCREENING TOOL, MAY UNDERESTIMATE HAZARDOUS DRINKING HABITS SCREENING RESULTS FROM THE AUDIT-3 AND THE HED SHOULD BE INTERPRETED WITH CAUTION WHEN APPLIED TO WOMEN BECAUSE OF THE RISK OF UNDERESTIMATION. PMID- 27236145 TI - Alcoholic hepatitis: How far are we and where are we going? AB - The burden of alcoholic liver disease continues to be a major public health problem worldwide. The spectrum of disease ranges from fatty liver to cirrhosis and hepatocellular carcinoma. Alcoholic hepatitis (AH) is a type of acute-on chronic liver failure and the most severe form of alcoholic liver disease. Severe AH carries a poor short-term prognosis and its management is still challenging, with scarce advances in the last decades. Corticosteroids are still the first line of therapy in severe cases. Unfortunately, many patients do not respond and novel targeted therapies are urgently needed. Liver transplantation has shown extraordinary results in non-responders to corticosteroids however; its applicability is very low. This review summarizes the epidemiology, natural history, risk factors and pathogenesis of alcoholic liver disease with special focus on the latest advances in prognostic stratification and therapy of patients with alcoholic hepatitis. PMID- 27236146 TI - Hepatorenal syndrome: Current concepts related to diagnosis and management. AB - Renal failure in cirrhotic patients is a very severe condition. Hepatorenal syndrome has the worst prognosis among all causes of kidney failure in such patients. Hepatorenal syndrome is diagnosed especially in cirrhotic patients with ascites who develop loss renal function, despite diuretic suspension and volume expansion with albumin and for whom other causes of kidney injury have been excluded. Patients with hepatorenal syndrome should be treated with a vasoconstrictor in combination with albumin as a bridge to receiving a liver transplant. The vasoconstrictor of choice is terlipressin or noradrenaline. In spite of higher drug-related costs associated to terlipressin, initial evidence demonstrates that, considering all direct medical costs involved, the treatment strategy using terlipressin is probably more economical than that using noradrenaline. PMID- 27236147 TI - Meta-analysis of the clinical value of oxymatrine on sustained virological response in chronic hepatitis B. AB - Introduction. Oxymatrine (OMTR) is widely used for the treatment of chronic hepatitis B (CHB) in China. Several recent reports revealed that OMTR together with interferon yielded a higher sustained virological response (SVR) than interferon alone. AIM: To elucidate this topic using meta-analysis of data from published randomized controlled trials (RCTs). MATERIAL AND METHODS: The Cochrane Central Register of Controlled Trials, Medline, Science Citation Index, EMBASE, China National Knowledge Infrastructure, Wanfang Database and China Biomedical Database were searched to identify RCTs that evaluated SVR to interferon therapies and interferon plus OMTR therapies in CHB patients. RESULTS: The literature search yielded 238 studies, and 11 RCTs comprising 968 patients matched the selection criteria. Overall, SVR was significantly higher in patients treated with interferon plus OMTR than in patients treated with interferon alone (SVR: 60.7 vs. 39.8%; relative risk: 1.56; 95% confidence interval: 1.37-1.77; p < 0.05). Combined therapy of interferon plus OMTR were also superior to interferon therapies alone in achieving the endof-treatment viral response, alaninetransaminase normalization, HBeAg loss, and HBeAg seroconversion. CONCLUSIONS: Combined therapy of interferon plus OMTR may yield a higher SVR than interferon therapies. The exact outcome needs to perform rigorously designed, multicenter, and large randomized controlled trials. PMID- 27236148 TI - The relation of fibrosis stage with nutritional deficiencies and bioelectrical impedance analysis of body composition in patients with chronic hepatitis C. AB - Background. Nutritional deficiencies may aggravate the course of chronic hepatitis C (CHC). Our aim has been to perform a comprehensive analysis of body composition and nutritional deficiencies in CHC patients in non-cirrhotic and compensated cirrhotic stages to correlate the detected deficiencies with the fibrosis stage. MATERIAL AND METHODS: Body multifrequency bioimpedance analysis (BIA) and a wide and simultaneous analytical profile were prospectively performed in 74 CHC patients (36 male) with known METAVIR fibrosis stage established with liver biopsy or transient elastography. Results were analyzed to identify deviations from the normal range and variations according to the fibrosis stage. RESULTS: Body fat compartment was greater in women. Body composition did not change among the 4 stages of liver fibrosis. Low levels (< 30 MUg/L) of vitamin D were detected in 74.3% of patients irrespective of the fibrosis stage. Most analytical results remained into the normal range with the exceptions of thrombocytopenia and vitamin A deficiency, that were limited to the stage 4 of fibrosis, and low Zn and LDL-cholesterol values, that were frequently found in patients with advanced (F3 and F4) fibrosis stage. CONCLUSION: Body composition and most biochemical parameters, including cyanocobalamin, folic acid and vitamin E, are well preserved in compensated patients with CHC, with the exception of generalized vitamin D insufficiency and of deficiencies of vitamin A and zinc that are restricted to the more advanced, although still compensated, stages of the disease. PMID- 27236149 TI - Meta-analysis of prophylactic entecavir or lamivudine against hepatitis B virus reactivation. AB - Introduction and aim. Studies suggest that entecavir and lamivudine are useful as prophylactics against hepatitis B virus (HBV) reactivation in patients undergoing chemotherapy or immunosuppressive therapy, but which drug is more effective is unclear. Here we meta-analyzed available evidence on relative efficacy of prophylactic entecavir or lamivudine therapy in patients with chronic or resolved hepatitis B infection who were undergoing chemotherapy or immunosuppressive therapy. MATERIAL AND METHODS: Two reviewers searched PubMed, EMBASE and Google Scholar as well as reference lists in relevant articles to find studies published between January 2005 and May 2015 that met inclusion and exclusion criteria. Data on HBV reactivation, HBV-related hepatitis and all-cause mortality were extracted from the studies and meta-analyzed. RESULTS: A total of eight studies involving 593 patients were included in the meta-analysis, which was performed using a fixed-effect model since no significant heterogeneity was found. Entecavir was associated with significantly lower risk of HBV reactivation than lamivudine (RR 0.29, 95% CI 0.17 to 0.52) as well as lower risk of HBV related hepatitis (RR 0.11, 95% CI 0.03 to 0.40). The two drugs were associated with similar risk of all-cause mortality (RR 1.12, 95% CI 0.54 to 2.35). Egger's test suggested no significant publication bias in the meta-analysis. CONCLUSIONS: The available evidence suggests that entecavir is more effective than lamivudine for preventing HBV reactivation and HBVrelated hepatitis in patients with chronic or resolved HBV infection who are undergoing chemotherapy or immunosuppressive therapy. PMID- 27236150 TI - Efficacy of telaprevir-based therapy in stable liver transplant patients with chronic genotype 1 hepatitis C. AB - Background and rationale. The REPLACE study (NCT01571583) investigated telaprevir-based triple therapy in patients who have recurrent genotype 1 hepatitis C virus (HCV) infection following liver transplantation and are on a stable immunosuppressant regimen of tacrolimus or cyclosporin A. Patients received telaprevir 750 mg 8-hourly with pegylated interferon 180 ?g weekly and ribavirin 600 mg daily, followed by a further 36 weeks of pegylated interferon and ribavirin alone and 24 weeks of follow-up. Efficacy (sustained virological response [SVR] 12 weeks after last planned study dose), safety and tolerability of telaprevir throughout the study were assessed. Pharmacokinetics of telaprevir, tacrolimus and cyclosporin A were also examined. RESULTS: In total, 74 patients were recruited. Overall, 72% (53/74; 95% CI: 59.9 to 81.5) of patients achieved SVR at 12 weeks following completion of treatment. Anticipated increases in plasma concentrations of tacrolimus and cyclosporin A occurred during telaprevir treatment and were successfully managed through immunosuppressant dose reduction and, for tacrolimus, reduced dosing frequency. Safety and tolerability of telaprevir-based triple therapy were generally comparable with previous data in non-transplant patients, although rates of reported anemia (55% [41/74]) were higher. Elevated plasma creatinine (46% [34/74]) was observed during REPLACE - consistent with the post-liver transplant population and the co-administered immunosuppressants. CONCLUSION: Telaprevir-based triple therapy in patients with recurrent genotype 1 HCV infection following liver transplantation produced high rates of SVR. Therapeutic concentrations of immunosuppressants were maintained successfully through dose modification during telaprevir treatment. PMID- 27236151 TI - Effects of a multidisciplinary approach on the effectiveness of antiviral treatment for chronic hepatitis C. AB - Background. Despite the introduction of direct antiviral agents, pegylated interferon remains the mainstay of treatment for chronic hepatitis C. However, pegylated interferon is associated with a high rate of severe adverse events and decreased quality of life. Specific interventions can improve adherence and effectiveness. We aimed to determine whether implementing a multidisciplinary approach improved outcomes in the treatment of chronic hepatitis C. MATERIAL AND METHODS: We analyzed consecutive patients treated with pegylated interferon plus ribavirin between August 2001 and December 2011. We compared patients treated before and after the implementation of a multidisciplinary approach in 2007. We compared the baseline demographic and clinical characteristics and laboratory findings between groups, and used bivariate logistic regression models to detect factors involved in attaining a sustained virological response, calculating the odds ratios with their respective 95% confidence intervals. To evaluate the effect of the multidisciplinary team, we fitted a multivariate logistic regression model to compare the sustained virological response after adjusting for unbalanced variables and predictive factors. RESULTS: We included 514 patients [228 (44.4%) in the pre-intervention cohort]. Age, viral genotype, previous treatment, aspartate transaminase, ferritin, and triglyceride were prognostic factors of sustained virological response. After adjusting for prognostic factors, sustained virological response was higher in the multidisciplinary cohort (58 vs. 48%, p = 0.038). Despite higher psychiatric comorbidity and age in the multidisciplinary cohort, we observed a trend toward a lower rate of treatment abandonment in this group (2.2 vs. 4.9%, p = 0.107). CONCLUSION: Multidisciplinary management of chronic hepatitis C improves outcomes. PMID- 27236152 TI - Association of HLA-DQ and IFNL4 polymorphisms with susceptibility to hepatitis B virus infection and clearance. AB - Background and aim. Leukocyte antigen DQ (HLA-DQ) and interferon-lambda4 (IFNL4) gene polymorphisms were associated with susceptibility to chronic hepatitis B and C virus infection. This study further confirmed that variants of these genes were associated with susceptibility and spontaneous clearance of HBV infection in a Chinese population. MATERIAL AND METHODS: A total of 1,069 subjects were recruited and divided into three groups i.e. 397 with CLD (HBV-related chronic liver disease), 434 with SC (spontaneous clearance), and 238 HC (healthy controls). HLA-DQrs9275319 and IFNL4rs368234815, rs12971396, rs12979860, and rs8099917SNPs were genotyped using the Sequenom MassARRAY MALDI-TOF system. RESULTS: HLA-DQ rs9275319 showed a significant association with HBV infection (allele model, OR, 0.514; 95% CI, 0.359-0.738, adjusted p = 0.0003) and with natural clearance (allele model, OR, 1.659; 95% CI, 1.197-2.300, adjusted. However, there was no association between IFNL4 polymorphism and HBV susceptibility or natural clearance (all p > 0.05). The multifactor dimensionality reduction (MDR) test with permutation correction showed that a three-way interaction between IFNL4 and HLA-DQ SNPs was identified for HBV susceptibility (permutation p = 0.009 for the best factor model) and clearance (permutation p = 0.014 for the best factor model). CONCLUSIONS: The data from the current study provided additional evidence for an SNP-SNP interaction between HLA DQ and IFNL4 in regulation to HBV infection and natural clearance. PMID- 27236153 TI - Increased hepatocellular carcinoma recurrence in women compared to men with high alpha fetoprotein at liver transplant. AB - Introduction. Men have higher risk for hepatocellular carcinoma (HCC) than women. Pre liver transplant (LT) alpha fetoprotein (AFP) levels strongly predict post LT HCC recurrence. Though women with HCC have higher AFP, the contribution of AFP level by gender to post LT HCC recurrence is unknown. MATERIAL AND METHODS: In this UNOSbased, retrospective cohort study we investigate sex differences in HCC recurrence among LT recipients with MELD exception between 2006-2010. Covariates include race, disease etiology, co-morbidities, AFP at listing and LT, tumor burden, loco-regional therapy, and donor risk index. HCC recurrence was assessed by competing risks regression. RESULTS: Of the eligible cohort (n = 5,002) included 3,872 men and 1,130 women. HCC recurred in 258 men (7%) and 66 women (6%). Median listing AFP was higher in women than men (14 vs. 11 ng/dL, p < 0.001). While no sex difference in overall HCC recurrence was detected (HR 0.9, 95% CI 0.7-1.2, p = 0.38), there was a strong interaction between gender and AFP on recurrence risk (p = 0.02). HCC recurrence was nearly three times higher in women (HR 4.2, 95% CI 2.2-8.2, p < 0.001) than men (HR 1.5, 95% CI 1.1-2.1, p = 0.02) with AFP at LT between 101-500 ng/dL. CONCLUSION: This study reveals novel sex differences in post LT HCC recurrence, which was nearly three times higher in women than men with high AFP at LT. Pre-LT AFP levels appear to carry a different prognosis in women than men, and a subset of female LT recipients may benefit from more intensive HCC surveillance after LT. PMID- 27236154 TI - Elevated circulating levels of IL-21 and IL-22 define a cytokine signature profile in type 2 autoimmune hepatitis patients. AB - Background and aims. Autoimmune hepatitis (AIH) is a chronic inflammatory condition of the liver in which the immunological mechanisms involved in tissue destruction and/or repair are still unclear. Different pro-inflammatory cytokines have been shown to play a determinant role in AIH pathogenesis. Here, we aim to compare the circulating levels of pro- and anti-inflammatory cytokines such as IL 6, TNF-?, IL-17A/F, IL-21, IL-22, IL-23, and IL-10 in patients with type 2 AIH compared to patients with type 1 AIH and healthy controls (HC). Fourty-six Mexican patients with AIH were recruited in our study. Patients were classified as type 1 or 2 AIH based on immune serological markers. Fourty-four serum samples from healthy individuals were included as controls. Serum cytokine levels were determined by ELISA technique. RESULTS: Compared to healthy controls, serum levels of IL-17F, IL-21, IL-23, IL-10, IL-6, and TNF-?, but not IL-17A and IL-22, were significantly increased in AIH patients. When patients were grouped by aminotransferase activity, a biomarker of active disease, a positive correlation between serum IL-17F and alanine transaminase (rs: 0.4739; P = 0.0009) and aspartate transaminase (rs: 0.4984; P = 0.0004) levels was found. A cytokine signature profile associated with type 2 AIH was characterized by high serum IL 21 (type 1 AIH: 0.66 pg/mL; type 2 AIH: 331.1 pg/mL; P = 0.0042) and IL-22 (type 1 AIH: 0.1 pg/mL; type 2 AIH: 55.26 pg/mL; P = 0.0028) levels. CONCLUSIONS: We show for the first time, differential regulation of certain pro-inflammatory cytokines associated with disease progression and AIH type in Mexican patients. PMID- 27236155 TI - Rapid identification system of frontal dysfunction in subclinical hepatic encephalopathy. AB - Introduction and aim. Liver disease is associated with cognitive dysfunction also at early stages, and minimal hepatic encephalopathy, affecting 20-70% of patients, is frequently under-recognized. The main purpose of this work was to demonstrate that a substantial number of patients, enrolled due to an acute confusional state in absence of a diagnosis of liver disease, suffers of hepatic encephalopathy. MATERIAL AND METHODS: Before a diagnosis of a well-compensated liver diseases was performed, 410 patients with an acute confusional state were enrolled in this study. RESULTS: Even in the presence of minimal alterations of hepatic function, the psychometric tests applied demonstrated early signs of cerebral frontal alteration. The alteration was associated with the severity of liver disease, paralleling the progression of the patient to minimal hepatic failure or chronic liver disease. CONCLUSIONS: These psychometric tests are essential to detect early and subclinical frontal failure. Frontal dysfunction may be a useful tool in the follow-up of these patients. PMID- 27236156 TI - CUL4B, NEDD4, and UGT1As involve in the TGF-beta signalling in hepatocellular carcinoma. AB - Introduction and Aim. TGF-beta signalling is involved in pathogenesis and progress of hepatocellular carcinoma (HCC). This bioinformatics study consequently aims to determine the underlying molecular mechanism of TGF- beta activation in HCC cells. MATERIAL AND METHODS: Dataset GSE10393 was downloaded from Gene Expression Omnibus, including 2 Huh-7 (HCC cell line) samples treated by TGF- beta (100 pmol/L, 48 h) and 2 untreated samples. Differentially expressed genes (DEGs) were screened using Limma package (false discovery rate < 0.05 and |log2 fold change| > 1.5), and then enrichment analyses of function, pathway, and disease were performed. In addition, protein-protein interaction (PPI) network was constructed based on the PPI data from multiple databases including INACT, MINT, BioGRID, UniProt, BIND, BindingDB, and SPIKE databases. Transcription factor (TF)-DEG pairs (Bonferroni adjusted p-value < 0.01) from ChEA database and DEG-DEG pairs were used to construct TF-DEG regulatory network. Furthermore, TF pathway-DEG complex network was constructed by integrating DEG-DEG pairs, TF-DEG pairs, and DEG-pathway pairs. RESULTS: Totally, 209 DEGs and 30 TFs were identified. The DEGs were significantly enriched in adhesion-related functions. PPI network indicted hub genes such as CUL4B and NEDD4. According to the TF-DEG regulatory network, the two hub genes were targeted by SMAD2, SMAD3, and HNF4A. Besides, the 11 pathways in TF-pathway-DEG network were mainly enriched by UGT1A family and CYP3A7, which were predicted to be regulated by SMAD2, SMAD3, SOX2, TP63, and HNF4A. CONCLUSIONS: TGF- beta might influence biological processes of HCC cells via SMAD2/SMAD3-NEDD4, HNF4A-CUL4B/NEDD4, SOX2/TP63/HNF4A-CYP3A7, and SMAD2/SMAD3/SOX2/TP63/HNF4A-UGT1As regulatory pathways. PMID- 27236157 TI - Thymosin beta10 as a predictive biomarker of response to 5-fluorouracil chemotherapy in cholangiocarcinoma. AB - Introduction and aim. 5-Fluorouracil (5-FU) is the most commonly used chemotherapeutic drug in the treatment of cholangiocarcinoma (CCA). Since development of drug resistance to 5-FU in CCA patients is the primary cause of treatment failure, a better understanding of the mechanism of drug resistance of this cancer is essential to improve the efficacy of 5-FU in CCA therapy. MATERIAL AND METHODS: A 5-FU resistant CCA cell line (M214-5FUR) for a comparative chemo resistance study was established. Real time RT-PCR was used to determine gene expression levels. Cell cytotoxicity was measured by the MTT assay. Protein expression levels were detected by the immunofluorescene method. RESULTS: It was found that 5-FU resistance was associated with the overexpression of T?10 in CCA cell lines. 5-FU treatment at various concentrations induced the expressions of T?10 and ABC transporters (ABCB1, ABCG2 ABCA3) in two CCA cell lines, KKU-M055 and KKU-M214. M214-5FUR, a 5-FU-resistant cell line, exhibited a 5-FU resistant phenotype with a 16-fold extremely high expression of T?10 and ABC transporters, as compared to the parental cells, KKU-M214. siRNA targeted to T?10 significantly reduced expression of ABC transporters tested in the M214-5FUR cells (P < 0.05). CONCLUSIONS: The present novel findingsof T?10 connected with drug resistance as shown in this study provides a new insight for the therapeutic value of T?10 as a predictive biomarker of 5-FU chemoresistance. Inhibiting T?10 may be a valuable adjunct for suppression of ABC transporters and sensitizing chemotherapy treatment, especially 5-FU in CCA patients. PMID- 27236158 TI - Giant cavernous hemangiomata of the liver: Watchful waiting, resection or transplantation? PMID- 27236159 TI - An autoimmune polyglandular syndrome complicated with celiac disease and autoimmune hepatitis. AB - Autoimmune polyglandular syndrome (APS) is a combination of different autoimmune diseases. The close relationship between immune-mediated disorders makes it mandatory to perform serological screening periodically in order to avoid delayed diagnosis of additional autoimmune diseases. We studied a patient with type 1 diabetes (T1D) who later developed an autoimmune thyroid disease (ATD) and was referred to our hospital with a serious condition of his clinical status. The patient was suffering from an advance stage of celiac disease (CD), the delay in its diagnosis and in the establishment of a gluten-free dietled the patient to a severe proteincalorie malnutrition. Later, the patient developed an autoimmune hepatitis (AIH). We consider that clinical deterioration in patients with APS should alert physicians about the possible presence of other immune-mediated diseases. Periodic screening for autoantibodies would help to prevent delayed diagnosis and would improve patient's quality of life. PMID- 27236160 TI - Liver transplantation followed by autologous stem cell transplantation for acute liver failure caused by AL amyloidosis. Case report and review of the literature. AB - Hepatic involvement in AL amyloidosis may present as acute liver failure. Historically, liver transplantation in these cases has achieved poor outcomes due to progress of amyloidosis and non-hepatic organ damage. In the era of bortezomib treatment, the prognosis of AL amyloidosis has been markedly improved and may also result in better post-transplant outcomes. We present a case of isolated acute liver failure caused by AL amyloidosis, bridged to transplantation with bortezomib and treated with sequential orthotopic liver transplantation (OLT) and autologous stem cell transplantation. The patient is in stable remission 3 years after OLT. PMID- 27236161 TI - Pigmented hepatocellular adenoma with beta-catenin activation: case report and literature review. AB - Hepatocellular adenomas (HCAs) are benign liver tumors recently characterized into 4 different types according to genetic, pathological and clinical features. The prognosis is not well established yet and malignant transformation has been recently associated with beta-catenin activation. We aimed to describe a case of a pigmented HCA with beta-catenin nuclear expression and inflammatory features and to review the cases of pigmented HCAs in the literature. We report a case of a young female patient without contraceptive use, with a liver tumor diagnosis. Liver biopsy revealed diffuse expression of beta-catenin and a partial hepatic resection was performed. The histologic analysis revealed a hepatocellular tumor composed of uniform trabeculae of hepatocytes and solid areas, the later with a significant amount of black pigment highlighted by Masson-Fontana stain. Immunohistochemistry showed co-expression of C-reactive protein and serum amyloid A in the tumor. Literature review revealed that pigmented HCAs, previously reported as dark adenomas, are rare tumors. In HCAs, the presence of beta-catenin activation should be searched for due to the higher risk of malignant transformation in hepatocarcinoma. We describe a pigmented HCA with beta-catenin nuclear expression and inflammatory features being the fifth case reported so far. PMID- 27236162 TI - Elafibranor for the treatment of NAFLD: One pill, two molecular targets and multiple effects in a complex phenotype. PMID- 27236164 TI - Greenhouse gas emissions of waste management processes and options: A case study. AB - Increasing concern about climate change is prompting organisations to mitigate their greenhouse gas emissions. Waste management activities also contribute to greenhouse gas emissions. In the waste management sector, there has been an increasing diversion of waste sent to landfill, with much emphasis on recycling and reuse to prevent emissions. This study evaluates the carbon footprint of the different processes involved in waste management systems, considering the entire waste management stream. Waste management data from the Royal Borough of Kingston upon Thames, London (UK), was used to estimate the carbon footprint for its (Royal Borough of Kingston upon Thames) current source segregation system. Second, modelled full and partial co-mingling scenarios were used to estimate carbon emissions from these proposed waste management approaches. The greenhouse gas emissions from the entire waste management system at Royal Borough of Kingston upon Thames were 12,347 t CO2e for the source-segregated scenario, and 11,907 t CO2e for the partial co-mingled model. These emissions amount to 203.26 kg CO2e t(-1) and 196.02 kg CO2e t(-1) municipal solid waste for source segregated and partial co-mingled, respectively. The change from a source segregation fleet to a partial co-mingling fleet reduced the emissions, at least partly owing to a change in the number and type of vehicles. PMID- 27236165 TI - Combined heating and chemical treatment for oil recovery from aging crude oil. AB - With increasing use of chemical oil displacement agents in tertiary recovery and the application of various demulsifiers for crude oil dehydration, a large amount of aging crude oil containing a high ratio of water is produced, and it is very difficult for processing and utilisation. In this article, we chose aging crude oil samples from a union station in an oilfield in China. Sample composition was analysed to demonstrate that the key of aging crude oil dehydration is the removal of solid impurities. Thus, an efficient method of combining heating and chemical treatments was developed to treat aging crude oil. It includes two steps: The first step is washing of aging crude oil with hot water with sodium dodecylbenzene sulfonate; the second step is chemical demulsification of the above mixture with hydrochloric acid and sodium chloride solution. The result showed that 2.9% of solid impurities and 29.2% of water were removed in the first step; 27.2% of oil, 24.3% of water, and 3.47% of solid impurities in the aging crude oil were recycled in the second step. A total 87.07% of aging crude oil could be solved with this method. The present two-step treatment method can ensure that the dehydration process runs normally and efficiently in the union station, making it a promising method in the recycling of aging crude oil. PMID- 27236166 TI - True-Threat Doctrine and Mental State at the Time of Speech. PMID- 27236167 TI - The Relevance of Modern Neuroscience to Forensic Psychiatry Practice. PMID- 27236168 TI - Treating ADHD in Prison: Focus on Alpha-2 Agonists (Clonidine and Guanfacine). AB - Attention deficit/hyperactivity disorder (ADHD) is prevalent in prison populations, but optimal treatment recommendations in prison are uncertain. Stimulants are problematic because of the potential for abuse. This article is a review of medication options for ADHD, focusing on the alpha2 agonists clonidine and guanfacine, which, in their extended-release (ER) forms, are U.S. Food and Drug Administration (FDA) approved for the treatment of ADHD, although they are probably less efficacious, overall, than stimulants. Advantages of alpha2 agonists in prison include: they are not controlled substances and have no known abuse potential; they may be particularly helpful for ADHD with associated aggression and other features of conduct disorder; they may reduce anxiety and symptoms of posttraumatic stress disorder; and they are somewhat sedating. The pharmacology of these agents and the presumed mechanism of action are discussed, including the fact that guanfacine more specifically affects alpha2A receptors, which are postsynaptic in the frontal cortex. Other differences between clonidine and guanfacine and between the generic immediate-release (IR) forms and the ER forms are also discussed. The IR forms, while themselves not FDA approved for ADHD, may, with dosage adjustment, be reasonable alternatives (with considerable cost savings). Overall, given the FDA-accepted evidence of efficacy, the lack of abuse potential, and the favorable side effect profile, alpha agonists may be the treatment of choice for prison inmates with ADHD. PMID- 27236169 TI - Atomoxetine for the Treatment of ADHD in Incarcerated Adolescents. AB - Effective interventions for adolescents with attention deficit/hyperactivity disorder (ADHD) in the correctional setting may improve care during incarceration, decrease risk of substance relapse, and reduce recidivism after release from the correctional setting of these individuals. The present report delineates the epidemiology of adolescent ADHD in the correctional setting and its association with substance use disorders and comorbid psychiatric illnesses. Evidence suggests that adolescents with ADHD have a higher risk of arrest and incarceration during adulthood. The present report examines evidence related to efficacy of atomoxetine, a nonstimulant medication for the treatment of adolescent ADHD, and presents data from a case series evaluating the effectiveness of atomoxetine for the treatment of adolescent ADHD in the Connecticut correctional setting. The results from the case series suggest that atomoxetine is effective for the treatment of adolescent ADHD in the context of significant past substance use. In summary, adolescents with ADHD have an elevated risk of incarceration and developing substance use disorders. The present review and pilot case series suggest that atomoxetine is an effective treatment for adolescents with ADHD in the correctional setting. PMID- 27236170 TI - Challenges and Limitations to Treating ADHD in Incarcerated Populations. AB - An often underappreciated and hard-to-treat condition in correctional institutions is attention-deficit/hyperactivity disorder (ADHD). Although there are many effective psychopharmacologic treatments for ADHD, such as various formulations of amphetamines, many physicians are hesitant to prescribe controlled stimulants in correctional settings because of concerns about abuse and safety. Although nonstimulant alternatives are available, they are generally seen as less effective than stimulants. However, there are many unique factors regarding corrections populations and their responses to treatment, which makes it difficult to know what the ideal treatment regimen would be for this population. We review the standard treatments for ADHD, for prescribing in correctional institutions, barriers to using medications for off-label treatment of ADHD, and suggest future research that could better guide correctional treatment staff on how to approach patients with ADHD. PMID- 27236171 TI - When Restoration Fails: One State's Answer to the Dilemma of Permanent Incompetence. AB - The landmark 1972 U.S. Supreme Court decision in Jackson v. Indiana prohibited the indefinite commitment of criminal defendants on grounds of incompetence to stand trial if there was no substantial probability of restoration to competency in the foreseeable future. Such defendants are still subject to ordinary civil commitment; however, not all will meet civil commitment criteria, given that the criteria for a finding of incompetency to stand trial do not map directly onto the general criteria for involuntary psychiatric hospitalization. If a person charged with a serious crime, such as murder, has no substantial probability of being restored to competency, but does not meet standard civil commitment criteria, compliance with Jackson would seem to require release into the community. This article describes a legislative response to this possibility that became law in California four decades ago, as well as the outcome of its main legal challenge a few years later. Although the law has received harsh criticism from some quarters, it has survived, and provides a legally straightforward, if ethically controversial, means of answering the question of what to do with a permanently incompetent defendant who is charged with a serious violent offense and does not meet traditional civil commitment criteria. PMID- 27236172 TI - Not Competent, Not Restorable, and Not Committable. AB - I comment on the problem discussed by Simpson of criminal defendants who are found not competent, not restorable, and subject to involuntary civil commitment. He presents the 2010 case of Donn Thomas Spinosa in Oregon as an exemplar of serial nonrestorability. The facts of the Spinosa case are illustrative of a prosecutor who is frustrated by not being able to bring a criminal prosecution against a person who is not competent to stand trial and a state hospital that is proposing discharge of the person because he can no longer be civilly committed. I review and apply the longstanding constitutional principles of Jackson v. Indiana to the Spinosa case. PMID- 27236173 TI - Trauma as a Contributor to Violence in Autism Spectrum Disorder. AB - In examining contributors to violence among individuals with autism spectrum disorder (ASD), one factor that has received little attention is a history of psychological trauma. This study's purpose was to explore the possible mechanisms for an association between trauma and violence in persons with ASD. The literature regarding the neurobiology and theoretical underpinnings of ASD is reviewed and compared with the literature on the neurobiology and theoretical underpinnings of trauma as a risk factor for violence in individuals without ASD. Information from this comparison is then used to formulate possible mechanisms for a trauma-violence association in ASD. Individuals with ASD may possess sensitized prefrontal-cortical-limbic networks that are overloaded in the face of trauma, leading to unchecked limbic output that produces violent behavior, and/or cognitive dysfunction (including deficits in theory of mind, central coherence, and executive function) that impacts trauma processing in ways that portend violence. While these mechanisms for a trauma-violence association in ASD may have case-based support, more research is needed to confirm these mechanisms and clarify whether in fact trauma increases violence risk in ASD. To facilitate the investigation, it would be helpful for clinical and forensic evaluators to obtain a careful trauma history when evaluating all individuals, including those with ASD. PMID- 27236174 TI - Forensic Implications of Neuroscientific Advancements. AB - Im draws a parallel between the neurobiology of individuals with autism spectrum disorder (ASD) and that of trauma survivors, to explain why individuals with ASD may be more vulnerable to trauma as a risk factor for violence. This commentary raises questions about how we use this information in a forensic context, including its potential misuses. It urges caution in not overstating the data before we have a more nuanced understanding of how our neural circuitry influences specific behaviors and mental states, while not allowing the science to advance faster than we can harness it, overstepping its bounds in decisions we make regarding fairness and justice. It raises these concerns against a backdrop of the diametrically opposed assumptions about human behavior embraced by the two disciplines, mental health and the law, that come together in the forensic arena. PMID- 27236175 TI - Trauma and Violence in Autism. AB - Comorbidities of autism spectrum disorder are discussed as an introduction to the argument that, although ASD may modify presentation, it does not confer any protection against other disorder, including the negative effects of trauma (e.g., posttraumatic stress disorder). Dr. Im's hypotheses are discussed, and a case example of childhood disintegrative disorder (CDD) is raised to give clinical support to his hypotheses. CDD is a rare form of ASD that is defined by late onset, a traumatic prodrome, onset of behaviors including some with similarities to PTSD, and aggression. PMID- 27236176 TI - Detained Adolescents: Mental Health Needs, Treatment Use, and Recidivism. AB - Although approximately 60 to 70 percent of detained adolescents meet criteria for a mental disorder, few receive treatment upon community re-entry. Given that mental health treatment can reduce recidivism, we examined detained adolescents' mental health needs and their postdetention mental health treatment and recidivism. Altogether, 1,574 adolescents (<=18 years) completed a mental health screening at a detention center. Scores on the screening, mental health treatment utilization (60 days after detention), and recidivism (6 months after detention) were measured. About 82.2 percent of adolescents had elevated scores on the mental health screening, but only 16.4 percent obtained treatment and 37.2 percent reoffended. Logistic regression models revealed adolescents with insurance and higher angry-irritable scores were significantly more likely to obtain treatment, whereas males, black and older adolescents, and those endorsing a trauma history were less likely. Black adolescents, insured adolescents, and those with higher alcohol and drug use scores were significantly more likely to reoffend. Mental health treatment increased the likelihood of recidivism. The prevalence of mental health needs among detained adolescents was high, but treatment utilization was low, with notable treatment disparities across race, gender, and age. The use of mental health treatment predicted recidivism, suggesting that treatment acts as a proxy measure of mental health problems. Future research should assess the impact of timely and continuous mental health services on recidivism among detained adolescents. PMID- 27236177 TI - Conducted-Energy Device (Taser) Usage in Subjects With Mental Illness. AB - Use of a conducted-energy device (CED), or Taser, by law enforcement officers (LEOs) is recommended over more lethal forms of force. LEOs interact with a wide variety of people including individuals with mental illness and those with substance use disorders. The literature is devoid of data regarding the effect of CEDs on this special population. We used data collected by LEOs from 2008 to 2009. There were 233 cases over the two-year period. Of the 233 individuals on whom the Taser was used, 38 had a mental illness and 91 were under the influence of substances (not mutually exclusive). The average number of shocks necessary to achieve compliance was 1.92 for persons with a mental illness (t(231) = 2.565; p = .011, versus nonintoxicated control subjects without mental illness and 2.55 for persons under the influence of stimulants (t(143) = 3.027; p = .003, versus nonintoxicated control subjects without mental illness). The results of this study serve to inform LEOs and administrators of the patterns of use of CEDs in communities. PMID- 27236178 TI - Neurocognitive Deficits Associated with Antisocial Personality Disorder in Non treatment-seeking Young Adults. AB - Antisocial personality disorder (ASPD) is a relatively common problem, but the neuropsychological profile of affected individuals has seldom been studied outside of criminal justice recruitment settings. Non-treatment-seeking young adults (18-29 years) were recruited from the general community by media advertisements. Participants with ASPD (n = 17), free from substance use disorders, were compared with matched controls (n = 229) using objective computerized neuropsychological tasks tapping a range of cognitive domains. Compared with controls, individuals with ASPD showed significantly elevated pathological gambling symptoms, previous illegal acts, unemployment, greater nicotine consumption, and relative impairments in response inhibition (Stop Signal Task) and decision-making (less risk adjustment, Cambridge Gamble Task). General response speed, set-shifting, working memory, and executive planning were intact. ASPD was also associated with higher impulsivity and venturesomeness on the Eysenck Questionnaire. These findings implicate impaired inhibitory control and decision-making in the pathophysiology of ASPD, even in milder manifestations of the disorder. Future work should explore the neural correlates of these impairments and use longitudinal designs to examine the temporal relationship between these deficits, antisocial behavior, and functional impairment. PMID- 27236179 TI - The Ethics of APA's Goldwater Rule. AB - Section 7.3 of the code of ethics of the American Psychiatric Association (APA) cautions psychiatrists against making public statements about public figures whom they have not formally evaluated. The APA's concern is to safeguard the public perception of psychiatry as a scientific and credible profession. The ethic is that diagnostic terminology and theory should not be used for speculative or ad hominem attacks that promote the interests of the individual physician or for political and ideological causes. However, the Goldwater Rule presents conflicting problems. These include the right to speak one's conscience regarding concerns about the psychological stability of high office holders and competing considerations regarding one's role as a private citizen versus that as a professional figure. Furthermore, the APA's proscription on diagnosis without formal interview can be questioned, since third-party payers, expert witnesses in law cases, and historical psychobiographers make diagnoses without conducting formal interviews. Some third-party assessments are reckless, but do not negate legitimate reasons for providing thoughtful education to the public and voicing psychiatric concerns as acts of conscience. We conclude that the Goldwater Rule was an excessive organizational response to what was clearly an inflammatory and embarrassing moment for American psychiatry. PMID- 27236180 TI - Reflections on the Legal Battles Over Prisoners with Gender Dysphoria. AB - Momentum has shifted in the legal battles over the provision of sex reassignment surgery (SRS) for male prisoners. In 2015, two court decisions granted the operation and were not appealed by the California Department of Corrections and Rehabilitation. The author, who has participated in some of these battles as an expert, analyzes the strengths and limitations of the medical illness, developmental, and minority rights paradigms for Gender Dysphoria that are used to reach psychiatric opinions about medical necessity. Courts are influenced by the recommendation of the World Professional Association for Transgender Health (WPATH) that inmates should be treated as are individuals in the community. This is a compassionate assertion, but one not fully informed by practical experience with SRS among prisoners. Most inmates requesting SRS through litigation are serving very long or life sentences. Their backgrounds are quite unlike most transgendered individuals encountered in the community. If long-term prisoners are provided with SRS, the study of their adaptations may enable future decisions to be based on adaptation data rather than the competing opinions of experts. Gathering such data may be challenged as an experiment, however, and viewed as unethical. PMID- 27236181 TI - A Conceptual Overview and Commentary on Gender Dysphoria. AB - Gender Dysphoria is a distressed state of mind that is of interest to psychiatrists, including forensic psychiatrists. Forensic matters can be best addressed only after one has a good appreciation of relevant psychiatric knowledge and concepts. In this commentary I review the nature of Gender Dysphoria, its relationship to cross-dressing and erotic arousal, and the question of whether it should be thought of as a psychiatric disorder. I also review the complexity of sex and gender; alternative conceptualizations of Gender Dysphoria, its etiology, its multicultural history, and its typical course over time in a given individual. Finally, I summarize treatment options, treatment outcomes, and difficulties of treating Gender Dysphoria within an inmate population. PMID- 27236183 TI - International Handbook of Threat Assessment. PMID- 27236182 TI - Correctional Management and Treatment of Autism Spectrum Disorder. AB - Over the past two decades, the recognition and diagnosis of autism spectrum disorders (ASDs) has grown. One result is the parallel recognition of a substantial prevalence of individuals with ASD who, because of life-long social and emotional deficits, have become involved with the criminal justice system (CJS). It is generally acknowledged that many CJS professionals who encounter individuals with ASD are ill equipped to treat or advocate for them. Currently, there is no universal training on ASD for CJS professionals, nor are there service standards for individuals with ASD during incarceration, to support their community re-entry and reduce recidivism. In this article, we review the background and context for management and treatment during incarceration for individuals with ASD. PMID- 27236184 TI - Philosophy and Psychiatry: Problems, Intersections, and New Perspectives. PMID- 27236185 TI - Forensic Psychiatry: Essential Board Review. PMID- 27236188 TI - A Father's Illness. PMID- 27236187 TI - FGFR2 risk SNPs confer breast cancer risk by augmenting oestrogen responsiveness. AB - The fibroblast growth factor receptor 2 (FGFR2) locus is consistently the top hit in genome-wide association studies for oestrogen receptor-positive (ER(+)) breast cancer. Yet, its mode of action continues to be controversial. Here, we employ a systems biology approach to demonstrate that signalling via FGFR2 counteracts cell activation by oestrogen. In the presence of oestrogen, the oestrogen receptor (ESR1) regulon (set of ESR1 target genes) is in an active state. However, signalling by FGFR2 is able to reverse the activity of the ESR1 regulon. This effect is seen in multiple distinct FGFR2 signalling model systems, across multiple cells lines and is dependent on the presence of FGFR2. Increased oestrogen exposure has long been associated with an increased risk of breast cancer. We therefore hypothesized that risk variants should reduce FGFR2 expression and subsequent signalling. Indeed, transient transfection experiments assaying the three independent variants of the FGFR2 risk locus (rs2981578, rs35054928 and rs45631563) in their normal chromosomal context show that these single-nucleotide polymorphisms (SNPs) map to transcriptional silencer elements and that, compared with wild type, the risk alleles augment silencer activity. The presence of risk variants results in lower FGFR2 expression and increased oestrogen responsiveness. We thus propose a molecular mechanism by which FGFR2 can confer increased breast cancer risk that is consistent with oestrogen exposure as a major driver of breast cancer risk. Our findings may have implications for the clinical use of FGFR2 inhibitors. PMID- 27236194 TI - Longitudinal genomic characterization of brain tumors for identification of therapeutic vulnerabilities. PMID- 27236195 TI - Powering and puzzling in global public health. PMID- 27236199 TI - Vasculotide, an Angiopoietin-1 mimetic, ameliorates several features of experimental atopic dermatitis-like disease. AB - BACKGROUND: Earlier studies by our group have demonstrated that a transgenic animal engineered to express Tie2 under the control of the Tie2 promoter produced animals with a scaly skin phenotype that recapitulated many of the hallmarks of atopic dermatitis (AT-Derm). To test the hypothesis that this model of AT-Derm is driven by dysregulated Tie2-signalling, we have bred AT-Derm transgenic (TG) animals with TG-animals engineered to overexpress Angiopoietin-1 or -2, the cognate Tie2 ligands. These two ligands act to antagonize one another in a context-dependent manner. To further evaluate the role of Ang1-driven-Tie2 signalling, we examined the ability of Vasculotide, an Ang1-mimetic, to modulate the AT-Derm phenotype. RESULTS: AT-Derm+Ang2 animals exhibited an accentuated phenotype, whereas AT-Derm+Ang1 presented with a markedly reduced skin disease, similarly VT-treated AT-Derm animals present with a clear decrease in the skin phenotype. Moreover, a decrease in several important inflammatory cytokines and a decrease in the number of eosinophils was noted in VT-treated animals. Bone marrow differentiation in the presence of VT produced fewer CFU-G colonies, further supporting a role for Tie2-signalling in eosinophil development. Importantly, we demonstrate activation of Tie2, the VT-target, in lung tissue from naive animals treated with increasing amounts of VT. CONCLUSIONS: The AT Derm phenotype in these animals is driven through dysregulation of Tie2 receptor signalling and is augmented by supplemental Ang2-dependent stimulation. Overexpression of Ang1 or treatment with VT produced a similar amelioration of the phenotype supporting the contention that VT and Ang1 have a similar mechanism of action on the Tie2 receptor and can both counteract the signalling driven by Ang2. Our results also support a possible role for Tie2-signalling in the development of eosinophilic diseases and that activation of Tie2 may directly or indirectly modulate the differentiation of eosinophils, which express Tie2. In summary, these data support the hypothesis that this AT-Derm mouse model is driven by dysregulation of the Tie2 signalling pathway and increased Ang2 levels can aggravate it, whereas it can be reversed by either Ang1-overexpression or VT treatment. Moreover, our data supports the contention that VT acts as an Angiopoietin-1 mimetic and may provide a novel entry point for Tie2-agonist-based therapies for atopic diseases. PMID- 27236198 TI - Differentiation-related glycan epitopes identify discrete domains of the muscle glycocalyx. AB - The neuromuscular junction (NMJ) is enriched with glycoproteins modified with N acetylgalactosamine (GalNAc) residues, and four nominally GalNAc-specific plant lectins have historically been used to identify the NMJ and the utrophin glycoprotein complex. However, little is known about the specific glycan epitopes on skeletal muscle that are bound by these lectins, the glycoproteins that bear these epitopes or how creation of these glycan epitopes is regulated. Here, we profile changes in cell surface glycosylation during muscle cell differentiation and identify distinct differences in the binding preferences of GalNAc-specific lectins, Wisteria floribunda agglutinin (WFA), Vicia villosa agglutinin (VVA), soybean agglutinin (SBA) and Dolichos biflorus agglutinin (DBA). While we find that all four GalNAc binding lectins specifically label the NMJ, each of the four lectins binds distinct sets of muscle glycoproteins; furthermore, none of the major adhesion complexes are required for binding of any of the four GalNAc specific lectins. Analysis of glycosylation-related transcripts identified target glycosyltransferases and glycosidases that could potentially create GalNAc containing epitopes; reducing expression of these transcripts by siRNA highlighted differences in lectin binding specificities. In addition, we found that complex N-glycans are required for binding of WFA and SBA to murine C2C12 myotubes and for WFA binding to wild-type skeletal muscle, but not for binding of VVA or DBA. These results demonstrate that muscle cell surface glycosylation is finely regulated during muscle differentiation in a domain- and acceptor substrate-specific manner, suggesting that temporal- and site-specific glycosylation are important for skeletal muscle cell function. PMID- 27236197 TI - Carbohydrates as T-cell antigens with implications in health and disease. AB - Glycosylation is arguably the most ubiquitous post-translational modification on proteins in microbial and mammalian cells. During the past few years, there has been intensive research demonstrating that carbohydrates, either in pure forms or in conjunction with proteins or lipids, evoke and modulate adaptive immune responses. We now know that carbohydrates can be directly recognized by T cells or participate in T-cell stimulation as components of T-cell epitopes. T-cell recognition of carbohydrate antigens takes place via their presentation by major histocompatibility complex pathways on antigen-presenting cells. In this review, we summarize studies on carbohydrates as T-cell antigens modulating adaptive immune responses. Through discussion of glycan-containing antigens, such as glycoproteins, glycolipids, zwitterionic polysaccharides and carbohydrate-based glycoconjugate vaccines, we will illustrate the key molecular and cellular interactions between carbohydrate antigens and T cells and the implications of these interactions in health and disease. PMID- 27236200 TI - Process evaluation of an environmental health risk audit and action plan intervention to reduce alcohol related violence in licensed premises. AB - BACKGROUND: Alcohol-related violence is associated with licensed premise environments and their management. There is a lack of evidence for effective interventions to address these, and there are significant barriers to implementation. This study aims to understand how development and implementation processes can facilitate intervention reach, fidelity and receipt and therefore provides key process data necessary to interpret the results of the randomised controlled trial conducted in parallel. METHODS: A process evaluation, embedded within a randomised controlled trial. Intervention development and implementation were assessed via focus groups (n = 2) and semi-structured interviews (n = 22) with Environmental Health Practitioners (EHPs). Reach and fidelity were assessed via routinely collected intervention data, which was was collected from 276 licenced premises across Wales, UK. Case study semi-structured interviews with licensed premises proprietors (n = 30) explored intervention receipt. RESULTS: Intervention co-production with senior EHPs facilitated organisational adoption and implementation. Training events for EHPs played an important role in addressing wider organisational concerns regarding partnership working and the contextual integration of the intervention. EHPs delivered the intervention to 98 % of intervention premises; 35 % of premises should have received a follow up enforcement visit, however EHP confidence in dealing with alcohol risk factors meant only 7 % of premises received one. Premises therefore received a similar intervention dose regardless of baseline risk. Intervention receipt appeared to be greatest in premises with an existing commitment to prevention and those in urban environments. CONCLUSIONS: The study suggests that a collaborative approach to the development and diffusion of interventions is associated with high levels of organisational adoption, implementation and reach. However, the lack of enforcement visits represents implementation failure for a key mechanism of action that is likely to influence intervention effectiveness. To be effective, any future intervention may require a longer implementation period to develop EHP confidence in using enforcement approaches in this area and multiagency enforcement support, which includes the police, to deliver an adequate intervention dose. PMID- 27236201 TI - What shapes the oral jaws? Accommodation of complex dentition correlates with premaxillary but not mandibular shape. AB - BACKGROUND: Teeth are integrated into the vertebrate oral jaws to provide a functional unit for feeding, however little is known about how this integration occurs during growth and development. The purpose of this study is to identify the ontogenetic changes in oral jaw shape that are associated with the transition of the oral dentition from unicuspid teeth to multicuspid teeth. Here, we compare the shape of the occluding upper (premaxilla) and lower (mandible) jaws of the toothed Mexican tetra (Astyanax mexicanus) and the toothless (oral teeth present, pharyngeal teeth absent) zebrafish (Danio rerio) over development. Gross morphology combined with morphometric analyses were used to analyse shape changes of the occluding oral jaws in each species. Histological analyses were also used to examine the development of the mandibular symphysis. RESULTS: The occluding edge of the premaxilla is the first region to ossify in the Mexican tetra, but the last to ossify in zebrafish. Morphometric analyses revealed that the early shape of the premaxillae (in fish younger than 8mm SL) is the same in each species but that the premaxilla shape changes significantly at larger sizes. These changes are apparent in the tooth bearing region of the Mexican tetra. The rostral region of the mandible also houses teeth, however ossification and shape in this region were surprisingly similar between species despite differences in the presence of oral dentition. Furthermore, we found that the mandibular symphysis of the Mexican tetra is composed of interdigitating bone, while the symphyseal region of the zebrafish is composed of fibrous connective tissue. CONCLUSIONS: These differences in the jaw skeleton have likely evolved due to different feeding strategies utilised by each species. Our results show that premaxillae shape correlates strongly with the development of complex dentitions unlike in the mandible. This study provides important insights into the relationship between jaw and tooth development in bony fishes and suggests that these mechanisms may be similar amongst vertebrates. PMID- 27236202 TI - Evaluation of Hydroxyl Radical Diffusion and Acidified Thiourea as a Scavenger during Intracoronal Bleaching. AB - INTRODUCTION: The diffusion of hydroxyl radicals in intracoronal bleaching is associated with a risk of invasive cervical resorption. The use of acidified thiourea has been recommended as a scavenger of residual radicals generated during intracoronal bleaching. The aims of this study were to quantify hydroxyl radical diffusion to external root surfaces after intracoronal bleaching with commonly used materials and to evaluate the effect of using acidified thiourea with hydrogen peroxide (H2O2) on hydroxyl radical diffusion. METHODS: Eighty-two human premolars were prepared, stained, root filled, and allocated to experimental and control groups as follows: group 1: sodium perborate (SP) and water (n = 21), group 2: H2O2 (n = 21), group 3: acidified thiourea and H2O2 (n = 21), group 4: neutral thiourea and H2O2 (n = 10), control group 1: negative control (water) (n = 10), and control group 2: positive control (SP and H2O2) (n = 10). Materials were placed into the pulp chamber, sealed, and placed in 5 mmol/L terephthalic acid at 37 degrees C for 48 hours. Hydroxyl radicals were quantified using a fluorescence microplate reader and high-performance liquid chromatography with fluorescence detection. RESULTS: The H2O2 and SP mixture resulted in the greatest hydroxyl radical diffusion and was significantly greater than SP and water (P < .05) and H2O2 (P < .05). The addition of acidified thiourea resulted in higher radical diffusion, whereas the addition of neutral thiourea resulted in lower diffusion than H2O2 alone. CONCLUSIONS: The SP and water mixture resulted in the lowest hydroxyl radical diffusion, and the H2O2 and SP mixture resulted in the greatest. Although the addition of acidified thiourea to H2O2 did not reduce radicals detected, the addition of neutral thiourea had a positive effect. PMID- 27236203 TI - Contamination Controls for Analysis of Root Canal Samples by Molecular Methods: An Overlooked and Unsolved Problem. AB - INTRODUCTION: It has been almost 20 years since molecular methods were first described for the analysis of root canal microbial flora. Contamination control samples are essential to establish DNA decontamination before taking root canal samples, and this review assessed those studies. METHODS: Using PubMed, a search was conducted for studies using molecular microbial analysis for the investigation of endodontic samples. Studies were grouped according to the cleaning protocol, acquisition methods, and processing of control samples taken to check for contamination. RESULTS: Of 136 studies applying molecular analysis to root canal samples, 21 studies performed surface cleaning and checking nucleotide decontamination with contamination control samples processed by polymerase chain reaction. Only 1 study described disinfection, sampling from the access cavity, and processing by polymerase chain reaction and reported the result; that study reported that all samples contained contaminating bacterial DNA. CONCLUSIONS: Cleaning, disinfection, and checking for contamination are basic scientific prerequisites for this type of investigation; yet, this review identifies it as an overlooked issue. On the basis of this review, we call for improved scientific practice in this field. PMID- 27236204 TI - Co-dominant effect of selected natural dye sensitizers in DSSC performance. PMID- 27236205 TI - New in situ generated acylhydrazidate-coordinated complexes and acylhydrazide molecules: Synthesis, structural characterization and photoluminescence property. AB - By utilizing the hydrothermal in situ acylation of organic acids with N2H4, three acylhydrazidate-coordinated compounds [Mn(L1)2(H2O)2] (L1=2,3 quinolinedicarboxylhydrazidate; HL1=2,3-dihydropyridazino[4,5-b] quinoline-1,4 dione) 1, [Mn2(ox)(L2)2(H2O)6].2H2O (L2=benzimidazolate-5,6-dicarboxylhydrazide; HL2=6,7-dihydro-1H-imidazo[4,5-g]phthalazine-5,8-dione; ox=oxalate) 2, and [Cd(HL3)(bpy)] (L3=4,5-di(3'-carboxylphenyl)phthalhydrazidate; H3L3=6,7-dihydro 1H-imidazo[4,5-g]phthalazine-5,8-dione; bpy=2,2'-bipyridine) 3, as well as two acylhydrazide molecules L4 (L4=oxepino[2,3,4-de:7,6,5-d'e']diphthalazine 4,10(5H,9H)-dione) 4 and L5 (L5=4,5-dibromophthalhydrazide; L5=6,7-dibromo-2,3 dihydrophthalazine-1,4-dione) 5 were obtained. X-ray single-crystal diffraction analysis reveals that (i) 1 only possesses a mononuclear structure, but it self assembles into a 2-D supramolecular network via the NhydrazineH?Nhydrazine and OwH?Ohydroxylimino interactions; (ii) 2 exhibits a dinuclear structure. Ox acts as the linker, while L2 just serves as a terminal ligand; (iii) In 3, L3 acts as a 3-connected node to propagate the 7-coordinated Cd(2+) centers into a 1-D double-chain structure; (iv) 4 is a special acylhydrazide molecule. Two OH groups for the intermediates 3,3'-biphthalhydrazide further lose one water molecule to form 4; (v) 5 is a common monoacylhydrazide molecule. Via the NhydrazineH?Ohydrazine, OhydroxyliminoH?Oacylamino and the pi?pi interactions, it self-assembles into a 2-D supramolecular network. The photoluminescence analysis reveals that 4 emits light with the maxima at 510nm. PMID- 27236206 TI - Photocatalytic activity enhancement of anatase-graphene nanocomposite for methylene removal: Degradation and kinetics. AB - In the present research, the TiO2-graphene nanocomposite was synthesized by an eco-friendly method. The blackberry juice was introduced to graphene oxide (GO) as a reducing agent to produce the graphene nano-sheets. The nanocomposite of anatase-graphene was developed as a photocatalyst for the degradation of methylene blue, owing to the larger specific surface area and synergistic effect of reduced graphene oxide (RGO). The UV spectroscopy measurements showed that the prepared nanocomposite exhibited an excellent photocatalytic activity toward the methylene blue degradation. The rate of electron transfer of redox sheets is much higher than that observed on GO, indicating the applicability of proposed method for the production of anatase-RGO nanocomposite for treatment of water contaminated by cationic dye. The prepared materials were characterized with Fourier transform infrared spectroscopy, X-ray diffraction, Brunauer-Emmett Teller surface area measurement, scanning electron microscopy and transmission electron microscopy. A facile and rapid route was applied for the uniform deposition of anatase nanoparticles on the sheets. The resulting nanocomposite contained nanoparticles with a mean diameter of 10nm. A mechanism for the photocatalytic activity of nanocomposite was suggested and the degradation reaction obeyed the second-order kinetics. It was concluded that the degradation kinetics is changed due to the reduction of GO in the presence of blackberry juice. PMID- 27236207 TI - Efficacy of oral corticosteroids therapy in anti-glutamic acid decarboxylase antibodies cerebellar ataxia. PMID- 27236208 TI - Cricotracheostomy: new technique to open an airway in emergencies with partial resection of the cricoid cartilage. AB - Cricotracheostomy is suitable for use in high-risk situations when urgent endotracheal intubation and conventional open tracheostomy cannot be achieved. We successfully removed the anterior portion of the cricoid cartilage to establish access to the airways in seven patients with cancer of the head and neck without complications, and the stomas were closed in three patients who had no stenosis of the larynx. PMID- 27236209 TI - Ego-resiliency development from late adolescence to emerging adulthood: A ten year longitudinal study. AB - This study examined the development of ego-resiliency from late adolescence to emerging adulthood, using a 10-year cohort-sequential design. Participants were 335 Italian adolescents (173 females and 162 males), living, at the time of the study, in Genzano, a small city near to Rome. Latent growth curve analyses indicated that the developmental trajectory of ego-resiliency from 15 to 25 years is adequately described by a piecewise model that included separate growth profiles corresponding to different developmental stages. Essentially, ego resiliency remained remarkably stable until the end of high school, and then encountered a phase of relative increase. Moreover, the trajectory of ego resiliency from ages 15 to 19 was predicted by self-efficacy beliefs in managing negative emotions, and the trajectory from age 19 to 25 was predicted by experienced familial support and self-efficacy beliefs in expressing positive emotions at age 15. Experienced stressful life events also accounted for individuals' deviation from the typical ego-resiliency trajectory. PMID- 27236210 TI - Southern Ocean phytoplankton physiology in a changing climate. AB - The Southern Ocean (SO) is a major sink for anthropogenic atmospheric carbon dioxide (CO2), potentially harbouring even greater potential for additional sequestration of CO2 through enhanced phytoplankton productivity. In the SO, primary productivity is primarily driven by bottom up processes (physical and chemical conditions) which are spatially and temporally heterogeneous. Due to a paucity of trace metals (such as iron) and high variability in light, much of the SO is characterised by an ecological paradox of high macronutrient concentrations yet uncharacteristically low chlorophyll concentrations. It is expected that with increased anthropogenic CO2 emissions and the coincident warming, the major physical and chemical process that govern the SO will alter, influencing the biological capacity and functioning of the ecosystem. This review focuses on the SO primary producers and the bottom up processes that underpin their health and productivity. It looks at the major physico-chemical drivers of change in the SO, and based on current physiological knowledge, explores how these changes will likely manifest in phytoplankton, specifically, what are the physiological changes and floristic shifts that are likely to ensue and how this may translate into changes in the carbon sink capacity, net primary productivity and functionality of the SO. PMID- 27236211 TI - Occupational Radiation Exposure during Pregnancy: A Survey of Attitudes and Practices among Interventional Radiologists. AB - PURPOSE: To assess attitudes of interventional radiologists toward occupational ionizing radiation exposure in pregnancy and to survey practice patterns and outcomes. MATERIALS AND METHODS: A 34-question anonymous online survey on attitudes and work practices toward interventional radiologists who worked during pregnancy was sent to active SIR members, including 582 women. RESULTS: There were 534 (10%) respondents, including 142 women and 363 men. Among respondents, men were statistically older than women (P < .001) and had practiced interventional radiology (IR) longer (P < .001). Of female interventional radiologists, 55% had worked during pregnancy and reported no specific mutagenic events in their offspring. Spontaneous abortions (11%) and use of reproductive technology (17%) matched that of women with similar age and socioeconomic background. Although more women changed their work practice because of concerns of occupational exposure than men (23% vs 13%), this change was largely limited to the duration of a pregnancy. Among pregnant interventional radiologists, 4 (6%) completely abstained from performing fluoroscopically guided interventions (FGIs), whereas 31 (46%) continued to spend > 80% of their work week doing FGIs with additional protection. Perceptions of impact of pregnancy on daytime work redistribution varied significantly with gender (P < .001); however, perceptions regarding impact of pregnancy on on-call hours, distribution of complex cases, and need to hire for temporary coverage were similar between the genders. CONCLUSIONS: Most pregnant interventional radiologists continue to practice IR while pregnant. Pregnancy and fetal outcomes parallel that of the general population when matched for demographics. However, perceptions of impact of pregnancy on work lives of colleagues vary notably. PMID- 27236212 TI - Insights into the complex levels of regulation imposed on Escherichia coli DNA polymerase V. AB - It is now close to 40 years since the isolation of non-mutable umu/uvm strains of Escherichia coli and the realization that damage induced mutagenesis in E.coli is not a passive process. Early models of mutagenesis envisioned the Umu proteins as accessory factors to the cell's replicase that not only reduced its normally high fidelity, but also allowed the enzyme to traverse otherwise replication-blocking lesions in the genome. However, these models underwent a radical revision approximately 15 years ago, with the discovery that the Umu proteins actually encode for a DNA polymerase, E.coli pol V. The polymerase lacks 3'->5' exonucleolytic proofreading activity and is inherently error-prone when replicating both undamaged and damage DNA. So as to limit any "gratuitous" mutagenesis, the activity of pol V is strictly regulated in the cell at multiple levels. This review will summarize our current understanding of the myriad levels of regulation imposed on pol V including transcriptional control, posttranslational modification, targeted proteolysis, activation of the catalytic activity of pol V through protein-protein interactions and the very recently described intracellular spatial regulation of pol V. Remarkably, despite the multiple levels at which pol V is regulated, the enzyme is nevertheless able to contribute to the genetic diversity and evolutionary fitness of E.coli. PMID- 27236214 TI - "Polymorphisms in double strand break repair related genes influence radiosensitivity phenotype in lymphocytes from healthy individuals" [DNA Repair 40 (2016) 27-34]. PMID- 27236213 TI - DNA damage tolerance by recombination: Molecular pathways and DNA structures. AB - Replication perturbations activate DNA damage tolerance (DDT) pathways, which are crucial to promote replication completion and to prevent fork breakage, a leading cause of genome instability. One mode of DDT uses translesion synthesis polymerases, which however can also introduce mutations. The other DDT mode involves recombination-mediated mechanisms, which are generally accurate. DDT occurs prevalently postreplicatively, but in certain situations homologous recombination is needed to restart forks. Fork reversal can function to stabilize stalled forks, but may also promote error-prone outcome when used for fork restart. Recent years have witnessed important advances in our understanding of the mechanisms and DNA structures that mediate recombination-mediated damage bypass and highlighted principles that regulate DDT pathway choice locally and temporally. In this review we summarize the current knowledge and paradoxes on recombination-mediated DDT pathways and their workings, discuss how the intermediate DNA structures may influence genome integrity, and outline key open questions for future research. PMID- 27236215 TI - Radial distribution function imaging by STEM diffraction: Phase mapping and analysis of heterogeneous nanostructured glasses. AB - Characterizing heterogeneous nanostructured amorphous materials is a challenging topic, because of difficulty to solve disordered atomic arrangement in nanometer scale. We developed a new transmission electron microscopy (TEM) method to enable phase analysis and mapping of heterogeneous amorphous structures. That is to combine scanning TEM (STEM) diffraction mapping, radial distribution function (RDF) analysis, and hyperspectral analysis. This method was applied to an amorphous zirconium oxide and zirconium iron multilayer system, and showed extreme sensitivity to small atomic packing variations. This approach helps to understand local structure variations in glassy composite materials and provides new insights to correlate structure and properties of glasses. PMID- 27236216 TI - Coronary Artery Disease: Why We should Consider the Y Chromosome. AB - Coronary artery disease (CAD) is one of the leading causes of morbidity and mortality globally. In the last few years our understanding of the genetic and molecular mechanisms that promote CAD in individuals has increased with the advent of the genome era. This complex inflammatory disease has well-defined environmental risk factors. However, in the last 10 years, studies including genome-wide association studies (GWAS) have clearly demonstrated a genetic influence on CAD. Recently, studies on the human Y chromosome have also demonstrated that genetic variation within the male-specific region of the Y chromosome (MSY) could play a part in determining cardiovascular risk in men, confirming the notion that the increased risk for CAD in men cannot be fully explained through common CAD risk factors. Here, we review the literature about the pathophysiology of CAD, its potential causes and environmental risk factors known so far. Furthermore, we review the genetics of CAD, especially the latest discoveries regarding the implication of the Y chromosome, the most underexplored portion of the human genome to date, highlighting methods and difficulties arising in this research field, and discussing the importance of considering the Y chromosome in CAD research. PMID- 27236217 TI - 20% subcutaneous immunoglobulin dosed biweekly for primary immunodeficiency. PMID- 27236218 TI - Association of FEF25%-75% and bronchodilator reversibility with asthma control and asthma morbidity in inner-city children with asthma. PMID- 27236219 TI - Adoptive transfer of food allergy via unrelated allogeneic bone marrow transplant. PMID- 27236220 TI - Occupational allergic respiratory disease due to royal jelly. PMID- 27236221 TI - Selecting radiomic features from FDG-PET images for cancer treatment outcome prediction. AB - As a vital task in cancer therapy, accurately predicting the treatment outcome is valuable for tailoring and adapting a treatment planning. To this end, multi sources of information (radiomics, clinical characteristics, genomic expressions, etc) gathered before and during treatment are potentially profitable. In this paper, we propose such a prediction system primarily using radiomic features (e.g., texture features) extracted from FDG-PET images. The proposed system includes a feature selection method based on Dempster-Shafer theory, a powerful tool to deal with uncertain and imprecise information. It aims to improve the prediction accuracy, and reduce the imprecision and overlaps between different classes (treatment outcomes) in a selected feature subspace. Considering that training samples are often small-sized and imbalanced in our applications, a data balancing procedure and specified prior knowledge are taken into account to improve the reliability of the selected feature subsets. Finally, the Evidential K-NN (EK-NN) classifier is used with selected features to output prediction results. Our prediction system has been evaluated by synthetic and clinical datasets, consistently showing good performance. PMID- 27236222 TI - Renal compartment segmentation in DCE-MRI images. AB - Renal compartment segmentation from Dynamic Contrast-Enhanced MRI (DCE-MRI) images is an important task for functional kidney evaluation. Despite advancement in segmentation methods, most of them focus on segmenting an entire kidney on CT images, there still lacks effective and automatic solutions for accurate segmentation of internal renal structures (i.e. cortex, medulla and renal pelvis) from DCE-MRI images. In this paper, we introduce a method for renal compartment segmentation which can robustly achieve high segmentation accuracy for a wide range of DCE-MRI data, and meanwhile requires little manual operations and parameter settings. The proposed method consists of five main steps. First, we pre-process the image time series to reduce the motion artifacts caused by the movement of the patients during the scans and enhance the kidney regions. Second, the kidney is segmented as a whole based on the concept of Maximally Stable Temporal Volume (MSTV). The proposed MSTV detects anatomical structures that are homogeneous in the spatial domain and stable in terms of temporal dynamics. MSTV based kidney segmentation is robust to noises and does not require a training phase. It can well adapt to kidney shape variations caused by renal dysfunction. Third, voxels in the segmented kidney are described by principal components (PCs) to remove temporal redundancy and noises. And then k-means clustering of PCs is applied to separate voxels into multiple clusters. Fourth, the clusters are automatically labeled as cortex, medulla and pelvis based on voxels' geometric locations and intensity distribution. Finally, an iterative refinement method is introduced to further remove noises in each segmented compartment. Experiments on 14 real clinical kidney datasets and 12 synthetic dataset demonstrate that results produced by our method match very well with those segmented manually and the performance of our method is superior to the other five existing methods. PMID- 27236223 TI - Identification of lesion images from gastrointestinal endoscope based on feature extraction of combinational methods with and without learning process. AB - The gastrointestinal endoscopy in this study refers to conventional gastroscopy and wireless capsule endoscopy (WCE). Both of these techniques produce a large number of images in each diagnosis. The lesion detection done by hand from the images above is time consuming and inaccurate. This study designed a new computer aided method to detect lesion images. We initially designed an algorithm named joint diagonalisation principal component analysis (JDPCA), in which there are no approximation, iteration or inverting procedures. Thus, JDPCA has a low computational complexity and is suitable for dimension reduction of the gastrointestinal endoscopic images. Then, a novel image feature extraction method was established through combining the algorithm of machine learning based on JDPCA and conventional feature extraction algorithm without learning. Finally, a new computer-aided method is proposed to identify the gastrointestinal endoscopic images containing lesions. The clinical data of gastroscopic images and WCE images containing the lesions of early upper digestive tract cancer and small intestinal bleeding, which consist of 1330 images from 291 patients totally, were used to confirm the validation of the proposed method. The experimental results shows that, for the detection of early oesophageal cancer images, early gastric cancer images and small intestinal bleeding images, the mean values of accuracy of the proposed method were 90.75%, 90.75% and 94.34%, with the standard deviations (SDs) of 0.0426, 0.0334 and 0.0235, respectively. The areas under the curves (AUCs) were 0.9471, 0.9532 and 0.9776, with the SDs of 0.0296, 0.0285 and 0.0172, respectively. Compared with the traditional related methods, our method showed a better performance. It may therefore provide worthwhile guidance for improving the efficiency and accuracy of gastrointestinal disease diagnosis and is a good prospect for clinical application. PMID- 27236224 TI - New insight into microbial diversity and functions in traditional Vietnamese alcoholic fermentation. AB - The roles of microorganisms in traditional alcoholic fermentation are often assumed based on abundance in the starter and activity in pure culture. There is a serious lack of hard evidence on the behavior and activity of individual microbial species during the actual fermentation process. In this study, microbial succession and metabolite changes during 7days of traditional Vietnamese alcoholic fermentation were monitored. Special attention was devoted to starch degradation. In total, 22 microbial species, including 6 species of filamentous fungi (Rhizopus microsporus, Rhizopus arrhizus, Mucor indicus, Mucor circinelloides, Cunninghamella elegans, Aspergillus niger), 1 yeast-like fungus (Saccharomycopsis fibuligera), 7 yeasts (Saccharomyces cerevisiae, Clavispora lusitaniae, Wickerhamomyces anomalus, Lindnera fabianii, Pichia kudriavzevii, Candida rugosa, Candida tropicalis), and 8 bacteria (Stenotrophomonas maltophilia, Lactobacillus brevis, Lactobacillus helveticus, Acinetobacter baumannii, Staphylococcus hominis, Bacillus megaterium, Enterobacter asburiae, Pediococcus pentosaceus) were identified. Despite the presence of a complex microbiota in the starter, the fermentation process is consistent and involves a limited number of functional species. Rapid change in microbial composition of fermentation mash was observed and it was correlated with ethanol content. Microbial biomass reached maximum during first 2days of solid state fermentation. Acidification of the medium took place in day 1, starch degradation in days 2, 3, 4, and alcohol accumulation from day 3. Although Sm. fibuligera dominated by cell count amongst potential starch degraders, zymography indicated that it did not produce amylase in the fermentation mash. In mixed culture with Rhizopus, amylase production by Sm. fibuligera is regulated by the moisture content of the substrate. Rhizopus was identified as the main starch degrader and S. cerevisiae as the main ethanol producer. Bacterial load was high but unstable in species composition and dominated by acid producers. M. indicus, Sm. fibuligera, W. anomalus and bacteria were regarded as satellite microorganisms. Their possible influence on organoleptic quality of fermentation product was discussed. PMID- 27236225 TI - Impact of the sampling method and chilling on the Salmonella recovery from pig carcasses. AB - Differences in recovery of Salmonella on pig carcasses using non-destructive and destructive sampling methods is not well understood in respect to the chilling processes applied in slaughterhouses. Therefore, in two slaughterhouses, four strains at two different concentrations were inoculated onto pork skin. Inoculated skin samples were sampled before and after chilling with two sampling methods: swabbing and destruction. Both slaughterhouses were visited three times and all tests were performed in triplicate. All samples were analysed using the ISO-method and recovered isolates were confirmed by PFGE. The chilling system (fast or conventional cooling) nor the sampling step (before and after chilling) did not significantly influence the recovery of Salmonella. However, swabbing after chilling leads to an underestimation of the real number of contaminated carcasses. Therefore, destructive sampling is the more designated sampling method after chilling. PMID- 27236226 TI - Metabolic variations in different citrus rootstock cultivars associated with different responses to Huanglongbing. AB - Huanglongbing (HLB) is one of the most destructive bacterial diseases of citrus. No resistant cultivars have been identified, although tolerance has been observed in the genus Poncirus and some of its hybrids with Citrus that are commonly used as rootstocks. In this study we exploited this tolerance by comparing five different tolerant hybrids with a cultivar that shows pronounced HLB sensitivity to discern potential contributing metabolic factors. Whole leaves of infected and non-infected greenhouse-grown seedlings were extracted and subjected to untargeted GC-TOF MS based metabolomics. After BinBase data filtering, 342 (experiment 1) and 650 (experiment 2) unique metabolites were quantified, of which 122 and 195, respectively, were assigned by chemical structures. The number of metabolites found to be differently regulated in the infected state compared with the non-infected state varied between the cultivars and was largest (166) in the susceptible cultivar Cleopatra mandarin (Citrus reticulata) and lowest (3) in the tolerant cultivars US-897 (C. reticulata 'Cleopatra' * Poncirus trifoliata) and US-942 (C. reticulata 'Sunki' * P. trifoliata) from experiment 2. Tolerance to HLB did not appear to be associated with accumulation of higher amounts of protective metabolites in response to infection. Many metabolites were found in higher concentrations in the tolerant cultivars compared with susceptible Cleopatra mandarin and may play important roles in conferring tolerance to HLB. Lower availability of specific sugars necessary for survival of the pathogen may also be a contributing factor in the decreased disease severity observed for these cultivars. PMID- 27236227 TI - Identification of differentially expressed genes and signalling pathways in bark of Hevea brasiliensis seedlings associated with secondary laticifer differentiation using gene expression microarray. AB - The natural rubber of Para rubber tree, Hevea brasiliensis, is the main crop involved in industrial rubber production due to its superior quality. The Hevea bark is commercially exploited to obtain latex, which is produced from the articulated secondary laticifer. The laticifer is well defined in the aspect of morphology; however, only some genes associated with its development have been reported. We successfully induced secondary laticifer in the jasmonic acid (JA) treated and linolenic acid (LA)-treated Hevea bark but secondary laticifer is not observed in the ethephon (ET)-treated and untreated Hevea bark. In this study, we analysed 27,195 gene models using NimbleGen microarrays based on the Hevea draft genome. 491 filtered differentially expressed (FDE) transcripts that are common to both JA- and LA-treated bark samples but not ET-treated bark samples were identified. In the Eukaryotic Orthologous Group (KOG) analysis, 491 FDE transcripts belong to different functional categories that reflect the diverse processes and pathways involved in laticifer differentiation. In the Kyoto Encyclopedia of Genes and Genomes (KEGG) and KOG analysis, the profile of the FDE transcripts suggest that JA- and LA-treated bark samples have a sufficient molecular basis for secondary laticifer differentiation, especially regarding secondary metabolites metabolism. FDE genes in this category are from the cytochrome (CYP) P450 family, ATP-binding cassette (ABC) transporter family, short-chain dehydrogenase/reductase (SDR) family, or cinnamyl alcohol dehydrogenase (CAD) family. The data includes many genes involved in cell division, cell wall synthesis, and cell differentiation. The most abundant transcript in FDE list was SDR65C, reflecting its importance in laticifer differentiation. Using the Basic Local Alignment Search Tool (BLAST) as part of annotation and functional prediction, several characterised as well as uncharacterized transcription factors and genes were found in the dataset. Hence, the further characterization of these genes is necessary to unveil their role in laticifer differentiation. This study provides a platform for the further characterization and identification of the key genes involved in secondary laticifer differentiation. PMID- 27236228 TI - The pathogenicity and host adaptation of livestock-associated MRSA CC398. AB - The presence of methicillin-resistant Staphylococcus aureus (MRSA) CC398 in livestock and their transmission to humans followed by their introduction into hospitals led to a significant burden for the human healthcare system, especially in regions with a high density of livestock breeding. The CC398 lineage made two host changes in its evolutionary history: From humans to pigs and other livestock associated animals and back to the human host. These adaptation processes are mirrored by changes of the equipment with virulence factors necessary for successful host change. Here, we consider these factors and their special role during human colonization and infection. Host adaptation of S. aureus CC398 is accompanied by genetic changes that are mainly driven by exchanges of mobile genetic elements. So far, it is not clear, which virulence or adhesion factors are important for S. aureus CC398 in host interaction. Among human and animal derived MRSA CC398 virulence factors, e.g. (entero-) toxins, were rarely found. Overall, this review provides a comprehensive overview on the emerging S. aureus lineage CC398 by summarizing current knowledge from microbiological, molecular and cellular interaction studies in relation to clinical and epidemiological perspectives. PMID- 27236229 TI - Total petroleum hydrocarbon degradation by hybrid electrobiochemical reactor in oilfield produced water. AB - The crude oil drilling and extraction operations are aimed to maximize the production may be counterbalanced by the huge production of contaminated produced water (PW). PW is conventionally treated through different physical, chemical, and biological technologies. The efficiency of suggested hybrid electrobiochemical (EBC) methods for the simultaneous removal of total petroleum hydrocarbon (TPH) and sulfate from PW generated by petroleum industry is studied. Also, the factors that affect the stability of PW quality are investigated. The results indicated that the effect of biological treatment is very important to keep control of the electrochemical by-products and more TPH removal in the EBC system. The maximum TPH and sulfate removal efficiency was achieved 75% and 25.3%, respectively when the detention time was about 5.1min and the energy consumption was 32.6mA/cm(2). However, a slight increasing in total bacterial count was observed when the EBC compact unit worked at a flow rate of average 20L/h. Pseudo steady state was achieved after 30min of current application in the solution. Also, the results of the study indicate that when the current intensity was increased above optimum level, no significant results occurred due to the release of gases. PMID- 27236230 TI - Response of rocky shore communities to anthropogenic pressures in Albania (Mediterranean Sea): Ecological status assessment through the CARLIT method. AB - The lower mid-littoral and shallow subtidal communities were studied in the district of Vlora (Albania), three years after the establishment of a Marine Protected Area, with particular attention to the long-lived species. The bioconstructions built in the mid-littoral zone by the calcified rhodobiont Lithophyllum byssoides were in poor condition and sometimes even dead. In contrast, the brown alga Cystoseira amentacea constituted lush stands. For assessing the ecological status of the studied area, the CARLIT method, based upon macroalgal communities, was applied. The observed range of ecological status was wide ('high' through 'bad') and was overall among the lowest assessed to date in the Mediterranean Sea. The occurrence of extensive sea-urchin barren-grounds, though not taken into consideration by the CARLIT index, confirmed the poor condition of large sectors of the study area. Overall, the CARLIT index is well correlated with anthropogenic pressures, as assessed by the LUSI index. PMID- 27236231 TI - The status and management of the lionfish, Pterois sp. in Trinidad and Tobago. AB - Trinidad and Tobago was the last Caribbean island to be invaded by the lionfish and since its invasion in 2012 they have spread to most coral reef and hard bottom environments. Standard reef fish surveys were used to assess lionfish population densities and size distributions from 2013-2015. Total lengths ranged between 6.2-40.4cm and 2.2-950g in weight. The length-weight relationship was described by W=0.0002L(2.5654). Fish densities were highest in the northeast Tobago at 326lionfish/ha and the lowest in the southwest Tobago at 10.5lionfish/ha. In order to curtail the spread of this invasive species, a culling programme was initiated at selected reefs to regularly remove lionfish at monthly intervals. On the selected reefs 26-30% reduction in mean lionfish biomass and 25-27% reduction in abundance was noted compared to control sites (p<0.05). PMID- 27236232 TI - Master Plan Jakarta, Indonesia: The Giant Seawall and the need for structural treatment of municipal waste water. AB - In order to take actions against the annual flooding in Jakarta, the construction of a Giant Seawall has been proposed in the Master Plan for National Capital Integrated Coastal Development. The seawall provides a combination of technical solutions against flooding, but these will heavily modify the mass transports in the near-coastal area of Jakarta Bay. This study presents numerical simulations of river flux of total nitrogen and N,N-diethyl-m-toluamide, a molecular tracer for municipal waste water for similar scenarios as described in the Master Plan. Model results demonstrate a strong accumulation of municipal wastes and nutrients in the planned reservoirs to extremely high levels which will result in drastic adverse eutrophication effects if the treatment of municipal waste water is not dealt with in the same priority as the construction of the Giant Seawall. PMID- 27236233 TI - Copper and lead removal from aqueous solutions by bacterial consortia acting as biosorbents. AB - A bacterial consortium was selected in the presence of Cu from sediment samples taken from Sepetiba Bay, Brazil, which is a site historically contaminated by metals. Bacteria were exposed to 0, 1, 6, 12.5, 25 and 50MUg.mL(-1) Cu, Pb and Cu+Pb for 11days of bioassay. Results showed Alcanivorax dominance (81%) and cell counts of 10(8)cells.mL(-1). However, a reduction in dehydrogenase activity was observed from the fifth day of exposure for all Cu, Pb, and Cu+Pb concentrations tested. Esterase activity tended to increase, indicating higher energy demand to complete the bacterial lifecycle. Pb concentrations in the filtered culture medium (0.2MUm) were below the detection limit, indicating biosorption, whereas concentrations of Cu were close to the tested concentrations, indicative of efflux. Results suggest the need for biomarkers, such as esterase and dehydrogenase enzymatic activity, in the assessment of resistance and tolerance of communities previously exposed to stressors. PMID- 27236234 TI - Polycyclic aromatic hydrocarbons in surface sediments from the Coast of Weihai, China: Spatial distribution, sources and ecotoxicological risks. AB - This study was conducted to measure the polycyclic aromatic hydrocarbon (PAH) concentrations and evaluate the distribution, sources in surface sediments from various coastal sites in Weihai, which create good conditions for rapid development because of their excellent geographical location and abundant marine resources. The results indicated that the total PAHs contents in the sediments of Weihai ranged from 2.69 to 166.50ngg(-1), with an average of 67.44ngg(-1). Phenanthrene, Fluoranthene, Benzo(b)fluoranthene, Chrysene, and Pyrene were dominant in sediments, primarily as a result of high temperature combustion and biomass. Molecular ratios suggested that these PAHs in the sediments of Weihai were predominantly from pyrogenic sources such as grass, wood and charcoal combustion, as well as engine exhaust which is similar to the result of the study of the Yellow River Delta, China. The result of probability risk assessment additionally elucidated low PAH ecological risk in the surface sediments of Weihai, China. PMID- 27236235 TI - Methods for determining the antimicrobial susceptibility of mycobacteria. AB - Mycobacteria are a large group of microorganisms, multiple species of which are major causes of morbidity and mortality, such as tuberculosis and leprosy. At present, the emergence and spread of multidrug-resistant strains of Mycobacterium tuberculosis complex are one of the most serious health problems worldwide. Furthermore, in contrast to M. tuberculosis and Mycobacterium leprae, non tuberculous mycobacteria (NTM) are more frequently isolated and, in many cases, treatment is based on drug susceptibility testing. This article is a review of the different methods to determine the in vitro drug susceptibility of M. tuberculosis complex and the most relevant NTM isolates. The molecular techniques currently used for rapid detection of resistance of clinical specimens are also analysed. PMID- 27236237 TI - Microwave assisted green synthesis of fluorescent N-doped carbon dots: Cytotoxicity and bio-imaging applications. AB - A fast and facile microwave approach for the synthesis of fluorescent nitrogen doped carbon dots (N-CDs) is reported. The N-CDs were hydrothermally synthesized using l-ascorbic acid (AA) and beta-alanine (BA) as the carbon precursor and the nitrogen dopant, respectively. The morphology of synthesized N-CDs was characterized by high resolution transmission electron microscopy (HR-TEM) and the elemental composition was analyzed using elemental mapping method. The crystallinity and graphitation of N-CDs were examined by X-ray diffraction (XRD) and Raman spectroscopy. The doping of nitrogen over the carbon dots (CDs) was revealed by attenuated total reflection conjunction with Fourier transform infrared (ATR-FTIR) spectroscopy and X-ray photo electron spectroscopy (XPS). The optical properties of synthesized N-CDs were examined by UV-Visible (UV-Vis) and fluorescence spectroscopy. The synthesized N-CDs emit strong blue fluorescence at 401nm under excitation of 325nm. The excitation dependent emission property of synthesized N-CDs was exposed from fluorescence results. The quantum yield of synthesized N-CDs is about 14% against the reference quinine sulfate. The cytotoxicity of synthesized N-CDs on Madin-Darby Canine Kidney (MDCK) and HeLa cells were evaluated through Cell Counting Kit-8 (CCK-8) cytotoxicity assay. The results implied that the fluorescent N-CDs showed less cytotoxicity, further which was successfully applied as a staining probe for the confocal imaging of MDCK and HeLa cells. PMID- 27236236 TI - Community outbreak of cutaneous leishmaniasis in La Ribera region of Valencia, Spain: Public Health measures. AB - INTRODUCTION: Outbreaks of human leishmaniasis are not very common in Spain, despite being considered an endemic disease. In this study, a new outbreak in the Valencian Community is presented. Its principal objective is to describe the clinical-epidemiological characteristics and to present the main Public Health measures established to contain the outbreak. METHODS: A case was defined as anyone residing in the village of Tous (in Valencian Community), diagnosed with leishmaniasis according to clinical and laboratory criteria, defined by the Epidemiological Surveillance Network, and date of symptoms onset between 1 January 2012 and 31 December 2013. A descriptive analysis was performed on the epidemiological variables collected. RESULTS: A total of 19 cases were reported from the 28th week of 2012 to the 30th week of 2013. Adults were most affected by the disease (73%). The most common clinical form was cutaneous leishmaniasis (89%). More than three-quarters (79%) of cases were confirmed by PCR. Species typing was performed on seven samples, with the parasite Leishmania infantum being identified. Patient outcome was favourable after physical (31%), or pharmacological (69%) treatment. Some kind of residual damage was observed in 37% of cases. Different measures were applied, aimed at health professionals, and vector and reservoir control, as well as general recommendations to the population for the containment of the outbreak. CONCLUSIONS: This cutaneous leishmaniasis outbreak confirms the endemic nature and the high prevalence of the disease in the Mediterranean area. The most commonly used treatment was intralesional meglumine antimoniate. A comprehensive plan of action had to be developed in order to control the outbreak. PMID- 27236238 TI - Voltage-sensitive styryl dyes as singlet oxygen targets on the surface of bilayer lipid membrane. AB - Photosensitizers are widely used as photodynamic therapeutic agents killing cancer cells by photooxidation of their components. Development of new effective photosensitive molecules requires profound knowledge of possible targets for reactive oxygen species, especially for its singlet form. Here we studied photooxidation of voltage-sensitive styryl dyes (di-4-ANEPPS, di-8-ANEPPS, RH-421 and RH-237) by singlet oxygen on the surface of bilayer lipid membranes commonly used as cell membrane models. Oxidation was induced by irradiation of a photosensitizer (aluminum phthalocyanine tetrasulfonate) and monitored by the change of dipole potential on the surface of the membrane. We studied the drop of the dipole potential both in the case when the dye molecules were adsorbed on the same side of the lipid bilayer as the photosensitizer (cis-configuration) and in the case when they were adsorbed on the opposite side (trans-configuration). Based on a simple model, we determined the rate of oxidation of the dyes from the kinetics of change of the potential during and after irradiation. This rate is proportional to steady-state concentration of singlet oxygen in the membrane under irradiation. Comparison of the oxidation rates of various dyes reveals that compounds of ANEPPS series are more sensitive to singlet oxygen than RH type dyes, indicating that naphthalene group is primarily responsible for their oxidation. PMID- 27236239 TI - Effects of alogliptin on fractional flow reserve evaluated by coronary computed tomography angiography in patients with type 2 diabetes: Rationale and design of the TRACT study. AB - BACKGROUND: Patients with type 2 diabetes are at high risk for developing coronary artery disease (CAD). Noninvasive anatomic assessment by coronary computed tomography angiography (CCTA) is being increasingly used for detecting or excluding CAD. Recently, fractional flow reserve (FFR) using routinely acquired CCTA datasets (FFRCT) has been developed. Although intensive glycemic control can reduce the risk of microvascular complications, intensive glucose control does not seem to be beneficial in preventing major cardiovascular events when compared with standard therapy. However, it has been reported that dipeptidyl peptidase-4 (DPP-4) inhibitors have anti-atherogenic effects in an animal model. In addition, DPP-4 inhibitors attenuate the progression of carotid intima-media thickness in patients with type 2 diabetes. Therefore, this study will be performed to evaluate the effects of alogliptin, a DPP-4 inhibitor, on coronary atherosclerosis using FFRCT in patients with type 2 diabetes. METHODS AND DESIGN: This study will be a prospective, non-randomized, multicenter trial performed in Japan. Patients with type 2 diabetes who have intermediate coronary artery stenosis (diameter stenosis <70%) as evaluated by CCTA will be treated with 25mg/day of alogliptin. After 48 weeks' treatment, CCTA will be repeated. The primary endpoint will be changes in FFRCT, and the secondary endpoint will be the change in plaque volume from baseline to the 48-week follow-up. CONCLUSION: This study will be the first multicenter trial to evaluate the effects of alogliptin on coronary atherosclerosis using the newly developed FFRCT as the primary endpoint, and the findings will clarify the anti-atherogenic effects of alogliptin. PMID- 27236240 TI - Impact of moderate to severe renal impairment on long-term clinical outcomes in patients with atrial fibrillation. AB - BACKGROUND: The deleterious effect of renal impairment in non-valvular atrial fibrillation (AF) patients has recently been reported. We investigated the impact of moderate to severe renal impairment on long-term clinical outcomes in AF patients. METHODS: A total of 2126 AF patients were enrolled and divided into two groups according to >= or <60mL/min estimated glomerular filtration rate (eGFR). Clinical outcomes including all-cause death, cardiac death, ischemic stroke (IS), bleeding, and admission for heart failure (HF) were analyzed. RESULTS: Compared to the >=60mL/min eGFR group, <60mL/min eGFR patients were older; had a higher proportion of females; were more likely to have diabetes, hypertension, and history of stroke; and had higher CHADS2, CHA2DS2-VASc, and HAS-BLED scores. During the follow-up period (median 6.23 years), all-cause death, bleeding, admission for HF, and progression to persistent or permanent AF were significantly increased in the <60mL/min eGFR group compared to the >=60mL/min eGFR group. After multivariate Cox regression analyses, <60mL/min eGFR increased the risk of all-cause death [hazard ratio (HR): 1.84; 95% confidence interval (CI): 1.03-3.28, p=0.04] and bleeding (HR: 1.28; 95% CI: 1.04-1.57, p=0.02). IS was only significantly increased in the <60mL/min eGFR group not receiving antithrombotic treatment. CONCLUSION: Moderate to severe renal impairment is a poor prognostic factor of long-term clinical outcomes in AF patients. PMID- 27236241 TI - Most antidepressant drugs are safe for patients with epilepsy at therapeutic doses: A review of the evidence. AB - For a long time, there has been a misconception that all antidepressant drugs have proconvulsant effects. Yet, antidepressants of the selective serotonin reuptake inhibitor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) families have been not only shown to be safe when used in patients with epilepsy (PWE) but have been found to display antiepileptic properties in animal models of epilepsy. In humans randomized to SSRIs vs. a placebo for the treatment of primary major depressive episodes, the incidence of epileptic seizures was significantly lower among those treated with the antidepressants. On the other hand, SSRIs and SNRIs can display proconvulsant properties at toxic doses. This article reviews the preclinical and clinical data of antiepileptic and proconvulsant properties of these drugs and addresses special considerations to take when prescribing them for PWE. PMID- 27236242 TI - Uterine Incarceration: Imaging Findings on Magnetic Resonance Imaging. PMID- 27236243 TI - Reply. PMID- 27236244 TI - Infective Endocarditis Presenting with Intracranial Bleeding. AB - BACKGROUND: Infective endocarditis (IE) can be complicated by intracranial bleeding (ICB) caused by different pathologic mechanisms. The occurrence of ICB in patients with IE significantly influences therapeutic decisions and has a negative impact on outcome. CASE REPORT: We describe the clinical courses of 3 patients with aortic prosthetic valve IE presenting with ICB. Patients 1 and 2 experienced subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH), respectively, caused by rupture of an intracranial infectious aneurysm (IIA). Both underwent endovascular treatment of IIA with good outcome. In patient 3, ICB was the hemorrhagic conversion of an acute ischemic lesion from septic brain embolization. In the subacute phase of the disease, aortic valve replacement was performed, with excellent outcome. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: ICB is a relevant complication and sometimes the first clinical feature of IE. Imaging of brain vessels should be performed to investigate the pathologic mechanism underlying ICB. The prevalence of IIA is probably underestimated and may influence the therapeutic strategy. Cerebrovascular imaging may therefore also be considered in asymptomatic subjects with left-sided IE. Withdrawal of anticoagulant treatment and delay of cardiac surgery are recommended in all cases of IE complicated by ICB. Because of the impact of ICB on IE management and outcome, a high level of clinical suspicion and prompt recognition and treatment of this complication are necessary. PMID- 27236245 TI - Reply. PMID- 27236246 TI - Factors Associated with Misplaced Endotracheal Tubes During Intubation in Pediatric Patients. AB - BACKGROUND: Correct positioning of the endotracheal tube (ETT) during emergent pediatric intubations can be challenging, and incorrect placement may be associated with higher rates of complications. OBJECTIVES: The aims of this study are to: 1) assess the prevalence of clinically undetected misplaced ETTs after intubation in the pediatric emergency department; 2) identify predictors of ETT misplacement; and 3) evaluate for any association between intubation-related complications and ETT position. METHODS: In this retrospective cross-sectional study, the primary outcome was rate of unrecognized low or high ETTs detected on confirmatory chest radiographs. The secondary outcome was frequency of complications (i.e., hypoxemia, difficult ventilation, atelectasis, pneumothorax, pneumomediastinum, and aspiration) associated with misplaced ETTs. Multivariable analyses were used to evaluate the associations between patient and procedural characteristics and misplaced ETTs and between ETT position and complications. RESULTS: Seventy-seven of 201 (38.3%) intubations performed in the emergency department resulted in clinically unrecognized misplaced ETTs. Of the misplaced tubes, 45 of 77 (58%) were identified as low and 32 (42%) were high. In multivariable analyses, female sex and decreasing age were associated with increased risk of low tube placement (odds ratio for female sex, 2.4 [95% confidence interval, 1.1-5.1]; odds ratio of decreasing age, 1.16 [95% confidence interval, 1.0-1.3]). Low tube misplacement was associated with an increased risk of intubation-related complications compared to both correct and high tube placement (p < 0.05, Chi-square). CONCLUSION: Clinically unrecognized ETT misplacement occurs frequently in the pediatric emergency department, with low placement being most common, particularly in girls and younger children. Measures to improve clinical or radiographic recognition of incorrect tube position should be considered. PMID- 27236247 TI - Spontaneous Compartment Syndrome of the Thigh in the Absence of Trauma. AB - BACKGROUND: Compartment syndrome occurs when an increase in pressure results in vascular and functional impairment of the underlying nerve and muscles. Thigh compartment syndrome (TCS) is uncommon, but clinical suspicion warrants emergent surgical consultation and fasciotomy. CASE REPORT: We present a 42-year-old man evaluated for right lateral thigh pain, without a history of trauma, deep venous thrombosis (DVT), previous surgery, or intravenous drug use. He was febrile, tachycardic, with a mild leukocytosis, an elevated C-reactive protein level, and an elevated creatinine kinase level. Radiographs showed no abnormality and right lower extremity duplex ultrasound showed no DVT. A computed tomography scan of the right lower extremity was concerning for compartment syndrome. Surgical consultation was obtained, and the patient was taken to the operating room for fasciotomy. He was diagnosed with compartment syndrome intraoperatively. The patient was discharged on hospital day 10. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: TCS is exceedingly rare, especially in the absence of underlying traumatic and nontraumatic etiologies. The diagnosis is challenging because more elastic fascia with larger space in the thigh allows for accommodation of acute increases in pressure. Consequently, there may not be the expected acute rise in compartment pressures; increased compartment pressure may only be a late sign, when underlying neurovascular damage has already occurred. TCS is complicated by high morbidity and mortality. Emergent surgical consultation should be obtained when there is a high clinical suspicion for TCS, and limb-saving fasciotomy should not be delayed. This case shows the importance of a high level of suspicion for TCS in patients with no identifiable etiology and no historical risk factors for development of compartment syndrome, because TCS may not present with classic symptoms. PMID- 27236249 TI - Phenotyping, endotyping and clinical decision-making. PMID- 27236248 TI - Real-time in vivo dosimetry in high dose rate prostate brachytherapy. AB - BACKGROUND AND PURPOSE: Single fraction treatments of 15Gy or 19Gy are common in HDR prostate brachytherapy. In vivo dosimetry (IVD) is therefore important to ensure patient safety. This study assesses clinical IVD and investigates error detection thresholds for real-time treatment monitoring. MATERIALS AND METHODS: IVD was performed for 40 treatments planned using intra-operative trans-rectal ultrasound (TRUS) with a MOSFET inserted into an additional needle. Post treatment TRUS images were acquired for 20 patients to assess needle movement. Monte Carlo simulations of treatment plans were performed for 10 patients to assess impact of heterogeneities. Per-needle and total plan uncertainties were estimated and retrospectively applied to the measured data as error detection thresholds. RESULTS: The mean measured dose was -6.4% compared to prediction (range +5.1% to -15.2%). Needle movement and heterogeneities accounted for -1.8% and -1.6% of this difference respectively (mean values for the patients analysed). Total plan uncertainty (k=2) ranged from 11% to 17% and per needle uncertainty (k=2) ranged from 18% to 110% (mean 31%). One out of 40 plans and 5% of needles were outside k=2 error detection threshold. CONCLUSIONS: IVD showed good agreement with predicted dose within measurement uncertainties, providing reassurance in the accuracy of dose delivery. Thresholds for real-time error detection should be calculated on an individual plan/needle basis. PMID- 27236250 TI - Relation of Baseline Renal Dysfunction With Outcomes in Patients Undergoing Popliteal and Infrapopliteal Percutaneous Peripheral Arterial Interventions. AB - Renal dysfunction is a major risk factor for peripheral arterial disease (PAD). Infrapopliteal PAD is associated with more co-morbid conditions and worse prognosis than suprapopliteal PAD. Long-term outcomes of patients with renal dysfunction and popliteal or infrapopliteal PAD undergoing peripheral vascular intervention (PVI) are not well described. We retrospectively evaluated long-term outcomes in 726 patients undergoing infrapopliteal PVI categorized into 3 glomerular filtration rate (GFR)-based groups: GFR (>=60 ml/min/1.73 m(2)), GFR (<60 ml/min/1.73 m(2)), and those on dialysis. At mean follow-up of 36 +/- 20 months, amputation rates were 3%, 5%, and 11% with mortality rates of 23%, 36%, and 56% in normal renal function, chronic kidney disease (adjusted odds ratio [OR] for amputation 1.75, 95% CI 0.73 to 4.21; adjusted OR for mortality 1.53, 95% CI 1.05 to 2.23, p = 0.028), and dialysis (adjusted OR for amputation 2.43, 95% CI 0.84 to 7.02, p = 0.100; adjusted OR for mortality 4.51, 95% CI 2.46 to 8.26, p <0.0001) groups, respectively. Repeat revascularization was similar in all 3 groups at roughly 25%. In conclusion, chronic kidney disease and dialysis were associated with increased major amputations and mortality in patients who received PVI for popliteal and infrapopliteal PAD. PMID- 27236251 TI - Comparison of Rates of Coronary Angiography and Combined Testing Procedures in Patients Seen in the Emergency Room With Chest Pain (But No Objective Acute Coronary Syndrome Findings) Having Coronary Computed Tomography Versus Exercise Stress Testing. AB - Coronary computed tomography angiography (CCTA) appears comparable to standard care, including exercise stress testing (EST), in diagnosing acute coronary syndrome in emergency department (ED) patients with chest pain but may increase downstream testing. The objective of this study was to investigate rates of post CCTA versus post-EST testing for (1) invasive angiography and (2) all combined cardiac testing. This was a retrospective cohort study performed at 2 urban Canadian EDs involving patients aged up to 65 years with chest pain but no objective ACS findings that were evaluated with CCTA or EST at the physician's discretion. The primary outcome was the proportion of patients who had 30-day invasive angiography in each group; secondary outcomes included all subsequent 30 day cardiac testing, including nuclear medicine scanning. From July 1, 2012, to June 30, 2014, we collected 1,700 patients: 521 CCTA and 1,179 EST. Demographics and risk factors were similar in both cohorts. In the following 30 days, 30 CCTA (5.8%) and 297 EST (25.2%) patients underwent any type of additional cardiac testing (difference 19.4%, 95% CI 16.0 to 22.6), whereas 12 CCTA (2.3%) and 20 EST patients (1.7%) underwent angiography (difference 0.6%, 95% CI -0.8% to 2.6%). No patients in either group died or had a myocardial infarction within 30 days. For ED patients with chest pain who underwent brief observation, CCTA and EST had similar 30-day angiography rates, but CCTA patients underwent significantly less overall cardiac investigations. PMID- 27236252 TI - Relation of Stature to Outcomes in Korean Patients Undergoing Primary Percutaneous Coronary Intervention for Acute ST-Elevation Myocardial Infarction (from the INTERSTELLAR Registry). AB - Although epidemiologic studies have shown the impact of height on occurrence and/or prognosis of cardiovascular diseases, the underlying mechanism is unclear. In addition, the relation in patients with ST-segment elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention (PCI) remains unknown. We sought to assess the influence of height on outcomes of patients with acute STEMI undergoing primary PCI and to provide a pathophysiological explanation. All 1,490 patients with STEMI undergoing primary PCI were analyzed. Major adverse cardiac and cerebrovascular events (MACCE) were defined as all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, and unplanned hospitalization for heart failure (HF). Patients were divided into (1) MACCE (+) versus MACCE (-) and (2) first- to third-tertile groups according to height. MACCE (+) group was shorter than MACCE (-) group (164 +/- 8 vs 166 +/- 8 cm, p = 0.012). Prognostic impact of short stature was significant in older (>=70 years) male patients even after adjusting for co-morbidities (hazard ratio 0.951, 95% confidence interval 0.912 to 0.991, p = 0.017). The first-tertile group showed the worst MACCE-free survival (p = 0.035), and most cases of MACCE were HF (n, 17 [3%] vs 6 [1%] vs 2 [0%], p = 0.004). On post-PCI echocardiography, left atrial volume and early diastolic mitral velocity to early diastolic mitral annulus velocity ratio showed an inverse relation with height (p <0.001 for all) despite similar left ventricular ejection fraction. In conclusion, short stature is associated with occurrence of HF after primary PCI for STEMI, and its influence is prominent in aged male patients presumably for its correlation with diastolic dysfunction. PMID- 27236253 TI - Mathematically Derived Criteria for Detecting Functionally Significant Stenoses Using Coronary Computed Tomographic Angiography-Based Myocardial Segmentation and Intravascular Ultrasound-Measured Minimal Lumen Area. AB - The lack of practical method for quantifying myocardial territories has made it difficult to link anatomic lesion morphology to the hemodynamic significance of coronary artery stenosis. The aim of this study was to develop and validate mathematically derived morphologic criteria for predicting fractional flow reserve (FFR) <0.80 using intravascular ultrasound (IVUS) parameters and a coronary artery-based myocardial segmentation (CAMS) of the affected myocardial territory. Coronary computed tomography angiography, IVUS, and FFR data were analyzed in 103 non-left main intermediate coronary artery lesions (30% to 80% of angiographic stenosis). Using CAMS method, the total left ventricular myocardial volume and the myocardial volume subtended by a stenotic coronary segment (Vsub) were assessed. The morphologic criteria for detecting an FFR <0.80 using the IVUS and CAMS parameters were mathematically derived. Overall, an IVUS-measured minimal lumen area (MLA) <2.79 mm(2) predicted an FFR <0.80 with sensitivity of 76%, specificity of 78%, positive predictive value of 71%, and negative predictive value of 82%. A Vsub/MLA(2) >4.04 best predicted an FFR <0.80 (sensitivity 88%, specificity 90%, positive predictive value 86%, and negative predictive value 92%, area under curve = 0.944). There was a significant difference in the areas under the curves between IVUS-MLA versus Vsub/MLA(2) (difference = 0.068, p = 0.005). Conversely, adjusting for body or vessel size did not improve the diagnostic accuracy. PMID- 27236254 TI - Usefulness of Psoas Muscle Area to Predict Mortality in Patients Undergoing Transcatheter Aortic Valve Replacement. AB - Frailty has become high-priority theme in cardiovascular diseases because of aging and increasingly complex nature of patients. Low muscle mass is characteristic of frailty, in which invasive interventions are avoided if possible because of decreased physiological reserve. This study aimed to determine if the psoas muscle area (PMA) could predict mortality and to investigate its utility in patients who underwent transcatheter aortic valve replacement (TAVR). We retrospectively reviewed 232 consecutive patients who underwent TAVR. Cross-sectional areas of the psoas muscles at the level of fourth lumbar vertebra were measured by computed tomography and normalized to body surface area. Patients were divided into tertiles according to the normalized PMA for each gender (men: tertile 1, 1,708 to 1,178 mm(2)/m(2); tertile 2, 1,176 to 1,011 mm(2)/m(2); and tertile 3, 1,009 to 587 mm(2)/m(2); women: tertile 1, 1,436 to 962 mm(2)/m(2); tertile 2, 952 to 807 mm(2)/m(2); and tertile 3, 806 to 527 mm(2)/m(2)). Smaller normalized PMA was independently correlated with women and higher New York Heart Association classification. After adjustment for multiple confounding factors, the normalized PMA tertile was independently associated with mortality at 6 months (adjusted hazard ratio 1.53, 95% confidence interval 1.06 to 2.21). Kaplan-Meier analysis showed that tertile 3 had higher mortality rates than tertile 1 at 6 months (14% and 31%, respectively, p = 0.029). Receiver operating characteristic analysis showed that normalized PMA provided the increase of C-statistics for predicting mortality for a clinical model and gait speed. In conclusion, PMA is an independent predictor of mortality after TAVR and can complement a clinical model and gait speed. PMID- 27236255 TI - Long-Term Population-Based Cerebral Ischemic Event and Cognitive Outcomes of Direct Oral Anticoagulants Compared With Warfarin Among Long-term Anticoagulated Patients for Atrial Fibrillation. AB - Direct oral anticoagulants (DOACs) have been used in clinical practice in the United States for the last 4 to 6 years. Although DOACs may be an attractive alternative to warfarin in many patients, long-term outcomes of use of these medications are unknown. We performed a propensity-matched analysis to report patient important outcomes of death, stroke/transient ischemic attack (TIA), bleeding, major bleeding, and dementia in patients taking a DOAC or warfarin. Patients receiving long-term anticoagulation from June 2010 to December 2014 for thromboembolism prevention with either warfarin or a DOAC were matched 1:1 by index date and propensity score. Multivariable Cox hazard regression was performed to determine the risk of death, stroke/TIA, major bleed, and dementia by the anticoagulant therapy received. A total of 5,254 patients were studied (2,627 per group). Average age was 72.4 +/- 10.9 years, and 59.0% were men. Most patients were receiving long-term anticoagulation for AF management (warfarin: 96.5% vs DOAC: 92.7%, p <0.0001). Rivaroxaban (55.3%) was the most commonly used DOAC, followed by apixaban (22.5%) and dabigatran (22.2%). The use of DOACs compared with warfarin was associated with a reduced risk of long-term adverse outcomes: death (p = 0.09), stroke/TIA (p <0.0001), major bleed (p <0.0001), and bleed (p = 0.14). No significant outcome variance was noted in DOAC-type comparison. In the AF multivariable model patients taking DOAC were 43% less likely to develop stroke/TIA/dementia (hazard ratio 0.57 [CI 0.17, 1.97], p = 0.38) than those taking warfarin. Our community-based results suggest better long term efficacy and safety of DOACs compared with warfarin. DOAC use was associated with a lower risk of cerebral ischemic events and new-onset dementia. PMID- 27236256 TI - Relation of Anxiety and Depressive Symptoms to Coronary Artery Calcium (from the ELSA-Brasil Baseline Data). AB - Previous studies of the association between symptoms of anxiety or depression and coronary artery calcium (CAC) have produced heterogeneous results. Our aim was to investigate whether psychopathological symptoms were associated with CAC in a cross-sectional analysis of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) baseline. We analyzed data from 4,279 ELSA-Brasil subjects (aged 35 to 74 years) from the Sao Paulo site without previous cardiovascular disease who underwent CAC score assessment at baseline. Prevalent CAC was defined as a CAC score >0. Anxiety and depressive symptoms were assessed using the Clinical Interview Schedule-Revised (CIS-R). We built binary logistic regression models to determine whether CIS-R scores, anxiety, or depression were associated with prevalent CAC. Prevalent CAC was found in 1,211 subjects (28.3%). After adjustment for age and gender, a direct association between CIS-R scores and prevalent CAC was revealed (odds ratio for 1-SD increase: 1.12; 95% confidence interval [CI] 1.04 to 1.22). This association persisted after multivariate adjustment (odds ratio for 1-SD increase 1.11; 95% CI 1.02 to 1.20). No independent associations were found for specific diagnoses of anxiety or depression and prevalent CAC. In post hoc models, a significant interaction term (p = 0.019) suggested a stronger association in older subjects. In conclusion, psychopathological symptoms were directly associated with coronary atherosclerosis in the ELSA-Brasil baseline in adjusted models, and this association seems to be stronger in older subjects. PMID- 27236257 TI - Making the Case for Universal Treatment of Hypercholesterolemia. PMID- 27236258 TI - Anti-SRP auto-antibodies are not specific for myositis: Report of 8 cases. PMID- 27236259 TI - Pyogenic vertebral osteomyelitis caused by Yersinia pseudotuberculosis. AB - Septic vertebral osteomyelitis caused by Yersinia pseudotuberculosis is extremely rare. We report the first case of pyogenic vertebral osteomyelitis due to Y. pseudotuberculosis. A 65-year-old man presented with low back pain and fever. He had a history of psoriasis vulgaris treated with adalimumab. The patient reported drinking adequate amounts of well water daily. Clinical examination revealed no neurological deficit of the lower limbs. Laboratory findings included increased inflammatory reactions. Magnetic resonance imaging showed diffuse changes in intensity at the T10 and L3 vertebrae, and multiple nodular lesions in the thoracic, lumbar, sacral, and iliac regions. We performed an open biopsy. Y. pseudotuberculosis was cultured from both the T10 and L3 vertebrae lesions. Y. pseudotuberculosis is sensitive to almost all antibiotics. After initiating antibiotic treatment, the laboratory parameters normalized and the patient recovered completely, without any neurological deficits. To our knowledge, our report represents the first case of pyogenic vertebral osteomyelitis due to Y. pseudotuberculosis. PMID- 27236260 TI - Gout and rheumatoid arthritis, both to keep in mind in cardiovascular risk management: A primary care retrospective cohort study. AB - OBJECTIVES: To assess in one time window cardiovascular risks for both patients with gout and patients with rheumatoid arthritis in a Dutch primary care population. METHODS: Retrospective matched cohort study with data from the electronic health records of 51 Dutch general practices. Participants were patients aged 30 years or older with an incident diagnosis of gout (n=2655) or rheumatoid arthritis (n=513), and matched non-disease controls (n=7891 and n=1850 respectively). At disease incidence date, patients and controls were compared for prevalence of hypertension, diabetes mellitus, hypercholesterolemia, and prior cardiovascular diseases. Patients without prior cardiovascular disease were followed for a first cardiovascular disease, and compared to controls using Kaplan-Meier survival curves and Cox proportional hazard analyses. RESULTS: Compared to controls, gout patients suffered more from hypertension (44.8%), diabetes (20.1%), hypercholesterolemia (13.7%), and prior cardiovascular disease (30%) (P<0.01), whereas rheumatoid arthritis patients (hypertension 28.5%; diabetes 11.7%; hypercholesterolemia 7.4%; prior cardiovascular disease 11.3%) did not (P>0.05). After adjustment, both gout and rheumatoid arthritis patients without prior cardiovascular disease were more likely to get a cardiovascular disease: hazard ratio (95% confidence interval) 1.44 (1.18 to 1.76), and 2.06 (1.34 to 3.16) respectively. CONCLUSIONS: This primary care study indicates that gout and rheumatoid arthritis are both independent risk factors for cardiovascular diseases, rheumatoid arthritis to some greater extent, whereas gout patients at first diagnosis had already an increased cardiovascular risk profile. It gives strong arguments for implementation of both rheumatic diseases in primary care guidelines on cardiovascular risk management. PMID- 27236261 TI - Subchondral bone sclerosis and cancellous bone loss following OA induction depend on the underlying bone phenotype. AB - OBJECTIVES: Osteoarthritis (OA) is increasingly considered a disease of the whole joint, yet the interplay between the articular cartilage and the subchondral bone remains obscure. We here set out to investigate the impact of bone mass on the progression of surgically induced knee OA in the mouse. METHODS: OA was induced in the right knees of female C57BL/6 (low bone mass) and STR/ort (high bone mass) mice via anterior cruciate ligament transection and destabilization of the medial meniscus. At 36 weeks of age, left and right knee joints were histologically compared for cartilage degeneration and via microCT analysis for subchondral bone plate thickness. In addition, femora were analyzed for bone mass at diaphysis and distal meta- and epiphysis. RESULTS: The severity of cartilage deterioration did not differ under high and low bone mass conditions. However, the extent of bone sclerosis differed and was proportional to the baseline subchondral bone plate thickness. Moreover, the cancellous bone loss following OA progression was inversely related to the bone mass: high bone mass restricted the loss to the epiphysis, whereas low bone mass allowed for a more widespread loss extending into the metaphysis. CONCLUSIONS: Our results suggest that cartilage degeneration is independent of the underlying bone mass. In contrast, subchondral bone remodeling associated with OA progression seem to correlate with the initial bone mass and suggest an enhanced crosstalk between the deteriorating cartilage and the subchondral bone under low bone mass conditions. PMID- 27236262 TI - Bone infarcts: Unsuspected gray areas? AB - There is agreement to label as bone infarcts avascular necrosis (AVN) occurring in the metaphyses or diaphyses of long bones, the terms AVN or osteonecrosis being used at the epiphyses. One might expect bone infarction to hold no mysteries. Oddly enough, however, scientific evidence about bone infarcts is extraordinarily scant. The prevalence of bone infarcts is unknown. The main sites of involvement are the distal femur, proximal tibia, and distal tibia. In patients without sickle cell disease or Gaucher's disease, involvement of the upper limbs and lesions confined to the diaphysis are so rare as to warrant a reappraisal of the diagnosis. Although widely viewed as a generally silent event, bone infarcts causes symptoms in half the cases. Standard radiographs are normal initially then show typical high-density lesions in the center of the marrow cavity. A periosteal reaction is common and may be the first and only radiographic change. Magnetic resonance imaging consistently shows typical features and therefore, in principle, obviates the need for other investigations. Bone infarcts are multifocal in over half the cases and, when multifocal, are usually accompanied with multiple foci of epiphyseal avascular necrosis. Thus, bone infarcts, whose prognosis is good per se (with the exception of the very low risk of malignant transformation), are usually a marker for systemic avascular necrosis. Consequently, patients with bone infarcts must be investigated both for known risk factors and for other foci of avascular necrosis, which may, in contrast, have function-threatening effects. PMID- 27236263 TI - Anti-TNF treatment of reactive arthritis. A monocentric experience. PMID- 27236264 TI - Severe deformans tophaceous gouty arthritis. PMID- 27236265 TI - Cervical transverse ligament calcification associated with Eagle syndrome. PMID- 27236266 TI - Magnetic resonance imaging of dynamic scapular winging secondary to a lesion of the long thoracic nerve. PMID- 27236267 TI - Childhood maltreatment and adulthood domestic and sexual violence victimisation among people with severe mental illness. AB - PURPOSE: To investigate the association between childhood maltreatment and adulthood domestic and sexual violence victimisation among people with severe mental illness (SMI), and to explore this association in terms of gender differences and potential mediators. METHOD: A cross-sectional survey of 318 people living in the community who were receiving care from Community Mental Health Teams. Associations were assessed using logistic regression of multiply imputed data. RESULTS: 63 % (95 % CI 55-71 %) of men and 71 % (95 % CI 63-79 %) of women reported childhood maltreatment, 46 % (95 % CI 37-54 %) of men and 67 % (95 % CI 59-76 %) of women reported adulthood domestic violence victimisation, and 22 % (95 % CI 15-28 %)of men and 62 % (95 % CI 53-70 %)of women reported adulthood sexual violence victimisation. Men and women with SMI who reported experiences of childhood maltreatment were two to five times more likely to report domestic and sexual violence victimisation in adulthood after adjusting for confounders. The associations held for each of emotional, physical and sexual childhood abuse. CONCLUSION: People with severe mental illness have high prevalence of experiences of childhood maltreatment and adulthood domestic and sexual violence victimisation. Childhood maltreatment appears to be an independent risk factor for adulthood victimisation among men and women with SMI. PMID- 27236268 TI - Psychotic-like experiences in a conflict-affected population: a cross-sectional study in South Sudan. AB - PURPOSE: This study investigates the prevalence of psychotic-like experiences (PLEs) and examines exposure to potentially traumatic events and other relevant risk factors for PLEs in the general population of a conflict-affected, low income country. METHODS: We conducted a cross-sectional community based study of four Greater Bahr el Ghazal States, South Sudan (n = 1200). The Harvard Trauma Questionnaire was applied to investigate exposure to potentially traumatic events. The Mini-International Neuropsychiatric Interview was used to detect PLEs. RESULTS: The estimated prevalence of lifetime PLEs was 23.3 % and the rate of PLEs which were evaluated as bizarre was 9.5 %. Exposure to higher number of potentially traumatic events, younger age, rural residency, being unemployed, not having a regular income and having traditional religion were significantly associated with having PLEs. PLEs were significantly associated with reporting of psychological distress when controlling for other covariates. CONCLUSIONS: The finding of association between traumatic exposure and PLEs calls for greater attention to the diversity of negative mental health outcomes in conflict affected populations. PMID- 27236269 TI - A ring closing metathesis strategy for carbapyranosides of xylose and arabinose. AB - The synthesis of beta-carba-xylo and arabino pyranosides of cholestanol is described. The synthetic strategy, which is analogous to the Postema approach to C-glycosides, centers on the ring closing metathesis of an enol ether-alkene precursor to give a cyclic enol ether that is elaborated to a carba-pyranoside via hydroboration-oxidation on the olefin. The method, which is attractive for its modularity and stereoselectivity, may find wider applications to carba hexopyranosides and other complex cycloalkyl ether frameworks. PMID- 27236270 TI - Genetic mutations in high grade gliomas of the adult spinal cord. PMID- 27236271 TI - Expanded Spectrum of Congenital Ocular Findings in Microcephaly with Presumed Zika Infection. AB - PURPOSE: To describe the ocular findings of 3 cases of suspected congenital Zika viral infection with microcephaly and maculopathy. DESIGN: Retrospective, consecutive case series. PARTICIPANTS: Three male infants born in northern Brazil whose mothers demonstrated a viral syndrome during the first trimester and who subsequently were born with microcephaly. METHODS: Observational report of macular findings. MAIN OUTCOME MEASURES: Continued observation. RESULTS: Three male infants were born with microcephaly to mothers who had a viral syndrome during the first trimester of gestation in an area that subsequently has demonstrated epidemic Zika infection, a flavivirus related to Dengue. Ocular examination was performed. All 6 eyes demonstrated a pigmentary maculopathy ranging from mild to pronounced. In 4 eyes, well-delineated macular chorioretinal atrophy with a hyperpigmented ring developed. Three eyes demonstrated vascular tortuosity and 2 eyes demonstrated a pronounced early termination of the retinal vasculature on photographic evaluation. Two eyes demonstrated a washed out peripheral retina with a hypolucent spot. One eye had scattered subretinal hemorrhages external to the macula. Finally, 1 eye demonstrated peripheral pigmentary changes and clustered atrophic lesions resembling grouped congenital albinotic spots (polar bear tracks). CONCLUSIONS: Zika virus has been linked to microcephaly in children of mothers with a viral syndrome during the first trimester of pregnancy. Ocular findings previously described a pigmentary retinopathy and atrophy that now can be expanded to include torpedo maculopathy, vascular changes, and hemorrhagic retinopathy. Ophthalmologic screening guidelines need to be defined to determine which children would benefit from newborn screening in affected regions. PMID- 27236273 TI - Octogenarians: Too Old for Surgical Myocardial Revascularization? PMID- 27236272 TI - Enhanced Benefit in Diabetic Macular Edema from AKB-9778 Tie2 Activation Combined with Vascular Endothelial Growth Factor Suppression. AB - PURPOSE: To assess the effect of AKB-9778 alone or in combination with ranibizumab in subjects with diabetic macular edema (DME). DESIGN: A phase IIa, randomized, placebo- and sham injection-controlled, double-masked clinical trial. PARTICIPANTS: Subjects (n = 144) with decreased vision from DME and central subfield thickness (CST) >=325 MUm measured by spectral-domain optical coherence tomography (SD OCT) enrolled at 36 sites. METHODS: Subjects were randomized to (1) AKB-9778 monotherapy: subcutaneous AKB-9778 15 mg twice per day (BID) + monthly sham intraocular injections; (2) combination therapy: subcutaneous AKB 9778 15 mg BID + monthly 0.3 mg ranibizumab; or (3) ranibizumab monotherapy: subcutaneous placebo injections BID + monthly 0.3 mg ranibizumab. Best-corrected visual acuity (BCVA) and CST were measured at baseline and every 4 weeks. MAIN OUTCOME MEASURES: Primary outcome measure was mean change from baseline CST at week 12. Other outcomes included BCVA, safety assessments, and Diabetic Retinopathy Severity Score (DRSS). RESULTS: At week 12, mean change from baseline CST was significantly greater in the combination group (-164.4+/-24.2 MUm) compared with the ranibizumab monotherapy group (-110.4+/-17.2 MUm; P = 0.008) and was 6.2+/-13.0 MUm in the AKB-9778 monotherapy group. Mean CST at week 12 and percentage of eyes with resolved edema was 340.0+/-11.2 MUm and 29.2%, respectively, in the combination group versus 392.1+/-17.1 MUm and 17.0%, respectively, in the ranibizumab monotherapy group. Mean change from baseline BCVA (letters) was 6.3+/-1.3 in the combination group, 5.7+/-1.2 in the ranibizumab monotherapy group, and 1.5+/-1.2 in the AKB-9778 monotherapy group. The percentage of study eyes that gained >=10 or >=15 letters was 8.7% and 4.3%, respectively, in the AKB-9778 monotherapy group, 29.8% and 17.0%, respectively, in the ranibizumab monotherapy group, and 35.4% and 20.8%, respectively, in the combination group. Improvements in DRSS in study eyes were similar across groups, and the percentage of qualified fellow eyes with a >=2-step change was 11.4% in all AKB-9778-treated subjects compared with 4.2% in the ranibizumab monotherapy group. AKB-9778 was well tolerated, with no clear by-treatment differences in adverse events. CONCLUSIONS: Activation of Tie2 by subcutaneous injections of AKB 9778 combined with suppression of vascular endothelial growth factor (VEGF) causes a significantly greater reduction in DME than that seen with suppression of VEGF alone. PMID- 27236274 TI - Multistate Models for Survival Analysis of Cardiovascular Disease Process. PMID- 27236275 TI - About the Micra Transcatheter Pacing System. PMID- 27236276 TI - The Social Impact of Cardiology Research: Beyond Management. PMID- 27236277 TI - Natriuretic Peptides: Consensus Call for Use. PMID- 27236278 TI - About the Micra Transcatheter Pacing System. Response. PMID- 27236280 TI - Risk factors for suicide in children and young people: common yet complex. PMID- 27236279 TI - Suicide in children and young people in England: a consecutive case series. AB - BACKGROUND: There is concern about the mental health of children and young people and a possible rise in suicidal behaviour in this group. We have done a comprehensive national multi-agency study of suicide in under 20s in England. We aimed to establish how frequently suicide is preceded by child-specific and young person-specific suicide risk factors, as well as all-age factors, and to identify contact with health-care and social-care services and justice agencies. METHODS: This study is a descriptive examination of suicide in a national consecutive sample of children and young people younger than 20 years who died by suicide in England between Jan 1, 2014, and April 30, 2015. We obtained general population mortality data from the Office for National Statistics (ONS). We collected information about antecedents considered to be relevant to suicide (eg, abuse, bullying, bereavement, academic pressures, self-harm, and physical health) from a range of investigations and inquiries, including coroner inquest hearings, child death investigations, criminal justice system reports, and the National Health Service, including data on people in contact with mental health services in the 12 months before their death. FINDINGS: 145 suicides in people younger than 20 years were notified to us during the study period, of which we were able to obtain report data about antecedents for 130 (90%). The number of suicides rose sharply during the late teens with 79 deaths by suicide in people aged 18-19 years compared with 66 in people younger than 18 years. 102 (70%) deaths were in males. 92 (63%) deaths were by hanging. Various antecedents were reported among the individuals for whom we had report data, including academic (especially exam) pressures (35 [27%] individuals), bullying (28 [22%]), bereavement (36 [28%]), suicide in family or friends (17 [13%]), physical health conditions (47 [36%]), family problems (44 [34%]), social isolation or withdrawal (33 [25%]), child abuse or neglect (20 [15%]), excessive drinking (34 [26%]), and illicit drug use (38 [29%]). Suicide-related internet use was recorded in 30 (23%) cases. In the week before death 13 (10%) individuals had self-harmed and 35 (27%) had expressed suicidal ideas. 56 (43%) individuals had no known contact with health-care and social-care services or justice agencies. INTERPRETATION: Improved services for self-harm and mental health are crucial to suicide prevention, but the wide range of antecedents emphasises the roles of schools, primary care, social services, and the youth justice system. FUNDING: The Healthcare Quality Improvement Partnership. PMID- 27236281 TI - Deficient Surrounding Rims in Patients Undergoing Transcatheter Atrial Septal Defect Closure. AB - BACKGROUND: The influence of deficient rims surrounding atrial septal defects (ASDs) in patients undergoing transcatheter closure has yet to be clarified. The aim of this study was to assess the influence of a deficient surrounding rim on the procedural success and clinical outcome of transcatheter ASD closure using an Amplatzer septal occluder. METHODS: A total of 474 patients (mean age, 46 +/- 22 years) with ostium secundum ASDs measuring <=40 mm in diameter who had undergone attempted transcatheter closure using Amplatzer septal occluders from September 2007 to August 2013 were assessed. A comprehensive transesophageal echocardiographic examination was done to assess the morphologic characteristics of the defects in all patients. Subjects were classified into three groups by the extent and location of rim deficiency (<5 mm): patients without deficient rims (sufficient group, n = 101), patients with single deficient rims, (single group, n = 338), and patients with multiple rim deficiencies (multiple group, n = 35). RESULTS: There was a significant difference in the maximal defect diameter among the sufficient, single, and multiple groups (15 +/- 6, 18 +/- 6, and 29 +/- 7 mm, respectively, P < .001). Transcatheter closure was successfully accomplished in 463 patients (98%). The prevalence of procedural success differed significantly among the sufficient, single, and multiple groups (100%, 98%, and 86%, respectively, P < .001). There was no significant difference in the occurrence of cardiovascular events among the three groups during a mean follow-up period of 25 +/- 19 months (P = .926, log-rank test). CONCLUSIONS: In patients with ASDs with multiple rim deficiencies as determined by transesophageal echocardiography, successful transcatheter ASD closure using Amplatzer septal occluders is more difficult to accomplish. However, if closure is successful, rim deficiencies rarely affect intermediate-term outcomes. PMID- 27236282 TI - One-step preparation of [(18)F]FPBM for PET imaging of serotonin transporter (SERT) in the brain. AB - Serotonin transporters (SERT) in the brain play an important role in normal brain function. Selective serotonin reuptake inhibitors such as fluoxetine, sertraline, paroxetine, escitalopram, etc., specifically target SERT binding in the brain. Development of SERT imaging agents may be useful for studying the function of SERT by in vivo imaging. A one-step preparation of [(18)F]FPBM, 2-(2' (dimethylamino)methyl)-4'-(3-([(18)F]fluoropropoxy)phenylthio)benzenamine, for positron emission tomography (PET) imaging of SERT binding in the brain was achieved. An active OTs intermediate, 9, was reacted with [(18)F]F(-)/K222 to produce [(18)F]FPBM in one step and in high radiochemical yield. This labeling reaction was evaluated and optimized under different temperatures, bases, solvents, and varying amounts of precursor 9. The radiolabeling reaction led to the desired [(18)F]FPBM in one step and the crude product was purified by HPLC purification to give no-carrier-added [(18)F]FPBM (radiochemical yield, 24-33%, decay corrected; radiochemical purity >99%). PET imaging studies in normal monkeys (n=4) showed fast, pronounced uptakes in the midbrain and thalamus, regions known to be rich in SERT binding sites. A displacement experiment with escitalopram (5mg/kg iv injection at 30min after [(18)F]FPBM injection) showed a rapid and complete reversal of SERT binding, suggesting that binding by [(18)F]FPBM was highly specific and reversible. A one-step radiolabeling method coupled with HPLC purification for preparation of [(18)F]FPBM was developed. Imaging studies suggest that it is feasible to use this method to prepare [(18)F]FPBM for in vivo PET imaging of SERT binding in the brain. PMID- 27236283 TI - Brain penetrant small molecule (18)F-GnRH receptor (GnRH-R) antagonists: Synthesis and preliminary positron emission tomography imaging in rats. AB - INTRODUCTION: The gonadotropin releasing hormone receptor (GnRH-R) has a well described neuroendocrine function in the anterior pituitary. However, little is known about its function in the central nervous system (CNS), where it is most abundantly expressed in hippocampus and amygdala. Since peptide ligands based upon the endogenous decapetide GnRH do not pass the blood-brain-barrier, we are seeking a high-affinity small molecule GnRH-R ligand suitable for brain imaging by positron emission tomography. We have previously reported the radiosynthesis and in vitro evaluation of two novel [(18)F]fluorinated GnRH-R ligands belonging to the furamide class of antagonists, with molecular weight less than 500 Da. We now extend this work using palladium coupling for the synthesis of four novel radioligands, with putatively reduced polar surface area and hydrophilicity relative to the two previously described compounds, and report the uptake of these (18)F-labeled compounds in brain of living rats. METHODS: We synthesized reference standards of the small molecule GnRH-R antagonists as well as mesylate precursors for (18)F-labeling. The antagonists were tested for binding affinity for both human and rat GnRH-R. Serum and blood stability in vitro and in vivo were studied. Biodistribution and PET imaging studies were performed in male rats in order to assess brain penetration in vivo. RESULTS: A palladium coupling methodology served for the synthesis of four novel fluorinated furamide GnRH receptor antagonists with reduced heteroatomic count. Radioligand binding assays in vitro revealed subnanomolar affinity of the new fluorinated compounds for both human and rat GnRH-R. The (18)F-GnRH antagonists were synthesized from the corresponding mesylate precursors in 5-15% overall radiochemical yield. The radiolabeled compounds demonstrated good in vivo stability. PET imaging with the (18)F-radiotracers in naive rats showed good permeability into brain and rapid washout, but absence of discernible specific binding in vivo. CONCLUSIONS: The novel small molecule (18)F-fluorinated GnRH-R antagonist compounds show high receptor affinity in vitro, and may prove useful for quantitative autoradiographic studies in vitro. The compounds were permeable to the blood brain barrier, but nonetheless failed to reveal significant specific binding in brain of living rats. Nonetheless, our approach may serve as a foundation for designing PET ligands suitable to image the GnRH-R distribution in brain. PMID- 27236284 TI - [(18)F]FMeNER-D2: A systematic in vitro analysis of radio-metabolism. AB - INTRODUCTION: The norepinephrine transporter (NET) presents an important target for therapy and diagnosis of ADHD and other neurodegenerative and psychiatric diseases. Thus, PET is the diagnostic method of choice, using radiolabeled NET ligands derived from reboxetine. So far, [(18)F]FMeNER-D2 showed best pharmacokinetic and -dynamic properties. However, the disadvantage of reboxetine derived PET tracers is their high metabolic cleavage-resulting in impeding signals in the PET scans, which hamper a proper quantification of the NET in cortical areas. METHODS: Metabolic stability testing was performed in vitro using a plethora of human and murine enzymes. RESULTS: No metabolism was observed using monoamine oxidase A and B or catechol-O-methyl transferase. Incubation of [(18)F]FMeNER-D2 with CYP450-enzymes, predominantly located in the liver, led to a significant and fast metabolism of the tracer. Moreover, the arising three radiometabolites were found to be more polar than [(18)F]FMeNER-D2. Surprisingly, definitely no formation of free [(18)F]fluoride was observed. CONCLUSION: According to our in vitro data, the interfering uptake in cortical regions might be attributed to these emerging radiometabolites but does not reflect bonding in bone due to defluorination. Further research on these radiometabolites is necessary to elucidate the in vivo situation. This might include an analysis of human blood samples after injection of [(18)F]FMeNER-D2, to enable a better correction of the PET-input function. PMID- 27236286 TI - Effect of Massed Versus Interleaved Teaching Method on Performance of Students in Radiology. AB - PURPOSE: Radiology instruction is based on the principle that grouped (or massed) repetition of an intellectual activity leads to expertise. The aim of this study was to test the hypothesis that the spaced (or interleaved) method of teaching chest x-ray interpretation is more effective than the massed method. METHODS: After institutional review board approval was obtained, 40 first- and second-year medical students were randomized into two groups matched by age, gender, and education experience. Both groups saw six examples of 12 common chest radiographic patterns, one grouped, the other scrambled randomly without repeating strings. After a distraction, participants took a multiple-choice test consisting of two cases in each radiographic pattern, one previously shown, one new. Results were analyzed using two-tailed Student's t test of proportion. RESULTS: Comparing interleaved and massed groups, the average overall score was 57% versus 43% (P = .03), the recollection score was 61% versus 47% (P = .03), and the induction score was 53% versus 40% (P = 0.10), respectively. Comparing second- and first-year students, average scores were 67% and 39%, respectively (P < .01). First-year students in the interleaved and massed groups scored 55% and 36% (P = .02) in recall and 40% and 28% (P = .10) in induction. Second-year students in the interleaved and massed groups scored 71% and 63% (P = .36) in recall and 74% and 59% (P = .03) in induction. CONCLUSIONS: The interleaved method of instruction leads to better results than the massed method across all levels of education. A higher level of medical education improves performance independent of method of instruction. PMID- 27236285 TI - Detection of atherosclerotic plaques in ApoE-deficient mice using (99m)Tc duramycin. AB - Apoptosis of macrophages and smooth muscle cells is linked to atherosclerotic plaque destabilization. The apoptotic cascade leads to exposure of phosphatidylethanolamine (PE) on the outer leaflet of the cell membrane, thereby making apoptosis detectable using probes targeting PE. The objective of this study was to exploit capabilities of a PE-specific imaging probe, (99m)Tc duramycin, in localizing atherosclerotic plaque and assessing plaque evolution in apolipoprotein-E knockout (ApoE(-/-)) mice. METHODS: Atherosclerosis was induced in ApoE(-/-) mice by feeding an atherogenic diet. (99m)Tc-duramycin images were acquired using a small-animal SPECT imager. Six ApoE(-/-) mice at 20weeks of age (Group I) were imaged and then sacrificed for ex vivo analyses. Six additional ApoE(-/-) mice (Group II) were imaged at 20 and 40weeks of age before sacrifice. Six ApoE wild-type (ApoE(+/+)) mice (Group III) were imaged at 40weeks as controls. Five additional ApoE(-/-) mice (40weeks of age) (Group IV) were imaged with a (99m)Tc-labeled inactive peptide, (99m)Tc-LinDUR, to assess (99m)Tc duramycin targeting specificity. RESULTS: Focal (99m)Tc-duramycin uptake in the ascending aorta and aortic arch was detected at 20 and 40weeks in the ApoE(-/-) mice but not in ApoE(+/+) mice. (99m)Tc-duramycin uptake in the aortic lesions increased 2.2-fold on quantitative imaging in the ApoE(-/-) mice between 20 and 40weeks. Autoradiographic and histological data indicated significantly increased (99m)Tc-duramycin uptake in the ascending aorta and aortic arch associated with advanced plaques. Quantitative autoradiography showed that the ratio of activity in the aortic arch to descending thoracic aorta, which had no plaques or radioactive uptake, was 2.1 times higher at 40weeks than at 20weeks (6.62+/-0.89 vs. 3.18+/-0.29, P<0.01). There was barely detectable focal uptake of (99m)Tc duramycin in the aortic arch of ApoE(+/+) mice. No detectable (99m)Tc-LinDUR uptake was observed in the aortas of ApoE(-/-) mice. CONCLUSIONS: PE-targeting properties of (99m)Tc-duramycin in the atherosclerotic mouse aortas were noninvasively characterized. (99m)Tc-duramycin is promising in localizing advanced atherosclerotic plaques. PMID- 27236287 TI - Baby Steps Toward Getting Paid for Value in Radiology. PMID- 27236288 TI - Radiology's Emerging Role in 3-D Printing Applications in Health Care. AB - From its inception as a tool for prototype development in the early 1980s, three dimensional (3-D) printing has made inroads into almost every sector of industry, including health care. Medical applications range from extra- and intracorporeal orthopedic devices to complex, temporal reconstructions of patient-specific anatomy that allow operative planning and education. In the contemporary climate of personalized medicine, the utility of tangible 3-D models extrapolated directly from patient imaging data seems boundless. The purpose of this review is to briefly outline the development of 3-D printing, discuss its applications across the many medical and surgical specialties, and attempt to address obstacles and opportunities facing radiology as this technology continues to be integrated into patient care. PMID- 27236289 TI - Glasgow prognostic score and neutrophil-lymphocyte ratio are good prognostic indicators after radical neck dissection for advanced squamous cell carcinoma in the hypopharynx. AB - PURPOSE: Locally advanced carcinomas arising in the hypopharynx have been traditionally treated by resection of the hypopharynx, larynx, and cervical esophagus. However, the prognosis of these patients is still low. In the present study, we retrospectively analyzed the long-term survival of patients with locally advanced hypopharyngeal squamous cell carcinoma (HSCC) reconstructed by jejunal graft. METHODS: Between 2004 and 2014, 68 patients with HSCC were treated at Tottori University Hospital. Nine patients with synchronous esophageal cancer were excluded. We analyzed the overall survival of 59 patients with clinical stage III and IV HSCC who underwent pharyngo-laryngo-cervical esophagectomy with definitive tracheostomy followed by free jejunal graft reconstruction. Additionally, prognostic significances of preoperative patients' Glasgow prognostic score (GPS), neutrophil-lymphocyte ratio (NLR), and prognostic nutritional index were analyzed. RESULTS: Postoperative complications occurred in 18.6 % of 59 patients. There were no cases of graft loss, and no patient died from complications. Preoperative poor performance status of patients was a risk factor for postoperative complications. The 5-year overall survival rate of the 59 patients was 46.1 %, and the median survival time was 28 months. In univariate and multivariate survival analyses, high GPS (1 or 2), and high NLR (>=5) were recognized as independent poor prognostic markers for patients with HSCCs. CONCLUSIONS: Pharyngo-laryngo-cervical esophagectomy followed by free jejunal reconstruction was performed safely. Additional treatment, such as chemoradiotherapy, should be introduced for patients with high preoperative GPS or NLR after curative operation. PMID- 27236290 TI - Cholangitis in the postoperative course after biliodigestive anastomosis. AB - BACKGROUND: Hepatobiliary surgery with biliodigestive anastomosis (BDA) results in a loss of the sphincter of Oddi with consecutive ascension of bacteria into the bile system which may cause cholangitis in the postoperative course. METHODS: Patients who received reconstruction with a BDA after hepatobiliary surgery were analyzed retrospectively for their postoperative course of disease depending on intraoperatively obtained bile cultures and antibiotic prophylaxis. RESULTS: Two hundred forty-three patients were included in the analysis, 49.4 % of whom had received endoscopic stenting before the operation. Stenting was significantly associated with the presence of drug-resistant bacteria in the intraoperatively obtained bile sample (p < 0.001, OR = 4.09). Of all patients, 14.4 % developed postoperative cholangitis. This was significantly associated with the postoperative length of stay in the intensive care unit (p = 0.002, OR = 1.035). The highest incidence of postoperative cholangitis was found in patients with cholangiocellular carcinoma (n = 12, p = 0.046, OR = 2.178). Patients were more likely to harbor strains with resistance against the antibiotic that was given intraoperatively. CONCLUSION: The risk for the presence of drug-resistant bacteria is increased by preoperative stenting of the common bile duct. Bile culture by intraoperative swabs can be altered by the perioperative antibiotic prophylaxis as it induces microbiological selection in the common bile duct. PMID- 27236291 TI - Forest composition modifies litter dynamics and decomposition in regenerating tropical dry forest. AB - We investigated how forest composition, litter quality, and rainfall interact to affect leaf litter decomposition across three successional tropical dry forests in Costa Rica. We monitored litter stocks and bulk litter turnover in 18 plots that exhibit substantial variation in soil characteristics, tree community structure, fungal communities (including forests dominated by ecto- or arbuscular mycorrhizal host trees), and forest age. Simultaneously, we decomposed three standard litter substrates over a 6-month period spanning an unusually intense drought. Decay rates of standard substrates depended on the interaction between litter identity and forest type. Decomposition rates were correlated with tree and soil fungal community composition as well as soil fertility, but these relationships differed among litter types. In low fertility soils dominated by ectomycorrhizal oak trees, bulk litter turnover rates were low, regardless of soil moisture. By contrast, in higher fertility soils that supported mostly arbuscular mycorrhizal trees, bulk litter decay rates were strongly dependent on seasonal water availability. Both measures of decomposition increased with forest age, as did the frequency of termite-mediated wood decay. Taken together, our results demonstrate that soils and forest age exert strong control over decomposition dynamics in these tropical dry forests, either directly through effects on microclimate and nutrients, or indirectly by affecting tree and microbial community composition and traits, such as litter quality. PMID- 27236292 TI - Effect of low-level laser therapy after rapid maxillary expansion: a clinical investigation. AB - To evaluate the effectiveness low-level laser therapy (LLLT) on the repair of the mid palatal suture, after rapid maxillary expansion (RME). A single-operator, randomized single-blind placebo-controlled study was performed at the Orthodontic Department at the Dental Hospital of Bellvitge. Barcelona University, Hospitalet de Llobregat, Spain. Thirty-nine children (range 6-12 years old), completed RME and were randomized to receive active LLLT (n = 20) or placebo (n = 19). The laser parameters and dose were 660 nm, 100 mW, CW, InGaAlP laser, illuminated area 0.26 cm(2), 332 mW/cm(2), 60 s to four points along midpalatal suture, and 30 s to a point each side of the suture. A total of seven applications were made on days 1, 7, 14, 28, 42, 56, and 70 of the retention phase RME. A cone beam computed tomography (CBCT) scan was carried out on the day of the first laser treatment, and at day 75, a second CBCT scan was performed. Two radiologists synchronized the slices of two scans to be assessed. P = 0.05 was considered to be statistically significant. At day 75 of the suture, the irradiated patients presented a greater percentage of approximate zones in the anterior (p = 0.008) and posterior (p = 0.001) superior suture-and less approximation in the posterior superior suture (p = 0.040)-than the placebo group. LLLT appears to stimulate the repair process during retention phase after RME. PMID- 27236293 TI - Sedentary Time and Central Adiposity in Children. PMID- 27236295 TI - Sharing data of clinical trials. PMID- 27236294 TI - Oleanolic Acid Inhibits High Salt-Induced Exaggeration of Warburg-like Metabolism in Breast Cancer Cells. AB - Cancer cells have a proliferative advantage by utilizing intermediates of aerobic glycolysis (Warburg effect) for their macromolecule synthesis. Although the exact causes of this Warburg effect are unclear, high osmotic stress in solid tumor microenvironment is considered one of the important factors. Oleanolic acid (OA) is known to exert anti-inflammatory and anti-cancer effect. In our current studies, using breast cancer cell lines, we determined the protective role of OA in high salt-mediated osmotic stress-induced cancer growth. Hypertonic (0.16 M NaCl) culture conditions enhanced the cancer cell growth (26 %, p < 0.05) and aerobic glycolysis as marked by increased glucose consumption (34 %, p < 0.05) and lactate production (25 %, p < 0.05) over untreated cells. This effect was associated with increased expression and activity of key rate-limiting enzymes of aerobic glycolysis, namely hexokinase, pyruvate kinase type M2, and lactate dehydrogenase A. Interestingly, this high salt-mediated enhanced expression of aerobic glycolytic enzymes was efficiently reversed by OA along with the decreased cancer cell proliferation. In cancer cells, enhanced aerobic glycolysis is associated with the decreased mitochondrial activity and mitochondrial associated caspase activity. As expected, high salt further inhibited the mitochondrial related cytochrome oxidase and caspase-3 activity. However, OA efficiently reversed the high salt-mediated inhibition of cytochrome oxidase, caspase activity, and pro-apoptotic Bax expression, thus suggesting that OA induced mitochondrial activity and enhanced apoptosis. Taken together, our data indicate that OA efficiently reverses the enhanced Warburg-like metabolism induced by high salt-mediated osmotic stress along with potential application of OA in anti-cancer therapy. PMID- 27236296 TI - Could lung function be modified by repeated blood donations? PMID- 27236297 TI - Role of cardiovascular biomarkers for the assessment of mitral stenosis and its complications. PMID- 27236298 TI - The nomogram conundrum: a demonstration of why a prostate cancer risk model in Turkish men underestimates prostate cancer risk in the USA. AB - PURPOSE: The utility of a nomogram is based on the patient population it is designed for-and their inherent properties and biases. Our aim was to demonstrate the variability in predictive model accuracy and utility between different populations. METHODS: Our model is based on 761 men who underwent initial TRUS biopsy at a single institution in Turkey. Patients were included if they had at least 10 cores on biopsy and PSA level <20 ng/ml. Multivariable logistic regression models were used to develop a new nomogram. External validity was tested with two different cohorts one from another institution in Turkey (N = 136) and cohort from USA (N = 2242). RESULTS: Prostate cancer (PCa) and high grade PCa was diagnosed in 249/761 (32.7 %) and 101/761 (13.3 %) patients from Ankara, Turkey, respectively. Predictors of PCa were age (p < 0.0001, OR 2.11), PSA (p = 0.044, OR 1.44), PV (p < 0.0001, OR 0.38), %fPSA (p = 0.016, OR 0.72), and abnormal DRE (p < 0.0001, OR 2.05). The predictive accuracy (c-index) of our nomogram was 73 %. C-indices of 71 and 70 % were recorded in external validation cohorts from Turkey and the USA, respectively. Virtually ideal calibration was recorded for the internal validated predictive model, and good calibration was recorded when applied to the Istanbul cohort. However, the model/nomogram underestimates PCa risk in the US cohort. CONCLUSION: This is the first nomogram predicting the risk of PCa at initial biopsy in a Turkish population and provides a good risk estimation tool with good predictive accuracy and calibration in the Turkish populations. However, our study demonstrates the poor transferability of predictive tools to widely different populations. PMID- 27236299 TI - Paeoniflorin suppresses IL-6/Stat3 pathway via upregulation of Socs3 in dendritic cells in response to 1-chloro-2,4-dinitrobenze. AB - Mounting evidence has suggested that inflammation is associated with IL-6/Stat3 pathway in dendritic cells (DCs) and Th17 cells, which are critical for development of allergic contact dermatitis (ACD). Paeoniflorin (PF) has been clinically proved to be effective in the treatment of inflammatory skin diseases such as ACD. We have previously demonstrated the effect of PF on DCs stimulated with 1-chloro-2,4-dinitrobenze (DNCB) and naive CD4(+)CD45RA(+) T cells for Th17 cell differentiation. However, whether PF down-regulates IL-6/Stat3 in DCs and Th17 cells remains to be explored. In this study, we show clearly that PF markedly decreases IL-6/Stat3 in DCs stimulated with DNCB at both gene and protein levels compared with control DCs in vitro. Meanwhile, PF up-regulates suppressor of cytokine signaling 3 (Socs3). Such decreased expression of IL 6/Stat3 is abolished in DCs that were transfected with Socs3 short interfering RNA (siRNA). When mice CD4(+)CD45 RA(+) T cells were co-cultured with PF-treated DCs stimulated with/without DNCB, the gene expression of the Th17 cell markers such as retinoic acid-related orphan nuclear hormone receptor gammat (RORgammat), IL-17A, and IL-23R decreased, in accordance with the less secretions of IL-17 and IL-23 in vitro and in vivo. Finally, the suppressed Th17 differentiation induced by PF can be abolished by additional recombinant mouse IL-6. Our results suggest that the anti-inflammatory mechanisms introduced by depletion of Socs3 expression or inactivation of the negative regulator such as Socs3 may represent a promising strategy for the prevention of ACD. PMID- 27236300 TI - Administration of SB239063, a potent p38 MAPK inhibitor, alleviates acute lung injury induced by intestinal ischemia reperfusion in rats associated with AQP4 downregulation. AB - Acute lung injury (ALI), induced by intestinal ischemia reperfusion (II/R) injury, is characterized by pulmonary edema and inflammation. Aquaporin 4 (AQP4), has been pointed out recently involving in edema development. Previous studies have shown that p38 mitogen activated protein kinase (MAPK) activation resulted in lung inflammation, while p38 MAPK inhibitor can alleviate the pathology injury of lung tissue. However, the regulated mechanism of p38 MAPK in ALI induced by II/R is unclear. In this study, we established II/R rats' model by clamping the superior mesenteric artery (SMA) and coeliac artery (CA) for 40min and subsequent reperfusion for 16h, 24h, 48h. Subsequently, SB239063, a specific inhibitor of the activity of p38 MAPK, was injected (10mg/kg) intraperitoneally 60min before the operation. The severity of ALI was determined by histology analysis (HE staining and ALI scoring) and lung edema (lung wet/dry weight ratio) assessment. Western blot (WB) was applied to detect the expression level of AQP4 and phosphorylated (P)-p38 MAPK, and the localization of AQP4 was detected by immunofluorescent staining (IF). We found that AQP4 could express in the lung tissue. II/R could significantly induce lung injury, confirmed by lung injury scores and lung wet/dry weight ratios. The level of P-p38 MAPK and AQP4 were largely up-regulated in lung tissues. Moreover, inhibition of p38 MAPK activity could effectively down-regulate AQP4 expression and diminish the severity of II/R induced ALI. These novel findings suggest that inhibition of p38 MAPK function should be a potential strategy for the prevention or treatment of ALI, by targeting AQP4 in future clinic trial. PMID- 27236301 TI - Catalytic DNA: Scope, Applications, and Biochemistry of Deoxyribozymes. AB - The discovery of natural RNA enzymes (ribozymes) prompted the pursuit of artificial DNA enzymes (deoxyribozymes) by in vitro selection methods. A key motivation is the conceptual and practical advantages of DNA relative to proteins and RNA. Early studies focused on RNA-cleaving deoxyribozymes, and more recent experiments have expanded the breadth of catalytic DNA to many other reactions. Including modified nucleotides has the potential to widen the scope of DNA enzymes even further. Practical applications of deoxyribozymes include their use as sensors for metal ions and small molecules. Structural studies of deoxyribozymes are only now beginning; mechanistic experiments will surely follow. Following the first report 21 years ago, the field of deoxyribozymes has promise for both fundamental and applied advances in chemistry, biology, and other disciplines. PMID- 27236302 TI - Combined T2 and diffusion-weighted MR imaging with template prostate biopsies in men suspected with prostate cancer but negative transrectal ultrasound-guided biopsies. AB - PURPOSE: Transperineal template prostate (TPB) biopsy has been shown to improve prostate cancer detection in men with rising PSA and previous negative TRUS biopsies. Diagnostic performance of this approach especially MR imaging and using reliable reference standard remains scantly reported. MATERIALS AND METHODS: A total of 200 patients, who were previously TRUS biopsy negative, were recruited in this study. All the participants had at least 28-core TPB under general anesthetic within 8 weeks of previous negative TRUS biopsies. In 15 men undergoing laparoscopic radical prostatectomy, prostate specimens were sectioned using custom-made molds and analyzed by experienced pathologist as a feasibility study. RESULTS: In total, 120 of 200 patients (60 %) had positive TPB biopsy results. All of these men had at least one negative biopsy from transrectal route. T2 diffusion-weighted MR imaging showed no lesion in almost one-third of these men (61/200; 30.5 %). Out of these, 33 (33/61; 54 %) showed malignancy on TPB including high-grade tumors (>Gleason 7). Out of 15 patients underwent surgery with a total of 52 lesions (mean 3.5) on radical prostatectomy histology analyses, TPB detected 36 (70 %) lesions only. Some of these lesions were Gleason 7 and more mostly located in the posterior basal area of prostate. CONCLUSIONS: Transperineal template biopsy technique is associated with significantly high prostate cancer detection rate in men with previous negative TRUS biopsies, however compared to radical prostatectomy histology map, a significant number of lesions can still be missed in the posterior and basal area of prostate. PMID- 27236304 TI - Limited transmission of emergent H7N9 influenza A virus in a simulated live animal market: Do chickens pose the principal transmission threat? AB - Emergent H7N9 influenza A virus has caused multiple public health and financial hardships. While some epidemiological studies have recognized infected chickens as an important bridge for human infections, the generality of this observation, the minimum infectious dose, and the shedding potential of chickens have received conflicting results. We experimentally tested the ability of domestic chickens (Gallus gallus domesticus) to transmit H7N9 to co-housed chickens and to several other animal species in an experimental live animal market. Results indicated that an infected chicken failed to initiate viral shedding of H7N9 to naive co housed chickens. The infected chicken did, however, successfully transmit the virus to quail (Coturnix sp.) located directly below the infected chicken cage. Oral shedding by indirectly infected quail was, on average, greater than ten-fold that of directly inoculated chickens. Best management practices in live animal market systems should consider the position of quail in stacked-cage settings. PMID- 27236303 TI - Oral Paracoccidioidomycosis Granulomas are Predominantly Populated by CD163+ Multinucleated Giant Cells. AB - Multinucleated giant cells (MGC) are considered to be a hallmark of granulomatous inflammation; thus, they may play an essential role in the host response against pathogens, particularly Paracoccidioides brasiliensis. This study characterizes the MGC found in oral paracoccidioidomycosis and assesses the correlation of MGC with the amount of fungi within oral tissues. Twenty-six cases were included. They were classified as loose or dense granulomas, and the total MGC, including foreign-body and Langhans giant cells, besides the total and intracellular fungi, were taken into consideration. CD163 immunoexpression was performed, and CD163+ multinucleated giant cells were also quantified. Dense granulomas revealed more foreign-body type and total giant cells than loose granulomas (P < 0.05). Total giant cells showed a positive linear correlation with the CD163+ cells (P = 0.003; r = 0.56) and intracellular fungi quantification (P = 0.045; r = 0.40). Oral paracoccidioidomycosis lesions contain MGC that mainly belong to a CD163+ phenotype, also showing both Langhans and foreign-body arrangements. Additionally, the higher the presence of MGC, the higher the amount of phagocytized fungi. PMID- 27236305 TI - Virus-induced gene silencing reveals signal transduction components required for the Pvr9-mediated hypersensitive response in Nicotiana benthamiana. AB - Resistance to pathogens mediated by plant resistance (R) proteins requires different signaling transduction components and pathways. Our previous studies revealed that a potyvirus resistance gene in pepper, Pvr9, confers a hypersensitive response (HR) to pepper mottle virus in Nicotiana benthamiana. Our results show that the Pvr9-mediated HR against pepper mottle virus infection requires HSP90, SGT1, NDR1, but not EDS1. These results suggest that the Pvr9 mediated HR is possibly related to the SA pathway but not the ET, JA, ROS or NO pathways. PMID- 27236307 TI - Erratum to: Genetic Biomarkers of Barrett's Esophagus Susceptibility and Progression to Dysplasia and Cancer: A Systematic Review and Meta-Analysis. PMID- 27236306 TI - The genome of AR9, a giant transducing Bacillus phage encoding two multisubunit RNA polymerases. AB - Bacteriophage AR9 and its close relative PBS1 have been extensively used to construct early Bacillus subtilis genetic maps. Here, we present the 251,042bp AR9 genome, a linear, terminally redundant double-stranded DNA containing deoxyuridine instead of thymine. Multiple AR9 genes are interrupted by non-coding sequences or sequences encoding putative endonucleases. We show that these sequences are group I and group II self-splicing introns. Eight AR9 proteins are homologous to fragments of bacterial RNA polymerase (RNAP) subunits beta/beta'. These proteins comprise two sets of paralogs of RNAP largest subunits, with each paralog encoded by two disjoint phage genes. Thus, AR9 is a phiKZ-related giant phage that relies on two multisubunit viral RNAPs to transcribe its genome independently of host transcription apparatus. Purification of one of PBS1/AR9 RNAPs has been reported previously, which makes AR9 a promising object for further studies of RNAP evolution, assembly and mechanism. PMID- 27236308 TI - Lactobacillus rhamnosus GR-1 Limits Escherichia coli-Induced Inflammatory Responses via Attenuating MyD88-Dependent and MyD88-Independent Pathway Activation in Bovine Endometrial Epithelial Cells. AB - Intrauterine Escherichia coli infection after calving reduces fertility and causes major economic losses in the dairy industry. We investigated the protective effect of the probiotic Lactobacillus rhamnosus GR-1 on E. coli induced cell damage and inflammation in primary bovine endometrial epithelial cells (BEECs). L. rhamnosus GR-1 reduced ultrastructure alterations and the percentage of BEECs apoptosis after E. coli challenge. Increased messenger RNA (mRNA) expression of immune response indicators, including pattern recognition receptors (toll-like receptor [TLR]2, TLR4, nucleotide-binding oligomerization domain [NOD]1, and NOD2), inflammasome proteins (NOD-like receptor family member pyrin domain-containing protein 3, apoptosis-associated speck-like protein, and caspase-1), TLR4 downstream adaptor molecules (myeloid differentiation antigen 88 [MyD88], toll-like receptor adaptor molecule 2 [TICAM2]), nuclear transcription factor kB (NF-kB), and the inflammatory cytokines tumor necrosis factor (TNF) alpha, interleukin (IL)-1beta, IL-6, IL-8, IL-10, IL-18, and interferon (IFN) beta, was observed following E. coli challenge. However, these increases were attenuated by L. rhamnosus GR-1 pretreatment. Our data indicate that L. rhamnosus GR-1 ameliorates the E. coli-induced disruption of cellular ultrastructure, subsequently reducing the percentage of BEECs apoptosis and limiting inflammatory responses, partly via attenuation of MyD88-dependent and MyD88-independent pathway activation. Certain probiotics could potentially prevent postpartum uterine diseases in dairy cows, ultimately reducing the use of antibiotics. PMID- 27236309 TI - Health Literacy, Mammogram Awareness and Screening Among Tertiary Hospital Women Patients. AB - In spite of high mortality rates and prevalence, breast cancer awareness and screening is low among Turkish women. This study aimed to determine level of health literacy, mammogram awareness, and screening among tertiary hospital women patients. A cross-sectional study was conducted with 519 patients aged between 40 and 69. A questionnaire was applied to women patients including demographic characteristics, health behaviors, mammogram awareness and screening, and health literacy tool. Mammogram awareness and screening were questioned according to the Turkish Breast Cancer Screening Standard. To assess health literacy level, the Rapid Estimate of Adult Literacy in Medicine was used. Over half of the women were aware of the mammogram age and 23.1 % had a mammogram within 2 years. Limited health literacy was high among patients, and it was significantly associated with lower mammogram awareness (OR 6.53; 95% CL 1.46-9.13) and screening (OR 1.12; 95% CL 0.45-2.80). Health literacy can be an advantageous opportunity on focal point of national cancer screening. Breast cancer education program and public health campaigns should be arranged according to women health literacy level. PMID- 27236310 TI - Rapid detection of hazardous chemicals in textiles by direct analysis in real time mass spectrometry (DART-MS). AB - Residues of chemicals on clothing products were examined by direct analysis in real-time (DART) mass spectrometry. Our experiments have revealed the presence of more than 40 chemicals in 15 different clothing items. The identification was confirmed by DART tandem mass spectrometry (MS/MS) experiments for 14 compounds. The most commonly detected hazardous substances were nonylphenol ethoxylates (NPEs), phthalic acid esters (phthalates), amines released by azo dyes, and quinoline derivates. DART-MS was able to detect NPEs on the skin of the person wearing the clothing item contaminated by NPE residuals. Automated data acquisition and processing method was developed and tested for the recognition of NPE residues thereby reducing the analysis time. PMID- 27236311 TI - Determination of polyphenol content and colour index in wines through PEDOT modified electrodes. AB - Poly(3,4-ethylenedioxythiophene)-modified electrodes have been used for the estimation of the polyphenolic content and of the colour index of different samples of wines. Synthetic wine solutions, prepared with different amount of oenocyanins, have been analysed spectrophotometrically and electrochemically in order to find a correlation between the total polyphenolic content or colour index and the current peak. The regression curves obtained have been used as external calibration lines for the analysis of several commercial wines, ranging from white to dark red wines. In this way, a rapid estimation of the total polyphenolic content and of the colour index may be accomplished from a single voltammetric measurement. Furthermore, principal component analysis has also been used to evaluate the effect of total polyphenolic content and colour index on the whole voltammetric signals within a selected potential range, both for the synthetic solutions and for the commercial products. Graphical abstract Electrochemical sensors for the rapid determination of colour index and polyphenol content in wines. PMID- 27236313 TI - Label-free electrochemical genosensor based on mesoporous silica thin film. AB - A novel label-free electrochemical strategy for nucleic acid detection was developed by using gold electrodes coated with mesoporous silica thin films as sensing interface. The biosensing approach relies on the covalent attachment of a capture DNA probe on the surface of the silica nanopores and further hybridization with its complementary target oligonucleotide sequence, causing a diffusion hindering of an Fe(CN)6 (3-/4-) electrochemical probe through the nanochannels of the mesoporous film. This DNA-mesoporous silica thin film modified electrodes allowed sensitive (91.7 A/M) and rapid (45 min) detection of low nanomolar levels of synthetic target DNA (25 fmol) and were successfully employed to quantify the endogenous content of Escherichia coli 16S ribosomal RNA (rRNA) directly in raw bacterial lysate samples without isolation or purification steps. Moreover, the 1-month stability demonstrated by these biosensing devices enables their advanced preparation and storage, as desired for practical real life applications. Graphical abstract Mesoporous silica thin films as scaffolds for the development of novel label-free electrochemical genosensors to perform selective, sensitive and rapid detection of target oligonucleotide sequences. Application towards E. coli determination. PMID- 27236314 TI - An LC/ESI-SRM/MS method to screen chemically modified hemoglobin: simultaneous analysis for oxidized, nitrated, lipidated, and glycated sites. AB - Proteins are continuously exposed to various reactive chemical species (reactive oxygen/nitrogen species, endogenous/exogenous aldehydes/epoxides, etc.) due to physiological and chemical stresses, resulting in various chemical modifications such as oxidation, nitration, glycation/glycoxidation, lipidation/lipoxidation, and adduct formation with drugs/chemicals. Abundant proteins with a long half life, such as hemoglobin (Hb, t 1/2 63 days, ~150 mg/mL), are believed to be major targets of reactive chemical species that reflect biological events. Chemical modifications on Hb have been investigated mainly by mechanistic in vitro experiments or in vivo/clinical experiments focused on single target modifications. Here, we describe an optimized LC/ESI-SRM/MS method to screen oxidized, nitrated, lipidated, and glycated sites on Hb. In vivo preliminary results suggest that this method can detect simultaneously the presence of oxidation (+16 Da) of alpha-Met(32), alpha-Met(76), beta-Met(55), and beta Trp(15) and adducts of malondialdehyde (+54 Da) and glycation (+162 Da) of beta Val(1) in a blood sample from a healthy volunteer. Graphical Abstract Screening chemical modifications on hemoglobin. PMID- 27236316 TI - Enantioselective separation of defined endocrine-disrupting nonylphenol isomers. AB - Nonylphenol is in the focus of worldwide endocrine-disrupter research and accounted for as a priority hazardous substance of the Water Framework Directive of the European Union. Technical nonylphenol consists of a very complex mixture of isomers and enantiomers. As estrogenic effect and degradation behavior in environmental processes of single nonylphenols are heavily dependent on the structure of the nonyl side chain, it is absolutely necessary to consider the nonylphenol problem from an isomer and enantiomer-specific viewpoint. In this study, an enantiomer-specific separation of eight defined synthesized nonylphenol isomers by five different special chiral cyclodextrin columns was performed underivatized and after methylation, silylation, and acylation. This work demonstrates that three columns out of the investigated five show an excellent separation behavior for the studied different nonylphenol isomers and can be used for the enantiomer-specific determination of nonylphenols in food, other biological matrices, and environmental samples in the future. Graphical abstract Enantiomeric pair of 4-NP170 (4-[1-ethyl-1,3,3-trimethylbutyl]phenol). PMID- 27236315 TI - Synthesis of bifunctional TiO2@SiO2-B(OH)2@Fe3O4@TiO2 sandwich-like nanosheets for sequential selective enrichment of phosphopeptides and glycopeptides for mass spectrometric analysis. AB - In this work, the bifunctional TiO2@SiO2-B(OH)2@Fe3O4@TiO2 sandwich-like nanosheets were designed and synthesized for the sequential selective enrichment of phosphopeptides and glycopeptides. Due to the bifunctional property of the titanium dioxide and the boronic acid group, the nanosheets were successfully applied to the enrichment of phosphopeptides and glycopeptides sequentially, evaluated by capturing phosphopeptides from tryptic digestion of model phosphoprotein bovine beta-casein diluted to 0.02 ng/MUL (8 * 10(-16) mol/MUL) and glycopeptides from tryptic digestion of model glycoprotein horseradish peroxidase (HRP) diluted to 0.1 ng/MUL (2.5 * 10(-15) mol/MUL). The enrichment selectivity of the bifunctional nanosheets was evaluated by capturing phosphopeptides from a peptide mixture of beta-casein and bovine serum albumin (BSA) with the molar ratio of 1:1000 (8.3 * 10(-12) mol of beta-casein and 8.3 * 10(-9) mol of BSA in 100 MUL) and glycopeptides from a peptide mixture of HRP and BSA up to the ratio of 1:50 (5.0 * 10(-11) mol of HRP and 2.5 * 10(-9) mol of BSA in 100 MUL). Graphical Abstract A workflow of the sequential enrichment strategy for phosphopeptides and glycopeptides by the bifunctional TiO2@SiO2 B(OH)2@Fe3O4@TiO2 sandwich-like nanosheets. PMID- 27236317 TI - Site-specific analysis of advanced glycation end products in plasma proteins of type 2 diabetes mellitus patients. AB - Advanced glycation end products (AGEs) are posttranslational modifications formed non-enzymatically from the reaction of carbohydrates and their degradation products with proteins. Accumulation of AGEs is associated with the progression of severe diabetic complications, for example, and elevated tissue levels of AGEs might even predict these pathologies. As AGE formation is often site-specific, mapping of these modification sites may reveal more sensitive and specific markers than the global tissue level. Here, 42 AGE modifications were identified in a bottom-up proteomic approach by tandem mass spectrometry, which corresponded to 36 sites in 22 high to medium abundant proteins in individual plasma samples obtained from type 2 diabetes mellitus (T2DM) patients with long disease duration (>10 years). Major modifications were glarg (11 modification sites) and carboxymethylation (5) of arginine and formylation (8), acetylation (7), and carboxymethylation (7) of lysine residues. Relative quantification of these sites in plasma samples obtained from normoglycemic individuals (n = 47) and patients with T2DM being newly diagnosed (n = 47) or of medium (2-5 years, n = 20) and long disease duration (>10 years, n = 20) did not reveal any significant differences. PMID- 27236318 TI - An internal standard approach for homogeneous TR-FRET immunoassays facilitates the detection of bacteria, biomarkers, and toxins in complex matrices. AB - The recent development of a homogeneous time-resolved Forster resonance energy transfer (TR-FRET) immunoassay enables one-step, rapid (minutes), and direct detection compared to the multistep, time-consuming (hours), heterogeneous ELISA type immunoassays. The use of the time-resolved effect of a donor lanthanide complex with a delay time of microseconds and large Stokes shift enables the separation of positive signals from the background autofluorescence of the sample. However, this study shows that the sample matrices directly interfere with donor fluorescence and that interference cannot be eliminated by time resolved settings alone. Moreover, the reduction in donor emission did not appear to be equivalent to the reduction in acceptor emission, resulting in incorrect FRET signal measurements. To overcome this limitation, an internal standard approach was developed using an isotype control antibody. This new approach was used to develop TR-FRET assays for rapid detection (15-30 min) of Bacillus anthracis spores and botulinum toxin (type E) in beverages, which are major concerns in bioterrorism involving deliberate food contamination. Additionally, we demonstrate the detection of B. anthracis-secreted protective antigen (PA) and the Yersinia pestis-secreted markers F1 and LcrV in blood cultures, which are early markers of bacteremia in infected hosts following a possible bioterror attack. The use of an internal standard enables the calculation of correct DeltaF values without the need for an external standard. Thus, the use of the internal standard approach in homogeneous immunoassays facilitates the examination of any sample regardless of its origin, and therefore expands the applicability of TR FRET assays for complex matrices. PMID- 27236319 TI - Determination of silver ions based on the electrogenerated chemiluminescence of silver ions/peroxydisulfate. AB - In this work, a simple, sensitive, and selective method for the determination of silver ions (Ag(+)) was proposed on the basis of the enhancement of Ag(+) on the electrogenerated chemiluminescence (ECL) of peroxydisulfate (S2O8 (2-)), which can be attributed to the obvious electrocatalytic reduction of S2O8 (2-) by Ag(+), giving rise to more abundant sulfate radical anion (SO4 (*-)). Under optimal conditions, a linear range from 4 to 500 nM (R = 0.997) with a detection limit of 2.5 nM (S/N = 3) was achieved for the detection of Ag(+). The Ag(+)/S2O8 (2-) ECL system could not only provide an assay protocol for the determination of Ag(+) but also offer an effective way to enhance the ECL of S2O8 (2-), which may act as a promising platform for the detection of other species such as 4 chlorophenol. Graphical abstract ECL-potential curves of 0.1 M PBS (pH 8.5) containing (a) 500 nM AgNO3, (b) 50 mM K2S2O8, PMID- 27236320 TI - Dose-Dependent Bioavailability and CYP3A Inhibition Contribute to Non-Linear Pharmacokinetics of Voriconazole. AB - Voriconazole is both a substrate and a potent inhibitor of cytochrome P450 (CYP) 3A. It has a high bioavailability and non-linear pharmacokinetics. We investigated the pharmacokinetics and metabolism of 50 mg and 400 mg doses of intravenous and oral voriconazole in 14 healthy volunteers. Concurrently, we determined systemic and presystemic CYP3A activity with microdosed midazolam. Bioavailability of voriconazole 50 mg was 39 % compared with 86 % of the 400 mg dose. Voriconazole area under the concentration-time curve extrapolated to infinity (AUCinfinity) was 416 and 16,700 h.ng/mL for the 50 and 400 mg oral doses, respectively, and 1110 and 19,760 h.ng/mL for the 50 and 400 mg intravenous doses, respectively. Midazolam metabolism was dose-dependently inhibited by voriconazole. Dose-dependent autoinhibition of CYP3A-dependent first pass metabolism and systemic metabolism is a possible explanation for the dose dependent bioavailability and elimination of voriconazole, either as additional mechanism to, or instead of, saturation of presystemic metabolism. Higher bioavailability and non-linear pharmacokinetics are expected to be a common property of drugs that are substrates and inhibitors of CYP3A, e.g. clarithromycin. PMID- 27236321 TI - Rare or rarely detected? Ceraceosorus guamensis sp. nov.: a second described species of Ceraceosorales and the potential for underdetection of rare lineages with common sampling techniques. AB - Ceraceosorales is a monotypic order in Ustilaginomycotina. Its namesake, Ceraceosorus bombacis, was described as a phytopathogen of Bombax ceiba in India. In this study, we describe Ceraceosorus guamensis sp. nov., collected on the South Pacific island of Guam, which appears to represent the second isolation of any member of this order in over 40 years. Ceraceosorus species are monokaryotic and filamentous in culture, producing conidia on potato dextrose agar. However, both species behave yeast-like when cultured on corn meal agar. The internal transcribed spacer (ITS) region (spanning the ITS1-5.8S-ITS2) in both species of Ceraceosorus is highly heterogeneous containing multiple disparate copies that can vary intragenomically by up to 3.5 %. Moreover, this region could not be amplified using the fungal ITS primers most frequently used for culture independent methods of assessing fungal biodiversity. This fact, combined with the extremely slow growth rates on commonly employed media, may indicate that members of this lineage are potentially underdetected by current sampling methods. PMID- 27236322 TI - Use of a new integrated table motion for the da Vinci Xi in colorectal surgery. PMID- 27236323 TI - Narrow band imaging in giant pituitary adenoma surgery. PMID- 27236324 TI - Effect(s) of Language Tasks on Severity of Disfluencies in Preschool Children with Stuttering. AB - Speech disfluency in children can be increased or decreased depending on the type of linguistic task presented to them. In this study, the effect of sentence imitation and sentence modeling on severity of speech disfluencies in preschool children with stuttering is investigated. In this cross-sectional descriptive analytical study, 58 children with stuttering (29 with mild stuttering and 29 with moderate stuttering) and 58 typical children aged between 4 and 6 years old participated. The severity of speech disfluencies was assessed by SSI-3 and TOCS before and after offering each task. In boys with mild stuttering, The mean stuttering severity scores in two tasks of sentence imitation and sentence modeling were [Formula: see text] and [Formula: see text] respectively ([Formula: see text]). But, in boys with moderate stuttering the stuttering severity in the both tasks were [Formula: see text] and [Formula: see text] respectively ([Formula: see text]). In girls with mild stuttering, the stuttering severity in two tasks of sentence imitation and sentence modeling were [Formula: see text] and [Formula: see text] respectively ([Formula: see text]). But, in girls with moderate stuttering the mean stuttering severity in the both tasks were [Formula: see text] and [Formula: see text] respectively ([Formula: see text]). In both gender of typical children, the score of speech disfluencies had no significant difference between two tasks ([Formula: see text]). In preschool children with mild stuttering and peer non-stutters, performing the tasks of sentence imitation and sentence modeling could not increase the severity of stuttering. But, in preschool children with moderate stuttering, doing the task of sentence modeling increased the stuttering severity score. PMID- 27236326 TI - MRI features of calcifying aponeurotic fibroma in the upper arm: a case report and review of the literature. AB - Calcifying aponeurotic fibroma is a rare soft tissue tumor that occurs in the distal extremities of children and adolescents. We report a case of pathologically proven calcifying aponeurotic fibroma in the left upper arm of a 23-year-old female. Radiographs revealed increased soft tissue density with multiple stippled calcifications in the mid-portion of the patient's left upper arm. Magnetic resonance imaging (MRI) showed a well-defined soft tissue mass with low to intermediate signal intensity on T1-weighted images, heterogeneously low signal intensity on T2-weighted images, and heterogeneous enhancement on fat suppressed, contrast-enhanced T1-weighted images. Histologically, spindle cell proliferation with scattered calcifications and hyalinization was present. Seven years after surgery, there was no evidence of local recurrence. This is the first report of MRI findings of calcifying aponeurotic fibroma in the upper arm. We also summarize the MRI findings of 16 previously reported cases of calcifying aponeurotic fibroma originating in the upper or lower extremities. PMID- 27236325 TI - Activation of Cold-Sensitive Channels TRPM8 and TRPA1 Inhibits the Proliferative Airway Smooth Muscle Cell Phenotype. AB - PURPOSE: Airway smooth muscle cell (ASMC) phenotypic modulation is one of the key factors contributing to asthma. Temperature changes may induce asthma, and these changes are known to be related to the temperature-sensitive transient receptor potential channels (TS-TRPs). The present study was designed to investigate the cellular functions of cold-sensitive channels, TRPM8 and TRPA1, in the phenotypic modulation of ASMCs. METHODS: A rat asthma model was constructed and the expression of TS-TRPs in ASM was tested. Using the agonists and antagonists for both TRPM8 and TRPA1, the effects of cold-sensitive channels on the phenotypic modulation of ASMCs were evaluated by measurement of contractile protein expression and cell proliferation and migration. Signaling pathways and matrix metalloproteinase-2 (MMP-2) activity were assayed with Western blotting and gelatin zymography. RESULTS: TRPM8 and TRPA1 were decreased in the ASM of the rat asthma model. Icilin and menthol, agonists for TRPM8 and TRPA1, inhibited ASMC proliferation and migration induced by fetal bovine serum (FBS) or platelet derived growth factor (PDGF). Moreover, icilin reversed the FBS-induced inhibition of the expression of contractile phenotype markers, smooth muscle alpha-actin, and SM22alpha. Icilin also antagonized the activation of p38 and MMP 2 and the repression of p21 caused by FBS. CONCLUSIONS: Our findings show, for the first time, that the activation of TRPM8 and TRPA1 inhibits ASMC proliferative phenotype. These data suggest that TRPM8 and TRPA1 agonists may be promising new therapies for asthma. PMID- 27236327 TI - Malignant gliomas induce and exploit astrocytic mesenchymal-like transition by activating canonical Wnt/beta-catenin signaling. AB - The complex microenvironment of malignant gliomas plays a dynamic and usually cancer-promoting role in glioma progression. Astrocytes, the major stromal cells in the brain, can be activated by glioma microenvironment, resulting in a layer of reactive astrocytes surrounding the gliomas. Reactive astrocytes are universally characterized with the upregulation of glial fibrillary protein and glycoprotein podoplanin. In this work, we investigated the role of reactive astrocytes on malignant glioma microenvironment and the potential mechanism by which glioma cells activated the tumor-associated astrocytes (TAAs). The reactive astrocytes were observed around gliomas in the intracranial syngeneic implantation of rat C6 and mouse GL261 glioma cells in vivo, as well as primary astrocytes cultured with glioma cells condition medium in vitro. Besides, reactive astrocytes exhibited distinct epithelial-to-mesenchymal (-like) transition and enhanced migration and invasion activity, with the decrease of E cadherin and concomitant increase of vimentin and matrix metalloproteinases. Furthermore, canonical Wnt/beta-catenin signaling was activated in TAAs. The Wnt/beta-catenin pathway inhibitor XAV939 and beta-catenin plasmid were used to verify the regulation of Wnt/beta-catenin signaling on TAAs and their invasion ability. Taken together, our findings established that glioma cells remarkably activated astrocytes via upregulating Wnt/beta-catenin signaling, with obviously mesenchymal-like transition and increased migration and invasion ability, indicating that glioma cells may stimulate adjacent astrocytes to degrade extracellular matrix and thereby promoting tumor invasiveness. PMID- 27236328 TI - Accuracy of point of care ultrasound to identify the source of infection in septic patients: a prospective study. AB - Sepsis is a rapidly evolving disease with a high mortality rate. The early identification of sepsis and the implementation of early evidence-based therapies have been recognized to improve outcome and decrease sepsis-related mortality. The aim of this study was to compare the accuracy of the standard diagnostic work up of septic patients with an integrated approach using early point of care ultrasound (POCUS) to identify the source of infection and to speed up the time to diagnosis. We enrolled a consecutive sample of adult patients admitted to the ED who met the Surviving Sepsis Campaign (SSC) criteria for sepsis. For every patient, the emergency physician was asked to identify the septic source after the initial clinical assessment and after POCUS. Patients were then addressed to the standard predefined work-up. The impression at the initial clinical assessment and POCUS-implemented diagnosis was compared with the final diagnosis of the septic source, determined by independent review of the entire medical record after discharge. Two hundred consecutive patients entered the study. A final diagnosis of the septic source was obtained in 178 out of 200 patients (89 %). POCUS-implemented diagnosis had a sensitivity of 73 % (95 % CI 66-79 %), a specificity of 95 % (95 % CI 77-99 %), and an accuracy of 75 %. Clinical impression after the initial clinical assessment (T0) had a sensitivity of 48 % (CI 95 % 41-55 %) and a specificity of 86 % (CI 95 % 66-95 %). POCUS improved the sensitivity of the initial clinical impression by 25 %. POCUS-implemented diagnoses were always obtained within 10 min. Instead the septic source was identified within 1 h in only 21.9 % and within 3 h in 52.8 % with a standard work-up. POCUS-implemented diagnosis is an effective and reliable tool for the identification of septic source, and it is superior to the initial clinical evaluation alone. It is likely that a wider use of POCUS in an emergency setting will allow a faster diagnosis of the septic source, leading to more appropriate and prompt antimicrobial therapy and source control strategies. PMID- 27236329 TI - Minimal invasive treatment of life-threatening bleeding caused by cardiopulmonary resuscitation-associated liver injury: a case report. AB - BACKGROUND: Life-threatening bleeding caused by liver injury due to chest compressions is a rare complication in otherwise successful cardiopulmonary resuscitation. Surgical intervention has been suggested to achieve bleeding control; however, reported mortality is high. In this report, we present a brief literature review and a case report in which use of a less invasive strategy was followed by an uneventful recovery. CASE PRESENTATION: A 37-year-old white woman was admitted after out-of-hospital cardiac arrest. Bystander cardiopulmonary resuscitation was immediately performed, followed by advanced cardiopulmonary resuscitation that included tracheal intubation, mechanical chest compressions, and external defibrillation with return of spontaneous circulation. Upon hospital admission, the patient's blood pressure was 94/45 mmHg and her heart rate was 110 beats per minute. Her electrocardiogram showed no signs of ST-segment elevations or Q-wave development. Coronary angiography revealed a proximal thrombotic occlusion of the left anterior descending coronary artery. Successful recanalization, after thrombus aspiration and balloon dilation followed by stent implant, was verified with normalized anterograde flow. Immediately after the patient's arrival in the intensive cardiac care unit, a drop in her blood pressure to 60/30 mmHg and a hemoglobin concentration of 4.5 g/dl were noticed. Transfusion was started, and bedside abdominal ultrasound examination revealed free intraperitoneal fluid. Computed tomography of the abdomen revealed liver injury with active extravasation from the cranial surface of the right lobe and a massive hemoperitoneum. The patient was coagulopathic and acidotic with a body temperature of 33.5 degrees C. A minimally invasive treatment strategy, including angiography and selective trans-catheter arterial embolization, were performed in combination with percutaneous evacuation of 4.5 L of intraperitoneal blood. After completion of these procedures, the patient was hemodynamically stable. She was weaned off mechanical ventilation 2 days later and made an uneventful recovery. She was discharged to a local hospital on day 13 without neurological disability. CONCLUSIONS: Although rare, bleeding caused by liver injury due to chest compressions can be life-threatening after successful cardiopulmonary resuscitation. Reported mortality is high after surgical intervention, and patients may benefit from less invasive treatment strategies such as those presented in this case report. PMID- 27236330 TI - Perspectives of frontline health workers on Ghana's National Health Insurance Scheme before and after community engagement interventions. AB - BACKGROUND: Barely a decade after introduction of Ghana's National Health Insurance Scheme (NHIS), significant successes have been recorded in universal access to basic healthcare services. However, sustainability of the scheme is increasingly threatened by concerns on quality of health service delivery in NHIS accredited health facilities coupled with stakeholders' discontentment with the operational and administrative challenges confronting the NHIS. The study sought to ascertain whether or not Systematic Community Engagement (SCE) interventions have a significant effect on frontline health workers' perspectives on the NHIS and its impact on quality health service delivery. METHODS: The study is a randomized cluster trial involving clinical and non-clinical frontline health workers (n = 234) interviewed at baseline and follow-up in the Greater Accra and Western regions of Ghana. Individual respondents were chosen from within each intervention and control groupings. Difference-in-difference estimations and propensity score matching were performed to determine impact of SCE on staff perceptions of the NHIS. The main outcome measure of interest was staff perception of the NHIS based on eight (8) factor-analyzed quality service parameters. RESULTS: Staff interviewed in intervention facilities appeared to perceive the NHIS more positively in terms of its impact on "availability and quality of drugs (p < 0.05)" and "workload on health staff/infrastructure" than those interviewed in control facilities (p < 0.1). Delayed reimbursement of service providers remained a key concern to over 70 % of respondents in control and intervention health facilities. CONCLUSION: Community engagement in quality service assessment is a potential useful strategy towards empowering communities while promoting frontline health workers' interest, goodwill and active participation in Ghana's NHIS. PMID- 27236331 TI - Transcription Factor NF-kappaB: An Update on Intervention Strategies. AB - The nuclear factor (NF)-kappaB family of transcription factors are ubiquitous and pleiotropic molecules that regulate the expression of more than 150 genes involved in a broad range of processes including inflammation, immunity, cell proliferation, differentiation, and survival. The chronic activation or dysregulation of NF-kappaB signaling is the central cause of pathogenesis in many disease conditions and, therefore, NF-kappaB is a major focus of therapeutic intervention. Because of this, understanding the relationship between NF-kappaB and the induction of various downstream signaling molecules is imperative. In this review, we provide an updated synopsis of the role of NF-kappaB in DNA repair and in various ailments including cardiovascular diseases, HIV infection, asthma, herpes simplex virus infection, chronic obstructive pulmonary disease, and cancer. Furthermore, we also discuss the specific targets for selective inhibitors and future therapeutic strategies. PMID- 27236332 TI - Comprehensive analyses of the annexin gene family in wheat. AB - BACKGROUND: Annexins are an evolutionarily conserved multigene family of calcium dependent phospholipid binding proteins that play important roles in stress resistance and plant development. They have been relatively well characterized in model plants Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa), but nothing has been reported in hexaploid bread wheat (Triticum aestivum) and barely (Hordeum vulgare), which are the two most economically important plants. RESULTS: Based on available genomic and transcriptomic data, 25 and 11 putative annexin genes were found through in silico analysis in wheat and barley, respectively. Additionally, eight and 11 annexin genes were identified from the draft genome sequences of Triticum urartu and Aegilops tauschii, progenitor for the A and D genome of wheat, respectively. By phylogenetic analysis, annexins in these four species together with other monocots and eudicots were classified into six different orthologous groups. Pi values of each of Ann1-12 genes among T. aestivum, T. urartu, A. tauschii and H. vulgare species was very low, with the exception of Ann2 and Ann5 genes. Ann2 gene has been under positive selection, but Ann6 and Ann7 have been under purifying selection among the four species in their evolutionary histories. The nucleotide diversities of Ann1-12 genes in the four species were 0.52065, 0.59239, 0.60691 and 0.53421, respectively. No selective pressure was operated on annexin genes in the same species. Gene expression patterns obtained by real-time PCR and re-analyzing the public microarray data revealed differential temporal and spatial regulation of annexin genes in wheat under different abiotic stress conditions such as salinity, drought, cold and abscisic acid. Among those genes, TaAnn10 is specifically expressed in the anther but fails to be induced by low temperature in thermosensitive genic male sterile lines, suggesting that specific down regulation of TaAnn10 is associated with conditional male sterility in wheat. CONCLUSIONS: This study analyzed the size and composition of the annexin gene family in wheat and barley, and investigated differential tissue-specific and stress responsive expression profiles of the gene family in wheat. These results provided significant information for understanding the diverse roles of plant annexins and opened a new avenue for functional studies of cold induced male sterility in wheat. PMID- 27236333 TI - Clinical results of mean GTV dose optimized robotic guided SBRT for liver metastases. AB - BACKGROUND: We retrospectively evaluated the efficacy and toxicity of gross tumor volume (GTV) mean-dose-optimized and real-time motion-compensated robotic stereotactic body radiation therapy (SBRT) in the treatment of liver metastases. METHODS: Between March 2011 and July 2015, 52 patients were treated with SBRT for a total of 91 liver metastases (one to four metastases per patient) with a median GTV volume of 12 cc (min 1 cc, max 372 cc). The optimization of mean GTV dose was prioritized during treatment planning at the potential cost of planning target volume (PTV) coverage reduction while adhering to safe normal tissue constraints. The delivered median GTV biological effective dose (BED10) was 142.1 Gy10 (range, 60.2 Gy10 -165.3 Gy10) and the prescribed PTV BED10 ranged from 40.6 Gy10 to 112.5 Gy10 (median, 86.1 Gy10). We analyzed local control (LC), progression-free interval (PFI), overall survival (OS), and toxicity. RESULTS: Median follow-up was 17 months (range, 2-49 months). The 2-year actuarial LC, PFI, and OS rates were 82.1, 17.7, and 45.0 %, and the median PFI and OS were 9 and 23 months, respectively. In univariate analysis histology (p < 0.001), PTV prescription BED10 (HR 0.95, CI 0.91-0.98, p = 0.002) and GTV mean BED10 (HR 0.975, CI 0.954 0.996, p = 0.011) were predictive for LC. Multivariate analysis showed that only extrahepatic disease status at time of treatment was a significant factor (p = 0.033 and p = 0.009, respectively) for PFI and OS. Acute nausea or fatigue grade 1 was observed in 24.1 % of the patients and only 1 patient (1.9 %) had a side effect of grade >= 2. CONCLUSIONS: Robotic real-time motion-compensated SBRT is a safe and effective treatment for one to four liver metastases. Reducing the PTV prescription dose and keeping a high mean GTV dose allowed the reduction of toxicity while maintaining a high local control probability for the treated lesions. PMID- 27236334 TI - Single-stranded DNA binding protein Ssbp3 induces differentiation of mouse embryonic stem cells into trophoblast-like cells. AB - BACKGROUND: Intrinsic factors and extrinsic signals which control unlimited self renewal and developmental pluripotency in embryonic stem cells (ESCs) have been extensively investigated. However, a much smaller number of factors involved in extra-embryonic trophoblast differentiation from ESCs have been studied. In this study, we investigated the role of the single-stranded DNA binding protein, Ssbp3, for the induction of trophoblast-like differentiation from mouse ESCs. METHODS: Gain- and loss-of-function experiments were carried out through overexpression or knockdown of Ssbp3 in mouse ESCs under self-renewal culture conditions. Expression levels of pluripotency and lineage markers were detected by real-time quantitative reverse-transcription polymerase chain reaction (qRT PCR) analyses. The global gene expression profile in Ssbp3-overexpressing cells was determined by affymetrix microarray. Gene ontology and pathway terms were analyzed and further validated by qRT-PCR and Western blotting. The methylation status of the Elf5 promoter in Ssbp3-overexpressing cells was detected by bisulfite sequencing. The trophoblast-like phenotype induced by Ssbp3 was also evaluated by teratoma formation and early embryo injection assays. RESULTS: Forced expression of Ssbp3 in mouse ESCs upregulated expression levels of lineage associated genes, with trophoblast cell markers being the highest. In contrast, depletion of Ssbp3 attenuated the expression of trophoblast lineage marker genes induced by downregulation of Oct4 or treatment with BMP4 and bFGF in ESCs. Interestingly, global gene expression profiling analysis indicated that Ssbp3 overexpression did not significantly alter the transcript levels of pluripotency associated transcription factors. Instead, Ssbp3 promoted the expression of early trophectoderm transcription factors such as Cdx2 and activated MAPK/Erk1/2 and TGF-beta pathways. Furthermore, overexpression of Ssbp3 reduced the methylation level of the Elf5 promoter and promoted the generation of teratomas with internal hemorrhage, indicative of the presence of trophoblast cells. CONCLUSIONS: This study identifies Ssbp3, a single-stranded DNA binding protein, as a regulator for mouse ESCs to differentiate into trophoblast-like cells. This finding is helpful to understand the regulatory networks for ESC differentiation into extra embryonic lineages. PMID- 27236335 TI - Evaluation of a multicomponent programme for the management of musculoskeletal pain and depression in primary care: a cluster-randomised clinical trial (the DROP study). AB - BACKGROUND: Chronic musculoskeletal pain and depression are very common in primary care patients. Furthermore, they often appear as comorbid conditions, resulting in additive effect on adverse health outcomes. On the basis of previous studies, we hypothesise that depression and chronic musculoskeletal pain may benefit from an integrated management programme at primary care level. We expect positive effects on both physical and psychological distress of patients. METHODS: OBJECTIVE: To determine whether a new programme for an integrated approach to chronic musculoskeletal pain and depression leads to better outcomes than usual care. DESIGN: Cluster-randomised controlled trial involving two arms: a) control arm (usual care); and b) intervention arm, where patients participate in a programme for an integrated approach to the pain-depression dyad. SETTINGS: Primary care centres in the province of Tarragona, Catalonia, Spain, Participants: We will recruit 330 patients aged 18-80 with moderate or severe musculoskeletal pain (Brief Pain Inventory, average pain subscale >=5) for at least 3 months, and with criteria for major depression (DSM-IV). INTERVENTION: A multicomponent programme according to the chronic care model. The main components are care management, optimised antidepressant treatment, and a psychoeducational group action. Blind measurements: The patients will be monitored through blind telephone interviews held at 0, 3, 6 and 12 months. OUTCOMES: Severity of pain and depressive symptoms, pain and depression treatment response rates, and depression remission rates. ANALYSIS: The outcomes will be analysed on an intent to-treat basis and the analysis units will be the individual patients. This analysis will consider the effect of the study design on any potential lack of independence between observations made within the same cluster. ETHICS: The protocol was approved by the Research Ethics Committee of the Jordi Gol Primary Care Research Institute (IDIAP), Barcelona, (P14/142). DISCUSSION: This project strengthens and improves treatment approaches for a major comorbidity in primary care. The design of the intervention takes into account its applicability under typical primary care conditions, so that if the programme is found to be effective it will be feasible to apply it in a generalised manner. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02605278 ; Registered 28 September, 2015. PMID- 27236336 TI - Defects in MAP1S-mediated autophagy turnover of fibronectin cause renal fibrosis. AB - Excessive deposition of extracellular matrix proteins in renal tissues causes renal fibrosis and renal function failure. Mammalian cells primarily use the autophagy-lysosome system to degrade misfolded/aggregated proteins and dysfunctional organelles. MAP1S is an autophagy activator and promotes the biogenesis and degradation of autophagosomes. Previously, we reported that MAP1S suppresses hepatocellular carcinogenesis in a mouse model and predicts a better prognosis in patients suffering from clear cell renal cell carcinomas. Furthermore, we have characterized that MAP1S enhances the turnover of fibronectin, and mice overexpressing LC3 but with MAP1S deleted accumulate fibronectin and develop liver fibrosis because of the synergistic impact of LC3 induced over-synthesis of fibronectin and MAP1S depletion-caused impairment of fibronectin degradation. Here we show that a suppression of MAP1S in renal cells caused an impairment of autophagy clearance of fibronectin and an activation of pyroptosis. Depletion of MAP1S in mice leads to an accumulation of fibrosis related proteins and the development of renal fibrosis in aged mice. The levels of MAP1S were dramatically reduced and levels of fibronectin were greatly elevated in renal fibrotic tissues from patients diagnosed as renal atrophy and renal failure. Therefore, MAP1S deficiency may cause the accumulation of fibronectin and the development of renal fibrosis. PMID- 27236337 TI - Color attributes and oxidative stability of longissimus lumborum and psoas major muscles from Nellore bulls. AB - The influence of muscle source on color stability of fresh beef from purebred Bos indicus cattle was investigated. Longissimus lumborum (LL) and psoas major (PM) muscles obtained from twelve (n=12) Nellore bull carcasses (24h post-mortem) were fabricated into 2.54-cm steaks, aerobically packaged, and stored at 4 degrees C for nine days. Steaks were analyzed on day 0 for proximate composition and myoglobin concentration, whereas pH, instrumental color, metmyoglobin reducing activity (MRA), lipid oxidation, and protein oxidation were evaluated on days 0, 3, 6, and 9. LL steaks exhibited greater (P<0.05) redness, color stability, and MRA than PM counterparts. On the other hand, PM steaks demonstrated greater (P<0.05) myoglobin content, lipid oxidation, and protein oxidation than LL steaks. These results indicated the critical influence of muscle source on discoloration of fresh beef from Bos indicus animals and suggested the necessity to engineer muscle-specific strategies to improve color stability and marketability of beef from Bos indicus cattle. PMID- 27236338 TI - A gene and protein expression study on four porcine genes related to intramuscular fat deposition. AB - Intramuscular fat (IMF) content has a prominent role in meat quality, affecting sensory attributes such as flavour and texture. In the present research, we studied in samples of porcine Semimembranosus muscle four genes related to lipid metabolism and whose gene expressions have been associated to IMF deposition: FASN, SCD, LIPE and LPL. We analysed both mRNA and protein expressions in two groups of Italian Large White pigs divergent for Semimembranosus IMF deposition, with the aim of comparing the levels of four genes and enzymes between the two groups and identifying possible coexpression links. The obtained results suggest a prominent role of LIPE enzyme in IMF hydrolysis, as the samples with low IMF deposition show a significantly higher amount of this lipase. Finally, a poorly known correlation was found between LIPE and FASN enzymes only in female individuals. These results provide new information for the understanding of IMF deposition. PMID- 27236339 TI - [OCT-angiography characteristics of focal choroidal excavation]. PMID- 27236340 TI - [A rare cause of optic neuropathy: Cassava]. AB - INTRODUCTION: Cassava root is a staple food for almost 500 million people worldwide. Excessive consumption of it is a rare cause of optic neuropathy. METHOD: Ten patients diagnosed with cassava root related optic neuropathy were included in this retrospective study. Diagnostic criteria were a bilateral optic neuropathy preceded by significant cassava root consumption. Differential diagnoses were excluded through a neuro-ophthalmic examination, blood tests and a brain MRI. All patients had visual field examination and OCT retinal nerve fiber layer (RNFL) analysis as well as an evaluation of their cassava consumption. RESULTS: All patients had a bilateral optic nerve head atrophy or pallor predominantly located into the temporal sector. Visual field defects consisted of a central or cecocentral scotoma for all patients. RNFL showed lower values only in the temporal sector. Mean duration of cassava consumption prior to the appearance of visual symptoms was 22.7+/-11.2 years with a mean of 2.57+/-0.53 cassava-based meals per week. Cassava related optic neuropathy is possibly due to its high cyanide content and enabled by a specific amino-acid deficiency. CONCLUSION: Cassava root chronic consumption is a rare, underappreciated cause of optic neuropathy and its exact mechanism is still uncertain. PMID- 27236341 TI - [Central retinal vein occlusion secondary to celiac disease: A case report]. PMID- 27236342 TI - Occurrence, spatial and temporal distributions of perfluoroalkyl substances in wastewater, seawater and sediment from Bohai Sea, China. AB - In this study, surface seawater and sediment samples were collected from Bohai Sea, China, to investigate the temporal and spatial distributions of perfluoroalkyl substances (PFASs) in that area. The total concentrations of PFASs in seawater and sediment samples ranged from below method limit of quantification (5 years after the operation. All extrapancreatic recurrences occurred within 5 years. We found that the positive pancreatic transection margin was the only independent risk factor for remnant pancreatic recurrence (P < .001), whereas the risk factors for extrapancreatic recurrence were invasive intraductal papillary mucinous neoplasm (P < .001), mixed-type (P = .008), elevated serum CA19-9 (P = .019), and intraoperative transfusion (P = .025) in the multivariate analysis. CONCLUSION: Our data suggest that all intraductal papillary mucinous neoplasm patients should be subject to continual surveillance every 6 months for >5 years after operation to evaluate the remnant pancreatic recurrence; furthermore, the data indicate that strict 5-year surveillance, including every 3 months for 1 year after the operation and every 6 months thereafter, is necessary for intraductal papillary mucinous neoplasm patients at risk for extrapancreatic recurrence. PMID- 27236361 TI - Systemic Thrombolysis for Ischemic Stroke after Antagonizing Dabigatran with Idarucizumab-A Case Report. AB - We here describe our experience of systemic thrombolysis therapy for severe ischemic stroke in a patient taking dabigatran for atrial fibrillation. After administration of the monoclonal antibody fragment idarucizumab, the anticoagulative effects of dabigatran were efficiently antagonized and application of alteplase was safe and feasible in our patient. This case report may illustrate a novel treatment option in the neurological emergency setting. PMID- 27236362 TI - Mortality related to cold and heat. What do we learn from dairy cattle? AB - Extreme temperatures are associated with increased mortality among humans. Because similar epidemiologic studies in animals may add to the existing evidence, we investigated the association between ambient temperature and the risk of mortality among dairy cattle. We used data on 87,108 dairy cow deaths in Belgium from 2006 to 2009, and we combined a case-crossover design with distributed lag non-linear models. Province-specific results were combined in a multivariate meta-analysis. Relative to the estimated minimum mortality temperature of 15.4 degrees C (75th percentile), the pooled cumulative relative risks over lag 0-25 days were 1.26 (95% CI: 1.11, 1.42) for extreme cold (1st percentile, -3.5 degrees C), 1.35 (95% CI: 1.19, 1.54) for moderate cold (5th percentile, -0.3 degrees C), 1.09 (95% CI: 1.02, 1.17) for moderate heat (95th percentile, 19.7 degrees C), and 1.26 (95% CI: 1.08; 1.48) for extreme heat (99th percentile, 22.6 degrees C). The temporal pattern of the temperature-mortality association was similar to that observed in humans, i.e. acute effects of heat and delayed and prolonged effects of cold. Seasonal analyses suggested that most of the temperature-related mortality, including cold effects, occurred in the warm season. Our study reinforces the evidence on the plausibility of causal effects in humans. PMID- 27236364 TI - Reflection and transmission coefficients of the SH0 mode in the adhesive structures with imperfect interface. AB - Compared with body waves, ultrasonic guided waves can provide more local characteristic information about the interface in the defect detection of adhesive structures. In the paper, the expressions of the reflection and transmission coefficients of the lowest SH mode (SH0) in multilayered plate-like adhesive structure were deduced on the basis of wave propagation controlling equations and tangential stiffness coefficient KT was contained in the expressions. Then, the expressions were compared with the previous results to verify their applicability and correctness. Then, aluminum/epoxy resin/aluminum adhesive structures were used to explore the effects of the changes in incident angle, frequency-thickness product and tangential stiffness coefficient on SH wave propagation characteristics in adhesive structures with different interface quality (perfect, weak bonding, and slip/debonding interfaces). The results showed that the propagation mode of SH wave in adhesive structures was mainly determined by the incident angle, frequency, adhesive layer thickness and tangential stiffness coefficient. With the increase in the frequency-thickness product, multi-order resonance is generated in the reflection and transmission coefficient curves of SH wave under the perfect and weak bonding interfaces. If proper values of the incident angle of acoustic waves and frequency-thickness product are selected, the perfect, weak bonding, and slip/debonding interfaces can be differentiated from each other, but the slip and debonding interfaces cannot be distinguished from each other. The study provides theoretical contribution to the detection of multilayered plate-like adhesive structure by SH wave. PMID- 27236365 TI - Does Self-Assessment Improve the Effectiveness of Grand Rounds Lectures in a Community-Based Teaching Hospital? AB - OBJECTIVE: To determine whether use of self-assessment (SA) questions affects the effectiveness of weekly didactic grand rounds presentations. DESIGN: From 26 consecutive grand rounds presentations from August 2013 to April 2014, a 52 question multiple-choice test was administered based on 2 questions from each presentation. SETTING: Community teaching institution. PARTICIPANTS: General surgery residents, students, and attending physicians. RESULTS: The test was administered to 66 participants. The mean score was 41.8%. There was no difference in test score based on experience with similar scores for junior residents, senior residents, and attending surgeons (43%, 46%, and 44%; p = 0.13). Most participants felt they would be most interested in presentations directly related to their surgical specialty. Participants, however, did not score differently on topics which were the focus of the program (40% vs. 42%; p = 0.85). Journal club presentations (39% vs. others 42%; p = 0.33) also did not affect the score. The Pearson correlation coefficient for attendance was 0.49 (p < 0.0001) demonstrated that attendance was very important. Participation in the weekly SA was significantly associated with improved score as those who participated in SA scored over 20% higher than those who did not (59% vs. 38%; p < 0.0001). Based on multiple linear regression for mean score, SA explained the variation in score more than attendance. CONCLUSIONS: The current study found that without preparation approximately 40% of material presented is retained after 10 months. Participation in weekly SA significantly improved retention of information from grand rounds presentations. PMID- 27236363 TI - Regulation of the T Cell Response by CD39. AB - The ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1, or CD39) catalyzes the phosphohydrolysis of extracellular ATP (eATP) and ADP (eADP) released under conditions of inflammatory stress and cell injury. CD39 generates AMP, which is in turn used by the ecto-5'-nucleotidase CD73 to synthesize adenosine. These ectonucleotidases have a major impact on the dynamic equilibrium of proinflammatory eATP and ADP nucleotides versus immunosuppressive adenosine nucleosides. Indeed, CD39 plays a dominant role in the purinergic regulation of inflammation and the immune response because its expression is influenced by genetic and environmental factors. We review the specific role of CD39 in the kinetic regulation of cellular immune responses in the evolution of disease. We focus on the effects of CD39 on T cells and explore potential clinical applications in autoimmunity, chronic infections, and cancer. PMID- 27236366 TI - Commentary to "Undergraduate Suture and Local Anaesthetic Training in the United Kingdom". PMID- 27236367 TI - Antipsychotics - Postmortem fatal and non-fatal reference concentrations. AB - Making the diagnosis fatal intoxication is a challenging task for the forensic pathologist and toxicologist, particularly when the cases involve substances where reference information is scarce or not at all available. This study presents postmortem femoral blood concentrations for 24 antipsychotic substances, based on samples collected and analyzed from 4949 autopsy cases in Sweden during 1992-2010. In addition our study provides information about the prevalence of different antipsychotics in accidental, suicidal, homicidal and uncertain deaths. The data have been selected and evaluated according to strict inclusion and exclusion criteria as well as a manual, multi-reviewer, case-by-case evaluation. The reference information is subdivided into intoxications by one specific substance only (group A, n=259), multi-substance intoxications (group B, n=614) and postmortem controls, consisting of deaths not involving incapacitation by substances (group C, n=507). Moreover, the results are compared with data based on therapeutic drug monitoring, and data collected from driving under the influence cases. Median concentrations in group A were significantly higher than in group C for all substances evaluated. For 17 of 24 substances, the median concentrations in group B were significantly higher than in group C. In general, the therapeutic drug monitoring and driving under the influence concentrations were similar to, or lower than, the concentrations in group C. PMID- 27236368 TI - Effects of temperature and diet on black soldier fly, Hermetia illucens (L.) (Diptera: Stratiomyidae), development. AB - The black soldier fly, Hermetia illucens, is recognised for its use in a forensic context as a means for estimating the time of colonisation and potentially postmortem interval of decomposing remains. However, little data exist on this species outside of its use in waste management. This study offers a preliminary assessment of the development, and subsequent validation, of H. illucens. Larvae of H. illucens were reared at three temperatures (24.9 degrees C, 27.6 degrees C and 32.2 degrees C) at 55% RH on beef loin muscle, pork loin muscle and a grain based diet (control). Each of the temperatures and diets were found to significantly (P<0.05) affect all stages of immature growth except for pupation time. Overall, those reared on the pork diet required on average ~23.1% and ~139.7% more degree hours to complete larval development than those reared on the beef and grain-based diets, respectively. Larvae reared at 27.6 degrees C and 32.2 degrees C required on average ~8.7% more degree hours to complete development and had a final larval weight ~30% greater than larvae reared at 24.9 degrees C. The validity of the laboratory larval length and weight data sets was assessed via estimating the age of field-reared larvae. Grain-diet data lacked accuracy when used to estimate larval age in comparison to estimates made with beef and pork-diet data, which were able to predict larval age for ~55.6% and ~88.9% of sampling points, respectively, when length and weight data were used in conjunction. Field-reared larval sizes exceeded the maximum observed under laboratory conditions in almost half of the samples, which reduced estimate accuracy. Future research should develop additional criteria for identifying development of each specific instar, which may aid in improving the accuracy and precision of larval age estimates for this species. PMID- 27236369 TI - Morphologic evaluation of Chinese cervical endplate and uncinate process by three dimensional computed tomography reconstructions for helping design cervical disc prosthesis. AB - BACKGROUND: Cervical disc prostheses have been used increasingly in recent years. The successful design of cervical disc prostheses depends on accurate morphometric parameters. However, the morphologic dimensions of the cervical endplate area have not been investigated in the Chinese population. METHODS: A total of 1360 cervical endplates and 680 pairs of uncinate processes was retrospectively accessed in 136 Chinese adults. Eleven parameters of each cervical vertebra were measured by three-dimensional computed tomography reconstructions from C3 to C7. These obtained parameters were compared between sexes, bilateral sides, vertebral segments, and different populations. RESULTS: Five parameters regarding the cervical endplate increased from C3 to C7 in general. Concerning parameters with regard to the uncinate process, the uncinate process distance gradually increased among vertebral segments, and anterior distance was always larger than the posterior distance. The value of left uncinate process angle was on average 0.84 degrees larger than that of the right side, and lower cervical segments had an obviously larger angle. Uncinate process length increased among segments, and no significant difference existed between bilateral sides. Parameters displayed significant difference between sexes. The morphometric parameters of various populations also showed differences. CONCLUSION: There is a morphologic discrepancy in dimensions of cervical vertebrae regarding sexes, bilateral sides, vertebral segments, and different populations. It is essential to design cervical disc prostheses suited specifically for Chinese patients, for whom the morphometric parameters in our study concerning the cervical endplate and uncinate process can be utilized. PMID- 27236370 TI - Stacking denoising auto-encoders in a deep network to segment the brainstem on MRI in brain cancer patients: A clinical study. AB - Delineation of organs at risk (OARs) is a crucial step in surgical and treatment planning in brain cancer, where precise OARs volume delineation is required. However, this task is still often manually performed, which is time-consuming and prone to observer variability. To tackle these issues a deep learning approach based on stacking denoising auto-encoders has been proposed to segment the brainstem on magnetic resonance images in brain cancer context. Additionally to classical features used in machine learning to segment brain structures, two new features are suggested. Four experts participated in this study by segmenting the brainstem on 9 patients who underwent radiosurgery. Analysis of variance on shape and volume similarity metrics indicated that there were significant differences (p<0.05) between the groups of manual annotations and automatic segmentations. Experimental evaluation also showed an overlapping higher than 90% with respect to the ground truth. These results are comparable, and often higher, to those of the state of the art segmentation methods but with a considerably reduction of the segmentation time. PMID- 27236371 TI - Beyond the consensus criteria: multiple cognitive profiles in amyotrophic lateral sclerosis? AB - The Strong consensus recommendations (2009) propose behavioural (ALSbi) and/or dysexecutive (ALSci) impairment as the two main clinical profiles of non-motor manifestations in non-demented amyotrophic lateral sclerosis (ALS) patients. We aimed at assessing whether clustering pattern of neuropsychological performance of ALS patients suggest the existence of additional clinical syndromes beyond the currently recognized phenotypes. We applied principal component analysis (PCA) to a comprehensive neuropsychological evaluation of 71 non-demented ALS patients in order to identify clusters of variables correlating highly with each other, with the aim of detecting distinct patterns of neuropsychological test performance. The outcome of PCA demonstrated the existence of three main test clusters. Two, accounting for 27% of the patients, were compatible with the recognised ALSbi and ALSci profiles. An additional third cluster loaded on social cognition, language and memory tests and accounted for 24% of the patients. Of these, 15% had defective performance on at least two tests belonging to the latter non-executive cluster, and were thus unclassifiable according to current criteria. Our data driven approach indicated a third dimension of cognitive impairment, including language, social cognition and episodic memory, as a distinct pattern of non motor manifestations in ALS patients, in addition to the recognized ALSci and ALSbi profiles. PMID- 27236372 TI - The blink reflex magnitude is continuously adjusted according to both current and predicted stimulus position with respect to the face. AB - The magnitude of the hand-blink reflex (HBR), a subcortical defensive reflex elicited by the electrical stimulation of the median nerve, is increased when the stimulated hand is close to the face ('far-near effect'). This enhancement occurs through a cortico-bulbar facilitation of the polysynaptic medullary pathways subserving the reflex. Here, in two experiments, we investigated the temporal characteristics of this facilitation, and its adjustment during voluntary movement of the stimulated hand. Given that individuals navigate in a fast changing environment, one would expect the cortico-bulbar modulation of this response to adjust rapidly, and as a function of the predicted spatial position of external threats. We observed two main results. First, the HBR modulation occurs without a temporal delay between when the hand has reached the stimulation position and when the stimulus happens (Experiments 1 and 2). Second, the voluntary movement of the hand interacts with the 'far-near effect': stimuli delivered when the hand is far from the face elicit an enhanced HBR if the hand is being moved towards the face, whereas stimuli delivered when the hand is near the face elicit an enhanced HBR regardless of the direction of the hand movement (Experiment 2). These results indicate that the top-down modulation of this subcortical defensive reflex occurs continuously, and takes into account both the current and the predicted position of potential threats with respect to the body. The continuous control of the excitability of subcortical reflex circuits ensures appropriate adjustment of defensive responses in a rapidly-changing sensory environment. PMID- 27236373 TI - Social representations and contextual adjustments as two distinct components of the Theory of Mind brain network: Evidence from the REMICS task. AB - Theory of mind (ToM) refers to the ability to infer the mental states of others. Behavioral measures of ToM usually present information about both a character and the context in which this character is placed, and these different pieces of information can be used to infer the character's mental states. A set of brain regions designated as the ToM brain network is recognized to support (ToM) inferences. Different brain regions within that network could however support different ToM processes. This functional magnetic resonance imaging (fMRI) study aimed to distinguish the brain regions supporting two aspects inherent to many ToM tasks, i.e., the ability to infer or represent mental states and the ability to use the context to adjust these inferences. Nineteen healthy subjects were scanned during the REMICS task, a novel task designed to orthogonally manipulate mental state inferences (as opposed to physical inferences) and contextual adjustments of inferences (as opposed to inferences that do not require contextual adjustments). We observed that mental state inferences and contextual adjustments, which are important aspects of most behavioral ToM tasks, rely on distinct brain regions or subregions within the classical brain network activated in previous ToM research. Notably, an interesting dissociation emerged within the medial prefrontal cortex (mPFC) and temporo-parietal junctions (TPJ) such that the inferior part of these brain regions responded to mental state inferences while the superior part of these brain regions responded to the requirement for contextual adjustments. This study provides evidence that the overall set of brain regions activated during ToM tasks supports different processes, and highlights that cognitive processes related to contextual adjustments have an important role in ToM and should be further studied. PMID- 27236374 TI - Clinical implication of the serum periostin level for differentiating phenotypes of NSAID hypersensitivity. PMID- 27236375 TI - Allergy to fish collagen: Thermostability of collagen and IgE reactivity of patients' sera with extracts of 11 species of bony and cartilaginous fish. AB - BACKGROUND: Parvalbumin was identified as a major fish allergen, and has been well investigated. Collagen was identified as a second allergen; however, its allergenic properties remain uncharacterized. Although fish is an important staple in coastal countries, its thermostability is unknown. Therefore, we aimed to determine the thermostability of fish collagen as an allergen. METHODS: Meat of seven bony and four cartilaginous fishes was heated at various temperatures and times, and extracts were analyzed using SDS-PAGE, IgE-ELISA, and SPTs. RESULTS: Collagen was dissolved from heated meat of Pacific mackerel into a crude extract. Collagen in the extracts was degraded at a high heating load-140 degrees C (10 min) or 100 degrees C (320 min). However, ELISA revealed the IgE reactivities of patients' sera with the extracts were unchanged even after heating the samples. Patients strongly reacted to extract proteins of other bony fish, which were detected by patients' IgE even after heating at 100 degrees C (320 min). In contrast, reactivities of the extracts of cartilaginous fish were lower than those of bony fish. SPTs in one patient revealed that all bony and cartilaginous fish extracts prepared from heated meat elicited allergic reactions. CONCLUSIONS: The IgE reactivity of patients' sera to fish collagen in extracts was retained even when fish meat was treated by a high heating load. As for the fish collagen, the IgE reactivities to cartilaginous fish were lower than that to bony fish. Reducing IgE reactivity to fish meat using heat is difficult, and other modalities will be required to produce hypoallergenic fish meat. PMID- 27236376 TI - Tissue localization of GM-CSF receptor in bovine ovarian follicles and its role on glucose uptake by mural granulosa cells. AB - The granulocyte-macrophage colony stimulating factor (GM-CSF) is a multifunctional cytokine implicated in proliferation, differentiation, and activation of several cell types including those involved in hematopoiesis and reproduction. In the present study, the expression of the alpha- and beta-subunit genes of GM-CSF receptor during follicular development in cattle was assessed. The spatial association of alpha- and beta-subunits of GM-CSF with follicle stimulating hormone receptor (FSHR) and 3beta-hydroxysteroid dehydrogenase (3beta HSD), and the temporal associations with gene expression of hexose transporters (GLUTs) in granulosa cells of cattle were also evaluated. The effect of GM-CSF on the functionality of hexose transporters was also determined in an in vitro primary culture of granulosa cells. The spatial association of subunits of the GM CSF receptor with 3beta-HSD and FSHR suggests a potential steroidogenic regulation of GM-CSF in granulosa cells. Immunodetection of GLUTs and uptake kinetic assays confirmed expression and functionality of these genes for hexose transporters in granulosa cells of cattle. Treatment of granulosa cells with GM CSF, FSH or insulin- like growth factor-I (IGF-I) alone increased 2-deoxyglucose (DOG) or 3-0-methylglucose (OMG) uptake; however, when cells were treated with various combination of these factors there were no additive effect. Unexpectedly, the combination of GM-CSF and FSH decreased DOG uptake compared to FSH treatment alone. Thus, the expression pattern of GM-CSF receptor subunit genes during follicle development in cattle and promotion of DOG and OMG uptake in granulosa cells indicate a role for GM-CSF, FSH and/or IGF-I alone in regulating granulosa cell metabolic activity, specifically by promoting glucose uptake. PMID- 27236378 TI - Genome-wide association study for sperm membrane integrity in frozen-thawed semen of Holstein-Friesian bulls. AB - The aim of the study was to screen the entire bull genome to identify SNP markers and propose candidate genes potentially involved in the variation of sperm membrane integrity in Holstein-Friesian bulls. Two hundred eighty eight bulls kept in one AI center were included in the study. Each bull was genotyped for 54.001 Single Nucleotide Polymorpisms (SNP) by the Illumina BovineSNP50 BeadChip. Commercial straws of frozen-thawed semen were used for the evaluation of sperm plasma membrane integrity (SYBR-14/PI staining) and sperm mitochondrial function (JC1/PI staining). An additive model for Linear Regression Analysis was applied to estimate the effect of SNP marker for sperm membrane integrity (by the use of GoldenHelix SVS7 software). Five significant markers (encompassing 2,2 MB region located on chromosome 6) for SYBR-14/PI were found. Among them one marker rs41570391 passed Bonferroni correction test. Within approximately 3 Mb genomic region including significant markers three candidate genes: SGMS2 (Sphingomyelin Synthase 2), TET2 (Methylcytosine dioxygenase 2) and GSTCD genes (Gluthatione S transferase C terminal domain) were proposed as potentially involved in sperm membrane integrity in frozen-thawed semen of Holstein-Friesian bulls. PMID- 27236377 TI - Commercial-scale out-of-season cryopreservation of Eurasian perch (Perca fluviatilis) sperm and its application for fertilization. AB - The quality and fertilizing capacity of perch (Perca fluviatilis) sperm collected outside of the spawning season (off-season) and cryopreserved at a commercial scale, were tested. Basic parameters (equilibration time, dilution ratio, sperm concentration, post-thaw motility duration) which can have a significant effect on cryopreservation success were systematically investigated for effects on sperm quality using computer assisted sperm analysis (CASA). No significant decrease in progressive motility (pMOT) and straightness (STR) of fresh-diluted sperm was recorded among groups equilibrated for 0, 30 or 60min in an extender with cryoprotectants. Curvilinear velocity (VCL) was reduced significantly after 30min (30min: 146+/-15MUm/s, 60min: 124+/-18MUm/s) of equilibration compared to the control (174+/-9MUm/s). After thawing, no decrease in pMOT or VCL was observed at different equilibration times in any of the analyzed groups. No correlation was observed among progressive motility, dilution ratios (p=0.7) and cell concentrations (p=0.1). The use of different activating solutions resulted in similar pMOT and VCL in the first 120s post-thaw. Nevertheless, post-thaw sperm motility was reduced after 30s using all activators. Motility parameters with low variation were recorded after thawing of 57 straws (pMOT: 37+/-7%, VCL: 92+/ 10MUm/s, STR: 89+/-3%). Ten randomly selected straws from commercial-scale cryopreservation resulted in a high fertilization rate (cryopreserved sperm: 72+/ 14%, fresh control: 94+/-2%). An optimized commercial-scale cryopreservation protocol was successfully developed for Eurasian perch. The applicability of the off-season collected perch sperm for cryopreservation and fertilization was demonstrated. PMID- 27236379 TI - Clinical outcomes of duodenal switch with a 200-cm common channel: a matched, controlled trial. AB - BACKGROUND: Biliopancreatic diversion with duodenal switch (BPD-DS) with a 100-cm common channel has been our treatment of choice for morbid obesity since the early 1990s. This procedure offers excellent long-term weight loss but can be associated with significant side effects. OBJECTIVES: To assess the effect on clinical and nutritional parameters of increasing the common channel to 200 cm. SETTINGS: University-affiliated tertiary care center. METHODS: Patients who underwent a BPD-DS with a 200-cm common channel (study group, n = 36) were matched 1:1 for age, sex, body mass index (BMI), and main co-morbidities with patients who underwent a BPD-DS with a 100-cm common channel (control group). The strict alimentary limb was 150 cm in both groups. RESULTS: The mean age was 55+/ 9 versus 53+/-7 years (P = .3), with 50% women and a BMI of 49+/-8 kg/m(2) versus 50+/-6 kg/m(2) (P = .9). Follow-up rate was 97%, with a minimum follow-up of 3 years. There were no significant differences in the remission rate of major co morbidities between the 2 groups. At 3 years, the excess weight loss was 61+/-22% versus 68+/-18% (P = .18) and the total weight loss was 33+/-11% versus 38+/-9% (P = .055) in the study group versus control group, respectively. The study group had a lower incidence of severe protein deficiency (11% versus 19%, P = .3) and hyperparathyroidism (17.1% versus 35.3%, P = .17); required a lower amount of vitamins A and D (P<.05); and had a decreased number of daily bowel movements (2.0 versus 2.9, P = .03). CONCLUSION: In this population, BPD-DS with a 200-cm common channel offered similar remission rate of co-morbidities compared with standard BPD-DS. It was associated with similar weight loss at nadir, followed by a more significant weight regain. It might yield a lower rate of nutritional complications. Long-term randomized data are needed to detect other potential advantages. PMID- 27236380 TI - Agent-Based Modeling of Chronic Diseases: A Narrative Review and Future Research Directions. AB - The United States is experiencing an epidemic of chronic disease. As the US population ages, health care providers and policy makers urgently need decision models that provide systematic, credible prediction regarding the prevention and treatment of chronic diseases to improve population health management and medical decision-making. Agent-based modeling is a promising systems science approach that can model complex interactions and processes related to chronic health conditions, such as adaptive behaviors, feedback loops, and contextual effects. This article introduces agent-based modeling by providing a narrative review of agent-based models of chronic disease and identifying the characteristics of various chronic health conditions that must be taken into account to build effective clinical- and policy-relevant models. We also identify barriers to adopting agent-based models to study chronic diseases. Finally, we discuss future research directions of agent-based modeling applied to problems related to specific chronic health conditions. PMID- 27236381 TI - Clustering of Five Health-Related Behaviors for Chronic Disease Prevention Among Adults, United States, 2013. AB - INTRODUCTION: Five key health-related behaviors for chronic disease prevention are never smoking, getting regular physical activity, consuming no alcohol or only moderate amounts, maintaining a normal body weight, and obtaining daily sufficient sleep. The objective of this study was to estimate the clustering of these 5 health-related behaviors among adults aged 21 years or older in each state and the District of Columbia and to assess geographic variation in clustering. METHODS: We used data from the 2013 Behavioral Risk Factor Surveillance System (BRFSS) to assess the clustering of the 5 behaviors among 395,343 BRFSS respondents aged 21 years or older. The 5 behaviors were defined as currently not smoking cigarettes, meeting the aerobic physical activity recommendation, consuming no alcohol or only moderate amounts, maintaining a normal body mass index (BMI), and sleeping at least 7 hours per 24-hour period. Prevalence of having 4 or 5 of these behaviors, by state, was also examined. RESULTS: Among US adults, 81.6% were current nonsmokers, 63.9% obtained 7 hours or more sleep per day, 63.1% reported moderate or no alcohol consumption, 50.4% met physical activity recommendations, and 32.5% had a normal BMI. Only 1.4% of respondents engaged in none of the 5 behaviors; 8.4%, 1 behavior; 24.3%, 2 behaviors; 35.4%, 3 behaviors; and 24.3%, 4 behaviors; only 6.3% reported engaging in all 5 behaviors. The highest prevalence of engaging in 4 or 5 behaviors was clustered in the Pacific and Rocky Mountain states. Lowest prevalence was in the southern states and along the Ohio River. CONCLUSION: Additional efforts are needed to increase the proportion of the population that engages in all 5 health-related behaviors and to eliminate geographic variation. Collaborative efforts in health care systems, communities, work sites, and schools can promote all 5 behaviors and produce population-wide changes, especially among the socioeconomically disadvantaged. PMID- 27236382 TI - Clinical and Economic Burden of Mental Disorders Among Children With Chronic Physical Conditions, United States, 2008-2013. AB - INTRODUCTION: The prevalence of chronic physical and mental disorders is increasing among children and adolescents in the United States. In this study, we investigated the association between mental health disorders and chronic physical conditions among children, and we assessed whether having mental disorders is associated with increased health care costs for children with chronic physical conditions, using Medical Expenditure Panel Survey data from 2008 through 2013. METHODS: Children aged 5 to 17 with at least 1 chronic physical condition were included in the study. Chronic physical conditions and mental disorders were identified using International Classification of Diseases, 9th Revision, Clinical Modification codes. We used logistic regression to assess the relationship between mental disorders and chronic physical conditions, and we used generalized linear models with gamma distribution and log link to estimate direct medical costs. RESULTS: Of 42,130 children, 4,640 had at least 1 chronic physical condition. After controlling for sociodemographic and health care access characteristics, we found that children with at least 1 chronic physical condition were 62% more likely to have a mental health disorder than were children without chronic physical conditions (odds ratio = 1.62; 95% confidence interval [CI], 1.37-1.92). Having a mental disorder was a significant predictor of total health care cost (beta = 0.64; 95% CI, 0.43-0.85; P < .001). The adjusted annual incremental cost due to mental disorders among children with chronic physical conditions was $2,631 (P < .001). CONCLUSION: Having chronic physical conditions in childhood is a significant predictor of mental health disorders and total health care expenditures. PMID- 27236383 TI - Letter to the Editor. PMID- 27236384 TI - MicroRNA-126 Targeting PIK3R2 Inhibits NSCLC A549 Cell Proliferation, Migration, and Invasion by Regulation of PTEN/PI3K/AKT Pathway. AB - BACKGROUND: Our study explored whether the microRNA-126 (miR-126)-mediated PTEN/PI3K/AKT (phosphatase and tensin homology deleted on chromosome 10/phosphatidylinositol 3-kinase regulatory subunit-beta/AKT) signaling pathway by targeting PIK3R2 affects the proliferation, migration, and invasion of non small-cell lung cancer (NSCLC) A549 cells. MATERIALS AND METHODS: Quantitative real-time polymerase chain reaction was used to measure the expression of miR-126 in A549 cells. The MTT (methyl thiazolyl tetrazolium) assay, cell scratch test, Transwell assay, and Western blot were used to detect the proliferation, migration, and invasion of A549 cells and protein expression in A549 cells, respectively. RESULTS: The expression of miR-126 decreased and the expression of PIK3R2 increased in A549 cells (P < .05, for both). Upregulation of miR-126 resulted in the decrease of the proliferation, migration, and invasive abilities of A549 cells, the downregulation of the expression of PIK3R2, PI3K, and phosphorylated Akt (p-Akt) protein, and the upregulation of PTEN expression (P < .05 for all). Also, these abilities of A549 cells increased, and the expression of these 3 proteins was upregulated with downregulation of miR-126 (P < .05 for all). The results of the dual luciferase reporter gene assay showed that PIK3R2 was the target gene of miR-126. PIK3R2, PI3K, and p-Akt proteins were downregulated, but PTEN protein was upregulated as PIK3R2 was silenced or the inhibitor of the PTEN/PI3K/AKT signaling pathway increased. Also, downregulation of miR-126 with silencing of PIK3R2 or increasing the inhibitor of the pathway caused increased PI3K and p-Akt protein expression and increased active proliferation, migration, and invasive abilities of A549 cells (P < .05 for all). CONCLUSION: The upregulation of miR-126 in NSCLC A549 cells can reduce the expression of the target gene PIK3R2 and influence the PTEN/PI3K/AKT signaling pathway, suppressing the proliferation, migration, and invasive abilities of A549 cells. PMID- 27236385 TI - Meta-Analysis of First-Line Pemetrexed Plus Platinum Treatment in Compared to Other Platinum-Based Doublet Regimens in Elderly East Asian Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer. AB - BACKGROUND: Pemetrexed plus platinum has become a standard of care in first-line treatment for patients with advanced nonsquamous non-small-cell lung cancer. However, elderly lung cancer patients are generally understudied and undertreated in clinical practice in East Asia because of safety concerns. This analysis aimed to provide a picture of the clinical benefit of pemetrexed/platinum in the first line setting for elderly (age >= 65 years) East Asian patients. PATIENTS AND METHODS: Individual patient data from 3 randomized controlled phase 3 trials that enrolled East Asian patients were analyzed in this meta-analysis. RESULTS: In elderly East Asian patients (63 in the pemetrexed/platinum group and 42 in the control group), pemetrexed/platinum treatment achieved more benefits compared to other platinum-based doublets, including better overall response rate (32.8% vs. 7.5%), favorable progression-free survival (not statistically significant in adjusted hazard ratio), and significantly longer (3.15 vs. 1.54 months) survival without drug-related grade 3/4 toxicity. Overall survival was numerically prolonged (16.33 vs. 13.77 months; not statistically significant). These benefit trends were similar to those in all-age East Asian patients. In elderly East Asians, pemetrexed/platinum treatment was also associated with a lower incidence rate of drug-related grade 3/4 adverse events. The adverse event profile was similar to that in all-age East Asians. There were no unexpected adverse events. CONCLUSION: Pemetrexed/platinum had good efficacy and also resulted in better overall response and tolerability than other platinum-based doublets as first line treatment in nonsquamous non-small cell lung cancer in elderly East Asians, which was consistent with data observed in all-age East Asians. PMID- 27236386 TI - Impact of Age on Long-Term Outcomes of Surgery for Malignant Pleural Mesothelioma. AB - BACKGROUND: Although malignant pleural mesothelioma (MPM) is generally a disease associated with more advanced age, the association of age, treatment, and outcomes has not been well-characterized. We evaluated the impact of age on outcomes in patients with MPM to provide data for use in the treatment selection process for elderly patients with potentially resectable disease. PATIENTS AND METHODS: Overall survival (OS) of patients younger than 70 and 70 years or older with Stage I to III MPM who underwent cancer-directed surgery or nonoperative management in the Surveillance, Epidemiology, and End Results database (2004 2010) was evaluated using multivariable Cox proportional hazard models and propensity score-matched analysis. RESULTS: Cancer-directed surgery was used in 284 of 879 (32%) patients who met inclusion criteria, and was associated with improved OS in multivariable analysis (hazard ratio, 0.71; P = .001). Cancer directed surgery was used much less commonly in patients 70 years and older compared with patients younger than 70 years (22% [109/497] vs. 46% [175/382]; P < .001), but patients 70 years and older had improved 1-year (59.4% vs. 37.9%) and 3-year (15.4% vs. 8.0%) OS compared with nonoperative management. The benefit of surgery in patients 70 years and older was observed even after propensity score-matched analysis was used to control for selection bias. CONCLUSION: Surgical treatment is associated with improved survival compared with nonoperative management for both patients younger than 70 years and patients aged 70 years or older. PMID- 27236388 TI - Teaching attachment behaviors to pregnant women: a randomized controlled trial of effects on infant mental health from birth to the age of three months. AB - BACKGROUND: Maternal-fetal attachment, which forms as soon as pregnancy starts, is essential to an infant's mental development. OBJECTIVE: This study aimed to explore the effect of teaching attachment behaviors to pregnant women on infant mental health from birth to 3 months of age. DESIGN: Randomized controlled trial. SETTING: Hafiz Hospital, Shiraz University of Medical Sciences, Iran, from February to November 2014. PATIENTS AND METHODS: The participants were randomly divided into an intervention and a control group at 28-34 weeks gestation. The participants in the intervention group attended six educational sessions each lasting for 60-90 minutes. After delivery, the infants of mothers in each group were compared in terms of mental health indexes (total mean scores and scores derived from a checklist of questions for infant mental health with results categorized as low, average and high). Maternal anxiety levels were also recorded at birth and at 3 months. MAIN OUTCOME MEASURE(S): Infant mental health index. RESULTS: In 190 pregnant women (96 in the intervention group and 94 in the control group), the total mean (SD) scores for infant mental health at birth were 16.66 (1.51) in the intervention group and 16.07 (1.74) in the control group (P=.013). At 3 months, the total mental health scores infants were 31.05 (1.88) in the intervention group and 30.25 (2.10) in the control group (P=.007). Differences in checklist scores between the groups at 3 months were not statistically significant, except for crying intensity at 3 months (P=.021). Women in the control group had higher anxiety levels at 3 months (P=.01). CONCLUSION: Teaching attachment skills to mothers increased the attachment between the mothers and their infants, and consequently, improved infant mental health. Thus, teaching attachment skills should be incorporated into routine prenatal care. LIMITATIONS: Use of phone calls by the researcher to assess mental health. PMID- 27236389 TI - Trends in evidence-based treatment and mortality for ST elevation myocardial infarction in Malaysia from 2006 to 2013: time for real change. AB - BACKGROUND: The administration of evidence-based pharmacotherapy and timely primary percutaneous coronary intervention have been shown to improve outcome in ST elevation myocardial infarction (STEMI). However, implementation remains a challenge due to the limitations in facilities, expertise and funding. OBJECTIVES: To investigate adherence to guideline-based management and mortality of STEMI patients in Malaysia. DESIGN: Retrospective analysis. SETTINGS: STEMI patients from 18 participating hospital across Malaysia included in the National Cardiovascular Database-Acute Coronary Syndrome (NCVD-ACS) registry year 2006 to 2013. PATIENTS AND METHODS: Patients were categorized into four subgroups based on the year of admission (2006 to 2007, 2008 to 2009, 2010 to 2011 and 2012 to 2013). Baseline characteristics and clinical presentation, in-hospital pharmacotherapy, invasive revascularization and in-hospital/30-day mortality were analysed and compared between the subgroups. MAIN OUTCOME MEASURE(S): Rate of in hospital catheterization/percutaneous coronary intervention. RESULTS: The registry contained data on 19483 patients. Intravenous thrombolysis was the main reperfusion therapy. Although the overall rate of in-hospital catheterisation/PCI more than doubled over the study period, while the use of primary PCI only slowly increased from 7.6% in 2006/2007 to 13.6% in 2012/2013. The use of evidence-based oral therapies increased steadily over the years except for ACe-inhibitors and angiotensin-receptor blockers. The adjusted risk ratios (RR) for in-hospital mortality for the four sub-groups have not shown any significant improvement. The 30-day adjusted risk ratios however showed a significant albeit gradual risk reduction (RR 0.773 95% CI 0.679-0.881, P < .001). CONCLUSION: Adherence to evidence-based treatment in STEMI in Malaysia is still poor especially in terms of the rate of primary PCI. Although there is a general trend toward reduced 30 day mortality, the reduction was only slight over the study period. Drastic effort is needed to improve adherence and clinical outcomes. LIMITATION: Retrospective registry data with inter-hospital variation. PMID- 27236387 TI - Balloon kyphoplasty or percutaneous vertebroplasty for osteoporotic vertebral compression fracture? An updated systematic review and meta-analysis. AB - BACKGROUND: Both kyphoplasty (KP) and vertebroplasty (VP) are effective for patients with osteoporotic vertebral compression fracture (OVCF), but which approach might be more effective remains unclear, so we decided to update earlier systematic reviews. OBJECTIVE: Review and analyze studies published as of August 2015 that compared clinical outcomes and complications of KP versus VP. DESIGN: Systematic review and meta-analysis. SEARCH METHOD: Published reports up to August 2015 were found in PubMed, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL). SELECTION CRITERIA: Randomized controlled trials (RCTs) and prospective and retrospective cohort stud.ies comparing KP and VP in patients with OVCF. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the studies and extracted data. RESULTS: Thirty-two studies involving 3274 patients fulfilled the inclusion criteria. There were significant differences between the two groups in short- and long-term postoperative changes in measures of pain intensity and dysfunction (P < .01), in anterior and middle height (P < .01), kyphotic angle (P < .01), and time to injury, but not in posterior height (P=.178). There were no significant differences in the rate of postoperative fractures including adjacent and total fractures, but cement leakage to the intraspinal space was greater in the VP group (P=.035). KP surgery took longer and required a greater volume of injected cement. CONCLUSIONS: KR resulted in better pain relief, improvements in Oswestry dysfunction and radiographic outcomes with less cement leakage, but further RCTs are needed to verify this conclusion. LIMITATIONS: Only four RCTs with a certain of risk of bias. Most studies were observational. PMID- 27236390 TI - Tocilizumab efficacy and safety in rheumatoid arthritis patients after inadequate response to disease-modifying anti-rheumatic drugs oranti-tumor necrosis factor. AB - BACKGROUND: Tocilizumab (TCZ) is a humanized anti-human IL-6R antibody, a novel therapy for rheumatoid arthritis (RA) patients who fail treatment with disease modifying anti-rheumatic drugs (DMARDs) or anti-tumor necrosis factor (anti TNFs). OBJECTIVE: To assess the safety and efficacy of TCZ monotherapy or in combination with non-biologic DMARDs or anti-TNFs in moderate to severe active RA. DESIGN: Prospective, phase III, multi-center, open-label, single arm, 24-week trial. SETTING: Three centers in Saudi Arabia. PATIENTS AND METHODS: The study included consecutive RA patients infused with TCZ (8 mg/kg) over 60 minutes every 4 weeks (up to 6 times), either alone or with non-biologic DMARDs. Patients were followed for 24 weeks. Patients with good/moderate European League Against Rheumatism responses, continued on TCZ as long as commerically available or for 1 year. MAIN OUTCOME MEASURE(S): Disease activity measured by DAS28 score. RESULTS: Of 28 patients enrolled from 2 November 2011 to 12 May 2013 (18 months), 21 completed (77.8%) and 7 (25%) discontinued TCZ therapy. One patient was excluded from the intent-to-treat analysis. Efficacy analysis showed a significant difference (P < .0001) in the Disease Activity Score based on 28 joints and on swollen and tender joint counts. Three (10.7%) patients experienced at least one AE that was considered related to study drug (one probably and two possibly). Only one (3.6%) patient reported a severe adverse event (neutropenia and thrombocytopenia). No adverse events led to dose modification or death. CONCLUSION: TCZ monotherapy or in combination with non-biologic DMARDs resulted in a significant effect on the endpoints in moderate to severe RA in Saudi Arabia, which is consistent with other published reports. LIMITATIONS: No information on tapering of steroid therapy, lack of follow-up data of all 28 patients, lack of data on long-term effects of TCZ on lipid levels and the need for statins. (ClinicalTrials.gov identifier: NCT01326962). PMID- 27236391 TI - Trends in one-year mortality for stroke in a tertiary academic center in Saudi Arabia: a 5-year retrospective analysis. AB - BACKGROUND: Numerous studies have reported a decline in stroke-related mortality in developed countries. OBJECTIVE: To assess trends in one-year mortality following a stroke diagnosis in Saudi Arabia. DESIGN: Retrospective longitudinal cohort study. SETTING: Single tertiary care center from 2010 through 2014. PATIENTS: All patients admitted with a primary admitting diagnosis of stroke. METHODS: Demographic data (age, gender, nationality), risk factor profile, stroke subtypes, in-hospital complications and mortality data as well as cause of death were collected for all patients. A multivariable logistic regression model was used to assess factors associated with one-year mortality following a stroke admission. MAIN OUTCOME MEASURE(S): One-year mortality. RESULTS: In 548 patients with a mean age of 62.9 years (SD 16.9), the most frequent vascular risk factors were hypertension (90.6%), diabetes (65.5%), and hyperlipidemia (27.2%). Hemorrhagic stroke was diagnosed in 9.9%. The overall mortality risk was 26.9%. Non-Saudis had a significantly higher one-year mortality risk compared with Saudis (25% vs. 16.8%, respectively; P=.025). The most frequently reported causes of mortality were neurological and related to the underlying stroke (32%), sepsis (30%), and cardiac or other organ dysfunction-related (each 9%) in addition to other etiologies (collectively 9.5%) such as pulmonary embolism or an underlying malignancy. Significant predictors in the multivariate model were age (P < .0001), non-Saudi nationality (OR 1.8, CI 95 1.1 to 2.9; P=.019), and hospital length of stay (OR 1.01, CI 95 1 to 1.004; P=.001). CONCLUSION: We observed no decline in stroke mortality in our center over the 5-year span. The establishment of stroke systems of care, use of thrombolytic agents, and opening of a stroke unit should play an important role in a decline in stroke mortality. LIMITATIONS: Retrospective single center study. Mortality data were available only for patients who died in our hospital. PMID- 27236392 TI - Metabolic syndrome in drug-nave Chinese patients with insulin-sensitive and insulin-resistant type 2 diabetes. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by impaired insulin sensitivity (Si) and insulin secretion. Previous studies may have underestimated differences in the incidence of risk factors in insulin-sensitive diabetes mellitus (IS-DM) and insultin-resistant diabetes mellitus (IR-DM) patients and have not been conducted in the Chinese population. OBJECTIVES: We explored differences in metabolic risk factors between Chinese patients with newly diagnosed, insulin-resistant (IR) and insulin-sensitive (IS) T2DM. DESIGN: Cross sectional study. SETTING: Cardinal Tien Hospital, Taiwan in 2011. METHODS: All participants received a frequently sampled intravenous glucose tolerance test. The acute insulin response after a glucose load (AIRg), Si, disposition index (DI), and glucose effectiveness (GE) were determined. Using the median Si value from 90 people without diabetes as a cutoff (1.19.10-4 mU/L/min), patients were divided into two groups, IS-DM and IR-DM. Multivariate regression analysis was used to examine the independent influence of MetS components on Si and AIRg. MAIN OUTCOME MEASURE(S): Insulin sensitivity. RESULTS: We enrolled 122 participants. In addition to higher probabilities of having MetS, IR-DM patients had a significantly higher body mass index (BMI), AIRg, and GE but a lower DI than IS DM patients. Si correlated with BMI and triglycerides, and AIRg correlated with BMI and high-density lipoprotein cholesterol. BMI was the only component related to Si in the multivariate analysis. Furthermore, the AIRg was associated with BMI and fasting plasma glucose. Because BMI was the most critical factor, a cutoff value (25.0 kg/m2) was obtained from the receiver operating characteristic curve for predicting IR-DM. It showed a sensitivity and specificity of 60.8% and 60.9%, respectively. CONCLUSIONS: IR-DM patients had more MetS components than IS-DM patients. In Chinese patients obesity is the most critical factor for discriminating IR-DM from IS-DM. Patients with a BMI higher than 25 kg/m2 were prone to develop IR-DM. LIMITATIONS: The size of our study cohort was relatively small, which may weaken the statistical power of the study. PMID- 27236393 TI - Evaluation of the cutting seton as a method of treatment for perianal fistula. AB - BACKGROUND: Perianal fistulas are distressing for the patient and sometimes a challenge for the surgeon. Different methods for the treatment of perianal fistulas have a range of success rates and use of the cutting seton is still debatable. OBJECTIVES: We evaluated the recurrence, success rate and incontinence with the cutting seton method for treating perianal fistula. DESIGN: Prospective, descriptive study. SETTING: Al-Hada Armed Forces Hospital, Department of General Surgery, Taif, Saudi Arabia. PATIENTS AND METHODS: We studied all patients with high perianal fistula admitted to the department of general surgery in our hospital with a diagnosis of perianal fistula in the period from December 2012 to December 2013 (12 months). Patients were followed for postoperative recurrence and incontinence rate. MAIN OUTCOME MEASURE(S): The primary outcome measured was either complete cure or recurrence. RESULTS: Fifty-one patients underwent cutting seton insertion for fistula in ano. The recurrence rate was 9.8%. The postoperative rate of incontinence was 15.7% to flatus and 5.9% to fluid stools. There was no incontinence to solid stools. CONCLUSION: The cutting seton is a valid option for a complex fistula in ano, but in female patients and those with previous peri-anal surgery, other surgical options are advised. LIMITATIONS: Patients with low perianal fistula, Crohn's disease, acute perianal abscess and patients with major incontinence were excluded. PMID- 27236395 TI - Molecular investigation of extended-spectrum beta-lactamase genes and potential drug resistance in clinical isolates of Morganella morganii. AB - BACKGROUND: Resistance to beta-lactam antibiotics has become more common in Morganella morganii, which can cause of outbreaks of bacteremia and septicemia in postoperative patients. OBJECTIVE: Investigate drug susceptibility of M morganii, identify the gene responsible for extended-spectrum beta-lactamase (ESBL) production and explore treatment options. DESIGN: Descriptive study. SETTING: Hospitals in An Najaf, Iraq. METHODS: M morganii isolates were identified based on morphology, biochemical tests and VITEK(r) 2 compact system using (GN-ID) card. M morganii isolates were subjected to antibiotic resistance tests using the minimum inhibitory concentration (MIC) technique and an antibiogram was produced. Molecular studies were conducted using the polymerase chain reaction technique. MAIN OUTCOME MEASURE(S): Minimum inhibitory concentration. RESULTS: From 395 gram negative bacteria, only 17 isolates M morganii grew on MacConkey agar. M morganii isolates strongly resistant to several antibiotics were considered multidrug resistant. All M morganii isolates were ESBL producers. Four genes (CTX-M, SHV, TEM and OXA) encoding the b-lactamase enzyme were detected. Meropenem and imipenem were highly active against the M morganii isolates. CONCLUSIONS: All isolates showed resistance to most common antibiotics, which limits options for treatment. This study provided useful information for selecting antibiotics to precisely target infections caused by M morganii. LIMITATIONS: Limited to antibiotic susceptibility and genotype. PMID- 27236396 TI - Metastatic malignant pleural mesothelioma masquerading as a case of acute abdomen secondary to small bowel perforation. AB - Metastatic pleural mesothelioma is a rare disease. The present study aimed to report a rare presentation of metastatic malignant mesothelioma (MM). The patient was an elderly man who presented with small bowel (jejunal) perforation secondary to metastatic pleural mesothelioma deposits. This was a rare presentation of a rare disease and the first reported case in the published studies in which MM masqueraded as bowel perforation prior to the primary diagnosis. SIMILAR CASES PUBLISHED: 1. PMID- 27236394 TI - Risk factors for infection with colistin-resistant gram-negative microorganisms: a multicenter study. AB - BACKGROUND: Knowing risk factors for colistin resistance is important since colistin is the only remaining choice for the treatment of infections caused by multi-drug resistant microorganisms. OBJECTIVE: Evaluate risk factors associated with infection by colistin-resistant microorganisms. DESIGN: Retrospective study. SETTING: Tertiary healthcare centers. PATIENTS AND METHODS: An e-mail including the title and purpose of the study was sent to 1500 infec.tious disease specialists via a scientific and social web portal named "infeksiyon dunyasi (infection world)". Demographic and clinical data was requested from respondents. MAIN OUTCOME MEASURE(S): Colistin-resistance. RESULTS: Eighteen infectious disease specialists from twelve tertiary care centers responded to the invitation data was collected on 165 patients, 56 cases (39.9%) and 109 (66.0%) age- and sex matched controls. The colistin-resistant microorganisms isolated from cases were 29 Acinetobacter baumannii (51.8%), 18 Pseudomonas aeruginosa (32.1%) and 9 Klebsiella spp. Colistin, carbapenem, and quinolone use in the last three months were risk factors for colistin resistance in the univariate analysis. Previous quinolone use in the last three months (P=.003; RR:3.2; 95% Ci:1.5-6,7) and previous colistin use in the last three months (P=.001; RR: 3.6; 95% CI: 1.63 7.99) were significant risk factors in the multivariate analysis. CONCLUSION: Clinicians should limit the use of quinolones and remain aware of the possibility of resistance developing during colistin use. LIMITATIONS: The lack of a heteroresistance analysis on the isolates. no data on use of a loading dose or the use of colistin in combination. PMID- 27236397 TI - Pulmonary arterial cement embolization: arare complication of vertebroplasty. PMID- 27236398 TI - Mean platelet volume as one part of platelet function determining inflammation. PMID- 27236399 TI - Neuroscience Forum: a scientific group on smartphones. PMID- 27236400 TI - Nutrient removal and lipid production by Coelastrella sp. in anaerobically and aerobically treated swine wastewater. AB - Coelastrella sp. QY01, a microalgae species isolated from a local pond, was identified and used for the treatment of anaerobically and aerobically treated swine wastewater (AnATSW). Microalgal growth characteristics, nutrient removal and lipid accumulation of QY01 cultivated in the initial concentration of AnATSW ranged from 63 to 319mg NH3-N/L were examined. The specific growth rate of QY01 cultivated in cultures ranged from 0.269 to 0.325day(-1) with a biomass productivity from 42.77 to 57.46mgL(-1)day(-1). Removal rates for NH3-N, TP and inorganic carbon in AnATSW at the various nutrient concentrations ranged from 90% to 100%, from 90% to 100% and from 74% to 78%, respectively. The lipid content of QY01 ranged from 22.4% to 24.8%. The lipid productivity was positive correlation with the biomass productivity. 40% AnATSW was optimal for QY01 cultivation, in which nutrient removal and productivity of biomass and lipid were maximized. PMID- 27236401 TI - Impact of biochar on the anaerobic digestion of citrus peel waste. AB - In this study, the impact of different types of biochar and biochar ratios on the anaerobic digestion of citrus peel waste was investigated. Citrus peel has an inhibitory effect on anaerobic digestion. The presence of biochar had two effects: a reduction in the length of the lag phase and greater production of methane relative to citrus peel waste only incubations. The microbial lag phases decreased with increase in citrus peel to biochar ratios, with 2:1 having the longest lag phase of 9.4days and 1:3, the shortest, with the value of 7.5days. The cumulative methane production in incubations containing biochar and citrus peel ranged from 163.9 to 186.8ml CH4 gVS(-1), while citrus peel only produced 165.9ml CH4 gVS(-1). Examination of the biochar material revealed colonies of putative methanogens. The synergy of d-limonene adsorption and microbial immobilization by biochar appears to improve the performance of anaerobic digestion. PMID- 27236402 TI - Temperature regulates methane production through the function centralization of microbial community in anaerobic digestion. AB - Temperature is crucial for the performance of anaerobic digestion process. In this study of anaerobic digestion of swine manure, the relationship between the microbial gene expression and methane production at different temperatures (25-55 degrees C) was revealed through metatranscriptomic analysis. Daily methane production and total biogas production increased with temperature up to 50 degrees C, but decreased at 55 degrees C. The functional gene expression showed great variation at different temperatures. The function centralization (opposite to alpha-diversity), assessed by the least proportions of functional pathways contributing for at least 50% of total reads positively correlated to methane production. Temperature regulated methane production probably through reducing the diversity of functional pathways, but enhancing central functional pathways, so that most of cellular activities and resource were invested in methanogenesis and related pathways, enhancing the efficiency of conversion of substrates to methane. This research demonstrated the importance of function centralization for efficient system functioning. PMID- 27236403 TI - Characteristics of the organic fraction of municipal solid waste and methane production: A review. AB - Anaerobic digestion of the organic fraction of municipal solid waste (OFMSW) is a viable alternative for waste stabilization and energy recovery. Biogas production mainly depends on the type and amount of organic macromolecules. Based on results from different authors analysing OFMSW from different cities, this paper presents the importance of knowing the OFMSW composition to understand how anaerobic digestion can be used to produce methane. This analysis describes and discusses physical, chemical and bromatological characteristics of OFMSW reported by several authors from different countries and cities and their relationship to methane production. The main conclusion is that the differences are country and not city dependant. Cultural habits and OFMSW management systems do not allow a generalisation but the individual analysis for specific cities allow understanding the general characteristics for a better methane production. Not only are the OFMSW characteristics important but also the conditions under which the methane production tests were performed. PMID- 27236404 TI - Evolution of microbial dynamics during the maturation phase of the composting of different types of waste. AB - During composting, facilities usually exert greater control over the bio oxidative phase of the process, which uses a specific technology and generally has a fixed duration. After this phase, the material is deposited to mature, with less monitoring during the maturation phase. While there has been considerable study of biological parameters during the thermophilic phase, there is less research on the stabilization and maturation phase. This study evaluates the effects of the type of starting material on the evolution of microbial dynamics during the maturation phase of composting. Three waste types were used: sludge from the fish processing industry, municipal sewage sludge and pig manure, each independently mixed with shredded pine wood as bulking agent. The composting system for each waste type comprised a static reactor with capacity of 600L for the bio-oxidative phase followed by stabilization and maturation phase in triplicate 200L boxes for 112days. Phospholipid fatty acids, enzyme activities and physico-chemical parameters were measured throughout the maturation phase. The evolution of the total microbial biomass, Gram + bacteria, Gram - bacteria, fungi and enzymatic activities (beta-glucosidase, cellulase, protease, acid and alkaline phosphatase) depended significantly on the waste type (p<0.001). The predominant microbial community for each waste type remained present throughout the maturation process, indicating that the waste type determines the microorganisms that are able to develop at this stage. While fungi predominated during fish sludge maturation, manure and municipal sludge were characterized by a greater proportion of bacteria. Both the structure of the microbial community and enzymatic activities provided important information for monitoring the composting process. More attention should be paid to the maturation phase in order to optimize composting. PMID- 27236405 TI - Suppression of dioxins after the post-combustion zone of MSWIs. AB - Thiourea was selected as representative of combined S- and N-inhibitors and injected after the post-combustion zone of two full-scale municipal solid waste incinerators (MSWIs) using a dedicated feeder. Firstly, the operating conditions were scrutinised by monitoring the concentrations of SO2, NH3 and HCl in the clean flue gas. The suppression experiment showed that in MSWI A thiourea could reduce the total I-TEQ value in flue gas by 73.4% from 1.41ng I-TEQ/Nm(3) to 0.37I-TEQ/Nm(3), those in fly ash by 87.1% from 14.3ng I-TEQ/g to 1.84I-TEQ/g and the total dioxins emission factor by 87.0wt.%, with a (S+N)/Cl molar ratio of 9.4. The suppression efficiencies of PCDD/Fs in flue gas and fly ash in MSWI B could be up to 69.2% and 83.0% when the (S+N)/Cl molar ratio attained 7.51. Furthermore, the congener distributions of dioxins were also analysed in the flue gas and fly ash, before and after addition of thiourea, to find cues to some suppression mechanism. In addition, the filtered fly ash was explored by the Scanning Electron Microscope (SEM) and Energy Dispersive Spectrometer (EDS) analysis of fly ash. These results suggest that poisoning the metal catalyst and blocking the chlorination are most probably responsible for suppression. PMID- 27236406 TI - The current state and future directions of marine turtle toxicology research. AB - Chemical contamination of marine turtles has been well documented in the literature, although information on the toxicological effects of these contaminants is poorly understood. This paper systematically and quantitatively presents the available marine turtle toxicological research (excluding oil chemicals and natural toxins) and the related fields of cell line establishment and biomarkers as indicators of exposure. Examination of the published literature identified a total of 49 papers on marine turtle toxicology, which were split into three categories: toxicity studies (n=33, 67%), cell line establishment (n=7, 14%), and publications using biomarkers (n=13, 27%). Toxicity studies were further broken down into four subcategories: those correlating contaminants with toxicological endpoints (n=16, 48%); in vitro exposure experiments (n=11, 33%); in vivo exposure experiments (n=5, 15%); and screening risk assessments using hazard quotients (n=3, 9%). In quantitatively assessing the literature, trends and gaps in this field of research were identified. This paper highlights the need for more marine turtle toxicology research on all species, particularly using high throughput and non-invasive in vitro assays developed for marine turtle cells, including investigations into further toxicological endpoints and mixture effects. This will provide more comprehensive species-specific assessment of the impacts of chemical contaminants on these threatened animals, and improve conservation and management strategies globally. PMID- 27236407 TI - Effects of prenatal exposure to perfluoroalkyl acids on prevalence ofallergic diseases among 4-year-old children. AB - Perfluoroalkyl acids (PFAAs) are ubiquitous chemicals extremely resistant and widespread throughout the environment, frequently being detected in human blood samples. Animal studies have revealed that exposure to PFAAs results in immunotoxicity. However, the association between PFAAs, especially long-chain PFAAs, and allergies in humans is not well established. We examined whether prenatal exposure to PFAAs is associated with allergic diseases among 4-year-old children in a large-scale prospective birth cohort in Hokkaido, Japan. In total, 1558 mother-child pairs were included in this study and prenatal levels of eleven PFAAs were measured in maternal plasma samples obtained between 28 and 32weeks of pregnancy by using ultra-performance liquid chromatography-tandem mass spectrometry. Participant demographic and characteristic information were obtained from self-administered pre- and postnatal questionnaires and medical birth records. Infant allergies were assessed using the Japanese version of the International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three questionnaire, which was administered 4years post-delivery. Symptoms included eczema, wheezing and rhinoconjunctivitis with a prevalence of 19.0%, 18.7%, and 5.4%, respectively. Associations of PFAA quartiles with allergic outcomes were examined using logistic models. Adjusted odds ratios (ORs) in the 4th quartile vs. 1st quartile (Q4 vs. Q1) for total allergic diseases (including at least one allergic outcome) significantly decreased for perfluorododecanoic acid (PFDoDa) (Q4 vs. Q1 OR: 0.621; 95% confidence interval (CI): 0.454, 0.847) and perfluorotridecanoic acid (PFTrDA) (Q4 vs. Q1 OR: 0.712; 95% CI: 0.524, 0.966) in all children. We obtained similar results when examining the association between PFAAs and eczema. The adjusted OR (Q4 vs. Q1) for wheezing in relation to higher maternal PFHxS levels was 0.728 (95% CI: 0.497, 1.06) in all children. In conclusion, prenatal exposure to long-chain PFAAs, such as PFDoDa and PFTrDA may have an immunosuppressive effect on allergic diseases in 4-year-old children. PMID- 27236409 TI - Childhood maltreatment increases the risk of suicide attempt in schizophrenia. AB - OBJECTIVES: In this study, we evaluated the effect of several types of childhood trauma on lifetime suicide attempt in patients with schizophrenia spectrum disorders. METHODS: We interviewed 361 participants with schizophrenia. Childhood trauma was collected using the Childhood Trauma Questionnaire (CTQ). Suicidal attempts were confirmed using subjective and objective validated scales. We applied an observational study design using propensity scores to match individuals with history of childhood trauma to those without past history of trauma. We used logistic regression models to estimate the effect of each type of childhood maltreatment on suicidal attempts controlling for demographics and known suicidal risk factors. RESULTS: In our sample, 39.1% of the subjects had lifetime suicide attempt. After matching the two groups and controlling for demographics and clinical confounders, total trauma score and the majority of childhood maltreatment subtypes predicted suicide attempt (odds ratios ranged from 1.74 to 2.49 with p-values ranging from 0.001 to 0.02). Physical neglect was not significantly associated with suicide attempt in our sample (p=0.94). CONCLUSION: Childhood maltreatment is confirmed to be a strong independent risk factor for suicidal attempts in schizophrenia. The risk is probably aggravated by the development of depressive symptoms and feeling of hopelessness in the adult life. Early screening and modified psychosocial treatment are recommended for psychotic individuals with trauma history. PMID- 27236408 TI - Ten-year outcomes in first episode psychotic major depression patients compared with schizophrenia and bipolar patients. AB - We aimed to investigate long-term outcomes in psychotic major depression patients compared to schizophrenia and bipolar/manic psychosis patients, in an incidence sample, while accounting for diagnostic change. Based on Aetiology and Ethnicity in Schizophrenia and Other Psychoses (AESOP and AESOP-10), a first episode psychosis cohort was followed-up 10years after first presentation. The Schedules for Clinical Assessment in Neuropsychiatry, WHO Life Chart and Global Assessment of Functioning were used to assess clinical, social and service use outcomes. Seventy-two PMD patients, 218 schizophrenia patients and 70 psychotic bipolar disorder/mania patients were identified at baseline. Differences in outcome between PMD and bipolar patients based on baseline and lifetime diagnosis were minimal. Differences in clinical, social and service use outcomes between PMD and schizophrenia were more substantial with PMD patients showing better outcomes on most variables. However, there was some weak evidence (albeit not quite statistically significant at p<0.05) based on lifetime diagnoses that PMD patients were more likely to attempt suicide (OR 2.31, CI 0.98-5.42, p0.055) and self-harm (OR 2.34, CI 0.97-5.68, p0.060). PMD patients have better social and service use outcomes compared to people with schizophrenia, but may be more likely to attempt suicide or self-harm. This unique profile is important for clinicians to consider in any risk assessment. PMID- 27236411 TI - WITHDRAWN: Adaptive Swarm Balancing Algorithms for rare-event prediction in imbalanced healthcare data. 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- 27236410 TI - Altered CSNK1E, FABP4 and NEFH protein levels in the dorsolateral prefrontal cortex in schizophrenia. AB - Schizophrenia constitutes a complex disease. Negative and cognitive symptoms are enduring and debilitating components of the disorder, highly associated to disability and burden. Disrupted neurotransmission circuits in dorsolateral prefrontal cortex (DLPFC) have been related to these symptoms. To identify candidates altered in schizophrenia, we performed a pilot proteomic analysis on postmortem human DLPFC tissue from patients with schizophrenia (n=4) and control (n=4) subjects in a pool design using differential isotope peptide labelling followed by liquid chromatography tandem mass spectrometry (LC-MS/MS). We quantified 1315 proteins with two or more unique peptides, 116 of which showed altered changes. Of these altered proteins, we selected four with potential roles on cell signaling, neuronal development and synapse functioning for further validation: casein kinase I isoform epsilon (CSNK1E), fatty acid-binding protein 4 (FABP4), neurofilament triplet H protein (NEFH), and retinal dehydrogenase 1 (ALDH1A1). Immunoblot validation confirmed our proteomic findings of these proteins being decreased in abundance in the schizophrenia samples. Additionally, we conducted immunoblot validation of these candidates on an independent sample cohort comprising 23 patients with chronic schizophrenia and 23 matched controls. In this second cohort, CSNK1E, FABP4 and NEFH were reduced in the schizophrenia group while ALDH1A1 did not significantly change. This study provides evidence indicating these proteins are decreased in schizophrenia: CSNK1E, involved in circadian molecular clock signaling, FABP4 with possible implication in synapse functioning, and NEFH, important for cytoarchitecture organization. Hence, these findings suggest the possible implication of these proteins in the cognitive and/or negative symptoms in schizophrenia. PMID- 27236413 TI - Cholangiopancreatoscopy. PMID- 27236415 TI - Ciliated hepatic foregut cysts: A differential diagnosis in hepatic lesions located in segment iv. PMID- 27236412 TI - Cognitive function and risperidone long-acting injection vs. paliperidone palmitate in schizophrenia: a 6-month, open-label, randomized, pilot trial. AB - BACKGROUND: Recently, long-acting injection (LAI) of second-generation antipsychotics has become a valuable strategy for the treatment of schizophrenia. However, few studies have compared the effects of different LAI antipsychotics on cognitive functions so far. The present study aimed to compare the influence of risperidone LAIs (RLAI) and paliperidone palmitate LAIs (PP) on cognitive function in outpatients with schizophrenia. METHODS: In this 6-month, open-label, randomized, and controlled study, 30 patients with schizophrenia who were treated with RLAIs were randomly allocated to the RLAI-continued group or the PP group. At baseline and 6 months, the patients were evaluated using the Brief Assessment of Cognition in Schizophrenia (BACS) that was the primary outcome of the study. The Subjective Well-being under Neuroleptic drug treatment-Short form (SWNS), the Positive and Negative Syndrome Scale (PANSS), and the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) scores were secondary outcome variables and they were tested at the same time points. RESULTS: The two groups did not differ in terms of PANSS, DIEPSS, or SWNS total score changes. However, the BACS score for the attention and processing speed item showed higher improvement in the PP group than the RLAI group (p = 0.039). CONCLUSIONS: The results of this preliminary study suggest that PPs may improve attention and processing speed more than RLAIs. Anyway, a replication in a larger and double-blind study is needed. TRIAL REGISTRATION: UMIN000014470 . Registered 10 July 2014. PMID- 27236414 TI - Beyond the "Choosing wisely": a possible attempt. AB - Since the fundamental principles of the medical profession were clearly defined in a physician charter in 2002, special considerations have been expressed about the adequate distribution of health care resources taking in account the individual patient needs to optimize the health care service. The correct application of procedures represents a key point in order to reach the appropriateness of care, that means to avoid unnecessary or inappropriate procedures as well as the underutilization of the necessary procedures. In this context, the Choosing wisely campaign have been widely used and disclosed and even the Italian Society of Pediatric Allergology and Immunology - SIAIP has been working to make recommendations in order to ensure the appropriateness of care in the field of allergy and optimize the use of health care resources. PMID- 27236416 TI - Efficient protein knockdown of HaloTag-fused proteins using hybrid molecules consisting of IAP antagonist and HaloTag ligand. AB - We previously reported a protein knockdown system for HaloTag-fused proteins using hybrid small molecules consisting of alkyl chloride, which binds covalently to HaloTag, linked to BE04 (2), a bestatin (3) derivative with an affinity for cellular inhibitor of apoptosis protein 1 (cIAP1, a kind of ubiquitin ligase). This system addressed several limitations of prior protein knockdown technology, and was applied to degrade two HaloTag-fused proteins. However, the degradation activity of these hybrid small molecules was not potent. Therefore, we set out to improve this system. We report here the design, synthesis and biological evaluation of novel hybrid compounds 4a and 4b consisting of alkyl chloride linked to IAP antagonist MV1 (5). Compounds 4a and 4b were confirmed to reduce the levels of HaloTag-fused tumor necrosis factor alpha (HaloTag-TNFalpha), HaloTag-fused cell division control protein 42 (HaloTag-Cdc42), and unfused HaloTag protein in living cells more potently than did BE04-linked compound 1b. Analysis of the mode of action revealed that the reduction of HaloTag-TNFalpha is proteasome-dependent, and is also dependent on the linker structure between MV1 (5) and alkyl chloride. These compounds appear to induce ubiquitination at the HaloTag moiety of HaloTag-fused proteins. Our results indicate that these newly synthesized MV1-type hybrid compounds, 4a and 4b, are efficient tools for protein knockdown for HaloTag-fused proteins. PMID- 27236417 TI - Kidney Donation Before Imminent Circulatory Death. PMID- 27236418 TI - A Novel Lineage of 'Naked Filose Amoebae'; Kraken carinae gen. nov. sp. nov. (Cercozoa) with a Remarkable Locomotion by Disassembly of its Cell Body. AB - The term 'filose amoebae' describes a highly polyphyletic assemblage of protists whose phylogenetic placement can be unpredictable based on gross morphology alone. We isolated six filose amoebae from soils of two European countries and describe a new genus and species of naked filose amoebae, Kraken carinae gen. nov. sp. nov. We provide a morphological description based on light microscopy and small subunit rRNA gene sequences (SSU rDNA). In culture, Kraken carinae strains were very slow-moving and preyed on bacteria using a network of filopodia. Phylogenetic analyses of SSU sequences reveal that Kraken are core (filosan) Cercozoa, branching weakly at the base of the cercomonad radiation, most closely related to Paracercomonas, Metabolomonas, and Brevimastigomonas. Some Kraken sequences are >99% similar to an environmental sequence obtained from a freshwater lake in Antarctica, indicating that Kraken is not exclusively soil dwelling, but also inhabits freshwater habitats. PMID- 27236419 TI - Atmospheric depression-mediated water temperature changes affect the vertical movement of chum salmon Oncorhynchus keta. AB - The Sanriku coastal area, Japan, is one of the southern-most natural spawning regions of chum salmon Oncorhynchus keta. Here, we report their behavioral response to changes in ambient temperature after the passage of an atmospheric depression during the early spawning season. Before the passage, all electrically tagged fish moved vertically for several hours to depths below the shallow thermocline at >100 m. However, during the atmospheric depression, the salmon shortened the duration of their vertical movements and spent most time at the surface. The water column was homogenous at <150 m deep except for the surface. The descending behavior may have been discontinued because the cooler water below the thermocline was no longer in a thermally defined layer, due to strong vertical mixing by high wave action. Instead, they likely spent time within the cooler water temperatures at the surface of bays to minimize metabolic energy cost during migration. PMID- 27236420 TI - A tribo-mechanical analysis of PVA-based building-blocks for implementation in a 2-layered skin model. AB - Poly(vinyl) alcohol hydrogel (PVA) is a well-known polymer widely used in the medical field due to its biocompatibility properties and easy manufacturing. In this work, the tribo-mechanical properties of PVA-based blocks are studied to evaluate their suitability as a part of a structure simulating the length scale dependence of human skin. Thus, blocks of pure PVA and PVA mixed with Cellulose (PVA-Cel) were synthesised via freezing/thawing cycles and their mechanical properties were determined by Dynamic Mechanical Analysis (DMA) and creep tests. The dynamic tests addressed to elastic moduli between 38 and 50kPa for the PVA and PVA-Cel, respectively. The fitting of the creep compliance tests in the SLS model confirmed the viscoelastic behaviour of the samples with retardation times of 23 and 16 seconds for the PVA and PVA-Cel, respectively. Micro indentation tests were also achieved and the results indicated elastic moduli in the same range of the dynamic tests. Specifically, values between 45-55 and 56-81kPa were obtained for the PVA and PVA-Cel samples, respectively. The tribological results indicated values of 0.55 at low forces for the PVA decreasing to 0.13 at higher forces. The PVA-Cel blocks showed lower friction even at low forces with values between 0.2 and 0.07. The implementation of these building blocks in the design of a 2-layered skin model (2LSM) is also presented in this work. The 2LSM was stamped with four different textures and their surface properties were evaluated. The hydration of the 2LSM was also evaluated with a corneometer and the results indicated a gradient of hydration comparable to the human skin. PMID- 27236422 TI - Ten Years on the Juggernaut Keeps on Rolling: Comments on the STAMPEDE Trial from the Front Line. PMID- 27236423 TI - Drug Approvals in Oncology: Striking the Right Balance Between Saving Lives and Patient Safety. PMID- 27236421 TI - Diagnosis and management of gastrointestinal neuroendocrine tumors: An evidence based Canadian consensus. AB - The majority of neuroendocrine tumors originate in the digestive system and incidence is increasing within Canada and globally. Due to rapidly evolving evidence related to diagnosis and clinical management, updated guidance on the diagnosis and treatment of gastrointestinal neuroendocrine tumors (GI-NETs) are of clinical importance. Well-differentiated GI-NETs may exhibit indolent clinical behavior and are often metastatic at diagnosis. Some NET patients will develop secretory disease requiring symptom control to optimize quality of life and clinical outcomes. Optimal management of GI-NETs is in a multidisciplinary environment and is multimodal, requiring collaboration between medical, surgical, imaging and pathology specialties. Clinical application of advances in pathological classification and diagnostic technologies, along with evolving surgical, radiotherapeutic and medical therapies are critical to the advancement of patient care. We performed a systematic literature search to update our last set of published guidelines (2010) and identified new level 1 evidence for novel therapies, including telotristat etiprate (TELESTAR), lanreotide (CLARINET), everolimus (RADIANT-2; RADIANT-4) and peptide receptor radionuclide therapy (PRRT; NETTER-1). Integrating these data with the clinical knowledge of 16 multi disciplinary experts, we devised consensus recommendations to guide state of the art clinical management of GI-NETs. PMID- 27236424 TI - Strength of Validation for Surrogate End Points Used in the US Food and Drug Administration's Approval of Oncology Drugs. AB - OBJECTIVE: To determine the strength of the surrogate-survival correlation for cancer drug approvals based on a surrogate. PARTICIPANTS AND METHODS: We performed a retrospective study of the US Food and Drug Administration (FDA) database, with focused searches of MEDLINE and Google Scholar. Among cancer drugs approved based on a surrogate end point, we examined previous publications assessing the strength of the surrogate-survival correlation. Specifically, we identified the percentage of surrogate approvals lacking any formal analysis of the strength of the surrogate-survival correlation, and when conducted, the strength of such correlations. RESULTS: Between January 1, 2009, and December 31, 2014, the FDA approved marketing applications for 55 indications based on a surrogate, of which 25 were accelerated approvals and 30 were traditional approvals. We could not find any formal analyses of the strength of the surrogate survival correlation in 14 out of 25 accelerated approvals (56%) and 11 out of 30 traditional approvals (37%). For accelerated approvals, just 4 approvals (16%) were made where a level 1 analysis (the most robust way to validate a surrogate) had been performed, with all 4 studies reporting low correlation (r<=0.7). For traditional approvals, a level 1 analysis had been performed for 15 approvals (50%): 8 (53%) reported low correlation (r<=0.7), 4 (27%) medium correlation (r>0.7 to r<0.85), and 3 (20%) high correlation (r>=0.85) with survival. CONCLUSIONS: The use of surrogate end points for drug approval often lacks formal empirical verification of the strength of the surrogate-survival association. PMID- 27236425 TI - 76-Year-Old Man With Abdominal Pain, Fever, and Maculopapular Rash. PMID- 27236427 TI - 62-Year-Old Woman With Acute Hypotension and Hypoxia After Surgical Repair of Hip. PMID- 27236426 TI - Association Between Use of Dipeptidyl Peptidase-4 Inhibitors and the Risk of Acute Kidney Injury: A Nested Case-Control Study. AB - OBJECTIVE: To examine the risk of acute kidney injury (AKI) in a nationwide cohort of patients with type 2 diabetes initiating dipeptidyl peptidase-4 (DPP-4) inhibitors. PATIENTS AND METHODS: This nested case-control study of a cohort of adult DPP-4 inhibitor users with type 2 diabetes who were hospitalized for AKI between January 1, 2010, and December 31, 2013, was conducted using Taiwan's National Health Insurance Research Database. Each AKI case was matched with one control subject according to duration of follow-up, age, sex, urbanization level, monthly income, comorbidity severity, and well-known predisposing factors for AKI. Odds ratios (ORs) for AKI were calculated according to current, recent, or past use of DPP-4 inhibitors. RESULTS: A total of 6752 cases with AKI and 6752 matched controls were analyzed. The exposure prevalence of DPP-4 inhibitor use in the previous year was higher among patients with AKI (adjusted OR, 1.20; 95% CI, 1.05-1.36; P=.006). In a stratified analysis, the association was significant for current DPP-4 inhibitor use (adjusted OR, 1.26; 95% CI, 1.08-1.48; P=.004), but not for recent or past use. CONCLUSION: In this large contemporary cohort, DPP-4 inhibitor users had an increased risk of AKI development compared with nonusers. Further research is warranted to investigate the mechanism underlying this association. PMID- 27236428 TI - Early Computerization of Patient Care at Mayo Clinic. PMID- 27236429 TI - The spatial distribution patterns of condensed phase post-blast explosive residues formed during detonation. AB - The continued usage of explosive devices, as well as the ever growing threat of 'dirty' bombs necessitates a comprehensive understanding of particle dispersal during detonation events in order to develop effectual methods for targeting explosive and/or additive remediation efforts. Herein, the distribution of explosive analytes from controlled detonations of aluminised ammonium nitrate and an RDX-based explosive composition were established by systematically sampling sites positioned around each firing. This is the first experimental study to produce evidence that the post-blast residue mass can distribute according to an approximate inverse-square law model, while also demonstrating for the first time that distribution trends can vary depending on individual analytes. Furthermore, by incorporating blast-wave overpressure measurements, high-speed imaging for fireball volume recordings, and monitoring of environmental conditions, it was determined that the principle factor affecting all analyte dispersals was the wind direction, with other factors affecting specific analytes to varying degrees. The dispersal mechanism for explosive residue is primarily the smoke cloud, a finding which in itself has wider impacts on the environment and fundamental detonation theory. PMID- 27236430 TI - Salisbury biochar did not affect the mobility or speciation of lead in kaolin in a short-term laboratory study. AB - Salisbury biochar (produced from British broadleaf hardwood) with two different particle sizes (<=2mm and <=0.15mm) was applied on a kaolin with three different lead (Pb(2+)) contamination levels (50mg/kg, 300mg/kg and 1000mg/kg) at the dosage of 1% in w/w. The short-term impact of biochar on the mobility and speciation of Pb(2+) in the kaolin was investigated using attenuation periods of 1, 7 and 28 days. The leachability and extractability of Pb(2+) in carbonic acid leaching and EDTA extraction tests as well as the speciation of Pb(2+) in soils were not significantly affected by biochar treatment during all periods. The insignificant effects of biochar on Pb(2+) immobilisation were most likely attributed to the high adsorption capacity of Pb(2+) on the kaolin and biochar failed to competitively adsorb Pb(2+) against kaolin. The kaolin immobilised Pb(2+) primarily through cation exchange, which represents the readily bioavailable fractions of Pb(2+) in soils and may still pose environmental risks. This paper suggests the inefficiency of biochar treament on heavy-metal contaminated clay-rich soils. Therefore a laboratory treatablity study with respect to the soil type may be crucial when large-scale biochar applications in heavy-metal associated soil remediation are evaluated. PMID- 27236431 TI - Interplay between mitogen-activated protein kinase and nitric oxide in brassinosteroid-induced pesticide metabolism in Solanum lycopersicum. AB - Nitric oxide (NO) and mitogen-activated protein kinase (MPK) play important roles in brassinosteroid (BR)-induced stress tolerance, however, their functions in BR induced pesticides metabolism remain unclear. Here, we showed that MPK activity and transcripts of SlMPK1 and SlMPK2 were induced by chlorothalonil (CHT), a widely used fungicide, in tomato leaves. However, cosilencing of SlMPK1/2 compromised the 24-epibrassinolide (EBR)-induced upregulation of detoxification genes and CHT metabolism in tomato leaves. In addition, cosilencing of SlMPK1/2 inhibited the accumulation of S-nitrosothiol (SNO), the reservoir of nitric oxide (NO) in plants, whereas tungstate, the inhibitor of nitrate reductase (NR), blocked EBR-induced SNO accumulation and MPK activity. Inhibiting the accumulation of NO by cPTIO, the specific scavenger and tungstate abolished the EBR-induced upregulation of detoxification genes, glutathione accumulation and CHT metabolism. The results showed that MPK and NR-dependent NO were involved in BR-induced CHT metabolism. Notably, there was a positive crosstalk between the MPK and NO production. PMID- 27236432 TI - Efficient transformation of DDTs with Persulfate Activation by Zero-valent Iron Nanoparticles: A Mechanistic Study. AB - In this study, persulfate (PS) activation by nano-Fe(0) was used to degrade dichlorodiphenyltrichloroethane (DDT), and the mechanism of this process was elucidated with EPR, GC-MS and free-radical quenching studies. It was found that DDT was degraded efficiently in PS/nano-Fe(0), and GC-MS analysis showed that benzoic acid, benzyl alcohol, dichlorobenzophenone and 2,2-bis(p-chlorophenyl) ethane were the dominant products of DDT degradation, while only dechlorination products (DDD and DDE) were observed in nano-Fe(0) without persulfate. EPR results showed that persulfate activation by nano-Fe(0) led to the production of more sulfate radicals and hydroxyl radicals, which accounted for DDT degradation. But the free radical quenching studies suggested that the addition of ethanol to PS/nano-Fe(0) favored the reductive dechlorination of DDT, which was ascribed that the formed ethanol radical (CH(CH3)OH) enhanced the reductive dechlorination of DDT. Furthermore, the nano-Fe(0) loading not only affected the degradation efficiency of DDT, but also influenced the intermediate product distribution of DDT degradation in the PS/nano-Fe(0) process. PMID- 27236433 TI - Mental health services costs within the Alberta criminal justice system. AB - BACKGROUND: Mental illness has been widely cited as a driver of costs in the criminal justice system. OBJECTIVE: The objective of this paper is to estimate the additional mental health service costs incurred within the criminal justice system that are incurred because of people with mental illnesses who go through the system. Our focus is on costs in Alberta. METHODS: We set up a model of the flow of all persons through the criminal justice system, including police, court, and corrections components, and for mental health diversion, review, and forensic services. We estimate the transitional probabilities and costs that accrue as persons who have been charged move through the system. Costs are estimated for the Alberta criminal justice system as a whole, and for the mental illness component. RESULTS: Public expenditures for each person diverted or charged in Alberta in the criminal justice system, including mental health costs, were $16,138. The 95% range of this estimate was from $14,530 to $19,580. Of these costs, 87% were for criminal justice services and 13% were for mental illness related services. Hospitalization for people with mental illness who were reviewed represented the greatest additional cost associated with mental illnesses. CONCLUSION: Treatment costs stemming from mental illnesses directly add about 13% onto those in the criminal justice system. PMID- 27236434 TI - [Membranous nephropathy: Diagnosis, new insights in pathophysiology, and therapeutic approach]. AB - Membranous nephropathy (MN) accounts for about 20% of cases of nephrotic syndrome in the adult. Thickening of glomerular capillary walls results from subepithelial formation of immune deposits containing IgG and the membrane attack complex of complement, which is the major mediator of proteinuria, and antigens. Idiopathic forms of MN (IMN) represent 70 to 80% of all cases. A major breakthrough was the identification of the podocyte antigen PLA2R as the target of circulating antibodies in about 70% of IMN, which confirmed that the disease was auto-immune in nature. The optimal treatment of patients with IMN is still a matter of debate. Thirty to 40% of affected patients will undergo spontaneous remission, usually within one year from disease onset, whereas about one third will progress to end-stage kidney disease. Both the evidence that B cells play a key role in the pathogenesis of IMN and drug toxicity led to target B-cells with rituximab. Rituximab induced remission of nephrotic syndrome in 60 to 80% of the patients with long-lasting proteinuria despite blockade of the renin-angiotensin system and in patients who had previously failed other treatments. Because of the lack of randomized controlled trial (RCT) using rituximab and of high rate of spontaneous remission, a French non-blinded, parallel group RCT was performed to compare rituximab added to supportive therapy, to supportive therapy alone, in patients with persistent nephrotic syndrome. PMID- 27236435 TI - Impact of Completion Lymph Node Dissection on Patients with Positive Sentinel Lymph Node Biopsy in Melanoma. AB - BACKGROUND: Whether patients with positive SLNB should undergo complete lymph node dissection (CLND) is an important unanswered clinical question. STUDY DESIGN: Patients diagnosed with positive SLNB at a melanoma referral center from 1991 to 2013 were studied. Outcomes of patients who underwent CLND were compared with those who did not undergo immediate CLND (observation [OBS] group). RESULTS: There were 471 patients who had positive SLNB; 375 (79.6%) in the CLND group and 96 (20.4%) in the OBS group. The groups were similar except that the CLND group was younger and had more sentinel nodes removed. Five-year nodal recurrence-free survival was significantly better in the CLND group compared with the OBS group (93.1% vs 84.4%; p = 0.005). However, 5-year (66.4% vs 55.2%) and 10-year (59.5% vs 45.0%) distant metastasis-free survival rates were not significantly different (p = 0.061). The CLND group's melanoma-specific survival (MSS) rate was superior to that of the OBS group; 5-year MSS rates were 73.7% vs 65.5% and 10-year MSS rates were 66.8% vs 48.3% (p = 0.015). On multivariate analysis, CLND was associated with improved MSS (hazard ratio = 0.60; 95% CI, 0.40-0.89; p = 0.011) and lower nodal recurrence (hazard ratio = 0.46; 95% CI, 0.24-0.86; p = 0.016). Increased Breslow thickness, older age, ulceration, and trunk melanoma were all associated with worse outcomes. On subgroup analysis, the following factors were associated with better outcomes from CLND: male sex, nonulcerated primary, intermediate thickness, Clark level IV or lower extremity tumors. CONCLUSIONS: Treatment of positive SLNB with CLND was associated with improved MSS and nodal recurrence rates. Follow-up beyond 5 years was needed to see a significant difference in MSS rates. PMID- 27236436 TI - Arsenic Speciation of Waters from the Aegean Region, Turkey by Hydride Generation: Atomic Absorption Spectrometry. AB - Arsenic in drinking water is a serious problem for human health. Since the toxicity of arsenic species As(III) and As(V) is different, it is important to determine the concentrations separately. Therefore, it is necessary to develop an accurate and sensitive method for the speciation of arsenic. It was intended with this work to determine the concentrations of arsenic species in water samples collected from Izmir, Manisa and nearby areas. A batch type hydride generation atomic absorption spectrometer was used. As(V) gave no signal under the optimal measurement conditions of As(III). A certified reference drinking water was analyzed by the method and the results showed excellent agreement with the reported values. The procedure was applied to 34 water samples. Eleven tap water, two spring water, 19 artesian well water and two thermal water samples were analyzed under the optimal conditions. PMID- 27236437 TI - Early clinical outcomes of right ventricular outflow tract reconstruction with small caliber bovine jugular vein conduit (Contegra(r)) in small children. AB - This study reviewed early clinical outcomes of right ventricular outflow tract reconstruction with Contegra(r) valved conduits in pediatric patients. Between April 2013 and July 2014, thirteen pediatric patients underwent right ventricular outflow tract reconstruction with Contegra valved conduits. The size of the implanted conduits were 12 mm in 5 patients, 14 mm in 3, 16 mm in 3, and then 2 patients were implanted with bicuspidized conduits for downsizing the conduit to 9 and 10 mm in each. Follow-ups were completed in all patients. One conduit was explanted 7 days after a neonatal biventricular repair for Ebstein's anomaly and pulmonary atresia, timed to be at the point of conversion to a single ventricular palliation. Among the 5 patients who developed significant pulmonary insufficiency and/or conduit stenosis, 3 patients exhibited persistent pulmonary hypertension. Both the bicuspidized conduits resulted in early pulmonary insufficiency. One patient implanted with a ring-supported conduit developed coronary artery stenosis, caused by suppression between the ring of the implanted conduit and the annulus of the mechanical vale. Although the small caliber Contegra valved conduit might be an alternative to RVOT reconstruction, the indication should be carefully considered. More than mild pulmonary hypertension, and low body weight at operation of less than 3.0 kg caused early conduit dysfunction. PMID- 27236438 TI - Genetic differences stratified by PCR-based microsatellite analysis in gastric intramucosal neoplasia. AB - BACKGROUND: Although genetic alterations in patients with advanced gastric cancer have been extensively studied, those in patients with intramucosal neoplasia (IMN) are still poorly understood. METHODS: We evaluated genetic differences in 158 IMNs, including 51 low-grade dysplasias, 58 high-grade dysplasias (HGDs), 30 intramucosal cancers (IMCs), and 19 mixed tumors (composed of IMC and HGD within the same tumor), using PCR-based microsatellite analysis [allelic imbalance (AI) and microsatellite instability (MSI)]. We classified the DNA methylation status as a hypermethylated epigenome, a moderately methylated epigenome, or a hypomethylated epigenome. In addition, p53 overexpression, beta-catenin nuclear localization, and mucin expression were also examined. RESULTS: From cluster analysis, the IMNs examined were categorized into four subgroups as follows. Tumors in subgroup 1 were characterized by MSI-high status, a hypermethylated epigenome, and loss or reduction of expression of MLH-1. Tumors in subgroup 2 showed a mixed pattern consisting of AI and MSI. In contrast, tumors in subgroup 3, which showed accumulation of multiple AIs, were closely associated with HGD, IMC, or mixed tumor and exhibited nuclear expression of beta-catenin. Tumors in subgroup 4, which were generally low-grade dysplasias, exhibited a low frequency of AIs and no MSI. Although the mucin phenotype was not correlated with any subgroup, expression of mucin was associated with some subgroups. Overexpression of p53 was common in all subgroups. CONCLUSION: The approach described herein was useful for studying genetic differences in IMNs. In addition, we suggest that stratification of genetic differences may help to identify genetic molecular profiles in IMNs. PMID- 27236439 TI - Cancer cachexia, sarcopenia and biochemical markers in patients with advanced non small cell lung cancer-chemotherapy toxicity and prognostic value. AB - PURPOSE: Cancer cachexia and sarcopenia are frequently observed in cancer patients and associated with poor survival. The majority of studies of cancer cachexia and sarcopenia have been done in patients with solid tumors of different origins, and there are currently no good predictors of the benefit of chemotherapy or factors that predict survival in advanced cancer. The purpose of our prospective study was to evaluate prevalence of cachexia and sarcopenia using international consensus definition and criteria for diagnosis in patients with diagnosed advanced non-small cell lung cancer (NSCLC) stage IIIB and IV and their relation to chemotherapy toxicity and survival prediction. A secondary aim was to compare several biochemical markers (CRP, IL-6, protein, and albumin) with time to tumor progression in order to assess prognostic value or to guide a treatment. METHODS: Between December 2013 and April 2015, the prospective cohort study of 100 Caucasian patients with advanced NSCLC stage IIIB or IV, who were referred consecutively to Department for Respiratory Diseases "Jordanovac," was evaluated. Anthropometric measurements and biochemical data (CRP, albumin, protein, IL-6, haemoglobin) together with body composition measurements (total muscle cross sectional area, lumbar skeletal muscle index) were obtained for each patient before starting with platinum-doublet therapy. Skeletal muscle cross-sectional area at the third lumbar vertebra was measured by computerized tomography, and sarcopenia was defined using a previously published cutoff point. Toxicity was assessed after cycle 1 of treatment and time-to-tumor progression was determined prospectively. RESULTS: One hundred patients with advanced lung cancer were recruited: 67 were male and median age was 64 years. The median time to disease progression was 187 days. The prevalence of cachexia and sarcopenia in study cohort was 69 and 47 %, respectively. CRP, IL-6, and albumin concentration in cachectic compared to non-cachectic patients demonstrated statistically significant difference (p = 0.020, p = 0.040, p = 0.003). Cachexia and sarcopenia were not found to be predictors of chemotoxicity nor was time to tumor progression. On the contrary, albumin concentration with established cutoff point of 37.5 g/L was clearly proved as the predictive factor of both chemotoxicity (OR (95 % CI) = 0.85; p < 0.001) and survival (HR (95 % CI) = 0.55). CONCLUSIONS: Albumin level has been shown to be more important predictive marker of chemotherapy toxicity and survival than cachexia and sarcopenia are. This approach in clinical settings can be used to guide the choice of oncologic treatment. PMID- 27236440 TI - Zika Virus Infection: Current Concerns and Perspectives. AB - The Zika virus outbreaks highlight the growing importance need for a reliable, specific and rapid diagnostic device to detect Zika virus, as it is often recognized as a mild disease without being identified. Many Zika virus infection cases have been misdiagnosed or underreported because of the non-specific clinical presentation. The aim of this review was to provide a critical and comprehensive overview of the published peer-reviewed evidence related to clinical presentations, various diagnostic methods and modes of transmission of Zika virus infection, as well as potential therapeutic targets to combat microcephaly. Zika virus is mainly transmitted through bites from Aedes aegypti mosquito. It can also be transmitted through blood, perinatally and sexually. Pregnant women are advised to postpone or avoid travelling to areas where active Zika virus transmission is reported, as this infection is directly linked to foetal microcephaly. Due to the high prevalence of Guillain-Barre syndrome and microcephaly in the endemic area, it is vital to confirm the diagnosis of Zika virus. Zika virus infection had been declared as a public health emergency and of international concern by the World Health Organisation. Governments and agencies should play an important role in terms of investing time and resources to fundamentally understand this infection so that a vaccine can be developed besides raising awareness. PMID- 27236441 TI - Metal contamination status of the soil-plant system and effects on the soil microbial community near a rare metal recycling smelter. AB - Four heavy metals (Cd, Cu, Pb and Zn), two metalloids (As and Sb) and two rare metals (In and Tl) were selected as target elements to ascertain their concentrations and accumulation in the soil-plant system and their effects on the structure of the soil microbial community in a typical area of rare metal smelting in south China. Twenty-seven soil samples 100, 500, 1000, 1500 and 3000 m from the smelter and 42 vegetable samples were collected to determine the concentrations of the target elements. Changes in soil micro-organisms were investigated using the Biolog test and 454 pyrosequencing. The concentrations of the eight target elements (especially As and Cd) were especially high in the topsoil 100 m from the smelter and decreased markedly with increasing distance from the smelter and with increasing soil depth. Cadmium bio-concentration factors in the vegetables were the highest followed by Tl, Cu, Zn, In, Sb, Pb, and then As. The concentrations of As, Cd and Pb in vegetables were 86.7, 100 and 80.0 %, respectively, over the permissible limits and possible contamination by Tl may also be of concern. Changes in soil microbial counts and average well colour development were also significantly different at different sampling distances from the smelter. The degree of tolerance to heavy metals appears to be fungi > bacteria > actinomycetes. The 454 pyrosequencing indicates that long-term metal contamination from the smelting activities has resulted in shifts in the composition of the soil bacterial community. PMID- 27236442 TI - Fecal contamination of wastewater treatment plants in Portugal. AB - Reutilization of effluents from wastewater treatment plants (WWTP) for non potable applications is increasing due to the reduction of sustainable water resources. These products mostly come from municipal WWTP and also from slaughterhouses effluents. The microbiological certification of these products is mandatory before their discharge into the environment. This study evaluates if the treatment applied in WWTP to municipal waters or to poultry slaughterhouse effluents distributed over the Portuguese continental territory is efficient in reducing the microbiological risk associated with the reutilization of those wastewaters and sludges. Fecal indicators Escherichia coli and enterococci were evaluated in 42 and 24 wastewater samples from 14 municipal WWTP and 8 poultry slaughterhouse treatment plants, respectively, by the conventional culture method and a rapid Fluorescent in situ hybridization (FISH) technique. Bacterial enumeration in inflow water from most WWTP was rather high (generally >10(5) cells/ml), for both E. coli and Enterococcus spp., and the bacterial quantification by FISH was generally higher than enumeration by the conventional culture method. In both types of treatment plants studied, bacterial load from effluents and sludges was not statistically different from the inflows, indicating that the treatment applied seems to be equally unable to reduce the microbiological load of the effluents. These findings may jeopardize the safe reuse of treated wastewaters in agriculture and the quality of the water environment. Therefore, products like water, sewage sludge, and biosolids originated from the municipal and slaughterhouse WWTP studied should not be reutilized, and effluents treatment should be urgently reviewed. PMID- 27236443 TI - CO2 sequestration by mineral carbonation of steel slags under ambient temperature: parameters influence, and optimization. AB - This work focuses on the influence of different parameters on the efficiency of steel slag carbonation in slurry phase under ambient temperature. In the first part, a response surface methodology was used to identify the effect and the interactions of the gas pressure, liquid/solid (L/S) ratio, gas/liquid ratio (G/L), and reaction time on the CO2 removed/sample and to optimize the parameters. In the second part, the parameters' effect on the dissolution of CO2 and its conversion into carbonates were studied more in detail. The results show that the pressure and the G/L ratio have a positive effect on both the dissolution and the conversion of CO2. These results have been correlated with the higher CO2 mass introduced in the reactor. On the other hand, an important effect of the L/S ratio on the overall CO2 removal and more specifically on the carbonate precipitation has been identified. The best results were obtained L/S ratios of 4:1 and 10:1 with respectively 0.046 and 0.052 gCO2 carbonated/g sample. These yields were achieved after 10 min reaction, at ambient temperature, and 10.68 bar of total gas pressure following direct gas treatment. PMID- 27236444 TI - Silicate application increases the photosynthesis and its associated metabolic activities in Kentucky bluegrass under drought stress and post-drought recovery. AB - Drought stress is the most pervasive threat to plant growth, which disrupts the photosynthesis and its associated metabolic activities, while silicate (Si) application may have the potential to alleviate the damaging effects of drought on plant growth. In present study, the role of Si in regulating the photosynthesis and its associated metabolic events in Kentucky bluegrass (cv. Arcadia) were investigated under drought stress. Drought stress and four levels (0, 200, 400, 800 mg L(-1)) of Si (Na2SiO3.9H2O) were imposed on 1-year-old plants removed from field and cultured under glasshouse conditions. After 20 days of drought stress, the plants were re-watered to reach soil field capacity for the examination of recovery on the second and the seventh day. The experiment was arranged in completely randomized design replicated four times. Drought stress severely decreased the photosynthesis, water use efficiency, stomatal conductance, cholorophyll contents, Rubisco activity, and Rubisco activation state in Kentucky bluegrass. Nevertheless, application of Si had a positive influence on all these attributes, particularly under stress conditions. As compared to control, Si application at 400 mg L(-1) recorded 78, 64, and 48 % increase in photosynthesis, Rubisco initial activity, and Rubisco total activity, respectively, at 20 days of drought. Higher photosynthesis and higher Rubisco activity in Si-applied treatments suggest that Si may have possible (direct or indirect) role in maintenance of more active Rubisco enzyme and Rubisco activase and more stable proteins for carbon assimilation under stress conditions, which needs to be elucidated in further studies. PMID- 27236445 TI - Fine structure of the Arabidopsis stem cuticle: effects of fixation and changes over development. AB - MAIN CONCLUSION: The Arabidopsis cuticle, as observed by electron microscopy, consists primarily of the cutin/cutan matrix. The cuticle possesses a complex substructure, which is correlated with the presence of intracuticular waxes. The plant cuticle is composed of an insoluble polyester, cutin, and organic solvent soluble cuticular waxes, which are embedded within and coat the surface of the cutin matrix. How these components are arranged in the cuticle is not well understood. The Arabidopsis cuticle is commonly understood as 'amorphous,' lacking in ultrastructural features, and is often observed as a thin (~80-100 nm) electron-dense layer on the surface of the cell wall. To examine this cuticle in more detail, we examined cuticles from both rapidly elongating and mature sections of the stem and compared the preservation of the cuticles using conventional chemical fixation methods and high-pressure freezing/freeze substitution (HPF/FS). We found that HPF/FS preparation revealed a complex cuticle substructure, which was more evident in older stems. We also found that the cuticle increases in thickness with development, indicating an accretion of polymeric material, likely in the form of the non-hydrolyzable polymer, cutan. When wax was extracted by chloroform immersion prior to sample preparation, the contribution of waxes to cuticle morphology was revealed. Overall, the electron dense cuticle layer was still visible but there was loss of the cuticle substructure. Furthermore, the cuticle of cer6, a wax-deficient mutant, also lacked this substructure, suggesting that these fine striations were dependent on the presence of cuticular waxes. Our findings show that HPF/FS preparation can better preserve plant cuticles, but also provide new insights into the fine structure of the Arabidopsis cuticle. PMID- 27236446 TI - The characteristics of indoor and outdoor fungi and their relation with allergic respiratory diseases in the southern region of Turkey. AB - Indoor and outdoor fungal exposure has been shown to be associated with the development of allergic respiratory diseases. The aim of the study was to investigate the types and concentrations of airborne fungi inside and outside homes and evaluate the association between fungal levels and allergic diseases in the southern region of Turkey. A total of 61 children admitted with respiratory complaints to the pediatric allergy clinic between September 2007 and November 2008 were included in this study. The air samples were obtained using the Air IDEAL volumetric air sampler longitudinally for 1 year. A comprehensive questionnaire was used for medical history and housing conditions. Skin prick test was performed to determine fungal sensitivity and spirometric indices were employed. The predominant indoor fungal species were Cladosporium (69.3 %), Penicillium (18.9 %), Aspergillus (6.5 %), and Alternaria (3.1 %). A strong correlation between indoor and outdoor fungal levels was detected for the Cladosporium species (p < 0.001, r = 0.72) throughout the year. Living in a detached home (p = 0.036) and the presence of cockroaches (p = 0.005) were associated with total indoor fungal levels. The presence of cockroaches (aOR 3.5; 95 % CI 0.95-13.10, p = 0.059) was also associated with fungal sensitization at the edge of significance. The statistical cutoff values of indoor and outdoor Cladosporium levels to predict symptomatic asthma were found to be >176 CFU/m(3) (p = 0.003, AUC 0.696; sensitivity 65.5 %; specificity 68.7 %) and >327 CFU/m(3) (p = 0.038; AUC 0.713; sensitivity 66.6 %; specificity 76.9 %), respectively. Children with respiratory symptoms are exposed to a considerable level of fungi inside and outside their homes. The prevention of fungal exposure may provide valuable intervention for respiratory diseases. PMID- 27236448 TI - Levetiracetam vs. brivaracetam for adults with refractory focal seizures: A meta analysis and indirect comparison. AB - PURPOSE: The study aimed to compare the efficacy and tolerability of levetiracetam (LEV) and brivaracetam (BRV) in adults with refractory focal seizures. METHOD: We systematically queried Medline, Embase, and the Cochrane Library. We looked for additional studies in the references of all identified publications and ClinicalTrials.gov. The cutoff day was November 6, 2015. Randomized, double-blind, placebo-controlled trials were included. The indirect comparison for 50% responder rate, seizure-free rate, and adverse effects were conducted. RESULTS: Thirteen trials enrolling 1765 patients in the LEV group and 1919 patients in the BRV group were included. No statistically significant differences were found in efficacy between LEV and BRV at various dose levels. However, most risk ratios (RRs) at three dose levels and the overall RR were >1 for 50% response proportions. The majority of statistically significant differences for adverse events and withdrawal of LEV and BRV were found at high- and middle-dose levels. The indirect comparison of adverse effects (AEs) showed statistically statistical differences in dizziness. CONCLUSION: Our results suggested that LEV might have a slightly higher efficacy with a lower probability of dizziness compared with BRV for patients with refractory focal seizures. PMID- 27236447 TI - Understanding the remobilization of copper, zinc, cadmium and lead due to ageing through sequential extraction and isotopic exchangeability. AB - Artificial infiltration facilities (AIFs) are useful to control urban runoff and regulate combined sewer overflows. Over the years, AIFs accumulate significant amounts of soakaway sediments and organic matter. The prolonged retention of soakaway sediments in AIFs is likely to cause metal remobilization due to ageing processes. The measurement of the individual consequence of ageing demands homogeneity in physical and chemical profiles of samples. This leads to assessment of metal remobilization in a single soil core through solid-phase extractions and isotopic exchangeability (E value). Depth-wise variation in the physicochemical properties and metal content of the underlying soil (below 1 m of AIFs) was created through 2 weeks of continuous leaching with artificial road runoff (ARR). Ten samples obtained from a 50-cm core by sectioning it at 5-cm intervals were subsequently incubated for 18 months. The results suggest that degradation of organic matter and changes in functional groups due to ageing govern metal remobilization. In general, the top segment showed significant alteration due to ageing. Post incubation, Zn increased dramatically in contrast to subdued Cu and Pb levels in exchangeable fractions with concomitant rise in organic-bound fractions. Isotopic exchangeability of Cd and Zn showed pronounced effect of ageing, although the effect of ageing was distinct in chemical partitioning and isotopic exchangeability of metals; a comparative study of short term versus long-term incubation will benefit assessment of initial dynamics and final equilibrium. Consequently, the outcome from this work is a viable tool in risk prediction related to soakaway sediment accumulation in AIF. PMID- 27236449 TI - SCN1A gene sequencing in 46 Turkish epilepsy patients disclosed 12 novel mutations. AB - PURPOSE: The SCN1A gene is one of the most commonly mutated human epilepsy genes associated with a spectrum of phenotypes with variable degrees of severity. Despite over 1200 distinct mutations reported, it is still hard to draw clear genotype-phenotype relationships, since genetic and environmental modifiers contribute to the development of a particular disease caused by an SCN1A mutation. We aimed to initiate mutational screening of the SCN1A gene in Turkey and advance further our understanding of the relationship between the SCN1A sequence alterations and disease phenotypes such as GEFS+, DS and related epileptic encephalopathies. METHODS: Mutational analysis of the SCN1A gene was carried out in 46 patients with DS, late-onset DS, GEFS+ and unspecified EE using either direct Sanger sequencing of the coding regions and exon/intron boundaries or massively parallel sequencing. RESULTS: Nineteen point mutations, 12 of which were novel were identified, confirming the clinical diagnosis of the patients. Patients with a mutation (either truncating or missense) on linker regions had significantly later disease onset than patients with mutations in homology regions. The presence of SCN1A mutations in two clinically unclassified patients supported the association of SCN1A mutations with a wide range of phenotypes. CONCLUSION: The conventional Sanger sequencing method was successfully initiated for the detection of SCN1A point mutations in Turkey in epilepsy patients. Furthermore, a modified strategy of massively parallel pyro-sequencing was also established as a rapid and effective mutation detection method for large genes as SCN1A. PMID- 27236450 TI - How does a beta-barrel integral membrane protein insert into the membrane? PMID- 27236451 TI - Safety and complications of intravitreal injections performed in an Asian population in Singapore. AB - There has been a rapid rise in the use of intravitreal injections, such as anti vascular endothelial growth factor (anti-VEGF) agents, performed over the past few years for the treatment of ocular neovascular diseases. This study aims to review the systemic and ocular adverse events among patients treated at a tertiary eye center over a period of 8 years. A retrospective review of all intravitreal injections of anti-VEGF performed over an 8-year period at a tertiary eye care center in Singapore was done. We report the frequency of systemic and ocular adverse events and compared it among the various anti-VEGF agents. A total of 14 001 intravitreal injections were performed on 2225 patients from January 1, 2007 to December 31, 2014, and this included 9992 bevacizumab (71.4 %), 3306 ranibizumab (23.6 %) and 703 aflibercept (5.0 %) injections. Systemic complications related to treatment were 26 (1.17 %) deaths (from any cause), of which 11 (0.49 %) were from fatal thromboembolic events, 7 (0.31 %) non-fatal thromboembolic events and two (0.09 %) serious non-ocular hemorrhage. Ocular complications included one (0.007 %) endophthalmitis, three (0.021 %) traumatic cataracts, and one (0.007 %) retinal detachment. Rates of death and thromboembolic events were similar among ranibizumab (lucentis), bevacizumab (avastin) and aflibercept (Eylea). The systemic and ocular complications associated with intravitreal injections among Asian patients at a tertiary eye center are relatively low and reflect the safety of the treatments. PMID- 27236452 TI - Second-line tests in the differential diagnosis of ACTH-dependent Cushing's syndrome. AB - INTRODUCTION: Diagnosing Cushing's syndrome (CS) can be a challenge, especially in ACTH-dependent CS, when it comes to detecting the origin of ACTH secretion. MATERIALS AND METHODS: Retrospective data were collected on 170 patients with ACTH-dependent CS (149 CD, 21 EAS) referring to two endocrinology units, focusing on three non-invasive tests: dexamethasone 8 mg overnight challenge (HDDST); corticotrophin-releasing hormone (CRH) assay and the desmopressin (DDAVP) test. RESULTS: Patients with EAS were slightly older and had higher ACTH, serum and urinary cortisol levels than patients with CD (p < 0.01). CD patients had a stronger ACTH and cortisol response after CRH injection (p < 0.0001), and a more pronounced reduction in cortisol levels after HDDST (p < 0.0001). A threshold percentage ACTH increase after CRH stimulation of 72.4 % was able to identify CD with a sensitivity (SE) of 76 % (95 % CI 68-83) and a specificity (SP) of 100 % (95 % CI 83-100). As for HDDST, a cortisol suppression >52.7 % below the basal level suggested a pituitary origin with a SE of 88 % (95 % CI 81-93) and a SP of 90 % (95 % CI 68-99). There were no cases of EAS with positive responses to both these tests. Increases in ACTH and cortisol levels after the DDAVP test were also higher in CD than in EAS (p < 0.01), though the SE and SP were lower. CONCLUSIONS: Patients with CD showed a stronger response to HDDST and CRH, and the adopted cut-offs showed a good SE and SP in discriminating them from patients with EAS. Concordant tests indicated CD when positive, whereas no response to either test was highly suggestive of EAS. The DDAVP test was of limited utility in the diagnostic phase. In conclusion, the choice of tests may play an important part in the differential diagnosis of ACTH-dependent CS. PMID- 27236453 TI - Loudness-dependent behavioral responses and habituation to sound by the longfin squid (Doryteuthis pealeii). AB - Sound is an abundant cue in the marine environment, yet we know little regarding the frequency range and levels which induce behavioral responses in ecologically key marine invertebrates. Here we address the range of sounds that elicit unconditioned behavioral responses in squid Doryteuthis pealeii, the types of responses generated, and how responses change over multiple sound exposures. A variety of response types were evoked, from inking and jetting to body pattern changes and fin movements. Squid responded to sounds from 80 to 1000 Hz, with response rates diminishing at the higher and lower ends of this frequency range. Animals responded to the lowest sound levels in the 200-400 Hz range. Inking, an escape response, was confined to the lower frequencies and highest sound levels; jetting was more widespread. Response latencies were variable but typically occurred after 0.36 s (mean) for jetting and 0.14 s for body pattern changes; pattern changes occurred significantly faster. These results demonstrate that squid can exhibit a range of behavioral responses to sound include fleeing, deimatic and protean behaviors, all of which are associated with predator evasion. Response types were frequency and sound level dependent, reflecting a relative loudness concept to sound perception in squid. PMID- 27236454 TI - Piracetam for Aphasia in Post-stroke Patients: A Systematic Review and Meta analysis of Randomized Controlled Trials. AB - BACKGROUND: Aphasia is a common symptom in post-stroke patients. Piracetam is a commonly used nootropic agent that promises various benefits to brain function, including language improvement. OBJECTIVE: We performed a systematic review and meta-analysis to assess whether piracetam facilitates the rehabilitation of language performance in post-stroke patients. METHODS: Randomized controlled trials (RCTs) of piracetam treatment in post-stroke patients published in any language were included, excluding those involving pre-existing cognitive disorders such as dementia and mood disturbances. We searched several databases including PubMed, EMBASE, Cochrane Central, CINAHL, Web of Science, and PsycINFO for RCTs published up to 31 December 2015. We conducted a meta-analysis using RevMan (version 5.3), with standardized mean differences (SMDs) and fixed-effect models, and used StataSE (version 13) for the detection of publication bias. This study has been submitted to PROSPERO, and its registration number is CRD42016034088. RESULTS: We identified 1180 titles and abstracts, and finally included seven RCTs in this meta-analysis. The number of participants in each study ranged from 19 to 66, summing up to 261 patients overall. The dose of piracetam was consistent while the frequency and time of therapy varied. The assessment of the language at the end of trials showed no significant improvement in overall severity of aphasia [SMD 0.23, 95 % confidence interval (CI) -0.03 to 0.49, P = 0.08], but written language (SMD 0.35, 95 % CI 0.04 to 0.66, P = 0.03) showed pronounced improvement. Subgroup analyses indicated a dissociation of effectiveness between short- and long-term assessment in overall severity (P = 0.008, I (2) = 85.6 %) in terms of tests for subgroup differences, and a mild trend toward dissociation in written subtests (P = 0.30, I (2) = 5.1 %). Funnel plots and Egger's test identified no obvious publication bias in the primary variable. CONCLUSIONS: Piracetam plays a limited role in the rehabilitation of overall language impairment and only benefits written language ability at the end of trials. Its effect on overall linguistic level and written language tends to emerge within a short period and declines thereafter. PMID- 27236455 TI - Explaining fatigue in multiple sclerosis: cross-validation of a biopsychosocial model. AB - Fatigue is a common and disabling symptom in patients with multiple sclerosis (MS), but its pathogenesis is still poorly understood and consequently evidence based treatment options are limited. Bol et al. (J Behav Med 33(5):355-363, 2010) suggested a new model, which explains fatigue in MS from a biopsychosocial perspective, including cognitive-behavioral factors. For purposes of generalization to clinical practice, cross-validation of this model in another sample of 218 patients with MS was performed using structural equation modeling. Path analysis indicated a close and adequate global fit (RMSEA = 0.053 and CFI = 0.992). The cross-validated model indicates a significant role for disease severity, depression and a fear-avoidance cycle in explaining MS-related fatigue. Modifiable factors, such as depression and catastrophizing thoughts, propose targets for treatment options. Our findings are in line with recent evidence for the effectiveness of a new generation of cognitive behavioral therapy, including acceptance and mindfulness-based interventions, and provide a theoretical framework for treating fatigue in MS. PMID- 27236456 TI - Postural sway in men and women during nauseogenic motion of the illuminated environment. AB - We exposed standing men and women to motion relative to the illuminated environment in a moving room. During room motion, we measured the kinematics of standing body sway. Participants were instructed to discontinue immediately if they experienced any symptoms of motion sickness, however mild. For this reason, our analysis of body sway included only movement before the onset of motion sickness. We analyzed the spatial magnitude of postural sway in terms of the positional variability and mean velocity of the center of pressure. We analyzed the multifractality of postural sway in terms of the width of the multifractal spectrum and the degree of multiplicativity of center of pressure positions. Results revealed that postural sway differed between participants who later reported motion sickness and those who did not, replicating previous effects. In a novel effect, postural responses to motion of the illuminated environment differed between women and men. In addition, we identified statistically significant interactions that involved both Sex and motion sickness status. Effects were observed separately in the spatial magnitude and multifractality of sway. The results were consistent with the postural instability theory of motion sickness (Riccio and Stoffregen in Ecol Psychol 3:195-240, 1991) and suggest that Sex differences in motion sickness may be related to Sex differences in the control and stabilization of bodily activity. PMID- 27236457 TI - Mechanisms of Change in the ARC Organizational Strategy: Increasing Mental Health Clinicians' EBP Adoption Through Improved Organizational Culture and Capacity. AB - The development of efficient and scalable implementation strategies in mental health is restricted by poor understanding of the change mechanisms that increase clinicians' evidence-based practice (EBP) adoption. This study tests the cross level change mechanisms that link an empirically-supported organizational strategy for supporting implementation (labeled ARC for Availability, Responsiveness, and Continuity) to mental health clinicians' EBP adoption and use. Four hundred seventy-five mental health clinicians in 14 children's mental health agencies were randomly assigned to the ARC intervention or a control condition. Measures of organizational culture, clinicians' intentions to adopt EBPs, and job-related EBP barriers were collected before, during, and upon completion of the three-year ARC intervention. EBP adoption and use were assessed at 12-month follow-up. Multilevel mediation analyses tested changes in organizational culture, clinicians' intentions to adopt EBPs, and job-related EBP barriers as linking mechanisms explaining the effects of ARC on clinicians' EBP adoption and use. ARC increased clinicians' EBP adoption (OR = 3.19, p = .003) and use (81 vs. 56 %, d = .79, p = .003) at 12-month follow-up. These effects were mediated by improvement in organizational proficiency culture leading to increased clinician intentions to adopt EBPs and by reduced job-related EBP barriers. A combined mediation analysis indicated the organizational culture-EBP intentions mechanism was the primary carrier of ARC's effects on clinicians' EBP adoption and use. ARC increases clinicians' EBP adoption and use by creating proficient organizational cultures that increase clinicians' intentions to adopt EBPs. PMID- 27236458 TI - The Healthcare Needs of Latinos with Serious Mental Illness and the Potential of Peer Navigators. AB - Latinos with serious mental illness get sick and die much younger than other adults. In this paper, we review findings of a community based participatory research project meant to identify important healthcare needs, barriers to these needs, solutions to the barriers, and the promise of peer navigators as a solution. Findings from focus groups reflected general concerns of people with mental illness (e.g., insurance, engagement, accessibility) and Latinos with serious mental illness (e.g., immigration, language, and family). Feedback and analyses especially focused on the potential of peer navigators. Implications of these findings for integrated care of Latinos with serious mental illness are discussed. PMID- 27236459 TI - Soil-borne wheat mosaic virus infectious clone and manipulation for gene-carrying capacity. AB - A full-length infectious cDNA clone of soil-borne wheat mosaic virus (SBWMV; genus Furovirus; family Virgaviridae) was developed for agrobacterium delivery. The cloned virus can be agroinfiltrated to Nicotiana benthamiana for subsequent infection of wheat (Triticum aestivum, L.). The utility of the virus as a vector for gene silencing and expression was assessed through sequence insertions in multiple sites of RNA2. Virus-induced photobleaching was observed in N. benthamiana but not in wheat, despite the stability of the inserts. The SBWMV infectious clone can be used for further studies to investigate the biology of SBWMV through mutagenesis. PMID- 27236460 TI - Complete genome sequence of a coxsackievirus B3 recombinant isolated from an aseptic meningitis outbreak in eastern China. AB - Coxsackievirus B3 (CV-B3) has frequently been associated with aseptic meningitis outbreaks in China. To identify sequence motifs related to aseptic meningitis and to construct an infectious clone, the genome sequence of 08TC170, a representative strain isolated from cerebrospinal fluid (CSF) samples from an outbreak in Shandong in 2008, was determined, and the coding regions for P1-P3 and VP1 were aligned. The first 21 and last 20 residues were "TTAAAACAGCCTGTGGGTTGT" and "ATTCTCCGCATTCGGTGCGG", respectively. The whole genome consisted of 7401 nucleotides, sharing 80.8 % identity with the prototype strain Nancy and low sequence similarity with members of clusters A-C. In contrast, 08TC170 showed high sequence similarity to members of cluster D. An especially high level of sequence identity (>=97.7 %) was found within a branch constituted by 08TC170 and four Chinese strains that clustered together in all of the P1-P3 phylogenic trees. In addition, 08TC170 also possessed a close relationship to the Hong Kong strain 26362/08 in VP1. Similarity plot analysis showed that 08TC170 was most similar to the Chinese CV-B3 strain SSM in P1 and the partial P2 coding region but to the CV-B5 or E-6 strain in 2C and following regions. A T277A mutation was found in 08TC170 and other strains isolated in 2008 2010, but not in strains isolated before 2008, which had high sequence similarity and formed the cluster A277. The results suggested that 08TC170 was the product of both intertypic recombination and point mutation, whose effects on viral neurovirulence will be investigated in a further study. The high homology between 08TC170 and other strains revealed their co-circulation in mainland China and Hong Kong and indicates that further surveillance is needed. PMID- 27236461 TI - Eukaryotic elongation factor 1-beta interacts with the 5' untranslated region of the M gene of Nipah virus to promote mRNA translation. AB - Nipah virus belongs to the genus Henipavirus in the family Paramyxoviridae, and its RNA genome is larger than those of other paramyxoviruses because it has long untranslated regions (UTRs) in each gene. However, the functions of these UTRs are not fully understood. In this study, we investigated the functions of the 5' UTRs and found that the 5' UTR of the M gene upregulated the translation of a reporter gene. Using an RNA pull-down assay, we showed that eukaryotic elongation factor 1-beta (EEF1B2) interacts with nucleotides 81-100 of the M 5' UTR and specifically enhances its translation efficiency. Our results suggest that the M 5' UTR promotes the production of M protein and viral budding by recruiting EEF1B2. PMID- 27236463 TI - Antifungal sourdough lactic acid bacteria as biopreservation tool in quinoa and rice bread. AB - The use of sourdough fermented with specific strains of antifungal lactic acid bacteria can reduce chemical preservatives in bakery products. The main objective of this study was to investigate the production of antifungal carboxylic acids after sourdough fermentation of quinoa and rice flour using the antifungal strains Lactobacillus reuteri R29 and Lactobacillus brevis R2Delta as bioprotective cultures and the non-antifungal L. brevis L1105 as a negative control strain. The impact of the fermentation substrate was evaluated in terms of metabolic activity, acidification pattern and quantity of antifungal carboxylic acids. These in situ produced compounds (n=20) were extracted from the sourdough using a QuEChERS method and detected by a new UHPLC-MS/MS chromatography. Furthermore, the sourdough was applied in situ using durability tests against environmental moulds to investigate the biopreservative potential to prolong the shelf life of bread. Organic acid production and TTA values were lowest in rice sourdough. The sourdough fermentation of the different flour substrates generated a complex and significantly different profile of carboxylic acids. Extracted quinoa sourdough detected the greatest number of carboxylic acids (n=11) at a much higher concentration than what was detected from rice sourdough (n=9). Comparing the lactic acid bacteria strains, L. reuteri R29 fermented sourdoughs contained generally higher concentrations of acetic and lactic acid but also the carboxylic acids. Among them, 3-phenyllactic acid and 2 hydroxyisocaproic acid were present at a significant concentration. This was correlated with the superior protein content of quinoa flour and its high protease activity. With the addition of L. reuteri R29 inoculated sourdough, the shelf life was extended by 2 days for quinoa (+100%) and rice bread (+67%) when compared to the non-acidified controls. The L. brevis R2Delta fermented sourdough bread reached a shelf life of 4 days for quinoa (+100%) and rice (+33%). However, the shelf life was similar to the chemically acidified control indicating that the preservation effect of the carboxylic acids seems to have a minor contribution effect on the antifungal activity in gluten-free breads. PMID- 27236462 TI - The importance of nerve microenvironment for schwannoma development. AB - Schwannomas are predominantly benign nerve sheath neoplasms caused by Nf2 gene inactivation. Presently, treatment options are mainly limited to surgical tumor resection due to the lack of effective pharmacological drugs. Although the mechanistic understanding of Nf2 gene function has advanced, it has so far been primarily restricted to Schwann cell-intrinsic events. Extracellular cues determining Schwann cell behavior with regard to schwannoma development remain unknown. Here we show pro-tumourigenic microenvironmental effects on Schwann cells where an altered axonal microenvironment in cooperation with injury signals contribute to a persistent regenerative Schwann cell response promoting schwannoma development. Specifically in genetically engineered mice following crush injuries on sciatic nerves, we found macroscopic nerve swellings in mice with homozygous nf2 gene deletion in Schwann cells and in animals with heterozygous nf2 knockout in both Schwann cells and axons. However, patient mimicking schwannomas could only be provoked in animals with combined heterozygous nf2 knockout in Schwann cells and axons. We identified a severe re myelination defect and sustained macrophage presence in the tumor tissue as major abnormalities. Strikingly, treatment of tumor-developing mice after nerve crush injury with medium-dose aspirin significantly decreased schwannoma progression in this disease model. Our results suggest a multifactorial concept for schwannoma formation-emphasizing axonal factors and mechanical nerve irritation as predilection site for schwannoma development. Furthermore, we provide evidence supporting the potential efficacy of anti-inflammatory drugs in the treatment of schwannomas. PMID- 27236464 TI - A risk modelling approach for setting microbiological limits using enterococci as indicator for growth potential of Salmonella in pork. AB - Microbiological limits are widely used in food processing as an aid to reduce the exposure to hazardous microorganisms for the consumers. However, in pork, the prevalence and concentrations of Salmonella are generally low and microbiological limits are not considered an efficient tool to support hygiene interventions. The objective of the present study was to develop an approach which could make it possible to define potential risk-based microbiological limits for an indicator, enterococci, in order to evaluate the risk from potential growth of Salmonella. A positive correlation between the concentration of enterococci and the prevalence and concentration of Salmonella was shown for 6640 pork samples taken at Danish cutting plants and retail butchers. The samples were collected in five different studies in 2001, 2002, 2010, 2011 and 2013. The observations that both Salmonella and enterococci are carried in the intestinal tract, contaminate pork by the same mechanisms and share similar growth characteristics (lag phase and maximum specific growth rate) at temperatures around 5-10 degrees C, suggest a potential of enterococci to be used as an indicator of potential growth of Salmonella in pork. Elevated temperatures during processing will lead to growth of both enterococci and, if present, also Salmonella. By combining the correlation between enterococci and Salmonella with risk modelling, it is possible to predict the risk of salmonellosis based on the level of enterococci. The risk model used for this purpose includes the dose-response relationship for Salmonella and a reduction factor to account for preparation of the fresh pork. By use of the risk model, it was estimated that the majority of salmonellosis cases, caused by the consumption of pork in Denmark, is caused by the small fraction of pork products that has enterococci concentrations above 5logCFU/g. This illustrates that our approach can be used to evaluate the potential effect of different microbiological limits and therefore, the perspective of this novel approach is that it can be used for definition of a risk-based microbiological limit for enterococci. The limit for enterococci can then be used for development of a process hygiene criterion in cutting plants and retail butcher shops, with the purpose of reducing the risk of Salmonella for the consumer. PMID- 27236465 TI - Microbial population analysis improves the evidential value of faecal traces in forensic investigations. AB - The forensic science community has a growing interest in microbial population analysis, especially the microbial populations found inside and on the human body. Both their high abundance, microbes outnumber human cells by a factor 10, and their diversity, different sites of the human body harbour different microbial communities, make them an interesting tool for forensics. Faecal material is a type of trace evidence which can be found in a variety of criminal cases, but is often being ignored in forensic investigations. Deriving a human short tandem repeat (STR) profile from a faecal sample can be challenging. However, the microbial communities within faecal material can be of additional criminalistic value in linking a faecal trace to the possible donor. We present a microarray technique in which the faecal microbial community is used to differentiate between faecal samples and developed a decision model to predict the possible common origin of questioned samples. The results show that this technique may be a useful additional tool when no or only partial human STR profiles can be generated. PMID- 27236466 TI - Comparison of RECIST, EORTC criteria and PERCIST for evaluation of early response to chemotherapy in patients with non-small-cell lung cancer. AB - PURPOSE: To compare the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, the European Organization for Research and Treatment of Cancer (EORTC) criteria and the Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) 1.0 using PET volume computer-assisted reading (PET VCAR) for response evaluation in patients with advanced non-small-cell lung cancer (NSCLC) treated with chemotherapy. METHODS: A total of 35 patients with NSCLC were included in this prospective study. All patients received standard chemotherapy and underwent (18)F-FDG PET/CT scans before and after treatment. With the assistance of PET VCAR, the chemotherapeutic responses were evaluated according to the RECIST 1.1, EORTC criteria and PERCIST 1.0. Concordance among these protocols was assessed using Cohen's kappa coefficient and Wilcoxon's signed-ranks test. Progression free survival (PFS) was calculated using the Kaplan-Meier test. RESULTS: RECIST 1.1 and EORTC response classifications were discordant in 20 patients (57.1 %; kappa = 0.194, P < 0.05), and RECIST 1.1 and PERCIST 1.0 classifications were discordant in 22 patients (62.9 %; kappa = 0.139, P < 0.05). EORTC and PERCIST 1.0 classifications were discordant in only 4 patients (11.4 %), resulting in better concordance (kappa = 0.804, P > 0.05). Patients with a partial remission according to RECIST 1.1 had significantly longer PFS (P < 0.001) than patients with progressive disease, but not significantly longer than patients with stable disease (P = 0.855). According to both the EORTC criteria and PERCIST 1.0, patients with a partial metabolic response had a significantly longer PFS than those with stable metabolic disease and those with progressive metabolic disease (P = 0.020 and P < 0.001, respectively, for EORTC; both P < 0.001 for PERCIST 1.0). CONCLUSION: EORTC criteria and PERCIST 1.0 are more sensitive and accurate than RECIST 1.1 for the detection of an early therapeutic response to chemotherapy in patients with NSCLC. Although EORTC criteria and PERCIST 1.0 showed similar results, PERCIST 1.0 is preferred because detailed and unambiguous definitions are given. We also found that response evaluations with PERCIST 1.0 using a single lesion and multiple lesions gave similar response classifications. PMID- 27236467 TI - Assessment of Health-Related Quality of Life Among Caregivers of Patients with Cancer Diagnosis: A Cross-Sectional Study in Saudi Arabia. AB - A descriptive cross-sectional survey was conducted over 5 months in two tertiary hospitals in Riyadh, Saudi Arabia. The 5-month period was from November 2014 to March 2015. The survey instrument used was a Short-Form Health Survey SF-36 (the RAND 36-item) questionnaire that measure QOL of the caregivers. Our study subjects included 289 randomly selected Saudi caregivers. Almost all the mean scores were increased (higher than 50) with the exception of levels of energy/fatigue. Role functioning/physical scored the highest (81.02 +/- 35.33) followed by physical functioning (76.34 +/- 29.83). Other domains of QOL scored (71.02 +/- 35.33) for the role functioning/emotional; pain (71.15 +/- 28.48), emotional well-being (60.58 +/- 18.44); social functioning (58.39 +/- 25.83), and general health (54.32 +/- 17.08). In multivariate regression analysis, the model predicts that the contributions of age, gender, and the cancer type of patients were a statistically significant predictor with the QOL domains of caregivers. Cancer caregivers in Saudi Arabia caring for patients more than 1 year after diagnosis reported favorable QOL. Factors associated with QOL domains included age, gender of the caregivers, and the types of cancer patients. These findings are encouraging as a baseline for providing more information to future studies in QOL of caregivers. PMID- 27236469 TI - A case of primary pulmonary choriocarcinoma successfully treated by surgery. AB - Primary pulmonary choriocarcinoma is a very rare tumor and eventually diagnosed by pulmonary resection. A poor prognosis has been reported for this disease, but appropriate treatment has not been established. Here, we report the successful surgical treatment for a primary pulmonary choriocarcinoma. A 70-year-old male presented with cough and a 3.8-cm solid tumor was detected in the right upper lobe of the lung on CT scan. Results of an open lung biopsy indicated carcinoma with indeterminate histological subtype. Right upper lobectomy was performed and the permanent pathological diagnosis was choriocarcinoma. Right after surgery, systemic and genital screening was performed by urologist, but no abnormal findings were observed. Elevation of serum beta-hCG was confirmed at the same time and the value dropped within normal range in 2 months. According to diagnosis criteria, we reached final diagnosis of primary pulmonary choriocarcinoma. The patient has been alive with no recurrence for 2 years after surgery. PMID- 27236470 TI - Factor structure and psychometric properties of the Body Appreciation Scale-2 in Iran. AB - Tylka and Wood-Barcalow (2015b) developed the Body Appreciation Scale-2 (BAS-2) as a psychometrically robust measure that is conceptually consistent with recent findings on positive body image. The present study aimed to examine the factor structure and psychometric properties of the BAS-2 in Iran. Participants were 568 men and 525 women from seven universities in Tehran, Iran. Two exploratory factor analyses were performed on data from women and men separately. Similar to the original English version, the Persian BAS-2 had a one-factor solution. Persian BAS-2 scores had satisfactory convergent validity (indexed by significantly correlations with self-esteem and life satisfaction) and internal consistency. Men had significantly higher scores on BAS-2 compared to women. The present study suggests that the Persian BAS-2 has adequate psychometric properties to assess body appreciation. PMID- 27236468 TI - A clinical and biological perspective of human myeloid-derived suppressor cells in cancer. AB - Considering the large number of studies focused on myeloid-derived suppressor cells (MDSCs) to date, only a handful of well-defined relationships in human cancer have been established. The difficulty of assessing the impact of MDSCs in human cancer is partly due to the relatively small number of studies performed in humans. This is compounded in the literature by a common lack of clear indication of which species is being referred to for each characteristic described. These aspects may result in inappropriate extrapolation of animal studies to those in the human setting. This is especially the case for studies focused on investigating therapies which can be used to target MDSCs or those aimed at understanding their mechanism. Here, we attempt to rectify this by reviewing only studies on MDSC performed in humans. We survey studies which explore (1) whether MDSC levels are altered in cancer patients and if this is correlated with patient survival, (2) the so far identified mechanisms employed by MDSC to exert immune suppression, and (3) whether therapeutic agents can be used to target MDSCs by either altering their level, influencing their differentiation or inhibiting their suppressive function. Despite the fact that these studies clearly show that MDSCs are important in human cancer, the clinical employment of agents intended to target them has not yet been accomplished. We identify factors which have contributed to this and propose steps which may facilitate the translation of these therapies to the clinic in future. PMID- 27236471 TI - "You better not leave me shaming!": Conditional indirect effect analyses of anti fat attitudes, body shame, and fat talk as a function of self-compassion in college women. AB - The present investigation provided a theoretically-driven analysis testing whether body shame helped account for the predicted positive associations between explicit weight bias in the form of possessing anti-fat attitudes (i.e., dislike, fear of fat, and willpower beliefs) and engaging in fat talk among 309 weight diverse college women. We also evaluated whether self-compassion served as a protective factor in these relationships. Robust non-parametric bootstrap resampling procedures adjusted for body mass index (BMI) revealed stronger indirect and conditional indirect effects for dislike and fear of fat attitudes and weaker, marginal effects for the models inclusive of willpower beliefs. In general, the indirect effect of anti-fat attitudes on fat talk via body shame declined with increasing levels of self-compassion. Our preliminary findings may point to useful process variables to target in mitigating the impact of endorsing anti-fat prejudice on fat talk in college women and may help clarify who is at higher risk. PMID- 27236472 TI - Stress exposure and generation: A conjoint longitudinal model of body dysmorphic symptoms, peer acceptance, popularity, and victimization. AB - This study examined the bidirectional (conjoint) longitudinal pathways linking adolescents' body dysmorphic disorder (BDD) symptoms with self- and peer-reported social functioning. Participants were 367 Australian students (45.5% boys, mean age=12.01 years) who participated in two waves of a longitudinal study with a 12 month lag between assessments. Participants self-reported their symptoms characteristic of BDD, and perception of peer acceptance. Classmates reported who was popular and victimized in their grade, and rated their liking (acceptance) of their classmates. In support of both stress exposure and stress generation models, T1 victimization was significantly associated with more symptoms characteristic of BDD at T2 relative to T1, and higher symptom level at T1 was associated with lower perceptions of peer acceptance at T2 relative to T1. These results support the hypothesized bidirectional model, whereby adverse social experiences negatively impact symptoms characteristic of BDD over time, and symptoms also exacerbate low perceptions of peer-acceptance. PMID- 27236473 TI - Little girls in a grown up world: Exposure to sexualized media, internalization of sexualization messages, and body image in 6-9 year-old girls. AB - Despite widespread public concern about the early sexualization of young girls, as yet there has been little empirical examination of potential negative effects. In the present study a sample of 300 6-9 year-old girls completed individual interviews assessing exposure to sexualized media, internalization of sexualized messages (measured via preference for sexualized clothing), and body image attitudes (body esteem, body dissatisfaction). Exposure to sexualized media was found to be correlated with internalization of sexualization messages, itself correlated with negative body image. The findings provide preliminary evidence that sexualized messages appear to be internalized by very young girls which, in turn, has negative implications for how they feel about their bodies. PMID- 27236474 TI - Translation and psychometric evaluation of a Standard Chinese version of the Body Appreciation Scale-2. AB - The present study examined the factorial and construct validity of a Standard Chinese translation of the Body Appreciation Scale (BAS-2; Tylka & Wood-Barcalow, 2015b). Participants were 191 women and 154 men from mainland China who were resident in Hong Kong at the time of recruitment. Results of confirmatory factor analysis indicated that the one-dimensional model of the BAS-2, in which all 10 items loaded onto the same factor, had adequate fit, and was invariant across sex. Body appreciation scores had good internal consistency and were significantly correlated with self-esteem and life satisfaction, and, in women, with weight discrepancy and body mass index. There were no significant differences in body appreciation scores between women and men. The present findings suggest that the Standard Chinese translation of the BAS-2 has the same one-dimensional factor structure as its parent scale and may facilitate cross cultural studies of positive body image. PMID- 27236475 TI - Do parents or siblings engage in more negative weight-based talk with children and what does it sound like? A mixed-methods study. AB - The current mixed-methods study examined the prevalence of negative weight-based talk across multiple family members (i.e., mother, father, older/younger brother, older/younger sister) and analyzed qualitative data to identify what negative weight-based talk sounds like in the home environment. Children (n=60; ages 9-12) and their families from low income and minority households participated in the study. Children reported the highest prevalence of negative weight-based talk from siblings. Among specific family members, children reported a higher prevalence of negative weight-based talk from mothers and older brothers. In households with younger brothers, children reported less negative weight-based talk compared to other household compositions. Both quantitative and qualitative results indicated that mothers' negative weight-based talk focused on concerns about child health, whereas fathers' and siblings' negative weight-based talk focused on child appearance and included teasing. Results suggest that interventions targeting familial negative weight-based talk may need to be tailored to specific family members. PMID- 27236476 TI - Embodied possibilities and disruptions: The emergence of the Experience of Embodiment construct from qualitative studies with girls and women. AB - There are multiple indicators of disruption in the way girls and women inhabit their bodies. The qualitative research program examined lived experiences of embodiment among girls and women by conducting 171 interviews with 69 girls and women in three different studies: (a) A life history study of 30 interviews with 11 women, ages 20-27; (b) A 5-year prospective interview study of 87 interviews with 27 girls, ages 9-14 in the first phase of the study; and (c) A life history study of 54 interviews with 31 women, ages 50-68. Data analyses used a constructivist grounded theory approach. In all three studies the emergent core construct of Experience of Embodiment had five central dimensions, each with a positive and negative pole. These dimensions included: body-self connection, agency, desire, self-attunement, and resisting objectification. The Experience of Embodiment provides a new, integrated perspective on ways girls and women inhabit their bodies. PMID- 27236477 TI - Efforts to slacken antibiotic resistance: Labeling meat products from animals raised without antibiotics in the United States. AB - As bacteria and diseases spread due to climatic change, greater amounts of antibiotics will be used thereby exacerbating the problem of antibiotic resistance. To help slacken the development of resistant bacteria, the medical community is attempting to reduce unnecessary and excessive usage of antibiotics. One of the targets is the use of antibiotics for enhancing animal growth and promoting feed efficiency in the production of food animals. While governments can adopt regulations prohibiting nontherapeutic uses of antibiotics in food animals and strategies to reduce antibiotic usage, another idea is to publicize when antibiotics are used in food animal production by allowing labeled meat products. This paper builds upon existing labeling and marketing efforts in the United States to show how a government can develop a verified antibiotic-free labeling program that would allow consumers to purchase meat products from animals that had never received antibiotics. PMID- 27236479 TI - The National Adult Immunization Plan: Strengthening Adult Immunization Through Coordinated Action. PMID- 27236478 TI - Medical students' health behaviour and self-reported mental health status by their country of origin: a cross-sectional study. AB - BACKGROUND: Numerous previous studies have investigated the lifestyle and self perceived health status of medical students. This study examined whether students' country of origin contributed to their mental health and health risk behaviour. METHODS: We conducted our cross-sectional questionnaire survey over four consecutive years (2009-2012). The target population was fourth-year English and Hungarian-language course medical students at Semmelweis University, Hungary. We gathered data on medical students' health behaviour (tobacco smoking, alcohol consumption, dietary habits and exercise) and mental health status and used analysis of variance (ANOVA) to examine the association between country of origin and mental health. RESULTS: The response rate was 76.1 % for the Hungarian and 63.4 % for the English course students. The mean age of our sample was 24.1 years (SD = 2.42). Only 15.3 % of students reported following dietary recommendations, but 75.0 % reported engaging in vigorous and regular physical exercise. The prevalence of tobacco smoking was 18.6 % and 13.8 % overconsumed alcoholic beverages. Hungarian and Iranian students reported lower mental well being than Mediterranean, Israeli and Scandinavian students (F(4) = 18.943, p < 0.001, eta(2) = 0.103). Results of the multiway ANOVA indicated that both country of origin and exercise showed a significant relationship with mental health: vigorous exercise was associated with better mental health status (F(1) = 5.505, p = 0.019). CONCLUSIONS: Medical students' mental health and health behaviour are associated with multiple factors. One of these is country of origin but exercise may also influence mental health. Health promotion programmes organised for medical students should take their country of origin into consideration and should include physical activity. PMID- 27236481 TI - Polyoxometalate incorporated porous polymer monoliths, a versatile separation media for nano liquid chromatography. AB - Here in, we present a strategy to incorporate NBu4SiW11O39(SiCHCH2)2, an organic modified polyoxometalates (POM) monomer, into the monolithic poly(butyl methacrylate-co-ethylene glycol dimethacrylate) capillary columns. SEM analysis and permeability test indicated that the addition of POM lead to larger skeleton size and better permeability. BET and pore size distribution test confirmed the uniform porosity of the resulting POM incorporated monoliths. Hydrophobic, strong cation-exchange and H-bond interactions of the prepared monolith were evaluated by testing a series of chromatographic probes. The performance of monolith was further elaborated by separating 5 nucleobases, and 6 neurotransmitters. Chromatographic separation results showed that POM incorporated monolith exhibited much better resolution for the analytes as compared to the monolith without POM. This type of monolithic material has been reported for the first time and the work provided a promising way for preparation and application of various POM-incorporated monolithic materials in separation science. PMID- 27236480 TI - Urine sodium concentration to predict fluid responsiveness in oliguric ICU patients: a prospective multicenter observational study. AB - BACKGROUND: Oliguria is one of the leading triggers of fluid loading in patients in the intensive care unit (ICU). The purpose of this study was to assess the predictive value of urine Na(+) (uNa(+)) and other routine urine biomarkers for cardiac fluid responsiveness in oliguric ICU patients. METHODS: We conducted a prospective multicenter observational study in five university ICUs. Patients with urine output (UO) <0.5 ml/kg/h for 3 consecutive hours with a mean arterial pressure >65 mmHg received a fluid challenge. Cardiac fluid responsiveness was defined by an increase in stroke volume >15 % after fluid challenge. Urine and plasma biochemistry samples were examined before fluid challenge. We examined renal fluid responsiveness (defined as UO > 0.5 ml/kg/h for 3 consecutive hours) after fluid challenge as a secondary endpoint. RESULTS: Fifty-four patients (age 51 +/- 37 years, Simplified Acute Physiology Score II score 40 +/- 20) were included. Most patients (72 %) were not cardiac responders (CRs), and 50 % were renal responders (RRs) to fluid challenge. Patient characteristics were similar between CRs and cardiac nonresponders. uNa(+) (37 +/- 38 mmol/L vs 25 +/- 75 mmol/L, p = 0.44) and fractional excretion of sodium (FENa(+)) (2.27 +/- 2.5 % vs 2.15 +/- 5.0 %, p = 0.94) were not statistically different between those who did and those who did not respond to the fluid challenge. Areas under the receiver operating characteristic (AUROC) curves were 0.51 (95 % CI 0.35-0.68) and 0.56 (95 % CI 0.39-0.73) for uNa(+) and FENa(+), respectively. Fractional excretion of urea had an AUROC curve of 0.70 (95 % CI 0.54-0.86, p = 0.03) for CRs. Baseline UO was higher in RRs than in renal nonresponders (1.07 +/- 0.78 ml/kg/3 h vs 0.65 +/- 0.53 ml/kg/3 h, p = 0.01). The AUROC curve for RRs was 0.65 (95 % CI 0.53 0.78) for uNa(+). CONCLUSIONS: In the present study, most oliguric patients were not CRs and half were not renal responders to fluid challenge. Routine urinary biomarkers were not predictive of fluid responsiveness in oliguric normotensive ICU patients. PMID- 27236482 TI - Multiple capillary isotachophoresis with repetitive hydrodynamic injections for performance improvement of the electromigration preconcentration. AB - A novel electrokinetic preconcentration technique based on multiple isotachophoresis (M-ITP) realised in a micro-bored capillary to improve sensitivity for capillary electrophoresis with hydrodynamic injection was developed. The M-ITP operation relies on pressure-assisted pushing of a preconcentrated sample plug after the first ITP process back to the injection end of the capillary, followed by a large volume hydrodynamic injection prior to application of the second ITP step. This operational cycle was repeated as many times as desired with very good repeatability of the peak areas and peak heights at each ITP round (RSD less than 8%). Using imidazole and benzoate as models for cationic and anionic analytes, important insights into the mechanism of this electrokinetic preconcentration process with and without the presence of the electro-osmotic flow (EOF) at acidic and basic conditions were provided. Stacking of the benzoate ion, selected as one model analyte, in the presence of EOF and from a sample plug representing up to 300% of the total capillary length was successfully demonstrated. M-ITP was then demonstrated through the enrichment of the Abeta 1-40 amyloid peptide, considered as one of the biomarkers for biochemical diagnosis of Alzheimer's disease. Quantification of Abeta 1-40 down to 50nM with UV detection was made possible with 6 M-ITP cycles. PMID- 27236484 TI - Solid-phase microextraction may catalize hydrogenation when using hydrogen as carrier in gas chromatography. AB - When hydrogen is used as carrier gas, carbon-carbon double bonds may be hydrogenated in the hot gas chromatograph (GC) injector if introduced by solid phase microextraction (SPME). SPME fibers coated with polydimethylsiloxane (PDMS)/carboxen/divinylbenzene (DVB), PDMS/carboxen, polyacrylate, PDMS/DVB and PDMS on fused silica, stableflex or metal alloy core have been tested with fatty acid methyl esters (FAMEs) from olive oil. Using coatings containing DVB, hydrogenation took place with high conversion rates (82.0-92.9%) independently of the core material. With all fibers having a metal core, hydrogenation was observed to a certain extent (27.4-85.3%). PDMS, PDMS/carboxen and polyacrylate coated fibers with a fused silica or stableflex core resulted in negligible hydrogenation (0.2-2.5%). The occurrence of hydrogenation was confirmed also with other substances containing carbon-carbon double bonds (n-alkenes, alkenoic acids, mono- and polyunsaturated fatty acid methyl and ethyl esters). PMID- 27236483 TI - Quantification of cannabinoids and their free and glucuronide metabolites in whole blood by disposable pipette extraction and liquid chromatography-tandem mass spectrometry. AB - Identifying recent cannabis intake is confounded by prolonged cannabinoid excretion in chronic frequent cannabis users. We previously observed detection times <=2.1h for cannabidiol (CBD) and cannabinol (CBN) and Delta(9) tetrahydrocannabinol (THC)-glucuronide in whole blood after smoking, suggesting their applicability for identifying recent intake. However, whole blood collection may not occur for up to 4h during driving under the influence of drugs investigations, making a recent-use marker with a 6-8h detection window helpful for improving whole blood cannabinoid interpretation. Other minor cannabinoids cannabigerol (CBG), Delta9-tetrahydrocannabivarin (THCV), and its metabolite 11 nor-9-carboxy-THCV (THCVCOOH) might also be useful. We developed and validated a sensitive and specific liquid chromatography-tandem mass spectrometry method for quantification of THC, its phase I and glucuronide phase II metabolites, and 5 five minor cannabinoids. Cannabinoids were extracted from 200MUL whole blood via disposable pipette extraction, separated on a C18 column, and detected via electrospray ionization in negative mode with scheduled multiple reaction mass spectrometric monitoring. Linear ranges were 0.5-100MUg/L for THC and 11-nor-9 carboxy-THC (THCCOOH); 0.5-50MUg/L for 11-hydroxy-THC (11-OH-THC), CBD, CBN, and THC-glucuronide; 1-50MUg/L for CBG, THCV, and THCVCOOH; and 5-500MUg/L for THCCOOH-glucuronide. Inter-day accuracy and precision at low, mid and high quality control (QC) concentrations were 95.1-113% and 2.4-8.5%, respectively (n=25). Extraction recoveries and matrix effects at low and high QC concentrations were 54.0-84.4% and -25.8-30.6%, respectively. By simultaneously monitoring multiple cannabinoids and metabolites, identification of recent cannabis administration or discrimination between licit medicinal and illicit recreational cannabis use can be improved. PMID- 27236485 TI - Gas chromatography/atmospheric pressure chemical ionization/mass spectrometry for the analysis of organochlorine pesticides and polychlorinated biphenyls in human serum. AB - A method using a novel atmospheric pressure chemical ionization source for coupling gas chromatography (GC/APCI) to triple quadrupole mass spectrometry (MS/MS) for the determination of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) regulated by the Stockholm Convention is presented. One microliter injection of a six-point calibration curve of native PCBs and OCPs, ranging from 0.04 to 300pg/MUL, was performed. The relative standard deviation (RSD) of the relative response factors (RRFs) was less than 15% with a coefficient of determination (r(2))>0.995. Meanwhile, two calibration solutions (CS), CS 2 (0.4pg/MUL) and CS 3 (4pg/MUL) were analyzed to study the repeatability calculated for both area and RRFs. The RSD for RRF ranged from 3.1 to 16% and 3.6 to 5.5% for CS 2 and CS 3, respectively. The limits of detection (LOD) determined by peak-to-peak signal-to-noise ratio (S/N) of 3 were compared between the GC/APCI/MS/MS and a GC coupled to high resolution mass spectrometry (GC/HRMS) system. GC/APCI/MS/MS resulted in lower LOD for most of the compounds, except for PCB#74, cis-chlordane and trans-chlordane. GC/APCI/MS/MS and GC/HRMS were also compared by performing analysis on 75 human serum samples together with eight QA/QC serum samples. The comparison between GC/APCI/MS/MS system and GC/HRMS system for 16 of the targeted compounds was carried out. No statistically significant difference was discovered. Due to increased sensitivity and user friendly operation under atmospheric pressure, GC/APCI/MS/MS is a powerful alternative technique that can easily meet the specification of GC/HRMS. PMID- 27236486 TI - Single dose testosterone administration reduces loss chasing in healthy females. AB - Testosterone has been linked to modulation of impulsivity and risky choice, potentially mediated by changes in reward or punishment sensitivity. This study investigated the effect of testosterone on risk-taking and the adjustment of risk taking on trials following a gain or a loss. Loss chasing is operationalized herein as the propensity to recover losses by increasing risky choice. Healthy female participants (n=26) received a single-dose of 0.5mg sublingual testosterone in a double-blind, placebo-controlled crossover design. At 240min post-administration, participants performed a gambling task with a high and a low risk option. In the placebo condition, participants were more likely to choose the high risk option following losses compared to wins. This effect was abolished on the testosterone session. Ignoring prior outcomes, no overall changes in risk taking were observed. Our data indicate that testosterone affects human decision making via diminishing sensitivity to punishment. PMID- 27236487 TI - Longitudinal pattern of early maturation on morning cortisol and depressive symptoms: Sex-specific effects. AB - There is still insufficient understanding of the underlying processes that contribute to internalizing problems of early maturing adolescents. The purpose of this study is to examine the longitudinal pattern of early maturation and its effects on morning cortisol and depressive symptoms among a general population of adolescent cohort aged 8-11 years old at baseline (boys=424, girls=288). Results suggest newly-onset early maturation boys have 3-times more likely to have depressive symptoms at 1-year follow-up (adjusted odds ratio=3.197, 95% confidence interval=1.595-6.405); while in girls, stable early maturation individuals are more than 4 times as likely to have depressive symptoms (adjusted odds ratio=4.566, 95% confidence interval=1.882-11.077). Morning cortisol has moderating effects in the association of depressive symptoms with newly-onset early maturation in boys and stable early maturation in girls. These findings possibly explain current inconsistent results regarding association between earlier maturation and risk of depression in adolescents. Further longitudinal studies are needed to explore HPG-HPA interactions in adolescence, which may be critical to understanding the heightened susceptibility of mental health problems. PMID- 27236488 TI - Rare Cause of Chest Discomfort and Modest Exercise Intolerance in an Athlete. PMID- 27236489 TI - Reply: AKI Classification: One Size Doesn't Fit All. PMID- 27236490 TI - Obesity Does Not Affect Propofol Pharmacokinetics During Hypothermic Cardiopulmonary Bypass. AB - OBJECTIVE: Because of the lack of data regarding the impact of obesity on propofol pharmacokinetics in patients undergoing cardiac surgery using hypothermic cardiopulmonary bypass (CPB), the authors sought to explore propofol pharmacokinetics and develop a predictive pharmacokinetic model that characterizes and predicts propofol pharmacokinetics in this population. DESIGN: A prospective, observational study. SETTING: A teaching hospital. PARTICIPANTS: The study comprised 17 obese and 17 control (nonobese) patients undergoing hypothermic CPB. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Patients mainly underwent valve surgery. On initiation of hypothermic CPB (28 degrees C-32 degrees C), patients received a propofol (1%) bolus (1 mg/kg) immediately followed by a 2 mg/kg/h infusion. Blood samples were withdrawn at the following times: before dosing; 1, 3, 5, and 7 minutes after the propofol bolus dose; every 20 minutes during infusion; just before discontinuation of the infusion; and at 1, 3, 5, 7, 10, 20, 30, and 60 minutes after discontinuation of the infusion. The plasma propofol concentration was determined using high-performance liquid chromatography, and then data were imported into Monolix (Lixoft, Antony, France) for population pharmacokinetic modeling and pharmacokinetic parameters estimation. A 2-compartment pharmacokinetic model with age as a covariate on the peripheral volume of distribution (V2) best described the pooled data. The pooled data was internally evaluated successfully to describe and predict propofol pharmacokinetics in the addressed population. Propofol clearance, intercompartmental clearance, and central volume of distribution were 805 mL/min, 1140 mL/min and 18.8 L, respectively. V2 was calculated as 9.86*exp.(1.88*[age/40]) L. CONCLUSION: Propofol pharmacokinetic parameters were similar in obese and nonobese patients undergoing hypothermic CPB. Age was the major determinant of propofol V2 in the obese population. PMID- 27236491 TI - The Relationship Between Preoperative Hemoglobin Concentration, Use of Hospital Resources, and Outcomes in Cardiac Surgery. AB - OBJECTIVES: Preoperative anemia is an established risk factor associated with adverse perioperative outcomes after cardiac surgery. However, limited information exists regarding the relationship between preoperative hemoglobin concentration and outcomes. The aim of this study was to investigate how outcomes are affected by preoperative hemoglobin concentration in a cohort of patients undergoing cardiac surgery. DESIGN: A retrospective, observational cohort study. SETTING: A single-center tertiary referral hospital. PARTICIPANTS: The study comprised 1,972 adult patients undergoing elective and nonelective cardiac surgery. INTERVENTIONS: The independent relationship of preoperative hemoglobin concentration was explored on blood transfusion rates, return to the operating room for bleeding and/or cardiac tamponade, postoperative intensive care unit (ICU) and in-hospital length of stay, and mortality. MEASUREMENTS AND MAIN RESULTS: The overall prevalence of anemia was 32% (629/1,972 patients). For every 1-unit increase in hemoglobin (g/dL), blood transfusion requirements were reduced by 11%, 8%, and 3% for red blood cell units, platelet pools, and fresh frozen plasma units, respectively (adjusted incident rate ratio 0.89 [95% CI 0.87-0.91], 0.92 [0.88-0.97], and 0.97 [0.96-0.99]). For each 1-unit increase in hemoglobin (g/dL), the probability (over time) of discharge from the ICU and hospital increased (adjusted hazard ratio estimates 1.04 [1.00-1.08] and 1.12 [1.12-1.16], respectively). CONCLUSIONS: A lower preoperative hemoglobin concentration resulted in increased use of hospital resources after cardiac surgery. Each g/dL unit fall in preoperative hemoglobin concentration resulted in increased blood transfusion requirements and increased postoperative ICU and hospital length of stay. PMID- 27236492 TI - 3-Factor Prothrombin Complex Concentrates in Infants With Refractory Bleeding After Cardiac Surgery. PMID- 27236493 TI - A fundamental study on biological removal of N2O in the presence of oxygen. AB - The biodegradation of N2O by a non-acclimated secondary activated sludge in the presence of O2 was studied. Batch tests with a headspace containing an initial N2O concentration of ~400 mg m(-3) (~200 ppmv) and initial O2 gas concentrations of 0%, 1%, 2%, 5% and 21% were investigated. The effect of O2 on the biokinetic parameters qmax (maximum specific N2O uptake rate) and KS (half-saturation constant), as well as on the bacterial population structure, was evaluated. A complete N2O removal was recorded in the presence of up to 2% O2, while O2 at 5% and 21% mediated inhibitions of 37% and 95% in the removal of N2O compared with the control without O2. The elemental analysis of the biomass obtained at the end of the batch tests strongly suggested that NN2O was not used as a nitrogen source. The presence of O2 mediated decreases of up to 12.6- and 4.8-fold in qmax and KS, respectively, compared to the control without O2. Likewise, the presence of O2 induced changes in the structure of the bacterial population. The predominant microorganisms in the presence of O2 belonged to the phyla Proteobacteria, Firmicutes and Chlamydiae. Bacteria belonging to the Proteobacteria phylum, particularly the Dokdonella genus, were predominant at 2% O2, which was the highest O2 concentration without inhibitory effects on N2O biodegradation. PMID- 27236495 TI - Re: Alison J. Price, Ruth C. Travis, Paul N. Appleby, et al. Circulating Folate and Vitamin B12 and Risk of Prostate Cancer: A Collaborative Analysis of Individual Participant Data from Six Cohorts Including 6875 Cases and 8104 Controls. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2016.03.029: Serum Concentrations of Folate and Vitamin B12 and the Risk of Prostate Cancer According to Pooled Data: The Devil Is in the Detail. PMID- 27236494 TI - Microplastic interactions with freshwater microalgae: Hetero-aggregation and changes in plastic density appear strongly dependent on polymer type. AB - In this study, the interactions between microplastics, chosen among the most widely used in industry such as polypropylene (PP) and high-density polyethylene (HDPE), and a model freshwater microalgae, Chlamydomas reinhardtii, were investigated. It was shown that the presence of high concentrations of microplastics with size >400 MUm did not directly impact the growth of microalgae in the first days of contact and that the expression of three genes involved in the stress response was not modified after 78 days. In parallel, a similar colonization was observed for the two polymers. However, after 20 days of contact, in the case of PP only, hetero-aggregates constituted of microalgae, microplastics and exopolysaccharides were formed. An estimation of the hetero aggregates composition was approximately 50% of PP fragments and 50% of microalgae, which led to a final density close to 1.2. Such hetero-aggregates appear as an important pathway for the vertical transport of PP microplastics from the water surface to sediment. Moreover, after more than 70 days of contact with microplastics, the microalgae genes involved in the sugar biosynthesis pathways were strongly over-expressed compared to control conditions. The levels of over-expression were higher in the case of HDPE than in PP condition. This work presents the first evidence that depending on their chemical nature, microplastics will follow different fates in the environment. PMID- 27236496 TI - The Role of Multiparametric Magnetic Resonance Imaging/Ultrasound Fusion Biopsy in Active Surveillance. AB - BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI)/ultrasound fusion biopsy (targeted biopsy or TB) may improve detection of high-grade cancers when compared to systematic biopsy (SB). OBJECTIVE: To assess TB in active surveillance (AS). DESIGN, SETTING, AND PARTICIPANTS: We retrospectively evaluated SB (12-core sector) and TB among 103 AS men undergoing surveillance biopsy, 54 men undergoing confirmatory biopsy (CB), and 73 men referred for diagnostic biopsy (DB; comparison group). Regions of interest (ROIs) on mpMRI were assigned a PI-RADS score and targeted if the score was >=3. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Detection of Gleason score (GS) >=7 by TB and SB was the outcome of interest, except in a multivariable model, for which any cancer was the outcome. RESULTS AND LIMITATIONS: GS >=7was detected by either biopsy method in 25 men (24.3%) in the AS group, 12 men (22.2%) in the CB group, and 55 men (75.3%) in the DB group.GS >=7 was found in 24.3% by SB + TB versus 20.4% by SB in the AS group (p=0.13); in 22.2% by SB + TB versus 16.7% by SB in the CB group (p=0.25); and in 75.3% by SB + TB versus 58.9% by SB in the DB group (p=0.002). The sensitivity for GS >=7 detection was lower for TB than for SB (p=0.006) in the AS cohort (relative sensitivity ratio 0.33, 95% confidence interval 0.16-0.71). Higher PI-RADS score (4 vs 3, odds ratio [OR] 2.00, p=0.04; 5 vs 3, OR 4.74, p=0.02), lower MRI-estimated prostate volume (OR 1.20 per 10-cm3 lower volume, p=0.01), larger ROI (OR 1.04 per mm, p=0.02), and right-sided ROI (OR 2.27, p=0.01) were associated with finding cancer on TB. A potential limitation is that not all men who presented for biopsy underwent TB and the urologist was not blinded to MRI results before SB. CONCLUSIONS: Owing to the low relative sensitivity of mpMRI for detection of GS >=7 disease, SB still needs to be performed for men on AS. PATIENT SUMMARY: This study suggests that image guided prostate biopsy alone may not be informative for men enrolled in an active surveillance program for prostate cancer. PMID- 27236497 TI - Measuring Clinical Outcomes in Overactive Bladder Interventions: We Can Do Better. PMID- 27236498 TI - Anaphylactic reactions associated with omalizumab administration: Analysis of a case-control study. PMID- 27236499 TI - Epigenome-wide association study links site-specific DNA methylation changes with cow's milk allergy. PMID- 27236500 TI - Aeroallergen-induced IL-33 predisposes to respiratory virus-induced asthma by dampening antiviral immunity. AB - BACKGROUND: Frequent viral lower respiratory infections in early life are an independent risk factor for asthma onset. This risk and the development of persistent asthma are significantly greater in children who later become sensitized. OBJECTIVE: We sought to elucidate the pathogenic processes that underlie the synergistic interplay between allergen exposures and viral infections. METHODS: Mice were inoculated with a murine-specific Pneumovirus species (pneumonia virus of mice [PVM]) and exposed to low-dose cockroach extract (CRE) in early and later life, and airway inflammation, remodeling, and hyperreactivity assessed. Mice were treated with anti-IL-33 or apyrase to neutralize or block IL-33 release. RESULTS: PVM infection or CRE exposure alone did not induce disease, whereas PVM/CRE coexposure acted synergistically to induce the hallmark features of asthma. CRE exposure during viral infection in early life induced a biphasic IL-33 response and impaired IFN-alpha and IFN lambda production, which in turn increased epithelial viral burden, airway smooth muscle growth, and type 2 inflammation. These features were ameliorated when CRE induced IL-33 release was blocked or neutralized, whereas substitution of CRE with exogenous IL-33 recapitulated the phenotype observed in PVM/CRE-coexposed mice. Mechanistically, IL-33 downregulated viperin and interferon regulatory factor 7 gene expression and rapidly degraded IL-1 receptor-associated kinase 1 expression in plasmacytoid dendritic cells both in vivo and in vitro, leading to Toll-like receptor 7 hyporesponsiveness and impaired IFN-alpha production. CONCLUSION: We identified a hitherto unrecognized function of IL-33 as a potent suppressor of innate antiviral immunity and demonstrate that IL-33 contributes significantly to the synergistic interplay between respiratory virus and allergen exposures in the onset and progression of asthma. PMID- 27236501 TI - Complications in unilateral versus bilateral deep inferior epigastric artery perforator flap breast reconstructions: A multicentre study. AB - BACKGROUND: The deep inferior epigastric artery perforator (DIEP) flap is the first choice for autologous breast reconstruction. The aim of this retrospective cohort study was to analyse the recipient- and donor-site complications and compare them between unilateral and bilateral DIEP flap breast reconstructions. METHODS: Between January 2010 and December 2014, 530 DIEP flap reconstructions were performed in 426 consecutive patients in three Dutch hospitals. Major and minor complications were categorised into recipient- and donor-site complications. Post-operative flap re-explorations were recorded. RESULTS: Of the total 530 DIEP flap reconstructions performed (322 unilateral, 104 bilateral), recipient-site complications were major in 9.8% and minor in 20.2%. The patients developed fat necrosis (unilateral 14.0% vs. bilateral 7.7%; OR 1.950; 95% CI 1.071-3.550; p = 0.027) and infection (unilateral 5.6% vs. bilateral 1.9%; OR 3.020; 95% CI 1.007-9.052; p = 0.039) at the recipient site significantly more frequently in the unilateral DIEP flap reconstructions. The donor-site complications were major in 0.9% and minor in 19.5% of the cases. Body mass index (BMI) was significantly associated with complications (donor site: OR 1.137; 95% CI 1.075-1.201; p < 0.001, recipient site: OR 1.073; 95% CI 1.009-1.142; p = 0.026). Flap re-explorations were performed in 5.7% (n = 30) of the cases. Total flap loss occurred in 3.0% (n = 16) of the cases. CONCLUSIONS: Bilateral DIEP flap breast reconstructions can be performed with the same percentage of complications and re-explorations as unilateral reconstructions and even result in less fat necrosis and infection at the recipient site. Higher BMIs are significantly associated with recipient- and donor-site complications. PMID- 27236502 TI - Matthews device arthroplasty presents superior long-term mouth opening than interpositional arthroplasty in the management of temporomandibular joint ankylosis. AB - BACKGROUND: The aim of this study is to describe the surgical outcomes of a single-institution experience in the surgical management of temporomandibular joint ankylosis, comparing interpositional arthroplasty with autogenous tissue and Matthews device arthroplasty. METHODS: A retrospective analysis of temporomandibular joint ankylosis patients (n = 15), who underwent interpositional arthroplasty or Matthews device arthroplasty, was conducted. The surgical outcomes (preoperative, recent [4-6 weeks], intermediate [1 year], and late [3 years] postoperative maximal incisal opening, hospital stay, and complication, relapse, and reoperation rates) were compared. RESULTS: Significant (all p < 0.05) differences were recorded in temporomandibular joint ankylosis patients treated with interpositional arthroplasty with autogenous tissue (53.3%) versus Matthews device arthroplasty (46.7%) according to intermediate (25 +/- 7 vs. 34 +/- 5 mm) and late (19 +/- 8 vs. 33 +/- 5 mm) postoperative maximal incisal opening, intermediate (31% vs. 7%) and late (47% vs. 12%) postoperative relapse, and reoperation rate (38% vs. 0%). There was similarity (all p > 0.05) in preoperative (4.8 +/- 2.9 vs. 4.9 +/- 2.9 mm) and recent (35 +/- 4 vs. 37 +/- 4 mm) postoperative maximal incisal opening, hospital stay (3.5 +/- 0.8 vs. 3.6 +/- 0.8 days), and surgery-related complications (13% vs. 14%). CONCLUSION: Both surgical procedures evaluated were successful in initial management of temporomandibular joint ankylosis, but the Matthews device arthroplasty avoided postoperative relapse. PMID- 27236503 TI - Klippel-Feil syndrome associated with Pierre Robin sequence and mandibular duplication. PMID- 27236504 TI - Restrictive use of perioperative blood transfusion does not increase complication rates in microvascular breast reconstruction. AB - INTRODUCTION: With increasing appreciation of the possible adverse effects of peri-operative blood transfusion, restrictive policies regarding use of blood products have been adopted in many surgical specialties. Although microvascular breast reconstruction has become a routine procedure, high peri-operative transfusion rates continue to be reported in the literature. In this study we examine the impact of our restrictive approach on blood transfusion rates and postoperative complications in patients undergoing microvascular blood transfusion. METHODS: A retrospective review of patients undergoing microvascular breast reconstruction with abdominal flaps at a single institution was performed. Patient age and body mass index as well as type, timing and laterality of reconstruction was recorded. Pre-operative and post-operative hemoglobin and hematocrit were recorded. Peri-operative blood transfusion rates were calculated. Post-operative complication rates were compared between patients with higher and lower post-operative hemoglobin levels. RESULTS: Five hundred and twelve patients were included in this study. The peri-operative transfusion rate was 0.98% in this series. There was no significant difference between transfusion rates in unilateral and bilateral reconstructions (0.68 vs 1.36% p = 0.08) or immediate and delayed reconstructions (1.02 vs 0.51% p = 0.72 and 1.01 vs 1.60% p = 0.09 for unilateral and bilateral respectively). Lower post-operative hemoglobin levels were not associated with increased flap related, surgical or medical complications rates. CONCLUSION: A restrictive approach to peri-operative blood transfusion can be safely adopted in microvascular breast reconstruction without compromising flap viability or overall complication rates. PMID- 27236505 TI - Medical physics practice and training in Ghana. AB - Medical physics has been an indispensable and strategic stakeholder in the delivery of radiological services to the healthcare system of Ghana. The practice has immensely supported radiation oncology and medical imaging facilities over the years, while the locally established training programme continues to produce human resource to feed these facilities. The training programme has grown to receive students from other African countries in addition to local students. Ghana has been recognised by the International Atomic Energy Agency as Regional Designated Centre for Academic Training of Medical Physicists in Africa. The Ghana Society for Medical Physics collaborates with the School of Nuclear and Allied Sciences of the University of Ghana to ensure that training offered to medical physicists meet international standards, making them clinically qualified. The Society has also worked together with other bodies for the passage of the Health Profession's Regulatory Bodies Act, giving legal backing to the practice of medical physics and other allied health professions in Ghana. The country has participated in a number of International Atomic Energy Agency's projects on medical physics and has benefited from its training courses, fellowships and workshops, as well as those of other agencies such as International Organization for Medical Physics. This has placed Ghana's medical physicists in good position to practice competently and improve healthcare. PMID- 27236506 TI - Antigen dynamics govern the induction of CD4(+) T cell tolerance during autoimmunity. AB - Antigen-specific T cell tolerance holds great promise for the treatment of autoimmune diseases. However, strategies to induce durable tolerance using high doses of soluble antigen have to date been unsuccessful, due to lack of efficacy and the risk of hypersensitivity. In the current study we have overcome these limitations by developing a platform for tolerance induction based on engineering the immunoglobulin Fc region to modulate the dynamic properties of low doses (1 MUg/mouse; ~50 MUg/kg) of Fc-antigen fusions. Using this approach, we demonstrate that antigen persistence is a dominant factor governing the elicitation of tolerance in the model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), induced by immunizing B10.PL mice with the N-terminal epitope of myelin basic protein. Unexpectedly, our analyses reveal a stringent threshold of antigen persistence for both prophylactic and therapeutic treatments, although distinct mechanisms lead to tolerance in these two settings. Importantly, the delivery of tolerogenic Fc-antigen fusions during ongoing disease results in the downregulation of T-bet and CD40L combined with amplification of Foxp3(+) T cell numbers. The generation of effective, low dose tolerogens using Fc engineering has potential for the regulation of autoreactive T cells. PMID- 27236508 TI - The transport of drug in fibrosis: Comment on "Towards a unified approach in the modeling of fibrosis: A review with research perspectives" by Martine Ben Amar and Carlo Bianca. PMID- 27236507 TI - Involvement and prognosis value of CD8(+) T cells in giant cell arteritis. AB - CD8(+) T cells participate in the pathogenesis of some vasculitides. However, little is known about their role in Giant Cell Arteritis (GCA). This study was conducted to investigate CD8(+) T cell involvement in the pathogenesis of GCA. Analyses were performed at diagnosis and after 3 months of glucocorticoid treatment in 34 GCA patients and 26 age-matched healthy volunteers. Percentages of CD8(+) T-cell subsets, spectratype analysis of the TCR Vbeta families of CD8(+) T cells, levels of cytokines and chemokines and immunohistochemistry of temporal artery biopsies (TAB) were assessed. Among total CD8(+) T cells, percentages of circulating cytotoxic CD8 T lymphocytes (CTL, CD3(+)CD8(+)perforin(+)granzymeB(+)), Tc17 (CD3(+)CD8(+)IL-17(+)), CD63(+)CD8(+) T cells and levels of soluble granzymes A and B were higher in patients than in controls, whereas the percentage of Tc1 cells (CD3(+)CD8(+)IFN-gamma(+)) was similar. Moreover, CD8(+) T cells displayed a restricted TCR repertoire in GCA patients. Percentages of circulating CTL, Tc17 and soluble levels of granzymes A and B decreased after treatment. CXCR3 expression on CD8(+) T cells and its serum ligands (CXCL9, -10, -11) were higher in patients. Analyses of TAB revealed high expression of CXCL9 and -10 associated with infiltration by CXCR3(+)CD8(+) T cells expressing granzyme B and TiA1. The intensity of the CD8 T-cell infiltrate in TAB was predictive of the severity of the disease. This study demonstrates the implication and the prognostic value of CD8(+) T-cells in GCA and suggests that CD8(+) T-cells are recruited within the vascular wall through an interaction between CXCR3 and its ligands. PMID- 27236509 TI - Plasmacytoid dendritic cell role in cutaneous malignancies. AB - Plasmacytoid dendritic cells (pDCs) correspond to a specialized dendritic cell population that exhibit plasma cell morphology, express CD4, CD123, HLA-DR, blood derived dendritic cell antigen-2 (BDCA-2), and Toll-like receptor (TLR)7 and TLR9 within endosomal compartments. Through their production of type I interferons (IFNs) and other pro-inflammatory cytokines, pDCs provide anti-viral resistance and link the innate and adaptive immunity by controlling the function of myeloid DCs, lymphocytes, and natural killer (NK) cells. While lacking from normal skin, pDCs are usually recruited to the skin in several cutaneous pathologies where they appear to be involved in the pathogenesis of several infectious, inflammatory/autoimmune, and neoplastic entities. Among the latter group, pDCs have the potential to induce anti-tumour immunity; however, the complex interaction of pDCs with tumor cells and their micro-environment appears to contribute to immunologic tolerance. In this review, we aim at highlighting the role played by pDCs in cutaneous malignancies with special emphasis on the underlying mechanisms. PMID- 27236510 TI - Pharmacokinetics, biodistribution, in vitro cytotoxicity and biocompatibility of Vitamin E TPGS coated trans resveratrol liposomes. AB - The clinical application of trans resveratrol (RSV) in glioma treatment is largely limited because of its rapid metabolism, fast elimination from systemic circulation and low biological half life. Therefore, the objectives of this study were to enhance the circulation time, biological half life and passive brain targeting of RSV using d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) coated liposomes (RSV-TPGS-Lipo). In addition to basic liposomal characterizations, in vitro anticancer potential against C6 glioma cell lines and cellular internalization of liposomes were carried out by MTT assay and confocal laser scanning microscopy (CLSM), respectively. Pharmacokinetics and tissue distribution studies were also carried out after intravenous administration in Charles Foster rats. RSV-TPGS-Lipo 2 showed significantly higher cytotoxicity than RSV-Lipo (uncoated liposomes) and RSV. Both uncoated and TPGS coated liposomes showed excellent cellular uptake. RSV, RSV-Lipo and RSV-TPGS-Lipo 2 were found to be haemocompatible and safe after i.v. administration. Area under the curve (AUC) and plasma half life (t1/2) after i.v. administration of RSV-TPGS Lipo 2 was found to be approximately 5.73 and 6.72 times higher than that of RSV Lipo as well as 29.94 and 29.66 times higher than that of RSV, respectively. Thus, the outcome indicates that RSV-TPGS-Lipo 2 is a promising carrier for glioma treatment with improved pharmacokinetic parameters. Moreover, brain accumulation of RSV-Lipo and RSV-TPGS-Lipo 2 was found to be significantly higher than that of RSV (P<0.05). Results are suggesting that both RSV-Lipo and RSV-TPGS Lipo 2 are the promising tools of RSV for the treatment of brain cancer. PMID- 27236511 TI - Nano-polyplex based on oleoyl-carboxymethy-chitosan (OCMCS) and hyaluronic acid for oral gene vaccine delivery. AB - Here we described nano-polyplexes (NPs) made of oleoyl-carboxymethy-chitosan (OCMCS)/hyaluronic acid (HA) as novel potential carriers for oral gene vaccines delivery. Aerolysin gene (aerA) of Aeromonas hydrophila as microbial antigen was efficiently loaded to form OCMCS-HA/aerA (OHA) NPs. OHA NPs performed the optimal parameters, i.e. smallest (154.5+/-9.4nm), positive charged (+7.9+/-0.5mV) and monodispersed system with the N/P ratio of 5 and OCMCS/HA weight ratio of 4. Upon the introduction of HA, OHA NPs was beneficial for the DNA release in intestinal environments in comparison to OA NPs. The mean fluorescence intensity detected in Caco-2 cells incubated with OHA NPs was about 2.5-fold higher than that of OA NPs; however, it decreased significantly in the presence of excess free HA. The OHA NPs and OA NPs decreased the transepithelial electric resistance (TEER) of Caco-2 monolayers obviously and induced increasing the apparent permeability coefficient (Papp) of DNA by 5.45-6.09 folds compared with free DNA. Significantly higher (P<0.05) antigen-specific antibodies were detected in serum after orally immunized with OHA NPs than that immunized with OA NPs and DNA alone in carps. These results enable the OHA NPs might resolve challenges arising from gastrointestinal damage to gene antigens, and offer an approach applicable for oral vaccination. PMID- 27236512 TI - A recently developed MRI scoring system for hand osteoarthritis: its application in a clinical setting. AB - This study aimed to apply the recently proposed Oslo hand osteoarthritis magnetic resonance imaging (MRI) scoring system to evaluate MRI findings in a cohort of patients affected by long-standing erosive hand osteoarthritis (EHOA). Eleven female EHOA patients (median 59 [interquartile range 62-52] years, disease duration 9.5 [interquartile range 13-3.75] years) underwent MRI (1.5 T) of the dominant hand, and synovitis, bone marrow lesions (BMLs), joint space narrowing, osteophytes, cysts, malalignment, and erosions were scored using the Oslo scoring system. Intra- and inter-reader reliability were assessed. The patients also underwent X-ray examination, and bone features were evaluated using the same scoring system. Pain and tenderness were assessed during a physical examination. Spearman's non-parametric test was used to analyze the correlations between variables. MRI intra- and inter-reader reliability were found between good and moderate for many features. No statistical differences were found between the radiographs and MRI with regard to detection of JSN, malalignment, and bone erosions. Synovitis was detected in 39.8 % of the 80 joints examined (in a mild form in 80 %), erosions were found in 51.1 %, and BMLs were identified in 20.5 and 23.9 % at the distal and the proximal side, respectively. BMLs at both the proximal and distal ends were correlated with tender joints (BML distal p = 0.0013, BML proximal p = 0.012). The presence of synovitis was correlated with tenderness (p = 0.004) and erosions at both the distal and proximal joints (p = 0.004). The presence of erosions correlated with tender joints (p < 0.01) and the mean visual analog scale (VAS) score (distal p = 0.03, proximal p = 0.01). Synovitis and BMLs were correlated with clinical symptoms in our patients affected with long-standing EHOA. PMID- 27236513 TI - Tendon involvement in patients with gout: an ultrasound study of prevalence. AB - The objective of the present study is to evaluate, by ultrasonography (US), the prevalence in the quadriceps, patellar, and Achilles tendon involvement of gout compared to that of patients with osteoarthritis and asymptomatic marathon runners. This is a multicenter, multinational, transverse cross-sectional, and comparative study comprising 80 patients with the diagnosis of gout according to the American College of Rheumatology (ACR) criteria, compared with two control groups: 35 patients with generalized osteoarthritis according to the ACR criteria and 35 subjects who were healthy marathon runners. Demographics and clinical characteristics, such as age, gender, comorbidity, disease duration, pain at the enthesis in the knee and ankle, frequency of disease exacerbations, uric acid level more than 7.2 mg at the time of evaluation, and type of treatment, were recorded. All participants were examined by ultrasound at the quadriceps, the patellar at its proximal and distal insertion, and the Achilles tendon to detect intra-tendinous tophus or aggregates according to the OMERACT definitions. Descriptive statistics and differences between groups were analyzed by chi-square test. Sensitivity and specificity by US were calculated. The prevalence of intra tendinous aggregates and tophi in gout was significant compared with the other groups. Both lesions were the most frequent at the distal patellar insertion, followed by the quadriceps, Achilles, and proximal patellar insertion ones. In patients with osteoarthritis (OA), intra-tendinous hyperechoic aggregates were observed in 20 % of quadriceps tendons and in 11 % of patellar tendons at its proximal insertion, while in the healthy marathon runner group, the Achilles tendon had this kind of lesion in 17 % of the subjects. Neither the OA nor the healthy marathon runners had intra-tendinous tophi. The sensitivity and specificity of US to detect tophi or aggregates were 69.6 and 92 %, respectively, tendon involvement at the lower limbs in gout is very frequent, particularly in the patellar tendon, and US possesses good sensitivity and specificity for detecting intra-tendinous tophi. PMID- 27236514 TI - Development of an Efficient Genome Editing Method by CRISPR/Cas9 in a Fish Cell Line. AB - CRISPR/Cas9 system has been used widely in animals and plants to direct mutagenesis. To date, no such method exists for fish somatic cell lines. We describe an efficient procedure for genome editing in the Chinook salmon Oncorhynchus tshawytscha CHSE. This cell line was genetically modified to firstly overexpress a monomeric form of EGFP (cell line CHSE-E Geneticin resistant) and additionally to overexpress nCas9n, a nuclear version of Cas9 (cell line CHSE-EC, Hygromycin and Geneticin resistant). A pre-validated sgRNA was produced in vitro and used to transfect CHSE-EC cells. The EGFP gene was disrupted in 34.6 % of cells, as estimated by FACS and microscopy. The targeted locus was characterised by PCR amplification, cloning and sequencing of PCR products; inactivation of the EGFP gene by deletions in the expected site was validated in 25 % of clones. This method opens perspectives for functional genomic studies compatible with high throughput screening. PMID- 27236515 TI - Contamination of healthcare workers' hands with bacterial spores. AB - Clostridium species and Bacillus spp. are spore-forming bacteria that cause hospital infections. The spores from these bacteria are transmitted from patient to patient via healthcare workers' hands. Although alcohol-based hand rubbing is an important hand hygiene practice, it is ineffective against bacterial spores. Therefore, healthcare workers should wash their hands with soap when they are contaminated with spores. However, the extent of health care worker hand contamination remains unclear. The aim of this study is to determine the level of bacterial spore contamination on healthcare workers' hands. The hands of 71 healthcare workers were evaluated for bacterial spore contamination. Spores attached to subject's hands were quantitatively examined after 9 working hours. The relationship between bacterial spore contamination and hand hygiene behaviors was also analyzed. Bacterial spores were detected on the hands of 54 subjects (76.1%). The mean number of spores detected was 468.3 CFU/hand (maximum: 3300 CFU/hand). Thirty-seven (52.1%) and 36 (50.7%) subjects were contaminated with Bacillus subtilis and Bacillus cereus, respectively. Nineteen subjects (26.8%) were contaminated with both Bacillus species. Clostridium difficile was detected on only one subject's hands. There was a significant negative correlation between the hand contamination level and the frequency of handwashing (r = -0.44, P < 0.01) and a significant positive correlation between the hand contamination level and the elapsed time since last handwashing (r = 0.34, P < 0.01). Healthcare workers' hands may be frequently contaminated with bacterial spores due to insufficient handwashing during daily patient care. PMID- 27236516 TI - Genotype and allele frequencies of isoniazid-metabolizing enzymes NAT2 and GSTM1 in Latvian tuberculosis patients. AB - Pharmacogenomic testing of tuberculosis drug-metabolizing enzyme genes was proposed as a strategy to identify patients at risk for suboptimal responses to medications. However, variations of the genotype frequencies among ethnic groups exist and new alleles are been identified. The aim of this study was to identify polymorphisms of genes encoding metabolic enzymes NAT2 and GSTM1 in tuberculosis patients in Latvia and to estimate the frequency of NAT2 slow acetylator and GSTM1 null genotypes. In total, 85 DNA samples were genotyped, all individuals were Caucasian. An ethnic heterogeneity reflecting the multiethnic population of the country was observed. 49 patients were Latvians, 30 were Russians and 6 of other ethnicity. In total, 7 NAT2 alleles were identified: *4, *5, *6, *7, *11, *12, * and *13. The most frequent was the slow acetylation allele NAT2*6 (frequency 0.388) followed by the slow acetylation allele NAT2*5 and the rapid acetylation allele NAT2*4 (frequencies 0.306 and 0.194, respectively). The predominance of slow (51.8%) and intermediate (43.5%) acetylators compared with rapid acetylators (4.7%) was observed. The GSTM1 null genotype was detected in 48.2% of tuberculosis patients. When subgroup analysis was performed according to ethnicity, the results showed that neither NAT2 allele frequencies nor GSTM1 null genotype frequency did not differ significantly in TB patients of Latvian or Russian ethnicity. Overall, genotyping results were similar with previous reports of a NAT2 gene variation and GSTM1 null genotype frequency in Caucasians. Our findings have a contribution for the pharmacogenetics-based tuberculosis therapy in Latvia in future. PMID- 27236517 TI - Myocardial Characterization Using Dual-Energy CT in Doxorubicin-Induced DCM: Comparison With CMR T1-Mapping and Histology in a Rabbit Model. AB - OBJECTIVES: This study sought to evaluate whether patterns of myocardial change in doxorubicin-induced dilated cardiomyopathy determined using dual-energy computed tomography (CT) were similar to characterization by extracellular volume fraction (ECV) using cardiac magnetic resonance (CMR) T1-mapping and collagen volume fraction (CVF) measured using histology. BACKGROUND: Anthracycline chemoagents are effective against a wide range of malignant conditions. However, cardiotoxicity is a well-known adverse effect of these drugs. Dual-energy CT could be as useful as magnetic resonance (MR) to evaluate myocardial change in anthracycline-induced cardiotoxicity. METHODS: A dilated cardiomyopathy rabbit model was generated by injecting 11 adult New Zealand rabbits with 1.0 mg/kg of doxorubicin twice weekly for 16 weeks. Contrast-enhanced dual-energy CT and pre contrast and post-contrast T1-mapping CMR using a prototype modified Look-Locker inversion recovery on a clinical 3-T scanner were performed on 15 rabbits, including 4 control animals, to calculate ECV at baseline, and at 6, 12, and 16 weeks after doxorubicin administration. RESULTS: The mean ECV values (%) on CT and CMR at 6, 12, and 16 weeks after modeling were significantly higher than those measured at baseline (CT ECV: 35.3%, 41.9%, 42.1% vs. 28.5%; MR ECV: 32.6%, 35.8%, 41.3% vs. 28.8%, respectively; all p < 0.001). CT ECV and MR ECV values were well correlated (r = 0.888; p < 0.001). Both were well correlated with CVF on histology (CT ECV vs. CVF, r = 0.925, p < 0.001 and MR ECV vs. CVF, r = 0.961, p < 0.001, respectively). CONCLUSIONS: Dual-energy CT ECV correlated well with CMR and histology. Dual-energy CT is useful for characterizing doxorubicin induced cardiomyopathy by measuring ECV fraction; however, further technical improvements are desirable to lower motion artifact and improve image quality of the iodine map. PMID- 27236518 TI - Echocardiography-X-Ray Image Fusion. PMID- 27236519 TI - A Remedy for the Achilles' Heel of Echocardiography? PMID- 27236520 TI - 3D Echocardiography and Level III Training. PMID- 27236521 TI - The Authors Reply. PMID- 27236523 TI - Acute MI and Contrast-Enhanced CMR: We Need the Whole Map of the Archipelago, Not Just Half of It! PMID- 27236522 TI - Shear Wave Imaging of Passive Diastolic Myocardial Stiffness: Stunned Versus Infarcted Myocardium. AB - OBJECTIVES: The aim of this study was to investigate the potential of shear wave imaging (SWI), a novel ultrasound-based technique, to noninvasively quantify passive diastolic myocardial stiffness in an ovine model of ischemic cardiomyopathy. BACKGROUND: Evaluation of diastolic left ventricular function is critical for evaluation of heart failure and ischemic cardiomyopathy. Myocardial stiffness is known to be an important property for the evaluation of the diastolic myocardial function, but this parameter cannot be measured noninvasively by existing techniques. METHODS: SWI was performed in vivo in open chest procedures in 10 sheep. Ligation of a diagonal of the left anterior descending coronary artery was performed for 15 min (stunned group, n = 5) and 2 h (infarcted group, n = 5). Each procedure was followed by a 40-min reperfusion period. Diastolic myocardial stiffness was measured at rest, during ischemia, and after reperfusion by using noninvasive shear wave imaging. Simultaneously, end diastolic left ventricular pressure and segmental strain were measured with a pressure catheter and sonomicrometers during transient vena caval occlusions to obtain gold standard evaluation of myocardial stiffness using end-diastolic strain-stress relationship (EDSSR). RESULTS: In both groups, the end-systolic circumferential strain was drastically reduced during ischemia (from 14.2 +/- 1.2% to 1.3 +/- 1.6% in the infarcted group and from 13.5 +/- 3.0% to 1.9 +/- 1.8% in the stunned group; p <0.01). SWI diastolic stiffness increased after 2 h of ischemia from 1.7 +/- 0.4 to 6.2 +/- 2.2 kPa (p < 0.05) and even more after reperfusion (12.1 +/- 4.2 kPa; p < 0.01). Diastolic myocardial stiffening was confirmed by the exponential constant coefficient of the EDSSR, which increased from 8.8 +/- 2.3 to 25.7 +/- 9.5 (p < 0.01). In contrast, SWI diastolic stiffness was unchanged in the stunned group (2.3 +/- 0.4 kPa vs 1.8 +/- 0.3 kPa, p = NS) which was confirmed also by the exponential constant of EDSSR (9.7 +/- 3.1 vs 10.2 +/- 2.3, p = NS). CONCLUSIONS: Noninvasive SWI evaluation of diastolic myocardial stiffness can differentiate between stiff, noncompliant infarcted wall and softer wall containing stunned myocardium. PMID- 27236524 TI - Combined Pulmonary Vein and LA/LAA Thrombus Assessment: Can CMR Kill Two Birds With One Stone? PMID- 27236525 TI - PET Imaging: Hot on the Trail of the HDL Particle. PMID- 27236526 TI - Expanding CT Application to Myocardial Tissue Characterization. PMID- 27236527 TI - Prosthesis-Patient Mismatch: Another Reason for TAVR? PMID- 27236529 TI - Detection of LA and LAA Thrombus by CMR in Patients Referred for Pulmonary Vein Isolation. AB - OBJECTIVES: The goal of this study was to evaluate the diagnostic performance of a comprehensive, multicomponent cardiac magnetic resonance (CMR) study for assessment of left atrial (LA) and left atrial appendage (LAA) thrombus. BACKGROUND: Pre-operative evaluation for pulmonary vein isolation (PVI) typically requires tomographic imaging to define pulmonary venous anatomy and transesophageal echocardiogram (TEE) to assess for the presence of LA/LAA thrombus. CMR is increasingly being used to define pulmonary venous anatomy before PVI. Limited data are available on the utility of a multicomponent CMR protocol in assessing LA/LAA thrombus. METHODS: We studied patients who underwent multicomponent CMR for evaluation of pulmonary venous anatomy before PVI and underwent TEE within 7 days. LA and LAA thrombi were evaluated by using CMR as follows: 1) cine-CMR; 2) contrast-enhanced magnetic resonance angiography; and 3) equilibrium phase delayed enhancement (DE) CMR with a long inversion time (TI) of 600 ms (long TI DE-CMR). Components of the CMR study were evaluated for diagnostic performance for detection of LA or LAA thrombus using TEE as the reference standard. RESULTS: During the study period, 261 patients were assessed. The median CHA2DS2VASc (congestive heart failure, hypertension, age >=75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category) score was 2, and 73.6% of patients were undergoing anticoagulation therapy. CMR and TEE were performed within 1.3 +/- 2.3 days. LA/LAA thrombi were discovered in 9 patients (3.5%) by using TEE. Among the CMR techniques performed, long TI DE-CMR had the highest diagnostic accuracy (99.2%), sensitivity (100%), and specificity (99.2%), followed by contrast-enhanced magnetic resonance angiography (accuracy 94.3%; sensitivity 66.7%; and specificity 95.2%) and cine-CMR (accuracy 91.6%; sensitivity 66.7%; and specificity 92.5%). CONCLUSIONS: In patients referred for PVI, CMR could be a single complete diagnostic study for assessment of pulmonary venous anatomy as well as presence of LA/LAA thrombi, thus reducing the number of pre-operative tests before PVI. Long TI DE-CMR has the best diagnostic performance and should be used for the detection of LA/LAA thrombi. PMID- 27236528 TI - In Vivo PET Imaging of HDL in Multiple Atherosclerosis Models. AB - OBJECTIVES: The goal of this study was to develop and validate a noninvasive imaging tool to visualize the in vivo behavior of high-density lipoprotein (HDL) by using positron emission tomography (PET), with an emphasis on its plaque targeting abilities. BACKGROUND: HDL is a natural nanoparticle that interacts with atherosclerotic plaque macrophages to facilitate reverse cholesterol transport. HDL-cholesterol concentration in blood is inversely associated with risk of coronary heart disease and remains one of the strongest independent predictors of incident cardiovascular events. METHODS: Discoidal HDL nanoparticles were prepared by reconstitution of its components apolipoprotein A I (apo A-I) and the phospholipid 1,2-dimyristoyl-sn-glycero-3-phosphocholine. For radiolabeling with zirconium-89 ((89)Zr), the chelator deferoxamine B was introduced by conjugation to apo A-I or as a phospholipid-chelator (1,2 distearoyl-sn-glycero-3-phosphoethanolamine-deferoxamine B). Biodistribution and plaque targeting of radiolabeled HDL were studied in established murine, rabbit, and porcine atherosclerosis models by using PET combined with computed tomography (PET/CT) imaging or PET combined with magnetic resonance imaging. Ex vivo validation was conducted by radioactivity counting, autoradiography, and near infrared fluorescence imaging. Flow cytometric assessment of cellular specificity in different tissues was performed in the murine model. RESULTS: We observed distinct pharmacokinetic profiles for the two (89)Zr-HDL nanoparticles. Both apo A-I- and phospholipid-labeled HDL mainly accumulated in the kidneys, liver, and spleen, with some marked quantitative differences in radioactivity uptake values. Radioactivity concentrations in rabbit atherosclerotic aortas were 3- to 4-fold higher than in control animals at 5 days' post-injection for both (89)Zr-HDL nanoparticles. In the porcine model, increased accumulation of radioactivity was observed in lesions by using in vivo PET imaging. Irrespective of the radiolabel's location, HDL nanoparticles were able to preferentially target plaque macrophages and monocytes. CONCLUSIONS: (89)Zr labeling of HDL allows study of its in vivo behavior by using noninvasive PET imaging, including visualization of its accumulation in advanced atherosclerotic lesions. The different labeling strategies provide insight on the pharmacokinetics and biodistribution of HDL's main components (i.e., phospholipids, apo A-I). PMID- 27236530 TI - Predictors and Outcomes of Prosthesis-Patient Mismatch After Aortic Valve Replacement. AB - OBJECTIVES: This study sought to evaluate predictors of prosthesis-patient mismatch (PPM) and its association with the risk of perioperative and overall mortality. BACKGROUND: PPM is associated with increased mid- and long-term mortality after surgical aortic valve replacement. Conflicting results have been reported with regard to its association with perioperative mortality. METHODS: Databases were searched for studies published between 1965 and 2014. Main outcomes of interest were perioperative mortality and overall mortality. RESULTS: The search yielded 382 studies for inclusion. Of these, 58 articles were analyzed and their data extracted. The total number of patients included was 40,381 (39,568 surgical aortic valve replacement and 813 transcatheter aortic valve replacement). Perioperative (odds ratio: 1.54; 95% confidence interval: 1.25 to 1.91) and overall (i.e., perioperative and post-operative) mortality (hazard ratio: 1.26; 95% confidence interval: 1.16 to 1.36) was increased in patients with PPM. The impact of PPM on mortality was higher in those studies in which the mean age of the patients was <70 years of age (and/or AVR with associated coronary artery bypass graft was included). Severe PPM was associated with increased risk of both perioperative and overall mortality, whereas moderate PPM was associated with increased risk of perioperative mortality but not of overall mortality. The impact of PPM was less pronounced in patients with larger body mass index (>28 kg/m(2)) compared with those with lower index. Predictors of PPM were older age, female sex, hypertension, diabetes, renal failure, larger body surface area, larger body mass index, and the utilization of a bioprosthesis. CONCLUSIONS: PPM increases perioperative and overall mortality proportionally to its severity. The identification of predictors for PPM may be useful to identify patients who are at higher risk for PPM. The findings of this study support the implementation of strategies to prevent PPM especially in patients <70 years of age and/or with concomitant coronary artery bypass graft. PMID- 27236531 TI - Scar Detection by Pulse-Cancellation Echocardiography: Validation by CMR in Patients With Recent STEMI. AB - OBJECTIVES: This study sought to assess an echocardiographic approach (scar imaging echocardiography with ultrasound multipulse scheme [eSCAR]), based on existing multipulse ultrasound scheme, as a marker of myocardial scar in humans, compared with cardiac magnetic resonance assessing late gadolinium enhancement (CMR-LGE). BACKGROUND: The detection of myocardial scar impacts patient prognosis and management in coronary artery disease and other types of cardiac disease. The clinical experience with echocardiography suggests that the reflected ultrasound signal is often significantly enhanced in infarcted myocardial segments. METHODS: Twenty patients with a recent ST-segment elevation myocardial infarction (STEMI) (cases) and 15 patients with absent CMR-LGE (negative controls) were imaged with both the eSCAR pulse-cancellation echocardiography and CMR-LGE to assess their potential association. RESULTS: Scar was detectable at CMR-LGE in 19 of 20 STEMI patients (91%), whereas all (100%) demonstrated eSCAR at echocardiography. In the 19 STEMI patients in whom CMR-LGE was detected, regional matching between eSCAR and CMR-LGE was total, although the segmental extent of detected scar was not always superimposable, particularly in the most apical segments, a region in which eSCAR demonstrated undersensitivity for the true extent of scar. CONCLUSIONS: A 2-dimensional multipulse echocardiography allows detection of myocardial scar, reliably matching the presence and site of CMR-LGE at 30 days after STEMI, or its absence in negative controls. PMID- 27236532 TI - Quantification of vosaroxin and its metabolites N-desmethylvosaroxin and O desmethylvosaroxin in human plasma and urine using high-performance liquid chromatography-tandem mass spectrometry. AB - Vosaroxin is a first-in-class anticancer quinolone derivative topoisomerase II inhibitor that is currently in development in combination with cytarabine for the treatment of acute myeloid leukemia (AML). To investigate vosaroxin pharmacokinetics (PK) in patients, liquid chromatography tandem mass spectrometry (LC-MS/MS) assays to quantify vosaroxin and the two metabolites N desmethylvosaroxin and O-desmethylvosaroxin in human plasma and urine were developed and validated. Immediately after collection the samples were stored at 80 degrees C. Prior to analysis, the plasma samples were subjected to protein precipitation and the urine samples were diluted. For both assays the reconstituted extracts were injected on a Symmetry Shield RP8 column and gradient elution was applied using 0.1% formic acid in water and acetonitrile-methanol (50:50, v/v). Analyses were performed with a triple quadruple mass spectrometer in positive-ion mode. A deuterated isotope of vosaroxin was used as internal standard for the quantification. The validated assays quantify vosaroxin and N desmethylvosaroxin in the concentration range of 2-500ng/mL in plasma and urine. For O-desmethylvosaroxin the concentration range of 4-500ng/mL in plasma and urine was validated. Dilution integrity experiments show that samples can be diluted 25 fold in control matrix prior to analysis. The expanded concentration range for plasma and urine for vosaroxin and N-desmethylvosaroxin is therefore from 2 to 15,000ng/mL and in plasma for O-desmethylvosaroxin from 4 to 15,000ng/mL. PMID- 27236533 TI - Rapid screening for drugs of abuse in biological fluids by ultra high performance liquid chromatography/Orbitrap mass spectrometry. AB - We present a UPLC((r))-High Resolution Mass Spectrometric method to simultaneously screen for nineteen benzodiazepines, twelve opiates, cocaine and three metabolites, and three "Z-drug" hypnotic sedatives in both blood and urine specimens. Sample processing consists of a high-speed, high-temperature enzymatic hydrolysis for urine samples followed by a rapid supported liquid extraction (SLE). The combination of ultra-high resolution chromatography with high resolution mass spectrometry allows all 38 analytes to be uniquely detected with a ten minute analytical run. Limits of detection for all target analytes are 3ng/mL or better, with only 0.3mL of specimen used for analysis. The combination of low sample volume with fast processing and analysis makes this method a suitable replacement for immunoassay screening of the targeted drug classes, while providing far superior specificity and better limits of detection than can routinely be obtained by immunoassay. PMID- 27236534 TI - Synchronous Papillary Carcinoma of Thyroid and Lung. PMID- 27236535 TI - Design of an Internal Model Control strategy for single-phase grid-connected PWM inverters and its performance analysis with a non-linear local load and weak grid. AB - This paper presents the design of a controller based on Internal Model Control (IMC) applied to a grid-connected single-phase PWM inverter. The mathematical modeling of the inverter and the LCL output filter, used to project the 1-DOF IMC controller, is presented and the decoupling of grid voltage by a Feedforward strategy is analyzed. A Proportional - Resonant Controller (P+Res) was used for the control of the same plant in the running of experimental results, thus moving towards the discussion of differences regarding IMC and P+Res performances, which arrived at the evaluation of the proposed control strategy. The results are presented for typical conditions, for weak-grid and for non-linear local load, in order to verify the behavior of the controller against such situations. PMID- 27236536 TI - Moyamoya syndrome and 6p chromosome rearrangements: Expanding evidences of a new association. AB - BACKGROUND: Moyamoya syndrome represents an etiologically heterogeneous cerebral evolutive angiopathy. It can be associated with both well-characterized and recently described genetic conditions with mendelian inheritance. CASE REPORT: We report the case of a moyamoya angiopathy in a prematurely born girl affected by congenital heart defect, mild facial dysmorphism, mild neurodevelopmental delay and borderline cognitive profile, associated to a de novo complex rearrangement involving the terminal segment of the short arm of chromosome 6. CONCLUSION: To the best of our knowledge, this is the second case described of pediatric moyamoya syndrome associated with a 6p complex rearrangement. Adding this case to the pertinent literature, we discuss the pathogenic role of rearrangements in 6p region in moyamoya syndrome and suggest to investigate in this region potential genes involved in angiogenesis or vascular homeostasis. PMID- 27236537 TI - Erratum to: Size relationships of different body parts in the three dipteran species Drosophila melanogaster, Ceratitis capitata and Musca domestica. PMID- 27236538 TI - Overexpression of miR-203 sensitizes paclitaxel (Taxol)-resistant colorectal cancer cells through targeting the salt-inducible kinase 2 (SIK2). AB - MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression through the endogenous RNA interference machinery. Treatments with combination of chemotherapy with surgery are essential for advanced-stage colorectal cancer. However, the development of chemoresistance is a major obstacle for clinical application of anticancer drugs. In this study, we report a miR-203-SIK2 axis that involves in the regulation of Taxol sensitivity in colon cancer cells. MiR 203 is downregulated in human colon tumor specimens and cell lines compared with their normal counterparts. We report miR-203 is correlated with Taxol sensitivity: overexpression of miR-203 sensitizes colon cancer cells and the Taxol-resistant cells display downregulated miR-203 compared with Taxol-sensitive cells. We identify SIK2 as a direct target of miR-203 in colorectal cancer cells. Overexpression of miR-203 complementary pairs to the 3' untranslated region (UTR) of SIK2, leading to the sensitization of Taxol resistant cells. In addition, miR 203 and the salt-inducible kinase 2 (SIK2) are reverse expressed in human colorectal tumors. Finally, we demonstrate recovery of SIK2 by overexpression of SIK2-desensitized Taxol-resistant cells, supporting the miR-203-mediated sensitization to Taxol, is through the inhibition of SIK2. In general, our study will provide mechanisms of the microRNA-based anti-tumor therapy to develop anti chemoresistance drugs. PMID- 27236539 TI - "I Am the Only Child of my Parents:" Perspectives on Future Elder Care for Parents among Chinese only-Children Living overseas. AB - The 1979 One-Child Policy in China created a generation of only children, leading to increased elder care dilemmas for this generation and its aging parents, particularly for young adults studying or working abroad. The current study used in-depth, semi-structured interviews with Chinese young adults who were currently studying or working in Montreal, Canada (N = 20), whose parents still lived in China. The interviews focused on the following topics: elder care patterns of respondents' grandparents; family values and expectations; perceptions of professional long-term care institutions (in China and Canada); and future plans for taking care of aging parents. Respondents described their grandparents' care as following traditional elder care patterns with multiple familial caregivers, which they appreciated as a positive model that defined their own obligations towards parents. Respondents reported being very close to their parents. Some planned to settle down in Canada and bring their parents, others planned to go back to China. Citing the tradition of filial piety, they expected to take care of their parents in the future, but they also considered the dilemmas involved in caring for aging parents without siblings to share the task, potentially requiring them to find compromises between their personal lives and caring for older parents. Those who planned to settle in Canada raised additional concerns about the challenges of bringing over their parents, including acculturation and access to and communication with health and long-term care providers. The results are discussed in the context of contemporary demographic, economic, and policy concerns about aging, family care, and immigration. PMID- 27236540 TI - Preoperative haemoglobin cut-off values for the prediction of post-operative transfusion in total knee arthroplasty. AB - PURPOSE: The purpose of this study is to determine preoperative haemoglobin cut off values that could accurately predict post-operative transfusion outcome in patients undergoing primary unilateral total knee arthroplasty (TKA). This will allow surgeons to provide selective preoperative type and screen to only patients at high risk of transfusion. METHODS: A total of 1457 patients diagnosed with osteoarthritis and underwent primary unilateral TKA between January 2012 and December 2014 were retrospectively reviewed. Logistic regression analyses were applied to identify factors that could predict transfusion outcome. RESULTS: A total of 37 patients (2.5 %) were transfused postoperatively. Univariate analysis revealed preoperative haemoglobin (p < 0.001), age (p < 0.001), preoperative haematocrit (p < 0.001), and preoperative creatinine (p < 0.001) to be significant predictors. In the multivariate analysis with patients dichotomised at 70 years of age, preoperative haemoglobin remained significant with adjusted odds ratio of 0.33. Receiver operating characteristic curve identified the preoperative haemoglobin cut-off values to be 12.4 g/dL (AUC = 0.86, sensitivity = 87.5 %, specificity = 77.2 %) and 12.1 g/dL (AUC = 0.85, sensitivity = 69.2 %, specificity = 87.1 %) for age above and below 70, respectively. CONCLUSIONS: The authors recommend preoperative haemoglobin cut-off values of 12.4 g/dL for age above 70 and 12.1 g/dL for age below 70 to be used to predict post-operative transfusion requirements in TKA. To maximise the utilisation of blood resources, the authors recommend that only patients with haemoglobin level below the cut-off should receive routine preoperative type and screen before TKA. LEVEL OF EVIDENCE: IV. PMID- 27236541 TI - Surgical anatomy of medial open-wedge high tibial osteotomy: crucial steps and pitfalls. AB - PURPOSE: To give an overview of the basic knowledge of the functional surgical anatomy of the proximal lower leg and the popliteal region relevant to medial high tibial osteotomy (HTO) as key anatomical structures in spatial relation to the popliteal region and the proximal tibiofibular joint are usually not directly visible and thus escape a direct inspection. METHODS: The surgical anatomy of the human proximal lower leg and its relevance for HTO are illustrated with a special emphasis on the individual steps of the operation involving creation of the osteotomy planes and plate fixation. RESULTS: The posteriorly located popliteal neurovascular bundle, but also lateral structures such as the peroneal nerve, the head of the fibula and the lateral collateral ligament must be protected from the instruments used for osteotomy. Neither positioning the knee joint in flexion, nor the posterior thin muscle layer of the popliteal muscle offers adequate protection of the popliteal neurovascular bundle when performing the osteotomy. Tactile feedback through a loss-of-resistance when the opposite cortex is perforated is only possible when sawing and drilling is performed in a pounding fashion. Kirschner wires with a proximal thread, therefore, always need to be introduced under fluoroscopic control. Due to anatomy of the tibial head, the tibial slope may increase inadvertently. CONCLUSIONS: Enhanced surgical knowledge of anatomical structures that are at a potential risk during the different steps of osteotomy or plate fixation will help to avoid possible injuries. LEVEL OF EVIDENCE: Expert opinion, Level V. PMID- 27236542 TI - DNA transfer during laundering may yield complete genetic profiles. AB - In a number of child sexual abuse cases, the alleged perpetrator is a member of the nuclear family. In those cases, there is a possibility that the suspect's DNA was innocently deposited onto the child's clothing without acts of sexual assault ever occurring, for example via secondary transfer within the washing machine. To assess the quantity and quality of DNA that may be transferred among clothing during laundering, we conducted three series of experiments. First, we evaluated the level of spermatozoa that may be transferred by washing pristine pairs of underwear with bed sheets containing a varying number of ejaculates. Secondly, we explored whether current genetic methods may also detect the transfer of DNA from vaginal secretions during a machine wash. Finally, we analyzed the background levels of DNA on children's underwear collected from control families where sexual abuse never occurred. For both spermatozoa and vaginal secretions, we revealed that sufficient amounts of DNA may transfer onto laundered clothing to yield complete genetic profiles. Furthermore, DNA from relatives living within the same household was found in most cuttings taken from control children's underwear. Based on these findings, we present a framework for the handling and interpretation of intrafamilial sexual abuse cases. These suggestions should help determine whether DNA was deposited directly onto a fabric or merely transferred during a wash. PMID- 27236543 TI - MicroRNA-208b Alleviates Post-Infarction Myocardial Fibrosis in a Rat Model by Inhibiting GATA4. AB - BACKGROUND Myocardial infarction affects the health of many people. Post infarction myocardial fibrosis has attracted much attention, but details of the mechanism remain elusive. In this study, the role of microRNA-208b (miR-208b) in modulating post-infarction myocardial fibrosis and the related mechanism were investigated. MATERIAL AND METHODS A rat model of myocardial infarction induced by ligating the left anterior descending artery was used to analyze the expression and roles of miR-208b by overexpression with the lentivirus vector of pre-miR-208b. Myocardial function was assessed and the expression of fibrosis related factors type I collagen (COL1) and ACTA2 (alias alphaSMA) was detected. Myocardial fibroblasts isolated from newborn rats were transfected with luciferase reporter vectors containing wild-type or mutant Gata4 3' UTR to verify the relationship between Gata4 and miR-208b. We then transfected the specific small interference RNA of Gata4 to detect changes in COL1 and ACTA2. RESULTS miR 208b was down-regulated in hearts of model rats (P<0.01). Overexpressing miR-208b improved myocardial functions, such as reducing the infarction area (P<0.05) and promoting LVEF and LVFS (P<0.01), and inhibited COL1 and ACTA2 (P<0.01). Luciferase reporter assay proved Gata4 to be the direct target of miR-208b, with the target sequence in the 3'UTR. Inhibiting GATA4 resulted in the down regulation of COL1 and ACTA2, suggesting that the role of miR-208b was achieved via regulating GATA4. CONCLUSIONS This study demonstrates the protective function of miR-208b via GATA4 in post-infarction myocardial fibrosis, providing a potential therapeutic target for treating myocardial fibrosis. PMID- 27236544 TI - Analysis of Inappropriate Admissions of Residents of Medicalized Nursing Homes to Emergency Departments: A Prospective Multicenter Study in Burgundy. AB - OBJECTIVES: To determine the rate of inappropriate admissions to emergency departments (EDs) and to identify determinants of these admissions. DESIGN: Prospective multicenter study. SETTING: Burgundy (France), EDs and medical nursing homes (MNHs). PARTICIPANTS: 1000 Burgundy MNH residents admitted to EDs, from April 17 to June 20, 2013. MEASUREMENTS: For each subject, a questionnaire was completed. Data included age, gender, type of health professional who referred the resident to the ED (THP), whether or not a medical dispatcher organized the transfer to the ED, transport mode, reason for admission to the ED, level of independence according to the Groupes Iso-Ressource score (GIRS), and diagnosis made in the ED. The French version of the Appropriateness Evaluation Protocol grid was applied to each admission to the ED, and in some situations, the expert committee ruled on the appropriateness of the admission to the ED. MNH characteristics were also recorded. Two groups were constituted according to the appropriateness or not of admission to the ED. RESULTS: Mean age of the 1000 residents was 87. There were 706 women. Two-thirds were referred to the EDs by a physician, mainly a general practitioner. In 91.7%, the transfer to the ED was organized by a medical dispatcher, and 8.8% were transported by medicalized transport. More than 95% had a GIRS <=4. Among the admissions to EDs, 18.1% were inappropriate. Female gender (P = .017), nonmedicalized transport (P = .002), public MNH (P = .044), and nonaccess to a geriatric opinion in an emergency (P = .043) were determinants of inappropriate admission to EDs. CONCLUSION: In this first study on admissions to EDs of MNH residents using French data, we found a lower rate of admissions to the ED than that reported in the literature. Female gender, nonmedicalized transport, public MNH, and nonaccess to a geriatric opinion in an emergency were associated with inappropriate admission to EDs. PMID- 27236545 TI - Successful Aging and Frailty: Opposite Sides of the Same Coin? AB - OBJECTIVES: Operational definitions of successful aging place a strong emphasis on functional capacity, and strategies for successful aging include many factors common to frailty research. We explore the hypothesis that frailty and successful aging are two sides of the same coin and that walking speed may be an objective indicator of successful aging. DESIGN: Observational study of two Chinese cohorts using one to define "fast walkers" and applying this criteria to another cohort to examine associated factors. SETTING: Community survey in cities in China. PARTICIPANTS: A total of 1929 men and women aged 25 to 89 years of age in four cities in China and 4000 men and women 65 years old in Hong Kong SAR China. MEASUREMENTS: The top 25th percentile of walking speed for the whole cohort of 1929 men was determined, and the cutoff value was used to define "fast walkers." This value was applied to the Hong Kong Chinese population to examine factors associated with fast walking speed. These factors include age, gender, socioeconomic and lifestyle factors, medical history, quality of life, cognitive function, depressive symptoms, body mass index, body composition, and telomere length. RESULTS: Fast walkers had better self-rated health, lower prevalence of stroke, hypertension, cataracts, osteoporosis, and impaired cognitive function. They were more likely to be current alcohol users, more physically active, consumed more vegetables, had better physical component of health-related quality of life, and received more education. They also had lower body mass index, percentage whole body fat as well as appendicular fat, and higher appendicular muscle mass index. In multivariate analysis, the significant contributing variables were age, gender, current alcohol use, physical activity level, vegetable intake, quality of life, and appendicular fat. The area under the curve value on receiver-operating characteristic analysis was 0.77 for these seven variables. CONCLUSIONS: Frailty and successful aging may be considered two sides of the same entity, and fast walking speed may be used as an objective indicator of successful aging. PMID- 27236546 TI - Impact of dehydration on the forebrain preoptic recess walls in the mudskipper, Periophthalmus modestus: a possible locus for the center of thirst. AB - The forebrain lamina terminalis has not yet been examined for the role of osmosensing in teleosts, although the thirst center is well known to be present in this vascular permeable forebrain region in mammals. Here, we examined vascular permeability and neuronal responsiveness to dehydration in the lamina terminalis of the mudskipper, a euryhaline goby. Evans blue and N hydroxysulfosuccinimide-biotin both bind to blood proteins, and are impermeable to the blood-brain barrier. Intraperitoneal injection of these probes stained the walls of the preoptic recess (PR) of the third ventricle, indicating increased vascular permeability in this region. When mudskippers kept in isotonic brackish water (ca. 11 psu) were challenged to seawater (ca. 34 psu) for 3 h, body water content showed a 1 % decrease, compared with mudskippers without hypertonic challenge. Simultaneously, the number of immunohistochemically identified cFos expressing neurons in the anterior parvocellular preoptic nucleus (PPa) of the PR walls increased in a site-specific manner by approximately 1.6-fold compared with controls. Thus, these findings indicate that PPa neurons are activated, following dehydration in mudskippers. Taken together, the vascularly permeable PR walls may be involved in osmosensing, as in the mammalian thirst center. PMID- 27236547 TI - Efficacy of daclatasvir/asunaprevir according to resistance-associated variants in chronic hepatitis C with genotype 1. AB - BACKGROUND: The present study explored the treatment outcome of daclatasvir (DCV) and asunaprevir (ASV) therapy combining oral direct-acting antiviral agents (DAAs) for chronic hepatitis C (HCV) including liver cirrhosis according to resistance-associated variants (RAVs) in NS3/NS5A region. METHODS: Overall, 641 patients enrolled in Japan with HCV-1b received DCV and ASV for 24 weeks. Baseline drug-resistant mutations L31F/I/M/V, Q54H, P58S, A92K, and Y93H in the HCV NS5A region and V36A, T54A/S, Q80K/L/R, R155K/T/Q, A156S/V/T, and D168A/E/H/T/V in the HCV NS3/4A region were assessed by direct sequencing. RESULTS: Overall, 86.9 % (543/625) of patients had SVR12, which was significantly higher in NS5A 93Y (wild) (88.3 %) compared with NS5A 93H at baseline (48.0 %), indicating the SVR12 rate was significantly lower in patients with 93H mutations. Additionally, 66.7 % (18/27) of patients with prior triple therapy including simeprevir (SMV) failure had virological failure. The virological failure rate of DCV/ASV therapy after SMV failure was significantly higher in those with preexisting NS3/4A 168 substitutions compared with without substitutions at baseline [84.2 % (16/19) vs. 28.6 % (2/7), p = 0.014]. The number of patients with multiple RAVs or deletions in NS5A increased from 0 to 85 % in failed patients. Alanine aminotransferase elevation was a frequent adverse event causing discontinuation of DCV/ASV therapy, although 87.5 % (14/16) patients achieved SVR12, subsequently. CONCLUSIONS: History of SMV therapy and pre-existing NS5A Y93H were associated with virological failure of DCV/ASV therapy, resulting in the emergence of multiple RAVs. Patients with RAVs at baseline should be assessed to optimize future DAA therapies. PMID- 27236548 TI - Characterization, promoter analysis and expression of the interleukin-6 gene in blunt snout bream, Megalobrama amblycephala. AB - Interleukin-6 (IL-6) is one of the most important multifunctional cytokines, playing essential roles in mediating the innate and adaptive immune responses. In this study, il-6 gene and its promoter from blunt snout bream, Megalobrama amblycephala, were characterized, and its expression at the transcript level in healthy fish and after bacterial infection was determined by quantitative real time PCR. The results showed that the M. amblycephala il-6 (Mamil-6) cDNA had an ORF of 699 bp, encoding 232 amino acids, and contained 9 instable motifs in the 3' UTR. The deduced MamIL-6 possessed a 24-amino acid signal peptide and was located in the cytoplasm. Although sequence alignment and phylogenetic analysis revealed that IL-6 is poorly conserved in vertebrates, the protein and genomic structure of il-6 gene was well conserved. Analysis of the Mamil-6 promoter revealed the presence of a conserved TATA box and six major cis-regulatory elements, including C/EBPbeta (NF-IL6), AP-1, CRE, GRE, GATA and NF-kappaB binding sites. In healthy fish, Mamil-6 was the most abundant in the spleen. After Aeromonas hydrophila infection, Mamil-6 was significantly up-regulated in all 6 immune-related tissues examined, suggesting that Mamil-6 plays an important role in the blunt snout bream immune system. PMID- 27236549 TI - In Silico Prediction of Target-Inhibitor Interaction. AB - For a long time people are trying to predict interactions of molecules. The base for this is always a 3D structure of both partners. Based on the increasing numbers of X-Ray structures of proteins with and without bounded molecules algorithms were developed to predict the target-inhibitor interaction based on known structures of proteins. The 3D structure of inhibitors may be based on known structures or even composed during the prediction process.In most cases the problem is to find a molecule that could inhibit the function of a protein. In a second step the structure of the "inhibitor" has to be optimized.There are a lot of limitations using these technics to find a usable inhibitor, as in real world experiments the inhibitor shall only inhibit this protein and not knock out others essential functions of the cell or, in case of medical applications the host organism. PMID- 27236550 TI - Antibodies and Selection of Monoclonal Antibodies. AB - Monoclonal antibodies are universal binding molecules with a high specificity for their target and are indispensable tools in research, diagnostics and therapy. The biotechnological generation of monoclonal antibodies was enabled by the hybridoma technology published in 1975 by Kohler and Milstein. Today monoclonal antibodies are used in a variety of applications as flow cytometry, magnetic cell sorting, immunoassays or therapeutic approaches. First step of the generation process is the immunization of the organism with appropriate antigen. After a positive immune response the spleen cells are isolated and fused with myeloma cells in order to generate stable, long-living antibody-producing cell lines - hybridoma cells. In the subsequent identification step the culture supernatants of all hybridoma cells are screened weekly for the production of the antibody of interest. Hybridoma cells producing the antibody of interest are cloned by limited dilution till a monoclonal hybridoma is found. This is a very time consuming and laborious process and therefore different selection strategies were developed since 1975 in order to facilitate the generation of monoclonal antibodies. Apart from common automation of pipetting processes and ELISA testing there are some promising approaches to select the right monoclonal antibody very early in the process to reduce time and effort of the generation. In this chapter different selection strategies for antibody-producing hybridoma cells are presented and analysed regarding to their benefits compared to conventional limited dilution technology. PMID- 27236551 TI - Selection of Recombinant Human Antibodies. AB - Since the development of therapeutic antibodies the demand of recombinant human antibodies is steadily increasing. Traditionally, therapeutic antibodies were generated by immunization of rat or mice, the generation of hybridoma clones, cloning of the antibody genes and subsequent humanization and engineering of the lead candidates. In the last few years, techniques were developed that use transgenic animals with a human antibody gene repertoire. Here, modern recombinant DNA technologies can be combined with well established immunization and hybridoma technologies to generate already affinity maturated human antibodies. An alternative are in vitro technologies which enabled the generation of fully human antibodies from antibody gene libraries that even exceed the human antibody repertoire. Specific antibodies can be isolated from these libraries in a very short time and therefore reduce the development time of an antibody drug at a very early stage.In this review, we describe different technologies that are currently used for the in vitro and in vivo generation of human antibodies. PMID- 27236552 TI - Generation of Recombinant Antibodies Against Toxins and Viruses by Phage Display for Diagnostics and Therapy. AB - Antibody phage display is an in vitro technology to generate recombinant antibodies. In particular for pathogens like viruses or toxins, antibody phage display is an alternative to hybridoma technology, since it circumvents the limitations of the immune system. Phage display allows the generation of human antibodies from naive antibody gene libraries when either immunized patients are not available or immunization is not ethically feasible. This technology also allows the construction of immune libraries to select in vivo affinity matured antibodies if immunized patients or animals are available.In this review, we describe the generation of human and human-like antibodies from naive antibody gene libraries and antibodies from immune antibody gene libraries. Furthermore, we give an overview about phage display derived recombinant antibodies against viruses and toxins for diagnostics and therapy. PMID- 27236553 TI - Recent Advances with ER Targeted Intrabodies. AB - ER intrabodies are recombinant antibody fragments produced and retained in the endoplasmatic reticulum (ER) of a cell or an organism with the purpose to induce phenotypes generated by interfering with the intracellular processing or by changing the location of the recognized antigen. The most common application is the generation of functional knockdowns of membrane proteins, which cannot reach their natural location on the cell surface when they are retained in the ER by the intrabody. Phenotypes generated by interfering with the secretion of extracellular or plasma proteins can be analyzed in a similar way. So far, most ER intrabody studies relied on scFv fragments subcloned from hybridoma lines. Recently, several large international research consortia have started to provide antibodies, with the final goal to cover substantial parts of the human proteome. For practical reasons of throughput and effort, in these consortia the most appropriate method to generate the necessary large numbers of monoclonal antibodies is in vitro selection, typically employing phage or yeast display. These methods provide the antibody genes right from the start, thereby facilitating the application of ER antibody approaches. On the other end, the first transgenic mice expressing an ER intrabody has recently been described. This moves the ER intrabody approach finally to level with classic in vivo knockout strategies - but also offers novel capabilities to the researchers. Promising new perspectives may originate from the fact that the knockdown is restricted to the protein level, that a graded knockdown strength can be achieved, or that the targeting of individual posttranslational modifications will be possible with previously impossible specificity. Finally, the link of today's high throughput recombinant antibody generation to a knock down phenotype is now possible with a single cloning step. It can therefore be expected that we will see a much quicker growth of the number of successful applications of ER intrabody technology in the near future than it has been seen in its first two decades. PMID- 27236554 TI - Therapeutic Antibodies in Cancer Therapy. AB - The therapeutic arsenal in solid tumors comprises different anticancer strategies with diverse chemotherapeutic agents and a growing number of biological substances. Large clinical study-based chemotherapeutic protocols combined with biologicals have become an important component in (neo-) adjuvant therapy alongside surgery in solid cancers as well as radiation therapy in some instances. In recent years, monoclonal antibodies have entered the mainstream of cancer therapy. Their first use was as antagonists of oncogenic receptor tyrosine kinases, but today monoclonal antibodies have emerged as long-sought vehicles for the targeted delivery of potent chemotherapeutic agents and as powerful tools to manipulate anticancer immune responses. There is a growing number of FDA approved monoclonal antibodies and small molecules targeting specific types of cancer suggestive of the clinical relevance of this approach.Targeted cancer therapies , also referred to as personalized medicine, are being studied for use alone, in combination with other targeted therapies, and in combination with chemotherapy. The use of monoclonal antibodies in colorectal and gastric cancer for example have shown best outcome when combined with chemotherapy, even though single agent anti-EGFR antibodies seem to be active in particular setting of metastatic colorectal cancer patients. However, it is not well defined whether the addition of anti-VEGF - and anti-EGFR strategies to chemotherapy could improve outcome in those patients susceptible to colorectal cancer-related metastases resection. Among the most promising approaches to activating therapeutic antitumor immunity is the blockade of immune checkpoints, exemplified by the recently FDA-approved agent, Ipilimumab, an antibody that blocks the coinhibitory receptor CTLA-4. Capitalizing on the success of Ipilimumab, agents that target a second coinhibitory receptor, PD-1, or its ligand, PD-L1, are in clinical development. This section attempts to discuss recent progress of targeted agents and in tackling a more general target applicable to gastrointestinal cancer . PMID- 27236555 TI - Synthetic Cystine-Knot Miniproteins - Valuable Scaffolds for Polypeptide Engineering. AB - Peptides with the cystine-knot architecture, often termed knottins, are promising scaffolds for biomolecular engineering. These unique molecules combine diverse bioactivities with excellent structural, thermal, and proteolytical stability. Being different in the composition and structure of their amino acid backbone, knottins share the same core element, namely cystine knot, which is built by six cysteine residues forming three disulfides upon oxidative folding. This motif ensures a notably rigid framework that highly tolerates both rational and combinatorial changes in the primary structure. Being accessible through recombinant production and total chemical synthesis, cystine-knot miniproteins can be endowed with novel bioactivities by variation of surface-exposed loops and incorporation of non-natural elements within their non-conserved regions towards the generation of tailor-made peptidic compounds. In this chapter the topology of cystine-knot peptides, their synthesis and applications for diagnostics and therapy is discussed. PMID- 27236556 TI - Peptides and Peptide Analogs to Inhibit Protein-Protein Interactions. AB - Protein-protein interactions are governed by relatively few amino acid residues at the binding interface. Peptides derived from these protein regions may serve as mimics of one of the interaction partners in structural studies or as inhibitors to disrupt the respective interaction and investigate its biological consequences. Inhibitory peptides may also be lead structures for drug development if the respective protein-protein interaction is essential for a pathogen or disease mechanism. Binding peptides may be systematically derived from one of the binding partners or found in the screen of combinatorial peptide libraries. Molecular modelling based on structural data helps to refine existing peptides or even design novel binding peptides. This chapter gives an outline of the binding peptide discovery process and subsequent chemical modifications to further enhance affinity and specificity and to increase stability against degradation in vivo. Examples from the past three decades illustrate the great diversity of applications for protein binding peptides and peptide analogs. PMID- 27236557 TI - Allosteric Modulators of the Class A G Protein Coupled Receptors. AB - Allosteric modulation is the regulation of a protein by binding of an effector molecule at the proteins allosteric site (a site other than that of the endogenous ligand). Allosteric modulators, by virtue of the fact that they may stabilize different global conformations of a receptor, have the potential to disrupt protein-protein interactions of very large proteins and elicit diverse functional responses. The existence of ligands that allosterically modulate the G protein receptor (GPCR) functions provides both challenges and opportunities for drug development campaigns. A number of therapeutic advantages of allosteric modulators over classic orthosteric ligands were proposed, involving nature of response, improved selectivity and ligand-directed signaling. In this review I discuss various aspects of allosteric modulation of GPCRs, which arise from the interactions of receptors with synthetic or endogenous small molecules, ions, lipids and diverse proteins. Detection and quantification of allosteric modulation will be also addressed. In the conclusion I will present future opportunities and challenges in the development of allosteric modulators as therapeutics. PMID- 27236558 TI - Phosphatases: Their Roles in Cancer and Their Chemical Modulators. AB - Phosphatases are involved in basically all cellular processes by dephosphorylating cellular components such as proteins, phospholipids and second messengers. They counteract kinases of which many are established oncogenes, and therefore kinases are one of the most important drug targets for targeted cancer therapy. Due to this relationship between kinases and phosphatases, phosphatases are traditionally assumed to be tumour suppressors. However, research findings over the last years prove that this simplification is incorrect, as bona-fide and putative phosphatase oncogenes have been identified. We describe here the role of phosphatases in cancer, tumour suppressors and oncogenes, and their chemical modulators, and discuss new approaches and opportunities for phosphatases as drug targets. PMID- 27236559 TI - Selection and Application of Aptamers and Intramers. AB - Aptamers are auspicious nucleic acid ligands for targeting different molecules, such as small molecules, peptides, proteins, or even whole living cells. They are short single-stranded DNA or RNA oligonucleotides, which can fold into complex three-dimensional structures and bind selectively their targets. Using the combinatorial chemistry process SELEX (Systematic Evolution of Ligands by EXponential Enrichment), target specific aptamers can be selected. These aptamers have a variety of application possibilities and can be used as sensors, diagnostic, imaging or therapeutic agents, and in the field of regenerative medicine for tissue engineering. PMID- 27236560 TI - Inhibitors of Angiogenesis. AB - Angiogenesis plays a pivotal role in malignant, ischemic, inflammatory, infectious and immune disorders. The increasing molecular understanding of angiogenic processes fostered the development of strategies to induce or inhibit angiogenesis for therapeutic purposes. Here, we focus on anti-angiogenic therapies, which represent a standard of care in the treatment of different cancer types and in neovascular age-related macular degeneration. Specifically, strategies related to the blockade of angiogenic proteins and receptors will be outlined covering both preclinical and clinical aspects. Finally, examples of gene therapy based anti-angiogenic approaches are presented. PMID- 27236561 TI - Photoplethysmography respiratory rate monitoring in patients receiving procedural sedation and analgesia for upper gastrointestinal endoscopy. AB - The value of capnography during procedural sedation and analgesia (PSA) for the detection of hypoxaemia during upper gastrointestinal (UGI) endoscopic procedures is limited. Photoplethysmography respiratory rate (RRp) monitoring may provide a useful alternative, but the level of agreement with capnography during PSA is unknown. We therefore investigated the level of agreement between the RRp and capnography-based RR (RRc) during PSA for UGI endoscopy. This study included patients undergoing PSA for UGI endoscopy procedures. Pulse oximetry (SpO2) and RRc were recorded in combination with Nellcor 2.0 (RRp) monitoring (Covidien, USA). Bland-Altman analysis was used to evaluate the level of agreement between RRc and RRp. Episodes of apnoea, defined as no detection of exhaled CO2 for minimal 36 s, and hypoxaemia, defined as an SpO2 < 92 %, were registered. A total of 1054 min of data from 26 patients were analysed. Bland-Altman analysis between the RRc and RRp revealed a bias of 2.25 +/- 5.41 breath rate per minute (brpm), with limits of agreement from -8.35 to 12.84 brpm for an RR >= 4 brpm. A total of 67 apnoea events were detected. In 21 % of all apnoea events, the patient became hypoxaemic. Hypoxaemia occurred 42 times with a median length of 34 (19-141) s, and was preceded in 34 % of the cases by apnoea and in 64 % by an RRc >= 8 brpm. In 81 % of all apnoea events, photoplethysmography registered an RRp >= 4 brpm. We found a low level of agreement between capnography and the plethysmography respiratory rate during procedural sedation for UGI endoscopy. Moreover, respiratory rate derived from both the capnogram and photoplethysmogram showed a limited ability to provide warning signs for a hypoxaemic event during the sedation procedure. PMID- 27236562 TI - Long-term consequences of ovarian ablation for premenopausal breast cancer. AB - The TEXT and SOFT trials concluded that an aromatase inhibitor (AI) with ovarian ablation (OA) yields a higher 5-year disease-free survival than tamoxifen alone in premenopausal ER+ high-risk early breast cancer. However, the long-term health consequences and costs of OA, either by GnRH agonist or oophorectomy, have not been evaluated. The objective was to conduct a cost-effectiveness analysis comparing tamoxifen to OA with AI. Markov Monte Carlo simulation model estimated the costs and benefits of 3 endocrine strategies: (1) tamoxifen; (2) GnRH agonist with AI (GnRHa-AI); (3) bilateral salpingo-oophorectomy with AI (BSO-AI). Effectiveness was measured in life expectancy gain (years), and costs were averaged over a lifetime (USD 2015). Adverse events and deaths from each strategy were modeled in the United States population over a time horizon of 40 years. For women without prior chemotherapy (low-risk), tamoxifen alone was more effective (18.03 years) and less costly ($1566) than GnRHa-AI (17.66 years, $93,692) or BSO AI (17.63 years, $25,892). For those with prior chemotherapy (high-risk), BSO-AI was more costly but more effective (16.78 years, $25,368) than tamoxifen alone (16.55 years, $1523) with an ICER of $102,290, while GnRHa-AI yielded an ICER of $443,376. The simulation estimated 787 and 577 deaths attributable to OA among 9320 high-risk women after BSO-AI and GnRHa-AI, respectively. There may be a role for ovarian ablation in premenopausal women with ER+ high-risk early breast cancer; however, this analysis raises concerns about the long-term health consequences of ovarian ablation and the potential effects on overall survival. PMID- 27236564 TI - The symbiovar trifolii of Rhizobium bangladeshense and Rhizobium aegyptiacum sp. nov. nodulate Trifolium alexandrinum in Egypt. AB - In the present work we analyzed the taxonomic status of several Rhizobium strains isolated from Trifolium alexandrinum L. nodules in Egypt. The 16S rRNA genes of these strains were identical to those of Rhizobium bangladeshense BLR175(T) and Rhizobium binae BLR195(T). However, the analyses of recA and atpD genes split the strains into two clusters. Cluster II strains are identified as R. bangladeshense with >98% similarity values in both genes. The cluster I strains are phylogenetically related to Rhizobium etli CFN42(T) and R. bangladeshense BLR175(T), but with less than 94% similarity values in recA and atpD genes. DNA DNA hybridization analysis showed 42% and 48% average relatedness between the strain 1010(T) from cluster I with respect to R. bangladeshense BLR175(T) and R. etli CFN42(T), respectively. Phenotypic characteristics of cluster I strains also differed from those of their closest related Rhizobium species. Analysis of the nodC gene showed that the strains belong to two groups within the symbiovar trifolii which was identified in Egypt linked to the species R. bangladeshense. Based on the genotypic and phenotypic characteristics, the group I strains belong to a new species for which the name Rhizobium aegyptiacum sp. nov. (sv. trifolii) is proposed, with strain 1010(T) being designated as the type strain (= USDA 7124(T)=LMG 29296(T)=CECT 9098(T)). PMID- 27236563 TI - Cerebellar cortical infarct cavities and vertebral artery disease. AB - INTRODUCTION: Cerebellar cortical infarct cavities are a newly recognised entity associated with atherothromboembolic cerebrovascular disease and worse physical functioning. We aimed to investigate the relationship of cerebellar cortical infarct cavities with symptomatic vertebrobasilar ischaemia and with vascular risk factors. METHODS: We evaluated the MR images of 46 patients with a recent vertebrobasilar TIA or stroke and a symptomatic vertebral artery stenosis >=50 % from the Vertebral Artery Stenting Trial (VAST) for the presence of cerebellar cortical infarct cavities <=1.5 cm. At inclusion in VAST, data were obtained on age, sex, history of vertebrobasilar TIA or stroke, and vascular risk factors. Adjusted risk ratios were calculated with Poisson regression analyses for the relation between cerebellar cortical infarct cavities and vascular risk factors. RESULTS: Sixteen out of 46 (35 %) patients showed cerebellar cortical infarct cavities on the initial MRI, and only one of these 16 patients was known with a previous vertebrobasilar TIA or stroke. In patients with symptomatic vertebrobasilar ischaemia, risk factor profiles of patients with cerebellar cortical infarct cavities were not different from patients without these cavities. CONCLUSION: Cerebellar cortical infarct cavities are seen on MRI in as much as one third of patients with recently symptomatic vertebral artery stenosis. Since patients usually have no prior history of vertebrobasilar TIA or stroke, cerebellar cortical infarct cavities should be added to the spectrum of common incidental brain infarcts visible on routine MRI. PMID- 27236565 TI - Bifidobacterium aerophilum sp. nov., Bifidobacterium avesanii sp. nov. and Bifidobacterium ramosum sp. nov.: Three novel taxa from the faeces of cotton-top tamarin (Saguinus oedipus L.). AB - Forty-five microorganisms were isolated on bifidobacteria selective medium from one faecal sample of an adult subject of the cotton-top tamarin (Saguinus oedipus L.). All isolates were Gram-positive, catalase-negative, anaerobic, fructose-6 phosphate phosphoketolase positive, and asporogenous rod-shaped bacteria. In this study, only eight out of the forty-five strains were characterized more deeply, whereas the others are still currently under investigation. They were grouped by BOX-PCR into three clusters: Cluster I (TRE 17(T), TRE 7, TRE 26, TRE 32, TRE 33, TRE I), Cluster II (TRE C(T)), and Cluster III (TRE M(T)). Comparative analysis of 16S rRNA gene sequences confirmed the results from the cluster analysis and revealed relatively low level similarities to each other (mean value 95%) and to members of the genus Bifidobacterium. All eight isolates showed the highest level of 16S rRNA gene sequence similarities with Bifidobacterium scardovii DSM 13734(T) (mean value 96.6%). Multilocus sequence analysis (MLSA) of five housekeeping genes (hsp60, rpoB, clpC, dnaJ and dnaG) supported their independent phylogenetic position to each other and to related species of Bifidobacterium. The G+C contents were 63.2%, 65.9% and 63.0% for Cluster I, Cluster II and Cluster III, respectively. Peptidoglycan types were A3alpha l-Lys-l-Thr-l-Ala, A4beta l-Orn (Lys)-d-Ser-d-Glu and A3beta l-Orn-l-Ser-l-Ala in Clusters I, II and III, respectively. Based on the data provided, each cluster represented a novel taxon for which the names Bifidobacterium aerophilum sp. nov. (TRE 17(T)=DSM 100689=JCM 30941; TRE 26=DSM 100690=JCM 30942), Bifidobacterium avesanii sp. nov. (TRE C(T)=DSM 100685=JCM 30943) and Bifidobacterium ramosum sp. nov. (TRE M=DSM 100688=JCM 30944) are proposed. PMID- 27236566 TI - Diversity of Bradyrhizobium strains nodulating Lupinus micranthus on both sides of the Western Mediterranean: Algeria and Spain. AB - Lupinus micranthus is a lupine distributed in the Mediterranean basin whose nitrogen fixing symbiosis has not been described in detail. In this study, 101 slow-growing nodule isolates were obtained from L. micranthus thriving in soils on both sides of the Western Mediterranean. The diversity of the isolates, 60 from Algeria and 41 from Spain, was addressed by multilocus sequence analysis of housekeeping genes (16S rRNA, atpD, glnII and recA) and one symbiotic gene (nodC). Using genomic fingerprints from BOX elements, 37 different profiles were obtained (22 from Algeria and 15 from Spain). Phylogenetic analysis based on 16S rRNA and concatenated atpD, glnII and recA sequences of a representative isolate of each BOX profile displayed a homogeneous distribution of profiles in six different phylogenetic clusters. All isolates were taxonomically ascribed to the genus Bradyrhizobium. Three clusters comprising 24, 6, and 4 isolates, respectively, accounted for most of the profiles. The largest cluster was close to the Bradyrhizobium canariense lineage, while the other two were related to B. cytisi/B. rifense. The three remaining clusters included only one isolate each, and were close to B. canariense, B. japonicum and B. elkanii species, respectively. In contrast, phylogenetic clustering of BOX profiles based on nodC sequences yielded only two phylogenetic groups. One of them included all the profiles except one, and belonged to symbiovar genistearum. The remaining profile, constituted by a strain related to B. elkanii, was not related to any well-defined symbiotic lineage, and may constitute both a new symbiovar and a new genospecies. PMID- 27236567 TI - Adenosine produced from adenine nucleotides through an interaction between apoptotic cells and engulfing macrophages contributes to the appearance of transglutaminase 2 in dying thymocytes. AB - Transglutaminase 2 (TG2) has been known for a long time to be associated with the in vivo apoptosis program of various cell types, including T cells. Though the expression of the enzyme is strongly induced in mouse thymocytes following apoptosis induction in vivo, no significant induction of TG2 can be detected, when thymocytes are induced to die by the same stimuli in vitro indicating that signals arriving from the tissue environment are required for the proper in vivo induction of the enzyme. Previous studies from our laboratory have demonstrated that two of these signals, transforming growth factor-beta (TGF-beta) and retinoids, are produced by macrophages engulfing apoptotic cells. However, in addition to TGF-beta and retinoids, engulfing macrophages produce adenosine as well. Here, we show that in vitro adenosine, adenosine, and retinoic acid or adenosine, TGF-beta and retinoic acids together can significantly enhance the TG2 mRNA expression in dying thymocytes. The effect of adenosine is mediated via adenosine A2A receptors (A2ARs) and the A2AR-triggered adenylate cyclase signaling pathway. In accordance, loss of A2ARs in A2AR null mice significantly attenuates the in vivo induction of TG2 following apoptosis induction in the thymus indicating that adenosine indeed contributes in vivo to the apoptosis related appearance of the enzyme. We also demonstrate that adenosine is produced extracellularly during engulfment of apoptotic thymocytes, partly from adenine nucleotides released via thymocyte pannexin-1 channels. Our data reveal a novel crosstalk between macrophages and apoptotic cells, in which apoptotic cell uptake related adenosine production contributes to the appearance of TG2 in the dying thymocytes. PMID- 27236568 TI - Natural carcinogenic fiber and pleural plaques assessment in a general population: A cross-sectional study. AB - Natural carcinogenic fibers are asbestos and asbestiform fibers present as a natural component of soils or rocks. These fibers are released into the environment resulting in exposure of the general population. Environmental contamination by fibers are those cases occurred in: rural regions of Turkey, in Mediterranean countries and in other sites of the world, including northern Europe, USA and China. Fluoro-edenite(FE) is a natural mineral species first isolated in Biancavilla, Sicily. The fibers are similar in size and morphology to some amphibolic asbestos fibers, whose inhalation can cause chronic inflammation and cancer. The aim of the current study is to assess the presence and features of pleural plaques (PPs) in Biancavilla's general population exposed to FE through a retrospective cross-sectional study. All High-Resolution Computed Tomography (HRCT) chest scans carried out between June 2009 and June 2015 in Biancavilla municipality hospital site (exposed subjects) were reviewed. The exposed groups were 1:1 subjects, matched according to age and sex distributions, with unexposed subjects (n.1.240) randomly selected among HRCT chest scans carried out in a Hospital 30km away from Biancavilla. Subjects from Biancavilla with PPs were significantly more numerous than the control group ones (218 vs 38). Average age of either group was >60 years; the age of exposed subjects was significantly (p=0.0312) lesser than the unexposed group. In exposed subjects, in most PPs thickness ranged between 2 and 4.9cm(38%, n=83); while in unexposed ones PPs thickness was less than 2cm (55%, n=21). As to the size of PPs in exposed subjects, in most cases it ranged between 1cm and 24% of chest wall (53%, n=116); while in unexposed ones the size of PPs was lesser than 1cm (23%, n=58). Among exposed subjects, 36 cases (17%) PPs were detected with calcification, whereas in unexposed ones only three (8%) presented calcification. 137 lung parenchymal abnormalities were observed in exposed group; whereas, 12 lung parenchymal involvement were registered in unexposed subjects. The RR for PPs is 6,74 CI 95% (4,47-9,58) p<0,0001 in the exposed population. These findings, suggested the urge to extend the screening on the possible involvement of the respiratory tract to all Biancavilla's population, particularly in those aged more than 30. Besides, it seems essential to start indoor monitoring Biancavilla's municipality. PMID- 27236569 TI - Identifying heat-related deaths by using medical examiner and vital statistics data: Surveillance analysis and descriptive epidemiology - Oklahoma, 1990-2011. AB - OBJECTIVES: Approximately 660 deaths occur annually in the United States associated with excess natural heat. A record heat wave in Oklahoma during 2011 generated increased interest concerning heat-related mortality among public health preparedness partners. We aimed to improve surveillance for heat-related mortality and better characterize heat-related deaths in Oklahoma during 1990 2011, and to enhance public health messaging during future heat emergencies. METHODS: Heat-related deaths were identified by querying vital statistics (VS) and medical examiner (ME) data during 1990-2011. Case inclusion criteria were developed by using heat-related International Classification of Diseases codes, cause-of-death nomenclature, and ME investigation narrative. We calculated sensitivity and predictive value positive (PVP) for heat-related mortality surveillance by using VS and ME data and performed a descriptive analysis. RESULTS: During the study period, 364 confirmed and probable heat-related deaths were identified when utilizing both data sets. ME reports had 87% sensitivity and 74% PVP; VS reports had 80% sensitivity and 52% PVP. Compared to Oklahoma's general population, decedents were disproportionately male (67% vs. 49%), aged >=65 years (46% vs. 14%), and unmarried (78% vs. 47%). Higher rates of heat related mortality were observed among Blacks. Of 95 decedents with available information, 91 (96%) did not use air conditioning. CONCLUSIONS: Linking ME and VS data sources together and using narrative description for case classification allows for improved case ascertainment and surveillance data quality. Males, Blacks, persons aged >=65 years, unmarried persons, and those without air conditioning carry a disproportionate burden of the heat-related deaths in Oklahoma. PMID- 27236570 TI - Distributional changes in gene-specific methylation associated with temperature. AB - Temperature has been related to mean differences in DNA methylation. However, heterogeneity in these associations may exist across the distribution of methylation outcomes. This study examined whether the association between three week averaged of temperature and methylation differs across quantiles of the methylation distributions in nine candidate genes. We measured gene-specific blood methylation repeatedly in 777 elderly men participating in the Normative Aging Study (1999-2010). We fit quantile regressions for longitudinal data to investigate whether the associations of temperature on methylation (expressed as %5mC) varied across the distribution of the methylation outcomes. We observed heterogeneity in the associations of temperature across percentiles of methylation in F3, TLR-2, CRAT, iNOS, and ICAM-1 genes. For instance, an increase in three-week temperature exposure was associated with a longer left-tail of the F3 methylation distribution. A 5 degrees C increase in temperature was associated with a 0.15%5mC (95% confidence interval (CI): -0.27,-0.04) decrease on the 20th quantile of F3 methylation, but was not significantly related to the 80th quantile of this distribution (Estimate:0.06%5mC, 95%CI: -0.22, 0.35). Individuals with low values of F3, TLR-2, CRAT, and iNOS methylation, as well as a high value of ICAM-1 methylation, may be more susceptible to temperature effects on systemic inflammation. PMID- 27236571 TI - Polycyclic aromatic hydrocarbons are associated with insulin receptor substrate 2 methylation in adipose tissues of Korean women. AB - Polycyclic aromatic hydrocarbons (PAHs) are highly lipid soluble and are an increasing concern for general populations given their various adverse health effects, including obesity-related metabolic dysfunction. DNA methylation can act as a downstream effector for the biological effects of environmental exposures, but whether PAHs influence DNA methylation is unclear. To test for possible adverse effects of PAHs on adipose tissue (AT), we determined the promoter methylation status of 12 genes involved in glucose and lipid metabolism (CS, GLUT4, IR, IRS1, IRS2, LIPIN1, MCAD, PCK1, PCK2, PPARGC1Beta, SDHA, and SREBP1) in visceral AT of Korean women by using methylation-specific PCR (MSP). IRS2 methylation alone was significantly associated with concentrations of individual PAH chemicals. When the PAH summary measure was used, the odds ratios of IRS2 hypermethylation across quartile of the PAH summary measure were 1, 1.7, 2.0, and 11.2 (95% confidence interval: 1.5-84.0) after adjusting for age and BMI (P trend=0.02). The strength of association between PAH summary measure and IRS2 hypermethylation was as similar as that of BMI. Collectively, these results suggested that lipophilic PAHs might be contributing factors to the pathogenesis of insulin resistance through methylation-mediated suppression of the IRS2 gene. However, further studies with large sample size are needed to confirm our findings. PMID- 27236572 TI - Prenatal phthalate exposure and infant size at birth and gestational duration. AB - BACKGROUND: Phthalate exposure is widespread. Prior research suggests that prenatal phthalate exposure may influence birth size and gestational duration, but published results have been inconsistent. OBJECTIVE: We quantified the relationship between maternal urinary phthalate concentrations and infant birth weight z-scores, length, head circumference, and gestational duration. METHODS: In a cohort of 368 women from the HOME Study, based in Cincinnati, OH, we measured nine phthalate metabolites representing exposure to six parent phthalate diesters in urine collected at approximately 16 and 26 weeks gestation. Infant birth size and gestational duration were abstracted from medical records. We used multivariable linear regression to estimate covariate adjusted associations between urinary phthalate metabolite concentrations and infant outcomes. RESULTS: In unadjusted models, we observed a negative association between monoethyl phthalate (MEP) and birth weight z-scores, while mono-3-carboxypropyl phthalate (MCPP) was positively associated with gestational duration. After covariate adjustment, phthalate metabolite concentrations were no longer associated with birth size or gestational duration. CONCLUSIONS: In this cohort, urinary phthalate metabolite concentrations during pregnancy were not associated with infant birth size or gestational duration. Additional research is needed to determine if exposures during earlier periods of fetal development are associated with infant health. PMID- 27236573 TI - The Development of a Hospital-Wide Bereavement Program: Ensuring Bereavement Care for All Families of Pediatric Patients. AB - Although grief is a normal response to loss, the death of a child is believed to be one of the most difficult losses a person can endure, and bereaved parents are considered to be an "at-risk" group. Even though most deaths of children in the United States occur in hospitals, bereavement care provided by hospitals is highly variable, and little attention has been directed to how hospitals can best support grieving parents. In this article, we describe the development of a hospital-wide bereavement program at Boston Children's Hospital, where we conceptualize bereavement care as a preventive model of care. We identify the primary constructs of the program as education, guidance, and support and outline a template for use by other hospitals. We recommend that all pediatric hospitals implement basic, coordinated bereavement programs as the standard of care to ensure that all families receive bereavement care after the death of a patient. PMID- 27236574 TI - Optic surface changes in Intraocular lens scaffold: An ex vivo study. AB - PURPOSE: We aimed to assess the micro injuries on the intraocular lens (IOL) optic in the IOL scaffold technique by ex vivo study. SETTING: This study was conducted at the Tahira Research Laboratory, Dr Agarwal's Eye Hospital and Eye Research Centre, Chennai. DESIGN: This was an experimental study. METHODS: IOL scaffold technique was simulated in 12 caprine eyes with moderate lens changes using 12 IOLs (six acrylic hydrophilic and six polymethyl methacrylate IOL) in experimental set up. IOLs (6 mm optic diameter) were explanted from the caprine eyes immediately after the surgery and examined under light microscopy and phase contrast microscopy for anterior and posterior optic changes, and again after 24 hours. Scanning electron microscopy (SEM) was performed in IOLs with abnormalities. Two IOLs placed in caprine eyes that did not undergo scaffold procedure acted as controls. A trocar anterior chamber maintainer was used in four eyes. RESULTS: Four out of 12 IOLs showed mark defects on the surface in mid periphery. Linear mark defects measured IOL 1 (190 MUm), IOL 6 (18 MUm), IOL 2 (2.33 MUm, 2.3 MUm, 14 MUm, 14 MUm) and IOL 5 (12 MUm). The marks do not change after 24 hours. There were no mark defects (micro abrasions or scratches) seen on any of the IOL's in the central 4 mm of the optic anterior surface. The control IOLs showed no surface changes. The pre-experiment mark defects (n = 0) in study IOLs changed to post-experiment (n = 7), with no statistical significance obtained (p = 0.059). CONCLUSION: IOL scaffold technique can cause microscopic optic surface changes seen as linear marks defects in the mid periphery and intraoperative fluid maintenance can reduce its incidence. PMID- 27236575 TI - Diabetic retinal pigment epitheliopathy: fundus autofluorescence and spectral domain optical coherence tomography findings. PMID- 27236576 TI - Core needle biopsies and surgical excision biopsies in the diagnosis of lymphoma experience at the Lymph Node Registry Kiel. AB - Current guidelines of the European Society of Medical Oncology recommend surgical excision biopsies of lymph nodes for the diagnosis of lymphoma whenever possible. However, core needle biopsies are increasingly used. We aimed to understand the common practice to choose the method of biopsy in Germany. Furthermore, we wanted to understand performance of surgical excision and core needle biopsies of lymph nodes in the diagnosis of lymphoma. The files of 1510 unselected, consecutive lymph node specimens from a consultation center for lymphoma diagnosis were analyzed. Core needle biopsies were obtained frequently from lymph nodes localized in mediastinal, abdominal, retroperitoneal, or thoracic regions. Patients undergoing core needle biopsies were significantly older and suffered significantly more often from lymphoma than patients undergoing surgical excision biopsies. Although more immunohistochemical tests were ordered by the pathologist for core needle biopsies specimens than for surgical excision biopsies specimens, core needle biopsies did not yield a definite diagnosis in 8.3 % of cases, compared to 2.8 % for SEB (p = 0.0003). Restricting the analysis to cases with a final diagnosis of follicular lymphoma or diffuse large B-cell lymphoma, core needle biopsies identified a simultaneous low- and high-grade lymphoma (transformation) in 3.3 % of cases, compared to 7.6 % for surgical excision biopsies (p = 0.2317). In Germany, core needle biopsies are preferentially used in elderly patients with a high likelihood of suffering from lymphoma. Core needle appeared inferior to surgical excision biopsies at providing a definite diagnosis and at identifying multiple lymphoma differentiations and transformation. PMID- 27236577 TI - Bone marrow niche in immune thrombocytopenia: a focus on megakaryopoiesis. AB - Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by increased bleeding tendency and thrombocytopenia. In fact, the precise pathogenesis of this disease is still not clear. Megakaryopoiesis involves complete differentiation of megakaryocyte (MK) progenitors to functional platelets. This complex process occurs in specific bone marrow (BM) niches composed of several hematopoietic and non-hematopoietic cell types, soluble factors, and extracellular matrix proteins. These specialized microenvironments sustain MK maturation and localization to sinusoids as well as platelet release into circulation. However, MKs in ITP patients show impaired maturation and signs of degradation. Intrinsic defects in MKs and their extrinsic environment have been implicated in altered megakaryopoiesis in this disease. In particular, aberrant expression of miRNAs directing MK proliferation, differentiation, and platelet production; defective MK apoptosis; and reduced proliferation and differentiation rate of the MSC compartment observed in these patients may account for BM defects in ITP. Furthermore, insufficient production of thrombopoietin is another likely reason for ITP development. Therefore, identifying the signaling pathways and transcription factors influencing the interaction between MKs and BM niche in ITP patients will contribute to increased platelet production in order to prevent incomplete MK maturation and destruction as well as BM fibrosis and apoptosis in ITP. In this review, we will examine the interaction and role of BM niches in orchestrating megakaryopoiesis in ITP patients and discuss how these factors can be exploited to improve the quality of patient treatment and prognosis. PMID- 27236578 TI - A rare retrorectal presentation of a bronchogenic cyst: A case report. AB - INTRODUCTION: Bronchogenic cysts are rare abnormalities and a retrorectal presentation is exceptional. Its natural history is not known, but malignant transformation is quite rare. Retrorectal bronchogenic cysts are usually asymptomatic. PRESENTATION OF THE CASE: We present the case of a 36-year-old young man with a past medical history of HIV seropositivity who underwent a procedure to excise a sacral coccyx cyst at another surgical center in February 2009. A histological examination confirmed it was a sacral cyst that was resected in sano. The patient presented with a recurrence of the cyst, and this report describes the combined surgical procedure using a double sacrococcygeal and abdominal approach. DISCUSSION: A complete excision without cyst rupture is recommended to reduce the risk of local recurrence and malignant transformation, as previously reported. Resection can ben performed using multiple approaches depending on the cyst's location CONCLUSION: Herein, we report the case of a retrorectal bronchogenic cyst in a 36 years old man who was initially treated for a pilonidal cyst. A double surgical approach (abdominal and Kraske) resulted in complete resectioning with no reccurrence. PMID- 27236579 TI - Sacral nerve stimulation in the treatment of bowel dysfunction from imperforate anus: A case report. AB - INTRODUCTION: Bowel dysfunction (fecal incontinence and constipation) presents in over 50% of patients after treatment of congenital anal malformations. Sacral nerve stimulation (SNS) for the treatment of fecal incontinence improves function in the majority of patients. We present a case report of the treatment of bowel dysfunction with sacral nerve stimulation in a patient with a history of an imperforate anus. PRESENTATION OF CASE: A twenty year-old female with a history of imperforate anus at birth, repaired during infancy with anorectoplasty, presented with fecal incontinence and constipation. Since childhood, she had been suffering from intermittent constipation with worsening fecal incontinence in early adulthood. Examination revealed mild anal stenosis and mucosal prolapse. Endoanal ultrasound demonstrated intact internal and external sphincter with low resting and squeeze pressures on anal manometry. Flexible sigmoidoscopy was normal. The patient underwent permanent sacral nerve stimulation with a primary goal of improvement in continence and, secondarily, for the alleviation of intermittent chronic constipation. DISCUSSION: At 15 month follow-up, the patient had improvement in fecal incontinence (CCIS of 14 pre-SNS to 1 post-SNS), constipation (CCCS of 28 pre-SNS to 20 post-SNS), and quality of life (FIQOL improved in lifestyle (3.7), coping/behavior (3.4), self perception (3.9), and social embarrassment (4.5). CONCLUSION: Sacral nerve stimulation for the treatment of bowel dysfunction in adults secondary to imperforate anus can be performed safely and with good results. PMID- 27236580 TI - Reoperation after microdiscectomy of lumbar herniation: Case report. AB - INTRODUCTION: Annuloplasty is the modern pathogenetically substantiated surgical technique for managing lumbar disc herniation that improves the outcomes of limited microdiscectomy. Nevertheless, the rare complications require using a special strategy for managing and customizing treatment and reoperation. PRESENTATION OF CASE: We present a clinical case of a patient with transpedicular and interbody fixation reoperation after annuloplasty with Barricaid closure device. The aim of this article is to demonstrate the opportunities of surgical treatment of patients with lumbar disc herniation involving annuloplasty using the Barricaid closure device as the final stage and the ways to resolve possible complications requiring reoperation. DISCUSSION: Searching for the most effective methods for preventing recurrent disc herniation is far from being completed; the need for improving methods and techniques of surgical treatment of this pathology is still topical. Reconstruction of the fibrous ring defect is currently one of the promising areas in preventing recurrent lumbar disc herniation. CONCLUSION: Elimination of rare complications that have emerged after using the Barricaid annular closure device and require reoperation is possible and has satisfactory outcome. PMID- 27236582 TI - Molecular characterization of Ehrlichia canis infecting dogs, Buenos Aires. AB - Canine monocytic ehrlichiosis (CME) is a worldwide potentially fatal tick-borne rickettsial disease of dogs caused by Ehrlichia canis and transmitted by Rhipicephalus sanguineus sensu lato. CME diagnosis includes indirect (serology) and direct (e.g. blood smears and PCR) methods. PCR is more sensitive and specific than direct microscopic examination and positive PCR results confirm infection, whereas positive serologic test results only confirm exposure. The aim of the present study was to perform a molecular characterization of E. canis from canine samples of the Metropolitan Area of Buenos Aires. We studied 223 blood samples of dogs submitted to our institute for CME diagnoses. The samples were initially screened for Anaplasmataceae family by PCR, resulting in 30 positive dogs (13.4%). Subsequently, positive DNAs were analyzed by nested PCR 16S rRNA specific for E. canis or Anaplasma platys, resulting in 15 (6.7%) and 16 (7.2%) positive dogs, respectively. For molecular characterization, samples positive for E. canis were subjected to amplification of a fragment of the dsb and p28 genes. The nucleotide sequences obtained for the dsb fragment resulted in 100% identity with others E. canis found in dogs from different regions of worldwide. The nucleotide sequences obtained for p28 gene resulted in 100% of identity with each other and closely with E. canis str. Jaboticabal (Brazil). Identity with others sequences of E. canis ranged from 76.9 to 79.7%. The occurrence of canine cases molecularly confirmed in Metropolitan Area of Buenos Aires highlights the need for more studies in order to understand epidemiological factors associated with CME, especially the disease transmission dynamic in South America given the existence of two lineages of R. sanguineus sensu lato with different vectorial capacity for transmission of E. canis. PMID- 27236581 TI - Grandeur Alliances: Symbiont Metabolic Integration and Obligate Arthropod Hematophagy. AB - Several arthropod taxa live exclusively on vertebrate blood. This food source lacks essential metabolites required for the maintenance of metabolic homeostasis, and as such, these arthropods have formed symbioses with nutrient supplementing microbes that facilitate their host's 'hematophagous' feeding ecology. Herein we highlight metabolic contributions of bacterial symbionts that reside within tsetse flies, bed bugs, lice, reduviid bugs, and ticks, with specific emphasis on B vitamin and cofactor biosynthesis. Importantly, these arthropods can transmit pathogens of medical and veterinary relevance and/or cause infestations that induce psychological and dermatological distress. Microbial metabolites, and the biochemical pathways that generate them, can serve as specific targets of novel control mechanisms aimed at disrupting the metabolism of hematophagous arthropods, thus combatting pest invasion and vector borne pathogen transmission. PMID- 27236583 TI - Visual intraoperative estimation of range of motion is misleading in minimally invasive total hip arthroplasty. AB - INTRODUCTION: Generally range of motion (ROM) in total hip arthroplasty (THA) is intraoperatively assessed by eye. Can we assume that visual estimation of ROM is reliable? METHODS: 60 patients underwent cementless THA in a subgroup analysis of a clinical prospective trial using a minimally invasive anterolateral approach in lateral decubitus position. Four experienced surgeons intraoperatively estimated ROM visually by assessment of the femur relative to the alignment of the patient's pelvis. These estimations were compared with computer navigation measurements. RESULTS: We found a mean difference between navigation measurements and intraoperative estimations by eye of -5.6 degrees (+/-10.9 degrees ; -17 degrees to 30 degrees ) for flexion, respectively, -0.4 degrees (+/-10.7 degrees ; -24 degrees to 30 degrees ) for extension, 8.7 degrees (+/-9.0 degrees ; -10 degrees to 34 degrees ) for abduction, 5.9 degrees (+/-18.3 degrees ; -58 degrees to 68 degrees ) for external rotation and -5.8 degrees (+/-12.1 degrees ; -38 degrees to 22 degrees ) for internal rotation. Multivariate analysis showed no association between the visual accuracy of estimation of ROM and patient characteristics, such as BMI, sex, grade of osteoarthritis and treatment side except for a significant correlation of visual accuracy of estimation of extension and the level of professional experience. Otherwise, the level of professional experience had no impact on the accuracy of estimation of ROM by eye. CONCLUSIONS: Even the experienced surgeon's intraoperative estimation of ROM by eye is not reliable and differs up to 30 degrees compared to objective measurements in minimally invasive THA. For accurate intraoperative assessment of ROM, the use of technical devices is recommended. TRIAL REGISTRATION: DRKS00000739. PMID- 27236584 TI - The Penrod score: a prognostic instrument to balance an increasing geriatric fracture caseload with diminishing health care resources? AB - INTRODUCTION: Geriatric hip fracture patients are a highly heterogeneous collective, what distinctly aggravates the best possible treatment. Consequently, it is becoming more important to identify selection criteria that can distinguish those patients who can benefit the most from treatment in a geriatric fracture center. In our pilot study, we assessed the 2007 published Penrod score for its utility as a useful selection tool by prospectively comparing our own patient's outcome with the Penrod study. METHODS: 77 patients treated for geriatric hip fracture were preoperatively classified according to the Penrod score. Patients were divided into three clusters by age (1: <75 years, 2: 75-84 years, 3: >=85 years). Clusters 2 and 3 were then classified according to their ability to perform activities of daily living (ADL's) and cognitive status (presence or absence of dementia). In 51 out of these 77 patients, the ability to perform ADLs could be assessed 6 months postoperatively and was compared with the Penrod scores. RESULTS: 58 % of cluster 1 patients were able to perform 4 ADLs independently 6 months postoperatively (52.9 % Penrod study). In clusters 2A and 3A, 48 and 50 %, respectively, were able to perform 4 ADLs independently, compared with 40.6 and 31.5 % (Penrod collective). 22 % of our patients in 2B performed all ADLs independently (3.6 % Penrod) and 25 % in cluster 3B (9.4 % Penrod). CONCLUSION: Our preliminary results support the prognostic value of the Penrod score in the treatment of geriatric hip fracture patients. With the help of the Penrod score, it may be possible to identify patients, who are expected to significantly profit from an intensified treatment in a geriatric fracture center (clusters 2B, 3A, and 3B). By utilizing this score, improved outcomes and simultaneously a more effective utilization of valuable health care resources could be achieved. PMID- 27236586 TI - The association between social support and smoking status in cancer survivors with frequent and infrequent mental distress: results from 10 US states, 2010. AB - PURPOSE: This study examined the association between social support and smoking status among adult cancer survivors, with special emphasis on mental health differences using data from 10 US states. METHODS: Cross-sectional data from the 2010 Behavioral Risk Factor Surveillance System, Cancer Survivorship module on 8055 cancer survivors were analyzed. Sample weights were applied for the generalization of results to 2.6 million cancer survivors. RESULTS: In 2010, 15.6 % (418,700) were current, 38.4 % (1.03 million) former, and 46.0 % (1.2 million) never smokers. About 18.0 % of cancer survivors reported receiving the lowest level of social support and 12.1 % reported experiencing frequent mental distress in the past 30 days. Participants' mean age at the time of the first cancer diagnosis was 51.0 (standard error (SE) = 0.33) and mean time since their diagnosis was 11.3 years (SE = 0.18). Compared to those with infrequent mental distress, cancer survivors with frequent mental distress were diagnosed at a younger age (45.0 vs. 51.8), more likely to be current smokers (36.8 vs. 12.7 %), and less likely to always receive social support they needed (33.4 vs. 56.3 %). Cancer survivors who received higher levels of social support were less likely to be current smokers than those who received the lowest level of social support they needed. Among cancer survivors who reported frequent mental distress, non Hispanic blacks were more likely to be current smokers than non-Hispanic whites. CONCLUSIONS: Rates of current smokers were lower among cancer survivors who received social support and reported infrequent mental distress. IMPLICATIONS FOR CANCER SURVIVORS: Psychosocial screening may help health care professional identify smokers with frequent mental distress who require more intensive smoking cessation interventions. PMID- 27236587 TI - Systemic treatment for blepharokeratoconjunctivitis in children. AB - BACKGROUND: Blepharokeratoconjunctivitis (BKC) is a type of inflammation of the surface of the eye and eyelids which can affect children and adults. BKC involves changes of the eyelids, dysfunction of the meibomian glands, and inflammation of the conjunctiva and cornea. Chronic inflammation of the cornea can lead to scarring, vascularisation and opacity. BKC in children can cause significant symptoms which include irritation, watering, photophobia and loss of vision. Loss of vision in children with BKC may be due to corneal opacity, refractive error or amblyopia.BKC treatment is directed towards the obstruction of meibomian gland openings, the bacterial flora of lid margin and conjunctiva, and ocular surface inflammation. Dietary modifications that involve increased intake in essential fatty acids (EFAs) may also be beneficial. Both topical and systemic treatments are used; this Cochrane review focuses on systemic treatments. OBJECTIVES: To assess and compare data on the efficacy and safety of systemic treatments (including antibiotics, nutritional supplements and immunosuppressants), alone or in combination, for BKC in children aged between zero to 16 years. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to April 2016), EMBASE (January 1980 to April 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 21 April 2016. SELECTION CRITERIA: We searched for randomised controlled trials that involved systemic treatments in children aged between zero to 16 years with a clinical diagnosis of BKC. We planned to include studies that evaluated a single systemic medication versus placebo, and studies that compared two or multiple active treatments. We planned to include studies in which participants receive additional treatments, such as topical antibiotics, anti-inflammatories and lubricants, warm lid compresses and lid margin cleaning. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the literature search results (titles and abstracts) to identify studies that possibly met the inclusion criteria of the review. We divided studies into 'definitely include', 'definitely exclude' and 'possibly include' categories. We made a final judgement as to the inclusion or exclusion of studies in the 'possibly include' category after we obtained the full text of each article. MAIN RESULTS: No report or trial met the inclusion criteria of this Cochrane review; no randomised controlled trials have been carried out on this topic. There is a lack of standardised outcome measures. AUTHORS' CONCLUSIONS: There is currently no evidence from clinical trials regarding the safety and efficacy of systemic treatments for BKC. Trials are required to test efficacy and safety of current and future treatments. Outcome measures need to be developed which can capture both objective clinical and patient-reported aspects of the condition and treatments. PMID- 27236585 TI - Factors associated with the course of health-related quality of life after a hip fracture. AB - INTRODUCTION: The number of hip fracture patients is expected to grow the forthcoming decades. Knowledge of the impact of the fracture on the lives of elderly could help us target our care. The aim of the study is to describe HRQoL (Health-Related Quality of Life) after a hip fracture and to identify factors associated with the course of HRQoL in the first postoperative year. MATERIALS AND METHODS: 335 surgically treated hip fracture patients (mean age 79.4 years, SD 10.7, 68 % female) were included in a prospective observational cohort. HRQoL was measured with the SF-12 Health Survey, composed of the Physical and a Mental Component Summary Score (PCS, MCS), at admission (baseline) and at 3 and 12 months postoperatively. Eleven predefined factors known to be associated with the course of HRQoL were recorded: age, gender, physical status, having a partner at admission, living in an institution, prefracture level of mobility, anemia, type of fracture and treatment, delirium during hospital stay and length of stay. RESULTS: HRQoL declined between baseline and 3 months, and recovered between three and 12 months. PCS HRQoL did not recover to baseline values, MCS HRQoL did. Age younger than 80 years, ASA classification I and II, higher prefracture level of mobility, intracapsular fracture and treatment with osteosynthesis (compared to arthroplasty) were associated with greater initial decline in PCS HRQoL, none of the recorded factors were significant for decline in MCS HRQoL. CONCLUSIONS: Both PCS and MCS HRQoL declined after a hip fracture and PCS did not recover to baseline values. Healthier patients may need extra care to prevent them from having a steep decline in postoperative PCS HRQoL and arthroplasty should be considered with low threshold. PMID- 27236588 TI - Childhood physical neglect promotes development of mild cognitive impairment in old age - A case-control study. AB - This study aimed to investigate the role of early traumatic experiences in development of mild cognitive impairment (MCI) in Chinese elderly people. Seventy six patients and 61 controls were selected and assigned into two study groups, MCI and control, respectively. Childhood Trauma Questionnaire-Short Form (CTQ-SF) was used for assessment of early trauma, episodic memory and association learning scales for memory evaluation. In addition, event-related potentials (ERPs) were measured using electroencephalography (EEG) to indicate brain electrical activity of subjects during memory/cognitive tests. MCI patients showed higher scores of physical neglect and lower scores of emotional abuse in childhood than control group. Physical neglect score was negatively correlated with scores of MMSE, MoCA, episodic memory, calculation, and the amplitude of CzP300, FzP300 and PzP300, while a positive correlation was seen between the score of physical neglect and the latency of PzN200, FzN200, CzN200, CzP300, FzP300 and PzP300. The score of emotional abuse was weakly correlated with FzP300 amplitude, but not with any other ERP components. Our results suggested that early childhood exposure to physical neglect may lead to impairment in learning and memory, particularly in the associative learning and episodic memory, in old age. PMID- 27236589 TI - Enhancing self-efficacy improves episodic future thinking and social-decision making in combat veterans with posttraumatic stress disorder. AB - Posttraumatic Stress Disorder (PTSD) is associated with maladaptive changes in self-identity, including impoverished perceived self-efficacy. This study examined if enhancing perceptions of self-efficacy in combat veterans with and without symptoms of PTSD promotes cognitive strategies associated with positive mental health outcomes. Prior to completing a future thinking and social problem solving task, sixty-two OEF/OIF veterans with and without symptoms of PTSD were randomized to either a high self-efficacy (HSE) induction in which they were asked to recall three autobiographical memories demonstrating self-efficacy or a control condition in which they recalled any three autobiographical events. An interaction between HSE and PTSD revealed that individuals with symptoms of PTSD in the HSE condition generated future events with more self-efficacious statements than those with PTSD in the control condition, whereas those without PTSD did not differ in self-efficacy content across the conditions. In addition, individuals in the HSE condition exhibited better social problem solving than those in the control condition. Increasing perceptions of self-efficacy may promote future thinking and problem solving in ways that are relevant to overcoming trauma and adversity. PMID- 27236590 TI - Samaritan donation: A new challenge for the Italian transplant community. PMID- 27236592 TI - February 2015 (vol. 212, no. 2, page 196). PMID- 27236591 TI - Fluoropyrimidine-Based Chemotherapy as First-Line Treatment for Advanced Gastric Cancer: a Bayesian Network Meta-Analysis. AB - Fluoropyrimidine-based regimens are the most common treatments in advanced gastric cancer. We used a Bayesian network meta-analysis to identify the optimal fluoropyrimidine-based chemotherapy by comparing their relative efficacy and safety. We systematically searched databases and extracted data from randomized controlled trials, which compared fluoropyrimidine-based regimens as first-line treatment in AGC. The main outcomes were overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and grade 3 or 4 adverse events (AEs). A total of 12 RCTs of 4026 patients were included in our network meta analysis. Pooled analysis showed S-1 and capecitabine had a significant OS benefit over 5-Fu, with hazard ratios of 0.90 (95%CI = 0.81-0.99) and 0.88 (95%CI = 0.80-0.96), respectively. The result also exhibited a trend that S-1 and capecitabine prolonged PFS in contrast to 5-Fu, with hazard ratios of 0.84 (95%CI = 0.66-1.02) and 0.84 (95%CI = 0.65-1.03), respectively. Additionally, all the three fluoropyrimidine-based regimens were similar in terms of ORR and grade 3 or 4 AEs. Compared with regimens based on 5-Fu, regimens based on S-1 or capecitabine demonstrated a significant OS improvement without compromise of AEs as first-line treatment in AGC in Asian population. S-1 and capecitabine can be interchangeable according their different emphasis on AEs. PMID- 27236593 TI - Precision Obesity Treatments Including Pharmacogenetic and Nutrigenetic Approaches. AB - Five pharmaceutical strategies are currently approved by the US FDA for the treatment of obesity: orlistat, lorcaserin, liraglutide, phentermine/topiramate, and bupropion/naltrexone. The most effective treatment seems to be the combined administration of phentermine/topiramate followed by lorcaserin and bupropion/naltrexone. In relation to the management of excessive weight, other aspects also need to be considered, including comorbidities accompanying obesity, drug interactions, and the risk of negative collateral effects, as well as individualized treatments based on the genetic make-up. This review aims to provide an overview of the approved anti-obesity drugs and newer molecules that could affect different targets in the central nervous system or peripheral tissues, the molecular mechanisms, emerging dietary treatments and phytogenic compounds, and pharmacogenetic/nutrigenetic approaches for personalized obesity management. PMID- 27236594 TI - Quantification of human-associated fecal indicators reveal sewage from urban watersheds as a source of pollution to Lake Michigan. AB - Sewage contamination of urban waterways from sewer overflows and failing infrastructure is a major environmental and public health concern. Fecal coliforms (FC) are commonly employed as fecal indicator bacteria, but do not distinguish between human and non-human sources of fecal contamination. Human Bacteroides and human Lachnospiraceae, two genetic markers for human-associated indicator bacteria, were used to identify sewage signals in two urban rivers and the estuary that drains to Lake Michigan. Grab samples were collected from the rivers throughout 2012 and 2013 and hourly samples were collected in the estuary across the hydrograph during summer 2013. Human Bacteroides and human Lachnospiraceae were highly correlated with each other in river samples (Pearson's r = 0.86), with average concentrations at most sites elevated during wet weather. These human indicators were found during baseflow, indicating that sewage contamination is chronic in these waterways. FC are used for determining total maximum daily loads (TMDLs) in management plans; however, FC concentrations alone failed to prioritize river reaches with potential health risks. While 84% of samples with >1000 CFU/100 ml FC had sewage contamination, 52% of samples with moderate (200-1000 CFU/100 ml) and 46% of samples with low (<200 CFU/100 ml) FC levels also had evidence of human sewage. Load calculations in the in the Milwaukee estuary revealed storm-driven sewage contamination varied greatly among events and was highest during an event with a short duration of intense rain. This work demonstrates urban areas have unrecognized sewage inputs that may not be adequately prioritized for remediation by the TMDL process. Further analysis using these approaches could determine relationships between land use, storm characteristics, and other factors that drive sewage contamination in urban waterways. PMID- 27236595 TI - Analysis of tooth preparations for zirconia-based crowns and fixed dental prostheses using stereolithography data sets. AB - STATEMENT OF PROBLEM: Under clinical circumstances, it can be challenging for a dentist to achieve an adequate tooth preparation, which is essential for the long term success of fixed dental restorations. This is particularly true for zirconia restorations fabricated by computer-aided design and computer-aided manufacturing (CAD-CAM) because of the difficulties involved in the scanning and milling process. PURPOSE: The purpose of this retrospective study was to use a digital approach to evaluate dental tooth preparations for zirconia-based crowns and fixed dental prostheses (FDP) performed by general dental practitioners in Germany and to find out whether the type of prepared tooth or the type of restoration influenced the outcome. MATERIAL AND METHODS: Stereolithography data sets of 182 zirconia frameworks with a total of 305 abutment teeth obtained by the CAD-CAM process were analyzed regarding total occlusal convergence, abutment height, and finish line design using a 3-dimensional (3D) inspection and mesh processing software. The criteria for adequate preparations were defined based on current literature and compared with the measurement results. The Kruskal-Wallis 1-way analysis of variance and the Mann-Whitney U test were applied to detect significant differences (alpha=.05). RESULTS: Only 13 teeth (4.3%) met the clinical requirements for adequate zirconia-based tooth preparations. The mean total occlusal convergence was 17.9 +/-9.7 degrees. Molars (23.2 +/-10.1 degrees) showed statistically significant difference (P<.001) when compared with premolars (14.2 +/-8.2 degrees) and anterior teeth (16.4 +/-8.1 degrees). No significant difference was observed between the crown and FDP preparations. The mean abutment height was 5.6 +/-1.3 mm. Again, significant differences occurred when tooth types (4.8 +/-1.0 mm for molars, 5.2 +/-0.9 mm for premolars and 6.9 +/-1.2 mm for anterior teeth; P<=.01) were compared. In 92.5% of teeth, the finish line design was not ideal for zirconia-based restorations. CONCLUSION: The tooth preparations of general dental practitioners differ from the ideal clinical preparation recommended for zirconia-based restorations. Difficulties are primarily related to the total occlusal convergence and finish line design. Although the outcome is strongly influenced by the type of tooth, the type of restoration seems to have only a minor effect on the tooth preparation quality. PMID- 27236596 TI - Mandibular kinesiographic pattern of women with chronic TMD after management with educational and self-care therapies: A double-blind, randomized clinical trial. AB - STATEMENT OF PROBLEM: Limited mandibular movements are one of the most important signs of temporomandibular disorders (TMDs) and may cause functional difficulties. PURPOSE: The purpose of this double-blind, randomized clinical trial was to evaluate the effect of treatment with only educational or education associated with self-care therapies on the pattern of mandibular movements of women with chronic painful TMDs. MATERIAL AND METHODS: Forty-two women were selected and randomly divided into 3 groups, control group (CG, n=13), education group (EG, n=16), and education and self-care group (ESG, n=13), according to the sequence of treatment they received. A kinesiograph device recorded mandibular movements during maximum mouth opening and mastication at baseline (T0) and at 30 day (T1) and 60-day (T2) follow-up. Kinesiographic data were statistically analyzed using 1-way ANOVA, followed by the Bonferroni test for multiple comparisons of means (alpha=.05). RESULTS: The ESG group demonstrated an improvement in the maximum vertical opening (MVO= 5.1 +/-3.4 mm; P=.012) and anteroposterior mandibular movement (MAM) during maximum opening (7.4 +/-9.5; P=.019), significantly higher than that of the EG (MVO=1.8 +/-3.5 mm; MAM=0.8 +/ 5.0 mm) and the CG (MVO=0.9 +/-3.8 mm; MAM=0.8 +/-4.4 mm) after 30 days of follow up. Moreover, at T1, vertical mandibular movement during mastication was significantly higher in the ESG group (17.4 +/-1.7 mm) than in the EG group (15.0 +/-2.8, P=.027). No significant differences were found between the women who received treatment with educational and self-care therapies for 60 days and the women who received this treatment for 30 days. CONCLUSIONS: In the short-term, education and self-care treatment positively influenced the mandibular movement pattern of women with chronic painful TMDs. PMID- 27236597 TI - A comparison of two digital techniques for the fabrication of complete removable dental prostheses: A pilot clinical study. AB - STATEMENT OF PROBLEM: The introduction of digital techniques might improve the quality and cost-effectiveness of treatment with complete removable dental prostheses (CDs). PURPOSE: The purpose of this pilot clinical trial was to study and compare the clinical feasibility, complications during fabrication, and quality of 2 types of digitally designed CDs. MATERIAL AND METHODS: Five participants were recruited into this preliminary clinical trial. For each participant, 2 pairs of digital CDs were designed. Prosthesis bases were fabricated by using identical data, either by milling from polymethyl methacrylate blanks or by injection molding. The treatment involved 4 clinical appointments. Polyvinyl siloxane impressions were made with custom trays and were subsequently digitalized. After evaluating esthetics and function with trial dentures, the CD bases were fabricated. To evaluate the workflow and quality of the prostheses, the clinical outcome was measured on 6-point scales ranging from poor (grade 6) to excellent (grade 1). For both prosthesis types, the following aspects were examined: fit, retention, esthetics, phonetics, maxillomandibular relation, and occlusion. RESULTS: Both types of digital CDs could be fabricated without major complications. Only a few minor complications occurred during the fabrication process, predominantly esthetic issues. No pronounced difference was found between the prostheses concerning functional aspects. The definitive esthetic outcome was rated as very good. CONCLUSIONS: The CDs fabricated using digital technology met the clinical requirements. However, more research is needed to confirm the results of this investigation. PMID- 27236598 TI - Analysis of DNAJC13 mutations in French-Canadian/French cohort of Parkinson's disease. AB - DNAJC13 mutations have been suggested to cause Parkinson's disease (PD), yet subsequent studies reported conflicting results on this association. In the present study, we sequenced the coding region of DNAJC13 in a French Canadian/French cohort of 528 PD patients and 692 controls. A total of 62 (11.7%) carriers of rare DNAJC13 variants were identified among the PD patients compared with 82 (11.8%) among controls (p = 1.0). Two variants that were previously suggested to be associated with PD, p.R1516H and p.L2170W, were identified with similar directions of association as previously reported. The p.R1516H was found in 2 (0.4%) patients versus 6 (0.9%, nonsignificant) controls and the p.L2170W variant was found in 9 (1.7%) patients and 5 (0.7%, nonsignificant) controls. Meta-analysis with previous reports resulted in odds ratios of 0.32 (95% confidence interval = 0.15-0.68, p = 0.0037) and 2.68 (95% confidence interval = 1.32-5.42, p = 0.007), respectively. Our results provide some support for the possibility that specific DNAJC13 variants may play a minor role in PD susceptibility, although studies in additional populations are necessary. PMID- 27236599 TI - Body mass index, age and in-hospital mortality: The NutritionDay multinational survey. AB - BACKGROUND & AIMS: Several large and long-term prospective studies have assessed the association of body-mass index (BMI) next to age with the risk of death in the general population, but few have examined the association with in-hospital mortality. We investigated the association between BMI, age and in-hospital mortality. METHODS: We used data collected during 9 consecutive one-day/year surveys (NutritionDay in hospital 2006-2014) conducted in non-critically ill adult patients from 2,183 hospitals across 51 nations from 4 continents. We examined the association of BMI and age with the risk of in-hospital (30-day) death using logistic regression analysis adjusted for multiple confounders. RESULTS: Crude mortality rates were 3.6% (95%CI, 3.5-3.7) and 2.1% (95%CI, 2.0 2.3) in the overall cohort (N = 97,344) and in those assessed within 72 hours since admission (N = 32,363), respectively. BMI and age were independently associated with the risk of death (no interaction observed), which decreased with BMI and increased with age. In the overall cohort, compared to normal weight status (BMI 18.5-24.9 kg/m2), death odds ratios for underweight (BMI < 18.5), overweight (BMI 25.0-29.9) and obesity (BMI >=30) were 1.35 (95%CI, 1.20-1.53), 0.87 (95%CI, 0.77-0.97) and 0.73 (95%CI, 0.62-0.86), respectively. In patients assessed within 72 hours since admission, the associations were comparable: for underweight, 1.48 (95%CI, 1.11-1.96); for overweight, 0.80 (95%CI, 0.65-0.97); for obesity, 0.75 (95%CI, 0.58-0.96). CONCLUSION: In adult hospitalized patients BMI and age are independent predictors of in-hospital mortality. Low body weight is confirmed being a risk factor for death as in the general population, while overweight and obesity appear protective conditions. In the hospital setting, the use of normal weight status as reference low-risk category could also be challenged. PMID- 27236600 TI - MicroRNA signature of end-stage idiopathic pulmonary arterial hypertension: clinical correlations and regulation of WNT signaling. PMID- 27236601 TI - Asthma in pregnancy: association between the Asthma Control Test and the Global Initiative for Asthma classification and comparisons with spirometry. AB - OBJECTIVE: The aim of this study was to identify a possible association between the assessment of clinical asthma control using the Asthma Control Test (ACT) and the Global Initiative for Asthma (GINA) classification and to perform comparisons with values of spirometry. STUDY DESIGN: Through this cross-sectional study, 103 pregnant women with asthma were assessed in the period from October 2010 to October 2013 in the asthma pregnancy clinic at the Clinical Hospital of the Federal University of Pernambuco. Questionnaires concerning the level of asthma control were administered using the Global Initiative for Asthma classification, the Asthma Control Test validated for asthmatic expectant mothers and spirometry; all three methods of assessing asthma control were performed during the same visit between the twenty-first and twenty-seventh weeks of pregnancy. RESULTS: There was a significant association between clinical asthma control assessment using the Asthma Control Test and the Global Initiative for Asthma classification (p<0.001). There were also significant associations between the results of the subjective instruments of asthma (the GINA classification and the ACT) and evidence of lung function by spirometry. CONCLUSIONS: This study shows that both the Global Initiative for Asthma classification and the Asthma Control Test can be used for asthmatic expectant mothers to assess the clinical control of asthma, especially at the end of the second trimester, which is assumed to be the period of worsening asthma exacerbations during pregnancy. We highlight the importance of the Asthma Control Test as a subjective instrument with easy application, easy interpretation and good reproducibility that does not require spirometry to assess the level of asthma control and can be used in the primary care of asthmatic expectant mothers. PMID- 27236602 TI - A randomized, single-blind, prospective trial comparing three different gonadotropin doses with or without addition of letrozole during ovulation stimulation in patients with poor ovarian response. AB - OBJECTIVE: The aim of this randomized controlled trial (RCT) was to investigate whether IVF outcomes would differ between patients with POR who received three different gonadotropin doses with or without the addition of letrozole during ovulation stimulation. STUDY DESIGN: Only those who fulfilled two of the three Bologna criteria were included to the study. 95 patients met the inclusion criteria and agreed to participate in the study. In the first group, 31 patients were treated with 450IU gonadotropins. In the second group, 31 patients were treated with 300IU gonadotropins. The third group comprised 33 patients and was treated with 150IU gonadotropins in combination with letrozole. RESULTS: The results indicate that differences in doses of hMG and rFSH in patients with POR result in a similar number of retrieved MII and fertilized oocytes, similar fertilization rates, number of transferred embryos, implantation, cancelation, chemical, clinical, and ongoing pregnancy rates. CONCLUSIONS: Increasing the dose of gonadotropins during ovulation stimulation is an intuitively appealing approach when the patient is a poor responder. However, increasing the dose does not necessarily improve the reproductive outcome. Using a mild stimulation with addition of letrozole was as effective as stimulation with higher doses of gonadotropins alone in this patient population. PMID- 27236603 TI - Analysis of pregnancy outcomes for survivors of the vanishing twin syndrome after in vitro fertilization and embryo transfer. AB - OBJECTIVE: The purpose of this study was to compare pregnancy outcomes of in vitro fertilization (IVF) singletons diagnosed with vanishing twin syndrome with control pregnancies originating as singleton pregnancies and with twin pregnancies. STUDY DESIGN: The current research included 206 survivors of a vanished co-twin, 1730 primary singletons and 662 primary twins. The study group was subdivided according to gestational age at the time of vanishing to give groups of early (<=12 weeks, group A) and late (>12 weeks, group B) survivors. Pregnancy outcomes were compared among study groups and controls. RESULTS: 10.54% of all IVF singleton deliveries originated from a twin gestation. Group A showed similar mean gestational age (P=0.148) but higher proportion of preterm delivery (P=0.000), extremely preterm delivery (P=0.000), low birth weight (P=0.000) and very low birth weight (P=0.000) when compared with singleton controls. The comparison between group B and the singleton controls revealed dramatically higher frequency of preterm delivery (P=0.000), extreme preterm delivery (P=0.000), low birth weight (P=0.000), very low birth weight (P=0.000) and neonatal mortality (P=0.000). When compared with twin controls, group A showed lower risk of adverse pregnancy outcomes; in contrast, group B still showed significant higher adverse risk. CONCLUSIONS: IVF singletons with a vanished co twin had a higher rate of adverse pregnancy outcomes in terms of preterm delivery and low birth weight, compared with IVF pregnancies that were originally singleton and twins, and the risk is increased with increasing gestational age at the time of vanishing. PMID- 27236604 TI - The impact of premature progesterone rise on the outcome of intrauterine insemination cycles with controlled ovarian hyperstimulation in unexplained infertility. AB - OBJECTIVE: To ascertain the incidence of premature progesterone P rise and its impact on outcomes in controlled ovarian hyperstimulation and intrauterine insemination (COH-IUI) cycles, and also to identify variables related with premature P rise. STUDY DESIGN: Four hundred sixty cycles of 460 couples with unexplained infertility having COH-IUI treatment with a starting dose of 75IU recombinant FSH enrolled in this prospective study. Serum P levels were determined on the day of hCG trigger. Premature P rise was defined as progesterone >=1ng/mL. The primary outcome measure was live birth per cycle with regard to P levels of >=1ng/mL and >=1.5ng/mL. Secondary outcome measures were cycle characteristics associated with P rise. RESULTS: The incidence of premature P rise was 22.0%. P levels on hCG day were significantly lower in cycles with live birth as compared to cycles without live birth 0.49+/-0.51 vs. 0.73+/ 0.82ng/mL. Live birth rates were significantly lower in cycles with hCG day P levels >=1.0ng/mL (%7.9 vs. %22.6) and >=1.5ng/mL (%6.4 vs. %20.8). Among age, number of dominant follicles, estradiol, LH and P levels on the day of hCG trigger, it was found that P levels was the only significant variable to predict live birth on multivariate analysis. The number of dominant follicles on hCG day and premature LH surge were the only significant variables related with premature P rise. CONCLUSION: Premature P is a frequent feature of COH-IUI cycles and associated with decreased live birth rates. PMID- 27236605 TI - Underweight subjects with anorexia nervosa have an enhanced salivary cortisol response not seen in weight restored subjects with anorexia nervosa. AB - The cortisol response to awakening (CAR) has been reported to be enhanced in symptomatic patients with anorexia nervosa (AN). However, it has been not established whether the dysregulation of CAR was a primary phenomenon or a change secondary to malnutrition. Therefore, we aimed to explore the salivary CAR in both underweight and weigh-restored women with AN. Fifty-nine women volunteered for the study. They were 18 underweight AN women, 15 weight-restored AN women and 26 normal-weight healthy women. Saliva samples were collected in the morning, immediately on awakening and after 15, 30 and 60min to measure saliva levels of cortisol. Participants' anxiety levels in the morning of sampling were measured by the State-Trait Anxiety Inventory. As compared to control women, underweight AN patients showed an enhanced CAR whereas weight-restored patients had a normal CAR. These results could be not explained by group differences in body mass index or levels of anxiety. These findings show, for the first time, that the enhanced CAR occurring in the acute phase of AN is not seen in weight-recovered patients, suggesting that the dysregulated activity of the hypothalamus-pituitary-adrenal axis of symptomatic AN patients is a state-dependent phenomenon. PMID- 27236607 TI - New spectral thresholds improve the utility of the electroencephalogram for the diagnosis of hepatic encephalopathy. AB - OBJECTIVE: The utility of the electroencephalogram (EEG) for the diagnosis of hepatic encephalopathy, using conventional spectral thresholds, is open to question. The aim of this study was to optimise its diagnostic performance by defining new spectral thresholds. METHODS: EEGs were recorded in 69 healthy controls and 113 patients with cirrhosis whose neuropsychiatric status was classified using clinical and psychometric criteria. New EEG spectral thresholds were calculated, on the parietal P3-P4 lead derivation, using an extended multivariable receiver operating characteristic curve analysis. Thresholds were validated in a separate cohort of 68 healthy controls and 113 patients with cirrhosis. The diagnostic performance of the newly derived spectral thresholds was further validated using a machine learning technique. RESULTS: The diagnostic performance of the new thresholds (sensitivity 75.0%; specificity 77.4%) was better balanced than that of the conventional thresholds (58.3%; 93.2%) and comparable to the performance of a machine learning technique (72.9%; 76.8%). The diagnostic utility of the new thresholds was confirmed in the validation cohort. CONCLUSIONS: Adoption of the new spectral thresholds would significantly improve the utility of the EEG for the diagnosis of hepatic encephalopathy. SIGNIFICANCE: These new spectral EEG thresholds optimise the performance of the EEG for the diagnosis of hepatic encephalopathy and can be adopted without the need to alter data recording or the initial processing of traces. PMID- 27236606 TI - The developmental relationship between DHEA and visual attention is mediated by structural plasticity of cortico-amygdalar networks. AB - Humans and the great apes are the only species demonstrated to exhibit adrenarche, a key developmental event leading to increased production of dehydroepiandrosterone (DHEA), suggesting that this hormone may play an important evolutionary role. Similarly, visual attention networks have been shown to evolve in a human-specific manner, with some anatomical connections and elements of cortical organization exclusive to our species. Existing studies of human brain development support the notion that DHEA shows significant uptake in cortical structures and the amygdala, and as such, could be involved in the bottom-up regulation of visual attention. Here we examined associations between DHEA, structural covariance of the amygdala with whole-brain cortical thickness, and tests of visual attention, in a longitudinal sample of typically developing children and adolescents 6-22 years of age. We found that DHEA predicted covariance between amygdalar volume and the left occipital pole, right somatosensory parietal cortex and right anterior cingulate cortex. Amygdala occipital covariance predicted visual awareness; amygdala-parietal covariance predicted visuo-motor dexterity and processing speed; amygdala-prefrontal covariance predicted global attentional impairment. Further, effects of DHEA were above and beyond those of age and sex, as well as distinct from those of pubertal stage, estradiol and testosterone. These findings support the notion that DHEA may play a unique role in shaping amygdala-dependent cortical plasticity and in regulating 'bottom-up' visual attention processes from childhood to young adulthood. PMID- 27236608 TI - Quick and accurate quantification of the premature brain. PMID- 27236609 TI - Circumvent CO2 Effects in Volatile-Based Microbe-Plant Interactions. PMID- 27236610 TI - Orbital liposarcoma. AB - CASE REPORT: The case is presented of a 46-year-old male with right eye proptosis and conjunctival hyperaemia, of 18 months onset. A well-defined intraconal mass was found in the computed tomography. In magnetic resonance this was hypo-intense on T1, enhanced with gadolinium and hyperintense on T2. Excisional biopsy was performed, which was reported as a well-differentiated liposarcoma in the histopathology study. DISCUSSION: Liposarcoma is a malignant adipose tissue tumour. It is very rare in the orbit, with 5 histological types, the most common being myxoid. The treatment of choice is wide surgical excision and may be accompanied with radiotherapy. As it is an infiltrative tumour, It has a high rate of recurrence. PMID- 27236611 TI - In Vitro Comparison of Second- and Third-generation Dual-source CT for Coronary Stent Visualization at Different Tube Potentials. AB - RATIONALE AND OBJECTIVES: The study aimed to evaluate in vitro stent lumen visibility of coronary stents in a second- and third-generation dual-source computed tomography (CT) system at 100 and 120 kVp tube potential. MATERIALS AND METHODS: Twenty-six coronary stents ranging from 2.25 to 4.0 mm in diameter were implanted in a coronary vessel phantom. Scans were performed at 100 and 120 kVp tube potential. Evaluation was performed using a medium-sharp kernel in both systems (B46f in the second-generation and Bv49 in the third-generation model) and a sharp (Bv59) convolution kernel optimized for vascular imaging in the third generation CT. RESULTS: The median visible stent lumen diameter in the second generation system was higher at 120 kVp with a median of 62.0% compared to 56.3% at 100 kVp (P < 0.001). The median visible diameter in the third-generation system was significantly higher applying the Bv49 kernel with 66.7% at 120 kVp and 61.1% at 100 kVp (both P < 0.001). When applying the Bv59 kernel, visible stent lumen further increased to 69.3% at 120 kVp and 66.7% at 100 kVp. Additionally, stent lumen was assessed using full width at half maximum, resulting in a comparable increase in luminal diameter at corresponding tube potential. CONCLUSIONS: Third-generation dual-source CT provides superior stent lumen visibility at equivalent tube potential and at reduced tube potential of 100 kVp when compared to 120 kVp in a second-generation system, at least when manually assessed. PMID- 27236612 TI - Association between Breast Parenchymal Complexity and False-Positive Recall From Digital Mammography Versus Breast Tomosynthesis: Preliminary Investigation in the ACRIN PA 4006 Trial. AB - RATIONALE AND OBJECTIVES: We investigate associations between measures of mammographic parenchymal complexity and false-positive (FP) recall from screening with digital mammography (DM) versus digital breast tomosynthesis (DBT). MATERIALS AND METHODS: We retrospectively analyzed data from 541 women recruited by the American College of Radiology Imaging Network 4006 trial, designed to evaluate callback and detection rates from screening with DM versus combined DM and DBT. Of these, 68 and 56 were FPs based on DM alone versus the combined DM/DBT readings, respectively. Mammographic complexity was quantified with computerized texture analysis and percent density. Logistic regression was performed to evaluate associations between extracted features and FP recall, after adjusting for age and number of previous benign biopsies. Odds ratios and area under the curve (AUC) of the receiver operating characteristic were used to assess association strength. RESULTS: For DM, age, previous benign biopsies and texture features of correlation, inverse difference moment, sum average, and sum variance were deemed as significant predictors (P <.05) of FP recall, with an AUC = 0.77. For DBT, age was the only significant predictor of FP recall with AUC = 0.64. Using exploratory receiver operating characteristic thresholds for which no true-positives would be missed, a potential FP reduction of 23.5% and 8.9% was demonstrated, respectively, for DM alone versus DM/DBT. CONCLUSION: Measures of breast complexity measured on 2D digital mammograms are indicative of the likelihood for FP recall from screening with DM, and could help identify women who could benefit from supplemental screening, including DBT. PMID- 27236613 TI - [Catheter-associated bacteremia by Pandoraea pnomenusa in an infant with acute lymphoblastic leukemia]. PMID- 27236614 TI - [Relevance of laboratory diagnosis of Zika during pregnancy and its possible association with Guillain-Barre syndrome]. PMID- 27236615 TI - Fever, abdominal tenderness and peripheral eosinophilia in a frequent traveler. PMID- 27236616 TI - Corrigendum to "Undisturbed dust as a metric of long-term indoor insecticide exposure: Residential DDT contamination from indoor residual spraying and its association with serum levels in the VHEMBE cohort" [Environ. Int. 85C (2015) 163 167]. AB - Although approximately 123 million people may be exposed to high levels of insecticides through the use of indoor residual spraying (IRS) for malaria control, few studies exist on indoor insecticide contamination due to IRS and its relationship with human exposure. In the present study, we developed a sampling method to collect undisturbed dust from 50 homes in Limpopo, South Africa, a region where dichlorodiphenyltrichloroethane (DDT) has been used in IRS programs to prevent malaria for ~70years. We quantified DDT and its degradation products, dichlorodiphenyldichloroethylene (DDE), and dichlorodiphenyldichloroethane (DDD) in dust samples to determine dust loading levels and compared these levels to paired serum concentrations of p,p'-DDT and p,p'-DDE in women residents. p,p'-DDT and p,p'-DDE had the highest detection frequencies in both dust (58% and 34% detection, respectively) and serum samples (100% detection). Significantly higher detection frequencies for o,p'-DDT, p,p'-DDE, and p,p'-DDD were observed in dust samples collected in buildings that had been previously sprayed for malaria control. We also observed a significant, positive association between dust loading and serum concentrations of p,p'-DDT and p,p'-DDE (Spearman's rho=0.68 and 0.54, respectively). Despite the low detection frequency in dust, our results indicate that undisturbed dust may be a good metric to quantify long-term home exposure to DDT-related compounds and that contamination of the home environment may be an important determinant/source of DDT and DDE exposure. PMID- 27236617 TI - [Biomarkers in asthma]. AB - Identifying new biomarkers in asthma is attractive but requires assessing their relevance and their reliability to clinical practice. Beyond fashion, the improvement in identification of new candidate biomarkers benefited of scientific and biologic progresses, biobanks and platforms robustly backed on longitudinal cohorts and registries. Paradoxically, the main issue is now to stress up the good question, in other words to correctly characterize the unmet needs in asthma that might benefit of a biomarker. Chronicity, variability, weakness of diagnostic tools and the heterogeneity of the disease are features of asthma claiming for identifying new biomarkers. Unmet needs in asthma encompass areas such as diagnosis, prognosis, management and follow-up, therapeutic guidance and phenotypic/endotypic identification. FEV1 is an available biomarker largely tested in asthma worth in most of these areas. Albeit, mandatory features required for a new biomarker to emerge, pro/con debates on those already existing and currently used methods for identifying new ones are worth explorations. We reviewed and summarized the current literature focusing biomarkers in asthma. PMID- 27236618 TI - Tight junctions as regulators of tissue remodelling. AB - Formation of tissue barriers by epithelial and endothelial cells requires neighbouring cells to interact via intercellular junctions, which includes tight junctions. Tight junctions form a semipermeable paracellular diffusion barrier and act as signalling hubs that guide cell behaviour and differentiation. Components of tight junctions are also expressed in cell types not forming tight junctions, such as cardiomyocytes, where they associate with facia adherens and/or gap junctions. This review will focus on tight junction proteins and their importance in tissue homeostasis and remodelling with a particular emphasis on what we have learned from animal models and human diseases. PMID- 27236619 TI - Technogenic magnetic particles in soils as evidence of historical mining and smelting activity: A case of the Brynica River Valley, Poland. AB - In the area of Brynica River basin (Upper Silesia, southern Poland) the exploitation and smelting of iron, silver and lead ores was historically documented since early Middle Ages. First investigations showed that metallurgy industry had a large impact from 9th century (AD) until the Second World War. The aim of the study was to use magnetic prospection to detect traces of past mining and ore smelting in Brynica River Valley located in Upper Silesia (southern Poland). The field screening was performed by measurement magnetic susceptibility (kappa) on surface and in vertical profiles and was supported locally by gradiometric measurements. Vertical distribution of magnetic susceptibility values was closely associated with the type of soil use. Historical technogenic magnetic particles resulting from exploitation, processing, and smelting of iron, silver, and lead ores were accumulated in the soil layer at the depth 10 to 25cm. They were represented by sharp-edged particles of slag, coke, as well as various mineralogical forms of iron minerals and aggregates composed of carbon particles, aluminosilicate glass, and single particles of metallic iron. The additional geochemical study in adjacent peat bog supported by radiocarbon dating was also performed. The application of integrated geochemical-magnetic methods to reconstruct the historical accumulation of pollutants in the studied peat bog was effective. The magnetic peak, which was pointed out by magnetic analyses, is consistent with the presence of charcoal and pollution from heavy metals, such as Ag, Cd, Cu, Fe, Pb, or Sn. The results of this work will be helpful for the further study of human's impact on the environment related to the historical and even pre-historical ore exploitation and smelting and also used for better targeting the archeological excavations on such areas. PMID- 27236620 TI - Environmental Metabolic Footprinting: A novel application to study the impact of a natural and a synthetic beta-triketone herbicide in soil. AB - This study presents a novel approach for assessing the risk of agrochemicals in soil microcosms through the use of non-targeted metabolomics. The metabolome of treated soils was extracted and tested through LCMS profiling in order to generate an "Environmental Metabolic Footprint" (EMF). A dynamic characterization of pollution biomarkers was obtained through a multivariate statistical analysis of EMF data, where our results show the possible evolution towards a state of resilience. The EMF methodology was applied to two beta-triketone herbicides in soil microcosms: one natural, leptospermone, and one synthetic, sulcotrione. In spite of a four-fold higher application dose, leptospermone exhibited a lower resilience time than did sulcotrione (ca. 30 days vs ca. 45 days respectively). PMID- 27236621 TI - Factors governing the pre-concentration of wastewater using forward osmosis for subsequent resource recovery. AB - This study demonstrated a technique using forward osmosis (FO) to pre-concentrate the organic matter in raw wastewater, thereby transforming low strength wastewater into an anaerobically digestible solution. The chemical oxygen demand (COD) of raw wastewater was concentrated up to approximately eightfold at a water recovery of 90%. Thus, even low strength wastewater could be pre-concentrated by FO to the range suitable for biogas production via anaerobic treatment. Excessive salinity accumulation in pre-concentrated wastewater was successfully mitigated by adopting ionic organic draw solutes, namely, sodium acetate, and EDTA-2Na. These two draw solutes are also expected to benefit the digestibility of the pre concentrated wastewater compared to the commonly used draw solute sodium chloride. Significant membrane fouling was observed when operating at 90% water recovery using raw wastewater. Nevertheless, membrane fouling was reversible and was effectively controlled by optimising the hydrodynamic conditions of the cross flow FO system. PMID- 27236622 TI - Reclamation of river dredged sediments polluted by PAHs by co-composting with green waste. AB - Polluted dredged sediments are classified as waste and cannot be re-used in civil and environmental engineering nor in agriculture, posing serious logistical, economic and environmental problems for their management. We tested co-composting of sediments (S) slightly polluted by PAHs with urban green waste (GW), as a sustainable technique to both degrade the organic pollutants and lend to sediments suitable properties to be reused as technosol. Four treatments were tested: sediments only (S), GW only (GW), 1:1 w:w S:GW (SGW1:1), and 3:1 w:w S:GW (SGW3:1) for a co-composting period of one year. The co-composting materials underwent to an initial short and moderate thermophilic phase. However, at the end of the co-composting process, SGW3:1 and SGW1:1 achieved suitable physical and chemical properties as plant substrate in terms of organic C, N and humic substances contents, electrical conductivity and bulk density. In the first six months of treatment, the PAHs concentration in SGW3:1 and SGW1:1 was reduced by 26% and 57%, respectively, reaching values below under 1mgg(-1), whereas such a reduction in S alone was observed only after nine months. We concluded that co composting with green waste can be a suitable approach for reclamation of dredged sediments opening opportunities for their use as technosol or as plant growing substrate. PMID- 27236623 TI - Enhanced thermal destruction of toxic microalgal biomass by using CO2. AB - This work confirmed that dominant microalgal strain in the eutrophic site (the Han River in Korea) was Microcystis aeruginosa (M. aeruginosa) secreting toxins. Collected and dried microalgal biomass had an offensive odor due to microalgal lipid, of which the content reached up to 2+/-0.2wt.% of microalgal biomass (dry basis). This study has validated that the offensive odor is attributed to the C3 6 range of volatile fatty acids (VFAs), which was experimentally identified by the non-catalytic transformation of triglycerides (TGs) and free fatty acids (FFAs) in microalgal biomass into fatty acid methyl esters (FAMEs). In particular, this study mechanistically investigated the influence of CO2 in the thermal destruction (i.e., pyrolysis) of hazardous microalgal biomass in order to achieve dual purposes (i.e., thermal disposal of hazardous microalgal biomass and energy recovery). The influence of CO2 in pyrolysis of microalgal biomass was identified as 1) the enhanced thermal cracking behaviors of volatile organic compounds (VOCs) from the thermal degradation of microalgal biomass and 2) the direct gas phase reaction between CO2 and VOCs. These identified influences of CO2 in pyrolysis of microalgal biomass significantly enhanced the generation of CO: the enhanced generation of CO in the presence of CO2 was 590% at 660 degrees C, 1260% at 690 degrees C, and 3200% at 720 degrees C. In addition, two identified influences of CO2 (i.e., enhanced thermal cracking and direct gas phase reaction) occurred simultaneously and independently. The identified gas phase reaction in the presence of CO2 was only initiated at temperatures higher than 500 degrees C, which was different from the Boudouard reaction. Lastly, the experimental work justified that exploiting CO2 as a reaction medium and/or chemical feedstock will provide new technical approaches for controlling syngas ratio and in-situ air pollutant control without using catalysts. PMID- 27236624 TI - Ecosystem services capacity across heterogeneous forest types: understanding the interactions and suggesting pathways for sustaining multiple ecosystem services. AB - As ecosystem services supply from tropical forests is declining due to deforestation and forest degradation, much effort is essential to sustain ecosystem services supply from tropical forested landscapes, because tropical forests provide the largest flow of multiple ecosystem services among the terrestrial ecosystems. In order to sustain multiple ecosystem services, understanding ecosystem services capacity across heterogeneous forest types and identifying certain ecosystem services that could be managed to leverage positive effects across the wider bundle of ecosystem services are required. We sampled three forest types, tropical rainforests, sclerophyll forests, and rehabilitated plantation forests, over an area of 32,000m(2) from Wet Tropics bioregion, Australia, aiming to compare supply and evaluate interactions and patterns of eight ecosystem services (global climate regulation, air quality regulation, erosion regulation, nutrient regulation, cyclone protection, habitat provision, energy provision, and timber provision). On average, multiple ecosystem services were highest in the rainforests, lowest in sclerophyll forests, and intermediate in rehabilitated plantation forests. However, a wide variation was apparent among the plots across the three forest types. Global climate regulation service had a synergistic impact on the supply of multiple ecosystem services, while nutrient regulation service was found to have a trade-off impact. Considering multiple ecosystem services, most of the rehabilitated plantation forest plots shared the same ordination space with rainforest plots in the ordination analysis, indicating that rehabilitated plantation forests may supply certain ecosystem services nearly equivalent to rainforests. Two synergy groups and one trade-off group were identified. Apart from conserving rainforests and sclerophyll forests, our findings suggest two additional integrated pathways to sustain the supply of multiple ecosystem services from a heterogeneous tropical forest landscape: (i) rehabilitation of degraded forests aiming to provide global climate regulation and habitat provision ecosystem services and (ii) management intervention to sustain global climate regulation and habitat provision ecosystem services. PMID- 27236625 TI - Biomagnification of mercury and selenium in two lakes in southern Norway. AB - We have investigated bioaccumulation and trophic transfer of both mercury (Hg) and selenium (Se) in two lakes in southern Norway to reveal a suggested mitigating effect of Se on Hg biota accumulation. The study included analysis of total Se (Se), total Hg (Hg), and methyl-mercury (MeHg) in water, littoral and pelagic invertebrates and perch (Perca fluviatilis), together with stable isotope analysis (delta(15)N and delta(13)C) in biota. Mean dissolved Se ranged from 22 to 59ngL(-1), while Hg and MeHg in lake water ranged from 1 to 3ngL(-1) and 0.01 to 0.06ngL(-1). Biota Se and Hg concentrations (dry weight) ranged from 0.41mgSekg(-1) and 0.06mgHgkg(-1) in primary littoral invertebrates and up to 2.9mg Sekg(-1) and 3.6mgHgkg(-1) in perch. Both Hg and Se biomagnified in the food web, with a trophic magnification factor (TMF) of 4.64 for Hg and 1.29 for Se. The reported positive transfer of Se in the food web, despite the low measured dissolved Se, suggest that a major proportion of the Se in these lakes are both highly bioavailable and bioaccumulative. However, we did not find support for a Se-facilitated inhibition in the accumulation of Hg in perch, as Se and Hg concentrations in perch muscle correlated positively and Se did not explain any variations in Hg after we controlled for the effects of other important covariates. We postulate that this may be a result of insufficient concentrations of dissolved Se and subsequently in biota in our studied lakes for an efficient Hg sequestration up the food web. PMID- 27236626 TI - The influence of vegetation on soil water repellency-markers and soil hydrophobicity. AB - Soil water repellency (SWR) markers are defined as hydrophobic compounds in soil causing SWR and are mainly derived from plants. Previous studies have shown the types and abundance of SWR-markers in soils. However, how these SWR-markers are exactly related to SWR and their origin is poorly understood. This study aims to understand the relationship between SWR-markers, vegetation type and cover and SWR for a simple sandy soil ecosystem, consisting of oaks with sedge and six grass species. All the soil (at different depth) and vegetation samples were collected in the field along a 6m transect, starting from an oak tree. Further along the transect grasses and sedges became more abundant. Free and ester-bound lipids from soils and plant leaves/roots were obtained using a sequential extraction method and identified by gas chromatography-mass spectrometry. Significant linear correlations were found between the main soil characteristics, such as total organic carbon content, and SWR. Single long-chain (>C20) SWR markers derived from both plant leaf waxes and roots positively related to SWR. Both ester-bound omega-hydroxy fatty acids and C22 and C24 alpha,omega dicarboxylic acids were predominantly present in the grass roots, but to a lesser extent in the roots of oak and sedge. These suberin-derived omega-hydroxy fatty acids and alpha,omega-dicarboxylic acids characteristic of roots could well predict the SWR. Additionally, the SWR predictors abundantly present in the soils matched well with high concentrations of the corresponding biomarkers in the dominant vegetation species that covered the soils. Our analyses demonstrated that grass roots influenced SWR more due to their more substantial contribution of organic matter to the topsoils than oak roots. This led to a stronger SWR of the soils covered with grass than those covered with oak vegetation. PMID- 27236627 TI - Drained coastal peatlands: A potential nitrogen source to marine ecosystems under prolonged drought and heavy storm events-A microcosm experiment. AB - Over the past several decades there has been a massive increase in coastal eutrophication, which is often caused by increased runoff input of nitrogen from landscape alterations. Peatlands, covering 3% of land area, have stored about 12 21% of global soil organic nitrogen (12-20Pg N) around rivers, lakes and coasts over millennia and are now often drained and farmed. Their huge nitrogen pools may be released by intensified climate driven hydrologic events-prolonged droughts followed by heavy storms-and later transported to marine ecosystems. In this study, we collected peat monoliths from drained, natural, and restored coastal peatlands in the Southeastern U.S., and conducted a microcosm experiment simulating coupled prolonged-drought and storm events to (1) test whether storms could trigger a pulse of nitrogen export from drought-stressed peatlands and (2) assess how differentially hydrologic managements through shifting plant communities affect nitrogen export by combining an experiment of nitrogen release from litter. During the drought phase, we observed a significant temporal variation in net nitrogen mineralization rate (NMR). NMR spiked in the third month and then decreased rapidly. This pattern indicates that drought duration significantly affects nitrogen mineralization in peat. NMR in the drained site reached up to 490+/-110kgha(-1)year(-1), about 5 times higher than in the restored site. After the 14-month drought phase, we simulated a heavy storm by bringing peat monoliths to saturation. In the discharge waters, concentrations of total dissolved nitrogen in the monoliths from the drained site (72.7+/-16.3mgL( 1)) was about ten times as high as from the restored site. Our results indicate that previously drained peatlands under prolonged drought are a potent source of nitrogen export. Moreover, drought-induced plant community shifts to herbaceous plants substantially raise nitrogen release with lasting effects by altering litter quality in peatlands. PMID- 27236628 TI - Wetland ecosystem health assessment through integrating remote sensing and inventory data with an assessment model for the Hangzhou Bay, China. AB - Due to rapid urbanization, industrialization and population growth, wetland area in China has shrunk rapidly and many wetland ecosystems have been reported to degrade during recent decades. Wetland health assessment could raise the public awareness of the wetland condition and guide policy makers to make reasonable and sustainable policies or strategies to protect and restore wetland ecosystems. This study assessed the health levels of wetland ecosystem at the Hangzhou Bay, China using the pressure-state-response (PSR) model through synthesizing remote sensing and statistical data. Ten ecological and social-economic indicators were selected to build the wetland health assessment system. Weights of these indicators and PSR model components as well as the normalized wetland health score were assigned and calculated based on the analytic hierarchy process (AHP) method. We analyzed the spatio-temporal changes in wetland ecosystem health status during the past 20years (1990-2010) from the perspectives of ecosystem pressure, state and response. The results showed that the overall wetland health score was in a fair health level, but displayed large spatial variability in 2010. The wetland health score declined from good health level to fair health level from 1990 to 2000, then restored slightly from 2000 to 2010. Overall, wetland health levels showed a decline from 1990 to 2010 for most administrative units. The temporal change patterns in wetland ecosystem health varied significantly among administrative units. Our results could help to clarify the administrative responsibilities and obligations and provide scientific guides not only for wetland protection but also for restoration and city development planning at the Hangzhou Bay area. PMID- 27236629 TI - Erratum to "Porous titania/carbon hybrid microspheres templated by in situ formed polystyrene colloids" [J. Colloid Interface Sci. 469 (2016) 242-256]. PMID- 27236630 TI - The impact of prior stroke on the outcome of patients with severe aortic stenosis undergoing transcatheter aortic valve replacement. AB - AIMS: The present study aimed to evaluate the impact of prior cardiovascular events (CVE) on outcome in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). METHODS AND RESULTS: Patients with severe AS undergoing TAVR between May 2007 and March 2015 were included and categorized to patients with and without prior stroke, defined as embolic, hemorrhagic stroke and transit ischemic attack. Baseline, procedural characteristics, in-hospital outcomes, and 1-month and 1-year mortality were compared in accordance with the Valve Academic Research Consortium-2 consensus. A cohort of 662 consecutive patients with severe AS undergoing TAVR were included in the analysis. Of these, 120 patients had prior stroke, and 542 without. Transfemoral access was used in 78% (571), and pre-TAVR balloon aortic valvuloplasty was performed in 87% (574). Patients with prior stroke had a higher mean Society of Thoracic score compared to those without (10.1% versus 8.8%, respectively; p=0.006) and higher rates of atherosclerotic disease involving the coronary, peripheral, and carotid arteries. Patients with prior stroke also had more occurrence of in-hospital minor stroke (3.3% versus 0.7%; p=0.04). Nevertheless, similar mortality rates were recorded at 1, 6, and 12months, and there were no significant differences in major stroke, bleeding, or post procedure hospital stay between both groups. CONCLUSION: Prior history of stroke infers a higher risk for in-hospital minor stroke, yet no impact on other outcomes post TAVR. Therefore, history of prior stroke should not be considered an exclusion criterion for TAVR in patients with severe AS. PMID- 27236631 TI - Effect of conductive hearing loss on central auditory function. AB - INTRODUCTION: It has been demonstrated that long-term Conductive Hearing Loss (CHL) may influence the precise detection of the temporal features of acoustic signals or Auditory Temporal Processing (ATP). It can be argued that ATP may be the underlying component of many central auditory processing capabilities such as speech comprehension or sound localization. Little is known about the consequences of CHL on temporal aspects of central auditory processing. OBJECTIVE: This study was designed to assess auditory temporal processing ability in individuals with chronic CHL. METHODS: During this analytical cross-sectional study, 52 patients with mild to moderate chronic CHL and 52 normal-hearing listeners (control), aged between 18 and 45 year-old, were recruited. In order to evaluate auditory temporal processing, the Gaps-in-Noise (GIN) test was used. The results obtained for each ear were analyzed based on the gap perception threshold and the percentage of correct responses. RESULTS: The average of GIN thresholds was significantly smaller for the control group than for the CHL group for both ears (right: p=0.004; left: p<0.001). Individuals with CHL had significantly lower correct responses than individuals with normal hearing for both sides (p<0.001). No correlation was found between GIN performance and degree of hearing loss in either group (p>0.05). CONCLUSION: The results suggest reduced auditory temporal processing ability in adults with CHL compared to normal hearing subjects. Therefore, developing a clinical protocol to evaluate auditory temporal processing in this population is recommended. PMID- 27236632 TI - Deep neck abscesses: study of 101 cases. AB - INTRODUCTION: Although the incidence of Deep Cervical Abscess (DCA) has decreased mainly for the availability of antibiotics, this infection still occurs with considerable frequency and can be associated with high morbidity and mortality. OBJECTIVE: This study aimed to present our clinical-surgical experience with deep neck abscesses. METHODS: A retrospective study analyzed 101 patients diagnosed with deep neck abscesses caused by multiple etiologies, assisted at a medical school hospital during 6 years. One hundred one patients were included and 27 (26.7%) were younger than 18 years old (the children group), 74 patients (73.3%) were older than 18 years old (the adults group). The following clinical features were analyzed and compared: age, gender, clinical symptoms, leukocyte count, the affected cervical area, lifestyle habits, antibiotic therapy, comorbidities, etiology, bacterial culture, time of hospitalization, the need of tracheostomy and complications. RESULTS: There was predominance in the male gender (55.5%) and young people (mean age 28.1 years). All of the 51 patients with associated disease comorbidity were adults. The most frequent etiologies were bacterial tonsillitis (31.68%) and odontogenic infections (23.7%). The most common cervical areas affected were the peritonsillar (26.7%), submandibular/mouth floor (22.7%) and parapharyngeal spaces (18.8%). In children group, the site most commonly involved was the peritonsillar space (10 patients, 37%). In adults group, the site most commonly involved was multispace (31 patients, 41.8%). Streptococcus pyogenes (23.3%) was the most common microorganism present. Amoxicillin associated with clavulanate (82.1%) was the more used antibiotic. The main complications of abscesses were septic shock (16.8%), pneumonia (10.8%) and mediastinitis (1.98%). Tracheostomy was necessary in 16.8% of patients. The mortality rate was 1.98%. CONCLUSION: The clinical features and severity of DCA varied according to different age groups, perhaps due to the location of the infection and a higher incidence of comorbidity in adults. Thus, DCA in adults is more facile to have multispace involvement and lead to complications and seems to be more serious than that in children. PMID- 27236633 TI - Characteristics of 419 patients with acquired middle ear cholesteatoma. AB - INTRODUCTION: Cholesteatoma is a destructive lesion that can result in life threatening complications. Typically, it presents with hypoacusis and continuous otorrhea as symptoms. Because it is a rare disease, there are few studies in Brazil describing the characteristics of patients with the disease. OBJECTIVE: This study aimed to determine the prevalence of cholesteatoma in patients with chronic otitis media and describe clinical, audiological and surgical characteristics of patients with acquired middle ear cholesteatoma treated at a referral hospital in the public health system. METHODS: Cross-sectional and prospective cohort study, including 1710 patients with chronic otitis media, treated between August 2000 and June 2015, without prior surgery. Detailed clinical history, videotoscopy, and audiometry were performed, in addition to review of medical records to search for surgical data. Cholesteatomas were classified according to their route of formation. RESULTS: Of the patients with chronic otitis media, 419 (24.5%) had cholesteatoma; mean age of 34.49 years; 53.5% female and 63.8% adults. Bilateral cholesteatoma was observed in 17.1%. Anterior epitympanic cholesteatoma corresponded to 1.9%; posterior epitympanic, 32.9%; posterior mesotympanic, 33.7%; two routes, 14.8%; and indeterminate, 16.7%. The mean air-bone gap was 29.84dB and did not differ between routes of formation. There were no correlations between gap size and patient age or duration of symptoms. Of the surgical cases, 16.8% underwent closed tympanomastoidectomy and 75.2% open tympanomastoidectomy. CONCLUSION: The prevalence of cholesteatoma in patients with chronic otitis media was 24.5% and it was more common in adults than in children. Posterior mesotympanic cholesteatoma was more frequent, with no difference in mean air-bone gap between the different routes of formation. In patients undergoing surgery, open tympanomastoidectomy was the procedure most frequently chosen. PMID- 27236634 TI - Beneficial actions of magnesium in metabolic syndrome: Why and how? PMID- 27236635 TI - Economic impact of and satisfaction with a high resolution thyroid nodule clinic at the endocrinology department. AB - BACKGROUND AND OBJECTIVE: No conclusive data exist on the value of a high resolution thyroid nodule clinic for management of nodular thyroid disease. The aim of this study was to evaluate the economic impact of and user satisfaction with a high resolution thyroid nodule clinic (HRTNC) in coordination with primary care. PATIENTS AND METHOD: A prospective, observational, descriptive study was conducted to analyze data from 3,726 patients (mean age 61+/-12 years; 85% women) evaluated at an HRTNC during 2014 and 2015. Demographic data (sex and age), number of ultrasound examinations and fine needle aspiration cytologies (FNAC), referral center and consultation type were assessed. RESULTS: In 2014 and 2015, 3,726 neck ultrasound examinations and 926 FNACs (3.8% rated as non-diagnostic) were performed. Among the 1,227 patients evaluated for the first time, 21.5% did not require a second endocrine appointment, which resulted in mean estimated savings of 14,354.55 euros. Of all patients, 41.1% were referred from primary care, 33.4% from endocrinology, and 26.5% from other specialties. As compared to 2013, the number of thyroid ultrasound examinations requested decreased by 65.3% and 59.7% in 2014 and 2015 respectively, with mean estimated savings of 137,563.92 euros. Mean user satisfaction assessed was 4.0 points (95% confidence interval, 3.7-4.3) on a 5-point scale. CONCLUSIONS: HRTNCs at endocrinology departments, coordinated with primary care, are a viable, cost-effective alternative with a positive user perception. PMID- 27236636 TI - Association between triglyceride/HDL cholesterol ratio and carotid atherosclerosis in postmenopausal middle-aged women. AB - BACKGROUND AND OBJECTIVE: The triglyceride/HDL cholesterol ratio, as a surrogate marker of insulin resistance, may be associated to presence of subclinical carotid atherosclerosis in postmenopausal women. The aim of this study was to explore this association. PATIENTS AND METHODS: Women (last menstrual period>=2 years) in primary prevention up to 65 years of age were recruited. Association between the triglyceride/HDL cholesterol (HDL-C) ratio and presence of carotid plaque, assessed by ultrasonography, was analyzed. ROC analysis was performed, determining the precision of this ratio to detect carotid plaque. RESULTS: A total of 332 women (age 57+/-5 years) were recruited. Triglyceride/HDL-C ratio was 2.35+/-1.6. Prevalence of carotid plaque was 29%. Women with carotid plaque had higher triglyceride/HDL-C ratios (3.33+/-1.96 vs. 2.1+/-1.2, P<.001) than women with no carotid plaque. A positive relationship was seen between quintiles of this ratio and prevalence of carotid plaque (p<.001). Regardless of other risk factors, women with higher triglyceride/HDL-C ratios were more likely to have carotid plaque (odds ratio 1.47, 95% confidence interval 1.20-1.79, P<.001). The area under the curve of the triglyceride/HDL-C ratio to detect carotid plaque was .71 (95% confidence interval .65 to .76), and the optimal cut-off point was 2.04. CONCLUSIONS: In postmenopausal women in primary prevention, insulin resistance, estimated from the triglyceride/HDL-C ratio, was independently associated to a greater probability of carotid plaque. A value of such ratio greater than 2 may be used for assessing cardiovascular risk in this particular group of women. PMID- 27236637 TI - Spatiotemporal, kinematic, force and muscle activation outcomes during gait and functional exercise in water compared to on land: A systematic review. AB - BACKGROUND: Exercises replicating functional activities are commonly used in aquatic rehabilitation although it is not clear how the movement characteristics differ between the two environments. A systematic review was completed in order to compare the biomechanics of gait, closed kinetic chain and plyometric exercise when performed in water and on land. METHODS: Databases including MEDLINE, CINAHL, SPORTDiscus, Embase and the Cochrane library were searched. Studies were included where a functional lower limb activity was performed in water and on land with the same instructions. Standardized mean differences (SMD) and 95% confidence intervals were calculated for spatiotemporal, kinematic, force and muscle activation outcomes. FINDINGS: 28 studies included walking or running (19 studies), stationary running (three), closed kinetic chain exercise (two), plyometric exercise (three) and timed-up and go (one). Very large effect sizes showed self-selected speed of walking (SMD >4.66) and vertical ground reaction forces (VGRF) (SMD >1.91) in water were less than on land, however, lower limb range of movement and muscle activity were similar. VGRF in plyometric exercise was lower in water when landing but more similar between the two environments in propulsion. Maximal speed of movement for walking and stationary running was lower in water compared to on land (SMD>3.05), however was similar in propulsion in plyometric exercise. INTERPRETATION: Drag forces may contribute to lower self selected speed of walking. Monitoring speed of movement in water assists in determining the potential advantages or limitations of aquatic exercise and the task specificity to land-based function. PMID- 27236638 TI - Improvements in spinal alignment after high tibial osteotomy in patients with medial compartment knee osteoarthritis. AB - Since the correlation between spinal and lower extremity alignments is high, high tibial osteotomy (HTO) surgery may also affect spinal alignment, where the spinal alignment parameters are the most important parameters for the evaluation of spinal disorders. In this study, the effect of HTO surgery on spinal alignment during gait was investigated by comparing spinal alignment parameters between patients with knee osteoarthritis (OA) and healthy young controls. Eight patients (age, 55.0+/-5.1years; height, 160.3+/-7.0cm; weight, 71.3+/-14.1kg) with a medial compartment knee OA participated in the gait experiment two times approximately one week before and one year after HTO surgery and eight healthy young controls (age, 26.7+/-1.7years; height, 163.4+/-6.5cm; weight, 58.4+/ 11.3kg) participated only once. Cervical curvature angle, thoracic curvature angle, lumbar curvature angle, coronal vertical axis, and coronal pelvic tilt in the coronal plane and cervical lordosis, thoracic kyphosis, lumbar lordosis, sagittal vertical axis, and sagittal pelvic tilt in the sagittal plane were estimated using motion analysis system with skin markers. All spinal alignment parameters after HTO surgery were significantly closer to those of healthy young subjects than those before HTO, especially in the coronal plane. These findings suggest that the HTO had a positive effect on spinal alignment, as well as lower extremity alignment, and moreover, reduced the abnormality that may result in spinal problems such as degeneration or pain. PMID- 27236639 TI - Development of a permeability-limited model of the human brain and cerebrospinal fluid (CSF) to integrate known physiological and biological knowledge: Estimating time varying CSF drug concentrations and their variability using in vitro data. AB - A 4-compartment permeability-limited brain (4Brain) model consisting of brain blood, brain mass, cranial and spinal cerebrospinal fluid (CSF) compartments has been developed and incorporated into a whole body physiologically-based pharmacokinetic (PBPK) model within the Simcyp Simulator. The model assumptions, structure, governing equations and system parameters are described. The model in particular considers the anatomy and physiology of the brain and CSF, including CSF secretion, circulation and absorption, as well as the function of various efflux and uptake transporters existing on the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB), together with the known parameter variability. The model performance was verified using in vitro data and clinical observations for paracetamol and phenytoin. The simulated paracetamol spinal CSF concentration is comparable with clinical lumbar CSF data for both intravenous and oral doses. Phenytoin CSF concentration-time profiles in epileptic patients were simulated after accounting for disease-induced over-expression of efflux transporters within the BBB. Various 'what-if' scenarios, involving variation of specific drug and system parameters of the model, demonstrated that the 4Brain model is able to simulate the possible impact of transporter-mediated drug-drug interactions, the lumbar puncture process and the age-dependent change in the CSF turnover rate on the local PK within the brain. PMID- 27236640 TI - Relationship between the plasma fentanyl and serum 4beta-hydroxycholesterol based on CYP3A5 genotype and gender in patients with cancer pain. AB - This study aimed to evaluate the relationship between the concentrations of plasma fentanyl and serum 4beta-hydroxycholesterol based on CYP3A5 genotype and gender in cancer patients. Thirty-three Japanese cancer patients treated with transdermal fentanyl were enrolled. The concentrations of plasma fentanyl and norfentanyl, and serum 4beta-hydroxycholesterol and total cholesterol were determined at day 8 or later after starting the medication. The plasma fentanyl concentration was significantly higher in the CYP3A5*3/*3 group than in the *1 allele carrier group. The *3/*3 group had a lower metabolic ratio of fentanyl. The serum 4beta-hydroxycholesterol concentration and its ratio to total cholesterol were significantly lower in the CYP3A5*3/*3 group than in the *1 allele carrier group. The concentrations of plasma fentanyl and serum 4beta hydroxycholesterol were significantly higher in women than in men. Gender did not affect the metabolic ratio of fentanyl or the concentration ratio of 4beta hydroxycholesterol. The plasma fentanyl concentration was not correlated with the serum 4beta-hydroxycholesterol concentration, while the metabolic ratio of fentanyl was slightly correlated with the serum concentration ratio of 4beta hydroxycholesterol. In conclusion, CYP3A5*3 and gender affected the plasma fentanyl and serum 4beta-hydroxycholesterol concentrations in cancer patients. However, the plasma disposition of fentanyl was not determined using the serum 4beta-hydroxycholesterol concentration. PMID- 27236641 TI - Effect of diclofenac on SLC16A3/MCT4 by the Caco-2 cell line. AB - In the present study, we demonstrated that monocarboxylate transporter 4 (MCT4) is functionally expressed in Caco-2 cells. We studied the effects of 4 nonsteroidal anti-inflammatory drugs on the uptake of l-lactate as a good substrate of MCT4 by the cells. The monocarboxylate drugs inhibited the uptake of l-lactate into the cells. Diclofenac, as a member of the aryl-acetic acid group of nonsteroidal anti-inflammatory drugs, was the most potent inhibitor, with an inhibition constant of 20 MUM. In the next study, we determined the type of inhibition for diclofenac. An l-lactate carrier is non-competitively inhibitable by the drug. We also demonstrated, in Xenopus oocyte expression system, potential of diclofenac for MCT4 inhibitor. The present results could provide a useful tool to discover MCT4-specific inhibitors. PMID- 27236642 TI - Sociodemographic and Behavioral Factors Associated with Added Sugars Intake among US Adults. AB - BACKGROUND: Reducing added sugars intake is one of the Healthy People 2020 objectives. High added sugars intake may be associated with adverse health consequences. OBJECTIVE: This cross-sectional study identified sociodemographic and behavioral characteristics associated with added sugars intake among US adults (18 years and older) using the 2010 National Health Interview Survey data (n=24,967). METHODS: The outcome variable was added sugars intake from foods and beverages using scoring algorithms to convert dietary screener frequency responses on nine items to estimates of individual dietary intake of added sugars in teaspoons per day. Added sugars intake was categorized into tertiles (lowest, middle, highest) stratified by sex. The explanatory variables were sociodemographic and behavioral characteristics. Multinomial logistic regression was used to estimate the adjusted odds ratios for the highest and middle tertile added sugars intake groups as compared with the lowest tertile group. RESULTS: Estimated median added sugars intake was 17.6 tsp/d for men and 11.7 tsp/d for women. For men and women, those who had significantly greater odds for being in the highest tertile of added sugars intake (men: >=22.0 tsp/d; women: >=14.6 tsp/d) were younger, less educated, had lower income, were less physically active, were current smokers, and were former or current infrequent/light drinkers, whereas non-Hispanic other/multiracial and those living in the West had significantly lower odds for being in the highest tertile of added sugars intake. Different patterns were found by sex. Non-Hispanic black men had lower odds for being in the highest tertile of added sugars intake, whereas non-Hispanic black women had greater odds for being in the highest tertile. CONCLUSIONS: One in three men consumed >=22.0 tsp added sugars and one in three women consumed >=14.6 tsp added sugars daily. Higher added sugars intake was associated with various sociodemographic and behavioral characteristics; this information can inform efforts to design programs and policies specific to high-intake populations. PMID- 27236643 TI - Results of the Academy of Nutrition and Dietetics' Consumer Health Informatics Work Group's 2015 Member App Technology Survey. PMID- 27236644 TI - Clinical and corneal microbial profile of infectious keratitis in a high HIV prevalence setting in rural South Africa. AB - The purpose of this investigation was to determine the clinical and corneal microbial profile of infectious keratitis in a high human immunodeficiency virus (HIV) prevalence setting in rural South Africa. Data in this cross-sectional study were collected from patients presenting with symptoms of infectious keratitis (n = 46) at the ophthalmology outpatient department of three hospitals in rural South Africa. Corneal swabs were tested for herpes simplex virus type 1 (HSV-1) and 2 (HSV-2), varicella zoster virus (VZV) and adenovirus DNA by real time polymerase chain reaction (PCR) and for bacteria and fungi by culture. Based on clinical history, disease characteristics and laboratory results, 29 (63 %) patients were diagnosed as viral keratitis, including 14 (48 %) viral keratitis cases complicated by bacterial superinfection, and 17 (37 %) as bacterial keratitis. VZV and HSV-1 DNA was detected in 11 (24 %) and 5 (11 %) corneal swabs, respectively. Among clinically defined viral keratitis cases, a negative viral swab was predominantly (93 %) observed in cases with subepithelial inflammation and was significantly associated with an increased duration of symptoms (p = 0.003). The majority of bacteria cultured were Gram-positive (24/35), including Staphylococcus epidermidis and S. aureus. Viral aetiology was significantly associated with a history of herpes zoster ophthalmicus (p < 0.001) and a trend was observed between viral aetiology and HIV infection (p = 0.06). Twenty-one (47 %) keratitis cases were complicated by anterior uveitis, of which 18 (86 %) were HIV-infected cases with viral keratitis. The data implicate a high prevalence of herpetic keratitis, in part complicated by bacterial superinfection and/or uveitis, in HIV-infected individuals presenting with infectious keratitis in rural South Africa. PMID- 27236645 TI - Characterization of the mechanical behavior of the optic nerve sheath and its role in spaceflight-induced ophthalmic changes. AB - Visual impairment and intracranial pressure (VIIP) syndrome is characterized by a number of permanent ophthalmic changes, including loss of visual function. It occurs in some astronauts during long-duration spaceflight missions. Thus, understanding the pathophysiology of VIIP is currently a major priority in space medicine research. It is hypothesized that maladaptive remodeling of the optic nerve sheath (ONS), in response to microgravity-induced elevations in intracranial pressure (ICP), contributes to VIIP. However, little is known about ONS biomechanics. In this study, we developed a custom mechanical testing system that allowed for unconfined lengthening, twisting, and circumferential distension of the porcine ONS during inflation and axial loading. Data were fit to a four fiber family constitutive equation to extract material and structural parameters. Inflation testing showed a characteristic "cross-over point" in the pressure diameter curves under different axial loads in all samples that were tested; the cross-over pressure was [Formula: see text] mmHg ([Formula: see text]). Large sample-to-sample variations were observed in the circumferential strain, while only modest variations were observed in the circumferential stress. Multiphoton microscopy revealed that the collagen fibers of the ONS were primarily oriented axially when the tissue was loaded. The existence of this cross-over behavior is expected to be neuroprotective, as it would avoid optic nerve compression during routine changes in gaze angle, so long as ICP was within the normal range. Including these observations into computational models of VIIP will help provide insight into the pathophysiology of VIIP and could help identify risk factors and potential interventions. PMID- 27236646 TI - Malocclusion model of temporomandibular joint osteoarthritis in mice with and without receptor for advanced glycation end products. AB - OBJECTIVE: This study has two aims: 1. Validate a non-invasive malocclusion model of mouse temporomandibular joint (TMJ) osteoarthritis (OA) that we developed and 2. Confirm role of inflammation in TMJ OA by comparing the disease in the presence and absence of the receptor for advanced glycation end products (RAGE). DESIGN: The malocclusion procedure was performed on eight week old mice, either wild type (WT) or without RAGE. RESULTS: We observed TMJ OA at two weeks post misalignment/malocclusion. The modified Mankin score used for the semi quantitative assessment of OA showed an overall significantly higher score in mice with malocclusion compared to control mice at all times points (2, 4, 6 and 8 weeks). Mice with malocclusion showed a decrease in body weight by the first week after misalignment but returned to normal weight for their ages during the following weeks. The RAGE knock out (KO) mice had statistically lower modified Mankin scores compared to WT mice of the same age. The RAGE KO mice had statistically lower levels of Mmp-13 and HtrA1 but higher Tgf-beta1, as measured by immunohistochemistry, compared to WT mice at eight weeks post malocclusion. CONCLUSIONS: We demonstrate an inexpensive, efficient, highly reproducible and non-invasive model of mouse TMJ OA. The mechanical nature of the malocclusion resembles the natural development of TMJ OA in humans, making this an ideal model in future studies that aim to elucidate the pathogenesis of the disease leading to the discovery of a treatment. The RAGE plays a role in mouse TMJ OA. PMID- 27236647 TI - Interleukin-6, intracellular adhesion molecule-1, and glycodelin A levels in serum and peritoneal fluid as biomarkers for endometriosis. AB - OBJECTIVE: To compare levels of interleukin-6 (IL-6), intracellular adhesion molecule-1 (ICAM-1), and glycodelin A in serum and peritoneal fluid of patients with and without endometriosis, and to correlate levels with disease stage. METHODS: An observational study was undertaken at Mansoura University Hospital, Egypt, between March 2014 and June 2015. Patients aged 21-48 years laparoscopically diagnosed with endometriosis and those without endometriosis who underwent laparoscopy for tubal ligation were included. Levels of IL-6, ICAM-1, and glycodelin A were measured in samples of serum and peritoneal fluid. Receiver operating characteristic curves were used to evaluate diagnostic accuracy. RESULTS: Forty-eight women with endometriosis and 20 without the disorder were included. IL-6 and glycodelin A levels in serum and peritoneal fluid were higher in the endometriosis group than in the control group (P<0.001 for all); ICAM-1 levels did not differ. The sensitivity and specificity values were 93.8% and 80.0% for serum IL-6, 58.3% and 60.0% for serum ICAM-1, and 91.7% and 75.0% for serum glycodelin A. The corresponding values for peritoneal fluid markers were 85.4% and 89.0%, 60.4% and 50.0%, and 89.6% and 90.0%, respectively. IL-6 and glycodelin A levels in serum and peritoneal fluid increased with disease stage (P<0.001 for all). CONCLUSION: IL-6 and glycodelin A, but not ICAM-1, are potential biomarkers for endometriosis and are positively correlated with the disease stage. PMID- 27236648 TI - A snapshot of current gestational diabetes management practices from 26 low income and lower-middle-income countries. AB - OBJECTIVE: To identify screening and management practices for gestational diabetes mellitus (GDM) in low-income and lower-middle-income countries. METHODS: A cross-sectional survey was conducted between November 12, 2014 and May 11, 2015. Questionnaires were distributed to gynecologists, endocrinologists, and medical doctors who were representatives of national professional societies or were involved in providing care to patients with GDM in low-income or lower middle-income countries in Africa, South Asia, and Latin America. The data were descriptively analyzed. RESULTS: Questionnaires were sent to 182 individuals and 77 healthcare providers from 26 countries completed the survey. The results demonstrated high diversity in screening and management practices. Only 52 (68%) participants reported that any guidelines were available in their setting. Management of GDM was found to take place mainly at the tertiary level and reported practices, including the frequency of post-diagnosis follow-up, modalities of glucose surveillance, and treatment and practices surrounding delivery, varied and did not always reflect the most recent evidence. CONCLUSION: Attempts to ensure greater adherence to latest consensus guidelines are required, and should be accompanied by systemic changes to improve the detection and management of GDM at primary- and secondary-level healthcare facilities to facilitate patient access to GDM screening and treatment. PMID- 27236649 TI - Erratum to: The Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway as a Discovery Target in Stroke. PMID- 27236650 TI - Determination of Ancylostoma caninum ova viability using metabolic profiling. AB - Differentiation between viable and non-viable hookworm ova in environmental samples is necessary in order to implement strategies to mitigate re-infections in endemic regions. In this study, an untargeted metabolic profiling method was developed that utilised gas chromatography-mass spectrometry (GC-MS) in order to investigate hookworm ova viability. Ancylostoma caninum was used to investigate the metabolites within viable and non-viable ova. Univariate and multivariate statistical analyses of the data resulted in the identification of 53 significant metabolites across all hookworm ova samples. The major compounds observed in viable and non-viable hookworm ova were tetradecanoic acid, commonly known as myristic acid [fold change (FC) = 0.4], and dodecanoic acid, commonly known as lauric acid (FC = 0.388). Additionally, the viable ova had self-protecting metabolites such as prostaglandins, a typical feature absent in non-viable ova. The results of this study demonstrate that metabolic profiling using GC-MS methods can be used to determine the viability of canine hookworm ova. Further studies are needed to assess the applicability of metabolic profiling using GC-MS to detect viable hookworm ova in the mixed (viable and non-viable) populations from environmental samples and identify the metabolites specific to human hookworm species. PMID- 27236651 TI - Navigation system for robot-assisted intra-articular lower-limb fracture surgery. AB - PURPOSE: In the surgical treatment for lower-leg intra-articular fractures, the fragments have to be positioned and aligned to reconstruct the fractured bone as precisely as possible, to allow the joint to function correctly again. Standard procedures use 2D radiographs to estimate the desired reduction position of bone fragments. However, optimal correction in a 3D space requires 3D imaging. This paper introduces a new navigation system that uses pre-operative planning based on 3D CT data and intra-operative 3D guidance to virtually reduce lower-limb intra-articular fractures. Physical reduction in the fractures is then performed by our robotic system based on the virtual reduction. METHODS: 3D models of bone fragments are segmented from CT scan. Fragments are pre-operatively visualized on the screen and virtually manipulated by the surgeon through a dedicated GUI to achieve the virtual reduction in the fracture. Intra-operatively, the actual position of the bone fragments is provided by an optical tracker enabling real time 3D guidance. The motion commands for the robot connected to the bone fragment are generated, and the fracture physically reduced based on the surgeon's virtual reduction. To test the system, four femur models were fractured to obtain four different distal femur fracture types. Each one of them was subsequently reduced 20 times by a surgeon using our system. RESULTS: The navigation system allowed an orthopaedic surgeon to virtually reduce the fracture with a maximum residual positioning error of [Formula: see text] (translational) and [Formula: see text] (rotational). Correspondent physical reductions resulted in an accuracy of 1.03 +/- 0.2 mm and [Formula: see text], when the robot reduced the fracture. CONCLUSIONS: Experimental outcome demonstrates the accuracy and effectiveness of the proposed navigation system, presenting a fracture reduction accuracy of about 1 mm and [Formula: see text], and meeting the clinical requirements for distal femur fracture reduction procedures. PMID- 27236652 TI - Fusion of fibrous cap thickness and wall shear stress to assess plaque vulnerability in coronary arteries: a pilot study. AB - PURPOSE: Identification of rupture-prone plaques in coronary arteries is a major clinical challenge. Fibrous cap thickness and wall shear stress are two relevant image-based risk factors, but these two parameters are generally computed and analyzed separately. Accordingly, combining these two parameters can potentially improve the identification of at-risk regions. Therefore, the purpose of this study is to investigate the feasibility of the fusion of wall shear stress and fibrous cap thickness of coronary arteries in patient data. METHODS: Fourteen patients were included in this pilot study. Imaging of the coronary arteries was performed with optical coherence tomography and with angiography. Fibrous cap thickness was automatically quantified from optical coherence tomography pullbacks using a contour segmentation approach based on fast marching. Wall shear stress was computed by applying computational fluid dynamics on the 3D volume reconstructed from two angiograms. The two parameters then were co registered using anatomical landmarks such as side branches. RESULTS: The two image modalities were successfully co-registered, with a mean (+/-SD) error corresponding to [Formula: see text] of the length of the analyzed region. For all the analyzed participants, the average thinnest portion of each fibrous cap was [Formula: see text], and the average WSS value at the location of the fibrous cap was [Formula: see text]. A unique index was finally generated for each patient via the fusion of fibrous cap thickness and wall shear stress measurements, to translate all the measured parameters into a single risk map. CONCLUSION: The introduced risk map integrates two complementary parameters and has potential to provide valuable information about plaque vulnerability. PMID- 27236653 TI - Transient and persistent conduction abnormalities following transcatheter aortic valve replacement with the Edwards-Sapien prosthesis: a comparison between antegrade vs. retrograde approaches. AB - BACKGROUND: Electrocardiographic conduction abnormalities following transcatheter aortic valve replacement (TAVR) with the Edwards-Sapien valve (ESV) are not uncommon and may be transient. We sought to examine the clinical time-course of conduction abnormalities after TAVR with ESV and determine risk factors for persistent abnormalities. METHODS: In this single-center prospective study, 116 consecutive patients underwent implantation of the ESV after approval by the Food and Drug Administration (FDA). Demographic, clinical, and intra-procedural variables were collected in a registry, including ECGs before, immediately after, and at discharge from hospital. Conduction abnormalities were analyzed including PR interval lengthening, QRS widening, left bundle branch block (LBBB), and high grade AV block. RESULTS: There were 92 patients included in the analysis. A total of 41 new conduction abnormalities were observed in 31 (34 %) patients: 7 new PR prolongation, 14 QRS widening, 14 new LBBB, and 5 high-grade AV block requiring permanent pacemaker. Of the 41 new CAs, 11 (27 %) were transient; of the transient abnormalities, 9 (82 %) resolved within 24 h of the index procedure. Chronic kidney disease was a risk factor for the development of a persistent abnormality and for need for PPM. Antegrade approach was associated with the development of persistent LBBB and persistent QRS widening. CONCLUSIONS: A significant proportion of conduction abnormalities after ESV implantation improved prior to discharge from the hospital, usually within 24 h. CKD is associated with persistence of abnormalities and with need for PPM. Antegrade approach increases risk for new intraventricular conduction delays, including LBBB. PMID- 27236655 TI - Dose-dependent pulmonary vein reconnection in response to adenosine: relevance of atrioventricular block during infusion. AB - PURPOSE: Adenosine infusion during atrial fibrillation ablation is often used to evaluate for dormant pulmonary vein (PV) conduction. Several physiologic effects of adenosine may be seen during infusion, including atrioventricular (AV) block, hypotension, sinus tachycardia (as a reflex mechanism), and sinus bradycardia. However, hypotension and sinus tachycardia may be seen in the absence of AV block. Whether the dose required to achieve AV block versus any physiologic effect (e.g., hypotension) is relevant when evaluating for PV reconnection is unclear. METHODS: In consecutive patients undergoing first-time atrial fibrillation radiofrequency ablation for persistent or paroxysmal atrial fibrillation, adenosine testing was performed 30 min after successful PV isolation. When testing each PV after isolation, a circular mapping catheter was placed at the ostium and a 12-mg bolus of adenosine was given via peripheral line. The presence of some physiologic effect (e.g., sinus tachycardia or hypotension) versus AV block was recorded as was PV reconnection. If no AV block and no PV reconnection were seen, the dose was escalated by 6-mg increments to assess for PV reconnection until AV block or PV reconnection was achieved. RESULTS: Among 50 patients, there were 3 to 5 PVs isolated (median 4; mean 4.4). In 35 patients, a 12-mg bolus resulted in AV block and 16/155 (10 %) veins exhibited reconnection requiring additional ablation. In all other patients, sinus tachycardia and hypotension were seen in response to 12-mg infusion but no AV block and no PV reconnection was seen. No sinus bradycardia was seen in any patients. In 10/15 patients without AV block with 12 mg, 18 mg of adenosine was sufficient to achieve AV block and 5/43 (12 %) PVs exhibited reconnection. Among the remaining 5 patients, 3 patients required a dose of 24 mg to achieve AV block, and PV reconnection was seen in 1/14 (7 %) PVs. The remaining two patients required a dose of 30 mg to achieve AV block, but no PV reconnection was seen. There was no difference in symptomatic recurrence rate between those who exhibited adenosine-induced reconnection and those who did not after 1-year follow-up. CONCLUSION: A fixed dose of adenosine may be insufficient to assess for PV reconnection. Furthermore, the presence of a physiologic effect (e.g., sinus tachycardia or hypotension) in the absence of AV block may reflect an insufficient dose. The dose needed may vary between patients, and AV block may reflect a minimal requirement when administering adenosine to assess for PV reconnection. PMID- 27236654 TI - Increased hs-CRP and decreased 1,25-dihydroxyvitamin D are associated with increased left ventricle lead threshold. AB - PURPOSE: There are not enough data about threshold changes in patients with CRT. In this study, we aimed to investigate frequency of significant threshold increase of left ventricle lead and to determine clinical, demographic, medical and laboratory parameters that associated with threshold increase in CRT implanted patients. METHODS: We included CRT implanted 200 patients (124 males, 76 females; mean age 65.8 +/- 10.3 years) to this study. Basal and third month LV R wave amplitude, electrode impedance, and threshold values were recorded. Threshold increase was accepted as >=0.1 V and significant increase as >1 V. Patients were divided into two groups: increased threshold and non-increased threshold for LV lead. RESULTS: Number of patients with increased LV threshold was 68 (37.6 %). Furthermore, 8 % of patients had severe increase (>=1 V) in LV threshold. We observed that serum levels of hs-CRP and 1,25 (OH)2 vitamin D were independently associated with increased LV threshold. We showed that 1 mg/dl increase in hs-CRP and the 1 mg/dl decrease in vitamin D are associated with 25.3 and 4.5 % increase in the odds of increased LV threshold, respectively. CONCLUSIONS: Increased hs-CRP and decreased 1,25 (OH)2 vitamin D are the strongest predictors of increased LV lead thresholds. We suggest that hs-CRP and 1,25 (OH)2 vitamin D may be used as markers to predict and follow the patients with increased thresholds. It may be useful to finalize CRT procedure with more appropriate basal threshold in patients with high serum hs-CRP and low 1,25 (OH)2 vitamin D levels. PMID- 27236656 TI - Effect of irbesartan on development of atrial fibrosis and atrial fibrillation in a canine atrial tachycardia model with left ventricular dysfunction, association with p53. AB - Effects of an angiotensin II receptor blocker, irbesartan (IRB), on the development of atrial fibrosis and atrial fibrillation (AF) were assessed in a canine model of atrial tachycardia remodeling (ATR) with left ventricular dysfunction, together with its possible association with involvement of p53. Atrial tachypacing (400 bpm for 4 weeks) was used to induce ATR in beagles treated with placebo (ATR-dogs, n = 6) or irbesartan (IRB-dogs, n = 5). Non-paced sham dogs served as control (Control-dogs, n = 4). ATR- and IRB-dogs developed tachycardia-induced left ventricular dysfunction. Atrial effective refractory period (AERP) shortened (83 +/- 5 ms, p < 0.05), inter-atrial conduction time prolonged (72 +/- 2 ms, p < 0.05), and AF duration increased (29 +/- 5 s, p < 0.05 vs. baseline) after 4 weeks in ATR-dogs. ATR-dogs also had a larger area of atrial fibrous tissue (5.2 +/- 0.5 %, p < 0.05 vs. Control). All these changes, except for AERP, were attenuated in IRB-dogs (92 +/- 3 ms, 56 +/- 3 ms, 9 +/- 5 s, and 2.5 +/- 0.7 %, respectively; p < 0.05 vs. ATR for each). In ATR-dogs, p53 expression in the left atrium decreased by 42 % compared with Control-dogs (p < 0.05); however, it was highly expressed in IRB-dogs (+89 % vs. ATR). Transforming growth factor (TGF)-beta1 expression was enhanced in ATR-dogs (p < 0.05 vs. Control) but reduced in IRB-dogs (p < 0.05 vs. ATR). Irbesartan suppresses atrial fibrosis and AF development in a canine ATR model with left ventricular dysfunction in association with p53. PMID- 27236657 TI - Kinematic analysis of cervical spine canal diameter and its association with grade of degeneration. AB - OBJECTIVES: To investigate the cervical spinal canal diameters variance under positional MRI, and also the relationship between cervical canal diameter variance rate and grade of degeneration. METHODS: From January 2013 to January 2015, a consecutive of 273 symptomatic patients (166 males and 207 females) with an average age of 44.6 years (range 21-89 years) underwent positional cervical MRI. T2-weighted sagittal images of 1638 cervical intervertebral discs from 273 subjects were classified into five grades. The canal diameter and canal diameter variance rate at three positions and their comparison among five grade of degeneration were evaluated. The measurements were tabulated and analyzed using SPSS. 13.0. p values less than 0.05 were considered to indicate a statistically significant difference. RESULTS: The sagittal cervical canal diameter at the C5/6 level were the smallest compared with the other levels regardless of neutral, flexion or extension positions, C5/6 level had the largest canal diameter variance rate in both flexion and extension (8.14 ? 0.38 and 7.81 ? 0.31 %, respectively), second was C4/5 level (7.65 ? 0.39 and 7.67 ? 0.32 %, respectively). A total of 1638 discs were classified into 5 groups, each level showed the similar tendency that no matter what position, with the increasing grade of degenerative disc degree, spine canal diameter decreased gradually. For C5/6 under extension and flexion position, significant difference was also noted between grade 2 and 3; For C4/5 under extension position, significant difference existed between grade 1 and 2, grade 1 and 3, while under flexion position, significant difference existed between grade 2 and 4, and the results also showed no significant difference at the same degree of degeneration on both levels between extension and flexion position. CONCLUSIONS: C5/6 and C4/5 is of higher risk of suffering SCI than other levels, C4/5 level predispose SCI at earlier stage than C5/6, patients presenting with intermediate signal and slight decreased disc height on T2 weighted MRI at C4/5 level should be paid attention. PMID- 27236658 TI - Preclinical evaluation of posterior spine stabilization devices: can the current standards represent basic everyday life activities? AB - PURPOSE: To discuss whether the available standard methods for preclinical evaluation of posterior spine stabilization devices can represent basic everyday life activities and how to compare the results obtained with different procedures. METHODS: A comparative finite element study compared ASTM F1717 and ISO 12189 standards to validated instrumented L2-L4 segments undergoing standing, upper body flexion and extension. The internal loads on the spinal rod and the maximum stress on the implant are analysed. RESULTS: ISO recommended anterior support stiffness and force allow for reproducing bending moments measured in vivo on an instrumented physiological segment during upper body flexion. Despite the significance of ASTM model from an engineering point of view, the overly conservative vertebrectomy model represents an unrealistic worst case scenario. A method is proposed to determine the load to apply on assemblies with different anterior support stiffnesses to guarantee a comparable bending moment and reproduce specific everyday life activities. CONCLUSIONS: The study increases our awareness on the use of the current standards to achieve meaningful results easy to compare and interpret. PMID- 27236660 TI - CpSAT-1, a transcribed satellite sequence from the codling moth, Cydia pomonella. AB - Satellite DNA (satDNA) is a non-coding component of eukaryotic genomes, located mainly in heterochromatic regions. Relevance of satDNA began to emerge with accumulating evidence of its potential yet hardly comprehensible role that it can play in the genome of many organisms. We isolated the first satDNA of the codling moth (Cydia pomonella, Tortricidae, Lepidoptera), a species with holokinetic chromosomes and a single large heterochromatic element, the W chromosome in females. The satDNA, called CpSAT-1, is located on all chromosomes of the complement, although in different amounts. Surprisingly, the satellite is almost missing in the heterochromatic W chromosome. Additionally, we isolated mRNA from all developmental stages (1st-5th instar larva, pupa, adult), both sexes (adult male and female) and several tissues (Malpighian tubules, gut, heart, testes, and ovaries) of the codling moth and showed the CpSAT-1 sequence was transcribed in all tested samples. Using CpSAT-1 specific primers we amplified, cloned and sequenced 40 monomers from cDNA and gDNA, respectively. The sequence analysis revealed a high mutation rate and the presence of potentially functional motifs, mainly in non-conserved regions of the monomers. Both the chromosomal distribution and the sequence analysis suggest that CPSAT-1 has no function in the C. pomonella genome. PMID- 27236662 TI - Enhancing mental health literacy in young people. PMID- 27236661 TI - Identification of the Q969R gain-of-function polymorphism in the gene encoding porcine NLRP3 and its distribution in pigs of Asian and European origin. AB - The nucleotide-binding domain, leucine-rich-containing family, pyrin-domain containing-3 (NLRP3) inflammasome comprises the major components caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and NLRP3. NLRP3 plays important roles in maintaining immune homeostasis mediated by intestinal microorganisms and in the immunostimulatory properties of vaccine adjuvants used to induce an immune response. In the present study, we first cloned a complementary DNA (cDNA) encoding porcine ASC because its genomic sequence was not completely determined. The availability of the ASC cDNA enabled us to reconstitute porcine NLRP3 inflammasomes using an in vitro system that led to the identification of the immune functions of porcine NLRP3 and ASC based on the production of interleukin-1beta (IL-1beta). Further, we identified six synonymous and six nonsynonymous single-nucleotide polymorphisms (SNPs) in the coding sequence of NLRP3 of six breeds of pigs, including major commercial breeds. Among the nonsynonymous SNPs, the Q969R polymorphism is associated with an increased release of IL-1beta compared with other porcine NLRP3 variants, indicating that this polymorphism represents a gain-of-function mutation. This allele was detected in 100 % of the analyzed Chinese Jinhua and Japanese wild boars, suggesting that the allele is maintained in the major commercial native European breeds Landrace, Large White, and Berkshire. These findings represent an important contribution to our knowledge of the diversity of NLRP3 nucleotide sequences among various pig populations. Moreover, efforts to exploit the gain of function induced by the Q969R polymorphism promise to improve pig breeding and husbandry by conferring enhanced resistance to pathogens as well as contributing to vaccine efficacy. PMID- 27236663 TI - Mesenchymal Stromal Cells in Hematopoietic Stem Cell Transplantation. AB - Mesenchymal stromal cells (MSCs) comprise a heterogeneous population of multipotent cells that can be isolated from various human tissues and cultured ex vivo for clinical use. Thanks to their secretion of growth factors, immunomodulatory properties and cell-to-cell interactions, MSCs play a key role in the regulation of hematopoiesis and in the modulation of immune responses against allo- and autoantigens. In light of these properties, MSCs have been employed in clinical trials in the context of hematopoietic stem cell transplantation (HSCT) to prevent/treat graft rejection and to treat steroid resistant acute graft-versus-host disease (GvHD). The available clinical evidence derived from these studies indicates that MSC administration is safe; moreover, promising preliminary results in terms of efficacy have been reported in some clinical trials. This chapter focuses on recent advances in MSC therapy by reporting on the most important relevant studies in the field of HSCT. PMID- 27236664 TI - Bone Tissue Engineering: Past-Present-Future. AB - Bone is one of the few tissues to display a true potential for regeneration. Fracture healing is an obvious example where regeneration occurs through tightly regulated sequences of molecular and cellular events which recapitulate tissue formation seen during embryogenesis. Still in some instances, bone regeneration does not occur properly (i.e. critical size lesions) and an appropriate therapeutic intervention is necessary. Successful replacement of bone by tissue engineering will likely depend on the recapitulation of this flow of events. In fact, bone regeneration requires cross-talk between microenvironmental factors and cells; for example, resident mesenchymal progenitors are recruited and properly guided by soluble and insoluble signaling molecules. Tissue engineering attempts to reproduce and to mimic this natural milieu by delivering cells capable of differentiating into osteoblasts, inducing growth factors and biomaterials to support cellular attachment, proliferation, migration, and matrix deposition. In the last two decades, a significant effort has been made by the scientific community in the development of methods and protocols to repair and regenerate tissues such as bone, cartilage, tendons, and ligaments. In this same period, great advancements have been achieved in the biology of stem cells and on the mechanisms governing "stemness". Unfortunately, after two decades, effective clinical translation does not exist, besides a few limited examples. Many years have passed since cell-based regenerative therapies were first described as "promising approaches", but this definition still engulfs the present literature. Failure to envisage translational cell therapy applications in routine medical practice evidences the existence of unresolved scientific and technical struggles, some of which still puzzle researchers in the field and are presented in this chapter. PMID- 27236667 TI - Mesenchymal Stem Cells in Kidney Repair. AB - Every year 13.3 million people suffer acute kidney injury (AKI), which is associated with a high risk of death or development of long-term chronic kidney disease (CKD) in a substantial percentage of patients besides other organ dysfunctions. To date, the mortality rate per year for AKI exceeds 50 % at least in patients requiring early renal replacement therapy and is higher than the mortality for breast and prostate cancer, heart failure and diabetes combined.Until now, no effective treatments able to accelerate renal recovery and improve survival post AKI have been developed. In search of innovative and effective strategies to foster the limited regeneration capacity of the kidney, several studies have evaluated the ability of mesenchymal stem cells (MSCs) of different origin as an attractive therapeutic tool. The results obtained in several models of AKI and CKD document that MSCs have therapeutic potential in repair of renal injury, preserving renal function and structure thus prolonging animal survival through differentiation-independent pathways. In this chapter, we have summarized the mechanisms underlying the regenerative processes triggered by MSC treatment, essentially due to their paracrine activity. The capacity of MSC to migrate to the site of injury and to secrete a pool of growth factors and cytokines with anti-inflammatory, mitogenic, and immunomodulatory effects is described. New modalities of cell-to-cell communication via the release of microvesicles and exosomes by MSCs to injured renal cells will also be discussed. The translation of basic experimental data on MSC biology into effective care is still limited to preliminary phase I clinical trials and further studies are needed to definitively assess the efficacy of MSC-based therapy in humans. PMID- 27236665 TI - Mesenchymal Stem Cells for Osteochondral Tissue Engineering. AB - Mesenchymal stem cells (MSC) are of major interest in regenerative medicine, as they are easily harvested from a variety of sources (including bone marrow and fat aspirates) and they are able to form a range of mesenchymal tissues, in vitro and in vivo. We focus here on the use of MSCs for engineering of cartilage, bone, and complex osteochondral tissue constructs, using protocols that replicate some aspects of natural mesodermal development. For engineering of human bone, we discuss some of the current advances, and highlight the use of perfusion bioreactors for supporting anatomically exact human bone grafts. For engineering of human cartilage, we discuss the limitations of current approaches, and highlight engineering of stratified, mechanically functional human cartilage interfaced with bone by mesenchymal condensation of MSCs. Taken together, current advances enable engineering of physiologically relevant bone, cartilage and osteochondral composites, and physiologically relevant studies of osteochondral development and disease. PMID- 27236668 TI - Mesenchymal Stem Cells in Lipogems, a Reverse Story: from Clinical Practice to Basic Science. AB - The idea that basic science should be the starting point for modern clinical approaches has been consolidated over the years, and emerged as the cornerstone of Molecular Medicine. Nevertheless, there is increasing concern over the low efficiency and inherent costs related to the translation of achievements from the bench to the bedside. These burdens are also perceived with respect to the effectiveness of translating basic discoveries in stem cell biology to the newly developing field of advanced cell therapy or Regenerative Medicine. As an alternative paradigm, past and recent history in Medical Science provides remarkable reverse stories in which clinical observations at the patient's bedside have fed major advances in basic research which, in turn, led to consistent progression in clinical practice. Within this context, we discuss our recently developed method and device, which forms the core of a system (Lipogems) for processing of human adipose tissue solely with the aid of mild mechanical forces to yield a microfractured tissue product. PMID- 27236666 TI - Mesenchymal Stem Cells in Cardiology. AB - Cardiovascular disease (CVD) accounts for more deaths globally than any other single disease. There are on average 1.5 million episodes of myocardial infarction (heart attack) each year in the United States alone with roughly one third resulting in death. There is therefore a major need for developing new and effective strategies to promote cardiac repair. Intramyocardial transplantation of mesenchymal stem cells (MSCs) has emerged as a leading contender in the pursuit of clinical intervention and therapy. MSCs are potent mediators of cardiac repair and are therefore an attractive tool in the development of preclinical and clinical trials. MSCs are capable of secreting a large array of soluble factors, which have had demonstrated effects on pathogenic cardiac remolding, fibrosis, immune activation, and cardiac stem cell proliferation within the damaged heart. MSCs are also capable of differentiation into cardiomyocytes, endothelial cells, and vascular smooth muscle cells, although the relative contribution of trilineage differentiation and paracrine effectors on cardiac repair remains the subject of active investigation. PMID- 27236669 TI - Paracrine Mechanisms of Mesenchymal Stem Cells in Tissue Repair. AB - Tissue regeneration from transplanted mesenchymal stromal cells (MSC) either through transdifferentiation or cell fusion was originally proposed as the principal mechanism underlying their therapeutic action. However, several studies have now shown that both these mechanisms are very inefficient. The low MSC engraftment rate documented in injured areas also refutes the hypothesis that MSC repair tissue damage by replacing cell loss with newly differentiated cells. Indeed, despite evidence of preferential homing of MSC to the site of myocardial ischemia, exogenously administered MSC show poor survival and do not persist in the infarcted area. Therefore, it has been proposed that the functional benefits observed after MSC transplantation in experimental models of tissue injury might be related to the secretion of soluble factors acting in a paracrine fashion. This hypothesis is supported by pre-clinical studies demonstrating equal or even improved organ function upon infusion of MSC-derived conditioned medium (MSC-CM) compared with MSC transplantation. Identifying key MSC-secreted factors and their functional role seems a reasonable approach for a rational design of nextgeneration MSC-based therapeutics. Here, we summarize the major findings regarding both different MSC-mediated paracrine actions and the identification of paracrine mediators. PMID- 27236670 TI - Protocols for in vitro Differentiation of Human Mesenchymal Stem Cells into Osteogenic, Chondrogenic and Adipogenic Lineages. AB - Mesenchymal stem cells (MSC) possess high plasticity and the potential to differentiate into several different cell types; this characteristic has implications for cell therapy and reparative biotechnologies. MSC have been originally isolated from the bone marrow (BM-MSC), but they have been found also in other tissues such as adipose tissue, cord blood, synovium, skeletal muscle, and lung. MSC are able to differentiate in vitro and in vivo into several cell types such as bone, osteocytes, chondrocytes, adipocytes, and skeletal myocytes, just to name a few.During the last two decades, an increasing number of studies have proven the therapeutic potential of MSC for the treatment of neurodegenerative diseases, spinal cord and brain injuries, cardiovascular diseases, diabetes mellitus, and diseases of the skeleton. Their immuno privileged profile allows both autologous and allogeneic use. For all these reasons, the scientific appeal of MSC is constantly on the rise.The identity of MSC is currently based on three main criteria: plastic-adherence capacity, defined epitope profile, and capacity to differentiate in vitro into osteocytes, chondrocytes, and adipocytes. Here, we describe standard protocols for the differentiation of BM-MSC into the osteogenic, chondrogenic, and adipogenic lineages. PMID- 27236671 TI - Colony Forming Unit Assays. AB - Mesenchymal stem/stromal cells (MSCs) have been extensively investigated for their potential to regenerate tissue, to modulate the immune system, and their wound healing properties in over 350 clinical trials worldwide. MSCs from various tissues such as adipose, bone, and others are currently being studied in clinical trials in indications for ischemic, inflammatory, autoimmune, and degenerative disorders. As a result, numerous isolation protocols have been published. This chapter provides a simple protocol whereby a total of 80-100 million human MSCs, with an average viability greater than 90 %, can be produced from a relatively small (1-3 mL) bone marrow aspirate in 14-20 days using double stack culture chambers. MSCs were originally referred to as fibroblastoid colony forming cells because one of their characteristic features is adherence to tissue culture plastic and generation of colonies when plated at low densities. The efficiency with which they form colonies still remains an important assay for the quality of cell preparations. To assess the quality of cell preparations, two different colony forming unit (CFU) assays are also provided. PMID- 27236672 TI - Methods and Strategies for Lineage Tracing of Mesenchymal Progenitor Cells. AB - Mesenchymal progenitors (MP) are found to varying extents in most tissues and organs. Their relationship to bone marrow-derived mesenchymal stem cells (MSCs) remains unclear, however, both populations appear to share a number of properties as defined by functional assays, clonogenic activity, and genetic and cell surface markers. MSCs were originally defined by their in vitro colony forming unit-fibroblast (CFU-F) activity and their ability to contribute to various mesenchymal lineages (i.e. cartilage, bone, and fat). MSCs also appear to exhibit some unique properties, in that expanded clones in the absence of bone-inducing factors generate bone spicules/organs in vivo. Subsequent analysis of these elements has demonstrated that the transplanted cells directly contribute to multiple mesenchymal lineages. Our ability to study MP and/or MSC behavior and lineage potential in vivo has been hampered by a lack of suitable Cre lines in which to effectively genetically mark and follow the fate and activity of these cells in development, growth, homeostasis and following injury or in disease. The emergence of several new genetic lines is enabling us to now address critical questions regarding MP/MSC location, behavior, function, and fate. The use of these lines and others in conjunction with suitable reporter lines will be described for MP/MSC cell fate analysis. PMID- 27236673 TI - Isolation of Mouse Bone Marrow Mesenchymal Stem Cells. AB - Mesenchymal stem cells (MSCs) were initially characterized as connective tissue progenitors resident in bone marrow, but have now been isolated from a variety of tissues and organs and shown to also exhibit potent tissue regenerative properties mediated largely via paracrine actions. These findings have spurred the development of MSC-based therapies for treating a diverse array of nonskeletal diseases. Although genetic and experimental rodent models of disease represent important tools for developing efficacious MSC-based therapies, development of reliable methods to isolate MSCs from mouse bone marrow has been hampered by the unique biological properties of these cells. Indeed, few isolation schemes afford high yields and purity while maintaining the genomic integrity of cells. We recently demonstrated that mouse MSCs are highly sensitive to oxidative stress, and long-term expansion of these cells in atmospheric oxygen selects for immortalized clones that lack a functional p53 protein. Herein, we describe a protocol for the isolation of primary MSCs from mouse bone marrow that couples immunodepletion with culture in a low-oxygen environment and affords high purity and yield while preserving p53 function. PMID- 27236674 TI - Isolation of Pig Bone Marrow-Derived Mesenchymal Stem Cells. AB - Large animal models are an important preclinical tool for the evaluation of new interventions and their translation into clinical practice. The pig is a widely used animal model in multiple clinical fields, such as cardiology and orthopedics, and has been at the forefront of testing new therapeutics, including cell-based therapies. In the clinic, mesenchymal stem cells (MSCs) are used autologously, therefore isolated, and administrated into the same patient. For successful clinical translation of autologous approaches, the porcine model needs to test MSC in a similar manner. Since a limited number of MSCs can be isolated directly from the bone marrow, culturing techniques are needed to expand the population in vitro prior to therapeutic application. Here, we describe a protocol specifically tailored for the isolation and propagation of porcine derived bone marrow MSCs. PMID- 27236675 TI - Isolation, Culture, and Phenotypic Characterization of Mesenchymal Stromal Cells from the Amniotic Membrane of the Human Term Placenta. AB - During the past several years, the human placenta and in particular the amniotic fetal membrane have attracted much attention as a possible source of cells to be used in cell therapy approaches due to its putative stem cell potential associated with its early embryonic origin and its immunomodulatory potential associated with its role in fetomaternal tolerance.Within the human amniotic membrane, it is possible to isolate two main cell populations: amniotic epithelial cells (from the epithelial layer of the amniotic membrane) and amniotic mesenchymal cells (from the mesenchymal layer of the amniotic membrane). In this chapter, we will describe a method for the isolation of mesenchymal stromal cells (hAMSCs). We will also describe their optimal culture conditions and the phenotypic characterization of cells after passaging. PMID- 27236676 TI - Isolation, Culture, and Characterization of Human Umbilical Cord Blood-Derived Mesenchymal Stromal Cells. AB - Umbilical cord blood (CB) is considered one of the youngest available sources of adult stem cells. Besides hematopoietic stem cells, CB has been shown to contain endothelial progenitor cells as well as mesenchymal stromal/stem cells (MSC). To isolate MSC from cord blood, CB is collected into a sterile bag containing the anticoagulant citrate-phosphate-dextrose (CPD). The CB is then processed by density-gradient centrifugation to obtain mononuclear cells (MNC). These are cultured until the outgrowth of fibroblastoid cell colonies appears. After reaching a subconfluent stage, cells are harvested, expanded, and characterized as cord blood mesenchymal stromal cells (CB-MSC) according to standard criteria: plastic adherence, fibroblast morphology, CFU-f assay, proliferation potential, immune phenotype, and differentiation potential.Apparently, the frequency of MSC in CB is extremely low. Thus, not every CB unit will provide adequate MSC isolation yields. Different strategies have been proposed aiming to optimize the isolation success by selecting CB units of optimal quality. It is commonly agreed on that a high CB volume, a high cellular content, and a short time frame between birth and MSC isolation are criteria that will enhance the MSC isolation success.The procedures in this chapter are standardized protocols that were established and optimized in the authors' research laboratory; however, various modifications of the protocols are possible. PMID- 27236677 TI - Isolation, Expansion, and Immortalization of Human Adipose-Derived Mesenchymal Stromal Cells from Biopsies and Liposuction Specimens. AB - Human adipose tissue has proven to be an abundant, accessible, and rich source of adult mesenchymal stromal cells, suitable for tissue engineering and regenerative medicine. However, a major complication in fully investigating these cells may derive from their limited life span.Although methods to isolate, expand, and immortalize these cells have been widely reported in the literature, exhaustive explanations on the problems that can be encountered during these processes and how these can be solved have never been described. It is of fundamental importance to follow a common protocol to achieve reliable and reproducible results. Here, we describe a protocol to isolate and expand human adipose stromal cells from specimens obtained from tissue biopsies and liposuction surgical interventions. Finally, we broadly describe the cell immortalization technique, and particular attention is paid to some of the apparently "secondary" aspects. PMID- 27236678 TI - Optimization of Mesenchymal Stem Cells to Increase Their Therapeutic Potential. AB - The heart which has limited renewal and regenerative capacity is a prime target for cellular therapy. Stem cell transplantation has emerged as a promising therapeutic strategy to improve healing of the ischemic heart, repopulate the injured myocardium, and restore cardiac function. However, clinical usefulness is impacted by the quality and quantity of delivered cells, the suboptimal manipulations prior to transplantation, and the general poor viability of the cells transferred particularly to an ischemic microenvironment. Focus is now on developing new ways to enhance stem cell renewal and survival capacity before transplant. This can be done by physical, chemical, pharmacological, or genetic manipulation of cells followed by accurate evaluation of conditioning methods by validated tests.This chapter covers the proper handling of mesenchymal stem cells (human and rat lines) and methodologies to evaluate efficacy and the translational potential of conditioning methods. Specifically, we will cover stem cell culture methods, preconditioning protocols, viability assessment in hypoxic and oxidative challenges as encountered in an ischemic microenvironment, and the proliferative capacity of cells. PMID- 27236679 TI - Directed Differentiation of Human-Induced Pluripotent Stem Cells to Mesenchymal Stem Cells. AB - Multipotent stromal cells, also known as mesenchymal stem cells (MSCs), possess great potential to generate a wide range of cell types including endothelial cells, smooth muscle cells, bone, cartilage, and lipid cells. This protocol describes in detail how to perform highly efficient, lineage-specific differentiation of human-induced pluripotent stem cells (iPSCs) with an MSCs fate. The approach uses a clinically compliant protocol with chemically defined media, feeder-free conditions, and a CD105 positive and CD24 negative selection to achieve a single cell-based MSCs derivation from differentiating human pluripotent cells in approximately 20 days. Cells generated with this protocol express typical MSCs surface markers and undergo adipogenesis, osteogenesis, and chondrogenesis similar to adult bone marrow-derived MSCs (BM-MSCs). Nonetheless, compared with adult BM-MSCs, iPSC-MSCs display a higher proliferative capacity, up to 120 passages, without obvious loss of self-renewal potential and constitutively express MSCs surface antigens. MSCs generated with this protocol have numerous applications, including expansion to large scale cell numbers for tissue engineering and the development of cellular therapeutics. This approach has been used to rescue limb ischemia, allergic disorders, and cigarette smoke induced lung damage and to model mesenchymal and vascular disorders of Hutchinson Gilford progeria syndrome (HGPS). PMID- 27236680 TI - Isolation and Manufacture of Clinical-Grade Bone Marrow-Derived Human Mesenchymal Stromal Cells. AB - Mesenchymal stromal cells (MSCs) are multipotent cells with both regenerative and immunomodulatory capacities. These unique properties make them appealing as a biologic, with multiple phase 1-3 clinical trials currently testing their safety and efficacy. Although expanding MSCs does not require extensive manipulation, expanding MSCs for use in clinical trials does require the knowledge and safety that are delineated in current good manufacturing practices (GMPs). Here we briefly detail the characteristics of MSCs and considerations for expanding them for clinical use. We then include a step-by-step protocol for expanding MSCs for early phase clinical trials, with important notes to consider during the expansion of these MSCs. PMID- 27236681 TI - Quality Control Assays for Clinical-Grade Human Mesenchymal Stromal Cells: Methods for ATMP Release. AB - Mesenchymal stromal/stem cells (MSC) are promising candidates for the development of cell-based therapies for various diseases and are currently being evaluated in a number of clinical trials (Sharma et al., Transfusion 54:1418-1437, 2014; Ikebe and Suzuki, Biomed Res Int 2014:951512, 2014). MSC for therapeutic applications are classified as advanced therapy medicinal products (ATMP) (Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004) and must be prepared according to good manufacturing practices ( http://ec.europa.eu/health/documents/eudralex/vol-4 ). They may be derived from different starting materials (mainly bone marrow (BM), adipose tissue, or cord blood) and applied as fresh or cryopreserved products, in the autologous as well as an allogeneic context (Sharma et al., Transfusion 54:1418 1437, 2014; Ikebe and Suzuki, Biomed Res Int 2014:951512, 2014; Sensebe and Bourin, Transplantation 87(9 Suppl):S49-S53, 2009). In any case, they require an approved and well-defined panel of assays in order to be released for clinical use.This chapter describes analytical methods implemented and performed in our cell factory as part of the release strategy for an ATMP consisting of frozen autologous BM-derived MSC. Such methods are designed to assess the safety (sterility, endotoxin, and mycoplasma assays) and identity/potency (cell count and viability, immunophenotype and clonogenic assay) of the final product. Some assays are also applied to the biological starting material (sterility) or carried out as in-process controls (sterility, cell count and viability, immunophenotype, clonogenic assay).The validation strategy for each analytical method is described in the accompanying Chapter 20 . PMID- 27236682 TI - Quality Control Assays for Clinical-Grade Human Mesenchymal Stromal Cells: Validation Strategy. AB - The present chapter focuses on the validation of the following analytical methods for the control of mesenchymal stromal cells (MSC) for cell therapy clinical trials: Microbiological control for cellular product Endotoxin assay Mycoplasma assay Cell count and viability Immunophenotype Clonogenic potential (CFU-F assay) In our lab, these methods are in use for product release, process control or control of the biological starting materials. They are described in detail in the accompanying Chapter 19.For each method, validation goals and strategy are presented, and a detailed experimental scheme is proposed. PMID- 27236683 TI - Cryopreservation and Revival of Human Mesenchymal Stromal Cells. AB - Cell-based therapy is a promising and innovative new treatment for different degenerative and autoimmune diseases, and mesenchymal stromal cells (MSCs) from the bone marrow have demonstrated great therapeutic potential due to their immunosuppressive and regenerative capacities.The establishment of methods for large-scale expansion of clinical-grade MSCs in vitro has paved the way for their therapeutic use in clinical trials. However, the clinical application of MSCs also requires cryopreservation and banking of the cell products. To preserve autologous or allogeneic MSCs for future clinical applications, a reliable and effective cryopreservation method is required.Developing a successful cryopreservation protocol for clinical stem cell products, cryopreservation media, cryoprotectant agents (CPAs), the freezing container, the freezing temperature, and the cooling and warming rate are all aspects which should be considered.A major challenge is the selection of a suitable cryoprotectant which is able to penetrate the cells and yet has low toxicity.This chapter focuses on recent technological developments relevant for the cryopreservation of MSCs using the most commonly used cryopreservation medium containing DMSO and animal serum or human-derived products for research use and the animal protein-free cryopreservation media CryoStor (BioLife Solutions) for clinical use. PMID- 27236684 TI - Clinical-Grade Manufacturing of Therapeutic Human Mesenchymal Stem/Stromal Cells in Microcarrier-Based Culture Systems. AB - The therapeutic potential of mesenchymal stem/stromal cells (MSC) has triggered the need for high cell doses in a vast number of clinical applications. This demand requires the development of good manufacturing practices (GMP)-compliant ex vivo expansion protocols that should be effective to deliver a robust and reproducible supply of clinical-grade cells in a safe and cost-effective manner. Controlled stirred-tank bioreactor systems under xenogeneic (xeno)-free culture conditions offer ideal settings to develop and optimize cell manufacturing to meet the standards and needs of human MSC for cellular therapies. Herein we describe two microcarrier-based stirred culture systems using spinner flasks and controlled stirred-tank bioreactors under xeno-free conditions for the efficient ex vivo expansion of human bone marrow and adipose tissue-derived MSC. PMID- 27236685 TI - GMP-Compliant Expansion of Clinical-Grade Human Mesenchymal Stromal/Stem Cells Using a Closed Hollow Fiber Bioreactor. AB - This chapter describes a method for GMP-compliant expansion of human mesenchymal stromal/stem cells (hMSC) from bone marrow aspirates, using the Quantum((r)) Cell Expansion System from Terumo BCT. The Quantum system is a functionally closed, automated hollow fiber bioreactor system designed to reproducibly grow cells in either GMP or research laboratory environments. The chapter includes protocols for preparation of media, setup of the Quantum system, coating of the hollow fiber bioreactor, as well as loading, feeding, and harvesting of cells. We suggest a panel of quality controls for the starting material, the interim product, as well as the final product. PMID- 27236686 TI - Engineering Small-Scale and Scaffold-Based Bone Organs via Endochondral Ossification Using Adult Progenitor Cells. AB - Bone development, growth, and repair predominantly occur through the process of endochondral ossification, characterized by remodelling of cartilaginous templates. The same route efficiently supports engineering of bone marrow as a niche for hematopoietic stem cells (HSC). Here we describe a combined in vitro/in vivo system based on bone marrow-derived Mesenchymal Stem/Stromal Cells (MSC) that duplicates the hallmark cellular and molecular events of endochondral ossification during development. The model requires MSC culture with instructive molecules to generate hypertrophic cartilage tissues. The resulting constructs complete the endochondral route upon in vivo implantation, in the timeframe of up to 12 weeks. The described protocol is clearly distinct from the direct ossification approach typically used to drive MSC towards osteogenesis. Recapitulation of endochondral ossification allows modelling of stromal-HSC interactions in physiology and pathology and allows engineering processes underlying bone regeneration. PMID- 27236687 TI - Fabrication of Elasticity-Tunable Gelatinous Gel for Mesenchymal Stem Cell Culture. AB - Surface elasticity or stiffness of an underlying substrate may regulate cellular functions such as adhesion, proliferation, signaling, differentiation, and migration. Recent studies have reported on the development of biomaterials to control stem cell fate determination via the stiffness of the culture substrates. In this chapter, we provide a detailed protocol for fabricating elasticity tunable gelatinous hydrogels for stem cell culture with photo-induced or thermo induced crosslinking of well-developed styrenated gelatin (StG). We also include the detailed application of gelatinous gel for mesenchymal stem cell (MSC) culture and sample collection for transcriptional and proteomic analysis. PMID- 27236688 TI - Testing the Paracrine Properties of Human Mesenchymal Stem Cells Using Conditioned Medium. AB - Mesenchymal stem cells (MSC) produce and secrete a great variety of cytokines and chemokines that play beneficial paracrine actions when MSC are used for tissue repair. The conditioned medium (CM) derived from MSC can be used both in vitro and in vivo to test specific paracrine effects or to screen putative paracrine/autocrine mediators by proteomics.In this chapter, we describe a straightforward method to prepare MSC-derived CM. Furthermore, we summarize some in vitro assays useful for testing the cytoprotective, angiogenic, and regenerative activity of CM. These assays are very helpful when studying the role of MSC in cardiac repair and regeneration. PMID- 27236689 TI - Tips on How to Collect and Administer the Mesenchymal Stem Cell Secretome for Central Nervous System Applications. AB - Human mesenchymal stem cells (hMSCs) have been proposed as possible therapeutic agents for central nervous system (CNS) disorders. Recently, it has been suggested that their effects are mostly mediated through their secretome, which contains a number of neuroregulatory molecules capable of increasing cell proliferation, differentiation, and survival in different physiological conditions. Here, we present an overview of the hMSC secretome as a possible candidate in the creation of new cell-free therapies, demonstrating the process of its collection and route of administration, focusing our attention on their effects in CNS regenerative medicine. PMID- 27236690 TI - Soluble Factors from Human Fetal Bone Marrow-Derived Mesenchymal Stem Cells: Preparation of Conditioned Medium and Its Effect on Tumor Cells. AB - Mesenchymal stem cells (MSCs) possess some unique features (inherent tumor tropism, anti-inflammatory and immunosuppressive properties) that are not commonly found in conventional anti-cancer agents. These cells are known to secrete a vast array of proteins including growth factors, cytokines, chemokines, extracellular matrix metalloproteinases, and their corresponding inhibitors which exhibit profound effects on the microenvironment. However, the lack of a uniform method for culturing MSCs and their paracrine factors has hindered our understanding of MSC biology. In this chapter, we describe methods for the isolation, in vivo expansion, and phenotypic characterization of MSCs. In addition, methods for the collection and concentration of conditioned medium from these MSCs are described. Using tumor cells that constitutively express fluorescence reporter proteins, the effect of conditioned medium on tumor cell viability can be easily tested in vitro. PMID- 27236691 TI - Isolation and Characterization of Exosome from Human Embryonic Stem Cell-Derived C-Myc-Immortalized Mesenchymal Stem Cells. AB - Mesenchymal stem cells (MSC) are currently the cell type of choice in many cell therapy trials. The number of therapeutic applications for MSCs registered as product IND submissions with the FDA and initiation of registered clinical trials has increased substantially in recent years, in particular between 2006 and 2012. However, defined mechanisms of action underpinning the therapeutic efficacy of MSCs are lacking, but they are increasingly attributed to MSC trophic secretion rather than their differentiation potential. A promising secreted therapeutic candidate is an extracellular vesicle (EV) known as the exosome. The use of exosomes instead of cells as a therapeutic agent provides several advantages. A critical advantage is the prospect of a conventional pharmaceutical manufacturing process that is highly scalable and amenable to the stringent manufacturing process. For example, MSCs used as producers of therapeutics, and not as therapeutics per se, could be immortalized to generate infinitely expansible clonal lines to enhance the reproducible production of therapeutic exosomes. In this chapter, we will describe the immortalization of MSCs, and the production, isolation, and characterization of exosomes from immortalized MSC. PMID- 27236692 TI - Transcriptomic Analysis of Adult Renal Derived Mesenchymal Stem-Like Cells. AB - Mesenchymal stem cells (MSC) from bone marrow or adult tissues are widely studied to evaluate their potential for tissue repair. Differences in tissue of origin, donor variation, or in vitro handling exist and it is still unclear how they affect cell function and regenerative potential. Large-scale gene expression analysis of these cells not only allows researchers to compare and contrast the differences between each MSC subset but also allows for the development of better analytical tools for their characterization and utilization. Here, we describe a protocol for transcriptomics analysis of MSC-like cells derived from adult kidneys. PMID- 27236693 TI - Proteomic Analysis of Mesenchymal Stem Cells. AB - Mesenchymal stem or stromal cells (MSCs) are of great interest in biomedical sciences and disease treatment because of their multipotency and wide range of applications for tissue repair and suppression of the immune system. Proteomic analysis of these unique cells has contributed to the identification of important pathways utilized by MSCs to differentiate into distinct tissues as well as important proteins responsible for their special function in vivo and in vitro. However, comparison of proteomic studies in MSCs still suffers from the heterogeneity of MSC preparations. In addition, as proteomics technology advances, several studies can be revisited in order to increase the depth of analysis and, therefore, elucidate more refined mechanisms involved in MSC functionalities. Here, we present detailed protocols to obtain MSCs, as well as protocols to perform in-depth profiling and quantification of alterations in MSC proteomes. PMID- 27236694 TI - Unraveling Mesenchymal Stem Cells' Dynamic Secretome Through Nontargeted Proteomics Profiling. AB - The modulatory and regenerative potential shown by the use of MSC secretomes has emphasized the importance of their proteomics profiling. Proteomic analysis, initially focused on the targeted analysis of some candidate proteins or the identification of the secreted proteins, has been changing to an untargeted profiling also based on the quantitative evaluation of the secreted proteins.The study of the secretome can be accomplished through several different proteomics based approaches; however this analysis must overcome one key challenge of secretome analysis: the low amount of secreted proteins and usually their high dilution.In this chapter, a general workflow for the untargeted proteomic profile of MSC's secretome is presented, in combination with a comprehensive description of the major techniques/procedures that can be used. Special focus is given to the main procedures to obtain the secreted proteins, from secretome concentration by ultrafiltration to protein precipitation. Lastly, different proteomics-based approaches are presented, emphasizing alternative digestion techniques and available mass spectrometry-based quantitative methods. PMID- 27236695 TI - Identification of Factors Produced and Secreted by Mesenchymal Stromal Cells with the SILAC Method. AB - Mesenchymal stromal cells (MSCs) secrete a large variety of proteins and factors, which shape the secretome. These proteins participate in multiple cellular functions, including the promotion of regenerative processes in the damaged tissue. Secretomes derived from either undifferentiated MSCs or these cells undergoing osteogenic, chondrogenic, or adipogenic differentiation have been characterized using different liquid chromatography tandem mass spectrometry (LC MS/MS)-based quantitative proteomic approaches. In this chapter, we describe the use of the Stable Isotope Labeling by Amino Acids in Cell culture (SILAC) strategy for the identification and relative quantification of the mesenchymal stromal cell secretome, specifically during chondrogenesis. PMID- 27236696 TI - Expression of Sam68 Associates with Neuronal Apoptosis and Reactive Astrocytes After Spinal Cord Injury. AB - Src-associated in mitosis (Sam68; 68 kDa) is a novel RNA-binding protein that belongs to the signal transduction and activation of RNA family involved in various biological processes. However, the expression and roles of Sam68 in the central nervous system remain unknown. In the present study, we performed a spinal cord injury (SCI) model in adult rats and found a significant increase of Sam68 protein levels in this model, which reached a peak at day 3 and then gradually returned to normal levels at day 14 after SCI. We use immunohistochemistry analysis revealing a widespread distribution of Sam68 in the spinal cord. In addition, double-immunofluorescence staining showed that Sam68 immunoreactivity was found predominantly in neurons and astrocytes. Moreover, colocalization of Sam68/active caspase-3 has been respectively detected in neuronal nuclei, and colocalization of Sam68/PCNA has been detected in glial fibrillary acidic protein. In vitro, we found that depletion of Sam68 by short interfering RNA inhibits neuronal apoptosis and astrocyte proliferation and decreases cyclin D1 protein levels. In conclusion, this is the first study to find the Sam68 expression in SCI. Our results suggest that Sam68 might be illustrated in the apoptosis of neurons and proliferation of astrocytes after SCI. This research will provide new drug targets for clinical treatment of SCI. PMID- 27236697 TI - Effects of Folic Acid and Homocysteine on the Morphogenesis of Mouse Cephalic Neural Crest Cells In Vitro. AB - Folate deficiency and hyperhomocysteinemia have long been associated with developmental anomalies, particularly neural tube defects and neurocristopathies a group of diverse disorders that result from defective growth, differentiation, and migration of neural crest (NC) cells. However, the exact mechanisms by which homocysteine (Hcys) and/or folate deficiencies disrupt NC development are still poorly understood in mammals. In this work, we employed a well-defined culture system to investigate the effects of Hcys and folic acid (FA) supplementation on the morphogenetic processes of murine NC cells in vitro. We demonstrated that Hcys increases outgrowth and proliferation of cephalic NC cells and impairs their differentiation into smooth muscle cells. In addition, we showed that FA alone does not directly affect the developmental dynamics of the cephalic NC cells but is able to prevent the Hcys-induced effects. Our results, therefore, suggest that elevated Hcys levels per se cause dysmorphogenesis of the cephalic NC and might contribute to neurocristopathies in mammalian embryos. PMID- 27236699 TI - High efficiency of targeted mutagenesis in arabidopsis via meiotic promoter driven expression of Cas9 endonuclease. AB - KEY MESSAGE: The use of a meiosis I-specific promoter increased the efficiency of targeted mutagenesis and will facilitate the manipulation of homologous recombination. The CRISPR/Cas9 system has been harnessed for targeted engineering of eukaryotic genomes, including plants; however, CRISPR/Cas9 efficiency varies considerably in different plant tissues and species. In Arabidopsis, the generation of homozygous or bi-allelic mutants in the first (T1) generation is inefficient. Here, we used specific promoters to drive the expression of Cas9 during meiosis to maximize the efficiency of recovering heritable mutants in T1 plants. Our data reveal that the use of a promoter active in meiosis I resulted in high-efficiency (28 %) recovery of targeted mutants in the T1 generation. Moreover, this method enabled efficient simultaneous targeting of three genes for mutagenesis. Taken together, our results show that the use of meiosis-specific promoters will improve methods for functional genomic analysis and studying the molecular underpinnings of homologous recombination. PMID- 27236700 TI - PSI photoinhibition is more related to electron transfer from PSII to PSI rather than PSI redox state in Psychotria rubra. AB - Although it has been believed that wild-type plants are capable of protecting photosystem I (PSI) under high light, our previous study indicates that PSI is sensitive to high light in the shade-established tree species Psychotria rubra. However, the underlying physiological mechanisms are unclear. In this study, we examined the roles of electron transfer from PSII to PSI and PSI redox state in PSI photoinhibition in P. rubra by treatments with lincomycin (Lin), diuron (DCMU), and methyl viologen (MV). After exposure to 2000 MUmol photons m(-2) s( 1) for 2 h, PSI activity decreased by 35, 29, 3, and 49 % in samples treated with H2O, Lin, DCMU, and MV, respectively. Meanwhile, the MV-treated samples showed higher P700 oxidation ratio than the H2O-treated samples, suggesting the PSI photoinhibition under high light was accompanied by high levels of P700 oxidation ratio. PSI photoinhibition was alleviated in the DCMU-treated samples but was accelerated in the MV-treated samples, suggesting that PSI photoinhibition in P. rubra was mainly controlled by electron transfer from PSII to PSI. Taking together, PSI photoinhibition is more related to electron transfer from PSII to PSI rather than PSI redox state in P. rubra, which is different from the mechanisms of PSI photoinhibition in Arabidopsis thaliana and cucumber. PMID- 27236701 TI - Undernutrition Among Infants and Children in Nepal: Maternal Health Services and Their Roles to Prevent it. AB - Objectives Appropriate infant and young child feeding (IYCF) for children aged 6 23 months includes adequate dietary diversity, appropriate meal frequency, and continued breastfeeding. Mothers receiving antenatal care (ANC) and postnatal care (PNC) may adopt better IYCF. This study examined the association of ANC or PNC attendance with IYCF and child nutrition status. Methods A cross-sectional study was performed on 400 mother-child pairs in rural Nepal. Mothers were interviewed about their history of ANC and PNC attendance and IYCF; the height and weight of their children were measured. IYCF was measured with infant and child feeding index (ICFI) aggregating scores of dietary diversity, meal frequency, continued breastfeeding, and dietary variety. Lower ICFI scores indicated poorer IYCF practices. Multiple regression and logistic regression examined the association of ANC and PNC attendance with ICFI scores and undernutrition, respectively. Results Absence of ANC (beta = -1.01, P = 0.011) and absence of PNC (beta = -1.01, P = 0.011) were negatively associated with ICFI scores. Additionally, absence of ANC was positively associated with underweight (AOR 3.37; 95 % CI 1.42-9.92 for children 6-11 months, AOR 3.43; 95 % CI 1.41 8.32 for children 12-23 months) and stunting (AOR 6.51; 95 % CI 2.11-20.10 for children 6-11 months, AOR 3.32; 95 % CI 1.50-7.31 for children 12-23 months). Similarly, children tended to be underweight and stunted if their mothers did not receive any PNC. Conclusion Absence of ANC and PNC were associated with poor IYCF, underweight, and stunting in children. PMID- 27236702 TI - Systematic thematic review of e-health research in the Gulf Cooperation Council (Arabian Gulf): Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and United Arab Emirates. AB - Introduction The Gulf Cooperation Council (GCC or 'Arabian Gulf'), comprising Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and United Arab Emirates, is a political organization sharing a common history and culture. All GCC nations have made substantial investments in telecommunications and electronic health infrastructure since 2000. Methods We conducted a literature search in English and Arabic on peer-reviewed e-health research up to December 2014 originating in the GCC. The objective was to retrieve all research on e-health in the GCC and to categorize and analyse it qualitatively to reveal the current state of e-health research and development in the region. Inclusion criteria included peer-reviewed articles, books, book chapters, conference papers and graduate theses written on e-health in the GCC. Blogs, health websites and non-peer-reviewed literature were excluded. Results Three hundred and six articles were retrieved, categorized and analysed qualitatively to reveal the state of e-health research in the GCC. Both country-specific and GCC-wide major themes were identified using NVivo 10.0 qualitative software and summarized. The most common type of study was an overview (35.0%), with common study designs of case studies (26.8%) and descriptive articles (46.4%). Significant themes were: prospective national benefits from e-health, implementation and satisfaction with electronic health records, online technologies in medical education, innovative systems (case studies), and information security and personal health information. Discussion This is the first comprehensive analytical literature review of e-health in the GCC. Important research gaps were identified: few cost-benefit analyses, controlled interventional studies, or research targeting gender and religious issues were retrieved. PMID- 27236703 TI - Videoconferencing in a mental health service in The Netherlands: A randomized controlled trial on patient satisfaction and clinical outcomes for outpatients with severe mental illness. AB - Introduction The goal of the study was to determinate if there was added value in the use of videoconferencing (VCF) in outpatient care for people with severe mental illness (SMI). Methods A VCF-group was compared to a control group (care as usual) over a period of 18 months. Block randomization was used to assign patients to one of the two groups. The video communication was available to the patients on a 24/7 basis, so that emergency calls could also be made via VCF. The primary outcome was patient satisfaction, other outcomes were: quality of life, loneliness, daily functioning (psychologically and socially), and the fulfilment of needs of care. Eventually, 93 patients signed their informed consent and participated. Results For the primary outcome a statistically significant time by treatment interaction effect was found, where higher degree of satisfaction was associated with the patients in the VCF-group. The secondary outcomes revealed no differences between the two groups. Despite the participants not using the VCF units extensively during the project, they were reasonably satisfied with VCF; on average, they rated the service with a 7.5 grade (on a scale from 1-10). Discussion Although the study showed a positive result for patient satisfaction, overall the VCF seemed to have limited impact. So VCF might not offer much added value to care as usual. However, statistical power in this study dropped somewhat due to dropout. Furthermore, VCF usage was lower than expected. Assuming that VCF will be most effective if it is actually used, it seems likely that the actual effect-size reached in this study has been significantly lower than the anticipated effect-size. Finally, this study shows that VCF is a tool that can be used in the care for people with severe mental illness. PMID- 27236704 TI - LECANDUS study (LEsion CANdidate Detection in UltraSound Data): evaluation of image analysis algorithms for breast lesion detection in volume ultrasound data. AB - PURPOSE: This study aims at developing and evaluating a prototype of a lesion candidate detection algorithm for a 3D-US computer-aided diagnosis (CAD) system. METHODS: Additionally, to routine imaging, automated breast volume scans (ABVS) were performed on 63 patients. All ABVS exams were analyzed and annotated before the evaluation with different algorithm blob detectors characterized by different blob-radiuses, voxel-sizes and the quantiles of blob filter responses to find lesion candidates. Lesions found in candidates were compared to the prior annotations. RESULTS: All histologically proven lesions were detected with at least one algorithm. The algorithm with optimal sensitivity detected all cancers (sensitivity = 100 %) with a very low positive predictive value due to a high false-positive rate. CONCLUSIONS: ABVS is a new technology which can be analyzed by a CAD software. Using different algorithms, lesions can be detected with a very high and accurate sensitivity. Further research for feature extraction and lesion classification is needed aiming at reducing the false-positive hits. PMID- 27236705 TI - Acute hyperlipidemia initiates proinflammatory and proatherogenic changes in circulation and adipose tissue in obese women. AB - BACKGROUND: Obesity represents a high risk factor for the development of atherosclerosis and is associated with a low-grade inflammation and activation of immune cells. AIMS: The aim of our study was to investigate the effect of a short term lipid infusion on immune cells in blood and subcutaneous abdominal adipose tissue (SAAT) in obese women. METHODS: Seven-hour intravenous lipid/control infusions were performed in two groups of women (n = 15, n = 10, respectively). Before and at the end of the infusion, SAAT and blood samples were obtained and relative content and phenotype of immune cells were analyzed using flow cytometry. Analysis of immune cell markers, inflammation and angiogenesis markers was performed in SAAT by RT-PCR and in plasma by immunoassays. RESULTS: Relative content of CD45+/14+ and CD45+/14+/16+ populations of monocytes was reduced in circulation by 21% (p = 0.004) and by 46% (p = 0.0002), respectively, in response to hyperlipidemia, which suggested the increased adhesion of these cells to endothelium. In line with this, the levels of sICAM and sVCAM in plasma were increased by 9.4% (p = 0.016), 11.8% (p = 0.008), respectively. In SAAT, the relative content of M2 monocyte/macrophages subpopulation CD45+/14+/206+/16+ decreased by 27% (p = 0.012) and subpopulations CD14+/CD206- and CD14/+TLR4+ cells increased (p = 0.026; p = 0.049, respectively). Intralipid infusion promoted an increase of mRNA levels in SAAT: RORC (marker of proinflammatory Th17 lymphocytes) by 43% (p = 0.048), MCP-1 (78%, p = 0.028) and VEGF (68.5%, p = 0.0001). CONCLUSIONS: Acute hyperlipidemia induces a proinflammatory and proatherogenic response associated with altered relative content of immune cells in blood and SAAT in obese women. PMID- 27236706 TI - Resolvin E1 attenuates atherosclerosis in absence of cholesterol-lowering effects and on top of atorvastatin. AB - BACKGROUND AND AIMS: Besides LDL-cholesterol, local vascular inflammation plays a key role in atherogenesis. Efficient therapies to treat the inflammatory component of the disease have not been established. The discovery of specialized inflammation-resolving mediators, such as resolvins may provide new opportunities for treatment. This study examines whether the omega-3 fatty acid eicosapentaenoic acid-derived resolvin E1 (RvE1), can reduce atherosclerosis, when administered alone or in combination with a cholesterol-lowering statin. METHODS: ApoE*3Leiden mice were fed a hypercholesterolemic diet for 9 weeks and subsequently treated with RvE1-low (1 mg/kg/day), RvE1-high (5 mg/kg/day), atorvastatin (1.5 mg/kg/day) or the combination of atorvastatin and RvE1-low for the following 16 weeks. RESULTS: RvE1-low and RvE1-high reduced atherosclerotic lesion size to the same extent (-35%; p < 0.05), attenuated the formation of severe lesions, also seen as a proportional increase in the presence of mild lesions, but did not alter plasma cholesterol levels. Cholesterol-lowering atorvastatin reduced atherosclerosis (-27%, p < 0.05), and the combination of RvE1 and atorvastatin further attenuated lesion size (-51%, p < 0.01) and increased the content of mild lesions. RvE1 did not affect plasma SAA, E selectin, VCAM-1 or MCP-1 but did reduce plasma EPHX4 and down-regulated the local expression of pro-atherogenic genes in the aortae, (e.g. Cd74, Cd44, Ccl2, Ccr5 and Adam17) and significantly inactivated IFN-gamma (p < 0.001) and TNF alpha (p < 0.001) signalling pathways. CONCLUSIONS: RvE1 attenuates atherogenesis both alone and on top of a statin. The local effects of RvE1 are demonstrated by the modulated aortic expression of genes involved in inflammatory and immune responses, without altering plasma cholesterol or circulating SAA. PMID- 27236707 TI - Quantitative PCR Detection and Characterisation of Human Adenovirus, Rotavirus and Hepatitis A Virus in Discharged Effluents of Two Wastewater Treatment Facilities in the Eastern Cape, South Africa. AB - The occurrence of enteric viruses in reclaimed wastewater, their removal by efficient treatment processes and the public health hazards associated with their release into the environments are of great significance in environmental microbiology. In this study, TaqMan-based real-time polymerase chain reaction (qPCR) was used to assess the prevalence of human adenovirus (HAdV), rotavirus (RV) and hepatitis A virus (HAV) in the final effluents of two wastewater treatment plants in the Eastern Cape Province, South Africa, over a twelve-month sampling period. The correlation between the concentrations of viruses in the effluents samples and faecal coliform (FC) densities were assessed as to validate the use of FC as microbiological indicator in water quality assessment. HAdV was detected in 62.5 % (30/48) of the samples with concentrations ranging between 8.4 * 101 and 1.0 * 105 genome copies/L while HAV and RV were only detected at concentrations below the set detection limits. FCs densities ranged from 1 to 2.7 * 104 CFU/100 ml. Adenovirus species HAdV-B (serotype 2) and HAdV-F (serotype 41) were detected in 86.7 % (26/30) and 6.7 % (2/30) of the HAdV-positive samples, respectively. No consistent seasonal trend was observed in HAdV concentrations, however, increased concentrations of HAdV were generally observed in the winter months. Also, there was no correlation between the occurrence of HAdV and FC at both the treatment plants. The persistent occurrence of HAdV in the discharged treated effluents points to the potential public health risk through the release of HAdV into the receiving watersheds, and the possibility of their transmission to human population. PMID- 27236709 TI - Hypercoagulability detected by circulating microparticles in patients with hepatocellular carcinoma and cirrhosis. PMID- 27236708 TI - [Diagnostics of acute pulmonary embolism : An update]. AB - Pulmonary embolism is an acute and potentially life-threatening condition requiring a differentiated diagnostic algorithm. Assessment of the risk and clinical probability are of utmost importance in order to initiate early treatment or to reliably exclude a pulmonary embolism. Computed tomography of the pulmonary arteries (CTPA) has become the non-invasive gold standard for the diagnostic approach. Alternatively, scintigraphy can also be used. A negative CTPA excludes a pulmonary embolism with a high degree of probability. Furthermore, CTPA can supply additional information, such as estimation of the right ventricular strain (right ventricular dysfunction, RVD) or alternative diagnoses if pulmonary embolism has been ruled out as the primary cause of symptoms. An essential prerequisite is a high quality CTPA with sufficient contrast enhancement in the pulmonary arteries, avoidance of artifacts and optimization of both the radiation dosage as well as the amount of contrast medium, individually determined for each patient. PMID- 27236710 TI - Prolonged low-molecular-weight heparin use during pregnancy and subsequent bone mineral density. AB - INTRODUCTION: In contrast to unfractionated heparin (UFH), use of low-molecular weight heparin (LMWH) during pregnancy has not been reported to be associated with a significant decrease in bone mineral density (BMD). The aim of this study was to investigate whether long-term use of LMWH during pregnancy is associated with subsequent decrease in BMD or with increased number of osteoporotic fractures. MATERIALS AND METHODS: In this observational cohort study BMD was measured by dual energy X-ray absorptiometry (DEXA) 4-7years after the last delivery in 152 women. Ninety-two women had prolonged LMWH-exposure during pregnancy - 75 as prophylaxis and 17 as treatment for venous thromboembolic event (VTE). Dalteparin and enoxaparin were the LMWH-preparations used. Sixty women without LMWH-exposure served as controls. A questionnaire about lifestyle factors and medical history was filled out by the subjects. RESULTS: Lumbar spine BMD in the LMWH users was lower than that in the controls both in the prophylactic group (1.22g/cm(2) vs. 1.27g/cm(2); p=0.03), and in the treatment group (1.20g/cm(2) vs. 1.27g/cm(2); p=0.07). BMD in femoral neck did not differ between the LMWH users and controls. However, after adjusting for potential confounding factors, LMWH-exposure did not remain associated with decreased BMD in lumbar spine. Use of contraceptive pills was positively associated with BMD in lumbar spine. Incidence of osteopenia was 13% in the LMWH-group and 8% in the control-group, (p=0.4). No osteoporosis or osteoporotic fractures were found. CONCLUSIONS: Prolonged use of LMWH during pregnancy was not associated with subsequent decrease in BMD, osteopenia, osteoporosis, or osteoporotic fractures. PMID- 27236711 TI - Corrigendum to "Trends in mental health inequalities in England during a period of recession, austerity and welfare reform 2004 to 2013" [Social Sci. Med. 147C (2015) 324-331]. PMID- 27236712 TI - Increased circulating cell-derived microparticle count is associated with recurrent implantation failure after IVF and embryo transfer. AB - Cell-derived microparticles (cMPs) are small membrane vesicles that are released from many different cell types in response to cellular activation or apoptosis. Elevated cMP counts have been found in almost all thrombotic diseases and pregnancy wastage, such as recurrent spontaneous abortion and in a number of conditions associated with inflammation, cellular activation and angiogenesis. cMP count was investigated in patients experiencing unexplained recurrent implantation failure (RIF). The study group was composed of 30 women diagnosed with RIF (RIF group). The first control group (IVF group) (n = 30) comprised patients undergoing a first successful IVF cycle. The second control group (FER group) included 30 healthy women who had at least one child born at term and no history of infertility or obstetric complications. cMP count was significantly higher in the RIF group compared with the IVF and FER groups (P < 0.05 and P < 0.01, respectively) (RIF group: 15.8 +/- 6.2 nM phosphatidylserine equivalent [PS eq]; IVF group: 10.9 +/- 5.3 nM PS eq; FER group: 9.6 +/- 4.0 nM PS eq). No statistical difference was found in cMP count between the IVF and FER groups. Increased cMP count is, therefore, associated with RIF after IVF and embryo transfer. PMID- 27236713 TI - Infectious agents in congenital cataract in a tertiary care referral center in North India. AB - Congenital cataract has the potential for inhibiting early visual development. Intrauterine infections with Rubella virus, Herpes simplex virus (HSV) and Toxoplasma gondii plays an important role in the development of congenital cataract. The study included 120 children under the age of 6 years presenting with congenital cataract and diagnosed using serology and polymerase chain reaction (PCR). The IgM positivity for rubella, HSV, T. gondii was found to be 5.8%, 1.6% and 8.3% respectively. The overall PCR positivity was found to be 40(33.3%), 25 (20.8%) and 39 (32.5%) for rubella, HSV and T. gondii with mean copy number of 1599 copies/MUL; 1716 copies/MUL and 1503 copies/MUL respectively. Infective etiology significantly contributes to the causation of congenital cataract particularly for rubella virus which is a potentially eradicable disease. This study provides an epidemiological data for rubella, HSV and T. gondii in children with congenital cataract and highlights the need to introduce rubella vaccine in the National Immunization Programme of India. PMID- 27236715 TI - Insulinoma in a 5-Year-Old Dexter Cow. PMID- 27236714 TI - Rapid detection of blaOXA in carbapenem-susceptible Acinetobacter radioresistens bacteremia leading to unnecessary antimicrobial administration. AB - Rapid molecular techniques to identify resistant pathogens are revolutionizing antibiotic stewardship; however, it is important to recognize the limitations of these techniques. Herein we describe two cases of bacteremia that were both initially identified by genotypic testing as carbapenem-resistant Acinetobacter spp. and subsequently identified phenotypically as carbapenem-susceptible A. radioresistens. The genotypic results prompted unnecessary broad-spectrum antibiotic use and infection control concerns. PMID- 27236716 TI - [Health literacy in patients with heart failure treated in primary care]. AB - OBJECTIVES: The level of health literacy is examined, as well as its conditioning factors in patients with heart failure who are seen routinely in a Primary Health Care Area. DESIGN: A multicentre cross-sectional study. SETTING: 10 Primary care centres from the metropolitan area of Barcelona. PARTICIPANTS: Patients diagnosed with heart failure. INCLUSION CRITERIA: to have visited the Primary Health Care centre in the last year, being able to arrive at the primary care setting independently, and voluntarily participation. MAIN MEASUREMENTS: Health Literacy Survey-European Union - Questionnaire (HLS-EU-Q) and Spanish version of the European Heart Failure Self-care Behaviour Scale. An analysis was made of the relationships between health literacy, self-care practices, sociodemographic, and clinical variables using ANOVA test and a multiple linear regression model. RESULTS: The study included 318 patients (51.2% women) with a mean age of 77.9+/ 8.7 years. The index of health literacy of 79.6% (n=253) of the participants indicated problems in understanding healthcare information. Health literacy level was explained by academic level (P<.001), the extent of heart failure (P=.032), self-care, and age (P<.04).The academic level explained 61.6% of the health of literacy (95% bootstrap: 44.58%; 46.75%). CONCLUSIONS: In patients with stable heart failure, it is important to consider all factors that help patients to understand the healthcare information. Health literacy explains patient self-care attitude in heart failure. PMID- 27236717 TI - Comparison of the outcomes of hepatocellular carcinoma after hepatectomy between two regional medical centers in China and Japan. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignant disease of the liver in China and Japan. The purpose of this study was to compare the outcomes of HCC patients after hepatectomy between two regional medical centers in China and Japan. METHODS: Data on HCC after hepatectomy were collected from January 2005 to December 2014 from Nagasaki University Hospital in Nagasaki, Japan and the Second Affiliated Hospital of Nanchang University in Nanchang, China. The patient and tumor characteristics, HCC etiology, and overall survival rates after hepatectomy were investigated. RESULTS: Two hundred patients in the Nagasaki group and 238 patients in the Nanchang group were diagnosed with HCC and underwent hepatectomy. The major underlying liver diseases were hepatitis C infection (32%, 64/200) and nonalcoholic steatohepatitis (NASH) (34.5%, 69/200) in the Nagasaki group, while in the Nanchang group, hepatitis B infection (79.4%, 189/238) was the dominant etiology. Large tumors (> 5 cm), the presence of a tumor capsule and a high alpha-fetoprotein value (>= 400 U/L) were more frequently observed in the Nanchang group as compared with the Nagasaki group (p < 0.05). According to an outcome analysis, the Nanchang patients showed worse survival rates as compared with Nagasaki patients, particularly those with American Joint Committee on Cancer stages I and III due to the aggressive character of HCC in the Nanchang group. CONCLUSION: There are significant differences in the clinicopathologic features and outcomes of HCC patients from Japan and China. These differences may impact the eligibility for potentially curative therapy and the prognosis of patients with HCC. PMID- 27236718 TI - Improving clinical examination in acute tibial fractures by enhancing visual cues: the case for always 'cutting back' a tibial back-slab and marking the dorsalis pedis pulse. AB - Look, feel, move is a simple and widely taught sequence to be followed when undertaking a clinical examination in orthopaedics (Maher et al., 1994; McRae, 1999; Solomon et al., 2010). The splinting of an acute tibial fracture with a posterior back-slab is also common practice; with the most commonly taught design involving covering the dorsum of the foot with bandaging (Charnley, 1950; Maher et al., 1994; McRae, 1989). We investigated the effect of the visual cues provided by exposing the dorsum of the foot and marking the dorsalis pedis pulse. We used a clinical simulation in which we compared the quality of the recorded clinical examination undertaken by 30 nurses. The nurses were randomly assigned to assess a patient with either a traditional back-slab or one in which the dorsal bandaging had been cut back and the dorsalis pedis pulse marked. We found that the quality of the recorded clinical examination was significantly better in the cut-back group. Previous studies have shown that the cut-back would not alter the effectiveness of the back-slab as a splint (Zagorski et al., 1993). We conclude that all tibial back-slabs should have the bandaging on the dorsum of the foot cut back and the location of the dorsalis pedis pulse marked. This simple adaptation will improve the subsequent clinical examinations undertaken and recorded without reducing the back-slab's effectiveness as a splint. PMID- 27236719 TI - [Vaginal meshes for POP cure: What is the state of play beginning 2016?]. PMID- 27236720 TI - Natural cholinesterase inhibitors from Myristica cinnamomea King. AB - A new acylphenol, malabaricone E (1) together with the known malabaricones A-C (2 4), maingayones A and B (5 and 6) and maingayic acid B (7) were isolated from the ethyl acetate extract of the fruits of Myristica cinnamomea King. Their structures were determined by 1D and 2D NMR techniques and LCMS-IT-TOF analysis. Compounds 3 (1.84+/-0.19 and 1.76+/-0.21MUM, respectively) and 4 (1.94+/-0.27 and 2.80+/-0.49MUM, respectively) were identified as dual inhibitors, with almost equal acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes inhibiting potentials. The Lineweaver-Burk plots of compounds 3 and 4 indicated that they were mixed-mode inhibitors. Based on the molecular docking studies, compounds 3 and 4 interacted with the peripheral anionic site (PAS), the catalytic triad and the oxyanion hole of the AChE. As for the BChE, while compound 3 interacted with the PAS, the catalytic triad and the oxyanion hole, compound 4 only interacted with the catalytic triad and the oxyanion hole. PMID- 27236721 TI - Keeping the golden mean: plant stiffness and anatomy as proximal factors driving endophytic oviposition site selection in a dragonfly. AB - Oviposition site selection is a crucial component of habitat selection in dragonflies. The presence of appropriate oviposition plants at breeding waters is considered to be one of the key habitat determinants for species laying eggs endophytically. Thus, Lestes macrostigma, a species which is regarded as threatened in Europe because of its highly disjunct distribution, typically prefers to lay eggs in the sea club rush Bolboschoenus maritimus. However, little is known about how the anatomical and mechanical properties of plant tissues determine the choice of L. macrostigma females. We examined green shoots of six plant species used by L. macrostigma for oviposition, either in the field (actual oviposition plants) or under experimental conditions (potential oviposition plants), to analyse anatomical and mechanical properties of shoots in a framework of known preferences regarding plant substrates for oviposition. As expected, the anatomy of shoots differed between representatives of two plant families, Cyperaceae and Juncaceae, most essentially in the distribution of supporting bundles and the presence of large aeriferous cavities that may affect egg placing within a shoot. The force necessary to puncture the tested plant samples ranged from 360 to 3298 mN, and their local stiffness ranged from 777 to 3363N/m. We show that the shoots of B. maritimus, the plant most preferred by L. macrostigma, have intermediate characteristics regarding both the stiffness and specific anatomical characteristics. The bending stiffness of the ovipositor in L. macrostigma was estimated as 1414N/m, one of the highest values recorded for zygopteran dragonflies so far. The ecological and behavioural implications of plant choice mechanisms in L. macrostigma are discussed in the context of the disjunct distribution of this species. PMID- 27236722 TI - Dual-color encoded DNAzyme nanostructures for multiplexed detection of intracellular metal ions in living cells. AB - The detection of intracellular metal ions is of great importance in understanding metal homeostasis in cells and related diseases, and yet it remains a significant challenge to achieve this goal. Based on a new self-assembled and dual-color encoded DNAzyme nanostructure, we describe here an approach for multiplexed sensing of UO2(2+) and Pb(2+) in living cells. The fluorescently quenched nanoprobes can be prepared by simple thermal annealing of four ssDNAs containing the metal ion-dependent enzymatic and substrate sequences. The self-assembly formation of the nanostructures are verified by native polyacrylamide gel electrophoresis. The target metal ions can cleave the substrate sequences in the DNAzyme nanostructures to recover fluorescent emissions at different wavelengths for sensitive and selective in vitro multiplexed detection of UO2(2+) and Pb(2+) with the detection limits of 0.6nM and 3.9nM, respectively. Importantly, we demonstrate that these nanoprobes are stable in cell lysates and can enter cells without the aid of any transfection agents for simultaneous imaging intracellular UO2(2+) and Pb(2+). Moreover, the nanoprobes offer excellent biocompatibility and non-cytotoxicity. With these unique features, the dual-color encoded nanostructures presented here can thus offer new opportunities for multiplexed detection of specific intracellular species. PMID- 27236723 TI - Electrochemical immunosensor for detection of prostate specific antigen based on an acid cleavable linker into MSN-based controlled release system. AB - A mesoporous silica nanoparticle (MSN)-based controlled release system with acid cleavable linkage was developed to fabricate an electrochemical immunosensor for the quantitative detection of the prostate-specific antigen (PSA). 3,9-Bis(3 aminopropyl)-2,4,8,10-tetraoxaspiro[5.5]undecane functionalized mesoporous silica nanoparticles (MSN-Acetal) were used to immobilize the electron mediator thionine (Th). The encapsulation of Th molecules was achieved by capping the pores of MSN Acetal with carboxylic acid modified Au nanoparticles (defined as MSN-Th-Au). Under the acidic conditions, the capped Au nanoparticles were removed from MSN-Th Au through the hydrolysis of the acid-labile acetal linker, resulting in the release of encapsulated Th. In this work, the pH-responsive cargo release system was firstly used as the label of secondary anti-PSA for developing an electrochemical immunosensor, and amination Fe3O4 was used as the sensing matrix for immobilizing primary anti-PSA on magnetic carbon electrode surfaces. The specific recognition of PSA resulted in the attachment of MSN-Th-Au-secondary anti-PSA (MSN-Th-Au-Ab2) onto the electrode surfaces. Subsequently, the released Th was detected by differential pulse voltammetry under the acidic conditions. The developed cargo release system provided an innovative and reliable method for the detection of PSA because the response signal was correlated with the concentration of PSA. Under the optimal conditions, the electrochemical immunosensor exhibited a wide linear range of 0.001-5.0ng/mL with a low detection limit of 0.31pg/mL. Moreover, the developed immunosensor showed superior reproducibility and long-term stability, which has promising applications in bioassay and biosensing. PMID- 27236724 TI - Solvent-assisted morphology confinement of a nickel sulfide nanostructure and its application for non-enzymatic glucose sensor. AB - Morphology-controlled synthesis of nickel sulfide (Ni3S2) was performed directly on Ni foam using thioacetamide as a sulfur ion source. Various morphologies of nickel sulfide were fabricated using a hydrothermal process by adjusting the solvent composition of ethanol and water. In the water-dominant condition, a dendrite structure was obtained; otherwise, a flaky structure was achieved. A hierarchical cauliflower-like structure was obtained at a solvent mixture composition of 1:1 and was used as non-enzymatic glucose sensor. The hierarchical Ni3S2 electrode showed a high level of electro-catalytic activity toward the oxidation of glucose (16,460MUAmM(-1)cm(-2)) over a wide range of detection (0.0005-3mM) and a low detection limit (0.82MUM) with excellent selectivity in the presence of several electroactive species. PMID- 27236725 TI - A double responsive smart upconversion fluorescence sensing material for glycoprotein. AB - A novel strategy was developed to prepare double responsive smart upconversion fluorescence material for highly specific enrichment and sensing of glycoprotein. The novel double responsive smart sensing material was synthesized by choosing Horse radish peroxidase (HRP) as modal protein, the grapheme oxide (GO) as support material, upconversion nanoparticles (UCNPs) as fluorescence signal reporter, N-isopropyl acrylamide (NIPAAM) and 4-vinylphenylboronic acid (VPBA) as functional monomers. The structure and component of smart sensing material was investigated by transmission electron microscopy (TEM), Scanning electron microscopy (SEM), X-ray photoelectron spectroscopic (XPS) and Fourier transform infrared (FTIR), respectively. These results illustrated the smart sensing material was prepared successfully. The recognition characterizations of smart sensing material were evaluated, and results showed that the fluorescence intensity of smart sensing material was reduced gradually, as the concentration of protein increased, and the smart sensing material showed selective recognition for HRP among other proteins. Furthermore, the recognition ability of the smart sensing material for glycoprotein was regulated by controlling the pH value and temperature. Therefore, this strategy opens up new way to construct smart material for detection of glycoprotein. PMID- 27236726 TI - Detection of methyl salicylate using bi-enzyme electrochemical sensor consisting salicylate hydroxylase and tyrosinase. AB - Volatile organic compounds have been recognized as important marker chemicals to detect plant diseases caused by pathogens. Methyl salicylate has been identified as one of the most important volatile organic compounds released by plants during a biotic stress event such as fungal pathogen infection. Advanced detection of these marker chemicals could help in early identification of plant diseases and has huge significance for agricultural industry. This work describes the development of a novel bi-enzyme based electrochemical biosensor consisting of salicylate hydroxylase and tyrosinase enzymes immobilized on carbon nanotube modified electrodes. The amperometric detection using the bi-enzyme platform was realized through a series of cascade reactions that terminate in an electrochemical reduction reaction. Electrochemical measurements revealed that the sensitivity of the bi-enzyme sensor was 30.6+/-2.7uAcm(-2)uM(-1) and the limit of detection and limit of quantification were 13nM (1.80ppb) and 39nM (5.39ppb) respectively. Interference studies showed no significant interference from the other common plant volatile compounds. Synthetic analyte studies revealed that the bi-enzyme based biosensor can be used to reliably detect methyl salicylate released by unhealthy plants. PMID- 27236727 TI - Conformation-sensitive antibody-based point-of-care immunosensor for serum Ca(2+) using two-dimensional sequential binding reactions. AB - To assess the homeostasis of Ca(2+) metabolism, we have developed a rapid immunosensor for ionic calcium using a membrane chromatographic technique. As calcium-binding protein (CBP) is available for the recognition and undergone conformation change upon Ca(2+) binding, a monoclonal antibody sensitive to the altered structure of CBP has been employed. The sequential binding scheme was mathematically simulated and shown to match with the experimental results. At the initial stage, the rapid analytical system using lateral flow was constructed by immobilizing the antibody on the immuno-strip nitrocellulose membrane and labeling CBP with colloidal gold as a tracer. A major problem with this system in measuring ionic calcium levels was retarded migration of the gold tracer along the immuno-strip. It was conceivable that the divalent cation at a high concentration caused a change in the physical properties of the tracer, resulting in a non-specific interaction with the membrane surface. This problem was circumvented by first eluting a sample containing biotinylated CBP along the immuno-strip and then supplying the gold coupled to streptavidin across the signal generation pad of the strip. The color signal was then generated via biotin-SA linkage and measured using a smartphone-based detector developed in our laboratory. This two-dimensional chromatographic format completed the Ca(2+) analysis within 15min, the analytical performance covered the clinical dynamic range (0.25-2.5mM) and highly correlated with that of the reference system, i STAT. These results inspired us to eventually investigate a dual-immunoassay system that measures simultaneously ionic calcium and parathyroid hormone, which regulates the ionic calcium level in serum. This will significantly simplify the current diagnostic protocols, which involve separate devices. PMID- 27236728 TI - Corrigendum to "A new method for monitoring the extracellular proteolytic activity of wine yeasts during alcoholic fermentation of grape must" [J. Microbiol. Methods 119 (2015) 176-179]. PMID- 27236729 TI - When is a trauma surgeon not a trauma surgeon? PMID- 27236730 TI - Pathogenicity Island O-122 in enteropathogenic Escherichia coli strains is associated with diarrhea severity in children from Lima Peru. AB - EPEC is an attaching and effacing diarrheal pathogen that carries a large pathogenicity island, locus for enterocyte effacement (LEE). Recently, the pathogenicity island PAI O-122 was described among non-LEE effectors and found to be associated with diarrhea among atypical EPEC strains. It is unknown if incomplete PAI O-122 could be associated with diarrhea duration and severity. To identify these virulence determinants we analyzed 379 EPEC strains isolated from Peruvian children. EPEC was diagnosed by PCR(eae+, stx-) and classified as typical(t-EPEC) or atypical(a-EPEC). To characterize PAI O-122 we amplified three modules by PCR: Module 1(pagC), Module 2(senA, nleB and nleE) and Module 3(lifA/efa-1). To characterize the large ORF lifA/efa-1 we amplified the regions known as efa-N, efa-M and efa-C. Clinical information was obtained from the cohort study. A total of 379 EPEC strains were able to analyze PAI O-122 genes, 128 (10.4%) EPEC strains were isolated from 1235 diarrhea episodes and 251(9.2%) from 2734 healthy controls. t-EPEC strains were isolated from 14.8% (19/128) of children with diarrhea and 25/251(10.0%) from healthy controls. The most frequent PAI O-122 genes were nleE(37.7%), senA(34.6%) and nleB(37.5%), with similar prevalence among diarrhea and control samples. However, lifA/efa-1 was more common among diarrhea cases than healthy control cases (30.5% vs. 21.1%, p<0.05). The presence of complete PAI O-122 was associated with diarrhea episodes of higher severity among single pathogen infection (33.3% vs. 1.8%, p<0.05) mainly due to the presence of a complete lifA/efa-1 gene. In summary, the gene lifA/efa 1 is significantly associated with diarrheal episodes of higher severity, suggesting to be an important virulent factor. PMID- 27236731 TI - Personalized mapping of the deep brain with a white matter attenuated inversion recovery (WAIR) sequence at 1.5-tesla: Experience based on a series of 156 patients. AB - OBJECTIVE: Deep brain mapping has been proposed for direct targeting in stereotactic functional surgery, aiming to personalize electrode implantation according to individual MRI anatomy without atlas or statistical template. We report our clinical experience of direct targeting in a series of 156 patients operated on using a dedicated Inversion Recovery Turbo Spin Echo sequence at 1.5 tesla, called White Matter Attenuated Inversion Recovery (WAIR). METHODS: After manual contouring of all pertinent structures and 3D planning of trajectories, 312 DBS electrodes were implanted. Detailed anatomy of close neighbouring structures, whether gray nuclei or white matter regions, was identified during each planning procedure. We gathered the experience of these 312 deep brain mappings and elaborated consistent procedures of anatomical MRI mapping for pallidal, subthalamic and ventral thalamic regions. We studied the number of times the central track anatomically optimized was selected for implantation of definitive electrodes. RESULTS: WAIR sequence provided high-quality images of most common functional targets, successfully used for pure direct stereotactic targeting: the central track corresponding to the optimized primary anatomical trajectory was chosen for implantation of definitive electrodes in 90.38%. CONCLUSION: WAIR sequence is anatomically reliable, enabling precise deep brain mapping and direct stereotactic targeting under routine clinical conditions. PMID- 27236732 TI - [Treatment of brain AVMS (TOBAS): A randomized controlled trial and registry]. AB - OBJECTIVE: The management of unruptured and ruptured brain arteriovenous malformations (AVMs) remains controversial. The Treatment of Brain AVM Study (TOBAS) was designed to assess curative treatments in the management of AVMs. The purpose of our study is to provide a care trial context to brain AVM patients. METHODS: TOBAS is a pragmatic, prospective study including 2 randomized controlled trials and a registry. All AVM patients can be recruited. The preferred management modality will be predetermined prior to randomization by the team based on clinical judgment. Patients eligible for both conservative and interventional management will be randomly allocated conservative or curative treatment. Randomization will be stratified by a treatment modality (surgery, radiosurgery or embolization) and minimized according to a history of previous rupture and Spetzler-Martin grade. A second randomization will allocate eligible patients to embolization/no embolization prior to surgery or radiosurgery. The primary outcome of the study is death (any cause) or disabling stroke (mRS>2) at 10 years. All patients managed according to clinical judgment alone will be included in the registry. The study is registered under: wwwTrials.gov, ID: NCT02098252. EXPECTED RESULTS: A minimum recruitment of 540 patients is required to show that treatment can reduce the primary outcome by 10 % (from 25 to 15 %); 440 patients will be needed to show a 10 % increase in angiographic occlusion for a good clinical outcome with pre-embolization. CONCLUSION: The trial is designed to offer optimal and verifiable care to patients with brain AVMs in spite of the uncertainty. We are currently seeking the participation of multiple centers. PMID- 27236733 TI - [Immunohistochemical hormonal mismatch and human epidermal growth factor type 2 [HER2] phenotype of brain metastases in breast cancer carcinoma compared to primary tumors]. AB - INTRODUCTION: Phenotype changes between primary tumor and the corresponding brain metastases are recent reported data. Breast cancer, with biological markers predicting prognosis and guiding therapeutic strategy remains an interesting model to observe and evaluate theses changes. The objective of our study was to compare molecular features (estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor type 2, [HER2]) between brain metastases and its primary tumor in patients presenting with pathologically confirmed breast cancer. MATERIAL AND METHODS: This retrospective study was based on the immunohistochemical analysis of the brain metastases paraffin embedded samples stored in our institutional tumor bank, after surgical resection. The level of expression of hormonal receptors and HER2 on brain metastases were centrally reviewed and compared to the expression status in primary breast cancer from medical records. RESULTS: Forty-four samples of brain metastases were available for analysis. Hormonal receptor modification status was observed in 11/44 brain metastases (25%) for ER and 6/44 (13.6%) for PR. A modification of HER2 overexpression was observed in brain metastases in 6/44 (13.6%). Molecular subtype modification was shown in 17 cases (38.6%). A significant difference was demonstrated between time to develop brain metastases in cases without status modification (HER2, ER and PR) (med=49.5months [7.8-236.4]) and in cases in which brain metastases status differs from primary tumor (med=27.5months [0-197.3]), (P=0.0244, IC95=3.09-51.62, Mann and Whitney test). CONCLUSION: the main interest of this study was to focus on the molecular feature changes between primary tumor and their brain metastases. Time to develop brain metastases was correlated to phenotypic changes in brain metastases. PMID- 27236734 TI - Ruptured posterior ethmoidal artery aneurysm and Moyamoya disease in an adult patient. Case report. AB - The association between Moyamoya disease and intracranial aneurysms is well described. In our case, we describe a unique aneurismal location and its management. We report the case of a 74-year-old woman affected by a Moyamoya disease who displayed a frontal lobe hematoma. The origin of the bleeding came from the rupture of a posterior ethmoidal artery aneurysm that was treated surgically with favourable outcome. This case of a ruptured posterior ethmoidal artery aneurysm in a Moyamoya patient illustrates the polymorphism of the vascular complications encountered in this disease. It stresses the need to obtain information from an angiographic investigation in order to select the best therapeutic option and to reduce procedural complications. PMID- 27236735 TI - Role of preoperative embolization of intramedullary hemangioblastoma. AB - OBJECT: Hemangiobastomas (HB) are rare lesions accounting for 1 to 5% of all spinal cord tumors. Due to their hypervascular nature, an angiography may be proposed preoperatively in order to identify tumoral vascular anatomy. Preoperative embolization may be indicated to reduce intraoperative bleeding, thus facilitating tumor resection and minimizing surgical risk. The aim of this paper is to report our experience of preoperative embolization in intramedullary hemangioblastomas. METHODS: We performed a retrospective analysis of all patients operated on for intramedullary hemangioblastomas between 1995 and 2014 who had undergone embolization before surgery. RESULTS: Seven patients were analyzed: there were 6 females and 1 male, mean age 43years, 6 patients had Von Hippel Lindau disease. Four tumors were located in the cervical spine and three in the dorsal spine. The average maximum sagittal diameter was 19mm (range 8-32mm), while the average maximum axial diameter was 11.5mm (range 6-21mm). The embolic agent used was Histoacryl (NBCA). Endovascular embolization was routinely performed the day before surgery. One patient experienced a major preoperative complication with a vertebrobasilar infarctus with consequent unilateral cerebellar syndrome and gait instability. Minor extravasation of embolic agent was observed in two cases. In one of these two cases, there was also the penetration of the embolic agent in the tumor; the resection was impossible due to the hard consistency of the tumor. In the other 6 patients, the resection was total. Six patients had identical preoperative and postoperative McCormick score and one patient shifted to a better score at follow-up. CONCLUSION: Preoperative endovascular embolization is an effective adjunct treatment. It is useful in reducing the surgical bleeding and thus the operative risks. The procedure is not always safe and complications could occur. We recommend preoperative embolization in selected cases. PMID- 27236736 TI - [Are C2 pedicles always screwable? Calibration and planning with a pedicle-lamina angle]. AB - INTRODUCTION: Posterior cervical arthrodesis is associated with osteosynthesis. C2 pedicular screwing affords a good bone anchoring but involves neurological and vascular risks. PURPOSE: To determine C2 pedicular screwing feasibility from a large cohort of cervical CT scans. To describe the visible anatomical parameters during a surgical procedure in order to plan and secure it. MATERIALS AND METHODS: Retrospective consecutive series of 100 cervical CT scans was analyzed. Cases with upper cervical fracture were excluded. C2 surgical anatomy was assessed according to maximum length, minimum width and minimum height. Angular parameters were pedicle-transverse angle and sagittal angle. Original pedicle lamina angle was used as a visible mark during the procedure independent of the patient's position. Pedicular screwing feasibility was evaluated. It was arbitrarily defined by a lower minimum height less than 4mm. RESULTS: Two hundred C2 pedicles were analyzed with 7.5% that were not screwable. Their mean length was 26.2mm, with a mean width of 5.2mm and a mean height of 9.2mm. Mean pedicle transverse angle was 36.2 degrees , mean sagittal angle was 25.8 degrees and mean pedicle-lamina angle was 81.3 degrees . CONCLUSION: C2 pedicle screwing feasibility is inconstant due to anatomical variability. In fact, 13% of patients have at least one non-screwable pedicle. Preoperative planning is essential to achieve this procedure. A pedicle-lamina angle can be used which remains independent from the patient's position. PMID- 27236737 TI - Staging and follow-up of high-grade malignant salivary gland tumours: The role of traditional versus functional imaging approaches - A review. AB - Following up on the Consensus Conference on high-grade malignant salivary gland tumours (HGMSGT) in adult patients in Brescia, Italia, in October 2014, we review the current imaging modalities for diagnosing and staging these rare tumours. The advantages of functional MR imaging techniques such as diffusion weighted imaging (DWI) and dynamic contrast-enhanced MR imaging (DCEMRI) in comparison with traditional MRI will be outlined. The limited role of (18)FDG-PET CT and fMRI will be addressed. Finally, in view of new experimental treatment options, we will discuss the role of imaging during follow-up. PMID- 27236738 TI - High On-Treatment Platelet Reactivity in Peripheral Arterial Disease: A Pilot Study to Find the Optimal Test and Cut Off Values. AB - OBJECTIVE: Restenosis and stent thrombosis after endovascular intervention in patients with peripheral arterial disease (PAD) can potentially be tackled by more intensive antiplatelet therapy, such as dual antiplatelet therapy (DAPT) consisting of aspirin and P2Y12 inhibitor. Despite clopidogrel treatment, some patients still display high platelet reactivity (HCPR). Tailored antiplatelet therapy, based on platelet reactivity testing, might overcome HCPR. However, more data are warranted regarding the proportion of patients with HCPR in the PAD population, different platelet reactivity tests, their correlation, and the optimal timing for these tests as a stepping stone for a future trial investigating the potential benefit of tailored antiplatelet therapy in PAD patients. METHODS: Thirty patients on DAPT after percutaneous transluminal angioplasty underwent platelet reactivity testing by VerifyNow, vasodilator stimulated phosphoprotein (VASP) and platelet activation assay, and CYP2C19 polymorphism testing. RESULTS: The proportion of patients with HCPR measured by VerifyNow varied between 43.3% and 83.3%, depending on the cut off values used. Testing within 24 hours of initiation of DAPT gave a higher proportion of HCPR than testing after more than 24 hours. According to DNA testing, 14.8% were CYP2C19*2 homozygote, 22.2% heterozygote, and 63% CYP2C19*2 negative. VASP assay revealed 24% HCPR. The highest HCPR rate was found with a VerifyNow cut off of less than 40% inhibition, whereas the lowest HCPR rate was found with the VASP assay. There was a low correlation between the tests. CONCLUSION: HCPR is present in PAD patients and research on HCPR is needed in this population; timing of tests is relevant and standardisation of tests is needed. The optimal conditions for platelet function testing should be determined. PMID- 27236739 TI - Re: 'Predictors of Recanalization of the Great Saphenous Vein in Randomized Controlled Trials 1 Year After Endovenous Thermal Ablation'. PMID- 27236740 TI - Transforming properties of Felis catus papillomavirus type 2 E6 and E7 putative oncogenes in vitro and their transcriptional activity in feline squamous cell carcinoma in vivo. AB - Felis catus papillomavirus type 2 (FcaPV2) DNA is found in feline cutaneous squamous cell carcinomas (SCCs); however, its biological properties are still uncharacterized. In this study, we successfully expressed FcaPV2 E6 and E7 putative oncogenes in feline epithelial cells and demonstrated that FcaPV2 E6 binds to p53, impairing its protein level. In addition, E6 and E7 inhibited ultraviolet B (UVB)-triggered accumulation of p53, p21 and pro-apoptotic markers such as Cleaved Caspase3, Bax and Bak, suggesting a synergistic action of the virus with UV exposure in tumour pathogenesis. Furthermore, FcaPV2 E7 bound to feline pRb and impaired pRb levels, resulting in upregulation of the downstream pro-proliferative genes Cyclin A and Cdc2. Importantly, we demonstrated mRNA expression of FcaPV2 E2, E6 and E7 in feline SCC samples, strengthening the hypothesis of a causative role in the development of feline SCC. PMID- 27236741 TI - Complement factors alter the amount of PrP(Sc) in primary-cultured mouse cortical neurons associated with increased membrane permeability. AB - We examined the effects of complement factors on primary-cultured neurons infected with prions. The amount of protease K (PK)-resistant abnormal form of prion protein (PrP(Sc)) reached a maximum level at 12 and 16 days post exposure (dpe) in 22L- and Chandler-infected neurons, respectively. In Chandler-infected neurons, the reaction of complement factors C1q, C3 and C9 significantly increased membrane permeability. This was followed by a decrease of PK-resistant PrP(Sc) at 16 and 20dpe. In contrast, in 22L-infected neurons, the effects of complement factors were observed at 12 and 16dpe, but not at 20dpe. Membrane permeability also increased in 22L-infected neurons by reaction of complement factor C3, but interestingly, the amount of PK-resistant PrP(Sc) initially decreased, and then increased. These results suggest that the reactivity of complement factors in prion-infected neurons depends on the amount of PrP(Sc) and the prion strain. PMID- 27236742 TI - The Accuracy of Locating Lumbar Vertebrae When Using Palpation Versus Ultrasonography. AB - OBJECTIVE: The purpose of this study was to determine the accuracy of locating lumbar vertebrae using palpation vs ultrasonography. METHODS: In this study, ultrasonic imaging was used by 2 experienced clinicians to identify the third lumbar spinous process (target) of a female participant. The target was then located by 16 undergraduate chiropractic students using clinical palpation techniques learned in their academic program (with participant seated and prone) and ultrasonic imaging learned through a 5-minute training video. Presumed target locations identified by students were recorded by infrared motion capture equipment. The coordinates of the presumed target site were then compared statistically. RESULTS: There was no significant difference between the presumed target position identified by the students using sitting and prone palpation (P = .346). These positions were significantly different from the target location identified by expert clinicians using ultrasonic imaging (P < .0001 in both cases). The vertebra identified by ultrasonic imaging by the students was the same vertebra identified by the expert clinicians using ultrasound. This position error in the vertebra identified by palpation resulted in the students mistakenly identifying the L4 spinous process as the target vertebra. CONCLUSIONS: This study found that ultrasonography provided more accurate identification of a lumbar spinal landmark when compared with palpation. In addition, our data suggest that ultrasonic imaging to identify spinal landmarks can be learned easily and can improve accuracy of landmark detection. Although the time to use ultrasonic imaging was greater than with palpation, these results suggest that this procedure could potentially be used in clinical practice to identify spinal landmarks. PMID- 27236744 TI - Practice Management Strategies Among Current Members of the American Association of Hip and Knee Surgeons. AB - BACKGROUND: A survey was conducted at the 2015 annual meeting of the American Association of Hip and Knee Surgeons (AAHKS) to determine current practice management patterns among AAHKS members. METHODS: A survey was conducted by the session moderator during the annual AAHKS meeting using an audience response system. A series of practice management issues were reviewed with AAHKS members. The survey contained multiple choice and yes and no questions. The audience responses were collected in a central database and then immediately displayed for the audience to review. RESULTS: The survey responses provided interesting data on a variety of topics including: surgeon demographics, surgical activity, practice status, use of physician extenders, sources of ancillary income, the use of electronic medical records and surgeon satisfaction. Interestingly, 51% of AAHKS members remain in private practice and fee for service remains the most common form of compensation (48%). The vast majority of AAHKS members do not perform hip arthroscopy (86%) or hip preservation procedures (87%). CONCLUSION: Valuable information regarding practice patterns of AAHKS members was obtained from this survey. Future surveys will need to focus on 3 areas of activity: surgeon involvement in bundled payment programs frequency of submission of patient data to a joint registry and the frequency of outpatient total joint arthroplasty. PMID- 27236743 TI - Periprosthetic Bone Remodeling After Novel Short-Stem Neck-Sparing Total Hip Arthroplasty. AB - BACKGROUND: Short femoral stems have been designed with the aims of reducing proximal bone loss, improving load transfer, and increasing compressive loads at the medial proximal femoral calcar. This study examines bone mineral density (BMD) changes associated with a novel neck sparing short femoral stem design. METHODS: The study was a prospective, single-center, multi-investigator consecutive series, which assessed bone-remodeling changes after insertion of the MSA Stem (Global Orthopaedic Technology). Dual-energy X-ray absorptiometry scans were performed preoperatively and postoperatively at 6, 12, and 24 months assessing the BMD at the 7 Gruen zones. The secondary objectives assessed were the Harris Hip Score, 12-Item Short Form Health Survey preoperatively, and perioperative complications. RESULTS: Thirty-nine total hip arthroplasties were performed on 37 patients, with 27 patients completing the 24-month dual-energy X ray absorptiometry scan. The overall preoperative baseline BMD was 0.2. At 6 months, the Gruen zone BMD had increased significantly in all zones in comparison to the preoperative mean BMD. Between 6 months and 24 months, there were only slight changes in the Gruen zones, with small gains in zones 1-2 and zones 4-6, with no zone showing a significant decrease. The Harris Hip Score improved from a preoperative mean of 39.7-75.3, whereas the 12-Item Short Form Health Survey score also improved from 32.6 to 49 at 24 months. However, 5 patients had aseptic loosening requiring revision surgery (4 femoral and 1 acetabular component). CONCLUSION: Short-stem neck-sparing femoral stem prosthesis has the capacity to address the stress-shielding problem identified in femoral stems. However, the high early revision rate is a significant issue. PMID- 27236745 TI - Even the Intraoperative Knowledge of Femoral Stem Anteversion Cannot Prevent Impingement in Total Hip Arthroplasty. AB - BACKGROUND: In this prospective study of 66 patients undergoing cementless total hip arthroplasty through a minimally invasive anterolateral approach, we evaluated the impact of an intraoperative hybrid combined anteversion technique on postoperative range of motion (ROM). METHODS: After navigation of femoral stem anteversion, trial acetabular components were positioned manually, and their position recorded with navigation. Then, final components were implanted with navigation at the goals prescribed by the femur-first impingement detection algorithm. Postoperatively, three-dimensional computed tomographies were performed to determine achieved component position and model impingement-free ROM by virtual hip movement, which was compared with published values necessary for activities of daily living. This model was run a second time with the implants in the position selected by the surgeon rather than the navigation program. In addition, we researched into risk factors for ROM differences between the freehand and navigated cup position. RESULTS: We found a lower flexion of 8.3 degrees (8.8 degrees , P < .001) and lower internal rotation of 9.2 degrees (9.5 degrees , P < .001) for the freehand implanted cups in contrast to a higher extension of 9.8 degrees (11.8 degrees , P < .001) compared with the navigation guided technique. For activities of daily living, 58.9% (33/56) in the freehand group compared with 85.7% (48/56) in the navigation group showed free flexion (P < .001) and similarly 50.0% (28/56) compared with 76.8% (43/56) free internal rotation (P < .001). Body mass index, incision length, and cup size were identified as independent risk factors for reduced flexion and internal rotation in the freehand group. CONCLUSION: For implementation of a combined anteversion algorithm, intraoperative alignment guides for accurate cup positioning are required using a minimally invasive anterolateral approach. Obese patients are especially at risk of cup malpositioning. PMID- 27236746 TI - Impact of Cirrhosis on Resource Use and Inpatient Complications in Patients Undergoing Total Knee and Hip Arthroplasty. AB - BACKGROUND: Cirrhosis is a major cause of morbidity and mortality and is an important risk factor for complications in surgical patients. The purpose of this study was to investigate the association of cirrhosis with postoperative complications, length of stay (LOS), and costs among patients who underwent total knee arthroplasty (TKA) or total hip arthroplasty (THA). METHODS: Using the Nationwide Inpatient Sample between 2000 and 2011, we identified patients who had a primary TKA or primary THA. TKA patients were divided into 2 groups: (1) cirrhosis (n = 41,464) and (2) no cirrhosis (n = 5,721,297) and THA patients were divided into 2 groups: (1) cirrhosis (n = 27,401) and (2) no cirrhosis (n = 2,622,539). Patient demographics, comorbidities, perioperative complications, LOS, and incremental costs were analyzed. An additional subgroup analysis by cirrhosis etiology was performed. RESULTS: Multivariable analysis revealed cirrhosis was associated with 1.55 (95% confidence interval: 1.47-1.63) times higher odds of any complication after TKA and 1.59 (1.50-1.69) higher odds after THA. Adjusted outcomes showed cirrhotic TKA patients had $1857 higher costs and 0.30 days longer LOS and THA cirrhotic patients had $1497 higher costs and 0.48 longer LOS. We found similar results for each cirrhosis subtype but alcohol related had the highest resource use and complication rate. CONCLUSION: Patients with cirrhosis who are undergoing TKA or THA are at a significantly increased risk for perioperative complications, increased LOS, and higher costs. The perioperative complications and costs were highest among patients with alcohol related cirrhosis. PMID- 27236747 TI - Transdermal immunotherapy: Past, present and future. AB - The human skin plays an important role in thermal regulation, the maintenance of the correct water and electrolyte balance; it is also the main source of the vitamin D for the organism. Moreover, the skin forms an effective barrier against microorganisms, protecting the organism against xenobiotics and harmful external factors. It must also be mentioned that the skin is an essential organ involved in immunological mechanisms. This article summarizes current knowledge about skin induced suppression induced via epicutaneous (EC) application of an antigen and is described in both Th1- and Tc1-mediated contact sensitivity (CS) in mice. The skin-induced suppression is also considered in the regulation of experimental models of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE), collagen-induced arthritis (CIA) and colitis ulcerosa. Furthermore, the efficacy of treatment of multiple sclerosis (MS) patients with EC immunization is discussed. Second part of this review introduces new subject of immunopotentiation induced via EC immunization with an antigen in the presence of various pathogen-associated molecular patterns (PAMPs). Finally, the review describes dermal immunization in the therapy of allergic diseases. PMID- 27236748 TI - Human endothelial progenitor cells-derived exosomes accelerate cutaneous wound healing in diabetic rats by promoting endothelial function. AB - AIMS: Wound healing is deeply dependent on neovascularization to restore blood flow. The neovascularization of endothelial progenitor cells (EPCs) through paracrine secretion has been reported in various tissue repair models. Exosomes, key components of cell paracrine mechanism, have been rarely reported in wound healing. METHODS: Exosomes were isolated from the media of EPCs obtained from human umbilical cord blood. Diabetic rats wound model was established and treated with exosomes. The in vitro effects of exosomes on the proliferation, migration and angiogenic tubule formation of endothelial cells were investigated. RESULTS: We revealed that human umbilical cord blood EPCs derived exosomes transplantation could accelerate cutaneous wound healing in diabetic rats. We also showed that exosomes enhanced the proliferation, migration and tube formation of vascular endothelial cells in vitro. Furthermore, we found that endothelial cells stimulated with these exosomes would increase expression of angiogenesis-related molecules, including FGF-1, VEGFA, VEGFR-2, ANG-1, E-selectin, CXCL-16, eNOS and IL-8. CONCLUSION: Taken together, our findings indicated that EPCs-derived exosomes facilitate wound healing by positively modulating vascular endothelial cells function. PMID- 27236749 TI - Reply: Fibroblast growth factor 23 resistance is probably involved in the mechanism of type 2 diabetes-induced nephropathy. PMID- 27236750 TI - Von Willebrand factor regulates complement on endothelial cells. AB - Atypical hemolytic uremic syndrome and thrombotic thrombocytopenic purpura have traditionally been considered separate entities. Defects in the regulation of the complement alternative pathway occur in atypical hemolytic uremic syndrome, and defects in the cleavage of von Willebrand factor (VWF)-multimers arise in thrombotic thrombocytopenic purpura. However, recent studies suggest that both entities are related as defects in the disease-causing pathways overlap or show functional interactions. Here we investigate the possible functional link of VWF multimers and the complement system on endothelial cells. Blood outgrowth endothelial cells (BOECs) were obtained from 3 healthy individuals and 2 patients with Type 3 von Willebrand disease lacking VWF. Cells were exposed to a standardized complement challenge via the combination of classical and alternative pathway activation and 50% normal human serum resulting in complement fixation to the endothelial surface. Under these conditions we found the expected release of VWF-multimers causing platelet adhesion onto BOECs from healthy individuals. Importantly, in BOECs derived from patients with von Willebrand disease complement C3c deposition and cytotoxicity were more pronounced than on BOECs derived from normal individuals. This is of particular importance as primary glomerular endothelial cells display a heterogeneous expression pattern of VWF with overall reduced VWF abundance. Thus, our results support a mechanistic link between VWF-multimers and the complement system. However, our findings also identify VWF as a new complement regulator on vascular endothelial cells and suggest that VWF has a protective effect on endothelial cells and complement-mediated injury. PMID- 27236751 TI - The targeted proteins in tumor cells treated with the alpha-lactalbumin-oleic acid complex examined by descriptive and quantitative liquid chromatography tandem mass spectrometry. AB - An alpha-lactalbumin-oleic acid (alpha-LA-OA) complex has exhibited selective antitumor activity in animal models and clinical trials. Although apoptosis and autophagy are activated and the functions of several organelles are disrupted in response to alpha-LA-OA, the detailed antitumor mechanism remains unclear. In this study, we used a novel technique, isobaric tags for relative and absolute quantitation, to analyze the proteome of tumor cells treated with alpha-LA-OA. We identified 112 differentially expressed proteins: 95 were upregulated to satisfy the metabolism of tumor cells; 17 were downregulated and targets of alpha-LA-OA. According to the differentially expressed proteins, alpha-LA-OA exerted its antitumor activity by disrupting cytoskeleton stability and cell motility, and by inhibiting DNA, lipid, and ATP synthesis, leading to cellular stress and activation of programmed cell death. This study provides a systematic evaluation of the antitumor activity of alpha-LA-OA, identifying its interacting targets and establishing the theoretical basis of alpha-LA-OA for use in cancer therapy. PMID- 27236752 TI - A prognostic model to predict the success of artificial insemination in dairy cows based on readily available data. AB - A prognosis of the likelihood of insemination success is valuable information for the decision to start inseminating a cow. This decision is important for the reproduction management of dairy farms. The aim of this study was to develop a prognostic model for the likelihood of successful first insemination. The parameters considered for the model are readily available on farm at the time a farmer makes breeding decisions. In the first step, variables are selected for the prognostic model that have prognostic value for the likelihood of a successful first insemination. In the second step, farm effects on the likelihood of a successful insemination are quantified and the prognostic model is cross validated. Logistic regression with a random effect for farm was used to develop the prognostic model. Insemination and test-day milk production data from 2,000 commercial Dutch dairy farms were obtained, and 190,541 first inseminations from this data set were used for model selection. The following variables were used in the selection process: parity, days in milk, days to peak production, production level relative to herd mates, milk yield, breed of the cow, insemination season and calving season, log of the ratio of fat to protein content, and body condition score at insemination. Variables were selected in a forward selection and backward elimination, based on the Akaike information criterion. The variables that contributed most to the model were random farm effect, relative production factor, and milk yield at insemination. The parameters were estimated in a bootstrap analysis and a cross-validation was conducted within this bootstrap analysis. The parameter estimates for body condition score at insemination varied most, indicating that this effect varied most among Dutch dairy farms. The cross-validation showed that the prognosis of insemination success closely resembled the mean insemination success observed in the data set. Insemination success depends on physiological conditions of the cow, which are approximated indirectly by production and reproduction data that are routinely recorded on the farm. The model cannot be used as a detection model to distinguish cows that conceive from cows that do not. The model validation indicates, however, that routinely collected farm data and test-day milk yield records have value for the prognosis of insemination success in dairy cows. PMID- 27236753 TI - Development of a model describing regulation of casein synthesis by the mammalian target of rapamycin (mTOR) signaling pathway in response to insulin, amino acids, and acetate. AB - To improve dietary protein use efficiency in lactating cows, mammary protein synthesis responses to AA, energy substrates, and hormones must be better understood. These entities exert their effects through stimulation of mRNA translation via control of initiation and elongation rates at the cellular level. A central protein kinase of this phenomenon is the mammalian target of rapamycin (mTOR), which transfers the nutritional and hormonal stimuli onto a series of proteins downstream through a cascade of phosphorylation reactions that ultimately affect protein synthesis. The objective of this work was to further develop an existing mechanistic model of mTOR phosphorylation responses to insulin and total essential AA to include the effects of specific essential AA and acetate mediated by signaling proteins including protein kinase B (Akt), adenosine monophosphate activated protein kinase (AMPK), and mTOR and to add a representation of milk protein synthesis. Data from 6 experiments in MAC-T cells and mammary tissue slices previously conducted in our laboratory were assembled and used to parameterize the dynamic system of differential equations representing Akt, AMPK, and mTOR in their phosphorylated and dephosphorylated states and the resulting regulation of milk protein synthesis. The model predicted phosphorylated Akt, mTOR, AMPK, and casein synthesis rates with root mean square prediction errors of 16.8, 28.4, 33.0, and 54.9%, respectively. All other dependent variables were free of mean and slope bias, indicating an adequate representation of the data. Whereas mTOR was not very sensitive to changes in insulin or acetate levels, it was highly sensitive to leucine and isoleucine, and this signal appeared to be effectively transduced to casein synthesis. Although prior work had observed a relationship with additional essential AA, and data supporting those conclusions were present in the data set, we were unable to derive significant relationships with any essential AA other than leucine and isoleucine. The signaling properties and dynamics of AMPK under nutrient depletion and sufficiency, the responses to additional essential AA, and the consequent effects on protein synthesis remain to be better understood. PMID- 27236754 TI - Molecular typing and differences in biofilm formation and antibiotic susceptibilities among Prototheca strains isolated in Italy and Brazil. AB - Bovine mastitis caused by Prototheca is a serious and complex problem that accounts for high economic losses in the dairy industry. The main objective of this study was to identify and characterize at genetic level different Prototheca strains and provide the most complete data about protothecal antibiotic resistance. The study involves 46 isolates from Italian (13 strains) and Brazilian (33 strains) mastitic milk. These strains were identified by multiplex PCR and single strand conformation polymorphism analysis and characterized by randomly amplified polymorphic DNA (RAPD)-PCR. Moreover, biofilm production and antibiotic susceptibility were evaluated. Forty-two strains resulted as Prototheca zopfii genotype 2, whereas 4 isolates could belong to a potential new Prototheca species. The RAPD-PCR, performed with 3 primers (M13, OPA-4, and OPA 18), showed a notable heterogeneity among isolates and grouped the strains according to the species and geographical origin. Biofilm production was species dependent and P. zopfii genotype 2 strains were classified as strong biofilm producers. In vitro antibiotic susceptibility tests indicated that Prototheca strains were susceptible to antibacterial drugs belonging to aminoglycosides group; the highest activity against Prototheca strains was observed in the case of colistin sulfate, gentamicin, and netilmicin (100% of susceptible strains). It is interesting to note that all the Italian P. zopfii genotype 2 strains showed lower minimum inhibitory concentration values than the Brazilian ones. Nisin showed more efficacy than lysozyme and potassium sorbate, inhibiting 31% of the strains. Results obtained in this study confirmed that RAPD-PCR is a rapid, inexpensive, and highly discriminating tool for Prototheca strains characterization and could give a good scientific contribution for better understanding the protothecal mastitis in dairy herd. PMID- 27236755 TI - Particle length of silages affects apparent ruminal synthesis of B vitamins in lactating dairy cows. AB - Effects of particle length of silages on apparent ruminal synthesis (ARS) and postruminal supply of B vitamins were evaluated in 2 feeding trials. Diets containing alfalfa (trial 1) or orchardgrass (trial 2) silages, chopped to either 19mm (long cut, LC) or 10mm (short cut, SC) theoretical particle length, as the sole forage were offered to ruminally and duodenally cannulated lactating Holstein cows in crossover design experiments. Forages chopped to a theoretical particle length of 19 and 10mm had mean particles sizes of 14.1 and 8.1mm, respectively, in trial 1, and 15.3 and 11.3mm, respectively, in trial 2. Trial 1 was conducted with 13 multiparous cows in two 19-d treatment periods; both diets contained approximately 20% forage neutral detergent fiber (NDF), 25% total NDF, and forage-to-concentrate ratios were approximately 47:53. Trial 2 was conducted with 15 cows in two 18-d treatment periods; both diets contained approximately 23% forage NDF, 28% total NDF, and had a forage-to-concentrate ratio of 50:50. Thiamine, riboflavin, niacin, vitamin B6, folates, and vitamin B12 were measured in feed and duodenal content. Daily ARS was calculated as the duodenal flow minus the intake. In trial 1, daily intake of individual B vitamins was increased with the LC diet, but ARS of thiamine, riboflavin, vitamin B6, and folates was reduced. In trial 2, except for folates, intakes of the other B vitamins were decreased with the LC diets, whereas ARS of riboflavin, niacin, and vitamin B6 was increased. Daily ARS of thiamine, riboflavin, niacin, and vitamin B6 were correlated negatively with their intake, suggesting that ruminal bacteria reduced their synthesis when dietary supply increased. Microbial activity could have also reduced degradation of thiamine, riboflavin, and niacin, which is supported by (1) the negative correlation between ARS of these vitamins and ruminal pH or microbial N duodenal flow; and (2) the positive correlation between ARS and ruminal concentrations of volatile fatty acids. Folate ARS followed the opposite correlation pattern. Nevertheless, in spite of differences in intake and ARS, with both forages, decreasing particle length of silages had limited effects on the amounts of B vitamins reaching the sites of absorption in the small intestine of dairy cows. PMID- 27236756 TI - Metabolic responses, performance, and reticuloruminal pH of early-lactating cows fed concentrates treated with lactic acid, with or without inorganic phosphorus supplementation. AB - Recent data indicate beneficial effects of treating grains with lactic acid (LA) in alleviating the need for inorganic phosphorus supplementation during ruminal fermentation in vitro. The aim of this study was to evaluate the effects of feeding concentrates treated with LA with or without inorganic phosphorus supplementation on feed intake, performance, blood variables, and reticuloruminal pH in dairy cows. A total of 16 early-lactating cows (12 Simmental and 4 Brown Swiss) were included in this study from d 1 until d 37 postpartum. Cows were fed 3 total mixed rations differing in supplementation of inorganic phosphorus and treatment of concentrates. The control (CON) and LA (+P) diets included a concentrate mixture containing 0.8% monocalcium phosphate, and the LA (-P) diet contained no inorganic phosphorus source. The concentrates of the LA (+P) and LA (-P) diets were treated with 5% LA for 24h before feeding, and the concentrate of the CON diet was not treated. Dry matter intake and milk yield were recorded daily, and milk composition and blood variables were determined on several occasions during the trial. Reticuloruminal pH was measured using indwelling sensors that allowed for continuous measurement during the experimental period. Data showed depressed dry matter intake in cows receiving LA-treated concentrates, but milk yield, body weight, and body weight changes remained similar among treatment groups. Cows receiving the LA-treated diets had lower concentrations of serum nonesterified fatty acids, cholesterol, and insulin, and they tended to have higher serum phosphorus levels. On the other hand, reticuloruminal pH was lower and duration of the pH being <6.0 was longer in cows in the LA-treated groups. Aspartate aminotransferase, gamma-glutamyltransferase, and concentrations of bilirubin and bile acids were lower in the LA (-P) group. Taken together, the 5% LA-treated diet without inorganic phosphorus supplementation did not exert any negative effects on performance. The observed beneficial effects on blood metabolites related to lipid metabolism, insulin sensitivity, and liver variables, as well as the tendency for greater systemic phosphorus circulation, suggest that diets including concentrates treated with 5% LA may allow for savings of inorganic phosphorus supplementation in dairy cows. Treatment with 5% LA enhanced cows' risk of developing subacute rumen acidosis, although this condition showed no adverse effects with respect to liver variables and the inflammatory response. PMID- 27236757 TI - Effect of lipid supplementation on milk odd- and branched-chain fatty acids in dairy cows. AB - Eight ruminally fistulated, multiparous Holstein cows were arranged in a double 4*4 Latin square with 14-d periods to investigate the effects of lipid supplementation on performance, rumen parameters, the milk odd- and branched chain fatty acid (OBCFA) profile, and the relationships between milk OBCFA and rumen parameters. Lipid supplementation is known to inhibit microbial growth in the rumen, decrease de novo microbial fatty acid synthesis, and increase the uptake of circulating fatty acids by the mammary gland; treatments were selected to isolate these effects on the milk OBCFA profile. The 4 treatments were (1) a lipid-free emulsion medium infused in the rumen (CTL), (2) soybean oil as a source of polyunsaturated fatty acids infused in the rumen (RSO), (3) saturated fatty acids (38% 16:0, 40% 18:0) infused in the rumen (RSF), and (4) saturated fatty acids infused in the abomasum (ASF). Fat supplements were provided continuously as emulsions at a rate of 450g/d. Preplanned contrasts compared CTL to RSO, RSO to RSF, and RSF to ASF. Infusing RSO slightly decreased ruminal pH, but did not affect volatile fatty acids profile and milk fat concentration as compared with CTL. The yields of energy-corrected milk, fat, and protein were greater with RSF compared with RSO. The concentration of odd-chain fatty acids was decreased by RSO, whereas even-chain iso fatty acids were not affected. Milk fat concentration of 17:0 + cis-9 17:1 was higher for RSF than for RSO, due to the saturated fatty acids supplement containing 2% 17:0 + cis-9 17:1. Limited differences were observed in the milk OBCFA profile between RSF and ASF. A multiple regression analysis yielded the following equation for predicting rumen pH based on milk fatty acids: pH=6.24 - (0.56*4:0) + (1.67 * iso 14:0) + (4.22 * iso 15:0) + (9.41*22:0). Rumen propionate concentration was negatively correlated with milk fat concentration of iso 14:0 and positively correlated with milk 15:0, whereas the acetate-to-propionate ratio gave the opposite correlations with milk iso 14:0 and 15:0. Milk fat concentration of 17:0 + cis-9 17:1 was not related to rumen propionate or to acetate-to-propionate ratio, due to the presence of 17:0 and cis-9 17:1 in the saturated fatty acids supplement. The results suggest that although lipid supplementation can affect the profile of milk OBCFA, the promise remains of using these milk fatty acids to evaluate rumen function. PMID- 27236758 TI - Effect of dietary nitrate level on enteric methane production, hydrogen emission, rumen fermentation, and nutrient digestibility in dairy cows. AB - Nitrate may lower methane production in ruminants by competing with methanogenesis for available hydrogen in the rumen. This study evaluated the effect of 4 levels of dietary nitrate addition on enteric methane production, hydrogen emission, feed intake, rumen fermentation, nutrient digestibility, microbial protein synthesis, and blood methemoglobin. In a 4*4 Latin square design 4 lactating Danish Holstein dairy cows fitted with rumen, duodenal, and ileal cannulas were assigned to 4 calcium ammonium nitrate addition levels: control, low, medium, and high [0, 5.3, 13.6, and 21.1g of nitrate/kg of dry matter (DM), respectively]. Diets were made isonitrogenous by replacing urea. Cows were fed ad libitum and, after a 6-d period of gradual introduction of nitrate, adapted to the corn-silage-based total mixed ration (forage:concentrate ratio 50:50 on DM basis) for 16d before sampling. Digesta content from duodenum, ileum, and feces, and rumen liquid were collected, after which methane production and hydrogen emissions were measured in respiration chambers. Methane production [L/kg of dry matter intake (DMI)] linearly decreased with increasing nitrate concentrations compared with the control, corresponding to a reduction of 6, 13, and 23% for the low, medium, and high diets, respectively. Methane production was lowered with apparent efficiencies (measured methane reduction relative to potential methane reduction) of 82.3, 71.9, and 79.4% for the low, medium, and high diets, respectively. Addition of nitrate increased hydrogen emissions (L/kg of DMI) quadratically by a factor of 2.5, 3.4, and 3.0 (as L/kg of DMI) for the low, medium, and high diets, respectively, compared with the control. Blood methemoglobin levels and nitrate concentrations in milk and urine increased with increasing nitrate intake, but did not constitute a threat for animal health and human food safety. Microbial crude protein synthesis and efficiency were unaffected. Total volatile fatty acid concentration and molar proportions of acetate, butyrate, and propionate were unaffected, whereas molar proportions of formate increased. Milk yield, milk composition, DMI and digestibility of DM, organic matter, crude protein, and neutral detergent fiber in rumen, small intestine, hindgut, and total tract were unaffected by addition of nitrate. In conclusion, nitrate lowered methane production linearly with minor effects on rumen fermentation and no effects on nutrient digestibility. PMID- 27236759 TI - Evaluation of camelina meal as a feedstuff for growing dairy heifers. AB - The objective of this research was to compare the growth performance, metabolic profile, and nutrient utilization of dairy heifers fed camelina meal (CAM), linseed meal (LIN), or distillers dried grains with solubles (DDGS). A 12-wk randomized complete block design study was conducted using 33 Holstein and 9 Brown Swiss heifers (144.8+/-22d of age) with 3 treatments. Treatments were 10% of the diet as CAM, LIN, or DDGS (dry matter basis). All diets contained 60% grass hay and 40% concentrate mix. Diets were balanced with corn and soybean meal to be isonitrogenous and comparable in energy content. Diets were individually limit-fed to 2.65% of body weight using a Calan gate feeding system. Frame sizes, body weights, and body condition scores were measured on 2 consecutive days during wk 0, 2, 4, 6, 8, 10, and 12. Jugular blood samples were taken at the beginning of the study and then every 4wk throughout at 3.5h postfeeding for analysis of blood metabolites and metabolic hormones. Rumen fluid samples were taken at the same time as blood sampling via an esophageal tube during wk 8 and 12. Over the duration of the study, dry matter intake and average daily gain were similar among treatments. Body weights tended to be less for heifers fed CAM and greatest for LIN. Gain to feed was similar for the CAM and DDGS and greatest for the LIN. Overall, most frame measurements were similar among treatments. Body length had a tendency to be greater for CAM compared with LIN with DDGS similar to both. Body condition scores were greater for CAM and DDGS compared with LIN. Rumen total volatile fatty acids, acetate:propionate, and pH were similar among treatments. Butyrate was less in the CAM treatment, intermediate for LIN, and greatest for DDGS. Rumen ammonia was less in DDGS compared with CAM and LIN, which were similar. Blood concentrations of glucose, triglycerides, plasma urea N, and cholesterol were similar among treatments. Metabolic hormones, including insulin-like growth factor-1 and thyroid hormones triiodothyronine and free thyroxine, were similar among treatments. Heifers fed CAM had lesser insulin concentration than other treatments. Total-tract digestion of nutrients were similar among treatments, but CAM tended to have greater digestion of organic matter compared with LIN, with DDGS similar to both. Feeding CAM maintained growth performance compared with DDGS and LIN. This study demonstrates that CAM can be used as a protein source for growing dairy heifers. PMID- 27236760 TI - Effects of dietary crude protein and rumen-degradable protein concentrations on urea recycling, nitrogen balance, omasal nutrient flow, and milk production in dairy cows. AB - The objective of this study was to determine how interactions between dietary crude protein (CP) and rumen-degradable protein (RDP) concentrations alter urea nitrogen recycling, nitrogen (N) balance, omasal nutrient flow, and milk production in lactating Holstein cows. Eight multiparous Holstein cows (711+/ 21kg of body weight; 91+/-17d in milk at the start of the experiment) were used in a replicated 4*4 Latin square design with a 2*2 factorial arrangement of dietary treatments and 29-d experimental periods. Four cows in one Latin square were fitted with ruminal cannulas to allow ruminal and omasal sampling. The dietary treatment factors were CP (14.9 vs. 17.5%; dry matter basis) and RDP (63 vs. 69% of CP) contents. Dietary RDP concentration was manipulated by including unprocessed or micronized canola meal. Diet adaptation (d 1-20) was followed by 8d (d 21-29) of sample and data collection. Continuous intrajugular infusions of [(15)N(15)N]-urea (220mg/d) were conducted for 4d (d 25-29) with concurrent total collections of urine and feces to estimate N balance and whole-body urea kinetics. Proportions of [(15)N(15)N]- and [(14)N(15)N]-urea in urinary urea, and (15)N enrichment in feces were used to calculate urea kinetics. For the low-CP diets, cows fed the high-RDP diet had a greater DM intake compared with those fed the low-RDP diet, but the opposite trend was observed for cows fed the high-CP diets. Dietary treatment had no effect on milk yield. Milk composition and milk component yields were largely unaffected by dietary treatment; however, on the low-CP diets, milk fat yield was greater for cows fed the low-RDP diet compared with those fed the high-RDP diet, but it was unaffected by RDP concentration on the high-CP diets. On the high-CP diets, milk urea nitrogen concentration was greater in cows fed the high-RDP diet compared with those fed the low-RDP diet, but it was unaffected by RDP concentration on the low-CP diets. Ruminal NH3-N concentration tended to be greater in cows fed the high-CP diet compared with those fed the low-CP diet, and it was greater in cows fed the high-RDP diet as compared with those fed the low-RDP diet. Nitrogen intake and both total N and urea-N excretion in urine were greater for cows fed the high-CP diet compared with those fed the low-CP diet. However, N balance and urinary excretion of purine derivatives were unaffected by dietary treatment. Urea-N entry rate (UER) was greater in cows fed the high-CP diet compared with those fed the low-CP diet; however, UER was unaffected by dietary RDP concentration. The proportion of urea N recycled to the gastrointestinal tract (as a percentage of UER) was greater in cows fed the low-CP diet compared with those fed the high-CP diet. In summary, reducing dietary CP concentration decreased urinary N excretion but had no effect on milk yield, thus resulting in an overall improvement in milk N efficiency. PMID- 27236761 TI - Prevalence and distribution of foot lesions in dairy cattle in Alberta, Canada. AB - The objectives of this cross-sectional study were to determine the prevalence and distribution of foot lesions and associated cow- and herd-level risk factors in dairy cows in Alberta, Canada. Foot lesion data were recorded electronically by 7 hoof trimmers on 28,607 cows in 156 dairy farms from June 2009 to November 2012. Foot lesion prevalence estimates differed between farms that had the whole herd trimmed at once (>=80% of lactating cows were trimmed; n=69 farms and 8,020 cows) and farms on which part of the herd was trimmed (selection of cows was determined by farmer and <80% of lactating cows were trimmed; n=87 and 20,587 cows). Estimates were consistently higher for the latter likely because farmers presumably prioritized lame cows in partial-herd trims. On farms with whole-herd trims, digital dermatitis was the most common lesion among all housing types, present in 15% of cows and 94% of herds. Sole ulcers and white line disease were detected in 6 and 4% of the cows and 92 and 93% of herds, respectively. Other infectious and claw horn lesions each affected 1 to 2% of cows and 62 to 78% of herds. Intraclass correlation coefficients for hoof trimmers ranged from 0.01 to 0.20 for all lesions, indicating some clustering of recorded lesions by trimmer. Multilevel mixed logistic regression models were constructed (including hoof trimmer as fixed and farm as random effects) for the 3 most frequently identified lesions. Prevalence of digital dermatitis decreased with increasing parity, but this effect interacted with days in milk (DIM); primiparous cows had higher odds of digital dermatitis in mid lactation (100-199 DIM) and late lactation (>=200 DIM) compared with cows at other stages of lactation. In contrast, prevalence of sole ulcers and white line disease increased with increasing parity; compared with cows in parity 1, those in parity 4 had 5 or 7 times higher odds of having these lesions, respectively. Cows in mid lactation and late lactation had higher odds of sole ulcers and white line disease than cows at other stages of lactation, regardless of parity. Digital dermatitis prevalence was 2 times higher in herds housed in barns with access to an exercise area. The odds of sole ulcers and white line disease were >=2 times higher in cows housed in freestalls than those housed in deep-bedded packs. Therefore, preventive measures for control of digital dermatitis merit emphasis, especially in primiparous cows and on farms with exercise areas. In addition, improving housing environment by providing a deep-bedded area for older cows in mid lactation or late lactation could reduce prevalence of claw horn lesions. We inferred that foot lesion data recorded by hoof trimmers can provide useful information not only to develop effective foot health programs at herd level, but also for disease surveillance and genetic improvement at regional and national levels. PMID- 27236763 TI - Intramammary infection with coagulase-negative staphylococci at parturition: Species-specific prevalence, risk factors, and effect on udder health. AB - Coagulase-negative staphylococci (CNS) are the main cause of bovine intramammary infections (IMI) in many countries. Despite a high prevalence of CNS IMI at parturition, species-specific risk factor studies, relying on accurate identification methods, are lacking. Therefore, this observational study aimed at determining the prevalence and distribution of different CNS species causing IMI in fresh heifers and dairy cows in Flemish dairy herds and identifying associated species- and subgroup-specific risk factors at the herd, cow, and quarter level. The effect on udder health was investigated as well. Staphylococcus chromogenes, S. sciuri, and S. cohnii were the most frequently isolated species. The only CNS species causing IMI in fresh heifers and dairy cows in all herds was Staphylococcus chromogenes, whereas large between-herd differences in distribution were observed for the other species. Quarters from heifers and quarters with an inverted teat end had higher odds of being infected with S. chromogenes, S. simulans, or S. xylosus as well as with S. chromogenes solely. Prepartum teat apex colonization with S. chromogenes increased the likelihood of S. chromogenes IMI in the corresponding quarters at parturition. Quarters with dirty teat apices before calving were more likely to be infected with S. cohnii, S. equorum, S. saprophyticus, or S. sciuri, supporting the environmental nature of these CNS species. Three species (S. chromogenes, S. simulans, and S. xylosus) were associated with a higher quarter somatic cell count at parturition as compared with uninfected quarters. PMID- 27236762 TI - Microbiological characterization and functionality of set-type yogurt fermented with potential prebiotic substrates Cudrania tricuspidata and Morus alba L. leaf extracts. AB - The objective of this study was to investigate the effect of 2 plant leaf extracts on fermentation mechanisms and health-promoting activities and their potential as a nutraceutical prebiotics ingredient for application in dairy products. The individual active phenolic compounds in the plant extract supplemented milk and yogurts were also identified. Compared with control fermentation, the plant extracts significantly increased the growth and acidification rate of Streptococcus thermophilus and Lactobacillus delbrueckii ssp. bulgaricus. In particular, plant extract components, including monosaccharides, formic acid, and hydroxycinnamic acid, such as neo-chlorogenic, chlorogenic, and caffeic acid, together play a stimulatory role and cause this beneficial effect on the growth of yogurt culture bacteria through fermentation. In addition, supplementation with the plant extracts enhanced antioxidant activities with increased total phenolic contents, especially the highest antioxidant activity was observed in yogurt supplemented with Cudrania tricuspidata leaf extract. PMID- 27236764 TI - New insight on crystal and spot development in hard and extra-hard cheeses: Association of spots with incomplete aggregation of curd granules. AB - Chemical composition and structure of different types of macroparticles (specks, spots) and microparticles (microcrystals) present in hard and extra-hard cheeses were investigated. Light microscopy revealed that the small hard specks had the structure of crystalline tyrosine, as confirmed by amino acid analysis. Spots showed a complex structure, including several curd granules, cavities, and microcrystals, and were delimited by a dense protein layer. Spots contained less moisture and ash than the adjacent cheese area, and more protein, including significantly higher contents of valine, methionine, isoleucine, leucine, tyrosine, and phenylalanine. Microcrystals were observed by light and electron microscopy and analyzed by confocal micro-Raman. Among others, calcium phosphate crystals appeared to consist of a central star-shaped structure immersed in a matrix of free fatty acids plus leucine and phenylalanine in free form or in small peptides. A hypothetical mechanism for the formation of these structures has been formulated. PMID- 27236765 TI - Assessing liner performance using on-farm milk meters. AB - The primary objective of this study was to quantify and compare the interactive effects of liner compression, milking vacuum level, and pulsation settings on average milk flow rates for liners representing the range of liner compression of commercial liners. A secondary objective was to evaluate a methodology for assessing liner performance that can be applied on commercial dairy farms. Eight different liner types were assessed using 9 different combinations of milking system vacuum and pulsation settings applied to a herd of 80 cows with vacuum and pulsation conditions changed daily for 36d using a central composite experimental design. Liner response surfaces were created for explanatory variables milking system vacuum (Vsystem) and pulsator ratio (PR) and response variable average milk flow rate (AMF=total yield/total cups-on time) expressed as a fraction of the within-cow average flow rate for all treatments (average milk flow rate fraction, AMFf). Response surfaces were also created for between-liner comparisons for standardized conditions of claw vacuum and milk ratio (fraction of pulsation cycle during which milk is flowing). The highest AMFf was observed at the highest levels of Vsystem, PR, and overpressure. All liners showed an increase in AMF as milking conditions were changed from low to high standardized conditions of claw vacuum and milk ratio. Differences in AMF between liners were smallest at the most gentle milking conditions (low Vsystem and low milk ratio), and these between-liner differences in AMF increased as liner overpressure increased. Differences were noted with vacuum drop between Vsystem and claw vacuum depending on the liner venting system, with short milk tube vented liners having the greater vacuum drop than mouthpiece chamber vented liners. The accuracy of liner performance assessment in commercial parlors fitted with milk meters can be improved by using a central composite experimental design with a repeated center point treatment, rotating different clusters to different stalls (milk meters), and adjusting performance estimates for similar claw vacuum and pulsation conditions. PMID- 27236766 TI - Modeling lactose hydrolysis for efficiency and selectivity: Toward the preservation of sialyloligosaccharides in bovine colostrum whey permeate. AB - Enzymatic hydrolysis of lactose has been shown to improve the efficiency and selectivity of membrane-based separations toward the recovery of bioactive oligosaccharides. Achieving maximum lactose hydrolysis requires intrinsic process optimization for each specific substrate, but the effects of those processing conditions on the target oligosaccharides are not well understood. Response surface methodology was used to investigate the effects of pH (3.25-8.25), temperature (35-55 degrees C), reaction time (6 to 58 min), and amount of enzyme (0.05-0.25%) on the efficiency of lactose hydrolysis by beta-galactosidase and on the preservation of biologically important sialyloligosaccharides (3' siallylactose, 6'-siallylactose, and 6'-sialyl-N-acetyllactosamine) naturally present in bovine colostrum whey permeate. A central composite rotatable design was used. In general, beta-galactosidase activity was favored at pH values ranging from 3.25 to 5.75, with other operational parameters having a less pronounced effect. A pH of 4.5 allowed for the use of a shorter reaction time (19 min), lower temperature (40 degrees C), and reduced amount of enzyme (0.1%), but complete hydrolysis at a higher pH (5.75) required greater values for these operational parameters. The total amount of sialyloligosaccharides was not significantly altered by the reaction parameters evaluated, suggesting specificity of beta-galactosidase from Aspergillus oryzae toward lactose as well as the stability of the oligosaccharides at pH, temperature, and reaction time evaluated. PMID- 27236767 TI - Textural performance of crosslinked or reduced-calcium milk protein ingredients in model high-protein nutrition bars. AB - Transglutaminase (Tgase) crosslinking and calcium reduction were investigated as ways to improve the texture and storage stability of high-protein nutrition (HPN) bars formulated with milk protein concentrate (MPC) and micellar casein concentrate (MCC). The MPC and MCC crosslinked at none, low, and high levels, and a reduced-calcium MPC (RCMPC) were each formulated into model HPN bars. Hardness, crumbliness, moisture content, pH, color, and water activity of the HPN bars were measured during accelerated storage. The HPN bars prepared with MPC were harder and more cohesive than those prepared with MCC. Higher levels of Tgase crosslinking improved HPN bar cohesiveness and decreased hardening during storage. The RCMPC produced softer, yet crumblier HPN bars. Small textural differences were observed for the HPN bars formulated with the transglutaminase crosslinked proteins or RCMPC when compared with their respective controls. However, modification only slightly improved protein ingredient ability to slow hardening while balancing cohesion and likely requires further improvement for increased applicability in soft-texture HPN bars. PMID- 27236768 TI - Concentrate diet modulation of ruminal genes involved in cell proliferation and apoptosis is related to combined effects of short-chain fatty acid and pH in rumen of goats. AB - Short-chain fatty acids (SCFA) regulate cell proliferation and cell apoptosis in gastrointestinal tissue in vitro and in vivo. We have tested the hypothesis that a medium-concentrate intake induces mRNA abundance alterations of genes involved in cell proliferation and cell apoptosis in the rumen epithelium of goats, and that these changes in mRNA abundance are related to ruminal SCFA concentration and ruminal pH. Goats (n=16) were randomly allocated to 2 groups and fed either a low-concentrate (LC) diet (10% concentrate; n=8) or a medium-concentrate (MC) diet (35% concentrate; n=8) in 2 equal portions daily. The individually housed goats were fed separately with their respective diet for 3wk and were slaughtered 6h after the morning feed on d 22. In vivo, goats receiving the MC treatment exhibited a greater ruminal SCFA concentration (73.7mM) compared with those receiving the LC treatment (53.2mM), and the pH decreased from 6.9 to 6.5. The expression of proliferative genes of cyclin A, cyclin B1, cyclin D1, cyclin E1, CDK1, CDK2, CDK4, and CDK6 mRNA in the MC group was enhanced. The gene expression of apoptosis genes (caspase 3, caspase 8, caspase 9, p53, and Bax) was significantly higher, and the ratio of Bcl-2 to Bax (Bcl-2/Bax) expression was lower in the MC group than in the LC group. The same trend was observed in the population of apoptotic cells analyzed by terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling assay. The cell density in the stratum germinativum of the MC group was significantly increased compared with that in the LC group. During primary culture of rumen epithelial cells, SCFA or pH treatment alone of the culture medium had significant effects on the expression of most of the genes tested in the present study. Furthermore, SCFA and pH exerted combined effects on the expression of cyclin A, cyclin B1, cyclin E1, CDK6, p53, Bcl-2, and Bcl-2/Bax. Thus, the MC diet induces alteration of gene expression of the genes that regulate both cell proliferation and apoptosis. These genes are regulated by combined effect of ruminal SCFA and ruminal pH. PMID- 27236769 TI - Milk metabolome relates enteric methane emission to milk synthesis and energy metabolism pathways. AB - Methane (CH4) emission of dairy cows contributes significantly to the carbon footprint of the dairy chain; therefore, a better understanding of CH4 formation is urgently needed. The present study explored the milk metabolome by gas chromatography-mass spectrometry (milk volatile metabolites) and nuclear magnetic resonance (milk nonvolatile metabolites) to better understand the biological pathways involved in CH4 emission in dairy cattle. Data were used from a randomized block design experiment with 32 multiparous Holstein-Friesian cows and 4 diets. All diets had a roughage:concentrate ratio of 80:20 (dry matter basis) and the roughage was grass silage (GS), corn silage (CS), or a mixture of both (67% GS, 33% CS; 33% GS, 67% CS). Methane emission was measured in climate respiration chambers and expressed as CH4 yield (per unit of dry matter intake) and CH4 intensity (per unit of fat- and protein-corrected milk; FPCM). No volatile or nonvolatile metabolite was positively related to CH4 yield, and acetone (measured as a volatile and as a nonvolatile metabolite) was negatively related to CH4 yield. The volatile metabolites 1-heptanol-decanol, 3-nonanone, ethanol, and tetrahydrofuran were positively related to CH4 intensity. None of the volatile metabolites was negatively related to CH4 intensity. The nonvolatile metabolites acetoacetate, creatinine, ethanol, formate, methylmalonate, and N acetylsugar A were positively related to CH4 intensity, and uridine diphosphate (UDP)-hexose B and citrate were negatively related to CH4 intensity. Several volatile and nonvolatile metabolites that were correlated with CH4 intensity also were correlated with FPCM and not significantly related to CH4 intensity anymore when FPCM was included as covariate. This suggests that changes in these milk metabolites may be related to changes in milk yield or metabolic processes involved in milk synthesis. The UDP-hexose B was correlated with FPCM, whereas citrate was not. Both metabolites were still related to CH4 intensity when FPCM was included as covariate. The UDP-hexose B is an intermediate of lactose metabolism, and citrate is an important intermediate of Krebs cycle-related energy processes. Therefore, the negative correlation of UDP-hexose B and citrate with CH4 intensity may reflect a decrease in metabolic activity in the mammary gland. Our results suggest that an integrative approach including milk yield and composition, and dietary and animal traits will help to explain the biological metabolism of dairy cows in relation to methane CH4 emission. PMID- 27236770 TI - Are the Formulas Used to Estimate Renal Function Adequate for Patients Treated With Cisplatin-Based Chemotherapy After Nephroureterectomy for Upper Tract Urothelial Carcinoma? AB - OBJECTIVE: The relationship between endogenous creatinine clearance (eCrCl) and renal function values obtained using mathematical formulas has not yet been fully elucidated, especially in patients with upper tract urothelial carcinoma that are treated with radical nephroureterectomy followed by cisplatin-based chemotherapy. METHODS: Sixty patients who received cisplatin-based chemotherapy for locally advanced or metastatic upper tract urothelial carcinoma after radical nephroureterectomy between 2000 and 2012 were retrospectively identified. eCrCl was measured based on 24-hour urine specimens obtained immediately prior to each cycle of chemotherapy. Renal function was estimated with 4 different formulas: the Cockcroft-Gault, Modification of Diet in Renal Disease, Chronic Kidney Disease Epidemiology Collaboration, and Wright formulas. We evaluated the relationship between eCrCl and the renal function values obtained with each formula using the Pearson correlation coefficient and kappa statistics. RESULTS: The median eCrCl was 53.9 mL/min. The Pearson correlation coefficients and kappa statistics for the relationships between eCrCl and the renal function values obtained with each of the mathematical formulas ranged from 0.600 to 0.763 and from 0.29 to 0.67, respectively. Among the patients with eCrCl of >= 60 mL/min, 70%, 60%, 50%, and 20% were estimated to have the renal function values of < 60 mL/min by the Cockcroft-Gault, Modification of Diet in Renal Disease, Chronic Kidney Disease Epidemiology Collaboration, and Wright formulas, respectively. CONCLUSIONS: All 4 of the tested formulas underestimated eCrCl. The values obtained with the Wright formula were most closely associated with eCrCl. PMID- 27236771 TI - Using Interferon Alfa Before Tyrosine Kinase Inhibitors May Increase Survival in Patients With Metastatic Renal Cell Carcinoma: A Turkish Oncology Group (TOG) Study. AB - BACKGROUND: We aimed to investigate the outcomes of interferon alfa and sequencing tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: This multicenter study assessing the efficacy of TKIs after interferon alfa therapy in the first-line setting in patients with metastatic renal cell carcinoma. Patients (n = 104) from 8 centers in Turkey, who had been treated with interferon alfa in the first-line setting, were included in the study. Prognostic factors were evaluated for progression free survival (PFS). RESULTS: The median age of the patients was 57 years. The median PFS of the patients treated with interferon alfa in the first-line was 3.6 months. A total of 61 patients received TKIs (sunitinib, n = 58; sorafenib, n = 3) after progression while on interferon alfa. The median PFS among the TKI treated patients was 13.2 months. In the univariate analysis for interferon alfa treatment, neutrophil and hemoglobin level, platelet count, and Karnofsky performance status were the significant factors associated with PFS. In the univariate analysis for TKI treatment, neutrophil and hemoglobin levels were the significant factors for PFS. The median total PFS of the patients who had been treated with first-line interferon alfa and second-line TKIs was 24.9 months. CONCLUSION: This study showed that first-line interferon alfa treatment before TKIs may improve the total PFS in patients with metastatic renal cell carcinoma. PMID- 27236772 TI - Overall Survival Analysis From a Randomized Phase II Study of Axitinib With or Without Dose Titration in First-Line Metastatic Renal Cell Carcinoma. AB - BACKGROUND: In a randomized phase II trial in metastatic renal cell carcinoma (mRCC), objective response rate was significantly higher with axitinib versus placebo titration (54% vs. 34%; 1-sided P = .019). PATIENTS AND METHODS: Treatment-naive patients with mRCC (n = 213) received axitinib 5 mg twice per day (b.i.d.) for 4 weeks. Patients meeting dose titration criteria were randomized to receive axitinib 5 mg b.i.d. with axitinib or placebo titration (n = 56 each); 91 patients ineligible for randomization continued axitinib 5 mg b.i.d.; 10 discontinued before randomization. RESULTS: Median overall survival (95% confidence interval [CI]) was 42.7 months (24.7-not estimable) with axitinib titration versus 30.4 months (23.7-45.0) with placebo titration (stratified hazard ratio, 0.785; 95% CI, 0.485-1.272; 1-sided P = .162), and 41.6 months (95% CI, 33.0-not estimable) in nonrandomized patients. Safety data were consistent with previous reports. CONCLUSION: Median overall survival was numerically longer in patients with first-line mRCC who received axitinib versus placebo titration. No new safety signal was observed after long-term axitinib treatment in first line mRCC. PMID- 27236773 TI - Circulating angiopoietin-2 levels in children and adolescents with type 1 diabetes mellitus: relation to carotid and aortic intima-media thickness. AB - BACKGROUND: Angiopoietin-2 is a growth factor involved in the pathophysiology of vascular and inflammatory diseases such as arteriosclerosis. Carotid or aortic scans provide noninvasive screening tools for assessment of preclinical atherosclerosis in high-risk children. AIM: We assessed serum angiopoietin-2 in children and adolescents with type 1 diabetes mellitus as a potential marker for vascular complications in relation to glycemic control, inflammation and vascular structure. METHODS: Sixty patients with type 1 diabetes were divided into 2 groups according to the presence of micro-vascular complications and compared with 30 healthy controls. High-sensitivity C-reactive protein (hs-CRP), hemoglobin A1c (HbA1c), urinary albumin/creatinine ratio, serum angiopoietin-2, carotid and aortic intima-media thickness (CIMT and AIMT) were measured. RESULTS: CIMT, AIMT and serum angiopoietin-2 levels were significantly increased in patients with and without micro-vascular complications compared with controls, and the highest levels were in patients with complications (p < 0.001). Angiopoietin-2 was higher in patients with microalbuminuria than normoalbuminuric group (p < 0.001). Fasting blood glucose, HbA1c, hs-CRP, CIMT and AIMT were independently related to angiopoietin-2 in multiple regression analysis. Disease duration, hyperglycemia, poor glycemic control, hypercholesterolemia, inflammation and angiopoietin-2 were independent factors contributing to atherosclerosis risk. CONCLUSION: The relation between angiopoietin-2 and assessed parameters of vascular structure in type 1 diabetes reflects a state of endothelial injury and highlights the role of disturbed angiogenesis and vascular inflammation in the occurrence of diabetic complications. PMID- 27236774 TI - The dopamine beta-hydroxylase gene polymorphism rs1611114 is associated with schizophrenia in the Chinese Zhuang but not Chinese Han population. AB - Schizophrenia (SCZ) is a devastating neurodevelopmental disorder. However, the mechanism underlying this highly heritable disorder remains unclear. The dopamine beta-hydroxylase (DBH) gene encodes a key metabolic enzyme of dopamine. Consequently, DBH is considered a candidate gene for SCZ. However, previous studies on its association with SCZ susceptibility have shown conflicting results. Here, we examined association between the rs1611114 polymorphism of DBH and SCZ susceptibility and related clinical symptoms. A total of 691 SCZ patients and 698 age- and gender-matched healthy controls were examined. mRNA expression levels of DBH were measured by quantitative real-time polymerase chain reaction, and the rs1611114 polymorphism was genotyped using the Sequenom MassARRAY platform. Also, the Positive and Negative Syndrome Scale (PANSS) was used to assess SCZ clinical symptoms. Our results show lower DBH mRNA expression levels in SCZ patients than healthy controls (Zhuang: p = 0.000; Han: p = 0.037). Interestingly, the rs1611114 polymorphism was significantly associated with SCZ susceptibility (overdominant model: p = 0.010) in only the Chinese Zhuang population. Furthermore, the rs1611114 polymorphism was associated with PANSS total score (allele T/C: p = 0.015) and general psychopathology score (allele T/C: p = 0.027) in Chinese Zhuang SCZ patients. These results suggest that the DBH gene may play an important role in the occurrence of SCZ. Also, rs1611114 may be associated with SCZ susceptibility and related clinical symptoms in the Chinese Zhuang but not Han Chinese population. Further studies with larger samples of different ethnicities are needed to confirm the role of DBH in SCZ. PMID- 27236775 TI - Bilateral periprosthetic joint infection with Ureaplasma urealyticum in an immunocompromised patient. AB - This case study discusses how we diagnosed and treated a patient with a late haematogenous bilateral periprosthetic joint infection (PJI) after total knee arthroplasties caused by Ureaplasma urealyticum. This has never been reported before. We will discuss how we used a PET-CT, synovial fluid cell count, and synovial fluid analysis by 16S rRNA gene sequencing to diagnose this PJI. We will also discuss how we treated this patient to obtain full recovery. PMID- 27236776 TI - Scientific evidence on the use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in oral and maxillofacial surgery. AB - PURPOSE: This study aimed to identify the main indications for the use of recombinant human bone morphogenetic protein-2 (rhBMP-2) for bone repair and maintenance in the maxilla and mandible through a review of clinical trials evaluating the viability of using rhBMP-2 to delay the installation of dental implants, thus allowing satisfactory bone formation and long-term osseointegration. METHODS: Literature search of the PubMed/Medline databases was performed using the following MeSH index terms-"bone morphogenetic protein 2" and "dentistry". Only clinical trials necessarily published in English, related to dentistry, and focused on bone reconstruction in critical defects, post extraction alveoli, increasing the atrophic alveolar ridge, or surgery for maxillary sinus elevation were included, regardless of the age, sex, ethnicity, associated morbidities, or period of publication. RESULTS: Of the 17 studies identified based on the search filters, 2 were excluded. Therefore, 15 studies were finally included in this review. CONCLUSIONS: Based on the results of our review, we concluded that the use of rhBMP-2 for the preservation of the alveolar ridge after tooth extraction or for increasing the local defects is safe and viable. The use of rhBMP-2/Bio-Oss(r) for the elevation of the maxillary sinus membrane is unnecessary; however, it can improve and accelerate the maturation process in cases of guided bone regeneration in peri-implant defects. Compounds comprising rhBMP-2, allogenic bone, and plasma-rich platelet (PRP) can act as autograft substitutes in mandibular critical defects. PMID- 27236778 TI - Weak self-association of cytochrome c peroxidase molecules observed by paramagnetic NMR. AB - There is growing experimental evidence that many proteins exhibit a tendency for (ultra)weak homo- or hetero- oligomerization interactions. With the development of paramagnetic relaxation enhancement NMR spectroscopy it has become possible to characterize weak complexes experimentally and even detect complexes with affinities in the 1-25 mM range. We present evidence for a weak complex between cytochrome c peroxidase (CcP) molecules. In a previous study, we attached nitroxide based spin labels at three positions on CcP with the intent of observing intramolecular PRE effects. However, several intermolecular PRE effects were also observed suggesting a weak self-association between CcP molecules. The CcP-CcP complex was characterized using paramagnetic NMR and protein docking. The interaction occurs between the surface that is also part of the stereo-specific binding site for its physiological partner, cytochrome c (Cc), and several small, positively charged patches on the "back" of CcP. The CcP-CcP complex is not a stereo-specific complex. It is a dynamic ensemble of orientations, characteristic of an encounter state. The contact areas resemble those observed for CcP molecules in crystals. The CcP-CcP complex formation competes with that of the CcP-Cc complex. However, the affinity for Cc is much larger and thus it is expected that, under physiological conditions, auto-inhibition will be limited. A weak self-association between cytochrome c peroxidase molecules was characterized using paramagnetic NMR. PMID- 27236777 TI - Pulse Width-Dependent Effects of Intestinal Electrical Stimulation for Obesity: Role of Gastrointestinal Motility and Hormones. AB - INTRODUCTION: The goals of this experiment were to study therapeutic potential of intestinal electrical stimulation (IES) for obesity, its mechanisms involving gastrointestinal motility and hormones, and role of pulse width in diet-induced obese rats. METHODS: In a 4-week study, rats equipped with one pair of electrodes at the duodenum were assigned to receive either a sham or IES of varied pulse widths in a sequential way. Food intake was measured daily and body weight measured weekly. Blood samples were collected for the measurement of glucagon like peptide-1 (GLP-1). Solid gastric emptying (GE) and small bowel transit (SIT) tests were performed at the end of the experiment. RESULTS: The results of the study were as follows: (1) Daily food intake, not affected by IES of 0.3 ms, was pulse width-dependently reduced by 1.9 g with 1 ms and by 5.7 g with 3 ms. Accordingly, body weight was pulse width-dependently reduced by 2.4 g with 1 ms and by 12.8 g with 3 ms compared to a gain of 5.6 g in sham. (2) GLP-1 level was elevated by both 0.3 and 3 ms at 15 min, but was elevated only with 3 ms at 60 min. (3) GE was delayed to 52.3 % by IES of 3 ms but not 0.3 ms, compared to that at 64.4 % with sham IES. (4) Compared to the geometric center of 7.0 with sham IES, SIT was accelerated by 3 ms to 7.8 but not by 0.3 ms. CONCLUSION: IES pulse width-dependently reduces food intake and body weight, attributed to the delay of gastric emptying and the acceleration of small bowel transit, as well as the enhancement of GLP-1 secretion. PMID- 27236780 TI - Histopathology of the filum terminale in children with and without tethered cord syndrome with attention to the elastic tissue within the filum. AB - PURPOSE: To compare histologically transected fila from pediatric patients with tethered cord syndrome (TCS), with and without a low conus, with controls, focusing on collagenous and elastic tissue. METHODS: Thirty fila from patients with TCS, including 5 where minimal cautery was used prior to filum section, were compared with fila from 27 pediatric cadavers without TCS (controls). Sections of fila were stained with H&E, Masson trichrome and Verhoeff von Gieson elastic stains, and 7 with Gordon and Sweet's reticulin stain. RESULTS: Fila from controls showed loose fibrous connective tissue (FCT) with thin and evenly dispersed elastic fibers (EFs). Reticulin fibers (RFs) were seen in blood vessel walls and nerve twigs. Fat was identified microscopically in 2 fila. All fila from patients with TCS had dense FCT. The EFs were in normal numbers in 17, and focally or diffusely decreased in 13. All 25 patients where the fila were cauterized during resection had thick and coiled EFs. Coiling was not seen when minimal cautery was applied. RFs were seen in blood vessel walls and nerve twigs. Fat was identified in 19 patients. Findings were similar, whether the conus termination was normal or low. CONCLUSION: The fila of all patients with TCS, whether or not the conus was low, showed abnormal FCT. EFs were decreased in 48 % of patients; however, there were thick and coiled EFs in all patients. Coiling of EFs, initially thought to be an abnormality in patients, is considered most likely to be a result of cautery (i.e., artifactual/iatrogenic coiling). PMID- 27236779 TI - The survival outcome and prognostic factors for distal cholangiocarcinoma following surgical resection: a meta-analysis for the 5-year survival. AB - PURPOSE: To assess the available evidence on the prognostic factors for the 5 year survival for patients with distal cholangiocarcinoma (DCC) following surgical resection. METHODS: We performed a comprehensive search of abstracts included in databases where relevant studies were published between January 2000 and August 2015. Risk ratios (RRs), 95 % confidence intervals (95 % CIs), and random-effects model were calculated using RevMan 5.3 software. RESULTS: A total of 23 observational studies involving 2063 patients with DCC were analyzed. The meta-analysis showed that postoperative adjuvant chemotherapy was not confirmed as a prognostic factor, with similar 5-year survival rates between those receiving and not receiving chemotherapy (RR 0.71; 95 % CI 0.21-2.36; P = 0.57). Perineural invasion (RR 0.51; 95 % CI 0.40-0.64; P < 0.00001), lymph node metastasis (RR 0.51; 95 % CI 0.38-0.70; P < 0.0001), positive resection margin status (RR 2.11; 95 % CI 1.36-3.30; P = 0.001), and not-well-differentiated adenocarcinoma (RR 1.77; 95 % CI 1.39-2.25; P < 0.00001) were associated with shorter survival. CONCLUSIONS: Perineural invasion, lymph node metastasis, resection margin status, and tumor differentiation were the significant prognostic factors for the 5-year survival. PMID- 27236781 TI - Giant pericallosal lipoma with extension into anterior fontanelle: an uncommon case. PMID- 27236782 TI - Intraventricular hemorrhage in neonates born before 32 weeks of gestation retrospective analysis of risk factors. AB - INTRODUCTION: Intraventricular hemorrhage (IVH) affects 15-20 % of babies born before 32 weeks of pregnancy. A lot of risk factors of developing IVH are known. The making appropriate recommendations for dealing with infant born less than 32 weeks of gestation aimed at reducing the incidence of IVH is still needed. The study aim was to determine the incidence and analyze risk factors of IVH stage 3 and 4 in infants born before 32 + 0 weeks of pregnancy. METHODS: The retrospective analysis of 267 preterm babies (24 to 32 weeks of gestation) hospitalized in 2011-2013 at Department of Neonatology, Poznan University of Medical Sciences was performed. The diagnosis of IVH was confirmed by ultrasound scans according to Papille criteria. Stage 3 and 4 of IVH was confirmed in 14 (25 %) newborns from 23 to 24 weeks of gestation; 21 (37.5 %) from 25 to 26 weeks of gestation; 11 (19.6 %) from 27 to 28 weeks of gestation; 9 (16.1 %) from 29 to 30 weeks of gestation; and 1 (1.8 %) from 31 to 32 weeks of gestation. RESULT: The incidence of IVH stage 3 and 4 was higher in children: with less use of AST (OR 1.27; 0.62-2.61), born out of third-level hospitals (OR 2.25; 1.23-4.08), born with asphyxia (OR 3.46; 1.8-6.64), with acidosis treated with NaHCO3 (OR 6.67; 3.78-11.75), those who in the first days of life were treated for hypotension (OR 9.92; 5.12-19.21). CONCLUSION: No or uncompleted antenatal steroid therapy increased probability for development of severe intraventricular hemorrhage. Antenatal steroids therapy should be promoted among women at risk of a premature delivery. Hypotension therapy with catecholamines and acidosis with sodium hydrogen carbonate should be carefully considered. The use of appropriate prophylaxis of perinatal (antenatal steroids therapy women at risk of preterm birth, limiting the indications for the use of catecholamines for hypotension treatment and sodium hydrogen carbonate for acidosis therapy, limitation of preterm deliveries outside tertiary referral centeres) significantly reduces the incidence of intraventricular hemorrhage stage 3 and 4. The significance of intraventricular hemorrhage creates a need to carry out periodical analysis, at regional level, concerning its incidence, causes and effects to improve local treatment outcomes by identifying further courses of action. PMID- 27236783 TI - Spatial short-term memory is impaired in dependent betel quid chewers. AB - RATIONAL: Betel quid is regarded as a human carcinogen by the World Health Organization. It remains unknown whether chewing betel quid has a chronic effect on healthy betel quid chewers' memory. OBJECTIVES: The present study aims to investigate whether chewing betel quid can affect short-term memory (STM). METHODS: Three groups of participants (24 dependent chewers, 24 non-dependent chewers, and 24 non-chewers) were invited to carry out the matrix span task, the object span task, and the digit span task. All span tasks' results were adopted to assess spatial STM, visual STM, and verbal STM, respectively. Besides, there are three set sizes (small, medium, and large) in each span task. RESULTS: For the matrix span task, results showed that the dependent chewers had worse performances than the non-dependent chewers and the non-chewers at medium and large set sizes. For the object span task and digit span task, there were no differences in between groups. In each group, recognition performances were worse with the increasing set size and showing successful manipulation of memory load. CONCLUSIONS: The current study provided the first evidence that dependent betel quid chewing can selectively impair spatial STM rather than visual STM and verbal STM. Theoretical and practical implications of this result are discussed. PMID- 27236786 TI - Vascular endothelial growth factor levels in patients with obstructive sleep apnea: a meta-analysis. AB - Published articles regarding the blood levels of vascular endothelial growth factor (VEGF) in obstructive sleep apnea (OSA) patients are contradictory. The objective of this study was to explore whether VEGF levels is high or not in OSA subjects via quantitatively statistical analysis. The electronic databases of Pubmed, Web of Science, EMBASE were systematic searched. The VEGF levels and clinical characteristics of participants between OSA group and control group were extracted for analysis. Weighted mean difference (WMD) or standard mean difference (SMD) with 95 % confidence interval (CI) was calculated by fixed effects or random effects model. Appropriate statistical software was employed for data synthesis. Totaling 15 articles with 697 participants were included in this study. Pooled meta-analysis showed that blood VEGF concentrations were significantly higher in OSA patients than in control subjects (SMD 1.89, 95 % CI 0.92-2.87, p = 0.000). Subgroup analysis demonstrated that when compared with control group, OSA patients with age >=50 years (SMD 2.54, 95 % CI 1.28-3.80, p = 0.000), apnea hypopnea index >=30 events/h (SMD 2.47, 95 % CI 1.20-3.73, p = 0.000) had higher VEGF levels. Compared with control subjects, OSA patients had an elevated VEGF in serum (SMD 3.55, 95 % CI 1.82-5.28, p = 0.000) rather than in plasma. High blood VEGF concentrations were observed in OSA patients, particularly in the older and more serious patients. PMID- 27236785 TI - Differential interaction with the serotonin system by S-ketamine, vortioxetine, and fluoxetine in a genetic rat model of depression. AB - RATIONALE: The mechanisms mediating ketamine's antidepressant effect have only been partly resolved. Recent preclinical reports implicate serotonin (5 hydroxytryptamine; 5-HT) in the antidepressant-like action of ketamine. Vortioxetine is a multimodal-acting antidepressant that is hypothesized to exert its therapeutic activity through 5-HT reuptake inhibition and modulation of several 5-HT receptors. OBJECTIVES: The objective of this study was to evaluate the therapeutic-like profiles of S-ketamine, vortioxetine, and the serotonin reuptake inhibitor fluoxetine in response to manipulation of 5-HT tone. METHOD: Flinders Sensitive Line (FSL) rats, a genetic model of depression, were depleted of 5-HT by repeated administration of 4-chloro-DL-phenylalanine methyl ester HCl (pCPA). Using pCPA-pretreated and control FSL rats, we investigated the acute and sustained effects of S-ketamine (15 mg/kg), fluoxetine (10 mg/kg), or vortioxetine (10 mg/kg) on recognition memory and depression-like behavior in the object recognition task (ORT) and forced swim test (FST), respectively. RESULTS: The behavioral phenotype of FSL rats was unaffected by 5-HT depletion. Vortioxetine, but not fluoxetine or S-ketamine, acutely ameliorated the memory deficits of FSL rats in the ORT irrespective of 5-HT tone. No sustained effects were observed in the ORT. In the FST, all three drugs demonstrated acute antidepressant-like activity but only S-ketamine had sustained effects. Unlike vortioxetine, the antidepressant-like responses of fluoxetine and S-ketamine were abolished by 5-HT depletion. CONCLUSIONS: These observations suggest that the acute and sustained antidepressant-like effects of S-ketamine depend on endogenous stimulation of 5-HT receptors. In contrast, the acute therapeutic-like effects of vortioxetine on memory and depression-like behavior may be mediated by direct activity at 5-HT receptors. PMID- 27236784 TI - Dopamine receptor agonists modulate voluntary alcohol intake independently of individual levels of alcohol intake in rats. AB - RATIONALE: Individual susceptibility to alcohol use disorder has been related to functional changes in dopaminergic neurotransmission. OBJECTIVES: The aim of the current work was to assess the effects of selective dopamine D1 and D2 receptor agonists and antagonists on alcohol consumption in rats that differ in individual levels of alcohol intake. METHODS: The effects of the dopamine D1 receptor agonist SKF 82958, the dopamine D1 receptor antagonist SCH 23390, the dopamine D2 receptor agonist sumanirole and the dopamine D2 receptor antagonist L741,626 on alcohol consumption and preference were assessed at different time points after treatment in subgroups of low and high alcohol drinking rats (LD and HD) using an intermittent alcohol access paradigm. RESULTS: SKF 82958 decreased alcohol intake and alcohol preference throughout the 24-h session. Sumanirole decreased alcohol intake during the first 2 h, but increased alcohol intake during the remainder of the session. The effects of SKF 82958 and sumanirole on alcohol intake and alcohol preference were comparable in LD and HD. By contrast, the dopamine receptor antagonists SCH 23390 and L741,626 did not alter alcohol consumption in either group at any time point. CONCLUSIONS: These data indicate that stimulation of dopamine D1 receptors reduces alcohol intake, but that endogenous dopamine does not play a primary role in alcohol consumption. Moreover, the difference in alcohol consumption between LD and HD does not involve altered dopamine signaling. PMID- 27236787 TI - Systemic effects of AGEs in ER stress induction in vivo. AB - Emerging evidence indicates that accumulation of advanced glycation end products (AGEs) in human tissues may contribute to cell injury, inflammation and apoptosis through induction of endoplasmic reticulum (ER) stress. Human metabolism relies on ER homeostasis for the coordinated response of all metabolic organs by controlling the synthesis and catabolism of various nutrients. In vitro studies have demonstrated AGE-induced enhancement of unfolded protein response (UPR) in different cell types including endothelial, neuronal, pancreatic cells and podocytes, suggesting this crosstalk as an underlying pathological mechanism that contributes to metabolic diseases. In this minireview, we describe in vivo studies undertaken by our group and others that demonstrate the diverse systemic effects of AGEs in ER stress induction in major metabolic tissues such as brain, kidney, liver and pancreas of normal mice. Administration of high-AGEs content diet to normal mice for the period of 4 weeks upergulates the mRNA and protein levels of ER chaperone Bip (GRP78) indicative of UPR initiation in all major metabolic organs and induces activation of the pivotal transcription factor XBP1 that regulates glucose and lipid metabolism. Furthermore, animals with genetic ablation of UPR-activated transcription factor C/EBP homologous protein CHOP allocated in high-AGEs diet, exhibited relative resistance to UPR induction (BiP levels) and XBP1 activation in major metabolic organs. Since CHOP presents a critical mediator that links accumulation and aggregation of unfolded proteins with induction of oxidative stress and ER stress-related apoptosis, it is revealed as an important molecular target for the management of metabolic diseases. PMID- 27236788 TI - Is the Consumption of Energy Drinks Associated With Academic Achievement Among College Students? AB - Despite widely reported side effects, use of energy drinks has increased among college students, who report that they consume energy drinks to help them complete schoolwork. However, little is known about the association between energy drink use and academic performance. We explored the relationship between energy drink consumption and current academic grade point average (GPA) among first-year undergraduate students. Participants included 844 first-year undergraduates (58.1 % female; 50.7 % White). Students reported their health behaviors via an online survey. We measured energy drink consumption with two measures: past month consumption by number of drinks usually consumed in 1 month and number consumed during the last occasion of consumption. We used multiple linear regression modeling with energy drink consumption and current GPA, controlling for gender, race, weekend and weekday sleep duration, perceived stress, perceived stress management, media use, and past month alcohol use. We found that past month energy drink consumption quantity by frequency (p < 0.001), and energy drinks consumed during the last occasion (p < 0.001), were associated with a lower GPA. Energy drinks consumed during the last occasion of consumption (p = 0.01) remained significantly associated with a lower GPA when controlling for alcohol use. While students report using energy drinks for school-related reasons, our findings suggest that greater energy drink consumption is associated with a lower GPA, even after controlling for potential confounding variables. Longitudinal research is needed that addresses whether GPA declines after continued use of energy drinks or if students struggling academically turn to energy drinks to manage their schoolwork. PMID- 27236789 TI - Synthetic mRNA: Production, Introduction into Cells, and Physiological Consequences. AB - Recent advances have made it possible to synthesize mRNA in vitro that is relatively stable when introduced into mammalian cells, has a diminished ability to activate the innate immune response against exogenous (virus-like) RNA, and can be efficiently translated into protein. Synthetic methods have also been developed to produce mRNA with unique investigational properties such as photo cross-linking, fluorescence emission, and attachment of ligands through click chemistry. Synthetic mRNA has been proven effective in numerous applications beneficial for human health such as immunizing patients against cancer and infections diseases, alleviating diseases by restoring deficient proteins, converting somatic cells to pluripotent stem cells to use in regenerative medicine therapies, and engineering the genome by making specific alterations in DNA. This introductory chapter provides background information relevant to the following 20 chapters of this volume that present protocols for these applications of synthetic mRNA. PMID- 27236790 TI - Synthetic Capped mRNAs for Cap-Specific Photo-Cross-Linking Experiments. AB - The 7-methylguanosine triphosphate cap present at the 5' ends of eukaryotic mRNAs plays numerous roles in mRNA expression and metabolism. The identification and studies on cap-binding partners can be significantly advanced using tailored chemical tools such as synthetic cap analogues or RNAs carrying modified cap structures. Here we provide protocols for the production of mRNAs specifically labeled within the 5' cap with a nucleoside capable of being photo-activated, either 6-thioguanosine or 7-methyl-6-thioguanosine, which can be used in photo cross-linking experiments to identify or characterize cap-binding biomolecules. We also describe a protocol for the cross-linking experiments with capped RNAs to map histone H4 cap-binding pocket. PMID- 27236791 TI - Enzymatic Modification of 5'-Capped RNA and Subsequent Labeling by Click Chemistry. AB - The combination of enzymatic modification and bioorthogonal click chemistry provides a powerful approach for site-specific labeling of different classes of biomolecules in vitro and even in cellular environments. Herein, we describe a chemoenzymatic method to site specifically label 5'-capped model mRNAs independent of their sequence. A trimethylguanosine synthase was engineered to introduce alkyne, azido, or 4-vinylbenzyl moieties to the 5'-cap. These functional groups were then used for labeling using typical click reactions, such as the azide-alkyne cycloaddition or the tetrazine ligation. PMID- 27236792 TI - Preparation of Functional, Fluorescently Labeled mRNA Capped with Anthraniloyl m(7)GpppG. AB - Fluorescent mRNA molecules offer a wide range of applications for studying capping/decapping reactions, translation, and other biophysical studies. Furthermore, fluorescent tags prove invaluable for tracking RNA molecules in cells. Here, we describe an efficient synthesis of a fluorescent cap analog, anthranioyl-GTP, its purification, and in vitro cap labeling of transcribed mRNA catalyzed by the recombinant vaccinia capping enzyme to produce anthranioyl m(7)GpppG-capped RNA. PMID- 27236793 TI - Intronless beta-Globin Reporter: A Tool for Studying Nuclear RNA Stability Elements. AB - The intronless beta-globin reporter, whose mRNA is intrinsically unstable due to the lack of introns, is a useful tool to study RNA stability elements in a heterologous transcript. Insertion of a stability element leads to the accumulation of intronless beta-globin mRNA that can be visualized by conventional Northern blot analyses. In this chapter, we explain how to perform the beta-globin reporter assay using the ENE (expression and nuclear retention element), a triple-helix-forming RNA stability element that protects reporter mRNA from 3'- 5' decay. A list of considerations is included for the use of ENEs as a tool to stabilize other RNAs. In this chapter, we provide a brief description of how to insert an ENE sequence into the 3'-untranslated region of an intronless beta-globin reporter plasmid using basic cloning technology. Then, we provide a detailed protocol for quantitative measurements of steady-state levels of beta-globin mRNA. This entails the transient transfection of mammalian cells with beta-globin reporter plasmids, isolation of total cellular RNA, and detection of reporter mRNA via Northern blot. This methodology can be applied for the study of any nuclear RNA stability element using the intronless beta-globin reporter. PMID- 27236794 TI - Synthetic mRNA with Superior Properties that Mimics the Intracellular Fates of Natural Histone mRNA. AB - Since DNA and histone levels must be closely balanced for cell survival, histone expressions are highly regulated. The regulation of replication-dependent histone expression is mainly achieved at the mRNA level, as the mRNAs are rapidly removed when DNA replication is inhibited during S-phase. Histone mRNA degradation initiates with addition of multiple uridines (oligouridylation) following the 3' stem-loop (SL) catalyzed by terminal uridyltransferase (TUTase). Previous studies showed that histone mRNA degradation occurs through both 5' -> 3' and 3' -> 5' processes, but the relative contributions are difficult to dissect due to lack of established protocols. The translational efficiency and stability of synthetic mRNA in both cultured cells and whole animals can be improved by structural modifications at the both 5' and 3' termini. In this chapter, we present methods of utilizing modified cap dinucleotide analogs to block 5' -> 3' degradation of a reporter mRNA containing canonical histone mRNA 3' SL and monitoring how oligouridylation and 3' -> 5' degradation occur. Protocols are presented for synthesis of reporter mRNA containing the histone 3' SL and modified cap analogs, monitoring mRNA stability and unidirectional degradation either from 5' or 3' termini, and detection of oligo(U) tracts from degradation products by either traditional or deep sequencing. PMID- 27236795 TI - Engineering WT1-Encoding mRNA to Increase Translational Efficiency in Dendritic Cells. AB - Dendritic cells (DCs) are the orchestrators of the immune system and are frequently used in clinical trials in order to boost the immune system in cancer patients. Among several available techniques for DC modification, mRNA electroporation is an interesting technique due to the favorable characteristics of mRNA. Antigen expression level and duration can be increased by multiple optimizations of an antigen-encoding mRNA template. Here, we describe different molecular modifications to a WT1-encoding mRNA construct in order to increase antigen expression and the subsequent introduction of mRNA into DCs. PMID- 27236796 TI - Electroporation of Alphavirus RNA Translational Reporters into Fibroblastic and Myeloid Cells as a Tool to Study the Innate Immune System. AB - The ability to transfect synthetic mRNAs into cells to measure processes such as translation efficiency or mRNA decay has been an invaluable tool in cell biology. The use of electroporation over other methods of transfection is an easy, inexpensive, highly efficient, and scalable method to introduce synthetic mRNA into a wide range of cell types. More recently, coupling of noncoding RNA sequences or protein coding regions from viral pathogens to fluorescent or bioluminescence proteins in RNA "reporters" has permitted study of host-pathogen interactions. These can range from virus infection of cells to translation of the viral genome, replication and stability of viral RNAs, or the efficacy of host antiviral responses. In this chapter, we describe a method for electroporating viral RNA reporters into both fibroblastic and myeloid cells that encode firefly or Renilla luciferase, whose reaction with specific substrates and light emitting activity is a measure of viral RNA translation efficiency. We have used this method to examine host interferon-dependent responses that inhibit viral translation along with identifying secondary structures in the 5' nontranslated region (NTR) and microRNA binding sites in the 3' NTR that are responsible for antagonizing the host innate immune responses and restricting viral cell tropism. PMID- 27236797 TI - GMP-Grade mRNA Electroporation of Dendritic Cells for Clinical Use. AB - mRNA-electroporated dendritic cells (DC) are demonstrating clinical benefit in patients in many therapeutic areas, including cancer and infectious diseases. According to current good manufacturing guidelines, cell-based medicinal products have to be defined for identity, purity, potency, stability, and viability. In order to comply with the directives and guidelines defined by the regulatory authorities, we report here a standardized and reproducible method for the manufacturing of clinical-grade mRNA-transfected DC. PMID- 27236798 TI - Large-Scale mRNA Transfection of Dendritic Cells by Electroporation in Continuous Flow Systems. AB - Electroporation is well established for transient mRNA transfection of many mammalian cells, including immune cells such as dendritic cells used in cancer immunotherapy. Therapeutic application requires methods to efficiently electroporate and transfect millions of immune cells in a fast process with high cell survival. Continuous flow of suspended dendritic cells through a channel incorporating spatially separated microporous meshes with a synchronized electrical pulsing sequence can yield dendritic cell transfection rates of >75 % with survival rates of >90 %. This chapter describes the instrumentation and methods needed for the efficient transfection by electroporation of millions of dendritic cells in one continuous flow process. PMID- 27236799 TI - FLT3 Ligand as a Molecular Adjuvant for Naked RNA Vaccines. AB - Intranodal immunization with antigen-encoding naked mRNA has proven to be an efficacious and safe approach to induce antitumor immunity. Thanks to its unique characteristics, mRNA can act not only as a source for antigen but also as an adjuvant for activation of the immune system. The search for additional adjuvants that can be combined with mRNA to further improve the potency of the immunization revealed Fms-like tyrosine kinase 3 (FLT3) ligand as a potent candidate. Systemic administration of the dendritic cell-activating FLT3 ligand prior to or along with mRNA immunization-enhanced priming and expansion of antigen-specific CD8(+) T cells in lymphoid organs, T-cell homing into melanoma tumors, and therapeutic activity of the intranodally administered mRNA. Both compounds demonstrate a successful combination in terms of boosting the immune response. This chapter describes methods for intranodal immunization with naked mRNA by co administration of FLT3 ligand, which leads to strong synergistic effects. PMID- 27236800 TI - Transfecting Human Monocytes with RNA. AB - Targeting monocytes as a delivery system for drugs or nucleic acids, and thereby harnessing their natural tissue-infiltrating capacity, has become an area of intense investigation in both basic and clinical research. Herein we describe an efficient method to deliver mRNA (messenger RNA) or siRNA (small interfering RNA) into human monocytes by electroporation. This method can be applied in the laboratory to monocytes isolated via magnetic bead-based techniques, or in a clinical setting using monocytes that were collected via counterflow centrifugation elutriation using the Elutra((r)) Cell Separation System. We further demonstrate that electroporation of monocytes with RNA represents a robust and highly relevant approach to modify monocytes for cell-based therapies. Last, the procedure described can readily be adapted to monocytes from different species, hence facilitating research in animal models. PMID- 27236801 TI - In Vitro Synthesis, Delivery, and Bioavailability of Exogenous mRNA in Gene Transfer Mediated by PiggyBac Transposition. AB - Nowadays, nonviral gene transfer is currently of great importance for introducing exogenous genes into genomes and for ensuring that transgene expression is suitable for therapeutic and bioproduction purposes. The piggyBac transposon based system is particularly interesting since it is easy to engineer and has a large cargo capacity, up to 100 kb. In its setup, the system requires only the piggyBac transposase protein and the transgene delineated by the two piggyBac specific inverted terminal repeats. Usually the source of transposase is carried by a DNA plasmid. However, the principal drawback of this method is the lasting presence of the transposase, due to episomal persistence or possible integration of the transposase gene vector into the cell's genome. This can lead to genotoxic effects such as multiple genomic integration events and remobilization of the transposon vector once it has been integrated. One alternative to improve the safety of the system is to deliver the transposase as in vitro-synthesized messenger RNA in order to define a very narrow expression window during which a one-shot transposition process would occur. Issues that can be encountered when working on mRNA cell transfer are related to the quality of the synthetic mRNA, the system used to introduce mRNA into the cells and the bioavailability of the mRNA molecules. Here we describe a method to produce mRNA, verify its quality, determine which transfecting reagents can be used and how this mRNA is available to promote the transposition process in HeLa cells. Additionally, we illustrate this method in stromal mesenchymal cell lines in order to support hematopoiesis. PMID- 27236802 TI - Transfection of Human Keratinocytes with Nucleoside-Modified mRNA Encoding CPD Photolyase to Repair DNA Damage. AB - In vitro-synthesized mRNA containing nucleoside modifications has great therapeutical potential to transiently express proteins with physiological importance. One such protein is photolyase which rapidly removes UV-induced DNA damages, but this enzyme is absent in humans. Here, we apply a novel mRNA-based platform to achieve functional nonhuman photolyase production in cultured human keratinocytes. Transfection of nucleoside-modified mRNA encoding photolyase leads to accelerated repair of DNA photolesions in human keratinocytes. PMID- 27236803 TI - Delivery of Synthetic mRNA Encoding FOXP3 Antigen into Dendritic Cells for Inflammatory Breast Cancer Immunotherapy. AB - Dendritic cell (DC)-based vaccines are commonly used for cancer immunotherapy. To prepare vaccines, DCs are pulsed or transfected with either: (a) defined peptides of tumor-associated antigens, (b) total protein isolated from the tumor cell, (c) autologous total RNA isolated from the tumor cell, (d) synthetic tumor-antigen encoding mRNA, or (e) genes that encode for specific tumor-associated antigens. Introduction of tumor-associated antigen(s) and subsequent generation of mature DCs that can stimulate tumor-antigen-specific cytotoxic T lymphocytes comprise the critical steps of cancer vaccine preparation. Here, we described a method of: (a) preparing and delivering synthetic FOXP3 mRNA into human DCs, (b) generating mature DCs, PMID- 27236804 TI - Immune Monitoring Using mRNA-Transfected Dendritic Cells. AB - Dendritic cells are known to be the most potent antigen presenting cell in the immune system and are used as cellular adjuvants in therapeutic anticancer vaccines using various tumor-associated antigens or their derivatives. One way of loading antigen into the dendritic cells is by mRNA electroporation, ensuring presentation of antigen through major histocompatibility complex I and potentially activating T cells, enabling them to kill the tumor cells. Despite extensive research in the field, only one dendritic cell-based vaccine has been approved. There is therefore a great need to elucidate and understand the immunological impact of dendritic cell vaccination in order to improve clinical benefit. In this chapter, we describe a method for performing immune monitoring using peripheral blood mononuclear cells and autologous dendritic cells transfected with tumor-associated antigen-encoding mRNA. PMID- 27236805 TI - Transfection of Tumor-Infiltrating T Cells with mRNA Encoding CXCR2. AB - Adoptive T-cell therapy based on the infusion of patient's own immune cells after ex vivo culturing is among the most potent forms of personalized treatment among recent clinical developments for the treatment of cancer. However, despite high rates of successful initial clinical responses, only about 20 % of patients with metastatic melanoma treated with tumor-infiltrating lymphocytes (TILs) enter complete and long-term regression, with the majority either relapsing after initial partial regression or not benefiting at all. Previous studies have shown a positive correlation between the number infused T cells migrating to the tumor and the clinical response, but also that only a small fraction of adoptively transferred T cells reach the tumor site. In this chapter, we describe a protocol for transfection of TILs with mRNA encoding the chemokine receptor CXCR2 transiently redirecting and improving TILs migration toward tumor-secreted chemokines in vitro. PMID- 27236806 TI - mRNA Electroporation of Dendritic Cells with WT1, Survivin, and TriMix (a Mixture of caTLR4, CD40L, and CD70). AB - The immune system is a crucial player in the development of cancer. Once it is in imbalance and immunosuppressive mechanisms supporting tumor growth take over control, dendritic cell immunotherapy might offer a solution to restore the balance. There are several methods to manufacture dendritic cells but none of them has yet proven to be superior to others. In this chapter, we discuss the methodology using electroporation of mRNA encoding Wilms' tumor gene 1, survivin, and TriMix (mixture of caTLR4, CD40L, and CD70) to simultaneously load and mature dendritic cells. PMID- 27236807 TI - Redirecting T Cell Specificity Using T Cell Receptor Messenger RNA Electroporation. AB - Autologous T lymphocytes genetically modified to express T cell receptors or chimeric antigen receptors have shown great promise in the treatment of several cancers, including melanoma and leukemia. In addition to tumor-associated antigens and tumor-specific neoantigens, tumors expressing viral peptides can also be recognized by specific T cells and are attractive targets for cell therapy. Hepatocellular carcinoma cells often have hepatitis B virus DNA integration and can be targeted by hepatitis B virus-specific T cells. Here, we describe a method to engineer hepatitis B virus-specific T cell receptors in primary human T lymphocytes based on electroporation of hepatitis B virus T cell receptor messenger RNA. This method can be extended to a large scale therapeutic T cell production following current good manufacturing practice compliance and is applicable to the redirection of T lymphocytes with T cell receptors of other virus specificities such as Epstein-Barr virus, cytomegalovirus, and chimeric receptors specific for other antigens expressed on cancer cells. PMID- 27236808 TI - Measuring Hematocrit in Mice Injected with In Vitro-Transcribed Erythropoietin mRNA. AB - In vitro-transcribed (IVT) mRNA encoding therapeutic protein has the potential to treat a variety of diseases by serving as template for translation in the patient. To optimize conditions for such therapy, reporter protein-encoding mRNAs are usually used. One preferred reporter is erythropoietin (EPO), which stimulates erythropoiesis and leads to an increase in hematocrit. Measurement of hematocrit is a fast and reliable method to determine the potency of the in vitro transcribed EPO mRNA. However, frequent blood draw from mice can increase hematocrit due to blood loss. Therefore, instead of using conventional hematocrit capillary tubes, we adapted glass microcapillaries for hematocrit measurement. Daily monitoring of mice can be accomplished by drawing less than 20 MUL of blood, thus avoiding blood loss-related hematocrit increase. Due to the small volume of the withdrawn blood the hematocrit remains the same for mice injected with control mRNA, whereas significant hematocrit increase is measured between day 4 and 20 postinjection for those injected with pseudouridine-modified EPO mRNA. Following hematocrit measurement the microcapillaries are snapped easily to recover plasma for further analyses, including EPO measurement by ELISA. PMID- 27236809 TI - Genetic Modification of Human Pancreatic Progenitor Cells Through Modified mRNA. AB - In this chapter, we describe a highly efficient genetic modification strategy for human pancreatic progenitor cells using modified mRNA-encoding GFP and Neurogenin 3. The properties of modified mRNA offer an invaluable platform to drive protein expression, which has broad applicability in pathway regulation, directed differentiation, and lineage specification. This approach can also be used to regulate expression of other pivotal transcription factors during pancreas development and might have potential therapeutic values in regenerative medicine. PMID- 27236811 TI - Cloning, expression, and characterization of a four-component O-demethylase from human intestinal bacterium Eubacterium limosum ZL-II. AB - Eubacterium limosum ZL-II was described to convert secoisolariciresinol (SECO) to its demethylating product 4,4'-dihydroxyenterodiol (DHEND) under anoxic conditions. However, the reaction cascade remains unclear. Here, the O demethylase being responsible for the conversion was identified and characterized. Nine genes encoding two methyltransferase-Is (MT-I), two corrinoid proteins (CP), two methyltransferase-IIs (MT-II), and three activating enzymes (AE) were screened, cloned, and expressed in Escherichia coli. Four of the nine predicted enzymes, including ELI_2003 (MT-I), ELI_2004 (CP), ELI_2005 (MT-II), and ELI_0370 (AE), were confirmed to constitute the O-demethylase in E. limosum ZL-II. The complete O-demethylase (combining the four components) reaction system was reconstructed in vitro. As expected, the demethylating products 3-demethyl SECO and DHEND were both produced. During the reaction process, ELI_2003 (MT-I) initially catalyzed the transfer of methyl group from SECO to the corrinoid of ELI_2004 ([CoI]-CP), yielding demethylating products and [CH3-CoIII]-CP; then ELI_2005 (MT-II) mediated the transfer of methyl group from [CH3-CoIII]-CP to tetrahydrofolate, forming methyltetrahydrofolate and [CoI]-CP. Due to the low redox potential of [CoII]/[CoI], [CoI]-CP was oxidized to [CoII]-CP immediately in vitro, and ELI_0370 (AE) was responsible for catalyzing the reduction of [CoII]-CP to its active form [CoI]-CP. The active-site residues in ELI_2003, ELI_2005, and ELI_0370 were subsequently determined using molecular modeling combined with site-directed mutagenesis. To our knowledge, this is the first study on the identification and characterization of a four-component O demethylase from E. limosum ZL-II, which will facilitate the development of method to artificial synthesis of related bioactive chemicals. PMID- 27236810 TI - Interactions between Pseudomonas aeruginosa and Staphylococcus aureus during co cultivations and polymicrobial infections. AB - Pseudomonas aeruginosa and Staphylococcus aureus are versatile bacterial pathogens and common etiological agents in polymicrobial infections. Microbial communities containing both of these pathogens are shaped by interactions ranging from parasitic to mutualistic, with the net impact of these interactions in many cases resulting in enhanced virulence. Polymicrobial communities of these organisms are further defined by multiple aspects of the host environment, with important implications for disease progression and therapeutic outcomes. This mini-review highlights the impact of these interactions on the host and individual pathogens, the molecular mechanisms that underlie these interactions, and host-specific factors that drive interactions between these two important pathogens. PMID- 27236812 TI - Lesion characteristics of coronary arteries associated with a mismatch between angiographic severity of stenosis and fractional flow reserve. AB - We aimed to clarify the relationships between angiographic lesion characteristics and values of fractional flow reserve (FFR) on intermediate coronary artery stenosis. The clinical meaning and assessment for "visual-functional mismatches," including regular-mismatches [defined as angiographic percent diameter stenosis (%DS) >=50 % and FFR >0.80] and reverse-mismatches (defined as angiographic %DS <50 %, FFR <=0.80) remains unresolved in contemporary practice. We retrospectively enrolled 140 consecutive patients who underwent coronary angiography and FFR measurement. One hundred fifty-seven cases of intermediate coronary artery stenosis were evaluated. The relationship between clinical/lesion characteristics and regular- or reverse-mismatches were examined. Lesions in the left anterior descending artery (LAD) showed significantly lower frequency of regular-mismatch than did non-LAD lesions (26.7 vs. 73.3 %, respectively; p < 0.001). Conversely, almost all reverse-mismatches were observed in LAD lesions (93.8 %). The best cut-off value of %DS, derived from receiver operating characteristic (ROC) curve analysis, to predict FFR <=0.8 was 45.0 % in LAD lesions and 67.5 % in non-LAD lesions. FFR measurement should be considered in LAD intermediate lesions to avoid residual functional ischemia and in non-LAD lesions to avoid unnecessary coronary intervention. PMID- 27236813 TI - Implementing intelligent physical exercise training at the workplace: health effects among office workers-a randomized controlled trial. AB - PURPOSE: The aim was to assess 1-year cardiovascular health effects of Intelligent Physical Exercise Training, IPET. METHODS: Office workers from six companies were randomized 1:1 to a training group, TG (N = 194) or a control group, CG (N = 195). TG received 1-h supervised high intensity IPET every week within working hours for 1 year, and was recommended to perform 30-min of moderate intensity physical activity 6 days a week during leisure. The training program was based on baseline health check measures of cardiorespiratory fitness (CRF), body composition, blood pressure, blood profile, and musculoskeletal health. RESULTS: There were no baseline differences between groups. CRF assessed as VO2max in absolute values and relative to body weight was (mean +/- SD): 3.0 +/- 0.8 l/min and 35.4 +/- 10.9 ml/min/kg for females, 3.9 +/- 1.0 l/min and 37.9 +/- 11.79 ml/min/kg for males. Intention to treat analysis demonstrated a significant almost 5 % increase in VO2max in TG compared with CG. A per protocol analysis of those with an adherence of >=70 % demonstrated a significant increase in CRF of more than 10 % compared with CG, and a significant reduction in systolic blood pressure (-5.3 +/- 13.7 mm Hg) compared with CG. CONCLUSION: High intensity IPET combined with the recommendations of moderate intensity physical activity demonstrated significant clinical relevant improvements in CRF and systolic blood pressure. This underlines the effectiveness of health promotion by implementing physical exercise training at the workplace. PMID- 27236814 TI - Ultrasound of the coracoclavicular ligaments in the acute phase of an acromioclavicular disjonction: Comparison of radiographic, ultrasound and MRI findings. AB - OBJECTIVES: Acromioclavicular joint injuries are typically diagnosed by clinical and radiographic assessment with the Rockwood classification, which is crucial for treatment planning. The purpose of this study was to describe how the ultrasound findings of acromioclavicular joint injury compare with radiography and MRI findings. METHODS: Forty-seven patients with suspected unilateral acromioclavicular joint injury after acute trauma were enrolled in this prospective study. All patients underwent digital radiography, ultrasound and 3T MRI. A modified Rockwood classification was used to evaluate the coracoclavicular ligaments. The classifications of acromioclavicular joint injuries diagnosed with radiography, ultrasound and MRI were compared. MRI was used as the gold standard. RESULTS: The agreement between the ultrasound and MRI findings was very good, with a correlation coefficient of 0.83 (95 % CI: 0.72-0.90; p < 0.0001). Ultrasound detected coracoclavicular ligament injuries with a sensitivity of 88.9 %, specificity of 90.0 %, positive predictive value of 92.3 % and negative predictive value of 85.7 %. The agreement between the ultrasound and radiography findings was poor, with a correlation coefficient of 0.69 (95 % CI: 0.51-0.82; p < 0.0001). CONCLUSION: Ultrasound is an effective examination for the diagnostic work-up of lesions of the coracoclavicular ligaments in the acute phase of an acromioclavicular injury. KEY POINTS: * Ultrasound is appropriate for acute acromioclavicular trauma due to its accessibility. * Ultrasound contributes to the diagnostic work-up of acute lesions of the coracoclavicular ligaments. * Ultrasound is appropriate in patients likely to benefit from surgical treatment. * Ultrasound could be a supplement to standard radiography in acute acromioclavicular trauma. PMID- 27236816 TI - One-stop shop assessment for atrial septal defect closure using 256-slice coronary CT angiography. AB - OBJECTIVES: To investigate the feasibility and accuracy of measurement of the pulmonary to systemic blood flow ratio (Qp/Qs) and defect and rim sizes in secundum atrial septal defects (ASDs) using 256-slice CT, compared to the reference transoesophageal echocardiography (TEE) and right heart catheterization (RHC) measurements. METHODS: Twenty-three consecutive adult patients with secundum ASDs who underwent retrospective ECG-gated coronary CT angiography (CCTA), TEE and RHC were enrolled in this study. Right ventricular (RV) and left ventricular (LV) stroke volumes (SV) were calculated by biventricular volumetry of CCTA. Qp/Qs-CT was defined as RVSV/LVSV. The sizes of the defect and rim were measured by multi-planar reconstruction CT images. Correlations between Qp/Qs-CT and Qp/Qs-RHC and between the defect diameter obtained by CT and TEE were analyzed by Pearson's coefficient analysis. Rim sizes by CT and TEE were compared by paired t-test. RESULTS: Qp/Qs-CT was significantly correlated with Qp/Qs-RHC (r = 0.83, p < 0.0001), and the defect diameter by CT was significantly correlated with that by TEE (r = 0.95, p < 0.0001). There was no significant difference between CT and TEE in measurements of rim size. CONCLUSIONS: 256-slice CCTA allows measuring Qp/Qs and size of defects and rims in patients with secundum ASDs, accomplishing pretreatment evaluation non-invasively and comprehensively. KEY POINTS: * Quantification of left-to-right shunting can be performed reliably and accurately by CT. * The sizes of defects and rims can be measured accurately using 256-slice CT. * 256-slice CT permits pretreatment evaluation of ASD non-invasively and comprehensively. PMID- 27236815 TI - Quantitative ultrasound mapping of regional variations in shear wave speeds of the aging Achilles tendon. AB - OBJECTIVES: Evaluate the effects of aging on healthy Achilles tendon and aponeurosis shear wave speed (SWS), a quantitative metric which reflects tissue elasticity. METHODS: Shear wave elastography was used to measure spatial variations in Achilles tendon SWS in healthy young (n = 15, 25 +/- 4 years), middle-aged (n = 10, 49 +/- 4 years) and older (n = 10, 68 +/- 5 years) adults. SWS was separately measured in the free Achilles tendon, soleus aponeurosis and gastrocnemius aponeurosis in resting (R), stretched (dorsiflexed 15 degrees from R) and slack (plantarflexed 15 degrees from R) postures. RESULTS: SWS significantly increased with stretch and varied with age in all tendon regions. Slack free tendon SWS was significantly higher in older adults than young adults (p = 0.025). However, stretched soleus aponeurosis SWS was significantly lower in older adults than young adults (p = 0.01). Stretched gastrocnemius aponeurosis SWS was significantly lower in both middle-aged (p = 0.003) and older (p = 0.001) adults, relative to younger adults. CONCLUSION: These results suggest that aging alters spatial variations in Achilles tendon elasticity, which could alter deformations within the triceps surae muscle-tendon units, thus affecting injury potential. The observed location- and posture-dependent variations highlight the importance of controlling ankle posture and imaging location when using shear wave approaches clinically to evaluate tendon disorders. KEY POINTS: * Shear wave elastography shows promise as a clinical quantitative ultrasound-based technique. * Aging induces location-dependent changes in Achilles tendon shear wave speed. * Spatial and postural dependence necessitates careful integration of this approach clinically. PMID- 27236817 TI - Comparison of visibility of circumscribed masses on Digital Breast Tomosynthesis (DBT) and 2D mammography: are circumscribed masses better visualized and assured of being benign on DBT? AB - OBJECTIVE: To compare the visibility of circumscribed masses on digital breast tomosynthesis (DBT) images and 2D mammograms and determine the usefulness of DBT for differentiation between benign and malignant circumscribed masses. METHODS: Seventy-one (19 malignant and 52 benign) mammographic well-circumscribed masses were included. Visibility of the masses and halo signs on DBT images were retrospectively compared with 2D mammograms. The effects of mammographic breast density on mass visibility were also evaluated. RESULTS: For DBT, 83% were superior and 17% were equivalent in visibility of the masses to that of 2D, and superiority of DBT was significantly enhanced in the high breast density group compared with the low breast density group (91% vs 68%, respectively, p = 0.016). Three lesions were only detected on DBT. There was no significant difference in the superiority of DBT for lesion visibility between malignant and benign masses. The halo sign was detected in 58% lesions on DBT and in 4% on 2D (p < 0.001). CONCLUSION: Circumscribed masses were better visualized on DBT than on 2D mammograms, particularly in high-density breasts. The halo sign often appeared on DBT and gave a clearer mass margin. However, circumscribed masses on DBT are not assured of being benign. KEY POINTS: * Circumscribed masses were better visualized on breast tomosynthesis than on 2D mammography. * Tomosynthesis visualized circumscribed masses better than 2D for all breast density categories. * Halo signs often appeared on tomosynthesis and contributed to detect circumscribed margins. * Circumscribed masses on tomosynthesis images are not assured of being benign lesions. PMID- 27236819 TI - Factors associated with quality of life of caregivers of Mexican cancer patients. AB - PURPOSE: To evaluate factors associated with a poor quality of life (QoL) of caregivers of Mexican cancer patients. METHODS: This is a secondary analysis of a cross-sectional survey of 826 primary caregivers of adult cancer patients at the Oncology Hospital of the Mexican Institute of Social Security. Dependent variables were physical composite score (PCS) and mental composite score (MCS) of QoL of caregivers measured by the Short Form (SF-12) of Medical Outcomes Survey questionnaire. Independent variables included general characteristics of the caregivers, their unmet needs, caregiving and characteristics of cancer patients. Multiple linear regression analysis for each QoL composite score was carried out. RESULTS: The average PCS was 48.7 and MCS was 47.1. Lower PCS was associated with older age, symptoms of chronic illness, depression and unmet personal needs, while concerns about the future were associated with higher physical QoL. Lower MCS was associated with anxiety, depression, unmet personal and emotional needs, and surgery in the last month. Caring for patients with a high global health status was associated with a higher MCS. CONCLUSION: Information about caregivers' QoL and its associated factors is important in order to identify and address modifiable factors. Also, studies from different cultures like Mexico are essential in order to identify possible generalities and particularities in QoL and its associated factors. Given the limitations of the cross-sectional design of our study, future longitudinal studies on the changes of Mexican caregivers' quality of life and their determinants will be an important step to further understanding these phenomena. PMID- 27236821 TI - Implementing an ED Critical Incident Stress Management Team. PMID- 27236818 TI - Value of a noise-optimized virtual monoenergetic reconstruction technique in dual energy CT for planning of transcatheter aortic valve replacement. AB - OBJECTIVES: To evaluate objective and subjective image quality of a noise optimized virtual monoenergetic imaging (VMI+) reconstruction technique in dual energy computed tomography (DECT) angiography prior to transcatheter aortic valve replacement (TAVR). METHODS: Datasets of 47 patients (35 men; 64.1 +/- 10.9 years) who underwent DECT angiography of heart and vascular access prior to TAVR were reconstructed with standard linear blending (F_0.5), VMI+, and traditional monoenergetic (VMI) algorithms in 10-keV intervals from 40-100 keV. Signal-to noise ratio (SNR) and contrast-to-noise ratio (CNR) of 564 arterial segments were evaluated. Subjective analysis was rated by three blinded observers using a Likert scale. RESULTS: Mean SNR and CNR were highest in 40 keV VMI+ series (SNR, 27.8 +/- 13.0; CNR, 26.3 +/- 12.7), significantly (all p < 0.001) superior to all VMI series, which showed highest values at 70 keV (SNR, 18.5 +/- 7.6; CNR, 16.0 +/- 7.4), as well as linearly-blended F_0.5 series (SNR, 16.8 +/- 7.3; CNR, 13.6 +/- 6.9). Highest subjective image quality scores were observed for 40, 50, and 60 keV VMI+ reconstructions (all p > 0.05), significantly superior to all VMI and standard linearly-blended images (all p < 0.01). CONCLUSIONS: Low-keV VMI+ reconstructions significantly increase CNR and SNR compared to VMI and standard linear-blending image reconstruction and improve subjective image quality in preprocedural DECT angiography in the context of TAVR planning. KEY POINTS: * VMI+ combines increased contrast with reduced image noise. * VMI+ shows substantially less image noise than traditional VMI. * 40-keV reconstructions show highest SNR/CNR of the aortic and iliofemoral access route. * Observers overall prefer 60 keV VMI+ images. * VMI+ DECT imaging helps improve image quality for TAVR planning. PMID- 27236820 TI - Inhibition of p90 ribosomal S6 kinase attenuates cell migration and proliferation of the human lung adenocarcinoma through phospho-GSK-3beta and osteopontin. AB - p90 ribosomal S6 kinase (p90RSK) constitutes a family of serine/threonine kinases that have been shown to be involved in cell proliferation of various malignancies via direct or indirect effects on the cell-cycle machinery. We investigated the role of p90RSK in lung adenocarcinomas and whether the inhibition of p90RSK diminishes cancer progression. Moreover, we investigated the involvement of glycogen synthase kinase-3beta (GSK-3beta) and osteopontin (OPN) in the p90RSK induced lung adenocarcinoma progression. p90RSK, OPN, and GSK-3beta protein expressions were examined in the A549 human lung adenocarcinoma cell line in the presence and absence of BI-D1870 (BID), a p90RSK inhibitor. Gene expression of anti-apoptotic and pro-apoptotic markers namely Bcl2 and Bax, respectively, were studied by reverse transcription polymerase chain reaction. In addition, the A549 lung adenocarcinoma cell line was characterized for cell proliferation using the MTT assay and cell migration using the scratch migration assay. Our study revealed that total RSK1 protein expression is over expressed in the A549 human lung adenocarcinoma cell line, an effect which is significantly reduced upon pretreatment with BID (69.32 +/- 12.41 % of control; P < 0.05). The inhibition of p90RSK also showed a significant suppression of cell proliferation (54.3 +/- 6.73 % of control; P < 0.01) and cell migration (187.90 +/- 16.10 % of control; P < 0.01). Treatment of the A549 cells with BID regressed the expression of Bcl2 mRNA (56.92 +/- 6.07 % of control; P < 0.01). BID also regressed protein expression of OPN (79.57 +/- 5.32 % of control; P < 0.05) and phospho-GSK-3beta (73.04 +/- 8.95 % of control; P < 0.05). The p90RSK has an essential role in promoting tumor growth and proliferation in non-small cell lung cancer (NSCLC). BID may serve as an alternative cancer treatment in NSCLC. PMID- 27236822 TI - Quest for Excellence: Taking C.A.R.E. of the Psychiatric Emergency Patient. PMID- 27236823 TI - This bud's for you: mechanisms of cellular nucleocytoplasmic trafficking via nuclear envelope budding. AB - The nuclear envelope (NE) physically separates the cytoplasmic and nuclear compartments. While this barrier provides advantages, it also presents a challenge for the nuclear export of large ribonucleoprotein (RNP) complexes. Decades-old dogma holds that all such border-crossing is via the nuclear pore complex (NPC). However, the diameter of the NPC central channel limits the passage of large cargos. Here, we review evidence that such large RNPs employ an endogenous NE-budding pathway, previously thought to be exclusive to the nuclear egress of Herpes viruses. We discuss this and other models proposed, the likelihood that this pathway is conserved, and the consequences of disrupting NE budding for synapse development, localized translation of synaptic mRNAs, and laminopathies inducing accelerated aging. PMID- 27236825 TI - The best of both worlds: reaping the benefits from mammalian and bacterial therapeutic circuits. AB - Synthetic biology has revolutionized the field of biology in the last two decades. By taking apart natural systems and recombining engineered parts in novel constellations, it has not only unlocked a staggering variety of biological control mechanisms but it has also created a panoply of biomedical achievements, such as innovative diagnostics and therapies. The most common mode of action in the field of synthetic biology is mediated by synthetic gene circuits assembled in a systematic and rational manner. This review covers the most recent therapeutic gene circuits implemented in mammalian and bacterial cells designed for the diagnosis and therapy of an extensive array of diseases. Highlighting new tools for therapeutic gene circuits, we describe a future that holds a plethora of potentialities for the medicine of tomorrow. PMID- 27236824 TI - Depth of anaesthesia monitoring during procedural sedation and analgesia: A systematic review and meta-analysis. AB - OBJECTIVES: Processed electroencephalogram-based depth of anaesthesia monitoring devices provide an additional method to monitor level of consciousness during procedural sedation and analgesia. The objective of this systematic review was to determine whether using a depth of anaesthesia monitoring device improves the safety and efficacy of sedation. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Electronic databases (CENTRAL; Medline; CINAHL) were searched up to May 2015. REVIEW METHODS: Randomised controlled trials that compared use of a depth of anaesthesia monitoring device to a control group who received standard monitoring during procedural sedation and analgesia were included. Study selection, data extraction and risk of bias assessment (Cochrane risk of bias tool) were performed by two reviewers. Safety outcomes were hypoxaemia, hypotension and adverse events. Efficacy outcomes were amount of sedation used, duration of sedation recovery and rate of incomplete procedures. RESULTS: A total of 16 trials (2138 participants) were included. Evidence ratings were downgraded to either low or moderate quality due to study limitations and imprecision. Meta analysis of 8 trials (766 participants) found no difference in hypoxaemia (RR 0.87; 95% CI=0.67-1.12). No statistically significant difference in hypotension was observed in meta-analysis of 8 trials (RR 0.96; 95% CI=0.54-1.7; 942 participants). Mean dose of propofol was 51mg lower for participants randomised to depth of anaesthesia monitoring (95% CI=-88.7 to -13.3mg) in meta-analysis of results from four trials conducted with 434 participants who underwent interventional endoscopy procedures with propofol infusions to maintain sedation. The difference in recovery time between depth of anaesthesia and standard monitoring groups was not clinically significant (standardised mean difference 0.41; 95% CI=-0.8 to -0.02; I2=86%; 8 trials; 809 participants). CONCLUSIONS: Depth of anaesthesia monitoring did impact sedation titration during interventional procedures with propofol infusions. For this reason, it seems reasonable for anaesthetists to utilise a depth of anaesthesia monitoring device for select populations of patients if it is decided that limiting the amount of sedation would be beneficial for the individual patient. However, there is no need to invest in purchasing extra equipment or training staff who are not familiar with this technology (e.g. nurses who do not routinely use a depth of anaesthesia monitoring device during general anaesthesia) because there is no high quality evidence suggestive of clear clinical benefits for patient safety or sedation efficacy. PMID- 27236826 TI - Role of adiponectin gene variants, adipokines and hydrometry-based percent body fat in metabolically healthy and abnormal obesity. AB - OBJECTIVE: Metabolically healthy obesity (MHO) subjects have better metabolic parameters than metabolically abnormal obesity (MAO) subjects, but the possible mechanisms underlying this remain unknown. Our study was designed to investigate the interrelationships among genes, adipokines, body fat and its distribution in MHO and MAO. METHODS: From 2007 to 2009, 103 males and 131 females aged 18-50 years were enrolled by an intention-to-treat design in a weight management clinic. Participants were divided into MHO and MAO groups. Percent body fat (PBF) was measured by a deuterium oxide dilution method. Four polymorphic variants, including PPARgamma2 (Pro12Ala and C1431T) and adiponectin (T45G and G276T) genes, and three adipokines (adiponectin, leptin and resistin) were obtained. RESULTS: Of the 234 obese subjects, 130 (55.6%) were MHO. In the univariate analysis, the MAO group has significantly higher anthropometric, metabolic indices and leptin levels than the MHO group. Logistic regression analysis revealed that age, male gender, the T allele of adiponectin T45G polymorphism, leptin and PBF were positively associated with MAO. ANCOVA analysis revealed that the T allele of adiponectin T45G polymorphism was associated with higher fasting and postprandial glucose levels. We further found that TT genotype has a lower high molecular weight (HMW)/low molecular weight (LMW) adiponectin ratio than GG genotype. CONCLUSIONS: The factors associated with MAO are age, male gender, the T allele of adiponectin T45G polymorphism, leptin, and PBF. The net effects of T45G polymorphism on the MAO phenotype may be achieved by changes in the adiponectin oligomer ratio and glucose levels. PMID- 27236827 TI - The human gut microbiome impacts health and disease. AB - The human gut microbiome can now be characterized in unprecedented detail by an approach based on high-throughput sequencing of total stool DNA, that we name quantitative metagenomics. Central to the approach is a catalog that lists all the genes of intestinal microbes that are known - 9.9 millions, identified by the analysis of 1267 stool samples. Beyond the gene list, genetic units that carry them begun to be known; many of these correspond to bacterial species that were never isolated and cultured yet. Quantitative metagenomics allows developing powerful algorithms to diagnose a disease, monitor patients and identify individuals at risk to progress towards a disease. This lays ground for developing new approaches to better restore and even preserve the health by modulation of the altered microbiome, which contributes to promote or aggravate a disease. PMID- 27236828 TI - The origin and evolution of the sexes: Novel insights from a distant eukaryotic linage. AB - Sexual reproduction is an extraordinarily widespread phenomenon that assures the production of new genetic combinations in nearly all eukaryotic lineages. Although the core features of sexual reproduction (meiosis and syngamy) are highly conserved, the control mechanisms that determine whether an individual is male or female are remarkably labile across eukaryotes. In genetically controlled sexual systems, gender is determined by sex chromosomes, which have emerged independently and repeatedly during evolution. Sex chromosomes have been studied in only a handful of classical model organism, and empirical knowledge on the origin and evolution of the sexes is still surprisingly incomplete. With the advent of new generation sequencing, the taxonomic breadth of model systems has been rapidly expanding, bringing new ideas and fresh views on this fundamental aspect of biology. This mini-review provides a quick state of the art of how the remarkable richness of the sexual characteristics of the brown algae is helping to increase our knowledge about the evolution of sex determination. PMID- 27236829 TI - Recombinant bone morphogenetic protein in patients under 18 years of age. PMID- 27236831 TI - Phase structuring in metal alloys: Ultrasound-assisted top-down approach to engineering of nanostructured catalytic materials. AB - High intensity ultrasound (HIUS) is a novel and efficient tool for top-down nanostructuring of multi-phase metal systems. Ultrasound-assisted structuring of the phase in metal alloys relies on two main mechanisms including interfacial red/ox reactions and temperature driven solid state phase transformations which affect surface composition and morphology of metals. Physical and chemical properties of sonication medium strongly affects the structuring pathways as well as morphology and composition of catalysts. HIUS can serve as a simple, fast, and effective approach for the tuning of structure and surface properties of metal particles, opening the new perspectives in design of robust and efficient catalysts. PMID- 27236830 TI - Complications with allogeneic, cancellous bone blocks in vertical alveolar ridge augmentation: prospective clinical case study and review of the literature. AB - OBJECTIVES: Vertical bone augmentation in dental implantology is an indication for cancellous allogeneic bone blocks (ABB). However, these materials may lead to adverse reactions, which are known well in orthopedics but rarely published. Therefore, in this study, we performed an evaluation of the use of ABB in vertical bone augmentation in clinical dental implantology. STUDY DESIGN: The prospective clinical study included 20 cases with vertical augmentation using ABB and subsequent or simultaneous placement of implants in the lateral maxilla and mandible. Follow-up included panoramic radiography, tissue healing, and peri implantitis. Because of the limited number of patients, the report was planned to be descriptive only. Loss of ABB or peri-implantitis of more than 30% of the intraosseous implant length was deemed to indicate failure. RESULTS: The study was cancelled after six cases because of an unexpectedly high number of complications (5 of 6; 83%). The average surveillance time was 1460 days. Three types of unsatisfying outcome were observed: type I, early complete loss of the augmentation with soft tissue defects after 3 to 8 weeks (n = 2); type II, early soft tissue maceration (up to 8 weeks) without loss of coverage and complete early bone healing with later peri-implantitis and bone loss after prosthetic loading (6 months or later; n = 2); and type III, complication-free bone healing with subsequent peri-implantitis after prosthetic loading (6 months or later; n = 1). CONCLUSIONS: Complications were observed in vertical augmentation with ABB and implant placement. After careful consideration, literature data were found to support these results and also suggest that tissue level implants may be advantageous in vertical bone augmentation with ABB. PMID- 27236832 TI - Accelerator-based production of the (99m)Tc-(186)Re diagnostic-therapeutic pair using metal disulfide targets (MoS2, WS2, OsS2). AB - Novel, natural abundance metal disulfide targets were irradiated for 1h with a 10uA proton beam in a small, medical cyclotron. Osmium disulfide was synthesized by simple distillation and precipitation methods while MoS2 and WS2 were commercially available. The targets dissolved under mild conditions and were analyzed by gamma-spectroscopy. Production rates and potential applications are discussed, including target recovery and recycling schemes for OsS2 and WS2. PMID- 27236833 TI - (60)Co in cast steel matrix: A European interlaboratory comparison for the characterisation of new activity standards for calibration of gamma-ray spectrometers in metallurgy. AB - Two series of activity standards of (60)Co in cast steel matrix, developed for the calibration of gamma-ray spectrometry systems in the metallurgical sector, were characterised using a European interlaboratory comparison among twelve National Metrology Institutes and one international organisation. The first standard, consisting of 14 disc shaped samples, was cast from steel contaminated during production ("originally"), and the second, consisting of 15 similar discs, from artificially-contaminated ("spiked") steel. The reference activity concentrations of (60)Co in the cast steel standards were (1.077+/-0.019) Bqg(-1) on 1 January 2013 12h00 UT and (1.483+/-0.022) Bqg(-1) on 1 June 2013 12h00 UT, respectively. PMID- 27236834 TI - An improved formula for determination of the activity via the sum-peak method. AB - The sum-peak method principally enables determination of the absolute activity of gamma cascade emitting sources based only on the use of spectral data, without knowledge of the detector efficiencies. However, to achieve better accuracy of the activity results, corrections due to pile-up, accidental coincidences, electronic noise and angular correlations must be introduced into the proposed method. Such corrections usually require the collection of a few gamma spectra and additional extrapolations, thereby further complicating the experimental procedures. In this paper, it is shown that by using pile-up peaks for corrections of accidental coincidences, Monte Carlo techniques for angular correlation, and LLD corrections, the source activity can be measured with accuracy and reproducibility below 1% using only one gamma spectrum, without any additional extrapolations. PMID- 27236836 TI - Esophageal compression by an aberrant right subclavian artery in an elderly patient with aspiration pneumonia. PMID- 27236835 TI - National survey on the activity of internists in shared care-interconsultations in spanish hospitals. AB - OBJECTIVES: To analyse the activity of interconsultations conducted by the departments of internal medicine, communicating their importance to managers and offering information to these departments to improve their organisation. METHODS: A cross-sectional study was conducted using an interconsultation activity survey (on-demand consulting activity for other departments) and shared care (consulting activity provided in a regulated manner to other departments). RESULTS: We received 120 surveys that corresponded to 108 public and 12 private hospitals. Forty-five percent of the surveyed hospitals had a specialised interconsultation unit, and 31% had shared care. The department most frequently helped by the presence of a stable consultation unit (65% of the cases) was orthopaedic and trauma surgery. Fifty-five percent of the departments of internal medicine surveyed had an interconsultation activity record since the start of their activity. Ninety-two percent of the departments lacked a protocol that regulated interconsultations, and in 74% of the cases, the interconsultation was on demand. CONCLUSIONS: The interconsultation activity is generalised in the departments of internal medicine, but only 45% of these departments have interconsultation units, and only 33% provide the shared care modality. The survey reflects the shortcomings of training and some confusion in the concept of interconsultations. The considerable majority of departments lack organisational interconsultation protocols. PMID- 27236837 TI - Characterization of pharmaceutically active compounds in Beijing, China: Occurrence pattern, spatiotemporal distribution and its environmental implication. AB - Pharmaceutically active compounds (PhACs) as an important group of "emerging contaminants" (ECs), have been highlighted and received global attentions in last decade. China has tremendous consumption of PhACs and the most pharmaceutical manufacturers worldwide. In this study, 33 PhACs (19 antibiotics included) were monitored in the Beiyun River basin in Beijing, China. The seasonal occurrence, temporal-spatial distribution and potential source were investigated. The total levels were about 2MUgL-1. Non-antibiotics were more frequently detected. The highest median concentrations were observed for caffeine (558ngL-1) and erythromycin (319ngL-1). Acetaminophen, erythromycin, diclofenac and N,N-diethyl meta-toluamide showed highly significant seasonal variation, while caffeine, carbamazepine, metoprolol and most sulfonamides were more stable. The burden was most heavy in Qing River in both seasons (up to 4MUgL-1). Antibiotics from veterinary use accounted for minor contribution in this region. The characteristics and trends were overviewed by comparing with our previous survey. The total level of 15 PhACs dropped significantly by 37% on average from 2013 to 2015. The proportion of caffeine, once a major component in 2013, reduced from 77% to 47%. The burden of these ECs in surface water of Beijing is remarkably reduced, suggesting the overall situation has been improving. PMID- 27236838 TI - Extending surfactant-modified 2:1 clay minerals for the uptake and removal of diclofenac from water. AB - The presence and persistency of pharmaceuticals and personal care products (PPCPs) in the environment attracted great attention recently. Among them, antibiotics and pain-killers accounted for a large quantity. Although many works were devoted to the investigation of their removal in wastewater treatment processes, most of the PPCPs studied were of cationic nature. The net repulsive interactions between anionic PPCPs and negatively charged sorbents make them difficult to be removed in wastewater treatment. In this study, 2:1 clay minerals illite and montmorillonite (MMT) were modified with different amounts of cationic surfactant cetyltrimethylammoium bromide (CTAB). The types and sites of interactions between the surfactant-modified clays and the anionic drug diclofenac (DC) were investigated. The uptake of DC on the modified clays was controlled by the CTAB loading level and its surface configuration on the clays. The adsorption sites of DC were limited to the external surfaces of modified illite due to its non-swelling nature. On the contrary, both the external and interlayer sites were available for the adsorption of DC on modified MMT. A CTAB bilayer formation resulted in significant increase in DC adsorption due to the formation of extensive admicelles. FTIR results showed participation of the benzene ring, NH, and CH2CH3 for the interactions between DC and modified MMT, suggesting that partitioning of DC into the admicelles of CTAB played a significant role in DC uptake. The results could extend the application of surfactant-modified clays for the removal of anionic PPCPs in the wastewater treatment processes. PMID- 27236839 TI - On the role of a coumarin derivative for sensing applications: Nucleotide identification using a micellar system. AB - The recognition of nucleotides is of crucial importance because they are the basic constituents of nucleic acids. The present study is focused on the selective interaction between a novel amphiphilic fluorophore containing coumarin and imidazole, CI (1-methyl-3-(12-((2-oxo-2H-chromen-7-yl)oxy)dodecyl)-1H imidazol-3-ium bromide), and different nucleotide-monophosphates (NMPs). It was supposed that the solubilization of the low water soluble CI in a micelle system of hexadecyltrimethylammonium chloride (CTAC) would make the coumarin moiety of CI available to the interaction with the water-soluble NMPs. Changes in CTAC critical micelle concentration suggested that CI strongly interacted with the host cationic surfactant, thus forming a positively charged interface enriched with coumarin able to interact with the anionic NMPs. Steady-state fluorescence quenching revealed that CI/CTAC system was capable of distinguish between purine- and pyrimidine-based nucleotides. A modified Stern-Volmer equation permitted the use of a quenching model that accounted for the possible interactions between the micelles and the nucleotides. The data analysis allowed calculating selective parameters that differentiated according to the type of nucleotide either at 25 or 50 degrees C. Our results established the utility of the novel coumarin derivative fluorophore, supported by the simple and suitable micellar systems, as a tool for DNA sensing applications. PMID- 27236840 TI - The surface state of hematite and its wetting characteristics. AB - Apart from being a resource for iron/steel production, the iron oxide minerals, goethite and hematite, are used in the paint, cosmetics, and other industries as pigments. Surface characteristics of these minerals have been studied extensively both in resource recovery by flotation and in the preparation of colloidal dispersions. In this current research, the wetting characteristics of goethite (FeOOH) and hematite (Fe2O3) have been analyzed by means of contact angle, bubble attachment time, and Atomic Force Microscopy (AFM) measurements as well as by Molecular Dynamics Simulation (MDS). Goethite is naturally hydroxylated and wetted by water at all pH values. In contrast, the anhydrous hematite surface (001) was found to be slightly hydrophobic at natural pH values with a contact angle of about 50 degrees . At alkaline pH hydroxylation of the hematite surface occurs rapidly and the hematite becomes hydrophilic. The wetting characteristics of the hematite surface then vary between the hydrophobic anhydrous hematite and the completely hydrophilic hydroxylated hematite, similar to goethite. The hydrophobicity can be restored by heating of the hydroxylated hematite surface at 60 degrees C. The hydrophobic character of the anhydrous hematite (001) surface is confirmed by MDS which also reveals that after hydrolysis the hematite (001) surface can be wetted by water, similar to the goethite (001) surface. PMID- 27236841 TI - A facile and rapid room-temperature route to hierarchical bismuth oxyhalide solid solutions with composition-dependent photocatalytic activity. AB - The unique nanosheet-based flower-like BiOCl1-xBrx (x=0-1) hierarchical solid solutions have been prepared by the reaction of Bi2O3 and KCl/KBr in mixed solution of glacial acetic acid (HAc) and H2O in dozens of minutes under ambient conditions. During the preparation process, the intermediate bismuth oxide acetate (CH3COOBiO) plays a key role in the formation of BiOCl1-xBrx solid solutions in such a short time. The as-prepared hierarchical BiOCl1-xBrx solid solutions possess high specific surface areas and modified band structures, which exhibit enhanced photocatalytic activity for Rhodamine B (RhB) degradation in comparison with pure BiOCl and BiOBr under visible light irradiation, with the activity reaching the maximum at x=0.5. The photodegradation efficiency of the BiOCl0.5Br0.5 solid solution is twice and 12times higher than P25 TiO2 under UV and visible light irradiation, respectively. PMID- 27236842 TI - Down shifting in poly(vinyl alcohol) gels doped with terbium complex. AB - Novel poly(vinyl alcohol) (PVA) based soft gels with luminescent properties are detailed in this contribution. Lanthanide complex of terbium ions with anthranilic acid, Tb(ant)3.2H2O, was synthesized and incorporated into a DMSO/water solution, followed by addition of PVA, to attain soft gels at room temperature. Morphological and thermal analyses revealed homogeneous distribution of Tb(ant)3.2H2O into the PVOH/DMSO/water gel, and that incorporation of the terbium complex does not alter the thermal properties of the gels. The gels are transparent and luminescent, as they exhibit Large Stokes shift down shifting (LSS DS) up to 400nm, with very high emission quantum yield, that was found to be function of Tb complex concentration. PMID- 27236843 TI - Clinical epidemiology and resistance mechanisms of carbapenem-resistant Acinetobacter baumannii, French Guiana, 2008-2014. AB - This study investigated the clinical epidemiology and resistance mechanisms of Acinetobacter baumannii and characterised the clonal diversity of carbapenem resistant A. baumannii (CRAB) during an ICU-associated outbreak at Cayenne Hospital, French Guiana. All non-duplicate A. baumannii isolates from 2008 to 2014 were tested for antibiotic susceptibility by disk diffusion. Multilocus sequence typing, pulsed-field gel electrophoresis (PFGE) and characterisation of carbapenemase-encoding genes were performed on CRAB. Of the 441 A. baumannii isolates, most were from males (54.0%) and were detected mainly from the ICU (30.8%) and medicine wards (21.8%). In the ICU, strains were mainly isolated from the respiratory tract (44.1%) and bloodstream (14.0%), whereas in medicine wards they mainly were from wound/drainage (36.5%) and bloodstream (25.0%). A. baumannii showed the greatest susceptibility to piperacillin/tazobactam (92.7%), imipenem (92.5%), colistin (95.6%) and amikacin (97.2%), being lower in the ICU and medicine wards compared with other wards. An outbreak of OXA-23-producing CRAB occurred in the 13-bed ICU in 2010. CRAB strains were more co-resistant to other antimicrobials compared with non-CRAB. Molecular genetics analysis revealed five sequence types [ST78, ST107 and ST642 and two new STs (ST830 and ST831)]. Analysis of PFGE profiles indicated cross-transmissions of CRAB within the ICU, between the ICU and one medicine ward during transfer of patients, and within that medicine ward. This study provides the first clinical and molecular data of A. baumannii from French Guiana and the Amazon basin. The ICU was the highest risk unit of this nosocomial outbreak of OXA-23-producing CRAB, which could subsequently disseminate within the hospital. PMID- 27236844 TI - Dual targeting luminescent gold nanoclusters for tumor imaging and deep tissue therapy. AB - Dual targeting towards both extracellular and intracellular receptors specific to tumor is a significant approach for cancer diagnosis and therapy. In the present study, a novel nano-platform (AuNC-cRGD-Apt) with dual targeting function was initially established by conjugating gold nanocluster (AuNC) with cyclic RGD (cRGD) that is specific to alphavbeta3integrins over-expressed on the surface of tumor tissues and aptamer AS1411 (Apt) that is of high affinity to nucleolin over expressed in the cytoplasm and nucleus of tumor cells. Then, AuNC-cRGD-Apt was further functionalized with near infrared (NIR) fluorescence dye (MPA), giving a NIR fluorescent dual-targeting probe AuNC-MPA-cRGD-Apt. AuNC-MPA-cRGD-Apt displays low cytotoxicity and favorable tumor-targeting capability at both in vitro and in vivo level, suggesting its clinical potential for tumor imaging. Additionally, Doxorubicin (DOX), a widely used clinical chemotherapeutic drug that kill cancer cells by intercalating DNA in cellular nucleus, was immobilized onto AuNC-cRGD-Apt forming a pro-drug, AuNC-DOX-cRGD-Apt. The enhanced tumor affinity, deep tumor penetration and improved anti-tumor activity of this pro drug were demonstrated in different tumor cell lines, tumor spheroid and tumor bearing mouse models. Results in this study suggest not only the prospect of non toxic AuNC modified with two targeting ligands for tumor targeted imaging, but also confirm the promising future of dual targeting AuNC as a core for the design of prodrug in the field of cancer therapy. PMID- 27236845 TI - A visible-light-driven core-shell like Ag2S@Ag2CO3 composite photocatalyst with high performance in pollutants degradation. AB - A series of Ag2S-Ag2CO3 (4%, 8%, 16%, 32% and 40% Ag2S), Ag2CO3@Ag2S (32%Ag2S) and Ag2S@Ag2CO3 (32%Ag2S) composite photocatalysts were fabricated by coprecipitation or successive precipitation reaction. The obtained catalysts were analyzed by N2 physical adsorption, powder X-ray diffraction, scanning electron microscopy, transmission electron microscopy, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, Raman spectroscopy, UV-vis diffuse reflectance spectroscopy and photocurrent test. Under visible light irradiation, the influences of Ag2S content and core-shell property on photocatalytic activity and stability were evaluated in studies focused on the degradation of methyl orange (MO) dye, phenol, and bisphenol A. Results showed that excellent photocatalytic performance was obtained over Ag2S/Ag2CO3 composite photocatalysts with respect to Ag2S and Ag2CO3. With optimal content of Ag2S (32 wt%), the Ag2S Ag2CO3 showed the highest photocatalytic degradation efficiency. Moreover, the structured property of Ag2S/Ag2CO3 greatly influenced the activity. Compared with Ag2S-Ag2CO3 and Ag2CO3@Ag2S, core-shell like Ag2S@Ag2CO3 demonstrated the highest activity and stability. The main reason for the boosting of photocatalytic performance was due to the formation of Ag2S/Ag2CO3 well contacted interface and unique electron structures. Ag2S/Ag2CO3 interface could significantly increase the separation efficiency of the photo-generated electrons (e(-)) and holes (h(+)), and production of OH radicals. More importantly, the low solubility of Ag2S shell could effectively protect the core of Ag2CO3, which further guarantees the stability of Ag2CO3. PMID- 27236847 TI - Enhanced methylene blue oxidative removal by copper electrode-based plasma irradiation with the addition of hydrogen peroxide. AB - Submerged plasma irradiation (SPI)-based advanced oxidation processes have been studied for the oxidation of recalcitrant organic compounds because of their various physical and chemical properties. However, SPI technologies still have a few drawbacks such as relatively low efficiency for wastewater treatment and high energy consumption. In order to overcome these drawbacks, in this study, we proposed the combination of SPI and the Cu(II)-catalyzed Fenton-like system. The removal of methylene blue (MB) by the SPI system was significantly enhanced upon the addition of H2O2. The pseudo-first-order rate constants of MB removal increased with the increase of applied voltage. In addition, the optimum H2O2 dose and initial solution pH were 100 mM and 9, respectively. The reactive oxidants responsible for MB removal in copper electrode-based SPI/H2O2 systems are likely to be hydroxyl radicals (OH) or cupryl ion (Cu(III)), wherein Cu(III) is especially important. Furthermore, the copper electrode-based SPI/H2O2 system is a novel advanced oxidation process capable of oxidizing water recalcitrant and toxic organic pollutants at neutral pH. PMID- 27236846 TI - Leaching heavy metals from the surface soil of reclaimed tidal flat by alternating seawater inundation and air drying. AB - Leaching experiments were conducted in a greenhouse to simulate seawater leaching combined with alternating seawater inundation and air drying. We investigated the heavy metal release of soils caused by changes associated with seawater inundation/air drying cycles in the reclaimed soils. After the treatment, the contents of all heavy metals (Cd, Pb, Cr, and Cu), except Zn, in surface soil significantly decreased (P < 0.05), with removal rates ranging from 10% to 51%. The amounts of the exchangeable, carbonate, reducible, and oxidizable fractions also significantly decreased (P < 0.05). Moreover, prolonged seawater inundation enhanced the release of heavy metals. Measurement of diffusive gradients in thin films indicated that seawater inundation significantly increased the re-mobility of heavy metals. During seawater inundation, iron oxide reduction induced the release of heavy metals in the reducible fraction. Decomposition of organic matter, and complexation with dissolved organic carbon decreased the amount of heavy metals in the oxidizable fraction. Furthermore, complexation of chloride ions and competition of cations during seawater inundation and/or leaching decreased the levels of heavy metals in the exchangeable fraction. By contrast, air drying significantly enhanced the concentration of heavy metals in the exchangeable fraction. Therefore, the removal of heavy metals in the exchangeable fraction can be enhanced during subsequent leaching with seawater. PMID- 27236848 TI - Dynamics of organohalide-respiring bacteria and their genes following in-situ chemical oxidation of chlorinated ethenes and biostimulation. AB - Application of Fenton's reagent and enhanced reductive dechlorination are currently the most common remediation strategies resulting in removal of chlorinated ethenes. In this study, the influence of such techniques on organohalide-respiring bacteria was assessed at a site contaminated by chlorinated ethenes using a wide spectrum of molecular genetic markers, including 16S rRNA gene of the organohalide-respiring bacteria Dehaloccocoides spp., Desulfitobacterium and Dehalobacter; reductive dehalogenase genes (vcrA, bvcA) responsible for dechlorination of vinyl chloride and sulphate-reducing and denitrifying bacteria. In-situ application of hydrogen peroxide to induce a Fenton-like reaction caused an instantaneous decline in all markers below detection limit. Two weeks after application, the bvcA gene and Desulfitobacterium relative abundance increased to levels significantly higher than those prior to application. No significant decrease in the concentration of a range of chlorinated ethenes was observed due to the low hydrogen peroxide dose used. A clear increase in marker levels was also observed following in-situ application of sodium lactate, which resulted in a seven-fold increase in Desulfitobacterium and a three-fold increase in Dehaloccocoides spp. after 70 days. An increase in the vcrA gene corresponded with increase in Dehaloccocoides spp. Analysis of selected markers clearly revealed a positive response of organohalide-respiring bacteria to biostimulation and unexpectedly fast recovery after the Fenton-like reaction. PMID- 27236850 TI - Evaluating the influence of prophylactic central neck dissection on TNM staging and the recurrence risk stratification of cN0 differentiated thyroid carcinoma. AB - OBJECTIVE: The purpose of this study was to explore the risk factors that were associated with central lymph node metastasis (CLNM) in patients with clinical nodal negative differentiated thyroid carcinoma (cN0 DTC) after prophylactic central neck dissection (pCND). The influence of pCND on TNM staging and recurrence risk stratification (RRS) in patients with cN0 DTC was also evaluated in our study. METHODS: A total of 153 cN0 DTC patients in Guangdong general hospital who underwent thyroidectomy with pCND from March 2014 to October 2014 were enrolled in this study. The relations of CLNM with clinicopathologic characteristics of cN0 DTC were analyzed by univariate and multivariate logistic regression. The influence of pCND on migration of TNM staging and RRS in cN0 DTC was observed. RESULTS: In the present study, CLNM was found in 42.5% (65 of 153 cases) of patients with cN0 DTC. On univariate analysis, the age less than 45 years old, tumor size more than 2cm, pT staging, and a total number of central lymph nodes dissected more than 3 were significantly associated with CLNM (P<0.05); however, gender, tumors affecting both lobes, multifocality, capsular invasion, and Hashimoto's thyroiditis were not related with CLNM (P>0.05). On multivariate logistic regression, age<45 years (P=0.001) and a total number of central lymph nodes dissected >3 (P=0.002) were significantly associated with CLNM. Because of the identification of CLNM in the implementation of pCND, 15 (9.8%) of 153 cN0 DTC patients were upgraded in TNM staging; all these patients were older than 45 years. Fifty-six patients (36.6%) developed higher RRS (from low to intermediate) after pCND. CONCLUSIONS: For younger patients (age<45 years), careful preoperative assessment of the lymph node status must be done; surgeons should consider this risk factor when deciding whether to perform pCND. Thorough lymphadenectomy in the implementation of pCND can avoid residual lymph node metastasis and help to increase the incidence of CLNM. pCND can indentify occult CLNM which allows more precise TNM staging (for patients with age>=45 years) and RRS. PMID- 27236849 TI - Rhabdovirus-like endogenous viral elements in the genome of Spodoptera frugiperda insect cells are actively transcribed: Implications for adventitious virus detection. AB - Spodoptera frugiperda (Sf) cell lines are used to produce several biologicals for human and veterinary use. Recently, it was discovered that all tested Sf cell lines are persistently infected with Sf-rhabdovirus, a novel rhabdovirus. As part of an effort to search for other adventitious viruses, we searched the Sf cell genome and transcriptome for sequences related to Sf-rhabdovirus. To our surprise, we found intact Sf-rhabdovirus N- and P-like ORFs, and partial Sf rhabdovirus G- and L-like ORFs. The transcribed and genomic sequences matched, indicating the transcripts were derived from the genomic sequences. These appear to be endogenous viral elements (EVEs), which result from the integration of partial viral genetic material into the host cell genome. It is theoretically impossible for the Sf-rhabdovirus-like EVEs to produce infectious virus particles as 1) they are disseminated across 4 genomic loci, 2) the G and L ORFs are incomplete, and 3) the M ORF is missing. Our finding of transcribed virus-like sequences in Sf cells underscores that MPS-based searches for adventitious viruses in cell substrates used to manufacture biologics should take into account both genomic and transcribed sequences to facilitate the identification of transcribed EVE's, and to avoid false positive detection of replication-competent adventitious viruses. PMID- 27236851 TI - LifeQuestionnaire. A new tool for the evaluation of quality of life in patients with hearing loss-using WhatsApp. AB - OBJECTIVE: Develop an online application that sends questions at different times of the day over an interval set by the user. It consists of a web interface that sends out WhatsApp messages containing questions from already validated or customized questionnaires (previous license) and shows the evolution of each question and patient over time and their average. MATERIAL AND METHOD: The Laboratory of Psychoacoustics developed a platform that allows patients to answer surveys from remote locations. RESULTS: Hence, the developed tool allows to: (1) answer a test repeatedly under different personal situations and (2) evaluate the patient remotely. Hence, obtaining a more reliable assessment of the patient's QoL. CONCLUSION: Preliminary results using 5 teenagers aged 12-18 that answered the KINDL questionnaire is used to evidence the value of this new tool. PMID- 27236852 TI - AHL, SSD and bimodal CI results in children. AB - OBJECTIVE: This article aims to demonstrate that children with asymmetric hearing loss (AHL), specifically those with single side deafness (SSD condition) and pure SSD, with substantial hearing (>70% normal speech discrimination) in the ear with hearing aid (HA), obtain clinically relevant speech perception benefit after cochlear implantation in the contralateral side. RESULTS: Retrospective study of two groups: (1) 36 AHL children with bimodal hearing and (2) SSD children with SSD. They had follow-ups of 24 and 12 months duration, respectively. The AHL children where implanted on one ear and depending on the contralateral ear condition, they were divided into two groups: children who reach a disyllabic speech test score lower than 50% in quiet at 65dB-SPL without lip reading (27) and children with test score higher than 70% (9). The second group consisted on 2 children implanted to obtain SSD condition, as preliminary data, with 1 year of follow-up. They showed benefits of binaural stimulation. CONCLUSION: Children in a bimodal situation, with substantial hearing (>70% speech discrimination) in the ear with HA, obtain clinically relevant speech perception benefit after cochlear implantation in the contralateral side. PMID- 27236853 TI - More than 15 minutes of resuscitation prior to termination of resuscitation results in undue harm to the public health. PMID- 27236854 TI - Ischemia modified albumin in cardiovascular disease. PMID- 27236855 TI - Postsplinting x-rays of nondisplaced hand, wrist, ankle, and foot fractures are unnecessary. AB - BACKGROUND: Acute nondisplaced fractures (NDFs) are common in the emergency department (ED), and providers often obtain postsplinting x-rays to identify displacement that potentially occurs during the splinting process. Our objectives are to (1) determine how often x-rays are obtained after splinting of NDFs, (2) identify if postsplinting x-rays change treatment management in the ED, and (3) identify if there are medical complications at follow-up. METHODS: A retrospective chart review of ED patients who were discharged with hand, wrist, ankle, or foot fractures was conducted to determine patients with definite NDFs that were verified by a radiologist, underwent splinting, and either had postsplint x-rays or not. Bone displacement during the splinting procedure was determined by the postsplint x-rays in the ED. Internal movement of bones or management change was also determined for patients who did not undergo postsplint x-rays in the ED but had obtained an x-ray at their follow-up visit (in-network providers only). RESULTS: Our results demonstrate that no patients required further manipulation or operative management due to the splinting that occurred in the ED. These results take into account both patients who had postsplint x rays conducted in the ED (27 patients) and those who received x-rays in follow-up consults (179 patients). There was minimal incidence of interval movement in the latter group (14 patients), none of which resulted in management change. CONCLUSION: These data conclude that postsplinting x-rays of NDFs are unnecessary. Removal of this procedure from routine practice will help decrease patient and hospital cost, time, and radiation exposure. PMID- 27236856 TI - Interrater agreement of emergency medicine milestone levels: resident self evaluation vs clinical competency committee consensus. PMID- 27236857 TI - Global maternal group B streptococcus colonisation. PMID- 27236858 TI - Prevalence of maternal colonisation with group B streptococcus: a systematic review and meta-analysis. AB - BACKGROUND: The most important risk factor for early-onset (babies younger than 7 days) invasive group B streptococcal disease is rectovaginal colonisation of the mother at delivery. We aimed to assess whether differences in colonisation drive regional differences in the incidence of early-onset invasive disease. METHODS: We did a systematic review of maternal group B streptococcus colonisation studies by searching MEDLINE, Embase, Pascal Biomed, WHOLIS, and African Index Medicus databases for studies published between January, 1997, and March 31, 2015, that reported the prevalence of group B streptococcus colonisation in pregnant women. We also reviewed reference lists of selected studies and contacted experts to identify additional studies. Prospective studies in which swabs were collected from pregnant women according to US Centers for Disease Control and Prevention guidelines that used selective culture methods were included in the analyses. We calculated mean prevalence estimates (with 95% CIs) of maternal colonisation across studies, by WHO region. We assessed heterogeneity using the I(2) statistic and the Cochran Q test. FINDINGS: 221 full-text articles were assessed, of which 78 studies that included 73 791 pregnant women across 37 countries met prespecified inclusion criteria. The estimated mean prevalence of rectovaginal group B streptococcus colonisation was 17.9% (95% CI 16.2-19.7) overall and was highest in Africa (22.4, 18.1-26.7) followed by the Americas (19.7, 16.7-22.7) and Europe (19.0, 16.1-22.0). Studies from southeast Asia had the lowest estimated mean prevalence (11.1%, 95% CI 6.8-15.3). Significant heterogeneity was noted across and within regions (all p<=0.005). Differences in the timing of specimen collection in pregnancy, selective culture methods, and study sample size did not explain the heterogeneity. INTERPRETATION: The country and regional heterogeneity in maternal group B streptococcus colonisation is unlikely to completely explain geographical variation in early-onset invasive disease incidence. The contribution of sociodemographic, clinical risk factor, and population differences in natural immunity need further investigation to understand these regional differences in group B streptococcus maternal colonisation and early-onset disease. FUNDING: None. PMID- 27236859 TI - Regulation of Bacterial Peptidoglycan Polymerization. AB - How bacterial cells control the activity of peptidoglycan polymerases has remained mysterious. Biochemical characterization of derivatives of penicillin binding protein PBP1b that are functional in the absence of lipoprotein LpoB provides evidence for allosteric control of PBP1b glycosyltransferase activity via binding of LpoB to the PBP1b UBH1 domain. PMID- 27236860 TI - RIG-I-Like Receptors: One STrEP Forward. AB - RIG-I-like receptors detect cytosolic viral RNA and activate an antiviral innate immune response. A new study employs the one STrEP-purification technique and next generation sequencing to characterize physiological ligands in an infected cell. The view of all three RLRs bound to viral RNAs shows specialization, collaboration and new binding sites. PMID- 27236861 TI - Prognostic value of preoperative von Willebrand factor plasma levels in patients with Glioblastoma. AB - Circulating biomarker for malignant gliomas could improve both differential diagnosis and clinical management of brain tumor patients. Among all gliomas, glioblastoma (GBM) is considered the most hypervascularized tumor with activation of multiple proangiogenic signaling pathways that enhance tumor growth. To investigate whether preoperative antigen plasma level of von Willebrand Factor (VWF:Ag) might be possible marker for GBM onset, progression, and prognosis, we retrospectively examined 57 patients with histological diagnosis for GBM and 23 meningiomas (MNGs), benign intracranial expansive lesions, enrolled as controls. Blood samples were collected from all the patients before tumor resection. Plasma von Willebrand Factor (VWF):Ag levels were determined by using a latex particle enhanced immunoturbidimetric assay. The median levels of vWF:Ag were significantly higher in GBMs than in meningiomas (MNGs) (183 vs. 133 IU/dL, P = 0.01). The cumulative 1-year survival was significantly shorter in patients with VWF:Ag levels >200 IU/dL than in those with levels <200 IU/dL and increased VWF levels were associated with a threefold higher risk of death in GBM patients. Our data suggest that VWF:Ag could be a circulating biomarker of disease malignancy, that could be considered, in association with other genetic and epigenetic factors, currently available in the GBM management. Future studies should investigate whether plasma VWF:Ag levels could also be used to monitor therapeutic effects and whether it may have a prognostic value. PMID- 27236862 TI - Analysis of Temporal Change in Voice Quality After Thyroidectomy: Single institution Prospective Study. AB - OBJECTIVES: This study analyzed the temporal changes of voice quality after thyroidectomy and assessed the predictive perioperative parameters of postthyroidectomy voice disorder (PTVD). STUDY DESIGN: This is a prospective cohort study. METHODS: From March 2011 to July 2014, 559 patients who underwent thyroidectomy with or without central neck dissection were prospectively enrolled. All patients underwent prospective voice evaluation using the subjective and objective comprehensive battery of assessments, preoperatively and postoperatively at 1 week, 1 month, 3 months, 6 months, and 12 months. RESULTS: Fundamental frequency (F0) was not significantly decreased during the postoperative follow-up. Maximal vocal pitch (MVP) and maximal intensity were not recovered, even at 1 year postoperatively, whereas the Grade, Roughness, Breathiness, Asthenia, Strain scale reached preoperative value at postoperative 3 6 months and voice handicap index at 1 year. Postoperative 1-month MVP was the best predictor for PTVD, and the cut-off value was 80% of preoperative value. Wide surgical extent and high preoperative F0 were the parameters that significantly correlated with PTVD (P = 0.021 and P < 0.001, respectively), and large tumor, higher preoperative MVP, and lower postoperative 1-month F0 were significantly associated with permanent PTVD (P = 0.028, P < 0.001, and P = 0.003, respectively). CONCLUSIONS: Different recovery patterns of voice parameters should be considered in preoperative counseling. Intensive voice therapy may be needed for patients with the ability to produce higher pitch than normal preoperatively and wide surgical extent. PMID- 27236863 TI - Tissue plasminogen activator for mediastinal tube clearance in pediatric chylous effusion: A case report. PMID- 27236864 TI - Intravenous acetaminophen analgesia after cardiac surgery: A randomized, blinded, controlled superiority trial. AB - BACKGROUND: Pain after cardiac surgery traditionally has been controlled by intravenous opioids and nonsteroidal antiinflammatory drugs. An intravenous analgesic with fewer adverse effects is needed. Therefore, we tested the primary hypothesis that intravenous acetaminophen is more effective than placebo for pain management, which was defined a priori as superior on either pain intensity score and/or opioid consumption and not worse on either. METHODS: In this single center, double-blind trial, 147 patients having cardiac surgery via median sternotomy were randomized to receive either 1 g of intravenous acetaminophen (73 patients) every 6 hours for 24 hours or comparable placebo (74 patients) starting in the operating room after sternal closure. Cumulative opioid consumption (in morphine equivalents) and pain intensity scores (on a 0-10 Numeric Rating Scale) were measured at 4, 6, 8, 12, 16, 20, and 24 hours after surgery. We estimated ratio of mean opioid consumption by using multivariable linear regression (noninferiority delta = 1.15) and pain score difference by using repeated measures regression (noninferiority delta = 1). RESULTS: Acetaminophen was superior to placebo on mean pain intensity scores and noninferior on opioid consumption, with estimated difference in mean pain (95% confidence interval) of 0.90 (-1.39, -0.42), P < .001 (superior), and estimated ratio of means in opioid consumption (90% confidence interval) of 0.89 (0.73-1.10), P = .28 (noninferior; not superior). CONCLUSIONS: Intravenous acetaminophen reduced pain after cardiac surgery, but not opioid consumption. Intravenous acetaminophen can be an effective analgesic adjunct in patients recovering from median sternotomy. PMID- 27236865 TI - Age-related differences of intraischemic gap junction uncoupling in hearts during ischemia. AB - OBJECTIVE: Myocardial ischemia leads to energetic, morphologic, metabolic, and functional alterations. To evaluate differences in ischemia tolerance between neonatal and adult hearts, we investigated gap junction uncoupling (GJU) and its correlation to myocardial intracellular edema formation during normothermic ischemia. METHODS: Hearts of landrace piglets (neonates, 7.4 +/- 1.9 days of age, body weight 2.9 +/- 0.5 kg, n = 5 and adults, 84 +/- 9 days of age, body weight 30.5 +/- 3.9 kg, n = 5) were investigated. After we harvested the hearts, the bioelectrical impedance spectra were measured continuously during normothermic global ischemia (35 degrees C). Spectra of the dielectric permittivity, epsilon'(frequency), and conductivity, sigma(frequency), were calculated from the impedance measurements, and GJU was identified in the sigmoidal time course of epsilon' (13 kHz). The extracellular volume was estimated by the ratio sigma (100Hz)/sigma (1MHz). Dielectric data were correlated with electron-microscopical images. RESULTS: Intraischemic GJU was observed in neonates after 54 +/- 9 minutes of ischemia and thus significantly earlier than in adults (90 +/- 7 minutes, P < .05). A more than 20% increase of intercalated water was found in tissue samples of neonates after 20 +/- 2 minutes, in contrast to adults after 137 +/- 8 minutes (P < .05). CONCLUSIONS: Intraischemic formation of edema and earlier GJU indicate faster intraischemic changes in neonates compared with adults. Intraischemic GJU and determination of intracellular water shifts are an experimental approach to establish the period of life-threatening damage. Because both parameters are linked and occur significantly earlier in neonates, they distinctly demonstrate the lower ischemia tolerance of neonatal hearts as both events interact. PMID- 27236867 TI - Zika Virus: What Clinicians Need to Know. PMID- 27236866 TI - [Management of popliteal artery pseudoaneurysms as a result of limb trauma and orthopedic surgery or associated with osteochondromas]. AB - Most published articles regarding popliteal artery pseudoaneurysms (PAPs) are case reports and in English language literature. In this context, no study with robust data was previously published. The exact epidemiology of these APs is not well-known and their management is not yet codified. We wanted to summarize the current knowledge on diagnostic and therapeutic features of PAPs as a result of limb trauma and orthopedic surgery or associated with osteochondromas. An electronic research on MEDLINE and EMBASE between 1953 and March 2015 was performed; using the key words "popliteal pseudoaneurysm". The referenced articles were selectively read and this systematic review included 116 articles. Patient demographics; clinical presentations; diagnostic and therapeutic features were reviewed. In sum, 122 cases were analyzed. Overall young adult (average age=30.48+/-21.25 years old) represented the majority of the affected population with a masculine preponderance (79%). The main etiologies included femoral exostosis (63%), followed by the orthopedic surgery (25%) and direct trauma into the knee (10%). Painful swelling (44%) and/or pulsatile mass (39%) represented the most commonly presenting symptoms. The commonest radiological investigations used included arteriography (49%) and CTA (27%). The treatment was open surgical repair (85%) or endovascular stenting graft (14%). Post-therapeutic courses were often uneventful (98%). The morbidity rate was low at about 2%. The treatment of direct post-traumatic PAPs was usually open surgical repair (83%) with saphenous vein grafting. Endovascular stenting may be an ideal option for managing PAPs following orthopedic surgery (88%). Open surgery for vascular repair and maximum exostectomy must be undertaken concomitantly in the setting of APs associated with osteochondromas. PMID- 27236868 TI - Epidemic focus: Lassa Fever. PMID- 27236869 TI - Meeting of the Strategic Advisory Group of Experts on immunization, April 2016 - conclusions and recommendations. PMID- 27236870 TI - Food Labeling: Revision of the Nutrition and Supplement Facts Labels. Final rule. AB - The Food and Drug Administration (FDA or we) is amending its labeling regulations for conventional foods and dietary supplements to provide updated nutrition information on the label to assist consumers in maintaining healthy dietary practices. The updated information is consistent with current data on the associations between nutrients and chronic diseases, health-related conditions, physiological endpoints, and/or maintaining a healthy dietary pattern that reflects current public health conditions in the United States, and corresponds to new information on consumer understanding and consumption patterns. The final rule updates the list of nutrients that are required or permitted to be declared; provides updated Daily Reference Values and Reference Daily Intake values that are based on current dietary recommendations from consensus reports; amends requirements for foods represented or purported to be specifically for children under the age of 4 years and pregnant and lactating women and establishes nutrient reference values specifically for these population subgroups; and revises the format and appearance of the Nutrition Facts label. PMID- 27236871 TI - Food Labeling: Serving Sizes of Foods That Can Reasonably Be Consumed at One Eating Occasion; Dual-Column Labeling; Updating, Modifying, and Establishing Certain Reference Amounts Customarily Consumed; Serving Size for Breath Mints; and Technical Amendments. Final rule. AB - The Food and Drug Administration (FDA or we) is issuing a final rule to define a single-serving container; require dual-column labeling for certain containers; update, modify, and establish several reference amounts customarily consumed (RACCs); amend the label serving size for breath mints; and make technical amendments to various aspects of the serving size regulations. We are taking this action to provide consumers with more accurate and up-to-date information on serving sizes. PMID- 27236872 TI - Mitigation Strategies To Protect Food Against Intentional Adulteration. Final rule. AB - The Food and Drug Administration (FDA or we) is issuing this final rule to require domestic and foreign food facilities that are required to register under the Federal Food, Drug, and Cosmetic Act (the FD&C Act) to address hazards that may be introduced with the intention to cause wide scale public health harm. These food facilities are required to conduct a vulnerability assessment to identify significant vulnerabilities and actionable process steps and implement mitigation strategies to significantly minimize or prevent significant vulnerabilities identified at actionable process steps in a food operation. FDA is issuing these requirements as part of our implementation of the FDA Food Safety Modernization Act (FSMA). PMID- 27236873 TI - Medical Devices; Ophthalmic Devices; Classification of the Diurnal Pattern Recorder System. Final order. AB - The Food and Drug Administration (FDA) is classifying the diurnal pattern recorder 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 diurnal pattern recorder 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- 27236874 TI - [Not Available]. PMID- 27236875 TI - [New insights into adult muscle fiber-type diversity: involvement of Six homeoproteins]. AB - The mechanisms by which fast/slow muscle fiber diversity emerges during mammalian development are poorly understood, although fast/slow motoneuron activity is known to be an important stimulus controlling fiber-type maintenance and transition in adults. The key role of innervation in the maintenance of the slow phenotype of the mature adult fibers has been amply demonstrated through denervation and cross-innervation experiments, as well as by the use of various electrical stimulation paradigms. Several signaling pathways have been reported to link nerve stimulation (inducing intracellular calcium elevation) to the maintenance of the slow muscle fiber phenotype. Less is known about the transcription factors and signaling pathways responsible for the fast IIB glycolytic phenotype. Six1 homeoprotein accumulates at higher levels in the nuclei of adult fast-type myofibers, and Six transcription complexes are far more active in fast/glycolytic fibers than in slow/oxidative fibers. Ectopic expression of Six proteins in the slow soleus muscle leads to a switch from the slow/oxidative phenotype to the fast/glycolytic phenotype, confirming the involvement of this transcriptional complex in the fast/glycolytic phenotype. We have further shown that Six homeoprotein-mutant mice exhibit an impaired capacity to generate fast-type myofibers during embryonic development, and that adult myofibers deprived of Six1 have a slower phenotype. We have also characterized the gene networks controlled by Six homeoproteins at various developmental stages and have shown that, in the adult myofiber, Six proteins control the activity of an enhancer at the fast myosin heavy chain cluster. We identified a three-element genetic partnership in which this enhancer under the control of the myogenic homeoprotein Six1, functions as a regulatory hub that controls the fast fiber phenotype. In this partnership, the enhancer positively controls the expression of both the adjacent fast myosin heavy chain (MYH) gene cluster and Linc-MYH. Linc-MYH is present only in adult fast-type skeletal myofibers, where it suppresses slow-type gene expression. PMID- 27236876 TI - [Sarcomas: from pathology to molecular pathology and new nosology]. AB - Sarcomas are rare tumors the pathological classification of which is complex, leading to relatively common diagnostic discordances. In about half of the cases, simple and specific genomic abnormalities have been described. This currently allows a better definition and a more reproducible classification of sarcoma types. Also, knowledge of these abnormalities allows a better targeted and efficient therapeutic approach. PMID- 27236877 TI - [Not Available]. PMID- 27236878 TI - [Not Available]. PMID- 27236879 TI - [Analysis of the Puzzle between Acupuncture Community and Acupuncture Clinical Trials]. AB - Recently a number of acupuncture clinical trial projects mainly conducted by conventional scientists have generated many negative results. A large meta analysis of patient-level acupuncture data for the treatment of chronic pain conditions have demonstrated that the effects of verum acupuncture on pain improvement have statistically significant, but small, differences compared with sham-acupuncture procedures and no difference between acupuncture points and non points. These conclusions have puzzled the acupuncture community and made confusion for acupuncture research and practices. The purpose of this paper was to compare differences between acupuncture clinical practices and the trial studies, which include "acupuncture technical principles", "acupuncture clinical trial design", and "acupuncture practice based on the theory of traditional Chinese medicine". These factors contribute to the puzzle between the acupuncture community/practice and acupuncture clinical trials, which can be improved in future studies. PMID- 27236880 TI - [Scientific Positioning of Traditional Chinese Medicine]. AB - Whether traditional Chinese medicine (TCM) could be categorized as a kind of science or not has been a controversial issue over last century. Part of the confusion is caused by the indistinguishable usage of Chinese words "science" and "scientific" during discussion. According to western academic standards, TCM cannot be considered as pure or conventional science. However, in author's view, the foundation of a majority part of TCM practice is probably scientific, while many TCM theories remain unproved. In this article, medical theories and practices are classified based on scientific content into eight levels: medical science, scientific medicine, medical system, medical theory, medical opinion, medical belief, medical cultism, and medical fraud. Both Western medicine and TCM are positioned in this system accordingly. Currently, the scientific level of TCM is much lower than that of Western medicine, and more research is needed for its improvement. PMID- 27236881 TI - [Consensus on Using Chinese Patent Drugs in Palliative Therapy for Tumor (2013 ed)]. PMID- 27236882 TI - [Consensus on Standardized Using Xinmailong Injection for Treating Chronic Heart Failure]. PMID- 27236883 TI - [Effect of Dexmedetomidine Combined Electrical Stimulation on Coanitive Function of Patients Receiving Extracerebral Intervention]. AB - OBJECTIVE: To explore the effect of dexmedetomidine combined electrical stimulation on cognitive function of neurosurgical diseases patients treated by extracerebral intervention. METHODS: Totally 122 patients with neurosurgical diseases who underwent selective intervention were randomly assigned to the observation group and the control group, 61 cases in each group. Patients in the control group recieved anesthesia by dexmedetomidine. Those in the observation group received electrical stimulation at Baihui (DU20), Yintang ( EX-HN3), and Neiguan (PC6) before dexmedetomidine anesthesia. The cognitive function of patients at preoperative day 1 and postoperative day 1 was respectively evaluated by Mini-Mental State Examinations (MMSE). Serum NSE, S-100beta, IL-1beta, IL-6, and TNF-alpha levels were detected in the two groups before intervention and immediately after intervention using ELISA. RESULTS: MMSE scores of two groups were significantly reduced at post-intervention day 1, as compared with one day before intervention. MMSE score of the observation group at post-intervention day 1 was (23.15 +/- 1.87) points, significantly higher than that of the control group [ (19.34 +/- 1.64) points , (P < 0.05)]. The postoperative cognitive dysfunction (POCD) incidence rate of the observation group was 16.4% (10/61), significantly lower than that of the control group [39.3% (24/61); P < 0.05]. Compared with before intervention, NSE and S-100beta protein levels, IL-1beta, IL 6 and alpha-TNF levels of the two groups increased (P < 0.05). Post-intervention NSE and S-100beta protein levels, IL-1beta, IL-6 and alpha-TNF levels were significantly lower in the observation group than in the control group (P < 0.05). CONCLUSION: Dexmedetomidine combied electrical stimulation could effectively prevent the occurrence of postoperative cognition, and reduce levels of NSA, S-100beta, IL-1beta, IL-6 and TNF-alpha. PMID- 27236885 TI - [Imaging Observation of Scalp Acupuncture on Brain Gray Matter Injury in Stroke Patients with Cerebral Infarction]. AB - OBJECTIVE: To study features of brain gray matter injury in cerebral infarction patients and intervention of scalp acupuncture by using voxel-based morphology. METHODS: A total of 16 cerebral infarction patients were recruited in this study, and assigned to the scalp acupuncture group and the control group, 8 in each group. Another 16 healthy volunteers were recruited as a normal group. All patients received scanning of T1 structure. Images were managed using VBM8 Software package. Difference of the gray matter structure was compared among the scalp acupuncture group, the control group, and the healthy volunteers. RESULTS: Compared with healthy volunteers, gray matter injury of cerebral infarction patients mainly occurred in 14 brain regions such as cingulate gyrus, precuneus, cuneus, anterior central gyrus, insular lobe, and so on. They were mainly distributed in affected side. Two weeks after treatment when compared with healthy volunteers, gray matter injury of cerebral infarction patients in the scalp acupuncture group still existed in 8 brain regions such as bilateral lingual gyrus, posterior cingulate gyrus, left cuneus, right precuneus, and so on. New gray matter injury occurred in lingual gyrus and posterior cingulate gyrus. Two weeks after treatment when compared with healthy volunteers, gray matter injury of cerebral infarction patients in the control group existed in 23 brain regions: bilateral anterior cingulum, caudate nucleus, cuneate lobe, insular lobe, inferior frontal gyrus, medial frontal gyrus, precuneus, paracentral lobule, superior temporal gyrus, middle temporal gyrus, lingual gyrus, right postcentral gyrus, posterior cingulate gyrus, precentral gyrus, middle frontal gyrus, and so on. New gray matter injury still existed in 9 cerebral regions such as lingual gyrus, posterior cingulate gyrus, postcentral gyrus, and so on. CONCLUSIONS: Brain gray matter structure is widely injured after cerebral infarction. Brain gray matter volume gradually decreased as time went by. Combined use of scalp acupuncture might inhibit the progression of gray matter injury more effectively. PMID- 27236884 TI - [Analgesic and Sedative Effect of Acupuncture Combined with Medicine on Patients Undergiong Cardiac Surgery]. AB - OBJECTIVE: To observe analgesic and sedative effect of acupuncture combined with medicine (ACM) on patients undergiong cardiac surgery. METHODS: A total of 50 patients with cardiac surgery from January 2012 to October 2014 were randomly assigned to the conventional analgesia group (group A) and the ACM analgesia group (group B), 25 in each group. Patients in group A were subjected to analgesia and sedation by injecting dexmedetomidine, while patients in group B were subjected to analgesia and sedation by electro-acupuncture [EA, Shenting (GV24); Yintang (EX-HN3)] combined with injection of dexmedetomidine. Morphine hydrochloride injection was performed when analgesia and sedation effect was ineffective in the two groups. The indicators of patients at different time points in the two groups were observed, such as static and dynamic VAS scores, SAS scores, mean arterial pressure (MAP), heart rate (HR), oxygen saturation (SpO2). The injection dosage of dexmedetomidine and morphine hydrochloride, analgesia satisfaction rate, sedation satisfaction rate, the incidences of adverse reactions during treatment such as bradycardia and low blood pressure, mechanical ventilation time, ICU time, and hospitalization expense were observed and recorded in the two groups. RESULTS: There was no statistical difference in static and dynamic VAS scores, SAS score, MAP, HR and SpO2 between the two groups at different time points (P > 0.05). The injection dosage of dexmedetomidine and morphine hydrochloride was significantly reduced in group B than in group A (P < 0.05). The analgesia satisfaction rate of patients in group B was much higher than that in group A (P < 0.05). The incidence of bradycardia also obviously decreased more in group B than in group A (P < 0.05). There was no statistical difference in patients' sedation satisfaction rate, incidences of low blood pressure, delirium, vomiting; mechanical ventilation time, ICU time, or hospitalization expense between the two groups (P > 0.05). CONCLUSION: The analgesia method of ACM could reduce the dosage of traditional analgesic drugs and the occurrence of partial adverse reactions. PMID- 27236886 TI - [Scientific Evaluation of TCM Clinical Outcomes Rating Scale for Heart Failure Based on Patients Report]. AB - OBJECTIVE: To evaluate the reliability, validity, and responsiveness of traditional Chinese medicine (TCM) clinical outcomes rating scale for heart failure (HF) based on patients' report. METHODS: TCM clinical outcomes rating scale for HF (TCM-HF-PRO) were evaluated based on 340 HF patients' report from multiple centers. The completion of the investigation was recorded. Cronbach's alpha coefficient and split-half reliability were used for reliability analysis, and factor analysis was used to assess the construct validity of the rating scale. Pearson correlation analysis was then used for criterion validity analysis. Discriminant analysis was used to assess the responsiveness of the scale. All 340 HF patients having complete TCM-HF-PRO data were assigned to the treatment group and the control group by central randomization. The total TCM-HF PRO scores of the two groups were compared using paired t-test to reflect the longitude responsiveness of the scale before treatment and at week 2 after treatment. RESULTS: (1) The recycling rate of the scale was 100.0%. One of them was not filled completely, which was rejected thereby. So the completion rate was 99.7%. The completion time for TCM-HF-PRO scale ranged 15 to 25 min. (2) The Cronbach's alpha coefficient of rating scale was 0.903, split-half reliability was 0.844 and 0.849. (3) Confirmatory factor analysis showed that 7 factors and items formed according to maximum load factor basically coincided with the construct of the rating scale, 7 factors accumulated contribution rate was 43.8%. TCM clinical outcomes rating scale for HF based on patients' report was relatively better correlated with the Minnesota living with HF questionnaire (r = 0.726, P < 0.01). (4) Discriminant analysis showed that the rating scale correctly classified more than 78.8% of case studies having confirmed initial differential diagnosis by experts. The total scale of the rating scale decreased more in the two group after treatment, with significant difference as compared with before treatment (P < 0.01. CONCLUSION: TCM clinical outcomes rating scale for HF based on patients' report had good reliability, validity and responsiveness, hence it could be used to assess clinical efficacy for HF patients. PMID- 27236887 TI - [Effects of Early Goal-directed Therapy Combined with Yiqi Fumai Lyophilized Powder on P(cv-a) CO2 and S(cv)O2 in Patients with Septic Shock]. AB - OBJECTIVE: To explore the effect of early goal-directed therapy (EGDT) combined with Yiqi Fumai Lyophilized Powder (YFLP) on central venous-arterial carbon dioxide difference [P(cv-a)CO2] and central venous oxygen saturation (S(cv)O2) in patients with septic shock. METHODS: Totally 50 patients with septic shock were assigned to the control group and the treatment group according to random digit table, 25 cases in each group. Patients in the control group received treatment according to EGDT principle. Those in the treatment group were intravenously injected with YFLP (5.2 g adding in 500 mL normal saline) additionally. Changes of P(cv-a)CO2, S(cv)O2, lactic acid, central venous pressure (CVP), mean arterial pressure (MAP), and APACHE II score were observed in the two groups before and after treatment. The 6-h success rate and 28-day mortality were also observed. RESULTS: Compared with before treatment in the same group, lactic acid and APACHE II score decreased, levels of S(cv)O2, MAP, CVP increased in the two groups after treatment (P < 0.01). P(cv-a)CO2 decreased more obviously after treatment in the treatment group, and lower than that in the control group after treatment (P < 0. 05, P < 0. 01). The 6-h success rate was 48% (12/25) in the control group and 76% (19/25) in the treatment group (P < 0.05). The 28-day mortality was 36% (9/25) in the control group and 12% (3/25) in the treatment group (P < 0.05). CONCLUSION: EGDT combined with YFLP could significantly elevate S(cv)O2, decrease P(cv-a)CO2 and mortality in patients with septic shock, and obviously improve the clinical effect. PMID- 27236888 TI - [Effect of Xinfeng Capsule on AS Patients and Their Serum Immunoglobulin Subtypes and Peripheral Lymphocyte Autophagy]. AB - OBJECTIVE: To observe the effect of Xinfeng Capsule (XFC) on ankylosing spondylitis (AS) patients' symptoms and signs, serum immunoglobulin levels, peripheral blood lymphocyte autophagy protein, autophagy gene, and to explore its mechanism. METHODS: Totally 59 AS patients were assigned to the treatment group (39 cases) and the control group (20 cases) according to random digit table. Patients in the treatment group received XFC, 0.5 g each pill, three pills each time, 3 times per day, while those in the control group received sulfasalazine (SASP), 0.25 g per tablet, 4 tablets each time, twice per day. Three months consisted of one therapeutic course. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) were statistically calculated. Serum immunoglobulins (IgG1, IgG2, IgG3, IgG4, IgA , SIgA, and IgM) were detected using ELISA. Changes of Beclin1, LC3-II, phosphatidylinositol 3-kinase (PI3K), Akt, the mammalian target of rapamycin (mTOR) were detected using Western blot. Serum autophagy related genes such as Atg1, Atg5, Atg12, Atg13, and Atg17 were detected using the polymerase chain reaction (PCR). The correlation between immunoglobulin subtypes and autophagy gene in AS patients using Spearman correlation. RESULTS: Compared with before treatment, BASDAI, IgG1, lgG3, and IgA decreased (P < 0.01); PI3K, Akt, and mTOR protein expressions decreased (P < 0.01); ATG1, ATG12, ATG13, and ATG17 mRNA expressions decreased, ATG5 mRNA expression increased (P < 0.01) in the treatment group. But BASDAI, IgG1, and IgA levels decreased (P < 0.05, P < 0.01); PI3K, Akt, and mTOR protein expressions decreased (P < 0.05); ATG1 and ATG13 mRNA expressions decreased (P < 0.05, P < 0.01) in the control group. Compared with the control group, BASDAI, IgG1, and IgA levels decreased (P < 0.05); PI3K, Akt, mTOR protein expressions decreased (P < 0.01); ATG12 and ATG17 mRNA expression decreased, ATG5 mRNA expression increased (P < 0.01) in the XFC group. Correlation analysis showed AS patients' IgG1, IgG2, IgG3, IgA, SIgA, IgM had negative correlation with ATG17; IgG4 and ATG17 were positively correlated (P < 0.05, P < 0.01). CONCLUSION: XFC could elevate clinical efficacy of AS patients and enhance their autophagy, which might be achieved by acting on PI3K/Akt/mTOR signal, affecting autophagy gene and autophagy protein expression, taking part in the regulation of proliferation and differentiation of lymphocyte B, and strengthen humoral immunity. PMID- 27236889 TI - [Effect of Qingfei Quyu Decoction in Prevention of Radiation Pneumonitis Induced by Concurrent Chemoradiotherapy for Esophageal Carcinoma Patients]. AB - OBJECTIVE: To assess the effect of Qingfei Quyu Decoction (QQD) in preventing radiation pneumonitis in esophageal carcinoma patients by concurrent using it with chemoradiotherapy. METHODS: A total of 120 patients with mid-late stage esophageal carcinoma were randomly assigned to the treatment group (60 cases) and the control group (60 cases). All patients received concurrent radiochemotherapy. Patients in the treatment group additionally took QQD, one dose per day for 8 successive weeks. The incidence of radiation pneunonitis was compared between the two groups. The improvement rates of short-term benefit rate, Karnofsky performance scale (KPS), and body weight (BW) improvement rate were calculated between the two groups. The 1-and 2-year overall survival rates were compared between the two groups. RESULTS: The incidence of radiation pneunonitis was 8.93% (15/56) in the treatment group and 18.64% (11/59) in the control group (P < 0.05). The short-term benefit rate was 92.86% (52/56) in the treatment group and 69.49% (41/59) in the control group (P < 0.05). Besides, the KPS and BW improvement rate were higher in the treatment group [89.29% (50/56) and 83.05% (49/59) ] than in the control group [80.36% (45/56) and 66.10% (39/59)] (P < 0.05). The 1-and 2-year overall survival rate were 66.07% and 35.71% in the treatment group, higher than those of the control group (61.02% and 30.51%; P > 0.05). CONCLUSION: Concurrent using QQD with chemoradiotherapy for treating esophageal carcinoma patients could lower the incidence of radiation pneumonitis, attenuate the degree of radiation induced lung injury, improve clinical benefit rate, and elevate their QOL. PMID- 27236890 TI - [Effect of Electroacupuncture on Expression of Ghrelin and mRNA Expression of Its Receptor in Functional Dyspesia Rats]. AB - OBJECTIVE: To explore the effect of electroacupuncture (EA) on the expression of Ghrelin and mRNA expression of its receptor in functional dyspepsia (FD) rats. METHODS: Totally 80 rats were divided into the normal group, the model group, the drug therapy group, and the EA group according to random digit table, 20 in each group. FD model was duplicated by clipping tail modeling. Drug containing cisapride [2 mL/100 g, 0.09 g/(kg x d)] was administered to rats in the drug therapy group from the 3rd day after successful modeling, once per day. EA at Zusanli (ST36) (0.3-0.5 cun) and Taichong (LR3) (0.1-0.2 cun) was performed in the EA group. The twirling of needle was performed to the subsidence of needle, and then the needle was connected to HANS-200A Acupoint Nerve Stimulating Device using disperse-dense wave at 2 Hz, 2 mA, 30 min each time, once per day. Six days consisted of one therapeutic course, two courses in total with an interval of one day. The intestinal propulsive rate of ink was observed. Ghrelin protein expression in gastric tissue was detected by Western blot. mRNA expression of growth hormone secretagogue receptor (GHS-R) in stomach, hypothalamus, and hippocampus was detected using Real-time PCR respectively. RESULTS: Compared with the normal group, the intestinal propulsive rate of ink, Ghrelin protein expression in gastric tissue, mRNA expression of GHS-R in stomach, hypothalamus, and hippocampus decreased in the model group (P < 0.05, P < 0.01). Compared with the model group, the intestinal propulsive rate of ink, Ghrelin protein expression in gastric tissue, mRNA expression of GHS-R in stomach, hypothalamus, and hippocampus increased in the EA group (P < 0.01); mRNA expression of GHS-R in stomach, hypothalamus, and hippocampus increased in the drug therapy group (P < 0.01). Compared with the drug therapy group, Ghrelin protein expression in gastric tissue, mRNA expression of GHS-R in hypothalamus increased in the EA group (P < 0.05, P < 0.01). CONCLUSION: EA could regulate Ghrelin content and GHS R mRNA expression of FD rat hypothalamus, hippocampus, and gastric tissue, and promote the intestinal propulsive rate of ink. PMID- 27236891 TI - [Bushen Huoxue Recipe Inhibited Vascular Calcification in Chronic Renal Failure Rats by Regulating BMP-2/Runx2/Osterix Signal Pathway]. AB - OBJECTIVE: To observe the effect of Bushen Huoxue Recipe (BHR) on inhibiting vascular calcification (VC) in chronic renal failure (CRF) rats by regulating BMP 2/Runx2/Osterix signal pathway, and to explore its possible mechanism. METHODS: Thirty SD rats were randomly divided into the normal group, the model group, and the BHR group, 10 in each group. Rats in the model group and the BHR group were administered with 250 mg/kg adenine suspension by gastroagavage and fed with 1.8% high phosphorus forage, once per day in the first 4 weeks, and then gastric administration of adenine suspension was changed to once per two days in the following 5-8 weeks. Rats in the BHR group were administered with BHR at the daily dose of 55 g/kg by gastrogavage in the first 8 weeks, once per day. Equal volume of normal saline was given to rats in the normal group by gastrogavage for 8 weeks. Histological changes in renal tissue and aorta VC were observed by HE staining and alizarin red staining respectively. Levels of calcium (Ca), phosphorus (P), serum creatinine (Cr), blood urea nitrogen (BUN), and intact parathyroid hormone (iPTH) in serum were detected. Protein expression levels of bone morphogenetic protein (BMP-2), Runt related transcription factor (Runx2) , and Osterix were detected by Western blot. RESULTS: HE staining showed that compared with the normal group, disordered glomerular structure, tubular ectasia and dropsy, intracavitary inflammatory cell infiltration, dark brown crystal deposition in kidney tubules, renal interstitial fibrosis, and decreased number of renal blood vessels in the model group. Compared with the model group, normal glomerular numbers increased more, reduced degree of tubular ectasia, decreased number of inflammatory cells, and reduced adenine crystal deposition in the BHR group. Alizarin red staining showed that compared with the normal group, calcified nodes could be found in the model group, with extensive deposition of red particle in aorta. Compared with the model group, calcified nodes were reduced in the BHR group. Compared with normal group, serum levels of P, SCr, BUN, and iPTH significantly increased, serum Ca level significantly decreased, protein expressions of BMP-2, Runx2, Osterix also increased in the model group (P < 0.05, P < 0.01). Compared with the model group, serum levels of P, SCr, BUN, and iPTH levels significantly decreased, serum Ca level significantly increased, protein expressions of BMP-2, Runx2, Osterix also decreased in the BHD group (P < 0.05, P < 0.01). CONCLUSION: BHD could improve renal function, Ca-P metabolism, and renal histological changes in CHF rats, down-regulate the expression level of BMP-2/Runx2/Osterix signal pathway in vascular calcification of CRF, which might be one of the mechanisms for inhibiting VC in CHF. PMID- 27236892 TI - [Effect of Ginsenoside Rg2 and Its Stereoisomers on Oxygen-Glucose Deprivation and Reperfusion Induced Cortical Neuronal Injury Model]. AB - OBJECTIVE: To observe the effect of natural type ginsenoside Rg2 (Rg2) and its stereoisomers [20 (R)-Rg2 and 20 (S)-Rg2] at different concentrations on oxygen glucose deprivation/ reperfusion (OGD/R) induced cortical neuronal injury model in vitro, and to explore the mechanism, and compare their differences of action. METHODS: Cortical neurons after 7-day culture were randomly divided into 5 groups, i.e., the control group, the model group, the Rg2 group, 20 (R) -Rg2 group, and 20 (S) - Rg2 group. Cortical neurons in the Rg2 group, 20 (R)-Rg2 group, and 20(S)-Rg2 group were pretreated with 20, 40, and 80 MUmol/L Rg2, 20 (R) -Rg2, and 20 (S) -Rg2 for 24 h to prepare OGD/R model. The cell survival rate, the activity of Caspase-3, the intracellular Ca2+ concentration, contents of superoxide dismutase (SOD) and malondialdehyde (MDA) were detected 24 h later. RESULTS: Compared with the control group, cell survival rates and activities of SOD obviously decreased, the activity of Caspase-3, Ca2+ fluorescent optical gray value, and contents of MDA significantly increased with statistical difference (P < 0.05). Compared with the model group, cell survival rates and activities of SOD obviously increased, the activity of Caspase-3, Ca2+ fluorescent optical gray value, and contents of MDA significantly decreased in 20 MUmol/L Rg2 group, 40 MUmol/L 20 (R) -Rg2 group, and 80 MUmol/L 20 (S) -Rg2 group (P < 0.05). Compared with 20(S)-Rg2 group, cell survival rates increased and contents of MDA significantly decreased in 20, 40, and 80 MUmol/L Rg2 and 20 (R)-Rg2 groups (P < 0.05). The activity of Caspase-3 decreased and contents of SOD increased in 80 MUmol/L 20 (R)-Rg2 group, and 40, 80 MUmol/L Rg2 groups (P < 0.05). Ca2+ fluorescent optical gray value decreased in 40, 80 MUmol/L Rg2 and 20 (R)-Rg2 groups (P < 0.05). Compared with 20 (R)-Rg2 group, Ca2+ fluorescent optical gray value decreased in 80 MUmol/L Rg2 group (P < 0.05); contents of SOD increased in 40 and 80 MUmol/L Rg2 groups (P < 0.05); contents of MDA decreased in 20, 40, and 80 MUmol/L Rg2 groups (P < 0.05). CONCLUSIONS: Rg2 and its stereoisomers could improve cell vitality of cortical neurons against OGD/R induced injury. This might be related to improving anti-apoptotic capacities and antioxidant abilities, and reducing Ca2+ inflow. Besides, the neuroprotective effect of 20 (R) -Rg2 was better than that of 20 (S) -Rg2, but inferior to that of Rg2. PMID- 27236893 TI - [Inhibition of Paeoniflorin on TNF-alpha-induced TNF-alpha Receptor Type I /Nuclear Factor-kappaB Signal Transduction in Endothelial Cells]. AB - OBJECTIVE: To study the inhibitory effect of paeoniflorin (PAE) on TNF-alpha induced TNF receptor type I (TNFR1)-mediated signaling pathway in mouse renal arterial endothelial cells (AECs) and to explore its underlying molecular mechanisms. METHODS: Mouse AECs were cultured in vitro and then they were treated by different concentrations PAE or TNF-alpha for various time periods. Expression levels of intercellular cell adhesion molecule-1 (ICAM-1) were detected in the normal group (cultured by serum-free culture media), the TNF-alpha group (cultured by 2-h serum-free culture media plus 6-h TNF-alpha 30 ng/mL), the low dose PAE group (cultured by 2-h PAE 0.8 MUmo/L plus 6-h TNF-alpha 30 ng/mL), the middle dose PAE group (cultured by 2-h PAE 8 MUmol/L plus 6-h TNF-alpha 30 ng/mL), the high dose PAE group (cultured by 2-h PAE 80 MUmol/L plus 6-h TNF alpha 30 ng/mL) with Western blot analysis. Nuclear translocation of transcription factor NF-kappaB (NE-kappaB) was detected in the normal group (cultured by serum-free culture media), the TNF-alpha group (cultured by 2-h serum-free culture media plus 45-mm TNF-alpha 30 ng/mL), and the high dose PAE group (cultured by 2-h PAE 80 MUmol/L plus 45-min TNF-alpha 30 ng/mL) by immunofluorescent staining. Expression levels of the phosphorylation of extracellular signal-regulated (protein) kinase (ph-ERK) and p38 (ph- p38) were detected in the normal group (cultured by serum-free culture media) and the high dose PAE group (2-h PAE 80 MUmol/L culture) by Western blot. NF-kappaB inhibitor alpha (IkappaBalpha) protein expressions were detected in the normal group (cultured by serum-free culture media), the TNF-alpha group (cultured by 2-h serum-free culture media plus 30-min TNF-alpha 30 ng/mL), the high dose PAE group (cultured by 2-h PAE 80 MUmol/L plus 30-min TNF-alpha 30 ng/mL), the p38 inhibitor group (SB group, pretreatment with SB238025 25 MUmol/L for 30 min, then treated by PAE 80 MUmol/L for 2 h, and finally treated by TNF-alpha 30 ng/mL for 30 min), the ERK inhibitor group (PD group, treated by PD98059 50 MUmol/L for 30 min, then treated by PAE 80 MUmol/L for 2 h, and finally treated by TNF-alpha 30 ng/mL for 30 min) by Western blot. RESULTS: Compared with the normal group, ICAM 1 protein expression levels obviously increased (P < 0.01). Compared with the TNFalpha group, ICAM-1 protein expression levels were obviously inhibited in the high dose PAE group (P < 0.05). Protein expression levels of ph-p38 and ph-ERK were obviously higher in the hIgh dose PAE group (P < 0.05). Compared with the normal group, IkappaBalpha protein expression levels obviously decreased in the TNF-alpha group (P < 0.01). Compared with the TNFalpha group, TNF-alpha-induced IkappaBalpha degradation could be significantly inhibited in the high dose PAE group (P < 0.01); the inhibition of PAE on IkappaBalpha degradation could be significantly inhibited in the SB group (P < 0.05). NF-kappaB/p65 signal was mainly located in cytoplasm in the normal group. NF-kappaB/p65 was translocated from cytoplasm to nucleus after stimulated by 45 min TNF-alpha in the TNF-alpha group, while it could be significantly inhibited in the high dose PAE group. CONCLUSIONS: PAE inhibited TNF-alpha-induced expression of lCAM-1. Its action might be associated with inhibiting TNFR1/NF-kappaB signaling pathway. p38 participated and mediated these actions. PMID- 27236894 TI - [Effect of Modified Danggui Yinzi on Delayed Allergy in Model Mice with Qi-Blood Deficiency Syndrome]. AB - OBJECTIVE: To explore the effect of Danggui Yinzi (DY) on delayed allergy in model mice with qi-blood deficiency syndrome (QBDS). METHODS: QBDS model was established in 48 Kuming mice of SPF grade by using reserpine and acetophenone hydrazine. Forty of them were then randomly divided into the model group, the loratadine group, the high dose DY group, the middle dose DY group, and the low dose DY group, 8 in each group. Another 8 in line with the same standard were recruited as a blank group. Mice in high, middle, and low dose DY groups were administered with DY concentrated solution at 60, 30, 15 g/kg by gastrogavage. Mice in the loratadine group were administered with loratadine solution at 1.66 mg/kg by gastrogavage. Equal volume of normal saline was administered to mice in the model group and the blank group by gastrogavage. All medication was given once per day for 1 successive week. Except those in the blank group, the rest mice were evenly smeared with 1% DNCB solution on the abdomen. Five days after skin allergy, 1% DNCB solution was smeared to right ear of all mice to stimulate allergic reaction. Mice in the blank group were smeared in the same way without allergenic reaction. The auricle swelling and the inhibition ratio were determined at 24 h after attack. Blood was collected from orbit and serum IgE level detected using double-antibody sandwich ELISA. RESULTS: Compared with the blank group, auricle swelling obviously increased and serum IgE level was obviously elevated in the model group (P < 0.01). Compared with the model group, auricle swelling obviously decreased and serum IgE level was obviously reduced in the 3 dose DY groups (P < 0.05, P < 0.01). Meanwhile, the auricle swelling degree was superior in high and middle dose DY groups to that in the loratadine group (P < 0.05). The inhibition ratio of auricle swelling was sequenced from high to low as 67.3% in the high dose DY group, 56.0% in the middle dose DY group, 48.1% in the low dose DY group, 47.3% in the loratadine group. CONCLUSIONS: DY could inhibit auricle swelling and lower serum IgE level. It also could inhibit delayed allergic reaction in model mice with QBDS to some extent. PMID- 27236895 TI - [Effect of Coixenolide on Foxp3+ CD4+ CD25+ Regulatory T Cells in Collagen induced Arthritis Mice]. AB - OBJECTIVE: To study the effect of coixenolide on Foxp3+ CD4+ CD25+ regulatory T cells (Treg) in collagen induced arthritis (CIA) mice, and to explore its possible mechanism for treating rheumatiol arthritis. METHODS: Five mice were recruited as a normal control group from 25 mice, and the rest 20 were used in CIA modeling. After successful modeling they were randomly divided in the model control group and the coixenolide group, 10 in each group. Coixenolide injection at 25 mL/kg was intraperitoneally injected to mice in the coixenolide group, while normal saline at 25 mL/kg was intraperitoneally injected to mice in the normal control group and the model control group. The injection lasted for 21 days. Scoring for CIA was performed after injection and arthritis index was calculated. The peripheral blood Foxp3+ CD4+ CD25+ Treg ratio was determined by flow cytometry (FCM). RESULTS: Compared with the normal control group, the arthritis index obviously increased in the model control group (P < 0.01). The arthritis index obviously decreased more in the coixenolide group than in the model control group (P < 0.01). Foxp3+ CD4+ CD25+ Treg levels obviously decreased more in the model control group than in the normal control group (P < 0.01 ). Foxp3+ CD4+ CD25+ Treg levels obviously increased more in the coixenolide control group than in the model control group (P < 0.01). CONCLUSION: Coixenolide could up-regulate Foxp3+ CD4+ CD25+ Treg ratios in CIA mice, which might play certain immunoregulation roles in the incidence of CIA. PMID- 27236896 TI - [Effect of Chinese Herbal Extract HNA-1 on the Thymic Output Function in Simian Immunodeficiency Virus Chronically Infected Chinese Rhesus Macaques]. AB - OBJECTIVE: To observe the effect of Chinese herbal extract HuNan A-1 (HNA-1) on the thymic output function in Simian immunodeficiency virus (SIV) chronically infected rhesus macaques. METHODS: Eight Chinese rhesus macaques had been infected by SIVmac239 for 16 to 21 months, and then they were randomly divided into the treatment group and the control group, 4 in each group. Monkeys in the treatment group were administered with HNA-1 by gastrogavage, once daily for 2 successive months, while those in the control group were administered with equal volume of normal saline by gastrogavage, once daily for 2 successive months. The general condition and body weight of monkeys were observed. Plasma viral loads were detected using real-time fluorescent quantitative PCR assay. CD4 percentages and counts, as well as naive CD subsets were detected using flow cytometry. T cell receptor excision circles (TREC) were detected using real-time fluorescent quantitative PCR assay. The thymus tissue was pathologically observed using routine HE staining. The correlation between lesions of the thymus tissue, CD4 counts, naive CD counts, and TREC were analyzed. RESULTS: There was no statistical difference in body weight, viral loads, absolute CD ratios between the two groups after treatment (P > 0.05). The altered TREC multiple showed an obvious decreasing tendency in the control group, while it showed an increasing tendency in the treatment group (P < 0.05). In both groups, destroyed structures of the thymus tissue could be seen, filled with pink unstructured material. Increased connective tissues, lowered connective cell density, and confused arrangement could also be seen in the two groups, with no obvious difference. TREC contents were positively correlated with naive CD4 counts after removing extremum (r = 0.926, P = 0.001). Naive CD4 counts were positively correlated with CD4 counts (r = 0.961, P = 0.005). CONCLUSIONS: TREC content determination, as a marker of newly thymic emigrants, could be taken as a testing method for evaluating the thymic output function. Besides, HNA-1 treatment increased the thymic output significantly in SIV chronically infected monkeys. Correlation existed among TREC contents, naive CD4 counts, and pathologies of thymus tissues, especially in late infection stage. PMID- 27236897 TI - [Study on Serum Metabolite Profiling in Pi-deficiency Rats Based on LC-MS Technique]. AB - OBJECTIVE: To explore metabolite profiling changes in serum of rats with pi-qi deficiency syndrome (PQDS) and pi-yang deficiency syndrome (PYDS) based on liquid chromatograph-mass spectrometer (LC-MS) technique, and to explore the essence of Pi-deficiency syndrome (PDS) from small molecule metabolite level. METHODS: Totally 21 male SD rats of SPF grade were randomly divided into three groups, the normal control group, the PQDS group, and the PYDS group, 7 in each group. Rats in the PQDS group overate for 1 day and fasted for 2 days. They drank freely and then swam to be exhausted in water at 35 degrees C - 37 degrees C for 15 successive days. The PYDS model was established by the same method for PQDS rats plus drenching 20% Folium sennae water extract (2 mL/100 g), once in the morning and once in the evening for one successive week. After modeling, models were evaluated according to rat general state, changes in body weight and rectal temperature. Serum metabonomic profiles were detected using LC-MS technique. Difference in inter-group metabolite spectrograms was analyzed using orthogonal partial least squares discriminant analysis (OPLS-DA). Potential biomarkers related to syndrome types in rat serum were selected via the parameter of variable importance in the projection (VIP). RESULTS: The weight of rats in the PQDS group and the PYDS group decreased more significantly after modeling. The difference in prepost weight was statistically significant from that of the normal control group (P < 0.01). It was more obviously lowered in the PYDS group than in the PQDS group (P < 0.05). Compared with the normal control group, the rectal temperature of rats in the PYDS group and the PQDS group decreased (P < 0.05, P < 0.01). It decresed more in the PYDS group than in the PQDS group (P < 0.05, P < 0.01). Compared with the normal control group, levels of PC(19:0)/PE(22:0), PC(17:0)/PE(20:0), capric acid, oleic acid, stearic acid, succinic acid, fumaric acid, malic acid, glucose increased; arachidonic acid, linolenic acid, lauric acid, androsterone, 4-heptanone, dihydroxyacetonephosphate (DHAP) (6:0), and uridine decreased in the PYDS group and the PQDS group. Compared with the PQDS group, levels of PC(22:1), PC (22:6), PE (18:0)/PC (15:0), retinol, and deoxycytidine increased significantly in the PYDS group; PC (18:1), PC(19 :3), PC (20:3), PC (17:0)/PE (20:0), PC (19:1)/PE (22:1), PC (19:0)/PE (22:0), PC (17:1)/PE (20: 1), PC (16:1)/PE (19:1), cholic acid, hippuric acid, furoic acid, undecanedicarboxylic acid, palmitoleic acid, hydroxy stearic acid, eicosatrienoic acid, phenylalanine, tyrosine, glutamic acid, serine, carbamoyl aspartic acid, palmitoyl carnitine, tetradecanoyl carnitine, acetylcarnitine, and linoleylcarnitine decreased more significantly in the PYDS group. CONCLUSIONS: Comparative contents of various serum metabolites changed significantly in PQDS and PYQS model groups. Some potential small molecular biomarkers related to PDS were preliminarily identified. These results might provide some data reference for exploring scientific connotation and pathological mechanisms of PDS. PMID- 27236898 TI - [Antitumor Effect of Ganoderma lipsiense Extract on Triple-negative Breast Cancer Model Mice and Mechanism Study]. AB - OBJECTIVE: To study the inhibitory effect and mechanism of Ganoderma lipsiense extract (GLE) on the growth of triple-negative breast cancer (TNBC) cell line MDA MB-231-HM in a mouse model. METHODS: The mouse model of TNBC was established by subcutaneous injection of 1.5 x 10(6) of MDA-MB-231-HM cells into BALB/c-nu mouse. Twenty successfully modeled mice were divided into the GLE group and the negative control group according to random digit table, 10 in each group. GLE (0.2 mL 100 mg/mL) was peritoneally injected to mice in the GLE group, while equal dose of normal saline was peritoneally injected to mice in the negative control group. The medication was administered once per 3 days and discontinued after 45 days. The CD34 expression was detected using immunohistochemical assay for counting microvessels. Meanwhile, expressions of thrombospondin 1 (TSP-1) and cyclin D1 were detected using immunohistochemical assay. RESULTS: The average weight was obviously lower in the GLE group than in the negative control group [(0.33 +/- 0.16) g vs (0.68 +/- 0.37)g, P < 0.05]. The tumor inhibition rate was 51.4% in the GLE group. The volume of transplanted tumor was obviously lesser in the GLE group than in the negative control group (P < 0.05). Results of immunohistochemical staining showed, the microvessel density (MVD) under every field was (20.7 +/- 2.1), TSP-1 positive cell count was (66.2 +/- 9.2), cyclin D1 positive cell count was (33.8 +/- 16.4) in the GLE group, and they were 34.0 +/- 2.0, 24.0 +/- 6.6, and 168.2 +/- 32.6, respectively in the negative control group. There was statistical difference in all indices between the two groups (P < 0.05). CONCLUSION: GLE could inhibit malignant proliferation of tumor cells by suppressing angiogenesis of blood vessels in tumor tissues and regulating cell cycles, thereby inhibiting TNBC. PMID- 27236899 TI - [Correlation Research between Pharmacological Method State and Natural Attribute of Chinese Herbs]. AB - Pharmacological method state is a method to explain the principle of Chinese herb according to its external phenomenon such as shape, color, texture, features, and so on. The natural attribute of Chinese herb include shape, color, texture, smell, harvesting time, medicinal parts, chemical components, and so on. Though both of them have different key points, the natural attribute of Chinese herb can also be used to explain its medicinal mechanism. Therefore, the correlation research between pharmacological method state and the natural attribute of Chinese herb has some significance. PMID- 27236900 TI - [Study on Roles of Latin in Modern Globalization of Chinese Medicine]. PMID- 27236901 TI - [Cytokines and Hashimoto Thyroiditis, and Their Prevention and Diagnosis Progress]. PMID- 27236902 TI - [Summary of Summit Forum on International Intearative Medicine]. PMID- 27236903 TI - [Seeking the Truth by Combining Chinese medicine and Western Medicine Elements Ten-year Academic Annual Summary of the Founding of Fujian Institution of Integrative Medicine]. PMID- 27236904 TI - High-Resolution and Universal Visualization of Latent Fingerprints Based on Aptamer-Functionalized Core-Shell Nanoparticles with Embedded SERS Reporters. AB - Although fingerprints have been widely used in forensic investigations, low resolution and poor universality are still the main obstacles for the development of fingerprint visualization. In this paper, a facile and universal imaging protocol for latent fingerprints (LFPs) was developed by combining sandwiched SERS probes with the highly sensitive and selective recognition of aptamers. The embedded SERS probes (Au/pNTP/SiO2) successfully avoid the environment interference, ascertaining the stability and reproducibility of Raman signals, and simultaneously improve the efficiency of the fingerprint identification. This approach is operationally simple without complicated pre- or post-treatments. Moreover, the fingerprint images display the high resolution in which third-level details can be clearly identified. This is a general approach and can be used to detect various types of fingerprints, including sebaceous, eccrine, fresh LFPs, and aged LFPs on different substrates (such as smooth, scratching, semiporous, and porous surfaces). PMID- 27236906 TI - Doctor to Doctor. PMID- 27236905 TI - Endoscopic transventricular exploration with biopsy of the basal cisterns and the role of endoscopic third ventriculostomy in patients suffering with basal cistern meningitis and consecutive hydrocephalus. AB - OBJECTIVES: The purpose of this work is to elucidate the efficacy of endoscopic basal cisterns exploration, biopsy, and third ventriculostomy (ETV) in patients with basal cistern meningitis and arachnoiditis. MATERIALS AND METHODS: The cases and videos of all patients in whom flexible neuroendoscopy was performed during the period of January 2005-June 2012 at the University Hospital 'Dr. Ignacio Morones Prieto' in San Luis Potosi, Mexico. A group of 47 patients with radiological diagnosis of basal meningitis, arachnoiditis, and negative cerebrospinal fluid analysis were included. RESULTS: From the 28 (60%) patients with histological diagnosis, 22 (47%) were made from biopsy from the arachnoid membranes of the basal cisterns only, 4 (9%) only from the cerebral cortex, and 2 (4%) from both sites. There were no complications related to the endoscopic procedure. In 23 patients from the 42 with hydrocephalus, ETV was successful. The grade of diagnostic accuracy of both biopsies in detect etiology was 68% (28 of 47 patients), the diagnostic accuracy of arachnoid biopsy was 60%, and diagnostic accuracy of convexity brain biopsy was 21% with 24 and 6 patients, respectively. DISCUSSION: Endoscopic transventricular biopsy of the basal cisterns seems to be a safe and a relatively accurate procedure. As longs as frozen subarachnoid space was not seen, the possibilities of performing ETV in hydrocephalus condition are elevated depending on the causal micro-organism. PMID- 27236907 TI - Here Comes Sciatica Claus. PMID- 27236908 TI - The Medical Bookshelf. PMID- 27236910 TI - Literature Scan. PMID- 27236909 TI - Pearls. PMID- 27236914 TI - Healthy holiday eating. PMID- 27236911 TI - cme credit QUIZ. PMID- 27236915 TI - Erratum. PMID- 27236918 TI - Consideration of Cosegregation in the Pathogenicity Classification of Genomic Variants. AB - The American College of Medical Genetics and Genomics (ACMG) and Association of Molecular Pathology (AMP) recently published important new guidelines aiming to improve and standardize the pathogenicity classification of genomic variants. The Clinical Sequencing Exploratory Research (CSER) consortium evaluated the use of these guidelines across nine laboratories. One identified obstacle to consistent usage of the ACMG-AMP guidelines is the lack of a definition of cosegregation as criteria for pathogenicity classification. Cosegregation data differ from many other types of pathogenicity data in being quantitative. However, the ACMG-AMP guidelines do not define quantitative criteria for use of these data. Here, such quantitative criteria, in an easily implementable form, are proposed. PMID- 27236916 TI - Genomic Profiling of Thyroid Cancer Reveals a Role for Thyroglobulin in Metastasis. AB - Papillary thyroid carcinoma (PTC) has a wide geographic variation in incidence; it is most common in Saudi Arabia, where it is only second to breast cancer as the most common cancer among females. Genomic profiling of PTC from Saudi Arabia has not been attempted previously. We performed whole-exome sequencing of 101 PTC samples and the corresponding genomic DNA to identify genes with recurrent somatic mutations, then sequenced these genes by using a next-generation gene panel approach in an additional 785 samples. In addition to BRAF, N-RAS, and H RAS, which have previously been shown to be recurrently mutated in PTC, our analysis highlights additional genes, including thyroglobulin (TG), which harbored somatic mutations in 3% of the entire cohort. Surprisingly, although TG mutations were not exclusive to mutations in the RAS-MAP kinase pathway, their presence was associated with a significantly worse clinical outcome, which suggests a pathogenic role beyond driving initial oncogenesis. Analysis of metastatic PTC tissue revealed significant enrichment for TG mutations (p < 0.001), including events of apparent clonal expansion. Our results suggest a previously unknown role of TG somatic mutations in the pathogenesis of PTC and its malignant evolution. PMID- 27236917 TI - Loss-of-Function Mutations in FRRS1L Lead to an Epileptic-Dyskinetic Encephalopathy. AB - Glutamatergic neurotransmission governs excitatory signaling in the mammalian brain, and abnormalities of glutamate signaling have been shown to contribute to both epilepsy and hyperkinetic movement disorders. The etiology of many severe childhood movement disorders and epilepsies remains uncharacterized. We describe a neurological disorder with epilepsy and prominent choreoathetosis caused by biallelic pathogenic variants in FRRS1L, which encodes an AMPA receptor outer core protein. Loss of FRRS1L function attenuates AMPA-mediated currents, implicating chronic abnormalities of glutamatergic neurotransmission in this monogenic neurological disease of childhood. PMID- 27236919 TI - Efficient Integrative Multi-SNP Association Analysis via Deterministic Approximation of Posteriors. AB - With the increasing availability of functional genomic data, incorporating genomic annotations into genetic association analysis has become a standard procedure. However, the existing methods often lack rigor and/or computational efficiency and consequently do not maximize the utility of functional annotations. In this paper, we propose a rigorous inference procedure to perform integrative association analysis incorporating genomic annotations for both traditional GWASs and emerging molecular QTL mapping studies. In particular, we propose an algorithm, named deterministic approximation of posteriors (DAP), which enables highly efficient and accurate joint enrichment analysis and identification of multiple causal variants. We use a series of simulation studies to highlight the power and computational efficiency of our proposed approach and further demonstrate it by analyzing the cross-population eQTL data from the GEUVADIS project and the multi-tissue eQTL data from the GTEx project. In particular, we find that genetic variants predicted to disrupt transcription factor binding sites are enriched in cis-eQTLs across all tissues. Moreover, the enrichment estimates obtained across the tissues are correlated with the cell types for which the annotations are derived. PMID- 27236920 TI - A Recurrent Mosaic Mutation in SMO, Encoding the Hedgehog Signal Transducer Smoothened, Is the Major Cause of Curry-Jones Syndrome. AB - Curry-Jones syndrome (CJS) is a multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas. Cerebellar medulloblastoma has been described in a single affected individual; in another, biopsy of skin lesions showed features of trichoblastoma. The combination of asymmetric clinical features, patchy skin manifestations, and neoplastic association previously led to the suggestion that this could be a mosaic condition, possibly involving hedgehog (Hh) signaling. Here, we show that CJS is caused by recurrent somatic mosaicism for a nonsynonymous variant in SMO (c.1234C>T [p.Leu412Phe]), encoding smoothened (SMO), a G-protein-coupled receptor that transduces Hh signaling. We identified eight mutation-positive individuals (two of whom had not been reported previously) with highly similar phenotypes and demonstrated varying amounts of the mutant allele in different tissues. We present detailed findings from brain MRI in three mutation-positive individuals. Somatic SMO mutations that result in constitutive activation have been described in several tumors, including medulloblastoma, ameloblastoma, and basal cell carcinoma. Strikingly, the most common of these mutations is the identical nonsynonymous variant encoding p.Leu412Phe. Furthermore, this substitution has been shown to activate SMO in the absence of Hh signaling, providing an explanation for tumor development in CJS. This raises therapeutic possibilities for using recently generated Hh-pathway inhibitors. In summary, our work uncovers the major genetic cause of CJS and illustrates strategies for gene discovery in the context of low-level tissue specific somatic mosaicism. PMID- 27236924 TI - Facial Synthesis of Three-Dimensional Cross-Linked Cage for High-Performance Lithium Storage. AB - Silicon/C composite is a promising anode material for high-energy Li-ion batteries. However, synthesizing high-performance Si-based materials at large scale and low cost remains a huge challenge. Here, we for the first time report the preparation of an interconnected three-dimensional (3D) porous Si-hybrid architecture by using a spray drying method. In this unique structure, the highly robust C-CNT-RGO cages not only can improve the conductivity of the electrode and buffer the volume expansion but also suppress the Si nanoparticles aggregation. As a result, the 3D Si@po-C/CNT/RGO electrode achieves long-life cycling stability at high rates (a reversible capacity of 854.9 mA h g(-1) at 2 A g(-1) after 500 cycles and capacity decay less than 0.013% per cycle) and good rate capability (1454.7, 1198.8, 949.2, 597.8, and 150 mA h g(-1) at current densities of 1, 2, 4, 10, and 20 A g(-1), respectively). Moreover, this novel electrode could deliver high reversible capacities and long-life stabilities even with high mass loading density (764.9 mA h g(-1) at 1.0 mg cm(-2) after 500 cycles and 472.2 mA h g(-1) at 1.5 mg cm(-2) after 400 cycles, respectively). This cheap and scalable strategy can be extended to fabricate other materials with large volume expansion (Sn, Ge, transition-metal oxides) and 3D porous carbon for other potential applications. PMID- 27236923 TI - BGN Mutations in X-Linked Spondyloepimetaphyseal Dysplasia. AB - Spondyloepimetaphyseal dysplasias (SEMDs) comprise a heterogeneous group of autosomal-dominant and autosomal-recessive disorders. An apparent X-linked recessive (XLR) form of SEMD in a single Italian family was previously reported. We have been able to restudy this family together with a second family from Korea by segregating a severe SEMD in an X-linked pattern. Exome sequencing showed missense mutations in BGN c.439A>G (p.Lys147Glu) in the Korean family and c.776G>T (p.Gly259Val) in the Italian family; the c.439A>G (p.Lys147Glu) mutation was also identified in a further simplex SEMD case from India. Biglycan is an extracellular matrix proteoglycan that can bind transforming growth factor beta (TGF-beta) and thus regulate its free concentration. In 3-dimensional simulation, both altered residues localized to the concave arc of leucine-rich repeat domains of biglycan that interact with TGF-beta. The observation of recurrent BGN mutations in XLR SEMD individuals from different ethnic backgrounds allows us to define "XLR SEMD, BGN type" as a nosologic entity. PMID- 27236925 TI - Screening of hepatitis C NS5B polymerase inhibitors containing benzothiadiazine core: a steered molecular dynamics. AB - Hepatic C virus (HCV) is a global health problem, resulting in liver cirrhosis and inflammation that can develop to hepatocellular carcinoma and fatality. The NS5B polymerase of HCV plays an important role in viral RNA replication process, making it an attractive therapeutic target for design and development of anti-HCV drugs. To search new potent compounds against the HCV NS5B polymerase, the molecular docking and the steered molecular dynamics (SMD) simulation techniques were performed. The potential potent inhibitors of the NS5B polymerase were screened out from the ZINC database using structural similarity search and molecular docking technique. Five top-hit compounds (the ZINC compounds 49888724, 49054741, 49777239, 49793673, and 49780355) were then studied by the SMD simulations based on the hypothesis that a high rupture force relates to a high binding efficiency. The results demonstrated that the ZINC compound 49888724 had a greater maximum rupture force, reflecting a good binding strength and inhibitory potency than known inhibitors and the rest four ZINC compounds. Therefore, our finding indicated that the ZINC compound 49888724 is a potential candidate to be a novel NS5B inhibitor for further design. Besides, the van der Waals interaction could be considered as the main contribution for stabilizing the NS5B-ligand complex. PMID- 27236922 TI - RNA Interference Prevents Autosomal-Dominant Hearing Loss. AB - Hearing impairment is the most common sensory deficit. It is frequently caused by the expression of an allele carrying a single dominant missense mutation. Herein, we show that a single intracochlear injection of an artificial microRNA carried in a viral vector can slow progression of hearing loss for up to 35 weeks in the Beethoven mouse, a murine model of non-syndromic human deafness caused by a dominant gain-of-function mutation in Tmc1 (transmembrane channel-like 1). This outcome is noteworthy because it demonstrates the feasibility of RNA-interference mediated suppression of an endogenous deafness-causing allele to slow progression of hearing loss. Given that most autosomal-dominant non-syndromic hearing loss in humans is caused by this mechanism of action, microRNA-based therapeutics might be broadly applicable as a therapy for this type of deafness. PMID- 27236927 TI - Emergency nurse. AB - Another editorial asking us to embrace Change, to try new ideas, to look to the future? Yes I am afraid so, but it is imperative that accident and emergency nurses are fully informed and involved in the mammoth changes that are taking place for their own and their patients' sake. Changes are accelerating in health care as in all aspects of life. PMID- 27236921 TI - Polymorphism in a lincRNA Associates with a Doubled Risk of Pneumococcal Bacteremia in Kenyan Children. AB - Bacteremia (bacterial bloodstream infection) is a major cause of illness and death in sub-Saharan Africa but little is known about the role of human genetics in susceptibility. We conducted a genome-wide association study of bacteremia susceptibility in more than 5,000 Kenyan children as part of the Wellcome Trust Case Control Consortium 2 (WTCCC2). Both the blood-culture-proven bacteremia case subjects and healthy infants as controls were recruited from Kilifi, on the east coast of Kenya. Streptococcus pneumoniae is the most common cause of bacteremia in Kilifi and was thus the focus of this study. We identified an association between polymorphisms in a long intergenic non-coding RNA (lincRNA) gene (AC011288.2) and pneumococcal bacteremia and replicated the results in the same population (p combined = 1.69 * 10(-9); OR = 2.47, 95% CI = 1.84-3.31). The susceptibility allele is African specific, derived rather than ancestral, and occurs at low frequency (2.7% in control subjects and 6.4% in case subjects). Our further studies showed AC011288.2 expression only in neutrophils, a cell type that is known to play a major role in pneumococcal clearance. Identification of this novel association will further focus research on the role of lincRNAs in human infectious disease. PMID- 27236928 TI - Proud to be a nurse. AB - The nursing profession has made great strides in gaining recognition within the NHS and at government level, but there has been an insidious erosion of its powerbase. And this time the fault lies within: nurses are undermining the profession's influence. PMID- 27236926 TI - Coupling and Reactions of 5-Hydroxyconiferyl Alcohol in Lignin Formation. AB - The catechol alcohols, caffeyl and 5-hydroxyconiferyl alcohol, may be incorporated into lignin either naturally or through genetic manipulation. Due to the presence of o-OH groups, these compounds form benzodioxanes, a departure from the interunit connections found in lignins derived from the cinnamyl alcohols. In nature, lignins composed of caffeyl and 5-hydroxyconiferyl alcohol are linear homopolymers and, as such, may have properties that make them amenable for use in value-added products, such as lignin-based carbon fibers. In the current work, results from density functional theory calculations for the reactions of 5 hydroxyconiferyl alcohol, taking stereochemistry into account, are reported. Dehydrogenation and quinone methide formation are found to be thermodynamically favored for 5-hydroxyconiferyl alcohol, over coniferyl alcohol. The comparative energetics of the rearomatization reactions suggest that the formation of the benzodioxane linkage is under kinetic control. Ring-opening reactions of the benzodioxane groups show that the bond dissociation enthalpy of the alpha-O cleavage reaction is lower than that of the beta-O reaction. The catechol lignins represent a novel form of the polymer that may offer new opportunities for bioproducts and genetic targets. PMID- 27236930 TI - Emergency nurse A&E network. AB - The Royal College of Nursing Accident and Emergency Nursing Association is setting up a database of information on A&E nurses and teams who have particular interests and expertise which they would like to share. PMID- 27236931 TI - Emergency nurse news. AB - The RCN Accident and Emergency Nursing Association is to be congratulated on yet another initiative. Its new supplement to Nursing Standard, is specifically concerned with accident and emergency nursing and will be of interest to nurses in the specialty, and to those in a range of clinical areas. PMID- 27236929 TI - Emergency nurse news. AB - Accident and emergency nurses have always been at the forefront of advances in patient treatment. To remain up-to-date in clinical practice, I believe that nurses need access to the latest research and information. PMID- 27236932 TI - [Not Available]. AB - Any new publication brings with it a source of reference, a revitalisation and an opportunity for change. Therefore, it is invigorating for accident and emergency nurses to have this supplement dedicated to our specialty. PMID- 27236933 TI - Go ahead for Council's shake up proposals. AB - The UKCC is to press ahead with its proposals to shake up community education and practice after getting the go ahead from nurses, midwives and I health visitors in a three-month consultation exercise. PMID- 27236934 TI - Conference cancellation. AB - The Department of Health has cancelled the conference 'A strategy for nursing: achievements and challenges', which was due to take place at the Queen Elizabeth Conference Centre in London on March 27, because of the general election. The Department hopes the conference, being held jointly with Nursing Standard, will be rescheduled. Further details will appear in Nursing Standard. PMID- 27236935 TI - College shelves plans for membership ballot. AB - The RCN has shelved a membership . ballot on the admission of support workers after the motion was dismissed by a narrow majority in a mass consultation. PMID- 27236936 TI - Operation clean-up. AB - The Operation Clean-up campaign ends this week having secured pledges from the two main opposition parties that they will implement its targets. PMID- 27236938 TI - Nursing assessment of elderly people is crucial to discharge. AB - Nursing and social assessment of elderly people who present with minor fractures to accident and emergency departments is crucial to early and safe discharge, according to a new research report. PMID- 27236937 TI - Patients choose A&E for primary care. AB - People in manual occupations are most likely to use hospital accident and emergency departments for primary health care, a survey of patients in Camberwell has shown. The King's Fund survey involved 855 accident and emergency primary care attenders and 744 patients visiting their family doctor. It aimed to discover why people attended A&E instead of visiting their local GP. PMID- 27236939 TI - Management prejudice hinders named nursing. AB - Management opposition to 'named nursing' could hinder its implementation, according to Steve Wright, a member of the Patient's Charter Group, set up by Health Secretary William Waldegrave to smooth the way for its April 1 start. PMID- 27236940 TI - 'Nurses are overwhelmed by theory'. AB - Nurses have moved too far from patient care and are overly obsessed with theory, Dame Kathleen Raven, former Chief Nursing Officer for England, told the RCN Annual Dinner last week. PMID- 27236941 TI - Skill mix. AB - Nurses must be involved it skill mix reviews are to be successful, according to new guidelines for RCN members. Badly managed reviews can damage patient care and staff morale, says the guide. PMID- 27236942 TI - Health care focus in fight for votes. AB - Health care and the future of the National Health Service has inevitably emerged as a major issue in the general election with all three main parties spelling out how they want the service to develop - and nursing's role within it. PMID- 27236943 TI - Just another death? AB - Much has been written on the increasing number of disasters that have occurred in the UK, and the traumatic effects on the people involved who suffer from PTSD (Post Traumatic Stress Disorder). PMID- 27236944 TI - 'Inappropriate attended' in A&E. AB - With the current emphasis on reducing patient waiting times, accident and emergency nurses may be tempted to close the doors on what they consider to be 'inappropriate attendees'. The author warns that public perceptions of A &E are often at odds with the nurses view, and that all patients should have access to accident and emergency services. This article takes a critical look at triage since its inception as a means of assessing wounded soldiers during the first world war. He explores patient assessment in accident and emergency departments and nurses' attitudes to- wards the 'inappropriate attended, highlighting the need for caution when dealing with enquiries from the general public. PMID- 27236945 TI - Assessing the value of open learning courses. AB - Open learning courses for nurses represent a shift of power away from educational establishments, and into the lives of 'those who need to learn,' an English National Board conference heard last week. PMID- 27236947 TI - Foreign nurses used as cheap labour? AB - Racist and xenophobic attitudes among British nurses are causing misery for their overseas colleagues who seek registration in the UK, a conference was told. PMID- 27236946 TI - Enrolled nurses. AB - COHSE has set upan enrolled nurse forum to lobby on a new ten-point Bill of Rights. PMID- 27236948 TI - [Not Available]. AB - Looming large: One of the 22 exhibitions on show at the Royal College of Nursing Canterbury branch held as a finale to the College's 75th birthday celebrations. PMID- 27236949 TI - Development of the nurse practitioner. AB - In the first of two articles on the development of the emergency nurse practitioner, Peter Howie reports on a new scheme in Lincoln where all first level nurses have been trained as nurse practitioners. The initiative was introduced following a study in the theoretical management of patients by experienced accident and emergency sisters. The author outlines the training course provided and the protocols within which nurse practitioners work. PMID- 27236950 TI - Nurses have difficulty discussing cancer. AB - Nurses' communications with cancer patients have improved little in the past 20 years, according to research by Susie Wilkinson, Senior Nurse (Education) at Liverpool's Marie Curie Centre. PMID- 27236951 TI - Inquiry hears analysis of poor patient care. AB - The need for security at Ashworth Special Hospital is often used as an excuse by those who want to prevent therapeutic initiatives, a clinical nurse specialist in rehabilitation told the public inquiry in London last week. PMID- 27236952 TI - Equal opportunities. AB - Sexual and racial harassment has been made a disciplinary offence in the NHS under new rules agreed by the Whitley Council. Managers must also ensure that women returning after maternity leave, even part time, come back on the same grade and to a post of similar status. PMID- 27236954 TI - [Not Available]. AB - Archersstar Sudha Bhuchar, right, launches a video on breast screening for women from ethnic minorities, sponsored by the NHS. The video is available in six languages. Ms Bhuchar is pictured with programme co-ordinator Julietta Patrick. PMID- 27236957 TI - Link between violence and underfunding. AB - The Trades Union Congress (TUC) is to highlight the link between underfunding in the National Health Service and attacks on staff. PMID- 27236955 TI - Cash shortfall for care objectives. AB - Only one fifth of the actual money needed to meet objectives in residential care may be forthcoming from Government, David Tombs, social services director for Hereford and Worcester County Council, claimed last week. PMID- 27236958 TI - Emergency nurse practitioners. AB - Attendances in most accident and emergency departments increase by 1 per cent per annum, which results in longer waiting times for patients, the most disadvantaged being those who are considered lower priority. PMID- 27236959 TI - Whose problem - A&E or general practitioner? AB - Accident and emergency services are demand-led with little control over the pace or workload. Many A&E departments see a large proportion of patients who do not necessarily need the skills or resources of a hospital. In a study undertaken by Bellavia and Brown it was found that, of 200 patients interviewed, 33 per cent could have been treated by their GP, and 52 percent felt their problem was not an emergency. PMID- 27236960 TI - Resuscitation: should relatives be present? AB - A lively debate has begun following the publication of a letter suggesting relatives be allowed to remain in the room when a patient is being resuscitated. The letter was from a nurse in Vermont, USA, who prompted Texas nurse Christiana Osuagwu to undertake a straw poll of 12 nurses and eight doctors. PMID- 27236963 TI - Benzodiazepine dependence danger. AB - Nurse attitudes to hypnotics may be contributing to the risk of patients becoming dependent on benzodiazepines, although the risks associated with such drugs are well publicised. PMID- 27236962 TI - Resuscitation: when to call a halt. AB - If an ambulance crew have been unable to resuscitate a patient on the way to A&E, is it worthwhile continuing in the department? Probably not, according to some American researchers. PMID- 27236964 TI - [Not Available]. AB - People travelling abroad may no longer be able to obtain health information from practice nurses, a letter in the British Medical Journal suggests. A London GP says under new contract arrangements, nurses in a health promotion clinic were able to advise travellers about potential risks abroad, such as food poisoning, malaria, and the possible risk of HIV infection. But the GP's local family health services authority has said this sort of advice no longer counts as health promotion, and the L4.50 a patient for health promotion services is no longer payable. The nurses will not now have time to discuss these issues properly, says the GP. We would probably need to prevent only one case of AIDS in 10.000 patients seen, to be cost effective,' he adds. PMID- 27236965 TI - Caring for women who miscarry. AB - Good practice guidelines aimed at health professionals caring for women who miscarry have been produced by the Miscarriage Association. PMID- 27236966 TI - Psychological support for cancer patients. AB - All nursing care for cancer patients should include psychological support, it was claimed last week after new evidence that psychological therapy improves patients' quality of life was published by a team from The Royal Marsden Hospital. PMID- 27236967 TI - What stimulates liver regeneration? AB - Liver regeneration is regulated mainly by factors other than hepatocytes, researchers have found. PMID- 27236968 TI - Screening for CF gains broad acceptance. AB - There is broad acceptance of the concept of population screening for cystic fibrosis, researchers say. PMID- 27236969 TI - Second-hand exposure of children to cocaine. AB - Children might be being exposed to cocaine through the inhalation of 'second hand' smoke. PMID- 27236970 TI - Guided imagery and smoking abstinence. AB - Guided relaxation imagery might be a useful technique in maintaining abstinence in people who have given up smoking. PMID- 27236971 TI - Mobility improved, but only in the short term. AB - Intervention by a physiotherapist can improve mobility in patients seen late after a stroke, but the effects do not seem to be maintained. PMID- 27236972 TI - One bad apple? AB - Wops,' 'mess-pots' and 'slags'. Death threats, intimidation and oppression. The language is abusive, the atmosphere frightening and the place where it is alleged to have happened is a hospital. And it is nurses who are said to have perpetrated this verbal and physical abuse, and to have scared colleagues who did not conform. PMID- 27236973 TI - Cleaning up the campaign. AB - When we launched Operation Clean-up in January to ascertain and tackle the problem of hospital-acquired infections and hospital cleanliness we did not know what we would find - or achieve. PMID- 27236974 TI - Your hospital horror stories. AB - My 74-year-old husband was admitted to a Somerset hospital for what should have been a simple hernia repair under local anaesthetic - in one day and out the next. PMID- 27236975 TI - Primary nursing part time. AB - Although I agreed with the views expressed by Linda Nazarko in her article 'Primary or secondary' (Viewpoint, March 11), I was horrified by her example of the nurse who was rejected as a primary nurse because she worked part time. PMID- 27236976 TI - The other long waiting list. AB - I read with interest James Buchan's article 'Uncertainty on career prospects' (Clinical, March 11). As an enrolled nurse (general and psychiatric), it is depressing to be in a professional cul-de-sac with little prospect of furthering my career. I have struggled for some time to gain a place on a conversion course, but have found it particularly difficult because I work outside the National Health Service. PMID- 27236977 TI - Safe cleaning of instruments. AB - I am writing in response to a letter that dealt with the sluicing of used instruments (Letters, January 29). PMID- 27236978 TI - Catherine Burns 'expendable'? AB - The resignation of the Health Visitors' Association General Secretary Catherine Burns must be of grave concern to all those members who understood what she was fighting for, which was typified in the proposal that there should be only one seat for health visitors on the UKCC (News, March 11). PMID- 27236979 TI - Long wait for eye operation. AB - I cannot decide whether this constitutes whistle blowing, but as it concerns the care provided by the National Health Service, perhaps it does. PMID- 27236981 TI - Information exchange. AB - We are conducting a survey into wound measurement and would appreciate information from anybody who is using, or has used, a measurement tool or grid. PMID- 27236980 TI - Obituary. AB - Frances Fowler SRN, a founder member of the Royal College of Nursing, died on March 8 1992 at Chadwell Heath Hospital in Essex. Miss Fowler, who was 100 when she died, qualified at the Royal Gwent Hospital in 1916 at the age of 25. PMID- 27236985 TI - The honorary officers. PMID- 27236986 TI - Transplant nursing at Papworth Hospital. AB - Papworth Hospital is the cardiothoracic centre for East Anglia and also one of the I designated supra-regional centres for cardiac and cardiopulmonary transplantation. It was the first hospital in the UK to commission a cardiac transplant programme within the National Health Service, in 1979. PMID- 27236987 TI - Listings. AB - International April 24-25 A conference on education and employment opportunities, titled 'Health policies in transition', will be held at the F.ast Midland Conference Centre, University Park, Nottingham. It will be organised by Trent Regional Health Authority and the University of Nottingham. The fee is L250. Details from Angela Elliott, Trent Regional Health Authority, Fulwood House, Old Fulwood Road, Sheffield S10 3TH. Tel 0742 630300. PMID- 27236989 TI - If You Want to Go Far, Go Together. PMID- 27236988 TI - Associations of current marital status and living arrangements with HIV and syphilis risk: findings from a community-based sample of men who have sex with men in China. AB - Chinese men who have sex with men (MSM) are disproportionally affected by HIV and sexually transmitted infections (STIs), but little is known about the role of current marital status and living arrangements in shaping their HIV/syphilis risk. A cross-sectional study was conducted among MSM in Beijing, China to assess their sociodemographic/behavioral characteristics between married and single MSM, and test the hypothesis that currently married MSM have a lower odds of being HIV and/or syphilis-infected. Participants were recruited via short message services, peer referral, internet, and community outreach. Data collection was based on a questionnaire survey and self-report. Infection status was lab confirmed. Multivariable logistic regression modeling was used to assess the association of marital status and living arrangement with HIV/syphilis risk. Of the 3588 MSM, infection prevalence was high (HIV = 12.7%; syphilis = 7.5%). Compared to single MSM living with their boyfriends or male sex partners, single/alone MSM and married MSM living with wives were less likely to practice condomless insertive (CIAI) or receptive (CRAI) anal intercourse with men; while married MSM living with boyfriends or male sex partner were more likely to practice CIAI and CRAI, and married MSM were more likely to practice condomless vaginal sex. Compared to men living with boyfriends/sexual partners, significantly reduced odds of being HIV-positive were seen among married MSM who were living alone (aOR: 0.52; 95%CI: 0.28, 0.94) or living with their wives (aOR: 0.53; 95%CI: 0.31, 0.89). Similarly, single MSM living alone (aOR: 0.67; 95%CI: 0.48, 0.95) and married MSM living with their wives were comparatively less likely to be syphilis-infected (aOR: 0.43; 95%CI: 0.23, 0.79). Future efforts should consider characteristics of marital status and living arrangements for designing subgroup-specific risk reduction strategies among Chinese MSM. PMID- 27236990 TI - Beyond the Operatory and Into Opportunity. PMID- 27236991 TI - The American Dental Hygienists' Association Leads the Profession into 21st Century Workforce Opportunities. AB - With the dental hygiene profession undergoing tremendous transformation as greater and more diverse workplace opportunities present themselves, the American Dental Hygienists' Association (ADHA) is leading the effort to ensure that dental hygienists are prepared to take advantage of these growing opportunities in today's constantly evolving health care landscape. BACKGROUND AND PURPOSE: ADHA's vision statement calls for the integration of dental hygienists into the health care delivery system as essential primary care providers to expand access to oral health care. This article discusses changes in dental hygiene curriculum, as well as how changes in the health care environment and legislative outcomes are impacting workplace opportunities for dental hygienists in the 21st century. METHOD: Research from ADHA's Transforming Dental Hygiene Education and the Profession for the 21st Century white paper and other oral health-related literature, ADHA policies, and ADHA survey research describe the evolving dental hygiene workplace environment. The article discusses trends in education, health care, legislative and regulatory practice, and societal need that are creating new workforce opportunities for the dental hygiene profession. CONCLUSION: With rapid change in both the oral and overall health care environments, transformation in dental hygiene curriculum and competencies, and more states allowing the public to have direct access to dental hygienists, dental hygiene professionals are expanding their presence into all aspects of the health care system. ADHA is leading this effort to help dental hygienists provide that care by expanding workforce opportunities and allowing dental hygienists to practice to the full extent of their scope. The dental hygiene profession must be prepared and ready to embrace these opportunities. In doing so, new career pathways will be available for dental hygiene professionals that will also improve the public's access to oral health care. PMID- 27236992 TI - Commentary on an Innovative Interprofessional Dental Practice for 2026. AB - An innovative interprofessional model is described for the delivery of dental care in the year 2026 to optimize efficiency and profitability while enhancing quality of care. BACKGROUND: The dental practice of tomorrow may look different than today. Although not broken, the current system can be improved in efficiency and effectiveness. Although traditional private practices will continue to exist and many will thrive over the next decades, they may not present the optimal model for dental practice. To manage complex patient needs, a more collaborative model of multidisciplinary, interprofessional clinical teams capable of treating patients comprehensively has been suggested by the authors. They explore an alternative model of practice that may be possible in the next 10 years to better serve patients and improve outcomes while honoring the role of practitioners. METHODS: Landmark publications and reviews are used to examine evidence showing the potential benefits of an innovative interprofessional approach to the delivery of care in the oral health care setting. CONCLUSIONS: By examining key studies, the authors provide commentary on the potential for enhanced efficiency, profitability, and quality of care in the oral health care setting through a collaborative model of multidisciplinary, interprofessional clinical teams capable of treating patients comprehensively. PMID- 27236993 TI - Dental Hygienist-Led Chronic Disease Management System to Control Early Childhood Caries. AB - Management of the complex chronic disease of early childhood caries requires a system of coordinated health care interventions which can be led by a dental hygienist and where patient self-care efforts are paramount. BACKGROUND AND PURPOSE: Even after receiving costly surgical treatment under general anesthesia in the operating room, many children develop new and recurrent caries after only 6-12 months, a sequela that can be prevented. This article describes the chronic disease management (CDM) of dental caries, a science-based approach that can prevent and control caries. METHODS: In this article, we (1) introduce the concept of CDM of dental caries, (2) provide evidence that CDM improves oral health outcomes, and (3) propose a dental hygienist-led team-based oral health care approach to CDM. Although we will be describing the CDM approach for early childhood caries, CDM of caries is applicable in children, adolescents, and adults. CONCLUSIONS: Early childhood caries disease control requires meaningful engagement of patients and parents by the oral health care team to assist them with making behavioral changes in the unique context of their families and communities. The traditional dentist/hygienist/assistant model needs to evolve to a collaborative partnership between care providers and patients/families. This partnership will be focused on systematic risk assessment and behaviorally based management of the disease itself, with sensitivity toward the familial environment. Early pilot study results demonstrate reductions in the rates of new caries, dental pain, and referral to the operating room compared with baseline rates. Dental hygienists are the appropriate team members to lead this approach because of their expertise in behavior change and prevention. PMID- 27236994 TI - The Oral Health Care Manager in a Patient-Centered Health Facility. AB - The dental hygienist team member has an opportunity to coordinate care within an interprofessional practice as an oral health care manager. BACKGROUND AND PURPOSE: Although dental hygienists are currently practicing within interprofessional teams in settings such as pediatric offices, hospitals, nursing homes, schools, and federally qualified health centers, they often still assume traditional responsibilities rather than practicing to the full extent of their training and licenses. This article explains the opportunity for the dental hygiene professional to embrace patient-centered care as an oral health care manager who can facilitate integration of oral and primary care in a variety of health care settings. METHODS: Based on an innovative model of collaboration between a college of dentistry and a college of nursing, an idea emerged among several faculty members for a new management method for realizing continuity and coordination of comprehensive patient care. Involved faculty members began working on the development of an approach to interprofessional practice with the dental hygienist serving as an oral health care manager who would address both oral health care and a patient's related primary care issues through appropriate referrals and follow-up. This approach is explained in this article, along with the results of several pilot studies that begin to evaluate the feasibility of a dental hygienist as an oral health care manager. CONCLUSION: A health care provider with management skills and leadership qualities is required to coordinate the interprofessional provision of comprehensive health care. The dental hygienist has the opportunity to lead closer integration of oral and primary care as an oral health care manager, by coordinating the team of providers needed to implement comprehensive, patient-centered care. PMID- 27236995 TI - A New Practice Approach for Oral Health Professionals. AB - The oral health care paradigm presented here would broaden oral health services to include primary health care activities focusing on risk reduction and chronic disease screening. BACKGROUND AND PURPOSE: Changes in our nation's health care delivery system, shifting patient demographics, and availability of new health insurance programs have resulted in exploration of new practice models of health care delivery. Chronic diseases require coordinated care efforts over decades of a patient's life. Oral health professionals will be part of that care. METHODS: The practice model for this article was developed in the context of an academic medical center that promotes oral health care professionals as health care providers through interprofessional education. The combined experiences of the authors, including a diabetes predictive model for oral health settings, the efficacy and effectiveness of human immunodeficiency virus screening in a dental setting, the feasibility of using a decision support tool for tobacco cessation, and the effectiveness of integrating oral health education with comprehensive health services for people living with human immunodeficiency virus, have contributed to this concept. CONCLUSIONS: Prevention is increasingly recognized as a cost-effective means of reducing chronic disease burdens. To be effective, health promotion activities that encourage healthy living and early detection need to occur in a variety of health care settings. Oral health professionals represent an underutilized group of health care providers that can contribute to improved health of populations living with chronic diseases by broadening their scope of practice to include primary health screenings and tailored health promotion activities. PMID- 27236996 TI - Oral Health Care Delivery Within the Accountable Care Organization. AB - The accountable care organization (ACO) provides an opportunity to strategically design a comprehensive health system in which oral health works within primary care. A dental hygienist/therapist within the ACO represents value-based health care in action. BACKGROUND: Inspired by health care reform efforts in Minnesota, a vision of an accountable care organization that integrates oral health into primary health care was developed. Dental hygienists and dental therapists can help accelerate the integration of oral health into primary care, particularly in light of the compelling evidence confirming the cost-effectiveness of care delivered by an allied workforce. METHODS: A dental insurance Chief Operating Officer and a dental hygiene educator used their unique perspectives and experience to describe the potential of an interdisciplinary team-based approach to individual and population health, including oral health, via an accountable care community. CONCLUSIONS: The principles of the patient-centered medical home and the vision for accountable care communities present a paradigm shift from a curative system of care to a prevention-based system that encompasses the behavioral, social, nutritional, economic, and environmental factors that impact health and well-being. Oral health measures embedded in the spectrum of general health care have the potential to ensure a truly comprehensive healthcare system. PMID- 27236997 TI - Collaboration Between Medical Providers and Dental Hygienists in Pediatric Health Care. AB - Basic preventive oral services for children can be provided within the medical home through the collaborative care of medical providers and dental hygienists to expand access for vulnerable populations. BACKGROUND: Because dental caries is a largely preventable disease, it is untenable that it remains the most common chronic disease of childhood. Leveraging the multiple visits children have with medical providers has potential to expand access to early preventive oral services. Developing interprofessional relationships between dental providers, including dental hygienists, and medical providers is a strategic approach to symbiotically expand access to dental care. Alternative care delivery models that provide dental services in the medical home expand access to these services for vulnerable populations. The purpose of this article is to explore 4 innovative care models aimed to expand access to dental care. METHODS: Current activities in Colorado and around the nation are described regarding the provision of basic preventive oral health services (eg, fluoride varnish) by medical providers with referral to a dentist (expanded coordinated care), the colocation of dental hygiene services into the medical home (colocated care), the integration of a dental hygienist into the medical care team (integrated care), and the expansion of the dental home into the community setting through telehealth-enabled teams (virtual dental home). Gaps in evidence regarding the impacts of these models are elucidated. CONCLUSION: Bringing preventive and restorative dental services to the patient both in the medical home and in the community has potential to reduce long-standing barriers to receive these services, improve oral health outcomes of vulnerable patients, and decrease oral health disparities. PMID- 27236998 TI - Minnesota Extends Oral Healthcare Delivery to Impact Population Health. AB - Collaborative leadership and stakeholder engagement have created the concept of dental therapist intraprofessional dental team members who are expanding and extending the reach of oral health care to help meet the public need in Minnesota. BACKGROUND AND PURPOSE: Partially owing to inadequate access to affordable oral health care, health disparities exist within Minnesota's population with significant numbers of residents lacking access to basic oral health care. Policymakers, advocacy organizations, and dental professionals recommended action to address these issues. In 2009, Minnesota became the first state government in the United States to license 2 levels of practitioners, the dental therapist and the advanced dental therapist to primarily treat underserved patients. The purpose of this article is to explain the evolution of the dental therapist and guide other constituencies toward innovative dental hygiene-based workforce models. METHODS: The evolution and educational preparation of the dental therapist and advanced dental therapist are explained in the context of a unique working relationship between educators, legislators, educational institutions, and the Minnesota Department of Health. Pivotal societal, public health, and legislative issues are described from the initial stages in 2005 until 2014 when early data are emerging regarding the impact of dental therapists. CONCLUSIONS: Dental therapist oral health care providers are working in a variety of settings in Minnesota including community clinics, hospitals, and private practices. As of early February 2014, there were 32 licensed dental therapists, and 6 of whom also held certifications as advanced dental therapists. Initial public health impacts are positive; research regarding the benefits to the public is in its infancy. Further evaluation of outcomes will ascertain the viability of this new professional. PMID- 27236999 TI - Dental Hygienist Providers in Long-Term Care: Meeting the Need. AB - Dental hygienists with expertise in the policies, protocols, and practices of long-term care settings can provide oral health care services that complement the health complexities of residents. BACKGROUND: Adults in the United States are living longer and retaining more teeth, creating an increased demand for oral health care within long-term care facilities. Oral health has, in the past, been perceived as less important than other aspects of daily care and focused more on comfort than control of potential pathogens of oral origin. The concept in medicine of a care continuum from cradle to grave has not generally included provisions for oral health because historically few private dental practices have had provisions for continuation of care once an individual is unable to access the private office. This article supports the inclusion of dental hygienist care team members in long-term care settings. METHODS: The author has provided oral health care services in long-term care for many years, modeling this important career path for dental hygienists. Examples of the personal contributions of the dental hygienist author in helping to meet the extreme needs of this population illustrate this viable career option for dental hygienists. Resources used include federal and state health care publications, data from the American Dental Hygienists Association and selected state dental hygiene associations, published literature, and interviews with dental hygiene business owners, as well as the author's years of expertise. CONCLUSION: Oral health is a significant health concern for elders and others in long-term care settings. Daily oral care practices and optimal oral health are related to the well-being and quality of life that long-term care residents deserve. Pathways to providing preventive oral health services will gain momentum as dental hygienists become an integral part of the long-term care setting health care team. PMID- 27237000 TI - Preventing Advanced Carious Lesions with Caries Atraumatic Restorative Technique. AB - An alternative approach to controlling dental caries and preventing the associated pain, called atraumatic restorative technique (ART), is described for populations in need, where dental hygienists restore decayed teeth with glass ionomer restorations without prior removal of all decayed tooth structure. BACKGROUND AND PURPOSE: There are populations whose decay needs are not adequately being met within the current oral health care delivery system. These include those in poverty conditions, vulnerable children, and the elderly who are often in long-term care facilities without adequate resources or opportunities for traditional dentistry. ART provides a viable option for controlling caries and relieving the pain of untreated decay. The purpose of this article is to suggest that the evidence surrounding ART be viewed objectively and that dental hygienists, with additional education in this approach, can contribute to relieving the pain of untreated dental decay. CONCLUSION: Evidence suggests that teeth can be effectively restored with ART. Dental hygienists represent an appropriate workforce to provide ART with their current background and education combined plus a brief training program; it is suggested that dental hygiene educational programs include ART within the curriculum. Along with dental sealants and fluoride varnish application, ART can be an important component of a comprehensive preventive program to address the unmet needs of vulnerable populations. PMID- 27237001 TI - Periodontal Management by Risk Assessment: A Pragmatic Approach. AB - An evidence-based periodontal disease risk assessment and diagnosis system has been developed and combined with a clinical decision support and management program to improve treatment and measure patient outcomes. BACKGROUND: There is little agreement on a universally accepted periodontal risk assessment, periodontal diagnosis, and treatment management tool and their incorporation into dental practice to improve patient care. This article highlights the development and use of a practical periodontal management and risk assessment program that can be implemented in dental settings. METHODS: The approach taken by Willamette Dental Group to develop a periodontal disease risk assessment, periodontal diagnosis, and treatment management tool is described using evidence-based best practices. With goals of standardized treatment interventions while maintaining personalized care and improved communication, this process is described to facilitate its incorporation into other dental settings. CONCLUSIONS: Current electronic health records can be leveraged to enhance patient-centered care through the use of risk assessments and standardized guidelines to more effectively assess, diagnose, and treat patients to improve outcomes. Dental hygienists, and other committed providers, with their emphasis on prevention of periodontal disease can be principal drivers in creation and implementation of periodontal risk assessments and personalized treatment planning. Willamette Dental Group believes that such evidence-based tools can advance dentistry to new diagnostic and treatment standards. PMID- 27237002 TI - Improving Outcomes for Transplant Patients: Contribution of a Dental Hygienist. AB - A dental hygienist member of an interdisciplinary medical team can contribute to improved outcomes when cancer and transplant patients experience oral sequelae. BACKGROUND AND PURPOSE: Cancer and transplant patients benefit from care provided by an interdisciplinary team comprised of general and oral health care providers. Diagnostic and supportive care including assessment and stabilization of oral health as well as management of treatment and disease sequelae are essential treatment planning components. This article provides support for a dental hygienist team member contributing toward optimal care for this patient population at high risk for infection and other serious complications. METHODS: A dental hygienist manager of an oral medicine service that provides clinical care for transplant patients describes how her position within a cancer research center has evolved. Using case scenarios, the impact of an interdisciplinary medical transplant team on patient care is presented. CONCLUSIONS: A dental hygienist, interested in working with oncology or transplant patients, as part of an interdisciplinary medical team, can contribute toward the well-being of patients and experience a challenging and rewarding career that combines aspects of medicine and dentistry. PMID- 27237003 TI - Drivers Advancing Oral Health in a Large Group Dental Practice Organization. AB - Three change drivers are being implemented to high standards of patient centric and evidence-based oral health care within the context of a large multispecialty dental group practice organization based on the commitment of the dental hygienist chief operating officer and her team. BACKGROUND AND PURPOSE: A recent environmental scan elucidated 6 change drivers that can impact the provision of oral health care. Practitioners who can embrace and maximize aspects of these change drivers will move dentistry forward and create future opportunities. This article explains how 3 of these change drivers are being applied in a privately held, accountable risk-bearing entity that provides individualized treatment programs for more than 417,000 members. To facilitate integration of the conceptual changes related to the drivers, a multi-institutional, multidisciplinary, highly functioning collaborative work group was formed. METHODS AND APPROACH: The document Dental Hygiene at a Crossroads for Change(1) inspired the first author, a dental hygienist in a unique position as chief operating officer of a large group practice, to pursue evidence-based organizational change and to impact the quality of patient care. This was accomplished by implementing technological advances including dental diagnosis terminology in the electronic health record, clinical decision support, standardized treatment guidelines, quality metrics, and patient engagement to improve oral health outcomes at the patient and population levels. The systems and processes used to implement 3 change drivers into a large multi-practice dental setting is presented to inform and inspire others to implement change drivers with the potential for advancing oral health. CONCLUSIONS: Technology implementing best practices and improving patient engagement are excellent drivers to advance oral health and are an effective use of oral health care dollars. Improved oral health can be leveraged through technological advances to improve clinical practice. PMID- 27237004 TI - Complexities of Providing Dental Hygiene Services in Community Care Settings. AB - Direct access care provided by dental hygienists can reduce oral health disparities for the underserved, yet legal, regulatory, and ethical considerations create complexities and limits. BACKGROUND AND PURPOSE: Individual state dental practice acts regulate the scope of practice and level of supervision required when dental hygienists deliver care. Yet, inconsistent state practice act regulations contribute to ethical and legal limitations and dilemmas for practitioners. The dental hygienist is positioned to assume an increasingly larger role in the management of oral health disparities. However, there are several legal and ethical considerations that impact both dental hygienists and dentists providing care in complex community settings. This article informs dental hygienists and other related constituencies about conundrums that are encountered when providing care 'beyond the operatory.' METHODS: An evidence based view of ways in which dental hygienists are reducing oral health disparities illustrates the complex issues involved in providing such care. Potential scenarios that can occur during care provision in underserved settings provide the basis for a discussion of legal and other associated issues impacting dental hygiene practice. PMID- 27237005 TI - A Baccalaureate Education Curriculum to Prepare Dental Hygienists for Expanded Public Health Practice. AB - A baccalaureate dental hygiene education program was intentionally designed and implemented to prepare dental hygienists to work in expanded public health practice. BACKGROUND: Expanded practice dental hygienists (EPDH) in Oregon practice without the supervision of a dentist to provide dental hygiene services for underserved patients with limited access to dental care. Ten competencies were identified for the successful EPDH, and then these competencies were incorporated into the curriculum of a baccalaureate dental hygiene program. METHODS: When recent graduates of the innovative program were surveyed, results indicated that they felt well prepared for expanded practice, they had a high level of interest in working as an EPDH, and all were planning to apply for an expanded practice permit. Two graduates and their unique contributions to individuals in need are profiled. CONCLUSIONS: Intentional preparation of dental hygienists for expanded public health roles suggested the need for a baccalaureate curriculum designed specifically for that purpose. Advocacy and collaboration among educators, legislators, and administrators in Oregon led to the development and implementation of such an innovative dental hygiene education program at Pacific University. Graduates are likely to pursue opportunities working as EPDHs. Further research will document the viability of this purposefully designed curriculum to prepare dental hygienists to help meet the public need for optimal oral health. PMID- 27237006 TI - Advocacy for the Provision of Dental Hygiene Services Within the Hospital Setting: Development of a Dental Hygiene Student Rotation. AB - Educational preparation of dental hygiene students for hospital-based practice, and advocacy efforts promote inclusion of dental hygienists within hospital-based interdisciplinary health care teams. BACKGROUND AND PURPOSE: Although the value of attending to the oral care needs of patients in critical care units has been recognized, the potential impact of optimal oral health care for the general hospital population is now gaining attention. This article describes a hospital based educational experience for dental hygiene students and provides advocacy strategies for inclusion of dental hygienists within the hospital interdisciplinary team. METHODS: The dental hygienist authors, both educators committed to evidence-based oral health care and the profession of dental hygiene, studied hospital health care and recognized a critical void in oral health care provision within that setting. They collaboratively developed and implemented a hospital-based rotation within the curriculum of a dental hygiene educational program and used advocacy skills to encourage hospital administrators to include a dental hygiene presence within hospital-based care teams. CONCLUSIONS: Hospital-based dental hygiene practice, as part of interprofessional health care delivery, has the potential to improve patient well-being, shorten hospital stays, and provide fiscal savings for patients, institutions, and third party payers. Advocacy efforts can promote dental hygienists as members of hospital-based health care teams. Further research is needed to document: (1) patient outcomes resulting from optimal oral care provision in hospitals; (2) best ways to prepare dental hygienists for career opportunities within hospitals and other similar health care settings; and (3) most effective advocacy strategies to promote inclusion of dental hygienists within care teams. PMID- 27237008 TI - The Doctoral Degree in Dental Hygiene: Creating New Oral Healthcare Paradigms. AB - Doctoral dental hygiene education would prepare scholars and leaders to improve population health through changes in oral health policy and delivery. BACKGROUND: Discussions about doctoral education in dental hygiene have centered on the need to create a cadre of dental hygiene researchers and scholars who will expand the body of knowledge for the profession. It has been proposed that scholars are needed to lead the development of theory and disseminate knowledge unique to the discipline of dental hygiene. Transformation to doctoral education is not a new trend as many other health care disciplines have already implemented curricular models, establishing the doctoral degree for entry level into practice. The Institute of Medicine has called for the exploration of new models for care delivery. Dental hygienists need to be prepared with leadership skills enabling them to participate and lead interprofessional teams and develop policies designed to improve the delivery of oral health care services to enhance population health. Current educational models do not adequately prepare dental hygienists to serve in this capacity. METHODS: The purpose of this article is to present 2 models of doctoral education for dental hygiene that will illustrate how dental hygienists can be better prepared as scholars and leaders for the profession. CONCLUSION: These proposed models of doctoral education in dental hygiene present a paradigm shift in dental hygiene education. As with other disciplines that have evolved, both academically and professionally, dental hygiene will be positioned to achieve the hallmark of professional status with this terminal degree. PMID- 27237007 TI - The Baccalaureate-Educated Dental Hygienist. AB - The baccalaureate degree as entry level education will prepare dental hygienists to meet the basic challenges of evolving patient oral health care needs. BACKGROUND: The nature of health care is changing because of economic and societal developments. For example, the Affordable Care Act is allowing more individuals the opportunity to seek care. People are living longer with chronic disorders. Technological advances allow for treatment of disease to ultimately improve or extend lives. States are legislating broader scopes of practice for dental hygienists and other types of health care providers. Trends such as nontraditional work settings and patients exhibiting chronic diseases with comorbidities, suggest that dental hygienists have at least a baccalaureate education to be prepared to embrace expanded interprofessional roles, technological advances, and effective care for diverse populations. Advanced degrees beyond the baccalaureate level will be indicated for dental hygienist researchers and scholars who will lead theory and policy development to improve population health. METHODS: The importance of a baccalaureate education for dental hygienists is illustrated with insights from dental hygiene and dental education organizations, the American Association of Colleges and Universities and current literature. CONCLUSIONS: A baccalaureate education will equip dental hygienists to help provide basic oral care for a diverse population in a variety of health care settings. Health care providers with a broad range of knowledge and skills, flexibility and decision-making capacity, and a commitment to personal and social responsibility will be valued in the marketplace. More research is needed documenting the public health benefits of a baccalaureate educated dental hygienist and further advanced degrees in dental hygiene. PMID- 27237010 TI - Frontliners. PMID- 27237009 TI - A&E staff praised for disciplined response to London bomb attacks. AB - A spate of terrorist nail-bombs in Brixton, Brick Lane and Soho in London saw A&E nurses at King's College Hospital, Guy's, University College Hospital (UCH), The Royal London, and St Thomas' Hospital implementing major incident plans recently. Three people were killed and dozens injured in what were originally believed to be the work of far-right extremist groups. PMID- 27237011 TI - When a child is murdered: the needs of relatives left behind. AB - Losing a loved one to a murderer is 'like having a grenade going off inside you' the RCN Children in A&E network annual conference in Birmingham has been told. PMID- 27237012 TI - Campaign highlights A&E misuse. AB - One in three people with minor conditions clog up A&Es rather than treating themselves or visiting their GP or pharmacist, a national survey has found. PMID- 27237013 TI - Legal challenge over latex gloves. AB - The RCN has urged safety representatives across the UK to contact staff affected by latex allergies with a view to taking employers to court. They have also been encouraged to identify examples of bad practice at work. The move follows the launch of a campaign, Getting a Grip on Latex Allergy, in October last year. PMID- 27237014 TI - Manchester triage system 'a sensitive tool'. AB - The Manchester triage system (MTS) is now widely used in A&E departments in the UK. Researchers in Birmingham sought to determine whether the MTS can reliably detect those patients subsequently needing admission to critical care areas. Computerised records at City Hospital, Birmingham were analysed to retrieve all patients admitted from A&E to a critical care area (ICU, CCU or high dependency) in a one month period. The notes were compared with the original triage designation. Sixty one (67 per cent of the patients admitted to a critical care area were given triage category one or two (to be seen within 10 minutes of arrival). Eighteen cases given lower priority were due to incorrect coding by the triage nurse. Six cases were correctly coded by the MTS, of which five deteriorated after arrival in the A&E department. PMID- 27237015 TI - Mortality/morbidity in elderly patients. AB - Despite an increasing incidence, relatively few studies have examined the factors that predict morbidity and mortality in older patients, while several reports have found standard predictors, such as the Injury Severity Score to be less useful in this patient population. PMID- 27237016 TI - An environmental-economic assessment of residential curbside collection programs in Central Florida. AB - Inefficient collection and scheduling procedures negatively affect residential curbside collection (RCC) efficiency, greenhouse gas (GHG) emissions, and cost. As Florida aims to achieve a 75% recycling goal by 2020, municipalities have switched to single-stream recycling to improve recycling efficiency. Waste diversion and increased collection cost have forced some municipalities to reduce garbage collection frequency. The goal of this study was to explore the trade offs between environmental and economic factors of RCC systems in Florida by evaluating the RCC system design of 25 different Central Florida communities. These communities were grouped into four sets based on their RCC garbage, yard waste, and recyclables collection design, i.e., frequency of collection and use of dual-stream (DS) or single-stream (SS) recyclables collection system. For the 25 communities studied, it was observed that RCC programs that used SS recyclables collection system recycled approximately 15-35%, by weight of the waste steam, compared to 5-20% for programs that used DS. The GHG emissions associated with collection programs were estimated to be between 36 and 51kg CO2eq per metric ton of total household waste (garbage and recyclables), depending on the garbage collection frequency, recyclables collection system (DS or SS), and recyclables compaction. When recyclables offsets were considered, the GHG emissions associated with programs using SS were estimated between -760 and 560, compared to between -270 and -210kg CO2eq per metric ton of total waste for DS programs. These data suggest that RCC system design can significantly impact recyclables generation rate and efficiency, and consequently determine environmental and economic impacts of collection systems. Recycling participation rate was found to have a significant impact on the environmental and financial performance of RCC programs. Collection emissions were insignificant compared to the benefits of recycling. SS collection of recyclables provided cost benefits compared to DS, mainly due to faster collection time. PMID- 27237017 TI - Conformity to the neighborhood modifies the association between recreational walking and social norms among middle-aged Japanese people. AB - AIM: Recreational walking benefits the health of the middle-aged population. Social norms might generate an intention-behavior gap, the state of people forming adequate intentions but failing to translate these intentions into action. People living in a community where the neighbors conform to the average behaviors of those who live in the neighborhood might restrict behaviors that stray from the neighborhood's social norms. This cross-sectional study was conducted in order to examine whether the degree of conformity to the neighbors modified the association between social norms and recreational walking among middle-aged adults in Japan. METHODS: Using a questionnaire, data were collected from 730 participants in Japan. Among those who intended to recreationally walk, a multiple logistic regression was carried out separately for the participants with a high or low degree of conformity to the neighborhood social norms. RESULTS: Of the total number of respondents, 511 (70%) reported recreational walking intentions. The descriptive norm was significantly associated with recreational walking only among the participants with a high degree of conformity. In contrast, there was no such association among the participants with a low degree of conformity. CONCLUSION: The results confirmed that people who live in a community where people tend to conform translated walking intentions into action when they saw their neighbors walk recreationally. Public health nurses should evaluate the degree of conformity in neighborhoods and neighbors' descriptive norms when promoting walking. PMID- 27237018 TI - Multiple micronutrients in powder delivered through primary health care reduce iron and vitamin A deficiencies in young Amazonian children. AB - OBJECTIVE: We evaluated the effect of home fortification with multiple micronutrient powder (MNP) on anaemia and micronutrient status of young Amazonian children. DESIGN: A pragmatic controlled trial was performed. A control group (CG) of children aged 11-14 months was recruited in the routine of primary health care centres for assessing anaemia and micronutrient status. At the same time, an intervention group (IG) of infants aged 6-8 months was recruited in the same health centres to receive MNP daily in complementary feeding for 2 months. The IG children were assessed 4-6 months after enrolment (n 112) when they had reached the age of the CG participants (n 128) for comparisons. SETTING: Primary health centres in Rio Branco city, Brazilian Amazon. SUBJECTS: A total of 240 children aged<2 years. RESULTS: In the CG, the prevalence of anaemia (Hb8.3 mg/l) and vitamin A deficiency (VAD; serum retinol <0.70 MUmol/l) was 20.3 %, 72.4 % and 18.6 %, respectively. Among the IG participants (aged 11-14 months), the prevalence of anaemia, ID and VAD was 15.2 %, 25.2 % and 4.7 %, respectively. The IG had a lower likelihood of ID (prevalence ratio (95 % CI): 0.34 (0.24, 0.49)) and VAD (0.25 (0.09, 0.64)). CONCLUSIONS: Home fortification of complementary feeding delivered through primary health care was effective in reducing iron and vitamin A deficiencies among young Amazonian children. PMID- 27237019 TI - Editorial Comment to Novel strategy for cystitis glandularis: Oral treatment with cyclooxygenase-2 inhibitor. PMID- 27237021 TI - Factors affecting hospital costs in lung cancer patients in the United Kingdom. AB - INTRODUCTION: Rising healthcare costs and financial constraints are increasing pressure on healthcare budgets. There is little published data on the healthcare costs of lung cancer in the UK, with international studies mostly small and limited by data collection methods. Accurate assessment of healthcare costs is essential for effective service planning. METHODS: We conducted a retrospective, descriptive cohort study linking clinical data from a local electronic database of lung cancer patients at a large UK teaching hospital with recorded hospital income. Costs were adjusted to 2013-2014 prices. RESULTS: The study analysed secondary care costs of 3274 patients. Mean cumulative costs were L5852 (95% CI, L5694 to L6027) at 90 days and L10,009 (95% CI, L9717 to L10,278) at one year. The majority of costs (58.5%) were accumulated within the first 90 days, with acute inpatient costs the largest contributor at one year (42.1%). The strongest predictor of costs was active treatment, especially surgery. Costs were also affected by age, route to diagnosis, clinical stage and cell type. DISCUSSION: Successful early diagnosis initiatives that increase radical treatment rates and improve outcomes may significantly increase the secondary care costs of lung cancer management. The use of routine NHS clinical and financial data can enable efficient and effective analyses of large cohort health economic data. PMID- 27237020 TI - The novel one-step nucleic acid amplification (OSNA) assay for the diagnosis of lymph node metastasis in patients with non-small cell lung cancer (NSCLC): Results of a multicenter prospective study. AB - OBJECTIVES: The precise and rapid diagnosis of the presence or absence of lymph node (LN) metastasis is essential for deciding upon an appropriate therapeutic strategy for patients with non-small cell lung cancer (NSCLC). We conducted a prospective multicenter clinical trial in Japan to evaluate a rapid, automated and objective assay system, the one-step nucleic acid amplification (OSNA) assay (Sysmex Corp), which targets cytokeratin 19 mRNA, to detect LN metastasis of NSCLC. MATERIALS AND METHODS: A total of 410 Lymph nodes (LNs) from 111 patients with clinical stage IB to IIIA NSCLC who underwent lung resection with LN dissection were included in this study. The LNs were divided into 4 blocks and examined by either the OSNA assay or a 3-level histological examination. The results of each method were compared and further analyses were performed for discordant cases. The primary endpoint was a concordance rate of more than 85% between the two methods. RESULTS: The concordance rate between the two methods was 92.7% (95% CI, 89.7-95.0%), with a sensitivity of 79.7% (95% CI, 67.2-89.0%). Discordant results were observed in 30 LNs (5.8%), and were mainly due to a tissue allocation bias and/or contamination by CK19-expressing alveolar cells in LNs. CONCLUSION: The OSNA assay gave a diagnosis that was as accurate as a 3 level histological examination, which is more detailed than a histological examination in routine clinical practice. The OSNA assay might be useful in intraoperative decision-making in personalized lung cancer surgery based on the LN status. PMID- 27237022 TI - Palliative systemic therapy for advanced non-small cell lung cancer: Investigating disparities between patients who are treated versus those who are not. AB - BACKGROUND: Palliative systemic therapy (ST) in advanced non-small cell lung cancer (NSCLC) is associated with improved overall survival (OS) and quality of life, yet many patients remain untreated. We explored differences between patients who did and did not receive palliative ST in order to gain evidence to support and advocate for the untreated. METHODS: We performed a retrospective analysis of newly diagnosed patients with advanced, incurable NSCLC seen as outpatients at our institution between 2009 and 2012. Demographics, treatment, and survival data were collected. RESULTS: 528 patients were seen: 291 (55%) received palliative ST, while 237 (45%) received none. Demographics were as follows: Median age 67, 55% male, 50% ECOG performance status (PS) 0-1, 48% with weight loss. Untreated patients were older (median 71 vs. 64, p<0.01), less fit (PS 0-1 in 27% vs. 69%, p<0.01), and more likely to have lost weight (57% vs. 41%, p<0.01). Reasons for no treatment included poor PS (67%) and patient choice (23%). Median OS was shorter amongst untreated patients (3.9 vs. 10.7 months, HR 1.80 [95% CI 1.4-2.3], p<0.01). In multivariate analysis, not receiving ST was associated with shorter OS. CONCLUSION: Unsurprisingly, untreated patients had poorer prognostic features and worse OS. However, it is concerning that, despite being seen in an active academic center, nearly half of all referred patients with advanced NSCLC received no anti-cancer treatment. Current research primarily seeks to improve outcomes in treated patients with good PS. This review suggests that this is an inappropriate allocation of research effort. Our research should be more equitably split between good and poor performance patient groups if we are to improve the survival of all patients with advanced NSCLC. Potential strategies include more rapid diagnosis prior to functional decline, and the development of therapies effective and tolerated in a sicker population. PMID- 27237023 TI - Elderly patients undergoing SBRT for inoperable early-stage NSCLC achieve similar outcomes to younger patients. AB - OBJECTIVES: It is unclear whether elderly patients face an increased risk of complications following stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC), as has been reported following surgical resection. This study evaluates toxicity and outcomes achieved with SBRT in elderly versus non-elderly patients. MATERIALS AND METHODS: We retrospectively identified patients treated with SBRT for cT1-3N0M0 NSCLC between 2007 and 2013. We defined elderly and non-elderly cohorts by age >=75 and <75. We used chi square and logistic regression analyses to compare toxicity, and employed Kaplan Meier, log-rank, and multivariable Cox proportional hazard analyses to assess overall survival (OS), local control (LC), and distant control (DC). RESULTS: We identified 251 patients (126 elderly, 125 non-elderly) with a median follow-up of 3.0 years. No differences in acute or late grade >=3 toxicity were observed. Acute grade >=3 toxicity was 11.1% in elderly vs. 8.0% in non-elderly (p=0.66). Late grade >=3 toxicity was 10.3% in elderly vs. 7.2% in non-elderly (p=0.50). There was one grade 5 toxicity (hemoptysis). There were no 3-year OS or LC differences between elderly and non-elderly patients (OS 47.5% vs. 41.0%, p=0.75; LC 84.2% vs. 86.4%, p=0.89). However, 3-year DC was superior in elderly patients (89.1% vs. 76.0%, p=0.01). Improved DC remained associated with elderly age in Cox regression (HR 0.42, p=0.01). CONCLUSION: Elderly patients undergoing SBRT for early stage NSCLC appear to have similar risk of toxicity and rate of efficacy as in younger patients. These findings support the use of SBRT in appropriately selected elderly patients. PMID- 27237024 TI - The neutrophil to lymphocyte and platelet to lymphocyte ratios as biomarkers for lung cancer development. AB - OBJECTIVES: Elevated neutrophil-to-lymphocyte ratios (NLR) and platelet-to lymphocyte ratios (PLR) at time of cancer diagnosis have been associated to poor prognosis in various cancers. There is no data on their natural progression before the cancer diagnosis has been established. We aim to evaluate whether or not the annual changes in these ratios could be early indicators of lung cancer development. MATERIALS AND METHODS: Participants recruited into the Pamplona International Early Lung Cancer Action Program (P-IELCAP, n=3061) between 2001 and 2015 were considered. Complete blood counts (CBC) were registered at annual intervals between enrolment and time of diagnosis. Linear regression was used to calculate the mean annual change in NLR and PLR in participants with >=3CBCs. Changes were expressed relative to baseline values. Lung cancer incidence density and lung cancer risk (Cox regression analysis) were calculated for different NLR and PLR annual thresholds (<0%, >=0%, >=1%, >=2%, >=4%). Results were compared to a matched group of participants who did not develop lung cancer. RESULTS: After a median follow-up of 80 months and a median of 4 (IQR 3-6) CBCs, subjects who developed lung cancer (n=32) showed greater NLR and PLR annual changes than matched controls (n=103) (2.56% vs. 0.27% [p=0.25] per year; and 3.75% vs. 0.33% [p=0.053] per year, respectively). Lung cancer incidence density per 100 person years increased with higher annual NLR and PLR thresholds. On multivariable analysis (adjusting for emphysema and baseline lung-function), NLR and PLR were not significant lung cancer predictors. However, among individuals with emphysema, for each relative unit increase in PLR, lung cancer risk increased 5% (p=0.03). There was a significant supra-additive risk effect between PLR increase and emphysema. Annual NLR change was not a significant lung cancer predictor. CONCLUSION: In a lung cancer screening setting, the assessment of annual PLR change could help predict lung cancer development. PMID- 27237025 TI - Outcomes of lung cancers manifesting as nonsolid nodules. AB - This is a comprehensive review and re-analysis of available literature to assess the outcome of lung cancer presenting as nonsolid nodules (NSNs), a more indolent form of cancer. PubMed and EMBASE were searched for articles reporting on CT detected lung cancers manifesting as NSNs published in English on or before July 17, 2015. Only studies including clinicopathologic data, lung cancer-specific survival, or overall survival were included. Data extraction was performed by three independent reviewers using prespecified criteria. Twenty-four articles from 5 countries met criteria and they included 704 subjects with 712 lung cancers manifesting as NSNs. Each article reported from 2 to 100 lung cancer cases with a median follow up of 18-51 months. All NSNs were Stage I adenocarcinoma without pathologic nodal involvement upon resection, except for one case in which the NSN progressed to become part-solid nodule after 6 years of follow-up. The five-year lung cancer-specific survival rate was 100%. These findings suggest an indolent course for lung cancers manifesting as NSNs. PMID- 27237026 TI - Clinical impact of crizotinib on central nervous system progression in ALK positive non-small lung cancer. AB - BACKGROUND: The central nervous system (CNS) is a preferential progression site related to poor penetration of crizotinib into the CNS in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) patients treated with crizotinib. We evaluated the clinical impact of crizotinib on central nervous system progression in ALK-positive NSCLC. METHODS: Between January 2006 and September 2015, 59 ALK-positive NSCLC patients treated with crizotinib as the initial ALK inhibitor were retrospectively evaluated for baseline characteristics, initial response to crizotinib, brain metastasis (BM) status at baseline, and progression patterns. RESULTS: Among 59 patients, 48 (81%) received crizotinib as first-line or second-line treatment for advanced or recurrent disease. Out of the 26 (44%) patients who had BM, 13 had untreated BM, and 13 had previously undergone intracranial radiotherapy or surgery. The overall response rate for crizotinib was 66%, with a median progression-free survival (PFS) of 9.7 months. Disease progression assessed by response evaluation criteria in solid tumors-progressive disease (RECIST-PD) occurred in 48 patients. The CNS was the common initial progression site in 24 patients, which included isolated CNS progression in 18 patients. There was a significantly shorter median PFS in the BM versus the non-BM patients before crizotinib treatment (median PFS: 6.7 months vs. 10.2 months, P=0.0347). Multivariate analysis revealed that poor performance status (PS) (>=2) or untreated BM were associated with the PFS duration (poor PS: hazard ratio (HR) 3.322, 95% CI 1.402-7.353, P=0.0078; untreated BM: HR 2.314, 95% CI 1.153-4.400, P=0.0196). In addition, the time to the occurrence of CNS progression from the start of crizotinib was significantly shorter in the BM versus non-BM patients (11.1 vs. 22.1 months, P=0.0255). CONCLUSION: The common progression site in ALK-positive patients treated with crizotinib was the CNS. BM status was significantly associated with both PFS in crizotinib-treated patients and the occurrence of CNS progression. PMID- 27237027 TI - TPD52L1-ROS1, a new ROS1 fusion variant in lung adenosquamous cell carcinoma identified by comprehensive genomic profiling. AB - Crizotinib was approved for the treatment of ROS1-rearranged non-small cell lung cancer (NSCLC) patients in the US on 11 March, 2016. Interestingly no one companion diagnostic test (CDx) has been approved simultaneously with this approval of crizotinib. Hence, an ideal and adequate CDx will have to be able to identify ROS1 fusions without the knowledge of the fusion partners to ROS1, and as to date there are 13 fusion partners reported for ROS1 in NSCLC. Here we report a novel TPD52L1-ROS1 fusion variant in NSCLC. This novel TPD52L1-ROS1 fusion variant is generated by the fusion of exons 1-3 of TPD52L1 on chromosome 6q22-23 to the exons 33-43 of ROS1 on chromosome 6q22, likely from an intra chromosomal deletion and subsequent fusion event similar to the generation of EML4-ALK. The predicted TPD52L1-ROS1 protein product contains 655 amino acids comprising of the N-terminal amino acids 1-95 of TPD52L1 and C-terminal amino acids of 1789-2348 of ROS1. In summary, TPD52L1-ROS1 is a novel ROS1 fusion variant in NSCLC identified by comprehensive genomic profiling and should be included in any ROS1 detecting assays that depend on identifying the corresponding fusion partners, such as reverse transcriptase-polymerase chain reaction (RT-PCR). PMID- 27237028 TI - Stereotactic body radiotherapy (SBRT) for medically inoperable lung metastases-A pooled analysis of the German working group "stereotactic radiotherapy". AB - OBJECTIVES: The current literature on stereotactic body radiotherapy (SBRT) for oligometastatic disease is characterized by small patient cohorts with heterogeneous primary tumors, metastases location and dose regimes. Hence, this study established a multi-institutional database of 700 patients treated with SBRT for pulmonary metastases to identify prognostic factors influencing survival and local control. MATERIALS AND METHODS: All German radiotherapy departments were contacted and invited to participate in this analysis. A total number of 700 patients with medically inoperable lung metastases treated with SBRT in 20 centers between 1997 and 2014 were included in a database. Primary and metastatic tumor characteristics, treatment characteristics and follow-up data including survival, local control, distant metastases, and toxicity were evaluated. Lung metastases were treated with median PTV-encompassing single doses of 12.5Gy (range 3.0-33.0Gy) in a median number of 3 fractions (range 1-13). RESULTS: After a median follow-up time of 14.3 months, 2-year local control (LC) and overall survival (OS) were 81.2% and 54.4%, respectively. In multivariate analysis, OS was most significantly influenced by pretreatment performance status, maximum metastasis diameter, primary tumor histology, time interval between primary tumor diagnosis and SBRT treatment and number of metastases. For LC, independent prognostic factors were pretreatment performance status, biological effective dose (BED) at PTV isocenter (BEDISO) and single fraction (PTV-encompassing) dose in multivariate analysis. Radiation-induced pneumonitis grade 2 or higher was observed in 6.5% of patients. The only factor significantly influencing toxicity was BEDISO (p=0.006). CONCLUSION: SBRT for medically inoperable patients with pulmonary metastases achieved excellent local control and promising overall survival. Important prognostic factors were identified for selecting patients who might benefit most from this therapy approach. PMID- 27237029 TI - DNMT3a expression pattern and its prognostic value in lung adenocarcinoma. AB - OBJECTIVES: DNA methyltransferases (DNMTs) are an important part of the methylation pathway that is highly correlated with the pathophysiology of cancers. Several studies have reported overexpression of DNMTs in human lung cancer, but none have compared the expression pattern to pathological features. In this study, we clarified the association of DNMT3a expression pattern with pathological features and prognosis of lung adenocarcinoma. MATERIALS AND METHODS: 135 cases of surgically resected lung adenocarcinoma specimens were used for DNMT3a immunohistochemistry (IHC). IHC score was determined by counting the number of positive nuclei. The ROC curve was drawn to determine the best cut-off point of the score; this was set at 57.5. Western blot also implemented and confirmed the specificity of the antibody. Correlations between expression pattern and clinicopathological features and prognosis were analyzed using chi squared method and Cox proportional hazards model respectively. RESULT: Seventy nine of the 135 cases (58.5%) showed strong positive reactivity to anti-DNMT3a. In terms of histological subtypes, among invasive lung adenocarcinomas 41 out of 53 lepidic adenocarcinomas (77%) were strongly positive, while among the other histological subtypes only 23 out of 66 cases (34.8%) showed a positive reaction. Among non-invasive lung adenocarcinomas 15 out of 16 cases (93.8%) were strongly positive. The level of DNMT3a expression was associated with patient outcome, and patients with weak expression of DNMT3a had a poorer outcome than those with strong expression. Multivariate analysis also indicated that DNMT3a is an independent prognostic marker in lung adenocarcinoma. CONCLUSION: Our results indicate that DNMT3a expression in lung adenocarcinoma is associated with the histologically non-invasive type and lepidic subtype, and a favorable prognosis. We also showed that DNMT3a expression is an independent prognostic marker in lung adenocarcinoma. Since lack of DNMT3a is thought to facilitate tumor progression, DNMT3a might be clinically applicable as an indicator of favorable prognosis. PMID- 27237030 TI - Epidemiological changes in the histological subtypes of 35,018 non-small-cell lung cancer cases in Brazil. AB - OBJECTIVES: Regarding the fatality rates stemming from various existing forms of cancers worldwide, lung cancer (LC) is ranked as the main cause of death amongst those who suffer from cancer. Although the epidemiological, clinical, and histological profile of patients with this type of cancer is largely unknown, Brazil has made tremendous efforts to generate data for supporting healthcare policies concerning lung cancer. Taking these factors into account, this study aims to analyse the epidemiological, clinical, and histological profiles of patients with non-small-cell lung cancer (NSCLC) in Brazil. MATERIAL AND METHODS: For this study, a cross-sectional epidemiological study was conducted to nationally analyse patient's data within the cancer hospital registries found in the National Cancer Institute (INCA) and the Sao Paulo Cancer Foundation (FOSP) between 2000 and 2011. RESULTS: A total of 35,018 patients diagnosed with NSCLC in Brazil between 2000 and 2011 were analysed. The analysis demonstrated the occurrence of an epidemiological shift, related to the most prevalent histological type of NSCLC in the study population from 2003. The shift resulted in a higher percentage of adenocarcinoma (43.3%) over squamous cell carcinoma (36.5%). Additionally, there was a significant increase in both the number of cases of LC in women and in the rates of patients diagnosed with metastatic disease. CONCLUSION: The use of filtered cigarettes since the 60's and the increase in the number of LC cases in women, were one of the causes for the switch in the histological profile of NSCLC in Brazil. Consequently, adenocarcinoma is now the predominant type of cancer detected. Late diagnosis is a hallmark sign. PMID- 27237031 TI - Clinicopathological and prognostic significance of programmed cell death ligand-1 expression in lung adenocarcinoma and its relationship with p53 status. AB - INTRODUCTION: PD-L1 expression is a predictive biomarker for response to anti programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors and can be evaluated by immunohistochemistry. Results of the clinicopathologic characteristics of PD-L1-positive lung adenocarcinoma have been inconsistent in previous studies, and there are no reports on the relationship between PD-L1 expression and p53 status in lung adenocarcinoma. METHODS: We examined PD-L1 and p53 expression in a total of 323 surgically resected lung adenocarcinoma cases using anti-PD-L1 (clone SP142) and anti-p53 (clone DO-7) antibodies, and analyzed the clinicopathologic characteristics of PD L1-positive cases and their relationship with p53 status. RESULTS: PD-L1 expression in tumor cells was positive in 60 of 323 cases (18.6%). Higher PD-L1 expression (>=50%) was more prevalent in former or current smokers (p=0.026) and was associated with more pack-years (p=0.016). PD-L1-positive tumors were significantly associated with solid predominant type (p<0.001), p53 aberrant expression (p<0.001), and PD-L1 expression in tumor-infiltrating immune cells (p<0.001). Patients with stage I to III tumors harboring PD-L1-positive tumor cells showed poor recurrence-free survival (p<0.001) and overall survival (p<0.001) on univariate analysis. CONCLUSIONS: PD-L1 expression in tumor cells, solid predominant histology, p53 aberrant expression, and PD-L1 expression in tumor-infiltrating immune cells are closely related. These variables should be considered when analyzing the clinical outcomes of patients with lung adenocarcinomas treated with anti-PD1/PD-L1 immune checkpoint inhibitors. PMID- 27237032 TI - Assessment of indeterminate pulmonary nodules detected in lung cancer screening: Diagnostic accuracy of FDG PET/CT. AB - BACKGROUND: A major drawback of lung cancer screening programs is the high frequency of false-positive findings on computed tomography (CT). We investigated the accuracy of selective 2-[fluorine-18]-fluoro-2-deoxy-d-glucose (FDG) Positron Emission Tomography/Computed Tomography (PET/CT) scan in assessing radiologically indeterminate lung nodules detected in lung cancer screening. METHODS: FDG PET/CT was performed to characterize 64 baseline lung nodules >10mm and 36 incidence nodules detected on low-dose CT screening in asymptomatic current or former smokers (83 men, age range 40-83 years) at high risk for lung cancer. CT images were acquired without intravenous contrast. Nodules were analyzed by size, density, and metabolic activity and visual scored on a 5-point scale for FDG uptake. Nodules were classified as negative for malignancy when no FDG uptake was observed, or positive when focal uptake was observed in the visual analysis, and the maximum standardized uptake value (SUVmax) was measured. Final diagnosis was based on histopathological evaluation or at least 24 months of follow-up. RESULTS: A total of 100 nodules were included. The prevalence of lung cancer was 1%. The sensitivity, specificity, NPV and PPV of visual analysis to detect malignancy were 84%, 95%, 91%, and 91%, respectively, with an accuracy of 91% (AUC 0.893). FDG PET/CT accurately detected 31 malignant tumors (diameters 9 42mm, SUVmax range 0.6-14.2) and was falsely negative in 6 patients. With SUVmax thresholds for malignancy of 1.5, 2, and 2.5, specificity was 97% but sensitivity decreased to 65%, 49%, and 46% respectively, and accuracy decreased to 85%, 79%, and 78% respectively (AUC 0.872). CONCLUSIONS: The visual analysis of FDG PET/CT scan is highly accurate in characterizing indeterminate pulmonary nodules detected in lung cancer screening with low-dose CT. Semi-quantitative analysis does not improve the accuracy of FDG PET/CT over that obtained with a qualitative method for lung nodule characterization. PMID- 27237033 TI - MiR-145 and miR-203 represses TGF-beta-induced epithelial-mesenchymal transition and invasion by inhibiting SMAD3 in non-small cell lung cancer cells. AB - OBJECTIVES: MicroRNAs (miRNAs) have been proved to play important role in development of various cancers, including non-small cell lung cancer (NSCLC). Our previous studies have shown that miR-203 and miR-145 are associated with cellular invasion in NSCLC and nasopharyngeal cancer, respectively. However, the mechanistic role of miR-203 and miR-145 in TGF-beta-induced epithelial mesenchymal transition (EMT) has not yet been elucidated in human cancers, including NSCLC. MATERIALS AND METHODS: Real-time quantitative reverse transcriptase PCR (qRT-PCR), western blot analysis, luciferase reporter gene assays, small RNA interference and transwell migration and invasion assays were carried on human NSCLC cell lines A549 and 95C. Thirty-six paired NSCLC tissues and adjacent noncancerous lung tissues were collected. RESULTS: Both miR-145 and miR-203 can directly target the 3'-untranslated region (3'-UTR) of SMAD3, and overexpression of the two miRNAs in NSCLC cells inhibited the expression of SMAD3 mRNA and protein, whereas inhibition of endogenous miR-145 or miR-203 caused an increased expression of SMAD3. Moreover, miR-145 and/or miR-203 repressed TGF beta-induced EMT and attenuated cell migration and invasion in A549 and 95C cells. siRNA-mediated knockdown of SMAD3 copied the phenotype of miR-145 and miR 203 overexpression in A549 and 95C cells. CONCLUSION: MiR-145 and miR-203 inhibited TGF-beta-induced EMT and invasion through repression of SMAD3 in NSCLC cells. Our findings provided insights into the miRNA-based mechanism for controlling TGF-beta-induced EMT of NSCLC cells and a strategy for targeted therapy of NSCLC. PMID- 27237034 TI - High prevalence of ALK+/ROS1+ cases in pulmonary adenocarcinoma of adoloscents and young adults. AB - OBJECTIVES: To investigate prevalence and age-distribution of ALK- or ROS1 translocated adenocarcinomas in patients <=50 years of age. MATERIALS AND METHODS: Paraffin sections of pulmonary adenocarcinoma were analyzed for ALK (637 cases) and ROS1 (376 cases) translocations using FISH, and for EGFR mutations (789 cases) using mutant-specific Real-Time PCR. RESULTS: ALK or ROS1 fusions were detected in 55 of 637 cases (8.6%). When patients were stratified for age, it was found that six of six cases (100%) of lung adenocarcinoma diagnosed in patients <30 years of age were translocated for ALK (4 cases) or ROS1 (2 cases). With the increase of age, there was a gradual decrease in the percentage of positive cases. In fact, ALK-translocated or ROS1-translocated cases were 5 of 17 cases (29%) in the 31-40 years age-group, 6 of 46 cases (13%) in the 41-50 years age-group, and 38 of 568 cases (7.0%) in patients older than 50 years. The six patients <30 years of age (5F/1M), including two pediatric patients (<=18 years old), presented with stage IV disease, were never or light smoker, and had no family history of pulmonary tumours. Four of the six patients, were treated with crizotinib and had an objective response. CONCLUSIONS: Our findings provide evidence that ALK or ROS1 translocations are crucial events in tumourigenesis of pulmonary adenocarcinoma of very young patients, including pediatric patients. PMID- 27237036 TI - Assessment of polycyclic aromatic hydrocarbons (PAHs) in mussels (Mytilus galloprovincialis) of Prince Islands, Marmara Sea. AB - In this study, PAH analyses have been conducted on indigenous mussels. Mussel samples (Mytilus galloprovincialis) have been collected from seven stations of Prince Islands during September 2015. Concentrations of total determined PAHs (sum of 16 compounds) ranged between 664 and 9083ngg(-1). The origin of PAHs has been found to be pyrolytic according to the PHE/ANT and FA/PYR ratios in Buyukada. For other islands, PAH origins have been observed as pyrolytic and petrogenic together according to the PHE/ANT, FA/PYR and BaA/CHR ratios. PMID- 27237035 TI - Sunitinib in patients with advanced thymic malignancies: Cohort from the French RYTHMIC network. AB - BACKGROUND: Sunitinib is a potent oral tyrosine kinase inhibitor of VEGFRs, KIT, and PDGFRs. In a single arm phase II trial, sunitinib has demonstrated its potential activity in refractory thymic carcinoma (TC) and thymoma (T). Taking advantage of the French RYTHMIC network prospective database, we investigated the off-label efficacy of sunitinib in previously-treated thymic epithelial tumors (TETs) patients not included in a clinical trial. METHODS: RYTHMIC database started in 2012, and prospectively collects clinical, imaging, treatment, and follow-up data of all patients diagnosed with TET, for whom management is discussed at a national multidisciplinary tumor board. All patients who received sunitinib were selected for this analysis. RESULTS: 28 patients from 7 institutions were identified, including 20 TC and 8T; 32% of patients were females, and median age was 50 years. Fifteen patients (54%) received sunitinib as >=4th line treatment. The initial daily dose of sunitinib was 50mg in 11 patients, 37.5mg in 16 patients and 25mg in 1 patient. Sunitinib adverse events were all manageable and tolerable; 8 patients had to stop sunitinib due to toxicity after a median duration of treatment of 2.7 months. In the overall population, disease control rate was of 63% (86% for T, and 55% for TC); overall response rate was 22% (29% for T, and 20% for TC). Median PFS in the whole population was 3.7 months (5.4 months for T, and 3.3 months for TC, p=0.097). The median overall survival in the whole population was 15.4 months: survival was not reached for T, and was 12.3 months for TC patients (p=0.043). CONCLUSION: Sunitinib is an active treatment in TETs irrespective of histological subtype, supporting the use of tyrosine kinase inhibitors with anti-angiogenic activity as alternative treatment options in refractory disease. PMID- 27237037 TI - Effects of pollution on the geochemical properties of marine sediments across the fringing reef of Aqaba, Red Sea. AB - The Gulf of Aqaba is of significant strategic and economic value to all gulf bordering states, particularly to Jordan, where it provides Jordan with its only marine outlet. The Gulf is subject to a variety of impacts posing imminent ecological risk to its unique marine ecosystem. We attempted to investigate the status of metal pollution in the coastal sediments of the Jordanian Gulf of Aqaba. The distribution of Cd, Cr, Zn, Cu, Pb, Al, Fe, and Mn concentrations were determined in trapped and bottom-surface sediments at three selected sites at different depths. In addition, monthly sedimentation rates at varying water depths were also estimated at each sampling site using sediment traps. The high concentrations of Cd, Cr, Zn were recorded at the Phosphate Loading Birth (PLB) site followed by the Industrial Complex (IC) site indicating their dominant anthropogenic source (i.e., the contribution of industrial activities). However, Fe, Al, and Mn contents were related to inputs from the terrigenous (crustal) origin. Except for Al, Fe and Mn at the PLB site, the concentrations of metals exhibited a decreasing trend with increasing water depth (distance from the shoreline). The PLB site also showed the highest sedimentation rate which decreased with increasing water depth. The Enrichment factors (EFs) showed that Cd was the most enriched element in the sediment (indicating that Cd pollution is widespread), whereas the least enriched metal in sediments was Cu. EF values suggested that the coastal area is impacted by a combination of human and natural sources of metals, where the anthropogenic sources are intense in the PLB site (north of Gulf of Aqaba). The MSS area is potentially the least polluted, consistent with being a marine reserve. The IC sediments have been found to be impacted by human activities but less intensely compared to the PLB area. These results suggested that there are two sources of metals in sediments; the primary source is likely closer to PLB, while the secondary is nearby the IC. PMID- 27237038 TI - Evidence of microbeads from personal care product contaminating the sea. AB - Plastic microbeads in personal care products have been identified as a source of marine pollution. Yet, their existence in the environment is rarely reported. During two surface manta trawls in the coastal waters of Hong Kong, eleven blue, spherical microbeads were captured. Their sizes (in diameters) ranged from 0.332 to 1.015mm. These microbeads possessed similar characteristics in terms of colour, shape and size with those identified and extracted from a facial scrub available in the local market. The FT-IR spectrum of the captured microbeads also matched those from the facial scrub. It was likely that the floating microbeads at the sea surface originated from a facial scrub and they have bypassed or escaped the sewage treatment system in Hong Kong. Timely voluntary or legislative actions are required to prevent more microbeads from entering the aquatic environment. PMID- 27237039 TI - Distribution and characteristics of methylmercury in surface sediment in Minamata Bay. AB - This study was carried out to evaluate the present-day chemical properties of methylmercury in surface sediment in Minamata Bay where a dredging project was completed 28years ago. Present-day sediment from Minamata Bay consists of sandy silt, and the average loss-on-ignition in surface sediment was 7.0+/-2.3%. The average methylmercury concentrations in the upper sediment layers were significantly higher than those in the lower sediment layers. Currently, the concentrations in sediments in Minamata Bay do not exceed the Japanese regulatory standard value for mercury. The average concentration of methylmercury in Minamata Bay surface sediment was 1.74+/-1.0ng/g on a dry weight basis (n=107). The methylmercury concentration in Minamata Bay surface sediment was almost 16 times higher than that in surface sediment from Isahaya Bay surface sediment, which was 0.11+/-0.045ng/g on a dry weight basis (n=5). PMID- 27237040 TI - Pathogenesis of non-HLA antibodies in solid organ transplantation: Where do we stand? AB - Antibody-mediated rejection (ABMR) is associated with poor transplant outcome. Pathogenic alloantibodies are usually directed against human leukocyte antigens (HLAs). Histological findings suggestive of ABMR usually demonstrate an anti-HLA donor-specific antibody (DSA)-mediated injury, while a small subset of patients develop acute dysfunction with histological lesions suggestive of ABMR in the absence of anti-HLA DSAs. Although this non-HLA ABMR is not well recognized by current diagnostic classifications, it is associated with graft dysfunction and allograft loss. These clinical descriptions suggest a pathogenic role for non-HLA anti-endothelial cell antibodies. Diverse antigenic targets have been described during the last decade. This review discusses recent findings in the field and addresses the clinical relevance of anti-endothelial cell antibodies (AECAs). PMID- 27237042 TI - Pirfenidone inhibits p38-mediated generation of procoagulant microparticles by human alveolar epithelial cells. AB - Pirfenidone is a drug recently approved for idiopathic pulmonary fibrosis but its mechanisms of action are partially unknown. We have previously demonstrated that the airways of patients with idiopathic pulmonary fibrosis contain procoagulant microparticles that activate coagulation factor X to its active form, Xa, a proteinase that signals fibroblast growth and differentiation, thus potentially contributing to the pathogenesis of the disease. We also reported that in vitro exposure of human alveolar cells to H2O2 causes microparticle generation. Since p38 activation is involved in microparticle generation in some cell models and p38 inhibition is one of the mechanisms of action of pirfenidone, we investigated the hypothesis that H2O2-induced generation of microparticles by alveolar cells is dependent on p38 phosphorylation and is inhibited by pirfenidone. H2O2 stimulation of alveolar cells caused p38 phosphorylation that was inhibited by pirfenidone. The drug also inhibited H2O2 induced microparticle generation as assessed by two independent methods (solid phase thrombin generation and flow cytometry). The shedding of microparticle-bound tissue factor activity was also inhibited by pirfenidone. Inhibition of p38-mediated generation of procoagulant microparticle is a previously unrecognized mechanism of action of the antifibrotic drug, pirfenidone. PMID- 27237041 TI - Protocol and methodology of Study epidemiological mental health in Andalusia: PISMA-ep. AB - INTRODUCTION: This is the general methods describing paper of a cross-sectional study that aims to detect the prevalence of major mental disorders in Andalusia (Southern Spain), and their correlates or potential risk factors, using a large representative sample of community-dwelling adults. MATERIALS AND METHODS: This is a cross-sectional study. We undertook a multistage sampling using different standard stratification levels and aimed to interview 4,518 randomly selected participants living in all 8 provinces of the Andalusian region utilizing a door knocking approach. The Spanish version of the MINI International Neuropsychiatric Interview, a valid screening instrument ascertaining ICD-10/DSM-IV compatible mental disorder diagnoses was used as our main diagnostic tool. A large battery of other instruments was used to explore global functionality, medical comorbidity, personality traits, cognitive function and exposure to psychosocial potential risk factors. A saliva sample for DNA extraction was also obtained for a sub-genetic study. The interviews were administered and completed by fully trained interviewers, despite most tools used are compatible with lay interviewer use. RESULTS: A total of 3,892 (70.8%) of 5,496 initially attempted households had to be substituted for equivalent ones due to either no response (37.7%) or not fulfilling the required participant quota (33%). Thence, out of 5,496 eligible participants finally approached, 4,507 (83.7%) agreed to take part in the study, completed the interview and were finally included in the study (n=4,507) and 4,286 (78%) participants also agreed and consented to provide a saliva sample for DNA study. On the other hand, 989 (16.3%) approached potential participants refused to take part in the study. DISCUSSION: This is the largest mental health epidemiological study developed in the region of Spain (Andalusia). The response rates and representativeness of the sample obtained are fairly high. The method is particularly comprehensive for this sort of studies and includes both, personality and cognitive assessments, as well as a large array of bio psycho-social risk measures. PMID- 27237044 TI - The ventromedial hypothalamus oxytocin induces locomotor behavior regulated by estrogen. AB - Our previous studies demonstrated that excitation of neurons in the rat ventromedial hypothalamus (VMH) induced locomotor activity. An oxytocin receptor (Oxtr) exists in the VMH and plays a role in regulating sexual behavior. However, the role of Oxtr in the VMH in locomotor activity is not clear. In this study we examined the roles of oxytocin in the VMH in running behavior, and also investigated the involvement of estrogen in this behavioral change. Microinjection of oxytocin into the VMH induced a dose-dependent increase in the running behavior in male rats. The oxytocin-induced running activity was inhibited by simultaneous injection of Oxtr-antagonist, (d(CH2)5(1), Try(Me)(2), Orn(8))-oxytocin. Oxytocin injection also induced running behavior in ovariectomized (OVX) female rats. Pretreatment of the OVX rats with estrogen augmented the oxytocin-induced running activity twofold, and increased the Oxtr mRNA in the VMH threefold. During the estrus cycle locomotor activity spontaneously increased in the dark period of proestrus. The Oxtr mRNA was up regulated in the proestrus afternoon. Blockade of oxytocin neurotransmission by its antagonist before the onset of the dark period of proestrus decreased the following nocturnal locomotor activity. These findings demonstrate that Oxtr in the VMH is involved in the induction of running behavior and that estrogen facilitates this effect by means of Oxtr up-regulation, suggesting the involvement of oxytocin in the locomotor activity of proestrus female rats. PMID- 27237043 TI - Sex differences in age-related changes on peripheral warm and cold innocuous thermal sensitivity. AB - Cutaneous thermal sensitivity to a warm and cold stimulus was compared amongst 12 older (OF, 65.2+/-1.0year) and 29 younger (YF, 21.6+/-0.2years) female participants, and 17 older (OM, 66.2+/-1.5years) and 13 younger (YM, 21.2+/ 0.4years) male participants to examine the effects of ageing and sex. In a neutral condition (27.5 degrees C, 50% RH) during rest, warm and cold thermal sensitivity was measured on eight body regions (forehead, chest, back, forearm, hand, thigh, calf, and foot). Using the method of limits, a thermal stimulator was applied to the skin at an adapting temperature and either increased or decreased at a constant rate (0.3 degrees C/s) until the participants detected the temperature with a push button. Thermal sensitivity declined with ageing to both a cold (older: 1468.6+/-744.7W/m(2), younger: 869.8+/-654.7W/m(2), p<0.001) and warm (older: 2127.0+/-1208.3W/m(2), younger: 1301.7+/-1055.2W/m(2), p<0.001) innocuous stimulus. YF and OF were more sensitive than YM and OM to both a warm and cold stimulus (p<0.05). There was no interaction between age and sex suggesting that whilst thermal sensitivity decreases with age the decrease is similar between the sexes (p>0.05). There was an interaction between temperatures, age and location and it seemed that cold thermal sensitivity was more homogenous for young and older participants however warm thermal sensitivity was more heterogeneous especially in the younger participants (p<0.05). Although the pattern was not similar between ages or sexes it was evident that the forehead was the most sensitive region to a warm and cold stimulus. Interestingly the decline in sensitivity observed with ageing occurred for all locations but was attenuated at the forehead in both males and females (p>0.05). PMID- 27237046 TI - Eccrine poroma with calcification and metaplastic ossification. PMID- 27237045 TI - Carbon Flux Trapping: Highly Efficient Production of Polymer-Grade d-Lactic Acid with a Thermophilic d-Lactate Dehydrogenase. AB - High production of polymer-grade d-lactic acid is urgently required, particularly for the synthesis of polylactic acid. High-temperature fermentation has multiple advantages, such as lower equipment requirement and energy consumption, which are essential for lowering operating costs. We identified and introduced a unique d lactate dehydrogenase into a thermotolerant butane-2,3-diol-producing strain. Carbon flux "trapping" was achieved by a "trapping point" created by combination of the introduced enzyme and the host efflux pump, which afforded irreversible transport of d-lactic acid. The overall carbon flux of the engineered strain was significantly enhanced and was redistributed predominantly to d-lactic acid. Under optimized conditions at 50 degrees C, d-lactic acid reached the highest titer (226.6 g L(-1) ) reported to date. This discovery allows us to extend the carbon flux trapping strategy to engineering complex metabolic networks. PMID- 27237047 TI - Diagnostic phrasing is independently correlated with the decision to treat for graft-versus-host disease: retrospective review of colon biopsies with rare apoptosis. AB - AIMS: The risks of immunosuppression and the non-specific nature of rare crypt apoptosis has led to debate over the lower threshold for histological diagnosis of colonic graft-versus-host disease (GVHD). A recent study proposed the diagnostic category of indeterminate for GVHD (iGVHD) for cases with six or fewer apoptotic bodies per 10 crypts. Our aim was to assess colon biopsies with iGVHD histology to determine whether the diagnosis was retrospectively predictive of the decision to treat, and to correlate these findings with endoscopic and clinical findings. METHODS AND RESULTS: A retrospective search was performed for colonic biopsies taken to evaluate for GVHD from 2008 to 2014. Biopsies were blindly reviewed for the maximum number of apoptotic bodies per 10 contiguous crypts, evidence of crypt dropout, and ulceration. Clinical information was collected through chart review. One hundred and twenty-two biopsies from 84 transplant patients were included. Forty-seven cases met the histological criteria for iGVHD. Patients with an original diagnosis of iGVHD were more likely to be managed conservatively than those with a diagnosis of grade 1 GVHD (25% versus 0%). Eight symptomatic patients reclassified as iGVHD had resolution of symptoms without increased immunosuppression. A clinicopathologically similar group of 10 patients with iGVHD histology, normal or subtle endoscopic findings and no evidence of GVHD at other organ sites were treated with increased immunosuppression. On multivariate analysis, the original diagnostic category was the most significant predictor of the decision to treat. CONCLUSION: The use of the diagnostic category iGVHD alerts clinicians to the presence of minimal crypt apoptosis, and allows treatment based on clinical judgement. PMID- 27237048 TI - Three-year visual outcomes of intravitreal ranibizumab with or without photodynamic therapy for polypoidal choroidal vasculopathy. AB - PURPOSE: To compare 3-year visual outcomes after intravitreal ranibizumab (IVR) monotherapy and combination therapy of photodynamic therapy (PDT) with IVR for polypoidal choroidal vasculopathy (PCV). METHODS: Medical records for 45 eyes in 45 patients (34 men, 11 women; mean age, 73.8 years old; range, 62-86 years old) with treatment-naive PCV were reviewed retrospectively. Of the 45 eyes, 20 were treated with IVR monotherapy and 25 with combination therapy. Mean change in best corrected visual acuity, numbers of injections of IVR and length of treatment free period from baseline at month 36 were observed. Adverse events were monitored. RESULTS: The change in visual acuity after combination therapy was significantly better than that after IVR monotherapy (p = 0.0399). At 36 months, improvement in visual acuity was seen in five eyes (25.0%) in the IVR monotherapy group and 13 eyes (52.0%) in the combination therapy group. The treatment-free period was significantly longer in the combination therapy group (p = 0.0008). Additional IVR therapy was required significantly more frequently in the IVR monotherapy group (p = 0.0026). Post-treatment subretinal haemorrhage or retinal pigment epithelium tear occurred only in the IVR monotherapy group, in one eye (5.0%) and one eye (5.0%), respectively. CONCLUSION: Initial therapy consisting of a single session of PDT combined with IVR improves vision in treatment-naive PCV. Compared with IVR monotherapy, this combination therapy may be more effective for PCV. PMID- 27237050 TI - E3-Independent Constitutive Monoubiquitination Complements Histone Methyltransferase Activity of SETDB1. AB - Ubiquitination typically occurs through the sequential action of three enzymes catalyzing ubiquitin activation (E1), conjugation (E2), and ligation (E3) and regulates diverse eukaryotic cellular processes. Although monoubiquitination commonly confers nondegradative activities, mechanisms underlying its temporal and spatial regulation and functional plasticity still remain largely unknown. Here we demonstrate that SETDB1, a major histone H3K9 methyltransferase is monoubiquitinated at the evolutionarily conserved lysine-867 in its SET-Insertion domain. This ubiquitination is directly catalyzed by UBE2E family of E2 enzymes in an E3-independent manner while the conjugated-ubiquitin (Ub) is protected from active deubiquitination. The resulting constitutive lysine-867 monoubiquitination is essential for SETDB1's enzymatic activity and endogenous retrovirus silencing in murine embryonic stem cells. Furthermore, the canonical hydrophobic patch on the conjugated-Ub is critical for Ub protection and function. Together, our findings highlight an E3-independent mechanism for monoubiquitination and reveal mechanistic details of SETDB1's enzymatic activity and the functional significance of its SET-Insertion. PMID- 27237049 TI - Statin therapy and inflammation in patients with diabetes treated with high dose aspirin. AB - BACKGROUND: Statin and aspirin form the therapeutic cornerstone in patients with coronary artery disease (CAD) and diabetes. Little is known about relationship of statins with blood thrombogenicity and inflammation in these patients. METHODS: Two hundred nine consecutive patients with diabetes and suspected CAD undergoing elective cardiac catheterization were divided in groups based on statin treatment in the Multi-Analyte, Thrombogenic, and Genetic Markers Atherosclerosis study. Urinary 11-dehydrothromboxane B2 (11-dh-TxB2), lipid profile and oxLDL/beta2GPI were measured by AspirinWorksTM ELISA assay, vertical density gradient ultracentrifugation and immunoassay respectively. Thrombelastography, and ADP- and collagen-induced light transmittance aggregometry assessed thrombogenicity. CAD was classified as none/minor [<20% diameter stenosis (DS)], moderate (20-75% DS), or severe (>75% DS). RESULTS: Severe, moderate, and no CAD was observed in 66, 19, and 15% of patients respectively. Patients on statins had significantly lower 11-dh-TxB2, collagen-induced aggregation, total cholesterol, total LDL, LDL3, oxidized-LDL, Apo B100, and ApoB100/A1 ratio (p<0.01 for all). Statin therapy demonstrated a lower proportion of patients with high urinary 11-dh-TxB2 (>1500pg 11-dh-TxB2/mg creatinine) (25 vs. 57%, p=0.01). CONCLUSION: Statins along with aspirin, confers additional anti-inflammatory and antithrombotic effect in diabetics with CAD. Urinary 11-dh-TxB2 may be a useful biomarker for personalizing statin therapy. PMID- 27237051 TI - Inhibition of Rb Phosphorylation Leads to mTORC2-Mediated Activation of Akt. AB - The retinoblastoma (Rb) protein exerts its tumor suppressor function primarily by inhibiting the E2F family of transcription factors that govern cell-cycle progression. However, it remains largely elusive whether the hyper phosphorylated, non-E2F1-interacting form of Rb has any physiological role. Here we report that hyper-phosphorylated Rb directly binds to and suppresses the function of mTORC2 but not mTORC1. Mechanistically, Rb, but not p107 or p130, interacts with Sin1 and blocks the access of Akt to mTORC2, leading to attenuated Akt activation and increased sensitivity to chemotherapeutic drugs. As such, inhibition of Rb phosphorylation by depleting cyclin D or using CDK4/6 inhibitors releases Rb-mediated mTORC2 suppression. This, in turn, leads to elevated Akt activation to confer resistance to chemotherapeutic drugs in Rb-proficient cells, which can be attenuated with Akt inhibitors. Therefore, our work provides a molecular basis for the synergistic usage of CDK4/6 and Akt inhibitors in treating Rb-proficient cancer. PMID- 27237052 TI - Impairment of DNA Methylation Maintenance Is the Main Cause of Global Demethylation in Naive Embryonic Stem Cells. AB - Global demethylation is part of a conserved program of epigenetic reprogramming to naive pluripotency. The transition from primed hypermethylated embryonic stem cells (ESCs) to naive hypomethylated ones (serum-to-2i) is a valuable model system for epigenetic reprogramming. We present a mathematical model, which accurately predicts global DNA demethylation kinetics. Experimentally, we show that the main drivers of global demethylation are neither active mechanisms (Aicda, Tdg, and Tet1-3) nor the reduction of de novo methylation. UHRF1 protein, the essential targeting factor for DNMT1, is reduced upon transition to 2i, and so is recruitment of the maintenance methylation machinery to replication foci. Concurrently, there is global loss of H3K9me2, which is needed for chromatin binding of UHRF1. These mechanisms synergistically enforce global DNA hypomethylation in a replication-coupled fashion. Our observations establish the molecular mechanism for global demethylation in naive ESCs, which has key parallels with those operating in primordial germ cells and early embryos. PMID- 27237055 TI - Dissecting Hofmeister Effects: Direct Anion-Amide Interactions Are Weaker than Cation-Amide Binding. AB - Whereas there is increasing evidence for ion-induced protein destabilization through direct ion-protein interactions, the strength of the binding of anions to proteins relative to cation-protein binding has remained elusive. In this work, the rotational mobility of a model amide in aqueous solution was used as a reporter for the interactions of different anions with the amide group. Protein stabilizing salts such as KCl and KNO3 do not affect the rotational mobility of the amide. Conversely, protein denaturants such as KSCN and KI markedly reduce the orientational freedom of the amide group. Thus these results provide evidence for a direct denaturation mechanism through ion-protein interactions. Comparing the present findings with results for cations shows that in contrast to common belief, anion-amide binding is weaker than cation-amide binding. PMID- 27237053 TI - ppGpp Binding to a Site at the RNAP-DksA Interface Accounts for Its Dramatic Effects on Transcription Initiation during the Stringent Response. AB - Throughout the bacterial domain, the alarmone ppGpp dramatically reprograms transcription following nutrient limitation. This "stringent response" is critical for survival and antibiotic tolerance and is a model for transcriptional regulation by small ligands. We report that ppGpp binds to two distinct sites 60 A apart on E. coli RNA polymerase (RNAP), one characterized previously (site 1) and a second identified here at an interface of RNAP and the transcription factor DksA (site 2). The location and unusual tripartite nature of site 2 account for the DksA-ppGpp synergism and suggest mechanisms for ppGpp enhancement of DksA's effects on RNAP. Site 2 binding results in the majority of ppGpp's effects on transcription initiation in vitro and in vivo, and strains lacking site 2 are severely impaired for growth following nutritional shifts. Filling of the two sites at different ppGpp concentrations would expand the dynamic range of cellular responses to changes in ppGpp levels. PMID- 27237054 TI - Targeting of Mesenchymal Stromal Cells by Cre-Recombinase Transgenes Commonly Used to Target Osteoblast Lineage Cells. AB - The targeting specificity of tissue-specific Cre-recombinase transgenes is a key to interpreting phenotypes associated with their use. The Ocn-Cre and Dmp1-Cre transgenes are widely used to target osteoblasts and osteocytes, respectively. Here, we used high-resolution microscopy of bone sections and flow cytometry to carefully define the targeting specificity of these transgenes. These transgenes were crossed with Cxcl12gfp mice to identify Cxcl12-abundant reticular (CAR) cells, which are a perivascular mesenchymal stromal population implicated in hematopoietic stem/progenitor cell maintenance. We show that in addition to osteoblasts, Ocn-Cre targets a majority of CAR cells and arteriolar pericytes. Surprisingly, Dmp1-Cre also targets a subset of CAR cells, in which expression of osteoblast-lineage genes is enriched. Finally, we introduce a new tissue-specific Cre-recombinase, Tagln-Cre, which efficiently targets osteoblasts, a majority of CAR cells, and both venous sinusoidal and arteriolar pericytes. These data show that Ocn-Cre and Dmp1-Cre target broader stromal cell populations than previously appreciated and may aid in the design of future studies. Moreover, these data highlight the heterogeneity of mesenchymal stromal cells in the bone marrow and provide tools to interrogate this heterogeneity. (c) 2016 American Society for Bone and Mineral Research. PMID- 27237056 TI - Pharmacological effects of methamphetamine and alpha-PVP vapor and injection. AB - Vaporizing drugs in e-cigarettes is becoming a common method of administration for synthetic cathinones and classical stimulants. Heating during vaporization can expose the user to a cocktail of parent compound and thermolytic degradants, which could lead to different toxicological and pharmacological effects compared to ingesting the parent compound alone via injection or nasal inhalation. This study examined the in vivo toxicological and pharmacological effects of vaporized and injected methamphetamine (METH) and alpha-pyrrolidinopentiophenone (alpha PVP). Male and female ICR mice were administered METH or alpha-PVP through vapor or i.p. injection. Dose-effect curves were determined for locomotor activity and a functional observational battery (FOB). METH and alpha-PVP vapor were also evaluated for place preference in male mice. Vapor exposure and injection led to more similarities than differences in toxicological and pharmacological effects. In the FOB, both routes of administration produced typical stimulant effects, and injection also increased some bizarre behaviors (e.g. licking, teeth chattering, darting). Both METH and alpha-PVP vapor exposure produced conditioned place preference. The two routes of administration had comparable efficacy in locomotor activation, with vapor producing longer lasting effects than injection. Females showed greater METH-induced locomotor activity, and greater incidence of a few somatic signs in the FOB than males. These results explore the toxicology of stimulant vapor inhalation in mice using an e-cigarette device. Despite the current technological and methodological difficulties, studying drug vapor promises to allow determination of toxicological effects of thermolytic products and flavor additives. PMID- 27237057 TI - Germline transmission of LNKE208Q variant in a family with myeloproliferative neoplasms. PMID- 27237058 TI - Multicentre evaluation of a novel vaginal dose reporting method in 153 cervical cancer patients. AB - BACKGROUND AND PURPOSE: Recently, a vaginal dose reporting method for combined EBRT and BT in cervical cancer patients was proposed. The current study was to evaluate vaginal doses with this method in a multicentre setting, wherein different applicators, dose rates and protocols were used. MATERIAL AND METHODS: In a subset of patients from the EMBRACE study, vaginal doses were evaluated. Doses at the applicator surface left/right and anterior/posterior and at 5mm depth were measured. In addition, the dose at the Posterior-Inferior Border of Symphysis (PIBS) vaginal dose point and PIBS+/-2cm, corresponding to the mid and lower vagina, was measured. RESULTS: 153 patients from seven institutions were included. Large dose variations expressed in EQD2 with alpha/beta=3Gy were seen between patients, in particular at the top left and right vaginal wall (median 195 (range 61-947)Gy/178 (61-980)Gy, respectively). At 5mm depth, doses were 98 (55-212)Gy/91 (54-227)Gy left/right, and 71 (51-145)Gy/67 (49-189)Gy anterior/posterior, respectively. The dose at PIBS and PIBS+/-2cm was 41 (3 81)Gy, 54 (32-109)Gy and 5 (1-51)Gy, respectively. At PIBS+2cm (mid vagina) dose variation was coming from BT. The variation at PIBS-2cm (lower vagina) was mainly dependent on EBRT field border location. CONCLUSIONS: This novel method for reporting vaginal doses coming from EBRT and BT through well-defined dose points gives a robust representation of the dose along the vaginal axis. In addition, it allows comparison of vaginal dose between patients from different centres. The doses at the PIBS points represent the doses at the mid and lower parts of the vagina. Large variations in dose throughout the vagina were observed between patients and centres. PMID- 27237059 TI - Dynamic contrast enhanced MRI monitoring of primary proton and carbon ion irradiation of prostate cancer using a novel hypofractionated raster scan technique. AB - PURPOSE: To characterize parametric changes measured by sequential dynamic contrast enhanced perfusion MRI (DCE-MRI) during primary proton and carbon ion irradiation of prostate cancer using a novel hypofractionated raster scan technique to determine the potential of pharmacokinetic analysis for monitoring treatment effects of this novel irradiation scheme. MATERIALS AND METHODS: Ninety two patients were evaluated prospectively with DCE-MRI at baseline, day 10 during therapy, and 6weeks, 6months and 18months after treatment completion. After motion correction and co-registration to morphological T2-weighted images, tumors and normal appearing contralateral parenchyma (NACP) were segmented manually on T2W images and ROI statistics calculated for pharmacokinetic parameters K(trans), kep and ve using the standard Tofts model. RESULTS: The volume transfer constant (K(trans), p<0.001/p=0.010) and the leakage space partial volume (ve, p<0.001/p=0.005) showed a statistically significant increase during therapy with protons and carbon ions, respectively. Parametric increases occurred only in patients naive to antihormonal therapy (AHT), and were maximal 10days after the begining of treatment. The rate constant (kep) showed a significant increase only for proton, but not for carbon irradiation (p=0.021). Statistically significant differences between PC and NACP were observed for all parameters (p<0.001). AHT naive patients with persistent PSA elevation above 1ng/ml at 12months experienced statistically significant elevation of K(trans) and ve compared to those with PSA suppression (p=0.04/p=0.023). CONCLUSION: DCE parametric changes following ion particle irradiation of the prostate have not been previously reported. Their development into potential non-invasive imaging biomarkers for assessment of treatment response and efficacy is expected to be aided by the data on the magnitude and temporal evolution of parametric responses of cancer and normal tissue during and after therapy presented here, especially the changes of K(trans) and ve during therapy and their different measurement levels within tumors and in normal appearing contralateral tissue. PMID- 27237060 TI - Cystic echinococcosis: Future perspectives of molecular epidemiology. AB - Human cystic echinococcosis (CE) has been considered to be caused predominantly by Echinococcus granulosus sensu stricto (the dog-sheep strain). Molecular approaches on CE, however, have revealed that human cases are also commonly caused by another species, Echinococcus canadensis. All indices for classification and standardization of CE pathology including available images, epidemiology, diagnostics and treatment are currently based largely on a mixture of infections which include at least E. granulosus s.s. and E. canadensis. Involvement of other species of Echinococcus in CE including E. ortleppi or otherwise cryptic diversity demonstrated recently in Africa requires further elucidation. Molecular identification of the causative species in CE cases is essential for better understanding of pathogenesis and disease. This article stresses the importance of molecular species identification of human CE as a foundation for re-evaluation of evidence-based epidemiology. PMID- 27237061 TI - Specifying a target trial prevents immortal time bias and other self-inflicted injuries in observational analyses. AB - Many analyses of observational data are attempts to emulate a target trial. The emulation of the target trial may fail when researchers deviate from simple principles that guide the design and analysis of randomized experiments. We review a framework to describe and prevent biases, including immortal time bias, that result from a failure to align start of follow-up, specification of eligibility, and treatment assignment. We review some analytic approaches to avoid these problems in comparative effectiveness or safety research. PMID- 27237062 TI - 2016 American Thoracic Society International Conference. PMID- 27237063 TI - Oxidative stress in erythrocytes of banked ABO blood. AB - OBJECTIVE: To understand the responses of A, B, and O blood groups to oxidative stress (OS) induced through storage. METHODS: A, B, and O blood units were obtained from the blood bank at KIMS Hospital, Bangalore, and stored for 35 days at 4 degrees C in citrate phosphate dextrose adenine-1 solution. Every fifth day, hemoglobin (Hb) was assessed in whole blood and erythrocytes were isolated from each group. OS markers such as (i) antioxidant enzymes [superoxide dismutase and catalase] and superoxides were assessed in hemolysate; (ii) lipid peroxidation product - malondialdehyde (MDA) and protein oxidation products [protein carbonyls, advanced oxidation protein products (AOPP), and protein sulfhydryls] were assessed in membrane ghosts. RESULTS: Antioxidant enzymes and Hb were similar in all groups. Superoxides increased in blood group O. MDA and AOPP differed between the groups, where levels in blood group O were lower than blood groups A and B. Sulfhydryls were maintained throughout storage. DISCUSSION: The antioxidant defense in A, B, and O groups were similar as evident from our results of Hb, antioxidant enzymes and sulfhydryls. However, the response of blood group O diverged from that of A and B, substantiated by the results of MDA, AOPP, and superoxides. Thus blood group O endured oxidative insult more efficiently than A and B. This study forms the basis for future studies on erythrocyte membrane and exploring blood group O as a potential candidate for prolonging storage. PMID- 27237064 TI - Comparison between 4-MV and 6-MV radiotherapy in T1N0 glottic cancer. AB - OBJECTIVES/HYPOTHESIS: The purpose of this study was to report the outcomes of a retrospective consecutive cohort study of patients with T1N0M0 glottic carcinoma treated with 4-MV or 6-MV radiotherapy. STUDY DESIGN: Retrospective case-control study. METHODS: This was a retrospective review of all patients with T1N0M0 glottic carcinoma treated with radiotherapy between January 2000 and December 2012 in the Department of Radiation Oncology at National Cancer Center Singapore. A total of 124 patients were included. Clinical endpoints of interest were: local control (LC), overall survival (OS), and disease-specific survival (DSS). Other prognostic factors for LC were also analyzed: age, gender, smoking status, T substage, dose fraction, field size, anterior commissure involvement, total dose, and overall treatment time. RESULTS: Six-megavolt photon radiotherapy was used in 73 patients and 4-MV photon radiotherapy in 51 patients. Median follow-up was 4.9 years. The 5-year LC and OS were as follows: 4 MV, 91.6% and 83.4%; 6 MV, 88.8% and 82.8%; and the 5-year LC, OS, and DSS for all patients were 90.4%, 83.3%, and 98.3%. There was no significant difference in LR and OS between 4-MV and 6-MV radiotherapy (P = .92, P = .16, respectively). In the univariate analysis of LC, none of the prognostic factors was statistically significant. Twenty patients (23%) developed second primary cancers, the majority in the lungs. CONCLUSIONS: Six-megavolt photon radiotherapy yields comparable results to 4-MV photons. Bolus and computed tomographic simulation are useful to ensure adequate dose coverage of target volume. Follow-up postradiotherapy should incorporate chest imaging, smoking cessation advice, and thyroid function test. LEVEL OF EVIDENCE: 4 Laryngoscope, 127:1061-1067, 2017. PMID- 27237066 TI - Malleability and Machines: Glenn Gould and the Technological Self. AB - The Pianist Glenn Gould has often been portrayed as a musical idealist who embraced mundane recording media as a way of escaping the anxiety of the concert hall. In pursuing his musical ideals, however, Gould obsessed over material objects-the qualities of a chair, the action of piano keys, the placement of splices in magnetic tape. This paper argues that for him, the detailed properties of machines and electronic media were crucial, not just as tools for pursuing disembodied aesthetic aims, but as instruments and material sites for a moral project. Locating Gould's concerns among the techniques and technologies that inspired him, the concert hall he despised, and the jazz and chance music he tolerated, the paper explores how Gould's famed philosophy of technology was rooted in a "technological self" that tied morality and aesthetics, and intimacy and isolation, to concrete ideals for the kinds of people we ought to be. PMID- 27237067 TI - Richard Byrd, Technological Explorer: Polar Exploration, the Machine, and Heroic Masculinity in Interwar America. AB - In May 1926, U.S. newspapers were full of the story that Richard Byrd, an American aviator, had become the first person to reach the North Pole by air. The announcement triggered patriotic outpourings across the country and Byrd was widely hailed as a national hero. The young aviator's flight was part of a burgeoning interwar expeditionary practice that placed machines at the heart of new modes of exploration. This development, however, challenged preexisting notions of masculine heroism and threatened to undercut the explorer's heroic status. How then, could Byrd become a national hero? This article analyzes his depiction in the press as a means of exploring interwar Americans' efforts to renegotiate their notions of heroic masculinity in a way that could accommodate the machine without threatening the hero's status. In the process, it argues, these narratives and images defined a new sort of popular hero: the technological explorer. PMID- 27237065 TI - Comparison of Transpulmonary Thermodilution and Calibrated Pulse Contour Analysis with Pulmonary Artery Thermodilution Cardiac Output Measurements in Anesthetized Dogs. AB - BACKGROUND: Transpulmonary thermodilution (TPTDCO ) and calibrated pulse contour analysis (PCACO ) are alternatives to pulmonary artery thermodilution cardiac output (PATDCO ) measurement. HYPOTHESIS: Ten mL of ice-cold thermal indicator (TI10 ) would improve the agreement and trending ability between TPTDCO and PATDCO compared to 5 mL of indicator (TI5 ) (Phase-1). The agreement and TA between PCACO and PATDCO would be poor during changes in systemic vascular resistance (SVR) (Phase-2). ANIMALS: Eight clinically normal dogs (20.8-31.5 kg). METHODS: Prospective, experimental study. Simultaneous TPTDCO and PATDCO (averaged from 3 repetitions) using TI5 and TI10 were obtained during isoflurane anesthesia combined or not with remifentanil or dobutamine (Phase-1). Triplicate PCACO and PATDCO measurements were recorded during phenylephrine-induced vasoconstriction and nitroprusside-induced vasodilation (Phase-2). RESULTS: Mean bias (limits of agreement: LOA) (L/min), percentage bias (PB), and percentage error (PE) were 0.62 (-0.11 to 1.35), 16%, and 19% for TI5 ; and 0.33 (-0.25 to 0.91), 9%, and 16% for TI10 . Mean bias (LOA), PB, and PE were 0.22 (-0.63 to 1.07), 6%, and 23% during phenylephrine; and 2.12 (0.70-3.55), 43%, and 29% during nitroprusside. Mean angular bias (radial LOA) values were 2 degrees (-10 degrees to 14 degrees ) and -1 degrees (-9 degrees to 6 degrees ) for TI5 and TI10 , respectively (Phase-1), and 38 degrees (5 degrees -71 degrees ) (Phase 2). CONCLUSIONS AND CLINICAL IMPORTANCE: Although TI10 slightly improves the agreement and trending ability between TPTDCO and PATDCO in comparison to TI5 , both volumes can be used for TPTDCO in replacement of PATDCO . Vasodilation worsens the agreement between PCACO and PATDCO . Because of PCACO 's poor agreement and trending ability with PATDCO during SVR changes, this method has limited clinical application. PMID- 27237068 TI - Zoomar: Frank G. Back and the Postwar Television Zoom Lens. AB - In October 1946, optical engineer Frank G. Back introduced a new zoom lens designed for film and television cameras. The Zoomar lens was adopted by newsreel and television, and soon became ubiquitous in American television production. Zoomar lenses enhanced postwar television, and prepared the ground for the later popularity of zooms in film production. This article explores the wartime innovations and industrial collaborations which aided the development of the lens. It documents a neglected aspect of the history of American television technology, and sheds further light on relations between small inventors and large corporate bodies during the mid-twentieth century. PMID- 27237069 TI - An Architecture for the Electronic Church: Oral Roberts University in Tulsa, Oklahoma. AB - More than a university, Oral Roberts University in Tulsa, Oklahoma, was also the headquarters for evangelist Oral Roberts's electronic church. The electronic church in America, dominated by Christian evangelicals, used technology to spread the Gospel over radio airways and television signals to a dispersed audience. Yet evangelicals like Roberts also constructed ambitious campuses in real space and time. The architecture of Oral Roberts University visualized a modern and "populuxe" image for the electronic church in the 1960s and 1970s. The university's Prayer Tower purposely alluded to the Seattle Space Needle, aligning religion and the Space Age, and the campus's white, gold, and black color palette on late modern buildings created an image of aspirational luxury, conveying Roberts's health and wealth gospel. Oral Roberts University served as a sound stage for Roberts's radio and television shows, a pilgrimage point for his audience, and a university dedicated to training evangelicals in the electronic church. PMID- 27237070 TI - Contested Waterlines: The Wave-Line Theory and Shipbuilding in the Nineteenth Century. AB - Ship hydrodynamics in the nineteenth century was dominated by John Scott Russell's wave-line theory. Russell, a prominent British shipbuilder and scientist, argued that wavemaking was the primary source of resistance for ships, and that by designing ships according to trigonometric curves and proportions (the wave line) this resistance could effectively be eliminated. From the 1840s to the 1880s, shipbuilders such as John Willis Griffiths, Donald McKay and George Steers designed their clipper ships (like Sea Witch and Flying Cloud) and yachts (America) with wave-line hulls, while authors like Jules Verne referenced Russell's theory. The wave line slowly faded after William Froude developed his laws of ship resistance. The article examines how Russell's theory became accepted by technical experts and the wider public to become the most widely known ship hydrodynamic theory of the 1800s-a reminder of how a persuasive idea can take hold of an entire profession, and even the public, for a long time. PMID- 27237071 TI - Confronting the Second Deep Transition through the Historical Imagination. PMID- 27237072 TI - Designs and Dreams: Questions of Technology in Hayao Miyazaki's The Wind Rises. PMID- 27237073 TI - Adherence to guidelines strongly improves reproducibility of brachial artery flow mediated dilation. Common mistakes and methodological issue. PMID- 27237074 TI - Hypoglycemic episodes are associated with inflammatory status in patients with type 1 diabetes mellitus. AB - BACKGROUD: Glycemic control may be associated with inflammatory status in type 1 diabetes (T1DM). We examined the association between glucose control parameters and circulating inflammation markers in T1DM. METHODS: The study included 101 T1DM patients treated with personal insulin pumps (T1DM duration 15.2 + 7.3 years). The analysed glycemic parameters included HbA1c, mean glucose level, standard deviation and number of hypoglycemic episodes (glucose <55 mg/dL) from the last 7 days. Blood was collected for testing inflammatory markers (IL-6, VCAM, ICAM, E-selectin). RESULTS: The T1DM cohort had good glycemic control (HbA1c 7.1 +/- 0.8%, mean daily glucose 141.5 +/- 27.1 mg/dL and the mean number of hypoglycemic episodes was 5.6 +/- 4.0/week). In a forward stepwise multiple linear regression analysis the number of hypoglycemic episodes predicted the levels of the investigated markers (sICAM p = 0.0019, sVCAM p = 0.021, sE selectin p = 0.048, and IL-6 p = 0.049). None of the other glycemic parameters was shown to be an independent predictor. CONCLUSIONS: For the first time, we report an association between the number of mild hypoglycemic episodes, recorded in a real life setting, and the level of inflammatory markers in T1DM patients with good glycemic control. PMID- 27237075 TI - TRAF3IP2 mediates atherosclerotic plaque development and vulnerability in ApoE(-/ ) mice. AB - BACKGROUND AND AIMS: Atherosclerosis is a major cause of heart attack and stroke. Inflammation plays a critical role in the development of atherosclerosis. Since the cytoplasmic adaptor molecule TRAF3IP2 (TRAF3-Interacting Protein 2) plays a causal role in various autoimmune and inflammatory diseases, we hypothesized that TRAF3IP2 mediates atherosclerotic plaque development. METHODS: TRAF3IP2/ApoE double knockout (DKO) mice were generated by crossing TRAF3IP2(-/-) and ApoE(-/-) mice. ApoE(-/-) mice served as controls. Both DKO and control mice were fed a high-fat diet for 12 weeks. Plasma lipids were measured by ELISA, atherosclerosis by en face analysis of aorta and plaque cross-section measurements at the aortic valve region, plaque necrotic core area, collagen and smooth muscle cell (SMC) content by histomorphometry, and aortic gene expression by RT-qPCR. RESULTS: The plasma lipoprotein profile was not altered by TRAF3IP2 gene deletion in ApoE(-/-) mice. While total aortic plaque area was decreased in DKO female, but not male mice, the plaque necrotic area was significantly decreased in DKO mice of both genders. Plaque collagen and SMC contents were increased significantly in both female and male DKO mice compared to respective controls. Aortic expression of proinflammatory cytokine (Tumor necrosis factor alpha, TNFalpha), chemokine (Chemokine (C-X-C motif) Ligand 1, CXCL1) and adhesion molecule (Vascular cell adhesion molecule 1, VCAM1; and Intercellular adhesion molecule 1, ICAM1) gene expression were decreased in both male and female DKO mice. In addition, the male DKO mice expressed markedly reduced levels of extracellular matrix (ECM)-related genes, including TIMP1 (Tissue inhibitor of metalloproteinase 1), RECK (Reversion Inducing-Cysteine-Rich Protein with Kazal Motifs) and ADAM17 (A Disintegrin And Metalloproteinase 17). CONCLUSIONS: TRAF3IP2 plays a causal role in atherosclerotic plaque development and vulnerability, possibly by inducing the expression of multiple proinflammatory mediators. TRAF3IP2 could be a potential therapeutic target in atherosclerotic vascular diseases. PMID- 27237076 TI - Antifungal prophylaxis in liver transplant recipients: one size does not fit all. AB - BACKGROUND: Targeted antifungal prophylaxis against Candida species or against Candida species and Aspergillus species, according to individual patient risk factors (RFs), is recommended by experts. However, recent studies have reported fluconazole is as effective as broader spectrum antifungals for preventing invasive fungal infection (IFI) after liver transplantation (LT). METHODS: We performed a retrospective cohort study of all adult patients who underwent LT at our 1420-bed tertiary teaching hospital, from June 2010 to December 2014, to assess the rate and etiology of IFI within 100 days after LT, to investigate the compliance with targeted prophylaxis, and to analyze risk factors for developing IFI. RESULTS: In total, 303 patients underwent LT. Patients were classified as having low (no RFs), intermediate (1 RF for invasive candidiasis [IC]), and high risk (1 RF for invasive aspergillosis [IA] or >=2 RFs for IC) for IFI in 20%, 30%, and 50% of cases, respectively. A total of 139 patients received antifungal prophylaxis: 98 with a mold-active drug and 41 with fluconazole. Overall adherence to targeted prophylaxis was 53%. Nineteen patients (6.3%) developed IFI: 7 IC and 12 IA. Multivariate Cox regression analysis, adjusted for median model for end-stage liver disease score at LT, stratification risk group, and adherence to targeted prophylaxis, showed that graft dysfunction, renal replacement therapy, and prophylaxis with fluconazole were independent risk factors for IFI. Seven of the 9 patients who received fluconazole prophylaxis and developed IFI were classified as having high risk for IFI, and 6 developed IA. CONCLUSION: Recommended stratification is accurate for predicting patients at very high risk for IFI, who should receive prophylaxis with a mold-active drug. PMID- 27237077 TI - Evaluation of the effect of different mandibular fractures on the temporomandibular joint using magnetic resonance imaging: five years of follow up. AB - A prospective cohort study was performed to investigate concurrent and delayed temporomandibular joint (TMJ) injuries following different types of mandibular fracture using magnetic resonance imaging (MRI). One hundred adult male patients with a recent history of mandibular fracture were included. The patients were divided into five groups according to the site of fracture. The patients underwent MRI within 10 days of the primary injury. The same clinical, radiographic, and MRI examinations were performed 5 years later. The aetiological factor of the mandibular fractures was a road traffic accident in all cases. The results of the study suggest that there is no direct correlation between TMJ pain and the presence of MRI changes. Patients who had a condylar fracture associated with a fracture of the angle or body could develop more TMJ damage on both sides. TMJs on the same side as the fractures could develop internal derangement as a result of the acute stage of the trauma and its delayed consequences. Trauma caused more delayed TMJ derangement on the non-fractured side than on the fractured side of the mandible. Disturbances of the TMJ on the side of the fracture develop during both the acute stage and follow-up. PMID- 27237078 TI - Occurrence of a 'bad' split and success of initial mandibular healing: a review of 524 sagittal ramus osteotomies in 262 patients. AB - The purpose of this study was to assess the prevalence of a 'bad' split after sagittal ramus osteotomies (SRO) and report the results of initial mandibular healing. A retrospective cohort study derived from patients treated by a single surgeon at one institution between 2004 and 2013 was performed. An index group consisting of a series of subjects with a spectrum of bimaxillary dentofacial deformities also involving the chin and symptomatic chronic obstructive nasal breathing was identified. The SRO design, bicortical screw fixation technique, and perioperative management were consistent. Outcome variables included the occurrence of a 'bad' split and the success of initial SRO healing. Two hundred sixty-two subjects undergoing 524 SROs met the inclusion criteria. Their average age was 25 years (range 13-63 years) and 134 were female (51%). Simultaneous removal of a third molar was performed during 209 of the SROs (40%). There were no 'bad' splits. All subjects achieved successful bone union, the planned occlusion, and return to a chewing diet and physical activities by 5 weeks after surgery. The presence of a third molar removed during SRO was not associated with an increased frequency of a 'bad' split or delayed mandibular healing. PMID- 27237079 TI - Autogenous non-vascularized bone graft in segmental mandibular reconstruction: a systematic review. AB - The restoration of mandibular bone defects with non-vascularized bone grafts depends on the diagnosis, anatomical site, extent of the defect, and the patient's age, as well as the surgeon's experience. The aim of this study was to perform a systematic literature review on mandibular reconstruction for segmental mandibular bone defects using non-vascularized bone grafts to answer the following question: Is there scientific evidence to support the use of this technique? The initial literature search in PubMed, Scopus, and Cochrane databases identified 862 articles. Of these, 25 were included in the final review. These articles encompassed 926 procedures with non-vascularized bone grafts; 76.1% were from the iliac crest. Benign tumours were the major cause of these defects (56.8%), and 44.7% of defects were located in the lateral mandibular area. Although this technique showed a high occurrence of complications (290 in 873 patients, some with more than one complication), these did not account for treatment failure. The restoration of bone defects due to malignant tumours treated with radiation therapy had lower success rates, and these appear to be a contraindication for the technique. Although standardized randomized controlled clinical studies are needed to obtain better clinical evidence for treatment choices in general, the use of non-vascularized bone grafts for mandibular reconstruction showed an 87.6% success rate in this review. PMID- 27237080 TI - Lower and Better. PMID- 27237082 TI - Risk Selection under Public Health Insurance with Opt-Out. AB - This paper studies risk selection between public and private health insurance when some, but not all, individuals can opt out of otherwise mandatory public insurance. Using a theoretical model, I show that public insurance is adversely selected when insurers and insureds are symmetrically informed about health related risks, and that there can be adverse or advantageous selection when insureds are privately informed. Using data from the German Socio-Economic Panel, I find that (i) public insurance is, on balance, adversely selected under the German public health insurance with opt out scheme, (ii) individuals advantageously select public insurance based on risk aversion and residential location, and (iii) there is suggestive evidence of asymmetric information in the market for private health insurance. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27237081 TI - Improving the delivery of brief interventions for heavy drinking in primary health care: outcome results of the Optimizing Delivery of Health Care Intervention (ODHIN) five-country cluster randomized factorial trial. AB - AIM: To test if training and support, financial reimbursement and option of referring screen-positive patients to an internet-based method of giving advice (eBI) can increase primary health-care providers' delivery of Alcohol Use Disorders Identification Test (AUDIT)-C-based screening and advice to heavy drinkers. DESIGN: Cluster randomized factorial trial with 12-week implementation and measurement period. SETTING: Primary health-care units (PHCU) in different locations throughout Catalonia, England, the Netherlands, Poland and Sweden. PARTICIPANTS: A total of 120 PHCU, 24 in each of Catalonia, England, the Netherlands, Poland and Sweden. INTERVENTIONS: PHCUs were randomized to one of eight groups: care as usual, training and support (TS), financial reimbursement (FR) and eBI; paired combinations of TS, FR and eBI, and all of FR, TS and eBI. MEASUREMENTS: The primary outcome measure was the proportion of eligible adult (age 18+ years) patients screened during a 12-week implementation period. Secondary outcome measures were proportion of screen-positive patients advised; and proportion of consulting adult patients given an intervention (screening and advice to screen-positives) during the same 12-week implementation period. FINDINGS: During a 4-week baseline measurement period, the proportion of consulting adult patients who were screened for their alcohol consumption was 0.059 per PHCU (95% CI 0.034 to 0.084). Based on the factorial design, the ratio of the logged proportion screened during the 12-week implementation period was 1.48 (95% CI = 1.13-1.95) in PHCU that received TS versus PHCU that did not receive TS; for FR, the ratio was 2.00 (95% CI = 1.56-2.56). The option of referral to eBI did not lead to a higher proportion of patients screened. The ratio for TS plus FR was 2.34 (95% CI = 1.77-3.10), and the ratio for TS plus FR plus eBI was1.68 (95% CI = 1.11-2.53). CONCLUSIONS: Providing primary health-care units with training, support and financial reimbursement for delivering Alcohol Use Disorders Identification Test-C-based screening and advice to heavy drinkers increases screening for alcohol consumption. Providing primary health-care units with the option of referring screen-positive patients to an internet-based method of giving advice does not appear to increase screening for alcohol consumption. PMID- 27237083 TI - Skin biopsy and microneurography disclose selective noradrenergic dysfunction due to dopamine-beta-hydroxylase deficiency. AB - Skin biopsy and microneurography are autonomic tests directly evaluating adrenergic and cholinergic sympathetic fibers to identify selective deficiency of a specific peripheral sympathetic subdivision. We describe a patient with tomacular neuropathy due to a deletion of the PMP22 gene who complained of chronic orthostatic hypotension due to a dopamine-beta-hydroxylase deficiency confirmed by genetic analysis demonstrating two novel mutations in the DbetaH gene. To further characterize autonomic dysfunctions the proband underwent skin biopsy and microneurography. These tests disclosed a selective peripheral adrenergic dysfunction demonstrating the possibility to ascertain DbetaH deficiency. In conclusion, skin biopsy and microneurography may help to increase the diagnosis of this peculiar disorder particularly when routine autonomic nervous system tests show uncertain results. PMID- 27237084 TI - Electron correlation in the interacting quantum atoms partition via coupled cluster lagrangian densities. AB - The electronic energy partition established by the Interacting Quantum Atoms (IQA) approach is an important method of wavefunction analyses which has yielded valuable insights about different phenomena in physical chemistry. Most of the IQA applications have relied upon approximations, which do not include either dynamical correlation (DC) such as Hartree-Fock (HF) or external DC like CASSCF theory. Recently, DC was included in the IQA method by means of HF/Coupled Cluster (CC) transition densities (Chavez-Calvillo et al., Comput. Theory Chem. 2015, 1053, 90). Despite the potential utility of this approach, it has a few drawbacks, for example, it is not consistent with the calculation of CC properties different from the total electronic energy. To improve this situation, we have implemented the IQA energy partition based on CC Lagrangian one- and two electron orbital density matrices. The development presented in this article is tested and illustrated with the H2 , LiH, H2 O, H2 S, N2 , and CO molecules for which the IQA results obtained under the consideration of (i) the CC Lagrangian, (ii) HF/CC transition densities, and (iii) HF are critically analyzed and compared. Additionally, the effect of the DC in the different components of the electronic energy in the formation of the T-shaped (H2 )2 van der Waals cluster and the bimolecular nucleophilic substitution between F(-) and CH3 F is examined. We anticipate that the approach put forward in this article will provide new understandings on subjects in physical chemistry wherein DC plays a crucial role like molecular interactions along with chemical bonding and reactivity. (c) 2016 Wiley Periodicals, Inc. PMID- 27237085 TI - Nomogram of the Barcelona Clinic Liver Cancer System: external validation in European patients. PMID- 27237086 TI - Symposium theme: Integrated solutions for sustainable environmental health. PMID- 27237087 TI - Child development in primary care: a surveillance proposal. AB - OBJECTIVE: To evaluate a child development surveillance tool proposal to be used in primary care, with simultaneous use of the Denver II scale. METHODS: This was a cross-sectional study of 282 infants aged up to 36 months, enrolled in a public daycare in a countryside community in Rio Grande do Sul/Brazil. Child development was assessed using the surveillance tool and the Denver II scale. RESULTS: The prevalence of probable developmental delay was 53%; most of these cases were in the alert group and 24% had normal development, but with risk factors. At the Denver scale, the prevalence of suspected developmental delay was 32%. When risk factors and sociodemographic variables were assessed, no significant difference was observed. CONCLUSION: The evaluation of this surveillance tool resulted in objective and comparable data, which were adequate for a screening test. It is easily applicable as a screening tool, even though it was originally designed as a surveillance tool. The inclusion of risk factors to the scoring system is an innovation that allows for the identification of children with suspected delay in addition to developmental milestones, although the definition of parameters and choice of indicators should be thoroughly studied. PMID- 27237088 TI - Interference of heart and transcutaneous oxygen monitoring in the measurement of bioelectrical impedance analysis in preterm newborns. AB - OBJECTIVE: To verify if the connection of electrodes for heart and transcutaneous oxygen monitoring interfere with the measurement of electrical bioimpedance in preterm newborns. METHODS: This was a prospective, blinded, controlled, cross sectional, crossover study that assessed and compared paired measures of resistance (R) and reactance (Xc) by BIA, obtained with and without monitoring wires attached to the preterm newborn. The measurements were performed in immediate sequence, after randomization to the presence or absence of electrodes. The sample size calculated was 114 measurements or tests with monitoring wires and 114 without monitoring wires, considering for a difference between the averages of 0.1 ohms, with an alpha error of 10% and beta error of 20%, with significance <0.05. RESULTS: No differences were observed between the R (677.37+/ 196.07 vs. 677.46+/-194.86) and Xc (31.15+/-9.36 vs. 31.01+/-9.56) values obtained with and without monitoring wires, respectively, with good correlation between them (R: 0.997 and Xc: 0.968). CONCLUSION: The presence of heart and/or transcutaneous oxygen monitoring wires connected to the preterm newborn did not affect the values of R or Xc measured by BIA, allowing them to be carried out in this population without risks. PMID- 27237089 TI - Application of polystyrene disk substrates in cellular cultivation methods: generalized specimen preparation protocol for scanning electron microscopy. AB - Sample preparation for scanning electron microscopy (SEM) may vary by cellular type, composition and method of cultivation. It has been proposed here that a generalized method of sample preparation may be applied for the visualization of bacteria, fungi, and human cellular tissue without modification of protocol between cell types. The following protocol was developed to incorporate polystyrene disk substrates in the simplification of sample preparation for SEM and reduce the possibility of processing artefacts. The proposed method of preparation may be applied to samples grown in either liquid or solid cultural medium regardless of cell type. With the proposed protocol, centrifugation, isolation and critical point drying are not required, therefore increasing specimen integrity. The incorporation of polystyrene disks showed positive cellular adhesion and applications in SEM for bacterial, fungal and human neuronal tissue. In addition, the simplicity of the proposed protocol is highly adaptable and may be further incorporated to visually analyse the effects of antifungals, antibiotics and disease pathogenesis through pathogen-host interactions. The proposed method of specimen preparation was incorporated in either liquid or solid state growth mediums during the cultivation of the selected cellular samples and revealed great promise in the preservation and visualization under the scanning electron microscope. PMID- 27237090 TI - Exchange of chemical signals between cardiac cells. Fundamental role on cell communication and metabolic cooperation. AB - The exchange of chemical signals between cardiac cells and its relevance for cell communication and metabolic cooperation was reviewed. The role of gap junctions on the transfer of chemical information was discussed as well as the different factors involved in its regulation including changes in cell volume, high glucose, activation of the renin angiotensin aldosterone system including the intracrine effect of renin and angiotensin II on chemical coupling and cardiac energetics. Finally, the possible role of epigenetic changes of the renin angiotensin aldosterone system (RAAS) on the expression of components of the RAAS was discussed. The evidence available leads to the conception of the heart as a metabolic syncytium in which glucose as well nucleotides and hormones can flow from cell-to-cell though gap junctions, providing a new vision of how alterations in metabolic cooperation can induce cardiac diseases. These findings represent a stimulus for future research in this important area of cardiac physiology and pathology. PMID- 27237091 TI - TREM-1 activation modulates dsRNA induced antiviral immunity with specific enhancement of MAPK signaling and the RLRs and TLRs on macrophages. AB - Triggering receptor expressed on myeloid cells 1(TREM-1) is a newly identified member of the immunoglobulin superfamily and is extensively involved in the regulation of innate immunity. To determine the role of TREM-1 in innate antiviral immunity, we investigated TREM-1 expression and its downstream signaling effect in the murine bone marrow-derived macrophages or RAW264.7 macrophage-like mouse cell line by double-stranded RNA (dsRNA) stimulation. The level of TREM-1 expression was low at the baseline and could up-regulate markedly in dose- and time-dependent manners upon stimulation by dsRNA/poly IC. Inhibitor studies disclosed mitogen-activated protein kinase (MAPK) p38 and PI3K pathways were involved in dsRNA-induced up-regulation of TREM-1. Compared with lipopolysaccharide (LPS), the peak response of poly IC-induced TREM-1 expression is delayed, and cells pretreated with scrambled RNA presented higher expression of TREM-1 upon LPS challenge. After ligation with the agonist antibody, TREM-1 can potentiate type I interferon (IFN) production and antiviral inflammation induced by dsRNA, which is ralated to the enhanced phosphorylation of MAPKs and expression of RLRs and TLRs by TREM-1 ligation. This study is the first to show the regulatory role of TREM-1 in RLRs and TLRs expression, and these findings might enrich the understanding of the up-regulation mechanism and the function of TREM-1. PMID- 27237092 TI - Kushenin induces the apoptosis of HCV-infected cells by blocking the PI3K-Akt mTOR pathway via inhibiting NS5A. AB - With the increased burden induced by HCV, there is an urgent need to develop better-tolerated agents with good safety. In this study, we evaluated the anti HCV capability of kushenin, as well as the possible mechanism to Huh7.5-HCV cells. The results demonstrated that kushenin significantly inhibited the HCV-RNA level. Similarly, the expression of HCV-specific protein NS5A was also decreased. Molecular docking results displayed that kushenin bonded well to the active pockets of HCV NS5A, further confirming the effects of kushenin on HCV replication. Coimmunoprecipitation assay determined that kushenin suppressed the interaction between PI3K and NS5A in HCV-replicon cells. Furthermore, kushenin exerted an obviously induced function on HCV-replicon cells apoptosis by inhibiting PI3K-Akt-mTOR pathway, which could be ameliorated by the specific activator IGF-1 addition. Taken together, kushenin possesses the ability to inhibit HCV replication, and contributes to the increased apoptosis of HCV infected cells by blocking the PI3K-Akt-mTOR pathway via inhibiting NS5A. Our results provide important evidence for a better understanding of the pathogenesis of HCV infection, and suggest that kushenin has the potential to treat HCV disease. PMID- 27237093 TI - PNA-COMBO-FISH: From combinatorial probe design in silico to vitality compatible, specific labelling of gene targets in cell nuclei. AB - Recently, advantages concerning targeting specificity of PCR constructed oligonucleotide FISH probes in contrast to established FISH probes, e.g. BAC clones, have been demonstrated. These techniques, however, are still using labelling protocols with DNA denaturing steps applying harsh heat treatment with or without further denaturing chemical agents. COMBO-FISH (COMBinatorial Oligonucleotide FISH) allows the design of specific oligonucleotide probe combinations in silico. Thus, being independent from primer libraries or PCR laboratory conditions, the probe sequences extracted by computer sequence data base search can also be synthesized as single stranded PNA-probes (Peptide Nucleic Acid probes) or TINA-DNA (Twisted Intercalating Nucleic Acids). Gene targets can be specifically labelled with at least about 20 probes obtaining visibly background free specimens. By using appropriately designed triplex forming oligonucleotides, the denaturing procedures can completely be omitted. These results reveal a significant step towards oligonucleotide-FISH maintaining the 3d-nanostructure and even the viability of the cell target. The method is demonstrated with the detection of Her2/neu and GRB7 genes, which are indicators in breast cancer diagnosis and therapy. PMID- 27237094 TI - Shh mediates PDGF-induced contractile-to-synthetic phenotypic modulation in vascular smooth muscle cells through regulation of KLF4. AB - Platelet-derived growth factor (PDGF) is known to induce phenotypic switching of vascular smooth muscle cells (VSMCs) from contractile to a pathological synthetic state, which played an essential role in proliferation of VSMCs. Sonic hedgehog (Shh) contributes to the proliferation of VSMCs when induced by PDGF. Here, we investigated the probable role of Shh in PDGF-induced VSMC dedifferentiation and its underlying mechanisms. We found that PDGF stimulated Shh expression in VSMCs, which was mediated by activation of PDGFRbeta/ERK1/2 cell signaling pathway. Further, we found PDGF-induced VSMC phenotypic modulation was accompanied by up regulation of Shh/Gli family zinc finger 2 (Gli2) signaling and Kruppel-like factor 4 (KLF4). When inhibited Shh in the presence of PDGF, the expressions of KLF4 and VSMC dedifferentiation markers were down-regulated and the effect of PDGF in inducing VSMC dedifferentiation was blocked. In the absence of PDGF, Shh signaling activation increased the expression of KLF4 and promoted VSMC dedifferentiation. The results indicate Shh participated in the regulation of PDGF-induced VSMC dedifferentiation. Finally, we found that KLF4 was closely involved in this process. On inhibition of KLF4, PDGF induced VSMC dedifferentiation was abrogated, even in the presence of Shh. Taken together, the results provide critical insights into the newly discovered role of Shh in phenotypic modulation of VSMCs which depends on KLF4. PMID- 27237095 TI - Assessment of cellular materials generated by co-cultured 'inflamed' and healthy periodontal ligament stem cells from patient-matched groups. AB - Recently, stem cells derived from the'inflamed' periodontal ligament (PDL) tissue of periodontally diseased teeth (I-PDLSCs) have been increasingly suggested as a more readily accessible source of cells for regenerative therapies than those derived from healthy PDL tissue (H-PDLSCs). However, substantial evidence indicates that I-PDLSCs exhibit impaired functionalities compared with H-PDLSCs. In this study, patient-matched I-PDLSCs and H-PDLSCs were co-cultured at various ratios. Cellular materials derived from these cultures were investigated regarding their osteogenic potential in vitro and capacity to form new bone following in vivo transplantation. While patient-matched I-PDLSCs and H-PDLSCs could co-exist in co-culture systems, the proportion of I-PDLSCs tended to increase during in vitro incubation. Compared with H-PDLSC monoculture, the presence of I-PDLSCs in the co-cultures appeared to enhance the overall cell proliferation. Although not completely rescued, the osteogenic and regenerative potentials of the cellular materials generated by co-cultured I-PDLSCs and H PDLSCs were significantly improved compared with those derived from I-PDLSC monocultures. Notably, cells in co-cultures containing either 50% I-PDLSCs plus 50% H-PDLSCs or 25% I-PDLSCs plus 75% H-PDLSCs expressed osteogenesis-related proteins and genes at levels similar to those expressed in H-PDLSC monocultures (P>0.05). Irrespective of the percentage of I-PDLSCs, robust cellular materials were obtained from co-cultures with 50% or more H-PDLSCs, which exhibited equivalent potential to form new bone in vivo compared with sheets generated by H PDLSC monocultures. These data suggest that the co-culture of I-PDLSCs with patient-matched H-PDLSCs is a practical and effective method for increasing the overall osteogenic and regenerative potentials of resultant cellular materials. PMID- 27237096 TI - Hyaluronic acid enhances proliferation of human amniotic mesenchymal stem cells through activation of Wnt/beta-catenin signaling pathway. AB - This study investigated the pro-proliferative effect of hyaluronic acid (HA) on human amniotic mesenchymal stem cells (hAMSCs) and the underlying mechanisms. Treatment with HA increased cell population growth in a dose- and time-dependent manner. Analyses by flow cytometry and immunocytochemistry revealed that HA did not change the cytophenotypes of hAMSCs. Additionally, the osteogenic, chondrogenic, and adipogenic differentiation capabilities of these hAMSCs were retained after HA treatment. Moreover, HA increased the mRNA expressions of wnt1, wnt3a, wnt8a, cyclin D1, Ki-67, and beta-catenin as well as the protein level of beta-catenin and cyclin D1 in hAMSCs; and the nuclear localization of beta catenin was also enhanced. Furthermore, the pro-proliferative effect of HA and up regulated expression of Wnt/beta-catenin pathway-associated proteins - wnt3a, beta-catenin and cyclin D1 in hAMSCs were significantly inhibited upon pre treatment with Wnt-C59, an inhibitor of the Wnt/beta-catenin pathway. These results suggest that HA may positively regulate hAMSCs proliferation through regulation of the Wnt/beta-catenin signaling pathway. PMID- 27237097 TI - Inositol induces mesenchymal-epithelial reversion in breast cancer cells through cytoskeleton rearrangement. AB - Inositol displays multi-targeted effects on many biochemical pathways involved in epithelial-mesenchymal transition (EMT). As Akt activation is inhibited by inositol, we investigated if such effect could hamper EMT in MDA-MB-231 breast cancer cells. In cancer cells treated with pharmacological doses of inositol E cadherin was increased, beta-catenin was redistributed behind cell membrane, and metalloproteinase-9 was significantly reduced, while motility and invading capacity were severely inhibited. Those changes were associated with a significant down-regulation of PI3K/Akt activity, leading to a decrease in downstream signaling effectors: NF-kB, COX-2, and SNAI1. Inositol-mediated inhibition of PS1 leads to lowered Notch 1 release, thus contributing in decreasing SNAI1 levels. Overall, these data indicated that inositol inhibits the principal molecular pathway supporting EMT. Similar results were obtained in ZR 75, a highly metastatic breast cancer line. These findings are coupled with significant changes on cytoskeleton. Inositol slowed-down vimentin expression in cells placed behind the wound-healing edge and stabilized cortical F-actin. Moreover, lamellipodia and filopodia, two specific membrane extensions enabling cell migration and invasiveness, were no longer detectable after inositol addiction. Additionally, fascin and cofilin, two mandatory required components for F-actin assembling within cell protrusions, were highly reduced. These data suggest that inositol may induce an EMT reversion in breast cancer cells, suppressing motility and invasiveness through cytoskeleton modifications. PMID- 27237098 TI - Connectivity between mPFC and PCC predicts post-choice attitude change: The self referential processing hypothesis of choice justification. AB - Prior research shows that after making a choice, decision makers shift their attitudes in a choice-congruous direction. Although this post-choice attitude change effect is robust, the neural mechanisms underlying it are poorly understood. Here, we tested the hypothesis that decision makers elaborate on their choice in reference to self-knowledge to justify the choice they have made. This self-referential processing of the choice is thought to play a pivotal role in the post-choice attitude change. Twenty-four young American adults made a series of choices. They also rated their attitudes toward the choice options before and after the choices. In support of the current hypothesis, we found that changes in functional connectivity between two putative self-regions (medial prefrontal cortex and posterior cingulate cortex/precuneus]) during the post choice (vs. pre-choice) rating of the chosen options predicted the post-choice shift of the attitudes toward the chosen options. This finding is the first to suggest that cognitive integration of various self-relevant cognitions is instrumental in fostering post-choice attitude change. Hum Brain Mapp 37:3810 3820, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27237099 TI - Second primary pancreatic ductal carcinoma in the remnant pancreas after pancreatectomy for pancreatic ductal carcinoma: High cumulative incidence rates at 5 years after pancreatectomy. AB - OBJECTIVES: The aim of this study was to determine the incidence rate and clinical features of second primary pancreatic ductal carcinoma (SPPDC) in the remnant pancreas after pancreatectomy for pancreatic ductal carcinoma (PDC). METHODS: Data of patients undergoing R0 resection for PDC at a single high-volume center were reviewed. SPPDC was defined as a tumor in the remnant pancreas after R0 resection for PDC, and SPPDC met at least one of the following conditions: 1) the time interval between initial pancreatectomy and development of a new tumor was 3 years or more; 2) the new tumor was not located in contact with the pancreatic stump. We investigated the clinical features and treatment outcomes of patients with SPPDC. RESULTS: This study included 130 patients who underwent surgical resection for PDC between 2005 and 2014. Six (4.6%) patients developed SPPDC. The cumulative 3- and 5-year incidence rates were 3.1% and 17.7%, respectively. Four patients underwent remnant pancreatectomy for SPPDC. They were diagnosed with the disease in stage IIA or higher and developed recurrence within 6 months after remnant pancreatectomy. One patient received carbon ion radiotherapy and survived 45 months. One patient refused treatment and died 19 months after the diagnosis of SPPDC. CONCLUSIONS: The incidence rate of SPPDC is not negligible, and the cumulative 5-year incidence rate of SPPDC is markedly high. Post-operative surveillance of the remnant pancreas is critical for the early detection of SPPDC, even in long-term survivors after PDC resection. PMID- 27237100 TI - A meta-analysis of the diagnostic value of detecting K-ras mutation in pancreatic juice as a molecular marker for pancreatic cancer. AB - BACKGROUND: K-ras codon 12 mutation is one of the earliest genetic changes in the development of pancreatic cancer (PC) and accurate detection of K-ras mutations is gaining increasing attention in the field of molecular diagnosis. METHODS: Original research articles which evaluated the diagnostic accuracy of K-ras mutation detection in PC were selected. Data were presented as forest plots and summary receiver operating characteristic curve analysis was used to summarize the overall test performance. RESULTS: We assessed 16 studies from 15 published articles. The pooled sensitivity and specificity were 59% (95%CI: 54%-64%) and 87% (95%CI: 84%-89%), respectively. The pooled positive likelihood ratio and negative likelihood ratio were 4.13 (95%CI: 2.73-6.25) and 0.42 (95%CI: 0.32 0.56), respectively, and the pooled diagnostic odds ratio was 13.66 (95% CI: 7.25 25.74). CONCLUSIONS: Our results indicate that the analysis of K-ras mutations in pancreatic juice has a considerable diagnostic value in PC. Further studies with rigorous design, large sample size, and multi-regional co-operation are needed. PMID- 27237102 TI - Gelatinase and Vulnerability of Atherosclerotic Plaque. PMID- 27237101 TI - Beta-adrenoceptor Activation by Norepinephrine Enhances Lipopolysaccharide induced Matrix Metalloproteinase-9 Expression Through the ERK/JNK-c-Fos Pathway in Human THP-1 Cells. AB - AIM: Atherosclerosis is a chronic inflammatory disease, which leads to thrombosis and acute coronary syndrome. Matrix metalloproteinase-9 (MMP-9) is involved in the stability of the extracellular matrix (ECM) and atherosclerosis plaque. Until now, it is established that lipopolysaccharide (LPS) and norepinephrine (NE) are associated with the pathological process of atherosclerosis. However, the combined effect of LPS and NE on MMP-9 is unclear. We investigated the combined effect of LPS and NE on MMP-9 expression in human monocytes and the mechanism involved in the process. METHODS: THP-1 cells were cultured and treated with LPS and/or NE. MMP-9 and TIMP-1 gene and protein expression were detected by real time PCR and ELISA, respectively. MMP-9 activity was detected by gelatin zymography. Adrenoceptor antagonists and MAPKs inhibitors were used to clarify the mechanism. Pathway-related proteins were detected by Western blot. RESULTS: We found that NE enhances LPS-induced MMP-9 and TIMP-1 expression as well as MMP 9 activity in THP-1 cells. This effect is reversed by the beta (beta) adrenoceptor antagonist propranolol, extracellular signal-regulated kinases (ERK) inhibitor U0126, and c-Jun N-terminal kinase (JNK) inhibitor SP600125. NE enhances LPS-induced ERK/JNK phosphorylation. NE up-regulates LPS-induced c-Fos expression, which is counteracted by propranolol, U0126, and SP600125. Furthermore, c-Fos silence reverses the effect of NE on MMP-9 activity. CONCLUSIONS: Our results suggest that NE enhances LPS-induced MMP-9 expression through beta-adrenergic receptor and downstream ERK/JNK-c-Fos pathway. This study may help us to understand the combined effect and mechanism of NE/LPS on MMP-9 expression. PMID- 27237103 TI - Is Total Risk Management an Answer for Better Prognosis in Diabetic Patients? PMID- 27237104 TI - Haematological recovery in poor and good haematopoietic stem cell mobilisers. AB - OBJECTIVES: Evaluate whether poor mobilisers had delayed haematopoietic (neutrophil and platelet) recovery despite receiving similar cell dose as good mobilisers. BACKGROUND: Autologous haematopoietic progenitor cell (HPC) transplantation is indicated to treat some haematological malignancies. This procedure requires HPC mobilisation from bone marrow to peripheral blood. Cell dose is important for a fast haematological recovery. Despite being poor mobilisers, some patients can collect enough cell numbers for transplantation. RESULTS: Fifteen poor mobiliser patients (peak of CD34+ cells <=10 uL(-1) in peripheral blood) were transplanted at our institution. Haematological recovery (neutrophil >= 500 uL(-1) ) in this group was compared to that observed in the group of 16 patients of good mobilisers (peak of CD34+ cells >=20 uL(-1) in peripheral blood) who received similar cell dose (2.637 +/- 0.1744 * 10(6) kg( 1) vs 2.727 +/- 0.1746 * 10(6) kg(-1) ; P = 0.7177). The poor mobiliser group had neutrophil and platelet recovery later than the good mobiliser group (on day 12, range 9-14 vs day 10, range 9-22, P = 0.0381 for neutrophil, and on day 22.89 +/- 11.16 and 14.08 +/- 4.821, P = 0.0193 for platelet). Mortality rates and transfusion requirements were not different between the groups. CONCLUSION: Poor mobilisers have delayed neutrophil and platelet recovery after autologous HPC transplantation despite having received the same cell dose as good mobilisers. PMID- 27237105 TI - Speech prosody impairment predicts cognitive decline in Parkinson's disease. AB - BACKGROUND: Impairment of speech prosody is characteristic for Parkinson's disease (PD) and does not respond well to dopaminergic treatment. OBJECTIVES: We assessed whether baseline acoustic parameters, alone or in combination with other predominantly non-dopaminergic symptoms may predict global cognitive decline as measured by the Addenbrooke's cognitive examination (ACE-R) and/or worsening of cognitive status as assessed by a detailed neuropsychological examination. METHODS: Forty-four consecutive non-depressed PD patients underwent clinical and cognitive testing, and acoustic voice analysis at baseline and at the two-year follow-up. Influence of speech and other clinical parameters on worsening of the ACE-R and of the cognitive status was analyzed using linear and logistic regression. RESULTS: The cognitive status (classified as normal cognition, mild cognitive impairment and dementia) deteriorated in 25% of patients during the follow-up. The multivariate linear regression model consisted of the variation in range of the fundamental voice frequency (F0VR) and the REM Sleep Behavioral Disorder Screening Questionnaire (RBDSQ). These parameters explained 37.2% of the variability of the change in ACE-R. The most significant predictors in the univariate logistic regression were the speech index of rhythmicity (SPIR; p = 0.012), disease duration (p = 0.019), and the RBDSQ (p = 0.032). The multivariate regression analysis revealed that SPIR alone led to 73.2% accuracy in predicting a change in cognitive status. Combining SPIR with RBDSQ improved the prediction accuracy of SPIR alone by 7.3%. CONCLUSIONS: Impairment of speech prosody together with symptoms of RBD predicted rapid cognitive decline and worsening of PD cognitive status during a two-year period. PMID- 27237106 TI - Predictors of the placebo response in clinical trials on Parkinson's disease: A meta-analysis. AB - INTRODUCTION: Previous studies have assessed the placebo response in clinical trials on PD using the individual data of participants from the placebo-assigned group. The aim of this study was to examine the group predictors of the placebo response in randomized placebo-controlled trials on PD using a meta-analysis with meta-regression models. METHODS: The placebo response was defined as the mean change in the UPDRS part III score from baseline to the primary efficacy end point in the placebo group. The impacts of the predictors were assessed with meta regression analyses, and significant predictors were used in a multivariable analysis. Subgroup analyses were conducted in studies that enrolled PD patients with or without motor fluctuations. RESULTS: Forty-eight studies (consisting of 5618 participants on placebo) were included. Motor fluctuation and baseline UPDRS part III score were significant predictors in the univariable analyses. The high baseline UPDRS part III score (beta = -0.21, 95% CI -0.34, -0.08; p = 0.005) significantly increased the magnitude of the positive placebo response in the multivariable analysis. In the subgroup analyses, the positive placebo response was significant only in studies that enrolled patients with motor fluctuations; high baseline UPDRS part III score and low baseline daily levodopa dose increased the positive placebo response independently in the subgroup with motor fluctuations. CONCLUSION: Researchers should consider the positive placebo response when they design clinical trials in advanced PD patients with motor fluctuations and severe motor symptoms. Baseline daily levodopa dose may be the independent predictor in studies that enrolled fluctuating patients. PMID- 27237107 TI - Reply to letter: Exogenous melatonin for Parkinson's disease: 'Waking up' to the need for further trials. PMID- 27237108 TI - Tryptophan hydroxylase type 2 variants modulate severity and outcome of addictive behaviors in Parkinson's disease. AB - BACKGROUND: Impulse control disorders and compulsive medication intake may occur in a minority of patients with Parkinson's disease (PD). We hypothesize that genetic polymorphisms associated with addiction in the general population may increase the risk for addictive behaviors also in PD. METHODS: Sixteen polymorphisms in candidate genes belonging to five neurotransmitter systems (dopaminergic, catecholaminergic, serotonergic, glutamatergic, opioidergic) and the BDNF were screened in 154 PD patients with addictive behaviors and 288 PD control subjects. Multivariate analysis investigated clinical and genetic predictors of outcome (remission vs. persistence/relapse) after 1 year and at the last follow-up (5.1 +/- 2.5 years). RESULTS: Addictive behaviors were associated with tryptophan hydroxylase type 2 (TPH2) and dopamine transporter gene variants. A subsequent analysis within the group of cases showed a robust association between TPH2 genotype and the severity of addictive behaviors, which survived Bonferroni correction for multiple testing. At multivariate analysis, TPH2 genotype resulted the strongest predictor of no remission at the last follow-up (OR[95%CI], 7.4[3.27-16.78] and 13.2[3.89-44.98] in heterozygous and homozygous carriers, respectively, p < 0.001). The extent of medication dose reduction was not a predictor. TPH2 haplotype analysis confirmed the association with more severe symptoms and lower remission rates in the short- and the long-term (p < 0.005 for all analyses). CONCLUSION: The serotonergic system is likely to be involved in the pathophysiology of addictive behaviors in PD, modulating the severity of symptoms and the rate of remission at follow-up. If confirmed in larger independent cohorts, TPH2 genotype may become a useful biomarker for the identification of at-risk individuals. PMID- 27237109 TI - Assessing multiple paternity in three commercially exploited shark species: Mustelus mustelus, Carcharhinus obscurus and Sphyrna lewini. AB - In this study, multiple paternity (MP) was investigated in three commercially important shark species, common smoothhound Mustelus mustelus, dusky shark Carcharhinus obscurus and scalloped hammerhead Sphyrna lewini occurring in southern Africa. Reduced marker panels of between five and six microsatellite loci were constructed for each species and used to genotype and assess the presence of MP in a total of 60 M. mustelus individuals from six litters, 90 C. obscurus individuals from 14 litters and 54 S. lewini individuals from 13 litters. Analysis in GERUD and COLONY revealed the presence of MP in all three species. Multiple paternities were observed in 67, 35 and 46% of the litters of M. mustelus, C. obscurus and S. lewini, with corresponding average sire size of 1.6, 1.4 and 2.0, respectively. The variation in the rate of MP among the three species is in accordance with previous studies whilst the comparatively high frequency of MP observed for M. mustelus, matches what has previously been reported for shark species demonstrating aggregation behaviour. PMID- 27237110 TI - An Hydroalcoholic Chamomile Extract Modulates Inflammatory and Immune Response in HT29 Cells and Isolated Rat Colon. AB - Inflammatory bowel diseases (IBDs) are chronic disorders characterized by disruption and ulceration of the colonic mucosa or of any part of the digestive tract (Crohn's disease). Antioxidant/anti-inflammatory herbal extract supplementation could represent an innovative approach to contrast IBDs. Clinical trials demonstrated the efficacy of natural formulas, containing chamomile, in patients with gastrointestinal disorders. This is consistent, albeit in part, with the antioxidant and anti-inflammatory properties of chamomile. The aim of the present study was to explore the possible protective role of a chamomile extract, on human colorectal adenocarcinoma HT29 cell, and rat colon specimens treated with lipopolysaccharide (LPS) to induce an inflammatory stimulus, a well established model of acute ulcerative colitis. In this context, the activities of different biomarkers of inflammation and lipid peroxidation such as ROS, myeloperoxidase (MPO), serotonin (5-HT), prostaglandin (PG)E2 , 8-iso prostaglandin (8-iso-PG)F2alpha , NF-kB, tumor necrosis factor (TNF)alpha and interleukin (IL)-6 were assessed. We found that chamomile extract was as effective as sulfasalazine (2 mg/ml) in reducing the production of MPO, 5-HT, IL 6, NF-kB, TNFalpha, PGE2 and 8-iso-PGF2alpha , after inflammatory stimulus. The observed modulatory effects support a rationale use of chamomile supplementation as a promising pharmacological tool for the prevention and management of ulcerative colitis in humans. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27237111 TI - Lectin activity in mycelial extracts of Fusarium species. AB - Lectins are non-immunogenic carbohydrate-recognizing proteins that bind to glycoproteins, glycolipids, or polysaccharides with high affinity and exhibit remarkable ability to agglutinate erythrocytes and other cells. In the present study, ten Fusarium species previously not explored for lectins were screened for the presence of lectin activity. Mycelial extracts of F. fujikuroi, F. beomiformii, F. begoniae, F. nisikadoi, F. anthophilum, F. incarnatum, and F. tabacinum manifested agglutination of rabbit erythrocytes. Neuraminidase treatment of rabbit erythrocytes increased lectin titers of F. nisikadoi and F. tabacinum extracts, whereas the protease treatment resulted in a significant decline in agglutination by most of the lectins. Results of hapten inhibition studies demonstrated unique carbohydrate specificity of Fusarium lectins toward O acetyl sialic acids. Activity of the majority of Fusarium lectins exhibited binding affinity to d-ribose, l-fucose, d-glucose, l-arabinose, d-mannitol, d galactosamine hydrochloride, d-galacturonic acid, N-acetyl-d-galactosamine, N acetyl-neuraminic acid, 2-deoxy-d-ribose, fetuin, asialofetuin, and bovine submaxillary mucin. Melibiose and N-glycolyl neuraminic acid did not inhibit the activity of any of the Fusarium lectins. Mycelial extracts of F. begoniae, F. nisikadoi, F. anthophilum, and F. incarnatum interacted with most of the carbohydrates tested. F. fujikuroi and F. anthophilum extracts displayed strong interaction with starch. The expression of lectin activity as a function of culture age was investigated. Most species displayed lectin activity on the 7th day of cultivation, and it varied with progressing of culture age. PMID- 27237112 TI - Campylobacter in broiler slaughter samples assessed by direct count on mCCDA and Campy-Cefex agar. AB - Campylobacter spp. cause foodborne illnesses in humans primarily through the consumption of contaminated chicken. The aim of this study was to evaluate the United States Department of Agriculture's (USDA) recommended methodology, protocol MLG 41.02, for the isolation, identification and direct plate counting of Campylobacter jejuni and C. coli samples from the broiler slaughtering process. A plating method using both mCCDA and Campy-Cefex agars is recommended to recover Campylobacter cells. It is also possible to use this method in different matrices (cloacal swabs and water samples). Cloacal swabs, samples from pre-chiller and post-chiller carcasses and samples of pre-chiller, chiller and direct supply water were collected each week for four weeks from the same flock at a slaughterhouse located in an abattoir in southern Brazil. Samples were analyzed to directly count Campylobacter spp., and the results showed a high frequency of Campylobacter spp. on Campy-Cefex agar. For the isolated species, 72% were identified as Campylobacter jejuni and 38% as Campylobacter coli. It was possible to count Campylobacter jejuni and Campylobacter coli from different samples, including the water supply samples, using the two-agar method. These results suggest that slaughterhouses can use direct counting methods with both agars and different matrices as a monitoring tool to assess the presence of Campylobacter bacteria in their products. PMID- 27237114 TI - HIV and COPD: a conspiracy of risk factors. AB - Chronic obstructive pulmonary disease (COPD) is an under recognized complication of HIV infection. It is estimated that up to 25% of HIV infected people may have COPD. HIV is associated with COPD as a result of a complex interplay of multiple factors such as pulmonary inflammation, recurrent pulmonary infections especially tuberculosis (TB), increased cigarette smoking, socio-economic status, childhood respiratory illnesses and industrial and environmental exposures; each of which are risk factors for COPD in their own right. COPD presents at an earlier age in people with HIV infection. There are over 35 million people living with HIV, and most people infected with HIV live in developing regions of the world where they are faced with multiple risk factors for COPD and suboptimal access to health care. TB is the commonest infectious complication of HIV, and HIV infected persons often experience multiple episodes of TB. Cigarette smoking is increasing in developing countries where the greatest burden of TB and HIV is experienced. Cigarette smoking is associated with increased risk of TB and may be associated with acquisition of HIV infection and progression. It is not clear whether non infectious pulmonary inflammation persists in the lung when immune reconstitution occurs. Prevention and control of HIV infection must be part of the multiple interventions to reduce the global burden of COPD. A multidisciplinary approach, including behavioural science is required to address this challenge. It presents research opportunities that should be driven by the pulmonology community. PMID- 27237113 TI - Draft genome sequences of five Pseudomonas syringae pv. actinidifoliorum strains isolated in France. AB - Pseudomonas syringae pv. actinidifoliorum causes necrotic spots on the leaves of Actinidia deliciosa and Actinidia chinensis. P. syringae pv. actinidifoliorum has been detected in New Zealand, Australia, France and Spain. Four lineages were previously identified within the P. syringae pv. actinidifoliorum species group. Here, we report the draft genome sequences of five strains of P. syringae pv. actinidifoliorum representative of lineages 1, 2 and 4, isolated in France. The whole genomes of strains isolated in New Zealand, representative of P. syringae pv. actinidifoliorum lineages 1 and 3, were previously sequenced. The availability of supplementary P. syringae pv. actinidifoliorum genome sequences will be useful for developing molecular tools for pathogen detection and for performing comparative genomic analyses to study the relationship between P. syringae pv. actinidifoliorum and other kiwifruit pathogens, such as P. syringae pv. actinidiae. PMID- 27237116 TI - In this issue - June 2016: High-quality care improves outcome in recumbent dairy cattle . Corneal anaesthesia in clinically normal cattle . Severe hyponatraemia in foals . Ultrasonographically visible hepatic location in clinically normal horses . Long-term survival in canine tonsillar squamous cell carcinoma . Treatment of oral squamous cell carcinoma in an inshore bottlenose dolphin . Alphaherpesvirus-associated disease in greater bilbies. PMID- 27237115 TI - Family Perspectives on High-Quality Pediatric Subspecialty Referrals. AB - OBJECTIVE: Although children are frequently referred to subspecialist physicians, many inadequacies in referral processes have been identified from physician and system perspectives. Little is known, however, about how to comprehensively measure or improve the quality of the referral systems from a family-centered perspective. To foster family-centered improvements to pediatric subspecialty referrals, we sought to develop a framework for high-quality, patient-centered referrals from the perspectives of patients and their families. METHODS: We used stakeholder-informed qualitative analysis of parent, caregiver, and patient interviews to identify outcomes, processes, and structures of high-quality pediatric subspecialty referrals as perceived by patients and their family members. RESULTS: We interviewed 21 informants. Informants identified 5 desired outcomes of subspecialty referrals: improved functional status or symptoms; improved long-term outcomes; improved knowledge of their disease; informed expectations; and reduced anxiety about the child's health status. Processes that informants identified as supporting these outcomes centered around 6 key steps in subspecialty referrals, including the referral decision, previsit information transfer, appointment scheduling, subspecialist visit, postvisit information transfer, and ongoing care integration and communication. Health care delivery structures identified by informants as supporting these processes included physical infrastructure, human resources, and information technology systems. CONCLUSIONS: We identified family-centered outcomes, processes, and structures of high-quality pediatric subspecialty referrals. These domains can be used not only to improve measurement of the quality of existing referral systems but also to inform future interventions to improve patient-centered outcomes for children in need of specialty care. PMID- 27237117 TI - High-quality care improves outcome in recumbent dairy cattle. AB - OBJECTIVE: To investigate the influence of the quality of care on outcome and occurrence of secondary damage in recumbent dairy cows. METHODS: Recumbent dairy cows were monitored during their recumbency under field conditions in South Gippsland, Victoria, Australia. The cause of the original recumbency of 218 downer cows was determined and any secondary damage, day 7 status, final outcome and the nursing conditions of the cows were recorded. A four-tiered grading system describing nursing quality was developed to allow analysis of its influence on outcome and on the occurrence of secondary damage. RESULTS: Day 7 outcome, final outcome and occurrence of important secondary damage were very strongly associated with the level of overall care provided to the recumbent cows. There was a decrease in the percentage of cows recovering by day 7 from 33% to 0%, a decrease from 45% to 0% of cows eventually recovering and an increase from 68% to 100% of cows with clinically important secondary damage as overall care decreased. CONCLUSION: Management of recumbent cattle is potentially a significant animal welfare issue for the dairy industry and their care is a very important but often under-appreciated aspect of their management. Recovery is positively influenced by high-quality care by improving the chances of recovery from the initial cause of recumbency and by reducing the occurrence of secondary damage. Recumbent cows must either be nursed at a high level of care or euthanased promptly. PMID- 27237119 TI - Severe hyponatraemia in foals: clinical findings, primary diagnosis and outcome. AB - OBJECTIVE: To evaluate severe hyponatraemia in foals presenting as medical emergencies to an intensive care unit (ICU) in order to determine the prevalence, clinical findings, primary diagnosis and outcome. DESIGN: Retrospective case study of records from Thoroughbred foals aged less than 3 months presenting to an ICU as medical emergencies in 2002-12; foals with severe hyponatraemia (serum sodium <122 mmol/L) on admission laboratory data were identified. Data retrieved included signalment, clinical findings, laboratory results, primary diagnosis, treatment and outcome. RESULTS: Severe hyponatraemia was identified in 69/1718 Thoroughbred foals (4%) presenting to the ICU during the study period. Of the 69 foals, 11 (15.9%) presented with neurological signs attributable to hyponatraemic encephalopathy and 7 of these foals had seizures; other neurological signs included obtundation, ataxia and apparent blindness. The three most common primary diagnoses of the 69 foals with severe hyponatraemia were renal disease (18/69, 26.1%), enterocolitis (16/69, 23.2%) and uroperitoneum (15/69, 21.7%). Treatment was directed at the primary disease and correction of the hyponatraemia. A total of 50 of the 69 foals (72.5%) with severe hyponatraemia survived to hospital discharge and 38 of them (76%) survived at least 12 months following discharge. CONCLUSION: The prevalence of severe hyponatraemia in this study population was 4%. The majority of foals with severe hyponatraemia did not demonstrate direct clinical manifestations as a result of the low serum sodium concentration. The outcome of foals with severe hyponatraemia was mostly favourable. PMID- 27237118 TI - Degree of corneal anaesthesia after topical application of 0.4% oxybuprocaine hydrochloride and 0.5% proparacaine hydrochloride ophthalmic solution in clinically normal cattle. AB - OBJECTIVES: The use of corneal anaesthesia is necessary for a range of clinical purposes. Therefore, we assessed and compared the efficacy of corneal anaesthesia after application of 0.4% oxybuprocaine hydrochloride and 0.5% proparacaine hydrochloride ophthalmic solution in clinically normal cattle. METHODS: The 24 clinically normal cows were allocated into two groups. Cows in group 1 (n = 12) received 0.2 mL of 0.4% oxybuprocaine hydrochloride with fluorescein ophthalmic solution in one eye and 0.2 mL of sterile saline (0.9% NaCl) with fluorescein in the contralateral eye (control). Group 2 (n = 12) received 0.2 mL of 0.4% oxybuprocaine hydrochloride with fluorescein ophthalmic solution in one eye and 0.2 mL of 0.5% proparacaine hydrochloride with fluorescein in the contralateral eye (control). In each group, corneal touch threshold was determined by Cochet Bonnet aesthesiometer for both eyes immediately prior to topical administration of solutions, at 1 min and 5 min after administration of topical solutions and every 5 min thereafter for a total of 75 min. RESULTS: Significant corneal anaesthesia was noted immediately following topical application of both oxybuprocaine and proparacaine as compared with controls, with maximal corneal anaesthesia noted 1 min after administration. Both oxybuprocaine and proparacaine produced significant corneal anaesthesia for the duration of the 75-min study. Neither oxybuprocaine hydrochloride nor proparacaine hydrochloride treatment resulted in visible adverse effects. CONCLUSION: There are limited data available demonstrating the efficacy and duration of corneal anaesthetic agents in cattle. Both oxybuprocaine hydrochloride and proparacaine hydrochloride should be considered practical options for providing corneal anaesthesia in cattle in a clinical setting. PMID- 27237120 TI - Ultrasonographically visible hepatic location in clinically normal horses. AB - OBJECTIVE: Ultrasound is widely used for evaluating horses with suspected liver dysfunction. Although a change in size is considered suggestive of pathology, no clear guidelines exist to define the hepatic ultrasonographically visible locations (HUVL) in horses. The aim of the study was to describe the HUVL in normal horses and determine whether this is altered by signalment, height, weight and body condition score (BCS). DESIGN: Prospective observational study. PROCEDURE: Bilateral ultrasonographic evaluation was performed in 58 clinically normal horses with no history of hepatic disease. The most cranial/caudal intercostal spaces (ICS), total number of ICS in which the liver was visualised and the ventral extent of the liver were recorded. RESULTS: Liver was visualised on the right in 56/58 horses (97%), the left in 41/58 (71%) and on both sides in 39/58 (67%). The most cranial ICS was 5 (right) or 4 (left) and the most caudal was 16 (right) or 11 (left). Liver was visualised in ICS 0-11 (right) and ICS 0-5 (left). Liver was not visualised ventral to the costochondral junction. There was no significant effect of sex, breed, height, weight or BCS on HUVL. Liver was visible in significantly fewer ICS on the right in horses aged 24 years and older (median ICS 3.5) compared with younger horses (median ICS 7; P = 0.016). CONCLUSION: These findings suggest that the liver should be consistently visualised on the right side, but absence of ultrasonographically visible liver on the left is unlikely to be clinically relevant. Liver dimensions may be decreased in older horses. PMID- 27237121 TI - Evaluation of the factors contributing to long-term survival in canine tonsillar squamous cell carcinoma. AB - OBJECTIVES: To identify any prognostic factors that may be associated with the long-term survival of dogs diagnosed with tonsillar squamous cell carcinoma (TSCC). METHODS: The medical records of 15 dogs treated for TSCC were reviewed retrospectively. The signalment, presenting signs, clinical stage, treatments and outcome were documented. RESULTS: The overall median survival time (MST) of the dogs in the study was 243 days. There was a 1-and 2-year survival of 40% and 20%, respectively. The results of initial staging had a significant effect on survival, as dogs with only one tonsil affected and no evidence of metastatic disease had a longer MST (637.5 days) than the dogs with local (MST: 134 days) or distant (MST: 75 days) metastatic disease or bilateral tonsillar involvement at the time of initial presentation. Prolonged survival times were reported for dogs undergoing surgery and adjunctive chemotherapy (MST: 464.5 days) for treatment of their TSCC. CLINICAL SIGNIFICANCE: This is the first veterinary study demonstrating an association between prognosis of patients with TSCC and stage at the time of presentation, with long survival times demonstrated for dogs with early-stage disease following an initial treatment protocol that included surgery and chemotherapy. There was no clear association between long survival and additional surgeries for progressive disease; however; further investigation is warranted. PMID- 27237122 TI - Erratum. PMID- 27237124 TI - Emerging from the trauma bubble: Redefining 'normal' after burn injury. AB - BACKGROUND: Emotional trauma is recognised as a common feature in the experience of patients and families following burn injury and incidence may be unrelated to burn size and severity. AIM: The aim of this study was to interpret the lived experience of hospitalisation and recovery following burn injury in Australia. This paper explores the early stages of emotional recovery, how people begin to redefine normality and the needs and supports they describe as integral to this process. METHOD: We used Heideggerian phenomenology, framed by Merleau-Ponty's philosophy of the body. In-depth, semi-structured interviews with 18 patient and family participants were collected 1-3 weeks after hospital discharge. Median %TBSA was 25.3 (range 3-68%). RESULTS: From a point of being vulnerable, redefining normal was supported for all participants by family being close and involved, for family members by developing routines, and for patients by challenging physical otherness, rethinking work, finding empowerment through self care, acknowledging a shared recovery and recognising a gradual return of 'good days'. CONCLUSION: Emotional trauma is highly prevalent among patients and families in the early burn recuperation period where both distress and recovery may co-occur. Despite an initial sense of vulnerability, normality is gradually redefined through practices that keep family close, engage patients in early self care and allow time, space and support for return to work. Patients, initially confronted by their own physical otherness, share their recovery with fellow burns survivors and seek affirmation from family to negotiate a 'different' normal, integrated into a new self-concept. Early rehabilitation may be strengthened by promoting carer involvement, patient self-efficacy and peer support. PMID- 27237125 TI - LC-MS/MS detection of unaltered glucuronoconjugated metabolites of metandienone. AB - The aim of this study was to evaluate the direct detection of glucuronoconjugated metabolites of metandienone (MTD) and their detection times. Metabolites resistant to enzymatic hydrolysis were also evaluated. Based on the common mass spectrometric behaviour of steroid glucuronides, three liquid chromatography tandem mass spectrometry (LC-MS/MS) strategies were applied for the detection of unpredicted and predicted metabolites: precursor ion scan (PI), neutral loss scan (NL), and theoretical selected reaction monitoring (SRM) methods. Samples from four excretion studies of MTD were analyzed for both the detection of metabolites and the establishment of their detection times. Using PI and NL methods, seven metabolites were observed in post-administration samples. SRM methods allowed for the detection of 13 glucuronide metabolites. The detection times, measured by analysis with an SRM method, were between 1 and 22 days. The metabolite detected for the longest time was 18-nor-17beta-hydroxymethyl-17alpha-methyl-5beta androsta-1,4,13-triene-3-one-17-glucuronide. One metabolite was resistant to hydrolysis with beta-glucuronidase; however it was only detected in urine up to four days after administration. The three glucuronide metabolites with the highest retrospectivity were identified by chemical synthesis or mass spectrometric data, and although they were previously reported, this is the first time that analytical data of the intact phase II metabolites are presented for some of them. The LC-MS/MS strategies applied have demonstrated to be useful for detecting glucuronoconjugated metabolites of MTD, including glucuronides resistant to enzymatic hydrolysis which cannot be detected by conventional approaches. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27237126 TI - Using dynamic motor control to understand treatment outcomes. PMID- 27237128 TI - Central artery perforator propeller flap for nasal and medial canthal defects. AB - INTRODUCTION: Non-melanoma skin cancer is the most common type of skin cancer of the nasal dorsum and the medial canthal region, which is caused by chronic sun exposure. Limited adjacent tissue and the need for aesthetically pleasing result make the reconstruction of these regions very challenging. To overcome this challenge, we designed a perforator propeller flap based on the central artery. METHODS: Between January 2014 and November 2015, we covered the nasal or medial canthal defects of 22 patients with central artery perforator propeller flaps. RESULTS: The mean age of the patients was 60.4 years (range: 47-81 years). The median follow-up period was 7.5 months (range: 2-23 months). The pathological diagnoses were basal cell carcinoma for 14 patients and squamous cell carcinoma for the remaining eight patients. The size of the defects ranged from 2 * 2 to 3.5 * 4 cm, and that of the flaps ranged from 2 * 3.5 to 3.2 * 6 cm. We did not observe any major complications requiring surgery, such as total flap loss, hematoma, or dog-ear deformity. However, venous congestion was seen in five patients and partial flap necrosis (that healed without intervention) in two patients. CONCLUSION: The central artery perforator propeller flap is a reliable and versatile flap for the reconstruction of the nasal dorsum and medial canthal region. Reconstruction with this flap is a single-stage procedure that can cover large defects without causing dog-ear deformity or eyebrow asymmetry compared with other local flap options. PMID- 27237127 TI - Heightened cleavage of Axl receptor tyrosine kinase by ADAM metalloproteases may contribute to disease pathogenesis in SLE. AB - Systemic lupus erythematosus (SLE) is characterized by antibody-mediated chronic inflammation in the kidney, lung, skin, and other organs to cause inflammation and damage. Several inflammatory pathways are dysregulated in SLE, and understanding these pathways may improve diagnosis and treatment. In one such pathway, Axl tyrosine kinase receptor responds to Gas6 ligand to block inflammation in leukocytes. A soluble form of the Axl receptor ectodomain (sAxl) is elevated in serum from patients with SLE and lupus-prone mice. We hypothesized that sAxl in SLE serum originates from the surface of leukocytes and that the loss of leukocyte Axl contributes to the disease. We determined that macrophages and B cells are a source of sAxl in SLE and in lupus-prone mice. Shedding of the Axl ectodomain from the leukocytes of lupus-prone mice is mediated by the matrix metalloproteases ADAM10 and TACE (ADAM17). Loss of Axl from lupus-prone macrophages renders them unresponsive to Gas6-induced anti-inflammatory signaling in vitro. This phenotype is rescued by combined ADAM10/TACE inhibition. Mice with Axl-deficient macrophages develop worse disease than controls when challenged with anti-glomerular basement membrane (anti-GBM) sera in an induced model of nephritis. ADAM10 and TACE also mediate human SLE PBMC Axl cleavage. Collectively, these studies indicate that increased metalloprotease-mediated cleavage of leukocyte Axl may contribute to end organ disease in lupus. They further suggest dual ADAM10/TACE inhibition as a potential therapeutic modality in SLE. PMID- 27237129 TI - Research progress in NOS1AP in neurological and psychiatric diseases. AB - Nitric Oxide Synthase 1 Adaptor Protein (NOS1AP, previously named CAPON) was firstly identified in rat brain in 1998. Structurally, NOS1AP consists of a phosphotyrosine-binding (PTB) domain at its N-terminal and a PDZ (PSD-95/discs large/ZO-1) ligand motif at its C-terminal. The PTB domain of NOS1AP mediates the interactions with Dexras1, scribble, and synapsins. The PDZ ligand motif of NOS1AP binds to the PDZ domain of NOS1, the enzyme responsible for nitric oxide synthesis in the nervous system. NOS1AP is implicated in Dexras1 activation, neuronal nitric oxide production, Hippo pathway signaling, and dendritic development through the association with these important partners. An increasing body of evidence is pointing to the significant roles of NOS1AP in excitotoxic neuronal damage, traumatic nervous system injury, bipolar disorder, and schizophrenia. However, the study progress in NOS1AP in neurological or psychiatric diseases, has not been systematically reviewed. Here we introduce the expression, structure, and isoforms of NOS1AP, then summarize the physiological roles of NOS1AP, and discuss the relationships between NOS1AP alterations and the pathophysiology of some neurological and psychiatric disorders. The review will promote the further investigation of NOS1AP in brain disorders and the development of drugs targeting the NOS1AP PTB domain or PDZ-binding motif in the future. PMID- 27237130 TI - Does resuscitation status affect decision making in a deteriorating patient? Results from a randomised vignette study. AB - AIMS AND OBJECTIVES: The aim of this paper is to determine the influence of do not attempt cardiopulmonary resuscitation (DNACPR) orders and the Universal Form of Treatment Options ('UFTO': an alternative approach that contextualizes the resuscitation decision within an overall treatment plan) on nurses' decision making about a deteriorating patient. METHODS: An online survey with a developing case scenario across three timeframes was used on 231 nurses from 10 National Health Service Trusts. Nurses were randomised into three groups: DNACPR, the UFTO and no-form. Statements were pooled into four subcategories: Increasing Monitoring, Escalating Concern, Initiating Treatments and Comfort Measures. RESULTS: Reported decisions were different across the three groups. Nurses in the DNACPR group agreed or strongly agreed to initiate fewer intense nursing interventions than the UFTO and no-form groups (P < 0.001) overall and across subcategories of Increase Monitoring, Escalate Concern and Initiate Treatments (all P < 0.001). There was no difference between the UFTO and no-form groups overall (P = 0.795) or in the subcategories. No difference in Comfort Measures were observed (P = 0.201) between the three groups. CONCLUSION: The presence of a DNACPR order appears to influence nurse decision making in a deteriorating patient vignette. Differences were not observed in the UFTO and no-form group. The UFTO may improve the way nurses modulate their behaviours towards critically ill patients with DNACPR status. More hospitals should consider adopting an approach where the resuscitation decisions are contextualised within overall goals of care. PMID- 27237132 TI - Goblet Cell Carcinoid of the Rectum in a Patient with Neurofibromatosis Type 1. PMID- 27237133 TI - Clear Cell Papulosis: A Case Report. PMID- 27237131 TI - Status of HIV and hepatitis C virus infections among prisoners in the Middle East and North Africa: review and synthesis. AB - INTRODUCTION: The status of HIV and hepatitis C virus (HCV) infections among incarcerated populations in the Middle East and North Africa (MENA) and the links between prisons and the HIV epidemic are poorly understood. This review synthesized available HIV and HCV data in prisons in MENA and highlighted opportunities for action. METHODS: The review was based on data generated through the systematic searches of the MENA HIV/AIDS Epidemiology Synthesis Project (2003 to December 15, 2015) and the MENA HCV Epidemiology Synthesis Project (2011 to December 15, 2015). Sources of data included peer-reviewed publications and country-level reports and databases. RESULTS AND DISCUSSION: We estimated a population of 496,000 prisoners in MENA, with drug-related offences being a major cause for incarceration. Twenty countries had data on HIV among incarcerated populations with a median prevalence of 0.6% in Afghanistan, 6.1% in Djibouti, 0.01% in Egypt, 2.5% in Iran, 0% in Iraq, 0.1% in Jordan, 0.05% in Kuwait, 0.7% in Lebanon, 18.0% in Libya, 0.7% in Morocco, 0.3% in Oman, 1.1% in Pakistan, 0% in Palestine, 1.2% in Saudi Arabia, 0% in Somalia, 5.3% in Sudan and South Sudan, 0.04% in Syria, 0.05% in Tunisia, and 3.5% in Yemen. Seven countries had data on HCV, with a median prevalence of 1.7% in Afghanistan, 23.6% in Egypt, 28.1% in Lebanon, 15.6% in Pakistan, and 37.8% in Iran. Syria and Libya had only one HCV prevalence measure each at 1.5% and 23.7%, respectively. There was strong evidence for injecting drug use and the use of non-sterile injecting-equipment in prisons. Incarceration and injecting drugs, use of non-sterile injecting equipment, and tattooing in prisons were found to be independent risk factors for HIV or HCV infections. High levels of sexual risk behaviour, tattooing and use of non-sterile razors among prisoners were documented. CONCLUSIONS: Prisons play an important role in HIV and HCV dynamics in MENA and have facilitated the emergence of large HIV epidemics in at least two countries, Iran and Pakistan. There is evidence for substantial but variable HIV and HCV prevalence, as well as risk behaviour including injecting drug use and unprotected sex among prisoners across countries. These findings highlight the need for comprehensive harm-reduction strategies in prisons. PMID- 27237134 TI - The Value of Companion Diagnostics: Overcoming Access Barriers to Transform Personalised Health Care into an Affordable Reality in Europe. AB - Personalised health care is an evolution, moving away from a disease-focused model of care, translating scientific and technological advances into benefits for patients, and placing them at the centre of the patients' health and care. Companion diagnostics emerge as a very specific and special group of in vitro diagnostics among the different technologies shaping the personalised health care spectrum. Companion diagnostics provide highly valuable information, allowing patients, health practitioners and payers to decide with a higher level of certainty on the potential benefits of a treatment or care pathway. Decreasing uncertainty may result in a more efficient selection of treatments and care, targeted at subpopulations that are most likely to benefit. Companion diagnostics account for a minimal portion of the already small expenditure on in vitro diagnostics (far less than 1% of total health care expenditure), and yet they provide the means to limit inefficient use of health care resources while optimising patient outcomes. It is clear that equal access to personalised health care is still an issue across the EU. One of the most common perceived barriers is affordability. The investment in companion diagnostics can provide long-term value for patients and health care systems, shifting resources to areas of need. Health systems do not fully recognise yet the value that companion diagnostics bring to make personalised health care more affordable across the EU. This inhibits patient access to personalised treatments and care, preventing improved outcomes. In many countries, market access frameworks for diagnostic tests are fragmented and not aligned with specific funding and reimbursement mechanisms, discouraging the use of these tests. Emerging evidence shows that patients are missing out on the appropriate tests and treatments while a reduction in the inefficient use of health care resources is not realised. This article outlines some of these market access barriers for companion diagnostics in the EU, including reimbursement challenges specific to some member states (Germany, the UK, and France). Furthermore, proposals addressing barriers and increasing timely patient access to companion diagnostics in the EU are presented. PMID- 27237135 TI - Prevalence of Helicobacter pylori Infection in Patients with Squamous Cell Carcinoma of the Oesophagus. A Descriptive Case Series Study. AB - INTRODUCTION: Helicobacter pylori is an important causative factor in gastric carcinogenesis; its role in extra-gastric gastrointestinal malignancies such as oesophageal cancer is controversial. H. pylori is thought to cause extensive gastric atrophy associated with squamous cell carcinoma of the oesophagus. We conducted a study to determine the prevalence of H. pylori infection in patients with squamous cell carcinoma of the oesophagus. METHOD: We collected biopsies from the antrum and corpus of 59 patients with confirmed squamous cell carcinoma of the oesophagus, two from each area. These were then examined by an experienced histopathologist using methylene blue staining for the presence of H. pylori. RESULTS: H. pylori was found in 30 (51 %) of the patients, a prevalence similar to that of the general population in South Africa. Five patients were found to have associated intestinal metaplasia, and all but two had chronic inflammation. CONCLUSION: The prevalence of H. pylori in our patients with squamous cell carcinoma of the oesophagus is 51 %, similar to that previously reported in the general population. PMID- 27237136 TI - Radiosynthesis of [18F]-fluorobenzoate-doxorubicin Using Acylation Approach. AB - BACKGROUND: Previously, we have labeled doxorubicin with [99Tc] and evaluated its potential as a SPECT agent to detect cancer in tumor bearing mice. In this study, we sought to radiolabel doxorubicin with [18F] using acylation method. METHODS: A quaternary salt of the precursor pentamethylbenzyl-4-(trimethylammonium trifluoromethanesulfonate) benzoate was synthesized and characterized by 1H-NMR. As a first step, 4-[18F]- fluorobenzoic acid (FBA) was synthesized from precursor. In second step, [18F]-FBA was further converted to its corresponding acyl form to radiolabel doxorubicin via acylation reaction. RESULTS: The total reaction time for the synthesis of [18F]-fluorobenzoate-doxorubicin was about 60 minutes. The radiolabeling efficiency of the final product was estimated to be about 59.0% The radiochemical yield for the synthesis of [18F]-FBA and [18F] fluorobenzoate-doxorubicin were 19.0- 29.0% and 12.0-14.0% respectively. CONCLUSION: Radio synthesis of [18F]-fluorobenzoate-doxorubicin by acylation is a convenient method. However, further improvement in the labeling strategy is required to increase the radiolabeling efficiency and radio synthesis yield. Also, the radiolabeled product needs a detailed pre-clinical evaluation. PMID- 27237137 TI - Effect of Zr Content on the Wake-Up Effect in Hf1-xZrxO2 Films. AB - In this study, the changes in the structural and electrical properties of ferroelectric Hf1-xZrxO2 films with various Zr contents (0.26-0.70) were systematically examined during electric field cycling, resulting in a "wake-up" effect. To quantify the degree of wake-up effect, a "variable" polarization as the difference between remanent and saturation polarization was suggested as a new parameter, which could be calculated by excluding the linear dielectric contribution from the total electric displacement. Here, the variable polarization value could be minimized for an optimized Zr content of 0.43, which was slightly lower than the value for the largest remanent polarization. The polymorphism in Hf1-xZrxO2 thin films is known to be complicated due to the relatively small energy differences between various phases, such as the monoclinic, tetragonal, and orthorhombic phases. The variations in the polarization-electric field characteristics and dielectric constant values could be qualitatively and quantitatively understood based on the competition of various polymorphs that are dependent on the Zr content. Furthermore, a schematic model for the spatial distribution of mixed phases was suggested for Hf1-xZrxO2 films with various Zr contents based on the experimental observations. PMID- 27237138 TI - Ionic Liquid-Organic Carbonate Electrolyte Blends To Stabilize Silicon Electrodes for Extending Lithium Ion Battery Operability to 100 degrees C. AB - Fabrication of lithium-ion batteries that operate from room temperature to elevated temperatures entails development and subsequent identification of electrolytes and electrodes. Room temperature ionic liquids (RTILs) can address the thermal stability issues, but their poor ionic conductivity at room temperature and compatibility with traditional graphite anodes limit their practical application. To address these challenges, we evaluated novel high energy density three-dimensional nano-silicon electrodes paired with 1-methyl-1 propylpiperidinium bis(trifluoromethanesulfonyl)imide (Pip) ionic liquid/propylene carbonate (PC)/LiTFSI electrolytes. We observed that addition of PC had no detrimental effects on the thermal stability and flammability of the reported electrolytes, while largely improving the transport properties at lower temperatures. Detailed investigation of the electrochemical properties of silicon half-cells as a function of PC content, temperature, and current rates reveal that capacity increases with PC content and temperature and decreases with increased current rates. For example, addition of 20% PC led to a drastic improvement in capacity as observed for the Si electrodes at 25 degrees C, with stability over 100 charge/discharge cycles. At 100 degrees C, the capacity further increases by 3-4 times to 0.52 mA h cm(-2) (2230 mA h g(-1)) with minimal loss during cycling. PMID- 27237140 TI - Join the thinking voter. AB - It was widely expected that health would sooner or later emerge as a key election issue. And last week, true to form, the thorny issue of the NHS came to the fore but for all the wrong reasons. PMID- 27237139 TI - Application of Quantum Dot-Molecularly Imprinted Polymer Core-Shell Particles Sensitized with Graphene for Optosensing of N(epsilon)-Carboxymethyllysine in Dairy Products. AB - Hydrophobic CdSe/ZnS quantum dots (QDs) coated with a molecularly imprinted polymer (MIP) sensitized with graphene (Gra-QDs@MIP) were prepared through a one pot reverse microemulsion polymerization at room temperature. Gra-QDs@MIP was used as a molecular recognition element to construct a N(epsilon) carboxymethyllysine (CML) optosensor. Graphene was used as a polymerization platform to increase the stability and kinetic binding properties of the system. Reverse microemulsion polymerization can anchor silica spheres on the surface of the QDs. This provides functional groups on the surface of Gra-QDs@MIP, which can bind CML and improve the fluorescence stability. Selective and sensitive optosensing of CML is possible at concentrations down to 3.0 MUg L(-1) using Gra QDs@MIP. Gra-QDs@MIP can be applied to dairy samples, as a recognition and response element for determining CML concentrations. The optosensing method was validated by high-performance liquid chromatography-mass spectrometry. The optosensor is economically and easily prepared, and the method is simple, fast, accurate, and reproducible. PMID- 27237142 TI - Mistrust, vandalism and neglect' evoked. AB - Nurses at Ashworth Hospital who refuse to 'knuckle under' risk intimidation, including threats, abuse and hate mail, the public inquiry heard last week. PMID- 27237141 TI - Euroquan. AB - Leading nurses from 13 European countries were in London last week for the launch of a new initiative to promote high-quality care across national boundaries. PMID- 27237143 TI - NHS centre stage in election drama. AB - Nursing shortages added fuel to last week's election campaign as the focus shifted to the National Health Service. PMID- 27237145 TI - Disillusioned carers of elderly need support. AB - Many people caring tor elderly relatives with dementia have reached breaking point, according to jan Killeen, Director of Scottish Action on Dementia. PMID- 27237144 TI - Enrolled nurses. AB - The Mid-Cheshire Hospitals Trust hasbacked down on plans to push enrolled nurses into health care assistant posts if they refuse to convert to first level. PMID- 27237146 TI - Agreement to tackle appeals backlog. AB - New strategies to tackle the backlog of almost 25,000 outstanding clinical grading appeals have been agreed by unions and managers. PMID- 27237148 TI - NHS Trusts. AB - Those in favour: Pictured after signing the agreement are, from left: back row - Ray Holroyde, Nalgo: Roy Lilley, Homewood Trust: David Welsh, BMA; Eve Richardson. Trust executive; front row - Paul Scrivier, NUPE; Chris Wilson. Trust human resources: Tim Carter, COHSE, and Val Comerford. Royal College of Nursing. PMID- 27237147 TI - Arbitration accepted in landmark deal. AB - Unions have signed the first agreement of its kind with a National Health Service Trust, accepting binding arbitration in return for recognition and local collective bargaining. PMID- 27237149 TI - 75th anniversary. AB - Light supper: Royal College of (Nursing General Secretary Christine Hancock was guest of honour at a dinner and firework display organised by the RCN North East Thames Region to mark the College's 75th anniversary . PMID- 27237150 TI - Occupational health. AB - An occupational health nurse has been made head of a university department for the first time. PMID- 27237151 TI - Primary health buyers 'intellectually lazy'. AB - Purchasers have been condemned for 'intellectual laziness' in their approach to implementing the Community Care Act. PMID- 27237152 TI - Sacked nurses claim it was discrimination. AB - Two nurses who were sacked following an investigation into the hours they worked are to take their case to an industrial tribunal after losing their local appeal. PMID- 27237153 TI - Students used as cheap weekend labour. AB - Supernumerary students are being used as cheap labour to fill service gaps, delegates at last week's RCN Association of Nursing Students' conference have revealed. PMID- 27237154 TI - NVQs get backing as nursing entry route. AB - RCN Education Director Tom Bolger last week backed National Vocational (Qualifications as a nursing entry route, but criticised the United Kingdom Central Council for being 'ostrich-like' over the issue. PMID- 27237155 TI - Axe hangs over P2000 claims RCN. AB - Project 2000 faces the axe unless students and tutors fight off managers' demands for immediate dividends, Royal College of Nursing Education Director Tom Bolger warned last week. PMID- 27237156 TI - Damages award for injured nurse. AB - A nurse won over L100,000 damages in London's high court after she suffered severe head injuries when a car driven by her former boyfriend crashed in 1988. PMID- 27237158 TI - Battle to regain unions' bargaining rights. AB - Unions at St Mary's and Queen Alexandra hospitals in Portsmouth are in dispute with managers in a bid to 'regain' recognition. PMID- 27237160 TI - World news. AB - Cuba Cubans found to be HIV positive, even if they are not showing signs of AIDS, are likely to be held in special sanatoriums with little chance of release. PMID- 27237161 TI - New diet advice for people with diabetes. AB - Dietary recommendations for people with diabetes have been launched by the British Diabetic Association. PMID- 27237162 TI - Altering bad habits and women's health. AB - The potential for women to reduce their risk of coronary heart disease (CHD) by changes in lifestyle may be less than for men, according to a major survey. PMID- 27237164 TI - Vasectomies do not increase cancer risk. AB - Vasectomies do not increase the risk of testicular cancer, latest research from Oxford University shows. But the researchers have warned more evidence is needed before they can rule out a link with prostate cancer. PMID- 27237163 TI - Mental illness benefits home care. AB - Home care may offer 'slight advantages' over hospital-based care for patients with a serious mental illness and their relatives, according to a recent study. PMID- 27237165 TI - Shopping for health care. AB - All political parties have now published their manifestos. Of course, the content of these documents will have been planned and refined over a period of months. PMID- 27237166 TI - Nurses at the hustings Nursing Standard reporters Daniel Allen, Derek Hand and John Naish went 'on the stump' with three nurses hopeful of election to parliament. AB - There is a bit of a stink at Conservative campaign headquarters in Islington North. Not the whiff of political scandal or a malodorous dirty election campaign, but a problem with the drains. PMID- 27237167 TI - A changed relationship. AB - I am responding to the challenge of your editorial on distribution of places on the United Kingdom Central Council (March 11). The present UKCC is largely the creature of the National Boards, since it is made up of nominated members who were elected to the National Boards in the first place. This 'national' identity of the elected, as opposed to the appointed members, enabled a process of power sharing in the UK without proportionate representation, since the UKCC is required to consult with the National Boards. PMID- 27237168 TI - The equality we all deserve. AB - RCN General Secretary Christine Hancock claims that practice nurses could earn the same as GPs if we become equal team members (News, March 18). PMID- 27237169 TI - Obituary. AB - The announcement of the death in Bournemouth on February 18 1992 at the age of 82 years of Miss Muriel Hughes SRN, SCM, STD, lowers the curtain on a long and distinguished nursing career. PMID- 27237170 TI - Clearing up the Trust's role. AB - The trustees of the General Nursing Council for England and Wales Trust are concerned that the nursing profession continues to lack awareness of the monies available through the Trust and note Trevor Clay's reference to the monies 'stored away' (Nursing Standard November 6 1991). PMID- 27237171 TI - In praise of part-time nurses. AB - I felt I had to write to you on an issue which is often discussed in Nursing Standard: art-time nursing. I have worked part time in a large teaching hospital for seven and a half years. PMID- 27237172 TI - Information exchange. AB - I teach on a variety of health-related courses and am undertaking sociological research into health care as part of my Masters degree. I would be very grateful to hear from nurses who are interested in complementary therapies, particularly anyone who has already incorporated such therapies into their nursing practice. PMID- 27237173 TI - Preventing P2000 chaos. AB - Acceding to the dizzy heights of nurse tutorship implies a certain willingness on the tutor's part to take on challenges and to engage in self development. PMID- 27237175 TI - Music and movement. PMID- 27237174 TI - A pleasant discharge. AB - Mental health problems have long been the focus of Government interest. However, this has recently intensified and a large number of official documents have referred to the outcomes expected of mental health services. PMID- 27237179 TI - Listings. PMID- 27237176 TI - Heart Sounds and Murmurs: A Practical Guide B Erickson Heart Sounds and Murmurs: A Practical Guide 2nd edition Mosby Year Book 112pp L24.00 0-8016-6466-7. AB - A more apt title for Heart Sounds and Murmurs: A Practical Guide might have been 'Everything you I wanted to know about heart sounds and murmurs but were afraid to ask!' If heart I sounds and murmurs are your cup of tea, then this is certainly the book (and cassette) for you. PMID- 27237180 TI - Doctor to Doctor. PMID- 27237181 TI - Lyme disease. PMID- 27237183 TI - Literature Scan. PMID- 27237182 TI - A ballad for Maxwell Thomson. PMID- 27237186 TI - Motion sickness. PMID- 27237184 TI - cme credit Quiz. PMID- 27237187 TI - Provider perceptions of the value of same-day, electronic patient-reported measures for use in clinical HIV care. AB - Strong evidence suggests that patient-reported outcomes (PROs) aid in managing chronic conditions, reduce omissions in care, and improve patient-provider communication. However, provider acceptability of PROs and their use in clinical HIV care is not well known. We interviewed providers (n = 27) from four geographically diverse HIV and community care clinics in the US that have integrated PROs into routine HIV care, querying perceived value, challenges, and use of PRO data. Perceived benefits included the ability of PROs to identify less observable behaviors and conditions, particularly suicidal ideation, depression, and substance use; usefulness in agenda setting prior to a visit; and reduction of social desirability bias in patient-provider communication. Challenges included initial flow integration issues and ease of interpretation of PRO feedback. Providers value same-day, electronic patient-reported measures for use in clinical HIV care with the condition that PROs are (1) tailored to be the most clinically relevant to their population; (2) well integrated into clinic flow; and (3) easy to interpret, highlighting chief patient concerns and changes over time. PMID- 27237188 TI - Three-component synthesis and carbonic anhydrase inhibitory properties of novel octahydroacridines incorporating sulfaguanidine scaffold. AB - Novel sulfaguanidines incorporating acridine moiety were synthesized by the reaction of cyclohexane-1,3-dione, sulfaguanidine, and aromatic aldehydes. Synthesis of these compounds was performed in water at room temperature, and their structures were confirmed by using spectral analysis (IR, 1H-NMR, 13C-NMR, and HRMS). Human carbonic anhydrase isoenzymes (hCA I and II) were purified from erythrocyte cells with affinity chromatography. hCA I was purified 83.40-fold with a specific activity, 1060.9 EU mg protein-1, and hCA II was purified 262.32 fold with a specific activity, 3336.8 EU mg protein-1. The inhibitory effects of newly synthesized sulfaguanidines and acetazolamide, (AAZ) as a control compound, on hydratase and esterase activities of these isoenzymes have been studied in vitro. Synthesized compounds have moderate inhibition potentials on hCA I and hCA II isoenzymes. IC50 values of compounds for esterase activity are in the range of 118.4 +/- 7.0 MUM-257.5 +/- 5.2 MUM for hCA I and 86.7 +/- 3.0 MUM-249.4 +/- 10.2 MUM for hCA II, respectively. PMID- 27237191 TI - Frontliners. PMID- 27237190 TI - Simvastatin-loaded lyophilized wafers as a potential dressing for chronic wounds. AB - Wafers are an established drug delivery system for application to suppurating wounds. They can absorb wound exudates and are converted into a gel, offering a moist environment that is vital for wound healing. Simvastatin-loaded lyophilized wafers were developed using sodium carboxymethyl cellulose (CMC) and methyl cellulose (MC) and evaluated for their potential in the management of chronic wounds. Simvastatin (SIM) was chosen as the model drug since it is known to accelerate wound healing by promoting angiogenesis and lymphangiogenesis. Pre formulation studies were carried out with CMC, MC, and a mixture of CMC and MC. Wafers obtained from aqueous gels of 3% CMC and blend of CMC-MC in the % weight ratio of 2:1 and 1.5:1.5 were selected for further analysis. The formulated wafers were characterized by microscopic examination, texture analysis, hydration test, rheological studies, FTIR spectroscopy, water vapor transmission and drug release test. Among the selected formulations, simvastatin-loaded CMC-MC (2:1) wafers exhibited the most desired characteristics for wound dressing application, such as good flexibility, hardness, sponginess, and viscosity. It showed a sustained drug release, which is desirable in wound healing, and was more appropriate for suppurating wounds. In conclusion, simvastatin-loaded CMC-MC (2:1) wafers showing potential for wound dressing applications were successfully developed. PMID- 27237189 TI - Nutrient intake and cerebral metabolism in healthy middle-aged adults: Implications for cognitive aging. AB - OBJECTIVES: Growing evidence suggests dietary factors influence cognition, but the effects of nutrient intake on cerebral metabolism in adults are currently unknown. The present study investigated the relationship between major macronutrient intake (fat, carbohydrate, and protein) and cerebral neurochemical profiles in middle-aged adults. METHODS: Thirty-six adults recorded dietary intake for 3 days prior to completing cognitive testing and a proton magnetic resonance spectroscopy (1H-MRS) scan. 1H-MRS of occipitoparietal gray matter was used to assess glutamate (Glu), N-acetyl-aspartate (NAA), choline (Cho), and myo inositol (mI) relative to creatine (Cr) levels. RESULTS: Regression analyses revealed that high intake of polyunsaturated fatty acids (PUFAs) was associated with lower cerebral Glu/Cr (P = 0.005), and high intake of saturated fat (SFA) was associated with poorer memory function (P = 0.030) independent of age, sex, education, estimated intelligence, total caloric intake, and body mass index. DISCUSSION: In midlife, greater PUFA intake (omega-3 and omega-6) may be associated with lower cerebral glutamate, potentially indicating more efficient cellular reuptake of glutamate. SFA intake, on the other hand, was linked with poorer memory performance. These results suggest that dietary fat intake modification may be an important intervention target for the prevention of cognitive decline. PMID- 27237192 TI - Cash injection for 149 A&Es. AB - Details of a L115 million upgrade of 149 A&E departments in England has been announced by Frank Dobson, Secretary of State for Health (England). PMID- 27237193 TI - For your information. AB - A&E nurse seeks support Angela Sowter, an A&E staff nurse at St Mary's Hospital, London will be cycling 500 kms around Egypt along the River Nile to raise L2,000 for Mencap on behalf of adults and children with learning disabilities. Anyone wishing to offer support or sponsorship can contact Ms Sowter at St Mary's Hospital, Praed Street, London W2 1NY on 0171 8866401. PMID- 27237194 TI - Sex differences in acute asthma presentation. AB - Asthma is an increasing problem worldwide, particularly among women. Sex differences in acute asthma presentation, management, or outcome would imply important medical and economic implications. This American study sought to compare emergency department (ED) visits for acute asthma among women vs men. PMID- 27237195 TI - Patients do not receive sufficient analgesia. AB - This American study sought to compare patient and practitioner assessments of pain associated with commonly performed emergency department procedures and use of anaesthetics before these procedures. It was a prospective, observational, cross-sectional study conducted at a university-based ED with a convenience sample of ED patients. Research assistants recorded the procedure performed and historical and demographic information on standardised data collection instruments. After each procedure, both the patient and practitioner independently recorded assessments of patient pain on a 100-mm visual analog scale (VAS). Use of preprocedure anaesthetics and patient preferences regarding their use were also identified. Categorical variables were analysed by two tests. Correlation coefficients were calculated to assess correlation between patient and practitioner pain scores. PMID- 27237196 TI - Sickle cell/beta-thalassemia: Comparison of Sbeta0 and Sbeta+ Brazilian patients followed at a single institution. AB - OBJECTIVES: In sickle cell/beta-thalassemia, mutations in the corresponding beta globin genes are responsible for complex pathological events resulting in diverse clinical complications. The objective of this study was to provide an overview of the clinical and laboratory characteristics of patients with the syndrome, and of the degree of severity of clinical manifestations resulting from the beta thalassemia mutation. METHODS: A retrospective chart review was performed on 46 patients with sickle cell/beta-thalassemia (31 Sbeta degrees and 15 Sbeta+), evaluating hematological parameters and end organ damage. Statistical analyzes were carried out in order to highlight differences between the two groups according to the nature of the thalassemia mutation. RESULTS: As expected, patients with the Sbeta0 phenotype had a higher degree of hematological involvement in comparison to Sbeta+ patients; with lower hemoglobin levels, and signs of more intense chronic hemolysis. However, Sbeta+ patients were more prone to the occurrence of acute chest syndrome. The impact of the thalassemia mutation upon total body and bone composition was also evident, as Sbeta0 patients presented lower body mass index (BMI) and bone mineral density. The degree of bone damage correlated to lower BMI and hemoglobin levels, as well as plaquetosis, monocytosis and elevated lactate dehydrogenase, possibly reflecting the effects of hemolysis and inflammation upon bone metabolism and body constitution. CONCLUSIONS: This study identified significant differences among sickle cell/beta-thalassemia patients according to the beta mutation involvement, pointing to an important predictor of disease severity. PMID- 27237197 TI - Dental stem cells: Hope or hype? PMID- 27237198 TI - Burden of oral diseases. PMID- 27237200 TI - Clinical effects of photodynamic and low-level laser therapies as an adjunct to scaling and root planing of chronic periodontitis: A split-mouth randomized controlled clinical trial. AB - BACKGROUND: There are limited clinical experiments addressing the effects of photodynamic therapy (PDT) and low-level laser therapy (LLLT) as an adjunct to conventional scaling and root planing (SRP) alone. AIM: The aim of this clinical trial was to evaluate the clinical effects of adjunctive use of PDT, combination of PDT with LLLT as adjunct to conventional SRP alone in the treatment of chronic periodontitis. MATERIALS AND METHODS: In a single-centered randomized and controlled clinical trial, 24 patients (15 males and 9 females) with untreated chronic periodontitis were randomly assigned in a split-mouth design into three treatment groups which included Group I: SRP only, Group II: SRP and PDT (1% methylene blue [MB] solution), and Group III: SRP, PDT, and LLLT. Clinical parameters such as plaque index, gingival index, modified sulcular bleeding index, probing depth (PD), and clinical attachment level (CAL) were measured at baseline, 1, 3, and 6 months after therapy. RESULTS: Within each group, significant improvements (P < 0.001) were found for all variables in 6-month follow-up compared with baseline. The improvement in clinical parameters was significantly greater in Group III compared to Group I and Group II. The mean PD (mm) reduction from baseline to 6 months in Group I was 2.50 +/- 0.54, Group II was 2.57 +/- 0.53, and Group III was 3.14 +/- 0.50. The mean CAL (mm) gain from baseline to 6 months in Group I was 2.63 +/- 0.47, Group II was 2.55 +/- 0.44, and Group III was 3.07 +/- 0.55. CONCLUSION: In patients with chronic periodontitis, a combination of a single application of PDT (using a 980 nm laser and MB) and LLLT provide additional benefit to SRP in terms of clinical parameters 6 months following the intervention. PMID- 27237199 TI - Quality of reporting of randomized controlled trials in ten academic Indian dental journals. AB - BACKGROUND: Biased results from poorly reported trials can mislead decision making in health care at all levels, from treatment decisions for the individual patient to formulation of national public health policies. OBJECTIVE: To evaluate the quality of reporting of randomized controlled trials (RCTs) in ten Indian dental journals over the period 2011-2012. MATERIALS AND METHODS: This study included all RCTs published as full-text articles reported in ten Indian dental journals over the period from 2011 to 2012. The relevant trials were identified by searching Medline. Hand searching of the journals was also carried out by three of the authors to check if any potential trial was missing. Each article was assessed against the Consolidated Standards of Reporting Trials criteria tool, as described by Schulz et al. (2010). RESULTS: The mean number of criteria present per article was 12.2 (standard deviation [SD] =2.2) and only 5 of 106 articles got total possible score. Most of the articles (69%) did not mention about justification for sample size calculation, 89% of the articles did not mention about allocation concealment, 86% of the articles did not mention about funding and 63% of the articles did not mention about limitations of the study. CONCLUSION: The quality of reporting of Randomized clinical trials in ten Indian academic journals was poor. PMID- 27237201 TI - Association of edentulousness and removable prosthesis rehabilitation with severity of signs and symptoms of temporomandibular disorders. AB - CONTEXT: There are very few studies concerning the role of denture status in temporomandibular disorders (TMDs) and those show conflicting results. AIM: To evaluate the association of edentulousness and removable prosthesis rehabilitation with severity of TMD signs and symptoms. SETTINGS AND DESIGN: Data were collected from 2000 subjects reporting for dental treatment, above 30 years of age. SUBJECTS AND METHODS: The subjects were interviewed with a questionnaire and clinically examined for TMD on basis of Helkimo's index. The number of existing teeth, wearing of removable dentures, need for denture repair, and age of dentures was recorded. STATISTICAL ANALYSIS: The association between the TMD findings and recorded variable outcomes was analyzed by means of Chi-square test. RESULTS: Completely edentulous individuals associated more with TMD related findings in incidence and intensity than partially/fully dentate subjects. Complete denture wearers were more associated with TMD symptoms, limited mandibular mobility, muscle tenderness, and pain on mandibular movement. Partial denture wearers were more associated with severely impaired temporomandibular joint function and joint pain. Signs and symptoms of TMD were more prevalent and severe in patients who needed to get their dentures repaired, those wearing dentures more than 5-year-old, and in patients who had not got their dentures repaired during the past 5 years. CONCLUSIONS: Edentulousness, complete/partial denture wearing and poor condition of the dentures associate with greater incidence and intensity of TMD associated signs and symptoms. PMID- 27237202 TI - Oral health knowledge and practices of dentists practicing in a teaching hospital in Nigeria. AB - AIM: To assess the oral health practices and knowledge of practicing dentists at a tertiary health institution in Nigeria, and the possible association of age and sex with caries prevention practices. METHODOLOGY: A cross-sectional study was conducted. All practicing dentists in the institution were eligible to participate in the study. A questionnaire that assessed oral health practices and knowledge was administered. Respondents were expected to select the most appropriate responses that reflected their knowledge of oral health practices and caries prevention practices. Questions included assessment of knowledge and practice of tooth brushing, flossing, refined carbohydrate intake, and dental service utilization. Participants' responses were scored and dichotomized to poor and good knowledge, and poor and good practices, using the median scores. Bivariate analysis was conducted to identify factors associated with good and poor oral health practices, and good and poor knowledge. RESULTS: Fifty-two eligible study participants were accessible at the time of questionnaire administration. Only 46 respondents returned the filled questionnaire giving a response rate of 88.5%. The age of respondents ranged between 25 and 48 years. The majority of respondents had good oral health practices (65.2%) and good oral health knowledge (85%). However, few respondents had good caries prevention practices: 39.2% brushed at least twice daily, 45.7% took refined carbohydrate less than once daily, 36.9% used dental floss at least once daily, and 60.9% undertook preventive dental care. The correlation between the dentists' oral health knowledge score and oral health practices score was insignificant (0.90; P = 0.55). CONCLUSION: A large number of dentists practicing in the tertiary hospital had good oral health practices and good oral health knowledge. However, the proportion of dentists with good caries prevention practices was low. PMID- 27237203 TI - Effect of electron-beam irradiation on antimicrobial, antibiofilm activity, and cytotoxicity of mouth rinses. AB - BACKGROUND: Oral health diseases are common in all regions of the world. Mouth rinses are widely used generally by population as a port of daily oral care regimen. In addition to antimicrobial activity, mouth rinses possess certain cytotoxic effects. Electron-beam (E-beam) radiation is a form of ionizing energy known to induce structural, physical, and chemical changes in irradiated products. In this study, the modulatory effects of E-beam in irradiated mouth rinses were evaluated for its biological activities. MATERIALS AND METHODS: The antimicrobial activities of nonirradiated and irradiated mouth rinses were evaluated for its antimicrobial and antibiofilm activities against oral pathogens, Enterococcus faecalis, Streptococcus mutans, Staphylococcus aureus, and Candida albicans. The antimicrobial activity was evaluated by disc diffusion method and antibiofilm activity was evaluated by O'Toole method. The cytotoxicity was evaluated against human gingival fibroblast (HGF) cells by 3-(4, 5 Dimethythiazol-yl)-2,5-Diphenyl-tetrazolium bromide assay. RESULTS: Colgate Plax (CP) exhibited the antimicrobial activity against the tested pathogens, and a significant (P< 0.05) increase was observed against S. aureus at 750 Gy irradiation. Further, CP significantly (P< 0.05) suppressed S. mutans, S. aureus, and C. albicans biofilm. Listerine (LS) inhibited S. mutans and C. albicans biofilm. Whereas irradiated CP and LS significantly (P< 0.05) suppressed the biofilm formed by oral pathogens. The suppression of biofilm by irradiated mouth rinses was dose- and species-dependent. There was no significant (P > 0.05) difference in the cytotoxicity of irradiated and nonirradiated mouth rinses on HGF cells. However, an increased percentage viability of HGF cells was observed by mouth rinses irradiated at 750 Gy.xs CONCLUSION: The E-beam irradiation enhanced the antibiofilm activity of mouth rinses without modifying the cytotoxicity. PMID- 27237204 TI - Prevalence of dental fluorosis among primary school children in association with different water fluoride levels in Mysore district, Karnataka. AB - BACKGROUND: Fluoride intake at optimal level decreases the incidence of dental caries. However, excessive intake, especially during developmental stages can cause adverse effects such as dental and skeletal fluorosis. AIM: To assess the prevalence and severity of dental fluorosis in primary school children born and raised in three villages of Mysore District. The three selected villages have different water fluoride concentrations. MATERIALS AND METHODS: Three villages namely, Nerale (water fluoride 2.0 ppm), Belavadi (1.2 ppm) and Naganahally (0.4 ppm) were selected for the study. Then, a total of 405 children, 10-12-year-old (204 [50.4%] males and 201 [49.60%] females) were selected from three schools of the villages. Dean's fluorosis index recommended by World Health Organization was used to evaluate fluorosis among the study population. RESULTS: The overall prevalence of dental fluorosis was found to be 41.73%. An increase in the community fluorosis index (CFI) was higher among those living in high water fluoride area. CONCLUSION: A significantly positive correlation was found between CFI and water fluoride concentration in drinking water. PMID- 27237205 TI - Evaluation of plasma reactive oxygen metabolites levels in obese subjects with periodontal disease. AB - BACKGROUND: Obesity represents the systemic condition capable of influencing the onset and progression of periodontal disease. Obesity is associated with oxidative stress. Plasma level of reactive oxidative metabolites (ROMs) is measured as an indicator of oxidative stress in the body. The aim of this study is to assess and compare the plasma ROM levels in obese subjects with healthy and inflammatory periodontal status. MATERIALS AND METHODS: Sixty subjects selected were grouped as 15 obese or overweight subjects with generalized chronic periodontitis, 15 obese or overweight subjects with generalized chronic gingivitis, 15 obese or overweight subjects with healthy periodontium, and 15 nonobese and healthy periodontium. The clinical periodontal parameters such as plaque index, gingival index, probing pocket depth, and clinical attachment level were measured. Blood samples were obtained to measure the plasma levels of ROM. RESULT AND CONCLUSION: In this study, obese subjects with chronic periodontitis (Group I) had mean plasma ROM levels (442.3 +/- 15.65 Carratelli unit [CARR U]) showing 100% subjects with high oxidative stress. Obese subjects with chronic gingivitis (Group II) had mean plasma ROM levels (358.7 +/- 20.61 CARR U) indicating 86.7% subjects with oxidative stress. Obese subjects with healthy periodontium (Group III) had 46.7% subjects with slight oxidative stress, and the mean ROM level was 320.2 +/- 17.57. Nonobese subjects with healthy periodontium (Group IV) had 80% of subjects with normal oxidative stress and the mean plasma ROM level was 296.9 +/- 20.35 CARR U. The intra- and inter-group comparison showed significant difference (P < 0.001). From our study, we report that obese subjects with periodontitis have more oxidative stress compared to obese subjects with healthy periodontium. PMID- 27237206 TI - Aerosol, a health hazard during ultrasonic scaling: A clinico-microbiological study. AB - CONTEXT: Ultrasonic scaling is a routinely used treatment to remove plaque and calculus from tooth surfaces. These scalers use water as a coolant which is splattered during the vibration of the tip. The splatter when mixed with saliva and plaque of the patients causes the aerosol highly infectious and acts as a major risk factor for transmission of the disease. In spite of necessary protection, sometimes, the operator might get infected because of the infectious nature of the splatter. AIM: To evaluate the aerosol contamination produced during ultrasonic scaling by the help of microbiological analysis. MATERIALS AND METHODS: This clinico-microbiological study consisted of twenty patients. Two agar plates were used for each patient; the first was kept at the center of the operatory room 20 min before the treatment while the second agar plate was kept 40 cm away from the patient's chest during the treatment. Both the agar plates were sent for microbiological analysis. STATISTICAL ANALYSIS: The statistical analysis was done with the help of STATA 11.0 (StataCorp. 2013. Stata Statistical Software, Release 13. College Station, TX: StataCorp LP, 4905 Lakeway Drive College Station, Texas, USA). Statistical software was used for data analysis and the P < 0.001 was considered to be statistically significant. RESULTS: The results for bacterial count were highly significant when compared before and during the treatment. The Gram staining showed the presence of Staphylococcus and Streptococcus species in high numbers. CONCLUSIONS: The aerosols and splatters produced during dental procedures have the potential to spread infection to dental personnel. Therefore, proper precautions should be taken to minimize the risk of infection to the operator. PMID- 27237207 TI - Effect of increasing the vertical intrusive force to obtain torque control in lingual orthodontics: A three-dimensional finite element method study. AB - CONTEXT: Biomechanical differences between lingual and labial orthodontics (LiO and LaO). AIMS: To investigate the effects of intrusive forces in lingual technique during retraction treatment mechanics. SETTINGS AND DESIGN: Intrusive forces act differently in both techniques because of the different location of force vectors in relation to the center of resistance. Increasing the vertical intrusive force is one of the methods routinely used to prevent the uncontrolled tipping and obtain bodily tooth movement in LaO. However, its effects in lingual technique need to be investigated to derive at an optimal treatment mechanics. SUBJECTS AND METHODS: Finite element method which has been successfully used to simulate tooth movement and optimize orthodontic mechanics effectively was used in this study. An accurate model of the upper central and lateral incisors with the surrounding structures was developed, and the "ANSYS" version 7.0 software was used for analysis. RESULTS: Intrusive forces as high as 3.6N was required to obtain translation in LiO that too in an undesirable direction. Efforts to obtain torque control by increasing the intrusive force only would not be successful. CONCLUSION: Forces that produce a translation in LaO tends to produce uncontrolled tipping in lingual technique. To obtain adequate torque control in lingual technique, a combination of the reduction in horizontal retraction forces, increased lingual root torque application, and increase in vertical intrusive forces is desirable. PMID- 27237208 TI - Curing efficiency of three light emitting diode units at different curing profiles. AB - CONTEXT: High-intensity light emitting diode lamps with reduced exposure time to bond orthodontic attachments have been introduced to save the valuable clinical time. AIMS: To evaluate the shear bond strength of brackets cured using three different light emitting diode curing units having different intensities and curing times, to compare the effect of different exposure methods on bond strength, and to compare the amount of remnant adhesive on tooth after debonding. SETTINGS AND DESIGN: Study conducted on 120 brackets bonded to extracted premolar teeth cured by using three light-emitting diode (LED) units. METHODS: One hundred and twenty adhesive precoated metal brackets (Gemini series, 3M Unitek) were cured using three LED curing units (3M ESPE, ELIPAR, S10; OrtholuxTM LED; OrtholuxTM Luminous Curing Light). Universal testing machine was used to record shear bond strength. Residual adhesive remaining on the teeth was assessed by the modified adhesive remnant index. STATISTICAL ANALYSIS: After calculating mean and standard deviation for each group, post hoc Tukey and Kruskal-Wallis tests were employed to find the significant difference. RESULTS: Comparison showed highest shear bond strength for Group 1A followed by 3A and lowest for Group 3B. Statistically significant difference was noticed in comparing shear bond strength recorded in Group 1A, Group 2A, and Group 3A with Group 1B, Group 2B, and Group 3B. CONCLUSIONS: Reduction of exposure time to 6 s with high-intensity curing light seemed to be clinically acceptable and should be recommended. Curing of metal brackets with single exposure from buccal side showed lower shear bond strength values. PMID- 27237209 TI - Comparison of three diagnostic techniques for detecting occlusal dental caries in primary molars: An in vivo study. AB - AIM: To compare the accuracy and repeatability of three diagnostic systems; visual inspection, bitewing radiography, and CarieScan PRO for occlusal caries diagnosis in primary molars. MATERIALS AND METHODS: 216 occlusal surfaces of primary molars examined in turn by two examiners using each of three diagnostic systems (visual inspection, bitewing radiography, and CarieScan PRO). Examiners indicated operative intervention (validation method) for 104 teeth which were used for statistical analysis. The validation method was cavity preparation when the two examiners agreed about the presence of dentinal caries. Sensitivity, specificity, likelihood ratio, positive predictive value (PPV), and negative predictive value (NPV) were calculated for each diagnostic technique. Inter- and intra-examiner repeatability was calculated for each diagnostic system using the Cohen's kappa statistics. RESULTS: Visual inspection showed the highest sensitivity (0.93). The highest sensitivity and NPVs were provided by CarieScan PRO (0.97 and 0.95, respectively) however this was offset by a lower specificity (0.82) compared to other techniques. The CarieScan PRO gave the highest values of Cohen's kappa statistics. CONCLUSION: This study showed low sensitivity but substantial specificity with visual inspection. Bitewing radiography performed poorly overall when compared with the other two systems. The CarieScan PRO technique gave the highest overall combination of sensitivity and specificity for detection of occlusal caries. PMID- 27237210 TI - Evaluation of serum uric acid levels in patients with oral squamous cell carcinoma. AB - BACKGROUND: Worldwide, oral carcinoma is one of the most prevalent cancers and is one of the most common causes of death. Toxicity by oxygen radicals has been suggested as an important cause of cancer. Several researchers have reported an association of plasma/serum uric acid with different cancers. AIM: The aim was to determine the serum uric acid level in patients with newly diagnosed oral squamous cell carcinoma (OSCC) and then to compare and correlate it with those of normal subjects and also to determine the role of uric acid in the etiology of OSCC. MATERIALS AND METHODS: The study group included 41 OSCC patients and 40 age and sex- matched healthy subjects as a control group. Estimation of serum urate concentration was determined enzymatically with a commercially available reagent. The data were statistically evaluated with Student's t-test and Chi-square test using SPSS 11.5 software. RESULTS: The mean serum uric acid levels were very low with the study group as compared to control group and were very highly significant (t = 4.14, P < 0.001). It was also found that risk of OSCC was more in a study group with low serum uric acid levels with tobacco intake. CONCLUSION: This study showed that serum uric acid was lower in oral cancer patients compared with healthy volunteers and low serum uric acid was associated with increased risk of oral cancer development. PMID- 27237211 TI - Extracellular matrix in oral squamous cell carcinoma: Friend or foe? AB - BACKGROUND: Oral squamous cell carcinoma (OSCC) primarily spreads through direct invasion and/or lymphatic route. During the invasion, tumor cells break through the basement membrane, penetrate the connective tissue to interact with the extracellular matrix (ECM). An attempt was made to evaluate the connective tissue changes in different grades of OSCCs and their influence in predicting the biological behavior of these tumors. MATERIALS AND METHODS: A total of 30 histologically proven cases comprising 5 normal mucosa, 10 well-differentiated OSCC's, 10 moderately differentiated OSCC's, and 5 poorly differentiated OSCC's were examined for the presence of any ECM changes by using special stains. Interpretation of staining intensity was carried out and statistically analyzed. RESULTS: Van Gieson stain showed abundant thick collagen fibers, dispersed collagen fibers, thin few dispersed collagen fibers in well-, moderately- and poorly-differentiated OSCC's, respectively. Verhoeff's Van-Gieson showed negative staining for elastic fibers around tumor islands in different grades of OSCCs. PAS stain showed moderate staining for glycoprotein in well-differentiated OSCC and negative in moderately and poorly differentiated cases. Picrosirius red stain showed Type 1 collagen fibers in well and moderately differentiated OSCC cases and Type 3 collagen fibers in poorly differentiated cases. CONCLUSION: The observations of this study revealed altered staining reactions of the collagenous stroma and glycoproteins suggesting that tumor cells may release certain enzymes that play a role in the manipulation of ECM to enhance their own survival. PMID- 27237212 TI - Evaluation of effect of recasting of nickel-chromium alloy on its castability using different investment materials: An in vitro study. AB - CONTEXT: Castability has been found to be affected by many aspects of the entire casting system. Very few references in dental literature are available regarding recasting of the base metal alloys. AIMS: To evaluate and compare the castability of fresh and reused nickel-chromium alloy and to evaluate the effect of two brands of investment materials on castability of nickel-chromium alloy. SUBJECTS AND METHODS: For the experimental purpose of evaluation of the effect of recasting of nickel-chromium alloy on its castability, different percentages of new and casted alloy (Nickel-chromium alloy-(Wirolloy NB, Type 4 (Ni-67%; Cr-25%; Mo-5%; Si-1.5%; Mn, Nb, B, C each <1%) and two commercial brands of investment materials namely, Deguvest Impact (Degudent; Dentsply Germany) and Bellavest SH (Degudent; Dentsply Germany) was used to obtain 30 samples. Castability value was obtained using Whitlock's formula. Student t-test and one way ANOVA using SPSS 20.0 software was done. RESULTS: The results of this study confirm earlier works that demonstrate that there is no significant difference in castability values of new and recast alloys. In addition, it also demonstrated, there was no difference in castability using Deguvest Impact and Bellavest SH investment materials. CONCLUSIONS: Within the limitations of the study, it was concluded that there was no significant difference found in castability of different percentage combinations of new and once casted alloy using two investment materials. The addition of new alloy during recasting to maintain the castability of nickel chromium alloy may therefore not be required. PMID- 27237213 TI - Color stability of a resin composite: Effect of the immersion method and surface treatments. AB - BACKGROUND: In vitro staining methods expose the entire specimen to staining solutions. In a real clinical situation, this is not observed, since one should consider that the bonded surface is not exposed to the oral environment. Theoretically, the clinical condition would be the best simulated if the specimens were exposed to staining solutions by partial immersion. AIMS: To evaluate if different immersion methods and surface treatments influence the color stability of resin-based specimens. METHODOLOGY: A stainless steel matrix was used to prepare 30 disc-shaped specimens that were randomly allocated in three groups: Without polishing, polishing with abrasive discs, and surface sealant. Half of the specimens were isolated to maintain only the upper surface exposed to staining (partial immersion) and the other half was totally immersed in coffee solution for 48 h (total immersion). The coordinates DeltaE*, DeltaL*, Deltaa*, Deltab* were assessed by spectrophotometer. STATISTICAL ANALYSIS: Two way ANOVA and Tukey's post hoc tests (alpha =0.05). RESULTS: Specimens submitted to partial immersion showed lower values of DeltaE*, DeltaL*, Deltaa*, Deltab*, in comparison to total immersion (P = 0.000). Specimens covered by a surface sealant presented lower DeltaE* values regardless of the immersion method. CONCLUSIONS: Specimens totally immersed in staining solutions could in somehow overestimate the color change, once that in most clinical conditions not all of the restoration surfaces are exposed to the oral environment. Moreover, as the surface sealant application produces color change values that are clinically acceptable, it might be used in esthetic restorations as an adjunct treatment. PMID- 27237214 TI - Antimicrobial efficacy of three medicinal plants Glycyrrhiza glabra, Ficus religiosa, and Plantago major on inhibiting primary plaque colonizers and periodontal pathogens: An in vitro study. AB - INTRODUCTION: From ancient times, plants with medicinal values are being tested and used in treatment of various infectious disease. AIMS AND OBJECTIVES: The presentin vitro study was designed to assess the antimicrobial activity of three commonly available medicinal plants Glycyrrhiza glabra, Ficus religiosa, and Plantago major on inhibiting Primary plaque colonizers and periodontal pathogens. MATERIALS AND METHODS: Bark of G. glabra, Stem of F. religiosa, and husk of P. major were collected, crushed into fine powder, and dissolved in 67% ethanol. Extracts were then subjected to test antimicrobial efficacy against primary plaque colonizers and periodontal pathogens using Kirby-Bauer disc diffusion method. Mean zone of inhibition (ZOI) was measured by HI antibiotic zone scale. One-way ANOVA using Tukey's post hoc and t-test were applied for statistical analysis. RESULTS: G. glabra was found to have potential antibacterial activity against primary plaque colonizers and periodontal pathogens with highest mean ZOI measuring 9.2 +/- 1.09 mm and 10.6 +/- 0.54 mm at 24 h, respectively. F. religiosa showed antibacterial activity against primary plaque colonizers only at 48 h with mean ZOI of 2.6 +/- 0.54 mm. P. major showed no antibacterial activity against any of the microorganism in this study. Tukey's post hoc test showed statistically nonsignificant difference between G. glabra and standard antibiotic (vancomycin 10 mcg) for periodontal pathogens. CONCLUSION: G. glabra and F. religiosa showed antibacterial activity against primary plaque colonizers and periodontal pathogens. However, further studies should be undertaken to affirm the same and test their efficacy in different concentration and clinical utility. PMID- 27237215 TI - Total reconstruction of mandible by transport distraction after complete resection for benign and malignant tumors. AB - BACKGROUND: Distraction osteogenesis (DO) is a recognized technique for the bone lengthening and correction of various mandibular deformities. It has an aided advantage of both osteogenesis and histiogenesis in achieving a bone supported mandibular ridge covered with attached gingiva, forming an appropriate vestibule. AIM: The aim of this study was to present our clinical experience in using transport DO technique (TDO) for treating mandibular bony defects following tumor ablation in both benign and malignant tumor cases. MATERIALS AND METHODS: This is a retrospective analysis of patients who underwent mandibular TDO for the correction of mandibular segmental defect at authors' center from 2000 to 2014 with the inclusion criteria of segmental bony defect in the mandible with moderate soft tissue defect. After the latency period of 10 days, the distraction was initiated at a rate of 0.25-1 mm/day. The distraction period continued until the segment with the transport disc reached the distal base. The total consolidation periods ranged from 6 to 14 weeks. RESULTS: The study group consists of 9 cases of TDO for reconstruction of segmental defect following tumor resection, of which 5 cases of benign and 4 cases of malignant tumor resection. The mean (standard deviation [SD]) bony defect length was 48 mm (9.8). The mean (SD) distracted bone lengthening was 43 mm (9.7), with a mean (SD) consolidation period of 17.9 (3.4) weeks. The bony defect involved the hemimandibular angle in four patients, hemimandibular body in three patients, with greater involvement of the body, symphysis in two patients, and of the bilateral mandibular body in two patients. Except for two patients who required additional bone grafting to complete union with the residual bone, other seven patients in the distraction zone showed the complete ossification by radiological evaluation. The mean (SD) consolidation period of 13.56 (1.5) weeks ranging from 12-15 weeks with the mean (SD) follow-up years is about 8.7 years (2.95) for the cases. Out of the 9 cases, one case had recurrence in the follow-up period and underwent resection with reconstruction using reconstruction plate in the created bone. The overall success rate of TDO was 88.9% (8 out of 9) in spite of adequate case selection and TDO protocol. CONCLUSIONS: TDO potentially benefits patients with segmental bony defects following tumor ablation in mandible. It is an unswerving tool to achieve sufficient bone in mandible in patients who cannot undergo aggressive surgery or poor general health. Bone resorption remains a critical issue for this reconstruction technique, though blood supply is continuously maintained in TDO. PMID- 27237217 TI - Central granular cell odontogenic tumor: Report of an unusual case. AB - Central granular cell odontogenic tumor (CGCOT) is an unusual benign odontogenic neoplasm characterized by the presence of granular cells associated with apparently inactive odontogenic epithelium. These tumors tend to occur in the posterior mandible and usually present as well-defined unilocular or multilocular radiolucent lesions. So far, only <40 cases of CGCOT have been described in the literature under various terminologies. Though these tumors were not considered as distinct entity in the recent WHO classification of odontogenic tumors, long term follow-up is recommended as malignant counterpart of CGCOT has already been reported. The main aim of this article is to report an additional case of CGCOT to the literature, occurring in a 73-year-old male. PMID- 27237216 TI - Orthodontic treatment reduces the impact on children and adolescents' oral health related quality of life. AB - CONTEXT: Malocclusion is a chronic disability that is usually remedied by orthodontic treatment which can provide the patient with a satisfactory state of oral health. AIM: To assess the current evidence in the literature concerning the impact of malocclusion treatment on the oral health related quality of life (OHRQoL) of children and adolescents. SETTINGS AND DESIGN: Systematic review. MATERIALS AND METHODS: Four databases (PubMed, Web of Science, Scopus and Virtual Health Library) were searched using specified indexing terms, including a manual search for of the references listed in the studies. The articles that met the inclusion criteria were classified regarding methodological quality and risk of bias in categories of high, moderate, or low. RESULTS: The electronic search produced 426 titles and abstracts, and the manual search of their references detected another 1 article. After excluding duplicate abstracts and applying the inclusion and exclusion criteria, 3 studies were eligible for quality assessment. Among these, 1 was classified as high methodological quality/low risk of bias and 2 as moderate methodological quality/moderate risk of bias. These 3 articles were included in the final qualitative synthesis. CONCLUSIONS: Malocclusions treatment reduces the impact on children and adolescents' OHRQoL based on evidence assessed in the literature. The level of evidence was moderate to high to detect changes in the impact after orthodontic treatment. PMID- 27237218 TI - A rare nonsyndromic presentation of bilateral doughnut shaped lip pits in an Indian child. AB - Lip pits are a rare congenital anomaly that presents on the upper or lower lip or the commissure of the lips. Lip pits are an autosomal dominant trait occurring almost always in association with cleft lip or palate. They most commonly occur in association with developmental disturbances such as Van der Woude's syndrome, popliteal pterygium syndrome, oro-facial-digital syndrome, Marres-Cremers syndrome, and Hirschsprung disease. Its occurrence in nonsyndromic individuals is extremely rare with only a handful of cases reported. The identification of lip pits with other associated anomalies is crucial for genetic counseling; we report a case of nonsyndromic presentation of bilateral lip pits. PMID- 27237219 TI - Protection against vascular endothelial dysfunction by polyphenols in sea buckthorn berries in rats with hyperlipidemia. AB - Chronic hyperlipemia increases the incidence of vascular endothelial dysfunction and can even induce cardiovascular disease. Sea buckthorn contains a host of bioactives such as flavonoids and polyphenols that can prevent the development of cardiovascular disease. The current study isolated active ingredients, polyphenols, from sea buckthorn berries (SVP) and orally administered SVP at a dose of 7-28 mg/kg. This treatment significantly reduced serum lipids, it enhanced the activity of antioxidant enzymes, and it decreased the level of serum TNF-alpha and IL-6. SVP also alleviate vascular impairment by decreasing the expression of eNOS, ICAM-1, and LOX-1 mRNA and proteins in aortas of rats with hyperlipidemia. Based on these findings, SVP has antioxidant action and it protects endothelium. PMID- 27237221 TI - Patients with an Inflamed Atherosclerotic Plaque have Increased Levels of Circulating Inflammatory Markers. AB - AIM: Inflammation is highlighted in the pathogenesis and destabilization of atherosclerotic lesions. Noninvasive identification of inflammation of atherosclerotic lesions has been challenging. 18-Fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) is a useful technique for detecting inflamed atherosclerotic plaques in vivo. However, it is time consuming, expensive, and accompanied by radiation. Therefore, we investigated the relationship between levels of circulating inflammatory markers and the degree of inflammation of atherosclerotic plaques shown by 18F-FDG uptake. We aimed to identify high-risk patients with inflamed, unstable atherosclerotic plaques on the basis of the determination of inflammatory markers. METHODS: The study included 37 patients, 21 with high-grade stenosis of internal carotid artery (ICA group) and 16 with occlusion of common femoral artery (CFA group), who underwent endarterectomy. Mean age of the study population was 69.43+/-6.2 years. Eight out of 21 patients with ICA stenosis and all patients with CFA occlusion were symptomatic. In all patients before endarterectomy, 18F-FDG-PET imaging was performed and blood samples were obtained for determination of circulating inflammatory markers: high sensitivity C-reactive protein (hsCRP), tumor necrosis factor alpha (TNF-alpha), interleukins, and selectins. Both groups were compared with a sex- and age matched control group composed of 27 healthy volunteers. RESULTS: 18F-FDG uptake, calculated by target-to-background ratio (TBR) was not significantly different between the groups. Levels of inflammatory markers were elevated, and there were no significant differences between ICA and CFA groups, with an exception of interleukin 6 (IL-6) levels, which was higher in the ICA group (3.2+/-2.5 ng/L vs. 1.8+/-1.3 ng/L, p<0.05). There was a positive interrelationship between 18F FDG-PET and most of the systemic inflammatory markers: hsCRP (r=0.417, p=0.010), IL-6 (r=0.603, p<0.001), and TNF-alpha (r=0.374, p=0.023). However, correlation between 18F-FDG-PET and P-selectin, E-selectin, and t-PA was not found. CONCLUSION: Our study showed that an interrelationship exists between the intensity of inflammatory process of atherosclerotic lesions shown by FDG uptake and circulating inflammatory markers. Therefore, the determination of circulating inflammatory markers can have a potential to identify individuals with unstable, inflamed atherosclerotic plaques. PMID- 27237222 TI - Genome research in pre-dementia stages of Alzheimer's disease. AB - Genetic characterization of individuals at risk of Alzheimer's disease (AD), i.e. people having amyloid deposits in the brain without symptoms, people suffering from subjective cognitive decline (SCD) or mild cognitive impairment (MCI), has spurred the interests of researchers. However, their pre-dementia genetic profile remains mostly unexplored. In this study, we reviewed the loci related to phenotypes of AD, MCI and SCD from literature and performed the first meta analyses evaluating the role of apolipoprotein E (APOE) in the risk of conversion from a healthy status to MCI and SCD. For AD dementia risk, an increased number of loci have been identified; to date, 28 genes have been associated with Late Onset AD. In MCI syndrome, APOE is confirmed as a pheno-conversion factor leading from MCI to AD, and clusterin is a promising candidate. Additionally, our meta analyses revealed APOE as genetic risk factor to convert from a healthy status to MCI [OR = 1.849 (1.587-2.153); P = 2.80 * 10-15] and to a lesser extent from healthy status to SCD [OR = 1.151 (1.015-1.304); P = 0.028]. Thus, we believe that genetic studies in longitudinal SCD and MCI series may provide new therapeutic targets and improve the existing knowledge of AD. This type of studies must be completed on healthy subjects to better understand the natural disease resistance to brain insults and neurodegeneration. PMID- 27237220 TI - Mild Hyperbaric Oxygen Inhibits Growth-related Decrease in Muscle Oxidative Capacity of Rats with Metabolic Syndrome. AB - AIM: We examined the effects of mild hyperbaric oxygen on the properties of the soleus muscle in rats with metabolic syndrome. METHODS: Five-week-old metabolic syndrome (SHR/NDmcr-cp, cp/cp) rats were divided into normobaric (CP) and mild hyperbaric oxygen (CP-H) groups (n=5/group). In addition, 5-week-old Wistar rats were assigned as the normobaric control (WR) group (n=5). The CP-H group was exposed to 1.25 atmospheres absolute with 36% oxygen for 3 h daily for 16 weeks. Succinate dehydrogenase (SDH) activity and mRNA levels of peroxisome proliferator activated receptor gamma coactivator-1alpha (Pgc-1alpha) in the soleus muscle were examined. The fiber type composition, cross-sectional areas, and SDH staining intensity in the soleus muscle were also examined. RESULTS: The CP-H group showed lower fasting and nonfasting blood glucose, glycated hemoglobin, total cholesterol, triglyceride, insulin, and systolic blood pressure levels; higher adiponectin levels; and higher SDH activity and mRNA levels of Pgc-1alpha in the muscle than the CP group. Compared with the CP group, the CP-H group had a lower percentage of type I fibers and observed type IIA fibers in the muscle. The CP-H group also had higher SDH staining intensity of type I and type IIC fibers in the muscle than the CP group. No differences in these values were observed in the muscles of the WR and CP-H groups. CONCLUSION: Mild hyperbaric oxygen inhibited growth-related increase in blood glucose levels and decrease in muscle oxidative capacity of rats with metabolic syndrome because of improved oxidative metabolism. PMID- 27237223 TI - High Performance Flexible Piezoelectric Nanogenerators based on BaTiO3 Nanofibers in Different Alignment Modes. AB - Piezoelectric nanogenerators, harvesting energy from mechanical stimuli in our living environments, hold great promise to power sustainable self-sufficient micro/nanosystems and mobile/portable electronics. BaTiO3 as a lead-free material with high piezoelectric coefficient and dielectric constant has been widely examined to realize nanogenerators, capacitors, sensors, etc. In this study, polydimethylsiloxane (PDMS)-based flexible composites including BaTiO3 nanofibers with different alignment modes were manufactured and their piezoelectric performance was examined. For the study, BaTiO3 nanofibers were prepared by an electrospinning technique utilizing a sol-gel precursor and following calcination process, and they were then aligned vertically or horizontally or randomly in PDMS matrix-based nanogenerators. The morphological structures of BaTiO3 nanofibers and their nanogenerators were analyzed by using SEM images. The crystal structures of the nanogenerators before and after poling were characterized by X-ray diffraction. The dielectric and piezoelectric properties of the nanogenerators were investigated as a function of the nanofiber alignment mode. The nanogenerator with BaTiO3 nanofibers aligned vertically in the PDMS matrix sheet achieved high piezoelectric performance of an output power of 0.1841 MUW with maximum voltage of 2.67 V and current of 261.40 nA under a low mechanical stress of 0.002 MPa, in addition to a high dielectric constant of 40.23 at 100 Hz. The harvested energy could thus power a commercial LED directly or be stored into capacitors after rectification. PMID- 27237225 TI - Scattering and Spectroscopic Study on the Hydration and Phase Behavior of Aqueous Alcohol Ethoxylate and Methyl Ester Ethoxylate: Effects of Terminal Groups in Hydrophilic Chains. AB - Using dielectric relaxation spectroscopy (DRS), small-angle X-ray scattering (SAXS), dynamic light scattering (DLS), and viscometry, we have investigated the hydration behavior, static structures, Brownian dynamics, and mechanical properties of aqueous solutions of alcohol ethoxylate (C12E15) and methyl ester ethoxylate (C12MEE), hereafter abbreviated as AE and MEE, respectively, in which we especially focus on the effects of the endcaps of these nonionic surfactants. We find that AE and MEE exhibit fairly different phase behaviors in water: AE produces liquid crystalline phases at w (surfactant weight fraction) > 0.35, whereas MEE retains a liquid phase in an extremely wide concentration range (w < 0.7) at ambient temperature. The structure factor deduced from SAXS intensities using a generalized indirect Fourier transformation technique and the effective hydration number evaluated from the negative excess bulk water relaxation amplitude revealed by DRS unambiguously demonstrate that hydration water molecules, exhibiting about 4-times-slower collective reorientational dynamics than that of bulk water, contribute to the excluded volume of the micelles. The blocked terminal hydrogen-bond donor/acceptor site of MEE leads to smaller hydration number of MEE than compared to that of AE, and consequently the lower excluded volume of the MEE micelles. The effective micellar volume fraction, phi(eff), should be defined by incorporating such different hydration effects. Importantly, voluminosity, defined as the micellar volume fraction per unit mass, is clearly a decreasing function of w, demonstrating progressive dehydration at a higher w. The collective diffusion constants determined by DLS for the AE and MEE micelles show a monotonous increase up to phi(eff) ~ 0.5, as expected for the hard spheres. Low-shear-rate viscosities follow a Krieger-Dougherty model in the identical micellar packing fraction range. All static, dynamic, and mechanical properties of these micellar solutions can be explained in a consistent and quantitative manner only when the excluded volume of hydration water molecules is properly taken into account. PMID- 27237226 TI - Pre-Lithiation of Li(Ni1-x-yMnxCoy)O2 Materials Enabling Enhancement of Performance for Li-Ion Battery. AB - Transition metal oxide materials Li(NixMnyCoz)O2 (NMCxyz) based on layered structure are potential cathode candidates for automotive Li-ion batteries because of their high specific capacities and operating potentials. However, the actual usable capacity, cycling stability, and first-cycle Coulombic efficiency remain far from practical. Previously, we reported a combined strategy consisting of depolarization with embedded carbon nanotube (CNT) and activation through pre lithiation of the NMC host, which significantly improved the reversible capacity and cycling stability of NMC532-based material. In the present work we attempt to understand how pre-lithiation leads to these improvements on an atomic level with experimental investigation and ab initio calculations. By lithiating a series of NMC materials with varying chemical compositions prepared via a conventional approach, we identified the Ni in the NMC lattice as the component responsible for accommodating a double-layered Li structure. Specifically, much better improvements in the cycling stability and capacity can be achieved with the NMC lattices populated with Ni(3+) than those populated with only Ni(2+). Using the XRD we also found that the emergence of a double-layer Li structure is not only reversible during the pre-lithiation and the following delithiation, but also stable against elevated temperatures up to 320 degrees C. These new findings regarding the mechanism of pre-lithiation as well as how it affects the reversibility and stability of NMC-based cathode materials prepared by the conventional slurry approach will promote the possibility of their application in the future battery industry. PMID- 27237227 TI - Editorial. AB - Put human beings together with movable and immovable objects, sharp and blunt instruments and there will always be accidents. They remain the most common. PMID- 27237224 TI - Adaptations to chronic rapamycin in mice. AB - Rapamycin inhibits mechanistic (or mammalian) target of rapamycin (mTOR) that promotes protein production in cells by facilitating ribosome biogenesis (RiBi) and eIF4E-mediated 5'cap mRNA translation. Chronic treatment with encapsulated rapamycin (eRapa) extended health and life span for wild-type and cancer-prone mice. Yet, the long-term consequences of chronic eRapa treatment are not known at the organ level. Here, we report our observations of chronic eRapa treatment on mTORC1 signaling and RiBi in mouse colon and visceral adipose. As expected, chronic eRapa treatment decreased detection of phosphorylated mTORC1/S6K substrate, ribosomal protein (rpS6) in colon and fat. However, in colon, contrary to expectations, there was an upregulation of 18S rRNA and some ribosomal protein genes (RPGs) suggesting increased RiBi. Among RPGs, eRapa increases rpl22l1 mRNA but not its paralog rpl22. Furthermore, there was an increase in the cap-binding protein, eIF4E relative to its repressor 4E-BP1 suggesting increased translation. By comparison, in fat, there was a decrease in the level of 18S rRNA (opposite to colon), while overall mRNAs encoding ribosomal protein genes appeared to increase, including rpl22, but not rpl22l1 (opposite to colon). In fat, there was a decrease in eIF4E relative to actin (opposite to colon) but also an increase in the eIF4E/4E-BP1 ratio likely due to reductions in 4E-BP1 at our lower eRapa dose (similar to colon). Thus, in contrast to predictions of decreased protein production seen in cell-based studies, we provide evidence that colon from chronically treated mice exhibited an adaptive 'pseudo-anabolic' state, which is only partially present in fat, which might relate to differing tissue levels of rapamycin, cell-type-specific responses, and/or strain differences. PMID- 27237228 TI - Journal scan. AB - A study of formal nurse triage has failed to show the benefits that are claimed by its advocates. The study was conducted in the accident and emergency department of a Midland district general hospital with more than 60,000 new attendances annually. Nurse triage was practised for five years preceding the study. PMID- 27237229 TI - [Not Available]. AB - Early deiibrillation will become a standard of basic life support under proposals by the American Heart Association. The recommendations, agreed at the National Conference on Cardiopulmonary Resuscitation and Emergency Cardiac Care in Dallas also include a proposal to give high-dose adrenaline to paediatric patients, not adults. Recent research has revealed no statistical difference in the hospital admission and discharge rates of adults given the standard dose (0.01 mg/kg) and those given a high dose (0.1 mg/kg to 0.2 mg/kg). PMID- 27237230 TI - Tissue Viability Society. AB - The Tissue Viability Society, founded in 1981 as a branch of the Wessex Rehabilitation Association, was originally concerned with the prevention and healing of pressure sores. It has developed as a unique forum for considering all aspects of the problems of tissue viability. Its membership is open to all who have a common interest in rehabilitation and wound care. PMID- 27237231 TI - Look to the future. AB - The primary task of A&E departments is the care and treatment of ill or injured people, quickly and at any time. This includes minimising numbers ot deaths and degrees of disability. PMID- 27237232 TI - Editorial. AB - The UKCC document 'The Scope of Professional Practice ( 1 ) should be welcomed with open arms by readers of Nursing Practice, since it affords opportunities for enhancing the quality of nursing care and for the development of clinical nursing, which are two aims of this journal. PMID- 27237233 TI - Truth behind the rumours. AB - The honeymoon's over for Health Secretary Virginia Bottomley. Like her predecessors Messrs Waldegrave and Clarke, she's found herself in the firing line of some very unpopular decisions. PMID- 27237234 TI - Preparing for war... ready for disaster. AB - 'In Sweden we prepare for war, but are always ready for disasters.' It is a comment that encapsulates the Swedish philosophy towards emergency planning. That provision is soon to take a significant leap into the future with the opening of the Disaster and Emergency Medical and Training Centre (D & EMTC) in Stockholm. PMID- 27237235 TI - The integration of research in the clinical setting: obstacles and solutions. A review of the literature. AB - This paper examines the relationship between nursing research and nursing practice. It concentrates on the areas of eduction, communication and organisation. In studying these factors, I will look at some of the constraints to research utilisation and offer some solutions which might reduce these constraints. PMID- 27237237 TI - Eric caines departs from the executive. AB - Outspoken NHS Personnel Director Eric Caines, well known for his controversial views on nursing skill mix and the pay Review Body, has announced his departure. PMID- 27237236 TI - Leg ulcer clinics: advanced nursing. AB - The author describes the development of a leg ulcer clinic, based on an eclectic model of care, which draws on her experience as a clinical nurse specialist. 'The philosophy of the clinic recognises that a'legs specific' approach offers only short term solutions, and that a holistic method, which encourages patients to examine their own situation, is more appropriate. PMID- 27237238 TI - London opposition grows. AB - Opposition to the Tomlinson proposals grew last week with the launch of a campaign to save the London hospitals earmarked for closure and an appeal from nurses to the Prime Minister. PMID- 27237239 TI - Pay review held up as rumours grow. AB - Government evidence to the nurses' pay Review Body (RB) has been suspended until after the Chancellor's autumn statement - which is expected to impose a tight squeeze on public sector pay. PMID- 27237241 TI - Tomlinson recommendations: time will be the key factor. AB - If the Tomlinson recommendations are implemented in anything less than ten or 20 years the results will be 'absolutely devastating', a former RCN General Secretary warned last week. PMID- 27237240 TI - ENB Sheffield staff to move to London? AB - Unions are meeting this week to discuss a controversial English National Board proposal to close down its Sheffield office and shift staff to central London. PMID- 27237242 TI - [Not Available]. AB - Project 2000 has been grossly over funded due to a Department of Health error, nurse managers heard last week. John Birch, North Lincolnshire Health Authority Director of Quality Assurance told an RCN conference that the health department had got its Project 2000 funding formula 'very, very wrong' and had significantly overpaid districts to implement the education reforms. 'We were overpaid by L80,000 in the first year, by L500,000 last year and by a minimum of L.300,000 tills year,' he told the RCN NHS General Managers and Chief Nurses to Health Authorities Forum conference. Mr Birch said he was sure that the over funding was being repeated in other districts and added that although his region was checking how the over funding was being spent, he had used the windfall for related research projects. PMID- 27237243 TI - UKCC candidates announced. AB - Unions and professional organisations will ensure that their members know who they are supporting in the first direct elections to the UKCC when ballot papers go out later this month. The list of candidates for the 40 seats was published by the UKCC last week. Each of the four countries will elect seven nurses, two mid wives and one health visitor. PMID- 27237244 TI - A&E departments: value for money? AB - The National Audit Office (NAO) acts as the taxpayers' watchdog. Recently it has published two value for money reports on A&E departments in England and Scotland ( 1 , 2 ). The reports give a snapshot of the service, following visits to 11 English and six Scottish hospitals. These departments see more than half a million new attendances, out of about 12 million new attenders in England and Scotland. PMID- 27237245 TI - Chemical puts nurses at risk. AB - Nurses are risking serious damage to their health because they are using a powerful sterilising chemical without proper precautions, the Royal College of Nursing has warned. PMID- 27237247 TI - Bottomley 'will not ban tobacco advertising'. AB - Health Secretary Virginia Bottomley has come under fire for her failure to ban tobacco advertising, despite a Department of Health report confirming it increases consumption. PMID- 27237246 TI - Knowledge access must be guaranteed. AB - People with learning disabilities must be guaranteed access to specialist skills and knowledge, a position statement from the National Coalition to Promote Community Care for People with Learning Disabilities demands. But for this to happen the needs and interests of professional staff and carers must be recognised, the Coalition argues. PMID- 27237248 TI - New Bill says children must have 'named' school nurse. AB - A Bill to set up a national school health service available to all children was presented to Parliament this week by Labour MP Terry Davis. PMID- 27237249 TI - Mandatory tracing motion is defeated. AB - A proposition that contact tracing in HIV should be mandatory was overwhelmingly defeated by delegates. PMID- 27237250 TI - 'climate of discrimination' claim. AB - The continued discrimination against girls in access to education in some countries has profound implications for the continued spread of HIV, said Barbara Weller, an independent nurse consultant. PMID- 27237251 TI - Call for definition of AIDS to cover women's conditions. AB - The definition of AIDS should be changed to include gynaecological conditions, delegates heard. PMID- 27237252 TI - Clinical trials: comparing dressings. AB - This article describes results from one of the sites involved in a multi-centred comparative study designed to assess the performance of a collagen-alginate dressing used in the treatment of leg ulceration. The research methods used in the trial, as well as the results, will be of interest to practising nurses. Those involved in similar work are invited to submit articles to be considered for publication in future issues of this supplement. PMID- 27237253 TI - Visits to the wards by non ward-based personnel. AB - Fourteen acute hospital wards in five different hospitals were observed for three days. Observers recorded the number and type of non ward-based personnel coming onto the ward, the nature of their visit, the length of time they stayed and whether or not they contacted a member of staff. Wide differences between the wards were found, but the overall results indicate that the volume of visits to the wards was greater than even the ward sisters recognised. The author suggests that a clearer definition of the role of the ward clerk - and an upgrading of the role to prepare clerks for dealing with non nursing-related enquiries - could be of great assistance to sisters and would be a cost-effective investment. PMID- 27237254 TI - [Not Available]. AB - Golden mile: The RCN Blackpool, Wyre and Fylde Branch celebrated its 50th anniversary recently with a dinner dance. Founder members Roma Lomax, left, and Ellen McCloughlin are pictured with Trevor Ride. RCN North of England Regional Secretary. PMID- 27237256 TI - Invalidity benefit tax threat. AB - Government plans to tax the sick could result in a 'significant' drop in income for thousands of people relying on benefits, it emerged last week. PMID- 27237255 TI - Personal cost felt in education changes. AB - The recent changes in nurse education have been made at a personal cost to teachers' mental health, an English National Board conference on 'Quality education for quality care' has been told. PMID- 27237257 TI - 'HAs fail to consult Irish people in UK'. AB - Health authorities are failing to consult local people on their health needs, a conference on the mental health of Irish people living in the UK heard last week. Consulting Irish people was often only 'symbolic', despite the requirements of the NHS and Community Care Act, conference Chair Padraic Kenna, Director of Innisfree Housing Association, told delegates. 'The Irish caught the boat in the 1950s only to miss the boat ever since,' he said. PMID- 27237258 TI - Mencap. AB - The charity MENCAP has shed its unpopular Little Stephen logo in a hid to transform the public perception of people with learning difficulties. 'The cartoon of a sad little boy, associated with the charity for more than 30 years, has been replaced by five images of people with learning difficulties enjoying life tn the community. PMID- 27237262 TI - Nurses campaign for clinton. AB - The last speech has been made, the final vote cast in the marathon that is election year in the United States. PMID- 27237264 TI - Products. AB - Algutat, a new haemostatic absorbent for use in surgery, has been produced by BritCair. PMID- 27237263 TI - Health dominates in US campaign. AB - The future of health care in the United States has dominated the election campaign. Abundant evidence exists to demonstrate that the system is failing to meet the needs of the American people. Currently 33 million people - 12.8 per cent of the population - have no health care insurance. Twenty three nations have lower infant mortality rates than the US. In immunising infants against polio, the US ranks behind 16 other nations, including Mexico. PMID- 27237265 TI - Health visitors urged to support pressure groups. AB - Health visitors were urged to back pressure groups like the Child Poverty Action Group, the Maternity Alliance and the National Council for One Parent Families. PMID- 27237266 TI - Community mothers 'not after your jobs'. AB - Health visitors were assured that the new breed of'community mothers' working alongside professionals in Tilbury, Essex were not after their jobs. PMID- 27237267 TI - HVs' role in assessing mental illness. AB - Health visitors should be playing a role in both identifying and preventing mental illness, Professor Tony Butterworth, professor of community nursing at Manchester University, told the conference recently. PMID- 27237269 TI - Ward culture resists new methods in wound care. AB - Ward culture is preventing nurses in some areas from implementing research findings which would promote improved wound healing, an RCN/Nursing Standard conference on 'Nurses in management' heard recently. PMID- 27237270 TI - Research awareness in treatment of wound care. AB - 'Research alongside care' in wound management featured as one of a series of seminars on Nursing Development Units held at the King's Fund recently. PMID- 27237271 TI - Mistaken beliefs are held about wound healing. AB - Too many nurses and doctors still believe that moisture and occlusion lead to infection, and that antiseptics and topical antibiotics prevent it, international experts on wound infection heard at a recent London conference. PMID- 27237273 TI - Substance abuse: crucial role for all nurses. AB - Nurses in all areas have a crucial role in preventing and ameliorating the effects of substance misuse, the Chair of the RCN's Substance Misuse Forum has said. PMID- 27237272 TI - Nurses' attitudes towards the sexuality of older people: an investigative study. AB - This article outlines a small scale investigative study into what factors influence nurses' attitudes towards the sexuality of older people. Thirty three trained nurses completed questionnaires designed to focus on three main areas: respondents' background details, attitudes towards sexuality as a general concept, and knowledge and attitudes specifically about the sexuality of older people. Results of the study indicate that nurses' attitudes about sexuality in general were the most influential factor in predicting their attitudes to older people's sexuality. This would suggest that nurses should be given the opportunity to explore their feelings about their own sexuality in order to change attitudes and practice. PMID- 27237274 TI - Air travel blamed for resurgence of diseases. AB - International air travel may be contributing to a resurgence of infectious diseases, some of which experts believed had been conquered. PMID- 27237275 TI - Mammography improves cancer survival rates. AB - A new study of young women with breast cancer has indicated that detection by mammography can improve survival. PMID- 27237276 TI - Bath psoralen might cause burns. AB - Patients undergoing PUVA where the psoralen is added to bath water might be at risk of phototoxic burns, researchers say. The problem has been seen in three patients undergoing the treatment in Dundee. One woman had a painful red line on her neck and chin which corresponded to the level of water in the bath. Another woman had burns to her back, while a man was affected on the shoulders and arms. PMID- 27237277 TI - Checking children's injection skills. AB - Periodic review and strategies to increase technical proficiency in young diabetics are recommended as the result of research. PMID- 27237278 TI - Perineal pain relief not research based. AB - Many treatments offered for the relief of postpartum perineal pain are not based on research, a new study suggests. PMID- 27237279 TI - Message in the bottle is the voice of experience. AB - There is little substitute for personal experience when it comes to treating patients, as a recent letter to The Lancet indicates. PMID- 27237280 TI - Amphotericin less toxic in fat emulsion. AB - Giving amphotericin in a fat emulsion instead of dextrose might reduce its clinical and renal toxicity. PMID- 27237281 TI - Nurse staffing levels and skill mix in accident and emergency departments. AB - There is currently great controversy about appropriate nurse staffing levels and skill mix in all areas. This has been brought about by changes in workloads, student allocation, the increasing use of support workers and persistent pressures on budgets. PMID- 27237282 TI - Curing a capital in crisis. AB - When Health Secretary Virginia Bottomley unveiled the Tomlinson report on London's health services, she said a great deal about the need to rationalise services and strengthen primary care. But she was conspicuously silent about who will pay for the changes. PMID- 27237284 TI - The single case experimental design: a quantitative method for everyday use. AB - Single case experimental (SCE) research is characterised, above all else, by a focus on the experience of individuals and by the translation of that experience into some measurable form. PMID- 27237283 TI - Setting out the proposals. AB - Every hospital in London must be prepared to relinquish some services if the government agrees to implement the radical package of proposals put forward in the Tomlinson Report. PMID- 27237285 TI - 'An active body, a healthy body': a new health survey for Northern Ireland. AB - Exercise may help prevent coronary heart disease ( 1 , 2 , 3 ), maintain a healthy weight, strengthen the bones ( 4 ), and preserve independence in the elderly and disabled ( 5 ). As the Department of Health has recently noted ( 5 ), 'appropriate physical activity or exercise is necessary for healthy living. PMID- 27237287 TI - Florence backs Tomlinson report. AB - In 1862, when St Thomas's Hospital was planned, Florence Nightingale campaigned for it to be built in 'purer air' on the outskirts of London. She declared that the proposed site on the Thames was 'the worst in London'. PMID- 27237286 TI - Auxiliaries should not be called nurses. AB - I find myself agreeing with Padraig OLuanaigh (The wide-ranging role of the auxiliary, September 30) with regards to the usage of the term 'nurse' ter describe people who do not appear on the United Kingdom Central Council's register. PMID- 27237288 TI - Maintaining a clinical level of correctness. AB - I wonder how many readers noted the positioning of the catheter tubing in the photograph illustrating Nursing Standard's clinical article, 'The bladder model: clinical implications' (October 21)? PMID- 27237289 TI - Uniforms reinforce nurses good image. AB - I disagree with the anonymous correspondent (Off-ward uniforms win no awards, October 21), who criticises the wearing of uniforms at events away from work. PMID- 27237290 TI - But they are best at teaching students. AB - I am a student entering the third year of the traditional registered general nurse course. PMID- 27237291 TI - Appreciation for even-handed overage. AB - I would like to congratulate Nursing Standard for its even-handedness in giving candidates for the forthcoming United Kingdom Central Council elections free space to publicise their manifestos. PMID- 27237292 TI - RCN criticised for one-sided debate. AB - I believe that it is wrong for the Royal College of Nursing to be seen to back pressure groups that support only one side of contentious issues. Doing so displays unacceptable bias. PMID- 27237293 TI - Help at hand for nurse placement. AB - After reading about the problems encountered by Annette Millage in her quest to further her children's nurse training (Information exchange, October 7), I suggest that anybody in a similar position may obtain help by contacting the Nurse Teachers Group of the British Association of British Paediatric Nurses. PMID- 27237294 TI - Careers item created wrong impression. AB - I would like co correct the impression given in the In Brief item (News, September 23) reporting the careers event organised by staff at the Newcastle College of Health Studies. The article stated that 'job shortages for final year Project 2000 students forced tutors to hold a careers convention'. PMID- 27237295 TI - Information exchange. AB - Information exchange exists as pait of our commitment to networking and nursing empowerment. If you need to know something the answer should be out there somewhere. Geographical isolation should not entail professional isolation. Address your queries to Information Exchange - and readers, do help enquirers it you can. And let us know if your request leads you to information that would be useful to the wider world of nursing. PMID- 27237296 TI - Success story. AB - An enthusiastic thumbs up: that was the overwhelming response from Nursing Standard readers who returned tlie Readership Survey forms sent out to subscribers in July. Alongside the success story of a steady increase in the number of subscriptions, the journal and its readers have good cause to celebrate in Nursing Standard's fifth birthday year. PMID- 27237297 TI - Respiratory Care Traver G Mitchell J Aspen 262pp L24.00 0-8342-0207-7. AB - Respiratory Care: A Clinical Approach, an American book, is intended for nurses caring for patients with pulmonary problems in all settings - acute, general or community. PMID- 27237298 TI - Alexander's Care of the Patient in Surgery, 9th edition Meeker M Huth Rothrock JC Alexander's Care of the Patient in Surgery, 9th edition Mosby /YearBook 1058pp L38.00 0-8016-3387-7. AB - The ninth edition of Alexander's Care of the Patient in Surgery is an all American publication. Its goal is to provide an up-to-date comprehensive reference for nurses working in the ; perioperative environment. PMID- 27237299 TI - Drugs and Pharmacology for Nurses Hopkins SJ Drugs and Pharmacology for Nurses 11th edition Churchill Livingstone L10.95 612pp 0-443-04389-2. AB - The cover of the eleventh edition of Drugs and Pharmacology for Nurses is embellished with the logo 'Project 2000', a useful reminder to recommend it to those students who are advanced beginners in their branch programme, particularly those who are completing the adult branch. PMID- 27237300 TI - Listings. AB - Nursing Standard regrets that it is no longer able to take listings over the telephone because of unprecedented demand. Readers are reminded that the listings section is for the use of charitable and professional organisations, unions and health authorities to publicise forthcoming events. Listings should contain all relevant details and be posted or faxed to Susan Bloodworth, Nursing Standard, Viking House, 17-19 Peterborough Road, Harrow, Middlesex HA 1 2AX. Pax: 081-423 3867. PMID- 27237301 TI - Clinical value of pathologic examination of non-neoplastic kidney in patients with upper urinary tract malignancies. AB - BACKGROUND/AIMS: While surgical resection remains the standard of care in the treatment of upper urinary tract malignancies, nephrectomy is a risk factor for the development of chronic kidney disease (CKD). The aim of this study was to determine whether histologic evaluation of non-neoplastic kidney could enable early identification of unrecognized kidney disease and could be of prognostic value in predicting postoperative renal outcomes. METHODS: We retrospectively analyzed 51 patients with upper urinary tract malignancies who received uninephrectomy or uninephroureterectomy. A thorough pathologic evaluation of non neoplastic kidney including special stains, immunofluorescence, and electron microscopic studies was performed. The degree of parenchymal changes was graded from 0 to 15. RESULTS: Of 51 patients, only 13 showed normal kidney pathology. Fifteen patients showed glomerular abnormalities, 14 showed diabetic nephropathy, and 11 showed vascular nephropathy. There was one case each of reflux nephropathy and chronic pyelonephritis. The median histologic score was 5 points. Only 25.4% of patients had <= 3 points. Score more than 5 was observed in 47.1% of patients. Postoperative estimated glomerular filtration rate (eGFR) at 3 to 36 months were obtained from 90.2% of patients, and of those, 34.8% had de novo CKD. Since no one had CKD in partial nephrectomized patients, we determined risk factors for CKD in radical nephrectomized patients. Cox regression analysis revealed that postoperative AKI, preoperative eGFR, and histologic score of non-neoplastic kidney were the independent predictors for CKD. CONCLUSIONS: We conclude that routine pathologic evaluation of non-neoplastic kidney provides valuable diagnostic and prognostic information. PMID- 27237304 TI - Coming in Postgraduate Medicine. PMID- 27237302 TI - Parental concerns on disclosure of HIV status to children living with HIV: children's perspective. AB - Disclosure is an important component of comprehensive management of children living with HIV infection (CLHIV). Many parental concerns are barriers for disclosure in children and only few studies addresses children's perspective on these concerns. Our study aims to understand children's perspective on parental concerns for disclosure and assess the knowledge of HIV. A questionnaire-based cross-sectional study involving CLHIV between 10 and 18 years attending HIV clinic in southern India, was conducted. Data were collected by directly interviewing only the children after obtaining consent from parents/caregivers. Initial open-ended questions were asked to assess the disclosure status and only fully disclosed children were included. Out of 362 enrolled eligible children, the prevalence of full and partial disclosure was 36.7% and 24%, respectively. The mean age of disclosure was 10.4 years (SD +/- 2.6) and non-parental family members in an informal setting were the most common source of disclosure (38.3%). Forty-six percentages of parents were unaware of their child's disclosure status. Only 2% had disclosed their status to others who were not part of their care. Among disclosed children, 33.8% became upset or sad upon knowing their status, 12% faced discrimination and 41.4% had complete knowledge about their illness. Though the prevalence of disclosure among CLHIV was high, a majority of them had incomplete knowledge about HIV infection. The parental concerns as reported in literature like the child is too young to disclose, concerns about coping, fear of stigma and discrimination and child disclosing to others were not expressed by children. PMID- 27237303 TI - A microbial model of mammalian metabolism: biotransformation of 4,5-dimethoxyl canthin-6-one using Cunninghamella blakesleeana CGMCC 3.970. AB - 1. A filamentous fungus, Cunninghamella blakesleeana CGMCC 3.970, was applied as a microbial system to mimic mammalian metabolism of 4,5-dimethoxyl-canthin-6-one (1). Compound 1 belongs to canthin-6-one type alkaloids, which is a major bioactive constituent of a traditional Chinese medicine (the stems of Picrasma quassioides). 2. After 72 h of incubation in potato dextrose broth, 1 was metabolized to seven metabolites as follows: 4-methoxyl-5-hydroxyl-canthin-6-one (M1), 4-hydroxyl-5-methoxyl-canthin-6-one (M2), canthin-6-one (M3), canthin-6-one N-oxide (M4), 10-hydroxyl-4,5-dimethoxyl-canthin-6-one (M5), 1-methoxycarbonl beta-carboline (M6), and 4-methoxyl-5-O-beta-D-glucopyranosyl-canthin-6-one (M7). 3. The structures of metabolites were determined using spectroscopic analyses, chemical methods, and comparison of NMR data with those of known compounds. Among them, M7 was a new compound. 4. The metabolic pathways of 1 were proposed, and the metabolic processes involved phase I (O-demethylation, dehydroxylation, demethoxylation, N-oxidation, hydroxylation, and oxidative ring cleavage) and phase II (glycosylation) reactions. 5. This was the first research on microbial transformation of canthin-6-one alkaloid, which could be a useful microbial model for producing the mammalian phase I and phase II metabolites of canthin-6-one alkaloids. 6. 1, M1-M5, and M7 are canthin-6-one alkaloids, whereas M6 belongs to beta-carboline type alkaloids. The strain of Cunninghamella blakesleeana can supply an approach to transform canthin-6-one type alkaloids into beta-carboline type alkaloids. PMID- 27237305 TI - Meetings and Courses. PMID- 27237307 TI - What's Happening in Medicine! PMID- 27237306 TI - Problems/Solutions. AB - Readers are invited to submit questions relating to problem cases. Inquiries will be answered by qualified consultants and replies forwarded by mail promptly. Selected problems and solutions are published every month in this section. PMID- 27237309 TI - Washington Report on Health. PMID- 27237312 TI - The Medical Muse. PMID- 27237311 TI - Introduction. PMID- 27237313 TI - Medicine From Abroad. PMID- 27237315 TI - Your Investments. PMID- 27237316 TI - Therapeutic Index. PMID- 27237317 TI - More novel diagnostic antibodies for celiac disease. PMID- 27237318 TI - Morphological Changes, Cadherin Switching, and Growth Suppression in Pancreatic Cancer by GALNT6 Knockdown. AB - Pancreatic cancer reveals the worst prognosis among human cancers with little improvement in its clinical outcome in the last three decades. We previously suggested that polypeptide N-acetylgalactosaminyltransferase 6 (GALNT6), which catalyzes O-type glycosylation of Mucin 1, might be a promising molecular target for drug development for breast cancer. In this study, we report upregulation of GALNT6 in pancreatic cancer cells where Mucin proteins are highly O-glycosylated. We found that knockdown of GALNT6 with small interfering RNA in pancreatic cancer cells decreased the amount of Mucin 4 protein as well as that of its transcript, reduced the levels of human epidermal growth factor receptor 2 and extracellular signal-regulated kinase, and significantly reduced pancreatic cancer cell viability. Interestingly, knockdown of GALNT6 caused drastic morphological changes of pancreatic cells, accompanied with the cadherin switching from P cadherin to E-cadherin. Considering important roles of Mucin 4 in growth and invasion, our findings imply that targeting GALNT6 is a very promising therapeutic strategy for treatment of pancreatic cancer patients who still have very limited treatment modalities. PMID- 27237319 TI - IL-6 Inhibition With MEDI5117 Decreases The Fraction of Head and Neck Cancer Stem Cells and Prevents Tumor Recurrence. AB - Head and neck squamous cell carcinomas (HNSCC) exhibit a small population of uniquely tumorigenic cancer stem cells (CSC) endowed with self-renewal and multipotency. We have recently shown that IL-6 enhances the survival and tumorigenic potential of head and neck cancer stem cells (i.e. ALDH(high)CD44(high) cells). Here, we characterized the effect of therapeutic inhibition of IL-6 with a novel humanized anti-IL-6 antibody (MEDI5117) using three low-passage patient-derived xenograft (PDX) models of HNSCC. We observed that single agent MEDI5117 inhibited the growth of PDX-SCC-M1 tumors (P < .05). This PDX model was generated from a previously untreated HNSCC. In contrast, MEDI5117 was not effective at reducing overall tumor volume for PDX models representing resistant disease (PDX-SCC-M0, PDX-SCC-M11). Low dose MEDI5117 (3 mg/kg) consistently decreased the fraction of cancer stem cells in PDX models of HNSCC when compared to IgG-treated controls, as follows: PDX-SCC-M0 (P < .001), PDX-SCC-M1 (P < .001), PDX-SCC-M11 (P = .04). Interestingly, high dose MEDI5117 (30 mg/kg) decreased the CSC fraction in the PDX-SCC-M11 model (P = .002), but not in PDX-SCC-M0 and PDX-SCC-M1. MEDI5117 mediated a dose-dependent decrease in the number of orospheres generated by ALDH(high)CD44(high) cells cultured in ultra-low attachment plates (P < .05), supporting an inhibitory effect on head and neck cancer stem cells. Notably, single agent MEDI5117 reduced the overall recurrence rate of PDX-SCC-M0, a PDX generated from the local recurrence of human HNSCC. Collectively, these data demonstrate that therapeutic inhibition of IL-6 with low-dose MEDI5117 decreases the fraction of cancer stem cells, and that adjuvant MEDI5117 inhibits recurrence in preclinical models of HNSCC. PMID- 27237320 TI - PIAS1-FAK Interaction Promotes the Survival and Progression of Non-Small Cell Lung Cancer. AB - The sequence of genomic alterations acquired by cancer cells during tumor progression and metastasis is poorly understood. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that integrates cytoskeleton remodeling, mitogenic signaling and cell survival. FAK has previously been reported to undergo nuclear localization during cell migration, cell differentiation and apoptosis. However, the mechanism behind FAK nuclear accumulation and its contribution to tumor progression has remained elusive. We report that amplification of FAK and the SUMO E3 ligase PIAS1 gene loci frequently co-occur in non-small cell lung cancer (NSCLC) cells, and that both gene products are enriched in a subset of primary NSCLCs. We demonstrate that endogenous FAK and PIAS1 proteins interact in the cytoplasm and the cell nucleus of NSCLC cells. Ectopic expression of PIAS1 promotes proteolytic cleavage of the FAK C-terminus, focal adhesion maturation and FAK nuclear localization. Silencing of PIAS1 deregulates focal adhesion turnover, increases susceptibility to apoptosis in vitro and impairs tumor xenograft formation in vivo. Nuclear FAK in turn stimulates gene transcription favoring DNA repair, cell metabolism and cytoskeleton regulation. Consistently, ablation of FAK by CRISPR/Cas9 editing, results in basal DNA damage, susceptibility to ionizing radiation and impaired oxidative phosphorylation. Our findings provide insight into a mechanism regulating FAK cytoplasm-nuclear distribution and demonstrate that FAK activity in the nucleus promotes NSCLC survival and progression by increasing cell-ECM interaction and DNA repair regulation. PMID- 27237324 TI - Corrigendum to: "Noninvasive Optical Tracking of Red Fluorescent Protein Expressing Cancer Cells in a Model of Metastatic Breast Cancer" by Paul T. Winnard Jr., Jessica B. Kluth, and Venu Raman published in Neoplasia, volume 8, number 10, October 2006, on pages 796-806. PMID- 27237321 TI - Glycan Sulfation Modulates Dendritic Cell Biology and Tumor Growth. AB - In cancer, proteoglycans have been found to play roles in facilitating the actions of growth factors, and effecting matrix invasion and remodeling. However, little is known regarding the genetic and functional importance of glycan chains displayed by proteoglycans on dendritic cells (DCs) in cancer immunity. In lung carcinoma, among other solid tumors, tumor-associated DCs play largely subversive/suppressive roles, promoting tumor growth and progression. Herein, we show that targeting of DC glycan sulfation through mutation in the heparan sulfate biosynthetic enzyme N-deacetylase/N-sulfotransferase-1 (Ndst1) in mice increased DC maturation and inhibited trafficking of DCs to draining lymph nodes. Lymphatic-driven DC migration and chemokine (CCL21)-dependent activation of a major signaling pathway required for DC migration (as measured by phospho-Akt) were sensitive to Ndst1 mutation in DCs. Lewis lung carcinoma tumors in mice deficient in Ndst1 were reduced in size. Purified CD11c+ cells from the tumors, which contain the tumor-infiltrating DC population, showed a similar phenotype in mutant cells. These features were replicated in mice deficient in syndecan-4, the major heparan sulfate proteoglycan expressed on the DC surface: Tumors were growth-impaired in syndecan-4-deficient mice and were characterized by increased infiltration by mature DCs. Tumors on the mutant background also showed greater infiltration by NK cells and NKT cells. These findings indicate the genetic importance of DC heparan sulfate proteoglycans in tumor growth and may guide therapeutic development of novel strategies to target syndecan-4 and heparan sulfate in cancer. PMID- 27237322 TI - Salmonella Protein AvrA Activates the STAT3 Signaling Pathway in Colon Cancer. AB - Salmonella infection in humans can become chronic, which leads to low-grade persistent inflammation. These chronic infections increase the risk of several gastrointestinal diseases, including cancer. Salmonella AvrA is a multifunctional protein that influences eukaryotic cell pathways by regulating ubiquitination and acetylation. In an animal model, we have demonstrated that infection with AvrA expressing Salmonella induces beta-catenin signals and enhances colonic tumorigenesis. Beta-catenin signaling is a key player in intestinal proliferation and tumorigenesis. The relative contributions of AvrA-induced proliferation and inflammation on tumorigenesis, however, are unknown. STAT3 is activated in chronically inflamed intestines in human inflammatory bowel diseases and in colitis-associated colon cancer. In the current study, mice were colonized with Salmonella AvrA-sufficient or AvrA-deficient bacterial strains. Then, inflammation-associated colon cancer was induced through the use of azoxymethane/dextran sulfate sodium. We determined that AvrA-expressing bacteria activated the STAT3 pathway, which is predicted to enhance proliferation and promote tumorigenesis. Transcriptional activity of STAT3 and its target genes were upregulated by Salmonella expressing AvrA, thus promoting proliferation and intestinal tumorigenesis. Our findings provide new insights regarding a STAT3 dependent mechanism by which the specific bacterial product AvrA enhances the development of infection-associated colon cancer. These insights might suggest future biomarkers to risk assessment and early detection of infection-related cancer. PMID- 27237323 TI - The Heterodimeric TWIST1-E12 Complex Drives the Oncogenic Potential of TWIST1 in Human Mammary Epithelial Cells. AB - The TWIST1 embryonic transcription factor displays biphasic functions during the course of carcinogenesis. It facilitates the escape of cells from oncogene induced fail-safe programs (senescence, apoptosis) and their consequent neoplastic transformation. Additionally, it promotes the epithelial-to mesenchymal transition and the initiation of the metastatic spread of cancer cells. Interestingly, cancer cells recurrently remain dependent on TWIST1 for their survival and/or proliferation, making TWIST1 their Achilles' heel. TWIST1 has been reported to form either homodimeric or heterodimeric complexes mainly in association with the E bHLH class I proteins. These complexes display distinct, sometimes even antagonistic, functions during development and unequal prometastatic functions in prostate cancer cells. Using a tethered dimer strategy, we successively assessed the ability of TWIST1 dimers to cooperate with an activated version of RAS in human mammary epithelial cell transformation, to provide mice with the ability to spontaneously develop breast tumors, and lastly to maintain a senescence program at a latent state in several breast cancer cell lines. We demonstrate that the TWIST1-E12 complex, unlike the homodimer, is an oncogenic form of TWIST1 in mammary epithelial cells and that efficient binding of both partners is a prerequisite for its activity. The detection of the heterodimer in human premalignant lesions by a proximity ligation assay, at a stage preceding the initiation of the metastatic cascade, is coherent with such an oncogenic function. TWIST1-E protein heterodimeric complexes may thus constitute the main active forms of TWIST1 with regard to senescence inhibition over the time course of breast tumorigenesis. PMID- 27237325 TI - Investigation of unprovoked venous thromboembolism: a case for a tempered approach? AB - AIM: To investigate and review the diagnostic yield for occult malignancy in patients who underwent abdominopelvic computed tomography (CT) after the diagnosis of unprovoked venous thromboembolism (VTE) with reference to the guidelines set by The National Institute for Health and Clinical Excellence (NICE). MATERIALS AND METHODS: We retrospectively reviewed all unprovoked VTE diagnosed within a large teaching hospital over a period of 21 months for subsequent imaging investigations and cancer diagnoses. The primary outcome was confirmed cancer diagnosis; patients were followed for a minimum of 12 months. RESULTS: Three hundred and five unprovoked VTEs were diagnosed in the study period, 31% of all VTEs. Of this cohort, 73.1% underwent further imaging for exclusion of occult malignancy. Fifteen (4.9%) cancers were diagnosed; with no subsequent malignancy reported in a 12-month follow-up period of the remaining 290 patients. Of the 15 cancers, seven were post-pulmonary emboli, all of which were identified on the initial CT pulmonary angiogram, thus abdominopelvic CT only was used to locate the primary and to undertake staging. Eight were post deep-vein thrombosis (DVT). Thus the diagnostic yield for malignancy on abdominopelvic CT post-unprovoked VTE was 2.3%. The majority of diagnosed cancers were advanced with 80% dying in the follow-up period with a mean survival of 3.4 months. CONCLUSION: The pick-up rate of occult malignancy on abdominopelvic CT post-unprovoked VTE in the present study was 2.3%, far less than the generally quoted rate of 10%; however, similar to other rates in the literature. The benefit abdominopelvic CT brings to the diagnosis of occult malignancy post unprovoked VTE is irresolute. PMID- 27237326 TI - Indole-based, Antiproliferative Agents Targeting Tubulin Polymerization. AB - Indole is a potential lead for drug design which has been found in numerous pharmaceutically important compounds due to its medicinal properties, such as anti-tumor, anti-bacterial, anti-virus and anti-inflammatory. In the last decade, interfering with microtubule polymerization, a potential orientation to cause cell cycle arrest and apoptosis has become a promising method for cancer therapy. Thus, indole-based agents capable to modulate the microtubule assembly have gained considerable interest among scientists. This review describes the synthesis, bioactivities and SARs of indole-based agents targeting tubulin polymerization during the past decade. PMID- 27237327 TI - The Impending Renaissance in Discovery & Development of Natural Products. AB - Antibiotics are wonder drugs. Unfortunately, owing to overuse, antibiotic resistance is now a serious problem. Society now finds itself in the post antibiotic era, and the threat of infectious diseases is on the rise. New antibiotics are sorely needed. There is strong evidence that suggests natural products are an attractive source of new antimicrobials. They posses desirable structural and chemical properties that make them potent thearpeutics. However, steep tehnological challenges associated with screening and manufacturing these molecules has stifled the discovery, development and marketing of new antimicrobials. To this end, two recent scientific developments are poised to redress this situation. The recent development of metagenomics and ancillary high throughput screening technologies has exponentiated the volume of useful genetic sequence information that can be screened for antimicrobial discovery. These approaches have been instrumental in the discovery of new antibiotics from soil and marine environments. Secondly, a new manufacturing paradigm employing metabolic engineering as its engine has greatly accelerated the path to market for these molecules, in addition to improving the atom and energy economy of antimicrobial manufacturing. We outine these developments in this review, and provide a perspective on integrating next-generation approaches such as metagenomics and metabolic engineering with traditional methodologies for discovering and manufacturing antimicrobial natural products in order to unleash a rennaissance in the discovery and development of antimicrobials. PMID- 27237328 TI - Natural Plant Extracts as Potential Therapeutic Agents for the Treatment of Cancer. AB - Cancer, the much dreaded name, is a multifactorial and genetically a difficult disease with less or so far no 100% cure available. Globally, it has become a major social concern and worsened the economical burden, with emergence of 1,658,370 new cancer cases and 589,430 cancer deaths in the United States only in 2015. In India, the scenario is no better with high cancer prevalence of around 2.5 million incidences, with over 800,000 new cases occurring each year. By 2015, WHO has predicted estimated deaths by cancer to be 700,000. The increase could be accounted to urbanization, industrialization, hectic and unhealthy lifestyle, increased life expectancy and population growth. The current treatment regimes are becoming inefficacious due to tumor heterogeneity and increased resistance to drugs. Bioactive compounds from natural resources have revolutionized the arena of drug chemistry and rapid researches in in vitro and in vivo studies are encouraging. These natural therapeutic agents have therefore, become important for the development of multi- treatment strategies to be deployed in cancer therapy. The review summarizes the various chemopreventive and bioactive compounds isolated from several herbs which have become milestone in various kinds of tumor treatments. Also emphasis is led on including latest research data obtained from animal cell culture, animal models and preclinical trials studies conducted by scientists around the world to derive potential anti-tumorigenic agents. Finally, the review examines mechanisms of action of these compounds which will add to our existing knowledge and effort to serve and enhance the current chemotherapeutic protocols. PMID- 27237329 TI - Structure-Specific Ligand Recognition of Multistranded DNA Structures. AB - Structural polymorphism is an extremely significant phenomenon of nucleic acids, in which DNA and RNA oligonucleotide sequences are able to adapt various canonical, alternative and multistranded structures. These alternative forms of DNA and RNA have an enormous potential of participating in various cellular processes by recognizing ligands such as proteins, drugs and metal ions in a sequence and structure-specific manner. Such DNA-ligand interactions prove to be highly beneficial when exploited for therapeutic purposes. Many of these DNA/ RNA structures recognizing drugs have already proved their potential as anticancer, antibacterial, anthelmintic and antiviral properties. Over the last 2-3 decades, many mechanisms of DNA-drug interactions have been documented, but still many other new mechanisms are being explored. Designing new drugs with improved efficacy and specificity is of prime concern for all researchers which not only deals with the experiments related to synthesizing drugs, but also takes care of searching novel routes or agents for administration or delivery of these therapeutic agents by increasing their nuclear and cellular uptake. This review aims at explaining the structural polymorphs/ multistranded DNA structures and their interactions with pharmaceutical drugs in a structure-specific manner, along with their modes of interactions and biological relevance. This detailed overview of multistranded DNA structures and interacting drugs might further facilitate our understanding about molecular targets and drug development in a more precise manner for the larger benefit of mankind. PMID- 27237330 TI - Isoindole Derivatives: Propitious Anticancer Structural Motifs. AB - Isoindole derivatives constitute an important class of biologically active heterocyclic compounds and continue to attract considerable attention due to their diverse pharmacological profile such as, antimicrobial, anthelmintic, insecticidal, cyclooxygenase isoenzyme (COX-2) and thrombin inhibition with special emphasis on anticancer activity. This review highlights anticancer properties of isoindole derivatives and its related structures and hoping that it would further help in generation of new concepts towards rational design and development of more potent and less toxic anticancer agents. PMID- 27237331 TI - Noscapine and its Analogs as Chemotherapeutic Agent: Current updates. AB - Recently, noscapine was reported as anticancer drug. Unlike, colchicine and podophyllotoxin, noscapine did not depolymerize microtubules even at stoichiometric concentrations but rather only mitigated their dynamics. Other microtubule-interacting chemotherapeutics, although quite effective, have therapy limiting toxicities including immunosuppression and peripheral neuropathies. Recurrent cancers often become resistant. Noscapine however remains effective in some such instances, e.g., taxane-resistant ovarian cancer. Noscapine and analogs also do not show signs of neurotoxicity or immunosuppression. In addition, 9 bromo noscapine, Red-9-Br-Nos and other analogs were characterized for their structure and further studied in detail. On the other hand, noscapine was shown to be neuroprotective in mouse model of neurodegenerative disease and in stroke patients. Like low doses of colchicine, noscapine and its analog 9-Br-Noscapine also show anti-inflammatory activities. There are indications of a preventive use of noscapine in ischemiareperfusion injury and fibrosis. The entire biosynthetic pathway of noscapine is encoded as gene cluster within 401 kilo bases of genomic DNA, opening up opportunities for the large-scale biotechnological production of noscapine for medicinal needs. Thus, noscapine and its derivatives (noscapinoids) might be cost-effective and safe components for cancer chemotherapy. Owing to its low toxicity, it also might be useful for preventive use in high-risk situations. This brief review is an update of current research activity and patents on noscapine and its analogs. PMID- 27237332 TI - Imidazo[1,2-a]pyridine Scaffold as Prospective Therapeutic Agents. AB - Imidazo[1,2-a]pyridine is one of the most potential bicyclic 5-6 heterocyclic rings that is recognized as a "drug prejudice" scaffold due to its broad range of applications in medicinal chemistry such as anticancer, antimycobacterial, antileishmanial, anticonvulsant, antimicrobial, antiviral, antidiabetic, proton pump inhibitor, insecticidal activities. This scaffold has also been represented in various marketed preparations such as zolimidine, zolpidem, alpidem. Therefore, several attempts were made to carry out the structural modifications of this scaffold to discover and develop novel therapeutic agents. This review provides a valuable insight into the research findings of wide range of derivatives of imidazo[1,2-a]pyridine scaffold leading to promising heterocyclic compounds which could be explored further for the synthesis of new derivatives as well as construction of potential drug-like chemical libraries for biological screening in search of new therapeutic agents. PMID- 27237333 TI - Aceclofenac: Species-Dependent Metabolism and Newer Paradigm Shift from Oral to Non-oral Delivery. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are the group of drugs prescribed in various pain related disorders and inflammatory conditions. Diclofenac (DI) is widely prescribed drug for chronic inflammatory conditions like osteoarthritis (OA), a highly prevalent musculoskeletal disorder of adults, projected to affect about 60 million people of total world population by 2020. The chronic oral administration of diclofenac is linked with many gastrointestinal complications like ulceration, bleeding and perforation. These issues paved the way for the development of a structurally similar drug Aceclofenac, which proved to be a safer and more efficient alternative. In spite of better tolerability of Aceclofenac, the oral use of it is not completely free from typical NSAID like side effects. Thus in this context, it becomes mandatory to explore the potential of newer delivery approaches. Amongst the varied newer carrier-systems, microemulsion systems, lipidic colloidal carrier systems and many other supramolecular systems promise to improve the delivery. They tend to place the molecules to the desired target site or in the vicinity without disturbing the unaffected normal surrounding tissues and also ensure enhanced permeation into the skin. The current investigation highlights and deals with the different conventional and novel approaches used thus far in oral delivery of Aceclofenac, their limitations and recent shift towards non oral routes. PMID- 27237334 TI - Benzothiazole Derivatives as Potential Anti-Infective Agents. AB - BACKGROUND: Severity of microbial infections and escalating resistance towards antibiotics has created a deep necessity for discovery of novel anti-infective agents. Heterocyclic chemistry of benzothiazole has become one of the most prolific areas in the field of drug discovery and development that has attracted great attention in recent time due to its increasing importance in the field of pharmaceuticals. METHOD: The importance of benzothiazole and derivatives as potential antimicrobial agents has been well established and a large number of papers have been published in this regard. RESULT: The present communication is an earnest attempt to review the chemistry, synthetic aspects including click chemistry and antimicrobial activities of benzothiazole derivatives reported in recent scientific literature. CONCLUSION: The scientific information of this manuscript may be worthwhile in encouraging the prospective researchers working on this heterocyclic scaffold. PMID- 27237335 TI - Emerging Advances inNanomedicine as aNanoscalePharmacotherapy in Rheumatoid Arthritis: State of the Art. AB - Nanomedicines have been widely investigated for rheumatoid arthritis (RA). There are several significant setbacks including limited bioavailability, high clearance, and further current therapies require higher and frequent dosing to gain desired therapeutic effects. Though, higher doses also increase the incidence of dreadful adverse effects. Further, nanocarrier properties are tuned by the use of different approaches likevaried methods of loading, hydrophilic polymers and targeting ligands, to change the physicochemical properties including higher encapsulation, better penetrating ability to biological barriers, thus preventing the uptake of various nanocarriers by liver and spleen. Along with these they provide longer circulation which enhances drug localization at the inflamed site and selective targeting to enhance the therapeutic index of anti-rheumatic drugs. However, the optimal properties also depend on the route of administration and nanocarrier size, thus larger size show more retention upon local injection and smaller sized ones are more optimal for passive targeting. The present review discusses the emergence of nano-carriers for anti-rheumatic drugs, which delivers drug molecule to the inflamed site by topical, intra articular (i.a) and intra-venous (i.v) administration to achieve therapeutic efficacy by passive and active drug targeting.Advancements have been made extensively but still better investigations are needed to optimize the risk benefit ratio for the development of safe and stable targeting nanocarriers for the effective treatment of rheumatoid arthritis (RA). PMID- 27237336 TI - Are virtual reality technologies effective in improving lower limb outcomes for patients following stroke - a systematic review with meta-analysis. AB - BACKGROUND: Stroke is one of the leading causes of disability worldwide with many survivors restricted to their immediate environment secondary to various impairments. OBJECTIVES: To review existing studies assessing effects of virtual reality (VR) on lower limb outcomes in stroke patients. DATA SOURCES: We searched MEDLINE, CINAHL, EMBASE, PEDro, and Cochrane Library from their beginning to August 2015. Eighteen meta-analyses were performed using weighted mean differences (WMD) and standardized mean differences (SMD) and 95% confidence intervals (CI) to summarize results. STUDY SELECTION: Randomized control trials using VR interventions within adult stroke populations for lower limb outcomes. Trials were screened by two independent authors for eligibility and bias. DATA EXTRACTION: Trials were grouped according to acute-subacute and chronic stroke populations and outcomes were classified as functional balance, static balance, functional gait/mobility, spatiotemporal gait parameters, or motor function. RESULTS: 22 studies with 552 participants were included. Significant differences in favor of VR group were found for functional balance (SMD 0.42, 95% CI 0.11 0.73), gait velocity (WMD 0.12, 95% CI 0.03-0.22), cadence (WMD 11.91, 95% CI 2.05-21.78), and stride length (WMD 9.79, 95% CI 0.74-18.84) within the chronic population. CONCLUSIONS: VR improves functional balance and various aspects of gait in chronic populations. Evidence also suggests that VR is just as effective as conventional therapy, hence its' use in practice is determined by affordability, and patient/practitioner preferences. PMID- 27237337 TI - Natural polysaccharides platforms for oral controlled release of ketoprofen lysine salt. AB - CONTEXT: Ketoprofen lysinate (KL) is one of the most widely used non-steroidal anti-inflammatory drugs in the symptomatic treatment of some chronic inflammatory diseases. Compared to ketoprofen, KL shows better pharmacokinetics and tolerability. However, due to its short half-life of 1-2 h, a multiple dose regimen is required for oral administration. Thus, the present work deals with its encapsulation in a hydrogel-based system by prilling in order to prolong its activity. OBJECTIVE: In this paper, we propose alginate and pectin as carriers and release tailoring agent for the development of hydrogel-based beads for KL retarded and sustained release. MATERIALS AND METHODS: Beads were produced by a Nisco Encapsulator(r) using alginate or pectin. Operative variables were optimized to produce beads with desired morphology and size. Solid state properties were analyzed by SEM and DSC. Drug release performance was studied by Pharmacopeia pH-change assay to simulate gastrointestinal environment. RESULTS AND DISCUSSION: Prilling technique was successfully used to encapsulate high soluble drugs as KL in polysaccharides-based hydrogels. Pectin proved to be a proper polymer able to encapsulate ketoprofen lysine salt. Formulation (F8) showed good morphological properties and size, high drug content (15.6%) and encapsulation efficiency (93.5%) and promising drug release profiles. Hosting F8 in an acid-resistant capsule (DR(r)caps) a delivery platform has been developed to control KL release in a delayed (90 min lag time) and prolonged way (270 min complete release). CONCLUSION: The platform may be proposed as potentially useful in the oral administration of NSAIDs in chronic inflammatory diseases affected by circadian rhythm. PMID- 27237340 TI - Welcome addition. AB - Deputy news editor of Nursing Standard, Nick Lipley, joins the editorial team of Emergency Nurse this month as managing editor. Nick has worked in health journalism for almost ten years and joined RCN Publishing Company Limited in 1998. He will be focusing initially on compiling the Emergency Nurse news section. Readers can contact him with stories or comments on 020 8872 3146 or by email on nick.lipley@rcn.org.uk. PMID- 27237339 TI - Web focus. AB - This regular feature highlights websites with useful information on clinical subjects. This edition focuses on cannulation. PMID- 27237341 TI - Scheme to avert industrial action fails to win over staff sceptics. AB - A L9.5 million A&E modernisation programme starts at The John Radcliffe Hospital, Oxford, this month in a move to ease staff concerns over patient safety. PMID- 27237338 TI - A Plasma-Based Protein Marker Panel for Colorectal Cancer Detection Identified by Multiplex Targeted Mass Spectrometry. AB - INTRODUCTION: Colorectal cancer (CRC) testing programs reduce mortality; however, approximately 40% of the recommended population who should undergo CRC testing does not. Early colon cancer detection in patient populations ineligible for testing, such as the elderly or those with significant comorbidities, could have clinical benefit. Despite many attempts to identify individual protein markers of this disease, little progress has been made. Targeted mass spectrometry, using multiple reaction monitoring (MRM) technology, enables the simultaneous assessment of groups of candidates for improved detection performance. MATERIALS AND METHODS: A multiplex assay was developed for 187 candidate marker proteins, using 337 peptides monitored through 674 simultaneously measured MRM transitions in a 30-minute liquid chromatography-mass spectrometry analysis of immunodepleted blood plasma. To evaluate the combined candidate marker performance, the present study used 274 individual patient blood plasma samples, 137 with biopsy-confirmed colorectal cancer and 137 age- and gender-matched controls. Using 2 well-matched platforms running 5 days each week, all 274 samples were analyzed in 52 days. RESULTS: Using one half of the data as a discovery set (69 disease cases and 69 control cases), the elastic net feature selection and random forest classifier assembly were used in cross-validation to identify a 15-transition classifier. The mean training receiver operating characteristic area under the curve was 0.82. After final classifier assembly using the entire discovery set, the 136 sample (68 disease cases and 68 control cases) validation set was evaluated. The validation area under the curve was 0.91. At the point of maximum accuracy (84%), the sensitivity was 87% and the specificity was 81%. CONCLUSION: These results have demonstrated the ability of simultaneous assessment of candidate marker proteins using high-multiplex, targeted-mass spectrometry to identify a subset group of CRC markers with significant and meaningful performance. PMID- 27237342 TI - Mandatory training urged to tackle violence. AB - Trusts managers have been urged to consider mandatory training of A&E staff faced with a high incidence of patient violence. PMID- 27237343 TI - Deprivation and triage category in children. AB - The purpose of this study was to determine the relation between deprivation category, triage score and A&E attendance for children under the age of 13. A retrospective study of all children attending an A&E department over one year was designed and all children attending the A&E department who had a postcode and a triage score were documented on attendance. Over the 12 months studied, there were 27,965 patients registered as attending A&E for the first time, that is, true 'first attenders'. Of these 26,325 (94 per cent) had reliable triage categories allocated and documented. The postcode was used to determine the deprivation category and the triage scored the severity of illness or injury. PMID- 27237344 TI - Nasal diamorphine better for children following fracture. AB - The objective of this study was to compare the effectiveness of nasal diamorphine spray with intramuscular morphine for analgesia in children and teenagers with acute pain due to a clinical fracture, and to describe the safety profile of the spray. A multicentre randomised controlled trial of emergency departments in eight UK hospitals was undertaken and patients aged between three and 16 years presenting with a clinical fracture of an upper or lower limb participated. PMID- 27237345 TI - The effect of integrating constructivist and evidence-based practice on baccalaureate nursing student's cognitive load and learning performance in a research course. AB - BACKGROUND: Baccalaureate nursing students perceive research as unattractive, doubt the value of nursing research, and do not appreciate the link of research with practice. No studies have examined students' cognitive load during an evidence-based practice research course versus a traditional research course. OBJECTIVES: To assess the effect of integrating constructivist theories and evidence-based practice on student cognitive load and learning performance in a research course. DESIGN: A true experimental study. SETTINGS: A Registered Nurse to-Bachelor of Science in Nursing program. PARTICIPANTS: Six classes of second year students. METHODS: Students were randomly allocated to the control group (two classes) or the experimental group (two classes) using cluster randomization. The control group underwent "traditional research"; the experimental group experienced "integrating evidence-based practice into research." Instruments for outcome assessment include the Cognitive Load Scale, cognitive test, team critique paper, and qualitative feedback on course satisfaction. The between-subjects effects were compared by Analysis of Covariance. RESULTS: The experimental group had significantly higher mental load (8.74 vs. 7.27, p<.001), mental effort (11.07 vs. 10.07, p=.009), mental efficiency (0.33 vs. -0.31, p<.001), and research knowledge (70.61 vs. 44.92, p<.001) than the control group. The experimental group had better critique paper scores in introduction (92.80%), literature review (91.70%), and assignment requirement and writing (89.40%). Some experimental learners expressed satisfaction with learning evidence-based practice (17.78%) and critiquing a research article (7.78%). CONCLUSIONS: Integrating evidence-based practice into a research course not only improved the research knowledge of baccalaureate nursing students, but also increased their mental load, mental effort, and mental efficiency. Additional studies may track learners' responses to different learning systems using the developed instrument to measure the three types of cognitive load. These findings may help educators design more effective and interesting curricula for integrating research and evidence-based practice into the studies of student nurses. PMID- 27237346 TI - The association of nurse educational preparation and patient outcomes: Systematic review and meta-analysis. PMID- 27237347 TI - Barriers and enablers to retention of Aboriginal Diploma of Nursing students in Western Australia: An exploratory descriptive study. AB - BACKGROUND: Nursing education appropriate to the learning needs of Aboriginal and Torres Strait Islander students is essential to prepare them for registration as nurses. Despite incentives to encourage the recruitment and retention of such students, a disproportionate number commence but do not finish their nursing studies. OBJECTIVES: To describe the barriers and enablers to the retention of Aboriginal students in a Diploma of Nursing course (Enrolled/Division 2) in Western Australia. DESIGN: An exploratory descriptive design was used. SETTINGS: One metropolitan educational facility catering for Aboriginal people offering an 18-month course in a block release format. PARTICIPANTS: A convenience sample of 16 students aged 18+years. METHODS: Newly enrolled students (n=10) participated in an investigator-developed survey to explore their motivation for entering the course. Nine of these students and a further seven students who were nearing the end of their course participated in focus groups to explore their experiences of nursing education. RESULTS: Survey respondents had a mean age of 32.7years; most were female, had nominated family as influential in the decision to enroll, and commenced with a friend. Regarding recruitment and retention, the qualitative data highlighted the importance of students': perceptions of the training organisation, characteristics, experiences of nursing education, and sources of support. CONCLUSIONS: Strategies that develop individual's resilience and engage supportive networks can assist Aboriginal students to negotiate tertiary nursing study. Academic skills assessments supplemented with tailored educational support at entry can resource students to navigate increasingly complex course content. Flexibility throughout the course enables students to negotiate study in a context of ongoing family and financial obligations. PMID- 27237348 TI - Does peer-assisted learning improve academic performance? A scoping review. AB - OBJECTIVES: Due to the diverse and ever-changing nature of the healthcare industry, teaching pedagogies such as peer-assisted learning (PAL) are being implemented to align with external competency standards. A scoping review was conducted in order to map the breadth of literature available on PAL and its impact on student performance. METHOD: This review used Arksey and O'Malley's six stage scoping methodology. The databases searched included: Cinahl, Ovid Medline, Proquest and Embase as well as grey literature sites and dissertations. RESULTS: 22 articles were included in this review, 10 of which were mixed methods randomised controlled trials, one retrospective study, four controlled trials, two randomised cross over controlled trial, three prospective randomised controlled trials, one thesis and one comparative research design. Analysis of the included articles identified three major themes outlining student performance. Student teachers themselves showed the most significant improvement in objective outcomes. The predominant healthcare field addressed were medical students with very few studies being completed on other professions. CONCLUSIONS: The search indicated an overall positive response to PAL with the measurable outcome of student tutors being of most significance. Further research is required to determine the relevance for the wider healthcare community. PMID- 27237349 TI - Clinical leadership and pre-registration nursing programmes: A model for clinical leadership and a prospective curriculum implementation and evaluation research strategy. AB - AIM: To present for wider debate a conceptual model for clinical leadership development in pre-registration nursing programmes and a proposed implementation plan. BACKGROUND: Globally, leadership in nursing has become a significant issue. Whilst there is continued support for leadership preparation in pre-registration nursing programmes, there have been very few published accounts of curriculum content and/or pedagogical approaches that foster clinical leadership development in pre-registration nursing. A doctoral research study has resulted in the creation of an overarching model for clinical leadership. DESIGN: A multi-method research study using theoretical and empirical literature 1974-2015, a focus group, expert opinion and a national on-line survey. DISCUSSION: A conceptual model of clinical leadership development in pre-registration nursing programme is presented, including the infinity loop of clinical leadership, an integral curriculum thread and a conceptual model: a curriculum-pedagogy nexus for clinical leadership. In order to test out usability and evaluate effectiveness, a multi method programme of research in one school of nursing in Australia is outlined. CONCLUSION: Implementation of the proposed conceptual model for clinical leadership development in pre-registration nursing programmes and a programme of (post-doctoral) research will contribute to what is known about curriculum content and pedagogy for nurse academics. Importantly, for nursing students and the profession as a whole, there is a clearer expectation of what clinical leadership might look like in the novice registered nurse. For nurse academics a model is offered for consideration in curriculum design and implementation with an evaluation strategy that could be replicated. PMID- 27237350 TI - Rocking the boat - nursing students' stories of moral courage: A qualitative descriptive study. AB - AIM: This paper profiles a qualitative study that examined how undergraduate nursing students demonstrate moral courage when confronted with clinical situations that negatively impact the quality of patient care and/or patient experience and the factors that encouraged or inhibited their willingness to speak up when they identified poor practice. BACKGROUND: Clinical placements are an essential component of nursing programmes. However, placements are a reported source of stress for students, with many witnessing, or feeling compelled to participate in, poor practice. In these instances, nursing students require the moral courage to raise concerns in order to protect patient safety and dignity. METHODS: This was a qualitative descriptive study. Nine nursing students and one nursing graduate from one semi-metropolitan university in Australia were interviewed and the data were thematically analysed. FINDINGS: Four key themes emerged: (1) patient advocate identity, which had two sub-themes of knowing one's own moral code and previous life experiences; (2) consequences to the patient and to the participant; (3) the impact of key individuals; and (4) picking your battles. CONCLUSION: This study demonstrates the importance of undergraduate nursing students identifying as patient advocates, the multitude of consequences students face when questioning the practice of a registered nurse, and the influence supervising nurses and clinical facilitators have on a student's decisions to intervene to protect patient safety. Further research is required to examine the factors, both intrinsic and extrinsic, that influence nursing students' moral courage and their decisions to intervene when poor practice is witnessed. PMID- 27237351 TI - Making it easy to do the right thing in healthcare: Advancing improvement science education through accredited pan European higher education modules. AB - BACKGROUND: Numerous international policy drivers espouse the need to improve healthcare. The application of Improvement Science has the potential to restore the balance of healthcare and transform it to a more person-centred and quality improvement focussed system. However there is currently no accredited Improvement Science education offered routinely to healthcare students. This means that there are a huge number of healthcare professionals who do not have the conceptual or experiential skills to apply Improvement Science in everyday practise. METHODS: This article describes how seven European Higher Education Institutions (HEIs) worked together to develop four evidence informed accredited inter-professional Improvement Science modules for under and postgraduate healthcare students. It outlines the way in which a Policy Delphi, a narrative literature review, a review of the competency and capability requirements for healthcare professionals to practise Improvement Science, and a mapping of current Improvement Science education informed the content of the modules. RESULTS: A contemporary consensus definition of Healthcare Improvement Science was developed. The four Improvement Science modules that have been designed are outlined. A framework to evaluate the impact modules have in practise has been developed and piloted. CONCLUSION: The authors argue that there is a clear need to advance healthcare Improvement Science education through incorporating evidence based accredited modules into healthcare professional education. They suggest that if Improvement Science education, that incorporates work based learning, becomes a staple part of the curricula in inter-professional education then it has real promise to improve the delivery, quality and design of healthcare. PMID- 27237352 TI - eHealth literacy among undergraduate nursing students. AB - BACKGROUND: The Internet has become a major source of health related information. Nursing students, as future healthcare providers, should be skilled in locating, using and evaluating online health information. AIM: The main purpose of this study was to assess eHealth literacy among nursing students in Jordan, as well as to explore factors associated with eHealth literacy. METHODS: A descriptive cross sectional survey was conducted in two universities in Jordan, one public and one private. A total of 541 students completed the eHealth literacy scale (eHEALS). Some additional personal and demographical variables were collected to explore their relation to eHealth literacy. RESULTS: Students have a moderate self perceived level of eHealth literacy (M=3.62, SD=0.58). They are aware of the available online health resources and know how to search, locate, and use these resources. Yet, they lack skills to evaluate them and cannot differentiate between high and low quality resources. Factors that are related to eHealth literacy include type of university, type of student admission, academic level, students' internet skills, and their perception of the usefulness and importance of the internet. On the other hand, age, gender, grade point average (GPA), and frequency of internet use were found not to significantly affect eHealth literacy. CONCLUSION: This study represents a baseline reference for eHealth literacy in Jordan. Students have some of the necessary skills, while others still need to be improved. Nursing educators and administrators should incorporate eHealth literacy skills into the curriculum. PMID- 27237353 TI - Use of videos to support teaching and learning of clinical skills in nursing education: A review. AB - Information and communications technology is influencing the delivery of education in tertiary institutions. In particular, the increased use of videos for teaching and learning clinical skills in nursing may be a promising direction to pursue, yet we need to better document the current research in this area of inquiry. The aim of this paper was to explore and document the current areas of research into the use of videos to support teaching and learning of clinical skills in nursing education. The four main areas of current and future research are effectiveness, efficiency, usage, and quality of videos as teaching and learning materials. While there is a clear need for additional research in the area, the use of videos seems to be a promising, relevant, and increasingly used instructional strategy that could enhance the quality of clinical skills education. PMID- 27237354 TI - Editorial for 35th Anniversary Issue: Nursing Education and 'Room 101'. PMID- 27237355 TI - Teaching students about maternal obesity without creating obesity stigma. PMID- 27237356 TI - Supporting completion of an online continuing professional development programme for newly qualified practitioners: A qualitative evaluation. AB - BACKGROUND: Development programmes to support newly qualified practitioners gain confidence in their first professional role often show varied levels of engagement, due to competing priorities and demands. In Scotland, the Flying Start NHS(r) programme uses a structured programme of online and work-based learning with associated mentoring, to support individuals through an often difficult transition to become capable, confident practitioners. Whilst the programme was generally well received, the factors leading to widely varying completion rates between professions and organisations were not well understood. AIM: The aim of this study was to identify the factors leading to successful completion of Flying Start, a transition programme for newly qualified practitioners. METHOD: A qualitative approach was adopted to gather data from two groups of participants. Semi-structured telephone interviews were conducted with strategic and management level participants (n=23), from five health boards in Scotland. Semi-structured interviews (n=22) and focus groups (n=11) were conducted with practitioners within 6months either side of completing the programme. The interviews were transcribed and analysed using framework analysis. RESULTS: Three key themes relating to successful completion emerged from the analysis: Management and Delivery; Content and Material; Participation and Completion. Factors leading to successful completion were identified at programme, organisational and individual levels. These included clear communication and signposting, up-to-date and relevant content, links with continuing professional development frameworks, effective leadership, mentor and peer support, setting clear standards for assessment, and facilitating appropriate IT access. CONCLUSIONS: A strong strategic commitment to embedding a development programme for newly qualified practitioners can ensure that the necessary support is available to encourage timely completion. The mentor's role to provide face-to-face support - is identified as a key factor in completion and is achieved through setting attainable targets, monitoring progress, and providing motivation. However organisational structures that facilitate the mentoring relationship are also necessary. PMID- 27237357 TI - The influence of perceived prejudice on willingness to be a nurse via the mediating effect of satisfaction with major: A cross-sectional study among chinese male nursing students. AB - BACKGROUND: The gender-based stereotype of nursing as a female profession has been a large obstacle to men entering the nursing profession. However, there is little quantitative research on the influence of prejudice induced by this stereotype on male nursing students' willingness to be nurses. OBJECTIVES: To examine the effect of perceived prejudice on willingness to be a nurse via the mediating effect of satisfaction with major among Chinese male nursing students. DESIGN: A cross-sectional survey was used. METHODS: Four hundred and sixty male nursing students who were enrolled either in bachelor's programs in universities or advanced diploma programs in colleges in Jinan, China, were surveyed using questionnaires measuring perceived prejudice, satisfaction with major, and willingness to be a nurse. Structural equation modeling with bias-corrected bootstrapping was employed to determine the influence of perceived prejudice on willingness to be a nurse with major satisfaction as a mediator. RESULTS: Male students who were in an advanced diploma nursing program and those for whom nursing was the first-choice major reported significantly less perceived prejudice, greater satisfaction with major, and greater willingness to be nurses than did those in a bachelor's nursing program and those for whom nursing was not the first-choice major, respectively. Moreover, although perceived prejudice had no significant direct effect on willingness to be a nurse (beta=0.07, p>0.05), it did have a strong indirect effect (full mediation) via satisfaction with major (beta=-0.59, p<0.001). CONCLUSIONS: Perceived prejudice strongly influenced male nursing students' willingness to be nurses via the full mediating effect of satisfaction with major. Because this obsolete stereotype of nursing as a female occupation gives birth to prejudice against male nursing students, effective measures should be taken to change this stereotype to recruit more men as nursing staff. PMID- 27237358 TI - Review of transnational nursing education programme curricula: process, findings, and recommendations. AB - BACKGROUND: The University of Wollongong (UOW) delivers two Transnational International Programmes (TNEP) in Hong Kong (HK): a 1-year undergraduate Bachelor of Nursing (Conversion) degree and a 2-year postgraduate Master of Nursing degree. A curriculum review of these programmes has been undertaken to ensure the quality of the programme remains consistently high and competitive in an international environment. AIM: The aim of the Curriculum Review Project was to utilise the experience of expert academic staff to review the TNEP curricula delivered by an Australian University in Hong Kong (HK) to ensure it met contemporary needs of students, the university, and the Hong Kong Authority. METHODS: The curriculum review projects followed a qualitative research methodology. Thematic analysis was undertaken utilising Braun and Clarke's six phase method (2006), as this method facilitated an inductive semantic approach where themes are strongly linked to the data and sourced from the explicit meaning of the discourse within the interview (Braun and Clarke, 2006). RESULTS: In total, there were 6 participants who were all permanent academic staff members within the School of Nursing at the UOW. The results of this project have been reported within a strengths, weaknesses, opportunity, and threats (SWOT) framework. Participants recognised the value and challenges to both individual students and the broader nursing profession in HK. Overall, there was a perception that being involved as an academic staff member in a TNEP developed both their subject knowledge and teaching skills. CONCLUSIONS: This project has demonstrated that the TNEP makes an important contribution to the nursing profession in HK, while also facilitating the growth and development of academic staff at UOW. PMID- 27237359 TI - Content and factor validation of the Sieloff-King-Friend Assessment of Group Empowerment within Educational Organizations. AB - BACKGROUND AND PURPOSE: Nursing education programs have responsibilities to their stakeholders to prepare graduates who can provide safe, effective patient centered care while leading health care changes. Empowered nurses have been associated with low nurse turnover and higher patient satisfaction; however, less is currently known about group empowerment in nursing education. In order to examine group empowerment in schools of nursing, the Sieloff-King Assessment of Group Empowerment in Organizations (SKAGEO(c)) was adapted and tested for content validity and confirmatory factor analysis. METHODS/RESULTS: The adapted instrument, the Sieloff-King-Friend Assessment of Group Empowerment within Educational Organizations (SKFAGEEO) was first reviewed by nurse experts who provided quantitative and qualitative data regarding each item. A total of 320 nurse deans and faculty comprised the final sample for the second order confirmatory 8 factor analysis. Findings revealed factor loadings ranging from .455 to .960.The overall fit of the propose model was Chi Square=1383. 24, df=566, p<.001; GFI=.786, RMSEA=0.69. CONCLUSIONS: The study results indicated that the SKFAGEEO has acceptable psychometric properties. PMID- 27237360 TI - RECIST 1.1 - Standardisation and disease-specific adaptations: Perspectives from the RECIST Working Group. AB - Radiologic imaging of disease sites plays a pivotal role in the management of patients with cancer. Response Evaluation Criteria in Solid Tumours (RECIST), introduced in 2000, and modified in 2009, has become the de facto standard for assessment of response in solid tumours in patients on clinical trials. The RECIST Working Group considers the ability of the global oncology community to implement and adopt updates to RECIST in a timely manner to be critical. Updates to RECIST must be tested, validated and implemented in a standardised, methodical manner in response to therapeutic and imaging technology advances as well as experience gained by users. This was the case with the development of RECIST 1.1, where an expanded data warehouse was developed to test and validate modifications. Similar initiatives are ongoing, testing RECIST in the evaluation of response to non-cytotoxic agents, immunotherapies, as well as in specific diseases. The RECIST Working Group has previously outlined the level of evidence considered necessary to formally and fully validate new imaging markers as an appropriate end-point for clinical trials. Achieving the optimal level of evidence desired is a difficult feat for phase III trials; this involves a meta analysis of multiple prospective, randomised multicentre clinical trials. The rationale for modifications should also be considered; the modifications may be proposed to improve surrogacy, to provide a more mechanistic imaging technique, or be designed to improve reproducibility of the imaging biomarker. Here, we present the commonly described modifications of RECIST, each of which is associated with different levels of evidence and validation. PMID- 27237361 TI - Modular construction of multi-subunit protein complexes using engineered tags and microbial transglutaminase. AB - Motivations for the hierarchical assembly of protein complexes are diverse spanning biosensing, biomedical and bioreactor applications. The assembly processes should be simple, scalable, versatile, and biologically benign to minimize loss of component parts. A "plug and play" methodology comprising a generic linking apparatus may enable rapid design and optimization. One application that desires these qualities is metabolon construction wherein multiple enzymes are organized in defined pathways to mediate biochemical flux. Here, we propose a modular design by incorporation of crosslinking-compliant amino acid tags comprised of lysine or glutamine residues at the N- or C-termini of the to-be-assembled proteins. These amino acid tags enable covalent crosslinking using microbial transglutaminase (mTG). Modularity is demonstrated where stoichiometries and relative positions of enzymes and other functional proteins are altered. Construction of multifunctional complexes is demonstrated by crosslinking domains of different function and origin. Namely, we built a two subunit quorum sensing (QS) biosynthetic metabolon on solid supports and altered stoichiometries of the limiting constituents to increase the overall rate of reaction. To display functionality beyond biosynthesis, we constructed a molecular communication 'device' (antibody binding Protein G-QS complex) to target bacterial cells and demonstrated tailored QS responses among targeted bacteria. We propose that this approach, solid phase mTG-mediated linkage of biological components, can be used for assembly within many environments including microreactors or lab-on-a-chip systems. Because the methodology is general, we envision construction of multi-functional protein complexes in a 'plug and play' fashion for a variety of biosensing and synthetic biology applications. PMID- 27237362 TI - [Prognostic factors for in-hospital cardiopulmonary arrests. A review of 760 cases]. AB - BACKGROUND AND OBJECTIVE: The aim of this study is to analyse in-hospital cardiopulmonary arrests (CA) that took place in conventional wards and evaluate their prognostic factors. PATIENTS AND METHOD: Retrospective review of in hospital CA which occurred in our hospital over a 9-year period. CA that took place in intensive care areas, emergency rooms and operating theatres were excluded from the study. The following data were collected: demographic data, cause and initial rhythm of CA, internal control data, time, place, methods and results after cardiopulmonary resuscitation (CPR) (recovery of spontaneous circulation, [ROSC], and survival at discharge [SAD]) and neurologic performance at discharge. Results were analysed with SPSS((r)) v. 20 predictive analytics software. RESULTS: Average age was 66.9+/-17.5 years; 63.5% male. CA team arrived in 1.75+/-0.74min on average, and the average length of CPR was 25.8+/-16.10min. First rhythm: a) shockable rhythms=22.1%; b) asystole=66.2%, and c) pulseless electrical activity=11.7%. ROSC=51% and SAD=24.8%. Factors associated with a better prognostic (P<.05): age, reason for hospital admission, patient's previous physical condition, principal cause of CA, number of defibrillations and average length of CPR. CONCLUSIONS: Despite having studied several variables as prognostic factors for CA and some of them being statistically significant, early prediction for survival for an in-hospital CA remains uncertain. Our study suggests that applying rational organisational measures, 25% of in-hospital CA could be discharged from hospital in good condition, and therefore, these organisational and educational measures should be extended to large hospitals. PMID- 27237363 TI - [Epidemiology of community-acquired severe sepsis. A population-based study]. AB - BACKGROUND AND OBJECTIVE: Most studies aimed at getting to know the incidence of severe sepsis have methodological limitations which condition results that are difficult to compare and are inapplicable when it comes to estimating the necessary resources. Our objective is to evaluate the incidence and epidemiological aspects of community-acquired severe sepsis which require intensive care unit admission. PATIENTS AND METHOD: Prospective observational population-based study in a population of 180,000 adults over 15 years old and a general hospital with 350 beds and 14 ICU beds. All episodes of community acquired infection requiring admission to ICU due to severe sepsis were registered over a period of 9 years. The variables analyzed were: age, sex, SAPS II score, length of stay in ICU, type of infection, isolated microorganism, and deaths during their ICU admission. A statistical bivariate analysis and a multiple logistic regression were performed. RESULTS: Nine hundred and seventeen episodes with an average age of 65.2 years. The most frequent infectious focus was pulmonary (55.2%). The average SAPS II severity score index was 37.87 and mortality 19.7%. The annual incidence was 51.54 episodes per 100,000 adult inhabitants, meaning 1.97 ICU beds per day. In the multivariate analysis, the SAPS II score and a known aetiology were demonstrated as mortality risk factors. CONCLUSIONS: This study brings us some epidemiological data from a population based perspective which help us to care for patients better in our geographical area. The average annual incidence is 51.5 cases per 100,000 adult inhabitants which means that 2 ICU beds per day to attend this population. PMID- 27237364 TI - Trypanosoma brucei Parasites Occupy and Functionally Adapt to the Adipose Tissue in Mice. AB - Trypanosoma brucei is an extracellular parasite that causes sleeping sickness. In mammalian hosts, trypanosomes are thought to exist in two major niches: early in infection, they populate the blood; later, they breach the blood-brain barrier. Working with a well-established mouse model, we discovered that adipose tissue constitutes a third major reservoir for T. brucei. Parasites from adipose tissue, here termed adipose tissue forms (ATFs), can replicate and were capable of infecting a naive animal. ATFs were transcriptionally distinct from bloodstream forms, and the genes upregulated included putative fatty acid beta-oxidation enzymes. Consistent with this, ATFs were able to utilize exogenous myristate and form beta-oxidation intermediates, suggesting that ATF parasites can use fatty acids as an external carbon source. These findings identify the adipose tissue as a niche for T. brucei during its mammalian life cycle and could potentially explain the weight loss associated with sleeping sickness. PMID- 27237365 TI - Immunological Consequences of Intestinal Fungal Dysbiosis. AB - Compared to bacteria, the role of fungi within the intestinal microbiota is poorly understood. In this study we investigated whether the presence of a "healthy" fungal community in the gut is important for modulating immune function. Prolonged oral treatment of mice with antifungal drugs resulted in increased disease severity in acute and chronic models of colitis, and also exacerbated the development of allergic airway disease. Microbiota profiling revealed restructuring of fungal and bacterial communities. Specifically, representation of Candida spp. was reduced, while Aspergillus, Wallemia, and Epicoccum spp. were increased. Oral supplementation with a mixture of three fungi found to expand during antifungal treatment (Aspergillus amstelodami, Epicoccum nigrum, and Wallemia sebi) was sufficient to recapitulate the exacerbating effects of antifungal drugs on allergic airway disease. Taken together, these results indicate that disruption of commensal fungal populations can influence local and peripheral immune responses and enhance relevant disease states. PMID- 27237366 TI - Acute infections, cost and time to reporting of HIV test results in three U.S. State Public Health Laboratories. AB - OBJECTIVE: In three U.S. State Public Health Laboratories (PHLs) using a fourth generation immunoassay (IA), an HIV-1/HIV-2 differentiation antibody IA and a nucleic acid test (NAT), we characterized the yield and time to reporting of acute infections, and cost per positive specimen. METHODS: Routine HIV testing data were collected from July 1, 2012-June 30, 2013 for Massachusetts and Maryland PHLs, and from November 27, 2012-June 30, 2013 for Michigan PHL. Massachusetts and Michigan used fourth-generation and differentiation IAs with NAT conducted by a referral laboratory. In Maryland, fourth-generation IA repeatedly reactive specimens were followed by a Western blot (WB), and those with negative or indeterminate results were tested with a differentiation IA and HIV-1 NAT, and if positive by NAT, confirmed by a different HIV-1 NAT. Specimens from WB-positive persons at risk for HIV-2 were tested with a differentiation IA and, if positive, with an HIV-2 WB and/or differential HIV-1/HIV-2 proviral DNA polymerase chain reaction. RESULTS: Among 7914 specimens from Massachusetts PHL, 6069 from Michigan PHL, and 36,266 from Maryland PHL, 0.10%, 0.02% and 0.05% acute infections were identified, respectively. Massachusetts and Maryland PHLs each had 1 HIV-2 positive specimen. The median time from specimen receipt to laboratory reporting of results for acute infections at Massachusetts, Michigan and Maryland PHLs was 8, 11, and 7 days respectively. The laboratory cost per HIV positive specimen was $336 (Massachusetts), $263 (Michigan) and $210 (Maryland). CONCLUSIONS: Acute and established infections were found by PHLs using fourth generation IA in conjunction with antibody tests and NAT. Time to reporting of acute HIV test results to clients was suboptimal, and needs to be streamlined to expedite treatment and interrupt transmission. PMID- 27237367 TI - Oncogene mutation profiling reveals poor prognosis associated with FGFR1/3 mutation in liposarcoma. AB - Liposarcoma (LPS) is one of the most prevalent soft tissue sarcomas. LPS shows a poor response to radiation and chemotherapy. The causes of death in patients with LPS include locally recurrent and metastatic disease. We sought to examine novel gene mutations and pathways in primary and matched recurrent LPSs to identify potential therapeutic targets. We conducted a high-throughput analysis of 238 known mutations in 19 oncogenes using Sequenom MassARRAY technology. Nucleic acids were extracted from 19 primary and recurrent LPS samples, encompassing 9 dedifferentiated LPSs (DDLPS), 9 myxoid/round cell LPSs, and 1 pleomorphic LPS. Mutation screening revealed missense mutations in 21.1% (4/19) of the LPS specimens, including 4 different genes (FGFR1, FGFR3, PIK3CA, and KIT). Based on histologic subtypes, 22.2% DDLPS (2/9) and 22.2% myxoid cell LPS (2/9) contained gene mutations. Specifically, 3 (23.1%) of 13 primary tumors harbored mutations. Furthermore, although gene mutations were identified in 1 (11.1%) of 9 recurrent LPS samples, the difference between the primary and the recurrence was not statistically significant. Analysis of patient survival data indicated that patients harboring FGFR1/3 mutations experienced reduced overall survival (P<.05). Despite the limited number of samples, our findings provide the first evidence of FGFR1/3 mutations in DDLPS, which were associated with poor clinical outcomes. The FGFR pathway may play an important role in the development and progression of DDLPS and warrants further investigation; moreover, PIK3CA mutation is a common event (11.1%) in myxoid cell LPS. PMID- 27237369 TI - Optical coherence tomography parameters in patients with photosensitive juvenile myoclonic epilepsy. PMID- 27237368 TI - Stratified mucin-producing intraepithelial lesion with invasive carcinoma: 12 cases with immunohistochemical and ultrastructural findings. AB - Stratified mucin-producing intraepithelial lesion (SMILE) is considered to be a variant of adenocarcinoma in situ (defined as intraepithelial malignant glandular epithelium without invasion) or adenosquamous carcinoma in situ of the uterine cervix. However, recent study suggested that SMILE is more similar to high-grade squamous epithelial lesion by their immunohistochemical findings. An invasive form of SMILE "invasive stratified mucin-producing carcinoma (ISMC)" has been also proposed, but immunohistochemical features are not well documented. Therefore, this study aimed to clarify the immunohistochemical characteristics of SMILE and ISMC. Twelve cases of SMILE were found among 445 patients (2.7%) with high-grade intraepithelial lesions or invasive carcinomas, 3 of whom had solely intraepithelial disease with SMILE component (mean age, 37 years; range, 30-48 years) and 9 with invasive carcinomas (mean age, 47 years; range, 37-66 years; including ISMC). Immunohistochemically, SMILE and ISMC were diffusely positive for p16 and CAM5.2, focally for IMP3, and almost negative or only focally positive for p63. Nuclear signals in SMILE and invasive carcinomas were detected by human papillomavirus (HPV) in situ hybridization; 5 cases showed HPV16 and/or HPV18 polymerase chain reaction products. The ultrastructural study of 1 case showed surface microvilli and small vacuolar structure in SMILE; ISMC had mucous like vacuoles, many mitochondria and intracytoplasmic lumen but lacked tonofilament. These findings were more similar to adenocarcinoma in situ or adenocarcinoma than squamous intraepithelial lesion or squamous cell carcinoma. We suggest that SMILE is an intraepithelial neoplasm and ISMC is an invasive form of SMILE. PMID- 27237370 TI - Gemcitabine-oxaliplatin (GEMOX) for epithelial ovarian cancer patients resistant to platinum-based chemotherapy. AB - BACKGROUND: Patients with platinum-resistant epithelial ovarian cancer (EOC) experience poor outcome. Currently, no clearly superior management strategy exists for platinum-resistant EOC patients. PURPOSE: Analyze the efficacy and safety of gemcitabine-oxaliplatin (GEMOX) in platinum resistant EOC patients. PATIENTS AND METHODS: Thirty-two patients with platinum-based resistant EOC were included. Studied patients had received GEM at the dose of 1000mg/m(2) on days 1 and 8 and OX 100mg/m(2) on day 1, administered over 2h 30min after GEM infusion of 3week treatment cycle. RESULTS: In the evaluation of tumor response, none of patients had achieved CR while PR, SD, were observed in 7 (21.9%), 9 (28.1%) respectively, clinical benefit (CR+PR+SD) was recorded in 50% of patients while PD was observed in 16 (50%) patients. In regard to survival, the median value of OS was 10.5months (range, 2.2-17.5months). The median value of PFS was 6.37months (range, 1-17.5months). The one-year OS rate was 34.4% and the one-year PFS rate was 12.5%. Concerning hematological toxicity grade 3 neutropenia was recorded in 4 (12.5%) patients while grade 4 febrile neutropenia was recorded in 2 (6.3%) patients and grade 4 anemia was represented by 3.1%. Grade 1-2 fatigue was the most common non-hematological toxicity and represented by 65.6% of patients. Grade 3 non hematological toxicity was recorded with nausea/vomiting and hepatic toxicity represented by 3.1% for both. CONCLUSION: The GEMOX combination is a regimen with a moderate therapeutic efficacy and tolerable toxic side effects in patients with platinum-resistant EOC. PMID- 27237371 TI - Adding an appropriate amino acid during crosslinking results in more stable crosslinked enzyme aggregates. AB - Carrier free immobilization, especially crosslinked enzyme aggregates (CLEAs), has become an important design for biocatalysis in several areas. Adding amino acids during formation of CLEAs was found to give biocatalysts more stable at 55 degrees C and in the presence of 60% acetonitrile. The half-lives of CLEAs prepared with and without Arg addition were 21 and 15 h (subtilisin) and 4 and 1.6 h (alpha-chymotrypsin) at 55 degrees C, respectively. The corresponding half lives during acetonitrile presence were 4.1 and 3.0 h (subtilisin) and 39 and 22 min (alpha-chymotrypsin), respectively. CLEAs made with Arg had higher percentages of alpha helix. CLEAs made by adding Lys, Ala, or Asp also were more stable. In the case of Thermomyces lanuginosus lipase (TLL), CLEA with Ala was even more stable than CLEA with Arg. The addition of a suitable amino acid, thus, enhances CLEA stabilities. The results are discussed in the light of earlier results on chemical modification of proteins and the observation that the Arg/Lys ratio is invariably high in the case of enzymes from thermophiles. PMID- 27237372 TI - Efficient non-enzymatic cleavage of Staphylococcus aureus plasmid DNAs mediated by neodymium ions. AB - Staphylococcus aureus plasmids are the main factor in the spreading of antibacterial resistance among bacterial strains that has emerged on a worldwide scale. Plasmids recovered from 12 clinical and food isolates of S. aureus were treated with 10 mM free lanthanide Nd(3+) ions (non-enzymatic cleavage agent) in Hepes buffer (pH 7.5) at 70 degrees C. Topological forms of plasmids-closed circular (ccc), open circular (oc), and linear (lin)-produced by cleavage at different times were separated using pulsed-field agarose gel electrophoresis. The method is proposed to detect and differentiate several plasmids in the same bacterial strain according to their size. PMID- 27237373 TI - Comparison and optimization of methods for the simultaneous extraction of DNA, RNA, proteins, and metabolites. AB - The challenge of performing a time-resolved comprehensive analysis of molecular systems has led to the quest to optimize extraction methods. When the size of a biological sample is limited, there is demand for the simultaneous extraction of molecules representing the four areas of "omics": genomics, transcriptomics, proteomics, and metabolomics. Here we optimized a protocol for the simultaneous extraction of DNA, RNA, proteins, and metabolites and compared it with two existing protocols. Our optimization comprised the addition of a methanol/chloroform metabolite purification before the separation of DNA/RNA and proteins. Extracted DNA, RNA, proteins, and metabolites were quantitatively and/or qualitatively analyzed. Of the three methods, only the newly developed protocol yielded all biomolecule classes of adequate quantity and quality. PMID- 27237374 TI - Evidence for the involvement of the CXCL12 system in the adaptation of skeletal muscles to physical exercise. AB - The chemokine CXCL12 and its primary receptor, CXCR4, not only promote developmental myogenesis, but also muscle regeneration. CXCL12 chemoattracts CXCR4-positive satellite cells/blood-borne progenitors to the injured muscle, promotes myoblast fusion, partially with existing myofibers, and induces angiogenesis in regenerating muscles. Interestingly, the mechanisms underlying muscle regeneration are in part identical to those involved in muscular adaptation to intensive physical exercise. These similarities now prompted us to determine whether physical exercise would impact the CXCL12 system in skeletal muscle. We found that CXCL12 and CXCR4 are upregulated in the gastrocnemius muscle of rats that underwent a four-week period of constrained daily running exercise on a treadmill. Double-staining experiments confirmed that CXCL12 and CXCR4 are predominantly expressed in MyHC-positive muscle fibers. Moreover, these training-dependent increases in CXCL12 and CXCR4 expression also occurred in rats with surgical coronary artery occlusion, implying that the muscular CXCL12 system is still active in skeletal myopathy resulting from chronic heart failure. Expression of the second CXCL12 receptor, CXCR7, which presumably acts as a scavenger receptor in muscle, was not affected by training. Attempts to dissect the molecular events underlying the training-dependent effects of CXCL12 revealed that the CXCL12-CXCR4 axis activates anabolic mTOR-p70S6K signaling and prevents upregulation of the catabolic ubiquitin ligase MurF-1 in C2C12 myotubes, eventually increasing myotube diameters. Together, these findings point to a pivotal role of the CXCL12-CXCR4 axis in exercise-induced muscle maintenance and/or growth. PMID- 27237375 TI - Isolation and characterization of the corticotropin-releasing factor-related diuretic hormone receptor in Rhodnius prolixus. AB - Rhodnius prolixus, the vector of human Chagas disease, is a hemipteran insect that undergoes rapid post-feeding diuresis following ingestion of a blood meal that can be up to 10 times its initial body weight. Corticotropin-releasing factor-related diuretic hormone (Rhopr-CRF/DH) and serotonin are neurohormones that are synergistic in increasing rates of fluid secretion by Malpighian tubules during this rapid post-feeding diuresis. A Rhopr-CRF/DH receptor transcript has now been isolated and characterized from fifth instar R. prolixus. The receptor is a family B1 (secretin) G protein-coupled receptor (GPCR) and was deorphaned in a heterologous cellular system using Chinese hamster ovary (CHO) cells stably expressing a promiscuous G-protein (Galpha16). This assay was also used to demonstrate the presence of Rhopr-CRF/DH in the haemolymph of R. prolixus in response to blood-gorging. Two additional cell lines were used in this heterologous assay to verify that the cyclic adenosine monophosphate (cAMP) pathway and not the inositol triphosphate (IP3) pathway was stimulated upon activation of the receptor. Lastly, quantitative PCR demonstrated strong receptor expression in digestive tissues, upper Malpighian tubules and reproductive tissues. Identification of the Rhopr-CRF/DH receptor now provides tools for a more detailed understanding into the precise coordination of diuresis and other physiological processes in R. prolixus. PMID- 27237377 TI - Kruppel-like Factor 4 Modulates Development of BMI1(+) Intestinal Stem Cell Derived Lineage Following gamma-Radiation-Induced Gut Injury in Mice. AB - In response to ionizing radiation-induced injury, the normally quiescent intestinal stem cells marked by BMI1 participate in the regenerative response. Previously, we established a protective role for Kruppel-like factor 4 (KLF4) in the intestinal epithelium where it reduces senescence, apoptosis, and crypt atrophy following gamma-radiation-induced gut injury. We also described a pro proliferative function for KLF4 during the regenerative phase post irradiation. In the current study, using a mouse model in which Klf4 is deleted from quiescent BMI1(+) intestinal stem cells, we observed increased proliferation from the BMI1(+) lineage during homeostasis. In contrast, following irradiation, Bmi1 specific Klf4 deletion leads to decreased expansion of the BMI1(+) lineage due to a combination of reduced proliferation and increased apoptosis. Our results support a critical role for KLF4 in modulating BMI1(+) intestinal stem cell fate in both homeostasis and the regenerative response to radiation injury. PMID- 27237376 TI - H1foo Has a Pivotal Role in Qualifying Induced Pluripotent Stem Cells. AB - Embryonic stem cells (ESCs) are a hallmark of ideal pluripotent stem cells. Epigenetic reprogramming of induced pluripotent stem cells (iPSCs) has not been fully accomplished. iPSC generation is similar to somatic cell nuclear transfer (SCNT) in oocytes, and this procedure can be used to generate ESCs (SCNT-ESCs), which suggests the contribution of oocyte-specific constituents. Here, we show that the mammalian oocyte-specific linker histone H1foo has beneficial effects on iPSC generation. Induction of H1foo with Oct4, Sox2, and Klf4 significantly enhanced the efficiency of iPSC generation. H1foo promoted in vitro differentiation characteristics with low heterogeneity in iPSCs. H1foo enhanced the generation of germline-competent chimeric mice from iPSCs in a manner similar to that for ESCs. These findings indicate that H1foo contributes to the generation of higher-quality iPSCs. PMID- 27237379 TI - New trends and challenges in the European regulation of innovative medicines. AB - Regulators' marketing authorizations for innovative medicines are linked into a complex process with successive crucial decisions. Objectives and decision criteria of the stakeholders in this process, e.g. health technology assessment (HTA) bodies, payers, physicians and patients, vary and may result not only in different but even mutually exclusive requirements. Reacting to changes in scientific, economic and social demands, European regulatory agencies alter content and format of their assessment procedures and their communication. New diagnostic options (e.g. genotyping and biomarkers) and pharmaceutical innovations (e.g. targeted medicines, nanomedicines) are the scientific drivers of this development. Social drivers are the price and reimbursement decisions by HTA bodies and payers, prerequisites for most patients' access to innovative medicines. The European Medicines Agency's adaptive licensing concept and priority medicines scheme foster the early authorization of innovative medicines. HTA builds on regulators' assessment, with additional requirements and economic components. An intensified exchange between all stakeholders, e.g. in multilateral scientific advice procedures has been initiated. Diminishing the differences in the requirements of regulators and HTA bodies is in the best interest of both patients and the pharmaceutical industry, avoiding duplication of work and accelerating patients' access by early decisions on price and reimbursement. PMID- 27237378 TI - Loss of Asxl1 Alters Self-Renewal and Cell Fate of Bone Marrow Stromal Cell, Leading to Bohring-Opitz-like Syndrome in Mice. AB - De novo ASXL1 mutations are found in patients with Bohring-Opitz syndrome, a disease with severe developmental defects and early childhood mortality. The underlying pathologic mechanisms remain largely unknown. Using Asxl1-targeted murine models, we found that Asxl1 global loss as well as conditional deletion in osteoblasts and their progenitors led to significant bone loss and a markedly decreased number of bone marrow stromal cells (BMSCs) compared with wild-type littermates. Asxl1(-/-) BMSCs displayed impaired self-renewal and skewed differentiation, away from osteoblasts and favoring adipocytes. RNA-sequencing analysis revealed altered expression of genes involved in cell proliferation, skeletal development, and morphogenesis. Furthermore, gene set enrichment analysis showed decreased expression of stem cell self-renewal gene signature, suggesting a role of Asxl1 in regulating the stemness of BMSCs. Importantly, re introduction of Asxl1 normalized NANOG and OCT4 expression and restored the self renewal capacity of Asxl1(-/-) BMSCs. Our study unveils a pivotal role of ASXL1 in the maintenance of BMSC functions and skeletal development. PMID- 27237380 TI - Advantages of using an abbreviated dossier for drug master file applications in Taiwan. AB - In Taiwan, the quality of active pharmaceutical ingredients is recorded in a drug master file (DMF), the applications for which can be submitted in two dossier types, either full (complete technical information) or abbreviated (partially complete technical information with an approved document issued by developed countries). However, the advantages of the abbreviated approach remain unknown. This study compared full and abbreviated dossier profiles and reviewed their outcomes in acceptance rates and deficiencies leading to rejection. Data were collected from new submissions of both dossier types that were completed in 2014 by the Center for Drug Evaluation, Taiwan. The results revealed that the abbreviated applications took shorter review time and had a higher acceptance rate. Among the eligible types of document for abbreviated applications, Certification of Suitability to the Monographs of the European Pharmacopeia (CEP) was the most frequently used. For categorical deficiencies, both dossier types presented the deficiencies in similar sections leading to rejection, namely Manufacture (3.2.S.2), Control of drug substance (3.2.S.4), and Stability (3.2.S.7). In summary, CEP serves a favorable document for the abbreviated DMF application in which it shortens the review time, increases the acceptance rate, and its deficiencies are similar to those of the full DMF application. PMID- 27237381 TI - [The history of pediatric plastic surgery]. AB - The history of pediatric plastic surgery is linked to that of paediatrics. Until the early 19th century, there was no children's hospital. Only some operations were performed before the discovery of anesthesia, aseptic and antisepsis: cleft lip repair, amputation for polydactyly. Many operations were described in the 19th century for cleft lip and palate repair, hypospadias, syndactylies. The first operation for protruding ears was performed in 1881. Pediatric plastic surgery is diversified in the 2nd half of the 20th century: cleft lip and palate, burns, craniofacial surgery, hand surgery become separate parts of the speciality. PMID- 27237383 TI - Interaction between renal function and percutaneous edge-to-edge mitral valve repair using MitraClip. AB - BACKGROUND: MitraClip (MC; Abbott Vascular, Menlo Park, CA, USA) is a treatment option for mitral regurgitation. Renal dysfunction is closely associated with cardiovascular disease. However, the influence of renal function in MC remains not fully understood. In this study, we aimed to clarify the association between renal function and MC. METHODS AND RESULTS: We examined 206 consecutive patients who underwent MC and divided patients into 3 groups according to estimated glomerular filtration rate (eGFR), normal eGFR (>=60mL/min/1.73m2) (n=70), mild chronic kidney disease (CKD) (30-59mL/min/1.73m2) (n=106), and severe CKD (<30mL/min/1.73m2) (n=30). N-terminal pro-B type natriuretic peptide (NT-pro BNP) levels increased with decreasing eGFR. Kaplan-Meier curves revealed that the long term survival rate significantly decreased with eGFR. After adjustment with the covariates, severe CKD was still associated with mortality. Improved renal function was observed in 30% and associated with baseline lower NT-pro BNP levels. Patients with improved renal function had higher chronic phase survival rate. CONCLUSION: Renal dysfunction is common in MC patients and the survival rate decreased with eGFR in association with increased NT-pro BNP levels. MC may improve renal function in approximately 30% of MC patients. Improved renal function is associated with lower NT-pro BNP levels and results in satisfactory prognosis. These results implies a close association between renal function and MC treatment. PMID- 27237382 TI - Damage in total knee replacements from mechanical overload. AB - The mechanical loads acting across the knee joint following total knee replacements (TKR) during activities of daily living have recently been measured using instrumented TKRs. Using a series of postmortem retrieved TKR constructs we investigated whether these mechanical loads could result in damage to the implant bone interface or supporting bone in the tibia. Eighteen cemented en bloc tibial components (0 to 22 years in service) were loaded under axial compression in increments from 1 to 10 times body weight and digital image correlation was used to measure bone strain and interface micromotion during loading and unloading. Failure was considered to occur when micromotion exceeded 150um or compressive bone strain exceeded 7300MUepsilon. The results show that all retrieved specimens had sufficient bone strength to support most activities of daily living, but ~40% would be at risk under larger physiologic loads that might occur secondary to a higher impacts such as jogging or a stumble. The tray-bone micromotion (regression model R(2)=0.48, p=0.025) was greater for donors with lower age at implantation (p=0.0092). Proximal bone strain (model R(2)=0.46, p=0.03) was greater for donors with longer time in service (p=0.021). Distal bone strain (model R(2)=0.58, p=0.005) was greater for donors with more time in service (p=0.0054) and lower peri-implant BMD (p=0.049). High mechanical overload of a single or repetitive nature may be an initiating factor in aseptic loosening of total joint arthroplasties and should be avoided in order to prolong the life of the implant. PMID- 27237385 TI - Description of an outbreak of highly pathogenic avian influenza in domestic ostriches (Struthio camelus) in South Africa in 2011. AB - In 2011, the commercial ostrich production industry of South Africa experienced an outbreak of highly pathogenic avian influenza (HPAI), subtype H5N2. Surveillance using antibody and antigen detection revealed 42 infected farms with a between-farm prevalence in the affected area of 16%. The outbreak was controlled using depopulation of infected farms, resulting in the direct loss of 10% of the country's domestic ostrich population. Various factors in the ostrich production system were observed that could have contributed to the spread of the virus between farms, including the large number of legal movements of ostriches between farms, access of wild birds to ostrich camps and delays in depopulation of infected farms. Negative effects on the ostrich industry and the local economy of the ostrich-producing area were observed as a result of the outbreak and the disease control measures applied. Prevention and control measures applied as a result of avian influenza in South Africa were informed by this large outbreak and the insights into epidemiology of avian influenza in ostriches that it provided, resulting in stricter biosecurity measures required on every registered ostrich farm in the country. PMID- 27237384 TI - Sero-survey of Avian Influenza in backyard poultry and wild bird species in Iran 2014. AB - In almost all villages in Iran backyard birds, especially chickens, are kept for egg and meat production. AI H9N2 subtype is endemic in Iran. Therefore, estimation of AI prevalence among these birds is important to determine the risk of transmission of infection to commercial farms. The aim of this study was to estimate subclinical infections or previous exposure to H5, H7, and H9 subtypes and to identify potentially important determinants of prevalence of this infectious at premises level in backyard poultry, bird gardens, zoos, and wild bird markets in Iran. A survey was conducted using a cross-sectional design throughout the entire country. A total of 329 villages, seven bird gardens, three zoos and five wild bird markets were included. In each village four families that kept birds were included in the collection of biological samples and background information. The Enzyme-Linked Immunosorbent Assay (ELISA) was used as the screening test and all ELISA-positive samples were examined with the HI test to differentiate H5, H7, and H9. Among the bird gardens, eight of 15 premises (53.3%) were positive in both the ELISA test and HI for H9N2. Testing of samples collected in the villages revealed that 296 out of 329 villages (90%) had positive ELISA tests and also HI tests for H9. The HI-H9 mean titers in positive units were significantly higher than negative units (P<.001). This study revealed no significant statistical differences between risk variables in seropositive and seronegative bird gardens in the case of H9 (P>.05). The results of this study showed that among the risk variables, mountainous area was a protective factor and lack of hygienic disposal of dead birds was a risk factor for AI; this was also observed in rural poultry. The high sero-prevalence of influenza H9N2 in rural domestic poultry indicates that the disease is endemic. It is necessary to include backyard poultry in any surveillance system and control strategy due to the existence of AIV in backyard poultry and the possibility of transmission of infection to commercial poultry farms. Implementation of an AI surveillance program and biosecurity measures can be useful to control this infection and prevent AI from spreading to commercial farms. Furthermore in Iran there is no program for destruction of birds infected with the H9N2, so an effective vaccination program with regard to issues such as acceptability and cost-benefit must play an important role in reducing infections in backyard poultry. PMID- 27237386 TI - A participatory approach to design monitoring indicators of production diseases in organic dairy farms. AB - Production diseases have an important negative effect on the health and welfare of dairy cows. Although organic animal production systems aim for high animal health levels, compliance with European organic farming regulations does not guarantee that this is achieved. Herd health and production management (HHPM) programs aim at optimizing herd health by preventing disease and production problems, but as yet they have not been consistently implemented by farmers. We hypothesize that one reason is the mismatch between what scientists propose as indicators for herd health monitoring and what farmers would like to use. Herd health monitoring is a key element in HHPM programs as it permits a regular assessment of the functioning of the different components of the production process. Planned observations or measurements of these components are indispensable for this monitoring. In this study, a participatory approach was used to create an environment in which farmers could adapt the indicators proposed by scientists for monitoring the five main production diseases on dairy cattle farms. The adaptations of the indicators were characterized and the farmers' explanations for the changes made were described. The study was conducted in France and Sweden, which differ in terms of their national organic regulations and existing advisory services. In both countries, twenty certified organic dairy farmers and their animal health management advisors participated in the study. All of the farmers adapted the initial monitoring plan proposed by scientists to specific production and animal health situation on their farm. This resulted in forty unique and farm-specific combinations of indicators for herd health monitoring. All but three farmers intended to monitor five health topics simultaneously using the constructed indicators. The qualitative analysis of the explanations given by farmers for their choices enabled an understanding of farmers' reasons for selecting and adapting indicators. This is valuable information for scientists involved in the design of HHPM programs. Advisors in the field also can benefit from this participatory approach because it transforms monitoring tools provided by scientists into farm-specific tools. PMID- 27237388 TI - Evaluation of two methodologies for lameness detection in dairy cows based on postural and gait abnormalities observed during milking and while restrained at headlock stanchions. AB - Lameness is a critical issue on dairies with an impact on production and animal welfare. Early lameness detection followed by effective treatments could improve prognosis and cure rate of lame cows. Current methods for lameness detection are based on locomotion score (LS) that requires observation of cows walking, preferably at the exit of the milking parlor. This is a time-consuming task that is difficult to implement on large dairies. Therefore, a common methodology for lameness detection is based on milkers' and cow pushers' observations of cows walking to the milking parlor or standing at the milking stall (MPP). Observation of postural abnormalities predictive of lameness while cows are locked at stanchions (S) can be used as an alternative detection method. The objective of this research was to study the association between postural and gait abnormalities observed with S and MPP methodologies and lameness using LS>=3 as the reference method, as well as to evaluate the epidemiological characteristics of those methods as a diagnostic test for lameness. A secondary objective was to describe the type of hoof lesions observed with postural and gait abnormalities detected with LS, MPP, and S methodologies. A cross-sectional study design was performed on 2274 cows from one farm in California (US). Arched back, cow-hocked, wide-stance, and favored-limb postures as well as uneven gait were observed. Both lameness detection methodologies, S and MPP, indicated that arched back and favored-limb were postural abnormalities associated with lameness. However, the epidemiological test characteristics for each of the postures evaluated as a diagnostic test for lameness indicated that both detection methods, S and MPP, had good specificity (>0.91) but poor sensitivity (0.04-0.39). A convenience sample of 104 cows, selected based on LS>3, favored-limb, presence of two or more abnormal postures, and gait anomalies with either S or MPP methods, received a hoof examination. Lesions were observed on cows selected by LS (17/24), MPP (21/30), and S (33/60) criteria, suggesting a lack of concordance between lameness detection methodologies and visible hoof lesions. Nevertheless, due to the lack of acceptance of LS as the lameness detection method on large commercial dairies in California, it is imperative that future research evaluates modifications of S and MPP lameness detection techniques, considering hoof lesion as reference method. PMID- 27237387 TI - Associations between feedlot management practices and bovine respiratory disease in Australian feedlot cattle. AB - Bovine respiratory disease (BRD) is the major cause of clinical disease and death in feedlot cattle. A prospective longitudinal study was conducted in a population of Australian feedlot cattle to assess associations between factors related to feedlot management and risk of BRD. In total, 35,131 animals in 170 pens (cohorts) inducted into 14 feedlots were included in statistical analyses. Causal diagrams were used to inform model building to allow separate estimation of total and direct effects. Multilevel mixed effects logistic regression models were fitted within the Bayesian framework. The placement of pen water troughs such that they could be accessed by animals in adjoining pens was associated with markedly increased risk of BRD (OR 4.3, 95% credible interval: 1.4-10.3). Adding animals to pens over multiple days was associated with increased risk of BRD across all animals in those pens compared to placing all animals in the pen on a single day (total effect: OR 1.9, 95% credible interval: 1.2-2.8). The much attenuated direct effect indicated that this was primarily mediated via factors on indirect pathways so it may be possible to ameliorate the adverse effects of adding animals to pens over multiple days by altering exposure to these intervening factors (e.g. mixing history). In pens in which animals were added to the pen over multiple days, animals added >=7 days (OR: 0.7, credible interval: 0.5-0.9) or 1-6 days (OR: 0.8, credible interval: 0.7-1.0) before the last animal was added were at modestly reduced risk of BRD compared to the animals that were added to the pen on the latest day. Further research is required to disentangle effects of cohort formation patterns at animal-level and higher levels on animal level risk of BRD. Vaccination against Bovine herpesvirus 1 at feedlot entry was investigated but results were inconclusive and further research is required to evaluate vaccine efficacy. We conclude that there are practical interventions available to feedlot managers to reduce the risk of cattle developing BRD at the feedlot. We recommend placement of water troughs in feedlot pens so that they cannot be accessed by animals in adjoining pens. Further research is required to identify practical and cost-effective management strategies that allow longer adaption times for cattle identified prior to induction as being at higher risk of developing BRD. PMID- 27237389 TI - Network, cluster and risk factor analyses for porcine reproductive and respiratory syndrome using data from swine sites participating in a disease control program. AB - The objectives of this study were to describe networks of Ontario swine sites and their service providers (including trucking, feed, semen, gilt and boar companies); to categorize swine sites into clusters based on site-level centrality measures, and to investigate risk factors for porcine reproductive and respiratory syndrome (PRRS) using information gathered from the above-mentioned analyses. All 816 sites included in the current study were enrolled in the PRRS area regional control and elimination projects in Ontario. Demographics, biosecurity and network data were collected using a standardized questionnaire and PRRS status was determined on the basis of available diagnostic tests and assessment by site veterinarians. Two-mode networks were transformed into one mode dichotomized networks. Cluster and risk factor analyses were conducted separately for breeding and growing pig sites. In addition to the clusters obtained from cluster analyses, other explanatory variables of interest included: production type, type of animal flow, use of a shower facility, and number of neighboring swine sites within 3km. Unadjusted univariable analyses were followed by two types of adjusted models (adjusted for production systems): a generalizing estimation equation model (GEE) and a generalized linear mixed model (GLMM). Results showed that the gilt network was the most fragmented network, followed by the boar and truck networks. Considering all networks simultaneously, approximately 94% of all swine sites were indirectly connected. Unadjusted risk factor analyses showed significant associations between almost all predictors of interest and PRRS positivity, but these disappeared once production system was taken into consideration. Finally, the vast majority of the variation on PRRS status was explained by production system according to GLMM, which shows the highly correlated nature of the data, and raises the point that interventions at this level could potentially have high impact in PRRS status change and/or maintenance. PMID- 27237390 TI - Estimating sensitivity and specificity of a PCR for boot socks to detect Campylobacter in broiler primary production using Bayesian latent class analysis. AB - The present study compares three different assays for sample collection and detection of Campylobacter spp. in broiler flocks, based on (i) the collection of faecal samples from intestinal organs (caecum), (ii) individual faecal droppings collected from the bedding and (iii) faecal material collected by socks placed on the outside of a pair of boots (boot socks) and used for walking around in the flock. The two first methods are examined for Campylobacter using a culture method (ISO-10272-2:2006), while the boot socks are tested using PCR. The PCR assay is a genus specific multiplex PCR with primers targeting 16S rDNA in Campylobacter and primers targeting Yersinia ruckerii. Sixty-seven broiler flocks from Austria and 83 broiler flocks from Denmark were included in this prospective study and 89 of these were found to be positive in at least one method (AT: 49 samples, DK: 40 samples) whereas 61 of these were negative in all assays. In Austria samples for the three assays were collected simultaneously, which facilitates a direct comparison of the diagnostic test performance. In Denmark, however, boot socks and faecal droppings were collected three days before slaughter while caecum samples were collected at slaughter. The results were evaluated in the absence of a gold standard using a Bayesian latent class model. Austrian results showed higher sensitivity for PCR detection in sock samples (0.98; Bayesian credible interval (BCI) [0.93-1]) than for culture of faecal droppings (0.86; BCI [0.76-0.91]) or caecal samples (0.92; BCI [0.85-0.97]). The potential impact of Campylobacter introduction within the final three days before slaughter was observed in Denmark, where four flocks were tested negative three days before slaughter, but were detected positive at the slaughterhouse. Therefore the model results for the PCR sensitivity (0.88; BCI [0.83-0.97]) and cultural ISO-method in faecal samples (0.84; BCI [0.76-0.92]) are lower than for caecal samples (0.93; BCI [0.85-0.98]). In our study, PCR detection on boot sock samples is more sensitive than conventional culture. In view of the advantage of rapid results before slaughter and low costs for sampling, especially in combination with existing Salmonella surveillance systems (just another pair of boot socks needed), this method-matrix combination could be a valuable surveillance tool in the broiler primary production. PMID- 27237391 TI - A real options approach to biotechnology investment policy-the case of developing a Campylobacter vaccine to poultry. AB - The aim of the article is to identify and analyse public-private incentives for the development and marketing of new animal vaccines within a real options methodological framework, and to investigate how real options methodology can be utilized to support economic incentives for vaccine development in a cost effective way. The development of a vaccine against Campylobacter jejuni in poultry is applied as a case study. Employing the real options methodology, the net present value of the vaccine R&D project becomes larger than a purely probabilistic expected present value throughout the different stages of the project - and the net present value becomes larger, when more types of real options are taken into consideration. The insight from the real options analysis reveals opportunities for new policies to promote the development of animal vaccines. One such approach might be to develop schemes combining stage-by-stage optimized subsidies in the individual development stages, with proper account taken of investors'/developers' economic incentives to proceed, sell or cancel the project in the respective stages. Another way of using the real options approach to support the development of desirable animal vaccines could be to issue put options for the vaccine candidate, enabling vaccine developers to hedge against the economic risk from market volatility. PMID- 27237392 TI - Use of a multiple choice questionnaire to assess UK prescribing channels' knowledge of helminthology and best practice surrounding anthelmintic use in livestock and horses. AB - Grazing livestock and equines are at risk of infection from a variety of helminths, for which the primary method of control has long been the use of anthelmintics. Anthelmintic resistance is now widespread in a number of helminth species across the globe so it is imperative that best practice control principles be adopted to delay the further spread of resistance. It is the responsibility of all who prescribe anthelmintics (in the UK, this being veterinarians, suitably qualified persons (SQPs) and pharmacists) to provide adequate information on best practice approaches to parasite control at the point of purchase. Poor uptake of best practice guidelines at farm level has been documented; this could be due to a lack of, or inappropriate, advice at the point of anthelmintics purchase. Therefore, the aim here was to evaluate levels of basic knowledge of helminthology, best practice guidelines and dispensing legislation among veterinarians and SQPs in the UK, through a Multiple Choice Question (MCQ) test, that was distributed online via targeted emails and social media sites. For each respondent, the percentage correct was determined (for the MCQ test overall and for subsections) and the results analysed initially using parametric and non-parametric statistics to compare differences between prescribing channels. The results showed that channels generally performed well; veterinarians achieved a mean total percentage correct of 79.7% (range 34.0-100%) and SQPs, a mean total percentage correct of 75.8% (range 38.5-100%) (p=0.051). The analysis indicated that veterinarians performed better in terms of knowledge of basic helminthology (p=0.001), whilst the SQP group performed better on legislation type questions (p=0.032). There was no significant difference in knowledge levels of best practice between the two channels. Multivariable linear regression analysis showed that veterinarians and those answering equine questions only performed significantly better than those answering all questions. Based on information gaps identified by analysis of individual questions, a number of areas for improvement in knowledge transfer to both channels are suggested to improve the quality of advice at the point of anthelmintics purchase. PMID- 27237393 TI - Comparison of alternatives to passive surveillance to detect foot and mouth disease incursions in Victoria, Australia. AB - This study aimed to evaluate strategies to enhance the early detection of foot and mouth disease incursions in Australia. Two strategies were considered. First, improving the performance of the current passive surveillance system. Second, supplementing the current passive system with active surveillance strategies based on testing animals at saleyards or through bulk milk testing of dairy herds. Simulation modelling estimated the impact of producer education and awareness by either increasing the daily probability that a farmer will report the presence of diseased animals or by reducing the proportion of the herd showing clinical signs required to trigger a disease report. Both increasing the probability of reporting and reducing the proportion of animals showing clinical signs resulted in incremental decreases in the time to detection, the size and the duration of the outbreak. A gold standard system in which all producers reported the presence of disease once 10% of the herd showed clinical signs reduced the median time to detection of the outbreak from 20 to 15days, the duration of the subsequent outbreak from 53 to 42days and the number of infected farms from 46 to 32. Bulk milk testing reduced the median time to detection by two days and the number of infected farms by six but had no impact on the duration of the outbreak. Screening of animals at saleyards provided no improvement over the current passive surveillance system alone while having significant resource issues. It is concluded that the most effective way to achieve early detection of incursions of foot and mouth disease into Victoria, Australia is to invest in improving producer reporting. PMID- 27237394 TI - Comparison of risk-based versus random sampling in the monitoring of antimicrobial residues in Danish finishing pigs. AB - In Denmark, a monitoring program for residues of antimicrobials in pork is in place involving annual testing of around 20,000 samples from finishing pigs corresponding to 0.1% of the animals slaughtered. Annually, zero to two samples are found above the maximum residue limit. Both authorities and industry have expressed interest in adjusting the monitoring to a risk-based system. The objective of this study was to assess the opportunities and consequences of the monitoring considering: 1) replacing the current bioassay with high-performance liquid chromatography-mass spectrometry (HPLC LC-MS/MS), 2) replacing kidney with muscles as sample matrix, and 3) using indicators to identify high-risk (HR) herds and increase sampling intensity in these herds, lowering sampling in the low-risk (LR) herds, while aiming at continued detection of similar numbers of test-positives at the lowest possible costs. A state-of-the-art stochastic scenario tree modelling approach including economic evaluation of different model outcomes was used. A total of six scenarios were run for penicillin and tetracycline, respectively. Relevant information was obtained through the literature, statistical analysis of existing data as well as consultations with laboratory and slaughterhouse experts. Abattoir recordings of chronic pleuritis were used as an indicator for finishing pig herds (HR=within-herd prevalence>40%). Such risk-based monitoring would have to use muscles and not kidneys, because of logistic challenges in identifying and storing of plucks until testing. However, the bioassay cannot be used on muscle tissue due to low sensitivity for tetracyclines. Different plausible combinations of sample sizes were also modelled. The HPLC LC-MS/MS method detected the same number of cases compared to the bioassay when kidney was used as matrix. HPLC LC-MS/MS has a higher sensitivity when used on muscle but it is almost twice as costly as the bioassay. Risk-based sampling resulted in detection of more residue cases with higher cost-effectiveness than random monitoring. Sampling 7500 HR pigs and 5000 LR pigs resulted in the most cost-effective monitoring among the alternative scenarios. The associated costs would increase by 4%. A scenario involving testing of 5000 HR and 5000 LR animals would result in slightly fewer positives, but 17% savings in costs. The advantages of using HPLC LC-MS/MS compared to the bioassay are a fast response and a high sensitivity for all relevant substances used in pigs. The Danish abattoir companies have implemented a risk-based monitoring similar to the above per January 2016. PMID- 27237395 TI - Bayesian estimation of prevalence of paratuberculosis in dairy herds enrolled in a voluntary Johne's Disease Control Programme in Ireland. AB - Bovine paratuberculosis is a disease characterised by chronic granulomatous enteritis which manifests clinically as a protein-losing enteropathy causing diarrhoea, hypoproteinaemia, emaciation and, eventually death. Some evidence exists to suggest a possible zoonotic link and a national voluntary Johne's Disease Control Programme was initiated by Animal Health Ireland in 2013. The objective of this study was to estimate herd-level true prevalence (HTP) and animal-level true prevalence (ATP) of paratuberculosis in Irish herds enrolled in the national voluntary JD control programme during 2013-14. Two datasets were used in this study. The first dataset had been collected in Ireland during 2005 (5822 animals from 119 herds), and was used to construct model priors. Model priors were updated with a primary (2013-14) dataset which included test records from 99,101 animals in 1039 dairy herds and was generated as part of the national voluntary JD control programme. The posterior estimate of HTP from the final Bayesian model was 0.23-0.34 with a 95% probability. Across all herds, the median ATP was found to be 0.032 (0.009, 0.145). This study represents the first use of Bayesian methodology to estimate the prevalence of paratuberculosis in Irish dairy herds. The HTP estimate was higher than previous Irish estimates but still lower than estimates from other major dairy producing countries. PMID- 27237396 TI - Spatially explicit modeling of animal tuberculosis at the wildlife-livestock interface in Ciudad Real province, Spain. AB - Eurasian wild boar (Sus scrofa) and red deer (Cervus elaphus) are the most important wildlife reservoirs for animal tuberculosis (TB) caused by the Mycobacterium tuberculosis complex (MTC), in Mediterranean Spain. These species are considered to play an important role in the transmission and persistence of MTC in cattle in some regions; however the factors contributing to the risk of transmission at the wildlife-livestock interface and the areas at highest risk for such transmission are largely unknown. This study sought to identify geographic areas where wildlife-livestock interactions are most likely to occur and to characterize the environmental and management factors at this interface contributing to persistence, incidence, and occurrence of TB on cattle farms, in one of the provinces with higher TB prevalence in Spain, Ciudad Real. We used spatially explicit, ecological niche models to evaluate the importance of factors such as wildlife demographics and hunting management, land use, climatic, and environmental variables as well as TB status in wildlife for TB breakdown (model 1), persistence (model 2) and new infection (model 3) on cattle farms and to generate high resolution maps of predicted TB occurrence to guide risk-based interventions. Models revealed that land use, particularly open area and woodland, high wild boar TB prevalence, and close proximity to fenced hunting estates were the most important factors associated with TB infection on cattle farms. This is the first time that local TB prevalence in wild boar for individual hunting estates has been significantly associated with TB occurrence on cattle farms at a local scale. Prediction maps identified two areas with high likelihood of TB occurrence in the southwest and northwest of the province where wildlife-livestock interactions and TB occurrence are highly likely and where TB preventative and mitigation strategies (e.g. targeted vaccination, increased biosecurity, etc.) should be prioritized. Methods and results of this study were aimed to inform the implementation of risk-based interventions to better prevent and control TB at the wildlife-livestock interface, a necessary step for the successful eradication of TB in cattle in Spain. PMID- 27237397 TI - Quantitative risk assessment of the introduction of rabies into Japan through the illegal landing of dogs from Russian fishing boats in the ports of Hokkaido, Japan. AB - Japan has been free from rabies since 1958 and various preventive measures are in place protecting the country from the introduction of the disease. Historical reviews indicate that the illegal landing of dogs from Russian fishing boats in the ports of Hokkaido occurred frequently especially in the early 2000s and this could potentially be a source of introduction of rabies into Japan. The method of scenario tree modelling was used and the following entry and exposure pathway was considered the most likely route of rabies entry: a rabies-infected dog arriving on a Russian fishing boat lands in a port of Hokkaido in Japan, it becomes infectious, contacts and infects a susceptible domestic animal (companion dog, stray dog or wildlife). Input parameter values were based on surveys of Russian fishermen, expert opinion and scientific data from the literature. At present (2006-2015), the probability of the introduction of rabies as a result of one Russian fishing boat arriving at a port of Hokkaido is 8.33*10(-10) (90% Prediction Interval (PI): 7.15*10(-11)-5.34*10(-9)), while this probability would have been 7.70*10(-9) (90% PI: 6.40*10(-10)-4.81*10(-8)) in the past (1998-2005). Under the current situation (average annual number of boat arrivals is 1106), rabies would enter Japan every 1,084,849 (90% PI: 169,215-20,188,348) years, while the disease would have been introduced every 18,309 (90% PI: 2929-220,048) years in the past (average annual number of boat arrivals is 7092). The risk of rabies introduction has decreased 59 fold due to both the effective control of the issue of illegal landing of dogs and the decline in the number of Russian boat arrivals. Control efforts include education of Russian fishermen, establishment of warning signs, daily patrols and regular port surveillance of potential dog landing activity. Furthermore, scenario analysis revealed that the policy of mandatory domestic dog vaccination does not contribute effectively to Japan's rabies prevention system under rabies-free situation. Although the current risk of rabies introduction is minimal, control measures against the illegal landing of dogs must be maintained. Further risk management measures, such as the removal of wildlife from the port area and regular monitoring of the rabies situation in Russia (particularly the easternmost regions), can be established to strengthen the current rabies prevention system in Hokkaido. PMID- 27237398 TI - Qualitative and quantitative impacts assessment of contagious bovine pleuropneumonia in Fulani pastoral herds of North-central Nigeria: The associated socio-cultural factors. AB - Contagious bovine pleuropneumonia is one of the most important trans-boundary disease affecting Fulani cattle herds of Nigeria and whose control is urgently needed. A Participatory Epidemiology approach and cross-sectional study were concurrently conducted to investigate qualitative and quantitative impacts of CBPP, respectively and associated socio-cultural factors that influenced exposure of Fulani nomadic pastoral communities to its risk in Niger State, North-central Nigeria between January and December 2013. A total of nine pastoral communities were purposively selected for qualitative impact assessment using Participatory Rural Appraisal tools, while 765 cattle randomly sampled from 125 purposively selected nomadic herds were analyzed using c-ELISA. Data on socio-cultural characteristics were collected using structured questionnaires administered on nomadic herd owners of the 125 selected herds. Kendall's Coefficient of Concordance W statistics and OpenEpi 2.3 were used for statistical analyses. Pastoralists' dependent factors associated with their socio-cultural activities were tested using Chisquare tests and likelihood backward logistic regressions. The mean proportional piles (relative qualitative impact) of CBPP was 12.6%, and nomads agreement on this impact was strong (W=0.6855) and statistically significant (P<0.001). This was validated by 16.2% (95% CI: 13.7, 19.0) sero positive (quantitative impact). Highest sero-prevalence of 25.3% was observed in Northern agro-ecological zone, while lowest of 6.2% was in Eastern zone. Pastoralists in the age groups 51-60 and 61-70 years were more likely (OR 13.07; 95% CI: 3.21, 53.12 and OR 7.10; 95% CI: 1.77, 28.33, respectively) to have satisfactory information/awareness on CBPP and lowland transhumance pastoralists were more likely (OR 5.21; 95% CI: 2.01, 13.54) to have satisfactory information. Socio-cultural activities of extensive husbandry system was six times more likely (OR 5.79; 95% CI: 2.55, 13.13) to be satisfactory practice that influenced CBPP occurrence in herds, while culture of borrowing and loaning of cattle was twenty times more likely (OR 19.94; 95% CI: 6.36, 62.48) to be satisfactory practice that influenced CBPP occurrence in herds. Also, sharing a water source that caused concentration of stocks in one point was fifty three times more likely (OR 53.08; 95% CI: 14.91, 189.00) to be satisfactory practice that influenced occurrence of the disease in herds. This study highlighted the critical gap that exists in terms of significant influence of socio-cultural factors on CBPP occurrence in pastoral herds in Nigeria. Thus, CBPP surveillance, control and prevention programs that take these factors into consideration will be beneficial to the livestock industry in Nigeria, and indeed Africa. PMID- 27237399 TI - Towards better-informed consent: Research with livestock-keepers and informal traders in East Africa. AB - With the rise of the One Health paradigm, ethicists have called for new research approaches, considering the interdependent relationships of humans, animals, and their environment. These relationships can be particularly complex within resource-poor, smallholder livestock systems, necessitating a rigorous informed consent process. Little has been published on informed consent beyond human subject research. This paper outlines two studies on informed consent, for research identifying diseases of animal and human importance, within smallholder livestock value chains. Firstly, a randomized independent-group study compared three communication tools (written, cartoons, and photographs) for informing 22 Tanzanian livestock-keepers before seeking their consent. A significant difference in comprehension and engagement in the informed-consent process was found between tools, and cartoons had the highest (i.e. best combined comprehension and engagement) scores. Most (21 out of 22) farmers answered half or more the questions correctly, but none were able to answer all questions. Comprehension testing allowed identification of common misunderstandings, such as immediate benefits the farmers would receive and the process to be used for relaying research results. Dialogue stimulated by cartoons and photographs allowed researchers to determine and respond to participants' varied relationships with their livestock. The second study assessed preferred methods for indicating consent among informal-sector milk vendors in Nairobi, Kenya. Of consenting participants, 61% (140/230) indicated consent verbally, 39% (90/230) signed consent and none chose thumbprint. There was a significant enumerator effect on both overall consent and the methods chosen. Several of these findings echo those published in human-medical research. Additionally, highlighted here is the importance of facilitating dialogue during the informed-consent process in One Health research, for a more nuanced understanding of relationships between humans, animals, and their environment. Also discussed is how a requirement to sign consent forms might limit consent among workers in informal markets, which are commonly studied in One Health research. We suggest expansion of these, and development of further, studies towards improving consent processes in One Health research. PMID- 27237400 TI - Reduced circulating oxytocin and High-Molecular-Weight adiponectin are risk factors for metabolic syndrome. AB - The neurohypophysial hormone, oxytocin, is involved in the regulation of energy metabolism. Adiponectin (APN) is an adipose tissue-specific serum protein that inversely associates with metabolic syndrome (MetS). High-molecular-weight adiponectin (HMW APN) is considered the active form. In the present study, we aimed to determine the relationships of oxytocin and HMW APN to MetS and investigate whether or not the combination of oxytocin and HMW APN is associated with further metabolic abnormalities compared to each of them alone. A total of 170 subjects (75 with MetS and 95 non-MetS) were enrolled. Anthropometric parameters, oral glucose tolerance test (OGTT), blood lipids, hs-CRP, oxytocin and HMW APN levels were measured. Compared with non-MetS subjects, serum oxytocin and HMW APN levels were significantly lower in subjects with MetS (P<0.01). We then classified the subjects into three groups: high oxytocin and high HMW APN levels (high score group), low oxytocin and low HMW APN levels (low score group) and others. Participants in low score group showed the worst metabolic profiles and were more likely to have MetS compared to the other two group. In Spearman rank correlation coefficient, the classification by the combination of oxytocin and HMW APN was significantly correlated with a larger number of metabolic risk factors compared with classification by each of them alone. Individuals with low circulating oxytocin levels coupled with low HMW APN levels were at significantly increased risk of MetS. The combination of both markers would be useful for identifying MetS high risk patients. PMID- 27237401 TI - Platelet-derived factor V promotes angiogenesis in a mouse hind limb ischemia model. AB - OBJECTIVE: Coagulation factor V (FV) is distributed in plasma and platelet pools, which are distinguished by physical and functional differences. FV has been extensively studied for its roles in coagulation. The roles of FV in other physiologic pathways remain understudied. METHODS: Hind limb ischemia was produced in transgenic mice by femoral artery ligation, with different levels of FV gene expression restricted to the plasma or platelets. RESULTS: Hind limb blood flow perfusion in mice with higher platelet FV was significantly increased. The expression of major angiogenesis-related factors was correlated with the level of FV during ischemia. Furthermore, a platelet depletion and transfusion procedure showed that the transfusion of platelets with higher levels of FV into transgenic mice with undetectable platelet FV significantly rescued the ischemia mediated impairments in blood flow perfusion. Immunohistochemistry analysis also indicated markedly increased capillary formation in the ischemic muscle of mice with higher platelet FV. Moreover, thrombin activity was significantly higher in the mice with higher platelet FV. Platelets expressing higher levels of FV stimulated increased endothelial cell migration. Hind limb blood flow perfusion was significantly blocked by thrombin inhibitor. CONCLUSIONS: These findings suggest that platelet-derived FV contributes to the control of angiogenesis and is likely associated with thrombin generation. PMID- 27237402 TI - Renal function changes after fenestrated endovascular aneurysm repair. AB - OBJECTIVE: Limited data exist regarding the effect of fenestrated endovascular aneurysm repair (fEVAR) on renal function. We performed a comprehensive analysis of acute and chronic renal function changes in patients after fEVAR. METHODS: This study included patients undergoing fEVAR at two institutions between September 2012 and March 2015. Glomerular filtration rate was estimated using the Modification of Diet in Renal Disease formula with serum creatinine levels obtained during the study period. Acute and chronic renal dysfunction was assessed using the RIFLE (Risk, Injury, Failure, Loss, End-stage renal disease) criteria and the chronic kidney disease (CKD) staging system, respectively. RESULTS: fEVAR was performed in 110 patients for juxtarenal or paravisceral aortic aneurysms, with a mean follow-up of 11.7 months. A total of 206 renal stents were placed, with a mean aneurysm size of 62.9 mm (range, 45-105 mm) and a mean neck length of 4.1 mm. Primary renal stent patency was 97.1% at the latest follow-up. Moderate kidney disease (CKD stage >= 3) was present in 51% of patients at baseline, with a mean preoperative glomerular filtration rate of 60.0 +/- 19.6 mL/min/1.73 m2. Acute kidney injury occurred in 25 patients (22.7%), although 15 of these (60%) were classified as having mild dysfunction. During follow-up, 59 patients (73.7%) were found to have no change or improved renal disease by CKD staging, and 19 (23.7%) had a CKD increase of one stage. Two patients were noted to have end-stage renal failure requiring hemodialysis. Clinically significant renal dysfunction was noted in 21 patients (26.2%) at the latest follow-up. Freedom from renal decline at 1 year was 76.1% (95% confidence interval, 63.2%-85.0%). Surrogate markers for higher operative complexity, including operating time (P = .001), fluoroscopy time (P < .001), contrast volume (P = .017), and blood loss (P = .002), served as dependent risk factors for acute kidney injury, although though no independent predictors were identified. Age (P = .008) was an independent risk factor for long-term decline, whereas paradoxically, baseline kidney disease (P = .032) and longer operative times (P = .014) were protective of future renal dysfunction. CONCLUSIONS: Acute and chronic renal dysfunction both occur in approximately one-quarter of patients after fEVAR; however, most of these cases are classified as mild according to consensus definitions of renal injury. The presence of mild or moderate baseline kidney disease should not preclude endovascular repair in the juxtarenal population. Routine biochemical analysis and branch vessel surveillance remain important aspects of clinical follow-up for patients undergoing fEVAR. PMID- 27237403 TI - Comparative effectiveness of peripheral vascular intervention versus surgical bypass for critical limb ischemia in the Vascular Study Group of Greater New York. AB - OBJECTIVE: In this study, the effectiveness of peripheral vascular intervention (PVI) was compared with surgical bypass grafting (BPG) for critical limb ischemia (CLI) in the Vascular Study Group of Greater New York (VSGGNY). METHODS: Patients undergoing BPG or PVI for CLI at VSGGNY centers (2011-2013) were included. The Society for Vascular Surgery objective performance goals for CLI were used to directly compare the safety and effectiveness of PVI and BPG. Propensity score matching was used for risk-adjusted comparisons of PVI with BPG. RESULTS: A total of 414 patients (268 PVI, 146 BPG) were treated for tissue loss (69%) or rest pain (31%). Patients undergoing PVI were more likely to have tissue loss (74.6% vs 57.5%; P < .001) and comorbidities such as diabetes (69.3% vs 57.5%; P = .02), heart failure (22% vs 13.7%; P = .04), and severe renal disease (13.1% vs 4.1%; P = .004). No significant differences were found between the groups across a panel of safety objective performance goals. In unadjusted analyses at 1 year, BPG was associated with higher rates of freedom from reintervention, amputation, or restenosis (90.4% vs 81.7%; P = .02) and freedom from reintervention or amputation (92.5% vs 85.8%, P = .045). After propensity score matching, PVI was associated with improved freedom from major adverse limb events and postoperative death at 1 year (95.6% vs 88.5%; P < .05). CONCLUSIONS: By unadjusted comparison, early reintervention and restenosis are more prevalent with PVI. However, risk adjusted comparison underscores the safety and effectiveness of PVI in the treatment of CLI. PMID- 27237404 TI - Safety and effectiveness of total percutaneous access for fenestrated endovascular aortic aneurysm repair. AB - BACKGROUND: Percutaneous femoral vascular access is frequently used for aortic endovascular procedures, with a local access complication rate of 5% to 16%. Fenestrated endovascular aneurysm repair (FEVAR) has recently emerged as a new technique for the repair of short-neck and juxtarenal abdominal aortic aneurysms. The safety and effectiveness of percutaneous access for FEVAR has not been established to date. METHODS: Since United States Food and Drug Administration approval of the Zenith fenestrated aortic endograft (Cook Medical, Bloomington, Ind), 94 patients (60 Zenith fenestrated, 6 p-Branch, and 28 custom-made devices) have undergone FEVAR. Percutaneous access was performed using the "preclose" technique with the Perclose Proglide device (Abbott Vascular, Redwood City, Calif). Open access was performed when severely disease or calcified femoral arteries prevented percutaneous access. Patient-based analysis was performed assessing outcomes for the access site used for the larger profile sheath of the main device. RESULTS: Percutaneous access was used in 90 patients (177 common femoral arteries) and open access in four (11 common femoral arteries). Arm access was used in 41 patients (44%). The median sheath size was 20F (interquartile range [IQR], 20F-22F). Median operative time was 207 minutes (IQR, 160-270 minutes), with a median blood loss of 500 mL (IQR, 300-700 mL). The percutaneous access success rate was 92%. No preoperative factors predicted technical failure. No 30-day deaths occurred. Patients with failed percutaneous closure and who required conversion to open repair had higher estimated median blood loss of 800 (IQR, 600-1200) vs 500 (IQR, 300-600) mL (P = .01) and a longer median time to start ambulation of 4 (IQR, 2-7) vs 2 (IQR, 1-3) days (P = .03). Patients undergoing percutaneous closure had lower median blood loss (500 mL; IQR, 300-600 mL) than patients who underwent open surgical access (800 mL; IQR, 750-800 mL). Postoperative complications related to vascular access occurred in 11 patients (12%). CONCLUSIONS: Percutaneous femoral access is a safe and effective alternative to open access for FEVAR. Operative blood loss and longer time to ambulation are significantly increased after failed percutaneous closure. PMID- 27237405 TI - The efficacy and durability of the Venous Window Needle Guide implanted on uncannulatable arteriovenous fistulas. AB - BACKGROUND: The Venous Window Needle Guide (VWING; Vital Access Corp, Salt Lake City, Utah) is a surgically implanted titanium device designed to facilitate cannulation of uncannulatable dialysis access arteriovenous fistulas (AVFs) because of excessive depth, aneurysm formation, or tortuosity but that exhibit sufficient flow volume to support hemodialysis. We report the 18-month fistula patency, functionality, and complications of the use of the VWING device. METHODS: This retrospective study examined AVF patency, VWING functionality, interventions, and device infections at 18 months after VWING implantation. The study population comprised the eligible patients enrolled in the VWING Salvage of AV Fistula (SAVE) trial. RESULTS: Fifty-four patients were originally enrolled in the SAVE trial, and 35 were enrolled in the follow-up study. At 18 months, when considering surgical or percutaneous interventions at the VWING site(s) only, the primary AVF patency rate was 78%. Interventions elsewhere on the AVF, outside the boundaries of the VWING, resulted in a primary patency rate of 38%. The VWING accounted for 13% loss of AVF primary patency compared with 53% loss from the remaining AVFs. The overall AVF assisted primary patency rate was 91%, and the primary patency rate was 21%. VWING secondary functionality, the continued ability to access the fistula through the VWING using a constant site cannulation technique, was 65%. During the 12 months after the SAVE Study 80% of patients did not require the use of a central venous catheter. Eleven VWING devices were removed from eight patients, all but one for cannulation difficulties. One device was removed during the SAVE trial because of infection. No device or systemic infection was identified in the ensuing 12 months, for an overall systemic infection rate of 0.014 per device-year. An intervention rate of 0.32 per device year was required to maintain device functionality during the 18-month follow-up period. CONCLUSIONS: Implantation of the VWING device is a safe and effective means of establishing hemodialysis access in an otherwise functional but uncannulatable AVF. The device infection rate is acceptably low. PMID- 27237406 TI - Plaque echodensity and textural features are associated with histologic carotid plaque instability. AB - BACKGROUND: Carotid plaque echodensity and texture features predict cerebrovascular symptomatology. Our purpose was to determine the association of echodensity and textural features obtained from a digital image analysis (DIA) program with histologic features of plaque instability as well as to identify the specific morphologic characteristics of unstable plaques. METHODS: Patients scheduled to undergo carotid endarterectomy were recruited and underwent carotid ultrasound imaging. DIA was performed to extract echodensity and textural features using Plaque Texture Analysis software (LifeQ Medical Ltd, Nicosia, Cyprus). Carotid plaque surgical specimens were obtained and analyzed histologically. Principal component analysis (PCA) was performed to reduce imaging variables. Logistic regression models were used to determine if PCA variables and individual imaging variables predicted histologic features of plaque instability. RESULTS: Image analysis data from 160 patients were analyzed. Individual imaging features of plaque echolucency and homogeneity were associated with a more unstable plaque phenotype on histology. These results were independent of age, sex, and degree of carotid stenosis. PCA reduced 39 individual imaging variables to five PCA variables. PCA1 and PCA2 were significantly associated with overall plaque instability on histology (both P = .02), whereas PCA3 did not achieve statistical significance (P = .07). CONCLUSIONS: DIA features of carotid plaques are associated with histologic plaque instability as assessed by multiple histologic features. Importantly, unstable plaques on histology appear more echolucent and homogeneous on ultrasound imaging. These results are independent of stenosis, suggesting that image analysis may have a role in refining the selection of patients who undergo carotid endarterectomy. PMID- 27237407 TI - Surgical Treatment of Tracheobronchomalacia: A novel approach. AB - Tracheobronchomalacia, as a whole, is likely misdiagnosed and underestimated as a cause of respiratory compromise in pediatric patients. Currently, there is no standardized approach for the overall evaluation of pediatric tracheobronchomalacia (TBM) and the concept of excessive dynamic airway collapse (EDAC); no grading score for the evaluation of severity; nor a standardized means to successfully approach TBM and EDAC. This paper describes our experience standardizing the approach to these complex patients whose backgrounds include different disease etiologies, as well as a variety of comorbid conditions. Preoperative and postoperative evaluation of patients with severe TBM and EDAC, as well as concurrent development of a prospective grading scale, has allowed us to ascertain correlation between surgery, symptoms, and effectiveness on particular tracheal-bronchial segments. Long-term, continued collection of patient characteristics, surgical technique, complications, and outcomes must be collected given the overall heterogeneity of this particular population. PMID- 27237408 TI - Question 9: What is the role for bronchoscopy and bronchoalveolar lavage in Cystic Fibrosis? PMID- 27237409 TI - N-methyl-N-nitrosourea-induced neuronal cell death in a large animal model of retinal degeneration in vitro. AB - N-methyl-N-nitrosourea (MNU) has been reported to induce photoreceptor-specific degeneration with minimal inner retinal impact in small animals in vivo. Pending its use within a retinal transplantation paradigm, we here explore the effects of MNU on outer and inner retinal neurons and glia in an in vitro large animal model of retinal degeneration. The previously described degenerative culture explant model of adult porcine retina was used and compared with explants receiving 10 or 100 MUg/ml MNU (MNU10 and MNU100) supplementation. All explants were kept for 5 days in vitro, and examined for morphology as well as for glial and neuronal immunohistochemical markers. Rhodopsin-labeled photoreceptors were present in all explants. The number of cone photoreceptors (transducin), rod bipolar cells (PKC) and horizontal cells (calbindin) was significantly lower in MNU treated explants (p < 0.001). Gliosis was attenuated in MNU10 treated explants, with expression of vimentin, glial fibrillary protein (GFAP), glutamine synthetase (GS), and bFGF comparable to in vivo controls. In corresponding MNU100 counterparts, the expression of Muller cell proteins was almost extinguished. We here show that MNU causes degeneration of outer and inner retinal neurons and glia in the adult porcine retina in vitro. MNU10 explants display attenuation of gliosis, despite decreased neuronal survival compared with untreated controls. Our results have impact on the use of MNU as a large animal photoreceptor degeneration model, on tissue engineering related to retinal transplantation, and on our understanding of gliosis related neuronal degenerative cell death. PMID- 27237410 TI - Patient and caregiver characteristics related to completion of advance directives in terminally ill patients. AB - OBJECTIVE: There is a growing body of literature describing the characteristics of patients who plan for the end of life, but little research has examined how caregivers influence patients' advance care planning (ACP). The purpose of this study was to examine how patient and caregiver characteristics are associated with advance directive (AD) completion among patients diagnosed with a terminal illness. We defined AD completion as having completed a living will and/or identified a healthcare power of attorney. METHOD: A convenience sample of 206 caregiver-patient dyads was included in the study. All patients were diagnosed with an advanced life-limiting illness. Trained research nurses administered surveys to collect information on patient and caregiver demographics (i.e., age, sex, race, education, marital status, and individual annual income) and patients' diagnoses and completion of AD. Multivariate logistic regression was employed to model predictors for patients' AD completion. RESULTS: Over half of our patient sample (59%) completed an AD. Patients who were older, diagnosed with amyotrophic lateral sclerosis, and with a caregiver who was Caucasian or declined to report an income level were more likely to have an AD in place. SIGNIFICANCE OF RESULTS: Our results suggest that both patient and caregiver characteristics may influence patients' decisions to complete an AD at the end of life. When possible, caregivers should be included in advance care planning for patients who are terminally ill. PMID- 27237411 TI - Long-term follow-up for the treatment of male urinary incontinence with the Remeex system. AB - OBJECTIVES: To relate our experience in treating postprostatectomy stress urinary incontinence (SUI) with the male Remeex system (MRS). We also list the elements that comprise this system, the implantation technique and its proper adjustment. Similarly, we attempt to determine whether the latest changes made to this device, which constitute the MRS-II, have resulted in fewer mesh readjustments. MATERIAL AND METHOD: From March 2007 to March 2014, we operated on 24 men with postprostatectomy SUI between the ages of 55 and 78 years (mean, 67 years), through the placement of a Remeex suburethral tension-adjustable sling. All patients had severe urinary incontinence, with considerable impact on their quality of life. RESULTS: All patients, except for 2 who required the removal of the system, remained continent. Nine of the patients (39%) occasionally required incontinence pads when performing intense physical exercise. The mean number of adjustments was 2.4 (range 0-6). The score on the Incontinence Impact Questionnaire (IIQ 7) performed before the surgery and 6 months after, went from 79+/-7 points to 11+/-3, with a very high degree of satisfaction. CONCLUSIONS: The MRS is a valid therapeutic option for postprostatectomy incontinence and is a reproducible technique that is easy to perform, has a low rate of complications and provides excellent and lasting results. There is also a clear trend towards reducing number of adjustments with the new MRS-II. PMID- 27237412 TI - Conservative management and follow up in patients with upper tract urothelial carcinoma: Present or future? PMID- 27237413 TI - Corynebacterium urealyticum: The historical importance of its discovery. PMID- 27237414 TI - Intracranial Aneurysms Associated with Moyamoya Disease in Children: Clinical Features and Long-Term Surgical Outcome. AB - BACKGROUND: Moyamoya disease (MMD) in children was rarely associated with intracranial aneurysms. The purpose of this study was to report the clinical characteristics and long-term surgical outcomes of pediatric intracranial aneurysms accompanied with MMD. METHODS: Between October 2002 and October 2013, our department treated 9 pediatric MMD patients (aged <=17 years) with intracranial aneurysms. Clinical and angiographic features, treatment selection, as well as follow-up information were obtained and analyzed. The efficacy of vascularization and the changes of intracranial aneurysms were evaluated with digital subtraction angiography (DSA). We also collected 7 previously published reports to analyze the characteristics of this rare condition. RESULTS: In our series of 9 patients, 7 were male. The mean age was 11 +/- 3.4 years (range 5 16). Seven patients presented with intracranial hemorrhage as the initial manifestation, while 2 patients suffered transient ischemic attacks. The most common aneurysm location was the posterior choroidal artery (4, 44.4%). One anterior choroidal artery aneurysm was completely embolized with Onyx (ev3, Irvine, California, USA). One posterior choroidal artery aneurysm failed due to inaccessibility to the parent artery. Bilateral encephalo-duro-arterio synangiosis (EDAS) surgery was performed for all the children. During the follow up period of 6.4 +/- 2.2 years (range 3-11), spontaneous occlusion of aneurysm was observed in 4 children, including 1 child with middle cerebral artery aneurysm, 1 with lenticulostriate artery aneurysm, and 2 with posterior choroidal artery aneurysm. Good or fair vascularization was observed in all the 9 children with DSA follow-up. No patients suffered intracranial hemorrhage during the follow-up period. CONCLUSIONS: The long-term survey showed EDAS surgery could effectively increase the cerebral blood flow and maintain good outcomes in children, which may further result in the disappearance of the intracranial aneurysms and decrease the incidence of recurrent hemorrhage. PMID- 27237415 TI - The Neurosurgical Curmudgeon-Of Pygmalion, Galatea, and Aurochs Arteriovenous Malformation Associated Intracerebral Hematoma Scores, AUROC Analyses, Representations, and Reality. PMID- 27237416 TI - Failed Ventriculoperitoneal Shunt: Is Retrograde Ventriculosinus Shunt a Reliable Option? AB - BACKGROUND: Currently, the treatment of hydrocephalus is mainly carried out through a ventriculoperitoneal shunt (VPS) insertion. However, in some cases, there may be surgical revisions and requirement of an alternative distal site for shunting. There are several described distal sites, and secondary options after VPS include ventriculopleural and ventriculoatrial shunt, which have technical difficulties and harmful complications. OBJECTIVES: In this preliminary report we describe our initial experience with retrograde ventriculosinus shunt (RVSS) after failed VPS. RESULTS: In 3 consecutive cases we applied RVSS to treat hydrocephalus in shunt-dependent patients who had previously undergone VPS revision and in which peritoneal space was full of adhesions and fibrosis. RVSS was performed as described by Shafei et al., with some modifications to each case. All 3 patients kept the same clinical profile after RVSS, with no perioperative or postoperative complications. However, revision surgery was performed in the first operative day in 1 out of 3 patients, in which the catheter was not positioned in the superior sagittal sinus. CONCLUSIONS: We propose that in cases where VPS is not feasible, RVSS may be a safe and applicable second option. Nevertheless, the long-term follow-up of patients and further learning curve must bring stronger evidence. PMID- 27237417 TI - Smith-Robinson Procedure with an Autologous Iliac Crest for Degenerative Cervical Disc Disease: A 28-Year Follow-Up of 95 Patients. AB - BACKGROUND: Long-term clinical results after anterior cervical discectomy and fusion (ACDF) with an autologous iliac crest are rare. The purpose of this study was to assess this, with special focus on pain, functional outcome, and repeat surgery for adjacent segment disease (ASD). METHODS: Hospital records of 212 patients who were affected by degenerative cervical disc disease and treated by the Smith-Robinson technique were reviewed. Information about diagnosis, surgery, pre- and postoperative clinical process, and complications was analyzed. Patients were reviewed with a standardized questionnaire including the current neurologic status, Neck Disability Index, EQ-5D, Patient Satisfaction Index, Odom criteria, and limitations in quality of life. RESULTS: Ninety-five patients with a mean follow-up of 28 years were evaluated. ACDF was performed at 1 level in 67 and 2 levels in 28 patients. Ninety-two patients reported pain before surgery and 68 patients remained pain free and did not require second surgery. At follow-up, the mean Neck Disability Index was 14%, and mean EQ-5D score was 5. Postoperatively, 96.8% of patients were satisfied and 84.2% of patients reported good to excellent functional recovery. One patient had a hairline fracture at the iliac crest donor site. Fourteen patients underwent second surgery because of degenerative changes, including 11 at the symptomatic ASD. CONCLUSIONS: ACDF yields significant decrease in pain, a significant increase in function, and a high degree of patient satisfaction. Overall prevalence for ASD was 12.0% after 25 years. Patients with reoperation had similar clinical outcome regarding pain, compared with patients without reoperation. PMID- 27237418 TI - Seizure Correlates with Prolonged Hospital Stay, Increased Costs, and Increased Mortality in Nontraumatic Subdural Hematoma. AB - BACKGROUND: Nontraumatic subdural hematoma (NTSDH) is a common neurosurgical disease process, with mortality reported as high as 13%. Seizure has a known association with NTSDH, although patient outcomes have not previously been well studied in this population. The purpose of this study was to examine the relationship between in-hospital seizure and inpatient outcomes in NTSDH. METHODS: Using the University HealthSystem Consortium (UHC) database, we performed a retrospective cohort study of adults with a principal diagnosis of NTSDH (International Classification of Diseases, Ninth Revision code 43.21) between 2011 and 2015. Patients with in-hospital seizure (International Classification of Diseases, Ninth Revision codes 34500-34591, 78033, 78039) were compared with those without. Patients with a history of seizure before arrival were excluded. Patient demographics, hospital length of stay (LOS), intensive care unit stay, in-hospital mortality, and direct costs were recorded. RESULTS: A total 16,928 patients with NTSDH were identified. Mean age was 69.2 years, and 64.7% were male. In-hospital seizure was documented in 744 (4.40%) patients. Hospital LOS was 17.64 days in patients with seizure and 6.26 days in those without (P < 0.0001). Mean intensive care unit stay increased from 3.36 days without seizure to 9.36 days with seizure. In-hospital mortality was 9.19% in patients without seizure and 16.13% in those with seizure (P < 0.0001). Direct costs were $12,781 in patients without seizure and $38,110 in those with seizure (P < 0.0001). CONCLUSIONS: Seizure in patients with NTSDH correlates with significantly increased total LOS and increased mortality. Direct costs are similarly increased. Further studies accounting for effects of illness severity are necessary to validate these results. PMID- 27237419 TI - Development of a Microsimulation Model to Predict Stroke and Long-Term Mortality in Adherent and Nonadherent Medically Managed and Surgically Treated Octogenarians with Asymptomatic Significant Carotid Artery Stenosis. AB - BACKGROUND: The primary study objective was to develop a microsimulation model to predict preventable first-ever and recurrent strokes and mortality for a population of medically or surgically managed octogenarians with substantial (>60%) asymptomatic carotid artery stenosis and comparing an adherent with a real world nonadherent best medical treatment (BMT) regimen subjected to sex. METHODS: A Monte Carlo microsimulation model was constructed with a 14-year time horizon and with 10,000 patients. Probabilities and values for clinical outcomes were obtained from the current literature. RESULTS: The stratification of the microsimulation estimates by treatment strategy within the female group of octogenarians showed a statistically significant lower stroke rate during follow up for carotid endarterectomy (CEA) compared with nonadherent BMT (P < 0.0001) as well as compared with adherent BMT (P < 0.0001). In male octogenarians, the CEA strategy was also associated with statistically significant lower stroke rates compared with adherent and nonadherent BMT (P < 0.0001 and P < 0.0001, respectively). For each treatment strategy, female octogenarians had a statistically significant longer overall long-term survival compared with male octogenarians (P < 0.0001, respectively). In terms of stratification by sex, in octogenarian men and women, long-term survival was significantly better for adherent BMT compared with nonadherent BMT, and CEA was associated with a significant better long-term survival compared with nonadherent BMT. CONCLUSIONS: In the present microsimulation, in real-world drug adherence, it was likely that a strategy of early endarterectomy was beneficial in octogenarians with significant asymptomatic carotid artery disease compared with BMT alone. PMID- 27237420 TI - Insular and Sylvian Fissure Dermoid Cyst with Giant Cell Reactivity: Case Report and Review of Literature. AB - BACKGROUND: Dermoid cysts are rare intracranial tumors that are most commonly found infratentorially and along the midline. Characterized by slow growth and often found incidentally, these lesions can nonetheless have severe complications, notably rupture leading to chemical meningitis. They infrequently present as a supratentorial and lateralized mass. As such, sylvian fissure dermoid cysts are exquisitely rare. We present a rare case of a dermoid cyst with giant cell reactivity suggestive of focal rupture and chronic inflammation. CASE DESCRIPTION: A 61-year-old female presented with new-onset seizures. Magnetic resonance imaging revealed a right insular mass measuring 4.3 * 4.5 cm with compression of the ipsilateral frontal and temporal lobes. The mass was nonenhancing; however, it was bright on diffusion-weighted imaging, suggesting a dermoid cyst. She underwent craniotomy for tumor resection. Histologic analysis revealed keratinizing squamous epithelium, sebaceous glands, and hair follicles associated with giant cell reaction involving the capsule of the cyst consisted with dermoid cyst. At 2.5 years post operation, she is seizure free and without evidence of recurrence. CONCLUSION: The dermoid cyst in our patient was not grossly ruptured, but histopathologic analysis revealed giant cell reactivity, which may indicate focal rupture or chronic inflammation. The relationship between rupture of dermoid cysts and inflammation is not well elucidated. It is not known whether symptoms occur immediately after rupture or as an acute manifestation of a chronic process following rupture. As these lesions are quite rare and rupture is even rarer, more diligence on our part regarding details of histopathology for dermoid cysts is necessary. PMID- 27237421 TI - Analysis of Clinical Features and Outcomes of Skull Base Chordoma in Different Age-Groups. AB - OBJECTIVE: The objective of the current study was to compare the clinical features and outcomes between younger and older patients with skull base chordoma (SBC). METHODS: In this retrospective study, patients with SBC who underwent surgical treatment between February 2005 and December 2014 were included. Clinical features were recorded, including the signal intensity ratio of tumor to brain stem in T1 (RT1), T2 (RT2), and enhanced T1 (REN) sequences in primary patients with complete preoperative magnetic resonance images. The clinical features and outcomes were compared between younger (<=24 years) and older patients (>=25 years). RESULTS: In the present study, 238 patients were included. Younger patients experience more aggressive resection than do older patients (P = 0.045), and the SBCs of younger patients tended to be located in the occipitocervical region compared with older patients (P = 0.007). REN value in the younger group was lower than in the older group (P = 0.014), and the value of RT2 was higher in younger patients than in older patients (P = 0.015). The risk of progression was higher in older patients compared with younger patients (P = 0.030); the risk of having a poor neurologic status in older patients was higher than in younger patients (P = 0.044). CONCLUSIONS: In younger patients, there were more SBCs located in the occipitocervical regions, and younger patients tended to undergo more aggressive resection. The tumor signal intensity of younger patients with SBC was higher in T2 images but lower in enhanced T1 images. A younger age was a favorable factor for a longer progression-free survival and a good neurologic status at follow-up. PMID- 27237422 TI - Distinct galactofuranose antigens in the cell wall and culture supernatants as a means to differentiate Fusarium from Aspergillus species. AB - Detection of carbohydrate antigens is an important means for diagnosis of invasive fungal infections. For diagnosis of systemic Aspergillus infections, galactomannan is commonly used, the core antigenic structure of which consists of chains of several galactofuranose moieties. In this study, we provide evidence that Fusarium produces at least two distinct galactofuranose antigens: Smaller amounts of galactomannan and larger quantities of a novel antigen recognized by the monoclonal antibody AB135-8. In A. fumigatus, only minor amounts of the AB135 8 antigen are found in supernatants and in the apical regions of hyphae. A galactofuranose-deficient A. fumigatus mutant lacks the AB135-8 antigen, which strongly suggests that galactofuranose is an essential constituent of this antigen. Using a combination of AB135-8 and a galactomannan-specific antibody, we were able to unambiguously differentiate A. fumigatus and Fusarium hyphae in immunohistology. Moreover, since Fusarium releases the AB135-8 antigen, it appears to be a promising target antigen for a serological detection of Fusarium infections. PMID- 27237424 TI - [Biomineralization of copper in Candida fukuyamaensis RCL-3]. AB - Candida fukuyamaensis RCL-3 yeast has the ability to decrease copper concentration in a culture medium. High copper concentrations change the cell color from white/cream to brown. The effect of color change ceases with the addition of KCN or when cells are grown in a culture medium without sulfate ions. These results could be associated with CuS bioaccumulation in the cell surface. This report revealed that mineralization would be a mechanism used by this yeast for copper bioremediation. PMID- 27237423 TI - Multicentre investigation of carbapenemase-producing Escherichia coli and Klebsiella pneumoniae in German hospitals. AB - Aim of this study was to determine the incidence and molecular epidemiology of carbapenemase-producing Escherichia coli and Klebsiella pneumoniae in Germany. E. coli and K. pneumoniae isolates from clinical samples which were non-susceptible to carbapenems were collected in laboratories serving 20 hospitals throughout Germany from November 2013 to April 2014. The isolates were tested for the presence of carbapenemases by PCR and phenotypic methods and typed by multilocus sequence typing. Risk factors including a previous hospitalization abroad were analysed. Carbapenemases were detected in 24 isolates from 22 patients out of 464,514 admissions. Carbapenemases included OXA-48 (n=14), KPC-2 (n=8) and NDM-1 (n=2). Except for two K. pneumoniae isolates with ST101, all OXA-48 producing strains belonged to different clones. In contrast, half of KPC-2 producing K. pneumoniae were of ST258 and both NDM-1 producing strains were of ST11. Compared to carbapenem-susceptible controls, patients with carbapenemase-producing strains differed by a significantly higher proportion of males, a higher proportion of isolates from wound samples and a more frequent previous stay abroad in univariate analysis. This multicentre study demonstrated an incidence of carbapenemase-producing E. coli and K. pneumoniae from clinical samples in Germany of 0.047 cases per 1000 admissions. OXA-48 was more frequent than KPC-2 and NDM-1 and showed a multiclonal background. PMID- 27237425 TI - [Interlaboratory test: Isolation of Mycobacterium bovis from granulomatous lesions in bovine]. AB - Mycobacterium bovis is the causative agent of bovine tuberculosis. The diagnostic laboratory confirmation is made through bacterial isolation. The aim of interlaboratory tests is to assess the performance of each participant in comparison with other of similar capacities. The test objective was to determine the efficiency of isolation of M. bovis. Four laboratories were part of the test and processed 25 blind tissue samples from granulomatous lesions and with previous M. bovis isolation. The laboratory that had the highest proportion of isolates was A (68%), followed by C (60%) and then B and D (both with 52%). The greatest concordance was observed between B-D and B-C laboratories (68%). The differences could be due to specific factors in each laboratory procedures. This type of interlaboratory tests highlights errors in the bacteriology and identifies critical points in the process to detect M. bovis accurately. PMID- 27237426 TI - Antimicrobial activity of chitosan coatings and films against Listeria monocytogenes on black radish. AB - The antibacterial activity of chitosan coatings prepared with acetic or lactic acid, as well as of composite chitosan-gelatin films prepared with essential oils, was evaluated in fresh shredded black radish samples inoculated with Listeria monocytogenes ATCC 19115 and L. monocytogenes ATCC 19112 during seven days of storage at 4 degrees C. The chitosan coating prepared with acetic acid showed the most effective antibacterial activity. All tested formulations of chitosan films exhibited strong antimicrobial activity on the growth of L. monocytogenes on black radish, although a higher inhibition of pathogens was achieved at higher concentrations of chitosan. The antimicrobial effect of chitosan films was even more pronounced with the addition of essential oils. Chitosan-gelatin films with thyme essential oils showed the most effective antimicrobial activity. A reduction of 2.4log10CFU/g for L. monocytogenes ATCC 19115 and 2.1log10CFU/g for L. monocytogenes ATCC 19112 was achieved in the presence of 1% chitosan film containing 0.2% of thyme essential oil after 24h of storage. PMID- 27237427 TI - Comparison of amorphous states prepared by melt-quenching and cryomilling polymorphs of carbamazepine. AB - The physical state of amorphous powder obtained by cryomilling forms I and III of carbamazepine (CBZ) were analyzed from low-wavenumber Raman spectroscopy investigations and compared to that of the quenched liquid. This analysis has shown subtle structural modifications between the amorphous states prepared by melt-quenching and cryomilling polymorphs I and III of CBZ. Moreover, two different non-isothermal crystallization mechanisms from these two different types of amorphous states were revealed, in agreement with calorimetric analyzes. Raman spectroscopy and differential scanning calorimetry experiments performed on cryomilled forms I and III of CBZ, provide information on the bimodal crystallization, observed upon heating several amorphous organic crystalline materials produced by milling. This study clearly shows that milling gives the opportunity to explore new amorphous states which cannot be achieved using the classical melt-quenching method. PMID- 27237428 TI - Nonalcoholic Fatty Liver Disease and Coronary Artery Calcification. PMID- 27237430 TI - Prevention of Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis: Medications and Techniques. AB - Over the past 2 decades, it increasingly has been recognized that endoscopic retrograde cholangiopancreatography (ERCP) is the most predictable provocateur of acute pancreatitis, with an incidence of more than 15% in high-risk patients. For this reason, there has been considerable interest in the effect of periprocedural drug administration as well as different ERCP techniques on both the incidence and severity of post-ERCP pancreatitis. Although many agents and techniques have shown promise in small clinical studies, the majority of these have failed to yield consistent benefit in larger randomized patient groups. This review summarizes the data on medications and ERCP techniques that have been studied for the prevention of post-ERCP pancreatitis. PMID- 27237429 TI - Efficacy of Sofosbuvir Plus Ribavirin in Veterans With Hepatitis C Virus Genotype 2 Infection, Compensated Cirrhosis, and Multiple Comorbidities. AB - BACKGROUND & AIMS: We conducted a phase 4, open-label study with limited exclusion criteria to evaluate the safety and efficacy of sofosbuvir and ribavirin in veterans with hepatitis C virus genotype 2 infection, and compensated cirrhosis. This population is often excluded from clinical studies. METHODS: We performed a prospective study of treatment-naive (n = 47) and treatment-experienced (n = 19) patients with chronic hepatitis C virus genotype 2 infection and compensated cirrhosis at 15 Department of Veterans Affairs sites. All subjects were given sofosbuvir (400 mg, once daily) plus ribavirin (1000-1200 mg/day) in divided doses for 12 weeks. Patients with major psychiatric diseases or alcohol or substance use disorders were not excluded. The primary endpoint was sustained virologic response 12 weeks after therapy. RESULTS: Fifty-two patients achieved a sustained virologic response 12 weeks after therapy (79%; 95% confidence interval, 67%-88%); 16 of these patients were treatment experienced (84%; 95% confidence interval, 60%-97%) and 36 were treatment naive (77%; 95% confidence interval, 62%-88%). All patients had at least 1 comorbidity. Thirty five percent had depression, 24% had posttraumatic stress disorder, and 30% had anxiety disorder. In addition, 29% had current substance use. Of the 7 patients (11%) who discontinued the study treatment prematurely, 3 did so because of adverse events. The most common adverse events were fatigue, anemia, nausea, and headache. Serious adverse events occurred in 8 patients. Only 2 of the serious adverse events (anemia and nausea) were considered to be related to study treatment. CONCLUSIONS: In a phase 4 study, 12 weeks treatment with sofosbuvir and ribavirin led to a sustained virologic response 12 weeks after therapy in almost 80% of veterans with hepatitis C virus genotype 2 infection, compensated cirrhosis, and multiple comorbidities, regardless of their treatment history. ClinicalTrials.gov, Number: NCT02128542. PMID- 27237431 TI - 2015 James W. Freston Single Topic Conference: A Renaissance in the Understanding and Management of Irritable Bowel Syndrome. PMID- 27237432 TI - Hematite Surface Activation by Chemical Addition of Tin Oxide Layer. AB - In this study, the effect of tin (Sn(4+) ) modification on the surface of hematite electrodes synthesized by an aqueous solution route at different times (2, 5, 10, 18, and 24 h) is investigated. As confirmed from X-ray diffraction results, the as-synthesized electrode exhibits an oxyhydroxide phase, which is converted into a pure hematite phase after being subjected to additional thermal treatment at 750 degrees C for 30 min. The tin-modified hematite electrode is prepared by depositing a solution of Sn(4+) precursor on the as-synthesized electrode, followed by thermal treatment under the same abovementioned conditions. This modification results in an enhancement of the photocurrent response for all hematite electrodes investigated and attains the highest values of around 1.62 and 2.3 mA cm(-2) at 1.23 and 1.4 V versus RHE, respectively, for electrodes obtained in short synthesis times (2 h). Contact angle measurements suggest that the deposition of Sn(4+) on the hematite electrode provides a more hydrophilic surface, which favors a chemical reaction at the interface between the electrode and electrolyte. This result generates new perspectives for understanding the deposition of Sn(4+) on the hematite electrode surface, which is in contrast with several studies previously reported; these studies state that the enhancement in photocurrent density is related to either the induction of an increased donor charge density or shift in the flat-band potential, which favors charge separation. PMID- 27237433 TI - Tunneling Electroresistance Effect with Diode Characteristic for Cross-Point Memory. AB - Cross-point memory architecture (CPMA) by using memristors has attracted considerable attention because of its high-density integration. However, a common and significant drawback of the CPMA is related to crosstalk issues between cells by sneak currents. This study demonstrated the sneak current free resistive switching characteristic of a ferroelectric tunnel diode (FTD) memristor for a CPMA by utilizing a novel concept of a ferroelectric quadrangle and triangle barrier switch. A FTD of Au/BaTiO3 (5 nm)/Nb-doped SrTiO3 (100) was used to obtain a desirable memristive effect for the CPMA. The FTD could reversibly change the shape of the ferroelectric potential from a quadrangle to a triangle. The effect included high nonlinearity and diode characteristics. It was derived from utilizing different sequences of carrier transport mechanisms such as the direct tunneling current, Fowler-Nordheim tunneling, and thermionic emission. The FTD memristor demonstrated the feasibility of sneak current-free high-density CPMA. PMID- 27237434 TI - Improving Defibrillation Efficiency in Area Schools. AB - OBJECTIVE: Sudden cardiac arrest (SCA) in the young is a rare event but the effects can be devastating. We sought to identify variables that would lead to an improvement in time to defibrillation (TDFB), a previously noted factor significantly influencing survival from cardiac arrest. DESIGN: During the 2013 2014 academic year, the Clark county school district performed quarterly drills to practice the coordinated automated external defibrillator (AED) response. Variables including school, AED carrier, and drill characteristics were measured to determine influence on TDFB. Schools were grouped by TDFB at a cutoff of three minutes. Characteristics were sought for schools with TDFB below three minutes. A mixed regression model taking into account repeated measures was created to determine which variables influenced TDFB. RESULTS: Time to overhead announcement, distance of AED from drill site, and time to setup AED were the variables influencing TDFB with statistical significance (P <.01). CONCLUSIONS: This study supports the notion of early recognition, announcement, and close proximity to an AED during a SCA to ensure an early TDFB. These results are consistent with basic life support and the chain of survival tenets of the American Heart Association. PMID- 27237435 TI - Letter From the Editors. PMID- 27237436 TI - Letter From the Guest Editors. PMID- 27237437 TI - Current Status of Nuclear Medicine Practice in the Middle East. AB - The practice of nuclear medicine (NM) in the Middle East region has experienced an important growth in the last 2 decades and has become crucial in providing healthcare to the region's population of about 395 million people. Even though there are some countries in which the services provided are limited to basic coverage of studies with (99m)Tc and (131)I, most have well-established practices covering most of the available studies in this medical specialty; this is the case in for example, Iran, Israel, Kuwait, Saudi Arabia, and Turkey. According to data provided by the NM professionals in the 17 countries included in the present publication, which was collected by the International Atomic Energy Agency in 2015, the total number of gamma cameras in the region is 910 with an average of 2.3 gamma cameras per million inhabitants. Out of these, 107 cameras, or 12%, are SPECT/CT cameras. There are 194 operating PET/CT scanners, translating to one PET/CT scanner for 2.04 million people on average. The availability of PET/CT scanners in relation to population is the highest in Lebanon and Kuwait, with 2.2 and 1.7 scanners per million people, respectively. There is a total of 628 NM centers in the 17 countries, whereas most NM centers belong to the public healthcare system and in most of the countries are widely spread and not confined exclusively to capital cities. As for the radionuclide therapies, (131)I is used regularly in diagnostic workup as well as in therapeutic applications in all the countries included in this analysis. Only five countries have the capability of assembling (99)Mo-(99m)Tc generators (Egypt, Iran, Saudi Arabia, Israel, and Turkey), and cold kits are produced in several countries. Although there are no capabilities in the region to produce (99)Mo from nuclear reactors, a total of 46 cyclotrons are operated for production of PET radionuclides. The most widely used PET tracer in the region is (18)F-FDG followed by (18)F-NaF; concomitantly, the availability of (68)Ge-(68)Ga generators is increasing and studies involving prostate-specific membrane antigen or DOTA-chelated peptides or both are performed in at least seven countries. Although therapeutic radionuclide agents are mostly imported from outside the region, this does not limit the availability of therapies with (90)Y, (153)Sm, (177)Lu, (131)I, (188)Re, and (89)Sr. Nevertheless, therapies based on alpha particle emitters are still largely not available in the region and are currently only available in Israel and Turkey. Regarding human resources, according to the data provided there are 1157 NM physicians, 1953 technologists, 586 medical physicists, and 173 radiopharmacists or radiochemists in the region. Approximately half of all available human resources are accounted for by Turkey. The region has great potential for expanding the applications of NM; this becomes especially important in view of the high prevalence of non-communicable diseases. Further increasing awareness of the clinical applications of NM in healthcare and strengthening technical and human capacities including the establishment of training programs for all professionals and disciplines in the field are recognized as key components in advancing the practice of NM in the Middle East. PMID- 27237438 TI - Novel Cadmium Zinc Telluride Devices for Myocardial Perfusion Imaging Technological Aspects and Clinical Applications. AB - Myocardial perfusion imaging plays an important role in the assessment of patients with known or suspected coronary artery disease and is well established for diagnosis and for prognostic evaluation in these patients. The dedicated cardiac SPECT cameras with solid-state cadmium zinc telluride (CZT) detectors were first introduced a decade ago. A large body of evidence is building up, showing the superiority of the new technology compared with conventional gamma cameras. Not only the CZT detectors, but also new collimator geometries, the ability to perform focused imaging optimized for the heart and advances in data processing algorithms all contribute to the significantly improved sensitivity up to 8-10 times, as well as improved energy resolution and improved reconstructed spatial resolution compared with conventional technology. In this article, we provide an overview of the physical characteristics of the CZT cameras, as well as a review of the literature published so far, including validation studies in comparison with conventional myocardial perfusion imaging and with invasive coronary angiography, significant reduction in radiation dose, and new imaging protocols enabled by the new technology. PMID- 27237440 TI - SPECT-PET in Epilepsy and Clinical Approach in Evaluation. AB - In epilepsy, a detailed history, blood chemistry, routine electroencephalography, and brain MRI are important for the diagnosis of seizure type or epilepsy syndrome for the decision of appropriate drug treatment. Although antiepileptic drugs are mostly successful for controlling epileptic seizures, 20%-30% patients are resistant to medical treatment and continue to have seizures. In this intractable patient group, surgical resection is the primarily preferred treatment option. This particular group of patients should be referred to the epilepsy center for detailed investigation and further treatment. When the results of electroencephalography, MRI, and clinical status are discordant or there is no structural lesion on MRI, ictal-periictal SPECT, and interictal PET play key roles for lateralization or localization of epileptic region and guidance for the subsequent subdural electrode placement in intractable epilepsy. SPECT and PET show the functional status of the brain. SPECT and PET play important roles in the evaluation of epilepsy sydromes in childhood by showing abnormal brain regions. Most of the experience has been gained with (18)FDG-PET, in this respect. (11)C-flumazenil-PET usually deliniates the seizure focus more smaller than (18)FDG-PET and is sensitive in identifying medial temporal sclerosis. (11)C-alpha-methyl-l-tryptophan is helpful in the differentiation of epileptogenic and nonepileptogenic regions in children especially in tuberous sclerosis and multifocal cortical dysplasia for the evaluation of surgery. Finally, when there is concordance among these detailed investigations, resective surgery or palliative procedures can be discussed individually. PMID- 27237439 TI - Breast Imaging Utilizing Dedicated Gamma Camera and (99m)Tc-MIBI: Experience at the Tel Aviv Medical Center and Review of the Literature Breast Imaging. AB - The scope of the current article is the clinical role of gamma cameras dedicated for breast imaging and (99m)Tc-MIBI tumor-seeking tracer, as both a screening modality among a healthy population and as a diagnostic modality in patients with breast cancer. Such cameras are now commercially available. The technology utilizing a camera composed of a NaI (Tl) detector is termed breast-specific gamma imaging. The technology of dual-headed camera composed of semiconductor cadmium zinc telluride detectors that directly converts gamma-ray energy into electronic signals is termed molecular breast imaging. Molecular breast imaging system has been installed at the Department of Nuclear medicine at the Tel Aviv Sourasky Medical Center, Tel Aviv in 2009. The article reviews the literature well as our own experience. PMID- 27237441 TI - Nuclear Medicine in Pediatric and Adolescent Tumors. AB - Nuclear medicine has an important role in the management of many cancers in pediatric age group with multiple imaging modalities and radiopharmaceuticals targeting various biological uptake mechanisms. 18-Flourodeoxyglucose is the radiotracer of choice especially in patients with sarcoma and lymphoma. (18)FDG PET, for sarcoma and lymphomas, is proved to be superior to conventional imaging in staging and therapy response. Although studies are limited in pediatric population, (18)FDG-PET/CT has found its way through international guidelines. Limitations and strengths of PET imaging must be noticed before adapting PET imaging in clinical protocols. Established new response criteria using multiple parameters derived from (18)FDG-PET would increase the accuracy and repeatability of response evaluation. Current data suggest that I-123 metaiodobenzylguanidine (MIBG) remains the tracer of choice in the evaluation of neuroblastoma (NB) because of its high sensitivity, specificity, diagnostic accuracy, and prognostic value. It is valuable in determining the response to therapy, surveillance for disease recurrence, and in selecting patients for I-131 therapy. SPECT/CT improves the diagnostic accuracy and the interpretation confidence of MIBG scans. (18)FDG-PET/CT is an important complementary to MIBG imaging despite its lack of specificity to NB. It is valuable in cases of negative or inconclusive MIBG scans and when MIBG findings underestimate the disease status as determined from clinical and radiological findings. F-18 DOPA is promising tracer that reflects catecholamine metabolism and is both sensitive and specific. F-18 DOPA scintigraphy provides the advantages of PET/CT imaging with early and short imaging times, high spatial resolution, inherent morphologic correlation with CT, and quantitation. Regulatory and production issues currently limit the tracer's availability. PET/CT with Ga-68 DOTA appears to be useful in NB imaging and may have a unique role in selecting patients for peptide receptor radionuclide therapy with somatostatin analogues. C-11 hydroxyephedrine PET/CT is a specific PET tracer for NB, but the C-11 label that requires an on-site cyclotron production and the high physiologic uptake in the liver and kidneys limit its use. I-124 MIBG is useful for I-131 MIBG pretherapeutic dosimetry planning. Its use for diagnostic imaging as well as the use of F-18 labeled MIBG analogues is currently experimental. PET/MR imaging is emerging and is likely to become an important tool in the evaluation. It provides metabolic and superior morphological data in one imaging session, expediting the diagnosis and lowering the radiation exposure. Radioactive iodines not only detect residual tissue and metastatic disease but also are used in the treatment of differentiated thyroid cancer. However, these are not well documented in pediatric age group like adult patients. Use of radioactivity in pediatric population is very important and strictly controlled because of the possibility of secondary malignities; therefore, management of oncological cases requires detailed literature knowledge. This article aims to review the literature on the use of radionuclide imaging and therapy in pediatric population with thyroid cancer, sarcomas, lymphoma, and NB. PMID- 27237442 TI - Intra-Arterial Radionuclide Therapies for Liver Tumors. AB - Intra-arterial radionuclide therapies serve essentially as internal radiation treatment options for both primary and metastatic liver tumors, which imply delivering implantable radioactive microspheres into branches of hepatic arteries that feed liver tumors to provide a high dose of targeted radiation to tumor tissue, while sparing the healthy liver tissue from hazardous effects of radiation. The principle of this therapeutic option depends on the unique preferential arterial supply of malignant liver tumors in contrast with mostly portal venous supply of normal hepatocytes as well as excess amount of arterial neovascularization in the tumor bed. Therefore, intra-arterial radionuclide therapy can provide very high radiation exposure to tumor tissue, which is impossible to reach with external radiation therapy due to serious side effects and moreover, radiation can be targeted to tumor tissue selectively with less side effects. Yttrium-90 (Y-90), a high-energetic beta emitter is the most preferred radionuclide, which is used to label microspheres. Two types of Y-90 microspheres are commercially available that are made of resin and glass. Many studies in the literature have demonstrated that Y-90 microsphere therapy is an efficient and safe locoregional therapeutic option for unresectable primary and metastatic liver tumors such as hepatocellular carcinoma and liver metastases from colorectal cancer and breast cancer as well as neuroendocrine tumors. Furthermore, limited number of studies has reported its use in some relatively uncommon metastatic liver tumors from melanoma, pancreatic, renal, and lung cancer. Besides Y-90 microspheres, Iodine-131 lipiodol, Rhenium-188 lipiodol, Rhenium-188 microspheres, Holmium-166 chitosan, and Holmium-166 microspheres have been introduced as alternative radiopharmaceuticals for intra-arterial therapy for liver tumors. PMID- 27237443 TI - Production and Clinical Applications of Radiopharmaceuticals and Medical Radioisotopes in Iran. AB - During past 3 decades, nuclear medicine has flourished as vibrant and independent medical specialty in Iran. Since that time, more than 200 nuclear physicians have been trained and now practicing in nearly 158 centers throughout the country. In the same period, Tc-99m generators and variety of cold kits for conventional nuclear medicine were locally produced for the first time. Local production has continued to mature in robust manner while fulfilling international standards. To meet the ever-growing demand at the national level and with international achievements in mind, work for production of other Tc-99m-based peptides such as ubiquicidin, bombesin, octreotide, and more recently a kit formulation for Tc-99m TRODAT-1 for clinical use was introduced. Other than the Tehran Research Reactor, the oldest facility active in production of medical radioisotopes, there is one commercial and three hospital-based cyclotrons currently operational in the country. I-131 has been one of the oldest radioisotope produced in Iran and traditionally used for treatment of thyrotoxicosis and differentiated thyroid carcinoma. Since 2009, (131)I-meta-iodobenzylguanidine has been locally available for diagnostic applications. Gallium-67 citrate, thallium-201 thallous chloride, and Indium-111 in the form of DTPA and Oxine are among the early cyclotron produced tracers available in Iran for about 2 decades. Rb-81/Kr-81m generator has been available for pulmonary ventilation studies since 1996. Experimental production of PET radiopharmaceuticals began in 1998. This work has culminated with development and optimization of the high-scale production line of (18)F-FDG shortly after installation of PET/CT scanner in 2012. In the field of therapy, other than the use of old timers such as I-131 and different forms of P-32, there has been quite a significant advancement in production and application of therapeutic radiopharmaceuticals in recent years. Application of (131)I-meta iodobenzylguanidine for treatment of neuroblastoma, pheochromocytoma, and other neuroendocrine tumors has been steadily increasing in major academic university hospitals. Also (153)Sm-EDTMP, (177)Lu-EDTMP, (90)Y-citrate, (90)Y-hydroxyapatite colloid, (188/186)Re-sulfur colloid, and (188/186)Re-HEDP have been locally developed and now routinely available for bone pain palliation and radiosynovectomy. Cu-64 has been available to the nuclear medicine community for some time. With recent reports in diagnostic and therapeutic applications of this agent especially in the field of oncology, we anticipate an expansion in production and availability. The initiation of the production line for gallium-68 generator is one of the latest exciting developments. We are proud that Iran would be joining the club of few nations with production lines for this type of generator. There are also quite a number of SPECT and PET tracers at research and preclinical stage of development preliminarily introduced for possible future clinical applications. Availability of fluorine-18 tracers and gallium-68 generators would no doubt allow rapid dissemination of PET/CT practices in various parts of our large country even far from a cyclotron facility. Also, local production and availability of therapeutic radiopharmaceuticals are going to open exciting horizons in the field of nuclear medicine therapy. Given the available manpower, local infrastructure of SPECT imaging, and rapidly growing population, the production of Tc-99m generators and cold kit would continue to flourish in Iran. PMID- 27237444 TI - Structure and Activities of Nuclear Medicine in Kuwait. AB - The practice of nuclear medicine in Kuwait began in 1965 as a clinic for treating thyroid diseases. The practice developed gradually and until 1981 when the Faculty of Medicine established the Division of Nuclear Medicine in the Department of Radiology, which later became a separate department responsible for establishing and managing the practice in all hospitals of Kuwait. In 1987, a nuclear medicine residency program was begun and it is administered by Kuwait Institute for Medical Specializations originally as a 4-year but currently as a 5 year program. Currently there are 11 departments in the ministry of health hospitals staffed by 49 qualified attending physicians, mostly the diplomats of the Kuwait Institute for Medical Specializations nuclear medicine residency program, 4 academic physicians, 2 radiopharmacists, 2 physicists, and 130 technologists. These departments are equipped with 33 dual-head gamma cameras, 10 SPET/CT, 5 PET/CT, 2 cyclotrons, 1 breast-specific gamma imaging, 1 positron emitting mammography, 10 thyroid uptake units, 8 technegas machines, 7 PET infusion systems, and 8 treadmills. Activities of nuclear medicine in Kuwait include education and training, clinical service, and research. Education includes nuclear medicine technology program in the Faculty of Allied Health Sciences, the 5-year residency program, medical school teaching distributed among different modules of the integrated curriculum with 14 didactic lecture, and other teaching sessions in nuclear medicine MSc program, which run concurrently with the first part of the residency program. The team of Nuclear Medicine in Kuwait has been active in research and has published more than 300 paper, 11 review articles, 12 book chapters, and 17 books in addition to 36 grants and 2 patents. A PhD program approved by Kuwait University Council would begin in 2016. PMID- 27237445 TI - The First Reported Case of Erdheim-Chester Disease in Egypt with Bilateral Exophthalmos, Loss of Vision, and Multi-Organ Involvement in a Young Woman. AB - BACKGROUND: Erdheim-Chester disease is a rare non-Langerhans-cell histiocytosis of unknown etiology with multi-organ involvement. CASE REPORT: A 19-year-old woman presented with orthopnea, severe fatigue, bilateral exophthalmos, and gradual loss of vision. She had anemia and mild leucocytosis related to chronic illness. Marked left side pleural effusion and massive pericardial effusion with bilateral hydronephrosis were detected by plain X-ray, echocardiography, and computed tomography, respectively. Retro-orbital tissue and bone marrow biopsy revealed histiocytic infiltration, which was CD68-positive and CD1a-negative. CONCLUSIONS: This report describes the first case presentation of Erdheim-Chester disease in our country. This case report may advance our understanding of an orphan disease. Our patient's young age and stable clinical status may allow long term follow-up of treatment results. PMID- 27237446 TI - Modified transperitoneal ports configuration and docking technique for renal surgeries with the da Vinci Surgical System Xi. PMID- 27237447 TI - Systematic review and meta-analysis of the diagnostic accuracy of the water swallow test for screening aspiration in stroke patients. AB - AIM: The aim of this study was to determine the diagnostic accuracy of the water swallow test for screening aspirations in stroke patients. BACKGROUND: The water swallow test is a simple bedside screening tool for aspiration among stroke patients in nursing practice, but results from different studies have not been combined before. DESIGN: A systematic review and meta-analysis was conducted to provide a synthetic and critical appraisal of the included studies. DATA SOURCES: Electronic literature in MEDLINE, EMBASE, CINAHL and other sources were searched systemically in this study. Databases and registers were searched from inception up to 30 April 2015. REVIEW METHODS: This systematic review was conducted using the recommendations from Cochrane Collaboration for Systematic Reviews of Diagnostic Test Accuracy. Bivariate random-effects models were used to estimate the diagnostic accuracy across those studies. The tool named Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) was used to evaluate the quality of the studies. RESULTS: There were 770 stroke patients in the 11 studies for the meta analysis. The water swallow test had sensitivities between 64-79% and specificities between 61-81%. Meta-regression analysis indicated that increasing water volume resulted in higher sensitivity but lower specificity of the water swallow test. CONCLUSIONS: This systematic review showed that the water swallow test was a useful screening tool for aspiration among stroke patients. The test accuracy was related to the water volume and a 3-oz water swallow test was recommended for aspiration screening in stroke patients. PMID- 27237448 TI - A Model of Charge-Transfer Excitons: Diffusion, Spin Dynamics, and Magnetic Field Effects. AB - In this Letter, we explore how the microscopic dynamics of charge-transfer (CT) excitons are influenced by the presence of an external magnetic field in disordered molecular semiconductors. This influence is driven by the dynamic interplay between the spin and spatial degrees of freedom of the electron-hole pair. To account for this interplay, we have developed a numerical framework that combines a traditional model of quantum spin dynamics with a stochastic coarse grained model of charge transport. This combination provides a general and efficient methodology for simulating the effects of magnetic field on CT state dynamics, therefore providing a basis for revealing the microscopic origin of experimentally observed magnetic field effects. We demonstrate that simulations carried out on our model are capable of reproducing experimental results as well as generating theoretical predictions related to the efficiency of organic electronic materials. PMID- 27237449 TI - Hypertrophic lupus erythematosus successfully treated with hydroxychloroquine. PMID- 27237450 TI - Lack of Association between NYD-SP18 Variant and Obesity. The Health Alcohol and Psychosocial Factors in Eastern Europe Study. AB - AIM: To replicate the finding that the polymorphism rs6971091 within the NYD-SP18 gene is associated with body mass index (BMI). METHOD: We analysed data of 29,284 adults (46.2% of males, mean age 58.9 (SD 7.3), mean BMI 28.6 (5.0 kg/m2)) examined within the Health Alcohol and Psychosocial Factors in Eastern Europe study in the Czech Republic, Poland, Lithuania and Russia. RESULTS: BMI did not differ by rs6971091 genotype. In men, the mean BMI (SEs) in GG, GA and AA carriers were 27.8 (0.05), 27.9 (0.06) and 27.9 (0.14) kg/m2, respectively, (p = 0.26); in women, the corresponding values were 29.2 (0.06), 29.1 (0.07) and 29.1 (0.16), p = 0.57. In Czech subjects (n = 6,752), for whom the FTO rs17817449 genotype was available, there was no interaction between the NYD-SP18 and FTO polymorphisms in determination of BMI. Adjustment for age, energy and fat intake and physical activity did not materially change the results. There was no association of the NYD-SP18 genotype with waist-hip ratio. CONCLUSION: This study in a large Slavonic population sample suggests that the rs6971091 variant within the NYD-SP18 gene is not an important determinant of obesity in middle-aged persons. PMID- 27237451 TI - Potential impact on blood availability and donor iron status of changes to donor hemoglobin cutoff and interdonation intervals. AB - BACKGROUND: A minimum male hemoglobin (Hb) level of 13.0 g/dL becomes a Food and Drug Administration requirement effective May 2016. In addition, extending whole blood (WB) interdonation intervals (IDIs) beyond 8 weeks has been considered to reduce iron depletion in repeat blood donors. This study estimates the impact these changes might have on blood availability and donor iron status. STUDY DESIGN AND METHODS: Six blood centers participating in Retrovirus Epidemiology Donor Study-II (REDS-II) collected information on all donation visits from 2006 to 2009. Simulations were developed from these data using a multistage approach that first sought to adequately reproduce the patterns of donor return, Hb and ferritin levels, and outcomes of a donor's visit (successful single- or double red blood cell donation, deferral for low Hb) observed in REDS-II data sets. Modified simulations were used to predict the potential impact on the blood supply and donor iron status under different Hb cutoff and IDI qualification criteria. RESULTS: More than 10% of WB donations might require replacement under many simulated scenarios. Longer IDIs would reduce the proportion of donors with iron depletion, but 80% of these donors may remain iron-depleted if minimal IDIs increased to 12 or 16 weeks. CONCLUSION: Higher Hb cutoffs and longer IDIs are predicted to have a potentially large impact on collections but only a modest impact on donor iron depletion. Efforts to address iron depletion should be targeted to at-risk donors, such as iron supplementation programs for frequent donors, and policy makers should try to avoid broadly restrictive donation requirements that could substantially reduce blood availability. PMID- 27237452 TI - A General Method for Growing Two-Dimensional Crystals of Organic Semiconductors by "Solution Epitaxy". AB - Two-dimensional (2D) crystals of organic semiconductors (2DCOS) have attracted attention for large-area and low-cost flexible optoelectronics. However, growing large 2DCOS in controllable ways and transferring them onto technologically important substrates, remain key challenges. Herein we report a facile, general, and effective method to grow 2DCOS up to centimeter size which can be transferred to any substrate efficiently. The method named "solution epitaxy" involves two steps. The first is to self-assemble micrometer-sized 2DCOS on water surface. The second is epitaxial growth of them into millimeter or centimeter sized 2DCOS with thickness of several molecular layers. The general applicability of this method for the growth of 2DCOS is demonstrated by nine organic semiconductors with different molecular structures. Organic field-effect transistors (OFETs) based on the 2DCOS demonstrated high performance, confirming the high quality of the 2DCOS. PMID- 27237453 TI - Enhanced Thermoelectric Properties of Polyaniline Nanofilms Induced by Self Assembled Supramolecules. AB - Polyaniline (PANI) is one of the most promising candidates for flexible organic thermoelectric (TE) applications owing to its relatively low cost and high stability. Herein, the self-assembled supramolecule (SAS) (3,6-dioctyldecyloxy 1,4-benzenedicarboxylic acid) was used as an additive and was introduced into PANI films as a template. Raman spectroscopy, X-ray diffraction, and conductive atomic force microscopy analyses demonstrated that the highly ordered chain structure of PANI was achieved by chemical interactions between PANI and the SAS. Moreover, the ordered regions in the PANI-SAS film increased with a decrease in the film thickness. Consequently, the TE properties of PANI-SAS films were not only much higher than those of PANI films, but they also increased with a decrease in film thickness. The maximum TE power factor of the PANI-SAS film reached 31 MUW m(-1) K(-2) , which is approximately six times higher than the power factor of a PANI film with a similar thickness. This work offers a promising way to prepare PANI thin films with enhanced TE properties. PMID- 27237454 TI - Understanding well-being and learning of Nigerian nurses: a job demand control support model approach. AB - AIM: This study investigated whether Nigerian nurses' emotional exhaustion and active learning were predicted by job demands, control and social support. BACKGROUND: Limited research has been conducted concerning nurses' work stress in developing countries, such as Nigeria. Accordingly, it is not clear whether work interventions for improving nurses' well-being in these countries can be based on work stress models that are developed in Western countries, such as the job demand control support model, as well as on empirical findings of job demand control support research. METHOD: Nurses from Nurses Across the Borders Nigeria were invited to complete an online questionnaire containing validated scales; 210 questionnaires were fully completed and analysed. Multiple regression analysis was used to test the hypotheses. RESULTS: Emotional exhaustion was higher for nurses who experienced high demands and low supervisor support. Active learning occurred when nurses worked under conditions of high control and high supervisor support. CONCLUSION: The findings suggest that the job demand control support model is applicable in a Nigerian nursing situation; the model indicates which occupational stressors contribute to poor well-being in Nigerian nurses and which work characteristics may boost nurses' active learning. IMPLICATIONS FOR NURSING MANAGEMENT: Job (re)design interventions can enhance nurses' well-being and learning by guarding nurses' job demands, and stimulating job control and supervisor support. PMID- 27237455 TI - Acute white matter changes following sport-related concussion: A serial diffusion tensor and diffusion kurtosis tensor imaging study. AB - Recent neuroimaging studies have suggested that following sport-related concussion (SRC) physiological brain alterations may persist after an athlete has shown full symptom recovery. Diffusion MRI is a versatile technique to study white matter injury following SRC, yet serial follow-up studies in the very acute stages following SRC utilizing a comprehensive set of diffusion metrics are lacking. The aim of the current study was to characterize white matter changes within 24 hours of concussion in a group of high school and collegiate athletes, using Diffusion Tensor and Diffusion Kurtosis Tensor metrics. Participants were reassessed a week later. At 24 hours post-injury, the concussed group reported significantly more concussion symptoms than a well-matched control group and demonstrated poorer performance on a cognitive screening measure, yet these differences were nonsignificant at the 8-day follow-up. Similarly, within 24 hours after injury, the concussed group exhibited a widespread decrease in mean diffusivity, increased axial kurtosis and, to a lesser extent, decreased axial and radial diffusivities compared with control subjects. At 8 days post injury, the differences in these diffusion metrics were even more widespread in the injured athletes, despite improvement of symptoms and cognitive performance. These MRI findings suggest that the athletes might not have reached full physiological recovery a week after the injury. These findings have significant implications for the management of SRC because allowing an athlete to return to play before the brain has fully recovered from injury may have negative consequences. Hum Brain Mapp 37:3821-3834, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27237456 TI - On the Development of Perfectionism: The Longitudinal Role of Academic Achievement and Academic Efficacy. AB - OBJECTIVE: Although perfectionism is a prominent personality disposition, only a few longitudinal studies have investigated how perfectionism develops. Theoretical models and qualitative studies have posited that academic success is a developmental antecedent of perfectionism. Yet, quantitative studies tend to interpret the cross-sectional relationships as academic success being an outcome of perfectionism. In light of these gaps in the literature, the present study was the first to investigate the longitudinal relationships between perfectionistic strivings, perfectionistic concerns, academic achievement, and academic efficacy by examining academic success as an antecedent of perfectionism. METHOD: The study examined 487 adolescents (aged 12-19 years, 54% female) using a cross lagged longitudinal design with three time points spaced 4-5 months apart. RESULTS: Results showed that academic achievement predicted relative increases in both perfectionistic strivings and perfectionistic concerns, even when including academic efficacy. In addition, academic efficacy predicted relative increases in perfectionistic strivings. CONCLUSIONS: This is the first study to show that academic achievement is a common factor in the development of perfectionistic strivings and perfectionistic concerns, whereas academic efficacy plays a role only in the development of perfectionistic strivings. Implications of the findings for the development of perfectionism are discussed. PMID- 27237458 TI - Compassion for Physicians. PMID- 27237457 TI - Caregiver reaction assessment: psychometric properties in caregivers of advanced cancer patients. PMID- 27237459 TI - Problems + Solutions. AB - Readers are invited to submit questions relating to problem cases. Inquiries will be answered by qualified consultants and replies forwarded by mail promptly. Selected problems and solutions are published every month in this section. PMID- 27237460 TI - Epilepsy. PMID- 27237461 TI - Classification of epilepsies. PMID- 27237462 TI - Cues/Tips. PMID- 27237463 TI - Primary Care Digest. PMID- 27237466 TI - Disseminated Hormographiella aspergillata infection with involvement of the lung, brain, and small intestine following allogeneic hematopoietic stem cell transplantation: case report and literature review. AB - Disseminated infection by Hormographiella aspergillata is extremely rare and small intestine involvement has not been reported previously. A 51-year-old man with myelodysplastic syndrome developed pneumonia after cord blood cell transplantation. Fungal growth from the biopsied lung was identified as H. aspergillata by morphology and the gene analysis. Although antifungal agents including voriconazole and liposomal amphotericin B were administered, he died of disseminated H. aspergillata infection. We review the literature and discuss the treatment and prognosis. PMID- 27237468 TI - Targeting obesity in COPD through allied health therapies. PMID- 27237469 TI - The impact of lower extremity pain conditions on clinical variables and health related quality of life in patients with stroke. AB - BACKGROUND: The presence of lower extremity pain may be associated with poorer motor recovery, impaired activities of daily living (ADL), reduced quality of life, and disability in patients with stroke. OBJECTIVE: The aims of the study were to describe the characteristics of lower extremity pain conditions and to evaluate the impact of lower extremity pain on clinical variables, and health related quality of life in patients with stroke. METHODS: One hundred and eighty five patients with stroke who have self-reported pain in the lower extremity were included in the study. Lower extremity pain characteristics of stroke survivors including etiology, intensity, onset time, frequency, aggravating factors, relieving factors, site, and location of pain were evaluated and recorded. The Brunnstrom motor recovery scale, the functional ambulation category, the mini mental state examination, the star cancellation test, the beck depression inventory, the Barthel Index, and the Short Form-36 Questionnaire (SF-36) were used. RESULTS: The causes of lower extremity pain were diagnosed as osteoarthritis (51.1%), central neuropathic pain (28.7%), mixed pain (10.3%), low back pain associated with leg pain (8.6%), greater trochanteric pain syndrome (5.2%), prior hip fracture (2.4%), heterotopic ossification (2%), developmental hip luxation (1%), hallux valgus (0.5%), and malignancy (0.5%). The intensity of lower extremity pain was a significant predictor of cognitive functions, ADL, depression, and all SF-36 subscales except emotional role and vitality. The duration of lower extremity pain was a significant predictor of depression and lower extremity spasticity. CONCLUSIONS: Since lower extremity pain conditions have a significant important influence on clinical variables and health-related quality of life in stroke survivors, early identification and appropriate treatment of the lower extremity pain conditions should be carried out in order to reduce the level of disability in stroke patients. PMID- 27237470 TI - Chemical potential and reaction electronic flux in symmetry controlled reactions. AB - In symmetry controlled reactions, orbital degeneracies among orbitals of different symmetries can occur along a reaction coordinate. In such case Koopmans' theorem and the finite difference approximation provide a chemical potential profile with nondifferentiable points. This results in an ill-defined reaction electronic flux (REF) profile, since it is defined as the derivative of the chemical potential with respect to the reaction coordinate. To overcome this deficiency, we propose a new way for the calculation of the chemical potential based on a many orbital approach, suitable for reactions in which symmetry is preserved. This new approach gives rise to a new descriptor: symmetry adapted chemical potential (SA-CP), which is the chemical potential corresponding to a given irreducible representation of a symmetry group. A corresponding symmetry adapted reaction electronic flux (SA-REF) is also obtained. Using this approach smooth chemical potential profiles and well defined REFs are achieved. An application of SA-CP and SA-REF is presented by studying the Cs enol-keto tautomerization of thioformic acid. Two SA-REFs are obtained, JA'(xi) and JA'' (xi). It is found that the tautomerization proceeds via an in-plane delocalized 3 center 4-electron O-H-S hypervalent bond which is predicted to exist only in the transition state (TS) region. (c) 2016 Wiley Periodicals, Inc. PMID- 27237467 TI - Alteration of lymphocyte phenotype and function in sickle cell anemia: Implications for vaccine responses. AB - Individuals with sickle cell anemia (SCA) have increased susceptibility to infections, secondary to impairment of immune function. Besides the described dysfunction in innate immunity, including impaired opsonization and phagocytosis of bacteria, evidence of dysfunction of T and B lymphocytes in SCA has also been reported. This includes reduction in the proportion of circulating CD4+ and CD8+ T cells, reduction of CD4+ helper: CD8+ suppressor T cell ratio, aberrant activation and dysfunction of regulatory T cells (Treg ), skewing of CD4+ T cells towards Th2 response and loss of IgM-secreting CD27 + IgM(high) IgD(low) memory B cells. These changes occur on the background of immune activation characterized by predominance of memory CD4+ T cell phenotypes, increased Th17 signaling and elevated levels of C-reactive protein and pro-inflammatory cytokines IL-6 and TNF alpha, which may affect the immunogenicity and protective efficacy of vaccines available to prevent infections in SCA. Thus, in order to optimize the use of vaccines in SCA, a thorough understanding of T and B lymphocyte functions and vaccine reactivity among individuals with SCA is needed. Studies should be encouraged of different SCA populations, including sub-Saharan Africa where the burden of SCA is highest. This article summarizes our current understanding of lymphocyte biology in SCA, and highlights areas that warrant future research. Am. J. Hematol. 91:938-946, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27237472 TI - Redescription of Hysteronotus megalostomus (Characiformes: Characidae: Stevardiinae), a poorly known characid from tributaries of the Rio Sao Fancisco, Brazil with comments on the conservation of the species. AB - Originally described from the upper Rio das Velhas, a tributary of the Rio Sao Francisco, state of Minas Gerais, Brazil, Hysteronotus megalostomus was recently collected in many tributaries of the Rio Sao Francisco north of the type locality. The specimens of the population samples collected outside the type locality share the morphological features present in the type material except for the presence of an adipose fin found only in two specimens within the more recently collected material. Presence or absence of the adipose fin has been extensively used by fish taxonomists to characterize different species and even genera, but in H. megalostomus the character is not consistent, indicating its use alone is not diagnostic. The species is redescribed and its phylogenetic relationships and conservation status are briefly discussed. PMID- 27237471 TI - Haplotypes of the MTHFR gene are associated with an increased risk of breast cancer in a Han Chinese population in Gansu province. AB - Elevated homocysteine levels are a risk factor for breast cancer, although the mechanism underlying this effect is unknown. Genome-wide association studies were used to systematically identify genetic variants which were significantly associated with the circulating homocysteine concentration. To examine the role of homocysteine-related variants in the occurrence of breast cancer, we investigated the association between these variants and breast cancer in a Han Chinese population. Five variants of genome-wide significant homocysteine-related genes were selected for the analysis in a case-control study, with a total of 487 patients with breast cancer and 605 controls. We found that none of the studied polymorphisms were related to the altered breast cancer risk. In the haplotypic analysis, the 5,10-methylenetetrahydrofolate reductase (MTHFR) haplotypes rs12085006A/rs1999594G/rs1801133C (OR = 3.44, 95% CI = 1.58-7.50, P = 0.0019) and rs12085006A/rs1999594G/rs1801133T (OR = 16.21, 95% CI = 2.19- 120.32, P = 0.0065) were significantly associated with an increased breast cancer risk when compared with the wild-type haplotype. Both of the risky MTHFR haplotypes were correlated with decreased MTHFR gene expression and elevated homocysteine concentrations, indicating a genetic component for hyperhomocysteinemia. The MTHFR haplotypes reconstructed with homocysteine-related variants were associated with the occurrence of breast cancer. This finding further emphasizes the importance of homocysteine metabolism genes in breast carcinogenesis and highlights the interplay of diet, genetics, and human cancers. (c) 2016 IUBMB Life, 68(7):526 534, 2016. PMID- 27237474 TI - [Not Available]. AB - To the Secretary of State for Health 'Dear Mr Clarke, I hope you don't mind me I setting out in this open letter the questions nurses all over the country are asking about the White Paper. As you know nurses care deeply about the future of the health services and are disturbed about many of the implications of the changes you propose. PMID- 27237473 TI - The formation, function and regulation of amyloids: insights from structural biology. AB - Amyloid diseases are characterized by the accumulation of insoluble, beta-strand rich aggregates. The underlying structural conversions are closely associated with cellular toxicity, but can also drive the formation of functional protein assemblies. In recent years, studies in the field of structural studies have revealed astonishing insights into the origins, mechanisms and implications of amyloid formation. Notably, high-resolution crystal structures of peptides in amyloid-like fibrils and prefibrillar oligomers have become available despite their challenging chemical nature. Nuclear magnetic resonance spectroscopy has revealed that dynamic local polymorphisms in the benign form of the prion protein affect the transformation into amyloid fibrils and the transmissibility of prion diseases. Studies of the structures and interactions of chaperone proteins help us to understand how the cellular proteostasis network is able to recognize different stages of aberrant protein folding and prevent aggregation. In this review, we will focus on recent developments that connect the different aspects of amyloid biology and discuss how understanding the process of amyloid formation and the associated defence mechanisms can reveal targets for pharmacological intervention that may become the first steps towards clinically viable treatment strategies. PMID- 27237475 TI - Over 100 hospitals lean towards opt out plan. AB - More than 100 hospitals and community units from across the country have expressed an interest in opting out of district health authority control under the Government's White Paper proposals for the NHS. PMID- 27237476 TI - ENB lists new proposals. AB - THE ENB has outlined major new proposals which would increase its responsibilities under the NHS White Paper plans. PMID- 27237477 TI - Extra L40m for health service. AB - HEALTH SECRETARY, Kenneth Clarke, has earmarked an extra L40 million which will go towards implementing the White Paper proposals for the health service. PMID- 27237479 TI - [Not Available]. AB - The RCN School Nurses' Forum and West Lambeth school nur[Illegible Word] staged a display at St Thomas' Hospital last week to celeb[Illegible Word] International Nurses' Day. PMID- 27237478 TI - Labour hears health groups' concerns. AB - REPRESENTATIVES OF health organisations nationwide reached a consensus last week that the NHS White Paper could jeopardise the care of the most vulnerable client groups. PMID- 27237480 TI - Mental illness research in danger, says report. AB - OPPORTUNITIES FOR advancement in the care and treatment of mental illness are being jeopardised through underfunding, says a major report. PMID- 27237482 TI - Health authorities outline underfunding statistics. AB - THE GOVERNMENT has this year underfunded health authorities by at least L490 million, the National Association of Health Authorities claimed last week. PMID- 27237481 TI - Extended role difficulties. AB - British law has rendered nurses professionally 'cold, impotent and sterile', Karen Rea, a barrister and nurse said last week. PMID- 27237483 TI - Students hear strike warning. AB - INDUSTRIAL ACTION by nurses could end any dialogue with the Government on pay and conditions, students have been warned. PMID- 27237484 TI - Oh nurses' image is vital. AB - OCCUPATIONAL HEALTH nurses must 'throw away their frilly hats' and sell themselves as proactive professionals, the RCN Occupational Health Managers Forum Conference heard last week. PMID- 27237485 TI - Private surgery attacked. AB - A HEALTH AUTHORITY with nearly 10,000 people on its waiting lists dismissed attacks last week on its drive to boost private patient numbers. PMID- 27237486 TI - P2000 funding raises concern. AB - THE PROJECT 2000 demonstration districts are making positive progress, but the question remains whether there will be enough money in the kitty to pay for it, an ENB education director warned last week. PMID- 27237487 TI - [Not Available]. AB - Victory farewell: Royal College of Nursing representatives from all over the Wessex region gathered on HMS Victory to bid farewell to their General Secretary Trevor Clay. Nurses representing all of Wessex region's branches and specialities attended the spe[Illegible word] reception to mark Mr Clay's retirement this autumn. They [Illegible word] him with a specially inscribed ship in a bottle model of the Victory. The region is also collecting for the Trevor Clay Scholarship Fund for nurses. Mr Clay is pictured with staff and College members, former President Dame Sheila Quinn, and ship's captain Lt Cmdr Whitehead. PMID- 27237490 TI - Admissions limited. AB - The major factor limiting emergency admissions to the Queens Medical Centre, Nottingham, after the M1 airplane crash was the shortage of intensive care beds, the hospital's A&E consultant has revealed. PMID- 27237489 TI - Hospital inadequate. AB - The Senior Casualty Sister at Bradford Royal Infirmary alerted the hospital that a major incident had occurred after the football stadium fire when casualties arrived on foot, by car, with police and in ambulances. PMID- 27237491 TI - [Not Available]. AB - A Major Disaster Symposium organised by Central Nottinghamshire Health Authority brought together delegates from many disciplines from all over the country. Julie Sylvester reports on some of the lessons learnt from recent tragic events. PMID- 27237493 TI - Rare leukaemia virus screening to go ahead. AB - A pilot study to determine the need to screen blood for a rare leukaemia virus looks set to get Government approval. PMID- 27237492 TI - Rapid transit saves lives. AB - 'Scoop and run' is the best way to deal with multiple injured patients in a major disaster such as the Ml airplane crash, Professor Angus Wallace told the Major Disaster Symposium. PMID- 27237494 TI - Record access scheme set up. AB - Parents will for the first time have access to their children's main medical records in a pioneering health authority scheme launched last week. PMID- 27237496 TI - Resolution outcomes. PMID- 27237495 TI - Breaking the mould The theme of the 1989 International Nurses' Day on May 12 was school health. Nursing Standard looks at the challenges facing this branch of the profession. Maura McNally reports. AB - School nurses across Britain last week celebrated International Nurses' Day with a drive to dispel their 'Nitty Norah' image. PMID- 27237497 TI - Government opposes EEC smoking ban. AB - EEC moves to ban smoking in all public places - including hospitals - are being opposed by the British Government. PMID- 27237499 TI - Waiting list rise sparks criticism. AB - Hospital waiting lists leapt by a further 30,000 last year, sparking off another party political row over the health service. PMID- 27237498 TI - Family credit scheme rolls on. AB - Employers have been urged to move fast in helping parents claim benefits due to them under the new Family Credit scheme. PMID- 27237500 TI - Leaflet to allay GPs white paper fears. AB - A campaign to allay GPs' fears about the effects of the National Health Service White Paper has been launched by the Scottish Office. PMID- 27237501 TI - No real polll tax benefit for pensioners. AB - Two-thirds of pensioners will be worse off or gain less than L1 per week under [Illegible word] Government's poll tax arrangements, David Blunkett, Labour's poll tax spokesman, has claimed. PMID- 27237502 TI - India. AB - The Supreme Court of India is facing a dilemma in allocating compensation for Bhopal Gas Leak Disaster victims because no agreement has been reached on the long term medical effects from methyliso-cyanate (MIC). PMID- 27237503 TI - Bulgaria. AB - The Bulgarian government has announced a mass HIV screening programme in which every adult under 65 living in the capital Sofia is to be tested. PMID- 27237504 TI - ICN. AB - Nurses in Greece, Israel and Puerto Rico have won major International Council of Nurses scholarships in recognition of their professional potential. PMID- 27237506 TI - Elderly pain perception. AB - The received wisdom that the elderly do not perceive pain as readily as the young, or tolerate it better, is unfounded according to researchers from Walton Hospital, Liverpool. PMID- 27237505 TI - Eire. AB - Irish Health Minister, Rory O'Hanlon, met Northern Ireland Health Minister, Richard Needham, recently for the latest in a series of discussions on Irish health care. PMID- 27237507 TI - Colorectal cancer. AB - Early diagnosis and simpler, less drastic treatment may be possible for people with colorectal cancer. PMID- 27237508 TI - Unemployment consultation. AB - The workload of general practitioners is likely to be higher and consultation times longer in areas of unemployment. PMID- 27237509 TI - Consciousness levels. AB - Indications other than obedience to commands should be considered to assess level of consciousness particularly in patients with left hemisphere intracerebral lesions. PMID- 27237510 TI - Oral comfort and hygiene. AB - Careful attention should be paid to oral comfort and hygiene in patients receiving morphine, according to researchers from the Royal Marsden Hospital, London. PMID- 27237511 TI - Opportunities in nurse education. AB - It is a rare student who starts out on a career in nursing with the intention of becoming a tutor. In an information package on the preparation for teachers sent out a couple of years ago, the English National Board described as 'endless' the qualities required to make a successful teacher, listing as important 'personality, sincerity, courage, resolution, efficiency, energy and tact'. The overall quality, it adds, is, perhaps, excellence. PMID- 27237513 TI - Listings. AB - Nursing Standard's listings section is a completely free service for its readers. To ensure maximum publicity for any event connected with your profession, be sure to let us know so that it can be included in our exhaustive nationwide guide to what's on in nursing. PMID- 27237512 TI - Resource management made easy. AB - Resource management is now one of the most frequently heard phrases within the health service. As a newcomer to the concept, it has been very difficult to find a straightforward description of just exactly what the phrase means and how it is achieved. This article is intended to present a general explanatory framework which might be helpful to other beginners. PMID- 27237514 TI - RNPFN. AB - The Royal National Pension Fund for Nurses (RNPFN) was founded over 100 years ago with the principal purpose of enabling nurses to make adequate provision for their retirement or ill-health. Although nurses still account for the majority of our members, we have widened our scope over the years to meet the ever-changing conditions in the world of health-care. PMID- 27237515 TI - Decisions, decisions. AB - In the present services for people with a mental handicap, moving away from the institutional type of care to a more normal home environment, my concern is the inability of so many managers to adjust to the new style of management that is needed for these services. That calls into question the quality of senior managers. PMID- 27237516 TI - Heart to heart. AB - As nurses, as part of our every day work, we help our patients to accept and come to terms with their illness. Throughout our careers we may ask ourselves how we would react if that role was to be reversed and we were to become the patients. PMID- 27237517 TI - Education and change. AB - The Government's White Paper 'Working for patients' amounts to a managerial, structural and financial upheaval for the National Health Service and has, in turn, major implications for nurse education. PMID- 27237521 TI - An international perspective The International Council of Nurses has its Congress every four years and hundreds of nurses from around the globe will congregate for the opening in Seoul on May 28. Nursing Standard previews the event and talks to Trevor Clay who adds his perspective from ten years of ICN involvement. AB - This month's ICN Congress is the 19th of its kind and focuses on the theme 'Nursing - A New Tomorrow'. Over a week, at the Inter-Continental Hotel, all kinds of nurses will congregate, give papers, swap experiences, hold meetings and air the most pressing issues facing the profession worldwide. The Royal College of Nursing is the UK representative and members pay a part of their subscription to the ICN. PMID- 27237522 TI - Reassessing income support. AB - The needs of the chronically sick are not acknowledged under the Income Support system introduced by the Department of Social Security in April '88. A year has now passed and the difficulties and shortfalls of the new system have become clear. PMID- 27237523 TI - Hillsborough response. AB - The comments put forward by Mike Walsh on the tragedy at Hillsborough ('You'll never walk alone', Nursing Standard week ending April 29) took many of my colleagues, including myself by surprise. The lessons to be learnt will only become more apparent when Lord Justice Taylor has completed his extensive enquiries into what exactly happened on that tragic day. Comments put forward at this moment in time by 'instant experts' are of benefit to no one especially when many aspects of the tragedy remain hidden and many more facts have yet to be brought to light. Your readers can be assured that my colleagues and I intend to prepare a full account of what happened within this department on that day, a day which will remain with many of us for a long time to come. Charge Nurse, A&E, Royal Hallamshire, Sheffield. PMID- 27237524 TI - Well in hand. AB - I was very disappointed at the RCN's recent Congress to hear health visitors and district nurses so adamantly saying they did not want to be employed by GPs. PMID- 27237525 TI - Praising the CPN. AB - At its last meeting, the Mental Nursing Committee of the English National Board, discussed the contribution of community psychiatric nurses in disaster situations. PMID- 27237526 TI - In need of help. AB - I am a school nurse working in St Francis School for the Handicapped. PMID- 27237527 TI - School health. AB - We were surprised to read that health visitors in Wales would like to devote more time to health promotion among school children (see Nursing Standard, 'Dissatisfied health visitors', week ending April 29). PMID- 27237528 TI - Testicular information. AB - l am a student nurse at a hospital in Buckinghamshire and part of our training is to complete a project essay on a health related topic. PMID- 27237529 TI - Student involvement. AB - Further to Anthony M Shannon's letter (Nursing Standard, week ending April 29) regarding the lack of student involvement at grass roots level within the Royal College of Nursing (real or not), I wondered if I might venture another point of view. PMID- 27237530 TI - On working together. AB - In January, 1989, Professor David James of Surrey University, writing about practice nurses, said that 'as in a young person growing up or a profession emerging and establishing itself, we see an evolution from dependency and constraint to autonomy and responsibility'. ! It is a clear and powerful statement with which practice nurses everywhere will identify. PMID- 27237531 TI - Leg bag for community patients. AB - A new leg bag designed for patients in the community with urinary catheters has been launched by InCare Medical Products. PMID- 27237532 TI - Convenient resuscitation outfit. AB - Vitalograph has introduced an emergency resuscitation outfit which, it claims, will provide the ultimate 'convenience store' for immediate care professionals. PMID- 27237533 TI - Comfortable casting tape. AB - A new easy-to-use orthopaedic casting tape is now available from Smith and Nephew Medical Limited. PMID- 27237534 TI - Disposable breathing systems. AB - A new range of disposable breathing systems for use in the inten sive care unit or theatre has just been launched by Intersurgical. PMID- 27237535 TI - Cupboards for surgeries. AB - A new range of storage cupboards specifically designed for use in surgeries or health centres has been launched by Doherty Medical. PMID- 27237536 TI - Head Start. AB - As anyone who has known a patient with a severe head injury will testify, the complications that ensue can be both traumatic and confusing. Brain damage, legal implications, financial cost, psychological effect - all these may play a part. PMID- 27237537 TI - Foreword. PMID- 27237538 TI - Clinical pearls in gastroenterology 2016. PMID- 27237539 TI - Correlation between Systemic Lupus Erythematosus Activity and Plasma Levels of Monomeric Prolactin and Macroprolactin. AB - The correlation of prolactin (PRL) levels with SLE activity is a controversial issue, which could be explained by the presence of macroprolactin (MPRL), a high molecular weight form of PRL with a lower in vivo biological activity. OBJECTIVES: We aimed to evaluate the prevalence of hyperprolactinemia, PRL and MPRL levels in SLE patients, and to correlate these levels with disease activity as measured by the SLE Disease Activity Index (SLEDAI). MATERIAL AND METHODS: We conducted a case-control, cross-sectional study with 73 SLE patients (L group), sixty-two of which were evaluated before and after treatment, and correlated the results with serum PRL and MPRL levels. These results were compared to those of 29 healthy women with ovulatory cycles (C group) and 34 women in the third trimester of pregnancy (G group). RESULTS: Mean PRL levels were: 8,8 ng/ml on C group; 12,0 ng/ml on L group (p = 0.02) and 158,5 ng/ml on G group. Hyperprolactinemia was present in 19.4% of SLE patients, but was not found on C group. The MPRL form was predominant among 20.5% of SLE patients, in none of the C group and in only 5.8% of pregnant women. There was a strong correlation between the PRL levels and SLE activity, regardless of the hormone's molecular form. SLE treatment was able to reduce levels of all forms of PRL. The predominance of MPRL, however, did not change after treatment. CONCLUSIONS: Despite its lower biological activity, MPRL levels correlated with LES activity as much as free prolactin. PMID- 27237540 TI - Evaluation of Explanted CorMatrix Intracardiac Patches in Children With Congenital Heart Disease. AB - BACKGROUND: Animal data demonstrate that intracardiac patches of decellularized porcine small intestine submucosa (CorMatrix; CorMatrix Cardiovascular, Inc, Atlanta, GA) become repopulated with native cells, suggesting the possibility of a substrate for regenerative tissue in humans. We report the only prospective series to date of explanted CorMatrix patches placed in infants with congenital heart disease. METHODS: CorMatrix patches were implanted as the hemi-Fontan baffle in patients during their second stage of palliation. The patch material was explanted as part of the standard Fontan operation. Specimens were analyzed with the use of hematoxylin and eosin, Movat pentachrome, and trichrome stains. RESULTS: Of the 12 implantations, 10 specimens were explanted. Two patients did not undergo Fontan because of unfavorable hemodynamics. Acellular material, chronic inflammation, fibrosis, and foreign body giant cell reaction was seen in all explanted patches. Also noted in explanted specimens was calcification (n = 2), elastic fibers (n = 2), and eosinophils (n = 2). No explanted CorMatrix material showed evidence of ingrowth of native cells or transformation into cardiac tissue at a median of 21 months after implantation. CONCLUSIONS: Although the CorMatrix remained pliable and most did not exhibit calcification, these intracardiac patches did not show evidence of native heart tissue ingrowth at a median of 21 months in vivo. PMID- 27237541 TI - Determination of Nursing Diagnoses in Children of Agricultural Laborer Families in South Eastern Regions of Turkey. AB - PURPOSE: Identifying functional health patterns and nursing diagnoses of migrant agricultural laborer families. METHODS: Interpretative-qualitative study based on interviews with 162 mothers of 0- to 2-year-old children in two Turkish provinces. FINDINGS: Health perception-health management: growth and development, risk for being delayed; health maintenance, ineffective; health behavior, risk prone; risk for contamination; risk for sudden infant death syndrome; and risk for injury. Nutritional-metabolic: Risk for infection; and breastfeeding, interrupted. Self-perception: risk for chronic low self-esteem, disturbed self esteem; and powerlessness. Role-relationship: impaired parenting; and dysfunctional family process. Coping-stress tolerance: coping, disabled family; violence, risk for other-directed. Cognitive-perceptive: knowledge deficit CONCLUSIONS: Nursing diagnoses of this population were reported for the first time. IMPLICATIONS: Addressing agricultural laborer families' diagnoses will positively affect maternal-child health. PMID- 27237542 TI - Corpus callosotomy outcomes in pediatric patients: A systematic review. AB - OBJECTIVE: Corpus callosotomy is a palliative neurosurgical treatment for patients with either generalized or multifocal refractory epilepsy and injurious drop attacks. This report aims to systematically review the pediatric literature. METHODS: Medline, Embase, Web of Knowledge, and Scopus were searched systematically for published articles on treatment outcomes of corpus callosotomy for refractory epilepsy. Studies were included if the patient population was younger than 18 at the time of surgery and median follow-up was >1 year. Studies were excluded if resective surgery was also performed. RESULTS: A total of 12 articles met inclusion criteria. All articles were retrospective case series, with the exception of one being a prospectively designed retrospective case series. There was very little agreement among authors on the definition of a good seizure outcome. Articles that used the Engel classification found that 88.2% of total corpus callosotomy patients had a worthwhile reduction in seizures compared with 58.6% of patients who underwent anterior corpus callosotomy (p < 0.05). Drop attacks improved from corpus callosotomy more than other generalized seizure types. Reported complications were minor in all but one patient, and one death was reported. Transient disconnection syndrome was significantly more likely in total corpus callosotomy than in anterior corpus callosotomy (12.5% vs. 0%; p < 0.05). Improvements in quality of life, behavior, and intelligence/development quotient, as well as parental satisfaction, were generally correlated with seizure outcome. There was no postcallosotomy change in the number of antiepileptic drugs. SIGNIFICANCE: Total corpus callosotomy was significantly more likely to result in a reduction in seizures. Anterior corpus callosotomy was unlikely to result in disconnection syndrome. Although all of the papers drew a similar conclusion, the quality of evidence was low. At best, the evidence raises the hypothesis that corpus callosotomy is a safe and effective treatment for refractory generalized epilepsy. It is clear that a case-control or randomized trial is warranted. PMID- 27237543 TI - The side-chain hydroxy groups of a cyclic alpha,alpha-disubstituted alpha-amino acid promote oligopeptide 310 -helix packing in the crystalline state. AB - A single chiral cyclic alpha,alpha-disubstituted amino acid with side-chain methoxymethyl (MOM) protecting groups, (3S,4S)-1-amino-(3,4 dimethoxymethoxy)cyclopentanecarboxylic acid [(S, S)-Ac5 c(dOMOM) ], or side chain hydroxy groups, (3S,4S)-1-amino-(3,4-dihydroxy)cyclopentanecarboxylic acid [(S, S)-Ac5 c(dOH) ], was attached to the N-terminal or C-terminal position of alpha-aminoisobutyric acid (Aib) tetrapeptide segments; i.e., we designed and synthesized four pentapeptides, Cbz-[(S, S)-Ac5 c(dOMOM) ]-(Aib)4 -OEt (1), Cbz [(S, S)-Ac5 c(dOH) ]-(Aib)4 -OEt (2), Cbz-(Aib)4 -[(S, S)-Ac5 c(dOMOM) ]-OMe (3), and Cbz-(Aib)4 -[(S, S)-Ac5 c(dOH) ]-OMe (4). We then analyzed the peptides' structures in the crystalline state. The four peptides all folded into 310 helical structures; 1 formed a left-handed (M) 310 -helix, 2 formed a mixture of right-handed (P) and (M) 310 -helices, 3 formed a mixture of (P) and (M) 310 helices, and 4 formed a (P) 310 -helix, respectively. In packing mode, the molecules of peptides 1 and 3, which both possessed an Ac5 c(dOMOM) residue, were connected by intermolecular hydrogen bonds along the peptide backbone (N?H...O type). On the other hand, the packing of peptides 2 and 4, which both contained an Ac5 c(dOH) residue, was based on intermolecular hydrogen bonds derived from both the peptide backbone and the side-chain hydroxy groups of the amino acid Ac5 c(dOH) (O?H...O type). (c) 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 757-768, 2016. PMID- 27237544 TI - Comparison between point-of-care dermatophyte test medium and mycology laboratory culture for diagnosis of dermatophytosis in dogs and cats. AB - BACKGROUND: Point-of-care Dermatophyte Test Medium (PoC-DTM) is a diagnostic procedure to rule in/rule out dermatophytosis in veterinary clinics. OBJECTIVE: To evaluate the performance of PoC-DTM in the clinic compared to DTM plate culture in a mycology laboratory and to compare results obtained by general practitioners and referral clinicians. ANIMALS: Hair samples were collected from 47 cats and 54 dogs with suspected dermatophytosis and from nine healthy controls (seven cats and two dogs). METHODS: This was a multicentre blinded study. In one group (65 suspected cases, 9 healthy controls), PoC-DTM results were evaluated by clinicians in a referral clinic (SP group) who examined the colony morphology macroscopically and microscopically. In the other group (36 suspected cases) PoC DTM results were evaluated by clinicians from general practice for colour change only, with no macroscopic or microscopic examination (GP group). All hair samples were also cultured on DTM plates in a mycology laboratory. Laboratory culture was considered the gold standard for comparison. RESULTS: Agreements between tests were 97% (two false positive; kappa = 0.839) and 80.6% (five false positives and two false negatives; kappa = 0.466) in the SP and GP groups, respectively. This difference between groups was significant (P = 0.024). CONCLUSION AND CLINICAL IMPORTANCE: When applying macroscopic and microscopic evaluation of the colony, PoC-DTM is accurate for diagnosing dermatophytes with only a 3% chance of error. However, when macroscopic and microscopic examination is not included there is significant (19.4%) chance for an incorrect diagnosis. PMID- 27237545 TI - Seroprevalence of seven pathogens transmitted by the Ixodes ricinus tick in forestry workers in France. AB - In order to assess the level of occupational exposure to the main pathogens transmitted by the Ixodes ricinus tick, a seroprevalence study was performed on serum samples collected in 2003 from 2975 forestry workers of northeastern France. The global seroprevalence estimated for the seven pathogens studied was 14.1% (419/2975) for Borrelia burgdorferi sl, 5.7% (164/2908) for Francisella tularensis, 2.3% (68/2941) for tick-borne encephalitis virus, 1.7% (50/2908) for Anaplasma phagocytophilum and 1.7% (48/2908) for Bartonella henselae. The seroprevalences of Babesia divergens and Babesia microti studied in a subgroup of participants seropositive for at least one of these latter pathogens were 0.1% (1/810) and 2.5% (20/810), respectively. Borrelia burgdorferi sl seroprevalence was significantly higher in Alsace and Lorraine and F. tularensis seroprevalence was significantly higher in Champagne-Ardenne and Franche-Comte. The results of this survey also suggest low rates of transmission of Bartonella henselae and F. tularensis by ticks and a different west/east distribution of Babesia species in France. The frequency and potential severity of these diseases justify continued promotion of methods of prevention of I. ricinus bites. PMID- 27237546 TI - Breast implant infection due to Paenibacillus residui in a cancer patient. PMID- 27237548 TI - Erratum. PMID- 27237547 TI - New clinical phenotypes of fungal infections in special hosts. AB - Incidence of invasive fungal infections increases over time with the rise in at risk populations; in particular, patients with acquired immunodeficiencies due to immunosuppressive therapies such as anti-tumour necrosis factor-alpha (TNF-alpha) treatment, cirrhosis or burns. Some primary immunodeficiencies (PID) can also predispose selectively to invasive fungal diseases. Conversely, some atypical fungal diseases can reveal new PID. Deep dermatophytosis, Candida central nervous system infections or gastrointestinal disease, or disseminated phaeohyphomycosis revealed CARD9 deficiency. Most patients with inherited chronic mucocutaneous candidiasis were found to carry STAT1 gain-of-function mutations. The spectrum of fungal susceptibility and clinical presentation varies according to the PID. Among acquired immunodeficiencies, immunosuppressive treatments such as TNF-alpha blocker therapy, which has revolutionized autoimmune disorder treatment, may be complicated by endemic mycosis, aspergillosis, pneumocystosis or cryptococcosis. Burn patients with damaged skin barrier protection are susceptible to severe Candida infections and filamentous fungal infections (such as Aspergillus spp., Mucorales). Moreover, patients with cirrhosis are at increased risk of fungal infections. Therefore, physicians should think of any potential underlying acquired or inherited immunodeficiency in a patient developing an atypical fungal infection, or of a potential fungal disease in the context of an atypical presentation in specific hosts. PMID- 27237549 TI - Erratum to (438) Efficacy of CL-108 Compared to Hydrocodone 7.5 mg/Acetaminophen 325 mg in Preventing Vomiting and the Use of Anti-Emetics, Opioid-Induced Nausea and Vomiting (OINV): J Pain 17:S84, 2016. PMID- 27237550 TI - Erratum to (440) Opioid-Induced Nausea and Vomiting (OINV) in Post-Operative Patients: A Comparison of CL-108 to Hydrocodone 7.5 mg/Acetaminophen 325 mg: J Pain 17:S84, 2016. PMID- 27237552 TI - Grabbing opportunities. AB - It would be churlish in the extreme to completely dismiss the emergency care reforms that have recently been announced by the Government, however, such is the world-weary, heard it all before, belief among emergency nurses these days that a L100m opportunity to reform emergency care with nursing at its centre like never before is in danger of being washed away by a tide of cynicism. PMID- 27237551 TI - The phenomenology of the intersubjective impairment. AB - Several studies suggest that the disorders of the self include a disturbance of the most elementary component of self - the minimal self. Characterizing these disorders and understanding the mechanisms involved remain a challenge to medical epistemology and health care professionals. In the present work, I bring together concepts of different fields, such as neuroscience, epistemology and phenomenology. The main goal is to show that the second-person perspective can be used to point out particular features of social cognition and its related psychopathology. Taking the hypothesis that the second-person perspective is the congruence point between an objective process and the subjective experience, I will attempt to explain schizophrenia as a self-related deficit, first in the light of the first-person and the third-person perspective and afterward, in the light of the poorly less understood second-person perspective. On the one hand, the first-person experience is correlated both with space and time. In fact, psychiatric patients report subjective experiences that can be understood within research on the bodily self, such as (1) spatially incongruent proprioception and (2) impaired sense of time as the basic mechanism that allows conscious experience. On the other hand, the second-person approach has already begun to prove productive within social cognition research, pointing out the importance of experiencing and interacting with others as our primarily way well-being. I will phenomenological analyse subjective and intersubjective experience in the disorders of the self and derive practical consequences to evidence-based medicine. PMID- 27237553 TI - Dependency tool under scrutiny. AB - Government advisers are considering the merits of a tool to assess patient dependency in emergency settings. PMID- 27237555 TI - Support for relatives witnessing attempts to resuscitate patients. AB - Nurse research has backed suggestions that patient relatives should be able to witness resuscitation attempts. PMID- 27237554 TI - Malone backing for faculty launch. AB - RCN council is to consider proposals in January that the long-awaited faculty of emergency nursing is launched in April. PMID- 27237556 TI - Trusts 'fail to value' nurses. AB - Trust managers are failing to value A&E nurses, RCN general secretary Beverly Malone told the conference. PMID- 27237557 TI - Guidelines to follow calls to end covert pregnancy testing of girls. AB - Emergency nurses are to meet with medical colleagues in December to start drawing up guidelines on the covert pregnancy testing of children. PMID- 27237558 TI - Trust guidance due on how to spend L118m emergency strategy funding. AB - NHS trusts have been urged to be flexible about how they use their share of the L40 million package to recruit extra A&E nurses. PMID- 27237559 TI - Plans for 'physician assistants' keep emergency nurses split. AB - Emergency nurses remain divided over proposals to develop US-style physician assistants in UK A&E settings. PMID- 27237561 TI - Cognitive theory 'helps' assess children. AB - Emergency nurses have been urged to assess the cognitive development of children attending A&E. PMID- 27237560 TI - Legal threat prompts course on casting. AB - The RCN A&E Nursing Association is to meet with the British Orthopaedic Association (BOA) in January to discuss casting courses aimed at emergency nurses. PMID- 27237562 TI - Links with US nurses. AB - President of the Emergency Nurses Association (ENA) Mary Jagim took the lead on a new exchange initiative with the RCN A&E Nursing Association. PMID- 27237563 TI - Conference call. AB - A&E adviser to the Winter and Emergency Services Team (WEST) Matthew Cooke is among the planned speakers at a conference examining new models for emergency care. PMID- 27237564 TI - Ombudsman focuses on A&E. AB - Health service ombudsman Michael Buckley has focused on A&E services in his report into investigations completed between April and July this year. PMID- 27237565 TI - web focus. AB - This regular feature highlights websites with information on clinical subjects. This edition focuses on deliberate self harm. PMID- 27237566 TI - Candidate deadline. AB - Would-be members of the RCN A&E Nursing Association steering committee have until January 9 to apply as election candidates. PMID- 27237567 TI - X-rated? AB - A&E staff nurse Mike Peters features in a 25-part documentary series focusing on staff at North Bristol NHS Trust. PMID- 27237568 TI - Turning the tables. AB - The government go-ahead in November for emergency services to ban violent or abusive patients means that ministers have kept their promise to roll out their zero tolerance scheme before the end of the year. PMID- 27237569 TI - Electronic boost to knowledge. AB - The Royal College of Nursing (RCN) is providing its members with free personal Internet access to a range of online nursing information products. Working with colleagues from Health Communication Network, an electronic healthcare provider, and the publisher, Blackwell Science, the RCN is now offering nurses the opportunity to tap into electronic journals, and a key nursing database as part of their RCN membership package. The service can be accessed whenever and wherever nurses need it - for example from home, any number of RCN Libraries and Resource Centres across the UK, from Cybercafes, and abroad. PMID- 27237571 TI - Effect of minor injuries on school attendance. AB - This study was designed to investigate the number of days missed from school after children attended one of three local emergency departments (EDs) with minor injuries. Minor injuries were defined as those not requiring hospital admission and not affecting mobility/ability of the child to care for herself. This case control study involved children resident in, and attending school full time in the Welsh counties of Swansea and Neath Port Talbot in the autumn term of 1999. PMID- 27237572 TI - Independent predictive value for nonspecific initial ECG. AB - Although previous studies have suggested that normal and nonspecific initial ECGs are associated with a favorable prognosis for patients with acute myocardial infarction (AMI), their independent predictive value for mortality has not been examined. This US study sought to compare inhospital mortality among patients with AMI who have normal or nonspecific initial ECGs with that of patients who have diagnostic ECGs. PMID- 27237573 TI - Planning a meeting. AB - It is time for the interdepartmental meeting to start, but only half of the participants are present and they appear lethargic and unprepared. As the meeting ends, you leave frustrated from spending too much time to accomplish too little. PMID- 27237574 TI - Citrus waste as feedstock for bio-based products recovery: Review on limonene case study and energy valorization. AB - The citrus peels and residue of fruit juices production are rich in d-limonene, a cyclic terpene characterized by antimicrobial activity, which could hamper energy valorization bioprocess. Considering that limonene is used in nutritional, pharmaceutical and cosmetic fields, citrus by-products processing appear to be a suitable feedstock either for high value product recovery or energy bio processes. This waste stream, more than 10MTon at 2013 in European Union (AIJN, 2014), can be considered appealing, from the view point of conducting a key study on limonene recovery, as its content of about 1%w/w of high value-added molecule. Different processes are currently being studied to recover or remove limonene from citrus peel to both prevent pollution and energy resources recovery. The present review is aimed to highlight pros and contras of different approaches suggesting an energy sustainability criterion to select the most effective one for materials and energy valorization. PMID- 27237575 TI - Characteristics of methane and nitrous oxide emissions from the wastewater treatment plant. AB - The nitrous oxide (N2O) and methane (CH4) emissions were measured from a municipal wastewater treatment plant (WWTP) using a flux chamber to determine the emission factors. The WWTP treats sewage using both the activated-sludge treatment and anaerobic/anoxic/aerobic (A(2)O) methods. Measurements were performed in the first settling, aeration, and secondary settling basins, as well as in the sludge thickener, sludge digestion tank, and A(2)O basins. The total emission factors of N2O and CH4 from the activated-sludge treatment were 1.256gN2O/kg total nitrogen (TN) and 3.734gCH4/kg biochemical oxygen demand (BOD5), respectively. Those of the advanced treatment (A(2)O) were 1.605gN2O/kg TN and 4.022gCH4/kgBOD5, respectively. These values are applicable as basic data to estimate greenhouse gas emissions. PMID- 27237576 TI - Moral decision-making in university students with self-reported mild head injury. AB - Converging evidence shows that the prefrontal cortex is involved in moral decision-making. Individuals who have suffered injury to the ventromedial prefrontal cortex are more willing to endorse personal moral transgressions (e.g., make their decisions faster, and have attenuated sympathetic responses to those violations). We examined whether university students who have experienced a mild head injury (MHI), and are asymptomatic, present with a similar pattern of responding to moral dilemmas. Students reporting a history of MHI responded more quickly when making moral choices and exhibited less reticence toward the endorsement of personal moral transgressions than their non-MHI counterparts. Our results are consistent with studies involving persons with more serious, and evident, neuronal injury, and emphasize the important relationship between head injury and moral decision-making. PMID- 27237577 TI - Non-alcoholic fatty liver disease and dyslipidemia: An update. AB - Non-alcoholic fatty liver (NAFLD) is the most common liver disease worldwide, progressing from simple steatosis to necroinflammation and fibrosis (leading to non-alcoholic steatohepatitis, NASH), and in some cases to cirrhosis and hepatocellular carcinoma. Inflammation, oxidative stress and insulin resistance are involved in NAFLD development and progression. NAFLD has been associated with several cardiovascular (CV) risk factors including obesity, dyslipidemia, hyperglycemia, hypertension and smoking. NAFLD is also characterized by atherogenic dyslipidemia, postprandial lipemia and high-density lipoprotein (HDL) dysfunction. Most importantly, NAFLD patients have an increased risk for both liver and CV disease (CVD) morbidity and mortality. In this narrative review, the associations between NAFLD, dyslipidemia and vascular disease in NAFLD patients are discussed. NAFLD treatment is also reviewed with a focus on lipid-lowering drugs. Finally, future perspectives in terms of both NAFLD diagnostic biomarkers and therapeutic targets are considered. PMID- 27237578 TI - Sleep and Cognitive Abnormalities in Acute Minor Thalamic Infarction. AB - In order to characterize sleep and the cognitive patterns in patients with acute minor thalamic infarction (AMTI), we enrolled 27 patients with AMTI and 12 matched healthy individuals. Questionnaires about sleep and cognition as well as polysomnography (PSG) were performed on days 14 and 90 post-stroke. Compared to healthy controls, in patients with AMTI, hyposomnia was more prevalent; sleep architecture was disrupted as indicated by decreased sleep efficiency, increased sleep latency, and decreased non-rapid eye movement sleep stages 2 and 3; more sleep-related breathing disorders occurred; and cognitive functions were worse, especially memory. While sleep apnea and long-delay memory recovered to a large extent in the patients, other sleep and cognitive function deficit often persisted. Patients with AMTI are at an increased risk for hyposomnia, sleep structure disturbance, sleep apnea, and memory deficits. Although these abnormalities improved over time, the slow and incomplete improvement suggest that early management should be considered in these patients. PMID- 27237579 TI - The Current Situation on Major Depressive Disorder in China: Research on Mechanisms and Clinical Practice. AB - Depression is the most disabling disorder worldwide that accounts for the highest proportion of global burden attributable to mental disorders. Major depressive disorder (MDD) is characterized by deep sadness, reduced energy, vegetative nervous system dysregulation, cognitive dysfunction, and even a high suicidal tendency. Although other treatment choices are available, antidepressant medication is the front-line treatment option for MDD. Regarding clinical efficacy, only ~50% of patients respond to frontline antidepressants, and <33% obtain remission. Currently, objective indexes to guide clinical decisions are still lacking. Furthermore, knowledge about the neurobiological mechanisms underlying discrepant antidepressant outcomes is still also fragmentary. In the present review, we discuss the current research progress and clinical opinions on MDD in China. PMID- 27237580 TI - Toward a National Initiative in Cancer Rehabilitation: Recommendations From a Subject Matter Expert Group. AB - The health care delivery system in the United States is challenged to meet the needs of a growing population of cancer survivors. A pressing need is to optimize overall function and reduce disability in these individuals. Functional impairments and disability affect most patients during and after disease treatment. Rehabilitation health care providers can diagnose and treat patients' physical, psychological, and cognitive impairments in an effort to maintain or restore function, reduce symptom burden, maximize independence and improve quality of life in this medically complex population. However, few care delivery models integrate comprehensive cancer rehabilitation services into the oncology care continuum. The Rehabilitation Medicine Department of the Clinical Center at the National Institutes of Health with support from the National Cancer Institute and the National Center for Medical Rehabilitation Research convened a subject matter expert group to review current literature and practice patterns, identify opportunities and gaps regarding cancer rehabilitation and its support of oncology care, and make recommendations for future efforts that promote quality cancer rehabilitation care. The recommendations suggest stronger efforts toward integrating cancer rehabilitation care models into oncology care from the point of diagnosis, incorporating evidence-based rehabilitation clinical assessment tools, and including rehabilitation professionals in shared decision-making in order to provide comprehensive cancer care and maximize the functional capabilities of cancer survivors. These recommendations aim to enable future collaborations among a variety of stakeholders to improve the delivery of high quality cancer care. PMID- 27237581 TI - The role of R-spondins and their receptors in bone metabolism. AB - R-spondins are a family of four secreted proteins and act as agonists of the canonical Wnt/beta-catenin signaling pathway. They are broadly expressed in different phases of skeleton tissues. Recently, three closely related leucine rich repeat containing G-protein-coupled receptors (Lgr4/5/6) have been identified as the new and exact receptors of R-spondins. On the cell surface, R spondins binding with Lgr4/5/6 and Znrf3/Rnf43 lead to reduced turnover of Wnts receptors and potentiate Wnt/beta-catenin signaling pathway which is critical for the control of bone development and remodeling. There has been a growing interest in understanding the role and mechanism of R-spondins and their receptors in multiple biological processes, including bone development and metabolism. Recent advances in the R-spondins revealed the potential modulatory effect on osteoblastogenesis and bone formation and provided a new avenue for the investigation of adult bone metabolism. The receptors of Lgr4/5/6 and stabilized beta-catenin are essential to the regulatory effect of Rspos on skeleton. The findings on Rspo/Lgr signaling might have clinical potentials for the treatment of bone loss related diseases. PMID- 27237582 TI - Inhibition of substance P signaling aggravates the bone loss in ovariectomy induced osteoporosis. AB - INTRODUCTION: Substance P signaling regulates the functions of both osteoblast and osteoclast. Available reports on the effects of substance P on bone mass are contradictory. The objective of this study was to determine the change of substance P expression in the osteoporotic bone of OVX mice. The effects of substance P signaling blockade by using its specific receptor antagonist L-703606 on bone remodeling in sham-operated mice and OVX mice were also investigated. METHODS: Forty-eight nine-week-old female C57BL/6J mice were evenly distributed into three groups with sham surgery, OVX or OVX with estrogen replacement. Substance P expression in the bones of each group of mice was evaluated by immunohistochemistry and enzyme immunoassay. Another thirty-two nine-week-old female C57BL/6J mice were divided into a SHAM group (sham surgery followed by vehicle treatment with DMSO), a SHAM + L group (sham surgery followed by 15 mg/kg/d L-703606 repeated intraperitoneal injections), an OVX group (ovariectomy with the same vehicle treatment) and an OVX + L group (ovariectomy with the same L-703606 injections), with 8 mice in each group. Treatment started 3 weeks after surgery and last for 3 weeks. A 2 * 2 factorial experimental design was used to detect the effects of substance P signaling blockade on bone remodeling in sham operated mice and OVX mice. Techniques including micro-computed tomography, biomechanical testing, histomorphometric analysis, enzyme immunoassay, and real time PCR were employed. RESULTS: Immunohistochemistry and enzyme immunoassay revealed that substance P expression significantly decreased in the bones of OVX mice both at 3 weeks and 6 weeks after surgery. Micro-CT tomography demonstrated that application of L-703606 led to bone loss in sham-operated mice, and aggravated the micro-structural deterioration of bones in OVX mice. This was shown by reduced BV/TV (Mean bone volume fraction), Tb.N (Mean trabecular number) and Tb.Th (Mean trabecular thickness), and increased Tb.Sp (Mean trabecular separation). Biomechanical analysis demonstrated that blockade of substance P signaling reduced the maximum stress and maximum load of L3 vertebrae and tibiae. Inhibited recruitment of bone mesenchymal stem cells (BMSCs) to bone remodeling sites, which was evidenced by increased number of osteoclasts, decreased number of osteoblasts and increased osteoid volume in the secondary spongiosa, was observed in the mice treated with L-703606. A significant decrease of OPG/RANKL ratio was also found in the bones of mice treated with L-703606. Body weight, uterine weight and serum estradiol level were not significantly different between the mice treated with L-703606 and those treated with vehicle. CONCLUSION: The results demonstrated that blocking substance P signaling led to bone loss in sham operated mice, and exacerbated the bone loss in OVX mice. Substance P signaling had an important role in the maintenance of bone mass. PMID- 27237583 TI - A brachytherapy photon radiation quality index Q(BT) for probe-type dosimetry. AB - INTRODUCTION: In photon brachytherapy (BT), experimental dosimetry is needed to verify treatment plans if planning algorithms neglect varying attenuation, absorption or scattering conditions. The detector's response is energy dependent, including the detector material to water dose ratio and the intrinsic mechanisms. The local mean photon energy E-(r) must be known or another equivalent energy quality parameter used. We propose the brachytherapy photon radiation quality indexQ(BT)(E-), to characterize the photon radiation quality in view of measurements of distributions of the absorbed dose to water, Dw, around BT sources. MATERIALS AND METHODS: While the external photon beam radiotherapy (EBRT) radiation quality index Q(EBRT)(E-)=TPR10(20)(E-) is not applicable to BT, the authors have applied a novel energy dependent parameter, called brachytherapy photon radiation quality index, defined as Q(BT)(E-)=Dprim(r=2cm,theta0=90 degrees )/Dprim(r0=1cm,theta0=90 degrees ), utilizing precise primary absorbed dose data, Dprim, from source reference databases, without additional MC calculations. RESULTS AND DISCUSSION: For BT photon sources used clinically, Q(BT)(E-) enables to determine the effective mean linear attenuation coefficient MU-(E) and thus the effective energy of the primary photons Eprim(eff)(r0,theta0) at the TG-43 reference position Pref(r0=1cm,theta0=90 degrees ), being close to the mean total photon energy E-tot(r0,theta0). If one has calibrated detectors, published E-tot(r) and the BT radiation quality correction factor [Formula: see text] for different BT radiation qualities Q and Q0, the detector's response can be determined and Dw(r,theta) measured in the vicinity of BT photon sources. CONCLUSIONS: This novel brachytherapy photon radiation quality indexQ(BT) characterizes sufficiently accurate and precise the primary photon's penetration probability and scattering potential. PMID- 27237584 TI - Similar frequencies, phenotype and activation status of intrahepatic NK cells in chronic HBV patients after long-term treatment with tenofovir disoproxil fumarate (TDF). AB - BACKGROUND: Currently, much effort is directed at further improving treatment for chronic hepatitis B patients by assessing the effect of immunomodulatory agents during therapy with nucleotide analogues (NUC). Although there are some reports on the effect of NUC therapy on peripheral natural killer (NK) cells, no studies investigated the long-term effects of NUC treatment on intrahepatic NK cells of chronic HBV patients. We aimed to prospectively investigate cell frequencies, phenotype, and activation status of intrahepatic NK cells of CHB patients on prolonged treatment with TDF. METHODS: Fine needle aspiration biopsies were collected from 11 chronic HBV patients at baseline, and at 12, 24, and 48 weeks of treatment with a daily 245 mg dose of TDF. Four patients underwent an additional aspiration biopsy after appoximately 6 years of treatment. RESULTS: Longitudinal evaluation of these patients during tenofovir therapy showed that all patients achieved a viral load reduction with undetectable DNA load after 48 weeks of therapy. Repeated sampling of the liver during therapy showed that the frequency of distinct lymphocyte populations in the liver remained unchanged despite viral load reduction. During the course of therapy, no modulation of the expression levels and frequencies of CD69, HLA-DR, NKG2A and NKG2D on liver NK cells were detected. However, evaluation of intrahepatic NK cell activation after continuous TDF therapy for 6 years demonstrated a mild increase in 3 out of 4 patients. CONCLUSIONS: Our findings provide a unique insight in the intrahepatic NK cell compartment in chronic HBV patients during prolonged treatment. We observed that long-term NUC-induced viral suppression, accompanied by gradual decrease of HBsAg levels, had no or only a limited effect on the frequencies, phenotype, and activation status of intrahepatic NK cells. PMID- 27237586 TI - Mutational signature of aristolochic acid: Clue to the recognition of a global disease. AB - Mutational signatures associated with specific forms of DNA damage have been identified in several forms of human cancer. Such signatures provide information regarding mechanisms of tumor induction which, in turn, can reduce exposure to carcinogens by shaping public health policy. Using a molecular epidemiologic approach that takes advantage of recent advances in genome sequencing while applying sensitive and specific analytical methods to characterize DNA damage, it has become increasingly possible to establish causative linkages between certain environmental mutagens and disease risk. In this perspective, we use aristolochic acid, a human carcinogen and nephrotoxin found in Aristolochia herbs, to illustrate the power and effectiveness of this multidisciplinary approach. The genome-wide mutational signature for this toxin, detected initially in cancers of the upper urinary tract, has subsequently been associated with cancers of the liver and kidney. These findings have significant implications for global public health, especially in China, where millions of individuals have used Aristolochia herbal remedies as part of traditional Chinese medicine and, thus, are at risk of developing aristolochic acid nephropathy and/or upper urinary tract carcinomas. The studies reported here set the stage for research into prevention and early detection, both of which will be required to manage a potentially devastating global disease. PMID- 27237585 TI - ALKBHs-facilitated RNA modifications and de-modifications. AB - The AlkB gene that protects E.coli against methylation damage to DNA was identified more than 3 decades ago. 20 years later, the AlkB protein was shown to catalyze repair of methylated DNA base lesions by oxidative demethylation. Two human AlkB homologs were characterized with similar DNA repair activities and seven additional human AlkB homologs were identified based on sequence homology. All these dioxygenases, ALKBH1-8 and FTO, contain a conserved alpha ketoglutarate/iron-dependent domain for methyl modifications and de modifications. Well-designed research over the last 10 years has identified unforeseen substrate heterogeneity for the AlkB homologs, including novel reversible methyl modifications in RNA. The discoveries of RNA demethylation catalyzed by AlkB family enzymes initiated a new realm of gene expression regulation, although the understanding of precise endogenous activities and roles of these RNA demethylases are still undeveloped. It is worth mentioning that the AlkB mechanism and use of alpha-ketoglutarate have also emerged to be essential for many enzymes in epigenetic reprogramming that modify and de-modify methylated bases in DNA and methylated amino acids in histones. PMID- 27237588 TI - Sodium fluoride and sulfur dioxide affected male reproduction by disturbing blood testis barrier in mice. AB - Fluoride and sulfur dioxide (SO2), two well-known environmental toxicants, have been implicated to have adverse effects on male reproductive health in humans and animals. The objective of this study to investigate if the BTB is one of the pathways that lead to reproductive toxicity of sodium fluoride and sulfur dioxide alone or in combination, in view of the key role of blood testis barrier (BTB) in testis. The results showed that a marked decrease in sperm quality, and altered morphology and ultrastructure of BTB in testis of mice exposure to fluoride (100 mg NaF/L in drinking water) or/and sulfur dioxide (28 mg SO2/m(3), 3 h/day). Meanwhile, the mRNA expression levels of some vital BTB-associated proteins, including occluding, claudin-11, ZO-1, Ncadherin, alpha-catenin, and connexin-43 were all strikingly reduced after NaF exposure, although only the reduction of DSG-2 was statistically significant in all treatment groups. Moreover, the proteins expressions also decreased significantly in claudin-11, N-cadherin, alpha-catenin, connexin-43 and desmoglein-2 in mice treated with fluoride and/or SO2. These changes in BTB structure and constitutive proteins may therefore be connected with the low sperm quality in these mice. The role of fluoride should deserves more attention in this process. PMID- 27237587 TI - DNA repair by RNA: Templated, or not templated, that is the question. AB - Cells are continuously exposed to both endogenous and exogenous sources of genomic stress. To maintain chromosome stability, a variety of mechanisms have evolved to cope with the multitude of genetic abnormalities that can arise over the life of a cell. Still, failures to repair these lesions are the driving force of cancers and other degenerative disorders. DNA double-strand breaks (DSBs) are among the most toxic genetic lesions, inhibiting cell ability to replicate, and are sites of mutations and chromosomal rearrangements. DSB repair is known to proceed via two major mechanisms: homologous recombination (HR) and non homologous end joining (NHEJ). HR reliance on the exchange of genetic information between two identical or nearly identical DNA molecules offers increased accuracy. While the preferred substrate for HR in mitotic cells is the sister chromatid, this is limited to the S and G2 phases of the cell cycle. However, abundant amounts of homologous genetic substrate may exist throughout the cell cycle in the form of RNA. Considered an uncommon occurrence, the direct transfer of information from RNA to DNA is thought to be limited to special circumstances. Studies have shown that RNA molecules reverse transcribed into cDNA can be incorporated into DNA at DSB sites via a non-templated mechanism by NHEJ or a templated mechanism by HR. In addition, synthetic RNA molecules can directly template the repair of DSBs in yeast and human cells via an HR mechanism. New work suggests that even endogenous transcript RNA can serve as a homologous template to repair a DSB in chromosomal DNA. In this perspective, we will review and discuss the recent advancements in DSB repair by RNA via non-templated and templated mechanisms. We will provide current findings, models and future challenges investigating RNA and its role in DSB repair. PMID- 27237589 TI - Individual variations in dose response for spatial memory learning among outbred wistar rats exposed from 5 to 20 cGy of (56) Fe particles. AB - Exposures of brain tissue to ionizing radiation can lead to persistent deficits in cognitive functions and behaviors. However, little is known about the quantitative relationships between exposure dose and neurological risks, especially for lower doses and among genetically diverse individuals. We investigated the dose relationship for spatial memory learning among genetically outbred male Wistar rats exposed to graded doses of (56) Fe particles (sham, 5, 10, 15, and 20 cGy; 1 GeV/n). Spatial memory learning was assessed on a Barnes maze using REL3 ratios measured at three months after exposure. Irradiated animals showed dose-dependent declines in spatial memory learning that were fit by a linear regression (P for slope <0.0002). The irradiated animals showed significantly impaired learning at 10 cGy exposures, no detectable learning between 10 and 15 cGy, and worsened performances between 15 and 20 cGy. The proportions of poor learners and the magnitude of their impairment were fit by linear regressions with doubling doses of ~10 cGy. In contrast, there were no detectable deficits in learning among the good learners in this dose range. Our findings suggest that genetically diverse individuals can vary substantially in their spatial memory learning, and that exposures at low doses appear to preferentially impact poor learners. This hypothesis invites future investigations of the genetic and physiological mechanisms of inter-individual variations in brain function related to spatial memory learning after low-dose HZE radiation exposures and to determine whether it also applies to physical trauma to brain tissue and exposures to chemical neurotoxicants. Environ. Mol. Mutagen. 57:331-340, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27237590 TI - Indoles - A promising scaffold for drug development. AB - Generally, heterocycles occupy a prominent place in chemistry due to their wide range of applications in the fields of drug design, photochemistry, agrochemicals, dyes and so on. Among them, indole scaffolds have been found in most of the important synthetic drug molecules and paved a faithful way to develop effective targets. Privileged structures bind to multiple receptors with high affinity, thus aiding the development of novel biologically active compounds. Among the indole class of compounds, 2-arylindoles appear to be a most promising lead for drug development. The derivatives of 2-arylindoles exhibits antibacterial, anticancer, anti-oxidants, anti-inflammatory, anti-diabetic, antiviral, antiproliferative, antituberculosis activity, etc. This article would provide a clear knowledge on the wide-ranging biological activities of 2 arylindoles over the past two decades, which would be beneficial for the designing of more potent drug targets in order to compete with the existing drugs. PMID- 27237591 TI - Gene-gene and gene-sex epistatic interactions of DNMT1, DNMT3A and DNMT3B in autoimmune thyroid disease. AB - The aim of this study was to investigate the associations of DNA methyltransferases (DNMTs) polymorphisms with susceptibility to autoimmune thyroid diseases (AITDs) and to test gene-gene/gene-sex epistasis interactions. Eight single-nucleotide polymorphisms (SNPs) in DNMT1, DNMT3A and DNMT3B were selected and genotyped by multiplex polymerase chain reaction combined with ligase detection reaction method (PCR-LDR). A total of 685 Graves' disease (GD) patients, 353 Hashimoto's thyroiditis (HT) patients and 909 healthy controls were included in the final analysis. Epistasis was tested by additive model, multiplicative model and general multifactor dimensionality reduction (general MDR). Rs2424913 (DNMT3B) and rs2228611 (DNMT1) were associated with susceptibility to AITD and GD in the dominant and overdominant model, respectively (rs2424913: P=0.009 for AITD, P=0.0041 for GD; rs2228611: P=0.035 for AITD, P=0.043 for GD). Multiplicative and multiple high dimensional gene-gene or gene-sex interactions were also observed in this study. We have found evidence for a potential role of rs2424913 (DNMT3B) and rs2228611 (DNMT1) in AITD susceptibility and identified novel gene-gene/gene-sex interactions in AITD. Our study may highlight sex and genes of DNMTs family as contributors to the pathogenesis of AITD. PMID- 27237593 TI - An in situ derivatization - dispersive liquid-liquid microextraction combined with gas-chromatography - mass spectrometry for determining biogenic amines in home-made fermented alcoholic drinks. AB - A novel dispersive liquid-liquid microextraction (DLLME) gas chromatography mass spectrometry (GC-MS) method was developed for the determination of 13 biogenic amines in home-made wine samples. The method allows to simultaneous extraction and derivatization of the amines providing a simple and fast mode of extract enrichment. During the study, two different procedures were examined. Statistical analysis was performed to choose better procedure, as well as the conditions of derivatization reaction. At least, a mixture of methanol (dispersive solvent; 215MUL), chloroform (extractive solvent; 400MUL), and isobutyl choloroformate (derivatizing reagent; 90MUL) was used as extractive/derivatizing reagent, added to 5mL of sample. The addition of mixture of pyridine and HCl was necessary to eliminate the by-products. The proposed method showed good linearity (correlation coefficients >0.9961), good recoveries (from 77 to 105%), and good intra-day precision (below 13%) and inter-day precision (below 10%). Moreover, detection limits were never over 4.1MUg/L. The developed method was successfully applied to the analysis of 17 home-made wine samples not regulated by law. All of the biogenic amines analyzed were found in most of the wines. PMID- 27237592 TI - Executive summary of the SEPAR recommendations for the diagnosis and treatment of non-small cell lung cancer. AB - The Thoracic Surgery and Thoracic Oncology groups of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) have backed the publication of a handbook on recommendations for the diagnosis and treatment of non-small cell lung cancer. Due to the high incidence and mortality of this disease, the best scientific evidence must be constantly updated and made available for consultation by healthcare professionals. To draw up these recommendations, we called on a wide-ranging group of experts from the different specialties, who have prepared a comprehensive review, divided into 4 main sections. The first addresses disease prevention and screening, including risk factors, the role of smoking cessation, and screening programs for early diagnosis. The second section analyzes clinical presentation, imaging studies, and surgical risk, including cardiological risk and the evaluation of respiratory function. The third section addresses cytohistological confirmation and staging studies, and scrutinizes the TNM and histological classifications, non-invasive and minimally invasive sampling methods, and surgical techniques for diagnosis and staging. The fourth and final section looks at different therapeutic aspects, such as the role of surgery, chemotherapy, radiation therapy, a multidisciplinary approach according to disease stage, and other specifically targeted treatments, concluding with recommendations on the follow-up of lung cancer patients and surgical and endoscopic palliative interventions in advanced stages. PMID- 27237594 TI - Liquid chromatography mass spectrometry determination of perfluoroalkyl acids in environmental solid extracts after phospholipid removal and on-line turbulent flow chromatography purification. AB - An on-line TFC (Turbulent Flow Chromatography) clean up procedures coupled with UHPLC-MS/MS (Ultra High Performance Liquid Chromatography Mass Spectrometry) multi-residue method was developed for the simultaneous determination of 8 perfluroalkyl carboxylic acids (PFCA, from 5 to 12 carbon atoms) and 3 perfluoroalkyl sulfonic acids (PFSA, from 4 to 8 carbon atoms) in environmental solid matrices. Fast sample preparation procedure was based on a sonication assisted extraction with acetonitrile. Phospholipids in biological samples were fully removed by an off-line SPE purification before injection, using HybridSPE((r)) Phospholipid Ultra cartridges. The development of the on-line TFC clean-up procedure regarded the choice of the stationary phase, the optimization of the mobile phase composition, flow rate and injected volume. The validation of the optimized method included the evaluation of matrix effects, accuracy and reproducibility. Signal suppression in the analysis of fortified extracts ranged from 1 to 60%, and this problem was overcome by using isotopic dilution. Since no certified reference materials were available for PFAS in these matrices, accuracy was evaluated by recoveries on spiked clam samples which were 98-133% for PFCAs and 40-60% for PFSAs. MLDs and MLQs ranged from 0.03 to 0.3ngg(-1) wet weight and from 0.1 to 0.9ngg(-1) wet weight respectively. Repeatability (intra-day precision) and reproducibility (inter-day precision) showed RSD from 3 to 13% and from 4 to 27% respectively. Validated on-line TFC/UHPLC-MS/MS method has been applied for the determination of perfluoroalkyl acids in different solid matrices (sediment, fish, bivalves and bird yolk). PMID- 27237595 TI - Causal identification: a charge of epidemiology in danger of marginalization. AB - The requirement for framing all causal questions as well-defined interventions is being promoted in the causal inference literature within epidemiology. One can consider this perspective as an intervention on the field which requires a refocusing of epidemiologic questions and retooling of epidemiologic methods. Although this intervention has produced many positive results, we think that its underlying assumptions and the possibilities of unintended consequences warrant examination. In so doing, we argue that this approach can lead to the neglect of causal identification as a useful link between associations and the estimation of intervention effects. PMID- 27237596 TI - Are Facultative Reserve ISCs the Cellular Origin of Familial Small Intestinal Neuroendocrine Tumors? PMID- 27237597 TI - Mouse Label-Retaining Cells Are Molecularly and Functionally Distinct From Reserve Intestinal Stem Cells. AB - BACKGROUND & AIMS: Intestinal homeostasis and regeneration after injury are controlled by 2 different types of cells: slow cycling, injury-resistant reserve intestinal stem cells (ISCs) and actively proliferative ISCs. Putative reserve ISCs have been identified using a variety of methods, including CreER insertions at Hopx or Bmi1 loci in mice and DNA label retention. Label-retaining cells (LRCs) include dormant stem cells in several tissues; in the intestine, LRCs appear to share some properties with reserve ISCs, which can be marked by reporter alleles. We investigated the relationships between these populations. METHODS: Studies were performed in Lgr5-EGFP-IRESCreERT2, Bmi1-CreERT2, Hopx CreERT2, and TRE-H2BGFP::Hopx-CreERT2::lox-stop-lox-tdTomato mice. Intestinal epithelial cell populations were purified; we compared reporter allele-marked reserve ISCs and several LRC populations (marked by H2B-GFP retention) using histologic flow cytometry and functional and single-cell gene expression assays. RESULTS: LRCs were dynamic and their cellular composition changed with time. Short-term LRCs had properties of secretory progenitor cells undergoing commitment to the Paneth or enteroendocrine lineages, while retaining some stem cell activity. Long-term LRCs lost stem cell activity and were a homogenous population of terminally differentiated Paneth cells. Reserve ISCs marked with HopxCreER were primarily quiescent (in G0), with inactive Wnt signaling and robust stem cell activity. In contrast, most LRCs were in G1 arrest and expressed genes that are regulated by the Wnt pathway or are in the secretory lineage. CONCLUSIONS: LRCs are molecularly and functionally distinct from reporter-marked reserve ISCs. This information provides an important basis for future studies of relationships among ISC populations. PMID- 27237598 TI - It is feasible and effective to help patients with severe mental disorders to quit smoking: An ecological pragmatic clinical trial with transdermal nicotine patches and varenicline. AB - Despite the proven association between smoking and high rates of medical morbidity and reduced life expectancy in people with severe mental disorders (SMD), their smoking rates do not decline as they do in the general population. We carried out a non-randomized, open-label, prospective, 9-month follow-up multicentre trial to investigate the clinical efficacy, safety and tolerability of a 12-week smoking cessation programme for patients with SMD in the community under real-world clinical conditions. Eighty-two adult outpatients with schizophrenic/bipolar disorder smoking >=15 cigarettes/day were assigned by shared decision between doctors and patients to transdermal nicotine patches (TNP) [36(46.2%)] or varenicline [39(50%)]. Short-term efficacy: The 12-week 7 day smoking cessation (self-reported cigarettes/day=0 and breath carbon monoxide levels<=9ppm) prevalence was 49.3%, without statistically significant differences between medications (TNP 50.0% vs varenicline 48.6%, chi-square=0.015, p=1.000). Long-term efficacy: At weeks 24 and 36, 41.3 and 37.3% of patients were abstinent, with no statistically significant differences between treatments. Safety and Tolerability: no patients made suicide attempts/required hospitalization. There was no worsening on the psychometric scales. Patients significantly increased weight [TNP 1.1(2.8) vs varenicline 2.5(3.3), p=0.063], without significant changes in vital signs/laboratory results, except significant decreases in alkaline phosphatase and low-density lipoprotein-cholesterol levels in the varenicline group. Patients under varenicline more frequently presented nausea/vomiting (p<0.0005), patients under TNP experienced skin reactions more frequently (p=0.002). Three patients under varenicline had elevated liver enzymes. In conclusion, we have demonstrated that in real-world clinical settings it is feasible and safe to help patients with stabilized severe mental disorders to quit smoking. PMID- 27237599 TI - Assessment of genetic risk for distribution of total interstitial white matter neurons in dorsolateral prefrontal cortex: role in schizophrenia. PMID- 27237601 TI - Identification of Candidate Target Cyp Genes for microRNAs Whose Expression Is Altered by PCN and TCPOBOP, Representative Ligands of PXR and CAR. AB - MicroRNAs (miRNAs) are small non-coding RNAs that are involved in mRNA post transcriptional regulation. The deregulation of miRNAs affects the expression of drug-metabolizing enzymes, drug transporters, and nuclear receptors, all of which are important in regulating drug metabolism. miRNA expression can be altered by several endogenous or exogenous agents, such as steroid hormones, carcinogens, and therapeutic drugs. However, it is unclear whether hepatic miRNA expression is regulated by nuclear receptors, such as pregnane X receptor (PXR) and constitutive androstane receptor (CAR), which are indispensable for the expression of the CYPs. Here we investigated the effects of the mouse PXR and CAR ligands pregnenolone-16alpha-carbonitrile (PCN) and 1,4-bis[(3,5-dichloropyridin 2-yl)oxy]benzene (TCPOBOP) on hepatic miRNA expression in mice. We found that the expression of 9 miRNAs was increased (>2-fold) and of 4 miRNAs was decreased (>50%) in response to PCN, while TCPOBOP treatment led to the up-regulation of 8 miRNAs and down-regulation of 6 miRNAs. Using several miRNA target prediction algorithms, we found that the predicted target genes included several lesser known Cyp genes (Cyp1a1, Cyp1b1, Cyp2b10, Cyp2c38, Cyp2u1, Cyp4a12a/b, Cyp4v3, Cyp17a1, Cyp39a1, and Cyp51). We analyzed the expression of these genes in response to PCN and TCPOBOP and found changes in their mRNA levels, some of which were negatively correlated with the expression of their corresponding miRNAs, suggesting that miRNAs may play a role in regulating Cyp enzyme expression. Further studies will be required to fully elucidate the miRNA regulatory mechanisms that contribute to modulating CYP expression. PMID- 27237600 TI - Altered serum levels of interleukin-3 in first-episode drug-naive and chronic medicated schizophrenia. AB - Elevated serum levels of Interleukin-3 (IL-3), a major component of the cytokines, have been observed in chronic and medicated patients with schizophrenia, but this elevation may reflect either or both medication and illness chronicity effects. Thus, we compared serum IL-3 levels in first-episode drug-naive (FEDN) to chronic medicated patients with schizophrenia and examined the association of IL-3 with their psychopathological symptoms. Serum IL-3 levels were assessed in 55 FEDN patients, 52 chronic medicated patients and 43 healthy controls. Schizophrenia symptomatology was assessed with the Positive and Negative Syndrome Scale (PANSS). Serum IL-3 levels were measured by sandwich enzyme-linked immunosorbent assay (ELISA). We found significantly lower IL-3 levels in FEDN patients than both chronic patients and healthy controls (both p<0.001), while IL-3 levels in chronic patients were markedly higher than in healthy controls. No significant association was observed between IL-3 and any clinical psychopathology in FEDN patients; however, we found a significant correlation between serum IL-3 levels and the PANSS general psychopathology subscore in chronic medicated patients (p<0.05). Decreased IL-3 levels in FEDN patients suggest that suppressed immune function may be associated with developing schizophrenia, but as the disease progresses IL-3 levels increase perhaps related to medication treatment or other factors that occur during chronic illness. PMID- 27237602 TI - Catabolism of N-glycoproteins in mammalian cells: Molecular mechanisms and genetic disorders related to the processes. AB - N-glycans on glycoproteins serve as one of the most important co- and post translational modifications of proteins, and it has been well established that they play pivotal roles in controlling the physicochemical and/or physiological properties of the carrier proteins. The biosynthetic/processing pathways for N glycans have been well characterized in mammalian cells. There are, however, issues that remain to be clarified concerning aspects of their degradation. While the molecular mechanism of the lysosomal degradation for N-glycoproteins has been well studied in relation to genetic disorders, which are collectively referred to as lysosomal storage disorders, evidence exists to suggest that there are also "non-lysosomal" degradation processes, which are now known to occur widely in eukaryotic cells. In this review, our current knowledge of the lysosomal/non lysosomal degradation of N-glycoproteins in mammalian cells, as well as in human genetic disorders caused by the defects of these processes, is reviewed. PMID- 27237603 TI - Feed Safe: a multidisciplinary partnership approach results in a successful mobile application for breastfeeding mothers. AB - Issue addressed: Mobile applications are increasingly being used in health promotion initiatives. Although there is evidence that developing these mobile health applications in multidisciplinary teams is good practice, there is a gap in the literature with respect to evaluation of the process of this partnership model and how best to disseminate the application into the community. The aim of this paper is twofold, to describe the partnership model in which the Feed Safe application was developed and to investigate what worked in terms of dissemination.Methods: The process of working in partnership was measured using the VicHealth partnership analysis tool for health promotion. The dissemination strategy and reach of the application was measured using both automated analytics data and estimates of community-initiated promotion.Results: The combined average score from the partnership analysis tool was 138 out of a possible 175. A multipronged dissemination strategy led to good uptake of the application among Australian women.Conclusions: Multidisciplinary partnership models are important in the development of health promotion mobile applications. Recognising and utilising the skills of each partner organisation can help expand the reach of mobile health applications into the Australian population and aid in good uptake of health promotion resources.So what?: Developing mobile applications in multidisciplinary partnerships is good practice and can lead to wide community uptake of the health promotion resource. PMID- 27237605 TI - [Glandular lesions of the uterine cervix: Introduction]. PMID- 27237604 TI - Real-time localization of articulated surgical instruments in retinal microsurgery. AB - Real-time visual tracking of a surgical instrument holds great potential for improving the outcome of retinal microsurgery by enabling new possibilities for computer-aided techniques such as augmented reality and automatic assessment of instrument manipulation. Due to high magnification and illumination variations, retinal microsurgery images usually entail a high level of noise and appearance changes. As a result, real-time tracking of the surgical instrument remains challenging in in-vivo sequences. To overcome these problems, we present a method that builds on random forests and addresses the task by modelling the instrument as an articulated object. A multi-template tracker reduces the region of interest to a rectangular area around the instrument tip by relating the movement of the instrument to the induced changes on the image intensities. Within this bounding box, a gradient-based pose estimation infers the location of the instrument parts from image features. In this way, the algorithm does not only provide the location of instrument, but also the positions of the tool tips in real-time. Various experiments on a novel dataset comprising 18 in-vivo retinal microsurgery sequences demonstrate the robustness and generalizability of our method. The comparison on two publicly available datasets indicates that the algorithm can outperform current state-of-the art. PMID- 27237606 TI - [RIHN: A new plan to support innovation in laboratory medicine and pathology by the French Ministry of Health. The analysis of the French Society of Pathology (SFP)]. PMID- 27237607 TI - Enabling Equal Access to Molecular Diagnostics: What Are the Implications for Policy and Health Technology Assessment? AB - Molecular diagnostics can offer important benefits to patients and are a key enabler of the integration of personalised medicine into health care systems. However, despite their promise, few molecular diagnostics are embedded into clinical practice (especially in Europe) and access to these technologies remains unequal across countries and sometimes even within individual countries. If research translation and the regulatory environments have proven to be more challenging than expected, reimbursement and value assessment remain the main barriers to providing patients with equal access to molecular diagnostics. Unclear or non-existent reimbursement pathways, together with the lack of clear evidence requirements, have led to significant delays in the assessment of molecular diagnostics technologies in certain countries. Additionally, the lack of dedicated diagnostics budgets and the siloed nature of resource allocation within certain health care systems have significantly delayed diagnostics commissioning. This article will consider the perspectives of different stakeholders (patients, health care payers, health care professionals, and manufacturers) on the provision of a research-enabled, patient-focused molecular diagnostics platform that supports optimal patient care. Through the discussion of specific case studies, and building on the experience from countries that have successfully integrated molecular diagnostics into clinical practice, this article will discuss the necessary evolutions in policy and health technology assessment to ensure that patients can have equal access to appropriate molecular diagnostics. PMID- 27237608 TI - Disruption of biomineralization pathways in spinal tissues of a mouse model of diffuse idiopathic skeletal hyperostosis. AB - Equilibrative nucleoside transporter 1 (ENT1) mediates passage of adenosine across the plasma membrane. We reported previously that mice lacking ENT1 (ENT1( /-)) exhibit progressive ectopic mineralization of spinal tissues resembling diffuse idiopathic skeletal hyperostosis (DISH) in humans. Here, we investigated mechanisms underlying aberrant mineralization in ENT1(-/-) mice. Micro-CT revealed ectopic mineralization of spinal tissues in both male and female ENT1(-/ ) mice, involving the annulus fibrosus of the intervertebral discs (IVDs) of older mice. IVDs were isolated from wild-type and ENT1(-/-) mice at 2months of age (prior to disc mineralization), 4, and 6months of age (disc mineralization present) and processed for real-time PCR, cell isolation, or histology. Relative to the expression of ENTs in other tissues, ENT1 was the primary nucleoside transporter expressed in wild-type IVDs and mediated the functional uptake of [(3)H]2-chloroadenosine by annulus fibrosus cells. No differences in candidate gene expression were detected in IVDs from ENT1(-/-) and wild-type mice at 2 or 4months of age. However, at 6months of age, expression of genes that inhibit biomineralization Mgp, Enpp1, Ank, and Spp1 were reduced in IVDs from ENT1(-/-) mice. To assess whether changes detected in ENT1(-/-) mice were cell autonomous, annulus fibrosus cell cultures were established. Compared to wild-type cells, cells isolated from ENT1(-/-) IVDs at 2 or 6months of age demonstrated greater activity of alkaline phosphatase, a promoter of biomineralization. Cells from 2 month-old ENT1(-/-) mice also showed greater mineralization than wild-type. Interestingly, altered localization of alkaline phosphatase activity was detected in the inner annulus fibrosus of ENT1(-/-) mice in vivo. Alkaline phosphatase activity, together with the marked reduction in mineralization inhibitors, is consistent with the mineralization of IVDs seen in ENT1(-/-) mice at older ages. These findings establish that both cell-autonomous and systemic mechanisms contribute to ectopic mineralization in ENT1(-/-) mice. PMID- 27237609 TI - Prospective study of dietary Non Enzymatic Antioxidant Capacity on the risk of hip fracture in the elderly. AB - BACKGROUND: Dietary antioxidants may play an important role in the prevention of bone loss and associated fractures by reducing levels of oxidative stress. We prospectively investigated the association between dietary Non Enzymatic Antioxidant Capacity (NEAC) and the risk of hip fracture and whether this effect was modified by smoking. METHOD: In the Swedish National March Cohort 13,409 men and women over the age of 55 who had not experienced cancer, cardiovascular disease or hip fracture, were followed through record-linkages from 1997 through 2010. NEAC was assessed by a validated food frequency questionnaire collected at baseline. We categorized the distribution of NEAC into sex-specific quartiles and used multivariable adjusted Cox proportional hazards regression models to estimate hazard ratios (HRs) with 95% confidence intervals (95% CI). RESULTS: During a mean follow-up time of 12.4years, we identified 491 incident cases of first hip fracture. Subjects in the highest quartile of dietary NEAC had a 39% lower risk of incident hip fracture compared to those in the lowest quartile (HR: 0.61; 95% CI: 0.44-0.85). The association was non-linear (p for non-linearity: 0.004) with a potential threshold between the first and the second quartile and no further risk reduction at higher levels of dietary NEAC. Due to a low smoking prevalence in our study population, we had limited power to detect effect modification between dietary NEAC and smoking on a multiplicative or additive scale. CONCLUSION: Higher dietary NEAC intake is associated with lower risk of hip fracture in the elderly. PMID- 27237610 TI - Capecitabine and lapatinib treatment in head and neck cancer. PMID- 27237611 TI - Paediatric lymphocyte-predominant Hodgkin's lymphoma. PMID- 27237612 TI - National Health Service England introduces dose banding. PMID- 27237613 TI - Cancer data in India show new patterns. PMID- 27237614 TI - Survival of European adolescents and young adults diagnosed with cancer in 2000 07: population-based data from EUROCARE-5. AB - BACKGROUND: Data from EUROCARE have consistently shown lower survival for adolescents and young adults (AYAs; aged 15-24 years) than for children (0-14 years) for most cancers that affect both groups, and modest survival improvements up to 2000-02. AYAs have longer survival than that of adults for most cancers. We used the latest definition of AYAs (aged 15-39 years) and provided estimates of 5 year relative survival for European AYAs with cancer diagnosed in 2000-07, compared with children and adults (40-69 years) with cancer, and assessed survival improvements over time. METHODS: We analysed data from population-based cancer registries of 27 European countries participating in EUROCARE-5. We used the so-called complete method to estimate 5-year, population-weighted relative survival for 19 cancers affecting AYAs and children, and for 27 cancers affecting AYAs and adults. We assessed relative-survival differences between children versus AYAs, and between AYAs versus adults, using the Z test. We used the period approach to estimate 5-year relative survival over time for children and AYAs, and used a generalised linear model to model survival time trends (1999-2007) and to assess the significance of changes over time. FINDINGS: We analysed 56 505 cancer diagnoses in children, 312 483 in AYAs, and 3 567 383 in adults. For all cancers combined, survival improved over time for AYAs (from 79% [95% CI 78.1 80.5] in 1999-2002 to 82% [81.1-83.3] in 2005-07; p<0.0001) and children (from 76% [74.7-77.1] to 79% [77.2-79.4]; p<0.0001). Survival improved significantly in children and AYAs for acute lymphoid leukaemia (p<0.0001) and non-Hodgkin lymphoma (p<0.0001 in AYAs and p=0.023 in children). Survival improved significantly in AYAs only for CNS tumours (p=0.0046), astrocytomas (p=0.040), and malignant melanomas (p<0.0001). Survival remained significantly worse in AYAs than in children for eight important cancers: acute lymphoid leukaemias, acute myeloid leukaemias, Hodgkin's lymphomas, non-Hodgkin lymphomas, astrocytomas, Ewing's sarcomas, and rhabdomyosarcomas (p<0.0001 in all cases), and osteosarcomas (p=0.011). INTERPRETATION: Notwithstanding the encouraging results for some cancers, and overall, we showed poorer survival in AYAs than in children for the eight important cancers. Recent European initiatives to improve outcomes in AYAs might reduce the survival gap between children and AYAs, but this reduction can only be verified by future population-based studies. FUNDING: Italian Ministry of Health, European Commission. PMID- 27237615 TI - Age at cancer diagnosis and interpretation of survival statistics. PMID- 27237616 TI - [Reply to Letter to the Editor: Comparison of self-concept between groups: bias of differences?] PMID- 27237617 TI - Endoscopic surgery of an extensive aneurysmatic bone cyst of the paranasal sinuses in a 12-year-old patient. PMID- 27237618 TI - Fully Automated Electro Membrane Extraction Autosampler for LC-MS Systems Allowing Soft Extractions for High-Throughput Applications. AB - The current work describes the implementation of electro membrane extraction (EME) into an autosampler for high-throughput analysis of samples by EME-LC-MS. The extraction probe was built into a luer lock adapter connected to a HTC PAL autosampler syringe. As the autosampler drew sample solution, analytes were extracted into the lumen of the extraction probe and transferred to a LC-MS system for further analysis. Various parameters affecting extraction efficacy were investigated including syringe fill strokes, syringe pull up volume, pull up delay and volume in the sample vial. The system was optimized for soft extraction of analytes and high sample throughput. Further, it was demonstrated that by flushing the EME-syringe with acidic wash buffer and reverting the applied electric potential, carry-over between samples can be reduced to below 1%. Performance of the system was characterized (RSD, <10%; R(2), 0.994) and finally, the EME-autosampler was used to analyze in vitro conversion of methadone into its main metabolite by rat liver microsomes and for demonstrating the potential of known CYP3A4 inhibitors to prevent metabolism of methadone. By making use of the high extraction speed of EME, a complete analytical workflow of purification, separation, and analysis of sample could be achieved within only 5.5 min. With the developed system large sequences of samples could be analyzed in a completely automated manner. This high degree of automation makes the developed EME autosampler a powerful tool for a wide range of applications where high throughput extractions are required before sample analysis. PMID- 27237620 TI - Evaluation of reconstituted high-density lipoprotein (rHDL) as a drug delivery platform - a detailed survey of rHDL particles ranging from biophysical properties to clinical implications. AB - During the last decade, and with increasing intensity, the potential for using reconstituted high-density lipoprotein (rHDL) particles to deliver hydrophobic drugs to impaired cells and tissues has been explored. Here, we evaluate various parameters that should be considered when utilizing discoidal rHDL particles as a drug delivery platform. Key parameters such as preparation basics, pronounced statistical variation in drug incorporation across rHDL particles, effects of lipid composition on HDL/rHDL in vivo and vitro dynamics/particle stability, and pharmacokinetic/safety data from rHDL infusion studies in human subjects will be addressed including the innate receptors and native functions of HDL. The broad but detailed information presented in this work could also be deployed in other rHDL-related research. However, the major aim of this review is to point out factors that have the potential to advance rHDL research toward realizing the 'magic bullet' for lipophilic and hydrophilic drug delivery in various clinical contexts. PMID- 27237621 TI - alpha-Fluoro-o-cresols: The Key Role of Intramolecular Hydrogen Bonding in Conformational Preference and Hydrogen-Bond Acidity. AB - The conformational preferences of o-cresols driven by fluorination were thoroughly investigated from a theoretical point of view with quantum-chemical methods, and the results were compared to those recently reported for benzyl alcohols. The key conformers of both families exhibit a six-membered intramolecular hydrogen-bond (IMHB) interaction. A significant enhancement in the strength of the IMHB is observed in alpha-fluoro-o-cresols, owing to a simultaneous increase in the hydrogen bond (HB) basicity of the aliphatic fluorine and the HB acidity of the aromatic hydroxyl relative to that observed for o-fluorobenzyl alcohols, which are characterized by aromatic fluorine atoms and aliphatic hydroxyl groups. In the cases of the di- and trifluorinated derivatives, the occurrence of a three-centered HB is emphasized, and its features are discussed. The impact of these structural predilections on the HB properties of o-cresol was characterized from the estimation of the HB acidity parameter, pKAHY , weighted according to their conformational populations. We found that alpha-fluorination led to a decrease in the HB acidity of the hydroxyl group (in contrast with the o-fluorination of benzyl alcohols), whereas alpha,alpha-difluorination resulted in no significant variation in pKAHY . Finally, an increase in the HB acidity was predicted upon methyl perfluorination, which was confirmed experimentally. Theoretical descriptors based on atoms in molecules, noncovalent interactions, and natural bond orbital analyses allowed rationalization of the predicted trends and revealed a relationship with the strength of the established OH???F IMHB. PMID- 27237619 TI - Up-regulation of BSEP and MRP2 by Calculus Bovis administration in 17alpha ethynylestradiol-induced cholestasis: Involvement of PI3K/Akt signaling pathway. AB - ETHNOPHARMACOLOGY RELEVANCE: Calculus Bovis, also known as Niuhuang, is a rare traditional Chinese medicine that has been widely used in China for 2000 years in pharmacology for sedation, anti-spasm, relieving fever, diminishing inflammation and recovering gallbladder functions. AIM OF THE STUDY: This study aimed to investigate the choleretic potential and molecular responses in rats to Calculus Bovis (CB) administration after 17alpha-ethynylestradiol (EE)-induced cholestasis. MATERIAL AND METHODS: CB (50 and 100mg/kg per day) was intragastrically (i. g.) given to experimental rats for five consecutive days in coadministration with EE (5mg/kg daily for five days, s.c.). The levels of serum biomarkers were determined biochemically. The histopathology of the liver tissue was evaluated. Expression of bile salt export pump (BSEP) and multidrug resistance-associated protein 2 (MRP2) were studied by western blot and immunohistochemical assay. The expression of Akt and phospho-Akt (pAkt) were also measured by western blot. RESULTS: In response to EE, CB treatment significantly prevented an increase in serum levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyltransferase (GGT) and total bilirubin (TBIL). CB treatment also repaired tissue lesions caused by EE. Western blots showed that EE significantly decreased the protein expression of BSEP and MRP2. EE also dramatically increased levels of pAkt and decreased levels of Akt. Compared to the EE group, CB treatment increased levels of hepatic BSEP and MRP2 while pAkt levels decreased and Akt levels increased. Immunohistochemistry also indicated that EE decreased the expression of BSEP and MRP2. LY294002 is a selective PI3K inhibitor and showed similar beneficial effects as CB. Decreased expression of BSEP and MRP2 caused by EE were also prevented by LY294002 treatment. CONCLUSION: Calculus Bovis administration can alleviate liver injury and up-regulate the expression of BSEP and MRP2 in 17alpha-ethynylestradiol-induced cholestasis by a mechanism that may involve inhibiting the activated PI3K/Akt signaling pathway. PMID- 27237622 TI - Growth Trajectory in Children with Trisomy 21 with and without Atrioventricular Septal Defect. AB - OBJECTIVE: Trisomy 21 is associated with poor weight gain and atrioventricular septal defects. The impact of atrioventricular septal defects on weight gain in the setting of Trisomy 21 has not previously been described in the recent era. This study aimed to determine if such an association is present. DESIGN: Patients with Trisomy 21 with and without atrioventricular septal defects were identified. Clinical, surgical, and postoperative data were collected were for these patients and then compared between patients. Specifically, weight for age z-scores were compared at various time points in a univariate and multivariate fashion. Effect of timing of surgery in those with an atrioventricular septal defect was also studied. RESULTS: A total of 86 patients were identified, 42 with an atrioventricular septal defect. There was a difference in weight for age z-scores between patients with and without atrioventricular septal defects only at 2 months (P value .038) and 6 months (P value .003) of age. This persisted after multivariate regression which demonstrated atrioventricular septal defects as an independent risk factor. There was no difference noted in weight at 2 years of age in patients undergoing atrioventricular septal defect repair before and 150 days of life. CONCLUSION: There was a statistically significant, but not clinically relevant, difference in weight between the patients with Trisomy 21 with and without atrioventricular septal defects in our cohort. Those with atrioventricular septal defects required more nutritional intervention, such as gastrostomy tube placement. Timing of repair did not alter outcomes at midterm follow-up. PMID- 27237623 TI - MoS2/CdS Nanosheets-on-Nanorod Heterostructure for Highly Efficient Photocatalytic H2 Generation under Visible Light Irradiation. AB - Semiconductor-based photocatalytic H2 generation as a direct approach of converting solar energy to fuel is attractive for tackling the global energy and environmental issues but still suffers from low efficiency. Here, we report a MoS2/CdS nanohybrid as a noble-metal-free efficient visible-light driven photocatalyst, which has the unique nanosheets-on-nanorod heterostructure with partially crystalline MoS2 nanosheets intimately but discretely growing on single crystalline CdS nanorod. This heterostructure not only facilitates the charge separation and transfer owing to the formed heterojunction, shorter radial transfer path, and fewer defects in single-crystalline nanorod, thus effectively reducing the charge recombination, but also provides plenty of active sites for hydrogen evolution reaction due to partially crystalline structure of MoS2 as well as enough room for hole extraction. As a result, the MoS2/CdS nanosheets-on nanorod exhibits a state-of-the-art H2 evolution rate of 49.80 mmol g(-1) h(-1) and an apparent quantum yield of 41.37% at 420 nm, which is the advanced performance among all MoS2/CdS composites and CdS/noble metal photocatalysts. These findings will open opportunities for developing low-cost efficient photocatalysts for water splitting. PMID- 27237624 TI - Meta-Analysis of Anticoagulation Use, Stroke, Thromboembolism, Bleeding, and Mortality in Patients With Atrial Fibrillation on Dialysis. AB - Atrial fibrillation (AF) is common in patients on dialysis. Although randomized trials of anticoagulation for AF have demonstrated striking reductions in stroke, these trials did not recruit patients on dialysis. We thus undertook this systematic review and meta-analysis of observational studies including patients with AF on dialysis that reported associations of anticoagulation use. Twenty studies involving 529,741 subjects and 31,321 patients with AF on dialysis were identified. Anticoagulation was associated with a 45% (95% CI 13% to 88%) increased risk of any stroke, reflecting a nonsignificant 13% (95% CI -4% to 34%) increased ischemic stroke risk and 38% (95% CI 3% to 85%) increased hemorrhagic stroke risk. There was also a 44% (95% CI 38% to 56%) lower risk of any thromboembolism, and a 31% (95% CI 12% to 53%) increased risk of any bleeding but no clear association with cardiovascular death (relative risk 0.99, 95% CI 0.86 to 1.15) or all-cause mortality (relative risk 0.97, 95% CI 0.90 to 1.04). Incident event rates were similar or worse in patients on anticoagulation. In conclusion, these observational analyses provide little supporting evidence of benefit, and instead suggest harm, from anticoagulation in patients on dialysis with AF. These results raise the possibility that the effects of anticoagulation in patients with AF on dialysis may not be similar to the clear benefit of anticoagulation seen in patients with AF without end-stage renal disease. Randomized trials are required to definitively evaluate the safety and efficacy of anticoagulation for AF in the dialysis setting. PMID- 27237625 TI - Usefulness of Cardiac MetaIodobenzylguanidine Imaging to Improve Prognostic Power of the Model for End-Stage Liver Disease Scoring System in Patients With Mild-to Moderate Chronic Heart Failure. AB - Liver dysfunction has a prognostic impact on the outcomes of patients with advanced heart failure (HF). The model for end-stage liver disease (MELD) score is a robust system for rating liver dysfunction, and a high score has been shown to be associated with a poor prognosis in ambulatory patients with HF. In addition, cardiac metaiodobenzylguanidine (MIBG) imaging provides prognostic information in patients with chronic HF (CHF). However, the long-term predictive value of combining the MELD score and cardiac MIBG imaging in patients with CHF has not been elucidated. To prospectively investigate whether cardiac MIBG imaging provides additional prognostic value to the MELD score in patients with mild-to-moderate CHF, we studied 109 CHF outpatients (New York Heart Association: 2.0 +/- 0.6) with left ventricular ejection fraction <40%. At enrollment, an MELD score was obtained, and the heart-to-mediastinal ratio on delayed imaging and MIBG washout rate (WR) were measured using cardiac MIBG scintigraphy. During a follow-up period of 7.5 +/- 4.2 years, 36 of 109 patients experienced cardiac death (CD). On multivariate Cox analysis, MELD score and WR were significantly independently associated with CD, although heart-to-mediastinal ratio showed an association with CD only on univariate Cox analysis. Patients with abnormal WR (>27%) had a significantly greater risk of CD than those with normal WR in both those with high MELD scores (>=10; hazard ratio 4.0 [1.2 to 13.6]) and with low MELD scores (<10; hazard ratio 6.4 [1.7 to 23.2]). In conclusion, cardiac MIBG imaging would provide additional prognostic information to the MELD score in patients with mild-to-moderate CHF. PMID- 27237626 TI - Arterial Spin Labeling and Blood Oxygen Level-Dependent MRI Cerebrovascular Reactivity in Cerebrovascular Disease: A Systematic Review and Meta-Analysis. AB - BACKGROUND: The cerebrovascular reactivity (CVR) results of blood oxygen level dependent (BOLD) and arterial spin labeling (ASL) MRI studies performed in patients with cerebrovascular disease (steno-occlusive vascular disease or stroke) were systematically reviewed. SUMMARY: Thirty-one articles were included. Twenty-three (74.2%) studies used BOLD MRI to evaluate the CVR, 4 (12.9%) studies used ASL MRI and 4 (12.9%) studies used both BOLD and ASL MRI. Thirteen studies (3 significant) found a lower BOLD CVR, 2 studies found a similar CVR and 3 studies found a higher CVR in the ipsilateral compared to the contralateral hemisphere. Nine (5 significant) out of 10 studies found a lower BOLD CVR in the ipsilateral hemispheres of patients compared to controls. Six studies (2 significant) found a lower ASL CVR in the ipsilateral compared to the contralateral hemispheres. Three out of 5 studies found a significant lower ASL CVR in the ipsilateral hemispheres of patients compared to controls. KEY MESSAGES: This review brings support for a reduced BOLD and ASL CVR in the ipsilateral hemisphere of patients with cerebrovascular disease. We suggest that future studies will be performed in a uniform way so reference values can be established and could be used to guide treatment decisions in patients with cerebrovascular disease. PMID- 27237627 TI - Response to Editorial Comment to Is it necessary to carry out intraoperative retrograde upper urinary tract cytology examination in bladder cancer patients with normal upper urinary tract appearance and suspicious or positive voided urine cytology? PMID- 27237628 TI - Meta-Analysis of Combination Therapy of Chinese Herbs Plus Interferon and Ribavirin in Patients with Chronic Hepatitis C. AB - BACKGROUND We aimed to evaluate the combination therapy of Chinese herbs plus interferon and ribavirin in treatment of patients with chronic hepatitis C (CHC). MATERIAL AND METHODS Related databases were searched to identify randomized controlled trials (RCTs) that evaluated biochemical response, virological response, histological response, and/or adverse reactions to combination therapy of interferon and ribavirin with and without Chinese herbs. The RR (relative risk) with a 95% confidence interval (CI) was calculated. Sensitivity analysis was conducted by omitting one study at a time. Publication bias among the eligible studies was evaluated by Egger's test. RESULTS A total of 17 RCTs matched the selection criteria. Overall, combination therapies of Chinese herbs plus interferon and ribavirin achieved significantly higher ALT (alanine transaminase) and ETVR (the end-of-treatment viral response), and significantly lower levels of HA (hyaluronic acid), LN (laminin), PC III (procollagen iii peptide), IV-C (type IV collagen), decreased LC (decreasing leukocyte count), ATF (abnormal thyroid function), psychosis, and anemia in CHC patients compared with those treated without Chinese herbs. Sensitivity analysis showed no changes and no potential publication bias was found. CONCLUSIONS The current evidence suggests that combination therapy of Chinese herb plus interferon and ribavirin yields better outcome and fewer adverse events in CHC patients than that of interferon plus ribavirin therapy. PMID- 27237629 TI - Investigation of Fucoidan-Oleic Acid Conjugate for Delivery of Curcumin and Paclitaxel. AB - Nanoparticles for a specific delivery are likely to be designed for cancer therapeutic effectiveness and improvement. In this study, a fucoidan-oleic acid conjugate was prepared and investigated in terms of loading capacity for poorly water-soluble anti-cancer drugs to maximize effectiveness of the treatment. Fucoidan was used as a hydrophilic portion of an amphiphilic structure for improving cancer therapeutic effects. Paclitaxel and curcumin were chosen as other model drugs loaded in the conjugates. The results showed that self assembled nanoparticles with different sizes and morphologies could be prepared with two different concentrations of oleic acid as hydrophobic portion. Moreover, loading efficiency and release patterns of these drugs were mainly dependent on the hydrophobic interaction between drugs and oleic acid. It was also revealed that fucoidan and curcumin were released higher at pH 4.5 than at the physiological condition (pH 7.4), thus, facilitating the delivery and maximizing effects of the anticancer agents on cancer cells. On the contrary, paclitaxel from fucoidan nanoparticles was released faster at pH 7.4. The exploration of fucoidan-oleic acid conjugate could be considered as promising nanomedicines for cancer therapeutics. PMID- 27237630 TI - Thermally Activated Point Defect Diffusion in Methylammonium Lead Trihalide: Anisotropic and Ultrahigh Mobility of Iodine. AB - We study the diffusion of point defects in crystalline methylammonium lead halide (MAPI) at finite temperatures by using all-atoms molecular dynamics. We find that, for what concerns intrinsic defects, iodine diffusion is by far the dominant mechanism of ionic transport in MAPI, with diffusivities as high as 7.4 * 10(-7) and 4.3 * 10(-6) cm(2) s(-1) at 300 K and single activation energies of 0.24 and 0.10 eV, for interstitials and vacancies, respectively. The comparison with common covalent and oxide crystals reveals the ultrahigh mobility of defects in MAPI. Though at room temperature the vacancies are about 1 order of magnitude more diffusive, the anisotropic interstitial dynamics increases more rapidly with temperature, and it can be dominant at high temperatures. Present results are fully consistent with the involvement of iodide ions in hysteresis and have implications for improvement of the material quality by better control of defect diffusion. PMID- 27237632 TI - Standards of worth. AB - In the hype about setting standards of care, one vital issue seems to have been forgotten. When nurses claimed that standards were dropping and patient care was unacceptably low, then managers and ministers were quick to refute their words as 'emotive'. The weakness in their argument was the lack of research and quantifiable evidence that standards were indeed at an unacceptable level. PMID- 27237633 TI - Growing pressures lead to new support initiative. AB - Rising concern about nurses who face victimisation when they report falling standards is among the issues which has led the Royal College of Nursing to embark on an wide-ranging support initiative. PMID- 27237634 TI - [Not Available]. AB - Backing a winner: this photograph, by Sandra Lousada, will be part of a major exhibition starting this month and touring the country. Taken by leading photographers, the pictures reflect the day to day running of the Great Ormond Street Hospital in London. The exhibition is intended to thank those who contributed to the hospital's Wishing Well appeal. PMID- 27237631 TI - Clinical significance of T-bet, GATA-3, and Bcl-6 transcription factor expression in bladder carcinoma. AB - BACKGROUND: The aim of this study was to investigate the clinical significance of three immune cell-related transcription factors, T-bet, GATA-3 and Bcl-6 in bladder cancer in Tunisian patients. METHODS: Expression of T-bet, GATA-3 and Bcl 6 genes was assessed using RT-qPCR in 65 bladder cancers from patients: 32 being diagnosed as low- and medium-grade, 31 as high-grade, 25 as muscle invasive stage and 39 as non-muscle invasive stage. Gene expression was statistically correlated according to the grade, the stage, tobacco consumption, the BCG response and disease severity. RESULTS: T-bet levels in patients with high-grade bladder cancer were significantly elevated compared to patients with low- or medium-grade bladder cancer (p = 0.005). In invasive carcinoma (T2-T4), the T-bet levels were significantly higher than in superficial non-invasive bladder tumors (Tis, Ta, and T1) (p = 0.02). However, T-bet is predictive of the response to BCG. Its expression is high in good responders to BCG (p = 0.02). In contrast, the expression of GATA-3 and Bcl-6 in non-invasive carcinoma (p = 0.008 and p = 0.0003) and in patients with low- and medium-grade cancers (p = 0.001 and p < 0.0001) is significantly higher than in invasive bladder tumors and in patients with high-grade bladder carcinoma, respectively. In addition, heavy smokers, whose tumors express low levels of GATA-3 and Bcl-6, are poor responders to BCG (p = 0.01 and p = 0.03). Finally, better patient survival correlated with GATA-3 (p = 0.04) and Bcl-6 (p = 0.04) but not T-bet expression. CONCLUSIONS: Our results suggest that T-bet expression in bladder tumors could be a positive prognostic indicator of BCG therapy, even if high levels are found in high-grade and stage of the disease. However, GATA-3 and Bcl-6 expression could be considered as predictive factors for good patient survival. PMID- 27237635 TI - Nurses urged to join support for action. AB - Health unions last week appealed for nurses to join a national action day to 'people pressure' the Government over the ambulance dispute. PMID- 27237636 TI - Torbay staff welcome management departures. AB - Nursing staff have welcomed the sacking and resignation of a health authority's husband and wife managers, COHSE claimed last week. PMID- 27237637 TI - 'Underestimate' on L200m funding. AB - Government money earmarked for administering an NHS internal market may be severely underestimated, according to a report from the King's Fund published last week. PMID- 27237638 TI - Currie on the offensive. AB - Edwina Currie, former Junior Health Minister, warned last week that nurses face a harsh future which can only be alleviated by better efficiency. PMID- 27237639 TI - Newspaper spying fails. AB - A Sunday newspaper has ditched its bid to recruit nurses to spy on consultants after the RCN refused to co-operate. PMID- 27237640 TI - Speculation over award. AB - As Nursing Standard went to press last week, speculation was growing that nurses may be due a relatively large pay award in the Review Body report going to the Prime Minister this month. PMID- 27237642 TI - Clay CBE: 'an honour for the profession'. AB - Former RCN General Secretary Trevor Clay last week hailed his CBF., awarded in the New Year's Honours list, as 'an honour for the profession'. PMID- 27237641 TI - New nursing homes bill. AB - Labour Health spokeswoman, Harriet Harman, has presented a Bill which aims to protect the growing number of people going into private nursing homes by ensuring that all homes have to be registered. PMID- 27237643 TI - [Not Available]. AB - Face of the future: Catherine Burns, the newly-elected General Secretary of the Health Visitors Association, took up post last week. 'One of my highest priorities is to get out and meet HVA members to hear their views and concerns.' she told Nursing Standard. 'I have already arranged a number of visits starting in the north west.' PMID- 27237644 TI - Funds needed to maintain quality services. AB - A substantial increase in the community charge will be needed to provide good quality services under the Government's Community Care proposals, independent health care providers believe. PMID- 27237648 TI - Low birth weight feed formula. AB - Cow and Gate have introduced their new 'Low Birth Weight Baby Formula', which is in line, they say, with current medical opinion on nutritional needs. PMID- 27237646 TI - Parliament. AB - Nationwide consultations are about to begin on the confidentiality of personal health records as the Government aims to issue new guidelines on how computerised data can be used. PMID- 27237649 TI - New irrigated fire curtain. AB - Nursing and residential homes can now introduce a new weapon to their fire protection armoury - following the introduction of Wormald UK's irrigated fire curtains. PMID- 27237650 TI - World news. AB - Romania The Red Cross last week declared the immediate Romanian revolution emergency over, and dismissed as exaggerated' claims that its relief operation had been reduced to shambles. PMID- 27237651 TI - Epidemic passes peak. AB - The flu epidemic has now' officially passed its peak after claiming more than 600 lives, latest figures have showm. PMID- 27237652 TI - Reducing the risks from wheelchairs. AB - A wheelchair which may prevent wasting of the muscles of the lower limbs and the formation of pressure sores is being developed by researchers in America. PMID- 27237654 TI - Needs of women with ovarian failure after TBI. AB - Hormone therapy should be considered virtually mandatory for women with ovarian failure as a result of total body irradiation (TBI). PMID- 27237653 TI - Good outlook for renal replacement treatment. AB - The outlook for patients with spinal cord injury and spina bifida treated for renal failure is good in the short and medium term, Glasgow researchers say. PMID- 27237655 TI - Effects of fear of crime on normal life. AB - Fear of crime may be preventing some groups from leading full lives, according to a report from the Home Office. PMID- 27237656 TI - Serum albumin levels and mortality. AB - Epidemiologists have found a strong association between serum albumin levels and mortality. PMID- 27237657 TI - Nurses of the 90s. AB - One clinical nurse practitioner who I believe will emerge as a leading nurse of the 90s is Rebecca Malby, who was seconded to the National Health Service Training Authority's Working Group on support worker competencies and is currently working at Whipps Cross Hospital in London. Becky has all the skills and talents of a natural leader and I believe she has just won a Florence Nightingale Fellowship to study quality of nursing care in the United States. PMID- 27237658 TI - A circle of care. AB - The characterisation of health care as a business and health as a product with patients (or doctors) as part of the market share is both a frightening and accurate reflection of today's reality. In this era of cost containment, high technology, and general longevity, the rehumanisation of the health care system is an absolute priority. In my view, it is not okay to think of health care as a business. Virginia Henderson ( 9 ), one of the most respected nurses in the world, says it more eloquently than I: 'It is generally conceded that the human desire to help others dominates the social services (as for instance education) and the profit motive dominates industry. "Professionals" are I said to be effective when their clients . learn enough from them to make their help unnecessary. Industrialists are successful to the extent that they promote dependence of the public on their products and create escalating needs or desires for more and more possessions. Health care systems in some countries are unabashedly industrious, directed by industrialists rather than experts in the service they offer . . .' PMID- 27237659 TI - Acquired infection study. AB - We are a group of student nurses about to sit our final examination, and have to undertake a project on 'The implications of hospital acquired infection'. We have been to the RCN central library and our own library and have found very little literature related to this subject. We wondered if anyone could let us know about any published articles and research related to this subject. PMID- 27237661 TI - War for equality. AB - In the November 29 - December 5 issue of Nursing Standard, we the readership, were treated to some rather interesting examples of sexism from no less than three separate sources. PMID- 27237660 TI - The continuing sexism saga. AB - It is with considerable surprise that I have been reading the continuing correspondence in your pages on the subject of sexism in nursing. Now, to add to comments about the male domination of senior nursing posts, we have Barry Clifton who introduces a new dimension (Nursing Standard December 13-19). He complains about the domination of nursing by yet another minority group - childless women, 'to the detriment of professional progress'. PMID- 27237662 TI - Catheter concern. AB - In the Nursing Standard supplement on catheter care, which I read and found very interesting, I came across a point which I intended to write about at the time but have been side tracked by other things. PMID- 27237663 TI - Another responsibility? AB - I read with interest Dr N Bird's letter to Nursing Standard 'Have you got it?' (November 15 - November 21 1989). PMID- 27237664 TI - Agricultural accidents. AB - I am undertaking the ENB 211 Accident and Emergency course part of which involves presenting a dissertation of which agriculture is my chosen subject. PMID- 27237665 TI - Events for scotland. AB - With reference to 'Scotland calling!' a letter in Nursing Standard December 6-12, may I heartily endorse the remarks by E N Robson from Ravenscraig Hospital, Greenock. PMID- 27237666 TI - Fiction file. PMID- 27237667 TI - Nursingeccentrics. AB - May I just report that I have had a limited but enthusiastic response to my letter 'Supporting the non-conformist'(Nursind Standard November 1 to 7) developed from Philip Burnard's article The nurse as a non-conformist' (Nursing Standard September 27 to October 3). PMID- 27237668 TI - Medical memories. AB - Arrangement of bed and kettle in cases of bronchitis c.1888. PMID- 27237669 TI - Obituary - Gill Geary. AB - Stockport Branch Royal College of Nursing deeply regret to announce the untimely passing of Gill Geary, Steward, who died suddenly on Monday 11 December 1989, age 55 years. PMID- 27237670 TI - The right person. AB - I have read with much interest the recent lively debate on the administration of IV drugs. Initiated by Dr Bird's letter (Nursing Standard November 15-21) it appears to me that all who have replied to that letter have been so busy arguing 'it's not my job' that they have failed to consider the patients. I have been on an intensive two day course, I have undergone a series of practical assessments and successfully gained a deserved certificate of competence. No doctor I have ever met has the same qualification or, come to think of it, any formal tuition regarding this procedure. It would therefore appear that I am the professional most highly qualified to administer IV drugs. I believe that patients deserve the highest quality of care that can be given by trained professionals. I therefore deem it my responsibility to give the IVs not to palm the task off on someone less able than myself. PMID- 27237671 TI - Demographic time bomb. AB - I recently had a letter published in the nursing press in which I invited working mothers who felt that they needed support to write to me. I was astonished by the response. PMID- 27237672 TI - The last taboo: sexual abuse of children The last taboo: sexual abuse of children G Search Penguin 178pp L3-99 0-14-011049-6. AB - Gay Search presents an honest and balanced study into the increasingly publicised problem of the sexual abuse of children. She shows a sensitive approach, without sensationalism, treating each area of study with equal consideration. There appears to be no expression of bias towards either abused or abuser. PMID- 27237673 TI - Spiritual dimensions of nursing practice Spiritual Dimensions of Nursing Practice V B Carson W B Saunders 386pp L15.75 0-7216-2249-6. AB - Initially, I saw Spiritual Dimensions of Nursing Practice as an unusual but not particularly relevant book, but once spirituality was defined as a universal need and human quality regardless of religious orientation, it took on a new meaning. PMID- 27237676 TI - Roz osborne on the support for the student bill of rights. AB - The Nursing Students Bill of Rights (NSBR) is probably one of the most discussed documents ever produced by the RCN. Since the RCN Council approved the second edition of the NSBR earlier this year, the discussion and criticism continue. PMID- 27237674 TI - About hepatitis B About hepatitis B Hepatitis B 16pp Scriptographic Booklet No 842351. AB - About Hepatitis B is an excellent booklet, ideal for nursing assistants and auxiliaries and the increasing number of care assistants employed by local authorities and charities caring for people in the community. Ambulance staff, prison and police officers will also find it most useful. PMID- 27237677 TI - Gossip. AB - * According to the Irish Independent, more than 10,000 men and 3,000 women were examined to discover this startling fact. PMID- 27237678 TI - Taking centre stage. AB - 'We got much closer to the needs of mothers and moved away from the technological methods which dominated the seventies,' is how Ruth Ashton sums up progressive trends in maternity care. PMID- 27237679 TI - Setting up a residental home. AB - With more and more emphasis being placed on closing large institutions and moving patients into the community, we can expect to see an enormous growth in residential and care homes, particularly in the private sector. While many will be owned and run by large organisations, there is still some scope for the independent individual to 'go it alone'. PMID- 27237680 TI - The microbe file. PMID- 27237685 TI - Taking it easy when playing ultimatum game with a Down syndrome proposer: Effects on behavior and medial frontal negativity. AB - The ultimatum game (UG) is an endowment sharing game in which a proposer suggests a division of an asset to a recipient, who must accept or reject it. Economic studies showed that despite recipients usually rejecting unfair offers, perception and reaction to unfairness are highly dependent on who is the proposer. Event-related potentials (ERPs) commonly detected in UG games are the medial frontal negativity (MFN), a component detected in recipients facing unfair offers, and the P300, a component related to attentional and memory processes. Given this, we aimed to investigate the behavioral and ERP responses of healthy people playing the UG game with Down syndrome (DS) and typical development (TD) proposers. Nineteen subjects participated in this study. The UG behavioral data were similar to previous studies. ERP analysis showed no MFN in participants facing unfair offers. A higher P300 amplitude was detected when participants faced fair offers from TD compared to DS fair offers. We also found a positive correlation between P300 amplitude for TD offers and self-esteem scale score. Together these findings indicate that insertion of an atypical player in the UG led to changes in participants' perception and expectancy of the game. PMID- 27237686 TI - Spring response to precipitation events using delta(18)O and delta(2)H in the Tanour catchment, NW Jordan. AB - The Tanour spring is one of the several karst springs located in the northern part of Jordan. Water samples from the Tanour spring and precipitation were collected in the area of Ajloun in NW Jordan for the analysis of stable oxygen and hydrogen isotopes to evaluate the spring response to precipitation events. Rainwater and snow samples were collected from different elevations during winters of 2013-2014 and 2014-2015. In addition, spring samples were collected between December 2014 and March 2015. delta(18)O values in rainwater vary from 3.26 to -17.34 0/00 (average: -7.84 +/- 3.23 0/00), while delta(2)H values range between -4.4 and -110.4 0/00 (average: -35.7 +/- 25.0 0/00). Deuterium excess ranges from 17.8 to 34.1 0/00 (average: 27.1 +/- 4.0 0/00). The Local Meteoric Water Line for the study area was calculated to be delta(2)H = 7.66*delta(18)O + 24.43 (R(2) = 0.98). Pre-event spring discharge showed variation in delta(18)O (range -6.29 to -7.17 0/00; average -6.58 +/- 0.19 0/00) and delta(2)H values (range -28.8 to -32.7 0/00; average: -30.5 +/- 1.0 0/00). In contrast, delta(18)O and delta(2)H rapidly changed to more negative values during rainfall and snowmelt events and persisted for several days before returning to background values. Spring water temperature, spring discharge, and turbidity followed the trend in isotopic composition during and after the precipitation events. The rapid change in the isotopic composition, spring discharge, water temperature, and turbidity in response to recharge events is related to fast water travel times and low storage capacity in the conduit system of the karst aquifer. Based on the changes in the isotopic composition of spring water after the precipitation events, the water travel time in the aquifer is in the order of 5 11 days. PMID- 27237688 TI - [Not Available]. AB - Safety drive: A&E charge nurse at the Bradford Royal Infirmary Steve Jones is helping to highlight the cost to the NHS of road traffic accidents. He is featuring in an advertising campaign by the road safety group, Brake, which claims that 300,000 NHS bed days are taken up as a result of road accidents every year. PMID- 27237687 TI - Team work in the proper sense. AB - Triage does seem to be a bit of an unloved child these days. However, rumours of its demise are greatly exaggerated. While there is a view that there is no evidence that triage is effective, as Jill Windle notes in her Editorial Board's eye view on page 9 , triage allows order to be borne of chaos and gives an ever changing and indeterminate patient caseload a sense of organisation. PMID- 27237689 TI - College issues guidance on witnessing resus. AB - The RCN has drawn up guidance on enabling patient relatives to witness resuscitation attempts. PMID- 27237690 TI - Conference calls. AB - The emergency nursing forum of Wales is holding a national study day in Rhyl on May 23. Topics include the management of cervical spine injuries, major incident planning and trauma debriefing. Cost from L25. Contact Llinos Howatson on 01745 534105. PMID- 27237692 TI - Extra lift. AB - Air ambulance staff in Yorkshire are among those thrown a L2.2 million funding lifeline by ministers in a bid to keep them off the ground. Five air ambulance charities are to receive the extra resources over the next year. PMID- 27237693 TI - Web focus. AB - This regular feature highlights websites with information on clinical subjects. PMID- 27237691 TI - Lessons from last winter prompt DoH to take hard line on targets. AB - Emergency care professionals have 'no good reason' for failing to meet waiting time targets, according to a Department of Health review of winter pressure management. PMID- 27237694 TI - ENP care receives vote of confidence. AB - Emergency nurse practitioners (ENPs) have been given a vote of confidence with research findings published in the British Medical Journal. PMID- 27237695 TI - How do NPS and doctors compare? AB - In an important paper for nurse practitioners (NPs) working in walk-in centres, minor injuries units as well as emergency departments, this systematic review of randomised controlled trials and prospective observational studies sought to determine whether NPs can provide care at first point of contact equivalent to doctors in a primary care setting. PMID- 27237696 TI - Setting the pace. AB - The launch of the faculty of emergency nursing (FEN) represents a spectacular coup for the RCN A&E Nursing Association. PMID- 27237697 TI - Thousands expected to join faculty following launch at RCN congress. AB - Around 13,000 nurses are expected to join the newly launched RCN faculty of emergency nursing (FEN) within five years, according to figures presented at RCN council. PMID- 27237698 TI - Use of heparin in burns management. AB - Burn studies in humans and animals that have tested large doses of heparin topically and parenterally have produced significant therapeutic results. Relieved pain, enhanced healing, and smooth skin were findings. Fewer resuscitation fluids, fewer lung and intestinal complications, and fewer infections were reported. These burn studies revealed that heparin had anti inflammatory, neoangiogenic, collagen-restoring, and epithelialising effects in addition to its anti-coagulating effects. PMID- 27237699 TI - COMPARISONS AMONG RADIOGRAPHY, ULTRASONOGRAPHY AND COMPUTED TOMOGRAPHY FOR EX VIVO CHARACTERIZATION OF STIFLE OSTEOARTHRITIS IN THE HORSE. AB - A better understanding of imaging characteristics of equine stifle osteoarthritis (OA) may allow earlier detection and improve prognosis. Objectives of this ex vivo, prospective, methods comparison study were to (1) describe the location and severity of naturally acquired OA lesions in the equine stifle using ultrasound (US), radiography (XR), computed tomography (CT), and macroscopic evaluation (ME); (2) compare the diagnostic performance of each imaging modality with ME; and (3) describe subchondral bone mineral density (BMD) in equine stifle joints with OA using CT. Radiographic, CT, and US evaluations were performed on 23 equine cadaver stifles and compared with ME. Significant associations were found between osteophyte global scores for all imaging modalities (CT, P ? 0.0001; XR, P = 0.005; US, P = 0.04) vs. ME osteophyte global scores. Osteophytes were detected most frequently in the medial femorotibial (MFT) joint. A specific pattern of osteophytes was observed, with a long ridge of new bone at the insertion of the MFT joint capsule cranially on the medial femoral condyle. A novel caudo-10 degrees proximo-5 degrees lateral-cranio-disto-medial oblique radiographic projection was helpful for detection of intercondylar osteophytes. Multiplanar CT reformatted images were helpful for characterizing all osteophytes. Osteophyte grades at most sites did not differ among modalities. Low sensitivity/specificity for subchondral bone sclerosis and flattening of femoral condyles suggested that these signs may not be reliable radiographic and CT indicators of equine stifle OA. Equine stifle OA was associated with a decrease in BMD and specific sites of focal subchondral bone resorption/cyst formation were found in some specimens. PMID- 27237701 TI - A Long-Lived Mononuclear Cyclopentadienyl Ruthenium Complex Grafted onto Anatase TiO2 for Efficient CO2 Photoreduction. AB - This work shows a novel artificial donor-catalyst-acceptor triad photosystem based on a mononuclear C5 H5 -RuH complex oxo-bridged TiO2 hybrid for efficient CO2 photoreduction. An impressive quantum efficiency of 0.56 % for CH4 under visible-light irradiation was achieved over the triad photocatalyst, in which TiO2 and C5 H5 -RuH serve as the electron collector and CO2 -reduction site and the photon-harvester and water-oxidation site, respectively. The fast electron injection from the excited Ru(2+) cation to TiO2 in ca. 0.5 ps and the slow backward charge recombination in half-life of ca. 9.8 MUs result in a long-lived D(+) -C-A(-) charge-separated state responsible for the solar-fuel production. PMID- 27237700 TI - Autotaxin interacts with lipoprotein(a) and oxidized phospholipids in predicting the risk of calcific aortic valve stenosis in patients with coronary artery disease. AB - BACKGROUND: Studies have shown that lipoprotein(a) [Lp(a)], an important carrier of oxidized phospholipids, is causally related to calcific aortic valve stenosis (CAVS). Recently, we found that Lp(a) mediates the development of CAVS through autotaxin (ATX). OBJECTIVE: To determine the predictive value of circulating ATX mass and activity for CAVS. METHODS: We performed a case-control study in 300 patients with coronary artery disease (CAD). Patients with CAVS plus CAD (cases, n = 150) were age- and gender-matched (1 : 1) to patients with CAD without aortic valve disease (controls, n = 150). ATX mass and enzymatic activity and levels of Lp(a) and oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) were determined in fasting plasma samples. RESULTS: Compared to patients with CAD alone, ATX mass (P < 0.0001), ATX activity (P = 0.05), Lp(a) (P = 0.003) and OxPL apoB (P < 0.0001) levels were elevated in those with CAVS. After adjustment, we found that ATX mass (OR 1.06, 95% CI 1.03-1.10 per 10 ng mL-1 , P = 0.001) and ATX activity (OR 1.57, 95% CI 1.14-2.17 per 10 RFU min-1 , P = 0.005) were independently associated with CAVS. ATX activity interacted with Lp(a) (P = 0.004) and OxPL-apoB (P = 0.001) on CAVS risk. After adjustment, compared to patients with low ATX activity (dichotomized at the median value) and low Lp(a) (<50 mg dL-1 ) or OxPL-apoB (<2.02 nmol L-1 , median) levels (referent), patients with both higher ATX activity (>=84 RFU min-1 ) and Lp(a) (>=50 mg dL-1 ) (OR 3.46, 95% CI 1.40-8.58, P = 0.007) or OxPL-apoB (>=2.02 nmol L-1 , median) (OR 5.48, 95% CI 2.45-12.27, P < 0.0001) had an elevated risk of CAVS. CONCLUSION: Autotaxin is a novel and independent predictor of CAVS in patients with CAD. PMID- 27237702 TI - Accuracy of Judging Affect and Accuracy of Judging Personality: How and When Are They Related? AB - OBJECTIVES: The present research is concerned with the relation between accuracy in judging targets' affective states and accuracy in judging the same targets' personality traits. In two studies, we test the link between these two types of accuracy with the prediction that accuracy of judging traits and of judging states will be associated when fundamental affective qualities are shared. METHOD: In Study 1, affective states and personality traits of 29 targets were rated by 124 judges whose individual accuracy was scored as the correlation between their ratings and target criterion scores (across targets). In Study 2, a comparable analysis was done using 30 different targets and 330 different judges. RESULTS: Accuracy in judging distressed affect was significantly positively correlated with accuracy in judging Neuroticism in both studies, as well as in a meta-analysis across the two studies. Accuracy in judging positive affect was significantly positively correlated with accuracy in judging Extraversion in one of the two studies, with the meta-analysis across the two studies being significant. CONCLUSIONS: These findings provide preliminary evidence for a new model (State and Trait Accuracy Model) that outlines when concordance in accuracy across traits and states should be expected. PMID- 27237704 TI - Silver(I)-Catalyzed Three-Component Reaction of Propargylic Alcohols, Carbon Dioxide and Monohydric Alcohols: Thermodynamically Feasible Access to beta Oxopropyl Carbonates. AB - A silver(I)-catalyzed three-component reaction of propargylic alcohols, CO2 , and monohydric alcohols was successfully developed for the synthesis of beta oxopropyl carbonates. As such, a series of beta-oxopropyl carbonates were exclusively produced in excellent yields (up to 98 %), even under atmospheric pressure of CO2 . The silver catalyst works efficiently for both the carboxylative cyclization of propargylic alcohols with CO2 and subsequent transesterification of alpha-alkylidene cyclic carbonates with monohydric alcohols; thus this tandem process performs smoothly under mild conditions. This work provides a versatile and thermodynamically favorable approach to dissymmetric dialkyl carbonates. PMID- 27237703 TI - The influence of intensive lifestyle intervention on patients with isolated impaired fasting glucose: a meta-analysis. AB - AIM: To evaluate the effect of intensive lifestyle intervention on patients with isolated impaired fasting glucose. BACKGROUND: The application of lifestyle intervention to clinical nursing can help improve outcomes of patients with impaired fasting glucose. DESIGN: We performed a meta-analysis of randomized controlled trials using methods outlined in the Cochrane Handbook. METHODS: We performed keyword searches of the literature databases up to September 2014 and performed manual searches of selected article reference lists. Data were extracted by the lead reviewer, cross-checked by the second reviewer, entered into RevMan5.3, and pooled and analysed using the fixed effect inverse-variance model or random effects model to determine the mean difference and calculate the weighted mean difference. The heterogeneity statistic (I2 ), overall effect (Z) and P-value were calculated. RESULTS: A total of five studies were included in our analysis. Following the heterogeneity test statistic, overall effect Z score with P-value was calculated. The targets of fasting plasma glucose, weight, body mass index, triglycerides, high-density lipoprotein cholesterol and total cholesterol all showed significant differences between the intervention and control groups. CONCLUSION: Lifestyle intervention can improve glycaemic control in patients with isolated impaired fasting glucose. It also reduces blood-lipid levels and promotes weight loss. Larger patient cohorts and adequate follow-up should be included in future trials. PMID- 27237705 TI - Hippocampal subfield volumes in short- and long-term lithium-treated patients with bipolar I disorder. AB - OBJECTIVES: Patients diagnosed with bipolar disorder (BP) may experience hippocampal atrophy. Lithium exposure has been associated with increased hippocampal volumes. However, its effects on hippocampal subfields remain to be clarified. METHODS: We investigated the effects of short- and long-term lithium exposure on the hippocampus and its subfields in patients affected by bipolar I disorder (BP-I). Hippocampal subfields and total hippocampal volumes were measured in 60 subjects divided into four groups: 15 patients with BP-I who were never exposed to lithium [no-exposure group (NE)], 15 patients with BP-I exposed to lithium for < 24 months [short-exposure group (SE)], 15 patients with BP-I exposed to lithium for > 24 months [long-exposure group (LE)], and 15 healthy control subjects (HC). RESULTS: The SE and NE groups showed smaller total hippocampal volumes and smaller bilateral cornu ammonis CA2-3, CA4-dentate gyrus (DG), presubiculum, and subiculum volumes compared with HC. The LE group showed larger total hippocampal volumes and bilateral CA2-3, left CA4-DG, left presubiculum, and right subiculum volumes compared with the NE group, and larger volumes of the right CA2-3, left CA4-DG, left presubiculum, and right subiculum compared with the SE group. No differences were found between the LE group and HC or between the SE and NE groups. CONCLUSIONS: Long-term, but not short-term, exposure to lithium treatment may exert neuroprotective effects on specific hippocampal subfields linked to disease progression. PMID- 27237706 TI - Vasculogenesis and Diabetic Erectile Dysfunction: How Relevant Is Glycemic Control? AB - Erectile dysfunction (ED) is a complication of diabetes, condition responsible for causing endothelial dysfunction (EDys) and hampering repair mechanisms. However, scarce information is available linking vasculogenesis mediated by Endothelial Progenitor Cells (EPCs) and diabetes-associated ED. Furthermore, it remains to be elucidated if glycemic control plays a role on EPCs functions, EPCs modulators, and penile vascular health. We evaluated the effects of diabetes and insulin therapy on bone marrow (BM) and circulating EPCs, testosterone, and systemic/penile Stromal Derived Factor-1 alpha (SDF-1alpha) expression. Male Wistar rats were divided into groups: age-matched controls, 8-weeks streptozotocin-induced type 1 diabetics, and insulin-treated 8-weeks diabetics. EPCs were identified by flow cytometry for CD34/CD133/VEGFR2/CXCR4 antigens. Systemic SDF-1alpha and testosterone levels were evaluated by ELISA. Penile SDF 1alpha protein expression was assessed, in experimental and human diabetic cavernosal samples, by immunohistochemical techniques. Diabetic animals presented a reduction of BM-derived EPCs and an increase in putative circulating endothelial cells (CECs) sloughed from vessels wall. These alterations were rescued by insulin therapy. In addition, glycemic control promoted an increase in systemic testosterone and SDF-1alpha levels, which were significantly decreased in animals with diabetes. SDF-1alpha protein expression was reduced in experimental and human cavernosal diabetic samples, an effect prevented by insulin in treated animals. Insulin administration rescued the effects of diabetes on BM function, CECs levels, testosterone, and plasmatic/penile SDF 1alpha protein expression. This emphasizes the importance of glycemic control in the prevention of diabetes-induced systemic and penile EDys, by the amelioration of endothelial damage, and increase in protective pathways. J. Cell. Biochem. 118: 82-91, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27237707 TI - Factors determining the balance between the wish to die and the wish to live in older adults. AB - BACKGROUND: The "Internal Struggle Hypothesis" (Kovacs and Beck, ) suggests that suicidal persons may have both a wish to live (WTL) and a wish to die (WTD). The current study investigates whether the three-group typology - "WTL", "ambivalent (AMB)", and "WTD" - is determined by common correlates of suicidality and whether these groups can be ordinally ranked. METHODS: The sample comprised 113 older inpatients. Discriminant analysis was used to create two functions (combining social, psychiatric, psychological, and somatic variables) to predict the assignment of older inpatients into the groups WTL, AMB, and WTD. RESULTS: The functions "Subjective Well-being" and "Social Support" allowed us to assign patients into these three distinct groups with good accuracy (66.1%). "Subjective Well-being" contrasted the groups WTD and WTL and "Social Support" discriminated between the groups WTD and AMB. "Social Support" was highest in the AMB group. CONCLUSIONS: Our results suggest a simultaneous presence of a WTL and a WTD in older inpatients, and also that the balance between them is determined by "Subjective Well-being" and "Social Support". Unexpectedly, the AMB group showed the highest scores on "Social Support". We hypothesize that higher social support might function as an important determinant of a remaining WTL when a WTD is present because of a lower sense of well-being. The study suggests that the groups WTL-AMB-WTD can not situated on a one-dimensional continuum. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27237710 TI - Is the imaging inconsistent with usual interstitial pneumonia? Think about idiopathic pulmonary fibrosis then! PMID- 27237711 TI - Doctor Shopping. PMID- 27237708 TI - Variants in genes belonging to the fibroblast growth factor family are associated with lower extremity amputation in non-Hispanic whites: Findings from the chronic renal insufficiency cohort study. AB - Diabetes is the major risk factor for nontraumatic lower extremity amputation (LEA). The role of genetic polymorphisms in predisposing diabetics to impaired wound healing leading to LEA has not been sufficiently explored. We investigated the association between a set of genes belonging to the angiogenesis/wound repair pathway with LEA in the Chronic Renal Insufficiency Cohort, a study of adults with chronic kidney disease (CKD) that includes a subgroup with diabetes. This study was performed on 3,772 Chronic Renal Insufficiency Cohort participants who were genotyped on the ITMAT-Broad-CARe array chip. A total of 1,017 single nucleotide polymorphisms (SNPs) in 22 genes belonging to the angiogenesis/would repair pathway were investigated. LEA was determined from patient self-report. The association between genetic variants and LEA status was examined using logistic regression and additive genetic models after stratifying the cohort by race/ethnicity and diabetic status. Unadjusted analyses as well as analyses adjusted for age, sex, estimated glomerular filtration rate, body mass index, peripheral vascular disease, hemoglobin A1c, and population stratification were performed. In non-Hispanic white participants with diabetes, rs11938826 and rs1960669, both intronic SNPs in the gene basic fibroblast growth factor-2 (FGF2), were significantly associated with LEA in covariate-adjusted analysis (OR: 2.83 (95% CI: 1.73, 4.62); p-value: 0.000034; Bonferroni adjusted p-value: 0.0006) and (OR: 2.61 (95% CI: 1.48, 4.61); p-value: 0.00095; Bonferroni adjusted p-value: 0.02). In the same subgroup, rs10883688, an FGF8 SNP of unknown functional effect, was also associated with LEA (OR: 1.72 (95% Confidence Interval: 1.14, 2.6); p-value: 0.00999; Bonferroni adjusted p-value: 0.04). No statistically significant associations were identified in the other ethnic groups. In conclusion, variant/s in FGF2 and FGF8 may predispose diabetics with CKD to LEA. Dysregulation of the FGF2 gene represents an opportunity to understand further, and possibly intervene upon, mechanisms of wound healing in diabetics with CKD. PMID- 27237712 TI - Problems+Solutions. AB - Readers are invited to submit questions relating to problem cases. Inquiries will be answered by qualified consultants and replies forwarded by mail promptly. Selected problems and solutions are published every month in this section. PMID- 27237714 TI - Sinusitis. PMID- 27237713 TI - Pelvic inflammatory disease. AB - Preview Pelvic inflammatory disease (PID) and its long-term sequelae exact a staggering toll in human suffering, not to mention treatment costs. To curb this escalating problem, the primary care physician needs answers to the following questions: Which pathogens cause PID? What clinical criteria and techniques are of most value in diagnosis? How is uncomplicated PID best treated? Dr King provides this critical information. PMID- 27237715 TI - Prostaglandins in peptic ulcer disease. AB - Preview The exact pathogenesis of peptic ulcer disease has not been established. However, an imbalance between the secretion of hydrochloric acid and of pepsin and the ability of the gastroduodenal mucosa to resist damage is the basic pathway. Prostaglandins have important effects on factors that can cause imbalance, such as secretion of gastric acid, bicarbonate, and mucus; synthesis of mucus; and regeneration of mucosal cells after injury. Dr Wilson reviews the research and summarizes the current thinking on the relationship between prostaglandins and these and other elements. PMID- 27237709 TI - Ferric maltol therapy for iron deficiency anaemia in patients with inflammatory bowel disease: long-term extension data from a Phase 3 study. AB - BACKGROUND: Ferric maltol was effective and well-tolerated in iron deficiency anaemia patients with inflammatory bowel disease during a 12-week placebo controlled trial. AIM: To perform a Phase 3 extension study evaluating long-term efficacy and safety with ferric maltol in inflammatory bowel disease patients in whom oral ferrous therapies had failed to correct iron deficiency anaemia. METHODS: After 12 weeks of randomised, double-blind treatment, patients with iron deficiency anaemia and mild-to-moderate ulcerative colitis or Crohn's disease received open-label ferric maltol 30 mg b.d. for 52 weeks. RESULTS: 111 patients completed randomised treatment and 97 entered the open-label ferric maltol extension. In patients randomised to ferric maltol ('continued'; n = 50), mean +/ s.d. haemoglobin increased by 3.07 +/- 1.46 g/dL between baseline and Week 64. In patients randomised to placebo ('switch'; n = 47), haemoglobin increased by 2.19 +/- 1.61 g/dL. Normal haemoglobin was achieved in high proportions of both continued and switch patients (89% and 83% at Week 64, respectively). Serum ferritin increased from 8.9 MUg/L (baseline) to 26.0 MUg/L (Week 12) in ferric maltol-treated patients, and to 57.4 MUg/L amongst all patients at Week 64. In total, 80% of patients reported >=1 adverse event by Week 64. Adverse events considered related to ferric maltol were recorded in 27/111 (24%) patients: 8/18 discontinuations due to adverse events were treatment-related. One patient was withdrawn due to increased ulcerative colitis activity. CONCLUSIONS: Normal haemoglobin was observed in >=80% of patients from weeks 20-64 of long-term ferric maltol treatment, with concomitant increases in iron storage parameters. Ferric maltol was well-tolerated throughout this 64-week study. PMID- 27237716 TI - Cues/Tips. PMID- 27237719 TI - Primary Care Digest. PMID- 27237717 TI - Did You Miss These? PMID- 27237721 TI - RETRACTED ARTICLE: The Impact of Breast Cancer on Women's Everyday Life in Eastern India. PMID- 27237722 TI - An Exploration of the Use of a Sensory Room in a Forensic Mental Health Setting: Staff and Patient Perspectives. AB - Despite the increased use of sensory rooms, there is little published evidence related to their benefits. The purpose of this study was to explore staff and patient perspectives of the use of a sensory room in an Australian forensic mental health setting. Staff and patients on a forensic hospital unit were recruited for this study. Focus group data was obtained from the perspective of the healthcare staff. A sensory assessment identified patients' sensory preferences. The details of the patients sensory room use and stress experienced before and after using the sensory room were recorded. The results showed a mean decrease in stress that was attributed to the use of the sensory room. Stress reducing benefits of sensory room use may improve a patient's experience within a forensic mental health facility while applying a recovery approach. As a limitation of the study, patient stress was rated on an un-validated scale. Further research is needed for greater insight and evidence in evaluating the use of sensory rooms in forensic mental health settings in reducing stress. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27237723 TI - Autosomal recessive congenital ichthyosis due to PNPLA1 mutation in a golden retriever-poodle cross-bred dog and the effect of topical therapy. AB - BACKGROUND: Ichthyoses represent a genetically and phenotypically heterogeneous syndrome of abnormal epidermal cornification. Although the clinical presentation, histopathological findings and genetic cause of autosomal recessive congenital ichthyosis (ARCI) in golden retriever dogs have been well investigated, the optimal management of this disease remains uncharacterized. OBJECTIVES: In this report we describe the beneficial effect of oral and topical fatty acids for management of a golden retriever and poodle cross-bred dog (goldendoodle) with ARCI due to a PNPLA1 (Patatin-like phospholipase domain containing 1) mutation. CASE REPORT: A six-month-old, intact female, second generation golden retriever and poodle cross-bred dog presented with a history of generalized scaling since the age of 6 weeks. Histopathology showed diffuse, laminated-to-compact hyperkeratosis with a single small perinuclear vacuole in occasional stratum granulosum keratinocytes. Genetic testing revealed a homozygotic insertion/deletion mutation in the gene PNPLA1. Daily oral fatty acid supplementation and humectant rinse, following weekly moisturizing shampoo, resulted in only mild improvement after two months. Weekly application of a topical essential oils and fatty acid product was then added. Thirteen months after the initial presentation the dog exhibited a marked improvement in clinical signs. The temporal discontinuation of topical therapy resulted in the worsening of scaling, which improved again after resuming this combination. CONCLUSIONS AND CLINICAL IMPORTANCE: To the best of the authors' knowledge, this is the first case report of ARCI with homozygous PNPLA1 mutation in a golden retriever-poodle cross-bred dog. The long-term combination of oral fatty acids and topical therapy appeared to be beneficial in this case. PMID- 27237724 TI - ADHD in childhood epilepsy: Clinical determinants of severity and of the response to methylphenidate. AB - OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is commonly observed in children with epilepsy. However, factors associated with the development of ADHD and which might help to guide its therapeutic management, remain an issue of debate. METHODS: We conducted a multicenter prospective observational study that included children, aged 6-16 years, with both epilepsy and ADHD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. After inclusion, patients entered a 12-16 week follow-up period during which they were either treated with methylphenidate or they did not receive specific ADHD treatment. ADHD was evaluated with the ADHD Rating Scale-IV. RESULTS: One hundred sixty-seven patients were included, of which 91 were seizure free during the preinclusion baseline period. At inclusion, the ADHD Rating Scale IV total score was 30.4 +/- (standard deviation) 9.2, the inattentive subscore was 17.3 +/- 4.4, and the hyperactive subscore was 13.2 +/- 6.6. We did not detect any difference of ADHD Rating Scale-IV scores across patients' age or gender, age at epilepsy onset, epilepsy syndrome, seizure frequency, or number of ongoing antiepileptic drugs. Methylphenidate was initiated in 61 patients, including 55 in whom a follow-up evaluation was available. At the last follow-up, 41 patients (75%) treated with methylphenidate and 39 (42%) of those who did not received ADHD therapy demonstrated >=25% decrease of ADHD Rating Scale-IV total score (p < 0.001). Response to methylphenidate was greater in girls but was not influenced by any epilepsy-related variables. SIGNIFICANCE: We did not detect any epilepsy-related factor associated with the severity of ADHD. Twenty-five percent of patients did not respond to methylphenidate. A better understanding of the pathologic process that underlies ADHD development in childhood epilepsy might be required to improve therapeutic strategies. PMID- 27237725 TI - Prepulse inhibition deficits in women with PTSD. AB - Prepulse inhibition (PPI) is an automatic and preattentive process, whereby a weak stimulus attenuates responding to a sudden and intense startle stimulus. PPI is a measure of sensorimotor filtering, which is conceptualized as a mechanism that facilitates processing of an initial stimulus and is protective from interruption by a later response. Impaired PPI has been found in (a) healthy women during the luteal phase of the menstrual cycle, and (b) individuals with types of psychopathology characterized by difficulty suppressing and filtering sensory, motor, or cognitive information. In the current study, 47 trauma-exposed women with or without posttraumatic stress disorder (PTSD) completed a PPI session during two different phases of the menstrual cycle: the early follicular phase, when estradiol and progesterone are both low, and the midluteal phase, when estradiol and progesterone are both high. Startle stimuli were 100 dB white noise bursts presented for 50 ms, and prepulses were 70 dB white noise bursts presented for 20 ms that preceded the startle stimuli by 120 ms. Women with PTSD showed deficits in PPI relative to the healthy trauma-exposed participants. Menstrual phase had no effect on PPI. These results provide empirical support for individuals with PTSD having difficulty with sensorimotor filtering. The potential utility of PPI as a Research Domain Criteria (RDoC) phenotype is discussed. PMID- 27237726 TI - Psychiatric comorbidity in temporal DNET and improvement after surgery. AB - BACKGROUND: "Alien tissue" may be responsible for a higher frequency of psychiatric disorders in patients with temporal lobe epilepsy (TLE). Also, ganglioglioma and dysembryoplastic neuroepithelial tumors (DNET) could represent a risk-factor for the development of post-surgical psychoses. Classically, severe psychiatric disorders contra-indicate epilepsy surgery. OBJECTIVES: Assessment of inter-ictal psychiatric disorders in 10 consecutive patients with temporal DNET, before and after epilepsy surgery with a minimum of a 2-year follow-up evaluation. METHODS: DNETs were confirmed on histological examination. Psychiatric disorders were classified according to the DSM-IV-TR. RESULTS: Five patients presented inter-ictal psychiatric disorders with, according to the DSM IV-TR, undifferentiated schizophrenia (one case), "borderline" personality (two cases), intermittent explosive disorder with slight mental retardation (one case), and personality disorders not otherwise specified but with some traits of dependent personality and with mythomania (one case). The condition of these five patients dramatically improved after surgery. No psychiatric behavior or "de novo" psychosis was observed after surgery in any of the patients. CONCLUSION: The prevalence of inter-ictal psychiatric disorders appears to be high in epileptic patients with a temporal lobe DNET primarily in relation to personality and behavioral problems with some degree of impulsivity and verbal aggressiveness. The improvements after surgery suggest that this therapy could be performed in these patients and severe psychiatric disorders do not contra indicate this procedure. PMID- 27237727 TI - SAP(E) - A cell-penetrating polyproline helix at lipid interfaces. AB - Cell-penetrating peptides (CPPs) are short membrane-permeating amino acid sequences that can be used to deliver cargoes, e.g. drugs, into cells. The mechanism for CPP internalization is still subject of ongoing research. An interesting family of CPPs is the sweet arrow peptides - SAP(E) - which are known to adopt a polyproline II helical secondary structure. SAP(E) peptides stand out among CPPs because they carry a net negative charge while most CPPs are positively charged, the latter being conducive to electrostatic interaction with generally negatively charged membranes. For SAP(E)s, an internalization mechanism has been proposed, based on polypeptide aggregation on the cell surface, followed by an endocytic uptake. However, this process has not yet been observed directly since peptide-membrane interactions are inherently difficult to monitor on a molecular scale. Here, we use sum frequency generation (SFG) vibrational spectroscopy to investigate molecular interactions of SAP(E) with differently charged model membranes, in both mono- and bi-layer configurations. The data suggest that the initial binding mechanism is accompanied by structural changes of the peptide. Also, the peptide-model membrane interaction depends on the charge of the lipid headgroup with phosphocholine being a favorable binding site. Moreover, while direct penetration has also been observed for some CPPs, the spectroscopy reveals that for SAP(E), its interaction with model membranes remains limited to the headgroup region, and insertion into the hydrophobic core of the lipid layer does not occur. PMID- 27237728 TI - Two successive calcium-dependent transitions mediate membrane binding and oligomerization of daptomycin and the related antibiotic A54145. AB - Daptomycin and A54145 are homologous lipopeptide antibiotics that permeabilize the cell membranes of Gram-positive bacteria. Membrane permeabilization depends on the presence of both phosphatidylglycerol (PG) and calcium, and it involves the formation of oligomeric transmembrane pores that consist of approximately 6-8 subunits. We here show that each lipopeptide molecule binds two calcium ions in separable, successive steps. The first calcium ion causes the lipopeptide molecule to bind to the target membrane, and likely to form a loosely associated oligomer. Higher calcium concentrations induce binding of a second ion, which produces the more tightly associated and more deeply membrane-inserted final, functional form of the oligomer. Both calcium-dependent steps are accompanied by fluorescence signals that indicate transition of specific amino acid residues into less polar environments, suggestive of insertion into the target membrane. Our findings agree with the earlier observation that two of the four acidic amino acid residues in the daptomycin molecule are essential for antibacterial activity. PMID- 27237730 TI - Updosing nonsedating antihistamines in patients with chronic spontaneous urticaria: a systematic review and meta-analysis. AB - There is a lack of large, randomized, double-blind studies that address antihistamine updosing for chronic spontaneous urticaria (CSU). The objective of this systematic review is to explore and analyse available data to provide clinical evidence for the efficacy of antihistamine updosing. We searched the literature in Medline, Scopus, Google Scholar, Embase, Web of Science and Cochrane databases using the keywords 'chronic, urticaria, antihistamines' to identify studies published between January 1990 and November 2014. We assessed quality using the Jadad score that evaluates quality of randomization, double blinding and losses to follow-up. We identified 1042 articles and 15 articles were included in the final evaluation. We performed two meta-analyses, one that included studies that analysed treatment response among groups receiving different antihistamine dosages vs. placebo, and another that analysed antihistamine updosing in those patients who did not respond to standard dosages. Only five articles obtained a high quality level score. We did not find significant differences in response rates or number of weals in those patients who received a standard dosage vs. a high dosage. We found a significant improvement only in the pruritus variable of the Urticaria Activity Score scale. The estimated relative risk for improvement by increasing the antihistamine dosage was 2.27 [95% confidence interval (CI) 1.68-3.06]; however, there was significant heterogeneity. The proportion of nonrespondent patients with CSU who responded to antihistamine updosing was 63.2% (95% CI 57-69.6). We found that updosing antihistamines significantly improved control of pruritus but not weal number. However, the relative weakness of the studies and the significant heterogeneity among them made it difficult to reach a final conclusion. PMID- 27237729 TI - [Strategies for improving care of oncologic patients: SHARE Project results]. AB - Cancer treatment is a major burden for the patient and its family that requires an individualized management by healthcare professionals. Nurses are in charge of coordinating care and are the closest healthcare professionals to patient and family; however, in Spain, there are not standard protocols yet for the management of oncology patients. The Spanish Oncology Nursing Society developed between 2012 and 2014 the SHARE project, with the aim of establishing strategies to improve quality of life and nursing care in oncology patients. It was developed in 3 phases. First, a literature search and review was performed to identify nursing strategies, interventions and tools to improve cancer patients' care. At the second stage, these interventions were agreed within a group of oncology nursing experts; and at the third phase, a different group of experts in oncology care categorized the interventions to identify the ones with highest priority and most feasible to be implemented. As a result, 3 strategic actions were identified to improve nursing care during cancer treatment: To provide a named nurse to carry out the follow up process by attending to the clinic or telephonic consultation, develop therapeutic education with adapted protocols for each tumor type and treatment and ensure specific training for nurses on the management of the cancer patients. Strategic actions proposed in this paper aim to improve cancer patients' healthcare and quality of life through the development of advanced nursing roles based on a higher level of autonomy, situating nurses as care coordinators to assure an holistic care in oncology patients. PMID- 27237731 TI - Does evidence-based health care have room for the self? AB - Evidence-based health care (EBHC) has consistently been attacked by opponents for being perniciously reductive. Although these attacks are overwhelmingly framed as critiques of evidence-based medicine, they standardly target the research wing of EBHC upon which evidence-based medicine is dependent, and increasingly extend to adjacent health care disciplines, such as nursing. One of the most persistent forms this line of attack has taken is the allegation that EBHC, with its emphasis on the hierarchy of evidence, grounded in the use of randomized controlled trials, and the clinical guidelines developed on their basis, fails to recognize the patient as the complex self she is, treating her instead as merely a quantifiable, medical-scientific object. By reducing the patient to certain quantifiable dimensions, the patient as self is allegedly 'erased'. In short, the complaint is that an evidence-based approach to health care has no room for the self. Contrary to this persistently held view, it is argued here that EBHC does have room for the self. Review of these critiques suggests they can be categorized into two groups: soft critiques and strong critiques. Soft critiques tend to take a more measured tone grounded in empirical concerns about the dangers of an evidence-based approach to health care, whereas strong critiques tend to make sweeping claims grounded in theoretical commitments to anti foundationalist philosophical frameworks. While both soft and strong critiques ultimately fail to make the case that EBHC has no room for the self, the empirical concerns of soft critiques nevertheless present a challenge EBHC advocates would do well to take seriously and address. PMID- 27237732 TI - Spectroscopic studies on the interaction of chromium (VI) and chromium (III) with keyhole limpet hemocyanin. AB - The interactions of keyhole limpet hemocyanin (KLH) with chromium nitrate, potassium dichromate, and chromate were investigated using fluorescence, UV-vis absorption and circular dichroism (CD) spectroscopy under simulated physiological conditions. The experimental results showed that the different forms of chromium could quench the intrinsic fluorescence of KLH following a static quenching mechanism rather than by dynamic collision, which indicated that a Cr-KLH complex was formed. The Stern-Volmer quenching constants for the interaction indicated that the binding reaction of KLH with Cr(VI) was stronger the binding of KLH with Cr(III). The thermodynamic values for binding of Cr(VI) to KLH are DeltaH > 0 and DeltaS > 0. By contrast, the values for the interaction of Cr(III) with KLH are DeltaH < 0 and DeltaS < 0. The results of synchronous fluorescence, UV-vis absorption and CD spectroscopy showed that the alpha-helical secondary structure and conformation of KLH were altered by different forms of chromium. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27237733 TI - Characterization and comparability of stress-induced oxidation and deamidation on vulnerable sites of etanercept products. AB - An etanercept biosimilar, TuNEX((r)), was compared to the innovator drug, Enbrel((r)), for its reaction to stress-induced oxidation and deamidation, which may affect drug efficacy. A tryptic peptide map of both etanercept products was generated by liquid chromatography (LC) using mass spectrometry (MS) and ultraviolet (UV) spectrophotometry detection methods. The sequence of each modified or non-modified peptide peak was assigned based on accurate measurement of the mass of the protein and analysis utilizing tandem MS. Similar profiles of intrinsic oxidation on methionine (M) and deamidation on asparagine (N) were obtained for the two products, regardless of a two-amino acid (AA) residue variance in the heavy chain (Fc) between them. The level of oxidative stress exerted by tert-butyl hydroperoxide (tBHP), and alkaline stress exerted by a pH 10.4 solution, was examined using an LC-UV method. The results indicated that TuNEX((r)) demonstrated a similar stress-induced modification profile compared to that of Enbrel((r)). For both products, oxidative stress increased the oxidation from an intrinsically low (0-6.9%) to moderate or high (42-100%) level for almost all M residues (M30, M174, M187, M223, M272, and M448); alkaline stress increased the deamidation level of N404 from a low (0.0 or 1.7%) to moderate (19-26%) level. Based the results of a cell-based bioactivity assay, TuNEX((r)) also exhibited a similar level of bioactivity as Enbrel((r)) in unstressed, oxidative stressed, or alkaline-stressed conditions. The bioactivity of both products remained unaltered by oxidative stress but was reduced by alkali stress. In conclusion, our data indicated that TuNEX((r)) exhibits a similar chemical stress profile as that of Enbrel((r)) in terms of oxidation and deamidation as well as bioactivity. PMID- 27237734 TI - A comprehensive study to protein retention in hydrophobic interaction chromatography. AB - The effect of different kosmotropic/chaotropic salt systems on retention characteristics of intact proteins has been examined in hydrophobic interaction chromatography (HIC). The performance was assessed using different column chemistries, i.e., polyalkylamide, alkylamine incorporating hydrophobic moieties, and a butyl chemistry. Selectivity in HIC is mainly governed by the salt concentration and by the molal surface tension increment of the salt. Typically, a linear relationship between the natural logarithm of the retention factor and the salt concentration is obtained. Using a 250mm long column packed with 5MUm polyalkylamide functionalized silica particles and applying a 30min linear salt gradient, a peak capacity of 78 was achieved, allowing the baseline separation of seven intact proteins. The hydrophobicity index appeared to be a good indicator to predict the elution order of intact proteins in HIC mode. Furthermore, the effect of adding additives in the mobile phase, such as calcium chloride (stabilizing the 3D conformation of alpha-lactalbumin) and isopropanol, on retention properties has been assessed. Results indicate that HIC retention is also governed by conformational in the proteins which affect the number of accessible hydrophobic moieties. PMID- 27237735 TI - The recent outbreaks and reemergence of poliovirus in war and conflict-affected areas. AB - BACKGROUND: Poliomyelitis is a highly infectious disease caused by poliovirus, which becomes difficult to manage/eradicate in politically unstable areas. The objectives of this study were to determine the movement and management of such polio outbreaks in endemic countries and countries with reoccurring cases of polio and to determine the effect of political instability on polio eradication. METHODS: In this study, the extent of polio outbreaks was examined and modeled using statistical methodologies and mapped with GIS software. Data on polio cases and immunization were collected for countries with polio cases for the period 2011 to 2014. Weekly data from the Global Polio Eradication Initiative were collected for selected countries. The recent virus origin and current movement was mapped using GIS. Correlations between immunization rates, the Global Peace Index (GPI), and other indicators of a country's political stability with polio outbreaks were determined. Data were analyzed using SAS 9.4 and ArcGIS 10. RESULTS: For several reasons, Pakistan remains highly vulnerable to new incidences of polio (306 cases in 2014). Overall immunization rates showed a steady decline over time in selected countries. Countries with polio cases were shown to have high rates of infant mortality, and their GPI ranked between 2.0 and 3.3; displaced populations, level of violent crime rating, and political instability also were ranked high for several countries. CONCLUSION: Polio was shown to be high in areas with increased conflict and instability. Displaced populations living in hard-to-reach areas may lack access to proper vaccination and health care. Wars and conflict have also resulted in the reemergence of polio in otherwise polio-free countries. PMID- 27237737 TI - Mitochondrial Dynamics Impacts Stem Cell Identity and Fate Decisions by Regulating a Nuclear Transcriptional Program. AB - Regulated mechanisms of stem cell maintenance are key to preventing stem cell depletion and aging. While mitochondrial morphology plays a fundamental role in tissue development and homeostasis, its role in stem cells remains unknown. Here, we uncover that mitochondrial dynamics regulates stem cell identity, self renewal, and fate decisions by orchestrating a transcriptional program. Manipulation of mitochondrial structure, through OPA1 or MFN1/2 deletion, impaired neural stem cell (NSC) self-renewal, with consequent age-dependent depletion, neurogenesis defects, and cognitive impairments. Gene expression profiling revealed ectopic expression of the Notch self-renewal inhibitor Botch and premature induction of transcription factors that promote differentiation. Changes in mitochondrial dynamics regulate stem cell fate decisions by driving a physiological reactive oxygen species (ROS)-mediated process, which triggers a dual program to suppress self-renewal and promote differentiation via NRF2 mediated retrograde signaling. These findings reveal mitochondrial dynamics as an upstream regulator of essential mechanisms governing stem cell self-renewal and fate decisions through transcriptional programming. PMID- 27237736 TI - In Vivo Tracking of Human Hematopoiesis Reveals Patterns of Clonal Dynamics during Early and Steady-State Reconstitution Phases. AB - Hematopoietic stem/progenitor cells (HSPCs) are capable of supporting the lifelong production of blood cells exerting a wide spectrum of functions. Lentiviral vector HSPC gene therapy generates a human hematopoietic system stably marked at the clonal level by vector integration sites (ISs). Using IS analysis, we longitudinally tracked >89,000 clones from 15 distinct bone marrow and peripheral blood lineages purified up to 4 years after transplant in four Wiskott Aldrich syndrome patients treated with HSPC gene therapy. We measured at the clonal level repopulating waves, populations' sizes and dynamics, activity of distinct HSPC subtypes, contribution of various progenitor classes during the early and late post-transplant phases, and hierarchical relationships among lineages. We discovered that in-vitro-manipulated HSPCs retain the ability to return to latency after transplant and can be physiologically reactivated, sustaining a stable hematopoietic output. This study constitutes in vivo comprehensive tracking in humans of hematopoietic clonal dynamics during the early and late post-transplant phases. PMID- 27237738 TI - Systematic Functional Annotation and Visualization of Biological Networks. AB - Large-scale biological networks represent relationships between genes, but our understanding of how networks are functionally organized is limited. Here, I describe spatial analysis of functional enrichment (SAFE), a systematic method for annotating biological networks and examining their functional organization. SAFE visualizes the network in 2D space and measures the continuous distribution of functional enrichment across local neighborhoods, producing a list of the associated functions and a map of their relative positioning. I applied SAFE to annotate the Saccharomyces cerevisiae genetic interaction similarity network and protein-protein interaction network with gene ontology terms. SAFE annotations of the genetic network matched manually derived annotations, while taking less than 1% of the time, and proved robust to noise and sensitive to biological signal. Integration of genetic interaction and chemical genomics data using SAFE revealed a link between vesicle-mediate transport and resistance to the anti-cancer drug bortezomib. These results demonstrate the utility of SAFE for examining biological networks and understanding their functional organization. PMID- 27237740 TI - Omics Meets Metabolic Pathway Engineering. AB - A principled approach to integrating metabolomics, proteomics, and genome-scale metabolic modeling facilitaties rational pathway engineering of E. coli. PMID- 27237742 TI - Dependence of juvenile reef fishes on semi-arid hypersaline estuary microhabitats as nurseries. AB - The differences between fish assemblages in three microhabitat types, in relation to vegetation and sediment characteristics of a hypersaline estuary located in an semi-arid zone in north-eastern Brazil, were investigated. Fishes were collected using a beach seine during the rainy and dry seasons in 2012. A total of 78 species were recorded, with the most common families being Gerreidae, Lutjanidae and Tetraodontidae. The majority of species were represented by juveniles, with Eucinostomus argenteus, Ulaema lefroyi and Sphoeroides greeleyi being the dominant species. The fish assemblage structures differed significantly among microhabitat types, with the narrow intertidal flat adjacent to the mangrove fringe supporting the most diverse fish fauna. In addition, only 27 species were common to all of the microhabitats. The results support the hypothesis that hypersaline estuaries serve as important nursery areas for various reef fish species, due to the structural complexity provided by their macroalgae beds and mangroves. PMID- 27237739 TI - Distinct NF-kappaB and MAPK Activation Thresholds Uncouple Steady-State Microbe Sensing from Anti-pathogen Inflammatory Responses. AB - The innate immune system distinguishes low-level homeostatic microbial stimuli from those of invasive pathogens, yet we lack understanding of how qualitatively similar microbial products yield context-specific macrophage functional responses. Using quantitative approaches, we found that NF-kappaB and MAPK signaling was activated at different concentrations of a stimulatory TLR4 ligand in both mouse and human macrophages. Above a threshold of ligand, MAPK were activated in a switch-like manner, facilitating production of inflammatory mediators. At ligand concentrations below this threshold, NF-kappaB signaling occurred, promoting expression of a restricted set of genes and macrophage priming. Among TLR-induced genes, we observed an inverse correlation between MAPK dependence and ligand sensitivity, highlighting the role of this signaling dichotomy in partitioning innate responses downstream of a single receptor. Our study reveals an evolutionarily conserved innate immune response system in which danger discrimination is enforced by distinct thresholds for NF-kappaB and MAPK activation, which provide sequential barriers to inflammatory mediator production. PMID- 27237741 TI - Insights into the Mechanisms of Basal Coordination of Transcription Using a Genome-Reduced Bacterium. AB - Coordination of transcription in bacteria occurs at supra-operonic scales, but the extent, specificity, and mechanisms of such regulation are poorly understood. Here, we tackle this problem by profiling the transcriptome of the model organism Mycoplasma pneumoniae across 115 growth conditions. We identify three qualitatively different levels of co-expression corresponding to distinct relative orientations and intergenic properties of adjacent genes. We reveal that the degree of co-expression between co-directional adjacent operons, and more generally between genes, is tightly related to their capacity to be transcribed en bloc into the same mRNA. We further show that this genome-wide pervasive transcription of adjacent genes and operons is specifically repressed by DNA regions preferentially bound by RNA polymerases, by intrinsic terminators, and by large intergenic distances. Taken together, our findings suggest that the basal coordination of transcription is mediated by the physical entities and mechanical properties of the transcription process itself, and that operon-like behaviors may strongly vary from condition to condition. PMID- 27237743 TI - Cell division cycle-associated protein 1 as a new melanoma-associated antigen. AB - Immune checkpoint inhibitors have increased the median survival of melanoma patients. To improve their effects, antigen-specific therapies utilizing melanoma associated antigens should be developed. Cell division cycle-associated protein 1 (CDCA1), which has a specific function at the kinetochores for stabilizing microtubule attachment, is overexpressed in various cancers. CDCA1, which is a member of cancer-testis antigens, does not show detectable expression levels in normal tissues. Quantitative reverse transcription polymerase chain reaction and immunoblotting analyses revealed that CDCA1 was expressed in all of the tested melanoma cell lines, 74% of primary melanomas, 64% of metastatic melanomas and 25% of nevi. An immunohistochemical analysis and a Cox proportional hazards model showed that CDCA1 could be a prognostic marker in malignant melanoma (MM) patients. CDCA1-specific siRNA inhibited the cell proliferation of SKMEL2 and WM115 cells, but did not reduce the migration or invasion activity. These results suggest that CDCA1 may be a new therapeutic target of melanoma. PMID- 27237744 TI - Sustained Interruption of Anterior Interfaces Between Adipose Tissues and Mammary Glands in Ultrasonography After Complete Pathological Remission After Neoadjuvant Chemotherapy for Primary Breast Cancer. AB - BACKGROUND: Interruptions of the anterior interfaces between adipose tissues and mammary glands ultrasonographically are considered highly indicative of invasive ductal carcinoma. However, ultrasonography (US) revealed sustained interruptions in some cases of complete pathological remission (pCR) after neoadjuvant chemotherapy (NAC), although invasive carcinomas remained absent. Thus, in the present study, we examined the influences of interruptions on pathology observations after pCR after NAC for primary breast cancer. PATIENTS AND METHODS: A total of 337 patients received NAC at St Luke's International Hospital from April 2004 to September 2006, and 46 had pCRs despite residual in situ lesions (pCR ratio, 13.6%). Subsequently, the medical records of these 46 patients were retrospectively reviewed and US findings were compared with pathological findings. RESULTS: On US, interruptions remained in 18 of 46 pCR patients. Complete fibril formations were detected in 15 cases and associated in situ lesions were detected in 4 cases. CONCLUSION: US findings of interruptions of the anterior interface between adipose tissues and mammary glands were pathologically correlated with fibril formations and might not always indicate the presence of residual invasive cancer after NAC. PMID- 27237745 TI - Fibroblast activation and senescence in oral cancer. AB - There is now compelling evidence that the tumour stroma plays an important role in the pathogenesis of cancers of epithelial origin. The pre-eminent cell type of the stroma is carcinoma-associated fibroblasts. These cells demonstrate remarkable heterogeneity with activation and senescence being common stress responses. In this review, we summarise the part that these cells play in cancer, particularly oral cancer, and present evidence to show that activation and senescence reflect a unified programme of fibroblast differentiation. We report advances concerning the senescent fibroblast metabolome, mechanisms of gene regulation in these cells and ways in which epithelial cell adhesion is dysregulated by the fibroblast secretome. We suggest that the identification of fibroblast stress responses may be a valuable diagnostic tool in the determination of tumour behaviour and patient outcome. Further, the fact that stromal fibroblasts are a genetically stable diploid cell population suggests that they may be ideal therapeutic targets and early work in this context is encouraging. PMID- 27237746 TI - Identification and gene cloning of a new major allergen Cha o 3 from Chamaecyparis obtusa (Japanese cypress) pollen. PMID- 27237747 TI - The effects of whole body vibration on muscle strength and functional mobility in persons with multiple sclerosis: A systematic review and meta-analysis. AB - OBJECTIVES: This review aimed to confirm the effects of the whole body vibration (WBV) on muscle performance and functional mobility in multiple sclerosis (MS) patients. METHODS: A systematic literature search was performed in databases of Pubmed, Web of Science, EMBASE and the Cochrane Library from 1990 to 2015. The risk of bias in the selected studies was assessed using the Cochrane Collaboration's Tool. Summary statistics was calculated using the Review Manager 5.2 software. RESULTS: Based on the inclusion and exclusion criteria, 7 trials including 201 subjects were included in this meta-analysis. The results showed that the WBV significantly improved the knee extensor strength (WMD=13.74, 95% CI 4.56 to 22.93, P=0.003). However, there were no significant differences between WBV and control groups on knee flexor strength (95% CI -26.22 to 41.83, P=0.65), Timed Up and Go test (TUG, WMD=0.31, 95% CI: -0.91 to 3.42, P=0.62) and walking speed (SMD=0.42, 95% CI: -0.78 to 1.62, P=0.49). CONCLUSIONS: These results indicate that the WBV may improve the knee extension muscle strength. However, the WBV does not show a meaningful improvement of functional mobility in MS patients. PMID- 27237748 TI - Neuromyelitis optica accompanied by nephrotic syndrome and autoimmune-related pancytopenia. AB - Neuromyelitis optica (NMO) associated with nephrotic syndrome and autoimmune related pancytopenia has not been reported previously. We report herein a young woman who initially presented with bilateral blurring of vision and numbness in her hands. MRI disclosed multiple white matter lesions and a long cervical spinal cord lesion extending to the medulla oblongata. Serum aquaporin-4 antibody was positive and the patient was diagnosed with NMO. While in the hospital, she presented with hypoproteinemia and heavy proteinuria, meeting the diagnostic criteria of nephrotic syndrome. After high-dose methylprednisolone treatment, her vision improved significantly and urine protein quantity decreased. However, the patient subsequently developed severe pancytopenia with a positive Coombs' test. Thrombocytopenia finally led to uncontrollable gastrointestinal bleeding as the direct cause of the patient's death. This case illustrates the extremely rare condition of concurrence of NMO, nephrotic syndrome, and autoimmune pancytopenia in one patient, which suggests the involvement of organs beyond the central nervous system in NMO spectrum disorders. PMID- 27237749 TI - How long is the presymptomatic phase of multiple sclerosis? PMID- 27237750 TI - Type 1 diabetes and susceptibility to multiple sclerosis: What is the truth? PMID- 27237751 TI - Characterizing retinal structure injury in African-Americans with multiple sclerosis. AB - To examine retinal structure injury in African-Americans (AA) with Multiple Sclerosis (MS) compared to Caucasians (CA) with MS, we used spectral domain optical-coherence tomography (OCT) in this cross sectional study. The peripapillary retinal nerve fiber layer (pRNFL) and macular volume of 234 MS patients (149 CA; 85 AA) and 74 healthy controls (60 CA; 17 AA) were measured. Intra-retinal segmentation was performed to obtain retinal nerve fiber (RNFL), ganglion cell (GCL), inner plexiform (IPL), inner nuclear (INL), outer plexiform (OPL), outer nuclear (ONL), retinal pigment epithelium (RPE), and photoreceptor (PR) layer volumes. Study was approved by IRB, and informed consent obtained from all participants. We found that pRNFL was thicker in AA v. CA healthy controls (100.9 vs 97.00MUm, p=0.004). Compared to HC, MS patients demonstrated thinner pRNFL (p<0.0001), and lower TMV (p<0.001), macular RNFL (p<0.0001), GCL (p<0.0001), and IPL (p<0.0001). AAMS patients had thinner pRNFL (87.2 vs 90.0MUm, and lower TMV (8.2 vs 8.4mm(3), p=0.0001), RNFL (0.73 vs 0.79mm(3), p=0.0001), and GCL (0.94 vs 0.98mm(3), p=0.007) than CAMS patients. Sub-analysis of patients without history of AON showed thinner pRNFL (88.9 vs 93.1um) and TMV (8.2 vs. 8.5mm(3), p<0.0001) in AAMS compared to CAMS patients. In conclusion, this cross sectional study provides evidence supporting greater retinal structure injury in AAMS compared to CAMS patients, irrespective of history of AON. Our findings are consistent with other studies demonstrating a more severe CNS tissue injury in AAMS patients. PMID- 27237752 TI - Neuromyelitis optica relapses: Race and rate, immunosuppression and impairment. AB - OBJECTIVE: Neuromyelitis optica (NMO) is a rare antibody-mediated CNS disease characterised by disabling relapses leading to high morbidity and mortality. Understanding relapse activity and severity is important for treatment decisions and clinical trial design. We assessed (1) whether clinical and demographic factors associate with different relapse rates and (2) the relative impact of immunosuppressive treatments on relapse rates and on attack-related residual disability. METHODS: Clinical, demographic and treatment data were prospectively collected from 79 consecutive aquaporin 4 antibody positive patients seen in the nationally commissioned Oxford NMO service. The influence of clinical features on annualised relapse rates (using multiple regression) and the effect of immunosuppression on relapse-associated residual disability for transverse myelitis and optic neuritis attacks (using a mixed effect model) were analysed. RESULTS: The mean annualised relapse rate was 0.93. Relapse rates were significantly higher in Afro-Caribbeans, children and in those of shorter disease duration. Relapse rates reduced on treatment (from 0.87 to 0.42). Delay to first treatment did not influence eventual on-treatment relapse rate. Immunosuppressive treatment significantly reduced the residual disability from ON (p<0.01), and TM (p=0.029) attacks. CONCLUSIONS: Relapse rates in NMO are influenced by multiple factors, including age, ethnicity and disease duration. Current immunosuppressive treatments reduce but do not abolish relapses, however, they appear to additionally lessen the chronic disabling effect of a relapse. PMID- 27237753 TI - The effects of fatigue, depression and the level of disability on the health related quality of life of glatiramer acetate-treated relapsing-remitting patients with multiple sclerosis in Hungary. AB - BACKGROUND: The common symptoms of multiple sclerosis are fatigue, depression, cognitive dysfunction, pain and sexual dysfunction, which influence the health related quality of life of the patients. OBJECTIVE: We aimed to determine the correlations between the health-related quality of life, the level of disability, fatigue and depression in glatiramer acetate-treated patients with multiple sclerosis in Hungary. METHODS: The Hungarian versions of the Multiple Sclerosis Quality of Life-54, Fatigue Impact Scale and Beck Depression Inventory questionnaires were completed by 428 relapsing-remitting multiple sclerosis patients treated with glatiramer acetate from 19 Hungarian centers. RESULTS: The prevalence of fatigue was found to be 62.4%. The prevalence of depression was lower (13.4%) than that described in previous studies (36-54%) among patients with multiple sclerosis. Significant differences in the health-related quality of life were found between fatigued and non-fatigued patients. The level of disability, fatigue, depression and the duration of the disease correlated significantly with the quality of life. However, linear regression analysis indicated that the quality of life was predicted by the level of disability, depression, social and cognitive fatigue, but not by physical fatigue. CONCLUSIONS: Decreasing the disease activity in multiple sclerosis with immunomodulatory therapy, together with improvements of the diagnostics and treatment of the accompanying depression and fatigue are of high priority to improve the health-related quality of life of patients with multiple sclerosis. PMID- 27237754 TI - Multiple sclerosis relapses are associated with increased fatigue and reduced health-related quality of life - A post hoc analysis of the TEMSO and TOWER studies. AB - BACKGROUND: Two pivotal phase 3 teriflunomide studies provided data on relapses, fatigue, and health-related quality of life (HRQoL) in patients with relapsing forms of multiple sclerosis (MS). OBJECTIVES: Using pooled data from the TEMSO (NCT00134563) and TOWER (NCT00751881) studies, we investigated the association between relapse severity, and changes from baseline to Week 108 in fatigue and HRQoL outcomes. METHODS: Four definitions of relapse severity were applied in this analysis: sequelae post-relapse; relapse leading to hospitalization; relapse requiring intravenous corticosteroids; and intense relapse. We assessed the association between relapse severity and changes in Fatigue Impact Scale score (n=959), physical and mental health component summary scores from the Short Form (SF)-36 questionnaire (n=904), and SF-6D utility index scores (n=820). RESULTS: Irrespective of the definition of relapse severity applied, in patients experiencing severe relapse(s), fatigue was increased and HRQoL was decreased; these changes were statistically significant (p<0.0001), and were also clinically significant in many cases. The greatest worsening in fatigue and HRQoL was observed in patients with relapses leading to hospitalization. CONCLUSIONS: Given that severe relapses adversely affect patient-reported fatigue and HRQoL, prevention of severe relapses should be an important therapeutic aim in the treatment of patients with MS. PMID- 27237755 TI - The Dress: Transforming a web viral event into a scientific survey. AB - BACKGROUND: The Dress picture recently has become a hot topic on the Internet, prompting a debate whether it was black and blue, or white and gold. OBJECTIVE: To investigate The Dress color perception in both multiple sclerosis (MS) patients, characterized by frequent visual system impairment with ensuing color vision effects, and general population. METHODS: We developed a questionnaire to record demographics, clinical features, and The Dress color perception, posted on general and MS-specific social networks. RESULTS: No statistically significant differences were observed in The Dress color perception between MS patients (n=103) and general population (n=441). Furthermore, white and gold color perception was positively associated with aging in the general population (p=0.04), whereas negatively associated with progressive course (p=0.03) and longer disease duration (p<0.001) in MS patients, independently from patients' age. CONCLUSION: The Dress black and blue or white and gold perception might be due to aging in the general population, whereas black and blue perception, despite of aging, might suggest a specific effect of the MS burden (i.e. disease duration and progression) on the visual structures specifically involved in the white and gold perception. PMID- 27237756 TI - HLA-DRB*1501 associations with magnetic resonance imaging measures of grey matter pathology in multiple sclerosis. AB - BACKGROUND: The HLA-DRB*1501 haplotype influences the risk of developing multiple sclerosis (MS), but it is not known how it affects grey matter pathology. AIM: To assess HLA-DRB(*)1501 effects on magnetic resonance imaging (MRI) cortical grey matter pathology. METHODS: Whole and lesional cortical grey matter volumes, lesional and normal-appearing grey matter magnetization transfer ratio were measured in 85 people with MS and 36 healthy control subjects. HLA-DRB(*)1501 haplotype was determined by genotyping (rs3135388). RESULTS: No significant differences were observed in MRI measures between the HLA-DRB(*)1501 subgroups. CONCLUSIONS: The HLA-DRB(*)1501 haplotype is not strongly associated with MRI visible grey matter pathology. PMID- 27237757 TI - Fingolimod-induced leukoencephalopathy in a patient with neuromyelitis optica spectrum disorder. AB - Fingolimod (FTY720) is used for reducing the annualized relapse rate and slowing progression of neurological disability in relapsing-remitting forms of multiple sclerosis (MS). However, its safety is not confirmed in patients with neuromyelitis optica spectrum disorder (NMOSD), who characteristically have positive aquaporin-4 (AQP-4) antibody. A 54-year-old female with a relapsing remitting course of optic neuritis and myelitis for six years, diagnosed initially as MS, had been treated with interferon beta-1b and oral corticosteroid. Magnetic resonance imaging (MRI) consistently revealed lesions on the optic nerve and spinal cord, but never on the brainstem or cerebral white matter during acute exacerbation. After treatment was switched to fingolimod from interferon beta-1b, multiple new lesions appeared at the brainstem and cerebral white matter. Following discontinuation of fingolimod, these lesions completely cleared, concomitantly with clinical improvement. During fingolimod treatment, she was recognized to be positive for AQP-4 antibody. Fingolimod may be contraindicated in patients with NMOSD. PMID- 27237758 TI - Distribution-based estimates of minimum clinically important difference in cognition, arm function and lower body function after slow release-fampridine treatment of patients with multiple sclerosis. AB - OBJECTIVE: To provide distribution-based estimates of the minimal clinical important difference (MCID) after slow release fampridine treatment on cognition and functional capacity in people with MS (PwMS). METHOD: MCID values were determined after SR-Fampridine treatment in 105 PwMS. Testing included the Timed 25 Foot Walk (T25FW), the Symbol Digit Modalities Test (SDMT), the Six Spot Step Test (SSST), the 9-Hole-Peg-Test (9-HPT), and the 5-Time-Sit-To-Stand test (5 STS). RESULTS: MCID values: T25FW 17.8% (9.1-17.8), SDMT 17.1% (9.2-17.1), SSST 16.7% (8.5-16.7), 9-HPT 15.3% (0-15.3), and 5-STS 34.6% (16.9-34.6). CONCLUSION: This study presents distribution-based estimates of MCID values for the SSST, the 9-HPT, and the 5-STS and confirms MCID estimates for the T25FW and the SDMT. PMID- 27237759 TI - Investigation of cerebral microbleeds in multiple sclerosis as a potential marker of blood-brain barrier dysfunction. AB - OBJECTIVE: In multiple sclerosis (MS) lesions blood-brain-barrier (BBB) breakdown is a common phenomenon delineating the phase of focal inflammation in developing MS lesions. In other pathologies like cerebral amyloid angiopathy or arteriosclerotic cerebral small vessel disease permanent cerebral microbleeds (CMB) have been shown to be sensitive markers indicating BBB dysfunction. We were interested in the potential role of T(2)*-weighted MRI and CMBs as BBB integrity markers in MS. METHODS: A large cohort of 189 MS patients (179 relapsing remitting MS and 10 secondary progressive MS) was investigated on a 3T MRI system with conventional and T(2)*-weighted gradient echo MRI (T(2)*w) sequences. T(2)*w images were analysed for CMBs by experienced raters. RESULTS: None of the MS patients showed a CMB. CONCLUSION: On T(2)*w MRI the prevalence of CMBs is not higher in MS patients than what is to be expected in young healthy people. In contrast to pathologies with structural vascular changes like small vessel disease or cerebral amyloid angiopathy, CMBs are not seen in MS where the immune reaction is causing a functional change in the BBB. PMID- 27237760 TI - An unusual infection in MS patient treated with dimethyl fumarate: A case report of omphalitis. AB - BACKGROUND: Notoriously the treatment of multiple sclerosis (MS) is based on the use of several different drugs, characterized by a diverse mechanism of action, efficacy and safety. Recently, progress has been made towards developing new oral immunotherapies, and dimethyl fumarate is the third oral agent approved for the treatment of relapsing-remitting forms. CASE: A 24-year-old patient, affected by relapsing remitting multiple sclerosis, started treatment in December 2014 with dimethyl fumarate. The common side effects (flushing and gastrointestinal events) of dimethyl fumarate occurred at the beginning of treatment, but resolved after 1 month. Six months later, the patient presented with serious recrudescence of the gastrointestinal event. In addition to this symptom, he had developed acute omphalitis-a very rare infection in adults. CONCLUSION: The pathogenic role of dimethyl fumarate to induce this rare infection was probably related to changes in immunological surveillance as well as to the irritant effect of this agent on the gastrointestinal epithelium. Therefore, post-marketing studies in clinical practice are still needed to provide the necessary long-term safety data. PMID- 27237761 TI - Transient hair loss during treatment with dimethyl-fumarate for multiple sclerosis. AB - INTRODUCTION: Dimethyl-fumarate is a recently approved drug for relapsing remitting Multiple Sclerosis in Italy. CLINICAL CASE: A 55-year-old woman started therapy with dimethyl-fumarate on June 2014; it was well-tolerated aside from moderate flushing. Starting September 2014 she noticed a progressive hair loss, that neither the dermatological examination nor clinical and medical history nor blood investigations could explain. The hair loss slowed down after two months and was followed by a hair growth back. DISCUSSION: Transient hair loss is not a reported side effect of dimethyl-fumarate therapy but by excluding any known cause we attributed it to the beginning of the new therapy. PMID- 27237762 TI - Effects of Pilates exercises on sensory interaction, postural control and fatigue in patients with multiple sclerosis. AB - BACKGROUND: Decreased postural control, sensory integration deficits and fatigue are important problems that cause functional impairments in patients with multiple sclerosis (pwMS). PURPOSE: To examine the effect of modified clinical Pilates exercises on sensory interaction and balance, postural control and fatigue in pwMS. METHODS: Eleven patients with multiple sclerosis and 12 healthy matched controls were recruited in this study. Limits of stability and postural stability tests were used to evaluate postural control by Biodex Balance System and sensory interaction assessed. Fatigue was assessed by Modified Fatigue Impact Scale. Pilates exercises were applied two times a week for 10 weeks and measurements were repeated to pwMS after exercise training. RESULTS: Postural control and fatigue (except psychosocial parameter) of pwMS were significantly worser than healthy controls (p<0.05). Significant improvements occurred in sensory interaction (eyes open, foam surface) and total, physical and cognitive scores of fatigue after 10-week modified clinical Pilates training (p<0.05). No significant changes were detected in postural control after the pilates exercises (p>0.05). CONCLUSIONS: Ten-week Pilates training is effective to improve sensory interaction and to decrease fatigue. Pilates exercises can be applied safely in ambulatory pwMS for enhance sensory interaction and balance and combat fatigue. More investigations are needed. PMID- 27237763 TI - NMOSD with an unusual cerebral radiologic manifestation. PMID- 27237765 TI - Pancolitis a novel early complication of Alemtuzumab for MS treatment. AB - The growing range of effective therapies for relapsing remitting multiple sclerosis (RRMS) brings with it a wider range of possible complications requiring broader considerations and greater vigilance. Alemtuzumab is a humanized monoclonal antibody against CD52 that is highly effective in the treatment of RRMS and approved in many countries around the world. We describe a case presenting with a complication not previously seen. PMID- 27237766 TI - Effects of motor-motor and motor-cognitive tasks on balance in patients with multiple sclerosis. AB - BACKGROUND: Dual tasking is frequently impaired in Multiple Sclerosis (MS), substantially impairing quality of life (QoL). We aimed to examine the effects of motor-motor and motor-cognitive tasks on balance in highly mobile patients with relapsing-remitting MS (RRMS), with mild disability. METHODS: Thirty-eight patients and 34 controls were included. Steady Stance Test (SST), Berg Balance Scale (BBS) and Activities-specific Balance Confidence Scale (ABC) were used to evaluate the balance. Expanded Disability Status Scale (EDSS), Mini-mental State Examination (MMSE), Beck Depression Inventory (BDI) and Fatigue Impact Scale (FIS) were used to evaluate disability, cognitive impairment, depression and fatigue, respectively. RESULTS: BBS and ABC scores were significantly different between the groups. Also, balance was significantly impaired in patients. Eyes open left single stance test was the most efficient test to reveal the balance impairment in RRMS patients independent of dual-task. Physical component of FIS affected this test independent of age and BMI. Visual input significantly increased the stance durations in majority of SST, especially in tough stance positions with reduced balance area. However, visual input during dual-tasking impaired the balance. In addition, eyes-closed left tandem stance test with MM dual task significantly improved the balance in patients. BBS was significantly correlated with EDSS(r: -0.336), ABC(r: 0.688), FIS physical subgroup(r: -0.614) and FIS social subgroup(r: -0.475). CONCLUSION: Dual-tasking improves balance and increases QoL in patients with RRMS. Eyes closed balance treatment with motor dual task could be beneficial. PMID- 27237764 TI - A pilot study of changes in functional brain activity during a working memory task after mSMT treatment: The MEMREHAB trial. AB - BACKGROUND: Working memory deficits are common in multiple sclerosis (MS). The modified Story Memory Technique (mSMT) has been shown to improve new learning and memory in MS, but its effects on working memory (WM) are currently unknown. OBJECTIVE: The present study presents a secondary analysis of data from a larger double-blind, placebo-controlled, randomized clinical trial and examines changes in cerebral activation on a WM task following mSMT treatment. METHODS: Sixteen participants with clinically definite MS were randomly assigned to treatment (n=7) or placebo-control groups (n=9) matched for gender, age and education. Baseline and immediate follow-up functional Magnetic Resonance Imaging (fMRI) was obtained for all subjects. During fMRI participants completed an N-back task, consisting of 0-, 1-and 2-back conditions. RESULTS: Significant increases in cerebral activation were noted in the dorsolateral prefrontal cortex, supplementary motor area and inferior parietal lobule at follow-up in the treatment group. No significant changes were noted in the placebo control group. CONCLUSION: Due to the small sample size, results of the current study should be interpreted as preliminary. However, the observed pattern of activation of the frontoparietal network involved in WM found in the treatment group, suggests that mSMT training increases recruitment of attention- and WM-related neural networks. We conclude that mSMT treatment leads to changes in WM-related cerebral activation. PMID- 27237767 TI - Association between Helicobacter pylori infection and multiple sclerosis: A systematic review and meta-analysis. AB - AIM: To investigate the association between Helicobacter pylori infection and multiple sclerosis. METHODS: A comprehensive search of the databases including PubMed/MEDLINE and EMBASE was performed from their dates of inception to January 2016. Inclusion criteria were the observational studies in adult assessing the association between Helicobacter pylori infection and multiple sclerosis. The main outcome was the prevalence of Helicobacter pylori infection comparing between participants with multiple sclerosis and controls. The between-study heterogeneity of effect-size was quantified using the Q statistic and I(2). RESULTS: The initial search yielded 103 articles. Seventeen articles underwent full-length review and data was extracted from six observational studies involving 1902 participants. There was a statistically significant lower odds Helicobacter pylori infection in multiple sclerosis with pooled odds ratio of 0.59 (95% CI: 0.37-0.94, P=0.03, I(2)=71%). We conducted a univariate meta regression analysis to assess potential source of heterogeneity. Age of patient and age of onset of multiple sclerosis were significant predictors of association between Helicobacter pylori infection and multiple sclerosis (beta-coefficient = 0.23, SE=0.10, p=0.02 and beta-coefficient =-0.34, SE=0.17, p=0.04, respectively). CONCLUSIONS: We demonstrate a significant lower prevalence of Helicobacter pylori infection in patients with multiple sclerosis. This pathogen might be a protective factor for developing multiple sclerosis. PMID- 27237768 TI - Effect of fingolimod on diffuse brain tissue damage in relapsing-remitting multiple sclerosis patients. AB - BACKGROUND: Multiple sclerosis (MS) affects all areas of the brain resulting in both focal and diffuse damage. In Phase 3 clinical trials, fingolimod showed significant reductions in both focal lesions and rate of brain volume loss (BVL) in patients with relapsing-remitting MS. OBJECTIVE: To investigate if the effects of fingolimod 0.5mg on BVL are mediated exclusively through its effects on focal damage or if fingolimod also acts independently in reducing diffuse damage. METHODS: This was a pooled post-hoc analysis of patients from two Phase 3 studies (FREEDOMS [N=1272] and FREEDOMS II [N=1083]), with no evidence of focal disease activity as defined by absence of gadolinium-enhancing lesions at baseline and new active lesions and clinical relapses at follow-up. The percent brain volume change (PBVC), as a measure of diffuse tissue damage, was assessed at Month (M) 12 and M24 by using the Structural Image Evaluation using Normalization of Atrophy (SIENA) method. A regression analysis was performed in the pooled intent to-treat (ITT) population to quantify the treatment effect of fingolimod on BVL vs. placebo (PBO) in the overall population (unadjusted model), and whether this effect is sustained after adjusting for new active lesions and on-study relapses (adjusted model). RESULTS: Of 1088 patients, 638 (PBO, n=127; fingolimod, n=511) at M12 and 450 patients (PBO, n=68; fingolimod, n=382) at M24 showed no focal activity. Fingolimod significantly reduced PBVC by 65.5% over 12M (fingolimod vs. PBO: -0.16 vs. -0.45; p=0.001) and by 48.2% over 24M (-0.42 vs. -0.81; p=0.004). An absolute difference in PBVC of -0.27% (p<0.001) in favor of fingolimod vs. PBO over 24M was still evident in the pooled ITT population, after adjusting for active lesions and on-study relapses. The regression model suggests that 54% ( 0.27%/-0.51%) of effects of fingolimod on PBVC are independent of its effects on visible focal damage. CONCLUSIONS: The effect of fingolimod on diffuse damage is partly independent of its treatment effect on focal damage, suggesting that both inflammatory and neurodegenerative components of MS are affected. PMID- 27237769 TI - Long-term efficacy and safety of intramuscular interferon beta-1a: Randomized postmarketing trial of two dosing regimens in Japanese patients with relapsing remitting multiple sclerosis. AB - OBJECTIVES: To evaluate the efficacy and safety of 2 years of treatment with intramuscular interferon beta-1a (IM IFN beta-1a) in Japanese patients with relapsing-remitting multiple sclerosis, with an exploratory analysis of the impact of initial dose titration on tolerability. METHODS: Japanese patients with relapsing-remitting multiple sclerosis were randomized to receive IM IFN beta-1a at dosages of either 30mcg once weekly (full-dose group, n=50) or 15mcg once weekly for 2 weeks then 30mcg once weekly thereafter (titration group, n=50). Key outcomes included annualized relapse rate (ARR) at 2 years (primary endpoint), change in disability measured using the Expanded Disability Status Scale (EDSS), safety, and tolerability. RESULTS: The ARR (95% CI) decreased from 1.540 (1.381 1.718) at baseline to 0.371 (0.240-0.571) at Year 1 and 0.351 (0.244-0.503) at Year 2. EDSS improvements were apparent from Week 24; the mean change from baseline EDSS score (2.1) at Year 2 was -0.34 (P=0.004). The most frequently reported adverse events were influenza-like illness (92%), nasopharyngitis (57%), relapse of multiple sclerosis (51%), and injection-site reaction (30%). The overall incidence and severity of influenza-like symptoms were similar in the full-dose group and titration group; only 1 participant, in the full-dose group (2%), experienced severe influenza-like symptoms. However, the incidence of influenza-like symptoms was slightly reduced at earlier timepoints in the titration group. CONCLUSIONS: The results of this 2-year study demonstrate that IM IFN beta-1a can be used effectively and safely in Japanese patients with relapsing-remitting multiple sclerosis for an extended period of time. PMID- 27237770 TI - A review of the ethics of the use of placebo in clinical trials for relapsing remitting multiple sclerosis therapeutics. AB - Randomized placebo-controlled clinical trials have been considered the most rigorous method of evaluating the efficacy of novel treatment interventions. The first effective disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) were approved in the 1990s after a number of pivotal placebo-controlled trials. Since then, the ethics of the continued use of placebo in clinical trials of new DMTs for RRMS has been the subject of repeated policy statements and recommendations by international committees. As further data have accumulated demonstrating a reduction in long-term morbidity and mortality with early initiation of DMT, a growing consensus has emerged that further inclusion of placebo arms in clinical trials of novel RRMS therapies is no longer ethical. PMID- 27237771 TI - Editors' Welcome. PMID- 27237772 TI - Treadmill training with an incline reduces ankle joint stiffness and improves active range of movement during gait in adults with cerebral palsy. AB - PURPOSE: We investigated if 30 min of daily treadmill training with an incline for 6 weeks would reduce ankle joint stiffness and improve active range of movement in adults with cerebral palsy (CP). METHODS: The study was designed as a randomized controlled clinical trial including 32 adults with CP (GMFCS 1-3) aged 38.1 SD 12 years. The training group (n = 16) performed uphill treadmill training at home daily for 30 min for 6 weeks in addition to their usual activities. Passive and reflex mediated stiffness and range of motion (ROM) of the ankle joint, kinematic and functional measures of gait were obtained before and after the intervention/control period. Intervention subjects trained 31.4 SD 10.1 days for 29.0 SD 2.3 min (total) 15.2 h. RESULTS: Passive ankle joint stiffness was reduced (F = 5.1; p = 0.031), maximal gait speed increased (F = 42.8, p < 0.001), amplitude of toe lift prior to heel strike increased (F = 5.3, p < 0.03) and ankle angle at heel strike was decreased (F = 12.5; p < 0.001) significant in the training group as compared to controls. CONCLUSION: Daily treadmill training with an incline for 6 weeks reduces ankle joint stiffness and increases active ROM during gait in adults with CP. Intensive gait training may thus be beneficial in preventing and reducing contractures and help to maintain functional gait ability in adults with CP. Implications for rehabilitation Uphill gait training is an effective way to reduce ankle joint stiffness in adult with contractures. 6 weeks of daily uphill gait training improves functional gait parameters such as gait speed and dorsal flexion during gait in adults with cerebral palsy. PMID- 27237773 TI - Hybrid Quadrupole-Orbitrap mass spectrometry for quantitative measurement of quorum sensing inhibition. AB - Drug resistant bacterial infections cause significant morbidity and mortality worldwide, and new strategies are needed for the treatment of these infections. The anti-virulence approach, which targets non-essential virulence factors in bacteria, has been proposed as one way to combat the problem of antibiotic resistance. Virulence in methicillin-resistant Staphylococcus aureus (MRSA) and many other Gram-positive bacterial pathogens is controlled by the quorum sensing system. Thus, there is excellent therapeutic potential for compounds that target this system. With this project, we have developed and validated a novel approach for measuring quorum sensing inhibition in vitro. Ultraperformance liquid chromatography coupled to mass spectrometry (UPLC-MS) was employed to directly measure one of the important outputs of the quorum sensing system in MRSA, auto inducing peptide I (AIP I) in bacterial cultures. The method for AIP detection was validated and demonstrated limits of detection and quantification of range of 0.0035MUM and 0.10MUM, respectively. It was shown that the known quorum sensing inhibitor ambuic acid inhibited AIP I production by a clinically relevant strain of MRSA, with an IC50 value of 2.6+/-0.2MUM. The new method performed similarly to previously published methods using GFP reporter assays, but has the advantage of being applicable without the need for engineering of a reporter strain. Additionally, the mass spectrometry-based method could be applicable in situations where interference by the inhibitor prevents the application of fluorescence-based methods. PMID- 27237774 TI - Quantitative real-time PCR normalization for gene expression studies in the plant pathogenic fungi Lasiodiplodia theobromae. AB - Lasiodiplodia theobromae is a highly virulent plant pathogen. It has been suggested that heat stress increases its virulence. The aim of this work was to evaluate, compare, and recommend normalization strategies for gene expression analysis of the fungus growing with grapevine wood under heat stress. Using RT qPCR-derived data, reference gene stability was evaluated through geNorm, NormFinder and Bestkeeper applications. Based on the geometric mean using the ranking position obtained for each independent analysis, genes were ranked from least to most stable as follows: glyceraldehyde-3-phosphate dehydrogenase (GAPDH), actin (ACT), beta-tubulin (TUB) and elongation factor-1alpha (EF1alpha). Using RNAseq-derived data based on the calculated tagwise dispersion these genes were ordered by increasing stability as follows: GAPDH, ACT, TUB, and EF1alpha. The correlation between RNAseq and RTqPCR results was used as criteria to identify the best RT-qPCR normalization approach. The gene TUB is recommended as the best option for normalization among the commonly used reference genes, but alternative fungal reference genes are also suggested. PMID- 27237776 TI - Effect of roll-compaction and milling conditions on granules and tablet properties. AB - Dry granulation is an agglomeration process used to produce size-enlarged particles (granules), improving the handling properties of powders such as flowability. In this process, powders are compacted using a roll press to produce ribbons, which are milled in granules used further in the tableting process. The granule and tablet properties are influenced by the existence of different designs of the roll compactors, milling systems and the interaction between process parameters and raw material properties. The main objective of this work was to investigate how different roll-compaction conditions and milling process parameters impact on ribbons, granules and tablet properties, highlighting the role of the sealing system (cheek plates and rimmed roll). In this context, two common excipients differing in their mechanical behaviour (MCC and mannitol) are used. The study is based on the analysis of granule size distribution together with the characterization of loss of compactability during die compaction. Results show that the tensile strength of tablets is lower when using granules than when the raw materials are compressed. Moreover, the plastic material (MCC) is more sensitive than the brittle one (mannitol). Regarding the roll-force, it is observed that the higher the roll force, the lower the tensile strength of tablets from granulated material is. These findings are in agreement with the literature. The comparison of sealing systems shows that the rimmed-roll system leads to slightly stronger tablets than the use of cheek plates. In addition, the use of the rimmed-roll system reduces the amount of fines, in particular when high roll force is applied. Overall, it can be concluded that roll-compaction effect is predominant over the milling effect on the production of fines but less significant on the tablet properties. This study points out that the balance between a good flowability by reducing the amount of fines and appropriate tablet strength is achieved with rimmed-roll and the highest roll-force used. PMID- 27237775 TI - Comparison of microbial DNA enrichment tools for metagenomic whole genome sequencing. AB - Metagenomic whole genome sequencing for detection of pathogens in clinical samples is an exciting new area for discovery and clinical testing. A major barrier to this approach is the overwhelming ratio of human to pathogen DNA in samples with low pathogen abundance, which is typical of most clinical specimens. Microbial DNA enrichment methods offer the potential to relieve this limitation by improving this ratio. Two commercially available enrichment kits, the NEBNext Microbiome DNA Enrichment Kit and the Molzym MolYsis Basic kit, were tested for their ability to enrich for microbial DNA from resected arthroplasty component sonicate fluids from prosthetic joint infections or uninfected sonicate fluids spiked with Staphylococcus aureus. Using spiked uninfected sonicate fluid there was a 6-fold enrichment of bacterial DNA with the NEBNext kit and 76-fold enrichment with the MolYsis kit. Metagenomic whole genome sequencing of sonicate fluid revealed 13- to 85-fold enrichment of bacterial DNA using the NEBNext enrichment kit. The MolYsis approach achieved 481- to 9580-fold enrichment, resulting in 7 to 59% of sequencing reads being from the pathogens known to be present in the samples. These results demonstrate the usefulness of these tools when testing clinical samples with low microbial burden using next generation sequencing. PMID- 27237777 TI - Assessment of the anti-metastatic properties of sanguiin H-6 in HUVECs and MDA-MB 231 human breast cancer cells. AB - The anti-metastatic properties of sanguiin H-6 were examined in human umbilical vein vascular endothelial cells (HUVECs) and MDA-MB-231 human breast cancer cells. In HUVECs, sanguiin H-6 inhibited the density of migrated cells compared to that observed after treatment with the vehicle. In addition, sanguiin H-6 at a concentration of 6.25MUM significantly blocked tube formation. Treatment with up to 25MUM sanguiin H-6 had no effect on MDA-MB-231 cells, whereas treatment with 200MUM sanguiin H-6 decreased cell viability. Sanguiin H-6 significantly decreased the expression levels of vascular endothelial growth factor (VEGF), phosphorylated Akt, and extracellular signal-regulated kinase 1/2 (ERK1/2) in MDA MB-231 cells. These findings suggest that sanguiin H-6 is potentially useful as an anti-metastatic agent. PMID- 27237778 TI - Reply to Letter to Editor Re: Endoscopic Management of Urolithiasis in the Horseshoe Kidney. PMID- 27237779 TI - Ectopic Prostatic Tissue May Cause Hydroureteronephrosis. AB - A 60-year-old man with left flank pain, fever, and nausea underwent an abdominal ultrasound and showed left hydroureteronephrosis without urinary calculi. Computed tomography urography showed moderate left hydroureteronephrosis and a hypodense paravesical mass of 1.7 cm with mild contrast enhancement just below the ipsilateral ureterovesical junction. Contrast-enhanced magnetic resonance imaging showed a 48 cc prostate and confirmed a roundish mass, protruding into the bladder, hyperintense on T2-weighted images, hypointense on T1-weighted images, and with mild inhomogeneous contrast enhancement. Cystoscopy with cold cup biopsy was carried out. Histologic analysis revealed the presence of ectopic prostatic tissue with no evidence of malignancy. PMID- 27237780 TI - Metastatic Paraganglioma Presenting as Incontinence in a 15-Year-Old Girl. AB - Chromaffin cell tumors are derived from neural crest cells and can produce and secrete catecholamines. Classic symptoms include headache, palpitations, diaphoresis, and hypertension. Diagnosis is typically in adulthood, and metastatic disease is rarely found. Genetic testing is suggested with young age, extra-adrenal tumors, malignant disease, or family history of associated tumors. Our young patient's presentation of incontinence is unique, but several other atypical findings can be accounted for relative to her germline mutation. Because of the rarity of our patient's case, follow-up procedure is undefined. Documenting atypical cases such as this is central to clinician awareness and development of follow-up protocol. PMID- 27237782 TI - An assessment of racial differences in the upper limits of normal ALT levels in children and the effect of obesity on elevated values. AB - OBJECTIVES: Childhood obesity is a risk factor for non-alcoholic fatty liver disease and poses important public health issues for children. Racial differences in alanine aminotransferase (ALT) levels among children have not been described. This study aimed to identify racial differences in upper limit normal (ULN) ALT levels and evaluate the effect of obesity on elevated levels in children without other metabolic risk factors. METHODS: National Health and Nutrition Examination Surveys and clinical data from the Loyola University Health System were used to determine ULN ALT by race and gender. Quantile regression was used to evaluate the impact of obesity on elevated ALT and to identify potential risk factors for ALT above the ULN. RESULTS: Upper limit normal (ULN) ALT was approximately 28.0 and 21.0-24.0 U/L for boys and girls, respectively. No significant difference in ULN ALT across race was observed. Obesity was significantly associated with elevated ALT; obese children with elevated ALT had values 10 U/L higher than normal-weight children. CONCLUSIONS: Racial differences in ALT levels among adults are not evident in children. Obesity, in the absence of metabolic risk factors and other causes of liver disease, is associated with elevated ALT, providing evidence against the concept of healthy obesity in children. PMID- 27237781 TI - Impact of Ureteroscopy Before Nephroureterectomy for Upper Tract Urothelial Carcinoma on Oncologic Outcomes. AB - OBJECTIVE: To compare the oncologic outcomes of patients with upper tract urothelial carcinoma undergoing nephroureterectomy (NU) with and without prior ureteroscopy (URS). METHODS: We reviewed records of all patients with no prior history of bladder cancer who underwent NU at our institution (n = 201). We compared patients who underwent URS before NU with patients who proceeded directly to NU based on imaging alone. After excluding patients undergoing URS with therapeutic intent, we used multivariable Cox proportional hazards models, adjusting for tumor characteristics with cancer-specific survival (CSS), intravesical recurrence-free survival, metastasis-free survival (MFS), and overall survival (OS) as end points. This study received institutional review board approval. RESULTS: A total of 144 (72%) patients underwent URS before NU, and 57 (28%) patients proceeded directly to NU. The median follow-up time for survivors was 5.4 years from diagnosis. The performance of diagnostic URS before NU was significantly associated with IR (hazard ratio 2.58; 95% CI 1.47, 4.54; P = .001), although it was not associated with CSS, MFS, or OS. The adjusted intravesical recurrence-free survival probability 3 years after diagnosis is 71% and 42% for patients who did not and did receive URS before NU, respectively (adjusted risk difference 30%; 95% CI 13%, 47%). CONCLUSION: We did not find evidence that URS adversely impacts disease progression and survival in patients with upper tract urothelial carcinoma. Although patients are at higher risk for IR after NU when they have undergone prior diagnostic URS, their CSS, MFS, and OS are not significantly affected. PMID- 27237783 TI - Mainstream smoke and sidestream smoke affect the cardiac differentiation of mouse embryonic stem cells discriminately. AB - Epidemiology studies suggest that maternal smoking and passive smoking have strongly resulted in the occurrence of congenital heart defects (CHD) in offspring. Cigarette smoke (CS) can be divided into mainstream smoke (MS) and sidestream smoke (SS); CS chemistry study indicates that significant differences exist in the composition of MS and SS. Therefore, MS and SS were suspected to process toxicity dissimilarly. However, much less was known about the difference in the developmental effects induced by MS and SS. In the current study, heart development was mimicked by mouse embryonic stem cells (ESCs) differentiation. After MS and SS exposure, by tracing the bone morphogenetic protein (BMP)-Smad4 signalling pathway, interruption of downstream gene expression was observed, including Gata4, Mef2c and Nkx2.5, as well as myosin heavy chain and myosin light chain. Specifically, SS caused inhibition of Gata4 expression, even at non cytotoxic concentration. Further, SS-induced hypoacetylation in promoter regions of Gata4 reflected the orchestration of CS-gene modulation-epigenetic regulation. Even though SS induced apoptosis in ESC-derived cardiomyocytes, the partial clearance in cells with down-regulated Gata4 caused these cells to survive and undergo further differentiation, which laid potential risk for abnormal heart development. These data uncovered the difference between MS and SS on heart development preliminarily. PMID- 27237784 TI - Warfarin-associated Intraspinal Hematoma. AB - Intracerebral hemorrhage is a well-known complication resulting from warfarin use; however, warfarin-associated intraspinal hematoma is very rare. Warfarin associated intraspinal hematoma may exhibit delayed progression, and patients may present with atypical symptoms, occasionally resulting in delayed diagnosis. We report the case of a 65-year-old man who visited our emergency department (ED) with acute urinary retention. He had been previously diagnosed with non-valvular atrial fibrillation, arterial hypertension, and benign prostatic hyperplasia, and he used warfarin for the prevention of systemic embolism. The patient was initially diagnosed with worsening of the prostatic hyperplasia. After 2 days, he revisited the ED with painless paraparesis. Magnetic resonance imaging of the thoracic spine revealed an intraspinal hematoma at Th7-8, and blood coagulation tests indicated a prothrombin time-international normalized ratio of 3.33. Despite attempts to reverse the effects of warfarin with vitamin K administration, the paraparesis progressed to paraplegia, necessitating urgent surgical removal of the hematoma. Partial recovery of motor function was evident after surgery. From the present case, we learned that intraspinal hematoma should be included in the differential diagnosis of patients using warfarin who present with acute urinary retention. Although there are no evidence-based treatment guidelines for warfarin-associated intraspinal hematoma, surgical treatment may be warranted for those who exhibit neurological deterioration. PMID- 27237785 TI - Clinical evaluation of unselected cardiac arrest survivors in a tertiary center over a 1-year period (the LAZARUZ study). AB - OBJECTIVES: When the cause of an aborted cardiac arrest is unclear the initiation of therapy, counseling and family screening is challenging. METHODS: We included 43 unselected, prospectively identified cardiac arrest survivors with or without a diagnosis. Family history for cardiac disease and supplemental electrocardiograms were evaluated for additional diagnostic information. RESULTS: 43 cardiac arrest survivors were included, 34 (79%) were male and the average age was 48years (range 23-64, SD 13.0). The most common etiologies identified in cardiac arrest survivors were ischemic heart disease (33%), cardiomyopathies (14%), miscellaneous (e.g. drug induced arrhythmias, coronary spasms) (12%) and channelopathies (5%). Family history of cardiac disease - even inheritable conditions - was not indicative of etiology in cardiac arrest survivors. Supplemental ECGs were abnormal in 10 of 43 patients; in the majority of these patients (7) no conclusive diagnosis was reached. CONCLUSIONS: In this study 16/43 (37%) of unselected, prospectively included cardiac arrest survivors remained without a diagnosis despite exhaustive investigations. We may extract additional diagnostic information from simple maneuvers during the recording of the electrocardiogram. We suggest that these ECG derived clues be investigated in future studies including genetic test results and data from relatives. PMID- 27237786 TI - EUS-guided biliary drainage after failed ERCP: a novel algorithm individualized based on patient anatomy. AB - BACKGROUND AND AIMS: EUS-guided biliary drainage (EUS-BD) has been offered for more than a decade as an alternative to percutaneous biliary drainage. Multiple approaches have been described. We propose an algorithm for biliary drainage based on patient anatomy. We aim to assess its validity and safety to guide EUS BD drainage. METHODS: All patients with biliary obstruction who underwent EUS-BD after failed ERCP from July 2011 through November 2015 underwent the drainage procedure according to the novel algorithm and were enrolled in a dedicated prospective registry. Patients with a dilated intrahepatic biliary tree (IHBT) on cross-sectional imaging received an intrahepatic (IH) approach with anterograde biliary stent placement or hepaticogastrostomy stent placement if anterograde placement was not feasible. Patients with a nondilated IHBT on cross-sectional imaging underwent an extrahepatic (EH) approach with a rendezvous (RDV) technique or a transenteric stent placement if the RDV technique was not feasible. If IH drainage was attempted but unsuccessful, conversion to an EH approach was performed. RESULTS: Fifty-two patients (mean age, 68 +/- 12 years; 52% men) were included in the registry. Technical success was achieved in 50 patients (96%). Twenty-seven of 52 patients (52%) underwent IH anterograde stent placement, 8 of 52 (15%) underwent hepaticogastrostomy, 11 of 52 (21%) underwent EH drainage with the RDV technique, and 6 of 52 (12%) underwent EH drainage with transenteric stent placement. Adverse events were observed in 5 patients (10%) and included a liver abscess requiring percutaneous drainage (n = 1) and bleeding (n = 4) with 1 postprocedural death secondary to bleeding. CONCLUSIONS: EUS-BD obstruction after failed conventional ERCP is successful and safe when this novel algorithm is used. (Clinical trial registration number: NCT01438385.). PMID- 27237788 TI - Detection of Nicotiana tabacum Leaf Contamination in Pharmaceutical Products. AB - Nicotiana tabacum (Solanaceae) is the only species whose leaves can be legally marketed as tobacco according to the Japanese Tobacco Business Act. Nicotine, a major alkaloid produced by N. tabacum leaves, is regulated in pharmaceuticals by the Japanese Pharmaceutical Affairs Law. However, the use of N. tabacum stems as an excipient in pharmaceuticals is permitted, because these contained only a small amount of nicotine. Recently, several reports showed that a substantial amount of nicotine was detected in an OTC pharmaceutical product, in which N. tabacum stems were used as an excipient. Therefore, products containing N. tabacum stems could be contaminated with the leaf material. In the present study, we established a method to detect contamination of N. tabacum stem materials with its leaves, using microscopy to obtain standard reference microphotographs for identification. Cultivated N. tabacum stems and leaves, commercial cigarette leaves, and N. tabacum tissue imported as excipient material were used for preparing the microphotographs. The characteristic N. tabacum leaf structures found in the powdered fragments included: epidermal cells with sinuous anticlinal cell walls, hairs, mesophyll parenchyma with crystalized calcium oxalate (calciphytoliths), and branching vascular bundles derived from reticulate net veins. A comparison of the microscopic characteristics of an OTC powder with those from the standard reference microphotographs was an effective method for N. tabacum stem and leaf identification. Thus, we evaluated the powdered pharmaceutical product containing N. tabacum stem tissue and Hydrangea serrata (Hydrangeaceae) leaf tissue as excipients, and confirmed the presence of N. tabacum leaf material. PMID- 27237787 TI - Angiogenic peptide (AG)-30/5C activates human keratinocytes to produce cytokines/chemokines and to migrate and proliferate via MrgX receptors. AB - BACKGROUND: In addition to their antimicrobial activities, antimicrobial peptides, also known as host defense peptides (HDPs) activate keratinocytes; promote wound healing; and improve the skin barrier. AG-30/5C is a novel angiogenic HDP that activates various functions of fibroblasts and endothelial cells, including cytokine/chemokine production and wound healing. OBJECTIVES: To investigate whether AG-30/5C activates human keratinocytes and to examine the underlying mechanisms. METHODS: Production of cytokines/chemokines was assessed by ELISA. Expression of Mas-related G-protein coupled receptors X (MrgXs) in keratinocytes was determined by real-time PCR and Western blot. MAPK and NF kappaB activation was analysed by Western blot. Cell migration was assessed by chemotaxis microchamber and in vitro wound closure assay, whereas cell proliferation was analysed using an XTT assay. RESULTS: We found that AG-30/5C was more efficient than its parent peptide AG-30 in increasing the production of various cytokines/chemokines and promoting keratinocyte migration and proliferation. Furthermore, MrgX3 and MrgX4 receptors were constitutively expressed in keratinocytes at higher levels than MrgX1 and MrgX2, and were up regulated upon stimulation with TLR ligands. Because MrgX3 and MrgX4 siRNAs suppressed AG-30/5C-mediated cytokine/chemokine production, keratinocyte migration and proliferation, we propose that AG-30/5C utilizes these MrgXs to stimulate keratinocytes. In addition, AG-30/5C-induced activation of keratinocytes was controlled by MAPK and NF-kappaB pathways, as evidenced by the inhibitory effects of ERK-, JNK-, p38- and NF-kappaB-specific inhibitors. Indeed, we confirmed that AG-30/5C enhanced phosphorylation of MAPKs and IkappaB. CONCLUSIONS: Our findings provide novel evidence that AG-30/5C may be a useful therapeutic agent for wound healing by activating human keratinocytes. PMID- 27237789 TI - Theaflavin Synthesized in a Selective, Domino-Type, One-Pot Enzymatic Biotransformation Method with Camellia sinensis Cell Culture Inhibits Weight Gain and Fat Accumulation to High-Fat Diet-Induced Obese Mice. AB - The polyphenolic compound theaflavin, which is the main red pigment present in black tea, is reported to elicit various physiological effects. Because of the extremely low concentration of theaflavin present in black tea, its extraction from black tea leaves in quantities sufficient for use in medical studies has been difficult. We have developed a simple, inexpensive, selective, domino-type, one-pot enzymatic biotransformation method for the synthesis of theaflavin that is suitable for use in medical studies. Subsequent administration of this synthetic theaflavin to high-fat diet-induced obese mice inhibited both body weight gain and visceral fat accumulation, with no significant difference in the amount of faeces between the experimental and control mice. PMID- 27237790 TI - SnoN Antagonizes the Hippo Kinase Complex to Promote TAZ Signaling during Breast Carcinogenesis. AB - SnoN regulates multiple signaling pathways, including TGF-beta/Smad and p53, and displays both pro-oncogenic and anti-oncogenic activities in human cancer. We have observed previously that both its intracellular localization and expression levels are sensitive to cell density, suggesting that it may crosstalk with Hippo signaling. Here we report that, indeed, SnoN interacts with multiple components of the Hippo pathway to inhibit the binding of Lats2 to TAZ and the subsequent phosphorylation of TAZ, leading to TAZ stabilization. Consistently, SnoN enhances the transcriptional and oncogenic activities of TAZ, and reducing SnoN decreases TAZ expression as well as malignant progression of breast cancer cells. Interestingly, SnoN itself is downregulated by Lats2 that is activated by the Scribble basolateral polarity protein. Thus, SnoN is a critical component of the Hippo regulatory network that receives signals from the tissue architecture and polarity to coordinate the activity of intracellular signaling pathways. PMID- 27237792 TI - A Galpha-Stimulated RapGEF Is a Receptor-Proximal Regulator of Dictyostelium Chemotaxis. AB - Chemotaxis, or directional movement toward extracellular chemical gradients, is an important property of cells that is mediated through G-protein-coupled receptors (GPCRs). Although many chemotaxis pathways downstream of Gbetagamma have been identified, few Galpha effectors are known. Galpha effectors are of particular importance because they allow the cell to distinguish signals downstream of distinct chemoattractant GPCRs. Here we identify GflB, a Galpha2 binding partner that directly couples the Dictyostelium cyclic AMP GPCR to Rap1. GflB localizes to the leading edge and functions as a Galpha-stimulated, Rap1 specific guanine nucleotide exchange factor required to balance Ras and Rap signaling. The kinetics of GflB translocation are fine-tuned by GSK-3 phosphorylation. Cells lacking GflB display impaired Rap1/Ras signaling and actin and myosin dynamics, resulting in defective chemotaxis. Our observations demonstrate that GflB is an essential upstream regulator of chemoattractant mediated cell polarity and cytoskeletal reorganization functioning to directly link Galpha activation to monomeric G-protein signaling. PMID- 27237791 TI - Transient Fcho1/2?Eps15/R?AP-2 Nanoclusters Prime the AP-2 Clathrin Adaptor for Cargo Binding. AB - Clathrin-coated vesicles form by rapid assembly of discrete coat constituents into a cargo-sorting lattice. How the sequential phases of coat construction are choreographed is unclear, but transient protein-protein interactions mediated by short interaction motifs are pivotal. We show that arrayed Asp-Pro-Phe (DPF) motifs within the early-arriving endocytic pioneers Eps15/R are differentially decoded by other endocytic pioneers Fcho1/2 and AP-2. The structure of an Eps15/R?Fcho1 MU-homology domain complex reveals a spacing-dependent DPF triad, bound in a mechanistically distinct way from the mode of single DPF binding to AP 2. Using cells lacking FCHO1/2 and with Eps15 sequestered from the plasma membrane, we establish that without these two endocytic pioneers, AP-2 assemblies are fleeting and endocytosis stalls. Thus, distinct DPF-based codes within the unstructured Eps15/R C terminus direct the assembly of temporary Fcho1/2?Eps15/R?AP-2 ternary complexes to facilitate conformational activation of AP-2 by the Fcho1/2 interdomain linker to promote AP-2 cargo engagement. PMID- 27237793 TI - Caring for the Acutely, Severely Ill Child-A Multifaceted Situation with Paradoxical Elements: Swedish Healthcare Professionals' Experiences. AB - The aim of this study was to describe healthcare professionals' experience of caring for acutely, severely ill children in hospital in Sweden. DESIGN AND METHODS: Five focus group interviews were conducted with nurses, nurse assistants and physicians comprising a total of 20 participants. Data were analyzed using qualitative content analysis. RESULTS: An overall theme emerged that describes healthcare professionals' experiences as: "being in a multifaceted area of tension with paradoxical elements". The theme is based on three categories: proficiency of the individuals and the team is the fundamental base; interactions are crucial in an area of tension; and wellbeing of the individual is a balance of contradictory emotions. With maintained focus on the ill child, proficiency is the fundamental base, interactions are crucial, and moreover contradictory emotions are described. CONCLUSIONS: The interplay based on proficiency may influence the assessments and treatments of acutely, severely ill children. PRACTICE IMPLICATIONS: Recognizing the multifaceted area of tension with paradoxical elements, practical teamwork exercises, a structured approach, and assessment tools could be a possible way to develop interprofessional team collaboration to improve the care of acutely, severely ill children in order to increase patient safety. PMID- 27237794 TI - [Vibratory urticaria: Implication of a protein causing degranulation]. PMID- 27237795 TI - Cryptic male choice: experimental evidence of sperm sex ratio and seminal fluid adjustment in relation to coital rate. AB - The differential allocation hypothesis suggests that a mother should adjust the sex of offspring in relation to her mate's attractiveness, thereby increasing future reproductive fitness when her sons inherit the attractive traits. More attractive males have been shown to sire more sons, but it is possible that the sex ratio skew could be a result of paternal rather than maternal manipulation, which would be a more parsimonious explanation. We manipulated coital rate (an indicator of attractiveness) in laboratory mice and showed that males that mate more often have higher levels of glucose in their semen despite lower blood glucose levels. Since peri-conceptual glucose levels in utero increase male conceptus survival, this could result in male-biased sex ratios. The males that mated most also had more remaining X-chromosome-bearing-spermatozoa, suggesting depletion of Y-chromosome-bearing-spermatozoa during mating. We hypothesise that males may alter both seminal fluids and X:Y ratios in an ejaculate to influence subsequent sex ratios. Our results further support a paternal role in sex allocation. PMID- 27237797 TI - The Importance of Single-Trial Analyses in Cognitive Neuroscience. AB - Theories of working memory typically assume that information is maintained via persistent neural activity. By contrast, Lundqvist et al. report that single trial delay activity is actually 'bursty'; the classic profile of persistent activity is an artefact of trial-wise averaging. Tackling brain-behaviour relationships at the single-trial level is an important future direction for cognitive neuroscience. PMID- 27237796 TI - Validity and reliability of a 4-compartment body composition model using dual energy x-ray absorptiometry-derived body volume. AB - BACKGROUND: Body volume (BV), one component of a four-compartment (4C) body composition model, is commonly assessed using air displacement plethysmography (BodPod). However, dual-energy x-ray absorptiometry (DEXA) has been proposed as an alternative method for calculating BV. AIMS: This investigation evaluated the validity and reliability of DEXA-derived BV measurement and a DEXA-derived 4C model (DEXA-4C) for percent body fat (%BF), fat mass (FM), and lean mass (LM). METHODS: A total sample of 127 men and women (Mean +/- SD; Age: 35.8 +/- 9.4 years; Body Mass: 98.1 +/- 20.9 kg; Height: 176.3 +/- 9.2 cm) completed a traditional 4C body composition reference assessment. A DEXA-4C model was created by linearly regressing BodPod BV with DEXA FM, LM, and bone mineral content as independent factors. The DEXA-4C model was validated in a random sub-sample of 27 subjects. Reliability was evaluated in a sample of 40 subjects that underwent a second session of identical testing. RESULTS: When BV derived from DEXA was applied to a 4C model, there were no significant differences in %BF (p = 0.404), FM (p = 0.295), or LM (p = 0.295) when compared to the traditional 4C model. The approach was also reliable; BV was not different between trials (p = 0.170). For BV, %BF, FM, and LM relative consistency values ranged from 0.995 to 0.998. Standard error of measurement for BV was 0.62 L, ranging from 0.831 to 0.960 kg. There were no significant differences between visits for %BF (p = 0.075), FM (p = 0.275), or LM (p = 0.542). CONCLUSION: The DEXA-4C model appears to be a valid and reliable method of estimating %BF, FM, and LM. The prediction of BV from DEXA simplifies the acquisition of 4C body composition by eliminating the need for an additional BV assessment. PMID- 27237798 TI - Professeur Gerard Siest. PMID- 27237799 TI - Placental growth factor (PlGF) and sFlt-1 during pregnancy: physiology, assay and interest in preeclampsia. AB - The placental growth factor (PlGF) and its soluble receptor (sFlt-1) are circulating angiogenic factors. During pregnancy these factors are released by the placenta into the maternal circulation. Preeclampsia affects 2-7% of pregnant women according to their risk factors and is characterized by high blood pressure and the onset of de novo proteinuria in the second half of pregnancy. Alterations of the sFlt-1/PlGF ratio in preeclampsia correlate with the diagnosis and adverse outcomes, particularly when the disease presents prematurely (<34 weeks). These factors can be assayed in maternal blood and measuring the sFlt-1/PlGF ratio is now available. We propose in this work to update the knowledge of these two molecules, describe their roles and evolution during normal pregnancy and preeclampsia, and finally to focus on the available assays. PMID- 27237800 TI - Droplet digital PCR, a new approach to analyze fetal DNA from maternal blood: application to the determination of fetal RHD genotype. AB - The discovery of free fetal DNA in the maternal circulation has inaugurated the era of non-invasive prenatal diagnosis. The latter has the advantage of avoiding the use of conventional obstetric procedures, such as chorionic villus sampling or aspiration of amniotic fluid, thus limiting the risks of miscarriage they induce. However, as free fetal DNA accounts for about 10% of cell-free DNA in maternal plasma, the presence of ambient maternal DNA can make it difficult to detect fetal alleles of paternal origin. Digital Droplet PCR (ddPCR) is a very sensitive method derived from quantitative real-time PCR (qPCR) for the detection of rare alleles and their absolute quantification by removing the necessity of standards. Here we show that this new technology can be applied in routine prenatal fetal RHD genotyping from maternal blood. In conclusion, the use of quantitative properties of digital PCR, in terms of accuracy, sensitivity and specificity, allows one to consider extending the applications of this new technology in non-invasive prenatal diagnosis of many diseases such as autosomal monogenic diseases, either dominant or recessive. PMID- 27237801 TI - Butyrylcholinesterase deficiency. AB - Butyrylcholinesterase (EC 3.1.1.8; BChE) is a sister enzyme of acetylcholinesterase. Though BChE lacks obvious physiological functions, it is of toxicological and pharmacological importance in detoxifying or catabolising ester containing drugs. Furthermore, individuals deficient in BChE appear asymptomatic, apart from a heightened sensitivity to the muscle relaxants suxamethonium and mivacurium, two BChE substrates used as myorelaxant. Although many acquired conditions may affect BChE activity, BChE deficiency is mainly due to mutations in the BCHE gene (OMIM 177400). Currently, more than 70 natural mutations have been documented in human BCHE. They have an adverse effect on BChE activity by affecting the catalytic functioning or the protein expression. However, the atypical variant (rs1799807) is the most frequently involved in prolonged apnea. PMID- 27237802 TI - Monoclonal gammapathy <5 g/L: the interest of T/O ratio. AB - There is currently no consensus for the quantification and identification of weak gammaglobulin monoclonal spike. We conducted a study of 12 months including 410 serum protein electrophoresis (SPE) with suspected weak monoclonal spike in gammaglobulin area without anteriority, which led to the realization of an immunofixation (IF); 276 SPE has a weak spike in gammaglobulins (defined with perpendicular drop method (orthogonal (O) quantification <5 g/L) but only 157 (57%) has monoclonal immunoglobulin by immunofixation of serum. The monitoring of 50 true positive monoclonal immunoglobulins showed the stability of the spike at more than half of the patients and its disappearance in 28% of cases. The number of true positives spike raise when using the tangent skimming method quantification (T) rather than the orthogonal method (O). The distribution of true positives based on T/O ratio propose a 6% threshold below which a monoclonal immunoglobulin is rarely found (VPNR>6%=73.7%), and a 10% threshold above more than 80% of true positives are detected (VPPR>10%=94.4%). The use of the T/O ratio could i) help to predict the presence of an IM when low intensity spike is detected, and help to choose between the realization of an immunofixation or a control of SPE later; ii) be a key tool for an inter-laboratory harmonization of IM follow up. PMID- 27237803 TI - Development of medians generators for the calculation of MoM for the first trimester Down syndrome maternal serum markers. AB - The Down syndrome risk calculation software, Fast Screen pre I plus, from Thermo Fisher Scientific, converts the First-trimester maternal serum markers concentrations (PAPP-A and hCGbeta) into degrees of extreme (DoE). To meet the requirements of the French legislation as well as those of the certified biologists for Down syndrome screening, a conversion tool for DoE into multiple of the median (MoM), intermediate reference value for the screening, was developed. In absence of any median polynomial allowing to obtain MoM easily, the calculations were made first on the basis of the polynomials centiles from the software. The subsequent reviews of the risk algorithms showed the fragility of this approach based on the Gaussian hypothesis. Medians generators, calculated from the data of the Kryptor club's biologists, were established. PMID- 27237804 TI - Immunoglobulin D and cardiac amyloidosis: development and a case illustration. AB - Amyloidosis results from extra-cellular deposition of proteins which interfere with tissue function. We report the case of a patient with pathological heart involvement which is caused by immunoglobulin D amyloidosis, and review current data on the amyloidois diagnosis and management. PMID- 27237805 TI - Discovery of a gamma heavy chain disease in a patient followed-up for a lymphoplasma cell proliferative disorder. AB - Gamma-heavy chains disease is a rare disease, with very few cases described in the literature. It is characterized by the presence of a monoclonal gamma-heavy chain without associated light chain. Its prevalence and prognosis are unknown. We report here the accidental discovery of a case of gamma-heavy chain disease during a pancytopenia exploration, performed in the hospital, in a patient known since 2002 for a lymphoplasmacytic type lymphoma first localized in bone marrow. PMID- 27237806 TI - Self-induced drug intoxication in baclofen: of the calm hypotonic coma in the status epilepticus. AB - Baclofen is an agonist of peripheral and central B gamma-aminobutyric acid receptors, whose activation causes a myorelaxation and a powerfull depression of the central nervous system. Moreover, it has an action against addiction, in reducing craving. Commercialized since 1975 in France, to control muscle spasticity due to medullar affection or multiple sclerosis, it receives a temporary recommendation of use in march 2014, as a last-line adjuvant treatment in alcohol withdrawal. Beyond its therapeutic use, baclofen is involved in many self-induced intoxications. We report the case of a patient who develops, after a massive ingestion of baclofen (supposed dose ingested: 1 200 mg), a hypotonic and calm coma, requiring her admission in our intensive care unit, and then a status epilepticus. PMID- 27237807 TI - Biological diagnosis of von Willebrand disease: analytical characteristics of Innovance vWF:Ac assay kit on STA-R Evolution Expert series analyzer (Stago). AB - The Innovance VWF:Ac test (Siemens) has the particularity to assess the binding capacity of von Willebrand factor (VWF) to recombinant platelet GPIb mutated in the absence of ristocetin. Our study aimed to evaluate and validate according to standard NF EN ISO 15189 the original protocol adaptation on STA-R Evolution series analyser (Diagnostica Stago). We evaluated the performance in terms of imprecision and we validate additional parameters necessary in range B as recommended by the SH GTA 04 (Cofrac). We compared the new assay with the reference assay: ristocetin cofactor activity (VWF:RCo) performed on the BCS-XP analyser by testing retrospectively samples from 82 healthy normal subjects and 61 patients with von Willebrand disease (VWD). This new assay is consistent with objectives set in terms of imprecision with CV around 4%. Excepted limit of quantification higher, additional parameters evaluated in range B have been validated. The Innovance VWF: Ac assay allowed the detection of all deficits of VWF already detected by the VWF:RCo test on the BCS-XP. This adjustment on STA-R analyser therefore has satisfactory analytical performance criteria. Apart from the limit of quantification, this reagent can be used according to the recommendations specified in the original protocol adaptation. Its performance and compatibility with the spot measurement allow the diagnosis and therapeutic monitoring of VWD according to current requirements and guidelines. PMID- 27237808 TI - E hepatitis seroprevalence in a population of patients with transaminases increased at Le Mans' hospital (France). AB - In Europe, infection through the hepatitis E virus presents itself under the form of autochthone, sporadic cases with zoonotic transmission. The diagnosis is more frequent in the case of male subjects above 50, with a generally severe clinical presentation. Moreover, a transition to chronicity is described in the case of immunocompromised patients. In France and in the world, seroprevalence has not clearly been established yet. In the hospital of Le Mans, Sarthe, France, the serologic status regarding the hepatitis E virus was established between October 1(st) 2012 and April 3(rd) 2015 on a population of 299 patients who presented hypertransaminasaemia and negative serology regarding hepatitis A, B and C viruses. According to the Wantai((r)) Assays technique, seroprevalence for IgG among this cohort was 26.1%, while 3.7% of patients presented acute hepatitis E and a positive IgM serology. Hepatitis E screening tests are indispensable in the context of acute hepatitis no A, no B, no C. PMID- 27237809 TI - Reply to the article Iron deficiency in elderly patients: use of biomarkers. PMID- 27237810 TI - Le dosage salivaire du cortisol doit etre reconnu comme utile en France. PMID- 27237811 TI - Lu pour vous dans.... PMID- 27237812 TI - Testez vos connaissances apres votre lecture. PMID- 27237813 TI - Metabolic and reproductive parameters in prepubertal gilts after omega-3 supplementation in the diet. AB - Polyunsaturated fatty acids may benefit reproductive performance of female swine. This study evaluated metabolic and reproductive parameters of prepubertal finishing gilts fed with fish oil as a natural source of omega-3 fatty acids (6.88g/d) (n=12) over a period of 45 d. Gilts in the control group were fed soybean oil (n=13). Body weight and backfat were determined at 15-d intervals. Serum levels of leptin, IGF-1, insulin, cholesterol and triglycerides were measured at the beginning (D0) and at the end of the period (D45). Immunolabeling intensity for leptin and its receptor (ObRb) was assessed in oocytes of preantral follicles. Gilts fed omega-3 presented slightly heavier uteri (P=0.09) than control gilts, but there was no effect on body weight and backfat (P>0.05). Cholesterol serum levels tended to be lower at D45 for omega-3 supplemented gilts than for controls (P=0.06). Triglycerides and IGF-1 serum levels were lower at D45 than at D0 for control gilts (P<0.05), but unaltered for supplemented gilts. Insulin levels were unaffected by supplementation (P>0.05), but were greater at D45 than at D0 in both treatments (P<0.05). Immunolabeling for leptin and ObRb in oocytes included in preantral follicles was more intense for supplemented gilts than for control gilts (P<0.05). Omega-3 supplementation was associated with reduced serum cholesterol level and more intense staining for leptin in oocytes of prepubertal gilts, which suggests some involvement on triggering puberty. PMID- 27237814 TI - A Conceptual Framework of Mapping Access to Health Care across EU Countries: The Patient Access Initiative. AB - Research evidence suggests that access to health care is the key influential factor for improved population health outcomes and health care system sustainability. Although the importance of addressing barriers in access to health care across European countries is well documented, little has been done to improve the situation. This is due to different definitions, approaches and policies, and partly due to persisting disparities in access within and between European countries. To bridge this gap, the Patient Access Partnership (PACT) developed (a) the '5As' definition of access, which details the five critical elements (adequacy, accessibility, affordability, appropriateness, and availability) of access to health care, (b) a multi-stakeholders' approach for mapping access, and (c) a 13-item questionnaire based on the 5As definition in an effort to address these obstacles and to identify best practices. These tools are expected to contribute effectively to addressing access barriers in practice, by suggesting a common framework and facilitating the exchange of knowledge and expertise, in order to improve access to health care between and within European countries. PMID- 27237815 TI - Immune Dysfunction as a Cause and Consequence of Malnutrition. AB - Malnutrition, which encompasses under- and overnutrition, is responsible for an enormous morbidity and mortality burden globally. Malnutrition results from disordered nutrient assimilation but is also characterized by recurrent infections and chronic inflammation, implying an underlying immune defect. Defects emerge before birth via modifications in the immunoepigenome of malnourished parents, and these may contribute to intergenerational cycles of malnutrition. This review summarizes key recent studies from experimental animals, in vitro models, and human cohorts, and proposes that immune dysfunction is both a cause and a consequence of malnutrition. Focusing on childhood undernutrition, we highlight gaps in current understanding of immune dysfunction in malnutrition, with a view to therapeutically targeting immune pathways as a novel means to reduce morbidity and mortality. PMID- 27237817 TI - Pompe Disease and Autophagy: Partners in Crime, or Cause and Consequence? AB - Pompe disease or glycogen storage disease type II (OMIM: 232300) is a lysosomal storage disorder resulting from a partial or total lack of acid alphaglucosidase, which may produce muscle weakness, gait abnormalities, or even death by respiratory failure. In the last decade, autophagy has been proposed as a mechanism involved in the severity of symptoms related to this disorder and as a potential therapeutic target to alleviate disease progression. This review summarizes the relationship between autophagy and Pompe disease, including what information has been recently discovered and what remains unclear. PMID- 27237816 TI - Carbocysteine counteracts the effects of cigarette smoke on cell growth and on the SIRT1/FoxO3 axis in bronchial epithelial cells. AB - BACKGROUND: Cigarette smoke may accelerate cellular senescence by increasing oxidative stress. Altered proliferation and altered expression of anti-aging factors, including SIRT1 and FoxO3, characterise cellular senescence. The effects of carbocysteine on the SIRT1/FoxO3 axis and on downstream molecular mechanisms in human bronchial epithelial cells exposed to cigarette smoke are largely unknown. AIMS: Aim of this study was to explore whether carbocysteine modulated SIRT1/FoxO3 axis, and downstream molecular mechanisms associated to cellular senescence, in a bronchial epithelial cell line (16-HBE) exposed to cigarette smoke. METHODS: 16HBE cells were stimulated with/without cigarette smoke extracts (CSE) and carbocysteine. Flow cytometry and clonogenic assay were used to assess cell proliferation; western blot analysis was used for assessing nuclear expression of SIRT1 and FoxO3. The nuclear co-localization of SIRT1 and FoxO3 was assessed by fluorescence microscopy. Beta galactosidase (a senescence marker) and SIRT1 activity were assessed by specific staining and colorimetric assays, respectively. ChiP Assay and flow cytometry were used for assessing survivin gene regulation and protein expression, respectively. RESULTS: CSE decreased cell proliferation, the nuclear expression of SIRT1 and FoxO3 and increased beta galactosidase staining. CSE, reduced SIRT1 activity and FoxO3 localization on survivin promoter thus increasing survivin expression. In CSE stimulated bronchial epithelial cells carbocysteine reverted these phenomena by increasing cell proliferation, and SIRT1 and FoxO3 nuclear expression, and by reducing beta galactosidase staining and survivin expression. CONCLUSIONS: The study shows for the first time that carbocysteine may revert some senescence processes induced by oxidative stress due to cigarette smoke exposure. PMID- 27237818 TI - Standardization of Epitopes for Human Chorionic Gonadotropin (hCG) Immunoassays. AB - hCG and its variants are markers for pregnancy tests, pregnancyrelated complications, trophoblastic diseases, pre-natal screening of Down's syndrome and doping controls. Strong demands are imposed on diagnostic methods by the dynamic changes in the absolute and relative levels of hCG protein backbone variants and glycosylation isoforms in serum and urine during development of pregnancy or the progression/remission of tumors. Observed differences in the results between commercial diagnostic immunoassays reflect the unequal molar recognition of the different metabolic hCG variants, in particular the hCG beta core fragment (hCGbetacf), by the diagnostic antibodies (Abs), as their epitopes are not standardized, and the fact that suboptimal hCG standards are used. To rapidly characterize Abs by their epitope recognition and specificity to evaluate their suitability for diagnostic immunoassays a procedure of comparative epitope mapping has been developed using epitope-defined reference Abs. Comparative epitope mapping of diagnostic Abs will provide the basis for the standardization of diagnostic antigenic domains/epitopes and consequently for improved reliability of hCG measurements. Diagnostic first line assays likely consist of pairs of Abs that recognize specific epitopes at the top of the neighboring peptide loops 1 and 3 (L1+3) and the cystine knot (ck) of hCGbeta, respectively. In future, significant improvements of reliability, robustness and comparability of the results of immunoassays for complex glycoproteins such as hCG will be achieved by the use (i) of standardized diagnostic Abs against welldefined epitopes and (ii) of the new International Standards for hCG and for five hCG variants established by WHO, that are calibrated in molar (SI) units. PMID- 27237819 TI - The Role of Cancer Biomarkers in HIV Infected Hosts. AB - A higher incidence of cancer has been observed in Human Immunodeficiency Virus (HIV) infected individuals as compared with healthy people of the same age. A complex relationship between HIV-induced immune suppression, chronic antigenic stimulation, and oncogenic virus co-infections may promote carcinogenesis and increase the risk of developing tumors in these patients. Cancers in HIV subjects include the AIDS-defining malignancies (ADMs) and other non-AIDS-defining malignancies (NADMs). Antiretroviral therapy has reduced the incidence of ADMs whereas a concurrent increase of NADMs was observed in the last years. Biomarkers are measurable parameters, characterizing normal or pathogenic processes, which could provide a high potential for risk evaluation and diagnosis of patients. Therefore, the early detection of cancer biomarkers in HIV-positive subjects would be useful to identify patients at most risk of tumor disease development. This review will focus principally on the risk assessment and diagnostic role of several biomarkers of malignancy in HIV patients including cellular and viral biomarkers, cytokines, immune activation molecules and genetic polymorphisms. PMID- 27237820 TI - Endocannabinoid System: A Promising Therapeutic Target for the Treatment of Haematological Malignancies? AB - BACKGROUND: The therapeutic properties of cannabinoids are well-known since ancient years. Growing evidence exist on endocannabinoid system (ECS) modulation related with human tumorigenesis. OBJECTIVE: Taking into account the substantial role of ECS on immune cell regulation, the present review is aimed to summarize the emerging evidence concerning cannabinoid receptor (CBR) expression and cannabinoid ligand effects on haematological malignancies. CONCLUSIONS: Most of cannabinoid actions, mainly CB2R-mediated against haematopoietic malignant cells, seem promising, as inhibition of cell proliferation and apoptosis and paraptosis induction have been documented. Cannabinoid ligands appear to activate rudimentary pathways for cell survival, such as ERK, JNK, p38 MAPK, and to induce caspase synthesis, in vitro. Such data are strongly recommended to be confirmed by in vivo experiments with emphasis on cannabinoid ligands' bioavailability and phytocannabinoid psychotropic properties. The preliminary antitumoral ECS effects and their relative lack of important side effects render ECS a promising therapeutic target for the treatment of haematological malignancies. PMID- 27237821 TI - Current Tools and Methods in Molecular Dynamics (MD) Simulations for Drug Design. AB - Molecular Dynamics (MD) simulations is a computational method that employs Newton's laws to evaluate the motions of water, ions, small molecules, and macromolecules or more complex systems, for example, whole viruses, to reproduce the behavior of the biological environment, including water molecules and lipid membranes. Specifically, structural motions, such as those that are dependent of the temperature and solute/ solvent are very important to study the recognition pattern of ligandprotein or protein-protein complexes, in that sense, MD simulations are very useful because these motions can be modeled using this methodology. Furthermore, MD simulations for drug design provide insights into the structural cavities required to design novel structures with higher affinity to the target. Also, the employment of MD simulations to drug design can help to refine the three-dimensional (3D) structure of targets in order to obtain a better sampling of the binding poses and more reliable affinity values with better structural advantages, because they incorporate some biological conditions that include structural motions compared to traditional docking procedures. This work analyzes the concepts and applicability of MD simulations for drug design because molecular structural motions are considered, and these help to identify hot spots, decipher structural details in the reported protein sites, as well as to eliminate sites that could be structural artifacts which could be originated from the structural characterization conditions from MD. Moreover, better free energy values for protein ligand recognition can also be obtained, and these can be validated under experimental procedures due to the robustness of the MD simulation methods. PMID- 27237822 TI - Nanomedicine for Intra-Articular Drug Delivery in Rheumatoid Arthritis. AB - Rheumatoid arthritis is characterized by chronic inflammation within the joint. Recent developments in the understanding of inflammation have led to an increased interest in the use of nanomedicine in the treatment and diagnosis of rheumatoid arthritis. The ability of nanomedicine, such as nanoparticles, to permeate into and/or retain within the inflamed joint after intravenous and/or intra-articular administration has proven to be beneficial in improving rheumatoid arthritis therapy while reducing systemic exposure of patients to potentially toxic anti arthritic drugs. This review aims at explaining the major applications of nanomedicine in rheumatoid arthritis treatment and diagnosis. PMID- 27237823 TI - Acute neck pain caused by pseudogout attack of calcified cervical yellow ligament: a case report. AB - BACKGROUND: Calcification of the yellow ligament sometimes compresses the spinal cord and can induce myelopathy. Usually, the calcification does not induce acute neck pain. We report a case of a patient with acute neck pain caused by calcium pyrophosphate dihydrate in a calcified cervical yellow ligament. CASE PRESENTATION: A 70-year-old Japanese woman presented with acute neck pain. She had a moderately high fever (37.5 degrees C), and her neck pain was so severe that she could not move her neck in any direction. Computed tomography showed a high-density area between the C5 and C6 laminae suspicious for calcification of the yellow ligament. Magnetic resonance imaging showed intermediate-signal intensity on T1-weighted imaging and high-signal intensity on T2-weighted imaging surrounding a low-signal region on both T1- and T2-weighted imaging with cord compression. There was a turbid, yellow fluid collection in the yellow ligament at the time of operation. Histologically, calcium pyrophosphate dihydrate crystals were found in the fluid, and she was diagnosed as having a pseudogout attack of the yellow ligament. CONCLUSIONS: Pseudogout attack of the cervical yellow ligament is rare, but this clinical entity should be added to the differential diagnosis of acute neck pain, especially when calcification of the yellow ligament exists. PMID- 27237824 TI - Suboptimal bone protection in geriatric inpatients and effect of a simple educational and mnemonic strategy. AB - AIM: Osteoporosis is underdiagnosed and undertreated in Australia, especially in hospitalised patients. We aimed to improve bone health management in geriatric inpatients by introducing a mnemonic into discharge summaries. METHODS: A retrospective review of patients discharged from our geriatric unit was performed before and after intervention. Outcomes assessed were as follows: vitamin D measurement, bone protection medication and communication to general practitioners. RESULTS: Sixty-one patients were included in the initial audit, and 82 in the reaudit. There was an increase in measurement of vitamin D levels (86.6% vs 57.4%, P < 0.001) and in the communication to the general practitioner (84.7% vs 28.6%, P < 0.001). Patients in the reaudit were more likely to have vitamin D initiated or increased (43.0% vs 7.4%, P = 0.001) and to have antiresorptive therapy commenced (9.8% vs 0%, P = 0.01). CONCLUSION: The introduction of simple education and mnemonic strategy has shown significant improvement in the assessment and management of bone health in at-risk patients. PMID- 27237825 TI - EGFR TKIs plus WBRT Demonstrated No Survival Benefit Other Than That of TKIs Alone in Patients with NSCLC and EGFR Mutation and Brain Metastases. AB - INTRODUCTION: Whether EGFR tyrosine kinase inhibitors (TKIs) plus whole brain radiation therapy (WBRT) provide a better survival benefit than EGFR TKIs alone remains undetermined in patients with NSCLC with EGFR mutation and brain metastases (BMs). METHODS: A total of 230 patients with NSCLC with EGFR mutation and BM were identified. Within this group, 116 patients received EGFR TKIs alone (as first-line therapy in 91 cases) and 51 patients received EGFR TKIs plus WBRT therapy (as first-line treatment in 30 cases). RESULTS: Compared with TKIs alone, EGFR TKIs plus WBRT had no superior intracranial progression-free survival (PFS) (6.9 versus 7.4 months [p = 0.232]) and systemic PFS (7.5 versus 7.9 months [p = 0.546]) but were associated with worse overall survival (OS) (21.6 versus 26.4 months [p = 0.049]) in NSCLC with EGFR mutation and BM. Chemotherapy plus WBRT was shown to have an intracranial PFS (5.2 versus 5.9 months [p = 0.339]) and OS (10.5 versus 11.0 months [p = 0.977]) similar to those with chemotherapy alone in patients with EGFR of unknown or wild-type status. In multivariate analysis, EGFR mutation was found to be an independent risk factor for BM (hazard ratio = 1.476, p = 0.039) and also a significant independent prognostic factor for OS in patients with NSCLC with BM (hazard ratio = 0.601, p = 0.028). CONCLUSIONS: The addition of WBRT to EGFR TKIs did not appear to have survival benefit superior to that of EGFR TKIs alone in with EGFR-mutant NSCLC with BM. WBRT also did not bring additional benefit to chemotherapy in patients with BM and EGFR of wild type or unknown status. PMID- 27237826 TI - Current Patterns of Care for Patients with Extensive-Stage SCLC: Survey of U.S. Radiation Oncologists on Their Recommendations Regarding Prophylactic Cranial Irradiation. AB - INTRODUCTION: Conflicting data from randomized clinical trials incite the debate over the appropriate use of prophylactic cranial irradiation (PCI) for patients with extensive-stage SCLC (ES-SCLC) who achieve clinical response to systemic chemotherapy. The current pattern of practice among U.S. radiation oncologists is unknown. METHODS: We surveyed practicing U.S. radiation oncologists through a short online questionnaire. Respondents' characteristics and their self-rated knowledge base were analyzed for association with their treatment recommendations. RESULTS: We received 473 responses from practicing U.S. radiation oncologists. More than half of the respondents had been practicing for more than 10 years after completing residency training, and 70% had treated more than 10 patients with lung cancer per year. Of the respondents, 90% recommended brain magnetic resonance imaging (MRI) before initiation of PCI and 98% recommended PCI for patients with ES-SCLC after systemic chemotherapy. Half of the respondents followed their patients with brain MRI after completion of PCI. One-third of the respondents prescribed memantine to patients undergoing PCI. Among the respondents, recent graduates (p = 0.004) and physicians practicing in academic centers (p = 0.005) were more likely to prescribe memantine. Self-rated knowledge base was not associated with any treatment recommendations. CONCLUSIONS: Our analysis revealed that among the respondents, there was a very high adherence to current National Comprehensive Cancer Network guidelines, which recommend providing universal PCI and obtaining brain MRI before initiation of PCI for patients with ES-SCLC with clinical response to systemic chemotherapy. These guidelines and practice patterns are not supported by clinical evidence because patients in the European Organization for Research and Treatment of Cancer trial did not undergo brain MRI before PCI and the Japanese randomized trial has shown a possible detrimental effect of PCI on overall survival when brain MRI was incorporated. A critical reevaluation of current guidelines is essential to determine the appropriate management of these patients. PMID- 27237827 TI - Extremely Accessible Potassium Nitrate (KNO3) as the Highly Efficient Electrolyte Additive in Lithium Battery. AB - The systematic investigation of RNO3 salts (R = Li, Na, K, and Cs) as electrolyte additives was carried out for lithium-battery systems. For the first time, the abundant and extremely available KNO3 was proved to be an excellent alternative of LiNO3 for suppression of the lithium dendrites. The reason was ascribed to the possible synergetic effect of K(+) and NO3(-) ions: The positively charged K(+) ion could surround the lithium dendrites by electrostatic attraction and then delay their further growth, while simultaneously the oxidative NO3(-) ion could be reduced and subsequently profitable to the reinforcement of the solid electrolyte interphase (SEI). By adding KNO3 into the practical Li-S battery, the discharging capacity was enhanced to average 687 mAh g(-1) from the case without KNO3 (528 mAh g(-1)) during 100 cycles, which was comparable to the one with the well-known LiNO3 additive (637 mAh g(-1)) under the same conditions. PMID- 27237828 TI - Visible-Light Induced Self-Powered Sensing Platform Based on a Photofuel Cell. AB - A self-powered sensing system possesses the capacity of harvesting energy from the environment and has no requirement for external electrical power supply during the chemical sensing of analytes. Herein, we design an enzyme-free self powered sensing platform based on a photofuel cell (PFC) driven by visible-light, using glucose as a model analyte. The fabricated PFC consists of a Ni(OH)2/CdS/TiO2 photoanode and a hemin-graphene (HG) nanocomposite coated cathode in separated chambers. Under visible-light irradiation, glucose in the anodic chamber is facilely oxidized on Ni(OH)2/CdS/TiO2 while H2O2 in the cathodic chamber is catalytically reduced by HG, which generates a certain cell output sensitive to the variation of glucose concentration. Thus, a PFC based self-powered sensor is realized for glucose detection. Compared to the existing enzymatic self-powered glucose sensors, our proposed PFC based strategy exhibits much lower detection concentration. Moreover, it avoids the limitation of conventional enzyme immobilized electrodes and has the potential to develop high performance self-powered sensors with broader analyte species. PMID- 27237829 TI - DIY-Bio - economic, epistemological and ethical implications and ambivalences. AB - Since 2008, we witness the emergence of the Do-It-Yourself Biology movement, a global movement spreading the use of biotechnology beyond traditional academic and industrial institutions and into the lay public. Practitioners include a broad mix of amateurs, enthusiasts, students, and trained scientists. At this moment, the movement counts nearly 50 local groups, mostly in America and Europe, but also increasingly in Asia. Do-It-Yourself Bio represents a direct translation of hacking culture and practicesfrom the realm of computers and software into the realm of genes and cells. Although the movement is still in its infancy, and it is even unclear whether it will ever reach maturity, the contours of a new paradigm of knowledge production are already becoming visible. We will subsequently sketch the economic, the epistemological and the ethical profile of Do-It-Yourself Bio, and discuss its implications and also its ambivalences. PMID- 27237830 TI - Abietane diterpenes from the cones of Abies numidica de Lannoy ex Carriere (Pinaceae) and in vitro evaluation of their antimicrobial properties. AB - Eight known abietane diterpenes (1-8) were isolated for the first time from Abies numidica cones (Pinaceae). The structures of all compounds were established by means of 1D and 2D NMR, and UV spectral analyses. The hydromethanolic extract of A. numidica cones was tested for its antimicrobial activity against 17 gram positive and gram-negative bacteria and against five yeasts by the use of liquid and solid medium and bioautography methods. The best antimicrobial activity was found against gram-positive bacteria (MIC <= 0.3 mg/mL) Bacillus subtilis, Enterococcus faecalis ATCC 1034, Staphylococcus aureus 8325.4, S. aureus CIP 53.154, Micrococcus luteus and Listeria innocua and against Candida yeasts. The determination of MIC's of isolated products showed a high activity of compounds 4 and 6 against S. aureus, L. innocua (MIC = 62.5 MUg/mL) and E. faecalis (MIC = 125 MUg/mL). PMID- 27237831 TI - Mothers and midwives perceptions of birthing position and perineal trauma: An exploratory study. AB - BACKGROUND: Studies have associated lithotomy position during childbirth with negative consequences and increased risk of perineal injuries. AIMS: To identify prevalence rates of different birthing position and episiotomy and to explore the differences in perspectives of mothers and midwives about birthing positions and perineal trauma. METHODS: A survey involving 110 mothers and 110 midwives at two hospitals. Participants were mothers who had a vaginal birth/perineal injury and midwives who attended births that resulted in perineal injuries. Perceptions of mothers and midwives were analysed. Pearson's chi-square test was used to measure association between birthing positions and perineal trauma. FINDINGS: Mothers, n=94 (85%) and midwives, n=108 (98%) reported high rates of lithotomy position for birth. N=63 (57%) of mothers perceived lithotomy position as not being helpful for birth. In contrast, a similar number of midwives perceived lithotomy position as helpful, n=65 (59%). However, a high majority of mothers, n=106 (96%) and midwives, n=97 (88%) reported they would be willing to use alternative positions. Majority of mothers had an episiotomy, n=80 (73%) and n=76 (69%) reported they did not give their consent. N=59 (53%) reported they were not given local anaesthesia for an episiotomy. n=30 (27%) of midwives confirmed they performed an episiotomy without local anaesthesia. CONCLUSION: Care is not based on current evidence and embedded practices, i.e. birthing in lithotomy position and routine episiotomies are commonly used. However, this survey did find a willingness to change, adapt practice and consider different birthing positions and this may lead to fewer episiotomies being performed. PMID- 27237832 TI - On-line database of voltammetric data of immobilized particles for identifying pigments and minerals in archaeometry, conservation and restoration (ELCHER database). AB - A web-based database of voltammograms is presented for characterizing artists' pigments and corrosion products of ceramic, stone and metal objects by means of the voltammetry of immobilized particles methodology. Description of the website and the database is provided. Voltammograms are, in most cases, accompanied by scanning electron microphotographs, X-ray spectra, infrared spectra acquired in attenuated total reflectance Fourier transform infrared spectroscopy mode (ATR FTIR) and diffuse reflectance spectra in the UV-Vis-region. For illustrating the usefulness of the database two case studies involving identification of pigments and a case study describing deterioration of an archaeological metallic object are presented. PMID- 27237833 TI - Review: LC coupled to low- and high-resolution mass spectrometry for new psychoactive substance screening in biological matrices - Where do we stand today? AB - The field of new psychoactive substances (NPS) is highly dynamic and the situation changes from year to year. Therefore, the current review provides a timely update about the latest developments to help analysts keep the pace with NPS distribution. It covers PubMed-listed studies published between January 2014 and January 2016 dealing with the application of liquid chromatography (LC) coupled low- and high-resolution mass spectrometry (MS) for broad screenings for NPS in clinical (CT) and forensic (FT) toxicology. Latest developments and applications are highlighted and selected papers critically discussed. Comprehensive tables summarizing all discussed articles complete the overview. Finally, an outlook on the future of LC coupled MS in CT and FT is provided and readers will learn why low-resolution mass spectrometry might remain the standard for the next couple of years at least for easy-to-use quantitative screening procedures. PMID- 27237834 TI - On the ambiguity of the reaction rate constants in multivariate curve resolution for reversible first-order reaction systems. AB - If for a chemical reaction with a known reaction mechanism the concentration profiles are accessible only for certain species, e.g. only for the main product, then often the reaction rate constants cannot uniquely be determined from the concentration data. This is a well-known fact which includes the so-called slow fast ambiguity. This work combines the question of unique or non-unique reaction rate constants with factor analytic methods of chemometrics. The idea is to reduce the rotational ambiguity of pure component factorizations by considering only those concentration factors which are possible solutions of the kinetic equations for a properly adapted set of reaction rate constants. The resulting set of reaction rate constants corresponds to those solutions of the rate equations which appear as feasible factors in a pure component factorization. The new analysis of the ambiguity of reaction rate constants extends recent research activities on the Area of Feasible Solutions (AFS). The consistency with a given chemical reaction scheme is shown to be a valuable tool in order to reduce the AFS. The new methods are applied to model and experimental data. PMID- 27237835 TI - New CNT/poly(brilliant green) and CNT/poly(3,4-ethylenedioxythiophene) based electrochemical enzyme biosensors. AB - A combination of the electroactive polymer poly(brilliant green) (PBG) or conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT) with carbon nanotubes to obtain CNT/PBG and CNT/PEDOT modified carbon film electrodes (CFE) has been investigated as a new biosensor platform, incorporating the enzymes glucose oxidase (GOx) as test enzyme, alcohol oxidase (AlcOx) or alcohol dehydrogenase (AlcDH). The sensing parameters were optimized for all biosensors based on CNT/PBG/CFE, CNT/PEDOT/CFE platforms. Under optimized conditions, both GOx biosensors exhibited very similar sensitivities, while in the case of AlcOx and AlcDH biosensors, AlcOx/CNT/PBG/CFE was found to give a higher sensitivity and lower detection limit. The influence of dissolved O2 on oxidase-biosensor performance was investigated and was shown to be different for each enzyme. Comparisons were made with similar reported biosensors, showing the advantages of the new biosensors, and excellent selectivity against potential interferents was successfully demonstrated. Finally, alcohol biosensors were successfully used for the determination of ethanol in alcoholic beverages. PMID- 27237836 TI - Design and testing of a new sampler for simplified vacuum-assisted headspace solid-phase microextraction. AB - The design and testing of a new and low-cost experimental setup used for vacuum assisted headspace solid-phase microextraction (Vac-HSSPME) is reported here. The device consists of a specially designed O-ring seal screw cap offering gas-tight seal to commercially available headspace vials. The new polytetrafluoroethylene (PTFE) cap was molded by a local manufacturer and had a hole that could tightly accommodate a septum. All operations were performed through the septum: air evacuation of the sampler, sample introduction and HSSPME sampling. The analytical performance of the new sampler was evaluated using 22 mL headspace vials with 9 mL water samples spiked with polychlorinated biphenyls (PCBs). Several experimental parameters were controlled and the optimized conditions were: 1000 rpm agitation speed; 30 min extraction time; 40 degrees C sampling temperature; polydimethylsiloxane-divinylbenzene (PDMS-DVB) fiber. The lack of accurate Henry's law constant (KH) values and information regarding how they change with temperature was a major limitation in predicting the phase location of evaporation resistance during Vac-HSSPME. Nevertheless, the combined effects of system conditions indicated the increasing importance of gas phase resistance with increasing degree of PCBs chlorination. Stirring enhancements were not recorded for the higher chlorinated PCBs suggesting that the hyperhydrophobic gas/water interface was the preferred location for these compounds. Analytically, the developed method was found to yield linear calibration curves with limits of detection in the sub ng L(-1) level and relative standard deviations ranging between 5.8 and 14%. To compensate for the low recoveries of the higher chlorinated PCB congeners in spiked river water the standard addition methodology was applied. Overall, the compact design of the new and reusable sample container allows efficient HSSPME sampling of organic analytes in water within short extraction times and at low sampling temperatures compared to other published HSSPME methods. PMID- 27237837 TI - Solid-phase microextraction of phthalate esters in water sample using different activated carbon-polymer monoliths as adsorbents. AB - In this study, the application of different activated carbon-polymer (AC-polymer) monoliths as adsorbents for the solid-phase microextraction (SPME) of phthalate esters (PAEs) in water sample were investigated. The activated carbon (AC) was embedded in organic polymers, poly(butyl methacrylate-co-ethylene dimethacrylate) (poly(BMA-EDMA)) or poly(styrene-co-divinylbenzene) (poly(STY-DVB)), via a 5-min microwave-assisted or a 15-min water bath heating polymerization. Preliminary investigation on the performance of the native poly(BMA-EDMA) and poly(STY-DVB) demonstrated remarkable adsorption efficiencies for PAEs. However, due to the strong hydrophobic, pi-pi, and hydrogen bonding interactions between the analytes and polymers, low extraction recoveries were achieved. In contrast, the presence of AC in native polymers not only enhanced the adsorption efficiencies but also assisted the PAE desorption, especially for AC-poly(STY-DVB) with extraction recovery ranged of 76.2-99.3%. Under the optimized conditions, the extraction recoveries for intra-, inter-day and column-to-column were in the range of 76.5 100.8% (<3.7% RSDs), 77.2-97.6% (<5.6% RSDs) and 75.5-99.7% (<6.2% RSDs), respectively. The developed AC-poly(STY-DVB) monolithic column showed good mechanical stability, which can be reused for more than 30 extraction times without any significant loss in the extraction recoveries of PAEs. The AC poly(STY-DVB) monolithic column was successfully applied in SPME of PAEs in water sample with extraction recovery ranged of 78.8%-104.6% (<5.5% RSDs). PMID- 27237838 TI - A sensitive and semi-quantitative method for determination of multi-drug residues in animal body fluids using multiplex dipstick immunoassay. AB - The objective of this research was to develop a multiplex dipstick immunoassay method for the simultaneous determination of multi-veterinary drug residues, such as beta-agonists, sulfonamides, and tetracyclines in milk, urine, and serum. The multiplex dipstick assay format was based on an indirect competitive approach: Three test lines (different antigens) and one control line (goat anti-mouse IgG) were located on the strip membrane. Labeled antibodies were freeze-dried in microwells. Samples did not require pretreatment and could be directly analyzed within 10 min. Threshold levels in different sample matrices were visually estimated at 0.3-0.45 ng mL(-1) for clenbuterol; 3-4 ng mL(-1) for sulfadiazine; and 4.5-6 ng mL(-1) for tetracycline, respectively. The linear relationship between the concentrations of veterinary drug residues and the Au nanoparticles plasmon absorbance allowed quantitative determination of these veterinary drug residues. The recoveries of clenbuterol, sulfadiazine and tetracycline in spiked samples ranged from 78.4% to 112.6%, and the relative standard deviations were below 11.2%. Analysis of animal samples suggested that the proposed multiplex dipstick assay method was consistent with the LC-MS/MS method. The percentage of false results was less than or equal to 5%. Thus, the proposed multiplex dipstick assay is inexpensive, easy-to-use, and suitable for the purposes of rapid and comprehensive screening of 3 families of beta-agonists, sulfonamides and tetracyclines including 26 drugs in animal body fluids. PMID- 27237839 TI - Development of a high-performance liquid chromatography - Tandem mass spectrometry urinary pterinomics workflow. AB - Pteridines have evoked considerable interest from the scientific community owing to their prominent roles in human health and disease. The availability of analytical methodologies suitable for comprehensive pteridine profiling, termed here as "pterinomics", has been limited by inconsistent sample preparation and the exclusion of lesser studied pteridine derivatives. In response, the present study describes a new pterinomics workflow using a high-performance liquid chromatography - tandem mass spectrometry (HPLC-MS/MS) methodology for the simultaneous analysis of 15 pteridine derivatives including four structural isomers, marking the largest quantitative pteridine panel that has been studied to-date. The validated method possessed excellent sensitivity with method detection limits (0.025 MUg L(-1) to 0.5 MUg L(-1)) that were comparable or superior to existing techniques. Spiked recovery studies demonstrated the technique was both accurate (88-112%) and precise (RSD: 0-6%). A comparative study of commonly used oxidative pretreatments, including triiodide, permanganate, and manganese dioxide, revealed that the oxidative mechanisms were inefficient, complex, and concentration dependent. Finally, 50 clinical urine specimens were examined with the new technique wherein 10 pteridine derivatives were quantified and population ranges have been given. This technique can be used to examine pteridine molecular epidemiology and biochemistry to support related research applications, and may further be readily extended to include additional pteridine derivatives and biological matrices for specific applications. PMID- 27237840 TI - An improved pseudotargeted metabolomics approach using multiple ion monitoring with time-staggered ion lists based on ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry. AB - Pseudotargeted metabolomics is a novel strategy integrating the advantages of both untargeted and targeted methods. The conventional pseudotargeted metabolomics required two MS instruments, i.e., ultra-high performance liquid chromatography/quadrupole-time- of-flight mass spectrometry (UHPLC/Q-TOF MS) and UHPLC/triple quadrupole mass spectrometry (UHPLC/QQQ-MS), which makes method transformation inevitable. Furthermore, the picking of ion pairs from thousands of candidates and the swapping of the data between two instruments are the most labor-intensive steps, which greatly limit its application in metabolomic analysis. In the present study, we proposed an improved pseudotargeted metabolomics method that could be achieved on an UHPLC/Q-TOF/MS instrument operated in the multiple ion monitoring (MIM) mode with time-staggered ion lists (tsMIM). Full scan-based untargeted analysis was applied to extract the target ions. After peak alignment and ion fusion, a stepwise ion picking procedure was used to generate the ion lists for subsequent single MIM and tsMIM. The UHPLC/Q TOF tsMIM MS-based pseudotargeted approach exhibited better repeatability and a wider linear range than the UHPLC/Q-TOF MS-based untargeted metabolomics method. Compared to the single MIM mode, the tsMIM significantly increased the coverage of the metabolites detected. The newly developed method was successfully applied to discover plasma biomarkers for alcohol-induced liver injury in mice, which indicated its practicability and great potential in future metabolomics studies. PMID- 27237841 TI - Quantitative analysis of deuterium using the isotopic effect on quaternary (13)C NMR chemical shifts. AB - Quantitative analysis of specifically deuterated compounds can be achieved by a number of conventional methods, such as mass spectroscopy, or by quantifying the residual (1)H NMR signals compared to signals from internal standards. However, site specific quantification using these methods becomes challenging when dealing with non-specifically or randomly deuterated compounds that are produced by metal catalyzed hydrothermal reactions in D2O, one of the most convenient deuteration methods. In this study, deuterium-induced NMR isotope shifts of quaternary (13)C resonances neighboring deuterated sites have been utilized to quantify the degree of isotope labeling of molecular sites in non-specifically deuterated molecules. By probing (13)C NMR signals while decoupling both proton and deuterium nuclei, it is possible to resolve (13)C resonances of the different isotopologues based on the isotopic shifts and the degree of deuteration of the carbon atoms. We demonstrate that in different isotopologues, the same quaternary carbon, neighboring partially deuterated carbon atoms, are affected to an equal extent by relaxation. Decoupling both nuclei ((1)H, (2)H) resolves closely separated quaternary (13)C signals of the different isotopologues, and allows their accurate integration and quantification under short relaxation delays (D1 = 1 s) and hence fast accumulative spectral acquisition. We have performed a number of approaches to quantify the deuterium content at different specific sites to demonstrate a convenient and generic analysis method for use in randomly deuterated molecules, or in cases of specifically deuterated molecules where back exchange processes may take place during work up. PMID- 27237842 TI - Chemiluminescent lateral-flow immunoassays by using in-situ synthesis of CdS NW photosensor. AB - A hypersensitive CdS nanowire (NW) photosensor was fabricated by an in-situ synthesis process that involved the direct synthesis of CdS NWs on an interdigitated electrode (IDE). Analysis of the photoresponse properties showed that the newly synthesized photosensor had enhanced sensitivity and a highly reproducible photoresponse compared to photosensors prepared from CdS NW suspensions. The NW photosensor was applied to measure the chemiluminescence of luminol, and the sensitivity was compared to a commercial photosensing system. Finally, the feasibility of the CdS NW photosensor for the application to the medical diagnosis of the human hepatitis B surface antigen (hHBsAg) was demonstrated using a lateral-flow immunoassay with a chemiluminescent signal band. PMID- 27237843 TI - Enhancement of gas-sensing abilities in p-type ZnWO4 by local modification of Pt nanoparticles. AB - Semiconducting ZnWO4 nanorods and nanoparticles are synthesized by adjusting the composition of the reaction solvent. The effect of Pt nanoparticles on the sensing property of ZnWO4 nanostructures were evaluated and investigated systemically in the first time. Pure ZnWO4 nanostructures exhibited the highest sensitivity towards ethanol against Volatile Organic Compounds (methanol, acetone). Their lower limit of detection can reach 100 ppm for ethanol at temperature of about 23 degrees C. Pt nanoparticles play a positive effect in improving the sensitivity of ZnWO4 towards H2. After loading of Pt nanoparticles, the response of ZnWO4 nanorods towards 1.5% H2 increased from 1.4 to 12.5 at room temperature. In addition, the structure exhibits more significant promoting effect than nanoparticle structure because of their different microstructure and exposed crystallographic planes. Furthermore, Pt nanoparticles could eliminate the effect of ambient humidity to avoid the baseline shift. The gas sensing mechanism of PtZnWO4 nanocomposites is discussed detailedly at the same time. The generation of Schottky barrier at the interface between metal and semiconductor, as well as the formation of PtO on the surface of Pt nanoparticles contribute to the enhanced sensing response. PMID- 27237844 TI - Ageing and free-living daily physical activity effects on salivary beta-defensin 2 secretion. AB - This study examined ageing and free-living daily physical activity effects on salivary human beta-defensin 2 (hBD2). A total of 168 healthy elderly and 26 healthy young volunteers underwent saliva sampling. Free-living step count, energy expenditure and activity durations at specific intensity levels (inactive, light, moderate and vigorous) were evaluated. The results show significantly lower salivary hBD2 secretion rates for elderly than for young participants (P < 0.05). Data from elderly participants were stratified by steps per day using quartiles (Q1-Q4) for distribution. Elderly in quartiles respectively showed step counts of 3145 +/- 129 in Q1, 5294 +/- 83 in Q2, 7001 +/- 86 in Q3 and 10,236 +/- 416 steps . day-1 in Q4. In elderly participants, significant differences were found in the mean step count, energy expenditure and activity duration with increasing pedometer-determined activity quartiles. hBD2 secretion rates were significantly higher for Q2, Q3 and Q4 than for Q1 (P < 0.05). Elderly participants in Q3 had the highest hBD2 secretion. In conclusion, these results suggest that moderate physical activity in daily living improves age-related impairment of oral immune function mediated by hBD2. For oral immune function enhancement and for prevention of upper respiratory tract infections in elderly people, we recommend accumulation of more than 7000 steps . day-1. PMID- 27237845 TI - Partial Anomalous Pulmonary Venous Return as Rare Cause of Right Ventricular Dilation: A Retrospective Analysis. AB - INTRODUCTION: Partial anomalous pulmonary venous return (PAPVR) is an uncommon cause of right ventricular dilation. It may be difficult to identify and often remains undiagnosed. METHODS: We reviewed the database of the Cardiac Magnetic Resonance (CMR) Laboratory of Niguarda Hospital, in order to identify the cases of PAPVR between 2008 and 2014. RESULTS: On a total number of 7832 CMR scans, we identified 24 patients with PAPVR (14 male, age 41 +/- 18 y) corresponding to 0.31% of the total population. Only 30% of patients had been referred for known or suspected PAPVR, 33% of patients had been referred for suspected right ventricular arrhythmogenic dysplasia and 37% had been referred for other cardiac disease. PAPVR involved mainly the right pulmonary veins (18 patients, 75%) and in 62% of our cases was associated with an atrial septal defect. Eight patients underwent corrective surgery in our institution, which confirmed and successfully repaired the anomalies. CONCLUSIONS: PAPVR is a rare congenital cardiac pathology which should be suspected in case of unexplained right chambers enlargement. CMR imaging allows an accurate anatomic and functional definition of this pathology and associated abnormalities. Early correction has an excellent prognosis and prevents long term complications like pulmonary hypertension, right ventricular failure and atrial fibrillation. PMID- 27237846 TI - Party time in Toronto. AB - Friday is PARTY day at Sunnybrook Health Science Centre (SHSC) and Lyndhurst Hospital, Toronto. This may create a confusing image of balloons and frivolity, but the reality is somewhat different. Although the ingredients for a party exist - young people, pizzas and sodas, this party means PARTY - prevent alcohol and risk related trauma in youth. PMID- 27237847 TI - Organ donation and transplantation. AB - Organ donation and transplantation are highly controversial and emotive areas of nursing ( 1 ). Nonetheless, sudden death is a continual issue in the A&E department, thus creating a potential source of donors for transplantation purposes ( 2 ). This article will consider what organs would be suitable for retrieval in A&E, what appears to be restricting this process, and means of improving the rate of retrieval. PMID- 27237848 TI - Hypothermia. PMID- 27237850 TI - Clinical supervision in nursing practice. AB - Clinical supervision is the latest buzzword to hit the nursing profession - its ultimate aim being to improve patient care. A dilemma exists, however, when interpreting the term in relation to the realities of nursing practice. PMID- 27237849 TI - Equipping the pre-hospital care team. AB - Of the 291 A&E departments in the United Kingdom, 121 (41.6 per cent) report to provide an A&E flying squad ( 1 ). A number of these teams have established a national reputation, while in other areas a flying squad is a purely hypothetical concept. Between these two extremes arc a number of teams with variable operational experience and suboptimal preparation for this role. PMID- 27237851 TI - Educational preparation: Research in A&E. AB - Just as there is an evergrowing number of educational opportunities for A&E (1), there is growing recognition of the importance of research in the development of the 'art and science' of nursing. In A&E nursing there is a need to develop the science of our specialty to further enhance the treatment and care of patients. This paper asks some fundamental questions about research and researchers in A&E and identifies key research priorities for the coming years. PMID- 27237853 TI - New this month. AB - Davidson's Principles and Practice of Medicine 17th edition CRW Edwards, IAD Bouchier, C Haslett, ER Chilvers, Editors Churchill Livingstone 1203pp ISBN 0-443 04961-0. PMID- 27237852 TI - Nursing the psychiatric emergency Martin F Ward Nursing the psychiatric emergency Butterworth-Heine-mann 212pp L12.99 0-7506-1592-3 0750615923. AB - Martin Ward, a highly respected mental health academic, has produced a beautifully written text which is crammed with sound, practical advice. PMID- 27237854 TI - Trauma nursing: The art and science Janet Neff Trauma nursing: The art and Science , Pamela Stinson Kidd (Editors) Mosby Year Book 808pp L45.00 0-8016-66554 0801666554. AB - Two famous American A&E authors and editors have combined to produce an excellent book which is founded on the philosophy that the best form of nursing is based on the blending of the art and science of our discipline. PMID- 27237855 TI - CD Rom. AB - A new CD-Rom has been launched by Guy's and St Thomas' Trust's poisonous unit to help health professionals discover which species have been involved in cases of plant poisoning. The unit says thousands of people are poisoned every year by eating or touching plants - the majority of those people affected being under the age of seven. The CD-Rom covers several thousand species of plant, and has been jointly researched with Kew Gardens. PMID- 27237856 TI - ABC of resuscitation ABC of resuscitation TR Evans MC Colquhon A Handley BMJ lOOpp L12.95 0-7279 0839-1 0727908391. AB - Extensively revised in line with the latest European Resuscitation Council's guidelines, the third edition of the ABC of Resuscitation is now available. PMID- 27237857 TI - Importance of eye disease in headache. AB - Patients who consult primary health care providers with headache accompanied by ocular symptoms should be referred to an ophthalmic casualty department. PMID- 27237858 TI - Protective gear in epistaxis treatment. AB - There is a high incidence of blood contamination during the treatment of epistaxis, particularly if nasal packing is required. To assess the risk of blood contamination during treatment, and to gauge patient's opinions on the use of protective clothing, 50 consecutive patients with epistaxis were studied. The staff treating them wore gloves, masks, face visors, hats and aprons. PMID- 27237860 TI - Editor's note. AB - 'Diary dates' and 'Information wanted' are free columns for those wishing to advertise their study day, seminar or conference, or seeking information on a subject related to A&E. Unfortunately, owing to the lengthy production process, these often arrive too late for inclusion in this column. If you wish to advertise your event, or seek the information you need, the details should arrive by the following dates. PMID- 27237859 TI - Stethoscopes: source of infection? AB - Stethoscopes used in A&E are often contaminated with staphylococci and therefore are a potential vector of infection, according to a recent American study. PMID- 27237861 TI - Information wanted. AB - I am a paediatric nurse in general A&E. I am trying to write a philosophy of care specifically to paediatrics in A&E and would appreciate any information from general and paediatric A&E departments, or copies of any philosophies being used in these areas. PMID- 27237862 TI - Waiting times. AB - Bent on measuring and publicising the success of its NHS reforms the Government has added the length of trolley waiting times to the Patient's Charter standards. PMID- 27237864 TI - Exposure to psychotropics in the French older population living with dementia: a nationwide population-based study. AB - BACKGROUND: Little is known about the level of psychotropic chronic exposure in all patients living with dementia. The aim of the study was to quantify chronic psychotropic exposure in older adults with dementia compared with the general population of the same age. METHODS: This prospective cohort study was conducted in France between 2009 and 2011. Aged at least 65 years, 10,781,812 individuals (440,215 of them with dementia) either community based or nursing home residents were included. The numbers of single or combined prescriptions, per year for antipsychotics, antidepressants, anxiolytics, or hypnotics were measured. RESULTS: Of patients with dementia, 15.5% are exposed to antipsychotics compared with 2.2% of the age-matched population (relative risk [RR] = 6.44, 95% confidence interval [CI] [6.39-6.48]), 39.5% to antidepressants compared with 12.6% (RR = 4.10, 95% CI [.4.07-4.12]), and 39.6% to anxiolytics or hypnotics compared with 26.9% (RR = 1.74, 95% CI [1.72-1.75]). Among older adults with dementia, 13.8% simultaneously consumed at least three psychotropics. All class age of older patients with dementia is more exposed to all psychotropics except for long-acting benzodiazepines. During the study period, chronic anxiolytic/hypnotic and antipsychotic exposure slightly decreased in population with dementia while chronic exposure to antidepressant drugs tended to increase. CONCLUSION: This nationwide, population-based, drug-used study showed for the first time that older patients with dementia are chronically overexposed not only to antipsychotics but also to psychotropics. PMID- 27237865 TI - Analysis of competition performance in dressage and show jumping of Dutch Warmblood horses. AB - Most Warmblood horse studbooks aim to improve the performance in dressage and show jumping. The Dutch Royal Warmblood Studbook (KWPN) includes the highest score achieved in competition by a horse to evaluate its genetic ability of performance. However, the records collected during competition are associated with some aspects that might affect the quality of the genetic evaluation based on these records. These aspects include the influence of rider, censoring and preselection of the data. The aim of this study was to quantify the impact of rider effect, censoring and preselection on the genetic analysis of competition data of dressage and show jumping of KWPN. Different models including rider effect were evaluated. To assess the impact of censoring, genetic parameters were estimated in data sets that differed in the degree of censoring. The effect of preselection on variance components was analysed by defining a binary trait (sport-status) depending on whether the horse has a competition record or not. This trait was included in a bivariate model with the competition trait and used all horses registered by KWPN since 1984. Results showed that performance in competition for dressage and show jumping is a heritable trait (h2 ~ 0.11-0.13) and that it is important to account for the effect of rider in the genetic analysis. Censoring had a small effect on the genetic parameter for highest performance achieved by the horse. A moderate heritability obtained for sport status indicates that preselection has a genetic basis, but the effect on genetic parameters was relatively small. PMID- 27237866 TI - Recent Advances in Transition-Metal-Free Oxygenation of Alkene C=C Double Bonds for Carbonyl Generation. AB - Carbonyl-forming reactions are a class of fundamental transformations in organic chemistry. Guided by the current importance of environmentally benign metal-free catalysis and synthesis, herein we review recent advances in carbonyl-generation reactions based on alkene C=C double oxygenation as well as related cascade reactions in the synthesis of diverse organic products. The content of this focus review consists of two important but different reaction models: oxygenation based on full C=C double-bond cleavage and oxygenation based on partial C=C double-bond cleavage. PMID- 27237867 TI - Accelerating the Development and Validation of New Value-Based Diagnostics by Leveraging Biobanks. AB - The challenges faced in developing value-based diagnostics has resulted in few of these tests reaching the clinic, leaving many treatment modalities without matching diagnostics to select patients for particular therapies. Many patients receive therapies from which they are unlikely to benefit, resulting in worse outcomes and wasted health care resources. The paucity of value-based diagnostics is a result of the scientific challenges in developing predictive markers, specifically: (1) complex biology, (2) a limited research infrastructure supporting diagnostic development, and (3) the lack of incentives for diagnostic developers to invest the necessary resources. Better access to biospecimens can address some of these challenges. Methodologies developed to evaluate biomarkers from biospecimens archived from patients enrolled in randomized clinical trials offer the greatest opportunity to develop and validate high-value molecular diagnostics. An alternative opportunity is to access high-quality biospecimens collected from large public and private longitudinal observational cohorts such as the UK Biobank, the US Million Veteran Program, the UK 100,000 Genomes Project, or the French E3N cohort. Value-based diagnostics can be developed to work in a range of samples including blood, serum, plasma, urine, and tumour tissue, and better access to these high-quality biospecimens with clinical data can facilitate biomarker research. PMID- 27237868 TI - Intralesional PV-10 for in-transit melanoma-A single-center experience. AB - BACKGROUND AND OBJECTIVES: Patients with in-transit melanoma metastasis have longer median survival than patients with distant metastatic disease. Furthermore, local disease control is an important endpoint for symptom management. The treatment of unresectable loco-regional recurrence or in-transit disease has been historically managed with a combination of treatments including surgery, radiotherapy, isolated limb infusion or perfusion as well as systemic therapies. Intralesional PV-10 has been used at Peter MacCallum Cancer Centre since 2010, and the current report presents a retrospective analysis of patient outcomes, reporting the response rates, durability of responses, and observed toxicities. METHODS: Records were analyzed retrieving details of 19 patients treated with PV-10 over a 4-year period from 2010 to 2014. Medical records were reviewed for these patients and data extracted. RESULTS: Nineteen patients with in-transit melanoma were treated with intralesional PV-10 between 2010 and 2014. Disease control (complete or partial response or disease stability) was achieved in 68% of patients with 26% having a complete response. This was achieved with minimal associated toxicity. CONCLUSIONS: PV-10 is an effective, durable, well tolerated treatment tool with an acceptable side effect profile for the management of unresectable in-transit melanoma. J. Surg. Oncol. 2016;114:380-384. (c) 2016 Wiley Periodicals, Inc. PMID- 27237869 TI - Polyvalent Catalysts Operating on Polyvalent Substrates: A Model for Surface Controlled Reactivity. AB - Unusually fast rates of nucleophilic catalysis of hydrazone ligation were observed when polyvalent anthranilic acid catalysts operating on polyvalent aldehyde substrates were used with PAMAM dendrimers as the common platform. When presented in this way, the catalyst has a strong accelerating effect at concentrations 40-400 times lower than those required for similar monovalent catalysts and displays unique kinetic parameters. We attribute these properties to polyvalent engagement between the dendrimer surface groups, and a potential "rolling" effect leading to fast interparticle kinetic turnover. The phenomenon is sensitive to the density of functional groups on each dendrimer, and insensitive to factors that promote or inhibit nonspecific particle aggregation. These findings constitute a rare experimental example of an underappreciated phenomenon in biological and chemical systems that are organized on interacting surfaces. PMID- 27237871 TI - What did you do at work today? AB - It's difficult to imagine that any nurse could face the dole queue in the current staffing crisis. The Department of Health launches the next phase of its costly nurse recruitment campaign this week and has ploughed L100,000 into a major 'Return to nursing' initiative announced at the RCN last week. PMID- 27237872 TI - Call for action on training chaos. AB - The United Kingdom Central Council for Nursing, Midwifery and Health Visiting (UKCC) is looking for a speedy decision and a firm commitment from Health Secretary, Kenneth Clarke, on the end of enrolled nurse training. PMID- 27237870 TI - Parental Infertility, Fertility Treatment, and Childhood Epilepsy: A Population Based Cohort Study. AB - BACKGROUND: A few studies have indicated an increased risk of epilepsy in children conceived by fertility treatment possibly due to characteristics of the infertile couple rather than the treatment. We therefore aimed to investigate the association between parental infertility, fertility treatment, and epilepsy in the offspring, including the subtypes of epilepsy; idiopathic generalised epilepsy and focal epilepsy. METHODS: This cohort included all pregnancies resulting in liveborn singletons from the Aarhus Birth Cohort, Denmark (1995 2013). Information on time to pregnancy and fertility treatment was obtained from pregnancy questionnaires in early pregnancy. Children developing epilepsy were identified from the Danish National Patient Register and the Danish National Prescription Registry until 2013. Data were analysed using Cox proportional hazards regression adjusted for potential confounders. RESULTS: A total of 60 440 pregnancies were included, and 0.8% of the children developed epilepsy.The primary analyses showed no association between parental infertility or fertility treatment, and the overall risk of childhood epilepsy (hazard rate ratios (HRs); 95% confidence intervals (CIs): 1.08 (0.73, 1.60) and 1.04 (0.71, 1.52)). In secondary analyses, both parental infertility and fertility treatment were associated with an increased risk of idiopathic generalised epilepsy (HRs and 95% CIs: 2.25 (1.10, 4.58) and 2.45 (1.26, 4.75)). No association was seen for focal epilepsy. CONCLUSION: Parental infertility or fertility treatment was not associated with an overall risk of childhood epilepsy. Parental infertility may be associated with an increased risk of idiopathic generalised epilepsy; a subtype of epilepsy believed to be of genetic origin. PMID- 27237874 TI - Paradox of recruitment and the dole. AB - More than 100 Glasgow nursing students are facing a future on the dole at the same time as the Government is sponsoring two national campaigns to attract more staff. PMID- 27237873 TI - College denies boycott threat. AB - Baroness Caroline Cox, a trained nurse, is to chair a major conference on AIDS organised by the RCN and the BMA, despite criticism reported in a London- based gay publication. Citing Baroness Cox as a supporter of Section 28, the newspaper Capital Gay alleged that RCN members were threatening to boycott the event in Cardiff in April unless she 'withdrew immediately'. PMID- 27237875 TI - Concerns mount for patient care. AB - The Royal College of Nursing has expressed its grave concern tor patient care as a result of the long-running ambulance dispute. PMID- 27237876 TI - Row at Guy's leads to freezing of appeals. AB - The Royal College of Nursing (RCN) demanded last week that sisters and charge nurses working with resource management be given senior nurses' salaries, after a hospital attempted to up a resource management initiative (RMI) nurse's clinical grade. PMID- 27237877 TI - Nursing organisation lays blame for problems firmly on the Government. AB - The Irish Nurses Organisation (INO) has protested strongly at Hire's burgeoning health service crisis, which was last week threatening the Government's survival. PMID- 27237878 TI - RCN initiates attack on racism. AB - A new initiative to tackle black and ethnic minority issues has been established by the Royal College of Nursing. PMID- 27237879 TI - TV focus for 'Return to nursing'. AB - A major 'back to nursing' campaign, involving national television and open learning education, was launched at the Royal College of Nursing last week. PMID- 27237881 TI - [Not Available]. AB - The Victorian conservatory at Whittlingham Geriatric Hospital in Norfolk has been restored to its former glory , two years after its windows were damaged by hurricane winds. PMID- 27237882 TI - Closure threat to unique psychotherapy hospital. AB - An internationally renowned hospital, in which nurses treat psychologically disturbed individuals and families with a history of child abuse without drugs, is being threatened w'ith closure. PMID- 27237883 TI - Rosy figures 'paint a false picture'. AB - Last week's rosy Government figures showing increased patient treatments have been obtained at the high cost of nurses' stress, the RCN has warned. PMID- 27237885 TI - Kidnap could shake confidence in HVs. AB - The abduction of baby Alexandra Griffiths by a woman posing as a health visitor could have happened anywhere, a midwife at St Thomas' Hospital warned last week. PMID- 27237886 TI - Nurse awarded education honour. AB - Margaret Green, Royal College of Nursing Director of Education, was last week awarded the honour of Visiting Professor at the Polytechnic of Central London. PMID- 27237884 TI - Pioneering psychiatric unit opens. AB - What is believed to be the first psychiatric nursing research unit has been established at the University of Wales College of Medicine. PMID- 27237888 TI - Screening over 65s could cut death rate. AB - The introduction of cervical cancer screening programmes for women over the age of 65 would significantly cut the number of deaths from the disease, a study in The Lancet shows. PMID- 27237887 TI - RCN warns Clarke about standards. AB - Health Secretary, Kenneth Clarke, was guest of honour at the Royal College of Nursing's Annual Dinner last week. PMID- 27237889 TI - Breakthrough could ease life for diabetics. AB - People with diabetes could benefit from new methods of administering drugs, according to researchers in California. PMID- 27237891 TI - Head lice remedies losing potency. AB - Some of the remedies available for treating head lice are not as effective since they lost their powerful smell, it was claimed last week. PMID- 27237890 TI - Last quarter decline in AIDS cases for '89. AB - Latest AIDS figures from the Department of Health (DoH) for the last quarter of 1989 reveal a drop in the number of cases reported compared to the previous quarter. PMID- 27237892 TI - New contraceptive for women by 1991. AB - A new type of contraceptive, the intra- vaginal ring, could be launched in Britain by the end of the year, the World Health Organization has announced. PMID- 27237893 TI - Study to trace Noonan's gene underway in UK. AB - What has been described as the largest ever research project aimed at tracing the gene believed to cause Noonan's Syndrome is underway in Britain. PMID- 27237894 TI - Earlier treatment needed for asthmatics. AB - Asthmatics could be suffering permananent lung damage through practice teams' failure to prescribe anti-inflammatory drugs early, a new campaign claimed last week. PMID- 27237895 TI - Aid for heavy, single handed lifting. AB - A lifting aid which the manufacturers claim allows patients to be raised single handed from a sitting position, has been produced by Medical and Surgical Supply Limited. The Somerquip Patient Lifting Aid can be used for moving immobilised or heavy patients to a standing or sitting position. PMID- 27237896 TI - Equipment washer. AB - A new' design washing machine which washes, dries and disinfects medical equipment in one go has been produced by Draeger Medical Limited. PMID- 27237899 TI - Parliament. AB - Welsh community nurses are to play a leading part in the Principality's latest campaign to reduce the levels of cancer, coronary heart disease and other major ailments. PMID- 27237900 TI - [Not Available]. AB - Operation Raleighis calling for volunteer nurses to join sight saving expeditions to the Northern Territories of Australia, Southern Chile, Zimbabwe and Botswana next year. PMID- 27237898 TI - World news. AB - Public health officials in Norwaybelieve that a frank information campaign and an effective testing programme are responsible for the fall in the number of people becoming infected with HIV. PMID- 27237901 TI - Vaccinating against cholera. AB - Vaccination against cholera is being over-prescribed and may lead to a false sense of security. PMID- 27237902 TI - Psychological response in breast cancer. AB - The psychological response of women to breast cancer may affect disease outcome, London researchers report. PMID- 27237903 TI - Fatal pulmonary embolism rate. AB - There may be a seasonal variation in the rate of fatal pulmonary embolism following elective hip surgery. PMID- 27237904 TI - Predicting disease severity in pancreatitis. AB - A reliable assay which gives an early prediction of disease severity in acute pancreatitis has been tested by London and Glasgow researchers. PMID- 27237905 TI - Preventing postoperative sepsis. AB - Single doses of cefotaxime and metronidazole are as efficacious as a more extensive regimen in preventing wound infection following colorectal surgery. PMID- 27237906 TI - Battling for peace. AB - 'Tell him he can't leave,' the head nurse urged the interpreter. 'His leg is still bad. '. PMID- 27237907 TI - Listings. AB - Nursing Standard's listings section is a completely free service for its readers. To ensure maximum publicity for any event connected with your profession, be sure to let us know so that it can be included in our exhaustive nationwide guide to what's on in nursing. PMID- 27237908 TI - Speaking up for the animals. AB - The recent campaign by Nursing Standard to encourage nurses to 'go green' was informative and effective. However, one issue was notable by its absence, the one of vivisection. PMID- 27237909 TI - The power of the people. AB - David Harding-Price Has the time not now come for all of us to follow the lead of the Eastern Europeans who, through people power, have gone a long way down the road of Liberal Democracy in a very short time? PMID- 27237910 TI - Legal contracts. AB - I refer to Joe Sheridan's article (Nursing Standard December 20 - January 2) in which he considers the legal capacity of probably the most common form of contract, namely employment. PMID- 27237911 TI - Cautionary tale. AB - I read with interest Saraswathi Vaidyanathan's article Rheumatoid arthritis: educating the patient in India' (Nursing Standard December 13-19), when she illustrated some very sound principles in establishing health education and teaching programme for sufferers of this disease. PMID- 27237913 TI - Fiction file. PMID- 27237912 TI - Sharing experience. AB - Nurses evolve their own ways of meeting the needs of individual patients within the framework of sound nursing practice. PMID- 27237914 TI - Nursing memories. AB - The restoration of the apparently drowned c.1888. The person is pressed downwards over the clothes (rolled in a bundle) and placed on the stomach. This is done to expel any water that may have entered the lungs. PMID- 27237915 TI - Nursing a sexist problem. AB - In reply to Elizabeth Sharp (Nursing Standard January 10-16), I would point out that in suggesting that two minority groups - men and childless women - dominate nursing, I am only paraphrasing Trevor Clay's interpretation of the feminist view, set out in 'Nurses, power and politics' which 'would be that decision making in the National Health Service is largely carried out by those who do not have domestic commitments (the unmarried) or by those whose domestic commitments are undertaken by others (men).' PMID- 27237916 TI - The Nightingale School Computer Assisted Learning Project S E Norman E J Chapman and T Hinton Ashdale 48pp L6.00 1-870899-02-4. AB - At first glance, I thought that at L6 this booklet was overpriced. On closer examination, I found it well-produced, with much of interest to anyone considering developing a computer assisted learning (CAL) package, a clear and readable style, avoids gratuitous jargon, and graphs and statistics are appropriately used. PMID- 27237917 TI - Alcohol Education B Howe Tavistock I77pp L9.95 0-415-01891-9. AB - Alcohol education is a neglected area of concern according to both Diane Haytor and Barbara Howe. PMID- 27237918 TI - Essentials of Rheumatology, 2nd edition H L F Currey Churchill Livingstone 196pp L7.95 0-443-03913-5. AB - The second edition of this popular rheumatology textbook is not just an update on new treatments for those suffering from arthritis and other forms of joint disease. It is expanded, has more illustrations and useful reference lists. For those not familiar w'ith the first edition, Essentials of Rheumatology is a medical pocketbook written for medical students using the traditional medical model. PMID- 27237919 TI - Project 2000: policy and possibilities. AB - The last year of this past decade saw an unprecedented interest in mental handicap nursing and its undoubted progress. It should now be clearer than ever that those who desire change by utilising professional education and training methods have taken a lead. Strategic plans should now reinforce their efforts. PMID- 27237920 TI - The Microbe file. PMID- 27237921 TI - Headache Prevalence at 4-11 Years After Deployment-Related Traumatic Brain Injury in Veterans of Iraq and Afghanistan Wars and Comparison to Controls: A Matched Case-Controlled Study. AB - OBJECTIVE: Evaluate the extent and severity of headache following deployment related TBI (D-TBI) in veterans of the Iraq (OIF) and Afghanistan (OEF) wars over a follow-up period of 4-11 years with comparison to age, sex, race, and time of deployment matched controls. BACKGROUND: TBI has been recognized as the "signature Injury" of the OEF/OIF campaigns occurring in 14-20% of deployed soldiers. Currently, there are very few data on the longer term follow-up of soldiers with D-TBI. This study deals with prevalence and severity of headache and headache burden at 4-11 years following D-TBI for OEF/OIF veterans with comparison to controls without D-TBI. METHODS: This is a matched case controlled study. All subjects were recruited from Operation New Dawn (OND), a voluntary program for OEF/OIF Veterans at the Oklahoma VAMC designed to assist with re integrating into civilian life. On entry into OND a medical questionnaire was administered that included a brief screen for D-TBI, and those with a possible D TBI were referred to a TBI clinic, For this study, the first 500 TBI clinic patients who were found to have had a D-TBI (TBIS) were matched by age, sex, race, and time of deployment to control subjects (CS), drawn from the 4411 OND program members with no D-TBI, creating a pool of 500 TBIS/CS pairs. From this pool, 55 pairs (11%) were randomly selected for this study. Data were collected from both TBIS and CS by telephone interview with questionnaires regarding the DTBI, headache, depression, and PTSD. TBI severity was measured by duration of loss of consciousness (LOC) as: [a] Very Mild (VMTBI, dazed only, no LOC), [b] Mild (MTBI, LOC 1-30 minutes), and [c] Moderate-Severe (MSTBI, LOC > 30 minutes). Intensity for individual headaches was measured by disability produced by the headache as: [a] Disabling (must be in bed), [b] Severe (50-90% decrease in activity), or [c] Mild-Moderate (>50% of usual activity possible). Statistical analysis employed Fisher's exact test and odds ratio. RESULTS: The 55 TBIS/CS pairs were segregated by severity of TBI for the TBIS. For the TBIS there were no significant differences among these three subgroups as to mechanism producing the TBI (blast injury or direct head trauma). Comparing TBIS vs CS for phenotypic classification of headaches, for TBIS - 89% had migraine, 2% probable migraine, 9% had tension, and 0% had no headaches, while for CS - 36% had migraine, 15% probable migraine, 27% tension, and 22% no headache (P < .0001). Migraine with aura occurred in 38% of TBIS and 6% of CS (P < .0001). As to headache frequency, for TBIS - chronic daily headache (CDH) occurred in 44%, frequent headache in 33%, and infrequent or no headache in 23%, while for CS - CDH occurred in 7%, frequent headache in 13%, and infrequent or no headache in 80% (P < .0001). For TBIS, 54% had severe or disabling headache >=2 days/week as opposed to only 16% of CS (OR 6.13 [2.5-14.9]). As to onset of most severe and frequent headaches, this occurred shortly after TBI in 89% of TBIS while only 27% of CS reported most severe headaches starting during deployment. There was no correlation of severity of headache problem with severity of TBI. Comparing TBIS at 4-7 vs 8-11 years after injury, there was no difference in frequency or severity of headache between these groups. CONCLUSIONS: At 4-11 years after D-TBI for TBIS, or after deployment for CS, the TBIS as compared to CS suffered much more frequent and severe headaches. For TBIS, there was no relation of headache intensity or phenotype to severity or cause of the TBI, and the Headache Burden has not improved over time up to 11 years after D-TBI. The process initiated by the D-TBI that relates to the headache has a prolonged effect up to and beyond 11 years. PMID- 27237922 TI - Dermoscopy of nail fold and elbow in the differential diagnosis of early psoriatic arthritis sine psoriasis and early rheumatoid arthritis. AB - Differentiation between psoriatic arthritis (PsA) sine psoriasis and rheumatoid arthritis (RA) may be a challenge, especially in the early stages, hence the need for new instrumental markers to assist their diagnosis. In this study, we investigated possible dermoscopic differences in vascular appearance of nail fold and elbow (a classic site of repeated trauma) in these two conditions. Fifteen patients with PsA sine psoriasis, 12 patients with RA and 12 controls were included in the study. Regarding the nail fold vascular appearance in PsA sine psoriasis and RA cohorts, the presence of diffuse reddish background with or without sparse dotted vessels was significant in the former, whereas the evidence of parallel dotted/short linear vessels ("fish school-like" pattern) or irregular/ramified, blurry, purple vessels were significant in the latter; none of these patterns were detected in the control group. Regarding the elbow, the pattern significantly associated with PsA sine psoriasis consisted of diffusely distributed, red, dotted vessels. On the other hand, RA patients and controls displayed similar dermoscopic findings, with three possible vascular patterns being observed: (i) irregular, blurry, purple vessels; (ii) avascular appearance; and (iii) sparse, dotted, purple vessels. In conclusion, dermoscopy may be a useful supportive tool for differentiating early PsA sine psoriasis from RA. PMID- 27237924 TI - [Nekrotiserende bloddelsinfektion]. PMID- 27237923 TI - Reference ranges for serum periostin in a population without asthma or chronic obstructive pulmonary disease. AB - BACKGROUND: The clinical utility of serum periostin as a type 2 biomarker in asthma is limited by lack of reference range values derived from a population without respiratory disease. OBJECTIVE: To derive age- and sex-related reference intervals for serum periostin from an adult population without asthma or COPD. METHODS: Serum periostin levels were measured in 480 individuals, comprising 60 female and 60 male adults in each of the 18- to 30-year, 31- to 45-year, 46- to 60-year and 61- to 75-year age groups. Key exclusion criteria included a doctor's diagnosis of asthma, chronic bronchitis or COPD, and a history of wheezing or use of respiratory inhalers in the last 12 months. The distribution of periostin and logarithm-transformed periostin levels was derived, and 90% confidence intervals for an individual prediction were calculated. RESULTS: The distribution of serum periostin was right skewed with a mean (SD) periostin of 51.2 (11.9) ng/mL, median (IQR) 50.1 (43.1 to 56.9) ng/mL and range 28.1 to 136.4 ng/mL. There was no association between logarithm periostin and age or sex, although levels were low in current smokers. The 90% confidence limits for periostin were 35.0 and 71.1 ng/mL. CONCLUSIONS AND CLINICAL RELEVANCE: Serum periostin levels in adults without asthma or COPD are similar to those in adults with asthma. Serum periostin measurements do not need to be adjusted to take account of a patient's age or sex, although levels are lower in current smokers. Reference values for serum periostin levels in adults without asthma or COPD are provided. PMID- 27237925 TI - [Treatment of peritoneal carcinomatosis with pressurized intraperitoneal aerosol chemotherapy]. AB - Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new treatment option in patients with peritoneal carcinomatosis (PC). PIPAC has proven efficacious in the treatment of PC from ovarian, colon and gastric cancer. PIPAC has a favourable profile regarding safety for patients and occupational health aspects. This study reviews the current evidence of PIPAC as a step towards implementation and evaluation in Denmark. PMID- 27237926 TI - [Two cases of takotsubo cardiomyopathy in patients treated with high doses of inhaled beta-2-agonists]. AB - Takotsubo cardiomyopathy (TCM) is characterised by reversible left ventricular dysfunction in patients presenting with acute coronary syndrome (ACS). TCM is considered multifactorial, and the repetitive exposure to inhaled beta-2-agonists has been suspected to induce TCM in predisposed individuals. We report two cases of TCM in female patients presenting with ACS both exposed to inhaled beta-2 agonists. Eccocardiography revealed apical ballooning and reduced left ventricular function. Coronary angiography was with no significant stenosis. Both patients recovered by anticongestive treatment. PMID- 27237927 TI - [Ectopic tooth as a rare cause of foreign body reaction of the nose]. AB - This is a case report of a 71-year-old male with three months of gradually increasing irritation, secretion and right-sided nasal stenosis. The patient had not experienced any facial trauma nor had he had any previous surgical intervention to the nasal or oral cavity. An examination of the nasal cavity raised the suspicion of a foreign body in the right nasal floor. A computed tomography was performed and a high-density, foreign body was identified. The patient was referred to the local department of otorhinolaryngology, where an ectopic tooth was successfully removed in local anaesthesia. PMID- 27237928 TI - Group-Based Compassion-Focused Therapy as an Adjunct to Outpatient Treatment for Eating Disorders: A Pilot Randomized Controlled Trial. AB - The current study sought to assess the acceptability and feasibility of a compassion-focused therapy (CFT) group as an adjunct to evidence-based outpatient treatment for eating disorders, and to examine its preliminary efficacy relative to treatment as usual (TAU). Twenty-two outpatients with various types of eating disorders were randomly assigned to 12 weeks of TAU (n = 11) or TAU plus weekly CFT groups adapted for an eating disorder population (CFT + TAU; n = 11). Participants in both conditions completed measures of self-compassion, fears of compassion, shame and eating disorder pathology at baseline, week 4, week 8 and week 12. Additionally, participants receiving the CFT group completed measures assessing acceptability and feasibility of the group. Results indicated that the CFT group demonstrated strong acceptability; attendance was high and the group retained over 80% of participants. Participants rated the group positively and indicated they would be very likely to recommend it to peers with similar symptoms. Intention-to-treat analyses revealed that compared to the TAU condition, the CFT + TAU condition yielded greater improvements in self compassion, fears of self-compassion, fears of receiving compassion, shame and eating disorder pathology over the 12 weeks. Results suggest that group-based CFT, offered in conjunction with evidence-based outpatient TAU for eating disorders, may be an acceptable, feasible and efficacious intervention. Furthermore, eating disorder patients appear to see benefit in, and observe gains from, working on the CFT goals of overcoming fears of compassion, developing more self-compassion and accessing more compassion from others. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27237930 TI - Lining prefabricated dowel(s) with fibre reinforced resin composite. AB - The study evaluated the adaptation and push-out bond force of two different lined fibre dowels in oval canals. Dowel spaces were prepared in 30 obturated mandibular premolars with oval roots. The samples were divided into three groups (n = 10). The first group received non-lined fibre dowels (NL). The fibre dowels in the second group were lined with a resin composite (PL). The fibre dowels in third group were lined with resin composite reinforced with polyethylene fibre ribbon (PFL). The proportion of surface area (PSA) occupied by the dowel and push out bond force were analysed. The data were statistically analysed using two-way anova with post-hoc Holm-Sidak and Tukey tests. The PSA was higher in lined dowels. Highest push-out bond forces were recorded in PFL. Fibre reinforced composite lining improves the adaptation and push-out bond force of fibre dowel in oval canals. PMID- 27237929 TI - Determination of total urinary 2,5-hexanedione in the Chinese general population. AB - OBJECTIVE: Determination of the urinary levels of 2.5-hexanedione (2,5-HD) was performed in subjects belonging to the Chinese general population to define the reference value for this metabolite. METHODS: Urine samples were collected from 8235 individuals (4216 men and 4019 women) from the healthy general population who had not been occupationally exposed to n-hexane or methyl-n-butyl ketone. The determination was performed by a gas chromatography mass spectrometry method using an ion-trap mass spectrometer. RESULTS: The result showed that the urinary 2,5-HD median level was 0.159mg/L for the total samples. Males had statistically significant higher excretion of 2,5-HD in urine than females (median 0.171mg/L compared to 0.147mg/L, Z=-8.21, P<0.001). There was a statistically significant difference in urinary 2,5-HD levels among age groups. The excretion of 2,5-HD in urine was related to increasing age (r=-0.160, P<0.05). There was statistically significant difference in urinary 2,5-HD levels among people from difference provinces. The results showed that there was also a statistically significant effect in urinary 2,5-HD levels between current smokers and non-smokers. CONCLUSION: Finding a measurable amount of 2,5-HD in urine does not mean that the level of 2,5-HD causes an adverse health effect. Biomonitoring studies on levels of urinary 2,5-HD can provide physicians and public health officials with reference values so that they can determine whether people have been exposed to higher levels of 2,5-HD than are found in the Chinese general population. These data can also provide a foundation for scientists to make a plan for further study. PMID- 27237931 TI - An Updated Meta-Analysis of the Efficacy and Safety of Acupuncture Treatment for Vascular Cognitive Impairment Without Dementia. AB - Vascular cognitive impairment with no dementia (VCIND) refers to a transitional state and will progress to dementia. Currently, effective medicines to control VCIND are surprisingly scarce. Acupuncture intervention is frequently advocated as an adjunct treatment for VCIND in recent studies. So the aim of this meta analysis was to assess the clinical efficacy and safety of acupuncture for VCIND. The literature search was conducted in English and Chinese databases from inception until July 2015, and 15 study populations were included in the meta analysis. Mean differences with their 95% confidence interval for continuous data were calculated with fixed effect model or random effect model using Rev Man 5.3 software. This review included 1148 subjects. The methodological qualities of the included studies were judged to be generally poor because plenty of trials had high or unclear risk of bias. The results of meta-analysis showed that acupuncture therapy was more effective in treating VCIND when compared with conventional therapy or pharmacological treatment. Two trials showed minor adverse events and two other trails mentioned no adverse events had existed. Current evidences cautiously suggest that acupuncture therapy can improve the clinical efficacy for VCIND. More rigorously designed studies are needed to further confirm effectiveness and safety of acupuncture therapy in patients with VCIND. PMID- 27237932 TI - Family presence during management of acute deterioration: Clinician attitudes, beliefs and perceptions of current practices. AB - BACKGROUND: The nature of acute clinical deterioration has changed over the last three decades with a decrease in in-hospital cardiac arrests and an increase in acute clinical deterioration. Despite this change, research related to family presence continues to focus on care during resuscitation rather than during acute deterioration. AIM: To explore healthcare clinician attitudes, beliefs and perceptions of current practices surrounding family presence during episodes of acute deterioration in adult Emergency Department patients. METHODS: Clinicians (n=156) from a single study site in Melbourne, Australia completed a 17-item survey. RESULTS: Participants disagreed that family members would interrupt (59.0%) or interfere (61.5%) with patient care if present during episodes of patient deterioration. Most (77.6%) participants stated that they included family during episodes of patient deterioration. Females, nurses and Australians/New Zealanders had a more positive attitude towards including family during episodes of patient deterioration when compared to males, doctors and clinicians of other ethnicities. Nurses with post-graduate qualifications and those with more years of experience had a more positive attitude towards including family during episodes of patient deterioration than nurses without post-graduation qualification and with less years of experience. CONCLUSIONS: Clinicians had predominantly positive attitudes towards including family during episodes of patient deterioration and perceived it to be a common day-to-day practice. Gender, profession, country of birth, education level and years of experience all impacted on clinician attitudes, beliefs and perceptions of family presence during acute deterioration. PMID- 27237933 TI - Blood levels of vitamin D and health-functional status in asymptomatic individuals: a cross sectional study. AB - BACKGROUND: Recently issued guidelines do not recommend screening for vitamin D deficiency in asymptomatic adults. The large range of health effects that have been associated with vitamin D deficiency raises the possibility that vitamin D levels may be a marker of poor health status rather than a cause of it. We investigated an association between vitamin D level and health-functional status. METHODS: This cross-sectional study comprised 205 individuals who had taken a first plasma vitamin D test and were not symptomatic for vitamin D deficiency. During an interview, participants responded to questions regarding demographic information and their exposure to the sun, as well as a health-functional status questionnaire - World Organization of Family Doctors/COOP charts. Correlations between study variables and vitamin D levels were calculated. A stepwise linear regression was performed to estimate variables that independently predict vitamin D levels. RESULTS: The participants were 51 men and 154 women, mean age 41 years. Vitamin D level was positively correlated with weekend sun exposure and negatively correlated with body mass index (BMI). A reported positive change in health over the previous 2 weeks correlated with a higher vitamin D level. Individuals with higher vitamin D levels were more likely to report participation in physical activity and to report capability of performing daily activities. A total of 176 (86%) of the study population was deficient in vitamin D, according to a level <30 ng mL-1 . Vitamin D deficiency was associated with older age, higher BMI, Arab compared with Jewish ethnicity (darker skin), and religious identification (more body covering). In the multivariate analysis older age, female gender, religious identification, Arab ethnicity, higher BMI, sunscreen use and low exposure to sun during the weekdays all associated with lower vitamin D levels. CONCLUSION: No parameter of functional health demonstrated capability of distinguishing vitamin D deficiency among healthy young to middle-aged adults. PMID- 27237934 TI - Experimentally evolved and phenotypically plastic responses to enforced monogamy in a hermaphroditic flatworm. AB - Sexual selection is considered a potent evolutionary force in all sexually reproducing organisms, but direct tests in terms of experimental evolution of sexual traits are still lacking for simultaneously hermaphroditic animals. Here, we tested how evolution under enforced monogamy affected a suite of reproductive traits (including testis area, sex allocation, genital morphology, sperm morphology and mating behaviour) in the outcrossing hermaphroditic flatworm Macrostomum lignano, using an assay that also allowed the assessment of phenotypically plastic responses to group size. The experiment comprised 32 independent selection lines that evolved under either monogamy or polygamy for 20 generations. While we did not observe an evolutionary shift in sex allocation, we detected effects of the selection regime for two male morphological traits. Specifically, worms evolving under enforced monogamy had a distinct shape of the male copulatory organ and produced sperm with shorter appendages. Many traits that did not evolve under enforced monogamy showed phenotypic plasticity in response to group size. Notably, individuals that grew up in larger groups had a more male-biased sex allocation and produced slightly longer sperm than individuals raised in pairs. We conclude that, in this flatworm, enforced monogamy induced moderate evolutionary but substantial phenotypically plastic responses. PMID- 27237935 TI - Anatomic Oblong Double Bundle Anterior Cruciate Ligament Reconstruction. AB - Double-bundle anterior cruciate ligament (ACL) reconstruction using hamstring tendon grafts is a standard procedure for ACL injury. However, its clinical effectiveness is not always satisfactory. One cause of this was problems with the graft-tunnel healing of the posterolateral bundle (PLB) on the femur. To solve this problem, we devised a new anatomic ACL reconstruction technique to improve the graft-tunnel healing of the femoral PLB by using a single-bundle with one bone tunnel on the femoral side and a double-bundle on the tibial side. We have performed 40 procedures with excellent results and no cases of intra- or postoperative complication. This procedure can help improve the graft-tunnel healing around the femoral bone tunnel aperture for the PLB. PMID- 27237936 TI - A New Training for Older Adults Using Combined Neuromuscular Electrical Stimulation and Volitional Contraction: A Pilot Study. AB - The hybrid training system (HTS) resists the motion of a volitionally contracting agonist muscle using force generated by its electrically stimulated antagonist. We have developed a new training method using the principle of HTS. This study was designed to evaluate the effect of HTS with electrical stimulation on muscle strength and physical function by comparing it against training without electrical stimulation in older adults. 16 subjects were randomly divided into two groups: the squat and single leg lift training (control, CTR) group, and the CTR with HTS training group. Some electrical stimulation was applied to the quadriceps and hamstring muscles in the HTS group. The subjects performed training for 25 min per session 3 times a week for 12 weeks. At points before and after the research maximal isokinetic torque, knee-flexors (KFT) and knee extensors (KET), a one-leg standing test (OLT), a functional reach test (FRT), a 10-meter maximal gait time (10MGT) and Timed up & go test (TUG) were conducted. None of the subjects had any injuries during the study period. TUG significantly improved after the training period in both the HTS group (7.15 sec to 6.01 sec P = 0.01) and in the CTR. PMID- 27237937 TI - Interaction between Macrophages and Fibroblasts during Wound Healing of Burn Injuries in Rats. AB - Analysis of the structural changes and cell-to-cell interactions occurring during wound healing of burn injuries is essential to elucidate the morphological characteristics of the reconstitution of tissue architecture. However, conventional approaches do not provide sufficient information with respect to cell-to-cell interactions during wound healing. The aim of this study was to evaluate the interaction between bone marrow-derived cells and resident stromal cells throughout the wound healing of burn injuries, using immunohistochemistry and focused ion beam/scanning electron microscope tomography. We induced third degree burn injuries on the backs of Wistar rats with a heated cylindrical aluminum block (2.0 cm in diameter). At 7 and 14 days after the burn injuries, the burned skin was immunostained with anti-Iba1 and anti-HSP47 antibodies for visualization of bone marrow-derived cells/macrophages and resident stromal cells/fibroblasts, respectively. Normal skin tissue was used as a control. Double staining immunohistochemistry revealed frequent contacts between macrophages and fibroblasts and a higher contact ratio in the 3 normal skin compared with burned skin, particularly in the areas of granuloma. Three-dimensional ultrastructural analysis with focused ion beam/scanning electron microscope tomography revealed that macrophages and fibroblasts were located closer together in the normal skin than in the burned skin, confirming the analysis by light microscopic observations and ultrastructural analysis from single sections. These results highlight the importance of contact between macrophages and fibroblasts in the maintenance of skin tissue structure and during wound healing. PMID- 27237939 TI - Relation of the Timing of Onset of Rhinitis and Cough to Asthma Attack in Children. AB - If the risk of progression to asthma could be predicted in patients with rhinitis, prevention of asthma might become possible. The purpose of this study was to clarify the relationship between the duration of rhinitis symptoms and acute asthma attacks in children with a history of asthma who were not on treatment for asthma. In 94 children with a history of asthma who were asymptomatic after completing asthma treatment, we investigated the onset and duration of nasal discharge and cough related to allergic rhinitis. Then the children were followed up for 2 weeks and were classified into either an asthma attack group (Group A) or non-asthma group(Group B). A total of 78 subjects were evaluated after 16 were excluded. The duration of nasal discharge was significantly shorter in Group A than in Group B (5.5+/-1.9 days vs. 10.4+/-3.1 days, P<0.0001). The interval between the onset of cough and nasal discharge was 1.0+/-3.1 days in Group A and -5.7+/-4.1 days in Group B (P<0.0001). The risk of progression to asthma attack may be higher when the onset of cough precedes nasal discharge or when nasal discharge has a short duration and cough shows an early onset. These results may provide assistance when selecting patients for early anti-allergy therapy from among those presenting with upper respiratory tract symptoms. PMID- 27237938 TI - Predictors of Abnormal Glucose Tolerance in the Early Postpartum Period in Patients with Gestational Diabetes. AB - This study was designed to investigate the clinical predictors of abnormal glucose tolerance 5-7 weeks after delivery. Subjects were 155 women diagnosed with gestational diabetes mellitus (GDM) between October 2005 and September 2013 whose pregnancy and delivery were managed at our center. Subjects were divided into a normal glucose tolerance group (NGT; n = 113), or abnormal glucose tolerance group (AGT; n = 42) with borderline or overt diabetes mellitus, based on 75-g oral glucose tolerance test (75 gOGTT) results 5-7 weeks after delivery. We extracted profiles by which abnormal glucose tolerance levels 5-7 weeks after delivery were predicted using a classification and regression tree (CART) from parameters measured at the time of GDM diagnosis. Logistic regression analysis was used to determine prediction accuracy. Subjects with fasting plasma glucose (FPG) >=92 mg/dL and immuno-reactive insulin level <100 MUU/mL 60 min after load (IRI60min) at time of diagnosis showed a significantly higher risk of developing abnormal glucose tolerance 5-7 weeks after delivery than subjects with FPG <92 mg/dL (p < 0.0001). Subjects with FPG >=92 mg/dL and IRI60min >= 100 MUU/mL had the same risk as those with FPG of <92 mg/dL. Patients with gestational diabetes who met the criteria specified above at diagnosis were at a higher risk of developing diabetes mellitus in the future. By explaining this issue to patients, we expect to improve the rate of postpartum follow-up. This should facilitate early detection of diabetes, and help prevent associated complications. PMID- 27237940 TI - Reproducibility of Dynamic Body Balance Measurement by Center of Foot Pressure Analysis Immediately after Single-Leg Hop Landing. AB - Dynamic balance was evaluated using the trajectory length of the center of foot pressure (COP) in the early phase from immediately after landing to the time of pastoral maintenance. Ten young volunteers with an average age of 23.8 years were asked to stand on one foot on a horizontal floor, hop forward half a step and land on one foot 10 times on each of 3 non-consecutive days. The peak of the vertical component of the floor reaction force (Fz), and the initiation time of the maximum value (tz) and COP trajectory length were measured by a force plate (AMTI, Ltd.). None of the subjects complained of any feeling of fear or loss of balance during the 3 days.The interclass correlation coefficient values of Fz and tz over the three days were 0.75 or higher. Single-leg hop for half a step as a motor task enabled safe measurement of COP trajectory length with high reproducibility. Fz reached its peak within 200 ms after landing and the COP trajectory length within 200 ms after landing accounted for approximately 50% of the total COP trajectory length at one second. Although the length differed in each subject, the interclass correlation coefficients for COP up to 100 ms and 200 ms were 0.68 and 0.80, respectively.The COP trajectory length within 200 ms after landing was considered to be useful as an objective criteria for the evaluation of dynamic balance in the early phase after landing. PMID- 27237942 TI - Anti-inflammatory effects of enemas containing an oily extract of curcumin in an experimental model of diversion colitis. AB - Curcumin has powerful anti-inflammatory and antioxidant effects and it has been used for treatment of distal ulcerative colitis. The therapeutic effects of curcumin have not yet been evaluated in diversion colitis. The aim of the present study was to evaluate the anti-inflammatory effects of curcumin on colonic mucosa devoid of a faecal stream. Thirty-six rats were subjected to a proximal colostomy and distal colonic fistulation. They were divided into two groups, which were sacrificed two or four weeks after the intervention. Each group was divided into three subgroups treated with the daily application of enemas containing saline or an oily extract of curcumin at 50 mg/kg/day or 200 mg/kg/day. Colitis was diagnosed by histological analysis. Inflammatory grades were assessed using a previously validated scoring system. The infiltration of neutrophils was evaluated based on the tissue expression of myeloperoxidase (MPO), as determined by immunohistochemistry, and a computer-assisted image analysis program. The Mann Whitney test was used to compare inflammation grades and myeloperoxidase levels among groups, and ANOVA was used to verify the variance over time, with the level of significance set at 5% (p<0.05) for both tests. Enemas containing curcumin improved the inflammation of the mucosa without a faecal stream and reduced the tissue contents of MPO. MPO tissue levels did not vary with time or between the concentrations of curcumin used. Enemas with curcumin improved the inflammation of the colonic mucosa, reduced the inflammatory grade and decreased the tissue content of MPO in colon segments without a faecal stream. PMID- 27237943 TI - Effect of Disjoining Pressure on Surface Nanobubbles. AB - In gas-oversaturated solutions, stable surface nanobubbles can exist thanks to a balance between the Laplace pressure and the gas overpressure, provided the contact line of the bubble is pinned. In this article, we analyze how the disjoining pressure originating from the van der Waals interactions of the liquid and the gas with the surface affects the properties of the surface nanobubbles. From a functional minimization of the Gibbs free energy in the sharp-interface approximation, we find the bubble shape that takes into account the attracting van der Waals potential and gas compressibility effects. Although the bubble shape slightly deviates from the classical one (defined by the Young contact angle), it preserves a nearly spherical-cap shape. We also find that the disjoining pressure restricts the aspect ratio (size/height) of the bubble and derive the maximal possible aspect ratio, which is expressed via the Young angle. PMID- 27237941 TI - Parental Monitoring, Association with Externalized Behavior, and Academic Outcomes in Urban African-American Youth: A Moderated Mediation Analysis. AB - African-American adolescents exposed to neighborhood disadvantage are at increased risk for engaging in problem behavior and academic underachievement. It is critical to identify the mechanisms that reduce problem behavior and promote better academic outcomes in this population. Based on social disorganization and socioecological theories, the current prospective study examined pathways from parental monitoring to academic outcomes via externalizing behavior at different levels of neighborhood disadvantage. A moderated mediation model employing maximum likelihood was conducted on 339 African-American students from 9th to 11th grade (49.3% females) with a mean age of 14.8 years (SD +/- 0.35). The results indicated that parental monitoring predicted low externalizing behavior, and low externalizing behavior predicted better academic outcomes after controlling for externalizing behavior in 9th grade, intervention status, and gender. Mediation was supported, as the index of mediation was significant. Conversely, neighborhood disadvantage did not moderate the path from parental monitoring to externalizing behavior. Implications for intervention at both community and individual levels and study limitations are discussed. PMID- 27237944 TI - Religious narratives and their implications for disaster risk reduction. AB - The role of religious factors in the disaster experience has been under investigated. This is despite evidence of their influence throughout the disaster cycle, including: the way in which the event is interpreted; how the community recovers; and the strategies implemented to reduce future risk. This qualitative study examined the role of faith in the disaster experience of four faith communities in the Hawaiian Islands of the United States. Twenty-six individuals from the Baha'i, Buddhist, Church of Jesus Christ of Latter-day Saints (LDS), and United Methodist Church communities participated, including 10 faith leaders and 16 laypersons. The results suggest that religious narratives provide a framework for interpretation of, preparedness for, and responses to disasters. Preparedness varied widely across faith communities, with the LDS community reporting greater levels of preparedness than other communities. Recommendations include the development of collaborative efforts between disaster managers and faith leaders to increase preparedness within faith communities, which may facilitate community wide disaster risk reduction. PMID- 27237945 TI - The new Australian after-hours general practice incentive payment mechanism: equity for rural general practice? AB - In July 2015, a national scheme for after-hours incentive funding for general practices was re-introduced in Australia, 2-years after funding was transferred to regional primary health care organisations (Medicare Locals). The re introduction was recommended in a 2014 review of after-hours primary care reflecting the "overwhelming desire" among general practice. Given the centrality of after-hours care provision in rural and remote practices identified in the review, we compare and contrast the current and historical after-hours incentive funding mechanisms focussing on fairness towards rural general practices. While there are similarities between the current and historical mechanisms, significant differences exist. The comparison is not straightforward. The major consistency is utilisation of practice standardised whole patient equivalents (SWPE) as the basis of funding, inherently favouring large urban general practices. This bias is expected to increase given a shift in focus from practices with no option but to provide 24/7 care to any practice providing 24/7 care; and an associated increased funding per SWPE. Differences primarily pertain to classification processes, in which the realities of rural service provision and recognition of regional support mechanisms are given minimal consideration. Rapid introduction of the new general practice after-hours incentive funding mechanism has led to inconsistencies and has exacerbated inherent biases, particularly inequity towards rural providers. Impact on morale and service provision in non-urban areas should be monitored. PMID- 27237946 TI - The 2011 proposal for Universal Health Insurance in Ireland: Potential implications for healthcare expenditure. AB - The Irish healthcare system has long been criticised for a number of perceived weaknesses, including access to healthcare based on ability-to-pay rather than need. Consequently, in 2011, a newly elected government committed to the development of a universal, single-tier system based on need and financed through Universal Health Insurance (UHI). This article draws on the national and international evidence to identify the potential impact of the proposed model on healthcare expenditure in Ireland. Despite a pledge that health spending under UHI would be no greater than in the current predominantly tax-funded model, the available evidence is suggestive that the proposed model involving competing insurers would increase healthcare expenditure, in part due to an increase in administrative costs and profits. As a result the proposed model of UHI appears to be no longer on the political agenda. Although the Government has been criticised for abandoning its model of UHI, it has done so based on national and international evidence about the relatively high additional costs associated with this particular model. PMID- 27237947 TI - Classification of Wolbachia (Alphaproteobacteria, Rickettsiales): No evidence for a distinct supergroup in cave spiders. PMID- 27237948 TI - Molecular characterization of the first G24P[14] rotavirus strain detected in humans. AB - Here we report the genome of a novel rotavirus A (RVA) strain detected in a stool sample collected during routine surveillance by the Centers for Disease Control and Prevention's New Vaccine Surveillance Network. The strain, RVA/human wt/USA/2012741499/2012/G24P[14], has a genomic constellation of G24-P[14]-I2-R2 C2-M2-A3-N2-T9-E2-H3. The VP2, VP3, VP7 and NSP3 genes cluster phylogenetically with bovine strains. The other genes occupy mixed clades containing animal and human strains. Strain RVA/human-wt/USA/2012741499/2012/G24P[14] most likely is the product of interspecies transmission and reassortment events. This is the second report of the G24 genotype and the first report of the G24P[14] genotype combination in humans. PMID- 27237950 TI - Traitement Des Infections Bronchopulmonaires Aigues Par Le Laurylsulfate De Tetracycline Intra-Musculaire. AB - 25 hospitalized patients, suffering from acute bronchopulmonary affections, received every 24 hours, one I.M. injection of 750 mg of tetracycline laurylsulfate (equivalent to 500 mg of tetracycline HCl). Positive clinical results were obtained in all cases. All isolated micro-organisms, sensitive in vitro to tetracycline, were eliminated by this treatment, which produces average tetracycline blood levels close to 2 ug/ml during 24 hours. PMID- 27237949 TI - Examination of endothelial cell-induced epidermal regeneration in a mice-based chimney wound model. AB - As wound contraction in the cutaneous layer occurs rapidly in mice, mechanical means are typically used to deliberately expose the wound to properly investigate healing by secondary intention. Previously, silicon rings and splinting models were attempted to analyze histological recovery but prevention of surrounding epidermal cell migration and subsequent closure was minimal. Here, we developed an ideal chimney wound model to evaluate epidermal regeneration in murine under hESC-EC transplantation through histological analysis encompassing the three phases of regeneration: migration, proliferation, and remodeling. Human embryonic stem cell derived endothelial cells (hESC-EC) were transplanted due to possessing a well-known therapeutic effect in angiogenesis which also enhances epidermal repair to depict the process of regeneration. Following a standard 1 mm biopsy punch, a chimney manufactured by modifying a 1.7 mL microtube was simply inserted into the excisional wound to complete the modeling process. Under this model, the excisional wound remained fully exposed for 14 days and even after 4 weeks, only a thin transparent layer of epidermal tissue covered the wound site. This approach is able to more accurately depict epidermal repair in relation to histology while also being a user-friendly and cost-effective way to mimic human recovery in rodents and evaluate epithelial repair induced by a form of therapy. PMID- 27237951 TI - Verworven Hypofibrinogenemie. AB - The pathogenesis of acquired hypofibrinogenemia has been investigated in 52 cases by several blood coagulation parameters and by clinical and pathological findings. Disseminated intravascular coagulation, fibrinolysis, deficiency of synthesis and combinations of decreased synthesis with disseminated intravascular coagulation or fibrinolysis were found. The pathogenesis of acquired hypofibrinogenemia and its treatment are discussed. PMID- 27237952 TI - Infectious Endocarditis Comparison Of Results Of The Period 1966-1972 With Earlier Experience. AB - Results of treatment of bacterial endocarditis in the period from 1966 to 1972 are compared with previously reported results from the same institution for earlier time periods. The main differences between these two series was the greater emphasis on early detection and laboratory studies during treatment in the later period. Also, the development of cardiac surgery has led to the appearance of a great number of cases of infectious endocarditis in operated patients. Although the increased attention for the problems of infectious endocarditis was accompanied by a significant decrease in the mortality of patients which had not undergone cardiac surgery, the mortality in patients who have been operated remained frightful. In this latter series, the length of time which elasped between the operation and the development of endocarditis suggested that the infection did not occur at the time of operation in the greatest number of cases. PMID- 27237953 TI - Een Geval Van Caverneus Lymfangioma Met Interne Complicaties. AB - The authors describe a case of cavernous lymphangioma of the thigh. This case was complicated by severe septicaemia and acute tubular necrosis. Intensive reanimation, with haemodialysis and tracheal intubation was required. A lymphography after surgical excision of the tumor, shows a lymphatic block at the right side, far below the tumor's level. There exists an important extravasation of contrast medium. The rapport between this lymphangiopathy and the tumor is discussed. The litterature about lymphangioma is reviewed. The cavernous lymphangioma and the cystic hygroma are considerated being a different evolution of the same entity. PMID- 27237954 TI - Acquired Complete Heart Block In Young Adults. AB - Two cases of acquired complete heart block in young adults, without apparent etiology, are presented. The anatomical and functional abnormalities are located probably distal to the bundle of Hiss in one patient, in the AV node and right bundle branch in the other. The time between occurrence of a first episode of complete heart and definite complete A-V block can be considerable. Treatment consists in implantation of a demand pacemaker. PMID- 27237955 TI - T3 Thyrotoxicosis A Recently Recognized Clinical Entity. AB - A case of T3-toxicosis is presented. The normal presentation and the incidence of this syndrome is discussed in the light of reports in the recent medical literature. PMID- 27237956 TI - Contribution Du Laboratoire De Microbiologie Au Diagnostic Virologique A L'Hopital. AB - Preliminary results obtained in a diagnostic virology unit working as a part of a general diagnostic microbiology laboratory within a hospital are presented. Such a laboratory makes possible earlier diagnosis of viral diseases. PMID- 27237958 TI - Juror decision making in not criminally responsible on account of mental disorder trials: Effects of defendant gender and mental illness type. AB - This study sought to examine the potential impact of defendant gender and mental illness type on Canadian juror decision making by manipulating the gender (man, woman) and mental illness (substance abuse disorder, schizophrenia, bipolar, depression) of the defendant in a second-degree murder case involving an insanity plea. Participants read a trial transcript that included definitions of second degree murder and the not criminally on account of mental disorder (NCRMD) defense. Participants then provided a verdict (guilty or NCRMD) and completed various scales measuring attributional judgments, perceptions of the defendant, and perceived dangerousness. Contrary to expectations, NCRMD was chosen over a guilty verdict in the majority of cases. Findings also indicated that participant decisions and perceptions regarding defendants diagnosed with substance abuse disorder differed from the other mental illness groups. The gender of the defendant had an influence on participants' perceptions of internal attributions, and the perceived stability of criminal behaviors. Results suggest that perceptions of mental illness influence verdicts in NCRMD cases, and that defendant gender plays a role in participants' perceptions of defendants. These findings contribute to the scarce literature on mental illness in the Canadian court system. Future research should examine the interaction between juror gender, defendant gender, and mental illness in insanity cases. PMID- 27237959 TI - How do emergency ambulance paramedics view the care they provide to people who self harm?: Ways and means. AB - The UK has one of the highest rates of self harm (SH) in Europe, and almost four times more people die by suicide than in road traffic collisions. Emergency ambulance paramedics are often the first health professionals involved in the care of people who have self-harmed, yet little is known about the care provided or issues raised in these encounters. The aim of this study is to explore paramedics' perceptions and experiences of caring for people who SH, to inform education and policy. Semi structured interviews were conducted with paramedics, and themes generated by constant comparison coding. This paper reports two emerging themes: Firstly, professional, legal, clinical and ethical tensions, linked to limited decision support, referral options and education. The second theme of relationships with police, revealed practices and surreptitious strategies related to care and detention, aimed at overcoming complexities of care. In the absence of tailored education, guidance or support for self-harm care, 'ways and means' have evolved which may negatively influence care and challenge ethical and legal frameworks. There is an urgent need to include evidence from this study in revised guidance and educational materials for paramedics working with people who self-harm in the prehospital emergency setting. PMID- 27237957 TI - Effect of flecainide derivatives on sarcoplasmic reticulum calcium release suggests a lack of direct action on the cardiac ryanodine receptor. AB - BACKGROUND AND PURPOSE: Flecainide is a use-dependent blocker of cardiac Na(+) channels. Mechanistic analysis of this block showed that the cationic form of flecainide enters the cytosolic vestibule of the open Na(+) channel. Flecainide is also effective in the treatment of catecholaminergic polymorphic ventricular tachycardia but, in this condition, its mechanism of action is contentious. We investigated how flecainide derivatives influence Ca(2) (+) -release from the sarcoplasmic reticulum through the ryanodine receptor channel (RyR2) and whether this correlates with their effectiveness as blockers of Na(+) and/or RyR2 channels. EXPERIMENTAL APPROACH: We compared the ability of fully charged (QX-FL) and neutral (NU-FL) derivatives of flecainide to block individual recombinant human RyR2 channels incorporated into planar phospholipid bilayers, and their effects on the properties of Ca(2) (+) sparks in intact adult rat cardiac myocytes. KEY RESULTS: Both QX-FL and NU-FL were partial blockers of the non physiological cytosolic to luminal flux of cations through RyR2 channels but were significantly less effective than flecainide. None of the compounds influenced the physiologically relevant luminal to cytosol cation flux through RyR2 channels. Intracellular flecainide or QX-FL, but not NU-FL, reduced Ca(2) (+) spark frequency. CONCLUSIONS AND IMPLICATIONS: Given its inability to block physiologically relevant cation flux through RyR2 channels, and its lack of efficacy in blocking the cytosolic-to-luminal current, the effect of QX-FL on Ca(2) (+) sparks is likely, by analogy with flecainide, to result from Na(+) channel block. Our data reveal important differences in the interaction of flecainide with sites in the cytosolic vestibules of Na(+) and RyR2 channels. PMID- 27237960 TI - Lipid droplets affect elimination of Porphyromonas gingivalis in HepG2 cells by altering the autophagy-lysosome system. AB - Recent studies have shown that infection with Porphyromonas gingivalis, a major periodontal pathogen, hastens the progression of non-alcoholic fatty liver disease (NAFLD). However, the intracellular fate of P. gingivalis in hepatocytes remains unknown. Here, using oleic-acid-induced HepG2 cells as an in vitro model for NAFLD, we found that lipid droplets increased the existence of P. gingivalis in the cells at an early phase of infection. Confocal microscopic analysis revealed that lipid droplets affected the formation of autolysosomes in infected cells. Thus, lipid droplets affect the elimination of P. gingivalis in HepG2 cells by altering the autophagy-lysosome system. PMID- 27237961 TI - Galleria mellonella as a model system to assess the efficacy of antimicrobial agents against Klebsiella pneumoniae infection. PMID- 27237962 TI - Phasic Modulation of Human Somatosensory Perception by Transcranially Applied Oscillating Currents. AB - BACKGROUND: Why are weak sensory stimuli sometimes perceived and other times not? Experimental paradigms using near-threshold stimuli suggest that spontaneous brain network dynamics are involved in separating relevant from irrelevant information. Recent findings in human visual perception provide evidence that the immediate spontaneous brain state, i.e. the phase of alpha oscillations, predicts whether a coinciding stimulus is further processed or not. OBJECTIVES: Here, we investigated whether this concept of a "pulsed inhibition" involved in sensory gating represents a general mechanism of conscious human perception and can be modulated with non-invasive brain stimulation. METHODS: Hence, we used transcranial alternating current stimulation (tACS) at the individualized mu alpha frequency to entrain somatosensory mu-alpha oscillations, and investigated the effect on somatosensory detection in healthy humans. tACS (or sham, respectively) was applied over primary somatosensory cortices (mu-tACS) while participants performed a detection task of somatosensory near-threshold stimuli. RESULTS: We found that mean perception thresholds during mu-tACS did not change as compared to sham stimulation. However, during mu-tACS, somatosensory detection thresholds varied as a function of the applied tACS phase. This effect was not found when tACS was applied over occipital areas at participant's individual visual alpha frequency. CONCLUSION: Our data indicate that tACS applied at an endogenous frequency is capable of modulating human somatosensory perception by inducing phase-dependent periods of excitation and inhibition, i.e. entraining ongoing mu-alpha oscillations. These findings support the idea that the "pulsed inhibition" framework for sensory gating applies to somatosensory mu-alpha oscillations and might therefore represent a general, but sensory-specific mechanism of conscious human perception. PMID- 27237963 TI - Selective Catalytic Synthesis Using the Combination of Carbon Dioxide and Hydrogen: Catalytic Chess at the Interface of Energy and Chemistry. AB - The present Review highlights the challenges and opportunities when using the combination CO2 /H2 as a C1 synthon in catalytic reactions and processes. The transformations are classified according to the reduction level and the bond forming processes, covering the value chain from high volume basic chemicals to complex molecules, including biologically active substances. Whereas some of these concepts can facilitate the transition of the energy system by harvesting renewable energy into chemical products, others provide options to reduce the environmental impact of chemical production already in today's petrochemical based industry. Interdisciplinary fundamental research from chemists and chemical engineers can make important contributions to sustainable development at the interface of the energetic and chemical value chain. The present Review invites the reader to enjoy this exciting area of "catalytic chess" and maybe even to start playing some games in her or his laboratory. PMID- 27237964 TI - Investigating the utility of clinical assessments to predict success with presbyopic contact lens correction. AB - PURPOSE: To determine the utility of a range of clinical and non-clinical indicators to aid the initial selection of the optimum presbyopic contact lens. In addition, to assess whether lens preference was influenced by the visual performance compared to the other designs trialled (intra-subject) or compared to participants who preferred other designs (inter-subject). METHODS: A double masked randomised crossover trial of Air Optix Aqua multifocal, PureVision 2 for Presbyopia, Acuvue OASYS for Presbyopia, Biofinity multifocal and monovision was conducted on 35 presbyopes (54.3+/-6.2years). Participant lifestyle, personality, pupil characteristics and aberrometry were assessed prior to lens fitting. After 4 weeks of wear, high and low contrast visual acuity (VA) under photopic and mesopic conditions, reading speed, Near Activity Visual Questionnaire (NAVQ) rating, subjective quality-of-vision scoring, defocus curves, stereopsis, halometry, aberrometry and ocular physiology were quantified. RESULTS: After trialling all the lenses, preference was mixed (n=12 Biofinity, n=10 monovision, n=7 Purevision, n=4 Air Optix Aqua, n=2 Oasys). Lens preference was not dependent on personality (F=1.182, p=0.323) or the hours spent working at near (p=0.535) or intermediate (p=0.759) distances. No intersubject or strong intrasubject relationships emerged between lens preference and reading speed, NAVQ rating, halo size, aberrometry or ocular physiology (p>0.05). CONCLUSIONS: Participant lifestyle and personality, ocular optics, contact lens visual performance and ocular physiology provided poor indicators of the preferred lens type after 4 weeks of wear. This is confounded by the wide range of task visual demands of presbyopes and the limited optical differences between current multifocal contact lens designs. PMID- 27237965 TI - A New Classification for the Varus Knee. AB - BACKGROUND: A new classification for osteoarthritis of the knee associated with varus deformity is presented. This classification is derived from the combination of conventional radiographs, stress radiographs (when needed), and clinical examination. METHODS: This study included the analysis of coronal alignment on full-leg standing radiographs of 526 patients awaiting knee arthroplasty for varus deformity in a single institution. Various mechanical and anatomic angles were measured, and these findings were combined with a basic clinical examination of patients. The radiographs were measured on 2 separate occasions to determine the intraobserver reliability. Cross-sectional studies such as computed tomography or magnetic resonance imaging were used to further refine observations about different wear patterns. RESULTS: Varus deformity can either be intra articular or extra-articular. Intra-articular deformities can be correctable or fixed. In fixed deformities, the status of the lateral ligament is taken into account. Extra-articular deformity can be metaphyseal or diaphyseal, and the possibility for intra-articular correction will depend on the degree of deformity and its distance from the joint. CONCLUSION: This new classification allows for better definition of varus deformity, which can help surgeons during preoperative planning, particularly with their choice of implant and potentially the degree of constraint. The classification can also be a tool for further prospective studies about varus deformity. PMID- 27237966 TI - Malnutrition Increases With Obesity and Is a Stronger Independent Risk Factor for Postoperative Complications: A Propensity-Adjusted Analysis of Total Hip Arthroplasty Patients. AB - BACKGROUND: Obesity is frequently associated with complications after total hip arthroplasty (THA) and is often concomitant with malnutrition. The purpose of this study was to investigate the independent morbidity risk of malnutrition relative to obesity. METHODS: The National Surgical Quality Improvement Program from 2005 to 2013 was queried for elective primary THA cases. Malnutrition was defined as albumin <3.5 g/dL. Propensity scores for having preoperative albumin data were determined from demographics, body mass index, and overall comorbidity burden. Patients were classified as nonobese (body mass index 18.5-29.9), obese I (30-34.9), obese II (35-39.9), or obese III (>=40). Complications were compared across nutritional and obesity classes. Multivariable propensity-adjusted logistic regressions were used to examine associations between obesity and malnutrition with 30-day outcomes. RESULTS: A total of 40,653 THA cases were identified, of which 20,210 (49.7%) had preoperative albumin measurements. Propensity score adjustment successfully reduced potential selection bias, with P > .05 for differences between those with and without albumin data. Malnutrition incidence increased from 2.8% in obese I to 5.7% in obese III patients. With multivariable propensity-adjusted logistic regression, malnutrition was a more robust predictor than any obesity class for any postoperative complication(s) (odds ratio [OR] 1.61, 95% confidence interval [CI] 1.25-2.08), major complications (OR 1.63, 95% CI 1.21-2.19), respiratory complications (OR 2.35, 95% CI 1.27-4.37), blood transfusions (OR 1.71, 95% CI 1.44-2.03), and extended length of stay (OR 1.35, 95% CI 1.14-1.59). CONCLUSION: Malnutrition incidence increased significantly from obese I to obese III patients and was a stronger and more consistent predictor than obesity of complications after THA. PMID- 27237967 TI - Are Preoperative Serologic Type and Screen Tests Necessary for Primary Total Joint Arthroplasty Patients in Specialty Surgical Hospitals? AB - BACKGROUND: Blood loss during total joint arthroplasty (TJA) has been a major concern requiring routine preoperative patient type and screen (T&S); however, with the implementation of blood conserving therapy, a marked decrease for perioperative transfusions has been observed. Many TJAs are now being performed in T&S mandated specialty surgical hospitals (SSHs) that lack on-site blood banks; therefore, the purpose of our study was to determine whether T&S (1) is necessary in SSH for TJA patients and (2) identifies patient risk factors associated with perioperative blood transfusion in SSH. METHODS: A retrospective study was conducted on 1034 consecutive primary TJAs performed between 2013 and 2014 at a 12-bed SSH who all received T&S. Patients were matched (1:1) to 964 inpatient TJA patients performed at a university hospital without routine T&S. Data on surgery type, patient demographics, hemoglobin and hematocrit results, and transfusion rates were collected. Multivariate logistic regression identified perioperative transfusion risk factors. RESULTS: Overall transfusion rates for the matched SSH (1.8% [17/964]) and university hospital populations (2.9% [28/964]) were similar (P = .13), with no emergent transfusions. SSH transfusion rates for simultaneous bilateral THA, simultaneous bilateral TKA, unilateral THA, and unilateral TKA were 21.1% (4/19), 3.1% (4/128), 2.7% (12/439), and 0.0% (0/448), respectively. Multivariate logistic regression identified unilateral THA (P <= .001), simultaneous bilateral TJA (P = .001), age (P = .05), and abnormal preoperative hemoglobin (P = .02) as significant transfusion risk factors at SSH. CONCLUSION: Due to low transfusion rates and lack of emergency transfusions, we recommend routinely ordering T&S for bilateral THA but not for unilateral TJA patients, at SSHs. PMID- 27237968 TI - Outcomes of Concomitant Total Aortic Arch Replacement with Coronary Artery Bypass Grafting. AB - OBJECTIVE: Total aortic arch replacement is a highly invasive procedure. Here, we have investigated patient outcomes following total aortic arch replacement with or without coronary artery bypass grafting. METHODS: One hundred and eighty-one patients underwent total aortic arch replacement without coronary artery bypass grafting, and 65 underwent with coronary artery bypass grafting. We compared preoperative, operative, and postoperative factors and analyzed survival outcomes. We used univariate and multivariate analyses to determine factors associated with long-term mortality. RESULTS: Cardiopulmonary bypass and surgical times were significantly longer in the concomitant total aortic arch replacement with coronary artery bypass grafting group. Hospital mortality was 3.3% in the total aortic arch replacement group and 7.7% in the concomitant total aortic arch replacement with coronary artery bypass grafting group. Perioperative myocardial infarction was not seen in either group. There were no significant differences in mortality between the groups. Multivariate analysis revealed preoperative age, ischemic heart disease, and estimated glemerular filtration rate (eGFR) as risk factors affecting long-term mortality, whereas concomitant total aortic arch replacement with coronary artery bypass grafting was not a risk factor. CONCLUSION: Although patients' backgrounds should be considered, total aortic arch replacement can be concomitantly performed with coronary artery bypass grafting surgery without additional mortality risk. PMID- 27237969 TI - Reprogrammable Logic Gate and Logic Circuit Based on Multistimuli-Responsive Raspberry-like Micromotors. AB - In this paper, we report a polymer-based raspberry-like micromotor. Interestingly, the resulting micromotor exhibits multistimuli-responsive motion behavior. Its on-off-on motion can be regulated by the application of stimuli such as H2O2, near-infrared light, NH3, or their combinations. Because of the versatility in motion control, the current micromotor has great potential in the application field of logic gate and logic circuit. With use of different stimuli as the inputs and the micromotor motion as the output, reprogrammable OR and INHIBIT logic gates or logic circuit consisting of OR, NOT, and AND logic gates can be achieved. PMID- 27237970 TI - Differential sensitivity of Chironomus and human hemoglobin to gamma radiation. AB - Chironomus ramosus is known to tolerate high doses of gamma radiation exposure. Larvae of this insect possess more than 95% of hemoglobin (Hb) in its circulatory hemolymph. This is a comparative study to see effect of gamma radiation on Hb of Chironomus and humans, two evolutionarily diverse organisms one having extracellular and the other intracellular Hb respectively. Stability and integrity of Chironomus and human Hb to gamma radiation was compared using biophysical techniques like Dynamic Light Scattering (DLS), UV-visible spectroscopy, fluorescence spectrometry and CD spectroscopy after exposure of whole larvae, larval hemolymph, human peripheral blood, purified Chironomus and human Hb. Sequence- and structure-based bioinformatics methods were used to analyze the sequence and structural similarities or differences in the heme pockets of respective Hbs. Resistivity of Chironomus Hb to gamma radiation is remarkably higher than human Hb. Human Hb exhibited loss of heme iron at a relatively low dose of gamma radiation exposure as compared to Chironomus Hb. Unlike human Hb, the heme pocket of Chironomus Hb is rich in aromatic amino acids. Higher hydophobicity around heme pocket confers stability of Chironomus Hb compared to human Hb. Previously reported gamma radiation tolerance of Chironomus can be largely attributed to its evolutionarily ancient form of extracellular Hb as evident from the present study. PMID- 27237971 TI - Vitamin K3 inhibits mouse uterine contraction in vitro via interference with the calcium transfer and the potassium channels. AB - Previous studies have demonstrated vitamin K3 had a great relief to smooth muscle spastic disorders, but no researches have yet pinpointed its possible anti contractile activity in the uterus. Here, we evaluated the effect of vitamin K3 on myometrial contractility and explored the possible mechanisms of vitamin K3 action. Myograph apparatus were used to record the changes in contractility of isolated mouse uterine strips in a tissue bath. Uterine strips were exposed to vitamin K3 or vehicle. Vitamin K3 suppressed spontaneous contractions in a concentration dependent manner. It significantly decreased the contractile frequency induced by PGF2alpha but not their amplitude (expect 58.0 MUM). Prior incubation with vitamin K3 reduced the effectiveness of PGF2alpha-induced contraction. The antispasmodic effect of vitamin K3 was also sensitive to potassium channel blockers, such as tetraethylammonium, 4-aminopyridine, iberiotoxin) but not to the nitric oxide related pathway blockers. High concentrations (29.0, 58.0 MUM) of vitamin K3 weakened the Ca(2+) dose response and inhibited phase 1 contraction (intracellular stored calcium release). These dates suggest that vitamin K3 specifically suppresses myometrial contractility by affecting calcium and potassium channels; thus, this approach has potential therapy for uterine contractile activity related disorders. PMID- 27237972 TI - TGF-beta1 accelerates the DNA damage response in epithelial cells via Smad signaling. AB - The evidence suggests that transforming growth factor-beta (TGF-beta) regulates the DNA-damage response (DDR) upon irradiation, and we previously reported that TGF-beta1 induced DNA ligase IV (Lig4) expression and enhanced the nonhomologous end-joining repair pathway in irradiated cells. In the present study, we investigated the effects of TGF-beta1 on the irradiation-induced DDRs of A431 and HaCaT cells. Cells were pretreated with or without TGF-beta1 and irradiated. At 30 min post-irradiation, DDRs were detected by immunoblotting of phospho-ATM, phospho-Chk2, and the presence of histone foci (gammaH2AX). The levels of all three factors were similar right after irradiation regardless of TGF-beta1 pretreatment. However, they soon thereafter exhibited downregulation in TGF-beta1 pretreated cells, indicating the acceleration of the DDR. Treatment with a TGF beta type I receptor inhibitor (SB431542) or transfections with siRNAs against Smad2/3 or DNA ligase IV (Lig4) reversed this acceleration of the DDR. Furthermore, the frequency of irradiation-induced apoptosis was decreased by TGF beta1 pretreatment in vivo, but this effect was abrogated by SB431542. These results collectively suggest that TGF-beta1 could enhance cell survival by accelerating the DDR via Smad signaling and Lig4 expression. PMID- 27237973 TI - G-protein-dependency of orexin/hypocretin receptor signalling in recombinant Chinese hamster ovary cells. AB - Multiple signalling pathways for orexin receptors have been discovered, and most thoroughly mapped in Chinese hamster ovary K1 (CHO-K1) cells. It is also known that orexin receptors can couple to the G-protein families Gi, Gs and Gq. However, the connection between the G-proteins and the downstream signals is only vaguely established, and we now set out to resolve this for human orexin receptors expressed in CHO-K1 cells. Adenylyl cyclase (AC), phospholipase A2, C and D, and diacylglycerol lipase activities were assessed by precursor radiolabelling and chromatographic separation, and calcium by fluorescent methods. Pertussis toxin, cholera toxin and the cyclic depsipeptide, UBO-QIC a.k.a. FR900359, were used to assess the involvement of Gi-, Gs- and Gq-family G proteins, respectively. Calcium elevations as well as activation of the phospholipases and diacylglycerol lipase were dependent on Gq, as they were fully blocked by UBO-QIC. The low-potency AC activation fully depended on Gs. Surprisingly, the assumed Gi-dependent inhibition of AC was (fully or partially) inhibited by UBO-QIC, in opposition to the previous findings of no sensitivity of Gi proteins to UBO-QIC. Orexin receptor signalling is indeed mostly Gq-driven in CHO-K1 cells, even with respect to the less clearly mapped cascades such as phospholipase A2 and C and calcium influx, underlining the importance of Gq even under physiological conditions. AC regulation warrants more studies. PMID- 27237974 TI - A nonsense mutation of Stim1 identified in stroke-prone spontaneously hypertensive rats decreased the store-operated calcium entry in astrocytes. AB - We previously identified a nonsense mutation in the stromal interaction molecule 1 (Stim1) resulting in expression of a truncated STIM1 in the stroke-prone spontaneously hypertensive rat (SHRSP). In this study, we evaluated activity of the store-operated Ca(2+)-entry (SOCE) regulated by STIM1 to clarify putative functional abnormalities of the truncated STIM1. As a result, reduced SOCE activity resulting in suppression of cyclooxygenase-2 expression induced by SOCE was found in cultured astrocytes with the truncated STIM1 when compared with those with the wild-type. Our results indicated that the truncated STIM1 impaired Ca(2+) signaling regulated by SOCE and that the impaired SOCE activity might be responsible for pathological phenotypes in SHRSP. PMID- 27237975 TI - Mitochondria related peptide MOTS-c suppresses ovariectomy-induced bone loss via AMPK activation. AB - Therapeutic targeting bone loss has been the focus of the study in osteoporosis. The present study is intended to evaluate whether MOTS-c, a novel mitochondria related 16 aa peptide, can protect mice from ovariectomy-induced osteoporosis. After ovary removal, the mice were injected with MOTS-c at a dose of 5 mg/kg once a day for 12 weeks. Our results showed that MOTS-c treatment significantly alleviated bone loss, as determined by micro-CT examination. Mechanistically, we found that the receptor activator of nuclear factor-kappaB ligand (RANKL) induced osteoclast differentiation was remarkably inhibited by MOTS-c. Moreover, MOTS-c increased phosphorylated AMPK levels, and compound C, an AMPK inhibitor, could partially abrogate the effects of the MOTS-c on osteoclastogenesis. Thus, our findings provide evidence that MOTS-c may exert as an inhibitor of osteoporosis via AMPK dependent inhibition of osteoclastogenesis. PMID- 27237976 TI - Transcriptome changes during TNF-alpha promoted osteogenic differentiation of dental pulp stem cells (DPSCs). AB - Dental pulp stem cells (DPSCs), due to the ease of isolation and their capacities of multi-lineage differentiation, are considered as attractive resources for regenerative medicine. In a previous study, we showed that TNF-alpha promoted the osteogenic differentiation of DPSCs via the NF-kappaB signaling pathway. However, the mechanisms of such differentiation were largely unknown. Here, we examined the gene expression profiles between undifferentiated, partially differentiated and fully differentiated DPSCs induced by TNF-alpha by performing the next generation sequencing technique (RNA-Seq). Our results revealed a continuous transition of the transcriptome changes during TNF-alpha promoted osteogenic differentiation of DPSC. Bioinformatics analysis revealed a relatively general to specific transformation of the involved signaling pathways from the early to late stages of differentiation. Gene regulatory network analysis highlighted novel, key genes that are essential for osteogenic differentiation at different time points. These results were further validated by quantitative RT-PCR, confirming the high reliability of the RNA-Seq. Our data therefore will not only provide novel insights into the molecular mechanisms that drive the osteogenic differentiation of DPSCs, but also promote the studies of bone tissue engineering that utilizes DPSCs as a crucial resource. PMID- 27237977 TI - CaMKII and at least two unidentified kinases phosphorylate regulatory light chain in non-contracting cardiomyocytes. AB - In cardiac tissue, regulatory light chain (RLC, myosin light chain 2) phosphorylation (Ser(15)) leads to modulation of muscle contraction through Ca(2+)-sensitization. To elucidate which kinases that are involved in the basal (diastolic phase) RLC phosphorylation, we studied non-contracting adult rat cardiomyocytes. RLC kinase activities in situ were unmasked by maximally inhibiting myosin light chain phosphatase (MLCP) by calyculin A in the absence and presence of various protein kinase inhibitors. Surprisingly MLCK did not contribute to the phosphorylation of RLC in the non-contracting cardiomyocytes. Two kinase activity groups were revealed by different sensitivities to staurosporine. The fraction with the highest sensitivity to staurosporine was inhibited by KN-93, a selective CaMKII inhibitor, producing a 23% +/- 7% reduction in RLC phosphorylation. Calmodulin antagonism (W7) and reduction in Ca(2+) (EGTA) combined with low concentration of staurosporine caused a larger decrease in RLC phosphorylation than staurosporine alone. These data strongly suggest that in addition to CaMKII, there is another Ca(2+)/calmodulin-dependent kinase and a Ca(2+)/calmodulin-independent kinase phosphorylating RLC. Thus the RLC phosphorylation seems to be ensured by redundant kinase activities. PMID- 27237978 TI - Conformational divergence in the HA-33/HA-17 trimer of serotype C and D botulinum toxin complex. AB - Clostridium botulinum produces a large toxin complex (L-TC) comprising botulinum neurotoxin associated with auxiliary nontoxic proteins. A complex of 33- and 17 kDa hemagglutinins (an HA-33/HA-17 trimer) enhances L-TC transport across the intestinal epithelial cell layer via binding HA-33 to a sugar on the cell surface. At least two subtypes of serotype C/D HA-33 exhibit differing preferences for the sugars sialic acid and galactose. Here, we compared the three dimensional structures of the galactose-binding HA-33 and HA-33/HA-17 trimers produced by the C-Yoichi strain. Comparisons of serotype C/D HA-33 sequences reveal a variable region with relatively low sequence similarity across the C. botulinum strains; the variability of this region may influence the manner of sugar-recognition by HA-33. Crystal structures of sialic acid- and galactose binding HA-33 are broadly similar in appearance. However, small-angle X-ray scattering revealed distinct solution structures for HA-33/HA-17 trimers. A structural change in the C-terminal variable region of HA-33 might cause a dramatic shift in the conformation and sugar-recognition mode of HA-33/HA-17 trimer. PMID- 27237979 TI - MiR-211 is epigenetically regulated by DNMT1 mediated methylation and inhibits EMT of melanoma cells by targeting RAB22A. AB - MiR-211 has strong inhibitive effects on melanoma cell growth, invasion and metastasis. However, how it is downregulated and whether other genes are involved its downstream regulation in melanoma are not clear. In this study, we firstly verified the expression of miR-211 in melanoma cell lines and observed that its downregulation is associated with increased DNMT1 expression. By performing qRT PCR and MSP analysis, we confirmed that DNMT1 is negatively correlated with miR 211 expression and can modulate DNA methylation in the promoter region of miR 211. By performing bioinformatics analysis, we found that RAB22A is a possible target of miR-211, which has two broadly conversed binding sites with miR-211 in the 3'UTR. Following dual luciferase assay, qRT-PCR and western blot analysis confirmed the direct binding between miR-211 and RAB22A and the suppressive effect of miR-211 on RAB22A expression. Knockdown of RAB22A increased epithelial properties and impaired mesenchymal properties of the melanoma cells, suggesting that miR-211 modulates epithelial mesenchymal transition (EMT) of melanoma cells via downregulating RAB22A. In summary, the present study firstly demonstrated that DNMT1 mediated promoter methylation is a mechanism of miRNA suppression in melanoma and revealed a new tumor suppressor role of the miR-211 by targeting RAB22A in melanoma. The DNMT1/miR-211/RAB22A axis provides a novel insight into the pathogenesis of melanoma, particularly in the EMT process. PMID- 27237980 TI - Detailed description of the anterior cerebral artery anomalies observed in a cadaver population. AB - Anomalies of the anterior cerebral artery (ACA) include the median ACA (MedACA), bihemispheric ACA (BihemACA) and the azygos ACA. Knowledge of these anomalies can be crucial to clinicians and neurosurgeons, especially during surgeries involving the interhemispheric region and in the interpretation of the clinical signs of a stroke. Since few reports exist on the origin, area supplied, diameter and length of the ACA anomalies, the aim of this study is to give a detailed description on the anatomy of the ACA anomalies. The ACAs of 60 brains were injected with a colored silicone. When an anomaly was observed, a detailed illustration of the course and pattern of the ACA and cortical branches were made. The origins and the areas supplied by the anomalous arteries were noted. The external diameter was measured using a digital micrometer and the length was measured using string and a ruler. There were seven cases (11.7%) of a MedACA and 12 cases (20.0%) of a BihemACA. The MedACA originated mostly from the anterior communicating artery, and from the A2 segment in one case. The MedACA was bilateral in four cases and unilateral in three cases. Excluding Cases 5 and 9, the BihemACA cases can be divided into two groups; one branch to the left hemisphere (n=3), and one branch to the right hemisphere (n=7). The average diameter of both the BihemACA and MedACA was 1.8mm. Studies rarely provide additional information on these anomalies. Therefore, the present study elaborated on the origin, diameter, length and the area supplied by these anomalies. The definitions are described in the literature, although additional criteria were still lacking and this was provided in the present study. Since information on these aspects of the ACA anomalies is scarce, future research should give detailed descriptions on the ACA anomalies. PMID- 27237981 TI - Sarcomeres and Cardiac Growth: Tension in the Relationship. AB - Genetic mutations in the cardiomyocyte contractile apparatus cause aberrant cardiac growth categorized morphologically as hypertrophic or dilated. A recent study leverages an array of mutant mouse models to extrapolate a new integrated parameter: the myofilament 'tension index', which predicts patterns of cardiac growth resulting from individual sarcomeric mutations. These findings may inform genotype-specific therapies. PMID- 27237982 TI - Molecular confirmation of shampoo as the putative source of Pseudomonas aeruginosa-induced postgrooming furunculosis in a dog. AB - BACKGROUND: An acute onset furunculosis due to Pseudomonas aeruginosa following grooming is a well recognized entity. Although contaminated shampoos have been suspected to be the source of the infection, a molecular confirmation of this association has been missing. OBJECTIVE: This case report describes a dog with postgrooming furunculosis in which Pseudomonas aeruginosa with an identical genetic fingerprint was isolated from the skin lesions as well as from the shampoo used prior to the disease onset. RESULTS: The dog presented for lethargy, anorexia, pain and rapidly progressing skin lesions consistent with haemorrhagic papules, pustules, coalescing ulcers and crusts localized to the dorsal and lateral aspects of the thorax and gluteal region, which developed within 24 h after a bath. Cytology demonstrated suppurative inflammation with occasional intracellular rod-shaped bacteria. Bacterial culture from skin lesions and the shampoo bottle yielded Pseudomonas aeruginosa with an identical pulsed-field gel electrophoresis pattern. Treatment with oral ciprofloxacin and topical antimicrobial shampoo resulted in a complete resolution of skin lesions within eight weeks. CONCLUSION AND CLINICAL IMPORTANCE: Our clinical investigation suggests a link between Pseudomonas-contaminated shampoo and development of postgrooming furunculosis, and underscores the need for hygienic management of shampoos to help limit this disease. PMID- 27237984 TI - A Day in the Life of Louis Guss, MD. PMID- 27237985 TI - Problems+Solutions. AB - Readers are invited to submit questions relating to problem cases. Inquiries will be answered by qualified consultants and replies forwarded by mail promptly. Selected problems and solutions are published every month in this section. PMID- 27237986 TI - Editor'S Mail. PMID- 27237983 TI - Romantic, sexual, and sexual risk behaviours of adolescent females with severe obesity. AB - BACKGROUND: There is an increasing adolescent population with severe obesity with impairments in social and romantic relationships that are seeking clinical weight management, including weight loss surgery (WLS). OBJECTIVE: To document romantic, sexual and sexual risk behaviours in a clinical sample of adolescent females with severe obesity (BMI > 40 kg/m2 ) compared to those of healthy weight (HW). METHODS: This multi-site study-an ancillary to a prospective longitudinal observational study documenting health in adolescents having WLS-presents pre operative/baseline data from 108 females undergoing WLS, 68 severely obese seeking lifestyle intervention and 118 of HW. Romantic and sexual risk behaviour and birth control information sources were assessed using the Sexual Activities and Attitudes Questionnaire (SAAQ). RESULTS: Severely obese females reported engaging in fewer romantic and sexual behaviours compared to HW. Similar to HW, a subgroup (25%) of severely females were engaging in higher rates of sexual risk behaviours and reported pregnancies and sexually transmitted infections (STIs). A considerable number (28-44%) reported receiving no birth control information from physicians. CONCLUSIONS: Discussion topics with the adolescent patient should extend beyond reproductive health needs (e.g. contraception, unintended pregnancies) to include guidance around navigating romantic and sexual health behaviours that are precursors to these outcomes. PMID- 27237988 TI - Cues/Tips. PMID- 27237987 TI - The Medical Bookshelf. PMID- 27237989 TI - Recent Medical Publications. PMID- 27237990 TI - Diabetes mellitus 1947-1987. PMID- 27237991 TI - Immunotherapy in type I diabetes. PMID- 27237992 TI - Nutritional Aspects of Ambulatory Care. PMID- 27237994 TI - Primary Care Digest. PMID- 27237993 TI - Predicting the value of a test. AB - This section is reserved for commentaries and brief essays dealing with matters of interest to physicians. Material for consideration should not exceed five double-spaced typewritten pages. An honorarium of $75 is offered at the time of publication. Submissions should be addressed to: Editor, POSTGRADUATE MEDICINE, 4530 W 77th St, Minneapolis, MN 55435. PMID- 27237998 TI - Listing of Plenary, Oral and Poster Presentations of the Abstracts of the 2016 World Congress of Brachytherapy. PMID- 27237997 TI - Increased plasma levels of competing amino acids, rather than lowered plasma tryptophan levels, are associated with a non-response to treatment in major depression. AB - Lowered plasma tryptophan (TRP) and TRP/competing amino acid (CAA) ratio may be involved in the pathophysiology of major depression (MDD). Increased cortisol and immune-inflammatory mediators in MDD may affect the availability of TRP to the brain. We investigated whether baseline or post-treatment TRP, CAAs and TRP/CAA ratio are associated with a treatment response in MDD and whether these effects may be mediated by cortisol or immune biomarkers. We included 50 medication-free MDD patients with a depressive episode (DSM diagnosis) and assessed symptom severity with the Inventory of Depressive Symptomatology (IDS) before and after treatment as usual for 12 weeks (endpoint). Plasma levels of TRP, CAAs, the ratio, cortisol, CRP and 6 selected cytokines were assayed. The primary outcome was a 50% reduction in the IDS, while the secondary was a remission of the depressive episode. In IDS non-responders, CAAs increased and the TRP/CAA ratio decreased, while in IDS responders CAAs decreased and the TRP/CAA ratio increased from baseline to endpoint. In patients who were still depressed at endpoint TRP and CAAs levels had increased from baseline, while in remitted patients no such effects were found. Increases in CAAs were inversely correlated with changes in interleukin-1 receptor antagonist levels. The results show that increased CAA levels from baseline to endpoint are associated with a non-response to treatment in MDD patients. This suggests that the mechanism underpinning the CAA-related treatment resistance may be related to changes in immune pathways. CAA levels and amino acid metabolism may be new drug targets in depression. PMID- 27237999 TI - An immuno-eco-epidemiological model of competition. AB - This paper introduces a novel immuno-eco-epidemiological model of competition in which one of the species is affected by a pathogen. The infected individuals from species one are structured by time-since-infection and the within-host dynamics of the pathogen and the immune response is also modelled. A novel feature of the model is the impact of the species two numbers on the ability of species one to mount an immune response. The within-host model has three equilibria: an extinction equilibrium, pathogen-only equilibrium and pathogen and immune response equilibrium which exists if the immune response reproduction number R0 > 1. The extinction equilibrium is always unstable, the pathogen-only equilibrium is stable if R0 < 1, and the coexistence equilibrium is stable whenever it exists. The between-host competition model has six equilibria: an extinction equilibrium, three disease-free equilibria: species one-only equilibrium, species two-only equilibrium and a disease-free species coexistence equilibrium. There are also two disease-present equilibria: species one-only disease equilibrium and disease coexistence equilibrium. The existence and stability of these equilibria are governed by six reproduction numbers. Results show that for a non-fatal disease, the disease coexistence equilibrium is stable whenever it exists. PMID- 27238001 TI - Evolution and Biogeography of Haemonchus contortus: Linking Faunal Dynamics in Space and Time. AB - History is the foundation that informs about the nuances of faunal assembly that are essential in understanding the dynamic nature of the host-parasite interface. All of our knowledge begins and ends with evolution, ecology and biogeography, as these interacting facets determine the history of biodiverse systems. These components, relating to Haemonchus, can inform about the complex history of geographical distribution, host association and the intricacies of host-parasite associations that are played out in physiological and behavioural processes that influence the potential for disease and our capacity for effective control in a rapidly changing world. Origins and evolutionary diversification among species of the genus Haemonchus and Haemonchus contortus occurred in a complex crucible defined by shifts in environmental structure emerging from cycles of climate change and ecological perturbation during the late Tertiary and through the Quaternary. A history of sequential host colonization associated with waves of dispersal bringing assemblages of ungulates from Eurasia into Africa and processes emerging from ecosystems in collision and faunal turnover defined the arena for radiation among 12 recognized species of Haemonchus. Among congeners, the host range for H. contortus is exceptionally broad, including species among artiodactyls of 40 genera representing 5 families (and within 12 tribes of Bovidae). Broad host range is dramatically reflected in the degree to which translocation, introduction and invasion with host switching, has characterized an expanding distribution over time in North America, South America, southern Eurasia, Australia and New Zealand, coincidental with agriculture, husbandry and global colonization by human populations driven particularly by European exploration after the 1500s. African origins in xeric to mesic habitats of the African savannah suggest that historical constraints linked to ecological adaptations (tolerances and developmental thresholds defined by temperature and humidity for larval stages) will be substantial determinants in the potential outcomes for widespread geographical and host colonization which are predicted to unfold over the coming century. Insights about deeper evolutionary events, ecology and biogeography are critical as understanding history informs us about the possible range of responses in complex systems under new regimes of environmental forcing, especially, in this case, ecological perturbation linked to climate change. A deeper history of perturbation is relevant in understanding contemporary systems that are now strongly structured by events of invasion and colonization. The relaxation of abiotic and biotic controls on the occurrence of H. contortus, coincidental with inception and dissemination of anthelmintic resistance may be synergistic, serving to exacerbate challenges to control parasites or to limit the socioeconomic impacts of infection that can influence food security and availability. Studies of haemonchine nematodes contribute directly to an expanding model about the nature of diversity and the evolutionary trajectories for faunal assembly among complex host-parasite systems across considerable spatial and temporal scales. PMID- 27238000 TI - Cost Analysis of Free Colonoscopies in an Uninsured Population at Increased Risk for Colorectal Cancer. AB - BACKGROUND: Uninsured patients have poor access to screening colonoscopy and subsequently present with advanced stages of colorectal cancer (CRC) that beget worse outcomes and higher total costs. Providing pro bono colonoscopies to uninsured patients at high risk for CRC can detect early stage disease and be cost-effective. STUDY DESIGN: Patients considered at increased risk for CRC were offered free screening colonoscopies. Patient data from these colonoscopies were collected during a 12-month period, and the incidence of CRC was compared with a control group of uninsured patients from the Surveillance, Epidemiology, and End Results (SEER) registry. Published estimates derived from SEER Medicare data of health expenditures by CRC stage were used to develop a cost model. To compare overall costs between our cohort and the SEER control, the mean initial cost of care (up to 1 year) was weighted by the stage-specific CRC incidence in each group. RESULTS: There were 682 uninsured patients screened, with 9 cancers identified (stage 0, n = 1; stage I, n = 3; stage II, n = 2; and stage III, n = 3) for an incidence of 1.3%. A total cost of $388,137 was estimated to be incurred during the initial phase of care. Compared with the SEER control, our cohort included more early stage cancers and subsequently had a marginally lower per-patient initial cost ($43,126 vs $43,736). CONCLUSIONS: Our screening criteria successfully identified a high-risk population with an overall 1.3% incidence of CRC. For these patients, the provision of free screening colonoscopies identified earlier-stage tumors and appears to be cost-neutral. PMID- 27238002 TI - Genetic Diversity and Population Structure of Haemonchus contortus. AB - Haemonchus contortus is one of the most successful and problematic livestock parasites worldwide. From its apparent evolutionary origins in sub-Saharan Africa, it is now found in small ruminants in almost all regions of the globe, and can infect a range of different domestic and wildlife artiodactyl hosts. It has a remarkably high propensity to develop resistance to anthelmintic drugs, making control increasingly difficult. The success of this parasite is, at least in part, due to its extremely high levels of genetic diversity that, in turn, provide a high adaptive capacity. Understanding this genetic diversity is important for many areas of research including anthelmintic resistance, epidemiology, control, drug/vaccine development and molecular diagnostics. In this article, we review the current knowledge of H. contortus genetic diversity and population structure for both field isolates and laboratory strains. We highlight the practical relevance of this knowledge with a particular emphasis on anthelmintic resistance research. PMID- 27238003 TI - The Biochemistry of Haemonchus contortus and Other Parasitic Nematodes. AB - Different life cycle stages of Haemonchus contortus adapt to different ecosystems. This adaptation is accompanied by alterations in gene transcription and expression associated with the energy, amino acid, nitrogen, lipid and/or nucleic acid metabolism of the respective stages. For example, the aerobic metabolism of larvae depends on an efficient citric acid cycle, whereas the anaerobic metabolism of adults requires glycolysis, resulting in the production of volatile fatty acids, such as acetic acid and propionic acid. There are only few anthelmintics targeting nematode energy metabolism. In addition, H. contortus has reduced pathways for amino acid metabolism, polyamine metabolism and nitrogen excretion pathways. Moreover, nucleic acid metabolism comprising purine and pyrimidine salvage pathways as well as lipid metabolism are reduced. In addition, nematodes possess a particular composition of their cuticle. Energy production of adult worms is mainly linked to egg production and complex regulation of the neuromuscular system in both females and males. In this context, microtubules consisting of alpha- and beta-tubulin heterodimers play a crucial role in the presynaptic vesicle transport. Due to the significant distinction of its quarternary structure in nematodes in comparison to other organisms, beta-tubulin was identified as a major target for benzimidazoles used for anthelmintic treatment. Concerning the function of the neuromuscular system, acetylcholine, a ligand of the nicotinic acetylcholine receptor (nAChR), is the major excitatory neurotransmitter in H. contortus. In contrast, glutamate-gated chloride channels, calcium- and voltage-dependent potassium channels as well as gamma-aminobutyric acid (GABA)A and its receptors act as inhibitory neurotransmitters and thus opponents to nAChR. For example, the calcium- and voltage-dependent potassium channel SLO-1 is an important target of emodepside, which is involved in the sensitive regulation of activatory and inhibitory receptors of the nervous system. Most of the modern anthelmintics target these different neuromuscular receptors. The mechanisms of resistance to anthelmintics, either specific or non specific, are associated with changes in the molecular targets of the drugs, changes in metabolism of the drug (inactivation, removal or prevention of its activation) and/or increased efflux systems. The biochemical and molecular analyses of key developmental, metabolic and structural process of H. contortus still require substantial efforts. The nAChR, glutamate-gated chloride channel and calcium- and voltage-dependent potassium channel SLO-1 have long been known as being essential for nematode survival. Therefore, future research should be intensified to fully resolve the three-dimensional structures of these receptors, as has already been started for glutamate-gated chloride channel. With this knowledge, it should be possible to design new anthelmintics, which possess improved binding capacities to corresponding receptors. PMID- 27238004 TI - The Pathophysiology, Ecology and Epidemiology of Haemonchus contortus Infection in Small Ruminants. AB - The parasitic nematode Haemonchus contortus occurs commonly in small ruminants, and it is an especially significant threat to the health and production of sheep and goats in tropical and warm temperate zones. The main signs of disease (haemonchosis) relate to its blood-feeding activity, leading to anaemia, weakness and frequently to deaths, unless treatment is provided. Due to the high biotic potential, large burdens of H. contortus may develop rapidly when environmental conditions favour the free-living stages, and deaths may occur with little prior warning. More chronic forms of haemonchosis, resulting in reduced animal production and eventually deaths, occur with smaller persistent infections, especially in situations of prolonged, poor nutrition. The global distribution of the main haemonchosis-endemic zones is consistent with the critical requirements of the egg and larval stages of H. contortus for moisture and moderate to relatively warm temperatures, but the seasonal propensity for hypobiosis (inhibition of the fourth-stage larvae within the host) largely explains the common, though sporadic, outbreaks of haemonchosis in arid and colder environments. The wide climatic distribution may also reflect the adaptation of local isolates to less favourable ecological conditions, while an apparent increase in the prevalence of outbreaks in environments not previously considered endemic for haemonchosis - especially cold, temperate zones - may be attributable to climatic changes. Although the risk of haemonchosis varies considerably on a local level, even where H. contortus is endemic, the extensive range of ecological investigations provides a sound basis for predictions of the relative geographical and seasonal risk in relation to climatic conditions. PMID- 27238005 TI - The Identification of Haemonchus Species and Diagnosis of Haemonchosis. AB - Diagnosis is often equated with identification or detection when discussing parasitic diseases. Unfortunately, these are not necessarily mutually exclusive activities; diseases and infections are generally diagnosed and organisms are identified. Diagnosis is commonly predicated upon some clinical signs; in an effort to determine the causative agent, identification of genera and species is subsequently performed. Both identification and diagnosis play critical roles in managing an infection, and involve the interplay of direct and indirect methods of detection, particularly in light of the complex and expanding problem of drug resistance in parasites. Accurate and authoritative identification that is cost- and time-effective, based on structural and molecular attributes of specimens, provides a foundation for defining parasite diversity and changing patterns of geographical distribution, host association and emergence of disease. Most techniques developed thus far have been grounded in assumptions based on strict host associations between Haemonchus contortus and small ruminants, that is, sheep and goats, and between Haemonchus placei and bovids. Current research and increasing empirical evidence of natural infections in the field demonstrates that this assumption misrepresents the host associations for these species of Haemonchus. Furthermore, the capacity of H. contortus to utilize a considerably broad spectrum of ungulate hosts is reflected in our understanding of the role of anthropogenic forcing, the 'breakdown' of ecological isolation, global introduction and host switching as determinants of distribution. Nuanced insights about distribution, host association and epidemiology have emerged over the past 30years, coincidently with the development of increasingly robust means for parasite identification. In this review and for the sake of argument, we would like to delineate the diagnosis of haemonchosis from the identification of the specific pathogen. As a foundation for exploring host and parasite biology, we will examine the evolution of methods for distinguishing H. contortus from other common gastrointestinal nematodes of agriculturally significant and free-ranging wild ruminants using morphological, molecular and/or immunological methods for studies at the species and genus levels. PMID- 27238006 TI - Diagnosis, Treatment and Management of Haemonchus contortus in Small Ruminants. AB - Haemonchus contortus is a highly pathogenic, blood-feeding nematode of small ruminants, and a significant cause of mortalities worldwide. Haemonchosis is a particularly significant threat in tropical, subtropical and warm temperate regions, where warm and moist conditions favour the free-living stages, but periodic outbreaks occur more widely during periods of transient environmental favourability. The clinical diagnosis of haemonchosis is based mostly on the detection of anaemia in association with a characteristic epidemiological picture, and confirmed at postmortem by the finding of large numbers of H. contortus in the abomasum. The detection of impending haemonchosis relies chiefly on periodic monitoring for anaemia, including through the 'FAMACHA' conjunctival colour index, or through faecal worm egg counts and other laboratory procedures. A range of anthelmintics for use against H. contortus is available, but in most endemic situations anthelmintic resistance significantly limits the available treatment options. Effective preventative programmes vary depending on environments and enterprise types, and according to the scale of the haemonchosis risk and the local epidemiology of infections, but should aim to prevent disease outbreaks while maintaining anthelmintic efficacy. Appropriate strategies include animal management programmes to avoid excessive H. contortus challenge, genetic and nutritional approaches to enhance resistance and resilience to infection, and the monitoring of H. contortus infection on an individual animal or flock basis. Specific strategies to manage anthelmintic resistance centre on the appropriate use of effective anthelmintics, and refugia-based treatment schedules. Alternative approaches, such as biological control, may also prove useful, and vaccination against H. contortus appears to have significant potential in control programmes. PMID- 27238007 TI - Interactions Between Nutrition and Infections With Haemonchus contortus and Related Gastrointestinal Nematodes in Small Ruminants. AB - Interactions between host nutrition and feeding behaviour are central to understanding the pathophysiological consequences of infections of the digestive tract with parasitic nematodes. The manipulation of host nutrition provides useful options to control gastrointestinal nematodes as a component of an integrated strategy. Focussed mainly on the Haemonchus contortus infection model in small ruminants, this chapter (1) illustrates the relationship between quantitative (macro- and micro-nutrients) and qualitative (plant secondary metabolites) aspects of host nutrition and nematode infection, and (2) shows how basic studies aimed at addressing some generic questions can help to provide solutions, despite the considerable diversity of epidemiological situations and breeding systems. PMID- 27238008 TI - Immunity to Haemonchus contortus and Vaccine Development. AB - Sheep are capable of developing protective immunity to Haemonchus contortus through repeated exposure to this parasite, although this immune protection is the result of a complex interaction among age, gender, physiological status, pregnancy, lactation, nutrition and innate and adaptive immunity in the host animal. There are multiple effectors of the protective immune response, which differ depending on the developmental stage of the parasite being targeted, and our understanding of the effector mechanisms has developed considerably in the 2000s. The rational design of vaccines based on 'natural' or 'exposed' antigens depends on an understanding of this exposure-induced immunity. However, the most effective current vaccines rely on protection via the induction of high circulating antibody levels to 'hidden' gut antigens of H. contortus. The success of this latter strategy has resulted in the launch of a vaccine, which is based on extracts of the parasite's gut, to aid in the control of Haemonchus in Australia. The development of recombinant subunit vaccines based on the components of the successful native vaccine has not yet been achieved and most of the recent successes with recombinant subunit vaccines have focussed on antigens unrelated to the gut antigens. The future integration of an understanding of the immunobiology of this parasite with advances in antigen identification, expression (or synthesis) and presentation is likely to be pivotal to the further development of these recombinant subunit vaccines. Recent progress in each of the components underpinning this integrated approach is summarized in this review. PMID- 27238009 TI - Anthelmintic Resistance in Haemonchus contortus: History, Mechanisms and Diagnosis. AB - Haemonchus contortus has shown a great ability to develop resistance to anthelmintic drugs. In many instances, resistance has appeared less than 10years after the introduction of a new drug class. Field populations of this species now show resistance to all major anthelmintic drug classes, including benzimidazoles (BZs), imidazothiazoles and macrocyclic lactones. In addition, resistance to the recently introduced amino-acetonitrile derivative class (monepantel) has already been reported. The existence of field populations showing resistance to all three major drug classes, and the early appearance of resistance to monepantel, threatens the sustainability of sheep and goat production systems worldwide. This chapter reviews the history of the development of resistance to the various anthelmintics in H. contortus and examines the mechanisms utilized by this species to resist the effects of these drugs. Some of these mechanisms are well understood, particularly for BZ drugs, while our knowledge and understanding of others are increasing. Finally, we summarize methods available for the diagnosis of resistance. While such diagnosis currently relies largely on the faecal egg count reduction test, which suffers from issues of expense and sensitivity, we describe past and current efforts to utilize cheaper and less laborious phenotypic assays with free-living life stages, and then describe progress on the development of molecular assays to provide sensitive resistance-detection tests. PMID- 27238010 TI - Haemonchus contortus: Applications in Drug Discovery. AB - Haemonchus contortus is an important pathogen of small ruminants and is therefore a crucially important target for anthelmintic chemotherapy. Its large size and fecundity have been exploited for the development of in vitro screens for anthelmintic discovery that employ larval and adult stages in several formats. The ability of the parasite to develop to the young adult stage in Mongolian jirds (Meriones unguiculatus) provides a useful small animal model that can be used to screen compounds prior to their evaluation in infected sheep. This chapter summarizes the use of H. contortus for anthelmintic discovery, offers a perspective on current strategies in this area and suggests research challenges that could lead to improvements in the anthelmintic discovery process. PMID- 27238011 TI - Gaining Insights Into the Pharmacology of Anthelmintics Using Haemonchus contortus as a Model Nematode. AB - Progress made in understanding pharmacokinetic behaviour and pharmacodynamic mechanisms of drug action/resistance has allowed deep insights into the pharmacology of the main chemical classes, including some of the few recently discovered anthelmintics. The integration of pharmaco-parasitological research approaches has contributed considerably to the optimization of drug activity, which is relevant to preserve existing and novel active compounds for parasite control in livestock. A remarkable amount of pharmacology-based knowledge has been generated using the sheep abomasal nematode Haemonchus contortus as a model. Relevant fundamental information on the relationship among drug influx/efflux balance (accumulation), biotransformation/detoxification and pharmacological effects in parasitic nematodes for the most traditional anthelmintic chemical families has been obtained by exploiting the advantages of working with H. contortus under in vitro, ex vivo and in vivo experimental conditions. The scientific contributions to the pharmacology of anthelmintic drugs based on the use of H. contortus as a model nematode are summarized in the present chapter. PMID- 27238012 TI - Understanding Haemonchus contortus Better Through Genomics and Transcriptomics. AB - Parasitic roundworms (nematodes) cause substantial mortality and morbidity in animals globally. The barber's pole worm, Haemonchus contortus, is one of the most economically significant parasitic nematodes of small ruminants worldwide. Although this and related nematodes can be controlled relatively well using anthelmintics, resistance against most drugs in common use has become a major problem. Until recently, almost nothing was known about the molecular biology of H. contortus on a global scale. This chapter gives a brief background on H. contortus and haemonchosis, immune responses, vaccine research, chemotherapeutics and current problems associated with drug resistance. It also describes progress in transcriptomics before the availability of H. contortus genomes and the challenges associated with such work. It then reviews major progress on the two draft genomes and developmental transcriptomes of H. contortus, and summarizes their implications for the molecular biology of this worm in both the free-living and the parasitic stages of its life cycle. The chapter concludes by considering how genomics and transcriptomics can accelerate research on Haemonchus and related parasites, and can enable the development of new interventions against haemonchosis. PMID- 27238013 TI - Haemonchus contortus: Genome Structure, Organization and Comparative Genomics. AB - One of the first genome sequencing projects for a parasitic nematode was that for Haemonchus contortus. The open access data from the Wellcome Trust Sanger Institute provided a valuable early resource for the research community, particularly for the identification of specific genes and genetic markers. Later, a second sequencing project was initiated by the University of Melbourne, and the two draft genome sequences for H. contortus were published back-to-back in 2013. There is a pressing need for long-range genomic information for genetic mapping, population genetics and functional genomic studies, so we are continuing to improve the Wellcome Trust Sanger Institute assembly to provide a finished reference genome for H. contortus. This review describes this process, compares the H. contortus genome assemblies with draft genomes from other members of the strongylid group and discusses future directions for parasite genomics using the H. contortus model. PMID- 27238014 TI - Functional Genomics Tools for Haemonchus contortus and Lessons From Other Helminths. AB - The availability of genome and transcriptome data for parasitic nematodes, including Haemonchus contortus, has highlighted the need to develop functional genomics tools. Comparative genomic analysis, particularly using data from the free-living nematode Caenorhabditis elegans, can help predict gene function. Reliable approaches to study function directly in parasitic nematodes are currently lacking. However, gene knockdown by RNA interference (RNAi) is being successfully used in schistosome and planarian species to define gene functions. Lessons from these systems may be applied to improve RNAi in H. contortus. Previous studies in H. contortus and related nematodes demonstrated reliable RNAi mediated silencing of some genes, but not others. Current data suggest that susceptibility to RNAi in these nematodes is limited to genes expressed in sites accessible to the environment, such as the gut, amphids and excretory cell. Therefore, RNAi is functional in H. contortus, but improvements are needed to develop this system as a functional genomics platform. Here, we summarize RNAi studies on H. contortus and discuss the optimization of RNA delivery and improvements to culture methods to enhance larval development, protein turnover and the induction of phenotypic effects in vitro. The transgenic delivery of RNA or dominant-negative gene constructs and the recently developed CRISPR/Cas genome editing technique are considered as potential alternative approaches for gene knockout. This is a key time to devote greater effort in progressing from genome to function, to improve our understanding of the biology of Haemonchus and identify novel targets for parasite control. PMID- 27238015 TI - Preface. PMID- 27238016 TI - Assessing the potential of the European Atlantic sturgeon Acipenser sturio to control bivalve invasions in Europe. AB - This pilot study explored the potential of juvenile European Atlantic sturgeon Acipenser sturio to feed on two invasive bivalve species, the Asian clam Corbicula fluminea and the Eurasian zebra mussel Dreissena polymorpha. Preliminary results indicate that native A. sturio were feeding on D. polymorpha at a very limited rate and their potential to prevent the establishment of invasive bivalve species, in new and previously invaded areas, is considered limited. PMID- 27238017 TI - Structural Insights into the Niemann-Pick C1 (NPC1)-Mediated Cholesterol Transfer and Ebola Infection. AB - Niemann-Pick disease type C (NPC) is associated with mutations in NPC1 and NPC2, whose gene products are key players in the endosomal/lysosomal egress of low density lipoprotein-derived cholesterol. NPC1 is also the intracellular receptor for Ebola virus (EBOV). Here, we present a 4.4 A structure of full-length human NPC1 and a low-resolution reconstruction of NPC1 in complex with the cleaved glycoprotein (GPcl) of EBOV, both determined by single-particle electron cryomicroscopy. NPC1 contains 13 transmembrane segments (TMs) and three distinct lumenal domains A (also designated NTD), C, and I. TMs 2-13 exhibit a typical resistance-nodulation-cell division fold, among which TMs 3-7 constitute the sterol-sensing domain conserved in several proteins involved in cholesterol metabolism and signaling. A trimeric EBOV-GPcl binds to one NPC1 monomer through the domain C. Our structural and biochemical characterizations provide an important framework for mechanistic understanding of NPC1-mediated intracellular cholesterol trafficking and Ebola virus infection. PMID- 27238018 TI - Circadian Amplitude Regulation via FBXW7-Targeted REV-ERBalpha Degradation. AB - Defects in circadian rhythm influence physiology and behavior with implications for the treatment of sleep disorders, metabolic disease, and cancer. Although core regulatory components of clock rhythmicity have been defined, insight into the mechanisms underpinning amplitude is limited. Here, we show that REV ERBalpha, a core inhibitory component of clock transcription, is targeted for ubiquitination and subsequent degradation by the F-box protein FBXW7. By relieving REV-ERBalpha-dependent repression, FBXW7 provides an unrecognized mechanism for enhancing the amplitude of clock gene transcription. Cyclin dependent kinase 1 (CDK1)-mediated phosphorylation of REV-ERBalpha is necessary for FBXW7 recognition. Moreover, targeted hepatic disruption of FBXW7 alters circadian expression of core clock genes and perturbs whole-body lipid and glucose levels. This CDK1-FBXW7 pathway controlling REV-ERBalpha repression defines an unexpected molecular mechanism for re-engaging the positive transcriptional arm of the clock, as well as a potential route to manipulate clock amplitude via small molecule CDK1 inhibition. PMID- 27238019 TI - Breaking Cryo-EM Resolution Barriers to Facilitate Drug Discovery. AB - Recent advances in single-particle cryoelecton microscopy (cryo-EM) are enabling generation of numerous near-atomic resolution structures for well-ordered protein complexes with sizes >= ~200 kDa. Whether cryo-EM methods are equally useful for high-resolution structural analysis of smaller, dynamic protein complexes such as those involved in cellular metabolism remains an important question. Here, we present 3.8 A resolution cryo-EM structures of the cancer target isocitrate dehydrogenase (93 kDa) and identify the nature of conformational changes induced by binding of the allosteric small-molecule inhibitor ML309. We also report 2.8-A and 1.8-A-resolution structures of lactate dehydrogenase (145 kDa) and glutamate dehydrogenase (334 kDa), respectively. With these results, two perceived barriers in single-particle cryo-EM are overcome: (1) crossing 2 A resolution and (2) obtaining structures of proteins with sizes < 100 kDa, demonstrating that cryo-EM can be used to investigate a broad spectrum of drug-target interactions and dynamic conformational states. PMID- 27238020 TI - Sensory Neurons that Detect Stretch and Nutrients in the Digestive System. AB - Neural inputs from internal organs are essential for normal autonomic function. The vagus nerve is a key body-brain connection that monitors the digestive, cardiovascular, and respiratory systems. Within the gastrointestinal tract, vagal sensory neurons detect gut hormones and organ distension. Here, we investigate the molecular diversity of vagal sensory neurons and their roles in sensing gastrointestinal inputs. Genetic approaches allowed targeted investigation of gut to-brain afferents involved in homeostatic responses to ingested nutrients (GPR65 neurons) and mechanical distension of the stomach and intestine (GLP1R neurons). Optogenetics, in vivo ganglion imaging, and genetically guided anatomical mapping provide direct links between neuron identity, peripheral anatomy, central anatomy, conduction velocity, response properties in vitro and in vivo, and physiological function. These studies clarify the roles of vagal afferents in mediating particular gut hormone responses. Moreover, genetic control over gut-to brain neurons provides a molecular framework for understanding neural control of gastrointestinal physiology. PMID- 27238021 TI - Mapping of Brain Activity by Automated Volume Analysis of Immediate Early Genes. AB - Understanding how neural information is processed in physiological and pathological states would benefit from precise detection, localization, and quantification of the activity of all neurons across the entire brain, which has not, to date, been achieved in the mammalian brain. We introduce a pipeline for high-speed acquisition of brain activity at cellular resolution through profiling immediate early gene expression using immunostaining and light-sheet fluorescence imaging, followed by automated mapping and analysis of activity by an open-source software program we term ClearMap. We validate the pipeline first by analysis of brain regions activated in response to haloperidol. Next, we report new cortical regions downstream of whisker-evoked sensory processing during active exploration. Last, we combine activity mapping with axon tracing to uncover new brain regions differentially activated during parenting behavior. This pipeline is widely applicable to different experimental paradigms, including animal species for which transgenic activity reporters are not readily available. PMID- 27238022 TI - Wiring and Molecular Features of Prefrontal Ensembles Representing Distinct Experiences. AB - A major challenge in understanding the cellular diversity of the brain has been linking activity during behavior with standard cellular typology. For example, it has not been possible to determine whether principal neurons in prefrontal cortex active during distinct experiences represent separable cell types, and it is not known whether these differentially active cells exert distinct causal influences on behavior. Here, we develop quantitative hydrogel-based technologies to connect activity in cells reporting on behavioral experience with measures for both brain wide wiring and molecular phenotype. We find that positive and negative-valence experiences in prefrontal cortex are represented by cell populations that differ in their causal impact on behavior, long-range wiring, and gene expression profiles, with the major discriminant being expression of the adaptation-linked gene NPAS4. These findings illuminate cellular logic of prefrontal cortex information processing and natural adaptive behavior and may point the way to cell-type-specific understanding and treatment of disease-associated states. PMID- 27238026 TI - Next pay round will be 'tight'. AB - Nurses were warned at this year's RCN Congress, by the new secretary of state for health, Frank Dobson, not to expect large pay increases under a Labour government. PMID- 27238025 TI - Clinical helplines: endangered species. AB - In this issue, we begin a series of clinical articles on the emergency management of poisoning written by members of the London Centre of the National Poisons Information Service. Future articles will consider the emergency management of patients following overdose of analgesics, antidepressants, drugs of abuse, as well as management of overdose from miscellaneous drugs, such as cardiac medications. PMID- 27238028 TI - Controversial proposal meets narrow defeat. AB - A MOTION CALLING for relatives to he allowed to witness the resuscitation of their loved ones was rejected at the RCN Congress in Harrogate last month. Proposing the motion, Helen Whyley (association of nursing students) said the resolution was about choice. 'And that means providing the ways and means for relatives to exercise that choice.' PMID- 27238027 TI - Action on elder abuse. AB - A report from Action on Elder Abuse (AEA) has shown that in a quarter of cases where older people are abused, the abuse has come from professional carers. The findings are published in Hearing the Despair: The Reality of Elder Abuse and were compiled by the charity from an analysis of phone calls to its helpline, suggesting that nurses might be involved in abuse, and also highlighting the problems of nurses working with colleagues who they suspect might be abusing patients. PMID- 27238023 TI - A Comprehensive, CRISPR-based Functional Analysis of Essential Genes in Bacteria. AB - Essential gene functions underpin the core reactions required for cell viability, but their contributions and relationships are poorly studied in vivo. Using CRISPR interference, we created knockdowns of every essential gene in Bacillus subtilis and probed their phenotypes. Our high-confidence essential gene network, established using chemical genomics, showed extensive interconnections among distantly related processes and identified modes of action for uncharacterized antibiotics. Importantly, mild knockdown of essential gene functions significantly reduced stationary-phase survival without affecting maximal growth rate, suggesting that essential protein levels are set to maximize outgrowth from stationary phase. Finally, high-throughput microscopy indicated that cell morphology is relatively insensitive to mild knockdown but profoundly affected by depletion of gene function, revealing intimate connections between cell growth and shape. Our results provide a framework for systematic investigation of essential gene functions in vivo broadly applicable to diverse microorganisms and amenable to comparative analysis. PMID- 27238029 TI - 'Hello' nurses are a waste of time. AB - So-called 'hello' nurses, employed by trusts to greet patients as they arrive at A&E departments, have been condemned as a waste of time. PMID- 27238024 TI - A Family of non-GPCR Chemosensors Defines an Alternative Logic for Mammalian Olfaction. AB - Odor perception in mammals is mediated by parallel sensory pathways that convey distinct information about the olfactory world. Multiple olfactory subsystems express characteristic seven-transmembrane G-protein-coupled receptors (GPCRs) in a one-receptor-per-neuron pattern that facilitates odor discrimination. Sensory neurons of the "necklace" subsystem are nestled within the recesses of the olfactory epithelium and detect diverse odorants; however, they do not express known GPCR odor receptors. Here, we report that members of the four-pass transmembrane MS4A protein family are chemosensors expressed within necklace sensory neurons. These receptors localize to sensory endings and confer responses to ethologically relevant ligands, including pheromones and fatty acids, in vitro and in vivo. Individual necklace neurons co-express many MS4A proteins and are activated by multiple MS4A ligands; this pooling of information suggests that the necklace is organized more like subsystems for taste than for smell. The MS4As therefore define a distinct mechanism and functional logic for mammalian olfaction. PMID- 27238030 TI - [Not Available]. AB - The 14th International AIDS Candlelight Memorial, organised by the London Lighthouse charity, was held in London's Trafalgar Square recently. Shortly after the event, American scientists reported in Nature magazine that a cocktail of drugs could, over three years, eliminate the HIV-1 virus from the body. PMID- 27238031 TI - Guidelines on infection control. AB - Hospital nurses are to be issued with guidelines on infection control following a study which found almost three in every 100 inpatients are at risk of contracting a hospital-acquired infection (HAI). PMID- 27238032 TI - New cot death findings. AB - NURSES AND MIDWIVES are calling for more research into the causes of cot deaths after a new report dismissed the theory that toxic gases from mattresses are to blame. PMID- 27238033 TI - Model policy to attack bullying at work. AB - A MODEL POLICY aimed at attacking bullying against nurses was launched by the Royal College of Nursing recently, as a survey revealed that up to 60 per cent of nurses have been victims of intimidation at work. PMID- 27238036 TI - A&E Association. PMID- 27238034 TI - Recordable review for NPs. AB - The UKCC is to look at how it can include nurse practitioner courses in its category of recordable qualifications for specialist practice. PMID- 27238037 TI - Skull x-rays not a reliable indicator of head injury. AB - The value of routine skull radiography as a method of predicting intracranial injury remains controversial. PMID- 27238039 TI - How useful are antibiotics in children with otitis media? AB - Acute otitis is extremely common in children. By the age of three months, 10 per cent of children will have suffered at least one episode, with the incidence peaking between six and 15 months. PMID- 27238038 TI - Should paracetamol sales be curtailed? AB - It has been suggested that making the means of suicide less accessible to patients may result in reductions in method specific suicide rates and in overall suicides. Researchers examined the trends in countries in paracetamol poisoning where the availability of paracetamol differs - England and Wales, and in France. PMID- 27238041 TI - The comprehensive emergency triage teaching package The comprehensive emergency triage teaching package L570.94 (Emergency Triage Teaching Package) 0-7279-1143-0 L12.95 (Emergency Triage) 0-7279-1126-0 0727911260 [Formula: see text]. AB - Since triage was introduced in the UK in the 1980s. many A&F. departments have developed ad hoc triage systems which have ranged from two point ('now' or 'later') scales to seven point scales. None have been comparable with one another and staff moving from one department to another have had to learn new systems of triage. PMID- 27238042 TI - New this month. PMID- 27238043 TI - Universal precautions This report highlights guidance recently issued by the Royal College of Nursing ( 1997 ) to help to prevent transmission of blood borne viruses from patients to healthcare professionals. AB - Healthcare workers who come into contact with patients' blood body tlu ids may be exposed to occupational risk from blood borne viral infections such as HIV infection or hepatitis B. PMID- 27238044 TI - Learning from a major incident exercise. AB - It was a beautiful October morning as the train sped along the track. The passengers, mostly children, were in a jovial mood unaware of the fate which was about to befall them. PMID- 27238045 TI - Adult resuscitation guidelines. AB - In April of this year at the international meeting in Brighton, the Resuscitation Council of the United Kingdom presented changes to its guidelines for resuscitation. The original guidelines, published in 1992 by the European Resuscitation Council ( ERC ), were the result of a consensus view from international groups of experts based on the most up to date information. The International Liaison Committee on Resuscitation (ILCOR) comprises the ERC, the American Heart Association (AHA), the Australian Resuscitation Council (ARC), the Resuscitation Council of Southern Africa (RCSA), the Heart and Stroke Foundation of Canada (HSFC). and the Cosejo Latinoamericano de Resuscitation (CLAR). PMID- 27238046 TI - Acute poisoning: initial management and sources of information. AB - Poisoning is responsible for 2-3 per cent of attendances to urban A&F. departments in the UK each year ( MacNamara et al 1996 ). It accounts for about 7 per cent of accidents in children under five years of age ( Consumer Safety Unit 1995 ). The National Poison Information Service (NPIS) deals with hundreds of emergency telephone enquiries every day. and the number of such calls has risen sharply in recent years. Figure 1 demonstrates the annual call load of NPIS (London). A&E nurses account for 42 per cent of these telephone enquiries. PMID- 27238047 TI - Pressure area care in A&E. AB - Although the literature specific to A&E and pressure sores is scant, Nicola Wickham argues that the treatment of pressure sores is fundamental to nursing care in any work area. In this first of a two part series she reviews the literature available in pressure area care, and discusses the importance of early intervention in treating this highly preventable condition. PMID- 27238048 TI - Triage in the children's A&E. AB - Continuing Education articles are run in conjunction with the Royal College of Nurisng Institute to help you to maintain and develop your clinical practice and which you can use to meet your UKCC requirements for professional updating. All you have to do is read through the article, follow the instructions in the Time Out boxes, then answer the assessment questions that follow. PMID- 27238049 TI - Radiographic Evaluation of Maxillary Sinus Lateral Wall and Posterior Superior Alveolar Artery Anatomy: A Cone-Beam Computed Tomographic Study. AB - OBJECTIVE: The purpose of the current study is to assess the thickness of the maxillary sinus lateral wall in dentate and edentulous patients using cone beam computed tomography (CBCT). This study also provides information about the diameter, prevalence, and course of the posterior superior alveolar artery (PSAA), and its relation to the maxillary sinus floor. MATERIALS AND METHODS: Four hundred and thirty CBCT scans of the maxillofacial complex (860 maxillary sinuses) were reviewed. Measurements of the lateral wall of the maxillary sinus and PSAA were performed on the CBCT images. RESULTS: Statistical analysis showed that dental status (edentulous, non-edentulous) of the patients had no significant effect on the lateral wall thickness. The mean thickness of the lateral wall of the maxillary sinus was 1.21 +/- 1.07 mm at the second molar (M2), 1.98 +/- 1.87 mm at the first molar (M1), 2.02 +/- 1.53 mm at the second premolar (P2) and 2.16 +/- 1.25 mm at the first premolar (P1). There was statistically significant difference between the left and right sides of the maxillary sinus only at P2 (p =.043). Detection rate of the PSAA on CBCT was reported as 60.58%. The mean diameter of the artery was 1.17 mm (range 0.4-2.8 mm). There was no significant correlation between age and the size of the PSAA. The most frequent path of the PSAA was intraosseous (69.6%), followed by intrasinusal (24.3%) and superficial (6.1%). The overall mean distance of the PSAA from the floor of the maxillary sinus is 8.16 mm. CONCLUSIONS: The results from this study suggest that using CBCT prior to the surgery provides valuable diagnostic information. However, undetected intraosseous canal in CBCT does not exclude its existence. Alteration in the lateral window design and the use of piezoelectric instruments are recommended if intraoperative complications are expected. PMID- 27238050 TI - Bis-Pyrano Prenyl Isoflavone Improves Glucose Homeostasis by Inhibiting Dipeptidyl Peptidase-4 in Hyperglycemic Rats. AB - Isoflavones widely distributed in plants prevent diabetes. This study investigated the in vivo and in vitro effect of 3',4'-dihydroxy-6",6",6"',6"' tetramethylbis(pyrano[2",3":5,6::2"',3"':7,8]isoflavone (bis-pyrano prenyl isoflavone) on glucose homeostasis in hyperglycemic rats. The ethyl acetate fraction from aerial parts of Polygala molluginifolia that contain isoflavones was assayed on glucose tolerance, on in vitro maltase activity and on protein glycation. The isoflavone bis-pyrano prenyl isolated from this fraction was investigated on glucose homeostasis. The in vivo action of the isoflavone exhibits an anti-hyperglycemic effect by improving glucose tolerance, augmenting the liver glycogen, inhibiting maltase activity, and stimulating glucagon-like peptide-1 (GLP-1) and insulin secretion. The in vitro isoflavone inhibits dipeptidyl peptidase-4 (DPP-4) activity since the glucose tolerance was improved in the presence of the isoflavone as much as sitagliptin, an inhibitor of DPP-4. However, the co-incubation with isoflavone and sitagliptin exhibited an additive anti-hyperglycemic action. The isoflavone increased the GLP-1 faster than the positive hyperglycemic group, which shows that the intestine is a potential target. Thus, to clarify the main site of action in which isoflavone improves glucose balance, the in vitro mechanism of action of this compound was tested in intestine using calcium influx as a trigger for the signal pathways for GLP-1 secretion. The isoflavone stimulates calcium influx in intestine and its mechanism involves voltage-dependent calcium channels, phospholipase C, protein kinase C, and stored calcium contributing for GLP-1 secretion. In conclusion, the isoflavone regulates glycaemia by acting mainly in a serum target, the DPP-4 inhibitor. Furthermore, the long-term effect of isoflavone prevents protein glycation. J. Cell. Biochem. 118: 92-103, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27238051 TI - Fibromyalgia and seizures. AB - The purpose of this case-matched study was to determine how frequently fibromyalgia is associated with different paroxysmal neurological disorders and explore the utility of fibromyalgia as a predictor for the diagnosis of psychogenic non-epileptic seizures. The billing diagnosis codes of 1,730 new, non selected patient encounters were reviewed over a three-year period for an epileptologist in a neurology clinic to identify all patients with historical diagnoses of fibromyalgia. The frequency with which epileptic seizures, psychogenic non-epileptic seizures, and physiological non-epileptic events were comorbid with fibromyalgia was assessed. Age and gender case-matched controls were used for a between-group comparison. Wilcoxon tests were used to analyse interval data, and Chi-square was used to analyse categorical data (p<0.05). Fibromyalgia was retrospectively identified in 95/1,730 (5.5%) patients in this cohort. Females represented 95% of the fibromyalgia sample (age: 53 years; 95% CI: 57, 51). Forty-three percent of those with fibromyalgia had a non-paroxysmal, neurological primary clinical diagnosis, most commonly chronic pain. Paroxysmal events were present in 57% of fibromyalgia patients and 54% of case-matched controls. Among patients with fibromyalgia and paroxysmal disorders, 11% had epileptic seizures, 74% had psychogenic non-epileptic seizures, and 15% had physiological non-epileptic events, compared to case-matched controls with 37% epileptic seizures, 51% psychogenic non-epileptic events, and 12% physiological non-epileptic events (p = 0.009). Fibromyalgia was shown to be a predictor for the diagnosis of psychogenic non-epileptic seizures in patients with undifferentiated paroxysmal spells. However, our results suggest that the specificity and sensitivity of fibromyalgia as a marker for psychogenic non epileptic seizures in a mixed general neurological population of patients is less than previously described. PMID- 27238052 TI - Posterior bulk-filled resin composite restorations: A 5-year randomized controlled clinical study. AB - OBJECTIVE: To evaluate in a randomized controlled study the 5-year clinical durability of a flowable resin composite bulk-fill technique in Class I and Class II restorations. MATERIAL AND METHODS: 38 pairs Class I and 62 pairs Class II restorations were placed in 44 male and 42 female (mean age 52.4 years). Each patient received at least two, as similar as possible, extended Class I or Class II restorations. In all cavities, a 1-step self-etch adhesive (Xeno V+) was applied. Randomized, one of the cavities of each pair received the flowable bulk filled resin composite (SDR), in increments up to 4mm as needed to fill the cavity 2mm short of the occlusal cavosurface. The occlusal part was completed with the nano-hybrid resin composite (Ceram X mono+). In the other cavity, the resin composite-only (Ceram X mono+) was placed in 2mm increments. The restorations were evaluated using slightly modified USPHS criteria at baseline and then yearly during 5 years. Caries risk and bruxing habits of the participants were estimated. RESULTS: No post-operative sensitivity was reported. At 5-year 183, 68 Class I and 115 Class II, restorations were evaluated. Ten restorations failed (5.5%), all Class II, 4 SDR-CeramX mono+ and 6 CeramX mono+ only restorations. The main reasons for failure were tooth fracture (6) and secondary caries (4). The annual failure rate (AFR) for all restorations (Class I and II) was for the bulk-filled-1.1% and for the resin composite-only restorations 1.3% (p=0.12). For the Class II restorations, the AFR was 1.4% and 2.1%, respectively. CONCLUSION: The stress decreasing flowable bulk-fill resin composite technique showed good durability during the 5-year follow-up. CLINICAL SIGNIFICANCE: The use of a 4mm incremental technique with the flowable bulk-fill resin composite showed during the 5-year follow up slightly better, but not statistical significant, durability compared to the conventional 2mm layering technique in posterior resin composite restorations. PMID- 27238053 TI - FDA labeling of NSAIDs: Review of nonsteroidal anti-inflammatory drugs in cardiovascular disease. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) have been extensively used worldwide for both chronic and acute musculoskeletal and inflammatory conditions. Extensive evidence has linked NSAID use with adverse cardiovascular events. This review article aims to review the existing evidence on the risk of cardiovascular and coronary events in both selective and nonselective NSAIDs, the time course of NSAIDs associated with cardiovascular risk, and specific populations that may be at increased risk. PMID- 27238054 TI - Editorial Commentary: Chronic obstructive pulmonary disease and sudden cardiac death: Cause and effect or simply an association? PMID- 27238055 TI - Wavelet-domain TI Wiener-like filtering for complex MR data denoising. AB - Magnetic resonance (MR) images are affected by random noises, which degrade many image processing and analysis tasks. It has been shown that the noise in magnitude MR images follows a Rician distribution. Unlike additive Gaussian noise, the noise is signal-dependent, and consequently difficult to reduce, especially in low signal-to-noise ratio (SNR) images. Wirestam et al. in [20] proposed a Wiener-like filtering technique in wavelet-domain to reduce noise before construction of the magnitude MR image. Based on Wirestam's study, we propose a wavelet-domain translation-invariant (TI) Wiener-like filtering algorithm for noise reduction in complex MR data. The proposed denoising algorithm shows the following improvements compared with Wirestam's method: (1) we introduce TI property into the Wiener-like filtering in wavelet-domain to suppress artifacts caused by translations of the signal; (2) we integrate one Stein's Unbiased Risk Estimator (SURE) thresholding with two Wiener-like filters to make the hard-thresholding scale adaptive; and (3) the first Wiener-like filtering is used to filter the original noisy image in which the noise obeys Gaussian distribution and it provides more reasonable results. The proposed algorithm is applied to denoise the real and imaginary parts of complex MR images. To evaluate our proposed algorithm, we conduct extensive denoising experiments using T1-weighted simulated MR images, diffusion-weighted (DW) phantom and in vivo data. We compare our algorithm with other popular denoising methods. The results demonstrate that our algorithm outperforms others in term of both efficiency and robustness. PMID- 27238056 TI - Letter by Dyverfeldt and Ebbers regarding article "Estimation of turbulent kinetic energy using 4D phase-contrast MRI: Effect of scan parameters and target vessel size". PMID- 27238059 TI - Here/In This Issue and There/Abstract Thinking: Reproducibility of Science. PMID- 27238058 TI - Genotypic and phenotypic presentation of transthyretin-related familial amyloid polyneuropathy (TTR-FAP) in Turkey. AB - Transthyretin-related familial amyloid polyneuropathy (TTR-FAP) is an autosomal dominant disorder caused by mutations of the transthyretin (TTR) gene. The mutant amyloidogenic transthyretin protein causes the systemic accumulation of amyloid fibrils that result in organ dysfunction. TTR-associated FAP is a progressive and fatal disease, if left untreated, and should be considered in the differential diagnosis of any person presenting with a progressive polyneuropathy, particularly with accompanying autonomic involvement. The clinical, electrophysiological, histopathological, and genetic characteristics of 17 patients from Turkey (5 female, 13 male) from nine families with polyneuropathy and mutations in TTR were evaluated. Sequence analysis of the TTR gene revealed five mutations (Val30Met, Glu89Gln, Gly53Glu, Glu54Gly and Gly47Glu). Mean age at disease onset was 40.4 +/- 13.9 years (range 21-66 years). The most commonly reported initial complaint was paresthesia in the feet (asymmetric in three patients). Three patients (2 male) with the Glu89Gln mutation presented with carpal tunnel syndrome. Two patients with the Gly53Glu mutation showed episodes of dysarthria and hemiparesis, consistent with this genotype. Seven patients died during the period of follow-up as a result of systemic involvement. Our study suggests that a cohort of patients from Turkey with TTR-FAP exhibits clinical and genetic heterogeneity. PMID- 27238057 TI - Idebenone reduces respiratory complications in patients with Duchenne muscular dystrophy. AB - In Duchenne muscular dystrophy (DMD), progressive loss of respiratory function leads to restrictive pulmonary disease and places patients at significant risk for severe respiratory complications. Of particular concern are ineffective cough, secretion retention and recurrent respiratory tract infections. In a Phase 3 randomized controlled study (DMD Long-term Idebenone Study, DELOS) in DMD patients 10-18 years of age and not taking concomitant glucocorticoid steroids, idebenone (900 mg/day) reduced significantly the loss of respiratory function over a 1-year study period. In a post-hoc analysis of DELOS we found that more patients in the placebo group compared to the idebenone group experienced bronchopulmonary adverse events (BAEs): placebo: 17 of 33 patients, 28 events; idebenone: 6 of 31 patients, 7 events. The hazard ratios (HR) calculated "by patient" (HR 0.33, p = 0.0187) and for "all BAEs" (HR 0.28, p = 0.0026) indicated a clear idebenone treatment effect. The overall duration of BAEs was 222 days (placebo) vs. 82 days (idebenone). In addition, there was also a difference in the use of systemic antibiotics utilized for the treatment of BAEs. In the placebo group, 13 patients (39.4%) reported 17 episodes of antibiotic use compared to 7 patients (22.6%) reporting 8 episodes of antibiotic use in the idebenone group. Furthermore, patients in the placebo group used systemic antibiotics for longer (105 days) compared to patients in the idebenone group (65 days). This post-hoc analysis of DELOS indicates that the protective effect of idebenone on respiratory function is associated with a reduced risk of bronchopulmonary complications and a reduced need for systemic antibiotics. PMID- 27238060 TI - The Transformative Power of the Dog: The Growing Use of Canine Assistants in Therapeutic Interventions and School Settings. PMID- 27238061 TI - Declining Rates of Adolescent Marijuana Use Disorders During the Past Decade May Be Due to Declining Conduct Problems. PMID- 27238062 TI - Vulnerability and Resilience Among Gender-Nonconforming Children and Adolescents: Mental Health Professionals Have a Key Role to Play. PMID- 27238064 TI - Antipsychotic Use Trends in Youth With Autism Spectrum Disorder and/or Intellectual Disability: A Meta-Analysis. AB - OBJECTIVE: Although irritability and aggression are relevant treatment targets in autism spectrum disorders (ASDs) and intellectual disability (ID) that may prompt antipsychotic use, antipsychotic prescribing patterns in such youth have not been systematically reviewed. METHOD: We systematically searched PubMed/MEDLINE/PsycInfo until March 2015 for studies reporting data on the frequency of youth diagnosed with ASDs and/or ID among antipsychotic-treated youth, as well as antipsychotic use in youth with ASD/ID, conducting a meta analysis and meta-regression analysis of potential moderators, including publication year, study time point, country, setting, sample size, age, sex, and race/ethnicity. RESULTS: A total of 39 studies were meta-analyzed (n = 365,449, age = 11.4 +/- 6.2 years, males = 70.0% +/- 10.0%). Among 27 studies (n = 273,139, age = 11.9 +/- 8.0 years, males = 67.0% +/- 12.9%) reporting on antipsychotic-treated youth, 9.5% (95% CI = 7.8%-11.5%) were diagnosed with ASD/ID. In 20 studies (n = 209,756) reporting data separately for ASD, 7.9% (95% CI = 6.2%-9.9%) had an ASD diagnosis. In 5 longitudinal studies, the proportion of antipsychotic-treated youth with ASD did not change significantly from 1996 to 2011 (6.7% to 5.8%, odds ratio = 0.9, 95% CI = 0.8-1.0, p =.17). However, later study time point moderated greater ASD/ID proportions (beta = 0.12, p < .00001). In 13 studies (n = 96,688, age = 9.8 +/- 1.2 years, males = 78.6% +/- 2.0%) reporting on antipsychotic use in ASD samples, 17.5% (95% CI = 13.7%-22.1%) received antipsychotics. Again, later study time point moderated higher antipsychotic use among patients with ASD (beta = 0.10, p = .004). CONCLUSION: Almost 1 in 10 antipsychotic-treated youth were diagnosed with ASD and/or ID, and 1 in 6 youth with ASD received antipsychotics. Both proportions increased in later years; however, clinical reasons and outcomes of antipsychotic use in ASD/ID require further study. PMID- 27238063 TI - Neurofeedback for Attention-Deficit/Hyperactivity Disorder: Meta-Analysis of Clinical and Neuropsychological Outcomes From Randomized Controlled Trials. AB - OBJECTIVE: We performed meta-analyses of randomized controlled trials to examine the effects of neurofeedback on attention-deficit/hyperactivity disorder (ADHD) symptoms and neuropsychological deficits in children and adolescents with ADHD. METHOD: We searched PubMed, Ovid, Web of Science, ERIC, and CINAHAL through August 30, 2015. Random-effects models were employed. Studies were evaluated with the Cochrane Risk of Bias tool. RESULTS: We included 13 trials (520 participants with ADHD). Significant effects were found on ADHD symptoms rated by assessors most proximal to the treatment setting, that is, the least blinded outcome measure (standardized mean difference [SMD]: ADHD total symptoms = 0.35, 95% CI = 0.11-0.59; inattention = 0.36, 95% CI = 0.09-0.63; hyperactivity/impulsivity = 0.26, 95% CI = 0.08-0.43). Effects were not significant when probably blinded ratings were the outcome or in trials with active/sham controls. Results were similar when only frequency band training trials, the most common neurofeedback approach, were analyzed separately. Effects on laboratory measures of inhibition (SMD = 0.30, 95% CI = -0.10 to 0.70) and attention (SMD = 0.13, 95% CI = -0.09 to 0.36) were not significant. Only 4 studies directly assessed whether learning occurred after neurofeedback training. The risk of bias was unclear for many Cochrane Risk of Bias domains in most studies. CONCLUSION: Evidence from well controlled trials with probably blinded outcomes currently fails to support neurofeedback as an effective treatment for ADHD. Future efforts should focus on implementing standard neurofeedback protocols, ensuring learning, and optimizing clinically relevant transfer. PMID- 27238065 TI - Severely Aggressive Children Receiving Stimulant Medication Versus Stimulant and Risperidone: 12-Month Follow-Up of the TOSCA Trial. AB - OBJECTIVE: The objective of this study was to evaluate 52-week clinical outcomes of children with co-occurring attention-deficit/hyperactivity disorder (ADHD), disruptive behavior disorder, and serious physical aggression who participated in a prospective, longitudinal study that began with a controlled, 9-week clinical trial comparing the relative efficacy of parent training + stimulant medication + placebo (Basic; n = 84) versus parent training + stimulant + risperidone (Augmented; n = 84). METHOD: Almost two-thirds (n = 108; 64%) of families in the 9-week study participated in week 52 follow-ups (Basic, n = 55; Augmented, n = 53) and were representative of the initial study sample. The assessment battery included caregiver and clinician ratings and laboratory tests. RESULTS: Only 43% of participants in the Augmented group and 36% in the Basic group still adhered to their assigned regimen (not significant [NS]); 23% of those in the Augmented group and 11% in the Basic group were taking no medication (NS). Both randomized groups improved baseline to follow-up, but the 3 primary parent-reported behavioral outcomes showed no significant between-group differences. Exploratory analyses indicated that participants in the Augmented group (65%) were more likely (p = .02) to have a Clinical Global Impressions (CGI) severity score of 1 to 3 (i.e., normal to mildly ill) at follow-up than those in the Basic group (42%). Parents rated 45% of children as impaired often or very often from ADHD, noncompliant, or aggressive behavior. The Augmented group had elevated prolactin levels, and the Basic group had decreased weight over time. Findings were generally similar whether groups were defined by randomized assignment or follow up treatment status. CONCLUSION: Both treatment strategies were associated with clinical improvement at follow-up, and primary behavioral outcomes did not differ significantly. Many children evidenced lingering mental health concerns, suggesting the need for additional research into more effective interventions. Clinical trial registration information-Treatment of Severe Childhood Aggression (the TOSCA Study); http://clinicaltrials.gov/; NCT00796302. PMID- 27238066 TI - Age of Onset, Duration, and Type of Medication Therapy for Attention Deficit/Hyperactivity Disorder and Substance Use During Adolescence: A Multi Cohort National Study. AB - OBJECTIVE: To examine whether age of onset, duration, or type of medication therapy for attention-deficit/hyperactivity disorder (ADHD) is associated with substance use during adolescence. METHOD: Nationally representative samples of high school seniors were surveyed via self-administered questionnaires. The sample consisted of 40,358 individuals from 10 independent cohorts (2005-2014) and represented a population that was 52% female, 62% white, 10% African American, 14% Hispanic, and 14% other race/ethnicity. Design-based logistic regression analyses were used to test the associations between age of onset, duration, and type of ADHD medication therapy and recent substance use, controlling for potential confounding factors. RESULTS: Individuals who initiated stimulant medication therapy for ADHD later (aged 10-14 years and 15 years and older) and for shorter duration (2 years or less and 3-5 years) as well as those who reported only nonstimulant medication therapy for ADHD had significantly greater odds of substance use in adolescence relative to individuals who initiated stimulant medication therapy for ADHD earlier (aged 9 years or less) and for longer duration (6 or more years). The odds of substance use generally did not differ between population controls (youth without ADHD and unmedicated youth with ADHD) and individuals who initiated stimulant medication for ADHD early (aged 9 years or less) and for longer duration (aged 6 or more years). CONCLUSION: Relative to later onset and shorter duration of stimulant treatment for ADHD, early onset and longer duration of stimulant treatment for ADHD was associated with a risk of substance use during adolescence that is lower than and similar to that in the general population. PMID- 27238067 TI - Declining Prevalence of Marijuana Use Disorders Among Adolescents in the United States, 2002 to 2013. AB - OBJECTIVE: Little is known about recent trends in marijuana use disorders among adolescents in the United States. We analyzed trends in the past-year prevalence of DSM-IV marijuana use disorders among adolescents, both overall and conditioned on past-year marijuana use. Potential explanatory factors for trends in prevalence were explored. METHOD: We assembled data from the adolescent samples of the 2002 to 2013 administrations of the National Survey on Drug Use and Health (N = 216,852; aged 12-17 years). The main outcome measures were odds ratios describing the average annual change in prevalence and conditional prevalence of marijuana use disorders, estimated from models of marijuana use disorder as a function of year. Post hoc analyses incorporated measures of potentially explanatory risk and protective factors into the trend analyses. RESULTS: A decline in the past-year prevalence of marijuana use disorders was observed (odds ratio = 0.976 per year; 95% CI = 0.968, 0.984; p < .001). This was due to both a net decline in past-year prevalence of use and a decline in the conditional prevalence of marijuana use disorders. The trend in marijuana use disorders was accounted for by a decrease in the rate of conduct problems among adolescents (e.g., fighting, stealing). CONCLUSION: Past-year prevalence of marijuana use disorders among US adolescents declined by an estimated 24% over the 2002 to 2013 period. The decline may be related to trends toward lower rates of conduct problems. Identification of factors responsible for the reduction in conduct problems could inform interventions targeting both conduct problems and marijuana use disorders. PMID- 27238068 TI - Brief Psychotherapy for Maternal Depression: Impact on Mothers and Children. AB - OBJECTIVE: Two-generation studies demonstrate that treating maternal depression benefits school-age children. Although mothers prefer psychotherapy to medication, little is known about how psychotherapy for maternal depression affects offspring, especially in very high-risk families in which both mothers and children concurrently meet syndromal criteria for psychiatric disorders. This trial evaluated the effects of 2 brief psychotherapies for maternal depression on very high-risk families. METHOD: Mothers with major depressive disorder were randomly assigned to 9 sessions of either brief interpersonal psychotherapy for mothers (IPT-MOMS; n = 85) or brief supportive psychotherapy (BSP; n = 83). Independent assessors evaluated mothers and their children, ages 7 to 18 years, diagnosed with at least 1 internalizing disorder, every 3 months over the course of 1 year. RESULTS: Symptoms and functioning of mothers and children improved significantly over time, with no between-group differences. However, children of mothers assigned to BSP had more outpatient mental health visits and were more likely to receive antidepressant medication. Mothers reported greater satisfaction with IPT-MOMS than BSP. Improvement in mothers' depressive symptoms was associated with improvement in child functioning in time-lagged fashion, with children improving 3 to 6 months after mothers improved. Antidepressant medication use and number of mental health visits received by children did not affect outcomes. CONCLUSION: IPT-MOMS and BSP demonstrated comparable beneficial effects on maternal depression. Children's functioning improved following maternal improvement, independent of youths' treatment. Children of mothers randomized to IPT-MOMS, compared with BSP, achieved comparable outcomes despite less follow-up treatment. Observation of lagged association between maternal improvement and change in child functioning should influence treatment planning for families. Clinical trial registration information-Psychotherapy for Depressed Mothers of Psychiatrically Ill Children; http://clinicaltrials.gov/; NCT00919594. PMID- 27238069 TI - Is There a Female Protective Effect Against Attention-Deficit/Hyperactivity Disorder? Evidence From Two Representative Twin Samples. AB - OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is more frequent in males than in females. The "female protective effect" posits that females undergo greater exposure to etiological factors than males in order to develop ADHD, leading to the prediction that relatives of females with ADHD will display more ADHD behaviors. We thus tested whether cotwins of females displaying extreme ADHD traits would display more ADHD traits than cotwins of males displaying extreme ADHD traits. METHOD: Parents of approximately 7,000 pairs of nonidentical twins in Sweden, and approximately 4,000 pairs of twins in England and Wales, completed dimensional assessments of ADHD traits. Probands were selected on the basis of scoring within the highest 10% of the distribution in each sample. Dimensional scores of cotwins of probands, as well as the categorical recurrence rate, were investigated by proband sex. RESULTS: Cotwins of female probands displayed higher mean ADHD trait scores (mean = 0.62-0.79) than cotwins of male probands (mean = 0.38-0.55) in both samples. This trend was significant in the Swedish sample (p < .01) and when the 2 samples were merged into a single, larger sample (p < .001). When the samples were merged, there was also a significant association between proband sex and cotwin's categorical status, with more cotwins of female probands also being probands than cotwins of male probands. CONCLUSION: These findings support a female protective effect against ADHD behaviors, suggesting that females require greater exposure to genetic and environmental factors associated with ADHD in order to develop the condition. PMID- 27238070 TI - Self-Harm and Suicidality in Children Referred for Gender Dysphoria. AB - OBJECTIVE: This study examined rates of self-harm and suicidality (ideation and behavior) in children referred clinically for gender dysphoria compared with their siblings, and referred and nonreferred children from the Child Behavior Checklist (CBCL) standardization sample. Predictors or correlates of self harm/suicidality were also examined. METHOD: The sample consisted of 572 gender referred children, 425 siblings, 878 referred children, and 903 nonreferred children. Parent report for 2 CBCL items was used to assess self-harm and suicidality. CBCL total behavior problems and a metric of peer relationship problems were also used. RESULTS: The gender-referred children and the referred children from the standardization sample had significantly higher scores than siblings and nonreferred children in terms of self-harm/suicidality, total behavior problems, and poor peer relations. Based on logistic regression analyses, gender-referred children were 5.1 times more likely than nonreferred children to talk about suicide and 8.6 times more likely to self-harm/attempt suicide, even after overall behavior problems and peer relationship problems were accounted for. In the final models, group, older age, and more total behavior problems, but not poor peer relations, were significantly associated with an increased likelihood of self-harm/suicidality. CONCLUSION: By parent report, children with gender dysphoria show an increased rate of self-harm/suicidality as they get older. This risk was not simply an artifact of the presence of behavioral and emotional problems, although these problems were significant correlates of self-harm/suicidality. Clinicians should routinely screen for the presence of suicidal ideation and behavior in children with gender dysphoria, particularly during the second half of childhood. PMID- 27238071 TI - Whole-Exome Sequencing Reveals Increased Burden of Rare Functional and Disruptive Variants in Candidate Risk Genes in Individuals With Persistent Attention Deficit/Hyperactivity Disorder. PMID- 27238072 TI - Eye Movements, Autism, and Environmental Exposure to Nitrous Oxide. PMID- 27238073 TI - Sympathy for the Devil. PMID- 27238074 TI - Distinction in EEG slow oscillations between chronic mild traumatic brain injury and PTSD. AB - Spectral information from resting state EEG is altered in acute mild traumatic brain injury (mTBI) and in disorders of consciousness, but there is disagreement about whether mTBI can elicit long term changes in the spectral profile. Even when identified, any long-term changes attributed to TBI can be confounded by psychiatric comorbidities such as PTSD, particularly for combat-related mTBI where postdeployment distress is commonplace. To address this question, we measured spectral power during the resting state in a large sample of service members and Veterans varying in mTBI history and active PTSD diagnosis but matched for having had combat blast exposure. We found that PTSD was associated with decreases in low frequency power, especially in the right temporoparietal region, while conversely, blast-related mTBI was associated with increases in low frequency power, especially in prefrontal and right temporal areas. Results support the idea that long-term neurophysiological effects of mTBI share some features with states of reduced arousal and cognitive dysfunction, suggesting a role for EEG in tracking the trajectory of recovery and persisting vulnerabilities to injury. Additionally, results suggest that EEG power reflects distinct pathophysiologies for current PTSD and chronic mTBI. PMID- 27238075 TI - Influence of attention on bimodal integration during emotional change decoding: ERP evidence. AB - Recent findings on audiovisual emotional interactions suggest that selective attention affects cross-sensory interaction from an early processing stage. However, the influence of attention manipulation on facial-vocal integration during emotional change perception is still elusive at this point. To address this issue, we asked participants to detect emotional changes conveyed by prosodies (vocal task) or facial expressions (facial task) while facial, vocal, and facial-vocal expressions were presented. At the same time, behavioral responses and electroencephalogram (EEG) were recorded. Behavioral results showed that bimodal emotional changes were detected with shorter response latencies compared to each unimodal condition, suggesting that bimodal emotional cues facilitated emotional change detection. Moreover, while the P3 amplitudes were larger for the bimodal change condition than for the sum of the two unimodal conditions regardless of attention direction, the N1 amplitudes were larger for the bimodal emotional change condition than for the sum of the two unimodal conditions under the attend-voice condition, but not under the attend-face condition. These findings suggest that selective attention modulates facial-vocal integration during emotional change perception in early sensory processing, but not in late cognitive processing stages. PMID- 27238076 TI - Stochastic Detection of MPSA-Gold Nanoparticles Using a alpha-Hemolysin Nanopore Equipped with a Noncovalent Molecular Adaptor. AB - We present the first study of a novel, more sensitive method for the characterization of nanoparticles (NPs). This approach combines detection via a protein nanopore with modification of its interaction behavior using a molecular adaptor. We identify different populations of 3-mercapto-1-propanesulfonate (MPSA)-modified-gold NPs using the biological nanopores alpha-hemolysin (alphaHL) and its M113N mutant equipped with a noncovalently bound gamma-cyclodextrin molecule as a stochastic sensor. Identification takes place on the basis of the extent of current blockades and residence times. Here, we demonstrate that noncovalently attached adaptors can be used to change the sensing properties of alphaHL nanopores, allowing the detection and characterization of different populations of MPSA NPs. This is an advance in sensitivity and diversity of NP sensing, as well as a promising and reliable technology to characterize NPs by using protein nanopores. PMID- 27238077 TI - Age-ordered shirt numbering reduces the selection bias associated with the relative age effect. AB - When placed into age groups for junior sporting competition, the relative differences in age between children leads to a bias in who is evaluated as being talented. While the impact of this relative age effect (RAE) is clear, until now there has been no evidence to show how to reduce it. The aim of this study was to determine whether the selection bias associated with the RAE could be reduced. Talent scouts from an elite football club watched junior games and ranked players on the basis of their potential. Scouts were allocated to one of three groups provided with contrasting information about the age of the players: (1) no age information, (2) players' birthdates or (3) knowledge that the numbers on the playing shirts corresponded to the relative age of the players. Results revealed a significant selection bias for the scouts in the no-age information group, and that bias remained when scouts knew the players' dates-of-birth. Strikingly though, the selection bias was eliminated when scouts watched the games knowing the shirt numbers corresponded to the relative ages of the players. The selection bias associated with the RAE can be reduced if information about age is presented appropriately. PMID- 27238078 TI - Repeated Courses of Oral Ibuprofen in Premature Infants with Patent Ductus Arteriosus: Efficacy and Safety. AB - BACKGROUND: There are limited data about the results of repeated oral ibuprofen (OIBU) treatment. This study aimed to describe patent ductus arteriosus (PDA) closure rates and adverse events after repeated courses of OIBU in premature infants with PDA. METHODS: Preterm infants with hemodynamically significant (hs)PDA were enrolled in the study. If the first course of OIBU treatment failed, a second and, if required, third course was administered. RESULTS: A total of 100 patients received OIBU. In six patients, treatment could not be completed due to death (n=3) and side effects (n=3). In three patients, adverse effects related to OIBU (thrombocytopenia and impairment of renal function) developed during the first course. During the second and third courses, no new adverse event occurred. After all courses, the PDA closure rate was determined as 88%. The rate was 71% after the first course, 40% after the second course, and 35% after the third course. Although the second course resulted in a significant increase in the closure rate (p<0.05), the rate did not increase significantly with the third course (p>0.05). The mean postnatal age at the start of the first dose of OIBU was not significantly different among the responders and non-responders to the first course (p>0.05). Clinical characteristics did not affect the closure rate significantly. The number of courses did not have a significant effect on death, when gestational age and birth weight were used as covariates [p=0.867, Exp(B)=0.901, 95% confidence interval=0.264-3.1]. CONCLUSION: A second course of OIBU seems effective and safe for use in preterm infants with hsPDA. Although a third course of OIBU results in PDA closure in some additional patients, the difference is not significant. Thus, surgical ligation should be considered after the second course, especially in patients with signs of severe heart failure. PMID- 27238079 TI - Evaluation of diagnostic value of AgNOR and PAP in early detection of dysplastic changes in leukoplakia and lichen planus - a preliminary case-control study. AB - BACKGROUND AND OBJECTIVES: Early detection of oral cancer has been the most effective approach to reduce morbidity and mortality of cancer patients. If a lesion is clinically considered suspicious, an easily practicable, non-invasive, painless, safe, and accurate screening method for detection of the dysplastic changes is necessary. In an attempt to procure this, a study was conducted with the aim of determining the diagnostic accuracy of rapid Papanicolaou stain (PAP) and silver-stained nucleolar organizer regions (AgNOR) in brush biopsies of potentially malignant lesions for early detection of oral cancer. METHODOLOGY: Brush biopsies taken from 25 cases of leukoplakia and lichen planus each were stained with rapid PAP and silver nitrate stains. Histopathological correlation was performed and further compared with rapid PAP and AgNOR for its diagnostic validity. RESULTS: Statistically significant increase in the mean AgNOR count was seen from normal epithelium to lichen planus to that of leukoplakia. When compared with rapid PAP, a linear correlation was seen in AgNOR counts and stages of dysplasia in leukoplakia which was also found to be statistically significant. Diagnostic accuracy for AgNOR in leukoplakia was found to be 84%, lichen planus 73%, whereas RAPID PAP showed 72% accuracy. CONCLUSION: AgNOR analysis may be useful as a quantitative marker of incipient cellular alterations and hence would be helpful in assessing suspicious lesions and thus can be regarded as a valuable adjunct. PMID- 27238080 TI - Science as a money-spinner? PMID- 27238081 TI - TRIM24 Is an Oncogenic Transcriptional Activator in Prostate Cancer. AB - Androgen receptor (AR) signaling is a key driver of prostate cancer (PC). While androgen-deprivation therapy is transiently effective in advanced disease, tumors often progress to a lethal castration-resistant state (CRPC). We show that recurrent PC-driver mutations in speckle-type POZ protein (SPOP) stabilize the TRIM24 protein, which promotes proliferation under low androgen conditions. TRIM24 augments AR signaling, and AR and TRIM24 co-activated genes are significantly upregulated in CRPC. Expression of TRIM24 protein increases from primary PC to CRPC, and both TRIM24 protein levels and the AR/TRIM24 gene signature predict disease recurrence. Analyses in CRPC cells reveal that the TRIM24 bromodomain and the AR-interacting motif are essential to support proliferation. These data provide a rationale for therapeutic TRIM24 targeting in SPOP mutant and CRPC patients. PMID- 27238082 TI - Compounds Triggering ER Stress Exert Anti-Melanoma Effects and Overcome BRAF Inhibitor Resistance. AB - We have discovered and developed a series of molecules (thiazole benzenesulfonamides). HA15, the lead compound of this series, displayed anti cancerous activity on all melanoma cells tested, including cells isolated from patients and cells that developed resistance to BRAF inhibitors. Our molecule displayed activity against other liquid and solid tumors. HA15 also exhibited strong efficacy in xenograft mouse models with melanoma cells either sensitive or resistant to BRAF inhibitors. Transcriptomic, proteomic, and biochemical studies identified the chaperone BiP/GRP78/HSPA5 as the specific target of HA15 and demonstrated that the interaction increases ER stress, leading to melanoma cell death by concomitant induction of autophagic and apoptotic mechanisms. PMID- 27238083 TI - Premature Bioprosthetic Aortic Valve Degeneration Associated with Allergy to Galactose-Alpha-1,3-Galactose. AB - We present the cases of two patients with bioprosthetic aortic valves who developed an allergy to alpha-gal. Each had premature degeneration of their bioprosthesis and demonstrated rapidly increasing transvalvular gradients after development of their allergy. Each underwent successful replacement with a mechanical aortic valve within 1-2 years of symptom onset. doi: 10.1111/jocs.12764 (J Card Surg 2016;31:446-448). PMID- 27238084 TI - Centralized primary care of advanced ovarian cancer improves complete cytoreduction and survival - A population-based cohort study. AB - OBJECTIVE: To evaluate centralized primary care of advanced ovarian and fallopian tube cancers in a complete population cohort in relation to complete cytoreduction, time interval from surgery to chemotherapy and relative survival. METHODS: A regional population-based cohort study of women diagnosed with primary ovarian and fallopian tube cancers and included in the Swedish Quality Registry (SQR) during 2008-2013 in a region where primary care of advanced stages was centralized in 2011. Surgical, oncological characteristics, outcomes, follow-ups and relative survivals were analyzed. RESULTS: There were 817 women diagnosed with ovarian and fallopian tube cancers during 2008-2013 and 523 were classified as FIGO stage III-IV and further analyzed. Primary debulking surgery (PDS) was performed in 81% and neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) in 11%. Complete cytoreduction at PDS was performed in 37% before compared to 49% after centralization (p<0.03). The chemotherapy protocols were identical in the cohorts and they received and completed the planned chemotherapy equally. The time interval between PDS and chemotherapy was 36days (median) before compared to 24days after centralization (p<0.01). The relative 3-year survival rate in women treated by PDS was 44% compared to 65% after centralization and the estimated excess mortality rate ratio (EMRR) was reduced (RR 0.58; 95% CI 0.42-0.79). Comparing the complete cohorts before and after centralization, regardless primary treatment, the relative 3-year survival rate increased from 40% to 61% with reduced EMRR (RR 0.59; 95% CI 0.45-0.76). CONCLUSION: Centralized primary care of advanced ovarian and fallopian tube cancers increases complete cytoreduction, decreases time interval from PDS to chemotherapy and improves relative survival significantly. PMID- 27238085 TI - Two new flavans from the trunk and leaves of Horsfieldia glabra. AB - Two new flavans, (2R, 4R)-4'-hydroxy-3',5'-methyl-6,7-methylenedioxy-4-O-2' cycloflavan (1), and (2R, 4R)-4'-hydroxy-3'-methyl-6,7-methylenedioxy-4-O-2' cycloflavan (2), along with six known compounds were isolated from the trunk and leaves of Horsfieldia glabra. Their structures were elucidated by means of extensive spectroscopic analysis. Compounds 1 and 2, together with 4-7 were assessed for their cytotoxicity against five human cancer cell lines (HL-60, SMMC 7721, A-549, MCF-7 and SW-480), and the result showed that they had no activity. PMID- 27238087 TI - Sarcolipin and uncoupling protein 1 play distinct roles in diet-induced thermogenesis and do not compensate for one another. AB - OBJECTIVE: It is well known that uncoupling protein 1 (UCP1) in brown adipose tissue plays an important role in diet-induced thermogenesis. In this study, whether sarcolipin (SLN), a regulator of sarco/endoplasmic reticulum Ca(2+) ATPase pump in muscle, is also an important player of diet-induced thermogenesis was investigated, as well as whether loss of SLN could be compensated by increased UCP1 expression and vice versa. METHODS: Age- and sex-matched UCP1(-/-) , SLN(-/-) , and double knockout for both UCP1 and SLN mice maintained in C57Bl/6J background were challenged to high-fat diet for 12 weeks and then analyzed for weight gain, alterations in serum metabolites, and changes in thermogenic protein expression. RESULTS: Loss of either SLN or UCP1 alone was sufficient to cause diet-induced obesity. No compensatory upregulation of UCP1 in SLN(-/-) mice or vice versa was found. Paradoxically, loss of both mechanisms failed to exacerbate the obesity phenotype. CONCLUSIONS: Data suggest that both SLN- and UCP1-based adaptive thermogenic mechanisms were essential for achieving maximal diet-induced thermogenesis. When both mechanisms were absent, less efficient thermogenic mechanisms were activated to counter energy imbalance. PMID- 27238086 TI - NEIGHBOURHOOD POVERTY, PERCEIVED DISCRIMINATION AND CENTRAL ADIPOSITY IN THE USA: INDEPENDENT ASSOCIATIONS IN A REPEATED MEASURES ANALYSIS. AB - This study examines the independent effects of neighbourhood context (i.e. neighbourhood poverty) and exposure to perceived discrimination in shaping risk of obesity over time. Weighted three-level hierarchical linear regression models for a continuous outcome were used to assess the independent effects of neighbourhood poverty and perceived discrimination on obesity over time in a sample of 157 non-Hispanic Black, non-Hispanic White and Hispanic adults in Detroit, USA, in 2002/2003 and 2007/2008. Independent associations were found between neighbourhood poverty and perceived discrimination with central adiposity over time. Residents of neighbourhoods with high concentrations of poverty were more likely to show increases in central adiposity compared with those in neighbourhoods with lower concentrations of poverty. In models adjusted for BMI, neighbourhood poverty at baseline was associated with a greater change in central adiposity among participants who lived in neighbourhoods in the second (B=3.79, p=0.025) and third (B=3.73, p=0.024) poverty quartiles, compared with those in the lowest poverty neighbourhoods. The results from models that included both neighbourhood poverty and perceived discrimination showed that both were associated with increased risk of increased central adiposity over time. Residents of neighbourhoods in the second (B=9.58, p<0.001), third (B=8.25, p=0.004) and fourth (B=7.66, p=0.030) quartiles of poverty were more likely to show greater increases in central adiposity over time, compared with those in the lowest poverty quartile, with mean discrimination at baseline independently and positively associated with increases in central adiposity over time (B=2.36, p=0.020). The results suggest that neighbourhood poverty and perceived discrimination are independently associated with a heightened risk of increase in central adiposity over time. Efforts to address persistent disparities in central adiposity in the USA should include strategies to reduce high concentrations of neighbourhood poverty as well as discrimination. PMID- 27238089 TI - Environmental (Per)chlorate Reduction: a collaborative effort in syntrophy? PMID- 27238088 TI - Persistence and immunogenicity of chemically attenuated blood stage Plasmodium falciparum in Aotus monkeys. AB - Malaria is a disease caused by a protozoan of the Plasmodium genus and results in 0.5-0.7million deaths per year. Increasing drug resistance of the parasite and insecticide resistance of mosquitoes necessitate alternative control measures. Numerous vaccine candidates have been identified but none have been able to induce robust, long-lived protection when evaluated in malaria endemic regions. Rodent studies have demonstrated that chemically attenuated blood stage parasites can persist at sub-patent levels and induce homologous and heterologous protection against malaria. Parasite-specific cellular responses were detected, with protection dependent on CD4+ T cells. To investigate this vaccine approach for Plasmodium falciparum, we characterised the persistence and immunogenicity of chemically attenuated P. falciparum FVO strain parasites (CAPs) in non splenectomised Aotus nancymaae monkeys following administration of a single dose. Control monkeys received either normal red blood cells or wild-type parasites followed by drug treatment. Chemical attenuation was performed using tafuramycin A, which irreversibly binds to DNA. CAPs were detected in the peripheral blood for up to 2days following inoculation as determined by thick blood smears, and for up to 8days as determined by quantitative PCR. Parasite-specific IgG was not detected in monkeys that received CAPs; however, in vitro parasite-specific T cell proliferation was observed. Following challenge, the CAP monkeys developed an infection; however, one CAP monkey and the infection and drug-cure monkeys showed partial or complete resistance. These experiments lay the groundwork for further assessment of CAPs as a potential vaccine against malaria. PMID- 27238090 TI - Nebulized liposomal amphotericin prophylaxis in lung transplantation: shall we take it or leave it? PMID- 27238091 TI - A universal and reliable assay for molecular sex identification of three-spined sticklebacks (Gasterosteus aculeatus). AB - In heterogametic species, biological differences between the two sexes are ubiquitous, and hence, errors in sex identification can be a significant source of noise and bias in studies where sex-related sources of variation are of interest or need to be controlled for. We developed and validated a universal multimarker assay for reliable sex identification of three-spined sticklebacks (Gasterosteus aculeatus). The assay makes use of genotype scores from three sex linked loci and utilizes Bayesian probabilistic inference to identify sex of the genotyped individuals. The results, validated with 286 phenotypically sexed individuals from six populations of sticklebacks representing all major genetic lineages (cf. Pacific, Atlantic and Japan Sea), indicate that in contrast to commonly used single-marker-based sex identification assays, the developed multimarker assay should be 100% accurate. As the markers in the assay can be scored from agarose gels, it provides a quick and cost-efficient tool for universal sex identification of three-spined sticklebacks. The general principle of combining information from multiple markers to improve the reliability of sex identification is transferable and can be utilized to develop and validate similar assays for other species. PMID- 27238093 TI - Time-varying coefficients models for recurrent event data when different varying coefficients admit different degrees of smoothness: application to heart disease modeling. AB - We consider a class of semiparametric marginal rate models for analyzing recurrent event data. In these models, both time-varying and time-free effects are present, and the estimation of time-varying effects may result in non-smooth regression functions. A typical approach for avoiding this problem and producing smooth functions is based on kernel methods. The traditional kernel-based approach, however, assumes a common degree of smoothness for all time-varying regression functions, which may result in suboptimal estimators if the functions have different levels of smoothness. In this paper, we extend the traditional approach by introducing different bandwidths for different regression functions. First, we establish the asymptotic properties of the suggested estimators. Next, we demonstrate the superiority of our proposed method using two finite-sample simulation studies. Finally, we illustrate our methodology by analyzing a real world heart disease dataset. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27238092 TI - Patterns of major wound complications following multidisciplinary therapy for lower extremity soft tissue sarcoma. AB - BACKGROUND AND OBJECTIVES: The purpose of this study was to determine the pattern and timing of major wound complications (MWCs) in patients at our institution who received multimodality treatment for lower extremity soft tissue sarcoma (LE-STS) and to evaluate the impact of MWCs on tumor control and patient outcomes. METHODS: The medical records of 102 LE-STS patients treated with limb-sparing surgery and radiation therapy were reviewed. MWCs were defined as secondary operations with anesthesia, seroma/hematoma aspiration, admission for IV antibiotics, or persistent deep packing. RESULTS: MWCs occurred in 22% of patients, with 45% of events occurring >120 days after resection. On multivariate analysis, preoperative external beam radiation therapy (EBRT) (OR 4.29, 95% CI 1.06-17.40, P = 0.042) and skin graft placement (OR 6.39, 95% CI 1.37-29.84, P = 0.018) were found to be independent predictors of MWCs. MWC occurrence did not predict for chronic toxicity and did not impact tumor control or survival. CONCLUSIONS: A considerable proportion of MWCs occur >120 days from surgical resection with preoperative EBRT and skin graft placement independent predictors for MWCs. While an additional source of morbidity, MWC occurrence did not impact tumor control, nor did it predict for chronic toxicity. J. Surg. Oncol. 2016;114:385-391. (c) 2016 Wiley Periodicals, Inc. PMID- 27238094 TI - A Modular Synthetic Approach to Monocyclic 1,4-Azaborines. AB - A simple and general method for the synthesis of a wide range of monocyclic 1,4 azaborines, including the first examples containing B heteroatoms is described. Post-heterocycle-formation olefin isomerization was employed as a key strategy. This new synthetic method provides fundamental insight into the resonance stabilization and photophysical properties of 1,4-azaborines. PMID- 27238095 TI - For the good of all. AB - The poll tax furore gathered momentum last week, with daily reports of civil disturbance at the doors of Council chambers where councillors have been attempting to set a rate. Thecharge's unpopularity among party faithfuls and opponents alike is having a dramatic effect on the opinion polls. The Conservative Party now faces the prospect of overturning its biggest evermid-term slump. Based on the widespread dissatisfaction with the community charge, the Government has no doubt won little favour with the hundreds of thousands of nurses who will face paying the poll tax from April 1. PMID- 27238096 TI - HVA report calls for huge staffing increase. AB - Greenwich health visitors launched a damning 'blue-print' report last week in their campaign for cash to prevent increasing infant and child deaths. PMID- 27238097 TI - Boosting nurses' autonomy. AB - Radical proposals to boost nurses' professional autonomy and end the current system of role extension and certificates of competence have been launched by the Welsh National Board (WNB). PMID- 27238098 TI - [Not Available]. AB - Britain's smoking nurses are urged to support National No Smoking Day by Royal College of Nursing General Secretary, Christine Hancock, pictured leafletting at RCN headquarters. Meanwhile, copies of the report Towards a smoke-free health service'have sold out because of huge demand from staff. 'We want to persuade the 40 percent of nurses who smoke that they should give up,' said Tom Hurst. Honorary Secretary of Quit. The report is available from: Tom Hurst, 20 Grange Meadow. Banstead. Surrey S.M7 3RD. Price L2 plus 50p postage. PMID- 27238099 TI - Social class indicatorsin cancer death figures. AB - Poor people are more likely to the fromcancer than men and women from highersocial classes, according to research published last week. The study from the Office of Population Censuses and Surveys shows poor people are more prone tothe disease and survive for a shorter timeafter diagnosis than the well-off. PMID- 27238100 TI - Budget appeal for tax exemptions on care. AB - Nurses have urged Chancellor John Major to boost the National Health Service by lifting the tax on childcare facilities in next Tuesday's Budget. PMID- 27238101 TI - Midwives welcome sample maternity contract. AB - Midwives last week gave a cautious welcome to a sample contract for maternity services contained in the Department of Health's guidance on how to set up contracts from April 1991. PMID- 27238102 TI - Rebate anomaly disqualifies students. AB - Student nurses on a Project 2000 pilot course are facing full poll tax bills because an anomaly disqualifies them from rebates. PMID- 27238103 TI - Elderly could be evicted over cash crisis. AB - Thousands of elderly residents of nursing homes could be evicted unless the Government changes its plans for community care, the Commons Social Services Committee has warned. PMID- 27238105 TI - [Not Available]. AB - Retired nurses Helen Onley (left) and Marion Holloway (second right), who helped start a Friends of Community Health Service in SW London, presented valuable health promotion equipment to a Richmond clinic last week. PMID- 27238104 TI - Nurses' dilemma over terminally ill patients. AB - Evidence that four out of five GPs would lie to a patient if an illness was terminal or if they thought they could not cope with the news poses serious ethical dilemmas for nurses, it was claimed last week. PMID- 27238106 TI - Unions under threat inself governing trusts. AB - Self-governing hospitals will be free toscrap nurses' union recognition and impose their own working conditions, Health Minister Virginia Bottomley confirmed last week. PMID- 27238107 TI - Damning report calls for contractor's removal. AB - The biggest NHS private cleaning contractor is accused in a trades union report of leaving operating theatres, wards and corridors dirty. The report calls on health authorities to remove the contractors from the approved lists of legitimate health service contractors. PMID- 27238109 TI - New approach key to P2000 success. AB - The success of Project 2000 depends onthe adoption of open learning on a largescale, nurse educationalists were told lastweek. PMID- 27238110 TI - Arsonist continues residence attacks. AB - An arsonist is still stalking nurses' residences in Colchester despite three months of vigilant security, the Royal College of Nursing has warned. PMID- 27238112 TI - World News. AB - United States Nurse practitioners and clinical nurse specialists working in rural areas of the United States will be eligible for direct Medicare reimbursement under new legislation. PMID- 27238113 TI - Parliament. AB - A health authority finance director has been sacked after protesting at colleagues booking into expensive hotels and restaurants while cash curbs were stopping nurse recruitment. PMID- 27238114 TI - Nurses in drive to detect early asthma. AB - Teams of nurses are touring West Country sports centres and shopping areas this month as part of a new drive to recruit members of the public in the battle for early detection of asthma. PMID- 27238116 TI - Risk of breast cancerfor late mothers. AB - Women who have their first full-termpregnancy when they are over 35 are at ahigher risk of breast cancer than womenwith no children, research has shown. PMID- 27238115 TI - HRT advice for menopausal women. AB - A new leaflet on hormone replacement therapy (HRT), which aims to answer common questions on HRT, has been published by the Amarant Trust (a medical charity concerned with the menopause). PMID- 27238117 TI - New DDI drug to slow AIDS process. AB - Trials on a new drug to combat AIDS have been announced by the Medical Research Council. PMID- 27238118 TI - Coffee increases risk of heart disease. AB - Drinking large amounts of coffee significantly increases the risk of coronary heart disease, a study of nearly 40,000 people in Norway has found. PMID- 27238120 TI - Risks associated with thrombolysis. AB - Enthusiasm for the use of thrombolyticagents may result in some patients beingtreated inappropriately, Southamptonresearchers report. PMID- 27238119 TI - Schizophrenia admissions have fallen. AB - The incidence of schizophrenia in England and Wales appears to be plummeting, according to research published last week. Doctors from the Institute of Psychiatry in South London say that over the last 34 years, hospital admissions for the condition have fallen by almost 50 per cent. The researchers offer no explanation for their findings, but state that misdiagnosis or greater emphasis on community care are unlikely to account for the results. PMID- 27238121 TI - New pump offers benefits in ischaemia. AB - Use of a new pumping device could reduce the need for urgent cardiac replacement or invasive methods of support for the failing heart. PMID- 27238122 TI - Treatment not helpful in Alzheimer's. AB - Treatment with the cholinesterase inhibitor tacrine and lecithin does not improve the symptoms of Alzheimer'sdisease and may induce hepatitis, researchers say. Following a report of beneficialeffects they performed a multicentre double blind, placebo controlled, crossovertrial involving 67 patients given a meanof ll4mg tacrine or placebo daily plus1,200mg lecithin for four weeks. Cognitive, behavioural and overall state weremeasured using rating scales. PMID- 27238123 TI - Monitors and sudden infant deaths. AB - Most of the apnoea monitors supplied for home use in the UK do not meet expert recommendations. PMID- 27238124 TI - Adequate kidneys for donation in Austria. AB - The shortfall in kidneys for transplantation in the United Kingdom is well known but researchers from Austria report that they have overcome a similar problem. PMID- 27238125 TI - Taking the road ahead. AB - Are you confident that you could show evidence of innovative practice, excellence in professional practice or further learning and compile a personal professional profile good enough to keep you on the nursing register? PMID- 27238126 TI - Hearty handshakes and brutal honesty. AB - Kenneth Clarke is forthright and honest, attimes brutally so, about his views on particular trades unions and opponents ofthe White Paper. PMID- 27238127 TI - Handling techniquesfor nurses. AB - Nurses are expected to be competent andknowdedgeable about patient handling techniques. Considering that this is so, it mightbe expected that nurses should be experts onthe subject. Yet far too many nurses sufferdisabling back injuries as a direct result of this activity. PMID- 27238128 TI - Listings. PMID- 27238129 TI - A Complete guide to what's on in nursing nationwide. AB - Nursing Standard's listings section is a completely free service for its readers. To ensure maximum publicity for any event connected with your profession, be sure to let us know so that it can be included in our exhaustive nationwide guide to what's on in nursing. PMID- 27238130 TI - Lack of compassion. AB - I am a gay nurse working with people with AIDS/HIV and Nursing Standard's February 28 - March 6 issue has three articles of particular interest to me: Tim Rice's interview with Baroness Cox, CharlotteAlderman's interview with a nurse who has AIDS and the World Health Organization news story about children exposed to HIV in Romania. PMID- 27238131 TI - Supporting another view. AB - Baroness Cox has been treated very badly. It is terrible that militant groups of homosexuals and socialists can threaten to boycott a conference of which she is co-chairman and cause her to withdraw. Their bluff should have been called. They are all holding us to ransom. PMID- 27238132 TI - Raising awareness. AB - Having just read the superb article about Shane Snape 'No Mr Average' (Nursing Standard February 28 - March 6), it is becoming increasingly obvious that HIV/AIDS sufferers and people working to improve their care are breaking new ground in exposing us all to the realities of coping with and caring for terminal illnesses. PMID- 27238133 TI - Baroness Coxand Section 28. AB - In reply to an article in Nursing Standard (February28 - March 6), 'Facts, please' by Baroness Cox, I feel I must reply. While welcoming the fact that Baroness Cox has with drawn from the chair of the forth coming RCN/BMA conference on HIV and AIDS, I would question her view that she has been the victim of 'unfounded', 'misguided' and 'possiblymalicious' attacks. Her accusation that some nurses who disagree with her are prejudiced, bigoted and even unprofessional cannot go unchallenged in the absence of evidence. PMID- 27238134 TI - Transsexual torment. AB - Name and address supplied I have read with interest articles on such subjects as homosexuality, AIDS and homophobia in theNursing Standard. I can feel a certain amount of empathy for these people but I believe what is more damaging within the nursing profession, is the neurotic behaviour of nurses towards transsexuals. PMID- 27238135 TI - The IANE - a clarification. AB - 'Organising professionally' by Paul Moorbath (Nursing Standard February 7 - 13) gave a somewhat misleading impression of the role and activities of the RCN Institute of Advanced Nursing Education (IANE).I write to clarify matters and to outline the role and the courses on offer. PMID- 27238136 TI - For the sake of humanity. AB - Having watchedCutting Edge, a documentary about the mentally handicapped, mentally ill and the disabled living together in an asylum on the Greek island of Leros, (February 26), I would like to express my feelings of outrage, anger, sadness and shame, that we as human beings can allow our fellow humans to be subjected to utter degredation and suffering. PMID- 27238138 TI - Crisis Intervention Verbatim Kfir N Crisis Intervention Verbatim Hemisphere Publishing 170pp L9.95 0-89116-837-0. AB - It is more than 30 years since Erik Lindemann and Gerald Caplan did their foundational work in elaborating the early theories of crisis intervention, and more than 20 years since these theories became popularised and the volume of literature on the subject burgeoned. PMID- 27238139 TI - Reasons to smile. AB - Another of our regular looks at the news in pictures. PMID- 27238140 TI - Learning through a loophole. AB - 'Not in my back yard' hasbecome a catchphrase todescribe local reluctance toaccept a factory, housingestate or other developmentas a neighbour. Aparticularly unwelcomeaddition to manycommunities is a landfillsite. Holes in the ground -usually old quarries - are thedestination ol over 80 percent of Britain's solid waste. Time-honoured as themethod is, public hostilityto new plans for landfillingis understandable. PMID- 27238141 TI - Gossip. AB - *No doubt whatsoever -this month's Royal College of Nursing Association of Nursing Students bash gets the 'Scorching conference of the year so far' award. PMID- 27238142 TI - The microbe file. AB - SPIROCHAETES - 2 Other Treponemata(non-venereal syphilis) Treponema pertenue causes yaws, a chronic disease in Africa and South America. Spread: direct contact with infected lesions. PMID- 27238143 TI - Stromal Cell-Derived Factor-1 Alpha Is Decreased in Women With Migraine With Aura. AB - BACKGROUND: Endothelial dysfunction may contribute to the pathophysiology of migraine with aura. Stromal cell-derived factor-1 alpha (SDF-1alpha) is involved in the maintenance of endothelial integrity via mobilization of vascular stem cells. OBJECTIVES: We sought to determine whether SDF-1alpha levels are decreased in women with MA. METHODS: In this post hoc analysis of a case-cohort study, levels of SDF-1alpha were determined by enzyme-linked immunosorbent assay. Endothelial function was assessed using peripheral arterial tonometry. Arterial stiffness was assessed by fingertip tonometry derived and heart-rate-adjusted augmentation index (AI). RESULTS: Twenty-eight women with MA and 27 age-matched healthy women were included in this study. Levels of SDF-1alpha were significantly lower in women with MA compared to age- and risk factor-matched healthy women (1763 +/- 281 vs 2013 +/- 263 pg/mL, P = 0.006). SDF-1alpha levels were positively correlated with AI in healthy women (r = 0.49, P = 0.009), but not in women with MA (r = 0.05, P = 0.78). SDF-1alpha levels were negatively correlated with CD144-positive endothelial microparticles (EMP; r = -0.31, P = .02), and activated CD62E-positive EMP (r = -0.35, P = .01). CONCLUSION: Levels of SDF-1alpha are decreased in women with MA and are associated with EMPs as a surrogate marker of endothelial dysfunction. This might contribute to the pathophysiology and vascular risk in MA, but evidence from larger prospective studies is warranted. PMID- 27238144 TI - Gene-Tailored Treatments for Brain Disorders: Challenges and Opportunities. AB - Brain disorders pose major challenges to medicine and treatment innovation. This is because their spectrum spans inflammatory, degenerative, traumatic/ischaemic, and neoplastic disease processes with a complex and often ill- understood aetiology. An improved genetic and genomic understanding of specific disease pathways offers new approaches to these challenges, but at present it is in its infancy. Here, we review different aspects of the challenges facing neuromedicine, give examples of where there are advances, and highlight challenges to be overcome. We see that some disorders such as Huntington's disease are the product of single gene mutations, whose discovery has been leading to the development of new targeted interventions. In the field of neurosurgery, the identification of a number of mutations allows an elaborated genetic analysis of brain tumours and opens the door to individualised therapies. Psychiatric disorders remain the area where progress is slow. Genetic analyses show that for major common disorders such as schizophrenia and depression there are no single gene alterations which offer options for targeted therapy development. However, new approaches are being developed to leverage genetic information to predict patients' responses to treatment. These recent developments hold promise for early diagnosis, follow-up with personalised treatments with adjusted therapeutic doses, predictable responses, reduced adverse drug reactions, and personal health planning. The scenario is promising but calls for increased support for curiosity-driven research into the mechanisms of normal brain functioning as well as challenging adaptations of health care and research infrastructures, encompassing legal frameworks for analysing large amounts of personal data, a flexible regulatory framework for correlating big data analyses in cooperative networks between academia and the drug development industry, and finally new strategies for brain banking in order to increase access to brain tissue samples. To make personalised medicine for brain disorders a reality, a joint effort between all relevant stakeholders - among which patients and patient organisations should play an important role - is required. PMID- 27238147 TI - [In Process Citation]. PMID- 27238145 TI - Increased blood flow and vasculature in solar lentigo. AB - Solar lentigo (SL) is a hallmark of ultraviolet (UV)-induced photoaged skin and growing evidence implicates blood vessels in UV-associated pigmentation. In this study, we investigated whether the vasculatures are modified in SL. Twenty-five women with facial SL were enrolled and colorimetric and blood flow studies were performed. There was a significant increase in erythema which was associated with increased blood flow in the lesional skin compared with perilesional normal skin. Immunohistochemical studies with 24 facial SL biopsies consistently revealed a significant increase in vessel density accompanied by increased levels of vascular endothelial growth factor expression. CD68 immunoreactivity was significantly higher in lesional skin suggesting increased macrophage infiltration in SL. In conclusion, SL is characterized by increased blood flow and vasculature. These findings suggest the possible influence of the characteristics of vasculature on development of SL. PMID- 27238148 TI - [In Process Citation]. PMID- 27238146 TI - Conformational IgE epitopes of peanut allergens Ara h 2 and Ara h 6. AB - BACKGROUND: Cross-linking of IgE antibody by specific epitopes on the surface of mast cells is a prerequisite for triggering symptoms of peanut allergy. IgE epitopes are frequently categorized as linear or conformational epitopes. Although linear IgE-binding epitopes of peanut allergens have been defined, little is known about conformational IgE-binding epitopes. OBJECTIVE: To identify clinically relevant conformational IgE epitopes of the two most important peanut allergens, Ara h 2 and Ara h 6, using phage peptide library. METHODS: A phage 12mer peptide library was screened with allergen-specific IgE from 4 peanut allergic patients. Binding of the mimotopes to IgE from a total of 29 peanut allergic subjects was measured by ELISA. The mimotope sequences were mapped on the surface areas of Ara h 2 and Ara h 6 using EpiSearch. RESULTS: Forty-one individual mimotopes were identified that specifically bind anti- Ara h 2/Ara h 6 IgE as well as rabbit anti-Ara h 2 and anti-Ara h 6 IgG. Sequence alignment showed that none of the mimotope sequences match a linear segment of the Ara h 2 or Ara h 6 sequences. EpiSearch analysis showed that all the mimotopes mapped to surface patches of Ara h 2 and Ara h 6. Eight of the mimotopes were recognized by more than 90% of the patients, suggesting immunodominance. Each patient had distinct IgE recognition patterns but the recognition frequency was not correlated to the concentration of peanut specific IgE or to clinical history. CONCLUSIONS: The mimotopes identified in this study represent conformational epitopes. Identification of similar surface patches on Ara h 2 and Ara h 6 further underscores the similarities between these two potent allergens. PMID- 27238149 TI - ["Kolibritegn" og "Mickey Mouse-tegn" ved progressiv supranukleaer parese]. PMID- 27238150 TI - [Bleeding oesophageal varices in a seven-year-old boy supposedly as a late complication to neonatal umbilical venous catheter]. AB - A seven-year-old boy was admitted with haematemesis. The boy was originally born at 27 weeks' gestational age. His neonatal period had been complicated by sepsis, for which he was treated with antibiotics through an umbilical venous catheter (UVC). A gastroscopy showed grade III oesophageal varices with bleeding. He was examined thoroughly for other causes of portal hypertension, but none were found. Portal hypertension caused by UVC in the neonatal period is a rare but very serious complication to neonatal UVC. PMID- 27238151 TI - [Onset of hereditary metabolic encephalopathy can be seen after the neonatal period]. AB - Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder causing accumulation of the branched amino acids valin, isoleucin, leucin and their toxic metabolites resulting in ketoacidosis, progressive neurological deterioration and cerebral oedema. The classical form presents in the first days of life. In contrast, the intermittent form of MSUD presents later in childhood and is difficult to diagnose biochemically. Clinical awareness is important due to high mortality if not treated. We here present two cases with late-onset intermittent MSUD. PMID- 27238152 TI - [Palliative treatment of malignant gastric outlet obstruction]. AB - In gastric outlet obstruction (GOO) the passage from the stomach to the intestine is obstructed. The condition is referred to as malignant GOO if cancer is the reason. Self-expanding metal stents (SEMS) and gastrojejunostomy (GEA) are the therapeutic options for palliation, with SEMS often being recommended as first choice. However, no major difference in terms of clinical success has been shown between SEMS and GEA in comparative studies. Thus, the choice between SEMS and GEA should be made on an individual basis. If SEMS is chosen, covered and uncovered stents offer equal success rates. PMID- 27238153 TI - Glycyrrhizic Acid Ameliorates Cognitive Impairment in a Rat Model of Vascular Dementia Associated with Oxidative Damage and Inhibition of Voltage-Gated Sodium Channels. AB - Vascular dementia (VD) is the second most common cause of cognitive impairment in the elderly population. Our study aims to investigate the neuroprotective effects of glycyrrhizic acid (GA), a major active constituent of Glycyrrhiza glabra root, in a VD rat model induced by permanent occlusion of the bilateral common carotid arteries. Spatial cognitive function was examined by the Morris water maze test and synaptic plasticity was explored by assessing long-term potentiation. The results showed that GA (20 mg/kg for 5 days) significantly improved the performance of learning and memory of VD rats in the Morris water maze test and attenuated induction of long-term potentiation. Histopathological studies showed that GA significantly attenuated cell damage in VD rats. Malondialdehyde levels and superoxide dismutase activity were analyzed in the hippocampus and cortex to investigate anti-oxidant status. The results showed that GA decreased the level of lipid peroxidation and increased the activity of superoxide dismutase in VD rats. Lastly, whole-cell patch-clamp analysis was used to examine the effect of GA on voltage-gated sodium channels (VGSCs) in hippocampal CA1 pyramidal neurons. GA (10, 20 and 50 MUM) inhibited the current amplitude of the VGSCs. These results suggest that the neuroprotective e.ects of GA in VD rats relate to the reduction of oxidative stress and inhibition of VGSCs. Our study provides experimental evidence for the application of GA in the treatment of cognitive deficits induced by Alzheimer's disease, stroke, or traumatic brain injury. PMID- 27238154 TI - Neuroinflammatory Markers in Spontaneously Hypertensive Rat Brain: An Immunohistochemical Study. AB - BACKGROUND: Spontaneously hypertensive rats (SHR) represent a model of hypertension and vascular injury. In the past decade, SHR were also considered as a model of vascular dementia. Several studies have shown that cerebrovascular changes in SHR may mimic brain vascular diseases of hypertensive individuals. Vascular and cerebrovascular changes during hypertension are often linked to inflammatory processes. Inflammation frequently affects vascular endothelium, perivascular astrocytes that form blood brain barrier. This inflammatory reaction may lead to neuro-inflammation with consequent damage of brain tissue. A significant brain atrophy, a reduction of white matter volumes, and BBB dysfunction were found in SHR. Micro- and macrogliosis in deep cortical regions were also observed. Based on these findings, this study was designed to define neuroinflammation entity in SHR, using immunohistochemistry technique for different inflammatory markers. METHODS: Thirty-two-week-old SHR and age-matched Wistar Kyoto rats were used. Brain was processed for immunohistochemistry. Astrogliosis markers for astrocytes (glial fibrillary acidic protein) and microglia (isolectin IB4) were used. The pro-inflammatory interleukins (IL-1b, IL 6) and tumor necrosis factor alpha (TNFa) expression were also evaluated. RESULTS: In SHR brain, an obvious glial reaction was found both for GFAP immunoreactive astrocytes and for microglia. The pro-inflammatory IL-1b was significantly increased in CA1 sub-field of SHR hippocampus. The TNFa expression was higher in frontal cortex of SHR compared to WKY. CONCLUSION: The above neuromorphological evidences indicate that SHR are predictive animal models for vascular brain disorders and neuroinflammation. Furthermore, this model may be useful to evaluate anti-inflammatory and neuroprotective effects of different molecules. PMID- 27238155 TI - Brain Magnetic Stimulation in Animal Models: A Valuable Lesson for Clinical Applications. AB - Transcranial magnetic stimulation (TMS) is more than a mere tool for clinical non invasive approaches to stimulate and synchronize the neuronal activity in the brain. Electromagnetic stimulation through TMS has recently emerged as a therapeutic alternative for the treatment of different neurological disorders. Among the many properties recently discovered for TMS, its action as an accounting factor for neuroplasticity and neurogenesis is among its most promising features. Translational studies in animal models offer various advantages and also bridge this knowledge gap due to their direct assessment of the brain stimulation impact at the neural level. These profiles have been obtained through the study of animal models, which, in turn, have served for the establishment of the action mechanisms of this method. In this review, we revise and discuss evidence collected on the promising properties of TMS after visiting the different animal models developed so far, and provide a practical perspective of its possible application for clinical purposes. PMID- 27238156 TI - Tubular Transport in Acute Kidney Injury: Relevance for Diagnosis, Prognosis and Intervention. AB - The clinical diagnosis and recovery of acute kidney injury (AKI) are mainly based on the rapid decline of glomerular filtration rate (GFR) and its subsequent recovery. The factors that determine kidney recovery and reduce the risk of subsequent progression to chronic kidney disease (CKD), however, are poorly understood. Thus, there is a need to better define the magnitude and time pattern of changes in kidney function during AKI and its recovery that go beyond GFR. Tubular transport regulates body homeostasis and the associated transport work is a primary determinant of the kidneys' energy needs. The tubular system is at the center of the pathophysiology of AKI and its recovery. In particular, proximal tubules and thick ascending limbs have been proposed to act as sensors, effectors and injury recipients of AKI stimuli. Surprisingly little attention has been given to aspects of tubular transport function in AKI and the relevance for kidney recovery. This review aims to outline changes in tubular transport function in AKI, discusses their potential consequences and relevance for the diagnosis and prognosis of AKI and its recovery, including changes in GFR, and poses the question whether tubular transport provides an opportunity for intervention to rest the tubular system, which may have consequences for the progression to CKD. (c) 2016 S. Karger AG, Basel. PMID- 27238157 TI - Changes in Object Relations over the Course of Psychodynamic Psychotherapy. AB - : This study explores whether object relations (OR) functioning improves over the course of psychodynamic psychotherapy, and whether this improvement is related to symptom decrease as well as therapist technique. The sample consisted of 75 outpatients engaged in short-term psychodynamic psychotherapy at a university based psychological service clinic. OR functioning was assessed pre- and post treatment by independent raters using the Social Cognition and Object Relations Scale from in-session patient relational narratives. The Comparative Psychotherapy Process Scale was used to assess therapist activity and psychotherapy techniques early in treatment. Independent clinical ratings of global OR and psychotherapy techniques were conducted, and rater agreement was found to be in the excellent range. Regarding the results, global OR (overall quality and level of interpersonal functioning) significantly improved with large effect size after psychodynamic therapy. Change in global OR functioning was significantly and positively related to the incidence of psychodynamic techniques in early sessions, as were number of psychotherapy sessions attended. Patient self-reported reliable change in symptomatology and reliable change in global OR were significantly related as well. Multilevel model analyses confirmed pairwise correlations accounting for therapist effects on a variety of process-outcome measures, number of sessions attended, initial levels of psychiatric symptoms, employment of therapeutic techniques as well overall OR functioning at outcome. Limitations of the present study, future research directions and implications for clinical practice are also discussed. Copyright (c) 2016 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Psychodynamic psychotherapy seems to be effective in improving object relations functioning. Consider use of psychodynamic techniques early in treatment with patients expressing more pathological object representations. Improvements in object relations functioning during psychodynamic psychotherapy are also related to adaptive changes in patient self reported symptomatology. Therapist effects were also present for the study. As such therapists should be mindful to assess patient change and their use of technique at several points in treatment and flexibly adjust their approach as necessary. PMID- 27238158 TI - In vitro evaluation of the apical seal of two different retrograde filling materials. AB - To determine whether the selection of retrograde filling material or the choice of instruments in root tip resection influences the seal of the retrograde root filling. Seventy-two single-rooted teeth were used. Root resection was performed using a Lindemann bone cutter, a Lindemann bone cutter with A-shaped cutting design or a diamond-coated bur. Retro-cavities were prepared by piezo-tips and filled with Super-EBA or MTA. Teeth were made transparent and dye penetration was assessed. Teeth filled with MTA, irrespective of the resection instrument, showed no measurable dye penetration. All groups filled with Super-EBA showed an apical leakage. There were no significant differences between the three groups filled with Super-EBA (P = 0.09). The comparison of MTA versus Super-EBA showed significant superiority in apical seal in favour of MTA (P < 0.0001). To use MTA as a retrograde filling material showed superior results in terms of the tightness of the apical seal as compared to Super-EBA. PMID- 27238159 TI - Anesthetic effects of a combination of medetomidine, midazolam and butorphanol on the production of offspring in Japanese field vole, Microtus montebelli. AB - Pentobarbital sodium (Somnopentyl) can induce surgical anesthesia with a strong hypnotic effect that causes loss of consciousness. Animals have been known to die during experimental surgery under anesthesia with Somnopentyl, causing it to be declared inadequate as a general anesthetic for single treatment. An anesthetic combination of 0.3 mg/kg medetomidine, 4.0 mg/kg midazolam and 5.0 mg/kg butorphanol (M/M/B:0.3/4/5) was reported to induce anesthesia for a duration of around 40 min in ICR mice; similar anesthetic effects were reported in both male and female BALB/c and C57BL/6J strains of mice. However, the anesthetic effects of this combination in Japanese field vole, Microtus montebelli, remain to be evaluated. In the present study, we assessed the effects of Somnopentyl and different concentrations of anesthetic combination (M/M/B:0.3/4/5, 0.23/3/3.75 or 0.15/2/2.5) in Japanese field voles, by means of anesthetic scores. We also examined effect of these anesthetics on production of offspring. Death of the animals was observed only with Somnopentyl. The anesthetic score of Somnopentyl was lower than those of the other anesthetics, although there were no significant differences in duration, body weight and frequency of respiratory among the evaluated anesthetics. Abortion rate with Somnopentyl was significantly higher than that with the M/M/B:0.23/3/3.75 combination, although there was no significant difference in the number of offspring between two. In conclusion, results of this study provide basic information for achieving appropriate anesthetic concentrations in addition to indicating a new, safe and effective surgical anesthetic for Japanese field voles. PMID- 27238161 TI - Estimation of breast, prostate, and colorectal cancer incidence using a French administrative database (general sample of health insurance beneficiaries). AB - AIM: The aim of this study was to compare incidence of breast, prostate, and colorectal cancer incidence estimated from a French administrative database with the incidences estimated from the cancer registry data. MATERIALS AND METHODS: A cohort of 426,410 people included in the general sample of health insurance beneficiaries (EGB) database as of January 1, 2007, was constituted. Several algorithms were developed to estimate cancer incidence between 2008 and 2012 using principal diagnosis (PD) of hospital discharge data (medical information systems program [PMSI]) and/or long-term disease (LTD) and together with a procedure necessary for histological diagnosis and indicating initial disease management. The incidence rates obtained were compared with those from the registry data using the standardized incidence ratio (SIR). RESULTS: The algorithm taking into account LTD and PD in the PMSI and the mandatory presence of a marker procedure provided estimates close to those from the registry data for breast cancer (SIR: 1.12 [1.07-1.18]) and colorectal cancer (SIR: 0.94 [0.88 1.02] in men and SIR: 0.93 [0.86-1.01] in women). For prostate cancer, taking into account specific procedures and drugs in addition to LTD and PD in the PMSI enhanced the estimation of incidence (SIR: 1.03 [0.98-1.08]). CONCLUSION: The PMSI together with reimbursement data (LTD, procedures, drugs) provided estimates of breast, prostate, and colorectal cancer incidence, at a national level, comparable to those from the cancer registry data. PMID- 27238160 TI - Tyrosol ameliorates lipopolysaccharide-induced ocular inflammation in rats via inhibition of nuclear factor (NF)-kappaB activation. AB - We evaluated the anti-inflammatory effect of tyrosol (Tyr) on endotoxin-induced uveitis (EIU) in rats. EIU was induced in male Lewis rats by subcutaneous injection of lipopolysaccharide (LPS). Tyr (10, 50 or 100 mg/kg) was intravenously injected 2 hr before, simultaneously and 2 hr after LPS injection. The aqueous humor (AqH) was collected 24 hr after LPS injection; the infiltrating cell number, protein concentration, and tumor necrosis factor (TNF)-alpha, prostaglandin (PG)-E2 and nitric oxide (NO) levels were determined. Histopathologic examination and immunohistochemical studies for nuclear factor (NF)-kappaB, inhibitor of kappaB (IkappaB)-alpha, cyclooxygenase (COX)-2 and inducible NO synthase (iNOS) in the iris-ciliary body (ICB) were performed at 3 or 24 hr after LPS injection. To further clarify the anti-inflammatory effects, RAW264.7 macrophages were stimulated with LPS in the presence or absence of Tyr. Tyr reduced, in a dose-dependent manner, the infiltrating cell number, protein concentration, and TNF-alpha, PGE2 and NO levels in AqH and improved histopathologic scores of EIU. Tyr also inhibited LPS-induced COX-2 and iNOS expression, IkappaB-alpha degradation and nuclear translocation of activated NF kappaB in ICB. Tyr significantly suppressed inflammatory mediator production in the culture medium and COX-2 and iNOS expression and activated NF-kappaB translocation in LPS-stimulated RAW264.7 cells. These results suggest that Tyr suppresses ocular inflammation of EIU by inhibiting NF-kappaB activation and subsequent proinflammatory mediator production. PMID- 27238162 TI - [Health status of populations living in French overseas territories in 2012, compared with metropolitan France: An analysis of the national health insurance database]. AB - BACKGROUND: This study uses healthcare consumption to compare the health status of beneficiaries of the French national health insurance general scheme between individuals living in French overseas territories (FOT) and those living in metropolitan France. METHODS: Data were extracted from the French national health insurance database (Sniiram) for 2012, using algorithms, 56 groups of diseases and 27 groups of hospital activity were isolated. Standardized morbidity ratio for age and sex (SMR) were used to compare FOT to mainland France. RESULTS: Compared with mainland France, people living in the four FOT had high SMR for diabetes care (Guadeloupe 1.9; Martinique 1.7; Guyane 1.9; La Reunion 2.3), dialysis (2.7; 2.4; 3.8; 4.4), stroke (1.2; 1.1; 2.0; 1.5), and hospitalization for infectious diseases (1.9; 2.5; 2.4; 1.4) and obstetrics (1.4; 1.2; 1.9; 1.2). Care for inflammatory bowel disease or cancer were less frequent except for prostate in Martinique and Guadeloupe (2.3). People living in Martinique, Guadeloupe and la Reunion had more frequently care for psychotic disorders (2.0; 1.7; 1.2), dementia (1.1; 1.3; 11), epileptic seizures (1.4; 1.4; 16) and hospitalizations for burns (2.6; 1.7; 2.9). In la Reunion, people had more frequently coronary syndrome (1.3), cardiac heart failure (1.6), chronic respiratory diseases except cystic fibrosis (1.5), drug addiction (1.4) and hospitalizations for cardiovascular catheterization (1.4) and toxicology, poisoning, alcohol (1.7). Other differences were observed by gender: HIV infection, peripheral arterial disease, some chronic inflammatory disease (lupus) were more frequent in women living in Martinique or Guadeloupe, compared to women from mainland France and psychotic disorders for men. From la Reunion, men had more frequently liver and pancreatic diseases and hospitalisation for toxicology, poisoning, alcohol than men from mainland France. CONCLUSION: This study highlights the utility of administrative database to compare and follow population health status considering healthcare use. Specific Public Health policies are justified for FOT, taking into account the specific context of each FOT, the necessity of prevention initiatives and screening to reduce the frequency of the chronic diseases. PMID- 27238163 TI - Public health impact of Infanrix hexaTM (DTPa-HBV-IPV/Hib) reimbursement: A study programme in France. Part 2: Evolution of the acceptability of infants' vaccination against hepatitis B in general and pediatric practices - the PRALINE study. AB - BACKGROUND: The reimbursement of the hexavalent vaccine (Infanrix hexaTM), comprising the DTPa-IPV-Hib components and the hepatitis B recombinant in a single vaccine, was approved in France in March of 2008. The impact of its reimbursement on physicians' decisions to vaccinate infants against hepatitis B was assessed in a study conducted with general practitioners and pediatricians. METHODS: The PRALINE study (NCT01777074) was a national, cross-sectional, repeated study with two measurement periods (T1 and T2) that measured the changes in physicians' acceptance of hepatitis B vaccination of infants before and for the 3 years after the approval of the hexavalent vaccine reimbursement. Two patient registers were created for each measurement period to enroll the first 15 12- to 15-month-old infants and the first 15 24- to 27-month-old children seen by the practitioners. The proportion of eligible children receiving a hepatitis B vaccine for each physician's practice was calculated. Practitioners also answered a vaccination practice questionnaire via telephone interviews. RESULTS: Across the two study periods, 418 general practitioners and 463 pediatricians were recruited and responded to the telephone interview on their vaccination practices. The overall number of children included in the study in both study periods reached almost 20,000. In the general practitioners group, there was a significant increase in the proportion of physicians "practicing hepatitis B vaccination" (i.e., at least 50% of eligible children receiving the initial hepatitis B vaccination) in children 24-27 months old (79% T2 versus 47% T1, P value [P]<0.001). Similarly, the proportion of pediatricians initiating hepatitis B vaccination increased from 51% (T1) to 94% (T2) (P<0.0001). General practitioners offered hepatitis B vaccination to infants more systematically in the second study period (87% T2 versus 73% T1, P<0.001) and also suggested the use of the hexavalent vaccine to more patients after reimbursement (92% T2 versus 78% T1, P<0.0001). The proportion of pediatricians offering vaccination to every infant was high at T1 (94%) and remained steady (97%) with a high use of the hexavalent vaccine (94% T1 and 96% T2). CONCLUSION: The PRALINE study shows a significant and immediate change in the hepatitis B vaccination practices of general practitioners and pediatricians following hexavalent vaccine reimbursement with a significant increase in hepatitis B vaccine coverage in infants. PMID- 27238164 TI - Covered metal stents in endoscopic therapy of biliary complications after liver transplantation. AB - There is growing interest in using covered self-expandable metal stents for the treatment of benign biliary conditions, and the presence of anastomotic biliary strictures and leaks after liver transplantation provide a valuable opportunity for testing them. The performance of the stents is encouraging, and the technical success rate is high. They provide larger diameter dilation and are easily removed, and can potentially limit costs by reducing the number of procedures needed to treat anastomotic biliary strictures. However, drawbacks such as sub optimal tolerability and migration may affect both patient management and costs. New stent designs are currently being evaluated. Randomized controlled trials and cost-effectiveness analyses comparing covered metal stents with multiple plastic stent endotherapy are warranted in order to define the role of the former as first-line or rescue treatment. PMID- 27238165 TI - The clinical differences of asthma in patients with molds allergy. AB - INTRODUCTION: Bronchial asthma is an increasing problem worldwide. The course of bronchial asthma is dependent on the type of inducing allergens. The differences between the clinical features of asthma in patients with monovalent allergies to molds and with other allergies were explored. MATERIAL AND METHODS: Randomly selected 1910 patients (924 women and 986 men) between 18-86 years in age were analyzed according to type of allergy and asthma. The diagnosis of asthma was confirmed on the basis of GINA criteria, physical examination and spirometry. Allergy diagnosis was confirmed on the basis of medical history, a positive skin prick test and the measurement of serum-specific IgE to inhalant allergens, using an extended profile of mold allergens. RESULTS: Patients with monovalent allergies to molds (4% of analyzed group) had significantly more frequent diagnoses of asthma than patients in the other group (53% vs. 27.1-32.4%, p < 0.05). Patients with allergies to Alternaria alternata had an odds ratio of 2.11 (95%CI: 1.86-2.32) for receiving a diagnosis of bronchial asthma. They had less control over their asthma, which was more severe compared to patients with other allergies. Patients with asthma and allergies to mold had significantly more frequent exacerbation of asthma requiring systemic corticosteroids and/or hospitalization. They used a significantly greater mean daily dose of inhaled steroids compared to other patients. CONCLUSION: Patients with monovalent IgE allergies to molds are at a higher risk for asthma than patients with other allergies. Their asthma is often more intense and less controlled compared to that of patients with other types of allergies. PMID- 27238166 TI - Low DLCO in idiopathic pulmonary arterial hypertension - clinical correlates and prognostic significance. AB - INTRODUCTION: Decreased diffusing capacity of the lung for carbon monoxide (DLCO) is observed in some idiopathic pulmonary arterial hypertension (IPAH) patients, but its clinical significance is uncertain. We aimed to assess clinical correlates and prognostic significance of low DLCO in IPAH patients. MATERIAL AND METHODS: In the group of 65 IPAH patients the cut off value for low DLCO was set up based on histogram as < 55% of predicted value. Demographic data, exercise capacity, lung function tests, hemodynamic parameters and survival of the patients were compared depending on DLCO value. RESULTS: Low DLCO was found in 18% of the patients, and it was associated with male sex, older age, worse functional status and exercise capacity, and higher prevalence of coronary artery disease. Low DLCO carried a 4-fold increase of death risk in 5-year perspective. CONCLUSIONS: Low DLCO was a marker of worse functional capacity and increased risk of death in studied IPAH patients. PMID- 27238167 TI - Prospective, population-based surveillance of the burden of Streptococcus pneumoniae in community-acquired pneumonia in older adults, Chrzanow County, Poland, 2010 to 2012. AB - INTRODUCTION: Community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae is a substantial cause of morbidity and mortality among older adults. This study estimated incidences of CAP, chest x-ray-confirmed CAP (CXR+CAP), S pneumonia- positive CAP, S pneumonia-positive CXR+CAP, and S. pneumoniae serotype distribution among 46,000 at-risk adults aged >= 50 years residing in Chrzanow County, Poland. MATERIAL AND METHODS: From January 2010 to January 2012, all facilities providing ambulatory and inpatient care enrolled all consenting resident patients with suspicion of CAP. Chest x-rays, urine, blood, and sputum samples were analyzed. Annualized incidence rates were determined. Presence of S pneumonia-positive CAP and/or S. pneumoniae serotype distribution was determined using the urine antigen detection assay (capable of detecting the serotypes in the 13-valent pneumococcal conjugate vaccine [PCV13]), BinaxNOW(r), and/or microbiology cultures. RESULTS: Among 5055 enrolled patients, 1195 (23.7%) were diagnosed with CAP and 1166 (23.4%) had CXR+CAP. S. pneumoniae was detected in 144 (12.1%) and 131 (11.2%) patients from the CAP and CXR+CAP cohorts, respectively. Annualized incidence rates of CAP, CXR+CAP, S pneumonia-positive CAP, and S. pneumonia-positive CXR+CAP were 12.8, 12.5, 1.6, and 1.4 per 1000 residents, respectively. Among CXR+CAP patients, 39.7% were aged 50 to 64 years and 60.3% were aged >= 65 years. Incidence rates generally increased with age. The most common serotypes in S. pneumoniae-positive CXR+CAP patients were 3 (n = 15), 23F (n = 10), 18C (n = 9), and 9V (n = 6). CONCLUSIONS: CAP due to PCV13 serotypes is a source of morbidity among adults >50 years and may be reduced by greater access to pneumococcal vaccines. PMID- 27238168 TI - Lifestyle factors and asthma in India - a case-control study. AB - INTRODUCTION: There has been a recent trend of increasing prevalence of asthma in developing countries; prevalence in the Indian population is reported to be 2%. The link between lifestyle factors and asthma has been mostly derived from western literature. The present study intended to study relationship if any, between life style factors and asthma in a representative Indian population. MATERIAL AND METHODS: The study is a case-control study performed for a period of one year, between 2014 and 2015. 125 asthma and correspondingly age and sex matched healthy controls were recruited for the purpose of study. A self-reported questionnaire has been prepared based on routine lifestyle habits of Indian population. RESULTS: The hours of TV watching and hours of sleep were significantly higher in asthma patients, and also duration of sports activity showed inverse relation with asthma. Smoking, tobacco, chewing as well as alcohol consumption were higher in asthma patients in comparison to controls, though neither was statistically significant. The mental stress as assessed on scale of 1-10, was significantly higher in asthma patients (p < 0.001). Asthma patients had significantly lower travel duration/week (p < 0.05). CONCLUSION: The present study concluded increased TV watching, increased mental stress, reduced hours of physical activity and travel may be correlated with asthma in India. With growing evidence of increasing association of asthma and sedentary lifestyle, it is imperative to reduce acquaintance to as well as incidence of these factors through public health policies, which may impact prevalence of asthma in Indian population. PMID- 27238169 TI - Primary ciliary dyskinesia in six patients with bronchiectasis. AB - INTRODUCTION: Primary ciliary dyskinesia [PCD] is generally considered as a rare autosomal recessive disorder. Previous studies reported various prevalence of PCD among patients with bronchiectasis. MATERIAL AND METHODS: Six PCD patients who were diagnosed during the investigation of 40 patients with bronchiectasis were enrolled in this study. Ultra structural studies for both epithelium and cilia were performed, and the deformities in detailed electron microscopic images confirmed the diagnosis of PCD. RESULTS: Four patients experienced the first symptoms shortly after the birth, 1 by the age of 1 and 1 by the age of 4 years. Except of 1 case that was diagnosed 2 months after the onset of disease, diagnosis delay was longer than 5 years in all patients. Consanguineous marriage was observed in the parents of all patients. Upper respiratory tract infections were documented for all patients. CONCLUSIONS: PCD should be considered as a probable underlying disorder in patients with bronchiectasis. Past medical history of otitis media and history of similar clinical findings in family members should raise suspicion toward PCD. PMID- 27238170 TI - Diffuse Idiopathic Skeletal Hyperostosis (DISH) and non small cell lung cancer: case presentation and review of the literature. AB - Diffuse idiopathic skeletal hyperostosis (DISH), also known as Forestier's disease, is a systemic non inflammatory disease of unknown cause. It is characterized by the presence of osteophytes due to calcification and ossification of spinal ligaments and entheses. Moreover, diffuse idiopathic skeletal hyperostosis has been associated with a variety of metabolic disorders. However, to the best of our knowledge no association with non small cell lung cancer (NSCLC) has been reported so far. In the present study we report a case of a patient with NSCLC and DISH. PMID- 27238171 TI - Cough-induced lung intercostal hernia. AB - A 73-year-old male with marked emphysema was admitted to the 2nd Department of Internal Medicine, University Hospital in Krakow because of chronic obstructive pulmonary disease (COPD) exacerbation. His medical history was significant for total laryngectomy due to laryngeal cancer in 2010. PMID- 27238172 TI - A case of systemic melioidosis: unravelling the etiology of chronic unexplained fever with multiple presentations. AB - Melioidosis, caused by the environmental saprophyte, Burkholderia pseudomallei, is an important public health problem in Southeast Asia and Northern Australia. It is being increasingly reported from other parts, including India, China, and North and South America expanding the endemic zone of the disease. We report a case of systemic melioidosis in a 58-year-old diabetic, occupationally-unexposed male patient, who presented with chronic fever, sepsis, pneumonia, pleural effusion and subcutaneous abscess, was undiagnosed for long, misidentified as Pseudomonas aeruginosa infection elsewhere, but was saved due to correct identification of the etiologic agent and timely institution of appropriate therapy at our institute. A strong clinical and microbiological suspicion for melioidosis should be considered in the differential diagnosis of acute pyrexia of unknown origin, acute respiratory distress syndrome and acute onset of sepsis, especially in the tropics. PMID- 27238173 TI - What factors may influence epidemiological situation of tuberculosis in Poland and in the world? AB - The authors present the review of factors influencing epidemiological situation of tuberculosis in Poland and in the world. The groups of increased risk of tuberculosis, and clinical conditions predisposing to activation of latent tuberculosis infection (LTBI) such as HIV, uremia, diabetes mellitus, transplantation of organs, treatment with glucocorticosteroids and with antibodies to TNF and to its receptors, were presented. The higher prevalence and worse prognosis of tuberculosis in elderly people was emphasised. The methods of LTBI recognition, according to recent recommendations, with special consideration to patients in immunosupression, were shown. Methods of treatment to prevent LTBI activation, according to WHO experts, were also presented. All data were discussed in relation to the actual epidemiological situation of tuberculosis in Poland. PMID- 27238174 TI - Methods of airway resistance assessment. AB - Airway resistance is the ratio of driving pressure to the rate of the airflow in the airways. The most frequent methods used to measure airway resistance are whole-body plethysmography, the interrupter technique and the forced oscillation technique. All these methods allow to measure resistance during respiration at the level close to tidal volume, they do not require forced breathing manoeuvres or deep breathing during measurement. The most popular method for measuring airway resistance is whole-body plethysmography. The results of plethysmography include among others the following parameters: airway resistance (Raw), airway conductance (Gaw), specific airway resistance (sRaw) and specific airway conductance (sGaw). The interrupter technique is based on the assumption that at the moment of airway occlusion, air pressure in the mouth is equal to the alveolar pressure . In the forced oscillation technique (FOT), airway resistance is calculated basing on the changes in pressure and flow caused by air vibration. The methods for measurement of airway resistance that are described in the present paper seem to be a useful alternative to the most common lung function test - spirometry. The target group in which these methods may be widely used are particularly the patients who are unable to perform spirometry. PMID- 27238175 TI - Tumor necrosis factor alpha as an asthma biomarker in early childhood. PMID- 27238176 TI - Prognostic value of TH1/TH2 cytokines in infants with wheezing in a three year follow-up study. AB - INTRODUCTION: The immune system is known to play a key role in the development of viral-induced wheeze, but the pattern of cytokine response is not clear. The aim of the study was to determine whether plasma cytokine levels during the acute wheezing illness in infants are associated with the subsequent development of persistent recurrent wheezing (PRW). MATERIAL AND METHODS: 43 infants admitted to Iashvili Central Children Hospital, Tbilisi, Georgia, were selected. The concentrations of IFN-g, TNF-a and IL-6 were determined by enzyme-linked immunosorbent assay (ELISA). Total serum IgE level was also determined. IgM and IgG antibodies to RSV, Chlamydophila pneumonia and Mycoplasma pneumonia were tested by ELISA. All children were followed-up during 3 years period. RESULTS: There was no significant association with PRW and atopy in the infant or parental atopy, low maternal age, low birth weight, serum level of IL-6, serum level of IFN-g, serum level of total IgE and the particular pathogen. There was a tendency for the association with male sex, bottle feeding and household cigarette smoking, although the relation was not significant. There was just TNF-a which was strongly associated with the risk of PRW after three years of follow up. CONCLUSION: We have identified TNF-a, as a biomarker, which can be detected in children under 3 years of age and may be useful in the prediction of development of persistence of wheezing later. To further evaluate the usefulness of this and other markers and establish cutoff levels for prediction and use in clinical practice, a larger prospective follow-up study is needed. PMID- 27238177 TI - Fungal infection of cystic fibrosis patients - single center experience. AB - INTRODUCTION: Cystic fibrosis (CF) is the most common monogenetic autosomal recessive disease in the human population. This systemic disease is characterized by changes in multiple organs, mainly in the lung tissue and digestive tract. More than 59% of CF patients become sensitized to fungal spores, mostly Aspergillus fumigatus. 5-15% of CF patients develop allergic bronchopulmonary aspergillosis. The aim of the study was to analyse the occurrence of yeast and filamentous fungi of the respiratory infections in CF patients and evaluation of drug resistance. MATERIAL AND METHODS: Between 2006 and 2014, mycological evaluation of 42 patients hospitalized at the National Institute of Tuberculosis and Lung Diseases was carried out. RESULTS: 217 specimens from pulmonary tract were collected from 42 patients with cystic fibrosis. 205 (68%) strains of yeast and 96 (32%) filamentous fungi strains were cultured. The most common mould strain was A. fumigatus - 22,2% (67 species). All isolates of filamentous fungi were in vitro 100% susceptible to itraconazole, voriconazole, posaconazole and amphotericin B. CONCLUSIONS: A. fumigatus and C. albicans were the most common etiological agents of fungal respiratory pathogens associated with CF patients. A. fumigatus strains were in vitro 100% susceptible to azole and amphotericin B. Two strains of C. albicans and one strain of C. tropicalis were non-susceptible to azole (fluconazole, itraconazole and voriconazole). Scedosporium apiospermum was resistant to amphotericin B (MIC > 32 mg/l) and susceptible to voriconazole (MIC 0.094 mg/l). PMID- 27238178 TI - Dietary pattern and asthma in India. AB - INTRODUCTION: The study aimed to evaluate the association between food consumption pattern and asthma in Indian population. MATERIAL AND METHODS: 125 asthma and corresponding age and sex matched healthy controls were recruited for the purpose of a study. A self- reported food-frequency questionnaire (NNR Dietary Pattern in Asthma Questionnaire) comprising of 80 food and drink items, belonging to 15 groups, was developed based on routine dietary habits and ISAAC phase two and phase three questionnaires. RESULTS: There was no significant difference of gender, height, weight, BMI and socioeconomic status between asthma and control groups (p > 0.05). The consumption of fast food, salted snacks, fried snacks; nuts and dry fruits were significantly higher in asthmatics (p < 0.05). Similarly, there was a tendency to higher consumption of fats and oil, sugar and carbonated drink in asthmatics (p > 0.05). On the contrary, consumption of cereals, milk and milk products, non-vegetarian food, fruits and fruit juice tends to be higher in healthy controls, though neither of them could reach a statistically significant (p > 0.05). CONCLUSION: Consumption of fast food, salted snacks, fried snacks, fats and oils nuts, dry fruits, carbonated drinks may be associated with asthma in India. Hence, it is imperative to reduce consumption and increase awareness of influence of fast food on asthma through public health policies. PMID- 27238179 TI - Association of interleukins genes polymorphisms with multi-drug resistant tuberculosis in Ukrainian population. AB - INTRODUCTION: Multi-drug resistant tuberculosis (MDR TB) is a significant health problem in some parts of the world. Three major cytokines involved in TB immunopathogenesis include IL-2, IL-4 and IL-10. The susceptibility to MDR TB may be genetically determined. The aim of the study was to assess the association of IL-2, IL-4, IL-10 gene polymorphisms with multi-drug resistant tuberculosis (MDR TB) in Ukrainian population. MATERIAL AND METHODS: We observed 140 patients suffering from infiltrative pulmonary tuberculosis (PT) and 30 apparently healthy subjects. The patients were assigned to two groups whether they suffer or do not suffer from pulmonary MDR TB. Interleukin gene (IL) polymorphisms, particularly T330G polymorphism in the IL-2 gene, C589T polymorphism in the IL-4 gene and G1082A polymorphism in the IL-10 gene were studied through polymerase chain reaction. Circulating levels of IL-2, IL-4 and IL-10 in venous blood were estimated using ELISA. RESULTS: Prior to treatment, patients with PT showed significant increase of IL-2 levels and decrease of IL-4 and IL-10 levels compared to apparently healthy subjects. Circulating IL-4 and IL-10 levels were significantly decreased whilst serum IL-2 level was significantly increased in patients with MDR TB compared to non-MDR TB. Low IL-4 and IL-10 secretion and considerable IL-2 alterations were shown to be significantly associated with mutations of homozygous and heterozygous genotypes affecting C589T polymorphism in the IL-4 gene, G1082A polymorphism in the IL-10 gene and T330G polymorphism in the IL-2 gene in patients with PT. CONCLUSIONS: Heterozygous genotype and mutations homozygous genotypes gene in polymorphisms determining specified cytokines' production is a PT risk factor and may lead to disease progression into chronic phase. Heterozygous genotype of aforementioned cytokine genetic polymorphisms was significantly the most frequent in patients with MDR TB. PMID- 27238180 TI - A case of DIPNECH presenting as usual interstitial pneumonia. AB - Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare disease that is classically described as presenting with cough, dyspnea, and wheezing in non-smoker middle aged females. Pulmonary function tests commonly demonstrate an obstructive pattern and CT of chest usually reveals diffuse air trapping with mosaic pattern. We present a case of patient with DIPNECH manifesting with restrictive pattern and as usual interstitial pneumonia on imaging. PMID- 27238181 TI - Pulmonary mycotic pseudo-aneurysm with a prior history of ventricular septal defect. Case report with review of literature. AB - In general aneurysms of the pulmonary arteries are less frequent than intracranial, aortic or other vascular locations. Infectious causes include bacteria such as Staphylococcus sp and Streptococcus sp, mycobacteria, Treponema pallidium (syphilis) and rarely fungi. We report a 7 year old female with two right-sided parahilar pseudo-aneurysm of fungal origin with a prior history of ventricular septal defect. Pulmonary mycotic pseudo-aneurysms are very rare and require a high suspicion to diagnose. If a patient is still symptomatic for fever and cough for a long time, and consolidation on x-ray is not improving on antibiotics, contrast-enhanced computed tomography is indicated. It can be suspected that the "friable mass attached to ventricular septal defect patch" was a source of fungeal emboli to pulmonary arteries thus giving weight to the infective endocarditis etiology. A prior history of ventricular septal defect repair could favour fungal endocarditis. PMID- 27238182 TI - Comorbidities in lung cancer. AB - Comorbidity is the occurrence of concomitant disease in addition to an index disease of interest or the simultaneous occurrence of multiple diseases in an individual. Lung cancer is associated with age and smoking, and both age and smoking are strongly associated with comorbidity. Lung cancer is the most common malignancy in the world. Comorbidity, such as diseases of cardiovascular, pulmonary and other systems may influence prognosis in lung cancer as well as complicate its treatment. In this paper we tried to conclude the significance of the individual comorbidities in lung cancer and their impact on particular treatment method. PMID- 27238183 TI - Standards for diagnosis and care of patients with inherited alpha-1 antitrypsin deficiency Recommendations of the Polish Respiratory Society, Polish Society of Pediatric Pulmonology and Polish Society of Pediatric Gastroenterology. PMID- 27238184 TI - Direct and Highly Selective Drug Optosensing in Real, Undiluted Biological Samples with Quantum-Dot-Labeled Hydrophilic Molecularly Imprinted Polymer Microparticles. AB - Quantum-dot (QD)-labeled hydrophilic molecularly imprinted polymer (MIP) microparticles were prepared for direct and highly selective optosensing of an antibiotic drug (i.e., tetracycline (Tc)) in pure bovine/goat milks and bovine/porcine serums. "Living" CdTe QD-SiO2 composite microparticles with alkyl bromide groups on their surfaces were first obtained via the one-pot sol-gel reaction, and they were subsequently grafted with a Tc-imprinted polymer layer and poly(glyceryl monomethacrylate) brushes via the successive surface-initiated atom transfer radical polymerizations. The resulting MIP microparticles with QD labeling and hydrophilic polymer brushes could function properly in biological samples and showed obvious template-binding-induced fluorescence quenching, which make them a useful fluorescent chemosensor with limits of detection down to 0.14 MUM in complex biological media. Moreover, a facile and effective approach was developed based on a newly derived equation to eliminate the false positives of the fluorescent chemosensor and provide it with wider linear detection concentration ranges in comparison with those obtained using the generally adopted Stern-Volmer equation. Furthermore, the fluorescent MIP chemosensor was also successfully applied for directly, sensitively, selectively, and accurately quantifying Tc in biological media, and the average recoveries were in the range of 95%~105% even when several other drugs and the fluorescently interfering chlortetracycline were present in the samples. PMID- 27238187 TI - Use of nonsteroidal anti-inflammatory drugs in early axial spondyloarthritis in daily practice: Data from the DESIR cohort. AB - OBJECTIVES: Nonsteroidal anti-inflammatory drugs (NSAID) are the cornerstone of treatment in axial spondyloarthritis (axSpA). We aimed to describe the real life NSAID use in early axSpA according to the disease characteristics. METHODS: The DESIR cohort is an observational study of patients presenting with inflammatory back pain suggestive of axSpA for less than 3 years. Patients who attended all 6 visits (every 6 months during the first 2 years and yearly at 3 years) were analysed. Data collected at every visit over 3 years was NSAID intake and the ASAS-NSAID score for the 6 months preceding the visit, where 100 reflects the full daily intake of an NSAID. RESULTS: In all, 627 patients were assessed: 46.1% males, mean age: 33.7 (standard deviation: 8.7) years, mean symptom duration: 1.5 (0.9) year and mean BASDAI: 44.3 (25.3). Over the 6 months preceding inclusion, 92.8% had received NSAIDs; this proportion significantly decreased over time, to 73% patients after 3 years (P<0.001). This decrease was not different with regard to the fulfillment (or not) of the ASAS criteria at baseline, nor with regard to the "arm" of the ASAS criteria fulfilled (i.e. imaging vs. clinical). The median ASAS-NSAID score was 36 [interquartile range: 13-72] at inclusion, and substantially decreased to reach 7 [0-44] after 3 years (P<0.001), although BASDAI at 3 years was 33.8 (21.7). CONCLUSION: NSAID prescription was very frequent in this early axSpA cohort, but the intake was low, and decreased significantly over time, even though symptoms remained present. Early axSpA patients may not be sufficiently treated with NSAIDs. PMID- 27238188 TI - Galectin-3: A key player in arthritis. AB - Arthritis is more and more considered as the leading reason for the disability in the world, particularly regarding its main entities, rheumatoid arthritis and osteoarthritis. The common feature of arthritis is inflammation, which is mainly supported by synovitis (synovial inflammation), although the immune system plays a primary role in rheumatoid arthritis and a secondary one in osteoarthritis. During the inflammatory phase of arthritis, many pro-inflammatory cytokines and mediators are secreted by infiltrating immune and resident joint cells, which are responsible for cartilage degradation and excessive bone remodeling. Amongst them, a beta-galactoside-binding lectin, galectin-3, has been reported to be highly expressed and secreted by inflamed synovium of rheumatoid arthritis and osteoarthritis patients. Furthermore, galectin-3 has been demonstrated to induce joint swelling and osteoarthritis-like lesions after intra-articular injection in laboratory animals. However, the mechanisms underlying its pathophysiological role in arthritis have not been fully elucidated. This review deals with the characterization of arthritis features and galectin-3 and summarizes our current knowledge of the contribution of galectin-3 to joint tissue lesions in arthritis. PMID- 27238185 TI - Bloom's syndrome: Why not premature aging?: A comparison of the BLM and WRN helicases. AB - Genomic instability is a hallmark of cancer and aging. Premature aging (progeroid) syndromes are often caused by mutations in genes whose function is to ensure genomic integrity. The RecQ family of DNA helicases is highly conserved and plays crucial roles as genome caretakers. In humans, mutations in three RecQ genes - BLM, WRN, and RECQL4 - give rise to Bloom's syndrome (BS), Werner syndrome (WS), and Rothmund-Thomson syndrome (RTS), respectively. WS is a prototypic premature aging disorder; however, the clinical features present in BS and RTS do not indicate accelerated aging. The BLM helicase has pivotal functions at the crossroads of DNA replication, recombination, and repair. BS cells exhibit a characteristic form of genomic instability that includes excessive homologous recombination. The excessive homologous recombination drives the development in BS of the many types of cancers that affect persons in the normal population. Replication delay and slower cell turnover rates have been proposed to explain many features of BS, such as short stature. More recently, aberrant transcriptional regulation of growth and survival genes has been proposed as a hypothesis to explain features of BS. PMID- 27238186 TI - Impact of lysosome status on extracellular vesicle content and release. AB - Extracellular vesicles (EVs) are nanoscale size bubble-like membranous structures released from cells. EVs contain RNA, lipids and proteins and are thought to serve various roles including intercellular communication and removal of misfolded proteins. The secretion of misfolded and aggregated proteins in EVs may be a cargo disposal alternative to the autophagy-lysosomal and ubiquitin proteasome pathways. In this review we will discuss the importance of lysosome functionality for the regulation of EV secretion and content. Exosomes are a subtype of EVs that are released by the fusion of multivesicular bodies (MVB) with the plasma membrane. MVBs can also fuse with lysosomes, and the trafficking pathway of MVBs can therefore determine whether or not exosomes are released from cells. Here we summarize data from studies of the effects of lysosome inhibition on the secretion of EVs and on the possibility that cells compensate for lysosome malfunction by disposal of potentially toxic cargos in EVs. A better understanding of the molecular mechanisms that regulate trafficking of MVBs to lysosomes and the plasma membrane may advance an understanding of diseases in which pathogenic proteins, lipids or infectious agents accumulate within or outside of cells. PMID- 27238190 TI - Gut microbiota and inflammatory joint diseases. AB - In most chronic inflammatory diseases, the cause remains unknown. Chronic infection is, however, among the current hypotheses. Recent technological advances have allowed in-depth studies of the gut microflora, or microbiota, which contains a vast array of organisms, most of which cannot be cultured. Inflammatory bowel disease has been associated with distinctive changes in the gut microbiota, which persist between disease flares and may play a pathogenic role. Links have been demonstrated between the gut microbiota and joint inflammation in murine models of arthritis but have received little attention in human patients. Recent work has nevertheless demonstrated substantial alterations in the gut microbiota in patients with rheumatoid arthritis, psoriatic arthritis, or spondyloarthritis, with differences across diagnoses and studies. Interestingly, some of these alterations resemble those now firmly established in inflammatory bowel disease; examples include decreased microbial diversity and lower frequencies of bacterial groups belonging to the Firmicutes phylum known to have immunoregulatory properties. These new findings open up important new horizons both for understanding disease and for developing novel biomarkers and treatment strategies. PMID- 27238189 TI - Alcohol-related diseases and alcohol dependence syndrome is associated with increased gout risk: A nationwide population-based cohort study. AB - OBJECTIVE: Alcohol intake is strongly associated with hyperuricemia, which may cause gout. This study evaluated the risk of gout in patients with alcohol related diseases and alcohol dependence syndrome. METHODS: We used the Taiwan National Health Insurance Research Database (NHIRD) to conduct a nationwide population-based cohort study to assess the risk of gout and gout incidence in patients with alcohol-related diseases and alcohol dependence syndrome (as defined by the International Classification of Diseases, Ninth Revision). In the NHIRD records from 1998 to 2008, we identified 11,675 cases of alcohol-related diseases. The control group comprised 23,350 cases without alcohol-related diseases propensity score-matched (1 case: 2 controls) for age, age group, and sex. RESULTS: The results revealed that alcohol-related diseases were significantly associated with gout risk (adjusted hazard ratio 1.88; P<0.0001). Of the alcohol-related disease cases, 34.1% of the patients had alcohol dependence syndrome (males 34.8%; females 32.4%), and alcohol dependence was independently associated with gout occurrence (relative risk [RR] 2.01; P<0.0001). Severe alcohol-dependent patients (who were also the heavy benzodiazepines users), were associated with an increased risk of gout (RR 1.71 to 4.21, P<=0.0182). CONCLUSION: Physicians should be aware of the association between alcohol dependence syndrome and gout occurrence, and alcohol use assessment and measures to prevent alcohol dependence should be implemented in the integrative care for patients with gout. PMID- 27238191 TI - Granulomatosis with polyangiitis presenting with pelvic mass leading to total hysterectomy: A case-letter. PMID- 27238192 TI - Factors associated with knowledge and safety skills of arthritis patients receiving biologics: A survey of 677 patients. AB - OBJECTIVE: We aimed to determine patient and rheumatologist factors associated with the safety skills of patients receiving bDMARDs for inflammatory arthritis. METHODS: Data were obtained from a descriptive observational cross-sectional nationwide survey performed in 2011 in France. Community- and hospital-based rheumatologists were selected at random. The BioSecure questionnaire was used to collect information on patient safety skills. RESULTS: Of the 677 patients included (mean age 53+/-13years old; 452 (67%) women, 411 (61%) had RA; 421 (64%) received subcutaneous bDMARDs). Patients had received information about their treatments from their physician 610 (90%), a nurse 207 (31%), by a written booklet 398 (59%), and/or during therapeutic patient education (TPE) sessions 99 (15%). The median BioSecure total score was 72/100 (IQR 60-82). In total, 99 (16.4%) patients had a low skill level; 321 (53.2%) a moderate skill level and 183 (30.3%) a high skill level. On multivariate regression analysis, as compared with high safety skills, low skills were associated with living alone (OR 2.8 [95% CI 1.3?6.0]), low educational level (OR 4.3 [2.1?8.9]), living in a large city (OR 3.1 [1.2?8.2]), being unemployed (OR 3.3 [1.6?6.7]) and not receiving written information, participating in TPE sessions or consulting a nurse (OR 3.8 [1.6?8.8]). One rheumatologist-related factor was a high number of patients receiving bDMARDs in the practice. CONCLUSION: We reveal factors associated with low safety skills of patients receiving bDMARDs for inflammatory arthritis, which should be addressed to improve safety skills in this population. PMID- 27238193 TI - Association of hidradenitis suppurativa and familial Mediterranean fever: A case series of 6 patients. AB - OBJECTIVES: Familial mediterranean fever (FMF) is the most common monogenic autoinflammatory disease. Hidradenitis suppurativa (HS) is an inflammatory cutaneous disease. Those diseases can occur simultaneously among the same individual. Our objective was to describe the features of patients displaying both FMF and HS. METHODS: We screened the French adult FMF reference center for FMF patients with HS. RESULTS: Six patients out of 151 (4%) with a median age of 36 years old were concerned. Among them, FMF was symptomatic at a median age of 11.5years old and colchicine was introduced at a median age of 20.5years old. HS was diagnosed at a median age of 31.5years old. An elderly patient displayed AA amyloidosis in the outcome of FMF, with a late diagnosis of HS, with response to anakinra. There was no temporal relation between FMF and HS attacks. Some patients had a persistent inflammatory syndrome under treatment. CONCLUSION: FMF and HS are both inflammatory diseases involving young patients, with HS possibly being an autoinflammatory disease. Although their association seems to be fortuitous, both can induce an important inflammation state that could lead to AA amyloidosis and require a close monitoring of clinical signs and acute-phase reactants. Anakinra was successful in treating the only patient with both HS, FMF and amyloidosis. PMID- 27238194 TI - Hemivertebra with accompanying costal deformity. PMID- 27238196 TI - Impact of urine dipstick abnormalities in patients on biotherapies. PMID- 27238195 TI - Osteoarticular manifestations associated with HIV infection. AB - About 150,000 people are HIV-positive in France, and the number of new cases is estimated at 7000-8000 per year, with no tendency to diminish over time. Admissions of HIV-positive patients have been decreasing, in contrast, since 2008, reflecting the dramatic improvements in quality of life and survival provided by triple antiretroviral regimens. HIV infection is now a chronic disease that exposes patients to the virus and antiretroviral drugs for many years. One consequence has been the emergence of new health conditions in HIV positive patients, such as tumors, cardiovascular disease, and osteoarticular complications. These epidemiological and clinical changes have made it necessary for rheumatologists to learn about the osteoarticular abnormalities associated with the HIV, which they are likely to encounter at some point during their everyday practice. Osteoporosis is one such abnormality, and this review article starts with a discussion of the literature on this topic. Bone loss is common, chiefly in males. Multiple factors are involved. Studies have demonstrated an increase in the fracture risk and, consequently, recommendations about the screening and treatment of osteoporosis have been issued. The focus of this review article then turns to the other rheumatic manifestations seen in HIV positive patients, including osteomalacia, avascular necrosis, and inflammatory joint disease. Osteoarticular pain is frequently reported by HIV-positive patients. Identifying the cause is essential to determine the best treatment strategy. Interestingly, immunosuppressant drugs, and even biotherapies, have shown a good safety profile in these immunodeficient patients. PMID- 27238197 TI - Osteitis fibrosa cystica. PMID- 27238198 TI - Metabolic syndrome is associated with disease activity in patients with rheumatoid arthritis. AB - OBJECTIVE: To investigate the association between metabolic syndrome (MS) and disease activity in patients with rheumatoid arthritis (RA). METHODS: Siriraj Rheumatoid Arthritis registry is a prospective cohort study establishing since May 2011. A total of 267 patients who had complete data in February 2015 were included in these analyses. All clinical and laboratory data related to disease activity, functional status, and parameters of MS according to the 2001 National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) were collected. Univariate and backward stepwise multivariate analyses were performed to identify factors associated with MS. RESULTS: Most (88%) were female with the mean age+/-standard deviation of 59+/-11.1 years old. MS was found in 43 patients (16%). Patients with MS had a significantly lower proportion of patients with remission (time-adjusted mean of disease activity score 28 or DAS28<2.6) than those with non-MS (2.3% vs. 16.5%, P=0.02). Multiple logistic regression analysis identified 3 independent factors associated with MS including body mass index [OR 1.2, 95% CI 1.1 to 1.3], educational level<=12 years [OR 5.92, 95% CI 1.47 to 23.83], and disease remission [OR 0.11, 95% CI 0.01 to 0.93]. This model correctly predicted 84% of cases. CONCLUSION: Remission rate is significantly lower in RA patients with MS. Disease activity of RA, body mass index, and educational level are associated with metabolic syndrome in patients with RA. PMID- 27238199 TI - Successful treatment of refractory lupus nephritis by the sequential use of rituximab and belimumab. PMID- 27238200 TI - Mapping Malaria Risk in Low Transmission Settings: Challenges and Opportunities. AB - As malaria transmission declines, it becomes increasingly focal and prone to outbreaks. Understanding and predicting patterns of transmission risk becomes an important component of an effective elimination campaign, allowing limited resources for control and elimination to be targeted cost-effectively. Malaria risk mapping in low transmission settings is associated with some unique challenges. This article reviews the main challenges and opportunities related to risk mapping in low transmission areas including recent advancements in risk mapping low transmission malaria, relevant metrics, and statistical approaches and risk mapping in post-elimination settings. PMID- 27238201 TI - New admission scoring criteria for patients with odontogenic infections: a pilot study. AB - Odontogenic infections are often referred to the oral and maxillofacial surgical department, which can cause a dilemma for junior clinicians who have to decide whether such patients require admission. We have devised a score to be used on admission to our unit to help junior on-call staff, and designed a prospective pilot study to assess it. PMID- 27238202 TI - Mid-upper arm circumference as a screening tool for identifying children with obesity: a 12-country study. AB - BACKGROUND: No studies have examined if mid-upper arm circumference (MUAC) can be an alternative screening tool for obesity in an international sample of children differing widely in levels of human development. OBJECTIVE: Our aim is to determine whether MUAC could be used to identify obesity in children from 12 countries in five major geographic regions of the world. METHODS: This observational, multinational cross-sectional study included 7337 children aged 9 11 years. Anthropometric measurements were objectively assessed, and obesity was defined according to the World Health Organization reference data. RESULTS: In the total sample, MUAC was strongly correlated with adiposity indicators in both boys and girls (r > 0.86, p < 0.001). The accuracy level of MUAC for identifying obesity was high in both sexes and across study sites (overall area under the curve of 0.97, sensitivity of 95% and specificity of 90%). The MUAC cut-off value to identify obesity was ~25 cm for both boys and girls. In country-specific analyses, the cut-off value to identify obesity ranged from 23.2 cm (boys in South Africa) to 26.2 cm (girls in the UK). CONCLUSIONS: Results from this 12 country study suggest that MUAC is a simple and accurate measurement that may be used to identify obesity in children aged 9-11 years. MUAC may be a promising screening tool for obesity in resource-limited settings. PMID- 27238204 TI - Reproductive parameters of rhinobatid and urolophid batoids taken as by-catch in the Queensland (Australia) east coast otter-trawl fishery. AB - Reproductive variables are provided for batoids regularly taken as by-catch in the east coast otter-trawl fishery on the inner-mid continental shelf off the south-east and central coasts of Queensland, Australia. Total length at maturity (LT50 and 95% c.i.) for the eastern shovelnose ray Aptychotrema rostrata was 639.5 mm (617.6-663.4 mm) for females and 597.3 mm (551.4-648.6 mm) for males. Litter size (n = 9) ranged from nine to 20 (mean +/- s.e. = 15.1 +/- 1.2). This species exhibited a positive litter size-maternal size relationship. Disc width at maturity (WD50 and 95% c.i.) for the common stingaree Trygonoptera testacea was 162.7 mm (155.8-168.5 mm) for females and 145.9 mm (140.2-150.2 mm) for males. Gravid T. testacea (n = 6) each carried a single egg in the one functional (left) uterus. Disc width at maturity (WD50 and 95% c.i.) for the Kapala stingaree Urolophus kapalensis was 153.7 mm (145.1-160.4 mm) for females and 155.2 mm (149.1-159.1 mm) for males. Gravid U. kapalensis (n = 16) each carried a single egg or embryo in the one functional (left) uterus. A single female yellowback stingaree Urolophus sufflavus carried an embryo in each uterus. A global review of the litter sizes of shovelnose rays (Rhinobatidae) and stingarees (Urolophidae) is provided. PMID- 27238203 TI - Pharmacological profile of Ascaris suum ACR-16, a new homomeric nicotinic acetylcholine receptor widely distributed in Ascaris tissues. AB - BACKGROUND AND PURPOSE: Control of nematode parasite infections relies largely on anthelmintic drugs, several of which act on nicotinic ACh receptors (nAChRs), and there are concerns about the development of resistance. There is an urgent need for development of new compounds to overcome resistance and novel anthelmintic drug targets. We describe the functional expression and pharmacological characterization of a homomeric nAChR, ACR-16, from a nematode parasite. EXPERIMENTAL APPROACH: Using RT-PCR, molecular cloning and two-electrode voltage clamp electrophysiology, we localized acr-16 mRNA in Ascaris suum (Asu) and then cloned and expressed acr-16 cRNA in Xenopus oocytes. Sensitivity of these receptors to cholinergic anthelmintics and a range of nicotinic agonists was tested. KEY RESULTS: Amino acid sequence comparison with vertebrate nAChR subunits revealed ACR-16 to be most closely related to alpha7 receptors, but with some striking distinctions. acr-16 mRNA was recovered from Asu somatic muscle, pharynx, ovijector, head and intestine. In electrophysiological experiments, the existing cholinergic anthelmintic agonists (morantel, levamisole, methyridine, thenium, bephenium, tribendimidine and pyrantel) did not activate Asu-ACR-16 (except for a small response to oxantel). Other nAChR agonists: nicotine, ACh, cytisine, 3-bromocytisine and epibatidine, produced robust current responses which desensitized at a rate varying with the agonists. Unlike alpha7, Asu-ACR-16 was insensitive to alpha-bungarotoxin and did not respond to genistein or other alpha7 positive allosteric modulators. Asu-ACR-16 had lower calcium permeability than alpha7 receptors. CONCLUSIONS AND IMPLICATIONS: We suggest that ACR-16 has diverse tissue-dependent functions in nematode parasites and is a suitable drug target for development of novel anthelmintic compounds. PMID- 27238205 TI - Microbial Synthesis of 5-Aminolevulinic Acid and Its Coproduction with Polyhydroxybutyrate. AB - 5-Aminolevulinic acid (ALA), an important cell metabolic intermediate useful for cancer treatments or plant growth regulator, was produced by recombinant Escherichia coli expressing the codon optimized mitochondrial 5-aminolevulinic acid synthase (EC: 2.3.1.37, hem1) from Saccharomyces cerevisiae controlled via the plasmid encoding T7 expression system with a T7 RNA polymerase. When a more efficient autoinduced expression approach free of IPTG was applied, the recombinant containing antibiotic-free stabilized plasmid was able to produce 3.6 g/L extracellular ALA in shake flask studies under optimized temperature. A recombinant E. coli expressing synthesis pathways of poly-3-hydroxybutyrate (PHB) and ALA resulted in coproduction of 43% PHB in the cell dry weights and 1.6 g/L extracellular ALA, leading to further reduction on ALA cost as two products were harvested both intracellularly and extracellularly. This was the first study on coproduction of extracellular ALA and intracellular PHB for improving bioprocessing efficiency. The cost of ALA production could be further reduced by employing a Halomonas spp. TD01 able to grow and produce ALA and PHB under continuous and unsterile conditions even though ALA had the highest titer of only 0.7 g/L at the present time. PMID- 27238206 TI - Microwave-Induced Interfacial Nanobubbles. AB - A new method for generating nanobubbles via microwave irradiation was verified and quantified. AFM measurement showed that nanobubbles with diameters ranging from 200 to 600 nm were generated at a water-HOPG surface by applying microwave radiation to aqueous solutions with 9.0-30.0 mg/L dissolved oxygen. Graphite displays strong microwave absorption and transmits high thermal energy to the surface. Because of the high dielectric constant (20 degrees C, 80 F/m) and dielectric loss factor, water molecules have a strong ability to absorb microwave radiation. The thermal and nonthermal effects of microwave radiation made contributions to decreasing the gas solubility, thus facilitating nanobubble nucleation. The yield of nanobubbles increased about 10-fold when the irradiation time increased from 60 to 120 s at 200 W of microwave radiation. The nanobubble density increased from 0.8 to 15 MUm-2 by improving the working power from 200 to 600 W. An apparent improvement in nanobubbles yield was obtained between 300 and 400 W, and the resulting temperature was 34-52 degrees C. When the initial dissolved oxygen increased from 11.3 to 30.0 mg/L, the density of nanobubbles increased from 1.2 to 13 MUm-2. The generation of nanobubbles could be well controlled by adjusting the gas concentration, microwave power, or irradiation time. The method may be valuable in preparing surface nanobubbles quickly and conveniently for various applications, such as catalysis, hypoxia/anoxia remediation, and templates for preparing nanoscale materials. PMID- 27238207 TI - Using meta-analytic path analysis to test theoretical predictions in health behavior: An illustration based on meta-analyses of the theory of planned behavior. AB - OBJECTIVE: Synthesizing research on social cognitive theories applied to health behavior is an important step in the development of an evidence base of psychological factors as targets for effective behavioral interventions. However, few meta-analyses of research on social cognitive theories in health contexts have conducted simultaneous tests of theoretically-stipulated pattern effects using path analysis. We argue that conducting path analyses of meta-analytic effects among constructs from social cognitive theories is important to test nomological validity, account for mediation effects, and evaluate unique effects of theory constructs independent of past behavior. We illustrate our points by conducting new analyses of two meta-analyses of a popular theory applied to health behaviors, the theory of planned behavior. METHOD: We conducted meta analytic path analyses of the theory in two behavioral contexts (alcohol and dietary behaviors) using data from the primary studies included in the original meta-analyses augmented to include intercorrelations among constructs and relations with past behavior missing from the original analysis. RESULTS: Findings supported the nomological validity of the theory and its hypotheses for both behaviors, confirmed important model processes through mediation analysis, demonstrated the attenuating effect of past behavior on theory relations, and provided estimates of the unique effects of theory constructs independent of past behavior. CONCLUSIONS: Our analysis illustrates the importance of conducting a simultaneous test of theory-stipulated effects in meta-analyses of social cognitive theories applied to health behavior. We recommend researchers adopt this analytic procedure when synthesizing evidence across primary tests of social cognitive theories in health. PMID- 27238208 TI - Trimer procyanidin oligomers contribute to the protective effects of cinnamon extracts on pancreatic beta-cells in vitro. AB - AIM: Cinnamon extracts rich in procyanidin oligomers have shown to improve pancreatic beta-cell function in diabetic db/db mice. The aim of this study was to identify the active compounds in extracts from two species of cinnamon responsible for the pancreatic beta-cell protection in vitro. METHODS: Cinnamon extracts were prepared from Cinnamomum tamala (CT-E) and Cinnamomum cassia (CC E). Six compounds procyanidin B2 (cpd1), (-)-epicatechin (cpd2), cinnamtannin B1 (cpd3), procyanidin C1 (cpd4), parameritannin A1 (cpd5) and cinnamtannin D1 (cpd6) were isolated from the extracts. INS-1 pancreatic beta-cells were exposed to palmitic acid (PA) or H2O2 to induce lipotoxicity and oxidative stress. Cell viability and apoptosis as well as ROS levels were assessed. Glucose-stimulated insulin secretion was examined in PA-treated beta-cells and murine islets. RESULTS: CT-E, CC-E as well as the compounds, except cpd5, did not cause cytotoxicity in the beta-cells up to the maximum dosage using in this experiment. CT-E and CC-E (12.5-50 MUg/mL) dose-dependently increased cell viability in both PA- and H2O2-treated beta-cells, and decreased ROS accumulation in H2O2-treated beta-cells. CT-E caused more prominent beta-cell protection than CC-E. Furthermore, CT-E (25 and 50 MUg/mL) dose-dependently increased glucose stimulated insulin secretion in PA-treated beta-cells and murine islets, but CC-E had little effect. Among the 6 compounds, trimer procyanidins cpd3, cpd4 and cpd6 (12.5-50 MUmol/L) dose-dependently increased the cell viability and decreased ROS accumulation in H2O2-treated beta-cells. The trimer procyanidins also increased glucose-stimulated insulin secretion in PA-treated beta-cells. CONCLUSION: Trimer procyanidins in the cinnamon extracts contribute to the pancreatic beta-cell protection, thus to the anti-diabetic activity. PMID- 27238209 TI - Phenylphthalazines as small-molecule inhibitors of urea transporter UT-B and their binding model. AB - AIM: Urea transporters (UT) are a family of transmembrane proteins that specifically transport urea. UT inhibitors exert diuretic activity without affecting electrolyte balance. The purpose of this study was to discover novel UT inhibitors and determine the inhibition mechanism. METHODS: The primary screening urea transporter B (UT-B) inhibitory activity was conducted in a collection of 10 000 diverse small molecules using mouse erythrocyte lysis assay. After discovering a hit with a core structure of 1-phenylamino-4-phenylphthalazin, the UT-B inhibitory activity of 160 analogs were examined with a stopped-flow light scattering assay and their structure-activity relationship (SAR) was analyzed. The inhibition mechanism was further investigated using in silico assays. RESULTS: A phenylphthalazine compound PU1424, chemically named 5-(4-((4 methoxyphenyl) amino) phthalazin-1-yl)-2-methylbenzene sulfonamide, showed potent UT-B inhibition activity, inhibited human and mouse UT-B-mediated urea transport with IC50 value of 0.02 and 0.69 MUmol/L, respectively, and exerted 100% UT-B inhibition at higher concentrations. The compound PU1424 did not affect membrane urea transport in mouse erythrocytes lacking UT-B. Structure-activity analysis revealed that the analogs with methoxyl group at R4 and sulfonic amide at R2 position exhibited the highest potency inhibition activity on UT-B. Furthermore, in silico assays validated that the R4 and R2 positions of the analogs bound to the UT-B binding pocket and exerted inhibition activity on UT-B. CONCLUSION: The compound PU1424 is a novel inhibitor of both human and mouse UT-B with IC50 at submicromolar ranges. Its binding site is located at the So site of the UT-B structure. PMID- 27238210 TI - Bufalin derivative BF211 inhibits proteasome activity in human lung cancer cells in vitro by inhibiting beta1 subunit expression and disrupting proteasome assembly. AB - AIM: Bufalin is one of the active components in the traditional Chinese medicine ChanSu that is used to treat arrhythmia, inflammation and cancer. BF211 is a bufalin derivative with stronger cytotoxic activity in cancer cells. The aim of this study was to identify the putative target proteins of BF211 and the signaling pathways in cancer cells. METHODS: A549 human lung cancer cells were treated with BF211. A SILAC-based proteomic analysis was used to detect the protein expression profiles of BF211-treated A549 cells. Cellular proteasome activities were examined using fluorogenic peptide substrates, and the binding affinities of BF211 to recombinant proteasome subunit proteins were evaluated using the Biacore assay. The expression levels of proteasome subunits were determined using RT-PCR and Western blotting, and the levels of the integral 26S proteasome were evaluated using native PAGE analysis. RESULTS: The proteomic analysis revealed that 1282 proteins were differentially expressed in BF211 treated A549 cells, and the putative target proteins of BF211 were associated with various cellular functions, including transcription, translation, mRNA splicing, ribosomal protein synthesis and proteasome function. In A549 cells, BF211 (5, 10, and 20 nmol/L) dose-dependently inhibited the enzymatic activities of proteasome. But BF211 displayed a moderate affinity in binding to proteasome beta1 subunit and no binding affinity to the beta2 and beta5 subunits. Moreover, BF211 (0.1, 1, and 10 nmol/L) did not inhibit the proteasome activities in the cell lysates. BF211 (5, 10, and 20 nmol/L) significantly decreased the expression level of proteasome beta1 subunit and the levels of integral 26S proteasome in A549 cells. Similarly, knockdown of the beta1 subunit with siRNA in A549 cells significantly decreased integral 26S proteasome and proteasome activity. CONCLUSION: BF211 inhibits proteasome activity in A549 cells by decreasing beta1 subunit expression and disrupting proteasome assembly. PMID- 27238211 TI - NMR-based platform for fragment-based lead discovery used in screening BRD4 targeted compounds. AB - AIM: Fragment-based lead discovery (FBLD) is a complementary approach in drug research and development. In this study, we established an NMR-based FBLD platform that was used to screen novel scaffolds targeting human bromodomain of BRD4, and investigated the binding interactions between hit compounds and the target protein. METHODS: 1D NMR techniques were primarily used to generate the fragment library and to screen compounds. The inhibitory activity of hits on the first bromodomain of BRD4 [BRD4(I)] was examined using fluorescence anisotropy binding assay. 2D NMR and X-ray crystallography were applied to characterize the binding interactions between hit compounds and the target protein. RESULTS: An NMR-based fragment library containing 539 compounds was established, which were clustered into 56 groups (8-10 compounds in each group). Eight hits with new scaffolds were found to inhibit BRD4(I). Four out of the 8 hits (compounds 1, 2, 8 and 9) had IC50 values of 100-260 MUmol/L, demonstrating their potential for further BRD4-targeted hit-to-lead optimization. Analysis of the binding interactions revealed that compounds 1 and 2 shared a common quinazolin core structure and bound to BRD4(I) in a non-acetylated lysine mimetic mode. CONCLUSION: An NMR-based platform for FBLD was established and used in discovery of BRD4-targeted compounds. Four potential hit-to-lead optimization candidates have been found, two of them bound to BRD4(I) in a non-acetylated lysine mimetic mode, being selective BRD4(I) inhibitors. PMID- 27238212 TI - Molecular Classification of Medulloblastoma. AB - Medulloblastoma (MB) is one of the most frequent malignant brain tumors in children. The current standard treatment regimen consists of surgical resection, craniospinal irradiation, and adjuvant chemotherapy. Although these treatments have the potential to increase the survival of 70-80% of patients with MB, they are also associated with serious treatment-induced morbidity. The current risk stratification of MB is based on clinical factors, including age at presentation, metastatic status, and the presence of residual tumor following resection. In addition, recent genomic studies indicate that MB consists of at least four distinct molecular subgroups: WNT, sonic hedgehog (SHH), Group 3, and Group 4. WNT and SHH MBs are characterized by aberrations in the WNT and SHH signaling pathways, respectively. WNT MB has the best prognosis compared to the other MBs, while SHH MB has an intermediate prognosis. The underlying signaling pathways associated with Group 3 and 4 MBs have not been identified. Group 3 MB is frequently associated with metastasis, resulting in a poor prognosis, while Group 4 is sometimes associated with metastasis and has an intermediate prognosis. Group 4 is the most frequent MB and represents 35% of all MBs. These findings suggest that MB is a heterogeneous disease, and that MB subgroups have distinct molecular, demographic, and clinical characteristics. The molecular classification of MBs is redefining the risk stratification of patients with MB, and has the potential to identify new therapeutic strategies for the treatment of MB. PMID- 27238213 TI - Malnutrition and body composition in urban and rural schoolchildren: A cross sectional study in San Rafael, Mendoza (Argentina). AB - OBJECTIVES: The aim of the present study was to analyze the nutritional status and body composition of children from San Rafael, Mendoza, avoiding urban and rural categorization by generating subpopulations as a function of their socio environmental characteristics. METHODS: A cross-sectional study was performed in 3,596 schoolchildren from 4.0 to 13.9 years of age. Body weight, height, upper arm circumference, and triceps skinfold were measured. Body mass index, total muscle, and fat areas of the arm were calculated. To estimate nutritional status and body composition, the NHANES III reference was used. The socio-environmental variables were surveyed using a structured questionnaire. These variables were processed by categorical principal-component analysis (catPCA). RESULTS: The catPCA allowed the differentiation of four groups, three with urban characteristics (high urban, medium urban, impoverished urban), and a rural group. Stunting occurred at a higher rate in the impoverished urban group, and the occurrence of underweight children was higher in the rural group. The prevalence of excess weight varied in the range of 20-26%. The latter value corresponded to children of the high urban group, who also did not show reduced muscle mass. CONCLUSION: Children from San Rafael presented differences in nutritional condition and body composition associated with pronounced socio environmental heterogeneity. Thus, we could observe a gradient from the "high urban" group, with better social, economic, and sanitation conditions and at the same time a more obesogenic environment to the "impoverished urban" and "rural" groups, whose vulnerability reflected a higher prevalence of child undernutrition and the association with excess weight and reduced muscle mass. Am. J. Hum. Biol. 28:796-803, 2016. (c) 2016Wiley Periodicals, Inc. PMID- 27238214 TI - Corrigendum. PMID- 27238215 TI - The redistribution of medicines: could it become a reality? AB - AIMS AND OBJECTIVES: Prescription medicines that are returned unused to pharmacies in the United Kingdom (UK) cannot be supplied (or redistributed) to other patients. The aim of the study was to investigate whether or not consensus could be achieved between pharmacists on the barriers and potential solutions they perceive towards the redistribution of returned medicines. METHODS: A two round electronic modified Delphi study was employed. Statements were generated following qualitative interviews (n = 29) with doctors, nurses and pharmacists from primary and secondary care from one Health Board (HB) in South East Wales. The Delphi panel were asked to rate the degree to which they agreed (or disagreed) with each statement. The panel was recruited via an email invitation forwarded to all hospital (n = 70), primary care (n = 11) and community pharmacists (n = 77) from one HB in South East Wales. KEY FINDINGS: Two rounds of Delphi were completed by 17 pharmacists. Consensus was achieved for seven (n = 26) 'barrier' and seven (n = 16) 'solution' statements. From the statements which achieved consensus, it was identified that the following criteria would need to be met for pharmacists to potentially accept the redistribution of medicines in solid dosage forms (tablets and capsules): protection for pharmacists; guidance from the professional regulator; tamper evident seals; 'as new' packaging; technologies to indicate inappropriate storage and public engagement. CONCLUSIONS: This study suggests that pharmacists would potentially be willing to redistribute medicines in solid dosage forms if certain criteria are met. PMID- 27238216 TI - Novel biomarker and easy to perform ELISA for monitoring complement inhibition in patients with atypical hemolytic uremic syndrome treated with eculizumab. PMID- 27238217 TI - Gene transfection of human mesenchymal stem cells with a nano-hydroxyapatite collagen scaffold containing DNA-functionalized calcium phosphate nanoparticles. AB - This study aimed to fabricate a growth factor-releasing biodegradable scaffold for tissue regeneration. We prepared multishell calcium phosphate (CaP) nanoparticles functionalized with DNA, polyethyleneimine (PEI), protamine and octa-arginine (R8) and compared their respective transfection activity and cell viability measures using human mesenchymal stem cells. DNA-protamine complexes improved the transfection efficiency of CaP nanoparticles with the exception of those functionalized with R8. These complexes also greatly reduced the cytotoxicity of PEI. In addition, we also fabricated DNA-protamine-functionalized CaP nanoparticle-loaded nano-hydroxyapatite-collagen scaffolds and investigated their gene transfection efficiencies. These experiments showed that the scaffolds were associated with moderate hMSC cell viability and were capable of releasing the BMP-2 protein into hMSCs following gene transfection. In particular, the scaffold loaded with protamine-containing CaP nanoparticles showed the highest cell viability and transfection efficiency in hMSCs; thus, it might be suitable to serve as an efficient growth factor-releasing scaffold. PMID- 27238218 TI - Retinal stimulation strategies to restore vision: Fundamentals and systems. AB - Retinal degeneration, a leading cause of blindness worldwide, is primarily characterized by the dysfunctional/degenerated photoreceptors that impair the ability of the retina to detect light. Our group and others have shown that bioelectronic retinal implants restore useful visual input to those who have been blind for decades. This unprecedented approach of restoring sight demonstrates that patients can adapt to new visual input, and thereby opens up opportunities to not only improve this technology but also develop alternative retinal stimulation approaches. These future improvements or new technologies could have the potential of selectively stimulating specific cell classes in the inner retina, leading to improved visual resolution and color vision. In this review we will detail the progress of bioelectronic retinal implants and future devices in this genre as well as discuss other technologies such as optogenetics, chemical photoswitches, and ultrasound stimulation. We will discuss the principles, biological aspects, technology development, current status, clinical outcomes/prospects, and challenges for each approach. The review will cover functional imaging documented cortical responses to retinal stimulation in blind patients. PMID- 27238219 TI - La Prevention Des 13-Thalassemies En Belgique Francophone. II. Proposition D'Une Strategie. AB - Medico-social surveys and pilot experiments, conducted by the authors in Wallonia and Brussels at the request of the Ministry for the French-Speaking Community, have allowed the definition of a community-scale prevention programme. High quality information, repeated at regular intervals and adapted to the different environments, is vital for effective voluntary screening. The contents of this information and distribution methods have been specified. Screening will take place on an occasional basis among people at risk who request it, or who accept it as an addition to other planned blood tests (curative or preventive consultations); microcytosis must be considered as a definite indication for further work up. Systematic screening is recommended in the framework of upper secondary education, through cooperation between volunteer teachers and the staff of school medical institutions; teaching methods and means have been reviewed. PMID- 27238220 TI - The Clinical Problem Solving Series: An Introduction. PMID- 27238221 TI - Clinical Problem Solving Series. PMID- 27238222 TI - Le Kala Azar A Propos D'Une Observation Chez Une Femme Belge. PMID- 27238224 TI - Resistance of Cu(Abeta4-16) to Copper Capture by Metallothionein-3 Supports a Function for the Abeta4-42 Peptide as a Synaptic Cu(II) Scavenger. AB - Abeta4-42 is a major species of Abeta peptide in the brains of both healthy individuals and those affected by Alzheimer's disease. It has recently been demonstrated to bind Cu(II) with an affinity approximately 3000 times higher than the commonly studied Abeta1-42 and Abeta1-40 peptides, which are implicated in the pathogenesis of Alzheimer's disease. Metallothionein-3, a protein considered to orchestrate copper and zinc metabolism in the brain and provide antioxidant protection, was shown to extract Cu(II) from Abeta1-40 when acting in its native Zn7 MT-3 form. This reaction is assumed to underlie the neuroprotective effect of Zn7 MT-3 against Abeta toxicity. In this work, we used the truncated model peptides Abeta1-16 and Abeta4-16 to demonstrate that the high-affinity Cu(II) complex of Abeta4-16 is resistant to Zn7 MT-3 reactivity. This indicates that the analogous complex of the full-length peptide Cu(Abeta4-42) will not yield copper to MT-3 in the brain, thus supporting the concept of a physiological role for Abeta4-42 as a Cu(II) scavenger in the synaptic cleft. PMID- 27238225 TI - Anti-inflammatory and anti-oxidative effects of alpha-lipoic acid in experimentally induced acute otitis media. AB - OBJECTIVES: To investigate the anti-inflammatory, anti-oxidative and tissue protective effects, as well as the potential therapeutic role, of alpha-lipoic acid in experimentally induced acute otitis media. METHODS: Twenty-five guinea pigs were assigned to one of five groups: a control (non-otitis) group, and otitis-induced groups treated with saline, penicillin G, alpha-lipoic acid, or alpha-lipoic acid plus penicillin G. Tissue samples were histologically analysed, and oxidative parameters in tissue samples were measured and compared between groups. RESULTS: The epithelial integrity was better preserved, and histological signs of inflammation and secretory metaplasia were decreased, in all groups compared to the saline treated otitis group. In the alpha-lipoic acid plus penicillin G treated otitis group, epithelial integrity was well preserved and histological findings of inflammation were significantly decreased compared to the saline, penicillin G and alpha-lipoic acid treated otitis groups. The most favourable oxidative parameters were observed in the control group, followed by the alpha-lipoic acid plus penicillin G treated otitis group. CONCLUSION: Alpha lipoic acid, with its antioxidant, anti-inflammatory and tissue protective properties, may decrease the clinical sequelae and morbidity associated with acute otitis media. PMID- 27238227 TI - Head and neck cancer immunology and immunotherapeutics: Basic concepts to clinical translational approaches. PMID- 27238226 TI - A Biomechanical Investigation of Selected Lumbopelvic Hip Tests: Implications for the Examination of Walking. AB - OBJECTIVE: The purpose of this study was to compare lumbopelvic hip ranges of motion during the Trendelenburg, Single Leg Squat, and Corkscrew Tests to walking and to describe the 3-dimensional lumbopelvic hip motion during the tests. This may help clinicians to select appropriate tests when examining gait. METHODS: An optoelectronic movement analysis tracking system was used to assess the lumbopelvic hip region of 14 healthy participants while performing Trendelenburg, Single Leg Squat, and Corkscrew Tests and walking. The lumbopelvic hip 3 dimensional ranges of movement for the clinical tests were compared with walking using a repeated-measures analysis of variance with pairwise comparisons. RESULTS: No significant differences were found between the pelvic obliquity during the Trendelenburg Test and walking (Trendelenburg Test: L, 11.3 degrees +/- 4.8 degrees , R, 10.8 degrees +/- 5.0 degrees vs walk: L, 8.3 degrees +/- 4.8 degrees , R 8.3 degrees +/- 5.1 degrees , L, P = .143, R, P = .068). Significant differences were found between the hip sagittal plane range of movement during the Single Leg Squat and walking (Single Leg Squat: L, 44.2 degrees +/-13.7 degrees , R, 41.7 degrees +/-10.9 degrees vs walk: 38.6 degrees +/-7.0 degrees , R 37.8 degrees +/-5.1 degrees , P < .05), the hip coronal plane range of movement (Single Leg Squat: L, 9.1 degrees +/-5.8 degrees , R, 9.0 degrees +/- 4.6 degrees vs walk: L, 9.4 degrees +/- 2.3 degrees , R 9.5 degrees +/- 2.0 degrees , P < .05), and the hip coronal plane range of movement during the Corkscrew Test and walking (Corkscrew: L, 5.7 degrees +/-3.3 degrees , R, 5.7 degrees +/-3.2 degrees vs walk: L, 9.4 degrees +/- 2.3 degrees , R 9.5 degrees +/- 2.0 degrees , P < .05). CONCLUSIONS: The results of the present study showed that, in young asymptomatic participants with no known lumbopelvic hip pathology, the pelvic obliquity during the Trendelenburg Test and walking is similar. During the Single Leg Squat, the hip moved more in the sagittal plane and less in the coronal plane when compared with walking. There was more movement in the hip transverse plane movement during the Corkscrew Test than during walking. These results suggest that for the Trendelenburg Test to be interpreted as normal, the pelvis should achieve at least 10 degrees of pelvic obliquity; during the Single Leg Squat, the hip should move through 43 degrees in the sagittal plane and under 10 degrees in the coronal plane; and for the Corkscrew Test to be interpreted as normal, the hip should move through 6 degrees of rotation and the trunk through 27 degrees of rotation. PMID- 27238228 TI - Increase of neurofilament-H protein in sensory neurons in antiretroviral neuropathy: Evidence for a neuroprotective response mediated by the RNA-binding protein HuD. AB - Nucleoside reverse transcriptase inhibitors (NRTIs) are key components of HIV/AIDS treatment to reduce viral load. However, antiretroviral toxic neuropathy has become a common peripheral neuropathy among HIV/AIDS patients leading to discontinuation of antiretroviral therapy, for which the underlying pathogenesis is uncertain. This study examines the role of neurofilament (NF) proteins in the spinal dorsal horn, DRG and sciatic nerve after NRTI neurotoxicity in mice treated with zalcitabine (2',3'-dideoxycitidine; ddC). ddC administration up regulated NF-M and pNF-H proteins with no effect on NF-L. The increase of pNF-H levels was counteracted by the silencing of HuD, an RNA binding protein involved in neuronal development and differentiation. Sciatic nerve sections of ddC exposed mice showed an increased axonal caliber, concomitantly to a pNF-H up regulation. Both events were prevented by HuD silencing. pNF-H and HuD colocalize in DRG and spinal dorsal horn axons. However, the capability of HuD to bind NF mRNA was not demonstrated, indicating the presence of an indirect mechanism of control of NF expression by HuD. RNA immunoprecipitation experiments showed the capability of HuD to bind the BDNF mRNA and the administration of an anti-BDNF antibody prevented pNF-H increase. These data indicate the presence of a HuD - BDNF - NF-H pathway activated as a regenerative response to the axonal damage induced by ddC treatment to counteract the antiretroviral neurotoxicity. Since analgesics clinically used to treat neuropathic pain are ineffective on antiretroviral neuropathy, a neuroregenerative strategy might represent a new therapeutic opportunity to counteract neurotoxicity and avoid discontinuation or abandon of NRTI therapy. PMID- 27238229 TI - Skp1: Implications in cancer and SCF-oriented anti-cancer drug discovery. AB - In the last decade, the ubiquitin proteasome system (UPS), in general, and E3 ubiquitin ligases, in particular, have emerged as valid drug targets for the development of novel anti-cancer therapeutics. Cullin RING Ligases (CRLs), which can be classified into eight groups (CRL1-8) and comprise approximately 200 members, represent the largest family of E3 ubiquitin ligases which facilitate the ubiquitination-derived proteasomal degradation of a myriad of functionally and structurally diverse substrates. S phase kinase-associated protein 1 (Skp1) Cullin1-F-Box protein (SCF) complexes are the best characterized among CRLs, which play crucial roles in numerous cellular processes and physiological dysfunctions, such as in cancer biology. Currently, there is growing interest in developing SCF-targeting anti-cancer therapies for clinical application. Indeed, the research in this field has seen some progress in the form of cullin neddylation- and Skp2-inhibitors. However, it still remains an underdeveloped area and needs to design new strategies for developing improved form of therapy. In this review, we venture a novel strategy that rational pharmacological targeting of Skp1, a central regulator of SCF complexes, may provide a novel avenue for SCF-oriented anti-cancer therapy, expected: (i) to simultaneously address the critical roles that multiple SCF oncogenic complexes play in cancer biology, (ii) to selectively target cancer cells with minimal normal cell toxicity, and (iii) to offer multiple chemical series, via therapeutic interventions at the Skp1 binding interfaces in SCF complex, thereby maximizing chances of success for drug discovery. In addition, we also discuss the challenges that might be posed regarding rational pharmacological interventions against Skp1. PMID- 27238230 TI - The core musculature in male prepubescent tennis players and untrained counterparts: a volumetric MRI study. AB - The effects of exercise on the core musculature have not been investigated in prepubescents. The main purpose of the present study was to determine the volume and degree of asymmetry of rectus abdominis, obliques and transversus abdominis, quadratus lumborum, iliopsoas, gluteus and paravertebralis muscles in prepubescent tennis players and in untrained boys. The muscle volume was determined using magnetic resonance imaging (MRI) in 7 male prepubescent tennis players and 10 untrained controls (mean age 11.0 +/- 0.8 years, Tanner 1-2). After accounting for height and body weight as covariates, the tennis players had 14-34% greater volume than the controls in all the muscles analysed (P < 0.05) except in paravertebralis, dominant quadratus lumborum and non-dominant gluteus, which had similar volumes in both groups (P = NS). Compared to controls, the tennis players displayed a greater degree of asymmetry in quadratus lumborum and rectus abdominis (3% vs. 15%, P < 0.01 and 8% vs. 17%, P = 0.06, respectively). The level of asymmetry of obliques and transversus abdominis, iliopsoas, gluteus and paravertebralis muscles was similar in both groups (P = NS). In conclusion, tennis playing at prepubertal ages induces a selective hypertrophy of the core musculature and exaggerates the degree of asymmetry of quadratus lumborum and rectus abdominis compared to untrained boys. PMID- 27238231 TI - Efficacy of insurance for organisational disaster recovery: case study of the 2010 and 2011 Canterbury earthquakes. AB - Insurance is widely acknowledged to be an important component of an organisation's disaster preparedness and resilience. Yet, little analysis exists of how well current commercial insurance policies and practices support organisational recovery in the wake of a major disaster. This exploratory qualitative research, supported by some quantitative survey data, evaluated the efficacy of commercial insurance following the sequence of earthquakes in Canterbury, New Zealand, in 2010 and 2011. The study found that, generally, the commercial insurance sector performed adequately, given the complexity of the events. However, there are a number of ways in which insurers could improve their operations to increase the efficacy of commercial insurance cover and to assist organisational recovery following a disaster. The most notable of these are: (i) better wording of policies; (ii) the availability of sector-specific policies; (iii) the enhancement of claims assessment systems; and (iv) risk-based policy pricing to incentivise risk reduction measures. PMID- 27238232 TI - A Novel NADPH-dependent flavoprotein reductase from Bacillus megaterium acts as an efficient cytochrome P450 reductase. AB - Cytochromes P450 (P450s) require electron transfer partners to catalyze substrate conversions. With regard to biotechnological approaches, the elucidation of novel electron transfer proteins is of special interest, as they can influence the enzymatic activity and specificity of the P450s. In the current work we present the identification and characterization of a novel soluble NADPH-dependent diflavin reductase from Bacillus megaterium with activity towards a bacterial (CYP106A1) and a microsomal (CYP21A2) P450 and, therefore, we referred to it as B. megaterium cytochrome P450 reductase (BmCPR). Sequence analysis of the protein revealed besides the conserved FMN-, FAD- and NADPH-binding motifs, the presence of negatively charged cluster, which is thought to represent the interaction domain with P450s and/or cytochrome c. BmCPR was expressed and purified to homogeneity in Escherichia coli. The purified BmCPR exhibited a characteristic diflavin reductase spectrum, and showed a cytochrome c reducing activity. Furthermore, in an in vitro reconstituted system, the BmCPR was able to support the hydroxylation of testosterone and progesterone with CYP106A1 and CYP21A2, respectively. Moreover, in view of the biotechnological application, the BmCPR is very promising, as it could be successfully utilized to establish CYP106A1- and CYP21A2-based whole-cell biotransformation systems, which yielded 0.3g/L hydroxy testosterone products within 8h and 0.16g/L 21-hydroxyprogesterone within 6h, respectively. In conclusion, the BmCPR reported herein owns a great potential for further applications and studies and should be taken into consideration for bacterial and/or microsomal CYP-dependent bioconversions. PMID- 27238233 TI - Cyanobacterial chemical production. AB - The increase in global temperatures caused by rising CO2 levels necessitates the development of alternative sources of fuel and chemicals. One appealing alternative that has been receiving increased attention in recent years is the photosynthetic conversion of atmospheric CO2 to biofuels and chemical products using genetically engineered cyanobacteria. This can help to not only provide an alternate "greener" source for some of the most popular petroleum based products but it can also help to reduce atmospheric CO2. Utilizing cyanobacteria rather than plants allows for reduced land requirements and reduces competition with food crops. This review discusses advancements in the field since 2012 with a particular emphasis on production of hydrocarbons. PMID- 27238235 TI - Doctor to Doctor. PMID- 27238234 TI - One-year clinical experience of perampanel in Spain: a multicentre study of efficacy and tolerability. AB - Perampanel, a non-competitive antagonist of the alpha-amino-3-hydroxy-5-methyl-4 isoxazole-propionic acid receptors, is the most recent antiepileptic drug available in Spain, marketed in January 2014. It was initially approved by the European Medicines Agency as adjunctive treatment for partial-onset seizures in patients 12 years and older, but recently also for primary generalized tonic clonic seizures. Although clinical trials provide essential information about the drug, they do not reflect daily clinical practice. This retrospective study shows the initial experience with perampanel in 11 Spanish hospitals during its first year post-commercialisation. All patients who started perampanel treatment were included, but efficacy and tolerability were only assessed in those patients with a minimum follow-up period of six months. In total, 256 patients were treated with perampanel before September 2014, and 253 had an observational period of one year. After six months, 216/256 patients (84%) continued on perampanel and 180/253 (71.1%) completed one year of treatment. The mean number of previous antiepileptic drugs used was 6.83 and the median number of concomitant antiepileptic drugs was 2. The mean perampanel dose was 7.06 mg and 8.26 mg at six and 12 months, respectively. The responder rate was 39.5% and 35.9% at both follow-up points, respectively. Adverse events were experienced by 91/253 (35.5%) and resulted in withdrawal in 37 (14.6%). The most common adverse events were somnolence, dizziness, and irritability. We found no significant differences between concomitant use of enzyme-inducing and non-inducing antiepileptic drugs, regarding efficacy, adverse effects, or withdrawals. Irritability was not influenced by concomitant use of levetiracetam, relative to other drugs, but was more frequently observed in patients with a history of psychiatric problems or learning disabilities. PMID- 27238236 TI - The Malpractice Mess. PMID- 27238238 TI - A Few Thoughts About Retirement. PMID- 27238237 TI - The Medical Bookshelf. PMID- 27238240 TI - Acute myocardial infarction. PMID- 27238239 TI - Acute myocardial infarction. PMID- 27238241 TI - Acute myocardial infarction. PMID- 27238242 TI - How many boards does it take to make a house? PMID- 27238243 TI - Heart attack. PMID- 27238245 TI - Body Fat Analysis in Predialysis Chronic Kidney Disease: Multifrequency Bioimpedance Assay and Anthropometry Compared With Dual-Energy X-Ray Absorptiometry. AB - OBJECTIVES: Body composition analysis is required for accurate assessment of nutritional status in patients with predialysis chronic kidney disease (CKD). The reference method for assessing body fat is dual-energy X-ray absorptiometry (DXA), but it is relatively expensive and often not available for widespread clinical use. There is only limited data on the utility of less expensive and easily available alternatives such as multifrequency bioimpedance assay (BIA) and skinfold thickness (SFT) measurements for assessing body fat in predialysis CKD. The study intends to assess the utility of BIA and SFT in measuring body fat compared to the reference method DXA in subjects with predialysis CKD. METHODS: Body composition analysis was done in 50 subjects with predialysis CKD using multifrequency BIA, SFT, and DXA. The agreement between the body fat percentages measured by reference method DXA and BIA/SFT was assessed by paired t-test, intraclass correlation coefficients (ICCs), regression, and Bland-Altman plots. RESULTS: Percentage of body fat measured by BIA was higher compared to the measurements by DXA, but the difference was not significant (30.44 +/- 9.34 vs. 28.62 +/- 9.00; P = .071). The ICC between DXA and BIA was 0.822 (confidence interval: 0.688, 0.899; P = .000). The mean values of body fat percentages measured by anthropometry (SFT) was considerably lower when compared to DXA (23.62 +/- 8.18 vs. 28.62 +/- 9.00; P = .000). The ICC between DXA and SFT was .851 (confidence interval: 0.739, 0.915; P = .000). Bland-Altman plots showed that BIA overestimated body fat by a mean of 1.8% (standard deviation, 6.98), whereas SFT underestimated body fat by 5% (standard deviation, 4.01). Regression plots showed a better agreement between SFT and DXA (R(2) = .79) than BIA (R(2) = .50). Overall, SFT showed better agreement with the DXA. Body mass index (BMI) showed a moderate positive correlation with body fat measured by DXA whereas serum albumin failed to show good correlation. CONCLUSIONS: SFT showed relatively better agreement with the reference method DXA, compared to BIA. SFT can be used as a tool for assessing nutritional status in predialysis patients with CKD. PMID- 27238246 TI - Conservation of the oligomeric state of native VDAC1 in detergent micelles. AB - The voltage-dependent anion-selective channel (VDAC) is an intrinsic beta-barrel membrane protein located within the mitochondrial outer membrane where it serves as a pore, connecting the mitochondria to the cytosol. The high-resolution structures of both the human and murine VDACs have been resolved by X-ray diffraction and nuclear magnetic resonance spectroscopy (NMR) in 2008. However, the structural data are not completely in line with the findings that were obtained after decades of research on biochemical and functional analysis of VDAC. This discrepancy may be related to the fact that structural biology studies of membrane proteins reveal specific static conformations that may not necessarily represent the physiological state. For example, overexpression of membrane proteins in bacterial inclusion bodies or simply the extraction from the native lipid environment using harsh purification methods (i.e. chaotropic agents) can disturb the physiological conformations and the supramolecular assemblies. To address these potential issues, we have developed a method, allowing rapid one step purification of endogenous VDAC expressed in the native mitochondrial membrane without overexpression of recombinant protein or usage of harsh chaotropic extraction procedures. Using the Saccharomyces cerevisiae isoform 1 of VDAC as a model, this method yields efficient purification, preserving VDAC in a more physiological, native state following extraction from mitochondria. Single particle analysis using transmission electron microscopy (TEM) demonstrated conservation of oligomeric assembly after purification. Maintenance of the native state was evaluated using functional assessment that involves an ATP-binding assay by micro-scale thermophoresis (MST). Using this approach, we were able to determine for the first time the apparent KD for ATP of 1.2 mM. PMID- 27238247 TI - Relationship between anemia and depressive mood in the last trimester of pregnancy. AB - OBJECTIVE: To compare the relationship between the severity of anemia and depressive mood in the last trimester of pregnancy. METHODS: A cross-sectional study, enrolled a total of 450 pregnant women who attended the antenatal clinics in their third trimester for their routine antenatal follow-up. Depressive symptoms were assessed by the Edinburgh Postnatal Depression Scale. The study group was divided into two groups according to presence of anemia; anemic group (Hb < 11 gr/L; n = 150) and non-anemic group (Hb >= 11 gr/L; n = 300) and depression scores were compared. RESULTS: One hundred and fourteen (25.3%) women scored >=13 points which were considered the cutoff value for depression on the EPDS. Anemia frequency was found as 33.3%. The total EPDS score was significantly higher in the anemic group (EPDS score 11 [min-max 0-29]) compared with the non anemic group (EPDS score 7 [min-max 0-21]) (p = 0.000). Multiple regression analysis also revealed that serum Hb level was an independent factor for antenatal depressive mood. CONCLUSIONS: As anemia is associated with higher depressive symptom levels, it should be carefully considered during pregnancy. Prospective studies are needed to confirm our results. PMID- 27238248 TI - Antibiotic consumption in Turkish hospitals; a multi-centre point prevalence study. AB - This multi-centre study aimed to determine the antibiotic consumption in Turkish hospitals by point prevalence. Antibiotic consumption of 14 centres was determined using the DDD method. Among hospitalized patients, 44.8% were using antibiotics and the total antibiotic consumption was 674.5 DDD/1000 patient-days (DPD). 189.6 (28%) DPD of the antibiotic consumption was restricted while 484.9 (72%) DPD was unrestricted. Carbapenems (24%) and beta lactam/beta lactamase inhibitors (ampicillin-sulbactam or amoxicillin-clavulanate; 22%) were the most commonly used restricted and unrestricted antibiotics. Antibiotics were most commonly used in intensive care units (1307.7 DPD). Almost half of the hospitalized patients in our hospitals were using at least one antibiotic. Moreover, among these antibiotics, the most commonly used ones were carbapenems, quinolones and cephalosporins, which are known to cause collateral damage. We think that antibiotic resistance, which is seen at considerably high rates in our hospitals, is associated with this level of consumption. PMID- 27238251 TI - 'A step not a journey'. AB - One of my favourite quotes among all the acres of coverage given over the nurses pay award was from Frank Dobson, who proudly declared that this year's pay rise was the best in ten years. My first reaction was 'well that's not something to be too proud of, not least because for the last five years we have received staged rises at below inflation levels'. PMID- 27238250 TI - Ciprofloxacin-loaded keratin hydrogels reduce infection and support healing in a porcine partial-thickness thermal burn. AB - Infection is a leading cause of morbidity and mortality in burn patients. Current therapies include silver-based creams and dressings, which display limited antimicrobial effectiveness and impair healing. The need exists for a topical, point-of-injury antibiotic treatment that provides sustained antimicrobial activity without impeding wound repair. Fitting this description are keratin based hydrogels, which are fully biocompatible and support the slow-release of antibiotics. Here we develop a porcine model of an infected partial-thickness burn to test the effects of ciprofloxacin-loaded keratin hydrogels on infection and wound healing. Partial-thickness burns were inoculated with either Pseudomonas aeruginosa or Methicillin-resistant Staphylococcus aureus, resulting in infections that persisted for >2 weeks that exceeded 10(5) and 10(6) cfu per gram of tissue, respectively. Compared to silver sulfadiazine, ciprofloxacin loaded keratin hydrogel treatment significantly reduced the amount of P. aeruginosa and S. aureus in the burn by >99% on days 4, 7, 11, and 15 postinjury. Further, burns treated with ciprofloxacin-loaded keratin hydrogels exhibited similar healing patterns as uninfected burns with regards to reepithelialization, macrophage recruitment, and collagen deposition and remodeling. The ability of keratin hydrogels to deliver antibiotics to fight infection and support healing of partial-thickness burns make them a strong candidate as a first-line burn therapy. PMID- 27238249 TI - Bacterial disease management: challenges, experience, innovation and future prospects: Challenges in Bacterial Molecular Plant Pathology. AB - Plant diseases caused by bacterial pathogens place major constraints on crop production and cause significant annual losses on a global scale. The attainment of consistent effective management of these diseases can be extremely difficult, and management potential is often affected by grower reliance on highly disease susceptible cultivars because of consumer preferences, and by environmental conditions favouring pathogen development. New and emerging bacterial disease problems (e.g. zebra chip of potato) and established problems in new geographical regions (e.g. bacterial canker of kiwifruit in New Zealand) grab the headlines, but the list of bacterial disease problems with few effective management options is long. The ever-increasing global human population requires the continued stable production of a safe food supply with greater yields because of the shrinking areas of arable land. One major facet in the maintenance of the sustainability of crop production systems with predictable yields involves the identification and deployment of sustainable disease management solutions for bacterial diseases. In addition, the identification of novel management tactics has also come to the fore because of the increasing evolution of resistance to existing bactericides. A number of central research foci, involving basic research to identify critical pathogen targets for control, novel methodologies and methods of delivery, are emerging that will provide a strong basis for bacterial disease management into the future. Near-term solutions are desperately needed. Are there replacement materials for existing bactericides that can provide effective disease management under field conditions? Experience should inform the future. With prior knowledge of bactericide resistance issues evolving in pathogens, how will this affect the deployment of newer compounds and biological controls? Knowledge is critical. A comprehensive understanding of bacterial pathosystems is required to not only identify optimal targets in the pathogens, but also optimal seasonal timings for deployment. Host resistance to effectors must be exploited, carefully and correctly. Are there other candidate genes that could be targeted in transgenic approaches? How can new technologies (CRISPR, TALEN, etc.) be most effectively used to add sustainable disease resistance to existing commercially desirable plant cultivars? We need an insider's perspective on the management of systemic pathogens. In addition to host resistance or reduced sensitivity, are there other methods that can be used to target these pathogen groups? Biological systems are variable. Can biological control strategies be improved for bacterial disease management and be made more predictable in function? The answers to the research foci outlined above are not all available, as will become apparent in this article, but we are heading in the right direction. In this article, we summarize the contributions from past experiences in bacterial disease management, and also describe how advances in bacterial genetics, genomics and host-pathogen interactions are informing novel strategies in virulence inhibition and in host resistance. We also outline potential innovations that could be exploited as the pressures to maximize a safe and productive food supply continue to become more numerous and more complex. PMID- 27238252 TI - 18th century art depicts a caring A&E. AB - The new L92 million Jubilee Wing of the Leeds Teaching Hospitals NHS Trust recently unveiled a reproduction of a painting depicting A&E services in Leeds in the late Eighteenth century. PMID- 27238253 TI - Un title. AB - A&E staff at Leeds General Infirmary recently tested the hospital's new helipad, constructed on top of its new L92 million Jubilee building. The trials, involving an RAF helicopter, were designed to test run the safety of the helipad, as well as ensure noise levels were not too high for local residents. At the moment, patients who are airlifted to the hospital by helicopter land on Woodhouse Moor or at the nearby airport before being ferried to A&E by ambulance. PMID- 27238254 TI - A&E nurses strike back at debilitating results of hospital snapshot survey. AB - Nurses have hit back at survey findings suggesting that their A&E department is the worst in the country. PMID- 27238255 TI - 'Grade D minimum' for all enrolled nurses. AB - This year's pay award, which has given newly qualified nurses a 12 per cent pay rise and others 4.7 per cent, has opened up a L485 gulf between the top of grade C and the bottom of grade D. About 4,000 ENs are employed on grade C. The move has prompted the RCN to call on the NHS Confederation, which represents health authorities and trusts, to ensure that 'grade D should be the minimum for all registered nurses'. In a letter to the Confederation, the RCN wrote: 'Enrolled nurses on grade C are dismayed that newly qualified registered nurses will earn nearly L500 more than them. This is despite the fact enrolled nurses will all have been qualified for at least eight years.' PMID- 27238256 TI - Frontliners. PMID- 27238258 TI - SIDS: Time to revise or reject term? AB - In what has become a controversial study, a leading authority on Munchausen syndrome by proxy undertook a study to identify features to help paediatricians differentiate between natural and unnatural infant deaths. Clinical features of 81 children judged by criminal and family courts to have been killed by their parents were studied. Health and social service records, court documents, and records from meetings with parents, relatives, and social workers were studied. PMID- 27238257 TI - Emergency contraception. AB - It has been suggested that A&E departments in the UK should be in the forefront of providing out of hours emergency contraception services because of the 24 hour availability, and to help meet the Health of the Nation targets in reducing unwanted pregnancy. PMID- 27238259 TI - Ready for peace, preparing for disaster Major incident planning in Craigavon A&E department is a necessary fact of life in preparing for the 'Drumcree situation' each year. Garrett Martin discusses how its potential for violence has affected his colleagues. AB - Over the past 30 years, emergency services in Northern Ireland have coped with more than their share of trauma and disaster. A&E nurses have been at the heart of this service, often working in extremely difficult and dangerous circumstances. Ironically, in April 1998, at a time when the whole community was experiencing unprecedented hope of peace, staff in Craigavon Area Hospital began making plans to prepare for what potentially could be violence on a massive scale. PMID- 27238260 TI - Biophysics of BK Channel Gating. AB - BK channels are universal regulators of cell excitability, given their exceptional unitary conductance selective for K(+), joint activation mechanism by membrane depolarization and intracellular [Ca(2+)] elevation, and broad expression pattern. In this chapter, we discuss the structural basis and operational principles of their activation, or gating, by membrane potential and calcium. We also discuss how the two activation mechanisms interact to culminate in channel opening. As members of the voltage-gated potassium channel superfamily, BK channels are discussed in the context of archetypal family members, in terms of similarities that help us understand their function, but also seminal structural and biophysical differences that confer unique functional properties. PMID- 27238262 TI - Posttranscriptional and Posttranslational Regulation of BK Channels. AB - Large conductance calcium- and voltage-activated potassium (BK) channels are ubiquitously expressed and play an important role in the regulation of an eclectic array of physiological processes. Their diverse functional role requires channels with a wide variety of properties even though the pore-forming alpha subunit is encoded by a single gene, KCNMA1. To achieve this, BK channels exploit some of the most fundamental posttranscriptional and posttranslational mechanisms that allow proteomic diversity to be generated from a single gene. These include mechanisms that diversify mRNA variants and abundance such as alternative pre mRNA splicing, editing, and control by miRNA. The BK channel is also subject to a diverse array of posttranslational modifications including protein phosphorylation, lipidation, glycosylation, and ubiquitination to control the number, properties, and regulation of BK channels in specific cell types. Importantly, "cross talk" between these posttranscriptional and posttranslational modifications typically converge on disordered domains of the BK channel alpha subunit. This allows both wide physiological diversity to be generated and a diversity of mechanisms to allow conditional regulation of BK channels and is emerging as an important determinant of BK channel function in health and disease. PMID- 27238263 TI - Protein Network Interacting with BK Channels. AB - The large conductance, voltage- and calcium-dependent potassium BK channel, also termed BKCa, Maxi-K, KCa1.1, or SLO1, regulates a wide array of key biological processes that are mediated by calcium ions. This broad regulatory function of BK channels requires the interactions of BK channels with diverse sets of proteins that have different molecular or cellular functions. Proteins that interact with BK channels range from the auxiliary subunits of BK channels to cytoskeletal proteins responsible for BK channel trafficking and localization. Furthermore, depending on cellular contexts, BK channels interact with proteins modifying channel properties, and with proteins that allow cell-specific responses. In this chapter, we review some of the relevant studies investigating the protein interaction network of BK channels with a focus on the biological roles of the interaction. PMID- 27238264 TI - Functional Role of Mitochondrial and Nuclear BK Channels. AB - BK channels are important for the regulation of many cell functions. The significance of plasma membrane BK channels in the control of action potentials, resting membrane potential, and neurotransmitter release is well established; however, the composition and functions of mitochondrial and nuclear BK (nBK) channels are largely unknown. In this chapter, we summarize the recent findings on the subcellular localization, biophysical, and pharmacological properties of mitochondrial and nBK channels and discuss their molecular identity and physiological functions. PMID- 27238261 TI - Modulation of BK Channel Function by Auxiliary Beta and Gamma Subunits. AB - The large-conductance, Ca(2+)- and voltage-activated K(+) (BK) channel is ubiquitously expressed in mammalian tissues and displays diverse biophysical or pharmacological characteristics. This diversity is in part conferred by channel modulation with different regulatory auxiliary subunits. To date, two distinct classes of BK channel auxiliary subunits have been identified: beta subunits and gamma subunits. Modulation of BK channels by the four auxiliary beta (beta1 beta4) subunits has been well established and intensively investigated over the past two decades. The auxiliary gamma subunits, however, were identified only very recently, which adds a new dimension to BK channel regulation and improves our understanding of the physiological functions of BK channels in various tissues and cell types. This chapter will review the current understanding of BK channel modulation by auxiliary beta and gamma subunits, especially the latest findings. PMID- 27238265 TI - Modulation of BK Channels by Small Endogenous Molecules and Pharmaceutical Channel Openers. AB - Voltage- and Ca(2+)-activated K(+) channels of big conductance (BK channels) are abundantly found in various organs and their relevance for smooth muscle tone and neuronal signaling is well documented. Dysfunction of BK channels is implicated in an array of human diseases involving many organs including the nervous, pulmonary, cardiovascular, renal, and urinary systems. In humans a single gene (KCNMA1) encodes the pore-forming alpha subunit (Slo1) of BK channels, but the channel properties are variable because of alternative splicing, tissue- and subcellular-specific auxiliary subunits (beta, gamma), posttranslational modifications, and a multitude of endogenous signaling molecules directly affecting the channel function. Initiatives to develop drugs capable of activating BK channels (channel openers) therefore need to consider the tissue specific variability of BK channel structure and the potential interference with endogenously produced regulatory factors. The atomic structural basis of BK channel function is only beginning to be revealed. However, building on detailed knowledge of BK channel function, including its single-channel characteristics, voltage- and Ca(2+) dependence of channel gating, and modulation by diffusible messengers, a multi-tier allosteric model of BK channel gating (Horrigan and Aldrich (HA) model) has become a valuable tool in studying modulation of the channel. Using the conceptual framework of the HA model, we here review the functional impact of endogenous modulatory factors and select small synthetic compounds that regulate BK channel activity. Furthermore, we devise experimental approaches for studying BK channel-drug interactions with the aim to classify BK modulating substances according to their molecular mode of action. PMID- 27238266 TI - Modulation of BK Channels by Ethanol. AB - In alcohol-naive systems, ethanol (<100mM) exposure of calcium-gated BK channels perturbs physiology and behavior. Brief (several minutes) ethanol exposure usually leads to increased BK current, which results from ethanol interaction with a pocket mapped to the BK channel-forming slo1 protein cytosolic tail domain. The importance of this region in ethanol-induced intoxication has been independently supported by an unbiased screen of Caenorhabditis elegans slo1 mutants. However, ethanol-induced BK activation is not universal as refractoriness and inhibition have been reported. The final effect depends on many factors, including intracellular calcium levels, slo1 isoform, BK beta subunit composition, posttranslational modification of BK proteins, channel lipid microenvironment, and type of ethanol administration. Studies in Drosophila melanogaster, C. elegans, and rodents show that protracted/repeated ethanol administration leads to tolerance to ethanol-induced modification of BK-driven physiology and behavior. Unveiling the mechanisms underlying tolerance is of major importance, as tolerance to ethanol has been proposed as predictor of risk for alcoholism. PMID- 27238268 TI - BK Channels and the Control of the Pituitary. AB - The pituitary gland provides the important link between the nervous system and the endocrine system and regulates a diverse range of physiological functions. The pituitary is connected to the hypothalamus by the pituitary stalk and is comprised primarily of two lobes. The anterior lobe consists of five hormone secreting cell types which are electrically excitable and display single-spike action potentials as well as complex bursting patterns. Bursting is of particular interest as it raises intracellular calcium to a greater extent than spiking and is believed to underlie secretagogue-induced hormone secretion. BK channels have been identified as a key regulator of bursting in anterior pituitary cells. Experimental data and mathematical modeling have demonstrated that BK activation during the upstroke of an action potential results in a prolonged depolarization and an increase in intracellular calcium. In contrast, the posterior lobe is primarily composed of axonal projections of magnocellular neurosecretory cells which extend from the supraoptic and paraventricular nuclei of the hypothalamus. In these neuroendocrine cells, BK channel activation results in a decrease in excitability and hormone secretion. The opposite effect of BK channels in the anterior and posterior pituitary highlights the diverse role of BK channels in regulating the activity of excitable cells. Further studies of pituitary cell excitability and the specific role of BK channels would lead to a greater understanding of how pituitary cell excitability is regulated by both hypothalamic secretagogues and negative feedback loops, and could ultimately lead to novel treatments to pituitary-related disorders. PMID- 27238269 TI - BK Channels in the Vertebrate Inner Ear. AB - The perception of complex acoustic stimuli begins with the deconstruction of sound into its frequency components. This spectral processing occurs first and foremost in the inner ear. In vertebrates, two very different strategies of frequency analysis have evolved. In nonmammalian vertebrates, the sensory hair cells of the inner ear are intrinsically electrically tuned to a narrow band of acoustic frequencies. This electrical tuning relies on the interplay between BK channels and voltage-gated calcium channels. Systematic variations in BK channel density and kinetics establish a gradient in electrical resonance that enables the coding of a broad range of acoustic frequencies. In contrast, mammalian hair cells are extrinsically tuned by mechanical properties of the cochlear duct. Even so, mammalian hair cells also express BK channels. These BK channels play critical roles in various aspects of mammalian auditory signaling, from developmental maturation to protection against acoustic trauma. This review summarizes the anatomical localization, biophysical properties, and functional contributions of BK channels in vertebrate inner ears. Areas of future research, based on an updated understanding of the biology of both BK channels and the inner ear, are also highlighted. Investigation of BK channels in the inner ear continues to provide fertile research grounds for examining both BK channel biophysics and the molecular mechanisms underlying signal processing in the auditory periphery. PMID- 27238270 TI - BK Channels in the Vascular System. AB - Autoregulation of blood flow is essential for the preservation of organ function to ensure continuous supply of oxygen and essential nutrients and removal of metabolic waste. This is achieved by controlling the diameter of muscular arteries and arterioles that exhibit a myogenic response to changes in arterial blood pressure, nerve activity and tissue metabolism. Large-conductance voltage and Ca(2+)-dependent K(+) channels (BK channels), expressed exclusively in smooth muscle cells (SMCs) in the vascular wall of healthy arteries, play a critical role in regulating the myogenic response. Activation of BK channels by intracellular, local, and transient ryanodine receptor-mediated "Ca(2+) sparks," provides a hyperpolarizing influence on the SMC membrane potential thereby decreasing the activity of voltage-dependent Ca(2+) channels and limiting Ca(2+) influx to promote SMC relaxation and vasodilation. The BK channel alpha subunit, a large tetrameric protein with each monomer consisting of seven-transmembrane domains, a long intracellular C-terminal tail and an extracellular N-terminus, associates with the beta1 and gamma subunits in vascular SMCs. The BK channel is regulated by factors originating within the SMC or from the endothelium, perivascular nerves and circulating blood, that significantly alter channel gating properties, Ca(2+) sensitivity and expression of the alpha and/or beta1 subunit. The BK channel thus serves as a central receiving dock that relays the effects of the changes in several such concomitant autocrine and paracrine factors and influences cardiovascular health. This chapter describes the primary mechanism of regulation of myogenic response by BK channels and the alterations to this mechanism wrought by different vasoactive mediators. PMID- 27238271 TI - Developing Molecular Pharmacology of BK Channels for Therapeutic Benefit. AB - High conductance, calcium-activated potassium (BK) channels (KCa1.1) are important in regulating physiologic responses in many types of tissues and, as such, present opportunities for development of new therapeutic agents. Both channel agonists and inhibitors could have therapeutic utility, depending on medical application under consideration. However, characterization of molecular pharmacology of BK channels is incomplete and has been difficult to accomplish because of paucity of chemical leads that are acceptable templates for Medicinal Chemistry investigation. Only through continued prosecution of new high throughput screening campaigns can this situation be rectified. Examples are presented of BK channel agonist and inhibitor discovery paradigms which will be useful for progressing BK channel future drug discovery strategies. PMID- 27238272 TI - Preface. PMID- 27238274 TI - "Peri-Implantitis": A Complication of a Foreign Body or a Man-Made "Disease". Facts and Fiction. AB - BACKGROUND: The discrepancy between some scientific views and the daily clinical experience with dental implants has made the topic of "periimplantitis" highly controversial, especially the discussion whether "periimplantitis" should even be considered a "disease" or whether marginal bone loss instead would represent a complication of having a foreign body placed in the oral cavity. PURPOSE: The aim of the present paper was to present the outcomes from a consensus meeting on "peri-implantitis" in Rome, Italy (January 8-10, 2016). MATERIALS AND METHODS: Seventeen clinical scientists were invited to, based on prepared reviews of the literature, discuss topics related to "periimplantitis." RESULTS AND CONCLUSIONS: Oral implants may lose bone or even display clinical failure. However, progressive bone loss threatening implant survival is rare and limited to a percent or two of all implants followed up over 10 years or more, provided that controlled implant systems are being used by properly trained clinicians. There is very little evidence pointing to implants suffering from a defined disease entity entitled "peri-implantitis." Marginal bone loss around implants is in the great majority of cases associated with immune-osteolytic reactions. Complicating factors include patient genetic disorders, patient smoking, cement or impression material remnants in the peri-implant sulcus, bacterial contamination of the implant components and technical issues such as loose screws, mobile components or fractured materials. These reactions combine to result in cellular responses with the end result being a shift in the delicate balance between the osteoblast and the osteoclast resulting in bone resorption. However, the great majority of controlled implants display a foreign body equilibrium resulting in very high survival rates of the implants over long term of follow-up. PMID- 27238275 TI - Trials of Vacuum Extraction. PMID- 27238273 TI - Gait mechanics 2 years after anterior cruciate ligament reconstruction are associated with longer-term changes in patient-reported outcomes. AB - This study tested the hypothesis that side-to-side differences in knee gait mechanics 2 years after anterior cruciate ligament (ACL) reconstruction are associated with long-term (~8 years post-reconstruction) changes in patient reported outcome scores. Sixteen subjects (5 males; age: 29.1 +/- 7.1 years) with primary unilateral ACL reconstruction were gait tested at baseline (2.2 +/- 0.3 years post-ACL reconstruction) and filled out KOOS and Lysholm surveys. At long term follow-up (7.7 +/- 0.7 years post-ACL reconstruction), the same subjects completed KOOS and Lysholm surveys. Pearson correlation coefficients assessed relationships between side-to-side differences in kinematics and kinetics at baseline and changes in Lysholm and KOOS Pain/QOL scores from 2 to 8 years post ACL reconstruction. Significant associations were seen between greater average varus rotation (Lysholm: R = -0.654, p = 0.006) and less anterior femoral displacement (Lysholm: R = 0.578, p = 0.019) during stance of the ACL reconstructed knee versus the contralateral knee at baseline and worse follow-up outcome scores. Significant associations were seen between greater peak knee flexion moment (KOOS Pain: R = -0.572, p = 0.026; KOOS QOL: R = -0.636, p = 0.011), peak knee adduction moment (Lysholm: R = -0.582, p = 0.018; KOOS Pain: R = -0.742, p = 0.002; KOOS QOL: R = -0.551, p = 0.033), and peak internal rotation moment (Lysholm: R = 0.525, p = 0.037; KOOS Pain: R = 0.815, p < 0.001; KOOS QOL: R = 0.777, p = 0.001) in the ACL reconstructed knee at baseline with worse follow up outcomes. The results of this study support the hypotheses that early changes in gait mechanics following ACL reconstruction are associated with longer-term clinical changes in patient-reported outcomes, suggesting that biomechanical markers obtained as early as 2 years after ACL reconstruction may be useful to understand clinical outcomes in this population. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:634-640, 2017. PMID- 27238267 TI - BK Channels in the Central Nervous System. AB - Large conductance Ca(2+)- and voltage-activated K(+) (BK) channels are widely distributed in the postnatal central nervous system (CNS). BK channels play a pleiotropic role in regulating the activity of brain and spinal cord neural circuits by providing a negative feedback mechanism for local increases in intracellular Ca(2+) concentrations. In neurons, they regulate the timing and duration of K(+) influx such that they can either increase or decrease firing depending on the cellular context, and they can suppress neurotransmitter release from presynaptic terminals. In addition, BK channels located in astrocytes and arterial myocytes modulate cerebral blood flow. Not surprisingly, both loss and gain of BK channel function have been associated with CNS disorders such as epilepsy, ataxia, mental retardation, and chronic pain. On the other hand, the neuroprotective role played by BK channels in a number of pathological situations could potentially be leveraged to correct neurological dysfunction. PMID- 27238276 TI - A SPME-based method for rapidly and accurately measuring the characteristic parameter for DEHP emitted from PVC floorings. AB - Semivolatile organic compounds (SVOCs) are present in many indoor materials. SVOC emissions can be characterized with a critical parameter, y0 , the gas-phase SVOC concentration in equilibrium with the source material. To reduce the required time and improve the accuracy of existing methods for measuring y0 , we developed a new method which uses solid-phase microextraction (SPME) to measure the concentration of an SVOC emitted by source material placed in a sealed chamber. Taking one typical indoor SVOC, di-(2-ethylhexyl) phthalate (DEHP), as the example, the experimental time was shortened from several days (even several months) to about 1 day, with relative errors of less than 5%. The measured y0 values agree well with the results obtained by independent methods. The saturated gas-phase concentration (ysat ) of DEHP was also measured. Based on the Clausius Clapeyron equation, a correlation that reveals the effects of temperature, the mass fraction of DEHP in the source material, and ysat on y0 was established. The proposed method together with the correlation should be useful in estimating and controlling human exposure to indoor DEHP. The applicability of the present approach for other SVOCs and other SVOC source materials requires further study. PMID- 27238277 TI - Have Americans Lost Their Minds? PMID- 27238278 TI - Extreme Morphogenesis and Ecological Specialization among Cretaceous Basal Ants. AB - Ants comprise one lineage of the triumvirate of eusocial insects and experienced their early diversification within the Cretaceous [1-9]. Their ecological success is generally attributed to their remarkable social behavior. Not all ants cooperate in social hunting, however, and some of the most effective predatory ants are solitary hunters with powerful trap jaws [10]. Recent evolutionary studies predict that the early branching lineages of extant ants formed small colonies of ground-dwelling, solitary specialist predators [2, 5, 7, 11, 12], while some Cretaceous fossils suggest group recruitment and socially advanced behavior among stem-group ants [9]. We describe a trap-jaw ant from 99 million year-old Burmese amber with head structures that presumably functioned as a highly specialized trap for large-bodied prey. These are a cephalic horn resulting from an extreme modification of the clypeus hitherto unseen among living and extinct ants and scythe-like mandibles that extend high above the head, both demonstrating the presence of exaggerated morphogenesis early among stem-group ants. The new ant belongs to the Haidomyrmecini, possibly the earliest ant lineage [9], and together these trap-jaw ants suggest that at least some of the earliest Formicidae were solitary specialist predators. With their peculiar adaptations, haidomyrmecines had a refined ecology shortly following the advent of ants. PMID- 27238280 TI - Direct Two-Dimensional Access to the Spatial Location of Covert Attention in Macaque Prefrontal Cortex. AB - Direct access to motor cortical information now enables tetraplegic patients to precisely control neuroprostheses and recover some autonomy. In contrast, explicit access to higher cortical cognitive functions, such as covert attention, has been missing. Indeed, this cognitive information, known only to the subject, can solely be inferred by an observer from the subject's overt behavior. Here, we present direct two-dimensional real-time access to where monkeys are covertly paying attention, using machine-learning decoding methods applied to their ongoing prefrontal cortical activity. Decoded attention was highly predictive of overt behavior in a cued target-detection task. Indeed, monkeys had a higher probability of detecting a visual stimulus as the distance between decoded attention and stimulus location decreased. This was true whether the visual stimulus was presented at the cued target location or at another distractor location. In error trials, in which the animals failed to detect the cued target stimulus, both the locations of attention and visual cue were misencoded. This misencoding coincided with a specific state of the prefrontal cortical population in which the shared variability between its different neurons (or noise correlations) was high, even before trial onset. This observation strongly suggests a functional link between high noise-correlation states and attentional failure. Overall, this real-time access to the attentional spotlight, as well as the identification of a neural signature of attentional lapses, open new perspectives both to the study of the neural bases of attention and to the remediation or enhancement of the attentional function using neurofeedback. PMID- 27238279 TI - The Minimal Energetic Requirement of Sustained Awareness after Brain Injury. AB - Differentiation of the minimally conscious state (MCS) and the unresponsive wakefulness syndrome (UWS) is a persistent clinical challenge [1]. Based on positron emission tomography (PET) studies with [(18)F]-fluorodeoxyglucose (FDG) during sleep and anesthesia, the global cerebral metabolic rate of glucose has been proposed as an indicator of consciousness [2, 3]. Likewise, FDG-PET may contribute to the clinical diagnosis of disorders of consciousness (DOCs) [4, 5]. However, current methods are non-quantitative and have important drawbacks deriving from visually guided assessment of relative changes in brain metabolism [4]. We here used FDG-PET to measure resting state brain glucose metabolism in 131 DOC patients to identify objective quantitative metabolic indicators and predictors of awareness. Quantitation of images was performed by normalizing to extracerebral tissue. We show that 42% of normal cortical activity represents the minimal energetic requirement for the presence of conscious awareness. Overall, the cerebral metabolic rate accounted for the current level, or imminent return, of awareness in 94% of the patient population, suggesting a global energetic threshold effect, associated with the reemergence of consciousness after brain injury. Our data further revealed that regional variations relative to the global resting metabolic level reflect preservation of specific cognitive or sensory modules, such as vision and language comprehension. These findings provide a simple and objective metabolic marker of consciousness, which can readily be implemented clinically. The direct correlation between brain metabolism and behavior further suggests that DOCs can fundamentally be understood as pathological neuroenergetic conditions and provide a unifying physiological basis for these syndromes. PMID- 27238281 TI - Ultra-High Foraging Rates of Harbor Porpoises Make Them Vulnerable to Anthropogenic Disturbance. AB - The question of how individuals acquire and allocate resources to maximize fitness is central in evolutionary ecology. Basic information on prey selection, search effort, and capture rates are critical for understanding a predator's role in its ecosystem and for predicting its response to natural and anthropogenic disturbance. Yet, for most marine species, foraging interactions cannot be observed directly. The high costs of thermoregulation in water require that small marine mammals have elevated energy intakes compared to similar-sized terrestrial mammals [1]. The combination of high food requirements and their position at the apex of most marine food webs may make small marine mammals particularly vulnerable to changes within the ecosystem [2-4], but the lack of detailed information about their foraging behavior often precludes an informed conservation effort. Here, we use high-resolution movement and prey echo recording tags on five wild harbor porpoises to examine foraging interactions in one of the most metabolically challenged cetacean species. We report that porpoises forage nearly continuously day and night, attempting to capture up to 550 small (3-10 cm) fish prey per hour with a remarkable prey capture success rate of >90%. Porpoises therefore target fish that are smaller than those of commercial interest, but must forage almost continually to meet their metabolic demands with such small prey, leaving little margin for compensation. Thus, for these "aquatic shrews," even a moderate level of anthropogenic disturbance in the busy shallow waters they share with humans may have severe fitness consequences at individual and population levels. PMID- 27238282 TI - Doublecortin Is Excluded from Growing Microtubule Ends and Recognizes the GDP Microtubule Lattice. AB - Many microtubule (MT) functions are mediated by a diverse class of proteins (+TIPs) at growing MT plus ends that control intracellular MT interactions and dynamics and depend on end-binding proteins (EBs) [1]. Cryoelectron microscopy has recently identified the EB binding site as the interface of four tubulin dimers that undergoes a conformational change in response to beta-tubulin GTP hydrolysis [2, 3]. Doublecortin (DCX), a MT-associated protein (MAP) required for neuronal migration during cortical development [4, 5], binds to the same site as EBs [6], and recent in vitro studies proposed DCX localization to growing MT ends independent of EBs [7]. Because this conflicts with observations in neurons [8, 9] and the molecular function of DCX is not well understood, we revisited intracellular DCX dynamics at low expression levels. Here, we report that DCX is not a +TIP in cells but, on the contrary, is excluded from the EB1 domain. In addition, we find that DCX-MT interactions are highly sensitive to MT geometry. In cells, DCX binding was greatly reduced at MT segments with high local curvature. Remarkably, this geometry-dependent binding to MTs was completely reversed in the presence of taxanes, which reconciles incompatible observations in cells [9] and in vitro [10]. We propose a model explaining DCX specificity for different MT geometries based on structural changes induced by GTP hydrolysis that decreases the spacing between adjacent tubulin dimers [11]. Our data are consistent with a unique mode of MT interaction in which DCX specifically recognizes this compacted GDP-like MT lattice. PMID- 27238283 TI - Spatial Working Memory in Humans Depends on Theta and High Gamma Synchronization in the Prefrontal Cortex. AB - Previous, albeit correlative, findings have shown that the neural mechanisms underlying working memory critically require cross-structural and cross-frequency coupling mechanisms between theta and gamma neural oscillations. However, the direct causality between cross-frequency coupling and working memory performance remains to be demonstrated. Here we externally modulated the interaction of theta and gamma rhythms in the prefrontal cortex using novel cross-frequency protocols of transcranial alternating current stimulation to affect spatial working memory performance in humans. Enhancement of working memory performance and increase of global neocortical connectivity were observed when bursts of high gamma oscillations (80-100 Hz) coincided with the peaks of the theta waves, whereas superimposition on the trough of the theta wave and low gamma frequency protocols were ineffective. Thus, our results demonstrate the sensitivity of working memory performance and global neocortical connectivity to the phase and rhythm of the externally driven theta-gamma cross-frequency synchronization. PMID- 27238285 TI - H-ras Inhibits the Hippo Pathway by Promoting Mst1/Mst2 Heterodimerization. AB - The protein kinases Mst1 and Mst2 have tumor suppressor activity, but their mode of regulation is not well established. Mst1 and Mst2 are broadly expressed and may have certain overlapping functions in mammals, as deletions of both Mst1 and Mst2 together are required for tumorigenesis in mouse models [1-3]. These kinases act via a three-component signaling cascade comprising Mst1 and Mst2, the protein kinases Lats1 and Lats2, and the transcriptional coactivators Yap and Taz [4-6]. Mst1 and Mst2 contain C-terminal SARAH domains that mediate their homodimerization as well as heterodimerization with other SARAH domain-containing proteins, which may regulate Mst1/Mst2 activity. Here we show that, in addition to forming homodimers, Mst1 and Mst2 heterodimerize in cells, this interaction is mediated by their SARAH domains and is favored over homodimers, and these heterodimers have much-reduced protein kinase activity compared to Mst1 or Mst2 homodimers. Mst1/Mst2 heterodimerization is strongly promoted by oncogenic H-ras, and this effect requires activation of the Erk pathway. Cells lacking Mst1, in which Mst1/Mst2 heterodimers are not possible, are resistant to H-ras-mediated transformation and maintain active hippo pathway signaling compared to wild-type cells or cells lacking both Mst1 and Mst2. Our results suggest that H-ras, via an Erk-dependent mechanism, downregulates Mst1/Mst2 activity by inducing the formation of inactive Mst1/Mst2 heterodimers. PMID- 27238287 TI - Erratum to "Integrative analyses of leprosy susceptibility genes indicate a common autoimmune profile" [J. Dermatol. Sci. 82 (2016) 18-27. PMID- 27238286 TI - Mixing Temperatures of Bilayers Not Simply Related to Thickness Differences between Lo and Ld Phases. AB - Micron-scale coexisting Lo and Ld liquid phases can appear in lipid bilayers composed of a ternary mixture of a low-melting temperature lipid, a high-melting temperature lipid, and cholesterol. A priori, temperatures at which membranes demix, Tmix, are not simply related to differences in thicknesses, Deltah, between Lo and Ld phases. Here, we use fluorescence microscopy to measure Tmix and we use atomic force microscopy at 22 degrees C to measure Deltah for a series of bilayers composed of different ratios of the three components. Our data illustrate cases in which a change in Tmix or Deltah does not result in a change in the other parameter. The data provide a context in which to evaluate recent reports of a correlation between Tmix and Deltah. PMID- 27238284 TI - Expansion of Signal Transduction Pathways in Fungi by Extensive Genome Duplication. AB - Plants and fungi use light and other signals to regulate development, growth, and metabolism. The fruiting bodies of the fungus Phycomyces blakesleeanus are single cells that react to environmental cues, including light, but the mechanisms are largely unknown [1]. The related fungus Mucor circinelloides is an opportunistic human pathogen that changes its mode of growth upon receipt of signals from the environment to facilitate pathogenesis [2]. Understanding how these organisms respond to environmental cues should provide insights into the mechanisms of sensory perception and signal transduction by a single eukaryotic cell, and their role in pathogenesis. We sequenced the genomes of P. blakesleeanus and M. circinelloides and show that they have been shaped by an extensive genome duplication or, most likely, a whole-genome duplication (WGD), which is rarely observed in fungi [3-6]. We show that the genome duplication has expanded gene families, including those involved in signal transduction, and that duplicated genes have specialized, as evidenced by differences in their regulation by light. The transcriptional response to light varies with the developmental stage and is still observed in a photoreceptor mutant of P. blakesleeanus. A phototropic mutant of P. blakesleeanus with a heterozygous mutation in the photoreceptor gene madA demonstrates that photosensor dosage is important for the magnitude of signal transduction. We conclude that the genome duplication provided the means to improve signal transduction for enhanced perception of environmental signals. Our results will help to understand the role of genome dynamics in the evolution of sensory perception in eukaryotes. PMID- 27238288 TI - Human herpesvirus 8-encoded chemokine vCCL2/vMIP-II is an agonist of the atypical chemokine receptor ACKR3/CXCR7. AB - The atypical chemokine receptor CXCR7/ACKR3 binds two endogenous chemokines, CXCL12 and CXCL11, and is upregulated in many cancers or following infection by several cancer-inducing viruses, including HHV-8. ACKR3 is a ligand-scavenging receptor and does not activate the canonical G protein pathways but was proposed to trigger beta-arrestin-dependent signaling. Here, we identified the human herpesvirus 8-encoded CC chemokine vCCL2/vMIP-II as a third high-affinity ligand for ACKR3. vCCL2 acted as partial ACKR3 agonist, inducing beta-arrestin recruitment to the receptor, subsequent reduction of its surface levels and its delivery to endosomes. In addition, ACKR3 reduced vCCL2-triggered MAP kinase and PI3K/Akt signaling through other chemokine receptors. Our data suggest that ACKR3 acts as a scavenger receptor for vCCL2, regulating its availability and activity toward human receptors, thereby likely controlling its function in HHV-8 infection. Our study provides new insights into the complex crosstalk between viral chemokines and host receptors as well as into the biology of ACKR3, this atypical and still enigmatic receptor. PMID- 27238289 TI - A Sinusoidally Architected Helicoidal Biocomposite. AB - A fibrous herringbone-modified helicoidal architecture is identified within the exocuticle of an impact-resistant crustacean appendage. This previously unreported composite microstructure, which features highly textured apatite mineral templated by an alpha-chitin matrix, provides enhanced stress redistribution and energy absorption over the traditional helicoidal design under compressive loading. Nanoscale toughening mechanisms are also identified using high-load nanoindentation and in situ transmission electron microscopy picoindentation. PMID- 27238290 TI - Social and health dimensions of climate change in the Amazon. AB - CONTEXT: The Amazon region has been part of climate change debates for decades, yet attention to its social and health dimensions has been limited. OBJECTIVE: This paper assesses literature on the social and health dimensions of climate change in the Amazon. A conceptual framework underscores multiple stresses and exposures created by interactions between climate change and local social environmental conditions. METHODS: Using the Thomson-Reuter Web of Science, this study bibliometrically assessed the overall literature on climate change in the Amazon, including Physical Sciences, Social Sciences, Anthropology, Environmental Science/Ecology and Public, Environmental/Occupational Health. From this assessment, a relevant sub-sample was selected and complemented with literature from the Brazilian database SciELO. RESULTS: This sample discusses three dimensions of climate change impacts in the region: livelihood changes, vector borne diseases and microbial proliferation, and respiratory diseases. This analysis elucidates imbalance and disconnect between ecological, physical and social and health dimensions of climate change and between continental and regional climate analysis, and sub-regional and local levels. CONCLUSION: Work on the social and health implications of climate change in the Amazon falls significantly behind other research areas, limiting reliable information for analytical models and for Amazonian policy-makers and society at large. Collaborative research is called for. PMID- 27238291 TI - Reverse membrane bioreactor: Introduction to a new technology for biofuel production. AB - The novel concept of reverse membrane bioreactors (rMBR) introduced in this review is a new membrane-assisted cell retention technique benefiting from the advantageous properties of both conventional MBRs and cell encapsulation techniques to tackle issues in bioconversion and fermentation of complex feeds. The rMBR applies high local cell density and membrane separation of cell/feed to the conventional immersed membrane bioreactor (iMBR) set up. Moreover, this new membrane configuration functions on basis of concentration-driven diffusion rather than pressure-driven convection previously used in conventional MBRs. These new features bring along the exceptional ability of rMBRs in aiding complex bioconversion and fermentation feeds containing high concentrations of inhibitory compounds, a variety of sugar sources and high suspended solid content. In the current review, the similarities and differences between the rMBR and conventional MBRs and cell encapsulation regarding advantages, disadvantages, principles and applications for biofuel production are presented and compared. Moreover, the potential of rMBRs in bioconversion of specific complex substrates of interest such as lignocellulosic hydrolysate is thoroughly studied. PMID- 27238292 TI - Critical shoulder angle: Measurement reproducibility and correlation with rotator cuff tendon tears. AB - BACKGROUND: Associations have been reported linking rotator cuff tears (RCTs) to both greater lateral extension of the acromion and greater inclination of the glenoid cavity. These two factors combined can be assessed using a recently introduced parameter, the critical shoulder angle (CSA). The primary objective of this study was to confirm the association linking a high CSA value to RCTs, and the secondary objective was to assess the reproducibility of CSA measurement using a goniometer. HYPOTHESIS: The null hypothesis was that the CSA value in a group of patients with RCTs was not significantly different from that in patients with anterior shoulder instability and a Bankart lesion, taken as the general population for this study. METHODS: After a power estimation, we retrospectively included 28 patients with a mean age of 55.5 years who had surgery for RCTs and 27 patients with a mean age of 27.2 years who underwent anterior labral repair. Two surgeons used a goniometer to measure the CSA in each patient. Reproducibility was assessed based on Bland-Altman plots and Pearson's correlation coefficient. RESULTS: The mean CSA was significantly higher (P=0.02) in the RCT group (36.4 degrees +/-4.4 degrees ; range: 30 degrees -46 degrees ) than in the labral-repair group (33.3 degrees +/-3.8 degrees ; range: 25 degrees 41 degrees ). Intra-observer reproducibility was 96.7% and inter-observer reproducibility was 95.5%. CONCLUSION: Our results support previously published evidence that the CSA is significantly greater in patients with RCTs. Thus, an anatomical difference seems to exist between patients with RCTs and the general population. The CSA measured on a standard radiograph using a goniometer provides a reproducible assessment of this anatomical difference. LEVEL OF EVIDENCE: IV, case-control epidemiological study with a power estimation. PMID- 27238293 TI - Mutations Closer to the Active Site Improve the Promiscuous Aldolase Activity of 4-Oxalocrotonate Tautomerase More Effectively than Distant Mutations. AB - The enzyme 4-oxalocrotonate tautomerase (4-OT), which catalyzes enol-keto tautomerization as part of a degradative pathway for aromatic hydrocarbons, promiscuously catalyzes various carbon-carbon bond-forming reactions. These include the aldol condensation of acetaldehyde with benzaldehyde to yield cinnamaldehyde. Here, we demonstrate that 4-OT can be engineered into a more efficient aldolase for this condensation reaction, with a >5000-fold improvement in catalytic efficiency (kcat /Km ) and a >10(7) -fold change in reaction specificity, by exploring small libraries in which only "hotspots" are varied. The hotspots were identified by systematic mutagenesis (covering each residue), followed by a screen for single mutations that give a strong improvement in the desired aldolase activity. All beneficial mutations were near the active site of 4-OT, thus underpinning the notion that new catalytic activities of a promiscuous enzyme are more effectively enhanced by mutations close to the active site. PMID- 27238294 TI - Bayesian adjustment for the misclassification in both dependent and independent variables with application to a breast cancer study. AB - In this paper, we propose a Bayesian method to address misclassification errors in both independent and dependent variables. Our work is motivated by a study of women who have experienced new breast cancers on two separate occasions. We call both cancers primary, because the second is usually not considered as the result of a metastasis spreading from the first. Hormone receptors (HRs) are important in breast cancer biology, and it is well recognized that the measurement of HR status is subject to errors. This discordance in HR status for two primary breast cancers is of concern and might be an important reason for treatment failure. To sort out the information on true concordance rate from the observed concordance rate, we consider a logistic regression model for the association between the HR status of the two cancers and introduce the misclassification parameters (i.e., sensitivity and specificity) accounting for the misclassification in HR status. The prior distribution for sensitivity and specificity is based on how HR status is actually assessed in laboratory procedures. To account for the nonlinear effect of one error-free covariate, we introduce the B-spline terms in the logistic regression model. Our findings indicate that the true concordance rate of HR status between two primary cancers is greater than the observed value. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27238295 TI - Watching China's weight. PMID- 27238296 TI - Addressing Bacterial Surface Contamination in Radiology Work Spaces. PMID- 27238297 TI - CoMuS: simulating coalescent histories and polymorphic data from multiple species. AB - The simultaneous analysis of intra- and interspecies variation is challenging mainly because our knowledge about patterns of polymorphisms where both intra- and interspecies samples coexist is limited. In this study, we present CoMuS (Coalescent of Multiple Species), a multispecies coalescent software that can simulate intra- and interspecies polymorphisms. CoMuS supports a variety of speciation models and demographic scenarios related to the history of each species. In CoMuS, speciation can be accompanied by either instant or gradual isolation between sister species. Sampling may also occur in the past, and thus, we can study simultaneously extinct and extant species. Our software supports both the infinite- and the finite-site model, with substitution rate heterogeneity among sites and a user-defined proportion of invariable sites. We demonstrate the usage of CoMuS in various applications: species delimitation, software testing, model selection and parameter inference involving present-day and ancestral samples, comparison between gradual and instantaneous isolation models, estimation of speciation time between human and chimpanzee using both intra- and interspecies variation. We expect that CoMuS will be particularly useful for studies where species have been separated recently from their common ancestor and phenomena such as incomplete lineage sorting or introgression still occur. PMID- 27238298 TI - Harlequin Syndrome in Cluster Headache. PMID- 27238299 TI - Mechanism for verification of mismatched and homoduplex DNAs by nucleotides-bound MutS analyzed by molecular dynamics simulations. AB - In order to understand how MutS recognizes mismatched DNA and induces the reaction of DNA repair using ATP, the dynamics of the complexes of MutS (bound to the ADP and ATP nucleotides, or not) and DNA (with mismatched and matched base pairs) were investigated using molecular dynamics simulations. As for DNA, the structure of the base-pairs of the homoduplex DNA which interacted with the DNA recognition site of MutS was intermittently disturbed, indicating that the homoduplex DNA was unstable. As for MutS, the disordered loops in the ATPase domains, which are considered to be necessary for the induction of DNA repair, were close to (away from) the nucleotide-binding sites in the ATPase domains when the nucleotides were (not) bound to MutS. This indicates that the ATPase domains changed their structural stability upon ATP binding using the disordered loop. Conformational analysis by principal component analysis showed that the nucleotide binding changed modes which have structurally solid ATPase domains and the large bending motion of the DNA from higher to lower frequencies. In the MutS mismatched DNA complex bound to two nucleotides, the bending motion of the DNA at low frequency modes may play a role in triggering the formation of the sliding clamp for the following DNA-repair reaction step. Moreover, MM-PBSA/GBSA showed that the MutS-homoduplex DNA complex bound to two nucleotides was unstable because of the unfavorable interactions between MutS and DNA. This would trigger the ATP hydrolysis or separation of MutS and DNA to continue searching for mismatch base-pairs. Proteins 2016; 84:1287-1303. (c) 2016 Wiley Periodicals, Inc. PMID- 27238301 TI - Healthy criticism. AB - Who supports the Government's NHS reforms? A cross-party group of Peers does not, 25 health care organisations don't, over a quarter of a million nurses don't, the British Medical Association doesn't and the health service trades unions don't. The list is endless. PMID- 27238300 TI - Defining the optimal timing of adjuvant therapy for resected pancreatic adenocarcinoma: A statewide cancer registry analysis. AB - BACKGROUND: Long-term results of the ESPAC-3 trial suggest that while completing adjuvant therapy (AT) is necessary after resection of pancreatic ductal adenocarcinoma (PDAC), early initiation (within 8 weeks) may not be associated with improved overall survival (OS). The primary aim of this study was to evaluate the OS impact of early versus late AT in a statewide analysis. METHODS: Patients with stages I-III PDAC in the Kentucky Cancer Registry (KCR) from 2004 to 2013, were evaluated. Those undergoing pancreatectomy were stratified into two groups ("early," <8 weeks, vs. "late," 8-16 weeks). RESULTS: Of 2,221 diagnosed patients with stages I-III, 831 (37.4%) underwent pancreatectomy upfront. Of these, only 420 (50.5%) received AT. Initiation date of AT was not associated with OS (median OS: early, 20.2 vs. late, 19.0 months, P = 0.97). On multivariate analysis, factors that affected OS included stage (II, HR-1.82, P = 0.017; III, HR-3.77, P < 0.001), node positivity (HR-1.51, P = 0.004), poorly/undifferentiated grade (HR-1.34; P = 0.011), but not AT initiation date. CONCLUSIONS: In this statewide analysis, there was no difference in OS between early and late AT initiation for resected PDAC. The ideal window for AT initiation remains unknown as tumor biology continues to trump regimens from the past decade. J. Surg. Oncol. 2016;114:451-455. (c) 2016 Wiley Periodicals, Inc. PMID- 27238303 TI - Overwhelming support for Bill amendments. AB - Congress gave its unanimous support to an emergency resolution seeking to amend the NHS and Community Care Bill after a heated debate last week. In the extended hour-long session speaker after speaker slammed the Government's proposals and called for the nursing voice to be heard and heeded. PMID- 27238302 TI - United bid to stop NHS reforms. AB - A final bid to stop the Government from going ahead with its reforms of the health service was launched at Congress. PMID- 27238304 TI - Parliament petitioned. AB - The RCN Association of Nursing Students last week presented over 1,000 signatures to Parliament, protesting at the community charge's full levy on conventional student nurses. PMID- 27238305 TI - Changes cause senior nurse casualties. AB - The introduction of unit general management in Northern Ireland is claiming its first casualties among senior nurses. It is set to emulate the storm over the issue which happened several years ago in other parts of the UK. PMID- 27238309 TI - Audit report leads to call for immediate review. AB - Royal College of Midwives General Secretary Ruth Ashton has called on all health authorities to launch an immediate review of their maternity services. PMID- 27238307 TI - [Not Available]. AB - Flanked by the Association of Nursing Student's graphic banner. Labour's Environment Spokesman Brian Gould, along with (from left) labour Local Government Spokesman Derek Blunkett and Youth Spokesman Derek Fatchett, accepted the South West Thames Regional petition from ANS Chair Jane Perry. PMID- 27238310 TI - Pilot study nursing home sale greeted with dismay. AB - Plans to sell off a pioneering National j Health Service nursing home to the independent sector have been greeted with anger and dismay. PMID- 27238311 TI - Later in life, most nurses suffer from the same complaint. AB - Nurses in the NHS Superannuation Scheme can expect a ' better pension than many when they retire. But, don't be too optimistic. PMID- 27238312 TI - Call for guidelines on student drug trials. AB - Student nurses are taking over in drug trials 'where beagles left off, Linda Bailey of the Association of Nursing Students (ANS) has warned. PMID- 27238313 TI - Resuscitation 'convenience' row. AB - Patients are being resuscitated for the first 24 hours in hospitals and then allow'ed to the so that the death doesn't have to be referred to the coroner, delegates were told at Congress last week. PMID- 27238315 TI - White Paper apathy needs shaking. AB - College members must be shaken out of their White Paper apathy by being told how the reforms will hit their pockets. Council member Steve Wright declared at Congress last week. PMID- 27238314 TI - RCN launches leaflet in quest for equality. AB - Royal College of Nursing General Secretary Christine Hancock launched a new leaflet, 'Meeting the challenge of racial equality in nursing', at a Congress Women s Group meeting. PMID- 27238316 TI - Nurses as 'disposable assets'. AB - Nurses are being made redundant or finding themselves without jobs when they qualify because managers see them as a 'disposable asset' when faced with financial problems, according to Royal College of Nursing General Secretary, Christine Hancock. PMID- 27238317 TI - Hostile reception greets Bottomley Congress speech. AB - Health Minister Virginia Bottomley's attempts to persuade delegates that there are 'exciting' opportunities for nurses in the Government's plans for the health service failed, as she faced growing hostility from the audience at RCN Congress last week. PMID- 27238318 TI - [Not Available]. AB - RCN President, Maude Storey received a standing ovation, in contrast to the icy reception for Virginia Bottomley. Miss Storey urged the minister to make nurses' concerns about the NHS Bill known to her Government colleagues. PMID- 27238319 TI - Radon exposure clanger. AB - Children in some areas are being exposed to the cancer-linked gas radon for 24 hours a day, Congress was told. PMID- 27238320 TI - Call to improve patients' complaints procedure. AB - Nursing must show the maturity to accept a better, impartial complaints procedure for the patients' sakes, Council member Steve Wright urged Congress. PMID- 27238321 TI - Congress approves inspectorate campaign. AB - Congress voted to continue the RCN's campaign for a nationally-trained, independent inspectorate to monitor and raise standards across the whole spectrum of health care. PMID- 27238322 TI - Promoting good health promotion. AB - First-time Congress speaker Sue James urged the Government to review its priorities and give health promotion as much emphasis as self-governing hospitals. 'Given the choice, consumers would prefer to prevent illness than to be cured,' she said, moving a resolution urging Council to press for greater commitment and resources for health promotion. PMID- 27238323 TI - 'Significant delay in progression to AIDS'. AB - A new drug treatment has been found to produce a 'significant delay' in the progression to AIDS, German researchers have reported. PMID- 27238325 TI - Mutation may lead to new lung treatment. AB - Identification of a genetic mutation in lung cancer may offer new strategies tor treatment. PMID- 27238324 TI - Asthmatic flow meters soon to be available. AB - Peak flow meters will soon be available to asthmatics through their general practitioners, the Department of Health has announced. PMID- 27238326 TI - Pregnancy vaccine has proved 100% effective. AB - A vaccination which protects against pregnancy has proved 100 per cent effective in early trials. PMID- 27238328 TI - Skin temperature in appendicitis diagnosis. AB - Measuring skin temperature may be a useful diagnostic aid in appendicitis. PMID- 27238329 TI - Managing perforated ulcers conservatively. AB - Patients with perforated peptic ulcers may be treated conservatively, provided strict criteria are used. PMID- 27238327 TI - Nutrition audio tape for community nurses. AB - An audio tape providing information on nutrition has been launched by the Royal College of Nursing. Aimed at community nurses, the tape has a magazine style and covers nutritional principles. It applies these principles to topics including pregnancy, breastfeeding and children's diets. PMID- 27238330 TI - Delaying the onset of parkinson's disease. AB - A drug is showing promise in delaying the onset of disabling Parkinsonism. PMID- 27238331 TI - Stabilisation of opiate misusers compared. AB - Misusers of opiates can be stabilised on either oral heroin or methadone. PMID- 27238332 TI - Provocation test for non-ulcer dyspepsia. AB - A method for determining which patients with non-ulcer dyspepsia are likely to respond to H2 antagonists has been devised by researchers. PMID- 27238333 TI - In the fast lane... AB - Glasgow's Lennox Castle Hospital has been the focus of considerable criticism over the years, most recently in a British Medical Journalreport on subnutrition. Like many hospitals for mentally handicapped people it has suffered years of neglect with the residents housed in conditions reminiscent of the workhouse. PMID- 27238334 TI - The healing waters. AB - Imagine a place where arthritic joints may move less painfully and handicapped children may become surprisingly mobile. It's not the stuff of fantasy: the place is the hydrotherapy pool. PMID- 27238335 TI - A letter from down under. AB - I had almost forgotten what it was like to live in a house after a year in Mont Park's nurses' hostel. PMID- 27238336 TI - A Jewish perspective on nursing. AB - We live in a multicultural and multiracial society. Increasingly people are exposed to, and come into contact with, other people with different traditions; a different history, perhaps, or a different religion; or perhaps even a different and unfamiliar language. PMID- 27238337 TI - Discrimination on all fronts. AB - As a male, I really do get fed up with this constant sex discrimination talk, implying it is only the female who is discriminated against. In this country the two most blatant acts of sex discrimination are against the male. Men, statistically, live shorter lives than their female partners, but have to work an extra five years I longer to gain their old-age , pension. PMID- 27238338 TI - The other side of the coin. AB - TheNursing Standarddisplayed another good article relating to the discrimination against women within the NHS ('Banking on success' March 21-27) but when am I going to read about the discrimination against men? My female district nursing colleagues can now retire at 55, 60, 65 or even later if they so wish but as a mere male I cannot retire before the age of 60. PMID- 27238339 TI - Surveying the elderly population. AB - The commentary 'Delegation in screening but to whom', Geriatric Medicine, (January 1990), has generated much discussion in nursing circles here at the Royal College of Nursing. In the commentary, Dr Mackintosh refers to the surveillance of old people as being an 'onerous annual obligation'. This indicates a somewhat negative attitude to meeting the health care needs of the elderly population. PMID- 27238340 TI - Continuing the AIDS debate. AB - I would like to contribute to the Baroness Cox debate. I read with interest her comments concerning her resignation of the joint chair-ship of the RCN/BMA conference on HIV and AIDS (Nursing Standard February 28-March 6). The Baroness pleads for tolerance. Her accusation that nurses who disagree with her are prejudiced, bigoted and even unprofessional cannot go unchallenged. PMID- 27238341 TI - Who were the candidates? AB - I am a member of the Royal College of Nursing Diabetes Nursing Group and the Royal College of Nursing Society of Orthopaedic Nursing and was recently sent voting forms for the election of honoury officers for both these forums. PMID- 27238343 TI - Practice and perfection. AB - My local GP practice is the sort that Kenneth Clarke dreams about. It's big enough to have its own budget - in Inner London, but one of the nice safe bits without too many homeless people, unemployed or other social misfits. PMID- 27238342 TI - The rights of the individual. AB - It is a rare occasion indeed that I come across an article that disturbs me to the extent that I put pen to paper in protest. Sadly, in this instance, the venomous, vitriolic diatribe by Betty Roll (Letters, Nursing Standard March 14 20) has compelled me to do so. It really has been quite a considerable time since I have come across anything so extreme, distasteful and completely lacking in understanding. PMID- 27238344 TI - Parent power. AB - The Child Development Programme is becoming increasingly known as a radically different form of health visiting and is now operating in more than ten per cent of the 200 health authorities in the United Kingdom. PMID- 27238345 TI - Abortion: the right choice. AB - One of the comforting things about returning to Chicago is that the health care news never changes. A survey of recent stories in the local media reveals some familiar topics. The trauma network, which co-ordinates major accident services, is in crisis because one of the largest private hospitals has pulled out leaving a sizeable gap in coverage for the poorer districts. PMID- 27238346 TI - Living with AIDS S Rettig G Hayton Frontliners Living with AIDS Terrence Higgins Trust 40pp L9-95 0-951-3002-0-2. AB - Living with AIDS is simple, clear, sensible and sensitive. Throughout is a positive message mixed with concern and compassion. PMID- 27238347 TI - The Counselling Handbook S Quilliam and I Grove-Stephensen The Counselling Handbook Thorsons , 240pp, L5.99 07225-1770-X. AB - The subtitle, A complete guide to what to expect and how to get the counselling you need, made me sceptical. Can anything be 'complete' in this area? A flick through, however, told me that there is really something complete here. PMID- 27238348 TI - The health visitor. AB - Health visitors already feeling insecure about changes in work practice are awaiting the effects of the new GP contract with some trepidation. PMID- 27238349 TI - Pervasive uncertainty. AB - The manager The feeling of uncertainty which is pervading the community at present highlights what will be a testing time for our ability to manage change, to boost staff morale, and to provide clear direction in what is going to be an exacting period for us, but with an outcome which must be beneficial to the patients to whom we provide services and care. PMID- 27238350 TI - The practice nurse. AB - That FPCs and the GPs see the practice nurses as taking on a high proportion of the work load which will be generated by the new GP contract is not in doubt. The nursing and medical press have had increased advertisements for: 'Practice nurses with special responsibility for screening and health promotion'. PMID- 27238351 TI - The district nurse. AB - Last July, Kenneth Clarke announced that district nurses would remain within the employment of the health authorities and be responsible for the caring of 'ill' patients, thus relinquishing to the local authority those patients who only require 'social care'. PMID- 27238352 TI - Alopecia, halo nevi and vitiligo in a pediatric case of Turner's syndrome. PMID- 27238353 TI - Building operative care capacity in a resource limited setting: The Mongolian model of the expansion of sustainable laparoscopic cholecystectomy. AB - BACKGROUND: The benefits of laparoscopic cholecystectomy, including rapid recovery and fewer infections, have been largely unavailable to the majority of people in developing countries. Compared to other countries, Mongolia has an extremely high incidence of gallbladder disease. In 2005, only 2% of cholecystectomies were performed laparoscopically. This is a retrospective review of the transition from open to laparoscopic cholecystectomy throughout Mongolia. METHODS: A cross-sectional, retrospective review was conducted of demographic patient data, diagnosis type, and operation performed (laparoscopic versus open cholecystectomy) from 2005-2013. Trends were analyzed from 6 of the 21 provinces (aimags) throughout Mongolia, and data were culled from 7 regional diagnostic referral and treatment centers and 2 tertiary academic medical centers. The data were analyzed by individual training center and by year before being compared between rural and urban centers. RESULTS: We analyzed and compared 14,522 cholecystectomies (n = 4,086 [28%] men, n = 10,436 [72%] women). Men and women were similar in age (men 52.2, standard deviation 14.8; women 49.4, standard deviation 15.7) and in the percentage undergoing laparoscopic cholecystectomy (men 39%, women 42%). By 2013, 58% of gallbladders were removed laparoscopically countrywide compared with only 2% in 2005. In 2011, laparoscopic cholecystectomy surpassed open cholecystectomy as the primary method for gallbladder removal countrywide. More than 315 Mongolian health care practitioners received laparoscopic training in 19 of the country's 21 aimags (states). CONCLUSION: By 2013, 58% of cholecystectomies countrywide were performed laparoscopically, a dramatic increase over 9 years. The expansion of laparoscopic cholecystectomy has transformed the care of biliary tract disease in Mongolia despite the country's limited resources. PMID- 27238355 TI - Response to commentary on: Risk factors for central lymph node metastasis in papillary thyroid carcinoma: A National Cancer Data Base (NCDB) study. PMID- 27238354 TI - Preoperative assessment of the risk for multiple complications after surgery. AB - BACKGROUND: The association between preoperative patient characteristics and the number of major postoperative complications after a major operation is not well defined. METHODS: In a retrospective, single-center cohort of 50,314 adult surgical patients, we used readily available preoperative clinical data to model the number of major postoperative complications from none to >=3. We included acute kidney injury; prolonged stay (>48 hours) in an intensive care unit; need for prolonged (>48 hours) mechanical ventilation; severe sepsis; and cardiovascular, wound, and neurologic complications. Risk probability scores generated from the multinomial logistic models were used to develop an online calculator. We stratified patients based on their risk of having >=3 postoperative complications. RESULTS: Patients older than 65 years (odds ratio 1.5, 95% confidence interval, 1.4-1.6), males (odds ratio 1.2, 95% confidence interval, 1.2-1.3), patients with a greater Charlson comorbidity index (odds ratio 3.9, 95% confidence interval, 3.6-4.2), patients requiring emergency operation (odds ratio 3.5, 95% confidence interval, 3.3.-3.7), and patients admitted on a weekend (odds ratio 1.4, 95% confidence interval, 1.3-1.5) were more likely to have >=3 postoperative complications than they were to have none. Patients in the medium- and high-risk categories were 3.7 and 6.3 times more likely to have >=3 postoperative complications, respectively. High-risk patients were 5.8 and 4.4 times more likely to die within 30 and 90 days of admission, respectively. CONCLUSION: Readily available, preoperative clinical and sociodemographic factors are associated with a greater number of postoperative complications and adverse surgical outcomes. We developed an online calculator that predicts probability of developing each number of complications after a major operation. PMID- 27238357 TI - Personalised Medicine and Scarce Resources: A Discussion of Ethical Chances and Challenges from the Perspective of the Capability Approach. AB - In the aftermath of the economic crisis that started in 2008, resources have become scarcer than ever in some countries, also in health care. Priority setting and rationalisation of existing resources also affect pharmaceutical innovations, including those that would contribute to what is called personalised medicine. In this paper, we will highlight the ethical issues surrounding rationalisation and its impact on personalised medicine through the lens of the capability approach. Thereby, challenges to and opportunities for personalised medicine will be examined, assessing how they affect patients' 'real options' to access innovative therapies. In our focus on the 'first challenge: citizens and patients' of the so called Strategic Research and Innovation Agenda, the strength of the capability approach becomes particularly apparent in identifying what different values are at stake in this context. PMID- 27238356 TI - Maternal age and asthma in Latino populations. AB - BACKGROUND: Younger maternal age at birth is associated with increased risk of asthma in offspring in European descent populations, but has not been studied in Latino populations. OBJECTIVES: We sought to examine the relationship between maternal age at birth and prevalence of asthma in a nationwide study of Latino children. METHODS: We included 3473 Latino children aged 8-21 years (1696 subjects with physician-diagnosed asthma and 1777 healthy controls) from five US centres and Puerto Rico recruited from July 2008 through November 2011. We used multiple logistic regression models to examine the effect of maternal age at birth on asthma in offspring overall and in analyses stratified by ethnic subgroup (Mexican American, Puerto Rican and other Latino). Secondary analyses evaluated the effects of siblings, acculturation and income on this relationship. RESULTS: Maternal age < 20 years was significantly associated with decreased odds of asthma in offspring, independent of other risk factors (OR = 0.73, 95% CI: 0.57-0.93). In subgroup analyses, the protective effect of younger maternal age was observed only in Mexican Americans (OR = 0.53, 95% CI: 0.36, 0.79). In Puerto Ricans, older maternal age was associated with decreased odds of asthma (OR = 0.65, 95% CI: 0.44-0.97). In further stratified models, the protective effect of younger maternal age in Mexican Americans was seen only in children without older siblings (OR = 0.44, 95% CI: 0.23-0.81). CONCLUSION AND CLINICAL RELEVANCE: In contrast to European descent populations, younger maternal age was associated with decreased odds of asthma in offspring in Mexican American women. Asthma is common in urban minority populations but the factors underlying the varying prevalence among different Latino ethnicities in the United States is not well understood. Maternal age represents one factor that may help to explain this variability. PMID- 27238358 TI - Methylene blue toxicity in zebrafish cell line is dependent on light exposure. AB - Methylene blue (MB) has been widely applied in the clinical area and is currently being used in aquaculture as biocide. Some recent studies have emphasized the importance of understanding the action mechanism and the MB cellular targets. In this sense, zebrafish is considered a relevant model to study the intrinsic pathway of apoptosis as well as the cellular responses involving DNA damage and repair. So, the aim of the present study was to compare MB action mechanisms in a zebrafish cell line, both in the absence (MB alone; dark toxicity) and in the presence of photosynthetically active radiation (MB+PAR; phototoxicity). There was a significant increase of the levels of reactive oxygen and nitrogen species 3 h after MB treatment, whereas this increase was only observed 12 h after treatment with MB+PAR. All treatments with MB resulted in an increase in DNA damage after 3 and 6 h. However, cell death by apoptosis was observed from 6 h after treatment with MB+PAR and 12 h after treatment with MB alone. The expression of genes related to apoptosis was altered after MB and MB+PAR treatment. Therefore, this zebrafish cell line is sensitive to the photodynamic action of MB; MB is able to generate DNA damage and induce apoptosis in this cell line both alone and in the presence of PAR. However, the pathways leading to apoptosis in this model appear to be dependent on the type of MB exposure (in the presence or absence of PAR). PMID- 27238359 TI - Respiratory symptoms increase health care consumption and affect everyday life - a cross-sectional population-based study from Finland, Estonia, and Sweden. AB - BACKGROUND: Even though respiratory symptoms are common in the adult population, there is limited research describing their impact on everyday life and association with health care consumption. AIM: The main objective of this population-based study was to estimate and compare the prevalence of respiratory symptoms among adults in Finland, Estonia, and Sweden in relation to health care consumption and to identify factors influencing health care consumption. A secondary aim was to assess to which extent the presence of respiratory symptoms affect everyday life. METHOD: In the population-based FinEsS studies consisting of random samples of subjects aged 20 to 69 years from Finland (n=1,337), Estonia (n=1,346), and Sweden (n=1,953), data on demographics, respiratory health, and health care consumption were collected by structured interviews. Prevalence was compared and multiple logistic regression analyses were performed. RESULTS: Respiratory symptoms were significantly more common in Finland (66.0%) and Estonia (65.2%) than in Sweden (54.1%). Among subjects with respiratory symptoms, the proportion reporting outpatient care during the past year was fairly similar in the three countries, while specialist consultations were more common in Finland (19.1%), and hospitalisations more common in Estonia (15.0%). Finnish and Estonian residency, female sex, and BMI>25 increased the risk for outpatient care consumption. Wheeze and attacks of shortness of breath in the past 12 months, recurrent sputum production, and cough were associated with an increased risk for health care consumption. Increasing number of respiratory symptoms increased the risk for consuming health care. A larger proportion of subjects in Estonia and Sweden experienced their everyday life being affected by respiratory symptoms compared with subjects in Finland. CONCLUSION: Respiratory symptoms are common in Finland, Estonia, and Sweden and contribute to a negative impact on everyday life as well as increased health care consumption. The observed differences in health care consumption between countries are probably related to national differences in health care structure. PMID- 27238360 TI - Health-related quality of life in a nationwide cohort of patients with COPD related to other characteristics. AB - BACKGROUND: In chronic obstructive pulmonary disease (COPD), various factors, such as dyspnoea, obstruction, exacerbations, smoking, exercise capacity, and body mass index, have been found to influence mortality and health-related quality of life (HRQOL). In order to identify subgroups of patients needing special attention, the aim of the present study was to explore the relationships between disease progression factors and HRQOL across COPD stages. METHODS: Baseline registrations from the Swedish COPD register of demographic, clinical, and patient-reported variables of 7,810 patients are presented. Dyspnoea was measured by the modified Medical Research Council (mMRC) dyspnoea scale and HRQOL by the Clinical COPD Questionnaire (CCQ). RESULTS: This study shows as expected that patients with spirometrically more severe COPD had a significantly higher number of exacerbations and hospitalisations, significantly increasing dyspnoea, significantly decreasing body mass index and exercise capacity, and significantly worsening HRQOL. When adjusting for spirometric stage of COPD, deteriorated HRQOL was predicted by increasing dyspnoea, depression/anxiety, increasing number of exacerbations, and decreased exercise capacity. Further, these data show that an mMRC value of 2 corresponds to a CCQ value of 1.9. CONCLUSION: The COPD patients suffered from a significant symptom burden, influencing HRQOL. A surprisingly great proportion of patients in spirometric stages II-IV showed marked changes of CCQ, indicating a need for an improved collaboration between clinical pulmonary medicine and palliative care. PMID- 27238361 TI - Invasive cervical cancer accompanied by IgG4-related disease. AB - IgG4-related disease (IgG4-RD) is a systemic disease that affects multiple organs and generates nodules or thickening. Discriminating these diseases from malignancy is important because glucocorticoid treatment is effective for patients with IgG4-RD. Coexistence of IgG4-RD with various malignant diseases has been reported, but there are few reports with regard to gynecologic malignant diseases. We encountered a case of invasive cervical cancer stage IIB accompanied by IgG4-RD. The patient was a 46-year-old woman. On pelvic magnetic resonance imaging, fluorodeoxyglucose-positron emission tomography and computed tomography, systemic multiple lymph node swelling was seen, including in the neck and the mediastinum in addition to uterine cervix. Diagnosis (and hence, appropriate treatment choice) was achieved on pathology of the submandibular gland and uterus, and analysis of serum IgG4. IgG4-RD should be suspected in patients presenting with malignancy and unusual multiple lymph node swelling. PMID- 27238362 TI - Synthesis, Structure Characterization and Antitumor Activity Study of a New Iron(III) Complex of 5-Nitro-8-hydroxylquinoline (HNOQ). AB - A new iron(III) complex (1) of 5-nitro-8-hydroxylquinoline (HNOQ) was synthesized and structurally characterized in its solid state and solution state by IR, UV Vis, electrospray ionization (ESI)-MS, elemental analysis, conductivity and X-ray single crystal diffraction analysis. The DNA binding study suggested that complex 1 interacted with calf thymus (ct)-DNA mainly via an intercalative binding mode. By 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the in vitro cytotoxicity of complex 1, comparing with HNOQ and cisplatin, was screened towards a series of tumor cell lines as well as the normal liver cell line HL-7702. Complex 1 showed higher cytotoxicity towards the tested tumor cell lines but lower cytotoxicity towards HL-7702 than HNOQ, in which the T-24 was the most sensitive cell line for 1. Complex 1 caused G2 phase cell cycle arrest and induced cell apoptosis in T-24 cells in a dose-dependent mode, evidenced by changes in cell morphology. Targeting the mitochondrial pathway due to the redox potential of Fe(III)/Fe(II), the apoptotic mechanism in T-24 cells treated by 1 was investigated by reactive oxygen species (ROS) detection, intracellular [Ca(2+)] measurement and caspase-9 and caspase-3 activity assay. It suggested that complex 1 induced cell apoptosis by triggering the caspase-9 and caspase-3 activation via a mitochondrion-mediated pathway. PMID- 27238364 TI - Repositioning the Old Fungicide Ciclopirox for New Medical Uses. AB - BACKGROUND: Ciclopirox (CPX) has been used as an antifungal agent in various formulations to treat superficial fungal infection for decades. Its effectiveness and safety in treatments have been demonstrated by multiple studies. METHODS: Here we briefly summarize the pharmacological and toxicological properties of CPX as an antifungal agent, the new medical uses of CPX, as well as the correspondent molecular mechanisms. RESULTS: Increasing evidence has demonstrated that CPX is able to inhibit tumor growth, ameliorate diabetes and its complications, prevent human immunodeficiency virus (HIV) infection, and improve age-associated cardiovascular defects. Interestingly, its antifungal activity and all those newly observed effects are more or less related to its capability of chelating iron and interfering with the related signaling pathways. Mechanistically, CPX is capable of modulating the activities of certain enzymes or signaling pathways, such as ribonucleotide reductase (RR), deoxyhypusine hydroxylase (DOHH)/eukaryotic translation initiation factor 5A (eIF5A), Wnt/beta-catenin, hypoxia-inducible factor-1alpha (HIF-1 alpha)/vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 3 (VEGFR-3)/extracellular signal-regulated protein kinases 1/2, mammalian target of rapamycin, and cyclin dependent kinases (CDKs). Most of these activities are related to its chelation of iron. CONCLUSION: CPX, as an antifungal agent, may be repositioned for treatment of cancer and other human diseases. PMID- 27238365 TI - Pharmacological Properties and Therapeutic Potential of Naringenin: A Citrus Flavonoid of Pharmaceutical Promise. AB - Naringenin chemically known as 5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one is a common dietary polyphenolic constituent of the citrus fruits. It has received considerable attention for pharmaceutical and nutritional development due to potent pharmacological activities and therapeutic potential. Accruing evidence from both in vitro and in vivo studies have unraveled numerous biological targets along with complex underlying mechanisms suggesting possible therapeutic applications of naringenin in various neurological, cardiovascular, gastrointestinal, rheumatological, metabolic and malignant disorders. Functionally, this ameliorative effect of naringenin is primarily attributed to its antiinflammatory (via inhibiting recruitment of cytokines and inflammatory transcription factors) and anti-oxidant (via scavenging of free radicals, bolstering of endogenous antioxidant defense system and metal ion chelation) effects. The present article provides a comprehensive review of the various studies that have evaluated the therapeutic potential of naringenin and its actions at the molecular level. It also summarizes the pharmacokinetic data and issues and challenges involved in pharmaceutical development and suggest that it may be a potential agent for further exploration as well as may be useful as a dietary adjunct in treatment of various human ailments. PMID- 27238366 TI - Management of non-necrotizing cellulitis in France. AB - OBJECTIVE: We aimed to assess medical practices of French infectious disease specialists or any other relevant physicians related to the management of non necrotizing cellulitis (NNC). METHODS: We sent an online questionnaire to members of the French Infectious Diseases Society (SPILF) mailing list in September 2015. RESULTS: A total of 108 specialists took part in the survey and 10% (11/107) declared to always admit NNC patients to hospital. As for the others, 18% declared to admit patients in more than 80% of cases, 49% in 50-80% of cases, 26% in 20-50% of cases, and 7% in less than 20% of cases. The most frequent criteria for hospital admission were severe sepsis/septic shock (99%), poor social conditions (99%), rapid extension of skin lesions (93%), high level of pain (86%), and failure of first-line antibiotic therapy (84%). Participants mentioned similar criteria for reasons to initiate the intravenous (IV) antibiotic therapy. Fifty-three percent of respondents declared initiating antibiotic therapy using the IV route in more than 80% of cases. Physicians declared that the usual antibiotic therapy duration were <7 days (6%), 8-10 days (57%), 11-14 days (34%), and >15 days (3%). CONCLUSION: Criteria for hospital admission and use of the IV route for antibiotic therapy as well as optimal treatment duration in patients presenting with NNC need to be detailed in guidelines and evaluated in prospective studies. PMID- 27238368 TI - Enhancement of the Rate Capability of LiFePO4 by a New Highly Graphitic Carbon Coating Method. AB - Low lithium ion diffusivity and poor electronic conductivity are two major drawbacks for the wide application of LiFePO4 in high-power lithium ion batteries. In this work, we report a facile and efficient carbon-coating method to prepare LiFePO4/graphitic carbon composites by in situ carbonization of perylene-3,4,9,10-tetracarboxylic dianhydride during calcination. Perylene 3,4,9,10-tetracarboxylic dianhydride containing naphthalene rings can be easily converted to highly graphitic carbon during thermal treatment. The ultrathin layer of highly graphitic carbon coating drastically increased the electronic conductivity of LiFePO4. The short pathway along the [010] direction of LiFePO4 nanoplates could decrease the Li(+) ion diffusion path. In favor of the high electronic conductivity and short lithium ion diffusion distance, the LiFePO4/graphitic carbon composites exhibit an excellent cycling stability at high current rates at room temperature and superior performance at low temperature (-20 degrees C). PMID- 27238369 TI - The analgesic effects of exogenous melatonin in humans. PMID- 27238367 TI - Genetics and plant development. AB - There are only three grand theories in biology: the theory of the cell, the theory of the gene, and the theory of evolution. Two of these, the cell and gene theories, originated in the study of plants, with the third resulting in part from botanical considerations as well. Mendel's elucidation of the rules of inheritance was a result of his experiments on peas. The rediscovery of Mendel's work in 1900 was by the botanists de Vries, Correns, and Tschermak. It was only in subsequent years that animals were also shown to have segregation of genetic elements in the exact same manner as had been shown in plants. The story of developmental biology is different - while the development of plants has long been studied, the experimental and genetic approaches to developmental mechanism were developed via experiments on animals, and the importance of genes in development (e.g., Waddington, 1940) and their use for understanding developmental mechanisms came to botanical science much later - as late as the 1980s. PMID- 27238363 TI - European Obesity Summit (EOS) - Joint Congress of EASOand IFSO-EC, Gothenburg, Sweden, June 1 - 4, 2016: Abstracts. PMID- 27238370 TI - Role of central hydrogen sulfide on ventilatory and cardiovascular responses to hypoxia in spontaneous hypertensive rats. AB - Central hydrogen sulfide (H2S) has been reported to act as a gaseous neuromodulator involved in the ventilatory and cardiovascular control of normotensive rats, whereas no information is available in spontaneously hypertensive rats (SHR). We recorded minute ventilation (VE), mean arterial pressure (MAP) and heart rate (HR) before and after blocking of enzyme Cystathionine beta-synthase (CBS) producing H2S in neural tissue by microinjection of aminooxyacetate (inhibitor of CBS) into the fourth ventricle of Wistar normotensive rats (WNR) and SHR followed by 30min of normoxia (21% inspired O2) or hypoxia (10% inspired O2) exposure. Microinjection of AOA or saline (1MUL) did not change VE, MAP and HR during normoxia in both WNR and SHR. In WNR, hypoxia caused an increase in VE, HR and a decrease in MAP and these responses were unaltered by AOA. In SHR, hypoxia produced a higher increase of VE, and decrease in MAP and HR when compared to WNR, and these responses were all blunted by AOA. In conclusion, endogenous H2S plays important modulatory roles on hypoxia-induced ventilatory and cardiovascular responses, inhibiting the cardiovascular and stimulating the respiratory systems in SHR. PMID- 27238371 TI - Andreas Vesalius' understanding of pulmonary ventilation. AB - The historical evolution of understanding of the mechanical aspects of respiration is not well recorded. That the anatomist Andreas Vesalius (1515-1564) first recorded many of these mechanics in De Humani Corporis Fabrica Libri Septem has received little attention. We searched a digital copy of De Fabrica (1543) and its English translation as provided by Richardson and Carman (1998-2009) for references to aspects of pulmonary ventilation. We found that Vesalius grasped the essentials of tidal and forced respiration. He recognized that atmospheric pressure carried air into the lungs, approximately 100 years before Borelli did. He described an in vivo experiment of breathing, some 120 years before John Mayow produced his artificial model. He reported on positive pressure ventilation through a tracheotomy and on its life-saving effect, some 100 years before Robert Hook did. In publicly recording his insights over 450 years ago, Vesalius laid a firm basis for our understanding of the physiology of respiration and the management of its disorders. PMID- 27238372 TI - Endometrial thickness as a predictor of pregnancy outcomes in 10787 fresh IVF ICSI cycles. AB - This retrospective study assessed the predictive value of endometrial thickness (EMT) on HCG administration day for the clinical outcome of fresh IVF and intracytoplasmic sperm injection (ICSI) cycles. A total of 8690 consecutive women undergoing 10,787 cycles over a 5-year period were included. The 5th, 50th and 95th centiles for EMT were determined as 8, 11 and 15 mm, respectively. Group analysis according to these centiles (Group 1: < 8 mm; Group 2: >= 8 and <=11 mm; Group 3: > 11 and <=15 mm; Group 4: > 15 mm) demonstrated significant differences (P < 0.001) in clinical pregnancy rates (23.0%, 37.2%, 46.2% and 53.3%, respectively), live birth rates per clinical pregnancy (63.3%, 72.0%, 78.1% and 80.3%, respectively), spontaneous abortion rates (26.7%, 23.8%, 19.9% and 17.5%, respectively), and ectopic pregnancy rates (10.0%, 4.3%, 2.1% and 2.2%, respectively). Logistic regression analyses showed EMT as one of the independent variables predictive of clinical pregnancy (OR = 1.097; P < 0.001), live birth (OR = 1.078; P < 0.001), spontaneous abortion (OR = 0.948; P < 0.001), and ectopic pregnancy (OR = 0.851; P < 0.001). Future research should aim to understand the underlying mechanisms relating EMT to conception, ectopic implantation and spontaneous abortion. PMID- 27238373 TI - In permanent atrial fibrillation, PDE3 reduces force responses to 5-HT, but PDE3 and PDE4 do not cause the blunting of atrial arrhythmias. AB - BACKGROUND AND PURPOSE: 5-HT increases force and L-type Ca(2) (+) current (ICa,L ) and causes arrhythmias through 5-HT4 receptors in human atrium. In permanent atrial fibrillation (peAF), atrial force responses to 5-HT are blunted, arrhythmias abolished but ICa,L responses only moderately attenuated. We investigated whether, in peAF, this could be due to an increased function of PDE3 and/or PDE4, using the inhibitors cilostamide (300 nM) and rolipram (1 MUM) respectively. EXPERIMENTAL APPROACH: Contractile force, arrhythmic contractions and ICa,L were assessed in right atrial trabeculae and myocytes, obtained from patients with sinus rhythm (SR), paroxysmal atrial fibrillation (pAF) and peAF. KEY RESULTS: Maximum force responses to 5-HT were reduced to 15% in peAF, but not in pAF. Cilostamide, but not rolipram, increased both the blunted force responses to 5-HT in peAF and the inotropic potency of 5-HT fourfold to sevenfold in trabeculae of patients with SR, pAF and peAF. Lusitropic responses to 5-HT were not decreased in peAF. Responses of ICa,L to 5-HT did not differ and were unaffected by cilostamide or rolipram in myocytes from patients with SR or peAF. Concurrent cilostamide and rolipram increased 5-HT's propensity to elicit arrhythmias in trabeculae from patients with SR, but not with peAF. CONCLUSIONS AND IMPLICATIONS: PDE3, but not PDE4, reduced inotropic responses to 5-HT in peAF, independently of lusitropy and ICa,L , but PDE3 activity was the same as that in patients with SR and pAF. Atrial remodelling in peAF abolished the facilitation of 5-HT to induce arrhythmias by inhibition of PDE3 plus PDE4. PMID- 27238374 TI - The ENPP1 K121Q polymorphism is associated with type 2 diabetes and related metabolic phenotypes in a Taiwanese population. AB - Increased risk of developing type 2 diabetes (T2D) has been associated with a single nucleotide polymorphism (SNP), rs1044498 (K121Q), in the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene, but this association is unclear among Asians. In this replication study, we reassessed whether the ENPP1 rs1044498 SNP is associated with T2D, obesity, and T2D/obesity-related metabolic traits in a Taiwanese population. A total of 1513 Taiwanese subjects were assessed in this study. The ENPP1 rs1044498 SNP was genotyped by the Taqman assay. T2D/Obesity-related quantitative traits, such as waist circumference and fasting glucose, were measured. Our data showed a significant association of the ENPP1 rs1044498 SNP with T2D (P < 0.001) among the subjects. Moreover, the ENPP1 rs1044498 SNP was significantly associated with T2D/obesity-related metabolic traits, such as waist circumference (P = 0.002) and fasting glucose (P < 0.001), among the subjects. However, we found no association of ENPP1 rs1044498 with obesity (BMI ? 27 kg/m(2)). Our study indicates that the ENPP1 rs1044498 SNP is associated with T2D, waist circumference, and fasting glucose in Taiwanese subjects. PMID- 27238375 TI - Core bead chromatography for preparation of highly pure, infectious respiratory syncytial virus in the negative purification mode. AB - Respiratory syncytial virus (RSV) is an important human pathogen, and is the most frequent viral cause of severe respiratory disease in infants. In addition, it is increasingly being recognized as an important cause of respiratory disease in the elderly and immunocompromised. Although a passive prophylactic treatment does exist for high-risk neonates and children, the overall disease burden warrants the development of a safe and effective prophylactic vaccine for use in otherwise healthy newborns and children. RSV is known to be an extremely labile virus, prone to aggregation and loss of infectious titer during virus handling and preparation procedures. To date infective RSV virions have been prepared by methods which are not readily scalable, such as density gradient ultracentrifugation. In this study we describe a scalable, chromatography-based purification procedure for preparation of highly pure, infectious RSV. The purification scheme is based on core bead technology and hollow fiber tangential flow filtration (TFF) and results in a ~60% recovery of infectious virus titer. This method can be used to prepare highly purified wild type or live-attenuated vaccine strain viruses with titers as high as 1*10(8) plaque forming units per mL. A live-attenuated RSV vaccine prepared by this method was found to be immunogenic and protective in vivo, and its purity was 50-200-fold greater with respect to host cell dsDNA and Vero host cell proteins, than the raw feed stream. The results presented here can be considered a starting point for downstream process development of a live-attenuated vaccine approach for prevention of disease by RSV. PMID- 27238377 TI - Intravital imaging technology reveals immune system dynamics in vivo. AB - Fluorescent 'intravital' imaging is a new research technique by which the interior of living tissues and organs (in living bodies, if possible) can be observed, revealing the kinetics of cell and molecular processes in real time. Recent technological innovations in optical equipment and fluorescence imaging techniques have enabled a variety of cellular phenomena in different tissues and organs to be characterized under completely native conditions. This shift from static to dynamic biology constitutes the beginning of a new era in biomedical sciences. PMID- 27238376 TI - Diagnostic Discrepancies in Retinopathy of Prematurity Classification. AB - PURPOSE: To identify the most common areas for discrepancy in retinopathy of prematurity (ROP) classification between experts. DESIGN: Prospective cohort study. PARTICIPANTS: A total of 281 infants were identified as part of a multicenter, prospective, ROP cohort study from 7 participating centers. Each site had participating ophthalmologists who provided the clinical classification after routine examination using binocular indirect ophthalmoscopy (BIO) and obtained wide-angle retinal images, which were independently classified by 2 study experts. METHODS: Wide-angle retinal images (RetCam; Clarity Medical Systems, Pleasanton, CA) were obtained from study subjects, and 2 experts evaluated each image using a secure web-based module. Image-based classifications for zone, stage, plus disease, and overall disease category (no ROP, mild ROP, type II or pre-plus, and type I) were compared between the 2 experts and with the clinical classification obtained by BIO. MAIN OUTCOME MEASURES: Inter-expert image-based agreement and image-based versus ophthalmoscopic diagnostic agreement using absolute agreement and weighted kappa statistic. RESULTS: A total of 1553 study eye examinations from 281 infants were included in the study. Experts disagreed on the stage classification in 620 of 1553 comparisons (40%), plus disease classification (including pre-plus) in 287 of 1553 comparisons (18%), zone in 117 of 1553 comparisons (8%), and overall ROP category in 618 of 1553 comparisons (40%). However, agreement for presence versus absence of type 1 disease was >95%. There were no differences between image-based and clinical classification except for zone III disease. CONCLUSIONS: The most common area of discrepancy in ROP classification is stage, although inter-expert agreement for clinically significant disease, such as presence versus absence of type 1 and type 2 disease, is high. There were no differences between image-based grading and clinical examination in the ability to detect clinically significant disease. This study provides additional evidence that image-based classification of ROP reliably detects clinically significant levels of ROP with high accuracy compared with the clinical examination. PMID- 27238378 TI - DsRNA disrupts airway epithelial barrier integrity through down-regulation of claudin members. PMID- 27238379 TI - Stigmatisation and rejection of survivors of sexual violence in eastern Democratic Republic of the Congo. AB - Studies report that between 6 per cent and 29 per cent of survivors of sexual violence in eastern Democratic Republic of the Congo (DRC) are rejected by their families and communities. This research project was designed to provide insights into survivors' experiences of stigmatisation and rejection. Surveys were conducted with 310 women as they sought psychosocial services in eastern DRC. In total, 44.3 per cent of women reported suffering rejection after sexual violence. The majority of women felt that their status in the household (58.0 per cent) and community (54.9 per cent) diminished after rape. The odds of rejection were greater among women reporting ongoing displacement, pregnancy owing to sexual violence, worsening family relations, and diminished community status. This work highlights the extremely high levels of loss associated with the war in eastern DRC, particularly among survivors of sexual violence. The rejection of a survivor of rape has concrete and devastating psychosocial consequences. PMID- 27238380 TI - Corrigendum to "Kinematics and kinetics during walking in individuals with gluteal tendinopathy" [Clin. Biomech. vol. 32 (February 2016) Pages 56-63]. PMID- 27238381 TI - Preoperative pyuria predicts advanced pathologic tumor stage and worse survival in patients with urothelial carcinoma of the upper urinary tract treated by radical nephroureterectomy. AB - OBJECTIVES: To investigate the association of preoperative pyuria with pathologic features and oncologic outcomes in patients with urothelial carcinoma of the upper urinary tract (UTUC) treated by radical nephroureterectomy (RNU). MATERIAL AND METHODS: A cohort of 176 patients treated with RNU from January 2001 to December 2014 were retrospectively reviewed. Logistic regression and survival analysis methodology was used to investigate the association of preoperative pyuria with clinicopathologic outcomes. RESULTS: Among this cohort, 36 (20.5%) presented with preoperative pyuria. Logistic regression revealed that pyuria was significantly associated with advanced pT stage (P = 0.001). During a median follow-up of 41 months (interquartile range: 22-60), 65 (37%) patients died, including 54 (31%) from UTUC. Overall survival rates at 3 year and 5 years in patients with pyuria were significantly lower than those in patients without pyuria (62.3% and 36.1% vs. 78.4% and 65.3%, respectively; P = 0.004). Also, cancer-specific survival rates at 3 year and 5 years in patients with pyuria were significantly lower than in patients without pyuria (65.7% and 50% vs. 80% and 67.6%, respectively; P = 0.016). Furthermore, in the multivariate analysis, after incorporating only preoperative factors, pyuria was found to be an independent predictor of overall survival and cancer-specific survival (P = 0.005 and P = 0.028, respectively). CONCLUSIONS: Preoperative pyuria among UTUC patients underwent RNU was significantly associated with advanced pathologic tumor stage and worse survival. Our data suggested that pyuria as a prognostic predictor could be valuable in preoperative risk stratification and guiding better therapeutic approaches, but further validation in a larger population is needed. PMID- 27238382 TI - Improvements in Rational Design Strategies of Inulin Derivative Polycation for siRNA Delivery. AB - The advances of short interfering RNA (siRNA)-mediated therapy provide a powerful option for the treatment of many diseases, including cancer, by silencing the expression of targeted genes involved in the progression of the pathology. On this regard, a new pH-responsive polycation derived from inulin, Inulin-g imidazole-g-diethylenetriamine (INU-IMI-DETA), was designed and employed to produce INU-IMI-DETA/siRNA "Inulin COmplex Nanoaggregates" (ICONs). The experimental results showed that INU-IMI-DETA exhibited strong cationic characteristics and high solubility in the pH range 3-5 and self-aggregation triggered by pH increase and physiological salt concentration. INU-IMI-DETA showed as well a high buffering capacity in the endosomal pH range of 7.4-5.1. In the concentration range between 25 and 1000 MUg/mL INU-IMI-DETA had no cytotoxic effect on breast cancer cells (MCF-7) and no lytic effect on human red blood cells. ICONs were prepared by two-step procedure involving complexation and precipitation into DPBS buffer (pH 7.4) to produce siRNA-loaded nanoaggregates with minimized surface charge and suitable size for parenteral administration. Bafilomycin A1 inhibited transfection on MCF-7 cells, indicating that the protonation of the imidazole groups in the endolysosome pathway favors the escape of the system from endolysosomal compartment, increasing the amount of siRNA that can reach the cytoplasm. PMID- 27238383 TI - Age and input effects in the acquisition of mood in Heritage Portuguese. AB - The present study analyzes the effect of age and amount of input in the acquisition of European Portuguese as a heritage language. An elicited production task centred on mood choice in complement clauses was applied to a group of fifty bilingual children (six- to sixteen-year-olds) who are acquiring Portuguese as a minority language in a German dominant environment. The results show a significant effect of the age at testing and the amount of input in the acquisition of the subjunctive. In general, acquisition is delayed with respect to monolinguals, even though higher convergence with the monolingual grammar is observed after twelve years of age. Results also reveal that children with more exposure to the heritage language at home show faster acquisition than children from mixed households: the eight- to nine-year-old age boundary seems relevant for those speakers with more exposure, and the twelve- to thirteen-year-old age boundary for those with less exposure. PMID- 27238384 TI - Biochemical and biomechanical drivers of cancer cell metastasis, drug response and nanomedicine. AB - Metastasis, drug resistance and recurrence in cancer are regulated by the tumor microenvironment. This review describes recent advances in understanding how cancer cells respond to extracellular environmental cues via integrins, how to build engineered microenvironments to study these interactions in vitro and how nanomaterials can be used to detect and target tumor microenvironments. PMID- 27238385 TI - Barriers and methods to improve office-based procedural training in a family medicine residency. PMID- 27238386 TI - Freshwater influences on embryos, hatching and larval survival of euryhaline Gulf killifish Fundulus grandis and potential constraints on habitat distribution. AB - The influence of fresh water on potential habitat occupancy of early life-history stages of euryhaline Gulf killifish Fundulus grandis was determined by evaluating fertilization of freshwater-spawned eggs and subsequent survival of embryos and larvae in comparison with saline water (salinity 7). Overall per cent fertilization of eggs was low (mean +/- s.e. = 20.21 +/- 0.03%). Embryo survival was greater in saline water, but hatching rate (mean +/- s.e. = 81.6 +/- 0.1%) and post-hatch survival of larvae in fresh water (mean +/- s.e. = 74.5 +/- 0.1%) was relatively high. Therefore, the relative limitation of fresh water on habitat distribution of F. grandis changes with development, stimulating further questions on factors that may constrain habitat distribution of euryhaline fishes. PMID- 27238388 TI - Directional asymmetry of upper limbs in a medieval population from Poland: A combination of linear and geometric morphometrics. AB - OBJECTIVES: Degrees of upper-limb bilateral asymmetry reflect habitual behavior and activity levels throughout life in human populations. The shoulder joint facilitates a wide range of combined motions due to the simultaneous motion of all three bones: clavicle, scapula, and humerus. Accordingly, we used three dimensional geometric morphometrics to analyze shape differences in the glenoid cavity and linear morphometrics to obtain the degree of directional asymmetry in a medieval population. METHODS: To calculate directional asymmetry, clavicles, humeri, and scapulae from 100 individuals (50 females, 50 males) were measured. Landmarks and semilandmarks were placed within a three-dimensional reconstruction of the glenoid cavity for analysis of shape differences between sides of the body within sexes. RESULTS: Linear morphometrics showed significant directional asymmetry in both sexes in all bones. Geometric morphometrics revealed significant shape differences of the glenoid cavity between sides of the body in females but not in males. Both indicators of directional asymmetry (%DA and %AA) did not show significant differences between sexes. PLS analysis revealed a significant correlation between glenoid shape and two humeral head diameters only in females on the left side of the body. CONCLUSIONS: The studied population, perhaps due to a high level of activity, exhibited slightly greater upper-limb bone bilateral asymmetry than other agricultural populations. Results suggest that the upper limbs were involved in similar activity patterns in both sexes but were characterized by different habitual behaviors. To obtain comprehensive results, studies should be based on sophisticated methods such as geometric morphometrics as well as standard measurements. Am. J. Hum. Biol. 28:817-824, 2016. (c) 2016Wiley Periodicals, Inc. PMID- 27238389 TI - Janus Reversal and Coulomb Blockade in Ferrocene-Perylenebisimide and N,N,N',N' Tetramethyl-para-phenylenediamine-Perylenebisimide D-sigma-A Rectifiers. AB - Sandwiches "EGaIn|Ga2O3|LB monolayer of 2|Au" and "EGaIn|Ga2O3|LB monolayer of 3|Au" rectify. They are formed from a Langmuir-Blodgett (LB) monolayer of 2 or 3 transferred onto thermally evaporated gold. Molecules 2 and 3 are of the donor sigma-acceptor (D-sigma-A) type and have the same perylenebisimide (PBI) acceptor as previously studied molecule 1. Molecule 1 has the weak donor pyrene, 2 has the good donor ferrocene, and 3 has the very strong donor N,N,N',N'-tetramethyl-p phenylenediamine (TMPD). All three molecules have a long swallowtail ending in a thioacetyl group, which ensures slow chemisorption onto the Au electrode. These molecules were contacted directly by a gallium indium eutectic (EGaIn) drop, covered by a defective oxide Ga2O3 layer. As before for 1, the direction of rectification for 2 is bias-dependent. In the +/-1.0 V range, the rectification is at positive V, with a rectification ratio (RR) that is initially greater than 5 and then decreases on successive scans to 2, while the currents decrease by as much as 2 orders of magnitude. In the +/-2.5 V range, the rectification direction for 2 reverses, while upon repeated scanning the rectification ratio (in the negative direction) increases and the currents decrease. For molecule 3, both directions have a charge-trapped state (Coulomb blockade) leading to Voffset in both biases, but at high potentials rectification set is, with large RR (up to 2,800) at +/-2.5 V. PMID- 27238387 TI - Genomic data reveal ancient microendemism in forest scorpions across the California Floristic Province. AB - The California Floristic Province (CFP) in western North America is a globally significant biodiversity hotspot. Elucidating patterns of endemism and the historical drivers of this diversity has been an important challenge of comparative phylogeography for over two decades. We generated phylogenomic data using ddRADseq to examine genetic structure in Uroctonus forest scorpions, an ecologically restricted and dispersal-limited organism widely distributed across the CFP north to the Columbia River. We coupled our genetic data with species distribution models (SDMs) to determine climatically suitable areas for Uroctonus both now and during the Last Glacial Maximum. Based on our analyses, Uroctonus is composed of two major genetic groups that likely diverged over 2 million years ago. Each of these groups itself contains numerous genetic groups that reveal a pattern of vicariance and microendemism across the CFP. Migration rates among these populations are low. SDMs suggest forest scorpion habitat has remained relatively stable over the last 21 000 years, consistent with the genetic data. Our results suggest tectonic plate rafting, mountain uplift, river drainage formation and climate-induced habitat fragmentation have all likely played a role in the diversification of Uroctonus. The intricate pattern of genetic fragmentation revealed across a temporal continuum highlights the potential of low-dispersing species to shed light on small-scale patterns of biodiversity and the underlying processes that have generated this diversity in biodiversity hotspots. PMID- 27238391 TI - Doctor to Doctor. PMID- 27238392 TI - The Medical Bookshelf. PMID- 27238390 TI - Innovative chemical synthesis and conformational hints on the lipopeptide liraglutide. AB - Liraglutide is a new generation lipopeptide drug used for the treatment of type II diabetes. In this work, we describe new approaches for its preparation fully by chemical methods. The key step of these strategies is the synthesis in solution of the Lys/gamma-Glu building block, Fmoc-Lys-(Pal-gamma-Glu-OtBu)-OH, in which Lys and Glu residues are linked through their side chains and gamma-Glu is N(alpha) -palmitoylated. This dipeptide derivative is then inserted into the peptide sequence on solid phase. As liraglutide is obtained with great purity and high yield, our approach can be particularly attractive for an industrial production. We also report here the results of a circular dichroism conformational analysis in a membrane mimetic environment that offers new insights into the mechanism of action of liraglutide. Copyright (c) 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID- 27238393 TI - The Patient with Diarrhea. PMID- 27238394 TI - Acute diarrhea in adults. PMID- 27238395 TI - A Father's good-bye. PMID- 27238397 TI - Primary care digest. PMID- 27238399 TI - Treating Diarrhea in Adults. PMID- 27238400 TI - Progress of dendritic cell-based cancer vaccines for patients with hematological malignancies. AB - INTRODUCTION: Dendritic cells (DCs) are the most professional antigen-presenting cells eliciting cellular and humoral immune responses against cancer cells by expressing these antigens on MHC class I/II complexes to T cells. Therefore, they have been employed in many clinical trials as cancer vaccines for patients with cancer. This review focuses on the use of DCs in leukemia patients expressing leukemia-associated antigens (LAAs). AREAS COVERED: The contribution of both stimulating vs. tolerogenic DCs as well as of other factors to the milieu of anti leukemia immune responses are discussed. Several DC vaccination strategies like leukemia lysate, proteins and peptides have been developed. Next generation DC vaccines comprise transduction of DCs with retroviral vectors encoding for LAAs, cytokines and costimulatory molecules as well as transfection of DCs with naked RNA encoding for LAAs. Published as well as ongoing clinical trials are reported and critically reviewed. EXPERT OPINION: Future results will demonstrate whether next-generation DCs are really superior to conventional pulsing with peptide, protein or tumor lysate. However, currently available methods based on nucleic acid transfection/transduction are tempting in terms of material production costs and time for clinical application according to good manufacturing practice (GMP). PMID- 27238401 TI - [Traumatic phacocele mimicking a tumor of the limbus]. PMID- 27238402 TI - Hypothyroidism Associated with Myeloid Neoplasia. AB - We report 2 cases of hypothyroidism in whom the associated haematological disturbances (macrocytic anaemia in both cases, mild leukopenia and thrombo-penia in one patient) failed to be corrected by thyroid hormone replacement therapy. Further investigations led to the diagnosis of acute myeloid leukaemia (AML) in the first patient and myelodysplasia syndrome (MDS) in the other. The reasons of the delayed diagnosis and the possible mechanisms explaining this rare combination are discussed. The hypothesis of a purely coincidental association seems most likely. PMID- 27238403 TI - La Nocardiose A Propos D'Une Observation. Revue De La Litterature. AB - We report the observation of a cutaneous, pulmonary and osseous nocardiosis in a 45-year-old man. He was iatrogenously immunocompromised because of a "self medication" with 32 mg per day of methy Iprednisolone during 30 months for gouty arthropathies. Under treatment with several antibiotics, a favourable evolution was obtained. PMID- 27238404 TI - Minutes of the annual meeting of the Belgian Society for Human and Animal Mycology (14 March 1992). PMID- 27238406 TI - Long-term Evaluation of Peri-implant Bone Level after Reconstruction of Severely Atrophic Edentulous Maxilla via Vertical and Horizontal Guided Bone Regeneration in Combination with Sinus Augmentation: A Case Series with 1 to 15 Years of Loading. AB - BACKGROUND: To the best of the authors' knowledge, there is very limited clinical data on the outcomes of simultaneous guided bone regeneration (GBR) for horizontal and/or vertical bone gain for the reconstruction of severely atrophic edentulous maxilla. Therefore, the purpose of the clinical series presented herein was to clinically evaluate long-term horizontal and vertical bone gain, as well as implant survival rate after reconstruction of severely atrophic edentulous maxillary ridges. MATERIAL AND METHODS: Sixteen patients (mean age: 64.6 +/- 14.6 years of age) were consecutively treated for vertical and/or horizontal bone augmentation via GBR in combination with bilateral sinus augmentation utilizing a mixture of autologous and anorganic bovine bone. Implant survival, bone gain, intraoperative/postoperative complications and peri-implant bone loss were calculated up to the last follow-up exam. RESULTS: Overall, 122 dental implants were placed into augmented sites and have been followed from 12 to 180 months (mean: 76.5 months). Implant survival was 100% (satisfactory survival rate of 97.5%). Mean bone gain was 5.6 mm (max: 9 mm; min: 3 mm) While vertical bone gain was 5.1 +/- 1.8 mm; horizontal bone gain was 7.0 +/- 1.5 mm. No intraoperative/postoperative complications were noted. Mean peri-implant bone loss values were consistent within the standards for implant success (1.4 +/- 1.0 mm). At patient-level, only one patient who had three implants presented with severe peri-implant bone loss. CONCLUSION: Complete reconstruction of an atrophied maxilla can be successfully achieved by means of guided bone regeneration for horizontal and/or vertical bone gain including bilateral sinus augmentation using a mixture of anorganic bovine bone and autologous bone. PMID- 27238407 TI - A novel HLA-B allele, HLA-B*56:40. AB - HLA-B*56:40 allele differs from B*56:01:01:01 by one nucleotide substitution at position 874. PMID- 27238408 TI - Pituitary Stalk Interruption Syndrome Presenting With Growth Retardation. PMID- 27238409 TI - Factors Influencing Patient Experience in Pediatric Neurology. AB - INTRODUCTION: Hospitals have begun to shift toward patient-centered care because of the pay-for-performance system that was established by the Patient Protection and Affordable Care Act. In pediatrics, the needs of both the caregiver and the pediatric patient have to be taken into account. Pediatric practices have been shifting toward a family-centered approach, although the primary drivers have not been well defined. Identifying the key patient experiences that lead to higher patient satisfaction would enable a more meaningful clinical encounter. To better understand patient experience, we examined waiting time and the elements of the physician-patient interaction in pediatric neurology. We predict that the determining factor in patient satisfaction is the physician-patient interaction. METHODS AND MATERIAL: Patient satisfaction surveys were sent to families via mail or e-mail after their ambulatory pediatric neurology visit. The visits took place between January 1, 2012, and December 31, 2014, at one of multiple locations in a children's health system spanning four states. A Likert scale was used for these surveys, and a top-box method (measuring percent of survey questions were rated 5 out of 5) was used to filter data from this database. Statistical analysis using a Pearson correlation was used for data analysis, with likelihood to recommend practice as the dependent variable. RESULTS: The five survey questions that correlated most with overall likelihood to recommend the practice were cheerfulness of practice (r = 0.79); staff working together (r = 0.76); cleanliness of practice (r = 0.70); wait time at clinic, from entering to leaving (r = 0.66); and likelihood of recommending care provider (r = 0.65). CONCLUSION: Pediatric neurologists striving to enhance overall patient satisfaction in their practices should work toward providing an atmosphere that supports office staff cheerfulness, teamwork, and visit efficiency provided in a clean and friendly environment. PMID- 27238410 TI - Correlation Among Genotype, Phenotype, and Histology in Neuronal Ceroid Lipofuscinoses: An Individual Patient Data Meta-Analysis. AB - BACKGROUND: Neuronal ceroid lipofuscinoses (NCL) are heterogeneous neurodegenerative disorders. A better understanding of genotype-phenotype histology correlation is expected to improve patient care and enhance understanding for phenotypic variability. This meta-analysis studies the correlation of NCL genotypes with clinical phenotypes, ages of onset, and pathologic findings. METHODS: A structured MEDLINE search was performed using search strings incorporating relevant Medical Subject Headings (MeSH) terms. Studies of NCL patients with genetic, clinical, and histologic data were included. Individual patient data were extracted. Chi-square statistic was used to test the genotype differences in clinical phenotypes and histology. The distribution of age(s) of onset as a function of genotype was explored. Pairwise comparisons were performed with robust analysis of variance. RESULTS: Sixty-eight studies including a total of 440 individuals with NCL were analyzed. Genetic testing was performed on 395 patients, and a pathologic mutation was identified in 372 of 395 of them. A significant clustering of genotypes into juvenile-onset (only CLN3) and infantile-onset (all others) phenotypes was observed (P < 0.0001). However, the CLN6 genotype showed a bimodal onset and included 14 of 17 subjects with the adult-onset phenotype. The estimated age of onset was respectively lower for subjects with CLN1 mutation (3.01 years, 95% confidence interval [CI] = 2.54 to 3.49) and higher for those with CLN6 mutation (16.33 years, 95% CI = 15.68 to 16.98), compared with other genotypes (P < 0.05 for pairwise comparisons). There was a significant (P < 0.0001) clustering of genotype observed according to the sampled tissue types and electron microscopic findings. CONCLUSIONS: NCL genotypes significantly differ in terms of ages of onset and clinical phenotypes. There is a distinct segregation of genotypes and electron microscopic findings and high-yield tissue types for pathologic study. This information can possibly facilitate testing and diagnosis in resource limited settings. PMID- 27238411 TI - Green synthesis and characterisation of platinum nanoparticles using quail egg yolk. AB - Nanotechnology is extensively used in all parts today. Therefore, nano synthesis is also significant in all explored areas. The results of studies conducted have revealed that nanoparticle synthesis is performed by using both chemical and physical methods. It is well known that these syntheses are carried out at high charge, pressure and temperature in harsh environments. Therefore, this study investigated green synthesis method that sustains more mild conditions. In this study, quail egg yolk having high vitamin and protein content was prepared for green synthesis reaction and used for the synthesis of platinum nanoparticles in the reaction medium. Reaction situations were optimised as a function of pH, temperature, time and concentration by using quail egg yolk. The results showed that the highest platinum nanoparticles were synthesised at 20 degrees C and pH6.0 for 4h. Also, optimal concentration of metal ions was established as 0.5mM. The synthesised platinum nanoparticles were characterised by using UV spectrum, X ray diffraction and scanning electron microscope. PMID- 27238413 TI - Corrigendum. PMID- 27238412 TI - Mesenchymal stem cells suppress cardiac alternans by activation of PI3K mediated nitroso-redox pathway. AB - BACKGROUND: The paracrine action of non-cardiac progenitor cells is robust, but not well understood. Mesenchymal stem cells (MSC) have been shown to enhance calcium (Ca(++)) cycling in myocytes. Therefore, we hypothesized that MSCs can suppress cardiac alternans, an important arrhythmia substrate, by paracrine action on Ca(++) cycling. METHODS AND RESULTS: Human cardiac myocyte monolayers derived from iPS cells (hCM) were cultured without or with human MSCs (hMSC) directly or plated on a transwell insert. Ca(++) transient alternans (Ca(++) ALT) and Ca(++) transient duration (CaD) were measured from hCM monolayers following application of 200MUM H2O2. Ca(++) ALT in hCM was significantly decreased when cultured with hMSCs directly (97%, p<0.0001) and when cultured with hMSC in the transwell insert (80%, p<0.0001). When hCM with hMSCs were pretreated with PI3K or eNOS inhibitors, Ca(++) ALT was larger than baseline by 20% (p<0.0001) and 36% (p<0.0001), respectively. In contrast, Ca(++) ALT was reduced by 89% compared to baseline (p<0.0001) when hCM monolayers without hMSCs were pretreated with 20MUM GSNO. In all experiments, changes in Ca(++) ALT were mirrored by changes in CaD. Finally, real time quantitative PCR revealed no significant differences in mRNA expression of RyR2, SERCA2a, and phospholamban between hCM cultured with or without hMSCs. CONCLUSION: Ca(++) ALT is suppressed by hMSCs in a paracrine fashion due to activation of a PI3K-mediated nitroso-redox pathway. These findings demonstrate, for the first time, how stem cell therapy might be antiarrhythmic by suppressing cardiac alternans through paracrine action on Ca(++) cycling. PMID- 27238415 TI - The Influence of an Isthmus on the Outcomes of Surgically Treated Molars: A Retrospective Study. AB - INTRODUCTION: The purpose of this study was to investigate the effects of an isthmus on the success rate of surgically treated molars. METHODS: The study included 106 maxillary and mandibular first molars with endodontic lesions limited to the periapical area. Endodontic microsurgical procedures were performed according to the Yonsei protocol reported in a previous study. When an isthmus was observed after a high-magnification inspection, it was included in the retrograde preparation design. When an isthmus was not observed, only the main root canal space was prepared. The patients were followed up periodically every year after treatment. Success was defined as the absence of clinical signs and symptoms and radiographic evidence of complete or incomplete healing. RESULTS: Of the 106 teeth included in the study, 72 teeth had an isthmus, and 34 did not. Kaplan-Meier analysis revealed that the cumulative survival rate after surgery was 61.5% and 87.4% for 4 years when an isthmus was present and absent, respectively. A multivariate Cox proportional hazards regression analysis showed that the adjusted hazard ratio for failure was 6.01 times higher for the isthmus present teeth than for the isthmus-absent teeth (P < .05). CONCLUSIONS: In this study, the success rate for endodontic microsurgery on isthmus-absent teeth was higher than that for isthmus-present teeth. Considering the success rate and potential risk of weakening the root after preparation, the techniques of isthmus preparation need to be improved. PMID- 27238414 TI - A Comparison of Cone-beam Computed Tomography with Periapical Radiography in the Detection of Separated Instruments Retained in the Apical Third of Root Canal filled Teeth. AB - INTRODUCTION: This study compared the diagnostic efficacies of cone-beam computed tomographic (CBCT) imaging and periapical radiography (PR) in the detection of retained separated instruments located at the apical third of filled root canals. METHODS: Sixty single-rooted extracted human teeth were instrumented to size #25 and were randomly divided to a simulated 2-mm #30 K-file (stainless steel or nickel-titanium) segment separation at the apical third of the canal (n = 40) or a control group without a separated instrument (n = 20). The canals were obturated to the separated instrument or the working length for the teeth without an instrument using gutta-percha with AH26 (Dentsply DeTrey GmbH, Konstanz, Germany) or Roth sealer (Roth International Ltd, Chicago, IL). The teeth were invested in a mandible model simulating the bone density and imaged using CBCT imaging and PR. The images were evaluated separately by 2 calibrated observers twice with an interval of 4 weeks. Cohen kappa was used to evaluate the observer agreement. Receiver operating characteristic curve analysis was used to evaluate the discrimination ability. RESULTS: The intraobserver kappa was 0.744 and 0.627, and between the observers, it was 0.593 and 0.275 for PR and CBCT imaging, respectively. Using PR, the mean sensitivity was 71.25%, and the specificity was 93.75%. Using CBCT imaging, the sensitivity and specificity were 41.25% and 71.25%, respectively. Although for PR the area under the curve values ranged between 0.75 and 0.91 (P < .05), for CBCT they ranged between 0.48 and 0.60 (P > .05), regardless of the instrument or the sealer type. CONCLUSIONS: PR performed better than CBCT imaging for the detection of retained separated instruments located at the apical third of extracted human root canal-filled teeth. PMID- 27238416 TI - Retinoic acid signalling in the development of the epidermis, the limbs and the secondary palate. AB - Retinoic acid (RA), the active derivative of vitamin A, is one of the major regulators of embryonic development, including the development of the epidermis, the limbs and the secondary palate. In the embryo, RA levels are tightly regulated by the activity of RA synthesizing and degrading enzymes. Aberrant RA levels due to genetic variations in RA metabolism pathways contribute to congenital malformations in these structures. In vitro and in vivo studies provide considerable evidence on the effects of RA and its possible role in the development of the epidermis, the limbs and the secondary palate. In conjunction with other regulatory factors, RA seems to stimulate the development of the epidermis by inducing proliferation and differentiation of ectodermal cells into epidermal cells. In the limbs, the exact timing of RA location and level is crucial to initiate limb bud formation and to allow chondrogenesis and subsequent osteogenesis. In the secondary palate, the correct RA concentration is a key factor for mesenchymal cell proliferation during palatal shelf outgrowth, elevation and adhesion, and finally to allow bone formation in the hard palate. These findings are highly relevant to understanding the mechanism of RA signalling in development and in the aetiology of specific congenital diseases. PMID- 27238419 TI - Stirring the Melting Pot. PMID- 27238420 TI - Ron R. Kopito: Unfolding the Secrets of Protein Aggregation. PMID- 27238421 TI - Does Longer Lifespan Mean Longer Healthspan? AB - Once thought to be impossible, it is now clear that changing the activity of several conserved genetic pathways can lead to lifespan extension in experimental organisms. In humans, however, the goal is to extend healthspan, the functional and disease-free period of life. Are the current pathways to lifespan extension also improving healthspan? PMID- 27238422 TI - Sprint and jump performances do not determine the promotion to professional elite soccer in Spain, 1994-2012. AB - The aims of this study are (a) to describe the evolution of neuromuscular performance over an 18 year period within a Spanish elite reserve team; (b) to check if there were any relation between the playing position and sprint and jump performances and (c) to look into the alleged impact of this factor on the top playing level attained by the soccer players. We considered the physical tests (5 m and 15 m sprint times and countermovement jump (CMJ) height) made by 235 players enrolled in the reserve team of the Club from 1994 to 2012 and the highest competitive-level they achieved: Spanish first (n = 39) and second divisions (n = 36) and semi-professional (n = 160). Furthermore, the players were classified according to their playing positions. The main findings were a very likely/most-likely lower neuromuscular performance (ES = 0.48-0.68, small to moderate) in the last six-season term (2006-2012) than in the first term (1994 2000); possibly/very-likely lower performances in sprinting and CMJ (ES = 0.22 0.55, small) by central defenders (CDs) and midfielders than by other playing positions; very-likely better performances in sprinting and jumping by first and second divisions central defenders than by semi-professional central defenders (ES = 0.90-1.02, moderate). Sprint and jump performances are not a relevant physical parameter to promote to the top level of soccer in Spain except for one in six of the playing positions: CDs. PMID- 27238423 TI - Perlecan is required for the chondrogenic differentiation of synovial mesenchymal cells through regulation of Sox9 gene expression. AB - We previously reported that perlecan, a heparan-sulfate proteoglycan (Hspg2), expressed in the synovium at the cartilage-synovial junction, is required for osteophyte formation in knee osteoarthritis. To examine the mechanism underlying this process, we examined the role of perlecan in the proliferation and differentiation of synovial mesenchymal cells (SMCs), using a recently established mouse synovial cell culture method. Primary SMCs isolated from Hspg2 /- -Tg (Hspg2-/- ;Col2a1-Hspg2Tg/- ) mice, in which the perlecan-knockout was rescued from perinatal lethality, lack perlecan. The chondrogenic-, osteogenic-, and adipogenic-potentials were examined in the Hspg2-/- -Tg SMCs compared to the control SMCs prepared from wild-type Hspg2+/+ -Tg (Hspg2+/+ ;Col2a1-Hspg2Tg/- ) littermates. In a culture condition permitting proliferation, both control and Hspg2-/- -Tg SMCs showed similar rates of proliferation and expression of cell surface markers. However, in micromass cultures, the cartilage matrix production and Sox9 and Col2a1 mRNA levels were significantly reduced in Hspg2-/- -Tg SMCs, compared with control SMCs. The reduced level of Sox9 mRNA was restored by the supplementation with exogenous perlecan protein. There was no difference in osteogenic differentiation between the control and Hspg2-/- -Tg SMCs, as measured by the levels of Runx2 and Col1a1 mRNA. The adipogenic induction and PPARgamma mRNA levels were significantly reduced in Hspg2-/- -Tg SMCs compared to control SMCs. The reduction of PPARgamma mRNA levels in Hspg2-/- -Tg SMCs was restored by supplementation of perlecan. Perlecan is required for the chondrogenic and adipogenic differentiation from SMCs via its regulation of the Sox9 and PPARgamma gene expression, but not for osteogenic differentiation via Runx2. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:837-846, 2017. PMID- 27238424 TI - Molecularly Imprinted Polymer Coated Quantum Dots for Multiplexed Cell Targeting and Imaging. AB - Advanced tools for cell imaging are of great interest for the detection, localization, and quantification of molecular biomarkers of cancer or infection. We describe a novel photopolymerization method to coat quantum dots (QDs) with polymer shells, in particular, molecularly imprinted polymers (MIPs), by using the visible light emitted from QDs excited by UV light. Fluorescent core-shell particles specifically recognizing glucuronic acid (GlcA) or N-acetylneuraminic acid (NANA) were prepared. Simultaneous multiplexed labeling of human keratinocytes with green QDs conjugated with MIP-GlcA and red QDs conjugated with MIP-NANA was demonstrated by fluorescence imaging. The specificity of binding was verified with a non-imprinted control polymer and by enzymatic cleavage of the terminal GlcA and NANA moieties. The coating strategy is potentially a generic method for the functionalization of QDs to address a much wider range of biocompatibility and biorecognition issues. PMID- 27238425 TI - Clinical Features and Treatment Outcomes of Patients With Necrobiotic Xanthogranuloma Associated With Monoclonal Gammopathies. AB - INTRODUCTION: Necrobiotic xanthogranuloma (NXG) is a rare chronic granulomatous disorder of the skin associated with a monoclonal gammopathy. PATIENTS AND METHODS: The present report describes the findings from a single tertiary medical center retrospective study, including the clinical features of 35 patients with NXG and monoclonal gammopathy from 2000 to 2015 and their subsequent disease course and treatment response. The median age at diagnosis was 56 years (range, 26-88 years). RESULTS: Most patients had a plasma cell dyscrasia consisting of monoclonal gammopathy of undetermined significance in 28 patients and smoldering multiple myeloma in 5 patients; the remaining 2 patients had chronic lymphocytic leukemia. An IgG isotype of monoclonal gammopathy was present in almost all the patients (97%). The most common site of cutaneous involvement of NXG was periorbital (66%). The treatments were heterogeneous and included excision, intralesional injection, radiotherapy, and systemic chemotherapy. The median follow-up period was 46 months (range, 4 to 234 months). The median overall survival had not been reached at the analysis, and 80% of the patients were still alive. Eight patients (23%) had disease progression to multiple myeloma at a median of 67 months (range, 21 to 107 months), demonstrating that although the clinical course is generally indolent, malignant transformation is not uncommon. At the last follow-up visit, 80% had signs of either clinical improvement or stable skin disease. CONCLUSION: Cutaneous objective responses can be achieved with treatment of lymphoplasmacytic malignancies. PMID- 27238426 TI - Effects of low molecular weight sodium alginate on growth performance, immunity, and disease resistance of tilapia, Oreochromis niloticus. AB - Present study was carried out to evaluate the effects of low molecular weight sodium alginate (LMWSA) as potential prebiotic source on growth performance, innate immunity and disease resistance of tilapia, Oreochromis niloticus. Three hundred twenty fish were divided into four treatments and fed following diets 0 (T1- Control), 10 (T2), 20 (T3) and 30 (T4) g kg(-1) LMWSA for period of 60 days. A Completely Randomized Design with four replications was applied. At the end of experiment, fish in each replication were weighed and specific growth rate (SGR) and feed conversion ratio (FCR) were calculated. Five randomly selected fish were used for innate immune response measurement. Another ten fish were randomly selected for challenge test against Streptococcus agalactiae for a period of 18 days. The lysozyme, complement, phagocytosis, and respiratory burst activities were detected after 60 days of feeding trial and after challenge test. The results indicated that fish fed diet 10 g kg(-1) LMWSA significantly improved SGR and FCR after 60 days of feeding trial. The lysozyme, phagocytosis, respiratory burst, and complement activities were significantly higher in fish fed LMWSA diets compared to control. Fish fed 10 g kg(-1) LMWSA had greatest values compared to fish fed 20 and 30 g kg(-1) LMWSA. The survival rate of O. niloticus was significantly improved in fish fed LMWSA diets after challenge with S. agalactiae for 18 days. However, no significant difference in survival rate was observed among LMWSA supplemented diets. It is indicated that fish fed 10, 20 and 30 g kg(-1) LMWSA diets can stimulate growth performance, innate immunity and disease resistance in tilapia against S. agalactiae. PMID- 27238427 TI - Identification, expression and antibacterial activities of an antimicrobial peptide NK-lysin from a marine fish Larimichthys crocea. AB - As fundamental immunologic mechanism, the innate immunity system is more important than the specific immunity system in teleost fishes during pathogens infection. Antimicrobial peptides are integral parts of the innate immune system, and play significant roles against pathogens infection. NK-lysin, the compounds of the natural killer cells and cytotoxic T cells, are potent and effective antimicrobial peptides widely distributed in animals. In this study, we reported the sequence characteristics, expression profiles and antibacterial activities of a NK-lysin gene (Lc-NK-lysin) from a commercially important marine fish, the large yellow croaker (Larimichthys crocea). The open reading frame of Lc-NK-lysin cDNA sequence was 447 bp in length, coding 148 amino acids. The genomic DNA of Lc NK-lysin has the common features of NK-lysin family, consisting of five exons and four introns, and in its deduced mature peptide, there are six well-conserved cysteine residues and a Saposin B domain. Lc-NK-lysin was expressed in all tested tissues (skin, muscle, gill, brain, head kidney, heart, liver, spleen, stomach and intestine) with different expression patterns. In pathogens infection the expression profiles of Lc-NK-lysin varied significantly in gill, head kidney, spleen and liver, indicating its role in immune response. Two peptides (Lc-NK lysin-1 and Lc-NK-lysin-2) divided from the core region of the Lc-NK-lysin mature polypeptide were chemically synthesized and their antibacterial activities were examined; the potential function on the inhibition of bacteria propagation was revealed. Our results suggested that Lc-NK-lysin is a typical member of the NK lysin family and as an immune-related gene it involves in the immune response when pathogens invasion. PMID- 27238428 TI - Identification of a retinoic acid-inducible gene I from Japanese eel (Anguilla japonica) and expression analysis in vivo and in vitro. AB - RIG-I (retinoic acid inducible gene-I) is one of the key cytosolic pattern recognition receptors (PRRs) for the recognition of cytosolic viral nucleic acids and the production of type I interferons (IFNs). The full-length cDNA sequence of RIG-I (AjRIG-I) in Japanese eel (Anguilla japonica) was identified and characterized in this article. The full-length cDNA of AjRIG-I was 3468 bp, including a 5'-untranslated region (UTR) of 52 bp, a 3'-UTR of 617 bp and an open reading frame (ORF) of 2799 bp encoding a polypeptide of 933 amino acid residues with a calculated molecular mass of 106.2 kDa. NCBI CDD analysis showed that the AjRIG-I protein had the typical conserved domains, including two adjacent caspase activation and recruitment domains (CARDs), a DEXDc domain, a HELICc domain and a C-terminal regulatory domain (RD). Quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed a broad expression for AjRIG-I in a wide range of tissues, with the predominant expression in liver, followed by the gills, spleen, kidney, intestine, skin, and the very low expression in muscle and heart. The AjRIG-I expressions in liver, spleen and kidney were significantly induced following injection with LPS, the viral mimic poly I:C, and Aeromonas hydrophila infection. In vitro, the AjRIG-I transcripts of Japanese eel liver cells were significantly enhanced by poly I:C and PGN stimulation, down-regulated with CpG-DNA treatment whereas no change of the expression level was found post LPS challenge. These results collectively suggested AjRIG-I transcripts expression possibly play an important role in fish defense against viral and bacterial infection. PMID- 27238429 TI - Identification and functional characterization of multiple interleukin 12 in amberjack (Seriola dumerili). AB - Interleukin (IL) -12 is a heterodimeric cytokine mainly produced by monocytes, macrophages, and dendritic cells in mammals. IL-12p70 composed of IL-12p35 and IL 12p40, is known to play a crucial role in promoting cell-mediated immunity (CMI) through Th1 differentiation and IFN-gamma production. Although two types of IL 12p35 (p35a, p35b) and three types of IL-12p40 (p40a, p40b and p40c) have been identified in several fish species, the knowledge on functional characteristics of teleost IL-12 is still limited. In the present study, we cloned two types of IL-12p35 and three types of IL-12p40 genes in amberjack and yellowtail, and analyzed their expressions in response to stimulation with Nocardia seriolae in amberjack. As a result, four types of IL-12 (IL-12p35a, p35b, p40a and p40b) and IFN-gamma mRNA were increased by live-N. seriolae stimulation but not by formalin killed N. seriolae, suggesting that four types of IL-12 (p35, p35b, p40a and p40c) participate in promoting CMI. Subsequently, we produced six types of recombinant IL-12p70 (rIL12p70) protein in insect cells. Head kidney leukocytes were cultured with formalin-killed N. seriolae and six types of rIL-12p70 to elucidate the role of amberjack IL-12p70 in induction of CMI. After stimulation, IFN-gamma expression was elevated whereas IL-10 expression was suppressed in Head kidney leukocytes stimulated with four types of rIL-12 (p40a/p35a, p40c/p35a, p40a/p35b, p40a/p35b). On the other hand, two types of rIL-12 (p40b/p35a, p40b/p35b) only elicited down regulation of IL-10 expression. These results indicate that all amberjack IL-12p70 isoforms are involved in Th1 differentiation and promotion of CMI with different manners. Fish IL-12 has a potential for the promising vaccine adjuvant. PMID- 27238430 TI - First characterization of three cyclophilin family proteins in the oyster, Crassostrea ariakensis Gould. AB - Cyclophilins (CyPs) are a family of proteins that bind the immunosuppressive agent cyclosporin A (CsA) with high-affinity and belong to one of the three superfamilies of peptidyl-prolyl cis-trans isomerases (PPIase). In this report, three cyclophilin genes (Ca-CyPs), including Ca-CyPA, Ca-CyPB and Ca-PPIL3, were identified from oyster, Crassostrea ariakensis Gould in which Ca-CyPA encodes a protein with 165 amino acid sequences, Ca-CyPB encodes a protein with 217 amino acid sequences and Ca-PPIL3 encodes a protein with 162 amino acid sequences. All of the three Ca-CyPs genes contain a typical CyP-PPIase domain with its signature sequences and Ca-CyPB contains an N-signal peptide sequences. Tissue distribution study revealed that Ca-CyPs were ubiquitously expressed in all examined tissues and the highest levels were observed in hemocytes. RLO incubation upregulated the mRNA expression levels of Ca-CyPs, indicating that three Ca-CyPs might be involved in oyster immune response against RLO infection. PMID- 27238431 TI - Ultra high performance liquid chromatography-tandem mass spectrometry vs. commercial immunoassay for determination of vancomycin plasma concentration in children. Possible implications for everyday clinical practice. AB - BACKGROUND: Vancomycin therapeutic drug monitoring (TDM) is necessary for effective and safetherapy. The aim of the this paper was to develop a specific and robust ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for vancomycin quantification starting from low plasma volumes to be applied for the routine TDM in children. METHODS: Samples from children receiving intravenous vancomycin were analysed using a TSQ Quantum Access MAX Triple Quadrupole system coupled with an Accela 1250 UHPLC system after a rapid protein precipitation. Gradient separation chromatography was carried out using a Hypersil GOLD aQ C18 column (50 * 2.1 mm, particle size 1.9 MUm). Method performance was validated following international guidelines. RESULTS: UHPLC-MS/MS allowed a rapid and specific quantification of vancomycin over the range 0.1-128 MUg/mL from 50 MUL of plasma with high reproducibility and accuracy in the absence of matrix effect. The comparison with the commercial immunoassay performed on 138 samples demonstrated the presence of a proportional bias. The concentrations of vancomycin measured with immunoassay were found to be 4.5% (95% CI: 1.3-7.7) higher than those determined with UHPLC-MS/MS. Importantly, a clinical discordance was found in about 10% of samples analysed. CONCLUSIONS: This new UHPLC-MS/MS method is accurate and specific for the measurement of vancomycin starting from small (50 MUL) plasma volumes. The use of UHPLC-MS/MS is recommended to prevent a misclassification of therapeutic or toxic vancomycin levels in paediatrics. PMID- 27238432 TI - Accuracy of a Chest X-Ray-Based Method for Predicting the Depth of Insertion of Endotracheal Tubes in Pediatric Patients Undergoing Cardiac Surgery. AB - OBJECTIVES: The incidence of endotracheal tube (ETT) malposition in children with various described methods is 15% to 30%. Chest x-ray (CXR) is the gold standard for confirming appropriate ETT position. The aim of this study was to measure the accuracy of a preoperative CXR-based method in determining depth of insertion of ETTs and to compare it with methods based on the intubation depth mark or formulae (age, height, and ETT internal diameter) in children undergoing cardiac surgery. DESIGN: Prospective observational study. SETTING: University-affiliated tertiary care hospital. PARTICIPANTS: Sixty-six consecutive children scheduled for elective pediatric cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The distance from carina to mid-trachea was measured for each child preoperatively on the CXR displayed as a computed radiography image in a picture archival and communications system computer. Following intubation, ETTs deliberately were pushed endobronchially and then pulled back to the carina; they were further withdrawn by the previously measured carina to mid-tracheal distance and secured. CXRs postoperatively were repeated to confirm ETT position. The ETT position was measured with other methods using the picture archival and communications system ruler on the postoperative CXR and compared with the CXR method. The proportion of appropriate ETT position with the CXR method was 98.5% (p<=0.001 v other methods). In children younger than 3 years, the appropriate proportion was 97.4%. CONCLUSION: The appropriate positioning of ETTs in the trachea by the CXR method is superior to other methods. PMID- 27238433 TI - Volatile Agents in Medical and Surgical Intensive Care Units: A Meta-Analysis of Randomized Clinical Trials. AB - OBJECTIVE: To comprehensively assess published randomized peer-reviewed studies related to volatile agents used for sedation in intensive care unit (ICU) settings, with the hypothesis that volatile agents could reduce time to extubation in adult patients. DESIGN: Systematic review and meta-analysis of randomized trials. SETTING: Intensive care units. PARTICIPANTS: Critically ill patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The BioMedCentral, PubMed, Embase, and Cochrane Central Register databases of clinical trials were searched systematically for studies on volatile agents used in the ICU setting. Articles were assessed by trained investigators, and divergences were resolved by consensus. Inclusion criteria included random allocation to treatment (volatile agents versus any intravenous comparator, with no restriction on dose or time of administration) in patients requiring mechanical ventilation in the ICU. Twelve studies with 934 patients were included in the meta-analysis. The use of halogenated agents reduced the time to extubation (standardized mean difference = -0.78 [-1.01 to -0.55] hours; p for effect<0.00001; p for heterogeneity = 0.18; I(2) = 32% in 7 studies with 503 patients). Results for time to extubation were confirmed in all subanalyses (eg, medical and surgical patients) and sensitivity analyses. No differences in length of hospital stay, ICU stay, and mortality were recorded. CONCLUSIONS: In this meta-analysis of randomized trials, volatile anesthetics reduced time to extubation in medical and surgical ICU patients. The results of this study should be confirmed by large and high-quality randomized controlled studies. PMID- 27238434 TI - Plasma Free Hemoglobin Is a Predictor of Acute Renal Failure During Adult Venous Arterial Extracorporeal Membrane Oxygenation Support. AB - OBJECTIVE: Hemolysis is a common and severe complication during extracorporeal membrane oxygenation (ECMO). Increased plasma free hemoglobin (PFHb) is related to renal injury. The aim of this study was to investigate whether increased PFHb during adult venous-arterial ECMO was associated with acute renal failure (ARF). DESIGN: A retrospective, observational, single-center study. SETTING: Fuwai Hospital in Beijing, China. PARTICIPANTS: The study comprised 84 venous-arterial ECMO patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 84 consecutive adult patients (>=18 years) with cardiac diseases requiring venous arterial ECMO support were studied retrospectively. Demographics of patients, clinical and ECMO characteristics, and PFHb level were collected within the first 3 days after ECMO. ARF was defined as a>=300% rise in serum creatinine from baseline or application of dialysis. Repeated measurement analysis of variance revealed that the main effect for the non-ARF group and ARF group in PFHb (p = 0.002) was significant. A significant main effect for time points (p<0.001) and time*group interaction (p = 0.014) in PFHb was obtained. In a multiple logistic regression model, peak PFHb during ECMO (odds ratio 1.052, 95% confidence interval 1.016-1.089, p = 0.005) was a risk factor for ARF during ECMO and patients who underwent heart transplantation (odds ratio 0.240, 95% confidence interval 0.060-0.964, p = 0.044) experienced less ARF. There was a linear correlation between peak serum creatinine and peak PFHb (Spearman's r = 0.223, p = 0.042). CONCLUSIONS: Increased PFHb is a predictor of ARF among adult patients on venous-arterial ECMO support. PMID- 27238435 TI - Vascular Occlusion Test to Dynamically Assess Microcirculation During Normothermic Pulsatile Cardiopulmonary Bypass. AB - OBJECTIVE: To evaluate parameters of the vascular occlusion test (VOT) before, during, and after pulsatile cardiopulmonary bypass (CPB). DESIGN: Prospective, observational study. SETTING: Single-center university hospital. PARTICIPANTS: Adult patients undergoing elective cardiac surgery with pulsatile CPB. INTERVENTIONS: An oximeter sensor and adult-sized pneumatic tourniquet were positioned at the right forearm. A VOT with a predefined ischemic time of 3 minutes was performed before, during, and after CPB. Changes in tissue oxygen saturation were recorded. MEASUREMENTS AND MAIN RESULTS: Thirty-four patients who underwent cardiac surgery were enrolled in the study. The lowest tissue oxygen saturation measured during the ischemic challenge differed among all 3 stages of surgery, with median values of 62.9% before, 57.5% during, and 59.3% after perfusion (p<0.05). Both occlusion (p<0.001) and reperfusion (p<0.05) slopes were steeper after bypass compared with before initiating bypass, whereas the reperfusion time remained constant among the different time points. CONCLUSIONS: The microcirculatory function as demonstrated by changes in VOT parameters was enhanced during and after normothermic pulsatile CPB. Clinical relevance, however, needs to be further explored. PMID- 27238436 TI - Evaluation of blood pressure and aortic elasticity of offspring of diabetic Wistar rats who have consumed flaxseed oil during pregnancy and lactation. AB - OBJECTIVE: This study aimed to investigate whether maternal use of flaxseed oil has effects on blood pressure and aorta elastic fibre in female offspring of diabetic mothers. METHODS: Diabetes was induced into the rats (n = 18) by a high fat diet and streptozotocin. After diabetes confirmation, rats were mated, and after pregnancy was confirmed, they were allocated into three groups: control group (CG); high-fat group (HFG); and flaxseed oil group (FOG). At weaning, female offspring (n = 6/group) received standard chow diet and were euthanized at 100 days of life. The following blood pressure and the percentage of the aortic elastic fibre were analysed. RESULTS: HFG showed higher blood pressure, and the use of flaxseed oil avoided this condition in FOG (p < 0.001) and increased the percentage of the aortic elastic fibre (p < 0.022). CONCLUSIONS: Flaxseed oil reduced the damage caused by maternal hyperglycaemia, promoting normal blood pressure and elasticity of the aorta in female offspring. PMID- 27238437 TI - Developmental Origins of Health and Disease in swine: implications for animal production and biomedical research. AB - The concept of Developmental Origins of Health and Disease (DOHaD) addresses, from a large set of epidemiological evidences in human beings and translational studies in animal models, both the importance of genetic predisposition and the determinant role of maternal nutrition during pregnancy on adult morphomics and homeostasis. Compelling evidences suggest that both overnutrition and undernutrition may modify the intrauterine environment of the conceptus and may alter the expression of its genome and therefore its phenotype during prenatal and postnatal life. In fact, the DOHaD concept is an extreme shift in the vision of the factors conditioning adult phenotype and supposes a drastic change from a gene-centric perspective, only modified by lifestyle and nutritional strategies during juvenile development and adulthood, to a more holistic approach in which environmental, parental, and prenatal conditions are strongly determining postnatal development and homeostasis. The implications of DOHaD are profound in all the mammalian species and the present review summarizes current knowledge on causes and consequences of DOHaD in pigs, both for meat production and as a well recognized model for biomedicine research. PMID- 27238438 TI - Pivotal periods for pregnancy loss during the first trimester of gestation in lactating dairy cows. AB - Loss of pregnancy can occur at many different stages of gestation and for a variety of causes but clearly produces a negative impact for reproductive and economic performances of dairy herds. This review describes four pivotal periods for pregnancy loss during the first trimester of gestation and discusses possible causes for pregnancy failure during these periods. The first period occurs during the first week after breeding with lack of fertilization and death of the early embryo producing major losses in pregnancy, particularly under specific environmental and hormonal conditions. In general, 20%-50% of high-producing lactating dairy cows have already experienced pregnancy loss during the first week of gestation with methods to decrease pregnancy loss during this period targeting improved oocyte quality by alleviating heat stress, inflammatory diseases, and body condition loss, and by increasing progesterone concentrations during preovulatory follicle development. The second pivotal period, from Days 8 to 27, encompasses embryo elongation and the classical "maternal recognition of pregnancy" period with losses averaging ~30% but with surprising variation between farms (25%-41%). Maintenance of the CL of pregnancy is produced by the embryonic signal interferon-tau and alteration in uterine secretory patterns of prostaglandins F2alpha, E1, and E2. Failures or delays in trophoblast elongation and/or embryonic development result in loss of pregnancy during the second pivotal period possibly due to suboptimal histotroph. The third pivotal period is during the second month of pregnancy, Days 28 to 60, with losses of ~12% based on a summary of published results from more than 20,000 pregnancies in high producing dairy cows. Delays or defects in development of the chorioallantoic placentomes or embryo result in CL regression or embryo death during this pivotal period. Finally, a fourth period during the third month of pregnancy has reduced pregnancy losses (~2%), compared with the first three periods but can be elevated in some cows, particularly in those carrying twins in the same uterine horn. Thus, there are varied causes for pregnancy losses during each pivotal period that correspond to key physiological changes in the embryo, uterine environment, and ovary. Similarly, strategies to reduce these losses are likely to require a multifaceted approach using rational methods that target the critical physiology in each pivotal period. PMID- 27238439 TI - Polymorphisms and genes associated with puberty in heifers. AB - Puberty onset is a multifactorial process influenced by genetic determinants and environmental conditions, especially nutritional status. Genes, genetic variations, and regulatory networks compose the molecular basis of achieving puberty. In this article, we reviewed the discovery of multiple polymorphisms and genes associated with heifer puberty phenotypes and discuss the opportunities to use this evolving knowledge of genetic determinants for breeding early pubertal Bos indicus-influenced cattle. The discovery of polymorphisms and genes was mainly achieved through candidate gene studies, quantitative trait loci analyses, genome-wide association studies, and recently, global gene expression studies (transcriptome). These studies are recapitulated and summarized in the current review. PMID- 27238440 TI - Evaluation of microparticulate ovarian cancer vaccine via transdermal route of delivery. AB - Ovarian cancer is the fifth most commonly occurring malignancy in women, with the highest mortality rate among all the gynecological tumors. Microparticulate vaccine can serve as an immunotherapeutic approach with a promising antigenic delivery system without a need for conventional adjuvants. In this study, a microparticulate vaccine using whole cell lysate of a murine ovarian cancer cell line, ID8 was prepared by spray drying. Further, the effect of interleukins (ILs) such as IL-2 and IL-12 was evaluated in a separate study group by administering them with vaccine particles to enhance the immune response. The vaccine microparticles were administered to C57BL/6 female mice via transdermal alone and in combination with the oral route. The transdermal vaccine was delivered using a metallic microneedle device, AdminPenTM. Orally administered microparticles also included an M-cell targeting ligand, Aleuria aurantia lectin, to enhance the targeted uptake from microfold cells (M-cells) in Peyer's patches of small intestine. In case of combination of routes, mice were given 5 transdermal doses and 5 oral doses administered alternatively, beginning with transdermal dose. At the end of vaccination, mice were challenged with live tumor cells. Vaccine alone resulted in around 1.5 times tumor suppression in case of transdermal and combination of routes at the end of 15th week when compared to controls. Inclusion of interleukins resulted in 3 times tumor suppression when administered with transdermal vaccine and around 9 times tumor suppression for the combination route of delivery in comparison to controls. These results were further potentiated by serum IgG, IgG1 and IgG2a titers. Moreover, CD8+ T-cell, CD4+ T cell and NK (natural killer) cell populations in splenocytes were elevated in case of vaccinated mice. Thus, vaccine microparticles could trigger humoral as well as cellular immune response when administered transdermally and via combination of route of delivery. However overall, vaccine administered with interleukins, via combination of route, was found to be the most efficacious to suppress the tumor growth and lead to a protective immune response. PMID- 27238441 TI - Influence of particle size on the in vivo potency of lipid nanoparticle formulations of siRNA. AB - Lipid nanoparticles (LNP) can provide a clinically effective method for delivering small interfering RNA (siRNA) to silence pathological genes in hepatocytes. The gene silencing potency of these LNP-siRNA systems has been shown to depend on a variety of factors including association with serum factors such as ApoE and the pKa of component ionizable lipids. Here we investigate the influence of LNP size, an important parameter affecting tissue penetration of LNP systems, on the pharmacokinetics, biodistribution, and hepatic gene silencing potency of LNP-siRNA systems following intravenous administration. For LNP systems stabilized by a polyethylene glycol (PEG)-lipid that can dissociate from the LNP following injection, it is shown that small (diameter<=30nm) systems are considerably less potent than their larger counterparts. This is attributed in part to the ability of other lipid components, particularly the ionizable amino lipid, to dissociate from the LNP following dissociation of the PEG-lipid. Small LNP stabilized by PEG-lipids with slow dissociation rates exhibited much reduced amino-lipid dissociation rates, however such systems are relatively impotent due to the continued presence of the PEG coating. These results demonstrate the delicate balance between the in vivo potency of LNP-siRNA systems and the residence times of component lipids in the LNP particle itself and suggest new directions to optimize the in vivo gene silencing potency of small LNP-siRNA systems. PMID- 27238442 TI - Green design "bioinspired disassembly-reassembly strategy" applied for improved tumor-targeted anticancer drug delivery. AB - In this study, a simple and green approach 'bioinspired disassembly-reassembly strategy' was employed to reconstitute lipoprotein nanoparticles (RLNs) using whole-components of endogenous ones (contained dehydrated human lipids and native apolipoproteins). These RLNs were engineered to mimic the configuration and properties of natural lipoproteins for efficient drug delivery. In testing therapeutic targeting to microtubules, paclitaxel (PTX) was reassembled into RLNs to achieve improved targeted anti-carcinoma treatment and minimize adverse effects, demonstrating ultimately more applicable than HDL-like particles which are based on exogenous lipid sources. We have characterized that apolipoprotein decoration of PTX-loaded RLNs (RLNs-PTX) led to favoring uniformly dispersed distribution, increasing PTX-encapsulation with a sustained-release pattern, while enhancing biostability during blood circulation. The innate biological RLNs induced efficient intracellular trafficking of cargos in situ via multi-targeting mechanisms, including scavenger receptor class B type I (SR-BI)-mediated direct transmembrane delivery, as well as other lipoprotein-receptors associated endocytic pathways. The resulting anticancer treatment from RLNs-PTX was demonstrated a half-maximal inhibitory concentration of 0.20MUg/mL, cell apoptosis of 18.04% 24h post-incubation mainly arresting G2/M cell cycle in vitro, and tumor weight inhibition of 70.51% in vivo. Collectively, green-step assembly-based RLNs provided an efficient strategy for mediating tumor-targeted accumulation of PTX and enhanced anticancer efficacy. PMID- 27238443 TI - Intraperitoneal chemotherapy of ovarian cancer by hydrogel depot of paclitaxel nanocrystals. AB - Intraperitoneal (IP) chemotherapy is a promising post-surgical therapy of ovarian cancer, but the full potential is yet to be realized. To facilitate IP chemotherapy of ovarian cancer, we developed an in-situ crosslinkable hydrogel depot containing paclitaxel (PTX) nanocrystals (PNC). PNC suppressed SKOV3 cell proliferation more efficiently than microparticulate PTX precipitates (PPT), and the gel containing PNC (PNC-gel) showed a lower maximum tolerated dose than PPT containing gel (PPT-gel) in mice, indicating greater dissolution and cellular uptake of PNC than PPT. A single IP administration of PNC-gel extended the survival of tumor-bearing mice significantly better than Taxol, but PPT-gel did not. These results support the advantage of PNC over PPT and demonstrate the promise of a gel depot as an IP drug delivery system. PMID- 27238444 TI - [Comparison of different nail polish in terms of photoprotective efficacy. Interest of their use as supportive care in patients with cancer]. AB - Many different chemotherapy drugs including cytotoxics and docetaxel in particular are responsible for side effects involving the nails. To prevent these negative effects, patients are advised to apply nail polish. The aim of this article is to study the photoprotective effect of various products applied in two layers. Sixty-five commercially-available products were tested in vitro. It was found that certain bases can provide non-negligible levels of photoprotection on their own. However, it was noted that nail polishes capable of forming an opaque film were the most interesting, with Sun protection factor (SPF) values of 500 or more, which is a lot higher than the values obtained with sun protection products and similar to levels which can be reached with protection through clothing. It appears that opaque nail polishes applied in two layers are likely to provide excellent protection for nails regarding ultraviolet radiation. If the dark colors are particularly effective towards the ultraviolet radiation, we can also obtain a very good protection with varied colors. The use of one or several UV filters in the formula of the mail polish does not appear to have a particular interest. PMID- 27238445 TI - [Effectiveness of "threshold" in the management of ovarian cancer: A review of the literature]. AB - OBJECTIVE: The "Institut national du cancer" has established since 2007 a minimum threshold of 20 patients per year per center to treat patients with gynecologic cancer. This review aims to assess whether the literature data validate this approach, and specifically for ovarian cancer. METHODS: A search of the MEDLINE database was conducted, to reference all relevant articles evaluating one hand the links between the survival of patients with ovarian cancer and the average volume of patients per center and by operator; and secondly the relationship between quality of oncological surgery and these volumes. RESULTS: Nineteen studies met our inclusion criteria; seventeen were retrospective and two were prospective; population samples ranged from 476 to 96,802 patients. The most important data, quantitatively and qualitatively, concern the evaluation of survival based on the average volume per center, with 8 out of 13 studies finding a statistically significant correlation between average volume per center and survival. Data on the quality of surgery are less abundant and more heterogeneous, depending on the definition of the "optimal" surgery by the authors. CONCLUSION: The establishment of threshold centers appears to be an effective way to improve survival in ovarian cancer. However, these thresholds would have to be specific to ovarian cancer and not extended to "gynecological cancers." PMID- 27238446 TI - Folate-/FAD-dependent tRNA methyltransferase from Thermus thermophilus regulates other modifications in tRNA at low temperatures. AB - TrmFO is a N(5) , N(10) -methylenetetrahydrofolate (CH2 THF)-/FAD-dependent tRNA methyltransferase, which synthesizes 5-methyluridine at position 54 (m(5) U54) in tRNA. Thermus thermophilus is an extreme-thermophilic eubacterium, which grows in a wide range of temperatures (50-83 degrees C). In T. thermophilus, modified nucleosides in tRNA and modification enzymes form a network, in which one modification regulates the degrees of other modifications and controls the flexibility of tRNA. To clarify the role of m(5) U54 and TrmFO in the network, we constructed the trmFO gene disruptant (?trmFO) strain of T. thermophilus. Although this strain did not show any growth retardation at 70 degrees C, it showed a slow-growth phenotype at 50 degrees C. Nucleoside analysis showed increase in 2'-O-methylguanosine at position 18 and decrease in N(1) methyladenosine at position 58 in the tRNA mixture from the ?trmFO strain at 50 degrees C. These in vivo results were reproduced by in vitro experiments with purified enzymes. Thus, we concluded that the m(5) U54 modification have effects on the other modifications in tRNA through the network at 50 degrees C. (35) S incorporations into proteins showed that the protein synthesis activity of ?trmFO strain was inferior to the wild-type strain at 50 degrees C, suggesting that the growth delay at 50 degrees C was caused by the inferior protein synthesis activity. PMID- 27238447 TI - The effect of MK-467, a peripheral alpha2 -adrenoceptor antagonist, on dexmedetomidine-induced sedation and bradycardia after intravenous administration in conscious cats. AB - OBJECTIVE: To determine a dose of MK-467, a peripheral alpha2 -adrenoceptor antagonist, which, when administered intravenously (IV) concomitantly with 25 MUg kg-1 of dexmedetomidine, will prevent bradycardia without altering sedation in cats. STUDY DESIGN: Prospective, randomized, controlled, blinded, experimental, crossover study. ANIMALS: Eight healthy, adult, purpose-bred cats. METHODS: Cats were administered seven IV treatments were administered at least 2 weeks apart, consisting of dexmedetomidine 12.5 MUg kg-1 (D12.5) and 25 MUg kg-1 (D25), MK-467 300 MUg kg-1 (M300), and D25 combined with 75, 150, 300 and 600 MUg kg-1 of MK 467 (D25M75, D25M150, D25M300 and D25M600, respectively). Heart rates (HR) were recorded via telemetry and sedation assessed with a simple descriptive score and a visual analogue scale prior to treatments and at intervals until 8 hours thereafter. RESULTS: Data from one cat were excluded because it developed renal failure. Heart rate decreased significantly from baseline after all treatments except M300 and D25M600. The lowest HR for each treatment with dexmedetomidine were 99 +/- 21 (D25), 103 +/- 22 (D12.5), 114 +/- 10 (D25M75), 117 +/- 17 (D25M150), 121 +/- 12 (D25M300) and 139 +/- 15 (D25M600) beats minute-1 . Sedation increased with all treatments that included dexmedetomidine, whereas M300 did not induce any central effects. In comparison with D25, the combination of MK-467 with dexmedetomidine reduced the duration of detectable sedation. CONCLUSIONS AND CLINICAL RELEVANCE: MK-467 dose-dependently attenuated the bradycardia associated with dexmedetomidine, and shortened the sedative effect without altering its quality. MK-467 may be useful in attenuating reductions in HR in conscious cats administered dexmedetomidine. PMID- 27238448 TI - Territorial shifts in clinical practice. AB - Junior doctors are frightened about the erosion of their role and the change of the power relationship between themselves and nurses, the 26th RCN A&E Nursing Association Annual Conference in Daresbury has been told. PMID- 27238449 TI - Colleague is mourned. AB - A&E stAff at the John Radcliffe Hospital in Oxford have been shocked by the untimely death of a colleague, following injuries sustained in a road traffic accident on 27 September. Tess Evans, who was 24, was described as 'enthusiastic and committed to critical care' by Elizabeth Bradbury, A&E SDU Manager. PMID- 27238451 TI - Information wanted. AB - Ian Llewellyn-Nash is investigating the use of pressure sore assessment tools on emergency medical units/admission wards. It would be a great help to hear from anyone using either the Waterlow or Braden score with regard to effectiveness. Contact Ian at the Emergency Medical Unit, Birmingham Heartlands Hospital, Bordesley Green East, Birmingham, B9 5SS. PMID- 27238450 TI - Consultancy pay for nurses. AB - Nurses working for NHS Direct could be paid at medical consultant level based on equal pay for equal work initiatives, according to Rob Crouch, Deputy Director and Research Fellow (A&E), Centre for the Advancement of Clinical Practice, University of Surrey. PMID- 27238452 TI - Remember, remember, firework safety. AB - A&E nurses at Blackburn Royal Infirmary talk to local youngsters to warn them about the dangers of being reckless with fireworks. Sister Alison Walmsley (left) and auxiliary Frances Walsh are pictured giving safety tips to ten-year-old Louise Greenwood at the hospital's awareness stand. PMID- 27238454 TI - Men's health a winner in poster competition. AB - The winner of the RCN A&E Nursing Association Health Promotion Poster competition is Piers Manser, a student nurse in Canterbury. PMID- 27238453 TI - Nursing unions blast 'appalling message'. AB - Nursing unions have blasted the decision not to take disciplinary action against a magistrate who told a nurse who had been assaulted 'the risk goes with the parish'. PMID- 27238455 TI - Many thanks. AB - Organising Committee members Gabby Lomas, Janet Lownie, and Di Rogers were thanked on behalf of the Conference for their hard work in ensuring everything went smoothly in what was the biggest A&E Conference ever. PMID- 27238456 TI - Ottawa ankle rules. AB - Nurse practitioners trained to use the Ottawa ankle rules are as effective as senior house officers in the implementation of the rules, a new study has found. PMID- 27238457 TI - Primary care in A&E. AB - The improvement of GP availability has been suggested as a factor influencing the rise in A&E attendance in the UK. PMID- 27238458 TI - Gene expression profiles in guided bone regeneration using combinations of different biomaterials: a pilot animal study. AB - OBJECTIVES: The aim of this study was to investigate the gene expression profile related to guided bone regeneration (GBR) at the early healing stage while using combinations of different biomaterials. MATERIALS AND METHODS: Cranial defects in 4 New Zealand rabbits were filled with A) biphasic calcium phosphate/experimental pericardium-derived collagen membrane, B) Bio-Oss(r) /Bio-Gide(r) , C) biphasic calcium phosphate/strontium hydroxyapatite-containing collagen membrane and D) Bio-Oss(r) /strontium hydroxyapatite-containing collagen membrane. Seven days after surgery, one animal was subjected to histological observation and histomorphometric analysis, and three animals to real-time quantitative reverse transcription polymerase chain reaction (PCR). An RT2 Profiler PCR Array (PANZ 026Z, QIAGEN, QIAGEN Sciences, Germantown, MD, USA) was conducted to observe the gene expression profile of groups A, C and D as compared with the control group B. RESULTS: The analysis showed 9 of the 84 genes on the array to be significantly different in the three experimental groups (six genes in group D, four in group C and one in group A). Group D demonstrated the most changes in gene expression profile at day 7. Genes that were significantly down-regulated (AHSG, EGF) or up-regulated (CDH11, MMP13, GLI1 and MCSF) are responsible for early-stage bone formation, bone remodeling and pre-osteoclast development. The gene expression profile of this group correlated with the histological findings, as this group showed the higher formation of osteoid as compared with the other groups. CONCLUSION: Gene expression patterns at early-stage healing of GBR treated defects appear to be related to the biomaterial used. The combination of Bio-Oss(r) and strontium hydroxyapatite-containing collagen membrane showed the most pro-osteogenic gene regulation profile (group D), implying the stimulation of key transcriptional factors, which appeared to translate into the up regulation of the osteogenic process and earlier bone formation. PMID- 27238459 TI - Spreading of genes encoding enterotoxins, haemolysins, adhesin and biofilm among methicillin resistant Staphylococcus aureus strains with staphylococcal cassette chromosome mec type IIIA isolated from burn patients. AB - The emergence of antibiotic-resistant Staphylococcus aureus in particular methicillin-resistant S. aureus (MRSA) is an important concern in burn medical centers either in Iran or worldwide. A total of 128 S. aureus isolates were collected from wound infection of burn patients during June 2013 to June 2014. Multiplex-polymerase chain reaction (MPCR) assay was performed for the characterization of the staphylococcal cassette chromosome mec (SCCmec). Genes encoding virulence factors and biofilm were targeted by PCR. Of 128 S. aureus isolates, 77 (60.1%) isolates were MRSA. Fifty four (70.1%) isolates were identified as SCCmec type IIIA. The most frequently detected toxin genes among MRSA isolates with SCCmec type IIIA were sea (64.1%) and hla (51.8%). The rate of coexistence of sea with hla and sea with hla and hlb was 37% and12.9%, respectively. The sec, eta, tst, pvl, hla and hlb genes were not detected in any of the MRSA isolates. The most prevalent genes encoding biofilm was eno, found in 61.1% of isolates, followed by fib and icaA found in 48.1% and 38.8% of the isolates, respectively. The rate of coexistence of fib + eno + icaA + icaD and fib + eno was 20.3% and 9.2%, respectively. The ebps gene was not detected in any of the isolates. In conclusion, our study indicated that the sea, hla, fib and icaA were most frequent genes encoding virulence factors among MRSA with SCCmec type IIIA isolated from burn wound infection. Moreover, the results of this study shows that the rate of coexistence of genes encoding different virulence factor were high. PMID- 27238460 TI - Clostridium difficile infection: Early history, diagnosis and molecular strain typing methods. AB - Recognised as the leading cause of nosocomial antibiotic-associated diarrhoea, the incidence of Clostridium difficile infection (CDI) remains high despite efforts to improve prevention and reduce the spread of the bacterium in healthcare settings. In the last decade, many studies have focused on the epidemiology and rapid diagnosis of CDI. In addition, different typing methods have been developed for epidemiological studies. This review explores the history of C. difficile and the current scope of the infection. The variety of available laboratory tests for CDI diagnosis and strain typing methods are also examined. PMID- 27238461 TI - Effect of Hydrodynamic Forces on meso-(4-Sulfonatophenyl)-Substituted Porphyrin J Aggregate Nanoparticles: Elasticity, Plasticity and Breaking. AB - The J aggregates of 4-sulfonatophenyl meso-substituted porphyrins are non covalent polymers obtained by self-assembly that form nanoparticles of different morphologies. In the case of high aspect-ratio nanoparticles (bilayered ribbons and monolayered nanotubes), shear hydrodynamic forces may modify their shape and size, as observed by peak force microscopy, transmission electron microscopy of frozen solutions, small-angle X-ray scattering measurements in a disk-plate rotational cell, and cone-plate rotational viscometry. These nanoparticles either show elastic or plastic behaviour: there is plasticity in the ribbons obtained upon nanotube collapse on solid/air interfaces and in viscous concentrated nanotube solutions, whereas elasticity occurs in the case of dilute nanotube solutions. Sonication and strong shear hydrodynamic forces lead to the breaking of the monolayered nanotubes into small particles, which then associate into large colloidal particles. PMID- 27238462 TI - Reversing gene expression in cardiovascular target organs following chronic depression of the paraventricular nucleus of hypothalamus and rostral ventrolateral medulla in spontaneous hypertensive rats. AB - BACKGROUND: Chronic overexpression of an inwardly rectifying potassium channel (hKir2.1) in the paraventricular nucleus of the hypothalamus (PVN) and in the rostral ventrolateral medulla (RVLM) to suppress neuronal excitability, resulted in a long term decrease of blood pressure and sympathetic output in spontaneously hypertensive rats (SHR). OBJECTIVE: Evaluate gene expression in end-organs of SHR after a chronic overexpression of hKir2.1 channels in either the PVN or RVLM. METHODS: mRNA levels of 16 genes known to be involved with blood pressure regulation were evaluated using RT-PCR in tissues from the heart, common carotid artery and kidney of SHR submitted to chronic depression of PVN and RVLM excitability using a lentiviral vector (LVhKir2.1). RESULTS: In SHR hearts in which either the PVN or RVLM were injected with LVhKir2.1, there was a downregulation of angiotensin II receptor 1b (AT1), ATPase, Ca(2+)-transporter, troponin T2 and tropomyosin2 (only in RVLM) relative to the sham group. In the kidney of SHR with LVhKir2.1 injections in PVN and RVLM, angiotensinogen, angiotensin II receptor2 (AT2) and endothelin1 were all upregulated compared to sham. In the carotid artery, endothelin2, endothelin receptor A and B were up regulated following LVhKir2.1 in to either the PVN or RVLM relative to sham. CONCLUSION: Chronic overexpression of hKir2.1 channels in PVN and RVLM, promoted a BP decrease with up-regulation of angiotensinogen and AT2 genes expression in the kidney and down-regulation of AT1 in the heart of SHR. Thus, we demonstrate the potential efficacy of central manipulation to protect against end-organ damage in essential hypertension. PMID- 27238463 TI - Electrophysiological correlates of the cognitive control processes underpinning mixing and switching costs. AB - Typically, in task-switching contexts individuals are slower and less accurate when repeating a task in mixed blocks compared to single-task blocks (mixing cost) and when switching to a new task compared to repeating a previous one (switch cost). Previous research has shown that distinct electrophysiological correlates underlie these two phenomena. However, this evidence is not a consistent result. The goal of this study was to better characterize differences between the control processes involved in mixing and switch costs. To this aim, we examined event-related potentials (ERPs) evoked during a cued task-switching experiment. In order to minimize the confounding effects of cognitive demands unrelated to task-switching, we asked participants to shift between two simple tasks (a letter identity task and a letter position task). The mixing cost was defined, in terms of ERPs, by contrasting repeat and single-task trials, whereas the ERP switch cost was obtained from the comparison of switch and repeat trials. Cue-locked ERPs showed that the mixing cost was mediated by two sustained components, an early posterior positivity and a late anterior negativity. On the other hand, the switch cost was associated with two early phasic positive components, one principally distributed over centro-parietal sites and the other located over left posterior sites. In target-locked ERPs the mixing cost was expressed by a frontal positivity, whereas the switch cost was expressed by a reduced parietal P3b. Overall, the results extend previous findings by providing elucidating ERP evidence on distinct proactive and reactive control processes involved in mixing and switch costs. PMID- 27238464 TI - Toward Applications for DNA Nanotechnology-More Bricks To Build With. AB - Another brick in the wall: DNA nanotechnology has come a long way since its initial beginnings. This would not be possible without the continued development of methods for DNA assembly and new uses for DNA as a material. This Special Issue highlights some of the newest building blocks for nanodevices based on DNA. PMID- 27238465 TI - Long-term outcome of early percutaneous coronary intervention in diabetic patients with acute coronary syndrome: insights from the BASE ACS trial. AB - BACKGROUND: The BASE ACS trial demonstrated an outcome of titanium-nitride-oxide coated bioactive stents (BAS) that was non-inferior to everolimus-eluting stents (EES) in patients with acute coronary syndrome (ACS). We performed a post-hoc analysis of diabetic versus non-diabetic patients from the trial. METHODS: We randomised 827 patients (1:1) with ACS to receive either BAS or EES. The primary endpoint was major adverse cardiac events (MACE): a composite of cardiac death, non-fatal myocardial infarction (MI) or ischaemia-driven target lesion revascularisation (TLR). Follow-up was planned yearly through 7 years. RESULTS: Of 827 patients, 140 (16.9%) were diabetic; of these, 36 (25.7%) were insulin treated. Mean follow-up duration was 4.2 +/- 1.9 years. MACE was more frequent in diabetics versus non-diabetics (23.6% versus 13.7%, respectively, p = 0.003), mainly driven by more frequent cardiac death (7.9% versus 2.2%, respectively, p = 0.002). The rates of non-fatal MI, ischaemia-driven TLR were comparable (p > 0.05 for all). In diabetic patients, MACE was comparable between the two stent arms (18.5% versus 28.0%, for BAS versus EES, respectively, p = 0.18). CONCLUSIONS: Diabetic patients treated with early percutaneous coronary intervention for ACS had worse long-term outcome, compared with non-diabetics, mainly driven by more frequent cardiac death. The long-term outcome of BAS was comparable to EES in diabetics. Key Messages Diabetic patients presenting with acute coronary syndrome who were treated with early percutaneous coronary intervention had worse long term clinical outcome, compared with non-diabetics, mainly driven by a high incidence of cardiac death. Age independently predicted both major adverse cardiac events and cardiac death in diabetic patients. The long-term clinical outcome of titanium-nitride-oxide-coated bioactive stents was comparable to that of everolimus-eluting stents in the diabetic, as well as in the non-diabetic subgroup. PMID- 27238467 TI - Rectal Cancer: The Radiation Oncologist: The Great Watchmaker. PMID- 27238466 TI - Exosomes mediate hepatitis B virus (HBV) transmission and NK-cell dysfunction. AB - Evidence suggests that exosomes can transfer genetic material between cells. However, their roles in hepatitis B virus (HBV) infection remain unclear. Here, we report that exosomes present in the sera of chronic hepatitis B (CHB) patients contained both HBV nucleic acids and HBV proteins, and transferred HBV to hepatocytes in an active manner. Notably, HBV nucleic acids were detected in natural killer (NK) cells from both CHB patients and healthy donors after exposure to HBV-positive exosomes. Through real-time fluorescence microscopy and flow cytometry, 1,1'-dioctadecyl-3,3,3',3',-tetramethylindodicarbocyanine, 4 chlorobenzenesulfnate salt (DiD)-labeled exosomes were observed to interact with NK cells and to be taken up by NK cells, which was enhanced by transforming growth factor-beta treatment. Furthermore, HBV-positive exosomes impaired NK-cell functions, including interferon (IFN)-gamma production, cytolytic activity, NK cell proliferation and survival, as well as the responsiveness of the cells to poly (I:C) stimulation. HBV infection suppressed the expression of pattern recognition receptors, especially retinoic acid inducible gene I (RIG-I), on NK cells, resulting in the dampening of the nuclear factor kappaB(NF-kappaB) and p38 mitogen-activated protein kinase pathways. Our results highlight a previously unappreciated role of exosomes in HBV transmission and NK-cell dysfunction during CHB infection. PMID- 27238468 TI - Timing of Therapies in the Multidisciplinary Treatment of Locally Advanced Rectal Cancer: Available Evidence and Implications for Routine Practice. AB - A multimodality disciplinary approach is paramount for the management of locally advanced rectal cancer. Over the last decade, (chemo)radiotherapy followed by surgery plus or minus adjuvant chemotherapy has represented the mainstay of treatment for this disease. Nevertheless, robust evidence suggesting the optimal timing and sequence of therapies in this setting has been overall limited. A number of questions are still unsolved including the length of the interval between neoadjuvant radiotherapy and surgery or the timing of systemic chemotherapy. Interestingly, emerging data support the contention that altering sequence or timing or both of the components of this multimodality approach may provide an opportunity to implement treatment strategies that far better address the risk and expectations of individual patients. In this article, we review the available evidence on timing of therapies in the multidisciplinary treatment of locally advanced rectal cancer and discuss the potential implications for routine practice that may derive from a change of the currently accepted treatment paradigm. PMID- 27238469 TI - Preoperative Treatment of Locally Advanced Rectal Cancer: Assets and Drawbacks of Short Course and Long Course in Clinical Practice. AB - Preoperative short-course radiotherapy and preoperative long-course chemoradiotherapy are the standards of care for high-risk rectal cancer in different parts of the world. Both treatments are effective in local control and carry a low morbidity. The advantage of short course is its simplicity, whereas long course has the advantage of downsizing tumors thus increasing the chance of sphincter preservation. Although 2 randomized trials comparing short course and long course have been performed, the better form of preoperative treatment remains a subject of discussion. This article reviews the evidence supporting each approach, and it discusses their relative merits and future directions. PMID- 27238470 TI - Magnetic Resonance Imaging and Other Imaging Modalities in Diagnostic and Tumor Response Evaluation. AB - Functional imaging is emerging as a valuable contributor to the clinical management of patients with rectal cancer. Techniques such as diffusion-weighted magnetic resonance imaging, perfusion imaging, and positron emission tomography can offer meaningful insights into tissue architecture, vascularity, and metabolism. Moreover, new techniques targeting other aspects of tumor biology are now being developed and studied. This study reviews the potential role of functional imaging for the diagnosis, treatment monitoring, and assessment of prognosis in patients with rectal cancer. PMID- 27238471 TI - Which Patients With Rectal Cancer Do Not Need Radiotherapy? AB - According to current guidelines, the standard treatment for locally advanced rectal cancer patients is preoperative (chemo)radiotherapy followed by total mesorectal excision surgery and adjuvant chemotherapy. Improvements in surgical techniques, imaging modalities, chemotherapy regimens, and radiotherapy delivery have reduced local recurrence rates to less than 10%. The current challenge in rectal cancer treatment lies in the prevention of distant metastases, which still occur in more than 25% of the patients. The decrease in local recurrence rates, the need for more effective systemic treatments, and the increased awareness of treatment-induced toxicity raise the question as to whether a more selective use of radiotherapy is advocated. PMID- 27238472 TI - Definitive Chemoradiotherapy ("Watch-and-Wait" Approach). AB - Preoperative chemoradiotherapy (CRT) followed by total mesorectal excision has been the standard of care for locally advanced patients with rectal cancer. Some patients achieve a pathologic complete response (pCR) to CRT and the oncologic outcomes are particularly favorable in this group. The role of surgery in patients with a pCR is now being questioned as radical rectal resection is associated with significant morbidity and long-term effects on quality of life. In an attempt to better tailor therapy, there is an interest in a "watch-and wait" approach in patients who have a clinical complete response (cCR) after CRT with the goal of omitting surgery and allowing for organ preservation. However, a cCR does not always indicate a pCR, and improved clinical and imaging modalities are needed to better predict which patients have achieved a pCR and therefore can safely undergo a "watch-and-wait" approach. This article reviews the current data on nonoperative management and on-going controversies associated with this approach. PMID- 27238474 TI - Advancing Techniques of Radiation Therapy for Rectal Cancer. AB - Since the advent of radiation therapy for rectal cancer, there has been continual investigation of advancing technologies and techniques that allow for improved dose conformality to target structures while limiting irradiation of surrounding normal tissue. For locally advanced disease, intensity modulated and proton beam radiation therapy both provide more highly conformal treatment volumes that reduce dose to organs at risk, though the clinical benefit in terms of toxicity reduction is unclear. For early stage disease, endorectal contact therapy and high-dose rate brachytherapy may be a definitive treatment option for patients who are poor operative candidates or those with low-lying tumors that desire sphincter-preservation. Finally, there has been growing evidence that supports stereotactic body radiotherapy as a safe and effective salvage treatment for the minority of patients that locally recur following trimodality therapy for locally advanced disease. This review addresses these topics that remain areas of active clinical investigation. PMID- 27238473 TI - Drug Combinations in Preoperative Chemoradiation for Rectal Cancer. AB - Preoperative radiotherapy has an accepted role in reducing the risk of local recurrence in locally advanced resectable rectal cancer, particularly when the circumferential resection margin is breached or threatened, according to magnetic resonance imaging. Fluoropyrimidine-based chemoradiation can obtain a significant down-sizing response and a curative resection can then be achieved. Approximately, 20% of the patients can also obtain a pathological complete response, which is associated with less local recurrences and increased survival. Patients who achieve a sustained complete clinical response may also avoid radical surgery. In unresectable or borderline resectable tumors, around 20% of the patients still fail to achieve a sufficient down-staging response with the current chemoradiation schedules. Hence, investigators have aspired to increase pathological complete response rates, aiming to improve curative resection rates, enhance survival, and potentially avoid mutilating surgery. However, adding additional cytotoxic or biological agents have not produced dramatic improvements in outcome and often led to excess surgical morbidity and higher levels of acute toxicity, which effects on compliance and in the global efficacy of chemoradiation. PMID- 27238475 TI - Irradiation of Very Locally Advanced and Recurrent Rectal Cancer. AB - Adjuvant therapy with chemoradiation or short-course radiation in addition to improvements in surgical technique has led to improved outcomes for patients with locally advanced rectal cancer. Local recurrence rates of less than 10% and 5 year survival rate of 60% or higher is expected. However, for patients with very locally advanced primary or locally recurrent disease in whom surgical resection is likely to be associated with incomplete resection, survival and disease control rates are poor and standard doses of adjuvant radiation or chemoradiation are relatively ineffective. Dose-escalation approaches with intraoperative radiation (IORT) have been explored in both the primary and recurrent setting. Although high-level evidence is lacking, available data suggest improvements in local and distant control leading to improved survival with IORT approaches. This review summarizes the evidence for dose-escalation approaches with IORT for patients with very locally advanced and recurrent rectal cancer. PMID- 27238476 TI - Toward Restored Bowel Health in Rectal Cancer Survivors. AB - As technology gets better and better, and as clinical research provides more and more knowledge, we can extend our ambition to cure patients from cancer with restored physical health among the survivors. This increased ambition requires attention to grade 1 toxicity that decreases quality of life. It forces us to document the details of grade 1 toxicity and improve our understanding of the mechanisms. Long-term toxicity scores, or adverse events as documented during clinical trials, may be regarded as symptoms or signs of underlying survivorship diseases. However, we lack a survivorship nosology for rectal cancer survivors. Primarily focusing on radiation-induced side effects, we highlight some important observations concerning late toxicity among rectal cancer survivors. With that and other data, we searched for a preliminary survivorship-disease nosology for rectal cancer survivors. We disentangled the following survivorship diseases among rectal cancer survivors: low anterior resection syndrome, radiation-induced anal sphincter dysfunction, gut wall inflammation and fibrosis, blood discharge, excessive gas discharge, excessive mucus discharge, constipation, bacterial overgrowth, and aberrant anatomical structures. The suggested survivorship nosology may form the basis for new instruments capturing long-term symptoms (patient-reported outcomes) and professional-reported signs. For some of the diseases, we can search for animal models. As an end result, the suggested survivorship nosology may accelerate our understanding on how to prevent, ameliorate, or eliminate manifestations of treatment-induced diseases among rectal cancer survivors. PMID- 27238477 TI - Electrospun fibrinogen-PLA nanofibres for vascular tissue engineering. AB - Here we report on the development of a new type of hybrid fibrinogen-polylactic acid (FBG-PLA) nanofibres (NFs) with improved stiffness, combining the good mechanical properties of PLA with the excellent cell recognition properties of native FBG. We were particularly interested in the dorsal and ventral cell response to the nanofibres' organization (random or aligned), using human umbilical endothelial cells (HUVECs) as a model system. Upon ventral contact with random NFs, the cells developed a stellate-like morphology with multiple projections. The well-developed focal adhesion complexes suggested a successful cellular interaction. However, time-lapse analysis shows significantly lowered cell movements, resulting in the cells traversing a relatively short distance in multiple directions. Conversely, an elongated cell shape and significantly increased cell mobility were observed in aligned NFs. To follow the dorsal cell response, artificial wounds were created on confluent cell layers previously grown on glass slides and covered with either random or aligned NFs. Time-lapse analysis showed significantly faster wound coverage (within 12 h) of HUVECs on aligned samples vs. almost absent directional migration on random ones. However, nitric oxide (NO) release shows that endothelial cells possess lowered functionality on aligned NFs compared to random ones, where significantly higher NO production was found. Collectively, our studies show that randomly organized NFs could support the endothelization of implants while aligned NFs would rather direct cell locomotion for guided neovascularization. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27238478 TI - Editorial. PMID- 27238479 TI - Editorial. PMID- 27238480 TI - Investigation of Dose-Dependent Factors Limiting Oral Bioavailability: Case Study With the PI3K-delta Inhibitor. AB - It is understood that a potential issue for drugs with poor aqueous solubility is low oral absorption. If oral exposure issues arise when working with a low solubility drug candidate, the common action is to rely on enabling formulations to solve the issue. However, this approach becomes troublesome in the pre clinical setting where compound absorption, distribution, metabolism, excretion properties are suboptimal and more factors limiting bioavailability may be at play. A narrow focus on solubility enhancement without a full understanding of compound absorption, distribution, metabolism, excretion properties can produce data that cloak the actual phenomena driving exposure. Compound 1 is a potent and selective PI3Kdelta inhibitor with poor aqueous solubility. In a pharmacokinetic study on dogs, exposure was found to be less than dose-linear. Besides the solubility, further investigations were conducted to identify other factors limiting oral exposure. It was observed that these limiting factors are dose dependent. Results from modeling pharmacokinetic under low-dose conditions suggest that exposure is significantly limited by metabolism and no exposure improvements should be expected from enabled formulations. Furthermore, enabling formulations are expected to exert a beneficial influence at higher doses. An in vivo test was conducted in dogs to verify this phenomenon. PMID- 27238482 TI - Hydrogen Peroxide Induced Protein Oxidation During Storage and Lyophilization Process. AB - Although the impact of hydrogen peroxide (HP) on proteins in liquid solutions has been studied extensively, the impact during lyophilization has been largely overlooked. The purpose of this work was to investigate the effect of HP on lyophilized proteins and HP removal by lyophilization. A protein formulation at 5 mg/mL and its placebo were spiked with HP up to 5.0 ppm and then lyophilized. HP concentration, protein oxidation, and aggregation were monitored before and after lyophilization, as well as during storage at 25 degrees C. The lyophilization process removed on average 94.1% of HP from protein formulation, but only 72.5% from the placebo. There were also significant increases in protein oxidization and aggregation. The oxidation increment correlated with the decrease of HP concentration in both the protein formulation and placebo at all temperatures. Protein oxidation at different freezing temperatures was also studied in follow up studies. Data from these studies suggest that (1) HP has a significant impact on oxidation and aggregation of protein during lyophilization; (2) significant oxidation can occur even when the protein formulation is frozen; (3) the oxidized protein is more prone to aggregation during lyophilization process. PMID- 27238481 TI - Mechanisms of Antigen Adsorption Onto an Aluminum-Hydroxide Adjuvant Evaluated by High-Throughput Screening. AB - The adsorption mechanism of antigen on aluminum adjuvant can affect antigen elution at the injection site and hence the immune response. Our aim was to evaluate adsorption onto aluminum hydroxide (AH) by ligand exchange and electrostatic interactions of model proteins and antigens, bovine serum albumin (BSA), beta-casein, ovalbumin (OVA), hepatitis B surface antigen, and tetanus toxin (TT). A high-throughput screening platform was developed to measure adsorption isotherms in the presence of electrolytes and ligand exchange by a fluorescence-spectroscopy method that detects the catalysis of 6,8-difluoro-4 methylumbelliferyl phosphate by free hydroxyl groups on AH. BSA adsorption depended on predominant electrostatic interactions. Ligand exchange contributes to the adsorption of beta-casein, OVA, hepatitis B surface antigen, and TT onto AH. Based on relative surface phosphophilicity and adsorption isotherms in the presence of phosphate and fluoride, the capacities of the proteins to interact with AH by ligand exchange followed the trend: OVA < beta-casein < BSA < TT. This could be explained by both the content of ligands available in the protein structure for ligand exchange and the antigen's molecular weight. The high throughput screening platform can be used to better understand the contributions of ligand exchange and electrostatic attractions governing the interactions between an antigen adsorbed onto aluminum-containing adjuvant. PMID- 27238483 TI - Comparison of Low-Molecular-Weight Heparins Prepared From Bovine Lung Heparin and Porcine Intestine Heparin. AB - Currently porcine intestine is the only approved source for producing pharmaceutical heparin in most countries. Enoxaparin, prepared by benzylation and alkaline depolymerization from porcine intestine heparin, is prevalent in the anticoagulant drug market. It is predicted that porcine intestine heparin-derived enoxaparin (PIE) will encounter shortage, and expanding its production from heparins obtained from other animal tissues may, therefore, be inevitable. Bovine lung heparin is a potential alternative source for producing enoxaparin. Critical processing parameters for producing bovine lung heparin-derived enoxaparin (BLE) are discussed. Three batches of BLEs were prepared and their detailed structures were compared with PIEs using modern analytical techniques, including disaccharide composition, intact chain mapping by liquid chromatography-mass spectrometry and 2-dimensional nuclear magnetic resonance spectroscopy. The results suggested that the differences between PIEs and BLEs mainly result from N acetylation differences derived from the parent heparins. In addition, bioactivities of BLEs were about 70% of PIEs based on anti-factor IIa and Xa chromogenic assays. We conclude that BLE has the potential to be developed as an analogue of PIE, although some challenges still remain. PMID- 27238484 TI - Protein Nitrogen Determination by Kjeldahl Digestion and Ion Chromatography. AB - We report development and validation of a simple, rapid, and accurate method for the quantitation of protein nitrogen, which combines Kjeldahl digestion and ion chromatography with suppressed conductivity detection and requires nanomolar amount of nitrogen in samples (>=10 MUg protein). The mechanism of suppressed conductivity detection does not permit analysis of samples containing copper (present in Kjeldahl digestion solution) and aluminum (present in many vaccines as adjuvants) due to precipitation of their hydroxides within the suppressor. We overcame this problem by including 10 MUM oxalic acid in Kjeldahl digests and in the eluent (30 mM methanesulfonic acid). The chromatography is performed using an IonPac CS-16 cation exchange column by isocratic elution. The method reduces the digestion time to less than 1 h and eliminates the distillation and titration steps of the Kjeldahl method, thereby reducing the analysis time significantly and improving precision and accuracy. To determine protein nitrogen in samples containing non-protein nitrogen, proteins are precipitated by a mixture of deoxycholate and trichloroacetic acid and the precipitates are analyzed after dissolving in KOH. The method is particularly useful for biological samples that are limited and can also be applied to food, environmental, and other materials. PMID- 27238485 TI - Survival of the Fittest: Time-To-Event Modeling of Crystallization of Amorphous Poorly Soluble Drugs. AB - The objective of this study was to gain a quantitative understanding of the link between physicochemical properties and long-term and time-censored amorphous stability of poorly water-soluble drugs using parametric time-to-event modeling. Previously published data on amorphous stability and physicochemical properties of 25 structurally diverse neutral, poorly soluble compounds were used. To describe the general shape of the survival curve (probability of event at time >t), Constant, Gompertz, and Weibull hazard functions and their linear combinations were tested. For a selected Weibull hazard base model, the effect of each physicochemical covariate was investigated, with combined influence of enthalpy of fusion (Hf) and molecular weight (Mr) showing the highest statistical significance. The covariate model was used to simulate survival curves and calculate the median survival time for different values of Hf and Mr. It was found that a decrease in Hf or an increase in Mr contribute to longer survival times. The derived model equation was validated against external data sets consisting of 11 compounds. It showed better predictive ability than a previously published multiple linear regression model incorporating Hf and Mr. The proposed Weibull covariate model may assist in faster and more cost-effective decision making in the pre-formulation phase of drug development, where compound properties and appropriate drug formulation strategies are investigated. PMID- 27238486 TI - Structure Elucidation of Poly-Faldaprevir: Polymer Backbone Solved Using Solid State and Solution Nuclear Magnetic Resonance Spectroscopy. AB - A large-scale synthesis of the hepatitis C virus drug Faldaprevir revealed precipitation of an unknown insoluble solid from methanol solutions of the drug substance. The unknown impurity was determined to be a polymer of Faldaprevir based on analytical methods that included size exclusion chromatography in combination with electrospray ionization mass spectrometry, solution nuclear magnetic resonance (NMR), matrix-assisted laser desorption ionization-time of flight, ultracentrifugation, elemental analysis, and sodium quantitation by atom absorption spectroscopy. Structure elucidation of the polymeric backbone was achieved using solid-state NMR cross-polarization/magic angle spinning (CP/MAS), cross polarization-polarization inversion, and heteronuclear correlation (HETCOR) experiments. The polymerization was found to occur at the vinyl cyclopropane via a likely free radical initiation mechanism. Full proton and carbon chemical shift assignments of the polymer were obtained using solution NMR spectroscopy. The polymer structure was corroborated with chemical synthesis of the polymer and solution NMR analysis. PMID- 27238487 TI - Thermodynamic Stability Analysis of Tolbutamide Polymorphs and Solubility in Organic Solvents. AB - Melting temperatures and enthalpies of fusion have been determined by differential scanning calorimetry (DSC) for 2 polymorphs of the drug tolbutamide: FI(H) and FV. Heat capacities have been determined by temperature-modulated DSC for 4 polymorphs: FI(L), FI(H), FII, FV, and for the supercooled melt. The enthalpy of fusion of FII at its melting point has been estimated from the enthalpy of transition of FII into FI(H) through a thermodynamic cycle. Calorimetric data have been used to derive a quantitative polymorphic stability relationship between these 4 polymorphs, showing that FII is the stable polymorph below approximately 333 K, above which temperature FI(H) is the stable form up to its melting point. The relative stability of FV is well below the other polymorphs. The previously reported kinetic reversibility of the transformation between FI(L) and FI(H) has been verified using in situ Raman spectroscopy. The solid-liquid solubility of FII has been gravimetrically determined in 5 pure organic solvents (methanol, 1-propanol, ethyl acetate, acetonitrile, and toluene) over the temperature range 278 to 323 K. The ideal solubility has been estimated from calorimetric data, and solution activity coefficients at saturation in the 5 solvents determined. All solutions show positive deviation from Raoult's law, and all van't Hoff plots of solubility data are nonlinear. The solubility in toluene is well below that observed in the other investigated solvents. Solubility data have been correlated and extrapolated to the melting point using a semiempirical regression model. PMID- 27238488 TI - Estimating the Aqueous Solubility of Pharmaceutical Hydrates. AB - Estimation of crystalline solute solubility is well documented throughout the literature. However, the anhydrous crystal form is typically considered with these models, which is not always the most stable crystal form in water. In this study, an equation which predicts the aqueous solubility of a hydrate is presented. This research attempts to extend the utility of the ideal solubility equation by incorporating desolvation energetics of the hydrated crystal. Similar to the ideal solubility equation, which accounts for the energetics of melting, this model approximates the energy of dehydration to the entropy of vaporization for water. Aqueous solubilities, dehydration and melting temperatures, and log P values were collected experimentally and from the literature. The data set includes different hydrate types and a range of log P values. Three models are evaluated, the most accurate model approximates the entropy of dehydration (DeltaSd) by the entropy of vaporization (DeltaSvap) for water, and utilizes onset dehydration and melting temperatures in combination with log P. With this model, the average absolute error for the prediction of solubility of 14 compounds was 0.32 log units. PMID- 27238490 TI - Toward Understanding Drug Release From Biodegradable Polymer Microspheres of Different Erosion Kinetics Modes. AB - Two generalized modes of erosion kinetics, that is, the power law mode and root type mode, respectively, were found to be able to better describe the reported weight loss data compared to the existing linear mode, for commonly used surface eroding polymer microspheres. Based on the newly identified modes, a set of drug release models were developed by extending the existing model. Model validation was achieved by comparing the model predictions to the reported experimental data for surface-eroding polymer microspheres (poly(ortho esters) and polyanhydrides), and good consistency was found. Parameter investigation was conducted to reveal the effects of various important parameters (the dimensionless ratio between diffusion and erosion rates (Er), the dimensionless ratio between erosion and dissolution rates (p), the dimensionless drug loading concentration (q), and the fitting parameter of erosion kinetics (a)) on drug release behavior, which has rarely been examined previously. In general, the effects of these parameters were more significant for an earlier stage, and p, q, and a could effectively vary the drug release percentage. Design-of-experiments-based sensitivity analysis was further carried out and it was found that the most sensitive parameters were p (2.97%) and q (2.97%) for the cases of the power law mode, while it was a ( 7.07%) for the cases of the root type mode. The information from the parameter investigation and sensitivity analysis could serve as a straightforward data bank for the practical designing of drug delivery processes. The proposed models are potential mathematical frameworks for the designing of drugs that are based on surface-eroding polymer microspheres in the future. PMID- 27238489 TI - Impact of Ice Morphology on Design Space of Pharmaceutical Freeze-Drying. AB - It has been known that the sublimation kinetics of a freeze-drying product is affected by its internal ice crystal microstructures. This article demonstrates the impact of the ice morphologies of a frozen formulation in a vial on the design space for the primary drying of a pharmaceutical freeze-drying process. Cross-sectional images of frozen sucrose-bovine serum albumin aqueous solutions were optically observed and digital pictures were acquired. Binary images were obtained from the optical data to extract the geometrical parameters (i.e., ice crystal size and tortuosity) that relate to the mass-transfer resistance of water vapor during the primary drying step. A mathematical model was used to simulate the primary drying kinetics and provided the design space for the process. The simulation results predicted that the geometrical parameters of frozen solutions significantly affect the design space, with large and less tortuous ice morphologies resulting in wide design spaces and vice versa. The optimal applicable drying conditions are influenced by the ice morphologies. Therefore, owing to the spatial distributions of the geometrical parameters of a product, the boundary curves of the design space are variable and could be tuned by controlling the ice morphologies. PMID- 27238491 TI - Theoretical Investigation of Dissolution Test Criteria for Waiver of Clinical Bioequivalence Study. AB - The purpose of the present study was to provide a theoretical basis for the dissolution test criteria of a biowaiver scheme. The critical dissolution number (Dncrit) was defined as a value to show bioequivalence of AUC and Cmax against infinitely rapid dissolution (Dn = infinity). The gastrointestinal tract was represented by the one-compartment model. The dissolution of a drug was expressed by the Noyes-Whitney equation. The permeation of a drug was expressed by the first-order equation. The approximate analytical solutions of Dncrit were derived from the analytical solution for the fraction of a dose absorbed [Fa = 1 - exp( 1/(1/Dn + Do/Pn)]; Do, the dose number; Pn, the permeation number). Numerical integration was also performed to calculate Dncrit more accurately. Dncrit was found to become smaller as Pn and Do became smaller. Dncrit for Cmax was found to be dependent on the elimination half-life of a drug as well as Pn and Do. The Fa equation can be an appropriate theoretical basis for a biowaiver scheme. PMID- 27238492 TI - Development of Novel Delivery System for Cardiovascular Drug Molsidomine: Influence of Synthesis Method and Conditions on Molsidomine Release From Its Composites With Hydrophilic Silica In Vitro. AB - Composites of cardiovascular drug molsidomine with silica materials (unmodified and mercaptopropyl modified) were prepared by 2 methods, adsorption and sol-gel technology. The effects of sol pH and release medium pH (1.6 and 7.4) as well as molsidomine loading on the drug release kinetics were also investigated. Mechanisms of molsidomine release from all the synthesized composites were elucidated. The obtained results showed that different principles of the composites formation (adsorption or sol-gel) lead to their different release behavior because the composites obtained by the indicated methods differ by distribution of the drug over the silica matrixes and their capability to degradation. The drug release from the composites prepared by adsorption is characterized by a high burst effect, sustained release up to 36 h irrespective of release medium pH. The release behavior of sol-gel composites depends on the amount of the loaded drug and release medium pH. These effects were explained by different stability of the sol-gel composites with high and low loading in acidic and neutral media. In general case, the ascertained effects are independent on chemistry of the silica surface organic groups. PMID- 27238493 TI - Enabling the Tablet Product Development of 5-Fluorocytosine by Conjugate Acid Base Cocrystals. AB - 5-Fluorocytosine (FC) is a high-dose antifungal drug that challenges the development of a tablet product due to poor solid-state stability and tabletability. Using 2 pharmaceutically acceptable conjugate acid base (CAB) cocrystals of FC with HCl and acesulfame, we have developed commercially viable high loading FC tablets. The tablets were prepared by direct compression using nano-coated microcrystalline cellulose Avicel PH105 as a tablet binder, which provided both excellent tabletability and good flowability. Commercial manufacturability of formulations based on both CAB cocrystals was verified on a compaction simulator. The results from an expedited friability study were used to set the compaction force, which yielded tablets with sufficient mechanical strength and rapid tablet disintegration. This work demonstrates the potential value of CAB cocrystals in drug product development. PMID- 27238494 TI - Determination of the Nip Angle in Roller Compactors With Serrated Rolls. AB - In roller compaction, the nip angle defines the critical transition interface between the slip and nip regions which is used to model material densification behavior and the properties of compacted ribbons. Current methods to determine the nip angle require either sophisticated instrumentation on smooth rolls or input parameters that are difficult to obtain experimentally. In this study, a practical method to determine nip angles for serrated rolls was developed based on mass balance considerations established around the nip region. Experimental input relating to roll geometry, powder density, and mass output from the compactor were required and they could be obtained reliably. The calculated nip angles were validated against those obtained from physical measurements during actual roll compaction. These nip angles were in agreement for various powder formulations containing plastic and brittle materials. The nip angles ranged from 4 degrees to 12 degrees and decreased significantly when the proportion of brittle material increased. Nip angles were also calculated using the widely used Johanson model. However, wall friction measurement on serrated roll surfaces could be impractical. The Johanson model-derived nip angles could differ by 3 degrees -8 degrees just by altering the roughness of the reference wall and this had compromised their reliability. PMID- 27238495 TI - Linking Suspension Nasal Spray Drug Deposition Patterns to Pharmacokinetic Profiles: A Proof-of-Concept Study Using Computational Fluid Dynamics. AB - The objective of this study was to link regional nasal spray deposition patterns of suspension formulations, predicted with computational fluid dynamics, to in vivo human pharmacokinetic plasma concentration profiles. This is accomplished through the use of computational fluid dynamics simulations coupled with compartmental pharmacokinetic modeling. Results showed a rapid initial rise in plasma concentration that is due to the absorption of drug particles deposited in the nasal middle passages, followed by a slower increase in plasma concentration that is governed by the transport of drug particles from the nasal vestibule to the middle passages. Although drug deposition locations in the nasal cavity had a significant effect on the shape of the concentration profile, the absolute bioavailability remained constant provided that all the drug remained in the nose over the course of the simulation. Loss of drug through the nostrils even after long periods resulted in a significant decrease in bioavailability and increased variability. The results of this study quantify how differences in nasal drug deposition affect transient plasma concentrations and overall bioavailability. These findings are potentially useful for establishing bioequivalence for nasal spray devices and reducing the burden of in vitro testing, pharmacodynamics, and clinical studies. PMID- 27238497 TI - Identification of novel microRNA genes in freshwater and marine ecotypes of the three-spined stickleback (Gasterosteus aculeatus). AB - The three-spined stickleback (Gasterosteus aculeatus L.) is an important model organism for studying the molecular mechanisms of speciation and adaptation to salinity. Despite increased interest to microRNA discovery and recent publication on microRNA prediction in the three-spined stickleback using bioinformatics approaches, there is still a lack of experimental support for these data. In this paper, high-throughput sequencing technology was applied to identify microRNA genes in gills of the three-spined stickleback. In total, 595 miRNA genes were discovered; half of them were predicted in previous computational studies and were confirmed here as microRNAs expressed in gill tissue. Moreover, 298 novel microRNA genes were identified. The presence of miRNA genes in selected 'divergence islands' was analysed and 10 miRNA genes were identified as not randomly located in 'divergence islands'. Regulatory regions of miRNA genes were found enriched with selective SNPs that may play a role in freshwater adaptation. PMID- 27238496 TI - Incidence and epidemiology of non-Hodgkin lymphoma and risk of second malignancy among 22 466 survivors in Israel with 30 years of follow-up. AB - Previous studies have shown an increase risk of second malignancies after non Hodgkin's lymphoma (NHL), which is probably related to a combination of factors including genetic predisposition, molecular background, host immunological status and therapy administered. Here, we determined the incidence of NHL and risk of second solid tumours and haematological malignancies among survivors of NHL diagnosed in Israel during 1980-2011. Data were collected from the records of the Israeli National Cancer Registry. The total cohort of 24 666 NHL-patients included 22 601 Jews and 2065 Arabs. Median age of diagnosis for Jews was 61.3 years and 48.2 for Arab patients. Of the Jews with NHL, 11 265 (50%) were of European-American origin, 5005 (22%) Asian or African and 6114 (27%) were born in Israel. Second cancers were recorded in 2010 NHL survivors, 1918 Jews and 92 Arabs, representing a rate of 8.5%, and 4.5% o, respectively. Second malignancies in all recorded sites were more frequent than in the general population, with a standardized incidence ratio (SIR) of 1.28 for Jewish men, 1.25 for Jewish women, 1.73 for Arab men and 1.98 for Arab women. This higher risk was even more pronounced for the 309 cases with secondary haematological malignancies (secondary haematological malignancies of 1.97, 1.81, 4.48 and 4.15, respectively). Our findings show that there is an increased risk of second malignancies occurring after diagnosis of NHL in Israel, particularly for haematological malignancies such as leukaemia and NHL. The differences we report in the incidence of NHL and the types of second malignancies occurring among Jews and Arabs suggest that ethnicity and genetic susceptibility may be important relevant risk factors. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27238499 TI - IgG4 orbital inflammatory pseudotumor associated to unilateral ethmoid and maxillary sinus aplasia. PMID- 27238500 TI - Solution structure of the lymphocyte receptor Nkrp1a reveals a distinct conformation of the long loop region as compared to in the crystal structure. AB - Mouse Nkrp1a receptor is a C-type lectin-like receptor expressed on the surface of natural killer cells that play an important role against virally infected and tumor cells. The recently solved crystal structure of Nkrp1a raises questions about a long loop region which was uniquely extended from the central region in the crystal. To understand the functional significance of the loop, the solution structure of Nkrp1a using nuclear magnetic resonance (NMR) spectroscopy was determined. A notable difference between the crystal and NMR structure of Nkrp1a appears in the conformation of the long loop region. While the extended loop points away from the central core and mediates formation of a domain swapped dimer in the crystal, the solution structure is monomeric with the loop tightly anchored to the central region. The findings described the first solution structure in the Nkrp1 family and revealed intriguing similarities and differences to the crystal structure. Proteins 2016; 84:1304-1311. (c) 2016 Wiley Periodicals, Inc. PMID- 27238498 TI - Elevated interleukin-27 levels in human neonatal macrophages regulate indoleamine dioxygenase in a STAT-1 and STAT-3-dependent manner. AB - Microbial infections are a major cause of infant mortality as a result of limitations in immune defences. Interleukin-27 (IL-27) is a heterodimeric cytokine produced primarily by leucocytes and is immunosuppressive toward lymphocytes and leucocytes. Our laboratory demonstrated that human neonatal macrophages express IL-27 more abundantly than adult macrophages. Similarly in mice, IL-27 expression is elevated early in life and maintained through infancy. To determine IL-27-regulated mechanisms that may limit immunity, we evaluated the expression of a number of genes in response to this cytokine in primary human neonatal macrophages. Indoleamine 2,3-dioxygenase (IDO) gene expression was increased dose-responsively by IL-27. We have previously demonstrated inhibition of T-cell proliferation and cytokine production by neonatal macrophage-generated IL-27, and IDO is often implicated in this negative regulation. An increase in IDO protein was demonstrated by immunofluorescence microscopy and was consistent with increased enzyme activity following treatment with IL-27. Inclusion of a soluble receptor to neutralize endogenous IL-27, decreased IDO expression and activity compared with untreated macrophages. In response to IL-27, neonatal macrophages phosphorylate signal transdcuer and activator of transcription 1 (STAT-1) and STAT-3. Both transcription factors are recruited to the IDO regulatory region. STAT-3 dominates during steady-state regulation by lower levels of endogenous IL-27 production. A shift to enhanced STAT-1 recruitment occurs during increased levels of exogenously supplied IL-27. These data suggest an interesting interplay of STAT-1 and STAT-3 to regulate IDO activity and immunosuppression in response to different levels of IL-27 in the microenvironment of the immune response that may further our understanding of this interesting cytokine. PMID- 27238501 TI - Does melatonin have a meaningful role as a sleep aid for jet lag recovery? PMID- 27238503 TI - Critical Care Care Plans Critical Care Care Plans Holloway NM Springhouse 338pp L16.95 0-87434-168-X. AB - Critical Care Care Plans, written as a guide for nurses working in high dependency areas, is obviously directed at North American nurses. This is very apparent as the terminology, abbreviations and some nursing actions are quite different from those used in the UK. PMID- 27238502 TI - The association of the severity of anorectal malformations and intestinal malrotation. AB - INTRODUCTION: Intestinal malrotation is a known association of anorectal malformations (ARM). Exact incidence, prognosis and surgical implications related to ARM are unknown. The aim of this study was to identify relevant associations between ARM and the presence of malrotation. METHODS: Records of patients from two referral centers were retrospectively analyzed looking for malrotation associated to ARM and its management, as well as factors for functional prognosis. RESULTS: 40 patients out of 2572 with ARM (1.6%) were found to have malrotation. Females were more commonly affected, and severe malformations were more frequent (cloaca, covered cloacal exstrophy in females and rectoprostatic and rectobladder neck fistula in males). Factors significantly associated with malrotation included Mullerian or Wolffian duct anomalies (P<0.05), while fecal continence status, presence of constipation, and use of laxatives or enemas were not. Detecting and correcting malrotation early on or at the time of colostomy creation represented a protective factor against additional surgeries for bowel obstruction and volvulus (P<0.001). Removal of the appendix during malrotation treatment required constructing a neoappendicostomy using a cecal flap in 9 out of 14 patients needing antegrade enema administration. CONCLUSIONS: Malrotation presence in patients with ARM has the same frequency as in the general population, but it is more common in severe malformations. Surgeons treating these patients should address the malrotation at the time of colostomy opening if detected. The appendix should be preserved for potential future use as an appendicostomy for antegrade administration of enemas. PMID- 27238505 TI - Nursing Care Plans, 2nd edition Nursing Care Plans, 2nd edition ME Doenges et al . F A Davies/Quest 964pp L21.97 0-8036-2661-4. AB - For nurses involved in planning patient care mainly in the acute sector, Nursing Care Plans comes as a standard reference. Many examples of care plans illustrate where nurses could improve on their approach to planning care, eg, a well-thought out discharge plan or the planning of learning and teaching with which so many of our patients with chronic ill health need to cope. PMID- 27238504 TI - Pediatric nursing JT Newman , and GR Scott L9-25 0-874340206-6. AB - Pediatric Nursing is designed as a 'quick dip' reference text for the student to augment previous study of paediatric nursing. PMID- 27238506 TI - Technological foundations in nursing Technological foundations in nursing JB Flynn R Hackel Appleton & Lange 1048pp L42.75 0-8385-8840-9. AB - Despite its massive size, Technological Foundations in Nursing is a most appropriate reference work for the current RGN educational programmes, certificated or accredited. The text is distinctly presented, well-supported by line drawings and photographs. The style has a clear, logical pattern, and the sequence of material readily matches a nursing curriculum. PMID- 27238508 TI - Comfort for carers. AB - The 'forgotten army' of carers looking after dependants at home is forgotten no more. Last week saw the publication of a report by the Social Services Committee ( 1 ) which, for once, goes beyond lip-service. For years, organisations representing the interests of so-called 'informal' carers have been pressing for more support, financial help and recognition for the estimated six million people who take on an open-ended commitment to care. PMID- 27238509 TI - Health Psychology N Niven Churchill Livingstone 380pp L8.95 0-443-03665-9. AB - Health Psychology is concerned with developing preventive programmes of health care, improving the quality of life and helping individuals to cope with everyday strains and stresses, and adapting to life crises. PMID- 27238510 TI - Handbook of Clinical Teaching Handbook of Clinical Teaching Watts N T Churchill Livingstone 276pp L14.95 0-443-03604-7. AB - Nancy Watts's flexible approach to the subject of teaching in the clinical setting makes her book suitable for anyone involved in teaching students, trained staff or patients and their relatives. It may be used for teaching on a one-to one basis or for groups. PMID- 27238511 TI - From Ward to X-Ray R Moshy C Phillips Austen Cornish 120pp L15 1-870065-09-3. AB - From Ward to X-Ray gives an important reference point for all nurses whose patients arc undergoing radiological investigations and is ideal for ward use and nurses in training. PMID- 27238512 TI - MPs urge nursing support for carers. AB - MPs called for a massive community nursing boost last week to support the army of informal carers looking after relatives at home. PMID- 27238513 TI - Overhaul could spell end of nurse leaders. AB - A management overhaul at a psychiatric hospital in Surrey could end nurse management above ward sister level. PMID- 27238514 TI - [Not Available]. AB - Green grin: staff nurse Lorna Gibbons (above) lues helped organise Strathcona Ward at the Middlesex Hospital into a green area'. Nurses and patients have joined the pressure group Friends of the Earth and are recycling paper and glass. PMID- 27238516 TI - Pay awards lead to ambulance withdrawal. AB - Elderly people in the West Midlands have been forced to cancel out-patient appointments after their health authority withdrew all but emergency hospital transport. PMID- 27238517 TI - 'Lives at risk' as number of tests falls significantly. AB - Labour health spokesman Robin Cook sparked a statistics war last week after claiming that the Government's eye test charge introduction is risking lives. PMID- 27238518 TI - Training faces cuts to balance books. AB - Student midwife training and staff HIV protection face reduction in a district's list of budget-balancing measures, Exeter Health Authority announced last week. PMID- 27238519 TI - Nursing Research: Methods, Critical Appraisal, and Utilization, 2nd edition G LoBiondo-Wood J Haber C V Mosby 470pp L24.50 0-8016-3269-2. AB - Nursing Research is a spacious text, heavy to hold but full of variety to the eye. The 11 contributors are all academic nurses in the USA. It is designed as 'an undergraduate textbook to systematically present the perspective of the nurse as a consumer of research', but also for nurses seeking to expand their knowledge. The editors assume that readers will have little experience of research or statistics. PMID- 27238520 TI - Nursing research Nursing research B S Thomas C V Mosby 320pp L21.50 0-8016-6061 0. AB - The steady development and growth of nursing research over recent years has produced the need for comprehensive textbooks such as Barbara Thomas's book. Most aspects of the research process are covered in depth and the book's main strength is the measured use of the problem-solving approach. She aims to involve readers actively in the experience of learning, understanding and then, subsequently, carrying out their own research. PMID- 27238521 TI - Interaction Strategies Interaction Strategies Porritt L Churchill Livingstone 178pp L7.50 0-443-04214-4. AB - Interaction Strategies is a book that practises what it preaches. After clearly stating in her introduction that 'There is often a gap between acknowledging the importance of communication and being an effective communicator' the author proceeds to remedy this situation by acknowledging, in some detail, the importance of communication and outlining, with clarity and precision, an abundance of ideas on how to overcome this theory/practice divide. PMID- 27238522 TI - Finance-led policies a 'disaster' for services. AB - Rehabilitation services are being decimated by a health care policy that is finance-led, a community nursing professor warned last week. PMID- 27238523 TI - Urgent programme needed to draw up plan. AB - Nurses are backing a call for action on accident prevention to be given a higher priority by the NHS. PMID- 27238524 TI - Accountability and audit vital to new Strategy. AB - Enhancing nurses' personal accountability for their practice is one of the key objectives in Scotland's Strategy for nursing, published by the Home and Health Department. PMID- 27238525 TI - Research needed to prove patient care underfunding. AB - Private nursing home nurses must produce research to prove how the Government is grossly underfunding their patient care, a former nurse educationalist has urged. PMID- 27238526 TI - Cancer nurse leaders must take risks'. AB - Nurse leaders will need to change dramatically if nursing is to be assured a voice in the increasingly complex health care system of tomorrow, cancer nurses were warned recently. PMID- 27238528 TI - Rivalries may cause case management problems. AB - Inter-professional rivalries, the absence of flexible service alternatives in many places and the cost of improving assessment procedures are major problems ahead for case management under the White Paper 'Caring for people'. PMID- 27238527 TI - [Not Available]. AB - Light work: Delia Hudson, Executive Director of the National Association of Quality Assurance, recently became 'Dame of the Order of the Guardian of the Light', an award from the World Health Organization (WHO) and the International Society of Quality Assurance. A former chief nurse of Gwent Health Authority, Mrs Hudson is the first UK recipient of the award initiated in 1984 for achievement in quality assurance. She was presented with the award by Dr Hannu Vuori of the WHO. PMID- 27238530 TI - Parliament. AB - Health Minister Virginia Bottomley is considering calls for urgent action to prevent Romanian babies being imported to Britain for cash. PMID- 27238531 TI - World news. AB - United States America's nursing shortage is being eased by better wages, better working conditions and the increased use of 'licensed practical nurses', a report in the New York Times claims. PMID- 27238532 TI - New blood test detects defective fetal genes. AB - A simpler test to reveal inherited disorders in unborn babies has been hailed as 'a fantastic breakthrough' by midwives. PMID- 27238533 TI - Nurses wary of opting for chemotherapy. AB - Four times more cancer patients than nurses would accept radically traumatic drug treatment with a one per cent success rate, new research has found. PMID- 27238534 TI - Chiropractic wins over conventional treatment. AB - Doctors have called for the alternative back therapy, chiropractic, to be introduced into the National Health Service, after a trial showed significant benefits over conventional outpatient treatment. PMID- 27238535 TI - Preventive asthma training launched. AB - A new asthma training programme for practice nurses has been launched by the Asthma Training Centre. PMID- 27238536 TI - Against all the odds. AB - A four-year-old child was admitted to a hospital in Bucharest; her father had stabbed her six times with a carving knife. Her tongue was cut out and she had cigarette burns all over her body. Only 24 hours earlier, this child was one of the thousands of children in Romania's orphanages, which, contrary to their title, do not only house orphans but, for the most part, children whose parents cannot afford to feed and keep them. PMID- 27238537 TI - Spring of discontent. AB - These are not easy times for the new Chief Executive of the English National Board (ENB) as he surveys the implementation of his radical restructuring of staff. PMID- 27238538 TI - NUPE drive to enrol converts? AB - I am writing in response to NUPE officer Len Bevan's call for automatic enrolled nurse conversion after three years' service (Nursing Standard May 30 - June 5). PMID- 27238540 TI - Runner up run down. AB - Oh, the irony of it all! Today I heard that I had won a runner's-up prize in the Glaxo/Nursing Standard/ RCN Cancer Nursing Society 1990 Student Essay Awards. Two days ago, I heard that I had failed my finals. You have got to laugh or you would cry - the L100-worth of nursing books will no doubt come in useful. PMID- 27238539 TI - Action needed not words. AB - Like Veronica Seddon in her letter in Nursing Standard May 16 - 22, I also read with interest Trevor Lee's proposals for more flexible approaches to enrolled nurse conversion. PMID- 27238541 TI - New light on the Royal Herbert. AB - Michael Wilson What a pity that Sylvia Turtle's excellent feature on the Royal Herbert Hospital, Woolwich (Nursing Standard April 18 - 25), only depicted the hospital in an early drawing and as an empty, cold mausoleum in subsequent photographs. PMID- 27238542 TI - Environmental exploration. AB - In Nursing Standard May 2-8 you featured some stunning photographs by Jeremy Webb of our expedition nurse Liz Burns in the Matumbi Hills, Tanzania. As the caption says, the project was initiated and co-ordinated by the newly-founded Society for Environmental Exploration. PMID- 27238543 TI - Information exchange. AB - I am a district nurse- student, working in West Essex Health Authority. PMID- 27238546 TI - An aspect of fear An aspect of fear Sheppard G Darton 112pp L5.95 0-232-51828-9. AB - The effects of agoraphobia are movingly illustrated by Grace Sheppard, the wife of the Bishop of Liverpool. She pulls no punches in sharing her experiences. Though she made much progress in her attempts to overcome the fear of leaving the security of her own home she still faces difficulties. PMID- 27238547 TI - Cutaneous spindle cell adenolipoma with a neural component: Potential evidence for a hamartomatous nature. PMID- 27238548 TI - Does age difference really matter? Facial markers of biological quality and age difference between husband and wife. AB - Information conveyed by facial attractiveness markers such as averageness, bilateral symmetry, and secondary sexual characteristics may play an important adaptive role in human sexual selection. Nonetheless, mate choice also relies on other non-physical characteristics such as, for instance, an individual's age. Women prefer and enter in relationships with older partners, whereas in men the inverse relation is observed. Surprisingly, the link between facial morphological markers of biological quality on the one hand and age disparity between partners on the other hand has been as yet subject of very little research. This study aims to fill this gap. We had used facial photographs and demographic data of heterosexual marriages. Facial cues of biological quality, such as averageness, bilateral symmetry, and sexual dimorphism, were digitally measured using geometric morphometric methods and then associated with spouses' age difference. It turned out that a greater age disparity between spouses correlates, in both partners, with higher scores in facial measures which indicate partners' biological quality. One exception is female facial masculinity - generally regarded as an unattractive marker of a low biological quality - which, too, is associated with higher spouse age disparity. In general, our results show that facial symmetry, averageness, and secondary sexual characteristics may play a role in age-dependent mate choice. We suggest that in marriages where the wife is considerably younger than the husband, wife's greater facial masculinity may increase her perceived age and with it, her perceived maturity. PMID- 27238549 TI - Impaired airway epithelial cell responses from children with asthma to rhinoviral infection. AB - BACKGROUND: The airway epithelium forms an effective immune and physical barrier that is essential for protecting the lung from potentially harmful inhaled stimuli including viruses. Human rhinovirus (HRV) infection is a known trigger of asthma exacerbations, although the mechanism by which this occurs is not fully understood. OBJECTIVE: To explore the relationship between apoptotic, innate immune and inflammatory responses to HRV infection in airway epithelial cells (AECs) obtained from children with asthma and non-asthmatic controls. In addition, to test the hypothesis that aberrant repair of epithelium from asthmatics is further dysregulated by HRV infection. METHODS: Airway epithelial brushings were obtained from 39 asthmatic and 36 non-asthmatic children. Primary cultures were established and exposed to HRV1b and HRV14. Virus receptor number, virus replication and progeny release were determined. Epithelial cell apoptosis, IFN-beta production, inflammatory cytokine release and epithelial wound repair and proliferation were also measured. RESULTS: Virus proliferation and release was greater in airway epithelial cells from asthmatics but this was not related to the number of virus receptors. In epithelial cells from asthmatic children, virus infection dampened apoptosis, reduced IFN-beta production and increased inflammatory cytokine production. HRV1b infection also inhibited wound repair capacity of epithelial cells isolated from non-asthmatic children and exaggerated the defective repair response seen in epithelial cells from asthmatics. Addition of IFN-beta restored apoptosis, suppressed virus replication and improved repair of airway epithelial cells from asthmatics but did not reduce inflammatory cytokine production. CONCLUSIONS: Collectively, HRV infection delays repair and inhibits apoptotic processes in epithelial cells from non-asthmatic and asthmatic children. The delayed repair is further exaggerated in cells from asthmatic children and is only partially reversed by exogenous IFN-beta. PMID- 27238550 TI - Perceived communicative intent in gesture and language modulates the superior temporal sulcus. AB - Behavioral evidence and theory suggest gesture and language processing may be part of a shared cognitive system for communication. While much research demonstrates both gesture and language recruit regions along perisylvian cortex, relatively less work has tested functional segregation within these regions on an individual level. Additionally, while most work has focused on a shared semantic network, less has examined shared regions for processing communicative intent. To address these questions, functional and structural MRI data were collected from 24 adult participants while viewing videos of an experimenter producing communicative, Participant-Directed Gestures (PDG) (e.g., "Hello, come here"), noncommunicative Self-adaptor Gestures (SG) (e.g., smoothing hair), and three written text conditions: (1) Participant-Directed Sentences (PDS), matched in content to PDG, (2) Third-person Sentences (3PS), describing a character's actions from a third-person perspective, and (3) meaningless sentences, Jabberwocky (JW). Surface-based conjunction and individual functional region of interest analyses identified shared neural activation between gesture (PDGvsSG) and language processing using two different language contrasts. Conjunction analyses of gesture (PDGvsSG) and Third-person Sentences versus Jabberwocky revealed overlap within left anterior and posterior superior temporal sulcus (STS). Conjunction analyses of gesture and Participant-Directed Sentences to Third-person Sentences revealed regions sensitive to communicative intent, including the left middle and posterior STS and left inferior frontal gyrus. Further, parametric modulation using participants' ratings of stimuli revealed sensitivity of left posterior STS to individual perceptions of communicative intent in gesture. These data highlight an important role of the STS in processing participant-directed communicative intent through gesture and language. Hum Brain Mapp 37:3444-3461, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27238551 TI - Amyotrophic lateral sclerosis: a comparison of two staging systems in a population-based study. AB - BACKGROUND AND PURPOSE: To compare two recently developed staging systems for amyotrophic lateral sclerosis (ALS) [King's College and Milano-Torino staging (MITOS) systems] in an incident, population-based cohort of patients with ALS. METHODS: Since 2009, a prospective registry has been recording all incident cases of ALS in the Emilia Romagna region in Italy. For each patient, detailed clinical information, including the ALS functional rating scale score, is collected at each follow-up. RESULTS: Our study on 545 incident cases confirmed that King's College stages occurred at predictable times and were quite evenly spaced out throughout the disease course (occurring at approximately 40%, 60% and 80% of the disease course), whereas MITOS stages were mostly skewed towards later phases of the disease. In the King's College system there was a decrease in survival and an increase in deaths with escalating stages, whereas in the MITOS system survival curves pertaining to intermediate stages overlapped and the number of deaths was fairly homogenous throughout most stages. CONCLUSIONS: The King's College staging system had a higher homogeneity (i.e. smaller differences in survival among patients in the same stage) and a higher discriminatory ability (i.e. greater differences in survival among patients in different stages), being more suitable for individualized prognosis and for measuring efficacy of therapeutic interventions. PMID- 27238552 TI - Association between Dietary Intake and Bone Mineral Density in Japanese Postmenopausal Women: The Yokogoshi Cohort Study. AB - Diet and food intake play an important role in the development of osteoporosis. However, apart from calcium and vitamin D, how nutrients affect bone status is not fully understood. The purpose of this study was to determine cross-sectional and longitudinal associations between dietary intake and bone mineral density (BMD) in Japanese postmenopausal women. This 5-year cohort study included 600 community-dwelling women aged 55-74 years at baseline in 2005. Information on demographics, nutrition, and lifestyle was obtained through interviews, and nutritional and dietary intake was assessed using a validated food frequency questionnaire. BMD measurements were performed by dual energy X-ray absorptiometry. In 2010, 498 women underwent follow-up BMD examinations. Multiple linear regression analysis was performed to determine associations of predictor variables with BMD, adjusting for confounders. In cross-sectional analyses, coffee or black tea consumption was positively associated with lumbar spine (P = 0.004) and total hip (P = 0.003) BMD, and alcohol intake was positively associated with femoral neck (P = 0.005) and total hip (P = 0.001) BMD. In longitudinal analyses, vitamin K (P = 0.028) and natto (fermented soybeans) (P = 0.023) were positively associated with lumbar spine BMD, and meat or meat product consumption was inversely associated with total hip (P = 0.047) BMD. In conclusion, dietary factors other than calcium and vitamin D intake are predictors of bone mass and bone loss in Japanese postmenopausal women. In particular, natto intake is recommended for preventing postmenopausal bone loss on the basis of current evidence. PMID- 27238553 TI - Early Patient Access to Medicines: Health Technology Assessment Bodies Need to Catch Up with New Marketing Authorization Methods. AB - National and international medicines agencies have developed innovative methods to expedite promising new medicines to the market and facilitate early patient access. Some of these approval pathways are the conditional approval and the adaptive pathways by the European Medicines Agency (EMA); the Promising Innovative Medicine (PIM) designation and the Early Access to Medicines Scheme (EAMS) by the Medicines and Healthcare Products Regulatory Agency (MHRA), as well as the Fast Track, Breakthrough or Accelerated Approval methods by the Food and Drug Administration (FDA). However, at least in Europe, these methods cannot achieve the goal of improving timely access for patients to new medicines on their own; the reimbursement process also has to become adaptive and flexible. In the past 2 years, the effective access (national patient access) to newly approved oncology drugs ranged from 1 to 30 months, with an extremely high variability between European countries. The goal of early patient access in Europe can only be achieved if the national health technology assessment bodies, such as NICE (ENG), HAS (FR), G-BA (DE) or AIFA (IT), provide harmonized, transparent, flexible, conditional and adaptive methods that adopt the level of evidence accepted by the medicines agencies. The efforts from medicines agencies are welcome but will be in vain if health technology assessments do not follow with similar initiatives, and the European 'postcode' lottery will continue. PMID- 27238554 TI - Energy balance and macronutrient distribution in relation to C-reactive protein and HbA1c levels among patients with type 2 diabetes. AB - BACKGROUND: Recently growing evidence indicates that obesity and diabetes are states of inflammation associated with elevated circulation of inflammatory mediators. Excess adiposity and oxidative stress, induced by feeding, may also lead to a state of low-grade inflammation. OBJECTIVE: This study aimed at investigating energy balance and distribution in relation to low-grade inflammation among patients with type 2 diabetes. DESIGN: A cross-sectional study included 198 male and female patients with type 2 diabetes. Patients' weight, height, waist circumference, total body fat and truncal fat percent, energy, and macronutrient intake were measured. Venous blood specimens were collected, and levels of HbA1c and serum levels of high-sensitivity C-reactive protein (hs-CRP) were determined. RESULTS: After adjusting for covariates (body mass index, total body fat, and truncal fat), energy balance was positively correlated with hs-CRP and HbA1c. A positive energy balance was also associated with increased waist circumference and truncal fat percent (p<0.05). Total energy intake, percent energy from fat (p=0.04), and percent energy from proteins (p=0.03), but not percent energy from carbohydrates (p=0.12), were also correlated with higher hs CRP levels among poorly glycemic-controlled patients. CONCLUSION: Positive energy balance is associated with elevations in hs-CRP. Increased energy intake and increased percentages of energy from fat and protein are associated with elevated hs-CRP among patients with poor glycemic control. PMID- 27238556 TI - An MLSA approach for the taxonomic update of the Splendidus clade, a lineage containing several fish and shellfish pathogenic Vibrio spp. AB - A multilocus sequence analysis was undertaken in order to redefine the Splendidus clade of the genus Vibrio, a large group of species containing several pathogenic members that affect fish and shellfish, and are difficult to identify through both phenotypic and genotypic approaches. The study included analysis of partial sequences of recA, gyrB, mreB, rpoD and pyrH genes, as well as the 16S rRNA gene. Seventeen type strain species were included that were complemented with other reference strains and a collection of isolates tentatively identified as members of this clade, as well as a set of other Vibrio species. The clade was well defined and stable in all analyses, and was confirmed to contain V. celticus, V. atlanticus, V. artabrorum, V. toranzoniae and V. hemicentroti, in addition to the twelve previously recognized species. While some species were well-defined members (e.g. Vibrio cyclitrophicus, V. chagasii) others formed tight groups that were related by sequence similarities and lineage topology, which suggested a synonymy among their members, particularly the V. splendidus-V. hemicentroti pair. Most of the isolates were related to two major groups: the V. celticus-V. crassostreae-V. gigantis subclade that contained all isolates from oysters sampled in the cold season, and V. chagasii that included oyster isolates from warm months. This suggested a sharp seasonal occurrence for these species. None of the single genes were able to mimic the resolving power of the five-gene MLSA and none worked well for the identification of the whole group of species in the clade. PMID- 27238555 TI - Nutritional and developmental status among 6- to 8-month-old children in southwestern Uganda: a cross-sectional study. AB - BACKGROUND: Undernutrition continues to pose challenges to Uganda's children, but there is limited knowledge on its association with physical and intellectual development. OBJECTIVE: In this cross-sectional study, we assessed the nutritional status and milestone development of 6- to 8-month-old children and associated factors in two districts of southwestern Uganda. DESIGN: Five hundred and twelve households with mother-infant (6-8 months) pairs were randomly sampled. Data about background variables (e.g. household characteristics, poverty likelihood, and child dietary diversity scores (CDDS)) were collected using questionnaires. Bayley Scales of Infant and Toddler Development (BSID III) and Ages and Stages questionnaires (ASQ) were used to collect data on child development. Anthropometric measures were used to determine z-scores for weight for-age (WAZ), length-for-age (LAZ), weight-for-length (WLZ), head circumference (HCZ), and mid-upper arm circumference. Chi-square tests, correlation coefficients, and linear regression analyses were used to relate background variables, nutritional status indicators, and infant development. RESULTS: The prevalence of underweight, stunting, and wasting was 12.1, 24.6, and 4.7%, respectively. Household head education, gender, sanitation, household size, maternal age and education, birth order, poverty likelihood, and CDDS were associated (p<0.05) with WAZ, LAZ, and WLZ. Regression analysis showed that gender, sanitation, CDDS, and likelihood to be below the poverty line were predictors (p<0.05) of undernutrition. BSID III indicated development delay of 1.3% in cognitive and language, and 1.6% in motor development. The ASQ indicated delayed development of 24, 9.1, 25.2, 12.2, and 15.1% in communication, fine motor, gross motor, problem solving, and personal social ability, respectively. All nutritional status indicators except HCZ were positively and significantly associated with development domains. WAZ was the main predictor for all development domains. CONCLUSION: Undernutrition among infants living in impoverished rural Uganda was associated with household sanitation, poverty, and low dietary diversity. Development domains were positively and significantly associated with nutritional status. Nutritional interventions might add value to improvement of child growth and development. PMID- 27238557 TI - Transdentinal photobiostimulation of stem cells from human exfoliated primary teeth. AB - AIM: To evaluate the effects of infrared light-emitting diode (LED) irradiation on stem cells from human exfoliated deciduous teeth (SHEDs). METHODOLOGY: Exfoliated primary teeth were obtained (n = 3), and SHEDs obtained from the teeth were seeded on the pulpal surface of 0.2-mm-thick dentine discs produced from permanent molars. The cells were incubated for 24 h by placing the discs in plain Dulbecco's modified Eagle's medium (DMEM). The DMEM was then replaced with new culture medium formulated for odontoblast differentiation. After 12 h in the second medium, SHEDs were irradiated through the dentine discs using an infrared LED (850 nm) with a power density of 80 mW cm-2 . Energy doses (EDs) delivered to the occlusal surface of the dentine discs were 0 (control), 2 and 4 J cm-2 (n = 6). Subsequent tests were performed 72 h after irradiation. These tests included cell viability (MTT), alkaline phosphatase activity (ALP), total protein production (TP), scanning electron microscopy (SEM), as well as gene expression for ALP, Col I, DSPP and DMP-1. Data were analysed using Kruskal-Wallis and Mann Whitney t-tests (alpha = 0.05). RESULTS: Both EDs (2 and 4 J cm-2 ) significantly increased cell viability and ALP activity. For TP, ALP and Col I gene expression, only the 4 J cm-2 group had significantly higher values compared to the control group. Cell morphology was not affected by irradiation. CONCLUSION: Infrared LED irradiation was capable of biostimulating SHEDs through a 0.2 mm thickness of dentine, especially at the 4 J cm-2 level. PMID- 27238558 TI - Reply. PMID- 27238559 TI - The impact of kiddy dentures on maxillary arch growth. AB - BACKGROUND: Kiddy dentures are used to restore the self-confidence, chewing function, and pronunciation of children or when a care provider is concerned about the loss of incisor teeth. However, most studies to date have investigated normal dental arch development, and only a few have explored the effect of kiddy dentures on upper arch development. METHODS: Fourteen Taiwanese children (7 male and 7 female) who were wearing kiddy dentures due to the loss of their upper anterior teeth were enrolled in this study. Inclusion criteria were the premature loss of maxillary incisors, the patient wearing kiddy dentures with both upper primary first molars as abutments, and the patient having complete records allowing a full longitudinal clinical follow-up. Dental casts were obtained immediately (T1), at 6 months (T2), and at 12 months (T3) after delivery of the kiddy dentures. The measured parameters included intercanine width (ICW, C1 to C2), interfirst molar width (IDW, D1 to D2), and intersecond molar width (IEW, E1 to E2). All the measurements were performed by one experienced examiner using a vernier caliper. RESULTS: The mean ages of the enrolled children for the periods T1, T2, and T3 were 43.8 +/- 8.3 months, 50.6 +/- 8.5 months, and 56.7 +/- 8.4 months, respectively. There was no significant difference in gender when ICW, IDW, and IEW were compared. The mean changes in ICW values were 23.6 +/- 6.2 mm, 24.2 +/- 5.9 mm, and 24.6 +/- 6.4 mm for T1, T2, and T3, respectively. There were statistically significant differences between T1 and T2, T2 and T3, and T1 and T3 for ICW (p < 0.05). The mean changes in IDW were 25.7 +/- 8.4 mm, 25.8 +/- 9.0 mm, and 25.8 +/- 9.1 mm for T1, T2, and T3, respectively. There was no statistically significant difference between T1 and T2, T2 and T3, and T1 and T3. The mean changes in IEW were 30.6 +/- 10.1 mm, 31.2 +/- 8.8 mm, and 31.3 +/- 8.2 mm for T1, T2, and T3, respectively. There was statistical significance between T1 and T2 or T1 and T3 for IDW (p < 0.05). CONCLUSION: Kiddy dentures do interfere with the transverse growth of the dental arch over the abutment tooth area during a 1-year follow-up period. However the teeth adjacent to the confined abutments still show transverse growth. PMID- 27238560 TI - Simple Interface Engineering of Graphene Transistors with Hydrophobizing Stamps. AB - We demonstrate a simple surface engineering method for fabricating graphene transistors by using hydrophobizing stamps. By simply contact-printing hydrophobizing stamp that is made with polydimethylsiloxane (PDMS) on a standard silicon substrate for a certain contact-time, it was possible to control the contact angle of the substrate and electrical characteristics of the graphene transistors supported on the substrate. Moreover, graphene transistors supported on the engineered silicon substrate showed improved performances, including an increase in carrier mobility and loss of hysteresis. As a proof-of-concept experiment, a simple logic gate operation was demonstrated by connecting a pristine graphene device with an interface-engineered device. PMID- 27238562 TI - Access for All: A Personalised Approach. PMID- 27238561 TI - Longitudinal evaluation of computerized cardiotocographic parameters throughout pregnancy in normal fetuses: a prospective cohort study. AB - INTRODUCTION: The longitudinal cardiotocographic (CTG) changes throughout pregnancy in normal fetuses have never been fully described. We aimed at characterizing the evolution of CTG parameters in healthy fetuses, from 24 to 41 weeks of gestation. MATERIAL AND METHODS: A prospective cohort study was conducted in singleton fetuses without structural abnormalities on second trimester ultrasound. At least one CTG was performed in each of the following intervals: 24-26 weeks(+6d) , 27-29 weeks(+6d) , 30-32 weeks(+6d) , 33-35 weeks(+6d) , 36-38 weeks(+6d) and >=39 weeks; tracings were analyzed by the OMNIVIEW-SISPORTO 3.6 system. Cases of preterm delivery, fetal death, birthweight under the 10th percentile, low five-minute Apgar, umbilical artery acidemia or neonatal intensive care unit admission were subsequently excluded. RESULTS: A total of 1049 eligible tracings were obtained from 145 fetuses. There was a significant increase over time in average long-term variability (LTV), average short-term variability (STV), number of accelerations and uterine contractions. Conversely, fetal heart rate (FHR) baseline and number of decelerations decreased. A high inter-fetal variability was observed, but there was considerable intra-fetal consistency. Fetuses showing a marked decrease in FHR baseline and those with a marked increase in average LTV had a significantly lower birthweight. Cesarean section rate was significantly higher in cases with a decrease in average STV throughout gestation. CONCLUSIONS: This prospective longitudinal study shows an evolution in computerized CTG parameters during pregnancy, indicating the need to adapt interpretation criteria based on gestational age. The high inter-fetal variability and considerable intra-fetal consistency suggests the possible value of using each fetus as its own reference in serial assessments. PMID- 27238563 TI - Evaluation of disulfide scrambling during the enzymatic digestion of bevacizumab at various pH values using mass spectrometry. AB - Disulfide linkages play an important role in protein stability and activity. Thus, it is critical to characterize disulfide bonds to ensure the quality and function of protein pharmaceuticals. There are, however, problems associated with maintaining disulfide linkages in the conventional procedures that are used to digest a protein. In order to preserve enzyme activity during the digestion of a protein, it is commonly carried out at neutral to basic environment which increases the possibilities of disulfide bond scrambling. However, it is not easy to differentiate whether the scrambled disulfide linkages are initiated by the sample itself or whether they are induced during the protease digestion process. In this study, the optimum pH for minimizing disulfide bond rearrangements during the digestion process was determined. Three sets of proteases, trypsin plus Glu C, Lys-C and thermolysin were used, followed by dimethyl labeling and mass spectrometry for a bevacizumab (Avastin) disulfide linkage analysis. No disulfide linkage scrambling was detected at pH6 when Lys-C or trypsin plus Glu-C were used as enzymes. When thermolysin was applied, some scrambled disulfide bonds were identified at pH5, 6 and 7. Nevertheless, there was less disulfide bond scrambling at a lower pH. All correct disulfide bonds on bevacizumab could be identified using this approach. The results demonstrated that by choosing the proper enzymes, using a lower pH environment for the digestion could reduce the degree of artifact disulfide scrambling. PMID- 27238564 TI - Comparative proteomic analysis of membrane microdomains isolated from two hyperlipidemic animal models. PMID- 27238565 TI - Kaj Blennow: the route to biomarkers and the Soderberg prize. PMID- 27238566 TI - Nalmefene is effective at reducing alcohol seeking, treating alcohol-cocaine interactions and reducing alcohol-induced histone deacetylases gene expression in blood. AB - BACKGROUND AND PURPOSE: The opioid antagonist nalmefene (selincro(r)) was approved for alcohol-related disorders by the European Medicines Agency in 2013. However, there have been no studies regarding the effectiveness of nalmefene when alcohol is used in combination with cocaine. EXPERIMENTAL APPROACH: Using operant alcohol self-administration in Wistar rats and qRT-PCR, we evaluated (i) the dose response curve for s.c. and p.o. nalmefene; (ii) the effects of nalmefene with increasing concentrations of alcohol; (iii) the efficacy of nalmefene on cocaine potentiated alcohol responding; and (iv) the gene expression profiles of histone deacetylases (Hdac1-11) in peripheral blood in vivo and in the prefrontal cortex, heart, liver and kidney post mortem. KEY RESULTS: S.c. (0.01, 0.05, 0.1 mg.kg(-1) ) and p.o. (10, 20, 40 mg.kg(-1) ) nalmefene dose-dependently reduced alcohol reinforced responding by up to 50.3%. This effect of nalmefene was not dependent on alcohol concentration (10, 15, 20%). Cocaine potentiated alcohol responding by approximately 40% and nalmefene (0.05 mg.kg(-1) ) reversed this effect of cocaine. Alcohol increased Hdac gene expression in blood and nalmefene prevented the increases in Hdacs 3, 8, 5, 7, 9, 6 and 10. In the other tissues, alcohol and nalmefene either did not alter the gene expression of Hdacs, as in the prefrontal cortex, or a tissue-Hdac-specific effect was observed. CONCLUSIONS AND IMPLICATIONS: Nalmefene might be effective as a treatment for alcohol-dependent patients who also use cocaine. Also, the expression of Hdacs in peripheral blood might be useful as a biomarker of alcohol use and drug response. PMID- 27238567 TI - Disulfiram targets cancer stem-like properties and the HER2/Akt signaling pathway in HER2-positive breast cancer. AB - HER2-positive breast tumors are known to harbor cancer stem-like cell populations and are associated with an aggressive tumor phenotype and poor clinical outcomes. Disulfiram (DSF), an anti-alcoholism drug, is known to elicit cytotoxicity in many cancer cell types in the presence of copper (Cu). The objective of the present study was to investigate the mechanism of action responsible for the induction of apoptosis by DSF/Cu and its effect on cancer stem cell properties in HER2-positive breast cancers in vitro and in vivo. DSF/Cu treatment induced apoptosis, associated with a marked decrease in HER2, truncated p95HER2, phospho HER2, HER3, phospho-HER3 and phospho-Akt levels, and p27 nuclear accumulation. This was accompanied by the eradication of cancer stem-like populations, concomitant with the suppression of aldehyde dehydrogenase 1 (ALDH1) activity and mammosphere formation. DSF administration resulted in a significant reduction in tumor growth and an enhancement of apoptosis, as well as HER2 intracellular domain (ICD) and ALDH1A1 downregulation. Our results demonstrate that DSF/Cu induces apoptosis and eliminates cancer stem-like cells via the suppression of HER2/Akt signaling, suggesting that DSF may be potentially effective for the treatment of HER2-positive cancers. PMID- 27238568 TI - Human uterus myoma and gene expression profiling: A novel in vitro model for studying secretory leukocyte protease inhibitor-mediated tumor invasion. AB - Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor that diminishes tissue destruction during inflammation. A recent report revealed high levels of SLPI expression in the oral carcinoma cell. In addition, overexpression of SLPI up-regulates metastasis in lung carcinoma cells. On the other hand, matrix metalloproteinases (MMPs) are proteinases that participate in extracellular matrix degradation. SLPI and MMPs are involved as accelerators of the tumor invasion process; however, their exact roles are not fully understood. Understanding the mechanism of tumor invasion requires models that take the effect of microenvironmental factors into account. In one such in vitro model, different carcinoma cells have been shown to invade myoma tissue in highly distinct patterns. We have used this myoma model, as it provides a more natural stroma-like environment, to investigate the role of SLPI in tumor invasion. Our results indicate that the model provides a relevant matrix for tumor invasion studies, and that SLPI is important for the invasion of oral carcinoma Ca9-22 cells in conjunction with MMPs. Furthermore, using bioinformatics analysis, we have identified candidates as key molecules involved in SLPI-mediated tumor invasion. PMID- 27238570 TI - EGF-stimulated activation of Rab35 regulates RUSC2-GIT2 complex formation to stabilize GIT2 during directional lung cancer cell migration. AB - Non-small cell lung cancer (NSCLC) remains one of the most metastasizing tumors, and directional cell migration is critical for targeting tumor metastasis. GIT2 has been known to bind to Paxillin to control cell polarization and directional migration. However, the molecular mechanisms underlying roles of GIT2 in controlling cell polarization and directional migration remain elusive. Here we demonstrated GIT2 control cell polarization and direction dependent on the regulation of Golgi through RUSC2. RUSC2 interacts with SHD of GIT2 in various lung cancer cells, and stabilizes GIT2 (Mazaki et al., 2006; Yu et al., 2009) by decreasing degradation and increasing its phosphorylation. Silencing of RUSC2 showed reduced stability of GIT2, defective Golgi reorientation toward the wound edge and decreased directional migration. Moreover, short-term EGF stimulation can increase the interaction between RUSC2 and GIT2, prolonged stimulation leads to a decrease of their interaction through activating Rab35. Silencing of Rab35 also reduced stability and phosphorylation of GIT2 and decreased cell migration. Taken together, our study indicated that RUSC2 participates in EGFR signaling and regulates lung cancer progression, and may be a new therapeutic target against lung cancer metastasis. PMID- 27238571 TI - Clinical and Imaging Findings of Temporomandibular Joint Synovial Chondromatosis: An Analysis of 10 Cases and Literature Review. AB - PURPOSE: This study investigated clinical and imaging features of synovial chondromatosis (SC) of the temporomandibular joint (TMJ) for use in clinical applications. MATERIALS AND METHODS: We analyzed clinical data from 10 patients with SC of the TMJ in our hospital from 2011 to 2015. We also reviewed and analyzed relevant literature included in the National Center for Biotechnology Information database in the past decade using the search terms "synovial chondromatosis" and "temporomandibular joint." RESULTS: The incidence of SC of the TMJ was higher in female patients than in male patients (male-to-female ratio, 1:2.22). It occurred most often in middle age (mean, 47.2 years). The characteristic symptoms of SC in the TMJ were pain (90.8%), swelling (67.1%), limited ability to open the mouth (68.4%), deviant jaw opening (34.2%), and crepitation (31.6%). Computed tomography (CT) (42.9%) and magnetic resonance imaging (45.4%) were the most common techniques used to assess SC in the TMJ, and cone-beam CT (10.9%) also was used to make preliminary diagnoses based on its imaging findings. Open surgery was the preferred treatment of SC of the TMJ, and the recurrence rate was low. CONCLUSIONS: The main clinical characteristics of SC of the TMJ are pain, swelling, limited mouth opening, joint sounds, and deviant jaw opening. Imaging features include abnormal high-density shadows, condyle hyperostosis or destruction, changes in the temporal bone, and widening of the joint space. Cone-beam CT is useful for diagnosis of SC of the TMJ. PMID- 27238569 TI - Induction of HEXIM1 activities by HMBA derivative 4a1: Functional consequences and mechanism. AB - We have been studying the role of Hexamethylene bisacetamide (HMBA) Induced Protein 1 (HEXIM1) as a tumor suppressor whose expression is decreased in tamoxifen resistant and metastatic breast cancer. HMBA was considered the most potent and specific inducer for HMBA inducible protein 1 (HEXIM1) prior to our studies. Moreover, the ability of HMBA to induce differentiation is advantageous for its therapeutic use when compared to cytotoxic agents. However, HMBA induced HEXIM1 expression required at mM concentrations and induced dose limiting toxicity, thrombocytopenia. Thus we structurally optimized HMBA and identified a more potent inducer of HEXIM1 expression, 4a1. The studies reported herein tested the ability of 4a1 to induce HEXIM1 activities using a combination of biochemical, cell phenotypic, and in vivo assays. 4a1 induced breast cell differentiation, including the stem cell fraction in triple negative breast cancer cells. Clinically relevant HEXIM1 activities that are also induced by 4a1 include enhancement of the inhibitory effects of tamoxifen and inhibition of breast tumor metastasis. We also provide mechanistic basis for the phenotypic effects of 4a1. Our results support the potential of an unsymmetrical HMBA derivative, such as 4a1, as lead compound for further drug development. PMID- 27238572 TI - Disorder in Milk Proteins: alpha-Lactalbumin. Part C. Peculiarities of Metal Binding. AB - This is a concluding part of the three-part article from a series of reviews on the abundance and roles of intrinsic disorder in milk proteins. In this paper, we describe the peculiarities of metal binding to a multifunctional milk protein, alpha-lactalbumin, which has two domains, a large alpha-helical domain and a small beta-sheet domain connected by a calcium binding loop. It is known that in addition to four disulfide bonds, the native fold of this protein is stabilized by binding of a calcium ion. In fact, although in various mammals, alpha lactalbumins are rather poorly conserved possessing the overall sequence identity of ~16%, the positions of all eight cysteines and a calcium binding site (residues DKFLDDDITDDI in human protein) are strongly conserved. Curiously, this conserved calcium binding loop is located within a region with increased structural flexibility. Besides canonical calcium binding, alpha-lactalbumin is known to interact with other metals, such as zinc (for which it has a specific binding site), and, in its apo-form, it can bind other divalent and monovalent cations. The binding of Mg2+, Na+, and K+ to the Ca2+ site increases alpha lactalbumin stability against action of heat and various denaturing agents, with the higher stabilization effects being imposed by the stronger bound metal ions. PMID- 27238573 TI - Ethnic sensitivity assessment of pharmacokinetics and pharmacodynamics of omalizumab with dosing table expansion. AB - A three-part license expansion for omalizumab (Xolair((r))), humanized anti-IgE antibody, was recently made in Japan for paediatric use, additional higher doses and revised dosing frequency in allergic asthma. The dosing level and frequency of omalizumab are guided by a dosing table based on the total serum IgE and bodyweight. Nonlinear mixed-effect pharmacokinetic (PK) and pharmacodynamic (PD) modeling and simulation techniques described the binding between omalizumab and its target IgE. The population PKPD analysis was conducted using data from the nine studies included originally in the European application of dosing table expansion together with three Japanese clinical studies to assess the influence of the ethnicity. Statistically significant differences between the ethnic groups were detected. These were small, within or close to bioequivalence criteria. The model described the primary pharmacology in Caucasian and Japanese patients, both adult and paediatric, with simulations showing that the interplay between the clearance, volume and binding affinity parameters was such that there was no clinical impact of the Japanese ethnic differences on either drug PK or free IgE suppression and hence the required posology. PMID- 27238574 TI - Foscarnet, an inhibitor of the sodium-phosphate cotransporter NaPi-IIa, inhibits phosphorylation of glycogen synthase kinase-3beta by lithium in the rat kidney cortex. AB - Lithium, which is used in the treatment of and prophylaxis for bipolar disease, inhibits glycogen synthase kinase-3beta (GSK3beta) by producing its phosphorylated form (p-GSK3beta). GSK3beta plays a role in apoptosis and some kinds of acute kidney injuries, and the formation of p-GSK3beta is considered to contribute to protection against acute kidney injury. We previously reported that the sodium-phosphate cotransporter NaPi-IIa (SLC34A1) mediated the reabsorption of lithium in the rat kidney. In the present study, the phosphorylation status of GSK3beta in the kidney cortex of rats administered lithium chloride and foscarnet, a typical inhibitor of NaPi-IIa, was examined using Western blotting. Under a 2-h infusion of lithium chloride, the plasma concentration of lithium was 1.06 mEq/l, and its renal clearance was calculated as 1.18 ml/min/kg, which was 29.6% of creatinine clearance. The abundance of p-GSK3beta in the kidney cortex was augmented by the administration of lithium. The simultaneous infusion of foscarnet increased the renal clearance of lithium and its ratio to creatinine clearance as well as the urinary excretion of phosphate. Foscarnet also inhibited the lithium-induced phosphorylation of GSK3beta. These results suggest that the reabsorption of lithium by NaPi-IIa triggers the phosphorylation of GSK3beta in the rat kidney cortex. PMID- 27238575 TI - Culture, local capacity, and outside aid: a community perspective on disaster response after the 2009 tsunami in American Samoa. AB - Research on diverse cultural contexts has indicated that aid organisations often fail to leverage local, culturally-grounded resources and capacities in disaster affected communities. Case-study methodology was employed to explore the relationship between local and external disaster response efforts in American Samoa following the earthquake and tsunami on 29 September 2009 in the southern Pacific Ocean, with a specific focus on the role of culture in defining that relationship. Interview and focus group data from 37 participants, along with observational data, suggested that the local response to the event was swift and grounded in Samoan cultural systems and norms. External aid was viewed as helpful in some respects, although, on the whole, it was seen as a disruption to village hierarchies, social networks, and local response efforts. The study discusses the implications for the role of outside aid in diverse cultural contexts, and makes suggestions for improving the ecological fit of post-disaster interventions. PMID- 27238576 TI - Hemophagocytic syndromes (HPSs) including hemophagocytic lymphohistiocytosis (HLH) in adults: A systematic scoping review. AB - Most knowledge of hemophagocytic syndromes (HPSs) including hemophagocytic lymphohistiocytosis (HLH) is derived from pediatric studies; literature on adult HPS/HLH predominantly consists of small retrospective studies with clinical and methodological heterogeneity. The aims of this systematic scoping review were to provide an overview of existing literature on adult HPS/HLH, describe current practices in diagnosis and treatment, and propose priorities for future research. Articles from Ovid Medline, Embase and Pubmed (1975-2015) describing 10 or more unique adults (age>15years) with HPS/HLH were included. 82 publications were eligible: 10 were prospective and 72 were retrospective. Of the six distinct diagnostic criteria, the HLH-2004 criteria were by far the most commonly used. A minority of studies tested for genetic abnormalities (12), soluble interleukin-2 receptor (11), and/or NK function (11) in a subset of patients. Most centers used steroids and either etoposide-based (HLH-94/HLH-2004) or doxorubicin-based (CHOP) initial therapy regimens. Allogeneic hematopoietic cell therapy for treatment of adult HLH has rarely been reported. Mortality in larger treatment focused studies ranged from 20 to 88%. Developing adult-specific diagnostic criteria based on widely evaluable features of secondary HPS/HLH and establishing standard initial therapies are priorities for future research. PMID- 27238577 TI - Detection of pan-allergens in commercial pollen extracts for allergen immunotherapy. AB - BACKGROUND: Up to 50% of patients with pollen allergy are sensitized to at least 1 of the 2 pollen pan-allergens profilin and polcalcin. These allergens could have clinical relevance but the content of profilin and polcalcin in commercial extracts for allergen immunotherapy (AIT) is unknown. OBJECTIVE: To detect these pan-allergens in commercial pollen extracts for AIT from various sources. METHODS: Immunoglobulin E (IgE) reactivity to Phl p 7 and Bet v 2 of sera from 18 adults hypersensitive to profilin and/or polcalcin was investigated by enzyme linked immunosorbent assay before and after absorption with grass, birch, ragweed, pellitory, and olive pollen extracts for AIT from different producers. Immunoblot inhibition experiments also were carried out using the same allergens. RESULTS: Birch, grass, ragweed, and olive pollen extracts for AIT contained large amounts of profilin, inducing 80% to 90% inhibition in most cases; Parietaria AIT extract appeared to contain little profilin. On immunoblot, grass and birch pollen extracts for sublingual AIT completely absorbed IgE specific for rBet v 2. Interestingly, only grass pollen extracts induced a significant inhibition of IgE binding to rPhl p 7 on enzyme-linked immunosorbent assay and immunoblot. A grass pollen allergoid lost most of its inhibitory potency, suggesting a much weakened affinity for specific IgE. CONCLUSION: With the exception of Parietaria, commercial extracts for AIT of most pollens are rich in profilin and, hence, potentially able to desensitize to this allergen; in contrast, only grass pollen extracts seem rich in polcalcin. These are the pollens to use in case of severe symptoms induced by pollen pan-allergens. PMID- 27238578 TI - Sensitization to mouse and cockroach allergens and asthma morbidity in urban minority youth: Genes-environments and Admixture in Latino American (GALA-II) and Study of African-Americans, Asthma, Genes, and Environments (SAGE-II). AB - BACKGROUND: Pest allergen sensitization is associated with asthma morbidity in urban youth but minimally explored in Latino populations. Specifically, the effect of mouse sensitization on the risk of asthma exacerbation has been unexplored in Latino subgroups. OBJECTIVE: To evaluate whether pest allergen sensitization is a predictor of asthma exacerbations and poor asthma control in urban minority children with asthma. METHODS: Latino and African American children (8-21 years old) with asthma were recruited from 4 sites across the United States. Logistic regression models evaluated the association of mouse or cockroach sensitization with asthma-related acute care visits or hospitalizations. RESULTS: A total of 1,992 children with asthma in the Genes environments and Admixture in Latino American (GALA-II) and Study of African Americans, Asthma, Genes, and Environments (SAGE-II) cohorts were studied. Asthmatic children from New York had the highest rate of pest allergen sensitization (42% mouse, 56% cockroach), with the lowest rate in San Francisco (4% mouse, 8% cockroach). Mouse sensitization, more than cockroach, was associated with increased odds of acute care visits (adjusted odds ratio [aOR], 1.47; 95% CI, 1.07-2.03) or hospitalizations (aOR, 3.07; 95% CI, 1.81-5.18), even after controlling for self-reported race and site of recruitment. In stratified analyses, Mexican youth sensitized to mouse allergen did not have higher odds of asthma exacerbation. Other Latino and Puerto Rican youth sensitized to mouse had higher odds of hospitalization for asthma (aORs, 4.57 [95% CI, 1.86-11.22] and 10.01 [95% CI, 1.77-56.6], respectively) but not emergency department visits. CONCLUSION: Pest allergen sensitization is associated with a higher odds of asthma exacerbations in urban minority youth. Puerto Rican and Other Latino youth sensitized to mouse were more likely to have asthma-related hospitalizations than Mexican youth. PMID- 27238580 TI - Molecular Dynamics Simulations of Aldol Condensation Catalyzed by Alkylamine Functionalized Crystalline Silica Surfaces. AB - Molecular dynamics simulations are performed to investigate the cooperatively catalyzed aldol condensation between acetone and 4-nitrobenzaldehyde on alkylamine (or alkylenamine)-grafted silica surfaces, focusing on the mechanism of the catalytic activation of the acetone and 4-nitrobenzaldehyde by the acidic surface silanols followed by the nucleophilic attack of the basic amine functional group toward the activated reactant. From the analysis of the correlations between the catalytically active acid-base sites and reactants, it is concluded that the catalytic cooperativity of the acid-base pair can be affected by two factors: (1) the competition between the silanol and the amine (or enamine) to form a hydrogen bond with a reactant and (2) the flexibility of the alkylamine (or alkylenamine) backbone. Increasing the flexibility of the alkylamine facilitates the nucleophilic attack of the amine on the reactants. From the molecular dynamics simulations, it is found that C3 propylamine and C4 butylamine linkers exhibit the highest probability of reaction, which is consistent with the experimental observation that the activity of the aldol reaction on mesoporous silica depends on the length of alkylamine grafted on the silica surface. This simulation work serves as a pioneering study demonstrating how the molecular simulation approach can be successfully employed to investigate the cooperative catalytic activity of such bifunctional acid-base catalysts. PMID- 27238579 TI - Gene-based analysis identified the gene ZNF248 is associated with late-onset asthma in African Americans. AB - BACKGROUND: Late-onset asthma (LOA) has distinct characteristics and its pathogenesis might rely on unique pathways. Although current studies are focused primarily on childhood asthma, more research is needed to show the mechanisms underlying LOA. OBJECTIVE: To conduct genomewide association analysis and gene based analysis to identify single-nucleotide polymorphisms and genes associated with LOA. METHODS: The Women's Health Initiative (WHI) observational cohort and the Multi-Ethnic Study of Atherosclerosis (MESA) were used to identify subjects with LOA. The association between LOA and body mass index and smoking was evaluated. In the discovery stage of the genetic analysis, 1,218 African American subjects from WHI with genotype data (271 cases and 947 controls) were used for single-nucleotide polymorphism and gene-based association analyses. Significant or suggestive results were subsequently investigated in an independent African American population from MESA (38 cases and 806 controls). RESULTS: In WHI, the relative odds for LOA in obese vs normal-weight subjects was 2.55 (95% confidence interval 1.74-3.76). Ever smokers also had greater odds for LOA compared with never smokers (odds ratio 1.59, 95% confidence interval 1.21-2.09). The same trends were observed in MESA. In WHI, 6 single-nucleotide polymorphisms were associated with LOA at a genomewide-suggestive significance level (P < 1.0 * 10( 5)). The gene ZNF248 was associated with LOA and reached genomewide significance (P = 4.0 * 10(-7)). In MESA, the association between ZNF248 and LOA was successfully replicated (P = .015). CONCLUSION: Smoking and obesity are risk factors for LOA. ZNF248 confers increased susceptibility to LOA in African Americans. PMID- 27238581 TI - Bilingual children's lexical strategies in a narrative task. AB - We investigated how bilinguals choose words in a narrative task, contrasting the possibilities of a developmental delay vs. compensatory strategies. To characterize a developmental delay, we compared younger (three to five years) and older (seven to ten years) children's lexicalization of target words (Study 1). The younger children told shorter stories, omitting many of the target concepts. To characterize compensatory strategies, we compared late second language learning adults to (seven- to ten-year-old) monolingual children (Study 2). The adults often lexicalized the target concepts even when not producing the target words. Finally, we compared French-English bilingual children with French and English monolinguals, all seven to ten years old (Study 3). The bilinguals produced fewer target words than the monolinguals. However, when not producing the target words, the bilinguals often lexicalized the concepts, sharing more in common with the adults (Study 2) in their use of compensatory strategies than with the younger children (Study 1). This interpretation was further corroborated by comparisons across studies (Study 4). PMID- 27238583 TI - Preparation and properties of novel hydrogel based on chitosan modified by poly(amidoamine) dendrimer. AB - Currently, chitosan (CTS) or chitosan derivatives hydrogels are applied in different fields, such as biological materials, medical materials and hygiene materials. In this study, novel chitosan hydrogels were successfully prepared by chitosan and poly(amidoamine) (PAMAM) dendrimer with glutaraldehyde serving as a cross-linking agent. Fourier transform infrared spectroscopy (FTIR), (1)H nuclear magnetic resonance ((1)H NMR) and gel permeation chromatography (GPC) were performed to characterize PAMAM. The structure and morphology of hydrogels were characterized by FTIR, thermo gravimetry analysis (TGA), and scanning electron microscopy (SEM). The swelling properties of the hydrogels were investigated in solutions of pH 1.0 and 7.4. The hydrogels showed good swelling capacities and pH sensitive swelling properties. Besides, the antibacterial activities of the hydrogels against Gram-negative Escherichia coli (E. coli) and Gram-positive Staphylococcus aureus (S. aureus) were tested by optical density. Compared with the pure chitosan hydrogel, their antibacterial activities were significantly improved with the increase in the blending ratio of PAMAM. And with the increase in cross-linking agent and concentration of CTS, the antibacterial activities increased firstly and then slightly decreased. The hydrogel was expected to be a novel antibacterial material. PMID- 27238582 TI - Unusual thiol-based redox metabolism of parasitic flukes. AB - Parasitic flukes are exposed to free radicals and, to a greater extent, reactive oxygen species (ROS) during their life cycle. Despite being relentlessly exposed to ROS released by activated immune cells, these parasites can survive for many years in the host. Cellular thiol-based redox metabolism plays a crucial role in parasite survival within their hosts. Evidence shows that oxidative stress and redox homeostasis maintenance are important clinical and pathobiochemical as well as effective therapeutic principles in various diseases. The characterization of redox and antioxidant enzymes is likely to yield good target candidates for novel drugs and vaccines. The absence of active catalase in fluke parasites offers great potential for the development of chemotherapeutic agents that act by perturbing the redox equilibrium of the cell. One of the redox-sensitive enzymes, thioredoxin glutathione reductase (TGR), has been accepted as a drug target against blood fluke infections, and related clinical trials are in progress. TGR is the sole enzyme responsible for Trx and GSH reduction in parasitic flukes. The availability of helminth genomes has accelerated the research on redox metabolism of flukes; however, significant achievements have yet to be attained. The present review summarizes current knowledge on the redox and antioxidant system of the parasitic flukes. PMID- 27238584 TI - Isolation and analysis of mannose/trehalose/maltose specific lectin from jack bean with antibruchid activity. AB - A lectin with insecticidal property against the stored product pest, Callosobruchus maculatus was successfully isolated from the seeds of Canavalia virosa using standard affinity chromatography. The isolated molecule typically behaved like a lectin in its characteristics. It agglutinated indicator red blood cells (RBC) in its native as well as enzyme treated conditions. The enzyme treated RBC types exhibited a very high hemagglutination (HA) titre values and this property of isolated molecule behaved like arcelin, the lectin-like molecules reported from several species of Phaseolus. As a characteristic feature of a lectin, the isolated molecule effectively inhibited the agglutination of indicator RBC types with simple and complex carbohydrates including glycoproteins. This nature of the isolated molecule also relate with characteristic feature of arcelin isoforms in inhibiting HA activity with complex glycoproteins as reported in many studies. Most interestingly, the present study disclosed trehalose as a potent inhibitor of C. virosa lectin. Therefore, feeding insect pests on the lectin like arcelin could serve as antibiosis factor/anti insect activity. The molecular characteristics of this isolated molecule and its mass studies too revealed its homology with arcelin, arcelin-1, 2 and 6 isoforms of P. vulgaris and lectin from Canavalia cathartica, C. lineata and C. brasiliensis. PMID- 27238585 TI - Exploring the use of NIR reflectance spectroscopy in prediction of free L Asparagine in solanaceae plants. AB - Much researches of Near-infrared spectroscopy modeling methods that are utilized to analyze the trace amount components, especially indirect modeling on complex system, have gained widely attraction in recent years. Amino acids in plants are essential nutrients of maintaining growth and ensuring health. As the important participants in various biochemical reactions in plants, nondestructive detection of free amino acids will provide meaningful observation on physiological changing in different steps of plant growth. In this research, two hundred and twenty-two samples were measured to obtain the concentration of free L-Asparagine in plant by amino acid analyzer. NIR spectra were also collected for conducting chemometrics modeling. Different spectral pretreatments and variables selecting methods were employed to optimize the NIR models. Independent validation set as well as unknown samples from different years were successfully predicted by using the slope intercept correction. Results in this study demonstrated that fast analysis of free L-Asparagine can be established by NIR modeling approach. PMID- 27238586 TI - Chitosan /Zeolite Y/Nano ZrO2 nanocomposite as an adsorbent for the removal of nitrate from the aqueous solution. AB - In the present study, a series of chitosan/Zeolite Y/Nano Zirconium oxide (CTS/ZY/Nano ZrO2) nanocomposites were made by controlling the molar ratio of chitosan (CTS) to Zeolite Y/Nano Zirconium oxide in order to remove nitrate (NO3 ) ions in the aqueous solution. The nanocomposite adsorbents were characterized by XRD, FTIR, BET, SEM and TEM. The influence of different molar ratios of CTS to ZY/Nano ZrO2, the initial pH value of the nitrate solution, contact time, temperature, the initial concentration of nitrate and adsorbent dose was studied. The adsorption isotherms and kinetics were also analyzed. It was attempted to describe the sorption processes by the Langmuir equation and the theoretical adsorption capacity (Q0) was found to be 23.58mg nitrate per g of the adsorbent. The optimal conditions for nitrate removal were found to be: molar ratio of CTS/ZY/Nano ZrO2: 5:1; pH: 3; 0.02g of adsorbent and temperature: 35 degrees C, for 60min. The adsorption capacities of CTS, ZY, Nano ZrO2, CTS/Nano ZrO2, CTS/ZY and CTS/ZY/Nano ZrO2 nanocomposites for nitrate removal were compared, showing that the adsorption ability of CTS/ZY/Nano ZrO2 nanocomposite was higher than the average values of those of CTS (1.95mg/g for nitrate removal), ZY, Nano ZrO2, CTS/Nano ZrO2, and CTS/ZY. PMID- 27238587 TI - Nano-TiO2/collagen-chitosan porous scaffold for wound repairing. AB - Collagen-Chitosan (COL-CS) porous scaffolds have been widely used as a dermal equivalent to induce fibroblasts infiltration and dermal regeneration. To improve the anti-bacterial properties, nano-TiO2 hydrosol was introduced into COL-CS scaffolds. TiO2/COL-CS porous scaffolds were fabricated through a freeze-drying process, and scanning electron microscopy (SEM) was employed to study the micro structure of the scaffolds. Fourier transform infrared spectroscopy (FT-IR) was used to study the intermolecular interactions in the scaffolds. The swelling property, porosity, degradation, antibacterial behavior, red blood cell aggregation, and cytotoxicity of the composite were investigated. The results showed that the scaffold is good in permeability and it may provide a humid environment for wound repairing. The degradation in lysozyme solution for 4 weeks showed that porous scaffolds are good in stability, which may satisfy the wound coverage protection in the repairing period. An obvious inhibitory effect on Staphylococcus aureus of the porous scaffolds was found, and the red blood cells were easy to form clusters aggregation to stop bleeding. It was suggested that the TiO2/COL-CS composite scaffolds could be a promising candidate for wound repairing dressing. PMID- 27238588 TI - Water-soluble yellow mustard mucilage: A novel ingredient with potent antioxidant properties. AB - The antioxidant properties of the water-soluble yellow mustard (Sinapis alba L.) mucilage (WSM) were compared with citrus pectin and xanthan gum using in vitro methods. The antioxidants ascorbic acid and butylated hydroxyanisole (BHA) were used as controls. The antioxidant activity, DPPH free radical scavenging ability, and reducing power on Fe were measured. Molecular weight (MW), uronic acid content, and viscosity for the three polysaccharides were obtained to investigate the relationships between the physicochemical properties and antioxidant activities of the three different polysaccharides. The results showed that the overall antioxidant activity of polysaccharides was lower than that for ascorbic acid and BHA. Of the three polysaccharides, WSM exhibited the strongest antioxidant properties, followed by citrus pectin and xanthan gum. Statistical analysis showed that the MW and uronic acid content had significant effects on antioxidant activity (P<0.05). MW, uronic acid and apparent viscosity had significant effects on reducing power on Fe (P<0.05). Concentration also significantly affected DPPH free radical scavenging effect and reducing power on Fe (P<0.05). The study indicated a great potential of using WSM as a novel ingredient in food industries due to its superior antioxidant activities compared to citrus pectin and xanthan gum. PMID- 27238589 TI - Momordica charantia polysaccharides mitigate the progression of STZ induced diabetic nephropathy in rats. AB - Diabetic nephropathy (DN) has become a primary cause of end-stage kidney disease. Several complex dynamics converge together to accelerate the advancement of DN. The present investigation was postulated to explore the mechanism of reno protective nature of Momordica Charantia polysaccharides (MCP) by evaluating the anti-hyperglycemic, anti-lipidemic as well as markers for oxidative stress and antioxidant proficiency in streptozotocin (STZ)-induced diabetic rats. The oral administration of MCP showed a significant normalization in the levels of kidney function test in the STZ-induced diabetic rats. The levels of blood urea nitrogen (BUN), urea protein and creatinine increased by 316.58%, 195.14% and 800.97% respectively, in STZ-induced diabetic rats when compared with normal rats. MCP treatment also illustrated a significant improvement in glutathione peroxidase, superoxide dismutase and catalase levels, with a significant decline in MDA in diabetic kidneys. Immunoblots of heme-oxygenase 1 (HO-1) and Nrf2 of MCP treated diabetic rats showed a significant up-regulation of HO-1 and Nrf2 protein. Histological and ultra-structural observations also reveal that MCP efficiently protects the kidneys from hyperglycemia-mediated oxidative damage. These findings illustrate that the reno-protective nature of MCP mitigates the progression of STZ induced DN in rats by suppression of oxidative stress and amelioration of the HO-1/Nrf2 pathway. PMID- 27238590 TI - Functional morphology of the tetra fish Astyanax lacustris differs between divergent habitats in the Pantanal wetlands. AB - This study investigated whether the body morphology of the tetra fish Astyanax lacustris (previously Astyanax asuncionensis) varied between populations inhabiting one lagoon (a lentic, shallow environment, with great habitat complexity created by aquatic macrophytes) and an adjacent river (a deeper, lotic environment where aquatic macrophytes are scarce) in a seasonally flooded wetland, despite population mixing during the wet season. Morphological differences matched a priori predictions of the theory relating functional body morphology and swimming performance in fishes between lagoon and river habitats. Observed morphological variation could have resulted from adaptive habitat choice by tetras, predation by piscivores and adaptive phenotypic plasticity during development. PMID- 27238591 TI - The importance of replicating genomic analyses to verify phylogenetic signal for recently evolved lineages. AB - Genomewide SNP data generated by nontargeted methods such as RAD and GBS are increasingly being used in phylogenetic and phylogeographic analyses. When these methods are used in the absence of a reference genome, however, little is known about the locations and evolution of the SNPs. In using such data to address phylogenetic questions, researchers risk drawing false conclusions, particularly if a representative number of SNPs is not obtained. Here, we empirically test the robustness of phylogenetic inference based on SNP data for closely related lineages. We conducted a genomewide analysis of 75 712 SNPs, generated via GBS, of southern bull-kelp (Durvillaea). Durvillaea chathamensis co-occurs with D. antarctica on Chatham Island, but the two species have previously been found to be so genetically similar that the status of the former has been questioned. Our results show that D. chathamensis, which differs from D. antarctica ecologically as well as morphologically, is indeed a reproductively isolated species. Furthermore, our replicated analyses show that D. chathamensis cannot be reliably distinguished phylogenetically from closely related D. antarctica using subsets (ranging in size from 400 to 10 000 sites) of the 40 912 parsimony-informative SNPs in our data set and that bootstrap values alone can give misleading impressions of the strength of phylogenetic inferences. These results highlight the importance of independently replicating SNP analyses to verify that phylogenetic inferences based on nontargeted SNP data are robust. Our study also demonstrates that modern genomic approaches can be used to identify cases of recent or incipient speciation that traditional approaches (e.g. Sanger sequencing of a few loci) may be unable to detect or resolve. PMID- 27238592 TI - Spatial variation of dental caries in late holocene samples of Southern South America: A geostatistical study. AB - OBJECTIVE: The spatial variation of dental caries in late Holocene southern South American populations will be analyzed using geostatistical methods. The existence of a continuous geographical pattern of dental caries variation will be tested. METHODS: The author recorded dental caries in 400 individuals, collated this information with published caries data from 666 additional individuals, and calculated a Caries Index. The caries spatial distribution was evaluated by means of 2D maps and scatterplots. Geostatistical analyses were performed by calculating Moran's I, correlograms and a Procrustes analysis. RESULTS: There is a relatively strong latitudinal continuous gradient of dental caries variation, especially in the extremes of the distribution. Moreover, the association between dental caries and geography was relatively high (m12 = 0.6). Although northern and southern samples had the highest and lowest frequencies of dental caries, respectively, the central ones had the largest variation and had lower rates of caries than expected. CONCLUSION: The large variation in frequencies of dental caries in populations located in the center of the distribution could be explained by their subsistence strategies, characterized either by the consumption of wild cariogenic plants or cultigens (obtained locally or by exchange), a reliance on fishing, or the incorporation of plants rich in starch rather than carbohydrates. It is suggested that dental caries must be considered a multifactorial disease which results from the interaction of cultural practices and environmental factors. This can change how we understand subsistence strategies as well as how we interpret dental caries rates. Am. J. Hum. Biol., 2016. (c) 2016 Wiley Periodicals, Inc. Am. J. Hum. Biol. 28:825-836, 2016. (c) 2016Wiley Periodicals, Inc. PMID- 27238593 TI - Thermoresponsive Polymers for Nuclear Medicine: Which Polymer Is the Best? AB - Thermoresponsive polymers showing cloud point temperatures (CPT) in aqueous solutions are very promising for the construction of various systems in biomedical field. In many of these applications these polymers get in contact with ionizing radiation, e.g., if they are used as carriers for radiopharmaceuticals or during radiation sterilization. Despite this fact, radiosensitivity of these polymers is largely overlooked to date. In this work, we describe the effect of electron beam ionizing radiation on the physicochemical and phase separation properties of selected thermoresponsive polymers with CPT between room and body temperature. Stability of the polymers to radiation (doses 0-20 kGy) in aqueous solutions increased in the order poly(N-vinylcaprolactam) (PVCL, the least stable) ? poly[N-(2,2-difluoroethyl)acrylamide] (DFP) < poly(N isopropylacrylamide) (PNIPAM) ? poly(2-isopropyl-2-oxazoline-co-2-n-butyl-2 oxazoline) (POX). Even low doses of beta radiation (1 kGy), which are highly relevant to the storage of polymer radiotherapeutics and sterilization of biomedical systems, cause significant increase in molecular weight due to cross linking (except for POX, where this effect is weak). In the case of PVCL irradiated with low doses, the increase in molecular weight induced an increase in the CPT of the polymer. For PNIPAM and DFP, there is strong chain hydrophilization leading to an increase in CPT. From this perspective, POX is the most suitable polymer for the construction of delivery systems that experience exposure to radiation, while PVCL is the least suitable and PNIPAM and DFP are suitable only for low radiation demands. PMID- 27238595 TI - Doctor to Doctor. PMID- 27238596 TI - The Medical Bookshelf. PMID- 27238594 TI - A dimer model of human calcitonin13-32 forms an alpha-helical structure and robustly aggregates in 50% aqueous 2,2,2-trifluoroethanol solution. AB - Determining the cause of human calcitonin (hCT) aggregation could be of help in the effort to utilize hCT for treatment of hypercalcemia. Here we report that a dimer model of hCT13-32 aggregated to a greater degree than native hCT under aqueous 2,2,2-trifluoroethanol conditions. Analyses using circular dichroism spectroscopy, thioflavine-T binding assays and atomic force microscopy suggest that the alpha-helical portion of hCT is important for initiation of the aggregation process, which yields long fibrils. Dimerization, which stabilizes the beta-sheet structure of hCT, enhances aggregation potency. Dimerization of hCT stabilizes the alpha-helix under aqueous TFE conditions, leading to the long fibril formation. Up to now, there have been no reports of using a dimer model to investigate the properties of hCT aggregation. Our findings could potentially serve as the basis for development of novel hCT derivatives that could be utilized for treatment of hypercalcemia, as well as for development of novel therapeutics for other ailments caused by amyloid peptides. Copyright (c) 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID- 27238597 TI - Off to a good start. PMID- 27238598 TI - The patient with a headache. PMID- 27238599 TI - Cues/Tips. PMID- 27238600 TI - Deficiency of vitamins A, B, and C. AB - Preview Although specific vitamin deficiency syndromes are relatively rare in the United States, primary care physicians may encounter them in elderly patients and persons who consume minimal diets. Knowledge of such deficiencies is crucial in the evaluation of these patients. The authors discuss manifestations of deficiency of vitamins A, B, and C and recommend appropriate methods of diagnosis and treatment. PMID- 27238602 TI - cme credit QUIZ. PMID- 27238601 TI - Primary Care Digest. PMID- 27238604 TI - Headaches. PMID- 27238607 TI - A listening perspective in psychotherapy with suicidal patients: Establishing convergence in therapists and patients private theories on suicidality and cure. AB - OBJECTIVE: To explore ways that psychotherapists and suicidal patients handle suicidality as a topic, and how it impacts the bond between them. METHOD: Nineteen suicidal patients and their therapists participated in a naturalistic study. Patients were interviewed before they started in therapy, and both patients and therapists were interviewed after three sessions and after one year. RESULTS: Whether suicidality was frequently or seldomly addressed during the sessions did not bear any direct influence on the establishment of a working alliance. Rather, the sense of being engaged in a process of change followed from the therapist's capacity to establish a wide listening perspective, with sensitivity towards their own uncertainties, as well as to implicit and explicit messages about the patient's state of mind. The "private theories" of suicidality and cure that were held by the two parties tended to converge as a result of their work together. If convergence was not established early on, what mattered was their capacity to detect and work on their divergences. Unaddressed divergences led to vicissitudes and eventually resignation. CONCLUSIONS: Listening and exploring divergences in private theories of cure mattered for the creation of a viable working alliance directed at the patient's efforts to live their life. PMID- 27238606 TI - Initial Testing (Stage 1) of MK-8242-A Novel MDM2 Inhibitor-by the Pediatric Preclinical Testing Program. AB - BACKGROUND: MK-8242 is an inhibitor of MDM2 that stabilizes the tumor suppressor TP53 and induces growth arrest or apoptosis downstream of TP53 induction. PROCEDURES: MK-8242 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro cell line panel at concentrations from 1.0 nM to 10.0 MUM and against the PPTP in vivo xenograft panels using oral gavage on Days 1-5 and Day 15-19 at a dose of 125 mg/kg (solid tumors) or 75 mg/kg (acute lymphoblastic leukemia [ALL] models). RESULTS: The median IC50 for MK-8242 was 0.07 MUM for TP53 wild-type cell lines versus >10 MUM for TP53 mutant cell lines. MK-8242 induced a twofold or greater delay in time to event in 10 of 17 (59%) of TP53 wild-type solid tumor xenografts, excluding osteosarcoma xenografts that have very low TP53 expression. Objective responses were observed in seven solid tumor xenografts representing multiple histotypes. For the systemic-disease ALL panel, among eight xenografts there were two complete responses (CRs) and six partial responses (PRs). Two additional MLL-rearranged xenografts (MV4;11 and RS4;11) grown subcutaneously showed maintained CR and PR, respectively. The expected pharmacodynamic responses to TP53 activation were observed in TP53 wild-type models treated with MK-8242. Pharmacokinetic analysis showed that MK-8242 drug exposure in SCID mice appears to exceed that was observed in adult phase 1 trials. CONCLUSIONS: MK-8242-induced tumor regressions across multiple solid tumor histotypes and induced CRs or PRs for most ALL xenografts. This activity was observed at MK-8242 drug exposures that appear to exceed those observed in human phase 1 trials. PMID- 27238609 TI - Investigation of Mycobacterium abscessus outbreak among cystic fibrosis patients, Hawaii 2012. PMID- 27238608 TI - Discovery of a novel HLA-B*13:01 variant, HLA-B*13:01:12, in a Taiwanese bone marrow stem cell donor. AB - One nucleotide substitution at codon 189 of HLA-B*13:01:01 results in a novel allele, HLA-B*13:01:12. PMID- 27238605 TI - Drug target identification in protozoan parasites. AB - INTRODUCTION: Despite the fact that diseases caused by protozoan parasites represent serious challenges for public health, animal production and welfare, only a limited panel of drugs has been marketed for clinical applications. AREAS COVERED: Herein, the authors investigate two strategies, namely whole organism screening and target-based drug design. The present pharmacopoeia has resulted from whole organism screening, and the mode of action and targets of selected drugs are discussed. However, the more recent extensive genome sequencing efforts and the development of dry and wet lab genomics and proteomics that allow high throughput screening of interactions between micromolecules and recombinant proteins has resulted in target-based drug design as the predominant focus in anti-parasitic drug development. Selected examples of target-based drug design studies are presented, and calcium-dependent protein kinases, important drug targets in apicomplexan parasites, are discussed in more detail. EXPERT OPINION: Despite the enormous efforts in target-based drug development, this approach has not yet generated market-ready antiprotozoal drugs. However, whole-organism screening approaches, comprising of both in vitro and in vivo investigations, should not be disregarded. The repurposing of already approved and marketed drugs could be a suitable strategy to avoid fastidious approval procedures, especially in the case of neglected or veterinary parasitoses. PMID- 27238610 TI - In-vitro evaluation of surgical helmet systems for protecting surgeons from droplets generated during orthopaedic procedures. AB - BACKGROUND: Operating theatres and surgical clothing are designed to protect the patient from surgical site infections. However, there is still a risk of infection of the surgical team with blood-borne pathogens via ocular or mucocutaneous exposure. Whereas conventional surgical clothing provides some protection against contamination, surgical helmet systems (SHS) are intended to provide a high level of protection by forming a barrier for particles, aerosols and fluids between surgeon and surgical field of work. AIM: The aim of this study was to quantify the contamination of the surgeon by droplets during orthopaedic procedures by an in-vitro simulation of hip and knee arthroplasty while wearing SHS versus conventional surgical clothing. METHODS: Hip and knee arthroplasty procedures were performed on artificial foam bone, which was continuously kept wet with a marker fluid. Each of the procedures was carried out by ten subjects wearing conventional surgical clothing or wearing SHS with integrated toga. After the simulated operation, pictures of the subjects were taken under ultraviolet illumination. Images wearing the full gown, and after removal of the gown, were evaluated for stained areas. FINDINGS: The contamination risk was 30% while wearing conventional clothing. In none of the 20 subjects using the SHS stains could staining be detected after removal of the protective clothing. CONCLUSION: This study has demonstrated that the protective properties of the SHS are superior to conventional surgical clothing. Using SHS in high-risk procedures could reduce occupational exposure to blood-borne infections in surgeons. PMID- 27238611 TI - Colistin-resistant Acinetobacter baumannii ventilator-associated pneumonia in a tertiary care hospital: an evolving threat. PMID- 27238612 TI - Cardiac bypass heater-coolers and mycobacteria: a problem well stated is a problem half-solved. PMID- 27238613 TI - alphal-Antitrypsin Deficiency: An Overview. AB - 1 alphal-antitrypsin is an antiprotease that inhibits the neutrophil elastase enzyme, and belongs to a family of structurally related serine proteinase inhibitors (serpins). Its methionine(358) residue determines the specificity for elastase. 2 The normal M-type al-antitrypsin is mainly synthesized in the liver parenchymal cells and transPorted to the plasma. Abnormal Z-mutant alphal antitrypsin is retained in the endoplasmic reticulum, which leads to its intracellular accumulation and to Markedly decreased plasma levels. 3 In normal conditions, al-antitrypsin protects the lungs from destruction by the proteolytic neutrophil elastase. A protease/antiprotease imbalance in the lung is responsible for the development of emphysema in severe al-antitrypsin deficiency and in cigarette smokers, and accounts for the marked acceleration of e lung disease in smoking al-antitrypsin deficient patients. Smoking has to be avoided in al antitrypsin deficient patients. Replacement therapy with plasma-derived al antitrypsin seems indicated in alphal-antitrypsin deficient patients with emphysema. Intracellular accumulation of abnormal Z-alphal-antitrypsin molecules in liver parenchymal cells may lead to liver disease, ranging from neonatal cholestasis to adulthood cirrhosis and hepatocellular carcinoma. PMID- 27238615 TI - Surgical Management of Stones: American Urological Association/Endourological Society Guideline, PART II. AB - PURPOSE: This Guideline is intended to provide a clinical framework for the surgical management of patients with kidney and/or ureteral stones. The summary presented herein represents Part II of the two-part series dedicated to Surgical Management of Stones: American Urological Association/Endourological Society Guideline. Please refer to Part I for introductory information and a discussion of pre-operative imaging and special cases. MATERIALS AND METHODS: A systematic review of the literature (search dates 1/1/1985 to 5/31/2015) was conducted to identify peer-reviewed studies relevant to the surgical management of stones. The review yielded an evidence base of 1,911 articles after application of inclusion/exclusion criteria. These publications were used to create the Guideline statements. Evidence-based statements of Strong, Moderate, or Conditional Recommendation were developed based on benefits and risks/burdens to patients. Additional directives are provided as Clinical Principles and Expert Opinions when insufficient evidence existed. RESULTS: The Panel identified 12 adult Index Patients to represent the most common cases seen in clinical practice. Three additional Index Patients were also created to describe the more commonly encountered special cases, including pediatric and pregnant patients. With these patients in mind, Guideline statements were developed to aid the clinician in identifying optimal management. CONCLUSIONS: Proper treatment selection, which is directed by patient- and stone-specific factors, remains the greatest predictor of successful treatment outcomes. This Guideline is intended for use in conjunction with the individual patient's treatment goals. In all cases, patient preferences and personal goals should be considered when choosing a management strategy. PMID- 27238616 TI - Surgical Management of Stones: American Urological Association/Endourological Society Guideline, PART I. AB - PURPOSE: This Guideline is intended to provide a clinical framework for the surgical management of patients with kidney and/or ureteral stones. The summary presented herein represents Part I of the two-part series dedicated to Surgical Management of Stones: American Urological Association/Endourological Society Guideline. Please refer to Part II for an in-depth discussion of patients presenting with ureteral or renal stones. MATERIALS AND METHODS: A systematic review of the literature (search dates 1/1/1985 to 5/31/2015) was conducted to identify peer-reviewed studies relevant to the surgical management of stones. The review yielded an evidence base of 1,911 articles after application of inclusion/exclusion criteria. These publications were used to create the Guideline statements. Evidence-based statements of Strong, Moderate, or Conditional Recommendation were developed based on benefits and risks/burdens to patients. Additional directives are provided as Clinical Principles and Expert Opinions when insufficient evidence existed. RESULTS: The Panel identified 12 adult Index Patients to represent the most common cases seen in clinical practice. Three additional Index Patients were also created to describe pediatric and pregnant patients with such stones. With these patients in mind, Guideline statements were developed to aid the clinician in identifying optimal management. CONCLUSIONS: Proper treatment selection, which is directed by patient- and stone specific factors, remains the greatest predictor of successful treatment outcomes. This Guideline is intended for use in conjunction with the individual patient's treatment goals. In all cases, patient preferences and personal goals should be considered when choosing a management strategy. PMID- 27238618 TI - Clinical Impact of Ventricular Tachycardia and/or Fibrillation During the Acute Phase of Acute Myocardial Infarction on In-Hospital and 5-Year Mortality Rates in the Percutaneous Coronary Intervention Era. AB - BACKGROUND: The aim of this study was to investigate the prognostic impact of acute-phase ventricular tachycardia and fibrillation (VT/VF) on ST-segment elevation myocardial infarction (STEMI) patients in the percutaneous coronary intervention (PCI) era. METHODS AND RESULTS: Using the database of the Osaka Acute Coronary Insufficiency Study (OACIS), we studied 4,283 consecutive patients with STEMI who were hospitalized within 12 h of STEMI onset and underwent emergency PCI. Acute-phase VT/VF, defined as >=3 consecutive ventricular premature complexes and/or VF within the 1st week of hospitalization, occurred in 997 (23.3%) patients. In-hospital mortality risk was significantly higher in patients with acute-phase VT/VF than inthose without (14.6% vs. 4.3%, adjusted hazard ratio (HR) 1.83, P=0.0013). Among patients discharged alive, 5-year mortality rates were comparable between patients with and without acute-phase VT/VF. Subgroup analysis showed that acute-phase VT/VF was associated with increased 5-year mortality after discharge in high-risk patients (GRACE Risk Score >=115; adjusted HR 1.60, P=0.043), but not in intermediate- or low-risk patients. CONCLUSIONS: Even in the PCI era, acute-phase VT/VF was associated with higher in-hospital deaths of STEMI patients. However, the 5-year prognostic impact of acute-phase VT/VF was limited to high-risk patients. (Circ J 2016; 80: 1539-1547). PMID- 27238619 TI - beta,beta-(1,4-Dithiino)subporphyrin Dimers Capturing Fullerenes with Large Association Constants. AB - beta,beta-(1,4-Dithiino)subporphyrin dimers 7-syn and 7-anti were synthesized by the nucleophilic aromatic substitution reaction of 2-bromo-3-(4 methoxyphenylsulfonyl)subporphyrin 4 with 2,3-dimercaptosubporphyrin 5 under basic conditions followed by axial arylation. Additions of C60 or C70 to a dilute solution of 7-anti (ca. 10(-6) m) in toluene did not cause appreciable UV/Vis spectral changes, while similar additions to a concentrated solution (ca. 10(-3) m) resulted in precipitation of complexes. In contrast, dimer 7-syn captured C60 and C70 in different complexation stoichiometries in toluene; a 1:1 manner and a 2:1 manner, respectively, with large association constants; Ka =(1.9+/-0.2)*10(6) m(-1) for C60 @7-syn, and K1 =(1.6+/-0.5)*10(6) and K2 =(1.8+/-0.9)*10(5) m(-1) for C70 @(7-syn)2 . These association constants are the largest for fullerenes capture by bowl-shaped molecules reported so far. The structures of C60 @7-anti, C70 @7-anti, C60 @7-syn, and C70 @7-syn have been determined by single-crystal X ray diffraction analysis. PMID- 27238617 TI - SPINK1 Defines a Molecular Subtype of Prostate Cancer in Men with More Rapid Progression in an at Risk, Natural History Radical Prostatectomy Cohort. AB - PURPOSE: Prostate cancer is clinically and molecularly heterogeneous. We determined the prognosis of men with ERG-ETS fusions and SPINK1 over expression. MATERIALS AND METHODS: Men were identified with intermediate or high risk localized prostate cancer treated with radical prostatectomy and no therapy before metastasis. A case-cohort design sampled a cohort (262) enriched with metastasis from the entire cohort and a cohort (213) enriched with metastasis from patients with biochemical recurrence. We analyzed transcriptomic profiles and subtyped tumors as m-ERG+, m-ETS+, m-SPINK1+ or Triple Negative (m-ERG?/m ETS?/m-SPINK1?), and multivariable logistic regression analyses, Kaplan-Meier and multivariable Cox models were used to evaluate subtypes as predictors of clinical outcomes. RESULTS: Overall 36%, 13%, 11% and 40% of prostate cancer was classified as m-ERG+, m-ETS+, m-SPINK1+ and Triple Negative, respectively. Univariable analysis demonstrated that m-SPINK1+ tumors were more common in African-American men (OR 5, 95% CI 1.6-16) but less commonly associated with positive surgical margins (OR 0.16, 95% CI 0.03-0.69) compared to the m-ERG+ group. Compared to the Triple Negative group, m-SPINK1+ showed similar associations with race and surgical margins in univariable and multivariable analyses across the entire cohort. Survival analyses did not show significant differences among m-ERG+, m-ETS+ and Triple Negative cases. m-SPINK1+ independently predicted prostate cancer specific mortality after metastasis (HR 2.48, 95% CI 0.96-6.4) and biochemical recurrence (HR 3, 95% CI 1.1-8). CONCLUSIONS: SPINK1 over expression is associated with prostate cancer specific mortality in at risk men with biochemical and clinical recurrence after prostatectomy. ERG-ETS alterations are not prognostic for outcome. PMID- 27238620 TI - Amygdala-Dependent Molecular Mechanisms of the Tac2 Pathway in Fear Learning. AB - Recently we determined that activation of the tachykinin 2 (Tac2) pathway in the central amygdala (CeA) is necessary and sufficient for the modulation of fear memories. The Tac2 pathway includes the Tac2 gene, which encodes the neuropeptide neurokinin B and its corresponding receptor neurokinin 3 receptor (NK3R). In this study, using Tac2-cre and Tac2-GFP mice, we applied a combination of in vivo (optogenetics) and multiple in vitro techniques to further explore the mechanisms of action within the Tac2 pathway. In transgenic mice that express ChR2 solely in Tac2 neurons, in vivo optogenetic stimulation of CeA Tac2-expressing neurons during fear acquisition enhanced fear memory consolidation and drove action potential firing in vitro. In addition, Tac2-CeA neurons were shown to co-express striatal-enriched protein tyrosine phosphatase, which may have an important role in regulating Nk3R signaling during fear conditioning. These data extend our current understanding for the underlying mechanism(s) for the role of the Tac2 pathway in the regulation of fear memory, which may serve as a new therapeutic target in the treatment of fear-related disorders. PMID- 27238622 TI - Six weeks of continuous joint distraction appears sufficient for clinical benefit and cartilaginous tissue repair in the treatment of knee osteoarthritis. AB - BACKGROUND: Knee joint distraction (KJD) is a surgical joint-preserving treatment in which the knee joint is temporarily distracted by an external frame. It is associated with joint tissue repair and clinical improvement. Initially, patients were submitted to an eight-week distraction period, and currently patients are submitted to a six-week distraction period. This study evaluates whether a shorter distraction period influences the outcome. METHODS: Both groups consisted of 20 patients. Clinical outcome was assessed by WOMAC questionnaires and VAS pain. Cartilaginous tissue repair was assessed by radiographic joint space width (JSW) and MRI-observed cartilage thickness. RESULTS: Baseline data between both groups were comparable. Both groups showed an increase in total WOMAC score; 24+/ 4 in the six-week group and 32+/-5 in the eight-week group (both p<0.001). Mean JSW increased 0.9+/-0.3mm in the six-week group and 1.1+/-0.3mm in the eight-week group (p=0.729 between groups). The increase in mean cartilage thickness on MRI was 0.6+/-0.2mm in the eight-week group and 0.4+/-0.1mm in the six-week group (p=0.277). CONCLUSIONS: A shorter distraction period does not influence short term clinical and structural outcomes statistically significantly, although effect sizes tend to be smaller in six week KJD as compared to eight week KJD. PMID- 27238621 TI - Large-Scale Hypoconnectivity Between Resting-State Functional Networks in Unmedicated Adolescent Major Depressive Disorder. AB - Major depressive disorder (MDD) often emerges during adolescence, a critical period of brain development. Recent resting-state fMRI studies of adults suggest that MDD is associated with abnormalities within and between resting-state networks (RSNs). Here we tested whether adolescent MDD is characterized by abnormalities in interactions among RSNs. Participants were 55 unmedicated adolescents diagnosed with MDD and 56 matched healthy controls. Functional connectivity was mapped using resting-state fMRI. We used the network-based statistic (NBS) to compare large-scale connectivity between groups and also compared the groups on graph metrics. We further assessed whether group differences identified using nodes defined from functionally defined RSNs were also evident when using anatomically defined nodes. In addition, we examined relations between network abnormalities and depression severity and duration. Finally, we compared intranetwork connectivity between groups and assessed the replication of previously reported MDD-related abnormalities in connectivity. The NBS indicated that, compared with controls, depressed adolescents exhibited reduced connectivity (p<0.024, corrected) between a specific set of RSNs, including components of the attention, central executive, salience, and default mode networks. The NBS did not identify group differences in network connectivity when using anatomically defined nodes. Longer duration of depression was significantly correlated with reduced connectivity in this set of network interactions (p=0.020, corrected), specifically with reduced connectivity between components of the dorsal attention network. The dorsal attention network was also characterized by reduced intranetwork connectivity in the MDD group. Finally, we replicated previously reported abnormal connectivity in individuals with MDD. In summary, adolescents with MDD show hypoconnectivity between large-scale brain networks compared with healthy controls. Given that connectivity among these networks typically increases during adolescent neurodevelopment, these results suggest that adolescent depression is associated with abnormalities in neural systems that are still developing during this critical period. PMID- 27238623 TI - The Reduction in Urinary Glutamate Excretion Is Responsible for Lowering Urinary pH in Pink Urine Syndrome. AB - We frequently encounter brownish-red, cloudy urine in some obese subjects, which occurs due to pink urine syndrome (PUS). PUS is a phenomenon in which uric acid precipitates into the urine due to reduced urinary pH (UpH). The mechanism underlying urinary acidification has not been elucidated so far. UpH level is adjusted by urinary excretion of ammonia synthesized from glutamate or glutamine, suggesting that renal synthesis of ammonia from glutamate or glutamine is decreased in PUS. However, this hypothesis has not been examined yet. We therefore examined the changes in the urinary excretion of these amino acids in PUS. One-hundred-fifty male students who had undergone a physical examination were enrolled. To determine the presence [PUS (+), n = 72] or absence [PUS (-), n = 78] of PUS, urinary amino acid excretion and UpH were evaluated. Independent risk factors of lower UpH were determined using multiple regression analyses. The PUS (+) subjects, who had lower UpH values than PUS (-) subjects, showed lower urinary excretion of glutamate and some other glucogenic amino acids. Thus, UpH correlated positively with the urinary excretion of glutamate in the PUS (+) subjects. A reduction in urinary glutamate but not in glutamine excretion proved to be an independent risk factor for reduced UpH. In conclusion, PUS appears to occur when a reduction in the synthesis of ammonia from glutamate causes a decrease in UpH. Our results showed that urinary glutamate excretion was reduced in PUS because renal glutamate was consumed by a reaction different from ammonia production. PMID- 27238624 TI - Successful Immunosuppressive Treatment of Mixed Connective Tissue Disease Complicated by Microscopic Polyangiitis. AB - Mixed connective tissue disease (MCTD) is characterized by a combination of clinical features of systemic lupus erythematosus, systemic sclerosis, and polymyositis with elevated antibodies to U1 small nuclear ribonucleoprotein (U1 RNP). MCTD is often accompanied by interstitial lung disease as pulmonary involvement. On the other hand, microscopic polyangiitis (MPA) is a systemic autoimmune disease characterized by the inflammation of small vessels (arterioles, capillaries, and venules) mainly affecting the lung and kidney. MPA is associated with elevated serum anti-neutrophil cytoplasmic antibody (ANCA). Complication of MPA in patients with MCTD is rare. So far, only nine case reports of MCTD complicated by MPA with serum myeloperoxidase-specific ANCA (MPO-ANCA) are available. Here, we describe a 64-year-old male suffering from MCTD with MPA. The patient developed interstitial pneumonia with alveolar hemorrhage accompanied by myositis, scleroderma, and elevated anti-U1-RNP antibody and MPO-ANCA levels with substantial systemic inflammation. Strong immunosuppressive therapy (corticosteroid, intravenous immunoglobulin, and cyclosporine A) ameliorated the myositis, interstitial lung disease, and inflammation, with the decrease of MPO ANCA levels, despite that severe lung complications are often associated with poor outcomes. In conclusion, MCTD may be accompanied by MPA with alveolar hemorrhage. Severe lung complications may indicate a poor outcome, and therefore prompt immunosuppressive treatment should be performed in such patients. PMID- 27238625 TI - Transmission of whole body vibration to the lower body in static and dynamic half squat exercises. AB - Whole body vibration (WBV) is used as a training method but its physical risk is not yet clear. Hence, the aim of this study is to assess the exposure to WBV by a measure of acceleration at the lower limb under dynamic and static postural conditions. The hypothesis of this paper is that this assessment is influenced by the frequency, position, and movement of the body. Fifteen healthy males are exposed to vertical sinusoidal vibration at different frequencies (20-60 Hz), while adopting three different static postures (knee extension angle: 180 degrees , 120 degrees and 90 degrees ) or performing a dynamic half-squat exercise. Accelerations at input source and at three joints of the lower limb (ankle, knee, and hip) are measured using skin-mounted accelerometers. Acceleration values (g) in static conditions show a decrease in the vibrational dose when it is measured at a more proximal location in the lower extremity. The results of the performed statistical test show statistically significant differences (p < 0.05) in the transmissibility values caused by the frequency, the position, and to the presence of the movement and its direction at the different conditions. The results confirm the initial hypothesis and justify the importance of a vibration assessment in dynamic conditions. PMID- 27238626 TI - Evolutionary determinants of polycystic ovary syndrome: part 1. AB - Polycystic ovary syndrome (PCOS) is a common and complex genetic disorder that develops under varying degrees of hyperandrogenemic and hyperinsulinemic conditions that cause phenotypic variability ranging from mild hirsutism to anovulation and infertility. In addition to increased risk of reproductive disability, PCOS is associated with metabolic diseases including type 2 diabetes, dyslipidemia, and cardiovascular disease. Similar prevalence rates and shared genetic susceptibility of PCOS among different populations suggest that genetic risk factors were already present in the ancestors of humans. Contemporary human genetic studies inform us that the origin of human ancestors is from Africa. Sharing common susceptibility loci between Chinese and European ancestry suggests that PCOS may have persisted for more than 50,000 years, before the migration of humans out of Africa. Although PCOS is the most common cause of anovulatory infertility, its high prevalence is still a paradox. From an evolutionary perspective, the pathogenic mechanisms underlying PCOS might be candidate factors for survival advantage of the human being. Former compensatory advantageous factors may become pathogenic mechanisms underlying complex metabolic disease with prolonged life expectancy and transition to sedentary lifestyle. PMID- 27238627 TI - Introduction: Determinants of polycystic ovary syndrome. AB - The polycystic ovary syndrome (PCOS) is recognized as one of the most common endocrine abnormalities of humans, with global prevalences so far generally 5% 15%. Overall, the disorder appears to be an ancient complex genetic trait, perhaps dating at least 50,000 years ago. The phenotype of PCOS can be subdivided into four different types. Phenotype A and B (hyperandrogenism + ovulatory dysfunction, with [A] and without [B] polycystic ovarian morphology [PCOM], respectively) can be considered to represent the "classic" form of the disorder. Phenotype C is the so-called "ovulatory" PCOS (hyperandrogenism + PCOM only). And phenotype D is often referred to as "nonhyperandrogenic" PCOS (ovulatory dysfunction + PCOM only). The different phenotypes vary in the degree to which they are associated with an increased risk for metabolic dysfunction and reproductive complications. There are a number of determinants of the epidemiology (prevalence) and presentation (phenotype) of PCOS, including environmental (e.g., socioeconomic, geographic, toxicologic, life-style, and dietary) and genetic (e.g., gene variants, epigenetic, and race/ethnicity) factors. Finally a better understanding of the evolutionary determinants of PCOS has the potential for providing additional insight into those factors determining the etiology, prevalence, and persistence of a disorder that appears to be, superficially at least, an evolutionary paradox. PMID- 27238628 TI - How to (and how not to) think about top-down influences on visual perception. AB - The question of whether cognition can influence perception has a long history in neuroscience and philosophy. Here, we outline a novel approach to this issue, arguing that it should be viewed within the framework of top-down information processing. This approach leads to a reversal of the standard explanatory order of the cognitive penetration debate: we suggest studying top-down processing at various levels without preconceptions of perception or cognition. Once a clear picture has emerged about which processes have influences on those at lower levels, we can re-address the extent to which they should be considered perceptual or cognitive. Using top-down processing within the visual system as a model for higher-level influences, we argue that the current evidence indicates clear constraints on top-down influences at all stages of information processing; it does, however, not support the notion of a boundary between specific types of information-processing as proposed by the cognitive impenetrability hypothesis. PMID- 27238629 TI - Parent reported outcomes of quality care and satisfaction in the context of a life-limiting fetal diagnosis. AB - OBJECTIVE: To identify which quality indicators (QI) predict patient satisfaction. METHODS: A cross-sectional design using a validated tool was administered using a Web-based platform. Parents (n = 405) who experienced a life limiting fetal diagnosis and opted to continue their pregnancy provided feedback on 37 QI and satisfaction with prenatal care. Descriptive analyses and logistic regression identified relationships among variables. RESULTS: Parental satisfaction with care was 75.6%. Statistically significant differences in mean scores were reported with satisfied patients reporting higher agreement with quality indicators. Parents who were satisfied with their care had 1.9 times the odds of reporting that consistent care was provided (CI: 1.4-2.4, p < 0.01), 1.8 times the odds of reporting compassionate care (CI: 1.4-2.5, p < 0.01) and 1.8 times the odds that they received help to cope with their emotions (CI: 1.4-2.3, p < 0.01). The model correctly predicted parent satisfaction 92% of the time. CONCLUSION: Provision of consistent prenatal care is an important quality indicator for this population of parents. The odds of securing satisfied parents increase when families are treated with compassion and given resources to help them cope with the emotionally devastating experiences associated with a life limiting fetal diagnosis. PMID- 27238630 TI - Big data to smart data in Alzheimer's disease: The brain health modeling initiative to foster actionable knowledge. AB - Massive investment and technological advances in the collection of extensive and longitudinal information on thousands of Alzheimer patients results in large amounts of data. These "big-data" databases can potentially advance CNS research and drug development. However, although necessary, they are not sufficient, and we posit that they must be matched with analytical methods that go beyond retrospective data-driven associations with various clinical phenotypes. Although these empirically derived associations can generate novel and useful hypotheses, they need to be organically integrated in a quantitative understanding of the pathology that can be actionable for drug discovery and development. We argue that mechanism-based modeling and simulation approaches, where existing domain knowledge is formally integrated using complexity science and quantitative systems pharmacology can be combined with data-driven analytics to generate predictive actionable knowledge for drug discovery programs, target validation, and optimization of clinical development. PMID- 27238631 TI - Assessing validity of observational intervention studies - the Benchmarking Controlled Trials. AB - BACKGROUND: Benchmarking Controlled Trial (BCT) is a concept which covers all observational studies aiming to assess impact of interventions or health care system features to patients and populations. AIMS: To create and pilot test a checklist for appraising methodological validity of a BCT. METHODS: The checklist was created by extracting the most essential elements from the comprehensive set of criteria in the previous paper on BCTs. Also checklists and scientific papers on observational studies and respective systematic reviews were utilized. Ten BCTs published in the Lancet and in the New England Journal of Medicine were used to assess feasibility of the created checklist. RESULTS: The appraised studies seem to have several methodological limitations, some of which could be avoided in planning, conducting and reporting phases of the studies. CONCLUSIONS: The checklist can be used for planning, conducting, reporting, reviewing, and critical reading of observational intervention studies. However, the piloted checklist should be validated in further studies. Key messages Benchmarking Controlled Trial (BCT) is a concept which covers all observational studies aiming to assess impact of interventions or health care system features to patients and populations. This paper presents a checklist for appraising methodological validity of BCTs and pilot-tests the checklist with ten BCTs published in leading medical journals. The appraised studies seem to have several methodological limitations, some of which could be avoided in planning, conducting and reporting phases of the studies. The checklist can be used for planning, conducting, reporting, reviewing, and critical reading of observational intervention studies. PMID- 27238632 TI - Double-gated myocardial ASL perfusion imaging is robust to heart rate variation. AB - PURPOSE: Cardiac motion is a dominant source of physiological noise (PN) in myocardial arterial spin labeled (ASL) perfusion imaging. This study investigates the sensitivity to heart rate variation (HRV) of double-gated myocardial ASL compared with the more widely used single-gated method. METHODS: Double-gating and single-gating were performed on 10 healthy volunteers (n = 10, 3F/7M; age, 23 34 years) and eight heart transplant recipients (n = 8, 1F/7M; age, 26-76 years) at rest in the randomized order. Myocardial blood flow (MBF), PN, temporal signal to-noise ratio (SNR), and HRV were measured. RESULTS: HRV ranged from 0.2 to 7.8 bpm. Double-gating PN did not depend on HRV, while single-gating PN increased with HRV. Over all subjects, double-gating provided a significant reduction in global PN (from 0.20 +/- 0.15 to 0.11 +/- 0.03 mL/g/min; P = 0.01) and per segment PN (from 0.33 +/- 0.23 to 0.21 +/- 0.12 mL/g/min; P < 0.001), with significant increases in global temporal SNR (from 11 +/- 8 to 18 +/- 8; P = 0.02) and per-segment temporal SNR (from 7 +/- 4 to 11 +/- 12; P < 0.001) without significant difference in measured MBF. CONCLUSION: Single-gated myocardial ASL suffers from reduced temporal SNR, while double-gated myocardial ASL provides consistent temporal SNR independent of HRV. Magn Reson Med 77:1975-1980, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27238633 TI - The Preparation of Complexes of Germanone from a Germanium MU-Oxo Dimer. AB - Complexes of germanone containing formal Ge=O->M bonds (M=Zn, B, Ge, Sn) were isolated and characterized. The compounds were prepared through a novel synthetic route using a germanium MU-oxo dimer 3 as the starting material. This method circumvents the need to employ germanones to prepare complexes of germanones. PMID- 27238634 TI - Beta-2 microglobulin as a significant prognostic factor and a new risk model for patients with diffuse large B-cell lymphoma. AB - Previous reports have evaluated the prognostic value of serum beta-2 microglobulin (B2MG) level in patients with non-Hodgkin lymphoma. However, its role in predicting clinical outcome of patients with diffuse large B-cell lymphoma (DLBCL) in the rituximab era has not been extensively investigated. Here, we evaluated the prognostic value of B2MG and proposed a new prognostic model including B2MG for patients with DLBCL. A total of 274 patients with newly diagnosed de novo DLBCL were retrospectively analyzed. We defined the best cutoff value as 3.2 mg/L by using a receiver operating characteristic curve. Patients with a B2MG level >=3.2 mg/L had significantly lower overall survival (OS) and progression-free survival than those with a B2MG level <3.2 mg/L (3-year OS, 50.9% vs. 89.4%, p < 0.001; 3-year progression-free survival, 45.3% vs. 79.7%, p < 0.001). Multivariate analysis showed that B2MG, age, performance status, and Ann Arbor stage were independent prognostic factors for OS. We developed a new prognostic model consisting of these four significant factors. We stratified patients into four-risk groups: low (L, 0 factor), low-intermediate (LI, 1-2 factors), high-intermediate (HI, 3 factors), high (H, 4 factors). This new prognostic model showed better risk discrimination compared with the National Comprehensive Cancer Network-International Prognostic Index (5-year OS: 100% and 23.4% vs. 100% and 27.1%, in L and H risk groups, respectively). Our study suggested that B2MG level is a significant prognostic factor in patients with DLBCL. A new prognostic index composed of age, performance status, stage, and B2MG could stratify the outcomes of patients with DLBCL effectively and appears to be a valuable risk model for these patients. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27238635 TI - International circumpolar surveillance interlaboratory quality control program for emm typing of Streptococcus pyogenes, 2011-2015. AB - In 2011, an interlaboratory quality control (QC) program for emm typing group A streptococci (GAS) was incorporated into existing international circumpolar surveillance QC programs. From 2011 - 2015, 35 GAS isolates were distributed to three laboratories; emm type-level concordance was 100%, while the overall sub type level concordance was 83%. PMID- 27238636 TI - metaBIT, an integrative and automated metagenomic pipeline for analysing microbial profiles from high-throughput sequencing shotgun data. AB - Micro-organisms account for most of the Earth's biodiversity and yet remain largely unknown. The complexity and diversity of microbial communities present in clinical and environmental samples can now be robustly investigated in record times and prices thanks to recent advances in high-throughput DNA sequencing (HTS). Here, we develop metaBIT, an open-source computational pipeline automatizing routine microbial profiling of shotgun HTS data. Customizable by the user at different stringency levels, it performs robust taxonomy-based assignment and relative abundance calculation of microbial taxa, as well as cross-sample statistical analyses of microbial diversity distributions. We demonstrate the versatility of metaBIT within a range of published HTS data sets sampled from the environment (soil and seawater) and the human body (skin and gut), but also from archaeological specimens. We present the diversity of outputs provided by the pipeline for the visualization of microbial profiles (barplots, heatmaps) and for their characterization and comparison (diversity indices, hierarchical clustering and principal coordinates analyses). We show that metaBIT allows an automatic, fast and user-friendly profiling of the microbial DNA present in HTS shotgun data sets. The applications of metaBIT are vast, from monitoring of laboratory errors and contaminations, to the reconstruction of past and present microbiota, and the detection of candidate species, including pathogens. PMID- 27238637 TI - Direct Hepatocyte Insulin Signaling Is Required for Lipogenesis but Is Dispensable for the Suppression of Glucose Production. AB - During insulin-resistant states such as type II diabetes mellitus (T2DM), insulin fails to suppress hepatic glucose production (HGP) yet promotes lipid synthesis. This metabolic state has been termed "selective insulin resistance" to indicate a defect in one arm of the insulin-signaling cascade, potentially downstream of Akt. Here we demonstrate that Akt-dependent activation of mTORC1 and inhibition of Foxo1 are required and sufficient for de novo lipogenesis, suggesting that hepatic insulin signaling is likely to be intact in insulin-resistant states. Moreover, cell-nonautonomous suppression of HGP by insulin depends on a reduction of adipocyte lipolysis and serum FFAs but is independent of vagal efferents or glucagon signaling. These data are consistent with a model in which, during T2DM, intact liver insulin signaling drives enhanced lipogenesis while excess circulating FFAs become a dominant inducer of nonsuppressible HGP. PMID- 27238639 TI - Zfp423 Maintains White Adipocyte Identity through Suppression of the Beige Cell Thermogenic Gene Program. AB - The transcriptional regulators Ebf2 and Prdm16 establish and maintain the brown and/or beige fat cell identity. However, the mechanisms operating in white adipocytes to suppress the thermogenic gene program and maintain an energy storing phenotype are less understood. Here, we report that the transcriptional regulator Zfp423 is critical for maintaining white adipocyte identity through suppression of the thermogenic gene program. Zfp423 expression is enriched in white versus brown adipocytes and suppressed upon cold exposure. Doxycycline inducible inactivation of Zfp423 in mature adipocytes, combined with beta adrenergic stimulation, triggers a conversion of differentiated adiponectin expressing inguinal and gonadal adipocytes into beige-like adipocytes; this reprogramming event is sufficient to prevent and reverse diet-induced obesity and insulin resistance. Mechanistically, Zfp423 acts in adipocytes to inhibit the activity of Ebf2 and suppress Prdm16 activation. These data identify Zfp423 as a molecular brake on adipocyte thermogenesis and suggest a therapeutic strategy to unlock the thermogenic potential of white adipocytes in obesity. PMID- 27238640 TI - Electrodiagnostic reference values for upper and lower limb nerve conduction studies in adult populations. AB - INTRODUCTION: To address the need for greater standardization within the field of electrodiagnostic medicine, the Normative Data Task Force (NDTF) was formed to identify nerve conduction studies (NCS) in the literature, evaluate them using consensus-based methodological criteria derived by the NDTF, and identify those suitable as a resource for NCS metrics. METHODS: A comprehensive literature search was conducted of published peer-reviewed scientific articles for 11 routinely performed sensory and motor NCS from 1990 to 2012. RESULTS: Over 7,500 articles were found. After review using consensus-based methodological criteria, only 1 study each met all quality criteria for 10 nerves. CONCLUSION: The NDTF selected only those studies that met all quality criteria and were considered suitable as a clinical resource for NCS metrics. The literature is, however, limited and these findings should be confirmed by larger, multicenter collaborative efforts. Muscle Nerve 54: 371-377, 2016. PMID- 27238638 TI - Brown Adipose Tissue Activation Is Linked to Distinct Systemic Effects on Lipid Metabolism in Humans. AB - Recent studies suggest that brown adipose tissue (BAT) plays a role in energy and glucose metabolism in humans. However, the physiological significance of human BAT in lipid metabolism remains unknown. We studied 16 overweight/obese men during prolonged, non-shivering cold and thermoneutral conditions using stable isotopic tracer methodologies in conjunction with hyperinsulinemic-euglycemic clamps and BAT and white adipose tissue (WAT) biopsies. BAT volume was significantly associated with increased whole-body lipolysis, triglyceride-free fatty acid (FFA) cycling, FFA oxidation, and adipose tissue insulin sensitivity. Functional analysis of BAT and WAT demonstrated the greater thermogenic capacity of BAT compared to WAT, while molecular analysis revealed a cold-induced upregulation of genes involved in lipid metabolism only in BAT. The accelerated mobilization and oxidation of lipids upon BAT activation supports a putative role for BAT in the regulation of lipid metabolism in humans. PMID- 27238643 TI - Strapped for cash.. AB - Paediatric trauma nurse Angie Lee helps launch a scheme by The British Helmet Initiative Trust to offer youngsters half-price cycle helmets on 'prescription'. PMID- 27238644 TI - Discretionary pay seen as 'ill timed' initiative. AB - The NHS Confederation has confirmed the slow implementation of discretionary payments for nurses on grades F to I. PMID- 27238642 TI - Association between depression and anemia in otherwise healthy adults. AB - OBJECTIVE: It remains debated whether anemia is associated with depression, independently of physical health factors. We report a large-scale cross-sectional study examining this association in adults free of chronic disease and medication from the general population. METHOD: Hemoglobin levels were measured among 44 173 healthy participants [63% men; mean [standard deviation] age = 38.4 (11.1) years] from the 'Investigations Preventives et Cliniques' (IPC) cohort study. Depression was measured with the Questionnaire of Depression 2nd version, Abridged. Logistic regression analyses were performed to examine the association between anemia and depression, while adjusting for a wide range of sociodemographic characteristics and health-related factors (i.e., sex, age, living status, education level, occupational status, alcohol intake, smoking status, physical activity, and body mass index). RESULTS: Depressed participants were significantly more likely to have anemia compared to non-depressed participants, even after adjustment for sociodemographic and health-related variables [odds ratio = 1.36; 95% confidence interval = (1.18; 1.57)]. Anemia prevalence increased with depression severity, suggesting a dose-response relationship (P for trend <0.001). CONCLUSION: In healthy adults from the general population, we found a significant and robust association between depression and anemia. Further studies are needed to assess the longitudinal relationship between both conditions and determine the mechanisms underlying this association. PMID- 27238645 TI - 'Time we stopped blaming patients'. AB - I decided to leave A&E after 18 years to work in a primary care led clinic, and was particularly struck by your recent editorial 'Whose need does A&E serve? (Emergency Nurse February, 1999). The clinic I now work in is staffed and run by nurses in a GP practice in Liverpool. PMID- 27238646 TI - [Not Available]. AB - Preparations for the annual Nurses Day event on May 12 - Florence Nightingale's birthday - continue with the publication of promotional materials. RCN packs have been sent to regional offices and activists. PMID- 27238647 TI - [Not Available]. PMID- 27238648 TI - RCNHQ makes temporary move. AB - THE RCN's London headquarters have recently closed for 18 months of refurbishment. PMID- 27238650 TI - Paracetamol overdose in episode of casualty. AB - The possibility that media representation of suicide and deliberate self harm may encourage suicidal behaviour in vulnerable individuals has attracted considerable attention. In a widely reported paper, researchers in Oxford sought to determine whether a paracetamol overdose in the television drama Casualty altered the incidence and nature of general hospital presentations for deliberate self poisoning. PMID- 27238649 TI - Zero tolerance towards patients behaving violently. AB - People who commit acts of violence against nurses should be prosecuted without exception, nursing delegates heard at the RCN Congress held in March. PMID- 27238651 TI - Telephone advice provision in a&e. AB - Telephone advice appears to be increasingly valued by the general public and it has been shown that a considerable proportion of callers to A&E departments could be managed without needing to attend the hospital. The purpose of this study was to establish current demand, practices, policies, and procedures relating to telephone advice from A&E departments and minor injuries units. PMID- 27238652 TI - Establishing a faith-based organisation nursing school within a national primary health care programme in rural Tanzania: an auto-ethnographic case study. AB - BACKGROUND: In 2007, the Tanzanian government called for improvements in its primary health care services. Part of this initiative was to accelerate the training rate for nurses qualified to work in rural areas. The aim of this study was to reflect on the issues experienced whilst establishing and implementing a faith-based organisation (FBO) nursing school and make recommendations for other similar initiatives. DESIGN: This paper describes an auto-ethnographic case study design to identify the key difficulties involved with establishing and implementing a new nursing school, and which factors helped the project achieve its goals. RESULTS: Six themes emerged from the experiences that shaped the course of the project: 1) Motivation can be sustained if the rationale of the project is in line with its aims. Indeed, the project's primary health care focus was to strengthen the nursing workforce and build a public-private partnership with an FBO. All these were strengths, which helped in the midst of all the uncertainties. 2) Communication was an important and often underrated factor for all types of development projects. 3) Managing the unknown and 4) managing expectations characterised the project inception. Almost all themes had to do with 5) handling conflicts. With so many participants having their own agendas, tensions were unavoidable. A final theme was 6) the need to adjust to ever changing targets. CONCLUSIONS: This retrospective auto-ethnographic manuscript serves as a small-scale case study, to illustrate how issues that can be generalised to other settings can be deconstructed to demonstrate how they influence health development projects in developing countries. From this narrative of experiences, key recommendations include the following: 1) Find the right ratio of stakeholders, participants, and agendas, and do not overload the project; 2) Be alert and communicate as much as possible with staff and do not ignore issues hoping they will solve themselves; 3) Think flexibly and do not stubbornly stick to original plans that might not be working; 4) Be realistic and do not romanticise. Embarking on such a project was a timely response to the Tanzanian's government call for strengthening Primary Health Care and for rapidly accelerating the training of nurses able to work in rural areas. PMID- 27238655 TI - High-flow oxygen therapy through nasal cannula: Prospective observational study in an intermediate care unit. PMID- 27238654 TI - Second-generation Androgen Receptor-targeted Therapies in Nonmetastatic Castration-resistant Prostate Cancer: Effective Early Intervention or Intervening Too Early? PMID- 27238656 TI - Xenotransplantation literature update, March-April 2016. PMID- 27238653 TI - Early Tumour Shrinkage: A Tool for the Detection of Early Clinical Activity in Metastatic Renal Cell Carcinoma. AB - BACKGROUND: The predictive role of objective remission remains undefined for targeted agents in metastatic renal cell carcinoma (mRCC); however, early tumour shrinkage (eTS) was shown to be predictive and/or prognostic for overall survival (OS) and progression-free survival (PFS) in mRCC in several small studies. OBJECTIVE: To evaluate the degree of eTS following systemic therapy that may predict survival in mRCC. DESIGN, SETTING, AND PARTICIPANTS: Data from 4334 patients with mRCC in phase 2 and 3 clinical trials between 2003 and 2013 were pooled for analyses. Early tumour shrinkage was assessed based on percentage change in sum of the longest diameters of target lesions at first postbaseline scan. Patients were categorised by a more or equal versus less optimal threshold of eTS, assessed using receiver operating characteristic (ROC) analysis. OS and PFS in patients with eTS were summarised using the Kaplan-Meier method. INTERVENTION: Axitinib, bevacizumab, interferon alpha, sorafenib, sunitinib, or temsirolimus. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We measured optimal thresholds of eTS and eTS as a predictor of OS or PFS. RESULTS AND LIMITATIONS: Optimal threshold of eTS for the prediction of OS and PFS was determined to be approximately 10%. In Cox proportional hazards models, compared with patients without eTS, those with eTS had significantly longer OS (hazard ratio [HR]: 0.615; p<0.0001; median: 28.5 vs 16.0 mo) and PFS (HR: 0.628; p<0.0001; median: 10.5 vs 5.3 mo). The major limitation was the retrospective nature of our analysis, including different lines and types of therapy, although subset analyses detected a similar predictive pattern for eTS across all lines and types of therapy. CONCLUSIONS: Early tumour shrinkage >=10% at first postbaseline assessment could serve as a putative early end point in patients with mRCC. A prospective evaluation of eTS in clinical trials is warranted. PATIENT SUMMARY: Early tumour shrinkage may be used to identify patients with metastatic renal cell carcinoma who would benefit from treatment with antitumour agents. TRIAL REGISTRATION: The clinical trials are registered on ClinicalTrials.gov (NCT00267748, NCT00338884, NCT00835978, NCT00065468, NCT00083889, NCT00631371, NCT00920816, NCT00077974, NCT00137423, NCT00054886, NCT00678392, and NCT00474786). PMID- 27238658 TI - A message of support. AB - There was a certain inevitability about the Gulf crisis. The Middle East has been no stranger to warfare during the past decade and following Iraq's seizure of Kuwait, the conflict was certain to touch all of our lives here in the United Kingdom. Up until now there was no real reason for the average citizen to become overly concerned with Middle East problems. The unreality of warfare in countries that appear geographically and culturally far away from us here in the UK rarely hits home. However, in the past weeks virtually all of us have anxiously watched news bulletins, digesting and analysing every move in this war of nerves. But the fear and sudden realisation that the conflict could escalate raises serious issues for medical and nursing staff. PMID- 27238657 TI - Furosemide. 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- 27238660 TI - Nurses told: work for free to help costs. AB - Theatres at the Royal Liverpool Children's hospital are to be run on nurses' 'goodwill' after 4.30pm as part of a cash saving measure. PMID- 27238659 TI - Regions may seek to keep awards low. AB - Nurses can expect only a 'moderate' salary increase in their 1990/91 pay award if the recommendations of regional health authority chairmen are taken on board by the Review Body. PMID- 27238661 TI - Appeals likely to be delayed even further. AB - Nurses throughout the UK are likely to wait even longer for their clinical grading appeals to be heard as a result of health authority restructuring, it was claimed last week. PMID- 27238662 TI - Standards of advocacy declining? AB - Many nurses and midwives appearing before Professional Conduct Committees receive 'unsatisfactory' representation from their union or professional body, the UK Central Council has warned. PMID- 27238663 TI - [Not Available]. AB - A healthy lead. Food of Love, ridden by John Carroll, romps home to win the 3.50pm at Gosforth Park on Bank Holiday Monday and the first Newcastle Health Plate. A local Finn put up the money to raise funds for the Care of the Elderly charity. It is expected to become an annual event. PMID- 27238664 TI - Library cash crisis to hit P2000 courses. AB - A Government decision not to provide extra money for libraries where Project 2000 courses are starting this year has been called disastrous and shortsighted. PMID- 27238665 TI - New nurses still need extended skills retraining. AB - Most health authorities still require newly-employed nurses to retrain in extended skills such as venepucture, regardless of their previous experience, the preliminary results of an RCN investigation show. PMID- 27238666 TI - Leadership for change. AB - Nursing staff in special hospitals are willing to change their practice if they are given proper leadership and training, Broadmoor Special Hospital Unit General manager believes. PMID- 27238667 TI - Should qualified nurses teach? AB - All qualified nurses should be involved in teaching student nurses, Julia Brooking, Professor of Nursing at Birmingham University, believes. PMID- 27238668 TI - Fight for your patients' rights. AB - Professionals working with people with a mental illness must be prepared to stand up in public for the rights of patients, forensic psychiatric nurses were told. PMID- 27238669 TI - Reform campaign gathers momentum. AB - Trade unionists will this week pledge to step up their campaign against the health service reforms when they meet in Blackpool for their annual congress. PMID- 27238670 TI - MIND appeals against a High Court ruling. AB - The mental health charity MIND last week presented a petition to a Bath property developer to appeal against a High Court ruling which will prohibit former psychiatric patients from being rehoused in the community. PMID- 27238672 TI - Students set to join the dole queues. AB - A whole set of student health visitors will be joining Scotland's dole queues this week even though Greater Glasgow Health Board has vacant health visitor posts. PMID- 27238673 TI - Higher education leads to nursing excellence. AB - Higher education is not the only route to nursing excellence the audience decided at the Nursing 1990 Debate hosted by Nursing Standard and the Royal Marsden Hospital. PMID- 27238674 TI - Poor pay and long hours must change. AB - First year student nurses should get an L82 per week pay rise according to the Irish Nurses Organisation (INO). Their current salary is about L68 weekly following a pay cut two years ago. PMID- 27238675 TI - Delayed care may lead to chronic problems. AB - Sexually abused children may develop chronic conditions because psychological help is not given quickly enough, the British Psychological Society warned last week. PMID- 27238676 TI - Hospices. AB - Health Authorities are providing support I to hospices in kind' rather than in hard cash, according to a snapshot survey of 22 health districts, carried out by the National Association of Health Authorities and Trusts (NAHAT). PMID- 27238679 TI - World news. AB - India Hundreds of women who are HIV positive are being held against their will in detention centres around India, some for as long as three years, according to a Guardian report. PMID- 27238677 TI - Smoking advert leads to ticking off. AB - Health visitors tore down a sponsored clock from the wall of their clinic in Leeds after discovering it carried an advert for a local newsagent selling cigarettes and sweets. PMID- 27238680 TI - [Not Available]. AB - Heard the one about the Welsh nurse, the Irish nurse and the Scottish nurse; RCN Welsh Board Secretary Anne Pegington and Scottish Board Secretary Isabel Duncan pictured with Rosemary Calvert, (centre) RCN Northern Ireland Board Secretary, at her leaving party at RCN headquarters in London. Ms Calvert had been at the Northern Ireland Board for 14 years, before which she was District Administrative Nursing Officer at the Eastern Health and Social Services Board. PMID- 27238681 TI - NCC urge proper deal for local patients. AB - Health authorities must include local people in negotiations over contracts or they could end up with deals which suit buyers and sellers, but not patients, the National Consumer Council has warned. PMID- 27238682 TI - New cancer drug set to begin trials. AB - The first clinical trials of a drug that may halt the spread of cancer could begin in Manchester next year. PMID- 27238683 TI - House dust mite link with child asthma. AB - The level of house dust mite a child is exposed to during its first year of life plays a crucial role in determining whether that child goes on to develop asthma, recent research funded by the National Asthma Campaign reveals. PMID- 27238684 TI - Osteoporosis cure undergoes tests. AB - Osteoporosis may be treated or even reversed by a drug which has previously been used in the management of Paget's Disease, two new studies have shown. PMID- 27238685 TI - Tests positive on aluminium absorption. AB - Aluminium can be absorbed through the gut and deposited in bone, new research has revealed. PMID- 27238686 TI - 'Caring for romania appeal'. AB - Romania Romanian Health Minister Dr Bogdan Marinescu gave the 'Caring for Romania Appeal' his seal of approval at a recent meeting with Appeal representatives in Bucharest. PMID- 27238688 TI - Islet cell transplant not justified. AB - Transplantation of pancreatic islet cells is feasible but widespread clinical trials cannot be justified at present. PMID- 27238689 TI - Contact lens measures ultraviolet exposure. AB - A contact lens which can measure the amount of ultraviolet light entering the eye has been developed by Australian researchers. PMID- 27238690 TI - Evidence mounts on aluminium dangers. AB - A researcher claims to have found the first clear evidence for an effect on mental ability from exposure to aluminium. PMID- 27238692 TI - Increase in allergic skin reactions found. AB - The prevalence of atopy may have increased in the UK over recent decades, researchers say. PMID- 27238691 TI - Drug resistant tuberculosis and HIV. AB - High frequencies of drug resistant tuberculosis in people who are HIV positive are reported from America. PMID- 27238693 TI - A Buddhist approach to hospice care. AB - The words 'hospice care' may well bring to mind images of sensitive professionalism in pleasant, hushed surroundings, with skilled nurses knowing how to tackle problems of imminent death and grieving. PMID- 27238694 TI - [Not Available]. PMID- 27238695 TI - RCN should be more thoughtful. AB - Bank name and account number; address of employer; date of completion of nurse training; RCN membership number and expiry date; even the address of the regional office: all this very personal information is available for anyone to see, everytime the RCN uses those blue plastic envelopes to send out its mailings in. 'Private and confidential' it says on the front. What a joke! PMID- 27238697 TI - Conclusion not supported by fact. AB - The conclusions drawn by Carol Auchterloni, the Association of Community Health Councils (ACHEW) Research and Information Officer, ('Large numbers fail to understand NHS reforms' Nursing Standard August 8-15 1990), are not supported by the facts of the survey. PMID- 27238696 TI - Nursing records prove invaluable. AB - In the light of a recent murder trial in which two defendants accused of murdering their child, which attracted considerable press coverage, I feel it is necessary to emphasise how important nursing records are. PMID- 27238698 TI - Say no to financial help? AB - With reference to your feature on multiple births and their financial implications (Nursing Standard August 22-28 1990), my concerns are: a) Were the parents informed prior to treatment that multiple births might result? PMID- 27238699 TI - An apology. AB - In Nursing Standard August 29-September 4, 1990 issue, one of the contributor's names was spelt incorrectly. The title of the article was 'Yuppie 'flu - a real illness' and the correct spelling of the interviewee's name is John Brodrick. PMID- 27238700 TI - Information exchange. AB - We are two health visitors currently working full time, hoping to commence a job share post next year. We have little information regarding the above. PMID- 27238701 TI - Answers to last week's crossword puzzle. AB - Across 1 Tranquilliser, 8 Moa, 9 Endurance, 10 Lightest, 11 Ague, 14 Stop-overs, 17 Tray, 18 Filigree, 20 Operative, 22 'Tis, 23 Elephantiasis. PMID- 27238703 TI - Anorexia Nervosa and the Wish to Change Anorexia nervosa and the wish to change Crisp A , Joughin N , Halek C , Bowyer C Dept Mental Health Sciences, St George's Hospital Medical School, London SW17 0RE 106pp L5.00 0-9515431-0-5. AB - As a ward sister running an acute medical ward specialising in nutrition, I had read little on the subject of anorexia nervosa and was, therefore, delighted to get this book to review. PMID- 27238705 TI - A fitting position. AB - Tom Bolger, nurse manager and senior educationalist has never been a man to disguise his ambition. PMID- 27238706 TI - Trained to Act. AB - The implementation date for the new Children's Act is approaching with speed but the professionals at the front line - community nurses - are being deprived of the training and support needed to ensure its laudible aims come to fruition. PMID- 27238707 TI - Placental growth factor as a marker of fetal growth restriction caused by placental dysfunction. AB - INTRODUCTION: Discriminating between placentally-mediated fetal growth restriction and constitutionally-small fetuses is a challenge in obstetric practice. Placental growth factor (PlGF), measurable in the maternal circulation, may have this discriminatory capacity. METHODS: Plasma PlGF was measured in women presenting with suspected fetal growth restriction (FGR; ultrasound fetal abdominal circumference <10th percentile for gestational age) at sites in Canada, New Zealand and the United Kingdom. When available, placenta tissue underwent histopathological examination for lesions indicating placental dysfunction, blinded to PlGF and clinical outcome. Lesions were evaluated according to pre specified severity criteria and an overall severity grade was assigned (0-3, absent to severe). Low PlGF (concentration <5th percentile for gestational age) to identify placental FGR (severity grade>=2) was assessed and compared with routine parameters for fetal assessment. For all cases, the relationship between PlGF and the sampling-to-delivery interval was determined. RESULTS: Low PlGF identified placental FGR with an area under the receiver-operator characteristic curve of 0.96 [95% CI 0.93-0.98], 98.2% [95% CI 90.5-99.9] sensitivity and 75.1% [95% CI 67.6-81.7] specificity. Negative and positive predictive values were 99.2% [95% CI 95.4-99.9] and 58.5% [95% CI 47.9-68.6], respectively. Low PlGF outperformed gestational age, abdominal circumference and umbilical artery resistance index in predicting placental FGR. Very low PlGF (<12 pg/mL) was associated with shorter sampling-to-delivery intervals than normal PlGF (13 vs. 29.5 days, P < 0.0001). DISCUSSION: Low PlGF identifies small fetuses with significant underlying placental pathology and is a promising tool for antenatal discrimination of FGR from fetuses who are constitutionally-small. PMID- 27238708 TI - Human extravillous trophoblasts bind but do not internalize antiphospholipid antibodies. AB - INTRODUCTION: Obstetric morbidity in women with antiphospholipid antibodies (aPLs) may reflect the adverse effects of aPLs on placental cells such as extravillous trophoblasts and the syncytiotrophoblast. Antiphospholipid antibodies may affect the syncytiotrophoblast after being internalised by members of the Low-density lipoprotein receptor (LDLR) family and the antigen of aPLs, beta2 glycoprotein I. AIM: This study aimed to determine whether aPL internalization was a mechanism by which aPLs adversely affect extravillous trophoblasts. METHOD: of STUDY: Fluorescently-labelled monoclonal aPLs IIC5 or ID2 were incubated with first trimester extravillous trophoblast outgrowths and visualized by microscopy. The subcellular expression of beta2 glycoprotein I and LDLR family members was investigated by live/permeabilised immunocytochemistry. RESULTS: Unlike the syncytiotrophoblast of anchoring villi, monoclonal aPLs were not internalised by extravillous trophoblasts, which expressed LDLR family members intracellularly. The aPL IIC5 bound to the surface of extravillous trophoblasts in a pattern similar to the extracellular expression of beta2 glycoprotein I. CONCLUSIONS: The mechanisms of action of aPLs are different in extravillous trophoblasts and the syncytiotrophoblast. The interaction of aPLs with the extravillous trophoblast surface, which may involve beta2 glycoprotein I, is consistent with reports that aPLs trigger intracellular signaling cascades through cell-surface receptors. PMID- 27238709 TI - Comprehensive investigation of DNA methylation and gene expression in trisomy 21 placenta. AB - INTRODUCTION: Trisomy 21 (T21) is the most common aneuploidy affecting humans and is caused by an extra copy of all or part of chromosome 21 (chr21). DNA methylation is an epigenetic event that plays an important role in human diseases via regulation of gene expression. However, the integrative association between DNA methylation and gene expression in T21 fetal placenta has yet to be determined. METHODS: We profiled expression of 207 genes on chr21 and their DNA methylation patterns in placenta samples from normal and DS fetuses using microarray analysis and predicted the functions of differentially expressed genes using bioinformatics tools. RESULTS: We found 47 genes with significantly increased expression in the T21 placenta compared to the normal placenta. Hypomethylation of the 47 genes was observed in the T21 placenta. Most of hypomethylated DNA positions were intragenic regions, i.e. regions inside a gene. Moreover, gene expression and hypomethylated DNA position showed significantly positive associations. By analyzing the properties of the gene-disease network, we found that increased genes in the T21 placenta were significantly associated with T21 and T21 complications such as mental retardation, neurobehavioral manifestations, and congenital abnormalities. DISCUSSION: To our knowledge, this is the first study to comprehensively survey the association between gene expression and DNA methylation in chr21 of the T21 fetal placenta. Our findings provide a broad overview of the relationships between gene expression and DNA methylation in the placentas of fetuses with T21 and could contribute to future research efforts concerning genes involvement in disease pathogenesis. PMID- 27238710 TI - The atrial natriuretic peptide (ANP) knockout mouse does not exhibit the phenotypic features of pre-eclampsia or demonstrate fetal growth restriction. AB - The ANP knockout mouse is reported to exhibit pregnancy-associated hypertension, proteinuria and impaired placental trophoblast invasion and spiral artery remodeling, key features of pre-eclampsia (PE). We hypothesized that these mice may provide a relevant model of human PE with associated fetal growth restriction (FGR). Here, we investigated pregnancies of ANP wild type (ANP(+/+)), heterozygous (ANP(+/-)) and knockout (ANP(-/-)) mice. Maternal blood pressure did not differ between genotypes (E12.5, E17.5), and fetal weight (E18.5) was unaffected. Placental weight was greater in ANP(-/-) versus ANP(+/+) mice. Therefore, in our hands, the ANP model does not express phenotypic features of PE with FGR. PMID- 27238711 TI - Coordinated expression of TNFalpha- and VEGF-mediated signaling components by placental macrophages in early and late pregnancy. AB - INTRODUCTION: Mononuclear phagocytes are thought to significantly contribute to cytokine regulation at the maternal-foetal interface, but the role of placental macrophages has been poorly investigated. TNFalpha and VEGF were demonstrated to have regulatory effects on basic structures of the placenta, particularly the trophoblast and blood vessels. The aims of this study were to determine the expression of TNFalpha, VEGF and related receptors in placental macrophages, and how does the participation of placental macrophages alter with gestational age in TNFalpha- and VEGF-mediated signaling. METHODS: Macrophages were isolated from placental villous tissue from normal pregnancies at either 9-12 or 38-40 weeks gestation. Cell surface receptors (TNFR1, TNFR2, VEGFR1, and VEGFR2) and intracellular TNFalpha and VEGF were quantified by flow cytometry after antibody staining. Basal and stimulated secretion of both cytokines and soluble TNF receptors was quantified by cytometric bead arrays. Secreted VEGFR1 was measured by ELISA. RESULTS: The expression of TNFR1 and VEGFR1 was remarkably variable and did not change from first to third trimester. There was minimal basal TNFalpha production in the placental macrophages, but nearly all cells in the population produced VEGF. TNFalpha and VEGF secretion increased with gestational age accompanied by decreased secretion of the antagonists sTNFR1 and sVEGFR. Macrophages isolated from early term placentas were less effective in responding to bacterial endotoxin. Lipopolysaccharide induced increases in the secretion of TNFalpha, TNFR1, TNFR2, and VEGFR1 but did not affect the production of VEGF. In late pregnancy, a significant correlation was observed between TNFR1 and VEGFR1. DISCUSSION: The progression of pregnancy is accompanied by the concerted increase in TNFalpha and VEGF secretion and decrease in the production of their soluble receptors, but the expression of cell surface receptors does not depend on gestational age. The observed patterns of basal and stimulated expression of TNFalpha and VEGF may reflect the dual immune and morphogenetic roles of placental macrophages in gestation. Compatible patterns of TNFR1 and VEGFR1 expression suggest common regulatory pathways for these receptors. PMID- 27238712 TI - Revisiting decidual vasculopathy. AB - INTRODUCTION: In the setting of preeclampsia (PE), decidual vasculopathy (DV) can be seen along the free membranes. METHODS: We describe DV using stains for CD31, CD34, Cd42b, CD68, desmin, fibrin and Masson's trichrome in patients with preeclampsia and fetal growth restriction. RESULTS: We first examined the "membrane roll" sections from the placentas of six patients with preeclampsia. Affected vessels showed endothelial proliferation with detachment. Remodeling of the media was characterized by smooth muscle loss with variable degrees of fibrin deposition. CD31 and CD34 highlighted the prominent endothelium and showed striking particulate staining throughout the media. All of these findings infer a sequence of endothelial injury, fragmentation and repair with incorporation of endothelial components into the vascular wall. We evaluated the frequency of DV by clinical presentation; in cases with PE with and without small for gestational age (SGA) (N = 15), and SGA with and without Doppler flow abnormalities (N = 15). All groups except the SGA without Doppler abnormalities showed DV. Among placentas with DV, the most severely affected group was PE with SGA; the least affected was PE without SGA. DISCUSSION: The association with SGA suggests that the DV is a subacute process of vascular injury that accelerates in the setting of PE. The majority of DV cases were not initially recognized suggesting a role for endothelial markers for DV detection. We also propose that the rampant endothelial injury seems to be a prominent finding in the decidual vessels of subjects with PE complicated by SGA and a similar process in the systemic vasculature may be responsible for the circulating endothelial microparticles reported in such patients. PMID- 27238713 TI - Association of first-trimester angiogenic factors with placental histological findings in late-onset preeclampsia. AB - OBJECTIVE: To explore in women with late-onset preeclampsia (PE) the association between maternal levels of angiogenic/antiangiogenic factors in the first trimester of pregnancy and histological findings attributable to placental underperfusion (PUP). METHODS: A nested case-control cohort study was conducted in 73 women with pregnancies complicated by late-onset PE (>34 weeks at delivery) matched with controls. First trimester uterine artery Doppler (UtA); maternal levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were retrieved. Placentas were histologically evaluated using a hierarchical and standardized classification system. One-way ANOVA with linear polynomial contrast or linear-by-linear association test was performed to test the hypothesis of a linear association across study groups (controls, PE without PUP and PE with PUP). RESULTS: In 54 (74%) placentas, 89 placental histological findings qualifying for PUP were found. Across study groups, significant values were observed in maternal levels of decreased PlGF (MoM values: 1.53, 1.41 and 1.37; p < 0.001), increased sFlt-1 (MoM values: 3.11, 3.11 and 3.22; p = 0.002), increased sFlt-1/PlGF ratio (MoM values: 2.3, 2.3 and 2.44; p < 0.001), abnormal UtA Doppler (MoM values: 1, 1.26 and 1.32; p < 0.001), and worse perinatal outcomes in terms of gestational age at delivery, cesarean section for not reassuring fetal status, birth weight and neonatal acidosis. DISCUSSION: In late onset PE an imbalance of circulating angiogenic and anti-angiogenic factors already present at 8-10 weeks of pregnancy was associated with histological findings reflecting placental insufficiency. An early first trimester screening by angiogenic factors might help to identify patients with placental involvement among late-onset PE cases. CONCLUSION: In late-onset preeclampsia, first trimester uterine Doppler and circulating levels of angiogenic/antiangiogenic factors are associated with placental underperfusion. PMID- 27238714 TI - Third trimester placental volume and biometry measurement: A method-development study. AB - OBJECTIVES: To test the hypothesis that third trimester placental biometry and volume can be measured by two-dimensional (2D) and three-dimensional (3D) ultrasound in utero, determining which method of measurement was most strongly correlated with true placental size ex vivo. METHODS: Singleton pregnancies underwent placental ultrasound within seven days of delivery (n = 87, 29(+3) 41(+5) weeks). Length and width (linear and curvilinear) and depth were estimated. Placental volume (PV) was estimated using 2D ellipse and shell techniques and 3D rotational (150 and 300 rotation angles) and multiplanar (5 and 10 mm slicing intervals) techniques. Measurements were compared to their true correlates following delivery. Intra- and inter-observer reliabilities of candidate placental size estimates were assessed by intraclass correlation coefficient (ICC). RESULTS: Curvilinear placental length (Rs = 0.24, p = 0.031), width (Rs = 0.27, p = 0.013) and depth (Rs = 0.31, p = 0.0056) correlated well with ex vivo measurements. All methods of PV estimation were related to ex vivo volume (Rs >= 0.32, p < 0.01) but not placental weight (p > 0.05); 30 degrees rotational estimation demonstrated the strongest biological correlation (Rs = 0.40, p = 0.0004). Intra- and inter-observer placental size measurements intraclass correlation coefficients were suboptimal (0.59-0.70 and 0.10-0.58 respectively). DISCUSSION: We have demonstrated that it is possible to obtain information about the size of the third trimester placenta in utero using 2D and 3D ultrasound. However it is essential that the reliability (particularly interobserver reliability) of these estimates is improved prior to prospective studies to determine their predictive value. PMID- 27238715 TI - The physiology of fetal membrane weakening and rupture: Insights gained from the determination of physical properties revisited. AB - Rupture of the fetal membranes (FM) is precipitated by stretch forces acting upon biochemically mediated, pre-weakened tissue. Term FM develop a para-cervical weak zone, characterized by collagen remodeling and apoptosis, within which FM rupture is thought to initiate. Preterm FM also have a weak region but are stronger overall than term FM. Inflammation/infection and decidual bleeding/abruption are strongly associated with preterm premature FM rupture (pPROM), but the specific mechanisms causing FM weakening-rupture in pPROM are unknown. There are no animal models for study of FM weakening and rupture. Over a decade ago we developed equipment and methodology to test human FM strength and incorporated it into a FM explant system to create an in-vitro human FM weakening model system. Within this model TNF (modeling inflammation) and Thrombin (modeling bleeding) both weaken human FM with concomitant up regulation of MMP9 and cellular apoptosis, mimicking the characteristics of the spontaneous FM rupture site. The model has been enhanced so that test agents can be applied directionally to the choriodecidual side of the FM explant consistent with the in-vivo situation. With this enhanced system we have demonstrated that the pathways involving inflammation/TNF and bleeding/Thrombin induced FM weakening overlap. Furthermore GM-CSF production was demonstrated to be a critical common intermediate step in both the TNF and the Thrombin induced FM weakening pathways. This model system has also been used to test potential inhibitors of FM weakening and therefore pPROM. The dietary supplement alpha-lipoic acid and progestogens (P4, MPA and 17alpha hydroxyprogesterone) have been shown to inhibit both TNF and Thrombin induced FM weakening. The progestogens act at multiple points by inhibiting both GM-CSF production and GM-CSF action. The use of a combined biomechanical/biochemical in vitro human FM weakening model system has allowed the pathways of fetal membrane weakening to be delineated, and agents that may be of clinical use in inhibiting these pathways to be tested. PMID- 27238717 TI - A simple histochemical method for the identification of cytotrophoblasts in tissue sections. AB - A simple method for the demonstration of placental cytotrophoblast cells is described, utilising the affinity of the lectin from Bandeiraea simplicifolia-II (BSA-II) for intracellular amylase-sensitive glycogen and a protocol using biotinylated BSA-II followed by an avidin-peroxidase revealing system. In early pregnancy, cytotrophoblast cells in chorionic and anchoring villi are deeply stained and with ongoing differentiation the staining gradually decreases in intensity, suggesting that this lectin can be a useful marker for these cells. PMID- 27238716 TI - Differential patterning of genes involved in serotonin metabolism and transport in extra-embryonic tissues of the mouse. AB - INTRODUCTION: Serotonin (5-HT) is an important neuromodulator, but recently has been shown to be involved in neurodevelopment. Although previous studies have demonstrated that the placenta is a major source of forebrain 5-HT during early forebrain development, the processes of how 5-HT production, metabolism, and transport from placenta to fetus are regulated are unknown. As an initial step in determining the mechanisms involved, we investigated the expression patterns of genes critical for 5-HT system function in mouse extraembryonic tissues. METHODS: Mid-through late gestation expression of 5-HT system-related enzymes, Tph1, Ddc, Maoa, and 5-HT transporters, Sert/Slc6a4, Oct3/Slc22a3, Vmat2/Slc18a2, and 5-HT in placenta and yolk sac were examined, with cell type-specific resolution, using multiplex fluorescent in situ hybridization to co-localize transcripts and immunocytochemistry to co-localize the corresponding proteins and neurotransmitter. RESULTS: Tph1 and Ddc are found in the syncytiotrophoblast I (SynT-I) and sinusoidal trophoblast giant cells (S-TGC), whereas Maoa is expressed in SynT-I, syncytiotrophoblast II (SynT-II) and S-TGC. Oct3 expression is observed in the SynT-II only, while Vmat2 is mainly expressed in S-TGC. Surprisingly, there were comparatively high expression of Tph1, Ddc, and Maoa in the yolk sac visceral endoderm. DISCUSSION: In addition to trophoblast cells, visceral endoderm cells in the yolk sac may contribute to fetal 5-HT production. The findings raise the possibility of a more complex regulation of 5-HT access to the fetus through the differential roles of trophoblasts that surround maternal and fetal blood space and of yolk sac endoderm prior to normal degeneration. PMID- 27238718 TI - Velamentous cord insertion in dichorionic and monochorionic twin pregnancies - Does it make a difference? AB - OBJECTIVE: To estimate the prevalence of velamentous cord insertion (VCI) in dichorionic (DC) and monochorionic (MC) twins with and without twin-twin transfusion syndrome (TTTS), and to study the associated outcomes. METHODS: We recorded the type of umbilical cord insertion in all consecutive DC and MC placentas examined in two European tertiary medical centers. The association between VCI and perinatal outcomes was estimated and compared. RESULTS: A total of 1498 twin placentas were included in this study (DC placentas n = 550, MC placentas without TTTS n = 513 and MC placentas with TTTS n = 435). The prevalence of VCI in DC, MC without TTTS and MC with TTTS groups was 7.6%, 34.7% and 36.1%, respectively (P < 0.001). In MC twins (non-TTTS and TTTS groups), VCI was associated with severe birth weight discordance (odds ratio [OR] 4.76 95% CI 2.43, 10.47 and OR 4.52 95% CI 1.30, 28.59, respectively). In MC twins without TTTS, VCI was associated with small for gestational age (OR 1.66, 95% CI 1.12, 2.50). VCI was significantly associated with increased risk of intrauterine fetal demise in MC twins, and this effect was greater in the non-TTTS group (OR 2.71 95% CI 1.38, 5.47). These associations did not occur in DC group. Gestational age at birth was lower in the presence of VCI in the DC and MC twins without TTTS. CONCLUSION: Our findings confirm that the prevalence of VCI is higher in MC twins than in DC twin pregnancies. VCI is an important indicator of adverse perinatal outcome, particularly in MC twins. PMID- 27238719 TI - Clustering and classical analysis of clinical and placental phenotypes in fetal growth restriction and constitutional fetal smallness. AB - This study aims to determine whether placental examination can be used to distinguish between pathologic fetal growth restriction (FGR) and constitutional fetal smallness. Data were extracted from a clinicoplacental database of high risk pregnancies during the period 1994-2013. These data were used to compare the 590 consecutive cases having birth weights below the 10th percentile with the 5201 remaining cases having gestational ages >=20 weeks. The authors analyzed 20 clinical and 46 placental phenotypes using classical statistics, clustering analysis, and multidimensional scaling. Of the low-birth-weight babies, the following types of cases were compared: Four categories of placental phenotypes (those with features of poor uteroplacental perfusion, postuterine placental pathology, chronic inflammation, and a mixed category) better defined the presumably true FGR than did the clinical phenotypes. Maternal smoking and oligohydramnios were associated with fewer abnormal placental phenotypes than were maternal hypertensive diseases and abnormal Dopplers. Early-onset cases of fetal smallness clustered with placental features of poor uteroplacental perfusion, whereas late onset cases did not. Placental examination helps to retrospectively distinguish constitutionally small fetuses from those that are pathologically growth restricted. The latter correlate best with the clinical risk for FGR and with early-onset FGR. This correlation may have prognostic significance for the child and for future pregnancies, since hypoxic placental lesions can occur without clinical risk factors but with a tendency to recur in future pregnancies. PMID- 27238720 TI - Leptin reduces apoptosis triggered by high temperature in human placental villous explants: The role of the p53 pathway. AB - Maternal fever is common during pregnancy and has for many years been suspected to harm the developing fetus. Whether increased maternal temperature produces exaggerated apoptosis in trophoblast cells remains unclear. Since p53 is a critical regulator of apoptosis we hypothesized that increased temperature in placenta produces abnormal expression of proteins in the p53 pathway and finally caspase-3 activation. Moreover, leptin, produced by placenta, is known to promote the proliferation and survival of trophoblastic cells. Thus, we aimed to study the possible role of leptin preventing apoptosis triggered by high temperature, as well as the molecular mechanisms underlying this effect. Fresh placental tissue was collected from normal pregnancies. Explants of placental villi were exposed to 37 degrees C, 40 degrees C and 42 degrees C during 3 h in the presence or absence of 10 nM leptin in DMEM-F12 medium. Western blotting and qRT PCR was performed to analyze the expression of p53 and downstream effector, P53AIP1, Mdm2, p21, BAX and BCL-2 as well as the activated cleaved form of caspase-3 and the fragment of cytokeratin-18 (CK-18) cleaved at Asp396 (neoepitope M30). Phosphorylation of the Ser 46 residue on p53, the expression of P53AIP1, Mdm2, p21, as well as caspase-3 and CK-18 were significantly increased in explants at 40 degrees C and 42 degrees C. Conversely, these effects were significantly attenuated by leptin 10 nM at both 40 degrees C and 42 degrees C. The BCL2/BAX ratio was also significantly decreased in explants at 40 degrees C and 42 degrees C compared with explants incubated at 37 degrees C, which was prevented by leptin stimulation. These data illustrate the potential role of leptin for reducing apoptosis in trophoblast explants, including trophoblastic cells, triggered by high temperature, by preventing the activation of p53 signaling. PMID- 27238721 TI - In vitro effects of vitamins C and E, n-3 and n-6 PUFA and n-9 MUFA on placental cell function and redox status in type 1 diabetic pregnant women. AB - The aim of this investigation was to determine the in vitro effects of vitamin C and E, n-3 and n-6 PUFA and n-9 MUFA on placental cell proliferation and function in type 1 diabetes. Placenta tissues were collected from 30 control healthy and 30 type 1 diabetic women at delivery. Placental cells were isolated and were cultured in RPMI medium supplemented with vitamin C (50 MUM), vitamin E (50 MUM), n-3 PUFA (100 MUM), n-6 PUFA (100 MUM) or n-9 MUFA (100 MUM). Cell proliferation, cell glucose uptake and intracellular oxidative status were investigated. Our results showed that basal placental cell proliferation, glucose uptake, malondialdehyde (MDA) and carbonyl proteins were higher while intracellular reduced glutathione (GSH) levels and catalase activities were lower in placentas from diabetic women as compared to controls. Vitamins C and E induced a modulation of placental cell proliferation and glucose consumption without affecting intracellular redox status in both diabetic and control groups. N-3 and n-6 PUFA diminished placental cell proliferation and enhanced intracellular oxidative stress while n-9 MUFA had no effects in the two groups. Co administration of n-3 or n-6 PUFA and vitamin C or E were capable of reversing back the PUFA-decreased cell proliferation and normalizing placental cell function and redox status especially in diabetes. In conclusion, PUFA and antioxidant vitamin combinations may be beneficial in improving placenta function and in reducing placental oxidative stress in type 1 diabetic pregnancy. PMID- 27238722 TI - An interim solution for a fractured complete-arch fixed implant-supported prosthesis using an Essix retainer. PMID- 27238724 TI - Genistein inhibition of OGD-induced brain neuron death correlates with its modulation of apoptosis, voltage-gated potassium and sodium currents and glutamate signal pathway. AB - In the present study, we established an in vitro model of hypoxic-ischemia via exposing primary neurons of newborn rats to oxygen-glucose deprivation (OGD) and observing the effects of genistein, a soybean isoflavone, on hypoxic-ischemic neuron viability, apoptosis, voltage-activated potassium (Kv) and sodium (Nav) currents, and glutamate receptor subunits. The results indicated that OGD exposure reduced the viability and increased the apoptosis of brain neurons. Meanwhile, OGD exposure caused changes in the current-voltage curves and current amplitude values of voltage-activated potassium and sodium currents; OGD exposure also decreased GluR2 expression and increased NR2 expression. However, genistein at least partially reversed the effects caused by OGD. The results suggest that hypoxic-ischemia-caused neuronal apoptosis/death is related to an increase in K(+) efflux, a decrease in Na(+) influx, a down-regulation of GluR2, and an up regulation of NR2. Genistein may exert some neuroprotective effects via the modulation of Kv and Nav currents and the glutamate signal pathway, mediated by GluR2 and NR2. PMID- 27238725 TI - Design and synthesis of N-substituted-2-hydroxyiminoacetamides and interactions with cholinesterases. AB - Within this study, we designed and synthesized four new oxime compounds of the N substituted 2-hydroxyiminoacetamide structure and evaluated their interactions with acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Our aim was to explore the possibility of extending the dual-binding mode of interaction between the enzyme and the inhibitor to a so-called triple-binding mode of interaction through the introduction of an additional binding moiety. N-substituted 2 hydroxyiminoacetamide 1 was prepared via BOP catalyzed amidation of hydroxyiminoacetic acid with 3-azido-1-phenylpropylamine. An azide group enabled us to prepare more elaborate structures 2-4 by the copper-catalyzed azide-alkyne cycloaddition. The new compounds 1-4 differed in their presumed AChE peripheral site binding moiety, which ranged from an azide group to functionalized heterocycles. Molecular docking studies revealed that all three binding moieties are involved in the non-covalent interactions with ChEs for all of the four compounds, albeit not always in the complete accordance with the proposed hypothesis. All of the four compounds reversibly inhibited the ChEs with their inhibition potency increasing in the same order for both enzymes (1 < 2 < 4 < 3). A higher preference for binding to BChE (KI from 0.30 MUmol/L to 130 MUmol/L) over AChE (KI from 50 MUmol/L to 1200 MUmol/L) was observed for all of the compounds. Compounds were screened for reactivation of cyclosarin-, sarin- and VX inhibited AChE and BChE. PMID- 27238726 TI - BOLD fMRI in awake prairie voles: A platform for translational social and affective neuroscience. AB - The advancement of neuroscience depends on continued improvement in methods and models. Here, we present novel techniques for the use of awake functional magnetic resonance imaging (fMRI) in the prairie vole (Microtus ochrogaster) - an important step forward in minimally-invasive measurement of neural activity in a non-traditional animal model. Imaging neural responses in prairie voles, a species studied for its propensity to form strong and selective social bonds, is expected to greatly advance our mechanistic understanding of complex social and affective processes. The use of ultra-high-field fMRI allows for recording changes in region-specific activity throughout the entire brain simultaneously and with high temporal and spatial resolutions. By imaging neural responses in awake animals, with minimal invasiveness, we are able to avoid the confound of anesthesia, broaden the scope of possible stimuli, and potentially make use of repeated scans from the same animals. These methods are made possible by the development of an annotated and segmented 3D vole brain atlas and software for image analysis. The use of these methods in the prairie vole provides an opportunity to broaden neuroscientific investigation of behavior via a comparative approach, which highlights the ethological relevance of pro-social behaviors shared between voles and humans, such as communal breeding, selective social bonds, social buffering of stress, and caregiving behaviors. Results using these methods show that fMRI in the prairie vole is capable of yielding robust blood oxygen level dependent (BOLD) signal changes in response to hypercapnic challenge (inhaled 5% CO2), region-specific physical challenge (unilateral whisker stimulation), and presentation of a set of novel odors. Complementary analyses of repeated restraint sessions in the imaging hardware suggest that voles do not require acclimation to this procedure. Taken together, awake vole fMRI represents a new arena of neurobiological study outside the realm of traditional rodent models. PMID- 27238727 TI - Social touch modulates endogenous MU-opioid system activity in humans. AB - In non-human primates, opioid-receptor blockade increases social grooming, and the endogenous opioid system has therefore been hypothesized to support maintenance of long-term relationships in humans as well. Here we tested whether social touch modulates opioidergic activation in humans using in vivo positron emission tomography (PET). Eighteen male participants underwent two PET scans with [11C]carfentanil, a ligand specific to MU-opioid receptors (MOR). During the social touch scan, the participants lay in the scanner while their partners caressed their bodies in a non-sexual fashion. In the baseline scan, participants lay alone in the scanner. Social touch triggered pleasurable sensations and increased MOR availability in the thalamus, striatum, and frontal, cingulate, and insular cortices. Modulation of activity of the opioid system by social touching might provide a neurochemical mechanism reinforcing social bonds between humans. PMID- 27238723 TI - Paraoxonases-1, -2 and -3: What are their functions? AB - Paraoxonase-1 (PON1), an esterase/lactonase primarily associated with plasma high density lipoprotein (HDL), was the first member of this family of enzymes to be characterized. Its name was derived from its ability to hydrolyze paraoxon, the toxic metabolite of the insecticide parathion. Related enzymes PON2 and PON3 were named from their evolutionary relationship with PON1. Mice with each PON gene knocked out were generated at UCLA and have been key for elucidating their roles in organophosphorus (OP) metabolism, cardiovascular disease, innate immunity, obesity, and cancer. PON1 status, determined with two-substrate analyses, reveals an individual's functional Q192R genotype and activity levels. The three dimensional structure for a chimeric PON1 has been useful for understanding the structural properties of PON1 and for engineering PON1 as a catalytic scavenger of OP compounds. All three PONs hydrolyze microbial N-acyl homoserine lactone quorum sensing factors, quenching Pseudomonas aeruginosa's pathogenesis. All three PONs modulate oxidative stress and inflammation. PON2 is localized in the mitochondria and endoplasmic reticulum. PON2 has potent antioxidant properties and is found at 3- to 4-fold higher levels in females than males, providing increased protection against oxidative stress, as observed in primary cultures of neurons and astrocytes from female mice compared with male mice. The higher levels of PON2 in females may explain the lower frequency of neurological and cardiovascular diseases in females and the ability to identify males but not females with Parkinson's disease using a special PON1 status assay. Less is known about PON3; however, recent experiments with PON3 knockout mice show them to be susceptible to obesity, gallstone formation and atherosclerosis. Like PONs 1 and 2, PON3 also appears to modulate oxidative stress. It is localized in the endoplasmic reticulum, mitochondria and on HDL. Both PON2 and PON3 are upregulated in cancer, favoring tumor progression through mitochondrial protection against oxidative stress and apoptosis. PMID- 27238729 TI - Trace element research-historical and future aspects. AB - During the last 30 years the International Society for Trace Element Research and the Nordic Trace Element Society has been active . During this period the importance of these elements for human diseases has been increasingly recognized, including their contribution to the global burden of disease. New analytical methods allow biomonitoring data to be related to health outcome. Future research using modern chemical methods will focus more on elemental speciation and on measuring lower concentrations leading to further identifying adverse effects and critical organs. Extensive knowledge about essentiality and toxicity of trace elements in humans has emerged during the last two decades and at present the difficulties in defining a range of acceptable oral intakes for essential elements has largely been overcome. Biological monitoring of trace element concentrations in various media such as blood or urine is of great importance and an overview is given. As an example, a more detailed description of biological monitoring of cadmium is given, explaining biokinetics including the role of metallothionein in modifying kinetics and toxicity. Finally future challenges related to risk assessment of newly developed metallic nanomaterials and metal containing medical devices are discussed. PMID- 27238728 TI - Fate of over 480 million inhabitants living in arsenic and fluoride endemic Indian districts: Magnitude, health, socio-economic effects and mitigation approaches. AB - During our last 27 years of field survey in India, we have studied the magnitude of groundwater arsenic and fluoride contamination and its resulting health effects from numerous states. India is the worst groundwater fluoride and arsenic affected country in the world. Fluoride results the most prevalent groundwater related diseases in India. Out of a total 29 states in India, groundwater of 20 states is fluoride affected. Total population of fluoride endemic 201 districts of India is 411 million (40% of Indian population) and more than 66 million people are estimated to be suffering from fluorosis including 6 million children below 14 years of age. Fluoride may cause a crippling disease. In 6 states of the Ganga-Brahmaputra Plain (GB-Plain), 70.4 million people are potentially at risk from groundwater arsenic toxicity. Three additional states in the non GB-Plain are mildly arsenic affected. For arsenic with substantial cumulative exposure can aggravate the risk of cancers along with various other diseases. Clinical effects of fluoride includes abnormal tooth enamel in children; adults had joint pain and deformity of the limbs, spine etc. The affected population chronically exposed to arsenic and fluoride from groundwater is in danger and there is no available medicine for those suffering from the toxicity. Arsenic and fluoride safe water and nutritious food are suggested to prevent further aggravation of toxicity. The World Health Organization (WHO) points out that social problems arising from arsenic and fluoride toxicity eventually create pressure on the economy of the affected areas. In arsenic and fluoride affected areas in India, crisis is not always having too little safe water to satisfy our need, it is the crisis of managing the water. PMID- 27238730 TI - Free abdominal fat transfer for partial and total parotidectomy defect reconstruction. AB - OBJECTIVES/HYPOTHESIS: A variety of techniques have been proposed for reconstruction of the parotidectomy defect. We reviewed our experience with free abdominal fat transfer (FAT) graft reconstruction of parotidectomy defects for benign and malignant disease. METHODS: The medical records of patients who underwent parotidectomy for benign or malignant disease from 2007 to 2015 were retrospectively reviewed. RESULTS: One hundred and five patients underwent 108 parotidectomies with FAT reconstruction, with bilateral parotidectomy performed in three patients. The majority of patients had benign pathology (71%) and tumors < 3 cm (57%). Prior surgery had been performed in 13 cases (12%) and prior radiation had been performed in three (3%). Superficial parotidectomy was performed in 62 patients (57%) and concurrent elective neck dissection was performed in eight (7%). A facelift incision was utilized in 59 patients (55%). Postoperative radiation was used in 21 patients (19%). Abdominal donor site complications occurred in 11 patients (10%), consisting of hematoma in eight patients (7%) and seroma in three (3%). Parotidectomy wound dehiscence occurred in six cases (6%); all responded to conservative management. There was no association between age, tumor size, comorbidity, smoking status, extent of surgery, incision, or prior radiation on the development of wound complications. Fat transfer graft debulking was required in three patients with persistent overcorrection beyond 6 months postoperatively. No patient demonstrated undercorrection or further FAT resorption beyond 6 months. CONCLUSION: Fat transfer reconstruction of the parotidectomy defect is safe and achieves a consistent and predictable long-term cosmetic result. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:2694-2698, 2016. PMID- 27238731 TI - Hypocomplementemia is a diagnostic clue for parvovirus B19 infection in adults. PMID- 27238732 TI - Potential treatment mechanisms in a mindfulness-based intervention for people with progressive multiple sclerosis. AB - OBJECTIVES: To explore putative mediators of a mindfulness-based intervention to decrease distress in people with multiple sclerosis (MS) and to explore the patients' perspectives on this intervention. DESIGN: We used an explanatory mixed methods design incorporating quantitative data from a pilot randomized control trial and a qualitative interview study with people who completed the mindfulness intervention. METHODS: People with MS (n = 40) completed standardized measures of distress (outcome), and acceptance, decentring, self-compassion, and self efficacy (potential mediators). Semi-structured interviews (n = 15) of patients' experiences of the mindfulness intervention were analysed deductively and inductively. RESULTS: Decentring post-intervention explained 13% of the 3-month change in distress and between 27% and 31% of concurrent changes in distress. Acceptance changed only slightly, and as a result, the indirect effect accounts for only 2% of future distress and between 3% and 11% of concurrent distress. Qualitative data showed that acceptance and self-compassion needed more time to develop, whereas decentring could be implemented readily after being introduced in the sessions. Self-efficacy also had a large mediating effect. Participants in their interviews talked about group dynamics and prior expectations as essential elements that determine their engagement with the course and their level of satisfaction. CONCLUSIONS: Mindfulness interventions for people with a chronic progressive condition may benefit from focusing on helping them to accept daily challenges and teach them to recognize their thoughts and feelings, allowing time for acceptance and self-compassion to develop. Group dynamics also play a fundamental role in the success of the mindfulness interventions. Statement of Contribution What is already known on this subject? Mindfulness courses improve psychological well-being for people with chronic conditions. Mindfulness courses have been successful in improving psychological well-being and symptom management for people with multiple sclerosis but we do not know how these courses work. What does this study add? Decentering and self-efficacy appear to be key mechanisms leading to reduced distress. Acceptance and self-compassion may need more time and practice to develop. Group dynamics and expectations of the mindfulness courses were also important elements of mindfulness. PMID- 27238733 TI - Long-term outcome of changes in cognitive function of young rats after various/different doses of whole brain irradiation. AB - OBJECTIVE: To characterize the early delayed and late-delayed cognitive dysfunction induced by various doses of whole brain irradiation in young rats. METHODS: One-month-old Sprague-Dawley male rats were divided randomly into the 0 (control), 0 (anesthesia control), 2, 10, 20, and 30-Gy groups. Each group was then subdivided into 4 groups according to the experimental intervals: 1, 2, 3, and 6 months after radiation. Rats were irradiated using a 4-MeV electron beam, which was generated by a linear accelerator. Sequential behavioral tests, including open field, novel location and novel object recognition and Morris water maze were performed after radiation. Changes in gross neurological symptoms, body weight, topical skin response, and histopathology were observed. RESULTS: In the open field test, there were no radiation-induced alterations found. In the novel location and novel object recognition tests, rats of the 20 Gy group spent less time exploring the novel object and novel location 3 months after irradiation. During the place navigation test, the spatial working memory of the 30 and 20-Gy irradiated rats were impaired from 1 to 2 months after irradiation, respectively. In the spatial probe test, the 20 and 30-Gy irradiated rats spent less time in the critical region compared to control rats at 3 and 6 months post-irradiation. Morphological changes, including edema, vascular dilation, focal necrosis, demyelination, and adjacent reactive gliosis were observed in the 30-Gy irradiation group. CONCLUSION: More than 20 Gy of whole brain irradiation dose can cause significant cognitive dysfunction in young rats. PMID- 27238735 TI - Dissipativity analysis for discrete singular systems with time-varying delay. AB - In this paper, the issue of dissipativity analysis for discrete singular systems with time-varying delay is investigated. By using a recently developed inequality, which is less conservative than the Jensen inequality, and the improved reciprocally convex combination approach, sufficient criteria are established to guarantee the admissibility and dissipativity of the considered system. Moreover, Hinfinity performance characterization and passivity analysis are carried out. Numerical examples are presented to illustrate the effectiveness of the proposed method. PMID- 27238734 TI - Drugs prescribed for patients hospitalized in a geriatric oncology unit: Potentially inappropriate medications and impact of a clinical pharmacist. AB - OBJECTIVES: The aim of this study was to assess the prevalence of potentially inappropriate medication (PIM) use upon admission and at discharge in a geriatric oncology unit after involving a clinical pharmacist. Although the few studies conducted in geriatric oncology units used the 2003 Beers criteria, this study used START and STOPP criteria, a more appropriate tool for European formularies. MATERIALS AND METHODS: Prospective study in older (>=70years) patients consecutively admitted to a geriatric oncology unit in a cancer center from July 2011 to April 2012. Clinical pharmacist conducted a complete comprehensive medication review including non-prescription and complementary (herbals) medications. This information coupled with the patient's medical history allows identifying PIMs using the STOPP and START criteria. The number of PIMs at admission and at discharge from the hospital was compared after clinical pharmacist intervention. RESULTS: Ninety-one older patients with cancer (mean age+/-SD=79+/-6years) were included in the study. START criteria identified 41 PIMs for 31 persons (34%) at admission compared to 7 PIMs for 6 persons (7%) at discharge. STOPP criteria identified 50 PIMs at admission for 29 persons (32%) compared to 16 PIMs at discharge for 14 persons (16%). Results showed significantly lower START scores at discharge than at admission (p<0.001); similarly, STOPP criteria demonstrated fewer PIMs at discharge than at admission (p<0.001). CONCLUSION: The use of START and STOPP criteria by a clinical pharmacist allows identifying PIMs and changing prescriptions for older patients with cancer in agreement with the oncologist and geriatrician of the team. PMID- 27238736 TI - A novel guidance law using fast terminal sliding mode control with impact angle constraints. AB - This paper is concerned with the question of, for a missile interception with impact angle constraints, how to design a guidance law. Firstly, missile interception with impact angle constraints is modeled; secondly, a novel guidance law using fast terminal sliding mode control based on extended state observer is proposed to optimize the trajectory and time of interception; finally, for stationary targets, constant velocity targets and maneuvering targets, the guidance law and the stability of the closed loop system is analyzed and the stability of the closed loop system is analyzed, respectively. Simulation results show that when missile and target are on a collision course, the novel guidance law using fast terminal sliding mode control with extended state observer has more optimized trajectory and effectively reduces the time of interception which has a great significance in modern warfare. PMID- 27238737 TI - Shooting for the Moon or Flying Too Near the Sun? Crossing the Value Rubicon in Precision Cancer Care. AB - In his last two State of the Union addresses, President Barack Obama has focused on the need to deliver innovative solutions to improve human health, through the Precision Medicine Initiative in 2015 and the recently announced Cancer Moonshot in 2016. Precision cancer care has delivered clear patient benefit, but even for high-impact medicines such as imatinib mesylate (Glivec) in chronic myeloid leukaemia, the excitement at the success of this practice-changing clinical intervention has been somewhat tempered by the escalating price of this 'poster child' for precision cancer medicine (PCM). Recent studies on the costs of cancer drugs have revealed significant price differentials, which are a major causative factor behind disparities in the access to new generations of immunological and molecularly targeted agents. In this perspective, we will discuss the benefits of PCM to modern cancer control, but also emphasise how increasing costs are rendering the current approaches to integrating the paradigm of PCM unsustainable. Despite the ever increasing pressure on cancer and health care budgets, innovation will and must continue. Value-based frameworks offer one of the most rational approaches for policymakers committed to improving cancer outcomes through a public health approach. PMID- 27238738 TI - Craniocervical manual lymphatic drainage and its impact on intracranial pressure a pilot study. AB - BACKGROUND AND PURPOSE: Theoretical considerations and the results of animal studies indicate that manual lymphatic drainage (MLD) might have an impact on intracranial pressure (ICP). There is a lack of clinically qualitative investigations on patients with severe cerebral diseases. METHODS: Between April 2013 and January 2015 a prospective observational study was performed on patients who were undergoing intracranial pressure measurement and treatment with MLD. ICP, cerebral perfusion pressure, mean arterial pressure (MAP), heart rate and oxygen saturation were recorded continuously 15 min before the procedure, during MLD (22 min) and for 15 min after the procedure. For analysis the data treatment units were divided into two groups: patients with a mean baseline ICP <15 mmHg (group 1) and patients with a mean ICP >=15 mmHg before MLD (group 2). RESULTS: A total of 133 treatment units (61 patients) were analysed (group 1 n = 99; group 2 n = 34). The mean baseline ICP was 10.4 mmHg overall, and 8.3 mmHg and 18.6 mmHg respectively in group 1 and group 2; ICP significantly decreased during therapy with MLD and this persisted during the follow-up period in group 2. MAP did not show any significant differences between the different periods. CONCLUSIONS: Our data showed a significant reduction of ICP during therapy with craniocervical MLD in patients with severe cerebral diseases. PMID- 27238739 TI - Computer assisted optical screening of human ovarian cancer using Raman spectroscopy. AB - Conventional screening tools for ovarian cancer such as cancer antigen (CA-125) and trans-pelvic ultrasound have poor sensitivity and specificity, indicating the need for better and more reliable screening methodologies. Here, we investigate the capability of Raman spectroscopy as a screening technique for ovarian cancer. Raman spectra from the blood serum of healthy control and ovarian cancer subjects were measured. Highly significant Raman shifts (p<0.0001) and intensity variations were observed in the cancer group as compared to the healthy group. These spectral differences were exploited by support vector machine classifier towards computer assisted classification. Calculated evaluation metrics such as sensitivity (=90), specificity (=100), positive predictive value (=100) and negative predictive value (=87.5) for such classification indicated that these results are promising, with potential future application of Raman spectroscopy for ovarian cancer screening. PMID- 27238740 TI - Stenotrophomonas maltophilia OleC-Catalyzed ATP-Dependent Formation of Long-Chain Z-Olefins from 2-Alkyl-3-hydroxyalkanoic Acids. AB - The bacterial pathway of olefin biosynthesis starts with OleA catalyzed "head-to head" condensation of two CoA-activated long-chain fatty acids to generate (R)-2 alkyl-3-ketoalkanoic acids. A subsequent OleD-catalyzed reduction generates (2R,3S)-2-alkyl-3-hydroxyalkanoic acids. We now show that the final step in the pathway is an OleC-catalyzed ATP-dependent decarboxylative dehydration to form the corresponding Z olefins. Higher kcat /Km values were seen for substrates with longer alkyl chains. All four stereoisomers of 2-hexyl-3-hydroxydecanoic acid were shown to be substrates, and GC-MS and NMR analyses confirmed that the product in each case was (Z)-pentadec-7-ene. LC-MS analysis supported the formation of AMP adduct as an intermediate. The enzymatic and stereochemical course of olefin biosynthesis from long-chain fatty acids by OleA, OleD and OleC is now established. PMID- 27238741 TI - Linear Dermatomyofibroma. PMID- 27238742 TI - Bullous Pemphigoid on the Areola of Breast. PMID- 27238743 TI - Dermatologic emergencies in a tertiary hospital: A descriptive study. AB - BACKGROUND AND OBJECTIVE: Dermatology in-house call is uncommon in the Spanish national health system. The objective of the present study was to define the groups of dermatologic diseases and conditions most frequently seen in the emergency department and to evaluate the need for dermatology in-house call in the training of medical residents. MATERIAL AND METHODS: We performed a descriptive study of all patients who attended the emergency department with a skin complaint during a 1-year period (June 2013 to May 2014) and were assessed by 9 dermatology residents. The study variables were date/day, sex, age, diagnosis, special surgical procedures, additional laboratory tests, and need for hospitalization and/or follow-up. We also evaluated patients attending their first scheduled visit to the dermatologist between January and June 2014 in order to compare the most frequent conditions in both groups. RESULTS: A total of 3084 patients attended the emergency room with a skin complaint (5.6% of all visits to the emergency department), and 152 different diagnoses were made. The most frequent groups of diseases were infectious diseases (23%) and eczema (15.1%). The specific conditions seen were acute urticaria (7.6%), contact dermatitis (6.1%), and drug-induced reactions (4.6%). By contrast, the most frequent conditions seen in the 1288 patients who attended a scheduled dermatology appointment were seborrheic keratosis (11.9%), melanocytic nevus (11.5%), and actinic keratosis (8%). A follow-up visit was required in 42% of patients seen in the emergency department. Fourth-year residents generated the lowest number of follow-up visits. CONCLUSIONS: We found that infectious diseases and eczema accounted for almost 40% of all emergency dermatology visits. Our results seem to indicate that the system of in-house call for dermatology residents is very useful for the hospital system and an essential component of the dermatology resident's training program. PMID- 27238744 TI - Trichogerminoma: A Neoplasm With Follicular Differentiation and a Characteristic Morphology. PMID- 27238745 TI - Subcutaneous Tumor Deep to the Lateral Right Eyebrow. PMID- 27238747 TI - BJ-1103, 6-aminopyridin-3-ol skeletal compound, modulates neuroprotective and anti-neuroinflammatory effects in murine hippocampal and microglial cells via Nrf2-mediated heme oxygenase-1 expression. AB - BJ-1103, as a 6-aminopyridin-3-ol skeletal compound, was originally developed as an antioxidant against free radicals and oxidative stress was prepared from pyridoxine.HCl by the reported procedure. In the present study, we examined the effect of BJ-1103 on neuroprotection and neuroinflammation. Our data showed that BJ-1103 can protect HT22 cells against glutamate-induced cell cytotoxicity. And, BJ-1103 also inhibited LPS-induced inflammatory action. In addition, BJ-1103 induced heme oxygenase-1 (HO-1) expression and elevated HO-1 activities in the two cell lines studied. Additionally, BJ-1103 treatment induced nuclear transcription factor erythroid-2 related factor 2 (Nrf2) and increased the promoter activity of antioxidant response elements (AREs). We have demonstrated using the Nrf2 siRNA, HO inhibitor or HO-1 siRNA that BJ-1103 suppressed neurotoxicity and neuroinflammation through the Nrf2-mediated HO-1 expression. These results demonstrated that BJ-1103 may have good therapeutic agent against neurodegenerative diseases that are induced by oxidative stress and neuroinflammation. PMID- 27238746 TI - Effects of xanthine oxidase inhibition with febuxostat on the development of nephropathy in experimental type 2 diabetes. AB - BACKGROUND AND PURPOSE: Elevated serum uric acid (UA) is a risk factor for the development of kidney disease. Inhibitors of xanthine oxidase (XOi), an enzyme involved in UA synthesis, have protective effects at early stages of experimental diabetic nephropathy (DN). However, long-term effects of XOi in models of DN remain to be determined. EXPERIMENTAL APPROACH: The development of albuminuria, renal structure and molecular markers of DN were studied in type 2 diabetic Zucker obese (ZO) rats treated for 18 weeks with the XOi febuxostat and compared with vehicle-treated ZO rats, ZO rats treated with enalapril or a combination of both agents, and lean Zucker rats without metabolic defects. RESULTS: Febuxostat normalized serum UA and attenuated the development of albuminuria, renal structural changes, with no significant effects on BP, metabolic control or systemic markers of oxidative stress (OS). Most of these actions were comparable with those of enalapril. Combination treatment induced marked decreases in BP and was more effective in ameliorating structural changes, expression of profibrotic genes and systemic OS than either monotherapy. Febuxostat attenuated renal protein expression of TGF-beta, CTGF, collagen 4, mesenchymal markers (FSP1 and vimentin) and a tissue marker of OS nitrotyrosine. Moreover, febuxostat attenuated TGF-beta- and S100B-induced increased expression of fibrogenic molecules in renal tubular cells in vitro in UA-free media in an Akt kinase dependent manner. CONCLUSIONS AND IMPLICATIONS: Febuxostat is protective and enhances the actions of enalapril in experimental DN. Multiple mechanisms might be involved, such as a reduction of UA, renal OS and inhibition of profibrotic signalling. PMID- 27238748 TI - Ggamma7 proteins contribute to coupling of nociceptin/orphanin FQ peptide (NOP) opioid receptors and voltage-gated Ca(2+) channels in rat stellate ganglion neurons. AB - The nociceptin/orphanin FQ peptide (NOP) opioid receptors regulate neurotransmitter release via inhibition of voltage-gated Ca(2+) channels (CaV2.2) in sympathetic and sensory neurons. Stimulation of NOP receptors by its endogenous agonist, nociception (Noc), leads to membrane-delimited, voltage dependent (VD) block of CaV2.2 channel currents mediated by Gbetagamma protein subunits. Previously we reported that the pertussis toxin-sensitive Galphai1 and Gbeta2/beta4 isoforms mediate the functional coupling of NOP opioid receptors with CaV channels in rat stellate ganglion (SG) sympathetic neurons. In the present report we extended our studies by identifying the Ggamma subunit that forms the heterotrimer within this signaling pathway. Small interference RNA (or siRNA) was employed to silence the expression of the natively expressed Ggamma subunits. Initial PCR assays indicated that SG neurons expressed seven Ggamma subunits. Silencing Ggamma3 subunits did not alter signaling between NOP receptors and Ca(2+) channels. However, after Ggamma7 isoforms were silenced, the Noc-mediated inhibition of CaV channels was significantly decreased when compared to SG neurons transfected with scrambled siRNA. We observed that Ggamma10 and Ggamma11 mRNA levels increased 2.5- and 2.7-fold, respectively, after Ggamma7 subunits were silenced. However, this compensatory increase in mRNA expression did not appear to fully rescue the NOP receptor coupling efficiency. Additionally, both Ggamma2 and Ggamma5 levels increased 50 and 75%, respectively, while Ggamma3 and Ggamma4 expression levels remained relatively unchanged. Taken together, our findings suggest that the Galphai1/Gbeta2(beta4)/Ggamma7 heterotrimeric G protein complex determines the NOP receptor-mediated modulation of CaV channels in SG neurons. PMID- 27238749 TI - Effects of uncertainty in head tissue conductivity and complexity on EEG forward modeling in neonates. AB - In this study, we investigated the impact of uncertainty in head tissue conductivities and inherent geometrical complexities including fontanels in neonates. Based on MR and CT coregistered images, we created a realistic neonatal head model consisting of scalp, skull, fontanels, cerebrospinal fluid (CSF), gray matter (GM), and white matter (WM). Using computer simulations, we investigated the effects of exclusion of CSF and fontanels, discrimination between GM and WM, and uncertainty in conductivity of neonatal head tissues on EEG forward modeling. We found that exclusion of CSF from the head model induced the strongest widespread effect on the EEG forward solution. Discrimination between GM and white matter also induced a strong widespread effect, but which was less intense than that of CSF exclusion. The results also showed that exclusion of the fontanels from the neonatal head model locally affected areas beneath the fontanels, but this effect was much less pronounced than those of exclusion of CSF and GM/WM discrimination. Changes in GM/WM conductivities by 25% with respect to reference values induced considerable effects in EEG forward solution, but this effect was more pronounced for GM conductivity. Similarly, changes in skull conductivity induced effects in the EEG forward modeling in areas covered by the cranial bones. The least intense effect on EEG was caused by changes in conductivity of the fontanels. Our findings clearly emphasize the impact of uncertainty in conductivity and deficiencies in head tissue compartments on modeling research and localization of brain electrical activity in neonates. Hum Brain Mapp 37:3604-3622, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27238750 TI - Common links between metabolic syndrome and inflammatory bowel disease: Current overview and future perspectives. AB - Metabolic syndrome (MS) features a constellation of central obesity, dyslipidemia, impaired glucose metabolism and often hypertension joined by insulin resistance and chronic inflammation. All these elements greatly raise patient's risk of cardiovascular disease and type 2 diabetes, resulting in an increased mortality. Metabolic syndrome affects approximately 20-25% of the world's adult population and thus it is essential to study its pathophysiology and seek new pharmacological targets. There is a thoroughly studied link between MS and inflammatory diseases of the gastrointestinal (GI) system, i.e. steatohepatitis. However, recent findings also indicate similarities in pathophysiological features between MS and inflammatory bowel disease (IBD), including adipose tissue dysregulation, inadequate immune response, and inflammation. In this review we aim to outline the pathophysiology of MS and emphasize the aspects revealed recently, such as mineralocorticoid activity, involvement of sex hormones and an accompanying increase in prolactin secretion. More importantly, we focus on the common links between MS and IBD. Finally, we describe new strategies and drug targets that may be utilized in MS therapy, namely adiponectin mimetics, GLP-1-based multi agonists, ABCA1 agonists and possible role of miRNA. We also discuss the possible utility of selected agents as adjuvants in IBD therapy. PMID- 27238751 TI - Laparoscopic transposition of lower-pole crossing vessels: Long-term follow-up of 33 patients at puberty. AB - PURPOSE: Laparoscopic transposition of lower-pole crossing vessels (LPCV) has been described as an effective alternative to dismembered pyeloplasty in selected indications of hydronephrosis, with purely extrinsic vascular PUJ obstruction. We hypothesized that the initial good results of laparoscopic transposition of LPCV in children presenting with pure extrinsic PUJO were sustained at puberty when these children go through statural growth, without inducing significant changes in systemic arterial blood pressure. Hence, we analysed the long-term follow-up of adolescents successfully treated with this technique during childhood, reviewed after they have reached puberty, focusing on the incidence of recurrent symptoms, renal dilatation, and systemic hypertension. PATIENTS AND METHODS: Early 2015, among a cohort of 70 patients prospectively followed-up since they had undergone laparoscopic transposition of LPCV during childhood (2005-2012), we performed systematic clinical assessment of the 33 adolescent patients (16 years; range 12-22) who had reached puberty age. Assessment focused on clinical examination, arterial blood pressure measurements, and renal ultrasonography (Table). RESULTS: The median delay since surgery was 67 months (31-113 months). Arterial blood pressure adjusted for age and height was within normal range in all patients. Three patients had occasional episodes of abdominal pain: two of them had normal US (including during pain episodes), one had persistent extra renal dilated pelvis with no calyceal dilatation. None of them showed obvious clinical characteristics linking the pain to a renal origin. Renal US showed residual SFU grade 2 pelvicalyceal dilatation in 2/33 asymptomatic patients; SFU grade 1 extra-renal pelvis dilatation in 3, and was normal in the remaining. When Doppler analysis was performed, there was no evidence of lower-pole parenchyma perfusion defect. DISCUSSION: In adolescents successfully treated during childhood with transposition of LPCV, there seemed to be no impact of this procedure on systemic arterial blood pressure in adolescents after puberty, nor any evidence of late recurrence of symptoms or hydronephrosis. The main limitation of the present study relies in its retrospective nature, the limited sample size, and the obvious difficulty in adequate selection of candidate patients to this technique. The present experience however reinforces the hypothesis that a vast majority of children can be definitely cured with transposition of LPCV when they represent the sole aetiology of obstruction. CONCLUSION: In the long-term follow-up, most adolescents successfully treated during childhood by laparoscopic transposition of LCPV for PUJ extrinsic obstruction remain asymptomatic, with normal arterial blood pressure, and normal renal ultrasound when they reach puberty. PMID- 27238752 TI - Response-guided peginterferon therapy in patients with HBeAg-positive chronic hepatitis B: A randomized controlled study. AB - BACKGROUND & AIMS: Response-guided therapy has been confirmed to be an effective strategy for the treatment of chronic hepatitis C in the pegylated interferon (PegIFN) era, but no randomized trial utilizing this strategy has been conducted in chronic hepatitis B. METHODS: In this open-label, multicenter, randomized trial, HBeAg positive patients were treated with PegIFN (180MUg/week) for 24weeks. Early responders (HBsAg <1500IU/ml and HBV DNA <10(5)copies/ml at week 24) received PegIFN for a further 24weeks (arm A), while non-early responders were randomized to PegIFN for another 24weeks (arm B), another 72weeks (arm C) or PegIFN for another 72weeks plus adefovir for 36weeks (arm D). The primary endpoint was the change of quantitative HBsAg from baseline to the end of follow up (EOF). RESULTS: For non-early responders, 96-week PegIFN monotherapy did not lead to a greater reduction of HBsAg from baseline to EOF, compared with 48-week PegIFN (-0.71 vs. -0.67log10IU/ml, P=0.407). The rate of HBeAg seroconversion with HBV DNA <2000IU/ml at EOF were similar for arms B, C and D (17.9%, 23.9% and 25.0% respectively). For patients with HBsAg <1500IU/ml or HBV DNA <10(5)copies/ml at week 24, 38.4% and 37.0% achieved HBeAg seroconversion with HBV DNA <2000IU/ml at EOF respectively. CONCLUSIONS: Patients with HBsAg <1500IU/ml or HBV DNA <10(5)copies/ml at week 24 would benefit from continued PegIFN treatment. Extending the duration of PegIFN with or without adding adefovir did not show superiority over 48weeks PegIFN monotherapy. LAY SUMMARY: Extending the duration of pegylated interferon (PegIFN) alfa-2a is not recommended in HBeAg positive patients as treatment extension beyond 48weeks did not show convincing benefit. Patients who achieved HBsAg <1500IU/ml or HBV DNA <10(5)copies/ml after 24-week PegIFNalpha-2a showed satisfactory outcome after the withdrawal of finite PegIFNalpha-2a treatment. CLINICAL TRIAL NUMBER: NCT01086085. PMID- 27238753 TI - Transient elastography in autoimmune hepatitis: Timing determines the impact of inflammation and fibrosis. AB - BACKGROUND & AIMS: There is an unmet need for the non-invasive monitoring of fibrosis progression in patients with autoimmune hepatitis (AIH). The aim of this study was to assess the diagnostic performance of transient elastography in patients with AIH and to investigate the impact of disease activity on its diagnostic accuracy. METHODS: Optimal cut-offs were defined in a prospective pilot study (n=34) and the diagnostic performance of transient elastography validated in an independent second cohort (n=60). To explore the impact of disease activity on liver stiffness, patients were stratified according to biochemical response and the time interval between start of immunosuppression and transient elastography. RESULTS: Liver stiffness strongly correlated with histological fibrosis stage (pilot study: rho=0.611, p<0.001; validation cohort: rho=0.777, p<0.0001). ROC curves defined an area under the receiver operating curve of 0.95 for diagnosing cirrhosis at the optimal cut-off of 16kPa. The performance of transient elastography was impaired when patients were analysed in whom transient elastography was performed within 3months from start of treatment. In this setting, liver stiffness correlated with histological grading (rho=0.558, p=0.001), but not with staging. In contrast, using the cut-off of 16kPa, the accuracy for diagnosing cirrhosis was excellent in patients treated for 6months or longer (area under the receiver operating curve 1.0). CONCLUSIONS: Liver inflammation has a major impact on liver stiffness in the first months of AIH treatment. However, transient elastography has an excellent diagnostic accuracy for separating severe from non-severe fibrosis after 6months of immunosuppressive treatment. LAY SUMMARY: Transient elastography is a special ultrasound scan, which assesses liver stiffness as a surrogate marker for liver fibrosis/scarring. Transient elastography has been shown to be a reliable non-invasive method to assess liver fibrosis in various chronic liver diseases, it takes less than 5min and has a high patient acceptance. The current study validated for the first time this technique in a large cohort of patients with autoimmune hepatitis (AIH) and demonstrates that it is a reliable tool to detect liver fibrosis in treated AIH. For the monitoring of potential disease progression under treatment, the validation of liver stiffness as non-invasive marker of liver fibrosis will greatly improve patient care in autoimmune hepatitis. PMID- 27238754 TI - Kidney biomarkers in cirrhosis. AB - Impaired renal function due to acute kidney injury (AKI) and/or chronic kidney diseases (CKD) is frequent in cirrhosis. Recurrent episodes of AKI may occur in end-stage cirrhosis. Differential diagnosis between functional (prerenal and hepatorenal syndrome) and acute tubular necrosis (ATN) is crucial. The concept that AKI and CKD represent a continuum rather than distinct entities, is now emerging. Not all patients with AKI have a potential for full recovery. Precise evaluation of kidney function and identification of kidney changes in patients with cirrhosis is central in predicting reversibility. This review examines current biomarkers for assessing renal function and identifying the cause and mechanisms of impaired renal function. When CKD is suspected, clearance of exogenous markers is the reference to assess glomerular filtration rate, as creatinine is inaccurate and cystatin C needs further evaluation. Recent biomarkers may help differentiate ATN from hepatorenal syndrome. Neutrophil gelatinase-associated lipocalin has been the most extensively studied biomarker yet, however, there are no clear-cut values that differentiate each of these conditions. Studies comparing ATN and hepatorenal syndrome in cirrhosis, do not include a gold standard. Combinations of innovative biomarkers are attractive to identify patients justifying simultaneous liver and kidney transplantation. Accurate biomarkers of underlying CKD are lacking and kidney biopsy is often contraindicated in this population. Urinary microRNAs are attractive although not definitely validated. Efforts should be made to develop biomarkers of kidney fibrosis, a common and irreversible feature of CKD, whatever the cause. Biomarkers of maladaptative repair leading to irreversible changes and CKD after AKI are also promising. PMID- 27238755 TI - EpCAM-regulated intramembrane proteolysis induces a cancer stem cell-like gene signature in hepatitis B virus-infected hepatocytes. AB - BACKGROUND & AIMS: Hepatocytes in which the hepatitis B virus (HBV) is replicating exhibit loss of the chromatin modifying polycomb repressive complex 2 (PRC2), resulting in re-expression of specific, cellular PRC2-repressed genes. Epithelial cell adhesion molecule (EpCAM) is a PRC2-repressed gene, normally expressed in hepatic progenitors, but re-expressed in hepatic cancer stem cells (hCSCs). Herein, we investigated the functional significance of EpCAM re expression in HBV-mediated hepatocarcinogenesis. METHODS: Employing molecular approaches (transfections, fluorescence-activated cell sorting, immunoblotting, qRT-PCR), we investigated the role of EpCAM-regulated intramembrane proteolysis (RIP) in HBV replicating cells in vitro, and in liver tumors from HBV X/c-myc mice and chronically HBV infected patients. RESULTS: EpCAM undergoes RIP in HBV replicating cells, activating canonical Wnt signaling. Transfection of Wnt responsive plasmid expressing green fluorescent protein (GFP) identified a GFP + population of HBV replicating cells. These GFP+/Wnt+ cells exhibited cisplatin- and sorafenib-resistant growth resembling hCSCs, and increased expression of pluripotency genes NANOG, OCT4, SOX2, and hCSC markers BAMBI, CD44 and CD133. These genes are referred as EpCAM RIP and Wnt-induced hCSC-like gene signature. Interestingly, this gene signature is also overexpressed in liver tumors of X/c myc bitransgenic mice. Clinically, a group of HBV-associated hepatocellular carcinomas was identified, exhibiting elevated expression of the hCSC-like gene signature and associated with reduced overall survival post-surgical resection. CONCLUSIONS: The hCSC-like gene signature offers promise as prognostic tool for classifying subtypes of HBV-induced HCCs. Since EpCAM RIP and Wnt signaling drive expression of this hCSC-like signature, inhibition of these pathways can be explored as therapeutic strategy for this subtype of HBV-associated HCCs. LAY SUMMARY: In this study, we provide evidence for a molecular mechanism by which chronic infection by the hepatitis B virus results in the development of poor prognosis liver cancer. Based on this mechanism our results suggest possible therapeutic interventions. PMID- 27238756 TI - The (unusual) aspartic acid in the metal coordination sphere of the prokaryotic zinc finger domain. AB - The possibility of choices of protein ligands and coordination geometries leads to diverse Zn(II) binding sites in zinc-proteins, allowing a range of important biological roles. The prokaryotic Cys2His2 zinc finger domain (originally found in the Ros protein from Agrobacterium tumefaciens) tetrahedrally coordinates zinc through two cysteine and two histidine residues and it does not adopt a correct fold in the absence of the metal ion. Ros is the first structurally characterized member of a family of bacterial proteins that presents several amino acid changes in the positions occupied in Ros by the zinc coordinating residues. In particular, the second position is very often occupied by an aspartic acid although the coordination of structural zinc by an aspartate in eukaryotic zinc fingers is very unusual. Here, by appropriately mutating the protein Ros, we characterize the aspartate role within the coordination sphere of this family of proteins demonstrating how the presence of this residue only slightly perturbs the functional structure of the prokaryotic zinc finger domain while it greatly influences its thermodynamic properties. PMID- 27238757 TI - Diet quality before or during pregnancy and the relationship with pregnancy and birth outcomes: the Australian Longitudinal Study on Women's Health. AB - OBJECTIVE: To assess whether diet quality before or during pregnancy predicts adverse pregnancy and birth outcomes in a sample of Australian women. DESIGN: The Dietary Questionnaire for Epidemiological Studies was used to calculate diet quality using the Australian Recommended Food Score (ARFS) methodology modified for pregnancy. SETTING: A population-based cohort participating in the Australian Longitudinal Study on Women's Health (ALSWH). SUBJECTS: A national sample of Australian women, aged 20-25 and 31-36 years, who were classified as preconception or pregnant when completing Survey 3 or Survey 5 of the ALSWH, respectively. The 1907 women with biologically plausible energy intake estimates were included in regression analyses of associations between preconception and pregnancy ARFS and subsequent pregnancy outcomes. RESULTS: Preconception and pregnancy groups were combined as no significant differences were detected for total and component ARFS. Women with gestational hypertension, compared with those without, had lower scores for total ARFS, vegetable, fruit, grain and nuts/bean/soya components. Women with gestational diabetes had a higher score for the vegetable component only, and women who had a low-birth-weight infant had lower scores for total ARFS and the grain component, compared with those who did not report these outcomes. Women with the highest ARFS had the lowest odds of developing gestational hypertension (OR=0.4; 95 % CI 0.2, 0.7) or delivering a child of low birth weight (OR=0.4; 95 % CI 0.2, 0.9), which remained significant for gestational hypertension after adjustment for potential confounders. CONCLUSIONS: A high-quality diet before and during pregnancy may reduce the risk of gestational hypertension for the mother. PMID- 27238758 TI - Hurricane Katrina-linked environmental injustice: race, class, and place differentials in attitudes. AB - Claims of environmental injustice, human neglect, and racism dominated the popular and academic literature after Hurricane Katrina struck the United States in August 2005. A systematic analysis of environmental injustice from the perspective of the survivors remains scanty or nonexistent. This paper presents, therefore, a systematic empirical analysis of the key determinants of Katrina induced environmental injustice attitudes among survivors in severely affected parishes (counties) in Louisiana and Mississippi three years into the recovery process. Statistical models based on a random sample of survivors were estimated, with the results revealing significant predictors such as age, children in household under 18, education, homeownership, and race. The results further indicate that African-Americans were more likely to perceive environmental injustice following Katrina than their white counterparts. Indeed, the investigation reveals that there are substantial racial gaps in measures of environmental injustice. The theoretical, methodological, and applied policy implications of these findings are discussed. PMID- 27238760 TI - Ensemble framework based real-time respiratory motion prediction for adaptive radiotherapy applications. AB - Successful treatment of tumors with motion-adaptive radiotherapy requires accurate prediction of respiratory motion, ideally with a prediction horizon larger than the latency in radiotherapy system. Accurate prediction of respiratory motion is however a non-trivial task due to the presence of irregularities and intra-trace variabilities, such as baseline drift and temporal changes in fundamental frequency pattern. In this paper, to enhance the accuracy of the respiratory motion prediction, we propose a stacked regression ensemble framework that integrates heterogeneous respiratory motion prediction algorithms. We further address two crucial issues for developing a successful ensemble framework: (1) selection of appropriate prediction methods to ensemble (level-0 methods) among the best existing prediction methods; and (2) finding a suitable generalization approach that can successfully exploit the relative advantages of the chosen level-0 methods. The efficacy of the developed ensemble framework is assessed with real respiratory motion traces acquired from 31 patients undergoing treatment. Results show that the developed ensemble framework improves the prediction performance significantly compared to the best existing methods. PMID- 27238759 TI - Modular development of a prototype point of care molecular diagnostic platform for sexually transmitted infections. AB - This paper presents the design of a modular point of care test platform that integrates a proprietary sample collection device directly with a microfluidic cartridge. Cell lysis, within the cartridge, is conducted using a chemical method and nucleic acid purification is done on an activated cellulose membrane. The microfluidic device incorporates passive mixing of the lysis-binding buffers and sample using a serpentine channel. Results have shown extraction efficiencies for this new membrane of 69% and 57% compared to the commercial Qiagen extraction method of 85% and 59.4% for 0.1ng/uL and 100ng/uL salmon sperm DNA respectively spiked in phosphate buffered solution. Extraction experiments using the serpentine passive mixer cartridges incorporating lysis and nucleic acid purification showed extraction efficiency around 80% of the commercial Qiagen kit. Isothermal amplification was conducted using thermophillic helicase dependant amplification and recombinase polymerase amplification. A low cost benchtop real-time isothermal amplification platform has been developed capable of running six amplifications simultaneously. Results show that the platform is capable of detecting 1.32*10(6) of sample DNA through thermophillic helicase dependant amplification and 1*10(5) copy numbers Chlamydia trachomatis genomic DNA within 10min through recombinase polymerase nucleic acid amplification tests. PMID- 27238761 TI - Role of structure, accessibility and microporosity on sorption of phenanthrene and nonylphenol by sediments and their fractions. AB - To better understand interaction mechanism of sediment organic matter with hydrophobic organic compounds, sorption of phenanthrene (Phen) and nonylphenol (NP) by bulk sediments and their fractions was investigated. Three surface sediments were selectively fractionated into different organic fractions, including the demineralized carbon (DM), lipid free carbon (LF), lipid (LP), and nonhydrolyzable carbon (NHC) fractions. The structure and microporosity of the isolated fractions were characterized by NMR and CO2 adsorption techniques, and used as sorbents for Phen and NP. The calculated micropore volumes (Vo) and specific surface area (SSA) values are positively related to the concentrations of aromatic C and char for the DM, LF and NHC fractions, suggesting that aromatic moieties and char component significantly contribute to the microporosity. The LF fractions exhibit greater sorption affinity than the DM fractions do, indicating that the presence of LP could block the accessibility of sorption sites for Phen and NP. Significant and positive correlations among log K'FOC values for Phen and NP and aromatic carbon and char contents, and Vo and SSA values suggest the aromatic moieties and microporosity dominate their sorption of HOCs by sediment organic matter (SOM). As the NHC fractions have much stronger sorption than other fractions do, they dominate the overall sorption by the bulk samples. This study indicated that the important roles of aromatic moieties, accessibility, and microporosity in the sorption of HOCs by SOM. PMID- 27238762 TI - Application of plow-tillage as an innovative technique for eliminating overwintering cyanobacteria in eutrophic lake sediments. AB - Surface sediment in eutrophic lakes is both a destination and a habitat for overwintering cyanobacteria. The resuspension and recovery of viable, overwintering cyanobacteria from the surface sediment during warm spring weather is usually the primary stage of cyanobacterial blooms (CBs) in shallow eutrophic lakes. Therefore, the elimination of overwintering cyanobacteria in sediment is vital to control CBs. In the present study, sediment plow-tillage (PT) was introduced as an innovative technique for eliminating overwintering cyanobacteria in sediments from Lake Chaohu. Four depths of PT (2, 5, 10, and 15 cm) were tested during the 42-day experiment. The results showed that rapid cell death during the first 0-7 d after PT was accompanied by high oxygen uptake rates. The viable cells in deeper sediment died more quickly and at a higher rate after PT. A PT depth of >10 cm effectively eliminated viable cyanobacteria (with a removal rate of 82.8%) from the sediment and prevented their resuspension. The activity of the viable cyanobacteria also decreased quickly as cyanobacteria were eliminated. It appears that the dark, anoxic environment of the deeper sediment after PT was responsible for the elimination of viable cells. Although high release rates of nitrogen and phosphorus were found to accompany the dying and decomposition of cyanobacteria during days 0-7 of the experiment, greater depth of PT was found to decrease nutrient concentrations in the overlying water. In conclusion, we recommend sediment PT as a new technique for eliminating overwintering algae in sediments. However, the release of nutrients from the sediment and the in situ control of CBs in lakes after PT should be further studied. PMID- 27238763 TI - Microplastic pollution of lakeshore sediments from remote lakes in Tibet plateau, China. AB - Tibetan Plateau is known as the world's third pole, which is characterized by a low population density with very limited human activities. Tibetan Plateau possesses the greatest numbers of high-altitude inland lakes in the world. However, no information is currently available on the characteristic of microplastic pollution in those lakes within this remote area. In this work, lakeshore sediments from four lakes within the Siling Co basin in northern Tibet were sampled and examined for microplastics (<5 mm). Microplastics were detected in six out of seven sampling sites with abundances ranging from 8 +/- 14 to 563 +/- 1219 items/m2. Riverine input might have contributed to the high abundance of microplastics observed in this remote area. Morphological features suggest that microplastics are derived from the breakdown of daily used plastic products. Polyethylene, polypropylene, polystyrene, polyethylene terephthalate, and polyvinyl chloride were identified from the microplastic samples using laser Raman spectroscopy, and oxidative and mechanical weathering textures were observed on the surface of microplastics using scanning electron microscope. These results demonstrate the presence of microplastics even for inland lakes in remote areas under very low human impact, and microplastic pollution can be a global issue. PMID- 27238764 TI - SND1 overexpression deregulates cholesterol homeostasis in hepatocellular carcinoma. AB - SND1 is a multifunctional protein participating, among others, in gene transcription and mRNA metabolism. SND1 is overexpressed in cancer cells and promotes viability and tumourigenicity of hepatocellular carcinoma cells. This study shows that cholesterol synthesis is increased in SND1-overexpressing hepatoma cells. Neither newly synthesised nor extracellularly supplied cholesterol are able to suppress this increase; however, inhibition of cholesterol esterification reverted the activated state of sterol-regulatory element-binding protein 2 (SREBP2) and cholesterogenesis. These results highlight SND1 as a potential regulator of cellular cholesterol distribution and homeostasis in hepatoma cells, and support the rationale for the therapeutic use of molecules that influence cholesterol management when SND1 is overexpressed. PMID- 27238765 TI - Acute inflammatory demyelinating polyradiculoneuropathy in a newborn infant. AB - BACKGROUND: Acute inflammatory demyelinating polyneuropathy (AIDP), also known as Guillain-Barre syndrome, is an immune-mediated polyneuropathy usually triggered by infections or vaccinations. In childhood AIDP is commonly described after the first year of life. Here, we present a case of a newborn infant with AIDP manifestation directly after delivery. CASE STUDY: A newborn girl with a healthy mother, without known exposure to immunomodulating factors, was admitted to the neuropediatric department due to ascending hypotonia, weakness, pain and areflexia in the lower extremities. The clinical presentation, laboratory and neurophysiological studies supported the diagnosis of AIDP. The infant showed first signs of clinical improvement following administration of intravenous immunoglobulin and her recovery was complete at one year. CONCLUSION: AIDP should be considered as a differential diagnosis in ascending hypotonia also in the neonatal period. PMID- 27238766 TI - Determination of Nicotine, Cotinine and Trans-3'-Hydroxycotinine using LC/MS/MS in Forensic Samples of a Nicotine Fatal Case by Oral Ingestion of e-cigarette Liquid. AB - Nicotine is a potent neurotoxin alkaloid and is used in e-cigarette liquid. The LC/MS/MS method was linear over 0.01-1.0 mg/L (r2 = 0.992-0.995). Limit of detection and limit of quantitation were 0.001 mg/L (S/N = 3) and 0.003 (S/N = 10). The inaccuracy and imprecision were <13.2%. The recoveries were >99.3%. A 39 year-old dentist was found dead lying on the floor under the couch in his dental clinic. The concentration of nicotine, cotinine, and trans-3'-hydroxycotinine (heart blood/peripheral blood) was analyzed as follows: 87.2/85.2 mg/L (ratio 1.0), 1.4/1.1 mg/L (ratio 1.3), and 0.012/0.0089 mg/L (ratio 1.3), respectively. The concentration of nicotine was determined to be 6734.8 mg/kg in gastric contents and 7262.0 mg/L in remaining e-liquid. Only, high concentration of nicotine was detected in the gastric contents as well as the two pieces of evidence collected from the death scene. This fatal case resulted from oral ingestion of e-cigarette liquid. It is estimated that at least 714 mg of nicotine was orally ingested. PMID- 27238767 TI - Metabarcoding reveals environmental factors influencing spatio-temporal variation in pelagic micro-eukaryotes. AB - Marine environments harbour a vast diversity of micro-eukaryotic organisms (protists and other small eukaryotes) that play important roles in structuring marine ecosystems. However, micro-eukaryote diversity is not well understood. Likewise, knowledge is limited regarding micro-eukaryote spatial and seasonal distribution, especially over long temporal scales. Given the importance of this group for mobilizing energy from lower trophic levels near the base of the food chain to larger organisms, assessing community stability, diversity and resilience is important to understand ecosystem health. Herein, we use a metabarcoding approach to examine pelagic micro-eukaryote communities over a 2.5 year time series. Bimonthly surface sampling (July 2009 to December 2011) was conducted at four locations within Mobile Bay (Bay) and along the Alabama continental shelf (Shelf). Alpha-diversity only showed significant differences in Shelf sites, with the greatest differences observed between summer and winter. Beta-diversity showed significant differences in community composition in relation to season and the Bay was dominated by diatoms, while the Shelf was characterized by dinoflagellates and copepods. The northern Gulf of Mexico is heavily influenced by the Mobile River Basin, which brings low-salinity nutrient rich water mostly during winter and spring. Community composition was correlated with salinity, temperature and dissolved silicate. However, species interactions (e.g. predation and parasitism) may also contribute to the observed variation, especially on the Shelf, which warrants further exploration. Metabarcoding revealed clear patterns in surface pelagic micro-eukaryote communities that were consistent over multiple years, demonstrating how these techniques could be greatly beneficial to ecological monitoring and management over temporal scales. PMID- 27238768 TI - Fatal hemoperitoneum due to bleeding from gallbladder varices in an end-stage cirrhotic patient A case report and review of the literature. AB - Gallbladder perforation with hemorrhage may be the source of massive hemoperitoneum under rare and extreme circumstances. In cirrhotic patients the bleeding may be associated with the tearing of gallbladder varices and represents a fatal complication, as reported in all the cases available in literature. The incidence of gallbladder varices in the setting of portal hypertension ranges 12 30%, although literature data are limited. We describe the case of an end-stage cirrhotic patient without portal thrombosis awaiting for orthotopic liver transplantation, who developed a fatal hemoperitoneum caused by massive bleeding from ruptured varices of both gallbladder wall and cholecystic fossa. The review of the literature was also performed. KEY WORDS: Cirrhosis, Gallbladder, Hemoperitoneum, Perforation, Portal hypertension, Varices. PMID- 27238769 TI - Characterization of Toll-like receptor gene expression in goldfish (Carassius auratus) during Dactylogyrus intermedius infection. AB - Toll-like receptors (TLRs), the first and best understood innate immune receptors, play a notable role in the innate immune system by sensing pathogenic agents and initiating appropriate immune responses. However, studies about the roles of fish TLRs in response to the infection of the ectoparasitic monogenean Dactylogyrus intermedius have been surprisingly vacant. In the present study, cDNA fragments of five members of TLRs family in goldfish (Carassius auratus) were cloned and the expression patterns of nine TLRs in five tissues at different time points during D. intermedius infection were subsequently investigated. We found that the expressions of TLR4, TLR5, TLR20 and TLR22 were significantly elevated after infection at some time points, of which the transcription of TLR5 was progressively increased nearly in all tissues, whereas the mRNA levels of other TLRs (TLR2, 3, 7, 9 and 21) were down-regulated or showed no significant change compared with the control at most time points. Additionally, this paper was also conducted to explore the expression of above TLRs after re-infected with D. intermedius. The results showed a significant upregulation of TLR4, TLR5 and TLR22 in all tested tissues at these two time points, especially the levels of TLR4 and TLR22 expression, were even higher comparing with the first infection. Besides, tissue-specific expression analysis revealed that spleen featured the highest expressions of almost all the TLR-encoding genes among detected tissues. The informations obtained here could be helpful towards understanding the functions of TLRs in response to parasitic infection in goldfish and provide new insights for the development of preventive and therapeutic approaches against D. intermedius infection. PMID- 27238771 TI - The interaction of cultural consonance and a polymorphism in the 2A serotonin receptor in relation to depression in Brazil: failure to replicate previous findings. AB - OBJECTIVES: To replicate a previously identified gene-environment interaction between a genetic polymorphism in the serotonin 2A receptor and cultural consonance in family life in relation to depressive symptoms (Dressler et al., 2009). METHODS: A sample of 402 individuals in a sample drawn from four different economic strata in Ribeirao Preto, Brazil was interviewed and genotyped. RESULTS: Cultural consonance in family life has an inverse association with depressive symptoms (beta = -0.439, P < 0.001) and with high depressive symptoms (OR = 2.36, P < 0.001), but the interaction with genotype was not statistically significant. CONCLUSION: The previously identified gene-environment interaction was not replicated. Limitations of the study are discussed. Am. J. Hum. Biol. 28:936-940, 2016. (c) 2016Wiley Periodicals, Inc. PMID- 27238770 TI - Distinct functional responses to stressors of bone marrow derived dendritic cells from diverse inbred chicken lines. AB - Differences in responses of chicken bone marrow derived dendritic cells (BMDC) to in vitro treatment with lipopolysaccharide (LPS), heat, and LPS + heat were identified. The Fayoumi is more disease resistant and heat tolerant than the Leghorn line. Nitric Oxide (NO) production, phagocytic ability, MHC II surface expression and mRNA expression were measured. NO was induced in BMDC from both lines in response to LPS and LPS + heat stimulation; Fayoumi produced more NO with LPS treatment. Fayoumi had higher phagocytic ability and MHC II surface expression. Gene expression for the heat-related genes BAG3, HSP25, HSPA2, and HSPH1 was strongly induced with heat and few differences existed between lines. Expression for the immune-related genes CCL4, CCL5, CD40, GM-CSF, IFN-gamma, IL 10, IL-12beta, IL-1beta, IL-6, IL-8, and iNOS was highly induced in response to LPS and different between lines. This research contributes to the sparse knowledge of genetic differences in chicken BMDC biology and function. PMID- 27238772 TI - [In Process Citation]. AB - La prevalencia de obesidad y de diabetes tipo 2 ha aumentado enormemente en las ultimas decadas hasta convertirse en una epidemia amenazante. El listado de factores de riesgo es amplio, pero lo encabeza el cambio del estilo de vida (alimentacion y actividad fisica) que constituye, ademas, la herramienta preventiva mas importante. El trabajo de Caravali-Meza y cols. en este numero de la revista hace hincapie en el consumo de bebidas azucaradas y su relacion con la obesidad. Sus autores concluyen que el consumo de azucares refinados de las bebidas en adolescentes mexicanos, conlleva un riesgo de incremento del perimetro de la cintura y, en el caso de mantenerse, tambien del indice de masa corporal. PMID- 27238773 TI - [In Process Citation]. AB - La desnutricion relacionada con la enfermedad (DRE) es un problema sanitario de elevada indole que impacta fuertemente en la morbilidad, mortalidad y calidad de vida de los pacientes ancianos ingresados en el hospital. Ademas, incrementa enormemente el gasto sanitario, sobre todo a traves del aumento de la estancia hospitalaria, incremento de las complicaciones y necesidad de centro de convalecencia u otros recursos sanitarios al alta hospitalaria. Conjuntamente con la osteoporosis y la sarcopenia, contribuye de forma directa a la discapacidad y a la perdida de autonomia del anciano, con las repercusiones familiares y sociales que ello implica. PMID- 27238774 TI - [In Process Citation]. AB - Introduccion y objetivos: el cobre (Cu) es un oligoelemento muy estudiado, pero poco se sabe de su evolucion en los pacientes alimentados por gastrostomia endoscopica (GEP). Pretendemos evaluar la evolucion del Cu serico desde la gastrostomia hasta 12 semanas despues de la intervencion en estos pacientes alimentados con preparaciones domesticas. Metodos: realizamos un estudio observacional prospectivo para evaluar el Cu serico, la albumina, la transferrina y el indice de masa corporal (IMC) en el momento de la GEP, tras 4 semanas y 12 semanas despues de la intervencion. Los datos incluyen edad, genero, NRS 2002 y enfermedad subyacente: canceres de cabeza y cuello (CCC) y disfagia neurologica (DN). Despues de la intervencion, estos pacientes fueron alimentados conpreparaciones domesticas. Resultados: 146 enfermos (89 hombres), entre 21-95 anos: CCC-56, DN-90. Valores de Cu entre 42-160 MUg/dl (normal: 70-140 MUg/dl); normales 89% (n = 130); bajos 11% (n = 16), albumina baja: 53% (n = 77), transferrina baja: 65% (n = 94), IMC bajo: 53% (n = 78). Despues de 4 semanas: valores normales de Cu en 93% y bajos en 7%, albumina baja en 34%, transferrina baja en 52%. Tras 12 semanas: valores normales de Cu en 95% y bajos en 5%, albumina baja en 25%, transferrina baja en 32%. No encontramos diferencias significativas en el Cuserico cuando se compara edad, genero, enfermedad subyacente, IMC, albumina y transferrina. Conclusiones: la mayoria de los enfermos presentan Cu serico normal en el momento de la gastrostomia. Para los enfermos con Cu serico bajo antes del procedimiento, la alimentacion con preparaciones domesticas parece suficiente para su normalizacion progresiva. PMID- 27238775 TI - [In Process Citation]. AB - Introduccion: la insuficiencia hepatica fulminante (IHF) es un sindrome clinico poco frecuente, que se caracteriza por una disfuncion hepatica severa y repentina. La tioacetamida (TAA) es una hepatotoxina cuya administracion puede inducir necrosis centrolobulillar en las celulas hepaticas y aumentar la formacion de especies reactivas de oxigeno y la peroxidacion lipidica en ratas. La glutamina es un precursor para la sintesis de glutation. Objetivo: el objetivo del estudio es evaluar los efectos antioxidantes de la glutamina en un modelo de rata de IHF inducida por TAA. Metodos: ratas macho Wistar se dividieron en cuatro grupos de acuerdo con el tratamiento y el tiempo de evaluacion: control, glutamina (25 mg/kg), tioacetamida (400 mg/kg) y tioacetamida mas glutamina. Los animales se evaluaron despues de 24, 36 y 48 horas. Se recogieron muestras de sangre para el analisis de los niveles de aspartato aminotransferasa (AST), alanina aminotransferasa (ALT), fosfatasa alcalina (AP), bilirrubina total (TB) y creatinina (CRE), y muestras de higado para evaluar la peroxidacion lipidica, las sustancias reactivas al acido tiobarbiturico (TBARS), la actividad de las enzimas antioxidantes superoxido dismutasa (SOD), glutation peroxidasa (GPx), catalasa (CAT) y glutation S-transferasa (GST). Ademas se midieron mediante inmunohistoquimica el factor nuclear kappa N (NF-kappaB), el fator de necrosis tumoral (TNF-alpha) y la oxido nitrico sintasa inducible (iNOS). Resultados: la TAA causo alteraciones en los parametros bioquimicos e histologicos, y el aumento de los marcadores del proceso inflamatorio. Los niveles de TBARS y la actividad de SOD y GST fueron significativamente inferiores en los grupos de glutamina en comparacion con TAA. La actividad de CAT se incremento en los animales tratados con glutamina en comparacion con la TAA. La actividad GPx tambien fue menor a las 36 y 48 h en los animales tratados com glutamina. El dano tisular y la expresion de NF-kappaB, TNF-alpha e iNOS fueron significativamente inferiores en los animales tratados con glutamina. Conclusion: la glutamina ha demostrado tener efectos protectores contra el dano hepatico en un modelo de IHF inducida por TAA en la rata. PMID- 27238776 TI - [In Process Citation]. AB - Introduccion: obesidad e inactividad fisica son importantes factores de riesgo para el desarrollo de hipertension en adultos. No obstante, hay poca evidencia sobre el efecto de estos factores de riesgo en el desarrollo de hipertension en poblacion infantil. Objetivo: investigar la asociacion del estado nutricional, niveles de actividad fisica y etnicidad con niveles de hipertension en escolares entre 6 y 13 anos de edad. Metodos: un total de 418 escolares de ascendencia etnica europea (n = 311) y mapuche (n = 107) fueron participantes de este estudio transversal. Se midio el peso, talla, indice de masa corporal (IMC) y presion arterial, utilizando protocolos estandarizados. Resultados: no se encontraron diferencias significativas en IMC, estado nutricional y presion arterial entre ninos con ascendencia europea y mapuche. No obstante, la prevalencia de prehipertension (21,3% vs. 11,1%) e hipertension (28,9% vs. 18,6%) fue significativamente mayor en escolares mapuches en comparacion con europeos, respectivamente. Escolares con ascendencia mapuche tienen un mayor riesgo de desarrollar prehipertension o hipertension que escolares con ascendencia europea (OR: 1,92 [1,19 a 3,06], p < 0,01). La prevalencia de hipertension aumenta significativamente en ambos grupos etnicos con el incremento de IMC y bajos niveles de actividad fisica. Conclusiones: el riesgo de desarrollar prehipertension o hipertension es mayor en poblacion infantil ascendiente de mapuches que ascendiente de europeos y este riesgo se ve acentuado con el incremento de obesidad y bajos niveles de actividad fisica. PMID- 27238777 TI - [In Process Citation]. AB - Objetivo: identificar los habitos alimentarios de adolescentes embarazadas en cuatro estados civiles diferentes: casada, cohabita con una pareja, soltera sin pareja y soltera con una pareja. Metodos: en estudio transversal, se incluyeron 321 adolescentes embarazadas de 13-19 anos que acudieron al Hospital Civil de Guadalajara Dr. Juan I Menchaca, Guadalajara (Jalisco, Mexico). Se encontraban sanas, en cualquier trimestre del embarazo y pertenecian a un nivel socioe conomico bajo o medio-bajo. El estado civil se estratifico en: casadas; en union libre; soltera con una pareja y soltera sin pareja. Se incluyeron datos socio demograficos, economicos y de habitos de alimentacion. Se utilizaron pruebas de ANOVA, pruebas post-hoc para Chi 2 , razon de momios y modelos de regresion logistica. Resultados: la frecuencia de las adolescentes casadas fue de 9,3%, 59,8% en union libre, 15,3% eran solteras sin pareja y 15,6% solteras con pareja. La baja escolaridad (RM 2,6 [1,5-4,4]) y la ocupacion en el hogar (RM 4,47 [1,99 10,0]) predominaron entre las adolescentes en union libre; la ocupacion en el hogar (RM 0,28 [0,127-0,61]) y cenar sin compania (RM 4,12 [1,62-10,8]) fueron significativamente mas frecuentes en adolescentes sin pareja. El consumo de verduras fue menor en las adolescentes casadas y en quienes cohabitaban con pareja; el consumo de frijoles y pan dulce fue menor en adolescentes embarazadas casadas. Conclusion: debido a que ciertas variables y habitos de alimentacion mostraron diferencias entre los grupos es pertinente analizar las adolescentes embarazadas de acuerdo a su estado civil. PMID- 27238778 TI - [In Process Citation]. AB - Introduccion: el recien nacido prematuro de muy bajo peso (RNMBP) es inmunologicamente inmaduro y ademas presenta una alteracion de las barreras naturales de defensa. Objetivo: evaluar los efectos que pueda tener la administracion de calostro orofaringeo, administrado durante los primeros 15 dias posnatales, sobre los niveles de inmunoglobulina A (IgA) serica en recien nacidos prematuros de muy bajo peso durante el primer mes de vida. Material y metodos: se desarrollo un estudio de intervencion no aleatorizado con grupo control, en el que se incluyeron 38 recien nacidos con <= 32 + 6 semanas de gestacion y/o menores de 1.500 g de peso. Los sujetos recibieron 0,2 ml de calostro de su madre cada 4 h, iniciandose el procedimiento en las primeras 24 h de vida hasta el 15.o dia postnatal. Se midieron los niveles de IgA en la sangre al nacimiento, 3. er , 15.o y 30.o dias de vida. Se registraron datos perinatales al nacimiento y durante el periodo de seguimiento. Resultados: IgA serica aumento de forma estadisticamente significativa en el grupo de intervencion (M1 15,84 MUg/ml, M2 20,07 MUg/ml, M3 23,65 MUg/ml, M4 30,34 MUg/ml, p 0,001) y en el grupo control (M1 12,48 MUg/ml, M2 16,48 MUg/ml, p 0,018; M3 19,41 MUg/ml, M4 22,48 MUg/ml, p 0,001). Al mes de vida, los niveles de IgA serica fueron significativamente mayores en el grupo de intervencion que en el grupo control (p 0,026). Conclusiones: este estudio sugiere que la administracion de calostro orofaringe. PMID- 27238779 TI - [In Process Citation]. AB - Introduccion: la obesidad es una enfermedad asociada a diferentes trastornos fisicos y emocionales que inciden en la calidad de vida y que representan un problema de elevada prevalencia en el mundo. La etiologia es multiple y compleja; se ha senalado la culpa como consecuencia del sobrepeso y, al mismo tiempo, como factor asociado al aumento de peso. En Mexico no existen instrumentos para evaluar la culpa por obesidad y sobrepeso en ninos y adolescentes. Objetivos: analizar la fiabilidad y validez de la Escala de Culpa por Obesidad o Sobrepeso para Ninos y Adolescentes (ECOSNA) en poblacion de Morelia (Mexico). Material y metodos: se elaboro una version preliminar basada en la bibliografia que se sometio a la revision de jueces expertos. La escala obtenida de 6 items se aplico a una muestra de 1.418 estudiantes de educacion basica de 7 a 15 anos. Se realizo un analisis factorial confir- matorio y se estudio la relacion de la escala con otras variables como autoestima, sintomatologia depresiva y ansiedad. Resultados: la escala resulto unifactorial, se obtuvo un indice alfa de Cronbach de 0,853. La escala ECOSNA mostro una correlacion moderada e inversa con la escala de autoestima, y directa y baja con la sintomatologia depresiva y la ansiedad clinica. Conclusion: los datos empiricos indican que la escala presenta una validez y confiabilidad satisfactorias. PMID- 27238780 TI - [In Process Citation]. AB - Objetivos: oligoelementos como zinc (Zn), hierro (Fe) y cobre (Cu) tienen una influencia significativa en el mantenimiento de la funcion inmune y del metabolismo normales; modulan la funcion immune e influyen en la susceptibilidad del organismo ante infecciones. Pero la relacion entre trazas de estos elementos y la bronconeumonia resulto incierta. Metodos: en este estudio fueron incluidos 28 ninos con bronconeumonia y 46 ninos sanos agrupados por edad. Se determinaron los niveles de Zn, Cu, Fe, calcio (Ca) y/o magnesio (Mg) en el suero de los ninos con bronconeumonia y sin ella mediante espectrofotometria de absorcion atomica. Resultados: los resultados muestran que varios niveles de microelementos como Zn, Ca, Mg y Fe en el grupo con bronconeumonia son menores que en el grupo control. En el grupo de ninos con bronconeumonia el nivel de Ca en el suero esta asociado positivamente con el zinc (Zn) (p < 0,05) y el hierro (Fe) (p < 0,05), mientras que hay una correlacion positiva entre el cobre (Cu) y el calcio (Ca) (p < 0,05), magnesio (mg) (p < 0,05). Conclusion: el nivel de oligoelemento en el suero puede estar asociado con el riesgo de bronconeumonia entre los ninos. PMID- 27238781 TI - [In Process Citation]. AB - Introduccion: dado el incremento del sobrepeso y obesidad infantil, es relevante estudiar no solo las consecuencias metabolicas, sino tambien aquellas de indole musculoesqueleticas que pueden afectar la funcionalidad motriz, como es el pie plano, en esta poblacion. Objetivo: identificar la asociacion entre el estado nutricional y la prevalencia de pie plano en ninos y ninas chilenos de 6 a 10 anos. Metodos: el z-score del indice de masa corporal (IMC) y el registro y analisis de las huellas plantares segun la metodologia de Hernandez-Corvo fue llevado a cabo en 388 escolares (52,3% ninas). Un test de diferencia para dos proporciones fue utilizado para evaluar las diferencias entre los grupos. Se considera una significancia estadistica con p <= 0,05. Resultados: la prevalencia del exceso de peso fue de mas del 40%. Esta prevalencia fue mas alta en las ninas (47,8%) que en los ninos (42,7%). La prevalencia de pie plano en todos los ninos fue del 17%, presentando valores mas elevados el pie derecho (18,3%) que el izquierdo (15,7%). Hay un incremento significativo de la prevalencia de pie plano en los ninos obesos en relacion con los ninos con sobrepeso y normopeso. Conclusion: el estado nutricional esta asociado con incrementos en la prevalencia de pie plano en ninos. En la poblacion infantil de 6 a 10 anos de edad, la obesidad esta asociada con la alteracion morfologica del pie. PMID- 27238782 TI - [In Process Citation]. AB - Introduccion: la sarcopenia se define como un sindrome geriatrico, multifactorial, caracterizado por la perdida progresiva de masa muscular esqueletica, asociada a consecuencias graves, tales como comorbideces, mala calidad de vida y mortandad. Objetivo: identificar la prevalencia y los factores asociados a la sarcopenia en ancianos atendidos ambulatoriamente. Metodos: estudio transversal y observacional realizado con pacientes ancianos de ambos sexos atendidos en ambulatorio geriatrico, entre junio y diciembre de 2014, en un hospital universitario ubicado en el nordeste brasileno. Se determino la sarcopenia a traves de la masa muscular (circunferencia de la pantorrilla < 31 cm), fuerza muscular (evaluada por la fuerza de prension palmar < 30 kg para hombres y < 20 kg para mujeres) y velocidad de marcha (< 0,8 metros/segundo). Entre las variables de asociacion, se consideraron aspectos socioeconomicos y demograficos, variables clinicas, estilo de vida y antropometria. La tabulacion y analisis de los datos se realizaron por medio del paquete estadistico SPSS version 13.0. Resultados: la muestra se compuso de 50 pacientes, con promedio de edad de 73,9 (+/- 7,4) anos, en la que se verifico una prevalencia de sarcopenia del 18%. La sarcopenia fue mas prevalente en individuos con edad >= 80 anos (p = 0,012), en los ancianos con bajo peso segun el IMC (p < 0,001), con desnutricion de acuerdo con la CB (p = 0,004) y en los pacientes sin hipertension arterial (p = 0,027), no encontrandose asociacion con variables socioeconomicas, clinicas y del estilo de vida. Conclusiones: la prevalencia de la sarcopenia fue significativa y semejante a la descrita por otros autores, encontrandose asociacion con la edad avanzada, desnutricion y ausencia de hipertension. PMID- 27238783 TI - [In Process Citation]. AB - Introduccion: la desnutricion relacionada con la enfermedad (DRE) es un problema sociosanitario frecuente que afecta preferentemente a los mayores de 65 anos, que aumenta la morbimortalidad y disminuye la calidad de vida. Objetivo: estudiar la prevalencia de DRE en mayores de 65 anos en diferentes centros sociosanitarios del Servicio Regional de Bienestar Social de la Comunidad de Madrid. Metodos: estudio transversal en 33 centros sociosanitarios de Madrid (6 centros de atencion primaria [AP], 9 centros de mayores [CM], 9 hospitales [H] y 9 residencias [R]) seleccionados mediante muestreo polietapico. Las variables estudiadas fueron edad, sexo, nivel de dependencia segun la escala de incapacidad de la Cruz Roja, motivo de ingreso y enfermedad de base, habitat (urbano periurbano-rural) y distribucion geografica (norte centro-sur). Como herramienta de cribado nutricional se utilizo el Mini Nutritional Assessment (MNA-cribaje) en todos los centros. En los pacientes con cribado positivo (en riesgo-desnutricion) se realizo el MNA-evaluacion. El estudio estadistico se realizo con el paquete SSS 21.0 e incluyo estadistica descriptiva, test de Chi-cuadrado y prueba exacta de Fisher, ANOVA de un factor, Kruskal-Wallis y analisis de regresion logistica (RL) binaria univariante y multivariante. Se considero significacion estadistica p < 0,05. Resultados: se reclutaron 1.103 sujetos (275 AP, 278 CM, 281 H, 269 R), edad media de 79,5 +/- 8,4 anos (41,2% varones, 58,8% mujeres). Los sujetos procedentes de H y R tuvieron un mayor grado de incapacidad (p < 0,001). La prevalencia global de DRE fue del 10%, encontrandose un 23,3% en riesgo de desnutricion, con diferencias entre los cuatro tipos de centros sociosanitarios (p < 0,001). El analisis univariante de RL mostro diferencia significativas en la prevalencia de desnutricion segun la edad, sexo, grado de dependencia, tipo de centro sociosanitario, habitat y zona geografica. Sin embargo, en el analisis multivariante solo el grado de dependencia, el tipo de centro y el habitat tuvieron significacion estadistica. Conclusiones: la prevalencia de DRE en mayores de 65 anos en la Comunidad de Madrid es del 10%, encontrandose ademas un 23,3% en riesgo de desnutricion. Las unicas variables que se relacionaron de forma independiente con la desnutricion en el analisis multivariante fueron el nivel de dependencia de los pacientes y el tipo y habitat de centro sociosanitario. PMID- 27238784 TI - [In Process Citation]. AB - Antecedentes: se ha reportado una asociacion entre el aumento del consumo de bebidas azucaradas y varias enfermedades metabolicas. Objetivo: evaluar el efecto del consumo de bebidas azucaradas sobre la obesidad en un periodo de 12 meses en mexicanos de 15 a 19 anos. Metodos: el diseno del estudio fue prospectivo, con 12 meses de seguimiento. Se midieron el peso, la talla y la circunferencia de cintura (CC), y se calculo el puntaje z de indice de masa corporal (IMC). Se aplico un cuestionario sobre consumo de 19 bebidas. Para evaluar la prediccion del aumento de IMC y de CC como resultado del consumo de bebidas, se utilizo analisis de regresion logistica binomial. Resultados: al final del estudio se evaluo al 89% (1.344). El promedio de edad fue de 15 anos, 55% fueron mujeres. La prevalencia de sobre- peso y obesidad al final del estudio fue del 33%. Al final del estudio, un 25% de los participantes consumian mas de 50 g de azucar proveniente de las bebidas. Quienes consumieron 50 g de azucar o mas al dia presentaron mayor riesgo de aumentar la CC >= 2 cm (RR = 1,19, IC 95%, 1,03-1,39, p = 0,02). Quienes mantuvieron el consumo de bebidas azucaradas durante 12 meses, al compararlo con los que disminuyeron el consumo a 10 g/dia, presentaron 71% mas probabilidades de aumentar a un puntaje de IMC >= 2 (RR = 1,71, IC 95%, 1,03 2,86, p = 0,039). Conclusion: el alto consumo de bebidas azucaradas aumento las probabilidades de aumentar de peso y de circunferencia de cintura. PMID- 27238785 TI - [In Process Citation]. AB - Introduccion: el tipo de acido graso de la dieta presenta diferentes efectos sobre la obesidad y sus complicaciones, pero estos efectos pueden verse influenciados por los genes y sus polimorfismos, tales como los receptores activados por el proliferador de los peroxisomas isoforma gamma2 (PPARgamma2). Ademas, no esta claro si el grado de insaturacion de los lipidos posee diferentes efectos en el metabolismo de los lipidos y de la glucosa y, particularmente, en la perdida de peso. Objetivos: evaluar la influencia de dietas ricas en acidos grasos poliinsaturados (AGPI) y monoinsaturados (AGMI) en las variables antropometricas y bioquimicas en el peso corporal y el perfil glucemico y lipemico en mujeres obesas con el genotipo Pro12Pro en el gen PPARgamma2. Metodos: dieciocho mujeres obesas con genotipo Pro12Pro fueron distribuidas aleatoriamente para una de las dietas, rica en AGPI (n = 8) o AGMI (n = 10). Las variables antropometricas (indice de masa corporal [IMC] y circunferencia de la cintura) y bioquimicas (glucosa, insulina, HOMA-IR, colesterol total, LDL colesterol, HDL colesterol y trigliceridos) fueron evaluadas antes y despues de un periodo de 45 dias. Resultados: las variables antropometricas y bioquimicas fueron similares entre los grupos antes y despues de la intervencion (p > 0,05). El IMC disminuyo despues de la ingesta de AGPI (p = 0,01), probablemente debido al menor contenido de lipidos. El AGMI redujo la glucosa (p = 0,03), insulina (p = 0,03) y HOMA-IR (p = 0,02). Conclusion: los AGMI fueron mas eficientes para reducir la resistencia a la insulina en mujeres obesas con el genotipo Pro12Pro en el gen PPARgamma2, aunque las mujeres presentaran una elevada ingesta de lipidos totales y acidos grasos saturados. PMID- 27238786 TI - [In Process Citation]. AB - Introduccion: existe una alta prevalencia de sedentarismo, sobrepeso y obesidad en jovenes universitarios. Objetivo: el proposito del estudio fue determinar los efectos de un programa de entrenamiento intervalado de alta intensidad (HIIT) sobre el perfil antropometrico, glicemia basal y VO 2 max (consumo maximo de oxigeno) de jovenes sedentarios con malnutricion por exceso. Material y metodos: 6 mujeres y 2 hombres (2 obesos y 6 con sobrepeso) se sometieron a un programa de entrenamiento de alta intensidad de 8 semanas de duracion (3 sesiones/semana). Se evaluo en ayuno y posterior a 72 horas de la ultima intervencion; peso, indice de masa corporal (IMC), contorno de cintura (CC), perimetro de cadera y glicemia de basal. El VO 2 max fue evaluado en condiciones normales previo a la primera sesion. Resultados: las variables de estudio no presentaron cambios significativos (p > 0,05), pero reportaron disminuciones porcentuales. El peso disminuyo un 0,18%, el IMC un 0,27%, el CC 2,67%, el perimetro de cadera un 1,15%, y el VO 2 max un 0,48%. La glicemia basal presento la mayor disminucion, paso de 95,13 +/- 23,91 a 89,88 +/- 12,45 mg/dl (5,52%), estabilizando y mejorando sus niveles en cada uno de los participantes. Conclusiones: el programa de entrenamiento intervalado de alta intensidad fue factible de realizar sin resultados adversos para la salud de los participantes, la glicemia basal mostro la mayor variacion, estabilizando sus valores en los participantes, lo que es un indicador positivo dentro del programa. Es necesario seguir investigando sobre esta metodologia HIIT y aumentar los tiempos de estudio para ver los cambios que se pueden producir en distintos parametros metabolicos, antropometricos y fisicos en poblacion con malnutricion por exceso. PMID- 27238787 TI - [Not Available]. PMID- 27238788 TI - [Not Available]. PMID- 27238789 TI - [Not Available]. PMID- 27238790 TI - [Not Available]. PMID- 27238791 TI - [Not Available]. PMID- 27238792 TI - [Not Available]. PMID- 27238793 TI - [Not Available]. PMID- 27238794 TI - [Not Available]. PMID- 27238795 TI - [Not Available]. PMID- 27238796 TI - [Not Available]. PMID- 27238797 TI - [Not Available]. PMID- 27238798 TI - [Not Available]. PMID- 27238799 TI - [Not Available]. PMID- 27238800 TI - [Not Available]. PMID- 27238801 TI - [Not Available]. PMID- 27238802 TI - [Not Available]. PMID- 27238803 TI - [Not Available]. PMID- 27238804 TI - [Not Available]. PMID- 27238805 TI - [Not Available]. PMID- 27238806 TI - [Not Available]. PMID- 27238807 TI - [Not Available]. PMID- 27238808 TI - [Not Available]. PMID- 27238809 TI - [Not Available]. PMID- 27238810 TI - [Not Available]. PMID- 27238811 TI - [Not Available]. PMID- 27238812 TI - [Not Available]. PMID- 27238813 TI - [Not Available]. PMID- 27238814 TI - [Not Available]. PMID- 27238816 TI - Doctor to Doctor. PMID- 27238815 TI - Anti-biofilm and sporicidal activity of peptides based on wheat puroindoline and barley hordoindoline proteins. AB - The broad-spectrum activity of antimicrobial peptides (AMPs) and low probability of development of host resistance make them excellent candidates as novel bio control agents. A number of AMPs are found to be cationic, and a small proportion of these are tryptophan-rich. The puroindolines (PIN) are small, basic proteins found in wheat grains with proposed roles in biotic defence of seeds and seedlings. Synthetic peptides based on their unique tryptophan-rich domain (TRD) display antimicrobial properties. Bacterial endospores and biofilms are highly resistant cells, with significant implications in both medical and food industries. In this study, the cationic PIN TRD-based peptides PuroA (FPVTWRWWKWWKG-NH2 ) and Pina-M (FSVTWRWWKWWKG-NH2 ) and the related barley hordoindoline (HIN) based Hina (FPVTWRWWTWWKG-NH2 ) were tested for effects on planktonic cells and biofilms of the common human pathogens including Pseudomonas aeruginosa, Listeria monocytogenes and the non-pathogenic Listeria innocua. All peptides showed significant bactericidal activity. Further, PuroA and Pina-M at 2 * MIC prevented initial biomass attachment by 85-90% and inhibited >90% of 6-h preformed biofilms of all three organisms. However Hina, with a substitution of Lys-9 with uncharged Thr, particularly inhibited Listeria biofilms. The PIN based peptides were also tested against vegetative cells and endospores of Bacillus subtilis. The results provided evidence that these tryptophan-rich peptides could kill B. subtilis even in sporulated state, reducing the number of viable spores by 4 log units. The treated spores appeared withered under scanning electron microscopy. The results establish the potential of these tryptophan-rich peptides in controlling persistent pathogens of relevance to food industries and human health. Copyright (c) 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID- 27238817 TI - What's in the Pockets? PMID- 27238818 TI - cme credit Quiz. PMID- 27238819 TI - Primary Care Digest. PMID- 27238821 TI - You have a virus. PMID- 27238822 TI - Comment on: DICER1-Negative Pleuropulmonary Blastoma in a Patient With Selective IgA Deficiency. PMID- 27238823 TI - Primary actinomycosis of breast-A diagnosis on cytology. AB - Primary actinomycosis of breast is a rare disease with only a few cases reported in the literature. We present a case of a 25-year-old lactating woman with primary actinomycosis of breast which was diagnosed on cytology. The patient presented with lump in left breast with dull aching pain. Fine-needle aspiration cytology smears showed acute suppurative inflammation with presence of fluffy basophilic colonies on Hematoxylin and Eosin staining and branched, Gram positive filamentous bacilli on Gram staining. The bacilli were non-acid fast with 1% Zeihl Neelsen stain. A diagnosis of actinomycosis was suggested on cytology. Histopathological examination revealed an abscess with few Gram positive basophilic granules surrounded by eosinophilic Splendore-Hoeppli material thus confirming the diagnosis of actinomycosis. Meticulous search for microorganisms with the aid of special stains should be done on cytology smears before labeling an inflammatory lesion as nonspecific. Diagn. Cytopathol. 2016;44:693-695. (c) 2016 Wiley Periodicals, Inc. PMID- 27238824 TI - Alternatives to the Conference Status Quo: Addressing the Learning Needs of Emergency Medicine Residents. PMID- 27238825 TI - Comparison of Ventilation With One-Handed Mask Seal With an Intraoral Mask Versus Conventional Cuffed Face Mask in a Cadaver Model: A Randomized Crossover Trial. AB - STUDY OBJECTIVE: We compare received minute volume with an intraoral mask versus conventional cuffed face mask among medics obtaining a 1-handed mask seal on a cadaver model. METHODS: This study comprised a randomized crossover trial of adult US Army combat medic volunteers participating in a cadaver laboratory as part of their training. We randomized participants to obtain a 1-handed mask seal during ventilation of a fresh unembalmed cadaver, first using either an intraoral airway device or conventional cuffed face mask. Participants obtained a 1-handed mask seal while a ventilator delivered 10 standardized 750-mL breaths during 1 minute. After a 5-minute rest period, they repeated the study with the alternative mask. The primary outcome measure was received minute volume as measured by a respirometer. RESULTS: Of 27 recruited participants, all completed the study. Median received minute volume was higher with the intraoral mask compared with conventional cuffed mask by 1.7 L (95% confidence interval 1.0 to 1.9 L; P<.001). CONCLUSION: The intraoral mask resulted in greater received minute volume received compared with conventional cuffed face mask during ventilation with a 1-handed mask seal in a cadaver model. The intraoral mask may prove a useful airway adjunct for ventilation. PMID- 27238826 TI - Can Noncontrast Head Computed Tomography Within 6 Hours of Symptom Onset Exclude Aneurysmal Subarachnoid Hemorrhage? PMID- 27238828 TI - Special Announcement Advances in Immunotherapy. PMID- 27238831 TI - Selected abstracts of the meeting of the Belgian Society oflnternal Medicine. (24 mei 1997). PMID- 27238827 TI - Duration of Coma in Out-of-Hospital Cardiac Arrest Survivors Treated With Targeted Temperature Management. AB - STUDY OBJECTIVE: We evaluate the time to awakening after out-of-hospital cardiac arrest in patients treated with targeted temperature management and determine whether there was an association with any patient or event characteristics. METHODS: This was a prospective, observational cohort study of consecutive adult survivors of out-of-hospital cardiac arrest of presumed cardiac cause who were treated with targeted temperature management between January 1, 2008, and March 31, 2014. Data were obtained from hospitals and emergency medical services agencies responding to approximately 90% of Arizona's population as part of a state-sponsored out-of-hospital cardiac arrest quality improvement initiative. RESULTS: Among 573 out-of-hospital cardiac arrest patients who completed targeted temperature management, 316 became responsive, 60 (19.0%) of whom woke up at least 48 hours after rewarming. Eight patients (2.5%) became responsive more than 7 days after rewarming, 6 of whom were discharged with a good Cerebral Performance Category score (1 or 2). There were no differences in standard Utstein variables between the early and late awakeners. The early awakeners were more likely to be discharged with a good Cerebral Performance Category score (odds ratio 2.93; 95% confidence interval 1.09 to 7.93). CONCLUSION: We found that a substantial proportion of adult out-of-hospital cardiac arrest survivors treated with targeted temperature management became responsive greater than 48 hours after rewarming, with a resultant good neurologic outcome. PMID- 27238832 TI - Surface and bulk properties of dental resin- composites after solvent storage. AB - OBJECTIVES: To investigate the surface micro-hardness and the diametral tensile strength (DTS) of bulk-fill and conventional resin-composites after storage in food simulating solvents. METHODS: Eight materials were investigated. For the micro-hardness measurement, Teflon mould with an internal dimensions of 10mm and 2mm (n=15). For the DTS measurement, Split stainless steel moulds were used to make disk-shaped specimens of 6mm diameter and 2mm thickness (n=15). Materials were subdivided in to three groups (water, 75% ethanol/water and MEK). Micro hardness measurements were made under a load of 300gm with a dwell time of 15s at 7, 30, and 90ds after storage. DTS was measured after 30ds at a cross head speed of 0.5mm/min. RESULTS: The storage time and type of solvent had a significant influence on the micro-hardness. MEK showed more drastic reduction in the material micro-hardness with an exception of G-aenial universal flo (GA-F) which showed similar results in water/ethanol and MEK. DTS values of materials stored in water ranged from 48.7MPa for the GA-F and 30.6MPa for Ever X posterior (EXP). Generally, the results are observed to decrease with increasing solvent power, except for GA-F. SIGNIFICANCE: Bulk-fill materials showed no superior results compared with the other materials. For the bulk-fill materials that are designed to be used as a base, their penetration by the solvents may be shielded and thus the changes observed in this study may not be of clinical importance. PMID- 27238833 TI - Cyclase inhibitor tripropylamine significantly enhanced lycopene accumulation in Blakeslea trispora. AB - Lycopene is a member of carotenoids that exhibits strong antioxidant activity. In this study, on the basis of screening suitable strain combination [ATCC 14271(+) and ATCC 14272(-)] and establishing the optimal inoculation proportion of mated culture (1/2, +/-, w/w) for carotenoid production, the efficiency of compounds, mainly tertiary amines, on enhancing the lycopene content of Blakeslea trispora was systematically assessed. Of these compounds, tripropylamine showed the best enhancing effect, and then sequentially followed by triethylamine, tributylamine, trimethylamine, diisopropylamine, and isopropylamine. After treated with 1.8 g/L tripropylamine for two days, the lycopene proportion was increased from 1.7% to 90.1%, while the beta-carotene proportion was decreased from 91.1% to 6.4% of the total carotenoids. In this case, the lycopene and total carotenoid contents were increased to 83.2 and 92.4 mg/gDW, which were 315.8- and 5.9-fold of that of the untreated control, respectively; while the growth of mycelia was only decreased at 6.0 g/L tripropylamine. Gene expression analysis showed that all the tested genes, especially genes encoding 3-hydroxy-3-methylglutaryl coenzyme A reductase (hmgr) and isopentenyl pyrophosphate isomerase (ipi) in mevalonate pathway, as well as phytoene desaturase (carB) in carotenoid biosynthesis process were upregulated. Therefore, tripropylamine enhanced lycopene content of B. trispora by inhibiting the cyclase activity, and by upregulating the expression of genes associated with terpenoid biosynthesis. Besides, a possible association between the structure and the lycopene-enhancing capability of these compounds was also discussed. PMID- 27238834 TI - Neurovascular Protective Function of Endothelial Nitric Oxide - Recent Advances. AB - In the central nervous system endothelial nitric oxide (NO) is an essential molecule responsible for the preservation of the functional integrity of the neurovascular unit. NO causes vasodilatation and is an important inhibitor of platelet aggregation, smooth muscle cell proliferation, and white blood cell adhesion. In addition, endothelium-derived NO exerts anti-inflammatory and pro angiogenic effects. More recently, it has been recognized that endothelial NO modulates the expression and processing of amyloid precursor protein in cerebrovascular endothelium and neuronal tissue. Studies in endothelial NO synthase (eNOS) knockout mice indicate that endothelial NO functions as a neurovascular protective molecule during aging. Indeed, genetic inactivation of eNOS exacerbates the detrimental effects of aging on cerebrovascular, microglial, and neuronal functions as well as on cognition. These findings suggest that the preservation of healthy endothelium and normal function of eNOS might be important therapeutic targets. Because the beneficial effects of NO are mostly mediated by the activation of guanylate cyclase/cyclic GMP signaling, inhibitors of phosphodiesterase isoforms, or activation of this signaling with exercise, may offer therapeutic opportunities in the prevention and treatment of aging-induced cognitive decline and Alzheimer's disease. Most recent advances in understanding the molecular mechanisms linking loss of endothelial NO with cognitive decline will be discussed in this review. (Circ J 2016; 80: 1499-1503). PMID- 27238835 TI - Validation of the Korean Genome Epidemiology Study Risk Score to Predict Incident Hypertension in a Large Nationwide Korean Cohort. AB - BACKGROUND: This study aimed to validate the Korean Genome Epidemiology Study (KoGES) risk score to predict the 4-year risk of hypertension (HT) in a large nationwide sample, and compare its discrimination and calibration with the Framingham and blood pressure (BP)-only models. METHODS AND RESULTS: This study analyzed 69,918 subjects without HT at baseline from the National Sample Cohort in the National Health Insurance Service database. We compared the Framingham, KoGES, and BP-only models for discrimination using area under the receiver operating characteristic curves (AROC), calibration using goodness-of-fit tests, and reclassification ability using the continuous net reclassification improvement (NRI) and integrated discrimination improvement. Of 69,918 subjects, 18.6% developed HT during the follow-up. AROC was significantly higher for the KoGES (0.733) than for the Framingham (0.729) or BP-only (0.707) model. Recalibrated Framingham model underestimated HT incidence in all deciles (P<0.001). BP-only model overestimated risk in the lower deciles (P<0.001). KoGES model accurately predicted risk in all except the highest decile (chi(2)=14.85, P=0.062). The KoGES model led to a significant improvement in risk reclassification compared with the Framingham and BP-only models (NRI, 0.354; 95% confidence interval [CI], 0.343-0.365 and 0.542; 95% CI, 0.523-0.561, respectively). CONCLUSIONS: In this validation study, the KoGES model demonstrated better discrimination, calibration, and reclassification ability than either the Framingham or BP-only model. The KoGES model may help identify Korean individuals at high risk for HT. (Circ J 2016; 80: 1578-1582). PMID- 27238836 TI - Serotonin differentially modulates excitatory and inhibitory synaptic inputs to putative sleep-promoting neurons of the ventrolateral preoptic nucleus. AB - The role of serotonin (5-HT) in sleep-wake regulation has been a subject of intense debate and remains incompletely understood. In the ventrolateral preoptic nucleus (VLPO), the main structure that triggers non-rapid eye movement (NREM) sleep, putative sleep-promoting (PSP) neurons were shown ex vivo to be either inhibited (Type-1) or excited (Type-2) by 5-HT application. To determine the complex action of this neurotransmitter on PSP neurons, we recorded spontaneous and miniature excitatory and inhibitory postsynaptic currents (sEPSCs, sIPSCs, mEPSCs and mIPSCs) in response to bath application of 5-HT. We established in mouse acute VLPO slices that 5-HT reduces spontaneous and miniature EPSC and IPSC frequencies to Type-1 neurons, whereas 5-HT selectively increases sIPSC and mIPSC frequencies to Type-2 VLPO neurons. We further determined that Type-1 neurons display a lower action potential threshold and a smaller soma size than Type-2 neurons. Finally, single-cell RT-PCR designed to identify the 13 serotonergic receptor subtypes revealed the specific mRNA expression of the 5-HT1A,B,D,F receptors by Type-1 neurons. Furthermore, the 5-HT2A-C,4,7 receptors were found to be equivalently expressed by both neuronal types. Altogether, our results establish that the excitatory and inhibitory inputs to Type-1 and Type-2 VLPO PSP neurons are differentially regulated by 5-HT. Electrophysiological, morphological and molecular differences were also identified between these two neuronal types. Our results provide new insights regarding the orchestration of sleep regulation by 5-HT release, and strongly suggest that Type-2 neurons could play a permissive role, whereas Type-1 neurons could have an executive role in sleep induction and maintenance. PMID- 27238837 TI - Generalization of the Copper to Late-Transition-Metal Transmetallation to Carbenes beyond N-Heterocyclic Carbenes. AB - Carbene transition-metal complexes have become a prevalent family of catalysts enabling numerous organic transformations. Their facile synthetic access is a matter of great importance. To this end, the Cu(I) -NHC transfer methodology has emerged as a powerful alternative presenting attractive advantages over other methods. Herein, we report the remarkable ability of copper to transfer not only NHCs but also other types of carbenes such as abnormal NHCs (aNHCs), cyclic (alkyl)(amino)carbenes (CAACs), and mesoionic carbenes (MICs) to various transition metal precursors. PMID- 27238839 TI - Facilitators and Barriers of Drop-In Center Use Among Homeless Youth. AB - Drop-in centers for homeless youth address basic needs for food, hygiene, and clothing but can also provide critical services that address youth's "higher level" needs (e.g., substance use treatment, mental health care, HIV-related programs). Unlike other services that have restrictive rules, drop-in centers typically try to break down barriers and take a "come as you are" approach to engaging youth in services. Given their popularity, drop-in centers represent a promising location to deliver higher level services to youth that may not seek services elsewhere. A better understanding of the individual-level factors (e.g., characteristics of homeless youth) and agency-level factors (e.g., characteristics of staff and environment) that facilitate and impede youth engagement in drop-in centers will help inform research and outreach efforts designed to engage these at-risk youth in services. Thus, the goal of this review was to develop a preliminary conceptual model of drop-in center use by homeless youth. Toward this goal, we reviewed 20 available peer-reviewed articles and reports on the facilitators and barriers of drop-in center usage and consulted broader models of service utilization from both youth and adult studies to inform model development. PMID- 27238838 TI - Foxp3 is a key downstream regulator of p53-mediated cellular senescence. AB - The downstream events and target genes of p53 in the process of senescence are not fully understood. Here, we report a novel function of the forkhead transcription factor Foxp3, which is a key player in mediating T-cell inhibitory functions, in p53-mediated cellular senescence. The overexpression of Foxp3 in mouse embryonic fibroblasts (MEFs) accelerates senescence, whereas Foxp3 knockdown leads to escape from p53-mediated senescence in p53-expressing MEFs. Consistent with these results, Foxp3 expression resulted in the induction of senescence in epithelial cancer cells, including MCF7 and HCT116 cells. Foxp3 overexpression also increased the intracellular levels of reactive oxygen species (ROS). The ROS inhibitor N-acetyl-l-cysteine rescued cells from Foxp3-expression induced senescence. Furthermore, the elevated ROS levels that accompanied Foxp3 overexpression were paralleled by an increase in p21 expression. Knockdown of p21 in Foxp3-expressing MEFs abrogated the Foxp3-dependent increase in ROS levels, indicating that Foxp3 acts through the induction of p21 and the subsequent ROS elevation to trigger senescence. Collectively, these results suggest that Foxp3 is a downstream target of p53 that is sufficient to induce p21 expression, ROS production and p53-mediated senescence. PMID- 27238840 TI - Psychological Abuse, Mental Health, and Acceptance of Dating Violence Among Adolescents. AB - PURPOSE: Existing literature indicates that acceptance of dating violence is a significant and robust risk factor for psychological dating abuse perpetration. Past work also indicates a significant relationship between psychological dating abuse perpetration and poor mental health. However, no known research has examined the relationship between acceptance of dating violence, perpetration of dating abuse, and mental health. In addition to exploring this complex relationship, the present study examines whether psychological abuse perpetration mediates the relationship between acceptance of dating violence and mental health (i.e., internalizing symptoms of depression, anxiety, and hostility). METHODS: Three waves of longitudinal data were obtained from 1,042 ethnically diverse high school students in Texas. Participants completed assessments of psychological dating abuse perpetration, acceptance of dating violence, and internalizing symptoms (hostility and symptoms of anxiety and depression). RESULTS: As predicted, results indicated that perpetration of psychological abuse was significantly associated with acceptance of dating violence and all internalizing symptoms. Furthermore, psychological abuse mediated the relationship between acceptance of dating violence and internalizing symptoms. CONCLUSIONS: Findings from the present study suggest that acceptance of dating violence is an important target for the prevention of dating violence and related emotional distress. PMID- 27238841 TI - Design, biological evaluation and 3D QSAR studies of novel dioxin-containing triaryl pyrazoline derivatives as potential B-Raf inhibitors. AB - A series of novel dioxin-containing triaryl pyrazoline derivatives C1-C20 have been synthesized. Their B-Raf inhibitory and anti-proliferation activities were evaluated. Compound C6 displayed the most potent biological activity against B Raf(V600E) and WM266.4 human melanoma cell line with corresponding IC50 value of 0.04MUM and GI50 value of 0.87MUM, being comparable with the positive controls and more potent than our previous best compounds. Moreover, C6 was selective for B-Raf(V600E) from B-Raf(WT), C-Raf and EGFR and low toxic. The docking simulation suggested the potent bioactivity might be caused by breaking the limit of previous binding pattern. A new 3D QSAR model was built with the activity data and binding conformations to conduct visualized SAR discussion as well as to introduce new directions. Stretching the backbone to outer space or totally reversing the backbone are both potential orientations for future researches. PMID- 27238843 TI - Surveillance of Asymptomatic Pancreatic Cysts - How Long is Long Enough? PMID- 27238842 TI - Synthesis, biological evaluation, and physicochemical property assessment of 4 substituted 2-phenylaminoquinazolines as Mer tyrosine kinase inhibitors. AB - Current results identified 4-substituted 2-phenylaminoquinazoline compounds as novel Mer tyrosine kinase (Mer TK) inhibitors with a new scaffold. Twenty-one 2,4 disubstituted quinazolines (series 4-7) were designed, synthesized, and evaluated against Mer TK and a panel of human tumor cell lines aimed at exploring new Mer TK inhibitors as novel potential antitumor agents. A new lead, 4b, was discovered with a good balance between high potency (IC50 0.68MUM) in the Mer TK assay and antiproliferative activity against MV4-11 (GI50 8.54MUM), as well as other human tumor cell lines (GI50<20MUM), and a desirable druglike property profile with low logP value (2.54) and high aqueous solubility (95.6MUg/mL). Molecular modeling elucidated an expected binding mode of 4b with Mer TK and necessary interactions between them, thus supporting the hypothesis that Mer TK might be a biologic target of this kind of new active compound. PMID- 27238845 TI - Determining Which Phenotypes Underlie a Pleiotropic Signal. AB - Discovering pleiotropic loci is important to understand the biological basis of seemingly distinct phenotypes. Most methods for assessing pleiotropy only test for the overall association between genetic variants and multiple phenotypes. To determine which specific traits are pleiotropic, we evaluate via simulation and application three different strategies. The first is model selection techniques based on the inverse regression of genotype on phenotypes. The second is a subset based meta analysis ASSET [Bhattacharjee et al., ], which provides an optimal subset of nonnull traits. And the third is a modified Benjamini-Hochberg (B-H) procedure of controlling the expected false discovery rate [Benjamini and Hochberg, ] in the framework of phenome-wide association study. From our simulations we see that an inverse regression-based approach MultiPhen [O'Reilly et al., ] is more powerful than ASSET for detecting overall pleiotropic association, except for when all the phenotypes are associated and have genetic effects in the same direction. For determining which specific traits are pleiotropic, the modified B-H procedure performs consistently better than the other two methods. The inverse regression-based selection methods perform competitively with the modified B-H procedure only when the phenotypes are weakly correlated. The efficiency of ASSET is observed to lie below and in between the efficiency of the other two methods when the traits are weakly and strongly correlated, respectively. In our application to a large GWAS, we find that the modified B-H procedure also performs well, indicating that this may be an optimal approach for determining the traits underlying a pleiotropic signal. PMID- 27238844 TI - Probiotic Gut Bacteria Enhance Cancer Immunotherapy in a Mouse Model of Melanoma. PMID- 27238846 TI - Palladium(IV) in an Oxoanionic Environment: The XeF2 Assisted Synthesis of [Pd(S2 O7 )3 ](2.). AB - For the first time tetravalent palladium is detected, coordinated exclusively by simple oxoanions. Stabilization was achieved by formation of the [Pd(S2 O7 )3 ](2 ) complex in which three chelating disulfate groups surround the metal atom. The salt K2 [Pd(S2 O7 )3 ] could only be obtained if the reaction of K2 [PdCl6 ] and neat SO3 was performed in the presence of XeF2 . PMID- 27238847 TI - Clinical characterization and long-term follow-up of Schnitzler syndrome. AB - BACKGROUND: Schnitzler syndrome (SchS) is an acquired autoinflammatory disease characterized by chronic urticarial rash in association with monoclonal gammopathy. Patients may progress to lymphoproliferative disorders, but the associated factors and exact risk of progression are still not well defined. AIM: To characterize the clinical findings, laboratory abnormalities and histopathology of patients with SchS and their respective outcomes. METHODS: We retrospectively reviewed the clinical files and the histological specimens of patients with SchS diagnosed from 1988 to 2015. RESULTS: Nine patients (two women, seven men) were diagnosed with SchS. Mean age at diagnosis was 61.1 years (range 29-80), with a mean time to diagnosis of 3.7 years and a mean follow-up period of 10.1 years (range 3-25). Four patients displayed an association of fever and arthralgia, and all nine patients consistently showed laboratory markers of inflammation. Serum values of the monoclonal component, IgMkappa in eight patients and IgGlambda in one patient, progressively increased over time. During follow-up, carried out in association with the haematology department five patients progressed to lymphoproliferative disease, namely, lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinaemia (n = 4) and diffuse large B-cell lymphoma (n = 1). CONCLUSIONS: SchS is a rare chronic inflammatory disease with a substantial impact on quality of life. Our study highlights the importance of lifelong follow-up for individuals with SchS, owing to the risk of progression to a lymphoproliferative disorder. PMID- 27238848 TI - The relation between monocyte to HDL ratio and no-reflow phenomenon in the patients with acute ST-segment elevation myocardial infarction. AB - BACKGROUND: No-reflow phenomenon is a prognostic value in ST-segment elevation myocardial infarction (STEMI). Monocyte to high density lipoprotein ratio (MHR) has recently emerged as a marker of inflammation and oxidative stress in the cardiovascular disease. PURPOSE: In this study, we aimed to investigate the relation between MHR and no-reflow phenomenon in patients with STEMI undergoing primary percutaneous coronary intervention (pPCI). MATERIAL AND METHODS: A total of 600 patients with STEMI (470 men; mean age, 62 +/- 12 years) admitted within 12 hours from symptom onset were included into this study. Patients were classified into 2 groups based on postintervention Thrombolysis in Myocardial Infarction (TIMI) flow grade: no-reflow-TIMI flow grade 0, 1, or 2 (group 1); angiographic success-TIMI flow grade 3 (group 2). RESULTS: According to admission whole-blood cell count results, the patients in the no-reflow group had significantly higher monocyte count and MHR values when compared with those of the reflow patients. After multivariate backward logistic regression, MHR remained independent predictors of no reflow after pPCI. Adjusted odds ratios were calculated as 1.09 for MHR (P< .001; confidence interval [CI], 1.07-1.12). Receiver operating characteristic curve analysis suggested that the optimum MHR level cutoff point for patients with no-reflow was 22.5, with a sensitivity and specificity of 70.2% and 73.3%, respectively (area under curve, 0.768; 95% CI, 0.725-0.811). CONCLUSION: In conclusion, MHR levels are one of the independent predictors of no reflow in patients with STEMI after pPCI. PMID- 27238850 TI - Accuracy of bedside ultrasonography for the diagnosis of phalanx fractures. PMID- 27238849 TI - Propofol administration for procedural sedation in the ED. PMID- 27238851 TI - Hyperthermia , Rhabdomyolysis and Synthetic Cannabinoids - the authors respond. PMID- 27238852 TI - When to activate a multidisciplinary team for an acute abdominal aortic aneurysm? AB - BACKGROUND: It is often difficult to determine when a multidisciplinary aneurysm team should be summoned based on the (often limited) pre-hospital information provided METHOD: We performed a retrospective cohort study of patients brought to our hospital between January 1st 2013 and October 1st 2014 by the emergency medical services (EMS) with a clinical suspicion of an acute AAA. Within this group we compared patients with a documented acute AAA and without an acute AAA in order to identify patient characteristics that could be used for the development of evidence based activation criteria for multidisciplinary acute aneurysm teams. RESULTS: Of the 63 patients presented by the EMS with a clinical suspicion of an acute AAA, 16 had an acute AAA. The optimal age cut-off value to discriminate patients with- from patients without an acute AAA was 70 years, whereas the optimal cut-off systolic blood pressure was 137 mmHg. "Age> 70" (LR+ 2.6 [1.8-3.8], "SBP <137mm Hg" (LR+ 2.6 [1.5-4.9], the "presence of diaphoresis " (LR+ 2.5 [1.7-3.8] and a "prior history of AAA" (LR+ 2.9 [1.5-5.7] were independent predictors of the presence of an acute AAA. The presence of any of these factors increased the pre-test probability of an acute AAA to > 50%. CONCLUSION: Pre-hospital information regarding the patient's age, history (known AAA), blood pressure and general appearance (presence of diaphoresis) can be useful when EMS services announce the arrival of a patient with suspected acute AAA in order to improve appropriate triage and minimize time to definitive care. PMID- 27238853 TI - Acute pancreatitis with normal lipase and amylase: an ED dilemma. PMID- 27238854 TI - Beneficial action of magnesium sulfate in bronchial asthma: how and why? PMID- 27238855 TI - Bicyclists found at fault for bicycle crashes in California. PMID- 27238856 TI - Acute dilated cardiomyopathy and myocardial injury after combined 4 fluoroamphetamine and modafinil ingestion. PMID- 27238857 TI - Visual outcome in Sturge-Weber syndrome: a systematic review and Dutch multicentre cohort. AB - Visual functions in Sturge-Weber syndrome (SWS) may be impaired by glaucoma, diffuse choroidal haemangioma (DCH) or leptomeningeal angioma. The aim of this study was to gain better insight in the visual deficits of SWS patients. A systematic literature search using PubMed and Embase medical databases was performed to identify articles describing visual acuity (VA) and/or visual field (VF) findings in SWS patients. In addition, a Dutch multicentre cohort with 33 SWS patients was collected and the combined results of VA and VF findings are presented. Visual acuity results of 25 studies and VF results of 12 studies were suitable for data extraction. Description of the combination of both VA and VF findings was scarce. Homonymous hemianopia (HH) was present in 42% of SWS patients. Seventy per cent of eyes had a (near) normal vision, while VA of eyes with glaucoma or DCH was severely impaired in 28% and 67%, respectively. In the Dutch cohort, only 18% (6/33) of patients had (near) normal findings of both visual parameters. In addition, half of the patients with glaucoma suffered from a combination of a HH and VA impairment. In conclusion, although SWS patients are exposed to severe functional visual impairment due to the possible cumulative consequences of glaucoma, DCH and cerebral injury, description of the combination of both VA and VF results is scarce in the literature. Particularly, the combination of visual impairment due to glaucoma or DCH, and HH might be invalidating. PMID- 27238858 TI - Establishing high-quality reference values for nerve conduction studies: A report from the normative data task force of the American Association Of Neuromuscular & Electrodiagnostic Medicine. AB - INTRODUCTION: There are not uniform standards for nerve conduction testing across the United States. The objective of this study is to present a set of methodologically sound criteria to evaluate the literature for the purpose of identifying high-quality normative nerve conduction studies (NCS) suitable for widespread use. METHODS: The Normative Data Task Force (NDTF) was formed to review published studies on methodological issues related to NCS. A set of criteria was then developed to evaluate the literature. These criteria and their rationale are described. RESULTS: We identified 7 key issues that reflect high quality in NCS. For each issue, specific review criteria were developed. CONCLUSION: Rigorous criteria enable identification of high-quality studies dealing with nerve conduction reference values. This represents the first step toward the overarching goal of recommending NCS techniques and reference values for electrodiagnostic medicine. Muscle Nerve 54: 366-370, 2016. PMID- 27238859 TI - Ultrasound-guided subcostal transversus abdominis plane blocks with liposomal bupivacaine vs. non-liposomal bupivacaine for postoperative pain control after laparoscopic hand-assisted donor nephrectomy: a prospective randomised observer blinded study. AB - We compared the effect of subcostal transversus abdominis plane (TAP) block with liposomal bupivacaine to TAP block with non-liposomal bupivacaine on postoperative maximal pain scores in patients undergoing donor nephrectomy. Sixty patients were prospectively randomly assigned to receive ultrasound-guided bilateral TAPs with either 1.3% liposomal bupivacaine and normal saline or 0.25% non-liposomal bupivacaine with adrenaline. There was a significant decrease in maximal pain scores in the liposomal bupivacaine TAP group when compared with the non-liposomal bupivacaine group median (IQR [range]), 24-48 h after injection, 5 (3.0-5.2 [0-10]) vs. 6 (4.5-7.0 [1--9]) p = 0.009; 48-72 h after injection, 3 (2.0-5.0 [0-8]) vs. 5 (3.0-7.0 [0-10]) p = 0.02; and in opioid use 48-72 h after injection, mean (SD) MUg equivalents of fentanyl 105 (97) vs. 182 (162) p = 0.03. Liposomal bupivacaine via subcostal TAP infiltration provided superior analgesia up to 72 h after injection when compared with non-liposomal bupivacaine. PMID- 27238860 TI - Transendoscopic Electrosurgery for Partial Removal of a Gastric Adenomatous Polyp in a Horse. PMID- 27238861 TI - Enteral nutrition in Crohn's disease with a high output enteroatmospheric fistula. PMID- 27238862 TI - Ileo-enteric fistula caused by an infiltrating rectal cancer. PMID- 27238863 TI - Bilateral intrahepatic pancreatic pseudocyst. PMID- 27238865 TI - A Central Role for Mixed Acetylcholine/GABA Transmission in Direction Coding in the Retina. AB - A surprisingly large number of neurons throughout the brain are endowed with the ability to co-release both a fast excitatory and inhibitory transmitter. The computational benefits of dual transmitter release, however, remain poorly understood. Here, we address the role of co-transmission of acetylcholine (ACh) and GABA from starburst amacrine cells (SACs) to direction-selective ganglion cells (DSGCs). Using a combination of pharmacology, optogenetics, and linear regression methods, we estimated the spatiotemporal profiles of GABA, ACh, and glutamate receptor-mediated synaptic activity in DSGCs evoked by motion. We found that ACh initiates responses to motion in natural scenes or under low-contrast conditions. In contrast, classical glutamatergic pathways play a secondary role, amplifying cholinergic responses via NMDA receptor activation. Furthermore, under these conditions, the network of SACs differentially transmits ACh and GABA to DSGCs in a directional manner. Thus, mixed transmission plays a central role in shaping directional responses of DSGCs. PMID- 27238864 TI - Inhibitory Input from the Lateral Hypothalamus to the Ventral Tegmental Area Disinhibits Dopamine Neurons and Promotes Behavioral Activation. AB - Projections from the lateral hypothalamus (LH) to the ventral tegmental area (VTA), containing both GABAergic and glutamatergic components, encode conditioned responses and control compulsive reward-seeking behavior. GABAergic neurons in the LH have been shown to mediate appetitive and feeding-related behaviors. Here we show that the GABAergic component of the LH-VTA pathway supports positive reinforcement and place preference, while the glutamatergic component mediates place avoidance. In addition, our results indicate that photoactivation of these projections modulates other behaviors, such as social interaction and perseverant investigation of a novel object. We provide evidence that photostimulation of the GABAergic LH-VTA component, but not the glutamatergic component, increases dopamine (DA) release in the nucleus accumbens (NAc) via inhibition of local VTA GABAergic neurons. Our study clarifies how GABAergic LH inputs to the VTA can contribute to generalized behavioral activation across multiple contexts, consistent with a role in increasing motivational salience. VIDEO ABSTRACT. PMID- 27238866 TI - Endocannabinoid Modulation of Orbitostriatal Circuits Gates Habit Formation. AB - Everyday function demands efficient and flexible decision-making that allows for habitual and goal-directed action control. An inability to shift has been implicated in disorders with impaired decision-making, including obsessive compulsive disorder and addiction. Despite this, our understanding of the specific molecular mechanisms and circuitry involved in shifting action control remains limited. Here we identify an endogenous molecular mechanism in a specific cortical-striatal pathway that mediates the transition between goal-directed and habitual action strategies. Deletion of cannabinoid type 1 (CB1) receptors from cortical projections originating in the orbital frontal cortex (OFC) prevents mice from shifting from goal-directed to habitual instrumental lever pressing. Activity of OFC neurons projecting to dorsal striatum (OFC-DS) and, specifically, activity of OFC-DS terminals is necessary for goal-directed action control. Lastly, CB1 deletion from OFC-DS neurons prevents the shift from goal-directed to habitual action control. These data suggest that the emergence of habits depends on endocannabinoid-mediated attenuation of a competing circuit controlling goal directed behaviors. PMID- 27238868 TI - Ventral Pallidum Neurons Encode Incentive Value and Promote Cue-Elicited Instrumental Actions. AB - The ventral pallidum (VP) is posited to contribute to reward seeking by conveying upstream signals from the nucleus accumbens (NAc). Yet, very little is known about how VP neuron responses contribute to behavioral responses to incentive cues. Here, we recorded activity of VP neurons in a cue-driven reward-seeking task previously shown to require neural activity in the NAc. We find that VP neurons encode both learned cue value and subsequent reward seeking and that activity in VP neurons is required for robust cue-elicited reward seeking. Surprisingly, the onset of VP neuron responses occurs at a shorter latency than cue-elicited responses in NAc neurons. This suggests that this VP encoding is not a passive response to signals generated in the NAc and that VP neurons integrate sensory and motivation-related information received directly from other mesocorticolimbic inputs. PMID- 27238870 TI - Morphometric analysis of NADPH diaphorase reactive neurons in a rat model of focal excitotoxic striatal injury. AB - Excitotoxicity is the major component in neuropathological conditions, related to harmful action of imbalanced concentrations of glutamate and its agonists in the nervous tissue, ultimately resulting in cell death. In the present study, we evaluated the effects of an acute striatal lesion induced by a focal N-methyl-D aspartate (NMDA) microinjection on the morphometry of NADPH diaphorase-reactive neurons (NADPH-d+ ), a subset of cells which release nitric oxide (NO) in the brain and are known by its resistance in pathological conditions. Two hundred and forty NADPH-d neurons from NMDA-lesioned striatum and contralateral counterpart were tridimensionally reconstructed at 1, 3 and 7 post-lesion days (PLDs). Cell body and dendritic field areas, length of dendrites by order and fractal dimension were analyzed. There were no significant morphometric differences when NADPH-d+ neurons from lesioned and control striatal regions were compared among PLDs evaluated. Conversely, a conspicuous pallor in striatal neuropil reactivity was evidenced, especially in latter survival time. In addition, we observed a noticeable inflammatory response induced by NMDA. Our results suggest that NADPH d+ neurons were spared from deleterious effects of acute NMDA excitotoxic damage in the striatum, reinforcing the notion that this cell group is selectively resistant to injury in the nervous system. PMID- 27238867 TI - Experience-Dependent Bimodal Plasticity of Inhibitory Neurons in Early Development. AB - Inhibitory neurons are heterogeneous in the mature brain. It is unclear when and how inhibitory neurons express distinct structural and functional profiles. Using in vivo time-lapse imaging of tectal neuron structure and visually evoked Ca(2+) responses in tadpoles, we found that inhibitory neurons cluster into two groups with opposite valence of plasticity after 4 hr of dark and visual stimulation. Half decreased dendritic arbor size and Ca(2+) responses after dark and increased them after visual stimulation, matching plasticity in excitatory neurons. Half increased dendrite arbor size and Ca(2+) responses following dark and decreased them after stimulation. At the circuit level, visually evoked excitatory and inhibitory synaptic inputs were potentiated by visual experience and E/I remained constant. Our results indicate that developing inhibitory neurons fall into distinct functional groups with opposite experience-dependent plasticity and as such, are well positioned to foster experience-dependent synaptic plasticity and maintain circuit stability during labile periods of circuit development. PMID- 27238871 TI - Acrolein enhances epigenetic modifications, FasL expression and hepatocyte toxicity induced by anti-HIV drug Zidovudine. AB - Zidovudine (AZT) remains the mainstay of antiretroviral therapy against HIV in resource-poor countries; however, its use is frequently associated with hepatotoxicity. Not all HIV patients on AZT develop hepatotoxicity, and the determining factors are unclear. Alcohol consumption and cigarette smoking are known risk factors for HIV hepatotoxicity, and both are significant sources of acrolein, a highly reactive and toxic aldehyde. This study examines the potential hepatotoxic interactions between acrolein and AZT. Our data demonstrate that acrolein markedly enhanced AZT-induced transcriptionally permissive histone modifications (H3K9Ac and H3K9Me3) allowing the recruitment of transcription factor NF-kB and RNA polymerase II at the FasL gene promoter, resulting in FasL upregulation and apoptosis in hepatocytes. Notably, the acrolein scavenger, hydralazine prevented these promoter-associated epigenetic changes and inhibited FasL upregulation and apoptosis induced by the combination of AZT and acrolein, as well as AZT alone. Our data strongly suggest that acrolein enhancement of promoter histone modifications and FasL upregulation are major pathogenic mechanisms driving AZT-induced hepatotoxicity. Moreover, these data also indicate the therapeutic potential of hydralazine in mitigating AZT hepatotoxicity. PMID- 27238873 TI - Early Treatment With Enalapril and Later Renal Injury in Programmed Obese Adult Rats. AB - Obesity-related kidney disease should be prevented or retarded. We aimed to investigate whether early treatment with enalapril ameliorates later renal injury induced by early postnatal overnutrition. Three or ten male pups per mother were assigned to either the Obese or Lean group during the first 21 days of life. These pups were treated with enalapril (Obese enalapril, OE; Lean enalapril, LE) or vehicle (Obese control, OC; Lean control, LC) for 15-28 days. Body weight, blood pressure (BP), and renal alterations were determined at 3 months. Enalapril decreased body weight only in the Lean group at 3 months (P < 0.05). Systemic BP levels were higher in the LE, OC, and OE groups than in the LC group at 3 months (P < 0.05). Fewer glomeruli per section area were found in the LE, OC, and OE groups than in the LC group and in the OE group than in the OC group (P < 0.05). The LE and OE groups had higher index scores of glomerulosclerosis and tubulointerstitial fibrosis than the controls (P < 0.05). LE pups showed increased intrarenal angiotensin II receptor type (AT)2 and matrix metalloproteinase (MMP)-9 and decreased renin and tissue inhibitor of MMP (TIMP) 1 expression than the LC rats (P < 0.05). OE pups showed increased intrarenal AT2 and decreased AT1 and TIMP-1 expression than the OC rats (P < 0.05). In conclusion, early treatment with enalapril can induce detrimental renal effects in later life and may not be renoprotective in programmed obese adult rats. J. Cell. Physiol. 232: 447-455, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27238872 TI - Developing a reference system for the IFCC standardization of HbA2. AB - The importance of hemoglobin A2 (HbA2) as an indicator of the presence of beta thalassemia was established many years ago. However, clinical application of recommended HbA2 cut off values is often hampered due to poor equivalence of HbA2 results among methods and laboratories. Thus, the IFCC standardization program for HbA2 was initiated in 2004 with the goal of achieving a complete reference system for this measurand. HbA2 standardization efforts are still in progress, including the development of a higher-order HbA2 reference measurement procedure and the preparation of a certified reference material in collaboration with the IRMM. Here, we review the past, present and future of HbA2 standardization and describe the current status of HbA2 testing. PMID- 27238874 TI - Impact of Laparoscopic Adrenalectomy on Overall Survival in Patients with Nonmetastatic Adrenocortical Carcinoma. AB - BACKGROUND: Appropriate use of laparoscopic adrenalectomy (LA) for adrenocortical carcinoma (ACC) remains controversial because complete resection with negative margins is the best chance for potential cure. This study compared the oncologic outcomes and overall survival (OS) of LA and open adrenalectomy (OA) for ACC. STUDY DESIGN: A retrospective analysis of the National Cancer Data Base (NCDB) between 2010 and 2014 identified 423 European Network for the Study of Adrenal Tumors (ENSAT) stage I to III ACC patients who had LA (n = 137) or OA (n = 286). Outcomes and OS were compared between the 2 groups. RESULTS: Patients who underwent OA had more advanced stage disease (p = 0.0001), larger (>=5 cm) tumors (p < 0.0001), and were younger (age less than 55 years, p = 0.05). Nodal assessment was rare in LA (n = 4) compared with OA (n = 88) (p < 0.0001). Margin positivity was affected only by surgical approach in patients with T3 tumors (LA 54.6% vs OA 21.7%; p = 0.0009). Neither surgical procedure nor any socio demographic factor(s) affected OS for the entire cohort. Only positive margins (p = 0.007), positive nodes (p = 0.02), tumor extension (p = 0.01), and more advanced ENSAT stage (p = 0.004) increased mortality. When stratified by disease stage, LA decreased OS for patients with stage II disease (p = 0.04), and remained an independent risk factor for death on multivariate analysis (hazard ratio [HR] 1.86, 95% CI 1.02 to 3.38; p = 0.04). Only positive margins decreased OS in the entire cohort (HR 2.17, 95% CI 1.32 to 3.57; p = 0.002). CONCLUSIONS: Use of LA may decrease OS in select patients with ACC. Because margin status remains the strongest predictor of mortality, caution should be used in selecting LA for patients with ACC. PMID- 27238875 TI - National Survey of Burnout among US General Surgery Residents. AB - BACKGROUND: Burnout is a complex syndrome of emotional distress that can disproportionately affect individuals who work in health care professions. STUDY DESIGN: For a national survey of burnout in US general surgery residents, we asked all ACGME-accredited general surgery program directors to email their general surgery residents an invitation to complete an anonymous, online survey. Burnout was assessed with the Maslach Burnout Inventory; total scores for Emotional Exhaustion (EE), Depersonalization (DP), and Personal Accomplishment (PA) subscales were calculated. Burnout was defined as having a score in the highest tertile for EE or DP or lowest tertile for PA. Chi-square tests and one way ANOVA were used to test associations between burnout tertiles for each subscale and various resident and training-program characteristics as appropriate. RESULTS: From April to December 2014, six hundred and sixty-five residents actively engaged in clinical training had data for analysis; 69% met the criterion for burnout on at least one subscale. Higher burnout on each subscale was reported by residents planning private practice careers compared with academic careers. A greater proportion of women than men reported burnout on EE and PA. Higher burnout on EE and DP was associated with greater work hours per week. Having a structured mentoring program was associated with lower burnout on each subscale. CONCLUSIONS: The high rates of burnout among general surgery residents are concerning, given the potential impact of burnout on the quality of patient care. Efforts to identify at-risk populations and to design targeted interventions to mitigate burnout in surgical trainees are warranted. PMID- 27238876 TI - Clinical benefit of intra-articular saline as a comparator in clinical trials of knee osteoarthritis treatments: A systematic review and meta-analysis of randomized trials. AB - OBJECTIVES: Hyaluronic acid and corticosteroids are common intra-articular (IA) therapies widely used for the management of mild to moderate knee osteoarthritis (OA). Many trials evaluating the efficacy of IA administered therapies commonly use IA saline injections as a placebo comparator arm. Using a systematic review and meta-analysis, our objective was to assess the clinical benefit associated with use of IA saline in trials of IA therapies in the treatment of patients with painful knee OA. METHODS: MEDLINE and Embase databases were searched for articles published up to and including August 14th, 2014. Two reviewers assessed the eligibility of potential reports and the risk of bias of included trials. We analyzed short (<=3 months) and long-term (6-12 months) pain reduction of the saline arm of included trials using standardized mean differences (SMDs; estimated assuming a null effect in a comparator group) that were combined and weighted using a random effects model. Treatment-related adverse events (AEs) were tabulated and presented using descriptive statistics. RESULTS: From 40 randomized controlled trials (RCTs) eligible for inclusion only 38 provided sufficient data to be included in the meta-analysis. Based on data with moderate inconsistency IA saline was found to significantly improve short-term knee pain in 32 studies involving 1705 patients (SMD = -0.68; 95% CI: -0.78 to -0.57; P < 0.001; I(2) = 50%). Long-term knee pain was significantly decreased following IA injection with saline in 19 studies involving 1445 patients (SMD = -0.61; 95% CI: -0.76 to -0.45; P < 0.001) with a substantial degree of inconsistency (I(2) = 74%). Overall, 29 of the included trials reported on adverse events, none of which found any serious treatment-related AEs following IA injection with saline. CONCLUSIONS: Pain relief observed with IA saline should prompt health care providers to consider the additional effectiveness of current IA treatments that use saline comparators in clinical studies, and challenges of identifying IA saline injection as a "placebo." PMID- 27238877 TI - Predictors of musculoskeletal flares and Jaccoud's arthropathy in patients with systemic lupus erythematosus: A 5-year prospective study. AB - OBJECTIVE: To investigate the prognostic value of US in predicting musculoskeletal flares and Jaccoud's arthropathy (JA) in systemic lupus erythematosus (SLE). METHODS: A total of 80 out of 94 patients (76 female; age 45.5 +/- 13.2 years) with non-deforming non-erosive (NDNE) arthritis and 48/60 healthy controls (42 female; age 49.6 +/- 11.6 years) completed the 5-year follow up study. Each patient was prospectively assessed for the occurrence of musculoskeletal flares using BILAG2004 and hand deformities according to Jaccoud's articular index. Baseline clinical, serological, semi-quantitative (0-3 scale) ultrasound (US) findings, PD-synovitis and PD-tenosynovitis scores were used as covariates to identify predictors of study outcomes. Short Form 36 v2 (SF36v2) health survey questionnaire was administered. RESULTS: Overall, 12 MS flares in 10 (12.5%) patients were recorded and the incidence rate was 3.0 per 100 patient-year. Baseline PD-synovitis score independently predicted MS flare (p < 0.001; RR = 2.0; 95% CI: 1.4-3.0) within 2 years since US examination. In all, 5 (6.2%) patients developed JA whose incidence rate was 1.25 per 100 patient year. Independent risk factors for development of JA were higher longitudinal BILAG score in the musculoskeletal domain (p = 0.005; RR = 2.4; 95% CI: 1.3-4.6) and longer disease duration (p = 0.013; RR 1.2; 95% CI: 1.1-1.3). JA and active musculoskeletal inflammation (BILAG >= C), but not US erosions, were associated with lower results in SF36v2 physical and mental summary components. CONCLUSIONS: Performing musculoskeletal US can be useful in order to predict MS flares. Jaccoud's deformities may arise in patients with long-standing SLE and prolonged, even subclinical, joint and tendon inflammation. PMID- 27238878 TI - Short-term outcome of patients with history of significant coronary artery disease following acute pulmonary embolism. PMID- 27238879 TI - Establishing a danger zone: An anatomic study of the lingual artery in base of tongue surgery. AB - OBJECTIVES/HYPOTHESIS: To contrast the changes in measurement of the hypoglossal/lingual artery neurovascular bundle (HLNVB) to constant surface landmarks in the base of tongue (BOT) during surgically simulated retraction versus resting anatomic position, and to identify a safe zone for BOT robotic surgery to avoid injury to the HLNVB. STUDY DESIGN: Human cadaver study. METHODS: Five fresh-frozen head and neck complexes were obtained, and seven HLNVBs were dissected. A microcaliper was used to measure the distance from the HLNVB to constant surface landmarks in resting and surgically simulated positions using a Feyh-Kastenbauer retractor. RESULTS: Measurements from foramen cecum to palatoglossus muscle (P < 0.042) was significantly different when comparing anatomical to surgically simulated positions. Importantly, the location of the lingual artery in reference to the surface landmarks measured was dramatically altered with tongue retraction. With retraction, the branches of the dorsal lingual artery were not encountered posterior to a horizontal line between midway circumvallate papilla (mCVP). CONCLUSION: Measurements of the HLNVB to surface landmarks in the BOT differs significantly between resting and a surgically simulated tongue position. The dorsal branch of the lingual artery seems more superficial in the BOT than previously described. A safe zone may exist posterior to an imaginary horizontal line between mCVP; however, further studies are needed to confirm this. LEVEL OF EVIDENCE: NA Laryngoscope, 127:110-115, 2017. PMID- 27238880 TI - Case of severe ulceration induced by pazopanib. PMID- 27238881 TI - Virulence factors and resistance to antimicrobials in Listeria monocytogenes serotype 1/2c isolated from food. AB - AIMS: The aim of this study was to assess the potential risk posed to the human population by the presence of Listeria monocytogenes serotype 1/2c in food based on the characterization of virulence factors of Listeria involved in the invasion of host cells and sensitivity to antimicrobial agents. METHODS AND RESULTS: In addition to sequencing of the inlA and inlB genes, the presence of genes lapB, aut, fbpA, ami, vip and llsX was tested. A premature stop codon (PMSC) in the inlA gene was detected in all tested strains of serotype 1/2c and, concurrently, two novel PMSC mutation types were identified. However, neither PMSC in the inlB gene nor deletion of the lapB, aut, fbpA, ami and vip genes were found in any of the strains. The presence of the llsX gene was not confirmed. Even though all L. monocytogenes strains showed sensitivity to the tested antimicrobials on the basis of their phenotype, sequencing revealed the presence of IS1542 insertion in the inlA gene, indicating the possibility of sharing of mobile genetic elements associated with antimicrobial resistance among strains. CONCLUSIONS: Other than the presence of PMSCs in the inlA gene, no PMSC in inlB or deletion of other factors linked to the invasiveness of listeria were detected. Tested strains showed sensitivity to antibiotics used in the therapy of listeriosis. SIGNIFICANCE AND IMPACT OF THE STUDY: Strains of L. monocytogenes serotype 1/2c typically carry a PMSC in the inlA gene, but these strains still represent a potential threat to public health. The possibility of transfer of IS1542, associated with resistance to vancomycin, between enterococci and Listeria spp. was revealed. PMID- 27238882 TI - Prevalence of Bell's palsy in Qena Governorate, Egypt. AB - BACKGROUND AND PURPOSE: There have been few studies to estimate the prevalence of Bell's palsy (BP) in Arab countries. A community-based study was conducted to estimate the prevalence, incidence rates, precipitating factors, and outcome of BP in Qena Governorate, Egypt. SUBJECTS AND METHODS: A door-to-door survey was carried out, with random sampling of 10 districts, involving 9303 inhabitants, 51.1% males and 48.9% females. Seventeen subjects were positive in screening questionnaire and referred to Qena University hospital and were subjected to a full clinical examination, House Brackmann's Facial grading system. RESULTS: In a total population of 9303 individuals, 15 cases were confirmed as having BP giving a prevalence rate (PR) 161/10(5) for all ages 95%CI (80-243). It was slightly but not significantly higher among women and the rural community. The incidence rate of BP was 107/10(5). The highest age-specific rate was 40-49 years age. The most frequent precipitating factors for an episode of BP were exposure to air draft in 40%, physical stress (13.3%), and upper respiratory tract infection (13.3%). Moreover, 46.7% had predisposing risk factors, DM and hypertension in 33.3%. Sixty percent of cases had complication and poor outcome. CONCLUSION: The overall prevalence and incidence rates of BP in Qena governorate were high. This could be related to the variation in day and night temperature in our community and the susceptibility to air draft exposure during the night. The high frequency of poor outcome among studied cases suggests that better local guidelines should be implemented to recognize and treat BP. PMID- 27238883 TI - Targeting of blood safety measures to affected areas with ongoing local transmission of malaria. AB - An outbreak of locally acquired Plasmodium vivax malaria in Greece started in 2009 and peaked in 2011. Targeting of blood safety measures to affected areas with ongoing transmission of malaria raised questions of how to define spatial boundaries of such an area and when to trigger any specific blood safety measures, including whether and which blood donation screening strategy to apply. To provide scientific advice the European Centre for Disease Prevention and Control (ECDC) organised expert meetings in 2013. The outcomes of these consultations are expert opinions covering spatial targeting of blood safety measures to affected areas with ongoing local transmission of malaria and blood donation screening strategy for evidence of malaria infection in these areas. Opinions could help EU national blood safety authorities in developing a preventive strategy during malaria outbreaks. PMID- 27238884 TI - Bond strength of a chairside autopolymerizing reline resin to injection-molded thermoplastic denture base resins. AB - PURPOSE: This study evaluated the shear bond strength of a chairside autopolymerizing reline resin to injection-molded thermoplastic denture base resins. METHODS: Four kinds of injection-molded thermoplastic resins (two polyamides, a polyethylene terephthalate copolymer and a polycarbonate) and PMMA, as a control, were tested. The eight types of surface treatment: ((1) no treatment, (2) air abrasion, (3) dichloromethane, (4) ethyl acetate, (5) 4 META/MMA-TBB resin, (6) air abrasion and 4-META/MMA-TBB resin, (7) tribochemical silica coating, and (8) tribochemical silica coating and 4-META/MMA-TBB resin) were applied to each specimen. The chairside autopolymerizing reline resins were bonded to disks of the injection-molded thermoplastic denture base resins. All of the specimens were immersed in water for 4 months and then thermocycled for 10,000 cycles in water between 5 and 55 degrees C. The shear bond strengths were determined. RESULTS: The shear bond strengths of the two polyamides treated using air abrasion, dichloromethane and ethyl acetate and no treatment were exceedingly low. The greatest bond strength was recorded for the polyethylene terephthalate copolymer specimens treated with tribochemical silica coating and 4-META/MMA-TBB resin (22.5MPa). The bond strengths of the other injection-molded thermoplastic denture base resins increased using 4-META/MMA-TBB resin. CONCLUSIONS: Tribochemical silica coating and 4-META/MMA-TBB resin were the most effective surface treatments among all denture base resins tested. PMID- 27238885 TI - Application of an innovative computerized virtual planning system in acetabular fracture surgery: A feasibility study. AB - INTRODUCTION: Acetabular fracture surgery is amongst the most challenging tasks in the field of trauma surgery and careful preoperative planning is crucial for success. The aim of this paper is to describe the preliminary outcome of the utilization of an innovative computerized virtual planning system for acetabular fractures. METHODS: 3D models of acetabular fractures and surrounding soft tissues from six patients were constructed from preoperative CT scans. A novel highly-automatic segmentation technique was performed on the 3D model to separate each fracture fragment, then 3D virtual reduction was performed. Additionally, the models were used to assess potential surgical approaches with reference to both the fracture and the surrounding soft tissues. The time required for virtual planning was recorded. After surgery, the virtual plan was compared to the real surgery with respect to surgical approach and reduction sequence. A Likert scale questionnaire was completed by the surgeons to evaluate their satisfaction with the system. RESULTS: Virtual planning was successfully completed in all cases. The planned surgical approach was followed in all cases with the planned reduction sequence followed completely in five cases and partially in one. The mean time required for virtual planning was 38.7min (range 21-57, SD=15.5). The mean time required for planning of B-type fractures was 25.0min (range 21-30, SD=4.6), of C-type fracture 52.3min (range 49-57, SD=4.2). The results of the questionnaire demonstrated a high level of satisfaction with the planning system. CONCLUSION: This study demonstrates that the virtual planning system is feasible in clinical settings with high satisfaction and acceptability from the surgeons. It provides a viable option for the planning of acetabular fracture surgery. PMID- 27238886 TI - Effects of binge drinking and hangover on response selection sub-processes-a study using EEG and drift diffusion modeling. AB - Effects of binge drinking on cognitive control and response selection are increasingly recognized in research on alcohol (ethanol) effects. Yet, little is known about how those processes are modulated by hangover effects. Given that acute intoxication and hangover seem to be characterized by partly divergent effects and mechanisms, further research on this topic is needed. In the current study, we hence investigated this with a special focus on potentially differential effects of alcohol intoxication and subsequent hangover on sub processes involved in the decision to select a response. We do so combining drift diffusion modeling of behavioral data with neurophysiological (EEG) data. Opposed to common sense, the results do not show an impairment of all assessed measures. Instead, they show specific effects of high dose alcohol intoxication and hangover on selective drift diffusion model and EEG parameters (as compared to a sober state). While the acute intoxication induced by binge-drinking decreased the drift rate, it was increased by the subsequent hangover, indicating more efficient information accumulation during hangover. Further, the non-decisional processes of information encoding decreased with intoxication, but not during hangover. These effects were reflected in modulations of the N2, P1 and N1 event related potentials, which reflect conflict monitoring, perceptual gating and attentional selection processes, respectively. As regards the functional neuroanatomical architecture, the anterior cingulate cortex (ACC) as well as occipital networks seem to be modulated. Even though alcohol is known to have broad neurobiological effects, its effects on cognitive processes are rather specific. PMID- 27238887 TI - Multiple giant cell lesions in a patient with Noonan syndrome with multiple lentigines. AB - A patient with Noonan syndrome with multiple lentigines (NSML) and multiple giant cell lesions (MGCL) in mandibles and maxillae is described. A mutation p.Thr468Met in the PTPN11-gene was found. This is the second reported NSML patient with MGCL. Our case adds to the assumption that, despite a different molecular pathogenesis and effect on the RAS/MEK pathway, NSML shares the development of MGCL, with other RASopathies. PMID- 27238888 TI - Xq11.1-11.2 deletion involving ARHGEF9 in a girl with autism spectrum disorder. AB - We report an 8-year-old female with autism spectrum disorder (ASD), intellectual disability and speech delay who was found to carry a de novo 82 kb deletion of chromosome Xq11.1-11.2 involving the ARHGEF9 gene on chromosomal microarray. So far, 11 patients with point mutations, disruptions due to chromosomal rearrangements and deletions involving ARHGEF9 have been reported in the literature. ARHGEF9-related disorders comprise a wide phenotypic spectrum, including behavior disorders, autism spectrum disorder, intellectual disability, hyperekplexia and infantile epileptic encephalopathy. ARHGEF9 encodes for collybistin which plays an important role in post synaptic clustering of glycine and inhibitory gamma-aminobutyric acid receptors along with its scaffolding partner, gephyrin. The reduction of inhibitory receptor clusters in brain has been proposed as a plausible underlying pathophysiological mechanism. With this report, we provide further evidence for the role of ARHGEF9 in neurocognitive function, its implication in ASD, and review the clinical features of previously published individuals with ARHGEF9-related intellectual disability. PMID- 27238889 TI - Treatment of acute leukemia in children with ataxia telangiectasia (A-T). AB - Early onset ataxia telangiectasia (A-T) is a neurodegenerative DNA-instability disorder, which presents early in childhood. Hallmarks of A-T are progressive ataxia and a dramatic increased risk of developing malignancies (25%), especially of hematological origin. In children these malignancies mainly concern aggressive Non-Hodgkin lymphoma, acute leukemias and Hodgkin lymphoma. Of the acute leukemias, T-cell lymphoblastic leukemia (T-ALL) is by far the most common. Since patients with A-T experience increased toxicity to radio- and chemotherapeutic treatment, the optimal treatment strategy of acute leukemia remains subject of debate. Review of literature of treatment of T-ALL in patients with A-T (n = 18) showed that many patients are not diagnosed with A-T at time of presentation of T ALL. This implicates that physicians must be aware of symptoms of A-T in young patients presenting with T-ALL. Complete remission rates are high following upfront modified as well as unmodified treatment strategies. Treatment of ALL in children with A-T is feasible and should be performed. Definitive treatment strategy must be determined by shared decision making with patient, caretakers and medical team. Future prospective studies are needed to elucidate optimal treatment strategy. PMID- 27238890 TI - A Selective Na(+) Aptamer Dissected by Sensitized Tb(3+) Luminescence. AB - A previous study of two RNA-cleaving DNAzymes, NaA43 and Ce13d, revealed the possibility of a common Na(+) aptamer motif. Because Na(+) binding to DNA is a fundamental biochemical problem, the interaction between Ce13d and Na(+) was studied in detail by using sensitized Tb(3+) luminescence spectroscopy. Na(+) displaces Tb(3+) from the DNAzyme, and thus quenches the emission from Tb(3+) . The overall requirement for Na(+) binding includes the hairpin and the highly conserved 16-nucleotide loop in the enzyme strand, along with a few unpaired nucleotides in the substrate. Mutation studies indicate good correlation between Na(+) binding and cleavage activity, thus suggesting a critical role of Na(+) binding for the enzyme activity. Ce13d displayed a Kd of ~20 mm with Na(+) (other monovalent cations: 40-60 mm). The Kd values for other metal ions are mainly due to non-specific competition. With a single nucleotide mutation, the specific Na(+) binding was lost. Another mutant improved Kd to 8 mm with Na(+) . This study has demonstrated a Na(+) aptamer with important biological implications and analytical applications. It has also defined the structural requirements for Na(+) binding and produced an improved mutant. PMID- 27238891 TI - Interfaces at equilibrium: A guide to fundamentals. AB - The fundamentals of the thermodynamics of interfaces are reviewed and concisely presented. The discussion starts with a short review of the elements of bulk thermodynamics that are also relevant to interfaces. It continues with the interfacial thermodynamics of two-phase systems, including the definition of interfacial tension and adsorption. Finally, the interfacial thermodynamics of three-phase (wetting) systems is discussed, including the topic of non-wettable surfaces. A clear distinction is made between equilibrium conditions, in terms of minimizing energies (internal, Gibbs or Helmholtz), and equilibrium indicators, in terms of measurable, intrinsic properties (temperature, chemical potential, pressure). It is emphasized that the equilibrium indicators are the same whatever energy is minimized, if the boundary conditions are properly chosen. Also, to avoid a common confusion, a distinction is made between systems of constant volume and systems with drops of constant volume. PMID- 27238892 TI - Distinct temporal spike and local field potential activities in the thalamic parafascicular nucleus of parkinsonian rats during rest and limb movement. AB - Several studies have suggested that the thalamic centromedian-parafascicular (CM/PF or the PF in rodents) is implicated in the pathophysiology of Parkinson's disease (PD). However, inconsistent changes in the neuronal firing rate and pattern have been reported in parkinsonian animals. To investigate the impact of a dopaminergic cell lesion on PF extracellular discharge in behaving rats, the PF neural activities in the spike and local field potential (LFP) were recorded in unilaterally 6-hydroxydopamine- (6-OHDA) lesioned and neurologically intact control rats during rest and limb movement. During rest, the two PF neuronal subtypes was less spontaneously active, with no difference in the spike firing rates between the control and lesioned rats; only the lesioned rats reshaped their spike firing pattern. Furthermore, the simultaneously recorded LFP in the lesioned rats exhibited a significant increase in power at 12-35 and 35-70Hz and a decrease in power at 0.7-12Hz. During the execution of a voluntary movement, two subtypes of PF neurons were identified by a rapid increase in the discharge activity in both the control and lesioned rats. However, dopamine lesioning was associated with a decrease in neuronal spiking fire rate and reshaping in the firing pattern in the PF. The simultaneously recorded LFP activity exhibited a significant increase in power at 12-35Hz and a decrease in power at 0.7-12Hz compared with the control rats. These findings indicate that 6-OHDA induces modifications in PF spike and LFP activities in rats during rest and movement and suggest that PF dysfunction may be an important contributor to the pathophysiology of parkinsonian motor impairment. PMID- 27238893 TI - Anabolic-androgenic steroids decrease dendritic spine density in the nucleus accumbens of male rats. AB - Recent studies have demonstrated that anabolic-androgenic steroids (AAS) modify cognitive processes such as decision making and behavioral flexibility. However, the neural mechanisms underlying these AAS-induced cognitive changes remain poorly understood. The mesocorticolimbic dopamine (DA) system, particularly the nucleus accumbens (Acb), is important for reward, motivated behavior, and higher cognitive processes such as decision making. Therefore, AAS-induced plasticity in the DA system is a potential structural substrate for the observed cognitive alterations. High doses of testosterone (the most commonly-used AAS) increase dendritic spine density in limbic regions including the amygdala and hippocampus. However, effects on Acb are unknown. This was the focus of the present study. Adolescent male Long-Evans rats were treated chronically for 8weeks with high dose testosterone (7.5mg/kg in water with 13% cyclodextrin) or vehicle sc. Brains were stained by Golgi-Cox to analyze neuronal morphology in medium spiny neurons of the shell region of Acb (AcbSh). Eightweeks of testosterone treatment significantly decreased spine density in AcbSh compared to brains of vehicle treated rats (F1,14=5.455, p<0.05). Testosterone did not significantly affect total spine number, dendritic length, or arborization measured by Sholl analysis. These results show that AAS alter neuronal morphology in AcbSh by decreasing spine density throughout the dendritic tree, and provides a potential mechanism for AAS to modify cognition and decision-making behavior. PMID- 27238894 TI - Natural-enriched environments lead to enhanced environmental engagement and altered neurobiological resilience. AB - The mammalian brain has evolved in close synchrony with the natural environment; consequently, trends toward disengagement from natural environments in today's industrialized societies may compromise adaptive neural responses and lead to psychiatric illness. Investigations of rodents housed in enriched environments indicate enhanced neurobiological complexity; yet, the origin of these stimuli, natural vs. manufactured, has not been sufficiently explored. In the current study, groups of rats were exposed to one of three environments: (1) a standard environment with only food and water, (2) an artificial-enriched environment with manufactured stimuli and (3) a natural-enriched environment with natural stimuli. Results indicated that, during the dark phase, natural-enriched animals exhibited longer durations interacting with objects than the artificial-enriched group; further, the natural-enriched group engaged in more social behavior than the other two groups. Both enriched groups exhibited less anxiety in response to a novel object but the natural-enriched rats exhibited less anxiety-typical behavior in response to a predator odor than the other groups. Less fos activation in the amygdala was observed in both enriched groups following a water escape task whereas an increase in fos activation in the nucleus accumbens was observed in the natural-enriched animals. Thus, the current findings indicate the potential importance of exposure to complex environments, especially natural-like habitats, in the maintenance of emotional health, perhaps providing a buffer against the emergence of anxiogenic responses. PMID- 27238896 TI - Recurrent peripheral facial palsy as a complication of celiac disease. PMID- 27238897 TI - Which way and how far? Tracking of translation and rotation information for human path integration. AB - Path integration, the constant updating of the navigator's knowledge of position and orientation during movement, requires both visuospatial knowledge and memory. This study aimed to develop a systems-level understanding of human path integration by examining the basic building blocks of path integration in humans. To achieve this goal, we used functional imaging to examine the neural mechanisms that support the tracking and memory of translational and rotational components of human path integration. Critically, and in contrast to previous studies, we examined movement in translation and rotation tasks with no defined end-point or goal. Navigators accumulated translational and rotational information during virtual self-motion. Activity in hippocampus, retrosplenial cortex (RSC), and parahippocampal cortex (PHC) increased during both translation and rotation encoding, suggesting that these regions track self-motion information during path integration. These results address current questions regarding distance coding in the human brain. By implementing a modified delayed match to sample paradigm, we also examined the encoding and maintenance of path integration signals in working memory. Hippocampus, PHC, and RSC were recruited during successful encoding and maintenance of path integration information, with RSC selective for tasks that required processing heading rotation changes. These data indicate distinct working memory mechanisms for translation and rotation, which are essential for updating neural representations of current location. The results provide evidence that hippocampus, PHC, and RSC flexibly track task-relevant translation and rotation signals for path integration and could form the hub of a more distributed network supporting spatial navigation. Hum Brain Mapp 37:3636-3655, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27238895 TI - Effect of probiotics on clinical and immune parameters in enthesitis-related arthritis category of juvenile idiopathic arthritis. AB - Gut microflora and dysbiosis as an environmental factor has been linked to the pathogenesis of enthesitis-related arthritis (JIA-ERA); thus, we performed a proof-of-concept study of probiotics to modulate the gut-flora and study the effects on immune and clinical parameters of children having JIA-ERA. Forty-six children with active JIA-ERA were randomized to placebo or probiotic therapy along with non-steroidal anti-inflammatory drugs (NSAIDs) for 12 weeks. Patients were assessed using a six-point composite disease activity index (mJSpADA) based on morning stiffness, joint count, enthesitis count, sacroiliitis/inflammatory back pain, uveitis and erythrocyte sedimentation rate/C-reactive protein (ESR/CRP). Frequencies of T helper type 1 (Th1), Th2, Th17 and regulatory T cells in blood were measured using flow cytometry. Serum cytokines interferon (IFN) gamma, interleukin (IL)-4, IL-17, IL-10, tumour necrosis factor (TNF)-alpha and IL-6 were measured by cytokine bead array using flow cytometer. The average age of 46 children (44 boys) was 15 +/- 2.5 years and duration of disease was 3.5 +/- 3 years. There was no significant difference in improvement in mJSpADA between the two groups (P = 0.16). Serum IL-6 levels showed a decrease (P < 0.05) in the probiotic-group. Th2 cell frequency (P < 0.05) and serum IL-10 levels (P < 0.01) showed an increase in the placebo group, but again the probiotic use did not show a significant change in immune parameters when compared to the placebo. Adverse effects among the probiotic and placebo groups were diarrhea (36 versus 45%), abdominal pain (9 versus 20%), minor infections (4.5 versus 20%) and flatulence (23 versus 15%), respectively. Thus, we can conclude that probiotic therapy in JIA-ERA children is well tolerated, but failed to show any significant immune or clinical effects over NSAID therapy. PMID- 27238898 TI - Effect of meal size reduction and protein enrichment on intake and satiety in vital community-dwelling older adults. AB - Undernutrition risk among community-dwelling older adults is partly caused by inadequate protein intake. Enriching readymade meals with protein could be beneficial in increasing protein intake. Moreover, reduced-size meals could suit older adults with diminished appetite. In this single-blind randomized crossover study with 120 participants (age: 70.5 +/- 4.5 y, BMI: 27.2 +/- 4.4 kg/m(2)), 60 participants consumed four beef meals and another 60 consumed four chicken meals on four different days, once per week. These meals were produced according to a 2 * 2 factorial design: the protein content was either ~25 g (lower) or ~30 g (enriched), and the portion size was either 450 g (normal) or of 400 g (reduced). Palatability evaluation, meal intake, and subsequent satiety ratings after 120 min were measured. No significant differences in palatability among meals were found. While absolute intake (g) of the normal-size meals was significantly higher than that of the reduced-size meals, the relative intake (%) of the served meals did not differ between the four meals. Both protein and energy intakes were significantly higher for the enriched meals, regardless of portion size. Protein intakes were 5.4 g and 5.1 g higher in the normal-size and reduced-size enriched beef meals, respectively, and 6.1 g and 7.1 g higher in the enriched chicken meals, respectively. The normal-size enriched beef meal and reduced-size enriched chicken meal led to slightly but significantly higher ratings of satiety than the non-enriched meals. Due to these mixed satiety findings, separate effects of meal size reduction and protein enrichment could not be distinguished in this study. The intake findings show that palatable protein-enriched meals support higher protein and energy intakes in vital community-dwelling older adults during a single meal. PMID- 27238899 TI - Mid-childhood fruit and vegetable consumption: The roles of early liking, early consumption, and maternal consumption. AB - Previous studies have shown that early liking, early consumption, and maternal consumption of fruits and vegetables (F&V) each predict children's F&V consumption, but no one has examined the independent contributions of these three correlated factors. We aim to examine the extent to which each of these 3 factors is associated with F&V consumption in mid-childhood after accounting for the other 2 in the analysis. We analyzed data from 901 mother-child dyads from Project Viva, a prospective pre-birth cohort study. Mothers reported their child's early liking and consumption of F&V at age 2 years and later consumption at mid-childhood (median age 7.7 years). They also reported their own consumption of F&V at 6 months postpartum. We used multivariable linear regression models to examine the independent associations of these 3 factors with mid-childhood consumption, adjusting for socio-demographic, pregnancy, and child confounders. At 2 years, 53% of the mothers strongly agreed that their child liked fruit and 25% strongly agreed that their child liked vegetables. F&V consumption was 2.5 (1.3) and 1.8 (1.1) times/d at age 2 y and 1.5 (1.1) and 1.3 (0.8) times/d in mid childhood. Maternal F&V consumption was 1.4 (1.1) and 1.5 (1.0) times/d, respectively. Children's early consumption played the most predominant role. For every 1 time/d increment in children's early consumption of F&V, mid-childhood consumption was higher by 0.25 (95% confidence interval [CI]: 0.19, 0.30) times/d for fruits and 0.21 (95% CI: 0.16, 0.26) times/d for vegetables, adjusted for confounders plus the other 2 exposures. In conclusion, children's early F&V consumption has the most significant influence on children's later consumption. PMID- 27238900 TI - Optical Windows for Imaging the Metastatic Tumour Microenvironment in vivo. AB - Intravital imaging enables to study dynamic tumour-stroma interactions within primary and metastatic sites, including the lung. The combination of optical windows with specific molecular probes targeting the tumour microenvironment will provide new insights into prometastatic stromal interactions and lead to novel therapeutic strategies for metastatic diseases. PMID- 27238901 TI - Factors That Influence Women to Disclose Sexual Assault History to Health Care Providers. AB - OBJECTIVE: To examine women's experiences with sexual assault screening by health care professionals and identify factors that influence women to disclose their sexual assault history to providers. DESIGN: Cross-sectional descriptive survey with correlational analysis. SETTING: On-line survey distributed nationally. PARTICIPANTS: One hundred forty-three women. METHODS: Participants were recruited through social media; the authors e-mailed organizations across the nation and asked them to share links to a Facebook page connected to the survey. Descriptive statistics, Spearman's rho, and contingency tables were calculated, and qualitative content analysis was performed by thematic analysis. RESULTS: Most (n = 103, 72.5%) participants reported that they felt comfortable with being asked about sexual assault, but only 41 (28.7%) participants were screened for sexual assault by health care professionals. Positive attitude and increased comfort level with screening were associated with increased intention to disclose past assault (p < .05). A total of 113 (82.5%) women reported intentions to disclose sexual assault to a provider if asked, whereas only 35 (24.6%) women would voluntarily disclose. Women identified prevention of medical and physical consequences as main facilitators to disclosure, and provider attitude and demeanor as the main barriers. Sixty-nine (48.9%) participants were victims of sexual assault. Women with a history of sexual assault were no more likely than women not victimized to have been screened for sexual assault. CONCLUSION: Study findings suggest that women are often not screened for sexual assault despite being receptive to inquiry. Health care professionals often do not identify those who have been sexually assaulted because they do not ask. Thus, many victims do not receive needed sexual assault resources and support. PMID- 27238902 TI - Incidence, etiology, and outcome of pleural effusions in allogeneic hematopoietic stem cell transplantation. AB - Pleural effusion is a known entity in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT); however, the incidence, risk factors, and morbidity-mortality outcomes associated with pleural effusions remain unknown. We retrospectively evaluated pleural effusions in 618 consecutive adult patients who underwent allogeneic HSCT from January 2008 to December 2013 at our institution. Seventy one patients developed pleural effusion at a median of 40 days (range, 1 - 869) post-HSCT with the cumulative incidence of 9.9% (95% CI, 7.7 - 12.5%) at 1 year. Infectious etiology was commonly associated with pleural effusions followed by volume overload and serositis type chronic GVHD. In multivariate analysis, higher comorbidity index (P = 0.03) and active GVHD (P = 0.018) were found to be significant independent predictors for pleural effusion development. Higher comorbidity index, very high disease risk index, <=7/8 HLA matching, and unrelated donor were associated with inferior overall survival (OS) (P < 0.03). More importantly, patients with pleural effusion were noted to have poor OS in comparison to patients without pleural effusion (P < 0.001). Overall, pleural effusion is a frequently occurring complication after allogeneic HSCT, adding to morbidity and mortality and hence, early identification is required. Am. J. Hematol. 91:E341-E347, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27238903 TI - Corrigendum to 'Income-related inequalities in cardiovascular disease from mid life to old age in a Northern Swedish cohort: A decomposition analysis' [Soc. Sci. Med. 149C (2016) 135-144]. PMID- 27238904 TI - Hotel fire safety for international travellers. PMID- 27238906 TI - Methodologies for measuring travelers' risk perception of infectious diseases: A systematic review. AB - Numerous studies in the past have stressed the importance of travelers' psychology and perception in the implementation of preventive measures. The aim of this systematic review was to identify the methodologies used in studies reporting on travelers' risk perception of infectious diseases. A systematic search for relevant literature was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. There were 39 studies identified. In 35 of 39 studies, the methodology used was that of a knowledge, attitude and practice (KAP) survey based on questionnaires. One study used a combination of questionnaires and a visual psychometric measuring instrument called the 'pictorial representation of illness and self-measurement" or PRISM. One study used a self-representation model (SRM) method. Two studies measured psychosocial factors. Valuable information was obtained from KAP surveys showing an overall lack of knowledge among travelers about the most frequent travel associated infections and associated preventive measures. This methodological approach however, is mainly descriptive, addressing knowledge, attitudes, and practices separately and lacking an examination of the interrelationships between these three components. Another limitation of the KAP method is underestimating psychosocial variables that have proved influential in health related behaviors, including perceived benefits and costs of preventive measures, perceived social pressure, perceived personal control, unrealistic optimism and risk propensity. Future risk perception studies in travel medicine should consider psychosocial variables with inferential and multivariate statistical analyses. The use of implicit measurements of attitudes could also provide new insights in the field of travelers' risk perception of travel-associated infectious diseases. PMID- 27238905 TI - Ophthalmologic aspects of chikungunya infection. AB - Chikungunya fever, a viral disease epidemic in some parts of the world is newly introduced in the Americas. This is of considerable international concern, with a growing incidence owing to developing urbanization, tourism, and trade. Ocular manifestations of chikungunya fever are not frequent, but of great relevance. Common manifestations include conjunctivitis, optic neuritis, iridocyclitis, episcleritis, retinitis and uveitis. Diagnostic and monitoring investigations would include optical coherence tomography, fundus fluorescein and indocyanine green angiography, visual field analysis, and electrophysiologic tests. There have been no prospective, randomized therapeutic trials, and it is unclear if the disease is self-limiting or if treatment is actually beneficial. Prognosis varies, ranging from full resolution to permanent vision loss despite intervention. PMID- 27238907 TI - Cost effectiveness of interferon-gamma release assay for tuberculosis screening using three months of rifapentine and isoniazid among long-term expatriates from low to high incidence countries. AB - BACKGROUND: Long-term expatriates from low to high tuberculosis (TB) incidence countries get high rates of active TB and latent TB infection (LTBI). TB screening for expatriates is important for occupational health. Interferon-gamma release assays are more accurate than tuberculin skin test (TST). Rifapentine plus isoniazid for 3 months (3HP) is as effective as 9 months of isoniazid (9H) with a higher treatment-completion rate. METHODS: Decision trees and Markov models were constructed using a societal perspective on a lifetime horizon. The target population was a hypothetical cohort of 30 year-old expatriates. Seven strategies; TST with 3HP or 9H, QuantiFERON(r)-TB Gold In-Tube (QFT) with 3HP or 9H, T-SPOT(r).TB (TSPOT) with 3HP or 9H and chest X-ray examination (CXR) were modeled. The main outcome measure of effectiveness was quality-adjusted life years (QALYs) gained. RESULTS: QFT with 3HP yielded the greatest benefits with the lowest cost ($US 674.8; 25.95660 QALYs [year 2012 values]). CXR was the least cost-effective ($US 13,666.8; 24.62917 QALYs). Cost-effectiveness was sensitive to adherence rate of 3HP and QFT specificity, but not to BCG vaccination rate. CONCLUSIONS: Entry LTBI screening using QFT treated with 3HP is recommended on the basis of cost effectiveness among long-term expatriates from low to high incidence countries. PMID- 27238908 TI - Late manifestation of a mixed Plasmodium falciparum and Plasmodium malariae infection in a non-immune toddler after traveling to Chad. PMID- 27238909 TI - Travelers to the FIFA world cup 2014 in Brazil: Health risks related to mass gatherings/sports events and implications for the Summer Olympic Games in Rio de Janeiro in 2016. AB - BACKGROUND: Health threats during mass gatherings, such as the FIFA world cup 2014 differ from traditional health risks. The influence of event type, demographics of attendees and environmental conditions are still not fully understood. METHODS: An observational, prospective case-control survey conducted at the Frankfurt international airport in Germany on 544 travelers to the FIFA world cup 2014 and 432 regular travelers to Brazil departing after the end of the world cup. RESULTS: Travelers to the FIFA world cup 2014 were predominantly male whereas the gender distribution in the control group was more balanced. The majority in both groups obtained insect bites and sunburns as environmental risk factors. Every third traveler suffered from diarrheal complaints in both groups, whereas the proportion of travelers with flu-like symptoms was higher in the case group. Travelers to the FIFA world cup 2014 indicated alcohol intake and sexual contacts outside of a relationship more frequently than travelers in the control group. CONCLUSIONS: The additional health risks of travelers to sporting events as the FIFA world cup 2014 should be addressed in addition to traditional health threats in pre-travel counseling for the Summer Olympic Games 2016 in Brazil. PMID- 27238911 TI - Nonlinear least squares regression for single image scanning electron microscope signal-to-noise ratio estimation. AB - A new method based on nonlinear least squares regression (NLLSR) is formulated to estimate signal-to-noise ratio (SNR) of scanning electron microscope (SEM) images. The estimation of SNR value based on NLLSR method is compared with the three existing methods of nearest neighbourhood, first-order interpolation and the combination of both nearest neighbourhood and first-order interpolation. Samples of SEM images with different textures, contrasts and edges were used to test the performance of NLLSR method in estimating the SNR values of the SEM images. It is shown that the NLLSR method is able to produce better estimation accuracy as compared to the other three existing methods. According to the SNR results obtained from the experiment, the NLLSR method is able to produce approximately less than 1% of SNR error difference as compared to the other three existing methods. PMID- 27238910 TI - Pilot study of newborn screening for six lysosomal storage diseases using Tandem Mass Spectrometry. AB - BACKGROUND: There is current expansion of newborn screening (NBS) programs to include lysosomal storage disorders because of the availability of treatments that produce an optimal clinical outcome when started early in life. OBJECTIVE: To evaluate the performance of a multiplex-tandem mass spectrometry (MS/MS) enzymatic activity assay of 6 lysosomal enzymes in a NBS laboratory for the identification of newborns at risk for developing Pompe, Mucopolysaccharidosis-I (MPS-I), Fabry, Gaucher, Niemann Pick-A/B, and Krabbe diseases. METHODS AND RESULTS: Enzyme activities (acid alpha-glucosidase (GAA), galactocerebrosidase (GALC), glucocerebrosidase (GBA), alpha-galactosidase A (GLA), alpha-iduronidase (IDUA) and sphingomyeline phosphodiesterase-1 (SMPD-1)) were measured on ~43,000 de-identified dried blood spot (DBS) punches, and screen positive samples were submitted for DNA sequencing to obtain genotype confirmation of disease risk. The 6-plex assay was efficiently performed in the Washington state NBS laboratory by a single laboratory technician at the bench using a single MS/MS instrument. The number of screen positive samples per 100,000 newborns were as follows: GAA (4.5), IDUA (13.6), GLA (18.2), SMPD1 (11.4), GBA (6.8), and GALC (25.0). DISCUSSION: A 6-plex MS/MS assay for 6 lysosomal enzymes can be successfully performed in a NBS laboratory. The analytical ranges (enzyme-dependent assay response for the quality control HIGH sample divided by that for all enzyme independent processes) for the 6-enzymes with the MS/MS is 5- to 15-fold higher than comparable fluorimetric assays using 4-methylumbelliferyl substrates. The rate of screen positive detection is consistently lower for the MS/MS assay compared to the fluorimetric assay using a digital microfluidics platform. PMID- 27238912 TI - The role of living context in prescription opioid injection and the associated risk of hepatitis C infection. AB - BACKGROUND AND AIMS: Prescription opioid injection (POI) is a leading risk factor for hepatitis C virus (HCV). Residential context relates to high-risk injection behaviour. This study assessed whether residence in the inner city (versus surrounding areas in Montreal Island) modified the effects of correlates of POI or the relationship between POI and HCV incidence. DESIGN: Prospective cohort study. SETTING: Montreal, Canada. PARTICIPANTS: A total of 854 people who inject drugs (18% female, 25% age < 30 years), living on Montreal Island, were interviewed every 3-6 months from 2004 to 2012. MEASUREMENTS: Study visits included HCV antibody testing and an interviewer-administered questionnaire. Generalized estimating equations were used to test whether place of residence modified the effects of correlates of POI. Cox regression was used to test whether place of residence modified the relationship between POI and HCV incidence. FINDINGS: At baseline, inner-city participants were more likely to report POI in the past month (40 versus 25%, P < 0.001). The association between POI and heroin injection, syringe sharing and sharing of injecting equipment varied according to place of residence and was greater in the inner city. The hazard of HCV infection associated with POI was greater among inner-city participants compared to those in the surrounding areas [adjusted hazard ratio (HR) = 3.38, 95% confidence interval (CI) = 1.88-6.07 versus HR = 1.26, 95% CI = 0.65-2.42, P = 0.025]. CONCLUSIONS: Among people who inject prescription opioids in Montreal, Canada, those who live in inner-city areas are more likely to engage in injecting-related risk behaviours and have a higher risk of hepatitis C virus infection than those who live in the suburbs. PMID- 27238913 TI - Preclinical models of conduct disorder - principles and pharmacologic perspectives. AB - The translational value of preclinical research was recently enhanced by abnormal aggression models, which focus on deviant behaviors induced by the exposure of rodents to etiological factors of aggression-related psychopathologies. Prompted by similar trials in other psychiatric disorders, here we investigate models of abnormal aggression from the perspective of DSM5 criteria. After proposing principles based on which analogies can be established between psychopathology symptoms and rodent behavioral dysfunctions, we show that rodents submitted to abnormal aggression models fulfill basic criteria of aggression-related psychopathologies; moreover, some models can be considered specific to particular disorders e.g. conduct disorder. We also show that abnormal and species-typical aggressions differ in terms of both brain mechanisms and pharmacological responsiveness, which mimics differences observed in psychiatric disorders. We conclude that evaluating abnormal aggression models from a DSM5 perspective is not only possible but also worthwhile, and such models may contribute to the development of novel treatment strategies not only for aggression as a symptom but also for specific aggression-related disorders or multi-symptom clusters at least. PMID- 27238914 TI - A Quantitative Method Using Head Noncontrast CT Scans to Detect Hyperacute Nonvisible Ischemic Changes in Patients With Stroke. AB - PURPOSE: Because clinical evaluation of noncontrast computed tomography (CT) has a poor sensitivity in the evaluation of acute ischemic stroke, computer-aided diagnosis may be able to facilitate the performance. Recently, we introduced a computational method for the detection and localization of visible infarcts. Herein, we aimed to evaluate and extend a previous method, the Stroke Imaging Marker (SIM), to localize nonvisible hyperacute ischemia. MATERIALS AND METHODS: On the basis of the SIM and its components-the ratio of percentile differences in subranges of Hounsfield Unit (HU) distribution (P-ratio), ratio of voxels count in ranges of brain CT intensity, median HU attenuation value-the infarct localization was performed in 140 early and follow-up scans of 70 patients. In none of the early scans was the infarct visible to a radiologist or an experienced stroke neuroradiologist. The infarcted hemisphere detection rate (HDR) and sensitivity of infarct localization were measured by overlapping the region of detected tissue in the initial scan, with the gold standard set for the fully visible stroke in the follow-up scan. RESULTS: The best performance of the algorithm was found for the P-ratio including seven percentile subranges within the range of 35th-75th percentile. The modified SIM provided a 76% ischemic HDR and 54% sensitivity in spatial localization of hyperacute ischemia (68% among properly detected infarct sides). CONCLUSION: The improved SIM is a dedicated and potentially useful tool for hyperacute nonvisible brain infarct detection from CT scans and may contribute to reduction of image-to-needle time in patients eligible for revascularization therapy. PMID- 27238915 TI - E-Cadherin, CD44v6, and Insulin-Like Growth Factor-II mRNA-Binding Protein 3 Expressions in Different Stages of Hydatidiform Moles. AB - E-cadherin, CD44v6, and IMP3 expression in partial, complete, and invasive hydatidiform moles (HMs) was evaluated. High E-cadherin expression with low CD44v6 expression was observed in partial, complete, and invasive HMs, as well as in normal placental tissues; and there was no significant difference in E cadherin and CD44v6 expression among the four groups. However, IMP3 expression was gradually decreased in the order of normal placental tissues, partial HMs, complete HMs, and invasive HMs; wherein, invasive HMs had the lowest level. Low IMP3 expression may serve as a prognostic biomarker for HMs, and IMP3 may play a certain role in HMs progression. PMID- 27238916 TI - High Serum sTREM-1 Correlates With Myocardial Dysfunction and Predicts Prognosis in Septic Patients. AB - OBJECTIVE: This study aimed to evaluate the predictive and prognostic value of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in patients with myocardial dysfunction induced by severe sepsis and septic shock. MATERIALS AND METHODS: A total of 84 patients with severe sepsis and septic shock were enrolled between May 2013 and December 2014.The patients were monitored by pulse indicator continuous cardiac output system and divided into myocardial depression group (cardiac function index [CFI] < 4.1/minute, n = 37) and nonmyocardial depression group (CFI >= 4.1/minute, n = 47 ). Additionally, the patients were divided into survival group (n = 40) and nonsurvival group (n = 44) based on 28 day mortality. Hemodynamic parameters and serum sTREM-1, B-type natriuretic peptide (BNP) and cardiac troponin I (cTnI) levels were collected on days 1, 3 and 5 after admission to intensive care unit. RESULTS: (1) The serum values of sTREM-1, BNP and cTnI in myocardial depression group were higher than those in nonmyocardial depression group (P < 0.01); and CFI, cardiac index, stroke volume, global ejection fraction and left ventricular contractility index (dpmax) in myocardial depression group were lower than those in nonmyocardial depression group on day 1 (P < 0.05); (2) serum sTREM-1 negatively correlated with left ventricular ejection fraction, CFI, cardiac index, global ejection fraction and dpmax, and it positively correlated with BNP and cTnI (P < 0.01); (3) the area under the receiver operating characteristics curve for sTREM-1 in the prediction of myocardial depression was 0.671 with a sensitivity of 83.8% and a specificity of 46.8% when cutoff point was 174.5ng/mL, the power of predicting septic depression for sTREM-1 was lower than that of BNP; logistic regression analysis showed that serum sTREM-1 was not an independent predictor of septic myocardial depression; the area under the receiver operating characteristics curve was 0.773 for sTREM-1 in predicting outcome with a sensitivity of 86.4% and a specificity of 80% when cutoff point was 182.3ng/mL, the power of predicting prognosis for sTREM-1 was superior to those of BNP and cTnI; (4) there was a decrease trend for sTREM-1 levels and an increasing trend for CFI in the survival group (P < 0.05). CONCLUSIONS: Myocardial dysfunction is common in patients with severe sepsis and septic shock and high serum levels of sTREM-1 correlates with myocardial dysfunction to some extent but is not an independent predictor, which more importantly showed prognostic value for septic shock outcome. PMID- 27238917 TI - Morfeo Study II: Clinical Course and Complications in Patients With Long-Term Disorders of Consciousness. AB - BACKGROUND: The life expectancy of patients with disorders of consciousness (DOCs) is ever-increasing, but little is known about their clinical course over late stages. Several issues (premorbid conditions, complications and pressure sores) are to be considered for their effect on clinical outcome, risk of death and recovery of functional performance. Unfortunately, in late stages of long term rehabilitation, these aspects are still more neglected than in acute and postacute stages. The aim of this study was to investigate the clinical course and the complications of patients in the late stages of DOCs and to explore the relationship between mortality and specific biomarkers. MATERIALS AND METHODS: A total of 112 patients, admitted over 10 years in a dedicated ward, were retrospectively studied. Sociodemographic data, preadmission and inpatient clinical features were collected. Disability Rating Scale scores, complications including pressure sores and blood markers were assessed monthly. Data were analyzed through descriptive statistics and correlations using SPSS. RESULTS: Most patients were men older than 50 years with a nontraumatic etiology and a history of hypertension (42.86%). The most common complication was pneumonia (76.79%). No association was found between sex and mortality or between etiology and mortality (P > 0.05). Mortality correlated significantly with sepsis (rho = 0.253), albumin (rho = -0.558), hemoglobin (rho = -0.354) and white blood cells (rho = 0.243). Only 42% of patients remained unchanged at Disability Rating Scale evaluation. CONCLUSIONS: These data confirmed that DOCs are not static conditions and they require ongoing monitoring and assessment of clinical status, level of consciousness and laboratory biomarkers. PMID- 27238918 TI - Getting the SCOOP-Survey of Cardiovascular Outcomes From Oncology Patients During Survivorship. AB - BACKGROUND: Cardiovascular (CV) disease is the second most common cause of mortality and morbidity in cancer survivors (CS). Limited data exist on the knowledge and awareness of CS about CV effects of cancer therapies and its effect on lifestyle of survivors. It is important to identify gaps in CV care of CS. MATERIALS AND METHODS: A brief voluntary, anonymous, web-based questionnaire was designed to assess the awareness of CS about the interaction between CV disease, CV symptoms and lifestyle changes from cancer treatment. RESULTS: A total of 213 volunteers (181 women) with mean age of 56 years responded to the survey. Breast cancer was the most prevalent cancer diagnosis. In all, 15% reported CV disease before therapy with a higher incidence of CV disease in survivors more than 5 years from diagnosis (20% >5 years versus 10% <5 years of survivorship, P = 0.05). The reported use of beta blockers (9%) and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (9%) was rare despite the high incidence of CV disease. Only one-fourth of survivors were offered CV screening during treatment, whereas 36% of survivors had unanswered questions about CV symptoms from therapy. The CV symptoms adversely affected lifestyle in 27% of CS. One-fifth of survivors received exercise counseling even though half would have liked counseling. CONCLUSIONS: The survey demonstrates that CS have self-reported CV symptoms and there may be unmet needs for CV preventive services. Further work is needed to develop collaborative patient counseling and management strategies between oncology and cardiology for improving CV health and symptoms of CS. PMID- 27238919 TI - Effect of Electronic Health Record Implementation in Critical Care on Survival and Medication Errors. AB - BACKGROUND: Electronic health records (EHR) with computerized physician order entry have become exceedingly common and government incentives have urged implementation. The purpose of this study was to ascertain the effect of EHR implementation on medical intensive care unit (MICU) mortality, length of stay (LOS), hospital LOS and medication errors. MATERIALS AND METHODS: Prospective, observational study from July 2010-June 2011 in MICU at an urban teaching hospital in Atlanta, Georgia of 797 patients admitted to the MICU; 281 patients before the EHR implementation and 516 patients post-EHR implementation. RESULTS: Compared with the preimplementation period (N = 43 per 281), the mortality risk at 4 months post-EHR implementation (N = 41 per 247) and at 8 months post-EHR implementation (N = 26 per 269) significantly decreased (P < 0.001). In addition, the mean MICU LOS statistically decreased from 4.03 +/- 1.06 days pre-EHR to 3.26 +/- 1.06 days 4 months post-EHR and to 3.12 +/- 1.05 days 8 months post-EHR (P = 0.002). However, the mean hospital LOS was not statistically decreased. Although medication errors increased after implementation (P = 0.002), this was attributable to less severe errors and there was actually a decrease in the number of severe medication errors (both P < 0.001). CONCLUSIONS: We report a survival benefit following the implementation of EHR with computerized physician order entry in a critical care setting and a concomitant decrease in the number of severe medication errors. Although overall hospital LOS was not shortened, this study proposes that EHR implementation in a busy urban hospital was associated with improved ICU outcomes. PMID- 27238920 TI - Seniority of Emergency Physician, Patient Disposition and Outcome Following Disposition. AB - OBJECTIVES: The relationship between the seniority of emergency physicians (EPs) and disposition decision-making is not well defined. As most responsibility by EPs involves developing an appropriate disposition plan, this study aimed to examine the influence of EP seniority on decisions regarding patient dispositions in the emergency department (ED). MATERIALS AND METHODS: This retrospective, 1 year, cohort study was conducted in 3 EDs including all day-shift nontraumatic adult patients. The outcome involves patient dispositions at the end of the shift, patient final dispositions and patient 72-hour ED return. The EPs were categorized into the following 3 groups according to seniority: junior group (<=5 years of work experience), intermediate group (6-10 years) and senior group (>10 years). RESULTS: The dispositions of 68,333 ED patients as determined by the 59 full-time EPs were studied. Compared to junior and intermediate EPs, senior EPs kept more patients in the ED (2.7% more than junior EP, 2.3% more than intermediate EP); they had the lowest patient mortality rate especially in first triage patients (3.4% fewer than junior EP, 1.3% fewer than intermediate EP); they took more time for patient discharge (0.2 more hours than junior EP, 0.1 more hours than intermediate EP); they had fewer patients return to the ED within 72 hours after discharge (0.5% fewer than junior EP, 0.3% fewer than intermediate EP). CONCLUSIONS: Senior EPs had the best quality of care (lowest mortality, fewest 72-hour returns). This best quality of care is accompanied with a slightly longer length of stay. PMID- 27238922 TI - Administer but Do Not Dispense: Effect of Change in Medication Handling by Nurses on Outcomes of Home Dialysis Patients. AB - BACKGROUND: To come into compliance with South Carolina statute, we changed how nurses handle medications (antibiotics, erythropoietin [EPO], calcitriol and heparin) in our outpatient home dialysis clinic. Nurses continued to administer medications in the clinic but no longer dispensed medications for patients to take home; instead, medications were dispensed from pharmacies to the patients by mail. We hypothesized that the abovementioned change in medication handling worsened clinical outcomes. There is very little medical literature on this topic. MATERIALS AND METHODS: A retrospective case series of quality and safety in 31 patients in a community-based, medical center-affiliated home dialysis program was performed. We compared laboratory values and adverse clinical events relevant to the medications mentioned above during 4-8 months before and during 5 months after September 1, 2014 (the day when medication handling was changed). RESULTS: We observed no changes in the incidences of dialysis access dysfunction, access infections, antibiotic inaccessibility to patients for access-related infections, infection outcomes, parathyroid hormone concentrations, hemoglobin concentrations, monthly EPO dose and missed monthly clinic visits after September 1, 2014. However, we noted significantly fewer subcutaneous EPO administrations per month and less time between phlebotomy and laboratory review with patients by their nephrologists at monthly clinic visits after September 1, 2014. CONCLUSIONS: The change in handling of medications by nurses in our outpatient home dialysis program to comply with the state statute did not worsen patient outcomes relevant to the affected medications and in fact caused several unexpected improvements. PMID- 27238923 TI - Risk Factors and Outcomes in Patients With Hypernatremia and Sepsis. AB - BACKGROUND: Hypernatremia is an uncommon but important electrolyte abnormality in intensive care unit patients. Sepsis is one of the most common causes of intensive care unit admission, but few studies about the role of hypernatremia in sepsis has been published yet. In this study, we aimed to explore the risk factors for developing hypernatremia in patients with sepsis, and the prognosis of patients with sepsis with or without hypernatremia was also assessed. MATERIALS AND METHODS: In this retrospective cohort study of 51 septic intensive care unit patients at a single center, we examined the risk factors for the development of hypernatremia and the association of hypernatremia with clinical outcomes using univariate and multivariable analyses. Clinical outcomes such as mortality and hospital duration of patients with or without hypernatremia were also compared. RESULTS: Acute Physiology and Chronic Health Evaluation II score (odds ratio = 1.15; 95% CI: 1.022-1.294) was found to be the only independent risk factor for hypernatremia in patients with sepsis. Moreover, patients developing hypernatremia during hospitalization showed significantly higher morbidity and mortality. CONCLUSIONS: Acute Physiology and Chronic Health Evaluation II score may be an independent risk factor for hypernatremia in patients with sepsis. Moreover, hypernatremia is strongly associated with worse outcome in sepsis. PMID- 27238924 TI - Riding the Roller Coaster of Fluid Resuscitation and Fluid De-Escalation: A Lot to Learn Still. PMID- 27238921 TI - Changes in Inflammatory and Bone Turnover Markers After Periodontal Disease Treatment in Patients With Diabetes. AB - BACKGROUND: The underlying mechanisms for increased osteopenia and fracture rates in patients with diabetes are not well understood, but may relate to chronic systemic inflammation. We assessed the effect of treating periodontal disease (POD), a cause of chronic inflammation, on inflammatory and bone turnover markers in patients with diabetes. MATERIALS AND METHODS: Using an investigator administered questionnaire, we screened a cross-section of patients presenting for routine outpatient diabetes care. We recruited 22 subjects with POD. Inflammatory and bone turnover markers were measured at baseline and 3 months following POD treatment (scaling, root planing and subantimicrobial dose doxycycline). RESULTS: There were nonsignificant reductions in high-sensitivity C reactive protein (6.34-5.52mg/L, P = 0.626) and tumor necrosis factor-alpha (10.37-10.01pg/mL, P = 0.617). There were nonsignificant increases in urinary C terminal telopeptide (85.50-90.23pg/mL, P = 0.684) and bone-specific alkaline phosphatase (7.45-8.79pg/mL, P = 0.074). Patients with >90% adherence with doxycycline were 6.4 times more likely to experience reduction in tumor necrosis factor-alpha (P = 0.021) and 2.8 times more likely to experience reductions in high-sensitivity C-reactive protein (P = 0.133). CONCLUSIONS: Treatment of POD in patients with diabetes resulted in nonsignificant lowering of inflammatory markers and nonsignificant increase in bone turnover markers. However, adherence to doxycycline therapy resulted in better treatment effects. PMID- 27238925 TI - Antioxidant, Antiapoptotic and Inflammatory Effects of Interleukin-18 Binding Protein on Kidney Damage Induced by Hepatic Ischemia Reperfusion. AB - OBJECTIVE: Acute kidney injury (AKI) is a serious condition that can be induced by liver transplantation, major hepatic resection or prolonged portal vein occlusion. The AKI can increase the frequency of postoperative complications. In the current study, we aimed to investigate whether interleukin-18 binding protein (IL-18BP) pretreatment has a protective effect against possible kidney injury mediated liver ischemia-reperfusion (IR) achieved by Pringle maneuver in an experimental rat model. MATERIALS AND METHODS: A total of 21 Wistar albino rats were included in this study. Animals were equally and randomly separated into 3 groups as follows: Sham (n = 7), IR group (n = 7) and IR + IL-18BP group (n = 7). Serum aspartate transaminase, alanine aminotransaminase and lactate dehydrogenase enzyme activities and serum urea and creatinine levels were determined. Tumor necrosis factor-alpha, IL-6, IL-1beta, interferon gamma, total oxidant status, total antioxidant status and oxidative stress index were measured in kidney tissue homogenate samples. Histopathological examination and immunohistochemical Caspase-3 staining were applied to examine the general morphologic structure and apoptosis. RESULTS: Renal total oxidant status; oxidative stress index; IL-18 levels; serum aspartate transaminase, alanine aminotransaminase and lactate dehydrogenase activities and creatinine levels were significantly lower in IR + IL-18BP group, when compared with the IR group. Beside this, total antioxidant status levels were remarkably higher in IR + IL-18BP group, when compared with the IR group. The caspase-3 expression degree in IR group was remarkably higher than other groups. CONCLUSIONS: It has been demonstrated that IL-18BP pretreatment may have inflammatory, antioxidant and antiapoptotic effects against AKI induced by hepatic IR. PMID- 27238927 TI - Only Jesus Can Call My Son. PMID- 27238926 TI - The Effect of Sympathetic Denervation on Cerebral Arteriogenesis After Chronic Cerebral Hypoperfusion. AB - OBJECTIVE: To explore the effect of perivascular sympathetic nerve on cerebral collateral arteriogenesis in chronic cerebral hypoperfusion models of rats. MATERIALS AND METHODS: Chronic cerebral hypoperfusion model was established by right common carotid artery ligation for 8 weeks, while sympathetic denervation was performed by superior cervical ganglionectomy. The male Sprague-Dawley rats were randomly divided into 4 groups including sham group (n = 21), denervation group (n = 21), artery ligation group (n = 21) and combined group with both artery ligation and denervation (n = 21). After 8 weeks of surgery, the rats in each group were randomly divided into 3 subgroups including subgroup A (n = 7), subgroup B (n = 7) and subgroup C (n = 7). The 3 subgroups were subjected to latex perfusion, permanent right middle cerebral artery occlusion and immunohistochemical staining, respectively. RESULTS: The diameters of right leptomeningeal anastomoses in artery ligation group significantly enlarged compared with sham group. When sympathetic denervation was performed in the presence of artery ligation, diameter of collateral vessel decreased, although larger than in sham group. After 8 weeks of permanent right middle cerebral artery occlusion, the cerebral perfusion over the right middle cerebral artery area in combined group was significantly lower than in artery ligation group, although both were higher than in denervation group and sham group. Triphenyltetrazolium chloride staining showed that cerebral infarct volume in combined group was significantly larger than in artery ligation group, and smaller than in denervation group and sham group. Neurologic functional scoring showed that scores in combined group were significantly higher than in artery ligation group, and lower than in denervation group and sham group. Immunohistochemical staining for alpha-smooth muscle actin showed that compared with sham group, tunica media thickness of right leptomeningeal anastomoses in artery ligation group increased significantly. Thickness in combined group was thinner than in artery ligation group, although thicker than in sham group. CONCLUSIONS: Perivascular sympathetic denervation can impair the cerebral collateral arteriogenesis under condition of chronic cerebral hypoperfusion. PMID- 27238928 TI - Raindrop Pigmentation in Chronic Arsenic Toxicity. PMID- 27238929 TI - An Expanded View of Progressive Cardiorenal Disorders. AB - Chronic renal diseases and congestive heart failure are progressive disorders, which cannot be completely controlled by established therapies. It has been argued that intracrine biology involving the formation of self-sustaining intracrine regulatory loops accounts for the progression of these disorders and for the inability of standard therapies to stop disease spread. The renin angiotensin system is a prime candidate to be involved in any such process, and an amplifying role for mineralocorticoid activation is also consistent with this view. Here, the notion of intracrine participation in congestive heart failure and chronic renal disease is expanded to include consideration of the participation of other intracrines including transforming growth factor beta 1, parathyroid hormone-related protein and vascular endothelial growth factor among others. The possibility that intracrine expression patterns account for disease phenotypes is explored. The therapeutic implications of this view are discussed. PMID- 27238930 TI - Sodium-glucose Cotransporter 2 Inhibitor-induced Diabetic Ketoacidosis in a Type 2 Diabetic Patient. PMID- 27238931 TI - A Masked Case of Vancomycin-induced Immune Thrombocytopenia. PMID- 27238932 TI - Systemic Emboli Associated With Lung Cancer. PMID- 27238933 TI - Peak Pressures and PaO2/FiO2 Ratios Are Associated With Adverse Outcomes in Patients on Mechanical Ventilators. AB - BACKGROUND: Patients requiring mechanical ventilation can have complications related to their underlying diseases and hospital-related events. It is possible that easily obtained information early in the course of mechanical ventilation can provide information about important outcomes. METHODS: Medical records from 281 episodes of mechanical ventilation in the medical intensive care unit were reviewed to collect information on patient demographics, admitting diagnoses, laboratory tests, duration of mechanical ventilation, the development of ventilator-associated events and mortality. Ventilator pressures from day 2 were analyzed for this study. RESULTS: Most patients (72.7%) were >=50 years, 53.8% were men and 66.3% had a body mass index (BMI) >= 25kg/m(2).The mean Acute Physiology and Chronic Healthy Evaluation II score was 13.6 +/- 5.9. The median initial PaO2/FiO2 was 240 with interquartile range of 177-414. The median duration of ventilation was 4 days (interquartile range: 2-9 days). A PaO2/FiO2 ratio < 100 was associated with increased mortality compared with PaO2/FiO2 ratio > 500, and a BMI > 30kg/m(2) was associated with decreased mortality compared with normal BMIs. A PaO2/FiO2 ratio < 100 and BMIs <18.5kg/m(2) or >30kg/m(2) were all associated with having a ventilator-associated event. There was a positive correlation between peak pressure (day 2) and the duration of ventilation (r = 0.263, P = 0.007). CONCLUSIONS: Easily available information collected on day 2 of mechanical ventilation can help identify patients at risk for poor outcomes, including the duration of mechanical ventilation, the development of ventilator-associated complications and mortality. Prospective studies measuring peak pressures are needed to evaluate the utility of this simple measurement in the management of patients requiring mechanical ventilation. PMID- 27238934 TI - Blunt Neck Trauma Causing Thyroid Hemorrhage. PMID- 27238935 TI - Association of ABCB1 (C3435T) and ABCC1 (G2012T) Polymorphisms with Clinical Response to Atorvastatin in Iranian Patients with Primary Hyperlipidemia. AB - BACKGROUND: Atorvastatin is prescribed for the primary and the secondary prevention of coronary artery diseases. A wide variation in inter-individual statin response suggests that genetic differences may contribute to this variation. This study investigated the association of ABCB1 (C3435T) and ABCC1 (G2012T) polymorphisms with clinical response to atorvastatin in Iranian primary hyperlipidemic patients. METHODS: Individuals (n=179) with primary hypercholesterolemia were enrolled, and peripheral blood samples were collected. Genotyping of two polymorphisms were performed by amplification refractory mutation system PCR. RESULTS: Following four weeks of treatment, a significant reduction of LDL-C was observed in variant groups (CT+TT) of ABCB1 (P=0.018) and wild-type group (GG) of ABCC1 genes (P=0.029). Logistic regression analysis revealed a significant difference between male and female responses to 10 mg/day atorvastatin (P=0.004, odds ratio=0.2, CI 95%=0.06-0.6). CONCLUSION: Our finding indicated that these polymorphisms may be attributed to LDL-C serum levels in the primary hypercholesterolemia patients receiving atorvastatin. PMID- 27238936 TI - A Newly Isolated Bacteriophage, PBES 02, Infecting Cronobacter sakazakii. AB - A novel bacteriophage, PBES 02, infecting Cronobacter sakazakii was isolated and characterized. It has a spherical head of 90 nm in diameter and a tail of 130 nm in length, and belongs to Myoviridae as observed under a transmission electron microscope. The major virion protein appears to be 38 kilodaltons (kDa) in size. The latent period of PBES 02 is 30 min and the burst size is 250. Infectivity of the phage remained intact after exposure to temperatures ranging from 4 degrees C to 55 degrees C for 1 h. It was also stable after exposure to pHs ranging from 6 to 10 for 1 h. The phage effectively removed contaminating Cronobacter sakazakii from broth infant formula. PBES 02 has a double-stranded DNA genome of 149,732 bases. Its GC ratio is 50.7%. Sequence analysis revealed that PBES 02 has 299 open reading frames (ORFs) and 14 tRNA genes. Thirty-nine ORFs were annotated, including 24 related to replication and regulation functions, 10 related to structural proteins, and 5 related to DNA packaging. The genome of PBES 02 is closely related to that of two other C. sakazakii phages, CR3 and CR8. Comparison of DNA sequences of genes encoding the major capsid protein revealed a wide geographical distribution of related phages over Asia, Europe, and America. PMID- 27238937 TI - Pathways Regulating the pbgP Operon and Colistin Resistance in Klebsiella pneumoniae Strains. AB - In this study, we investigated colistin resistance mechanisms associated with the regulation of the pbgP operon in Klebsiella pneumoniae, using four isogenic pairs of colistin-susceptible strains and their colistin-resistant derivatives and two colistin-resistant clinical isolates. Amino acid sequence alterations of PhoPQ, PmrAB, and MgrB were investigated, and mRNA expression levels of phoQ, pmrB, pmrD, and pbgP were measured using quantitative real-time PCR. The phoQ and pmrB genes were deleted from two colistin-resistant derivatives, 134R and 063R. We found that phoQ, pmrD, and pbgP were significantly upregulated in all colistin resistant derivatives. However, pmrB was significantly upregulated in only two colistin-resistant derivatives and one clinical strain. pmrB was not overexpressed in the other strains. The minimum inhibitory concentration of colistin was drastically lower in both phoQ- and pmrB-deleted mutants from a colistin-resistant derivative (134R) that was overexpressing phoQ and pmrB. However, colistin susceptibility was restored only in a phoQ-deleted mutant from a colistin-resistant derivative (063R) without overexpression of pmrB. In conclusion, two different regulations of the pbgP operon may associate with the development of colistin-resisant K. pneumoniae. PMID- 27238938 TI - A Synthetic Tul4 and FopA Peptide Cocktail of Francisella tularensis Induces Humoral and Cell-Mediated Immune Responses in Mice. AB - Francisella tularensis is a highly virulent pathogen of humans and other mammals. Moreover, F. tularensis has been designated a category A biothreat agent, and there is growing interest in the development of a protective vaccine. In the present study, we determine the in vitro and in vivo immune responses of a subunit vaccine composed of recombinant peptides Tul4 and FopA from epitopes of the F. tularensis outer membrane proteins. The recombinant peptides with adjuvant CpG induced robust immunophenotypic change of dendritic cell (DC) maturation and secretion of inflammatory cytokines (IL-6, IL-12). In addition, the matured DCs enabled ex vivo proliferation of naive splenocytes in a mixed lymphocyte reaction. Lastly, we determined the in vivo immune response by assessment of antibody production in C57BL/ 6 mice. Total IgG levels were produced after immunization and peaked in 6 weeks, and moreover, Tul4-specific IgG was confirmed in the mice receiving peptides with or without CpG. Based on these results, we concluded that the recombinant peptides Tul4 and FopA have immunogenicity and could be a safe subunit vaccine candidate approach against F. tularensis. PMID- 27238939 TI - Optimization of Hyaluronidase Inhibition Activity from Prunus davidiana (Carriere) Franch Fruit Extract Fermented by its Isolated Bacillus subtilis Strain SPF4211. AB - Strain SPF4211, having hyaluronidase (HAase) inhibition activity, was isolated from P. davidiana (Carriere) Franch fruit (PrDF) sugar extract. The phenotypic and biochemical properties based on 16S rDNA sequencing and an API 50 CHB kit suggested that the organism was B. subtilis. To optimize the HAase inhibition activity of PrDF extract by fermentation of strain SPF4211, a central composite design (CCD) was introduced based on three variables: concentration of PrDF extract (X1: 1-5%), amount of starter culture (X2: 1-5%), and fermentation time (X3: 0-7 days). The experimental data were fitted with quadratic regression equations, and the accuracy of the equations was analyzed by ANOVA. The statistical model predicted the highest HAase inhibition activity of 37.936% under the optimal conditions of X1 = 1%, X2 = 2.53%, and X3 = 7 days. The optimized conditions were validated by observation of an actual HAase inhibition activity of 38.367% from extract of PrDF fermented by SPF4211. These results agree well with the predicted model value. PMID- 27238940 TI - Relevance of charge balance and hyaluronic acid on alginate-chitosan sponge microstructure and its influence on fibroblast growth. AB - The study of biomaterials by electrical charge scaling to explore the role of net charge on biocompatibility and suitability for tissue regeneration has been limited as has the search for products that could improve this first-rate variable. In the present study, we prepared sponges composed of chitosan/alginate (CS/ALG) with or without hyaluronic acid (HA) by mixing polymer stock solutions of different net electric charge ratios (n(+/) n(-) ), and then lyophilizing them to obtain porous materials. The electric charge ratios n(+/) n(-) studied were 0.3, 0.8, 1.0, and 2.5 for CS/ALG and 0.3, 1.0, 1.9, and 3.7 for CS/ALG/HA sponges. Under these conditions a role for net electric charge balance over sponge microstructure rearrangement, protection to dissolution, cellular proliferation, and cell-cell interactions was apparent, effects that were enhanced by copolymer modification with HA. Mass balance, electric charge, and specific products that influence both such as HA, have a potential in biomaterials for wound healing. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2537-2543, 2016. PMID- 27238941 TI - A pilot study to assess the effectiveness and cost of routine universal use of peracetic acid sporicidal wipes in a real clinical environment. AB - BACKGROUND: Peracetic acid sporicidal wipes have been shown to be an effective disinfectant, but in controlled test environments. Their high cost may restrict use. AIMS: This pilot study investigated the efficacy and compared the costs of routine universal use of peracetic acid sporicidal wipes versus sporicidal quaternary ammonium compound and alcohol wipes in the disinfection of a hospital environment. METHODS: The routine universal use of peracetic acid wipes (Clinell Sporicidal; GAMA Healthcare Ltd, London, UK) was allocated to a study ward, whereas the control ward continued with the use of quaternary ammonium compound wipes (Tuffie 5; Vernacare, Bolton, UK) and alcohol wipes (PDI Sani-Cloth 70; PDI, Flint, UK). Twenty high-touch areas in the 2 wards were sampled for the presence of indicator organisms. The weekly detection rates of indicator organisms and weekly healthcare associated infection (HCAI) rates in the 2 wards were compared and examined for decreasing trends over the trial period. RESULTS: The detection rates of indicator organisms and HCAI rates were not significantly different in the 2 wards, and did not decrease significantly over the trial period. However, the peracetic acid wipes seem to be more effective against gram negative organisms but at a significantly higher cost. CONCLUSIONS: Further prospective studies are needed to assess the cost-effectiveness of peracetic acid wipes. PMID- 27238942 TI - A targeted educational intervention to reduce ventilator-associated complications. AB - The optimal approach for the prevention of ventilator-associated complications (VACs) is currently unknown. A retrospective pre-post intervention analysis was conducted to assess a multifaceted educational intervention targeting the most common causes for VACs and VAC risk factors. Results indicated that the addition of this intervention to existing infection control and treatment protocols did not demonstrate a decrease in VAC occurrence or duration of mechanical ventilation. PMID- 27238944 TI - Indian hepatitis C drug patent decision shakes public health community. PMID- 27238943 TI - Vaccination for child clients and employees in St Louis childcare agencies: Vaccine uptake and policies versus parents' perceptions. AB - BACKGROUND: Little is known about childcare agency staff vaccination requirements, parents' perceptions of these requirements, or vaccine uptake in these populations. METHODS: A questionnaire was administered to St Louis parents and childcare agency staff in fall of 2014. The chi(2) tests compared staff's versus parents' uptake of hepatitis A, pertussis, and seasonal influenza vaccines. Multivariate logistic regression was used to examine individuals being fully immunized (ie, having received influenza, hepatitis A, and pertussis vaccines). RESULTS: Overall, 351 parents and staff from 23 agencies participated (response rate, 32%). One-third of staff (34.4%, n = 33) and parents (37.6%, n = 96) were fully immunized. Parents and staff were equally likely to have received the influenza vaccine (48.8% and 47.3%, respectively), but more staff received the hepatitis A vaccine (85.3% vs 67.5%, chi(2)=11.0, P < .001), and more parents received the pertussis vaccine (66.5% vs 45.8%, chi(2)=12.5, P < .001). Determinants of being fully immunized included having previously received the influenza vaccine, being offered the vaccines, belief that vaccination is important, having immunization recommendation awareness, and not having vaccine misperceptions. CONCLUSIONS: Childcare agency staff vaccination can protect employees and children from disease, but their uptake of vaccines needs improvement. Future interventions should be aimed at increasing uptake to lower disease transmission in childcare settings. PMID- 27238945 TI - Does HubBLe spell trouble for HAL? PMID- 27238946 TI - The origin of the biomechanical bias in apparent body movement perception. AB - The perception of apparent body movement sometimes follows biologically plausible paths rather than paths along the shortest distance as in the case for inanimate objects. For numerous authors, this demonstrates that the somatosensory and motor representations of the observer's own body support and constrain the perception of others' body movements. In this paper, we report evidence that calls for a re examination of this account. We presented an apparent upper limb movement perception task to typically developed participants and five individuals born without upper limbs who were, therefore, totally deprived of somatosensory or motor representations of those limbs. Like the typically developed participants, they showed the typical bias toward long and biomechanically plausible path. This finding suggests that the computations underlying the biomechanical bias in apparent body movement perception is intrinsic to the visual system. PMID- 27238947 TI - The effect of rotating random dot motion on visuospatial line orientation in patients with right-sided stroke. AB - Spatial deficits are frequent after brain damage, particularly right hemisphere stroke. Visual judgments of line orientation (LINE) are often impaired after right parietal lesions. Perception of line orientation is an important visuoperceptual component of visuoconstructive capacities. Yet, little is known about modulating factors in LINE and effective treatments are rare for this disorder. Studies in patients with spatial neglect show that horizontal random dot motion (RDM) significantly modulates horizontal spatial disorders, both transiently and permanently after treatment. In the current study, we investigated whether rotational RDM modulates judgements in an oblique LINE task in 20 patients with right-hemispheric first ever stroke (10 of them with a disorder in LINE and 10 without such a disorder), and 10 healthy, age-matched subjects. Subjects were tested under three experimental conditions: (1) with a static background of small white dots, (2) with slow clockwise or (3) counterclockwise circular RDM of these background stimuli, while they performed the LINE task. In the baseline condition with static background, the impaired patient group showed a significant counterclockwise tilt. Clockwise rotating RDM normalized this deficit transiently but completely, while counterclockwise rotating RDM slightly aggravated it, though not significantly. Tilts in the LINE task were significantly correlated with left visuospatial neglect. Similar but much smaller effects were obtained in the spatially unimpaired patients and the normal controls. These results show that rotational RDM modulates deficits of line orientation in patients with right-sided stroke, possibly by influencing higher spatial representations devoted to the perception of oblique lines. PMID- 27238948 TI - ALK-positive large B-cell lymphoma with strong CD30 expression; a diagnostic pitfall and resistance to brentuximab and crizotinib. PMID- 27238949 TI - Epidemiological and financial indicators of hypertension in older adults in Mexico: challenges for health planning and management in Latin America. AB - This study estimated the epidemiological and financial indicators of hypertension in order to identify challenges in strategic planning and management for health systems in Latin America. This is a longitudinal study with a population base of 187 326 reported cases of older adults with hypertension, diagnosed at public health institutions in Mexico. The cost-evaluation method that was used was based on the instrumentation and consensus techniques. To estimate the epidemiological changes and financial consequences for 2015-2017, time series analyses and probabilistic models were constructed according to the Box-Jenkins technique. Regarding epidemiological changes for 2015 versus 2017, an increase of 8-12% is expected (p < 0.001). Comparing the economic impact in 2015 versus 2017 (p < 0.001), there is a 22% increase in financial requirements. The total amount estimated for hypertension in 2015 (in US dollars) was $1 575 671 330. It included $747 527 259 as direct costs and $829 144 071 as indirect costs. If the risk factors and the different healthcare services for older adults remain as they are currently, the financial consequences of epidemiological changes in older adults will have a major impact on the users' pockets, following in order of importance, on social security providers and on public assistance providers. The challenges and implications of our findings in the context of universal coverage reforms in Latin America reinforce the urgent need to develop more and better strategic planning for the prevention of chronic diseases. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27238950 TI - [Proposed model of vascular trauma by mean of mechanical characterization of endovascular prostheses (stents) based on structural analysis by FEA]. AB - OBJECTIVE: The accumulated evidence on angioplasty techniques with stents has raised a controversy about the factors that influence the final vascular response. Indeed, several studies have shown there might be re-stenosis between 30% to 40% about 6 months after placement, relating to the design of the device as one of the main causes. This paper proposes the functional characterization of endovascular stents, analyzing its mechanical influence in the vascular system and predicting implicit traumatic factors in the vessel. METHODS: A structural analysis was made for several computational models of endovascular stents using Finite Element Analysis in order to predict the mechanical behavior and the vascular trauma. In this way, the stents were considered as tubular devices composed of multiple links under radial pressure loads, reflecting stress concentration effects. RESULTS: The analysis allowed to visualize how the geometry of stents is adjusted under several load conditions, in order to obtain the response of "solid-solid" interaction between the stent and the arterial wall. Thus, an analysis was performed in order to calculate stress, and a conceptual model that explains its mechanical impact on the stent-vessel interaction, was raised, to infer on the functionality from the design of the devices. CONCLUSIONS: The proposed conceptual model allows to determine the relationship between the conditions of mechanical interaction of the stents, and warns about the effects in what would be the operation of the device on the vascular environment. PMID- 27238951 TI - [Ebstein anomaly and congenital long QT syndrome. Report of a case]. PMID- 27238953 TI - Fibrinogen concentrate improves clot strength in patients with haematological malignancies requiring platelet transfusion. AB - BACKGROUND: Patients with bone marrow failure secondary to chemotherapy often develop thrombocytopenia and require platelet transfusion. Fibrinogen plays an important role in platelet aggregation and the establishment of the primary haemostatic plug. OBJECTIVES: To compare the effects of in vivo platelet transfusion on clot firmness in thrombocytopenic patients with in vitro-performed fibrinogen concentrate substitution. MATERIALS AND METHODS: Thirty patients with haematological malignancy admitted for platelet transfusion were included. Haemostatic effects from platelet transfusion and ex vivo addition of fibrinogen concentrate at three different doses were evaluated by thromboelastometry, with clot firmness as the primary endpoint (A30 ExTEM assay). Secondary endpoints were other thromboelastometry parameters, thrombin generation parameters, activated partial thromboplastin time (APTT), prothrombin time PT, fibrinogen and factor XIII levels and a clinical bleeding score. RESULTS: Twenty patients (66%) had clinical bleeding signs by prior to transfusion. Platelets increased from 17 (range, 1-109) to 40 (range 2-139) * 10(9) L(-1) following transfusion, with a median corrected count increment of 16.7 (range, 0.8-43.5). The A30 value increased significantly by platelet transfusion from 35 +/- 11 to 47 +/- 10 mm, with no changes in thrombin generation. Fibrinogen concentrate dose-dependently increased A 30 (to 43 +/- 10, 49 +/- 9 and 50 +/- 9 mm, respectively) and reduced parameters of thrombin generation at high doses. Platelet transfusion, together with fibrinogen concentrate, further increased clot firmness. APTT and PT were within normal range, whereas fibrinogen levels were slightly elevated. CONCLUSION: Fibrinogen concentrate increased clot firmness to the same degree as platelet transfusion in patients with low platelet count requiring platelet transfusion. PMID- 27238952 TI - Epidemiologic characteristics of retinal detachment surgery at a specialized unit in Denmark. AB - PURPOSE: To examine the incidence of retinal detachments and to evaluate patient profiles and surgical characteristics. METHODS: Retrospective review of patients operated for primary retinal detachment (RD) and redetachment between 2010 and 2012 at the Department of Ophthalmology, Odense University Hospital, Denmark. We included all RD such as rhegmatogenous retinal detachment (RRD), tractional retinal detachment (TRD) and exudative retinal detachment (ERD). RESULTS: In total, 779 RD surgeries were performed: 83.7% (n = 652) primary operations and 16.3% (n = 127) reoperation. For primary operation, pars plana vitrectomy (PPV), scleral buckling and combined operations were performed in 95.1% (n = 620), 4.6% (n = 30) and 0.3% (n = 2) respectively. Over time there was less use of silicone oil and greater use of gas tamponade (p = <0.001), less simultaneous cataract operations (p = <0.001), less use of cryotherapy (p = 0.045) and more use of peeling procedures (p = <0.001) in primary operations. The annual incidence of surgery for primary RD was 22.0 [95% confidence interval (CI) 20.4-23.8] per 100 000 inhabitants aged >15 years. Retinal detachment (RD) was more common in males than females (1.8:1), and mean age at presentation was 61.8 years (standard deviations +/- 12.3). The annual incidence for RRD and TRD operation was 20.72 (95% CI 19.11-22.43) and 1.25 (95% CI 0.9-1.7) per 100 000 inhabitants >15 years. CONCLUSION: This study presents the first overall incidence for RD in Denmark. The highest incidence of RRD was among males aged 60 to 79 years, whereas TRD was among females at same age. Pars plana vitrectomy (PPV) was the preferred surgical technique, and during 2012 all RD patients were treated with PPV, independent of lens status and age. PMID- 27238954 TI - Where do People with Joint Hypermobility Syndrome Present in Secondary Care? The Prevalence in a General Hospital and the Challenges of Classification. PMID- 27238955 TI - Novel strategy for cystitis glandularis: Oral treatment with cyclooxygenase-2 inhibitor. AB - Cystitis glandularis, a proliferative disease of the bladder, is resistant to antibiotics, non-steroidal anti-inflammatory drugs, anti-allergy drugs and transurethral resection. Cystectomy or partial cystectomy is occasionally required for refractory cystitis glandularis. It has not been defined if cystitis glandularis is a premalignant lesion. We experienced a case of remission from cystitis glandularis after combination of oral treatment with selective cyclooxygenase-2 inhibitor, celecoxib and transurethral resection. Immunohistochemistry showed positive signals of cyclooxygenase-2 in the epithelium of pretreatment specimens, suggesting the pathophysiological role of cyclooxygenase-2 in cystitis glandularis. Here, we show the effectiveness of celecoxib against cystitis glandularis for the first time. Celecoxib could be one of the therapeutic strategies for cystitis glandularis. PMID- 27238956 TI - Determinants and morbidities of multiple anthropometric deficits in southwest rural Ethiopia. AB - OBJECTIVE: The aim of this study was to compare undernutrition with child morbidity and their determinants according to a composite index of anthropometrical failures and conventional indices. METHODS: We used data generated from three rounds of a longitudinal panel survey conducted in nine districts in Oromiya Region and the Southern Nations, Nationality and Peoples Region of Ethiopia. We estimated undernutrition using conventional indices and composite index of anthropometrical failures. Included in this analysis were 579, 674, and 674 children age <5 y in rounds 1, 2, and 3, respectively. The households were recruited using the expanded program on immunization sampling method. The hierarchical nature of the data Applied nutritional investigation was taken into account during the statistical analysis using a two-level mixed effects logistic regression model. RESULTS: A composite index of anthropological failure, estimated 45.1%, 42.4%, and 46.4% of the children were undernourished in round 1, 2, and 3, respectively. The conventional indices estimated 24.4%, 24.2%, and 30.4% underweight in round 1, 2, and 3, respectively. Being female (odds ratio [OR], 7.4; 95% confidence interval [CI], 3.9-14.0); low dietary diversity (OR, 3.1; 95% CI, 1.6-5.9); medium dietary diversity (OR, 1.9; 95% CI, 1.1-3.3), and no special foods during illness (OR, 1.8; 95% CI, 1.2-2.8) were determinant of multiple anthropometrical failures. Children with multiple anthropometric failures were 2.6 times more likely to report child morbidities (OR, 2.6; 95% CI, 1.1-5.9). However, none of the conventional indices were associated with any of the reported child morbidities, such as stunting (OR, 1.1; 95% CI, 0.8-1.4), wasting (OR, 0.9; 95% CI, 0.5-1.6), or underweight (OR, 1.4; 95% CI, 1.0-2.0). CONCLUSION: The conventional indices underestimated the prevalence of undernutrition by 20.7%. Children with multiple anthropometric failures are at high risk for developing child morbidities and should benefit from nutrition intervention to reduce child morbidities. PMID- 27238957 TI - Prenylated chalcones and flavonoids for the prevention and treatment of cancer. AB - Prenylated chalcones and flavonoids gained increasing attention not only in nutrition but also in cancer prevention because of their biological and molecular activities in humans, which have been extensively investigated in vitro or in preclinical studies. These naturally occurring compounds exhibit antioxidant effects, modulate metabolism of carcinogens by inhibition of distinct phase 1 metabolic enzymes and activation of phase 2 detoxifying enzymes, and display antiinflammatory properties. In particular, their potential to prevent proliferation of tumor cells is noteworthy. Some representatives of this subclass of secondary plant compounds exert pronounced anti-tumor-initiating capacities and directly inhibit growth of cancer cells, whereas their toxic effects on healthy tissues are remarkably low. These promising pharmacologic characteristics are countered by low ingestion, low bioavailability, and little knowledge of their metabolism. This review focuses on the great potential of these plant- and nutrient-derived compounds for cancer prevention and therapy. Provided here is a comprehensive summary of the current knowledge and inherent modes of action, focusing on the prenylated chalcones xanthohumol, desmethylxanthohumol, and xanthogalenol, as well as the prenylated flavonoids isoxanthohumol, 6 prenylnaringenin, 8-prenylnaringenin, 6-geranylnaringenin, 8-geranylnaringenin, and pomiferin. PMID- 27238958 TI - Associations between dietary energy density and obesity: A systematic review and meta-analysis of observational studies. AB - OBJECTIVE: Although many studies have shown an association between dietary energy density (DED) and obesity, there has been no systematic review and meta-analysis on this topic. Therefore, the objective of this study was to qualitatively and quantitatively review and summarize the literature on association between DED and obesity. METHODS: We searched titles, abstracts, and keywords of articles indexed in ScienceDirect, ProQuest, MEDLINE, and Google Scholar databases until January 2015 to identify eligible studies. We excluded studies that did not examine DED for whole diet and studies that included patients with cancer, pregnant women, the elderly (>60 y old), and children (<2 y old). There were no language or publication date restrictions. RESULTS: Of the 37 studies included in this review, most articles reported a direct association between DED and obesity. We performed a meta-analysis on 23 of these studies. In comparison with the lowest NTILE of DED, subjects in the highest NTILE of DED had significant weight gain (2.26 kg, 95% confidence interval [CI]: 1.00-3.53), greater adjusted mean body mass index (BMI) (0.50 kg/m(2), 95% CI: 0.02-0.98 for males and 0.85 kg/m(2), 95% CI: 0.51-1.19 for females), and risk of excess adiposity (odds ratio [OR]: 1.27, 95% CI: 1.04-1.55). We did not observe significant associations between DED and risk of elevated BMI (OR: 1.13, 95% CI: 1.00-1.27) and abdominal obesity (OR: 1.17, 95% CI: 0.19-7.38). We found no evidence of publication bias. CONCLUSION: The present review showed that DED was directly associated with risk of excess adiposity, higher weight change, and BMI. Lower DED should be considered a prevention strategy for obesity. PMID- 27238959 TI - Rosacea and dementia: relative vs. absolute effect sizes. PMID- 27238960 TI - Moving the goalposts - towards cardiovascular prevention. PMID- 27238961 TI - The vulnerable elderly and bladder dysfunction: is this 'urinary incompetence'? PMID- 27238962 TI - Innovative health informatics as an effective modern strategy in diabetes management: a critical review. AB - OBJECTIVE: Diabetes mellitus is the most common metabolic disorder in developing countries. Mobile health applications are helpful in improving the diabetes management. However, the effectiveness of these techniques needs to be assessed rigorously. Therefore, the authors have systematically reviewed the recent clinical studies using mobile health applications for diabetes management. MATERIALS AND METHODS: Original articles that were published in ISI indexed journals listed in PubMed from the year 2007 till 2014 were searched using specific search key phrases. The intervention technology and study methodology were analysed to have a better understanding of the outcomes of each study. RESULTS: Twenty-one articles were selected for the review. Most studies (76%) reported positive outcomes after use of the mobile health applications. Smartphone apps significantly improved the clinical outcomes. User-friendliness of the systems often influence the patient compliance and the clinical outcomes. CONCLUSION: Smartphone/web applications offer significant benefits for patient care, education and behavioural modifications. Providing a continuous patient support using mobile may be a challenging task and would require adequate infrastructure and personnel. PMID- 27238963 TI - Efficacy and safety of fulranumab as monotherapy in patients with moderate to severe, chronic knee pain of primary osteoarthritis: a randomised, placebo- and active-controlled trial. AB - AIMS: The efficacy and safety of monotherapy with fulranumab, a monoclonal antibody that neutralises human nerve growth factor (NGF), was evaluated compared with placebo and an active comparator, controlled-release (CR) oxycodone, in patients with moderate to severe chronic knee pain of primary osteoarthritis (OA). METHODS: In this phase-2, double-blind (DB), double-dummy, placebo- and active-controlled study, patients (40-80 years) were randomised (1:1:1:1) to placebo, fulranumab 3 or 9mg every 4 weeks (Q4 wk), or oxycodone CR twice-daily. Primary efficacy end-point: responder rates based on percent improvement in average osteoarthritis-related pain intensity (OAPI) scores from baseline to week 12 or when Food and Drug Administration (FDA) put a clinical hold on all anti-NGF trials, whichever was earlier. Secondary efficacy end-points: average OAPI score (week-16), Western Ontario and McMaster Osteoarthritis Index Global Score and subscales (pain, physical function, stiffness), and Patient Global Assessment. RESULTS: As of an FDA clinical hold on all anti-NGF trials, only 196/300 patients were randomised and 33% (65/196) had completed 12 weeks of the 16-week DB phase. Responders were patients who did not withdraw and whose pain improved. Responder rates were not significantly different between fulranumab treatment groups (3mgQ4wk: 71%, p = 0.739; 9mgQ4wk: 80%, p = 0.843) and placebo (77%), whereas, oxycodone CR (56%) had significantly lower responder rates in comparison to both fulranumab (3mgQ4wk: p = 0.008; 9mgQ4wk: p = 0.012) and placebo (p = 0.0021). Secondary efficacy results were consistent with primary. None of the joint replacements (four in three patients) were adjudicated as rapidly progressing OA/osteonecrosis. CONCLUSION: Low sample size because of early termination make interpretation of this study difficult, but fulranumab monotherapy resulted in significantly better pain relief and function compared with oxycodone CR (but not against placebo) and was generally well-tolerated. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01094262. PMID- 27238964 TI - Effectiveness of treatment with biologic- and disease-modifying antirheumatic drugs in rheumatoid arthritis patients in Colombia. AB - AIMS: Rheumatoid arthritis (RA) is an autoimmune disease cause of disability and high costs. To determine the effectiveness of therapy with biologic- and disease modifying antirheumatic drugs (DMARDs) in patients with RA and factors associated with the control of the disease. METHODS: Retrospective cohort study of RA patients receiving treatment with DMARDs in a rheumatologic healthcare institution in five Colombian cities from December 2009 to August 2013. The effectiveness was assessed by Disease Activity Score-28 (DAS-28) and a lower value of 2.6 was considered remission. RESULTS: A total of 827 patients were studied for an average observation period of 17.3 +/- 11.0 months, with mean age 54.3 +/- 13.1 years. The most frequently used DMARDs were methotrexate, leflunomide and chloroquine. The most frequently used biological DMARDs were etanercept and abatacept. Initially, 17.8% of the patients received some biological DMARDs in comparison with 28.7% at the end of the observation period. A median DAS28 of 3.5 was found, which was reduced by the end of the observation period to 2.8 (p < 0.001), and cases of patients who were in remission increased from 30.1% to 42.9%. Treatment with leflunomide (OR: 0.47; CI 95%: 0.35-0.64, p < 0.001) or rituximab (OR: 0.37; CI 95%: 0.17-0.83, p = 0.016) was associated with a lesser probability of reaching remission. To be treated in the city of Manizales (OR: 2.56; CI 95%: 1.36-4.82, p = 0.004) was associated with a high probability of remission. CONCLUSIONS: Biological and DMARDs therapy for RA was effective in a relevant proportion of Colombian patients as a consequence of management with strategies set on remission aims quantified using DAS28. Cost effectiveness of the therapy must be evaluated. PMID- 27238965 TI - Identifying and addressing drug-related problems in nursing homes: an unmet need in Malaysia? PMID- 27238966 TI - Phospho-Pon Binding-Mediated Fine-Tuning of Plk1 Activity. AB - In Drosophila neuroblasts (NBs), the asymmetrical localization and segregation of the cell-fate determinant Numb are regulated by its adaptor Partner of Numb (Pon) and the cell-cycle kinase Polo. Polo phosphorylates the Pon localization domain, thus leading to its basal distribution together with Numb, albeit through an unclear mechanism. Here, we find that Cdk1 phosphorylates Pon at Thr63, thus creating a docking site for the Polo-box domain (PBD) of Polo-like kinase 1 (Plk1). The crystal structure of the Plk1 PBD/phospho-Pon complex reveals that two phospho-Pon bound PBDs associate to form a dimer of dimers. We provide evidence that phospho-Pon binding-induced PBD dimerization relieves the autoinhibition of Plk1. Moreover, we demonstrate that the priming Cdk1 phosphorylation of Pon is important for sequential Plk1 phosphorylation. Our results not only provide structural insight into how phosphoprotein binding activates Plk1 but also suggest that binding to different phosphoproteins might mediate the fine-tuning of Plk1 activity. PMID- 27238968 TI - Molecular Mechanism for Fungal Cell Wall Recognition by Rice Chitin Receptor OsCEBiP. AB - Chitin is the major component of fungal cell wall and serves as a molecular pattern that can be recognized by the receptor OsCEBiP in rice, a lysine motif (LysM) receptor-like protein (RLP), to trigger immune responses. The molecular mechanisms underlying chitin recognition remain elusive. Here we report the crystal structures of the ectodomain of OsCEBiP (OsCEBiP-ECD) in free and chitin bound forms. The structures reveal that OsCEBiP-ECD contains three tandem LysMs followed by a novel structure fold of cysteine-rich domain. The structures showed that chitin binding induces no striking conformational changes in OsCEBiP. Structural comparison among N-acetylglucosamine (NAG) oligomer-bound LysMs revealed a highly conserved recognition mechanism, which is expected to facilitate study of other LysM-containing proteins for their NAG binding. Modeling study showed that chitin induces OsCEBiP homodimerization in a "sliding mode". Our data provide insights into rice chitin receptor-mediated immunity triggered by fungal cell wall. PMID- 27238967 TI - Dissecting Dynamic Allosteric Pathways Using Chemically Related Small-Molecule Activators. AB - The allosteric mechanism of the heterodimeric enzyme imidazole glycerol phosphate synthase was studied in detail with solution nuclear magnetic resonance spectroscopy and molecular dynamics simulations. We studied IGPS in complex with a series of allosteric activators corresponding to a large range of catalytic rate enhancements (26- to 4,900-fold), in which ligand binding is entropically driven. Conformational flexibility on the millisecond timescale plays a crucial role in intersubunit communication. Carr-Purcell-Meiboom-Gill relaxation dispersion experiments probing Ile, Leu, and Val methyl groups reveal that the apo- and glutamine-mimicked complexes are static on the millisecond timescale. Domain-wide motions are stimulated in the presence of the allosteric activators. These studies, in conjunction with ligand titrations, demonstrate that the allosteric network is widely dispersed and varies with the identity of the effector. Furthermore, we find that stronger allosteric ligands create more conformational flexibility on the millisecond timescale throughout HisF. This domain-wide loosening leads to maximum catalytic activity. PMID- 27238969 TI - Structures of Human Peroxiredoxin 3 Suggest Self-Chaperoning Assembly that Maintains Catalytic State. AB - Peroxiredoxins are antioxidant proteins primarily responsible for detoxification of hydroperoxides in cells. On exposure to various cellular stresses, peroxiredoxins can acquire chaperone activity, manifested as quaternary reorganization into a high molecular weight (HMW) form. Acidification, for example, causes dodecameric rings of human peroxiredoxin 3 (HsPrx3) to stack into long helical filaments. In this work, a 4.1-A resolution structure of low-pH instigated helical filaments was elucidated, showing a locally unfolded active site and partially folded C terminus. A 2.8-A crystal structure of HsPrx3 was determined at pH 8.5 under reducing conditions, wherein dodecameric rings are arranged as a short stack, with symmetry similar to low-pH filaments. In contrast to previous observations, the crystal structure displays both a fully folded active site and ordered C terminus, suggesting that the HsPrx3 HMW form maintains catalytic activity. We propose a new role for the HMW form as a self-chaperoning assembly maintaining HsPrx3 function under stress. PMID- 27238971 TI - Inhibitory effects of Tyrphostin AG-related compounds on oxidative stress sensitive transient receptor potential channel activation. AB - Some transient receptor potential (TRP) proteins including TRPA1, TPRM2 and TRPV1 are oxidative stress-sensitive Ca(2+)-permeable channels. Ca(2+) signaling via these TRP channels activated by oxidative stress has been implicated in the aggravation of various inflammatory diseases and pain sensation. We recently reported that Tyrphostin AG490 exerted inhibitory effects on H2O2-induced TRPM2 activation by scavenging the hydroxyl radical. In order to identify stronger inhibitors of oxidative stress-sensitive TRP channels than AG490, we examined the inhibitory effects of Tyrphostin AG-related compounds on H2O2-induced TRP channel activation in human embryonic kidney 293 cells expressing TRP channels. AG555 and AG556 blocked the activation of TRPM2 by H2O2 more strongly than AG490. Regarding TRPV1 and TRPA1, none of the three compounds tested affected H2O2-induced TRPV1 activation; however, AG555 and AG556 reduced H2O2-induced TRPA1 activation more than AG490. Thus, we herein identified AG555 and AG556 as new compounds that exert stronger inhibitory effects on H2O2-induced TRPM2 and TRPA1 activation than AG490. Edaravone, a hydroxyl radical scavenger used in the treatment of cerebral hemorrhage and cerebral infarction, did not affect H2O2-induced TRPM2 or TRPA1 activation. AG555 and AG556 may be useful seed compounds as therapeutic agents for several TRP-related diseases associated with oxidative stress. PMID- 27238972 TI - Roles of aldosterone in vascular calcification: An update. AB - Both clinical and experimental studies have demonstrated that vascular calcification (VC) is a common pathology shared in many chronic diseases such as chronic kidney disease (CKD) and diabetes. It's an independent risk factor for cardiovascular events. Since the pathogenesis of VC is complicated, current therapies have limited effects on the regression of VC. Therefore, it is urgent to investigate the potential mechanisms and find new targets for the treatment of VC. Aldosterone (Aldo), a mineralocorticoid hormone, is the metabolite of renin angiotensin-aldosterone system (RAAS) activation, which can exert genomic and non genomic effects on the cardiovascular system. Recent data suggests that Aldo can promote VC. Here, we summarized the roles of Aldo in the process of VC and a series of findings indicated that Aldo could act as a potentially therapeutic target for treating VC. PMID- 27238970 TI - An Engineered Switch in T Cell Receptor Specificity Leads to an Unusual but Functional Binding Geometry. AB - Utilizing a diverse binding site, T cell receptors (TCRs) specifically recognize a composite ligand comprised of a foreign peptide and a major histocompatibility complex protein (MHC). To help understand the determinants of TCR specificity, we studied a parental and engineered receptor whose peptide specificity had been switched via molecular evolution. Altered specificity was associated with a significant change in TCR-binding geometry, but this did not impact the ability of the TCR to signal in an antigen-specific manner. The determinants of binding and specificity were distributed among contact and non-contact residues in germline and hypervariable loops, and included disruption of key TCR-MHC interactions that bias alphabeta TCRs toward particular binding modes. Sequence fitness landscapes identified additional mutations that further enhanced specificity. Our results demonstrate that TCR specificity arises from the distributed action of numerous sites throughout the interface, with significant implications for engineering therapeutic TCRs with novel and functional recognition properties. PMID- 27238973 TI - Stereoselectivity of butylidenephthalide on non-adrenergic prejunctional voltage dependent Ca(2+) channels in prostatic portion of rat vas deferens. AB - The naturally occurring and synthetic butylinenephthalide (Bdph) has two geometric isomers. Z- and E-Bdph were reported to have geometric stereoselectivity for voltage-dependent calcium channels (VDCCs) in guinea-pig ileum. The aim of this study was to investigate whether the binding of Z- and E Bdph on prejunctional VDCCs of rat vas deferens (RVD) is stereoselective. The twitch responses to electrical field stimulation (EFS, supramaximal voltage, 1 ms, 0.2Hz) were recorded on a polygraph. Z- and E-Bdph concentration-dependently inhibited the twitch responses to EFS in full tissue, prostatic portion and epididymal portion of RVD. The pIC50 value of Z-Bdph was greater than that of E Bdph in the electrically stimulated prostatic portion of RVD, suggesting that the binding of Bdph on the non-adrenergic prejunctional VDCCs of cell membrane is stereoselective. In the prostatic portion, exogenous Ca(2+) only partially reversed the twitch inhibition by Z-Bdph, but effectively reversed those by Ca(2+) channel blockers, such as verapamil, diltiazem and aspaminol, suggesting that the action mechanisms may be different from those of Ca(2+) channel blockers. K(+) channel blockers, such as tetraethylammonium (TEA) and 4 aminopyridine (4-AP), may prolong duration of action potential to allow greater Ca(2+) entry and induced more release of transmitters. Therefore both blockers via their prejunctional actions reversed the twitch inhibition induced by Z-Bdph in all preparations of RVD by a non-specific antagonism. PMID- 27238974 TI - Effects of nicotine in combination with drugs described as positive allosteric nicotinic acetylcholine receptor modulators in vitro: discriminative stimulus and hypothermic effects in mice. AB - Some drugs that are positive allosteric nAChR modulators in vitro, desformylflustrabromine (dFBr), PNU-120596 and LY 2087101, have not been fully characterized in vivo. These drugs were examined for their capacity to share or modify the hypothermic and discriminative stimulus effects of nicotine (1mg/kg s.c.) in male C57Bl/6J mice. Nicotine, dFBr, and PNU-120596 produced significant hypothermia, whereas LY 2087101 (up to 100mg/kg) did not. Nicotine dose dependently increased nicotine-appropriate responding and decreased response rate; the respective ED50 values were 0.56mg/kg and 0.91mg/kg. The modulators produced no more than 38% nicotine-appropriate responding up to doses that disrupted operant responding. Rank order potency was the same for hypothermia and rate-decreasing effects: nicotine>dFBr>PNU-120596=LY 2087101. Mecamylamine and the alpha4beta2 nAChR antagonist dihydro-beta-erythroidine, but not the alpha7 antagonist methyllycaconitine, antagonized the hypothermic effects of nicotine. In contrast, mecamylamine did not antagonize the hypothermic effects of the modulators. The combined discriminative stimulus effects of DFBr and nicotine were synergistic, whereas the combined hypothermic effects of nicotine with either dFBr or PNU-120596 were infra-additive. PNU-120596 did not modify the nicotine discriminative stimulus, and LY 2087101 did not significantly modify either effect of nicotine. Positive modulation of nicotine at nAChRs by PNU 120596 and LY 2087101 in vitro does not appear to confer enhancement of the nAChR mediated hypothermic or discriminative stimulus effects of nicotine. However, dFBr appears to be a positive allosteric modulator of some behavioral effects of nicotine at doses of dFBr smaller than the doses producing unwanted effects (e.g. hypothermia) through non-nAChR mechanisms. PMID- 27238975 TI - Involvement of IGF-1 receptor signaling pathway in the neuroprotective effects of Icaritin against MPP(+)-induced toxicity in MES23.5 cells. AB - Icaritin, a natural derivative of Icariin, is the major bioactive component of Epimedium Genus. The present study tested the hypothesis that the neuroprotective effects of Icaritin against 1-Methyl-4-phenylpyridinium ion (MPP(+))-induced toxicity involved activation of the insulin-like growth factor-1 receptor (IGF 1R) signaling pathway in MES23.5 cells. Our results revealed that Icaritin pretreatment attenuated the MPP(+)-induced decrease of cell viability in a dose dependent fashion. Co-pretreatment with phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002, mitogen-activated protein kinase (MEK) inhibitor PD98059 or IGF-1 receptor antagonist JB-1 could completely block the protective effects of Icaritin. Moreover, Icaritin pretreatment down-regulated MPP(+)-induced increase of Bax/Bcl-2 ratio transcriptionally and post-transcriptionally. Further study revealed that Icaritin pretreatment could restore the decreased protein expression of Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) induced by MPP(+) and these effects could be completely abolished by LY294002, PD98059 or JB-1. Additionally, Icaritin treatment alone time-dependently enhanced the phosphorylation of Akt and ERK1/2 in MES23.5 cells. The activation of Akt and ERK1/2 by Icaritin could be completely blocked by JB-1, LY294002 or PD98059. Taken together, our data demonstrate that IGF-1 receptor mediated activation of PI3K/Akt and MEK/ERK1/2 signaling pathways are involved in the protective effects of Icaritin against MPP(+)-induced toxicity in MES23.5 cells. PMID- 27238977 TI - Hybrid Ultra-Microporous Materials for Selective Xenon Adsorption and Separation. AB - The demand for Xe/Kr separation continues to grow due to the industrial significance of high-purity Xe gas. Current separation processes rely on energy intensive cryogenic distillation. Therefore, less energy intensive alternatives, such as physisorptive separation, using porous materials, are required. Herein we show that an underexplored class of porous materials called hybrid ultra microporous materials (HUMs) affords new benchmark selectivity for Xe separation from Xe/Kr mixtures. The isostructural materials, CROFOUR-1-Ni and CROFOUR-2-Ni, are coordination networks that have coordinatively saturated metal centers and two distinct types of micropores, one of which is lined by CrO4 (2-) (CROFOUR) anions and the other is decorated by the functionalized organic linker. These nets offer unprecedented selectivity towards Xe. Modelling indicates that the selectivity of these nets is tailored by synergy between the pore size and the strong electrostatics afforded by the CrO4 (2-) anions. PMID- 27238976 TI - Suppression of ischaemia-induced injuries in rat brain by protease-activated receptor-1 (PAR-1) activating peptide. AB - Ischaemic stroke has become one of the leading causes of death and disability worldwide. The role of protease activated receptor-1 (PAR-1) in this disease is uncertain. In the present study, the actions of a protease activated receptor-1 activating peptide (PAR-1 AP) SFLLRN-NH2 were investigated in an in vivo rat model of ischaemic stroke induced by middle cerebral artery occlusion (MCAO) and in an in vitro model induced by oxygen and glucose deprivation (OGD) in primary cultured rat embryonic cortical neurones. Rats subjected to MCAO exhibited increased brain infarct volume, oedema, and neurological deficit. Rat cortical neurones subjected to OGD showed increased lactate dehydrogenase, caspase-3 activity and TUNEL positive cells, whereas, mitochondrial membrane potential and cell viability were decreased. Furthermore, both models had elevated levels of reactive oxygen species, nitrite, and malondialdehyde, while anti-oxidant enzymes and bcl-2/bax ratio were decreased. These detrimental changes were suppressed by SFLLRN-NH2, and its protective actions were inhibited by a PAR-1 antagonist (BMS 200261). In summary, SFLLRN-NH2 was found to possess anti-oxidant and anti apoptotic properties, and it produced marked inhibition on the detrimental effects of ischaemia in in vivo and in vitro models of ischaemic stroke. The present findings suggest PAR-1 is a promising target for development of novel treatments of ischaemic brain disease. PMID- 27238978 TI - The Impact of Physician Specialization on Clinical and Hospital Outcomes in Patients Undergoing EVAR and TEVAR. AB - BACKGROUND: Endovascular aneurysm repair (EVAR) and Thoracic endovascular aortic repair (TEVAR) are commonly performed by interventional radiologists, cardiologists, general surgeons, cardiothoracic surgeons, and vascular surgeons, with each specialty having differences in residency structure, operative experience, and subspecialty training. The aim of this study is to evaluate the impact of surgeon specialty on outcomes following EVAR and TEVAR. METHODS: Patients who underwent EVAR and TEVAR were identified from the 2007 to 2009 Nationwide Inpatient Sample (NIS). Physician identifiers in the NIS were used to determine surgical specialty and operative experience. Multivariate analysis adjusted for mortality risk was used to compare differences in demographics, complications, outcomes, and hospital covariates. RESULTS: A total of 5147 EVARs were identified within the NIS, of which 88.3% were completed by vascular surgeons. There were no significant differences in demographics between the specialties. Cardiothoracic surgeons were more likely to have a postoperative stroke (3.1% vs. 0.2%, odds ratio [OR] 14.6, 95% confidence interval [CI] 1.8 117.8, P < 0.05) and cardiac complications (9.4% vs. 2.0%, OR 5.0, 95% CI 1.5 16.6, P < 0.01) compared with other specialties. Costs were lowest for vascular surgeons ($32,094), and highest for cardiothoracic surgeons ($41,663, P < 0.05). Only vascular surgeons completed more than 10 EVARs per year. A total of 2531 TEVAR cases were completed during the study period, of which 73.8% were completed by vascular surgeons, 15.8% by cardiothoracic surgeons, 8.0% by interventional radiologists, and the remainder by interventional cardiologists and general surgeons. Interventional radiologists had significantly more elective cases (77.8%, P < 0.001) than cardiothoracic surgeons (47.2%) or vascular surgeons (53.8%), but had a significantly higher rate of stroke (7.6% vs. 1.1%, P < 0.001) and cardiac events (7.2% vs. 3.6%, P < 0.001). Length of stay (LOS, 10.7 days) and median costs ($52,156) were similar across specialties. Vascular surgeons have a low stroke rate (1.1%, P < 0.05 vs. interventional radiologists) and lower rate of cardiac events (3.6% vs. 6.1%, P < 0.01) despite caring for patients with higher diagnosis-related group mortality scores (3.6 vs. 3.4, P < 0.05). CONCLUSIONS: Vascular surgeons appear to have a comparative advantage over other specialties for EVAR because not only are their complication and mortality rates comparable but overall LOS and hospital charges are lower. Furthermore, primarily only vascular surgeons are performing the high volume of annual EVARs necessary to ensure optimal patient outcomes. For TEVAR, vascular surgeons have the lowest overall morbidity compared with the other specialties, and lower mortality compared with cardiothoracic surgeons. These findings may impact patient referral patterns and hospital privileges for providers. PMID- 27238979 TI - Ultralow Iodine Dose Transarterial Catheter-Directed CT Angiography for Fenestrated Endovascular Aortic Repair Planning. AB - BACKGROUND: Preoperative planning for fenestrated endovascular aortic repair (fEVAR) requires high-quality cross-sectional imaging, most commonly computed tomography angiography (CTA). However, in the setting of chronic kidney disease (CKD), the iodine load delivered during conventional CTA is associated with risk for acute kidney injury (AKI). In this report, we describe the feasibility of using transarterial catheter directed CT angiography (tcd-CTA) with ultralow-dose iodine as an alternative for fEVAR planning in patients with stage 3-4 CKD to lower the risk of AKI. METHODS: Preserum and postserum creatinine levels were retrospectively evaluated from 8 patients with stage 3-4 CKD who underwent tcd CTA with 20 mL of Iohexol for fEVAR planning for the treatment of pararenal abdominal aortic aneurysms. The tcd-CTA images were evaluated by two vascular surgeons for adequacy for fEVAR planning and progression to fEVAR completion was recorded. RESULTS: The mean serum creatinine before tcd-CTA was 2.1 +/- .32 mg/dL, and the mean estimated glomerular filtration rate was 29.7 +/- 6.31 mL/min/1.73 m(2). After tcd-CTA, the mean serum creatinine was 1.9 +/- .25 mg/dL and the mean estimated glomerular filtration rate was 32.9 +/- 5.12 mL/min/1.73 m(2). All 8 of the studies were determined to be adequate for fEVAR planning independently by two vascular surgeons. Six of the patients underwent successful fEVAR and 2 opted for watchful waiting. CONCLUSIONS: tcd-CTA with ultralow-dose iodine is a feasible option for pre-fEVAR planning in patients with stage 3-4 CKD. PMID- 27238980 TI - Ten-Year Experience with Management of Aortoiliac Aneurysms Using Retrograde Endovascular Internal Iliac Artery Preservation. AB - BACKGROUND: To evaluate the use of retrograde endovascular internal iliac artery preservation (REIIAP) technique for treating aortoiliac aneurysms. METHODS: We reviewed our database for all patients with aortoiliac aneurysms who underwent REIIAP technique between April 2004 and April 2014. Patients underwent implantation of an Apollo aortomonoiliac (Nano Endoluminal, Florianopolis, Brazil), contralateral implantation of a Viabahn stent graft (Gore Medical, Flagstaff, AZ) positioned from the external iliac artery into the internal iliac arteries as a bridging stent and femorofemoral bypass. The outcomes that we evaluated included technical success, operative mortality and morbidity, endoleak, aneurysm diameter, bridging stent occlusion, and reintervention during follow-up. RESULTS: A total of 21 patients (19 men, mean age 73 +/- 2.3 years) were identified. Technical success was achieved in all cases, and none of the patients died during the follow-up (mean follow-up 52 +/- 38.5 months). Type IB endoleak was diagnosed in 2 patients, bridging stent occlusion was diagnosed in 1 patient, and reintervention was required for 2 patients. Diameter regression was observed in the aorta (P = 0.15), left common iliac artery (P = 0.37), and right common iliac artery (P = 1.22). CONCLUSIONS: This study demonstrates the feasibility of the REIIAP technique presenting high success rate and similar complication rates compared with other therapeutic options during follow-up. These results demonstrated that it is a useful option for selected patients with aortoiliac aneurysms unfit for other techniques. PMID- 27238981 TI - Strain Pattern on Electrocardiogram Is Associated with Increased Carotid Intima Media Thickness in Patients with Aortic Valve Stenosis. AB - BACKGROUND: Coronary artery disease is present in at least 30% of patients with degenerative aortic stenosis (AS). Atherosclerosis also performs an important role in the progression of AS, because of the similarities of pathological mechanisms in both conditions. The electrocardiogram (EKG) strain pattern is associated with structural myocardial change and subendocardial ischemia and has been worldwide used as a marker of AS severity. We hypothesized that EKG strain pattern would be a marker of atherosclerosis as well in AS patients. The aim of this study was to associate the presence of EKG strain pattern in AS patients with the carotid intima-media thickness (CIMT). METHODS: Fifty-two consecutive patients referred from the cardiology clinic with moderate or severe AS were included in the study and underwent clinical evaluation, EKG, transthoracic echocardiography, and carotid ultrasonography, following statistical analysis of the results. RESULTS: There was a significant association between left ventricular EKG strain and increased CIMT (P = 0.001). The presence of strain increased the odds of abnormal CIMT (P = 0.004, odds ratio 9.7, 95% confidence interval 2.4-45.0), in a model adjusted for age and clinical diagnosis of systemic arterial hypertension. Additionally, EKG strain was associated with the presence of atherosclerotic plaque in at least one carotid artery (P = 0.011). CONCLUSION: Our results suggest that AS patients with EKG strain pattern should be further investigated for the diagnosis of subclinical atherosclerotic disease. PMID- 27238982 TI - Aortic Epithelioid Angiosarcoma after Endovascular Aneurysm Repair. AB - We report a case of epithelioid angiosarcoma of the abdominal aortic wall after endovascular treatment for abdominal aortic aneurysm (EVAR). A 60-year-old male, treated 7 years before with EVAR, presented with abdominal back pain, general fatigue, and fever. It was assumed to be a graft infection with periaortic tissue compatible with an inflammatory reaction. The endograft was therefore completely removed and a Dacron silver aorto-bisiliac graft was implanted. After a few days the patient worsened, the angio-computed tomography scan showed a progressive increase of the periaortic mass and numerous small nodules in the abdomen were also detected. The patient was again brought to surgery, an axillo-bifemoral bypass was performed, and the aorto-bisiliac graft was removed but the patient died after surgery. The histological examination showed an aortic epithelioid angiosarcoma with peritoneal metastasis. PMID- 27238983 TI - Lone Stent-Graft Treatment of Symptomatic Gluteal Artery Aneurysm. AB - We report the case of a large superior gluteal artery aneurysm treated with covered stent-graft insertion. Exclusion of the aneurysm was achieved, with resolution of symptoms and shrinkage of the sac, without the need for embolization. PMID- 27238984 TI - Iliac Stent Grafting to Facilitate Distal Suture during Abdominal Aortic Aneurysm Open Repair. AB - BACKGROUND: We report a hybrid technique that aims to facilitate revascularization of heavily calcified iliac arteries during open repair of abdominal aortic aneurysms. METHODS: It consists of performing the prosthetic graft limb anastomosis on the proximal edge of an iliac leg stent graft that is deployed anterogradely or retrogradely in the common iliac artery and externalized in the retroperitoneum. RESULTS: We used this technique in 2 cases with satisfactory results and preserved patency of the implanted stent grafts. CONCLUSION: This technique avoids anastomoses on heavily calcified iliac arteries or anastomoses on right femoral arteries during left retroperitoneal aortic approaches. PMID- 27238985 TI - A Pulsatile Mass in the Right Buttock. AB - Gluteal artery pseudoaneurysms are a rare cause of buttock pain, with few cases reported in the recent literature. Although small pseudoaneurysms are usually asymptomatic, larger can be painful and require treatment. Most of these cases are pseudoaneurysms resulting from local trauma. We report in this case a patient with a gluteal artery pseudoaneurysm. The pseudoaneurysm was successfully thrombosed using ultrasound-guided thrombin injection. This article reviews the literature, discusses the imaging diagnostics and the treatment of gluteal artery aneurysms. PMID- 27238986 TI - Tibioperoneal Trunk Aneurysm Resulting in Compartment Syndrome with Associated Aneurysms of the Popliteal and Dorsalis Pedis Arteries. AB - True aneurysms of the tibioperoneal trunk are rare. Given the scarcity of reports, the clinical presentation and treatment is not well defined. This is a case report of a 50-year-old male patient presenting with severe lower extremity swelling and compartment syndrome with neurological compromise secondary to a tibioperoneal trunk aneurysm. He was also noted to have discrete ipsilateral popliteal and dorsalis pedis artery aneurysms. Given the location and size of the aneurysm, the severe leg swelling, and venous hypertension, aneurysmorrhaphy or aneurysm sac excision with arterial reconstruction was prohibitively dangerous. Thus, following fasciotomies, a hybrid repair utilizing a saphenous vein superficial femoral to anterior tibial artery bypass along with coil embolization of the aneurysm sac was performed. The patient recovered full function of his leg and follow-up computed tomography angiogram demonstrated thrombosis and regression of the aneurysm sac with a patent bypass. PMID- 27238987 TI - Unusual Acute Onset of Abdominal Aortic Endograft Infection by Propionibacterium acnes after Coil Embolization for Type II Endoleak. AB - Propionibacterium acnes, an anaerobic gram-positive bacillus that inhabits the skin, has rarely been incriminated in abdominal aortic endograft infection. It is usually responsible for typical delayed and low-grade postoperative infections. We report the case of a 66-year-old patient who developed acute P. acnes aortic stent-graft infection 9 days after percutaneous embolization for type II endoleak. The stent graft had been implanted 2 years before. Because of persistent signs of sepsis and discovery of a posterior periaortic abscess formation on the computed tomography scan, removal of the stent graft was necessary. Despite being described as a low virulence and slow growth bacteria, P. acnes was responsible for acute onset of postoperative infection with extensive life-threatening damages necessitating multiple interventions associated with long-term antibiotherapy. PMID- 27238988 TI - Frailty and Geriatric Syndromes in Vascular Surgical Ward Patients. AB - BACKGROUND: Preoperative frailty is an important predictor of poor outcomes but the relationship between frailty and geriatric syndromes is less clear. The aims of this study were to describe the prevalence of frailty and incidence of geriatric syndromes in a cohort of older vascular surgical ward patients, and investigate the association of frailty and other key risk factors with the occurrence of one or more geriatric syndromes (delirium, functional decline, falls, and/or pressure ulcers) and two hospital outcomes (acute length of stay and discharge destination). METHODS: This prospective cohort study was conducted in a vascular surgical ward in a tertiary teaching hospital in Brisbane, Australia. Consecutive patients aged >=65 years, admitted for >=72 hr, were eligible for inclusion. Frailty was defined as one or more of functional dependency, cognitive impairment, or nutritional impairment at admission. Delirium was identified using the Confusion Assessment Method and a validated chart extraction tool. Functional decline from admission to discharge was identified from daily nursing documentation of activities of daily living. Falls were identified according to documentation in the medical record cross-checked with the incident reporting system. Pressure ulcers, acute length of stay, and discharge destination were identified by documentation in the medical record. Risk factors associated with geriatric syndromes, acute length of stay, and discharge destination were assessed using multivariable logistic regression models. RESULTS: Of 110 participants, 43 (39%) patients were frail and geriatric syndromes occurred in 40 (36%). Functional decline occurred in 25% of participants, followed by delirium (20%), pressure ulcers (12%), and falls (4%). In multivariable logistic analysis, frailty [odds ratio (OR) 6.7, 95% confidence interval (CI) 2.0-22.1, P = 0.002], nonelective admission (OR 7.2, 95% CI 2.2 25.3, P = 0.002), higher physiological severity (OR 5.5, 95% CI 1.1-26.8, P = 0.03), and operative severity (OR 4.6, 95% CI 1.2-17.7, P = 0.03) increased the likelihood of any geriatric syndrome. Frailty was an important predictor of longer length of stay (OR 2.6, 95% CI 1.0-6.8, P = 0.06) and discharge destination (OR 4.2, 95% CI 1.2-13.8, P = 0.02). Nonelective admission significantly increased the likelihood of discharge to a higher level of care (OR 5.3, 95% CI 1.3-21.6, P = 0.02). CONCLUSIONS: Frailty and geriatric syndromes were common in elderly vascular surgical ward patients. Frail patients and nonelective admissions were more likely to develop geriatric syndromes, have a longer length of stay, and be discharged to a higher level of care. PMID- 27238989 TI - Open versus Endovascular Treatment of Visceral Artery Aneurysms and Pseudoaneurysms. AB - BACKGROUND: Visceral artery aneurysms and pseudoaneurysms (VAAP) represent a rare and potential life-threatening disease with a documented incidence of 0.1-2.0%. Treatment options for VAAP vary from open approach with aneurysm excision, exclusion and revascularization to endovascular techniques. Aneurysm anatomy and pathogenesis dictate treatment choice. The purpose of this study was to compare the perioperative, short- and mid-term outcomes of open and endovascular approaches. METHODS: Between January 2007 to April 2015, patients with VAAP who underwent surgical treatment, either by endovascular technique (endovascular surgery [EV] group) or by open surgery (OS group), were selected for analysis. Aneurysm's anatomy and pathogenesis dictated treatment choice. Demographic variables, surgical data, and postoperative follow-up were retrospectively analyzed. Preoperative computed tomography scans were evaluated for aneurysm characteristics. RESULTS: A total of 296 consecutive patients were identified with VAAP. Surveillance without intervention occurred in 183 patients, and 113 underwent surgical treatment: 57 by EV technique and 56 by OS. The VAAP sites were: splenic (50.9/5.4%), renal (7.0/50%), superior mesenteric (7.0/7.1%), celiac (12.3/17.9%), hepatic (14.0/5.4%), gastroduodenal (7.0/7.1%), and pancreaticoduodenal (1.8/7.1%). Eight urgent surgeries occurred in EV and 5 in OS group (P = 0.39). Operative time and estimated blood loss were 122 +/- 54 vs. 312 +/- 157 min (P < 0.001) and 5 (interquartile range [IR], 0-50) vs. 550 (IR, 200 980) mL (P < 0.001) in groups EV and OS, respectively. The intraoperative and postoperative major complications, including end-organ infarction, and reinterventions were comparable between the groups. Transfusion of blood products was necessary in 12.3% (EV) and 42.9% (OS; P < 0.001). Median hospital length of stay was 1 (IR, 1-3) and 6 (IR, 4-9) days in groups EV and OS, respectively (P < 0.001). Short-term technical success was achieved in 98.2% (EV) and 96.4% (OS). During the median follow-up period of 16 (IR, 7.1-43.9) months, the clinical success was 91.2% and 92.9% (P = 0.74), and the overall survival was 94.7% and 96.4% (P = 1.0) in groups EV and OS, respectively. CONCLUSIONS: Open and endovascular approaches have similar rates of technical and clinical success, as well as mortality during follow-up. However, periprocedural morbidity was significantly higher in cases treated by OS. Although longer-term follow-up is needed to access the durability of the endovascular treatment, initial successful outcomes and low reintervention rates make it a safe and feasible approach. PMID- 27238990 TI - Updates in Pathophysiology, Diagnosis and Management of Takayasu Arteritis. AB - BACKGROUND: Takayasu arteritis (TA) is a rare, systemic, inflammatory vasculitis of granulomatous nature, and still of unknown etiology. It mainly involves the aorta and its major branches and is more commonly seen in women of childbearing age and Asians. TA leads to stenosis, occlusion, or aneurysmal degeneration of large arteries, and its pathogenesis seems to be mainly due to an abnormal cell mediated immunity, although other molecular and genetic abnormalities may contribute. The diagnosis and treatments lie on clinical and arteriographic findings. Because of its fluctuating course, both clinical scores and biomarkers are currently evaluated. The aim of this review is to report a comprehensive and methodologically robust state of the art about Takayasu arteritis, including the latest data and evidences in the definition, epidemiology, pathogenesis and etiology, clinical manifestations and classification, diagnosis, assessment of disease activity and progression, biomarkers, and treatment. METHODS: We searched all publications addressing definition, epidemiology, pathogenesis, etiology, classification, diagnosis, biomarkers, and treatment of TA. Randomized trials, cohort studies, and reviews were contemplated to give a breadth of clinical data. PubMed and Scopus were searched from August 2010 to November 2015. RESULTS: Of the 3,056 records found, 267 matched our inclusion criteria. After reading the full-text articles, we decided to exclude 169 articles because of the following reasons: (1) no innovative or important content; (2) no multivariable analysis; (3) insufficient data; (4) no clear potential biases or strategies to solve them; (5) no clear end-points; and (6) inconsistent or arbitrary conclusions. The final set included 98 articles. CONCLUSIONS: This review presents the last updates in all fields of Takayasu arteritis. Still today, large areas of TA pathogenesis and disease-activity assessment need to be further investigated to better treat patients with TA. PMID- 27238991 TI - Omental Flow-Through Flap: Experimental Hemodynamic Study. AB - BACKGROUND: The omental flow-through flap (OFTF) is based on the use of an anatomic unit composed of the right gastro-omental artery (bypass) with its omental branch or branches supplying the greater omentum (flap). The greater omentum flap is known for its capacity of resistance to infection, for its use in the treatment of ischemic lesions and as a high-flow tissue. Several hypotheses regarding the hemodynamic behavior of a distal bypass with a flap were discussed in the literature. We made the assumption that the OFTF was a low peripheral resistance flap and that the greater omentum did not induce a steal phenomenon. We demonstrated the anatomical feasibility of the experimental model with a morphologic study in the pig. The mail objective of this study was to measure the blood flow to evaluate the hemodynamic effects of the OFTF. METHODS: Twelve domestic pigs were used for this study. Four cadavers of pigs were dissected for the anatomic study of the OFTF, and 8 live pigs were used for the experimental surgery and hemodynamic measurements. Hemodynamic measurements were taken before transplantation on in situ arteries using periarterial ultrasonic flow transducers. After transplantation of the OFTF, flows were measured before, then during clamping and unclamping of the flap. RESULTS: OFTF was feasible in the porcine model. With the experimental model, the flow increased by 56.15% in the distal part of the bypass after the implantation of the flap with decrease of peripheral resistances. CONCLUSIONS: Our results suggest that the OFTF is a low resistance flap and that the greater omentum does not induce a steal phenomenon. This anatomic unit could be used to carry out simultaneously limb revascularization and cover a tissue loss. PMID- 27238992 TI - Effects of Sarpogrelate Combined with Aspirin in Patients Undergoing Carotid Endarterectomy in China: A Single-Center Retrospective Study. AB - BACKGROUND: Patients undergoing carotid artery stenosis who are prescribed aspirin, clopidogrel, or sarpogrelate as treatment options to inhibit platelet aggregation continues to increase. The purpose of this study was to compare the efficacy and safety of clopidogrel combined with aspirin (CA) versus sarpogrelate combined with aspirin (SA) treatment in carotid endarterectomy (CEA) patients. METHODS: This retrospective study included 197 CEA patients (mean age 61.4 years, mean follow-up time 42.5 months), who were divided into a CA group (Group A: 65 male and 44 female patients) and an SA group (Group B: 58 male and 30 female patients). Preoperative demographic and clinical characteristics and postoperative results were compared between the 2 groups and statistically analyzed. RESULTS: Preoperative demographic and clinical characteristics, transfusions, hospital stay, occurrence of transient ischemic attack, stroke, myocardial infarction, restenosis, general or life-threatening bleeding, and 30 day mortality showed no significant differences between the 2 CEA patient groups. However, the mean operative blood loss (P = 0.023) and the operative time (P = 0.040) were significantly higher in Group A compared with Group B. A highly significant incidence of neck hematoma (P = 0.024) was observed in patients of Group A. CONCLUSIONS: In this study on CEA patients, antiplatelet treatment with CA resulted in a significant risk of developing neck hematoma, increased operative blood loss, and operative time compared with SA treatment. Long-term prospective studies with larger study populations are needed to further confirm the utility of SA treatment for CEA patients. PMID- 27238993 TI - Vascular Complications after Renal Transplantation: Another Brick in the Wall. PMID- 27238994 TI - Successful Endovascular Repair in a Patient with Isolated Proximal Subclavian Artery Dissecting Aneurysm: Case Report and Literature Review. AB - Spontaneous isolated subclavian artery dissecting aneurysm is rare. This is to our knowledge the first case in the world's literature to report a patient with subclavian artery dissecting aneurysm. Although the endovascular approach of treating subclavian artery pathologies is not challenging, the choice of using a covered stent for this patient was a new attempt in treating subclavian artery dissections. This case report highlights the possibility and safety of using covered stent in treating patients with subclavian artery dissecting aneurysms after reassuring the patency of the cerebral circulation system. PMID- 27238995 TI - Association of Obesity with Short-Term Adverse Outcomes after Abdominal Aortic Aneurysm Repair. PMID- 27238997 TI - Mycotic Aneurysm of the Extracranial Internal Carotid Artery, Resect and Ligate or Reconstruct? AB - Mycotic aneurysmal disease of the extracranial carotid arteries (ECA) is a rare entity associated with a high morbidity, including rupture, hemorrhage, airway obstruction, and stroke. Surgical management is challenging due to difficult dissection through infected or inflamed tissue. This report highlights a case of ECA-aneurysm infection presenting with stroke and an occluded internal carotid artery, likely due to microbial arteritis on a background of osteomyelitis. Operative intervention was performed to definitively treat the infection and prevent the potential associated complications. In this case, the incident vessel was 100% occluded at presentation, allowing vessel ligation and resection without carotid complex reconstruction. PMID- 27238996 TI - Vascular Injuries in Combat-Specific Soldiers during Operation Iraqi Freedom and Operation Enduring Freedom. AB - BACKGROUND: This study sought to identify vascular injury patterns among combat specific cavalry scout personnel within the Iraq and Afghanistan Wars. METHODS: The Armed Forces Medical Examiner System and Joint Theater Trauma Registry were queried for all injuries with the cavalry scout designation from 2003 to 2011, including those both wounded in action (WIA) and killed in action (KIA). A description of vascular injury, combat causality care statistics, mechanism of injury, and demographic data were recorded. RESULTS: Sixteen percent (n = 111) of the 701 cavalry scouts with a combat wound sustained a vascular injury. Among cavalry scouts sustaining vascular injuries, 69% were caused by an explosive mechanism of injury, 63% were KIA, and 29% had a major extremity amputation. Cavalry scout soldiers with a vascular injury were significantly more likely to result from explosion (P < 0.0001), be KIA (P < 0.0001), and occur in Iraq (P < 0.0001). The rate of noncompressible arterial injury was 65%. WIA cavalry scout soldiers with a compressible vascular injury with clear documentation of prehospital tourniquet utilization arrived at a Medical Treatment Facility in 67% of cases with a tourniquet in place. Of these transported with a prehospital tourniquet 83% survived. CONCLUSIONS: The high rates of KIA and extremity amputation among cavalry scout soldiers with a vascular injury denotes the lethality of these combat injuries. Uniformly equipping soldiers with battlefield tourniquets and educating them on their prehospital use might improve the survivorship of those servicemembers sustaining a compressible vascular injury. PMID- 27238999 TI - Anterior Retroperitoneal Spine Exposure following Prior Endovascular Aortic Aneurysm Repair. AB - BACKGROUND: We describe successful anterior retroperitoneal spine exposure to facilitate anterior lumbar interbody fusion (ALIF) in a patient with a prior endovascular aneurysm repair (EVAR). METHODS: A 74-year-old male with an extensive spine surgical history presented with progressive neurogenic claudication and paresthesia involving both feet. In addition, his surgical history was notable for an EVAR performed elsewhere 5 years earlier, with subsequent right renal stent placement for encroachment of the right renal artery. Diagnostic evaluation identified severe L3-4 and L4-5 canal stenosis, and a 48 * 36-mm aneurysm sac with a type II endoleak. Revision L3-L5 fusion from an anterior approach with vascular surgery assistance was recommended. RESULTS: The retroperitoneum was accessed through a left paramedian abdominal incision. The abdominal aortic aneurysm sac was visualized and noted to be nonpulsatile. The distal aorta and left iliac vessels were dissected and retracted medially to facilitate anterior exposure of the L3-4 and L4-5 disk spaces. Successful ALIF of the L3-5 vertebrae was then performed. Retractors were removed and the aortoiliac vessels were carefully returned to anatomic position. The aneurysm sac remained nonpulsatile, with normal pulses in the iliac arteries. Postoperative imaging demonstrated stable appearance of aortic stent graft. At 1-year follow-up, the patient reports complete resolution of symptoms and imaging demonstrates a patent aortic stent graft with a stable type II endoleak. CONCLUSIONS: Widespread application of ALIF will inevitably include an increasing subgroup of patients with previous EVAR. Such patients require thorough clinical and radiographic perioperative considerations for the access surgeon. PMID- 27238998 TI - Outcomes and Influence of the Pedal Arch in Below-the-Knee Angioplasty in Patients with End-Stage Renal Disease and Critical Limb Ischemia. AB - BACKGROUND: Management of dialysis patients with critical limb ischemia (CLI) still represents a challenge to vascular medicine, whereas the effects of the pedal arch quality in these patients with predominant affection of the infrapopliteal vessels have rarely been evaluated. Therefore, our aim was to analyze the outcomes of infrapopliteal angioplasty in the setting of chronic renal failure (end-stage renal disease) and evaluate the influence of the pedal arch involvement on clinical success. METHODS: Prospective follow-up of 32 ERSD patients on hemodialysis (mean age, 72 years) with CLI and consecutive infrapopliteal angioplasty over a 5-year period 2010-2014 was performed. Mean follow-up was 10 months (range, 0-51 months). Statistical end points were defined for amputation-free survival, overall survival, and wound healing. Each patient's pedal arch was classified in 4 categories according to patency on completion angiography and the influence of the pedal arch quality on end points was assessed. RESULTS: A total of 44 vessels in 32 ischemic legs were treated. Technical success was achieved in 96% of patients, no major complications were observed. A 30-day mortality rate amounted 6% with no procedure-related deaths. The 1-year amputation-free survival rate was 56% and 34% at 2 years. Two major amputations were required. Subsequent revascularization procedures were necessary in 11 patients (10 redo angioplasty, 1 pedal bypass graft). The pedal arch was classified as category I in 1 patient (3%), category IIa in 12 (38%), IIb in 3 (9%), and III in 16 patients (50%). No statistical significant differences in terms of survival or wound-healing rate were observed between those groups, and the pedal arch quality had no impact on predefined end points. CONCLUSIONS: End stage renal disease patients represent a subgroup with poor prognosis of limb salvage in CLI. Amputation-free survival remains poor and based on these data, an endovascular therapy is feasible and safe in these highly multimorbid patients. The quality of the pedal arch was not found to have any impact on wound healing or survival in the present study. PMID- 27239000 TI - Simple Predictive Model of Early Failure among Patients Undergoing First-Time Arteriovenous Fistula Creation. AB - BACKGROUND: Native arteriovenous fistulas (AVFs) have a high 1 year failure rate leading to a need for secondary procedures. We set out to create a predictive model of early failure in patients undergoing first-time AVF creation, to identify failure-associated factors and stratify initial failure risk. METHODS: The Vascular Study Group of New England (VSGNE) (2010-2014) was queried to identify patients undergoing first-time AVF creation. Patients with early (within 3 months postoperation) AVF failure (EF) or no failure (NF) were compared, failure being defined as any AVF that could not be used for dialysis. A multivariate logistic regression predictive model of EF based on perioperative clinical variables was created. Backward elimination with alpha level of 0.2 was used to create a parsimonious model. RESULTS: We identified 376 first-time AVF patients with follow-up data available in VSGNE. EF rate was 17.5%. Patients in the EF group had lower rates of hypertension (80.3% vs. 93.2%, P = 0.003) and diabetes (47.0% vs. 61.3%, P = 0.039). EF patients were also more likely to have radial artery inflow (57.6% vs. 38.4%, P = 0.011) and have forearm cephalic vein outflow (57.6% vs. 36.5%, P = 0.008). Additionally, the EF group was noted to have significantly smaller mean diameters of target artery (3.1 +/- 0.9 vs. 3.6 +/- 1.1, P = 0.002) and vein (3.1 +/- 0.7 vs. 3.6 +/- 0.9, P < 0.001). Multivariate analyses revealed that hypertension, diabetes, and vein larger than 3 mm were protective of EF (P < 0.05). The discriminating ability of this model was good (C-statistic = 0.731) and the model fits the data well (Hosmer-Lemeshow P = 0.149). beta-estimates of significant factors were used to create a point system and assign probabilities of EF. CONCLUSIONS: We developed a simple model that robustly predicts first-time AVF EF and suggests that anatomical and clinical factors directly affect early AVF outcomes. The risk score has the potential to be used in clinical settings to stratify risk and make informed follow-up plans for AVF patients. PMID- 27239001 TI - Rhizobium radiobacter Endocarditis in an Intravenous Drug User: Clinical Presentation, Diagnosis, and Treatment. AB - Rhizobium radiobacter, a soil-based organism, is not, usually, pathogenic unless in the immunecompromised. Endocarditis, in the immunocompromised, is a typical presentation generally as a result of catheter-based infections. We describe the presentation of R. radiobacter prosthetic valve endocarditis and the inherent challenges in its presentation and diagnosis. A patient presented with acute limb ischemia secondary to R. radiobacter-mediated endocarditis and subsequent thromboembolization of the distal superior femoral and proximal popliteal arteries in the left lower limb. He underwent an uneventful thrombolectomy that restored blood flow distal to the occlusion and restored the patency of the affected arteries. Postoperatively, the patient maintained several unexplained febrile episodes. Blood cultures remained negative for infection. A cardiac work up demonstrated the presence of vegetative growth on the prosthetic mitral and native aortic valves. Histopathologic analysis of the extracted thrombus confirmed the presence of R. radiobacter. On further history, it was elucidated that the patient was an intravenous drug user who routinely stored drug paraphernalia in plant beds. The patient recovered uneventfully after Piptazobactam was administered. R. radiobacter, and similarly other soil-based pathogens, should be considered as a potential source of endocarditic infection and thromboembolization in patients who similarly describe a history of intravenous drug use. PMID- 27239002 TI - Comparison of severe drug eruptions in Japan between 2005-2009 and 2010-2014 based on data from the relief system of the Pharmaceuticals and Medical Devices Agency. PMID- 27239003 TI - Kinematic Magnetic Resonance Imaging for Evaluation of Disc-Associated Cervical Spondylomyelopathy in Doberman Pinschers. AB - BACKGROUND: The dynamic component of disc-associated cervical spondylomyelopathy (DA-CSM) currently is evaluated using traction magnetic resonance imaging (MRI), which does not assess changes in flexion and extension of the cervical vertebral column. In humans with cervical spondylotic myelopathy, kinematic MRI is used to identify dynamic compressions. HYPOTHESIS/OBJECTIVES: To evaluate the feasibility and utility of kMRI in Doberman Pinschers with DA-CSM using a novel positioning device. We hypothesized that kMRI would identify compressive lesions not observed with neutral positioning and change the dimensions of the spinal cord and cervical vertebral canal. ANIMALS: Nine client-owned Doberman Pinschers with DA CSM. METHODS: Prospective study. After standard MR imaging of the cervical spine confirmed DA-CSM, dogs were placed on a positioning device to allow imaging in flexion and extension. Morphologic and morphometric assessments were compared between neutral, flexion, and extension images. RESULTS: Flexion was associated with improvement or resolution of spinal cord compression in 4/9 patients, whereas extension caused worsening of compressions in 6/9 patients. Extension identified 6 new compressive lesions and was significantly associated with dorsal and ventral compression at C5-C6 (P = .021) and C6-C7 (P = .031). A significant decrease in spinal cord height occurred at C6-C7 from neutral to extension (P = .003) and in vertebral canal height at C5-C6 and C6-C7 from neutral to extension (P = .011 and .017, respectively). CONCLUSIONS AND CLINICAL IMPORTANCE: Our results suggest that kMRI is feasible and provides additional information beyond what is observed with neutral imaging, primarily when using extension views, in dogs with DA-CSM. PMID- 27239004 TI - Expression of dmrt1 and vtg genes during gonad formation, differentiation and early maturation in cultured Russian sturgeon Acipenser gueldenstaedtii. AB - Expression of the dmrt1 and vtg genes was described using the real-time PCR (rt PCR) method from 25 to 1600 days post-hatch (dph) in cultured Russian sturgeon Acipenser gueldenstaedtii. The level of dmrt1 transcription in gonads in subsequent studied periods increased exponentially while vtg expression increased in gonads and livers of A. gueldenstaedtii examined, but in later stages of development. Both dmrt1 and vtg genes showed elevated expression in intersex individuals probably caused by dietary exposure to phyto-oestrogens. PMID- 27239005 TI - Primary Neuroendocrine Tumor of Seminal Vesicle: An Extremely Rare Clinical Entity Emphasizing Diagnostic Role of 68-Ga DOTANOC PET-CT Scan and Therapeutic Potential of Long-Acting Depot Octreotide Injection in Maintenance. PMID- 27239006 TI - Identification and analytical characterization of four synthetic cannabinoids ADB BICA, NNL-1, NNL-2, and PPA(N)-2201. AB - Since the first appearance as psychotropic drugs in illegal markets in 2008, the spread of synthetic cannabinoids is becoming a serious problem in many countries. This paper reports on the analytical properties and structure elucidation of four cannabimimetic derivatives in seized material: 1-benzyl-N-(1-carbamoyl-2,2 dimethylpropan-1-yl)-1H-indole-3-carboxamide (ADB-BICA, 1), N-(1-carbamoylpropan 1-yl)-1-(5-fluoropentyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (NNL-1, 2), (4 benzylpiperazin-1-yl)(1-(5-fluoropentyl)-1H-indol-3-yl)methanone (NNL-2, 3), and N-(1-carbamoyl-2-phenylethyl)-1-(5-fluoropentyl)-1H-indazole-3-carboxamide (PPA(N)-2201, 4). The identifications were based on liquid chromatography quadrupole-time-of-flight-mass spectrometry (LC-QTOF-MS), gas chromatography-mass spectrometry (GC-MS), Fourier transform infrared spectroscopy (FT-IR), and nuclear magnetic resonance (NMR) spectroscopy. No chemical or pharmacological data about compounds 1-3 have appeared until now, making this the first report on these compounds. The GC-MS data of 4 has been reported, but this study added the LC-MS, FT-IR, and NMR data for additional characterization. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27239007 TI - Transcatheter mitral valve regurgitation treatment: State of the art and a glimpse to the future. AB - Since the first transcatheter heart valve implantation in the pulmonary position in 2000 and in the aortic position in 2002, a large number of transcatheter heart valves have reached the clinical arena and thousands of high-risk patients have been treated successfully, in particular those with severe aortic stenosis. In contrast, the experience of transcatheter mitral valve repair or implantation started relatively more recently, and only a few devices are available at the moment. The aim of this review is to describe the different percutaneous systems for the treatment of mitral regurgitation. PMID- 27239008 TI - Is right axillary artery cannulation safe in type A aortic dissection with involvement of the innominate artery? AB - OBJECTIVE: In patients with acute type A aortic dissection involving the innominate artery, it is unclear whether right axillary artery cannulation for arterial inflow is safe. We evaluated the surgical outcomes of patients with dissected innominate artery according to different arterial cannulation sites. METHODS: From 2005 to 2014, of 416 patients with acute type A aortic dissection and preoperative computed tomography angiography in 2 centers, 186 (aged 63 +/- 13 years; 43% were female; 95% with DeBakey type I) had dissected innominate artery (84%, 9%, and 7% involving its entire length or more or less than half of its length, respectively). Neurologic complications, in-hospital mortality, and survival were compared between patients with right axillary (N = 84) and non right axillary (N = 102) cannulation sites. Median follow-up was 30 months (range, 0-130 months). RESULTS: In-hospital mortality was 9.5% and 10.8% (P = .97) for patients with right and non-right axillary cannulation, respectively. Seven patients (8.3%) with right axillary cannulation and 9 patients (8.8%; P = .89) with non-right axillary cannulation had a new-onset postoperative stroke. The axillary artery was cannulated (although dissected) in 8 patients. None of them had a new-onset stroke or died perioperatively. The innominate artery remodeling was observed on follow-up computed tomography in 12% of right axillary cases and 14% of non-right axillary cases (P = .82). Survival did not differ between right axillary and non-right axillary cases, and measured 92% +/- 3% versus 87% +/- 4% and 85% +/- 5% versus 73% +/- 9% at 1 and 5 years, respectively (log rank, P = .29). CONCLUSIONS: The right axillary artery is safe to cannulate for arterial inflow in patients with type A aortic dissection with dissected innominate artery. PMID- 27239009 TI - Adverse outcomes from reoperation after cardiac surgery: There's more to it than blood. PMID- 27239010 TI - Bubble, bubble, toil and trouble? PMID- 27239012 TI - Impact of chronic obstructive pulmonary disease on patients undergoing laryngectomy for laryngeal cancer. AB - OBJECTIVES/HYPOTHESIS: Although chronic obstructive pulmonary disease (COPD) is a common comorbidity in patients undergoing laryngeal cancer surgery, the impact of this comorbidity in this setting is not well established. In this analysis, we used the Nationwide Inpatient Sample (NIS) to elucidate the impact of COPD on outcomes after laryngectomy for laryngeal cancer. METHODS: The NIS was queried for patients admitted from 1998 to 2010 with laryngeal cancer who underwent total or partial laryngectomy. Patient demographics, type of admission, length of stay, hospital charges, and concomitant diagnoses were analyzed. RESULTS: Our inclusion criteria yielded a cohort of 40,441 patients: 3,051 with COPD and 37,390 without. On average, COPD was associated with an additional $12,500 (P < 0.001) in hospital charges and an additional 1.4 days (P < 0.001) of hospital stay. There was no significant difference in incidence of in-hospital mortality between the COPD and non-COPD groups after total laryngectomy (1.1% in COPD vs. 1.0% in non COPD; P = 0.776); however, there was an increased incidence of in-hospital mortality in the COPD group compared to the non-COPD group after partial laryngectomy (3.4% in COPD vs. 0.4% in non-COPD; P < 0.001). Multivariate adjusted logistic regression revealed that COPD was associated with greater odds of pulmonary complications after both partial laryngectomy (odds ratio [OR] = 3.198; P < 0.001) and total laryngectomy (OR = 1.575; P < 0.001). CONCLUSION: Chronic obstructive pulmonary disease appears to be associated with greater hospital charges, length of stay, and postoperative pulmonary complications in patients undergoing laryngectomy for laryngeal cancer. Chronic obstructive pulmonary disease after partial, but not total, laryngectomy appears to be associated with increased risk of in-hospital mortality. LEVEL OF EVIDENCE: 2C. Laryngoscope, 2016 127:417-423, 2017. PMID- 27239011 TI - Results of an international drug testing service for cryptomarket users. AB - INTRODUCTION: User surveys indicate that expectations of higher drug purity are a key reason for cryptomarket use. In 2014-2015, Spain's NGO Energy Control conducted a 1-year pilot project to provide a testing service to cryptomarket drug users using the Transnational European Drug Information (TEDI) guidelines. In this paper, we present content and purity data from the trial. METHODS: 219 samples were analyzed by gas chromatography associated with mass spectrometry (GC/MS). Users were asked to report what substance they allegedly purchased. RESULTS: 40 different advertised substances were reported, although 77.6% were common recreational drugs (cocaine, MDMA, amphetamines, LSD, ketamine, cannabis). In 200 samples (91.3%), the main result of analysis matched the advertised substance. Where the advertised compound was detected, purity levels (m+/-SD) were: cocaine 71.6+/-19.4%; MDMA (crystal) 88.3+/-1.4%; MDMA (pills) 133.3+/ 38.4mg; Amphetamine (speed) 51.3+/-33.9%; LSD 123.6+/-40.5MUg; Cannabis resin THC: 16.5+/-7.5% CBD: 3.4+/-1.5%; Ketamine 71.3+/-38.4%. 39.8% of cocaine samples contained the adulterant levamisole (11.6+/-8%). No adulterants were found in MDMA and LSD samples. DISCUSSION: The largest collection of test results from drug samples delivered from cryptomarkets are reported in this study. Most substances contained the advertised ingredient and most samples were of high purity. The representativeness of these results is unknown. PMID- 27239013 TI - Instrument Motion Metrics for Laparoscopic Skills Assessment in Virtual Reality and Augmented Reality. AB - OBJECTIVE: To determine the construct and concurrent validity of instrument motion metrics for laparoscopic skills assessment in virtual reality and augmented reality simulators. STUDY DESIGN: Evaluation study. SAMPLE POPULATION: Veterinarian students (novice, n = 14) and veterinarians (experienced, n = 11) with no or variable laparoscopic experience. METHODS: Participants' minimally invasive surgery (MIS) experience was determined by hospital records of MIS procedures performed in the Teaching Hospital. Basic laparoscopic skills were assessed by 5 tasks using a physical box trainer. Each participant completed 2 tasks for assessments in each type of simulator (virtual reality: bowel handling and cutting; augmented reality: object positioning and a pericardial window model). Motion metrics such as instrument path length, angle or drift, and economy of motion of each simulator were recorded. RESULTS: None of the motion metrics in a virtual reality simulator showed correlation with experience, or to the basic laparoscopic skills score. All metrics in augmented reality were significantly correlated with experience (time, instrument path, and economy of movement), except for the hand dominance metric. The basic laparoscopic skills score was correlated to all performance metrics in augmented reality. The augmented reality motion metrics differed between American College of Veterinary Surgeons diplomates and residents, whereas basic laparoscopic skills score and virtual reality metrics did not. CONCLUSION: Our results provide construct validity and concurrent validity for motion analysis metrics for an augmented reality system, whereas a virtual reality system was validated only for the time score. PMID- 27239014 TI - Literature Review of Periclitoral Cysts in the Prepubertal Population. AB - STUDY OBJECTIVE: Clitoral cysts in the pediatric population are rare conditions that require careful evaluation. In this review of the literature we discuss the evaluation of clitoral abnormalities in the pediatric population, the development of clitoral cysts, and how to differentiate benign from malignant tumors. In addition, a summary of relevant cases of clitoral tumors in the literature are discussed. DESIGN: Literature review. DATA SOURCE: A MedLine and advanced PubMed search was conducted of all English language articles published using the search terms "clitoris" and "cyst" until February 2015. Reference tracing was completed for all articles for completeness. MAIN OUTCOME: Literature review of clitoral cysts in the prepubertal population. RESULTS: In total, we found 15 cases of benign, spontaneously forming clitoral cysts reported. Eleven of those cases document symptom onset before puberty. Reports of other benign clitoral lesions in the pediatric population include 1 angiokeratoma, 1 hemangiopericytoma, 1 granular cell tumor, 6 hemangiomas, and approximately 30 neurofibromas. Clitoral malignancies in the pediatric population are even more rare with only 3 cases of clitoral schwannomas, 2 rhabdomyosarcomas, 1 lymphoma, and 1 endodermal sinus tumor documented in the literature. CONCLUSION: Clitoral cysts must be considered as a possible cause of clitoral enlargement in the prepubertal population. Clitoral tumors are distinguished clinically from hormonal abnormalities and intersex disorders by their hormonal profile, and the presence of an underlying mass. Ultrasound and magnetic resonance imaging might be useful imaging modalities to further characterize the clitoral enlargement. When confirmed as the most likely diagnosis, surgical resection is the mainstay of treatment for clitoral cysts. PMID- 27239015 TI - Reply to: Risk factors for infection in total knee artrhoplasty, including previously unreported intraoperative fracture and deep venous thrombosis. PMID- 27239016 TI - Risk factors for infection in total knee arthroplasty, including a previously unreported intraoperative fracture and deep venous thrombosis. PMID- 27239017 TI - In vivo bactericidal efficacy of farnesol on Ti6Al4V implants. AB - OBJECTIVE: To evaluate the in vivo anti-staphylococcal bactericidal activity of farnesol on Ti6Al4V surfaces. MATERIAL AND METHODS: An experimental model of infection in biomaterials was developed by inoculation of Staphylococcus aureus ATCC 29213 into the canal of both femurs of 15 Wistar rats. A Ti6Al4V pin impregnated with 30mM of farnesol was inserted into study femur, and a Ti6Al4V control was inserted into the control femur. To evaluate the bactericidal efficacy, a comparison was made between the median of the colony forming units recovered after inoculation in the study group and the control group for different times of euthanasia and inoculum size. RESULTS: The median expressed as Log10 CFU counts obtained with farnesol titanium pin was 4.26, and in control group, it was 4.86, which was statistically significant (P=.001) on applying the Student t test for related samples. The median reduction obtained in farnesol pins relative to the control was 74%. CONCLUSIONS: Treatment with farnesol 30mM on Ti6Al4V pins appears to decrease the rate of colonisation by Staphylococcus aureus. PMID- 27239018 TI - Hip arthrodiastasis in Legg-Calve-Perthes disease. AB - INTRODUCTION AND OBJECTIVE: Arthrodiastasis consists of the mobilisation of the hip while distracted by a hinged distractor. The aim of our study is to show the results of the treatment of late-onset Perthes disease with this technique in our institution. MATERIAL AND METHODS: Ambispective review of all the cases that underwent this surgery in our Department of Paediatric Orthopaedics between 2010 and 2014 with the following inclusion criteria: patients over 8 years old, with minimal deformity, and poor prognosis. Mobility, pain, Trendelenburg sign, radiographic sphericity, and complications were assessed. RESULTS: A total of 13 patients (9 male, 4 female) were included. The mean age was 11.93 years. Radiographic risk signs were present in 7 cases. The mean decrease in pain measured with a visual analogue scale (VAS) after the surgery was 3.83 points (P<.05). Cephalic sphericity was maintained in 11 cases during follow up (1.75 years). Complications were observed complications in 84.6% of the patients, with infection of the screw tract being the most frequent. All of them were easy to treat. CONCLUSIONS: Arthrodiastasis is a minimally invasive technique, useful in the treatment of late onset Perthes disease. It improves clinical results and maintains cephalic shape when applied in early stages. However, it is not free of complications, which can involve as many as 8 out of 10 patients treated with the technique. PMID- 27239019 TI - Morphine-induced inhibition of Ca2+ -dependent d-serine release from astrocytes suppresses excitability of GABAergic neurons in the nucleus accumbens. AB - The nucleus accumbens (NAc) plays a critical role in addictive drug-induced behavioral changes. d-serine is present at high levels in the brain and is involved in the regulation of N-methyl-d-aspartate glutamate (NMDA)-dependent synaptic activity. In this study, we aimed to examine the involvement of d-serine in morphine addiction. Morphine decreased the NMDA receptor-mediated excitatory postsynaptic currents and excitability of GABAergic neurons in the NAc, while exogenous d-serine alleviated the effects of morphine. Morphine reduced extracellular d-serine levels in rat NAc or in primary culture of astrocytes through inhibition of intracellular Ca2+ signals and blockade of d-serine release from cell vesicles. Morphine induced robust internalization of alpha-amino-3 hydroxy-5-methyl-4-isoxazole-propionate acid receptor (AMPAR) in primary cultured astrocytes. Moreover, administration of exogenous d-serine to rats inhibited the development of locomotor sensitization to morphine, attenuated the morphine induced potentiation on conditioned place preference and suppressed the morphine enhanced expression of p-CREB and DeltaFosB in the NAc. Overall, our results showed that morphine inhibited d-serine release from astrocytes through modulation of AMPAR-mediated Ca2+ influx, and led to the inhibition of postsynaptic excitability of GABAergic neurons in the NAc. This work may provide a new insight into the underlying mechanisms of morphine addiction. PMID- 27239020 TI - PEGylated Cationic Serum Albumin for Boosting Retroviral Gene Transfer. AB - Retroviral vectors are common tools for introducing genes into the genome of a cell. However, low transduction rates are a major limitation in retroviral gene transfer, especially in clinical applications. We generated cationic human serum albumin (cHSA) protected by a shell of poly(ethylene glycol) (PEG); this significantly enhanced retroviral gene transduction with potentially attractive pharmacokinetics and low immunogenicity. By screening a panel of chemically optimized HSA compounds, we identified a very potent enhancer that boosted the transduction rates of viral vectors. Confocal microscopy revealed a drastically increased number of viral particles attached to the surfaces of target cells. In accordance with the positive net charge of cationic and PEGylated HSA, this suggests a mechanism of action in which the repulsion of the negatively charged cellular and viral vector membranes is neutralized, thereby promoting attachment and ultimately transduction. Importantly, the transduction-enhancing PEGylated HSA derivative evaded recognition by HSA-specific antibodies and macrophage activation. Our findings hold great promise for facilitating improved retroviral gene transfer. PMID- 27239021 TI - Comparison of 1-Year Outcome in Patients With Severe Aorta Stenosis Treated Conservatively or by Aortic Valve Replacement or by Percutaneous Transcatheter Aortic Valve Implantation (Data from a Multicenter Spanish Registry). AB - The factors that influence decision making in severe aortic stenosis (AS) are unknown. Our aim was to assess, in patients with severe AS, the determinants of management and prognosis in a multicenter registry that enrolled all consecutive adults with severe AS during a 1-month period. One-year follow-up was obtained in all patients and included vital status and aortic valve intervention (aortic valve replacement [AVR] and transcatheter aortic valve implantation [TAVI]). A total of 726 patients were included, mean age was 77.3 +/- 10.6 years, and 377 were women (51.8%). The most common management was conservative therapy in 468 (64.5%) followed by AVR in 199 (27.4%) and TAVI in 59 (8.1%). The strongest association with aortic valve intervention was patient management in a tertiary hospital with cardiac surgery (odds ratio 2.7, 95% confidence interval 1.8 to 4.1, p <0.001). The 2 main reasons to choose conservative management were the absence of significant symptoms (136% to 29.1%) and the presence of co-morbidity (128% to 27.4%). During 1-year follow-up, 132 patients died (18.2%). The main causes of death were heart failure (60% to 45.5%) and noncardiac diseases (46% to 34.9%). One-year survival for patients treated conservatively, with TAVI, and with AVR was 76.3%, 94.9%, and 92.5%, respectively, p <0.001. One-year survival of patients treated conservatively in the absence of significant symptoms was 97.1%. In conclusion, most patients with severe AS are treated conservatively. The outcome in asymptomatic patients managed conservatively was acceptable. Management in tertiary hospitals is associated with valve intervention. One-year survival was similar with both interventional strategies. PMID- 27239022 TI - Radiation Exposure of the Operator During Coronary Interventions (from the RADIO Study). AB - We sought to compare operator radiation exposure during procedures using right femoral access (RFA), right radial access (RRA), and left radial access (LRA) during coronary angiography (CA) and percutaneous coronary intervention (PCI). Because of an increased incidence of long-term malignancy in interventional cardiologists, operator radiation exposure is of rising concern. This prospective study included all consecutive patients who underwent elective or emergency CA +/ PCI from September 2014 to March 2015. The primary end point was operator radiation exposure, quantified as the ratio of operator cumulative dose (CD) and patient radiation reported as dose-area product (DAP) (CD/DAP). Secondary end points included CD, DAP, and fluoroscopy time (FT). Overall 830 procedures (457 CA [55%] and 373 PCI [45%]) were performed, 455 (55%) through RFA, 272 (33%) through RRA, and 103 (12%) through LRA. The CD/DAP was lower in RFA (0.09 MUSv/Gycm(2) [0.02 to 0.20]) compared with RRA (0.47 MUSv/Gycm(2) [0.25 to 0.75], p <0.001). The LRA showed lower CD/DAP compared with RRA (p <0.001). CD was significantly lower in RFA (3 MUSv [1 to 7]) compared with RRA (12 MUSv [6 to 29], p <0.001). The LRA showed lower CD compared with RRA (p <0.001). There were no significant differences in DAP among the 3 access sites. FT was similar for the 3 groups (RFA 7 +/- 7, RRA 5 +/- 5, LRA 6 +/- 5 minutes, RFA vs RRA: p = 1, RFA vs LRA: p = 0.16, RRA vs LRA: p = 0.52). In conclusion, the use of RFA during CA +/- PCI is associated with significantly lower operator radiation exposure compared with RRA. LRA is associated with significantly lower operator radiation exposure compared with RRA. PMID- 27239023 TI - Quality of Life in Survivors of Peripartum Cardiomyopathy. AB - Little data exist with regard to the effect of peripartum cardiomyopathy (PPCM) on quality of life. The aim of this study was to determine the impact of PPCM on quality of life and emotional well-being. We sought to determine the feasibility of using social media to perform quality of life research. We conducted a study using a survey distributed to established members of "Peripartum Cardiomyopathy Survivors" support group on the social networking site Facebook. A total of 116 women completed the survey (age 36 +/- 6.4 years; 91% white, 75% married, 46% college educated), with 4.9 +/- 0.5 years (range 0.02 to 24 years) since the initial diagnosis. Most women (41%) never returned to their baseline level of activity, and 28% discontinued their job because of the diagnosis. Most respondents (56%) were not limited or only slightly limited by heart failure symptoms over the past 2 months. Most respondents (56%) never returned to their baseline emotionally after the diagnosis of PPCM, and most patients (73%) were dissatisfied with their current level of heart failure symptoms. Most patients (67%) felt discouraged frequently (more than several times per month) because of heart failure. Only 26% of women were satisfied with the counseling they received from their providers. The emotional and physical burden of PPCM on young mothers with PPCM years after the diagnosis is striking. Identifying strategies that promote better emotional health and potential treatment strategies may be required. PMID- 27239024 TI - Reply to "Predictable Superiority of Everolimus-Eluting Stent Over Paclitaxel Eluting Balloon in Patients with In-Stent Restenosis". PMID- 27239025 TI - Epileptic encephalopathy with continuous spike-and-wave during sleep maps to a homozygous truncating mutation in AMPA receptor component FRRS1L. PMID- 27239027 TI - Concordant but Varied Phenotypes among Duchenne Muscular Dystrophy Patient Specific Myoblasts Derived using a Human iPSC-Based Model. AB - Duchenne muscular dystrophy (DMD) remains an intractable genetic disease. Althogh there are several animal models of DMD, there is no human cell model that carries patient-specific DYSTROPHIN mutations. Here, we present a human DMD model using human induced pluripotent stem cells (hiPSCs). Our model reveals concordant disease-related phenotypes with patient-dependent variation, which are partially reversed by genetic and pharmacological approaches. Our "chemical-compound-based" strategy successfully directs hiPSCs into expandable myoblasts, which exhibit a myogenic transcriptional program, forming striated contractile myofibers and participating in muscle regeneration in vivo. DMD-hiPSC-derived myoblasts show disease-related phenotypes with patient-to-patient variability, including aberrant expression of inflammation or immune-response genes and collagens, increased BMP/TGFbeta signaling, and reduced fusion competence. Furthermore, by genetic correction and pharmacological "dual-SMAD" inhibition, the DMD-hiPSC derived myoblasts and genetically corrected isogenic myoblasts form "rescued" multi-nucleated myotubes. In conclusion, our findings demonstrate the feasibility of establishing a human "DMD-in-a-dish" model using hiPSC-based disease modeling. PMID- 27239026 TI - Active and Inactive Enhancers Cooperate to Exert Localized and Long-Range Control of Gene Regulation. AB - V(D)J recombination relies on the presence of proximal enhancers that activate the antigen receptor (AgR) loci in a lineage- and stage-specific manner. Unexpectedly, we find that both active and inactive AgR enhancers cooperate to disseminate their effects in a localized and long-range manner. Here, we demonstrate the importance of short-range contacts between active enhancers that constitute an Igk super-enhancer in B cells. Deletion of one element reduces the interaction frequency between other enhancers in the hub, which compromises the transcriptional output of each component. Furthermore, we establish that, in T cells, long-range contact and cooperation between the inactive Igk enhancer MiEkappa and the active Tcrb enhancer Ebeta alters enrichment of CBFbeta binding in a manner that impacts Tcrb recombination. These findings underline the complexities of enhancer regulation and point to a role for localized and long range enhancer-sharing between active and inactive elements in lineage- and stage specific control. PMID- 27239028 TI - Duplication of a Single Neuron in C. elegans Reveals a Pathway for Dendrite Tiling by Mutual Repulsion. AB - Simple cell-cell interactions can give rise to complex cellular patterns. For example, neurons of the same type can interact to create a complex patchwork of non-overlapping dendrite arbors, a pattern known as dendrite tiling. Dendrite tiling often involves mutual repulsion between neighboring neurons. While dendrite tiling is found across nervous systems, the nematode Caenorhabditis elegans has a relatively simple nervous system with few opportunities for tiling. Here, we show that genetic duplication of a single neuron, PVD, is sufficient to create dendrite tiling among the resulting ectopic neurons. We use laser ablation to show that this tiling is mediated by mutual repulsion between neighbors. Furthermore, we find that tiling requires a repulsion signal (UNC-6/Netrin and its receptors UNC-40/DCC and UNC-5) that normally patterns the PVD dendrite arbor. These results demonstrate that an apparently complex cellular pattern can emerge in a simple nervous system merely by increasing neuron number. PMID- 27239030 TI - Presenilin 2 Modulates Endoplasmic Reticulum-Mitochondria Coupling by Tuning the Antagonistic Effect of Mitofusin 2. AB - Communication between organelles plays key roles in cell biology. In particular, physical and functional coupling of the endoplasmic reticulum (ER) and mitochondria is crucial for regulation of various physiological and pathophysiological processes. Here, we demonstrate that Presenilin 2 (PS2), mutations in which underlie familial Alzheimer's disease (FAD), promotes ER mitochondria coupling only in the presence of mitofusin 2 (Mfn2). PS2 is not necessary for the antagonistic effect of Mfn2 on organelle coupling, although its abundance can tune it. The two proteins physically interact, whereas their homologues Mfn1 and PS1 are dispensable for this interplay. Moreover, PS2 mutants associated with FAD are more effective than the wild-type form in modulating ER mitochondria tethering because their binding to Mfn2 in mitochondria-associated membranes is favored. We propose a revised model for ER-mitochondria interaction to account for these findings and discuss possible implications for FAD pathogenesis. PMID- 27239029 TI - Dysregulation of RBFOX2 Is an Early Event in Cardiac Pathogenesis of Diabetes. AB - Alternative splicing (AS) defects that adversely affect gene expression and function have been identified in diabetic hearts; however, the mechanisms responsible are largely unknown. Here, we show that the RNA-binding protein RBFOX2 contributes to transcriptome changes under diabetic conditions. RBFOX2 controls AS of genes with important roles in heart function relevant to diabetic cardiomyopathy. RBFOX2 protein levels are elevated in diabetic hearts despite low RBFOX2 AS activity. A dominant-negative (DN) isoform of RBFOX2 that blocks RBFOX2 mediated AS is generated in diabetic hearts. DN RBFOX2 interacts with wild-type (WT) RBFOX2, and ectopic expression of DN RBFOX2 inhibits AS of RBFOX2 targets. Notably, DN RBFOX2 expression is specific to diabetes and occurs at early stages before cardiomyopathy symptoms appear. Importantly, DN RBFOX2 expression impairs intracellular calcium release in cardiomyocytes. Our results demonstrate that RBFOX2 dysregulation by DN RBFOX2 is an early pathogenic event in diabetic hearts. PMID- 27239031 TI - Complexin 3 Increases the Fidelity of Signaling in a Retinal Circuit by Regulating Exocytosis at Ribbon Synapses. AB - Complexin (Cplx) proteins modulate the core SNARE complex to regulate exocytosis. To understand the contributions of Cplx to signaling in a well-characterized neural circuit, we investigated how Cplx3, a retina-specific paralog, shapes transmission at rod bipolar (RB)->AII amacrine cell synapses in the mouse retina. Knockout of Cplx3 strongly attenuated fast, phasic Ca(2+)-dependent transmission, dependent on local [Ca(2+)] nanodomains, but enhanced slower Ca(2+)-dependent transmission, dependent on global intraterminal [Ca(2+)] ([Ca(2+)]I). Surprisingly, coordinated multivesicular release persisted at Cplx3(-/-) synapses, although its onset was slowed. Light-dependent signaling at Cplx3(-/-) RB->AII synapses was sluggish, owing largely to increased asynchronous release at light offset. Consequently, propagation of RB output to retinal ganglion cells was suppressed dramatically. Our study links Cplx3 expression with synapse and circuit function in a specific retinal pathway and reveals a role for asynchronous release in circuit gain control. PMID- 27239032 TI - CRISPR-Mediated Drug-Target Validation Reveals Selective Pharmacological Inhibition of the RNA Helicase, eIF4A. AB - Targeting translation initiation is an emerging anti-neoplastic strategy that capitalizes on de-regulated upstream MAPK and PI3K-mTOR signaling pathways in cancers. A key regulator of translation that controls ribosome recruitment flux is eukaryotic initiation factor (eIF) 4F, a hetero-trimeric complex composed of the cap binding protein eIF4E, the scaffolding protein eIF4G, and the RNA helicase eIF4A. Small molecule inhibitors targeting eIF4F display promising anti neoplastic activity in preclinical settings. Among these are some rocaglate family members that are well tolerated in vivo, deplete eIF4F of its eIF4A helicase subunit, have shown activity as single agents in several xenograft models, and can reverse acquired resistance to MAPK and PI3K-mTOR targeted therapies. Herein, we highlight the power of using genetic complementation approaches and CRISPR/Cas9-mediated editing for drug-target validation ex vivo and in vivo, linking the anti-tumor properties of rocaglates to eIF4A inhibition. PMID- 27239033 TI - Promotion of RAD51-Mediated Homologous DNA Pairing by the RAD51AP1-UAF1 Complex. AB - The UAF1-USP1 complex deubiquitinates FANCD2 during execution of the Fanconi anemia DNA damage response pathway. As such, UAF1 depletion results in persistent FANCD2 ubiquitination and DNA damage hypersensitivity. UAF1-deficient cells are also impaired for DNA repair by homologous recombination. Herein, we show that UAF1 binds DNA and forms a dimeric complex with RAD51AP1, an accessory factor of the RAD51 recombinase, and a trimeric complex with RAD51 through RAD51AP1. Two small ubiquitin-like modifier (SUMO)-like domains in UAF1 and a SUMO-interacting motif in RAD51AP1 mediate complex formation. Importantly, UAF1 enhances RAD51 mediated homologous DNA pairing in a manner that is dependent on complex formation with RAD51AP1 but independent of USP1. Mechanistically, RAD51AP1-UAF1 co-operates with RAD51 to assemble the synaptic complex, a critical nucleoprotein intermediate in homologous recombination, and cellular studies reveal the biological significance of the RAD51AP1-UAF1 protein complex. Our findings provide insights into an apparently USP1-independent role of UAF1 in genome maintenance. PMID- 27239036 TI - Effects of a Single Escape Mutation on T Cell and HIV-1 Co-adaptation. AB - The mechanistic basis for the progressive accumulation of Y(135)F Nef mutant viruses in the HIV-1-infected population remains poorly understood. Y(135)F viruses carry the 2F mutation within RW8 and RF10, which are two HLA-A(*)24:02 restricted superimposed Nef epitopes recognized by distinct and adaptable CD8(+) T cell responses. We combined comprehensive analysis of the T cell receptor repertoire and cross-reactive potential of wild-type or 2F RW8- and RF10-specific CD8(+) T cells with peptide-MHC complex stability and crystal structure studies. We find that, by affecting direct and water-mediated hydrogen bond networks within the peptide-MHC complex, the 2F mutation reduces both TCR and HLA binding. This suggests an advantage underlying the evolution of the 2F variant with decreased CD8(+) T cell efficacy. Our study provides a refined understanding of HIV-1 and CD8(+) T cell co-adaptation at the population level. PMID- 27239034 TI - Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis. AB - Genome sequencing studies have revealed a number of cancer-associated mutations in the telomere-binding factor POT1. Here, we show that when combined with p53 deficiency, depletion of murine POT1a in common lymphoid progenitor cells fosters genetic instability, accelerates the onset, and increases the severity of T cell lymphomas. In parallel, we examined human and mouse cells carrying POT1 mutations found in cutaneous T cell lymphoma (CTCL) patients. Inhibition of POT1 activates ATR-dependent DNA damage signaling and induces telomere fragility, replication fork stalling, and telomere elongation. Our data suggest that these phenotypes are linked to impaired CST (CTC1-STN1-TEN1) function at telomeres. Lastly, we show that proliferation of cancer cells lacking POT1 is enabled by the attenuation of the ATR kinase pathway. These results uncover a role for defective telomere replication during tumorigenesis. PMID- 27239035 TI - A Diet Mimicking Fasting Promotes Regeneration and Reduces Autoimmunity and Multiple Sclerosis Symptoms. AB - Dietary interventions have not been effective in the treatment of multiple sclerosis (MS). Here, we show that periodic 3-day cycles of a fasting mimicking diet (FMD) are effective in ameliorating demyelination and symptoms in a murine experimental autoimmune encephalomyelitis (EAE) model. The FMD reduced clinical severity in all mice and completely reversed symptoms in 20% of animals. These improvements were associated with increased corticosterone levels and regulatory T (Treg) cell numbers and reduced levels of pro-inflammatory cytokines, TH1 and TH17 cells, and antigen-presenting cells (APCs). Moreover, the FMD promoted oligodendrocyte precursor cell regeneration and remyelination in axons in both EAE and cuprizone MS models, supporting its effects on both suppression of autoimmunity and remyelination. We also report preliminary data suggesting that an FMD or a chronic ketogenic diet are safe, feasible, and potentially effective in the treatment of relapsing-remitting multiple sclerosis (RRMS) patients (NCT01538355). PMID- 27239037 TI - Comprehensive RNA Polymerase II Interactomes Reveal Distinct and Varied Roles for Each Phospho-CTD Residue. AB - Transcription controls splicing and other gene regulatory processes, yet mechanisms remain obscure due to our fragmented knowledge of the molecular connections between the dynamically phosphorylated RNA polymerase II (Pol II) C terminal domain (CTD) and regulatory factors. By systematically isolating phosphorylation states of the CTD heptapeptide repeat (Y1S2P3T4S5P6S7), we identify hundreds of protein factors that are differentially enriched, revealing unappreciated connections between the Pol II CTD and co-transcriptional processes. These data uncover a role for threonine-4 in 3' end processing through control of the transition between cleavage and termination. Furthermore, serine-5 phosphorylation seeds spliceosomal assembly immediately downstream of 3' splice sites through a direct interaction with spliceosomal subcomplex U1. Strikingly, threonine-4 phosphorylation also impacts splicing by serving as a mark of co transcriptional spliceosome release and ensuring efficient post-transcriptional splicing genome-wide. Thus, comprehensive Pol II interactomes identify the complex and functional connections between transcription machinery and other gene regulatory complexes. PMID- 27239038 TI - An In Vivo Gain-of-Function Screen Identifies the Williams-Beuren Syndrome Gene GTF2IRD1 as a Mammary Tumor Promoter. AB - The broad implementation of precision medicine in cancer is impeded by the lack of a complete inventory of the genes involved in tumorigenesis. We performed in vivo screening of ~1,000 genes that are associated with signaling for positive roles in breast cancer, using lentiviral expression vectors in primary MMTV-ErbB2 mammary tissue. Gain of function of five genes, including RET, GTF2IRD1, ADORA1, LARS2, and DPP8, significantly promoted mammary tumor growth. We further studied one tumor-promoting gene, the transcription factor GTF2IRD1. The mis-regulation of genes downstream of GTF2IRD1, including TbetaR2 and BMPR1b, also individually promoted mammary cancer development, and silencing of TbetaR2 suppressed GTF2IRD1 driven tumor promotion. In addition, GTF2IRD1 is highly expressed in human breast tumors, correlating with high tumor grades and poor prognosis. Our in vivo approach is readily expandable to whole-genome annotation of tumor-promoting genes. PMID- 27239039 TI - De Novo Mutations in DENR Disrupt Neuronal Development and Link Congenital Neurological Disorders to Faulty mRNA Translation Re-initiation. AB - Disruptions to neuronal mRNA translation are hypothesized to underlie human neurodevelopmental syndromes. Notably, the mRNA translation re-initiation factor DENR is a regulator of eukaryotic translation and cell growth, but its mammalian functions are unknown. Here, we report that Denr influences the migration of murine cerebral cortical neurons in vivo with its binding partner Mcts1, whereas perturbations to Denr impair the long-term positioning, dendritic arborization, and dendritic spine characteristics of postnatal projection neurons. We characterized de novo missense mutations in DENR (p.C37Y and p.P121L) detected in two unrelated human subjects diagnosed with brain developmental disorder to find that each variant impairs the function of DENR in mRNA translation re-initiation and disrupts the migration and terminal branching of cortical neurons in different ways. Thus, our findings link human brain disorders to impaired mRNA translation re-initiation through perturbations in DENR (OMIM: 604550) function in neurons. PMID- 27239040 TI - PIAS1 Promotes Lymphomagenesis through MYC Upregulation. AB - The MYC proto-oncogene is a transcription factor implicated in a broad range of cancers. MYC is regulated by several post-translational modifications including SUMOylation, but the functional impact of this post-translational modification is still unclear. Here, we report that the SUMO E3 ligase PIAS1 SUMOylates MYC. We demonstrate that PIAS1 promotes, in a SUMOylation-dependent manner, MYC phosphorylation at serine 62 and dephosphorylation at threonine 58. These events reduce the MYC turnover, leading to increased transcriptional activity. Furthermore, we find that MYC is SUMOylated in primary B cell lymphomas and that PIAS1 is required for the viability of MYC-dependent B cell lymphoma cells as well as several cancer cell lines of epithelial origin. Finally, Pias1-null mice display endothelial defects reminiscent of Myc-null mice. Taken together, these results indicate that PIAS1 is a positive regulator of MYC. PMID- 27239041 TI - The Hemogenic Competence of Endothelial Progenitors Is Restricted by Runx1 Silencing during Embryonic Development. AB - It is now well-established that hematopoietic stem cells (HSCs) and progenitor cells originate from a specialized subset of endothelium, termed hemogenic endothelium (HE), via an endothelial-to-hematopoietic transition. However, the molecular mechanisms determining which endothelial progenitors possess this hemogenic potential are currently unknown. Here, we investigated the changes in hemogenic potential in endothelial progenitors at the early stages of embryonic development. Using an ETV2::GFP reporter mouse to isolate emerging endothelial progenitors, we observed a dramatic decrease in hemogenic potential between embryonic day (E)7.5 and E8.5. At the molecular level, Runx1 is expressed at much lower levels in E8.5 intra-embryonic progenitors, while Bmi1 expression is increased. Remarkably, the ectopic expression of Runx1 in these progenitors fully restores their hemogenic potential, as does the suppression of BMI1 function. Altogether, our data demonstrate that hemogenic competency in recently specified endothelial progenitors is restrained through the active silencing of Runx1 expression. PMID- 27239043 TI - A Derived Allosteric Switch Underlies the Evolution of Conditional Cooperativity between HOXA11 and FOXO1. AB - Transcription factors (TFs) play multiple roles in development. Given this multifunctionality, it has been assumed that TFs are evolutionarily highly constrained. Here, we investigate the molecular mechanisms for the origin of a derived functional interaction between two TFs, HOXA11 and FOXO1. We have previously shown that the regulatory role of HOXA11 in mammalian endometrial stromal cells requires interaction with FOXO1, and that the physical interaction between these proteins evolved before their functional cooperativity. Here, we demonstrate that the derived functional cooperativity between HOXA11 and FOXO1 is due to derived allosteric regulation of HOXA11 by FOXO1. This study shows that TF function can evolve through changes affecting the functional output of a pre existing protein complex. PMID- 27239042 TI - Hepatocyte DACH1 Is Increased in Obesity via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance. AB - Defective insulin signaling in hepatocytes is a key factor in type 2 diabetes. In obesity, activation of calcium/calmodulin-dependent protein kinase II (CaMKII) in hepatocytes suppresses ATF6, which triggers a PERK-ATF4-TRB3 pathway that disrupts insulin signaling. Elucidating how CaMKII suppresses ATF6 is therefore essential to understanding this insulin resistance pathway. We show that CaMKII phosphorylates and blocks nuclear translocation of histone deacetylase 4 (HDAC4). As a result, HDAC4-mediated SUMOylation of the corepressor DACH1 is decreased, which protects DACH1 from proteasomal degradation. DACH1, together with nuclear receptor corepressor (NCOR), represses Atf6 transcription, leading to activation of the PERK-TRB3 pathway and defective insulin signaling. DACH1 is increased in the livers of obese mice and humans, and treatment of obese mice with liver targeted constitutively nuclear HDAC4 or DACH1 small hairpin RNA (shRNA) increases ATF6, improves hepatocyte insulin signaling, and protects against hyperglycemia and hyperinsulinemia. Thus, DACH1-mediated corepression in hepatocytes emerges as an important link between obesity and insulin resistance. PMID- 27239045 TI - Differential Binding Partners of the Mis18alpha/beta YIPPEE Domains Regulate Mis18 Complex Recruitment to Centromeres. AB - The Mis18 complex specifies the site of new CENP-A nucleosome assembly by recruiting the CENP-A-specific assembly factor HJURP (Holliday junction recognition protein). The human Mis18 complex consists of Mis18alpha, Mis18beta, and Mis18 binding protein 1 (Mis18BP1/hsKNL2). Although Mis18alpha and Mis18beta are highly homologous proteins, we find that their conserved YIPPEE domains mediate distinct interactions that are essential to link new CENP-A deposition to existing centromeres. We find that Mis18alpha directly interacts with the N terminus of Mis18BP1, whereas Mis18beta directly interacts with CENP-C during G1 phase, revealing that these proteins have evolved to serve distinct functions in centromeres of higher eukaryotes. The N terminus of Mis18BP1, containing both the Mis18alpha and CENP-C binding domains, is necessary and sufficient for centromeric localization. Therefore, the Mis18 complex contains dual CENP-C recognition motifs that are combinatorially required to generate robust centromeric localization that leads to CENP-A deposition. PMID- 27239044 TI - In Silico Modeling of Liver Metabolism in a Human Disease Reveals a Key Enzyme for Histidine and Histamine Homeostasis. AB - Primary hyperoxaluria type I (PH1) is an autosomal-recessive inborn error of liver metabolism caused by alanine:glyoxylate aminotransferase (AGT) deficiency. In silico modeling of liver metabolism in PH1 recapitulated accumulation of known biomarkers as well as alteration of histidine and histamine levels, which we confirmed in vitro, in vivo, and in PH1 patients. AGT-deficient mice showed decreased vascular permeability, a readout of in vivo histamine activity. Histamine reduction is most likely caused by increased catabolism of the histamine precursor histidine, triggered by rerouting of alanine flux from AGT to the glutamic-pyruvate transaminase (GPT, also known as the alanine-transaminase ALT). Alanine administration reduces histamine levels in wild-type mice, while overexpression of GPT in PH1 mice increases plasma histidine, normalizes histamine levels, restores vascular permeability, and decreases urinary oxalate levels. Our work demonstrates that genome-scale metabolic models are clinically relevant and can link genotype to phenotype in metabolic disorders. PMID- 27239046 TI - Pathway to neural resilience: Self-esteem buffers against deleterious effects of poverty on the hippocampus. AB - Human neuroimaging studies have shown that people living in poverty tend to suffer hippocampal atrophy, which leads to impaired memory and learning throughout life. However, behavioral studies demonstrate that poor people with high self-esteem are often exempt from the deleterious effect of poverty and instead possess a happy and successful life. Here we investigated whether high self-esteem can buffer against the deleterious effects of poverty, as indicated by low subjective socioeconomic status (SSS), on the hippocampal gray matter volume (GMV) in a large cohort of young participants (N = 280). As expected, findings revealed that although low (vs. high) SSS was linked with a smaller hippocampal GMV, the deleterious effect of low SSS on hippocampal GMV was alleviated when the participants have high self-esteem. Commonality analyses further confirmed this observation. The current study suggests that positive psychological resources such as self-esteem may provide protection for the hippocampal atrophy in adversity. Hum Brain Mapp 37:3757-3766, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27239047 TI - Whey peptide Isoleucine-Tryptophan inhibits expression and activity of matrix metalloproteinase-2 in rat aorta. AB - Aortic stiffness is an independent risk factor for development of cardiovascular diseases. Activation of renin-angiotensin-aldosterone system (RAAS) including angiotensin converting enzyme (ACE) activity leads to overproduction of angiotensin II (ANGII) from its precursor angiotensin I (ANGI). ANGII leads to overexpression and activation of matrix metalloproteinase-2 (MMP2), which is critically associated with pathophysiology of aortic stiffness. We previously reported that the whey peptide Isoleucine-Tryptophan (IW) acts as a potent ACE inhibitor. Herein, we critically elucidate the mechanism of action by which IW causes inhibition of expression and activity of MMP2 in aortic tissue. Effects of IW on expression and activity of MMP2 were assessed on endothelial and smooth muscle cells (ECs and SMCs) in vitro and ex vivo (isolated rat aorta). As controls we used the pharmaceutical ACE inhibitor - captopril and the ANGII type 1 receptor blocker - losartan. In vitro, both ANGII and ANGI stimulation significantly (P<0.01) increased expression of MMP2 assessed with western blot. Similarly, to captopril IW significantly (P<0.05) inhibited ANGI, but not ANGII mediated increase in expression of MMP2, while losartan also blocked effects of ANGII. Signaling pathways regulating MMP2 expression in ECs and SMCs were similarly inhibited after treatment with IW or captopril. In ECs IW significantly (P<0.05) inhibited JNK pathway, whereas in SMCs JAK2/STAT3 pathway, assessed with western blot. In vitro findings were fully consistent with results in isolated rat aorta ex vivo. Moreover, IW not only inhibited the MMP2 expression, but also its activation assessed with gelatin zymography. Our findings demonstrate that IW effectively inhibits expression and activation of MMP2 in rat aorta by decreasing local conversion of ANGI to ANGII. Thus, similar to pharmaceutical ACE inhibitor captopril the dipeptide IW may effectively inhibit ACE activity and prevent the age and hypertension associated rise of aortic stiffness. PMID- 27239048 TI - Successful management of mixed chimerism after bone marrow transplant in beta thalassemia major. PMID- 27239049 TI - White Matter Tract Injury is Associated with Deep Gray Matter Iron Deposition in Multiple Sclerosis. AB - BACKGROUND AND PURPOSE: With respect to healthy controls (HCs), increased iron concentrations in the deep gray matter (GM) and decreased white matter (WM) integrity are common findings in multiple sclerosis (MS) patients. The association between these features of the disease remains poorly understood. We investigated the relationship between deep iron deposition in the deep GM and WM injury in associated fiber tracts in MS patients. METHODS: Sixty-six MS patients (mean age 50.0 years, median Expanded Disability Status Scale 5.25, mean disease duration 19.1 years) and 29 HCs, group matched for age and sex were imaged on a 1.5T scanner. Susceptibility-weighted imaging and diffusion tensor imaging (DTI) were used for assessing high-pass filtered phase values in the deep GM and normal appearing WM (NAWM) integrity in associated fiber tracts, respectively. Correlation analyses investigated the associations between filtered phase values (suggestive of iron content) and WM damage. RESULTS: Areas indicative of increased iron levels were found in the left and right caudates as well as in the left thalamus. MS patients presented with decreased DTI-derived measures of tissue integrity in the associated WM tracts. Greater mean, axial and radial diffusivities were associated with increased iron levels in all three GM areas (r values .393 to .514 with corresponding P values .003 to <.0001). Global NAWM diffusivity measures were not related to mean filtered phase values within the deep GM. CONCLUSIONS: Increased iron concentration in the deep GM is associated with decreased tissue integrity of the connected WM in MS patients. PMID- 27239050 TI - New method for the fabrication of highly osteoconductive beta-1,3-glucan/HA scaffold for bone tissue engineering: Structural, mechanical, and biological characterization. AB - Recent studies have shown that thermal method for beta-1,3-glucan (curdlan) gelation performed at temperature above 80 degrees C enables fabrication of biocompatible bone scaffolds. The aim of this study was to establish new method for fabrication of beta-1,3-glucan/hydroxyapatite (glu/HA) scaffold using ion exchanging dialysis for curdlan gelation that allows for the modifications of the glu/HA material with thermo-sensitive agents like growth factors or adhesive proteins. Obtained results reveal that fabricated scaffold appears to be highly osteoconductive as it is nontoxic, promotes osteoblast growth and proliferation as well as increases bone alkaline phosphatase level thereby enhancing cell differentiation. It was demonstrated that developed new method for the glu/HA scaffold fabrication allows to obtain material that not only can be modified with thermo-sensitive agents at the stage of production process but also is a promising candidate for bone tissue engineering applications to act as a framework for osteoblasts to spread and form new bone. It should be noted that dialysis method for curdlan gelation has never been used before to fabricate bone scaffold. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2528 2536, 2016. PMID- 27239051 TI - Can synaptophysin be used as a marker of breast cancer diagnosed by core-needle biopsy in epithelial proliferative diseases of the breast? AB - The differential diagnosis of epithelial proliferative disease using core needle biopsy (CNB) is problematic because it is difficult to differentiate between intraductal papilloma, ductal hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma. Many studies have reported that breast cancer lesions are positive for neuroendocrine (NE) markers, whereas only a small number of studies have reported immunopositivity for NE markers in normal mammary tissues or benign lesions. We asked whether NE factors could be used as markers of breast cancer. We determined the immunopositivity rate of synaptophysin, an NE marker, in 204 lesions excised from the breast using CNB in patients who visited a university affiliated comprehensive medical facility and examined whether synaptophysin is a marker of breast cancer. The specimens were classified as synaptophysin-negative cases (56 benign, 99 malignant); equivocal cases (<1 %: 2 benign, 15 malignant); and synaptophysin-positive cases (1 benign, 31 malignant). The sensitivity, specificity, positive predictive value, and negative predictive value for malignancy of the lesions classified as synaptophysin positive were 23.3 %, 98.2 %, 96.9 %, and 36.1 %, respectively. The respective values for lesions classified as equivocal were 11.6 %, 96.6 %, 88.2 %, and 36.1 %. Synaptophysin may provide a marker of breast cancer diagnosed by CNB. PMID- 27239052 TI - Craving cannabis: a meta-analysis of self-report and psychophysiological cue reactivity studies. AB - AIMS: To estimate the magnitude of cannabis cue-reactivity responses in people who regularly use cannabis. METHODS: EMBASE, PUBMED, PsycINFO, PsycEXTRA and Project CORK were searched for within-subject comparison studies published between January 2000 and December 2014. Eligible studies compared regular cannabis users' subjective craving or psychophysiological responding when exposed to cannabis cues to their responses to neutral cues and/or to their responses during a baseline assessment. Eligible studies presented original data and were written in English. Fourteen studies met inclusion criteria, but data were not available for two. The 12 included studies contained 393 participants (12-97 participants per study; mean age range: 16.4-32.6 years). Standardized effects sizes were computed for heart rate, skin conductance, skin temperature, blood pressure, event-related potentials (Pz P300) and self-reported craving (Visual Analogue Scales and Marijuana Craving Questionnaire) and synthesized using a multivariate meta-regression model. RESULTS: On average, cannabis users experienced moderate cue-reactivity, as determined by comparisons with baseline conditions [d = 0.59, 95% confidence interval (CI) = 0.43, 0.74, P < 0.001] and with neutral cue comparisons (d = 0.47, 95% CI = 0.32, 0.62, P < 0.001). This model, which excluded studies at a greater than low risk of bias and included PzP300 studies as a moderator (due to having larger effect sizes), had a moderately low level of heterogeneity of effect size (I2 = 45.6%, Q = 56.97, P = 0.003) and showed no evidence of publication bias. Cue-reactivity was most noticeable (large effect size) when assessed by Pz P300 waves (d = 1.71, 95% CI = 0.77, 2.64, P = 0.0003; I2 = 86%, Q = 36.30, P < 0.001) and least noticeable (trivial effect size) when examining heart rate (d = 0.14, 95% CI = -0.34, 0.62, P = 0.58; I2 = 80%, Q = 20.0, P < 0.001). These subgroup models demonstrated high heterogeneity of effect size. CONCLUSIONS: Regular cannabis users experience moderate to extremely intense cue-reactivity, such that their attentional biases towards cannabis cues are much stronger than their perceptions of craving for the drug. PMID- 27239053 TI - Titanium diffusion in shinbone of rats with osseointegrated implants. AB - Dental implants are composed of commercially pure Ti (which is actually an alloy of titanium, and minor or trace components such as aluminium and vanadium). When the implant is inserted, its surface undergoes a number of chemical and mechanical processes, releasing particles of titanium to the medium. The metabolism of free ions of titanium is uncertain; the uptaking processes in the body are not well known, nor their toxic dose. In addition, physical properties of newly formed bone, such as diffusivity and activation energy, are scarce and rarely studied. In this study, we analysed the diffusion of titanium in the titanium-implanted shinbones of six adult male Wistar rats by spatially resolved micro x-ray fluorescence. The measurements were carried out at the microfluorescence station of the x-ray fluorescence (XRF) beamline of the Brazilian synchrotron facility LNLS (from Portuguese 'Laboratorio Nacional de Luz Sincrotron'). For each sample, XRF spectra were taken by linear scanning in area near the new bone formed around the Ti implant. The scanning line shows a clear effect of titanium diffusion whereas calcium intensity presents a different behaviour. Moreover, a clear correlation among the different structures of bones is observed in the Ti and Ca intensities. The results obtained in these measurements may allow determining quantitatively the parameters of diffusion rates and other physical properties of new bone like diffusion coefficients. PMID- 27239054 TI - Hydrocortisone use in ventilated extremely preterm infants decreased bronchopulmonary dysplasia with no effects on neurodevelopment after two years. AB - AIM: We assessed the outcomes of ventilated extremely premature infants treated with late postnatal corticosteroids from 2005-2008, according to permissive or restrictive policies in two centres. METHODS: This retrospective study included inborn infants below 27 weeks of gestational age who were ventilator dependent after 14 days. Centre P permitted postnatal corticosteroids but centre R restricted their use. The effects on infants were assessed in hospital and after two years using multivariable analysis. RESULTS: We compared 62 infants from centre P, including 92% who received hydrocortisone, and 48 infants from centre R, including 13% who received betamethasone. Infants from both centres had comparable baseline characteristics and perinatal management, but bronchopulmonary dysplasia (BPD) rates were significantly lower in centre P (30% versus 71%, p < 0.001) and this centre was significantly associated with a younger post-conceptional age at oxygen weaning, with an adjusted hazard ratio (aHR) of 0.45 and an aHR of 0.51at discharge. At two years of corrected age, 18% of centre P infants and 30% of centre R infants showed poor neurodevelopmental outcome (p = 0.18). CONCLUSION: Using hydrocortisone after 14 days on ventilated extremely preterm infants was associated with decreased BPD, with no apparent effects on neurodevelopment at two years of corrected age. PMID- 27239055 TI - Editorial Comment to Reconstructive option after radical mutilating surgery in children with genitourinary rhabdomyosarcoma: When sparing the bladder is not an option. PMID- 27239056 TI - Outcomes after discontinuation of routine use of transanastomotic biliary stents in pediatric liver transplantation at a single site. AB - Routine use of transanastomotic biliary stents (RTBS) for biliary reconstruction in liver transplantation (LT) is controversial, with conflicting outcomes in adult randomized trials. Pediatric literature contains limited data. This study is a retrospective review of 99 patients who underwent first LT (2005-2014). In 2011, RTBS was discontinued at our center. This study describes biliary complications following LT with and without RTBS. 56 (56%) patients had RTBS. Median age at LT was 1.9 yr (IQR 0.7, 8.6); 55% were female. Most common indication for LT was biliary atresia (36%). Most common biliary reconstruction was Roux-en-Y choledochojejunostomy (75% with RTBS, 58% without RTBS, p = 0.09). Biliary complications (strictures, bile leaks, surgical revision) occurred in 23% without significant difference between groups (20% with RTBS, 28% without RTBS, p = 0.33). Patients with RTBS had routine cholangiography via the tube at 6-8 wk; thus, significantly more patients with RTBS had cholangiograms (91% vs. 19%, p < 0.0001). There was no difference in the number of patients who required therapeutic intervention via endoscopic or percutaneous transhepatic cholangiography (11% with RTBS, 19% no RTBS, p = 0.26). Routine use of RTBS for biliary reconstruction in pediatric LT may not be necessary, and possibly associated with need for costlier, invasive imaging without improvement in outcomes. PMID- 27239057 TI - Capture and Recycling of Sortase A through Site-Specific Labeling with Lithocholic Acid. AB - Enzyme-mediated protein modification often requires large amounts of biocatalyst, adding significant costs to the process and limiting industrial applications. Herein, we demonstrate a scalable and straightforward strategy for the efficient capture and recycling of enzymes using a small-molecule affinity tag. A proline variant of an evolved sortase A (SrtA 7M) was N-terminally labeled with lithocholic acid (LA)-an inexpensive bile acid that exhibits strong binding to beta-cyclodextrin (betaCD). Capture and recycling of the LA-Pro-SrtA 7M conjugate was achieved using betaCD-modified sepharose resin. The LA-Pro-SrtA 7M conjugate retained full enzymatic activity, even after multiple rounds of recycling. PMID- 27239058 TI - PATENTS AND RESEARCH INVESTMENTS: ASSESSING THE EMPIRICAL EVIDENCE. AB - A well-developed theoretical literature - dating back at least to Nordhaus (1969) - has analyzed optimal patent policy design. We re-present the core trade-off of the Nordhaus model and highlight an empirical question which emerges from the Nordhaus framework as a key input into optimal patent policy design: namely, what is the elasticity of R&D investment with respect to the patent term? We then review the - surprisingly small - body of empirical evidence that has been developed on this question over the nearly half century since the publication of Nordhaus's book. PMID- 27239059 TI - SPECTROSCOPIC AND ELECTROCHEMICAL CHARACTERIZATION OF IRON(II) AND 2,4 DINITROTOLUENE. AB - The objective of this work was the development of reliable methods to determine 2,4-dinitrotoluene, a precursor to explosives. A complex between Fe(II) ion and 2,4-dinitrotoluene was formed in solution and characterized by ultraviolet visible absorption spectroscopy using Job's plots and attenuated total reflection Fourier transform infrared spectroscopy. Surface modification of glassy carbon electrodes were performed with iron nanoparticles via electrochemical reduction of iron(II). The modified electrode was employed for the determination of 2,4 dinitrotoluene. Scanning electron micrographs showed that the iron nanoparticles were incorporated on the surface of glassy carbon electrode. The electrochemical determination of 2,4-dinitrotoluene was performed by cyclic voltammetry using the modified electrode. The iron modified electrode produced larger reduction currents than the unmodified electrode for the same concentration of 2,4 dinitrotoluene. Concentrations of 2,4-dinitrotoluene as low as 10 parts per billion were determined using the modified electrode. PMID- 27239060 TI - Significance of Ovarian Function Suppression in Endocrine Therapy for Breast Cancer in Pre-Menopausal Women. AB - Ovarian function suppression (OFS) for treating breast cancer in pre-menopausal women was introduced for the first time in the late 19th century as bilateral oophorectomy. It was not until the 1960s that the oestrogen receptor was identified and a test for detecting endocrine sensitivity of the breast cancer was developed. A weakness of early trials on OFS for breast cancer treatment is therefore their failure to take receptor sensitivity into account when selecting participants. A meta-analysis performed in the early 1990s first proved that adjuvant OFS significantly improved the cure rate of oestrogen receptor-positive breast cancer in pre-menopausal women regardless of whether it was carried out through oophorectomy, radiation-induced ablation or drug therapy. In the 1970s, tamoxifen was synthesized. It became one of the most important cancer drugs and today constitutes the gold standard for endocrine adjuvant therapy. Taking tamoxifen for a five-year period lowers mortality by 30 % over 15 years. Ten years of tamoxifen therapy reduces mortality even further, with increased side effects, however. Research over the past ten years has proven that for post menopausal women, aromatase inhibitors have benefits over tamoxifen. Current trial results have rekindled the debate about the combination of OFS with tamoxifen or with aromatase inhibitors for adjuvant breast cancer treatment of pre-menopausal women. These trials have reported an improvement in disease-free survival in patients with a high risk of recurrence when they are treated with a combination of OFS plus tamoxifen or aromatase inhibitors, especially in women younger than 35. However, combination therapy causes significantly more side effects, which could negatively impact compliance. Endocrine treatments administered over a period of many years show waning compliance, which tends to be only around 50 % after five years. Inadequate compliance compromises efficacy and increases the risk of mortality. For this reason, when indicating and supporting endocrine adjuvant therapy, physicians must ensure that compliance will be good. To prevent recurrence in the long run, it is much more effective to prescribe a somewhat less effective therapy that will actually be carried out than to prescribe one that is theoretically more effective, but is not adhered to consistently. PMID- 27239061 TI - Metronomic Chemotherapy for Metastatic Breast Cancer - a Systematic Review of the Literature. AB - Conventional chemotherapy is generally administered in high doses followed by a treatment-free period to give the body needful time to recover. This "maximum tolerated dose" approach results in high response rates. However, long periods between therapy cycles can lead to development of resistance mechanisms and consequently disease progression. One of the most interesting alternative strategies is metronomic chemotherapy. This concept relies on the continuous administration of chemotherapy at low doses and aims at targeting endothelial cells in the tumor bed as well. Recently, metronomic chemotherapy has been incorporated into the recommendations issued by the German AGO expert panel (www.ago-online.de). A systematic review of PubMed/Medline, ClinicalTrials.gov, the European Clinical Trials Database (EudraCT) and the Cochrane Database was conducted. In the present review, we discuss the current evidence on metronomic chemotherapy in metastatic breast cancer. PMID- 27239062 TI - Willingness of Patients with Breast Cancer in the Adjuvant and Metastatic Setting to Use Electronic Surveys (ePRO) Depends on Sociodemographic Factors, Health related Quality of Life, Disease Status and Computer Skills. AB - Introduction: Because of the often unfavorable prognosis, particularly for patients with metastases, health-related quality of life is extremely important for breast cancer patients. In recent years, data on patient-relevant endpoints is being increasingly collected electronically; however, knowledge on the acceptance and practicability of, and barriers to, this form of data collection remains limited. Material and Methods: A questionnaire was completed by 96 patients to determine to what extent existing computer skills, disease status, health-related quality of life and sociodemographic factors affect patients' potential willingness to use electronics methods of data collection (ePRO). Results: 52 of 96 (55 %) patients reported a priori that they could envisage using ePRO. Patients who a priori preferred a paper-based survey (pPRO) tended to be older (ePRO 53 years vs. pPRO 62 years; p = 0.0014) and typically had lower levels of education (p = 0.0002), were in poorer health (p = 0.0327) and had fewer computer skills (p = 0.0003). Conclusion: Barriers to the prospective use of ePRO were identified in older patients and patients with a lower quality of life. Given the appropriate conditions with regard to age, education and current health status, opportunities to participate should be provided to encourage patients' willingness to take part and ensure the validity of survey results. Focusing on ease of use of ePRO applications and making applications more patient oriented and straightforward appears to be the way forward. PMID- 27239063 TI - Toxicity Assessment of a Phase III Study Evaluating FEC-Doc and FEC-Doc Combined with Gemcitabine as an Adjuvant Treatment for High-Risk Early Breast Cancer: the SUCCESS-A Trial. AB - Introduction: This paper aims to evaluate the toxicity profile of additive gemcitabine to adjuvant taxane-based chemotherapy in breast cancer patients. Methods: Patients enrolled in this open-label randomized controlled Phase III study were treated with 3 cycles of epirubicin-fluorouracil-cyclophosphamide (FEC) chemotherapy followed by 3 cycles of docetaxel with those receiving 3 cycles of FEC followed by 3 cycles of gemcitabine-docetaxel (FEC-DG). 3690 patients were evaluated according to National Cancer Institute (NCI) toxicity criteria (CTCAE). The study medications were assessed by the occurrence of grade 3-4 adverse events, dose reductions, postponements of treatment cycles and granulocyte colony-stimulating factor (G-CSF) support. Results: No differences in neutropenia or febrile neutropenia were demonstrated. However, thrombocytopenia was significantly increased with FEC-DG treatment (2.0 vs. 0.5 %, p < 0.001), as was leukopenia (64.1 vs. 58.5 %, p < 0.001). With FEC-DG significantly more G-CSF support in cycles 4 to 6 (FEC-DG: 57.8 %, FEC-D: 36.3 %, p < 0.001) was provided. Transaminase elevation was significantly more common with FEC-DG (SGPT: 6.3 %, SGOT: 2 %), whereas neuropathy (1.2 %), arthralgia (1.6 %) and bone pain (2.6 %) were more common using FEC-D. Dose reductions > 20 % (4 vs. 2.4 %) and postponement of treatment cycles (0.9 vs. 0.4 %) were significantly more frequent in the FEC-DG arm. Eight deaths occurred during treatment in the FEC-DG arm and four in the FEC-D arm. Conclusion: The addition of gemcitabine increased hematological toxicity and was associated with more dose reductions and postponements of treatment cycles. PMID- 27239064 TI - Targets for Neoadjuvant Therapy - The Preferences of Patients with Early Breast Cancer. AB - Background: Therapists and administrative bodies consider a pathological complete remission as an independent and relevant endpoint in evaluations of the clinical utility of neoadjuvant therapy for early breast cancer. The present study aims to investigate which treatment outcomes of a neoadjuvant therapy are considered by the patients themselves to be relevant. Materials and Methods: With the help of analytic hierarchy process (AHP) methods patient preferences about the treatment targets of neoadjuvant therapy were assessed quantitatively. All participants had undergone a neoadjuvant therapy in the form of chemotherapy and, in HER2-positive cases, as a targeted antibody therapy against HER2 for the primary diagnosis of early breast cancer 12-36 months prior to the interview. The criteria for the hierarchy model were identified in an earlier qualitative survey. The patient interviews were conducted by 4 experienced female interviewers. Results: Forty one patients participated in the quantitative survey, of these 15 (36.6 %) had suffered from HER2-positive disease. The achievement of pCR was the most important therapeutic target for the patients, even before disease-free survival, overall survival and the option for breast-preserving operation. Avoidance of side effects was considered to be the least important. In a comparison of the side effects the patients judged fatigue to be most important before nausea and loss of hair. Conclusion: For the patients the achievement of a pathological complete remission is considered to be an independent, relevant and highly desired target of neoadjuvant therapy. PMID- 27239065 TI - Follow-up Reality for Breast Cancer Patients - Standardised Survey of Patients and Physicians and Analysis of Treatment Data. AB - Introduction: Currently, about 360 000 breast cancer patients who could, after completion of their primary therapy, take advantage of follow-up options are living in Germany. Up to now very little is known about the extent to which the available options are used and as to how the follow-up reality is experienced and evaluated. Thus, an explorative examination among the patients and their physicians was undertaken. Patients and Methods: All patients who underwent surgery in a certified breast centre between 2007 and 2013 received a standardised questionnaire; at the same time the physicians responsible for the follow-up were invited to answer a standardised questionnaire. Results: 920 patients (response rate: 61 %) with a median age of 65 years (32-95) could be analysed. 99 % of the participants stated that they regularly attended follow ups. The personal contact with the physician (mean value: 4.4) and the reassurance that the cancer disease had not recurred (mean value: 4.5) were described on a scale of 0 to 5 to be two of the most important factors of the follow-up. Deficits were expressed with regard to psychosocial care (70 %) and the perception and treatment of physical complaints (55 %). In addition, 105 physicians returned completed questionnaires (response rate: 12 %). For asymptomatic patients the physicians performed the following examinations most frequently: anamnesis (92 %), physical examination (87 %) as well as laboratory tests (63 %) and tumour marker determinations (40 %). Conclusion: On the whole it became clear that the vast majority of the patients took advantage of the follow up options. From the patient's perspective the importance of the follow-up lies in contact to the physician and the comforting assurance that the breast cancer has not relapsed. Deficits are seen in the psychosocial care and the perception and treatment of physical impairments. Not recommended examinations were employed by a significant proportion of the surveyed physicians. PMID- 27239066 TI - Senology in Gynaecology Specialist Training: a Baseline Survey from 2014. AB - Introduction: Qualified training in senology is essential for maintaining adequate, high quality patient care. In order to meet the needs of doctors in training and those of the medical infrastructure it is necessary to assess the quality of training regularly, to enable its adaption and optimisation. Methods: We developed a comprehensive, 10 item online questionnaire to assess the quality of specialised training in senology. This questionnaire was sent to 4000 speciality trainees and young specialists countrywide via the DGGG newsletter and was accessible for over four weeks. Results: 111 obstetrics and gynaecology speciality trainees participated in this national survey, 79 % of whom were female. 33 % of participants were working at university hospitals, 29 % at hospitals offering maximal level care without an associated medical faculty, 37 % at hospitals offering primary and secondary level care and 2 % at gynaecology practices. 25 % of participants could imagine working in the field of senology in future. On average the current perception of general specialist training was satisfactory. Specialist trainees at university hospitals rated training in senology highest (score: 2.95) compared to those at other hospitals. A fixed rotation through a breast centre offering comprehensive advanced training was seen as a potential improvement to senology training. Conclusions: This is the first survey of specialised training in senology to be conducted in Germany. Results showed that there is significant potential for young doctors to enter the speciality in future. There are also significant differences in the perceived quality of senology training between training facilities. This survey aimed to determine the quality of specialised training at senology centres and hopes to contribute to a sustainable improvement in training. The intention is to continue to make senology attractive to gynaecologists and to ensure well-grounded training. PMID- 27239067 TI - Vitamin D and Mammographic Findings. AB - Introduction: Pleiotropic immune-modulatory and anti-proliferative effects of vitamin D and hopes to stop cancerogenesis have led to an increased interest in possible reduction of breast cancer with higher vitamin D levels. Mammographic density is an established risk factor for breast cancer risk, and its association with serum vitamin D is complex, as recent studies have shown. Patients and Methods: In this cross-sectional study, 1103 participants were recruited in the breast diagnostic unit of the Klinikum rechts der Isar, TU Munich. A standardised questionnaire and blood samples for 25-OH-vitamin D were taken on the day of mammography. Histologic results of biopsies in suspicious mammographies were documented. Results: In the 1090 data-sets analysed, vitamin D-deficiency was common among women under 40. Highest vitamin D values were observed in participants aged 60-69 years, but average values for all age cohorts were below 20 ng/ml of vitamin D. 15.6 % of all participants had very low vitamin D values (< 10 ng/ml), 51.3 % were vitamin D-deficient (10-19 ng/ml) and only 5.7 % were above 30 ng/ml, i.e. showed sufficient vitamin D. Patients with malignant results had vitamin D < 10 ng/ml more often (16.9 %; p = 0.61), and only 3.4 % in this group had sufficient vitamin D supply (> 30 ng/ml). There were no significant differences in vitamin D-levels between density groups according to the American College of Radiology (ACR) criteria. Conclusion: Vitamin D values were lower than in comparable US women. Up to now, there is no direct clinical evidence for a relationship between the risk for breast cancer and a specific vitamin D value. PMID- 27239068 TI - A Case of Choroidal Melanoma Metastatic to the Breast. AB - A 61-year-old woman developed blurred vision in her left eye in December 2006. A clinical diagnosis of choroidal melanoma was made. The patient underwent excision of the left lens, followed by vitrectomy and stereotactic radiotherapy. She remained systemically healthy until 50 months later when, during a CT scan done for staging purposes, a newly visible lump was noted in the lower quadrant of her left breast. Core needle biopsy of the lesion in the left breast was performed, and histologic examination revealed metastasis from the choroidal melanoma. The patient underwent breast-conserving surgery of the left breast. Definitive histological examination showed clear tumor margins in the resected specimen and one sentinel lymph node without evidence of metastatic cells. Twenty-nine months after surgery, a similar nodule was detected in the upper quadrant of the left breast. Core biopsy again showed metastatic melanoma, and similar breast conserving surgery was performed. Systemic examination, including magnetic resonance imaging of the head and computed tomography of the pelvis, abdomen, and chest, was done regularly and revealed no significant findings. Solitary breast metastases from choroidal melanoma are extremely rare. Nevertheless, clinicians should be aware of this rare form of metastasis when treating patients with suspicious breast lesions and a history of choroidal melanoma. If solitary metastasis is confirmed, then breast-conserving surgery may be recommended. PMID- 27239069 TI - Postmortem Presence of Drugs and Method of Violent Suicide. AB - The link between substance use and suicide is well established. However, little research analyzes how substance use is related to the method of suicide. This paper analyzes how specific drugs are associated with method of suicide, a critical topic because drug use bears on the etiology of suicide and may lead to policies aimed at deterring suicide. We use the COVDRS and logistic regression to examine postmortem presence of drugs among 3,389 hanging and firearm suicides in Colorado from 2004-2009. Net of demographic controls, we find that opiates are positively associated with firearms (OR: 1.92, 95% L: 1.27, 95% U: 2.86]) while antidepressants are positively associated with hanging (OR: 1.45, 95% L: 1.04, 95% U: 2.03). For cocaine and opiates, the association between drug use and violent method vary by educational attainment. Importantly, knowledge of the presence and type of specific drug is strongly associated with the method of suicide. PMID- 27239070 TI - Microwave Rotational Spectral Study of SO2-CO. AB - The microwave spectrum of the molecular complex of sulfur dioxide (SO2) with carbon monoxide (CO) has been studied with a pulsed-beam Fourier Transform Microwave Spectrometer (FTMW) from a pair of gas samples of 1 % by volume of SO2 and CO in Ar, and introduced via separate capillary inputs to the flow nozzle. The frequency coverage was about 7 GHz to 16 GHz for various isotopomers. The molecular structure was determined with the aid of spectral studies of isotopically substituted monomers containing 13C, 18O and 34S. The rotational analyses provide the rotational and centrifugal distortion constants for all of the isotopomers analyzed. The structure determination is compared to detailed ab initio structural calculations. The electric dipole moment components along the a and c-axis were determined from Stark effect measurements. PMID- 27239072 TI - Preservational bias controls the fossil record of pterosaurs. AB - Pterosaurs, a Mesozoic group of flying archosaurs, have become a focal point for debates pertaining to the impact of sampling biases on our reading of the fossil record, as well as the utility of sampling proxies in palaeodiversity reconstructions. The completeness of the pterosaur fossil specimens themselves potentially provides additional information that is not captured in existing sampling proxies, and might shed new light on the group's evolutionary history. Here we assess the quality of the pterosaur fossil record via a character completeness metric based on the number of phylogenetic characters that can be scored for all known skeletons of 172 valid species, with averaged completeness values calculated for each geological stage. The fossil record of pterosaurs is observed to be strongly influenced by the occurrence and distribution of Lagerstatten. Peaks in completeness correlate with Lagerstatten deposits, and a recovered correlation between completeness and observed diversity is rendered non significant when Lagerstatten species are excluded. Intervals previously regarded as potential extinction events are shown to lack Lagerstatten and exhibit low completeness values: as such, the apparent low diversity in these intervals might be at least partly the result of poor fossil record quality. A positive correlation between temporal patterns in completeness of Cretaceous pterosaurs and birds further demonstrates the prominent role that Lagerstatten deposits have on the preservation of smaller bodied organisms, contrasting with a lack of correlation with the completeness of large-bodied sauropodomorphs. However, we unexpectedly find a strong correlation between sauropodomorph and pterosaur completeness within the Triassic-Jurassic, but not the Cretaceous, potentially relating to a shared shift in environmental preference and thus preservation style through time. This study highlights the importance of understanding the relationship between various taphonomic controls when correcting for sampling bias, and provides additional evidence for the prominent role of sampling on observed patterns in pterosaur macroevolution. PMID- 27239071 TI - Electrochemical lectin based biosensors as a label-free tool in glycomics. AB - Glycans and other saccharide moieties attached to proteins and lipids, or present on the surface of a cell, are actively involved in numerous physiological or pathological processes. Their structural flexibility (that is based on the formation of various kinds of linkages between saccharides) is making glycans superb "identity cards". In fact, glycans can form more "words" or "codes" (i.e., unique sequences) from the same number of "letters" (building blocks) than DNA or proteins. Glycans are physicochemically similar and it is not a trivial task to identify their sequence, or - even more challenging - to link a given glycan to a particular physiological or pathological process. Lectins can recognise differences in glycan compositions even in their bound state and therefore are most useful tools in the task to decipher the "glycocode". Thus, lectin-based biosensors working in a label-free mode can effectively complement the current weaponry of analytical tools in glycomics. This review gives an introduction into the area of glycomics and then focuses on the design, analytical performance, and practical utility of lectin-based electrochemical label-free biosensors for the detection of isolated glycoproteins or intact cells. PMID- 27239073 TI - Modelling the type and timing of consecutive events: application to predicting preterm birth in repeated pregnancies. AB - Predicting the occurrence and timing of adverse pregnancy events such as preterm birth is an important analytical challenge in obstetrical practice. Developing statistical approaches that can be used to assess the risk and timing of these adverse events will provide clinicians with tools for individualized risk assessment that account for a woman's prior pregnancy history. Often adverse pregnancy outcomes are subject to competing events; for example, interest may focus on the occurrence of pre-eclampsia-related preterm birth, where preterm birth for other reasons may serve as a competing event. We propose modelling the type and timing of adverse outcomes in repeated pregnancies. We formulate a joint model, where types of adverse outcomes across repeated pregnancies are modelled by using a polychotomous logistic regression model with random effects, and gestational ages at delivery are modelled conditionally on the types of adverse outcome. The correlation between gestational ages conditional on the adverse pregnancies is modelled by the semiparametric normal copula function. We present a two-stage estimation method and develop the asymptotic theory for the estimators proposed. The model and estimation procedure proposed are applied to the National Institute of Child Health and Human Development consecutive pregnancies study data and evaluated by simulations. PMID- 27239074 TI - The Haselgebirge evaporitic melange in central Northern Calcareous Alps (Austria): Part of the Permian to Lower Triassic rift of the Meliata ocean? AB - For the reconstruction of Alpine tectonics of the Eastern Alps, the evaporitic Permian to Lower Triassic Haselgebirge Formation plays a key role in (1) the origin of Haselgebirge bearing nappes, (2) the inclusion of magmatic and metamorphic rocks revealing tectonic processes not preserved in other units, and (3) the debated mode of emplacement of the nappes, namely gravity-driven or tectonic. Within the Moosegg quarry of the central Northern Calcareous Alps gypsum/anhydrite bodies are tectonically mixed with lenses of sedimentary rocks and decimeter- to meter-sized tectonic clasts of plutonic and subvolcanic rocks and rare metamorphics. We examined various types of (1) widespread biotite diorite, meta-syenite, (2) meta-dolerite and rare ultramafic rocks (serpentinite, pyroxenite) as well as (3) rare metamorphic banded meta-psammitic schists and meta-doleritic blueschists. The apparent 40Ar/39Ar biotite ages from three biotite-diorite, meta-dolerite and meta-doleritic blueschist samples with variable composition and fabrics range from 248 to 270 Ma (e.g., 251.2 +/- 1.1 Ma) indicating a Permian age of cooling after magma crystallisation or metamorphism. The chemical composition of biotite-diorite and meta-syenite indicates an alkaline trend interpreted to represent a rift-related magmatic suite. These, as well as Permian to Jurassic sedimentary rocks, were incorporated during Cretaceous nappe emplacement forming the sulphatic Haselgebirge melange. The scattered 40Ar/39Ar white mica ages of a meta-doleritic blueschist (of N-MORB origin) and banded meta-psammitic schist are ca. 349 and 378 Ma, respectively, proving the Variscan age of pressure-dominated metamorphism. These ages are similar to detrital white mica ages reported from the underlying Rossfeld Formations, indicating a close source-sink relationship. According to our new data, the Haselgebirge bearing nappe was transported over the Lower Cretaceous Rossfeld Formations, which include many clasts derived from the Haselgebirge Formation and its exotic blocks deposited in front of the incoming nappe comprising the Haselgebirge Formation. PMID- 27239076 TI - Paternal Incarceration and Adolescent Well-Being: Life Course Contingencies and Other Moderators. AB - Parental incarceration has been found to be associated with a wide range of negative outcomes in both childhood and adolescence. This Article uses data from the National Longitudinal Study of Adolescent Health (Add Health) to focus on the conditions under which associations of paternal incarceration with adolescent delinquency and depression are strongest. Paternal incarceration is most consistently and positively associated with adolescent delinquency. Associations of paternal incarceration with adolescent depression are weaker and more contingent on gender and other moderating factors. One important moderator is the respondent's retrospective reports that he or she was physically or sexually abused by a parent or other adult caregiver during childhood. For example, in the absence of sexual abuse, paternal incarceration is associated with higher depression among girls. When coupled with reports of sexual abuse, in contrast, paternal incarceration is not associated with girls' depression, suggesting a potential protective effect. The child having ever coresided with his or her father is also found to moderate associations, with paternal incarceration most strongly associated with delinquency and depression among girls who had ever coresided with their fathers. Examination of the duration and timing of paternal incarceration also pointed to gender differences. PMID- 27239075 TI - Hedgehog Signaling Components Are Expressed in Choroidal Neovascularization in Laser-induced Retinal Lesion. AB - Choroidal neovascularization is one of the major pathological changes in age related macular degeneration, which causes devastating blindness in the elderly population. The molecular mechanism of choroidal neovascularization has been under extensive investigation, but is still an open question. We focused on sonic hedgehog signaling, which is implicated in angiogenesis in various organs. Laser induced injuries to the mouse retina were made to cause choroidal neovascularization. We examined gene expression of sonic hedgehog, its receptors (patched1, smoothened, cell adhesion molecule down-regulated by oncogenes (Cdon) and biregional Cdon-binding protein (Boc)) and downstream transcription factors (Gli1-3) using real-time RT-PCR. At seven days after injury, mRNAs for Patched1 and Gli1 were upregulated in response to injury, but displayed no upregulation in control retinas. Immunohistochemistry revealed that Patched1 and Gli1 proteins were localized to CD31-positive endothelial cells that cluster between the wounded retina and the pigment epithelium layer. Treatment with the hedgehog signaling inhibitor cyclopamine did not significantly decrease the size of the neovascularization areas, but the hedgehog agonist purmorphamine made the areas significantly larger than those in untreated retina. These results suggest that the hedgehog-signaling cascade may be a therapeutic target for age-related macular degeneration. PMID- 27239077 TI - Is the promotion of research reflected in bibliometric data? A network analysis of highly cited papers on the Clusters of Excellence supported under the Excellence Initiative in Germany. AB - Under the Excellence Initiative, a number of Clusters of Excellence in Germany have been supported since 2006 and 2007-including each a limited number of cooperating institutions. The aim of the present study is to investigate whether support for Clusters of Excellence since 2006 and 2007 is reflected in bibliometric network data. For this purpose, a comparison is made between network data in the period before support started (2003-2005) and in the period after support started (2009-2011). For these two periods, a co-authorship network is generated (based on the funded institutions). This is based on publications which are among the 1 % most frequently cited publications in their respective fields and publication year and which have at least one author from Germany. As the results show, the outcomes this yields for life sciences and natural sciences differ from each other. Whereas natural sciences display an effect of establishment of Clusters of Excellence on the bibliometric networks, this was not true of life sciences. After establishment of the Clusters of Excellence, the network in natural sciences not only contained more institutions of a Cluster of Excellence, but these institutions were distributed across fewer bibliometric clusters in the network than before establishment. In other words the structure of the Clusters of Excellence was better reflected in the network. PMID- 27239078 TI - Influence of international co-authorship on the research citation impact of young universities. AB - We investigated the effect of international collaboration (in the form of international co-authorship) on the impact of publications of young universities (<50 years old), and compared to that of renowned old universities (>100 years old). The following impact indicators are used in this study, they are: (1) the 5 year citations per paper (CPP) data, (2) the international co-authorship rate, (3) the CPP differential between publications with and without international co authorships, and (4) the difference between the percentage of international co authored publications falling in the global top 10 % highly cited publications and the percentage of overall publications falling in the global top 10 % highly cited publications (Delta%Top10%). The increment of 5-year (2010-2014) field weighted citation impact (FWCI) of internationally co-authored papers over the 5 year overall FWCI of the institutions in SciVal(r) is used as another indicator to eliminate the effect of discipline difference in citation rate. The results show that, for most top institutions, the difference between the citations per paper (CPP) for their publications with and without international co-authorship is positive, with increase of up to 5.0 citations per paper over the period 1996 2003. Yet, for some Asian institutions, by attracting a lot of researchers with international background and making these collaborating "external" authors as internal researchers, these institutions have created a special kind of international collaboration that are not expressed in co-authorship, and the CPP gaps between publications with and without international co-authorship are relatively small (around 0-1 citations per paper increment) for these institutions. The top old institutions have higher CPP than young institutions, and higher annual research expenditures; while young universities have a higher relative CPP increment for the current 5-year period over the previous 5-year period. The Delta%Top10% for international co-authored publications is generally higher than that for all journal publications of the same institution. With the increase of international co-authorship ratio, the mean geographical collaboration distance (MGCD, an indication of increased international co authorship) of one institution based on the Leiden Ranking data also increases, and young institutions have relatively higher CPP increment over MGCD increment. International co-authorship has a positive contribution to the FWCI of the institution, yet there are untapped potential to enhance the collaboration among young institutions. PMID- 27239079 TI - How to normalize Twitter counts? A first attempt based on journals in the Twitter Index. AB - One possible way of measuring the broad impact of research (societal impact) quantitatively is the use of alternative metrics (altmetrics). An important source of altmetrics is Twitter, which is a popular microblogging service. In bibliometrics, it is standard to normalize citations for cross-field comparisons. This study deals with the normalization of Twitter counts (TC). The problem with Twitter data is that many papers receive zero tweets or only one tweet. In order to restrict the impact analysis on only those journals producing a considerable Twitter impact, we defined the Twitter Index (TI) containing journals with at least 80 % of the papers with at least 1 tweet each. For all papers in each TI journal, we calculated normalized Twitter percentiles (TP) which range from 0 (no impact) to 100 (highest impact). Thus, the highest impact accounts for the paper with the most tweets compared to the other papers in the journal. TP are proposed to be used for cross-field comparisons. We studied the field-independency of TP in comparison with TC. The results point out that the TP can validly be used particularly in biomedical and health sciences, life and earth sciences, mathematics and computer science, as well as physical sciences and engineering. In a first application of TP, we calculated percentiles for countries. The results show that Denmark, Finland, and Norway are the countries with the most tweeted papers (measured by TP). PMID- 27239080 TI - An analysis of bibliometric indicators to JCR according to Benford's law. AB - Journal Citation Reports (JCR) is the main source of bibliometric indicators known by the scientific community. This paper presents the results of a study of the distributions of the first and second significant digits according to Benford's law (BL) of the number of articles, citations, impact factors, half life and immediacy index bibliometric indicators in journals indexed in the JCR Sciences and Social Sciences Editions from 2007 to 2014. We also performed the data analysis to country's origin and by journal's category, and we verified that the second digit has a better adherence to BL. The use of the second digit is important since it provides a more sound, complete and consistent analysis of the bibliometric indicators. PMID- 27239081 TI - Difficulties with Emotion Regulation and Psychopathology Interact to Predict Early Smoking Cessation Lapse. AB - There is little knowledge about how emotion regulation difficulties interplay with psychopathology in terms of smoking cessation. Participants (n = 250; 53.2 % female, Mage = 39.5, SD = 13.85) were community-recruited daily smokers (>=8 cigarettes per day) who self-reported motivation to quit smoking; 38.8 % of the sample met criteria for a current (past 12-month) psychological disorder. Emotion regulation deficits were assessed pre-quit using the Difficulties with Emotion Regulation Scale (DERS; Gratz and Roemer in J Psychopathol Behav Assess 26(1):41 54, 2004) and smoking behavior in the 28 days post-quit was assessed using the Timeline Follow-Back (TLFB; Sobell and Sobell in Measuring alcohol consumption: psychosocial and biochemical methods. Humana Press, Totowa, 1992). A Cox proportional-hazard regression analysis was used to model the effects of past year psychopathology, DERS (total score), and their interaction, in terms of time to lapse post-quit day. After adjusting for the effects of gender, age, pre-quit level of nicotine dependence, and treatment condition, the model revealed a non significant effect of past-year psychopathology (OR = 1.14, CI95 % = 0.82-1.61) and difficulties with emotion regulation (OR = 1.01, CI95 % = 1.00-1.01) on likelihood of lapse rate. However, the interactive effect of psychopathology status and difficulties with emotion regulation was significant (OR = 0.98, CI95 % = 0.97-0.99). Specifically, there was a significant conditional effect of psychopathology status on lapse rate likelihood at low, but not high, levels of emotion regulation difficulties. Plots of the cumulative survival functions indicated that for smokers without a past-year psychological disorder, those with lower DERS scores relative to elevated DERS scores had significantly lower likelihood of early smoking lapse, whereas for smokers with past-year psychopathology, DERS scores did not differentially impact lapse rate likelihood. Smokers with emotion regulation difficulties may have challenges quitting, and not having such difficulties, especially without psychopathology, decreases the potential likelihood of early lapse. PMID- 27239082 TI - Molecular characterization of Pseudo-nitzschia community structure and species ecology in a hydrographically complex estuarine system (Puget Sound, Washington, USA). AB - Species within the toxic marine diatom genus Pseudo-nitzschia coexist in coastal and estuarine waters globally and are difficult to distinguish by microscopy. Here, we describe a sensitive, high throughput PCR-based Automated Ribosomal Intergenic Spacer Analysis (ARISA) approach to determine the relative abundance of Pseudo-nitzschia species within natural communities over space and time. The method was quantitatively validated using simplified mixtures of DNA or ITS1 standards from isolates of P. pungens, P. multiseries, and P. delicatissima. Relative abundance calculations based on ARISA profiles from these mixtures reflected input ratios, with minor deviations resulting from intraspecific variability. ARISA was used to identify and quantify at least eight species within Puget Sound and the eastern Strait of Juan de Fuca, Washington, USA: P. americana, P. australis/P. seriata, P. cuspidata, P. delicatissima, P. fraudulenta, P. fryxelliana, P. multiseries, and P. pungens; genotypes corresponding to P. pungens var. pungens and P. pungens var. cingulata were identified by environmental sequencing. The different species were significantly correlated with physical (temperature, salinity), biological (chlorophyll a fluorescence, oxygen), and/or chemical (ammonium, nutrient ratios) factors. The ability to determine shifts in the relative abundance of Pseudo-nitzschia species over spatial and temporal scales relevant to dispersion and selection facilitates dissection of the varied mechanisms driving vertical and horizontal species distribution patterns in hydrographically complex systems. PMID- 27239083 TI - Early Cretaceous araucarian driftwood from hemipelagic sediments of the Puez area, South Tyrol, Italy. AB - We describe a calcareously permineralised fossil tree-trunk, preserved as driftwood, within hemipelagic sediments of the Cretaceous Puez Formation near Wolkenstein, South Tyrol, Italy. Planktic foraminiferal assemblages recovered from the marls containing the fossil wood indicate a latest middle Albian age. Based on its wood anatomy, the trunk is assigned to Agathoxylon and probably has an affinity with the conifer family Araucariaceae. The wood lacks pronounced tree rings consistent with tree growth within the broad humid tropical belt that existed at that time. The trunk contains cylindrical chambers filled within faecal pellets, demonstrating that oribatid mites infested the tree, either during life, or shortly after death. Prior to final burial, the tree-trunk drifted out into the open sea for a considerable period as indicated by extensive borings assigned to the ichnospecies Teredolites longissimus and produced by teredinid bivalves. Relatively little is known about the Cretaceous floras of Italy, so this new finding fills a gap in our knowledge of the composition and ecology of the vegetation of this region. PMID- 27239084 TI - Super-resolution Reconstruction for Tongue MR Images. AB - Magnetic resonance (MR) images of the tongue have been used in both clinical medicine and scientific research to reveal tongue structure and motion. In order to see different features of the tongue and its relation to the vocal tract it is beneficial to acquire three orthogonal image stacks-e.g., axial, sagittal and coronal volumes. In order to maintain both low noise and high visual detail, each set of images is typically acquired with in-plane resolution that is much better than the through-plane resolution. As a result, any one data set, by itself, is not ideal for automatic volumetric analyses such as segmentation and registration or even for visualization when oblique slices are required. This paper presents a method of super-resolution reconstruction of the tongue that generates an isotropic image volume using the three orthogonal image stacks. The method uses preprocessing steps that include intensity matching and registration and a data combination approach carried out by Markov random field optimization. The performance of the proposed method was demonstrated on five clinical datasets, yielding superior results when compared with conventional reconstruction methods. PMID- 27239085 TI - Extremely sensitive dual imaging system in solid phantoms. AB - Herein we describe promising results from the combination of fluorescent lifetime imaging microscopy (FLIM) and diffusion reflection (DR) medical imaging techniques. Three different geometries of gold nanoparticles (GNPs) were prepared: spheres of 20nm diameter, rods (GNRs) of aspect ratio (AR) 2.5, and GNRs of AR 3.3. Each GNP geometry was then conjugated using PEG linkers estimated to be 10nm in length to each of 3 different fluorescent dyes: Fluorescein, Rhodamine B, and Sulforhodamine B. DR provided deep-volume measurements (up to 1cm) from within solid, tissue-imitating phantoms, indicating GNR presence corresponding to the light used by recording light scattered from the GNPs with increasing distance to a photodetector. FLIM imaged solutions as well as phantom surfaces, recording both the fluorescence lifetimes as well as the fluorescence intensities. Fluorescence quenching was observed for Fluorescein, while metal enhanced fluorescence (MEF) was observed in Rhodamine B and Sulforhodamine B - the dyes with an absorption peak at a slightly longer wavelength than the GNP plasmon resonance peak. Our system is highly sensitive due to the increased intensity provided by MEF, and also because of the inherent sensitivity of both FLIM and DR. Together, these two modalities and MEF can provide a lot of meaningful information for molecular and functional imaging of biological samples. PMID- 27239086 TI - Predicting detection performance with model observers: Fourier domain or spatial domain? AB - The use of Fourier domain model observer is challenged by iterative reconstruction (IR), because IR algorithms are nonlinear and IR images have noise texture different from that of FBP. A modified Fourier domain model observer, which incorporates nonlinear noise and resolution properties, has been proposed for IR and needs to be validated with human detection performance. On the other hand, the spatial domain model observer is theoretically applicable to IR, but more computationally intensive than the Fourier domain method. The purpose of this study is to compare the modified Fourier domain model observer to the spatial domain model observer with both FBP and IR images, using human detection performance as the gold standard. A phantom with inserts of various low contrast levels and sizes was repeatedly scanned 100 times on a third-generation, dual source CT scanner at 5 dose levels and reconstructed using FBP and IR algorithms. The human detection performance of the inserts was measured via a 2-alternative forced-choice (2AFC) test. In addition, two model observer performances were calculated, including a Fourier domain non-prewhitening model observer and a spatial domain channelized Hotelling observer. The performance of these two mode observers was compared in terms of how well they correlated with human observer performance. Our results demonstrated that the spatial domain model observer correlated well with human observers across various dose levels, object contrast levels, and object sizes. The Fourier domain observer correlated well with human observers using FBP images, but overestimated the detection performance using IR images. PMID- 27239087 TI - An Open Library of CT Patient Projection Data. AB - Lack of access to projection data from patient CT scans is a major limitation for development and validation of new reconstruction algorithms. To meet this critical need, we are building a library of CT patient projection data in an open and vendor-neutral format, DICOM-CT-PD, which is an extended DICOM format that contains sinogram data, acquisition geometry, patient information, and pathology identification. The library consists of scans of various types, including head scans, chest scans, abdomen scans, electrocardiogram (ECG)-gated scans, and dual energy scans. For each scan, three types of data are provided, including DICOM-CT PD projection data at various dose levels, reconstructed CT images, and a free form text file. Several instructional documents are provided to help the users extract information from DICOM-CT-PD files, including a dictionary file for the DICOM-CT-PD format, a DICOM-CT-PD reader, and a user manual. Radiologist detection performance based on the reconstructed CT images is also provided. So far 328 head cases, 228 chest cases, and 228 abdomen cases have been collected for potential inclusion. The final library will include a selection of 50 head, chest, and abdomen scans each from at least two different manufacturers, and a few ECG-gated scans and dual-source, dual-energy scans. It will be freely available to academic researchers, and is expected to greatly facilitate the development and validation of CT reconstruction algorithms. PMID- 27239088 TI - CYC1 Predicts Poor Prognosis in Patients with Breast Cancer. AB - Cytochrome c-1 (CYC1) is an important subunit of mitochondrial complex III. However, its role in tumor progression is unclear. We found that CYC1 was upregulated in breast tumor tissues, especially in tissues with lymph node metastasis. And higher expression of CYC1 correlates with poor prognosis in breast cancer patients using online databases and tools. Then we confirmed that CYC1 contributed to metastasis and proliferation in two highly metastatic human breast cancer cell lines. Digging into the biological function of CYC1, we found the activity of mitochondrial complex III decreased due to silencing CYC1. Then the ratio of AMP to ATP increased and AMPK was activated. Analyzing units of other mitochondrial complexes, we did not find knockdown of CYC1 expression reduced expression of any other unit of OXPHOS. We concluded that CYC1 promoted tumor metastasis via suppressing activation of AMPK and contributed to tumor growth via facilitating production of ATP. Our results indicated that CYC1 plays crucial roles in breast cancer progression and might be a predictive factor assisting future patient diagnosis. PMID- 27239090 TI - Fitting Cox Models with Doubly Censored Data Using Spline-Based Sieve Marginal Likelihood. AB - In some applications, the failure time of interest is the time from an originating event to a failure event, while both event times are interval censored. We propose fitting Cox proportional hazards models to this type of data using a spline-based sieve maximum marginal likelihood, where the time to the originating event is integrated out in the empirical likelihood function of the failure time of interest. This greatly reduces the complexity of the objective function compared with the fully semiparametric likelihood. The dependence of the time of interest on time to the originating event is induced by including the latter as a covariate in the proportional hazards model for the failure time of interest. The use of splines results in a higher rate of convergence of the estimator of the baseline hazard function compared with the usual nonparametric estimator. The computation of the estimator is facilitated by a multiple imputation approach. Asymptotic theory is established and a simulation study is conducted to assess its finite sample performance. It is also applied to analyzing a real data set on AIDS incubation time. PMID- 27239089 TI - TP53 Mutations and Survival in Osteosarcoma Patients: A Meta-Analysis of Published Data. AB - Several research groups have examined the association between TP53 mutations and prognosis in human osteosarcoma. However, the results were controversial. The purpose of this study was to evaluate the prognostic value of TP53 mutations in osteosarcoma patients. A meta-analysis was conducted with all eligible studies which quantitatively evaluated the relationship between TP53 mutations and clinical outcome of osteosarcoma patients. Eight studies with a total of 210 patients with osteosarcoma were included in this meta-analysis. The risk ratio (RR) with a 95% confidence interval (95% CI) was calculated to assess the effect of TP53 mutations on 2-year overall survival. The quantitative synthesis of 8 published studies showed that TP53 mutations were associated with 2-year overall survival in osteosarcoma patients. These data suggested that TP53 mutations had an unfavorable impact on 2-year overall survival when compared to the counterparts with wild type (WT) TP53 (RR: 1.79; 95% CI: 1.12 to 2.84; P = 0.01; I (2) = 0%). There was no between-study heterogeneity. TP53 mutations are an effective prognostic marker for survival of patients with osteosarcoma. However, further large-scale prospective trials should be performed to clarify the prognostic value of TP53 mutations on 3- or 5-year survival in osteosarcoma patients. PMID- 27239092 TI - Assessing Quality of Life Dimensions in Deteriorated Inner Areas: A case from Javadieh Neighborhood in Tehran Metropolis. AB - Quality of life is a noticeable concept in urban deteriorated areas where people suffer from multidimensional and complex problems. According to Tehran Renovation Organization (TRO), a deteriorated area is defined just by three physical indicators of fine grain, lack of permeability and lack of durability. But deteriorated areas suffer from other physical as well as socio economic problems which need to be considered in planning processes. Consequently, assessing the QOL in deteriorated inner areas is the main purpose of this paper to survey the overall life satisfaction, to extract main and different aspects of QOL and to determine the extent that overall life satisfaction is explained by different components of life. Javadieh neighbourhood, located in Tehran metropolis, one of the most deteriorated neighbourhoods in the city has been chosen as a case for this study. Forty nine indicators which cover different dimensions of quality of life have been selected through literature review. Multi-stage sampling technique for sampling has been applied. In first stage by application of Cochran sampling method, the required sample size has been determined. Then by use of systematic sampling method, questionnaires have been distributed among the residents of the neighbourhood. After data collection, a confirmatory factors analysis indentified 11 factors as identical components of QOL. A stepwise regression is performed to investigate the overall life satisfaction and the extent that QOL is determined by identified domains. Results show that traffic, mobility, housing and infrastructure are the most important aspects of QOL which affect the overall life satisfaction of the residents of the surveyed deteriorated neighbourhood. Also a negative relationship was found between overall satisfaction and private life. The findings of the study also show that the three physical indicators used by the TRO for identifying the deteriorated areas are not adequate to address the deterioration issues. Other physical and socio economic aspects which are incorporated with different QOL dimensions also affect the overall life satisfaction, which have to be addressed in planning and policy making to upgrade quality of life for people in deteriorated neighbourhoods. PMID- 27239091 TI - The Social Consequences of Poverty: An Empirical Test on Longitudinal Data. AB - Poverty is commonly defined as a lack of economic resources that has negative social consequences, but surprisingly little is known about the importance of economic hardship for social outcomes. This article offers an empirical investigation into this issue. We apply panel data methods on longitudinal data from the Swedish Level-of-Living Survey 2000 and 2010 (n = 3089) to study whether poverty affects four social outcomes-close social relations (social support), other social relations (friends and relatives), political participation, and activity in organizations. We also compare these effects across five different poverty indicators. Our main conclusion is that poverty in general has negative effects on social life. It has more harmful effects for relations with friends and relatives than for social support; and more for political participation than organizational activity. The poverty indicator that shows the greatest impact is material deprivation (lack of cash margin), while the most prevalent poverty indicators-absolute income poverty, and especially relative income poverty-appear to have the least effect on social outcomes. PMID- 27239093 TI - Family and Friends: Which Types of Personal Relationships Go Together in a Network? AB - We examine the link between family and personal networks. Using arguments about meeting opportunities, competition and social influence, we hypothesise how the presence of specific types of family members (i.e., a partner, children, parents and siblings) and non-family members (i.e., friends, neighbours and colleagues) in the network mutually affect one another. In addition, we propose that-beyond their mere presence-the active role of family members in the network strongly affects the presence of non-family members in the network. Data from the third wave of the Survey on the Social Networks of the Dutch, collected in 2012 and 2013, show that active involvement is of key importance; more than merely having family members present in one's personal network, the active involvement of specific types of family members in the personal network is associated with having disproportionally more other family members and having somewhat fewer non family members in the network. PMID- 27239094 TI - The Relationship Between Employment Equity Perceptions and Psychological Ownership in a South African Mining House: The Role of Ethnicity. AB - Psychological ownership is a cognitive-affective construct based on individuals' feelings of possessiveness towards and of being psychologically tied/attached to objects that are material (e.g. tools or work) and immaterial (e.g. ideas or workspace) in nature. Research suggests that psychological ownership could be influenced by various individual, organisational and contextual factors. The South African Employment Equity Act, which was implemented to grant equitable opportunities to previously disadvantaged employees, could be a significant contextual factor affecting psychological ownership, due to perceptions associated with inequality. Ethnicity may also act as a moderator for the relationship between perceptions of employment equity and psychological ownership. The objective of this study was to investigate the relationship between employment equity perceptions and psychological ownership and to explore whether ethnicity plays a moderating role in the relationship. A cross-sectional survey design was employed with a purposeful sample of 202 respondents employed in a large South African mining house. Pearson product-moment correlations and structural equation modelling confirmed that employment equity perceptions could predict the five components of psychological ownership. However, the results revealed that ethnicity has no moderating effect on the relationship between perceptions of employment equity and the emergence of psychological ownership. By implication, organisations that seek to retain employees targeted through equity initiatives need to find ways to enhance and develop the psychological ownership of these employees. The research contributes new insights into and knowledge of how contextual factors could influence employees' psychological ownership. PMID- 27239095 TI - LOGIC ANALYSIS: TESTING PROGRAM THEORY TO BETTER EVALUATE COMPLEX INTERVENTIONS. AB - Evaluating complex interventions requires an understanding of the program's logic of action. Logic analysis, a specific type of program theory evaluation based on scientific knowledge, can help identify either the critical conditions for achieving desired outcomes or alternative interventions for that purpose. In this article, we outline the principles of logic analysis and its roots. We then illustrate its use with an actual evaluation case. Finally, we discuss the advantages of conducting logic analysis prior to other types of evaluations. This article will provide evaluators with both theoretical and practical information to help them in conceptualizing their evaluations. PMID- 27239096 TI - Development and Validation of a Brief Version of the Difficulties in Emotion Regulation Scale: The DERS-16. AB - The Difficulties in Emotion Regulation Scale (DERS) is a widely-used, theoretically-driven, and psychometrically-sound self-report measure of emotion regulation difficulties. However, at 36-items, the DERS may be challenging to administer in some situations or settings (e.g., in the course of patient care or large-scale epidemiological studies). Consequently, there is a need a briefer version of the DERS. The goal of the present studies was to develop and evaluate a 16-item version of the DERS - the DERS-16. The reliability and validity of the DERS-16 were examined in a clinical sample (N = 96) and two large community samples (Ns = 102 and 482). The validity of the DERS-16 was evaluated comparing the relative strength of the association of the two versions of the DERS with measures of emotion regulation and related constructs, psychopathology, and clinically-relevant behaviors theorized to stem from emotion regulation deficits. Results demonstrate that the DERS-16 has retained excellent internal consistency, good test-retest reliability, and good convergent and discriminant validity. Further, the DERS-16 showed minimal differences in its convergent and discriminant validity with relevant measures when compared to the original DERS. In conclusion, the DERS-16 offers a valid and brief method for the assessment of overall emotion regulation difficulties. PMID- 27239097 TI - Repair of dentin defects from DSPP knockout mice by PILP mineralization. AB - Dentinogenesis imperfecta type II (DGI-II) lacks intrafibrillar mineral with severe compromise of dentin mechanical properties. A Dspp knockout (Dspp-/-) mouse, with a phenotype similar to that of human DGI-II, was used to determine if poly-L-aspartic acid [poly(ASP)] in the "polymer-induced liquid-precursor" (PILP) system can restore its mechanical properties. Dentin from six-week old Dspp-/- and wild-type mice was treated with CaP solution containing poly(ASP) for up to 14 days. Elastic modulus and hardness before and after treatment were correlated with mineralization from Micro x-ray computed tomography (Micro-XCT). Transmission electron microscopy (TEM)/Selected area electron diffraction (SAED) were used to compare matrix mineralization and crystallography. Mechanical properties of the Dspp-/- dentin were significantly less than wild-type dentin and recovered significantly (P < 0.05) after PILP-treatment, reaching values comparable to wild-type dentin. Micro-XCT showed mineral recovery similar to wild type dentin after PILP-treatment. TEM/SAED showed repair of patchy mineralization and complete mineralization of defective dentin. This approach may lead to new strategies for hard tissue repair. PMID- 27239098 TI - Danger zone: Men, masculinity and occupational health and safety in high risk occupations. AB - The workplace is a key setting where gender issues and organizational structures may influence occupational health and safety practices. The enactment of dominant norms of masculinity in high risk occupations can be particularly problematic, as it exposes men to significant risks for injuries and fatalities. To encourage multi-disciplinary collaborations and advance knowledge in the intersecting areas of gender studies, men's health, work and workplace health and safety, a national network of thirteen researchers and health and safety stakeholders completed a critical literature review examining the intersection between masculinities and men's workplace health and safety in order to: (i) account for research previously undertaken in this area; (ii) identify themes that may inform our understanding of masculinity and workplace health and safety and; (iii) identify research and practice gaps in relation to men's workplace health and safety. In this paper we present key themes from this review. Recommendations are made regarding: (i) how to define gender; (ii) how to attend to and identify how masculinities may influence workers' identities, perceptions of occupational risks and how institutionalized practices can reinforce norms of masculinity; (iii) the importance of considering how masculinities may intersect with other variables (e.g. historical context, age, class, race, geographical location) and; (iv) the added significance of present-day labour market forces on men's occupational health and safety. PMID- 27239099 TI - Dragon's blood secretion and its ecological significance. AB - Dragon's blood is the name given to a red exudate produced by some plant species belonging to the genera Daemonorops, Dracaena, Croton and Pterocarpus. These are endemic to various parts of the globe. It is classified as a resin or latex depending on its mode of secretion and its chemical composition, which is species specific. This red substance functions in defence and is produced (a) constitutively and stored in preformed anatomical structures, or (b) by induction in response to traumatic events, such as mechanical injury, pathogen attack or invasion by insects. Apart from its defensive role in plants, dragon's blood is also a valuable natural resource renowned since antiquity for its diverse medicinal properties and uses in art. Despite the great importance of dragon's blood, our knowledge of the biological basis for its secretion is still incomplete. This review summarizes recent advances in the study of the anatomical basis for its secretion, and discusses its classification and ecological function. Bringing some clarity to these issues may also help in the commercial sourcing of dragon's blood. PMID- 27239100 TI - Administration of Myelin Basic Protein Peptides Encapsulated in Mannosylated Liposomes Normalizes Level of Serum TNF-alpha and IL-2 and Chemoattractants CCL2 and CCL4 in Multiple Sclerosis Patients. AB - We have previously shown that immunodominant MBP peptides encapsulated in mannosylated liposomes (Xemys) effectively suppressed experimental allergic encephalomyelitis (EAE). Within the frames of the successfully completed phase I clinical trial, we investigated changes in the serum cytokine profile after Xemys administration in MS patients. We observed a statistically significant decrease of MCP-1/CCL2, MIP-1beta/CCL4, IL-7, and IL-2 at the time of study completion. In contrast, the serum levels of TNF-alpha were remarkably elevated. Our data suggest that the administration of Xemys leads to a normalization of cytokine status in MS patients to values commonly reported for healthy subjects. These data are an important contribution for the upcoming Xemys clinical trials. PMID- 27239101 TI - Inverse Relationship of the CMKLR1 Relative Expression and Chemerin Serum Levels in Obesity with Dysmetabolic Phenotype and Insulin Resistance. AB - BACKGROUND: In obesity there is a subclinical chronic low-grade inflammatory response where insulin resistance (IR) may develop. Chemerin is secreted in white adipose tissue and promotes low-grade inflammatory process, where it expressed CMKLR1 receptor. The role of chemerin and CMKLR1 in inflammatory process secondary to obesity is not defined yet. METHODS: Cross-sectional study with 134 individuals classified as with and without obesity by body mass index (BMI) and IR. Body fat storage measurements and metabolic and inflammatory markers were measured by routine methods. Soluble chemerin and basal levels of insulin by ELISA and relative expression of CMKLR1 were evaluated with qPCR and 2( DeltaDeltaCT) method. RESULTS: Differences (P < 0.05) were observed between obesity and lean individuals in body fat storage measurements and metabolic inflammatory markers. Both CMKLR1 expression and chemerin levels were increased in obesity without IR. Soluble chemerin levels correlate with adiposity and metabolic markers (r = 8.8% to 38.5%), P < 0.05. CONCLUSION: The increment of CMKLR1 expression was associated with insulin production. Increased serum levels of chemerin in obesity were observed, favoring a dysmetabolic response. The results observed in this study suggest that both chemerin and CMKLR1 have opposite expression in the context of low-grade inflammatory response manifested in the development of IR. PMID- 27239102 TI - A Pathophysiological Insight into Sepsis and Its Correlation with Postmortem Diagnosis. AB - BACKGROUND: Sepsis is among the leading causes of death worldwide and is the focus of a great deal of attention from policymakers and caregivers. However, sepsis poses significant challenges from a clinical point of view regarding its early detection and the best organization of sepsis care. Furthermore, we do not yet have reliable tools for measuring the incidence of sepsis. Methods based on analyses of insurance claims are unreliable, and postmortem diagnosis is still challenging since autopsy findings are often nonspecific. AIM: The objective of this review is to assess the state of our knowledge of the molecular and biohumoral mechanisms of sepsis and to correlate them with our postmortem diagnosis ability. CONCLUSION: The diagnosis of sepsis-related deaths is an illustrative example of the reciprocal value of autopsy both for clinicians and for pathologists. A complete methodological approach, integrating clinical data by means of autopsy and histological and laboratory findings aiming to identify and demonstrate the host response to infectious insults, is mandatory to illuminate the exact cause of death. This would help clinicians to compare pre- and postmortem findings and to reliably measure the incidence of sepsis. PMID- 27239103 TI - Effects of Acute Endurance Exercise on Plasma Protein Profiles of Endurance Trained and Untrained Individuals over Time. AB - Acute physical exercise and repeated exercise stimuli affect whole-body metabolic and immunologic homeostasis. The aim of this study was to determine plasma protein profiles of trained (EET, n = 19) and untrained (SED, n = 17) individuals at rest and in response to an acute bout of endurance exercise. Participants completed a bicycle exercise test at an intensity corresponding to 80% of their VO2max. Plasma samples were taken before, directly after, and three hours after exercise and analyzed using multiplex immunoassays. Seventy-eight plasma variables were included in the final analysis. Twenty-nine variables displayed significant acute exercise effects in both groups. Seven proteins differed between groups, without being affected by acute exercise. Among these A2Macro and IL-5 were higher in EET individuals while leptin showed elevated levels in SED individuals. Fifteen variables revealed group and time differences with elevated levels for IL-3, IL-7, IL-10, and TNFR2 in EET individuals. An interaction effect could be observed for nine variables including IL-6, MMP-2, MMP-3, and muscle damage markers. The proteins that differ between groups indicate a long-term exercise effect on plasma protein concentrations. These findings might be of importance in the development of exercise-based strategies in the prevention and therapy of chronic metabolic and inflammatory diseases and for training monitoring. PMID- 27239104 TI - Neuropilin-1highCD4+CD25+ Regulatory T Cells Exhibit Primary Negative Immunoregulation in Sepsis. AB - Regulatory T cells (Tregs) appear to be involved in sepsis-induced immune dysfunction; neuropilin-1 (Nrp-1) was identified as a surface marker for CD4(+)CD25(+)Tregs. In the current study, we investigated the negative immunoregulation of Nrp-1(high)CD4(+)CD25(+)Tregs and the potential therapeutic value of Nrp-1 in sepsis. Splenic CD4(+)CD25(+)Tregs from cecal ligation and puncture (CLP) mouse models were further segregated into Nrp-1(high)Tregs and Nrp 1(low)Tregs; they were cocultured with CD4(+)CD25(-) T cells. The expression of forkhead/winged helix transcription factor-3 (Foxp-3), cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), membrane associated transforming growth factor beta (TGF-beta(m+)), apoptotic rate, and secretive ability [including TGF-beta and interleukin-10 (IL-10)] for various types of Tregs, as well as the immunosuppressive ability of Tregs on CD4(+)CD25(-) T cells, were determined. Meanwhile, the impact of recombinant Nrp-1 polyclonal antibody on the demethylation of Foxp-3-TSDR (Treg-specific demethylated region) was measured in in vitro study. Sepsis per se markedly promoted the expression of Nrp-1 of CD4(+)CD25(+)Tregs. Foxp-3/CTLA-4/TGF-beta(m+) of Nrp-1(high)Tregs were upregulated by septic challenge. Nrp-1(high)Tregs showed strong resilience to apoptosis and secretive ability and the strongest immunosuppressive ability on CD4(+)CD25(-) T cells. In the presence of lipopolysaccharide (LPS), the recombinant Nrp-1 polyclonal antibody reduced the demethylation of Foxp-3-TSDR. Nrp-1(high)Tregs might reveal primary negative immunoregulation in sepsis; Nrp-1 could represent a new potential therapeutic target for the study of immune regulation in sepsis. PMID- 27239105 TI - When a liver transplant recipient goes back to alcohol abuse: Should we be more selective? AB - Alcoholic liver disease (ALD) is one of the most common indications for liver transplantation (LT). However, it has always remained as a complicated topic from both medical and ethical grounds, as it is seen for many a "self-inflicted disease". Over the years, the survival rate of transplanted patients has significantly improved. The allocation system and the inclusion criteria for LT has also undergone some modifications. Early LT for acute alcoholic hepatitis has been subject to recent clinical studies with encouraging results in highly selected patients. We have learned from studies the importance of a multidisciplinary evaluation of candidates for LT. Complete abstinence should be attempted to overcome addiction issues and to allow spontaneous liver recovery. Risk factors for relapse include the presence of anxiety or depressive disorder, short duration of sobriety pre-LT and lack of social support. The identification of risk factors and the strengthen of social support system may decrease relapse among these patients. Family counseling of candidates is highly encouraged to prevent relapse to alcohol. Relapse has been associated with different histopathological changes, graft damage, graft loss and even decrease in survival among some studies. Therefore, each patient should be carefully selected and priority is to continue to lean on patients with high probability of success. The ethical issue remains as to the patient returning to drinking after the LT, hindering the way for other patients who could have received the same organ. PMID- 27239107 TI - Hydradenitis suppurativa and inflammatory bowel disease: An unusual, but existing association. AB - Inflammatory bowel disease (IBD) could be associated with several extra intestinal manifestations (EIMs) involving musculoskeletal, hepatopancreatobiliary, ocular, renal, and pulmonary systems, as well as the skin. In the last years, hidradenitis suppurativa (HS) is acquiring an increasing interest. IBD, especially Crohn's disease (CD), is among the most reported associated diseases in HS patients. The aim of this paper is to give a brief overview of data showing a possible epidemiologic and pathogenetic association between IBD and HS. We performed a pooled-data analysis of four studies and pooled prevalence of HS in IBD patients was 12.8%, with a 95%CI of 11.7%-13.9%. HS was present in 17.3% of subjects with CD (95%CI: 15.5%-19.1%) and in 8.5% of UC patients (95%CI: 7.0%-9.9%). Some items, especially altered immune imbalance, are generally involved in IBD pathogenesis as well as invoked by HS. Smoking is one of the most relevant risk factors for both disorders, representing a predictor of their severity, despite, actually, there being a lack of studies analyzing a possible shared pathway. A role for inheritance in HS and CD pathogenesis has been supposed. Despite a genetic susceptibility having been demonstrated for both diseases, further studies are needed to investigate a genetic mutual route. Although the pathogenesis of IBD and HS is generally linked to alterations of the immune response, recent findings suggest a role for intestinal and skin microbiota, respectively. In detail, the frequent finding of Staphylococcus aureus and coagulase-negative staphylococci on HS cutaneous lesions suggests a bacterial involvement in disease pathogenesis. Moreover, microflora varies in the different cutaneous regions of the body and, consequently, two different profiles of HS patients have been identified on these bases. On the other hand, it is well-known that intestinal microbiota may be considered as "the explosive mixture" at the origin of IBD despite the exact relationship having not been completely clarified yet. A better comprehension of the role that some bacterial species play in the IBD pathogenesis may be essential to develop appropriate management strategies in the near future. A final point is represented by some similarities in the therapeutic management of HS and IBD, since they may be controlled by immunomodulatory drugs. In conclusion, an unregulated inflammation may cause the lesions typical of both HS and IBD, particularly when they coexist. However, this is still a largely unexplored field. PMID- 27239106 TI - Inflammatory bowel disease and cancer: The role of inflammation, immunosuppression, and cancer treatment. AB - In patients with inflammatory bowel disease (IBD), chronic inflammation is a major risk factor for the development of gastrointestinal malignancies. The pathogenesis of colitis-associated cancer is distinct from sporadic colorectal carcinoma and the critical molecular mechanisms underlying this process have yet to be elucidated. Patients with IBD have also been shown to be at increased risk of developing extra-intestinal malignancies. Medical therapies that diminish the mucosal inflammatory response represent the foundation of treatment in IBD, and recent evidence supports their introduction earlier in the disease course. However, therapies that alter the immune system, often used for long durations, may also promote carcinogenesis. As the population of patients with IBD grows older, with longer duration of chronic inflammation and longer exposure to immunosuppression, there is an increasing risk of cancer development. Many of these patients will require cancer treatment, including chemotherapy, radiation, hormonal therapy, and surgery. Many patients will require further treatment for their IBD. This review seeks to explore the characteristics and risks of cancer in patients with IBD, and to evaluate the limited data on patients with IBD and cancer, including management of IBD after a diagnosis of cancer, the effects of cancer treatment on IBD, and the effect of IBD and medications for IBD on cancer outcomes. PMID- 27239108 TI - Current and emerging therapies in unresectable and recurrent gastric cancer. AB - Gastric cancer is one of the most lethal cancers worldwide despite many advances and options in therapy. As it is often diagnosed at an advanced stage, prognosis is poor with a median overall survival of less than twelve months. Chemotherapy remains the mainstay of treatment for these patients but it confers only a moderate survival advantage. There remains a need for new targeted treatment options and a way to better define patient populations who will benefit from these agents. In the past few years, there has been a better understanding of the biology, molecular profiling, and heterogeneity of gastric cancer. Our increased knowledge has led to the identification of gastric cancer subtypes and to the development of new targeted therapeutic agents. There are now two new targeted agents, trastuzumab and ramucirumab, that have recently been approved for the treatment of advanced and metastatic gastric cancer. There are also many other actively investigated targets, including epidermal growth factor receptor, the phosphatadylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway, c-Met, poly ADP-ribose polymerase, and immune checkpoint inhibition. In this review, we discuss the current management of advanced gastric cancer as well as emerging targeted therapies and immunotherapy. PMID- 27239109 TI - Multiplex qPCR for serodetection and serotyping of hepatitis viruses: A brief review. AB - The present review describes the current status of multiplex quantitative real time polymerase chain reaction (qPCR) assays developed and used globally for detection and subtyping of hepatitis viruses in body fluids. Several studies have reported the use of multiplex qPCR for the detection of hepatitis viruses, including hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), and hepatitis E virus (HEV). In addition, multiplex qPCR has also been developed for genotyping HBV, HCV, and HEV subtypes. Although a single step multiplex qPCR assay for all six hepatitis viruses, i.e., A to G viruses, is not yet reported, it may be available in the near future as the technologies continue to advance. All studies use a conserved region of the viral genome as the basis of amplification and hydrolysis probes as the preferred chemistries for improved detection. Based on a standard plot prepared using varying concentrations of template and the observed threshold cycle value, it is possible to determine the linear dynamic range and to calculate an exact copy number of virus in the specimen. Advantages of multiplex qPCR assay over singleplex or other molecular techniques in samples from patients with co infection include fast results, low cost, and a single step investigation process. PMID- 27239111 TI - Immunological changes in different patient populations with chronic hepatitis C virus infection. AB - AIM: To investigate killer inhibitory and activating receptor expression by natural killer (NK), natural killer T-like (NKT-like) and CD8+ T lymphocytes in patients with chronic hepatitis C virus (HCV) infection with elevated and with persistently normal alanine aminotransferase (PNALT). METHODS: The percentage of peripheral blood Treg cells, KIR2DL3, ILT-2, KIR3DL1, CD160, NKG2D, NKG2C expressing NK, T and NKT-like cells, cytokine production and NK cytotoxicity were determined by flow cytometry. Twenty-one patients with chronic HCV infection with elevated alanine aminotransferase, 11 HCV carriers with persistently normal alanine aminotransferase and 15 healthy volunteers were enrolled. RESULTS: No significant differences were observed in the percentage of total T, NK or NKT like cells between study groups. Comparing the activating and inhibitory receptor expression by NK cells obtained from HCV carriers with PNALT and chronic HCV hepatitis patients with elevated alanine aminotransferase, NKG2D activating receptor expression was the only receptor showing a significant difference. NKG2D expression of NK cells was significantly lower in patients with elevated alanine aminotransferase. The expression of CD160, NKG2D and NKG2C activating receptor by CD8+ T cells were significantly lower in patients with chronic HCV hepatitis than in healthy controls and in HCV carriers with PNALT. Plasma TGF-beta1 levels inversely correlated with NKG2D expression by NK cells. In vitroTGF-beta1 treatment inhibited NK cells cytotoxic activity and downregulated NKG2D expression. CD8+ T cells from HCV carriers with PNALT showed significantly elevated expression of CD160, NKG2D and NKG2C activating receptors compared to chronic HCV patients with elevated alanine aminotransferase. Enhanced expression of inhibitory KIR2DL3 receptor, and decreased ILT-2 expression on NK cells were also found in chronic hepatitis C patients compared to healthy controls. CONCLUSION: Our study demonstrated a complex dysregulation of activating and inhibitory receptor expression, such as decreased NKG2D and CD160 activating receptor expression and increased KIR2DL3 inhibitory receptor expression by NK and cytotoxic T cells and may provide further mechanism contributing to defective cellular immune functions in chronic hepatitis C. Increased NKG2D receptor expression in HCV patients with persistently normal ALT suggests an important pathway for sustaining NK and CD8 T cell function and a protective role against disease progression. PMID- 27239112 TI - Gastric emptying, postprandial blood pressure, glycaemia and splanchnic flow in Parkinson's disease. AB - AIM: To determine gastric emptying, blood pressure, mesenteric artery blood flow, and blood glucose responses to oral glucose in Parkinson's disease. METHODS: Twenty-one subjects (13 M, 8 F; age 64.2 +/- 1.6 years) with mild to moderate Parkinson's disease (Hoehn and Yahr score 1.4 +/- 0.1, duration of known disease 6.3 +/- 0.9 years) consumed a 75 g glucose drink, labelled with 20 MBq (99m)Tc calcium phytate. Gastric emptying was quantified with scintigraphy, blood pressure and heart rate with an automated device, superior mesenteric artery blood flow by Doppler ultrasonography and blood glucose by glucometer for 180 min. Autonomic nerve function was evaluated with cardiovascular reflex tests and upper gastrointestinal symptoms by questionnaire. RESULTS: The mean gastric half emptying time was 106 +/- 9.1 min, gastric emptying was abnormally delayed in 3 subjects (14%). Systolic and diastolic blood pressure fell (P < 0.001) and mesenteric blood flow and blood glucose (P < 0.001 for both) increased, following the drink. Three subjects (14%) had definite autonomic neuropathy and 8 (38%) had postprandial hypotension. There were no significant relationships between changes in blood pressure, heart rate or mesenteric artery blood flow with gastric emptying. Gastric emptying was related to the score for autonomic nerve function (R = 0.55, P < 0.01). There was an inverse relationship between the blood glucose at t = 30 min (R = -0.52, P < 0.05), while the blood glucose at t = 180 min was related directly (R = 0.49, P < 0.05), with gastric emptying. CONCLUSION: In mild to moderate Parkinson's disease, gastric emptying is related to autonomic dysfunction and a determinant of the glycaemic response to oral glucose. PMID- 27239110 TI - Advanced imaging techniques in the therapeutic response of transarterial chemoembolization for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the major causes of morbidity and mortality in patients with chronic liver disease. Transarterial chemoembolization (TACE) can significantly improve the survival rate of patients with HCC and is the first treatment choice for patients who are not suitable for surgical resections. The evaluation of the response to TACE treatment affects not only the assessment of the therapy efficacy but also the development of the next step in the treatment plan. The use of imaging to examine changes in tumor volume to assess the response of solid tumors to treatment has been controversial. In recent years, the emergence of new imaging technology has made it possible to observe the response of tumors to treatment prior to any morphological changes. In this article, the advances in studies reporting the use of computed tomography perfusion imaging, diffusion-weighted magnetic resonance imaging (MRI), intravoxel incoherent motion, diffusion kurtosis imaging, magnetic resonance spectroscopy, magnetic resonance perfusion-weighted imaging, blood oxygen level dependent MRI, positron emission tomography (PET)/computed tomography and PET/MRI to assess the TACE treatment response are reviewed. PMID- 27239113 TI - Wortmannin influences hypoxia-inducible factor-1 alpha expression and glycolysis in esophageal carcinoma cells. AB - AIM: To investigate the influence of phosphatidylinositol-3-kinase protein kinase B (PI3K/AKT)-HIF-1alpha signaling pathway on glycolysis in esophageal carcinoma cells under hypoxia. METHODS: Esophageal carcinoma cell lines Eca109 and TE13 were cultured under hypoxia environment, and the protein, mRNA and activity levels of hypoxia inducible factor-1 alpha (HIF-1alpha), glucose transporter 1, hexokinase-II, phosphofructokinase 2 and lactate dehydrogenase-A were determined. Supernatant lactic acid concentrations were also detected. The PI3K/AKT signaling pathway was then inhibited with wortmannin, and the effects of hypoxia on the expression or activities of HIF-1alpha, associated glycolytic enzymes and lactic acid concentrations were observed. Esophageal carcinoma cells were then transfected with interference plasmid with HIF-1alpha-targeting siRNA to assess impact of the high expression of HIF-1alpha on glycolysis. RESULTS: HIF-1alpha is highly expressed in the esophageal carcinoma cell lines tested, and with decreasing levels of oxygen, the expression of HIF-1alpha and the associated glycolytic enzymes and the extracellular lactic acid concentration were enhanced in the esophageal carcinoma cell lines Eca109 and TE13. In both normoxia and hypoxic conditions, the level of glycolytic enzymes and the secretion of lactic acid were both reduced by wortmannin. The expression and activities of glycolytic enzymes and the lactic acid concentration in cells were reduced by inhibiting HIF 1alpha, especially the decreasing level of glycolysis was significant under hypoxic conditions. CONCLUSION: The PI3K/AKT pathway and HIF-1alpha are both involved in the process of glycolysis in esophageal cancer cells. PMID- 27239114 TI - miR-29a up-regulation in AR42J cells contributes to apoptosis via targeting TNFRSF1A gene. AB - AIM: To investigate the expression of miR-29a in rat acute pancreatitis and its functional role in AR42J cell apoptosis. METHODS: Twelve SD rats were divided into a control group and an acute edematous pancreatitis (AEP) group randomly. AEP was induced by intraperitoneal injection of L-arginine (150 mg/kg) in the AEP group and equal volume of 0.9% NaCl was injected in the control group. The apoptosis of acinar cells in pancreatic tissue was determined by TUNEL assay. miRNA chip assay was performed to examine the expression of miRNAs in two groups. Besides, to further explore the role of miR-29a in apoptosis in vitro, recombinant rat TNF-alpha (50 ng/mL) was administered to treat the rat pancreatic acinar cell line AR42J for inducing AR42J cell apoptosis. Quantitative real-time PCR (qRT-PCR) was adopted to measure miR-29a expression. Then, miRNA mimic, miRNA antisense oligonucleotide (AMO) and control vector were used to transfect AR42J cells. The expression of miR-29a was confirmed by qRT-PCR and the apoptosis rate of AR42J cells was detected by flow cytometry analysis. Western blot was used to detect the expression of activated caspase3. Moreover, we used bioinformatics software and luciferase assay to test whether TNFRSF1A was the target gene of miR 29a. After transfection, qRT-PCR and Western blot was used to detect the expression of TNFRSF1A in AR42J cells after transfection. RESULTS: The expression of miR-29a was much higher in the AEP group compared with the control group as displayed by the miRNA chip assay. After inducing apoptosis of AR42J cells in vitro, the expression of miR-29a was significantly increased by 1.49 +/- 0.04 times in comparison with the control group. As revealed by qRT-PCR assay, the expression of miR-29a was 2.68 +/- 0.56 times higher in the miR-29a mimic group relative to the control vector group, accompanied with an obviously increased acinar cell apoptosis rate (42.83 +/- 1.25 vs 24.97 +/- 0.15, P < 0.05). Moreover, the expression of miR-29a in the miRNA AMO group was 0.46 +/- 0.05 times lower than the control vector group, and the cell apoptosis rate was much lower accordingly (17.27 +/- 1.36 vs 24.97 +/- 0.15, P < 0.05). The results of bioinformatics software and luciferase assay showed that TNFRSF1A might be a target gene of miR-29a. TNFRSF1A expression was up-regulated in the miR-29a mimic group, while the miR-29a AMO group showed the reverse trend. CONCLUSION: miR-29a might promote the apoptosis of AR42J cells via up-regulating the expression of its target gene TNFRSF1A. PMID- 27239115 TI - Rectal cancer staging: Multidetector-row computed tomography diagnostic accuracy in assessment of mesorectal fascia invasion. AB - AIM: To assess the diagnostic accuracy of multidetector-row computed tomography (MDCT) as compared with conventional magnetic resonance imaging (MRI), in identifying mesorectal fascia (MRF) invasion in rectal cancer patients. METHODS: Ninety-one patients with biopsy proven rectal adenocarcinoma referred for thoracic and abdominal CT staging were enrolled in this study. The contrast enhanced MDCT scans were performed on a 256 row scanner (ICT, Philips) with the following acquisition parameters: tube voltage 120 KV, tube current 150-300 mAs. Imaging data were reviewed as axial and as multiplanar reconstructions (MPRs) images along the rectal tumor axis. MRI study, performed on 1.5 T with dedicated phased array multicoil, included multiplanar T2 and axial T1 sequences and diffusion weighted images (DWI). Axial and MPR CT images independently were compared to MRI and MRF involvement was determined. Diagnostic accuracy of both modalities was compared and statistically analyzed. RESULTS: According to MRI, the MRF was involved in 51 patients and not involved in 40 patients. DWI allowed to recognize the tumor as a focal mass with high signal intensity on high b-value images, compared with the signal of the normal adjacent rectal wall or with the lower tissue signal intensity background. The number of patients correctly staged by the native axial CT images was 71 out of 91 (41 with involved MRF; 30 with not involved MRF), while by using the MPR 80 patients were correctly staged (45 with involved MRF; 35 with not involved MRF). Local tumor staging suggested by MDCT agreed with those of MRI, obtaining for CT axial images sensitivity and specificity of 80.4% and 75%, positive predictive value (PPV) 80.4%, negative predictive value (NPV) 75% and accuracy 78%; while performing MPR the sensitivity and specificity increased to 88% and 87.5%, PPV was 90%, NPV 85.36% and accuracy 88%. MPR images showed higher diagnostic accuracy, in terms of MRF involvement, than native axial images, as compared to the reference magnetic resonance images. The difference in accuracy was statistically significant (P = 0.02). CONCLUSION: New generation CT scanner, using high resolution MPR images, represents a reliable diagnostic tool in assessment of loco-regional and whole body staging of advanced rectal cancer, especially in patients with MRI contraindications. PMID- 27239116 TI - Clinical and ABCB11 profiles in Korean infants with progressive familial intrahepatic cholestasis. AB - AIM: To investigate clinical profiles and mutations of ABCB11 in Koreans with progressive familial intrahepatic cholestasis 2 and review the differences between Koreans and others. METHODS: Of 47 patients with neonatal cholestasis, five infants had chronic intrahepatic cholestasis with normal gamma-glutamyl transpeptidase. Direct sequencing analyses of ABCB11, including exons and introns, were performed from peripheral blood. RESULTS: Living donor-liver transplantation was performed in four patients because of rapidly progressive hepatic failure and hepatocellular carcinoma. Three missense mutations were found in two patients: compound heterozygous 677C>T (S226L)/3007G>A (G1003R) and heterozygous 2296G>A (G766R). The mutations were located near and in the transmembranous space. CONCLUSION: Alterations in the transmembrane of the bile salt export pump in the Korean infants were different from those previously reported in Chinese, Japanease, Taiwanese, and European patients. PMID- 27239117 TI - Primary hepatic epithelioid angiomyolipoma: A malignant potential tumor which should be recognized. AB - AIM: To improve the clinical diagnosis and recognition of hepatic epithelioid angiomyolipoma (HEAML). METHODS: Four cases of primary HEAML were confirmed based on the pathology archive system in our hospital from January 2009 to November 2015. The general state, clinical symptoms, imaging manifestations, histological results and immunohistochemistry of these patients were retrospectively reviewed and analyzed. Studies of HEAML published in the last 15 years were collected from PubMed and MEDLINE to summarize the clinical symptoms, imaging characteristics, pathological features and management of HEAML. RESULTS: Four cases of primary HEAML were retrieved from our archives. These included three female patients and one male patient, with a mean age of 41.8 +/- 11.5 years (ranging from 31 to 56 years). The mean tumor size was 7.3 +/- 5.5 cm (ranging from 3.0 to 15 cm). In the contrast-enhanced imaging, the tumor was obviously enhanced in the arterial phase, but enhanced continuously or exhibited a slow-density masse during the venous and delayed phases. Histologically, the tumors mainly consisted of epithelioid cells that comprised approximately 95% of the total neoplastic mass. Although no metastases occurred in our patients, pathological studies revealed necrosis, mitotic figures and liver invasion in two patients, which indicates aggressive behavior. Immunohistochemical staining revealed that human melanoma black 45 (HMB-45) and Melan-A were positive in 4 cases. We only identified 81 cases with primary HEAML, including our present patients, from 26 articles available from PubMed and MEDLINE. The majority of the papers were published as case reports. Only 5 (5/75, 6%) cases were associated with tuberous sclerosis complex (TSC). More than half (35/66) were discovered incidentally upon physical examination. Approximately 65% (22/34) of the patients were misdiagnosed with HCC or other tumors before surgery. Approximately 10% (8/81) of the patients with HEAML had recurrence or metastasis after surgery, which was a very high and alarming rate. CONCLUSION: HEAML is a very rare primary hepatic tumor that is often misdiagnosed before surgery. Patients should be followed closely after surgery because of its malignant potential. PMID- 27239118 TI - Efficacy of peroral endoscopic myotomy vs other achalasia treatments in improving esophageal function. AB - AIM: To assess and compare the esophageal function after peroral endoscopic myotomy (POEM) vs other conventional treatments in achalasia. METHODS: Chart review of all achalasia patients who underwent POEM, laparoscopic Heller myotomy (LHM) or pneumatic dilation (PD) at our institution between January 2012 and March 2015 was performed. Patient demographics, type of achalasia, prior treatments, pre- and post-treatment timed barium swallow (TBE) and high resolution esophageal manometry (HREM) findings were compared between the three treatment groups. Patients who had both pre- and 2 mo post-treatment TBE or HREM were included in the final analysis. TBE parameters compared were barium column height, width and volume of barium remaining at 1 and 5 min. HREM parameters compared were basal lower esophageal sphincter (LES) pressures and LES-integrated relaxation pressures (IRP). Data are presented as mean +/- SD, median [25(th), 75(th) percentiles] or frequency (percent). Analysis of variance, Kruskal-Wallis test, Pearsons chi(2) test and Fishers Exact tests were used for analysis. RESULTS: A total of 200 achalasia patients were included of which 36 underwent POEM, 22 underwent PD and 142 underwent LHM. POEM patients were older (55.4 +/- 16.8 years vs 46.5 +/- 15.7 years, P = 0.013) and had higher BMI than LHM (29.1 +/- 5.9 kg/m(2) vs 26 +/- 5.1 kg/m(2), P = 0.012). More number of patients in POEM and PD groups had undergone prior treatments compared to LHM group (72.2% vs 68.2% vs 44.3% respectively, P = 0.003). At 2 mo post-treatment, all TBE parameters including barium column height, width and volume remaining at 1 and 5 min improved significantly in all three treatment groups (P = 0.01 to P < 0.001) except the column height at 1 min in PD group (P = 0.11) . At 2 mo post treatment, there was significant improvement in basal LES pressure and LES-IRP in both LHM (40.5 mmHg vs 14.5 mmHg and 24 mmHg vs 7.1 mmHg respectively, P < 0.001) and POEM groups (38.7 mmHg vs 11.4 mmHg and 23.6 mmHg vs 6.6 mmHg respectively, P < 0.001). However, when the efficacy of three treatments were compared to each other in terms of improvement in TBE or HREM parameters at 2 mo, there was no significant difference (P > 0.05). CONCLUSION: POEM, PD and LHM were all effective in improving esophageal function in achalasia at short-term. There was no difference in efficacy between the three treatments. PMID- 27239119 TI - Acoustic radiation force impulse imaging for assessing liver fibrosis in alcoholic liver disease. AB - AIM: To evaluate the performance of elastography by ultrasound with acoustic radiation force impulse (ARFI) in determining fibrosis stage in patients with alcoholic liver disease (ALD) undergoing alcoholic detoxification in relation to biopsy. METHODS: Eighty-three patients with ALD undergoing detoxification were prospectively enrolled. Each patient underwent ARFI imaging and a liver biopsy on the same day. Fibrosis was staged according to the METAVIR scoring system. The median of 10 valid ARFI measurements was calculated for each patient. RESULTS: Sixty-nine males and thirteen females (one patient excluded due to insufficient biopsy size) were assessed with a mean alcohol consumption of 132.4 +/- 128.8 standard drinks per week and mean cumulative year duration of 17.6 +/- 9.5 years. Sensitivity and specificity were respectively 82.4% (0.70-0.95) and 83.3% (0.73 0.94) (AUROC = 0.87) for F >= 2 with a cut-off value of 1.63m/s; 82.4% (0.64 1.00) and 78.5% (0.69-0.89) (AUROC = 0.86) for F >= 3 with a cut-off value of 1.84m/s; and 92.3% (0.78-1.00] and 81.6% (0.72-0.90) (AUROC = 0.89) for F = 4 with a cut-off value of 1.94 m/s. CONCLUSION: ARFI is an accurate, non-invasive and easy method for assessing liver fibrosis in patients with ALD undergoing alcoholic detoxification. PMID- 27239120 TI - Longitudinal molecular characterization of endoscopic specimens from colorectal lesions. AB - AIM: To compare molecular profiles of proximal colon, distal colon and rectum in large adenomas, early and late carcinomas. To assess feasibility of testing directed at molecular markers from this study in routine clinical practice. METHODS: A prospective 3-year study has resulted in the acquisition of samples from 159 large adenomas and 138 carcinomas along with associated clinical parameters including localization, grade and histological type for adenomas and localization and stage for carcinomas. A complex molecular phenotyping has been performed using multiplex ligation-dependent probe amplification technique for the evaluation of CpG-island methylator phenotype (CIMP), PCR fragment analysis for detection of microsatellite instability and denaturing capillary electrophoresis for sensitive detection of somatic mutations in KRAS, BRAF, TP53 and APC genes. RESULTS: Molecular types according to previously introduced Jass classification have been evaluated for large adenomas and early and late carcinomas. An increase in CIMP+ type, eventually accompanied with KRAS mutations, was notable between large adenomas and early carcinomas. As expected, the longitudinal observations revealed a correlation of the CIMP+/BRAF+ type with proximal location. CONCLUSION: Prospective molecular classification of tissue specimens is feasible in routine endoscopy practice. Increased frequency of some molecular types corresponds to the developmental stages of colorectal tumors. As expected, a clear distinction is notable for tumors located in proximal colon supposedly arising from the serrated (methylation) pathway. PMID- 27239121 TI - Colorectal cancer screening in countries of European Council outside of the EU 28. AB - AIM: To provide an update on colorectal cancer (CRC) screening programmes in non European Union (EU)-28 Council of Europe member states as of December 2015. METHODS: The mission of the Council of Europe is to protect and promote human rights in its 47 member countries. Its 19 non-EU member states are Albania, Andorra, Armenia, Azerbaijan, Bosnia and Herzegovina, Republika Srpska, Georgia, Iceland, Liechtenstein, Republic of Moldova, Monaco, Montenegro, Norway, Russian Federation, San Marino, Serbia, Switzerland, FYR of Macedonia, Turkey, and Ukraine (EU-19). The main data source were GLOBOCAN, IARC, WHO, EUCAN, NORDCAN, ENCR, volume X of the CI5, the ministerial and Public Health Agency websites of the individual countries, PubMed, EMBASE, registries of some websites and the www.cochranelibrary.com, Scopus, www.clinicaltrials.gov, www.clinicaltrialsregister.eu, Research gate, Google and data extracted from screening programme results. RESULTS: Our results show that epidemiological data quality varies broadly between EU-28 and EU-19 countries. In terms of incidence, only 30% of EU-19 countries rank high in data quality as opposed to 86% of EU-28 states. The same applies to mortality data, since 52% of EU-19 countries as against all EU-28 countries are found in the high ranks. Assessment of the method of collection of incidence data showed that only 32% of EU-19 countries are found in the top three quality classes as against 89% of EU-28 countries. For the mortality data, 63% of EU-19 countries are found in the highest ranks as opposed to all EU-28 member states. Interestingly, comparison of neighbouring countries offering regional screening shows, for instance, that incidence and mortality rates are respectively 38.9 and 13.0 in Norway and 29.2 and 10.9 in Sweden, whereas in Finland, where a national organised programme is available, they are respectively 23.5 and 9.3. CONCLUSION: Cancer screening should be viewed as a key health care tool, also because investing in screening protects the weakest in the population, decreases the social burden of cancer, and reduces all types of health care costs, including those for radical surgery, long-term hospitalisation, and chemotherapy. PMID- 27239122 TI - Idiopathic abdominal cocoon syndrome with unilateral abdominal cryptorchidism and greater omentum hypoplasia in a young case of small bowel obstruction. AB - Abdominal cocoon syndrome (ACS) is a rare cause of intestinal obstruction due to total or partial encapsulation of the small intestine by a fibrocollagenous membrane. Idiopathic ACS with abdominal cryptorchidism and greater omentum hypoplasia is even rarer clinically. We successfully treated a 26-year-old male case of small bowel obstruction with acute peritonitis. He was finally diagnosed with idiopathic ACS with unilateral abdominal cryptorchidism and greater omentum hypoplasia during exploratory laparotomy. He then underwent enterolysis, cryptorchidectomy, and appendectomy. He recovered gradually from the operations and early postoperative inflammatory ileus. There has been no recurrence of intestinal obstruction since the operation, and he is still in follow-up. We analyzed his clinical data and retrospectively reviewed the literature, and our findings may be helpful for the clinical diagnosis and treatment on ACS. PMID- 27239123 TI - Evolution of surgical treatment of intrahepatic lithiasis in China. PMID- 27239124 TI - Ultrastructural observation of liver tissue ablation induced by high-intensity focused ultrasound. AB - AIM: To observe the ultrastructural changes of liver tissues on normal rabbit ablated by high-intensity focused ultrasound (HIFU). METHODS: A single shot of 1.1 MHz focused ultrasound at an intensity of 500 W/cm(2) with 20-s duration of continuous exposure was applied intraoperatively in normal rabbit livers. Ultrastructural changes of the sonoablated lesion, as viewed by light and electron microscopy, were observed. RESULTS: Liver cells at the center of the sonoablated lesion showed irreversible degeneration immediately after HIFU treatment; electron microscopy showed that although the liver cells appeared normal histologically, irregularly shaped cavities of about 0.3-0.5 MUm in diameter were present in the cytoplasm. CONCLUSION: Thermal damages may be the main mechanism of HIFU-induced ablation of liver tissues besides cavitation effect. PMID- 27239125 TI - Endoscopic monitoring in small bowel transplantation. AB - AIM: To investigate the role of endoscopic monitoring in small bowel transplantation. METHODS: This study was conducted in two parts-an initial experimental study followed by a clinical study. In the experimental study, segmental small bowel allotransplantation was performed on white outbred pigs. Stomas were created for exteriorization of the proximal and distal ends of the intestines (Thiry-Vella loop). The grafts were monitored by endoscopy via stomas, with or without immunosuppressive therapy. For the clinical study, the whole small-bowel allograft of a woman with short bowel syndrome was endoscopically monitored via distal stoma. RESULTS: The most common endoscopic findings of graft rejection following small bowel allotransplantation were mucosal erythema, erosion, and ulceration. Diffuse ulceration with bleeding occurred in the late phase of rejection. CONCLUSION: Endoscopic monitoring is essential to small bowel transplantation. PMID- 27239126 TI - Construction of retroviral vectors to induce a strong expression of human class interferon gene in human hepatocellular carcinoma cells in vitro. AB - AIM: To establish the hepatoma cell-specific expression of human interferon (IFN) gene mediated by retroviral vectors METHODS: Human interferon alpha and interferon beta complementary DNA (IFN cDNA) were cloned into the polylinker site of pMNSM retroviral vector to construct recombinant retroviral vectors pMNSIFNA and pMNSIFNB, with the transcription of IFN gene being driven by Simian virus 40 early region promoter (SV40) early region promoter. IFN cDNAs were also cloned into pMNAIFNA, pAMNSIFNA, and pMNAIFNB, with the transcription of IFN gene being driven by SV40 early region promoter regulated by alpha-fetoprotein enhancer. Next, the retroviral constructs were introduced into retroviral amphotropic packaging cells using the lipofectamine-mediated gene transfer procedure. The rate of plasmid transfection was (4-40) * 10(3) colonies/MUg DNA/10(6) PA317 cells. The rate of retrovirus infection was (5-500) * 10(4) colony forming units (CFU)/mL. Further, the recombinant retroviruses were used to infect human hepatoma cells, renal carcinoma cells, and melanoma cell lines in the presence of 4 MUmg/L polybrene. RESULTS: Northern and Dot hybridization of total RNA from the neomycin-resistant colonies and IFN expression assay indicated that human alpha fetoprotein enhancer induced efficient and specific transcription and expression of IFN genes driven by the promoter of different origins in human hepatoma cells, leading to high production of alpha fetoprotein. CONCLUSION: Cis active element of alpha-fetoprotein gene can drive specific expression of IFN genes in human hepatoma cells, which provides some valuable data for the hepatoma-specific immune gene therapy. PMID- 27239128 TI - Source of blood supply and embolization treatment in cavernous hemangioma and sclerosis of the liver. AB - AIM: To investigate the source of the blood supply in carvenous hemangioma of liver (CHL), and provide a feasible treatment for CHL via thehepatic artery. METHODS: (1) Portovenography, hepatic arteriography and portal vein staining were performed in 5 patients to determine the origin of the blood supply. Two casts of hepatic blood vessels from resected specimens were observed. (2) Clinical data from 75 patients (30 males, 45 females, aged 25-57 years, mean of 37.4) were obtained. Of these, 56 were of solitary type (44 on the right lobe, 12 on the left, with 4 having intraparenchyma), and 19 were of multiple type (9 on the right, 2 the left, 8 whole liver). Twenty-two patients were treated with sclerosis, 50 by embolization via hepatic artery, and 3 were excised. RESULTS: In the 5 cases where portography was used, the contrast medium did not enter the tumor, and the tumor appeared as low density area, with the intrahepatic branches of the portal vein pushed aside. In the 5 cases with where portal vein staining was used, the normal liver parenchyma stained a deep blue; however, the tumor was not stained. The tumor area appeared as a round vacant cavity in the 2 specimen casts. For the 72 patients treated with sclerosis or embolization via hepatic artery or through interventional method, the tumors diminished by 10%-30% in diameter, and no tumors grew larger. CONCLUSION: The blood supply of CHL originates from the hepatic artery. Tumors treated with sclerosis and embolization decreased in size or got fibrotic. PMID- 27239127 TI - Hepatitis G virus infection in patients with chronic non-A-E hepatitis. AB - AIM: To elucidate the role of hepatitis G virus (HGV) infection in chronic non-A E hepatitis and sequence the partial NS5 genome of HGV isolated from the serum of a Chinese patient with chronic non-A-E hepatitis METHODS: Serum samples of patients with chronic non-A-E hepatitis were collected and total nucleic acids were extracted and subjected to reverse transcriptase-nested-polymerase chain reaction (RT-nested-PCR) using primers from the putative NS5 region of HGV genome. Then, 994bp cDNA was prepared from the positive serum, purified with electrophoresis of polyacrylamide gels, and directly sequenced using the dideoxy mediated chain-termination method. RESULTS: HGV-RNA was detected in 1 of the 35 patients with chronic non-A-E hepatitis. Compared with the 2 HGV isolates (PNF2161 and R10291) obtained from American patients, the HGV NS5 gene of this Beijing isolate (HG-G) showed homology of 88.0% and 89.2% respectively. On the other hand, in comparison with the West African isolate (GBV-C), the Beijing isolate showed homology of 93.5%. The patient showed persistent increase of alanine transaminase, but normal levels were achieved after interferon therapy with persistent positive HGV RNA. CONCLUSION: HGV is one of the causes of chronic non-A-E hepatitis, but it may not be a very important cause. The nucleotide sequence of partial NS5 gene of HG-G was found to be highly homologous to the West Africa isolate. PMID- 27239129 TI - Survival and malignant phenotype changes of human hepatoma SMMC-7721 cell line induced by cryopreservation at -50 degrees C. AB - AIM: To investigate the effect of cryopreservation at -50 degrees C on the human hepatoma SMMC-7721 cell line. METHODS: With 15% DMSO as a cryoprotectant, the SMMC-7721 cells were cryopreserved at -50 degrees C, then thawed and recultured. The survival rate, mitotic index and LDH isoenzymes were compared between pre- and post-cryopreservation. RESULTS: Thirteen hours after the thaw, the mitotic index of cryopreserved SMMC-7721 cells decreased by 1.09%. The mode scope of chromosome number (46-53) after cryopreservation tended to transfer to that of normal human cells, and the percentage of metaphases containing 46 chromosomes changed from 0% to 16%. LDH isoenzymes changed from H-like model (LDH3(29.3%) > LDH4 (26.8%) > LDH2 (25.3%) > LDH5 (14.9%) > LDH1 (3.6%) to M-like model (LDH4 (48.3%) > LDH5 (28.3%) > LDH3 (18.9%) > LDH2 (4.4%) > LDH1 (0%)). This suggests that the survival rate could reach over 95%. CONCLUSION: Cryopreservation at -50 degrees C can be a convenient method for the cryopreservation of cell lines. However, cryopreservation at -50 degrees C is likely involved in the changes of the malignant phenotypes of the human hepatoma SMMC-7721 cell line, and may induce the differentiation of malignant cells. PMID- 27239130 TI - Effects of Linomide on growth and metastasis of implanted human gastric cancer in nude mice. AB - AIM: To elucidate the effect of angiogenesis inhibitor, Linomide, on tumor growth and metastasis in nude mice implanted with human gastric cancer. METHODS: A metastatic model of gastric cancer was established using orthotopic implantation of histologically intact tumor tissues into the gastric wall of nude mice. Linomide (0, 80, 160 mg.kg(-1)) was given p.o. every day after the implantation, and the mice were sacrificed after 10 wk to detect tumor size and metastasis. The microvessel counts were measured by immunohistochemical staining using a monoclonal antibody against Human Factor VIII related antigen. RESULTS: Linomide treatment significantly decreased the size of the implanted tumors (control group: 1.36 +/- 0.81 cm(3) vs Linomide treated group: 0.84 +/- 0.51 cm(3) and 0.62 +/- 0.35 cm(3), P < 0.05 and 0.01, respectively). Additionally, an antimetastatic effect of Linomide was clearly demonstrated in a dose dependent manner: mice given 80 mg.kg(-1) Linomide developed liver metastasis in 4 of 10 cases, mice given 160 mg/kg developed metastasis in only 1 of 10 mice, while it developed in 19 of 28 mice of the control group (P < 0.05 and 0.01, respectively). The number of metastatic foci was also significantly less in the treated group. Furthermore, the microvessel counts in tumors of treated mice was reduced by 33%-42% as compared with the control tumors (P < 0.01). CONCLUSION: Linomide has a strong inhibitory activity against in vivo tumor growth and metastasis of gastric cancer, effectively suppressing the growth of the primary tumor, preventing liver metastasis, and attenuating the rate of neovascularization. PMID- 27239131 TI - Loss of heterozygosity and mRNA expression at deleted in colorectal cancer gene locus in gastric cancer. AB - AIM: To assess the effects of the deleted in colorectal cancer (DCC) gene changes on the development and progression of gastric cancer. METHODS: The loss of heterozygosity (LOH) and mRNA expression DCC gastric cancer using a PCR-based detection method. RESULTS: LOH was found in 35.3% (18/51) of the specimens, and the LOH was more frequently detected in tumors from patients with stage III or IV cancer (50.5%) than those in stages I or II (14.3%) (P < 0.05). The occurrence of LOH was not found to correlate with the histological type, tumor size, invasion depth and lymph node metastasis of gastric cancer. The mRNA expression of the DCC gene was studied in 26 of the 51 cases, of which LOE was found in 30.8% (8/26). LOE was not significantly correlated to LOH or other clinicopathological parameters. CONCLUSION: LOH and LOE of DCC gene are frequently encountered in gastric cancer, and the LOH of DCC gene is a late event associated with progression of gastric cancer. PMID- 27239132 TI - Significance of monoclonal antibody SC3A expression in gastric carcinoma and precancerous lesion. AB - AIM: To study the significance of monoclonal antibody SC3A expression in gastric carcinoma and precancerous lesions. METHODS: Immunohistochemical staining and mucin histochemical staining were performed on paraffin-embedded sections from gastric benign and malignant lesions from 101 patients. RESULTS: SC3A positive rate was 80.3% (57/71) in lesions of gastric carcinoma. The expression of SC3A was not related to the classification, differentiation, metastasis and or survival rates. The positive rate of SC3A in cancers secreting acid mucin (90.2%) or sulphomucin (91.3%) was higher than that in cancers without acid mucin (20.0%) or sulphomucin (60.0%) (P < 0.01). The positive rate of sulphomucin was higher in cases of intestinal metaplasia with cancer (88.9%) than that of cases of intestinal metaplasia with a benign lesion (35.3%) (P < 0.01). Additionally, the positive rate of SC3A with sulphomucin in intestinal metaplasia (60.9%) was higher than that without sulphomucin (31.3%) (P < 0.05). CONCLUSION: SC3A monoclonal antibody might be helpful in the diagnosis of gastric cancer and the discernment of histogenesis. PMID- 27239133 TI - Preliminary study on the loss of heterozygosity at 17p13 in gastric and colorectal cancers. AB - AIM: To evaluate the role of p53 in the development and progression of colorectal cancer and gastric carcinoma by analyzing the loss of heterozygosity (LOH) at 17p13.1 and 17p13.3. METHODS: LOH at the p53 gene locus and 17p13.3 were examined in 22 cases of gastric carcinoma and 14 cases of colorectal cancer by Southern blot analysis. RESULTS: Of the 22 gastrocarcinoma cases, 12 (54%) were heterozygous and LOH was detected in 6 (50%) of the 12 informative cases. In the 14 colorectal cancer cases, 10 (71%) were heterozygous, and LOH was detected in 6 (60%) of the 10 informative cases. CONCLUSION: LOH at the p53 gene locus is a frequent event in multiple step carcinogenesis progression. The high frequency of LOH at 17p13.3 suggests that there may be another tumor suppresser gene in that chromosome region. PMID- 27239134 TI - Clinicopathogenic studies of acute diarrhea in children. AB - AIM: To identify etiologic pathogens of acute diarrhea in children and to determine the diagnostic value of stool pH. METHODS: From May 1988 to April 1992, 368 children with acute diarrhea were studied. Fresh stools were routinely examined, and stool pH was tested with pH paper. Samples were placed in Cary Blair culture medium and were sent to the lab for bacterial isolation and identification. Rotavirus was identified in the supernatant by ELISA. RESULTS: Thirty-one pathogens and 385 bacterial strains were found in the 368 samples, with a detection rate of 67.7%, including 37.8% of mixed infections. Among the bacteria families, vibrionaceae was the most common (39.7%), and among bacteria genera, aeromonas was the most common (26.8%). In bacterial diarrhea, stool pH tended to be basic, while in viral diarrhea it tended to be acidic. CONCLUSION: There are 31 pathogens for children's acute diarrhea in this area. It is quite difficult to make an etiologic diagnosis only by clinical signs. However, stool pH is of some value for early disease diagnosis. PMID- 27239135 TI - P21 and CEA expression and AgNOR counts in dimethylhydrazine-induced colon carcinoma in rats. AB - AIM: To study P21 and carcinoembryonic antigen (CEA) expression and to measure argyrophilic nucleolar organizer region (AgNOR) counts in various lesions of colonic mucosa and the mechanism of carcinogenesis. METHODS: Thirty-eight male Wistar rats were injected with dimethylhydrazine (DMH) once a week for 25 wk. P21 and CEA expression was detected by immunohistochemical methods, and AgNOR was counted by silver staining paraffin sections from various colonic lesions. RESULTS: The incidence of colonic carcinoma in DMH-treated rats was 71.05% (27/38), and lymph node metastasis occurred in six rats. Immunohistochemical studies showed that P21 was primarily expressed in dysplasia and carcinomas, while CEA was expressed in carcinomas and metastatic tumors. AgNOR counts were higher in dysplasia and carcinomas. There were significant differences in P21 and CEA expression between benign and malignant lesions (P < 0.05). The difference in AgNOR counts was also significant between normal and dysplastic tissues, and between dysplasia and malignant lesions (P < 0.05). CONCLUSION: Dysplasia is a premalignant change of colonic carcinoma. The detection of P21 via immunohistochemistry and AgNOR counting may be an important clinical screening technique for colon carcinoma and premalignant lesions. PMID- 27239136 TI - Double-bullet radioimmunotargeting therapy in 31 primary liver cancer patients. AB - AIM: To observe the effect of double bullet immunotargeting therapy with chemotherapy and internal radiotherapy on primary liver cancer. METHODS: The polyclonal horse antibody against human AFP (anti-AFPAb) and the monoclonal murine antibody against human AFP (anti-AFPMcAb) were used as carriers, and (131)I and mitomycin C (MMC) were used as warheads to form double bullet, i.e. (131)I anti-AFPMcAb-MMC (double bullet 1) and (131)I anti-AFPAb-MMC (double bullet 2) prepared using the modified chloramine T method. Double bullet targeting therapy was administered by intravenous drip once a month in 31 patients (treatment group) with unresectable primary liver cancer. Among them, 4, 17 and 10 patients were administered 1, 2 and 3 times, and the median radiation dose (MBq/case) was 193.5 +/- 37.74; 651.9 +/- 232.4, and 992.0 +/- 230.5 respectively. METHODS: Tumor shrinkage, decrease in AFP, and 1 and 2 -year survival rates were significantly higher than the control groups who received transarterial infusion (TAI) or transarterial chemoembolization (TACE) at the same time (50.0%, 15/30 vs 30.0%, 9/30, P < 0.05; 66.7%, 18/27 vs 28.0%, 7/25, P < 0.01 and 50.0%, 34.0% vs 33.0%, 3.3%, P < 0.01, respectively). Furthermore, the tumor progression rate (10%) in the treatment group was significantly lower than that of the control group (40.0%, P < 0.01). CONCLUSION: Double bullet target therapy is more effective than traditional therapies due to the synergistic effects of the antibody, radioisotope, and anticancer agents, which together, enhance tumor killing. PMID- 27239138 TI - Difference between periportal and pericentral Kupffer cells in lipopolysaccharide uptake in rats. AB - AIM: To reveal the difference in the ability of Kupffer cells in the periportal and pericentral regions of the liver to uptake lipopolysaccharides (LPS) injected into the portal vein. METHODS: Male Wistar rats were divided into two groups: normal control group (n = 6) and GdCl3-treated group (n = 8). Sixteen hours before the experiment, rats in the GdCl3-treated group were injected with GdCl3 via the tail vein to eliminate Kupffer cell function specifically in the periportal region. LPS at a dose of 20 MUg/100 g body weight was injected into rats of both groups via the portal vein. Zero, 2, 5, 10, 30, and 60 min after LPS injection, liver samples were obtained and the distribution of LPS in Kupffer cells was observed by immunofluorescence imaging of monoclonal antibody-specific LPS staining using a confocal laser scanning microscope. RESULTS: In the normal control group, positive reactions to LPS were found in Kupffer cells in the periportal region with the peak at two minutes after LPS injection. Kupffer cells in the pericentral region showed the peak at five minutes after LPS injection, but its fluorescent intensity to LPS at the peak time in the cytoplasm was significantly lower than that of Kupffer cells in the pericentral region. In the GdCl3-treated group, Kupffer cells in the pericentral region showed the peak at two minutes following LPS injection, and the LPS fluorescent intensity showed no significant difference from that of the normal control rats at the peak point. No significant changes of LPS fluorescent intensities were found in Kupffer cells in the periportal region at various time points following LPS injection in GdCl3 treated rats. CONCLUSION: Kupffer cells in the periportal and pericentral regions showed differences in LPS uptake via the portal vein. PMID- 27239137 TI - Diagnostic value of occult fecal blood testing for colorectal cancer screening. AB - AIM: To evaluate the diagnostic value of occult fecal blood testing in mass colorectal cancer screening. METHODS: A reverse passive hemagglutination reaction fecal occult blood test (RPHA-FOBT) and colorectal cancer risk factor quantitative method were used as preliminary screening for colorectal cancer. A 60-cm fiber optic colonoscopy was used to validate the preliminary screen and was used to detect colorectal cancer in a community of 75813 subjects. RESULTS: Compared to the 60-cm fiber optic colonoscopy as a standard reference, FOBT has a sensitivity of 41.9%, specificity of 95.8%, Youden's index of 0.38, and positive predictive value of 0.68%. These results increased with subject age from the first detection. A 3-year follow up in the target mass showed that all new cases had initially been FOBT-negative. CONCLUSION: The value of FOBT as an indicator of colorectal cancer in mass screening is limited. PMID- 27239140 TI - Characteristics of upper digestive tract diseases in Bohai Bay fishermen. AB - AIM: To study the characteristics of upper digestive tract diseases (UDTDs) in fishermen who live in Bohai Bay. METHODS: An investigation was carried out in 1488 fishermen with symptoms of UDTDs (aside from liver, biliary and pancreatic diseases) during the time period between December 1991 and February 1995. This investigation included medical history evaluations, physical, gastroscopic and pathological examinations, tests for Helicobacter pylori (H. pylori) infection, and analysis of the nitrate content in their drinking water. RESULTS: Among the 1488 subjects investigated, 1467 suffered from one or more of the 14 UDTD diseases, most of which were chronic atrophic gastritis (CAG, 1103 cases), peptic ulcers (268 cases), and cancer of the upper digestive tract (25 cases). CONCLUSION: The incidence rate of UDTDs tends to be high among fishermen due to their particular living habits, the high nitrate content of their drinking water, etc. In addition, the clinical manifestations of UDTDs in fishermen are significantly different from those of the inland residents. PMID- 27239139 TI - Effects of metoclopramide on gastrointestinal myoelectric activity in rats. AB - AIM: To investigate the effects of metoclopramide (MCP) action on myoelectric activity in the antrum and small intestine. METHODS: Ten healthy male Wistar rats, weighing 250-350 g, were anesthetized with ketamine hydrochloride (100 mg/kg, intramuscularly). Four pairs of bipolar stainless steel electrodes 3 mm apart were implanted on the serosal surface of the antrum at one, 10 and 20 cm distal to the pylorus. Five to ten days following the operation, the gastrointestinal myoelectric activity of fasted rats after intramuscular injection of 2.5, six and 12 mg/kg MCP was recorded using a 8-channel EEG machine, and these values were quantitatively compared with the myoelectric activity after saline injection. RESULTS: In fasted rats, 2.5 mg/kg MCP increased the amplitude of spike activity (402.0 +/- 138.4 MUV, vs 345 +/- 163.4 MUV, P < 0.05) and the percentage of the slow wave-containing spike bursts (60.4% +/- 22.0% vs 47.4% +/- 22.5%, P < 0.01) of small intestine (1 cm distal to the pylorus), but did not affect the myoelectric activity of the antrum. Six and 12 mg/kg MCP increased the amplitude of both the slow wave (332.8 +/- 200.1 MUV vs 191.2 +/- 143.9 MUV, P < 0.01; 330.0 +/- 197.1 MUV vs 191.2 +/- 143.9 MUV, P < 0.05) and the spike activity of the antrum (180.5 +/- 69.7 MUV vs 121.8 +/- 63.3 MUV, P < 0.05; 174.5 +/- 71.7 MUV vs 123.8 +/- 63.3 MUV, P < 0.05), while in small intestine (1 cm distal to the pylorus) only the amplitude of spike activity (407.3 +/- 179.0 MUV vs 345.0 +/- 163.4 MUV, P < 0.05; 456.0 +/- 145.4 MUV vs 345.0 +/- 163.4 MUV, P < 0.05) and the percentage of the slow wave containing spike bursts (61.7% +/- 26.5% vs 47.4% +/- 22.5%, P < 0.01; 59.1% +/- 17.3% vs 47.4% +/- 22.5%, P < 0.01) was increased and the latent period significantly prolonged (2.5 +/- 0.35 min vs 0.77 +/- 0.18 min, P < 0.01). CONCLUSION: Different mechanisms may be involved in enhancing the myoelectric activity of the antrum and small intestine following MCP administration. PMID- 27239141 TI - Relation between bile acids and myocardial damage in obstructive jaundice. AB - AIM: To investigate the morphologic changes of the myocardium and its relationship to serum bile acids in obstructive jaundice. METHODS: Part 1: 35 rats were randomly assigned to three groups: Group I (BDL1, n = 11), the common bile duct (CBD) was ligated and severed and mice were then sacrificed after one week. Group I (BDL2, n = 11), the CBD was ligated and severed and mice were then killed after two weeks. Group I (SO, n = 13), the CBD was isolated. Hearts were collected for morphologic studies and blood was taken to determine the total serum bile acids (TAB). Part 2: 13 rats received gastric intubation of 10% 4 mL/kg sodium cholate. Their serum TBA and the heart's morphologic changes were then examined. RESULTS: One to two weeks after the CBD was ligated and severed, damage was evident in the mitochondria within the myocardium and the serum TBA was significantly increased. When rats were administered sodium cholate to make their peak blood concentration mimic the average blood concentration in BDL2, a similar degree of myocardial damage was observed. CONCLUSION: An increase in endogenous bile acids is one causative factor of myocardial damage in obstructive jaundice. PMID- 27239142 TI - Immunohistochemical study on endocrine-like tumor cells in colorectal carcinomas. AB - AIM: To evaluate the clinical significance of endocrine-like tumor cells in human colorectal carcinomas. METHODS: The immunohistochemistry method (ABC) using a rabbit polyclonal antibody against human chromogranin A (CGA) was employed to determine changes in endocrine-like tumor cells from the surgically resected colorectal carcinoma tissues of patients (35 males and 27 females, aged from 19 to 78 years, with a mean age of 50.3 years). Of the 62 specimens, 44 were from rectal carcinomas, 18 from colonic carcinomas, 14 from lymph nodes and 48 from non-involvement. Dukes classification revealed 19 of the cases were in stage A, 29 cases were in stage B and 14 cases were in stage C. All of the specimens were fixed with 10% formalin, embedded with paraffin and cut into 5 MUm sections. Additionally, the correlations among CGA-positive tumor cells, as well as the clinicopathologic data, age and sex of the patients, were also investigated. RESULTS: CGA-positive tumor cells were found in 35.5% of the patients with colorectal cancers, representing 20.0% (5 of 25) and 45.9% (17 of 37) of the aged and non-aged, respectively. These differences were significant (chi(2) test, P < 0.05). Nevertheless, no significant correlations were found between the CGA positive tumor cells and the sex, Dukes stages, tumor location, degree of histological differentiation or presence of lymph node metastasis. CONCLUSION: The low incidence of endocrine-like tumor cells found in the aged patients may be a new pathological feature for colorectal carcinomas, which could explain why the aged patients usually had a better prognosis. The exact significance of these findings requires further characterization. PMID- 27239143 TI - Analysis of fibronectin, fibronectin receptor and interleukin-1 in patients with cirrhosis treated by the Yanggan Jieyu decoction. AB - AIM: To investigate the effects of the Yanggan Jieyu (YGJY, nourishing the liver and alleviating mental depression) decoction on the plasma concentrations of fibronectin (FN), fibronectin receptor (FNR), tumor necrosis factor alpha (TNF alpha), and the activity of interleukin-1 (IL-1) in patients with cirrhosis. METHODS: Thirty-four cases of decompensated cirrhosis were divided into the YGJY decoction treatment group and the control group (patients received standard treatment). FN, FNR and TNF-alpha were measured by ELISA and expressed as mg/L (FN, FNR) and ng/L (TNF-alpha). IL-1 was measured by mice thymocyte proliferation using a beta scintillation counter and was expressed as cpm. RESULTS: In the YGJY decoction treatment group, FN and TNF-alpha levels increased significantly (P < 0.01 and P < 0.05, respectively), and FNR and IL-1 levels decreased significantly (P < 0.05 and P < 0.05, respectively). In the control group, FN, FNR, TNF-alpha, and IL-1 levels did not significantly change. CONCLUSION: YGJY decoction could prevent hepatic fibrosis by adjusting the plasma levels of FN, FNR, TNF-alpha and IL-1, which could mediate cirrhosis formation. This data is of clinical significance. PMID- 27239144 TI - Effects of electro-acupuncture on 5-HT, NOS and the gastric mucosa of stress rats. AB - AIM: To study the effects of electro-acupuncture (EA) on 5-hydroxytryptophan (5 HT) levels, nitrous oxide (NOS) levels, nitric oxide (NO) levels, and the gastric mucosa in stress rats. METHODS: The changes of 5-HT and NOS were measured in the gastric mucosa, and NO and 5-HT were measured in the serum by biochemical methods. The gastric mucosa was examined pathohistologically in the stress rats with gastric mucosa damage after EA. The changes before and after stress by EA were compared. RESULTS: EA decreased the gastric mucosa damage index in the stress rats (2.71 +/- 0.40 to 1.86 +/- 0.69, P < 0.01). EA normalized NOS level in gastric mucosa to the control group. The changes before stress by EA was more obvious than that after stress. EA lowered the 5-HT levels in the gastric mucosa (MUg/g wet weight, 6.91 +/- 3.08 to 4.51 +/- 1.62, P < 0.01). EA recovered the NO level in serum of the stress rats (MUmol/L, 5.78 +/- 1.49 to 7.91 +/- 1.11, P < 0.05), and increased the levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in serum continuously. CONCLUSION: EA stimulation normalizes the NOS and NO levels in the gastric mucosa of stress rats. EA also lowers the high 5-HT levels and induces NO release. PMID- 27239145 TI - Alterations of erythrocyte ATPase activity and oxygen consumption in patients with liver-blood deficiency syndrome. AB - AIM: To investigate the pathophysiology of erythrocyte energy metabolic changes of patients with the traditional Chinese Medicine (TCM) liver-blood deficiency syndrome (LBDS). METHODS: Erythrocyte membrane ATPase activity and oxygen consumption rate (OCR) were determined in 66 patients with LBDS, including 35 patients with iron deficiency anemia and 31 patients with chronic aplastic anemia. Thirty healthy adults served as controls. RESULTS: ATPase activity and OCR were decreased in patients with LBDS. CONCLUSION: The decreased erythrocyte ATPase activity and OCR might cause the energy hypometabolism in LBDS patients. PMID- 27239146 TI - The effects of Astragalus membranaceus on oxygen consumption in the intestine. AB - AIM: To investigate the effects of Astragalus membranaceus (AM) on intestinal oxygen consumption both in vivo and in vitro. METHODS: The oxygen consumption of the intestine was measured using an arteriovenous (A-V) O2 difference analyzer after treatment with AM in the intestinal lumen of ten healthy, anesthetized mongrel dogs. The effects of AM on the oxygen consumption of the intestinal mucosa in vitro were observed using constant volume manometers. RESULTS: The oxygen consumption of the intestine in vivo increased significantly (P < 0.05 or P < 0.01) after treatment with AM compared to the saline control. The oxygen consumption significantly increased after treatment with the 30% AM dilution and the 50% AM dilution compared to that of the 10% AM dilution (P < 0.05). There was no significant difference between the 30% AM dilution and the 50% AM dilution (P > 0.05). The effects of AM on oxygen consumption of the intestinal mucosa in vivo were similar to those in vivo. After treatment with the 5% AM dilution and the 1% AM dilution, the intestinal oxygen consumption increased compared to the control (Krebs Ringer phosphate buffer (KRPB)) (P < 0.05 and P < 0.01, respectively). There was no significant difference between treatment with the 10% AM dilution and the KRPB control (P > 0.05). CONCLUSION: AM improved the function of intestinal oxidative metabolism. PMID- 27239147 TI - Ultrastructural observation of the gastric mucosa in chronic gastritis patients treated by traditional Chinese medicine. AB - AIM: To demonstrate the relationship between the ultrastructural changes of the gastric mucosa and the syndrome differentiation in chronic gastritis. METHODS: Sixteen chronic gastritis patients with Piweixuhan (PXG, the cold of insufficiency syndrome of the spleen and the stomach) and fifteen chronic gastritis patients with Ganweibuhe (GBG, incoordination syndrome of the liver and the stomach) were treated with Jianpiwenwei decoction (JWD, invigorating the spleen and warming the stomach) or Shuganhewei decoction (SHD, dispersing the stagnated Liver Qi and regulating the stomach), respectively for three months. Before and after treatment, a gastroscopy was performed and the gastric mucosa was collected from the lesser curvature of the antrum of each patient. The ultrasections were observed and photographed under the JEM-100C X electron microscope. RESULTS: The common ultrastructural anomalies of the two types of chronic gastritis were the plasmacyte infiltration and the lesions of the mucosal epithelial cells, chief cells and antral mucous cells. There were obvious differences between the two types. In PXG, the predominant lesion of the chief cells was swelling of the mitochondria, while in GBG the rough endoplasmic reticulum was enlarged in the chief cells and the plasmacytes. After treatment, most cases of the ultrastructural lesions reverted to normal or improved. CONCLUSION: There was a close relationship between the ultrastructural changes of gastric mucosa and the syndrome differentiation of chronic gastritis. JWD and SHD could significantly improve the ultrastructural lesions of the gastric mucosa. PMID- 27239148 TI - Characteristics of saliva secreted by patients with TCM-Piyinxu. AB - AIM: To investigate various characteristics of saliva secreted by patients with TCM-Piyinxu (Spleen-yin deficiency). METHODS: Twenty-five individuals with Piyinxu (15 males and 10 females; age range 26-70 years, mean age = 45 years) diagnosed based on criteria used in traditional Chinese medicine, were compared with 20 individuals with Shenyinxu (Kidney-yin deficiency) (11 males, 9 females; age range 35-75 years, mean age = 50) and 30 normal individuals (17 males, 13 females; age range 35-65 years, mean age = 49 years). After acid stimulation, the saliva flow in each group was measured, and the levels of amylase and protein in saliva were determined using an automatic biochemical analyzer. The resultant data were analyzed using the Kruskal-Wallis test and one-way factorial ANOVA test. RESULTS: The flow rates of saliva and amylase in Piyinxu patients (0.27 +/- 0.016 mL/min and 2134.13 +/- 343.51 IU/min, respectively) were lower than those in normal subjects (0.46 +/- 0.027 mL/min and 3501.63 +/- 1099.63 IU/min, respectively, P < 0.01), but higher than those in the Shenyinxu group (0.13 +/- 0.051 mL/min and 951.62 +/- 383.17 IU/min, respectively, P < 0.01). The three groups showed no significant difference in their level of total salivary protein (Piyinxu group, 3.07 +/- 0.60 g/L; Shenyinxu group, 3.01 +/- 0.90 g/L, and control group, 2.94 +/- 1.13 g/L, P = 0.869), amount of amylase per saliva volume, or their ratio of amylase to protein in secreted saliva (P = 0.173 and P = 0.436, respectively). CONCLUSION: Piyinxu patients showed altered rates of saliva and amylase secretion when compared with those parameters in patients with Shenyinxu and normal subjects. PMID- 27239149 TI - Treatment of postoperative gastric cancer with the Fuzheng Huoxue anticancer prescription. AB - AIM: To study effects of the Fuzheng Huoxue anticancer prescription (Traditional Chinese Medicine) in treatment of gastric cancer. METHODS: Sixty-nine patients with histologically confirmed mid- or late-stage gastric cancer were assigned to two groups. The treatment group included 35 cases (26 males and 9 females; 2 patients aged 33-40 years, 18 patients aged 41-60 years, and 15 patients aged 61 75 years; mean group age = 58.4 years). The control group included 34 cases (23 males and 11 females; 4 patients aged 33-40 years, 16 patients aged 41-60 years, and 14 patients aged 61-75 years; mean group age = 56.8 years. The two groups were not significantly different in sex, age, their clinical and pathological stages of disease or operation mode. The two groups of patients were given similar treatments; however, patients in the treatment group were given the Fuzheng Huoxue anticancer prescription. In animal studies, SGC-7901 gastric cancers cells were inoculated into the backs of 30 nude mice under sterile conditions. After inoculation, the nude mice were randomly allocated to a control group, a traditional Chinese medicine group, and a chemotherapy group (n = 10 mice per group). The total weight of the 10 mice in each group was similar. Each nude mouse in the control group received 0.5 mL of saline solution each day. Mice in the traditional Chinese medicine group received 0.5 mL of the Fuzheng Huoxue anticancer prescription (containing 1.5 g crude drug) each day, while mice in the chemotherapy group were intraperitoneally injected with 1 mg of 5-Fu once a week for 8 wk. RESULTS: Prior to treatment, the mean OKT8 percentage among gastric patients in the treatment group was 45.94% +/- 8.45%, the mean OKT4/OKT8 ratio was 0.89 +/- 0.19, the mean AT-III concentration was 29.9 +/- 7.9 mg/dL, the mean Fa value was 50.4% +/- 24.4%, and the mean beta-TG concentration was 91.0 +/- 25.9 ng/dL. Prior to treatment, the mean percentage of OKT8 cells among patients in the control group was 49.21% +/- 6.60%, the OKT4/OKT8 ratio was 0.94 +/- 0.20, the AT-III concentration was 32.3 +/- 7.2 mg/dL, the mean Fa value was 57.3% +/- 24.6%, and the mean beta-TG concentration was 87.5 +/- 34.2 ng/dL. After treatment, the mean OKT8 percentage among patients in the treatment group was 33.52% +/- 7.80%, the mean OKT4/OKT8 ratio was 1.47 +/- 0.51, the mean AT-III concentration was 38.8 +/- 5.5 mg/dL, the mean Fa value was 102.6% +/- 31.6%, and the mean beta-TG concentration was 62.3 +/- 15.1 ng/dL. After treatment, the mean OKT8 percentage among patients in the control group was 42.22% +/- 7.07%, the mean OKT4/OKT8 ratio was 1.12 +/- 0.24, the mean AT-III concentration was 30.9 +/ 8.0 mg/dL, the mean Fa value was 64.6% +/- 26.9%, and the mean beta-TG concentration was 67.0 +/- 42.1 ng/dL. These data indicate that after treatment, the immunologic function of the T lymphocytes of gastric cancer patients in the treatment group was significantly improved (P < 0.01). Additionally, the hypercoagulability in the treatment group was also improved (P < 0.001), and the mean OKT4/OKT8 ratio, antithrombin III (AT-III) concentration, and fibrinolytic activity, etc. had all beome normalized. The one-year (86%), 3-year (69%), and 5 year (40%) survival rates in the treatment group were all higher than those in the control group (P < 0.05). The mean tumor weights in the control, traditional medicine, and chemotherapy groups were 0.895 +/- 0.289 g, 0.433 +/- 0.177 g, and 0.357 +/- 0.142 g, respectively. The tumor-inhibition rates in the traditional Chinese medicine group and chemotherapeutic group (51.6% and 60.1%, respectively) were significantly better than that in the control group (P < 0.001). The mean tumor weight in the traditional Chinese medicine group (24.68 +/- 1.93 g) was significantly higher than that in both the treatment group (22.96 +/- 1.87 g) and control group (22.47 +/- 2.18 g). CONCLUSION: The Fuzheng Huoxue anticancer prescription can not only replenish vital functions (Zhengqi), correct a hypercoagulatory state, improve immunologic function, and extend patient survival times, but may also directly inhibit gastric tumor growth without producing toxic side effects. PMID- 27239150 TI - Effects of tetrandrine on gastric mucosa and liver in portal hypertensive rats. AB - AIM: To study the effects of tetrandrine on portal hypertensive gastric mucosal lesions. METHODS: Portal hypertensive models were induced in Wistar rats by 60% CCl4 3 mL/kg body weight through subcutaneous injection, once every 4 d for 56 d. The animals were randomly divided into portal hypertension, tetrandrine and propranolol groups and subsequently, treated by normal saline, tetrandrine and propranolol respectively for 15 d. Some healthy rats were used as control group. Portal venous pressure (PVP), gastric mucosal prostaglandin E2 (PGE2) content, gastric mucosal blood flow (GMBF), gastric adherent mucus (GAM), ALT, ALP and serum total bilirubin (STB), were measured and liver tissues were observed histologically. RESULTS: In tetrandrine group and propranolol group, PVP was significantly lower (1.43 +/- 0.13, 1.45 +/- 0.12 vs 1.89 +/- 0.18 kPa; P < 0.01) and gastric mucosal PGE2 content (138.59 +/- 12.68, 129.98 +/- 14.31 vs 104.65 +/ 12.97 pg/mg; P < 0.01), GMBF (11.80 +/- 3.47, 10.54 +/- 3.63 vs 6.61 +/- 2.82 mL.h.kg; P < 0.05) and GAM (3.01 +/- 0.15, 2.98 +/- 0.21 vs 2.24 mg +/- 0.26 mg; P < 0.01) was significantly higher than that in portal hypertension control group. In tetrandrine group intrahepatic proliferative fibrous tissues were reduced and serum ALT (47.67 +/- 25.90 vs 189.33 +/- 41.21 King U; P < 0.01), ALP (0.22 +/- 0.04 vs 0.31 +/- 0.06 MUmol.s(-1)/L; P < 0.01) and STB (4.75 +/- 0.76 vs 11.12 +/- 2.93 MUmol/L; P < 0.01) were lowered as compared with those in portal hypertension control group. ALT (209.34 +/- 36.91 vs 189.33 +/- 41.21 King U; P > 0.05) and STB (11.63 +/- 3.01 vs 11.12 +/- 2.93 MUmol/L; P > 0.05) in propranolol group were not different from that in portal hypertension control group, but it showed more marked hepatocellular degeneration and necrosis and elevation of ALP (0.46 +/- 0.05 vs 0.31 +/- 0.06 MUmol.s(-1)/L; P < 0.01). CONCLUSION: Tetrandrine can improve the functions of gastric mucosa and liver, and facilitate the absorption of intrahepatic proliferative fibrous tissues. Propranolol can aggravate hepatosis though it may improve portal hypertensive gastric mucosal lesions. PMID- 27239151 TI - Cost-effectiveness study on treatment of duodenal ulcer. AB - AIM: To compare the efficiency of therapy with a 2-week regimen of amoxicillin plus metronidazole and six weeks of Tagamet (AMT group) vs the efficacy of therapy with 6 wk of omeprazole plus 2 wk of amoxicillin (OA group) for ulcer healing, Helicobacter pylori (Hp) eradication, and decreasing the recurrence of duodenal ulcers. METHODS: This cost-effectiveness analysis was based on results shown in a randomized controlled trial conducted in 1995 in patients with a duodenal ulcer (OA group, 46 patients; AMT group, 43 patients) and treated at class grade III A hospitals in Shanghai, China. RESULTS: The costs of treatment in the AMT group were less than those in the OA group for ulcer healing (?546.25 vs ?1296.76 per case, P < 0.01), Hp eradication (?702.32 vs ?1742.53 per case, P < 0.01), and decreasing ulcer recurrence (?640.39 vs 1424.54 per case, P < 0.01). Direct costs comprised the major cost involved in treatment of duodenal ulcers. The difference in the cost of treating ulcers in the two groups was primarily due to the costs of the different drugs. There was no significant difference between the two groups regarding their direct non-medical costs and indirect costs. CONCLUSION: When based on therapeutic effectiveness and financial costs, AMT therapy was more cost-efficient than OA therapy. AMT therapy is recommended for its low cost, acceptable ulcer healing rates, ability to cure of an Hp infection, and especially when treating patients with an ulcer < 1 cm in diameter. PMID- 27239152 TI - Endoscopic ligation for benign and malignant lesions of upper digestive tract. PMID- 27239153 TI - Changes in mucosal permeability to lipopolysaccharide in the colon of chronic alcoholic rats. AB - AIM: To evaluate the effects of chronic alcohol abuse on mucosal permeability to lipopolysaccharide (LPS) in the colon of rats. METHODS: Escherichia coli LPS (20 mg/L) was injected into the colon of chronic alcoholic rats (n = 10) that had been supplied with Lieber diet every other day for six weeks. Before and 5, 10, 20, and 30 min after LPS injection, portal vein blood samples were obtained and the LPS levels in the blood were measured. The distribution of LPS in the colon tissues was observed with confocal laser scanning microscopy by immunofluorescence technique using a monoclonal antibody specific to the lipid A region of LPS. Normal rats were used as the controls (n = 6). RESULTS: Before LPS injection, LPS levels in the portal vein blood of chronic alcoholic rats were significantly higher than that of the normal controls (3.56 +/- 0.67 ng/L vs 2.45 +/- 0.15 ng/L, P < 0.01). At 5, 10, 20, and 30 min after LPS injection, LPS levels were significantly higher than that before LPS injection (173.56 +/- 3.45 ng/L, 154.78 +/- 0.57 ng/L, 43.89 +/- 0.67 ng/L, 45.38 +/- 0.89 ng/L vs 3.56 +/- 0.67 ng/L, respectively, P < 0.01). Most mucosal cells in the chronic alcoholic rats showed strong positive reactions to LPS, but in the normal rats, there were no significant changes in portal vein blood LPS levels and in the fluorescence reactions to LPS in the mucosal cells after LPS injection. CONCLUSION: Chronic alcohol abuse results in a significant increase in LPS permeability in the colon mucosa cells of rats. PMID- 27239154 TI - Effects of Radix Rehmanniae on gastric acid secretion and gastric ulcer formation in rats. PMID- 27239155 TI - Detection method for peripheral venous AFP mRNA in hepatocellular carcinoma. PMID- 27239156 TI - Clinicopathological risk factors and prognostic evaluation in hepatocellular carcinoma recurrence after surgery. AB - AIM: To analyze the clinicopathological risk factors in hepatocellular carcinoma recurrence after surgery. METHODS: We used significance testing (chi(2) and Student's t-test) of single and multiple factors, and Wilcoxon Cox tropic examination; a retrospective clinicopathological analysis was performed on 156 cases of hepatocellular carcinoma after hepatectomy. RESULTS: Of the 156 cases, 68.4%, 57.3%, 46.7%, 31.5%, and 28.6% had one, two, three, four, and five postoperative tumor-free years, respectively; the total recurrence rate was 53.2% (83/156). In the 83 recurrent cases, 65 were intrahepatic subclinical, with a resection rate of 78.3% (65/83). The relevant factors involved in recurrence were: male gender, tumor number and size, capsule infiltration, and portal vein involvement. These factors were an obvious influence on the prognosis of the patients with postoperative hepatocellular carcinoma (P < 0.05). In the recurrent liver carcinomas, 63.1% of tumor nodes (41/65) were at the ipsilateral segment of the primary tumor nodes. CONCLUSION: Male gender, tumor number and size, capsule infiltration, and portal vein involvement are factors for postoperative hepatocellular carcinoma recurrence. Recurrence is mainly unicentral. The right front liver lobe is the segment with a high rate of recurrence. PMID- 27239157 TI - Endoscopic haemoclip ligation of pedunculated polyp before polypectomy. PMID- 27239158 TI - NIH Peer Review: Scored Review Criteria and Overall Impact. AB - The National Institutes of Health (NIH) is the largest source of funding for biomedical research in the world. Funding decisions are made largely based on the outcome of a peer review process that is intended to provide a fair, equitable, timely, and unbiased review of the quality, scientific merit, and potential impact of the research. There have been concerns about the criteria reviewers are using, and recent changes in review procedures at the NIH now make it possible to conduct an analysis of how reviewers evaluate applications for funding. This study examined the criteria and overall impact scores recorded by assigned reviewers for R01 grant applications. The results suggest that all the scored review criteria, including innovation, are related to the overall impact score. Further, good scores are necessary on all five scored review criteria, not just the score for research methodology, in order to achieve a good overall impact score. PMID- 27239159 TI - Enhancing Performance of Liquid Sample Desorption Electrospray Ionization Mass Spectrometry Using Trap and Capillary Columns. AB - Desorption electrospray ionization mass spectrometry (DESI-MS) is a recent and important advance in the field that has extensive applications in surface analysis of solid samples but has also been extended to analysis of liquid samples. The liquid sample DESI typically employs a piece of fused silica capillary to transfer liquid sample for ionization. In this study, we present the improvement of liquid sample DESI-MS by replacing the sample transfer silica capillary with a trap column filled with chromatographic stationary phase materials (e.g., C4, C18). This type of trap column/liquid sample DESI can be used for trace analysis of organics and biomolecules such as proteins/peptides (in nM concentration) in high salt content matrices. Furthermore, when the sample transfer capillary is modified with enzyme covalently bound on its inside capillary wall, fast digestion (< 6 min) of proteins such as phosphoproteins can be achieved and the online digested proteins can be directly ionized using DESI with high sensitivity. The latter is ascribed to the freedom to select favorable spray solvent for the DESI analysis. Our data shows that liquid sample DESI-MS with a modified sample transfer capillary has significantly expanded its utility in bioanalysis. PMID- 27239160 TI - Characterization of the ATP-Dependent Lon-Like Protease in Methanobrevibacter smithii. AB - The Lon protease is highly evolutionarily conserved. However, little is known about Lon in the context of gut microbial communities. A gene encoding a Lon-like protease (Lon-like-Ms) was identified and characterized from Methanobrevibacter smithii, the predominant archaeon in the human gut ecosystem. Phylogenetic and sequence analyses showed that Lon-like-Ms and its homologs are newly identified members of the Lon family. A recombinant form of the enzyme was purified by affinity chromatography, and its catalytic properties were examined. Recombinant Lon-like-Ms exhibited ATPase activity and cleavage activity toward fluorogenic peptides and casein. The peptidase activity of Lon-like-Ms relied strictly on Mg(2+) (or other divalent cations) and ATP. These results highlight a new type of Lon-like protease that differs from its bacterial counterpart. PMID- 27239161 TI - Educating for health service reform: clinical learning, governance and capability - a case study protocol. AB - BACKGROUND: The nurse practitioner is a growing clinical role in Australia and internationally, with an expanded scope of practice including prescribing, referring and diagnosing. However, key gaps exist in nurse practitioner education regarding governance of specialty clinical learning and teaching. Specifically, there is no internationally accepted framework against which to measure the quality of clinical learning and teaching for advanced specialty practice. METHODS: A case study design will be used to investigate educational governance and capability theory in nurse practitioner education. Nurse practitioner students, their clinical mentors and university academic staff, from an Australian university that offers an accredited nurse practitioner Master's degree, will be invited to participate in the study. Semi-structured interviews will be conducted with students and their respective clinical mentors and university academic staff to investigate learning objectives related to educational governance and attributes of capability learning. Limited demographic data on age, gender, specialty, education level and nature of the clinical healthcare learning site will also be collected. Episodes of nurse practitioner student specialty clinical learning will be observed and documentation from the students' healthcare learning sites will be collected. Descriptive statistics will be used to report age groups, areas of specialty and types of facilities where clinical learning and teaching is observed. Qualitative data from interviews, observations and student documents will be coded, aggregated and explored to inform a framework of educational governance, to confirm the existing capability framework and describe any additional characteristics of capability and capability learning. DISCUSSION: This research has widespread significance and will contribute to ongoing development of the Australian health workforce. Stakeholders from industry and academic bodies will be involved in shaping the framework that guides the quality and governance of clinical learning and teaching in specialty nurse practitioner practice. Through developing standards for advanced clinical learning and teaching, and furthering understanding of capability theory for advanced healthcare practitioners, this research will contribute to evidence-based models of advanced specialty postgraduate education. PMID- 27239162 TI - Barriers to timely treatment-seeking in patients with acute myocardial infarction in Malaysia: a qualitative study. AB - BACKGROUND: Persisting delay in seeking treatment among Acute Myocardial Infarction (AMI) patients was reported in Malaysia despite intensified efforts in educating the public on symptoms of AMI and the importance of seeking prompt treatment. Studies outside Malaysia have shown that patients' personal thoughts during symptom onset could contribute to the delay. The purpose of this study is to explore the barriers of AMI patients prior to the decision of seeking treatment in Malaysia. METHODS: A qualitative descriptive research approach was chosen. Individual in-depth interviews were conducted among 18 patients with AMI. Data were analysed using thematic analysis. Recordings were transcribed and coded, codes were subsequently organized into categories. The stages of coding and identifying categories were repeated before themes were identified. RESULTS: Three meaningful themes with nine sub-themes that may have influenced the delayed decision to seek treatment were identified. Some themes identified were culturally bound. CONCLUSIONS: The findings of this study give insights on barriers prior to the decision of seeking treatment when patients were experiencing AMI. Findings indicates that interventions targeted at increasing knowledge about AMI symptoms and correct actions using an informative approach at the current practice may not be adequate to reduce patient delay. The findings of this study could provide basis for the development of interventions that are culturally relevant to the Malaysians setting to promote behavioural change in the population and reduce pre-hospital delay. PMID- 27239163 TI - Context-sensitive trace inlining for Java. AB - Method inlining is one of the most important optimizations in method-based just in-time (JIT) compilers. It widens the compilation scope and therefore allows optimizing multiple methods as a whole, which increases the performance. However, if method inlining is used too frequently, the compilation time increases and too much machine code is generated. This has negative effects on the performance. Trace-based JIT compilers only compile frequently executed paths, so-called traces, instead of whole methods. This may result in faster compilation, less generated machine code, and better optimized machine code. In the previous work, we implemented a trace recording infrastructure and a trace-based compiler for [Formula: see text], by modifying the Java HotSpot VM. Based on this work, we evaluate the effect of trace inlining on the performance and the amount of generated machine code. Trace inlining has several major advantages when compared to method inlining. First, trace inlining is more selective than method inlining, because only frequently executed paths are inlined. Second, the recorded traces may capture information about virtual calls, which simplify inlining. A third advantage is that trace information is context sensitive so that different method parts can be inlined depending on the specific call site. These advantages allow more aggressive inlining while the amount of generated machine code is still reasonable. We evaluate several inlining heuristics on the benchmark suites DaCapo 9.12 Bach, SPECjbb2005, and SPECjvm2008 and show that our trace-based compiler achieves an up to 51% higher peak performance than the method-based Java HotSpot client compiler. Furthermore, we show that the large compilation scope of our trace-based compiler has a positive effect on other compiler optimizations such as constant folding or null check elimination. PMID- 27239164 TI - A Consistent Information Criterion for Support Vector Machines in Diverging Model Spaces. AB - Information criteria have been popularly used in model selection and proved to possess nice theoretical properties. For classification, Claeskens et al. (2008) proposed support vector machine information criterion for feature selection and provided encouraging numerical evidence. Yet no theoretical justification was given there. This work aims to fill the gap and to provide some theoretical justifications for support vector machine information criterion in both fixed and diverging model spaces. We first derive a uniform convergence rate for the support vector machine solution and then show that a modification of the support vector machine information criterion achieves model selection consistency even when the number of features diverges at an exponential rate of the sample size. This consistency result can be further applied to selecting the optimal tuning parameter for various penalized support vector machine methods. Finite-sample performance of the proposed information criterion is investigated using Monte Carlo studies and one real-world gene selection problem. PMID- 27239166 TI - A MATHEMATICAL FRAMEWORK FOR EXACT MILESTONING. AB - We give a mathematical framework for Exact Milestoning, a recently introduced algorithm for mapping a continuous time stochastic process into a Markov chain or semi-Markov process that can be efficiently simulated and analyzed. We generalize the setting of Exact Milestoning and give explicit error bounds for the error in the Milestoning equation for mean first passage times. PMID- 27239165 TI - Creating Systems Change to Support Goals for HIV Continuum of Care: The Role of Community Coalitions to Reduce Structural Barriers for Adolescents and Young Adults. AB - Routine population-wide HIV screening, early linkage and long-term retention in healthcare for HIV-infected individuals are key nodes of the HIV continuum of care and are essential elements of the National HIV/AIDS Strategy. Despite this, up to 80% of youth are unaware of their HIV infection status and only 29% are linked to HIV healthcare; less than half are engaged in long-term HIV healthcare, and far fewer maintain viral suppression. To fill this gap and to address the national call to action to establish a seamless system for immediate linkage to continuous and coordinated quality healthcare after diagnosis, this paper describes the processes and mechanisms by which the SMILE Program worked within the infrastructure of the ATN-affiliated Connect to Protect(r) (C2P) community coalitions to address structural barriers that hindered youth in their communities from being tested for HIV infection or linked and engaged in healthcare after an HIV positive diagnosis. PMID- 27239167 TI - Robust Multi-Network Clustering via Joint Cross-Domain Cluster Alignment. AB - Network clustering is an important problem that has recently drawn a lot of attentions. Most existing work focuses on clustering nodes within a single network. In many applications, however, there exist multiple related networks, in which each network may be constructed from a different domain and instances in one domain may be related to instances in other domains. In this paper, we propose a robust algorithm, MCA, for multi-network clustering that takes into account cross-domain relationships between instances. MCA has several advantages over the existing single network clustering methods. First, it is able to detect associations between clusters from different domains, which, however, is not addressed by any existing methods. Second, it achieves more consistent clustering results on multiple networks by leveraging the duality between clustering individual networks and inferring cross-network cluster alignment. Finally, it provides a multi-network clustering solution that is more robust to noise and errors. We perform extensive experiments on a variety of real and synthetic networks to demonstrate the effectiveness and efficiency of MCA. PMID- 27239168 TI - Feasibility and Acceptability of an Impact of Crime Group Intervention with Jail Inmates. AB - The current study evaluated the feasibility and acceptability of a manualized Impact of Crime (IOC) group intervention implemented with male inmates (N = 108) at a county jail. Facilitator adherence to the intervention and participant attendance, homework completion, and feedback were assessed. On average facilitators covered 93.7% of each manual topic. Victim speaker recruitment was a challenge-43.5% of relevant sessions lacked victim speakers. Findings suggested significant participant engagement-67.3% attended at least 75% of sessions and 93.3% of homework assignments were submitted on time. Overall, participants indicated satisfaction with the intervention. Successful strategies, challenges, and potential enhancements are discussed. PMID- 27239169 TI - Immunological Mechanisms in Breast Cancer - from Bench to Bedside. PMID- 27239170 TI - Tumor-Infiltrating Lymphocytes: A Promising Biomarker in Breast Cancer. AB - There is clear evidence that the immune system plays an essential role in tumor defense. By determining tumor-infiltrating lymphocytes (TILs), the individual immunological response becomes more apparent and measurable. In breast cancer, high levels of TILs are associated with a more favorable clinical course. In this review, we describe how TILs are determined with emphasis on daily routine diagnostics. We further discuss their impact as a prognostic and predictive biomarker in the neoadjuvant and adjuvant therapy setting as well as in residual disease. We also discuss their potential future implications on further stratifying prognostic subgroups of breast cancer, thereby possibly influencing future therapy considerations. PMID- 27239171 TI - Cellular Immune Responses and Immune Escape Mechanisms in Breast Cancer: Determinants of Immunotherapy. AB - More recently, immunotherapy has emerged as a novel potentially effective therapeutic option also for solid malignancies such as breast cancer (BC). Relevant approaches, however, are determined by the 2 main elements of cancer immunoediting - the elimination of nascent transformed cells by immunosurveillance on the one hand and tumor immune escape on the other hand. Correspondingly, we here review the role of the various cellular immune players within the host-protective system and dissect the mechanisms of immune evasion leading to tumor progression. If the immune balance of disseminated BC cell dormancy (equilibrium phase) is lost, distant metastatic relapse may occur. The relevant cellular antitumor responses and translational immunotherapeutic options will also be discussed in terms of clinical benefit and future directions in BC management. PMID- 27239172 TI - Checkpoint Inhibitors and Their Application in Breast Cancer. AB - Immune checkpoints are crucial for the maintenance of self-tolerance and for the modulation of immune responses in order to minimize tissue damage. Tumor cells take advantage of these mechanisms to evade immune recognition. A significant proportion of tumors, including breast cancers, can express co-inhibitory molecules that are important formediating the escape from T cell-mediated immune surveillance. The interaction of inhibitory receptors with their ligands can be blocked by specific molecules. Monoclonal antibodies (mAbs) directed against the cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and, more recently, against the programmed cell death protein 1 (PD1), have been approved for the therapy of melanoma (anti-CTLA4 and anti-PD1 mAbs) and non-small cell lung cancer (anti-PD1 mAbs). Moreover, inhibition of PD1 signaling has shown extremely promising signs of activity in breast cancer. An increasing number of molecules directed against other immune checkpoints are currently under clinical development. In this review, we summarize the evidence supporting the implementation of checkpoint inhibition in breast cancer by reviewing in detail data on PD-L1 expression and its regulation. In addition, opportunities to boost anti-tumor immunity in breast cancer with checkpoint inhibitor-based immunotherapies alone and in combination with other treatment options will be discussed. PMID- 27239174 TI - Differentiation between Phyllodes Tumors and Fibroadenomas Based on Mammographic Sonographic and MRI Features. AB - BACKGROUND: This study was performed to compare the mammographic, sonographic, and magnetic resonance imaging (MRI) characteristics of phyllodes tumors and fibroadenomas, which may resemble each other. METHODS: Preoperative mammograms, B mode and Doppler sonograms, and dynamic breast MRIs of 72 patients with pathologically proven fibroadenomas and 70 patients with pathologically proven phyllodes tumor were evaluated in this retrospective study. Statistical significance was evaluated using chi-square and Fisher's exact tests. Correlations in lesion size among radiological methods were examined by Pearson's correlation analysis. RESULTS: The features that differed on mammogram were size, shape, and margin of the mass. Sonograms showed significant differences in size, shape, margin, echo pattern, and vascularization of the mass. Pearson's correlation analysis showed strong agreement among radiological methods in terms of assessment of size. Tumor size >= 3 cm, irregular shape, microlobulated margins, complex internal echo pattern, and hypervascularity were significant findings of phyllodes tumors. Internal cystic areas on MRI were frequently associated with phyllodes tumors. CONCLUSION: Mammographic, sonographic, and MRI findings of fibroadenomas and phyllodes tumors could help radiologists to ascertain imaging-histological concordance and guide clinicians in their decision making regarding adequate follow-up or the necessity of biopsy. PMID- 27239173 TI - Clinical Development of the E75 Vaccine in Breast Cancer. AB - E75 is an immunogenic peptide derived from the human epidermal growth factor receptor 2 (HER2) protein. A large amount of preclinical work evaluated the immunogenicity of E75, after which phase I trials investigated using E75 mixed with an immunoadjuvant as a vaccine. Those studies showed the vaccine to be safe and capable of stimulating an antigen-specific immune response. Subsequent to that, our group conducted trials evaluating E75 + granulocyte macrophage colony stimulating factor (GM-CSF) in the adjuvant setting. The studies enrolled node positive and high-risk node-negative breast cancer patients, with the goal being to determine if vaccination could decrease the recurrence risk. The studies included 187 evaluable patients: 108 vaccinated ones and 79 controls. The 5-year disease-free survival for the vaccinated patients was 89.7% compared to 80.2% for the control patients, a 48% reduction in relative risk of recurrence. Based on these data, E75 + GM-CSF, now known as NeuVaxTM, is being evaluated in a phase III trial. In this article, we review preclinical data and results of the early phase trials and provide an update on the ongoing phase III study. We also present additional strategies for employing the vaccine to be included as a component of combination immunotherapy as well as in the setting of ductal carcinoma in situ as an initial step towards primary prevention. PMID- 27239175 TI - The Role of Blue Dye in Sentinel Node Detection for Breast Cancer: A Retrospective Study of 203 Patients. AB - OBJECTIVE: We aimed at examining the potential benefits of blue dye in sentinel node biopsy (SNB) in comparison with its proven drawbacks. PATIENTS AND METHODS: In 2007, 203 T1 primary breast carcinomas had been operated on in our institute. The patients had undergone a lumpectomy and SNB. Sentinel node (SN) detection was exclusively isotopic (ISO) in 77 patients and performed with blue dye combined with a radioactive isotope (COMBI) in 126 patients. We compared the number of SNs and the rate of SN positivity in both groups. RESULTS: The detection rate was 99% in both groups: 76/77 in the ISO group and 125/126 in the COMBI group. The mean number of SNs was 2.14 and 1.91 in the ISO group and the COMBI group, respectively (difference not significant (NS)). SN positivity was found in 26.1% and 24.6% in the ISO group and the COMBI group, respectively (NS). Only 1 SN had been removed in 26% of the patients in the ISO group versus 45.2% of the patients in the COMBI group (p = 0.004). No significant differences were observed in the tumor characteristics. CONCLUSION: The systematic use of patent blue dye combined with isotopic detection does not appear to increase the overall performance of the SNB technique in this retrospective study. PMID- 27239176 TI - Anti-HER2 Therapy Beyond Second-Line for HER2-Positive Metastatic Breast Cancer: A Short Review and Recommendations for Several Clinical Scenarios from a Spanish Expert Panel. AB - BACKGROUND: The aim of this project was to provide an expert opinion regarding anti-human epidermal growth factor receptor 2 (HER2) therapy beyond second-line treatment of metastatic breast cancer (mBC). METHODS: A group of experts discussed specific issues concerning anti-HER2 therapy in late-line settings in mBC. RESULTS: Trastuzumab emtansine (T-DM1) or dual HER2 blockade appeared to be good options for HER2-positive mBC after >= 2 HER2-targeted therapies. Once an objective response has been achieved with anti-HER2-containing therapy, the anti HER2 agent can be continued until progression of the disease, unacceptable toxicity or patient decision. mBC treated with >= 3 consecutive lines of anti-HER therapy, >= 1 being a dual HER2 blockade and with early progression of disease during a fourth or later-line treatment, are clinically resistant to anti-HER therapy. For progression of metastasis in the brain after anti-HER2 therapy, lapatinib and chemotherapy appear to be a good alternative after best local treatment. CONCLUSIONS: Further clinical trials are needed to provide valuable knowledge about the best treatment options in the later settings of mBC. PMID- 27239177 TI - Investigating Respondents and Nonrespondents of a Postal Breast Cancer Questionnaire Survey Regarding Differences in Age, Medical Conditions, and Therapy. AB - BACKGROUND: Collecting patient-reported data via postal questionnaires is a common and frequently used technique. Selection bias may occur through lost data from nonrespondents. This study investigated differences in characteristics between respondents and nonrespondents of a postal breast cancer survey. PATIENTS AND METHODS: The investigation was based on a cross-sectional postal questionnaire survey for the mandatory annual routine (re-)certification of accredited breast centers in North Rhine-Westphalia in 2010. Out of 4,444 patients meeting the inclusion criteria who gave their consent to participate, 3,856 respondents sent back a questionnaire and 588 nonrespondents did not. Using logistic regression, differences between respondents and nonrespondents regarding information gathered through hospital staff concerning age, affected breast, UICC (Union for International Cancer Control) staging and grading, ASA (American Society of Anesthesiologists) classification, neoadjuvant chemotherapy, and type of surgery were assessed. RESULTS: Very young and very old patients sent back their questionnaire significantly less frequently, as did patients who showed a later cancer stage and poorer general health and those who underwent mastectomy. CONCLUSION: Differences exist between respondents and nonrespondents with regard to age, disease, and therapy characteristics that need to be considered for the interpretation and generalizability of survey results due to selection bias. PMID- 27239178 TI - Appropriate Clinical Strategies for Breast Cancer Coexisting with Acute Myeloid Leukemia in the Genomic-Molecular Era: A Case Report. AB - BACKGROUND: The coexistence of breast cancer (BC) and acute myeloid leukemia (AML) has rarely been reported. Considering the fatality of AML, the management of this condition is based on treating the AML immediately while putting BC treatment on hold. CASE REPORT: Here, we report a synchronous occurrence of BC and AML. Prognostic factors for both BC and AML were determined by genomic and molecular evaluation. The evaluation for AML showed a relatively good prognosis, and we simultaneously conducted treatment for AML and BC. The patient has survived for more than 3 years, which makes this the case with the longest survival reported. CONCLUSION: In patients with BC and AML, it is essential to determine the prognosis through a genomic and molecular evaluation. For a certain group of patients whose prognosis of AML is good, simultaneous or initial treatment of BC before treatment of AML may be appropriate. PMID- 27239179 TI - Pulmonary Tumor Thrombotic Microangiopathy: A New Paraneoplastic Syndrome? AB - This report, based on data from a clinical case, proposes that pulmonary tumor thrombotic microangiopathy, an underdiagnosed cause of pulmonary hypertension and death in patients with adenocarcinoma, is a paraneoplastic syndrome (PNS). Clinicians in general must be alert to the presence or development of PNS that may precede, coincide with, follow, or herald the recurrence or the primary diagnosis of malignancy since early recognition facilitates prompt diagnosis and treatment. PMID- 27239180 TI - Successful Treatment of Metastatic Anal Canal Adenocarcinoma with mFOLFOX6 + Bevacizumab. AB - Anal canal adenocarcinoma is a relatively rare malignancy without established diagnostic and treatment criteria. Case reports of chemotherapy for anal canal adenocarcinoma with distant metastasis are limited, and there is no convincing evidence for treatment effectiveness. A 62-year-old man complained of difficulty in defecation, anal pain, and bleeding during bowel movement. He was diagnosed with moderately differentiated primary anal canal adenocarcinoma. A computed tomography scan revealed multiple metastases in the lung and liver. The patient was treated with abdominoperineal resection to control local tumor growth and then with chemotherapy consisting of mFOLFOX6 + bevacizumab. Because he had an activating KRAS mutation, anti-EGFR therapy was not considered. A reduction in the size of lung and liver metastases was observed after 4 courses of mFOLFOX6 + bevacizumab, and after 22 courses, maximum reduction in the metastatic lesions was achieved. The patient demonstrated tolerable levels of oxaliplatin-related peripheral neurotoxicity (grades 1-2) and was considered as having partial response to treatment. He is currently at the partial response state for 1 year. We plan to continue the treatment unless the patient develops progressive disease or intolerable adverse reactions. This case demonstrates that anal canal adenocarcinoma with distant metastases could be successfully treated with mFOLFOX6 + bevacizumab therapy according to the guidelines for rectal carcinoma. However, as anal canal carcinoma has multiple histological subtypes, it is important to establish subtype-specific treatment strategies. PMID- 27239181 TI - Well-Differentiated Grade 2, Type 3 Gastrointestinal Neuroendocrine Tumour with Bilateral Metastatic Ovarian Involvement: Report of an Unusual Case. AB - Treatment of metastatic gastric neuroendocrine tumours (NETs) is challenging. In oligometastatic cases, surgical resection is recommended whenever possible. Somatostatin analogues have been used to decrease gastrin levels, and available evidence suggests that these drugs can also reduce recurrences. Here we present a highly unusual case involving a patient with a well-differentiated grade 2, type 3 gastric NET with exclusive metastatic bilateral ovarian involvement. To our knowledge, this is the first such case reported in the literature, as the cause of ovarian involvement is usually due to local invasion rather than metastasis. We believe this case is of interest not only due to the unusual presentation, but also because it makes us consider adjuvant treatment with somatostatin analogues in patients with low-grade tumours and a positive postoperative octreoscan. PMID- 27239182 TI - Balloon Cell Malignant Melanoma in a Young Female: A Case Report and Review of the Literature. AB - Balloon cell malignant melanoma (BCMM) is a very rare malignant melanoma subtype. The clinical appearance of BCMM varies; it may be nodular, ulcerated, polypoid, papillomatous and often non-pigmented. The tumor cells histologically appear large, polygonal or round and contain abundant granular or vacuolated cytoplasm. We herein report the case of a 32-year-old female who presented with a focal eccentric pigmented mass in the left lumbar region of 15 mm in diameter that had been present for several years. She underwent tumor excision. The histopathological analysis showed epithelioid melanocytes with clear cytoplasm. An immunohistochemical analysis revealed that the cells were positive for HMB-45 and S-100 protein and negative for cytokeratin. The balloon cell component stained negative for Fontana-Masson. A month later, the patient underwent excision of the bilateral inguinal lymph nodes and metastatic BCMM was revealed. The lymph node metastases showed the complete replacement of lymph nodes by balloon cells. A diagnosis of BCMM (Breslow depth 10 mm, Clark level V) without ulcer was rendered. Staining with Ki-67 was positive in almost 44% of the balloon cells. PMID- 27239184 TI - mFOLFOX6 Chemotherapy after Resection of Anal Canal Mucinous Adenocarcinoma. AB - Because of their rarity, there are no clear guidelines for the treatment of anal carcinomas; such tumors are normally subjected to the same modalities as recommended for rectal cancer. We report a patient with anal canal mucinous adenocarcinoma, with metastases in the pararectal and right inguinal lymph nodes, who was treated with abdominoperineal resection followed by mFOLFOX6 chemotherapy for 6 months (12 cycles). The patient has remained recurrence-free thus far, approximately 2 years since the surgery. As the optimal treatments for anal carcinomas have not been fully elucidated, we present this case to highlight a possible course of action for such patients that appears to be effective and promising. PMID- 27239183 TI - Pulmonary Artery Intimal Sarcoma: A Case Report. AB - Pulmonary artery intimal sarcomas are rare and lethal malignant tumors that typically affect larger vessels: the aorta, inferior vena cava, and pulmonary arteries. Since symptoms and imaging of pulmonary arterial intimal sarcomas mimic pulmonary thromboembolism, the differential diagnosis of a patient presenting with chest pain, dyspnea, and filling defect within the pulmonary arteries should include intimal sarcoma. Often right ventricular failure is observed due to pulmonary hypertension caused by the obstructive effect of the tumor and concomitant chronic thromboembolism. We report the case of a 72-year-old African American male with arterial intimal sarcoma of the left and right pulmonary artery with extension through the right artery into the bronchus and right lung. PMID- 27239185 TI - Cauda Equina Syndrome Secondary to Leptomeningeal Carcinomatosis of Gastroesophageal Junction Cancer. AB - Leptomeningeal carcinomatosis (LMC) is a diffuse or multifocal malignant infiltration of the pia matter and arachnoid membrane. The most commonly reported cancers associated with LMC are breast, lung, and hematological malignancies. Patients with LMC commonly present with multifocal neurological symptoms. We report a case of LMC secondary to gastroesopha-geal junction cancer present initially with cauda equina syndrome. A 51-year-old male patient with treated adenocarcinoma of the gastroesophageal junction presented with left leg pain, mild weakness, and saddle area numbness. Initial radiological examinations were unremarkable. Subsequently, he had worsening of his leg weakness, fecal incontinence, and urine retention. Two days later, he developed rapidly progressive cranial neuropathies including facial diplegia, sensorineural hearing loss, dysarthria, and dysphagia. MRI with and without contrast showed diffuse enhancement of leptomeninges surrounding the brain, spinal cord, and cauda equina extending to the nerve roots. Cerebrospinal fluid cytology was positive for malignant cells. The patient died within 10 days from the second presentation. In cancer patients with cauda equina syndrome and absence of structural lesion on imaging, LMC should be considered. To our knowledge, this is the first case of LMC secondary to gastroesophageal cancer presenting with cauda equina syndrome. PMID- 27239186 TI - Neuroleptic Malignant Syndrome Associated with Refractory Acute Disseminated Encephalomyelitis. AB - We present the case of a young man who was transferred to our hospital with worsening acute disseminated encephalomyelitis (ADEM) despite treatment with intravenous methylprednisolone, intravenous immunoglobulin and plasma exchange. He developed neuroleptic malignant syndrome (NMS) without the use of dopamine modulating drugs. His progressive clinical improvement started after treatment with intravenous cyclophosphamide and methylprednisolone. In our patient, acute demyelination with severe bilateral inflammation of the basal ganglia could have caused a state of central dopamine depletion, creating proper conditions for the development of NMS. Significant clinical improvement of our case after treatment with intravenous cyclophosphamide and steroids provides further evidence for a possible role of the inflammatory lesions in the pathogenesis of NMS in association with ADEM. PMID- 27239187 TI - A Case of Severe Panuveitis Associated with Psoriasis Vulgaris Successfully Treated with Infliximab. AB - PURPOSE: Uveitis associated with psoriasis vulgaris is usually seen as an anterior segment inflammation, and it is very rare that the inflammation extends to the posterior segment. We herein report a case of severe panuveitis associated with psoriasis vulgaris presenting as retinal neovascularization, leading to vitreous hemorrhages that were successfully treated with infliximab (IFX). CASE REPORT: A 27-year-old male with psoriasis vulgaris was referred to our hospital due to prolonged severe uveitis OU. He showed a severe anterior chamber inflammation with fibrin formation and total posterior iris synechia OU. With topical corticosteroid treatment, these conditions were relieved for a short time; however, the intraocular inflammation was exacerbated with vitreous hemorrhages caused by retinal neovascularization OS. After the administration of IFX therapy, the intraocular inflammation and retinal neovascularization was resolved, and so far, no severe recurrences have been seen for 3 years with the therapy. CONCLUSION: When we see patients with severe panuveitis associated with psoriasis extending to the posterior segment, IFX treatment may be a good therapeutic option. PMID- 27239188 TI - A Psychometric Evaluation of the Threadgold Communication Tool for Persons with Dementia. AB - BACKGROUND: The objective of this study was to investigate the psychometric properties of the Threadgold Communication Tool (TCT). METHOD: Internal consistency reliability was measured using Cronbach's alpha coefficient and inter item correlation. Test-retest was performed to examine the instrument's stability. Exploratory principal component analysis (PCA) with oblimin rotation was carried out to evaluate construct validity. Finally, the score on each item of the TCT was correlated with the person's Mini Mental State Examination (MMSE) and Barthel Index of activities of daily living scores. RESULTS: A total of 51 persons participated, with a mean age of 86.7 (SD 6.6) years, of whom 46 were women with moderate-to-severe dementia [mean MMSE score 7.5 (SD 6.7)]. There were two measurement points 2 weeks apart. The results showed a satisfactory level for internal consistency and a high test-retest reliability (r = 0.76). The corrected item-total correlation ranged between 0.50 and 0.87, and a two-factor structure was revealed at the PCA. 'Vocalizing' seemed to measure another aspect of communication and was the only item which was negatively loaded. CONCLUSION: Despite the low sample size in this study, the results revealed the TCT as a reliable and valid instrument, suitable for measuring communication among people with dementia. We suggest clarifying the understanding of 'vocalizing' before considering removing it from the scale. PMID- 27239189 TI - Simulation of Code Spectrum and Code Flow of Cultured Neuronal Networks. AB - It has been shown that, in cultured neuronal networks on a multielectrode, pseudorandom-like sequences (codes) are detected, and they flow with some spatial decay constant. Each cultured neuronal network is characterized by a specific spectrum curve. That is, we may consider the spectrum curve as a "signature" of its associated neuronal network that is dependent on the characteristics of neurons and network configuration, including the weight distribution. In the present study, we used an integrate-and-fire model of neurons with intrinsic and instantaneous fluctuations of characteristics for performing a simulation of a code spectrum from multielectrodes on a 2D mesh neural network. We showed that it is possible to estimate the characteristics of neurons such as the distribution of number of neurons around each electrode and their refractory periods. Although this process is a reverse problem and theoretically the solutions are not sufficiently guaranteed, the parameters seem to be consistent with those of neurons. That is, the proposed neural network model may adequately reflect the behavior of a cultured neuronal network. Furthermore, such prospect is discussed that code analysis will provide a base of communication within a neural network that will also create a base of natural intelligence. PMID- 27239190 TI - Characterization of Visual Scanning Patterns in Air Traffic Control. AB - Characterization of air traffic controllers' (ATCs') visual scanning strategies is a challenging issue due to the dynamic movement of multiple aircraft and increasing complexity of scanpaths (order of eye fixations and saccades) over time. Additionally, terminologies and methods are lacking to accurately characterize the eye tracking data into simplified visual scanning strategies linguistically expressed by ATCs. As an intermediate step to automate the characterization classification process, we (1) defined and developed new concepts to systematically filter complex visual scanpaths into simpler and more manageable forms and (2) developed procedures to map visual scanpaths with linguistic inputs to reduce the human judgement bias during interrater agreement. The developed concepts and procedures were applied to investigating the visual scanpaths of expert ATCs using scenarios with different aircraft congestion levels. Furthermore, oculomotor trends were analyzed to identify the influence of aircraft congestion on scan time and number of comparisons among aircraft. The findings show that (1) the scanpaths filtered at the highest intensity led to more consistent mapping with the ATCs' linguistic inputs, (2) the pattern classification occurrences differed between scenarios, and (3) increasing aircraft congestion caused increased scan times and aircraft pairwise comparisons. The results provide a foundation for better characterizing complex scanpaths in a dynamic task and automating the analysis process. PMID- 27239191 TI - A Framework for the Comparative Assessment of Neuronal Spike Sorting Algorithms towards More Accurate Off-Line and On-Line Microelectrode Arrays Data Analysis. AB - Neuronal spike sorting algorithms are designed to retrieve neuronal network activity on a single-cell level from extracellular multiunit recordings with Microelectrode Arrays (MEAs). In typical analysis of MEA data, one spike sorting algorithm is applied indiscriminately to all electrode signals. However, this approach neglects the dependency of algorithms' performances on the neuronal signals properties at each channel, which require data-centric methods. Moreover, sorting is commonly performed off-line, which is time and memory consuming and prevents researchers from having an immediate glance at ongoing experiments. The aim of this work is to provide a versatile framework to support the evaluation and comparison of different spike classification algorithms suitable for both off line and on-line analysis. We incorporated different spike sorting "building blocks" into a Matlab-based software, including 4 feature extraction methods, 3 feature clustering methods, and 1 template matching classifier. The framework was validated by applying different algorithms on simulated and real signals from neuronal cultures coupled to MEAs. Moreover, the system has been proven effective in running on-line analysis on a standard desktop computer, after the selection of the most suitable sorting methods. This work provides a useful and versatile instrument for a supported comparison of different options for spike sorting towards more accurate off-line and on-line MEA data analysis. PMID- 27239192 TI - Vaccinating Adult Patients with Cirrhosis: Trends over a Decade in the United States. AB - Introduction. The progression of chronic liver disease to cirrhosis involves both innate and adaptive immune system dysfunction resulting in increased risk of infectious complications. Vaccinations against pneumococcus, hepatitis A virus (HAV), and hepatitis B virus (HBV) are well tolerated and effective in disease prevention and reduction in morbidity and mortality. Prior studies assessing vaccination rates in patients with cirrhosis have specific limitations and to date no study has provided a comprehensive evaluation of vaccination rates in patients with cirrhosis in the United States. Aim. This study assessed vaccination rates for pneumococcus, HAV, and HBV in patients with cirrhosis. Results. Overall 59.7% of patients with cirrhosis received at least 1 vaccination during the study period. Vaccination rates within the same or following year of cirrhosis diagnosis were 19.9%, 7.7%, and 11.0% against pneumococcus, HAV, and HBV, respectively. Trend analysis revealed significant increases in vaccination rates for pneumococcus in all patients with cirrhosis and within subgroups based on age, gender, and presence of concomitant diabetes. Conclusion. The study demonstrated that vaccination rates in patients with cirrhosis remain suboptimal. Ultimately, the use of electronic medical record (EMR) reminders improved communication between healthcare professionals and public health programs to increase awareness are fundamental to reducing morbidity, mortality, and health care related costs of vaccine preventable diseases in patients with cirrhosis. PMID- 27239193 TI - Factor Analysis Influencing Postoperative Hospital Stay and Medical Costs for Patients with Definite, Suspected, or Unmatched Diagnosis of Acute Cholecystitis according to the Tokyo Guidelines 2013. AB - Purpose. To identify significant independent preoperative factors influencing postoperative hospital stay (PHS) and medical costs (MC) in 171 patients who underwent cholecystectomy for benign gallbladder diseases and had definite, suspected, or unmatched acute cholecystitis (AC) diagnosis according to the Tokyo Guidelines 2013 (TG13). Methods. The 171 patients were classified according to the combination of diagnostic criteria including local signs of inflammation (A), systemic signs of inflammation (B), and imaging findings (C): A+ B+ C (definite diagnosis, n = 84), A+ B (suspected diagnosis, n = 25), (A or B) + C (n = 10), A (n = 41), and B (n = 11). Results. The A+ B + C and (A or B) + C groups had equivalent PHS and MC, suggesting that imaging findings were essential for AC diagnosis. PHS and MC were significantly increased in the order of severity grades based on TG13. Performance status (PS), white blood cell count, and severity grade were identified as preoperative factors influencing PHS by multivariate analysis, and significant independent preoperative factors influencing MC were age, PS, preoperative biliary drainage, hospital stay before surgery, albumin, and severity grade. Conclusion. PS and severity grade significantly influenced prolonged PHS and increased MC. PMID- 27239194 TI - Dyspepsia: When and How to Test for Helicobacter pylori Infection. AB - Dyspepsia is defined as symptoms related to the upper gastrointestinal tract. Approximately 25% of western populations complain of dyspeptic symptoms each year. 70% of them do not have an organic cause and symptoms are related to the so called functional dyspepsia, characterized by epigastric pain, early satiety, and/or fullness during or after a meal occurring at least weekly and for at least 6 months according to ROME III criteria. In order to avoid invasive procedures and adverse effects, to minimize costs, to speed up diagnosis, and to provide the most appropriate treatments, primary care physicians need to recognize functional dyspepsia. Because symptoms do not reliably discriminate between organic and functional forms of the disease, anamnesis, family history of peptic ulcer and/or of gastric cancer, medication history, especially for nonsteroidal anti inflammatory drugs, age, and physical examination could help the physician in discerning between functional dyspepsia and organic causes. For patients without alarm symptoms, noninvasive testing for H. pylori, with either carbon-13-labeled urea breath testing or stool antigen testing, is recommended as a first-line strategy. In this review, we provide recommendations to guide primary care physicians for appropriate use of diagnostic tests and for H. pylori management in dyspeptic patients. PMID- 27239196 TI - Excisional Treatment of Cervical Dysplasia in Australia 2004-2013: A Population Based Study. AB - Background. Excisional treatment of preinvasive cervical dysplasia has been associated with adverse pregnancy outcomes. We aimed to examine trends in the rate of excisional treatment in reproductive age women in the era of HPV vaccination. Methods. National data for Australia regarding histological diagnoses of cervical dysplasia and excisional treatment for the period from 2004 to 2013 inclusive were obtained from two datasets and used to calculate age stratified incidence rates of excisional treatment and of excisional treatments per diagnosis of dysplasia. Results. The incidence of low-grade squamous dysplasia fell in all age groups, while the incidence of high-grade dysplasia fell in the 20-to-24-year group but rose slightly for older age groups. The rate of excisional treatment fell in women aged under 35 but there was no significant change for women 35 years or older. The rate of all excisional treatments (loop excision + cone biopsy) per high-grade diagnosis (CIN2 + CIN3 + adenocarcinoma in situ) fell across all three age-bands in both datasets. Conclusion. To ensure that the use of excisional treatment is appropriate, with lower rates for younger HPV-vaccinated women, close surveillance, audit, and ongoing education will be required. PMID- 27239195 TI - Lipid Profile in Adolescent Girls with Type 1 Diabetes Mellitus and Hyperandrogenemia. AB - Study Objectives. The study aim was to evaluate whether hyperandrogenemia in adolescent girls with type 1 diabetes mellitus (T1DM) may adversely influence lipid profile. Design and Participants. Lipid levels in 16 diabetic girls with biochemical hyperandrogenemia (T1DM-H) aged 16.3 +/- 1.2 years were compared to 38 diabetic girls with normal androgen levels (T1DM-N) aged 15.8 +/- 1.2 years. 15 healthy girls served as controls (CG). In all patients, anthropometric measurements were done, and androgens and SHBG were assessed. Results. In T1DM-H, total cholesterol (TC) and low density cholesterol (LDL-ch) were significantly higher than in CG (196.1 +/- 41.2 versus 162.7 +/- 31.7 mg/dL, p = 0.01; 117.3 +/ 33.1 versus 91.3 +/- 27.8 mg/dL, p = 0.01, resp.). Their LDL-ch, non-high density cholesterol (non-HDL-ch) concentrations, and LDL/HDL ratio were also significantly higher than in T1DM-N (117.3 +/- 33.1 versus 97.7 +/- 26.7 mg/dL, p = 0.03; 137.3 +/- 42.9 versus 113.3 +/- 40.4 mg/dL, p = 0.04; 2.8 +/- 3.7 versus 1.6 +/- 0.5, p = 0.04, resp.). In stepwise multiple linear regression, free androgen index (FAI) and waist-to-hip ratio (WHR) were associated with TC (R (2) = 0.4, p < 0.0006), non-HDL-ch (R (2) = 0.4, p < 0.0003), and LDL-ch (R (2) = 0.4, p < 0.0008). Triglycerides and LDL/HDL ratio were (R (2) = 0.7, p < 0.0001, R (2) = 0.6, p < 0.0003 resp.) related to testosterone, FAI, WHR, and mean HbA1c. Conclusion. Lipid profile in diabetic adolescent girls is adversely influenced by the androgens level, particularly in the group with higher WHR and poorer glycemic control. PMID- 27239197 TI - Coffee Consumption and the Incidence of Colorectal Cancer in Women. AB - Background. Higher coffee consumption has been associated with decreased incidence of colorectal cancer. Our objective was to examine the relationship of coffee intake to colorectal cancer incidence in a large observational cohort of postmenopausal US women. Methods. Data were collected for the Women's Health Initiative Observational Study providing a follow-up period of 12.9 years. The mean age of our sample (N = 83,778 women) was 63.5 years. Daily coffee intake was grouped into 3 categories: None, moderate (>0-<4 cups), and high (4+ cups). Proportional hazards modeling was used to evaluate the relationship between coffee intake and colorectal cancer. Results. There were 1,282 (1.53%) new cases of colorectal cancer during follow-up. Compared to nondrinkers, moderate and high coffee drinkers had an increased incidence of colorectal cancer in multivariate analysis (HR 1.15, 1.02-1.29; HR 1.14, 0.93-1.38). Moderate drip brew coffee intake (HR 1.20, 1.05-1.36) and high nondrip brew coffee intake (HR 1.43, 1.01 2.02) were associated with increased odds. Conclusion. Our results suggesting increased incidence of colorectal cancer associated with higher coffee consumption contradict recent meta-analyses but agree with a number of other studies showing that coffee increases risk or has no effect. Brew method results are novel and warrant further research. PMID- 27239199 TI - Predictive Factors for Medical Consultation for Sore Throat in Adults with Recurrent Pharyngotonsillitis. AB - Objects. To seek patient- and episode-related factors that associate with medical consultation for acute sore throat because these factors may affect the patient being referred to specialist care and tonsillectomy for recurrent pharyngotonsillitis. Methods. In a secondary analysis of two prior randomised controlled trials, sore throat episodes and medical visits were explored among 156 adult patients referred for tonsillectomy because of recurrent pharyngotonsillitis. Results. The 156 patients (104 females, mean age of 26 years) suffered from 208 acute pharyngotonsillitis episodes during 5-6 months of follow-up. Forty (25%) patients visited a physician, and female gender (adjusted hazard ratio, HR, 3.3; 95% confidence interval 1.4-8.0) and finding of chronically infected tonsils (HR 2.7; 1.2-6.1) were associated with medical consultation. Thirty-six (17%) episodes led to medical consultation during the first 7 days of symptoms. Presence of severe throat pain was related to medical visit (HR 4.3; 1.0-18.5). Conclusions. Even among patients with recurrent pharyngotonsillitis, the acute sore throat episodes were usually mild and only few resulted in medical consultation, with female gender, chronically infected tonsils, and having severe throat pain increasing the consultation rate. PMID- 27239198 TI - Combined Bone Marrow and Kidney Transplantation for the Induction of Specific Tolerance. AB - The induction of specific tolerance, in order to avoid the detrimental effects of lifelong systemic immunosuppressive therapy after organ transplantation, has been considered the "Holy Grail" of transplantation. Experimentally, tolerance has been achieved through clonal deletion, through costimulatory blockade, through the induction or infusion of regulatory T-cells, and through the establishment of hematopoietic chimerism following donor bone marrow transplantation. The focus of this review is how tolerance has been achieved following combined bone marrow and kidney transplantation. Preclinical models of combined bone marrow and kidney transplantation have shown that tolerance can be achieved through either transient or sustained hematopoietic chimerism. Combined transplants for patients with multiple myeloma have shown that organ tolerance and prolonged disease remissions can be accomplished with such an approach. Similarly, multiple clinical strategies for achieving tolerance in patients without an underlying malignancy have been described, in the context of either transient or durable mixed chimerism or sustained full donor hematopoiesis. To expand the chimerism approach to deceased donor transplants, a delayed tolerance approach, which will involve organ transplantation with conventional immunosuppression followed months later by bone marrow transplantation, has been successful in a primate model. As combined bone marrow and organ transplantation become safer and increasingly successful, the achievement of specific tolerance may become more widely applicable. PMID- 27239200 TI - Bone Cutting Forceps: A Safe Approach for Saving Strangulated Penis. AB - Penile strangulation is considered a rare andrological emergency that may lead to a wide range of complications. Penile strangulation may be related to mental retardation in children or hypersexuality, abnormal sexual preferences in adults. This case report shows a 23-year-old male who presented to the emergency room with agonizing pain related to a metallic ring placed at the base of the penis for more than 8 hours during an attempt of masturbation. Removing this metallic ring and saving the patient's penis from gangrene without causing injury were very challenging. Patient was successfully managed and had an uneventful recovery. PMID- 27239202 TI - Comparison of the Biological Characteristics of Mesenchymal Stem Cells Derived from Bone Marrow and Skin. AB - Mesenchymal stem cells (MSCs) exhibit high proliferation and self-renewal capabilities and are critical for tissue repair and regeneration during ontogenesis. They also play a role in immunomodulation. MSCs can be isolated from a variety of tissues and have many potential applications in the clinical setting. However, MSCs of different origins may possess different biological characteristics. In this study, we performed a comprehensive comparison of MSCs isolated from bone marrow and skin (BMMSCs and SMSCs, resp.), including analysis of the skin sampling area, separation method, culture conditions, primary and passage culture times, cell surface markers, multipotency, cytokine secretion, gene expression, and fibroblast-like features. The results showed that the MSCs from both sources had similar cell morphologies, surface markers, and differentiation capacities. However, the two cell types exhibited major differences in growth characteristics; the primary culture time of BMMSCs was significantly shorter than that of SMSCs, whereas the growth rate of BMMSCs was lower than that of SMSCs after passaging. Moreover, differences in gene expression and cytokine secretion profiles were observed. For example, secretion of proliferative cytokines was significantly higher for SMSCs than for BMMSCs. Our findings provide insights into the different biological functions of both cell types. PMID- 27239201 TI - Human Embryonic Stem Cells: A Model for the Study of Neural Development and Neurological Diseases. AB - Although the mechanism of neurogenesis has been well documented in other organisms, there might be fundamental differences between human and those species referring to species-specific context. Based on principles learned from other systems, it is found that the signaling pathways required for neural induction and specification of human embryonic stem cells (hESCs) recapitulated those in the early embryo development in vivo at certain degree. This underscores the usefulness of hESCs in understanding early human neural development and reinforces the need to integrate the principles of developmental biology and hESC biology for an efficient neural differentiation. PMID- 27239203 TI - Tissue Inhibitor of Matrix Metalloproteinases-1 Knockdown Suppresses the Proliferation of Human Adipose-Derived Stem Cells. AB - Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a multifunctional matrix metalloproteinase, and it is involved in the regulation of cell proliferation and apoptosis in various cell types. However, little is known about the effect of TIMP-1 expression on the proliferation of adipose-derived stem cells (ADSCs). Therefore, TIMP-1 expression in the ADSCs was firstly detected by western blotting, and TIMP-1 gene was knocked down by lentivirus-mediated shRNA. Cell proliferation was then evaluated by MTT assay and Ki67 staining, respectively. Cell cycle progression was determined by flow cytometry. The changes of p51, p21, cyclin E, cyclin-dependent kinase 2 (CDK2), and P-CDK2 caused by TIMP-1 knockdown were detected by western blotting. The results indicated that ADSCs highly expressed TIMP-1 protein, and the knockdown of TIMP-1 inhibited cell proliferation and arrested cell cycle progression at G1 phase in the ADSCs possibly through the upregulation of p53, p21, and P-CDK2 protein levels and concurrent downregulation of cyclin E and CDK2 protein levels. These findings suggest that TIMP-1 works as a positive regulator of cell proliferation in ADSCs. PMID- 27239204 TI - A Comparative Evaluation of the Mechanical Properties of Two Calcium Phosphate/Collagen Composite Materials and Their Osteogenic Effects on Adipose Derived Stem Cells. AB - Adipose-derived stem cells (ADSCs) are ideal seed cells for use in bone tissue engineering and they have many advantages over other stem cells. In this study, two kinds of calcium phosphate/collagen composite scaffolds were prepared and their effects on the proliferation and osteogenic differentiation of ADSCs were investigated. The hydroxyapatite/beta-tricalcium phosphate (HA/beta-TCP) composite scaffolds (HTPSs), which have an additional beta-tricalcium phosphate, resulted in better proliferation of ADSCs and showed osteogenesis-promoting effects. Therefore, such composite scaffolds, in combination with ADSCs or on their own, would be promising for use in bone regeneration and potential clinical therapy for bone defects. PMID- 27239205 TI - Hepatic Stellate Cell-Derived Microvesicles Prevent Hepatocytes from Injury Induced by APAP/H2O2. AB - Hepatic stellate cells (HSCs), previously described for liver-specific mesenchymal stem cells (MSCs), appear to contribute to liver regeneration. Microvesicles (MVs) are nanoscale membrane fragments, which can regulate target cell function by transferring contents from their parent cells. The aim of this study was to investigate the effect of HSC-derived MVs on xenobiotic-induced liver injury. Rat and human hepatocytes, BRL-3A and HL-7702, were used to build hepatocytes injury models by n-acetyl-p-aminophenol n-(APAP) or H2O2 treatment. MVs were prepared from human and rat HSCs, LX-2, and HST-T6 and, respectively, added to injured BRL-3A and HL-7702 hepatocytes. MTT assay was utilized to determine cell proliferation. Cell apoptosis was analyzed by flow cytometry and hoechst33258 staining. Western blot was used for analyzing the expression of activated caspase-3. Liver injury indicators, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) in culture medium were also assessed. Results showed that (1) HSC-MVs derived from LX-2 and HST-T6 were positive to CD90 and annexin V surface markers; (2) HSC-MVs dose dependently improved the viability of hepatocytes in both injury models; (3) HSC MVs dose-dependently inhibited the APAP/H2O2 induced hepatocytes apoptosis and activated caspase-3 expression and leakage of LDH, ALT, and AST. Our results demonstrate that HSC-derived MVs protect hepatocytes from toxicant-induced injury. PMID- 27239207 TI - Sex Differences in the Use of Complementary and Alternative Medicine among Adults with Multiple Chronic Conditions. AB - Objective. To examine sex differences in complementary and alternative medicine (CAM) use among adults with multiple chronic conditions. Methods. This study used a cross-sectional design with data from the 2012 National Health Interview Survey. The participants were interviewed in 2012 and the reference period for the questions in the survey varied from 1 week to 12 months prior to the interview date. The study included adults (age > 21 years) with no missing data on CAM use variables and who had multiple chronic conditions. Multivariable regression analyses were used to examine the association between sex and CAM use. Results. A significantly higher percentage of women compared to men had ever used CAM (51.5% versus 44.3%); women were more likely to have ever used CAM (AOR = 1.49, 95% CI = 1.35-1.65). Among CAM users, a higher percentage of women compared to men used CAM in the past 12 months (53.5% vs. 42.7%); women were more likely to use CAM in the past 12 months (AOR = 1.71, 95% CI = 1.49-1.97). Factors associated with CAM use in the past 12 months were different for men and women; income and obesity were associated with CAM use in the past 12 months among women and not among men. Conclusion. Among adults with multiple chronic conditions, women were more likely to use CAM as compared to men. PMID- 27239206 TI - Antioxidant and Anti-Inflammatory Effects of Rhei Rhizoma and Coptidis Rhizoma Mixture on Reflux Esophagitis in Rats. AB - The purpose of this study was to investigate the antioxidant and anti inflammatory effects of the combined extract of Rhei rhizoma and Coptidis rhizoma (RC-mix) in experimental model of acute reflux esophagitis. The antioxidant activity was assessed by in vitro 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2' azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays. RC-mix was given at 100, 200, and 400 mg/kg body weight 2 h prior to induction of reflux esophagitis (RE). After 5 h, the effects of RC-mix treated rats were compared with those of normal and control rats. The representative flavonoid contents of RC-mix, such as sennoside A, epiberberine, coptisine, palmatine, and berberine, were detected using HPLC. The elevated esophageal mucosa damage was markedly ameliorated by RC-mix treatment in a dose-dependent manner. Furthermore, the administration of RC-mix reduced the increase of serum reactive oxygen species (ROS) and peroxynitrite (ONOO(-)). The improvement of superoxide dismutase (SOD) and heme oxygenase-1 (HO-1) levels were marked in the group given RC-mix. Moreover, the elevation of inflammatory mediators and cytokines by nuclear factor kappa B (NF-kappaB) activation in control rats decreased by RC-mix pretreatment. These results indicate that RC-mix treatment reduces the pathological states of esophagitis via regulating NF-kappaB mediated inflammation related to oxidative stress. PMID- 27239208 TI - Korean Medicine in General Practice: Current Status, Challenges, and Vision in Clinical Evidence. PMID- 27239209 TI - Intravenous Mistletoe Treatment in Integrative Cancer Care: A Qualitative Study Exploring the Procedures, Concepts, and Observations of Expert Doctors. AB - Background. Mistletoe therapy (MT) is widely used in patient-centered integrative cancer care. The objective of this study was to explore the concepts, procedures, and observations of expert doctors, with a focus on intravenous MT. Method. A qualitative interview study was conducted with 35 highly experienced doctors specialized in integrative and anthroposophic medicine. Structured qualitative content analysis was applied. For triangulation, the results were compared with external evidence that was systematically collected, reviewed, and presented. Results. Doctors perform individualized patient assessments that lead to multimodal treatment approaches. The underlying goal is to help patients to live with and overcome disease. Mistletoe infusions are a means of accomplishing this goal. They are applied to stabilize disease, achieve responsiveness, induce fever, improve quality of life, and improve the tolerability of conventional cancer treatments. The doctors reported long-term disease stability and improvements in patients' general condition, vitality, strength, thermal comfort, appetite, sleep, pain from bone metastases, dyspnea in pulmonary lymphangitis carcinomatosa, fatigue, and cachexia; chemotherapy was better tolerated. Also patients' emotional and mental condition was reported to have improved. Conclusion. Individualized integrative cancer treatment including MT aims to help cancer patients to live well with their disease. Further research should investigate the reported observations. PMID- 27239210 TI - Antibacterial and Antimetastatic Potential of Diospyros lycioides Extract on Cervical Cancer Cells and Associated Pathogens. AB - Cervical cancer is among the most prevalent forms of cancer in women worldwide. Diospyros lycioides was extracted using hexane, ethyl acetate, acetone, and methanol and finger print profiles were determined. The leaf material was tested for the presence of flavonoids, tannins, saponins, terpenoids, and cardiac glycosides using standard chemical methods and the presence of flavonoids and phenolics using thin layer chromatography. The total phenolic content was determined using Folin-Ciocalteu procedure. The four extracts were tested for antibacterial activity using bioautography against Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa, and Escherichia coli. The acetone extract with the highest number of antibacterial and antioxidant compounds was assessed for its cytotoxicity on BUD-8 cells using the real-time xCELLigence system and its potential effects on metastatic cervical cancer (HeLa) cell migration and invasion were assessed using wound healing migration and invasion assays. The leaf extract tested positive for flavonoids, tannins, and terpenoids while the four different extracts tested in the antimicrobial assay contained constituents active against one or more of the organisms tested, except E. coli. The cytotoxicity of the acetone extract in real-time was concentration-dependent with potent ability to suppress the migration and invasion of HeLa cells. The finding demonstrates the acetone extract to contain constituents with antibacterial and antimetastatic effects on cervical cancer cells. PMID- 27239211 TI - Cognitive-Enhancing Effect of Aronia melanocarpa Extract against Memory Impairment Induced by Scopolamine in Mice. AB - Aronia melanocarpa (A. melanocarpa) berries are a fruit with a marked antioxidant effect. The objective of this study was to confirm the effect of A. melanocarpa berries extract against scopolamine-induced memory impairment in mice using the Morris water maze and passive avoidance test. Moreover, we determined a possible mechanism of the cognitive-enhancing effect involving AChE activity and BDNF and p-CREB expression in the hippocampus of mice. A. melanocarpa berries extract attenuated the learning and memory impairment induced by scopolamine in the Morris water maze (79.3 +/- 0.8 s of 200 mg/kg and 64.4 +/- 10.7 s of 400 mg/kg on day 4) and passive avoidance tests (46.0 +/- 41.1 s of 200 mg/kg and 25.6 +/- 18.7 s of 400 mg/kg). A. melanocarpa berries extract reduced the acetylcholinesterase level in the hippocampus of scopolamine-injected mice and increased BDNF and p-CREB expression in the hippocampus. The major compound, cyanidin-3-O-galactoside, also reversed memory impairment. These results showed that A. melanocarpa berries extract improved memory impairment by inhibiting AChE and increasing BDNF and p-CREB expression, and cyanidin-3-O-galactoside may be responsible for the effect of A. melanocarpa berries extract. PMID- 27239212 TI - Du-Huo-Ji-Sheng-Tang Attenuates Inflammation of TNF-Tg Mice Related to Promoting Lymphatic Drainage Function. AB - To investigate whether Du-Huo-Ji-Sheng-Tang (DHJST) attenuate inflammation of RA related to lymphatic drainage function in vivo, we treated eight 3-month-old TNF Tg mice with DHJST (12 g/kg) or the same volume of physiological saline once every day for 12 weeks, and 3-month-old WT littermates were used as negative control. After twelve weeks, we performed NIR-ICG imaging and found that DHJST increased the ICG clearance at the footpad and the pulse of efferent lymphatic vessel between popliteal lymph node and footpad. Histology staining at ankle joints showed that DHJST decreases synovial inflammation, bone erosion, cartilage erosion, and TRAP+ osteoclast area in TNF-Tg mice. Immunohistochemical staining by using anti-Lyve-1 and anti-podoplanin antibody showed that DHJST stimulated lymphangiogenesis in ankle joints of TNF-Tg mice. And zebrafish study suggested that DHJST promoted the formation of lymphatic thoracic duct. In conclusion, DHJST inhibits inflammation severity and promotes lymphangiogenesis and lymphatic drainage function of TNF-Tg mice. PMID- 27239213 TI - Cortex phellodendri Extract Relaxes Airway Smooth Muscle. AB - Cortex phellodendri is used to reduce fever and remove dampness and toxin. Berberine is an active ingredient of C. phellodendri. Berberine from Argemone ochroleuca can relax airway smooth muscle (ASM); however, whether the nonberberine component of C. phellodendri has similar relaxant action was unclear. An n-butyl alcohol extract of C. phellodendri (NBAECP, nonberberine component) was prepared, which completely inhibits high K(+)- and acetylcholine- (ACH-) induced precontraction of airway smooth muscle in tracheal rings and lung slices from control and asthmatic mice, respectively. The contraction induced by high K(+) was also blocked by nifedipine, a selective blocker of L-type Ca(2+) channels. The ACH-induced contraction was partially inhibited by nifedipine and pyrazole 3, an inhibitor of TRPC3 and STIM/Orai channels. Taken together, our data demonstrate that NBAECP can relax ASM by inhibiting L-type Ca(2+) channels and TRPC3 and/or STIM/Orai channels, suggesting that NBAECP could be developed to a new drug for relieving bronchospasm. PMID- 27239214 TI - Berberine Inhibition of Fibrogenesis in a Rat Model of Liver Fibrosis and in Hepatic Stellate Cells. AB - Aim. To examine the effect of berberine (BBR) on liver fibrosis and its possible mechanisms through direct effects on hepatic stellate cells (HSC). Methods. The antifibrotic effect of BBR was determined in a rat model of bile duct ligation- (BDL-) induced liver fibrosis. Multiple cellular and molecular approaches were introduced to examine the effects of BBR on HSC. Results. BBR potently inhibited hepatic fibrosis induced by BDL in rats. It exhibited cytotoxicity to activated HSC at doses nontoxic to hepatocytes. High doses of BBR induced apoptosis of activated HSC, which was mediated by loss of mitochondrial membrane potential and Bcl-2/Bax imbalance. Low doses of BBR suppressed activation of HSC as evidenced by the inhibition of alpha-smooth muscle actin (alpha-SMA) expression and cell motility. BBR did not affect Smad2/3 phosphorylation but significantly activated 5' AMP-activated protein kinase (AMPK) signalling, which was responsible for the transcriptional inhibition by BBR of profibrogenic factors alpha-SMA and collagen in HSC. Conclusion. BBR is a promising agent for treating liver fibrosis through multiple mechanisms, at least partially by directly targeting HSC and by inhibiting the AMPK pathway. Its value as an antifibrotic drug in patients with liver disease deserves further investigation. PMID- 27239215 TI - Systems Pharmacology Uncovers the Multiple Mechanisms of Xijiao Dihuang Decoction for the Treatment of Viral Hemorrhagic Fever. AB - Background. Viral hemorrhagic fevers (VHF) are a group of systemic diseases characterized by fever and bleeding, which have posed a formidable potential threat to public health with high morbidity and mortality. Traditional Chinese Medicine (TCM) formulas have been acknowledged with striking effects in treatment of hemorrhagic fever syndromes in China's history. Nevertheless, their accurate mechanisms of action are still confusing. Objective. To systematically dissect the mechanisms of action of Chinese medicinal formula Xijiao Dihuang (XJDH) decoction as an effective treatment for VHF. Methods. In this study, a systems pharmacology method integrating absorption, distribution, metabolism, and excretion (ADME) screening, drug targeting, network, and pathway analysis was developed. Results. 23 active compounds of XJDH were obtained and 118 VHF-related targets were identified to have interactions with them. Moreover, systematic analysis of drug-target network and the integrated VHF pathway indicate that XJDH probably acts through multiple mechanisms to benefit VHF patients, which can be classified as boosting immune system, restraining inflammatory responses, repairing the vascular system, and blocking virus spread. Conclusions. The integrated systems pharmacology method provides precise probe to illuminate the molecular mechanisms of XJDH for VHF, which will also facilitate the application of traditional medicine in modern medicine. PMID- 27239216 TI - Chinese Herbal Medicine as an Adjunctive Therapy for Breast Cancer: A Systematic Review and Meta-Analysis. AB - Chinese herbal medicine (CHM) has been widely used as an adjunctive therapy for breast cancer, while its efficacy remains unexplored. The purpose of this study is to evaluate the efficacy of CHM combined with chemotherapy for breast cancer. The study results showed that CHM combined with chemotherapy significantly increased tumor response and KPS as compared to using chemotherapy alone (RR = 1.36; 95% CI = 1.24-1.48; P < 0.00001; RR = 1.38; 95% CI = 1.26-1.52; P < 0.00001, resp.). Besides, CHM as an adjunctive therapy significantly reduced the nausea and vomiting at toxicity grade of III-IV (RR = 0.37; 95% CI = 0.27-0.52; P < 0.00001). Moreover, the combined therapy significantly prevented the decline of WBC in patients under chemotherapy at toxicity grade of III-IV (RR = 0.49; 95% CI = 0.34-0.69; P < 0.00001) and prevented the decline of platelet at toxicity grade of III-IV or I-IV (RR = 0.29; 95% CI = 0.12-0.73; P = 0.008; RR = 0.77; 95% CI = 0.63-0.94; P = 0.009, resp.). This study suggests that CHM combined with chemotherapy in comparison with chemotherapy alone can significantly enhance tumor response, improve KPS, and alleviate toxicity induced by chemotherapy in breast cancer patients. However, a firm conclusion could not be reached due to the lack of high quality trials and large-scale RCTs, so further trials with higher quality and larger scale are needed. PMID- 27239217 TI - Influence of the Melissa officinalis Leaf Extract on Long-Term Memory in Scopolamine Animal Model with Assessment of Mechanism of Action. AB - Melissa officinalis (MO, English: lemon balm, Lamiaceae), one of the oldest and still most popular aromatic medicinal plants, is used in phytomedicine for the prevention and treatment of nervous disturbances. The aim of our study was to assess the effect of subchronic (28-fold) administration of a 50% ethanol extract of MO leaves (200 mg/kg, p.o.) compared with rosmarinic acid (RA, 10 mg/kg, p.o.) and huperzine A (HU, 0.5 mg/kg, p.o.) on behavioral and cognitive responses in scopolamine-induced rats. The results were linked with acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and beta-secretase (BACE-1) mRNA levels and AChE and BuChE activities in the hippocampus and frontal cortex of rats. In our study, MO and HU, but not RA, showed an improvement in long-term memory. The results were in line with mRNA levels, since MO produced a decrease of AChE mRNA level by 52% in the cortex and caused a strong significant inhibition of BACE1 mRNA transcription (64% in the frontal cortex; 50% in the hippocampus). However, the extract produced only an insignificant inhibition of AChE activity in the frontal cortex. The mechanisms of MO action are probably more complicated, since its role as a modulator of beta-secretase activity should be taken into consideration. PMID- 27239218 TI - Role of androgens in dhea-induced rack1 expression and cytokine modulation in monocytes. AB - BACKGROUND: Over the past fifteen years, we have demonstrated that cortisol and dehydroepiandrosterone (DHEA) have opposite effects on the regulation of protein kinase C (PKC) activity in the context of the immune system. The anti glucocorticoid effect of DHEA is also related to the regulation of splicing of the glucocorticoid receptor (GR), promoting the expression of GRbeta isoform, which acts as a negative dominant form on GRalpha activity. Moreover, it is very well known that DHEA can be metabolized to androgens like testosterone, dihydrotestosterone (DHT), and its metabolites 3alpha-diol and 3beta-diol, which exert their function through the binding of the androgen receptor (AR). Based on this knowledge, and on early observation that castrated animals show results similar to those observed in old animals, the purpose of this study is to investigate the role of androgens and the androgen receptor (AR) in DHEA-induced expression of the PKC signaling molecule RACK1 (Receptor for Activated C Kinase 1) and cytokine production in monocytes. RESULTS: Here we demonstrated the ability of the anti-androgen molecule, flutamide, to counteract the stimulatory effects of DHEA on RACK1 and GRbeta expression, and cytokine production. In both THP-1 cells and human peripheral blood mononuclear cells (PBMC), flutamide blocked the effects of DHEA, suggesting a role of the AR in these effects. As DHEA is not considered a direct AR agonist, we investigated the metabolism of DHEA in THP-1 cells. We evaluated the ability of testosterone, DHT, and androstenedione to induce RACK1 expression and cytokine production. In analogy to DHEA, an increase in RACK1 expression and in LPS-induced IL-8 and TNF-alpha production was observed after treatment with these selected androgens. Finally, the silencing of AR with siRNA completely prevented DHEA-induced RACK1 mRNA expression, supporting the idea that AR is involved in DHEA effects. CONCLUSIONS: We demonstrated that the conversion of DHEA to active androgens, which act via AR, is a key mechanism in the effect of DHEA on RACK1 expression and monocyte activation. This data supports the existence of a complex hormonal balance in the control of immune modulation, which can be further studied in the context of immunosenescence and endocrinosenescence. PMID- 27239219 TI - Quantum-limited heat conduction over macroscopic distances. AB - The emerging quantum technological apparatuses1, 2, such as the quantum computer3 6, call for extreme performance in thermal engineering7. Cold distant heat sinks are needed for the quantized electric degrees of freedom due to the increasing packaging density and heat dissipation. Importantly, quantum mechanics sets a fundamental upper limit for the flow of information and heat, which is quantified by the quantum of thermal conductance8-10. However, the short distance between the heat-exchanging bodies in the previous experiments11-14 hinders their applicability in quantum technology. Here, we present experimental observations of quantum-limited heat conduction over macroscopic distances extending to a metre. We achieved this improvement of four orders of magnitude in the distance by utilizing microwave photons travelling in superconducting transmission lines. Thus, it seems that quantum-limited heat conduction has no fundamental distance cutoff. This work establishes the integration of normal-metal components into the framework of circuit quantum electrodynamics15-17 which provides a basis for the superconducting quantum computer18-21. Especially, our results facilitate remote cooling of nanoelectronic devices using far-away in-situ-tunable heat sinks22, 23. Furthermore, quantum-limited heat conduction is important in contemporary thermodynamics24, 25. Here, the long distance may lead to ultimately efficient mesoscopic heat engines with promising practical applications26. PMID- 27239220 TI - High-throughput quantification of more than 100 primary- and secondary metabolites, and phytohormones by a single solid-phase extraction based sample preparation with analysis by UHPLC-HESI-MS/MS. AB - BACKGROUND: Plant metabolites are commonly functionally classified, as defense- or growth-related phytohormones, primary and specialized metabolites, and so forth. Analytical procedures for the quantifications of these metabolites are challenging because the metabolites can vary over several orders of magnitude in concentrations in the same tissues and have very different chemical characteristics. Plants clearly adjust their metabolism to respond to their prevailing circumstances in very sophisticated ways that blur the boundaries among these functional or chemically defined classifications. But if plant biologists want to better understand the processes that are important for a plant's adaptation to its environment, procedures are needed that can provide simultaneous quantifications of the large range of metabolites that have the potential to play central roles in these adjustments in a cost and time effective way and with a low sample consumption. RESULTS: Here we present a method that combines well-established methods for the targeted analysis of phytohormones, including jasmonates, salicylic acid, abscisic acid, gibberellins, auxins and cytokinins, and extends it to the analysis of inducible and constitutive defense compounds, as well as the primary metabolites involved in the biosynthesis of specialized metabolites and responsible for nutritional quality (e.g., sugars and amino acids). The method is based on a single extraction of 10-100 mg of tissue and allows a broad quantitative screening of metabolites optimized by their chemical characteristics and concentrations, thereby providing a high throughput analysis unbiased by the putative functional attributes of the metabolites. The tissues of Nicotiana attenuata which accumulate high levels of nicotine and diterpene glycosides, provide a challenging matrix that thwarts quantitative analysis; the analysis of various tissues of this plant are used to illustrate the robustness of the procedure. CONCLUSIONS: The method described has the potential to unravel various, until now overlooked interactions among different sectors of plant metabolism in a high throughput manner. Additionally, the method could be particularly beneficial as screening method in forward genetic approaches, as well as for the investigation of plants from natural populations that likely differ in metabolic traits. PMID- 27239221 TI - Lattice Boltzmann Model of 3D Multiphase Flow in Artery Bifurcation Aneurysm Problem. AB - This paper simulates and predicts the laminar flow inside the 3D aneurysm geometry, since the hemodynamic situation in the blood vessels is difficult to determine and visualize using standard imaging techniques, for example, magnetic resonance imaging (MRI). Three different types of Lattice Boltzmann (LB) models are computed, namely, single relaxation time (SRT), multiple relaxation time (MRT), and regularized BGK models. The results obtained using these different versions of the LB-based code will then be validated with ANSYS FLUENT, a commercially available finite volume- (FV-) based CFD solver. The simulated flow profiles that include velocity, pressure, and wall shear stress (WSS) are then compared between the two solvers. The predicted outcomes show that all the LB models are comparable and in good agreement with the FVM solver for complex blood flow simulation. The findings also show minor differences in their WSS profiles. The performance of the parallel implementation for each solver is also included and discussed in this paper. In terms of parallelization, it was shown that LBM based code performed better in terms of the computation time required. PMID- 27239222 TI - Review of 58 patients with necrotizing fasciitis in the Netherlands. AB - BACKGROUND: Necrotizing fasciitis is a rare, life threatening soft tissue infection, primarily involving the fascia and subcutaneous tissue. In a large cohort of patients presenting with Necrotizing fasciitis in the Netherlands we analysed all available data to determine the causative pathogens and describe clinical management and outcome. METHODS: We conducted a retrospective, multicentre cohort study of patients with a necrotizing fasciitis between January 2003 and December 2013 in an university medical hospital and three teaching hospitals in the Netherlands. We only included patients who stayed at the Intensive Care Unit for at least one day. RESULTS: Fifty-eight patients were included. The mortality rate among those patients was 29.3 %. The central part of the body was affected in 28 patients (48.3 %) and in 21 patients (36.2 %) one of the extremities. Most common comorbidity was cardio vascular diseases in 39.7 %. Thirty-nine patients (67.2 %) were operated within 24 h after presentation. We found a type 1 necrotizing fasciitis in 35 patients (60.3 %) and a type 2 in 23 patients (39.7 %). CONCLUSIONS: Our study, which is the largest study in Europe, reaffirmed that Necrotizing fasciitis is a life threatening disease with a high mortality. Early diagnosis and adequate treatment are necessary to improve the clinical outcome. Clinical awareness off necrotizing fasciitis remains pivotal. PMID- 27239223 TI - Methodological considerations when assessing restricted and repetitive behaviors and aggression. AB - Methodological issues impacting the relationship between aggression and restricted, repetitive, and stereotyped behaviors and interests (RRSBI) were examined in 2648 children and adolescents with autism spectrum disorders (ASD) using a multi-method, multi-informant analysis model to assess the effects of informant, assessment method, and aggression phenotype. Overall, a significant, but small relationship was found between RRSBI and aggression (p < .05). There was significant heterogeneity of estimates with large effect sizes observed when utilizing teacher report and a broad phenotype of aggression. Variance in estimates was attributed to differences in informant and assessment method with two times greater effect attributed to informant. Results suggest strategies to optimize future investigations of the relationship between RRSBI and aggression. Findings also provide the opportunity for the development of targeted interventions for aggression in youth with ASD. PMID- 27239224 TI - Determination of adapalene in gel formulation by conventional and derivative synchronous fluorimetric approaches. Application to stability studies and in vitro diffusion test. AB - BACKGROUND: Adapalene is a retinoid analogue with actions similar to those of tretinoin. It is used in topical treatment of mild to moderate acne. A survey of the literature reveals that no spectrofluorimetric method has been reported yet for determination of ADP, so it was thought necessary to develop a highly sensitive stability indicating spectrofluorimetric method. RESULTS: Two highly sensitive spectrofluorimetric approaches were conducted for the assay of adapalene (ADP) in its gel. In the first approach, ADP exhibits an intense native fluorescence at 389 nm after excitation at 312 nm using borate buffer (pH 7.0)/ethanol system. This approach was successfully applied for routine analysis of ADP in its gel and ideally suited to the in vitro diffusion test. To elucidate the inherent stability of ADP, bulk sample was subjected to different stress conditions as specified by ICH guidelines. The acidic and oxidative degradation products were resolved from the intact drug using second and first derivative synchronous fluorimetry at 346 and 312.45 nm, respectively (the second approach). The synchronous fluorescence was scanned at Delta lambda of 80 nm in case of acidic degradation and at Delta lambda of 100 nm in case of oxidative degradation. Good linearity was obtained for ADP over the range 2.0-14.0 ng/mL with good correlation coefficient 0.999 in each approach. The approaches were carefully examined in terms of linearity, accuracy and precision. They were suitable for routine quality control laboratory. Moreover, the stability indicating power of the second approach was ascertained via forced degradation studies. CONCLUSIONS: The proposed approaches were validated and successfully applied for the quantitative assay of a small concentration of ADP in its pharmaceutical gel. The conventional spectrofluorimetry was ideally suited for in vitro diffusion test. Stability studies were also conducted using different forced degradation condition according to ICH recommendation.Graphical abstractSimultaneous determination of ADP and its degradation products. PMID- 27239225 TI - Preparation and characterization of a highly stable phenoxazinone synthase nanogel. AB - BACKGROUND: Phenoxazinone synthase (PHS) is a laccase-like multicopper oxidase originating from Streptomyces with great industrial application potential. In this paper, we prepared the PHS nanogel retaining 82 % of its initial activity by aqueous in situ polymerization at pH 9.3. RESULTS: The average diameter of the PHS nanogel was 50.8 nm based on dynamic light scattering (DLS) analysis. Fluorescence analysis indicated the impressive preservation of the enzyme molecular structure upon modification. The PHS nanogel exhibited the most activity at pH 4.0-4.5 and 50 degrees C while the corresponding values were pH 4.5 and 40 degrees C for the native PHS. The K m and V max of the PHS nanogel were found to be 0.052 mM and 0.018 mM/min, whereas those of the native PHS were 0.077 mM and 0.021 mM/min, respectively. In addition, the PHS nanogel possessed higher thermal and storage stability and solvent tolerance compared with the native one. The half-life of the PHS nanogel was 1.71 h and multiplied around ninefold compared to 0.19 h for the native one. CONCLUSION: In summary, the PHS nanogel could be a promising biocatalyst in industry. PMID- 27239226 TI - Use of health care services by patients with co-occurring severe mental illness and substance use disorders. AB - BACKGROUND: To better respond to the health care needs of people with co occurring mental illness and substance use disorders, it is vital to understand their itinerary through the health care system. AIM: To describe the characteristics of service utilization among patients with co-occurring disorders in a large urban area. METHOD: We used a sample (n = 5467) constituted from administrative and clinical databases. Those identified as having substance use disorders and psychoses were followed over 12 months with respect to their utilization of medical services. A descriptive analysis of the data and a two step cluster analysis were undertaken. RESULTS: Our analyses revealed a relatively high utilization of emergency services, outpatient clinics, private practices and hospitalization among patients with co-occurring disorders of severe mental illness and substance use. The two-step cluster analysis produced four heterogeneous groups in terms of service utilization. CONCLUSIONS: This study demonstrates the need to develop strategies for organizing health care and services that are adapted to various sites of service utilization and to diverse profiles of patients with co-occurring mental illness and substance use disorders. PMID- 27239227 TI - Clinical and molecular characterization of a de novo 19p13.3 microdeletion. AB - BACKGROUND: Structural rearrangements of chromosome 19p13.3 are a rare condition, and their phenotypic consequences remain not well defined, because of the variability of clinical manifestations. Increasing knowledge of new 19p13.3 microdeletion is useful to clarify the phenotypic variability observed in some patients. In a small number of recent papers, patients with intellectual disabilities, multiple congenital anomalies and microdeletion of the chromosome band 19p13.3 have been described. However, little is known about genes responsible for clinical features in patients carriers of 19p13.3 microdeletion; thus, increasing number of reported cases will be helpful to investigate the contribution of candidate genes, providing bases for future investigations. CASE PRESENTATION: Here, we report on a 10-years-old girl referred to our genetics clinic due to intellectual disability, attention deficit, behavioral and speech delay, hypotonia, facial dysmorphisms, eye anomalies and congenital malformations. Using an high resolution SNP array, we identified a de novo microdeletion of chromosome 19p13.3, resulting in the heterozygous loss of 27 RefSeq genes and a miRNA, partially overlapping with three others deletions already reported in literature, but extending downstream (centromeric) for additional 386 Kb. This chromosomal region includes 13 genes amongst of which we suggest for the first time the APC2, PLK5 and MBD3 genes as potential functional candidates for neurodevelopmental and behavioral phenotypes observed. CONCLUSIONS: Here we describe a patient with a 19p13.3 microdeletion that spans to the downstream chromosomal region with respect to the overlapping deletions previously reported in several other cases. The neurobehavioral features observed in our case has extended the phenotypic spectrum associated with the 19p13.3 microdeletion. New candidate genes are proposed for the neurobehavioral phenotype observed in our case. PMID- 27239228 TI - Inherent bacterial DNA contamination of extraction and sequencing reagents may affect interpretation of microbiota in low bacterial biomass samples. AB - BACKGROUND: The advent and use of highly sensitive molecular biology techniques to explore the microbiota and microbiome in environmental and tissue samples have detected the presence of contaminating microbial DNA within reagents. These microbial DNA contaminants may distort taxonomic distributions and relative frequencies in microbial datasets, as well as contribute to erroneous interpretations and identifications. RESULTS: We herein report on the occurrence of bacterial DNA contamination within commonly used DNA extraction kits and PCR reagents and the effect of these contaminates on data interpretation. When compared to previous reports, we identified an additional 88 bacterial genera as potential contaminants of molecular biology grade reagents, bringing the total number of known contaminating microbes to 181 genera. Many of the contaminants detected are considered normal inhabitants of the human gastrointestinal tract and the environment and are often indistinguishable from those genuinely present in the sample. CONCLUSIONS: Laboratories working on bacterial populations need to define contaminants present in all extraction kits and reagents used in the processing of DNA. Any unusual and/or unexpected findings need to be viewed as possible contamination as opposed to unique findings. PMID- 27239229 TI - Analysis of cultivable microbiota and diet intake pattern of the long-lived naked mole-rat. AB - BACKGROUND: A variety of microbial communities exist throughout the human and animal body. Genetics, environmental factors and long-term dietary habit contribute to shaping the composition of the gut microbiota. For this reason the study of the gut microbiota of a mammal exhibiting an extraordinary life span is of great importance. The naked mole-rat (Heterocephalus glaber) is a eusocial mammal known for its longevity and cancer resistance. METHODS: Here we analyzed its gut microbiota by cultivating the bacteria under aerobic and anaerobic conditions and identifying their species by mass spectrometry. RESULTS: Altogether, 29 species of microbes were identified, predominantly belonging to Firmicutes, and Bacteroidetes. The most frequent species were Bacillus megaterium (45.2 %), followed by Bacteroides thetaiotaomicron (19.4 %), Bacteroides ovatus, Staphylococcus sciuri and Paenibacillus spp., each with a frequency of 16.1 %. CONCLUSION: Overall, the gut of the naked mole-rat is colonized by diverse, but low numbers of cultivable microbes compared with humans and mice. The primary food plants of the rodents are rich in polyphenols and related compounds, possessing anti-microbial, anti-inflammatory, anti-oxidative as well as anti cancer activity which may contribute to their exceptionally healthy life. PMID- 27239230 TI - Badapple: promiscuity patterns from noisy evidence. AB - BACKGROUND: Bioassay data analysis continues to be an essential, routine, yet challenging task in modern drug discovery and chemical biology research. The challenge is to infer reliable knowledge from big and noisy data. Some aspects of this problem are general with solutions informed by existing and emerging data science best practices. Some aspects are domain specific, and rely on expertise in bioassay methodology and chemical biology. Testing compounds for biological activity requires complex and innovative methodology, producing results varying widely in accuracy, precision, and information content. Hit selection criteria involve optimizing such that the overall probability of success in a project is maximized, and resource-wasteful "false trails" are avoided. This "fail-early" approach is embraced both in pharmaceutical and academic drug discovery, since follow-up capacity is resource-limited. Thus, early identification of likely promiscuous compounds has practical value. RESULTS: Here we describe an algorithm for identifying likely promiscuous compounds via associated scaffolds which combines general and domain-specific features to assist and accelerate drug discovery informatics, called Badapple: bioassay-data associative promiscuity pattern learning engine. Results are described from an analysis using data from MLP assays via the BioAssay Research Database (BARD) http://bard.nih.gov. Specific examples are analyzed in the context of medicinal chemistry, to illustrate associations with mechanisms of promiscuity. Badapple has been developed at UNM, released and deployed for public use two ways: (1) BARD plugin, integrated into the public BARD REST API and BARD web client; and (2) public web app hosted at UNM. CONCLUSIONS: Badapple is a method for rapidly identifying likely promiscuous compounds via associated scaffolds. Badapple generates a score associated with a pragmatic, empirical definition of promiscuity, with the overall goal to identify "false trails" and streamline workflows. Unlike methods reliant on expert curation of chemical substructure patterns, Badapple is fully evidence-driven, automated, self-improving via integration of additional data, and focused on scaffolds. Badapple is robust with respect to noise and errors, and skeptical of scanty evidence. PMID- 27239231 TI - Characteristics of Print in Books for Preschool Children. AB - Children begin to learn about the characteristics of print well before formal literacy instruction begins. Reading to children can expose them to print and help them learn about its characteristics. This may be especially true if the print is visually salient, for studies suggest that prereaders pay more attention to such print than to print that is visually less salient. To shed light on the characteristics of the print that US children see in books, especially those characteristics that may contribute to visual salience, we report a quantitative analysis of 73 books that were chosen to be representative of those seen by preschoolers. We found that print that is visually salient due to color, variation, and other features tends to be more common on the covers of books than in the interiors. It also tends to be more common in recently published books than in older books. Even in recent books, however, the print is much less visually salient than the accompanying pictures. Many studies have examined the behavior of adults and children during shared reading, but little research has examined the characteristics of books themselves. Our results provide quantitative information about this topic for one set of characteristics in books for young US children. PMID- 27239232 TI - Treatment approach in patients with hyperbilirubinemia secondary to liver metastases in gastrointestinal malignancies: a case series and review of literature. AB - BACKGROUND: Treatment of patients with severe liver dysfunction including hyperbilirubinemia secondary to liver metastases of gastrointestinal (GI) cancer is challenging. Regimen of oxaliplatin and fluoropyrimidine (FP)/folinic acid (FA) +/- a monoclonal antibody (moAb), represents a feasible option considering the pharmacokinetics. Clinical data on the respective dosage and tolerability are limited and no recommendations are available. METHODS: Consecutive patients with severe hyperbilirubinemia [>2 * upper limit of the normal range (ULN) and >2.4 mg/dl] due to liver metastases of GI cancer without options for drainage receiving oxaliplatin, FP/FA +/- moAb were analyzed. To collect further data a review of the literature was performed. RESULTS: A total of 12 patients were identified between 2011 and 2015. At treatment start, median bilirubin level was 6.1 mg/dl (>5 * ULN, range 2.7-13.6). The majority of patients (n = 11) received dose-reduced regimen with oxaliplatin (60-76%) and FP/FA (0-77%), rapidly escalating to full dose regimen. During treatment, bilirubin levels dropped more than 50% within 8 weeks or normalized within 12 weeks in 6 patients (responders). Median overall survival was 5.75 months (range 1.0-16.0 months) but was significantly prolonged in responders compared to nonresponders [9.7 and 3.0 months, p = 0.026 (two-sided test); 95% confidence interval (CI): 1.10-10.22]. In addition, case reports or series comprising a further 26 patients could be identified. Based on the obtained data a treatment algorithm was developed. CONCLUSION: Treatment with oxaliplatin, FP/FA +/- moAb is feasible and may derive relevant benefits in patients with severe liver dysfunction caused by GI cancer liver metastases without further options of drainage. PMID- 27239233 TI - Phase II study of gemcitabine plus S-1 chemotherapy in recurrent and metastatic nasopharyngeal carcinoma patients after failure of platinum-based chemotherapy. AB - PURPOSE: No standard salvage regimen has been established for patients with recurrent and metastatic nasopharyngeal carcinoma (NPC) and disease progression after prior platinum-based chemotherapy. This phase II study was designed to evaluate the efficacy and safety of gemcitabine plus S-1 (GS) chemotherapy as a remedial regimen in this setting. METHODS: In this multicenter phase II study, 49 patients with recurrent and metastatic NPC who failed previous platinum-based chemotherapy received gemcitabine (1.0 g/m(2) on days 1 and 8) plus oral S-1 chemotherapy (twice daily from day 1 to 14). Each cycle was repeated every 3 weeks for two cycles at least. The dose of S-1 was determined according to the body surface area (BSA): 40 mg twice a day for BSA <1.25 m(2); 50 mg twice a day for 1.25 m(2) ? BSA <1.5 m(2); and 60 mg twice a day for BSA ?1.5 m(2). RESULTS: Treatment was generally well-tolerated. A total of seven patients (14.3%) had grade 3 toxicities and the main toxicity was myelosuppression, whereas the nonhematology adverse events were minimal. There were 3 complete responses (6.4%), 17 partial responses (36.2%), and the overall response rate was 42.6% (95% confidence interval: 27.3-61.2). Median time to progression was 5.8 months and median survival was 14.8 months. The 1- and 2-year survival rates were 64% and 30%, respectively. CONCLUSIONS: Gemcitabine plus S-1 offers a satisfactory clinical activity and an acceptable safety profile for recurrent and metastatic NPC patients after failure of platinum-based chemotherapy. PMID- 27239234 TI - The preoperative platelet-lymphocyte ratio versus neutrophil-lymphocyte ratio: which is better as a prognostic factor in oral squamous cell carcinoma? AB - OBJECTIVE: Recent studies have shown that the presence of systemic inflammation and platelet status correlate with poor survival in various cancers. The aim of this study was to evaluate the prognostic value of the preoperative platelet lymphocyte ratio (PLR) and the neutrophil-lymphocyte ratio (NLR) in patients with oral squamous cell carcinoma (OSCC) undergoing surgery. METHODS: In this study, 306 patients with OSCC who had surgery were enrolled. The optimal cutoff value of PLR and NLR was determined by receiver operating characteristic (ROC) curve analysis. The prognostic significance of both markers was determined by uni- and multivariate analysis. RESULTS: The results showed that high NLR and PLR were classified using a cutoff value of 2.7 and 135, respectively, based on ROC curve analysis. Only PLR was associated with decreased disease-free survival [hazard ratio (HR) = 2.237; 95% confidence interval (CI): 1.401-3.571; p = 0.001] and overall survival [HR = 2.022; 95% CI: 1.266-3.228; p = 0.003] by both uni- and multivariate analysis. CONCLUSION: The preoperative PLR is superior to NLR as an independent indicator in predicting disease-free survival and overall survival in patients who undergo oral cancer resection for OSCC. PMID- 27239235 TI - Immunotherapy for head and neck cancer: latest developments and clinical potential. AB - Head and neck squamous cell cancer (HNSCC) is a malignancy with a rapidly changing demographic profile, given the recent epidemic of human papilloma virus related cancers. Most patients present with locally advanced disease and receive combination therapeutic approaches with curative potential, albeit with significant toxicity. Up to a third of patients, however, will eventually develop recurrent or metastatic disease. The prognosis of such patients is dismal, as palliative treatment options remain limited. Immune-directed therapies offer a novel therapeutic strategy beyond cytotoxic chemotherapy and are currently being evaluated in a wide variety of malignancies. HNSCC is a particularly favorable disease for immunotherapy, as immune evasion and dysregulation have been shown to play a key role in the initiation and progression of HNSCC. This review focuses on the latest developments in immunotherapy in HNSCC, with a particular focus on checkpoint inhibitors, adoptive cellular therapies, and vaccines. PMID- 27239236 TI - Overcoming resistance to first/second generation epidermal growth factor receptor tyrosine kinase inhibitors and ALK inhibitors in oncogene-addicted advanced non small cell lung cancer. AB - Epidermal growth factor receptor (EGFR) activating mutations and anaplastic lymphoma kinase (ALK) gene rearrangement in advanced non-small cell lung cancer (NSCLC) represent the two oncogenic events with an impact on current clinical practice. EGFR tyrosine kinase inhibitors (TKIs) and crizotinib are the standard of care for the treatment of EGFR mutant and ALK gene rearranged advanced NSCLC patients. Unfortunately, despite initial clinical benefit, acquired resistance to EGFR-TKIs or crizotinib usually develops after an average of 10-12 months of treatment. The aim of this review is to describe the mechanisms of resistance to first/second generation EGFR-TKIs and crizotinib. In particular, we focus on strategies to overcome resistance due to secondary EGFR T790M mutation and mutations of the ALK domain. PMID- 27239237 TI - Nintedanib in NSCLC: evidence to date and place in therapy. AB - The treatment of advanced non-small cell lung cancer (NSCLC) is currently driven by the detection of targetable oncogenic drivers, i.e. epidermal growth factor receptor, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase, etc. Those patients who are wildtype for known and valuable oncogenes can receive standard chemotherapy as first-line treatment, with the possibility of adding bevacizumab. With regard to second-line treatment, nintedanib can improve the efficacy of docetaxel. Nintedanib is a tyrosine kinase inhibitor targeting three angiogenesis-related transmembrane receptors. The usefulness of nintedanib as an anticancer agent for NSCLC has been proved by both preclinical and clinical phase I and II trials; however, its approval for the use in clinical practice has been possible because of the positive results of the LUME-Lung 1 trial (nintedanib + docetaxel versus docetaxel alone) in terms of progression-free survival and overall survival, and a manageable tolerability profile. Therefore, the good results seen in the clinical trials with nintedanib in the second-line setting for NSCLC patients with adenocarcinoma subtype are encouraging enough to recommend it in clinical practice. PMID- 27239238 TI - Pemetrexed for advanced stage nonsquamous non-small cell lung cancer: latest evidence about its extended use and outcomes. AB - Non-small cell lung cancer (NSCLC) is still the leading cause of cancer-related death, and the treatment of advanced NSCLC relies on systemic treatments. During the last decade, pemetrexed, an antifolate agent, gradually became a key component of the treatment for patients with advanced nonsquamous NSCLC. It has indeed been shown to be efficient for first-line, maintenance and second- or third-line treatment in this subgroup of NSCLC. Moreover, it is usually well tolerated, with few grade 3 and 4 toxicities. Several studies have tried to identify predictive biomarkers of pemetrexed efficacy. Due to pemetrexed's mechanism of action, thymidilate synthase expression predictive value was investigated but could not be demonstrated. Currently, more than 400 trials of pemetrexed for the treatment of nonsquamous NSCLC are ongoing. PMID- 27239239 TI - Targeted chemotherapy with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in metastatic breast cancer: which benefit for which patients? AB - The therapeutic goals in metastatic breast cancer (MBC) remain palliative in nature, aimed at controlling symptoms, improving or maintaining quality of life and prolonging survival. The advent of new drugs and new formulations of standard agents has led to better outcomes in patients with advanced or metastatic disease. These developments have also allowed a tailored therapeutic approach, in which the molecular biology of the tumour, the treatment history, and patient attitudes are taken into account in the decision-making process. Targeting drug delivery to the tumour is a promising mean of increasing the therapeutic index of highly active agents such as the taxanes, and nanoparticle albumin-bound paclitaxel (nab-paclitaxel), the first nanotechnology-based drug developed in cancer treatment, is one such advance. Data from randomized trials support the efficacy of single-agent nab-paclitaxel as first-line and further treatment lines in MBC at the registered 3-weekly schedule of 260 mg/m(2), but emerging evidence suggests its activity as a weekly regimen or combined with other agents in various clinical scenarios. Thus, nab-paclitaxel seems to offer flexibility in terms of dosing schedules, allowing physicians to tailor the dose according to different clinical situations. This paper reviews the clinical trial background for nab-paclitaxel in MBC, focusing on specific 'difficult-to-treat' patient populations, such as taxane-pretreated or elderly women, as well as those with triple-negative, HER2-positive and poor-prognostic-factors disease. Moving beyond evidence-based information, 'real life' available experiences are also discussed with the aim of providing an update for daily clinical practice. PMID- 27239240 TI - Ramucirumab in metastatic colorectal cancer: evidence to date and place in therapy. AB - Colorectal cancer is the third most frequent cancer worldwide. Overall survival rates have improved greatly over the last few years due, at least in part, to the addition of targeted therapies to standard of care chemotherapy. Angiogenesis plays an important role in colorectal cancer, and therapies directed against the vascular endothelial growth factor (VEGF) axis have contributed significantly to improving the outcome of patients with metastatic colorectal cancer. Over the past few years, several new targeted antiangiogenic agents have been approved for this patient population, confirming the value of inhibiting tumour angiogenesis. The most recent among them is ramucirumab, a fully humanized monoclonal antibody that targets the extracellular domain of VEGF receptor 2. It has proven valuable in multiple tumour types including colorectal cancer. Several phase I and II clinical trials showed a favourable toxicity profile and promising clinical antitumour efficacy in colorectal cancer patients. In the phase III RAISE clinical trial, the addition of ramucirumab to FOLFIRI-based chemotherapy resulted in an improvement of overall survival in patients with metastatic colorectal cancer who had been previously treated with bevacizumab, oxaliplatin and a fluoropyrimidine. On the basis of these results, ramucirumab was approved by the US Food and Drug Administration for this setting. We present an overview of the key preclinical and clinical studies in the development of ramucirumab in the context of metastatic colorectal cancer. PMID- 27239241 TI - Sensory-motor training targeting motor dysfunction and muscle weakness in long term care elderly combined with motivational strategies: a single blind randomized controlled study. AB - BACKGROUND: This study evaluated the effects of a combined innovative training regime consisting of stochastic resonance whole-body vibration (SR-WBV) and a dance video game (DVG) on physical performance and muscle strength in long-term care dwelling elderly. METHODS: Thirthy long-term-care elderly were randomly allocated to an intervention group (IG; n = 16) receiving combined SR-WBV training and DVG, or a sham group (SG; n = 14). IG performed five sets one minute of SR-WBV, with one minute rest between sets (base frequency 3 Hz up to 6 Hz, Noise 4) during the first five weeks on three days per week. From week five to eight a DVG was added to SR-WBV for IG on three days per week. SG performed a five-set SR-WBV program (1 Hz, Noise 1) lasting five times one minute, with one minute rest in between, three days a week. From week five to eight stepping exercises on a trampoline were added on three days per week. PRIMARY OUTCOME: Short physical performance battery (SPPB). Secondary outcome: isometric maximal voluntary contraction (IMVC), and sub phases of IMVC (Fsub), isometric rate of force development (IRFD) and sub time phases of IRFD (IRFDsub) were measured at baseline, after four and eight weeks. ANOVA with repeated measures was used for analyses of time and interaction effects and MANOVA determined between group intervention effects. RESULTS: Between group effects revealed significant effects on the SPPB primary outcome after four weeks F(1, 27) = 6.17; p = 0.02) and after eight weeks F(1,27) = 11.8; p = 0.002). Secondary muscle function related outcome showed significant between group effects in IG on IRFD, Fsub 30 ms, 100 ms, 200 ms and IRFDsub 0-30 ms, 0-50 ms, 0-100 ms and 100-200 ms compared to SG (all p < 0.05). CONCLUSIONS: Eight weeks SR-WBV and DVG intervention improved lower extremity physical function and muscle strength compared to a sham intervention in long-term-care elderly. SR-WBV and DVG seems to be effective as a training regime for skilling up in long-term-care elderly. PMID- 27239243 TI - A novel approach to screen and compare emission inventories. AB - A methodology is proposed to support the evaluation and comparison of different types of emission inventories. The strengths and weaknesses of the methodology are presented and discussed based on an example. The approach results in a "diamond" diagram useful to flag out anomalous behaviors in the emission inventories and to get insight in possible explanations. In particular, the "diamond" diagram is shown to provide meaningful information in terms of: discrepancies between the total emissions reported by macro-sector and pollutant, contribution of each macro-sector to the total amount of emissions released by pollutant, and the identification and quantification of the different factors causing the discrepancies between total emissions. A practical example in Barcelona is used for testing and to provide relevant information for the analyzed emission datasets. The tests show the capability of the proposed methodology to flag inconsistencies in the existing inventories. The proposed methodology system may be useful for regional and urban inventory developers as an initial evaluation of the consistency of their inventories. PMID- 27239244 TI - Gaming Simulation as Health and Safety Training for Home Healthcare Workers. PMID- 27239242 TI - Polycomb repressive complex's evolutionary conserved function: the role of EZH2 status and cellular background. AB - When assembled in multiprotein polycomb repressive complexes (PRCs), highly evolutionary conserved polycomb group (PcG) proteins epigenetically control gene activity. Although the composition of PRCs may vary considerably, it is well established that the embryonic ectoderm development (EED) 1, suppressor of zeste (SUZ) 12, and methyltransferase enhancer of zeste (EZH2)-containing complex, PRC2, which is abundant in highly proliferative cells (including cancer cells), establishes a repressive methylation mark on histone 3 (H3K27me3). From the perspective of molecular cancer pathogenesis, this effect, when directed towards a promoter of tumor suppressor genes, represents pro-tumorigenic effect. This mode of action was shown in several cancer models. However, EZH2 function extends beyond this scenario. The highly specific cellular background, related to the origin of cell and numerous external stimuli during a given time-window, may be the trigger for EZH2 interaction with other proteins, not necessarily histones. This is particularly relevant for cancer. This review provides a critical overview of the evolutional importance of PRC and discusses several important aspects of EZH2 functioning within PRC. The review also deals with mutational studies on EZH2. Due to the existence of several protein (and messenger RNA (mRNA)) isoforms, these mutations were stratified, using the protein sequence which is considered canonical. This approach showed that there is an urgent need for the uniformed positioning of currently known EZH2 mutations (somatic-in tumors, as well as germline mutations in the Weaver's syndrome). Finally, we discuss EZH2 function with respect to amount of trimethylated H3K27, in a specific cellular milieu, through presenting the most recent data related to EZH2 H3K27m3 relationship in cancer. All these points are significant in considering EZH2 as a therapeutic target. PMID- 27239245 TI - Bright focused ion beam sources based on laser-cooled atoms. AB - Nanoscale focused ion beams (FIBs) represent one of the most useful tools in nanotechnology, enabling nanofabrication via milling and gas-assisted deposition, microscopy and microanalysis, and selective, spatially resolved doping of materials. Recently, a new type of FIB source has emerged, which uses ionization of laser cooled neutral atoms to produce the ion beam. The extremely cold temperatures attainable with laser cooling (in the range of 100 MUK or below) result in a beam of ions with a very small transverse velocity distribution. This corresponds to a source with extremely high brightness that rivals or may even exceed the brightness of the industry standard Ga+ liquid metal ion source. In this review we discuss the context of ion beam technology in which these new ion sources can play a role, their principles of operation, and some examples of recent demonstrations. The field is relatively new, so only a few applications have been demonstrated, most notably low energy ion microscopy with Li ions. Nevertheless, a number of promising new approaches have been proposed and/or demonstrated, suggesting that a rapid evolution of this type of source is likely in the near future. PMID- 27239246 TI - Size- and Shape-Controlled Synthesis and Properties of Magnetic-Plasmonic Core Shell Nanoparticles. AB - Magnetic-plasmonic core-shell nanomaterials offer a wide range of applications across science, engineering and biomedical disciplines. However, the ability to synthesize and understand magnetic-plasmonic core-shell nanoparticles with tunable sizes and shapes remains very limited. This work reports experimental and computational studies on the synthesis and properties of iron oxide-gold core shell nanoparticles of three different shapes (sphere, popcorn and star) with controllable sizes (70 to 250 nm). The nanoparticles were synthesized via a seed mediated growth method in which newly formed gold atoms were added onto gold seeded iron oxide octahedrons to form gold shell. The evolution of the shell into different shapes was found to occur after the coalescence of gold seeds, which was achieved by controlling the amount of additive (silver nitrate) and reducing agent (ascorbic acid) in the growth solution. First principles calculation, together with experimental results, elucidated the intimate roles of thermodynamic and kinetic parameters in the shape-controlled synthesis. Both discrete dipole approximation calculation and experimental results showed that the nanopopcorns and nanostars exhibited red-shifted plasmon resonance compared with the nanospheres, with the nanostars giving multispectral feature. This research has made a great step further in manipulating and understanding magnetic plasmonic hybrid nanostructures and will make important impact in many different fields. PMID- 27239247 TI - Singlet Oxygen Generation by Laser Irradiation of Gold Nanoparticles. AB - The formation of singlet oxygen by irradiation of gold nanoparticles in their plasmon resonance band with continuous or pulsed laser light has been investigated. Citrate-stabilized nanoparticles were found to facilitate the photogeneration of singlet oxygen, albeit with low quantum yield. The reaction caused by pulsed laser irradiation makes use of the equilibrated hot electrons that can reach temperatures of several thousand degrees during the laser pulse. Although less efficient, continuous irradiation, which acts via the short-lived directly excited primary "hot" electrons only, can produce enough singlet oxygen for photodynamic cancer therapy and has significant advantages for practical applications. However, careful design of the nanoparticles is needed, since even a moderately thick capping layer can completely inhibit singlet oxygen formation. Moreover, the efficiency of the process also depends on the nanoparticle size. PMID- 27239248 TI - Repeated Self- and Peer-Review Leads to Continuous Improvement in Child Interviewing Performance. AB - The present study examined whether a training model that focuses on consistent exposure to protocol procedure, self-evaluation, and intensive peer-review sessions could improve interviewers' ability to adhere to best practices. Law students (N = 19) interviewed 5- to 10-year-old children on a weekly basis as part of a semester-long forensic child interviewing class. They transcribed their interviews, and participated in one-hour self and peer-reviews. The proportion of each question type was calculated (option-posing, Wh-, and open-invitations) within each interview for each interviewer. Across ten weeks of interviews, interviewers consistently improved their performance, decreasing the proportion of option-posing questions by 31% and increasing the proportion of open invitations by 47%. All interviewers improved. The present study suggests that with consistent self-evaluation and peer-review, forensic interviewers can incrementally improve their performance. PMID- 27239249 TI - Approaches to retrospective sampling for longitudinal transition regression models. AB - For binary diseases that relapse and remit, it is often of interest to estimate the effect of covariates on the transition process between disease states over time. The transition process can be characterized by modeling the probability of the binary event given the individual's history. Designing studies that examine the impact of time varying covariates over time can lead to collection of extensive amounts of data. Sometimes it may be possible to collect and store tissue, blood or images and retrospectively analyze this covariate information. In this paper we consider efficient sampling designs that do not require biomarker measurements on all subjects. We describe appropriate estimation methods for transition probabilities and functions of these probabilities, and evaluate efficiency of the estimates from the proposed sampling designs. These new methods are illustrated with data from a longitudinal study of bacterial vaginosis, a common relapsing-remitting vaginal infection of women of child bearing age. PMID- 27239250 TI - A penalized likelihood approach for robust estimation of isoform expression. AB - Ultra high-throughput sequencing of transcriptomes (RNA-Seq) has enabled the accurate estimation of gene expression at individual isoform level. However, systematic biases introduced during the sequencing and mapping processes as well as incompleteness of the transcript annotation databases may cause the estimates of isoform abundances to be unreliable, and in some cases, highly inaccurate. This paper introduces a penalized likelihood approach to detect and correct for such biases in a robust manner. Our model extends those previously proposed by introducing bias parameters for reads. An L1 penalty is used for the selection of non-zero bias parameters. We introduce an efficient algorithm for model fitting and analyze the statistical properties of the proposed model. Our experimental studies on both simulated and real datasets suggest that the model has the potential to improve isoform-specific gene expression estimates and identify incompletely annotated gene models. PMID- 27239251 TI - Oxidative Stress in Cancer-Prone Genetic Diseases in Pediatric Age: The Role of Mitochondrial Dysfunction. AB - Oxidative stress is a distinctive sign in several genetic disorders characterized by cancer predisposition, such as Ataxia-Telangiectasia, Fanconi Anemia, Down syndrome, progeroid syndromes, Beckwith-Wiedemann syndrome, and Costello syndrome. Recent literature unveiled new molecular mechanisms linking oxidative stress to the pathogenesis of these conditions, with particular regard to mitochondrial dysfunction. Since mitochondria are one of the major sites of ROS production as well as one of the major targets of their action, this dysfunction is thought to be the cause of the prooxidant status. Deeper insight of the pathogenesis of the syndromes raises the possibility to identify new possible therapeutic targets. In particular, the use of mitochondrial-targeted agents seems to be an appropriate clinical strategy in order to improve the quality of life and the life span of the patients. PMID- 27239252 TI - Rutin Attenuates Hepatotoxicity in High-Cholesterol-Diet-Fed Rats. AB - Background and Objective. High-cholesterol diet (HCD) intends to increase the oxidative stress in liver tissues inducing hepatotoxicity. Rutin is a natural flavonoid (vitamin p) which is known to have antioxidative properties. The aim of the present study was to investigate the potential effects of Rutin on hypercholesterolemia-induced hepatotoxicity in rats. Materials and Methods. Male Wistar rats were divided into four groups: G-I control, G-II Rutin, G-III HCD, and G-IV Rutin + HCD. The liver functions and lipid profile were used to evaluate the HCD-induced hepatotoxicity. Quantitative real time-PCR was carried out to evaluate the expression levels of genes in TGF-beta/Smad signaling pathway. Results. Rutin in combination with HCD showed a significant protective effect against hepatotoxicity. HCD caused significant increase in the mRNA expression of transforming growth factor beta (TGF-beta), Mothers Against Decapentaplegic Homolog 2 (Smad-2), Mothers Against Decapentaplegic Homolog 4 (Smad-4), Bcl-2 binding component 3 (Bbc3), caspase-3, P53 and Interleukin-6 (IL-6) and decrease in the expression levels of Cyclin depended kinase inhibitor (P21) and Interleukin-3 (IL-3) in hepatic cells. Conclusion. TGF-beta/Smad signaling pathway is involved in HCD-induced hepatotoxicity and Rutin inhibits the hepatotoxicity via suppressing this pathway. Therefore, Rutin might be considered as a protective agent for hepatotoxicity. PMID- 27239253 TI - Cytoprotective and Cytotoxic Effects of Rice Bran Extracts in Rat H9c2(2-1) Cardiomyocytes. AB - This study was aimed at preliminarily assessing the cytoprotective and antioxidative effects of rice bran extracts (RBEs) from a Sarawak local rice variety (local name: "BJLN") and a commercial rice variety, "MR219," on oxidative stress in rat H9c2(2-1) cardiomyocytes. The cardiomyocytes were incubated with different concentrations of RBE and hydrogen peroxide (H2O2), respectively, to identify their respective IC50 values and safe dose ranges. Two nonlethal and close-to-IC50 doses of RBE were selected to evaluate their respective effects on H2O2 induced oxidative stress in cardiomyocytes. Both RBEs showed dose-dependent cytotoxicity effects on cardiomyocytes. H2O2 induction of cardiomyocytes pretreated with RBE further revealed the dose-dependent cytoprotective and antioxidative effects of RBE via an increase in IC50 values of H2O2. Preliminary analyses of induction effects of RBE and H2O2 on cellular antioxidant enzyme, catalase (CAT), also revealed their potential in regulating these activities and expression profile of related gene on oxidative stress in cardiomyocytes. Pretreated cardiomyocytes significantly upregulated the enzymatic activity and expression level of CAT under the exposure of H2O2 induced oxidative stress. This preliminary study has demonstrated the potential antioxidant effects of RBE in alleviating H2O2-mediated oxidative injuries via upregulation in enzymatic activities and expression levels of CAT. PMID- 27239254 TI - Basal Glutathionylation of Na,K-ATPase alpha-Subunit Depends on Redox Status of Cells during the Enzyme Biosynthesis. AB - Many viruses induce oxidative stress and cause S-glutathionylation of Cys residues of the host and viral proteins. Changes in cell functioning during viral infection may be associated with glutathionylation of a number of key proteins including Na,K-ATPase which creates a gradient of sodium and potassium ions. It was found that Na,K-ATPase alpha-subunit has a basal glutathionylation which is not abrogated by reducing agent. We have shown that acute hypoxia leads to increase of total glutathionylation level of Na,K-ATPase alpha-subunit; however, basal glutathionylation of alpha-subunit increases under prolonged hypoxia only. The role of basal glutathionylation in Na,K-ATPase function remains unclear. Understanding significance of basal glutathionylation is complicated by the fact that there are no X-ray structures of Na,K-ATPase with the identified glutathione molecules. We have analyzed all X-ray structures of the Na,K-ATPase alpha-subunit from pig kidney and found that there are a number of isolated cavities with unresolved electron density close to the relevant cysteine residues. Analysis of the structures showed that this unresolved density in the structure can be occupied by glutathione associated with cysteine residues. Here, we discuss the role of basal glutathionylation of Na,K-ATPase alpha-subunit and provide evidence supporting the view that this modification is cotranslational. PMID- 27239255 TI - A Multi-state Model for Designing Clinical Trials for Testing Overall Survival Allowing for Crossover after Progression. AB - In designing a clinical trial for comparing two or more treatments with respect to overall survival (OS), a proportional hazards assumption is commonly made. However, in many cancer clinical trials, patients pass through various disease states prior to death and because of this may receive treatments other than originally assigned. For example, patients may crossover from the control treatment to the experimental treatment at progression. Even without crossover, the survival pattern after progression may be very different than the pattern prior to progression. The proportional hazards assumption will not hold in these situations and the design power calculated on this assumption will not be correct. In this paper we describe a simple and intuitive multi-state model allowing for progression, death before progression, post-progression survival and crossover after progression and apply this model to the design of clinical trials for comparing the OS of two treatments. For given values of the parameters of the multi-state model, we simulate the required number of deaths to achieve a specified power and the distribution of time required to achieve the requisite number of deaths. The results may be quite different from those derived using the usual PH assumption. PMID- 27239257 TI - Outcome analysis of management of liver trauma: A 10-year experience at a trauma center. AB - AIM: To review the outcomes of liver trauma in patients with hepatic injuries only and in patients with associated injuries outside the liver. METHODS: Data of liver trauma patients presented to our center from January 2003 to October 2013 were reviewed. The patients were divided into two groups. Group 1 consisted of patients who had hepatic injuries only. Group 2 consisted of patients who also had associated injuries outside the liver. RESULTS: Seven (30.4%) patients in group 1 and 10 (28.6%) patients in group 2 received non-operative management; the rest underwent operation. Blunt trauma occurred in 82.8% (48/58) of the patients and penetrative trauma in 17.2% (10/58). A higher injury severity score (ISS) was observed in group 2 (median 45 vs 25, P < 0.0001). More patients in group 1 were hemodynamically stable (65.2% vs 37.1%, P = 0.036). Other parameters were comparable between groups. Group 1 had better 30-d survival (91.3% vs 71.4%, P = 0.045). On multivariate analysis using the logistic regression model, ISS was found to be associated with mortality (P = 0.004, hazard ratio = 1.035, 95%CI: 1.011-1.060). CONCLUSION: Liver trauma patients with multiple injuries are relatively unstable on presentation. Despite a higher ISS in group 2, non operative management was possible for selected patients. Associated injuries outside the liver usually account for morbidity and mortality. PMID- 27239256 TI - Hepatitis B surface antigen clearance in inactive hepatitis B surface antigen carriers treated with peginterferon alfa-2a. AB - AIM: To examine the association between interferon (IFN) therapy and loss of hepatitis B surface antigen (HBsAg) in inactive HBsAg carriers. METHODS: This was a retrospective cohort study in inactive HBsAg carriers, who were treatment naive, with a serum HBsAg level < 100 IU/mL and an undetectable hepatitis B virus (HBV) DNA level (< 100 IU/mL). All the 20 treated patients received subcutaneous PEG-IFN alfa-2a 180 MUg/wk for 72 wk and were then followed for 24 wk. There were 40 untreated controls matched with 96 wk of observation. Serum HBsAg, HBV DNA, and alanine aminotransferases were monitored every 3 mo in the treatment group and every 3-6 mo in the control group. RESULTS: Thirteen (65.0%) of 20 treated patients achieved HBsAg loss, 12 of whom achieved HBsAg seroconversion. Mean HBsAg level in treated patients decreased to 6.69 +/- 13.04 IU/mL after 24 wk of treatment from a baseline level of 26.22 +/- 33.00 IU/mL. Serum HBV DNA level remained undetectable (< 100 IU/mL) in all treated patients during the study. HBsAg level of the control group decreased from 25.72 +/- 25.58 IU/mL at baseline to 17.11 +/- 21.62 IU/mL at week 96 (P = 0.108). In the control group, no patient experienced HBsAg loss/seroconversion, and two (5.0%) developed HBV reactivation. CONCLUSION: IFN treatment results in HBsAg loss and seroconversion in a considerable proportion of inactive HBsAg carriers with low HBsAg concentrations. PMID- 27239258 TI - Hepatitis C virus infection in Argentina: Burden of chronic disease. AB - AIM: To estimate the progression of the hepatitis C virus (HCV) epidemic and measure the burden of HCV-related morbidity and mortality. METHODS: Age- and gender-defined cohorts were used to follow the viremic population in Argentina and estimate HCV incidence, prevalence, hepatic complications, and mortality. The relative impact of two scenarios on HCV-related outcomes was assessed: (1) increased sustained virologic response (SVR); and (2) increased SVR and treatment. RESULTS: Under scenario 1, SVR raised to 85%-95% in 2016. Compared to the base case scenario, there was a 0.3% reduction in prevalent cases and liver related deaths by 2030. Given low treatment rates, cases of hepatocellular carcinoma and decompensated cirrhosis decreased < 1%, in contrast to the base case in 2030. Under scenario 2, the same increases in SVR were modeled, with gradual increases in the annual diagnosed and treated populations. This scenario decreased prevalent infections 45%, liver-related deaths 55%, liver cancer cases 60%, and decompensated cirrhosis 55%, as compared to the base case by 2030. CONCLUSION: In Argentina, cases of end stage liver disease and liver-related deaths due to HCV are still growing, while its prevalence is decreasing. Increasing in SVR rates is not enough, and increasing in the number of patients diagnosed and candidates for treatment is needed to reduce the HCV disease burden. Based on this scenario, strategies to increase diagnosis and treatment uptake must be developed to reduce HCV burden in Argentina. PMID- 27239259 TI - Host factors are dominant in the development of post-liver transplant non alcoholic steatohepatitis. AB - Non-alcoholic fatty liver disease (NAFLD) is a recognized problem in patients after orthotopic liver transplantation and may lead to recurrent graft injury. As the increased demand for liver allografts fail to match the available supply of donor organs, split liver transplantation (SLT) has emerged as an important technique to increase the supply of liver grafts. SLT allows two transplants to occur from one donor organ, and provides a unique model for observing the pathogenesis of NAFLD with respect to the role of recipient environmental and genetic factors. Here we report on two recipients of a SLT from the same deceased donor where only one developed non-alcoholic steatohepatitis (NASH), suggesting that host factors are critical for the development of NASH. PMID- 27239260 TI - Evaluation of the National Weather Service Extreme Cold Warning Experiment in North Dakota. AB - Dangerously cold weather threatens life and property. During periods of extreme cold due to wind chill, the National Weather Service (NWS) issues wind chill warnings to prompt the public to take action to mitigate risks. Wind chill warnings are based on ambient temperatures and wind speeds. Since 2010, NWS has piloted a new extreme cold warning issued for cold temperatures in wind and nonwind conditions. The North Dakota Department of Health, NWS, and the Centers for Disease Control and Prevention collaborated in conducting household surveys in Burleigh County, North Dakota, to evaluate this new warning. The objectives of the evaluation were to assess whether residents heard the new warning and to determine if protective behaviors were prompted by the warning. This was a cross sectional survey design using the Community Assessment for Public Health Emergency Response (CASPER) methodology to select a statistically representative sample of households from Burleigh County. From 10 to 11 April 2012, 188 door-to door household interviews were completed. The CASPER methodology uses probability sampling with weighted analysis to estimate the number and percentage of households with a specific response within Burleigh County. The majority of households reported having heard both the extreme cold and wind chill warnings, and both warnings prompted protective behaviors. These results suggest this community heard the new warning and took protective actions after hearing the warning. PMID- 27239261 TI - Pesticide exposures in a malarious and predominantly farming area in Central Ghana. AB - In areas where malaria is endemic, pesticides are widely deployed for vector control, which has contributed to reductions in malaria deaths. Pesticide use for agrarian purposes reduces pest populations, thus improving crop production and post-harvest losses. However, adverse health effects have been associated with pesticide exposure, ranging from skin irritation to neurotoxicity and carcinogenicity. Though misuse of these pesticides can lead to widespread potential dangers, the debilitating effects are usually underappreciated in many developing countries. To evaluate the pattern of pesticide usage among rural communities in the Kintampo area of Ghana, a cross-sectional survey was conducted among 1455 heads of households randomly sampled from among 29,073 households in the Kintampo Health and Demographic Surveillance System area of Ghana to estimate the prevalence of pesticide use and indications for use among this rural populace. Seventy-one percent (1040/1455) of household heads reported having used pesticides on either their farms or homes, most commonly for control of weeds (96.4%, 1003/1040) or insects (85.4%, 888/1040). Dichlorodiphenyltrichloroethane (DDT) was used by 22.9% (238/1040) of respondents. The majority of households who reported use of pesticides said women in their households assisted in the spraying efforts (69.3%, 721/1040); of these women, 50.8% (366/721) did so while carrying their babies on their backs. Only 28.9% (301/1040) of the study participants wore protective devices during pesticide applications. Frequent symptoms that were reported after spraying, included cough (32.3%; 336/1040), difficulty in breathing (26.7%; 278/1040) and skin irritation (39.0%; 406/1040). Pesticide use among community members in the Kintampo area of Ghana is common and its potential health impacts warrant further investigation. PMID- 27239263 TI - Morphogenesis and morphometric scaling of lung airway development follows phylogeny in chicken, quail, and duck embryos. AB - BACKGROUND: New branches within the embryonic chicken lung form via apical constriction, in which epithelial cells in the primary bronchus become trapezoidal in shape. These branches form at precise locations along the primary bronchus that scale relative to the size of the organ. Here, we examined the extent to which this scaling relationship and branching mechanism are conserved within lungs of three species of birds. FINDINGS: Analyzing the development of embryonic lungs from chicken, quail, and duck, as well as lungs explanted and cultured ex vivo, revealed that the patterns of branching are remarkably conserved. In particular, secondary bronchi form at identical positions in chicken and quail, the patterns of which are indistinguishable, consistent with the close evolutionary relationship of these two species. In contrast, secondary bronchi form at slightly different positions in duck, the lungs of which are significantly larger than those of chicken and quail at the same stage of development. Confocal analysis of fixed specimens revealed that each secondary bronchus forms by apical constriction of the dorsal epithelium of the primary bronchus, a morphogenetic mechanism distinct from that used to create branches in mammalian lungs. CONCLUSIONS: Our findings suggest that monopodial branching off the primary bronchus is driven by apical constriction in lungs of chicken, quail, and duck. The relative positions at which these branches form are also conserved relative to the evolutionary relationship of these species. It will be interesting to determine whether these mechanisms hold in more distant species of birds, and why they differ so significantly in mammals. PMID- 27239262 TI - Structure and function of the telomeric CST complex. AB - Telomeres comprise the ends of eukaryotic chromosomes and are essential for cell proliferation and genome maintenance. Telomeres are replicated by telomerase, a ribonucleoprotein (RNP) reverse transcriptase, and are maintained primarily by nucleoprotein complexes such as shelterin (TRF1, TRF2, TIN2, RAP1, POT1, TPP1) and CST (Cdc13/Ctc1, Stn1, Ten1). The focus of this review is on the CST complex and its role in telomere maintenance. Although initially thought to be unique to yeast, it is now evident that the CST complex is present in a diverse range of organisms where it contributes to genome maintenance. The CST accomplishes these tasks via telomere capping and by regulating telomerase and DNA polymerase alpha primase (polalpha-primase) access to telomeres, a process closely coordinated with the shelterin complex in most organisms. The goal of this review is to provide a brief but comprehensive account of the diverse, and in some cases organism-dependent, functions of the CST complex and how it contributes to telomere maintenance and cell proliferation. PMID- 27239265 TI - An improved neutral landscape model for recreating real landscapes and generating landscape series for spatial ecological simulations. AB - Many studies have assessed the effect of landscape patterns on spatial ecological processes by simulating these processes in computer-generated landscapes with varying composition and configuration. To generate such landscapes, various neutral landscape models have been developed. However, the limited set of landscape-level pattern variables included in these models is often inadequate to generate landscapes that reflect real landscapes. In order to achieve more flexibility and variability in the generated landscapes patterns, a more complete set of class- and patch-level pattern variables should be implemented in these models. These enhancements have been implemented in Landscape Generator (LG), which is a software that uses optimization algorithms to generate landscapes that match user-defined target values. Developed for participatory spatial planning at small scale, we enhanced the usability of LG and demonstrated how it can be used for larger scale ecological studies. First, we used LG to recreate landscape patterns from a real landscape (i.e., a mountainous region in Switzerland). Second, we generated landscape series with incrementally changing pattern variables, which could be used in ecological simulation studies. We found that LG was able to recreate landscape patterns that approximate those of real landscapes. Furthermore, we successfully generated landscape series that would not have been possible with traditional neutral landscape models. LG is a promising novel approach for generating neutral landscapes and enables testing of new hypotheses regarding the influence of landscape patterns on ecological processes. LG is freely available online. PMID- 27239264 TI - The lysine methyltransferase Ehmt2/G9a is dispensable for skeletal muscle development and regeneration. AB - BACKGROUND: Euchromatic histone-lysine N-methyltransferase 2 (G9a/Ehmt2) is the main enzyme responsible for the apposition of H3K9 di-methylation on histones. Due to its dual role as an epigenetic regulator and in the regulation of non histone proteins through direct methylation, G9a has been implicated in a number of biological processes relevant to cell fate control. Recent reports employing in vitro cell lines indicate that Ehmt2 methylates MyoD to repress its transcriptional activity and therefore its ability to induce differentiation of activated myogenic cells. METHODS: To further investigate the importance of G9a in modulating myogenic regeneration in vivo, we crossed Ehmt2 (floxed) mice to animals expressing Cre recombinase from the Myod locus, resulting in efficient knockout in the entire skeletal muscle lineage (Ehmt2 (DeltamyoD) ). RESULTS: Surprisingly, despite a dramatic drop in the global levels of H3K9me2, knockout animals did not show any developmental phenotype in muscle size and appearance. Consistent with this finding, purified Ehmt2 (DeltamyoD) satellite cells had rates of activation and proliferation similar to wild-type controls. When induced to differentiate in vitro, Ehmt2 knockout cells differentiated with kinetics similar to those of control cells and demonstrated normal capacity to form myotubes. After acute muscle injury, knockout mice regenerated as efficiently as wildtype. To exclude possible compensatory mechanisms elicited by the loss of G9a during development, we restricted the knockout within adult satellite cells by crossing Ehmt2 (floxed) mice to Pax7 (CreERT2) and also found normal muscle regeneration capacity. CONCLUSIONS: Thus, Ehmt2 and H3K9me2 do not play significant roles in skeletal muscle development and regeneration in vivo. PMID- 27239266 TI - Do the antipredator strategies of shared prey mediate intraguild predation and mesopredator suppression? AB - Understanding the conditions that facilitate top predator effects upon mesopredators and prey is critical for predicting where these effects will be significant. Intraguild predation (IGP) and the ecology of fear are hypotheses used to describe the effects of top predators upon mesopredators and prey species, but make different assumptions about organismal space use. The IGP hypothesis predicts that mesopredator resource acquisition and risk are positively correlated, creating a fitness deficit. But if shared prey also avoid a top predator, then mesopredators may not have to choose between risk and reward. Prey life history may be a critical predictor of how shared prey respond to predation and may mediate mesopredator suppression. We used hierarchical models of species distribution and abundance to test expectations of IGP using two separate triangular relationships between a large carnivore, smaller intraguild carnivore, and shared mammalian prey with different life histories. Following IGP, we expected that a larger carnivore would suppress a smaller carnivore if the shared prey species did not spatially avoid the large carnivore at broad scales. If prey were fearful over broad scales, we expected less evidence of mesopredator suppression. We tested these theoretical hypotheses using remote camera detections across a large spatial extent. Lagomorphs did not appear to avoid coyotes, and fox detection probability was lower as coyote abundance increased. In contrast, white-tailed deer appeared to avoid areas of increased wolf use, and coyote detection probability was not reduced at sites where wolves occurred. These findings suggest that mesopredator suppression by larger carnivores may depend upon the behavior of shared prey, specifically the spatial scale at which they perceive risk. We further discuss how extrinsic environmental factors may contribute to mesopredator suppression. PMID- 27239268 TI - Enteropathogenic E. coli: breaking the intestinal tight junction barrier. AB - Enteropathogenic E. coli (EPEC) causes acute intestinal infections in infants in the developing world. Infection typically spreads through contaminated food and water and leads to severe, watery diarrhea. EPEC attaches to the intestinal epithelial cells and directly injects virulence factors which modulate multiple signaling pathways leading to host cell dysfunction. However, the molecular mechanisms that regulate the onset of diarrhea are poorly defined. A major target of EPEC is the host cell tight junction complex which acts as a barrier and regulates the passage of water and solutes through the paracellular space. In this review, we focus on the EPEC effectors that target the epithelial barrier, alter its functions and contribute to leakage through the tight junctions. PMID- 27239267 TI - Case Report: A case report of dry tap during ventriculostomy. AB - Pneumocephalus following ventriculoperitoneal (VP) shunt insertion is an exceptionally rare occurrence. We report such an event after attempting ventricular puncture (ventriculostomy) for VP shunt insertion and then discuss the management of the same. Dry tap can lead to multiple attempts for ventriculostomy with the associated added risks of complications, as well as complicating the subsequent management. In addition, there is an increased risk of tension pneumocephalus, seizure and shunt failure due to a blockage by air bubbles. Our patient presented with features of raised intracranial pressure two months following craniotomy and evacuation of traumatic subdural hematoma. External ventricular puncture revealed egress of CSF under pressure. Upon attempting VP shunting for post-traumatic hydrocephalus, we experienced dry tap during ventricular puncture that complicated further management. We placed the proximal shunt in the presumed location of the foramen of Monro of ipsilateral frontal horn of lateral ventricle and did not remove the external ventricular drain. Post-operative CT scan revealed pneumoventriculi as the cause for the dry tap during ventricular puncture. Patient was managed with 100% oxygen. He showed gradual improvement and was later discharged. This case shows that variations in the procedure, including head down positioning, adequate cruciate dural incision prior to cortex puncture, and avoiding excessive egress of CSF can help to prevent such complications. PMID- 27239269 TI - Rapid assessment of iron in blood plasma and serum by spectrophotometry with cloud-point extraction. AB - Rapid photometric assessment of iron in blood plasma and serum by a simple procedure after the extraction of iron(II) complex with 1-nitroso-2-naphthol in the micellar phase of a nonionic surfactant at the cloud point upon heating (pH range is 4.5-6.3) is proposed. The procedure trueness was verified using a standard reference protocol using bathophenanthroline. The advantages of the procedure are higher sensitivity than the reference protocol: the limit of detection is 0.03 MUg/mL, the limit of quantitation is 0.1 MUg/mL, the determination range is 0.1 - 2.8 MUg/mL (RSD 0.02-0.10). Copper does not interfere with the iron assessment. PMID- 27239270 TI - Double blinding requirement for validity claims in cognitive-behavioral therapy intervention trials for major depressive disorder. Analysis of Hollon S, et al., Effect of cognitive therapy with antidepressant medications vs antidepressants alone on the rate of recovery in major depressive disorder: a randomized clinical trial. AB - This paper will focus on problems in the inability to double-blind cognitive behavioral therapy (CBT) studies for major depressive disorder (MDD), and provides an analysis of a recently published study to show how this problem can lead to faulty conclusions. A study by Hollon et al. published in JAMA Psychiatry that compared an antidepressant medication-only arm with a combined CBT/antidepressant arm concluded that the cognitive therapy/antidepressant combination enhanced the recovery rates compared with antidepressant alone, and that the magnitude of this increment nearly doubled for patients with more severe depression. We propose that for subjects with greater severity, there could have been both antidepressant efficacy as well as more hope and expectation in the group who knew they had received combined cognitive therapy/medication, leading to an erroneous conclusion of greater efficacy for the combined group. The large subject number in this study could easily lead to an erroneous finding on statistical testing as a small amount of bias in the subjects adds-up. We opine that the conclusions of unblind CBT outcome research in conditions with subjective endpoints such as MDD need to be given with great caution. The validity of CBT (and its derivatives such as dialectical behavioral therapy) for indications other than MDD is also part of a larger problem in the inability to blind outcome studies for these interventions. PMID- 27239271 TI - Macrophage migration inhibitory factor and placental malaria infection in an area characterized by unstable malaria transmission in central Sudan. AB - BACKGROUND: The pathogenesis of malaria during pregnancy is not fully understood. A proinflammatory cytokine, macrophage migration inhibitory factor (MIF) is suggested as a factor involved in the pathogenesis of malaria during pregnancy. METHODS: A cross-sectional study was conducted in Medani Hospital, Sudan to investigate MIF levels in placental malaria. Obstetrical and medical characteristics were gathered from each parturient woman using questionnaires. All women (151) were investigated for malaria using blood film and placental histology. MIF levels were measured using ELISA in paired maternal and cord blood samples. RESULTS: There were no P. falciparum-positive blood films obtained from maternal peripheral blood, placenta or cord samples. Out of 151 placentae, four (2.6%), one (0.7%), 32 (21.2%) showed acute, chronic and past infection on histopathology examinations respectively, while the rest (114; 75.5%) of them showed no signs of infection.There was no significant difference in the median (interquartile) of maternal [5.0 (3.7?8.8) vs 6.2(3.5?12.0) ng/ml, P=0.643] and cord [8.1(3.3?16.9) vs 8.3(4.2?16.9), ng/ml, P= 0.601] MIF levels between women with a positive result for placental malaria infection (n=37) and women with a negative result for placental malaria infection (n=114). In regression models placental malaria was not associated with maternal MIF, hemoglobin or birth weight. MIF was not associated with hemoglobin or birth weight . CONCLUSION: There was no association between maternal and cord MIF levels, placental malaria, maternal hemoglobin and birth weight. PMID- 27239272 TI - Effect of LXR/RXR agonism on brain and CSF Abeta40 levels in rats. AB - Alzheimer's disease (AD) is characterized pathologically by the presence of amyloid plaques and neurofibrillary tangles. The amyloid hypothesis contends that the abnormal accumulation of Abeta, the principal component of amyloid plaques, plays an essential role in initiating the disease. Impaired clearance of soluble Abeta from the brain, a process facilitated by apolipoprotein E (APOE), is believed to be a contributing factor in plaque formation. APOE expression is transcriptionally regulated through the action of a family of nuclear receptors including the peroxisome proliferator-activated receptor gamma and liver X receptors (LXRs) in coordination with retinoid X receptors (RXRs). It has been previously reported that various agonists of this receptor family can influence brain Abeta levels in rodents. In this study we investigated the effects of LXR/RXR agonism on brain and cerebrospinal fluid (CSF) levels of Abeta40 in naive rats. Treatment of rats for 3 days or 7 days with the LXR agonist, TO901317 or the RXR agonist, Bexarotene did not result in significant changes in brain or CSF Abeta40 levels. PMID- 27239273 TI - How blockchain-timestamped protocols could improve the trustworthiness of medical science. AB - Trust in scientific research is diminished by evidence that data are being manipulated. Outcome switching, data dredging and selective publication are some of the problems that undermine the integrity of published research. Here we report a proof-of-concept study using a 'blockchain' as a low cost, independently verifiable method that could be widely and readily used to audit and confirm the reliability of scientific studies. PMID- 27239274 TI - Acceptance of animal research in our science community. AB - Animal research is debated highly controversial, as evident by the "Stop Vivi section" initiative in 2015. Despite widespread protest to the initiative by researchers, no data is available on the European medical research community's opinion towards animal research. In this single-center study, we investigated this question in a survey of students and staff members at the Medical University of Vienna. A total of 906 participants responded to the survey, of which 82.8% rated the relevance of animal research high and 62% would not accept a treatment without prior animals testing. Overall, animal research was considered important, but its communication to the public considered requiring improvement. PMID- 27239275 TI - Promoting development and uptake of health innovations: The Nose to Tail Tool. AB - Introduction Health sector management is increasingly complex as new health technologies, treatments, and innovative service delivery strategies are developed. Many of these innovations are implemented prematurely, or fail to be implemented at scale, resulting in substantial wasted resources. Methods A scoping review was conducted to identify articles that described the scale up process conceptually or that described an instance in which a healthcare innovation was scaled up. We define scale up as the expansion and extension of delivery or access to an innovation for all end users in a jurisdiction who will benefit from it. Results Sixty nine articles were eligible for review. Frequently described stages in the innovation process and contextual issues that influence progress through each stage were mapped. 16 stages were identified: 12 deliberation and 4 action stages. Included papers suggest that innovations progress through stages of maturity and the uptake of innovation depends on the innovation aligning with the interests of 3 critical stakeholder groups (innovators, end users and the decision makers) and is also influenced by 3 broader contexts (social and physical environment, the health system, and the regulatory, political and economic environment). The 16 stages form the rows of the Nose to Tail Tool (NTT) grid and the 6 contingency factors form columns. The resulting stage-by-issue grid consists of 72 cells, each populated with cell specific questions, prompts and considerations from the reviewed literature. Conclusion We offer a tool that helps stakeholders identify the stage of maturity of their innovation, helps facilitate deliberative discussions on the key considerations for each major stakeholder group and the major contextual barriers that the innovation faces. We believe the NTT will help to identify potential problems that the innovation will face and facilitates early modification, before large investments are made in a potentially flawed solution. PMID- 27239277 TI - Use of cidofovir in pediatric patients with adenovirus infection. AB - BACKGROUND: Adenoviruses contribute to morbidity and mortality among immunocompromised pediatric patients including stem cell and solid organ transplant recipients. Cidofovir (CDV), an antiviral compound approved by the FDA in 1996, is used for treatment of adenoviral (ADV) infections in immunocompromised patients despite concern of potential nephrotoxicity. METHODS: We conducted a retrospective 5-year review at Boston Children's Hospital of 16 patients (mean age = 6.5 years) receiving 19 courses of CDV. During therapy all pertinent data elements were reviewed to characterize potential response to therapy and incidence of renal dysfunction. RESULTS: Of the 19 CDV courses prescribed, 16 courses (84%) were in patients who had a positive blood ADV Polymerase chain reaction (PCR) alone or in combination with positive ADV PCR/ Direct Immunofluorescence Assay (DFA) at another site. Respiratory symptoms with or without pneumonia were the most common presentation (10/19, 53%). In the majority of blood positive courses (10/16, 63%), viral clearance was also accompanied by clinical response. This was not the case in four courses where patients expired despite viral clearance, including one in which death was directly attributable to adenovirus. There was reversible renal dysfunction observed during the use of CDV. CONCLUSIONS: CDV appeared safe and reasonably tolerated for treatment of ADV in this pediatric population and was associated with viral response and clinical improvement in the majority of patients but reversible renal dysfunction was a side effect. Further studies of the efficacy of CDV for immunocompromised children with ADV infection are warranted. PMID- 27239276 TI - Flagellar membrane fusion and protein exchange in trypanosomes; a new form of cell-cell communication? AB - Diverse structures facilitate direct exchange of proteins between cells, including plasmadesmata in plants and tunnelling nanotubes in bacteria and higher eukaryotes. Here we describe a new mechanism of protein transfer, flagellar membrane fusion, in the unicellular parasite Trypanosoma brucei. When fluorescently tagged trypanosomes were co-cultured, a small proportion of double positive cells were observed. The formation of double-positive cells was dependent on the presence of extracellular calcium and was enhanced by placing cells in medium supplemented with fresh bovine serum. Time-lapse microscopy revealed that double-positive cells arose by bidirectional protein exchange in the absence of nuclear transfer. Furthermore, super-resolution microscopy showed that this process occurred in <=1 minute, the limit of temporal resolution in these experiments. Both cytoplasmic and membrane proteins could be transferred provided they gained access to the flagellum. Intriguingly, a component of the RNAi machinery (Argonaute) was able to move between cells, raising the possibility that small interfering RNAs are transported as cargo. Transmission electron microscopy showed that shared flagella contained two axonemes and two paraflagellar rods bounded by a single membrane. In some cases flagellar fusion was partial and interactions between cells were transient. In other cases fusion occurred along the entire length of the flagellum, was stable for several hours and might be irreversible. Fusion did not appear to be deleterious for cell function: paired cells were motile and could give rise to progeny while fused. The motile flagella of unicellular organisms are related to the sensory cilia of higher eukaryotes, raising the possibility that protein transfer between cells via cilia or flagella occurs more widely in nature. PMID- 27239278 TI - Combined analysis of trabectome and phaco-trabectome outcomes by glaucoma severity. AB - Prior glaucoma severity staging systems were mostly concerned with visual field function and retinal nerve fiber layer, but did not include intraocular pressure or medications to capture resistance to treatment. We recently introduced a simple index that combines pressure, medications, and visual field damage and applied it to stratify outcomes of trabectome surgery. This microincisional glaucoma surgery removes the primary resistance to outflow in glaucoma, the trabecular meshwork, and has been mostly used in mild glaucoma. Traditional glaucoma surgeries have a relatively high complication rate and have been reserved for more advanced disease stages. In the analysis presented here we include our data of trabectome combined with cataract surgery. This is a common practice pattern as both occur in the same age group with increasing frequency. For patients in higher glaucoma index (GI) groups, the intraocular pressure (IOP) reduction was 2.34+/-0.19 mmHg more than those in a GI group one level lower while holding everything else constant. Those who had undergone trabectome combined with phacoemulsification had an IOP reduction that was 1.29+/-0.39 mmHg less compared to those with trabectome alone. No statistically significant difference was found between genders and age groups while holding everything else constant. Hispanics had a 3.81+/-1.08 mmHg greater IOP reduction. Pseudoexfoliation and steroid glaucoma patients had an IOP reduction that was greater by 2.91+/-0.56 and 3.86+/-0.81 mmHg, respectively, than those with primary open angle glaucoma. These results suggest a role for trabectome-mediated ab interno trabeculectomy beyond mild forms of glaucoma. Additionally, the multifactorial glaucoma index demonstrates a role in staging patients when comparing glaucoma surgical modalities. PMID- 27239279 TI - Socioeconomic gradients in general and oral health of primary school children in Shiraz, Iran. AB - BACKGROUND: Health status is largely determined by socio-economic status. The general health of individuals at higher social hierarchy is better than people in lower levels. Likewise, people with higher socio-economic status have better oral health than lower socio-economic groups. There has not been much work regarding the influence of socio-economic status on the health conditions of children in developing countries, particularly in Iran. The aim of this study was to compare the oral and general health conditions of primary school children of three different socio-economic areas in the city of Shiraz, Iran. METHODS: This cross sectional study was conducted on 335, 8- to 11-year-old primary schoolchildren in Shiraz. The children were selected by a three-stage cluster sampling method from three socio-economically different areas. Tools and methods used by the United Kingdom's Medical Research Council were used to obtain anthropometric variables as indicators of general health. The Decay, Missing, Filled Teeth (DMFT) Index for permanent teeth, dmft Index for primary teeth, the Modified Developmental Defects of Enamel (DDE) Index, the Gingival Index (GI) and the Debris Index Simplified (DI-S) were used for oral health assessment. RESULTS: Height (P<0.001), weight (P<0.001), and BMI (P=0.001) significantly increased as the socio-economic status of area increased. GI score (P<0.001), DI-S score (P<0.001), number of permanent teeth with DDE (P=0.008), and number of DDE lesions in permanent teeth (P=0.008) significantly decreased as the socio economic status of area increased. DISCUSSION: Findings of this study generally confirmed that social gradients exist in both general and oral health status of the primary schoolchildren of Shiraz. The influence of socio-economic status on health condition means children have different life chances based on their socio economic conditions. These findings emphasize the significance of interventions for tackling socio-economic inequalities in order to improve the health status of children in lower socio-economic areas. PMID- 27239280 TI - Is erythropoietin a worthy candidate for traumatic brain injury or are we heading the wrong way? AB - Traumatic brain injury (TBI) is a leading cause of death and disability in the modern society. Although primary prevention is the only strategy that can counteract the primary brain damage, numerous preclinical studies have been accumulated in order to find therapeutic strategies against the secondary damage. In this scenario erythropoietin (EPO) has been shown to be a promising candidate as neuroprotective agent. A recent clinical trial, however, has shown that EPO has not an overall effect on outcomes following TBI thus renewing old concerns. However, the results of a prespecified sensitivity analysis indicate that the effect of EPO on mortality remains still unclear. In the light of these observations, further investigations are needed to resolve doubts on EPO effectiveness in order to provide a more solid base for tailoring conclusive clinical trials. PMID- 27239281 TI - Hox genes and evolution. AB - Hox proteins are a deeply conserved group of transcription factors originally defined for their critical roles in governing segmental identity along the antero posterior (AP) axis in Drosophila. Over the last 30 years, numerous data generated in evolutionarily diverse taxa have clearly shown that changes in the expression patterns of these genes are closely associated with the regionalization of the AP axis, suggesting that Hox genes have played a critical role in the evolution of novel body plans within Bilateria. Despite this deep functional conservation and the importance of these genes in AP patterning, key questions remain regarding many aspects of Hox biology. In this commentary, we highlight recent reports that have provided novel insight into the origins of the mammalian Hox cluster, the role of Hox genes in the generation of a limbless body plan, and a novel putative mechanism in which Hox genes may encode specificity along the AP axis. Although the data discussed here offer a fresh perspective, it is clear that there is still much to learn about Hox biology and the roles it has played in the evolution of the Bilaterian body plan. PMID- 27239282 TI - Current clinical immunotherapeutic approaches for head and neck cancer. AB - It was estimated that 59,340 new cases of head and neck cancer would be diagnosed in the US alone in 2015 and that 12,290 deaths would be attributed to the disease. Local and regional recurrences may be treated with chemotherapy and radiation; however, metastatic head and neck cancer is fatal and is treated with chemotherapy for palliation. Recent successful treatment of a variety of solid and hematological malignancies by immunotherapeutic approaches (i.e. harnessing the body's own immune system to combat disease) has added a fourth therapeutic option for the treatment of cancer. This commentary will review the status of immunotherapies in clinical development for the specific treatment of head and neck cancer. PMID- 27239284 TI - Highlights of the 2 (nd) Bioinformatics Student Symposium by ISCB RSG-UK. AB - Following the success of the 1 (st) Student Symposium by ISCB RSG-UK, a 2 (nd) Student Symposium took place on 7 (th) October 2015 at The Genome Analysis Centre, Norwich, UK. This short report summarizes the main highlights from the 2 (nd) Bioinformatics Student Symposium. PMID- 27239285 TI - Cell cycle regulated transcription: from yeast to cancer. AB - Recent studies have revealed exciting new functions for forkhead transcription factors in cell proliferation and development. Cell proliferation is a fundamental process controlled by multiple overlapping mechanisms, and the control of gene expression plays a major role in the orderly and timely division of cells. This occurs through transcription factors regulating the expression of groups of genes at particular phases of the cell division cycle. In this way, the encoded gene products are present when they are required. This review outlines recent advances in our understanding of this process in yeast model systems and describes how this knowledge has informed analysis in more developmentally complex eukaryotes, particularly where it is relevant to human disease. PMID- 27239283 TI - Substance use during pregnancy. AB - Prenatal substance use is a critical public health concern that is linked with several harmful maternal and fetal consequences. The most frequently used substance in pregnancy is tobacco, followed by alcohol, cannabis and other illicit substances. Unfortunately, polysubstance use in pregnancy is common, as well as psychiatric comorbidity, environmental stressors, and limited and disrupted parental care, all of which can compound deleterious maternal and fetal outcomes. There are few existing treatments for prenatal substance use and these mainly comprise behavioral and psychosocial interventions. Contingency management has been shown to be the most efficacious of these. The purpose of this review is to examine the recent literature on the prenatal use of tobacco, alcohol, cannabis, stimulants, and opioids, including the effects of these on maternal and fetal health and the current therapeutic options. PMID- 27239286 TI - Intracerebral haemorrhage in Down syndrome: protected or predisposed? AB - Down syndrome (DS), which arises from trisomy of chromosome 21, is associated with deposition of large amounts of amyloid within the central nervous system. Amyloid accumulates in two compartments: as plaques within the brain parenchyma and in vessel walls of the cerebral microvasculature. The parenchymal plaque amyloid is thought to result in an early onset Alzheimer's disease (AD) dementia, a phenomenon so common amongst people with DS that it could be considered a defining feature of the condition. The amyloid precursor protein ( APP) gene lies on chromosome 21 and its presence in three copies in DS is thought to largely drive the early onset AD. In contrast, intracerebral haemorrhage (ICH), the main clinical consequence of vascular amyloidosis, is a more poorly defined feature of DS. We review recent epidemiological data on stroke (including haemorrhagic stroke) in order to make comparisons with a rare form of familial AD due to duplication (i.e. having three copies) of the APP region on chromosome 21, here called 'dup-APP', which is associated with more frequent and severe ICH. We conclude that although people with DS are at increased risk of ICH, this is less common than in dup-APP, suggesting the presence of mechanisms that act protectively. We review these mechanisms and consider comparative research into DS and dup-APP that may yield further pathophysiological insight. PMID- 27239287 TI - Network science for the identification of novel therapeutic targets in epilepsy. AB - The quality of life of children with epilepsy is a function of seizures and associated cognitive and behavioral comorbidities. Current treatments are not successful at stopping seizures in approximately 30% of patients despite the introduction of multiple new antiepileptic drugs over the last decade. In addition, modification of seizures has only a modest impact on the comorbidities. Therefore, novel approaches to identify therapeutic targets that improve seizures and comorbidities are urgently required. The potential of network science as applied to genetic, local neural network, and global brain data is reviewed. Several examples of possible new therapeutic approaches defined using novel network tools are highlighted. Further study to translate the findings into clinical practice is now required. PMID- 27239288 TI - Molecular pathogenesis of hepatocellular carcinoma and impact of therapeutic advances. AB - Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality and has an increasing incidence worldwide. HCC can be induced by multiple etiologies, is influenced by many risk factors, and has a complex pathogenesis. Furthermore, HCCs exhibit substantial heterogeneity, which compounds the difficulties in developing effective therapies against this highly lethal cancer. With advances in cancer biology and molecular and genetic profiling, a number of different mechanisms involved in the development and progression of HCC have been identified. Despite the advances in this area, the molecular pathogenesis of hepatocellular carcinoma is still not completely understood. This review aims to elaborate our current understanding of the most relevant genetic alterations and molecular pathways involved in the development and progression of HCC, and anticipate the potential impact of future advances on therapeutic drug development. PMID- 27239289 TI - Central control of body temperature. AB - Central neural circuits orchestrate the behavioral and autonomic repertoire that maintains body temperature during environmental temperature challenges and alters body temperature during the inflammatory response and behavioral states and in response to declining energy homeostasis. This review summarizes the central nervous system circuit mechanisms controlling the principal thermoeffectors for body temperature regulation: cutaneous vasoconstriction regulating heat loss and shivering and brown adipose tissue for thermogenesis. The activation of these thermoeffectors is regulated by parallel but distinct efferent pathways within the central nervous system that share a common peripheral thermal sensory input. The model for the neural circuit mechanism underlying central thermoregulatory control provides a useful platform for further understanding of the functional organization of central thermoregulation, for elucidating the hypothalamic circuitry and neurotransmitters involved in body temperature regulation, and for the discovery of novel therapeutic approaches to modulating body temperature and energy homeostasis. PMID- 27239290 TI - Intravital imaging reveals new ancillary mechanisms co-opted by cancer cells to drive tumor progression. AB - Intravital imaging is providing new insights into the dynamics of tumor progression in native tissues and has started to reveal the layers of complexity found in cancer. Recent advances in intravital imaging have allowed us to look deeper into cancer behavior and to dissect the interactions between tumor cells and the ancillary host niche that promote cancer development. In this review, we provide an insight into the latest advances in cancer biology achieved by intravital imaging, focusing on recently discovered mechanisms by which tumor cells manipulate normal tissue to facilitate disease progression. PMID- 27239291 TI - Upper extremity nerve block: how can benefit, duration, and safety be improved? An update. AB - Upper extremity blocks are useful as both sole anaesthesia and/or a supplement to general anaesthesia and they further provide effective postoperative analgesia, reducing the need for opioid analgesics. There is without doubt a renewed interest among anaesthesiologists in the interscalene, supraclavicular, infraclavicular, and axillary plexus blocks with the increasing use of ultrasound guidance. The ultrasound-guided technique visualising the needle tip and solution injected reduces the risk of side effects, accidental intravascular injection, and possibly also trauma to surrounding tissues. The ultrasound technique has also reduced the volume needed in order to gain effective block. Still, single shot plexus block, although it produces effective anaesthesia, has a limited duration of postoperative analgesia and a number of adjuncts have been tested in order to prolong analgesia duration. The addition of steroids, midazolam, clonidine, dexmedetomidine, and buprenorphine has been studied, all being off label when administered by perineural injection, and the potential neurotoxicity needs further study. The use of perineural catheters is an effective option to improve and prolong the postoperative analgesic effect. Upper extremity plexus blocks have an obvious place as a sole anaesthetic technique or as a powerful complement to general anaesthesia, reducing the need for analgesics and hypnotics intraoperatively, and provide effective early postoperative pain relief. Continuous perineural infusion is an effective option to prolong the effects and improve postoperative quality. PMID- 27239292 TI - Recent advances in microscopic techniques for visualizing leukocytes in vivo. AB - Leukocytes are inherently motile and interactive cells. Recent advances in intravital microscopy approaches have enabled a new vista of their behavior within intact tissues in real time. This brief review summarizes the developments enabling the tracking of immune responses in vivo. PMID- 27239294 TI - Toxic epidermal necrolysis. AB - Toxic epidermal necrolysis (TEN) is a rare, life-threatening drug-induced skin disease with a mortality rate of approximately 30%. The clinical hallmark of TEN is a marked skin detachment caused by extensive keratinocyte cell death associated with mucosal involvement. The exact pathogenic mechanism of TEN is still uncertain. Recent advances in this field have led to the identification of several factors that might contribute to the induction of excessive apoptosis of keratinocytes. In addition, specific human leukocyte antigen types seem to be associated with certain drugs and the development of TEN. As well-controlled studies are lacking, patients are treated with various immunomodulators (e.g. intravenous immunoglobulin) in addition to the best supportive care. PMID- 27239293 TI - Cannabinoid receptor type-1: breaking the dogmas. AB - The endocannabinoid system (ECS) is abundantly expressed in the brain. This system regulates a plethora of physiological functions and is composed of cannabinoid receptors, their endogenous ligands (endocannabinoids), and the enzymes involved in the metabolism of endocannabinoids. In this review, we highlight the new advances in cannabinoid signaling, focusing on a key component of the ECS, the type-1 cannabinoid receptor (CB 1). In recent years, the development of new imaging and molecular tools has demonstrated that this receptor can be distributed in many cell types (e.g., neuronal or glial cells) and intracellular compartments (e.g., mitochondria). Interestingly, cellular and molecular effects are differentially mediated by CB 1 receptors according to their specific localization (e.g., glutamatergic or GABAergic neurons). Moreover, this receptor is expressed in the periphery, where it can modulate periphery brain connections. Finally, the better understanding of the CB 1 receptor structure led researchers to propose interesting and new allosteric modulators. Thus, the advances and the new directions of the CB 1 receptor field will provide new insights and better approaches to profit from its interesting therapeutic profile. PMID- 27239295 TI - Biomarkers of acute kidney injury and associations with short- and long-term outcomes. AB - Acute kidney injury is strongly associated with increased mortality and other adverse outcomes. Medical researchers have intensively investigated novel biomarkers to predict short- and long-term outcomes of acute kidney injury in many patient care settings, such as cardiac surgery, intensive care units, heart failure, and transplant. Future research should focus on leveraging this relationship to improve enrollment for clinical trials of acute kidney injury. PMID- 27239297 TI - Bilateral Chest X-Ray Shadowing and Bilateral leg lesions - A case of Pulmonary Kaposi Sarcoma. AB - We report a case of a 30 year old gentleman seen on the respiratory ward with no significant past medical history presenting with a three week history of worsening dyspnoea, productive cough, fever, bilateral leg swelling and bilateral leg swelling. Initial differential diagnosis included community-acquired pneumonia, cellulitis and deep vein thrombosis. After much investigation a diagnosis of AIDS-related kaposi's sarcoma with visceral manifestations was made. PMID- 27239296 TI - Recent advances in metabolic and bariatric surgery. AB - Obesity and its associated medical conditions continue to increase and add significant burden to patients, as well as health-care systems, worldwide. Bariatric surgery is the most effective treatment for severe obesity and its comorbidities, and resolution of diabetes is weight loss-independent in the case of some operations. Although these weight-independent effects are frequently described clinically, the mechanisms behind them are not well understood and remain an intense area of focus in the growing field of metabolic and bariatric surgery. Perceptions of the mechanisms responsible for the beneficial metabolic effects of metabolic/bariatric operations have shifted from being mostly restrictive and malabsorption over the last 10 to 15 years to being more neuro hormonal in origin. In this review, we describe recent basic and clinical findings of the major clinical procedures (adjustable gastric banding, vertical sleeve gastrectomy, Roux-en-Y gastric bypass, and biliopancreatic diversion) as well as other experimental procedures (ileal interposition and bile diversion) that recapitulate many of the metabolic effects of these complex operations in a simpler fashion. As the role of bile acids and the gut microbiome on metabolism is becoming increasingly well described, their potential roles in these improvements following metabolic surgery are becoming better appreciated. Bile acid and gut microbiome changes, in light of recent developments, are discussed in the context of these surgical procedures, as well as their implications for future study. PMID- 27239299 TI - Variability of anti-staphylococcal antibodies in healthy volunteers and pre cardiac surgery patients. AB - BACKGROUND: Pre-operative antibody levels have been shown to be inversely related to development of post-operative complications. Staphylococcal infection is a major source of morbidity following surgery. METHODS: We examined the variability of anti-staphylococcal antibody levels across a group of healthy volunteers and compared this with patients scheduled to undergo cardiac surgery. RESULTS: Pre operative cardiac surgical patients exhibited significantly higher levels of staphylococcal antibodies compared with healthy volunteers. CONCLUSIONS: The relationship between pre-surgery staphylococcal antibody levels and outcome warrants further investigation. PMID- 27239298 TI - Care of elderly patients: a prospective audit of the prevalence of hypotension and the use of BIS intraoperatively in 25 hospitals in London. AB - BACKGROUND: Anaesthesia is frequently complicated by intraoperative hypotension (IOH) in the elderly, and this is associated with adverse outcome. The definition of IOH is controversial, and although management guidelines for IOH in the elderly exist, the frequency of IOH and typical clinically applied treatment thresholds are largely unknown in the UK. METHODS: We audited frequency of intraoperative blood pressure against national guidelines in elderly patients undergoing surgery. Depth of anaesthesia (DOA) monitoring was also audited due to the association between low DOA values and IOH with increased mortality (as part of "double" and "triple low" phenomena) and because it is a suggested management strategy to reduce IOH. RESULTS: Twenty-five hospitals submitted data on 481 patients. Hypotension varied depending on the definition, but affected 400 patients (83.3 %) using the AAGBI standard. Furthermore, 2.9, 13.5, and 24.6 % had mean arterial blood pressures <50, <60, and <70 mmHg for 20 min, respectively, and 136 (28.4 %) had systolic blood pressure decrease by 20 % for 20 min. DOA monitors were used for 45 (9.4 %) patients. CONCLUSIONS: IOH is common and use of DOA monitors is less than implied by guidelines. Improved management of IOH may be a simple intervention with real potential to reduce morbidity in this vulnerable group. PMID- 27239300 TI - Effects of benzoic acid (VevoVitall(r)) on the performance and jejunal digestive physiology in young pigs. AB - BACKGROUND: As a organic acid, benzoic acid has become one of the most important alternatives for antibiotics, and its beneficial effect on performance in animals has been proven for a decade. However, knowledge of the effects of benzoic acid on jejunal digestive physiology, especially the antioxidant capacity and mucosal glucagon-like peptide 2 (GLP-2) concentrations is lacking. METHODS: A total of 20 barrows [Duroc * (Yorkshire * Landrace)] with an average body weight (BW) of 18.75 +/- 0.2 kg were used in a 14-d trial to determine the potential mechanisms of benzoic acid supplementation on the performance, nutrient digestibility and jejunal digestive physiology in young pigs. All pigs were randomly allotted to 1 of 2 diets supplemented with 0 or 5000 mg/kg benzoic acid. RESULTS: Relative to the control, benzoic acid supplementation increased the average daily feed intake (ADFI), and average daily gain (ADG) in young pigs (P < 0.05), improved the apparent total tract digestibility of dry matter (DM), crude protein (CP), ether extract (EE), gross energy (GE) and crude ash (P < 0.05), and enhanced the activities of trypsin, lipase and amylase in the jejunum (P < 0.05). Similarly, relative to the control, supplementing benzoic acid in the diet resulted in a trend to reduce the pH values of the digesta (P = 0.06), decreased crypt depth and increased the villus height to crypt depth ratio (P < 0.05) in the jejunum of pigs. Finally, benzoic acid supplementation increased the mRNA expression and concentration of glucagon-like peptide 2 and the activities of glutathione peroxidase and superoxide dismutase in the jejunal mucosa of young pigs (P < 0.05). CONCLUSIONS: In conclusion, supplementation with 5000 mg/kg benzoic acid improved the performance of young pigs through promoting nutrient digestion, improving jejunal antioxidant capacity, and maintaining the jejunal morphology in young pigs. PMID- 27239301 TI - Improving patient reported outcome measures (PROMs) in total knee replacement by changing implant and preserving the infrapatella fatpad: a quality improvement project. AB - Patient reported outcome measures (PROMs) were introduced in 2009 to allow patient perspectives to potentially influence change and improvement. In collaboration with the national joint registry (NJR), PROMs data has been examined on a national basis to compare surgical factors in total knee replacement (TKR). Initial results demonstrated there were statistically significant differences in Oxford Knee Score (OKS) when using different brands of implant. Preservation of the infrapatella fatpad (IFP) has also been shown improve outcomes. This led Northumbria Healthcare NHS Foundation Trust to make a mass move to the Zimmer Nexgen TKR and later change surgeons' routine practice to preserving the IFP. The PROMs were recorded pre and six months post operation to obtain improvement scores. The baseline improvement in OKS was 14.0. After changing implant to the Zimmer Nexgen in Plan-Do-Study-Act (PDSA) cycle 1 the average improvement score was 16.7. After implementing default preservation of the IFP in PDSA cycle 2 the average OKS improvement score was 17.3. The results from this project demonstrate a significant improvement in local services after implementing changes based on national and local evaluations. This initiative is an excellent example of improvement by evidence based practice and success of the English National Health Service PROMs scheme. PMID- 27239302 TI - Introducing routine HIV screening for patients on an internal medicine residency inpatient service: a quality improvement project. AB - The US Centers for Disease Control and Prevention (CDC) recommend human immunodeficiency virus (HIV) screening for all persons aged 13 to 64 years who present to a health care provider. We sought to improve adherence to the CDC guidelines on the Internal Medicine Resident Hospital Service. We surveyed residents about the CDC guidelines, sent email reminders, provided education, and engaged them in friendly competition. Credit for guideline adherence was awarded if an offer of HIV screening was documented at admission, if a screening test was performed, or if a notation in the resident sign out sheet indicated why screening was not performed. We examined HIV screening of a postintervention group of patients admitted between August 8, 2012, and June 30, 2013, and compared them to a preintervention group admitted between August 1, 2011, and June 30, 2012. Postintervention offers of HIV screening increased significantly (7.9% [44/559] vs 55.5% [300/541]; P<.001), as did documentation of residents' contemplation of screening (8.9% [50/559] vs 67.5% [365/541]; P<.001). A significantly higher proportion of HIV screening tests was ordered postintervention (7.7% [43/559] vs 44.4% [240/541]; P<.001). Monthly HIV screening documentation ranged from 0% (0/53) to 17% (9/53) preintervention, whereas it ranged from 30.6% (11/36) to 100% (62/62) postintervention. HIV screening adherence can be improved through resident education, friendly competition, and system reminders. Barriers to achieving sustained adherence to the CDC guidelines include a heterogeneous patient population and provider discomfort with the subject. PMID- 27239303 TI - Seeking Sepsis in the Emergency Department- Identifying Barriers to Delivery of the Sepsis 6. AB - The Sepsis 6 is an internationally accepted management bundle that, when initiated within one hour of identifying sepsis, can reduce morbidity and mortality. This management bundle was advocated by the Scottish Patient Safety Programme as part of its Acute Adult campaign launched in 2008 and adopted by NHS Tayside in 2012. Despite this, the Emergency Department (ED) of Ninewells Hospital, a tertiary referral centre and major teaching hospital in Scotland, was displaying poor success in the Sepsis 6. We therefore set out to improve compliance by evaluating the application of all aspects of the NHS Tayside Sepsis 6 bundle within one hour of ED triage time, to identify what human factors may influence achieving the one hour The Sepsis 6 bundle. This allowed us to tailor a number of specific interventions including educational sessions, regular audit and personal feedback and check list Sepsis 6 sticker. These interventions promoted a steady increase in compliance from an initial rate of 51.0% to 74.3%. The project highlighted that undifferentiated patients create a challenge in initiating the Sepsis 6. Pyrexia is a key human factor-trigger for recognising sepsis with initial nursing assessment being vital in recognition and identifying the best area (resus) of the department to manage severely septic patients. EDs need to recognise these challenges and develop educational and feedback plans for staff and utilise available resources to maximise the Sepsis 6 compliance. PMID- 27239304 TI - Simple Interventions Improve the Quality of a Missed Lab Appointment Process. AB - Simple interventions resolve the problem of missed lab appointments. It is essential that patients complete ordered laboratory studies. This maintains clinical quality and, potentially, keeps patients safe from harm. In our academic family medicine practice, baseline data demonstrated patients completed 94.7% of labs as ordered (26850/28348 patients per year) while 1498 (5.3%) did not. Our baseline patient reminder process, a mail or portal based generic letter, resulted in only 449 (30%) of patients ultimately completing them (1049 [70%] did not). Our baseline system was 96.3 % reliable. This process did not allow for provider review or input, and was not personalized for patients. We designed a quality improvement project involving three PDSA (Plan, Do, Study, and Act) cycles of about two months each. Desk staff created weekly reports of unresolved lab orders. A message in the electronic medical record (EMR) solicited provider input. Providers could elect to cancel studies (if already completed, reordered, or no longer clinically indicated) or have the patient receive a personalized reminder, including provider name and associated diagnoses. This reminder was sent by patient portal secure messaging (if an account existed) or with a mailed letter. These interventions resulted in 98.8 % process reliability. The frequency of unresolved lab orders decreased from 70% at baseline to 25%. In the second PDSA cycle, we contacted patients by the portal only if there was evidence of an active account. Otherwise, they were contacted by telephone. Patients without a portal account continued to receive a letter by mail. These modified processes resulted in an overall reliability rate of 99.2%. The frequency of unresolved lab orders decreased to 17%. A final PDSA cycle utilized only telephone contact with patients with unresolved lab orders. Schedulers offered patients a choice of appointment dates if they spoke personally. Otherwise, they were left messages with a future lab appointment date two weeks later.Overall process reliability now increased to 100%. The frequency of unresolved lab orders decreased to 0%. Our interventions resulted in increased system reliability.Provider input was not perceived as burdensome. Desk staff work effort was not increased.Telephone patient contact resulted in more frequent lab order completion than other methods. PMID- 27239305 TI - Improving early childhood literacy and school readiness through Reach Out and Read (ROR) program. AB - Reach out and Read program (ROR) prepares young children to succeed in school by partnering with physicians and training them in handing out age appropriate books and to counsel parents about the importance of reading aloud to their children. Children served by ROR enter kindergarten with stronger vocabulary and language skills. The aim of this project was to improve the rate of distribution of books and physician advice about reading, to the families at each well child visit in the age range of six months to five years. This Quality Improvement (QI) project was conducted in a large inner-city pediatric residency clinic serving a lower socio-economic status under-served population. After reviewing the data from the past two years, we noticed that there was a tremendous drop in the percentage of books handed out at well visits and advice given to parents about benefits of reading aloud and self-reporting of parents reading to their child for four or more days in a week. Two goals were established: 1. To increase the rate of distributing books at every well child visit (WCV) from six months to five years of age by at least 80%. 2. To improve the rate of counseling given by the resident physicians to the families by at least 75%. A workflow was created to efficiently distribute books at well visits. A presentation about the ROR program was attended by all the physicians and residents. Reading tips in each exam room were posted to serve as a reminder for all providers and for the parents. A three question survey was collected from the families at the end of their well visit. A total of 210 surveys were collected from parents over a six month period. The percentage of handing out books at all well child visits increased from 30% to 96%. The rate of providers giving advice about the benefits of reading increased from 26% to 87%. The percentage of parents reading to their child greater than four days per week increased from 56% to 80%. Reading aloud is widely recognized as the single most important activity leading to literacy acquisition. With the above interventions, families participating in the ROR model at our clinic were more likely to read to their children, more likely to report reading aloud at bedtime, and to read aloud four or more days per week. PMID- 27239306 TI - A Quality Improvement Project to Assess Timing of Initial Investigations in Stroke Medicine. AB - There are several investigations that can be completed in the acute phase of admission for patients with suspected stroke.These include receiving a CT Head scan and also blood tests specific for stroke. The national guidelines regarding CT Head scans detail they should be completed within 12 hours of admission(1) and the trust guidelines, local to where this quality improvement project was based, advise a CT Head should be completed within four hours of admission.(2) The current national guidelines do not specify exact stroke blood tests, however trust guidelines give a specific set of blood tests that would be appropriate to be taken when a patient presents to A&E with a suspected stroke. These included FBC, U&E, blood glucose, ESR, cholesterol, TFTs, and coagulation screen.(2) The aim of this quality improvement project was to assess the timing of CT Head scans and blood tests and to implement a tool to ensure these are done in a timely fashion, within the emergency care setting. The project was completed through three PSDA cycles. The first was undertaken in an A&E department, which was soon to be closed and moved to a different site. The second cycle was then completed at the new site, to assess if there had been any change in timings of these interventions. In the previous site it was found that 97% of patients audited received a CT Head scan within four hours. At the new site it was found 94% patients received a CT Head within four hours, therefore both meeting trust targets on the whole. A full set of stroke blood tests were completed at the old site in 53% of patients and this decreased to 22% of patients at the new site. At this point it was decided an intervention should be implemented to ensure this did not continue. The intervention used was updating a stroke panel on the trust computer system (an easy to use, one-click button entitled "Stroke/TIA") with the correct blood tests and the use of this was promoted throughout the trust. A post intervention audit was completed three months after the tool was promoted and patients receiving the correct blood tests whilst in the A&E department increased to 75%. The amount of patients receiving a CT Head scan within four hours was 100% therefore meeting both trust and national guidelines. In conclusion, the stroke blood panel appears to have improved the amount of patients receiving the correct blood tests when admitted with suspected stroke and will continue to stay in place at the trust. PMID- 27239307 TI - Improving the safety of prescriptions of domperidone in primary care: implementing MHRA advice. AB - Domperidone is a dopamine D2 receptor antagonist acting on the chemoreceptor trigger zone in the medulla and also in the gut, causing antiemetic and gastrokinetic effects respectively. In the past, domperidone was considered largely safe, with many indications and few contraindications listed in the product literature. In 2014, Domperidone became indicated only for the prevention of nausea and vomiting and the duration of treatment was limited to seven days. Furthermore, the maximum daily dose was limited to thirty milligrams. A quality improvement project was undertaken at Holland Park Surgery to improve compliance with MHRA guidelines. Prescriptions of domperidone in the previous nine months were assessed for compliance with the MHRA advice. Domperidone was prescribed for 23 patients; of these 4 were single acute prescriptions, 3 were repeats which had been stopped and 16 were on active repeat at the time of the search. All patients who had active repeat prescriptions had exceeded the recommended duration of treatment. MHRA contraindications were found in 6 (37%) of active repeat prescriptions. The strategy for improvement involved three PDSA cycles and involved engaging with patients for medication reviews and staff to improve prescribing practices. After the third PDSA cycle we demonstrated that all repeat prescriptions had been stopped and that new prescriptions were compliant with MHRA advice. PMID- 27239308 TI - Improving analgesia in fractured neck of femur with a standardised fascia iliaca block protocol. AB - Fractured neck of femur (NOF) causes significant morbidity and pain for patients; adequate analgesia is an essential component of patient centred care. Patients experiencing greater pain during treatment for fractured NOF are slower to mobilise and have poorer health-related quality of life. NICE guidance suggests considering adding nerve blocks if paracetamol and opioids do not provide sufficient preoperative pain relief. We set out to audit pain levels in this group of patients in a small District General Hospital and to develop a protocol to improve analgesia provision if required. We identified that patients waiting a long time for fixation of fractured NOF could benefit from safe, effective analgesia by way of fascia iliaca compartment block (FICB). We drew up a protocol and held training sessions bringing about a culture change to provide an excellent standard of analgesia for these patients. Most patients reported much better levels of analgesia post-block and junior doctors felt more empowered. Further developments considered are training of senior ED nurses to administer FICB (in keeping with the AAGBI position statement) and a fascia iliaca catheter placement service. PMID- 27239309 TI - Improving the Laboratory Add-On Process and Increasing Housestaff Satisfaction with an EMR Intervention. AB - At a community hospital in Brooklyn, New York, the process for ordering add-on testing to drawn blood tubes involved filling out a paper sheet, then faxing and bulleting that sheet to the lab. It was a very inefficient, cumbersome, and unsatisfactory way of completing the process. In light of this, an EMR intervention was implemented in which the add-on order was placed as an EMR order. The study spanned over almost five years, over a year of which was post intervention. There was a statistically significant increase in the number of add on orders being placed as a result of the intervention. This has greatly improved housestaff satisfaction with the overall process. In conclusion, the project was a great success and met its goals of simplifying a difficult and cumbersome process while increasing user satisfaction. PMID- 27239310 TI - Survive On Call - A QI Project to Improve Access to Hospital Clinical Guidelines. AB - Accessing clinical guidelines and telephone numbers can be time consuming for junior doctors, particularly during a busy on-call shift. Smartphones allow instant access to this information, without leaving a patient's bedside. This overcomes the relative paucity of fixed desktop computers available in most clinical areas. In this project, a trainee doctor developed a clinical smartphone app to improve the access of clinical and hospital-specific information. A representative sample of ten junior doctors were recruited to quantify the amount of time spent accessing guidelines using desktop computers, versus the App. The average time to access a common guideline (Hypokalaemia management) with the App was 12.4 seconds (95% CI 2.3), versus 76.8 seconds (95% CI 30.6) using a computer. A difference of 64.4 seconds (p < 0.001). The average time to access an Amiodarone prescribing guideline with the App was 25.9 seconds (95% CI 12.9), versus 142.0 seconds (95% CI 44.8) using a computer. A difference of 116.1 seconds (p < 0.001). User feedback was collected after each stage of release within the hospital. Following final release, users rated how much time they felt it saved them. 96.1% of respondents felt it either saved them time a 'few times a week' (53.85%) or 'significantly saved time every day' (42.31%). The project has significantly improved staff satisfaction with how easily they can access clinical guidelines and telephone numbers. They clearly feel it has improved their working efficiency. This has been supported by quantitative measures of actual time saved using the App. The ability to access such information in as little time as possible may be even more pertinent where decision-making is time critical - for example in Anaesthesia and Emergency Medicine. Further study into these specialties is warranted to determine whether mobile information can impact upon patient safety and clinical outcomes. PMID- 27239311 TI - Tunable self-assembly of Irinotecan-fatty acid prodrugs with increased cytotoxicity to cancer cells. AB - The development of a clinical chemotherapeutic is not an easy task. One challenge is how to deliver the agent to cancer cells. Nano-formulation of prodrugs, which combines the strengths of nanotechnology and prodrugs, possesses many advantages for chemotherapeutic drug delivery, including high drug loading efficiency, improved drug availability and enhanced accumulation in cancer cells. Here, we have constructed a small library of Irinotecan-derived prodrugs, in which the 20 hydroxyl group was derived with fatty-acid moieties through esterification. This conjugation fine-tuned the polarity of the Irinotecan molecule, thus enhancing the lipophilicity of the prodrugs and inducing their self-assembly into nanoparticles with different morphologies. These nano-formulated prodrugs accumulated at higher levels in cancer cells and were much more cytotoxic than free drugs. The rational design of prodrug-based nano-formulations opens a new avenue for the engineering of more efficient drug-delivery systems. PMID- 27239313 TI - Assessment and selection of the best treatment alternative for infectious waste by modified Sustainability Assessment of Technologies methodology. AB - BACKGROUND: Improper treatment of infectious waste can cause numerous adverse environmental and health effects such as transmission of diseases through health personnel and other susceptible groups,who come in contact with such wastes. On the other hand, selection of appropriate treatment alternatives in infectious waste management has become a challenging task for public health authorities especially in developing countries. The objective of this paper is to select the best infectious waste treatment alternative by the modified Sustainability Assessment of Technologies (SAT) methodology, developed by the International Environmental Technology Center of the United Nations Environment Program (IETC UNEP). METHODS: SAT methodology consists of three main components, including screening, scoping and detailed assessment. In screening, different infectious waste treatment alternatives undergo screening using the finalized environmental and technical criteria. Short-listed treatment options from the previous step, then go through the comprehensive scoping and detailed assessment (2nd and 3rd components) which is more qualitative and quantitative in nature. An empirical case in Tehran, the largest city in Iran, is provided to illustrate the potential of the proposed methodology. RESULTS: According to the final score, "Hydroclave", was the most suitable infectious treatment technology. The ranking order of the treatment alternatives were "Autoclave with a shredder", "Autoclave", "Central Incineration" and "chemical treatment" on the basis of technical, economical, social and environmental aspects and their related criteria. CONCLUSIONS: According to the results it could be concluded that the top ranking technologies basically have higher scores in all the aspects. Hence it is easier to arrive at a decision for the final technology selection based on the principles of sustainability. PMID- 27239312 TI - Neurocritical care update. AB - This update comprises six important topics under neurocritical care that require reevaluation. For post-cardiac arrest brain injury, the evaluation of the injury and its corresponding therapy, including temperature modulation, is required. Analgosedation for target temperature management is an essential strategy to prevent shivering and minimizes endogenous stress induced by catecholamine surges. For severe traumatic brain injury, the diverse effects of therapeutic hypothermia depend on the complicated pathophysiology of the condition. Continuous electroencephalogram monitoring is an essential tool for detecting nonconvulsive status epilepticus in the intensive care unit (ICU). Neurocritical care, including advanced hemodynamic monitoring, is a fundamental approach for delayed cerebral ischemia following subarachnoid hemorrhage. We must be mindful of the high percentage of ICU patients who may develop sepsis-associated brain dysfunction. PMID- 27239314 TI - Prediction of protective sensory loss, neuropathy and foot ulceration in type 2 diabetes. AB - OBJECTIVES: To prospectively determine clinical and biochemical characteristics associated with the development of peripheral neuropathy, loss of protective sensation, and foot ulceration in persons with type 2 diabetes mellitus (DM) over 7 years. RESEARCH DESIGN AND METHODS: Graded monofilament (MF) testing, vibration perception threshold, and neuropathy symptom questionnaires were undertaken in 206 participants with type 2 DM without peripheral vascular disease or history of foot ulceration and 71 healthy participants without DM at baseline and after 7 years. 6 monthly glycosylated hemoglobin (HbA1c) levels and annual serum lipid profiles were measured during follow-up of those with DM. Incident foot ulceration was recorded at follow-up. RESULTS: Taller stature and higher quartiles of serum triglyceride and HbA1c levels were associated with neuropathy at follow-up (p=0.008). Remission of baseline neuropathy was observed in 7 participants at follow-up. 9 participants with type 2 DM developed foot ulcers by the end of the study, only 1 at low risk. Mean HbA1c levels were higher in those who developed foot ulceration (p<0.0001). 1 participant with neuropathy throughout developed a Charcot foot. Failure to perceive 2 or more 2, 4 and 6 g MF stimuli at baseline predicted loss of protective sensation at follow-up. CONCLUSIONS: Tall stature and worse metabolic control were associated with progression to neuropathy. Mean HbA1c levels were higher in those who developed foot ulcers. Graded MF testing may enrich recruitment to clinical trials and assignation of high risk for foot ulceration. PMID- 27239315 TI - Gender-related affecting factors of prediabetes on its 10-year outcome. AB - OBJECTIVE: To investigate the gender-related affecting factors of prediabetes on its 10-year outcome, in a longitudinal study. METHODS AND RESULTS: This longitudinal population-based study was performed in the Ping Liang community, Yangpu district, Shanghai, between November 2002 and October 2014. There were 334 participants with prediabetes enrolled in the final analysis. While a certain proportion of the prediabetic population progress to diabetes, the majority remain at the same level or even revert to normal glucose regulation. No gender difference was observed in the change of glucose regulation. However, results from an adjusted logistic regression analysis in males showed that physical activity was significantly associated with both elevated odds of reverting to normal glucose regulation (active vs inactive, OR 3.00, 95% CI 1.09 to 8.30) and developing diabetes (OR 0.34, 95% CI 0.13 to 0.92). Age, baseline 2 h glucose, triglycerides and smoking status were also risk factors significantly associated with diabetes development; while for females, waist circumference played a key role in the outcome. Every unit elevation of waist circumference was associated with lower odds of reverting to normal glucose regulation (OR, 0.94; 95% CI 0.89 to 0.98) and higher odds of progressing to diabetes (OR, 1.05; 95% CI 1.01 to 1.10). Baseline hypertension and family history of diabetes carried higher risk for developing diabetes as well. CONCLUSIONS: Physical activity in males and waist circumference in females are important factors predicting both progression to diabetes and regression to normal glucose regulation, indicating that more exercise for males and lower waist circumference for females are beneficial for prediabetes to achieve reversion. PMID- 27239316 TI - Socioeconomic status and glycemic control in adult patients with type 2 diabetes: a mediation analysis. AB - OBJECTIVE: The purpose of this study is to examine the contribution of health behaviors (self-management and coping), quality of care, and individual characteristics (depressive symptoms, self-efficacy, illness representations) as mediators in the relationship between socioeconomic status (SES) and glycemic control. METHODS: A sample of 295 adult patients with type 2 diabetes was recruited at the end of a diabetes education course. Glycemic control was evaluated through glycosylated hemoglobin (HbA1c). Living in poverty and education level were used as indicators of SES. RESULTS: Bootstrapping analysis showed that the significant effects of poverty and education level on HbA1c were mediated by avoidance coping and depressive symptoms. The representation that diabetes is unpredictable significantly mediated the relationship between living in poverty and HbA1c, while healthy diet mediated the relationship between education level and HbA1c. CONCLUSIONS: To improve glycemic control among patients with low SES, professionals should regularly screen for depression, offering treatment when needed, and pay attention to patients' illness representations and coping strategies for handling stress related to their chronic disease. They should also support patients in improving their self management skills for a healthy diet. PMID- 27239318 TI - Integrative health coaching: a behavior skills approach that improves HbA1c and pharmacy claims-derived medication adherence. AB - OBJECTIVE: Medication adherence requires underlying behavior skills and a supporting mindset that may not be addressed with education or reminders. Founded in the study of internal motivation and health psychology, integrative health coaching (IHC) helps patients gain insight into their behaviors and make long term, sustainable lifestyle changes. The purpose of the study is to determine whether IHC improves oral medication adherence, glycated hemoglobin (HbA1c), and psychosocial measures, and to assess whether adherence changes are sustained after the intervention. METHODS: Using a prospective observational design, participants (n=56) received 14 coaching calls by telephone over 6 months. Medication possession ratio (MPR) was calculated for time intervals before, during, and after the intervention. HbA1c and patient-reported psychosocial outcomes were obtained to test interactions with MPR. RESULTS: Medication adherence (MPR) increased from 0.74+/-0.197 to 0.85+/-0.155 during coaching, and was sustained at 0.82+/-0.175 during a 6-month period after the study. Better adherence correlated with a greater decrease in HbA1c. HbA1c decreased from 8.0+/ 1.92% to 7.7+/-1.70% over the 6-month intervention. All psychosocial measures showed significant improvement. In addition to discussing medication adherence strategies with their coach, patients discussed nutrition and exercise (86.9% of calls), stress management (39.8%), and social support and relationships (15.4%). CONCLUSIONS: IHC targets internal motivation and supports behavior change by facilitating patients' insight into their own behaviors, and it uses this insight to foster self-efficacy. This approach may yield sustainable results for medication adherence and warrants further exploration for health-related behavior change. PMID- 27239317 TI - Stages of change for physical activity and dietary habits in persons with type 2 diabetes included in a mobile health intervention: the Norwegian study in RENEWING HEALTH. AB - OBJECTIVE: The aim of this study was to investigate stages of change for physical activity and dietary habits using baseline data from persons with type 2 diabetes included in a mobile health intervention. We examined the associations between stages of change for physical activity change and dietary change, and between stages of change for each behavior and individual characteristics, health-related quality of life, self-management, depressive symptoms, and lifestyle. RESEARCH DESIGN AND METHODS: We examined 151 persons with type 2 diabetes with an glycated hemoglobin (HbA1c) level >=7.1%, aged >=18 years at baseline of a randomized controlled trial, before testing a mobile app with or without health counseling. Stages of change were dichotomized into 'pre-action' and 'action'. Self management was measured using the Health Education Impact Questionnaire (heiQ) where a higher score reflects increased self-management, and health-related quality of life was measured with the Short-Form-36 (SF-36). Logistic regression modeling was performed. RESULTS: The median HbA1c level was 7.9% (7.1-12.4), 90% were overweight or obese, and 20% had >=3 comorbidities. 58% were in the preaction stage for physical activity change and 79% in the preaction stage for dietary change. Higher scores of self-management were associated with an increased chance of being in the action stage for both dietary change and physical activity change. Higher body mass index was associated with an 8% reduced chance of being in the action stage for physical activity change (OR 0.92, 95% CI 0.86 to 0.99). CONCLUSIONS: Being in the action stage was associated with higher scores of self-management, crucial for type 2 diabetes. Over half of the participants were in the preaction stage for physical activity and dietary change, and many had a high disease burden with comorbidities and overweight. TRIAL REGISTRATION NUMBER: NCT01315756. PMID- 27239319 TI - Association of diabetes with tooth loss in Hispanic/Latino adults: findings from the Hispanic Community Health Study/Study of Latinos. AB - OBJECTIVES: To investigate the association between diabetes mellitus and missing teeth in Hispanic/Latino adults from diverse heritage groups who reside in the USA. RESEARCH DESIGN AND METHODS: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a multicenter, population-based study of 18-74 years old who underwent a physical and oral examination (n=15 945). Glycemic status was categorized as diabetes, impaired, or normal, based on medication use, and American Diabetes Association criteria for fasting glucose and glycosylated hemoglobin (HbA1c). HbA1c<7% indicated good glycemic control, and HbA1c>7% indicated uncontrolled diabetes. We estimated ORs and 95% CIs for missing >9 teeth and being edentulous (missing all natural teeth), after adjustment for age, income, education, Hispanic background, study site/center, nativity, last dental visit, health insurance, diet quality, cigarette smoking, obesity, periodontitis, and C reactive protein. RESULTS: Persons with uncontrolled diabetes had a significant increased likelihood of missing >9 teeth and being edentulous as compared with persons with normal glycemic status (adjusted OR=1.92, 95% CI 1.44 to 2.55 and adjusted OR=1.73, 95% CI 1.22 to 2.46, respectively). The association appeared to be stronger at younger ages (18-44 years old; p for interaction <0.0001). However, we found no associations of either impaired glycemia or controlled diabetes with tooth loss in adjusted models. CONCLUSIONS: Dentists should be aware of their Hispanic patients' diabetes status and whether or not they are well controlled, because these may affect tooth loss and impair oral function, which can lead to poor nutrition and complications of diabetes. PMID- 27239320 TI - Effect of soy on faecal dry matter content and excretion of Brachyspira hyodysenteriae in pigs. AB - The aim of this study was to investigate the effect of a soy diet on the excretion of Brachyspira hyodysenteriae in five farms with subclinically infected pigs. The effects on general health, faecal consistency and dry matter were analysed. In total, 200 pigs of different ages (group 1 <100 days of age (n=120) and group 2 >=100 days (n=80)) were randomly assigned to the control (C) and the treatment (T) groups. Group C received the farm's standard diet. In group T half of the daily feed ration was replaced by pure soy on two consecutive days. Faecal scores were used to determine faecal consistency and a microwave method to assess faecal dry matter content (FDMC). In age group 1, soy feeding resulted in a statistically significant decrease of the FDMC of 2.5 per cent compared with group C and in age group 2 in a significant increase of 2.2 per cent compared with group C at day 2. Overall seven (T: 5, C: 2) out of 597 faecal samples tested positive for B hyodysenteriae by PCR. In conclusion, a high soy diet applied over two days influenced the faecal consistency and the FDMC in growers, finishers and sows under field conditions. Further investigations with more sensitive diagnostic methods are needed to prove a potential influence of a high soy diet on the detection rate of B hyodysenteriae in subclinically infected herds. PMID- 27239322 TI - Body composition and ankle-brachial index in Ghanaians with asymptomatic peripheral arterial disease in a tertiary hospital. AB - BACKGROUND: Ankle-brachial index (ABI) and indices of obesity are both use to indicate cardiovascular risk. However, association between body composition indices and ABI, a measure of peripheral arterial disease, is inconsistent in various study reports. In this study, we investigated the relationship between ABI and general and central indices of obesity in Ghanaians without history of cardiovascular diseases. METHOD: In a case-control design, ABI was measured in a total of 623 subjects and categorised into PAD (ABI <= 0.9, n = 261) and non-PAD (ABI > 0.9, n = 362) groups. Anthropometric indices, BMI, waist circumference (WC), waist-hip ratio (WHR) and waist-height ratio (WHtR) were also measured. RESULTS: PAD subjects had higher mean BMI (29.8 +/- 8.7 vs. 26.5 +/- 7.6 kg/m(2), p = 0.043) and waist circumference (95 +/- 15 vs. 92 +/- 24 cm, p = 0.034) than non-PAD subjects. In multivariable logistic regression models, having BMI >= 30 kg/m(2) increased the odds of both unilateral [OR (95 % CI): 2 (1.14-3.51), p < 0.01] and overall PAD [2 (1.22-3.27), p < 0.01]. CONCLUSION: In indigenous Ghanaians in our study, PAD participants had higher BMI and waist circumference than non-PAD participants. Also, halving BMI >= 30 kg/m(2) was associated with twofold increase in the odds of PAD. PMID- 27239321 TI - The Pro12Ala polymorphism in the PPAR-gamma2 gene is not associated to obesity and type 2 diabetes mellitus in a Cameroonian population. AB - BACKGROUND: Peroxisome proliferator-activated receptor gamma 2 (PPAR-gamma2) is a transcription factor with a key role in adipocyte differentiation, lipid storage and glucose homeostasis. The Ala allele of the common Pro12Ala polymorphism in the isoform PPAR-gamma2 is at the center of many controversies because in some populations, it has been observed to be associated with T2DM or obesity but, not in others. The aim of this study was to investigate the association of Pro12Ala polymorphism in the PPAR-gamma2 gene with susceptibility to obesity or T2DM in a Cameroonian population. METHODS: This case-control study included 62 obese, 60 T2DM patients and 120 controls (60 non obese and 60 patients without T2DM), all unrelated and of Cameroonian origin. PPAR-gamma2 was examined by genotyping for Pro12Ala using the Restriction Fragment Length Polymorphism - Polymerase Chain Reaction (PCR - RFLP). RESULTS: A portion of the 270 base pair bands of the PPAR gamma2 gene was successfully amplified. The Ala12 variant was totally absent from the study population, all participants being homozygote Pro/Pro. CONCLUSION: PPAR gamma2 Pro12Ala gene polymorphism may not be associated with obesity and T2DM. These results suggest that, PPAR-gamma2 is unlikely a major gene for obesity or T2DM in the study population. PMID- 27239323 TI - Can meta-omics help to establish causality between contaminant biotransformations and genes or gene products? AB - There is increasing interest in using meta-omics association studies to investigate contaminant biotransformations. The general strategy is to characterize the complete set of genes, transcripts, or enzymes from in situ environmental communities and use the abundances of particular genes, transcripts, or enzymes to establish associations with the communities' potential to biotransform one or more contaminants. The associations can then be used to generate hypotheses about the underlying biological causes of particular biotransformations. While meta-omics association studies are undoubtedly powerful, they have a tendency to generate large numbers of non-causal associations, making it potentially difficult to identify the genes, transcripts, or enzymes that cause or promote a particular biotransformation. In this perspective, we describe general scenarios that could lead to pervasive non causal associations or conceal causal associations. We next explore our own published data for evidence of pervasive non-causal associations. Finally, we evaluate whether causal associations could be identified despite the discussed limitations. Analysis of our own published data suggests that, despite their limitations, meta-omics association studies might still be useful for improving our understanding and predicting the contaminant biotransformation capacities of microbial communities. PMID- 27239324 TI - Effects of the small molecule SIRT1 activator, SRT2104 on arterial stiffness in otherwise healthy cigarette smokers and subjects with type 2 diabetes mellitus. AB - OBJECTIVE: Arterial stiffness increases with age, and is associated with adverse cardiovascular outcome including increased mortality. The effect of the oral small molecule SIRT1 activator, SRT2104, on arterial stiffness was examined in otherwise healthy cigarette smokers and participants with type 2 diabetes mellitus. METHODS: 24 otherwise healthy cigarette smokers and 15 people with stable type 2 diabetes were randomised in a double-blind placebo-controlled crossover trial and received 28 days of oral SRT2104 (2.0 g/day) or matched placebo. Blood pressure was measured using non-invasive oscillatory sphygmomanometry. Pulse wave analysis and velocity were measured using applanation tonometry at baseline and the end of each treatment period. Owing to the small sample size and similar trends for both groups, data for the two groups were pooled (post hoc analysis). RESULTS: Compared to placebo, treatment with SRT2104 was associated with a significant reduction in augmentation pressure (p=0.0273) and a trend towards improvement in the augmentation index and corrected augmentation index (p>0.05 for both). However, no changes were observed in pulse wave velocity and time to wave reflection (p>0.05). Systolic and diastolic blood pressures remained unchanged throughout the study. Treatment by cohort interaction was not significant for any of the pulse wave parameters, suggesting that the response to SRT2104 in otherwise healthy smokers and people with diabetes was consistent. CONCLUSIONS: SRT2104 may improve measures of arterial stiffness in otherwise healthy cigarette smokers and in participants with type 2 diabetes. Definitive conclusions are not possible given the small sample size and exploratory nature of this analysis. TRIAL REGISTRATION NUMBER: NCT01031108. PMID- 27239325 TI - Time to spontaneous ductus arteriosus closure in full-term neonates. AB - OBJECTIVE: The mean closure time of the ductus arteriosus (DA) in full-term neonates is presumed to be 1-2 days after birth; however, whether this rate is accurate throughout the neonatal period is still unclear. In addition, the clinical determinants that influence DA closure remain unknown. METHODS: Echocardiography was performed 1826 times (897 in boys, 929 in girls) in 1442 participants (732 boys, 710 girls). An iE33 colour Doppler echocardiograph supplied by Philips Electronics was employed to examine DA flow. Data regarding sex, birth date, examination date, method of delivery, mother's age, past deliveries, neonatal body weight and body height were also collected. The Statistical Analysis System makes statistical clarification of these queries possible. We examined the persistence of DA in full-term neonates and appropriate for gestational age (AGA) neonates in the early neonatal period using colour Doppler echocardiography, and a subsequent analysis with SAS. RESULTS: After performing multivariable analyses, the median DA persistency times were 27.42 and 45.10 h after birth in boys and girls, respectively. A statistically significant sex difference was observed (p<0.0001). Additionally, significant time differences were observed between vaginal and scheduled caesarean deliveries, at 26.97 and 28.93 h, respectively (p=0.0245). No significant differences were observed in the other variables. CONCLUSIONS: Spontaneous DA closure time curves were clarified for the first time throughout the early neonatal period in full term and AGA neonates. It was revealed that both sex and delivery method play important roles in time to DA closure. PMID- 27239326 TI - Arm exercise stress testing: diagnostic options in stable coronary artery disease. PMID- 27239327 TI - The Blunt-Edged Sword: Genetic Explanations of Misbehavior Neither Mitigate Nor Aggravate Punishment. AB - Links between genetic variants and negatively valenced behaviors have stimulated intense commentary about the implications for responsibility and punishment. Previous research has suggested that behavioral genetic evidence of a predisposition to negative behaviors has modest to no impact on mitigation of punishment, at least for serious crimes. Data are presented on the effect of such evidence in a representative sample of the general population (n=640) asked to consider 3 vignettes describing lesser offenses, dealt with in less-formal adjudicatory settings and in everyday life. Genetic explanations of behavior had no effect on the severity of the punishment selected in any case, in contrast to the egregiousness of the behavior and respondents' beliefs in free-will. Public views of genetic influences on behavior may be less deterministic and more nuanced than is often thought, or genetic explanations may simply not have the salience for decision makers that is frequently attributed to them. PMID- 27239328 TI - Faecal microbiota transplantation: applications and limitations in treating gastrointestinal disorders. AB - The process of stool transfer from healthy donors to the sick, known as faecal microbiota transplantation (FMT), has an ancient history. However, only recently researchers started investigating its applications in an evidence-based manner. Current knowledge of the microbiome, the concept of dysbiosis and results of preliminary research suggest that there is an association between gastrointestinal bacterial disruption and certain disorders. Researchers have studied the effects of FMT on various gastrointestinal and non-gastrointestinal diseases, but have been unable to precisely pinpoint specific bacterial strains responsible for the observed clinical improvement or futility of the process. The strongest available data support the efficacy of FMT in the treatment of recurrent Clostridium difficile infection with cure rates reported as high as 90% in clinical trials. The use of FMT in other conditions including inflammatory bowel disease, functional gastrointestinal disorders, obesity and metabolic syndrome is still controversial. Results from clinical studies are conflicting, which reflects the gap in our knowledge of the microbiome composition and function, and highlights the need for a more defined and personalised microbial isolation and transfer. PMID- 27239329 TI - Effectiveness of budesonide MMX (Cortiment) for the treatment of mild-to-moderate active ulcerative colitis: study protocol for a prospective multicentre observational cohort study. AB - INTRODUCTION: A study has been developed to assess the use and effectiveness of budesonide MMX for mild-to-moderate active ulcerative colitis (UC) in routine clinical practice. METHODS AND ANALYSIS: A prospective, multicentre, observational, cohort study of 300 patients prescribed budesonide MMX for the treatment of mild-to-moderate active UC will be conducted in Europe, Israel and Canada. Patients will be treated with budesonide MMX9 mg daily for induction of remission for <=8 weeks. Data on effectiveness, including patient-reported outcomes, tolerability and use will be recorded at the end of treatment and at >=2 weeks after. The primary outcome (improvement >=3 point in the clinical subscores of the UC Disease Activity Index score at the end of treatment) will be compared in: patients who receive budesonide MMX added to mesalazine >2 weeks after increased/optimised mesalazine dose for the treatment of flare (late add on); patients who receive budesonide MMX added to mesalazine <=2 weeks since mesalazine increased/optimised for the treatment of flare, or without mesalazine dose modification (early add-on); and patients who receive budesonide MMX as monotherapy for the treatment of flare (mono). Propensity scoring will be used to minimise bias and confounding inherent in observational studies. ETHICS AND DISSEMINATION: First ethical approval: Ethikkommission der Arztekammer Hamburg (12/22/2015). The results will be published in full. DISCUSSION: Completion of primary data collection is expected in December 2017. Our results will provide further evidence on the effectiveness of budesonide MMX to support clinicians in their daily practice and inform therapeutic guidelines. TRIAL REGISTRATION NUMBER: NCT02586259. PMID- 27239330 TI - Increased body mass index may be associated with greater risk of end-stage renal disease in whites compared to blacks: A nested case-control study. AB - BACKGROUND: The relationship between body mass index (BMI) and end-stage renal disease (ESRD) may differ between blacks and whites due to underlying metabolic differences. METHODS: We conducted a nested case-control study of 631 incident ESRD cases and 1,897 matched controls within the Southern Community Cohort Study. Current weight, height, and weight at age 21 were reported at enrollment. Occurrence of ESRD was ascertained by linkage with the United States Renal Data System. With normal BMI (18.5-24.9 kg/m2) as reference, conditional logistic regression was used to calculate adjusted odds ratios (OR) and corresponding 95% confidence intervals (CI) for ESRD across other BMI categories by race. In subsequent analysis, BMI at age 21 was modeled using restricted cubic splines with 5 knots. Predicted probabilities of incident ESRD were computed from the multivariable logistic models and plotted against BMI at age 21. RESULTS: Among blacks, odds of ESRD were significantly increased among those who were overweight (OR: 1.41; 95%CI: 1.09, 1.83) or obese (OR: 2.56; 95%CI: 1.88, 3.47) at age 21. Among whites, the association between ESRD and BMI at age 21 was more pronounced, with corresponding ORs of 2.13 (95%CI: 0.92, 4.93) and 7.46 (95%CI: 2.90, 19.21; p-interaction 0.05). Only among whites was high BMI at enrollment associated with ESRD risk; OR for BMI>=40 kg/m2, was 3.31 (95%CI: 1.08, 10.12). The plot of the predicted probabilities of incident ESRD vs BMI at age 21 showed a monotonic increase in the probability of ESRD after a BMI cutoff ~ 25Kg/m2 in both whites and blacks but the slope of the curve for whites appeared greater. CONCLUSIONS: Our results suggest racial differences in the relationship between BMI, both in early adulthood and middle age, and ESRD. These findings warrant further research into understanding the underlying metabolic differences that may explain these differences. PMID- 27239331 TI - Altered maternal lipid metabolism is associated with higher inflammation in obese women during late pregnancy. AB - Inflammation is elevated in obese pregnant women and is associated with adverse maternal and neonatal outcomes. Maternal lipid metabolism and its relationships with maternal inflammation, insulin resistance and neonatal metabolic health are poorly understood in obese pregnant women. 18 lean (age: 26.1 +/- 5.0 years, pre pregnancy BMI: 21.5 +/- 1.9 kg/m2) and 16 obese (age: 25.0 +/- 4.8 years, pre pregnancy BMI: 36.3 +/- 4.3 kg/m2) women participated in this case-control study during the third trimester of pregnancy. Maternal plasma markers of insulin resistance (HOMA-IR) and inflammation (C-reactive protein (CRP)) were measured at rest, and lipid concentration and kinetics (lipid oxidation rate and lipolysis) were measured at rest, during a 30-minute bout of low-intensity (40% VO2peak) exercise, and during a recovery period. Umbilical cord blood was collected for measurement of neonatal plasma insulin sensitivity, inflammation, and lipid concentration. Neonatal body composition was measured via air displacement plethysmography. Pregnant obese women had higher plasma CRP (9.1 +/- 4.0 mg/L versus 2.3 +/- 1.8 mg/L, p<0.001) and higher HOMA-IR (3.8 +/- 1.9 versus 2.3 +/- 1.5, p=0.009) compared to pregnant lean women. Obese women had higher lipid oxidation rates during recovery from low-intensity exercise (0.13 +/- 0.03 g/min versus 0.11 +/-0.04 g/min, p=0.02) that was associated with higher maternal CRP (r=0.55, p=0.001). Maternal CRP was positively associated with maternal HOMA-IR (r=0.40, p<0.02) and systolic blood pressure (r=0.40, p<0.02). Maternal lipid metabolism-associated inflammation may contribute to insulin resistance and higher blood pressure in obese women during pregnancy. PMID- 27239332 TI - Mimicking Cdk2 phosphorylation of Bcl-xL at Ser73 results in caspase activation and Bcl-xL cleavage. AB - Cisplatin is a widely used chemotherapeutic agent, yet its efficacy is limited by nephrotoxicity. The severity of nephrotoxicity is associated with the extent of kidney cell death. Previously, we found that cisplatin-induced kidney cell death was dependent on Cdk2 activation, and inhibition of Cdk2 protected cells from cisplatin-induced apoptosis. Using an in vitro kination assay, we showed that Cdk2 phosphorylated Bcl-xL, an anti-apoptotic member of Bcl-2 family proteins, at serine 73. We also found that this phosphorylated Bcl-xL participated in cell death, as a phosphomimetic mutant of Bcl-xL at the serine 73 site (S73D-Bcl-xL) activated caspases. We now find that S73D-Bcl-xL was cleaved at D61 and D76, which are putative caspase cleavage sites, to generate 15-kDa and 12-kDa fragments. Unlike full-length Bcl-xL, these cleavage products of Bcl-xL were previously reported to be pro-apoptotic. We sought to determine whether these Bcl xL fragments were necessary for the induction of cell death by S73D-Bcl-xL. Mutation of these caspase cleavage sites prevented the formation of the 15-kDa and 12-kDa Bcl-xL cleavage products, but apoptosis still persisted in a S73D modified Bcl-xL. Our findings show that Cdk2 phosphorylation of Bcl-xL at Ser73, but not the Bcl-xL cleavage products, is necessary and sufficient to induce cell death. PMID- 27239333 TI - Horizontal Gene Transfers from Bacteria to Entamoeba Complex: A Strategy for Dating Events along Species Divergence. AB - Horizontal gene transfer has proved to be relevant in eukaryotic evolution, as it has been found more often than expected and related to adaptation to certain niches. A relatively large list of laterally transferred genes has been proposed and evaluated for the parasite Entamoeba histolytica. The goals of this work were to elucidate the importance of lateral gene transfer along the evolutionary history of some members of the genus Entamoeba, through identifying donor groups and estimating the divergence time of some of these events. In order to estimate the divergence time of some of the horizontal gene transfer events, the dating of some Entamoeba species was necessary, following an indirect dating strategy based on the fossil record of plausible hosts. The divergence between E. histolytica and E. nuttallii probably occurred 5.93 million years ago (Mya); this lineage diverged from E. dispar 9.97 Mya, while the ancestor of the latter separated from E. invadens 68.18 Mya. We estimated times for 22 transferences; the most recent occurred 31.45 Mya and the oldest 253.59 Mya. Indeed, the acquisition of genes through lateral transfer may have triggered a period of adaptive radiation, thus playing a major role in the evolution of the Entamoeba genus. PMID- 27239334 TI - Comparison of the Early Clinical Outcomes between Combined Small-Incision Lenticule Extraction and Collagen Cross-Linking versus SMILE for Myopia. AB - Background. To compare the early outcome of combined SMILE and collagen crosslinking (SMILE Xtra) with SMILE. Method. Prospective, comparative interventional study of 21 eyes receiving SMILE Xtra using a low energy protocol and 32 control eyes receiving SMILE only. The outcomes were compared at 1, 3, and 6 months postoperatively. Results. Both groups had myopia with spherical equivalent refraction (SEQ) > 4.00 D. The SMILE Xtra group had thinner preoperative central corneal thickness and residual stromal bed thickness (p < 0.021). At 6 months, no eyes lost more than 1 line in corrected distance visual acuity. The safety index was 0.96 +/- 0.06 and 1.00 +/- 0.00 in SMILE Xtra and control, respectively (p < 0.001). 89% and 94% of eyes were within +/-0.50 D of target refraction, respectively, with the mean error in SEQ correction being 0.17 +/- 0.26 D for SMILE Xtra and +0.03 +/- 0.25 D for control (p = 0.021). The efficacy index was 0.88 +/- 0.13 and 0.97 +/- 0.06, respectively (p = 0.005). Conclusion. SMILE Xtra had good overall safety profile and predictability at 6 months. However, when compared with control, the safety index and efficacy index were statistically significantly lower in the early postoperative period. PMID- 27239335 TI - Retinal Electrophysiology Is a Viable Preclinical Biomarker for Drug Penetrance into the Central Nervous System. AB - Objective. To examine whether retinal electrophysiology is a useful surrogate marker of drug penetrance into the central nervous system (CNS). Materials and Methods. Brain and retinal electrophysiology were assessed with full-field visually evoked potentials and electroretinograms in conscious and anaesthetised rats following systemic or local administrations of centrally penetrant (muscimol) or nonpenetrant (isoguvacine) compounds. Results. Local injections into the eye/brain bypassed the blood neural barriers and produced changes in retinal/brain responses for both drugs. In conscious animals, systemic administration of muscimol resulted in retinal and brain biopotential changes, whereas systemic delivery of isoguvacine did not. General anaesthesia confounded these outcomes. Conclusions. Retinal electrophysiology, when recorded in conscious animals, shows promise as a viable biomarker of drug penetration into the CNS. In contrast, when conducted under anaesthetised conditions confounds can be induced in both cortical and retinal electrophysiological recordings. PMID- 27239336 TI - Comparison between Subjective Sensations during First and Second Phacoemulsification Eye Surgeries in Patients with Bilateral Cataract. AB - Purpose. To evaluate and compare the subjective sensations reported by patients during first and second cataract extractions. Methods. Consecutive patients undergoing bilateral sequential cataract extraction using phacoemulsification were recruited. Following cataract surgery, patients completed questionnaires designed to evaluate subjective sensations, including anxiety, eye bulges, pain, and light sensitivity. Changes in painful sensations experienced by patients between the two surgeries were also recorded. Comparisons were also performed for each subjective sensation between different age groups (<50, 50-59, 60-69, 70-79, and >79 years). Results. A total of 127 patients were included in the final evaluation. Statistical comparison of the results showed that there were significant differences in perception of anxiety, eye bulges, and pain scores between the first and second cataract surgeries (P < 0.05). However, there was no statistically significant difference for light sensitivity scores between the two surgeries (P = 0.555). The differences in anxiety, perception of eye bulges, pain, and light sensitivity scores between both the surgeries showed no correlation with age (P > 0.05 for all). Conclusions. Our research confirms the common observation that patients with bilateral cataracts often report more ocular discomfort during the second surgery. There are, therefore, additional factors that should be considered upon treating patients with bilateral cataracts, and the provision of preoperative counseling could play an important role in providing adequate patient care. PMID- 27239337 TI - Canaloplasty: Current Value in the Management of Glaucoma. AB - Canaloplasty is a nonpenetrating blebless surgical technique for open-angle glaucoma, in which a flexible microcatheter is inserted within Schlemm's canal for the entire 360 degrees. When the microcatheter exits the opposite end, a 10-0 prolene suture is tied and it is then withdrawn, by pulling microcatheter back through the canal in the opposite direction. Ligation of prolene suture provides tension on the canal and facilitates aqueous outflow. The main advantage of canaloplasty is that this technique avoids the major complications of fistulating surgery related to blebs and hypotony. Currently, canaloplasty is performed in glaucoma patients with early to moderate disease and combination with cataract surgery is a suitable option in patients with clinically significant lens opacities. PMID- 27239338 TI - Loop Myopexy Surgery for Strabismus Associated with High Myopia. AB - Strabismus associated with high myopia is a rare abnormality of ocular motility, leading to the impairment of abduction and supraduction. Loop myopexy of the superior rectus (SR) and lateral rectus (LR) muscles is now the most preferred surgery for restoring the dislocated eye globe back into the muscle cone. Various procedural modifications have been made based on this concept, and satisfactory outcomes have been reached in most cases. In this paper, we review various surgical modifications published in the literature that are based on the loop myopexy surgery in patients with high myopic strabismus and summarize the applicable scope of different surgical procedures for patients with different degrees of strabismus. Three major surgical procedures are identified and different modifications have been applied based on their concept. Most of these modifications have been proven to be safe and effective and result in good ocular alignments. The selection of such modifications is of great importance in different patients. Careful evaluation before surgery should be made not only to make the correct diagnosis but also to choose an appropriate surgical procedure and offer individualized modifications in the surgery. PMID- 27239339 TI - Stage of Change and Motivation to a Healthier Lifestyle before and after an Intensive Lifestyle Intervention. AB - OBJECTIVE: Lifestyle modification programs are different but typically include both nutritional aspects and physical activity as main domains with different behavioral and/or psychological strategies designed to affect change. A fundamental role in modifying unhealthy habits is played by personal motivation for change. The present study sought to investigate, in a group of 100 overweight/obese outpatients with and/or without TMD2, treatment seeking, the effect of an intensive lifestyle program on medical measures and motivational profile for physical activity (PA) and healthy nutrition (NUTR). METHOD: Subjects participated in an intensive multidisciplinary lifestyle intervention at C.U.R.I.A.MO. Before and after the intervention, patients received a comprehensive evaluation of their clinical, anthropometric, and metabolic states and motivation to lifestyle changes. RESULTS: Data showed differences before and after intervention in both medical and motivational measures. Before the intervention patients reported to be ready, open, and determined to change and gave importance to healthy habits. After the intervention patients continued to be determined but increased the actions toward the change showing a higher degree of maintenance and of acquisition of habits especially in the physical domain of the new lifestyle. CONCLUSION: Data support the notion that the motivation should be followed during all the lifestyle interventions to support the change on both domains of the lifestyle program. PMID- 27239340 TI - Prevalence of HIV and Associated Risks of Sex Work among Youth in the Slums of Kampala. AB - Purpose. The purpose of this study is to examine the prevalence of and risk factors for engaging in sex work among youth living in Kampala, Uganda. Methods. Analyses are based on a cross-sectional study (N = 1,134) of youth aged 12-18 years, living in the slums of Kampala, conducted in Spring of 2014. The analytic sample consisted of only sexually active youth (n = 590). Youth who reported engaging in sex work were compared to youth who did not report sex work. Multivariable analyses were conducted to examine factors associated with sex work. Results. Among the youth who had ever had sexual intercourse (n = 590), 13.7% (n = 81) reported engaging in sex work. Self-reported HIV prevalence was 13.9% among the total sample (n = 81) and 22.5% (n = 18) among youth engaged in sex work. Engaging in sex work was associated with being female (AOR 10.4; 95% CI: 3.9, 27.4), being an orphan (AOR 3.8; 95% CI: 1.7, 8.4), ever drinking alcohol (AOR 8.3; 95% CI 3.7, 19.0), and experiencing any rape (AOR 5.3; 95% CI: 2.9, 9.5). Discussion. The reported prevalence of sex work is high among youth in the slums of Kampala and is associated with high HIV prevalence, ever drinking alcohol, previously being raped, and being an orphan. PMID- 27239341 TI - Utility of Plasmapheresis in Autoimmune-Mediated Encephalopathy in Children: Potentials and Challenges. AB - Autoimmune-mediated encephalopathy in children continues to constitute a diagnostic and therapeutic challenge in pediatric population. Utility and usefulness in this clinical setting of plasmapheresis have seldom been evaluated in current pediatric literature. Children with immune-mediated encephalopathies represent a uniquely different group among patients presenting to intensive care units or neurological services worldwide. Arriving at a final diagnosis is not an easy task for treating physicians. It is very crucial to consider early use of first-line immunotherapy modalities, save those children's lives and improve outcomes. Plasmapheresis is an emerging, potentially beneficial first-line therapy in such patients. However, indications, value, logistics, and procedural difficulties are often faced. This study is mainly meant to review the current knowledge in regard to the clinical value of plasmapheresis in children with immune-mediated encephalopathy. PMID- 27239342 TI - Infrapatellar Fat Pad: An Alternative Source of Adipose-Derived Mesenchymal Stem Cells. AB - Introduction. The Infrapatellar fat pad (IPFP) represents an emerging alternative source of adipose-derived mesenchymal stem cells (ASCs). We compared the characteristics and differentiation capacity of ASCs isolated from IPFP and SC. Materials and Methods. ASCs were harvested from either IPFP or SC. IPFPs were collected from patients undergoing total knee arthroplasty (TKA), whereas subcutaneous tissues were collected from patients undergoing lipoaspiration. Immunophenotypes of surface antigens were evaluated. Their ability to form colony forming units (CFUs) and their differentiation potential were determined. The ASCs karyotype was evaluated. Results. There was no difference in the number of CFUs and size of CFUs between IPFP and SC sources. ASCs isolated from both sources had a normal karyotype. The mesenchymal stem cells (MSCs) markers on flow cytometry was equivalent. IPFP-ASCs demonstrated significantly higher expression of SOX-9 and RUNX-2 over ASCs isolated from SC (6.19 +/- 5.56-, 0.47 +/- 0.62 fold; p value = 0.047, and 17.33 +/- 10.80-, 1.56 +/- 1.31-fold; p value = 0.030, resp.). Discussion and Conclusion. CFU assay of IPFP-ASCs and SC-ASCs harvested by lipoaspiration technique was equivalent. The expression of key chondrogenic and osteogenic genes was increased in cells isolated from IPFP. IPFP should be considered a high quality alternative source of ASCs. PMID- 27239343 TI - Phytochemical Evaluation of Moth Bean (Vigna aconitifolia L.) Seeds and Their Divergence. AB - In the present study, phytochemical contents of 25 moth bean (Vigna aconitifolia) seed accessions were evaluated. This includes protease inhibitors, phytic acid, radical scavenging activity, and tannins. The studies revealed significant variation in the contents of theses phytochemicals. Presence of photochemical composition was correlated with seed storage proteins like albumin and globulin. Qualitative identification of total seed storage protein abundance across two related moth bean accessions using two-dimensional gel electrophoresis (2D-GE) was performed. Over 20 individual protein fractions were distributed over the gel as a series of spots in two moth bean accessions. Seed proteome accumulated spots of high intensity over a broad range of pI values of 3-10 in a molecular weight range of 11-170 kDa. In both seed accessions maximum protein spots are seen in the pI range of 6-8. PMID- 27239345 TI - 8-Hydroxyeicosapentaenoic Acid Decreases Plasma and Hepatic Triglycerides via Activation of Peroxisome Proliferator-Activated Receptor Alpha in High-Fat Diet Induced Obese Mice. AB - PPARs regulate the expression of genes involved in lipid homeostasis. PPARs serve as molecular sensors of fatty acids, and their activation can act against obesity and metabolic syndromes. 8-Hydroxyeicosapentaenoic acid (8-HEPE) acts as a PPAR ligand and has higher activity than EPA. However, to date, the PPAR ligand activity of 8-HEPE has only been demonstrated in vitro. Here, we investigated its ligand activity in vivo by examining the effect of 8-HEPE treatment on high fat diet-induced obesity in mice. After the 4-week treatment period, the levels of plasma and hepatic triglycerides in the 8-HEPE-fed mice were significantly lower than those in the HFD-fed mice. The expression of genes regulated by PPARalpha was significantly increased in 8-HEPE-fed mice compared to those that received only HFD. Additionally, the level of hepatic palmitic acid in 8-HEPE-fed mice was significantly lower than in HFD-fed mice. These results suggested that intake of 8-HEPE induced PPARalpha activation and increased catabolism of lipids in the liver. We found no significant differences between EPA-fed mice and HFD-fed mice. We demonstrated that 8-HEPE has a larger positive effect on metabolic syndrome than EPA and that 8-HEPE acts by inducing PPARalpha activation in the liver. PMID- 27239346 TI - Unmet Supportive Care Needs among Breast Cancer Survivors of Community-Based Support Group in Kuching, Sarawak. AB - Background. Recognizing the needs of cancer survivors is one of the important aspects in healthcare delivery. This study aimed to determine the prevalence of unmet supportive care needs and its associated factors among the breast cancer survivors of community-based support group in Kuching, Sarawak. Materials and Methods. This was a cross-sectional study using Supportive Care Needs Survey (SCNS-SF34). All the members of community-based breast cancer support groups in Kuching were invited. A total of 101 respondents were face-to-face interviewed after the consent was obtained. Data was entered and analyzed using SPSS version 20. Results. The respondents endorsed health system and information domain with the highest mean score (2.48; 95% CI: 2.32-2.64). Top 10 items with "moderate to high" level unmet needs had a prevalence of 14.9% to 34.7% of respondents indicating need. Significantly higher level of unmet needs was associated with survivors who were younger (less than 60 years old), had higher education attainment, were unemployed, had survival duration of up to 5 years, and were undergoing active treatment. Conclusion. Systematic delivery of health information which is targeted, culturally sensitive, and linguistically appropriate for addressing younger age, education level, employment status, length of survivorship, and treatment stage should be considered not only at hospital-based setting but also at the community-based support groups. PMID- 27239347 TI - Comment on "A Systematic Literature Review of Three Modalities in Technologically Assisted TKA". PMID- 27239344 TI - Human Decidual Stromal Cells as a Component of the Implantation Niche and a Modulator of Maternal Immunity. AB - The human decidua is a specialized tissue characterized by embryo-receptive properties. It is formed during the secretory phase of menstrual cycle from uterine mucosa termed endometrium. The decidua is composed of glands, immune cells, blood and lymph vessels, and decidual stromal cells (DSCs). In the process of decidualization, which is controlled by oestrogen and progesterone, DSCs acquire specific functions related to recognition, selection, and acceptance of the allogeneic embryo, as well as to development of maternal immune tolerance. In this review we discuss the relationship between the decidualization of DSCs and pathological obstetrical and gynaecological conditions. Moreover, the critical influence of DSCs on local immune cells populations as well as their relationship to the onset and maintenance of immune tolerance is described. PMID- 27239348 TI - Mechanisms Underlying Adaptation of Respiratory Network Activity to Modulatory Stimuli in the Mouse Embryo. AB - Breathing is a rhythmic behavior that requires organized contractions of respiratory effector muscles. This behavior must adapt to constantly changing conditions in order to ensure homeostasis, proper body oxygenation, and CO2/pH regulation. Respiratory rhythmogenesis is controlled by neural networks located in the brainstem. One area considered to be essential for generating the inspiratory phase of the respiratory rhythm is the preBotzinger complex (preBotC). Rhythmogenesis emerges from this network through the interplay between the activation of intrinsic cellular properties (pacemaker properties) and intercellular synaptic connections. Respiratory activity continuously changes under the impact of numerous modulatory substances depending on organismal needs and environmental conditions. The preBotC network has been shown to become active during the last third of gestation. But only little is known regarding the modulation of inspiratory rhythmicity at embryonic stages and even less on a possible role of pacemaker neurons in this functional flexibility during the prenatal period. By combining electrophysiology and calcium imaging performed on embryonic brainstem slice preparations, we provide evidence showing that embryonic inspiratory pacemaker neurons are already intrinsically sensitive to neuromodulation and external conditions (i.e., temperature) affecting respiratory network activity, suggesting a potential role of pacemaker neurons in mediating rhythm adaptation to modulatory stimuli in the embryo. PMID- 27239351 TI - Complete Maxillary Crossbite Correction with a Rapid Palatal Expansion in Mixed Dentition Followed by a Corrective Orthodontic Treatment. AB - This case report presents the interceptive orthodontic treatment of a boy, aged 8 years 4 months with a Class I malocclusion with severe transverse maxillary deficiency and complete maxillary crossbite and correction using Haas expansion and fixed appliance. The treatment goals were to correct the posterior crossbite and anterior crossbite and restore the normality of the dentition and occlusion. In phase I, the patient was treated with a modified Haas-type palatal expander, which provided a clinically significant palatal expansion and increased the maxillary arch perimeter with favorable conditions for orthodontic treatment with fixed appliances in phase II. The optimization of E-space and the use of intermaxillary Class III elastics helped to maintain the mandibular incisors upright. A removable wraparound type appliance and a bonded lingual canine-to canine retainer were used as retention. Although the literature has reported a high rate of relapse after palatal expansion, after 2 years 9 months of posttreatment follow-up, the occlusal result was stable and no skeletal reversals could be detected. PMID- 27239349 TI - Fractalkine Attenuates Microglial Cell Activation Induced by Prenatal Stress. AB - The potential contribution of inflammation to the development of neuropsychiatric diseases has recently received substantial attention. In the brain, the main immune cells are the microglia. As they are the main source of inflammatory factors, it is plausible that the regulation of their activation may be a potential therapeutic target. Fractalkine (CX3CL1) and its receptor CX3CR1 play a crucial role in the control of the biological activity of the microglia. In the present study, using microglial cultures we investigated whether fractalkine is able to reverse changes in microglia caused by a prenatal stress procedure. Our study found that the microglia do not express fractalkine. Prenatal stress decreases the expression of the fractalkine receptor, which in turn is enhanced by the administration of exogenous fractalkine. Moreover, treatment with fractalkine diminishes the prenatal stress-induced overproduction of proinflammatory factors such as IL-1beta, IL-18, IL-6, TNF-alpha, CCL2, or NO in the microglial cells derived from prenatally stressed newborns. In conclusion, the present results revealed that the pathological activation of microglia in prenatally stressed newborns may be attenuated by fractalkine administration. Therefore, understanding of the role of the CX3CL1-CX3CR1 system may help to elucidate the mechanisms underlying the neuron-microglia interaction and its role in pathological conditions in the brain. PMID- 27239352 TI - Multiple Coronary Artery Microfistulas in a Girl with Kleefstra Syndrome. AB - Kleefstra syndrome is characterized by hypotonia, developmental delay, dysmorphic features, congenital heart defects, and so forth. It is caused by 9q34.3 microdeletions or EHMT1 mutations. Herein a 20-month-old girl with Kleefstra syndrome, due to a de novo subterminal deletion, is described. She exhibits a rare and complex cardiopathy, encompassing multiple coronary artery microfistulas, VSD/ASD, and PFO. PMID- 27239353 TI - Tuberculous Gastric Abscess in a Patient with AIDS: A Rare Presentation. AB - Tuberculosis is a healthcare concern that affects millions of individuals around the globe. Coinfection with HIV has changed both the clinical presentation and the outcome of the disease dramatically in the last few decades. Extrapulmonary tuberculosis is seen more frequently in the immunocompromised host. An unusual case of gastric tuberculosis in an AIDS patient is reported here. A 49-year-old female with AIDS was admitted for fever and epigastric pain. A gastric submucosal abscess was observed on imaging and confirmed by biopsy showing numerous neutrophils and acid-fast bacilli. Aspirate grew Mycobacterium tuberculosis. This report highlights a very unusual presentation of tuberculosis in an immunodeficient patient. High clinical suspicion for opportunistic infections in unusual locations should be maintained in these patients presenting with clinical syndromes that do not respond to standard treatments. New diagnostic modalities facilitate accurate identification of these infections. PMID- 27239350 TI - Synaptic Plasticity, a Prominent Contributor to the Anxiety in Fragile X Syndrome. AB - Fragile X syndrome (FXS) is an inheritable neuropsychological disease caused by expansion of the CGG trinucleotide repeat affecting the fmr1 gene on X chromosome, resulting in silence of the fmr1 gene and failed expression of FMRP. Patients with FXS suffer from cognitive impairment, sensory integration deficits, learning disability, anxiety, autistic traits, and so forth. Specifically, the morbidity of anxiety in FXS individuals remains high from childhood to adulthood. By and large, it is common that the change of brain plasticity plays a key role in the progression of disease. But for now, most studies excessively emphasized the one-sided factor on the change of synaptic plasticity participating in the generation of anxiety during the development of FXS. Here we proposed an integrated concept to acquire better recognition about the details of this process. PMID- 27239354 TI - Neuroinfection as a Mask of Lung Cancer: A Case Series. AB - Introduction. The diagnosis of lung cancer may still be difficult due to the fact that the first symptoms very often mimic symptoms of other diseases. Case Presentation. In this paper we present two cases, in which initial diagnosis of neuroinfection delayed proper diagnosis. Conclusion. Based on our experience we concluded that neurological symptoms in the area endemic for tick-borne diseases suggesting neuroinfection require careful differential diagnosis. Moreover, neurological symptoms in heavy smokers may be associated with metastases of lung cancer. PMID- 27239355 TI - Miller-Fisher Syndrome: Are Anti-GAD Antibodies Implicated in Its Pathophysiology? AB - Miller-Fisher syndrome (MFS) is considered as a variant of the Guillain-Barre syndrome (GBS) and its characteristic clinical features are ophthalmoplegia, ataxia, and areflexia. Typically, it is associated with anti-GQ1b antibodies; however, a significant percentage (>10%) of these patients are seronegative. Here, we report a 67-year-old female patient who presented with the typical clinical features of MFS. Workup revealed antibodies against glutamic acid decarboxylase (GAD) in relatively high titers while GQ1b antibodies were negative. Neurological improvement was observed after intravenous gamma globulin and follow-up examinations showed a continuous clinical amelioration with simultaneous decline of anti-GAD levels which finally returned to normal values. This case indicates that anti-GAD antibodies may be associated with a broader clinical spectrum and future studies in GQ1b-seronegative patients could determine ultimately their clinical and pathogenetic significance in this syndrome. PMID- 27239356 TI - Neurological Complications of Middle East Respiratory Syndrome Coronavirus: A Report of Two Cases and Review of the Literature. AB - Middle East Respiratory Syndrome Coronavirus (MERS-CoV) was first discovered in September 2012 in Saudi Arabia. Since then, it caused more than 1600 laboratory confirmed cases and more than 580 deaths among them. The clinical course of the disease ranges from asymptomatic infection to severe lower respiratory tract illness with multiorgan involvement and death. The disease can cause pulmonary, renal, hematological, and gastrointestinal complications. In this paper, we report neurological complications of MERS-CoV in two adult patients, and we hypothesize the pathophysiology. The first patient had an intracerebral hemorrhage as a result of thrombocytopenia, disseminated intravascular coagulation, and platelet dysfunction. The second case was a case of critical illness polyneuropathy complicating a long ICU stay. In these cases, the neurological complications were secondary to systemic complications and long ICU stay. Autopsy studies are needed to further understand the pathological mechanism. PMID- 27239358 TI - Retracted: Prenatal Diagnosis of Concurrent Achondroplasia and Klinefelter Syndrome. AB - [This retracts the article DOI: 10.1155/2015/980749.]. PMID- 27239357 TI - Low-Grade Endometrial Stromal Sarcoma with Intravenous and Intracardiac Extension: A Multidisciplinary Approach. AB - Background. A rare case of low-grade endometrial stromal sarcoma (LG-ESS) extending to inferior vena cava (IVC) and cardiac chambers. Case Report. A 40 year-old woman had IVC tumor, which was incidentally detected by abdominal ultrasonography during a routine medical checkup. CT scan revealed a tumor in IVC, right iliac and ovarian veins, which was derived from the uterus and extended into the right atrium and ventricle. The operation was performed, the heart and IVC were exposed, and cardiopulmonary bypass was initiated. A right atriotomy was performed, and the intracardiac mass was removed. Then the tumor in IVC and the right internal iliac vein were removed after longitudinal venotomies in the suprarenal and infrarenal vena cava, the right common iliac vein. Next the pelvis was explored. Tumors were found originating from the posterior wall of the uterus and continuing into both the right uterine and ovarian vein. The patient underwent total hysterectomy with bilateral salpingooophorectomy. Complete tumor resection was achieved. Histopathological analysis confirmed a diagnosis of LG ESS. She showed no evidence of disease for 2 years and 3 months. Conclusions. Our case highlights the importance of a multidisciplinary approach in treating this rare cardiovascular pathological condition through preoperative assessment to final operation. PMID- 27239359 TI - Ectomesenchymal Chondromyxoid Tumour of the Dorsal Tongue Presenting with Impaired Speech. AB - Ectomesenchymal chondromyxoid tumours (ECTs) are rare mesenchymal soft tissue neoplasms that typically present as a slow-growing asymptomatic mass on the anterior dorsum of the tongue. Our patient presented with impaired speech articulation and pain associated with upper respiratory tract infections when the lesion on his dorsal tongue would swell, and he would accidentally bite down on it. Microscopically, ECTs appear as unencapsulated, well-circumscribed proliferations of uniform round to fusiform cells embedded within chondromyxoid matrices. Most cases of ECT have been detected in the third to the sixth decades of life, with no sex preference. ECT may cause a range of symptoms that negatively impact patients' quality of life, including pain, dysphagia, odynophagia, bleeding, and, in the case of our patient, impairment of speech. We provide a unique preoperative clinical photograph and case description that should help readers in recognizing this neoplasm. Considering the rarity of ECT presenting clinically as well as in the literature, we believe this report will add to our growing understanding of ECT and its management. We report a case of ECT presenting on the anterior dorsal tongue that was successfully surgically resected under local anesthesia with clear margins, accompanied by a review of the pertinent literature. PMID- 27239360 TI - Huge Congenital Segmental Dilatation of the Sigmoid Colon in a Neonate: A "Rarity to Meet" and a "Challenge to Treat". AB - Only ten cases of neonatal congenital segmental dilatation (CSD) of the colon have been described so far. We present a full-term female newborn with trisomy 21, ventricular septal defect, and gross abdominal distension. Plain abdominal radiographs revealed a huge cystic lesion occupying the left hemiabdomen. Upon laparotomy on day 4 a CSD of the distal sigmoid and proximal rectum was confirmed and resected. The proximal colon was exteriorized and the distal part closed as a Hartmann pouch. Histology confirmed a huge segmental dilatation of the sigmoid without dysganglionosis or pseudodiverticula, but normal intestinal architecture. After correction of the ventricular septal defect a low rectal end-to-end anastomosis could be performed at an age of 5 months. The postoperative course was uneventful. CSD of the sigmoid colon is extremely "rare to meet" and a "challenge to treat" in the newborn period, but clinical awareness of this entity prompts pediatric surgical success. PMID- 27239361 TI - First Autologous Cord Blood Therapy for Pediatric Ischemic Stroke and Cerebral Palsy Caused by Cephalic Molding during Birth: Individual Treatment with Mononuclear Cells. AB - Intracranial laceration due to traumatic birth injury is an extremely rare event affecting approximately one newborn per a population of 4.5 million. However, depending on the mode of injury, the resulting brain damage may lead to lifelong sequelae, for example, cerebral palsy for which there is no cure at present. Here we report a rare case of neonatal arterial ischemic stroke and cerebral palsy caused by fetal traumatic molding and parietal depression of the head during delivery caused by functional cephalopelvic disproportion due to a "long pelvis." This patient was treated by autologous cord blood mononuclear cells (45.8 mL, cryopreserved, TNC 2.53 * 10e8) with a remarkable recovery. Active rehabilitation was provided weekly. Follow-up examinations were at 3, 18, 34, and 57 months. Generous use of neonatal head MRI in case of molding, craniofacial deformity, and a sentinel event during parturition is advocated to enhance diagnosis of neonatal brain damage as a basis for fast and potentially causative treatment modalities including autologous cord blood transplantation in a timely manner. PMID- 27239362 TI - False Positive B-Cells Crossmatch after Prior Rituximab Exposure of the Kidney Donor. AB - Crossmatching is essential prior to kidney transplantation to confirm compatibility between the donor and the recipient, particularly to prevent acute antibody-mediated rejection. An unexpected positive crossmatch may be obtained in recipients with an autoimmune disease or preexisting antibodies not detected by single-antigen bead array due to complement interference or who have been previously treated by desensitization protocols such as rituximab, antithymocyte globulin, or intravenous immunoglobulins. We report donor and recipient investigations that revealed unexpected positive B-cells crossmatch, probably due to donor cells, as the donor had received rituximab therapy shortly before organ harvesting, in a context of severe idiopathic thrombocytopenic purpura. We consequently detected unexpected Class II IgG complement-dependent cytotoxicity for all sera tested. Other laboratory investigations failed to elucidate the reasons for this recipient-related positivity. PMID- 27239364 TI - Challenges in the Diagnosis and Management of Acquired Nontraumatic Urethral Strictures in Boys in Yaounde, Cameroon. AB - Introduction. Urethral strictures in boys denote narrowing of the urethra which can be congenital or acquired. In case of acquired strictures, the etiology is iatrogenic or traumatic and rarely infectious or inflammatory. The aim of this study was to highlight the diagnostic and therapeutic difficulties of acquired nontraumatic urethral strictures in boys in Yaounde, Cameroon. Methodology. The authors report five cases of nontraumatic urethral strictures managed at the Pediatric Surgery Department of the YGOPH over a two-year period (November 2012 November 2014). In order to confirm the diagnosis of urethral stricture, all patients were assessed with both cystourethrography and urethrocystoscopy. Results. In all the cases the urethra was inflammatory with either a single or multiple strictures. The surgical management included internal urethrotomy (n = 1), urethral dilatation (n = 1), vesicostomy (n = 2), and urethral catheterization (n = 3). With a median follow-up of 8.2 months (4-16 months) all patients remained symptoms-free. Conclusion. The authors report the difficulties encountered in the diagnosis and management of nontraumatic urethral strictures in boys at a tertiary hospital in Yaounde, Cameroon. The existence of an inflammatory etiology of urethral strictures in boys deserves to be considered. PMID- 27239363 TI - Solitary Fibrous Tumor of the Kidney Developing Local Recurrence. AB - Solitary fibrous tumor (SFT) of the kidney is a rare entity and usually displays a favorable prognosis. We herein report a second case of renal SFT developing local recurrence. A 50-year-old man was referred to our hospital because of a left renal mass. An abdominal CT detected a large renal tumor and radical nephrectomy was performed with a possible diagnosis of renal cell carcinoma. The resected tumor size was measured at 17 * 11 * 8 cm. Grossly, necrosis was observed in central lesion of the tumor but hemorrhage was not observed. Microscopically, the tumor consisted of spindle-shaped cells with scant cytoplasm accompanied by hyalinized collagenous tissue, which displayed hemangiopericytomatous patterns. The cellularity was normal and nuclear pleomorphism was not observed. Ki-67 labeling index was less than 3%. The pathological diagnosis of SFT was made without obvious malignant findings. Three years after the surgery, a follow-up CT scan detected a mass lesion in the tumor bed. Surgical resection was performed and the resected tumor was compatible with local recurrence of the SFT without obvious malignant findings. Renal SFT should be carefully monitored even in the absence of obvious malignant findings. PMID- 27239365 TI - A Very Rare Complication of Acute Appendicitis: Appendicovesical Fistula. AB - Appendicovesical fistula (AVF) is an uncommon type of enterovesical fistula and a very rare complication of acute appendicitis. Herein, we report a case of 39-year old male patient who presented with persistent urinary tract infection, recurrent abdominal pain, and pneumaturia. Imaging techniques including ultrasonography (USG), computed tomography (CT), and magnetic resonance imaging (MRI) were performed to identify the abnormality. However, definitive diagnosis of AVF was made by cystoscopy. PMID- 27239366 TI - Cross-Calibration of GE Healthcare Lunar Prodigy and iDXA Dual-Energy X-Ray Densitometers for Bone Mineral Measurements. AB - In long-term prospective studies, dual-energy X-ray absorptiometry (DXA) devices need to be inevitably changed. It is essential to assess whether systematic differences will exist between measurements with the new and old device. A group of female volunteers (21-72 years) underwent anteroposterior lumbar spine L2-L4 (n = 72), proximal femur (n = 72), and total body (n = 62) measurements with the Prodigy and the iDXA scanners at the same visit. The bone mineral density (BMD) measurements with these two scanners showed a high linear association at all tested sites (r = 0.962-0.995; p < 0.0001). The average iDXA BMD values were 1.5%, 0.5%, and 0.9% higher than those of Prodigy for lumbar spine (L2-L4) (p < 0.0001), femoral neck (p = 0.048), and total hip (p < 0.0001), respectively. Total body BMD values measured with the iDXA were -1.3% lower (p < 0.0001) than those measured with the Prodigy. For total body, lumbar spine, and femoral neck, the BMD differences as measured with these two devices were independent of subject height and weight. Linear correction equations were developed to ensure comparability of BMD measurements obtained with both DXA scanners. Importantly, use of equations from previous studies would have increased the discrepancy between these particular DXA scanners, especially at hip and at spine. PMID- 27239367 TI - Dysautonomia Differentially Influences the Effect of Affective Pain Perception on Quality of Life in Parkinson's Disease Patients. AB - Background. Our aim was to evaluate the real effect of dysautonomic symptoms on the influence of affective pain perception on quality of life in PD patients. Methods. An observational cross-sectional study was carried out using 105 Parkinson's disease (PD) patients of the Movement Disorders Unit, Hospital de Cruces (Bilbao, Spain) [men 59 (56.2%), women 46 (43.85%)]. Statistical analysis was made in order to evaluate the possible association of pain with life quality. Results. Quality of life measured by PDQ-39 (Parkinson's Disease Questionnaire for quality of life) was statistically associated with affective dimension of pain (PRIA, affective pain rating index). However, the influence of this dimension on PDQ-39 was different in the specific case of PD patients that experimented a high score (>12) in SCOPA-AUT (Scale for Outcomes in PD-Autonomic scale). Conclusions. These results confirm the effect of affective perception of pain in life quality of PD patients, indicating the critical role of autonomic symptoms in the modulation of the influence of pain on quality of life and showing the possible utility of dysautonomia as clinical prognostic indicator of quality of life in PD patients affected by pain. PMID- 27239368 TI - Association Analysis of NALCN Polymorphisms rs1338041 and rs61973742 in a Chinese Population with Isolated Cervical Dystonia. AB - Background. A genome-wide association study (GWAS) demonstrated a possible association between cervical dystonia (CD) and a sodium leak channel, nonselective (NALCN) gene. However, the association between NALCN and CD was largely unknown in Asian population. The present study was carried out to examine the associations between the two single nucleotide polymorphisms (SNPs) rs1338041 and rs61973742 in the NALCN gene and CD in a Chinese population. Methods. In a cohort of 201 patients with isolated CD, we genotyped the two SNPs rs1338041 and rs61973742 using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). We also included 289 unrelated, age- and sex-matched healthy controls (HCs) from the same region. Result. No significant differences were observed in either the genotype distributions or the minor allele frequencies (MAFs) of the two SNPs between the CD patients and the HCs. There were no significant differences between early-onset and late-onset CD patients, between patients with and without a positive family history of dystonia, or between patients with and without tremor or sensory tricks. Conclusion. Lack of association between the SNPs of NALCN and CD suggests that the SNPs of NALCN do not play a role in CD in a Chinese population. PMID- 27239369 TI - Serological and Molecular Evidence of Q Fever in Domestic Ruminants in Bangladesh. AB - The objective of this study was to know the herd and animal level prevalence of Q fever in domestic ruminants in some selected districts in Bangladesh. Randomly collected 111 bulk milk and 94 sera samples of cattle, sheep, and goats were tested by indirect ELISA (iELISA). DNA extracted from 23 aborted fetal membranes was analyzed by real time (rt) PCR. The positive cut-off value of iELISA in bulk milk and individual animal sera was >=30% and >=40%, respectively. The overall herd level prevalence of Q fever in dairy cattle was 15.6%. The prevalence of Q fever in dairy cattle was significantly higher in Sirajganj in comparison to Satkhira District (P < 0.01). The overall seroprevalence of Q fever in domestic ruminants was 5.06%. Although statistically insignificant, the seroprevalence of Q fever was relatively higher in sheep (9.52%) in comparison to goats (3.33%) and cattle (3.57%). Out of 23 aborted fetal membranes, only one sheep placenta was positive in rt PCR. Q fever is present in all of the three important species of domestic ruminants in Bangladesh. It may have some role in sheep abortion as the seroprevalence is relatively higher and also one sheep placenta is rt PCR positive. PMID- 27239370 TI - Status and Trend of Regal Fritillary (Speyeria idalia) (Lepidoptera: Nymphalidae) in the 4th of July Butterfly Count Program in 1977-2014. AB - Regal Fritillary (Speyeria idalia) primarily inhabits prairie, a native grassland of central North America, and occurs rarely in nonprairie grasslands further east. This butterfly has experienced widespread decline and marked range contraction. We analyze Regal Fritillary incidence and abundance during 1977-2014 in 4th of July Butterfly Counts, an annual census of butterflies in North America. Volunteers count within the same 24 km diameter circle each year. Only 6% of counts in range reported a Regal, while 18% of counts in core range in the Midwest and Great Plains did. 99.9% of Regal individuals occurred in core range. Only four circles east of core range reported this species, and only during the first half of the study period. All individuals reported west of its main range occurred in two circles in Colorado in the second half of the study. The number of counts per year and survey effort per count increased during the study. During 1991-2014, >31 counts occurred per year in core Regal range, compared to 0-23 during 1975-1990. During 1991-2014, all measures of Regal presence and abundance declined, most significantly. These results agree with other sources that Regal Fritillary has contracted its range and declined in abundance. PMID- 27239371 TI - Effects of Temperature and Precipitation on Breeding Migrations of Amphibian Species in Southeastern Norway. AB - To reveal the effects of climate, a generalized linear mixed model was used to explore the variation in onset of spawning migration for the two newt species T. cristatus and L. vulgaris in southern Norway. Amphibians are highly influenced by the physical environment, such as temperature and rainfall. The first migrating newts were observed subsequently to the three first consecutive days with mean temperature close to or above 4 degrees C. Further, migration of L. vulgaris was facilitated at lower temperatures compared to T. cristatus, but the migration was dependent on higher precipitation levels. Northern populations of T. cristatus and L. vulgaris may already benefit from a warmer climate due to increased recruitment and juvenile survival. However, an offset in the migration phenology due to climate change might further alter the recruitment and survival rates with either positive or negative outcome. Thus, variations in migration phenology for newts due to climate change may have implications for management and protection status in many systems. In a general context, we should increase emphasis on protecting newts and support increased populations and distribution. PMID- 27239374 TI - Revisiting the Factors Underlying Maxillary Midline Diastema. AB - Aim. The aim of this study is to analyze the etiological factors underlying the presence of maxillary midline diastema in a sample of orthodontic patients. Materials and Methods. One hundred patients who fulfill the inclusion criteria were selected from 1355 patients seeking orthodontic treatment. The pretreatment orthodontic records were analyzed. The width of the maxillary midline diastema was measured clinically with a digital caliper at two levels: the mesioincisal angles of the central incisors and five millimeters from the incisal edge. The two measurements were averaged, and patients with diastema of more than 0.5 millimeter in width were enrolled. Results. Diastema is a multifactorial clinical finding with more than one underlying etiological cause. The interrelationship between the familial pattern of midline diastema and the microdontia, macroglossia, labial frenum, and alveolar cleft conforms was clear. The effect of a mesiodens and the upper lateral incisor whether bilaterally missing, unerupted, or peg shaped was minimal. Conclusion. Etiological factors underlying maxillary midline diastema are interconnected. Using a checklist as a guide during handling maxillary midline diastema is important in the different stages of treatment. PMID- 27239373 TI - Role of Wheat Based Diet on the Pathology of Necrotic Enteritis in Turkeys. AB - The study was conducted to investigate the effects of wheat based diet on the pathology of necrotic enteritis in turkeys. Turkeys were divided into four groups. Groups A and B were kept as noninoculated and fed normal commercial diet while groups C and D were challenged orally with C. perfringens and fed wheat based diet to promote the development of experimental disease. Infected turkeys showed clinical signs of depression, ruffled feathers, and dark yellowish faeces showing the most prominent disease signs in turkeys of group D with 30% mortality. Similarly, turkeys of group D showed more striking gross and histopathologic lesions as compared to turkeys of group C. The most severe gross lesions comprised intestinal distension, small necrotic spots and haemorrhages on intestine, fragile intestinal wall, and gas bubble formation in the small intestine. Histologically, inoculated turkeys showed patchy necrosis, desquamation of intestinal epithelium, and intense leukocyte infiltration in the intestine. Microscopic examination showed significant decrease in the height of intestinal villi of inoculated birds. Haematological studies showed significant influence of necrotic enteritis on the blood profile of turkeys in group D. The findings revealed that simultaneous feeding of wheat enhanced the pathology of necrotic enteritis in turkeys. PMID- 27239372 TI - Assessing Risk in Patients with Stable Coronary Disease: When Should We Intensify Care and Follow-Up? Results from a Meta-Analysis of Observational Studies of the COURAGE and FAME Era. AB - Background. A large number of clinical and laboratory markers have been appraised to predict prognosis in patients with stable angina, but uncertainty remains regarding which variables are the best predictors of prognosis. Therefore, we performed a meta-analysis of studies in patients with stable angina to assess which variables predict prognosis. Methods. MEDLINE and PubMed were searched for eligible studies published up to 2015, reporting multivariate predictors of major adverse cardiac events (MACE, a composite endpoint of death, myocardial infarction, and revascularization) in patients with stable angina. Study features, patient characteristics, and prevalence and predictors of such events were abstracted and pooled with random-effect methods (95% CIs). Major adverse cardiovascular event (MACE) was the primary endpoint. Results. 42 studies (104,559 patients) were included. After a median follow-up of 57 months, cardiovascular events occurred in 7.8% of patients with MI in 6.2% of patients and need for repeat revascularization (both surgical and percutaneous) in 19.5% of patients. Male sex, reduced EF, diabetes, prior MI, and high C-reactive protein were the most powerful predictors of cardiovascular events. Conclusions. We show that simple and low-cost clinical features may help clinicians in identifying the most appropriate diagnostic and therapeutic approaches within the broad range of outpatients presenting with stable coronary artery disease. PMID- 27239375 TI - Examination of Hearing in a Rheumatoid Arthritis Population: Role of Extended High-Frequency Audiometry in the Diagnosis of Subclinical Involvement. AB - Objective. The aim of this study is to analyze the high-frequency hearing levels in patients with rheumatoid arthritis and to determine the relationship between hearing loss, disease duration, and immunological parameters. Materials and Methods. A descriptive cross-sectional study including fifty-three patients with rheumatoid arthritis was performed. The control group consisted of 71 age- and sex-matched patients from the study population (consecutively recruited in Madrid "Area 9," from January 2010 to February 2011). Both a pure tone audiometry and an extended-high-frequency audiometry were performed. Results. Extended-high frequency audiometry diagnosed sensorineural hearing loss in 69.8% of the patients which exceeded the results obtained with pure tone audiometry (43% of the patients). This study found significant correlations in patients with sensorineural hearing loss related to age, sex, and serum anti-cardiolipin (aCL) antibody levels. Conclusion. Sensorineural hearing loss must be considered within the clinical context of rheumatoid arthritis. Our results demonstrated that an extended-high-frequency audiometry is a useful audiological test that must be performed within the diagnostic and follow-up testing of patients with rheumatoid arthritis, providing further insight into a disease-modifying treatment or a hearing loss preventive treatment. PMID- 27239376 TI - Foodborne Listeria monocytogenes: A Real Challenge in Quality Control. AB - Listeria monocytogenes is a foodborne pathogen, and the detection and differentiation of this bacterium from the nonpathogenic Listeria species are of great importance to the food industry. Differentiation of Listeria species is very difficult, even with the sophisticated MALDI-TOF MS technique because of the close genetic relationship of the species and the usual gene transfer. The present paper emphasizes the difficulties of the differentiation through the standardized detection and confirmation according to ISO 11290-1:1996 and basic available L. monocytogenes detection methods and tests (such as API Listeria test, MALDI-TOF MS analysis, and hly gene PCR). With the increase of reports on the pathogenesis of atypical Listeria strains in humans, the significance of species level determination has become questionable, especially in food quality control, and the detection of pathogenic characteristics seems to be more relevant. PMID- 27239377 TI - Utility of the Measurement of Carboxyhemoglobin Level at the Site of Acute Carbon Monoxide Poisoning in Rural Areas. AB - Objective. This study examined the hypothesis that correlations exist between the carbon monoxide exposure time and the carboxyhemoglobin concentration at the site of carbon monoxide poisoning, using a pulse carbon monoxide oximeter in rural areas or the carboxyhemoglobin concentration measured at a given medical institution. Background. In previous studies, no definitive relationships between the arterial blood carboxyhemoglobin level and the severity of carbon monoxide poisoning have been observed. Method. The subjects included patients treated for acute carbon monoxide poisoning in whom a medical emergency team was able to measure the carboxyhemoglobin level at the site of poisoning. We examined the relationship between the carboxyhemoglobin level at the site of poisoning and carbon monoxide exposure time and the relationships between the arterial blood carboxyhemoglobin level and carbon monoxide exposure time. Results. A total of 10 patients met the above criteria. The carboxyhemoglobin levels at the site of poisoning were significantly and positively correlated with the exposure time (rs = 0.710, p = 0.021), but the arterial blood carboxyhemoglobin levels were not correlated with the exposure time. Conclusion. In rural areas, the carboxyhemoglobin level measured at the site of carbon monoxide poisoning correlated with the exposure time. PMID- 27239378 TI - Nanotechnology Based Approaches for Enhancing Oral Bioavailability of Poorly Water Soluble Antihypertensive Drugs. AB - Oral administration is the most convenient route among various routes of drug delivery as it offers high patient compliance. However, the poor aqueous solubility and poor enzymatic/metabolic stability of drugs are major limitations in successful oral drug delivery. There are several approaches to improve problems related to hydrophobic drugs. Among various approaches, nanotechnology based drug delivery system has potential to overcome the challenges associated with the oral route of administration. Novel drug delivery systems are available in many areas of medicine. The application of these systems in the treatment of hypertension continues to broaden. The present review focuses on various nanocarriers available in oral drug administration for improving solubility profile, dissolution, and consequently bioavailability of hydrophobic antihypertensive drugs. PMID- 27239379 TI - Orthogeriatric Service Reduces Mortality in Patients With Hip Fracture. AB - INTRODUCTION: Orthogeriatric service has been shown to improve outcomes in patients with hip fracture. The purpose of this study is to evaluate the effect of orthogeriatrics at Bispebjerg University Hospital, Denmark. The primary outcome is mortality inhospital and after 1, 3, and 12 months for patients with hip fracture. The secondary outcome is mortality for home dwellers and nursing home inhabitants. MATERIALS AND METHODS: This is a retrospective clinical cohort study with an historic control group including all patients with hip fracture admitted from 2007 to 2011. Patients with hip fracture are registered in a local database, and data are retrieved retrospectively using the Danish Civil Registration Number. RESULTS: We included 993 patients in the intervention group and 989 patients in the control group. A univariate analysis showed only significantly decreased mortality inhospital 6.3% vs 3.1% (P = .009) after orthogeriatrics. However, when adjusting for age, gender, and American Society of Anaesthesiologists (ASA) score in a multivariate analysis, including all patients with hip fracture, we find significantly reduced mortality inhospital (odds ratio [OR] 0.35), after 30 [OR 0.66] and 90 days [OR 0.72] and 1 year [OR 0.79]). When using a univariate analysis for home-dwelling patients, we found significantly reduced mortality inhospital (8.3-2.0%, P < .0001), after 30 days (12.2-6.8%, P = .004) and 90 days (20.5-13.0%, P = .002). One-year mortality was not significant. Patients from nursing homes had no significant decreasing mortality at any point of time in the univariate analysis. CONCLUSION: We have shown significant decreases for inhospital, 30 day, 90 day, and 1-year mortality after implementation of orthogeriatric service at Bispebjerg Hospital when adjusting for age, gender, and ASA score. Future trials should include frail patients with other fracture types who can benefit from orthogeriatrics. PMID- 27239380 TI - Outcome of the Cementless Zweymuller BICON-PLUS Cup and SL-PLUS Stem in the Very Elderly Individuals. AB - INTRODUCTION: There is current debate about which type of total hip prosthesis implants are best for the elderly patient. Implanting uncemented total hip arthroplasty (THA) in elderly people remains contested. The aim of present study was to evaluate the outcome of the uncemented Zweymuller BICON-PLUS THA in those with a minimum of 80 years of age. MATERIALS AND METHODS: A retrospective data collection was performed in a regional teaching hospital in the Netherlands. The primary outcome of interest was the operation-free period. Secondary outcomes included the revision rates of the femoral and acetabular components and postoperative complications of the procedure. After a follow-up of at least 7 years, the surviving patients were reviewed on functionality using validated scores (Hip Disability and Osteoarthritis Outcome Score, Timed Up and Go, and Harris Hip Score) and radiographic analysis. RESULTS: Between January 1999 and September 2004, 124 patients (128 THAs), aged 80 years and older, received an uncemented THA with a BICON-PLUS cup and SL-PLUS stem. The overall operation-free period was 6.5 years. One case of loosening of the cup was found among participants, with a survival rate of 99.2% of the BICON-PLUS cup in the analyzed group. In all, 28.8% of this group could be followed for a postoperative period of at least 7 years. The remainder of the patients died prior to the end of the 7 year period. Of these, 16.0% were eligible for clinical review. This group showed good function without evident signs of prosthetic loosening. CONCLUSION: The uncemented Zweymuller THA system, with threaded BICON-PLUS cup and SL-PLUS stem, showed good results, compared to outcome of other THA systems in elderly individuals. Therefore, it is a reliable option in older patients requiring THA. PMID- 27239381 TI - Effectiveness of a Multidisciplinary Clinical Pathway for Elderly Patients With Hip Fracture: A Multicenter Comparative Cohort Study. AB - INTRODUCTION: The use of a multidisciplinary clinical pathway (MCP) for patients with hip fracture tends to be more effective than usual care (UC). The aim of this study was to evaluate the effects of an MCP approach on time to surgery, length of stay, postoperative complications, and 30-day mortality, compared to UC. MATERIALS AND METHODS: This multicenter retrospective cohort study included patients aged 50 years or older with a proximal hip fracture who underwent surgery in one of the 6 hospitals in the Limburg trauma region of the Netherlands in 2012. Data such as demographics, process outcome measures, and clinical outcome were collected. RESULTS: This study included a total of 1193 patients (665 and 528 patients in the MCP and UC groups, respectively). There were no differences in patient demographics present. Time to surgery was significantly shorter in the MCP compared to the UC group (19.2 vs 24.4 hours, P < .01). The mean length of stay was 10 versus 12 days (P < .01). In the MCP group, significantly lower rates of postoperative complications were observed and significantly more patients were institutionalized than in the UC group. Mortality within 30 days after admission was comparable between the groups (overall mortality 6%). CONCLUSION: An MCP approach is associated with reduced time to surgery, postoperative complications, and length of stay, without a significant difference in 30-day mortality. The institutionalization rate was significantly higher in the MCP group. PMID- 27239382 TI - One-Year Results of an Educational Program on Osteoarthritis: A Prospective Randomized Controlled Trial in Brazil. AB - INTRODUCTION: Knee osteoarthritis (KOA) is the most prevalent form of osteoarthritis. Low socioeconomic level, age, and obesity are directly correlated with the incidence of the disease. Education, exercise, and diet are the core recommendations of all KOA treatment guidelines. OBJECTIVE: To evaluate the impact of a multiprofessional educational program on patients with KOA. METHODS: Of a total of 198 participants, 150 patients with KOA attended 2 days of lectures (at 1- to 3-month intervals) and received educational material on osteoarthritis, and a control group (48 patients) received educational materials only. Body mass index (BMI), frequency, and intensity of physical activity, pain, function, and quality-of-life scores were assessed at baseline and at 4 and 12 months after the educational program. Bimonthly telephone calls were made to half of the participants. Correlations between BMI, level of education, coping skills, functional, and pain results was procured. RESULTS: The groups were similar in terms of race, gender, affected side, and osteoarthritis severity. The results were not affected by the telephone calls or the patients' level of education. At baseline, 25 performed physical activity, whereas 123 performed at 1 year. Seventy-two (36.36%) patients decreased BMI (45 by 1 point and 27 by more than 2 points). There were some weak correlations such as BMI reduction with pain and functional improvements and with coping results. Significant improvements in function and quality of life were found at 4 months. Quality of life remained improved at 1 year. CONCLUSION: The effect of this educational program in function and quality of life of patients with KOA is very subtle. Interval between classes (1, 2, or 3 months) is not an important issue. PMID- 27239383 TI - Factors Influencing Discharge Destination After Total Knee Arthroplasty: A Database Analysis. AB - INTRODUCTION: The demand for total knee arthroplasty (TKA) continues to challenge hospital financial resources. Hospitals have countered this economic demand by reducing patient length of stay (LoS), thus requiring a higher utilization of extended care facilities (ECF) and home with home health care (HHC). With an increase in the number of insured low-income families following the Affordable Care Act (ACA), TKA patients' demographics are anticipated to change. Both trends have significant economic implications, and predicting the discharge destinations of TKA patients would help plan for future health expenditures. The purpose of this study was to determine which variables are significant in predicting discharge destinations of patients treated with TKA. METHODS: We utilized the California Hospital Discharge data set of the year 2010. For each hospitalization, the data set includes information about patient demographics (age, gender, race, and ethnicity), insurance type, diagnoses and procedures, and patient disposition. Discharge to home was the reference category. Discharges to a skilled nursing home and discharge to home with home care were the 2 additional alternatives. Independent variables included the Charlson comorbidity index, payer category (private, Medicare, Medical, and other), race, ethnicity, age, and gender. RESULTS: Over 28 611 TKAs were reviewed with 45.9% discharged to HHC, 29.9% going to ECF, and 24.2% going home without home health care. Race, age, insurance, and morbidity proved to be highly significant factors influencing patient discharge destination (P < .001). Medicare coverage relative to private payers was a strong predictor for discharge destination (relative risk ratio (RRR) 1.69, P < .001). The strongest predictors were black and Asian races relative to whites (RRR 1.54, P < .01). Male gender was the only factor that lowered the risk of discharge to a nursing home (RRR 0.43, P < .001). CONCLUSIONS: This study provides insight on which patient characteristics influence discharge destination after TKA. Race, age, insurance, and morbidity were highly significant (P < .001) factors on patient discharge destination. PMID- 27239384 TI - Review of Postoperative Delirium in Geriatric Patients Undergoing Hip Surgery. AB - Postoperative delirium is a serious complication following hip surgery in elderly patients that can adversely affect outcomes in both hip fracture and arthroplasty surgery. Recently, the incidence of hip fracture in the Medicare population was estimated at approximately 500 000 patients per year, with the majority treated surgically. The annual volume of total hip arthroplasty is nearly 450 000 patients and is projected to increase over the next 15 to 20 years. Subsequently, the incidence of postoperative delirium will rise. The incidence of postoperative delirium after hip surgery in the elderly patients ranges between 4% and 53%, and it is identified as the most common surgical complication of older patients. The most common risk factors include advanced age, hip fracture surgery (vs elective hip surgery), and preoperative delirium/cognitive impairment. Exact pathophysiology has not been fully defined. It is hypothesized that imbalances in cortical neurotransmitters or inflammatory cytokine pathway mechanisms contribute to delirium. Development of postoperative delirium is associated with longer hospital stay, increased medical complications, and poorer short-term functional outcome. Patients who develop postoperative delirium are also at increased risk for cognitive decline beyond the acute phase. Following acute care, postoperative delirium is associated with the need for a higher level of care, an additional cost. Management of postoperative delirium centers on prevention and early recognition. Medical prophylaxis has been demonstrated to have limited utility. Utilization of delirium detection methods contributed to early recognition. The most effective means of prevention involved a multidisciplinary team focused on adequate hydration, optimization of analgesia, reduction in polypharmacy, aggressive physiotherapy, and early recognition of the delirium symptoms. PMID- 27239385 TI - The Geriatric Driver: Factors That Influence When to Stop Driving. AB - The increase in the growth of the elderly population in the past 2 decades has been paralleled by an increase in the number of active elderly drivers. Consequentially, this growth has been accompanied by a rise in fatal road-related accidents. Due to age-related fragility, elderly drivers are more susceptible to injuries and death following a road-related accident. The increased risk of accidents has become a growing public health issue and has led to certain guidelines and restrictions for elderly drivers. Moreover, the cognitive and physiological decline that exacerbates with age has encouraged preventative measures aimed at optimizing their ability to operate motor vehicles. Some of these include yearly vision, cognitive, motor, and mental assessment tests. Results obtained from these tests may help suggest when an elderly driver becomes unsuitable to drive. PMID- 27239386 TI - Delayed Emergency Analgesia for Patients With Dementia and Hip Fracture. PMID- 27239387 TI - Single Cell Multiplex Protein Measurements through Rare Earth Element Immunolabeling, Laser Capture Microdissection and Inductively Coupled Mass Spectrometry. AB - Complex diseases such as heart disease, stroke, cancer, and aging are the primary causes of death in the US. These diseases cause heterogeneous conditions among cells, conditions that cannot be measured in tissue homogenates and require single cell approaches. Understanding protein levels within tissues is currently assayed using various molecular biology techniques (e.g., Western blots) that rely on milligram to gram quantities of tissue homogenates or immunofluorescent (IF) techniques that are limited by spectral overlap. Tissue homogenate studies lack references to tissue structure and mask signals from individual or rare cellular events. Novel techniques are required to bring protein measurement sensitivity to the single cell level and offer spatiotemporal resolution and scalability. We are developing a novel approach to protein quantification by exploiting the inherently low concentration of rare earth elements (REE) in biological systems. By coupling REE-antibody immunolabeling of cells with laser capture microdissection (LCM) and ICP-QQQ, we are achieving multiplexed protein measurement in histological sections of single cells. This approach will add to evolving single cell techniques and our ability to understand cellular heterogeneity in complex biological systems and diseases. PMID- 27239388 TI - Teaching by Teleconference: A Model for Distance Medical Education across Two Continents. AB - INTRODUCTION: In Uganda, an estimated 120 obstetrician/gynecologists serve a population of 30 million people demonstrating the need to train additional skilled clinician leaders in reproductive health. In 2012, a partnership was formed with the Mbarara Regional Referral Hospital (MRRH) in southwest Uganda and the Massachusetts General Hospital (MGH) in Boston, USA, in part to increase access to specialist training. This report presents an update in the development of a teaching conference between the institutions. METHODS: In June 2012, a didactic teleconference between the institutions was instituted. Various conferencing tools were tried: direct telephone connection, VentriloTM conferencing system and SkypeTM via personal computer or smart phone. In Mbarara, Internet was accessed via cellular data. In Boston, Internet was accessed via hospital network or cellular data. All lectures were HIPAA compliant. PowerPoint lectures were stored in a collective DropboxTM that could be accessed and downloaded prior to lecture dates. RESULTS: Over 30 months, 30 lectures were given. Lecturers included faculty and fellows from maternal fetal medicine, gynecology oncology, urogynecology, family planning, psychiatry and obstetric anesthesia. A patient case pertinent to the teaching topic framed the discussion. About 20 participants attended each lecture. Internet connectivity was the biggest challenge. Ultimately audio Skype via cellular data proved the most successful modality and became the method of choice. CONCLUSION: A successful collaboration in medical education via teleconference is sustainable, low cost, and beneficial to both resource-rich and resource-poor institutions. Expertise can be shared bilaterally and internationally by individuals potentially unable travel. PMID- 27239389 TI - Patient perspectives of a diagnosis of myeloproliferative neoplasm in a case control study. AB - BACKGROUND: Myeloproliferative neoplasms (MPNs) including the classic entities; polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis are rare diseases with unknown aetiology. The MOSAICC study, is an exploratory case-control study in which information was collected through telephone questionnaires and medical records. METHODS: As part of the study, 106 patients with MPN were asked about their perceived diagnosis and replies correlated with their haematologist's diagnosis. For the first time, a patient perspective on their MPN diagnosis and classification was obtained. Logistic regression analyses were utilised to evaluate the role of variables in whether or not a patient reported their diagnosis during interview with co-adjustment for these variables. Chi square tests were used to investigate the association between MPN subtype and patient reported categorisation of MPN. RESULTS: Overall, 77.4 % of patients reported a diagnosis of MPN. Of those, 39.6 % recognised MPN as a 'blood condition', 23.6 % recognised MPN as a 'cancer' and 13.2 % acknowledged MPN as an 'other medical condition'. There was minimal overlap between the categories. Patients with PV were more likely than those with ET to report their disease as a 'blood condition'. ET patients were significantly more likely than PV patients not to report their condition at all. Patients from a single centre were more likely to report their diagnosis as MPN while age, educational status, and WHO re classification had no effect. CONCLUSIONS: The discrepancy between concepts of MPN in patients could result from differing patient interest in their condition, varying information conveyed by treating hematologists, concealment due to denial or financial concerns. Explanations for the differences in patient perception of the nature of their disease, requires further, larger scale investigation. PMID- 27239390 TI - Free Volume in Membranes: Viscosity or Tension? AB - Many papers have used fluorescent probe diffusion to infer membrane viscosity but the measurement is actually an assay of the free volume of the membrane. The free volume is also related to the membrane tension. Thus, changes in probe mobility refer equally well to changes in membrane tension. In complicated structures like cell membranes, it appears more intuitive to consider variations in free volume as referring to the effect of domains structures and interactions with the cytoskeleton than changes in viscosity since tension is a state variable and viscosity is not. PMID- 27239391 TI - Self-Debriefing vs Instructor Debriefing in a Pre-Internship Simulation Curriculum: Night on Call. AB - This study sought to determine if learner self-performance assessment (SPA) and team-performance assessment (TPA) were different when simulation based education (SBE) was supported by self-debriefing (S-DB), compared to traditional facilitator-led debriefing (F-DB). "One-Night-On-Call," an internship preparation curriculum, was selected to provide SBE. Participants worked as team members in 4 sequential bedside acute care problem-solving scenarios. Fifty-seven learners were randomized to 9 F-DB and 10 S-DB Teams. Participants completed SPA and TPA assessment checklist questionnaires immediately following the first and fourth (final) scenarios. Learner SPA and TPA scores improved overall from the first to the fourth scenarios (P <.05). F-DB versus S-DB cohorts did not differ in overall SPA scores. The F-DB average TPA score was 12.8 (SD+/-2.1) compared to a S-DB score of 14.1 (SD+/-2.1) (P =.001). F-DB participants' increase in TPA was due to increases in the Patient Assessment and Treatment sub-domains that exceeded corresponding improvements in the S-DB cohort. Self- debriefing strategies are equivalent to facilitator-led debriefing in some situations. Self-debriefing offers opportunities to enable simulation-based education by decreasing the number of required faculty debriefers, and may be uniquely well matched to simulation-based teamwork training. PMID- 27239392 TI - Cerebral Venous Air Embolism Secondary to Mesenteric Infarction. AB - Cerebral air embolism is a rare, yet potentially fatal condition. We present a case of retrograde cerebral venous air emboli arising from the hepatic portal venous system, secondary to a mesenteric infarction. A 69-year-old man with a history of gastrointestinal amyloidosis presented with fever and lethargy. Computed tomography of the brain detected multiple foci of air in the right frontal, fronto-parietal, and left lateral frontal sulci consistent with cerebral venous air emboli. Computed tomography of the abdomen and pelvis revealed moderate thickening and dilatation of the small bowel with diffuse scattered intestinal pneumatosis suggestive of mesenteric infarction with resultant extensive intrahepatic portal venous air. The patient was deemed a poor candidate for surgical intervention and died as a result of septic shock. We believe the cerebral venous air emboli was a result of retrograde flow of air arising from the hepatic venous air ascending via the inferior and superior vena cava to the cerebral venous system. To our knowledge, there have been no reported cases of retrograde cerebral venous air embolism arising from hepatic portal venous system secondary to mesenteric infarction. The clinical significance and prognosis in this setting requires further investigation. PMID- 27239393 TI - Health Disparities in Native Hawaiians and Other Pacific Islanders Following Hysterectomy for Endometrial Cancer. AB - The current study was undertaken to assess disparities in 5 year admission rates and mortality following hysterectomy for endometrial cancer in the State of Hawai'i. Data from the Hawai'i Health Information Corporation was utilized to determine five-year admission rates and overall mortality. Native Hawaiian and Other Pacific Islander (NHOPI) patients were compared to non-NHOPI patients for the period January 1, 2007 to December 31, 2013. Secondary admission rates were significantly higher for NHOPI patients compared to non-NHOPI patients (P=.02). Overall mortality was not different. NHOPI patients living on Oahu were less likely to live in Honolulu (P=.01), were more likely to have government insurance (P=.01), and were significantly younger (P=.02) than non-NHOPI patients. The findings suggest that race, insurance, and demographic factors are interrelated and are associated with disparities following surgery for endometrial cancer. PMID- 27239394 TI - Medical School Hotline: Liaison Committee for Medical Education Accreditation, Part VI: Academic, Career, Personal Counseling/Student Health and Well-Being. PMID- 27239395 TI - Insights in Public Health: Safe Messaging for Youth-Led Suicide Prevention Awareness: Examples from Hawai'i. PMID- 27239396 TI - The Daniel K. Inouye College of Pharmacy Scripts: Transition from Traditional to Western Medicine in Hawai'i (Part 2) Western Legislative Impacts on Traditional Medical Practices. PMID- 27239398 TI - Targeting the Psychosexual Challenges Faced by Couples with Breast Cancer: Can Couples Group Psychotherapy Help? AB - The need for the psychosexual rehabilitation of breast cancer survivors and their intimate partners is underscored by the high prevalence of multiple psychosexual difficulties encountered by this patient population. Concerns about health, sexuality, and emotional distress are common among women with breast cancer and are often related to the side effects of cancer treatment. Additionally, both intimate relationship problems and partners' distress are likely to influence patients' psychosexual health. A clearer understanding of these complex clinical issues is needed in order to implement effective psychosexual rehabilitation interventions. In this article, we extended the use of the manualized and empirically validated Supportive-Expressive Group Therapy (SEGT) model to target the specific psychosexual needs of couples with breast (as well as other types of) cancer. In view of the pertinent literature in this area and based on our clinical experience utilizing this group therapy model with different patient populations, we have discussed how clinicians involved in the psychosexual care of oncology patients could apply such a model within a couples group therapy format. PMID- 27239400 TI - Re-irradiation of Recurrent Pineal Germ Cell Tumors with Radiosurgery: Report of Two Cases and Review of Literature. AB - Primary intracranial germ cell tumors are rare, representing less than 5% of all central nervous system tumors. Overall, the majority of germ cell tumors are germinomas and approximately one-third are non-germinomatous germ cell tumors (NGGCT), which include teratoma, embryonal carcinoma, yolk sac tumor (endodermal sinus tumor), choriocarcinoma, or mixed malignant germ cell tumor. Germ cell tumors may secrete detectable levels of proteins into the blood and/or cerebrospinal fluid, and these proteins can be used for diagnostic purposes or to monitor tumor recurrence. Germinomas have long been known to be highly curable with radiation therapy alone. However, many late effects of whole brain or craniospinal irradiation have been well documented. Strategies have been developed to reduce the dose and volume of radiation therapy, often in combination with chemotherapy. In contrast, patients with NGGCT have a poorer prognosis, with about 60% cured with multimodality chemoradiation. There are no standard approaches for relapsed germ cell tumors. Options may be limited by prior treatment. Radiation therapy has been utilized alone or in combination with chemotherapy or high-dose chemotherapy and transplant. We discuss two cases and review options for frameless radiosurgery or fractionated radiotherapy. PMID- 27239399 TI - The role of IL-17 signaling in regulation of the liver-brain axis and intestinal permeability in Alcoholic Liver Disease. AB - Alcoholic liver disease (ALD) progresses from a normal liver, to steatosis, steatohepatitis, fibrosis and hepatocellular carcinoma (HCC). Despite intensive studies, the pathogenesis of ALD is poorly understood, in part due to a lack of suitable animal models which mimic the stages of ALD progression. Furthermore, the role of IL-17 in ALD has not been evaluated. We and others have recently demonstrated that IL-17 signaling plays a critical role in development of liver fibrosis and cancer. Here we summarize the most recent evidence supporting the role of IL-17 in ALD. As a result of a collaborative effort of Drs. Karin, Gao, Tsukamoto and Kisseleva, we developed several improved models of ALD in mice: 1) chronic-plus-binge model that mimics early stages of steatohepatitis, 2) intragastric ethanol feeding model that mimics alcoholic steatohepatitis and fibrosis, and 3) diethylnitrosamine (DEN)+alcohol model that mimics alcoholic liver cancer. These models might provide new insights into the mechanism of IL-17 signaling in ALD and help identify novel therapeutic targets. PMID- 27239401 TI - Variational Data Assimilative Modeling of the Gulf of Maine Circulation in Spring and Summer 2010. AB - A data assimilative ocean circulation model is used to hindcast the Gulf of Maine (GOM) circulation in spring and summer 2010. Using the recently developed incremental strong constraint 4D Variational data assimilation algorithm, the model assimilates satellite sea surface temperature and in situ temperature and salinity profiles measured by expendable bathythermograph, Argo floats, and shipboard CTD casts. Validation against independent observations shows that the model skill is significantly improved after data assimilation. The data assimilative model hindcast reproduces the temporal and spatial evolution of the ocean state, showing that a sea level depression southwest of the Scotian Shelf played a critical role in shaping the gulf-wide circulation. Heat budget analysis further demonstrates that both advection and surface heat flux contribute to temperature variability. The estimated time scale for coastal water to travel from the Scotian Shelf to the Jordan Basin is around 60 days, which is consistent with previous estimates based on in situ observations. Our study highlights the importance of resolving upstream and offshore forcing conditions in predicting the coastal circulation in the GOM. PMID- 27239402 TI - Stromal derived factor-1 and granulocyte-colony stimulating factor treatment improves regeneration of Pax7-/- mice skeletal muscles. AB - BACKGROUND: The skeletal muscle has the ability to regenerate after injury. This process is mediated mainly by the muscle specific stem cells, that is, satellite cells. In case of extensive damage or under pathological conditions, such as muscular dystrophy, the process of muscle reconstruction does not occur properly. The aim of our study was to test whether mobilized stem cells, other than satellite cells, could participate in skeletal muscle reconstruction. METHODS: Experiments were performed on wild-type mice and mice lacking the functional Pax7 gene, that is, characterized by the very limited satellite cell population. Gastrocnemius mice muscles were injured by cardiotoxin injection, and then the animals were treated by stromal derived factor-1 (Sdf-1) with or without granulocyte-colony stimulating factor (G-CSF) for 4 days. The muscles were subjected to thorough assessment of the tissue regeneration process using histological and in vitro methods, as well as evaluation of myogenic factors' expression at the transcript and protein levels. RESULTS: Stromal derived factor 1 alone and Sdf-1 in combination with G-CSF significantly improved the regeneration of Pax7-/- skeletal muscles. The Sdf-1 and G-CSF treatment caused an increase in the number of mononucleated cells associated with muscle fibres. Further analysis showed that Sdf-1 and G-CSF treatment led to the rise in the number of CD34+ and Cxcr4+ cells and expression of Cxcr7. CONCLUSIONS: Stromal derived factor-1 and G-CSF stimulated regeneration of the skeletal muscles deficient in satellite cells. We suggest that mobilized CD34+, Cxcr4+, and Cxcr7+ cells can efficiently participate in the skeletal muscle reconstruction and compensate for the lack of satellite cells. PMID- 27239403 TI - MAP3K11/GDF15 axis is a critical driver of cancer cachexia. AB - BACKGROUND: Cancer associated cachexia affects the majority of cancer patients during the course of the disease and thought to be directly responsible for about a quarter of all cancer deaths. Current evidence suggests that a pro-inflammatory state may be associated with this syndrome although the molecular mechanisms responsible for the development of cachexia are poorly understood. The purpose of this work was the identification of key drivers of cancer cachexia that could provide a potential point of intervention for the treatment and/or prevention of this syndrome. METHODS: Genetically engineered and xenograft tumour models were used to dissect the molecular mechanisms driving cancer cachexia. Cytokine profiling from the plasma of cachectic and non-cachectic cancer patients and mouse models was utilized to correlate circulating cytokine levels with the cachexia phenotype. RESULTS: Utilizing engineered tumour models we identified MAP3K11/GDF15 pathway activation as a potent inducer of cancer cachexia. Increased expression and high circulating levels of GDF15 acted as a key mediator of this process. In animal models, tumour-produced GDF15 was sufficient to trigger the cachexia phenotype. Elevated GDF15 circulating levels correlated with the onset and progression of cachexia in animal models and in patients with cancer. Inhibition of GDF15 biological activity with a specific antibody reversed body weight loss and restored muscle and fat tissue mass in several cachectic animal models regardless of their complex secreted cytokine profile. CONCLUSIONS: The combination of correlative observations, gain of function, and loss of function experiments validated GDF15 as a key driver of cancer cachexia and as a potential therapeutic target for the treatment and/or prevention of this syndrome. PMID- 27239404 TI - Accelerometer-determined physical activity, muscle mass, and leg strength in community-dwelling older adults. AB - INTRODUCTION: The aim of this study was to describe the relationship between accelerometer-determined physical activity (PA), muscle mass, and lower-limb strength in community-dwelling older adults. METHODS: Six hundred thirty-six community-dwelling older adults (66 +/- 7 years) were studied. Muscle mass was measured using dual-energy x-ray absorptiometry, whilst lower limb strength was measured via dynamometry. We measured minutes/day spent in sedentary, light, moderate, and vigorous intensity activity using Actigraph GT1M accelerometers. RESULTS: Participants spent a median of 583(Interquartile ratio (IQR) 522-646), 225(176-271), 27(12-45) and 0(0-0) min in sedentary, light, moderate, and vigorous activity, respectively. PA intensity was positively associated with both lean mass percentage and lower limb strength in a dose-response fashion. Sedentary activity was negatively associated with lean mass percentage, but not lower-limb strength. There was a positive association between PA and appendicular lean mass in men only. There was an interaction between age and activity; as age increased, the magnitude of the association of PA with lean mass percentage decreased. Those who adhered to the Australian Department of Health PA guidelines (moderate/vigorous PA >/=150 min/week) had greater lean mass percentage, appendicular lean mass, and lower limb strength. CONCLUSIONS: Using accelerometer technology, both the amount and intensity of accelerometer-determined PA had an independent, dose-response relationship with lean mass percentage and lower limb strength, with the largest effect for vigorous activity. Time spent in sedentary activity was negatively associated with lean mass percentage, but was not associated with lower limb strength. The magnitude of the association between PA and lean mass percentage decreased with age, suggesting that PA programmes may need to be modified with increasing age. PMID- 27239405 TI - Patient-centred physical therapy is (cost-) effective in increasing physical activity and reducing frailty in older adults with mobility problems: a randomized controlled trial with 6 months follow-up. AB - BACKGROUND: Despite the well-known health benefits of physical activity, it is a great challenge to stay physically active for frail-older adults with mobility limitations. The aim of this study was to test the (cost-) effectiveness of a patient-centred physical therapy strategy (Coach2Move) in which individualized treatment (motivational interviewing, physical examination, individualized goal setting, coaching and advice on self management, and physical training) is combined to increase physical activity level and physical fitness and, thereby, to decrease the level of frailty. METHODS: A randomized controlled trial was performed in 13 physical therapy practices with measurements at 3 and 6 months. Eligible patients were aged 70 years or over and had mobility problems (i.e. difficulties with walking, moving, getting up and changing position from bed or chair to standing, or stair climbing). The primary outcome was physical activity (total and moderate intensity) in minutes per day. Secondary outcomes were as follows: frailty, walking speed and distance, mobility, and quality of life. Data were analysed using linear mixed models for repeated measurements. Healthcare costs and quality-adjusted life years (QALYs) were computed and combined using net monetary benefit (NMB) for different willingness to pay thresholds. Data on costs, QALYs, and NMBs were analysed using linear mixed models. RESULTS: One hundred and thirty patients participated in this study. At 6 months, the between group difference was significant for moderate-intensity physical activity in favour of the Coach2Move group [mean difference: 17.9 min per day; 95% confidence interval (CI) 4.0 to 34.9; P = 0.012]. The between-group difference for total physical activity was 14.1 min per day (95% CI -6.6 to 34.9; P = 0.182). Frailty decreased more in the Coach2Move group compared with usual care [mean difference: -0.03 (95% CI: -0.06 to -0.00; P = 0.027)]. Compared with usual treatment, the Coach2Move strategy resulted in cost savings (?849.8; 95% CI: 1607 to 90; P = 0.028), an improvement in QALYs, (0.02; 95% CI: 0.00 to 0.03; P = 0.03), and a higher NMB at every willingness to pay threshold. CONCLUSIONS: Older adults with mobility problems are able to safely increase physical activity in their own environment and reduce frailty. This study emphasizes both the potential cost effectiveness of a patient-centred approach in the frail elderly and the importance of physical activity promotion in older adults with mobility limitations. PMID- 27239406 TI - Growth differentiation factor-15 is associated with muscle mass in chronic obstructive pulmonary disease and promotes muscle wasting in vivo. AB - BACKGROUND: Loss of muscle mass is a co-morbidity common to a range of chronic diseases including chronic obstructive pulmonary disease (COPD). Several systemic features of COPD including increased inflammatory signalling, oxidative stress, and hypoxia are known to increase the expression of growth differentiation factor 15 (GDF-15), a protein associated with muscle wasting in other diseases. We therefore hypothesized that GDF-15 may contribute to muscle wasting in COPD. METHODS: We determined the expression of GDF-15 in the serum and muscle of patients with COPD and analysed the association of GDF-15 expression with muscle mass and exercise performance. To determine whether GDF-15 had a direct effect on muscle, we also determined the effect of increased GDF-15 expression on the tibialis anterior of mice by electroporation. RESULTS: Growth differentiation factor-15 was increased in the circulation and muscle of COPD patients compared with controls. Circulating GDF-15 was inversely correlated with rectus femoris cross-sectional area (P < 0.001) and exercise capacity (P < 0.001) in two separate cohorts of patients but was not associated with body mass index. GDF-15 levels were associated with 8-oxo-dG in the circulation of patients consistent with a role for oxidative stress in the production of this protein. Local over expression of GDF-15 in mice caused wasting of the tibialis anterior muscle that expressed it but not in the contralateral muscle suggesting a direct effect of GDF-15 on muscle mass (P < 0.001). CONCLUSIONS: Together, the data suggest that GDF-15 contributes to the loss of muscle mass in COPD. PMID- 27239407 TI - High risk of fall, poor physical function, and low grip strength in men with fracture-the STRAMBO study. AB - BACKGROUND: Several studies assessed the association of prevalent fractures with muscle mass, strength, and physical capacity in men. Clinical impact of these associations is not clear, and they could be influenced by confounders. Our aim was to assess the association of the prevalent fractures with muscle strength, physical function, and the risk of subsequent falls in older men after adjustment for muscle mass and potential confounders. METHODS: In a cohort of 890 men aged 50 and older, we assessed appendicular skeletal muscle mass (ASM) by DXA, grip strength, physical function (chair stands, static, and dynamic balance). Relative ASM (RASM) was calculated as ASM / (height)(2). Then, 813 men aged 60 and over were followed up prospectively for 5 years and 144 sustained >1 incident falls. All the analyses were adjusted for lifestyle factors, co-morbidities, and hormones known to influence muscle and physical function. RESULTS: Low leisure physical activity, very high occupational physical activity, Parkinson's disease, diabetes mellitus, low apparent free testosterone concentration (AFTC), as well as Grade 2 and 3 vertebral fractures and multiple fractures were associated with lower grip strength when adjusted for confounders including upper limb RASM. Low leisure physical activity, very high occupational physical activity, diabetes mellitus, prior stroke, low AFTC and 25-hydroxycholecalciferol, high C-reactive protein, vertebral fractures, and non-vertebral fractures were associated with poor physical function (lowest quintile of the score of tests) when adjusted for confounders including lower limb RASM. Grade 2 and 3 and multiple vertebral fractures were associated with twofold higher risk of multiple falls after adjustment for confounders. Men having multiple fractures had a twofold higher risk of multiple falls after adjusting for confounders. In multivariable models, risk of falls increased proportionally to the increasing severity and number of vertebral fractures as well as to the increasing number of all fractures. CONCLUSIONS: In older men, Grade 2 and 3 vertebral fractures and multiple vertebral and non-vertebral fractures are associated with lower grip strength, poor physical function, and higher risk of multiple falls after adjustment for multiple confounders. This suggests a real direct association. One fracture can initiate a vicious circle leading to another fracture; thus, patients with fractures need physical therapy regardless of their general health status. PMID- 27239408 TI - UBE2B is implicated in myofibrillar protein loss in catabolic C2C12 myotubes. AB - BACKGROUND: Skeletal muscle protein loss is an adaptive response to various patho physiological situations, and the ubiquitin proteasome system (UPS) is responsible for the degradation of the bulk of muscle proteins. The role of E2 ubiquitin-conjugating enzymes is still poorly understood in skeletal muscle. METHODS: We screened for E2s expression levels in C2C12 myotubes submitted to the catabolic glucocorticoid dexamethasone (Dex). RESULTS: One micromolar Dex induced an accumulation of proteasome substrates (polyUb conjugates) and an overexpression of the muscle-specific E3 ligase MuRF1 and of six E2 enzymes, UBE2A, UBE2B, UBE2D1, UBE2D2, UBE2G1, and UBE2J1. However, only MuRF1 and UBE2B were sensitive to mild catabolic conditions (0.16 MUM Dex). UBE2B knockdown induced a sharp decrease of total (-18%) and K48 (-28%) Ub conjugates, that is, proteasome substrates, indicating an important role of UBE2B in the overall protein breakdown in catabolic myotubes. CONCLUSIONS: Interestingly, these results indicate an important role of UBE2B on muscle protein homeostasis during catabolic conditions. PMID- 27239410 TI - Sarcopenia and mortality among a population-based sample of community-dwelling older adults. AB - BACKGROUND: Sarcopenia is a risk-factor for all-cause mortality among older adults, but it is unknown if sarcopenia predisposes older adults to specific causes of death. Further, it is unknown if the prognostic role of sarcopenia differs between males and females, and obese and non-obese individuals. METHODS: A population-based cohort study among 4425 older adults from the Third National Health and Nutrition Survey (1988-1994). Muscle mass was quantified using bioimpedance analysis, and muscle function was quantified using gait speed. Multivariable-adjusted Cox regression analysis examined the relationship between sarcopenia and mortality outcomes. RESULTS: The mean age of study participants was 70.1 years. The prevalence of sarcopenia was 36.5%. Sarcopenia associated with an increased risk of all-cause mortality [hazard ratio (HR): 1.29 (95% confidence interval (95% CI): 1.13-1.47); P < 0.001] among males and females. Sarcopenia associated with an increased risk of cardiovascular-specific mortality among females [HR: 1.61 (95% CI: 1.22-2.12); P = 0.001], but not among males [HR: 1.07 (95% CI: 0.81-1.40; P = .643); P interaction = 0.079]. Sarcopenia was not associated with cancer-specific mortality among males and females [HR: 1.07 (95% CI: 0.78-1.89); P = 0.672]. Sarcopenia associated with an increased risk of mortality from other causes (i.e. non-cardiovascular and non-cancer) among males and females [HR: 1.32 (95% CI: 1.07-1.62); P = 0.008]. Obesity, defined using body mass index (P interaction = 0.817) or waist circumference (P interaction = 0.219) did not modify the relationship between sarcopenia and all-cause mortality. CONCLUSIONS: Sarcopenia is a prevalent syndrome that is associated with premature mortality among community-dwelling older adults. The prognostic value of sarcopenia may vary by cause-specific mortality and differ between males and females. PMID- 27239409 TI - Adiponectin resistance in skeletal muscle: pathophysiological implications in chronic heart failure. AB - Skeletal muscle wasting is a common complication of chronic heart failure (CHF) and linked to poor patient prognosis. In recent years, adiponectin was postulated to be centrally involved in CHF-associated metabolic failure and muscle wasting. This review discusses current knowledge on the role of adiponectin in CHF. Particular emphasis will be given to the complex interaction mechanisms and the intracellular pathways underlying adiponectin resistance in skeletal muscle of CHF patients. In this review, we propose that the resistance process is multifactorial, integrating abnormalities emanating from insulin signalling, mitochondrial biogenesis, and ceramide metabolism. PMID- 27239411 TI - Effect of the specific proteasome inhibitor bortezomib on cancer-related muscle wasting. AB - BACKGROUND: Muscle wasting, a prominent feature of cancer cachexia, is mainly caused by sustained protein hypercatabolism. The enhanced muscle protein degradation rates rely on the activity of different proteolytic systems, although the Adenosine triphosphate (ATP)-ubiquitin-proteasome-dependent pathway and autophagy have been shown to play a pivotal role. Bortezomib is a potent reversible and selective proteasome and NF-kappaB inhibitor approved for the clinical use, which has been shown to be effective in preventing muscle wasting in different catabolic conditions. The aim of the present study has been to investigate whether pharmacological inhibition of proteasome by bortezomib may prevent skeletal muscle wasting in experimental cancer cachexia. METHODS: Cancer cachexia was induced in rats by intraperitoneal injection of Yoshida AH-130 ascites hepatoma cells and in mice by subcutaneous inoculation of C26 carcinoma cells. Animals were then further randomized to receive bortezomib. The AH-130 hosts were weighted and sacrificed under anaesthesia, on Days 3, 4, 5, and 7 after tumour inoculation, while C26-bearing mice were weighted and sacrificed under anaesthesia 12 days after tumour transplantation. NF-kappaB and proteasome activation, MuRF1 and atrogin-1 mRNA expression and beclin-1 protein levels were evaluated in the gastrocnemius of controls and AH-130 hosts. RESULTS: Bortezomib administration in the AH-130 hosts, although able to reduce proteasome and NF kappaB DNA-binding activity in the skeletal muscle on Day 7 after tumour transplantation, did not prevent body weight loss and muscle wasting. In addition, bortezomib exerted a transient toxicity, as evidenced by the reduced food intake and by the increase in NF-kappaB DNA-binding activity in the AH-130 hosts 3 days after tumour transplantation. Beclin-1 protein levels were increased by bortezomib treatment in Day 3 controls but were unchanged on both Days 3 and 7 in the AH-130 hosts, suggesting that an early compensatory induction of autophagy may exist in healthy but not in tumour-bearing animals. Regarding C26-bearing mice, bortezomib did not prevent as well body and muscle weight loss 12 days after tumour implantation. CONCLUSIONS: The results obtained suggest that proteasome inhibition by bortezomib is not able to prevent muscle wasting in experimental cancer cachexia. Further studies are needed to address the issue whether a different dosage of bortezomib alone or in combination with other drugs modulating different molecular pathways may effectively prevent muscle wasting during cancer cachexia. PMID- 27239412 TI - Factors associated with skeletal muscle mass, sarcopenia, and sarcopenic obesity in older adults: a multi-continent study. AB - BACKGROUND: The aim of this study was to evaluate the factors associated with low skeletal muscle mass (SMM), sarcopenia, and sarcopenic obesity using nationally representative samples of people aged >=65 years from diverse geographical regions of the world. METHODS: Data were available for 18 363 people aged >=65 years who participated in the Collaborative Research on Ageing in Europe survey conducted in Finland, Poland, and Spain, and the World Health Organization Study on global AGEing and adult health survey conducted in China, Ghana, India, Mexico, Russia, and South Africa, between 2007 and 2012. A skeletal muscle mass index (SMI) was created to reflect SMM. SMM, SMI, and percent body fat (%BF) were calculated with specific indirect population formulas. These estimates were based on age, sex, weight, height, and race. Sarcopenia and sarcopenic obesity were defined with specific cut-offs. RESULTS: The prevalence of sarcopenia ranged from 12.6% (Poland) to 17.5% (India), and that of sarcopenic obesity ranged from 1.3% (India) to 11.0% (Spain). Higher %BF was associated with lower SMM in all countries, and with sarcopenia in five countries (p < 0.001). Compared to high levels of physical activity, low levels were related with higher odds for sarcopenia [OR 1.36 (95%CI 1.11-1.67)] and sarcopenic obesity [OR 1.80 (95%CI 1.23-2.64)] in the overall sample. Also, a dose-dependent association between higher numbers of chronic diseases and sarcopenic obesity was observed. CONCLUSIONS: Physical activity and body composition changes such as high %BF are key factors for the prevention of sarcopenia syndrome. PMID- 27239413 TI - Anti-sarcopenic effects of diamino-diphenyl sulfone observed in elderly female leprosy survivors: a cross-sectional study. AB - BACKGROUND: It has been reported that 4,4'-diamino-diphenyl sulfone (DDS), the longtime treatment of choice for leprosy, prolongs the lifespan and increases mobility in animal models by reducing the levels of reactive oxygen species and inhibiting muscle pyruvate kinase activity. This study aimed to investigate whether sarcopenic status in leprosy survivors was influenced by recent history of DDS medication. METHODS: Forty-one elderly female leprosy survivors were recruited. The DDS group was defined as survivors who had been taking the drug for the past year or more. Body composition measured by dual energy X-ray absorptiometry, limb muscle strength, short physical performance battery, and International Physical Activity Questionnaire in Korean were compared. RESULTS: The DDS group tended to have higher skeletal muscle mass index (24.4 +/- 2.7 vs. 22.6 +/- 2.2%, P = 0.066) and regional skeletal muscle mass index in non-dominant leg (8.9 +/- 1.0 vs. 7.9 +/- 0.9%, P = 0.018) than those of the control group although they had significantly worse leprosy disability than the control group (P = 0.027). The DDS group had greater strength than the control group in non dominant shoulder abductor, elbow flexor, hip flexor, and knee extensor (P = 0.005, P = 0.029, P = 0.021, and P = 0.002, respectively). Weekly walking amount was significantly longer (P = 0.020) in the DDS group than the control group. The total lifetime DDS exposure significantly correlated with skeletal muscle mass of the lower extremity in non-dominant leg (r = 0.379, P = 0.015). CONCLUSIONS: DDS taking leprosy survivors had larger skeletal muscle mass and greater muscle strength over non-taking survivors. There was a dose-response relationship between total lifetime DDS exposure and skeletal muscle mass of lower extremity. These findings might suggest potential anti-sarcopenic effects of DDS. PMID- 27239414 TI - Cancer cachexia causes skeletal muscle damage via transient receptor potential vanilloid 2-independent mechanisms, unlike muscular dystrophy. AB - BACKGROUND: Muscle wasting during cancer cachexia contributes to patient morbidity. Cachexia-induced muscle damage may be understood by comparing its symptoms with those of other skeletal muscle diseases, but currently available data are limited. METHODS: We modelled cancer cachexia in mice bearing Lewis lung carcinoma/colon adenocarcinoma and compared the associated muscle damage with that in a murine muscular dystrophy model (mdx mice). We measured biochemical and immunochemical parameters: amounts/localization of cytoskeletal proteins and/or Ca(2+) signalling proteins related to muscle function and abnormality. We analysed intracellular Ca(2+) mobilization and compared results between the two models. Involvement of Ca(2+)-permeable channel transient receptor potential vanilloid 2 (TRPV2) was examined by inoculating Lewis lung carcinoma cells into transgenic mice expressing dominant-negative TRPV2. RESULTS: Tumourigenesis caused loss of body and skeletal muscle weight and reduced muscle force and locomotor activity. Similar to mdx mice, cachexia muscles exhibited myolysis, reduced sarcolemmal sialic acid content, and enhanced lysosomal exocytosis and sarcolemmal localization of phosphorylated Ca(2+)/CaMKII. Abnormal autophagy and degradation of dystrophin also occurred. Unlike mdx muscles, cachexia muscles did not exhibit regeneration markers (centrally nucleated fibres), and levels of autophagic proteolytic pathway markers increased. While a slight accumulation of TRPV2 was observed in cachexia muscles, Ca(2+) influx via TRPV2 was not elevated in cachexia-associated myotubes, and the course of cachexia pathology was not ameliorated by dominant-negative inhibition of TRPV2. CONCLUSIONS: Thus, cancer cachexia may induce muscle damage through TRPV2-independent mechanisms distinct from those in muscular dystrophy; this may help treat patients with tumour induced muscle wasting. PMID- 27239415 TI - Doxorubicin caused severe hyperglycaemia and insulin resistance, mediated by inhibition in AMPk signalling in skeletal muscle. AB - BACKGROUND: Cancer is considered the second leading cause of death in the world, and for the treatment of this disease, pharmacological intervention strategies are frequently based on chemotherapy. Doxorubicin (DOX) is one of the most widely used chemotherapeutic agents in clinical practice for treating a number of solid tumours. The treatment with DOX mimics some effects of cancer cachexia, such as anorexia, asthenia, decreases in fat and skeletal muscle mass and fatigue. We observed that treatment with DOX increased the systemic insulin resistance and caused a massive increase in glucose levels in serum. Skeletal muscle is a major tissue responsible for glucose uptake, and the positive role of AMPk protein (AMP activated protein kinase) in GLUT-4 (Glucose Transporter type 4) translocation, is well established. With this, our aim was to assess the insulin sensitivity after treatment with DOX and involvement of AMPk signalling in skeletal muscle in this process. METHODS: We used Wistar rats which received a single dose of doxorubicin (DOX group) or saline (CT group) intraperitoneally at a dose of 15 mg/kg b.w. The expression of proteins involved in insulin sensitivity, glucose uptake, inflammation, and activity of electron transport chain was assessed in extensor digitorum longus muscle, as well as the histological evaluation. In vitro assays were performed in L6 myocytes to assess glucose uptake after treatment with DOX. Agonist of AMPk [5-aminoimidazole-4-carboxamide (AICAR)] and the antioxidant n-acetyl cysteine were used in L6 cells to evaluate its effect on glucose uptake and cell viability. RESULTS: The animals showed a significant insulin resistance, hyperglycaemia, and hyperinsulinemia. A decrease in the expression of AMKP and GLUT-4 was observed in the extensor digitorum longus muscle. Also in L6 cells, DOX leads to a decrease in glucose uptake, which is reversed with AICAR. CONCLUSIONS: DOX leads to conditions similar to cachexia, with severe glucose intolerance both in vivo and in vitro. The decrease of AMPk activity of the protein is modulated negatively with DOX, and treatment with agonist of AMPk (AICAR) has proved to be a possible therapeutic target, which is able to recover glucose sensitivity in skeletal muscle. PMID- 27239416 TI - Expression of protocadherin gamma in skeletal muscle tissue is associated with age and muscle weakness. AB - BACKGROUND: The skeletal muscle system plays an important role in the independence of older adults. In this study we examine differences in the skeletal muscle transcriptome between healthy young and older subjects and (pre )frail older adults. Additionally, we examine the effect of resistance-type exercise training on the muscle transcriptome in healthy older subjects and (pre )frail older adults. METHODS: Baseline transcriptome profiles were measured in muscle biopsies collected from 53 young, 73 healthy older subjects, and 61 frail older subjects. Follow-up samples from these frail older subjects (31 samples) and healthy older subjects (41 samples) were collected after 6 months of progressive resistance-type exercise training. Frail older subjects trained twice per week and the healthy older subjects trained three times per week. RESULTS: At baseline genes related to mitochondrial function and energy metabolism were differentially expressed between older and young subjects, as well as between healthy and frail older subjects. Three hundred seven genes were differentially expressed after training in both groups. Training affected expression levels of genes related to extracellular matrix, glucose metabolism ,and vascularization. Expression of genes that were modulated by exercise training was indicative of muscle strength at baseline. Genes that strongly correlated with strength belonged to the protocadherin gamma gene cluster (r = -0.73). CONCLUSIONS: Our data suggest significant remaining plasticity of ageing skeletal muscle to adapt to resistance-type exercise training. Some age-related changes in skeletal muscle gene expression appear to be partially reversed by prolonged resistance-type exercise training. The protocadherin gamma gene cluster may be related to muscle denervation and re-innervation in ageing muscle. PMID- 27239417 TI - Increased expression of H19/miR-675 is associated with a low fat-free mass index in patients with COPD. AB - BACKGROUND: Loss of muscle mass and strength is a significant comorbidity in patients with chronic obstructive pulmonary disease (COPD) that limits their quality of life and has prognostic implications but does not affect everyone equally. To identify mechanisms that may contribute to the susceptibility to a low muscle mass, we investigated microRNA (miRNA) expression, methylation status, and regeneration in quadriceps muscle from COPD patients and the effect of miRNAs on myoblast proliferation in vitro. The relationships of miRNA expression with muscle mass and strength was also determined in a group of healthy older men. METHODS: We identified miRNAs associated with a low fat-free mass (FFM) phenotype in a small group of patients with COPD using a PCR screen of 750 miRNAs. The expression of two differentially expressed miRNAs (miR-675 and miR-519a) was determined in an expanded group of COPD patients and their associations with FFM and strength identified. The association of these miRNAs with FFM and strength was also explored in a group of healthy community-dwelling older men. As the expression of the miRNAs associated with FFM could be regulated by methylation, the relative methylation of the H19 ICR was determined. Furthermore, the proportion of myofibres with centralized nuclei, as a marker of muscle regeneration, in the muscle of COPD patients was identified by immunofluorescence. RESULTS: Imprinted miRNAs (miR-675 and from a cluster, C19MC which includes miR-519a) were differentially expressed in the quadriceps of patients with a low fat-free mass index (FFMI) compared to those with a normal FFMI. In larger cohorts, miR-675 and its host gene (H19) were higher in patients with a low FFMI and strength. The association of miR-519a expression with FFMI was present in male patients with severe COPD. Similar associations of miR expression with lean mass and strength were not observed in healthy community dwelling older men participating in the Hertfordshire Sarcopenia Study. Relative methylation of the H19 ICR was reduced in COPD patients with muscle weakness but was not associated with FFM. In vitro, miR-675 inhibited myoblast proliferation and patients with a low FFMI had fewer centralized nuclei suggesting miR-675 represses regeneration. CONCLUSIONS: The data suggest that increased expression of miR-675/H19 and altered methylation of the H19 imprinting control region are associated with a low FFMI in patients with COPD but not in healthy community dwelling older men suggesting that epigenetic control of this loci may contribute to a susceptibility to a low FFMI. PMID- 27239418 TI - Dihydrotestosterone treatment rescues the decline in protein synthesis as a result of sarcopenia in isolated mouse skeletal muscle fibres. AB - BACKGROUND: Sarcopenia, the progressive decline in skeletal muscle mass and function with age, is a debilitating condition. It leads to inactivity, falls, and loss of independence. Despite this, its cause(s) and the underlying mechanism(s) are still poorly understood. METHODS: In this study, small skeletal muscle fibre bundles isolated from the extensor digitorum longus (a fast-twitch muscle) and the soleus (a slow-twitch muscle) of adult mice of different ages (range 100-900 days old) were used to investigate the effects of ageing and dihydrotestosterone (DHT) treatment on protein synthesis as well as the expression and function of two amino acid transporters; the sodium-coupled neutral amino acid transporter (SNAT) 2, and the sodium-independent L-type amino acid transporter (LAT) 2. RESULTS: At all ages investigated, protein synthesis was always higher in the slow-twitch than in the fast-twitch muscle fibres and decreased with age in both fibre types. However, the decline was greater in the fast-twitch than in the slow-twitch fibres and was accompanied by a reduction in the expression of SNAT2 and LAT2 at the protein level. Again, the decrease in the expression of the amino acid transporters was greater in the fast-twitch than in the slow-twitch fibres. In contrast, ageing had no effect on SNAT2 and LAT2 expressions at the mRNA level. Treating the muscle fibre bundles with physiological concentrations (~2 nM) of DHT for 1 h completely reversed the effects of ageing on protein synthesis and the expression of SNAT2 and LAT2 protein in both fibre types. CONCLUSION: From the observations that ageing is accompanied by a reduction in protein synthesis and transporter expression and that these effects are reversed by DHT treatment, we conclude that sarcopenia arises from an age-dependent reduction in protein synthesis caused, in part, by the lack of or by the low bioavailability of the male sex steroid, DHT. PMID- 27239419 TI - Megestrol acetate improves cardiac function in a model of cancer cachexia-induced cardiomyopathy by autophagic modulation. AB - BACKGROUND: Cachexia is a complex metabolic syndrome associated with cancer. One of the features of cachexia is the loss of muscle mass, characterized by an imbalance between protein synthesis and protein degradation. Muscle atrophy is caused by the hyperactivation of some of the main cellular catabolic pathways, including autophagy. Cachexia also affects the cardiac muscle. As a consequence of the atrophy of the heart, cardiac function is impaired and mortality is increased. Anti-cachectic therapy in patients with cancer cachexia is so far limited to nutritional support and anabolic steroids. The use of the appetite stimulant megestrol acetate (MA) has been discussed as a treatment for cachexia. METHODS: In this study the effects of MA were tested in cachectic tumour-bearing rats (Yoshida AH-130 ascites hepatoma). Rats were treated daily with 100 mg/kg of MA or placebo starting one day after tumour inoculation, and for a period of 16 days. Body weight and body composition were assessed at baseline and at the end of the study. Cardiac function was analysed by echocardiography at baseline and at day 11. Locomotor activity and food intake were assessed before tumour inoculation and at day 11. Autophagic markers were assessed in gastrocnemius muscle and heart by western blot analysis. RESULTS: Treatment with 100 mg/kg/day MA significantly attenuated the loss of body weight (-9 +/- 12%, P < 0.05) and the wasting of lean and fat mass (-7.0 +/- 6% and -22.4 +/- 3 %, P < 0.001 and P < 0.05, respectively). Administration of 100 mg/kg/day MA significantly protected the heart from general atrophy (633.8 +/- 30 mg vs. placebo 474 +/- 13 mg, P < 0.001). Tumour-bearing rats displayed cardiac dysfunction, as indicated by the significant impairment of the left ventricular ejection fraction, the left ventricular fractional shortening, the stroke volume, the end dyastolic volume, and the end systolic volume. In contrast, MA significantly improved left ventricular ejection fraction, left ventricular fractional shortening, and left ventricular end systolic volume. Western blotting analysis showed an upregulation of the autophagic pathway in the gastrocnemius and hearts of the placebo-treated tumour-bearing rats. Treatment with MA, however, was able to modulate the autophagic markers (e.g. Beclin-1, p62, TRAF6, and LC3) in the gastrocnemius and in the hearts of tumour-bearing rats. Most importantly, 100 mg/kg/day MA reduced mortality [hazard ratio (HR): 0.44; 95%CI: 0.20-1.00; P = 0.0486]. CONCLUSIONS: Megestrol acetate improved survival and reduced wasting through a marked downregulation of autophagy, occurring in both skeletal and heart muscle, the latter effect leading to a significant improvement of cardiac function. Our data suggest that MA might represent a valuable strategy to counteract the development of cancer cachexia-induced cardiomyopathy. PMID- 27239420 TI - Docosahexaenoic acid-supplementation prior to fasting prevents muscle atrophy in mice. AB - BACKGROUND: Muscle wasting prevails in numerous diseases (e.g. diabetes, cardiovascular and kidney diseases, COPD,...) and increases healthcare costs. A major clinical issue is to devise new strategies preventing muscle wasting. We hypothesized that 8-week docosahexaenoic acid (DHA) supplementation prior to fasting may preserve muscle mass in vivo. METHODS: Six-week-old C57BL/6 mice were fed a DHA-enriched or a control diet for 8 weeks and then fasted for 48 h. RESULTS: Feeding mice a DHA-enriched diet prior to fasting elevated muscle glycogen contents, reduced muscle wasting, blocked the 55% decrease in Akt phosphorylation, and reduced by 30-40% the activation of AMPK, ubiquitination, or autophagy. The DHA-enriched diet fully abolished the fasting induced-messenger RNA (mRNA) over-expression of the endocannabinoid receptor-1. Finally, DHA prevented or modulated the fasting-dependent increase in muscle mRNA levels for Rab18, PLD1, and perilipins, which determine the formation and fate of lipid droplets, in parallel with muscle sparing. CONCLUSIONS: These data suggest that 8 week DHA supplementation increased energy stores that can be efficiently mobilized, and thus preserved muscle mass in response to fasting through the regulation of Akt- and AMPK-dependent signalling pathways for reducing proteolysis activation. Whether a nutritional strategy aiming at increasing energy status may shorten recovery periods in clinical settings remains to be tested. PMID- 27239421 TI - Eating-related distress and need for nutritional support of families of advanced cancer patients: a nationwide survey of bereaved family members. AB - BACKGROUND: A number of advanced cancer patients are suffering from physical and psychosocial burdens because of cancer cachexia, and these burdens also greatly impact on their family members and relationships between patients and family members. It is necessary to consider the psychosocial impact of cancer cachexia on family members of advanced cancer patients. METHODS: A cross-sectional anonymous nationwide survey was conducted involving 925 bereaved family members of cancer patients who had been admitted to 133 inpatient hospices throughout Japan. RESULTS: A total of 702 bereaved family members returned the questionnaires (response rate, 75.9%). Concerning eating-related distress, 'I served what the patient wanted without consideration of calories and nutritional composition' was highest (75.1%), and 'I tried making many kinds of meals for the patient' and 'I was concerned about planning meals for the patient every day' followed (63.0% and 59.4%, respectively). The top 5 of the 19 items were categorized as 'fighting back'. Need for nutritional support was high (72.2%), and need for explanations about the reasons for anorexia and weight loss of patients was moderate (41.4%). Explanatory factor analysis of eating-related distress identified the following four domains: (factor 1) feeling that family members forced the patient to eat to avoid death, (factor 2) feeling that family members made great efforts to help the patient eat, (factor 3) feeling that eating was a cause of conflicts between the patient and family members, and (factor 4) feeling that correct information was insufficient. Results of multiple logistic regression analysis showed that spouse, fair/poor mental status, factors 1, and 4 were identified as independent determinants of major depression {odds ratio [OR] 3.27 [95% confidence interval (CI) 1.24-8.60], P = 0.02; OR 4.50 [95% CI 2.46-8.25], P < 0.001; OR 2.51 [95% CI 1.16-5.45], P = 0.02; OR 2.33 [95% CI 1.13-4.80], P = 0.02, respectively}. CONCLUSIONS: A number of family members of advanced cancer patients experienced high levels of eating-related distress and had a need for nutritional support. PMID- 27239422 TI - Cachexia research in Japan: facts and numbers on prevalence, incidence and clinical impact. AB - Even though most clinical data on cachexia have been reported from Western countries, cachexia may be a growing problem in Asia as well, as the population in this area of the world is considerably larger. Considering the current definitions of obesity and sarcopenia in Japan, which are different from the ones in Western countries, the lack of a distinct cachexia definition in Japan is strinking. Only one epidemiological study has reported the prevalence of cachexia using weight loss as part of the definition in patients with stage III or IV non small cell lung cancer. Although the reported prevalence of 45.6% is within the range of that in Western countries (28-57% in advanced cancer), we cannot compare the prevalence of cachexia in other types of cancer, heart failure, chronic obstructive pulmonary disease (COPD), and kidney disease (CKD) between Japan and Western countries. In patients with heart failure, one third of Japanese patients has a body mass index <20.3 kg/m2 whereas the prevalence of underweight is 13.6% in reports from Western countries. These results may suggest that there are more cachectic heart failure patients in Japan, or that using the same definition like Western countries leads to gross overestimation of the prevalence of cachexia in Japan. The rate of underweight patients in COPD has been reported as 31-41% in COPD and seems to be high in comparison to the prevalence of cachexia in Western countries (27-35%). The reported lowest quartile value of BMI (19.6 kg/m2) in CKD may match with the prevalence of cachexia in Western countries (30-60%). The number of clinical trials targeting cachexia is very limited in Japan so far. PMID- 27239423 TI - Impact of creatine supplementation in combination with resistance training on lean mass in the elderly. AB - BACKGROUND: Human ageing is a process characterized by loss of muscle mass, strength, and bone mass. We aimed to examine the efficacy of low-dose creatine supplementation associated with resistance training on lean mass, strength, and bone mass in the elderly. METHODS: This was a 12-week, parallel-group, double blind, randomized, placebo-controlled trial. The individuals were randomly allocated into one of the following groups: placebo plus resistance training (PL + RT) and creatine supplementation plus resistance training (CR + RT) . The participants were assessed at baseline and after 12 weeks. The primary outcomes were lean mass and strength, assessed by dual energy X-ray absorptiometry (DXA) and ten-repetition maximal tests (10 RM), respectively. Secondary outcomes included the lumbar spine, right and left femoral neck, both femur and whole body bone mineral density (BMD), and whole body bone mineral content (BMC), assessed by DXA. RESULTS: The CR + RT group had superior gains in lean mass when compared with the PL + RT group (P = 0.02). Changes in the 10 RM tests in bench press and leg press exercises, body composition, BMD, and BMC of all assessed sites did not significantly differ between the groups (P > 0.05). CONCLUSIONS: Twelve weeks of low-dose creatine supplementation associated with resistance training resulted in increases in lean mass in the elderly. PMID- 27239424 TI - Malnutrition and sarcopenia predict post-liver transplantation outcomes independently of the Model for End-stage Liver Disease score. AB - BACKGROUND: Although malnutrition and sarcopenia are prevalent in cirrhosis, their impact on outcomes following liver transplantation is not well documented. METHODS: The associations of nutritional status and sarcopenia with post transplant infections, requirement for mechanical ventilation, intensive care (ICU) and hospital stay, and 1 year mortality were assessed in 232 consecutive transplant recipients. Nutritional status and sarcopenia were assessed using the Royal Free Hospital-Global Assessment (RFH-GA) tool and the L3-psoas muscle index (L3-PMI) on CT, respectively. RESULTS: A wide range of RFH-SGA and L3-PMI were observed within similar Model for End-stage Liver Disease (MELD) sub-categories. Malnutrition and sarcopenia were independent predictors of all outcomes. Post transplant infections were associated with MELD (OR = 1.055, 95%CI = 1.002-1.11) and severe malnutrition (OR = 6.55, 95%CI = 1.99-21.5); ventilation > 24 h with MELD (OR = 1.1, 95%CI = 1.036-1.168), severe malnutrition (OR = 8.5, 95%CI = 1.48 48.87) and suboptimal donor liver (OR = 2.326, 95%CI = 1.056-5.12); ICU stay > 5 days, with age (OR = 1.054, 95%CI = 1.004-1.106), MELD (OR = 1.137, 95%CI = 1.057 1.223) and severe malnutrition (OR = 7.46, 95%CI = 1.57-35.43); hospital stay > 20 days with male sex (OR = 2.107, 95%CI = 1.004-4.419) and L3-PMI (OR = 0.996, 95%CI = 0.994-0.999); 1 year mortality with L3-PMI (OR = 0.996, 95%CI = 0.992 0.999). Patients at the lowest L3-PMI receiving suboptimal grafts had longer ICU/hospital stay and higher incidence of infections. CONCLUSIONS: Malnutrition and sarcopenia are associated with early post-liver transplant morbidity/mortality. Allocation indices do not include nutritional status and may jeopardize outcomes in nutritionally compromised individuals. PMID- 27239425 TI - Skeletal muscle satellite cells are located at a closer proximity to capillaries in healthy young compared with older men. AB - BACKGROUND: Skeletal muscle satellite cells (SC) are instrumental in maintenance of muscle fibres, the adaptive responses to exercise, and there is an age-related decline in SC. A spatial relationship exists between SC and muscle fibre capillaries. In the present study, we aimed to investigate whether chronologic age has an impact on the spatial relationship between SC and muscle fibre capillaries. Secondly, we determined whether this spatial relationship changes in response to a single session of resistance exercise. METHODS: Muscle biopsies were obtained from the vastus lateralis of previously untrained young men (YM, 24 +/- 3 years; n = 23) and older men (OM, 67 +/- 4 years; n = 22) at rest. A subset of YM (n = 9) performed a single bout of resistance exercise, where additional muscle biopsies taken at 24 and 72 h post-exercise recovery. Skeletal muscle fibre capillarization, SC content, and activation status were assessed using immunofluorescent microscopy of muscle cross sections. RESULTS: Type II muscle fibre SC and capillary content was significantly lower in the YM compared with OM (P < 0.05). Furthermore, type II muscle fibre SC were located at a greater distance from the nearest capillary in OM compared with YM (21.6 +/- 1.3 vs. 17.0 +/- 0.8 um, respectively; P < 0.05). In response to a single bout of exercise, we observed a significant increase in SC number and activation status (P < 0.05). In addition, activated vs. quiescent SC were situated closer (P < 0.05) to capillaries. CONCLUSIONS: We demonstrate that there is a greater distance between capillaries and type II fibre-associated SC in OM as compared with YM. Furthermore, quiescent SC are located significantly further away from capillaries than active SC after single bout of exercise. Our data have implications for how muscle adapts to exercise and how aging may affect such adaptations. PMID- 27239426 TI - Improvement of skeletal muscle performance in ageing by the metabolic modulator Trimetazidine. AB - BACKGROUND: The loss of muscle mass (sarcopenia) and the associated reduced muscle strength are key limiting factors for elderly people's quality of life. Improving muscle performance does not necessarily correlate with increasing muscle mass. In fact, particularly in the elderly, the main explanation for muscle weakness is a reduction of muscle quality rather than a loss of muscle mass, and the main goal to be achieved is to increase muscle strength. The effectiveness of Trimetazidine (TMZ) in preventing muscle functional impairment during ageing was assessed in our laboratory. METHODS: Aged mice received TMZ or vehicle for 12 consecutive days. Muscle function was evaluated at the end of the treatment by a grip test as well as by an inverted screen test at 0, 5, 7 and 12 days of TMZ treatment. After sacrifice, muscles were stored for myofiber cross sectional area assessment and myosin heavy chain expression evaluation by western blotting. RESULTS: Chronic TMZ treatment does not affect the mass of both gastrocnemius and tibialis anterior muscles, while it significantly increases muscle strength. Indeed, both latency to fall and grip force are markedly enhanced in TMZ-treated versus untreated mice. In addition, TMZ administration results in higher expression of slow myosin heavy chain isoform and increased number of small-sized myofibers. CONCLUSIONS: We report here some data showing that the modulation of skeletal muscle metabolism by TMZ increases muscle strength in aged mice. Reprogramming metabolism might therefore be a strategy worth to be further investigated in view of improving muscle performance in the elderly. PMID- 27239428 TI - S2k guideline on diagnosis and treatment of atopic dermatitis - short version. AB - Atopic dermatitis (AD) represents a pruritic, non-contagious, chronic or chronically relapsing, inflammatory skin disease. The course of the disease may be complicated by bacterial or viral superinfections. The first manifestation of the disease and further flare-ups are due to genetic predisposition and also to a variety of further trigger factors. The therapy regimen should be adapted to disease symptoms that are actually present and consider individual features of the disease as reported by the patients or their parents. This short version of the German guideline on AD provides an overview of evidence-based diagnostic and treatment options. All recommendations made here are the result of a consensus of the scientific medical societies, working groups and support groups based on scientific data published to date. Abstracts and details of the studies cited are provided in the long version of this guideline (see: www.awmf.org). PMID- 27239429 TI - MicROS-drt: supporting real-time and scalable data distribution in distributed robotic systems. AB - A primary requirement in distributed robotic software systems is the dissemination of data to all interested collaborative entities in a timely and scalable manner. However, providing such a service in a highly dynamic and resource-limited robotic environment is a challenging task, and existing robot software infrastructure has limitations in this aspect. This paper presents a novel robot software infrastructure, micROS-drt, which supports real-time and scalable data distribution. The solution is based on a loosely coupled data publish-subscribe model with the ability to support various time-related constraints. And to realize this model, a mature data distribution standard, the data distribution service for real-time systems (DDS), is adopted as the foundation of the transport layer of this software infrastructure. By elaborately adapting and encapsulating the capability of the underlying DDS middleware, micROS-drt can meet the requirement of real-time and scalable data distribution in distributed robotic systems. Evaluation results in terms of scalability, latency jitter and transport priority as well as the experiment on real robots validate the effectiveness of this work. PMID- 27239427 TI - Health Impacts of the Great Recession: A Critical Review. AB - The severity, sudden onset, and multipronged nature of the Great Recession (2007 2009) provided a unique opportunity to examine the health impacts of macroeconomic downturn. We comprehensively review empirical literature examining the relationship between the Recession and mental and physical health outcomes in developed nations. Overall, studies reported detrimental impacts of the Recession on health, particularly mental health. Macro- and individual-level employment- and housing-related sequelae of the Recession were associated with declining fertility and self-rated health, and increasing morbidity, psychological distress, and suicide, although traffic fatalities and population-level alcohol consumption declined. Health impacts were stronger among men and racial/ethnic minorities. Importantly, strong social safety nets in some European countries appear to have buffered those populations from negative health effects. This literature, however, still faces multiple methodological challenges, and more time may be needed to observe the Recession's full health impact. We conclude with suggestions for future work in this field. PMID- 27239430 TI - Prevalence and Impact of Anemia on Basic Trainees in the US Air Force. AB - BACKGROUND: Anemia has been implicated in adverse health outcomes of athletes and military trainees, ranging from overuse injuries to degraded physical and cognitive performance. The purpose of this study was to investigate prevalence of anemia among US Air Force (USAF) basic trainees, to compare physical performance and discharge rates between anemic and non-anemic trainees, and to determine the risks and relative risks of being discharged for anemic versus non-anemic women and men. METHODS: All USAF basic trainees were screened for anemia between July 2013 and January 2014, during an 8-week basic training course at Joint Base San Antonio-Lackland, TX. Age, sex, screening hemoglobin, anthropometric measurements, initial/final physical fitness assessment scores, and discharge data were collected from trainees. Those identified as anemic (hemoglobin <13.5 g/dL for males and <12.0 g/dL for females) received additional labwork, nutritional counseling, and oral iron-replacement, if indicated. Mean percent improvement was calculated for all performance parameters from beginning to end of training. Anemic trainees were compared to non-anemic trainees by t test with Welch modification. Results were stratified by sex and anemia severity with post hoc Bonferroni correction. RESULTS: Prevalence of anemia was 12.6 % (N = 18,827). Respective prevalence of borderline, moderate, and severe anemia was 12.6, 10.9, and 1.9 % for females and 4.8, 3.8, and 0.3 % for males. Mean 1.5-mile run-time, push-up and sit-up counts improved from beginning to end of training for both anemic and non-anemic trainees (p < 0.001 both). Non-anemic trainees had slightly greater run-time improvements than borderline and moderate anemics (female: 17.7 vs. 15.2, and 15.1 % improvement, p < 0.05 both; male: 14.9 vs. 13.2, and 13.5 % improvement, p < 0.05 both). One-way ANOVA demonstrated statistically significant differences between initial and final fitness data for all measures and both genders (p < 0.001) with the exception of final sit-up counts for male trainees (p = 0.082). Discharge rate for anemic trainees was 9.0 % (20 % for severely anemic trainees) as compared to 5.7 % for non-anemics. CONCLUSIONS: Anemia was prevalent among USAF basic trainees. Identification and treatment of anemia may optimize physical performance and decrease the rate of medical discharge. PMID- 27239431 TI - Semaphorin 3A promotes activation of Pax7, Myf5, and MyoD through inhibition of emerin expression in activated satellite cells. AB - We previously showed that Semaphorin 3A (Sema3A) expression was induced when quiescent muscle satellite cells were stimulated by hepatocyte growth factor and became activated satellite cells (ASCs). However, how Sema3A regulates genes in the early phase of ASCs remains unclear. In this study, we investigated whether Sema3A signaling can regulate the early phase of ASCs, an important satellite cell stage for postnatal growth, repair, and maintenance of skeletal muscle. We showed that expression of the myogenic proliferation regulatory factors Pax7 and Myf5 was decreased in myoblasts transfected with Sema3A siRNA. These cells failed to activate expression MyoD, another myogenic proliferation regulatory factor, during differentiation. Interestingly, some of the Sema3A-depleted cells did not express Pax7 and MyoD and had enlarged nuclei and very large cytoplasmic areas. We also observed that Pax7 and Myf5 expression was increased in Myc-Sema3A overexpressing myoblasts. BrdU analysis indicated that Sema3A regulated proliferation of ASCs. These findings suggest that Sema3A signaling can modulate expression of Pax7, Myf5, and MyoD. Moreover, we found that expression of emerin, an inner nuclear membrane protein, was regulated by Sema3A signaling. Emerin was identified by positional cloning as the gene responsible for the X-linked form of Emery-Dreifuss muscular dystrophy (X-EDMD). In conclusion, our results support a role for Sema3A in maintaining ASCs through regulation, via emerin, of Pax7, Myf5, and MyoD expression. PMID- 27239432 TI - Combination of 5-aminolevulinic acid and ferrous ion reduces plasma glucose and hemoglobin A1c levels in Zucker diabetic fatty rats. AB - Mitochondrial dysfunction is associated with type 2 diabetes mellitus (T2DM). 5 Aminolevulinic acid (ALA), a natural amino acid produced only in the mitochondria, is a precursor of heme. Cytochromes that contain heme play an important role in aerobic energy metabolism. Thus, ALA may help reduce T2DM associated hyperglycemia. In this study, we investigated the effect of ALA combined with sodium ferrous citrate (SFC) on hyperglycemia in Zucker diabetic fatty (ZDF) rats. We found that the gavage administration of ALA combined with SFC (ALA/SFC) for 6 weeks reduced plasma glucose and hemoglobin A1c (HbA1c) levels in rats without affecting plasma insulin levels. The glucose-lowering effect depended on the amount of ALA/SFC administered per day. Furthermore, the glucose tolerance was also significantly improved by ALA/SFC administration. Although food intake was slightly reduced in the rats administered ALA/SFC, there was no effect on their body weight. Importantly, ALA/SFC administration induced heme oxygenase-1 (HO-1) expression in white adipose tissue and liver, and the induced expression levels of HO-1 correlated with the glucose-lowering effects of ALA/SFC. Taken together, these results suggest that ALA combined with ferrous ion is effective in reducing hyperglycemia of T2DM without affecting plasma insulin levels. HO-1 induction may be involved in the mechanisms underlying the glucose lowering effect of ALA/SFC. PMID- 27239433 TI - In vivo fluorescence correlation spectroscopy analyses of FMBP-1, a silkworm transcription factor. AB - Fibroin modulator-binding protein 1 (FMBP-1) is a silkworm transcription factor that has a unique DNA-binding domain called the one score and three amino acid peptide repeat (STPR). Here we used fluorescence correlation spectroscopy (FCS) to analyze the diffusion properties of an enhanced green fluorescent protein tagged FMBP-1 protein (EGFP-FMBP-1) expressed in posterior silk gland (PSG) cells of Bombyx mori at the same developmental stage as natural FMBP-1 expression. EGFP FMBP-1 clearly localized to cell nuclei. From the FCS analyses, we identified an immobile DNA-bound component and three discernible diffusion components. We also used FCS to observe the movements of wild-type and mutant EGFP-FMBP-1 proteins in HeLa cells, a simpler experimental system. Based on previous in vitro observation, we also introduced a single amino acid substitution in order to suppress stable FMBP-1-DNA binding; specifically, we replaced the ninth Arg in the third repeat within the STPR domain with Ala. This mutation completely disrupted the slowest diffusion component as well as the immobile component. The diffusion properties of other FMBP-1 mutants (e.g. mutants with N-terminal or C terminal truncations) were also analyzed. Based on our observations, we suggest that the four identifiable movements might correspond to four distinct FMBP-1 states: (a) diffusion of free protein, (b) and PMID- 27239434 TI - Mutational probing of protein aggregates to design aggregation-resistant proteins. AB - Characterization of amorphous protein aggregates may offer insights into the process of aggregation. Eleven single amino acid mutants of lipase (LipA of Bacillus subtilis) were subjected to temperature-induced aggregation, and the resultant aggregates were characterized for recovery of activity in the presence of guanidinium chloride (GdmCl). Based on activity recovery profiles of the aggregates, the mutants could be broadly assigned into four groups. By including at least one mutation from each group, a mutant was generated that showed an increase of ~ 10 degrees C in melting temperature (T m) compared to the wild type and did not aggregate even at 75 degrees C. This method explores characterization of amorphous protein aggregates in the presence of GdmCl and helps in identifying mutations involved in protein aggregation. PMID- 27239435 TI - Genetic engineering of AtAOX1a in Saccharomyces cerevisiae prevents oxidative damage and maintains redox homeostasis. AB - This study aimed to validate the physiological importance of Arabidopsis thaliana alternative oxidase 1a (AtAOX1a) in alleviating oxidative stress using Saccharomyces cerevisiae as a model organism. The AOX1a transformant (pYES2AtAOX1a) showed cyanide resistant and salicylhydroxamic acid (SHAM) sensitive respiration, indicating functional expression of AtAOX1a in S. cerevisiae. After exposure to oxidative stress, pYES2AtAOX1a showed better survival and a decrease in reactive oxygen species (ROS) when compared to S. cerevisiae with empty vector (pYES2). Furthermore, pYES2AtAOX1a sustained growth by regulating GPX2 and/or TSA2, and cellular NAD (+)/NADH ratio. Thus, the expression of AtAOX1a in S. cerevisiae enhances its respiratory tolerance which, in turn, maintains cellular redox homeostasis and protects from oxidative damage. PMID- 27239436 TI - Clinical significance of long noncoding RNA SPRY4-IT1 in melanoma patients. AB - Long noncoding RNA SPRY4-IT1 has been reported to promote melanoma cell growth and invasion, and to block apoptosis. The purpose of this study was to investigate the clinical significance of SPRY4-IT1 in patients with malignant melanoma. The relative expression levels of SPRY4-IT1 were measured in plasma samples from 70 patients and 79 healthy controls by quantitative reverse transcriptase polymerase chain reaction. SPRY4-IT1 expression is high in melanoma patients but low in healthy controls, and is closely associated with tumor site and tumor stage. Elevated SPRY4-IT1 significantly reduces overall survival rates of patients and is considered as an independent prognostic factor in patients with melanoma. The prognostic nomogram shows a good prediction of the probability of 5-year overall survival of patients with melanoma (c-index: 0.72). The calibration curve for the probability of survival presents good agreement between actual outcomes and predictive consequences. In summary, SPRY4-IT1 may be a potential prognostic marker and a potential therapeutic target. PMID- 27239437 TI - microRNA-497 inhibits cell proliferation and induces apoptosis by targeting YAP1 in human hepatocellular carcinoma. AB - microRNAs (miRNAs) function as oncogenes or tumor suppressors in human cancers by targeting mRNAs for degradation and/or translational repression. miR-497 has been proposed as a tumor suppressive miRNA and its deregulation is observed in human cancers. However, the prognostic value of miR-497 and its underlying molecular pathways involved in the initiation and development of hepatocellular carcinoma (HCC) are poorly investigated. In the present study, we found that the mean level of miR-497 in HCC tissues was lower than that in adjacent nontumor tissues. Clinical data indicated that low expression of miR-497 was prominently associated with adverse prognostic features of HCC including high serum alpha-fetoprotein (AFP) level, large tumor size, high Edmondson-Steiner grading and advanced tumor node-metastasis (TNM) stage. Furthermore, miR-497 was an independent prognostic factor for indicating both 5-year overall survival and disease-free survival of HCC patients. Gain- and loss-of-function studies showed that miR-497 reduced cell proliferation and induced apoptosis in HCC cells. Yes-associated protein 1 (YAP1) was identified as a direct target of miR-497 in HCC. An inverse correlation between YAP1 and miR-497 expression was observed in HCC tissues. Notably, YAP1 knockdown abrogated the effects of miR-497 deletion on HCC cells with decreased cell proliferation and increased apoptosis. In conclusion, we report that miR-497 is a potent prognostic indicator and may suppress tumor growth of HCC by targeting YAP1. PMID- 27239438 TI - A targeted DNA substrate mechanism for the inhibition of HIV-1 integrase by inhibitors with antiretroviral activity. AB - We recently reported that viral DNA could be the primary target of raltegravir (RAL), an efficient anti-HIV-1 drug, which acts by inhibiting integrase. To elucidate this mechanism, we conducted a comparative analysis of RAL and TB11, a diketoacid abandoned as an anti-HIV-1 drug for its weak efficiency and marked toxicity, and tested the effects of the catalytic cofactor Mg(2+) (5 mm) on drug binding properties. We used circular dichroism and fluorescence to determine drug affinities for viral DNA long terminal repeats (LTRs) and peptides derived from the integrase active site and DNA retardation assays to assess drug intercalation into DNA base pairs. We found that RAL bound more tightly to LTR ends than did TB11 (a diketo acid bearing an azido group) and that Mg(2+) significantly increased the affinity of both RAL and TB11. We also observed a good relationship between drug binding with processed LTR and strand transfer inhibition. This unusual type of inhibition was caused by Mg(2+)-assisted binding of drugs to DNA substrate, rather than to enzyme. Notably, while RAL bound exclusively to the cleavable/cleaved site, TB11 further intercalated into DNA base pairs and interacted with the integrase-derived peptides. These unwanted binding sites explain the weaker bioavailability and higher toxicity of TB11 compared with the more effective RAL. PMID- 27239439 TI - miRNA expression profiling of Epstein-Barr virus-associated NKTL cell lines by Illumina deep sequencing. AB - The aim of this work was to establish the microRNA profile of SNK6 and SNT16, two Epstein-Barr virus (EBV)-infected cell lines derived from nasal NK/T-cell lymphoma (NKTL). The oncogenic EBV is strongly associated with the pathogenesis of nasal and extranodal NK/T-cell lymphoma and expresses 44 mature microRNAs and two noncoding EBV-encoded RNAs (EBERs). miRNAs are 19-25nt noncoding RNAs that affect host and viral gene expression post-transcriptionally. Deregulated miRNA patterns are frequently linked to a variety of human cancers including lymphomas. miRNA profiling of the two NK/T cell lines vs. primary cells revealed 10 and 4 up regulated and 10 and 12 down-regulated miRNAs in SNK6 and SNT16 cells respectively. The results were validated by qRT-PCR for selected miRNAs. Target gene analyses confirmed cullin 5 (CUL5) and sphingosin-1-phosphate receptor 1 (S1PR1) as targets for the down-regulated hsa-miR-148a and viral ebv-miR-BART16 respectively. As recently demonstrated for the regulation of IL1-alpha by miR-142 3p, coexpression of the EBERs selectively exerted corepression of S1PR1 by BART16 but not of CUL5 by miR-148a, indicating selective corepression by the EBERs. PMID- 27239440 TI - Reconstruction and applications of consensus yeast metabolic network based on RNA sequencing. AB - One practical application of genome-scale metabolic reconstructions is to interrogate multispecies relationships. Here, we report a consensus metabolic model in four yeast species (Saccharomyces cerevisiae, S. paradoxus, S. mikatae, and S. bayanus) by integrating metabolic network simulations with RNA sequencing (RNA-seq) datasets. We generated high-resolution transcriptome maps of four yeast species through de novo assembly and genome-guided approaches. The transcriptomes were annotated and applied to build the consensus metabolic network, which was verified using independent RNA-seq experiments. The expression profiles reveal that the genes involved in amino acid and lipid metabolism are highly coexpressed. The diverse phenotypic characteristics, such as cellular growth and gene deletions, can be simulated using the metabolic model. We also explored the applications of the consensus model in metabolic engineering using yeast-specific reactions and biofuel production as examples. Similar strategies will benefit communities studying genome-scale metabolic networks of other organisms. PMID- 27239441 TI - Sexually dimorphic expression of Dmrt1 and gammaH2AX in germ stem cells during gonadal development in Xenopus laevis. AB - In many animals, primordial germ cells (PGCs) migrate into developing gonads. There, they proliferate and differentiate into female and male germ stem cells (GSCs), oogonia and spermatogonia, respectively. Few studies have focused on the molecular mechanisms underlying the development of GSC sex determination. Here, we investigated the expression of the transcription factor Dmrt1 and a phosphorylated form of the histone variant H2AX (gammaH2AX) during gonadal development in Xenopus laevis. During early sexual differentiation, Dmrt1 was expressed in the GSCs of the ZW (female) and ZZ (male) gonads as well as somatic cells of the ZZ gonads. Notably, the PGCs and primary GSCs contained large, unstructured nuclei, whereas condensed, rounder nuclei appeared only in primary oogonia during tadpole development. After metamorphosis, Dmrt1 showed its expression in secondary spermatogonia, but not in secondary oogonia. Like Dmrt1, gammaH2AX was expressed in the nuclei of primary GSCs in early developing gonads. However, after metamorphosis, gammaH2AX expression continued in primary and secondary spermatogonia, but was barely detected in the condensed nuclei of primary oogonia. Taken together, these observations indicate that spermatogonia tend to retain PGC characteristics, compared to oogonia, which undergo substantial changes during gonadal differentiation in X. laevis. Our findings suggest that Dmrt1 and gammaH2AX may contribute to the maintenance of stem cell identity by controlling gene expression and epigenetic changes, respectively. PMID- 27239442 TI - Chimerism in piglets developed from aggregated cloned embryos. AB - Porcine chimeras are valuable in the study of pluripotency, embryogenesis and development. It would be meaningful to generate chimeric piglets from somatic cell nuclear transfer embryos. In this study, two cell lines expressing the fluorescent markers enhanced green fluorescent protein (EGFP) and tdTomato were used as donor cells to produce reconstructed embryos. Chimeric embryos were generated by aggregating two EGFP-cell derived embryos with two tdTomato-cell derived embryos at the 4-cell stage, and embryo transfer was performed when the aggregated embryos developed into blastocysts. Live porcine chimeras were successfully born and chimerism was observed by their skin color, gene integration, microsatellite loci composition and fluorescent protein expression. The chimeric piglets were largely composed of EGFP-expressing cells, and this phenomenon was possibly due to the hyper-methylation of the promoter of the tdTomato gene. In addition, the expression levels of tumorigenicity-related genes were altered after tdTomato transfection in bladder cancer cells. The results show that chimeric pigs can be produced by aggregating cloned embryos and that the developmental capability of the cloned embryo in the subsequent chimeric development could be affected by the growth characteristics of its donor cell. PMID- 27239444 TI - mTOR inhibition by rapamycin increases ceramide synthesis by promoting transforming growth factor-beta1/Smad signaling in the skin. AB - Although mammalian target of rapamycin (mTOR) mediates a wide variety of biological functions, little information is available on the effect of mTOR on the functions of skin cells. In this study, we investigated effects of mTOR inhibition by rapamycin on ceramide synthesis in the skin of rats and human keratinocytes and its regulatory mechanisms. The phosphorylation of p70 S6 kinase, which indicates mTOR activation, was induced in the skin of rats fed a high-fat diet, but this abnormality was reversed by supplementation with rapamycin. Ceramide levels and the mRNA levels of serine palmitoyltransferase (SPT) and transforming growth factor (TGF)-beta1 were suppressed in the skin of rats fed high-fat diets, but this abnormality was reversed by supplementation with rapamycin. TGF-beta1-induced SPT mRNA expression was blocked by SB525334, an inhibitor of TGF-beta1-induced Smad2/3 nuclear localization, in human keratinocytes. Rapamycin-induced SPT mRNA expression was blocked by an anti-TGF beta1 antibody or SB525334 in human keratinocytes. These results show that mTOR inhibition by rapamycin increases ceramide synthesis by promoting TGF-beta1/Smad signaling in the skin. PMID- 27239443 TI - Adaptive response to l-serine deficiency is mediated by p38 MAPK activation via 1 deoxysphinganine in normal fibroblasts. AB - Reduced availability of l-serine limits cell proliferation and leads to an adaptation to l-serine-deficient environment, the underlying molecular mechanism of which remain largely unexplored. Genetic ablation of 3-phosphoglycerate dehydrogenase (Phgdh), which catalyzes the first step of de novo l-serine synthesis, led to diminished cell proliferation and the activation of p38 MAPK and stress-activated protein kinase/Jun amino-terminal kinase in mouse embryonic fibroblasts under l-serine depletion. The resultant l-serine deficiency induced cyclin-dependent kinase inhibitor 1a (Cdkn1a; p21) expression, which was mediated by p38 MAPK. Survival of the Phgdh-deficient mouse embryonic fibroblasts was markedly reduced by p38 MAPK inhibition under l-serine depletion, whereas p38 MAPK could be activated by 1-deoxysphinganine, an atypical alanine-derived sphingoid base that was found to accumulate in l-serine-depleted mouse embryonic fibroblasts. These observations provide persuasive evidence that when the external l-serine supply is limited, l-serine synthesized de novo in proliferating cells serves as a metabolic gatekeeper to maintain cell survival and the functions necessary for executing cell cycle progression. DATABASE: Gene Expression Omnibus, accession number GSE55687. PMID- 27239445 TI - SNAI1 promotes the development of HCC through the enhancement of proliferation and inhibition of apoptosis. AB - SNAI1, a zinc-finger transcription factor, plays an important role in the induction of epithelial-mesenchymal transition (EMT) in various cancers. However, the possible functions of SNAI1 in the proliferation and apoptosis of hepatocellular carcinoma have not been clearly identified. In this study, we investigated the effects and mechanisms of SNAI1 in the proliferation and apoptosis of hepatocellular carcinoma using clinical samples and cell lines. We found that SNAI1 is highly expressed in the tissues of liver cancer compared with adjacent nontumor tissues. SNAI1 is also highly expressed in the hepatoma cell lines HepG2, SMMC-7721, and BEL-7402 compared with the human normal liver cell line L02. We also observed that SNAI1 expression was correlated with distal metastasis, incomplete tumor capsule formation, and histological differentiation in hepatocellular carcinoma (HCC). Moreover, we demonstrated that knockdown of SNAI1 via lentiviral vectors of RNAi against SNAI inhibited cell proliferation by inducing G1 arrest, which was accompanied by the downregulation of cyclin D1 but not that of cyclin A. In addition, knockdown of SNAI1 promoted apoptosis by decreasing the expression of Bcl-2. In conclusion, our findings revealed that SNAI1 is involved in the development of hepatocellular carcinoma via regulating the growth and apoptosis of tumor cells. PMID- 27239446 TI - Production of biologically active IL-36 family cytokines through insertion of N terminal caspase cleavage motifs. AB - Recent evidence has strongly implicated IL-36 cytokines as key initiators of inflammation in the skin barrier. IL-36 cytokines belong to the extended IL-1 family and, similar to most members of this family, are expressed as inactive precursors that require proteolytic processing for activation. Because the proteases responsible for activation of members of the IL-36 subfamily have not been reported, we have developed a method for the production of biologically active IL-36 through introduction of a caspase cleavage motif, DEVD, within the N termini of these cytokines. Here, we show that DEVD-modified IL-36alpha, IL 36beta and IL-36gamma cytokines were highly soluble and were readily processed and activated by caspase-3. Caspase-3-processed IL-36 family cytokines exhibited robust biological activity on a range of responsive cell types, including primary keratinocytes. We also generated specific polyclonal antibodies against all three IL-36 family members through immunization with purified recombinant IL-36 cytokines. The modified forms of IL-36 described herein will be useful for production of large quantities of biologically active IL-36 for structure and function studies on these important proinflammatory cytokines. PMID- 27239447 TI - Ca(2+)-binding protein centrin 4 is a novel binding partner of rat Eag1 K(+) channels. AB - Eag1 is neuron-specific K(+) channel abundantly expressed in the brain and retina. Subcellular localization and physiological analyses in neurons reveal that Eag1 may participate in Ca(2+)-signaling processes in the synapse. Here, we searched for rat Eag1 (rEag1)-binding proteins that may contribute to Ca(2+) regulation of the K(+) channel. Yeast two-hybrid screening identified centrin 4, a member of the centrin family of Ca(2+)-binding proteins. GST pull-down and immunoprecipitation assays in brain and retina lysates confirm the interaction of centrin with rEag1 in neurons. Centrin 4 binds to rEag1 in the absence of Ca(2+). Raising Ca(2+) concentration enhances the association efficiency of centrin 4 and rEag1, and is required for the suppression of rEag1 currents by centrin 4. Altogether, our data suggest that centrin 4 is a novel binding partner that may contribute to Ca(2+) regulation of rEag1 in neurons. PMID- 27239448 TI - Pre-mRNA splicing is modulated by antifungal drugs in the filamentous fungus Neurospora crassa. AB - For this study, we sought to identify pre-mRNA processing events modulated by changes in extracellular pH, inorganic phosphate, and antifungal drugs. We examined genes with at least four putative introns whose transcriptional level responded to these effectors. We showed that the intron retention levels of genes encoding asparagine synthetase 2, C6-zinc finger regulator (fluffy), and a farnesyltransferase respond to amphotericin B, ketoconazole, and other effectors. In general, the assayed antifungals promoted the disruption of the structural domains of these proteins probably leading to their inactivation, which emphasize the complexity of the metabolic modulation exerted by antifungal signaling. PMID- 27239450 TI - Clinical Presentation and Genetic Paradigm of Diffuse Infiltrating Retinoblastoma: A Review. AB - Retinoblastoma is the most common childhood cancer. Thanks to modern technology and good medical access, mortality in Europe has decreased to about 5%. Diffuse infiltrating retinoblastoma is a very rare subtype of this neoplasm and is characterized by its atypical growth pattern. Diffuse infiltrating retinoblastoma may mimic other more innocuous diseases and may therefore be misdiagnosed. The purpose of this paper was to provide a short review of the main symptoms of diffuse infiltrating retinoblastoma presenting to the ophthalmologist and give a comparison to typical retinoblastoma. The second purpose was to set up a discussion of the genetic paradigm of diffuse infiltrating retinoblastoma. It has often been described to occur sporadically; however, in the last years, it has been shown that it might be heritable. A literature search concerning diffuse infiltrating retinoblastoma considering English, German and Spanish cases and case series identified 77 patients. Moreover, an overview of general data, main symptoms, clinical findings and initial working diagnoses or referral diagnoses is given. Males were significantly more often affected than females. Diffuse infiltrating retinoblastoma can be heritable. Genetic analysis should be offered to the patient and relatives. Interdisciplinary medical follow-up care is needed to detect associated cancers. PMID- 27239451 TI - Lipomatous Change in Uveal Melanoma: Histopathological, Immunohistochemical and Cytogenetic Analysis. AB - PURPOSE: The aim of this study was to describe a case of lipomatous change in uveal melanoma. PROCEDURES: The patient presented with a 2-year history of blurry vision. A full examination of the right eye revealed a dome-shaped pigmented subretinal mass in the choroid with a thickness of 9 mm and a diameter of 15 mm. The eye was enucleated and prepared for histopathologic, genetic and molecular investigation. RESULTS: Histopathology revealed a small circumscribed area consisting of mature adipocytic appearing cells with abundant clear cytoplasm and small peripheral flattened nuclei within a spindle-cell melanoma of the uvea. The cytoplasm of the adipocytic cells stained negative for periodic acid-Schiff and Alcian blue and positive for Melan-A, HMB-45 and tyrosinase, confirming melanocytic lineage. Fluorescence in situ hybridization analysis confirmed trisomy of chromosome 6p22 and disomy of chromosome 3p13 in the nuclei of both the tumor spindle type B cells and in the nuclei of lipomatous tumor cells. CONCLUSIONS: Lipomatous change can be added to the many histopathologic faces of uveal melanoma. To our knowledge, this is the first report of lipomatous change in uveal melanoma performed with cytogenetic investigations. PMID- 27239452 TI - Progressive Scleral Necrosis following I-125 Plaque Radiotherapy for Ciliochoroidal Melanoma with Protruding Extraocular Mass. AB - PURPOSE: The aim of this study was to describe the side effects of I-125 brachytherapy in the treatment of uveal melanoma. METHODS: This study was conducted as a case report. RESULTS: We report a case of scleral necrosis and protruding episcleral mass following the treatment of uveal melanoma with I-125 brachytherapy. CONCLUSIONS: Scleral necrosis after plaque radiotherapy can clinically simulate tumor recurrence with extraocular extension. The management of uveal melanoma requires a careful clinical follow-up, weighing the implications of treatment morbidity and mortality. PMID- 27239449 TI - Pigment Epithelium-Derived Factor (PEDF) is a Determinant of Stem Cell Fate: Lessons from an Ultra-Rare Disease. AB - PEDF is a secreted glycoprotein that is widely expressed by multiple organs. Numerous functional contributions have been attributed to PEDF with antiangiogenic, antitumor, anti-inflammatory, and neurotrophic properties among the most prominent. The discovery that null mutations in the PEDF gene results in Osteogenesis Imperfecta Type VI, a rare autosomal recessive bone disease characterized by multiple fractures, highlights a critical developmental function for this protein. This ultra-rare orphan disease has provided biological insights into previous studies that noted PEDF's effects on various stem cell populations. In addition to bone development, PEDF modulates resident stem cell populations in the brain, muscle, and eye. Functional effects on human embryonic stem cells have also been demonstrated. An overview of recent advances in our understanding by which PEDF regulates stem cells and their potential clinical applications will be evaluated in this review. PMID- 27239453 TI - Uveal Melanoma Mimicking Advanced Coats' Disease in a Young Patient. AB - BACKGROUND/AIMS: To report a case and the unique histopathology of a necrotic uveal melanoma mimicking advanced Coats' disease in a young adult. METHOD: A 26 year-old male presented with a blind, painful eye, total exudative retinal detachment, and bulbous aneurysms consistent with Coats' disease. No masses were visualized on ultrasound or CT scan, and the patient underwent enucleation of the eye. RESULTS: Histopathology of the involved eye confirmed a necrotic uveal melanoma with persistent spindle cells forming a collar around residual tumor vessels. CONCLUSION: Careful consideration is needed in approaching any patient with a blind, painful eye and opaque media, even in younger populations. PMID- 27239454 TI - Orbital Extension of an Unsuspected Choroidal Melanoma Presumably through an Aqueous Tube Shunt. AB - AIMS: To report a patient with unrecognized small macular melanoma, who gradually developed neovascular glaucoma that was treated with an Ahmed valve. We presume that tumor cells gained access to the orbit through this aqueous drainage device. METHODS: The medical records pertaining to 5 different centers, the results of imaging studies, the clinical course of the patient and histopathological findings were retrospectively reviewed. RESULTS: A 61-year-old man presented with a blind and painful proptotic right eye. Retinal hemorrhage had been suspected 3 years earlier and followed accordingly thereafter. Yearly performed MRI studies demonstrated the steady growth of the hemorrhagic lesion/tumor. Meanwhile, he developed neovascular glaucoma first treated unsuccessfully with cyclocryotherapy then with implantation of an Ahmed valve. Right proptosis became evident within a year, and a final MRI study revealed a large retrobulbar mass. Orbital exenteration was performed and histopathological examination showed intraocular and orbital epithelioid cell melanoma. Tumor cells were also found within the reservoir of the Ahmed valve. The patient died of widespread metastases 1 year later. CONCLUSIONS: Ahmed valve implantation in an eye with unsuspected macular choroidal melanoma may ultimately be associated with extraocular extension and orbital tumor formation. PMID- 27239455 TI - Detection and Intraretinal Localization of an 'Invisible' Retinoblastoma Using Optical Coherence Tomography. AB - PURPOSE: To report the use of handheld spectral-domain optical coherence tomography (HHSD OCT) to identify and define the intraretinal location of a small retinoblastoma that was not detectable by indirect ophthalmoscopy. METHODS: This is a retrospective case report of a tumor identified with HHSD OCT in a single patient. RESULTS: A 7-week-old male was diagnosed with unilateral group E retinoblastoma in the right eye. An enucleation was completed successfully with histopathologic confirmation of the diagnosis. The normal left eye was monitored for the development of retinoblastoma, and 10 weeks after diagnosis, three new small retinoblastomas were noted in the posterior pole. Identification of the smallest of the three tumors was facilitated by HHSD OCT; it was adjacent to the optic nerve head, and involved the outer nuclear layer, outer plexiform layer, and inner nuclear layer, with the inner retina draping over the tumor. CONCLUSION: HHSD OCT can aid the ocular oncologist in the identification of very small retinoblastomas before they are visible to the eye, which allows for earlier and potentially vision-sparing treatment of these lesions. Additionally, the ability to identify these very small tumors and to localize them anatomically within the retinal layers may aid in our understanding of retinoblastoma tumorigenesis. PMID- 27239456 TI - Amelanotic Irido-Ciliary Ring Melanoma: A Clinicopathological Correlation. AB - PURPOSE: To report a case of an amelanotic irido-ciliary ring melanoma. DESIGN: Interventional case report. RESULTS: A 44-year-old male was followed for asymptomatic amelanotic iris nevus of the right eye that was noted to have a localized ciliary body mass with ring extension along the trabecular meshwork. Fine needle aspiration biopsy was consistent with malignant melanoma. The patient underwent enucleation and remains disease free at 9 years of follow-up. Histopathology revealed malignant melanoma involving the iris and ciliary body with a 360-degree extension along the trabecular meshwork. The tumor was composed of a mixture of spindled and epithelioid cells with scant pigmentation. CONCLUSIONS: Amelanotic irido-ciliary ring melanoma with growth along the trabecular meshwork is a rare form of uveal melanoma that could present as an inconspicuous amelanotic iris mass. PMID- 27239457 TI - Eyelid Metastatic Thyroid Papillary Carcinoma. AB - PURPOSE: The aim of this study was to report the clinical and histopathological features of an eyelid metastasis in a 70-year-old male with no prior medical history. METHODS: A 70-year-male presented with a painless, hard, red nodular growth in his left lower medial eyelid of 6 months duration, involving the canaliculus and punctum. He did not complain of any other ocular or systemic abnormality. The clinical differential diagnosis included lymphoma or a primary adnexal tumour. The lesion was excised under local anaesthetic cover and sent for routine histopathological analysis. RESULTS: The histology revealed a carcinoma involving the posterior and anterior lamella of the lower lid. It was composed of papillary and follicular areas. The tumour nuclei were optically clear, overlapping, had nuclear grooves and were associated with eosinophilic colloid material. The tumour cells were strongly positive for nuclear thyroid transcription factor-1 and thyroglobulin (which also stained some of the eosinophilic colloid material). The histological and immunohistochemical features were those of metastatic papillary carcinoma of the thyroid. Unfortunately, the patient's thyroid has yet to be examined because of loss to follow-up. CONCLUSION: To the best of our knowledge, this is the first report of thyroid papillary carcinoma metastasizing to the eyelid as the presenting feature of the disease. A review of the literature of metastatic thyroid carcinoma to the eyelids is presented, to place the findings of this case report in context. PMID- 27239458 TI - Reduction of Nodular Growth Pattern of Metastatic Uveal Melanoma after Radioembolization of Hepatic Metastases. AB - AIM: The aim of this study was to report a case of metastatic uveal melanoma in which radioembolized nodular liver metastases decreased in size while infiltrative sinusoidal metastases progressed, leading to jaundice without obstruction of the biliary ducts. METHODS: The relevant clinical features, imaging, and histopathologic findings of this case are reviewed. RESULTS: A 61 year-old Caucasian male with a history of uveal melanoma of the left eye status post plaque brachytherapy developed numerous liver metastases. After progression on systemic therapies, he underwent palliative radioembolization. Despite some radiographic improvement in the liver metastases, he developed hyperbilirubinemia without biliary tract obstruction or signs of liver failure. A biopsy of radiographically normal liver demonstrated extensive sinusoidal infiltration with melanoma. CONCLUSIONS: Distinct angiographic and histopathologic growth patterns of metastatic uveal melanoma differ in their amenability to radioembolization. Sinusoidal infiltration may lead to hyperbilirubinemia in the absence of overt obstruction or liver failure. PMID- 27239459 TI - Unilateral Eye Findings: A Rare Herald of Acute Leukemia. AB - BACKGROUND/AIM: Unilateral choroidal infiltration as the initial manifestation of leukemic relapse in adults is rare, particularly after an extended period of remission. This report describes this unique ophthalmic presentation, highlights the associated diagnostic challenges, and reviews the literature. METHODS: Two cases are described and an extensive literature review was conducted. RESULTS: A 59-year-old male with acute lymphoid leukemia, in remission for 18 months, presented with unilateral scleritis, exudative retinal detachment, and choroidal thickening. A 57-year-old male with a history of acute myeloid leukemia, in remission for 4 years, presented with unilateral choroidal thickening leading to secondary angle closure. In both cases, there was a significant lag from the onset of eye symptoms to establishing a systemic diagnosis of acute leukemia, leading to a delay in definitive systemic treatment, despite a high suspicion of disease based on ophthalmic findings. CONCLUSIONS: These two cases illustrate the fundus findings consistent with leukemic choroidal infiltration that can represent the first sign of relapsed leukemia. The successful treatment of these patients hinges on collaboration between ophthalmologists and oncologists to optimize patient outcomes, highlighting the need for both groups to be aware of this rare ophthalmic presentation. PMID- 27239460 TI - Investigation of Somatic GNAQ, GNA11, BAP1 and SF3B1 Mutations in Ophthalmic Melanocytomas. AB - PURPOSE: The aim of this study was to use massively parallel DNA sequencing to identify GNAQ/11, BAP1 and SF3B1 mutations in ophthalmic melanocytoma. PROCEDURES: Six ophthalmic melanocytoma specimens (1 iridociliary and 5 optic nerve) were profiled for genomic alterations in GNAQ/11, BAP1 and SF3B1 using a custom deep sequencing assay. This assay uses solution phase hybridization-based exon capture and deep-coverage massively parallel DNA sequencing to interrogate all protein-coding exons and select introns. RESULTS: The only iridociliary melanocytoma showed a mutation in GNAQ but not in BAP1. Of the 2 optic-nerve melanocytomas that developed into melanoma, one had a GNAQ mutation and both a BAP1 mutation and monosomy 3. The remaining 3 optic-nerve melanocytomas did not reveal mutations in GNAQ/11 or BAP1. SF3B1 mutations were not detected in any specimen. CONCLUSIONS: The presence of GNAQ mutation in some iridociliary and optic-nerve melanocytomas suggests a possible relationship between ophthalmic melanocytoma and other ophthalmic melanocytic neoplasms. BAP1 mutation may accompany the transformation of ophthalmic melanocytoma to melanoma. PMID- 27239461 TI - Optic Nerve Assessment Using 7-Tesla Magnetic Resonance Imaging. AB - PURPOSE: The purpose of this study was to correlate high-resolution magnetic resonance imaging (MRI) and histologic findings in a case of juxtapapillary choroidal melanoma with clinical evidence of optic nerve invasion. METHODS: With institutional review board approval, an enucleated globe with choroidal melanoma and optic nerve invasion was imaged using a 7-tesla MRI followed by histopathologic evaluation. RESULTS: Optical coherence tomography, B-scan ultrasonography, and 1.5-tesla MRI of the orbit (1-mm sections) could not detect optic disc invasion. Ex vivo, 7-tesla MRI detected optic nerve invasion, which correlated with histopathologic features. CONCLUSIONS: Our case demonstrates the potential to document the existence of optic nerve invasion in the presence of an intraocular tumor, a feature that has a major bearing on decision making, particularly for consideration of enucleation. PMID- 27239462 TI - Late Presentation of Retinoblastoma in a Teen with Aicardi Syndrome. AB - BACKGROUND/AIMS: Retinoblastoma (Rb) generally presents in children <8 years of age. Aicardi syndrome (AS) is a congenital, neurodevelopmental disorder that has been associated with various ophthalmic abnormalities, but no reports have related it to a delayed presentation of Rb. This report describes the late presentation of Rb in a teenage patient with AS and suggests modifications in ophthalmic screening to facilitate early detection. METHODS: A chart review was conducted of a patient with AS. We examined the ophthalmic history, fundus images and B-scan ultrasonography. Histopathological analysis was conducted on globe sections. RESULTS: The patient's ophthalmic history was consistent with normal findings of AS: fundus images and B-scan ultrasonography revealed chorioretinal lacunae and an area of retinal detachment, respectively. The patient presented with chronic irritation and mydriasis of the blind left eye. This was enucleated as treatment. Histopathology revealed a focally differentiated Rb. Immunohistochemistry demonstrated that the tumor cells were positive for synaptophysin and negative for the wild-type Rb protein, and a high Ki-67 proliferation index was shown. CONCLUSION: Our patient was diagnosed with Rb at age 16. AS has been associated with numerous ophthalmic findings, but this is the first report relating it to a late Rb presentation. Meticulous ophthalmic examinations should be considered through the teenage years and early adulthood of AS patients. PMID- 27239463 TI - Vascular Steal Syndrome, Optic Neuropathy, and Foreign Body Granuloma Reaction to Onyx-18 Embolization for Congenital Orbito-Facial Vascular Malformation. AB - A 34-year-old patient presented with a right orbito-facial mass since childhood, consistent with a congenital arteriovenous (AV) malformation. Prior to presentation, she had multiple incomplete surgical resections and embolizations with N-butyl acetyl acrylate and Onyx-18. The patient reported gradual, progressive vision loss shortly after Onyx-18 embolization. Five months after embolization, she presented with decreased vision, disfigurement and mechanical ptosis relating to a large subcutaneous mass affecting the medial right upper eyelid and forehead. Significant exam findings included a visual acuity of 20/400 (20/60 prior to embolization), an afferent pupillary defect, and optic disc pallor. MRI and angiography revealed a persistent AV malformation with feeders from the ophthalmic artery and an absent choroidal flush to the right eye. Pathology from surgical resection showed a significant foreign body giant cell reaction to the embolization material adjacent to the vessels. We suggest that an incomplete embolization with Onyx-18 may have caused vascular steal syndrome from the ophthalmic artery. PMID- 27239464 TI - On the Classification and Grading of Medulloepithelioma of the Eye. AB - Medulloepithelioma is a rare congenital tumor of the ciliary body and iris. The current classification and grading of medulloepithelioma shows inconsistencies and does not reflect clinical behavior. This position paper discusses the backgrounds of the current classification and intends to initiate a discussion on an alternative classification and grading scheme. PMID- 27239465 TI - Ocular Gnathostomiasis in Brazil: A Case Report. AB - Gnathostomiasis is a parasitic disease caused by nematode larvae ingestion of 15 known species of the genus Gnathostoma (one of the Gnathostomatidae family members). This parasite uses freshwater fish as a host and can infect - through the consumption of raw fish or their viscera - other animals such as dogs, cats, chickens, pigs, and humans. This parasitic disease, with humans acting as hosts, has been known since 1945 (India), and ocular complications have been known since 2004 (intravitreal; also described in India). Latin American countries, especially Mexico and Peru, have reported cases of the disease since 1970. The first dermatological case was reported in Brazil in 2009 (the individual had acquired the disease in Peru). This article describes the first reported ophthalmic case of the disease in Brazil and refers to a male patient, 30 years old, living in the municipality of Jurua, Amazonas State. The disease evolved within 30 days through a fistulized tumor in the inner corner of the lower eyelid. Following excision, the anatomical and histopathological examination revealed the presence of a different parasite species from other previously known genera. PMID- 27239466 TI - Metachronous Diffuse Large B-Cell Lymphoma and Kaposi Sarcoma of the Right Eyelid and Lacrimal Gland in a Patient with Granulomatous Common Variable Immunodeficiency. AB - PURPOSE: To describe the ophthalmic and histopathological features of a female with granulomatous common variable immunodeficiency (CVID) who presented with upper-lid swelling. PROCEDURES: The patient underwent a biopsy of the right upper lid/palpebral lacrimal gland with imaging showing a left-sided nasopharyngeal mass, multiple lymph nodes within the mediastinum, bilateral lung nodules and a peritoneal nodule in the right iliac fossa. The right upper-lid swelling progressed and was subject to a second biopsy. RESULTS: The first right upper-lid biopsy revealed a diffuse large B-cell lymphoma (DLBCL), confirmed with clonal IgH gene rearrangement with PCR. The nasopharyngeal mass and lymph nodes were suspected clinically to be DLBCL. However, a biopsy of the nasopharyngeal mass showed Kaposi sarcoma (KS). The second biopsy of the right upper lid/palpebral lacrimal gland revealed KS with no evidence of DLBCL. CONCLUSION: This is the first documentation of periocular/orbital metachronous DLBCL and KS in a patient with granulomatous CVID. We discuss the role of fluctuating immunity in CVID to explain the spontaneous regression of the DLBCL and the varying clinical picture. PMID- 27239467 TI - Polarizable Material from a Conjunctival Biopsy in a Patient with Sarcoidosis. AB - PURPOSE: Conjunctival biopsies may contain polarizable material in patients with sarcoidosis despite no history of prior trauma or eye surgeries. PROCEDURES: A 39 year-old male with uveitic glaucoma presented with decreased vision and throbbing pain in his right eye. His intraocular pressure was elevated, and his vision was reduced to hand motion. Due to persistently elevated intraocular pressure refractory to medical treatment, the patient underwent a glaucoma drainage device procedure. During the procedure, a yellow, nodular conjunctival growth was noted and biopsied. RESULTS: Histopathological examination revealed multiple nonnecrotizing granulomata, some of which contained polarizable material. CONCLUSIONS: Biopsies of patients with sarcoidosis may contain polarizable material without evidence of foreign body inoculation. PMID- 27239469 TI - Biomechanical, Topological and Chemical Features That Influence the Implant Success of an Urogynecological Mesh: A Review. AB - Synthetic meshes are normally used to treat several diseases in the field of urogynecological surgery. Not-optimal selection of mesh and/or its not-correct implant may increase patient's pain and discomfort. The knowledge of mechanical behaviour and topological and chemical properties of a mesh plays a fundamental role to minimize patient's suffering and maximize the implant success. We analysed several papers reporting the meshes application for urogynecological pathologies, to extrapolate the principal parameters that normally are used to characterise the biomechanical, topological, and chemical properties, and to verify their influence on implant success. In this way we want demonstrate that, knowing these features, it is possible to foresee the success of a mesh implant. This review shows that the application of a mesh strictly depends on elastic modulus, failure load, porosity and pore size, filament diameter, polymer weight, and crystallinity. To increase the success of the implant and to help choice of optimal mesh for a clinical need, two indexes have been proposed for comparing, in an easier way, the mechanical performance of different commercially available meshes. PMID- 27239470 TI - Personalized Medicine Based on Theranostic Radioiodine Molecular Imaging for Differentiated Thyroid Cancer. AB - Molecular imaging based personalized therapy has been a fascinating concept for individualized therapeutic strategy, which is able to attain the highest efficacy and reduce adverse effects in certain patients. Theranostics, which integrates diagnostic testing to detect molecular targets for particular therapeutic modalities, is one of the key technologies that contribute to the success of personalized medicine. Although the term "theranostics" was used after the second millennium, its basic principle was applied more than 70 years ago in the field of thyroidology with radioiodine molecular imaging. Differentiated thyroid cancer, which arises from follicular cells in the thyroid, is the most common endocrine malignancy, and theranostic radioiodine has been successfully applied to diagnose and treat differentiated thyroid cancer, the applications of which were included in the guidelines published by various thyroid or nuclear medicine societies. Through better pathophysiologic understanding of thyroid cancer and advancements in nuclear technologies, theranostic radioiodine contributes more to modern tailored personalized management by providing high therapeutic effect and by avoiding significant adverse effects in differentiated thyroid cancer. This review details the inception of theranostic radioiodine and recent radioiodine applications for differentiated thyroid cancer management as a prototype of personalized medicine based on molecular imaging. PMID- 27239468 TI - Copy Number Variations in DISC1 and DISC1-Interacting Partners in Major Mental Illness. AB - Robust statistical, genetic and functional evidence supports a role for DISC1 in the aetiology of major mental illness. Furthermore, many of its protein-binding partners show evidence for involvement in the pathophysiology of a range of neurodevelopmental and psychiatric disorders. Copy number variants (CNVs) are suspected to play an important causal role in these disorders. In this study, CNV analysis of DISC1 and its binding partners PAFAH1B1, NDE1, NDEL1, FEZ1, MAP1A, CIT and PDE4B in Scottish and Northern Swedish population-based samples was carried out using multiplex amplicon quantification. Here, we report the finding of rare CNVs in DISC1, NDE1 (together with adjacent genes within the 16p13.11 duplication), NDEL1 (including the overlapping MYH10 gene) and CIT. Our findings provide further evidence for involvement of DISC1 and its interaction partners in neuropsychiatric disorders and also for a role of structural variants in the aetiology of these devastating diseases. PMID- 27239471 TI - Differential Proteomics Analysis of Colonic Tissues in Patients of Slow Transit Constipation. AB - Objective. To investigate and screen the different expression of proteins in STC and normal group with a comparative proteomic approach. Methods. Two-dimensional electrophoresis was applied to separate the proteins in specimens from both 5 STC patients and 5 normal controls. The proteins with statistically significant differential expression between two groups were identified by computer aided image analysis and matrix assisted laser desorption ionization tandem time of flight mass spectrometry (MALDI-TOF-MS). Results. A total of 239 protein spots were identified in the average gel of the normal control and 215 in patients with STC. A total of 197 protein spots were matched and the mean matching rate was 82%. There were 14 protein spots which were expressed with statistically significant differences from others. Of those 14 protein spots, the expression of 12 spots increased markedly, while that of 2 spots decreased significantly. Conclusion. The proteomics expression in colonic specimens of STC patients is statistically significantly different from that of normal control, which may be associated with the pathogenesis of STC. PMID- 27239472 TI - miR-145a-5p Promotes Myoblast Differentiation. AB - MicroRNAs are a class of 18-22-nucleotide noncoding RNAs that posttranscriptionally regulate gene expression and have been shown to play an important role during myoblast differentiation. In this study, we found that the expression of miR-145a-5p was gradually increased during C2C12 myoblast differentiation, and miR-145a-5p inhibitors or mimics significantly suppressed or promoted the relative expression of specific myogenesis related marker genes. Moreover, overexpression or inhibition of miR-145a-5p enhanced or repressed the expression of some special genes involved in the endogenous Wnt signaling pathway during C2C12 myoblast differentiation, including Wnt5a, LRP5, Axin2, and beta catenin. These results indicated that miR-145a-5p might be considered as a new myogenic differentiation-associated microRNA that can promote C2C12 myoblast differentiation by enhancing genes related to myoblasts differentiation. PMID- 27239473 TI - Psoralen and Isopsoralen Ameliorate Sex Hormone Deficiency-Induced Osteoporosis in Female and Male Mice. AB - Osteoporosis is a systemic skeletal disease, which is characterized by a systemic destruction of bone mass and microarchitecture. With life standard improved, the treatment of osteoporosis attracted more attention. The aim of this study is to verify the osteoprotective effect of psoralen and isopsoralen in females and males. Female and male mice were divided into 7 groups in this study: control group (sham-operation), model group (by ovariectomy or orchidectomy), positive control group (females given estradiol valerate; males given alendronate sodium), psoralen groups (10 mg/kg and 20 mg/kg), and isopsoralen groups (10 mg/kg and 20 mg/kg). After administration of psoralen and isopsoralen for 8 weeks, osteoporosis was ameliorated with increasing bone strength and improving trabecular bone microstructure as indicated by CT scan and pathology. Serum alkaline phosphatase (ALP), tartrate resistant acid phosphatase (TRACP), osteocalcin (OC), and C-terminal cross-linking telopeptides of type I collagen (CTX-1) were examined. Decreased TRACP and increased ALP/TRACP suggested restoring from bone destruction. These results suggest that psoralen and isopsoralen may be used as good natural compounds for the treatment of osteoporosis in males, as well as females. PMID- 27239474 TI - Genomic Analysis Unravels Reduced Inorganic Sulfur Compound Oxidation of Heterotrophic Acidophilic Acidicaldus sp. Strain DX-1. AB - Although reduced inorganic sulfur compound (RISC) oxidation in many chemolithoautotrophic sulfur oxidizers has been investigated in recent years, there is little information about RISC oxidation in heterotrophic acidophiles. In this study, Acidicaldus sp. strain DX-1, a heterotrophic sulfur-oxidizing acidophile, was isolated. Its genome was sequenced and then used for comparative genomics. Furthermore, real-time quantitative PCR was performed to identify the expression of genes involved in the RISC oxidation. Gene encoding thiosulfate: quinone oxidoreductase was present in Acidicaldus sp. strain DX-1, while no candidate genes with significant similarity to tetrathionate hydrolase were found. Additionally, there were genes encoding heterodisulfide reductase complex, which was proposed to play a crucial role in oxidizing cytoplasmic sulfur. Like many heterotrophic sulfur oxidizers, Acidicaldus sp. strain DX-1 had no genes encoding enzymes essential for the direct oxidation of sulfite. An indirect oxidation of sulfite via adenosine-5'-phosphosulfate was proposed in Acidicaldus strain DX-1. However, compared to other closely related bacteria Acidiphilium cryptum and Acidiphilium multivorum, which harbored the genes encoding Sox system, almost all of these genes were not detected in Acidicaldus sp. strain DX 1. This study might provide some references for the future study of RISC oxidation in heterotrophic sulfur-oxidizing acidophiles. PMID- 27239475 TI - Guitar: An R/Bioconductor Package for Gene Annotation Guided Transcriptomic Analysis of RNA-Related Genomic Features. AB - Biological features, such as genes and transcription factor binding sites, are often denoted with genome-based coordinates as the genomic features. While genome based representation is usually very effective in correlating various biological features, it can be tedious to examine the relationship between RNA-related genomic features and the landmarks of RNA transcripts with existing tools due to the difficulty in the conversion between genome-based coordinates and RNA-based coordinates. We developed here an open source Guitar R/Bioconductor package for sketching the transcriptomic view of RNA-related biological features represented by genome based coordinates. Internally, Guitar package extracts the standardized RNA coordinates with respect to the landmarks of RNA transcripts, with which hundreds of millions of RNA-related genomic features can then be efficiently analyzed within minutes. We demonstrated the usage of Guitar package in analyzing posttranscriptional RNA modifications (5-methylcytosine and N6-methyladenosine) derived from high-throughput sequencing approaches (MeRIP-Seq and RNA BS-Seq) and show that RNA 5-methylcytosine (m(5)C) is enriched in 5'UTR. The newly developed Guitar R/Bioconductor package achieves stable performance on the data tested and revealed novel biological insights. It will effectively facilitate the analysis of RNA methylation data and other RNA-related biological features in the future. PMID- 27239476 TI - Discovery of Azurin-Like Anticancer Bacteriocins from Human Gut Microbiome through Homology Modeling and Molecular Docking against the Tumor Suppressor p53. AB - Azurin from Pseudomonas aeruginosa is known anticancer bacteriocin, which can specifically penetrate human cancer cells and induce apoptosis. We hypothesized that pathogenic and commensal bacteria with long term residence in human body can produce azurin-like bacteriocins as a weapon against the invasion of cancers. In our previous work, putative bacteriocins have been screened from complete genomes of 66 dominant bacteria species in human gut microbiota and subsequently characterized by subjecting them as functional annotation algorithms with azurin as control. We have qualitatively predicted 14 putative bacteriocins that possessed functional properties very similar to those of azurin. In this work, we perform a number of quantitative and structure-based analyses including hydrophobic percentage calculation, structural modeling, and molecular docking study of bacteriocins of interest against protein p53, a cancer target. Finally, we have identified 8 putative bacteriocins that bind p53 in a same manner as p28 azurin and azurin, in which 3 peptides (p1seq16, p2seq20, and p3seq24) shared with our previous study and 5 novel ones (p1seq09, p2seq05, p2seq08, p3seq02, and p3seq17) discovered in the first time. These bacteriocins are suggested for further in vitro tests in different neoplastic line cells. PMID- 27239477 TI - Isolation and Characterization of a Broad Spectrum Bacteriocin from Bacillus amyloliquefaciens RX7. AB - We isolated a Bacillus strain, RX7, with inhibitory activity against Listeria monocytogenes from soil and identified it as Bacillus amyloliquefaciens based on 16S rRNA gene sequencing. The inhibitory activity was stable over a wide range of pH and was fully retained after 30 min at 80 degrees C, after which it decreased gradually at higher temperatures. The activity was sensitive to the proteolytic action of alpha-chymotrypsin, proteinase-K, and trypsin, indicating its proteinaceous nature. This bacteriocin was active against a broad spectrum of bacteria and the fungus Candida albicans. Direct detection of antimicrobial activity on a sodium dodecyl sulfate-polyacrylamide gel suggested an apparent molecular mass of approximately 5 kDa. Ammonium sulfate precipitation and anion exchange and gel permeation chromatography integrated with reverse phase-high performance liquid chromatography were used for bacteriocin purification. Automated N-terminal Edman degradation of the purified RX7 bacteriocin recognized the first 15 amino acids as NH2-X-Ala-Trp-Tyr-Asp-Ile-Arg-Lys-Leu-Gly-Asn-Lys-Gly Ala, where the letter X in the sequence indicates an unknown or nonstandard amino acid. Based on BLAST similarity search and multiple alignment analysis, the obtained partial sequence showed high homology with the two-peptide lantibiotic haloduracin (HalA1) from Bacillus halodurans, although at least two amino acids differed between the sequences. A time-kill study demonstrated a bactericidal mode of action of RX7 bacteriocin. PMID- 27239478 TI - The Impact of Serum Amyloid P-Component on Gene Expression in RAW264.7 Mouse Macrophages. AB - Serum amyloid P-component (SAP) contributes to host defense and prevents fibrosis. Macrophages are the most abundant inflammatory cell type in atherosclerotic plaques. In the present study, using (3)H-cholesterol-labeled counting radioactivity assay, we demonstrated that the apoAI-mediated cholesterol efflux in RAW264.7 macrophages was increased by SAP treatment in a time- and dose dependent manner. We analyzed global gene expression changes upon SAP treatment using RNA sequencing. As a result, a total of 175 differentially expressed genes were identified, of which 134 genes were downregulated and 41 genes were upregulated in SAP treated cells compared to control cells. Quantitative RT-PCR analysis confirmed decreased expression of 5 genes and an increase in expression of 1 gene upon SAP treatment. Gene ontology analysis showed that genes involved in response to stimulus were significantly enriched in differentially expressed genes. Beyond protein-coding genes, we also identified 8 differentially expressed long noncoding RNAs. Our study may provide new insights into mechanisms underlying the functional role of SAP in macrophages. PMID- 27239479 TI - Modeling and Measurement of Correlation between Blood and Interstitial Glucose Changes. AB - One of the most effective methods for continuous blood glucose monitoring is to continuously measure glucose in the interstitial fluid (ISF). However, multiple physiological factors can modulate glucose concentrations and affect the lag phase between blood and ISF glucose changes. This study aims to develop a compensatory tool for measuring the delay in ISF glucose variations in reference to blood glucose changes. A theoretical model was developed based on biophysics and physiology of glucose transport in the microcirculation system. Blood and interstitial fluid glucose changes were measured in mice and rats by fluorescent and isotope methods, respectively. Computer simulation mimicked curves were fitted with data resulting from fluorescent measurements of mice and isotope measurements of rats, indicating that there were lag times for ISF glucose changes. It also showed that there was a required diffusion distance for glucose to travel from center of capillaries to interstitial space in both mouse and rat models. We conclude that it is feasible with the developed model to continuously monitor dynamic changes of blood glucose concentration through measuring glucose changes in ISF with high accuracy, which requires correct parameters for determining and compensating for the delay time of glucose changes in ISF. PMID- 27239480 TI - Comparison of Intranasal Outer Membrane Vesicles with Cholera Toxin and Injected MF59C.1 as Adjuvants for Malaria Transmission Blocking Antigens AnAPN1 and Pfs48/45. AB - Purified protein vaccines often require adjuvants for efficient stimulation of immune responses. There is no licensed mucosal adjuvant on the market to adequately boost the immune response to purified antigens for intranasal applications in humans. Bacterial outer membrane vesicles (OMV) are attractive candidates potentially combining antigenic and adjuvant properties in one substance. To more precisely characterize the potential of Escherichia coli OMV for intranasal vaccination with heterologous antigens, immune responses for AnAPN1 and Pfs48/45 as well as ovalbumin as a reference antigen were assessed in mice. The intranasal adjuvant cholera toxin (CT) and parenteral adjuvant MF59C.1 were used in comparison. Vaccinations were administered intranasally or subcutaneously. Antibodies (total IgG and IgM as well as subclasses IgG1, IgG2a, IgG2b, and IgG3) were measured by ELISA. T cell responses (cytotoxic T cells, Th1, Th17, and regulatory T cells) were determined by flow cytometry. When OMV were used as adjuvant for intranasal immunization, antibody and cellular responses against all three antigens could be induced, comparable to cholera toxin and MF59C.1. Antigen-specific IgG titres above 1 : 10(5) could be detected in all groups. This study provides the rationale for further development of OMV as a vaccination strategy in malaria and other diseases. PMID- 27239482 TI - Generation of Mouse Lung Epithelial Cells. AB - Although in vivo models are excellent for assessing various facets of whole organism physiology, pathology, and overall response to treatments, evaluating basic cellular functions, and molecular events in mammalian model systems is challenging. It is therefore advantageous to perform these studies in a refined and less costly setting. One approach involves utilizing cells derived from the model under evaluation. The approach to generate such cells varies based on the cell of origin and often the genetics of the cell. Here we describe the steps involved in generating epithelial cells from the lungs of KrasLSL-G12D/+; p53LSL R172/+ mice (Kasinski and Slack, 2012). These mice develop aggressive lung adenocarcinoma following cre-recombinase dependent removal of a stop cassette in the transgenes and subsequent expression of Kra-G12D and p53R172 . While this protocol may be useful for the generation of epithelial lines from other genetic backgrounds, it should be noted that the Kras; p53 cell line generated here is capable of proliferating in culture without any additional genetic manipulation that is often needed for less aggressive backgrounds. PMID- 27239483 TI - In vitro Differentiation of Murine Innate Lymphoid Cells from Common Lymphoid Progenitor Cells. AB - Subtypes of innate lymphoid cells (ILC), defined based on their cytokine secretion profiles and transcription factor expression, are important for host protection from pathogens and maintaining tissue homeostasis. ILCs develop from common lymphoid progenitors (CLP) in the bone marrow. Using the methods described here, we have previously shown that loss of the transcriptional regulator TOX (Thymocyte-selection associated HMG-box protein) leads to specific changes in ILC development and differentiation. Here, we describe how to obtain ILCs from in vivo isolated CLP grown in vitro. PMID- 27239481 TI - CryJ-LAMP DNA Vaccines for Japanese Red Cedar Allergy Induce Robust Th1-Type Immune Responses in Murine Model. AB - Allergies caused by Japanese Red Cedar (JRC) pollen affect up to a third of Japanese people, necessitating development of an effective therapeutic. We utilized the lysosomal targeting property of lysosomal-associated membrane protein-1 (LAMP-1) to make DNA vaccines that encode LAMP-1 and the sequences of immunodominant allergen CryJ1 or CryJ2 from the JRC pollen. This novel strategy is designed to skew the CD4 T cell responses to the target allergens towards a nonallergenic Th1 response. CryJ1-LAMP and CryJ2-LAMP were administrated to BALB/c mice and antigen-specific Th1-type IgG2a and Th2-type IgG1 antibodies, as well as IgE antibodies, were assayed longitudinally. We also isolated different T cell populations from immunized mice and adoptively transferred them into naive mice followed by CryJ1/CryJ2 protein boosts. We demonstrated that CryJ-LAMP immunized mice produce high levels of IFN-gamma and anti-CryJ1 or anti-CryJ2 IgG2a antibodies and low levels of IgE antibodies, suggesting that a Th1 response was induced. In addition, we found that CD4(+) T cells are the immunological effectors of DNA vaccination in this allergy model. Together, our results suggest the CryJ-LAMP Vaccine has a potential as an effective therapeutic for JRC induced allergy by skewing Th1/Th2 responses. PMID- 27239484 TI - "I Don't Have a Problem With It, But Other Guys Do": An Exploration of Condom Negotiation among Young Black Men Who Have Sex with Men in the South. AB - Condom negotiation among young Black men who have sex with men in the Southern United States was explored using the theory of reasoned action. Fifty-four (18- to 29-year-old) males participated in nine focus group interviews. Discussions elicited condom use and negotiation attitudes, beliefs and social norms. Positive personal attitudes (respect of self, personal health concerns) and high negotiation self-efficacy was emphasized. Conversely, social norms revealed non prioritized condom use behavior. Divergence between individual and community indicates theoretical models targeting sexual communication must address external factors (social, economic, political context), which intersects with individual intentions, attitudes to influence HIV prevalence in this community. PMID- 27239487 TI - Introducing Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, an open access journal of the Alzheimer's Association. PMID- 27239486 TI - Sleep health literacy in head start families and staff: exploratory study of knowledge, motivation, and competencies to promote healthy sleep. AB - CONTEXT: Healthy child development requires sufficient, quality sleep. Sleep problems in early childhood impair social-emotional and cognitive function and increase obesity risk. From a health literacy framework, "sleep health literacy" denotes the knowledge, motivation, and competencies to promote healthy sleep and to recognize a sleep problem. DESIGN: To explore the untapped potential of early childhood education (ECE) programs to promote sleep health literacy, we surveyed staff (n=63) and parents (n=196) in Head Start about sleep-related knowledge, attitudes/beliefs, sleep hygiene, and sleep problems. Head Start is the largest ECE program in the United States. RESULTS: Most parents believed that their child had healthy sleep habits (81%); few believed that he or she had a sleep problem (10%). Yet, unhealthy bedtime practices and insufficient sleep for age were reported in 50% and 33% of children, respectively. Between 10% and 12% of children had 1 or more sleep onset or awakening problems. Every unhealthy bedtime practice but one was associated with a sleep problem; parental presence at bedtime was associated with the most problems. Insufficient sleep was significantly associated with unhealthy sleep practices. More children with late vs early bedtimes (48% vs14%, P < .01) and frequent vs less frequent parental presence at bedtime (50% vs 26%-30%, P < .02) failed to obtain sufficient sleep. Staff members are more comfortable discussing healthy sleep with parents (87%) than counseling them (45%). CONCLUSION: Among parents, there is a "disconnect" between actual and perceived sleep hygiene. Similarly, staff perceived a gap between their competencies to promote healthy sleep in families and their capacity to address sleep problems. US health literacy goals include the need to embed accurate, accessible, and actionable health information in ECE programs. Study findings strongly support the need to work toward sleep health literacy in ECE programs. PMID- 27239488 TI - A systematic review and meta-analysis of (18)F-labeled amyloid imaging in Alzheimer's disease. AB - BACKGROUND: Amyloid imaging using fluorine 18-labeled tracers florbetapir, florbetaben, and flutemetamol has recently been reported in Alzheimer's disease (AD). METHODS: We systematically searched MEDLINE and EMBASE for relevant studies published from January 1980 to March 2014. Studies comparing imaging findings in AD and normal controls (NCs) were pooled in a meta-analysis, calculating pooled weighted sensitivity, specificity, and diagnostic odds ratio (OR) using the DerSimonian-Laird random-effects model. RESULTS: Nineteen studies, investigating 682 patients with AD, met inclusion criteria. Meta-analysis demonstrated a sensitivity of 89.6%, a specificity of 87.2%, and an OR of 91.7 for florbetapir in differentiating AD patients from NCs, and a sensitivity of 89.3%, a specificity of 87.6%, and a diagnostic OR of 69.9 for florbetaben. There were insufficient data to complete analyses for flutemetamol. CONCLUSIONS: Results suggest favorable sensitivity and specificity of amyloid imaging with fluorine 18 labeled tracers in AD. Prospective studies are required to determine optimal imaging analysis methods and resolve outstanding clinical uncertainties. PMID- 27239485 TI - Stem cells, growth factors and scaffolds in craniofacial regenerative medicine. AB - Current reconstructive approaches to large craniofacial skeletal defects are often complicated and challenging. Critical-sized defects are unable to heal via natural regenerative processes and require surgical intervention, traditionally involving autologous bone (mainly in the form of nonvascularized grafts) or alloplasts. Autologous bone grafts remain the gold standard of care in spite of the associated risk of donor site morbidity. Tissue engineering approaches represent a promising alternative that would serve to facilitate bone regeneration even in large craniofacial skeletal defects. This strategy has been tested in a myriad of iterations by utilizing a variety of osteoconductive scaffold materials, osteoblastic stem cells, as well as osteoinductive growth factors and small molecules. One of the major challenges facing tissue engineers is creating a scaffold fulfilling the properties necessary for controlled bone regeneration. These properties include osteoconduction, osetoinduction, biocompatibility, biodegradability, vascularization, and progenitor cell retention. This review will provide an overview of how optimization of the aforementioned scaffold parameters facilitates bone regenerative capabilities as well as a discussion of common osteoconductive scaffold materials. PMID- 27239489 TI - Atrophy of presubiculum and subiculum is the earliest hippocampal anatomical marker of Alzheimer's disease. AB - BACKGROUND: There is no consensus about which hippocampal subfields become atrophic earliest in the course of Alzheimer's disease (AD). METHODS: Thirty AD patients, 41 mild cognitive impairment (MCI) patients, and 38 healthy controls (HCs) underwent cerebral magnetic resonance imaging (with an automated segmentation protocol for the volumetric analysis of hippocampal subfields) and a test of immediate and delayed recall of a 15-word list. RESULTS: The volumes of the presubiculum and subiculum presented the most remarkable reduction in the patient's groups. In the MCI group, only the volumes of presubiculum and subiculum predicted performance on the memory tests. In AD patients, the volumes of all hippocampal subfields (with the notable exception of the CA1) predicted memory scores. CONCLUSIONS: Our data point to a prevalent atrophy of the presubicular-subicular complex from the early phases of AD. This finding is consistent with neuropathological observations in AD patients and probably reflects the severe degeneration of the perforant pathway while penetrating the hippocampus through the subicular field in its course from the entorhinal cortex to the dentate gyrus. PMID- 27239490 TI - Neuroimaging referral for dementia diagnosis: The specialist's perspective in Ireland. AB - BACKGROUND: Neuroimaging is an increasingly important tool in the diagnostic workup of dementia. Neurologists, geriatricians, and old-age psychiatrists are involved in key tasks in the diagnostic process, frequently referring patients with suspected dementia for neuroimaging. METHODS: The research design was a postal survey of all geriatricians, old-age psychiatrists, and neurologists in the Republic of Ireland (N = 176) as identified by the Irish Medical Directory 2011-2012 and supplementary listings. RESULTS: Almost 65% of specialists did not have access to 2-[18F]fluoro-2-deoxy-D-glucose positron emission (FDG-PET) or FDG PET/computed tomography (CT), and 80.3% did not have access to perfusion hexamethylpropyleneamine oxime single-photon emission computed tomography (SPECT) or dopaminergic iodine-123-radiolabeled 2beta-carbomethoxy-3beta-(4-iodophenyl)-N (3-fluoropropyl) nortropane SPECT. Most specialists (88.7%) referred patients with mild cognitive impairment or suspected dementia for magnetic resonance imaging (MRI), 81.7% referred for CT, and 26.8% for FDG-PET or FDG-PET/CT. Only 44.6% of respondents were aware of dementia-specific protocols for referrals for neuroimaging. CONCLUSION: Specialist access to imaging modalities other than CT and MRI is restricted. Improved access may affect patient treatment and care. PMID- 27239492 TI - Molecular markers of neuropsychological functioning and Alzheimer's disease. AB - BACKGROUND: The current project sought to examine molecular markers of neuropsychological functioning among elders with and without Alzheimer's disease (AD) and determine the predictive ability of combined molecular markers and select neuropsychological tests in detecting disease presence. METHODS: Data were analyzed from 300 participants (n = 150, AD and n = 150, controls) enrolled in the Texas Alzheimer's Research and Care Consortium. Linear regression models were created to examine the link between the top five molecular markers from our AD blood profile and neuropsychological test scores. Logistical regressions were used to predict AD presence using serum biomarkers in combination with select neuropsychological measures. RESULTS: Using the neuropsychological test with the least amount of variance overlap with the molecular markers, the combined neuropsychological test and molecular markers was highly accurate in detecting AD presence. CONCLUSION: This work provides the foundation for the generation of a point-of-care device that can be used to screen for AD. PMID- 27239491 TI - Blood protein predictors of brain amyloid for enrichment in clinical trials? AB - BACKGROUND: Measures of neocortical amyloid burden (NAB) identify individuals who are at substantially greater risk of developing Alzheimer's disease (AD). Blood based biomarkers predicting NAB would have great utility for the enrichment of AD clinical trials, including large-scale prevention trials. METHODS: Nontargeted proteomic discovery was applied to 78 subjects from the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing with a range of NAB values. Technical and independent replications were performed by immunoassay. RESULTS: Seventeen discovery candidates were selected for technical replication. alpha2 Macroglobulin, fibrinogen gamma-chain (FGG), and complement factor H-related protein 1 were confirmed to be associated with NAB. In an independent cohort, FGG plasma levels combined with age predicted NAB had a sensitivity of 59% and specificity of 78%. CONCLUSION: A single blood protein, FGG, combined with age, was shown to relate to NAB and therefore could have potential for enrichment of clinical trial populations. PMID- 27239493 TI - Reduced plasma desmosterol-to-cholesterol ratio and longitudinal cognitive decline in Alzheimer's disease. AB - BACKGROUND: We here examined whether plasma desmosterol-to-cholesterol ratio (DES/CHO) is decreased in patients with Alzheimer's disease (AD) and investigated the association between plasma DES/CHO and longitudinal cognitive decline. METHODS: Plasma DES/CHO of AD patients and age-matched controls in a Japanese cross-sectional cohort was determined. Plasma DES/CHO at baseline and follow-up visits was assessed in relation to cognitive decline in Japanese and Swedish longitudinal cohorts. RESULTS: Plasma DES/CHO was significantly reduced in Japanese AD patients and significantly correlated with Mini-Mental State Examination (MMSE) score. The longitudinal analysis revealed that plasma DES/CHO in AD patients shows a significant decrease at follow-up intervals. The decline in plasma DES/CHO is larger in the AD group with rapid progression than in that with slow progression. The changes in plasma DES/CHO significantly correlated with changes in the MMSE score. CONCLUSION: Plasma DES/CHO is decreased in AD patients and may serve as a longitudinal surrogate marker associated with cognitive decline. PMID- 27239494 TI - Can agrin cerebrospinal fluid concentration be used as an early biomarker for Alzheimer's disease? AB - The need for effective treatments halting Alzheimer's disease (AD) urges the discovery of the earliest possible biomarkers. Agrin is increased in the early stages of AD and is involved in amyloid-beta (Abeta) fibrillation and synaptogenesis. We investigated the potential of agrin as an early AD cerebrospinal fluid (CSF) biomarker. We analyzed the agrin CSF concentration in nondemented controls (n = 20) and those with mild (n = 20) and severe (n = 20) AD. The levels of agrin CSF were not significantly divergent among the different patient groups and did not correlate with the concentration of Abeta42, total tau, phosphorylated tau, or the Mini Mental State Examination scores. However, agrin strongly correlated with age in those with dementia. The results indicate that agrin cannot be used as an early AD CSF biomarker using the current immunoassay. However, our population was relatively young; thus, the correlation between agrin and age suggests that stronger differences in agrin concentrations might be found in older groups with more heterogeneous AD pathologic features. PMID- 27239495 TI - Rates of formal diagnosis of dementia in primary care: The effect of screening. AB - BACKGROUND: Screening could improve recognition of dementia in primary care. We sought to determine the effect of screening for dementia in primary care practices on the formal diagnosis rate; the distribution of differential diagnoses; and the factors associated with receiving a formal diagnosis. METHODS: The "Dementia: life- and person-centered help in Mecklenburg-Western Pomerania" is an ongoing general practitioner (GP)-based, randomized, controlled intervention trial. A total of 4064 community dwelling patients (aged >=70 years) were screened for dementia in 108 GP practices. Of these patients, 692 (17%) had positive screening results (DemTect score <9). Of these 692 patients, 406 (59%) provided informed consent. The analyses included the data from 243 patients with a complete baseline assessment (preliminary data; January 2014). RESULTS: Of 146 patients without a formal diagnosis of dementia, 72 (49%) received a formal diagnosis after a positive screening outcome (69% with "unspecified dementia"). Female sex was significantly associated with receiving a formal diagnosis (multivariate analyses). CONCLUSION: Screening improved the identification of dementia considerably. Because of the risk of receiving a false-positive diagnosis, additional diagnostic assessment should be mandatory. PMID- 27239496 TI - Practice and retest effects in longitudinal studies of cognitive functioning. PMID- 27239497 TI - Practice effects due to serial cognitive assessment: Implications for preclinical Alzheimer's disease randomized controlled trials. AB - INTRODUCTION: Practice effects are characteristic of nearly all standard cognitive tasks when repeated during serial assessments and are frequently important confounders in clinical trials. METHODS: We summarize evidence that gains in neuropsychological test performance scores associated with practice effects occur as artifactual changes associated with serial testing within clinical trials. We identify and emphasize such gains in older, non-cognitively impaired individuals and estimate an effect size of 0.25 for composite cognitive measures in older populations assessed three times in a 6- to 12-month period. RESULTS: We identified three complementary approaches that can be used to attenuate practice effects: (1) massed practice in a prebaseline period to reduce task familiarity effects; (2) tests designed to reduce practice-related gains so that item-specific driven improvements are minimized by using tasks that minimize strategy and/or maximize interitem interference; and (3) well-matched alternate forms. DISCUSSION: We have drawn attention to and increased awareness of practice effect-related gains that could result in type 1 or type 2 errors in trials. Successfully managing practice effects will eliminate a large source of error and reduce the likelihood of misinterpretation of clinical trials outcomes. PMID- 27239498 TI - Automatic speech analysis for the assessment of patients with predementia and Alzheimer's disease. AB - BACKGROUND: To evaluate the interest of using automatic speech analyses for the assessment of mild cognitive impairment (MCI) and early-stage Alzheimer's disease (AD). METHODS: Healthy elderly control (HC) subjects and patients with MCI or AD were recorded while performing several short cognitive vocal tasks. The voice recordings were processed, and the first vocal markers were extracted using speech signal processing techniques. Second, the vocal markers were tested to assess their "power" to distinguish among HC, MCI, and AD. The second step included training automatic classifiers for detecting MCI and AD, using machine learning methods and testing the detection accuracy. RESULTS: The classification accuracy of automatic audio analyses were as follows: between HCs and those with MCI, 79% +/- 5%; between HCs and those with AD, 87% +/- 3%; and between those with MCI and those with AD, 80% +/- 5%, demonstrating its assessment utility. CONCLUSION: Automatic speech analyses could be an additional objective assessment tool for elderly with cognitive decline. PMID- 27239499 TI - Conversion of MoCA to MMSE scores. PMID- 27239500 TI - Behavioral testing affects the phenotypic expression of APOE epsilon3 and APOE epsilon4 in targeted replacement mice and reduces the differences between them. AB - Apolipoprotein E4 (APOE epsilon4) is the most prevalent genetic risk factor for Alzheimer's disease (AD). Targeted replacement mice that express either APOE epsilon4 or its AD benign isoform, APOE epsilon3, are used extensively in behavioral, biochemical, and physiological studies directed at assessing the phenotypic effects of APOE epsilon4 and at unraveling the mechanisms underlying them. Such experiments often involve pursuing biochemical and behavioral measurements on the same cohort of mice. In view of the possible cross-talk interactions between brain parameters and cognitive performance, we presently investigated the extent to which the phenotypic expression of APOE epsilon4 and APOE epsilon4 in targeted replacement mice is affected by behavioral testing. This was performed using young, naive APOE epsilon4 and APOE epsilon3 mice in which the levels of distinct brain parameters are affected by the APOE genotype (e.g., elevated levels of amyloid beta [Abeta] and hyperphosphorylated tau and reduced levels of vesicular glutamate transporter (VGLUT) in hippocampal neurons of APOE epsilon4 mice). These mice were exposed to a fear-conditioning paradigm, and the resulting effects on the brain parameters were examined. The results obtained revealed that the levels of Abeta, hyperphosphorylated tau, VGluT, and doublecortin of the APOE epsilon4 and APOE epsilon3 mice were markedly affected following the exposure of APOE epsilon4 and APOE epsilon3 mice to the fear conditioning paradigm such that the isoform-specific effects of APOE epsilon4 on these parameters were greatly diminished. The finding that behavioral testing affects the APOE epsilon3 and APOE epsilon4 phenotypes and masks the differences between them has important theoretical and practical implications and suggests that the assessment of brain and behavioral parameters should be performed using different cohorts. PMID- 27239501 TI - A systematic review and meta-analysis of retinal nerve fiber layer change in dementia, using optical coherence tomography. AB - INTRODUCTION: Retinal nerve fiber layer (RNFL) thinning, assessed by optical coherence tomography (OCT), has recently been reported in various dementias. METHODS: We conducted a systematic review and meta-analysis to investigate the diagnostic utility of RNFL thickness measurement using OCT in dementia (including Alzheimer's disease [AD] and mild cognitive impairment [MCI]) compared with healthy controls (HC). RESULTS: Seventeen studies comparing AD with HC (702 AD eyes and 790 HC eyes) were included, demonstrating a significant reduction in mean RNFL thickness in AD (weighted mean difference [WMD] 12.44, 95% confidence interval or CI [-16.64, -8.25], P <.0001). Five studies comparing MCI and HC (214 MCI eyes and 421 HC eyes) were included demonstrating a significant reduction in mean RNFL thickness in MCI (WMD -8.23, 95% CI [-14.00, -2.45], P =.005). No relevant studies were identified for other dementias. DISCUSSION: OCT measurement of RNFL thickness appears diagnostically useful in discriminating between AD, or MCI, and HC. PMID- 27239502 TI - Retinal blood flow in mild cognitive impairment and Alzheimer's disease. AB - BACKGROUND: Patients with Alzheimer's disease (AD) demonstrate the narrowing of retinal veins and decreased retinal venous blood flow compared with control subjects. We assessed whether these abnormalities are present in patients with mild cognitive impairment (MCI). METHODS: After the determination of the global clinical dementia rating, 52 subjects (10 AD, 21 MCI, and 21 normal controls) underwent retinal hemodynamic profiling. Blood column diameter, blood speed, and blood flow were measured in a major temporal retinal vein using retinal laser Doppler flowmetry. In addition, peripapillary retinal nerve fiber layer (RNFL) thickness was measured using optical coherence tomography. RESULTS: Blood column diameter in AD was narrower than in both MCI (P = .004) and controls (P = .002). However, blood speed in both AD (P = .024) and MCI (P = .005) was lower than in controls. As a result, the differences in blood flow between AD and MCI (P = .036), AD and controls (P < .0001), and MCI and controls (P = .009) were significant. Although there were no differences in RNFL thickness among the groups, blood flow was correlated (P = .047) with superior RNFL thickness in the AD group, but not in the MCI (P = .40) or control (P = .84) groups. CONCLUSIONS: Retinal blood flow in MCI is intermediate between what is measured in control subjects and in AD patients. Our findings suggest that blood flow abnormalities may precede the neurodegeneration in AD. PMID- 27239503 TI - Subjective memory impairment: No suitable criteria for case-finding of dementia in primary care. AB - INTRODUCTION: Subjective memory impairment (SMI) might be used for the case finding of dementia. Present analyses aim to determine the diagnostic value and the predictive ability of SMI and related worries for the discrimination of patients screened positive or negative for dementia. METHODS: The analyses are based on data derived from the ongoing German general practioner (GP)-based, randomized controlled trial DelpHi-MV. A total of 5106 patients (age >= 70, living at home) were first asked for SMI and related worries and then screened for dementia in 110 participating GP practices (November 2011 to August 2014; preliminary data) using the DemTect. RESULTS: A total number of 2556 patients (50%) stated that they experience SMI and 892 patients (17%) screened positive for dementia. The sensitivity of SMI for the correct classification of positively screened patients was 54%, the positive predictive value (PPV) 19%. The specificity of SMI was 51%; the negative predictive value (NPV) 84%. Among 2480 patients with SMI, 45% reported SMI-related worries (sensitivity 52%; specificity 57%; PPV 22%; NPV 84%). Receiver operating characteristics analyses showed no statistically significant improvement in the area under the curves when using SMI or related worries as predictors (additional to age and sex) for the discrimination between positively and negatively screened patients. DISCUSSION: The analyses showed that the risk of overlooking cognitive impairment in the subgroup of patients who state that they do not experience SMI would be unreasonable high. Thus, the results provide clear evidence that neither SMI nor related worries can be used as a valid criteria to decide whether an elderly primary care patient should be tested for dementia. TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT01401582. PMID- 27239504 TI - Cognitive performance before and after the onset of subjective cognitive decline in old age. AB - BACKGROUND: Our objectives were (1) to test the association between the report of subjective cognitive decline (SCD) and prospective objective cognitive performance in high age individuals and (2) to study the course of longitudinal cognitive performance before and after the first report of SCD. METHODS: Cognitively normal elderly participants of the German Study on Ageing, Cognition, and Dementia study (N = 2330) with SCD (subjective decline in memory with and without associated concerns) and without SCD at baseline were assessed over 8 years with regard to immediate and delayed verbal recall, verbal fluency, working memory, and global cognition. Baseline performance and cognitive trajectories were compared between groups. In addition, cognitive trajectories before and after the initial report of SCD (incident SCD) were modelled in those without SCD at baseline. RESULTS: Baseline performance in the SCD group was lower and declined more steeply in immediate and delayed verbal recall than in the control group (no SCD at baseline). This effect was more pronounced in the SCD group with concerns. Incident SCD was preceded by decline in immediate and delayed memory and word fluency. CONCLUSIONS: SCD predicts future memory decline. Incident SCD is related to previous cognitive decline. The latter finding supports the concept of SCD indicating first subtle decline in cognitive performance that characterizes preclinical Alzheimer's disease. PMID- 27239505 TI - Multimodal prediction of conversion to Alzheimer's disease based on incomplete biomarkers. AB - BACKGROUND: This study investigates the prediction of mild cognitive impairment to-Alzheimer's disease (MCI-to-AD) conversion based on extensive multimodal data with varying degrees of missing values. METHODS: Based on Alzheimer's Disease Neuroimaging Initiative data from MCI-patients including all available modalities, we predicted the conversion to AD within 3 years. Different ways of replacing missing data in combination with different classification algorithms are compared. The performance was evaluated on features prioritized by experts and automatically selected features. RESULTS: The conversion to AD could be predicted with a maximal accuracy of 73% using support vector machines and features chosen by experts. Among data modalities, neuropsychological, magnetic resonance imaging, and positron emission tomography data were most informative. The best single feature was the functional activities questionnaire. CONCLUSION: Extensive multimodal and incomplete data can be adequately handled by a combination of missing data substitution, feature selection, and classification. PMID- 27239506 TI - Hippocampus and basal forebrain volumes modulate effects of anticholinergic treatment on delayed recall in healthy older adults. AB - INTRODUCTION: Volumes of hippocampus and cholinergic basal forebrain are associated with delayed recall performance and may modulate the effect of a muscarinic receptor antagonist on delayed recall in healthy volunteers. METHODS: We studied 15 older adults before and after the oral administration of a single dose of 1 or 2 mg of the preferential M1 muscarinic receptor antagonist trihexyphenidyl (ArtaneTM) or placebo in a double-blind randomized cross-over design. Hippocampus and basal forebrain volumes were measured using magnetic resonance imaging. RESULTS: We found a significant interaction between treatment and hippocampus volume and a trend level effect between treatment and anterior basal forebrain volume on task performance, with an attenuation of the association between volume size and performance with trihexyphenidyl. DISCUSSION: These findings suggest a reduction of delayed recall performance with increasing doses of the muscarinic antagonist that is related to an uncoupling of the association of task performance with cholinergic basal forebrain and hippocampus volumes. PMID- 27239507 TI - Association between air pollutants and dementia risk in the elderly. AB - BACKGROUND: The aging rate in Taiwan is the second highest in the world. As the population ages quickly, the prevalence of dementia increases rapidly. There are some studies that have explored the association between air pollution and cognitive decline, but the association between air pollution and dementia has not been directly evaluated. METHODS: This was a case-control study comprising 249 Alzheimer's disease (AD) patients, 125 vascular dementia (VaD) patients, and 497 controls from three teaching hospitals in northern Taiwan from 2007 to 2010. Data of particulate matter <10 MUm in diameter (PM10) and ozone were obtained from the Taiwan Environmental Protection Administration for 12 and 14 years, respectively. Blood samples were collected to determine the apolipoprotein E (APOE) E4 haplotype. Bayesian maximum entropy was used to estimate the individual exposure level of air pollutants, which was then tertiled for analysis. Conditional logistic regression models were used to estimate adjusted odds ratios (AORs) and 95% confidence intervals between the association of PM10 and ozone exposure with AD and VaD risk. RESULTS: The highest tertile of PM10 (>=49.23 MUg/m(3)) or ozone (>=21.56 ppb) exposure was associated with increased AD risk (highest vs. lowest tertile of PM10: AOR = 4.17; highest vs. lowest tertile of ozone: AOR = 2.00). Similar finding was observed for VaD. The association with AD and VaD risk remained for the highest tertile PM10 exposure after stratification by APOE E4 status and gender. CONCLUSIONS: Long-term exposure to the highest tertile of PM10 or ozone was significantly associated with an increased risk of AD and VaD. PMID- 27239509 TI - Invited commentary: The importance of studying environmental risk factors for dementia. PMID- 27239508 TI - Evidence for age-associated cognitive decline from Internet game scores. AB - INTRODUCTION: Lumosity's Memory Match (LMM) is an online game requiring visual working memory. Change in LMM scores may be associated with individual differences in age-related changes in working memory. METHODS: Effects of age and time on LMM learning and forgetting rates were estimated using data from 1890 game sessions for users aged 40 to 79 years. RESULTS: There were significant effects of age on baseline LMM scores (beta = -.31, standard error or SE = .02, P < .0001) and lower learning rates (beta = -.0066, SE = .0008, P < .0001). A sample size of 202 subjects/arm was estimated for a 1-year study for subjects in the lower quartile of game performance. DISCUSSION: Online memory games have the potential to identify age-related decline in cognition and to identify subjects at risk for cognitive decline with smaller sample sizes and lower cost than traditional recruitment methods. PMID- 27239510 TI - Amyloid-beta sequester proteins as blood-based biomarkers of cognitive decline. AB - INTRODUCTION: There are no blood-based biomarkers for cognitive decline in aging, or mild cognitive impairment (MCI) and Alzheimer's disease (AD). Cumulative evidence suggests that apolipoproteins, complement system, and transthyretin are involved in AD pathogenesis by sequestration of amyloid beta. However, there is no clinical study to assess the utility of "sequester proteins" in risk assessment and/or diagnosis of MCI and AD. METHODS: Serum levels of sequester proteins and their clinical potential in cognitive decline assessment were analyzed by longitudinal and cross-sectional studies using independent cohorts and were confirmed by a prospective study. RESULTS: A combination of apolipoprotein A1, complement C3, and transthyretin achieved an area under the curve of 0.89 (sensitivity 91% and specificity 80%) in MCI versus healthy controls and also discriminated individuals with mild cognitive decline from healthy controls. DISCUSSION: A set of sequester proteins could be blood-based biomarkers for assessment of early stages of cognitive decline. PMID- 27239511 TI - Scientific and ethical features of English-language online tests for Alzheimer's disease. AB - INTRODUCTION: Freely accessible online tests for the diagnosis of Alzheimer's disease (AD) are widely available. The objective of this study was to evaluate these tests along three dimensions as follows: (1) scientific validity; (2) human computer interaction (HCI) features; and (3) ethics features. METHODS: A sample of 16 online tests was identified through a keyword search. A rating grid for the tests was developed, and all tests were evaluated by two expert panels. RESULTS: Expert analysis revealed that (1) the validity of freely accessible online tests for AD is insufficient to provide useful diagnostic information; (2) HCI features of the tests are adequate for target users, and (3) the tests do not adhere to accepted ethical norms for medical interventions. DISCUSSION: The most urgent concerns raised center on the ethics of collecting and evaluating responses from users. Physicians and other professionals will benefit from a heightened awareness of these tools and their limitations today. PMID- 27239512 TI - Concordance of the Montreal cognitive assessment with standard neuropsychological measures. AB - INTRODUCTION: The concordance of the Montreal cognitive assessment (MoCA) with more comprehensive neuropsychological measures remains unclear. This study examined the individual MoCA domains with more comprehensive and commonly used neuropsychological measures to determine the degree of overlap. METHODS: Data included individuals seen in an outpatient neurology clinic specializing in neurodegenerative disease who were administered the MoCA and also underwent neuropsychological assessment (n = 471). A principal component analysis with varimax rotation was completed using the MoCA domain scores and comprehensive neuropsychological evaluation measures. RESULTS: Four factors emerged accounting for 55.6% of the variance: (1) visuospatial/executive functioning; (2) memory; (3) attention; and (4) language. The individual MoCA domain scores demonstrated high factor loadings with standard neuropsychological measures purported to measure similar cognitive constructs. DISCUSSION: These findings provide empirical validation for the MoCA domain classifications, lending further support for the use of the MoCA as a cognitive screen that reflects similar constructs as those measured by a comprehensive battery. PMID- 27239513 TI - Why do we need national guidelines for adults with intellectual disability and dementia? PMID- 27239514 TI - The CAIDE Dementia Risk Score App: The development of an evidence-based mobile application to predict the risk of dementia. AB - BACKGROUND: The CAIDE (Cardiovascular Risk Factors, Aging, and Incidence of Dementia) Dementia Risk Score is a validated tool to predict late-life dementia risk (20 years later), based on midlife vascular risk factors. The goal was to render this prediction tool widely accessible. METHODS: The CAIDE Risk Score (mobile application) App was developed based on the CAIDE Dementia Risk Score, involving information on age, educational level, hypertension, hypercholesterolemia, obesity, and physical inactivity. RESULTS: The CAIDE Risk Score App is an evidence-based practical tool, which allows users to detect their individual risk, provides guidance for risk modification, and suggests consulting a health care practitioner if needed. Moreover, it allows practitioners to discuss preventive measures and monitor risk reduction. CONCLUSIONS: The CAIDE Risk Score App is the first to predict the risk for dementia through an important evidence-based tool. The App can encourage users to actively decrease their modifiable risk factors and postpone cognitive impairment and dementia. PMID- 27239515 TI - Alterations of membrane protein expression in red blood cells of Alzheimer's disease patients. AB - Preventive measures, prognosis, or selected therapy in multifactorial maladies, including Alzheimer's disease (AD), require the application of a wide range of diagnostic assays. There is a large unmet need for relatively simple, blood-based biomarkers in this regard. We have recently developed a rapid and reliable flow cytometry and antibody-based method for the quantitative measurement of various red blood cell (RBC) membrane proteins from a drop of blood. Here, we document that the RBC expression of certain membrane proteins, especially that of the GLUT1 transporter and the insulin receptor (INSR), is significantly higher in AD patients than in age-matched healthy subjects. The observed differences may reflect long-term metabolic alterations relevant in the development of AD. These findings may pave the way for a diagnostic application of RBC membrane proteins as relatively stable and easily accessible personalized biomarkers in AD. PMID- 27239516 TI - Clinical use of amyloid-positron emission tomography neuroimaging: Practical and bioethical considerations. AB - Until recently, estimation of beta-amyloid plaque density as a key element for identifying Alzheimer's disease (AD) pathology as the cause of cognitive impairment was only possible at autopsy. Now with amyloid-positron emission tomography (amyloid-PET) neuroimaging, this AD hallmark can be detected antemortem. Practitioners and patients need to better understand potential diagnostic benefits and limitations of amyloid-PET and the complex practical, ethical, and social implications surrounding this new technology. To complement the practical considerations, Eli Lilly and Company sponsored a Bioethics Advisory Board to discuss ethical issues that might arise from clinical use of amyloid-PET neuroimaging with patients being evaluated for causes of cognitive decline. To best address the multifaceted issues associated with amyloid-PET neuroimaging, we recommend this technology be used only by experienced imaging and treating physicians in appropriately selected patients and only in the context of a comprehensive clinical evaluation with adequate explanations before and after the scan. PMID- 27239517 TI - Late-onset behavioral variant of frontotemporal lobar degeneration versus Alzheimer's disease: Interest of cerebrospinal fluid biomarker ratios. AB - INTRODUCTION: Cerebrospinal fluid (CSF) biomarker ratios were never evaluated in late-onset (>65 years) behavioral variant of frontotemporal lobar degeneration (bvFTLD) versus Alzheimer's disease (AD). METHODS: A retrospective monocentric study on 44 clinically suspected amnestic AD or bvFTLD patients with onset after 65 years and available CSF and clinical data. RESULTS: The final clinical diagnosis was AD (n = 28; 64%), late-onset bvFTLD (n = 14; 32%), and others (n = 2; 4%). Applying the CSF cutoff total-tau/Abeta1-42 of 1.06, all the bvFTLD were in the FTLD range (<1.06, bvFTLD/FTLD), whereas the AD patients were either in the AD (>1.06, AD/AD) or in the FTLD range (<1.06, AD/FTLD); CSF biomarkers were significantly different in these three groups, but not neuroradiological features or presence of episodic memory deficit. DISCUSSION: Late-onset bvFTLD is underdiagnosed. The available CSF biomarker ratio cutoff need further improvement and overestimated late-onset bvFTLD but could potentially differentiate it from AD, notably in case of conflicting results. PMID- 27239519 TI - Letter to the editor regarding: Summary of the evidence on modifiable risk factors for cognitive decline and dementia: A population-based perspective. PMID- 27239518 TI - Do cerebrospinal fluid transfer methods affect measured amyloid beta42, total tau, and phosphorylated tau in clinical practice? AB - INTRODUCTION: Cerebrospinal fluid (CSF) neurodegenerative markers are measured clinically to support a diagnosis of Alzheimer's disease. Several preanalytical factors may alter the CSF concentrations of amyloid beta 1-42 (Abeta1-42) in particular with the potential to influence diagnosis. We aimed to determine whether routine handling of samples alters measured biomarker concentration compared with that of prompt delivery to the laboratory. METHODS: Forty individuals with suspected neurodegenerative diseases underwent diagnostic lumbar punctures using a standardized technique. A sample of each patient's CSF was sent to the laboratory by four different delivery methods: (1) by courier at room temperature; (2) by courier, on ice; (3) using standard hospital portering; and (4) after quarantining for >24 hours. Abeta1-42, total tau (t-tau), and phosphorylated tau (p-tau) levels measured using standard enzyme-linked immunosorbent assay techniques were compared between transfer methods. RESULTS: There were no significant differences in Abeta1-42, t-tau, or p-tau concentrations measured in samples transported via the different delivery methods despite significant differences in time taken to deliver samples. DISCUSSION: When CSF is collected in appropriate tubes, transferred at room temperature, and processed within 24 hours, neurodegenerative markers can be reliably determined. PMID- 27239520 TI - A clinical trial to validate event-related potential markers of Alzheimer's disease in outpatient settings. AB - INTRODUCTION: We investigated whether event-related potentials (ERP) collected in outpatient settings and analyzed with standardized methods can provide a sensitive and reliable measure of the cognitive deficits associated with early Alzheimer's disease (AD). METHODS: A total of 103 subjects with probable mild AD and 101 healthy controls were recruited at seven clinical study sites. Subjects were tested using an auditory oddball ERP paradigm. RESULTS: Subjects with mild AD showed lower amplitude and increased latency for ERP features associated with attention, working memory, and executive function. These subjects also had decreased accuracy and longer reaction time in the target detection task associated with the ERP test. DISCUSSION: Analysis of ERP data showed significant changes in subjects with mild AD that are consistent with the cognitive deficits found in this population. The use of an integrated hardware/software system for data acquisition and automated data analysis methods make administration of ERP tests practical in outpatient settings. PMID- 27239521 TI - Longitudinal cerebrospinal fluid biomarker measurements in preclinical sporadic Alzheimer's disease: A prospective 9-year study. AB - INTRODUCTION: Ascertainment of the pattern and temporal change of biomarkers in preclinical (asymptomatic) sporadic Alzheimer's disease (AD) will increase knowledge about early pathogenesis and facilitate interventional therapeutic trials. METHODS: In this prospective longitudinal study, repeated cerebrospinal fluid (CSF) collections and cognitive evaluations were performed in cognitively healthy elderly individuals during a 9-year period. RESULTS: Low CSF beta-amyloid (Abeta)42 levels predicted subsequent development of clinical AD 9 years later. Noteworthy, one-third of individuals with pathologically low baseline Abeta42 levels remained cognitively intact during follow-up. No further decrease in Abeta42 was seen in those with low levels already at baseline. DISCUSSION: CSF Abeta42 predicts sporadic AD at least 9 years before dementia onset and has plateaued already at this time. However, many individuals can harbor brain amyloid accumulation over a decade without signs of cognitive deterioration, which could implicate how CSF biomarkers are used to identify preclinical AD in future interventional therapeutic trials. PMID- 27239522 TI - Revolutionizing Alzheimer's disease and clinical trials through biomarkers. AB - The Alzheimer's Association's Research Roundtable met in May 2014 to explore recent progress in developing biomarkers to improve understanding of disease pathogenesis and expedite drug development. Although existing biomarkers have proved extremely useful for enrichment of subjects in clinical trials, there is a clear need to develop novel biomarkers that are minimally invasive and that more broadly characterize underlying pathogenic mechanisms, including neurodegeneration, neuroinflammation, and synaptic dysfunction. These may include blood-based assays and new neuropsychological testing protocols, as well as novel ligands for positron emission tomography imaging, and advanced magnetic resonance imaging methodologies. In addition, there is a need for biomarkers that can serve as theragnostic markers of response to treatment. Standardization remains a challenge, although international consortia have made substantial progress in this area and provide lessons for future standardization efforts. PMID- 27239523 TI - Predicting conversion to dementia in a memory clinic: A standard clinical approach compared with an empirically defined clustering method (latent profile analysis) for mild cognitive impairment subtyping. AB - INTRODUCTION: Mild cognitive impairment (MCI) has clinical value in its ability to predict later dementia. A better understanding of cognitive profiles can further help delineate who is most at risk of conversion to dementia. We aimed to (1) examine to what extent the usual MCI subtyping using core criteria corresponds to empirically defined clusters of patients (latent profile analysis [LPA] of continuous neuropsychological data) and (2) compare the two methods of subtyping memory clinic participants in their prediction of conversion to dementia. METHODS: Memory clinic participants (MCI, n = 139) and age-matched controls (n = 98) were recruited. Participants had a full cognitive assessment, and results were grouped (1) according to traditional MCI subtypes and (2) using LPA. MCI participants were followed over approximately 2 years after their initial assessment to monitor for conversion to dementia. RESULTS: Groups were well matched for age and education. Controls performed significantly better than MCI participants on all cognitive measures. With the traditional analysis, most MCI participants were in the amnestic multidomain subgroup (46.8%) and this group was most at risk of conversion to dementia (63%). From the LPA, a three-profile solution fit the data best. Profile 3 was the largest group (40.3%), the most cognitively impaired, and most at risk of conversion to dementia (68% of the group). DISCUSSION: LPA provides a useful adjunct in delineating MCI participants most at risk of conversion to dementia and adds confidence to standard categories of clinical inference. PMID- 27239524 TI - Cerebrospinal fluid biomarkers in Alzheimer's disease: Diagnostic accuracy and prediction of dementia. AB - INTRODUCTION: Guidelines for the use of cerebrospinal fluid (CSF) biomarkers in the diagnosis of Alzheimer's disease (AD) establish that each laboratory must use internally qualified cutoff values. We determined the concentrations of biomarkers that discriminate cases from controls and combinations that predict the progression to dementia in a Brazilian cohort. METHODS: Concentrations of amyloid-beta peptide (Abeta1-42), total tau (T-tau), and (181)Thr-phosphorylated tau (P-tau) were determined in CSF samples from 184 older adults (68 mild cognitive impairment, 41 AD, 34 non-AD cognitive impairment, and 41 controls) by the INNO-BIA AlzBio3 assay. RESULTS: Cutoff values discriminating AD from controls are as follows: Abeta1-42: 416.0 pg/mL (sensitivity [SE]: 83%, specificity (SP): 70%); T-tau: 76.7 pg/mL (SE: 82%, SP: 67%); P-tau: 36.1 pg/mL (SE: 83%, SP: 49%); Abeta1-42/P-tau <9.53 (SE: 88%, SP: 78%); and Abeta1-42/T-tau <4.13 (SE: 80%; SP: 80%). Combining values Abeta1-42 <416.5 pg/mL and Abeta1-42/P tau <9.5 best predicted the conversion in 2 years (Cox regression: hazard ratio 7.24 [2.09-25.06], P = .002, SE: 74%, Sp: 73%). DISCUSSION: Our findings are in line with most of the available evidence in this field; yet, our cutoff values are different from those derived from other laboratories. PMID- 27239525 TI - Lipoprotein-associated phospholipase A2, homocysteine, and Alzheimer's disease. AB - INTRODUCTION: Lipoprotein-associated phospholipase A2 (Lp-PLA2) and homocysteine (Hcy) have been linked to inflammation and Alzheimer's disease (AD). Using a case control design, we examined their independent effects and interactions with cardiovascular disease equivalent (CVDE), on AD risk. METHODS: AD cases and controls were from the Texas Alzheimer's Research and Care Consortium study. Lp PLA2 was determined using the PLAC test (diaDexus, Inc), and Hcy by recombinant cycling assay (Roche Hitachi 911). Logistic regression was used to predict AD case status. We assayed for Lp-PLA2 in the brain tissue of cases and controls. RESULTS: AD case status was independently associated with Lp-PLA2 and Hcy above the median (odds ratio [OR] = 1.91; 95% confidence interval [CI] = 1.22-2.97; P < .001 and OR = 1.81; 95% CI = 1.16-2.82; P = .009, respectively). Lp-PLA2, but not Hcy, interacted with CVDE to increase risk. Lp-PLA2 was absent from the brain tissue in both groups. DISCUSSION: Higher Lp-PLA2 and Hcy are independently associated with AD. The association of Lp-PLA2 with AD may be mediated through vascular damage. PMID- 27239526 TI - Semantic and nonfluent aphasic variants, secondarily associated with amyotrophic lateral sclerosis, are predominant frontotemporal lobar degeneration phenotypes in TBK1 carriers. AB - INTRODUCTION: TBK1 mutations represent a rare novel genetic cause of amyotrophic lateral sclerosis (ALS) without or with dementia. The full spectrum of TBK1 phenotypes has not been completely defined so far. METHODS: We describe the clinical and neuroimaging characteristics of loss-of-function mutation carriers initially presenting with frontotemporal lobar degeneration (FTLD) phenotypes. RESULTS: Two carriers initially presented semantic variant of FTLD (svFTLD); two other developed nonfluent variant of FTLD (nfvFTLD) and corticobasal syndrome (CBS), associated with severe anterior temporal and opercular atrophy. All secondarily developed ALS. DISCUSSION: This study enlarges the phenotypic spectrum of TBK1 mutations, including svFTLD and nfvFTLD/CBS, not reported so far. Aphasic presentations seem to be more evocative of TBK1 genotype than behavioral variant of FTLD, and TBK1 should be analyzed in patients with isolated FTLD at onset, particularly in rare aphasic cases secondarily associated with ALS. PMID- 27239527 TI - Cerebral atrophy in mild cognitive impairment: A systematic review with meta analysis. AB - INTRODUCTION: Although mild cognitive impairment (MCI) diagnosis is mainly based on cognitive assessment, reliable estimates of structural changes in specific brain regions, that could be contrasted against normal brain aging and inform diagnosis, are lacking. This study aimed to systematically review the literature reporting on MCI-related brain changes. METHODS: The MEDLINE database was searched for studies investigating longitudinal structural changes in MCI. Studies with compatible data were included in the meta-analyses. A qualitative review was conducted for studies excluded from meta-analyses. RESULTS: The analyses revealed a 2.2-fold higher volume loss in the hippocampus, 1.8-fold in the whole brain, and 1.5-fold in the entorhinal cortex in MCI participants. DISCUSSION: Although the medial temporal lobe is likely to be more vulnerable to MCI pathology, atrophy in this brain area represents a relatively small proportion of whole brain loss, suggesting that future investigations are needed to identify the source of unaccounted volume loss in MCI. PMID- 27239528 TI - Discriminative and prognostic potential of cerebrospinal fluid phosphoTau/tau ratio and neurofilaments for frontotemporal dementia subtypes. AB - INTRODUCTION: A decreased cerebrospinal fluid (CSF) p-Tau181 to total tau ratio (p/t-tau) is a biomarker for frontotemporal lobar degeneration with TDP43 inclusions (FTLD-TDP) and for amyotrophic lateral sclerosis (ALS). CSF light chain neurofilaments (NfL) are increased in ALS. We examined whether CSF p/t-tau and NfL are related to ALS status in FTLD-TDP. METHODS: We compared CSF p/t-tau and NfL levels between patients with FTLD-TDP with ALS (n = 15), FTLD-TDP without ALS (n = 17), FTLD-Tau (n = 6), Alzheimer's disease (AD; n = 25), and subjective memory complaints (SMC, n = 24). RESULTS: Apart from FTLD-Tau, all groups differed significantly with increasing p/t-tau ratios from FTLD-TDP with ALS to FTLD-TDP without ALS to AD and SMC. CSF NfL was very high in FTLD-TDP with ALS followed by FTLD-TDP without ALS, AD, and SMC. Both biomarkers correlated with survival. DISCUSSION: CSF p/t-tau ratio and NfL levels are strongly driven by ALS status. These markers, therefore, appear to be more of prognostic than diagnostic significance. PMID- 27239531 TI - Using quantile regression to create baseline norms for neuropsychological tests. AB - INTRODUCTION: The Uniform Data Set (UDS) contains neuropsychological test scores and demographic information for participants at Alzheimer's disease centers across the United States funded by the National Institute on Aging. Mean regression analysis of neuropsychological tests has been proposed to detect cognitive decline, but the approach requires stringent assumptions. METHODS: We propose using quantile regression to directly model conditional percentiles of neuropsychological test scores. An online application allows users to easily implement the proposed method. RESULTS: Scores from 13 different neuropsychological tests were analyzed for 5413 cognitively normal participants in the UDS. Quantile and mean regression models were fit using age, gender, and years of education. Differences between the mean and quantile regression estimates were found on the individual measures. DISCUSSION: Quantile regression provides more robust estimates of baseline percentiles for cognitively normal adults. This can then serve as standards against which to detect individual cognitive decline. PMID- 27239529 TI - A priori collaboration in population imaging: The Uniform Neuro-Imaging of Virchow-Robin Spaces Enlargement consortium. AB - INTRODUCTION: Virchow-Robin spaces (VRS), or perivascular spaces, are compartments of interstitial fluid enclosing cerebral blood vessels and are potential imaging markers of various underlying brain pathologies. Despite a growing interest in the study of enlarged VRS, the heterogeneity in rating and quantification methods combined with small sample sizes have so far hampered advancement in the field. METHODS: The Uniform Neuro-Imaging of Virchow-Robin Spaces Enlargement (UNIVRSE) consortium was established with primary aims to harmonize rating and analysis (www.uconsortium.org). The UNIVRSE consortium brings together 13 (sub)cohorts from five countries, totaling 16,000 subjects and over 25,000 scans. Eight different magnetic resonance imaging protocols were used in the consortium. RESULTS: VRS rating was harmonized using a validated protocol that was developed by the two founding members, with high reliability independent of scanner type, rater experience, or concomitant brain pathology. Initial analyses revealed risk factors for enlarged VRS including increased age, sex, high blood pressure, brain infarcts, and white matter lesions, but this varied by brain region. DISCUSSION: Early collaborative efforts between cohort studies with respect to data harmonization and joint analyses can advance the field of population (neuro)imaging. The UNIVRSE consortium will focus efforts on other potential correlates of enlarged VRS, including genetics, cognition, stroke, and dementia. PMID- 27239530 TI - Five-year biomarker progression variability for Alzheimer's disease dementia prediction: Can a complex instrumental activities of daily living marker fill in the gaps? AB - INTRODUCTION: Biomarker progressions explain higher variability in cognitive decline than baseline values alone. This study examines progressions of established biomarkers along with a novel marker in a longitudinal cognitive decline. METHODS: A total of 215 subjects were used with a diagnosis of normal, mild cognitive impairment (MCI) or Alzheimer's disease (AD) at baseline. We calculated standardized biomarker progression rates and used them as predictors of outcome within 5 years. RESULTS: Early cognitive declines were more strongly explained by fluorodeoxyglucose-positron emission tomography, precuneus and medial temporal cortical thickness, and the complex instrumental activities of daily living (iADL) marker progressions. Using Cox proportional hazards model, we found that these progressions were a significant risk factor for conversion from both MCI to AD (adjusted hazard ratio 1.45; 95% confidence interval 1.20-1.93; P = 1.23 * 10(-5)) and cognitively normal to MCI (adjusted hazard ratio 1.76; 95% confidence interval 1.32-2.34; P = 1.55 * 10(-5)). DISCUSSION: Compared with standard biological biomarkers, complex functional iADL markers could also provide predictive information for cognitive decline during the presymptomatic stage. This has important implications for clinical trials focusing on prevention in asymptomatic individuals. PMID- 27239532 TI - Sensitivity of composite scores to amyloid burden in preclinical Alzheimer's disease: Introducing the Z-scores of Attention, Verbal fluency, and Episodic memory for Nondemented older adults composite score. AB - INTRODUCTION: Cognitive composite scores developed for preclinical Alzheimer's disease (AD) often consist of multiple cognitive domains as they may provide greater sensitivity to detect beta-amyloid (Abeta)-related cognitive decline than episodic memory (EM) composite scores alone. However, this has never been empirically tested. We compared the rate of cognitive decline associated with high Abeta (Abeta+) and very high Abeta (Abeta++) in cognitively normal (CN) older adults on three multidomain cognitive composite scores and one single domain (EM) composite score. METHODS: CN older adults (n = 423) underwent Abeta neuroimaging and completed neuropsychological assessments at baseline, and at 18 , 36-, 54-, and 72-month follow-ups. Four cognitive composite scores were computed: the ADCS-PACC (ADCS-Preclinical Alzheimer Cognitive Composite), ADCS PACC without the inclusion of the mini-mental state examination (MMSE), an EM composite, and the Z-scores of Attention, Verbal fluency, and Episodic memory for Nondemented older adults (ZAVEN) composite. RESULTS: Compared with Abeta+ CN older adults, Abeta++ CN older adults showed faster rates of decline across all cognitive composites, with the largest decline observed for ZAVEN composite (d = 1.07). Similarly, compared with Abeta- CN older adults, Abeta+ CN older adults also showed faster rates of cognitive decline, but only for the ADCS-PACC no MMSE (d = 0.43), EM (d = 0.53), and ZAVEN (d = 0.50) composites. DISCUSSION: Abeta related cognitive decline is best detected using validated neuropsychological instruments. Removal of the MMSE from the ADCS-PACC and replacing it with a test of executive function (verbal fluency; i.e., the ZAVEN) rendered this composite more sensitive even in detecting Abeta-related cognitive decline between Abeta+ and Abeta++ CN older adults. PMID- 27239533 TI - Prediction of Alzheimer's disease pathophysiology based on cortical thickness patterns. AB - INTRODUCTION: Recent studies have shown that pathologically defined subtypes of Alzheimer's disease (AD) represent distinctive atrophy patterns and clinical characteristics. We investigated whether a cortical thickness-based clustering method can reflect such findings. METHODS: A total of 77 AD subjects from the Alzheimer's Disease Neuroimaging Initiative 2 data set who underwent 3-T magnetic resonance imaging, [(18)F]-fluorodeoxyglucose-positron emission tomography (PET), [(18)F]-Florbetapir PET, and cerebrospinal fluid (CSF) tests were enrolled. After clustering based on cortical thickness, diverse imaging and biofluid biomarkers were compared between these groups. RESULTS: Three cortical thinning patterns were noted: medial temporal (MT; 19.5%), diffuse (55.8%), and parietal dominant (P; 24.7%) atrophy subtypes. The P subtype was the youngest and represented more glucose hypometabolism in the parietal and occipital cortices and marked amyloid beta accumulation in most brain regions. The MT subtype revealed more glucose hypometabolism in the left hippocampus and bilateral frontal cortices and less performance in memory tests. CSF test results did not differ between the groups. DISCUSSION: Cortical thickness patterns can reflect pathophysiological and clinical changes in AD. PMID- 27239534 TI - Selective familiarity deficits in otherwise cognitively intact aging individuals with genetic risk for Alzheimer's disease. AB - INTRODUCTION: Familiarity has been associated with integrity of the rhinal cortex. Thus, impairment in familiarity is expected in very early stages of Alzheimer's disease (AD). The apolipoprotein E (APOE) epsilon4 allele is a major risk factor for AD. Here, we investigated the effect of the APOE epsilon4 status on familiarity in cognitively normal aging individuals. METHODS: Eighty-one individuals aged between 55 and 80 years, 21 carriers and 60 noncarriers, were used in these analyses. A cognitive evaluation was performed on all participants to document the absence of objective cognitive deficits. The effect of APOE epsilon4 status on familiarity was tested using independent sample t test and an analysis of covariance controlling for age, gender, and education. RESULTS: The groups did not differ in term of age, education, and male/female ratio. APOE epsilon4 carriers showed a significant reduction in familiarity. No other cognitive deficit was observed in the group of epsilon4 carriers, relative to noncarriers. DISCUSSION: APOE epsilon4 is associated with a reduction in familiarity in the absence of other cognitive deficits. These results suggest that performance in familiarity could represent an early cognitive marker for individuals at risk of AD. PMID- 27239535 TI - Learning to classify neural activity from a mouse model of Alzheimer's disease amyloidosis versus controls. AB - The mechanisms underlying Alzheimer's disease (AD) onset and progression are not yet elucidated. The extent to which alterations in the activity of individual neurons of an AD model are significant, and the phase at which they can be captured, point to the intensity of the pathology and imply the stage at which it can be detected. Using a machine-learning algorithm, we present a successful cell by-cell classification of intracellularly recorded neurons from the B6C3 APPswe/PS1dE9 AD model, versus wildtypes controls, at both a late stage and at an early stage, when the plaque pathology and behavioral deficits are absent or rare. These results suggest that the deficits present in neuronal networks of both old and young transgenic animals are large enough to be apparent at the level of individual neurons, and that the pathology could be detected in nearly any given sample, even before pathologic signs. PMID- 27239537 TI - Predicting progression from mild cognitive impairment to Alzheimer's disease using longitudinal callosal atrophy. AB - INTRODUCTION: We investigate whether longitudinal callosal atrophy could predict conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD). METHODS: Longitudinal (baseline + 1-year follow-up) MRI scans of 132 MCI subjects from the Alzheimer's Disease Neuroimaging Initiative were used. A total of 54 subjects did not convert to AD over an average (+/-SD) follow-up of 5.46 (+/ 1.63) years, whereas 78 converted to AD with an average conversion time of 2.56 (+/-1.65) years. Annual change in the corpus callosum thickness profile was calculated from the baseline and 1-year follow-up MRI. A logistic regression model with fused lasso regularization for prediction was applied to the annual changes. RESULTS: We found a sex difference. The accuracy of prediction was 84% in females and 61% in males. The discriminating regions of corpus callosum differed between sexes. In females, the genu, rostrum, and posterior body had predictive power, whereas the genu and splenium were relevant in males. DISCUSSION: Annual callosal atrophy predicts MCI-to-AD conversion in females more accurately than in males. PMID- 27239536 TI - Periodontal disease's contribution to Alzheimer's disease progression in Down syndrome. AB - People with Down syndrome (DS) are at an increased risk for Alzheimer's disease (AD). After 60 years of age, >50% of DS subjects acquire dementia. Nevertheless, the age of onset is highly variable possibly because of both genetic and environmental factors. Genetics cannot be modified, but environmental risk factors present a potentially relevant intervention for DS persons at risk for AD. Among them, inflammation, important in AD of DS type, is potential target. Consistent with this hypothesis, chronic peripheral inflammation and infections may contribute to AD pathogenesis in DS. People with DS have an aggressive form of periodontitis characterized by rapid progression, significant bacterial and inflammatory burden, and an onset as early as 6 years of age. This review offers a hypothetical mechanistic link between periodontitis and AD in the DS population. Because periodontitis is a treatable condition, it may be a readily modifiable risk factor for AD. PMID- 27239538 TI - Amyloid-related imaging abnormalities from trials of solanezumab for Alzheimer's disease. AB - INTRODUCTION: Solanezumab, a humanized monoclonal antibody that binds soluble amyloid beta peptide, is being developed for treatment of Alzheimer's disease (AD). METHODS: Patients (n = 2042) with mild and moderate AD were randomized 1:1 to 400-mg solanezumab or placebo infusion every 4 weeks for 80 weeks and 1457 patients entered an open-label extension. Magnetic resonance imaging scans monitored for amyloid-related imaging abnormalities-edema/effusion (ARIA-E) and amyloid-related imaging abnormalities-hemorrhage/hemosiderin deposition. RESULTS: Sixteen patients (solanezumab, n = 11; placebo, n = 5) developed ARIA-E during the double-blind phase, and 7 patients developed ARIA-E during the open-label extension as of July 31, 2014. Unique cases are discussed including solanezumab patients who were given solanezumab, while ARIA-E was present and a patient who developed ARIA-E during placebo treatment and again during solanezumab treatment. DISCUSSION: Asymptomatic ARIA-E was detected in solanezumab-treated and placebo treated AD patients. ARIA-E occurs infrequently during solanezumab and placebo treatments but may occur repeatedly in some patients. PMID- 27239539 TI - Novel diagnostic cerebrospinal fluid biomarkers for pathologic subtypes of frontotemporal dementia identified by proteomics. AB - INTRODUCTION: Reliable cerebrospinal fluid (CSF) biomarkers enabling identification of frontotemporal dementia (FTD) and its pathologic subtypes are lacking. METHODS: Unbiased high-resolution mass spectrometry-based proteomics was applied on CSF of FTD patients with TAR DNA-binding protein 43 (TDP-43, FTD-TDP, n = 12) or tau pathology (FTD-tau, n = 8), and individuals with subjective memory complaints (SMC, n = 10). Validation was performed by applying enzyme-linked immunosorbent assay (ELISA) or enzymatic assays, when available, in a larger cohort (FTLD-TDP, n = 21, FTLD-tau, n = 10, SMC, n = 23) and in Alzheimer's disease (n = 20), dementia with Lewy bodies (DLB, n = 20), and vascular dementia (VaD, n = 18). RESULTS: Of 1914 identified CSF proteins, 56 proteins were differentially regulated (fold change >1.2, P < .05) between the different patient groups: either between the two pathologic subtypes (10 proteins), or between at least one of these FTD subtypes and SMC (47 proteins). We confirmed the differential expression of YKL-40 by ELISA in a partly independent cohort. Furthermore, enzyme activity of catalase was decreased in FTD subtypes compared with SMC. Further validation in a larger cohort showed that the level of YKL-40 was twofold increased in both FTD pathologic subtypes compared with SMC and that the levels in FTLD-tau were higher compared to Alzheimer's dementia (AD), DLB, and VaD patients. Clinical validation furthermore showed that the catalase enzyme activity was decreased in the FTD subtypes compared to SMC, AD and DLB. DISCUSSION: We identified promising CSF biomarkers for both FTD differential diagnosis and pathologic subtyping. YKL-40 and catalase enzyme activity should be validated further in similar pathology defined patient cohorts for their use for FTD diagnosis or treatment development. PMID- 27239540 TI - Effects of vascular risk factors, statins, and antihypertensive drugs on PiB deposition in cognitively normal subjects. AB - INTRODUCTION: Hypertension, hypercholesterolemia, and obesity increase the risk of dementia. Although their detection is commonly followed by an introduction of treatment, little is known about how medications frequently used to treat vascular risk affect amyloid deposition. METHODS: A cross-sectional study of 156 subjects who underwent positron emission tomography with PiB. Using linear regression, we tested whether blood pressure, cholesterol, overweight/obese status, angiotensin receptor blockers (ARBs), beta-blockers, diuretics, angiotensin converting enzyme inhibitors, and statins predicted amyloid deposition. RESULTS: The use of ARBs (beta = -.15, P = .044) and diuretics (beta = -.20, P = .006) predicted less amyloid accumulation; older age (beta = .29, P < .001) and statins (beta = .23, P = .004) were related to greater amyloid deposition. Overweight and/or obese women had more cortical amyloid than their peers. DISCUSSION: Prospective studies should confirm effects of drugs and increased body weight on amyloid accumulation and establish whether they translate into measurable clinical outcomes. Women may be more susceptible to harmful effects of obesity. PMID- 27239541 TI - Function and clinical meaningfulness of treatments for mild Alzheimer's disease. AB - INTRODUCTION: Effectiveness of Alzheimer's disease (AD) treatments is commonly evaluated with coprimary outcomes; cognition with function to ensure clinical meaningfulness of a cognitive effect. METHODS: We reviewed the literature for functional outcomes in mild AD or mild cognitive impairment (MCI) patients (distinct from combined mild-moderate/severe AD) treated with approved AD drugs. Cognitive and functional treatment differences in mild AD patients in solanezumab EXPEDITION/EXPEDITION2 studies were compared across time. RESULTS: Seven publications provided MCI/mild AD functional outcomes, one of which reported a significant functional treatment effect. Secondary analyses of EXPEDITION studies suggested a smaller functional effect of solanezumab relative to cognition. An increasing effect of solanezumab over 18 months was shown for cognition and function. DISCUSSION: Function as the sole measure to demonstrate clinical meaningfulness of cognitive effects in mild AD may have limitations. For disease modifying treatments, point differences on cognitive and functional scales should be qualified with duration of treatment. PMID- 27239542 TI - Novel verbal fluency scores and structural brain imaging for prediction of cognitive outcome in mild cognitive impairment. AB - INTRODUCTION: The objective of this study was to assess the utility of novel verbal fluency scores for predicting conversion from mild cognitive impairment (MCI) to clinical Alzheimer's disease (AD). METHOD: Verbal fluency lists (animals, vegetables, F, A, and S) from 107 MCI patients and 51 cognitively normal controls were transcribed into electronic text files and automatically scored with traditional raw scores and five types of novel scores computed using methods from machine learning and natural language processing. Additional scores were derived from structural MRI scans: region of interest measures of hippocampal and ventricular volumes and gray matter scores derived from performing ICA on measures of cortical thickness. Over 4 years of follow-up, 24 MCI patients converted to AD. Using conversion as the outcome variable, ensemble classifiers were constructed by training classifiers on the individual groups of scores and then entering predictions from the primary classifiers into regularized logistic regression models. Receiver operating characteristic curves were plotted, and the area under the curve (AUC) was measured for classifiers trained with five groups of available variables. RESULTS: Classifiers trained with novel scores outperformed those trained with raw scores (AUC 0.872 vs 0.735; P < .05 by DeLong test). Addition of structural brain measurements did not improve performance based on novel scores alone. CONCLUSION: The brevity and cost profile of verbal fluency tasks recommends their use for clinical decision making. The word lists generated are a rich source of information for predicting outcomes in MCI. Further work is needed to assess the utility of verbal fluency for early AD. PMID- 27239543 TI - Developmental lead exposure and lifespan alterations in epigenetic regulators and their correspondence to biomarkers of Alzheimer's disease. AB - INTRODUCTION: Early life lead (Pb) exposure results in a latent increase in Alzheimer's disease (AD)-related proteins, and cognitive deficits late in life in both rodents and primates. This study was conducted to investigate if these late life changes were accompanied by epigenetic alterations. METHODS: Western blot analysis and RT-PCR were used to measure Deoxyribonucleic acid methylation regulators (DNMT1, DNMT3a, MeCP2, MAT2A) and histone proteins (H3K9Ac, H3K4me2, H3K27me3). RESULTS: Cerebral levels of DNMT1 and MeCP2 were significantly reduced in mice exposed to Pb early in life, whereas the expression of DNMT3a was not altered. Levels of MAT2a were increased in the Pb-exposed mice across the lifespan. H3K9Ac and H3K4me2, involved in gene activation, were decreased, whereas the repressive mark H3K27me3 was elevated. DISCUSSION: Epigenetic modifiers are affected by the developmental exposure to Pb and may play a role in mediating the latent increases in AD-related proteins in the brain. PMID- 27239544 TI - Repeated systemic inflammation was associated with cognitive deficits in older Britons. AB - INTRODUCTION: The relationship of C-reactive protein (CRP) to cognition in the older old group (>=75 years) has recently been found positive on both sides of the Atlantic. We hypothesized that higher levels of CRP and fibrinogen are related to worse episodic memory throughout later life (>=50 years). METHODS: Data are drawn from older Britons free of dementias in the English Longitudinal Study of Aging 2004-2013. We applied growth trajectory models to repeated observations of episodic memory, CRP, and fibrinogen levels (and sociodemographic confounders). We accounted for practice effects in repeated tests of cognition. RESULTS: Higher levels of both inflammatory markers were associated with worse episodic memory, where a fibrinogen effect is evident throughout later life (coefficient -0.154; 95% confidence interval [CI] -0.254 to -0.054). Most importantly, the CRP effect is strongly negative among the older old group (coefficient -0.179; CI -0.320 to -0.038). DISCUSSION: Higher levels of fibrinogen are detrimental to older people's cognition, and among the older old, raised CRP levels are comparably deleterious. Repeated measures of inflammation can be considered in clinical practice as part of a response to the challenge of dementias. PMID- 27239546 TI - Plasma apolipoprotein J as a potential biomarker for Alzheimer's disease: Australian Imaging, Biomarkers and Lifestyle study of aging. AB - INTRODUCTION: For early detection of Alzheimer's disease (AD), the field needs biomarkers that can be used to detect disease status with high sensitivity and specificity. Apolipoprotein J (ApoJ, also known as clusterin) has long been associated with AD pathogenesis through various pathways. The aim of this study was to investigate the potential of plasma apoJ as a blood biomarker for AD. METHODS: Using the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, the present study assayed plasma apoJ levels over baseline and 18 months in 833 individuals. Plasma ApoJ levels were analyzed with respect to clinical classification, age, gender, apolipoprotein E (APOE) epsilon4 allele status, mini mental state examination score, plasma amyloid beta (Abeta), neocortical Abeta burden (as measured by Pittsburgh compound B-positron emission tomography), and total adjusted hippocampus volume. RESULTS: ApoJ was significantly higher in both mild cognitive impairment (MCI) and AD groups as compared with healthy controls (HC; P < .0001). ApoJ significantly correlated with both "standardized uptake value ratio" (SUVR) and hippocampus volume and weakly correlated with the plasma Abeta1-42/Abeta1-40 ratio. Plasma apoJ predicted both MCI and AD from HC with greater than 80% accuracy for AD and greater than 75% accuracy for MCI at both baseline and 18-month time points. DISCUSSION: Mean apoJ levels were significantly higher in both MCI and AD groups. ApoJ was able to differentiate between HC with high SUVR and HC with low SUVR via APOE epsilon4 allele status, indicating that it may be included in a biomarker panel to identify AD before the onset of clinical symptoms. PMID- 27239545 TI - MicroRNA deregulation and chemotaxis and phagocytosis impairment in Alzheimer's disease. AB - INTRODUCTION: Mononuclear phagocytes play a critical role during Alzheimer's disease (AD) pathogenesis due to their contribution to innate immune responses and amyloid beta (Abeta) clearance mechanisms. METHODS: Blood-derived monocytes (BDMs) and monocyte-derived macrophages (MDMs) were isolated from blood of AD, mild cognitive impairment (MCI) patients, and age-matched healthy controls for molecular and phenotypic comparisons. RESULTS: The chemokine/chemokine receptor CCL2/CCR2 axis was impaired in BDMs from AD and MCI patients, causing a deficit in cell migration. Changes were also observed in MDM-mediated phagocytosis of Abeta fibrils, correlating with alterations in the expression and processing of the triggering receptor expressed on myeloid cells 2 (TREM2). Finally, immune related microRNAs (miRNAs), including miR-155, -154, -200b, -27b, and -128, were found to be differentially expressed in these cells. DISCUSSION: This work provides evidence that chemotaxis and phagocytosis, two crucial innate immune functions, are impaired in AD and MCI patients. Correlations with miRNA levels suggest an epigenetic contribution to systemic immune dysfunction in AD. PMID- 27239547 TI - Thrombopoietin is associated with delta's intercept, and only in Non-Hispanic Whites. AB - INTRODUCTION: Serum thrombopoietin (THPO) is a biomarker of Alzheimer's disease (AD) and the latent dementia phenotype, "delta". Both associations may be specific to non-Hispanic whites (NHW), not Mexican-Americans (MA). In this analysis, we examine ethnicity's effect on THPO's association with change in delta scores, in the Texas Alzheimer's Research and Care Consortium (TARCC). METHODS: We constructed an ethnicity equivalent delta homolog ("dEQ") among n = 1113 MA and n = 1958 NHW. dEQ was output as a composite "dEQ-score" for each of five annual TARCC waves. Those composites were used as indicators of a latent growth curve (LGC). The mean dEQ intercept (idEQ) and slope (DeltadEQ) were estimated in a random subset of N = 1528 participants and replicated in the remainder (n = 1544). THPO was regressed onto idEQ and DeltadEQ. Those associations were tested separately in MA and NHW. RESULTS: dEQ correlated strongly with CDR-SB (r = 0.99, P < .001) and achieved high AUCs for AD diagnosis at each wave (range = 0.95-0.99). THPO was significantly associated with idEQ but not DeltadEQ. That effect was observed in NHW only. In MA, THPO had no associations with either idEQ or DeltadEQ. DISCUSSION: We confirm THPO's ethnicity-specific association with delta in NHW. It is further clarified that this association is specific to delta's intercept and not its slope. This analysis provides a model for how dementia's specific serum biomarkers can be characterized. PMID- 27239549 TI - Z-Distance Based IF-THEN Rules. AB - Decision making, reasoning, and analysis in real-world problems are complicated by imperfect information. Real-world imperfect information is mainly characterized by two features. In view of this, Professor Zadeh suggested the concept of a Z-number as an ordered pair Z = (A, B) of fuzzy numbers A and B, the first of which is a linguistic value of a variable of interest, and the second one is a linguistic value of probability measure of the first one, playing a role of its reliability. The concept of distance is one of the important concepts for handling imperfect information in decision making and reasoning. In this paper, we, for the first time, apply the concept of distance of Z-numbers to the approximate reasoning with Z-number based IF-THEN rules. We provide an example on solving problem related to psychological issues naturally characterized by imperfect information, which shows applicability and validity of the suggested approach. PMID- 27239550 TI - Corrigendum to "Herbal Mouthwash Containing Extracts of Baccharis dracunculifolia as Agent for the Control of Biofilm: Clinical Evaluation in Humans". AB - [This corrects the article DOI: 10.1155/2015/712683.]. PMID- 27239548 TI - Detection of Alzheimer's disease at mild cognitive impairment and disease progression using autoantibodies as blood-based biomarkers. AB - INTRODUCTION: There is an urgent need to identify biomarkers that can accurately detect and diagnose Alzheimer's disease (AD). Autoantibodies are abundant and ubiquitous in human sera and have been previously demonstrated as disease specific biomarkers capable of accurately diagnosing mild-moderate stages of AD and Parkinson's disease. METHODS: Sera from 236 subjects, including 50 mild cognitive impairment (MCI) subjects with confirmed low CSF Abeta42 levels, were screened with human protein microarrays to identify potential biomarkers for MCI. Autoantibody biomarker performance was evaluated using Random Forest and Receiver Operating Characteristic curves. RESULTS: Autoantibody biomarkers can differentiate MCI patients from age-matched and gender-matched controls with an overall accuracy, sensitivity, and specificity of 100.0%. They were also capable of differentiating MCI patients from those with mild-moderate AD and other neurologic and non-neurologic controls with high accuracy. DISCUSSION: Autoantibodies can be used as noninvasive and effective blood-based biomarkers for early diagnosis and staging of AD. PMID- 27239551 TI - Energy Conservation Using Dynamic Voltage Frequency Scaling for Computational Cloud. AB - Cloud computing is a new technology which supports resource sharing on a "Pay as you go" basis around the world. It provides various services such as SaaS, IaaS, and PaaS. Computation is a part of IaaS and the entire computational requests are to be served efficiently with optimal power utilization in the cloud. Recently, various algorithms are developed to reduce power consumption and even Dynamic Voltage and Frequency Scaling (DVFS) scheme is also used in this perspective. In this paper we have devised methodology which analyzes the behavior of the given cloud request and identifies the associated type of algorithm. Once the type of algorithm is identified, using their asymptotic notations, its time complexity is calculated. Using best fit strategy the appropriate host is identified and the incoming job is allocated to the victimized host. Using the measured time complexity the required clock frequency of the host is measured. According to that CPU frequency is scaled up or down using DVFS scheme, enabling energy to be saved up to 55% of total Watts consumption. PMID- 27239552 TI - Osteogenic Potential of Multipotent Adult Progenitor Cells for Calvaria Bone Regeneration. AB - Osteogenic cells derived from rat multipotent adult progenitor cells (rMAPCs) were investigated for their potential use in bone regeneration. rMAPCs are adult stem cells derived from bone marrow that have a high proliferation capacity and the differentiation potential to multiple lineages. They may also offer immunomodulatory properties favorable for applications for regenerative medicine. rMAPCs were cultivated as single cells or as 3D aggregates in osteogenic media for up to 38 days, and their differentiation to bone lineage was then assessed by immunostaining of osteocalcin and collagen type I and by mineralization assays. The capability of rMAPCs in facilitating bone regeneration was evaluated in vivo by the direct implantation of multipotent adult progenitor cell (MAPC) aggregates in rat calvarial defects. Bone regeneration was examined radiographically, histologically, and histomorphometrically. Results showed that rMAPCs successfully differentiated into osteogenic lineage by demonstrating mineralized extracellular matrix formation in vitro and induced new bone formation by the effect of rMAPC aggregates in vivo. These outcomes confirm that rMAPCs have a good osteogenic potential and provide insights into rMAPCs as a novel adult stem cell source for bone regeneration. PMID- 27239553 TI - Determinants of Short Interbirth Interval among Reproductive Age Mothers in Arba Minch District, Ethiopia. AB - Background. One of the key strategies to reduce fertility and promote the health status of mothers and their children is adhering to optimal birth spacing. However, women still have shorter birth intervals and studies addressing their determinants were scarce. The objective of this study, therefore, was to assess determinants of birth interval among women who had at least two consecutive live births. Methods. Case control study was conducted from February to April 2014. Cases were women with short birth intervals (<3 years), whereas controls were women having history of optimal birth intervals (3 to 5 years). Bivariate and multivariable analyses were performed. Result. Having no formal education (AOR = 2.36, 95% CL: [1.23-4.52]), duration of breast feeding for less than 24 months (AOR: 66.03, 95% CI; [34.60-126]), preceding child being female (AOR: 5.73, 95% CI; [3.18-10.310]), modern contraceptive use (AOR: 2.79, 95% CI: [1.58-4.940]), and poor wealth index (AOR: 4.89, 95% CI; [1.81-13.25]) of respondents were independent predictors of short birth interval. Conclusion. In equalities in education, duration of breast feeding, sex of the preceding child, contraceptive method use, and wealth index were markers of unequal distribution of inter birth intervals. Thus, to optimize birth spacing, strategies of providing information, education and communication targeting predictor variables should be improved. PMID- 27239554 TI - Plasma Cytokine Profiles in Long-Term Strenuous Exercise. AB - The open window theory indicates altered immunity 3 to 72 hours after exercise. The J-curve describes the risk of illness in response to exercise. The aim of this study was to examine the secretion of proinflammatory and anti-inflammatory cytokines before and after long-term strenuous exercise. Fourteen marathon and 16 half-marathon runners and 10 military cadets participating in a military ranger training course were recruited to this study. Within-subject design was used measuring levels of plasma cytokines before, during, and after exercise. Plasma cytokines were measured using Luminex multiplex technology and ELISA. Comparing pre/post plasma levels both the marathon- and the half-marathon runners showed heavily increased levels of IL-6, IL-10, and IL-8 (P < 0.001). LPS stimulation among the half-marathon runners decreased the postrace levels of IL-6, IL-1b, and TNFalpha by 45%, 24%, and 43%, respectively (P < 0.01). During the ranger training course the spontaneous and LPS-stimulated levels of IL-6, IL-8, IL-10, IL-1b, and TNFalpha changed in a similar fashion as in the half-marathon runners although the fluctuations were smaller. Our study supports the open window and the J-curve theory; the immune system is more activated and the subjects are more threatened to infectious pathogens after intensive physical activity and in the period after exercise. PMID- 27239556 TI - The Protege Project: A Look Back and a Look Forward. PMID- 27239557 TI - Defining Airflow Obstruction. AB - Airflow obstruction has been defined using spirometric test results when the forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) ratio is below a fixed cutoff (<70%) or lower limits of normal (LLN) from reference equations that are based on values from a normal population. However, similar to other positive or abnormal diagnostic test results that are used to identify the presence of disease, perhaps airflow obstruction should be defined based on the values of FEV1/FVC for a population of individuals with known disease such as chronic obstructive pulmonary disease (COPD). Unfortunately, we do not know such a distribution of values of FEV1/FVC for patients with COPD since there is no gold standard for this syndrome or condition. Yet, we have used this physiologic definition of airflow obstruction based on a normal population to identify patients with COPD. In addition, we have defined airflow obstruction as either being present or absent. Instead, we should use a different approach to define airflow obstruction based on the probability or likelihood that the airflow obstruction is present which in turn would give us the probability or likelihood of a disease state such as COPD. PMID- 27239555 TI - Oxidative stress, innate immunity, and age-related macular degeneration. AB - Age-related macular degeneration (AMD) is a leading cause of vision loss affecting tens of millions of elderly worldwide. Early AMD is characterized by the appearance of soft drusen, as well as pigmentary changes in the retinal pigment epithelium (RPE). These soft, confluent drusen can progress into two forms of advanced AMD: geographic atrophy (GA, or dry AMD) or choroidal neovascularization (CNV, or wet AMD). Both forms of AMD result in a similar clinical progression in terms of loss of central vision. The exact mechanism for developing early AMD, as well as triggers responsible for progressing to advanced stage of disease, is still largely unknown. However, significant evidence exists demonstrating a complex interplay of genetic and environmental factors as causes of AMD progression. Multiple genes and/or single nucleotide polymorphisms (SNPs) have been found associated with AMD, including various genes involved in the complement pathway, lipid metabolism and extracellular matrix (ECM) remodeling. Of the known genetic contributors to disease risk, the CFH Y402H and HTRA1/ARMS polymorphisms contribute to more than 50% of the genetic risk for AMD. Environmentally, oxidative stress plays a critical role in many aging diseases including cardiovascular disease, cancer, Alzheimer's disease and AMD. Due to the exposure to sunlight and high oxygen concentration, the oxidative stress burden is higher in the eye than other tissues, which can be further complicated by additional oxidative stressors such as smoking. Increasingly, evidence is accumulating suggesting that functional abnormalities of the innate immune system incurred via high risk genotypes may be contributing to the pathogenesis of AMD by altering the inflammatory homeostasis in the eye, specifically in the handling of oxidation products. As the eye in non-pathological instances maintains a low level of inflammation despite the presence of a relative abundance of potentially inflammatory molecules, we have previously hypothesized that the tight homeostatic control of inflammation via the innate immune system is likely critical for avoidance of disease progression. However, the presence of a multitude of potential triggers of inflammation results in a sensitive balance in which perturbations thereof would subsequently alter the inflammatory state of the retina, leading to a state of chronic inflammation and pathologic progression. In this review, we will highlight the background literature surrounding the known genetic and environmental contributors to AMD risk, as well as a discussion of the potential mechanistic interplay of these factors that lead to disease pathogenesis with particular emphasis on the delicate control of inflammatory homeostasis and the centrality of the innate immune system in this process. PMID- 27239558 TI - Fatigue in Parkinson's disease: report from a mutidisciplinary symposium. AB - Fatigue is a severe problem for many people living with Parkinson's disease (PD). Best estimates suggest that more than 50% of patients experience this debilitating symptom. Little is known about its etiology or treatment, making the understanding of fatigue a true unmet need. As part of the Parkinson's Disease Foundation Community Choice Research Program, patients, caregivers, and scientists attended a symposium on fatigue on 16 and 17 October 2014. We present a summary of that meeting, reviewing what is known about the diagnosis and treatment of fatigue, its physiology, and what we might learn from multiple sclerosis (MS), depression, and cancer-disorders in which fatigue figures prominently too. We conclude with focused recommendations to enhance our understanding and treatment of this prominent problem in PD. PMID- 27239559 TI - STIM1 activation is regulated by a 14 amino acid sequence adjacent to the CRAC activation domain. AB - Oligomerization of the Ca2+ sensor, STIM1, in the endoplasmic reticulum (ER) membrane, caused by depletion of ER Ca2+ stores, results in STIM1 coupling to the plasma membrane Ca2+ channel protein, Orai1, to activate Ca2+ influx in a process known as store-operated Ca2+ entry. We use fluorimetry-based fluorescence resonance energy transfer (FRET) to monitor changes in STIM1 oligomerization in COS7 cells transfected with STIM1 constructs containing selected truncations, deletions, and point mutations, and labeled with donor and acceptor fluorescent proteins at either the luminal (N-terminal) or the cytoplasmic (C-terminal) ends. Our results with sequential truncations of STIM1 from the C-terminus support previous evidence that the CRAC activation domain (CAD/SOAR, human sequence 342 448) is an oligomer-promoting segment of STIM1, and they show that truncation just after CAD/SOAR (1-448) causes significantly elevated basal cytoplasmic Ca2+ and spontaneous STIM1 clustering. We find that a 14 amino acid sequence just C terminal of CAD/SOAR (449-462) prevents spontaneous clustering and activation of STIM1 in COS7 cells. In response to store depletion, C-terminally labeled STIM1 without CAD/SOAR clusters together with CAD/SOAR-containing STIM1 constructs. However, these donor-acceptor pairs do not undergo a stimulated increase in FRET, exhibiting instead a decrease in FRET consistent with a stimulated conformational extension in full length STIM1. We find that the 14 amino acid sequence plays a regulatory role in this process. Overall, our FRET results provide evidence in live cells that Ca2+ store depletion stimulates a conformational extension in the cytoplasmic segment of STIM1 that accompanies its oligomerization. PMID- 27239560 TI - Platelet-Activating Factor-Receptor and Tumor Immunity. AB - First described in 1972 by Benveniste and colleagues, platelet-activating factor (PAF) remains one of the potent phospholipid known to date. The role of PAF produced enzymatically in mediating diverse biological and pathophysiological processes including inflammatory and allergic diseases and cancers in response to various stimuli has been extensively studied. However, little is known about the role of non-enzymatically-generated PAF-like lipids produced in response to pro oxidative stressors, particularly in modulating the host immune responses to tumor immunity, which is the focus of this review. PMID- 27239561 TI - Molecular profiling of dilated cardiomyopathy that progresses to heart failure. AB - Dilated cardiomyopathy (DCM) is defined by progressive functional and structural changes. We performed RNA-seq at different stages of disease to define molecular signaling in the progression from pre-DCM hearts to DCM and overt heart failure (HF) using a genetic model of DCM (phospholamban missense mutation, PLNR9C/+). Pre-DCM hearts were phenotypically normal yet displayed proliferation of nonmyocytes (59% relative increase vs. WT, P = 8 * 10-4) and activation of proinflammatory signaling with notable cardiomyocyte-specific induction of a subset of profibrotic cytokines including TGFbeta2 and TGFbeta3. These changes progressed through DCM and HF, resulting in substantial fibrosis (17.6% of left ventricle [LV] vs. WT, P = 6 * 10-33). Cardiomyocytes displayed a marked shift in metabolic gene transcription: downregulation of aerobic respiration and subsequent upregulation of glucose utilization, changes coincident with attenuated expression of PPARalpha and PPARgamma coactivators -1alpha (PGC1alpha) and -1beta, and increased expression of the metabolic regulator T-box transcription factor 15 (Tbx15). Comparing DCM transcriptional profiles with those in hypertrophic cardiomyopathy (HCM) revealed similar and distinct molecular mechanisms. Our data suggest that cardiomyocyte-specific cytokine expression, early fibroblast activation, and the shift in metabolic gene expression are hallmarks of cardiomyopathy progression. Notably, key components of these profibrotic and metabolic networks were disease specific and distinguish DCM from HCM. PMID- 27239562 TI - Antibiotic-Induced Alterations of the Gut Microbiota Alter Secondary Bile Acid Production and Allow for Clostridium difficile Spore Germination and Outgrowth in the Large Intestine. AB - It is hypothesized that the depletion of microbial members responsible for converting primary bile acids into secondary bile acids reduces resistance to Clostridium difficile colonization. To date, inhibition of C. difficile growth by secondary bile acids has only been shown in vitro. Using targeted bile acid metabolomics, we sought to define the physiologically relevant concentrations of primary and secondary bile acids present in the murine small and large intestinal tracts and how these impact C. difficile dynamics. We treated mice with a variety of antibiotics to create distinct microbial and metabolic (bile acid) environments and directly tested their ability to support or inhibit C. difficile spore germination and outgrowth ex vivo. Susceptibility to C. difficile in the large intestine was observed only after specific broad-spectrum antibiotic treatment (cefoperazone, clindamycin, and vancomycin) and was accompanied by a significant loss of secondary bile acids (deoxycholate, lithocholate, ursodeoxycholate, hyodeoxycholate, and omega-muricholate). These changes were correlated to the loss of specific microbiota community members, the Lachnospiraceae and Ruminococcaceae families. Additionally, physiological concentrations of secondary bile acids present during C. difficile resistance were able to inhibit spore germination and outgrowth in vitro. Interestingly, we observed that C. difficile spore germination and outgrowth were supported constantly in murine small intestinal content regardless of antibiotic perturbation, suggesting that targeting growth of C. difficile will prove most important for future therapeutics and that antibiotic-related changes are organ specific. Understanding how the gut microbiota regulates bile acids throughout the intestine will aid the development of future therapies for C. difficile infection and other metabolically relevant disorders such as obesity and diabetes. IMPORTANCE Antibiotics alter the gastrointestinal microbiota, allowing for Clostridium difficile infection, which is a significant public health problem. Changes in the structure of the gut microbiota alter the metabolome, specifically the production of secondary bile acids. Specific bile acids are able to initiate C. difficile spore germination and also inhibit C. difficile growth in vitro, although no study to date has defined physiologically relevant bile acids in the gastrointestinal tract. In this study, we define the bile acids C. difficile spores encounter in the small and large intestines before and after various antibiotic treatments. Antibiotics that alter the gut microbiota and deplete secondary bile acid production allow C. difficile colonization, representing a mechanism of colonization resistance. Multiple secondary bile acids in the large intestine were able to inhibit C. difficile spore germination and growth at physiological concentrations and represent new targets to combat C. difficile in the large intestine. PMID- 27239564 TI - Synthesis of Substituted 2,2'-Dinitrobiphenyls by a Novel Solvent-Free High Yielding Ullmann Coupling Biarylation. AB - Solvent-free reaction using a high-speed ball milling technique has been applied to the classical Ullmann coupling reaction for the first time. Biarylation of 2 iodonitrobenzene was achieved in quantitative yield when performed in a custom made copper vial through continuous shaking without additional copper or solvent. The product was solid, NMR ready and required no lengthy extraction for purification. This reaction was cleaner, and faster than solution phase coupling which requires longer reaction time in high boiling solvents, added copper catalyst, and lengthy extraction and purification steps. Gram quantities of the biaryl compound were synthesized in larger copper vials. This is a general method that can be used to effectively reduce industrial waste en route to sustainability. PMID- 27239565 TI - Regioselective Nitration of Halogenated Benzo[c]cinnolines and Benzenoids. AB - Electrophilic nitration of halo-substituted benzo[c]cinnolines and benzenoids has been achieved regioselectively. The nitro group entry was always ortho to the halo group or/and the aromatic ring. This regioselective electrophilic ortho nitration was accomplished in mixed acid/mild temperature conditions. Regioselectivity ortho to the halo/ring group(s) was observed with or without proximal steric hindrance. Chlorides and bromides worked equally well in directing these high-yielding ortho-selective reactions. PMID- 27239566 TI - This issue at a glance. PMID- 27239563 TI - Metabolic Model-Based Integration of Microbiome Taxonomic and Metabolomic Profiles Elucidates Mechanistic Links between Ecological and Metabolic Variation. AB - : Multiple molecular assays now enable high-throughput profiling of the ecology, metabolic capacity, and activity of the human microbiome. However, to date, analyses of such multi-omic data typically focus on statistical associations, often ignoring extensive prior knowledge of the mechanisms linking these various facets of the microbiome. Here, we introduce a comprehensive framework to systematically link variation in metabolomic data with community composition by utilizing taxonomic, genomic, and metabolic information. Specifically, we integrate available and inferred genomic data, metabolic network modeling, and a method for predicting community-wide metabolite turnover to estimate the biosynthetic and degradation potential of a given community. Our framework then compares variation in predicted metabolic potential with variation in measured metabolites' abundances to evaluate whether community composition can explain observed shifts in the community metabolome, and to identify key taxa and genes contributing to the shifts. Focusing on two independent vaginal microbiome data sets, each pairing 16S community profiling with large-scale metabolomics, we demonstrate that our framework successfully recapitulates observed variation in 37% of metabolites. Well-predicted metabolite variation tends to result from disease-associated metabolism. We further identify several disease-enriched species that contribute significantly to these predictions. Interestingly, our analysis also detects metabolites for which the predicted variation negatively correlates with the measured variation, suggesting environmental control points of community metabolism. Applying this framework to gut microbiome data sets reveals similar trends, including prediction of bile acid metabolite shifts. This framework is an important first step toward a system-level multi-omic integration and an improved mechanistic understanding of the microbiome activity and dynamics in health and disease. IMPORTANCE: Studies characterizing both the taxonomic composition and metabolic profile of various microbial communities are becoming increasingly common, yet new computational methods are needed to integrate and interpret these data in terms of known biological mechanisms. Here, we introduce an analytical framework to link species composition and metabolite measurements, using a simple model to predict the effects of community ecology on metabolite concentrations and evaluating whether these predictions agree with measured metabolomic profiles. We find that a surprisingly large proportion of metabolite variation in the vaginal microbiome can be predicted based on species composition (including dramatic shifts associated with disease), identify putative mechanisms underlying these predictions, and evaluate the roles of individual bacterial species and genes. Analysis of gut microbiome data using this framework recovers similar community metabolic trends. This framework lays the foundation for model based multi-omic integrative studies, ultimately improving our understanding of microbial community metabolism. PMID- 27239567 TI - Facial asymmetry in ocular torticollis. AB - Torticollis can arise from nonocular (usually musculoskeletal) and ocular conditions. Some facial asymmetries are correlated with a history of early onset ocular torticollis supported by the presence of torticollis on reviewing childhood photographs. When present in an adult, this type of facial asymmetry with an origin of ocular torticollis should help to confirm the chronicity of the defect and prevent unnecessary neurologic evaluation in patients with an uncertain history. Assessment of facial asymmetry consists of a patient history, physical examination, and medical imaging. Medical imaging and facial morphometry are helpful for objective diagnosis and measurement of the facial asymmetry, as well as for treatment planning. The facial asymmetry in congenital superior oblique palsy is typically manifested by midfacial hemihypoplasia on the side opposite the palsied muscle, with deviation of the nose and mouth toward the hypoplastic side. Correcting torticollis through strabismus surgery before a critical developmental age may prevent the development of irreversible facial asymmetry. Mild facial asymmetry associated with congenital torticollis has been reported to resolve with continued growth after early surgery, but if asymmetry is severe or is not treated in the appropriate time, it might remain even with continued growth after surgery. PMID- 27239569 TI - Cost-effectiveness analysis of confocal scan laser ophthalmoscope (HRT II) versus GDX for diagnosing glaucoma. AB - PURPOSE: The aim of this study was to assess the cost-effectiveness of confocal scan laser ophthalmoscopy (HRT II) and compare it with scanning laser polarimetry (GDx) for diagnosing glaucoma. METHODS: A cost-effectiveness analysis was performed at two eye hospitals in Iran. The outcome was measured as the proportion of correctly diagnosed patients based on systematic review and Meta analysis. Costs were estimated at two hospitals that used the HRT II (Noor Hospital) and current diagnostic testing technology GDx (Farabi Hospital) from the perspective of the healthcare provider. The incremental cost-effectiveness ratio (ICER) was estimated on the base scenario. RESULTS: Annual average costs were estimated as 12.70 USD and 13.59 USD per HRT II and GDx test in 2012, respectively. It was assumed that 80% of the maximum feasible annual tests in a work shift would be performed using HRT II and GDx and that the glaucoma-positive (Gl+) proportion would be 56% in the referred eyes; the estimated diagnostic accuracies were 0.753 and 0.737 for GDx and HRT II, respectively. The incremental cost-effectiveness ratio (ICER) was estimated at USD44.18 per additional test accuracy. In a base sensitivity sampling analysis, we considered different proportions of Gl+ patients (30%-85%), one or two work shifts, and efficiency rate (60%-100%), and found that the ICER ranged from USD29.45to USD480.26, the lower and upper values in all scenarios. CONCLUSION: Based on ICER, HRT II as newer diagnostic technology is cost-effective according to the World Health Organization threshold of <1 Gross Domestic Product (GDP) per capita in Iran in 2012 (USD7228). Although GDx is more accurate and costly, the average cost effectiveness ratio shows that HRT II provided diagnostic accuracy at a lower cost than GDx. PMID- 27239568 TI - Pseudoexfoliation syndrome: Effect of phacoemulsification on intraocular pressure and its diurnal variation. AB - PURPOSE: To evaluate the effect of phacoemulsification on intraocular pressure (IOP) in pseudoexfoliation (PEX) syndrome and its diurnal variation. METHODS: In this prospective, non-comparative, interventional case series, phacoemulsification was done for patients with PEX and concomitant visually significant cataract. Follow-up examinations including IOP measurement were done at postoperative day 1, week 1, month 1, month 3, and month 6. All IOP measurements were performed twice daily: once in the morning between 8 and 10 AM and the other in the evening between 6 and 8 PM. The minimum and maximum IOP and the mean IOP were recorded. IOP variation was defined as the difference between maximum and minimum pressures. RESULTS: Sixty-eight eyes of 68 patients were analyzed. The mean IOP dropped from 17.45 +/- 3.32 mm Hg to 12.57 +/- 1.58 mm Hg at 6 months. The minimum and maximum IOP dropped from 14.97 +/- 3.46 mm Hg and 20.03 +/- 3.39 to 11.53 +/- 1.79 mm Hg and 13.01 +/- 1.81 after 6 months, respectively. Diurnal IOP variation dropped from 5.06 +/- 1.85 mm Hg (range 2-10) at baseline to 1.49 +/- 0.93 mm Hg (range 0-4) at postoperative month 6 (p < 0.001 for all). This drop was not correlated with age and CCT, but was strongly correlated with baseline IOP variation (r = 0.847, p < 0.001). CONCLUSION: Phacoemulsification without any additional intervention can be an attractive choice in managing the IOP and its diurnal variations in pseudoexfoliation patients, even with elevated IOP, who do not have advanced optic nerve damage. PMID- 27239570 TI - White-to-white corneal diameter distribution in an adult population. AB - PURPOSE: To determine the normal distribution of corneal diameter in a 40- to 64 year-old population and its association with other biometric components. METHODS: In a cross-sectional population-based study, subjects were selected through multistage cluster sampling from the 40- to 64-year-old citizens of Shahroud in northern Iran. After obtaining informed consents, optometry tests including refraction and visual acuity and ophthalmic exams including slit lamp exams and retinoscopy were done for all participants. Biometric components and white-to white (WTW) corneal diameter were measured with the LENSTAR/BioGraph. RESULTS: Of the 6311 invitees, 5190 (82.2%) participated in the study. After applying exclusion criteria, analysis was done on data from 4787 people. Mean WTW corneal diameter in this study was 11.80 mm (confidence interval: 11.78-11.81), and based on two standard deviations from the mean, the normal range for this index was from 10.8 to 12.8 mm. WTW corneal diameter strongly correlated with corneal radius of curvature (r = 0.422) and axial length (r = 0.384). According to multiple linear regression, lower age, thinner cornea, longer AL, thicker lens, and flatter cornea were significantly related to higher WTW corneal diameter. Spherical equivalent significantly increased at higher corneal diameters (hyperopic shift). CONCLUSION: The average and normal range of corneal diameter, as measured with the BioGraph, was studied in an Iranian population for the first time. The corneal diameter strongly correlates with AL and radius of curvature. WTW is larger at younger ages. PMID- 27239571 TI - Outcome of intrastromal corneal ring segment relative to depth of insertion evaluated with scheimpflug image. AB - PURPOSE: To report the results of intrastromal corneal ring segment (KeraRing; Mediphcose, Belo Horizonte, Brazil) implantation relative to depth of insertion in keratoconic patients. METHODS: In this retrospective, observational study, we evaluated 29 eyes of 27 patients with keratoconus who underwent implantation of KeraRing SI-5 with mechanical tunnel creation. In the mean follow-up of 8.8 months, all eyes underwent scheimpfluge image of pentacam (Oculus, Germany) to determine insertion depth. Based on the measured implantation depth, cases were categorized into: 40-59% thickness group, 60-79% thickness group, and >=80% thickness group. Visual, refractive, and shape outcomes were evaluated relative to implantation depth. RESULTS: The mean insertion depth was 61.7%.We had 41.4% of cases were in the 40-59% thickness group, 51.7% in the 60-79% group, and 6.9% in the >80% group. Results were similar in 40-59% and 60-79% thickness groups: uncorrected visual acuity (UCVA) and best spectacle corrected VA (BSCVA) improved 3 and 2 lines, respectively, maximum keratometry (Kmax) decreased 2.6 D, refractive cylinder improved 2.04 D, and Q value 8 mm anterior changed by 0.35. In the >=80% thickness group, UCVA and BSCVA improved less than 1 lines, Kmax change was less than 0.5 D, and RC decreased less than 0.25 D. CONCLUSION: Implantation of KeraRing with mechanical tunnel creation in 40-80% of stromal thickness despite the variable insertion depth is effective. PMID- 27239572 TI - Comparison of quality of life between myopic patients with spectacles and contact lenses, and patients who have undergone refractive surgery. AB - PURPOSE: The present study aims at investigating and comparing the vision-related quality of life of myopic persons who wear spectacles or contact lenses with those who have undergone refractive surgery. It also compares the vision-related quality of life of these two groups with that of emmetropes. METHOD: In this study, the questionnaire of evaluation instrument of refractive error in quality of life (NEI/RQL-42) was used to compare the quality of life between 154 myopic patients with spectacles and contact lenses, and 32 patients who have undergone refractive surgery. The two groups were also compared with 54 emmetropes. The questionnaire included 13 different subgroups (score 0-100) related to vision. Data was analyzed using SPSS software. RESULTS: The overall score of quality of life in emmetropes (95.11 +/- 4.23) was more than that in persons who had undergone refractive surgery (86.98 +/- 4.73), and it was the least in the group wearing spectacles or contact lenses (78.30 +/- 9.21), (P < 0/001). Furthermore, except for a glare variable, the studied groups indicated a statistically significant difference in all the thirteen subgroups of vision-related quality of life. CONCLUSION: Quality of life for people with myopia who had the refractive surgery was better than people with myopia who wore spectacles or contact lenses. Although quality of life in people with myopia who had the refractive surgery was less than emmetropia, it seems that refractive surgery improves quality of life of myopic patients. PMID- 27239573 TI - Survey of 274 patients with conjunctival neoplastic lesions in Farabi Eye Hospital, Tehran 2006-2012. AB - PURPOSE: To evaluate conjunctival epithelial neoplastic lesions in a 7-year period. MATERIALS AND METHODS: The data of all primary cases of conjunctival neoplasia diagnosed in the Pathology Department of Farabi Eye Hospital were analyzed. RESULTS: The patient group consisted of 179 (65.3%) males and 95 (34.6%) females, with an age range of 14-90 years and a mean age of 57.9 years. The most common primary conjunctival epithelial neoplastic lesion was invasive squamous cell carcinoma (SCC) (40.8%), followed by dysplasia (17%), papilloma (16.4%), In situ SCC (16%), actinic keratosis (7.3%), basal cell carcinoma (0.7%), xeroderma pigmentosum (0.7%), and mucoepidermoid carcinoma (0.3%). Of 274 lesions, 47 (17.1%) were benign, 159 (58%) were malignant, and 68 (24.8%) were precancerous. Compared to the results of a previous study of this center (1990 2004), the incidence of precancerous lesions has slightly increased whereas the incidence of SCC has decreased (22.1% vs. 24.8% and 59% vs. 40.8%, respectively). CONCLUSION: SCC is the most common conjunctival epithelial neoplasm in this study, and its prevalence in males is nearly two times higher than in females. The high percentage of squamous cell carcinoma can likely be attributed to elevated sun exposure and ultraviolet light in Iran. PMID- 27239574 TI - Monosomy 3 by chromogenic in situ hybridization (CISH) in Iranian patients with uveal melanoma. AB - PURPOSE: The aim of this study was to investigate the rate of monosomy 3 by CISH technique in Iranian patients with uveal melanoma (UM) and its correlation with clinical and histopathological features. METHOD: Archival formalin fixed, paraffin-embedded material from 50 patients who had undergone enucleation for large uveal melanomas was obtained. Monosomy of chromosome 3 alteration by chromogenic in situ hybridization (CISH) was investigated. Clinical and histopathological features of tumors were collected. RESULTS: The patients had a mean age of 56.6+/-7.6 years. Mean basal diameter and thickness of tumors were 14.1 mm and 10.2 mm, respectively. Four patients (8%) were identified to harbor monosomy of chromosome 3. In the mean follow-up of 5.3 years (range, 3.2-9.5 y), only one case with monosomy 3 died of UM metastasis. The most common type of cellularity was mixed cell (86%). There was not any statistically significant correlation between monosomy of chromosome 3 and type of cellularity, ciliary body involvement, and largest basal diameter. CONCLUSION: The low rate of monosomy chromosome 3 and the consequent low rate of mortality may be indicative of good prognosis in Iranian patients with uveal melanoma. PMID- 27239575 TI - Ophthalmic findings in Behcet's disease: Cases without apparent ocular signs. AB - PURPOSE: To evaluate the fluorescein angiography and infrared autofluorescence finding in patients with confirmed Behcet's disease (BD) but without clinical ocular signs. METHODS: In this prospective, non-interventional case series, montage fluorescein angiography (MFA) and infrared autofluorescence imaging were performed for all patients with confirmed BD but without ocular signs in clinical examination. RESULTS: Fifty BD patients (100 eyes) without clinical ocular manifestations were investigated. In MFA, we found fluorescein angiography (FA) leakage in 22 cases (44%) in both eyes, mostly at the periphery of retina. In infrared autofluorescence, profound changes were found in 43 patients, 86 eyes (86%). Twenty-five patients, 50 eyes (50%), presented retinal vascular branching modifications, straightening, tortuosity, and shunt. CONCLUSION: MFA of retina may be useful in patients with presumed BD for early diagnosis, early treatment, and follow-up of patients. PMID- 27239576 TI - The prevalence of refractive errors in 6- to 15-year-old schoolchildren in Dezful, Iran. AB - PURPOSE: To determine the prevalence of refractive errors, among 6- to 15-year old schoolchildren in the city of Dezful in western Iran. METHODS: In this cross sectional study, 1375 Dezful schoolchildren were selected through multistage cluster sampling. After obtaining written consent, participants had uncorrected and corrected visual acuity tests and cycloplegic refraction at the school site. Refractive errors were defined as myopia [spherical equivalent (SE) -0.5 diopter (D)], hyperopia (SE >= 2.0D), and astigmatism (cylinder error > 0.5D). RESULTS: 1151 (83.7%) schoolchildren participated in the study. Of these, 1130 completed their examinations. 21 individuals were excluded because of poor cooperation and contraindication for cycloplegic refraction. Prevalence of myopia, hyperopia, and astigmatism were 14.9% (95% confidence interval (CI): 10.1-19.6), 12.9% (95% CI: 7.2-18.6), and 45.3% (95% CI: 40.3-50.3), respectively. Multiple logistic regression analysis showed an age-related increase in myopia prevalence (p << 0.001) and a decrease in hyperopia prevalence (p << 0.001). There was a higher prevalence of myopia in boys (p<<0.001) and hyperopia in girls (p = 0.007). CONCLUSION: This study showed a considerably high prevalence of refractive errors among the Iranian population of schoolchildren in Dezful in the west of Iran. The prevalence of myopia is considerably high compared to previous studies in Iran and increases with age. PMID- 27239577 TI - Eye problems in children with hearing impairment. AB - PURPOSE: To compare the prevalence of refractive errors, amblyopia, and strabismus between hearing-impaired and normal children (7-22 years old) in Mashhad. METHODS: In this cross-sectional study, cases were selected from hearing impaired children in Mashhad. The control group consisted of children with no hearing problem. The sampling was done utilizing the cluster sampling method. All of the samples underwent refraction, cover test, and visual examinations. RESULTS: 254 children in the hearing-impaired group (case) and 506 children in the control group were assessed. The mean spherical equivalent was 1.7 +/- 1.9 D in the case group, which was significantly different from the control group (0.2 +/- 1.5) (P < 0.001). The prevalence of hyperopia was 57.15% and 21.5% in deaf and normal children, respectively, but myopia was mostly seen in the control group (5.5% versus 11.9%, P = 0.007). The mean cylinder was 0.65 +/- 1.3 D and 0.43 +/- 0.62 D in deaf and normal subjects, respectively (P = 0.002). 12.2% of deaf subjects and 1.2% of normal subjects were amblyopic (P < 0.001), and the prevalence of strabismus was 3.1% in the case group and 2.6% in the control group (P = 0.645). CONCLUSION: In a comparison of children of the same ages, hearing impaired children have significantly more eye problems; therefore, a possible relation between deafness and eye problems must exist. Paying attention to eye health assessment in hearing-impaired children may help prevent adding eye problems to hearing difficulties. PMID- 27239578 TI - Perfluorocarbon liquid migration into the subarachnoid space in a patient with morning glory syndrome. AB - PURPOSE: To report a case of perfluorocarbon liquid (PFCL) migration into the subarachnoid space at the time of vitreoretinal surgery in a patient with morning glory syndrome associated retinal detachment. CASE REPORT: A 9-year-old girl underwent pars plana vitrectomy and silicone oil injection for retinal detachment associated with morning glory syndrome. PFCL was used for retinal stabilization before endolaser photocoagulation. The retina detached, and repeated vitrectomy and silicone oil injection was performed. Postoperative magnetic resonance imaging revealed PFCL in the subarachnoid space. CONCLUSION: The migration of perfluorocarbon into the subarachnoid space is a rare complication of vitrectomy in patients with morning glory syndrome. PMID- 27239579 TI - Unilateral idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome (IRVAN) in a young female. AB - PURPOSE: To report a case of Idiopathic retinal vasculitis, arteriolar macroaneurysms, and neuroretinitis (IRVAN). syndrome in a young female. CASE REPORT: A 21-year-old woman presented with unilateral visual acuity (VA) loss. Ophthalmological examination disclosed unilateral optic disc swelling, star shaped macular exudation, multiple aneurysms surrounded by perivascular exudation, retinal vasculitis, and mild vitreous reaction. The left eye examination was entirely normal. Clinical and paraclinical findings were compatible with IRVAN syndrome criteria. The patient was treated with a short course of oral steroid, a trans-septal triamcinolone acetonide injection, selective laser photocoagulation in peripheral non-perfusion areas, and intravitreal bevacizumab. In spite of primary good response, after each treatment cessation, VA dropped with increasing central macular thickness (CMT), but response to intravitreal triamcinolone (4 mg/0.1 cc) was permanent and good. CONCLUSION: IRVAN syndrome can have unilateral presentation. All treatment options were temporary except intravitreal steroid injection in our case. The effect of steroid in IRVAN will need further evaluation. PMID- 27239580 TI - This issue at a glance. PMID- 27239581 TI - Early phacoemulsification in patients with acute primary angle closure. AB - PURPOSE: To compare long term efficacy of phacoemulsification in the early management of acute primary angle closure (APAC) after aborting an acute attack and performing laser peripheral iridotomy (LPI). METHODS: In this nonrandomized comparative prospective study, we included 35 subjects presenting with APAC who had responded to medical treatment and LPI with intraocular pressure (IOP) less than 25 mmHg. Twenty patients with visually significant cataract with visual acuity of <20/30 were assigned to the "Phaco/LPI" group and underwent phacoemulsification within 6 weeks of the attack. Fifteen subjects with clear lens were assigned to the "LPI Only" group and were followed clinically. The primary measured outcome was the prevalence of IOP rise after 1 month (treatment failure), defined as 1) if a patient developed IOP rise resulting in IOP >21 mmHg with or without medication, or 2) if a patient required any medication to have IOP <=21 mmHg after 1 month. Patients were followed for at least one year. RESULT: IOP, number of medications, gonioscopy grading, and amount of synechiae were not significantly different at baseline between the two groups. Acute attack did not recur in any patient. There was more significant failure in the LPI Only group compared with the Phaco/LPI group (40% vs. 5%; p = 0.02). There was a significant difference in final IOP between the two study groups (13.90 +/- 2.17 vs. 17.8 +/- 4.16 in the Phaco/LPI and LPI Only groups, respectively; p = 0.001). Patients in the Phaco-LPI group needed less medication than the other group at final follow-up. No serious complications have arisen from the immediate LPI or phacoemulsification. CONCLUSION: Phacoemulsification is a safe procedure for preventing IOP rise after aborting acute primary angle closure if performed within a few weeks of the attack. PMID- 27239582 TI - Implantable collamer lens V4b and V4c for correction of high myopia. AB - PURPOSE: To evaluate the visual outcome and intraocular pressure changes after Visian Implantable Collamer Lens (ICL) implantation V4b and V4c (with central hole) for correction of high myopia. METHODS: A prospective, consecutive, interventional comparative case series of V4b and V4c ICL implantation was done in high myopic patients who were unsuitable for laser vision. The main outcome measures studied were uncorrected and corrected distant visual acuity (UDVA, CDVA), ICL vault, intraocular pressure (IOP), endothelial cell count (ECC), and development of subcapsular lens opacities. The patients were evaluated at postoperative 1,3,6, and 9 months. RESULTS: A total of 62 eyes of 32 patients (24.56 +/- 4.8 years) underwent V4b ICL implantation (21 non-toric, 41 toric ICL TICL) with intraoperative peripheral iridectomy (PI), and 10 eyes of 5 patients (26.13 +/- 3.8 years) had implantation of V4c ICL (4 non-toric, 6 TICL). The mean preoperative manifest spherical equivalent (MSE) was -9.98 +/- 2.8 D and -9.14 +/ 2.4 D in the V4b and V4c groups, respectively, which reduced to postoperative values of -0.24 +/- 1.3 D and -0.2 +/- 1.18 D, respectively. At the end of 9 months follow-up, mean ECC loss was 6.4% and 6.1%, mean vault was 573.13 +/- 241.13 MU, and 612 +/- 251.14 MU, respectively, in the V4b and V4c groups. Anterior subcapsular opacities were present in 6.9% and 3.14% of eyes with V4b and V4c groups, respectively. Four eyes from V4b (9.75%) and 1 eye from V4c (16.66%) had rotation of more than 30 degrees and required realignment surgery, which was done successfully. Two eyes (3.22%) with V4b ICL implantation had high postoperative IOP (>35 mm Hg) due to blocked PI and required Nd:Yag laser iridotomy, which was done with successful control of IOP. The safety indices were 1.11 and 1.14, and efficacy indices were 1.4 and 1.5 in the V4b and V4c groups, respectively, at the end of 9 months. CONCLUSION: ICL implantation is a safe and effective surgery for correction of high myopia. Implantation of ICL with a central hole showed negligible postoperative IOP fluctuations without a peripheral iridectomy. PMID- 27239583 TI - Effectiveness of Technolas torsional eye tracking system on visual outcomes after photorefractive keratectomy. AB - PURPOSE: To investigate the efficacy of Technolas 217Z eye tracking system (torsional component) in corneal surface irregularity and high order aberrations (HOAs) after photorefractive keratectomy. METHODS: Patients with compound myopic astigmatism among persons demanding refractive surgery in Khatam-al-Anbia Eye Hospital with the mean age of 29 years were enrolled in this double-blind randomized interventional study. The mean spherical equivalent (SE) of refractive error was -4.75 diopters(D) (range: -1.5 to -7.0), and the mean astigmatism was 3 D (range:1.0-4). Many studies were performed for each patient including: A complete eye examination, visual acuity and Monocular contrast sensitivity evaluation, and refraction. Corneal topography, Orbscan II, and wavefront aberrometry were conducted. One eye was randomly assigned for aspheric treatment and applying eye tracking system. The other eye was treated without torsional eye tracking system. The outcome measures were uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA), contrast sensitivity, corneal irregularity index in 3 mm and 5 mm optical zones in Orbscan II, and mean total HOAs at the 6 monthvisit. RESULTS: Fifty eyes of 25 patients were enrolled. Mean UCVA was improved significantly in both the study and control groups in the 6-month post operative follow-up. There was no significant difference between the 2 groups in UCVA and BCVA (P = 0.185 and P = 0.176, respectively). Total HOAs increased in both groups after PRK. However, they were lower in eyes treated with the eye tracking system (P < 0.001). Corneal irregularity index in 3 mm and 5 mm central zones in Orbscan II was significantly lower in the study group (P = 0.045 and P = 0.031 respectively). Contrast sensitivity function was not different in the 2 groups (P = 0.15). CONCLUSION: Our study findings suggest that applying 'Technolas 217z' eye tracker system (Bausch and Lomb Advanced) results in a more regular anterior surface of cornea. Therefore, we recommend it for surface laser refractive surgery. PMID- 27239584 TI - Comparison of the effect of cycloplegic versus NSAID eye drops on pain after photorefractive keratectomy. AB - PURPOSE: To compare the effect of Homatropine and Diclofenac eye drops for reducing pain after photorefractive keratectomy (PRK). METHODS: This randomized, double-masked, interventional study included 32 patients (64 eyes) who underwent bilateral PRK. After operation, patients received Homatropine eye drops in one eye and Diclofenac eye drops in the fellow eye for 48 h. The level of pain was evaluated using visual analogue scale (VAS), verbal rating scale (VRS), and pain rating index (PRI) at 0.5, 24, and 48 h after operation. RESULTS: The level of pain was statistically similar between the two eyes half an hour after operation; however, Diclofenac eyes had significantly less pain 24 h after operation (1.7 +/ 1.4 vs 5.8 +/- 2.1, P < 0.001 for VAS, 0.6 +/- 0.6 vs 2.4 +/- 1.1, P < 0.001 for VRS, and 3.4 +/- 3.4 vs 12.0 +/- 6.9, P < 0.001 for PRI, respectively). Also, 48 h after surgery, the pain scores were less in the Diclofenac eyes (1.6 +/- 1.8 vs 3.4 +/- 2.8, P < 0.001 for VAS, 0.6 +/- 0.6 vs 1.2 +/- 0.9, P < 0.001 for VRS, and 3.3 +/- 3.7 vs 6.5 +/- 6.2, P < 0.001 for PRI). No case with delayed epithelial healing in both groups was observed. CONCLUSION: The effect of Homatropine seems to be lower compared to Diclofenac for reducing pain after photorefractive keratectomy. PMID- 27239585 TI - Corneal elevation and keratoconus indices in a 40- to 64-year-old population, Shahroud Eye Study. AB - PURPOSE: To determine the corneal elevation values and keratoconus indices in the 40- to 64-year-old population and their changes with aging. METHODS: The 6311 invitees of this study were selected through random cluster sampling, and 5190 of them participated in the study (response rate = 82.2%). Here, we analyzed results of Pentacam acquisitions in 4148 respondents. Cases of keratoconus and forme fruste keratoconus (FFKC) were determined using topography and clinical data. Studied variables included keratoconus indices, central corneal thickness readings, maximum elevations on the anterior and posterior surfaces, and elevation values at the thinnest point, anterior steepest point, and posterior steepest point in healthy, FFKC, and keratoconus groups. RESULTS: In all subjects, the mean maximum elevations were 6.80 +/- 5.0 MUm and 16.60 +/- 7.7 MUm on the anterior and posterior corneal surfaces, respectively. Maximum elevation values on the anterior and posterior corneal surfaces showed significant correlations in the keratoconus, FFKC, and healthy groups (P < 0.002). Maximum anterior elevation correlated with age (r = 0.11, P < 0.001), but maximum posterior elevation showed no such correlation (P = 0.476). Keratoconus indices demonstrated significant changes with age (P < 0.001). CONCLUSION: Anterior elevation values slightly increase with age, and keratoconus indices change as well. Elevation readings and keratoconus indices in the keratoconus group and FFKC cases are higher than the healthy corneas although their values could be compared with other studies on younger participants. PMID- 27239586 TI - Utility of orthokeratology contact lenses; efficacy of myopia correction and level of patient satisfaction in Iranian myopic/myope-astigmatic patients. AB - PURPOSE: To investigate the medical profiles of patients referred to Iran Lens Clinic with myopic/myope-astigmatic refractive errors. METHODS: Medical records of 182 patients (364 eyes) with myopic/myope-astigmatic refractive errors that underwent orthokeratology contact lens wear and fulfilled a 6-month period of follow-up were recruited. Efficacy and safety of these contact lenses in improving the visual acuity and correction of the refractive errors were investigated. Time needed to achieve final targeted visual acuity and association of various factors in this time course and level of acuity were investigated. Complications related to these lenses that were recorded in the medical profiles were studied. RESULTS: In manifest refraction, the amount of spherical equivalent and myopia decreased significantly after orthokeratology contact lens wear (P < 0.001). A significant negative association was found between amount of mean baseline spherical equivalent and final achieved mean uncorrected visual acuity (P < 0.001). None of the parameters of age, gender, and keratometric findings influenced the outcomes significantly (P > 0.1). CONCLUSION: Patients with myopic refractive error lower than -5.0 Diopters achieved higher final visual acuities rather than patients with higher amounts of myopic refractive errors. PMID- 27239587 TI - Long-term visual outcome of congenital cataract at a Tertiary Referral Center from 2004 to 2014. AB - PURPOSE: To assess the long-term visual acuity (VA) outcome after congenital cataract surgery at Imam Hossein Medical Center (Tertiary Referral Center) (2004 2014). METHODS: In this descriptive study, records of 120 patients with a history of congenital cataract surgery were studied. Those with traumatic, metabolic cataract, aged <5 years at the last visit who were not able to respond VA testing accurately and follow-up < 6 months were excluded. Cases with incomplete files were recalled and reexamined. Finally, the records of 42 patients (71 eyes) were included. RESULTS: In this study, 20 males and 22 females with a mean age of 11.80 +/- 6 years at their last visit were studied. Bilateral and unilateral cataract was seen in 69% and 31% of cases, respectively. Posterior and anterior subcapsular opacity was the most common (53.70%) and rarest (1.90%) type of congenital cataract, respectively. The mean age at the time of operation and surgical interval was 65 +/- 66.6 (range: 1-200) and 12.9 +/- 23.5 (range: 0-96) months, respectively. The most common method of refractive error correction was pseudophakia plus glasses (56.3%) with the mean best corrected visual acuity (BCVA) of 0.29 +/- 0.28 LogMAR., The mean BCVA was 0.7 +/- 0.53 LogMAR for aphakic patients correcting by glasses. In our study, amblyopia (56%), glaucoma (23.90%), and posterior capsular opacity (16.40%) were observed during their follow-ups on an average of 76 +/- 65 months (median: 60, range: 6-240). Unilateral cataract, aphakia, nystagmus, female gender, and strabismus were risk factors of VA loss. CONCLUSION: Based on our results, 56% of cases showed amblyopia. It could be due to late operation (especially in unilateral cases), longer surgical interval between two eyes, and no compliance of amblyopia therapy. Early detection through screening may reduce the rate of amblyopia. Refractive errors, visual acuity, amblyopia, glaucoma, posterior capsular opacity, and compliance of amblyopia therapy should be checked regularly at follow-up visits. PMID- 27239588 TI - Comparison of ocular biometry measurements by applanation and immersion A-scan techniques. AB - PURPOSE: The study compared ocular biometry values using applanation and immersion techniques to determine the most applicable method for our tertiary training centre where personnel with different levels of experience and expertise in biometry take measurements used in calculation of required intraocular lens before cataract surgery. METHODS: The study was a prospective cross-sectional comparative study of different techniques of ocular biometry from diagnostic equipment (biometry probe 10 MHz Sonomed((r)) A-scan (PACSCAN 300A, USA). Measurement variables were obtained among children and adults undergoing cataract surgery. Scleral (Prager) shell was used for the immersion technique followed by the contact technique by the same examiner. RESULTS: The biometry values of 92 eyes of 92 adult were taken. Their ages ranged from 18 to 95 years with a mean of 64.7 (SD +/- 12.9) years. There were 55 (59.8%) males and 37 (40.2%) females, with a male to female ratio of 1.5:1. Average axial length (22.0-24.4 mm) eyes were the most common eyes measured in 75 (81.5%) of the cases. The means of the axial lengths biometry values with immersion and contact technique were 23.66(+/ 1.36) and 23.46 mm (+/-1.46); the axial length differences was 0.2 +/- 0.26 mm (range 0.0-0.94 mm) and statistically significant (95% CI of the Difference 0.15 to 0.26, p = 0.000). The Standard deviation SD (mm) of Individual Eye Axial Length showed a mean of 0.03 +/- 0.04 (0.0-0.3) mm for immersion and for contact technique 0.14 +/- 0.12(0.0-0.6)mm. CONCLUSION: There was a significant difference in ocular biometry measurement with the contact and immersion ultrasound techniques. The immersion technique had better repeatability, thus it is ideal in a training hospital setting in a typical in sub-Saharan Africa who have limited resources to employ a dedicated person to do biometry; and where the different operators of A-scan machines have different levels of experience and expertise. PMID- 27239589 TI - Higher order aberrations in a normal adult population. AB - PURPOSE: To determine the distribution of Zernike coefficients and higher order aberrations in a normal population and its relationship with age, gender, biometric components, and spherical equivalent. METHODS: During the first phase of the Shahroud cohort study, 6311 people of the 40-64-year-old population of Shahroud city were selected through random cluster sampling. A subsample of participants was examined with Zywave aberrometer (The Bausch & Lomb, Rochester, NY) to measure aberrations. Measurements of aberrations were done before cycloplegic refraction, and values generated from a minimum pupil diameter of 5 mm were reported in this analysis. RESULTS: After applying exclusion criteria, 904 eyes of 577 people were analyzed in this study and mean age in this study was 49.5 +/- 5.7 years and 62.9% were female. Mean root-mean-square (RMS) of the third-, fourth-, and fifth-order aberrations was 0.194 MUm (95%CI: 0.183 to 0.204), 0.115 MUm (95%CI: 0.109 to 0.121), and 0.041 MUm (95%CI: 0.039 to 0.043), respectively. Total RMS coma (Z3 (-1,) Z3 (1), Z5 (-1), Z5 (1)), Total RMS trefoil (Z3 (-3,) Z3 (3), Z5 (-3), Z5 (3)), and spherical aberration (Z4 (0)) in the studied population was 0.137 MUm (95% CI:0.129-0.145), 0.132 MUm (95% CI: 0.123-0.140), and -0.161 MUm (95%CI:-0.174 to -0.147), respectively. Mean higher order Zernike RMS in this study was 0.306 (95% CI: 0.295-0.318) micrometer, and in the multiple model, it significantly correlated with older age and short axial length. The highest amounts of higher-order RMS were observed in hyperopes, and the smallest in emmetropes. Increased nuclear opacity was associated with a significant increase in HO RMS (p < 0.001). Analysis of Zernike coefficients demonstrated that spherical aberration (Z4 (0)) significantly correlated with nuclear cataract only (age-adjusted Coef = 0.37 and p = 0.012). CONCLUSION: This report is the first to describe the distribution of higher-order aberrations in an Iranian population. Higher-order aberrations in this study were on average higher that those reported in previous studies. PMID- 27239590 TI - Macular thickness measurement in clinically significant macular edema before and after meal. AB - PURPOSE: To evaluate the macular thickness changes in diabetic macular edema after meal. METHODS: In this prospective case series, macular thicknesses of diabetic patients with clinically significant macular edema (CSME) were measured after 7 h of fasting and repeated 2 h after breakfast. RESULTS: Thirty six eyes of 20 diabetic patients were evaluated. The mean central subfield thickness (CST) and maximum retinal thickness (MRT) significantly decreased after meal (mean change of -10.3 +/- 14.3 MUm and -13.1 +/- 12.7 MUm, respectively, both P < 0.001). A decrease in CST and MRT values was found in 23 (63.8%) and 28 (77.7%) eyes, respectively, and no eye had an increase in retinal thickness measurements. Significant correlation was found between CST and MRT change and fasting thickness measurements (P = 0.001 and P = 0.01, respectively) and intraretinal cystic spaces (P = 0.001 and P = 0.03, respectively). Mean MRT change was significantly higher in the presence of subretinal fluid (P = 0.01). CONCLUSION: Retinal thickness measurements may change after meal. So, fasting state of diabetic patient should be considered in measurement of macular thickness of patients with CSME. PMID- 27239591 TI - Transient complete visual loss after intracameral anesthetic injection in cataract surgery. AB - PURPOSE: We describe a case of transient visual loss following cataract surgery with unpreserved intracameral lidocaine. METHOD: A 50-year-old man with posterior polar cataract underwent phacoemulsification. Following capsulorhexis and hydrodelineation with 0.5 cc of unpreserved lidocaine 1%, a portion of fluid reached behind the crystalline lens and caused the posterior capsule rupture. Cataract extraction and anterior vitrectomy were performed. Anesthetic administration was repeated to relieve the discomfort felt by the patient. A three-piece hydrophobic acrylic intraocular lens was implanted in the ciliary sulcus. RESULTS: On the first postoperative morning, the patient's vision was recorded as having no light perception. The relative afferent pupillary defect (RAPD) was found to be 4+. The retina and optic nerve head appeared normal. In the afternoon, the visual acuity (VA) was improved to 3-m count-finger. On the second postoperative morning, the patient's VA was improved to 4/10. On the third postoperative day, his VA returned to normal at 20/20 without RAPD. CONCLUSION: In the event of posterior capsular rupture, to reduce retinal toxicity risks, intracameral lidocaine should not be repeated. PMID- 27239593 TI - Letter to Editor, a scientific forum for discussion. PMID- 27239592 TI - Diabetes mellitus, diabetes insipidus, optic atrophy, and deafness: A case of Wolfram (DIDMOAD) syndrome. AB - PURPOSE: To report a case of Wolfram syndrome (WS) characterized by diabetes mellitus, diabetes insipidus, progressive optic atrophy, and deafness. CASE REPORT: A 19-year-old female patient, a known case of diabetes mellitus type I from six years before, presented with progressive vision loss since four years earlier. On fundoscopic examination, she had bilateral optic atrophy without diabetic retinopathy. The patient also had diabetes insipidus, neurosensory deafness, and neurogenic bladder. CONCLUSION: WS should be considered a differential diagnosis in patients with diabetes mellitus who present with optic atrophy, and it is necessary to perform a hearing test as well as collecting 24-h urine output. PMID- 27239594 TI - This issue at a glance. PMID- 27239596 TI - A comparative study on visual and optical performance of Akreos AO and Kontur AB IOLs after phacoemulsification cataract surgery. AB - PURPOSE: Akreos AO and Kontur AB are two commonly used intraocular lenses (IOLs) in Iran. This study was designed to evaluate the visual performance of these lenses. METHODS: In a comparative interventional study, 35 patients (70 eyes) were recruited, and each IOL was implanted in one eye of the patients, randomly. Best corrected visual acuity (BCVA), contrast sensitivity, aberrometric analysis, and depth of focus were evaluated 1 month and 3 months postoperatively. A visual quality questionnaire was also filled for each eye, and the results were compared. RESULTS: Mean age of the patients was 60.97 +/- 7.00 years. BCVA was not significantly different between the two eyes, before, 1 month, and 3 months postoperatively (p > 0.05 for all). Photopic and mesopic contrast sensitivity was not different between the two lenses instead of photopic 18 cycles per degree, 3 months postoperatively and in mesopic 6 cycles per degree 1 month postoperatively (p = 0.034 and p = 0.002, respectively). Aberrometric factors including HoRMS, Total RMS, and Higher order without Z(4,0) were not significantly different between the two lenses (p > 0.05 for all), but they were slightly lower for Akreos AO. Post-operative distance-corrected visual acuity for intermediate and near vision were not different between the two groups (p > 0.05, respectively). CONCLUSION: Visual performance of Akreos AO and Kontur AB is similar. However, contrast sensitivity and aberrometric parameters are slightly better for Akreos AO IOL. PMID- 27239595 TI - Erythropoietin in ophthalmology: A literature review. AB - PURPOSE: To review the current literature on ocular application of erythropoietin (EPO). METHODS: A comprehensive search was performed on Pubmed and Scopus databases. All selected articles were reviewed thoroughly by the authors to review current applications of the EPO in ocular diseases. RESULTS: Various aspects of administration of EPO for different ischemic, traumatic, vascular, and degenerative disorders have been explained. The articles are generally preclinical with few small studies reporting clinical outcomes. CONCLUSION: EPO has been used for the treatment of different ophthalmic conditions with promising results. Further studies are needed to elaborate the role of EPO in management of ocular diseases. PMID- 27239597 TI - Stereoacuity after photorefractive keratectomy in myopia. AB - PURPOSE: Stereopsis, as a part of visual function, is the ability of differentiating between the two eyes' views (binocular disparity), due to the eyes' different positions. The aim of this study was to compare stereoscopic vision before and after photorefractive keratectomy (PRK) in myopia. METHODS: In a prospective interventional case series study clinical trial, forty-eight myopic individuals (age range: 18-34 years) who had undergone PRK surgery by a Bausch & Lomb Technolas 217z excimer laser were included. In all patients, stereoscopic vision was assessed using TNO test charts at 40 cm distance preoperatively and at 3 and 6 months postoperatively. RESULTS: A total of 48 cases (96 eyes, 69% female) with a mean age of 26.70 +/- 4.89 years (range: 18-34 years) were treated. Uncorrected visual acuity (UCVA) was improved and refraction was corrected significantly after PRK surgery. The stereoscopic vision in patients was 246.56 +/- 98.43 s of arc before PRK surgery. Postoperatively, the stereoacuities were recorded as 365.38 +/- 112.65 s of arc and 343.51 +/- 88.96 s of arc at 3 and 6 months, respectively. These differences were statistically significant (p < 0.001). CONCLUSION: PRK was successful and safe in improving refractive error and UCVA, but it may deteriorate the stereoscopic vision. It may be due to an increase in higher order aberrations. PMID- 27239598 TI - Pentacam top indices for diagnosing subclinical and definite keratoconus. AB - PURPOSE: To determine pachymetric, aberrometric, and topometric indices in patients with definite and subclinical keratoconus and the validity of these indices in the diagnosis of keratoconus. METHODS: We evaluated 262 keratoconic and 97 healthy eyes in this study. Pentacam HR examination was performed for all participants, and the data of all pachymetric, aberrometric, and topometric indices was extracted for the study population. RESULTS: The average of all evaluated pachymetric and topometric indices and the 3rd and 5th order vertical coma aberrations showed a significant difference between the study groups (p < 0.001). Belin/Ambrosio Deviation Display (BAD_D), Index of Vertical Asymmetry (IVA), Index of Surface Variance (ISV), and 5th order vertical coma aberration were identified as the best diagnostic criteria for the diagnosis of subclinical keratoconus (R (2) = 0.65, p <0.001), and BAD_D, mean keratometry and 3rd order vertical coma aberration were identified as the best diagnostic criteria for the diagnosis of definite keratoconus (R (2) = 0.91, p <0.001). The sensitivity and specificity of the above-mentioned models were 83.6% and 96.9%, and 97.9% and 96.9%, respectively. CONCLUSION: Simultaneous evaluation of BAD_D, 5th order vertical coma aberration, IVA, and ISV, especially when the pattern of the corneal curvature is normal, can detect subclinical keratoconus with high sensitivity and specificity. As for definite keratoconus, each of the BAD_D, mean keratometry, and 3rd order vertical coma aberration indices has a desirable diagnostic validity. However, the aforementioned indices do not negate the importance of widely recognized and acceptable indices like keratometry and central corneal thickness. PMID- 27239599 TI - Visual management of aphakia with concomitant severe corneal irregularity by mini scleral design contact lenses. AB - PURPOSE: To evaluate visual results, comfort of use, safety, and efficacy of mini scleral contact lenses in optical management in patients with traumatic aphakia and severe concomitant irido-corneal injury. METHODS: In a case series, eight eyes with post traumatic aphakia and severe concomitant irido-corneal injury that were evaluated at the Contact Lens Clinic of Farabi Eye Hospital, Tehran, Iran for contact lens fitting and could not be corrected with conventional corneal RGP contact lenses were fitted with miniscleral contact lenses. Uncorrected visual acuity (UCVA), best spectacle corrected visual acuity (BSCVA), and BCVA (Best corrected visual acuity) with miniscleral lens were recorded. Slit lamp examination, comfortable daily wearing time, and any contact lens-related complication were documented in each follow-up visit. RESULTS: The mean UCVA and BSCVA of the cases was >2.7 and 0.41 LogMAR, respectively (BSCVA could not be assessed in one case due to severe corneal irregularity). The mean final BCVA with the miniscleral lens was 0.05 LogMAR (range from 0.4 to -0.04 LogMAR). The mean follow-up period was 14.6 months. The mean comfortable daily wearing time (CDWT) was 11.6 h, ranging from 8 to 16 h. The only contact lens-related complication was mild redness and irritation that was observed in 2 patients during the follow-up visits. All patients were comfortable with handling these lenses. CONCLUSION: Miniscleral contact lenses can be considered a safe and effective option in aphakia patients with concurrent corneal scarring secondary to ocular injury for whom surgical intervention would be complicated. PMID- 27239600 TI - Complement factor H and LOC387715/ARMS2/HTRA1 variant's frequencies and phenotypic associations in neovascular age-related macular degeneration, a pilot study. AB - PURPOSE: To evaluate the frequency of 12 single nucleotide polymorphisms (SNPs) of complement factor H (CFH) and LOC387715/ARMS2/HRTA1 and their association with some of the presenting clinical features of neovascular age-related macular degeneration (AMD). METHODS: In this prospective non-comparative case series forty four naive patients with neovascular AMD were genotyped using sequencing or Sequenom iPLEX technology. Descriptive tests were used for displaying the magnitude of each allele, gender distribution, and age at diagnosis. Fisher exact test was used to evaluate the correlation between visual acuity (VA) and different alleles. Also Kruskal-Wallis test was used for comparison between age at the time of diagnosis and different alleles. RESULTS: The most frequent SNP among studied patients was rs1061147 with 100% frequency rate. The least common was rs2672598 with a frequency of 52.27%. Only the allele rs800292 of CFH locus on 1q32 was associated with VA better than 20/200 (p value = 0.034). The frequency of this allele was 77.27% (34 patients) in this study. There was no significant association between any of alleles, and VA worse than 20/200(p > 0.05). Fifteen patients had bilateral exudative AMD (34.09%). There was no significant difference between alleles in bilateral neovascular AMD and unilateral disease. Also bilateral and unilateral patients were not different in terms of age, gender or VA (p value: 0.330, 0.764 and 0.456 respectively). There was also no significant association between any of SNPs and bilaterality of disease. CONCLUSION: We designated the frequencies of SNPs of CFH and LOC387715/ARMS2/HRTA1 in neovascular AMD in a sample of Iranian patients. Only the allele rs800292 of CFH locus on chromosome 1q32 was associated with better VA. PMID- 27239601 TI - Combined external and endonasal approach to fronto-ethmoidal mucocele involving the orbit. AB - PURPOSE: To present a technique to improve the surgical treatment of frontal sinus mucocele and its recurrence. METHODS: Nine procedures performed on eight patients by a team of ENT and Ophthalmic orbital surgeons. Data collected included patient demographics, surgical details, pathological findings and complications. The surgical technique involved an external approach via the upper eyelid skin crease combined with an internal approach with a rigid 4 mm endoscope described below. Following evacuation of the mucocele the sinus was anastomosed to nasal cavity with insertion of silicon stent. All patients had preoperative and postoperative CT scans of the orbit and paranasal sinuses. RESULT: There were nine operations on eight patients (six males, two female patients, mean age of 57.25: range, 15-71). Two patients had inverted papillomas. All patients presented with non-axial proptosis and diplopia. The mean follow up period was 38.7 months (range 11-99). The only intraoperative complication noted was a cerebrospinal fluid (CSF) leak in a patient with a post traumatic mucocele. Post operative complications included lid scarring in 2 patients. One of the patients had a fistula overlying the affected sinus at presentation. Both patients underwent dermis fat grafting as a second stage procedure and responded well. One patient presented with asymptomatic superior oblique weakness that could be attributed to trauma to the superior oblique intra operatively. There was no case of recurrence of mucocele in our series. One of the inverted papillomas had an early recurrence (within 6 months) that required repeat surgery. CONCLUSION: Fronto nasal anastomosis restores the anatomy and reduces the chance of recurrence in our experience. The final cosmetic result is excellent and the patient's satisfaction is high. PMID- 27239602 TI - Cataract surgical rate in Fars Province: Distribution and trend from 2006 to 2010. AB - PURPOSE: To determine changes in cataract surgical rate (CSR) in Fars Province from 2006 to 2010 and identify the contributions of public and private sectors. METHODS: This descriptive report is part of the Iranian Cataract Surgery Survey. To determine the provincial CSR, weights of major (>3000 annual surgeries) and minor (<=3000) centers were calculated based on the number of centers chosen for each year and multiplied by their numbers of surgeries. To determine public and private sectors' contributions, the numbers of surgeries in each sector were estimated based on the number of sampled centers. RESULTS: Overall, CSR improved by 25%; the number of CS decreased by 16% in the public sector and increased by 157% in the private sector. In 2006, the public sector contributed to 69% of the CSR, and by 2010, this rate had decreased to 43%. CONCLUSION: The decreasing contribution of the public sector calls for studies to identify causes and remove potential barriers. PMID- 27239603 TI - Post-thyroidectomy iatrogenic Horner's syndrome with heterochromia. AB - PURPOSE: To present a case of iatrogenic Horner's syndrome seen together with the heterochromia in the post-thyroidectomy period. METHODS: A 23-year-old female patient was admitted to our clinic with complaints of low vision in the eye and difference in eye color that developed over the past two years. In the left eye, myosis and minimal ptosis (~1 mm) was detected, and the color of the iris was lighter than the right eye. RESULTS: The pre-diagnosis of left iatrogenic Horner's syndrome was finalized after 0.5% topical apraclonidine test. CONCLUSION: Heterochromia can be observed in iatrogenic Horner's syndrome. PMID- 27239604 TI - Spontaneous retrobulbar hemorrhage in a patient with breast cancer: A case report. AB - PURPOSE: We present spontaneous retrobulbar hemorrhage in a 52-year-old woman with history of breast cancer and tamoxifen intake which was first thought to be an orbital metastasis. CASE REPORT: A 52-year-old woman with history of breast cancer and tamoxifen intake was referred due to severe proptosis and visual loss. Orbital imaging showed an intra-conal mass. After exploration, multiple fragments of dark brown mass in the retrobulbar area were excised. Microscopic diagnosis was blood clot. All of clinical signs and symptoms were improved 1 week after operation. CONCLUSION: Spontaneous retrobulbar hemorrhage is a rare condition that may have unknown etiologies, and its symptoms may mimic orbital metastasis. Since both breast cancer and tamoxifen intake can cause coagulation disorders, they might be possible causes for retrobulbar hemorrhage in this case. PMID- 27239605 TI - A rare intraabdominal emergency. PMID- 27239606 TI - There is something wrong but where? Dislocation or fracture? PMID- 27239607 TI - Low oxygen saturation is associated with pre-hospital mortality among non traumatic patients using emergency medical services: A national database of Thailand. AB - BACKGROUND: Pre-hospital emergency medical services are an important network for Emergency Medicine. It has been shown to reduce morbidity and mortality of patients by medical procedures. The Thai government established pre-hospital emergency medical services in 2008 to improve emergency medical care. Since then, there are limited data at the national level on mortality rates with pre-hospital care and the risk factors associated with mortality in non-traumatic patients. AIMS: To study the pre-hospital mortality rate and factors associated with mortality in non-traumatic patients using the emergency medical service in Thailand. METHODS: This study retrieved medical data from the National Institute for Emergency Medicine, NIEMS. The inclusion criteria were adult patients above the age of 15 who received medical services by the emergency medical services in Thailand (except Bangkok) from April 1st, 2011 to March 31st, 2012. Patients were excluded if there was no treatment during pre-hospital period, if they were trauma patients, or if their medical data was incomplete. Patients were categorized as either in the survival or non-survival group. Factors associated with mortality were examined by multivariate logistic regression analysis. RESULTS: During the study period, there were 127,602 non-traumatic patients who used pre-hospital emergency medical services in Thailand. Of those, 98,587 patients met the study criteria. For the statistical analyses, there were 66,760 patients who had complete clinical investigations. The mortality rate in this group was 1.89%. Only oxygen saturation was associated with mortality by multivariate logistic regression analysis. The adjusted OR was 0.922 (95% CI 0.8550.994). CONCLUSION: Low oxygen saturation is significantly associated with pre-hospital mortality in a national database of non-traumatic patients using emergency medical services in Thailand. During pre-hospital care, oxygen level should be monitored and promptly treated. Pulse oximetry devices should be available in all pre-hospital services. PMID- 27239608 TI - Retrospective analysis of whole-body multislice computed tomography findings taken in trauma patients. AB - OBJECTIVES: Using whole-body multislice computed tomography (MSCT) excessively or with irrelevant indications can be seen in many centers. The aim of this study was to analyze retrospectively the MSCT findings in trauma patients admitted to the emergency department. METHODS: Records of the patients who have applied to the emergency department due to blunt trauma in a 12 month period and whose whole body MSCT images have been taken, were evaluated using the "Nucleus Medical Information System". RESULTS: The most frequent type of trauma was traffic accidents in 61.4%, falling down from the height in 22.4%, and motorcycle accidents in 11.4% of patients. Of the patients, 25.2% were discharged from the emergency, while 73.8% were hospitalized. At least one CT findings associated with trauma was present in 61.4% of our patients. Pathological findings in MSCT were most frequently detected in the head and face (35.3%) and thoracic (28.6%) regions, respectively. The most common finding in the head and face region was fractures. The most common pathological findings in the thoracic region were pulmonary contusion and rib fractures. A significant relationship was detected between trauma type and spinal MSCT result (p < 0.001). In a large percentage of the patients, MSCT findings were normal in the abdominal region and genitourinary system. Vertebral fractures were most frequently detected in the thoracolumbar region. CONCLUSIONS: In our study, our rate of negative CT was found to be 38.6%, which is a higher ratio compared to other studies conducte on this topic. PMID- 27239609 TI - Assessment of prehospital medical care for the patients transported to emergency department by ambulance. AB - OBJECTIVES: In our study we aimed to investigate the quality and quantity of medical management inside ambulances for 14 and over 14 years old patients transported to a level three emergency department (ED). MATERIAL AND METHODS: Our study was conducted prospectively at a level three ED. 14 and over 14 years old patients who were transported to the ED by ambulance were included in the study consecutively. "Lack of vital rate" was described as missing of one or more of five vital rates during ambulance transportation. Both of two attending emergency physicians evaluated the medical procedures and management of patients at the ambulance simultaneously and this was recorded on the study forms. RESULTS: Four hundred and fifty six patients were included in the study. Missing vital signs were identified for 90.1% (n = 322) of the patients that were transported by physicians and 92.4% (n = 73) of the patients that were transported by paramedics. For five patients with cardiac arrest two (33.3%) had cardiopulmonary resuscitation (CPR), one (20%) was intubated, one (20%) received adrenaline. Out of 120 patients, needed spinal immobilization, 69 (57.5%) had spinal board. Cervical collar usage was 65.1% (n = 69) We have revealed that 316 (69.3%) patients did not receive at least one of the necessary medical intervention or treatment. CONCLUSION: During ambulance transportation, life-saving procedures like cardiopulmonary resuscitation, vital sign measurement, crucial treatment administration, endotracheal intubation, defibrillation, fracture immobilization were not performed adequately. Increasing the training on the deficient interventions and performing administrative inspections may improve quality of patient care. PMID- 27239611 TI - The approach of prehospital health care personnel working at emergency stations towards forensic cases. AB - OBJECTIVES: The objective of this study is to determine the states of health care personnel, working at 112 emergency stations in the province of Artvin, to encounter with regarding forensic cases and determine their practices aimed at recognizing, protecting, and reporting the evidences that may affect the forensic process. MATERIALS AND METHODS: This descriptive study was conducted with nurses and emergency medicine technicians working at 112 emergency stations in Artvin between January 2013 and February 2014. RESULTS: Of 141 health personnel that constituted sample of the study, 48.9% were nurses, 9.9% emergency medicine technicians, and 41.1% ambulance and emergency care technicians. The rate of feeling sufficient in coping with forensic cases and incidents was 20.6%. There was a lower rate of receiving education about the approach towards forensic cases (15.6%). In the study, the frequency of encountering with at least one forensic case was 88.7%. Traffic accidents (72.5%), suicides (41.5%) and assaults (41.5%) were among the most frequent reasons of forensic cases. The practices of nurses were more successful in woundings by firearms compared to other health personnel (p < 0.05). The rate of recognizing the evidences was 81.6-96.5%. Almost one fourth of the personnel had no sufficient information about storing and protecting the evidences. CONCLUSIONS: The personnel working at 112 emergency stations in the province of Artvin frequently encounter with forensic cases. The personnel with higher educational level and nurses have more successful practices in forensic cases. Health personnel have approaches that may negatively affect the solution of forensic cases. PMID- 27239610 TI - Effects of the institutional structure and legislative framework on ambulance accidents in developing emergency medical services systems. AB - OBJECTIVE: Turkey is a developing country undergoing a system change in the prehospital emergency medical services (EMS). The purpose of this study was to evaluate the effects of the institutional structure and legislative framework on the number of ambulance accidents in Turkey. METHODS: During the first phase of the study, ambulance accident data was requested and obtained from the Ministry of the Interior. Similarly, data on ambulance numbers were requested and obtained from the Ministry of Health through the Right to Information law. During the second phase of the study, a survey consisting of 112 EMS personnel viewpoints about the effects of the institutional structure and legislative framework on ambulance accidents was conducted using a structured questionnaire. A total of 209 EMS personnel completed the survey. RESULTS: The number of ambulance accidents increased by 42.5% over the last five years, whereas the area of coverage increased by 57.3% during the same period. The rate of EMS personnel experiencing ambulance accidents was 69.4%. When age, sex, and profession variables were considered, the varying profiles of the ambulance operators were found to have no significant effect on the number of ambulance accidents following the system change. CONCLUSION: The rise in the number of ambulance accidents in Turkey was not significant when compared with the increase in the area of responsibility. The present system change was also found to have no effect on the number of accidents. On the other hand, problematic areas in the institutional structure and the legislative framework increased the risk of accidents. PMID- 27239612 TI - Traumatic pseudocyst due to blunt trauma: Case report. AB - Damage to lung parenchyma due to blunt thoracic trauma often appears as contusion or hematoma. Cavitary lung lesions or pseudocyst formation due to trauma is a rare phenomenon. In the literature traumatic pseudocysts are also known as pseudocystic hematomas, traumatic lung cavity and traumatic pneumotocel. Traumatic pseudocysts usually have good clinical prognosis, recover spontaneously with supportive treatment and do not require surgery. In this article, we present the case of 52 year old male who was brought to the emergency department after a fall from height and was diagnosed with lung contusions and traumatic cyst. PMID- 27239613 TI - The lucky patient who aspirated a needle. AB - Foreign body aspiration is seen frequently in pediatric and geriatric patients, but it can also be seen in adults. Needle aspiration is a common problem in our country. Foreign body aspiration can lead to complete airway obstruction, asphyxia and death but sometimes symptoms may not be evident during the early period of aspiration and patients may present with complications afterwards. Early diagnosis is important in foreign body aspiration for prevention of mortality and complications. Suspicion aroused by patient history is the first step towards a diagnosis. Plain radiography and tomography may be used for imaging. Bronchoscopy is performed for diagnosis if there is uncertainty after imaging and may also be used for the treatment of diagnosed cases. In this article, we present a foreign body aspiration case that presented with difficulty and pain while swallowing, subsequently found to be the result of a needle that was stuck between the oropharynx and epiglottis. PMID- 27239614 TI - Non-traumatic atlanto-axial rotatory subluxation: A rare cause of neck stiffness. AB - Atlanto-axial rotatory subluxation is a rare condition in childhood. A sudden onset of pain and limitation in neck movements are the most common presenting features. Usually, a previous trauma history exists. This study presents a case of an 18-month-old male with neck stiffness and pain in neck through palpation without trauma in his history but with rotatory subluxation of 30 degrees in atlanto-axial joint observed in his cervical imaging. With this case, the aim was to emphasize the necessity for considering the atlanto-axial subluxation in patients less than five years old diagnosed with neck stiffness in differential diagnosis even if a trauma is not available in their histories. PMID- 27239615 TI - Small bowel perforation due to fish bone: A case report. AB - Accidental ingestion of foreign bodies are a common condition in clinical practice. However, small bowel perforation which dues to ingestion foreign bodies has been rarely seen. In this article, we report a case of small bowel perforation which dues to ingestion foreign body. A 80-year-old female patient, presenting with complaints of acute abdomen, was admitted to the emergency department. She denied abdominal pain, nausea and vomiting. The patient had tenderness and defense on the right lower quadrant. Contrast enhanced abdominal computed tomography has been used on the patient's diagnosis. This revealed small bowel perforation due to the ingestion of foreign body. The patient was operated emergency. A microperforation due to fish bone was detected on the terminal ileum. The patient underwent debridement and primary repair. The patient was discharged postoperative 7th day without problem. Bowel perforation due to the ingestion of foreign bodies should be considered in the differential diagnosis of acute abdomen. PMID- 27239616 TI - Rare etiological causes of iliofemoral deep venous thrombosis: Reports of 2 cases. AB - Deep venous thrombosis is frequently seen in lower extremities. However, when seen in the iliac level, mass effect of an underlying pathology must be considered. In this report, we present two cases with upper region deep venous thrombosis, which had underlying pathologies of appendicitis and non-Hodgkin lymphoma. PMID- 27239617 TI - Analysis of ectopic pregnancies admitted to emergency department. AB - OBJECTIVES: Ectopic pregnancy (EP) may cause significant morbidity and mortality. In this study, we aimed to evaluate the demographic characteristics, presence of risk factors and diagnostic parameters of the patient with EP and predicting parameters for ruptured EP. METHODS: Patients who presented to emergency department (ED) and diagnosed as EP within one year were included to the study. The demographic characteristics, beta-human chorionic gonadotropin (beta-HCG) levels, transvaginal ultrasonography (TVUSG) findings, treatment protocols, pathology reports and hemoglobin levels at the time of admission to ED were obtained from patient files and hospital automation system and statistical analysis was performed. RESULTS: Total 35 patients were included to the study. The mean age of the patients was 30 +/- 5.6 years. Among the patients, 46% had a history of caesarean section (C-section). The complaints of the patients at presentation, their age, gestational week and the beta-HCG levels were found to be inefficient in predicting ruptured EPs. TVUSG was found statistically significant in terms of demonstrating ruptures in EP. The ratio of salpingectomies was observed to be higher in the surgical treatment of ruptured EPs. CONCLUSIONS: C-section was most frequently seen with EP. There is no absolute diagnostic parameter for predicting ruptured EPs and TVUSG may be a clue for diagnosis. The final diagnosis is made through surgery. PMID- 27239618 TI - An investigation of the emergency medicine journals published in Turkey. AB - INTRODUCTION: There are many academic journals in Turkey and the world. Medical journals have a significant place among those publications. The aim of this study is to examine qualitatively and categorize the scientific studies of the two journals in Turkey. It also aims to contribute the related literature in the area. MATERIAL-METHOD: Academic journals of medical emergencies published in Turkey between January 1, 2003 and December 20, 2014 were investigated in detail. All the works in journals were categorized briefly as research articles, case presentations, review articles, and other works. Moreover, research articles were investigated as observational and experimental, and discussed according to the including topics. RESULTS: 943 scientific works in 86 issues were fully investigated. The total number was found to be 472 for research articles (50.1%), 242 for case presentations (25.7%), 108 for review articles (11.5%), and finally it was 12.8% for other works. Research articles included 450 observational (95.3%) and 22 experimental studies (4.7%). The key topics covered in research articles were the management and training of medical emergencies, trauma 96 (20.3%), toxicology 50 (10.6%), and gastrointestinal tract 36 (7.6%). CONCLUSION: Despite its relatively short history, medical emergencies have improved progressively in Turkey. The number of domestic research articles has demonstrated an increase over the years. However, extra efforts are needed in order to improve the quality of articles. The most common contents encountered in research articles were the management and training of medical emergencies, trauma and toxicology. PMID- 27239619 TI - Analysis of patients presenting to the emergency department with carbon monoxide intoxication. AB - OBJECTIVES: Carbon monoxide is a potentially fatal form of poisoning. The exact incidence is unclear, due to cases being undiagnosed or reported as fewer than the real number. Hyperbaric oxygen therapy (HBOT) is of proven efficacy in the treatment of CO intoxication. The purpose of this study was to describe the general characteristics of carbon monoxide (CO) intoxications presenting to the emergency department and to investigate troponin I values and the effectiveness of hyperbaric oxygen therapy (HBOT) in these patients. MATERIAL AND METHODS: Patients presenting to the emergency department with CO intoxication over one year and patients with such intoxications receiving HBOT were examined retrospectively. RESULTS: One hundred seventy-one patients were included; 140 (81.9%) were poisoned by stoves, 18 (10.5%) by hot water boilers and 10 in (5.8%) by fires. COHb levels were normal in 49 of the 163 patients whose values were investigated, and were elevated in 114 patients. Mean COHb value was 16.6. Troponin I values were investigated in 112 patients. These were normal in 86 patients and elevated in 26. Mean troponin I value was 0.38 ng/ml. One hundred twenty-three of the 171 patients in the study were discharged in a healthy condition after receiving normobaric oxygen therapy, while 48 patients received HBOT. Forty-two (87.5%) of the patients receiving HBOT were discharged in a healthy condition while sequelae persisted in five (10.4%). One patient died after 15 session of HBOT. CONCLUSION: Although elevated carboxyhemoglobin confirms diagnosis of CO intoxication, normal levels do not exclude it. Troponin I levels may rise in CO intoxication. No significant relation was observed between carboxyhemoglobin and receipt of HBOT. A significant correlation was seen, however, between troponin I levels and receipt of HBOT. PMID- 27239620 TI - Risk factors of delayed pre-hospital treatment seeking in patients with acute coronary syndrome: A prospective study. AB - OBJECTIVES: Despite enormous efforts in public education, treatment seeking time still remains more than optimal in patients with acute coronary syndrome. This prospective study tries to determine the risk factors of pre-hospital delay in patients with acute coronary syndrome. METHODS: Descriptive data of 190 patients with diagnosis of acute coronary syndrome attending in 2 tertiary level teaching hospital emergency departments were analyzed to determine risk factors of delayed pre-hospital treatment seeking. Demographic, social and clinical characteristics of patients were obtained and they were asked to fully describe their symptoms and the actions they had done after their symptoms onset. RESULTS: Thirty nine (20.52%) of patients were arrived in emergency department in <1 h of their symptoms onset, 73 (38.43%) were arrived between 1 and 6 h and 78 (41.05%) were arrived in >6 h. Sex, route of transport, scene-to-hospital distance, attributing the symptoms to non-cardiac causes and outpatient physician consultation and cigarette smoking were the risk factors of delayed treatment seeking in our studied patients with acute coronary syndrome. Patients with previous history of ischemic heart disease and Coronary Care Unit admission and patients with underlying diseases like diabetes mellitus, hypertension and hyperlipidemia showed a trend to have more delayed treatment seeking behavior but not with a statistically significant difference. Patients with positive family history of acute coronary syndrome arrived in emergency department earlier than other patients but again with not a statistically significant difference. CONCLUSION: Most patients with acute coronary syndrome arrived in emergency department in >6 h of their symptoms onset. Sex, route of transport, scene-to-hospital distance, attributing the symptoms to non-cardiac origins, outpatient physician consultation and cigarette smoking were risk factors of delayed treatment seeking in studied patients. PMID- 27239621 TI - Investigation of anxiety levels of patients with chest pain admitted to emergency department. AB - INTRODUCTION: We aimed to investigate the demographical features, anxiety levels and clinical findings of the patients admitted to our Emergency department (ED) due to chest pain. METHODS: Patients with chest pain older than 18 years were included into the study. Demographical features such as age, sex and education level, initial diagnosis in the ED, whether they were hospitalized or coronary intervention performed, were recorded. To determine the anxiety levels of the patients, State-trait Anxiety Inventory (STAI) was performed. RESULTS: Two hundred and eight adult patients with chest pain were included into the study. We could not determine a relationship between STAI levels of patients according to demographical findings, however, STAI scores tended to decrease by age. Considering the education levels of the patients, it was determined that STAI scores of university graduates were higher than others. The STAI scores of patients discharged from the ED were higher than those hospitalized. When patients were compared according to whether coronary intervention (CI) was performed or not, it was determined that patients who did not require CI had higher STAI scores. When coronary lesion localization of the patients hospitalized was investigated, any relationship could not be determined. CONCLUSION: In this study, we determined that anxiety levels of the patients with chest pain do not correlate with the severity of the disease. Higher anxiety levels of patients discharged from ED when compared to those with ACS is a challenging problem for both ED physicians and cardiologists. PMID- 27239622 TI - Health response to Hajj mass gathering from emergency perspective, narrative review. AB - Hajj is a unique gathering with Mecca and Kaaba being spiritually important to many faiths across the globe, especially Muslims. This is because of the proclamation of the prophet's father, Ibrahaam, when he called all mankind to perform Hajj. That is why all Muslims on Earth feel that they have to visit Mecca and Kaaba on a specific date and time, and that is the reason this small location hosts one of the largest human gatherings in the world. Hajj is one of the five pillars of Islam that every financially and physically able Muslim must perform once in his/her lifetime. For 14 centuries countless millions of Muslim men and women from the four corners of the earth have undertaken pilgrimage to Mecca. In conclusion this review article confirm that Hajj is oldest and largest mass gathering in all mankind and there is some issues influence the health response such as size of gathering. diversity of population, climate and health facilities around hajj site, also we discuss the infectious and non infectious related illness in hajj and their prevention methods. PMID- 27239623 TI - Importance of back blow maneuvers in a 6 month old patient with sudden upper airway obstruction. AB - Foreign body aspiration in children under four years old is one of the most frequently observed reasons for accident related deaths. It is more common in this age group due to inadequate swallowing functions and exploration of objects with the mouth. The most frequently encountered foreign bodies are food and toy parts. Life threatening complete laryngeal obstruction is rarely observed. Dyspnea, hypersalivation, cough and cyanosis can be seen. The basic and life saving treatment approach is complete removal of foreign body maneuvers in the sudden onset of total obstruction. Here we report a six-month old male, who ingested a foreign body and was treated with back blow maneuvers successfully. In this case we emphasized the importance of back blow maneuvers. PMID- 27239625 TI - Methemoglobinemia caused by dapsone overdose: Which treatment is best? AB - Increase of methemoglobin level is named as methemoglobinemia characterized by functional anemia and tissue hypoxia. Methemoglobinemia can be congenital, but acquired form are more often caused by various drugs and toxins. Methylene blue is the most effective antidote for acquired methemoglobinemia. When methylene blue is not available, alternative treatments such as ascorbic acid and hyperbaric oxygen can be useful. In this paper we presented a case of methomoglobinemia due to dapsone overdose. PMID- 27239624 TI - Wellens' Syndrome - Report of two cases. AB - Wellens' Syndrome is a pattern of electrocardiographic T-wave changes associated with critical, proximal left anterior descending (LAD) artery stenosis. Diagnostic criteria of Wellens' Syndrome are history of chest pain, little or no cardiac enzyme elevation, little or no ST-segment elevation, no loss of precordial R waves, no pathologic precordial Q waves and typical T-wave changes. Urgent cardiac catheterization is vital to prevent myocardial necrosis. Here we are presenting two cases with Wellens' Syndrome who had been sent for catheterization before marked myocardial infarction developed. The first case was 63 years old woman admitted to emergency room with a typical chest pain lasting for 7 h. Electrocardiography (ECG) revealed characteristic Type A Wellens' Syndrome. The second case was also a 64 years old female patient. She was admitted to emergency room with a chest pain lasting for 2 days. Type B Wellens' Syndrome was considered according to ECG and clinical findings. Emergency angiography revealed critical LAD occlusions which were resolved before marked MI occurred in both of the cases. It is important for the emergency physicians, to recognize the typical ECG findings of Wellens' Syndrome, because these characteristic ECG findings are considered as a marker for critical LAD occlusions. PMID- 27239626 TI - A case of acute hepatitis following mad honey ingestion. AB - Acute hepatitis is characterized by liver inflammation and liver cell necrosis. The most frequently observed underlying cause thereof is viruses, but various other causes, such as alcohol, medication, or toxins may also lead thereto. In this paper, a case of acute hepatitis presenting with bradycardia, hypotension, and a prominent increase in liver enzymes following mad honey ingestion is discussed. Since there are only few cases of acute hepatitis following mad honey ingestion in the literature, we want to present this subject matter. PMID- 27239627 TI - Rapid onset mediastinal hematoma due to vertebral fracture and review of relevant literature. AB - Patients with vertebral fractures are frequently encountered and those with thoracic and lumbar spine fractures are likely to have associated injuries. Detection of a widened mediastinum after trauma is very nonspecific and most of the time it is related to aortic injury or mediastinal hematoma. Vertebral or sternal fractures can also be the cause of mediastinal hematoma with or without aortic injury. This report reviews an unusual case of rapid onset mediastinal hematoma due to vertebral fracture after a fall. In the case, there was a mediastinal hematoma adjacent to a burst fracture of the T8 vertebral body. There was a rapid increase in identified hematoma during the emergency follow up and urgent erythrocyte transfusion was carried out. We would like to raise awareness of this infrequent presentation of mediastinal hematoma, as it is insidious and possibly fatal. In the evaluation of mediastinal hematoma, the detection of osseous injuries is a requirement. PMID- 27239628 TI - Lower abdominal pain in an immunocompromised diabetes mellitus patient. PMID- 27239629 TI - Is contrast-enhanced MRI efficient in testicular infarction mimicking testicular tumor on scrotal ultrasound? PMID- 27239630 TI - Comparison of diagnostic and prognostic utility of lactate and procalcitonin for sepsis in adult cancer patients presenting to emergency department with systemic inflammatory response syndrome. AB - OBJECTIVES: Differentiating sepsis from other noninfectious causes of systemic inflammatory response syndrome (SIRS) in cancer patients is often challenging. Although lactate and procalcitonin have been studied extensively regarding sepsis management, little is known about their utility in cancer patients. This study aimed to compare the diagnostic and prognostic utility of lactate and procalcitonin for sepsis in cancer patients. MATERIAL AND METHODS: This prospective case-control study was conducted with adult cancer patients presenting to emergency department (ED) with at least two SIRS criteria. The infection status of each patient was determined retrospectively. Main diagnostic variables were calculated for diagnostic and prognostic utilities of lactate and procalcitonin. RESULTS: Among 86 patients, mean age was 61. Twenty-two (25.6%) were determined in the sepsis group. In the ROC analysis, a lactate value of 1 mmol/L predicted sepsis with 86.36% (95%CI: 65.1%-97.1%) sensitivity and 28.12% (95%CI: 17.6%-40.76%) specificity. A procalcitonin value of 0.8 ng/mL yielded a sensitivity of 63.64% (95%CI: 40.7%-82.8%) and 76.56% (95%CI: 63.4%-86.2%) specificity for differential diagnosis of sepsis in cancer patients. Lactate and procalcitonin showed similar abilities in differentiating sepsis from non infective SIRS in cancer patients [AUROCs of 0.638 (95%CI:0.527-0.739) vs 0.637 (95%CI:0.527-0.738), respectively. p = 0.994]. They were also similar in predicting poor clinical outcome with AUROCs of 0.629 (95%CI:0.518-0.731) and 0.584 (95%CI: 0.473-0.69), respectively (p = 0.577). CONCLUSIONS: The results of this study indicated that, none of the lactate and procalcitonin can be recommended alone to differentiate sepsis from non-infectious SIRS and to predict the poor clinical outcomes in adult cancer patients with SIRS in the ED. PMID- 27239631 TI - Correlation of ischemia-modified albumin levels and histopathologic findings in experimental ovarian torsion. AB - OBJECTIVES: Ischemia modified albumin (IMA) levels significantly increased and may be used as a diagnostic marker in ovarian torsion. The aim of this study is to investigate whether there was any correlation between IMA levels and histopathologic changes in experimental ovarian torsion. MATERIAL AND METHODS: Fourteen Sprague-Dawley rats, each weighing 220-250 g were divided randomly into 2 groups; in Group 1, the control group (n = 7), only laparotomy was performed and in Group 2, the experimental group (n = 7), ovarian torsion was performed. Ischemia was performed for 3 h; following the ischemia period, the torsion was relieved by detwisting the adnexa and then the ovarian I/R protocol was applied for 3 h. Blood samples were taken from all of the rats to measure the IMA levels and the ovaries were surgically removed for histologic examination. A blinded pathologist examined and scored the samples. RESULTS: The median (minimum maximum) IMA values were 921.00 (870.00-966.00) ABSUs in the ovarian torsion group and 853.00 (782.00-869.00) ABSUs in the control group. The difference was statistically significant. In the correlation analysis, a significant and strong correlation was found between IMA levels and histopathologic changes (Spearman's rho = +0.987, p < 0.001). CONCLUSION: Positive correlation was found between the IMA levels and the histopathologic severity of the disease. This finding is important for both diagnosis of the disease and patient follow-up. As a new marker in ovarian torsion, IMA may also indicate the severity of the ovarian histopathology. PMID- 27239632 TI - Assessment of ventricular wall motion with focused echocardiography during cardiac arrest to predict survival. AB - OBJECTIVES: Our primary goal is to investigate the hypothesis that in patients with a detectable ventricular wall motion (VWM) in cardiac ultrasonography (US) during cardiopulmonary resuscitation (CPR), survival rate is significantly more than in patients without VWM in US. MATERIAL AND METHODS: In our prospective, single center study, 129 adult cardiac arrest (CA) patients were enrolled. Cardiac US according to Focus Assessed Transthoracic Echo (FATE) protocol was performed before CPR. Presence of VWM was recorded on forms along with demographic data, initial rhythm, CA location, presence of return of spontaneous circulation (ROSC) and time until ROSC was obtained. RESULTS: 129 patients were included. ROSC was obtained in 56/77 (72.7%) patients with VWM and 3/52 (5.8%) patients without VWM which is statistically significant (p > 0.001). Presence of VWM is 95% (95% CI: 0.95-0.99) sensitive and 70% (95% CI: 0.58-0.80) specific for ROSC. 43/77 (55.8%) patients with VWM and 1 (1.9%) of 52 patients without VWM survived to hospital admission which was statistically significant (p < 0.001). Presence of VWM was 100% (95% CI: 0.87-1.00) sensitive and 54% (95% CI: 0.43 0.64) specific for survival to hospital admission. CONCLUSION: No patient without VWM in US survived to hospital discharge. Only 3 had ROSC in emergency department and only 1 survived to hospital admission. This data suggests no patient without VWM before the onset of CPR survived to hospital discharge and this may be an indication to end resuscitative efforts early in these patients. PMID- 27239633 TI - Retrospective evaluation of patients with elevated digoxin levels at an emergency department. AB - OBJECTIVES: We investigated the demographic characteristics, clinical and laboratory findings, treatment strategies and clinical outcomes of patients presenting at emergency department (ED) with digoxin levels at or above 1.2 ng/ml. MATERIALS AND METHODS: The demographic and clinical characteristics of patients with serum digoxin levels at or above 1.2 ng/ml admitted to an ED between January 2010 and July 2011 were investigated in this cross-sectional descriptive study. Patients with ECG and clinical findings consistent with digoxin toxicity and no additional explanation of their symptoms were evaluated for digoxin toxicity. RESULTS: In this study 137 patients were included, and 68.6% of patients were women with mean age 76.1 +/- 12.2. There was no significant difference between gender and digoxin intoxication. The mean age of intoxicated group was significantly higher than the non-intoxicated group (P = 0.03). The most common comorbidities were congestive heart failure (n = 91) and atrial fibrillation (n = 74). The most common symptoms were nausea, vomiting and abdominal pain. The levels of hospitalization and mortality in this group were significantly higher. CONCLUSION: Digoxin intoxication must be suspected in patients present in the ED, particularly those with complaints that include nausea and vomiting, as well as new ECG changes; serum digoxin levels must be determined. PMID- 27239634 TI - Is non-operative approach applicable for penetrating injuries of the left thoraco abdominal region? AB - OBJECTIVES: Currently, diagnostic laparoscopy (DL) is recommended for the left thoraco-abdominal region penetrating injuries (LTARP). However, organ and diaphragmatic injury may not be detected in all of these patients. Our aim is to focus on this LTARP patient group without any operative findings and to highlight the evaluation of diagnostic tools in the high-tech era for a possible selected conservative treatment. MATERIAL AND METHODS: The patients who were admitted to ED due to LTARP, and who underwent routine DL were evaluated retrospectively in terms of demographic, clinical, radiological, and operative findings of the patients. RESULTS: The current study included 79 patients with LTARP. In 44 of 79 patients, abdominal injury was not detected. In 30 patients an isolated diaphragmatic injury was revealed and in 4 patients a visceral injury was accompanying to diaphragmatic injury. Surgical findings revealed that the diaphragm was the organ most likely to sustain injury. In patients with more than one positive diagnostic findings need for surgery rate was 61.5%, however; in patients with one positive diagnostic finding (n = 53), positive surgical finding rate was only 35.8%, (p = 0.03). Regarding the combined use of all diagnostic tools in these patients; such as physical examination, plain chest X-ray, and computed tomography, when this method was used for pre-operative diagnosis, sensitivity was measured as 82.7%, specificity 84.1%, PPV 77.4% and NPV 88.1%. CONCLUSION: Although DL is reliable for diagnosis of diaphragmatic and visceral injury in patients with LTARP. However, individual decision making for laparoscopic intervention is needed to prevent morbidity of an unnecessary operation under emergent setting due to high rates of negative intraabdominal findings. PMID- 27239635 TI - Ruptured superior gluteal artery pseudoaneurysm with hemorrhagic shock: Case report. AB - Pseudoaneurysm of the superior gluteal artery (SGA) is very rare and the most common causes are blunt or penetrating pelvic traumas. Although pseudoaneurysm can be asymptomatic at the time of initial trauma, it can be symptomatic weeks, months, even years after initial trauma. We present a case of a ruptured superior gluteal artery pseudoaneurysm with hemorrhagic shock twenty days after a bomb injury in the Syria civil war. In addition, we review the anatomy of the SGA, clinical presentation and pitfalls of pseudoaneurysm, and imaging and treatment options. PMID- 27239636 TI - Gluteal compartment syndrome secondary to superior gluteal artery injury following pelvis fracture: A case report and review of literature. AB - Acute gluteal artery syndrome secondary to superior gluteal artery injury following pelvic fracture is a rare entity with potential for significant morbidity and mortality. In this report we present such a case resulting with a favorable outcome with prompt diagnosis and appropriate treatment. PMID- 27239637 TI - A rare entity in ED: Normal lipase level in acute pancreatitis. AB - Acute pancreatitis can have a variable presentation and diagnosis is based on clinical presentation, serum amylase and lipase levels and computed tomography. Negative predictive value of serum lipase in diagnosing acute pancreatitis is approximately to 100 percent and a normal blood lipase level in acute pancreatitis is an extremely rare condition. Here we reported two cases with normal serum amylase and lipase levels. PMID- 27239638 TI - Chronic anabolic androgenic steroid usage associated with acute coronary syndrome in bodybuilder. AB - INTRODUCTION: It has been argued in current studies that anabolic androgenic steroids (AAS) are misused by a great number of bodybuilders and athletes. However, there is diverse and often conflicting scientific data on the cardiac and metabolic complications caused by the misuse of AAS. There may be various reasons for myocardial infarction (MI) with normal coronary arteries. However, for the majority of patients, the exact cause is still unknown. CASE REPORT: A 32 year-old male who was complaining about severe chest pain was admitted to our emergency department. He had been taking methenolone acetate 200 mg weekly for a period of three years for body building. His cardiac markers were significantly elevated and electrocardiogram (ECG) showed peaked T waves in all derivations, which did not show ST elevation or depression. Both right and left coronary artery systems were found to be completely normal as a result of the angiogram. CONCLUSION: The purpose of this study is to show that AAS induced MI can be encountered with normal coronary arteries during acute coronary syndrome. PMID- 27239639 TI - Acute bilateral vision loss in emergency department: A case report. AB - Stroke occurs due to the interruption of blood flow to the brain and it is divided into ischemic and hemorrhagic. In the ischemic strokes, while the most commonly affected vessel is median cerebral artery (MCA), it is particularly affected bilateral posterior cerebral artery (PCA) is very rare condition. In this study, a case of sudden loss of vision and bilateral occipital infarct associated with bilateral vertebral system pathology and methylene tetrahydrofolate reductase (MTHFR) gene mutation were reported. A 62-year-old man was admitted with sudden loss of vision complaint starting 10 h before applying to emergency department. The patient was oriented and cooperative. On neurological examination, there was complete loss of vision in the right eye and only a response to light in the left eye. On the brain computerized tomography (CT), ischemic lesions were observed in the bilateral occipital areas and on magnetic resonance imaging (MRI), there were foci showing diffusion limitation in cortico-subcortical areas of bilateral parieto-occipital region. On the detailed examination at the clinic, MTHFR (a1298c) gene mutation was detected. Bilateral occipital infarction is rare and its diagnosis can be difficult because of its atypical symptoms. Therefore, occipital infarction should be suspected when the only sign is isolated vision loss in patients with risk factor for thromboembolism in their history and detailed visual-neurological examination of these patients should be performed. PMID- 27239640 TI - Abdominal pain etiology in cirrhotic patient. PMID- 27239641 TI - A rare cause of elbow injury. AB - We present the case of a patient who presented to the emergency department complaining of elbow pain after falling. Radiographic views of the elbow were shown. PMID- 27239642 TI - Susuk: Mysterious incidental finding. PMID- 27239644 TI - Deformable Registration of Multimodal Tongue MR Images. PMID- 27239643 TI - Forced Complementation between Subgenomic RNAs: Does Human Immunodeficiency Type 1 Virus Reverse Transcription Occur in Viral Core, Cytoplasm, or Early Endosome? AB - Although the process of reverse transcription is well elucidated, it remains unclear if viral core disruption provides a more cellular or viral milieu for HIV 1 reverse transcription. We have devised a method to require mixing of viral cores or core constituents to produce infectious progeny virus by a bipartite subgenomic RNA (sgRNA) system, in which HIV-1 cplt_R/U5/gag/Deltapol and nfl sgRNAs are complementary to each other and when together can complete viral reverse transcription. Only the heterodiploid virus containing both the nfl and cplt_R/U5/gag/Deltapol sgRNAs can complete reverse transcription and propagate infectious virus upon de novo infection. Dual exposure of U87.CD4.CXCR4 cells with high titers of the homodimeric nfl and cplt_R/U5/gag/Deltapol virus particles did not result in productive virus infection. On the other hand, in early endosomes, the HIV-1 sgRNAs released from viral cores can retain function and complete the reverse transcription and result in productive infection. These findings confirm the assumptions that, in natural infection, HIV-1 cores, and likely other retrovirus cores, remain largely intact and do not mix/fuse in the cytoplasm during the reverse transcription process, and circulating cytoplasmic HIV-1 sgRNA (produced through transfection) could not help the complementary sgRNA in the viral core to complement the reverse transcription process. PMID- 27239645 TI - Ultrasound: "one stop shop" in hepatology. PMID- 27239646 TI - Comparison of three ultrasound based elastographic techniques in children and adolescents with chronic diffuse liver diseases. AB - Non-invasive techniques for liver fibrosis assessment were developed for adults and recent researches tested their accuracy in children. The only validated elastographic method for non-invasive liver fibrosis evaluation in children is Transient Elastography (TE). The aim of our study was to investigate the feasibility of liver stiffness (LS) measurement in paediatric patients with chronic liver diseases by means of Acoustic Radiation Force Impulse Elastography (ARFI) and 2D-Shear Wave Elastography (2D-SWE), compared to TE as reference method. MATERIAL AND METHODS: We enrolled 54 consecutive children and adolescents with different chronic liver diseases. All patients were examined by means of TE, ARFI, and 2D-SWE. All measurements were performed in the right liver lobe, in the same session, in fasting condition. We considered reliable LS elastographic measurements as follows: for TE and ARFI - the median value of ten measurements with a success rate >/=60% and an interquartile range<30%, for 2D-SWE - the median value of five measurements. RESULTS: The successful measurement rate for TE was 94.4% (51/54). Taking TE as a reference method, sensitivity of ARFI for detecting fibrosis F1 was 71.42%, for F2-77.77%, for F3-62.5% and for F4-71.42%. Sensitivity of 2D-SWE for detecting F1 was 92.85%, for F2-83.33%, for F3-87.5% and for F4-85.71%. We found significant correlations between TE and 2D-SWE on the entire lot (Kappa correlation factor=0.843, p=0.001). Analyzing the subgroup with SR=60%-70%, we did not find significant correlation between TE and ARFI (Kappa correlation factor=0.172, p=0.452). Assessing the subgroup with SR>70%, we found a significant correlation between TE and ARFI (Kappa correlation factor=0.761, p=0.001). CONCLUSIONS: Overall, 2D-SWE correlate better with TE compared to ARFI in children. Excluding patients with less satisfactory technical parameters, we obtained significant correlations between all three methods. Both SWE and ARFI are non-invasive techniques feasible of performing on paediatric patients along with TE. PMID- 27239647 TI - The influence of acute physical effort on liver stiffness estimation using Virtual Touch Quantification (VTQ). Preliminary results. AB - AIM: Food intake and acutely decompensated cardiac failure may impair liver stiffness estimations, mainly because these methods are influenced by liver blood flow variation encountered in these conditions. It is well known that also during physical effort liver blood flow changes, due to the redistribution of blood flow mainly to the skeletal muscles. The aim of this study is to assess the change of liver shear- wave velocities immediately after cessation of an acute physical effort. A secondary aim was to find the proper timing for accurate liver stiffness estimation after physical exhaustion. MATERIAL AND METHODS: Liver shear wave velocities were measured using virtual touch quantification (VTQ) in seven apparently healthy volunteers, in fasting conditions. All subjects underwent a complete abdominal ultrasound study, including the liver VTQ. Then, all subjects performed a spiroergometry and thereafter, another series of three liver shear wave velocity measurements were performed: immediately after spiroergometry, five min, and ten min after spiroergometry, respectively. RESULTS: Before spiroergoemetry, the mean liver shear-wave velocity was 1.05+/-0.12 m/sec. Immediately after spiroergometry, mean liver shear-wave velocities increased significantly, measuring 1.34+/-0.16 m/sec (p <0.01). The mean liver shear-wave velocities at five and ten minutes after exhausting were 1.23+/-0.14 m/sec and 1.05+/-0.11 m/sec respectively. CONCLUSIONS: Liver stiffness estimation using VTQ was influenced by acute physical exercise in our study group. Despite the small number of subjects, the preliminary results show that if patients had done physical effort before VTQ elastography, they should rest at least ten minutes before reliable liver stiffness estimations can be performed. PMID- 27239648 TI - Endoscopic ultrasound guided injection of iron oxide magnetic nanoparticles for liver and pancreas: a feasibility study in pigs. AB - AIMS: Pancreatic cancer and hepatocellular carcinoma are two of the most aggressive types of cancer with limited therapeutic options in stages of advanced disease. Our objective is to assess the safety and feasibility of injecting iron oxide nanoparticles (IONs) via endoscopic ultrasound (EUS)-guidance, both systemically and locally in the liver and pancreas in order to study new potential therapies for liver and pancreatic tumors. MATERIAL AND METHODS: Six domestic pigs were used for our study design, and divided into three groups: two were injected in the portal vein, and other four were subjected to local exposure of IONs in the liver and pancreas, two each. The pigs were on a 7 days follow-up and necropsy was performed with their organs harvested. A 3T MRI scan was also performed. RESULTS: All animals underwent an endoscopic ultrasound fine needle injection (EUS-FNI) procedure without any complications. EUS-FNI procedure had an average time of 5 minutes and 21 seconds and consisted of 2 ml of ION injection. No perforations and no risk of potential bleeding were recorded. Macroscopic changes were observed only after pancreatic EUS-FNI. A significant amount of IONs was observed in the liver after local injection and after vascular EUS-FNI. The imaging results were confirmed by pathological examination with most of the IONs accumulated in Ito-like cells, Kupfer cells, and sinusoids. CONCLUSIONS: IONs have been widely studied for both diagnostic and therapeutic purposes. Their injection through EUS-guidance may develop new diagnosis strategies as well as curative or palliative therapies in pancreatic and liver tumors. PMID- 27239649 TI - Contrast-Enhanced Ultrasound for differential diagnosis of pancreatic mass lesions: a meta-analysis. AB - AIM: To evaluate the diagnostic accuracy of contrast-enhanced ultrasound (CEUS) as a method for diagnosing pancreatic lesions with regard to the ductal pancreatic carcinoma and the differentiation of neoplastic from non-neoplastic lesions. MATERIAL AND METHODS: Relevant studies published by September 6, 2015 were retrieved from PubMed, Embase, and Cochrane Central Trials databases. The articles included were mainly based on the following criteria: use of CEUS as the diagnostic tool, and the use of histology as the reference method. Two independent reviewers inspected all these papers to confirm the matching of the inclusion criteria. One reviewer with methodological expertise extracted the data from the included studies. Sensitivity, specificity and diagnostic odds ratio (DOR) were used to obtain overall estimates. RESULTS: Eighteen studies out of 734 articles initially identified met the inclusion criteria. The primary study objective with respect to ductal adenocarcinoma was verified in 15 studies. The pooled estimate of CEUS sensitivity for the differential diagnosis of duct adenocarcinomas was 0.90 (95 % CI, 0.89-0.92), and the specificity was 0.88 (0.84 0.90). The pooled estimate for DOR was 56.38 (29.91-106.33). The area under the curve under the summary receiver operating characteristic (SROC) was 0.95. 12 out of 18 studies examined CEUS sensitivity and the average specificity with regard to the secondary study objective, distinguishing between neoplastic lesions and non-neoplastic lesions, were 0.95 (0.94-0.96) and 0.83 (0.77-0.87). The pooled estimate for DOR was 73.25 (45.31-118.43). The area under the SROC curve was 0.96. CONCLUSIONS: CEUS is a promising, reliable modality for the differential diagnosis of pancreatic adenocarcinoma in patients with pancreatic mass lesions. The presence of a hypoenhanced lesion was a sensitive predictor of pancreatic adenocarcinomas. It seems to be a useful tool in clinical practice. PMID- 27239650 TI - Relationship of side dominance and ultrasonographic measurements of pronator quadratus muscle along with handgrip and pinch strength. AB - AIMS: We ascertained effects of hand dominance in both right and left-handed volunteers on the thickness and cross sectional area (CSA) of pronator quadratus (PQ) muscle as measured by the axial and sagittal views of ultrasound imaging. Secondly, we also aimed to document the extent of the relationship between the PQ measurements and handgrip. MATERIALS AND METHODS: Healthy adults from the volunteer medical staff were included in the study. Handedness was assessed via The Flinders Handedness survey. The sonographic appearance of the PQ was evaluated on sagittal and axial images for both hands. CSA of PQ muscle was digitally drawn and calculated on the axial plane. Handgrip was measured by using adjustable-handle dynamometer. RESULTS: Eighty-nine healthy volunteers were included (54 right and 35 left-handed). Significant difference was detected between dominant and non-dominant hands in CSA and muscle thickness in both right and left-handed volunteers (p<0.05). These measurements were correlated with the handgrip strength (p<0.05, r=0.55, and r=0.43 for right-handed volunteers, r=0.67 and r=0.48 for left-handed volunteers, respectively). There were also significantly high correlations between the measurements of CSA and PQ thickness of the corresponding extremity in both right-handed and left-handed volunteers (p<0.05). CONCLUSIONS: A statistically significant difference exists between dominant and non-dominant hands in CSA and muscle thickness measured by US in both right and left handed volunteers, and this is correlated with handgrip strength. Hand dominance should be considered to compare healthy and affected sites during US of PQ while investigating for occult fractures of distal forearm or PQ atrophy due to anterior interosseous nerve injury. PMID- 27239651 TI - A novel approach to assess pulmonary function in patients with chronic obstructive pulmonary disease using tissue velocity imaging. AB - AIMS: To explore the feasibility of quantitative evaluation of pulmonary function in patients with chronic obstructive pulmonary disease (COPD) using tissue velocity imaging (TVI) and strain rate imaging (SRI) via transthoracic lung ultrasonography. MATERIAL AND METHODS: Eighty inpatients with clinically diagnosed COPD underwent pulmonary function test and transthoracic lung ultrasound on the same day. Lung ultrasound variables and pulmonary function parameters were analyzed. RESULTS: All patients with COPD had faster breathing and significant reduced lung function compared with healthy participants (p<0.05). The lung ultrasound parameters, velocity (max-min, cm/s), displacement (max-min, mm), strain (max-min, %) and strain rate (max-min, 1/s) were significantly higher in patients with COPD (p<0.05). A good negative correlation was found between lung ultrasound variables and pulmonary function parameters in patients with COPD. Stepwise multiple regression analysis indicated that the velocity (max-min, cm/s) was the only independent determinant of FEV1/FVC (%). With the use of FEV1/FVC<70% as the criteria of irreversible pulmonary function impairment to distinguish an abnormal pulmonary function, the area under the ROC was 0.99 for the velocity (max-min, cm/s) of the lung tissue in the process of breathing. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of the cut off value (1.19 cm/s) was 97.63%, 100%, 100%, 80%, and 98%, respectively (p<0.001). CONCLUSIONS: Tissue velocity imaging via transthoracic lung ultrasound is a useful modality in the assessment of pulmonary function in patients with COPD. PMID- 27239652 TI - Assessment of the arterial stiffness in patients with acute ischemic stroke using longitudinal elasticity modulus measurements obtained with Shear Wave Elastography. AB - AIM: Arterial wall elasticity including the circumferential and longitudinal modulus is a measure of sub-clinical cardiovascular disease; the circumferential modulus is increased in acute ischemic stroke (AIS). There are still no reports of non-invasive measurement of longitudinal elastic modulus of arterial wall and its prospect of clinical application. In this study, the longitudinal elastic modulus of the arterial wall was assessed using real-time shear wave elastography in patients with AIS. The technique's feasibility and its related factors were studied initially. MATERIALS AND METHODS: In this study 179 patients with AIS and 168 age- and sex-matched controls were examined. The pulse wave velocity (PWV) of the bilateral carotid arteries was measured using radio frequency ultrasound technology. The 20 areas of superficial walls of bilateral carotid artery were analyzed by real-time shear wave elastography (SWE), and the average values of longitudinal average elastic modulus (ME-mean), maximum elastic modulus (ME-max), minimum elastic modulus (ME-min), and elastic modulus standard deviation (MESD) were measured. RESULTS: The PWV, ME-mean, ME-max and ME-sp of the carotid artery in patients with AIS were greater than those in the control group. Age, systolic blood pressure, PWV, and low-density lipoprotein were positively related to ME mean and ME-max (r=0.221and r=0.248, r=0.174 and r=0.176, r=0.776 and r=0.716, r=0.173 and r=0.200, p<0.05) and were independent risk factors for ME-mean and ME max ROC curves for detection of ischemic stroke as decided by PWV, ME-mean and ME max. The area under the curves were 0.55+/-0.03 (p0.05). The correlations between the coronary sinus flow and the infusion volume in left anterior descending coronary artery (LAD), left circumflex coronary artery (LCX), LAD and LCX, and LAD, LCX and right coronary artery (RCA) were all higher than 0.85 (p<0.01), and those of RCA, LAD and RCA, and LCX and RCA were between 0.6 and 0.8 (p<0.05). The areas under the receiver operating characteristics curve (AUC) were all higher than 0.90 (p<0.05) in predicting any two coronaries occlusion (<50% and 100%) and three coronaries occlusion (<50%) with a >85% sensitivity and specificity. Excepting RCA mild occlusion (<50%), AUCs in predicting one coronary occlusion (<50% and 100%) were between 0.7 and 0.9, with >80% sensitivity and specificity. Conclusions The coronary sinus flow measured by pulsed Doppler ultrasound can effectively and exactly reflect the infusion volume in coronaries, which is a powerful indicator of coronary blood supply. PMID- 27239654 TI - Qualitative strain elastography - strain ratio evaluation - an important tool in breast cancer diagnostic. AB - AIMS: To assess the quality of real time elastography as a differential diagnosis tool for breast nodules and to compare it with standard ultrasonography. MATERIAL AND METHODS: In this prospective study we enrolled 174 patients in which 174 dominant breast nodules were considered for the final diagnosis. The results of ultrasonography and real time elastography, both qualitative and quantitative, were compared with pathology findings from the biopsy specimens. RESULTS: Pathology examinations determined 102 nodules were benign and 72 malignant. Qualitative elastography had a better diagnostic performance (82.4% sensitivity and 81.9% specificity) than ultrasonography plus Doppler evaluation (70.3% sensitivity and 73.5% specificity). Quantitative elastography, assessed using the fat-to-lesion ratio, was a good discriminant for malignancy (AUROC = 0.93, p < 0.001). Our results pointed to an optimal threshold for malignancy of > 4.88; by using this threshold, the diagnostic reliability of the fat-to-lesion ratio was better than both ultrasonography and qualitative elastography (86.5% sensitivity and 90.4% specificity). CONCLUSION: Real time elastography is superior to ultrasonography in diagnosing malignant breast nodules. The evaluation of nodules using a fat-to-lesion ratio was a better discriminant for malignancy than qualitative elastography. PMID- 27239655 TI - The prediction of myometrial infiltration by three-dimensional ultrasonography in patients with endometrial carcinoma: a validation study from Ege University Hospital. AB - AIM: To predict the myometrial invasion with three-dimensional (3D) ultrasonography in a cohort of patients with endometrial carcinoma by a previously described technique. MATERIAL AND METHODS: The moyometrial infiltration was evaluated by 3D ultrasonography before surgery in 54 patients with endometrial carcinoma. After scanning the whole uterus by ultrasonography, three perpendicular planes were identified to find the shortest myometrial tumor free distance to serosa (TDS) by examining the lateral, anterior, posterior, and fundal parts of the myometrium. Myometrial infiltration was also estimated by the subjective impression of the examiner. The reference standards consist of myometrial infiltration and TDS which are measured by an experienced pathologist. RESULTS: Forty-five patients (age range 45-86 years) were included for the final analysis. Myometrial invasion was ?50% in 36 and >=50% in 9 cases at histologic sections. The TDS which is measured with 3D ultrasonography was positively correlated with histologically measured TDS (r=0.474, p=0.001). The best cut-off value for ultrasonographically measured TDS was 9 mm with a sensitivity of 89%, specificity of 61%, positive predictive value of 36%, and negative predictive value of 96%. Subjective impression has a sensitivity of 100%, specificity of 88%, positive predictive value of 69%, and negative predictive value of 100%. Cervical involvement was correctly identified in all 6 cases by subjective impression. CONCLUSION: This validation study confirms the 3D ultrasonography as a valuable tool for the evaluation of myometrial infiltration in patients with endometrial carcinoma. PMID- 27239656 TI - Assessment of modified myocardial performance index in foetuses with growth restriction. AB - AIM: To evaluate the modified myocardial performance index (Mod-MPI) in foetuses with growth restriction and compare this index with appropriate for gestational age foetuses. MATERIAL AND METHODS: A prospective cross-sectional case-control study was conducted involving 76 singleton foetuses between 24 and 34 weeks of gestation divided into three groups (24 appropriate growth foetuses, 30 foetuses with estimated weight between the 3rd and 10th percentiles and 22 foetuses with estimated weight < 3rd percentile, according to the Hadlock table). The Mod-MPI was obtained in the plane of the four chamber view, and the spectral Doppler sample volume was placed in the lateral wall of the aorta, close to the mitral valve. Doppler of umbilical artery was normal in all cases. Analysis of variance (ANOVA) was used to compare the groups and the intra-class correlation coefficient (ICC) was used to assess intra- and inter-observer reproducibility. RESULTS: The mean Mod-MPI in the groups of appropriate for gestational age, estimated weight between the 3rd and 10th percentiles, and estimated weight < 3rd percentile was 0.32 +/- 0.05, 0.35 +/- 0.05 and 0.36 +/- 0.06, respectively; there was no statistical difference between the groups (p = 0.072). There was good intra- and inter-observer reproducibility (ICC = 0.726 and 0.760, respectively). CONCLUSION: Mod-MPI was not significantly different between foetuses appropriate for gestational age and those with growth restriction. Mod MPI proved to be a feasible and reproducible technique. PMID- 27239657 TI - Ultrasonographic features of the persistence of superior left vena cava and pathological cardiac associations in fetus. Case series. AB - The persistence of superior left vena cava (PLSVC) is a pathological condition in fetus with risk of association with abnormalities like heterotaxy, cardiac abnormalities - atrioventricular septum defect, and conotruncal anomalies. In this paper we report 23 cases of fetuses with PLSVCs, reviewing their diagnosis, co-morbidities, and evolution in the newborns. PMID- 27239659 TI - The role of lymph node ultrasound evaluation in melanoma - review of the literature. AB - Melanoma is an aggressive tumour, resistant to treatment, derived from melanocytes, with an increasing incidence in the last years in the majority of countries. The most important prognostic factor in the initial stages (I/II) is the presence of metastases at the level of lymph nodes. Ultrasound (US) is a non invasive method, used in the pre- and post-operative node evaluation due to its high availability, the reduced cost and easy reproducibility. The US accuracy is however dependent on operator expertise. The present article proposes a presentation of the US role in the evaluation of lymph nodes in melanoma patients. PMID- 27239658 TI - Portal vein thrombosis in liver cirrhosis - the added value of contrast enhanced ultrasonography. AB - Portal vein thrombosis (PVT) is a frequent complication of liver cirrhosis and its prevalence increases with the severity of liver disease. Patients with liver cirrhosis and hepatocellular carcinoma may have either malignant or blunt (benign) PVT. In these patients, the diagnosis and characterization of PVT is important for the prognosis and further treatment. Ultrasound (US) is the modality of choice for the diagnosis of PVT. The features of PVT on B-mode (gray scale) US include: dilatation of the portal vein, visualization of the thrombus and, in chronic PVT- cavernous transformation. Sensitivity of US in the diagnosis of PVT is improved by the use of Doppler US and of ultrasound contrast agents. In the latter years, contrast enhanced ultrasound (CEUS) showed high sensitivity in the differential diagnosis between benign and malignant PVT and could be the diagnostic method of choice for the characterization of PVT. Blunt thrombi are avascular and will not enhance during CEUS examination, while a hyperenhancement pattern of the portal thrombus in the arterial phase, with "wash out" in the portal or late phase is typical for malignant PVT. PMID- 27239660 TI - US-guided peripheral vascular interventions, comments on the EFSUMB guidelines. AB - Peripheral venous as well as arterial punctures have traditionally been performed on the basis of designated anatomical landmarks. However, due to patients' individual anatomy and vessel pathology and depending on individual operators' skill, this landmark approach is associated with a significant failure rate and complication risk. This review comments on the evidence-based recommendations on ultrasound (US)-guided vascular access which have been published recently within the framework of Guidelines on Interventional Ultrasound (INVUS) of the European Federation of Societies for US in Medicine and Biology (EFSUMB) from a clinical practice point of view. Part 1 of the review had its focus on general aspects of US- guidance and on central venous access, whereas part 2 refers to peripheral vascular access. PMID- 27239661 TI - The ultrasonographic diagnosis of cystic cervical lesions: a pictorial essay. AB - The importance of ultrasonographic (US) examination in the evaluation of the superficial structures of the head and neck region is increasing due to the widespread availability of modern equipment (such as high-frequency transducers) and modern techniques. In the case of a cervical lesion, ultrasound is usually the first imaging method used to assess the changes. First of all, US is capable of differentiating between cystic and solid structures, and based on the US appearance correlated with the age of the patient, location and growing pattern, the appropriate diagnosis is possible with a high accuracy. The aim of the present paper is to describe the US features of the most common cystic lesions encountered in the head and neck region. PMID- 27239662 TI - Three-dimensional ultrasound radiance mode imaging of a uterine lipoleiomyoma. AB - In this case report the diagnosis of a uterine lipoleiomyoma is depicted by means of a three-dimensional radiance mode. The advent of radiance or silhouette mode as a new tool in ultrasound diagnosis is intended to assist by generating additional realistic image visualization and a better distinction among different tissues. PMID- 27239663 TI - Quadricuspid aortic valve: an unexpected echocardiographic finding. AB - Quadricuspid aortic valve (QAV) is an anatomic valvular variant, with a prevalence of 0.008% to 0.033% in the general population, and 1.46% in patients that undergo aortic valve replacement. The QAV can be an isolated valvular abnormality or associated with other congenital heart defects. In this article, we present three of the few reported cases of QAV in the Hispanic population, all of which were asymptomatic and without evidence of hemodynamic alterations or other associated heart defects. Additionally a literature review is provided. PMID- 27239664 TI - The value of transthoracic and transesophageal echocardiography for the diagnosis of the native aortic infective endocarditis valve complications: a case report and literature review. AB - Despite its current limitations transthoracic echocardiography is still widely used for the anatomical and functional evaluation of patients with infective endocarditis. However, all these limitations can be overcome by using transesophageal echocardiography. We present the case of a 42-year-old male patient, diagnosed with aortic valve infective endocarditis, whose transthoracic echocardiography showed only a cusp vegetation and aortic regurgitation, but raised the suspicion of periannular complications. The transesophageal echocardiography revealed a circular aortic root abscess and a ventricular septal defect with left-to-right shunt, and consequently leads to a complete different surgical tactical approach. The patient was urgently referred for surgery due to the rapid deterioration of the hemodynamic status, and had a good outcome on the short-term follow-up. PMID- 27239665 TI - Appendicular mucinous adenocarcinoma associated with pseudomyxoma peritonei, a rare and difficult imaging diagnosis. AB - Pseudomyxoma peritonei (PMP) is a rare disease, caused by primary mucinous tumors that arise most frequently from appendix, ovary, or pancreas. Usually diagnosis is made by computed tomography, but ultrasonography can be a very useful imagistic method, if this diagnosis is taken into account by the observer. We present a case of a PMP caused by an appendiceal mucinous carcinoma, in a 34-year old male patient, with family history of malignancies, diagnosed in our department. He was thereafter surgically treated - appendiceal resection, peritoneal lavage - followed by chemotherapy. We underline the importance of ultrasonography, even though at first encounter, the diagnosis of PMP being generally difficult. PMID- 27239666 TI - Non-anatomical polymer phantoms: a new tool to develop and assess technical skills in ultrasound guided procedures. PMID- 27239667 TI - A very rare cause of recurrent back pain: hematocolpometra. PMID- 27239668 TI - Successful management of a second trimester cesarean scar pregnancy using local methotrexate injection. PMID- 27239669 TI - Comment on "The use of Doppler ultrasonography for pre- and post-surgery monitoring of abdominal aortic aneurysm. A case report". PMID- 27239671 TI - Retraction Note: Targeted immune therapy of ovarian cancer. PMID- 27239670 TI - Family history of myocardial infarction, stroke and diabetes and cardiometabolic markers in children. AB - AIMS/HYPOTHESIS: Despite the overlap in occurrence of cardiovascular disease (CVD) and type 2 diabetes and their risk factors, family history of these diseases has not yet been investigated simultaneously in relation to cardiometabolic markers in offspring. We examined how a family history of CVD and/or diabetes relates to cardiometabolic markers in offspring, and to what extent these diseases independently contribute to cardiometabolic markers. METHODS: We used data from 1,374 12-year-old children and their parents participating in a birth cohort study in the Netherlands. Family history of CVD (myocardial infarction [MI] and stroke) and diabetes were reported by the parents. Children were classified as 'no', 'moderate' or 'strong' family history, based on early/late onset of disease in parents and grandparents. Cardiometabolic markers were measured at 12 years of age: waist circumference, cholesterol, blood pressure and HbA1c. RESULTS: Compared with those with no family history, children with a strong family history of MI and/or stroke and/or diabetes (29% of the study population) had 0.13 mmol/l higher total cholesterol (TC) (95% CI 0.03, 0.23) and 0.18 higher TC/HDL-cholesterol (HDLC) ratio (95% CI 0.04, 0.32). A strong family history of MI or diabetes was independently associated with unfavourable cardiometabolic markers specific to those diseases. These associations remained after adjusting for BMI. Children with a moderate family history had no unfavourable cardiometabolic markers. CONCLUSIONS/INTERPRETATION: One-third of the children had a strong family history of CVD and/or diabetes. These children had higher TC levels and TC/HDLC ratios than children with no family history. A strong family history of MI or diabetes was independently associated with unfavourable cardiometabolic markers specific to those diseases. PMID- 27239673 TI - PGRN Suppresses Inflammation and Promotes Autophagy in Keratinocytes Through the Wnt/beta-Catenin Signaling Pathway. AB - Psoriasis is a chronic, immune-mediated inflammatory skin disease that has a major impact on patients' quality of life. Progranulin (PGRN) is highly expressed in skin diseases and plays an important role in inflammation response and autophagy. However, the function of PGRN in the immune system and autophagy in psoriasis has not been clearly identified and elaborated on. Thus, this study aimed to investigate the role of PGRN on the inflammatory and autophagy process underlying inflammation in HaCaT cells. We showed that PGRN was markedly highly expressed in psoriasis lesions and inflammatory HaCaT cells. Specific silencing of PGRN promoted the production of the inflammatory cytokines IL-1beta, IL-6, COX 2, iNOs, and MCP-1. Furthermore, PGRN siRNA promoted autophagy-related gene p62 and suppressed LC3II and Atg7 in HaCaT cells, while overexpression of PGRN showed a contrary effect. Moreover, knockdown of PGRN upregulated the expression levels of beta-catenin, cyclin D1, and c-myc proteins. Finally, we demonstrated that IWP 2, an inhibitor of the Wnt/beta-catenin signaling pathway, stemmed the pro inflammatory and anti-autophagy effect of PGRN siRNA in TNF-alpha-treated HaCaT cells. Collectively, our findings suggest that PGRN is upregulated in psoriasis lesions and that the overexpression of PGRN inhibits the inflammation in keratinocytes induced by TNF-alpha by negatively regulating the production of inflammatory factors and positively mediating autophagy through the Wnt/beta catenin signaling pathway; this indicated that overexpression of PGRN may be a potential therapeutic option in psoriasis. PMID- 27239674 TI - Endocrine manifestations of systemic mastocytosis in bone. AB - Systemic Mastocytosis (SM) is characterized by accumulation of clonal, neoplastic proliferations of abnormal mast cells (MC) in one or more organ system other than skin. Presence of these multifocal clusters of abnormal mast cells is an essential feature of SM. Frequently associated with D816V (KIT) mutation, the presence of this mutation and elevated serum tryptase are minor criteria for diagnosis. SM manifestations depend on the degree of mast cell proliferation, activation and degranulation. SM has a variable prognosis and presentation, from indolent to "smoldering" to life-threatening disease. Bone manifestations of SM include: osteopenia with or without lytic lesions, osteoporosis with or without atraumatic fracture, osteosclerosis with increased bone density, and isolated lytic lesions. Male sex, older age, higher bone resorption markers, lower DKK1 level, lower BMD, absence of urticaria pigmentosa, and alcohol intake are all associated with increased risk of fracture. Treatment of SM is generally palliative. Most therapy is symptom-directed; and, infrequently, chemotherapy for refractory symptoms is indicated. Anti-histamines may alleviate direct bone effects of histamine. Bisphosphonates, including alendronate, clodronate, pamidronate and zoledronic acid are recommended as a first line treatment of SM and osteoporosis. Interferon alpha may act synergistically with bisphosphonates. As elevation of RANKL and OPG is reported in SM, denosumab could be an effective therapy for bone manifestations of SM. PMID- 27239675 TI - Molasses melanoidin promotes copper uptake for radish sprouts: the potential for an accelerator of phytoextraction. AB - Phytoextraction has been proposed as an alternative remediation technology for heavy metal contamination, and it is well known that chelators may alter the toxicity of heavy metals and the bioavailability in plants. Our previous work demonstrated that an adsorbent-column chromatography can effectively separate melanoidin-like product (MLP) from sugarcane molasses. The aim of this study was to examine the chelating property of MLP and to evaluate the facilitatory influence on the phytoextraction efficiency of Japanese radish. The result showed that MLP binds to all the metal ions examined and the binding capacity of MLP toward Cu(2+) seems to be the highest among them. The metal detoxification by MLP followed the order of Pb(2+) > Zn(2+) > Ni(2+) > Cu(2+) > Fe(2+) > Cd(2+) > Co(2+). Furthermore, in the phytoextraction experiment using copper sulfate, the application of MLP accelerated the detoxification of copper and the bioavailability in radish sprouts. Thus, these results suggest that MLP possesses the potential for an accelerator of phytoextraction in the copper-contaminated media. PMID- 27239676 TI - Arsenic and chromium topsoil levels and cancer mortality in Spain. AB - Spatio-temporal cancer mortality studies in Spain have revealed patterns for some tumours which display a distribution that is similar across the sexes and persists over time. Such characteristics would be common to tumours that shared risk factors, including the chemical soil composition. The objective of the present study is to assess the association between levels of chromium and arsenic in soil and the cancer mortality. This is an ecological cancer mortality study at municipal level, covering 861,440 cancer deaths in 7917 Spanish mainland towns from 1999 to 2008. Chromium and arsenic topsoil levels (partial extraction) were determined by ICP-MS at 13,317 sampling points. To estimate the effect of these concentrations on mortality, we fitted Besag, York and Mollie models, which included, as explanatory variables, each town's chromium and arsenic soil levels, estimated by kriging. In addition, we also fitted geostatistical-spatial models including sample locations and town centroids (non-aligned data), using the integrated nested Laplace approximation (INLA) and stochastic partial differential equations (SPDE). All results were adjusted for socio-demographic variables and proximity to industrial emissions. The results showed a statistical association in men and women alike, between arsenic soil levels and mortality due to cancers of the stomach, pancreas, lung and brain and non-Hodgkin's lymphomas (NHL). Among men, an association was observed with cancers of the prostate, buccal cavity and pharynx, oesophagus, colorectal and kidney. Chromium topsoil levels were associated with mortality among women alone, in cancers of the upper gastrointestinal tract, breast and NHL. Our results suggest that chronic exposure arising from low levels of arsenic and chromium in topsoil could be a potential risk factor for developing cancer. PMID- 27239678 TI - Determination of Serum Trace Elements (Zn, Cu, and Fe) in Pakistani Patients with Rheumatoid Arthritis. AB - Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, which mainly involves the joints. RA is prevalent worldwide with increasing prevalence in elderly people. The mechanism of RA pathogenesis is still undefined, and it is interplaying between genetic susceptibility and environmental factors. Although risk factors for RA are not fully established, various studies have focused on the role of trace elements in association with RA. Trace elements act as co factors for most of the enzymes, and their deficiency is associated with many untoward effects on human health. The homeostatic alterations in the metabolism of trace elements may partly be due to inflammatory response in RA. The objective of the present study was to determine the serum concentrations and correlation of zinc, copper, and iron in RA patients and healthy controls. The study comprised of 61 RA patients and 61 age- and sex-related healthy individuals of Pakistani population. Serum levels of Zn, Cu, and Fe were measured in all the participants by atomic absorption spectrophotometer. Serum Zn and Fe were significantly reduced in the RA patients than those in the healthy controls. Serum Cu concentrations were found elevated in the RA patients. Correlation studies of trace elements determine that there was negative correlation between Zn and Cu in the RA patients and no correlation in the control group. It is very important to explore the deficiency of essential trace metals in biological samples of the RA patients in different populations which may be helpful for diagnosis and supplementary management of rheumatoid arthritis patients. PMID- 27239677 TI - Sodium Selenite Protects Against Silver Nanoparticle-Induced Testicular Toxicity and Inflammation. AB - Metal nanomaterials hold great potential and play an important role in consumer products. However, the increasing use of nanomaterials has raised concern over inadvertent exposure and potential risks for human health and the environment. Henceforth, in vivo testing of nanoparticles and protection against its toxicity is required. Using rat as an animal model, effect of sodium selenite (Se), an essential trace element, on rat testes exposed to silver nanoparticles (AgNPs) was evaluated. Male rats were treated with AgNPs (5 mg/kg/b.w) i/p or Se (0.2 mg/kg/b.w) by gavage. AgNP administration decreased Glutathione (GSH) levels and activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) and increased levels of malondialdehyde (MDA) and expression of interleukin-1 beta (IL-1beta), IL-6, and tumor necrosis factor alpha (TNF-alpha). However, treatment with Se increased GSH levels and activities of SOD, CAT, and GPx compared with AgNP-treated group and decreased the level of MDA and inflammatory biomarkers significantly (p < 0.05) as compared with AgNP-treated group. Light microscopic analyses also revealed that AgNP induced histopathological changes in testes tissue. Further, protection by Se on biochemical results was confirmed by alleviation of the histopathological changes in the tissue. Results show the adverse effects of AgNPs on the male reproductive tract, particularly spermatogenesis, and suggest that Se possesses significant potential in reducing AgNP-induced testicular toxicity. PMID- 27239679 TI - Minichromosome Maintenance Complex Is a Critical Node in the miR-183 Signaling Network of MYCN-Amplified Neuroblastoma Cells. AB - MYCN and HDAC2 jointly repress the transcription of tumor suppressive miR-183 in neuroblastoma. Enforced miR-183 expression induces neuroblastoma cell death and inhibits xenograft growth in mice. Here we aimed to focus more closely on the miR 183 signaling network using a label-free mass spectrometric approach. Analysis of neuroblastoma cells transfected with either control or miR-183 expression vectors identified 85 differentially expressed proteins. All six members of the minichromosome maintenance (MCM) complex, which is indispensable for initiation and elongation during DNA replication and transcriptionally activated by MYCN in neuroblastoma, emerged to be down-regulated by miR-183. Subsequent annotation category enrichment analysis revealed a ~14-fold enrichment in the "MCM" protein module category, which highlighted this complex as a critical node in the miR-183 signaling network. Down-regulation was confirmed by Western blotting. MCMs 2-5 were predicted by in silico methods as direct miR-183 targets. Dual-luciferase reporter gene assays with 3'-UTR constructs of the randomly selected MCMs 3 and 5 experimentally confirmed them as direct targets of miR-183. Our results reveal the MCM complex to be a critical and directly regulated node within the miR-183 signaling network in MYCN-amplified neuroblastoma cells. PMID- 27239680 TI - Bottom-Up Fabrication of Activated Carbon Fiber for All-Solid-State Supercapacitor with Excellent Electrochemical Performance. AB - Activated carbon (AC) is the most extensively used electrode material for commercial electric double layer capacitors (EDLC) given its high specific surface area (SSA) and moderate cost. However, AC is primarily used in the forms of powders, which remains a big challenge in developing AC powders into continuous fibers. If AC powders can be processed into fiber, then they may be scaled up for practical applications to supercapacitors (SCs) and satisfy the rapid development of flexible electronics. Herein, we report a bottom-up method to fabricate AC fiber employing graphene oxide (GO) as both dispersant and binder. After chemical reduction, the fiber has high electrical conductivity (185 S m(-1)), high specific surface area (1476.5 m(2) g(-1)), and good mechanical flexibility. An all solid-state flexible SC was constructed using the prepared fiber as electrode, which is free of binder, conducting additive, and additional current collector. The fiber-shaped SC shows high capacitance (27.6 F cm(-3) or 43.8 F g(-1), normalized to the two-electrode volume), superior cyclability (90.4% retention after 10 000 cycles), and good bendability (96.8% retention after bending 1000 times). PMID- 27239681 TI - Acute effects of exercise and active video games on adults' reaction time and perceived exertion. AB - The purpose of the present study was to examine the acute effects of resting, aerobic exercise practised alone, and aerobic exercise with active video games (AVG), on complex reaction time (CRT) and the post-exercise acute rate of perceived exertion (RPE) in young healthy adults. The experimental group was composed of 92 healthy young adults, 78 males and 13 females (age M = 21.9 +/- 2.7 years) who completed two sessions, A and B. In session A, participants rode 30 min on an ergometer, while in session B they exercised for 30 min on an ergometer while playing an AVG on a Wii. The control group was composed of 30 young adults, 26 males and 4 females (age M = 21.4 +/- 2.9 years) who rested for 30 min. In each session, a CRT task was performed before and after exercising or resting, and post-exercise global RPE was noted. Repeated measures general linear model (GLM) and Wilcoxon tests were performed. (1) Both aerobic exercise alone and aerobic exercise combined with AVG improved CRT, while resting did not; (2) aerobic exercise combined with AVG did not improve CRT more than aerobic exercise only; and (3) RPE was lower after aerobic exercise combined with AVG compared with aerobic exercise only. In young adults, exercise produces acute benefits on CRT, and practising exercise with AVG helps to decrease RPE. PMID- 27239683 TI - Maternal food restriction in rats of the F0 generation increases retroperitoneal fat, the number and size of adipocytes and induces periventricular astrogliosis in female F1 and male F2 generations. AB - The present study investigated whether male offspring (F2 generation) from female rats (F1 generation) whose mothers (F0 generation) were food restricted during gestation inherit a phenotypic transgenerational tendency towards being overweight and obese in the juvenile period, in the absence of food restriction in the F1/F2 generations. Dams of the F0 generation were 40% food restricted during pregnancy. Bodyweight, the number and size of larger and small hypodermal adipocytes (HAs), total retroperitoneal fat (RPF) weight and the expression of glial fibrillary acidic protein (GFAP) in periventricular hypothalamic astrocytes (PHAs), as determined by immunohistochemistry, were evaluated in both generations. In the female F1 generation, there was low bodyweight gain only during the juvenile period (30-65 days of age), a decrease in the size of small adipocytes, an increase in the number of small adipocytes, an increase in RPF weight and an increase in GFAP expression in PHAs at 90-95 days of age. In males of the F2 generation at 50 days of age, there was increased bodyweight and RPF weight, and a small number of adipocytes and GFAP expression in PHAs. These data indicate that the phenotypic transgenerational tendency towards being overweight and obese was observed in females (F1) from mothers (F0) that were prenatally food restricted was transmitted to their male offspring. PMID- 27239682 TI - Influence of breastfeeding in the first months of life on blood pressure levels of preschool children. AB - OBJECTIVE: To investigate whether breastfeeding in early life affects blood pressure of preschoolers. METHODS: Cross-sectional study nested in a cohort from a municipality in the state of Minas Gerais, Brazil. All children in the cohort were invited for this study. Thus, between 2009 and 2010, blood pressure of 230 preschool children and their mothers, in addition to anthropometric variables, previous history, and socioeconomic status were evaluated. Blood pressure measurement was assessed in the morning, using automatic Omron(r) HEM-714INT and HEM-781INT devices to measure the blood pressure of preschool children and their mothers, respectively. Logistic regression was used to study the association between breastfeeding and blood pressure. The significance level was set at 5%. RESULTS: This study identified 19 (8.26%) preschool children with high blood pressure (values above the 90th percentile). High systolic blood pressure was associated with low birth weight (OR=5.41; 95% CI=1.45-20.23) and total breastfeeding duration of less than six months (OR=4.14; 95% CI=1.40-11.95). High diastolic blood pressure was not associated with any variable, whereas high systolic blood pressure/diastolic blood pressure ratio was associated with breastfeeding duration of less than six months (OR=3.48; 95% CI=1.34-9.1). CONCLUSION: The results of this study indicate that preschoolers breastfed for a period of less than six months were more likely to have high blood pressure when compared to those breastfed for a longer period, suggesting a protective effect of breastfeeding against high blood pressure in this population. PMID- 27239684 TI - Menstrual Cycle and Hormonal Contraceptive-Dependent Changes in Intrinsic Connectivity of Resting-State Brain Networks Correspond to Behavioral Changes Due to Hormonal Status. AB - Menstrual cycle-dependent changes have been reported for a variety of functions, including cognition, attention, emotion, inhibition, and perception. For several of these functions, an effect of hormonal contraceptives has also been discussed. Cognitive, attentional, emotional, inhibitory, and perceptual functions have been linked to distinct intrinsic connectivity networks during the resting state. However, changes in resting-state connectivity across the menstrual cycle phase and due to hormonal contraceptive use have only been investigated in two selected networks and without controlling for the type of hormonal contraceptives. In the present study, we demonstrate menstrual cycle and hormonal contraceptive dependent changes in several intrinsic connectivity networks, including networks that have been related to emotion processing, olfaction, audition, vision, coordination, and two lateralized frontoparietal networks related to a variety of cognitive functions. These changes parallel behavioral changes in the functions associated with these networks. Changes in connectivity and changes in behavior occur during the same cycle phases. Furthermore, hormonal contraceptive-dependent effects were observed in the same networks and same target sites as menstrual cycle-related changes and were dependent on the androgenicity of the progestin component contained in the hormonal contraceptive. PMID- 27239685 TI - The biomechanical structure of swim start performance. AB - The aim of this study was to analyse the significance of various biomechanical parameters in swim start performance for the grab and track start techniques. To do so, structural equation models were analysed, incorporating measurements for the take-off phase, flight phase and entry phase. Forty-six elite German swimmers (18 female and 28 male; age: 20.1 +/- 4.2 yrs; PB (100 m Freestyle): 53.6 +/- 2.9 s) participated in the study. Their swim start performance was examined within a 25-m sprint test. Structural equation modelling was conducted in separate models for the block time, flight time and water time and in a combined model for swim start time. Our main finding was that swim start time is predominantly related to water time and determined to a lesser extent by block time and flight time. We conclude that more emphasis should be given to the water immersion behaviour and the gliding phase when analysing swim start performance. Furthermore, significant differences were found between the grab start and track techniques as regards the biomechanical parameters representing the take-off phase and water phase. PMID- 27239686 TI - Physical growth curves of indigenous Xavante children in Central Brazil: results from a longitudinal study (2009-2012). AB - BACKGROUND: The nutritional profile of Indigenous children in Brazil is comparable to those observed in some of the least developed regions of the world. AIM: Weight and height growth curves were characterised based on longitudinal data from a local Indigenous population experiencing the double burden of child under-nutrition and adult obesity. SUBJECTS AND METHODS: Anthropometric data were collected in six waves from 2009-2011 for children <10 in two proximate Xavante villages in Central Brazil. Prevalence rates for stunting, wasting and thinness were calculated using WHO references. Weight and height data were adjusted for generalised additive mixed models to generate growth curves. RESULTS: Prevalence rates of stunting and wasting were high, but cases of thinness and excess weight were negligible. Weight and height began close to WHO medians, but fell substantially before 12 months. Boys but not girls were able to catch-up in weight before age 10. From 3-10 years, height for both sexes remained between -2 and 0 z-scores. CONCLUSION: Impaired Xavante growth before 1 year followed by inconsistent recovery before 10 years reflects health and wellbeing disparities with regard to the Brazilian national population and a complex epidemiology of growth involving rapid nutritional change. PMID- 27239687 TI - Can heavy metal pollution defend seed germination against heat stress? Effect of heavy metals (Cu(2+), Cd(2+) and Hg(2+)) on maize seed germination under high temperature. AB - Heavy metal pollution, as well as greenhouse effect, has become a serious threat today. Both heavy metal and heat stresses can arrest seed germination. What response can be expected for seed germination under both stress conditions? Here, the effects of heavy metals (Cu(2+), Cd(2+) and Hg(2+)) on maize seed germination were investigated at 20 degrees C and 40 degrees C. Compared with 20 degrees C, heat stress induced thermodormancy. However, this thermodormancy could be significantly alleviated by the addition of a low concentration of heavy metals. Heavy metals, as well as heat stress induced H2O2 accumulation in germinating seeds. Interestingly, this low concentration of heavy metal that promoted seed germination could be partly blocked by DMTU (a specific ROS scavenger), irrespective of temperature. Accordingly, H2O2 addition reinforced this promoting effect on seed germination, which was induced by a low concentration of heavy metal. Furthermore, we found that the NADPH oxidase derived ROS was required for seed germination promoted by the heavy metals. Subsequently, treatment of seeds with fluridone (a specific inhibitor of ABA) or ABA significantly alleviated or aggravated thermodormancy, respectively. However, this alleviation or aggravation could be partly attenuated by a low concentration of heavy metals. In addition, germination that was inhibited by high concentrations of heavy metals was also partly reversed by fluridone. The obtained results support the idea that heavy metal-mediated ROS and hormone interaction can finally affect the thermodormancy release or not. PMID- 27239688 TI - TBBPA exposure during a sensitive developmental window produces neurobehavioral changes in larval zebrafish. AB - Tetrabromobisphenol A (TBBPA), one of the most widely used brominated flame retardants (BFRs), is a ubiquitous contaminant in the environment and in the human body. This study demonstrated that zebrafish embryos exposed to TBBPA during a sensitive window of 8-48 h post-fertilization (hpf) displayed morphological malformations and mortality. Zebrafish exposed exclusively between 48 and 96 hpf were phenotypically normal. TBBPA was efficiently absorbed and accumulated in zebrafish embryos, but was eliminated quickly when the exposure solution was removed. Larval behavior assays conducted at 120 hpf indicated that exposure to 5 MUM TBBPA from 8 to 48 hpf produced larvae with significantly lower average activity and speed of movement in the normal condition than in those exposed from 48 to 96 hpf. Specifically, 8-48 hpf-exposed larvae spent significantly less time in both activity bursts and gross movements compared to control or 48-96 hpf exposed larvae. Consistent with the motor deficits, TBBPA induced apoptotic cell death, delayed cranial motor neuron development, inhibited primary motor neuron development and loosed muscle fiber during the early developmental stages. To further explore TBBPA-induced developmental and neurobehavioral toxicity, RNA-Seq analysis was used to identify early transcriptional changes following TBBPA exposure. In total, 1969 transcripts were significantly differentially expressed (P < 0.05, FDR < 0.05, 1.5-FC) upon TBBPA exposure. Functional and pathway analysis of the TBBPA transcriptional profile identified biological processes involved in nerve development, muscle filament sliding and contraction, and extracellular matrix disassembly and organization changed significantly. In addition, TBBPA also led to an elevation in the expression of genes encoding uridine diphosphate glucuronyl transferases (ugt), which could affect thyroxine (T4) metabolism and subsequently lead to neurobehavioral changes. In summary, TBBPA exposure during a narrow, sensitive developmental window perturbs various molecular pathways and results in neurobehavioral deficits in zebrafish. PMID- 27239689 TI - Habitat- and species-dependent accumulation of organohalogen pollutants in home produced eggs from an electronic waste recycling site in South China: Levels, profiles, and human dietary exposure. AB - Organohalogen pollutants (OHPs) including chlorinated paraffins (CPs), polybrominated diphenyl ethers (PBDEs) and other halogenated flame retardants (OHFRs) (dechlorane plus (DP), decabromodiphenyl ethane (DBDPE), 1,2-bis(2,4,6 tribromophenoxy) ethane (BTBPE), hexabromobenzene (HBB), hexabromocyclododecanes (HBCDs) and tetrabromobisphenol A (TBBPA)) originating from an e-waste recycling area in Guiyu, southern China were investigated in chicken and goose eggs. As expected, OHP concentrations were higher in chicken eggs collected from the location (site 1) approaching the e-waste recycling center than from the location (site 2) far from the e-waste recycling center. Also, much higher OHP levels were observed in goose eggs foraging in residential area (site 2) than that in agricultural area (site 1), suggesting a clear habitat dependent OHP bioaccumulation pattern both concerning distance from e-waste activities and type of foraging habitat. Goose eggs exhibited higher short chain chlorinated paraffins (SCCPs) concentrations but lower PBDE and OHFR levels than chicken eggs. The proportion of high brominated PBDEs (hepta-to deca-BDEs) was lower in goose eggs than that in chicken eggs and showed a clear decrease from site 1 to site 2. DP isomeric composition fanti values (the ratio of the anti-DP to the sum of the anti- and syn-DP) in goose eggs were significantly lower than those in chicken eggs (p < 0.001). These differences are likely a reflection of factors such as the species-specific differences in habitat preference and the differing environmental behaviors of the pollutants owing to their inherent properties (such as solubility and vapor pressure). Our findings suggested a high dietary intake of OHPs via home-produced eggs. For BDE99 there is a potential health concern with respect to the current dietary exposure via eggs. PMID- 27239690 TI - Arsenic(V) adsorption-desorption in agricultural and mine soils: Effects of organic matter addition and phosphate competition. AB - High total and bioavailable concentrations of As in soils represent a potential risk for groundwater contamination and entry in the food chain. The use of organic amendments in the remediation of As-contaminated soils has been found to produce distinct effects on the solubility of As in the soil. Therefore, knowledge about As adsorption-desorption processes that govern its solubility in soil is of relevance in order to predict the behaviour of this element during these processes. In this paper, the objective was to determine As adsorption and desorption in four different soils, with and without compost addition, and also in competition with phosphate, through the determination of sorption isotherms. Batch experiments were carried out using three soils affected differently by previous mining activity of the Sierra Minera of La Union-Cartagena (SE Spain) and an agricultural soil from Segovia province (central Spain). Adsorption was higher in the mining soils (and highest in the acidic one) than in the agricultural soils, although the latter were not affected negatively by organic matter or phosphate competition for sorption sites. The results show that As adsorption in most soils, both with and without compost, fitted better a multimolecular layer model (Freundlich), whereas As adsorption in competition with P fitted a monolayer model (Langmuir). Moreover, the use of compost and phosphate reduced the adsorption of As in the mining soils, while in the agricultural soils compost increased their low adsorption capacity. Therefore, the use of compost can be a good option to favour As immobilisation in soils of low adsorption, but knowledge of the soil composition will be crucial to predict the effects of organic amendments on As solubility in soils and its associated environmental risk. PMID- 27239691 TI - Sources of hydrocarbons in urban road dust: Identification, quantification and prediction. AB - Among urban stormwater pollutants, hydrocarbons are a significant environmental concern due to their toxicity and relatively stable chemical structure. This study focused on the identification of hydrocarbon contributing sources to urban road dust and approaches for the quantification of pollutant loads to enhance the design of source control measures. The study confirmed the validity of the use of mathematical techniques of principal component analysis (PCA) and hierarchical cluster analysis (HCA) for source identification and principal component analysis/absolute principal component scores (PCA/APCS) receptor model for pollutant load quantification. Study outcomes identified non-combusted lubrication oils, non-combusted diesel fuels and tyre and asphalt wear as the three most critical urban hydrocarbon sources. The site specific variabilities of contributions from sources were replicated using three mathematical models. The models employed predictor variables of daily traffic volume (DTV), road surface texture depth (TD), slope of the road section (SLP), effective population (EPOP) and effective impervious fraction (EIF), which can be considered as the five governing parameters of pollutant generation, deposition and redistribution. Models were developed such that they can be applicable in determining hydrocarbon contributions from urban sites enabling effective design of source control measures. PMID- 27239692 TI - Increasing CO2 differentially affects essential and non-essential amino acid concentration of rice grains grown in cadmium-contaminated soils. AB - Environmental pollution by both ambient CO2 and heavy metals has been steadily increasing, but we do not know how fluctuating CO2 concentrations influence plant nutrients under high Cd pollution, especially in crops. Here, we studied the effects of elevated CO2 and Cd accumulation on proteins and amino acids in rice under Cd stress. In this pot experiment, we analyzed the amino-acid profile of 20 rice cultivars that accumulate Cd differently; the plants were grown in Cd containing soils under ambient conditions and elevated CO2 levels. We found that although Cd concentrations appeared to be higher in most cultivars under elevated CO2 than under ambient CO2, the effect was significant only in seven cultivars. Combined exposure to Cd and elevated CO2 strongly decreased rice protein and amino acid profiles, including essential and non-essential amino acids. Under elevated CO2, the ratios of specific amino acids were either higher or lower than the optimal ratios provided by FAO/WHO, suggesting that CO2 may flatten the overall amino-acid profile, leading to an excess in some amino acids and deficiencies in others when the rice is consumed. Thus, Cd-tainted rice limits the concentration of essential amino acids in rice-based diets, and the combination with elevated CO2 further exacerbates the problem. PMID- 27239693 TI - Effects of microplastics on European flat oysters, Ostrea edulis and their associated benthic communities. AB - Plastic pollution is recognised as an emerging threat to aquatic ecosystems, with microplastics now the most abundant type of marine debris. Health effects caused by microplastics have been demonstrated at the species level, but impacts on ecological communities remain unknown. In this study, impacts of microplastics on the health and biological functioning of European flat oysters (Ostrea edulis) and on the structure of associated macrofaunal assemblages were assessed in an outdoor mesocosm experiment using intact sediment cores. Biodegradable and conventional microplastics were added at low (0.8 MUg L(-1)) and high (80 MUg L( 1)) doses in the water column repeatedly for 60 days. Effects on the oysters were minimal, but benthic assemblage structures differed and species richness and the total number of organisms were ~1.2 and 1.5 times greater in control mesocosms than in those exposed to high doses of microplastics. Notably, abundances of juvenile Littorina sp. (periwinkles) and Idotea balthica (an isopod) were ~2 and 8 times greater in controls than in mesocosms with the high dose of either type of microplastic. In addition, the biomass of Scrobicularia plana (peppery furrow shell clam) was ~1.5 times greater in controls than in mesocosms with the high dose of microplastics. This work indicates that repeated exposure to high concentrations of microplastics could alter assemblages in an important marine habitat by reducing the abundance of benthic fauna. PMID- 27239694 TI - Assessing the uptake of arsenic and antimony from contaminated soil by radish (Raphanus sativus) using DGT and selective extractions. AB - The enrichment of soil arsenic (As) and antimony (Sb) is putting increasing pressure on the environment and human health. The biogeochemical behaviour of Sb and its uptake mechanisms by plants are poorly understood and generally assumed to be similar to that of As. In this study, the lability of As and Sb under agricultural conditions in historically contaminated soils was assessed. Soils were prepared by mixing historically As and Sb-contaminated soil with an uncontaminated soil at different ratios. The lability of As and Sb in the soils was assessed using various approaches: the diffusive gradients in thin films technique (DGT) (as CDGT), soil solution analysis, and sequential extraction procedure (SEP). Lability was compared to the bioaccumulation of As and Sb by various compartments of radish (Raphanus sativus) grown in these soils in a pot experiment. Irrespective of the method, all of the labile fractions showed that both As and Sb were firmly bound to the solid phases, and that Sb was less mobile than As, although total soil Sb concentrations were higher than total soil As. The bioassay demonstrated low bioaccumulation of As and Sb into R. sativus due to their low lability of As and Sb in soils and that there are likely to be differences in their mechanisms of uptake. As accumulated in R. sativus roots was much higher (2.5-21 times) than that of Sb, while the Sb translocated from roots to shoots was approximately 2.5 times higher than that of As. As and Sb in R. sativus tissues were strongly correlated with their labile concentrations measured by DGT, soil solution, and SEP. These techniques are useful measures for predicting bioavailable As and Sb in the historically contaminated soil to R. sativus. This is the first study to demonstrate the suitability of DGT to measure labile Sb in soils. PMID- 27239695 TI - Ertapenem in outpatient parenteral antimicrobial therapy for complicated urinary tract infections. AB - BACKGROUND: Ertapenem is a broad-spectrum antibiotic that is increasingly being utilized. Its dosing convenience renders it suitable for outpatient therapy, and its pharmacokinetic characteristics favour its use against complicated urinary tract infections (cUTIs). Despite this, sufficient clinical data are lacking for its use against cUTIs in the outpatient setting. We assessed the microbiological and clinical cure rates associated with ertapenem treatment for cUTIs in two outpatient parenteral antimicrobial therapy (OPAT) departments. METHODS: We undertook a prospective observational study of adult patients who received ertapenem for cUTIs between August 2010 and August 2014. Data on patient characteristics, clinical progress and microbiological results were collected and analysed. RESULTS: Sixty-one patients were enrolled. The median age was 59 years (range 24, 83) and 61% were male. The most common diagnoses were pyelonephritis (39%) and prostatitis (15%). The most common causative organism was Escherichia coli (67%). Extended-spectrum beta-lactamase (ESBL)-producing organisms were detected in 72% of infections. Microbiological cure was achieved in 67% overall, and was less likely in those with Klebsiella pneumoniae infection (OR = 0.21 [95%CI: 0.05 to 0.85] p = 0.029). Clinical cure was observed in 92% of patients. CONCLUSION: In this study of treating cUTIs with ertapenem, we have demonstrated good clinical outcomes. A lower than expected microbiological cure rate was observed in those with Klebsiella pneumoniae infection. PMID- 27239696 TI - Uncoupling the Structure-Activity Relationships of beta2 Adrenergic Receptor Ligands from Membrane Binding. AB - Ligand binding to membrane proteins may be significantly influenced by the interaction of ligands with the membrane. In particular, the microscopic ligand concentration within the membrane surface solvation layer may exceed that in bulk solvent, resulting in overestimation of the intrinsic protein-ligand binding contribution to the apparent/measured affinity. Using published binding data for a set of small molecules with the beta2 adrenergic receptor, we demonstrate that deconvolution of membrane and protein binding contributions allows for improved structure-activity relationship analysis and structure-based drug design. Molecular dynamics simulations of ligand bound membrane protein complexes were used to validate binding poses, allowing analysis of key interactions and binding site solvation to develop structure-activity relationships of beta2 ligand binding. The resulting relationships are consistent with intrinsic binding affinity (corrected for membrane interaction). The successful structure-based design of ligands targeting membrane proteins may require an assessment of membrane affinity to uncouple protein binding from membrane interactions. PMID- 27239697 TI - Mannose 6-phosphate-dependent targeting of lysosomal enzymes is required for normal craniofacial and dental development. AB - Mucolipidosis II (MLII) is a severe systemic genetic disorder caused by defects in mannose 6-phosphate-dependent targeting of multiple lysosomal hydrolases and subsequent lysosomal accumulation of non-degraded material. MLII patients exhibit marked facial coarseness and gingival overgrowth soon after birth, accompanied with delayed tooth eruption and dental infections. To examine the pathomechanisms of early craniofacial and dental abnormalities, we analyzed mice with an MLII patient mutation that mimic the clinical and biochemical symptoms of MLII patients. The mouse data were compared with clinical and histological data of gingiva and teeth from MLII patients. Here, we report that progressive thickening and porosity of calvarial and mandibular bones, accompanied by elevated bone loss due to 2-fold higher number of osteoclasts cause the characteristic craniofacial phenotype in MLII. The analysis of postnatal tooth development by microcomputed tomography imaging and histology revealed normal dentin and enamel formation, and increased cementum thickness accompanied with accumulation of storage material in cementoblasts of MLII mice. Massive accumulation of storage material in subepithelial cells as well as disorganization of collagen fibrils led to gingival hypertrophy. Electron and immunofluorescence microscopy, together with (35)S-sulfate incorporation experiments revealed the accumulation of non-degraded material, non-esterified cholesterol and glycosaminoglycans in gingival fibroblasts, which was accompanied by missorting of various lysosomal proteins (alpha-fucosidase 1, cathepsin L and Z, Npc2, alpha-l-iduronidase). Our study shows that MLII mice closely mimic the craniofacial and dental phenotype of MLII patients and reveals the critical role of mannose 6-phosphate-dependent targeting of lysosomal proteins for alveolar bone, cementum and gingiva homeostasis. PMID- 27239698 TI - Aldehyde dehydrogenase 2 deficiency blunts compensatory cardiac hypertrophy through modulating Akt phosphorylation early after transverse aorta constriction in mice. AB - AIMS: This study was designed to examine the impact of mitochondrial aldehyde dehydrogenase 2 (ALDH2) on transverse aorta constriction (TAC)-induced cardiac hypertrophy and related molecular mechanisms using an ALDH2 knockout (ALDH2-/-) murine model. METHODS: Male wild-type and ALDH2-/- mice were subjected to TAC or sham operation (n=6-8 for each group). After two weeks, cardiac function was assessed by echocardiography and hemodynamic measurements. Myocardial phosphorylated and total PI3K, the catalytic subunit of PI3Ks (p110alpha and p110gamma), Akt, and total PTEN levels were detected by Western blotting. Cardiomyocytes were stretched for 6h in vitro in the presence or absence of Alda 1 (a small-molecule activator of ALDH2) prior to assessment of phosphorylated PI3K, Akt and total PTEN expressions by Western blot. RESULTS: Heart to body weight ratio and left ventricular posterior wall thickness as well as the cross sectional area of cardiomyocyte were significantly lower in ALDH2-/- mice than in wild-type mice following TAC. Western blot analysis showed p110gamma was upregulated post TAC in both wild-type mice and ALDH2-/- mice, phosphorylation of Akt was disrupted, PTEN expression was upregulated in ALDH2-/- mice post TAC while phosphorylated PI3K, p110alpha and p110gamma expression was similar between ALDH2-/- and wild-type mice post TAC. In vitro, phosphorylation of Akt was significantly accentuated and PTEN expression was reduced while PI3K phosphorylation remained unchanged in stretched cardiomyocytes pretreated by Alda 1 compared to stretched cardiomyocytes treated by saline. CONCLUSIONS: Our results show that ALDH2 deficiency attenuates compensatory cardiac hypertrophy through regulating Akt but not PI3K phosphorylation early after TAC in mice. PMID- 27239700 TI - Nuclear speckles are detention centers for transcripts containing expanded CAG repeats. AB - The human genetic disorders caused by CAG repeat expansions in the translated sequences of various genes are called polyglutamine (polyQ) diseases because of the cellular "toxicity" of the mutant proteins. The contribution of mutant transcripts to the pathogenesis of these diseases is supported by several observations obtained from cellular models of these disorders. Here, we show that the common feature of cell lines modeling polyQ diseases is the formation of nuclear CAG RNA foci. We performed qualitative and quantitative analyses of these foci in numerous cellular models endogenously and exogenously expressing mutant transcripts by fluorescence in situ hybridization (FISH). We compared the CAG RNA foci of polyQ diseases with the CUG foci of myotonic dystrophy type 1 and found substantial differences in their number and morphology. Smaller differences within the polyQ disease group were also revealed and included a positive correlation between the foci number and the CAG repeat length. We show that expanded CAA repeats, also encoding glutamine, did not trigger RNA foci formation and foci formation is independent of the presence of mutant polyglutamine protein. Using FISH combined with immunofluorescence, we demonstrated partial co localization of CAG repeat foci with MBNL1 alternative splicing factor, which explains the mild deregulation of MBNL1-dependent genes. We also showed that foci reside within nuclear speckles in diverse cell types: fibroblasts, lymphoblasts, iPS cells and neuronal progenitors and remain dependent on integrity of these nuclear structures. PMID- 27239699 TI - Treatment with polyamine oxidase inhibitor reduces microglial activation and limits vascular injury in ischemic retinopathy. AB - Retinal vascular injury is a major cause of vision impairment in ischemic retinopathies. Insults such as hyperoxia, oxidative stress and inflammation contribute to this pathology. Previously, we showed that hyperoxia-induced retinal neurodegeneration is associated with increased polyamine oxidation. Here, we are studying the involvement of polyamine oxidases in hyperoxia-induced injury and death of retinal vascular endothelial cells. New-born C57BL6/J mice were exposed to hyperoxia (70% O2) from postnatal day (P) 7 to 12 and were treated with the polyamine oxidase inhibitor MDL 72527 or vehicle starting at P6. Mice were sacrificed after different durations of hyperoxia and their retinas were analyzed to determine the effects on vascular injury, microglial cell activation, and inflammatory cytokine profiling. The results of this analysis showed that MDL 72527 treatment significantly reduced hyperoxia-induced retinal vascular injury and enhanced vascular sprouting as compared with the vehicle controls. These protective effects were correlated with significant decreases in microglial activation as well as levels of inflammatory cytokines and chemokines. In order to model the effects of polyamine oxidation in causing microglial activation in vitro, studies were performed using rat brain microvascular endothelial cells treated with conditioned-medium from rat retinal microglia stimulated with hydrogen peroxide. Conditioned-medium from activated microglial cultures induced cell stress signals and cell death in microvascular endothelial cells. These studies demonstrate the involvement of polyamine oxidases in hyperoxia-induced retinal vascular injury and retinal inflammation in ischemic retinopathy, through mechanisms involving cross-talk between endothelial cells and resident retinal microglia. PMID- 27239701 TI - The pivotal role of uridine-cytidine kinases in pyrimidine metabolism and activation of cytotoxic nucleoside analogues in neuroblastoma. AB - Uridine-cytidine kinase (UCK) catalyzes the phosphorylation of uridine and cytidine as well as the pharmacological activation of several cytotoxic pyrimidine ribonucleoside analogues. In this study, we investigated the functional role of two isoforms of UCK in neuroblastoma cell lines. Analysis of mRNA coding for UCK1 and UCK2 showed that UCK2 is the most abundantly expressed UCK in a panel of neuroblastoma cell lines. Transient and stable overexpression of UCK2 in neuroblastoma cells increased the metabolism of uridine and cytidine as well as the cytotoxicity of 3-deazauridine. Knockdown of endogenous UCK2 as well as overexpression of UCK1 resulted in decreased metabolism of uridine and cytidine and protected the neuroblastoma cells from 3-deazauridine-induced toxicity. Subcellular localization studies showed that UCK1-GFP and UCK2-GFP were localized in the cell nucleus and cytosol, respectively. However, co-expression of UCK1 with UCK2 resulted in a nuclear localization of UCK2 instead of its normal cytosolic localization, thereby impairing its normal function. The physical association of UCK1 and UCK2 was further demonstrated through pull-down analysis using his-tagged UCK. The discovery that UCK2 is highly expressed in neuroblastoma opens the possibility for selectively targeting neuroblastoma cells using UCK2-dependent pyrimidine analogues, while sparing normal tissues. PMID- 27239702 TI - Gender inequality and the 'East-West' divide in contraception: An analysis at the individual, the couple, and the country level. AB - Despite generally low fertility rates in Europe, contraceptive behavior varies to a substantial extent. The dichotomy between Western, and Central and Eastern European countries is particularly relevant. Whereas the former are characterized by the widespread use of modern contraception, the latter show a high prevalence of traditional methods to control fertility. The current study aims to examine whether these differences can be attributed to differences in women's individual status, and in gender inequality at the couple and the country level. We combine data from the Generations and Gender Survey (2004-2011) and the Demographic Health Survey (2005-2009), covering seventeen European countries, to perform multinomial multilevel analyses. The results confirm that higher educated and employed women, and women who have an equal occupational status relative to their partner are more likely to use modern reversible contraception instead of no, traditional, or permanent methods. Absolute and relative employment are also positively related to using female instead of male methods. Furthermore, it is shown that higher levels of country-level gender equality are associated with a higher likelihood of using modern reversible and female methods, but not sterilization. Particularly country levels of gender equality are linked to the East-West divide in type of contraceptive method used. Our findings underscore that women's higher status is closely related to their use of effective, female contraception. PMID- 27239703 TI - Forced removals embodied as tuberculosis. AB - South Africa has one of the worst tuberculosis burdens in the world. Several ecological forces have contributed to this, including high HIV prevalence; failing TB control strategies; crowded, poorly ventilated indoor environments including the complex web of political and economic interests which produce them; the development of racial capitalism; and mining and migration. In the following study, we measure CO2 levels in public transport to investigate the role extended commutes from peri-urban settlements to urban sites of work-a direct result of forced removals-potentially play in propagating the TB epidemic in Cape Town, South Africa. PMID- 27239704 TI - Equally inequitable? A cross-national comparative study of racial health inequalities in the United States and Canada. AB - Prior research suggests that racial inequalities in health vary in magnitude across societies. This paper uses the largest nationally representative samples available to compare racial inequalities in health in the United States and Canada. Data were obtained from ten waves of the National Health Interview Survey (n = 162,271,885) and the Canadian Community Health Survey (n = 19,906,131) from 2000 to 2010. We estimated crude and adjusted odds ratios, and risk differences across racial groups for a range of health outcomes in each country. Patterns of racial health inequalities differed across the United States and Canada. After adjusting for covariates, black-white and Hispanic-white inequalities were relatively larger in the United States, while aboriginal-white inequalities were larger in Canada. In both countries, socioeconomic factors did not explain inequalities across racial groups to the same extent. In conclusion, while racial inequalities in health exist in both the United States and Canada, the magnitudes of these inequalities as well as the racial groups affected by them, differ considerably across the two countries. This suggests that the relationship between race and health varies as a function of the societal context in which it operates. PMID- 27239705 TI - Living with sickle cell disease and depression in Lagos, Nigeria: A mixed methods study. AB - Sickle cell disorders (SCD) and depression are both chronic illnesses of global significance. Past research on SCD and depression struggles to make sense of statistical associations, essentializes depression within the person with SCD, and treats stigma as an automatic correlate of chronic illness. A mixed methods study (March 2012-April 2014) was undertaken with people living with SCD and depression in Lagos, Nigeria, examining depression-as disease (questionnaires); depression-as-illness-experience (individual depth interviews), and depression-as societal-sickness (focus groups). 103 people with SCD attending an outpatients clinic were administered the Patient Health Questionnaire-9, and 82 self identified with some level of depression. Fifteen were subsequently interviewed about their illness experience. Their lives were characterized by being extensively subjected to vicious discriminatory remarks, including from significant others, negative experiences they felt contributed to their depression and even to suicidal thoughts and actions. Contrary to misconceptions of the relational nature of stigma, respondents recognized that stigma resulted not from their SCD but from assumed broken social norms and expectations, norms to do with educability, employability and parenthood. They recounted either that they successfully met such expectations in their own lives, or that they could conceivably do so with reasonable societal adjustments. Ten respondents with SCD and depression further took part in two series of three focus groups with five people in each series of groups. In groups people living with SCD were able to challenge negative assumptions about themselves; to begin to recognize collective social interests as a group, and to rehearse backstage, in discussions between themselves, social actions that they might engage in frontstage, out in wider society, to challenge discriminatory societal arrangements they held to contribute to their depression. To the extent that depression in SCD has social origins, then social interventions, such as anti-discrimination laws and policies, are key resources in improving mental health. PMID- 27239706 TI - A psychosocial resilience curriculum provides the "missing piece" to boost adolescent physical health: A randomized controlled trial of Girls First in India. AB - RATIONALE AND OBJECTIVES: Despite a recent proliferation of interventions to improve health, education, and livelihoods for girls in low and middle income countries, psychosocial wellbeing has been neglected. This oversight is particularly problematic as attending to psychosocial development may be important not only for psychosocial but also physical wellbeing. This study examines the physical health effects of Girls First, a combined psychosocial (Girls First Resilience Curriculum [RC]) and adolescent physical health (Girls First Health Curriculum [HC]) intervention (RC + HC) versus its individual components (i.e., RC, HC) and a control group. We expected Girls First to improve physical health versus HC and controls. METHODS: Over 3000 girls in 76 government middle schools in rural Bihar, India participated. Interventions were delivered through in-school peer-support groups, facilitated by pairs of local women. Girls were assessed before and after program participation on two primary outcomes (health knowledge and gender equality attitudes) and nine secondary outcomes (clean water behaviors, hand washing, menstrual hygiene, health communication, ability to get to a doctor when needed, substance use, nutrition, safety, vitality and functioning). Analyses included Difference-in-Difference Ordinary Least-Squares Regressions and F-tests for equality among conditions. RESULTS: Girls First significantly improved both primary and eight secondary outcomes (all except nutrition) versus controls. Additionally, Girls First demonstrated significantly greater effects, improving both primary and six secondary outcomes (clean water behaviors, hand washing, health communication, ability to get to a doctor, nutrition, safety) versus HC. CONCLUSIONS: This study is among the first to assess the impact of a combined psychosocial and adolescent health program on physical health. We found that combining these curricula amplified effects achieved by either curriculum alone. These findings suggest that psychosocial wellbeing should receive much broader attention, not only from those interested in improving psychosocial outcomes but also from those interested in improving physical health outcomes. PMID- 27239708 TI - [Quality Assurance using routine data: Overdiagnosis by radiological imaging for back pain]. PMID- 27239707 TI - Predictors of depressive symptoms following the Great East Japan earthquake: A prospective study. AB - We sought to investigate prospectively the association between exposure to disaster (the 2011 East Japan Earthquake) and change in depressive symptoms among community-dwelling older adult survivors. We used two waves of data from the Japan Gerontological Evaluation Study (JAGES), an ongoing population-based, prospective cohort study in Japan. A unique feature of our study was the availability of information about mental health status pre-dating the disaster. Our sample comprised community-dwelling survivors aged 65 and older, who responded to surveys in 2010 (i.e. one year before the disaster) and in 2013 (n = 3464). We categorized disaster exposure according to three types of experiences: loss of family/friends, property damage, and disruption in access to medical service. Our main outcome was change in depressive symptoms, measured by the 15 item geriatric depression scale (GDS). Among the participants, 917 (26.5%) reported losing a family member to the disaster, while a further 537 (15.5%) reported losing a friend. More than half of the participants reported some damage to their homes. After adjusting for demographics and baseline mental health, people whose homes were completely destroyed had significantly elevated depressive symptom scores three years later (+1.22 points, 95%CI: 0.80, 1.64, p < 0.0001). Disruption of psychiatric care was also associated with change in GDS scores (+2.51 points, 95%CI: 1.28, 3.74, p < 0.0001). By contrast, loss of family/friends was no longer associated with GDS after 3 years; +0.18 points (95%CI: -0.018, 0.37, p = 0.08) for loss of family, and -0.045 points (95%CI: 0.28, 0.19, p = 0.71) for loss of friends. Three years after the disaster, survivors of the 2011 earthquake and tsunami appeared to have recovered from loss of loved ones. By contrast, property loss and disruption of psychiatry care were associated with persistent adverse impact on mental health. PMID- 27239709 TI - Circulating levels of perfluoroalkyl substances are associated with dietary patterns - A cross sectional study in elderly Swedish men and women. AB - BACKGROUND: In our daily life, we are exposed to perfluoroalkyl substances (PFAS) with possible health implications. The main exposure route for these substances is diet but comparative studies on how dietary habits influence exposure are lacking. OBJECTIVES: To examine the relations between blood levels of PFAS and adherence to three predefined dietary patterns (a WHO recommended diet, a Mediterranean-like diet, and a Low-Carbohydrate High-Protein (LCHP) diet) in an elderly Swedish population. METHODS: Dietary data from 7-day food records and serum concentrations of PFAS were obtained from a 70-year-old Swedish population (n=844), the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. The Healthy Diet Indicator score (based on WHO recommendations), the Mediterranean Diet Score and LCHP score were used to assess adherence. Multivariate linear regression was used to assess the associations between eight major PFAS and adherence to each dietary pattern. RESULTS: The WHO recommended diet was positively associated with perfluorohexane sulfonic acid (PFHxS). The LCHP diet was positively related to four out of eight PFAS; namely, perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA) and perfluoroundecanoic acid (PFUnDA). The Mediterranean-like diet was positively associated with most PFAS; namely perfluorooctanoic acid (PFOA), perfluorooctane sulfonamide (PFOSA), PFHxS, PFNA, PFDA, and PFUnDA. CONCLUSIONS: All dietary patterns were positively associated with blood levels of PFAS. The highest body burden of PFAS was found in individuals with high adherence to a Mediterranean-like diet, whilst individuals who more closely followed the officially recommended diet displayed a lower body burden of these compounds. PMID- 27239710 TI - Prediction of future methane emission from irrigated rice paddies in central Thailand under different water management practices. AB - There is concern about positive feedbacks between climate change and methane (CH4) emission from rice paddies. However, appropriate water management may mitigate the problem. We tested this hypothesis at six field sites in central Thailand, where the irrigated area is rapidly increasing. We used DNDC-Rice, a process-based biogeochemistry model adjusted based on rice growth data at each site to simulate CH4 emission from a rice-rice double cropping system from 2001 to 2060. Future climate change scenarios consisting of four representative concentration pathways (RCPs) and seven global climate models were generated by statistical downscaling. We then simulated CH4 emission in three water management practices: continuous flooding (CF), single aeration (SA), and multiple aeration (MA). The adjusted model reproduced the observed rice yield and CH4 emission well at each site. The simulated CH4 emissions in CF from 2051 to 2060 were 5.3 to 7.8%, 9.6 to 16.0%, 7.3 to 18.0%, and 13.6 to 19.0% higher than those from 2001 to 2010 in RCPs 2.6, 4.5, 6.0, and 8.5, respectively, at the six sites. Regionally, SA and MA mitigated CH4 emission by 21.9 to 22.9% and 53.5 to 55.2%, respectively, relative to CF among the four RCPs. These mitigation potentials by SA and MA were comparable to those from 2001 to 2010. Our results indicate that climate change in the next several decades will not attenuate the quantitative effect of water management practices on mitigating CH4 emission from irrigated rice paddies in central Thailand. PMID- 27239711 TI - Coral skeletal geochemistry as a monitor of inshore water quality. AB - Coral reefs maintain extraordinary biodiversity and provide protection from tsunamis and storm surge, but inshore coral reef health is degrading in many regions due to deteriorating water quality. Deconvolving natural and anthropogenic changes to water quality is hampered by the lack of long term, dated water quality data but such records are required for forward modelling of reef health to aid their management. Reef corals provide an excellent archive of high resolution geochemical (trace element) proxies that can span hundreds of years and potentially provide records used through the Holocene. Hence, geochemical proxies in corals hold great promise for understanding changes in ancient water quality that can inform broader oceanographic and climatic changes in a given region. This article reviews and highlights the use of coral-based trace metal archives, including metal transported from rivers to the ocean, incorporation of trace metals into coral skeletons and the current 'state of the art' in utilizing coral trace metal proxies as tools for monitoring various types of local and regional source-specific pollution (river discharge, land use changes, dredging and dumping, mining, oil spills, antifouling paints, atmospheric sources, sewage). The three most commonly used coral trace element proxies (i.e., Ba/Ca, Mn/Ca, and Y/Ca) are closely associated with river runoff in the Great Barrier Reef, but considerable uncertainty remains regarding their complex biogeochemical cycling and controlling mechanisms. However, coral-based water quality reconstructions have suffered from a lack of understanding of so called vital effects and early marine diagenesis. The main challenge is to identify and eliminate the influence of extraneous local factors in order to allow accurate water quality reconstructions and to develop alternate proxies to monitor water pollution. Rare earth elements have great potential as they are self-referencing and reflect basic terrestrial input. PMID- 27239712 TI - An analysis on how switching to a more balanced and naturally improved milk would affect consumer health and the environment. AB - This study compares a premium brand of UHT milk, Unicla, characterised by an improved nutritional composition, to conventional milk, in terms of health effects and environmental impacts. Unlike enriched milks, in which nutrients are added to the final product, Unicla is obtained naturally by improving the diet of the dairy cows. Health effects have been analysed based on literature findings, while the environmental analysis focused on those spheres of the environment where milk is expected to cause the higher impacts, and thus carbon (CF) and water footprints (WF) have been determined. Five final products have been compared: 3 conventional (skimmed, semi-skimmed, whole) and 2 Unicla (skimmed, semi-skimmed) milks. As a functional unit, one litre of packaged UHT milk entering the regional distribution centre has been chosen. The improved composition of Unicla milk is expected to decrease the risk of cardiovascular disease and to protect consumers against oxidative damage, among other health benefits. Concerning the environmental aspect, CF of Unicla products are, on average, 10% lower than their conventional equivalents, mainly due to the lower enteric emissions of caused by the Unicla diet. No significant differences were found between the WF of Unicla and conventional milk. Raw milk is the main contributor to both footprints (on average, 83.2 and 84.3% of the total CF of Unicla and conventional milk, respectively, and 99.9% of WF). The results have been compared to those found in literature, and a sensitivity analysis has been performed to verify their robustness. The study concludes that switching to healthier milk compositions can help slowing down global warming, without contributing to other environmental issues such as water scarcity. The results should encourage other milk companies to commit to the development of healthier, less environmentally damaging products, and also to stimulate consumers to bet on them. PMID- 27239713 TI - 'The past is the future of the present': Learning from long-time series of marine monitoring. AB - Using a long-term (1995-2014) monitoring network, from 51 sampling stations in estuaries and coasts of the Basque Country (Bay of Biscay), the objective of this investigation was to assess the responsiveness of 83 variables in water (18), sediments (27), biota (26), phytoplankton (2), macroinvertebrates (5) and fishes (5) to different human pressures and management actions. We used a total of 3247 series of data to analyse trends of improvement and worsening in quality. In a high percentage of the cases, the management actions taken have resulted in positive effects in the environment, as shown by the trend analysis in this investigation. Overall, much more trends of improvement than of worsening have been observed; this is true for almost all the media and biological components studied, with the exception of phytoplankton; and it applies as well to almost all the stations and water bodies, with the exception of those corresponding to areas with water treatment pending of accomplishment. In estuaries with decreasing human pressures during the period, the percentage of series showing quality improvement was higher (approx. 30%) than those showing worsening of quality (12%). Moreover, in those water bodies showing an increase of pressure, variables which can be considered indicators of anthropogenic effects showed negative trends (quality worsening). On the other hand, some of the variables analysed were more affected by natural variability than by changes in pressures. That was the case of silicate, nitrate and suspended solids, which followed trends correlated to salinity, which, in turn, was related to the rainfall regime during the study period. PMID- 27239714 TI - Photochemical transformation of benzotriazole, relevant to sunlit surface waters: Assessing the possible role of triplet-sensitised processes. PMID- 27239716 TI - Effects of terbuthylazine-desethyl, a terbuthylazine degradation product, on red swamp crayfish (Procambarus clarkii). AB - Terbuthylazine is a widely used triazine pesticide. This, together with one of its degradation products, terbuthylazine-desethyl (TD), are frequently found in quantities exceeding the EU limit of 0.1MUg/L in aquatic ecosystems where they might constitute a serious risk to non-target organisms. The sub-chronic effects of TD at 2.9MUg/L (real environmental concentration) and at 580MUg/L were investigated in a non-target aquatic species, the red swamp crayfish (Procambarus clarkii). Gill and hepatopancreas histopathology, alterations in biochemical parameters of haemolymph, oxidative damage to hepatopancreas, and changes in antioxidant biomarkers in muscle and hepatopancreas were recorded at both tested concentrations after 14days exposure. A 14day recovery period in TD-free water was not sufficient for restoration of normal parameters. Chronic terbuthylazine desethyl exposure affected biochemical profile, and the antioxidant system, caused oxidative stress and histopathological changes in hepatopancreas of red swamp crayfish. PMID- 27239717 TI - How do soil organic carbon stocks change after cropland abandonment in Mediterranean humid mountain areas? AB - The effects of land use changes on soil carbon stocks are a matter of concern stated in international policy agendas on the mitigation of greenhouse emissions. Afforestation is increasingly viewed as an environmental restorative land use change prescription and is considered one of the most efficient carbon sequestration strategies currently available. Given the large quantity of CO2 that soils release annually, it is important to understand disturbances in vegetation and soil resulting from land use changes. The main objective of this study is to assess the effects of land abandonment, land use change and afforestation practices on soil organic carbon (SOC) dynamics. For this aim, five different land covers (bare soil, permanent pastureland, secondary succession, Pinus sylvestris (PS) and Pinus nigra (PN) afforestation), in the Central Spanish Pyrenees, were analysed. SOC dynamics have been studied in the bulk soil, and in the fractions separated according to two methodologies: (i) aggregate size distribution, and (ii) density fractionation, and rates of carbon mineralization have been determined by measuring CO2 evolution using an automated respirometer. The results showed that: (i) SOC contents were higher in the PN sites in the topsoil (10cm), (ii) when all the profiles were considered no significant differences were observed between pastureland and PN, (iii) SOC accumulation under secondary succession is a slow process, and (iv) pastureland should also be considered due to the relative importance in SOC stocks. The first step of SOC stabilization after afforestation is the formation of macro-aggregates promoted by large inputs of SOC, with a high contribution of labile organic matter. However, our respiration experiments did not show evidence of SOC stabilization. SOC mineralization was higher in the top layers and values decreased with depth. These results gain insights into which type of land management is most appropriate after land abandonment for SOC. PMID- 27239715 TI - Ecological restoration across the Mediterranean Basin as viewed by practitioners. AB - Restoration efforts in the Mediterranean Basin have been changing from a silvicultural to an ecological restoration approach. Yet, to what extent the projects are guided by ecological restoration principles remains largely unknown. To analyse this issue, we built an on-line survey addressed to restoration practitioners. We analysed 36 restoration projects, mostly from drylands (86%). The projects used mainly soil from local sources. The need to comply with legislation was more important as a restoration motive for European Union (EU) than for non-EU countries, while public opinion and health had a greater importance in the latter. Non-EU countries relied more on non-native plant species than EU countries, thus deviating from ecological restoration guidelines. Nursery-grown plants used were mostly of local or regional provenance, whilst seeds were mostly of national provenance. Unexpected restoration results (e.g. inadequate biodiversity) were reported for 50% of the projects and restoration success was never evaluated in 22%. Long term evaluation (>6years) was only performed in 31% of cases, and based primarily on plant diversity and cover. The use of non-native species and species of exogenous provenances may: i) entail the loss of local genetic and functional trait diversity, critical to cope with drought, particularly under the predicted climate change scenarios, and ii) lead to unexpected competition with native species and/or negatively impact local biotic interactions. Absent or inappropriate monitoring may prevent the understanding of restoration trajectories, precluding adaptive management strategies, often crucial to create functional ecosystems able to provide ecosystem services. The overview of ecological restoration projects in the Mediterranean Basin revealed high variability among practices and highlighted the need for improved scientific assistance and information exchange, greater use of native species of local provenance, and more long-term monitoring and evaluation, including functional and ecosystem services' indicators, to improve and spread the practice of ecological restoration. PMID- 27239718 TI - Drought versus heat: What's the major constraint on Mediterranean green roof plants? AB - Green roofs are gaining momentum in the arid and semi-arid regions due to their multiple benefits as compared with conventional roofs. One of the most critical steps in green roof installation is the selection of drought and heat tolerant species that can thrive under extreme microclimate conditions. We monitored the water status, growth and survival of 11 drought-adapted shrub species grown on shallow green roof modules (10 and 13cm deep substrate) and analyzed traits enabling plants to cope with drought (symplastic and apoplastic resistance) and heat stress (root membrane stability). The physiological traits conferring efficiency/safety to the water transport system under severe drought influenced plant water status and represent good predictors of both plant water use and growth rates over green roofs. Moreover, our data suggest that high substrate temperature represents a stress factor affecting plant survival to a larger extent than drought per se. In fact, the major cause influencing seedling survival on shallow substrates was the species-specific root resistance to heat, a single and easy measurable trait that should be integrated into the methodological framework for screening and selection of suitable shrub species for roof greening in the Mediterranean. PMID- 27239719 TI - Selection of forest species for the rehabilitation of disturbed soils in oil fields in the Ecuadorian Amazon. PMID- 27239720 TI - Triclosan: A review on systematic risk assessment and control from the perspective of substance flow analysis. AB - Triclosan (TCS) is a broad spectrum antibacterial agent mainly used in Pharmaceutical and Personal Care Products. Its increasing use over recent decades have raised its concentration in the environment, with commonly detectable levels found along the food web-from aquatic organisms to humans in the ecosystem. To date, there is shortage of information on how to investigate TCS's systematic risk on exposed organisms including humans, due to the paucity of systematic information on TCS flows in the anthroposphere. Therefore, a more holistic approach to mass flow balancing is required, such that the systematic risk of TCS in all environmental matrices are evaluated. From the perspective of Substance Flow Analysis (SFA), this review critically summarizes the current state of knowledge on TCS production, consumption, discharge, occurrence in built and natural environments, its exposure and metabolism in humans, and also the negative effects of TCS on biota and humans. Recent risk concerns have mainly focused on TCS removal efficiencies and metabolism, but less attention is given to the effect of mass flows from source to fate during risk exposure. However, available data for TCS SFA is limited but SFA can derive logical systematic information from limited data currently available for systematic risk assessment and reduction, based on mass flow analysis. In other words, SFA tool can be used to develop a comprehensive flow chart and indicator system for the risk assessment and reduction of TCS flows in the anthroposphere, thereby bridging knowledge gaps to streamline uncertainties related to policy-making on exposure pathways within TCS flow-lines. In the final analysis, specifics on systematic TCS risk assessment via SFA, and areas of improvement on human adaptation to risks posed by emerging contaminants are identified and directions for future research are suggested. PMID- 27239721 TI - Inhibitors of histone deacetylase as antitumor agents: A critical review. AB - Histone deacetylase (EC 3.5.1.98 - HDAC) is an amidohydrolase involved in deacetylating the histone lysine residues for chromatin remodeling and thus plays a vital role in the epigenetic regulation of gene expression. Due to its aberrant activity and over expression in several forms of cancer, HDAC is considered as a potential anticancer drug target. HDAC inhibitors alter the acetylation status of histone and non-histone proteins to regulate various cellular events such as cell survival, differentiation and apoptosis in tumor cells and thus exhibit anticancer activity. Till date, four drugs, namely Vorinostat (SAHA), Romidepsin (FK-228), Belinostat (PXD-101) and Panobinostat (LBH-589) have been granted FDA approval for cancer and several HDAC inhibitors are currently in various phases of clinical trials, either as monotherapy and/or in combination with existing/novel anticancer agents. Regardless of this, today scientific efforts have fortified the quest for newer and novel HDAC inhibitors that show isoform selectivity. This review focuses on the chemistry of the molecules of two classes of HDAC inhibitors, namely short chain fatty acids and hydroxamic acids, investigated so far as novel therapeutic agents for cancer. PMID- 27239722 TI - A novel electro-driven membrane for removal of chromium ions using polymer inclusion membrane under constant D.C. electric current. AB - In this study, the use of polymer inclusion membrane under constant electric current for the removal of Cr(VI) from water has investigated for the first time. Transport of Cr(VI) is performed by an electric current from the donor phase to the acceptor phase with a constant electric current of 0.5A. The optimized membrane includes of 12.1% 2-nitrophenyl octyl ether (2-NPOE), 77.6% cellulose triacetate (CTA), 10.3% tricapryl-methylammonium chloride (Aliquat 336) as a carrier. We tested the applicability of the selected membrane for Cr(VI) removal in real environmental water samples and evaluated its reusability. Electro membrane experiments were carried out under various parameters, such as the effect of electro membrane voltage at constant DC electric current; electro membrane current at constant voltage, acceptor phase pH, and stable electro membrane; and a comparison of polymer inclusion membrane and electro membrane transport studies. The Cr(VI) transport was achieved 98.33% after 40min under optimized conditions. An alternative method has been employed that eliminates the changing of electrical current by the application of constant electric current for higher reproducibility of electro membrane extraction experiments by combining the excellent selective and long-term use features of polymer inclusion membrane. PMID- 27239723 TI - Facile synthesis of AgI/BiOI-Bi2O3 multi-heterojunctions with high visible light activity for Cr(VI) reduction. AB - AgI sensitized BiOI-Bi2O3 composite (AgI/BiOI-Bi2O3) with multi-heterojunctions was prepared using simple etching-deposition process. Different characterization techniques were performed to investigate the structural, optical and electrical properties of the as-prepared photocatalysts. It was found that the ternary AgI/BiOI-Bi2O3 composite exhibited: (1) improved photocurrent response, (2) smaller band gap, (3) greatly reduced charge transfer resistance and (4) negative shift of flat band potential, which finally led to easier generation and more efficient separation of photo-generated electron-hole pairs at the hetero interfaces. Thus, for the reduction of Cr(VI), AgI/BiOI-Bi2O3 exhibited excellent photocatalytic activity under visible light irradiation at near neutral pH. AgI/BiOI-Bi2O3 was optimized when the initial molar ratio of KI to Bi2O3 and AgNO3 to Bi2O3 was 1:1 and 10%, respectively. The estimated kCr(VI) on optimized AgI/BiOI-Bi2O3 was about 16 times that on pure Bi2O3. Good stability was also observed in cyclic runs, indicating that the current multi-heterostructured photocatalyst is highly desirable for the remediation of Cr(VI)-containing wastewater. PMID- 27239724 TI - Self-floating graphitic carbon nitride/zinc phthalocyanine nanofibers for photocatalytic degradation of contaminants. AB - The effective elimination of micropollutants by an environmentally friendly method has received extensive attention recently. In this study, a photocatalyst based on polyacrylonitrile (PAN)-supported graphitic carbon nitride coupled with zinc phthalocyanine nanofibers (g-C3N4/ZnTcPc/PAN nanofibers) was successfully prepared, where g-C3N4/ZnTcPc was introduced as the catalytic entity and the PAN nanofibers were employed as support to overcome the defects of easy aggregation and difficult recycling. Herein, rhodamine B (RhB), 4-chlorophenol and carbamazepine (CBZ) were selected as the model pollutants. Compared with the typical hydroxyl radical-dominated catalytic system, g-C3N4/ZnTcPc/PAN nanofibers displayed the targeted adsorption and degradation of contaminants under visible light or solar irradiation in the presence of high additive concentrations. According to the results of the radical scavenging techniques and the electron paramagnetic resonance technology, the degradation of target substrates was achieved by the attack of active species, including photogenerated hole, singlet oxygen, superoxide radicals and hydroxyl radicals. Based on the results of ultra performance liquid chromatography and mass spectrometry, the role of free radicals on the photocatalytic degradation intermediates was identified and the final photocatalytic degradation products of both RhB and CBZ were some biodegradable small molecules. PMID- 27239725 TI - Fetal RHD genotyping after bone marrow transplantation. AB - BACKGROUND: Fetal RHD genotyping allows targeted diagnostic testing, fetal surveillance, and eventually intrauterine treatment to D-alloimmunized pregnant women who carry an RHD+ fetus. However, false-positive and false-negative results of noninvasive prenatal fetal RHD genotyping have been described due to a variety of causes. In this case report we present two cases where noninvasive fetal RHD typing was complicated by a previous bone marrow transplantation (BMT). CASE REPORT: We describe two women with a history of allogeneic BMT in early childhood. Both were born D+ and received a transplant of their D- male sibling. Anti-D were detected during pregnancy in one of them. The biologic father of this pregnancy was D+. In both cases polymerase chain reaction procedures specific for RHD on maternal plasma DNA were positive whereas a D- neonate was born in one case (Case 1). CONCLUSION: False-positive results of noninvasive fetal RHD genotyping occur in D+ women transplanted with marrow of a D- donor, due to circulating cell-free DNA originating from nonhematopoietic tissue. The cases highlight that health care professionals and laboratories should be aware that allogeneic BMT can be a cause for false-positive results in fetal RHD genotyping with cell-free DNA in maternal plasma, and likewise the wrong fetal sex can be reported in the case of a male donor and a female fetus. Based on one of the cases we also recommend giving D- blood products to young female patients who receive a BMT of D- donors. PMID- 27239726 TI - Morphology and Molecular Phylogeny of Coelomic Gregarines (Apicomplexa) with Different Types of Motility: Urospora ovalis and U. travisiae from the Polychaete Travisia forbesii. AB - Urosporids (Apicomplexa: Urosporidae) are eugregarines that parasitise marine invertebrates, such as annelids, molluscs, nemerteans and echinoderms, inhabiting their coelom and intestine. Urosporids exhibit considerable morphological plasticity, which correlates with their different modes of motility and variations in structure of their cortical zone, according to the localisation within the host. The gregarines Urospora ovalis and U. travisiae from the marine polychaete Travisia forbesii were investigated with an emphasis on their general morphology and phylogenetic position. Solitary ovoid trophozoites and syzygies of U. ovalis were located free in the host coelom and showed metabolic activity, a non-progressive movement with periodic changes of the cell shape. Solitary trophozoites of U. travisiae, attached to the host tissue or free floating in the coelom, were V-shaped. Detached trophozoites demonstrated gliding motility, a progressive movement without observable cell body changes. In both gregarines, the cortex formed numerous epicytic folds, but superfolds appeared exclusively on the surface of U. ovalis during metabolic activity. SSU rDNA sequences obtained from U. ovalis and U. travisiae revealed that they belong to the Lecudinoidea clade; however, they are not affiliated with other coelomic urosporids (Pterospora spp. and Lithocystis spp.), but surprisingly with intestinal lecudinids (Difficilina spp.) parasitising nemerteans. PMID- 27239728 TI - Influence of saddle setback on pedalling technique effectiveness in cycling. AB - Besides its regulation by Union Cycliste Internationale, the evidence relating saddle setback to pedalling performance remains inconclusive. This study investigates the influence of saddle setback on pedalling effectiveness through two indexes: an index of pedalling force effectiveness and an index of pedalling work effectiveness. Eleven cyclists were assessed six saddle setback conditions while pedalling at a steady power output of 200 W and cadence of 90 rpm. A force sensor was integrated within the seat post to compute the centre of pressure on the saddle. From instrumented pedals, an index of force effectiveness (ratio between the force directed perpendicular to the crank arm and the total force applied to the pedal) and an index of work effectiveness (based on the minimisation of negative crank work) were calculated. In comparison with a forward position, sitting backward significantly decreased 5% cumulative total work, increased index of work effectiveness (84.2 +/- 3.7 vs. 82.0 +/- 4.7%), and increased index of force effectiveness (41.7 +/- 2.9 vs. 39.9 +/- 3.7 and 36.9 +/ 0.7%). Thus, while it was previously reported that sitting more forward favours maximal power, this study demonstrates that it also leads to a decreased effectiveness in steady-state pedalling. PMID- 27239727 TI - Early changes in apoplast composition associated with defence and disease in interactions between Phaseolus vulgaris and the halo blight pathogen Pseudomonas syringae Pv. phaseolicola. AB - The apoplast is the arena in which endophytic pathogens such as Pseudomonas syringae grow and interact with plant cells. Using metabolomic and ion analysis techniques, this study shows how the composition of Phaseolus vulgaris leaf apoplastic fluid changes during the first six hours of compatible and incompatible interactions with two strains of P. syringae pv. phaseolicola (Pph) that differ in the presence of the genomic island PPHGI-1. Leaf inoculation with the avirulent island-carrying strain Pph 1302A elicited effector-triggered immunity (ETI) and resulted in specific changes in apoplast composition, including increases in conductivity, pH, citrate, gamma-aminobutyrate (GABA) and K(+) , that are linked to the onset of plant defence responses. Other apoplastic changes, including increases in Ca(2+) , Fe(2/3+) Mg(2+) , sucrose, beta cyanoalanine and several amino acids, occurred to a relatively similar extent in interactions with both Pph 1302A and the virulent, island-less strain Pph RJ3. Metabolic footprinting experiments established that Pph preferentially metabolizes malate, glucose and glutamate, but excludes certain other abundant apoplastic metabolites, including citrate and GABA, until preferred metabolites are depleted. These results demonstrate that Pph is well-adapted to the leaf apoplast metabolic environment and that loss of PPHGI-1 enables Pph to avoid changes in apoplast composition linked to plant defences. PMID- 27239729 TI - Improving the Stability and Performance of Perovskite Light-Emitting Diodes by Thermal Annealing Treatment. AB - A perovskite LED with a perovskite film treated under optimum thermal annealing conditions exhibits a significantly enhanced long-term stability with full coverage of the green electroluminescence emission due to the highly uniform morphology of the perovskite film. PMID- 27239730 TI - Orphanhood and fertility in young adults: Evidence from South Africa. AB - I study the relation between orphanhood and fertility patterns in young adults using a longitudinal survey from the city of Cape Town, South Africa. The data set combines two survey waves with a year-by-year life history calendar that records key outcomes (e.g., schooling, work, fertility). It also provides information on so-called 'parental investments' (time and material support), family background, and literacy and numeracy test scores. I find that orphans exhibit significantly higher rates of teenage pregnancy. In particular, teenage motherhood is 19% points more likely among (female) orphans. These results suggest that orphanhood may leave a long-lasting 'imprint' in terms of premature fertility, especially in teenage females. PMID- 27239731 TI - Arginase inhibition attenuates arteriogenesis and interferes with M2 macrophage accumulation. AB - l-Arginine is the common substrate for nitric oxide synthases (NOS) and arginase. Whereas the contribution of NOS to collateral artery growth (arteriogenesis) has been demonstrated, the functional role of arginase remains to be elucidated and was topic of the present study. Arteriogenesis was induced in mice by ligation of the femoral artery. Laser Doppler perfusion measurements demonstrated a significant reduction in arteriogenesis in mice treated with the arginase inhibitor nor-NOHA (N(omega)-hydroxy-nor-arginine). Accompanying in vitro results on murine primary arterial endothelial cells and smooth muscle cells revealed that nor-NOHA treatment interfered with cell proliferation and resulted in increased nitrate/nitrite levels, indicative for increased NO production. Immuno histological analyses on tissue samples demonstrated that nor-NOHA administration caused a significant reduction in M2 macrophage accumulation around growing collateral arteries. Gene expression studies on isolated growing collaterals evidenced that nor-NOHA treatment abolished the differential expression of Icam1 (intercellular adhesion molecule 1). From our data we conclude that arginase activity is essential for arteriogenesis by promoting perivascular M2 macrophage accumulation as well as arterial cell proliferation. PMID- 27239732 TI - Activation of the vitamin D receptor selectively interferes with calcineurin mediated inflammation: a clinical evaluation in the abdominal aortic aneurysm. AB - In vitro and in vivo studies attribute potent immune regulatory properties to the vitamin D receptor (VDR). Yet, it is unclear to what extend these observations translate to the clinical context of (vascular) inflammation. This clinical study evaluates the potential of a VDR agonist to quench vascular inflammation. Patients scheduled for open abdominal aneurysm repair received paricalcitol 1 MUg daily during 2-4 weeks before repair. Results were compared with matched controls. Evaluation in a parallel group showed that AAA patients are vitamin D insufficient (median plasma vitamin D: 43 (30-62 (IQR)) nmol/l). Aneurysm wall samples were collected during surgery, and the inflammatory footprint was studied. The brief paricalcitol intervention resulted in a selective 73% reduction in CD4+ T-helper cell content (P<0.024) and a parallel 35% reduction in T-cell (CD3+) content (P<0.032). On the mRNA level, paricalcitol reduced expression of T-cell-associated cytokines IL-2, 4, and 10 (P<0.019). No effect was found on other inflammatory mediators. On the protease level, selective effects were found for cathepsin K (P<0.036) and L (P<0.005). Collectively, these effects converge at the level of calcineurin activity. An effect of the VDR agonist on calcineurin activity was confirmed in a mixed lymphocyte reaction. In conclusion, brief course of the VDR agonist paricalcitol has profound effects on local inflammation via reduced T-cell activation. The anti-inflammatory potential of VDR activation in vitamin D insufficient patients is highly selective and appears to be mediated by an effect on calcineurin-mediated responses. PMID- 27239733 TI - Molecular mechanisms underlying attenuation of cisplatin-induced acute kidney injury by epicatechin gallate. AB - Cisplatin, a platinum compound, is used as a first-line agent against various forms of solid cancers. Nephrotoxicity is an important adverse effect of cisplatin therapy, which involves increased oxidative stress, inflammation, apoptosis, and activation of the mitogen-activated protein kinase (MAPK) pathway. It is well known that the bioactive compounds present in green tea are used to treat various disorders due to their biological activities. With this background, the present study was aimed to investigate the effect of epicatechin gallate (ECG), a green tea polyphenol, in cisplatin-induced nephrotoxicity in rats. To achieve this, ECG (1.25, 2.5, and 5 mg/kg; intraperitoneal (i.p.)) was administered to male albino Wistar rats for the period of 10 days. On the 7th day, a single i.p. injection of cisplatin (8 mg/kg) was injected into rats to produce kidney injury and the animals were then killed on the 10th day. Cisplatin toxicity was associated with enhanced oxidative stress, impaired renal function along with marked tubular necrosis in Histopathology. Furthermore, cisplatin activated the MAPK pathway, which contributed to inflammation and apoptosis in the kidney of treated rats. In contrast, ECG (5 mg/kg) pretreatment normalized cisplatin-induced oxidative stress, renal function, and histopathological changes. ECG also prevented the activation of the MAPK pathway, and attenuated inflammation and apoptosis in rats. These findings suggest that ECG prevented cisplatin-induced oxidative stress, inflammation, and apoptosis by downregulating the MAPK pathway and resulted in improved renal function. PMID- 27239735 TI - Allogeneic hematopoietic cell transplantation for adult patients with treatment related acute myeloid leukemia during first remission: Comparable to de novo acute myeloid leukemia. AB - Therapy-related acute myeloid leukemia (T-AML) is associated with poor prognosis after conventional therapy. Allogeneic hematopoietic cell transplantation (allo HCT) has been proposed as a treatment for T-AML; however, data comparing outcomes of transplants for patients with de novo AML and T-AML are limited. Sixteen adult patients with T-AML during first complete remission after malignant disease received allo-HCT at the Peking University Institute of Hematology between January 1, 2006 and December 31, 2014. Eighty patients with de novo AML were selected using the case-pair method. The 3-year overall survival and leukemia free survival for T-AML versus de novo AML patients were 66% vs. 79% (P=0.14) and 64% vs. 77% (P=0.13), respectively. The 3-year cumulative non-relapse mortality rates for T-AML versus de novo AML patients were 13% vs. 9% (P=0.47), respectively; the relapse rates were 20% vs. 13% (P=0.25), respectively. Our results suggest that the prognosis of T-AML is comparable to that of de novo AML after transplantation. Although T-AML shows poorer prognosis than de novo AML after conventional therapies, allo-HCT can markedly improve the prognosis of T AML. PMID- 27239736 TI - Defining the significance of IGF2BP1 overexpression in t(12;21)(p13;q22)-positive leukemia REH cells. AB - The IGF2 mRNA binding protein 1 (IGF2BP1) belongs to a family of regulatory RNA binding proteins and controls stability, transport or translation of its target transcripts. Re-expression of IGF2BP1 is frequently found in different tumors and has been associated with aggressive disease phenotypes. IGF2BP1 has also been identified to be exclusively specific for t(12;21)(p13;q22)-positive acute lymphoblastic leukemia (ALL) but biological significance of IGF2BP1 overexpression has not been investigated to date. We have recently reported that ETV6/RUNX1 transcript is a target of RNA-binding protein IGF2BP1 in t(12;21)(p13;q22)-positive ALL suggesting a direct role of IGF2BP1 in ETV6/RUNX1 mediated leukemogenesis. To address this question we have employed stable clones of REH cells - a model cell line of t(12;21)(p13;q22)-positive ALL - with downregulated IGF2BP1 expression. Here we show that downregulation of IGF2BP1 impairs proliferation by attenuating cell cycle progression and increasing the rate of spontaneous cell death. We also provide evidence that downregulation of IGF2BP1 induce reduction of STAT3 mRNA levels and augments sensitivity to STAT3 selective inhibitor S3I-201. These data imply that IGF2BP1 indirectly potentiates ETV6/RUNX1-RAC1-STAT3 signaling axis by sustaining appropriate ETV6/RUNX1 and STAT3 transcript levels in REH cells. Further studies are warranted to specify the role of IGF2BP1 in t(12;21)(p13;q22)-positive ALL. PMID- 27239734 TI - C/EBP homologous protein modulates liraglutide-mediated attenuation of non alcoholic steatohepatitis. AB - The CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), a major transcriptional regulator of endoplasmic reticulum (ER) stress-mediated apoptosis, is implicated in lipotoxicity-induced ER stress and hepatocyte apoptosis in non-alcoholic fatty liver disease (NAFLD). We have previously demonstrated that the glucagon-like peptide-1 (GLP-1) agonist, liraglutide, protects steatotic hepatocytes from lipotoxicity-induced apoptosis by improved handling of free fatty acid (FFA)-induced ER stress. In the present study, we investigated whether CHOP is critical for GLP-1-mediated restoration of ER homeostasis and mitigation of hepatocyte apoptosis in a murine model of NASH (non alcoholic steatohepatitis). Our data show that despite similar caloric intake, CHOP KO (CHOP(-/-)) mice fed a diet high in fat, fructose, and cholesterol (HFCD) for 16 weeks developed more severe histological features of NASH compared with wild-type (WT) controls. Severity of NASH in HFCD-fed CHOP(-/-) mice correlated with significant decrease in peroxisomal beta-oxidation, and increased de novo lipogenesis and ER stress-mediated hepatocyte apoptosis. Four weeks of liraglutide treatment markedly attenuated steatohepatitis in HFCD-fed WT mice by improving insulin sensitivity, and suppressing de novo lipogenesis and ER stress mediated hepatocyte apoptosis. However, in the absence of CHOP, liraglutide did not improve insulin sensitivity, nor suppress peroxisomal beta-oxidation or ER stress-mediated hepatocyte apoptosis. Taken together, these data indicate that CHOP protects hepatocytes from HFCD-induced ER stress, and has a significant role in the mechanism of liraglutide-mediated protection against NASH pathogenesis. PMID- 27239737 TI - Increase of endothelial progenitor cells in acute graft-versus-host disease after allogeneic haematopoietic stem cell transplantation for acute myeloid leukaemia. AB - INTRODUCTION: Circulating endothelial progenitor cells (EPCs; CD31+ CD34(bright)CD133+ CD45(dim) cells) are novel markers of endothelial dysfunction and related to inflammatory processes such as acute graft-versus-host disease (aGvHD). PATIENTS AND METHODS: 47 patients with acute myeloid leukaemia (AML) who were in complete remission as they underwent allogeneic hematopoietic stem cell transplantation with myeloablative conditioning with PBSC as stem cell source were enrolled in the study. Blood samples for the quantitative analysis of circulating EPC levels were drawn at different time points in patients with and without aGvHD. CD34+ VEGFR2/KDR+ CD133+ triple-positive cells identified among CD34+ cells by FACS. EPC were quantified and data are presented as cells/ml whole blood. RESULTS: Circulating EPC levels were not significantly different in patients with and without aGvHD prior to conditioning (baseline) and at the time of engraftment. However, at diagnosis of aGvHD>=grade 2, EPC levels increased whereas in patients without aGvHD the EPC levels remained significantly lower (3021+/-278 versus 2322+/-195 cells/ml; p<0.001). Patients with steroid refractory aGvHD had high levels of EPC throughout. EPC levels fell in responding patients. CONCLUSION: Our results demonstrate that the number of circulating EPCs is increased in patients with aGvHD compared to patients without aGvHD. PMID- 27239738 TI - Efficacy and tolerance of pegaspargase, gemcitabine and oxaliplatin with sandwiched radiotherapy in the treatment of newly-diagnosed extranodal nature killer (NK)/T cell lymphoma. AB - Extranodal nature killer (NK)/T cell lymphoma (ENKL), nasal type, is a highly aggressive and heterogeneous disease. Here we report a retrospective study of 38 newly-diagnosed ENKL patients treated with pegaspargase, gemcitabine, oxaliplatin (P-Gemox) and sandwiched radiotherapy in our department during 2012-2016. A median of 4 (range, 2-6) (total=141) cycles of P-Gemox were administered. Interim restaging after at least 2 cycles showed complete remission (CR) rate of 23.68%, partial remission (PR) rate of 63.16%, giving an overall response rate (ORR) of 86.84%. On treatment completion, the ORR became 92.1% (CR=86.84%, PR=5.26%). Only one patient experienced disease progression during therapy. Multivariate analysis showed gender was a significant independent factor impacting on CR. Hematologic toxicity was common yet nonhematologic toxicity was mild, both of them can be well controlled by supportive treatments and only one treatment-related death was observed. At a median follow-up of 15.5 months, 4 patients (10.53%) experienced disease progression and died of disease. 1-year progression-free survival (PFS) rate and 1-year overall survival (OS) rate for the whole cohort were 86.7% and 86.6%. The P-Gemox regimen with sandwiched radiotherapy may be a promising option in the treatment of newly-diagnosed ENKL due to its high efficacy yet low toxicity. PMID- 27239739 TI - Testing clinical competencies in undergraduate nursing education using Objective Structured Clinical Examination (OSCE) - a literature review of international practice AB - Background: In response to demographic trends in Germany nursing competencies are currently reevaluated. Since these have to be taught and trained in nursing education programs, efficient verification of the success is necessary. OSCEs are internationally well-recognized as a comprehensive tool for that. Aim: In this analysis we identified competencies worldwide, which are tested by OSCEs in undergraduate nursing education programs. Method: An international literature research was conducted. The selection criterion for an article was the specification of at least one verifiable competency. Afterwards the competencies were categorized into knowledge, skills and attitudes according to the German "Fachqualifikationsrahmen Pflege fur die hochschulische Bildung". Results: A total of 36 publications fulfilled all inclusion criteria. Relevant studies were predominantly initiated in the UK, Canada and Australia. Within all categories a total of n = 166 different competencies are mentioned. OSCEs are developed and performed in a broad range of methods. Most frequently skills were verified. The most common topic was sure handling of medication. Other important themes were communicative competencies in relation to patients and the ability of self evaluation. Discussion/Conclusions: A variation in examination methods is appropriate as different competencies are acquired in preparation of the test. Evaluation took place on an individual or institutional level. Further research is needed. PMID- 27239741 TI - Vaccination status among nurses in hospitals. Results of a cross sectional study at Harzklinikum Dorothea Christiane Erxleben Quedlinburg AB - Background: Health care workers can be multiplicators for infectious diseases due to their patient contacts. Vaccinations are not mandatory in Germany but there are recommendations for people at higher risk such as health care workers. There is no representative data regarding vaccination status of health care workers in Germany. Aim: We examined vaccination status among nurses regarding diphtheria, tetanus, pertussis, poliomyelitis, hepatitis A (HA) and hepatitis B (HB) as well as correlations between age, professional years, vaccination status and acceptance. Methods: An anonymous cross sectional survey concerning health burden and health behavior including vaccination was conducted among health care workers. Statistical analysis using SPSS included descriptive analysis, subgroup specific differences of distribution were tested by chi2-tests. Results: Regardless of age or professional years, 99 % of the nurses evaluated that vaccinations are at least "partly necessary". Sufficient vaccination status was reported more often concerning tetanus (82 %) and HB (70 %) but less often regarding diphtheria (52 %), poliomyelitis (49 %), HA (43 %) and pertussis (42 %). With respect to some vaccinations, proportion of nurses not knowing their vaccination status was higher than 20 %. Conclusions: Despite the high vaccination acceptance, vaccination status among participating nurses was not sufficient. Implementation of vaccination measures targeting health care workers should be strengthened to reach higher vaccination coverages to prevent vaccination preventable infectious diseases among health care workers and patients in hospitals. PMID- 27239742 TI - Psychometric survey of nursing competences illustrated with nursing students and apprentices AB - Background: The term competences is discussed differently in various disciplines of science. Furthermore there is no international or discipline comprehensive accepted definition of this term. Problem: So far, there are few practical, reliable and valid measuring instruments for a survey of general nursing skills. This article describes the adaptation process of a measuring instrument for medical skills into one for nursing competences. Method: The measurement quality of the questionnaire was audited using a sample of two different courses of studies and regular nursing apprentices. Another research question focused whether the adapted questionnaire is able to detect a change of nursing skills. For the validation of reliability and validity data from the first point of measurement was used (n = 240). The data from the second point of measurement, which was conducted two years later (n = 163), were used to validate, whether the questionnaire is able to detect a change of nursing competences. Results/Conclusions: The results indicate that the adapted version of the questionnaire is reliable and valid. Also the questionnaire was able to detect significant, partly even strong, effects of change in nursing skills (d = 0,17 - 1,04). It was possible to adapt the questionnaire for the measurement of nursing competences. PMID- 27239740 TI - "Don't let the world become too small" - How patients with advanced cancer and their significant others cope with transitions during the last year of life. A qualitative study AB - Background: In the last year of life, persons with advanced cancer and their significant others are affected by several transitions. They perform psychological adjustment processes during transformation. This requires strategies for patients and their significant others. Research in German about this theme is missing. Aim: We explored the experiences with illness management during transitions in the last year of life of patients with advanced cancer and their significant others. Method: In this qualitative study, we conducted structured interviews with five dyads, consisting of persons with Karnofsky Index >= 60 % and life expectancy of six to twelve months as well as their significant others. To interpret the interviews, we used qualitative content analysis according to Mayring. Results: The main theme "Don't let the world become too small" expresses that limitations diminished the lifeworld and the participants struggled against this process. This is revealed in three categories: "Being shocked by diagnosis - realigning again", "Bearing limitations and loss - finding new ways in daily life", "Living in uncertainty - holding out together". Conclusions: Patients and significant others live in changing lifeworlds caused by transitions. Health care professionals should be attentive and may gain deeper knowledge about transitions. Further research in German-speaking contexts will help to improve nursing care and psychooncological interventions. PMID- 27239743 TI - Nursing management of sensory overload in psychiatry - development of a theoretical framework model AB - Background: The concept of "removal from stimuli" has already been examined by a Delphi-Study. However, some knowledge gaps remained open, which have now been further investigated. Aim: Examination of the concept "management of sensory overload in inpatient psychiatry" including its sub-concepts and specific measures. Method: Analysis of qualitative data about "removal from stimuli" by content analysis according to Mayring. Results: A theoretical description and definition of the concept could be achieved. In addition, sub-concepts (removal from stimuli, modulation of environmental factors, help somebody to help him /herself) could be identified, theoretical defined and complemented by possible specific measures. Conclusions: The conceptual descriptions provide a further step to raise awareness of professionals in the subject area. Furthermore, we created a theoretical basis for further empirical studies. PMID- 27239744 TI - Internal consistency and construct validity of the Quality of Life in Alzheimer's Disease (QoL-AD) proxy - a secondary data analysis AB - Background: The maintenance and promotion of Quality of Life (QoL) of people with dementia is a major outcome in intervention studies and health care. The Quality of Life Alzheimer's Disease (QoL-AD) is an internationally recommended QoL measurement also available in German language. Until now, only a few results on the psychometric properties of the German QoL-AD were available. Objective: Evaluation of internal consistency and construct validity of the QoL-AD proxy. Method: A principal component analysis (secondary data analysis) of the 13 QoL-AD items was carried out based on the total sample of 234 people with dementia from nine nursing homes in Germany. Subsequently, the internal consistency of the identified factors was examined using Cronbach's alpha. Results: Two factors physical and mental health and social network were determined. Both factors explain 53 % of the total variance. The stability of both factors was validated in two sensitivity analyses. The internal consistency is good for both factors with a Cronbach's alpha of 0.88 (physical and mental health) and 0.75 (social network). Conclusion: The QoL-AD proxy allows the assessment of two relevant health-related QoL domains of people with dementia. However, in future studies especially the inter-rater reliability of the QoL-AD proxy has to be examined. PMID- 27239745 TI - Effectiveness of non-pharmacological interventions to promote urinary continence in stroke survivors - a systematic literature review AB - Background: Around half of the people who survive a cerebrovascular insult are suffering from urinary incontinence. This is a predictor for functional outcomes and affects the quality of life negatively. Until now, it is not clear, which the optimal method of treatment is. A systematic review of 2008 showed an insufficient data situation and couldn't make a recommendation. Research question: Which non-pharmacological interventions are effective to promote urinary continence in adult persons who have suffered a cerebrovascular insult? Method: To answer the question a systematic literature review was performed. The literature search was conducted in the databases PubMed, CINAHL, CENTRAL and PsycInfo. The period from March 2007 to May 2015 was taken into account. Results: There were a total of six studies included which examined 732 persons. The following interventions were explored for their effectiveness: transcutaneous electrical nerve stimulation, urodynamic assessment with recommendation of bladder emptying method and interventions that consist of several components (e. g. toilet training). All studies showed a positive effect in at least one outcome. Conclusions: There is limited evidence for interventions to promote urinary continence in people suffering a cerebrovascular insult. An intervention consisting of assessment and individual adapted measures currently appear to be the best treatment method. PMID- 27239746 TI - Health-related quality of life, sense of coherence and leisure-time physical activity in women after an acute myocardial infarction. AB - AIMS AND OBJECTIVES: To examine the relationship between leisure-time physical activity, health-related quality of life and sense of coherence in women after an acute myocardial infarction, and further to investigate whether these aspects were associated with age. BACKGROUND: Physical activity and health-related quality of life are vital aspects for patients after an acute myocardial infarction. DESIGN: Cross-sectional. METHOD: All eligible women diagnosed with acute myocardial infarction received a postal questionnaire two to three months after hospital discharge, and 142 women were included. To measure health-related quality of life and sense of coherence, The MacNew Heart disease questionnaire and the Sense of coherence-13 scale was used. RESULTS: Respondents reporting at least one type of physical activity had significantly higher health-related quality of life as compared to respondents reporting no kind of physical activity. Respondents reporting physical activity for at least 30 minutes twice a week had significantly higher health-related quality of life scores than respondents being active less than twice a week. A weak association was found between physical activity level and sense of coherence. Reduction in physical activity after the acute myocardial infarction was associated with reduced health related quality of life and sense of coherence. Sense of coherence was significantly associated with age, as respondents 75 years and older had significantly higher scores than respondents younger than 75 years. CONCLUSIONS: Physical activity, even at a low level, is significantly associated with increased health-related quality of life and to some extent to sense of coherence. RELEVANCE TO CLINICAL PRACTICE: Tailoring women after an acute myocardial infarction about lifestyle changes must include knowledge about the benefits of leisure-time physical activity, and that even a small amount of activity is associated with a better health-related quality of life. The utmost important assignment is to motivate the women for regular physical activity in their leisure-time. Older women need special attention. PMID- 27239747 TI - Visualizing heterogeneity of photosynthetic properties of plant leaves with two photon fluorescence lifetime imaging microscopy. AB - Two-photon fluorescence lifetime imaging microscopy (FLIM) was used to analyse the distribution and properties of Photosystem I (PSI) and Photosystem II (PSII) in palisade and spongy chloroplasts of leaves from the C3 plant Arabidopsis thaliana and the C4 plant Miscanthus x giganteus. This was achieved by separating the time-resolved fluorescence of PSI and PSII in the leaf. It is found that the PSII antenna size is larger on the abaxial side of A. thaliana leaves, presumably because chloroplasts in the spongy mesophyll are "shaded" by the palisade cells. The number of chlorophylls in PSI on the adaxial side of the A. thaliana leaf is slightly higher. The C4 plant M. x giganteus contains both mesophyll and bundle sheath cells, which have a different PSI/PSII ratio. It is shown that the time resolved fluorescence of bundle sheath and mesophyll cells can be analysed separately. The relative number of chlorophylls, which belong to PSI (as compared to PSII) in the bundle sheath cells is at least 2.5 times higher than in mesophyll cells. FLIM is thus demonstrated to be a useful technique to study the PSI/PSII ratio and PSII antenna size in well-defined regions of plant leaves without having to isolate pigment-protein complexes. PMID- 27239748 TI - The emergence of reasoning by the disjunctive syllogism in early childhood. AB - Logical inference is often seen as an exclusively human and language-dependent ability, but several nonhuman animal species search in a manner that is consistent with a deductive inference, the disjunctive syllogism: when a reward is hidden in one of two cups, and one cup is shown to be empty, they will search for the reward in the other cup. In Experiment 1, we extended these results to toddlers, finding that 23-month-olds consistently approached the non-empty location. However, these results could reflect non-deductive approaches of simply avoiding the empty location, or of searching in any location that might contain the reward, rather than reasoning through the disjunctive syllogism to infer that the other location must contain the reward. Experiment 2 addressed these alternatives, finding evidence that 3- to 5-year-olds used the disjunctive syllogism, while 2.5-year-olds did not. This suggests that younger children may not easily deploy this logical inference, and that a non-deductive approach may be behind the successful performance of nonhuman animals and human infants. PMID- 27239749 TI - The format of children's mental images: Evidence from mental scanning. AB - This study examined the development and format of children's mental images. Children (4-, 5-, 6-7-, 8-9-, and 11-year-olds) and adults (N=282) viewed a map of a fictitious island containing various landmarks and two misleading signposts, indicating that some equidistant landmarks were different distances apart. Five year-olds already revealed the linear time-distance scanning effect, previously shown in adults (Experiments 1 and 2): They took longer to mentally scan their image of the island with longer distances between corresponding landmarks, indicating the depictive format of children's mental images. Unlike adults, their scanning times were not affected by misleading top-down distance information on the signposts until age 8 (Experiment 1) unless they were prompted to the difference from the outset (Experiment 2). Findings provide novel insights into the format of children's mental images in a mental scanning paradigm and show that children's mental images can be susceptible to top-down influences as are adults'. PMID- 27239750 TI - Cognitive mapping in mental time travel and mental space navigation. AB - The ability to imagine ourselves in the past, in the future or in different spatial locations suggests that the brain can generate cognitive maps that are independent of the experiential self in the here and now. Using three experiments, we asked to which extent Mental Time Travel (MTT; imagining the self in time) and Mental Space Navigation (MSN; imagining the self in space) shared similar cognitive operations. For this, participants judged the ordinality of real historical events in time and in space with respect to different mental perspectives: for instance, participants mentally projected themselves in Paris in nine years, and judged whether an event occurred before or after, or, east or west, of where they mentally stood. In all three experiments, symbolic distance effects in time and space dimensions were quantified using Reaction Times (RT) and Error Rates (ER). When self-projected, participants were slower and were less accurate (absolute distance effects); participants were also faster and more accurate when the spatial and temporal distances were further away from their mental viewpoint (relative distance effects). These effects show that MTT and MSN require egocentric mapping and that self-projection requires map transformations. Additionally, participants' performance was affected when self-projection was made in one dimension but judgements in another, revealing a competition between temporal and spatial mapping (Experiment 2 & 3). Altogether, our findings suggest that MTT and MSN are separately mapped although they require comparable allo- to ego-centric map conversion. PMID- 27239751 TI - From dirt to industrial applications: Pseudomonas putida as a Synthetic Biology chassis for hosting harsh biochemical reactions. AB - The soil bacterium Pseudomonas putida is endowed with a central carbon metabolic network capable of fulfilling high demands of reducing power. This situation arises from a unique metabolic architecture that encompasses the partial recycling of triose phosphates to hexose phosphates-the so-called EDEMP cycle. In this article, the value of P. putida as a bacterial chassis of choice for contemporary, industrially-oriented metabolic engineering is addressed. The biochemical properties that make this bacterium adequate for hosting biotransformations involving redox reactions as well as toxic compounds and intermediates are discussed. Finally, novel developments and open questions in the continuous quest for an optimal microbial cell factory are presented at the light of current and future needs in the area of biocatalysis. PMID- 27239753 TI - Avatars of desire and the question of presence: Virtual and transitional spaces meet their liminal edge - from Pygmalion to Spike Jonze's Her, and beyond.... PMID- 27239752 TI - Front blind spot crashes in Hong Kong. AB - In 2012-2014, our laboratory had investigated a total of 9 suspected front blind spot crashes, in which the medium and heavy goods vehicles pulled away from rest and rolled over the pedestrians, who were crossing immediately in front of the vehicles. The drivers alleged that they did not see any pedestrians through the windscreens or the front blind spot mirrors. Forensic assessment of the goods vehicles revealed the existence of front blind spot zones in 3 out of these 9 accident vehicles, which were attributed to the poor mirror adjustments or even the absence of a front blind spot mirror altogether. In view of this, a small survey was devised involving 20 randomly selected volunteers and their goods vehicles and 5 out of these vehicles had blind spots at the front. Additionally, a short questionnaire was conducted on these 20 professional lorry drivers and it was shown that most of them were not aware of the hazards of blind spots immediately in front of their vehicles, and many did not use the front blind spot mirrors properly. A simple procedure for quick measurements of the coverage of front blind spot mirrors using a coloured plastic mat with dimensional grids was also introduced and described in this paper. PMID- 27239754 TI - Dietary dried plum increases bone mass, suppresses proinflammatory cytokines and promotes attainment of peak bone mass in male mice. AB - Nutrition is an important determinant of bone health and attainment of peak bone mass. Diets containing dried plum (DP) have been shown to increase bone volume and strength. These effects may be linked to the immune system and DP-specific polyphenols. To better understand these relationships, we studied DP in skeletally mature (6-month-old) and growing (1- and 2-month-old) C57Bl/6 male mice. In adult mice, DP rapidly (<2 weeks) increased bone volume (+32%) and trabecular thickness (+24%). These changes were associated with decreased osteoclast surface (Oc.S/BS) and decreased serum CTX, a marker of bone resorption. The reduction in Oc.S/BS was associated with a reduction in the osteoclast precursor pool. Osteoblast surface (Ob.S/BS) and bone formation rate were also decreased suggesting that the gain in bone in adult mice is a consequence of diminished bone resorption and formation, but resorption is reduced more than formation. The effects of DP on bone were accompanied by a decline in interleukins, TNF and MCP-1, suggesting that DP is acting in part through the immune system to suppress inflammatory activity and reduce the size of the osteoclast precursor pool. Feeding DP was accompanied by an increase in plasma phenolics, some of which have been shown to stimulate bone accrual. In growing and young adult mice DP at levels as low as 5% of diet (w/w) increased bone volume. At higher levels (DP 25%), bone volume was increased by as much as 94%. These data demonstrate that DP feeding dramatically increases peak bone mass during growth. PMID- 27239755 TI - Human apolipoprotein E allele and docosahexaenoic acid intake modulate peripheral cholesterol homeostasis in mice. AB - Carrying at least one apolipoprotein E epsilon4 allele (E4+) is the main genetic risk factor for Alzheimer's disease (AD). Epidemiological studies support that consuming fatty fish rich in docosahexaenoic acid (DHA; 22:6omega3) is protective against development of AD. However, this protective effect seems not to hold in E4+. The involvement of APOE genotype on the relationship between DHA intake and cognitive decline could be mediated through cholesterol. Many studies show a link between cholesterol metabolism and AD progression. In this study, we investigated whether cholesterol metabolism is improved in E3+ and E4+ mice consuming a diet rich in DHA. Plasma cholesterol was 36% lower in E4+ mice compared to E3+ mice fed the control diet (P=.02), and in the liver, there was a significant genotype effect where cholesterol levels were 18% lower in E4+ mice than E3+ mice. The low density lipoprotein receptor was overexpressed in the liver of E4+ mice. Plasma cholesterol levels were 33% lower after the DHA diet (P=.02) in E3+ mice only, and there was a significant diet effect where cholesterol level was 67% lower in the liver of mice fed DHA. Mice fed the DHA diet also had 62% less lipolysis stimulated lipoprotein receptor expression in the liver compared to mice fed the control diet (P<.0001), but there was no genotype effect. These findings suggest that plasma and liver cholesterol homeostasis and the receptors regulating uptake of cholesterol in the liver are modulated differently and independently by APOE allele and DHA intake. PMID- 27239756 TI - Higher insulin sensitivity in EDL muscle of rats fed a low-protein, high carbohydrate diet inhibits the caspase-3 and ubiquitin-proteasome proteolytic systems but does not increase protein synthesis. AB - Compared with the extensor digitorum longus (EDL) muscle of control rats (C), the EDL muscle of rats fed a low-protein, high-carbohydrate diet (LPHC) showed a 36% reduction in mass. Muscle mass is determined by the balance between protein synthesis and proteolysis; thus, the aim of this work was to evaluate the components involved in these processes. Compared with the muscle from C rats, the EDL muscle from LPHC diet-fed rats showed a reduction (34%) in the in vitro basal protein synthesis and a 22% reduction in the in vitro basal proteolysis suggesting that the reduction in the mass can be associated with a change in the rate of the two processes. Soon after euthanasia, in the EDL muscles of the rats fed the LPHC diet for 15days, the activity of caspase-3 and that of components of the ubiquitin-proteasome system (atrogin-1 content and chymotrypsin-like activity) were decreased. The phosphorylation of p70(S6K) and 4E-BP1, proteins involved in protein synthesis, was also decreased. We observed an increase in the insulin-stimulated protein content of p-Akt. Thus, the higher insulin sensitivity in the EDL muscle of LPHC rats seemed to contribute to the lower proteolysis in LPHC rats. However, even with the higher insulin sensitivity, the reduction in p E4-BP1 and p70(S6K) indicates a reduction in protein synthesis, showing that factors other than insulin can have a greater effect on the control of protein synthesis. PMID- 27239758 TI - In vitro metabolism of l-corydalmine, a potent analgesic drug, in human, cynomolgus monkey, beagle dog, rat and mouse liver microsomes. AB - l-Corydalmine (l-CDL) was under development as an oral analgesic agent, exhibiting potent analgesic activity in preclinical models. The objective of this study was to compare metabolic profiles of l-CDL in liver microsomes from mouse, rat, monkey, dog and human. Six metabolites (M1-M6) were identified using LC Q/TOF in liver microsomes from the five species. The metabolism of l-CDL included O-demethylation (M1-3) and hydroxylation (M4-6). The desmethyl metabolites were the major ones among the five species, which accounted for more than 84%. Data from chemical inhibition in human liver microsomes (HLM) and human recombinant CYP450s demonstrated that CYP2D6 exhibited strong catalytic activity towards M1 and M2 formations, while CYP2C9 and CYP2C19 also catalyzed M2 formation. Formations of M3 and hydroxyl metabolites (M4 and M5) were mainly catalyzed by CYP3A4. Further studies showed that M1 and M2 were main metabolites in HLM. The kinetics of M1 and M2 formations in HLM and recombinant CYP450s were also investigated. The results showed that M1 and M2 formations in HLM and recombinant CYP2D6 characterized biphasic kinetics, whereas sigmoid Vmax model was better used to fit M2 formation by recombinant CYP2C9 and CYP2C19. The contributions of CYP2D6 to M1 and M2 formations in HLM were estimated to be 75.3% and 50.7%, respectively. However, the contributions of CYP2C9 and CYP2C19 to M2 formation were only 5.0% and 4.1%, respectively. All these data indicated that M1 and M2 were main metabolites in HLM, and CYP2D6 was the primary enzyme responsible for their formations. PMID- 27239757 TI - The Organocatalytic Approach to Enantiopure 2H- and 3H-Pyrroles: Inhibitors of the Hedgehog Signaling Pathway. AB - A divergent approach to enantioenriched 2H- and 3H-pyrroles catalyzed by a spirocyclic phosphoric acid is reported that makes use of a Fischer-type indolization and a [1,5]-alkyl shift. Catalyzed by the chiral phosphoric acid STRIP, good to excellent yields and enantioselectivities could be obtained. Remarkably, biological evaluation reveals one of these novel 2H-pyrroles to be a potent but nontoxic inhibitor of the Hedgehog signaling pathway by binding to the Smoothened protein. PMID- 27239759 TI - Are fluorine-rich pharmaceuticals lost by partition into fluorous phases? AB - The recently developed technology of droplet microfluidics has demonstrated great potential for many applications such as biochemical assay, high throughput screening, cell culture, directed evolution, and chemical synthesis. Intrigued by its capabilities for miniaturization, flexible manipulation, rapid reagent mixing and high throughput experimentation and analysis, the pharmaceutical industry has begun to investigate droplet microfluidic implementation in medicinal and process chemistry. Segmented by an immiscible secondary phase, usually perfluorinated oil, aqueous or organic droplets serve as individual micro-reactors without suffering cross-contamination. As many drug molecules contain fluorines, it is necessary to investigate whether such compounds will be preferentially extracted into the fluorous phase via fluorophilic solvation, which could lead to erroneous analytical results. In this work, we chose drugs with up to 10 fluorines to probe their partition into perfluorodecalin (PFD) from a variety of organic solvents. A fast and straightforward MISER (Multiple Injections in a Single Experimental Run) LC-MS method was applied to measure the loss of drug after mixing with PFD. We found that no significant partition occurred, with the concentration of drugs in the 'experimental' group measured as +/-10% of the 'control' group. The RSD% of multiple injections is <5%. The finding was further validated by the conventional LC-MS approach. PMID- 27239760 TI - PD-1(+) and follicular helper T cells are responsible for persistent HIV-1 transcription in treated aviremic individuals. AB - The mechanisms responsible for the persistence of HIV-1 after many years of suppressive antiretroviral therapy (ART) have been only partially elucidated. Most of the studies investigating HIV-1 persistence have been performed with blood, although it is well known that germinal centers (GCs) within lymph nodes (LNs) serve as primary sites for HIV-1 replication. We sought to identify the memory CD4 T cell populations in blood and LNs that are responsible for the production of replication-competent and infectious HIV-1, as well as for active and persistent virus transcription in ART-treated (for 1.5-14.0 years), aviremic (<50 HIV RNA copies/ml) HIV-infected individuals. We demonstrate that LN CD4 T cells that express programmed cell death 1 (PDCD1; also known as PD-1), which are composed of about 65% T follicular helper cells as defined by the expression of the cell surface receptors CXCR5 and PD-1, are the major source of replication competent HIV-1 and of infectious virus, as compared to any other (CXCR5(-)PD-1( ) and CXCR5(+)PD-1(-)) blood or LN memory CD4 T cell populations. LN PD-1(+) cells accounted for 46% and 96% of the total pools of memory CD4 T cells containing inducible replication-competent or infectious virus, respectively. Notably, higher levels of cell-associated HIV-1 RNA were present in LN PD-1(+) cells after long-term (up to 12 years) ART than in other memory CD4 T cell subpopulations. These results indicate that LN PD-1(+) cells are the major CD4 T cell compartment in the blood and LNs for the production of replication-competent and infectious HIV-1, and for active and persistent virus transcription in long term-ART-treated aviremic individuals. Thus, these cells may represent a major obstacle to finding a functional cure for HIV-1 infection. PMID- 27239762 TI - Unmet needs, community integration and employment status four years after subarachnoid haemorrhage. AB - OBJECTIVE: To assess long-term unmet needs in relation to community integration and employment status 4 years after subarachnoid haemorrhage. DESIGN: Four-year follow-up of a prospective cohort. PATIENTS: Sixty-seven patients with subarachnoid haemorrhage. METHODS: Employment status was assessed and the Community Integration Questionnaire-Revised and Southampton Needs Assessment Questionnaire were used. RESULTS: The mean age of subarachnoid haemorrhage onset was 52.5 years (standard deviation (SD) 10.7 years) and 39% of subjects were male. Four years after subarachnoid haemorrhage, 23.9% of subjects had symptoms of depression, 43.3% had mild cognitive impairment, 67.2% were unemployed and 67.2% had one or more unmet needs. Most subjects reported a need for information (59.7%). Unemployed patients had more unmet needs than employed patients (p = 0.034), but no independent relationship was found. The community integration score was moderate (mean 15.1; SD 4.4). A higher level of unmet needs was independently related to a lower level of community integration (B = -0.25; p = 0.018), adjusted for age and comorbidity. CONCLUSION: A large proportion of patients have unmet needs and are unemployed 4 years after subarachnoid haemorrhage. There is an inverse relationship between unmet needs and community integration. Future research should investigate whether dealing with information needs during rehabilitation contributes to better community integration in these patients. PMID- 27239763 TI - Hepatocyte mitochondrial DNA released in microparticles and toll-like receptor 9 activation: A link between lipotoxicity and inflammation during nonalcoholic steatohepatitis. PMID- 27239764 TI - [Forensic medical characteristic of the damages to the skin and clothes by plastic knives]. AB - The present study was designed to characterize the group and individual properties of plastic knives with special reference to the classification of the damages inflicted to the human skin and textile fabric by these weapons including multiblade ones. It was shown in experiment that repeated impacts through a barrier (textile fabric) lead to a partial destruction of the blade. PMID- 27239761 TI - Adjuvant-dependent innate and adaptive immune signatures of risk of SIVmac251 acquisition. AB - A recombinant vaccine containing Aventis Pasteur's canarypox vector (ALVAC)-HIV and gp120 alum decreased the risk of HIV acquisition in the RV144 vaccine trial. The substitution of alum with the more immunogenic MF59 adjuvant is under consideration for the next efficacy human trial. We found here that an ALVAC simian immunodeficiency virus (SIV) and gp120 alum (ALVAC-SIV + gp120) equivalent vaccine, but not an ALVAC-SIV + gp120 MF59 vaccine, was efficacious in delaying the onset of SIVmac251 in rhesus macaques, despite the higher immunogenicity of the latter adjuvant. Vaccine efficacy was associated with alum-induced, but not with MF59-induced, envelope (Env)-dependent mucosal innate lymphoid cells (ILCs) that produce interleukin (IL)-17, as well as with mucosal IgG to the gp120 variable region 2 (V2) and the expression of 12 genes, ten of which are part of the RAS pathway. The association between RAS activation and vaccine efficacy was also observed in an independent efficacious SIV-vaccine approach. Whether RAS activation, mucosal ILCs and antibodies to V2 are also important hallmarks of HIV vaccine efficacy in humans will require further studies. PMID- 27239765 TI - [The morphofunctional features of the heart associated with acute morphine poisoning during the period of chronic drug intoxication]. AB - The objective of the present study was to improve forensic medical diagnostics of the cases of death associated with morphine poisoning based on the investigation into the biochemical changes in blood and pericardial fluid as well as morphological changes in the myocardial structures. The studies were carried out with the use of thin-layer chromatography, colorimetric and morphological methods including hematoxylin and eosin, Lee's methylene blue, and van Gieson's picrofuscin staining. These techniques were supplemented by light and polarization microscopy. The study has demonstrated the presence of morphine in 99.16% of the blood and pericardial samples obtained in the cases of poisoning. The comparison of the results of biochemical and pathomorphological studies of the myocardium made it possible to evaluate the functional and morphological conditions of the heart in the case of acute morphine poisoning during the period of chronic drug intoxication. PMID- 27239766 TI - [On the possibility to determine genetic identity of the tissues with malignant tumours imbedded in paraffin blocks]. AB - The results of analysis of the literature data were used to develop the forensic medical criteria for the assessment of the suitability of paraffin blocks containing the imbedded malignant tumours for the genetic identification of the tissues. The forensic medical criteria and the algorithm for the preliminary characteristic of the material of interest were proposed to avoid the potential errors. It is not recommended to use gastrointestinal carcinomas, breast tumours, and poorly differentiated ovarian tumours. Also unsuitable is the material formerly exposed to radio- and chemotherapeutic agents or paraffin blocks stored during more than 5-7 years. In the doubtful cases, immunohistochemical studies must be carried out to confirm microsatellite instability. Moreover, the tumour genotype and DNA composition from the patients' blood should be confirmed. PMID- 27239767 TI - [The specific age-related palmometric features of an adult subject]. AB - In connection with the variability and as a consequence of the poor diagnostic value of the external (planimetric) parameters of the palm traces, the new system of absolute and relative dimensional attributes based on the stable palmoglyphic reference points is considered. The purpose of the present study was the search for the new biological markers of biological age. The material for the study consisted of the palm prints obtained from 180 men and 120 women of the Caucasoid stock at the age from 16 to 80 years. The use of the descriptive statistics methods yielded the basic statistical characteristics of the traits being investigated and revealed the limits of their variability in the groups of men and women belonging to the age groups from 16 to 29 and from 30 to 80 years. The method of threshold values made it possible to identify 13 attributes the excess of which allows, with the probability of no less than 0.95, to perform diagnostics of the age group of an unknown subject. PMID- 27239768 TI - [The evaluation of concentration of certain NSAID in the procedure of screening medicinal and narcotic substances in blood]. AB - We have undertaken the metrological assessment of the method for the quantitative determination of a number of non-steroidal anti-inflammatory drugs (NSAID) including ibuprofen, ketorolac, diclofenac, indomethacin, naproxen, and ketoprofen with the use of gas chromatography mass spectrometry in the model blood samples in the framework of the screening survey of medicinal and narcotic substances. The method was evaluated in terms of the following characteristics: specificity, linearity, correctness, precision (reproducibility), and intra laboratory precision. The proposed method can be applied for the quantitative evaluation of indomethacin, ketoprofen, and naproxen content as well as for the preliminary quantitative determination of ibuprofen and diclofenac in the framework of the chemico-toxicological and forensic chemical analysis. The method can be employed for the quantitative determination of ketorolac from such characteristics as "linearity" and "reproducibility". PMID- 27239769 TI - [Peculiarities of detection of 4-nitro-3-(trifluoromethyl)-aniline in the biological material]. AB - The objective of the present work was to study peculiarities of detection of 4 nitro-3-(trifluoromethyl)-aniline in the biological material with the use of TLC, GC-MS, and electron spectrophotometry. We have proposed the rationale for the application of acetone as an insulating agent for the extraction of 4-nitro-3 (trifluoromethyl)-aniline from the cadaveric hepatic tissue and biological fluids. It was shown that this compound is possible to separate from endogenous biomaterials on the silicagel L column (40/100 mcm). The results of the quantitative evaluation of different amounts of 4-nitro-3-(trifluoromethyl) aniline in the cadaveric hepatic tissue, blood, plasma, and urine are presented. The proposed method makes it possible to determine a minimum of 0.12 mg of 4 nitro-3-(trifluoromethyl)-aniline in 100 g of the biological material (cadaveric hepatic tissue), 0.09 mg in 100 g of blood, 0.06 mg and 0.05 mg in 100 u of plasma and urine respectively. PMID- 27239770 TI - [Determining the shooting location by three-dimensional modeling]. AB - The objective of the present study was to improve the method for the calculation and graphical sighting with the use of the modern program products for three dimensional visualization. PMID- 27239771 TI - [Determining the car driver's position at the moment of the frontal crash with a moving KAMAZ truck]. AB - This article is designed to report the results of the comprehensive forensic medical and autotechnical expertise for determining the positions of the driver and the first seat passenger of the GAS-3110 car at the moment of the frontal crash with a KAMAZ-5312 truck. The comparative analysis of the injuries in two subjects one of whom died as a result of the given accident made it possible to conclude that he had occupied the driver's seat in the car. The differential diagnosis was based on the peculiarities of the injuries to the upper extremities with the predominance of the most severe wounds at the right side of the body. Also taken into consideration were the specific conditions of the given frontal collision, design of the GAS-3110 passenger compartment, winter season, night time, and possible neglect of the passive safety means, etc. PMID- 27239772 TI - [Establishing the fact of ricochet of a firearm projectile]. PMID- 27239774 TI - The effect of physical exhaustion on gait stability in young and older individuals. AB - Fatigue directly affects key features of the sensorimotor system which disorganizes voluntary control of movement accuracy. Local dynamic stability of walking is considered a sensitive measure for neuromuscular performance. To gain greater insight in the role of fatigue in motor behaviour in older and young adults during walking, the current experiment analyses gait patterns of healthy young but maximal fatigued individuals and gait patterns in submaximal fatigued older adults. Ten young and 18 older subjects performed a bicycle incremental exercise test on a cycle ergometer. In young subjects, the incremental test was performed until total physical exhaustion. In older subjects, the test was performed until submaximal fatigue. Prior to and after the test, the participants walked for 2.5min on a treadmill. Based on linear acceleration data of the trunk, local dynamic stability was assessed. Student's t-test was used to check if differences are statistically significant. In young individuals, we found a significant decrease in the finite-time maximal Lyapunov exponents between unfatigued walking and maximal fatigued walking. In older participants, significant increases in the finite-time maximal Lyapunov between unfatigued walking and submaximal fatigued walking were observed. The results indicate that (1) young and sporty subjects become more stable after having passed a maximum cardiopulmonary exercise test on a cycle ergometer while (2) older individuals walk less locally stable in a submaximal fatigued condition. Older cohorts might show a higher fall risk when they are physically fatigued. PMID- 27239773 TI - Biomechanical balance response during induced falls under dual task conditions in people with knee osteoarthritis. AB - OBJECTIVE: People with knee osteoarthritis (OA) are at twice the risk of falling compared to older people without knee OA, however the mechanism for this is poorly understood. This study investigated the biomechanical response of the trunk and lower limb joints during a forward induced fall under different task conditions in people with and without knee OA. METHOD: Twenty-four participants with OA (68.6+/-6.2 years) and 15 asymptomatic controls (72.4+/-4.8 years) participated in the study. Forward fall was induced by releasing participants from a static forward leaning position. Participants were required to recover balance during three conditions: normal, physical (obstacle clearance) and cognitive dual tasks (counting backwards). Spatiotemporal parameters, lower limb joint kinematics and kinetics of the recovery limb were compared between the two groups and across the three task conditions. RESULTS: The OA group demonstrated slower spatio-temporal characteristics and reduced hip and knee flexion angles, joint moments/powers and reduced muscle negative work at the knee and ankle (p<0.05). Cognitive dual task resulted in reduced centre of mass velocity and step length (p=0.03) compared to the physical dual task condition. Reduced knee (p=0.02) and hip joint powers (p=0.03) were demonstrated in the OA group in the physical task condition. CONCLUSION: When simulating a forward fall, participants with OA demonstrated difficulty in absorbing the impact and slowing down the forward momentum of the body during a recovery step. Moreover, poor dynamic postural control was demonstrated as task complexity increased. PMID- 27239775 TI - Selective serotonin reuptake inhibitor (SSRI) use during pregnancy and risk of preterm birth: a systematic review and meta-analysis. AB - BACKGROUND: Depression is a prevalent condition in pregnancy affecting about 10% of women. Maternal depression has been associated with an increase in preterm births (PTB), low birthweight and fetal growth restriction, and postnatal complications. Available treatments for depressive disorders are psychotherapeutic interventions and antidepressant medications including selective serotonin inhibitors (SSRIs). SSRI use during pregnancy has been associated with several fetal and neonatal complications; so far, however, the risk of PTB in women using SSRIs during pregnancy is still a subject of debate. OBJECTIVE: To evaluate the risk of preterm birth (PTB) in cases of exposure to SSRIs during pregnancy. SEARCH STRATEGY: Electronic databases (MEDLINE, Scopus, ClinicalTrials.gov, the PROSPERO International Prospective Register of Systematic Reviews, EMBASE and the Cochrane Central Register of Controlled Trials) were searched from their inception until May 2015 with the use of a combination of the following text words 'depression', 'pregnancy', 'exposure', 'antidepressant', 'SSRI', 'selective serotonin reuptake inhibitor', 'preterm birth', 'small for gestational age' and 'prematurity'. SELECTION CRITERIA: We included studies evaluating the effect of SSRIs exposure in utero and pregnancy outcomes. All cohort and case-control studies were eligible to be included if they reported the incidence of PTB after any exposure to SSRIs and had a comparison group of unexposed pregnant women. Studies without a control group were excluded. DATA COLLECTION AND ANALYSIS: The primary outcome was the incidence of PTB <37 weeks. Subgroup analysis of studies in which controls were defined as women with depression but without SSRI exposure during pregnancy were planned. MAIN RESULTS: Eight studies (1 237 669 women) were included: 93 982 in the exposure group and 1 143 687 in the control group. After adjusting for confounders, the incidence of PTB was significantly higher in the group of women treated with SSRIs compared with controls (i.e. both women with depression but without SSRI exposure and women without depression) (adjusted OR (aOR) 1.24, 95% CI 1.09-1.41). In the subgroup analysis of studies in which controls were defined as women with depression but without SSRI exposure during pregnancy, an increased risk of PTB (6.8 versus 5.8%; OR 1.17, 95% CI 1.10-1.25) in the SSRI group was found compared with controls (i.e. depressed women treated with psychotherapy alone). CONCLUSIONS: Women who received SSRIs during pregnancy had a significantly higher risk of developing PTB compared with controls. This higher risk remained significant even when comparing depressed women on SSRI with women not on SSRI. TWEETABLE ABSTRACT: Selective serotonin reuptake inhibitors may be associated with preterm birth. PMID- 27239776 TI - Biochemical and toxicological effects of organic (herbicide Primextra((r)) Gold TZ) and inorganic (copper) compounds on zooplankton and phytoplankton species. AB - In Europe, mainly in the Mediterranean region, an intensive usage of pesticides was recorded during the past 30 years. According to information from agricultural cooperatives of the Mondego valley (Figueira da Foz, Portugal), Primextra((r)) Gold TZ is the most used herbicide in corn crop fields and one of the 20 best selling herbicides in Portugal. Copper is mainly used in pesticide formulations. This study aims to determine the ecotoxicological and biochemical (namely fatty acid profiles) effects of the herbicide Primextra((r)) Gold TZ and the metal copper on marine plankton. The organisms used in this study are three planktonic species: the marine diatom Thalassiosira weissflogii, the estuarine copepod Acartia tonsa and nauplii of the marine brine shrimp Artemia franciscana. Fatty acids (FAs) are one of the most important molecules transferred across the plant animal interface in aquatic food webs and can be used as good indicators of stress. The conducted lab incubations show that T. weissflogii is the most sensitive species to the herbicide followed by A. tonsa (EC50=0.0078mg/L and EC50=0.925mg/L, respectively), whereas the copepod was the most sensitive species to the metal followed by T. weissflogii (EC50=0.234mg/L and EC50=0.383mg/L, respectively). A. franciscana was the most tolerant organism both to the herbicide and to the metal (EC50=20.35mg/L and EC50=18.93mg/L, respectively). Changes in the FA profiles of primary producer and primary consumers were observed, with the increase of saturated FA and decrease of unsaturated FA contents, especially of highly unsaturated FAs that can be obtained mainly from food and therefore are referred to as 'essential FA'. The study suggests that discharges of Primextra((r)) Gold TZ or other pesticides mainly composed by copper may be a threat to plankton populations causing changes in the FA contents and thus in their nutritive value, with severe repercussions for higher trophic levels and thus the entire food web. PMID- 27239777 TI - Heritable oxidative phosphorylation differences in a pollutant resistant Fundulus heteroclitus population. AB - Populations can adapt to stress including recent anthropogenic pollution. Our published data suggests heritable differences in hepatocyte oxidative phosphorylation (OxPhos) metabolism in field-caught killifish (Fundulus heteroclitus) from the highly polluted Elizabeth River, VA, USA, relative to fish from a nearby, relatively unpolluted reference site in King's Creek VA. Consistent with other studies showing that Elizabeth River killifish are resistant to some of the toxic effects of certain contaminants, OxPhos measurements in hepatocytes from field-caught King's Creek but not field-caught Elizabeth River killifish were altered by acute benzo [a] pyrene exposures. To more definitively test whether the enhanced OxPhos metabolism and toxicity resistance are heritable, we measured OxPhos metabolism in a laboratory-reared F3 generation from the Elizabeth River population versus a laboratory-reared F1 generation from the King's Creek population and compared these results to previous data from the field-caught fish. The F3 Elizabeth River fish compared to F1 King's Creek fish had significantly higher State 3 respiration (routine metabolism) and complex II activity, and significantly lower complex I activity. The consistently higher routine metabolism in the F3 and field-caught Elizabeth River fish versus F1 and field-caught King's Creek fish implies a heritable change in OxPhos function. The observation that LEAK, E-State, Complex I and Complex II were different in laboratory bred versus field-caught fish suggests that different physiological mechanisms produce the enhanced OxPhos differences. Finally, similar to field-caught Elizabeth River fish, acute benzo [a] pyrene exposure did not affect OxPhos function of the laboratory-reared F3 generation, supporting the heritability of the toxicity resistance. Overall, these results suggest that the Elizabeth River population has evolved genetic changes in physiological homeostasis that enhance routine metabolism, and we speculate that these genetic changes interact with environmental factors altering the physiological mechanisms (e.g., alter LEAK, Complex I, and electron transfer system capacity) used to achieve this enhanced metabolism. PMID- 27239778 TI - General Self-Template Synthesis of Transition-Metal Oxide and Chalcogenide Mesoporous Nanotubes with Enhanced Electrochemical Performances. AB - The development of a general strategy for synthesizing hierarchical porous transition-metal oxide and chalcogenide mesoporous nanotubes, is still highly challenging. Herein we present a facile self-template strategy to synthesize Co3 O4 mesoporous nanotubes with outstanding performances in both the electrocatalytic oxygen-evolution reaction (OER) and Li-ion battery via the thermal-oxidation-induced transformation of cheap and easily-prepared Co Asp(cobalt-aspartic acid) nanowires. The initially formed thin layers on the precursor surfaces, oxygen-induced outward diffusion of interior precursors, the gas release of organic oxidation, and subsequent Kirkendall effect are important for the appearance of the mesoporous nanotubes. This self-template strategy of low-cost precursors is found to be a versatile method to prepare other functional mesoporous nanotubes of transition-metal oxides and chalcogenides, such as NiO, NiCo2 O4 , Mn5 O8 , CoS2 and CoSe2 . PMID- 27239780 TI - Triptolide Inhibits Invasion and Tumorigenesis of Hepatocellular Carcinoma MHCC 97H Cells Through NF-kappaB Signaling. AB - BACKGROUND We investigated whether the plant-derived agent triptolide (TPL) could effectively inhibit the growth and invasion of human hepatocellular carcinoma (HCC) cells. MATERIAL AND METHODS MHCC-97H cells were treated with various concentration of TPL for various times. To detect the effect of NF-kappaB on TPL induced signal pathways, MHCC-97H cells were transfected with p65 siRNA or p65 cDNA, then treated with TPL. We detected cell survival and apoptosis by MTT, soft agar colony formation assay, flow cytometry, and TUNEL assay. Cell migration and invasion was determined by Matrigel invasion and a wound-healing assay. NF-kappaB activity was detected by electrophoretic mobility shift assay (EMSA); MMP-9 activity was detected by ELISA. Western blot and real-time PCR (RT-PCR) assays were used to detect p65 and MMP-9 protein and mRNA expression. A subcutaneously implanted tumor model of MHCC-97H cells in nude mice was used to assess the effects of TPL on tumorigenesis in vivo. RESULTS We showed that TPL treatment significantly suppressed growth and induced apoptosis of MHCC-97H cells in a dose and time-dependent manner in vitro. Furthermore, TPL treatment inhibited invasion in vitro and inhibited the growth and lung metastasis of MHCC-97H cells in vivo. NF-kappaB and MMP-9 were inactivated with TPL treatment. Overexpression of p65 restored MMP-9 activity and inhibited the TPL anti-tumor effect on MHCC 97H cells. Knockdown of p65 blocked MMP-9 activation and enhanced TPL-induced cell apoptosis and survival inhibition, and TPL inhibition of migration and invasion in vitro. CONCLUSIONS TPL treatment inhibited MHCC-97H cell growth, invasion, and metastasis in vitro and vivo, suggesting that TPL could be developed as a potential therapeutic agent for the treatment of HCC. PMID- 27239781 TI - Infinite Polyiodide Chains in the Pyrroloperylene-Iodine Complex: Insights into the Starch-Iodine and Perylene-Iodine Complexes. AB - We report the preparation and X-ray crystallographic characterization of the first crystalline homoatomic polymer chain, which is part of a semiconducting pyrroloperylene-iodine complex. The crystal structure contains infinite polyiodide Iinfinity (delta-) . Interestingly, the structure of iodine within the insoluble, blue starch-iodine complex has long remained elusive, but has been speculated as having infinite chains of iodine. Close similarities in the low wavenumber Raman spectra of the title compound and starch-iodine point to such infinite polyiodide chains in the latter as well. PMID- 27239779 TI - Pathogenesis and neuroimaging of cerebral large and small vessel disease in type 2 diabetes: A possible link between cerebral and retinal microvascular abnormalities. AB - Diabetes patients have more than double the risk of ischemic stroke compared with non-diabetic individuals, and its neuroimaging characteristics have important clinical implications. To understand the pathophysiology of ischemic stroke in diabetes, it is important to focus not only on the stroke subtype, but also on the size and location of the occlusive vessels. Specifically, ischemic stroke in diabetes patients might be attributed to both large and small vessels, and intracranial internal carotid artery disease and small infarcts of the posterior circulation often occur. An additional feature is that asymptomatic lacunar infarctions are often seen in the basal ganglia and brain stem on brain magnetic resonance imaging. In particular, cerebral small vessel disease (SVD), including lacunar infarctions, white matter lesions and cerebral microbleeds, has been shown to be associated not only with stroke incidence, but also with the development and progression of dementia and diabetic microangiopathy. However, the pathogenesis of cerebral SVD is not fully understood. In addition, data on the association between neuroimaging findings of the cerebral SVD and diabetes are limited. Recently, the clinical importance of the link between cerebral SVD and retinal microvascular abnormalities has been a topic of considerable interest. Several clinical studies have shown that retinal microvascular abnormalities are closely related to cerebral SVD, suggesting that retinal microvascular abnormalities might be pathophysiologically linked to ischemic cerebral SVD. We review the literature relating to the pathophysiology and neuroimaging of cerebrovascular disease in diabetes, and discuss the problems based on the concept of cerebral large and small vessel disease. PMID- 27239782 TI - Prevalence of germline mutations in the spindle assembly checkpoint gene BUB1B in individuals with early-onset colorectal cancer. AB - Germline mutations in BUB1B, encoding BUBR1, one of the crucial components of the spindle assembly checkpoint (SAC), have been shown to cause variable phenotypes, including the recessive mosaic variegated aneuploidy (MVA) syndrome, which predisposes to cancer. Reduced levels of the wild-type BUBR1 protein have been linked to the development of gastrointestinal neoplasms. To determine whether mutations in BUB1B are enriched in individuals with colorectal cancer (CRC), we performed amplicon-based targeted next-generation sequencing of BUB1B on germline DNA of 192 individuals with early-onset CRC (<=50 years). None of the individuals was found to be homozygous or compound heterozygous for mutations in BUB1B. However, we did identify two rare heterozygous variants, p.Glu390del and p.Cys945Tyr, in patients who developed CRC at the ages of 41 and 43 years, respectively. Both variants were shown not to affect BUBR1 protein expression levels and protein localization. Since the p.Glu390del variant is located in the BUB3-binding domain, we also performed immunoprecipitation to examine whether this variant affects the binding of BUB1 or BUB3 to BUBR1 but, compared to wild type BUBR1, no difference was observed. Our data suggest that mutations in BUB1B do not occur frequently in the germline of individuals with CRC and that BUB1B unlikely plays a major role in the predisposition to early-onset CRC. Whether carriers of pathogenic BUB1B mutations, such as the parents of MVA syndrome patients, have an increased risk for cancer remains of interest, as studies in mice have suggested that haploinsufficiency of BUB1B may cause an increase in carcinogen-induced tumors. (c) 2016 Wiley Periodicals, Inc. PMID- 27239783 TI - Screening and identification of hepatotoxic component in Evodia rutaecarpa based on spectrum-effect relationship and UPLC-Q-TOFMS. AB - Evodia rutaecarpa (E. rutaecarpa) has been used to treat aches, vomiting and dysentery in traditional Chinese medicine. However, as a mildly toxic herb its toxic components have not been elucidated. An attempt was made to illuminate the hepatotoxic constituents of E. rutaecarpa. The 50% ethanol extracts of E. rutaecarpa from 19 different sources were used to establish UPLC fingerprints and administered to mice at a dose of 35 g/kg (crude medicine weight/mouse weight) once daily for 14 days. Serum levels of alanine transaminase, aspartate aminotransferase and liver coefficient were used as indices of liver injury. Additionally, the characteristic peaks of 19 fingerprints were identified. Spectrum-effect relationships between fingerprints and hepatotoxic indicators were analyzed using bivariate correlation analysis (BCA). The UPLC fingerprints were established and a total of 28 main compounds were identified. Because of the inherent variations in chemical compositions, the liver injury levels were different among the E. rutaecarpa samples from 19 sites of production. BCA results indicated that compounds dihydrorutaecarpine, 6-acetoxy-5-epilimonin, goshuyuamide I, 1-methyl-2-[(Z)-5-undecenyl]-4(1H)-quinolone, 1-methyl-2-[(4Z,7Z) 4,7-tridecadienyl]-4(1H)-quinolone, evocarpine and 1-methyl-2-[(6Z,9Z)-6,9 pentadecadienyl]-4(1H)-quinolone were tentatively determined as the primary hepatotoxic components. The present study provides a valuable method for the discovery of hepatotoxic constituents by combination of fingerprints and hepatotoxicity index. PMID- 27239784 TI - Microtubule-dependent changes in morphology and localization of chloride transport proteins in gill mitochondria-rich cells of the tilapia, Oreochromis mossambicus. AB - The tilapia (Oreochromis mossambicus) is a euryhaline fish exhibiting adaptive changes in cell size, phenotype, and ionoregulatory functions upon salinity challenge. Na(+) /Cl(-) cotransporter (NCC) and Na(+) /K(+) /2Cl(-) cotransporter (NKCC) are localized in the apical and basolateral membranes of mitochondria-rich (MR) cells of the gills. These cells are responsible for chloride absorption (NCC) and secretion (NKCC), respectively, thus, the switch of gill NCC and NKCC expression is a crucial regulatory mechanism for salinity adaptation in tilapia. However, little is known about the interaction of cytoskeleton and these adaptive changes. In this study, we examined the time-course of changes in the localization of NKCC/NCC in the gills of tilapia transferred from fresh water (FW) to brackish water (200/00) and from seawater (SW; 350/00) to FW. The results showed that basolateral NKCC disappeared and NCC was expressed in the apical membrane of MR cells. To further clarify the process of these adaptive changes, colchicine, a specific inhibitor of microtubule-dependent cellular regulating processes was used. SW-acclimated tilapia were transferred to SW, FW, and FW with colchicine (colchicine-FW) for 96 h. Compared with the FW-treatment group, in the MR cells of colchicine-FW-treatment group, (1) the average size was significantly larger, (2) only wavy-convex-subtype apical surfaces were found, and (3) the basolateral (cytoplasmic) NKCC signals were still exhibited. Taken together, our results suggest that changes in size, phenotype, as well as the expression of NCC and NKCC cotransporters of MR cells in the tilapia are microtubule-dependent. J. Morphol. 277:1113-1122, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27239785 TI - Fabrication of 3D Biomimetic Microfluidic Networks in Hydrogels. AB - A laser-based hydrogel degradation technique is developed that allows for local control over hydrogel porosity, fabrication of 3D vascular-derived, biomimetic, hydrogel-embedded microfluidic networks, and generation of two intertwining, yet independent, microfluidic networks in a single construct. PMID- 27239786 TI - Tumorigenic Properties of Drosophila Epithelial Cells Mutant for lethal giant larvae. AB - BACKGROUND: Mutations in Drosophila tumor suppressor genes (TSGs) lead to the formation of invasive tumors in the brain and imaginal discs. RESULTS: Here we studied the tumorigenic properties of imaginal discs mutant for the TSG gene lethal giant larvae (lgl). lgl mutant cells display the characteristic features of mammalian tumor cells: they can proliferate indefinitely, induce additional tracheogenesis (an insect counterpart of vasculogenesis) and invade neighboring tissues. Lgl mutant tissues exhibit high apoptotic levels, which lead to the activation of the Jun-N-Terminal Kinase (JNK) pathway. We propose that JNK is a key factor in the acquisition of these tumorigenic properties; it promotes cell proliferation and induces high levels of Mmp1 and confers tumor cells capacity to invade wild-type tissue. Noteworthy, lgl RNAi-mediated down-regulation does not produce similar transformations in the central nervous system (CNS), thereby indicating a fundamental difference between the cells of developing imaginal discs and those of differentiated organs. We discuss these results in the light of the "single big-hit origin" of some human pediatric or developmental cancers. CONCLUSIONS: Down-regulation of lgl in imaginal discs is sufficient to enhance tracheogenesis and to promote invasion and colonization of other larval structures including the CNS. Developmental Dynamics 245:834-843, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27239787 TI - Zebrafish behavioral profiling identifies multitarget antipsychotic-like compounds. AB - Many psychiatric drugs act on multiple targets and therefore require screening assays that encompass a wide target space. With sufficiently rich phenotyping and a large sampling of compounds, it should be possible to identify compounds with desired mechanisms of action on the basis of behavioral profiles alone. Although zebrafish (Danio rerio) behavior has been used to rapidly identify neuroactive compounds, it is not clear what types of behavioral assays would be necessary to identify multitarget compounds such as antipsychotics. Here we developed a battery of behavioral assays in larval zebrafish to determine whether behavioral profiles can provide sufficient phenotypic resolution to identify and classify psychiatric drugs. Using the antipsychotic drug haloperidol as a test case, we found that behavioral profiles of haloperidol-treated zebrafish could be used to identify previously uncharacterized compounds with desired antipsychotic-like activities and multitarget mechanisms of action. PMID- 27239789 TI - Mitochondrial DNA repair and replication proteins revealed by targeted chemical probes. AB - Efficient and accurate replication and repair of mitochondrial DNA is essential for cellular viability, yet only a minimal complement of mitochondrial proteins with relevant activities have been identified. Here, we describe an approach to screen for new pathways involved in the maintenance of mitochondrial DNA (mtDNA) that leverages the activities of DNA-damaging probes exhibiting specific subcellular localization. By conducting a siRNA screen of known nuclear DNA maintenance factors, and monitoring synergistic effects of gene depletion on the activity of mitochondria-specific DNA-damaging agents, we identify a series of proteins not previously recognized to act within mitochondria. These include proteins that function in pathways of oxidative DNA damage repair and dsDNA break repair, along with a novel mitochondrial DNA polymerase, POLtheta, that facilitates efficient DNA replication in an environment prone to oxidative stress. POLtheta expression levels affect the mutational rate of mitochondrial DNA, but this protein also appears critical for efficient mtDNA replication. PMID- 27239788 TI - sigma1 receptor ligands control a switch between passive and active threat responses. AB - Humans and many animals show 'freezing' behavior in response to threatening stimuli. In humans, inappropriate threat responses are fundamental characteristics of several mental illnesses. To identify small molecules that modulate threat responses, we developed a high-throughput behavioral assay in zebrafish (Danio rerio) and evaluated 10,000 compounds for their effects on freezing behavior. We found three classes of compounds that switch the threat response from freezing to escape-like behavior. We then screened these for binding activity across 45 candidate targets. Using target profile clustering, we identified the sigma-1 (sigma1) receptor as having a role in the mechanism of behavioral switching and confirmed that known sigma1 ligands also disrupt freezing behavior. Furthermore, mutation of the gene encoding sigma1 prevented the behavioral effect of escape-inducing compounds. One compound, which we call finazine, potently bound mammalian sigma1 and altered threat-response behavior in mice. Thus, pharmacological and genetic interrogation of the freezing response revealed sigma1 as a mediator of threat responses in vertebrates. PMID- 27239790 TI - Report of a case with a spontaneous mesenteric hematoma that ruptured into the small intestine. AB - INTRODUCTION: A spontaneous mesenteric hematoma is a rare condition. Furthermore, it is extremely rare that the mesenteric hematoma caused gastrointestinal bleeding with an unknown etiology. We experienced a case with a spontaneous mesenteric hematoma that ruptured into the jejunum. PRESENTATION OF CASE: A 75 year-old man was referred to our hospital because of anal bleeding and anemia. Abdominal computed tomography (CT) showed a low density mass measuring 3.0cm in diameter, including an enhanced spot. This finding suggested that a pseudo aneurysm or mesenteric hematoma caused active bleeding into the jejunum. He underwent emergent laparotomy and partial resection of the jejunum and the mesentery including the tumor. A histological examination of the jejunum indicated no pathogenic findings causing active bleeding. And there were no findings suggesting the mesenteric aneurysm had developed. The patient had no history related to the development of a mesenteric hematoma, such as trauma, labor, surgery, or anticoagulant treatment. Therefore, we finally diagnosed that a spontaneous mesenteric hematoma had ruptured into the jejunum. DISCUSSION AND CONCLUSION: We reported extremely rare condition that the mesenteric hematoma was developed and ruptured into the jejunum without definitive etiology. PMID- 27239791 TI - Gastric lipoma excision during a laproscopic sleeve gastrecomy: A case report. AB - INTRODUCTION: Gastric lipomas are rare benign mesenchymal tumors of the stomach. CASE REPORT: We report a 41 year old, morbid obese male, admitted for elective laparoscopic sleeve gastrectomy. Thorough preoperative assessment revealed a gastric lipoma in the antrum of the stomach measuring 3*3cm. Due to the patient's preference, surgical resection of the lipoma was done along with the laparoscopic sleeve gastrectomy procedure. DISCUSSION: In our case, we report a rare case of submucosal gastric lipoma successfully removed during a laparoscopic sleeve gastrectomy. To our knowledge, this is the second case report in the medical English literature that reports removing this rare gastric tumor during an elective bariatric procedure. CONCLUSION: This case report presents an effective treatment option for patients in need of bariatric procedure and gastric lipoma resection. This case also highlights the importance of through preoperative and intraoperative assessment for all bariatric patients. PMID- 27239793 TI - Altered development and function of the placental regions in preeclampsia and its association with long-chain polyunsaturated fatty acids. AB - The placenta is an essential organ formed during pregnancy that mainly transfers nutrients from the mother to the fetus. Nutrients taken up by the placenta are required for its own growth and development and to optimize fetal growth. Hence, placental function is an important determinant of pregnancy outcome. Among various nutrients, fatty acids, especially long-chain polyunsaturated fatty acids (LCPUFAs), including omega 3 and omega 6 fatty acids, are essential for placental development from the time of implantation. Studies have associated these LCPUFAs with placental development through their roles in regulating oxidative stress, angiogenesis, and inflammation, which may in turn influence their transfer to the fetus. The placenta has a heterogeneous morphology with variable regional vasculature, oxidative stress, and LCPUFA levels in healthy pregnancies depending upon the location within the placenta. However, these regional structural and functional parameters are found to be disturbed in pathological conditions, such as preeclampsia (PE), thereby affecting pregnancy outcome. Hence, the alterations in LCPUFA metabolism and transport in different regions of the PE placenta as compared with normal placenta could potentially be contributing to the pathological features of PE. The regional variations in development and function of the placenta and its possible association with placental LCPUFA metabolism and transport in normal and PE pregnancies are discussed in this review. WIREs Dev Biol 2016, 5:582-597. doi: 10.1002/wdev.238 For further resources related to this article, please visit the WIREs website. PMID- 27239792 TI - Recommendations for cardiovascular disease research with lesbian, gay and bisexual adults. AB - AIMS AND OBJECTIVES: The purpose of this paper is to provide recommendations to strengthen cardiovascular disease research with lesbian, gay and bisexual adults, and highlight implications for practice. BACKGROUND: Lesbian, gay and bisexual individuals face significant discrimination that negatively impacts their health. Health disparities research in lesbian, gay and bisexual adults have focused on mental health, sexually transmitted infections and substance use. Although cardiovascular disease is the leading cause of death and many lesbian, gay and bisexual adults report increased risk factors for cardiovascular disease, there has been limited research in this area. DESIGN: This paper is a critical review. METHODS: A literature search was conducted that compared cardiovascular disease risk and/or prevalence between lesbian, gay and bisexual and heterosexual adults. RESULTS: Measures to assess cardiovascular disease risk factors and diagnoses varied widely across the 31 included studies. There was a lack of standardisation in definitions used for alcohol consumption, illicit drug use, mental health and self-rated physical health. Most studies that reported body mass index relied on participant self-report. Few studies included measures of physical activity and diet and those that did lacked standardisation. Only seven studies used laboratory data to establish diagnosis of cardiovascular disease. CONCLUSIONS: This study is the first comprehensive review on this topic. In cardiovascular disease research with lesbian, gay and bisexual adults, there is a need for: (1) inclusion of stress as a risk factor for cardiovascular disease, (2) standardised measures, (3) objective measures for determining the presence of cardiovascular disease, (4) data from electronic health records to strengthen the study of cardiovascular disease in this population. RELEVANCE TO CLINICAL PRACTICE: Strengthening cardiovascular disease research in lesbian, gay and bisexual adults is an important step in addressing health disparities in this population. Nurses and other healthcare professionals should assess sexual orientation in routine health assessments. PMID- 27239794 TI - Public Reporting of Mortality Rates for Hospitalized Medicare Patients and Trends in Mortality for Reported Conditions. AB - BACKGROUND: Public reporting is seen as a powerful quality improvement tool, but data to support its efficacy are limited. The Centers for Medicare & Medicaid Services' Hospital Compare program initially reported process metrics only but started reporting mortality rates for acute myocardial infarction, heart failure, and pneumonia in 2008. OBJECTIVE: To determine whether public reporting of mortality rates was associated with lower mortality rates for these conditions among Medicare beneficiaries. DESIGN: For 2005 to 2007, process-only reporting was considered; for 2008 to 2012, process and mortality reporting was considered. Changes in mortality trends before and during reporting periods were estimated by using patient-level hierarchical modeling. Nonreported medical conditions were used as a secular control. SETTING: U.S. acute care hospitals. PARTICIPANTS: 20 707 266 fee-for-service Medicare beneficiaries hospitalized from January 2005 through November 2012. MEASUREMENTS: 30-day risk-adjusted mortality rates. RESULTS: Mortality rates for the 3 publicly reported conditions were changing at an absolute rate of -0.23% per quarter during process-only reporting, but this change slowed to a rate of -0.09% per quarter during process and mortality reporting (change, 0.13% per quarter; 95% CI, 0.12% to 0.14%). Mortality for nonreported conditions was changing at -0.17% per quarter during process-only reporting and slowed slightly to -0.11% per quarter during process and mortality reporting (change, 0.06% per quarter; CI, 0.05% to 0.07%). LIMITATION: Administrative data may have limited ability to account for changes in patient complexity over time. CONCLUSION: Changes in mortality trends suggest that reporting in Hospital Compare was associated with a slowing, rather than an improvement, in the ongoing decline in mortality among Medicare patients. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute. PMID- 27239795 TI - Human BRCA1-BARD1 ubiquitin ligase activity counteracts chromatin barriers to DNA resection. AB - The opposing activities of 53BP1 and BRCA1 influence pathway choice in DNA double strand-break repair. How BRCA1 counteracts the inhibitory effect of 53BP1 on DNA resection and homologous recombination is unknown. Here we identify the site of BRCA1-BARD1 required for priming ubiquitin transfer from E2~ubiquitin and demonstrate that BRCA1-BARD1's ubiquitin ligase activity is required for repositioning 53BP1 on damaged chromatin. We confirm H2A ubiquitination by BRCA1 BARD1 and show that an H2A-ubiquitin fusion protein promotes DNA resection and repair in BARD1-deficient cells. BRCA1-BARD1's function in homologous recombination requires the chromatin remodeler SMARCAD1. SMARCAD1 binding to H2A ubiquitin and optimal localization to sites of damage and activity in DNA repair requires its ubiquitin-binding CUE domains. SMARCAD1 is required for 53BP1 repositioning, and the need for SMARCAD1 in olaparib or camptothecin resistance is alleviated by 53BP1 loss. Thus, BRCA1-BARD1 ligase activity and subsequent SMARCAD1-dependent chromatin remodeling are critical regulators of DNA repair. PMID- 27239796 TI - Visualizing chaperone-assisted protein folding. AB - Challenges in determining the structures of heterogeneous and dynamic protein complexes have greatly hampered past efforts to obtain a mechanistic understanding of many important biological processes. One such process is chaperone-assisted protein folding. Obtaining structural ensembles of chaperone substrate complexes would ultimately reveal how chaperones help proteins fold into their native state. To address this problem, we devised a new structural biology approach based on X-ray crystallography, termed residual electron and anomalous density (READ). READ enabled us to visualize even sparsely populated conformations of the substrate protein immunity protein 7 (Im7) in complex with the Escherichia coli chaperone Spy, and to capture a series of snapshots depicting the various folding states of Im7 bound to Spy. The ensemble shows that Spy-associated Im7 samples conformations ranging from unfolded to partially folded to native-like states and reveals how a substrate can explore its folding landscape while being bound to a chaperone. PMID- 27239798 TI - Statistical learning and the critical period: how a continuous learning mechanism can give rise to discontinuous learning. AB - Infants and children are generally more successful than adults in learning novel languages, a phenomenon referred to as a critical or sensitive period for language acquisition. One explanation for this critical period is the idea that children have access to a set of language learning processes or mechanisms unavailable to adults. From this perspective, developmental change is explained in terms of a discontinuity of learning processes. We suggest that this is not the only possible explanation for developmental change in language learning outcomes. Instead, we propose that the mechanisms underlying language acquisition (in particular, we highlight statistical learning) are largely continuous across the lifespan. From this perspective, developmental change is explained in terms of experience, differences in the input with age, and maturational changes in the cognitive architecture supporting learning, even while the learning process itself operates continuously across developmental time. WIREs Cogn Sci 2016, 7:276-288. doi: 10.1002/wcs.1394 For further resources related to this article, please visit the WIREs website. PMID- 27239797 TI - lnc-beta-Catm elicits EZH2-dependent beta-catenin stabilization and sustains liver CSC self-renewal. AB - Liver cancer stem cells (CSCs) may contribute to the high rate of recurrence and heterogeneity of hepatocellular carcinoma (HCC); however, the molecular mechanisms underlying their self-renewal and differentiation remain largely unknown. Through analysis of transcriptome microarray data, we identified a long noncoding RNA (lncRNA) called lnc-beta-Catm, which is highly expressed in human HCC tumors and liver CSCs. We found that lnc-beta-Catm is required for self renewal of liver CSCs and tumor propagation in mice. lnc-beta-Catm associates with beta-catenin and the methyltransferase EZH2, thereby promoting beta-catenin methylation. Methylation suppresses the ubiquitination of beta-catenin and promotes its stability, thus leading to activation of Wnt-beta-catenin signaling. Accordingly, the expression of lnc-beta-Catm, EZH2 and Wnt-beta-catenin targets is positively correlated with cancer severity and prognosis of people with HCC. PMID- 27239799 TI - Rapid Identification of Klebsiella pneumoniae by Matrix-Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry and Detection of Meropenem Resistance by Flow Cytometric Assay. AB - BACKGROUND: The aim of this study was to develop a rapid detection method of carbapenem-resistant Klebsiella pneumoniae (CRKP) strains both MALDI-TOF MS and flow cytometry (FCM). METHODS: A total of 174 K. pneumoniae strains were included in this study. Molecular characterization of carbapenemase gene was performed by PCR. Bacterial identification was performed by MALDI-TOF-MS. Meropenem susceptibility was tested at the concentrations of breakpoints described by the Clinical and Laboratory Standards Institute (CLSI) guide by FCM. RESULTS: Sixty two CRKP were positive for at least one carbapenemase gene. A total of 174 K. pneumoniae isolates obtained from clinically relevant material were correctly identified by Bruker MALDI-TOF MS with log (score) >2.0. These results were 100% concordant with the PhoenixTM Automated Microbiology System (BD, MD) and conventional identification results. Based on the analysis of the receiver operating characteristic (ROC) curves, the best validity and sensitivity data were obtained with a cut-off value of 18.88% by FCM. The concordance, sensitivity, and specificity for FCM by the selected cut-off values were 99.4%, 98.9%, and 100%, respectively. CONCLUSIONS: We conclude that reliable results on bacterial identification and meropenem susceptibility test can be obtained within 2 hr combined by MALDI-TOF-MS and FCM. PMID- 27239800 TI - A Concise Route to the Strongylophorines. AB - An efficient eight-step semisynthesis of strongylophorine-2 from the abundant building block isocupressic acid is reported. The route represents the first synthetic entry into this class of natural products and provides access to six additional family members. A novel iron(III)-mediated rearrangement-cyclization cascade and a directed photochemical sp(3) C-H delta-lactonization are the key transformations that enable concise assembly of these bioactive polycyclic meroterpenoids. PMID- 27239801 TI - Feasibility of using bulk metallic glass for self-expandable stent applications. AB - Self-expandable stents are widely used to restore blood flow in a diseased artery segment by keeping the artery open after angioplasty. Despite the prevalent use of conventional crystalline metallic alloys, for example, nitinol, to construct self-expandable stents, new biomaterials such as bulk metallic glasses (BMGs) are being actively pursued to improve stent performance. Here, we conducted a series of analyses including finite element analysis and molecular dynamics simulations to investigate the feasibility of using a prototypical Zr-based BMG for self expandable stent applications. We model stent crimping of several designs for different percutaneous applications. Our results indicate that BMG-based stents with diamond-shaped crowns suffer from severe localization of plastic deformation and abrupt failure during crimping. As a possible solution, we further illustrate that such abrupt failure could be avoided in BMG-based stents without diamond shape crowns. This work would open a new horizon for a quest toward exploiting superior mechanical and functional properties of metallic glasses to design future stents. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1874-1882, 2017. PMID- 27239802 TI - Aqueous humor immune factors and cytomegalovirus (CMV) levels in CMV retinitis through treatment - The CRIGSS study. AB - PURPOSE: This study aims to perform comprehensive longitudinal immune factor analysis of aqueous humor in relation to the aqueous CMV viral load and systemic CD4 counts during treatment of patients with co-infection of HIV and CMVR. METHODS: Aqueous humor samples were collected from 17 HIV-positive patients with CMVR scheduled to undergo weekly intravitreal ganciclovir therapy as part of the prospective CMV Retinitis Intravitreal Ganciclovir Singapore Study (CRIGSS) over the course of 1year. Full data across all the 4 time points was obtained and analyzed for CMV DNA viral load, 41 cytokine and chemokine factors using real time PCR with the FlexMAP 3D (Luminex(r)) platform and assessed using the Milliplex Human Cytokine(r) kit. RESULTS: The following immune factors (Spearman correlation coefficient r value in parenthesis, p<0.05) showed strong correlation with CMV DNA load in the aqueous - MCP-1 (0.80, IFN-g (0.83), IP-10 (0.82), IL-8 (0.81), fractalkine (0.73), RANTES (0.68) - while the following showed moderate correlation - PDGF-AA (0.58), Flt-3L (0.59) and G-CSF (0.53). Only PDGF-AA revealed a statistically significant negative correlation with serum CD4 levels (r=-0.74). CONCLUSION: Immune factors that correlate with intraocular CMV DNA load are identified. They are indicative of a Th1 and monocyte-macrophage mediated response, and exhibit a decreasing trend longitudinally through the course of treatment. These factors may be an important new consideration in individualizing the treatment of patients with CMVR. PMID- 27239803 TI - Sexual activity and functioning in women treated for gynaecological cancers. AB - AIMS AND OBJECTIVES: A description and comparison of sexual activity and function in relation to various gynaecological cancer diagnoses, treatment modalities, age groups, psychological distress and health-related quality of life. BACKGROUND: Various forms of gynaecological cancer have the potential to negatively influence sexual functioning, but there are few studies that describe and compare sexual activity and functioning according to diagnosis. DESIGN: A descriptive cross sectional study. METHODS: The study includes 129 women from an intervention study. The questionnaires addressed sexuality, psychological distress, health related quality of life and demographics. Disease and treatment characteristics were extracted from medical records. RESULTS: Close to two-thirds of the women were sexually active. However, 54% of the sexually active women reported that they were not satisfied or little satisfied with their sexual activity. About half of the women reported dryness in the vagina, and 41% reported pain and discomfort during penetration. There were no significant differences concerning pleasure and discomfort related to treatment modality, diagnoses or FIGO stage. CONCLUSION: Health personnel should make a priority of sexuality throughout a patient's cancer treatment and in the follow-up, as sexuality is a vital part of a good life. RELEVANCE TO CLINICAL PRACTICE: Since the patients experience relatively low satisfaction with their sexual activity and many report pain during penetration, health personnel need to be sensitive to the woman, her questions, and her needs. Of importance are also the personnel's ability to communicate and their expertise in diagnosing and treating difficulties relating to sexuality. PMID- 27239804 TI - Assessing the Potential Content of Ethyl Carbamate in White, Red, and Rose Wines as a Key Factor for Pursuing Urea Degradation by Purified Acid Urease. AB - The ethyl carbamate (EC) content of a wine after a given temperature-time storage was theoretically predicted from the potential concentration of ethyl carbamate (PEC), as determined via an accelerated EC formation test. Such information was used to decide whether an enzymatic treatment was needed to reduce the wine urea level before bottling/aging. To this end, 6 white, red, and rose wines, manufactured in Italy as such or enriched with urea, were tested for their PEC content either before or after enzymatic treatment using a purified acid urease preparation derived from Lactobacillus fermentum. The treatment was severely affected by the total phenolic content (TP) of the wine, the estimated pseudo first-order kinetic rate constant for NH3 formation reducing by a factor of approximately 2000 as the TP increased from 0 to 1.64 g L(-1) . Such a sensitivity to TP was by far greater than that pertaining to a killed cell-based enzyme preparation used previously. Urea hydrolysis was successful at reducing EC concentration in wines with low levels of TP and other EC precursors. PMID- 27239805 TI - New Fellows of the Royal Society: C. Abell, E. Kumacheva, and R. E. Morris / President of the Chemical Society of Japan: H. Yamamoto. PMID- 27239806 TI - C-C Coupling of Benzyl Fluorides Catalyzed by an Electrophilic Phosphonium Cation. AB - The activation and cleavage of benzyl fluorides by the electrophilic organofluorophosphonium catalyst, [(C6 F5 )3 PF][B(C6 F5 )4 ], is reported and used for the preparation of 1,1-diarylalkanes (37 examples) and substituted aryl homoallylic alkenes (14 examples). This procedure involves mild conditions, avoids harmful waste, and is compatible with a range of substituted arenes and allylic silanes. PMID- 27239807 TI - Adenine-induced chronic renal failure in rats decreases aortic relaxation rate and alters expression of proteins involved in vascular smooth muscle calcium handling. AB - AIM: Rats with adenine-induced chronic renal failure (A-CRF) develop a reduced rate of relaxation of the thoracic aorta. The aim of this study was to elucidate the mechanisms underlying this abnormality. METHODS: Male Sprague Dawley rats received either chow containing adenine or were pair-fed with normal chow (controls). After 8-14 weeks, arterial function was analysed ex vivo using wire myography and the expression of proteins involved in vascular smooth muscle excitation-contraction coupling in the thoracic aorta was analysed. RESULTS: The rate of relaxation following washout of KCl was reduced in A-CRF rats vs. controls in the thoracic aorta (P < 0.01), abdominal aorta (P < 0.05), and common carotid artery (P < 0.05), but not in the common femoral artery. Relaxation rates of thoracic aortas increased (P < 0.01), but were not normalized, in response to washout of KCl with Ca2+ -free buffer. Microarray and qRT-PCR analyses of genes involved in excitation-contraction coupling identified 10 genes, which showed significantly altered expression in A-CRF thoracic aortas. At the protein level, the alpha2 subunit of the Na,K-ATPase (P < 0.001) and SERCA2 (P < 0.05) was significantly downregulated, whereas stromal interaction molecule 1 and calsequestrin-1 and calsequestrin-2 were significantly upregulated (P < 0.05). CONCLUSIONS: Rats with A-CRF show a marked alteration in relaxation of larger conduit arteries localized proximal to the common femoral artery. This abnormality may be caused by reduced cytosolic Ca2+ clearance in vascular smooth muscle cells secondary to dysregulation of proteins crucially involved in this process. PMID- 27239808 TI - Improving hybrid statistical and physical forcefields through local structure enumeration. AB - Forcefields used in biomolecular simulations are comprised of energetic terms that are physical in nature, based on parameter fitting to quantum mechanical simulation or experimental data, or statistical, drawing off high-resolution structural data to describe distributions of molecular features. Combining the two in a single forcefield is challenging, since physical terms describe some, but not all, of the observed statistics, leading to double counting. In this manuscript, we develop a general scheme for correcting statistical potentials used in combination with physical terms. We apply these corrections to the sidechain torsional potential used in the Rosetta all-atom forcefield. We show the approach identifies instances of double-counted interactions, including electrostatic interactions between sidechain and nearby backbone, and steric interactions between neighboring Cbeta atoms within secondary structural elements. Moreover, this scheme allows for the inclusion of intraresidue physical terms, previously turned off to avoid overlap with the statistical potential. Combined, these corrections lead to a forcefield with improved performance on several structure prediction tasks, including rotamer prediction and native structure discrimination. PMID- 27239810 TI - Total Worker Health: A Promising Approach to a Safer and Healthier Workforce. PMID- 27239809 TI - Association between severity of hypoglycemia and loss of heart rate variability in patients with type 1 diabetes mellitus. AB - BACKGROUND: The occurrence of hypoglycemia has been associated with the presence of cardiovascular autonomic neuropathy. Cardiovascular autonomic reflex tests are the gold standard diagnostic method for cardiovascular autonomic neuropathy. Nevertheless, impaired heart rate variability indices on spectral analysis have been reported before cardiovascular autonomic reflex test abnormalities arise. The objective of the present study was to analyse the association between the severity of hypoglycemia and indices of heart rate variability on spectral analysis. METHODS: Consecutive type 1 diabetes patients were prospectively enrolled. Heart rate variability indices were assessed by spectral analysis. One abnormal test result was used to define impaired spectral analysis. The severity of hypoglycemia was evaluated by a hypoglycemia score and patients were classified into absent/minor or moderate/severe hypoglycemia groups. RESULTS: Patients with moderate/severe hypoglycemia were older, had longer duration of diabetes and had higher rates of diabetic complications. After adjusting for baseline clinical characteristics, impaired spectral analysis (OR: 3.85; 95% IC 1.23 - 12.02; p = 0.020), nephropathy (OR: 4.15, 95% IC 1.27 - 13.54; p = 0.018) and macrovascular complications (OR: 12.18, 95% IC 1.14 - 129.84; p = 0.038) remained independent predictors of moderate/severe hypoglycemia. Patients with moderate/severe hypoglycemia had lower heart rate variability in the high frequency band of spectral analysis, reflecting a decreased parasympathetic tonus on the heart. These patients also had higher low frequency/high frequency ratios, ultimately denoting the occurrence of cardiovascular autonomic imbalance. CONCLUSIONS: Impaired heart rate variability on spectral analysis, nephropathy and macrovascular complication were shown to independently predict moderate/severe hypoglycemia. Patients with moderate/severe hypoglycemia showed loss of the cardio protective effect of vagal activity according to spectral analysis. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27239811 TI - Comparative transcriptome profiling provides new insights into mechanisms of androgenetic alopecia progression. PMID- 27239812 TI - Protective Effects of Green Tea Polyphenol Against Renal Injury Through ROS Mediated JNK-MAPK Pathway in Lead Exposed Rats. AB - To investigate the potential therapeutic effects of polyphenols in treating Pb induced renal dysfunction and intoxication and to explore the detailed underlying mechanisms. Wistar rats were divided into four groups: control groups (CT), Pb exposure groups (Pb), Pb plus Polyphenols groups (Pb+PP) and Polyphenols groups (PP). Animals were kept for 60 days and sacrificed for tests of urea, serum blood urea nitrogen (BUN) and creatinine. Histological evaluations were then performed. In vitro studies were performed using primary kidney mesangial cells to reveal detailed mechanisms. Cell counting kit-8 (CCK-8) was used to evaluate cell viability. Pb induced cell apoptosis was measured by flow cytometry. Reactive oxygen species (ROS) generation and scavenging were tested by DCFH-DA. Expression level of tumor necrosis factor-alpha (TNF-alpha), interleukin-1-beta (IL-1-beta) and IL-6 were assayed by ELISA. Western blot and qPCR were used to measure the expression of ERK1/2, JNK1/2 and p38. Polyphenols have obvious protective effects on Pb induced renal dysfunction and intoxication both in vivo and in vitro. Polyphenols reduced Pb concentration and accumulation in kidney. Polyphenols also protected kidney mesangial cells from Pb induced apoptosis. Polyphenols scavenged Pb induced ROS generation and suppressed ROS-mediated ERK/JNK/p38 pathway. Downstream pro-inflammatory cytokines were inhibited in consistency. Polyphenol is protective in Pb induced renal intoxication and inflammatory responses. The underlying mechanisms lie on the antioxidant activity and ROS scavenging activity of polyphenols. PMID- 27239813 TI - Clearing and Labeling Techniques for Large-Scale Biological Tissues. AB - Clearing and labeling techniques for large-scale biological tissues enable simultaneous extraction of molecular and structural information with minimal disassembly of the sample, facilitating the integration of molecular, cellular and systems biology across different scales. Recent years have witnessed an explosive increase in the number of such methods and their applications, reflecting heightened interest in organ-wide clearing and labeling across many fields of biology and medicine. In this review, we provide an overview and comparison of existing clearing and labeling techniques and discuss challenges and opportunities in the investigations of large-scale biological systems. PMID- 27239815 TI - Fracture strength of implant abutments after fatigue testing: A systematic review and a meta-analysis. AB - PURPOSE: The use of implants and their respective suprastructures to replace missing teeth has become a common therapeutic option in dentistry. Prior to their clinical application, all implant components have to demonstrate suitable durability in laboratory studies. Fatigue tests utilising cyclic loading typically simulate masticatory function in vitro. The objectives of this systematic review were to assess the loading conditions used for fatigue testing of implant abutments and to compare the fracture strength of different types of implant abutment and abutment-connection types after cyclic loading. MATERIALS AND METHODS: Original scientific papers published in MEDLINE (PubMed) and Embase database in English between 01/01/1970 and 12/31/2014 on cyclic loading on implant abutments were included in this systematic review. The following MeSH terms, search terms and their combinations were used: "in vitro" or "ex vivo" or experimental or laboratory, "dental implants", "implants, experimental", "dental prosthesis, implant-supported", "fatigue", "dental abutments", "cyclic loading", "cyclic fatigue", "mechanical fatigue", "fatigue resistance", "bending moments", and "fracture". Two reviewers performed screening and data abstraction. Only the studies that reported, static fracture values before and after fatigue cycling of implant abutments, were included that allowed comparison of aging effect through cyclic loading. Data (N) were analyzed using a weighted linear regression analysis (alpha=0.05). RESULTS: The selection process resulted in the final sample of 7 studies. In general, loading conditions of the fatigue tests revealed heterogeneity in the sample but a meta-analysis could be performed for the following parameters: a) abutment material, b) implant-abutment connection, and (c) number of fatigue cycles. Mean fracture strength of titanium (508.9+/-334.6N) and for zirconia abutments (698.6+/-452.6N) did not show significant difference after cyclic loading (p>0.05). Internal implant-abutment connections demonstrated significantly higher fracture strength after cyclic loading compared to external ones (internal: 774.0+/-582.3N; external: 481.2+/-137.5N; p=0.022). The mean fracture strength of all abutment types decreased significantly when number of loading cycles exceeded 1,000,000 cycles (<1*10(-6): 1047.0+/-751.3N; >1*10(-6): 556.7+/-317.6N; p=0.032). CONCLUSION: The results of this meta-analysis, favour the use of internal implant-abutment connections in combination with either titanium or zirconia abutment materials. Number of cycles had a significant impact on the fracture strength after cyclic loading. PMID- 27239816 TI - The safety of salt pipes in asthmatic patients. PMID- 27239818 TI - Endoscopic removal of bands in Roux-en-Y gastric bypass: ask your friendly surgeon what he did! PMID- 27239814 TI - A New Insight of Salt Stress Signaling in Plant. AB - Many studies have been conducted to understand plant stress responses to salinity because irrigation-dependent salt accumulation compromises crop productivity and also to understand the mechanism through which some plants thrive under saline conditions. As mechanistic understanding has increased during the last decades, discovery-oriented approaches have begun to identify genetic determinants of salt tolerance. In addition to osmolytes, osmoprotectants, radical detoxification, ion transport systems, and changes in hormone levels and hormone-guided communications, the Salt Overly Sensitive (SOS) pathway has emerged to be a major defense mechanism. However, the mechanism by which the components of the SOS pathway are integrated to ultimately orchestrate plant-wide tolerance to salinity stress remains unclear. A higher-level control mechanism has recently emerged as a result of recognizing the involvement of GIGANTEA (GI), a protein involved in maintaining the plant circadian clock and control switch in flowering. The loss of GI function confers high tolerance to salt stress via its interaction with the components of the SOS pathway. The mechanism underlying this observation indicates the association between GI and the SOS pathway and thus, given the key influence of the circadian clock and the pathway on photoperiodic flowering, the association between GI and SOS can regulate growth and stress tolerance. In this review, we will analyze the components of the SOS pathways, with emphasis on the integration of components recognized as hallmarks of a halophytic lifestyle. PMID- 27239817 TI - Global distribution and environmental suitability for chikungunya virus, 1952 to 2015. AB - Chikungunya fever is an acute febrile illness caused by the chikungunya virus (CHIKV), which is transmitted to humans by Aedes mosquitoes. Although chikungunya fever is rarely fatal, patients can experience debilitating symptoms that last from months to years. Here we comprehensively assess the global distribution of chikungunya and produce high-resolution maps, using an established modelling framework that combines a comprehensive occurrence database with bespoke environmental correlates, including up-to-date Aedes distribution maps. This enables estimation of the current total population-at-risk of CHIKV transmission and identification of areas where the virus may spread to in the future. We identified 94 countries with good evidence for current CHIKV presence and a set of countries in the New and Old World with potential for future CHIKV establishment, demonstrated by high environmental suitability for transmission and in some cases previous sporadic reports. Aedes aegypti presence was identified as one of the major contributing factors to CHIKV transmission but significant geographical heterogeneity exists. We estimated 1.3 billion people are living in areas at-risk of CHIKV transmission. These maps provide a baseline for identifying areas where prevention and control efforts should be prioritised and can be used to guide estimation of the global burden of CHIKV. PMID- 27239819 TI - Bypassing user error in optical diagnosis of diminutive colorectal polyps - at what cost? PMID- 27239820 TI - Adenoma risk score for surveillance of colorectal neoplasm - a step forward? PMID- 27239821 TI - Treatment of gastric leaks after sleeve gastrectomy. PMID- 27239822 TI - Reply to Rebibo et al. PMID- 27239823 TI - The Boskoski-Costamagna ERCP Trainer: from dream to reality. PMID- 27239824 TI - Reply to Boskoski et al. PMID- 27239827 TI - French comment on article: Endoscopic treatment of food intolerance after a banded gastric bypass: inducing band erosion for removal using a plastic stent. PMID- 27239828 TI - French comment on article: Influence of reviewer's clinical backgrounds on interpretation of confocal laser endomicroscopy findings. PMID- 27239829 TI - French comment on article: Early precut sphincterotomy for difficult biliary access to reduce post-ERCP pancreatitis: a randomized trial. PMID- 27239830 TI - French comment on article: Risk factors for recurrent biliary obstruction following placement of self-expandable metallic stents in patients with malignant perihilar biliary stricture. PMID- 27239831 TI - French comment on article: Endoscopic management with multiple plastic stents of anastomotic biliary strictures following liver transplantation: long term results. PMID- 27239832 TI - French comment on article: Outcomes of double-balloon enteroscopy-assisted direct percutaneous endoscopic jejunostomy tube placement. PMID- 27239833 TI - French comment on article: In vivo real-time assessment of colorectal polyp histology using an optical biopsy forceps system based on laser-induced fluorescence spectroscopy. PMID- 27239834 TI - French comment on article: Rational and design of the European Polyp Surveillance (EPoS) trials. PMID- 27239835 TI - French comment on article: Developing a score chart to improve risk stratification of patients with colorectal adenoma. PMID- 27239836 TI - Video Comment on Miura et al. PMID- 27239837 TI - Video Comment on Al-Bawardy et al. PMID- 27239838 TI - Video Comment on Rath et al. PMID- 27239839 TI - Video Comment on Takahashi et al. PMID- 27239840 TI - Video Comment on Kais et al. PMID- 27239841 TI - [Key regulators of skeletal myogenesis]. AB - Skeletal myogenesis has been extensively studied at both morphological and molecular levels. This review considers the main stages of embryonic skeletal myogenesis and myogenic factors that trigger their initiation, focusing on specific protein interactions involved in somitic myogenesis, head myogenesis, and limb myogenesis. The second part of the review describes the role of noncoding RNAs (microRNAs and long noncoding RNAs) in myogenesis. This information is of particular interest, because regulation of cell processes by noncoding RNAs is an actively developing field of molecular biology. Knowledge of mechanisms of skeletal myogenesis is of applied significance. Various transcription factors, noncoding RNAs, and other myogenic regulators can be employed in the induction of myogenic reprogramming in stem cells and differentiated somatic cells. Current trends and strategies in the field of skeletal myogenic reprogramming are discussed in the last part of the review. PMID- 27239842 TI - [Role of the ABC transporters A1 and G1, key reverse cholesterol transport proteins, in atherosclerosis]. AB - Atherosclerosis is one of the most common causes of death worldwide. Epidemiology studies firmly established an inverse relationship between atherogenesis and distorted lipid metabolism, in particular, higher levels of total cholesterol, an accumulation of CH-laden macrophages (foam cells), and lower plasma levels of antiatherogenic high density lipoprotein (HDL). It is believed that the reverse cholesterol transport, a process that removes excess cholesterol from peripheral tissues/cells including macrophages to circulating HDL, is one of the main mechanisms responsible for anti-atherogenic properties of HDL. The key proteins of reverse cholesterol transport-ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1)-mediate the cholesterol efflux from macrophages and prevent their transformation into foam cells. This review focuses on the role of ABC transporters A1 and G1 in the pathogenesis of atherosclerosis. PMID- 27239843 TI - [Adenosine A2A receptor as a drug target for treatment of sepsis]. AB - Sepsis is a generalized infection accompanied by response of the body that manifests in a clinical and laboratory syndrome, namely, in the systemic inflammatory response syndrome (SIRS) from the organism to the infection. Although sepsis is a widespread and life-threatening disease, the assortment of drugs for its treatment is mostly limited by antibiotics. Therefore, the search for new cellular targets for drug therapy of sepsis is an urgent task of modern medicine and pharmacology. One of the most promising targets is the adenosine A(2A) receptor (A(2A)AR). The activation of this receptor, which is mediated by extracellular adenosine, manifests in almost all types of immune cells (lymphocytes, monocytes, macrophages, and dendritic cells) and results in reducing the severity of inflammation and reperfusion injury in various tissues. The activation of adenosine A(2A) receptor inhibits the proliferation of T cells and production of proinflammatory cytokines, which contributes to the activation of the synthesis of anti-inflammatory cytokines, thereby suppressing the systemic response. For this reason, various selective A(2A)AR agonists and antagonists may be considered to be drug candidates for sepsis pharmacotherapy. Nevertheless, they remain only efficient ligands and objects of pre-clinical and clinical trials. This review examines the molecular mechanisms of inflammatory response in sepsis and the structure and functions of A(2A)AR and its role in the pathogenesis of sepsis, as well as examples of using agonists and antagonists of this receptor for the treatment of SIRS and sepsis. PMID- 27239844 TI - [Gene Polymorphism of the c-fms, ITGB3,CCR2, and DBH genes in the populations of old believers of the Tyumen oblast and Russian residents of Novosibirsk]. AB - Old Believers of the Tyumen oblast have been studied compared with a control sample of Russian residents of the city of Novosibirsk. The former are a unique subpopulation, which has been relatively isolated from the rest of Russians in central and northern regions of Russia due to religious reasons since the middle of the 17th century. Polymorphisms in the genes for glycoprotein ITGB3, dopamine beta-hydroxylase (DBH), and chemokine receptor CCR2 and two mutations in the c fms gene have been analyzed. The populations are only similar in the c-fms indel. The frequencies of the rare alleles of CCR2, ITGB3, and 3'UTR of c-fms in the Old Believers are lower than in the sample of Novosibirsk Russians, and the rare allele of DBH is more frequent. A significant negative correlation is observed between DBH and CCR2 (r =-0.88; df = 4; P < 0.023). Apparently, these differences are related to the long-term isolation of Old Believers. This assumption is consistent with the fact that the levels of heterozygosity for most loci in Old Believers are lower than in Novosibirsk Russians. PMID- 27239845 TI - [Abnormal expression of genes that regulate retinoid metabolism and signaling in non-small-cell lung cancer]. AB - Retinoids are signaling molecules that control a wide variety of cellular processes and possess antitumor activity. This work presents a comprehensive description of changes in the expression of 23 genes that regulate retinoid metabolism and signaling in non-small-cell lung cancer tumors compared to adjacent normal tissues obtained using RT-PCR. Even at early stages of malignant transformation, a significant decrease in ADH1B, ADH3, RDHL, and RALDH1 mRNA levels was observed in 82, 79, 73, and 64% of tumor specimens, respectively, and a considerable increase in AKR1B10 mRNA content was observed in 80% of tumors. Dramatic changes in the levels of these mRNAs can impair the synthesis of all trans retinoic acid, a key natural regulatory retinoid. Apart from that, it was found that mRNA levels of nuclear retinoid receptor genes RXRgamma, RARalpha, RXRalpha, and gene RDH11 were significantly decreased in 80, 67, 57, and 66% of tumor specimens, respectively. Thus, neoplastic transformation of lung tissue cells is accompanied with deregulated expression of key genes of retinoid metabolism and function. PMID- 27239846 TI - [Influence of dexamethasone on the expression of immediate early genes c-fos and c-jun in different regions of the neonatal brain]. AB - The ratio of the expression levels of the immediate early genes c-jun and c-fos that encode components of the AP-1 transcription complex determines the direction of changes in the expression of genes controlled by the complex, including changes induced by glucocorticoids. The aim of the present work was to assess the levels of mRNA encoded by genes c-jun and c-fos and the ratio of expression levels of these genes in various regions of the neonatal rat brain after the administration of dexamethasone, a selective ligand of the glucocorticoid receptor. The level of mRNA encoded by the immediate early gene c-fos in the hippocampus and prefrontal cortex of 3-day-old rat pups was elevated at 30, 60, and 120 min after dexamethasone administration. The basal level of c-fos gene expression in the brainstem was higher than in the cortex and hippocampus, and administration of the hormone was followed by a reduction in the amount of transcript detectable in the brainstem after 2 h. As a result, the ratio of c-jun to c-fos transcript levels in the brainstem of neonatal rats was doubled after dexamethasone administration. The dexamethasone-induced shift of the ratio of c jun to c-fos transcript levels in the brainstem of neonatal rats towards a predominance of c-jun reported for the first time in the present work may induce the expression of genes that contain AP-1 response elements in the promoters, since the glucocorticoid receptor can be involved in protein-protein interactions with the Jun/Jun homodimer of the AP-1 complex. PMID- 27239847 TI - [PCR-based evaluation of sequence specificity of DNA fragmentation by ultrasound]. AB - Ultrasonic fragmentation, which is a simple and convenient method for the mechanical degradation of DNA, is widely used in modern genome studies as one of the sample preparation steps. It has been recently found that the DNA breaks occur more often in the regions containing 5'-CG-3' dinucleotides. We studied the influence of the 5'-CG-3' dinucleotides on the efficiency of the 28S rRNA gene amplification during PCR with sonicated DNA of Mantis religiosa. It was shown that the amplification rate depends on the template length and the number of 5' CG-3' dinucleotides. Amplification of the DNA regions with a higher 5'-CG-3' density is less efficient because of their higher sensitivity to ultrasound. The amount of the amplified DNA templates is inversely proportional to the 5'-CG 3'number. PMID- 27239848 TI - [Evaluation of miR-122 level in the plasma of chronically HCV infected patients]. AB - MicroRNAs (miRNAs) are small non-coding RNA molecules, which have an important function in regulating RNA stability and gene expression. They also can circulate in a cell-free form in the blood thatmakes them potential disease markers. The liver contains various classes of miRNAs in which miR-122 accounts for about 70% of all miRNAs and it has been proved that its level increases in case of liver damage. Here, we investigated plasma levels of miR-122 as a useful disease parameter in patients with chronic hepatitis C (CHC) infection. Thirty five hemophilia and thalassemia patients with CHC were studied. The total RNA was extracted from plasma samples, and miR-122 levels were measured by qPCR and then compared with the specific liver markers. The plasma levels of alanine transaminase (ALT) and aspartate transaminase(AST) were correlated with plasma miR-122 level in CHC patients, and the level of circulating miR-122 in healthy individual groups were rarely lower than those of patients with CHC. In our study, miR-122 levels correlated well with markers of liver inflammatory activity. Plasma miR-122 can be assumed to be another marker in liver similar to the currently used specific markers such as ALT and AST for evaluation of liver damage in hepatitis C virus (HCV) infected patients. Moreover, the correlation between miR-122 and ALT was shown to be higher than between miR-122 and AST. PMID- 27239849 TI - [Protective effects of S-adenosylmethionine against CCl4 - and ethanol-induced experimental hepatic fibrosis]. AB - In this study the effects of S-adenosylmethionine (SAM) on experimental hepatic fibrotic rats induced by carbon tetrachloride (CCl(4)) and ethanol and the relevant potential mechanisms were explored. Hepatic fibrotic rat models were established with CCl(4) diluted in olive oil being drunk with 10% ethanol in water. SAM was used both for prevention and treatment. Histological evaluation was carried out by hematoxylin-eosin (HE) and Masson staining of hepatic samples. Serum biochemical assays showed that alanine aminotransferase (ALT) was increased and albumin (ALB) was decreased by CCl(4) and ethanol, and both effects were suppressed by preventing and treating use of SAM. The model control rats got significantly higher scores in fatty degeneration, lobular inflammation, and hepatocyte ballooning. A significant improvement was observed in the SAM prevented rats and SAM-treated rats, which was consistent with the change of fibrosis scoring in each group. Smad3 was induced by CCl(4) and ethanol in the model control group, which was significantly down regulated by SAM. SAM reduced both total Smad3 and phospho-Smad3 in vitro. SAM had a protective effect on hepatic fibrosis in rats induced by CCl(4) combined with ethanol and the down regulation of activity and expression of Smad3 were involved in the potential mechanisms. PMID- 27239850 TI - [Effect of endonuclease G depletion on plasmid DNA uptake and levels of homologous recombination in hela cells]. AB - Endonuclease G (EndoG) is a mitochondrial apoptosis regulator that also has roles outside of programmed cell death. It has been implicated as a defence DNase involved in the degradation of exogenous DNA after transfection of mammalian cells and in homologous recombination of viral and endogenous DNA. In this study, we looked at the effect of EndoG depletion on plasmid DNA uptake and the levels of homologous recombination in HeLa cells. We show that the proposed defence role of EndoG against uptake of non-viral DNA vectors does not extend to the cervical carcinoma HeLa cells, as targeting of EndoG expression by RNA interference failed to increase intracellular plasmid DNA levels. However, reducing EndoG levels in HeLa cells resulted in a statistically significant reduction of homologous recombination between two plasmid DNA substrates. These findings suggest that non viral DNA vectors are also substrates for EndoG in its role in homologous recombination. PMID- 27239851 TI - [Influence of chronic alcohol treatment on the expression of the Bdnf, Bax, Bcl xL, and CASP3 genes in the mouse brain: Role of the C1473G polymorphism in the gene encoding tryptophan hydroxylase 2]. AB - Tryptophan hydroxylase 2 (Tph-2) is the key enzyme in serotonin biosynthesis. Serotonin is one of the main neurotransmitters involved in the regulation of various physiological functions and behavior patterns. The influence of chronic ethanol consumption on the expression of the Bdnf, Bax, Bcl-xL, and CASP3 genes was studied in the brain structures of B6-1473C (C/C) and B6-1473G (G/G) mice that had been obtained on the base of the C57BL/6 strain. The strains differed in the genotype for the C1473G single nucleotide polymorphism in the Tph-2 gene and in Tph-2 enzyme activity. It was found that chronic alcohol treatment led to a significant increase in the expression of the Bdnf gene in the midbrain of B6 1473G mice, but not in B6-1473S. Chronic alcohol treatment considerably decreased the expression of the ultimate brain apoptosis effector, caspase 3, in the frontal cortex, but increased it in the hippocampus of B6-1473G mice. At the same time, chronic ethanol administration reduced the level of the antiapoptotic Bcl xL mRNA in the midbrain of B6-1473C mice. Thus, the C1473G polymorphism in the Tph-2 gene considerably influenced the changes in the expression patterns of genes involved in the regulation of neurogenesis and neural apoptosis induced by chronic ethanol treatment. PMID- 27239852 TI - [Hydrogen peroxide induces oxidative stress and the mitochondrial pathway of apoptosis in RAT intestinal epithelial cells (IEC-6)]. AB - In order to investigate the mechanism of apoptosis in rat intestinal epithelial cells (IEC-6) induced by hydrogen peroxide (H(2)O(2)), IEC-6 cells were subjected to 20 MUmol/L H(2)O(2) and cell proliferation activity was determined using 3 (4,5-dimethyl-2-yl)-2,5-diphenyltetrazolium bromide. Cell morphology was observed by microscopy and cell apoptosis was detected by acridine orange and ethidium bromide staining and the portion of apoptotic cells was measured by flow cytometry. Genes and proteins related to cell apoptosis were detected by RT-PCR and Western blotting, and the mitochondrial membrane potential was evaluated by fluorescence probes. RESULTS: Significant morphology damage was caused by exposure to H(2)O(2), and results showed that ROS generation significantly increased (P < 0.01). The activity of superoxide dismutase decreased significantly (P < 0.05), malondialdehyde content increased (P < 0.05), and expression of both catalase and glutathione peroxidase decreased significantly (P < 0.05) in the H(2)O(2) treatment group. Mitochondrion membrane potential was reduced, cytochrome released into the cytoplasm and caspase-9 and caspase-3 were significantly increased (P < 0.01) after treatment with H(2)O(2). Moreover, the ratio of Bax/Bcl-2 and apoptosis were significantly increased (P < 0.01) in the H(2)O(2) group. In conclusion, the present study indicated that the mitochondrial pathway plays a vital role in H(2)O(2) induced IEC-6 cell apoptosis. PMID- 27239853 TI - [PHF10 isoforms are phosphorylated in the PBAF mammalian chromatin remodeling complex]. AB - Chromatin remodeling complex PBAF(SWI/SNF) alters the structure of chromatin and controls gene expression. PHF10 is a specific subunit of PBAF complex and is expressed as four isoforms in mammalian cells. We demonstrated that all isoforms are expressed in various human cell types of different histological origins. All four isoforms are extensively phosphorylated and their phosphorylation level is depended on the cell type. Phosphorylation of PHF10 isoforms occurs while they are incorporated as a subunit of the PBAF complex, and therefore phosphorylation of PHF10 isoforms may play an essential role in regulation of PBAF complex's function and mechanism of action. PMID- 27239854 TI - [Selection of microRNA for providing tumor specificity of transgene expression in cancer gene therapy]. AB - The use of tumor-specific microRNA loss to inhibit transgene expression in normal cells is considered as a way to increase the specificity of gene-therapeutic antitumor drugs. This method assumes the introduction of recognition sites of suppressed in tumor cells microRNAs into transgene transcipt. In the presented work, the efficiency of the strategy for providing the tumor specificity of transgene expression depending on parameters of microRNA expression in normal and tumor cells was studied. It was established that microRNA suppression in tumor cells and the determination of absolute microRNA levels in tumor and normal cells are not sufficient for the adequate estimation of the possibility of specific microRNA usage in the scheme of cancer gene therapy, and particularly do not allow to exclude a significant decrease in the efficiency of the gene-therapeutic drug upon the introduction of microRNA recognition sites. These parameters are only suitable for the preliminary selection of microRNA. The effect of introduction of microRNA recognition sites on transgene expression level in target tumor cells should be validated experimentally. It is suggested that this should be done directly in the cancer gene therapy scheme with monitoring of the therapeutic transgene activity. PMID- 27239855 TI - [Xenopus laevis peroxiredoxins: Gene expression during development and characterization of the enzymes]. AB - Reactive oxygen species (ROS) are produced via catabolic and anabolic processes during normal embryonic development, and ROS content in the cell is maintained at a certain level. Peroxiredoxins are a family of selenium-independent peroxidases and play a key role in maintaining redox homeostasis of the cell. In addition to regulating the ROS level, peroxiredoxins are involved in intracellular and intercellular signaling, cell differentiation, and tissue development. The time course of peroxiredoxin gene (prx1-6) expression was studied in Xenopus laevis during early ontogeny (Nieuwkoop and Faber stages 10-63). The highest expression level was observed for prx1 at these developmental stages. The prx1, prx3, and prx4 expression level changed most dramatically in response to oxidative stress artificially induced in X. laevis embryos. In X. laevis adults, prx1-6 were all intensely expressed in all organs examined, the prx1 expression level being the highest. The X. laevis prx1-6 genes were cloned and expressed in Escherichia coli, and physico-chemical characteristics were compared for the recombinant enzymes. The highest peroxidase activity and thermal stability were observed for Prx1 and Prx2. It was assumed that Prx1 plays a leading role in X. laevis early development. PMID- 27239856 TI - [Ribonuclease binase induces death in T-cell acute lymphoblastic leukemia cells by apoptosis]. AB - Bacterial ribonuclease binase is a potential anticancer agent. In the present study, we have determined the toxic effect of binase towards cell lines of T-cell acute lymphoblastic leukemia Jurkat and CEMss. We have shown that binase induces apoptosis in these cells. At the same time, binase does not cause toxic effects in leukocytes of healthy donors, which suggests that binase activity towards leukemic cells is selective. We have found that the treatment of cancer cells with binase leads to a reduction in reactive oxygen species and transcription factor NFkappaB levels, and demonstrated that these effects are a common feature of the action of RNases on cancer cells. PMID- 27239857 TI - [Nonstructural protein 1 of tick-borne encephalitis virus activates the expression of immunoproteasome subunits]. AB - The interaction of viral proteins with host cell components plays an important role in antiviral immune response. One of the key steps of antiviral defense is the formation of immunoproteasomes. The effect of nonstructural protein 1 (NS1) of tick-borne encephalitis virus on the immunoproteasome formation was studied. It was shown that cell expression of NS1 does not reduce the efficacy of the immunoproteasome generation in response to interferon-gamma stimulation and even increases the content of the immunoproteasome subunits without the interferon gamma treatment. Thus, NS1 of tick-borne encephalitis virus activates, rather than blocks the mechanisms of immune defense in the cell. PMID- 27239858 TI - [Binding of 1-substituted carbazolyl-3,4-dihydro-beta-carbolines with DNA: Molecular dynamics simulation and MM-GBSA analysis]. AB - Molecular Mechanics-Generalized Born-Solvent Accessibility free energy calculations were used to analyse DNA binding affinity of 1-substituted carbazolyl-3,4-dihydro-beta-carboline molecules. In this study, DNA structure with sequence of d(CGATCG)2 was used for simulations. 15 ns molecular dynamics simulations of the studied complexes were performed. The calculated free energy was compared with experimental antitumor activity (IC(50)). The predicted free energies decreased with the increase of IC(50) values. It was shown that molecules 1-6 bind to DNA via intercalation mode, while molecules 7-9 bind through groove binding mode. Also, it was found that the vdW energy term (DeltaE(vdW)) and the non-polar desolvation energy (DeltaG(SA)) are the favorable terms for binding energy, whereas net electrostatic energies (DeltaE(ele) + DeltaG(GB)) and conformational entropy energy (TDeltaS) are unfavorable ones. PMID- 27239859 TI - [Overexpression, homology modeling and coenzyme docking studies of the cytochrome P450nor2 from Cylindrocarpon tonkinense]. AB - Cytochrome P450nor catalyzes an unusual reaction that transfers electrons from NADP/NADPH to bound heme directly. To improve the expression level of P450nor2 from Cylindrocarpon tonkinense (C.P450nor2), Escherichia coli system was utilized to substitute the yeast system we constructed for expression of the P450nor2 gene, and the protein was purified in soluble form using Ni(+)-NTA affinity chromatography. In contrast to P450nor from Fusarium oxysporum (F.P450nor) and P450nor1 from Cylindrocarpon tonkinense (C.P450nor1), C.P450nor2 shows a dual specificity for using NADH or NADPH as electron donors. The present study developed a computational approach in order to illustrate the coenzyme specificity of C.P450nor2 for NADH and NADPH. This study involved homology modeling of C.P450nor2 and docking analyses of NADH and NADPH into the crystal structure of F.P450nor and the predictive model of C.P450nor2, respectively. The results suggested that C.P450nor2 and F.P450nor have different coenzyme specificity for NADH and NADPH; whilst the space around the B'-helix of the C.P450nor2, especially the Ser79 and Gly81, play a crucial role for the specificity of C.P450nor2. In the absence of the experimental structure of C.P450nor2, we hope that our model will be useful to provide rational explanation on coenzyme specificity of C.P450nor2. PMID- 27239860 TI - [Creation of DNA vaccine vector based on codon-optimized gene of rabies virus glycoprotein (G protein) with consensus amino acid sequence]. AB - An optimized design of the rabies virus glycoprotein (G protein) for use within DNA vaccines has been suggested. The design represents a territorially adapted antigen constructed taking into account glycoprotein amino acid sequences of the rabies viruses registered in the Russian Federation and the vaccine Vnukovo-32 strain. Based on the created consensus amino acid sequence, the nucleotide codon optimized sequence of this modified glycoprotein was obtained and cloned into the pVAX1 plasmid (a vector of the last generation used in the creation of DNA vaccines). A twofold increase in this gene expression compared to the expression of the Vnukovo-32 strain viral glycoprotein gene in a similar vector was registered in the transfected cell culture. It has been demonstrated that the accumulation of modified G protein exceeds the number of the control protein synthesized using the plasmid with the Vnukovo-32 strain viral glycoprotein gene by 20 times. Thus, the obtained modified rabies virus glycoprotein can be considered to be a promising DNA vaccine antigen. PMID- 27239861 TI - [Stalled RNA polymerase is a target of the Mfd factor]. PMID- 27239862 TI - Using Dicationic Ion-Pairing Compounds To Enhance the Single Cell Mass Spectrometry Analysis Using the Single-Probe: A Microscale Sampling and Ionization Device. AB - A unique mass spectrometry (MS) method has been developed to determine the negatively charged species in live single cells using the positive ionization mode. The method utilizes dicationic ion-pairing compounds through the miniaturized multifunctional device, the single-probe, for reactive MS analysis of live single cells under ambient conditions. In this study, two dicationic reagents, 1,5-pentanediyl-bis(1-butylpyrrolidinium) difluoride (C5(bpyr)2F2) and 1,3-propanediyl-bis(tripropylphosphonium) difluoride (C3(triprp)2F2), were added in the solvent and introduced into single cells to extract cellular contents for real-time MS analysis. The negatively charged (1- charged) cell metabolites, which form stable ion-pairs (1+ charged) with dicationic compounds (2+ charged), were detected in positive ionization mode with a greatly improved sensitivity. We have tentatively assigned 192 and 70 negatively charged common metabolites as adducts with (C5(bpyr)2F2) and (C3(triprp)2F2), respectively, in three separate SCMS experiments in the positive ion mode. The total number of tentatively assigned metabolites is 285 for C5(bpyr)2F2 and 143 for C3(triprp)2F2. In addition, the selectivity of dicationic compounds in the complex formation allows for the discrimination of overlapped ion peaks with low abundances. Tandem (MS/MS) analyses at the single cell level were conducted for selected adduct ions for molecular identification. The utilization of the dicationic compounds in the single-probe MS technique provides an effective approach to the detection of a broad range of metabolites at the single cell level. PMID- 27239864 TI - Vaccine Wastage Assessment After Introduction of Open Vial Policy in Surat Municipal Corporation Area of India. AB - BACKGROUND: As per the vaccine management policy of the Government of India all vaccine vials opened for an immunization session were discarded at the end of that session, irrespective of the type of vaccine or the number of doses remaining in the vial prior to 2013. Subsequently, open vial policy (OVP) was introduced in 2013 and should reduce both vaccine wastage as well as governmental healthcare costs for immunization. This study evaluates the vaccine wastage after introduction of the OVP and its comparison with the previous study of vaccine wastage in Surat city before implementation of OVP. It needs to mention that the vaccine policy for this period under comparison was uniform except for the OVP. METHODS: Information regarding vaccine doses consumed and children vaccinated during immunization sessions of 24 urban health centers (UHCs) of Surat city were retrieved for the period of January 1st, 2014 to March 31st, 2014. The data were analyzed to estimate vaccine wastage rate (WR) and vaccine wastage factor (WF). In order to assess the impact of OVP, vaccine WR of this study was compared with that of previous study conducted in Surat city during January 1st, 2012 to March 31st, 2012. RESULTS: The vaccine WR for oral polio vaccine (OPV) has decreased from 25% to 13.62%, while the WRs for DPT, hepatitis B virus (HBV) and the pentavalent vaccine combinedly have decreased from 17.94% to 8.05%. Thus, by implementation of OVP, an estimated 747 727 doses of OPV and 343 725 doses of diphtheria, pertussis and tetanus toxoid vaccine (DPT), HBV and the pentavalent vaccines combinedly have been saved in Surat city of India in a year. CONCLUSION: The implementation of the OVP in Surat city has led to a significant lowering in the vaccine wastage, leading to savings due to lower vaccine requirements. PMID- 27239863 TI - Priority Setting for Improvement of Cervical Cancer Prevention in Iran. AB - BACKGROUND: Cervical cancer is the fourth most common cancer among women worldwide. Organized cervical screening and vaccination against human papilloma virus (HPV) have been successful interventions for prevention of invasive cervical cancer (ICC). Because of cultural and religious considerations, ICC has low incidence in Iran and many other Muslim countries. There is no organized cervical screening in these countries. Therefore, ICC is usually diagnosed in advanced stages with poor prognosis in these countries. We performed a priority setting exercise and suggested priorities for prevention of ICC in this setting. METHODS: We invited experts and researchers to a workshop and asked them to list important suggestions for ICC prevention in Iran. After merging similar items and removing the duplicates, we asked the experts to rank the list of suggested items. We used a strategy grid and Go-zone analysis to determine final list of priorities for ICC prevention in Iran. RESULTS: From 26 final items suggested as priorities for prevention of ICC, the most important priorities were developing national guidelines for cervical screening and quality control protocol for patient follow-up and management of precancerous lesions. In addition, we emphasized considering insurance coverage for cervical screening, public awareness, and research priorities, and establishment of a cervical screening registry. CONCLUSION: A comprehensive approach and implementation of organized cervical screening program is necessary for prevention of ICC in Iran and other low incidence Muslim countries. Because of high cost for vaccination and low incidence of cervical cancer, we do not recommend HPV vaccination for the time being in Iran. PMID- 27239865 TI - Socio-economic Aspects of Health-Related Behaviors and Their Dynamics: A Case Study for the Netherlands. AB - BACKGROUND: Previous studies have mostly focused on socio-demographic and health related determinants of health-related behaviors. Although comprehensive health insurance coverage could discourage individual lifestyle improvement due to the ex-ante moral hazard problem, few studies have examined such effects. This study examines the association of a comprehensive set of factors including socio demographic, health status, health insurance, and perceived change in health insurance coverage with health-related behaviors and their dynamics (ie, changes in behavior). METHODS: Using Survey of Health, Aging, and Retirement in Europe (SHARE) data (a European aging survey among 50+ years old) for the Netherlands in 2004 and 2007 (sample size: 1745), binary and multinomial logit models are employed to study health-related behaviors (daily smoking, excessive alcohol use, and physical inactivity in 2004) and their corresponding changes (stopping or starting unhealthy behavior between 2004 and 2007). RESULTS: Our findings show that being older, being female, having higher education and living with a partner increase the likelihood not to be a daily smoker or to stop daily smoking. At the same time, being older (OR = 3.02 [1.31, 6.95]) and being female (OR = 1.77 [1.05, 2.96]) increases the likelihood to be or to become physically inactive. We also find that worse perceived health insurance coverage in 2007 is associated with a lower likelihood (OR = 0.19 [0.06, 0.57]) of stopping excessive alcohol use in that year. However, we do not find a strong association between the type of health insurance and health behavior. CONCLUSION: Our findings show that all above mentioned factors (ie, socio-demographic and health status factors) are associated with health-related behavior but not in a consistent way across all behaviors. Moreover, the dynamics of each behavior (positive or negative change) is not necessarily determined by the same factors that determine the state of that behavior. We also find that better perceived health insurance coverage is associated with a healthier lifestyle which is not compatible with an ex-ante moral hazard interpretation. Our results provide input to target policies towards elderly individuals in need of lifestyle change. However, further research should be done to identify the causal effect of health insurance on health-related behavior. PMID- 27239866 TI - Whistle Blowing: A Message to Leaders and Managers Comment on "Cultures of Silence and Cultures of Voice: The Role of Whistleblowing in Healthcare Organizations". AB - This comment argues that instead of worrying about the pros and cons of whistleblowing one should focus on the more general problem of the failure of upward communication around safety and quality problems and consider what leaders and managers must do to stimulate subordinates to communicate and reward such communication. The article analyzes why safety failures occur and introduces the concept of practical drift and adaptive moves as necessary for systemic safety to be understood and better handled. It emphasizes the key role of senior leadership in creating a climate in which critical upward communication will become more likely. PMID- 27239867 TI - Collaboration and Co-Production of Knowledge in Healthcare: Opportunities and Challenges. AB - Over time there has been a shift, at least in the rhetoric, from a pipeline conceptualisation of knowledge implementation, to one that recognises the potential of more collaboration, co-productive approaches to knowledge production and use. In this editorial, which is grounded in our research and collective experience, we highlight both the potential and challenge with collaboration and co-production. This includes issues about stakeholder engagement, governance arrangements, and capacity and capability for working in a co-productive way. Finally, we reflect on the fact that this approach is not a panacea, but is accompanied by some philosophical and practical challenges. PMID- 27239868 TI - Policy Options to Reduce Fragmentation in the Pooling of Health Insurance Funds in Iran. AB - There are fragmentations in Iran's health insurance system. Multiple health insurance funds exist, without adequate provisions for transfer or redistribution of cross subsidy among them. Multiple risk pools, including several private secondary insurance schemes, have resulted in a tiered health insurance system with inequitable benefit packages for different segments of the population. Also fragmentation might have contributed to inefficiency in the health insurance systems, a low financial protection against healthcare expenditures for the insured persons, high coinsurance rates, a notable rate of insurance coverage duplication, low contribution of well-funded institutes with generous benefit package to the public health insurance schemes, underfunding and severe financial shortages for the public funds, and a lack of transparency and reliable data and statistics for policy-making. We have conducted a policy analysis study, including qualitative interviews of key informants and document analysis. As a result we introduce three policy options: keeping the existing structural fragmentations of social health insurance (SHI)schemes but implementing a comprehensive "policy integration" strategy; consolidation of existing health insurance funds and creating a single national health insurance scheme; and reducing fragmentation by merging minor well-resourced funds together and creating two or three large insurance funds under the umbrella of the existing organizations. These policy options with their advantages and disadvantages are explained in the paper. PMID- 27239869 TI - Challenges Facing Healthwatch, a New Consumer Champion in England. AB - This article engages with debates about the conceptualisation and practical challenges of patient and public involvement (PPI) in health and social care services. Policy in this area in England has shifted numerous times but increasingly a consumerist discourse seems to override more democratic ideas concerning the relationship between citizens and public services. Recent policy change in England has seen the creation of new consumer champion bodies in the form of local Healthwatch. The article describes these new organisational structures for PPI and shows how those who seek to influence planning and delivery of services or comment or complain about aspects of their care face considerable complexity. This is due, in part, to the ambiguous remit set out for newly instigated Healthwatch organisations by government. Drawing on governance theory, we show that it can also be understood as a function of an increasingly polycentric governance arena. Challenges that flow from this include problems of specifying jurisdictional responsibility, accountability, and legitimacy. We review Healthwatch progress to date, then we set out four challenges facing local Healthwatch organisations before discussing the implications of these for patients and the public. The first challenge relates to non-coterminous boundaries and jurisdictional integrity. Secondly, establishing the unique features of Healthwatch is problematic in the crowded PPI arena. The third challenge arises from limited resources as well as the fact that resources flow to Healthwatch from the local authorities that Healthwatch are expected to hold to account. The fourth challenge we identify is how local Healthwatch organisations negotiate the complexity of being a partner to statutory and other organisations, while at the same time being expected to champion local people's views. PMID- 27239870 TI - A Wicked Problem? Whistleblowing in Healthcare Organisations Comment on "Cultures of Silence And Cultures of Voice: The Role Of Whistleblowing in Healthcare Organisations". AB - Mannion and Davies' article recognises whistleblowing as an important means of identifying quality and safety issues in healthcare organisations. While 'voice' is a useful lens through which to examine whistleblowing, it also obscures a shifting pattern of uncertain 'truths.' By contextualising cultures which support or impede whislteblowing at an organisational level, two issues are overlooked; the power of wider institutional interests to silence those who might raise the alarm and changing ideas about what constitutes adequate care. A broader contextualisation of whistleblowing might illuminate further facets of this multi dimensional problem. PMID- 27239872 TI - Political Impetus: Towards a Successful Agenda-Setting for Inclusive Health Policies in Low- and Middle-Income Countries Comment on "Shaping the Health Policy Agenda: The Case of Safe Motherhood Policy in Vietnam". AB - Agenda-setting is a crucial step for inclusive health policies in the low- and middle-income countries (LMICs). Enlightened by Ha et al manuscript, this commentary paper argues that 'political impetus' is the key to the successful agenda-setting of health policies in LMICs, though other determinants may also play the role during the process. This Vietnamese case study presents a good example for policy-makers of other LMICs; it offers insights for contexts where there are limited health resources and poor health performance. Further research which compares various stages of the health policy process across countries, is much needed. PMID- 27239871 TI - Digital Direct-to-Consumer Advertising: A Perfect Storm of Rapid Evolution and Stagnant Regulation Comment on "Trouble Spots in Online Direct-to-Consumer Prescription Drug Promotion: A Content Analysis of FDA Warning Letters". AB - The adoption and use of digital forms of direct-to-consumer advertising (also known as "eDTCA") is on the rise. At the same time, the universe of eDTCA is expanding, as technology on Internet-based platforms continues to evolve, from static websites, to social media, and nearly ubiquitous use of mobile devices. However, little is known about how this unique form of pharmaceutical marketing impacts consumer behavior, public health, and overall healthcare utilization. The study by Kim analyzing US Food and Drug Administration (FDA) notices of violations (NOVs) and warning letters regarding online promotional activities takes us in the right direction, but study results raise as many questions as it does answers. Chief among these are unanswered concerns about the unique regulatory challenges posed by the "disruptive" qualities of eDTCA, and whether regulators have sufficient resources and oversight powers to proactively address potential violations. Further, the globalization of eDTCA via borderless Internet based technologies raises larger concerns about the potential global impact of this form of health marketing unique to only the United States and New Zealand. Collectively, these challenges make it unlikely that regulatory science will be able to keep apace with the continued rapid evolution of eDTCA unless more creative policy solutions are explored. PMID- 27239873 TI - Advancing Global Health - The Need for (Better) Social Science Comment on "Navigating Between Stealth Advocacy and Unconscious Dogmatism: The Challenge of Researching the Norms, Politics and Power of Global Health". AB - In his perspective "Navigating between stealth advocacy and unconscious dogmatism: the challenge of researching the norms, politics and power of global health," Ooms argues that actions taken in the field of global health are dependent not only on available resources, but on the normative premise that guides how these resources are spent. This comment sets out how the application of a predominately biomedical positivist research tradition in global health, has potentially limited understanding of the value judgements underlying decisions in the field. To redress this critical social science, including health policy analysis has much to offer, to the field of global health including on questions of governance. PMID- 27239874 TI - Considering the Future of Pharmaceutical Promotions in Social Media Comment on "Trouble Spots in Online Direct-to-Consumer Prescription Drug Promotion: A Content Analysis of FDA Warning Letters". AB - This commentary explores the implications of increased social media marketing by drug manufacturers, based on findings in Hyosun Kim's article of the major themes in recent Food and Drug Administration (FDA) warning letters and notices of violation regarding online direct-to-consumer promotions of pharmaceuticals. Kim's rigorous analysis of FDA letters over a 10-year span highlights a relative abundance of regulatory action toward marketer-controlled websites and sponsored advertisements, compared to branded and unbranded social media messaging. However, social media marketing efforts are increasing, as is FDA attention to these efforts. This commentary explores recent developments and continuing challenges in the FDA's attempts to provide guidance and define pharmaceutical company accountability in marketer-controlled and -uncontrolled claims disseminated through social media. PMID- 27239876 TI - Learning Valuable Perspectives on Improving the World's Health Through the Post 2015 Development Agenda: A Response to Recent Commentaries. PMID- 27239875 TI - Still the Great Debate - "Fair Balance" in Direct-to-Consumer Prescription Drug Advertising Comment on "Trouble Spots in Online Direct-to-Consumer Prescription Drug Promotion: A Content Analysis of FDA Warning Letters". AB - The above titled paper examined the Food and Drug Administration's (FDA's) warning letters and notice of violations (NOV) over a 10-year period. Findings from this content analysis reinforced what has been the primary issue for prescription direct-to-consumer advertising (DTCA) since its beginning, the fair balance of risk and benefit information. As opposed to another analysis in 2026 about this still being an issue, is there anything that can be done to prevent this problem from continuing? PMID- 27239877 TI - Achieving Universal Health Coverage by Focusing on Primary Care in Japan: Lessons for Low- and Middle-Income Countries. AB - When the Japanese government adopted Western medicine in the late nineteenth century, it left intact the infrastructure of primary care by giving licenses to the existing practitioners and by initially setting the hurdle for entry into medical school low. Public financing of hospitals was kept minimal so that almost all of their revenue came from patient charges. When social health insurance (SHI) was introduced in 1927, benefits were focused on primary care services delivered by physicians in clinics, and not on hospital services. This was reflected in the development and subsequent revisions of the fee schedule. The policy decisions which have helped to retain primary care services might provide lessons for achieving universal health coverage in low- and middle-income countries (LMICs). PMID- 27239878 TI - An Implementation Research Approach to Evaluating Health Insurance Programs: Insights from India. AB - One of the distinguishing features of implementation research is the importance given to involve implementers in all aspects of research, and as users of research. We report on a recent implementation research effort in India, in which researchers worked together with program implementers from one of the longest serving government funded insurance schemes in India, the Rajiv Aarogyasri Scheme (RAS) in the state of undivided Andhra Pradesh, that covers around 70 million people. This paper aims to both inform on the process of the collaborative research, as well as, how the nature of questions that emerged out of the collaborative exercise differed in scope from those typically asked of insurance program evaluations. Starting in 2012, and over the course of a year, staff from the Aarogyasri Health Care Trust (AHCT), and researchers held a series of meetings to identify research questions that could serve as a guide for an evaluation of the RAS. The research questions were derived from the application of a Logical Framework Approach ("log frame") to the RAS. The types of questions that emerged from this collaborative effort were compared with those seen in the published literature on evaluations of insurance programs in low- and middle income countries (LMICs). In the published literature, 60% of the questions pertained to output/outcome of the program and the remaining 40%, relate to processes and inputs. In contrast, questions generated from the RAS participatory research process between implementers and researchers had a remarkably different distribution - 81% of questions looked at program input/processes, and 19% on outputs and outcomes. An implementation research approach can lead to a substantively different emphasis of research questions. While there are several challenges in collaborative research between implementers and researchers, an implementation research approach can lead to incorporating tacit knowledge of program implementers into the research process, research questions that are more relevant to the research needs of policy-makers, and greater knowledge translation of the research findings. PMID- 27239879 TI - Inequalities in Health Status from EQ-5D Findings: A Cross-Sectional Study in Low Income Communities of Bangladesh. AB - BACKGROUND: Measuring health status by using standardized and validated instrument has become a growing concern over the past few decades throughout the developed and developing countries. The aim of the study was to investigate the overall self-reported health status along with potential inequalities by using EuroQol 5 dimensions (EQ-5D) instrument among low-income people of Bangladesh. METHODS: A cross-sectional household survey was conducted in Chandpur district of Bangladesh. Bangla version of the EQ-5D questionnaire was employed along with socio-demographic information. EQ-5D questionnaire composed of 2-part measurements: EQ-5D descriptive system and the visual analogue scale (VAS). For measuring health status, UK-based preference weights were applied while higher score indicated better health status. For facilitating the consistency with EQ-5D score, VASs were converted to a scale with scores ranging from 0 to 1. Multiple logistic regression models were also employed to examine differences among EQ-5D dimensions. RESULTS: A total of 1433 respondents participated in the study. The mean EQ-5D and VAS score was 0.76 and 0.77, respectively. The females were more likely to report any problem than the males (P < 0.001). Compared to the younger, elderly were more than 2-3 times likely to report any health problem in all EQ-5D dimensions (OR [odds ratio] = 3.17 for mobility, OR = 3.24 for self-care). However, the respondents of the poorest income group were significantly suffered more from every EQ-5D dimension than the richest income quintile. CONCLUSION: Socio-economic and demographic inequalities in health status was observed in the study. Study suggests to do further investigation with country representative sample to measure the inequalities of overall health status. It would be helpful for policy-maker to find a new way aiming to reduce such inequalities. PMID- 27239880 TI - Power and Politics in the Global Health Landscape: Beliefs, Competition and Negotiation Among Global Advocacy Coalitions in the Policy-Making Process. AB - BACKGROUND: Advocacy coalitions play an increasingly prominent role within the global health landscape, linking actors and institutions to attract political attention and resources. This paper examines how coalitions negotiate among themselves and exercise hidden forms of power to produce policy on the basis of their beliefs and strategic interests. METHODS: This paper examines the beliefs and behaviours of health advocacy coalitions using Sabatier's Advocacy Coalition Framework (ACF) as an informal theoretical lens. Coalitions are further explored in relation to the concept of transnational advocacy networks (Keck and Sikkink) and of productive power (Shiffman). The ACF focuses on explaining how policy change takes place when there is conflict concerning goals and technical approaches among different actors. This study uses participant observation methods, self-reported survey results and semi-structured qualitative interviews to trace how a major policy project of the Millennium Development Goal (MDG) era, the Global Strategy for Women's and Children's Health, was constructed through negotiations among maternal, newborn, and child health (MNCH) and sexual and reproductive health and rights (SRHR) advocacy coalitions. RESULTS: The Global Strategy represented a new opportunity for high-level political attention. Despite differing policy beliefs, MNCH and SRHR actors collaborated to produce this strategy because of anticipated gains in political attention. While core beliefs did not shift fundamentally and collaboration was primarily a short-term tactical response to a time-bound opportunity, MNCH actors began to focus more on human rights perspectives and SRHR actors adopted greater use of quantifiable indicators and economic argumentation. This shift emphasises the inherent importance of SRHR to maternal and child health survival. CONCLUSION: As opportunities arise, coalitions respond based on principles and policy beliefs, as well as to perceptions of advantage. Global health policy-making is an arena of contested interests, power and ideas, shaped by the interaction of coalitions. Although policy-making is often seen as a process that should be guided by evidence rather than interest-based politics, this study concludes that a participatory process of debate among different actor-coalitions is vital to progress and can lend greater legitimacy, accountability and transparency to the policy process. PMID- 27239881 TI - Improving Injectable Medicines Prescription in Outpatient Services: A Path Towards Rational Use of Medicines in Iran. AB - Injection is one of the most common medical procedures in the health sector. Annually up to 16 billion injections are prescribed in low- and middle-income countries (LMICs), many of them are not necessary for the patients, increase the healthcare costs and may result in side effects. Currently over 40% of outpatient prescriptions in Iran contain at least one injectable medicine. To address the issue, a working group was established (August 2014 to April 2015) to provide a comprehensive policy brief to be used by national decision-makers. This report is the extract of methods that were followed and the main policy options for improving injectable medicines prescribing in outpatient services. Thirty-three potential policy options were developed focusing on different stakeholders. The panel reached consensus on seven policy options, noting effectiveness, cost, durability, and feasibility of each policy. The recommended policy options are targeted at patients and public (2 policies), insurers (2), physicians (1), pharmacies (1), and the Ministry of Health and Medical Education (MoHME) (1). PMID- 27239882 TI - In Search of the Third Eye, When the Two Others Are Shamefacedly Shut? Comment on "Are Sexual and Reproductive Health Policies Designed for All? Vulnerable Groups in Policy Documents of Four European Countries and Their Involvement in Policy Development". AB - Ivanova et al explored how vulnerable groups and principles of human rights are incorporated into national sexual and reproductive health (SRH) policies in 4 countries. They adapted the EquiFrame of Amin and colleagues of 2011, to SRH vulnerable groups which we believe could now be used for analysis of national SRH polices beyond those 4 countries. Although we fully agree with the authors' two main findings that vulnerable groups and human rights' principles are not sufficiently integrated in SRH policies nor granted the possibility to participate in the process of development in those four countries, we do believe that these shortcomings are not limited to those countries only nor to the identified vulnerable groups either. We are convinced that the issue of SRH as such is still framed within a very limited logic for all with vulnerable groups being perceived as an extra threat or an extra burden. PMID- 27239883 TI - The Tip of the Iceberg of Misleading Online Advertising Comment on "Trouble Spots in Online Direct-to-Consumer Prescription Drug Promotion: A Content Analysis of FDA Warning Letters". AB - Kim's overview of Food and Drug Administration (FDA) regulatory actions from 2005 to 2014 is a comprehensive analysis of the US regulatory experience with online direct-to-consumer advertising (DTCA) of prescription medicines. This experience is of relevance internationally as online DTCA reaches the English-speaking public globally, despite the illegality of DTCA in most countries. The most common violations were omissions or minimizations of risk information, overstatements of efficacy, unsubstantiated claims, and promotion of unapproved ("off-label") use. Nearly one fourth of violations involved cancer drugs, raising additional concerns about patient vulnerability, limited treatment advance, and high costs. Based on content analyses of online DTCA, these cases likely reflect a small proportion of unbalanced and misleading promotional information available on the web. The FDA is only able to review a small proportion of promotional materials submitted to them, due to limited staffing, and the delay between first posting and regulatory action means that many people may be exposed to messages that are found to be inaccurate and misleading. The sheer volume of online DTCA, combined with the ability for content to shift continually, poses unique regulatory challenges. PMID- 27239884 TI - Trouble Spots in Online Direct-to-Consumer Prescription Drug Promotion: Teaching Drug Marketers How to Inform Better or Spin Better? Comment on "Trouble Spots in Online Direct-to-Consumer Prescription Drug Promotion: A Content Analysis of FDA Warning Letters". AB - Hyosun Kim's report "Trouble Spots in Online Direct to Consumer Prescription Drug Promotion: A content Analysis of FDA Warning Letters" aims to teach marketers how to avoid breaching current Food and Drug Administration (FDA) guidelines in their online drug promotion. While Kim hopes to minimise the potential for online promotion to misinform consumers and the study is carefully conducted, teaching drug marketers how to avoid the common mistakes in online drug promotion is more likely to make marketers more adept at spinning information than appropriately balancing it. PMID- 27239885 TI - Searching for the Right to Health in the Sustainable Development Agenda Comment on "Rights Language in the Sustainable Development Agenda: Has Right to Health Discourse and Norms Shaped Health Goals?". AB - The United Nations (UN) Sustainable Development Agenda offers an opportunity to realise the right to health for all. The Agenda's "interlinked and integrated" Sustainable Development Goals (SDGs) provide the prospect of focusing attention and mobilising resources not just for the provision of health services through universal health coverage (UHC), but also for addressing the underlying social, structural, and political determinants of illness and health inequity. However, achieving the goals' promises will require new mechanisms for inter-sectoral coordination and action, enhanced instruments for rational priority-setting that involve affected population groups, and new approaches to ensuring accountability. Rights-based approaches can inform developments in each of these areas. In this commentary, we build upon a paper by Forman et al and propose that the significance of the SDGs lies in their ability to move beyond a biomedical approach to health and healthcare, and to seize the opportunity for the realization of the right to health in its fullest, widest, most fundamental sense: the right to a health-promoting and health protecting environment for each and every one of us. We argue that realizing the right to health inherent in the SDG Agenda is possible but demands that we seize on a range of commitments, not least those outlined in other goals, and pursue complementary openings in the Agenda - from inclusive policy-making, to novel partnerships, to monitoring and review. It is critical that we do not risk losing the right to health in the rhetoric of the SDGs and ensure that we make good on the promise of leaving no one behind. PMID- 27239886 TI - Health Rights and Realization Comment on "Rights Language in the Sustainable Development Agenda: Has Right to Health Discourse and Norms Shaped Health Goals?". AB - In their hypothesis published in IJHPM, Lisa Forman and colleagues examined the prominence of the right to health and sexual and reproductive health rights (as well as related language) in four of the key reports that fed into the process of negotiating the Sustainable Development Goals (SDGs). Now that the SDGs have been formally adopted, this comment builds on some of the insights of Forman and colleagues to examine the extent to which those rights have been incorporated in SDGs 3 and 5. I argue that sexual and reproductive health rights are relatively well-covered within the SDGs. In terms of the right to health, however, the picture is much less clear. Some of the elements that make up that right are present and correct, but the SDGs have delivered no coherent vision of how a 'right to health' might actually be realized. An important task facing global health and human rights advocates is to continue pushing human rights framings so that progress is made both on meeting the SDGs and on realizing the right to health. PMID- 27239887 TI - Towards a Global Social Support System: A Response to the Recent Commentaries. PMID- 27239888 TI - Correction: Expanded HTA: Enhancing Fairness and Legitimacy. AB - The authors would like to correct the name of the third author in this paper to Julian Urrutia. PMID- 27239889 TI - Outcome of secondary shoulder surgery in children with neonatal brachial plexus palsy with and without nerve surgery treatment history: A long-term follow-up study. AB - OBJECTIVE: Irrespective of treatment history, shoulder dysfunction may occur in children with neonatal brachial plexus palsy. Following internal contracture release and/or muscle tendon transfer (ICR/MTT) shoulder function gain is possible. This study describes the outcomes of ICR/MTT for children with neonatal brachial plexus palsy, with or without prior nerve surgery (a group with prior nerve surgery and a group without prior nerve surgery). PATIENTS AND METHODS: The study included children who underwent an ICR/MTT with a minimum follow-up of 6 months. Active/passive range of motion (aROM/pROM)/Mallet scores were recorded (pre-operatively, 6 months, and 1, 3, 5 and 10 years post-surgery). Changes over time within groups were analysed using a linear mixed model. RESULTS: A total of 115 children (60 boys) were included, 82 with nerve surgery history, mean age 4.7 years (standard deviation (SD) 3.3 years), mean follow-up 6 years (SD 3.2 years). Pre-operatively active external rotation, abduction and forward-flexion were worse in the group with prior nerve surgery. aROM, pROM and Mallet scores, improved at all time-points in both groups. The course and magnitude of these improvements were largely similar in both groups. In the long-term, the effects of ICR/MTT decrease, but remain significant. CONCLUSION: In children with neonatal brachial plexus palsy shoulder function improved after ICR/MTT, irrespective of treatment history. Pre-operative shoulder function was worse in the group with prior nerve surgery, resulting in less function in this group after ICR/MTT. Reporting on outcome after secondary shoulder surgery should be stratified into children with and without prior nerve surgery, in order to prevent over- or underestimation of results. LEVEL OF EVIDENCE: This study concerned a retrospective treatment case series study. LEVEL OF EVIDENCE: IV. PMID- 27239890 TI - Metal-Organic Framework Colloids: Disassembly and Deaggregation. AB - We demonstrate a high-resolution method as an efficient tool to in situ characterize partially reversible assembly and aggregation of metal-organic framework (MOF) colloids. Based on the gas-phase electrophoresis, the primary size and the degree of aggregation of the MOF-525 crystals are tunable by pH adjustment and mobility selection. These findings allow for the further size control of MOF colloids and prove the capability of semiquantitative analysis for the MOF-based platforms in a variety of aqueous formulations (e.g., biomedical applications). PMID- 27239891 TI - Global exponential stability of impulsive complex-valued neural networks with both asynchronous time-varying and continuously distributed delays. AB - This paper investigates the stability problem for a class of impulsive complex valued neural networks with both asynchronous time-varying and continuously distributed delays. By employing the idea of vector Lyapunov function, M-matrix theory and inequality technique, several sufficient conditions are obtained to ensure the global exponential stability of equilibrium point. When the impulsive effects are not considered, several sufficient conditions are also given to guarantee the existence, uniqueness and global exponential stability of equilibrium point. Two examples are given to illustrate the effectiveness and lower level of conservatism of the proposed criteria in comparison with some existing results. PMID- 27239892 TI - A note on finite-time and fixed-time stability. AB - In this letter, by discussing t(V)=MU(-1)(V), we provide a general approach to reveal the essence of finite-time stability and fixed-time convergence for the system V(t)=MU(V(t)). Thus, we derive some conditions for finite-time and fixed time convergence. As applications, we propose schemes to achieve finite-time and fixed-time synchronization in complex networked systems. PMID- 27239893 TI - Comparison of the force-, velocity-, and power-time curves recorded with a force plate and a linear velocity transducer. AB - This study aimed to correlate, compare, and determine the reliability of force, velocity, and power values collected with a force plate (FP) and a linear transducer during loaded jumps. Twenty-three swimmers performed an incremental loading test at 25, 50, 75, and 100% of their own body weight on a FP. A linear velocity transducer (LVT) was attached to the bar to assess the peak and the mean values of force, velocity, and power. Both the peak variables (r = 0.94 - 0.99 for peak force, r = 0.83 - 0.91 for peak velocity, and r = 0.90-0.94 for peak power; p < 0.001) and the mean variables (r = 0.96-0.99 for mean force, r = 0.87 0.89 for mean velocity, and r = 0.93-0.96 for mean power; p < 0.001) were strongly correlated between both measurement tools. Differences in the shape of the force-, velocity-, and power-time curves were observed. The LVT data showed a steeper increase in these variables at the beginning of the movement, while the FP recorded larger values in the latter part. Peak values were more reliable than mean values. These results suggest that the LVT is a valid tool for the assessment of loaded squat jump. PMID- 27239895 TI - Pre-formulation Study of Salicylidine-cephalexin-Zn(II) dihydrate, a New Derivative of Cefalexin. AB - BACKGROUND: Salicylidine-cefalexin-Zn(II).2H2O, a new derivative of cefalexin, has been reported to possess enhanced anti-microbial activity and lower toxicity than cefalexin. It is, therefore, desirable to carry out a pre-formulation study to determine its pharmaceutical properties which will be useful in conversion of the new molecule into various dosage forms. METHODS: The compound was synthesized by the previously reported method and characterized by elemental, Fourier transform infrared and electronic spectral analyses. Crystallinity was determined by powder x-ray diffraction. Particle size distribution was determined by a laser based sizer. Other properties including flow, density and compaction strength were determined by use of appropriate standard methods. The compound was also evaluated as a prodrug through dissolution study by the USP method. RESULTS: It was found that the new derivative is an amorphous powder with different bulk density, porosity, compressibility, plasticity and flow properties as compared to cefalexin. The amorphous character of the new compound suggests that it will have better bioavailability. The dissolution study indicated that this compound is hydrolyzed to produce cefalexin in water in a sustained manner, thus it will act as a prodrug in vivo. The release data fitted well into Highuchi model. CONCLUSION: Various pharmaceutical properties essentially required for formulation of salicylidine-cefalexin-Zn(II).2H2O into dosage forms were determined. This study has shown that the new drug would behave as a prodrug for cefalexin with better bioavailability. PMID- 27239894 TI - Parental loss of family members within two years of offspring birth predicts elevated absorption scores in college. AB - Liotti proposed that interactions during infancy with a parent suffering unresolved loss could lead to vulnerabilities to altered states of consciousness. Hesse and van IJzendoorn provided initial support for Liotti's hypothesis, finding elevated scores on Tellegen's Absorption Scale - a normative form of dissociation - for undergraduates reporting that their parents had experienced the loss of family members within two years of their birth. Here, we replicated the above findings in a large undergraduate sample (N = 927). Additionally, we investigated mother's and father's losses separately. Perinatal losses, including miscarriage, were also considered. Participants reporting that the mother or both parents had experienced loss within two years of their birth scored significantly higher on absorption than those reporting only perinatal, only father, or no losses. While not applicable to the assessment of individuals, the brief loss questionnaire utilized here could provide a useful addition to selected large scale studies. PMID- 27239896 TI - Single anterior approach for cervical spine fractures at C5-T1 complicating ankylosing spondylitis. AB - OBJECTIVES: To evaluate the outcomes of anterior approach for cervical spine fractures at C5-T1 in patients with ankylosing spondylitis (AS) and study the problems encountered in diagnosis and treatment. PATIENTS AND METHODS: Ten patients with AS (all males; mean age 43.7+/-9.4 years) underwent anterior surgeries to treat fractures at C5-T1. Skull tractions were performed on patients with fracture dislocation preoperatively. After operation, all the patients wore a cervical collar for 3 months. Plain radiographs at follow-up were reviewed. If bone fusion could not be confirmed on plain radiograph, CT scan was employed. The pre- and postoperative neurological statuses were evaluated according to the Frankel grading system. Problems encountered in diagnosis and treatments were analyzed. RESULTS: The mean follow-up was 41.2+/-22.7months. After operation, the displacements of fractures were significantly reduced(P<0.05). Bone fusions were observed in 9 patients at final follow-up. Frankel grades improved by 1.0+/-0.7 grade (P>0.05). Posterior complications occurred in four patients, including implants failure (n=1), subsidence of cage (n=1), hoarse voice (n=1) and pneumonias (n=2). The patient with implants failure required revision surgery and anterior-posterior fixation. Patient with subsidence of the titanium cage achieved bone fusion with prolonged cervical collar immobilization. CONCLUSION: The diagnosis and treatment of cervical spine fractures at C5-T1 in AS patients are challenging, with high risk of neurological compromise and postoperative complications. The single anterior approach followed by postoperative immobilization with a cervical collar can yield acceptable results if the cases are properly selected. PMID- 27239897 TI - Sciatic nerve injuries following femoral shaft fractures: Does the time interval from injury to surgery matter? AB - OBJECTIVES: Sciatic nerve injuries following fractures of femoral shaft are uncommon complications. The patients with such deficits present with sciatic nerve palsy. A few cases of sciatic nerve injuries secondary to femoral shaft fractures have thus far been reported. If such patients fail to improve spontaneously, they may require surgical exploration. The present paper gives an account of surgical exploration in patients presenting with sciatic nerve injuries following femoral shaft fractures. PATIENTS AND METHODS: Clinical outcomes were assessed in 14 patients undergoing surgical exploration of sciatic nerve injuries following femoral shaft fractures. RESULTS: There was a significant negative correlation between the time interval from injury to surgery and motor function recovery. Furthermore, a negative but non-significant correlation was seen between the time interval from injury to surgery and sensory recovery. CONCLUSIONS: Early exploration of sciatic nerve injuries following femoral shaft fractures can be beneficial if the nerve injury does not improve spontaneously. PMID- 27239898 TI - Transforaminal percutaneous endoscopic lumbar discectomy for very high-grade migrated disc herniation. AB - OBJECTIVES: Transforaminal percutaneous endoscopic lumbar discectomy (PELD) for high-grade migrated disc herniation has been regarded as a challenging task, but because of the remarkable improvement in navigable instruments and advanced epiduroscopic technique, it can be used for the treatment of high- or very high grade migrated disc herniation. The purpose of this study was to describe in detail the standardized technique of transforaminal PELD for very high-grade migrated disc herniation and demonstrate the clinical results. METHODS: Very high grade lumbar migrated disc herniation was defined as a disc migration beyond the inferior margin of the pedicle. Thirteen consecutive patients with very high grade lumbar migrated disc herniation were treated with transforaminal PELD, which has three stages: (1) direction-oriented transforaminal approach, (2) release of periannular anchorage, and (3) epiduroscopic fragmentectomy with navigable instruments. The surgical outcomes were assessed using the visual analogue pain score (VAS), Oswestry disability index (ODI), and modified Macnab criteria. RESULTS: The operated levels were L3-4 in 2 (15.4%) patients, L4-5 in 10 (76.9%), and L5-S1 in 1 (7.7%). The directions of migration were cranial in 8 patients and caudal in 5. The mean VAS for leg pain improved from 7.86+/-1.28 preoperatively to 2.54+/-1.51 at 6 weeks postoperatively and 1.85+/-1.07 at 1year postoperatively (P<0.01). The mean preoperative ODI improved from 84.92+/-6.36 preoperatively to 27.83+/-7.34 at 6 weeks postoperatively and 17.54+/-13.40 at 1year postoperatively (P<0.01). Excellent or good global outcomes were obtained in 84.6%, and the rate of symptomatic improvement was 92.3%. CONCLUSION: Transforaminal PELD can be effective for very high-grade migrated lumbar disc herniation, and a standardized technique may provide a reliable and reproducible result. PMID- 27239899 TI - Effects of ATP-sensitive potassium channel blockers on vascular hyporeactivity, mesenteric blood flow, and survival in lipopolysaccharide-induced septic shock model. AB - In this study, the possible therapeutic effects of various ATP-sensitive potassium channel (KATP) blockers (glibenclamide, repaglinide, 5-HD, HMR-1098) have been tested in experimental septic shock model. Rats were given lipopolysaccharide (1 mg.kg(-1)) to create experimental shock model and 4 h later, under 400 mg.kg(-1) chloral hydrate anesthesia, parameters such as blood pressure, mesenteric blood flow, the response of mesenteric circulation to phenylephrine (vasoconstrictor stimulation), and organ and oxidative damage were analyzed. Also 75 mg.kg(-1) lethal dose of lipopolysaccharide was given to mice and effects of KATP blockers on survival have been tested. Non-selective blocker glibenclamide with sulphonylurea structure and sarcolemmal KATP channel blocker HMR-1098, which have the similar chemical structure, have improved the pathological parameters such as decrease in mesenteric blood flow, vascular hyporeactivity, but could not prevent the decrease in blood pressure, and oxidative and organ damage that were observed in the shock model. Also, both blockers have decreased the mortality rate from 80% to 40%-50%. Similar (preventive) therapeutic effects were not observed with non-selective blocker repaglinide and mitochondrial KATP channel blocker 5-HD, which were non sulphonylurea structure. As a result, only KATP channel blockers that have sulphonylurea structure can be a new therapeutic approach in septic shock. PMID- 27239900 TI - Analytic process and dreaming about analysis. AB - Dreams about the analytic session feature a manifest content in which the analytic setting is subject to distortion while the analyst appears undisguised. Such dreams are a consistent yet infrequent occurrence in most analyses. Their specificity consists in never reproducing the material conditions of the analysis as such. This paper puts forward the following hypothesis: dreams about the session relate to some aspects of the analyst's activity. In this sense, such dreams are indicative of the transference neurosis, prefiguring transference resistances to the analytic elaboration of key conflicts. The parts taken by the patient and by the analyst are discussed in terms of their ability to signal a deepening of the analysis. PMID- 27239901 TI - A longitudinal analysis of cross-border ties and depression for Latino adults. AB - Recent scholarship suggests a significant association between cross-border ties, or ties maintained with family and friends in countries and communities of origin, and the mental health of immigrants and their descendants. To date, this research has been exclusively cross-sectional, precluding conclusions about a causal association between cross-border ties and mental health outcomes. In the present study we undertake a longitudinal analysis of the relationship between cross-border ties and depression measured over a ten-year period for a sample of immigrant and U.S.-born Latinos. Data are from the Sacramento Area Latino Study on Aging (1998-2008), a population-based, prospective study of Latin American origin adults 60 years and older. We find that cross-border ties reported at baseline were significantly associated with depression in subsequent study waves, even after controlling for the presence of depression at baseline, albeit with substantial differences by gender and nativity. Specifically, communication with family and friends in Latin America and travel to Latin America at baseline were each significantly associated with greater odds of depression for immigrant women, but with lower odds of depression for U.S.-born Latina women over the study period. Travel to Latin America at baseline was significantly associated with lower odds of depression for Latino men across the study. Across all models we control for depressive symptomatology at baseline to account for the reciprocal nature of depressive symptoms and engagement with social ties, including cross-border ties. Our findings suggest that cross-border ties may represent a unique source of both resilience and risk for the long-term mental health of immigrant Latinos and their descendants. PMID- 27239902 TI - Prevention of frailty through narrative intervention. AB - BACKGROUND: Frailty is a syndrome of increased vulnerability with adverse outcomes, increasing with age for elderly people. So far, intervention programs have mainly addressed the physical components of frailty. As biographical writing approaches have shown positive effects on cognition and health, the aim of this study is to investigate the effects of a biographical disclosure intervention on psychological frailty and health in older adults. METHODS: In total, 198 elderly people (mean age = 75.1 years) were recruited and randomly assigned to four disclosure conditions: oral biographical disclosure, written structured and unstructured biographical disclosure, daily diary and a control group. Frailty was measured with the Tilburg Frailty Indicator, and physical and mental health were assessed with the Short Form (12-item) Health Survey. Measurements were assessed pre- and post-intervention, and at a three month follow-up. Mixed design ANOVAs with repeated measures, correlations and Wilcoxon tests were calculated. RESULTS: The sample showed a frailty prevalence of 39.9% pre-intervention. Participants in the oral biographical disclosure, structured biographical writing, and daily diary groups showed improvements in their frailty and mental health, with small effect sizes. No effect for physical health was evident. People with high frailty symptoms and low mental health benefitted from the intervention. Frailty was negatively correlated with physical and mental health components. CONCLUSIONS: The results of the intervention indicate a short-term positive effect on frailty and mental health in elderly people, who benefitted from the disclosure intervention in terms of improved mental health and lower frailty levels. Early frailty detection is therefore crucial in the treatment and care of older adults, and biographical disclosure approaches can help to maintain health at old age. PMID- 27239903 TI - Prospective frequency correction for macromolecule-suppressed GABA editing at 3T. AB - PURPOSE: To investigate the effects of B0 field offsets and drift on macromolecule (MM)-suppressed GABA-editing experiments, and to implement and test a prospective correction scheme. "Symmetric" editing schemes are proposed to suppress unwanted coedited MM signals in GABA editing. MATERIALS AND METHODS: Full density-matrix simulations of both conventional (nonsymmetric) and symmetric MM-suppressed editing schemes were performed for the GABA spin system to evaluate their offset-dependence. Phantom and in vivo (15 subjects at 3T) GABA-edited experiments with symmetrical suppression of MM signals were performed to quantify the effects of field offsets on the total GABA+MM signal (designated GABA+). A prospective frequency correction method based on interleaved water referencing (IWR) acquisitions was implemented and its experimental performance evaluated during positive and negative drift. RESULTS: Simulations show that the signal from MM-suppressed symmetrical editing schemes is an order of magnitude more susceptible to field offsets than the signal from nonsymmetric editing schemes. The MM-suppressed GABA signal changes by 8.6% per Hz for small field offsets. IWR significantly reduces variance in the field offset and measured GABA levels (both P < 0.001 by F-tests), maintaining symmetric suppression of MM signal. CONCLUSION: Symmetrical editing schemes substantially increase the dependence of measurements on B0 field offsets, which can arise due to patient movement and/or scanner instability. It is recommended that symmetrical editing should be used in combination with effective B0 stabilization, such as that provided by IWR. J. Magn. Reson. Imaging 2016;44:1474-1482. PMID- 27239904 TI - Hemodynamic aspects of reduced platelet adhesion on bioinspired microstructured surfaces. AB - Occlusion by thrombosis due to the absence of the endothelial cell layer is one of the most frequent causes of failure of artificial vascular grafts. Bioinspired surface structures may have a potential to reduce the adhesion of platelets contributing to hemostasis. The aim of this study was to investigate the hemodynamic aspects of platelet adhesion, the main cause of thrombosis, on bioinspired microstructured surfaces mimicking the endothelial cell morphology. We tested the hypothesis that platelet adhesion is statistically significantly reduced on bioinspired microstructured surfaces compared to unstructured surfaces. Platelet adhesion as a function of the microstructure dimensions was investigated under flow conditions on polydimethylsiloxane (PDMS) surfaces by a combined experimental and theoretical approach. Platelet adhesion was statistically significantly reduced (by up to 78%; p<=0.05) on the microstructured PDMS surfaces compared to that on the unstructured control surface. Finite element method (FEM) simulations of blood flow dynamic revealed a micro shear gradient on the microstructure surfaces which plays a pivotal role in reducing platelet adhesion. On the surfaces with the highest differences of the shear stress between the top of the microstructures and the ground areas, platelet adhesion was reduced most. In addition, the microstructures help to reduce the interaction strength between fluid and surfaces, resulting in a larger water contact angle but no higher resistance to flow compared to the unstructured surface. These findings provide new insight into the fundamental mechanisms of reducing platelet adhesion on microstructured bioinspired surfaces and may lay the basis for the development of innovative next generation artificial vascular grafts with reduced risk of thrombosis. PMID- 27239905 TI - Mucoadhesive microparticulates based on polysaccharide for target dual drug delivery of 5-aminosalicylic acid and curcumin to inflamed colon. AB - In this work, thiolated chitosan/alginate composite microparticulates (CMPs) coated by Eudragit S-100 were developed for colon-specific delivery of 5 aminosalicylic acid (5-ASA) and curcumin (CUR), and the use of it as a multi drug delivery system for the treatment of colitis. The physicochemical properties of the CMPs were evaluated. In vitro release was performed in gradually pH-changing medium simulating the conditions of different parts of GIT, and the results showed that the Eudragit S-100 coating has a pH-sensitive release property, which can avoid drug being released at a pH lower than 7. An everted sac method was used to evaluate the mucoadhesion of CMPs. Ex vivo mucoadhesive tests showed CMPs have excellent mucosa adhesion for the colonic mucosa of rats. In vivo treatment effect of enteric microparticulates systems was evaluated in colitis rats. The results showed superior therapeutic efficiency of this drug delivery system for the colitis rats induced by TNBS. Therefore, the enteric microparticulates systems combined the properties of pH dependent delivery, mucoadhesive, and control release, and could be an available tool for the treatment of human inflammatory bowel disease. PMID- 27239906 TI - Efficient penetration of ceric ammonium nitrate oxidant-stabilized gamma maghemite nanoparticles through the oval and round windows into the rat inner ear as demonstrated by MRI. AB - We aimed to evaluate the magnetic resonance imaging (MRI) contrast effect and delivery efficiency through the middle ear into the inner ear using novel super paramagnetic maghemite (gamma-Fe2 O3 ) nanoparticles (NPs) generated using ceric ammonium nitrate (CAN)-mediated oxidation of Fe3 O4 NPs (CAN-gamma-Fe2 O3 NPs). The CAN-gamma-Fe2O3 NPs, having hydrodynamic diameters of 50-60 nm and potentials of +55.2 mV, displayed super-paramagnetic behavior characterized by a saturation magnetization Ms of 75.2 emu/g NPs. The r1 and r2* relaxivity (curve slopes) values were 0.0015 and 189 mmol-1 s-1 , respectively, indicating strong T2* relaxation maghemite-based NPs. The CAN-gamma-Fe2 O3 NPs were stable in the 7.0 T magnetic field. At 3 h after the tympanic medial wall administration, the NPs had significantly located to the cochlea and vestibule. The signal started to recover at 6 h in the ipsilateral cochlea and by 2 d in the vestibule post administration. There was no difference in the signal intensity between the left and right ears on the 14th d. Prussian blue staining for iron demonstrated NP distribution in the inner ear tissue. The novel CAN-gamma-Fe2 O3 NPs are a strong MRI T2 contrast agent and penetrated the round and oval windows and have potential application in the molecular imaging of the inner ear. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1883-1891, 2017. PMID- 27239907 TI - [Coronary artery bypass grafting using internal thoracic artery and saphenous vein via left thoracotomy]. PMID- 27239908 TI - [Endoscopic interventions in diagnosis and treatment of Mirizzi syndrome]. AB - AIM: To define the role of endoscopic interventions in diagnosis and treatment of Mirizzi syndrome. MATERIAL AND METHODS: Results of treatment of 41 patients with Mirizzi syndrome are presented. Endoscopic transpapillary interventions including cholangiography, papillosphincterotomy lithoextraction, nazobiliary drainage were used as a first step in all cases. RESULTS AND DISCUSSION: In 4 cases laparoscopic cholecystectomy was performed after biliary tree sanitation. In 6 advanced age patients with severe comorbidities common bile duct stenting alone was preferred. Open interventions were performed in 15 patients (36.6%) including cholecystectomy, choledocholithotomy with common bile duct drainage. CONCLUSION: It is shown that endoscopic transpapillary methods of diagnosis and treatment of Mirizzi syndrome provides adequate decompression and sanitation of the bile ducts in most cases and significantly reduces number of open surgical procedures. PMID- 27239909 TI - [Serum and bile cytokines dynamics in patients with non-tumoral obstructive jaundice and suppurative cholangitis]. AB - AIM: To study serum and bile cytokines dynamics in patients with non-tumoral obstructive jaundice and suppurative cholangitis. MATERIAL AND METHODS: Comparative study of serum and bile cytokines in 49 operated patients with biliary pathology was performed. Patients were divided into 3 groups. The first group included 24 patients with acute calculous cholecystitis (ACCh), the second group consisted of 12 patients with chronic calculous cholecystitis (CCCh) and the third group included 13 patients with choledocholithiasis complicated by obstructive jaundice and suppurative cholangitis. RESULTS AND DISCUSSION: All patients had increased level of TNF-alpha, IL-4 i IL-6. There was augmentation of biliary cytokines in patients with obstructive jaundice compared with those with acute and chronic calculous cholecystitis. In patients with obstructive jaundice and suppurative cholangitis the highest levels of cytokines were observed. Patients with obstructive jaundice (OJ), suppurative cholangitis (SCh) and chronic calculous cholecystitis had higher levels of cytokines in both blood and bile than in those with OJ, SCh and acute calculous cholecystitis that is explained by development of purulent inflammation on background of previous cytokines imbalance and chronic inflammation. In general, patients with acute calculous cholecystitis had higher levels of TNF-alpha and IL-6 in blood serum and IL-4 in bile. Patients with chronic calculous cholecystitis had higher concentration of TNF-alpha and IL-4 in bile and IL-6 - in blood serum. CONCLUSION: Both forms of cholecystitis and their complications are associated with increased cytokines in serum and bile. The level of augmentation depends on the type of inflammation and complications. Comparative study of cytokines can be the most informative criterion to monitor the postoperative period. PMID- 27239910 TI - [The results of open and laparoscopic appendectomy in pregnant women with acute appendicitis]. AB - AIM: To compare conventional and laparoscopic appendectomy in pregnant women. MATERIAL AND METHODS: The study included 86 patients with acute appendicitis who were surgically treated. In group 1 (42 women) laparoscopic approach was used, in group 2 (44 patients) - laparotomy. RESULTS: Postoperative complications were observed in 2 (4.8%) and 3 (6.8%) patients in groups 1 and 2 respectively. All complications related to Clavien-Dindo class I-II. There were no premature births and abortions in laparoscopy group. In case of conventional surgery premature births and abortions were observed in 2 (4.5%) and 1 (2.27%) observations respectively. Other women had timely childbirth in terms of 36-41 weeks. CONCLUSION: Risk of delay exceeds risk of vain appendectomy. All pregnant women with acute appendicitis should be examined by obstetrician-gynaecologist, surgeon, urologist, anesthesiologist. If acute appendicitis can not be excluded based on clinical data the patient should be operated. Diagnostic laparoscopy and laparoscopic appendectomy are advisable in case of pregnancy up to 24 weeks. Woman should be under observation of obstetrician-gynaecologist in perioperative period to prevent premature birth and abortion. PMID- 27239911 TI - [Ribs osteosynthesis in patients with isolated and combined chest trauma]. AB - INTRODUCTION: Rapid methods of costal fractures fixation using special costal plates are becoming more common. AIM: To evaluate the efficacy of ribs osteosynthesis in patients with isolated and combined chest trauma. MATERIAL AND METHODS: It is presented an experience of surgical treatment of patients with costal fractures in case of isolated (30) and combined (29) chest injury. System for ribs osteosynthesis was used predominantly in surgical tactics. RESULTS: Immediate surgical results were analyzed. Most patients had increase of blood gas parameters, oxygenation in the postoperative period. In case of isolated chest injury mean duration of mechanical ventilation was 1.3+/-1.1, incidence of complications - 3.3%, mortality rate - 0%. In group of combined injuries those indexes were 4.6+/-3.05, 13.8% and 13.8% respectively. CONCLUSION: The method of ribs osteosynthesis in patients with isolated and combined chest trauma showed high efficiency. PMID- 27239912 TI - [Endoscopic treatment of intestinal malrotation in newborns and infants]. AB - AIM: To compare treatment of intestinal malrotation in newborns and infants using laparoscopy and laparotomy. MATERIAL AND METHODS: For the period from January 2004 to December 2013 34 Ladd's procedures were performed. Children were divided into 2 groups by 17 patients: laparoscopic (group I) and open treatment (group II). RESULTS: Both groups had similar demographic and other preoperative parameters. There were significant differences in duration of operation between both groups (61 vs. 70 minutes). Nutrition was initiated earlier after mini invasive treatment (1.5 days vs. 3 days) and the time need for full enteral nutrition was also less (4.2 days vs. 6.9 days). Hospital-stay was shorter in group I (7.7 vs. 10.2 days). Number of early postoperative complications was similar in groups. Incidence of remote complications was higher in laparotomy group but the differences were not significant. CONCLUSION: Our results showed that endoscopic correction of congenital anomalies of intestinal rotation provides better postoperative results than open surgery and can be widely used in young children. PMID- 27239913 TI - [Intraperitoneal and retromuscular abdominal wall repair using ultra-light and titanium-containing polypropylene mesh (experimental research)]. AB - AIM: To study experimental possibility of light, ultra-light and titanium containing endoprostheses implantation for postoperative hernias correction. MATERIAL AND METHODS: Abdominal wall repair was simulated in 72 rabbits. In the first group polypropylene mesh with fibers diameter of 90 microns and surface density of 36 g/m2 was used. In the second group we applied polypropylene mesh with fibers diameter of 65 microns and thin layer of titanium. Their surface density was 16 g/m2. Intraperitoneal onlay mesh (IPOM) and sublay retromuscular (SRM) techniques were used in group 1 and 2 respectively. Animals were taken out from the experiment in 30 and 60 days. Adhesive process in implantation area was evaluated using the method of Egiev V.N. and Lyadov V.K. RESULTS: The most pronounced adhesive process was observed in IPOM series. Type of endoprosthesis and terms of postoperative period did not significant effect adhesive process. SRM method was associated with significantly less pronounced adhesions. Analysis of all data showed that severity of adhesive process was significantly higher in IPOM series compared with SRM technique. CONCLUSION: Our study showed that severity of abdominal adhesive process associated with repair using ultra-light mesh is completely determined by surgical technique and did not depend on type of endoprosthesis and terms of postoperative period. Described implants should be used for retromuscular implantation rather intraperitoneal position. PMID- 27239914 TI - [Effectiveness of Reamberin in orthopedic knee surgery]. AB - AIM: To study an efficacy of Reamberine in complex therapy in early postoperative period after knee-joint surgery. MATERIAL AND METHODS: It was analyzed treatment of 108 patients (47 men and 61 women) with degenerative diseases of knee-joint in postoperative period. Periarticular osteotomy of tibia and knee-joint replacement were performed. Patients were divided into 2 groups. Main group consisted of 43 patients who received Reamberine 400-800 ml with infusion rate 4-5 ml/min during 1-1,5 hours for 4-8 days postoperatively. Control group (65 patients) had conventional therapy with daily volume 400-800 ml. RESULTS: It was revealed that Reamberine increased efficacy of postoperative treatment. There were earlier (by 52.6% compared with control group) improvement of health including weakness disappearance, sleep and appetite recovery. Hemodynamic parameters were also improved (stabilization of blood pressure and pulse). It was observed earlier disappearance of pain and edematous syndrome (by 32.3%). There were also earlier postoperative wound healing (by 21.3%) and reducing of rehabilitation terms (by 72%, i.e. 2.1 +/- 0.7 vs. 7.5 +/- 0.9 days respectively). PMID- 27239915 TI - [Treatment of combined post-burn strictures of esophagus and trachea]. PMID- 27239916 TI - [Surgical treatment of recurrent right kidney cancer complicated by tumoral thrombosis of inferior vena cava and right heart combined with coronary artery disease]. PMID- 27239917 TI - [Radiological diagnosis and treatment of complications of injection contour breast reconstruction]. PMID- 27239918 TI - [Long-term results of surgical treatment of giant serous cystadenoma of left ovary]. PMID- 27239919 TI - [Synchronous primary multiple malignancies of colon and ovary followed by acute intestinal obstruction]. PMID- 27239920 TI - [Fixation-adaptive seam in flexor digitorum tendon reconstruction]. PMID- 27239921 TI - [Relationship between matrix metalloproteinase-3 levels and articular destructive changes in early and extended rheumatoid arthritis]. AB - AIM: To estimate a relationship between matrix metalloproteinase-3 (MMP-3) levels and articular radiographic changes in early and extended rheumatoid arthritis (RA); to analyze the role of this biomarker in predicting the progression of joint destruction in RA. SUBJECTS AND METHODS: Forty-five patients with early RA and 42 with extended RA were examined. Radiography of the hands and distal feet was performed before and one year after therapy. Serum MMP-3 levels were measured by an enzyme immunoassay prior to and 12 and 24 weeks after treatment. RESULTS: After 52 weeks, in the early RA group, 16 patients continued monotherapy with methotrexate (MT); because of its inefficiency, 29 additionally received a biological agent in different follow-up periods. The extended RA group took tocilizumab for 24 weeks, then the drug was discontinued and the patients continued the former therapy with disease-modifying antirheumatic drugs, nonsteroidal anti-inflammatory drugs, and glucocorticosteroids. One year later, radiographic progression was recorded in 20.5 and 22.5% of the patients with early and extended RA, respectively. ROC analysis indicated that in the early RA group the MMP-3 level of more than 34.3 ng/ml at 12 weeks of MT therapy was associated with the radiographic progression of articular destructive changes after 52 weeks of therapy (the area under the curve (AUC) was 0.7; 95% confidence interval (CI) 0.46 to 0.93). In the patients with extended RA, the baseline MMP-3 levels of <=51.3 ng/ml was related to no radiographic progression following 52 weeks (AUC, 0.587; 95% CI 0.33 to 0.84). CONCLUSION: MMP-3 may be regarded as an early marker for joint destruction in RA. The determination of MMP-3 level with other immunological markers may be useful to identify a group of patients who have a potentially severer disease course and need more intensive therapy. PMID- 27239922 TI - [N-terminal pro-brain natriuretic peptide levels and diastolic dysfunction in patients with early rheumatoid arthritis before the administration of disease modifying antirheumatic drugs]. AB - AIM: To determine N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in patients with early rheumatoid arthritis (RA) before the use of disease-modifying antirheumatic drugs (DMARDs); to compare NT-proBNP values with traditional risk factors (TRF), cardiovascular diseases (CVD), inflammatory markers, and left ventricular (LV) diastolic dysfunction (DD). SUBJECTS AND METHODS: The investigation enrolled 74 patients with a valid RA diagnosis (the 2010 ACR/EULAR criteria), 56 (74%) women, median (Me) age, 54 years; disease duration, 7 months; seropositive for IgM rheumatoid factor (87%) and/or anti-cyclic citrullinated peptide antibodies (100%) with no history of the use of DMARDs and glucocorticosteroids. Duplex scanning and echographic findings were used to assess TRF for CVD and carotid artery atherosclerosis (CAA) in all the patients with early RA prior to therapy. An E/A ratio was used as a criterion for LVDD. RESULTS: NT-proBNP concentrations in patients with early RA proved to be higher than those in the control group (p<0.0001). Higher-than-normal NT-proBNP levels were seen in 36 (49%) patients. The patients with early RA and elevated NT-proBNP values were older and had a higher body mass index (BMI) than those with normal NT-proBNP levels. Those with elevated NT-proBNP concentrations were more frequently found to have CAA, coronary calcification, and coronary heart disease; their intima-media thickness was also larger and C-reactive protein (CRP) levels higher than in those with normal NT-proBNP values. There were correlations between NT-proBNP levels and erythrocyte sedimentation rate, CRP, simplified disease activity index, and clinical disease activity index. Multivariate analysis revealed that chronic heart failure (CHF), CAA, CRP and low-density lipoprotein (LDL) levels, and BMI correlated with NT-proBNP concentrations. LVDD was detected in 35 (48%) patients with early RA. The level of NT-proBNP in patients with DD was higher than in those without DD. Higher-than-normal NT proBNP values were observed in 23 (65%) and 12 (32%) patients with and without LVDD, respectively. The optimal NT-proBNP level for CHF detection was equal to 237.4 pg/ml (86% sensitivity and 85% specificity); the area under the ROC curve was 0.879. CONCLUSION: Just at the early disease stage, the patients are noted to have a high NT-proBNP level that is influenced by higher BMI, low LDL levels, CAA, CHF, and high CRP values. In the patients with early RA, the diagnostically significant NT-proBNP concentration for CHF detection was higher (237 pg/ml) than in those without RA (125 pg/ml). The patients with early RA should undergo NT proBNP determination, LVDD screening, correction of TRF for CVD, atherosclerosis treatment, and remission achievement. PMID- 27239923 TI - [Psychopharmacotherapy for depression in rheumatic patients]. AB - AIM: To study attitude towards the disease in rheumatic patients during antidepressant therapy and during further follow-up. SUBJECTS AND METHODS: Examinations were made in 122 patients with degenerative joint and vertebral column disease (DJVCD) and in 30 patients with rheumatoid arthritis (RA) and concomitant affective disorders during antidepressant therapy for 3 months. RESULTS: Statistically significant differences were found between all components of the type of attitude towards disease (TATD) in patients with DJVCD or RA before the use of antidepressants. In the patients with RA, the mean value of adaptive types of TATD was significantly lower and that of disadaptive types significantly higher. After 3 months of treatment, the TATD profiles came closer. Only three components (anosognosia, hypochondriasis, and dysphoria) in the pattern of TATD remained significantly different after 6-month therapy. CONCLUSION: According to the TATD data, both the patients with DJVCD and those with inflammatory diseases of the locomotor apparatus showed unidirectional changes in attitude towards disease with a significant increase in the adaptive components and a reduction in the disadaptive ones. PMID- 27239924 TI - [Microcrystalline stress in the pathogenesis of osteoarthritis]. AB - AIM: To estimate the rate of articular cartilage microcrystallization in osteoarthritis (OA). SUBJECTS AND METHODS: The investigation included 110 people who had undergone total endoprosthetic replacement for coxarthrosis. A total of 50 patients with total hip endoprosthetic replacement for femoral neck fractures were recruited as a comparison group. An X-ray diffractometer was used to detect crystals. RESULTS: Cartilage mineralization was seen in 72% of the patients with late-stage OA. CONCLUSION: Articular cartilage microcrystalline stress is a constant sign of late-stage OA requiring further clinical interpretation. PMID- 27239925 TI - [Bone mineral density in patients with scleroderma systematica]. AB - AIM: To study the frequency and magnitude of a reduction in bone mineral density (BMD) and its association with clinical parameters in patients with scleroderma systematica (SDS). SUBJECTS AND METHODS: Fifty-six postmenopausal women aged 45 71 years (58.1+/-7.1 years) with a valid diagnosis of SDS and 44 age-matched healthy women were examined. Dual-energy X-ray absorptiometry (Hologic QDR 4500, Waltham, MA) was performed in all the included patients to measure BMD in the lumbar spine (L(I)-L(IV)), femoral neck, and proximal femur. RESULTS: The patients with SDS and the healthy women showed no differences in body mass index (BMI) (24.7+/-4.6 and 25.7+/-3.5 kg/m(2), respectively) and postmenopause duration (9.6+/-6.4 and 9.5+/-7.0 years, respectively); menopause occurred earlier in the patients with SDS than in the healthy women (46.9+/-3.6 and 49.7+/ 3.0 years, respectively (p<0.001). The patients with SDS versus the controls had a significantly lower BMD in the lumbar spine (0.821+/-0.121 and 0.861+/-0.092 g/cm(2); r<0.05), femoral neck (0.620+/-0.129 and 0.736+/-0.112 g/cm(2); p<0.0001), and proximal femur (0.736+/-0.148 and 0.884+/-0.124 g/cm(2); r<0.0001). Osteoporosis (OP) was detected in 29 (52%) of the 56 patients and in only 5 (11%) of the 44 control women (r<0.0001). The patients with diffuse SDS displayed a much greater reduction in BMD in all the regions than those with circumscribed SDS. BMD was significantly lower in the patients treated with glucocorticosteroids (GCS) than in the untreated ones. In the control group, BMD was associated with age, duration of menopause, and BMI. In the patients with SDS, BMD was correlated with BMI and inversely correlated with duration of menopause, and the magnitude of a BMD reduction was closely related to disease duration. The patients also showed an inverse correlation of BMD with the daily dose of GCS. CONCLUSION: The postmenopausal women with SDS were found to have a lower BMD in 80% of cases. In this category of women, the reduction in BMD was significantly commoner and more pronounced than in the age-matched healthy women. Low BMI, diffuse SDS, disease duration, and GCS use are risk factors for reduced BMD and OP. PMID- 27239926 TI - [Peripheral vessel wall changes in hypertensive patients with gout]. AB - AIM: To investigate the specific features of arterial wall endothelial dysfunction and stiffness in patients with hypertension concurrent with gout. SUBJECTS AND METHODS: A total of 54 patients were examined and divided into 2 groups. A study group consisted of 33 hypertensive patients with gout and a comparison group included 21 hypertensive patients without hyperuricemia. The patients did not differ in blood pressure (BP) readings. Uric acid was determined by the reaction with tungstophosphoric solution AT (Reagent, Dnepropetrovsk, Ukraine). The validity of results was checked using the control sera (Biocont C, Russia). Enzyme immunoassays and Doppler studies were used to investigate peripheral vasoregulation. Body mass index, intima-media thickness (IMT), pulse wave velocity (PWV), cardio-ankle vascular index (CAVI), endothelin-1 (ET-1), and endothelium-dependent vasodilation (EDVD) were determined. RESULTS: All the studied indicators have directly or indirectly a negative impact, by deteriorating the function of the vessel wall. The found arterial structural changes suggest that there is an early atheromatous process in the arterial wall of hypertensive patients with gout. Addition of gout promotes endothelial dysfunction and worsens the course of hypertension. An elevation of indicators, such as PWV, CAVI, and ET-1 levels, has the poorest prognosis for the course of hypertension. CONCLUSION: The determination of CAVI, PWV, ET-1 levels, arterial stiffness index along with additional criteria, such as EDVD and IMT, may be used as criteria for a cardiovascular risk in hypertensive patients. PMID- 27239927 TI - [The possibility of selecting optimal antiplatelet therapy in patients with coronary heart disease in terms of CYP2C19 polymorphism]. AB - AIM: To estimate whether optimal antiplatelet therapy can be selected in terms of CYP2C19 polymorphism. SUBJECTS AND METHODS: The prospective randomized trial included 124 patients (93 men and 31 women) who were to undergo percutaneous coronary intervention. They initially received dual antiplatelet therapy: clopidogrel 75 mg + acetylsalicylic acid (ASA) 300 mg. Genetic testing was performed in all the patients to reveal the carriage of allelic variants of the genes of cytochrome P-450 isoenzymes and the efficiency of antiplatelet therapy was evaluated. The carriers of one allele (CYP2C19*2/*1) were randomized into 3 subgroups according to further antiplatelet therapy. The therapy was not changed in Subgroup 1. The dose of clopidogrel was increased up to 150 mg/day and that of ASA remained unchanged in Subgroup 2. In Subgroup 3, the therapy was completely changed to the regimen: ASA 300 mg + ticagrelor 90 mg twice daily. Three days later, platelet aggregation was reinvestigated in all the three subgroups. RESULTS: In our investigation, the prevalence of carriage of at least one of the CYP2C19*2 alleles was about 35%. Comparison of the baseline platelet aggregation levels during the same platelet therapy showed statistically significant differences between the carriers and non-carriers: 32.7+/-11.6 and 44.8+/-12.9 (p=0.0024). Compared with the baseline values, there was a drug therapy switching induced reduction in platelet aggregation in Subgroups 2 and 3 (p=0.0001 and p=0.0056, respectively). No statistically significant differences were found in Subgroup 1. CONCLUSION: The determination of CYP2C19 gene polymorphism allows a personalized approach to be applied in antiplatelet therapy for all patients with coronary artery disease. PMID- 27239928 TI - [Effect of cytoflavin on the clinical and autonomic-psychological manifestations of hypertensive disease]. AB - AIM: To evaluate the impact of incorporating cytoflavin in a treatment regimen for patients with different stages of hypertensive disease (HD). SUBJECTS AND METHODS: The results of treatment were analyzed in 140 patients with HD (53 with Stage I, 50 with Stage II, and 37 with Stage III). According to the treatment regimen, the patients were divided into 2 groups. A study group (n=74) received combination treatment involving antihypertensive therapy and cytoflavin intravenously dropwisely in a single dose of 200 ml of 5% glucose solution for 10 days, then 2 tablets twice daily for 60 days, with a total cycle time being 70 days. A comparison group (n=66) had antihypertensive therapy only. Thirty apparently healthy individuals (a control group) were examined to have reference values. All the patients were examined using conventional clinical and laboratory studies. The patients' complaints and neurological status were assessed using respective questionnaires over time - before and after treatment. RESULTS: The incorporation of cytoflavin in a treatment regimen was ascertained to reduce the degree of anxiety, depressive, dissomnic, and cognitive disorders, improves quality of life in patients with Stage I HD, and lowers the degree of asthenic and autonomic disorders in all disease stages. CONCLUSION: The found efficacy and safety of the drug may recommend its incorporation in combination therapy regimens for Stages I-III HD. PMID- 27239929 TI - [Choice of optimal vaccination tactics against pneumococcal infection from immunological and clinical standpoints in patients with chronic obstructive pulmonary disease]. AB - AIM: To provide a rationale for choosing the optimal tactics of vaccination against pneumococcal infection in patients with chronic obstructive pulmonary disease (COPD) in the context of evidence-based medicine and on the basis of immunological and clinical data. SUBJECTS AND METHODS: Patients with COPD were examined during a year after vaccination with a 13-valent pneumococcal conjugate (Prevenar-13, PCV13) and a 23-valent pneumococcal polysaccharide (Pnemo-23, PPV23) vaccines. The following vaccination schemes were used: PCV13 monovaccination, PPV23 monovaccination, sequential vaccination with PPV23/PCV13, and sequential vaccination with PCV13/PPV23. RESULTS: Vaccination using all the analyzed schemes in the patients with COPD caused a statistically significant reduction in the frequency of exacerbations, the number of antibiotic cycles, and the number of hospital admissions, as shown by the results of analysis of short term data. The use of PCV13 was followed by additional effects that were unobserved in the use of PPV23, namely: it promoted the formation of immunological memory to Streptococcus pneumoniae antigens, resulted in the enhanced activity of nonspecific resistance factors, and caused activation of antiviral defense factors. CONCLUSION: If patients with COPD need to be vaccinated against pneumococcal infection, preference should be given to PCV13 monovaccination. Short-term observations have shown that the sequential use of pneumococcal conjugate and polysaccharide vaccines is redundant and gives no additional benefit to patients with COPD. However, the sequential application of both vaccines may have additional advantages in the long term. PMID- 27239930 TI - [The differential diagnosis of Erdheim-Chester disease and IgG4-related diseases]. AB - The paper describes Russia's first diagnosed case of Erdheim--Chester disease (systemic histiocytosis) in a 65-year-old man who has been long treated for Ormond's disease (idiopathic retroperitoneal fibrosis). It also gives the data available in the literature on the pathogenetic components of these diseases and on the similarity of many clinical, laboratory, and morphological characteristics of these two immunoinflammatory diseases and covers the issues of their differential diagnosis. Invasive procedures with a careful morphological/immunomorphological examination of biopsy specimens obtained from affected tissues are shown to be necessary for accurate diagnosis. PMID- 27239931 TI - [Pulmonary fibrosis as the first manifestation of scleroderma systematica overlap syndrome]. AB - The paper describes a clinical case of a female patient with signs of visceral scleroderma systematica and rheumatoid arthritis (RA). Interstitial pulmonary fibrosis was the first manifestation of overlap syndrome. The articular and cutaneous of the syndrome were moderate and cast doubts upon whether the systemic rheumatic disease was present. Postmortem examination confirmed the presence of pulmonary fibrosis, scleroderma, and RA. The case is of interest from the point of view of the atypical onset of the disease. PMID- 27239932 TI - [A rare complication of bariatric surgery: Polyradiculoneuropathy as a type of Guillain-Barre syndrome]. AB - The number of bariatric (weight loss) surgeries have increased steadily in the past decade. Along with the tangible benefit of this treatment, there is a risk for postoperative complications, the main cause of which is impaired absorption of nutrients. The paper describes polyradiculoneuropathy running as a type of Guillain-Barre syndrome. PMID- 27239933 TI - [Analysis of ineffective antiviral therapy with pegylated interferon and ribavirin in a patient with chronic hepatitis C infected with HCV genotype 2]. AB - The paper describes a case of ineffective dual antiviral therapy (pegylated interferon and ribavirin) in a patient with chronic hepatitis C infected with hepatitis C virus (HCV) genotype 2 according to the data from the use of a commercial test system. Analysis of the predictors of failure of antiviral therapy (AVT) (the HCV recombinant variant RF2k/1b, a high viral load before the start of therapy, an unfavorable IL-28B genotype, a high body mass index, and a need for a lower ribavirin dose after 12 weeks of AVT because of adverse reactions for less than 4 weeks) in this patient has shown that no virological response is mainly associated with the presence of the HCV recombinant variant, the treatment effectiveness of which is comparable with that in HCV genotype 1 and obesity. In this connection, when HCV genotype 2 is identified, sequencing the NS5B region of the HCV genome is additionally recommended to rule out the virus recombinant strain and, if it is detected, highly effective interferon-free therapy with direct-acting antivirals is indicated. PMID- 27239934 TI - [Current approaches to diagnosing and treating eosinophilic granulomatosis with polyangiitis: The 2015 international guidelines]. AB - The 2015 international guidelines for the diagnosis and treatment of eosinophilic granulomatosis with polyangiitis, formerly known as the Churg-Strauss syndrome, are detailed and an attempt is made to expand an evidence base, by attracting more recent available publications. The new guidelines should not be regarded as final standards; these are primarily to extend the possibilities of choosing a personified management strategy for patients with eosinophilic granulomatosis with polyangiitis and to serve as the starting point for further in-depth investigations. PMID- 27239935 TI - Maternal Pre-pregnancy Body Mass Index and Autism Spectrum Disorder among Offspring: A Population-Based Case-Control Study. AB - BACKGROUND: Previous studies have attributed high maternal weight gain during pregnancy and pre-pregnancy obesity to a higher risk for autism spectrum disorder (ASD). Maternal underweight was not previously explored with respect to ASD risk. METHODS: We evaluated the association between maternal pre-pregnancy body mass index (BMI) and ASD occurrence among singletons born into the General Practice Research Database from 1993 to 2008. Case subjects were children with a diagnosis of ASD from birth to 2010. Up to four control subjects were matched to each case subject on birth year, sex, and general practice. Restricted cubic splines were used to assess the non-linearity of the association between maternal BMI and ASD. All study subjects were classified as underweight, normal weight, overweight, or obese based on maternal pre-pregnancy BMI using the WHO Classification Standard. Conditional logistic regression was used to calculate unadjusted and multivariable adjusted odds ratios for the association between categorical BMI (reference=normal weight) and the occurrence of ASD. RESULTS: The association between maternal BMI and ASD occurrence was non-linear and J-shaped. The adjusted ORs for maternal underweight and obesity were 1.43 (95% CI 1.01, 2.04) and 1.54 (95% CI 1.26, 1.89) respectively. CONCLUSIONS: Results suggest that extremes in maternal BMI may be associated with modest increases in the risk for ASD among offspring. PMID- 27239936 TI - Hippocampal global remapping for different sensory modalities in flying bats. AB - Hippocampal place cells encode the animal's spatial position. However, it is unknown how different long-range sensory systems affect spatial representations. Here we alternated usage of vision and echolocation in Egyptian fruit bats while recording from single neurons in hippocampal areas CA1 and subiculum. Bats flew back and forth along a linear flight track, employing echolocation in darkness or vision in light. Hippocampal representations remapped between vision and echolocation via two kinds of remapping: subiculum neurons turned on or off, while CA1 neurons shifted their place fields. Interneurons also exhibited strong remapping. Finally, hippocampal place fields were sharper under vision than echolocation, matching the superior sensory resolution of vision over echolocation. Simulating several theoretical models of place-cells suggested that combining sensory information and path integration best explains the experimental sharpening data. In summary, here we show sensory-based global remapping in a mammal, suggesting that the hippocampus does not contain an abstract spatial map but rather a 'cognitive atlas', with multiple maps for different sensory modalities. PMID- 27239937 TI - Silencing CA3 disrupts temporal coding in the CA1 ensemble. AB - In addition to the place-cell rate code, hippocampal area CA1 employs a temporal code, both on the single-cell and ensemble level, to accurately represent space. Although there is clear evidence that this precise spike timing is organized by theta and gamma oscillations that are present in hippocampus, the circuit mechanisms underlying these temporal codes remain poorly understood. We found that the loss of CA3 input abolished temporal coding at the ensemble level in CA1 despite the persistence of both rate and temporal coding in individual neurons. Moreover, low gamma oscillations were present in CA1 despite the absence of CA3 input, but spikes associated with these periods carried significantly reduced spatial information. Our findings dissociate temporal coding at the single-cell (phase precession) and population (theta sequences) levels and suggest that CA3 input is crucial for temporal coordination of the CA1 ensemble code for space. PMID- 27239938 TI - An epigenetic mechanism mediates developmental nicotine effects on neuronal structure and behavior. AB - Developmental nicotine exposure causes persistent changes in cortical neuron morphology and in behavior. We used microarray screening to identify master transcriptional or epigenetic regulators mediating these effects of nicotine and discovered increases in Ash2l mRNA, encoding a component of a histone methyltransferase complex. We therefore examined genome-wide changes in trimethylation of histone H3 on Lys4 (H3K4me3), a mark induced by the Ash2l complex associated with increased gene transcription. A large proportion of regulated promoter sites were involved in synapse maintenance. We found that Mef2c interacts with Ash2l and mediates changes in H3K4me3. Knockdown of Ash2l or Mef2c abolished nicotine-mediated alterations of dendritic complexity in vitro and in vivo, and attenuated nicotine-dependent changes in passive avoidance behavior. In contrast, overexpression mimicked nicotine-mediated alterations of neuronal structure and passive avoidance behavior. These studies identify Ash2l as a target induced by nicotinic stimulation that couples developmental nicotine exposure to changes in brain epigenetic marks, neuronal structure and behavior. PMID- 27239939 TI - Olfactory receptor for prostaglandin F2alpha mediates male fish courtship behavior. AB - Pheromones play vital roles for survival and reproduction in various organisms. In many fishes, prostaglandin F2alpha acts not only as a female reproductive hormone, facilitating ovulation and spawning, but also as a sex pheromone inducing male reproductive behaviors. Here, we unravel the molecular and neural circuit mechanisms underlying the pheromonal action of prostaglandin F2alpha in zebrafish. Prostaglandin F2alpha specifically activates two olfactory receptors with different sensitivities and expression in distinct populations of ciliated olfactory sensory neurons. Pheromone information is then transmitted to two ventromedial glomeruli in the olfactory bulb and further to four regions in higher olfactory centers. Mutant male zebrafish deficient in the high-affinity receptor exhibit loss of attractive response to prostaglandin F2alpha and impairment of courtship behaviors toward female fish. These findings demonstrate the functional significance and activation of selective neural circuitry for the sex pheromone prostaglandin F2alpha and its cognate olfactory receptor in fish reproductive behavior. PMID- 27239941 TI - Nanophotonic Image Sensors. AB - The increasing miniaturization and resolution of image sensors bring challenges to conventional optical elements such as spectral filters and polarizers, the properties of which are determined mainly by the materials used, including dye polymers. Recent developments in spectral filtering and optical manipulating techniques based on nanophotonics have opened up the possibility of an alternative method to control light spectrally and spatially. By integrating these technologies into image sensors, it will become possible to achieve high compactness, improved process compatibility, robust stability and tunable functionality. In this Review, recent representative achievements on nanophotonic image sensors are presented and analyzed including image sensors with nanophotonic color filters and polarizers, metamaterial-based THz image sensors, filter-free nanowire image sensors and nanostructured-based multispectral image sensors. This novel combination of cutting edge photonics research and well developed commercial products may not only lead to an important application of nanophotonics but also offer great potential for next generation image sensors beyond Moore's Law expectations. PMID- 27239940 TI - Opposing mechanisms mediate morphine- and cocaine-induced generation of silent synapses. AB - Exposures to cocaine and morphine produce similar adaptations in nucleus accumbens (NAc)-based behaviors, yet produce very different adaptations at NAc excitatory synapses. In an effort to explain this paradox, we found that both drugs induced NMDA receptor-containing, AMPA receptor-silent excitatory synapses, albeit in distinct cell types through opposing cellular mechanisms. Cocaine selectively induced silent synapses in D1-type neurons, likely via a synaptogenesis process, whereas morphine induced silent synapses in D2-type neurons via internalization of AMPA receptors from pre-existing synapses. After drug withdrawal, cocaine-generated silent synapses became 'unsilenced' by recruiting AMPA receptors to strengthen excitatory inputs to D1-type neurons, whereas morphine-generated silent synapses were likely eliminated to weaken excitatory inputs to D2-type neurons. Thus, these cell type-specific, opposing mechanisms produced the same net shift of the balance between excitatory inputs to D1- and D2-type NAc neurons, which may underlie certain common alterations in NAc-based behaviors induced by both classes of drugs. PMID- 27239944 TI - The communication of suicidal intentions: a meta-analysis. AB - BACKGROUND: Among the myths that are often cited about suicide is that 'people who talk about killing themselves rarely die by suicide', but the evidence seems to contradict this statement. The aim of this study was to conduct a meta analysis of studies reporting a prevalence of suicide communication (SC), and to examine the diagnostic accuracy of SC towards suicide in case-control reports. METHOD: Eligible studies had to examine data relative to completed suicides and report the prevalence of SC. Data relative to sample characteristics, study definition, modality and recipient of the SC were coded. RESULTS: We included 36 studies, conducted on a total of 14 601 completed suicides. The overall proportion of SC was 44.5% [95% confidence interval (CI) 35.4-53.8], with large heterogeneity (I 2 = 98.8%) and significant publication bias. The prevalence of SC was negatively associated with the detection of verbal communication as the sole means of SC and, positively, with study methodological quality. Based on seven case-control studies, SC was associated with an odds ratio of 4.66 for suicide (95% CI 3.00-7.25) and was characterized by sufficient diagnostic accuracy only if studies on adolescents were removed. CONCLUSION: Available data suggest that SC occurs in nearly half of subjects who go on to die by suicide, but this figure is likely to be an underestimate given the operational definitions of SC. At present, SC seems associated with overall insufficient accuracy towards subsequent suicide, although further rigorous studies are warranted to draw definite conclusions on this issue. PMID- 27239942 TI - The oxadiazole antibacterials. AB - The oxadiazoles are a class of antibacterials discovered by in silico docking and scoring of compounds against the X-ray structure of a penicillin-binding protein. These antibacterials exhibit activity against Gram-positive bacteria, including against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococcus (VRE). They show in vivo efficacy in murine models of peritonitis/sepsis and neutropenic thigh MRSA infection. They are bactericidal and orally bioavailable. The oxadiazoles show promise in treatment of MRSA infection. PMID- 27239945 TI - Spinal fusion for low back pain; it's all over. PMID- 27239946 TI - A survey of sensor devices: use in sports biomechanics. AB - This paper examines the use of sensor devices in sports biomechanics, focusing on current frequency of use of Electromyography (EMG) device preferences. Researchers in the International Society of Biomechanics in Sports were invited to participate in an online survey. Responses on multiple sensor devices highlighting frequency of use, device features and improvements researchers sought in acquisition and analysis methods were obtained via an online questionnaire. Results of the investigation showed that the force platform is the most frequently used device, with inertial measurement units and EMG devices growing in popularity. Wireless functionality and ease of use for both the participant and the practitioner proved to be important features. The main findings of the survey demonstrated need for a simple, low power, multi-channel device which incorporates the various sensors into one single device. Biomechanists showed they were looking for more availability of wireless sensor devices with acquisition and analysis features. The study found there is a need to develop software analysis tools to accompany the multi-channel device, providing all the basic functions while maintaining compatibility with existing systems. PMID- 27239947 TI - Substituent effects on hydrogen bonding of aromatic amide-carboxylate. AB - N-(p-benzoyl)-anthranilic acid (BAA) derivatives have been synthesized with different substituents (X: Br, Cl, OCH3, CH3), and their crystal structures have been analyzed in order to understand the variations in their molecular geometries with respect to the substituents by using (1)H NMR, (13)C NMR, IR and X-ray single-crystal diffraction. The carboxylic acid group forms classic OH?O hydrogen bonded dimers in a centrosymmetric R2(2)(8) ring motifs for BAA-Br and BAA-Cl. However, no carboxylic acid group forms classic OH?O hydrogen bonded dimers in BAA-OCH3 and BAA-CH3. The asymmetric unit consists of two crystallographically independent molecules in BAA-OCH3. DFT computations show that the interaction energies between monomer and dimer are in the range of 0.5-3.8kcal/mol with the B3LYP/6-31+G*, B3LYP/6-31++G*, B3LYP/6-31++G**, and B3LYP/AUG-cc-pVDZ levels of theory. The presence of different hydrogen bond patterns is also governed by the substrate. For monomeric compounds studied herein, theoretical calculations lead to two low-energy conformers; trans (a) and cis (b). Former one is more stable than latter by about 4kcal/mol. PMID- 27239948 TI - Sensing behavior and logic operation of a colorimetric fluorescence sensor for Hg(2+)/Cu(2+) ions. AB - A BODIPY-based 1 as a colorimetric fluorescence sensor was synthesized, and its metal sensing property was investigated. 1 displayed high selectivity and sensitivity towards Hg(2+) and Cu(2+) ions among 15 different metal cations. The addition of Hg(2+) and Cu(2+) ions into 1 in CH3CN resulted in a significant bathochromic shift of the UV absorption spectra from 533nm to 560nm and 593nm, respectively, changing the corresponding colors from pink to purple and blue. When excited at 530nm, the fluorescence intensity of 1 was quenched over 75% upon addition of Hg(2+) ions, while 1 with Cu(2+) ions exhibited significant fluorescence enhancement with a 23nm red-shift. Based on these results, three logic gates (OR, IMPLICATION, and INHIBIT) were obtained by controlling the chemical inputs. PMID- 27239943 TI - The actions of relaxin on the human cardiovascular system. AB - : The insulin-like peptide relaxin, originally identified as a hormone of pregnancy, is now known to exert a range of pleiotropic effects including vasodilatory, anti-fibrotic, angiogenic, anti-apoptotic and anti-inflammatory effects in both males and females. Relaxin produces these effects by binding to a cognate receptor RXFP1 and activating a variety of signalling pathways including cAMP, cGMP and MAPKs as well as by altering gene expression of TGF-beta, MMPs, angiogenic growth factors and endothelin receptors. The peptide has been shown to be effective in halting or reversing many of the adverse effects including fibrosis in animal models of cardiovascular disease including ischaemia/reperfusion injury, myocardial infarction, hypertensive heart disease and cardiomyopathy. Relaxin given to humans is safe and produces favourable haemodynamic changes. Serelaxin, the recombinant form of relaxin, is now in extended phase III clinical trials for the treatment of acute heart failure. Previous clinical studies indicated that a 48 h infusion of relaxin improved 180 day mortality, yet the mechanism underlying this effect is not clear. This article provides an overview of the cellular mechanism of effects of relaxin and summarizes its beneficial actions in animal models and in the clinic. We also hypothesize potential mechanisms for the clinical efficacy of relaxin, identify current knowledge gaps and suggest new ways in which relaxin could be useful therapeutically. LINKED ARTICLES: This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc. PMID- 27239949 TI - Staff views about psychosocial aspects of recovery in psychosis: A systematic review. AB - PURPOSE: Mental health services remain largely set up to improve patient outcomes through symptom alleviation, but patient views of recovery are broader than symptom remission. Clinicians influence the nature of treatment patients received, but their views about recovery remain poorly understood. The aim of this study was to systematically review the literature examining staff views about psychosocial aspects of recovery in psychosis. METHOD: We systematically searched the PsycInfo, EMBASE, MEDLINE, and CINAHL databases. Of the 6,225 articles identified, 15 met inclusion criteria for review. RESULTS: The studies reviewed showed a relatively inconsistent picture. Although there was evidence of staff endorsing psychosocial views of recovery, the majority of studies suggested staff endorsed biomedical models of recovery in psychosis and emphasized the importance of pharmacological, over psychosocial, and interventions. CONCLUSIONS: The reviewed studies showed that biomedical views about recovery prevail among multidisciplinary mental health staff, despite recent advancements in patients' broader conceptualization of recovery. Clinical implications are discussed. PRACTITIONER POINTS: The psychosocial model of recovery has become widely accepted and now underpins most international recovery policies. Despite a dearth in research, existing studies indicate that mental health staff subscribe to biomedical models of recovery in psychosis, with more emphasis on pharmacological, over psychosocial, and interventions. Robust research targeting staff views about recovery in psychosis is needed. PMID- 27239950 TI - Using Single-Cell Amperometry To Reveal How Cisplatin Treatment Modulates the Release of Catecholamine Transmitters during Exocytosis. AB - The pretreatment of cultured pheochromocytoma (PC12) cells with cis diamminedichloroplatinum (cisplatin), an anti-cancer drug, influences the exocytotic ability of the cells in a dose-dependent manner. Low concentrations of cisplatin stimulate catecholamine release whereas high concentrations inhibit it. Single-cell amperometry reflects that 2 MUm cisplatin treatment increases the frequency of exocytotic events and reduces their duration, whereas 100 MUm cisplatin treatment decreases the frequency of exocytotic events and increases their duration. Furthermore, the stability of the initial fusion pore that is formed in the lipid membrane during exocytosis is also regulated differentially by different cisplatin concentrations. This study thus suggests that cisplatin influences exocytosis by multiple mechanisms. PMID- 27239951 TI - Near-peer education: a novel teaching program. AB - OBJECTIVE: This study aims to: 1) Evaluate whether a near-peer program improves perceived OSCE performance; 2) Identify factors motivating students to teach; 3) Evaluate role of near-peer teaching in medical education. METHODS: A near-peer OSCE teaching program was implemented at Monash University's Peninsula Clinical School over the 2013 academic year. Forty 3rd-year and thirty final-year medical students were recruited as near-peer learners and educators, respectively. A post program questionnaire was completed by learners prior to summative OSCEs (n=31), followed by post-OSCE focus groups (n=10). Near-peer teachers were interviewed at the program's conclusion (n=10). Qualitative data was analysed for emerging themes to assess the perceived value of the program. RESULTS: Learners felt peer led teaching was more relevant to assessment, at an appropriate level of difficulty and delivered in a less threatening environment than other methods of teaching. They valued consistent practice and felt confident approaching their summative OSCEs. Educators enjoyed the opportunity to develop their teaching skills, citing mutual benefit and gratitude to past peer-educators as strong motivators to teach others. CONCLUSIONS: Near-peer education, valued by near-peer learners and teachers alike, was a useful method to improve preparation and perceived performance in summative examinations. In particular, a novel year long, student-run initiative was regarded as a valuable and feasible adjunct to faculty teaching. PMID- 27239953 TI - Body mass index and suicide methods. AB - Overweight and obesity is associated with lower rates of suicide. However, little is known about the association with different suicide methods. We studied the association between groups of body mass index and suicide methods. We identified all medicolegal autopsy cases with a cause of death due to external causes in Sweden during 1999-2013 (N = 39,368) and included 11,715 suicides and 13,316 accidents or homicides as controls. We applied multinomial regression models adjusted for age, sex, year and season of death. Obesity was associated with suicidal intoxication, OR 1.15 [95% confidence interval (CI) 1.02, 1.30] and negatively associated with all other suicide methods studied. Underweight showed a negative association with suicidal drowning and there was an indication towards a negative association with hanging in men OR 0.81 (95% CI 0.65, 1.01). We conclude that body mass index (BMI) is associated with the choice of suicide method. This may be of importance in a public health perspective, e.g. potential for prevention of intoxications. In the practice of forensic medicine, the physician's level of suspicion may rise if the apparent suicidal method is less common for the individual characteristics of the deceased, such as BMI. PMID- 27239952 TI - Alarmingly high level of alcohol use among fishermen: A community based survey from a coastal area of south India. AB - INTRODUCTION: Though studies from western world have reported high prevalence of alcohol use among fishermen, there is lack of information from developing world. Hence this study was carried out among fishermen in a coastal area of southern India to 1) determine the prevalence of alcohol use among fishermen 2) describe the pattern of alcohol use 3) identify factors associated with alcohol use. METHODS: A community based cross-sectional study was carried out among fishermen in a coastal village of Puducherry, India. House to hose survey was conducted, fishermen aged above 18 years and involved in catching fish at least once in last three months, were included. Data on age, marital status, education, monthly income, duration in fishing occupation, owning a boat or wager, frequency of fishing per month/week, number of hours spent in sea, alcohol use in past one year, age at initiation, type of alcohol drink and presence of alcohol users in family. RESULTS: In total, 304 participants were interviewed. Mean (SD) age of the participants was 41 (11) and 82% were involved in fishing for more than 10 years. Of 304 participants, 241 (79%) reported alcohol use in past one year. Of 241 participants who used alcohol, 89% reported alcohol consumption during fishing activity. In multivariate analysis, alcohol use in other family members was independently associated with alcohol use (aRR 21.4; 95% CI 6.8-67.4). CONCLUSION: Very high prevalence of alcohol use is seen among fishermen. Of those who consume alcohol, nine out of ten use during fishing activities. PMID- 27239954 TI - Postmortem biochemistry in suspected starvation-induced ketoacidosis. AB - Significantly increased blood ketone body levels can be occasionally observed in the forensic setting in situations other than exposure to cold, diabetic or alcoholic ketoacidosis. Though infrequent, these cases do occur and deserve thorough evaluation in order to establish appropriate differential diagnoses and quantify the role that hyperketonemia may play in the death process. Starvation ketoacidosis is a rare cause of metabolic acidosis and is a phenomenon that occurs normally during fasting, as the body switches from carbohydrate to lipid energy sources. The levels of ketonemia in starvation ketoacidosis is usually mild in comparison to those seen in diabetic or alcoholic ketoacidosis. In the clinical setting, several cases of starvation-induced ketoacidosis mainly associated with gastric banding, pregnancy, malnutrition and low-carbohydrate diets have been reported. However, starvation ketosis causing severe metabolic acidosis has been rarely described in the medical literature. In the realm of forensic pathology, starvation-induced hyperketonemia has been rarely described. In this paper we present the postmortem biochemical results observed in situations of suspected starvation-induced hyperketonemia that underwent medico legal examination. In all these cases, the diagnosis of starvation induced hyperketonemia and the subsequent ketoacidosis was established per exclusionem based on all postmortem investigation findings. A review of the literature pertaining to the clinical diagnosis of starvation ketoacidosis is also provided. PMID- 27239955 TI - Predicting and Understanding the Enzymatic Inhibition of Human Peroxiredoxin 5 by 4-Substituted Pyrocatechols by Combining Funnel Metadynamics, Solution NMR, and Steady-State Kinetics. AB - Funnel metadynamics is a kind of computational simulation used to enhance the sampling of protein-ligand binding events in solution. By characterization of the binding interaction events, an estimated absolute binding free energy can be calculated. Nuclear magnetic resonance and funnel metadynamics were used to evaluate the binding of pyrocatechol derivatives (catechol, 4-methylcatechol, and 4-tert-butylcatechol) to human peroxiredoxin 5. Human peroxiredoxins are peroxidases involved in cellular peroxide homeostasis. Recently, overexpressed or suppressed peroxiredoxin levels have been linked to various diseases. Here, the catechol derivatives were found to be inhibitors against human peroxiredoxin 5 through a partial mixed type noncompetitive mechanism. Funnel metadynamics provided a microscopic model for interpreting the inhibition mechanism. Correlations were observed between the inhibition constants and the absolute binding free energy. Overall, this study showcases the fact that funnel metadynamics simulations can be employed as a preliminary approach to gain an in depth understanding of potential enzyme inhibitors. PMID- 27239956 TI - Sentinel surveillance for influenza among severe acute respiratory infection and acute febrile illness inpatients at three hospitals in Ghana. AB - BACKGROUND: Influenza epidemiology in Africa is generally not well understood. Using syndrome definitions to screen patients for laboratory confirmation of infection is an established means to effectively conduct influenza surveillance. METHODS: To compare influenza-related epidemiologic data, from October 2010 through March 2013, we enrolled hospitalized severe acute respiratory infection (SARI; fever with respiratory symptoms) and acute febrile illness (AFI; fever without respiratory or other localizing symptoms) patients from three referral hospitals in Ghana. Demographic and epidemiologic data were obtained from enrolled patients after which nasopharyngeal and oropharyngeal swabs were collected, and processed by molecular methods for the presence of influenza viruses. RESULTS: Of 730 SARI patients, 59 (8%) were influenza positive; of 543 AFI patients, 34 (6%) were positive for influenza. Both SARI and AFI surveillance yielded influenza A(H3N2) (3% versus 1%), A(H1N1)pdm09 (2% versus 1%), and influenza B (3% versus 4%) in similar proportions. Data from both syndromes show year-round influenza transmission but with increased caseloads associated with the rainy seasons. CONCLUSIONS: As an appreciable percentage of influenza cases (37%) presented without defined respiratory symptoms, and thus met the AFI but not the SARI definition, it is important to consider broader screening criteria (i.e., AFI) to identify all laboratory-confirmed influenza. The identified influenza transmission seasonality has important implications for the timing of related public health interventions. PMID- 27239957 TI - YAP1 homologue-mediated redox sensing is crucial for a successful infection by Monilinia fructicola. AB - Monilinia fructicola (G. Winter) Honey is a devastating pathogen on Rosaceae which causes blossom blight and fruit rot. Only a few studies related to the plant-pathogen interaction have been published and there is limited knowledge on the relationship between oxidative stress and successful infection in M. fructicola. In this study, we cloned and characterized a redox-responsive transcription factor MFAP1, a YAP1 homologue. MfAP1-silenced strains were generated by polyethylene glycol-mediated protoplast transformation or Agrobacterium T-DNA-mediated transformation. Pathogenicity assay demonstrated that MfAP1-silenced strains caused smaller lesions on rose and peach petals. Transformants carrying extra copies of MfAP1, driven by the native promoter, were generated for MfAP1 overexpression. Interestingly, MfAP1-overexpressing strains also caused smaller lesions on rose petals. Strains carrying two copies of MfAP1 accumulated reactive oxygen species (ROS) at higher levels and exhibited delayed accumulation of MfAP1 transcripts compared with the wild-type during pathogenesis. By the analysis of ROS production and the expression patterns of redox- and virulence-related genes in the wild-type strain and an MfAP1 overexpressing strain, we found that the M. fructicola wild-type strain responded to oxidative stress at the infection site, activated the expression of MfAP1 and up-regulated the genes required for ROS detoxification and fungal virulence. In contrast, MfAP1 expression in the MfAP1-overexpressing strain was suppressed after the induction of a strong oxidative burst at the infection site, altering the expression of ROS detoxification and virulence-related genes. Our results highlight the importance of MfAP1 and ROS accumulation in the successful infection of M. fructicola. PMID- 27239958 TI - Migration and invasion is inhibited by silencing ROR1 and ROR2 in chemoresistant ovarian cancer. AB - Ovarian cancer survival remains poor despite recent advances in our understanding of genetic profiles. Unfortunately, the majority of ovarian cancer patients have recurrent disease after chemotherapy and lack other treatment options. Wnt signalling has been extensively implicated in cancer progression and chemoresistance. Therefore, we investigated the previously described Wnt receptors ROR1 and ROR2 as regulators of epithelial-to-mesenchymal transition (EMT) in a clinically relevant cell line model. The parental A2780- and cisplatin resistant A2780-cis cell lines were used as a model of ovarian cancer chemoresistance. Proliferation, adhesion, migration and invasion were measured after transient overexpression of ROR1 and ROR2 in the parental A2780 cell line, and silencing of ROR1 and ROR2 in the A2780-cis cell line. Here we show that ROR1 and ROR2 expression is increased in A2780-cis cells, alongside beta-catenin independent Wnt targets. Knockdown of ROR1 and ROR2 significantly inhibited cell migration and invasion and simultaneous knockdown of ROR1 and ROR2 significantly sensitised cells to cisplatin, whilereas ROR overexpression in the parental cell line increased cell invasion. Therefore, ROR1 and ROR2 have the potential as novel drug targets in metastatic and recurrent ovarian cancer patients. PMID- 27239959 TI - PTEN negatively regulates mTORC2 formation and signaling in grade IV glioma via Rictor hyperphosphorylation at Thr1135 and direct the mode of action of an mTORC1/2 inhibitor. AB - To investigate the role of PTEN (phosphatase and tensin homolog) in mammalian target of rapamycin complex 2 (mTORC2) signaling in glioblastoma multiforme (GBM), we found higher activation of mTORC2 in PTEN(mu) cells, as evidenced by enhanced phosphorylation of mTOR (Ser2481), AKT (Ser473) and glycogen synthase kinase 3 beta (GSK3beta) (Ser9) as compared with PTEN(wt) cells. In addition, PTEN(wt) cells upon PTEN depletion showed mTORC2 activation. The reduced mTORC2 signaling in PTEN(wt) cells was related to higher Rictor phosphorylation at Thr1135 residue. Phosphorylation of Rictor at Thr1135 inhibited its association with mTORC and thus there was a reduction in mTORC2 complex formation. In addition, PTEN(wt) cells expressing mutated Rictor in which Thr1135 was substituted with alanine, showed enhanced mTORC2 formation and signaling. This enhanced mTORC2 signaling promoted inactivation of GSK3beta. Thus, we established the reciprocal activation of mTORC2 and GSK3beta in GBM. To the best of our knowledge, this is the first report describing role of PTEN in mTORC2 formation by promoting Rictor phosphorylation (Thr1135) in GBM. Furthermore, the drug sensitivity of mTORC2 was evaluated. A newly identified carbazole alkaloid, mahanine, showed cytotoxicity in both PTEN(mu) and PTEN(wt) cells. It inhibited both mTORC1/2 and AKT completely in PTEN(mu) cells, whereas it inhibited only mTORC1 in PTEN(wt) cells. Cytotoxity and AKT-inhibitory activity of the mTORC1/2 inhibitor was increased either by depleting PTEN or in combination with phosphatidylinositol 3 kinase inhibitors in PTEN(wt) cells. In contrast, depletion of Rictor decreased the cytotoxicity of the mTORC1/2 inhibitor in PTEN(mu) cells. Thus, PTEN has an important role in mTORC2 formation and also influences the effectiveness of an mTORC1/2 inhibitor in GBM. PMID- 27239960 TI - Regulation of H-Ras-driven MAPK signaling, transformation and tumorigenesis, but not PI3K signaling and tumor progression, by plasma membrane microdomains. AB - In this study, we assessed the contributions of plasma membrane (PM) microdomain targeting to the functions of H-Ras and R-Ras. These paralogs have identical effector-binding regions, but variant C-terminal targeting domains (tDs) which are responsible for lateral microdomain distribution: activated H-Ras targets to lipid ordered/disordered (Lo/Ld) domain borders, and R-Ras to Lo domains (rafts). We hypothesized that PM distribution regulates Ras-effector interactions and downstream signaling. We used tD swap mutants, and assessed effects on signal transduction, cell proliferation, transformation and tumorigenesis. R-Ras harboring the H-Ras tD (R-Ras-tH) interacted with Raf, and induced Raf and ERK phosphorylation similar to H-Ras. R-Ras-tH stimulated proliferation and transformation in vitro, and these effects were blocked by both MEK and PI3K inhibition. Conversely, the R-Ras tD suppressed H-Ras-mediated Raf activation and ERK phosphorylation, proliferation and transformation. Thus, Ras access to Raf at the PM is sufficient for MAPK activation and is a principal component of Ras mitogenesis and transformation. Fusion of the R-Ras extended N-terminal domain to H-Ras had no effect on proliferation, but inhibited transformation and tumor progression, indicating that the R-Ras N-terminus also contributes negative regulation to these Ras functions. PI3K activation was tD independent; however, H Ras was a stronger activator of PI3K than R-Ras, with either tD. PI3K inhibition nearly ablated transformation by R-Ras-tH, H-Ras and H-Ras-tR, whereas MEK inhibition had a modest effect on Ras-tH-driven transformation but no effect on H Ras-tR transformation. R-Ras-tH supported tumor initiation, but not tumor progression. While H-Ras-tR-induced transformation was reduced relative to H-Ras, tumor progression was robust and similar to H-Ras. H-Ras tumor growth was moderately suppressed by MEK inhibition, which had no effect on H-Ras-tR tumor growth. In contrast, PI3K inhibition markedly suppressed tumor growth by H-Ras and H-Ras-tR, indicating that sustained PI3K signaling is a critical pathway for H-Ras-driven tumor progression, independent of microdomains. PMID- 27239961 TI - An ANCCA/PRO2000-miR-520a-E2F2 regulatory loop as a driving force for the development of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common malignancies in Asia especially in China. We previously identified that ANCCA/PRO2000 as an important proliferation-associated protein predicted poor prognosis of patients with HCC. However, the molecular mechanisms of ANCCA/PRO2000 leading to hepatocarcinogenesis and progression are still obscure. In the present study, we found that ANCCA/PRO2000 overexpression in HCC specimens correlated with aggressive tumor behavior and poor survival. Furthermore, ANCCA/PRO2000 exerts strong oncogenic function in HCC and promotes cell proliferation by regulating E2F2 expression, a critical cell cycle regulator. Notably, miR-520a is an intermediate regulator between ANCCA/PRO2000 and E2F2. Mechanistically, ANCCA/PRO2000 not only interacts with E2F2 but also negatively regulates miR-520a that inhibits E2F2 to cooperatively promote in vitro and in vivo growth of HCC cells. Moreover, we demonstrated that ANCCA/PRO2000 enhances the migratory capacity of HCC cells partially by suppressing ERO1L and G3BP2 expression. Additional research identified that miR-372, as a prognostic factor for HCC, could directly target ANCCA/PRO2000. Our results suggest the ANCCA/PRO2000-miR 520a-E2F2 regulatory loop as a driving force for HCC development and ANCCA/PRO2000 as a potential therapeutic target for HCC. PMID- 27239962 TI - Dietary fat overcomes the protective activity of thrombospondin-1 signaling in the Apc(Min/+) model of colon cancer. AB - Thrombospondin 1 is a glycoprotein that regulates cellular phenotype through interactions with its cellular receptors and extracellular matrix-binding partners. Thrombospondin 1 locally regulates angiogenesis and inflammatory responses that contribute to colorectal carcinogenesis in Apc(Min/+) mice. The ability of thrombospondin 1 to regulate responses of cells and tissues to a variety of stresses suggested that loss of thrombospondin 1 may also have broader systemic effects on metabolism to modulate carcinogenesis. Apc(Min/+):Thbs1(-/-) mice exhibited decreased survival and higher tumor multiplicities in the small and large intestine relative to Apc(Min/+) mice when fed a low (5%) fat western diet. However, the protective effect of endogenous thrombospondin 1 was lost when the mice were fed a western diet containing 21% fat. Biochemical profiles of liver tissue identified systemic metabolic changes accompanying the effects of thrombospondin 1 and dietary lipid intake on tumorigenesis. A high-fat western diet differentially regulated elements of amino acid, energy and lipid metabolism in Apc(Min/+):Thbs1(-/-) mice relative to Apc(Min/+):Thbs1(+/+)mice. Metabolic changes in ketone body and tricarboxylic acid cycle intermediates indicate functional interactions between Apc and thrombospondin 1 signaling that control mitochondrial function. The cumulative diet-dependent differential changes observed in Apc(Min/+):Thbs1(-/-) versus Apc(Min/+) mice include altered amino acid and lipid metabolism, mitochondrial dysfunction, eicosanoids and ketone body formation. This metabolic profile suggests that the protective role of thrombospondin 1 to decrease adenoma formation in Apc(Min/+) mice results in part from improved mitochondrial function. PMID- 27239963 TI - Vaginal pessaries: can an educational brochure help patients to better understand their care? AB - AIMS AND OBJECTIVES: Pelvic organ prolapse is a common condition, with reported incidence of up to 50%. We aimed to assess whether written information, in addition to face-to-face consultation, improved happiness with information, confidence to self-manage and prolapse knowledge in women attending a pessary clinic. BACKGROUND: Little is known about the effect of adding a written information brochure on clinical outcomes of patients using pessaries. DESIGN: This prospective study used a pretest-posttest method, conducted following Ethical approval. METHODS: Between February-December 2013, all women attending Pessary Clinic were eligible for participation. A questionnaire was developed to assess happiness with information, confidence regarding self-management (using a visual analogue scale, 1-10) and prolapse knowledge (using eight multiple-choice questions). Data were collected in person at baseline prior to distribution of a patient brochure and thereafter by telephone at one week and three months. Paired analysis was conducted using the McNemar test and related samples Wilcoxon signed rank test for VAS items with p < 0.05 significant. RESULTS: Sixty women were recruited. Fifty-eight completed all questionnaires. Improvement in happiness with information, confidence regarding self-management and knowledge scores occurred at one week (p < 0.05) and were maintained at three months (p < 0.05). Changes were unrelated to age (p > 0.05), education level (p > 0.05), first language (p > 0.05) or previous clinic visits (p > 0.05). CONCLUSION: A written information brochure, in addition to face-to-face consultation, improves happiness with information, confidence to self-manage and knowledge about pessaries compared to verbal instruction alone and helps patients better understand their care. The written brochure was equally effective in women with low education and advanced age, and occurred regardless of the number of clinic visits. PMID- 27239964 TI - Improved metagenome screening efficiency by random insertion of T7 promoters. AB - Metagenomes constitute a major source for the identification of novel enzymes for industrial applications. However, current functional screening methods are hindered by the limited transcription efficiency of foreign metagenomic genes. To overcome this constraint, we introduced the 'Enforced Transcription' technique, which involves the random insertion of the bi-directional T7 promoter into a metagenomic fosmid library. Then the effect of enforced transcription was quantitatively assessed by screening for metagenomic lipolytic genes encoding enzymes whose catalytic activity forms halos on tributyrin agar plates. The metagenomic library containing the enforced transcription system yielded a significantly increased number of screening hits with lipolytic activity compared to the library without random T7 promoter insertions. Additional sequence analysis revealed that the hits from the enforced transcription library had greater genetic diversity than those from the original metagenome library. Enhancing heterologous expression using the T7 promoter should enable the identification of greater numbers of diverse novel biocatalysts from the metagenome than possible using conventional metagenome screening approaches. PMID- 27239965 TI - Release behavior and formation mechanism of polycyclic aromatic hydrocarbons during coal pyrolysis. AB - Polycyclic aromatic hydrocarbons (PAHs) are major environmental pollutants. They have attracted considerable attention due to their severe potential carcinogenic, mutagenic and genotoxic effects on human health. In this study, five different rank coals from China were pyrolyzed using pyro-probe CDS 5250 and the release behavior of 16 PAHs under different pyrolysis conditions were studied by Gas Chromatography-Mass Spectrometer (GC-MS). The structural characteristics of the five coals were determined by Cross-Polarization/Magic Angle Spinning Carbon-13 Nuclear Magnetic Resonance (CP/MAS (13)C NMR) spectroscopy, and then the factors influencing the formation of PAHs during coal pyrolysis were discussed together with the coal structural data. It was shown that the amount of PAHs generated during coal pyrolysis was largely related to coal rank and followed the order of medium metamorphic coal > low metamorphic coal > high metamorphic coal. The amount of total PAHs varied as the temperature was increased from 400 degrees C to 1200 degrees C, which showed a trend of first increasing and then decreasing, with the maximum value at 800 degrees C. Moreover, the species of PAHs released varied with pyrolysis temperatures. When the temperature was lower than 800 degrees C, the small ring PAHs were the most abundant, while the proportion of heavy rings increased at higher temperature. The results indicate that the formation of PAHs during coal pyrolysis depends on the structure of the coal. The species and amounts of PAHs generated during coal pyrolysis are closely related to the contents of protonated aromatic carbons and bridging ring junction aromatic carbons present in the coal structure. PMID- 27239966 TI - Emission of unintentionally produced persistent organic pollutants (UPOPs) from municipal waste incinerators in China. AB - Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs), pentachlorobenzene (PeCBz) and hexachlorobenzene (HxCBz), which are listed in the Stockholm Convention, are commonly known as unintentionally produced persistent organic pollutants (UPOPs). As municipal waste incinerators (MWIs) have burgeoned in China, the emission of UPOPs is of great concerns. Compared to the extensive studies of PCDD/Fs emission, not much information of non-dioxin UPOPs (i.e., PCBs, HxCBz, and PeCBz) is available. In the present study, samples from raw gas (RG) after boiler, stack gas (SG) after air pollution control devices (APCDs) and fly ash (FA) samples were collected from typical MWIs in China. The analyses of SG samples indicate that PCDD/Fs are the major contributor to TEQ value, but non-dioxin UPOPs are the dominant compounds in terms of mass concentration. The mean emission factors of dl-PCBs, PeCBz, and HxCBz in SG are 0.372, 144, and 84.7 MUg/t, respectively. In contrast with gaseous samples, FA contains higher mass concentration of PCDD/Fs and PCBs than that of PeCBz and HxCBz. In terms of homologues distribution of PCBs, di- to tetra-CBs were the predominant species in both SG and FA samples. PCB-126 is the major contributor to the TEQ concentration. The comparison of UPOPs composition in SG and RG samples shows that activated carbon adsorption process is capable of removing most PCDD/Fs, but less efficient for the removal of non-dioxin UPOPs. PMID- 27239967 TI - Inhibition effect of cypermethrin mediated by co-regulators SRC-1 and SMRT in interleukin-6-induced androgen receptor activation. AB - It is hypothesized that the pesticide cypermethrin may induce androgen receptor (AR) antagonism via ligand-independent mechanisms. The Real-Time Cell Analysis (RTCA) iCELLigence system was used to investigate the inhibitory effect of cypermethrin on interleukin-6 (IL-6)-induced ligand-independent LNCaP cell growth. Then, the mammalian two-hybrid assays were applied to clarify whether the mechanism of IL-6-induced AR antagonism of cypermethrin was associated with the interactions of the AR and co-activator steroid receptor co-activator-1 (SRC-1) and co-repressor silencing mediator for retinoid and thyroid hormone receptors (SMRT). Cypermethrin inhibited the LNCaP cell growth induced by IL-6. The interactions of AR-SRC-1 and AR-SMRT mediated by IL-6 were suppressed by cypermethrin. The results indicate that the IL-6-mediated AR antagonism induced by cypermethrin is related to repress the recruitment of co-regulators SRC-1 and SMRT to the AR in a ligand-independent manner. Inhibition of the interactions of AR-SRC-1 and AR-SMRT mediated by IL-6 contributes to the AR antagonism induced by cypermethrin. PMID- 27239968 TI - Azo dye decolorization by a halotolerant exoelectrogenic decolorizer isolated from marine sediment. AB - Based on both capabilities of extracellular electron transfer and high salt tolerance, marine exoelectrogenic bacteria have the potential to serve as halotolerant/halophilic exoelectrogenic decolorizers (HEDs) for textile wastewater treatment. However, research in this area is still rare. In this study, we employed Shewanella marisflavi EP1 for this purpose. The results showed that EP1 could decolorize Xylidine Ponceau 2R (XP2R) under high NaCl concentrations up to 20%. Two different mechanisms were involved: degradation and bioflocculation. XP2R was decolorized by degradation in the range of 0-7.4% NaCl, by bioaugmented flocculation in 10-20% NaCl; and the range of 7.4-10% NaCl was the transition period from degradation to flocculation. Considering the property of flocculation by strain EP1, it is reasonable that XP2R was hard to penetrate into EP1 cells, thus it was an extracellular process of decolorization. The overall results further suggested that like EP1, marine exoelectrogenic bacteria might serve as a category of functional microbes (i.e., HEDs) for textile wastewater treatment. PMID- 27239969 TI - The global menace of arsenic and its conventional remediation - A critical review. AB - Arsenic is a ubiquitous element found in the earth crust with a varying concentration in the earth soil and water. Arsenic has always been under the scanner due to its toxicity in human beings. Contamination of arsenic in drinking water, which generally finds its source from arsenic-containing aquifers; has severely threatened billions of people all over the world. Arsenic poisoning is worse in Bangladesh where As(III) is abundant in waters of tube wells. Natural occurrence of arsenic in groundwater could result from both, oxidative and reductive dissolution. Geothermally heated water has the potential to liberate arsenic from surrounding rocks. Inorganic arsenic has been found to have more toxicity than the organic forms of arsenic. MMA and DMA are now been considered as the organic arsenic compounds having the potential to impair DNA and that is why MMA and DMA are considered as carcinogens. Endless efforts of researchers have elucidated the source, behavior of arsenic in various parts of the environment, mechanism of toxicity and various remediation processes; although, there are lots of areas still to be addressed. In this article, attempts have been made to lay bare an overview of geochemistry, toxicity and current removal techniques of arsenic together. PMID- 27239970 TI - Source apportionment of fluorine pollution in regional shallow groundwater at You'xi County southeast China. AB - Source apportionment of fluorine pollution in the regional shallow groundwater at You'xi County, southeast China, has been analyzed by means of monitoring F(-) ion change characteristics in this area. Meanwhile, pollution sources and influencing factors of the shallow groundwater have been uncovered by studying the correlation between F(-) and other related ions such as Na(+), Ca(2+), Cl(-), NO3(-), HCO3(-), as well as (K(+) + Na(+))/Ca(2+) ratio (R) and pH effect. The results show that F(-) ions in shallow groundwater at the study area come mainly from the dissolution of fluorinated minerals in a form of fluorite (CaF2), the so called water-rock interaction, and there is a higher possibility for the occurrence of fluorine water where the ratio of (K(+) + Na(+))/Ca(2+) exceeds a value of 2.1. Moreover, the release and migration of F(-) ions have been favored by the alkaline environment in this study area. PMID- 27239971 TI - A Selective C-H Deprotonation Strategy to Access Functionalized Arynes by Using Hypervalent Iodine. AB - Described here is an efficient method to access highly functionalized arynes from unsymmetrical aryl(mesityl)iodonium tosylate salts. The iodonium salts are prepared in a single pot from either commercially available aryl iodides or arylboronic acids. The aryne intermediates are generated by ortho-C-H deprotonation of aryl(mesityl)iodonium salt with a commercially available amide base and trapped in a cycloaddition reaction with furan in moderate to good yields. Coupling partners for the aryne intermediates beyond furan are also described, including benzyl azide and alicyclic amine nucleophiles. The regio- and chemoselectivity of this reaction is discussed and evidence for the spectator aryl ligand of the iodonium salt as a critical control element in selectivity is presented. PMID- 27239973 TI - Isolating Reactions at the Picoliter Scale: Parallel Control of Reaction Kinetics at the Liquid-Liquid Interface. AB - Miniaturized liquid-liquid interfacial reactors offer enhanced surface area and rapid confinement of compounds of opposite solubility, yet they are unable to provide in situ reaction monitoring at a molecular level at the interface. A picoreactor operative at the liquid-liquid interface is described, comprising plasmonic colloidosomes containing Ag octahedra strategically assembled at the water-in-decane emulsion interface. The plasmonic colloidosomes isolate ultrasmall amounts of solutions (<200 pL), allowing parallel monitoring of multiple reactions simultaneously. Using the surface-enhanced Raman spectroscopy (SERS) technique, in situ monitoring of the interfacial protonation of dimethyl yellow (p-dimethylaminoazobenzene (DY)) is performed, revealing an apparent rate constant of 0.09 min(-1) for the first-order reaction. The presence of isomeric products with similar physical properties is resolved, which would otherwise be indiscernible by other analytical methods. PMID- 27239974 TI - Effectiveness of therapeutic conversation intervention among caregivers of people with eating disorders: quasi-experimental design. AB - AIMS AND OBJECTIVES: The aim of this study was to evaluate the effectiveness of therapeutic conversation intervention in group and caregiver sessions on the supporting role of caregivers. BACKGROUND: Caregivers of people with eating disorders are known to suffer major difficulties and are in great need of support. Unhelpful parental support strategies can delay the recovery of an individual with an eating disorder. Skill training interventions can equip parents with skills, guidance and techniques by helping them to be a support person and making them one of the most important links in the treatment process. DESIGN: The therapeutic conversation intervention consisted of five group and caregiver sessions and three booster sessions. The Calgary Family Assessment and Calgary Family Intervention Models, the Illness Beliefs Model and the New Maudsley Method were used as theoretical frameworks. The content of the intervention consisted of work on difficult behaviours, feelings and helpful strategies. The participants (n = 58) included primary and secondary caregivers of 12- to 24-year-old patients with eating disorders. Eight caregivers dropped out of treatment. METHODS: This study had a quasi-experimental design with one pre- and two post-test measures. RESULTS: Between 90-96% of caregivers rated the therapeutic conversation intervention as supportive. Furthermore, the study revealed significant differences in caregiver emotional and cognitive support, illness beliefs, disruptive behaviour and quality of life, negative aspects of care giving demands and caregiver and patient behavioural difficulties after the intervention and/or at follow-up. CONCLUSIONS: Therapeutic conversation intervention with caregivers in group and private sessions proved to be beneficial. RELEVANCE TO CLINICAL PRACTICE: This outcome provides information for healthcare professionals on how they can help primary caregivers in their supporting role, which can, in turn, improve services in healthcare centres and psychiatric hospitals. PMID- 27239975 TI - Active Esters as Pseudostoppers for Slippage Synthesis of [2]Pseudorotaxane Building Blocks: A Straightforward Route to Multi-Interlocked Molecular Machines. AB - The efficient synthesis and very easy isolation of dibenzo[24]crown-8-based [2]pseudorotaxane building blocks that contain an active ester motif at the extremity of the encircled molecular axle and an ammonium moiety as a template for the dibenzo[24]crown-8 is reported. The active ester acts both as a semistopper for the [2]pseudorotaxane species and as an extensible extremity. Among the various investigated active ester moieties, those that allow for the slippage process are given particular focus because this strategy produces fewer side products. Extension of the selected N-hydroxysuccinimide ester based pseudorotaxane building block by using either a mono- or a diamino compound, both containing a triazolium moiety, is also described. These provide a pH-dependent two-station [2]rotaxane molecular machine and a palindromic [3]rotaxane molecular machine, respectively. Molecular machinery on both interlocked compounds through variation of pH was studied and characterized by means of NMR spectroscopy. PMID- 27239972 TI - Age-related differences in the neural correlates of trial-to-trial variations of reaction time. AB - Intra-subject variation in reaction time (ISVRT) is a developmentally-important phenomenon that decreases from childhood through young adulthood in parallel with the development of executive functions and networks. Prior work has shown a significant association between trial-by-trial variations in reaction time (RT) and trial-by-trial variations in brain activity as measured by the blood oxygenated level-dependent (BOLD) response in functional magnetic resonance imaging (fMRI) studies. It remains unclear, however, whether such "RT-BOLD" relationships vary with age. Here, we determined whether such trial-by-trial relationships vary with age in a cross-sectional design. We observed an association between age and RT-BOLD relationships in 11 clusters located in visual/occipital regions, frontal and parietal association cortex, precentral/postcentral gyrus, and thalamus. Some of these relationships were negative, reflecting increased BOLD associated with decreased RT, manifesting around the time of stimulus presentation and positive several seconds later. Critically for present purposes, all RT-BOLD relationships increased with age. Thus, RT-BOLD relationships may reflect robust, measurable changes in the brain behavior relationship across development. PMID- 27239976 TI - Risk factors for transfusion in cesarean section deliveries at a tertiary hospital. AB - BACKGROUND: The purpose of this study was to determine which variables are associated with different levels of transfusion for cesarean delivery. STUDY DESIGN AND METHODS: This was a retrospective study conducted in a tertiary hospital. A total of 271 patients receiving blood transfusions for postpartum hemorrhage (PPH) during a cesarean section and up to 24 hours after cesarean delivery between January 2006 and December 2013 were eligible for inclusion. Women in the transfused group were stratified into three subgroups according to number of units of red blood cells transfused: fewer than 5 units (mild transfusion), 5 to 10 units (moderate transfusion), and 10 or more units (massive transfusion). An additional 271 patients who delivered by cesarean section and suffered from PPH but did not require blood transfusion were selected as the nontransfused group. RESULTS: There were 271 patients who required a blood transfusion for PPH. The blood transfusion rate was 0.53% (271/50,699). After potential confounders were adjusted for, when compared with the nontransfused group, assisted reproductive technologies was a risk factor for mild transfusion (adjusted odds ratio [AOR] 2.452, 95% CI 1.250-4.808) and moderate transfusion (AOR 2.075, 95% CI 1.069-4.028); placenta previa was a risk factor for moderate transfusion (AOR 2.736, 95% CI 1536-4.874); and pernicious placenta previa was a risk factor for all transfusion subgroups (AOR 14.211, 95% CI 1.452-39.089; AOR 12.462, 95% CI 1.275-121.749; AOR 73.636, 95% CI 9.041-599.742). More women were treated with intrauterine balloon pressure and uterine compression sutures in the mild, moderate, and massive transfusion groups. CONCLUSION: Placenta previa was a risk factor associated with moderate transfusion, and pernicious placenta previa was the only modifiable prepartum risk factor independently associated with all transfused subgroups. PMID- 27239977 TI - Progress in the Fight Against Multidrug-Resistant Bacteria? A Review of U.S. Food and Drug Administration-Approved Antibiotics, 2010-2015. AB - A weak antibiotic pipeline and the increase in drug-resistant pathogens have led to calls for more new antibiotics. Eight new antibiotics were approved by the U.S. Food and Drug Administration (FDA) between January 2010 and December 2015: ceftaroline, fidaxomicin, bedaquiline, dalbavancin, tedizolid, oritavancin, ceftolozane-tazobactam, and ceftazidime-avibactam. This study evaluates the development course and pivotal trials of these antibiotics for their innovativeness, development process, documented patient outcomes, and cost. Data sources were FDA approval packages and databases (January 2010 to December 2015); the Red Book (Truven Health Analytics); Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations (FDA); and supplementary information from company filings, press releases, and media reports. Four antibiotics were approved for acute bacterial skin and skin-structure infection. Seven had similar mechanisms of action to those of previously approved drugs. Six were initially developed by small to midsized companies, and 7 are currently marketed by 1 of 3 large companies. The drugs spent a median of 6.2 years in clinical trials (interquartile range [IQR], 5.4 to 8.8 years) and 8 months in FDA review (IQR, 7.5 to 8 months). The median number of patients enrolled in the pivotal trials was 666 (IQR, 553 to 739 patients; full range, 44 to 1005 patients), and median trial duration was 18 months (IQR, 15 to 22 months). Seven drugs were approved on the basis of pivotal trials evaluating noninferiority. One drug demonstrated superiority on an exploratory secondary end point, 2 showed decreased efficacy in patients with renal insufficiency, and 1 showed increased mortality compared with older drugs. Seven of the drugs are substantially more expensive than their trial comparators. Limitations are that future research may show benefit to patients, new drugs from older classes may show superior effectiveness in specific patient populations, and initial U.S. prices for each new antibiotic were obtained from public sources. Recently marketed antibiotics are more expensive but have been approved without evidence of clinical superiority. PMID- 27239978 TI - Determination of residual 1,4-dioxane in surfactants and cleaning agents using headspace single-drop microextraction followed by gas chromatography-flame ionization detection. AB - OBJECTIVE: Polyethoxylated surfactants are widely used in the formulation of different cleaning agents such as shampoo, dish washing and hand washing products and lotion formulation. During the production of polyethoxylated surfactants, 1,4 dioxane as a toxic and carcinogenic by-product is formed. A simple low-cost method based on headspace single-drop microextraction combined with gas chromatography-flame ionization detection was developed for the determination of 1,4-dioxane in surfactants and cleaning agents. METHODS: In this method, 1,4 dioxane was extracted from 8.0 mL sample solution into a microdrop of an organic solvent, and then, it was injected to gas chromatography. The effects of such parameters as the solvent type, salt addition, microdrop volume, stirring rate, equilibrium time, extraction time and the temperature of sample solution on the extraction performance were studied and optimized. An ethoxylated surfactant containing 1,4-dioxane was used as the sample for the optimization of the extraction parameters. RESULTS: The linear range, determination coefficient, limit of detection and relative standard deviation of the method were 0.5-100 MUg g-1 , 0.9977, 0.4 MUg g-1 and 7.2% (n = 5), respectively. Different real samples including sodium lauryl ether sulphate, sodium lauryl sulphate (SLS), four brands of shampoo, and hand washing and dish washing liquids were analysed by the method. 1,4-Dioxane was detected at the concentration range of 2.4-201 MUg g-1 in the samples, except dish washing liquid and SLS. CONCLUSION: A new method with the merits of simplicity, low cost, low organic solvent consumption, short analysis time, good repeatability and suitable detection limit was developed for the analysis of 1,4-dioxane in surfactants and cleaning agents. PMID- 27239979 TI - Organ-to-Cell-Scale Health Assessment Using Geographical Information System Approaches with Multibeam Scanning Electron Microscopy. AB - This study combines novel multibeam electron microscopy with a geographical information system approach to create a first, seamless, navigable anatomic map of the human hip and its cellular inhabitants. Using spatial information acquired by localizing relevant map landmarks (e.g. cells, blood vessels), network modeling will enable disease epidemiology studies in populations of cells inhabiting tissues and organs. PMID- 27239980 TI - Mesoporous Silica Particles Integrated with All-Inorganic CsPbBr3 Perovskite Quantum-Dot Nanocomposites (MP-PQDs) with High Stability and Wide Color Gamut Used for Backlight Display. AB - All-inorganic CsPbX3 (X=I, Br, Cl) perovskite quantum dots (PQDs) have been investigated because of their optical properties, such as tunable wavelength, narrow band, and high quantum efficiency. These features have been used in light emitting diode (LED) devices. LED on-chip fabrication uses mixed green and red quantum dots with silicone gel. However, the ion-exchange effect widens the narrow emission spectrum. Quantum dots cannot be mixed because of anion exchange. We address this issue with a mesoporous PQD nanocomposite that can prevent ion exchange and increase stability. We mixed green quantum-dot-containing mesoporous silica nanocomposites with red PQDs, which can prevent the anion-exchange effect and increase thermal and photo stability. We applied the new PQD-based LEDs for backlight displays. We also used PQDs in an on-chip LED device. Our white LED device for backlight display passed through a color filter with an NTSC value of 113 % and Rec. 2020 of 85 %. PMID- 27239981 TI - The Prognostic Significance of Neutrophil-to-Lymphocyte and Platelet-to Lymphocyte Ratios in Patients With Multiple Myeloma. AB - OBJECT: Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are simple, inexpensive prognostic markers for various conditions. The objective of this study was to determine the prognostic significance of NLR and PLR in patients with multiple myeloma (MM) in terms of survival. METHOD: A retrospective chart review study was conducted for 175 patients who met the criterion of diagnosis for MM between January 2004 and September 2014. RESULT: The median age of diagnosis was 69 years. Patients were divided into high and low NLR and PLR groups according to cutoff points from the receiver operating characteristic curve (2.78 and 155.58, respectively). The high NLR and PLR groups were associated with lower albumin level and higher staging. The high NLR group experienced inferior median survival compared with the low NLR group (37 vs. 66 months; log-rank P-value 0.005). However, there was no significant difference in median survival between the high and low PLR groups (45 vs. 62 months; P = 0.077). Multivariate analysis demonstrated that NLR is an independent predictor for OS of MM (HR 2.892; P = 0.009). CONCLUSION: We conclude that NLR is an independent prognostic factor for OS in MM. PMID- 27239982 TI - Alternative Single-Solvent Electrolytes Based on Cyanoesters for Safer Lithium Ion Batteries. AB - To identify alternative single-solvent-based electrolytes for application in lithium-ion batteries (LIBs), adequate computational methods were applied to screen specified physicochemical and electrochemical properties of new cyanoester based compounds. Out of 2747 possible target compounds, two promising candidates and two structurally equivalent components were chosen. A constructive selection process including evaluation of basic physicochemical properties as well assessing the compatibility towards graphitic anodes was initiated to identify the most promising candidates. With addition of a film-forming additive in a low concentration, the most promising candidate showed an adequate long-term cycling stability with LiNi1/3 Mn1/3 Co1/3 O2 [NMC(111)] in a full-cell setup using graphite as anode material. The main advantages of the new electrolyte formulation are related to its good thermal behavior, especially with regard to safety in combination with satisfying electrochemical performance. PMID- 27239984 TI - Reliable measurement of the FRET sensitized-quenching transition factor for FRET quantification in living cells. AB - 3-cube-based Forster resonance energy transfer (FRET) microscopy, a sensitized acceptor FRET quantification method, has been widely used to visualize dynamic protein-protein interaction in living cells. Determining the FRET sensitized quenching transition factor (G factor) of a particular donor-acceptor pair and optical system is crucial for 3-cube FRET quantification. We here improved the acceptor photobleaching-based G factor determination method (termed as mPb-G) and the two-plasmid-based G factor determination method (termed as mTP-G) for rapid and reliable measurement of the G factor. mTP-G method determines G factor by simultaneously detecting three images of cells exclusively expressing each of two tandem constructs with multiple donors and multiple acceptors. This method circumvents switchover of the cells exclusively expressing each of the two constructs. mPb-G method images G factor by detecting three images of cells expressing a donor-acceptor tandem FRET construct before and after partially photobleaching acceptor. We performed the two methods on our dual-channel wide field FRET microscope to obtain reliable G factor, and also measured the FRET efficiency and acceptor-to-donor concentration ratio of tandem constructs with different acceptor-donor stoichiometries in living HepG2 cells. mTP-G and mPb-G methods provide two simple and reliable tools for determining the G factor, in turn, quantitatively measuring FRET signal and monitoring dynamic biochemical processes in living cells. PMID- 27239983 TI - Individual differences in the components of children's and adults' information processing for simple symbolic and non-symbolic numeric decisions. AB - How do speed and accuracy trade off, and what components of information processing develop as children and adults make simple numeric comparisons? Data from symbolic and non-symbolic number tasks were collected from 19 first graders (Mage=7.12 years), 26 second/third graders (Mage=8.20 years), 27 fourth/fifth graders (Mage=10.46 years), and 19 seventh/eighth graders (Mage=13.22 years). The non-symbolic task asked children to decide whether an array of asterisks had a larger or smaller number than 50, and the symbolic task asked whether a two-digit number was greater than or less than 50. We used a diffusion model analysis to estimate components of processing in tasks from accuracy, correct and error response times, and response time (RT) distributions. Participants who were accurate on one task were accurate on the other task, and participants who made fast decisions on one task made fast decisions on the other task. Older participants extracted a higher quality of information from the stimulus arrays, were more willing to make a decision, and were faster at encoding, transforming the stimulus representation, and executing their responses. Individual participants' accuracy and RTs were uncorrelated. Drift rate and boundary settings were significantly related across tasks, but they were unrelated to each other. Accuracy was mainly determined by drift rate, and RT was mainly determined by boundary separation. We concluded that RT and accuracy operate largely independently. PMID- 27239985 TI - Susceptibility of Alphitobius diaperinus in Texas to permethrin- and beta cyfluthrin-treated surfaces. AB - BACKGROUND: Effective control of the lesser mealworm beetle, Alphitobius diaperinus, relies heavily on insecticides. The susceptibility level of beetles to these insecticides can be dependent on active ingredient, population treated, formulation, surface treated and timing of observation. The susceptibility of adult beetles from six populations to beta-cyfluthrin was determined up to 48 h after exposure. The susceptibility of adult beetles to the label rate of beta cyfluthrin and permethrin formulations on concrete, wood-chip-type particle board and pressure-treated wood was determined up to 48 h post-exposure. RESULTS: Variation in LC50 values at 2 and 24 h was found within and between beetle populations from two regions of Texas. The permethrin formulation had lower mean mortality than the beta-cyfluthrin formulation on all surfaces tested. The permethrin formulation had high levels of recovery on all surfaces tested after 2 h. Surface affected the efficacy of the insecticides tested on killing adult beetles. CONCLUSION: Permethrin-based insecticide had lower knockdown and persistence on various surfaces over time than beta-cyfluthrin-based insecticide. Beetle recovery in less susceptible populations may necessitate longer observation periods for efficacy evaluations. Our study also shows that surfaces chosen can affect the efficacy of the compound on killing adult beetles. (c) 2016 Society of Chemical Industry. PMID- 27239986 TI - Determination of liquid's molecular interference function based on X-ray diffraction and dual-energy CT in security screening. AB - A method for deriving the molecular interference function (MIF) of an unknown liquid for security screening is presented. Based on the effective atomic number reconstructed from dual-energy computed tomography (CT), equivalent molecular formula of the liquid is estimated. After a series of optimizations, the MIF and a new effective atomic number are finally obtained from the X-ray diffraction (XRD) profile. The proposed method generates more accurate results with less sensitivity to the noise and data deficiency of the XRD profile. PMID- 27239987 TI - A dynamic material discrimination algorithm for dual MV energy X-ray digital radiography. AB - Dual-energy X-ray radiography has become a well-established technique in medical, industrial, and security applications, because of its material or tissue discrimination capability. The main difficulty of this technique is dealing with the materials overlapping problem. When there are two or more materials along the X-ray beam path, its material discrimination performance will be affected. In order to solve this problem, a new dynamic material discrimination algorithm is proposed for dual-energy X-ray digital radiography, which can also be extended to multi-energy X-ray situations. The algorithm has three steps: alpha-curve-based pre-classification, decomposition of overlapped materials, and the final material recognition. The key of the algorithm is to establish a dual-energy radiograph database of both pure basis materials and pair combinations of them. After the pre-classification results, original dual-energy projections of overlapped materials can be dynamically decomposed into two sets of dual-energy radiographs of each pure material by the algorithm. Thus, more accurate discrimination results can be provided even with the existence of the overlapping problem. Both numerical and experimental results that prove the validity and effectiveness of the algorithm are presented. PMID- 27239988 TI - The impact of early- and late-onset preeclampsia on umbilical cord blood cell populations. AB - Pregnancies complicated by preeclampsia (PE) are characterised by an enhanced maternal and fetal inflammatory response with increased numbers of leukocytes in maternal peripheral blood. The impact of PE on newborn umbilical cord blood cell (UCBC) populations however, has been scarcely studied. We hypothesise that PE deranges fetal haematopoiesis and subsequently UCBC populations. Therefore, the objective of this study was to investigate newborn umbilical cord blood cell populations in early- (EOPE) and late-onset PE (LOPE). A secondary cohort analysis in The Rotterdam Periconceptional Cohort was conducted comprising 23 PE cases, including 11 EOPE and 12 LOPE, and 195 controls, including 153 uncomplicated and 23 fetal growth restriction- and 19 preterm birth complicated controls. UCBC counts and differentials were quantified by flow cytometry and analysed as main outcome measures. Multivariable regression analysis revealed associations of EOPE with decreased leucocyte- (monocytes, neutrophils, eosinophils, immature granulocytes) and thrombocyte counts and increased NRBC counts (all p<0.05). EOPE remained associated with neutrophil- (beta-0.92, 95%CI 1.27,-0.57, p<0.001) and NRBC counts (beta1.11, 95%CI 0.27,1.95, p=0.010) after adjustment for gestational age and birth weight. LOPE did not reveal any significant association. We conclude that derangements of fetal haematopoiesis, in particular of neutrophil- and NRBC counts, are associated with EOPE only, with a potential impact for future health of the offspring. This heterogeneity in UCBC should be considered as confounder in epigenetic association studies examining EOPE. PMID- 27239989 TI - [Immunomorphology of oral lichen planus]. AB - The article is devoted to immunohistochemical study of reticular and erosive forms of oral lichen planus. Morphological examination of the reticular form revealed the increased number of Langerhans cells (CD1a), mast cells (CD25) and T lymphocytes (CD4, CD8, CD16) in the oral epithelium. Activation of these cells leads to the secretion of TNF-alpha and destruction of basal keratinocytes, which manifests as a focal reduction of intercellular protein expression of E-cadherin. Destruction of basal keratinocytes in a reticular form of oral lichen planus is accompanied by a significant decrease in proliferative activity of the basal cell layer (21.7+/-10.2%) compared with normal mucosa (33.6+/-7.0%), p=0.0045. In erosive form along with the above changes IgG and C3d complement's elements are revealed, which confirms the activation of immune complex mechanisms in the erosion area. PMID- 27239990 TI - [Study of mutual dependence of periodontal and colonic microbiome in health and pathology using NSG-sequencing]. AB - By using NGS-sequencing libraries of DNA from periodontal swabs with primers specific to V6 region of 16S rDNA prevalence of bacterial genera and species in periodontal and colonic microbiota of patients with periodontitis of different severity and healthy donors was analyzed. Hyper-colonization of the colon with Akkermansia muciniphila was found to be the most important maker of negative predisposition to periodontitis (t=133,7 at r=10(-6)). This result is in a good agreement with communications about positive impact of hyper-colonization of the colon with this species on type 2 diabetes, obesity, atopic dermatitis, and antibiotic-induced diarrhea associated with Clostridium dificile. Analysis of the periodontal protectors at the periodontium elucidated a number of close taxonomic relatives of the periodontal pathogens by Socransky, e.g. Aggregatibacter segnis and Aggregatibacter aphrophilus are closely related to Aggregatibacter actinomycetemcomitans; Treponema vencentii is a relative of Treponema denticola; Prevotella baroniae, Prevotella salivae and Prevotella spp. are relatives of Prevotella intermedia; Campylobacter concisus is a relative of Campylobacter jejuni, causative agent of enterocolitis. PMID- 27239991 TI - [The effectiveness of the combined use of energomonitor antioxidant and cognitive psychotherapy in the treatment of generalized periodontitis in elderly patients]. AB - The aim of the study was to evaluate the effect of combined use of Cytoflavin and cognitive therapy on the dynamics of psychosomatic status and effectiveness of the treatment of generalized periodontitis in elderly patients. The results of treatment of 103 patients aged 60 and older were analyzed. All patients received standard therapy for 10-14 days depending on the severity of the process. In addition, the patients of the main group (51 patients) received Cytoflavin: 2 tabs. 2 times a day with an interval between doses of 8-10 hours for 25 days, and cognitive therapy aimed at training alternative realistic way of life perception. Treatment results were monitored by PMA, Russell periodontal index (PI), Green Vermillion hygienic index. Psychosomatic dynamics was assessed by means of Spielberger anxiety scale and SUN" methods of before and after a month of treatment. The inclusion in the treatment regimen of Cytoflavin and cognitive therapy had a positive impact: reduction of PMA by 61.8%, PI by 45.3% and Green Vermillion index by 39.8%. The psychosomatic tests proved anxiety level decrease by 28.7% in terms of "reactive" anxiety and 31.5% in terms of "personal" anxiety, emotional status (21.2%), activity (21.7%) and mood (21.8%) improvement. PMID- 27239992 TI - [Specific features of emergency dental care in pregnant women]. AB - The aim of the study was to evaluate the algorithm of safe emergency dental care in pregnant patients. Eighty-five pregnant women aged 20-35 were included in the study. The paper presents elaborated state-of-the-art guidelines for emergency dental care in pregnant patients. Articaine 4% with epinephrine 1:200,000 is recommended as a choice agent for local anesthesia in these patients. PMID- 27239993 TI - [The impact of arterial hypertension in children on dental decay activity]. AB - One hundred and ninety-five children aged 8 to 13 years, of which 113 are diagnosed with essential arterial hypertension (EAH), and 82 children from the control group without somatic diseases including EAH were examined. All children underwent dental examination. The values of the substrates and the primary products of lipid peroxidation (LPO)--double bond (DB) and diene conjugates (DC) were determined. The index of caries intensity exceeded the similar indicator in comparison with the control group of children with EAH. The intensity of the oxidation of substrates of LPO in patients with EAH compared with healthy children was also higher. The article discusses the index of low value of DB in patients with 1st stage of caries in combination with EAH, as a potential negative factor limiting the generation of biologically active compounds in systemic blood flow involved in the prevention of caries process. PMID- 27239994 TI - [Salivation in children during anticancer chemotherapy]. AB - The study aimed to assess the needs and options for salivation management in children treated with antileukemic chemotherapy. In a preliminary cross-sectional study the saliva flow rate and viscosity were evaluated in 75 leukemic children that received chemotherapy with methotrexate in low dose (44 people, 44 episode, group 1), or in high-dose (31 people, 42 episode, group 2), and in 25 healthy children (group 3). Then, 26 children were randomly divided into two groups in the 70 episodes course of high-dosed chemotherapy, and received acetylcysteine (A) or only standard oral management (S) for 1-10 day of treatment. Parameters of salivation and children performance (Lansky et al.) were evaluated. Mann-Whitney U-test was used for analysis. In group 1, 2 and 3 the flow rate (Me [LQ/HQ]) was 0.5 [0.3; 0.8]; 0.9 [0.6; 1.2] and 0.5 [0.3; 0.6] ml/min respectively (p1-3>0.05; p<0.01; p1-2<0.05). Viscosity levels in group 1, 2 and 3 were 2.75 [3.67; 3.67], 10.05 [5.3; 26.0] and 3.9 [2.7; 6.5] unites respectively (p1-3>0.05; p2, 3<0.01; p1, 2<0.01). In group A and S the flow rate was 2.7 [0.5; 4.1] and 0.4 [0.1; 2.2] ml/min (r<0.05); viscosity was 1.5 [1.2; 4.1] and 6.4 [5.3; 8.1] unites (r<0.001), performance Lansky index was 80 [65; 90] and 70 [60; 80] (r<0.01) respectively. Salivation dysfunction complicates the chemotherapy with high-dosed methotrexate in children: it is indicated by high viscosity combined with elevated flow rate. Acetylcysteine normalizes saliva viscosity and improves children's performance. PMID- 27239995 TI - [Dynamics of tooth decay prevalence in children receiving long-term preventive program in school dental facilities]. AB - The paper presents the assessment of tooth decay prevalence in clinically homogenous groups of children receiving long-term preventive program (PP) in school dental facilities. Five-years PP were introduced in clinical practice in 2 Moscow schools. Preventive treatment was performed by dental hygienist. The results show that systematic preventive treatment in school dental offices starting from elementary school allows reducing dental caries incidence 46-53% and stabilize the incidence of caries complications. It should be mentioned though that analysis of individualized outcomes proves heterogeneity of study results despite of equal conditions of PP. Potentially significant hence is early diagnostics and treatment of initial caries forms as demineralization foci, especially in children with intensive tooth decay. Optimization of pediatric dentist and dental hygienist activity in school dental facilities is the main factor of caries prevention efficiency. PMID- 27239996 TI - [Application of semi-buried curvilinear distraction devices in complex management of lower micrognathia in children]. AB - The aim of the study was to apply an effective treatment protocol with low morbidity for children with syndromic and nonsyndromic micrognathia using curvilinear distractors, intraoral approach and early orthodontic treatment. We report 7 patients aged from 3 to 13 years with bilateral mandibular hypoplasia. These patients were characterized by severe malocclusion, esthetic facial deformation and respiratory disorders. In 3 patients mandibular hypoplasia was combined with anterior open bite. The intraoral surgical approach was used in all cases. Good functional and esthetic results were achieved during treatment. The less traumatic intraoral approach, curvilinear distractors, ultrasound callus formation control and early orthodontic treatment assure the good functional and esthetic results in severe cases facilitating the continuinty in complex rehabilitation of the growing child. PMID- 27239997 TI - [Orthodontic treatment need in school-age children in the Leningrad region]. AB - Epidemiology of dentoalveolar anomalies is undoubtedly important, but in terms of the organization of orthodontic care, greater interest are data on the needs in this type of treatment. In a situation of limited manpower and resources for the provision of orthodontic care information about needs in orthodontic treatment allows you to define a group of patients with the primary need for orthodontic treatment, and to identify priorities to optimize the organization of orthodontic care in the region. Such data can be obtained by using the Dental Aesthetics Index (DAI) and Index of Orthodontic Treatment Need (IOTN). The aim of the study was to analyze the epidemiology of various forms of dentoalveolar anomalies school-age children of Kirishi district of Leningrad region, as well as their needs in orthodontic treatment in accordance with objective evaluation indices. The study involved 734 pupils of Kirishi lyceum No1 of Leningrad region. Analysis of the prevalence of dentoalveolar anomalies, as well as needs in the orthodontic treatment was conducted in three age groups: I mixed dentition period (6-9 years), II mixed dentition period (10-13 years), and permanent dentition (14-17). To determine the needs in the orthodontic treatment were used two most common international index (DAI and IOTN). In Kirishi district of Leningrad region dentoalveolar anomalies were found in 88.8% of children of school age, which is in accordance with the indices and IOTN DAI needs in orthodontic treatment is 38.8% and 54.5%, respectively. In order to reduce unnecessarily high load volume medical institutions orthodontic profile, optimize utilization of financial resources, as well as reducing social tension it is recommended to introduce the practice of doctors-orthodontists methodology for determining the needs in orthodontic treatment by objective indices. PMID- 27239998 TI - [Laboratory evaluation of retraction cords properties]. AB - The aim of the study was the investigation of the effect of two factors on the diameter changings of different types of retraction cords. Using an optical microscope MBS-10 (x10) the diameter of the different retraction cords was measured. The measurement also was performed after tension and after wetting cords with distilled water. The cords diameter decreased after their tension and increased after wetting. The degree of diameter changes depends on the kind of cords weaving. Braided cords "00" and "1" sizes diameter after it tension decreased at 31% and 37%, knitted cords under tension changed the diameter at 53% and 48%, correspondingly. Cords features after wetting also varied. Wetting of the braided cords with distilled water did not lead to significant diameter changes while wetting of knitted cords increases their diameter at 13% (00) and 15% (1). PMID- 27239999 TI - [Comparative in vitro evaluation of modern glass ionomer cements for adhesion strength and fluoride release]. AB - The study proved similar adhesion strength and fluoride release level in aqueous extracts of glass ionomer cements Cemion (VladMiVa, Russia), Glassin Rest (Omega Dent, Russia), Cemfil 10 (StomaDent, Russia) and Fuji VIII (GC Corporation, Japan). Despite of close concentrations of fluoride in glasses, the rate of fluoride release in water from calcium and calcium-barium glasses is much higher than that of strontium glasses. PMID- 27240000 TI - [Intercortical osteotomy of alveolar bone in dental implantology]. PMID- 27240001 TI - [Out-patient dental service visit costs in obligatory insurance system]. AB - Significant vary of cost price is being observed in the medical organizations not only in the different subjects of the Russian Federation, but in the same federal region of the Russian Federation. So in the medical organizations of the Central Federal Region the fourfold difference of cost price of attendance with the prophylactic aim is observed. These facts make the planning of financial recourses difficult by elaborating the plans of state tasks and programs of state guarantees in general. PMID- 27240002 TI - Perception of effort in Exercise Science: Definition, measurement and perspectives. AB - Perception of effort, also known as perceived exertion or sense of effort, can be described as a cognitive feeling of work associated with voluntary actions. The aim of the present review is to provide an overview of what is perception of effort in Exercise Science. Due to the addition of sensations other than effort in its definition, the neurophysiology of perceived exertion remains poorly understood. As humans have the ability to dissociate effort from other sensations related to physical exercise, the need to use a narrower definition is emphasised. Consequently, a definition and some brief guidelines for its measurement are provided. Finally, an overview of the models present in the literature aiming to explain its neurophysiology, and some perspectives for future research are offered. PMID- 27240003 TI - Inflammatory bowel disease risk and the environment: Where to next? PMID- 27240004 TI - Outbreak of a new measles B3 variant in the Roma/Sinti population with transmission in the nosocomial setting, Italy, November 2015 to April 2016. AB - A measles outbreak occurred from November 2015 to April 2016 in two northern Italian regions, affecting the Roma/Sinti ethnic population and nosocomial setting. Overall, 67 cases were reported. Median age of 43 cases in three Roma/Sinti camps was four years, nosocomial cases were mainly adults. The outbreak was caused by a new measles virus B3.1 variant. Immunisation resources and strategies should be directed at groups with gaps in vaccine coverage, e.g. Roma/Sinti and healthcare workers. PMID- 27240005 TI - Validity of the iPhone M7 motion co-processor as a pedometer for able-bodied ambulation. AB - Physical activity benefits for disease prevention are well-established. Smartphones offer a convenient platform for community-based step count estimation to monitor and encourage physical activity. Accuracy is dependent on hardware software platforms, creating a recurring challenge for validation, but the Apple iPhone(r) M7 motion co-processor provides a standardised method that helps address this issue. Validity of the M7 to record step count for level-ground, able-bodied walking at three self-selected speeds, and agreement with the StepWatchTM was assessed. Steps were measured concurrently with the iPhone(r) (custom application to extract step count), StepWatchTM and manual count. Agreement between iPhone(r) and manual/StepWatchTM count was estimated through Pearson correlation and Bland-Altman analyses. Data from 20 participants suggested that iPhone(r) step count correlations with manual and StepWatchTM were strong for customary (1.3 +/- 0.1 m/s) and fast (1.8 +/- 0.2 m/s) speeds, but weak for the slow (1.0 +/- 0.1 m/s) speed. Mean absolute error (manual-iPhone(r)) was 21%, 8% and 4% for the slow, customary and fast speeds, respectively. The M7 accurately records step count during customary and fast walking speeds, but is prone to considerable inaccuracies at slow speeds which has important implications for certain patient groups. The iPhone(r) may be a suitable alternative to the StepWatchTM for only faster walking speeds. PMID- 27240006 TI - Detection of hepatitis b virus DNA in the blood of a stem cell donor after granulocyte colony-stimulating factor treatment. PMID- 27240007 TI - The nucleosome: orchestrating DNA damage signaling and repair within chromatin. AB - DNA damage occurs within the chromatin environment, which ultimately participates in regulating DNA damage response (DDR) pathways and repair of the lesion. DNA damage activates a cascade of signaling events that extensively modulates chromatin structure and organization to coordinate DDR factor recruitment to the break and repair, whilst also promoting the maintenance of normal chromatin functions within the damaged region. For example, DDR pathways must avoid conflicts between other DNA-based processes that function within the context of chromatin, including transcription and replication. The molecular mechanisms governing the recognition, target specificity, and recruitment of DDR factors and enzymes to the fundamental repeating unit of chromatin, i.e., the nucleosome, are poorly understood. Here we present our current view of how chromatin recognition by DDR factors is achieved at the level of the nucleosome. Emerging evidence suggests that the nucleosome surface, including the nucleosome acidic patch, promotes the binding and activity of several DNA damage factors on chromatin. Thus, in addition to interactions with damaged DNA and histone modifications, nucleosome recognition by DDR factors plays a key role in orchestrating the requisite chromatin response to maintain both genome and epigenome integrity. PMID- 27240008 TI - Three-dimensional graphene-like carbon frameworks as a new electrode material for electrochemical determination of small biomolecules. AB - Three-dimensional (3D) graphene-like carbon frameworks (3DGLCFs) were facilely prepared via copyrolysis of polyaniline and nickel nitrate powder, followed by acid etching. The as-prepared 3DGLCFs possess graphene-like network structure, high specific surface area, and high content nitrogen dopant. Because these features enable large electrochemically active surface area, rapid electron transfer, and fast transport of analytes to electrode surface, the 3DGLCFs modified glassy carbon electrode (GCE) shows current response much higher than commercial graphene (CG) modified GCE towards the oxidation of ascorbic acid (AA), dopamine (DA) and uric acid (UA). The anodic peak separations at 3DGLCFs/GCE are 0.23V between AA and DA, 0.13V between DA and UA, and 0.36V between AA and UA. For the simultaneous electrochemical determination of AA, DA and UA using differential pulse voltammetry, the 3DGLCFs/GCE shows linear response ranges of 1.25*10(-5)-4*10(-4)M for AA, 5*10(-8)-1.0*10(-5)M for DA, and 5*10(-8)-1.5*10(-5)M for UA, with low detection limits of 2*10(-6)M for AA, 1*10( 8)M for DA, and 1*10(-8)M for UA. The 3DGLCFs/GCE was also applied for the measurement of human serum, exhibiting satisfactory recoveries. PMID- 27240009 TI - Visual and fluorescent assays for selective detection of beta-amyloid oligomers based on the inner filter effect of gold nanoparticles on the fluorescence of CdTe quantum dots. AB - Beta-amyloid (Abeta) peptides are the major constituents of senile plaques in the brains of Alzheimer's disease (AD) patients. Abeta monomers (AbetaMs) can coalesce to form small, soluble oligomers (AbetaOs), followed by reorganization and assembly into long, thread-like fibrils (AbetaFs). Recently, soluble AbetaOs have been regarded as reliable molecular biomarkers for the diagnosis of AD because of their high toxicity for neuronal synapse and high concentration levels in the brains of AD patients. In this work, we reported a label-free, sensitive and selective method for visual and fluorescent detection of AbetaOs based on the inner filter effect (IFE) of gold nanoparticles (AuNPs) on the fluorescence of CdTe quantum dots (QDs). Specifically, the fluorescence of CdTe QDs was quenched significantly by AuNPs through the IFE. PrP(95-110), an AbetaOs-specific binding peptide from cellular prion protein, triggered the aggregation and color change of AuNPs suspension; thus, the IFE of AuNPs on the fluorescence of CdTe QDs was weakened and the fluorescence intensity was recovered. However, in the presence of AbetaOs, the specific interaction of AbetaOs and PrP(95-110) prevented the absorption of PrP(95-110) onto the surface of AuNPs. As a result, the aggregation of AuNPs was inhibited and the fluorescence intensity of CdTe QDs was quenched again. This label-free method is specific for detection of AbetaOs but not for AbetaMs and AbetaFs. The detection limits were found to be 0.5nM for the visual assay and 0.2nM for the fluorescent detection. We believe that this work would be valuable for many investigations related to AD diagnosis and drug discovery. PMID- 27240010 TI - Biofunctionalized magnetic nanospheres-based cell sorting strategy for efficient isolation, detection and subtype analyses of heterogeneous circulating hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is an awful threat to human health. Early-stage HCC may be detected by isolation of circulating tumor cells (CTCs) from peripheral blood samples, which is beneficial to the diagnosis and therapy. However, the extreme rarity and high heterogeneity of HCC CTCs have been restricting the relevant research. To achieve an efficient isolation, reliable detection and subtype analyses of heterogeneous HCC CTCs, herein, we present a cell sorting strategy based on anti-CD45 antibody-modified magnetic nanospheres. By this strategy, leukocyte depletion efficiency was up to 99.9% within 30min in mimic clinical samples, and the purity of the spiked HCC cells was improved 265 317-fold. Besides, the isolated HCC cells remained viable at 92.3% and could be directly recultured. Moreover, coupling the convenient, fast and effective cell sorting strategy with specific ICC identification via biomarkers AFP and GPC3, HCC CTCs were detectable in peripheral blood samples, showing the potential for HCC CTC detection in clinic. Notably, this immunomagnetic cell sorting strategy enabled isolating more heterogeneous HCC cells compared with the established EpCAM-based methods, and further achieved characterization of three different CTC subtypes from one clinical HCC blood sample, which may assist clinical HCC analyses such as prognosis or personalized treatment. PMID- 27240011 TI - A panel of promoter methylation markers for invasive and noninvasive early detection of NSCLC using a quantum dots-based FRET approach. AB - Non-small-cell lung cancer (NSCLC) leads to a significant proportion of cancer related deaths, and early detection of NSCLC can significantly increase cancer survival rates. A promising approach has been studied to exploit DNA methylation, which is closely correlated to early cancer diagnosis. Herein, in order to realize the early detection of NSCLC, we utilized the developed quantum dots based (QDs-based) fluorescence resonance energy transfer (FRET) nanosensor technique to analyze the promoter methylation in early stage NSCLC tissue samples and noninvasive bronchial brushing specimens. Using this method, the methylation levels can be quantitatively determined by measuring the signal amplification during FRET. A panel of three tumor suppressor genes (PCDHGB6, HOXA9 and RASSF1A) was assessed in 50 paired early stage NSCLC and their adjacent nontumorous tissue (NT) samples, and 50 early stage NSCLC bronchial brushing and normal specimens. The combined detection was able to identify not only tissue samples but noninvasive bronchial brushing specimens from control cases with a high degree of sensitivity of 92% (AUC=0.977, P<0.001) and 80% (AUC=0.907, P<0.001) respectively, indicating the versatility of promoter expression in invasive and noninvasive NSCLC samples. Therefore this approach can be used to sensitively analyze the methylation levels of cancer-related genes, which might be a potential tool for noninvasive early clinical diagnosis of cancers. PMID- 27240012 TI - A microfluidic biosensor using graphene oxide and aptamer-functionalized quantum dots for peanut allergen detection. AB - The increasing prevalence of food allergies and the intake of packing foods in the past two decades urge the need for more rapid, accurate, and sensitive assays to detect potential allergens in food in order to control the allergen content. Most of the commercial analytical tools for allergen detection rely on immunoassays such as ELISA. As far as disadvantages, ELISA can be time-consuming and expensive. Biosensors appear as a suitable alternative for the detection of allergens because they are rapid, highly sensitive, selective, less expensive, environmentally friendly, and easy to handle. In this study, we developed a microfluidic system integrated with a quantum dots (Qdots) aptamer functionalized graphene oxide (GO) nano-biosensor for simple, rapid, and sensitive food allergen detection. The biosensor utilized Qdots-aptamer-GO complexes as probes to undergo conformational change upon interaction with the food allergens, resulting in fluorescence changes due to the fluorescence quenching and recovering properties of GO by adsorption and desorption of aptamer-conjugated Qdots. This one-step 'turn on' homogenous assay in a ready-to-use microfluidic chip took ~10min to achieve a quantitative detection of Ara h 1, one of the major allergens appearing in peanuts. The results suggested this system had remarkable sensitivity and selectivity. The integration of a microfluidics platform in a homemade miniaturized optical analyzer provides a promising way for the rapid, cost effective, and accurate on-site determination of food allergens. This biosensor can also be extended to the detection of other food allergens with a selection of corresponding aptamers. PMID- 27240013 TI - Pt@AuNPs integrated quantitative capillary-based biosensors for point-of-care testing application. AB - Current diagnostic technologies primarily rely on bulky and costly analytical instruments. Therefore, cost-effective and portable diagnosis tools that can be used for point-of-care tests (POCT) are highly desirable. In this study, we report a cost-effective, portable capillary-based biosensor for quantitative detection of biomarkers by the naked eye. This capillary-based biosensor was tested by measuring the distance of blue ink movement, which was directly correlated with the oxygen (O2) produced by efficient core-shell Pt@Au nanoparticles (Pt@AuNPs) catalysts decomposed hydrogen peroxide (H2O2). By linking the Pt@AuNPs with antibodies, capillary-based biosensor sandwich immunoassays were constructed. The concentrations of the target proteins were positively correlated with the distances of ink movement. To demonstrate their performance, the biosensors were used to detect the cancer biomarker sprostate specific antigen (PSA) and carcinoembryonic antigen (CEA). The linear detection range (LDR) of the capillary-based biosensor for detecting PSA was from 0.02 to 2.5ng/mL, and the limit of detection (LOD) was 0.017ng/mL. LDR of the biosensor for detecting CEA was from 0.063 to 16ng/mL, and the LOD was 0.044ng/mL. For detection of PSA and CEA in clinical serum samples, the detection results of the capillary-based biosensor were well correlate with the results from of chemiluminescence immunoassays (CLIAs). Thus, the capillary-based biosensor may potentially be a useful strategy for point-of-care testing, in addition to being portable and cost effective. PMID- 27240014 TI - Electrochemical detection of glutathione based on Hg(2+)-mediated strand displacement reaction strategy. AB - Glutathione (GSH) plays an important role in numerous cellular functions, and the abnormal GSH expression is closely related with many dangerous human diseases. In this work, we have proposed a simple but sensitive electrochemical method for quantitative detection of GSH based on an Hg(2+)-mediated strand displacement reaction. Owing to the specific binding of Hg(2+) with T-T mismatches, helper DNA can bind to 3' terminal of probe DNA 1 and initiate the displacement of probe DNA 2 immobilized on an electrode surface. However, Hg(2+)-mediated strand displacement reaction can be inhibited by the chelation of GSH with Hg(2+), thereby leading to an obvious electrochemical response obtained from methylene blue that is modified onto the probe DNA. Our method can sensitively detect GSH in a wide linear range from 0.5nM to 5MUM with a low detection limit of 0.14nM, which can also easily distinguish target molecules in complex serum samples and even cell extractions. Therefore, this method may have great potential to monitor GSH in the physiological and pathological condition in the future. PMID- 27240015 TI - Solvent-Mediated Control of the Electrochemical Discharge Products of Non-Aqueous Sodium-Oxygen Electrochemistry. AB - The reduction of dioxygen in the presence of sodium cations can be tuned to give either sodium superoxide or sodium peroxide discharge products at the electrode surface. Control of the mechanistic direction of these processes may enhance the ability to tailor the energy density of sodium-oxygen batteries (NaO2 : 1071 Wh kg(-1) and Na2 O2 : 1505 Wh kg(-1) ). Through spectroelectrochemical analysis of a range of non-aqueous solvents, we describe the dependence of these processes on the electrolyte solvent and subsequent interactions formed between Na(+) and O2 ( ) . The solvents ability to form and remove [Na(+) -O2 (-) ]ads based on Gutmann donor number influences the final discharge product and mechanism of the cell. Utilizing surface-enhanced Raman spectroscopy and electrochemical techniques, we demonstrate an analysis of the response of Na-O2 cell chemistry with sulfoxide, amide, ether, and nitrile electrolyte solvents. PMID- 27240017 TI - Relationship between selected oxidative stress markers and lipid risk factors for cardiovascular disease in middle-aged adults and its possible clinical relevance. AB - OBJECTIVES: Decreased activity of HDL-associated paraoxonase 1 (PON1) and elevated levels of lipid peroxides together with abnormal lipid profile may prognosticate the progression of atherosclerosis. The aim of this study was to assess associations between selected oxidative stress markers (PON1, lipid peroxides) and lipid risk factors for cardiovascular disease in middle-aged subjects. DESIGN AND METHODS: Arylesterase activity of PON1; lipid peroxides; total-, HDL-, LDL-, non-HDL-cholesterol; triglycerides; apolipoproteins A-I (ApoA I) and B (ApoB), and lipid risk indexes were determined in serum of 75 volunteers (mean age 41.7+/-8.2years). Forty six volunteers were divided into normolipidemic (NL) and hyperlipidemic (HL) group. RESULTS: Elevated levels of atherogenic cholesterol (LDL, non-HDL), lipid risk indexes (p<0.0001), lipid peroxides (p<0.001), and decreased activity of PON1 (p<0.05) were found in HL group. Strong correlations between PON1 activity and HDL (r=0.635, p=0.0005), apolipoprotein A I (r=0.703, p<0.0001), ApoA-I/ApoB ratio (r=0.536, p=0.004), and non-HDL/HDL ratio (r=-0.445, p=0.013) were observed in NL group. There was no significant association between PON1 activity and these parameters in HL group. CONCLUSIONS: Significant abnormalities of lipid parameters, oxidative stress markers and associations between PON1, HDL and apolipoprotein A-I may influence the antioxidant and anti-atherogenic functions of HDL and result in the higher susceptibility of lipoproteins to oxidative modification. Monitoring of lipid profile together with oxidative stress markers in an asymptomatic population could be beneficial for early identification of atherosclerosis-related diseases. PMID- 27240016 TI - Shelf-Life Extension of Chill-Stored Beef Longissimus Steaks Packaged under Modified Atmospheres with 50% O2 and 40% CO2. AB - This study was conducted to compare the shelf-life of beef steaks stored in different packaging conditions: overwrapped (OW) packaging and 2 modified atmosphere packaging systems (MAP): 80% O2 MAP (80% O2 /20% CO2 ) and 50% O2 MAP (50% O2 /40% CO2 /10% N2 ). Steaks were stored at 2 degrees C for 20 d. Headspace gas composition, microbial counts, color stability, pH, purge loss, and lipid oxidation were monitored. Among the packaging types, 50% O2 MAP was superior to OW packaging and 80% O2 MAP in delaying bacterial growth and extending shelf-life to 20 d. 50% O2 MAP also gave steaks an acceptable color during storage. No significant differences were observed in color stability of steaks packaged in both 50% O2 MAP and 80% O2 MAP. This study reveals 50% O2 MAP is a realistic alternative to preserve beef steaks efficiently. PMID- 27240018 TI - The effect of pulmonary rehabilitation on COPD exacerbation frequency per year. AB - OBJECTIVE: We aimed to investigate the effect of pulmonary rehabilitation (PR) on the number of exacerbations in chronic obstructive pulmonary diseases (COPD) patients. METHODS: The study included 82 patients referred to our hospital's PR Unit between June 2013 and June 2014. Patients were divided into two groups, including those with low exacerbation risk (low number of exacerbations) (Groups A + B) and those experiencing frequent exacerbations (Groups C+ D) according to the combined COPD assessment. RESULTS: Patients were included in a PR program that consisted of 16 sessions in total, held twice a week over a period of 2 months. After one year, patients were called to find out about their COPD exacerbation frequency. Groups presented similar characteristics in terms of age, BMI and smoking duration prior to the PR program (P > .05). The frequent exacerbators had lower scores in exercise capacity, arterial oxygenation, health related quality of life and anxiety (P < .05). However, both groups exhibited significantly improved scores in the perceived dyspnea, FEV1 percentage, arterial oxygenation, exercise capacity, quality of life and anxiety after pulmonary rehabilitation (P < .05). The number of post-PR emergency referrals and hospitalization (P < .0001, P = .04), and depression score decreased significantly among the frequent exacerbators. Group 1 presented insignificant changes in the number of emergency referrals and hospitalizations (P < .05). CONCLUSION: Notwithstanding disease severity, PR treatment is reported to have positive effects on COPD patients in terms of perceived dyspnea, exercise capacity, arterial oxygenation, quality of life, anxiety and depression. This study found reduced number of emergency referrals and hospitalization among COPD patients with frequent exacerbations after PR. PMID- 27240019 TI - Cancer negatively impacts on sexual function in adolescents and young adults: The AYA HOPE study. AB - OBJECTIVE: This cohort study examined the impact of cancer on sexual function and intimate relationships in adolescents and young adults (AYAs). We also explored factors predicting an increased likelihood that cancer had negatively affected these outcomes. METHODS: Participants (n = 465, ages 15-39) in the Adolescent and Young Adult Health Outcomes and Patient Experience (AYA HOPE) study completed two surveys approximately 1 and 2 years post-cancer diagnosis. We used multivariable logistic regression to determine factors negatively affected by perceptions of sexual function at 2 years post-diagnosis. RESULTS: Forty-nine percent of AYAs reported negative effects on sexual function at 1 year post-cancer diagnosis and 70% of those persisted in their negative perceptions 2 years after diagnosis. Those reporting a negative impact at 2 years were more likely to be 25 years or older (OR, 2.53; 95% CI, 1.44-4.42), currently not raising children (OR, 1.81; 95% CI, 1.06-3.08), experiencing fatigue (OR, 0.99; 95% CI, 0.975-0.998) and more likely to report that their diagnosis has had a negative effect on physical appearance (OR, 3.08; 95% CI, 1.97-4.81). Clinical factors and mental health were not significant predictors of negative effects on sexual function. CONCLUSIONS: Many AYAs diagnosed with cancer experience a persistent negative impact on sexual life up to 2 years following diagnosis. The findings underscore the need to develop routine protocols to assess sexual function in AYAs with cancer and to provide comprehensive management in the clinical setting. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27240020 TI - Web-based ecosystem software for virtual crossmatching in transplant programs. AB - BACKGROUND: The compatibilities between donors and recipients are extremely important for evaluating the immunological risks of transplants. One challenge faced by data analysis tools is the transformation of complex data into simple, intuitive, and important information that can be used to resolve contemporary problems. To address this challenge, we developed the EpViX software to perform epitope reactivity analyses and automated epitope virtual crossmatching. EpViX is a facilitator of medical decision-making regarding the identification of the best donor for a high-immunologic risk recipient. The objective of this work is to describe the computational architecture of the EpViX ecosystem (http://www.epvix.com.br). MATERIALS AND METHODS: EpViX is a freeware on the web that was developed in the Ruby language. EpViX can be accessed from different platforms, e.g., PCs, tablets, and smartphones. It consists of an ecosystem of tools that are capable of integrating all of the stakeholders who are involved in a transplant process with a deceased donor. RESULTS: We successfully developed a program that allows people to work collaboratively and effectively during the donation process by accurately predicting negative crossmatches, saving time and other resources. CONCLUSIONS: EpViX represents a significant breakthrough for the organ transplant process and may meet the current needs of transplant programs because it increases the chances of the allocation of low-immunologic risk donors to highly sensitized recipients and assures greater equity among the recipients on a waiting list. EpViX was duly verified and tested in terms of data security. Moreover, usability tests demonstrated that EpViX is an intuitive and easy-to-use tool. PMID- 27240022 TI - The Effectiveness of Total Worker Health Interventions: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop. AB - BACKGROUND: The Total Worker Health (TWH) program of the National Institute for Occupational Safety and Health aims to advance worker well-being by integrating injury and illness prevention efforts with work-related safety and health hazard efforts. PURPOSE: To evaluate evidence on the benefits and harms of integrated TWH interventions. DATA SOURCES: MEDLINE, Cochrane Library, and PsycINFO (January 1990 through September 2015); clinical trial registries; and reference lists. STUDY SELECTION: English-language studies that enrolled employed adults and compared integrated interventions with usual work practice, no intervention, or another intervention. DATA EXTRACTION: Dual abstraction and risk-of-bias (ROB) assessment. DATA SYNTHESIS: Ten of the 15 included studies had high ROB, primarily because of selection and attrition bias. Findings graded as having low strength of evidence (SOE) supported the effectiveness of TWH interventions for improving smoking cessation, as measured by self-reported 7-day abstinence over 22 to 26 weeks (2 randomized, controlled trials [RCTs]; n = 737), and increasing consumption of fruits and vegetables over 26 to 104 weeks (3 RCTs; n = 6056); results apply to populations of blue-collar manufacturing and construction workers. Findings graded as having low SOE supported the effectiveness of TWH interventions for reducing sedentary work behavior in office workers over 16 to 52 weeks (2 RCTs; n = 262). Evidence was insufficient or lacking for other outcomes of interest, such as rates of work injuries, quality of life, and harms. LIMITATION: Small, diverse body of evidence with many methodological limitations; possible publication bias. CONCLUSION: Integrated TWH interventions might improve health behaviors (for example, reduce tobacco use and sedentary behavior and improve diet) of workers, but effects of these interventions on injuries and overall quality of life are not known. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. PMID- 27240021 TI - Entangled in a membranous web: ER and lipid droplet reorganization during hepatitis C virus infection. AB - Hepatitis C virus (HCV) is a major cause of liver disease worldwide. To establish and maintain chronic infection, HCV extensively rearranges cellular organelles to generate distinct compartments for viral RNA replication and virion assembly. Here, we review our current knowledge of how HCV proliferates and remodels ER derived membranes while preserving and expanding associated lipid droplets during viral infection. Unraveling the molecular mechanisms responsible for HCV-induced membrane reorganization will enhance our understanding of the HCV life-cycle, the associated liver pathology, and the biology of the ER:lipid droplet interface in general. PMID- 27240023 TI - Extraction and Purification of Quercitrin, Hyperoside, Rutin, and Afzelin from Zanthoxylum Bungeanum Maxim Leaves Using an Aqueous Two-Phase System. AB - In this study, an aqueous two-phase system (ATPS) based on ethanol/NaH2 PO4 was developed for the extraction and purification of quercitrin, hyperoside, rutin, and afzelin from Zanthoxylum bungeanum Maxim leaves. These 4 flavonoids were 1st extracted from dried Z. bungeanum leaves using a 60% ethanol solution and subsequently added to the ATPS for further purification. The partition behavior of the 4 flavonoids in ATPS was investigated. The optimal ATPS conditions were: 29% (w/w) NaH2 PO4 , 25% (w/w) ethanol concentration, 1% (w/w) added amount of leaf extracts, no pH adjustment, and repeated 1 h extractions at 25 degrees C. Under the optimal conditions for the 10 g ATPS, the absolute recovery of quercitrin, hyperoside, rutin, and afzelin reached 90.3%, 83.5%, 92.3%, and 89.1%, respectively. Compared to the 60% ethanol extracts, the content of quercitrin (44.8 mg/g), hyperoside (65.6 mg/g), rutin (56.4 mg/g), and afzelin (6.84 mg/g) in the extracts increased by 49.9%, 38.8%, 45.6%, and 36.8% respectively. The extracts after ATPS also exhibited stronger antioxidant activities, the 2,2-diphenyl-1-picrylhydrazyl IC50 value (10.5 MUg/mL) decreased by 41.8%, and the 2,2-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt value (966 MUmol Trolox/g) and ferric reducing power value (619 MUmol Trolox/g) increased by 29.8% and 53.7%, respectively. Furthermore, scale-up experiments indicated that a larger scale experiment was feasible for the purification of the 4 flavonoids. PMID- 27240024 TI - Raf kinase inhibitor protein1 is a myogenic inhibitor with conserved function in avians and mammals. AB - BACKGROUND: Raf Kinase Inhibitor Protein1 (RKIP) is a tumor suppressor that is present in several adult tissues. It functions as an inhibitor of both Raf/Mek/Erk and NFKB signaling when unphosphorylated, but following phosphorylation the ability to inhibit Raf/Mek/Erk signaling is lost and RKIP becomes an activator of G-protein coupled receptor signaling. In neonates and adults, RKIP is known to be expressed in muscle; however, its physiological function is currently unknown. RESULTS: In this study, we show by in situ hybridization and immunofluorescence that RKIP is also expressed in developing chick embryonic muscle, and mouse C2C12 myoblasts. Furthermore, we demonstrate that, in these systems, it functions as an inhibitor of myogenesis: increased levels of RKIP suppress myotube differentiation whereas decreasing RKIP promotes differentiation. Additionally, we show that the ability of RKIP to inhibit myogenesis is dependent upon its phosphorylation state as only the nonphosphorylated form of RKIP suppresses myogenesis. CONCLUSIONS: This study, therefore, clearly demonstrates that RKIP has conserved functions as a myogenic inhibitor in both mammalian and avian muscle. Developmental Dynamics 245:902-912, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27240025 TI - Is the Tunnel Technique More Effective Than Open Augmentation With a Titanium Reinforced Polytetrafluoroethylene Membrane for Horizontal Ridge Augmentation? AB - PURPOSE: Studies have shown that horizontal ridge augmentation with a nonresorbable membrane is subject to a relatively frequent occurrence of dehiscence and loss of the graft. This study was designed to compare the outcomes of a tunnel technique versus an open technique using a titanium-reinforced polytetrafluoroethylene (PTFE) membrane. MATERIALS AND METHODS: A retrospective cohort study, in which the data were collected by chart review, was designed to compare patients who had undergone horizontal ridge augmentation with a 1:1 ratio of mineralized freeze-dried allograft and particulate bovine hydroxyapatite by the tunnel technique with patients who had undergone an open technique with a titanium-reinforced PTFE membrane. The incidence of wound dehiscence or membrane exposure, the number of postoperative visits required, and the number of systemic antibiotic courses needed, as well as the number of grafted sites that subsequently were amenable to routine implant placement after graft maturation, were compared between the 2 techniques. The differences in implants placed between the 2 methods were analyzed with the Fisher exact test. The secondary hypothesis (regarding wound dehiscence, number of postoperative visits, and number of systemic antibiotic courses) was analyzed by Poisson regression. RESULTS: The chart review found 52 patients, with 21 treated by the tunnel technique and 31 treated with the open technique. Within 6 months after bone grafting, 18 patients (86%) treated with tunnel technique grafts received dental implants whereas 22 patients (71%) treated with the open technique received dental implants. Dehiscence developed in a greater proportion of ridge augmentations with the PTFE method (52% vs 19%). There was a trend toward an increased number of courses of antibiotics prescribed for this group (P = .11), as well as a significant increase in the number of postoperative visits required (P = .003). CONCLUSIONS: For horizontal defects amenable to either technique, the findings of this study show the tunnel technique is a more cost-effective option with similar success to the open technique. PMID- 27240026 TI - Predictive value of the APACHE II, SAPS II, SOFA and GCS scoring systems in patients with severe purulent bacterial meningitis. AB - BACKGROUND: Scoring systems in critical care patients are essential for predicting of the patient outcome and evaluating the therapy. In this study, we determined the value of the Acute Physiology and Chronic Health Evaluation II (APACHE II), Simplified Acute Physiology Score II (SAPS II), Sequential Organ Failure Assessment (SOFA) and Glasgow Coma Scale (GCS) scoring systems in the prediction of mortality in adult patients admitted to the intensive care unit (ICU) with severe purulent bacterial meningitis. METHODS: We retrospectively analysed data from 98 adult patients with severe purulent bacterial meningitis who were admitted to the single ICU between March 2006 and September 2015. RESULTS: Univariate logistic regression identified the following risk factors of death in patients with severe purulent bacterial meningitis: APACHE II, SAPS II, SOFA, and GCS scores, and the lengths of ICU stay and hospital stay. The independent risk factors of patient death in multivariate analysis were the SAPS II score, the length of ICU stay and the length of hospital stay. In the prediction of mortality according to the area under the curve, the SAPS II score had the highest accuracy followed by the APACHE II, GCS and SOFA scores. CONCLUSIONS: For the prediction of mortality in a patient with severe purulent bacterial meningitis, SAPS II had the highest accuracy. PMID- 27240027 TI - Thinking outside of the box: Transfer of shape-based reorientation across the boundary of an arena. AB - The way in which human and non-human animals represent the shape of their environments remains a contentious issue. According to local theories of shape learning, organisms encode the local geometric features of the environment that signal a goal location. In contrast, global theories of shape learning suggest that organisms encode the overall shape of the environment. There is, however, a surprising lack of evidence to support this latter claim, despite the fact that common behaviours seem to require encoding of the global-shape of an environment. We tested one such behaviour in 5 experiments, in which human participants were trained to navigate to a hidden goal on one side of a virtual arena (e.g. the inside) before being required to find the same point on the alternative side (e.g. the outside). Participants navigated to the appropriate goal location, both when inside and outside the virtual arena, but only when the shape of the arena remained the same between training and test (Experiments 1a and 1b). When the arena shape was transformed between these stages, participants were lost (Experiments 2a and 2b). When training and testing was conducted on the outside of two different-shaped arenas that shared local geometric cues participants once again explored the appropriate goal location (Experiment 3). These results provide core evidence that humans encode a global representation of the overall shape of the environments in, or around, which they navigate. PMID- 27240028 TI - The need to train trainers. PMID- 27240029 TI - Gender differences in myocardial infarction: health professionals' point of view. AB - Backgroud and aims: Aim of this study is contributing to an analysis of healthcare professionals' perceptions of gender differences in myocardial infarction. METHOD: For this purpose, the study examines bio-clinical and psychosocial aspects of myocardial infarction in men and women, thanks to 8 focus groups attended by healthcare professionals working at Milan Hospital (Niguarda Ca' Granda), Parma University Hospital, Catania Hospital (Ospedale Cannizzaro) and Ancona INRCA (Scientific Institute recognized in the area of Geriatrics and Gerontology). RESULTS: A qualitative analysis of the narratives have been aggregated in 5 code families: "pathophysiological peculiarities", "psycho relational peculiarities", "therapeutic problems", "protection and risk factors", and "no difference" between men and women, in particular as far as diagnostic therapeutic treatment is concerned. Pathophysiological peculiarities concern the acknowledgement of typically female characteristics which can affect clinical pathways, such as comorbidity and different symptoms. Psycho-relational peculiarities show women's attitudes toward symptoms underestimation and a high pain endurance. Therapeutic problems are connected to female physio-pathological peculiarities, which reduce treatment effectiveness. Protection and risk factors indicate peculiar protective conditions or potentially dangerous situations in female population, such as distress and greater responsibilities. CONCLUSIONS: The study confirms the "male model" of heart disease and a gap in evaluating and dealing with female infarction. The study takes into account differences in narratives. PMID- 27240030 TI - Motivational factors for choosing the degree course in nursing: a focus group study with nursing students. AB - BACKGROUND AND AIM OF THE WORK: Maintaining the number of new students entering nursing programs and remaining in the nursing occupation largely depends on the ability to recruit and retain young people. The motivational factors that induce young people to choose nursing as a career were investigated through a qualitative research approach. METHODS: Different focus groups were organised involving 32 students at the end of the first year of Nursing. Then the factors affecting their choice of course and the reasons for satisfaction and frustration connected with the course of study were analyzed. RESULTS: The main motivational factors for choosing Nursing that emerged include the following: having done voluntary work in the care area, attraction to the occupation since childhood/adolescence, failure of other plans, possibility to find work, personal acquaintance of nurses. The reasons for satisfaction with the course include: tutor support, workshop activities, placement experience. The reasons for frustration among the students included the complexity and extent of the study plan, elements that often they had not envisaged or had underestimated upon enrolment. CONCLUSIONS: Providing more information on the course of study, the working conditions and characteristics of the nursing occupation, could help young people to make an informed and aware decision, in order to reduce any disappointment and students dropping out of nursing education and attrition in the future. Improving the organisation of the course of study, supporting students' motivation through counselling activities and choosing suitable placement sites, could prevent drop outs. PMID- 27240031 TI - High-Fidelity in Urgency-Emergency Simulation: validation of a tool to determine the satisfaction of participants. AB - BACKGROUND AND AIM OF THE WORK: In literature there are some tools to measure the satisfaction level related to high-fidelity simulation experience. This paper reports the construction and validation of a specific unique questionnaire in Italian (SESAF - Satisfaction of High-Fidelity Simulation Experience). METHODS: After having reviewed various tools available in literature, and conducted some focus groups with high-fidelity simulation experts, the authors produced the SESAF tool. It was administered to 237 Physicians and nurses participated in high fidelity simulation of emergency codes. RESULTS: The factorial solution included 7 factors explaining the 71.65% of the total variance. Cronbach Alpha, reported an excellent reliability (0.97). CONCLUSIONS: SESAF can make comparable the satisfaction levels of HFS trainees among various centers. PMID- 27240032 TI - Care Case Managers' Job Satisfaction: a first contribution to the Italian validation of the Job Satisfaction Scale. AB - Background and aims of the work: From the analysis of the Italian literature emerges a lack of studies both about the work satisfaction of Case Care Manager Nurses (CCMN) and on their role in the sanitary context. This research aims to fill this gap through a first Italian validation of the Job Satisfaction Scale (JSS). METHOD: An Italian translation of JSS was provided by three independent judges. To verify the convergent validity of the scale the McCloskey Mueller Satisfaction Scale were used. A measure of the Organizational Wellbeing in the Operating Unit was used in order to verify the concurrent validity. A Professional Self-Efficacy evaluation allowed to verify the discriminant validity. Two open questions examined the role description and the difficulties met at work by the CCMN. The questionnaire was published on the Italian Association of Case Manager and in several Italian Professional Associations of Nurses, Sanitary Assistants and Pediatric nurses (IPASVI). RESULTS: 86 people (70 women) answered the questionnaire; 34 of which were Nurses and 52 CCMN. The convergent, the discriminant and the concurrent validity of the scale were proved. The participants were more satisfied with the quality and the kind of their job, and with the supervision and the colleagues, and less satisfied with the contingent recognitions, the marginal benefits, the promotions and with working and salary conditions. No relevant differences were found between Nurses and CCMN, but in authonomy, responsibility and professional opportunities the CCMN were more satisfied. CONCLUSIONS: This study aimed to offer a first validation contribution of the JSS Scale. Unfortunately the number of participants did not allow to testify a confirmatory factor analysis of the scale. Thus this work should be further improved. Finally, the data highlighted the need to investigate on the recognition of CCMN, since its absence is often the cause of a job dissatisfaction. PMID- 27240033 TI - The ambiguous role of healthcare providers: a new perspective in Human Resources Management. AB - BACKGROUND AND AIM: A strategic Human Resources Management approach, that overcomes anadministrative Personnel Management, is becoming crucial for hospital organizations. In this sense, the aimof this work was to examine the figure of healthcare provider using the concept of role, as expected behaviourin term of integration in the organizational culture. METHOD: The instrument used to analyse the healthcareprovider figure was "role mapping". Particularly, semistructured interviews were conducted and involved to36 health professionals of four units in order to examine the behaviour expectations system towards thehealthcare providers. RESULTS: The analysis revealed that the expectations of different professionals relatedto the healthcare provider were dissimilar. Physicians' expectations referred to technical preparation and efficiency,while nurses and nurse coordinators required collaboration in equip work and emotional support forpatients. In all Operating Units, directors were perceived as missing persons with vague expectations of efficiency.Differences concerned also the four Units. For example, in intensive care Unit, the role of healthcareprovider was clearer and this figure was perceived as essential for patients' care and for the equip teamwork.On the contrary, in Recovery Unit the healthcare provider was underestimated, the role was ambiguous andnot integrated in the equip even if there was a clear division of tasks between nurses and healthcare providers. CONCLUSION: The "role mapping" instrument allows to identify healthcare provider profile and find possible roleambiguity and conflicts in order to plan adequate human resources management interventions. PMID- 27240034 TI - Empowering workplace and wellbeing among healthcare professionals: the buffering role of job control. AB - BACKGROUND AND AIM: Health care workers are exposed to several job stressors that can adversely affect their wellbeing. Workplace incivility is a growing organizational concern with the potential to create workplaces harmful to individuals' wellbeing and increase occupational health risks. Based on the Job Demands-Resources (JD-R) model, the purpose of the present study was to investigate the role of two resources (organizational empowerment and job control) on individuals' well-being (emotional exhaustion) and attitude at work (unit affective commitment). MATERIALS AND METHODS: A total of 210 hospital workers completed a self-administered questionnaire that was used to measure organizational empowerment, workplace incivility, job control, exhaustion, and affective commitment. Data were collected in 2014. Data were examined via linear regression analyses. RESULTS: The results showed that workplace incivility was positively related to emotional exhaustion and negatively related to affective commitment. Workplace empowerment was positively related to affective commitment and negatively related to emotional exhaustion. Furthermore, the positive relationship between workplace empowerment and affective commitment was significantly moderated by job control. CONCLUSION: Our results found support for the JD-R model. Specifically, results showed the buffering effect of job control in the relationship between empowerment and affective commitment. Our findings may concretely contribute to the stress literature and offer additional suggestions to promote healthy workplaces. PMID- 27240035 TI - Transcultural validation of Activities Scale for Kids (ASK): translation and pilot test. AB - BACKGROUND AND AIM OF THE WORK: The Activities Scale for Kids performance (ASKp) is one of the few self-assessment questionnaires in pediatric rehabilitation that measures child perception in performance of daily routine activities. ASKp is composed of 30 questions designed to explore activities and participation in children and teenagers with musculoskeletal disorders. Scores assess level of physical ability, identify appropriate treatment and monitor changes over time. We undertook this cross-cultural validation study to achieve a culturally adapted Italian version of ASKp, to be tested on Italian children. METHODS: ASKp was converted into Italian by two independent certified translators, supported by two Italian research physiotherapists. Twelve children with musculoskeletal disorders, their parents and eleven expert pediatric physiotherapists independently assessed clarity of language and semantics of each item. Physiotherapists also evaluated content validity of each item. RESULTS: One item out of 30 did not reach inter-rater agreement >=80% for clarity and was modified according to suggestions given. A panel of three research physiotherapists improved clarity of some other items based on suggestions from study participants. Regarding content validity of ASKp, I-CVI was >=0.59 for all items and overall ASKp was deemed valid (S-CVI/Ave 0.93). CONCLUSIONS: The Italian version of ASKp is linguistically clear and culturally coherent with a high content validity. It can be extremely useful in assessing activity limitation perspectives in Italian children and adolescent ranging from five to 15 affected by musculoskeletal disorders. PMID- 27240036 TI - Clinical Research Nurse involvement to foster a community based transcultural research in RODAM European study. AB - BACKGROUND AND AIM OF THE WORK: The Clinical Research Nurse (CRN) can be considered the fulcrum of clinical studies, being a vital link between patient, principal investigator, study sponsor and administrative staff. The clinical research's way is still long and the contribution that CRNs can provide is crucial. In Italy, a CRN was employed in the study: Research on Obesity & Type 2 Diabetes among African Migrants (RODAM). The aim of the paper is to explore and describe the experience of this involvement. METHODS: The CRN managed the project in order to gain a complete collaboration from the Ghanaian population. From the first contact, the CRN decided to adopt a transcultural approach with the aim to create a relationship of understanding, mutual trust respect for each other's cultural diversity. The CRN also used organizational, technical and linguistic skills. RESULTS: The day-to-day trial management from CRN included the following activities: obtaining local Ethics Committee study approval; recruiting the study staff; planning the study activities; identifying potential study participants; collaborating with the mediators; managing contacts with other RODAM centers; conducting a follow-up of patients. The most important results of CRN involvement have been the empowerment of Ghanaian community and the effective healthcare promotion. CONCLUSIONS: The project encouraged the Ghanaian community to increase their healthcare awareness and encouraged the Ghanaian population to create new strategies to face the hard health challenges. PMID- 27240037 TI - Perangustols A and B, a pair of new azaphilone epimers from a marine sediment derived fungus Cladosporium perangustm FS62. AB - A pair of new azaphilone epimers, perangustols A-B (1-2), and two new natural products (3-4), together with two known metabolites (5-6) were isolated from the culture of the marine sediment-derived fungus Cladosporium perangustum FS62. The structures of these compounds were established on the basis of extensive spectroscopic analysis. The isolated compounds (1-6) were evaluated for their cytotoxic activities against the SF-268, MCF-7, NCI-H460, and HepG-2 tumor cell lines. Nonetheless, no significant activity was observed. PMID- 27240038 TI - Physical demand of seven closed agility drills. AB - The present study aimed to quantify the demand of seven generic, closed agility drills. Twenty males with experience in invasion sports volunteered to participate in this study. They performed seven, closed agility drills over a standardised 30-m distance. Physical demand measures of peak velocity, total foot contacts, peak impacts, completion time, and maximum heart rate were obtained via the use of wearable sensor technologies. A subjective rating of perceived exertion (RPE) was also obtained. All measures, with the exception of maximum heart rates and RPE were able to delineate drills in terms of physical and physiological demand. The findings of this study exemplify the differences in demand of agility-type movements. Drill demand was dictated by the type of agility movement initiated with the increase in repetitiveness of a given movement type also contributing to increased demand. Findings from this study suggest agility drills can be manipulated to vary physical and physiological demand. This allows for the optimal application of training principles such as overload, progression, and periodisation. PMID- 27240039 TI - Letter regarding 'characteristics of the relationship that develops from nurse caregiver communication during telecare'. PMID- 27240040 TI - Fair opportunities, social productivity and wellbeing in disability: Towards a theoretical foundation. AB - BACKGROUND: Theory-based approaches provide explanations of the impact of components of the International Classification of Functioning, Disability and Health (ICF) classification on outcomes such as health and wellbeing. METHODS: Here, one such approach is proposed, focusing on social participation and its association with wellbeing. In addition to elaborating a theoretical approach, a narrative review of research on labour market participation of persons with severe disability, spinal cord injury, is conducted to illustrate the utility of the proposed approach. Availability and good quality of productive activities, in particular paid work, are expected to improve wellbeing by strengthening favourable experiences of personal control and social recognition. As these opportunities are restricted among persons with disabilities, conditions that enable full social participation need to be strengthened. RESULTS: Research identified several such conditions at the individual (e.g. coping, social support, educational skills) and the contextual socio-political level (e.g. quality of care, medical and vocational rehabilitation), although their potential of improving wellbeing has not yet been sufficiently explored. DISCUSSION: In conclusion, supplementing the established ICF classification by theory-based approaches may advance explanations of adverse effects of reduced functioning and wellbeing in disability. This new knowledge can guide the development of interventions to improve participation in general and social productivity in particular. PMID- 27240041 TI - [The differential diagnosis of recurrent episodes of vertigo]. AB - Recurrent episodes of vertigo are one of the most frequent reasons of referrals for medical help. In the Russian medicine, the development of vertigo is traditionally associated with a cerebral vascular pathology. It is suggested that correctly planned clinical neurovestibular study may identify the signs of a balance disorder of peripheral and central genesis. OBJECTIVE: To increase the effectiveness of the differential diagnosis of peripheral and central vertigo in patients with recurrent episodes of balance disorders using the protocol of neurovestibular examination ALGORITM. MATERIAL AND METHODS: The study included 120 outpatients with preliminary diagnoses of cerebral ischemia and autonomic vascular dystonia. RESULTS: Signs of lesion of peripheral and central regions of the vestibular system were found in 43.5 and 17.5% patients, respectively. Benign positional vertigo was the most frequent cause of vertigo while chronic cerebral ischemia was identified in 16.5% of the patients. CONCLUSION: Neurovestibularexamnation using the protocol ALGORITM is important for assessment of the level of vestibular system lesion. Iitis necessary to use it in complex examination of patients with complaints of vertigo. PMID- 27240042 TI - [Cognitive disorders in patients with schizophrenia at different stages of the disease]. AB - OBJECTIVE: To study cognitive disorders in patients with schizophrenia at different stages of the disease. MATERIAL AND METHODS: Forty-five patients with paranoid schizophrenia with first and recurrent episodes were examined clinically and psychometrically using the PANSS. Neurocognitive functioning was assessed with the "Rey--Osterrieth Complex figure". RESULTS AND CONCLUSION: Differences were found not only between patients with chronic and first-episode schizophrenia, but also between first-time hospitalized and re-hospitalized patients within the first-episode group. PMID- 27240043 TI - [The efficacy of psychopharmacotherapy of late onset depression: the optimization of treatment duration]. AB - OBJECTIVE: To analyze possibilities of using different methods to increase the efficacy of psychopharmacotherapy of late onset depression, in particular to increase treatment duration. MATERIAL AND METHODS: The study included 378patients, aged from 50 to 82 years (mean age 60.6+/-8.4). Patients were stratified into groups with short (4--8 weeks), moderate (12 weeks) and long (20 34 weeks) duration of psychopharmacotherapy. RESULTS AND CONCLUSION: Treatment effect was much lower after <8 weeks of treatment compared with that after 12 weeks (the comparison of these groups was not available because the initial samples were not). To the 24th week, 63.9% of the patients responded to treatment, 43.4% achieved remission. Partial response and stable positive dynamics to the 12th week (about 1/2 of the patients achieved remission) were predictors of response with treatment duration <24 weeks. Based on the results obtained, the authors developed algorithms for choosing treatment tactics in patients with late onset depression in dependence of the results of the first 12 weeks of psychopharmacotherapy. PMID- 27240044 TI - [The system stress-limiting action of mexidol in chronic cerebral ischemia]. AB - OBJECTIVE: To clarify the mechanisms of the action of anti-stress antioxidant agent (mexidol) in patients with chronic cerebral ischemia. MATERIAL AND METHODS: Sixty-seven patients with chronic cerebral ischemia (TE stage II),48 women and 19 men, mean age 48.2 years, were examined. To assess the stateof multilevel stress system, the level of anxiety and depression, degree of autonomic imbalance, adaptive reactions of the blood and functional properties of erythrocyte membranes, level of average weight molecules in the blood plasma were studied. Therapeutic complexes consisted of standard therapy (vinpocetine and piracetam) and mexidol (10 ml intravenous drip 200 ml of physiological solution once a day every day for 10 days with subsequent transition to the oral ingestion of the drug (1 tablet (125 mg) 3 times a day for three months). RESULTS AND CONCLUSION: In group 1 treated with additional antioxidant mexidol, the more pronounced and prolonged positive effect on the clinical symptoms of TE was observed. There were the persistent decrease in the level of anxiety and reduction of autonomic imbalancein the main group. The dynamics of adaptive reactions of blood indicated the activation of the adrenal cortex. There was a decrease in the content of average weight molecules and recovery of the sorption capacity of red blood cells. The results indicate the multi-component multi-level stress-limiting effect of mexidol in patients with chronic cerebral ischemia stage II. PMID- 27240045 TI - [A role of motivation for treatment in the structure of compliance in psychopharmacologically treated patients]. AB - OBJECTIVE: To reveal an impact of specific motivation structures on the compliance in psychiatric inpatients. MATERIAL AND METHODS: The Treatment Motivation Questionnaire and the Medication Compliance Scale have been administered to 104 patients, including 67 patients with schizophrenia and schizophrenia-spectrum disorders, 15 with affective disorders, 13 with personality and neurotic disorders and 9 with organic disorders, of the department of integrative pharmaco- and psychotherapy. RESULTS: A motivational mechanism based on the subjective suffering from disease plays a key role in the formation of overall score of compliance. Amotivation syndrome has a negative impact on the compliance. "Passive agreement" attitude to treatment corresponds to a deficiency in both patient and physician compliance subsystems along with a reduction in insight and cognitive functions in the patient's subsystem. Extreme external motivation for treatment correlates with insufficiently constructive support on the part of significant others in patient's environment subsystem resulting in the delay of internal motivation development. Extremely low scores based on understanding of disease character leads to the deficiency of medication compliance subsystem. PMID- 27240046 TI - [Polysomnography in patients with amyotrophic lateral sclerosis]. AB - OBJECTIVE: To study the characteristics of nocturnal sleep and reveal breathing disorders during sleep in ALS patients using polysomnography. MATERIAL AND METHODS: The study included 29 patients with the established diagnosis of ALS, 17 women and 12 men, median age 65 [59; 68] years; mean illness duration 12 [22.9; 27.1] months. The control group consisted of 46 volunteers without complaints of sleep disorder and sleep apnea. The sleep diagnostic system Somnolab 2 Weinmann, Germany was used. RESULTS AND CONCLUSION: An increased level of awaketime and a significant decrease in amount of deep sleep and REM sleep were revealed in ALS patients. Sleep breathing disorders are found significantly more often in ALS patients, mainly as alveolar hypoventilation syndrome and less frequently as obstructive sleep apnea. The lower level of mean and minimum blood oxygen saturation and increased respiratory rate were detected. These changes are possibly due to the presence of restrictive respiratory disorders. These disturbances reduce the total duration of sleep, destroy it's structure, exerting a direct influence on the life quality in ALS patients, disrupting their domestic and social activity, contributing to the development of neuropsychological and behavioral disorders. PMID- 27240047 TI - [The association between the GRIN2B gene and verbal fluency and impairment of abstract thinking in schizophrenia]. AB - OBJECTIVE: To search for the association between the GRIN2B gene and signs of thought and speech disorders which may be the result of decreased accessibility to the mental lexicon. MATERIAL AND METHODS: The association between the GRIN2B polymorphism rs7301328 with semantic verbal fluency and five symptoms of thought and speech disorders, as assessed with the PANSS, was studied in 552 patients with schizophrenia-spectrum disorders. RESULTS AND CONCLUSION: There was the association of the GRIN2B gene with verbal fluency and the PANSS item "Difficulty in Abstract Thinking". The association was not modified by verbal fluency. The results suggest that the GRIN2B gene may modify the linguistic processes involved in the retrieval of information from the mental lexicon on the basis of semantic traits and, moreover, contribute to the variability of clinical symptoms of impairment of abstract thinking in patients with schizophrenia. The heterozygous genotype may be protective against the development of thought and speech disorders. PMID- 27240048 TI - [Antibodies to native and denatured DNA in the serum of patients with schizophrenia depending on the clinical features of the disease]. AB - OBJECTIVE: To study the correlations between the level of antibodies to native and denatured DNA and psychopathological symptoms and illness duration in patients with schizophrenia. MATERIAL AND METHODS: The level of antibodies to native (double-stranded) DNA and denatured (single-stranded) DNA was studied in the serum of 50 patients with schizophrenia, including 12 patients with tardive dyskinesia (TD). The control group consisted of 30 people. RESULTS: A significant twofold increase in antibodies to native DNA was detected in patients with TD. There was no correlation of the amount of antibodies to double-stranded DNA with the duration of disease and leading symptoms both between the groups of patients as well as in comparison with controls. A significant decrease in antibody levels to the denatured (single-stranded) DNA was found in schizophrenic patients compared to the control group (p=0.009). A significant decrease in the concentration of antibodies to single-stranded DNA in patients with increasing duration of the disease, as well as in patients with leading negative symptoms was revealed. CONCLUSION: The results suggest that anti-DNAantibodies may not play a major role in the pathogenesis of schizophrenia. PMID- 27240049 TI - [Early social isolation increases alcohol preference in experiment]. AB - OBJECTIVE: To study the formation of alcohol preference in rats subjected to early social isolation, a possible model of schizophrenia. MATERIAL AND METHODS: The study was carried out on 45 Wistar male rats, aged 21--24 days. The experimental animals were dropped from the parental cells in the individual cells for 35 days, control rats were kept in standard conditions (5 animals per cage). Allanimals were subjected to forced alcohol drinking for three and ahalf months according to the following scheme: access to the15% ethanol solution (Monday, Wednesday, Friday), drinking deprivation (Tuesday, Thursday), free access to the water (Saturday, Sunday). Alcohol preference was evaluated in the "two-bottle" test, behavior characteristics -- in the "open field" and the "behavioral despair" tests. RESULTS AND CONCLUSION: Rats subjected to isolation significantly more of ten preferred alcohol in the "two-bottle" test after 0.5, 2 and 3 months of forced alcohol drinking. After the end of isolation and before forced alcohol drin-king, the experimental rats showed greater locomotor activity in the "open field" test. According to the exploratory activity and emotionality, the rats in both groups had no significant differences. The rats subjected to isolation, were significantly more sensitive to the sound stimulus and lingered ongerin the start area in the "open field". Thus, the combination of early social isolation and forced alcohol drinking leads to greater alcohol preference in experimental animals. Significant differences in alcohol preference were observed after the start of forced alcohol drinking while immediately after isolation the rats of both groups had no differences in their relation to alcohol. After 3.5 months of forced alcohol drinking, the isolated rats demonstrated decreased behavioral despair in the same test. PMID- 27240050 TI - [Psychogenic non-epileptic seizures: issues of comorbidity in the diagnosis and treatment]. AB - The paper presents a case report of seizures in a man of 40 years who was assessed by neurologists and psychiatrists for 15 years. Due to the low efficacy of treatment and permanent health deterioration, the patient was recognized as disabled. Later initial diagnosis of psychogenic non-epileptic seizures was completed by comorbid diagnosis of bipolar affective disorder, type II. Treatment with lamotrigine improved the patient's condition. It has been regarded as a positive effect on organic changes in the brain that are associated with affective and epileptic disorders. PMID- 27240051 TI - [A case report of eating disorder in a medical worker]. PMID- 27240052 TI - [The criteria of early detection of biotinidase deficiency-based epilepsy]. AB - OBJECTIVE: An analysis of clinical and paraclinical symptomatology of three cases of infant epilepsy due to biotinidase deficiency is presented. MATERIAL AND METHODS: The diagnosis took 4 months in the first case and 1 day in the last one. RESULTS AND CONCLUSION: It is emphasized that early diagnosisbased on knowing the reference signs of this inherited metabolic disease provides an opportunity to avoid patient's disability or death. PMID- 27240053 TI - [Symptoms of obsessive-compulsive disorder in neurological diseases]. AB - Obsessive-compulsive disorder (OCD) is a common form of neurosis. Symptoms of OCD could develop as a sign of focal brain lesion, particularly in multiple sclerosis, extrapyramidal disorders, epilepsy, less frequently - in other diseases. Timely diagnosis and treatment of the symptoms of OCD is an important aspect in the management of mentioned neurological disorders. PMID- 27240054 TI - Recent innovations in mRNA vaccines. AB - Nucleic acid-based vaccines are being developed as a means to combine the positive attributes of both live-attenuated and subunit vaccines. Viral vectors and plasmid DNA vaccines have been extensively evaluated in human clinical trials and have been shown to be safe and immunogenic, although none have yet been licensed for human use. Recently, mRNA based vaccines have emerged as an alternative approach. They promise the flexibility of plasmid DNA vaccines, without the need for electroporation, but with enhanced immunogenicity and safety. In addition, they avoid the limitations of anti-vector immunity seen with viral vectors, and can be dosed repeatedly. This review highlights the key papers published over the past few years and summarizes prospects for the near future. PMID- 27240055 TI - Monitoring immune responses in the tumor microenvironment. AB - Immune monitoring in the tumor microenvironment allows for important insights into immune mechanisms of response and resistance to various cancer treatments; however clinical challenges exist using current strategies. Significant questions remain regarding monitoring of archival versus fresh tissue, assessment of static versus dynamic markers, evaluation of limited tissue samples, and the translation of insights gained from immunologically 'hot' tumors such as melanoma to other 'cold' tumor microenvironments prevalent in other cancer types. Current and emerging immune monitoring strategies will be examined herein, and genomic-based assays complementing these techniques will also be discussed. Finally, host genomic and external environmental factors influencing anti-tumor immune responses will be considered, including the role of the gut microbiome. Though optimal immune monitoring techniques are in evolution, great promise exists in recent advances that will help guide patient selection as far as type, sequence, and combination of therapeutic regimens to enhance anti-tumor immunity and clinical responses. PMID- 27240056 TI - Role of frameshift ubiquitin B protein in Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common neurodegenerative disease and is characterized by accumulation of misfolded and aggregated proteins. Since the ubiquitin-proteasome system (UPS) is the major intracellular protein quality control (PQC) system in eukaryotic cells, it is likely involved in the etiology of AD. The frameshift form of ubiquitin (Ubb(+1) ) accumulates in the neuritic plaques and neurofibrillary tangles in patients with AD. Ubb(+1) accumulates in an age-dependent manner as a result of RNA-polymerase mediated molecular misreading during transcription, which allows the formation of mutant proteins in the absence of gene mutations. The accumulation of the Ubb(+1) protein may act as an endogenous reporter for proteasome dysfunction and a growing number of studies have shown that Ubb(+1) may play more important pathogenic roles in AD etiology than previously hypothesized. The yeast Saccharomyces cerevisiae shares many conserved biological processes with all eukaryotic cells, including human neurons. This organism has been regarded as a model system for investigating the fundamental intracellular mechanisms, including those underlying neurodegeneration. We propose here that yeast systems biology approaches, combined with cell and molecular biology approaches will increase the relevant knowledge needed for advancement and elucidation of mechanisms and complex traits, which could provide new targets for therapeutic intervention in AD. WIREs Syst Biol Med 2016, 8:300-313. doi: 10.1002/wsbm.1340 For further resources related to this article, please visit the WIREs website. PMID- 27240058 TI - Liebe Leser des JDDG. PMID- 27240057 TI - Reply. PMID- 27240059 TI - Pathophysiologische Grundlagen der Systemtherapien bei Psoriasis. PMID- 27240060 TI - Pathophysiological basis of systemic treatments in psoriasis. AB - Over the past 15 years, the spectrum of systemic antipsoriatic treatments has dramatically expanded. Until the end of the last millennium, systemic therapy had been restricted to four oral agents: methotrexate, cyclosporine, acitretin, and fumaric acid esters. Today, there are additionally seven biologics and one new oral antipsoriatic drug, as well as the first available biosimilars. Six more biologics with novel target structures and at least four biosimilars are currently being developed (phase III). This progress has been based on new insights into the pathogenesis of psoriasis, in which tumor necrosis factor and especially Th17 immune responses with their associated cytokines interleukin 23 and 17 play a key role. The development of new-generation biologics as well as immunomodulatory small molecules can be attributed to these pathophysiological findings. Phosphodiesterase 4 inhibitors, dimethyl fumarate, and Janus kinase inhibitors all interact with Th17 immune responses. Some of these drugs are in advanced clinical development and are also beneficial in psoriatic arthritis. Today, psoriasis and psoriatic arthritis therefore rank among the most readily treatable inflammatory autoimmune disorders. Dermatology is increasingly becoming a specialty of modern targeted immunotherapies. PMID- 27240061 TI - Konsensuspapier zur symptomorientierten Therapie der chronischen Venenerkrankungen. AB - HINTERGRUND: Chronische Venenerkrankungen sind eine Volkskrankheit. Venose Symptome wie Schwellungs- und Schweregefuhl konnen bereits fruh ohne sichtbaren Befund auftreten und werden als belastend erlebt. Ein Fortschreiten im Sinne einer objektivierbaren Varikose bzw. chronischen venosen Insuffizienz schrankt die Lebensqualitat erheblich ein. METHODIK: Pubmed-gelistete Publikationen sowie relevante Leitlinien zur Therapie chronischer Venenkrankheiten bilden die Basis der vorliegenden Konsensusempfehlungen. Inkludiert in die Bewertung wurden ausschliebetalich aussagekraftige randomisierte Studien (RCT) und Ubersichtsarbeiten (Reviews/Metaanalysen). ERGEBNISSE: Die symptomorientierte Behandlung chronischer Venenerkrankungen stutzt sich auf drei Saulen mit nachgewiesener Wirksamkeit: invasive Therapie, Kompressionstherapie und orale medikamentose Therapie. Gemabeta Empfehlungen aktueller Leitlinien sollte zunachst eine Sanierung des venosen Gefabetabetts erwogen werden, um einen storungsfreien venosen Blutfluss wiederherzustellen und Symptome und pathologische Veranderungen zu beseitigen oder zu bessern. Ist ein invasiver Eingriff nicht moglich bzw. nicht erwunscht oder bestehen nach einem Eingriff noch Restsymptome, gilt es, die symptomatischen Therapieoptionen optimal auszuschopfen. Kompressionstherapie und medikamentose Therapie konnen allein oder in Kombination angewendet werden. Welche Strategie den grobetaten Erfolg verspricht, ist individuell zu entscheiden. SCHLUSSFOLGERUNGEN: Chronische Venenerkrankungen sollten auf der Basis der individuellen pathophysiologischen Storung behandelt werden. Sie symptomorientierte Behandlung chronischer Venenerkrankungen fubetat auf der invasiven Therapie, der Kompressionstherapie und der medikamentosen Therapie. Bei der Indikationsstellung sind objektive Symptome ebenso wie subjektive Beschwerden zu berucksichtigen. PMID- 27240062 TI - Consensus statement on the symptom-based treatment of chronic venous diseases. AB - BACKGROUND: Chronic venous diseases are very common. Early symptoms such as a sensation of swelling and heaviness may occur without objectifiable findings, but are nevertheless perceived as bothersome. Progressive disease - marked by varicose veins and symptoms of chronic venous insufficiency - is associated with considerable impairment in quality of life. METHODS: The present consensus recommendations are based on publications in Pubmed-listed journals as well as relevant international therapeutic guidelines on chronic venous diseases. Only conclusive randomized controlled trials (RCTs) and review articles/meta-analyses were included. RESULTS: Symptom-based treatment of chronic venous diseases is based on three therapeutic pillars with proven efficacy: invasive therapy, compression therapy, and oral pharmacological treatment. According to current therapeutic guidelines, invasive procedures aimed at restoring unimpaired venous blood flow as well as improving or eliminating pathological changes should be the first-line approach. If an invasive approach is infeasible or undesirable, or if symptoms persist following a therapeutic intervention, optimal use of symptom based treatment options is recommended. Compression and pharmacological therapy may each be used as sole treatment or in combination. To guarantee maximum therapeutic success, individual treatment decisions should be made on a case-by case basis. CONCLUSIONS: Chronic venous diseases should be treated on the basis of individual pathophysiological disturbances. Symptom-based treatment of chronic venous disorders encompasses invasive therapy, compression therapy, and oral pharmacological therapy. Considerations in choosing the appropriate treatment option should include both objective signs as well as subjective symptoms. PMID- 27240063 TI - Chirurgische Behandlung von Melanomen in der Schwangerschaft: eine praktische Anleitung. AB - Als ein Tumor, der primar eine chirurgische Behandlung erfordert, ist ein neu diagnostiziertes oder vorbestehendes Melanom in der Schwangerschaft eine klinische Raritat. In solchen Fallen steht der Chirurg vor der Herausforderung, ein geeignetes therapeutisches Vorgehen festlegen zu mussen. Auf der Grundlage unserer klinischen Erfahrung und einer Ubersicht uber die Literatur geben wir in der vorliegenden Arbeit eine Anleitung fur das praktische Vorgehen bei dieser seltenen klinischen Konstellation. Unserer Erfahrung nach mussen schwangere Melanom-Patientinnen im Hinblick auf ihre therapeutischen Optionen ausfuhrlich beraten werden. Naturgemabeta setzen sie ihr ungeborenes Kind an die erste Stelle und zogern, der erforderlichen Operation zuzustimmen, obwohl bei ihnen eine moglicherweise lebensbedrohliche Erkrankung diagnostiziert worden ist. Daher ist es entscheidend, diese Patientinnen klar daruber zu informieren, dass, wie die vorliegenden medizinischen Erfahrungen zeigen, eine Schwangerschaft per se kein Grund ist, eine notwendige Melanom-Operation aufzuschieben. Jedoch mussen bei einigen Parametern wie den praoperativen Bildgebungsverfahren, der Positionierung auf dem Operationstisch, der Uberwachung, Anasthesie und der perioperativen Medikation bestimmte Anpassungen vorgenommen werden, um der speziellen Situation Rechnung zu tragen. PMID- 27240064 TI - Surgical treatment of melanoma in pregnancy: a practical guideline. AB - A tumor primarily requiring surgical treatment, newly diagnosed or preexisting melanoma during pregnancy is a clinical rarity. In such cases, the surgeon faces the challenge of having to decide on the appropriate therapeutic course of action. Based on our clinical experience and a review of the literature, we herein provide a guideline on how to practically deal with this rare clinical conundrum. In our experience, pregnant melanoma patients require thorough counseling with respect to their therapeutic options. They naturally tend to put their unborn child first, and are hesitant to consent to necessary surgery despite a potentially life-threatening diagnosis. It is therefore crucial to clearly inform these patients that - based on existing medical experience - pregnancy by itself is no reason to hold off on any type of necessary melanoma surgery. However, various parameters such as preoperative imaging procedures, positioning on the operating table, monitoring, anesthesia, and perioperative medication require certain adjustments in order to comply with this special situation. PMID- 27240065 TI - Retrospektive Analyse von56 Weichteildefekten nach einzeitiger Rekonstruktion unter Verwendung von Dermisersatzpraparaten. AB - HINTERGRUND: Der Verschluss von Wunden mit ausgepragtem Weichteilschaden stellt eine chirurgische Herausforderung dar und erfordert haufig umfangreiche plastische Operationen sowie freie Lappenplastiken. Die Kombination von Dermisersatzpraparaten und Spalthauttransplantationen ist eine innovative Methode die zur Versorgung von komplexen Verletzungen der Extremitaten angewandt werden kann. Wir haben diese Technik in das Standard-Handwerkszeug bei komplexen Verletzungen der Extremitaten aufgenommen. Die klinischen Ergebnisse von 56 behandelten Patienten werden vorgestellt. PATIENTEN UND METHODEN: In 44 Fallen (78,6 %) wurde die beschriebene Methode an Defekten der unteren Extremitaten verwendet, einschliebetalich sieben Personen (12,5 %), die sich einer Stumpfdeckung nach Amputation unterzogen. Zwolf Defekte (21,4 %) befanden sich an den oberen Extremitaten. In zwei Fallen (3,6 %) wurde die Matriderm((r)) -Matrix verwendet, um Nerven von unmittelbar angrenzenden chirurgischen Implantaten zu schutzen. ERGEBNISSE: Bei 41 Patienten (73,2 %) kam es zur Einheilung des Transplantats ohne Komplikationen. Funfzehn Patienten (26,8 %) zeigten eine gestorte Wundheilung nach Defektverschluss, die unter konservativer Therapie zur Ausheilung gebracht werden konnte. Ein Patient (1,8 %) zeigte ein Transplantatversagen, was eine Revisionsoperation erforderlich machte. Umfangreiche plastische Rekonstruktionen mussten bei keinem Patienten angewandt werden. SCHLUSSFOLGERUNGEN: Bei Fallen, in denen ausgedehnte plastische Operationen nicht moglich oder nicht erwunscht sind, ist die Verwendung von Dermisersatzpraparaten in Kombination mit Spalthauttransplantationen eine vielversprechende Alternative zum Wundverschluss bei ausgedehnten Weichteilschaden. PMID- 27240066 TI - Retrospective analysis of 56 soft tissue defects treated with one-stage reconstruction using dermal skin substitutes. AB - BACKGROUND: The closure of wounds associated with soft tissue defects is surgically challenging, frequently requiring extensive plastic surgery and free flaps. The combination of dermal skin substitutes and split-thickness skin grafting is an innovative method used to cover such wounds. We incorporated this technique into the standard therapeutic armamentarium for complex injuries to the extremities. Clinical results of 56 patients thus treated are presented. PATIENTS AND METHODS: In 44 (78.6 %) cases, the method described was used for defects on the lower extremities, including seven (12.5 %) individuals undergoing amputation stump coverage. Twelve (21.4 %) defects were located on the upper extremities. In two (3.6 %) cases, Matriderm((r)) matrix was used to protect nerves from adjacent surgical implants. RESULTS: In 41 (73.2 %) patients, the graft healed without any complication. Fifteen (26.8 %) patients displayed impaired wound healing following defect closure and were subsequently managed conservatively. One patient (1.8 %) showed graft failure, leading to revision surgery. None of the patients required extensive plastic surgery. CONCLUSIONS: In cases where plastic surgery is unavailable or undesirable, the use of dermal skin substitutes in combination with split-thickness skin grafting represents a promising alternative for covering wounds associated with soft tissue defects. PMID- 27240067 TI - Plattenepithelkarzinom in Verbindung mit einer roten Tatowierung. AB - HINTERGRUND UND ZIELE: Obwohl Tatowierungen in den letzten Jahren aubetaerordentlich beliebt geworden sind, wurde in der Literatur bisher nur uber wenige Falle schwerer Reaktionen berichtet, die zu einer malignen Transformation fuhrten. Dies steht im Kontrast zu der praktisch unuberschaubaren Zahl an Tatowierungen weltweit. Die Zusammensetzung der fur Tatowierungen verwendeten Farbstoffe variiert stark, und selbst gleiche Farbtone konnen unterschiedliche Komponenten enthalten. Das Ziel unserer Studie war es zu untersuchen, auf welche Weise Tatowierungen moglicherweise Hautkrebs auslosen konnen. PATIENTEN UND METHODEN: Wir berichten uber den seltenen Fall einer 24-jahrigen Frau, bei der sich sieben Monate nachdem sie eine Tatowierung auf dem Fubetarucken erhalten hatte in unmittelbarer Nahe des verwendeten roten Farbstoffs ein Plattenepithelkarzinom entwickelte. Die Komplikationen begannen mit einer unspezifischen Schwellung. Die Lasion wurde histologisch untersucht. Die Zusammensetzung des inkorporierten Farbstoffs wurde mittels Rasterelektronenmikroskopie in Kombination mit energiedispersiver Elementanalyse analysiert. Zur weiteren Charakterisierung wurden Thermogravimetrie und Pulverdiffraktometrie eingesetzt. ERGEBNISSE UND SCHLUSSFOLGERUNGEN: Der Tatowierungsfarbstoff enthielt hauptsachlich Bariumsulfat; Spuren von Al, S, Ti, P, Mg und Cl liebetaen sich ebenfalls nachweisen. Bei der Analyse zeigten sich Pigmentgranula unterschiedlicher Grobetae. In seltenen Fallen kann Tatowierungstinte karzinogene Effekte haben, die multifaktoriell zu sein scheinen. PMID- 27240069 TI - Genital candidiasis presenting as pseudomembrane of the urethral meatus. PMID- 27240068 TI - Squamous cell carcinoma in association with a red tattoo. AB - BACKGROUND AND OBJECTIVES: Although tattoos have become exceedingly popular in recent years, only few cases of severe reactions leading to malignant transformation have been reported in the literature. This stands in contrast to the virtually innumerable number of tattoos worldwide. The composition of tattoo dyes is highly variable, and even the same colors may contain different compounds. The objective of our study was to investigate in what way tattoo dyes may potentially trigger skin cancer. PATIENT AND METHODS: We report the rare case of a 24-year-old woman who - seven months after getting a tattoo on the back of her foot - developed a squamous cell carcinoma in close proximity to the red dye used. Complications started in the form of nonspecific swelling. The lesion was histologically examined. The composition of the incorporated dye was analyzed using scanning electron microscopy in combination with energy dispersive element analysis. Thermogravimetry and powder diffraction were used for further characterization. RESULTS AND CONCLUSIONS: While the tattoo dye primarily consisted of barium sulfate, traces of Al, S, Ti, P, Mg, and Cl were also detected. The analysis showed pigment granules of varying sizes. In rare cases, tattoo inks may have carcinogenic effects, which appear to be multifactorial. PMID- 27240070 TI - Genitale Candidose in Form einer Pseudomembran der Harnrohrenoffnung. PMID- 27240071 TI - Primary breast carcinoma en cuirasse. PMID- 27240072 TI - Primares Mammakarzinom mit Ausbreitung auf die Brustwand - Carcinoma en Cuirasse. PMID- 27240073 TI - Erfolgreiche Behandlung von perianalen Condylomata acuminata mit Ingenolmebutat. PMID- 27240074 TI - Erfolgreiche Rituximab-Behandlung des bullosen Pemphigoids bei Jugendlichen mit osophagealer Vernarbung aufgrund von "epitope spreading". PMID- 27240075 TI - Successful rituximab treatment of juvenile bullous pemphigoid with esophageal scarring due to epitope spreading. PMID- 27240076 TI - Larva migrans cutanea: Erfolgreiche topische Behandlung mit Ivermectin - eine Kasuistik. PMID- 27240077 TI - Cutaneous larva migrans: successful topical treatment with ivermectin - a case report. PMID- 27240078 TI - Condyloma acuminatum und Bilharziasis cutanea tarda in derselben vulvaren Lasion. PMID- 27240079 TI - Condyloma acuminatum and bilharziosis cutanea tarda coexisting in the same vulvar lesion. PMID- 27240080 TI - Schmerzhafte Knoten. PMID- 27240081 TI - Painful nodules. PMID- 27240082 TI - Erythemato-squamous plantar plaque in a 69-year-old patient. PMID- 27240083 TI - Erythematosquamose Plaque an der Fubetasohle einer 69-jahrigen Patientin. PMID- 27240084 TI - Schonende Exzisionstechnik fur atypische Naevi im Bauchnabel. PMID- 27240085 TI - Surgical removal of atypical umbilical nevi made easy. PMID- 27240087 TI - 111 Top-Lernziele Dermatologie: Lernzielkatalog fur Haut- und Geschlechtskrankheiten der Deutschen Dermatologischen Gesellschaft. PMID- 27240088 TI - Laudatio. PMID- 27240090 TI - Kongresskalender 2016. PMID- 27240092 TI - Sublingual administration improves systemic exposure of tacrolimus in kidney transplant recipients: comparison with oral administration. AB - BACKGROUND: Tacrolimus (TCR) is an immunosuppressive drug used by oral administration. Intravenous (IV) TCR administration is required under conditions of gastrointestinal diseases or abdominal surgery at the onset of paralytic ileus. The infusion formulation needs a large dilution and therefore a careful technical management during continuous infusion by 24 h and may determine anaphylaxis, cardiac arrhythmia, QT prolongation and torsades de pointes. Sublingual (SL) TCR administration was suggested as an alternative route. DESIGN: The aim of this study was to compare in the same kidney transplanted patients the TCR pharmacokinetic profiles by both the routes coupled with the pharmacoeconomic analysis. The study enrolled eight subjects undergoing renal transplantation and treated with TCR and methylprednisolone. TCR was administered by oral route at the scheduled dosage while the 50% of oral dosage was used by SL route, taking into account the absence of liver first pass. RESULTS: Except for AUC, which resulted significantly increased after oral administration, all exposure parameters were not significantly different between the two routes of administration. Analysis of dose-adjusted exposure parameters showed significant increases in AUC and Cmin after SL administration confirming a better bioavailability of the SL route compared with oral route. Cost saving was obtained using the SL rather than the IV route of TCR delivery. CONCLUSION: When oral administration of TCR is not advised, SL delivery represents an attractive option to IV administration. PMID- 27240091 TI - Landscape of tumor-infiltrating T cell repertoire of human cancers. AB - We developed a computational method to infer the complementarity-determining region 3 (CDR3) sequences of tumor-infiltrating T cells in 9,142 RNA-seq samples across 29 cancer types. We identified over 600,000 CDR3 sequences, including 15% that were full length. CDR3 sequence length distribution and amino acid conservation, as well as variable gene usage, for infiltrating T cells in many tumors, except in brain and kidney cancers, resembled those for peripheral blood cells from healthy donors. We observed a strong association between T cell diversity and tumor mutation load, and we predicted SPAG5 and TSSK6 as putative immunogenic cancer/testis antigens in multiple cancers. Finally, we identified three potential immunogenic somatic mutations on the basis of their co-occurrence with CDR3 sequences. One of them, a PRAMEF4 mutation encoding p.Phe300Val, was predicted to result in peptide binding strongly to both MHC class I and class II molecules, with matched HLA types in its carriers. Our analyses have the potential to simultaneously identify immunogenic neoantigens and tumor-reactive T cell clonotypes. PMID- 27240093 TI - Polyaddition of Azide-Containing Norbornene-Based Monomer through Strain-Promoted 1,3-Dipolar Cycloaddition Reaction. AB - The azide-alkyne "click" reaction has been well known in the past decade, however, another kind of 1,3-dipolar cycloaddition, the azide-alkene reaction is not fully explored in polymer science to date. This contribution reports, for the first time, the discovery of a polyaddition of norbornene based monomer (NC11N3 ) containing both strained double bond and azide moieties. The reaction product is characterized by Fourier transform infrared spectroscopy (FTIR), NMR, gel permeation chromatography (GPC), and mass spectrometry (MS), which confirmed the mechanism that is through cycloaddition of azide to strained double bond on norbornene ring to form triazoline linkage. The reaction can proceed at room temperature as indicated by the increase of molecular weight and viscosity during storage. Monomer, dimer, trimer, tetramer, etc., and species with loss of N2 due to lability of triazoline moiety are identified in the mixture of reaction product. As a unique feature, elimination of N2 in the five-membered ring of triazoline affords a chance to form highly reactive materials, such as with aziridine, which can be a very powerful tool in chemical functionalizations, and find promising applications in reactive polymer resin industries. PMID- 27240094 TI - The Microbiome of the Lower Respiratory Tract in Premature Infants with and without Severe Bronchopulmonary Dysplasia. AB - Aim We determined whether the bacteria in the lower respiratory tract (LRT) in extremely premature infants with severe bronchopulmonary dysplasia (BPD) are different from those with nonsevere BPD. Study Design We conducted a retrospective study of extremely premature infants who were admitted to the neonatal intensive care unit of Fukushima Medical University Hospital, Japan between April 2005 and March 2014. We screened for the bacterial colonization of the LRT using tracheobronchial aspirate fluid. Results A total of 169 extremely premature infants were included. Overall, 102 did not experience severe BPD, whereas the remaining 67 experienced severe BPD. Corynebacterium species (Cs) were more frequently detected in the severe BPD than nonsevere BPD infants (p = 0.03). There were significant differences between infants with and without severe BPD in the duration of endotracheal ventilation (p = 0.00, odds ratio [OR], 1.03; 95% confidence interval [CI], 1.01-1.06), the duration of supplemental oxygen (p = 0.00, OR, 1.02; 95% CI, 1.01-1.03) before 36 weeks of postmenstrual age, and the frequency of sepsis after 7 postnatal days (p = 0.01, OR, 1.73; 95% CI, 1.18 2.54). Conclusion Cs are more likely to be present in the severe BPD infants with longer duration of endotracheal ventilation. PMID- 27240095 TI - Preventing Maternal Morbidity from Obstetric Hemorrhage: Implications of a Provider Training Initiative. AB - Objective The objective of this study was to compare severe morbidity due to obstetrical hemorrhage and its potential preventability before and after a mandated provider training initiative on obstetric hemorrhage. Study Design Cases of severe morbidity due to obstetric hemorrhage during 2006 (n = 64 before training initiative) and 2010 (n = 71 after training initiative) were identified by a two-factor scoring system of intensive care unit admission and/or transfusion of >= 3 units of blood products and reviewed by an expert panel. Preventable factors were categorized as provider, system, and/or patient related. Results Potential preventability did not differ between 2006 and 2010, p = 0.19. Provider factors remained the most common preventable factor (88.2% in 2006 vs. 97.4% in 2010, p = 0.18), but the distribution in types of preventable factors improved over time for delay or failure in assessment (20.6 vs. 0%, p < 0.01) and delay or inappropriate treatment (76.5 vs. 39.5%, p < 0.01). System factors also differed (32.4 vs. 7.9%, p = 0.015) with a notable decline in factors related to policies and procedures (26.5 vs. 2.6%, p < 0.01) between 2006 and 2010. Conclusion We found significant improvement in provider assessment and treatment of obstetric hemorrhage and a significant reduction in preventable factors related to policies and procedures after the training initiative. PMID- 27240096 TI - The Association between the Intertwin Interval and Adverse Neonatal Outcomes. AB - Objective Previous data examining the association between the interval between the delivery of the first and second twin (intertwin interval) and adverse neonatal outcomes are conflicting. We sought to evaluate whether intertwin interval is associated with adverse neonatal outcomes for the second twin in a contemporary U. S. cohort. Methods This is a cohort study of women who delivered twins at or after 32 weeks gestation between 2006 and 2014 and whose first twin was delivered vaginally vertex. The intertwin interval was dichotomized as < 10 minutes or >= 10 minutes. Adverse outcomes included arterial cord pH <= 7.1, admission to the neonatal intensive care unit, respiratory distress, intraventricular hemorrhage, and death. Results Of the 171 subjects, 61 (35.7%) had an intertwin interval of >= 10 minutes. There were no differences in maternal characteristics. Intertwin interval of >= 10 minutes was associated with an increased frequency of arterial pH <= 7.1 (22.0 vs. 8.2%, p = 0.03), which persisted after adjusting for confounders (adjusted odds ratio, 2.94; 95% confidence interval, 1.04-8.33). Other adverse outcomes did not differ. Conclusion Intertwin interval of >= 10 minutes was associated with increased frequency of arterial pH <= 7.1 in the second twin, but no other adverse neonatal outcomes. PMID- 27240097 TI - The Influence of Infectious Complications in Gastroschisis on Costs and Length of Stay. AB - Objective Outcomes for gastroschisis (GS) remain highly variable and avoiding infectious complications (ICs) may represent a significant improvement opportunity. Our objective was to provide estimates of the impact of IC on length of stay (LOS) and costs. Study Design Using a national database, 1,378 patients with GS were identified. Patient and hospital characteristics were compared and LOS and costs evaluated for patients with and without IC. Results Two-thirds of all GS patients had IC, and IC were common for simple and complex GS (65, 73%, respectively). After controlling for patient and hospital factors, LOS in patients with IC was significantly longer than in patients without IC (4.5-day increase, p = 0.001). Specifically, sepsis was associated with increasing median LOS by 11 days (p <= 0.001), candida infection by 14 days (p < 0.001), and wound infection by 7 days (p = 0.007). Although overall costs did not differ between patients with and without IC, costs were elevated based on specific IC. Sepsis increased median costs by $22,380 (95% confidence interval [CI]: $14,372-30,388; p <= 0.001), wound infection by $32,351 (95% CI: $17,221-47,481; p <= 0.001), catheter-related infection by $57,180 (95% CI: $12,834-101,527; p = 0.011), and candida infections by $24,500 (95% CI: $8,832-40,167; p = 0.002). Conclusion IC among GS patients are common and contribute to increased LOS and costs. Quantifying clinical and financial ramifications of IC may help direct future quality improvement efforts. PMID- 27240098 TI - Growth of Polar Hexagonal Boron Nitride Monolayer on Nonpolar Copper with Unique Orientation. AB - Suppressing the oppositely orientated hexagonal boron nitride (h-BN) domains during the growth is of great challenge due to its bipolar structure. It is found that h-BN domains grown on onefold symmetric Cu(102) or (103) share a unique orientation, with one zigzag edge of the h-BN triangles perpendicular to the symmetry axis of the substrate surface. PMID- 27240099 TI - Standards of care in cauda equina syndrome. AB - What constitutes cauda equina syndrome (CES), how it should be subclassified and how urgently to image and operate on patients with CES are all matters of debate. A structured review of the literature has led us to evaluate the science and to propose evidence-based guidelines for the management of CES. Our conclusions include this guidance: pain only; MRI negative - recommend: analgesia, ensure imaging complete (not just lumbar spine) adequate follow-up. Bilateral radiculopathy (CESS) with a large central disc prolapse - recommend: discuss with the patient and if for surgery, the next day (unless deteriorates to CESI in which case emergency surgery); CESI - recommend: the true emergency for surgery by day or night; a large central PLID with uncertainty as to whether CESI or CESR (e.g. catheterised prior to CESR) or where there is residual cauda equina nerve root function or early CESR - recommend: treat as an emergency by day or night. Where there has been prolonged CESR and/or no residual sacral nerve root function - recommend: treat on the following day's list. PMID- 27240100 TI - Predicting body appreciation in young women: An integrated model of positive body image. AB - This study examined a range of predictors, based on previous theoretical models, of positive body image in young adult women. Participants were 266 women who completed an online questionnaire measuring body appreciation, activity participation, media consumption, perceived body acceptance by others, self compassion, and autonomy. Potential mechanisms in predicting body appreciation assessed were self-objectification, social appearance comparison, and thin-ideal internalisation. Results indicated that greater perceived body acceptance by others and self-compassion, and lower appearance media consumption, self objectification, social comparison, and thin-ideal internalisation were related to greater body appreciation. An integrated model showed that appearance media (negatively) and non-appearance media and self-compassion (positively) were associated with lower self-objectification, social comparison, and thin-ideal internalisation, which in turn related to greater body appreciation. Additionally, perceived body acceptance by others was directly associated with body appreciation. The results contribute to an understanding of potential pathways of positive body image development, thereby highlighting possible intervention targets. PMID- 27240101 TI - The role of shoe design on the prediction of free torque at the shoe-surface interface using pressure insole technology. AB - The goal of the current study was to expand on previous work to validate the use of pressure insole technology in conjunction with linear regression models to predict the free torque at the shoe-surface interface that is generated while wearing different athletic shoes. Three distinctly different shoe designs were utilised. The stiffness of each shoe was determined with a material's testing machine. Six participants wore each shoe that was fitted with an insole pressure measurement device and performed rotation trials on an embedded force plate. A pressure sensor mask was constructed from those sensors having a high linear correlation with free torque values. Linear regression models were developed to predict free torques from these pressure sensor data. The models were able to accurately predict their own free torque well (RMS error 3.72 +/- 0.74 Nm), but not that of the other shoes (RMS error 10.43 +/- 3.79 Nm). Models performing self prediction were also able to measure differences in shoe stiffness. The results of the current study showed the need for participant-shoe specific linear regression models to insure high prediction accuracy of free torques from pressure sensor data during isolated internal and external rotations of the body with respect to a planted foot. PMID- 27240102 TI - Extreme cognitions are associated with diminished ability to use disconfirming evidence. AB - OBJECTIVES: An Integrative Cognitive Model of mood swings and bipolar disorder proposes that cognitive styles characterized by extreme self-referent appraisals of internal states (e.g., 'If I have a bad night's sleep it means that I am about to have a breakdown') interfere with mood regulation. The aim of this study is to determine whether strong endorsement of such appraisals is predicted by a diminished ability to access disconfirming counterexamples. DESIGN: We examined whether the ability to access two different categories of counterexample (known as Disabling Conditions and Alternative Causes) would predict endorsement of extreme appraisals (measured by the Hypomanic Attitudes and Positive Predictions Inventory; HAPPI) and mania risk (measured by the Hypomanic Personality Scale; HPS). METHOD: A non-clinical sample of 150 students completed the HAPPI, the HPS and a conditional reasoning task that indexed the ability to access Disabling Conditions and Alternative Causes. Current mood was controlled for using the Internal States Scale. RESULTS: The ability to make use of disabling counterexamples during the reasoning task was inversely related with scores on the HAPPI (r = -.19, p < .05); participants that were less able to make use of disabling counterexamples endorsed extreme self-referent appraisals to a greater extent. There was no association between the use of alternative cause counterexamples and the HAPPI, and no association between either measure of counterexample generation and the HPS. CONCLUSIONS: A diminished ability to use disconfirming evidence when reasoning about the world may reinforce problematic cognitive styles such as extreme, personalized appraisals of experience, which can interfere with mood regulation. PRACTITIONER POINTS: Problematic cognitive styles such as extreme, personalized appraisals of experience may be reinforced by the inability to produce or access evidence that disconfirms these maladaptive beliefs. This reasoning bias may be associated with cognitive styles underlying psychopathology. There may be clinical utility in exploring the use of disabler generation in psychological interventions, to help disconfirm maladaptive beliefs. PMID- 27240104 TI - The role of mineral and bone disorders in the development and progression of cardiac and renal pathology in patients with type 1 diabetes mellitus of long duration. AB - AIMS: The objective of our study was to evaluate the role of mineral and bone metabolism disorders associated with chronic kidney disease (MBD-CKD) in the development and progression of cardiac and renal pathology in patients with type 1 diabetes mellitus (T1DM) of long duration. METHODS: We investigated 96 patients with T1DM of long duration, with CKD at different stages (0-5), including patients on hemodialysis (HD) and with kidney transplantation (KT). Along with overall clinical examination, we assessed markers of MBD (calcium, phosphorus, parathormone, vitamin D, fibroblast growth factor (FGF) 23) and levels of cardiac injury marker (atrial natriuretic peptide, NT-proBNP). Multispiral computer tomography with Agatston index calculation was also included. RESULTS: Decreased kidney function was associated with increased of levels phosphorus, parathormone, FGF 23, and vitamin D deficiency, with the highest deviation from the reference ranges seen in patients on HD with a very high risk of cardiovascular events. In KT patients with satisfactory graft function, these parameters were at the same levels as in patients with CKD stages 0-4. Progression of cardiovascular pathology was accompanied by elevation of NT-proBNP levels as CKD duration increased, decreased glomerular filtration rate, and were correlated with the main parameters of mineral homeostasis. The severity of coronary arteries calcification was associated with patient age and duration of T1DM and arterial hypertension. CONCLUSIONS: Development and progression of kidney dysfunction is accompanied by MBD, a significant factor in progression of cardiac pathology, which remains a major cause of mortality in this patient population. PMID- 27240105 TI - A case of sarcoidosis with pleural involvement. AB - Sarcoidosis is a chronic, multisystem inflammatory disorder of unknown etiology that is characterized by noncaseating granulomas. Although lung involvement is common in sarcoidosis, pleural involvement is rare. Pleural involvement may manifest as a pleural effusion, pneumothorax, pleural thickening and nodules, hydropneumothorax, hemothorax, or chylothorax. Here, we describe a case of sarcoidosis with pleural nodular thickening. PMID- 27240103 TI - Os2 -Os4 Switch Controls DNA Knotting and Anticancer Activity. AB - Dinuclear trihydroxido-bridged osmium-arene complexes are inert and biologically inactive, but we show here that linking dihydroxido-bridged Os(II) -arene fragments by a bridging di-imine to form a metallacycle framework results in strong antiproliferative activity towards cancer cells and distinctive knotting of DNA. The shortened spacer length reduces biological activity and stability in solution towards decomposition to biologically inactive dimers. Significant differences in behavior toward plasmid DNA condensation are correlated with biological activity. PMID- 27240106 TI - Choice of primary outcomes evaluating treatment for heavy menstrual bleeding. AB - BACKGROUND: Heavy menstrual bleeding (HMB) is a common problem with a variety of treatment options and many studies have been performed evaluating treatment effects. Consistency in the choice and definition of primary and secondary outcomes is important for the interpretation of data and for the synthesis of data in systematic reviews or individual patient data meta-analysis (IPDMA). OBJECTIVE: To give insight into the primary endpoints and outcome measures chosen in randomised controlled trials (RCTs) and systematic reviews regarding the treatment of HMB. SEARCH STRATEGY: Published systematic reviews and RCTs. SELECTION CRITERIA: Full reports of RCTs or systematic reviews. DATA COLLECTION AND ANALYSIS: For RCTs, we used the primary outcomes, as they were used for the sample size calculation. For systematic reviews, all outcomes listed as primary were included. Four authors selected the studies. RESULTS: Twelve different primary outcomes were reported by 66 RCTs, most blood loss- related (44/66 studies). Amenorrhoea was the most common blood loss primary outcome (16/44 studies) and the Pictorial Blood Loss Assessment Chart (PBAC) was the most used measurement tool (27/44 studies). Satisfaction was the second most prevalent primary outcome measure (13/66 studies). In all, 14/26 (54%) systematic reviews prespecified a single primary outcome, whereas all other reviews used composite primary outcomes. Blood loss was the most studied outcome (12/26 reviews). CONCLUSIONS: The most used primary outcomes in HMB studies relate to blood loss but there is no consistency regarding the endpoints chosen or measurement tools used to describe blood loss. Standardising outcomes will aid valid comparison and interpretation of data pertaining to the treatment of HMB. TWEETABLE ABSTRACT: A standardised collection of outcomes in heavy menstrual bleeding research is urgently needed. PMID- 27240107 TI - Dynamical Disorder in the DNA Hydration Shell. AB - The reorientation and hydrogen-bond dynamics of water molecules within the hydration shell of a B-DNA dodecamer, which are of interest for many of its biochemical functions, are investigated via molecular dynamics simulations and an analytic jump model, which provide valuable new molecular level insights into these dynamics. Different sources of heterogeneity in the hydration shell dynamics are determined. First, a pronounced spatial heterogeneity is found at the DNA interface and explained via the jump model by the diversity in local DNA interfacial topographies and DNA-water H-bond interactions. While most of the hydration shell is moderately retarded with respect to the bulk, some water molecules confined in the narrow minor groove exhibit very slow dynamics. An additional source of heterogeneity is found to be caused by the DNA conformational fluctuations, which modulate the water dynamics. The groove widening aids the approach of, and the jump to, a new water H-bond partner. This temporal heterogeneity is especially strong in the minor groove, where groove width fluctuations occur on the same time scale as the water H-bond rearrangements, leading to a strong dynamical disorder. The usual simplifying assumption that hydration shell dynamics is much faster than DNA dynamics is thus not valid; our results show that biomolecular conformational fluctuations are essential to facilitate the water motions and accelerate the hydration dynamics in confined groove sites. PMID- 27240108 TI - Mechanosensitive subcellular rheostasis drives emergent single-cell mechanical homeostasis. AB - Mechanical homeostasis-a fundamental process by which cells maintain stable states under environmental perturbations-is regulated by two subcellular mechanotransducers: cytoskeleton tension and integrin-mediated focal adhesions (FAs). Here, we show that single-cell mechanical homeostasis is collectively driven by the distinct, graduated dynamics (rheostasis) of subcellular cytoskeleton tension and FAs. Such rheostasis involves a mechanosensitive pattern wherein ground states of cytoskeleton tension and FA determine their distinct reactive paths through either relaxation or reinforcement. Pharmacological perturbations of the cytoskeleton and molecularly modulated integrin catch-slip bonds biased the rheostasis and induced non-homeostasis of FAs, but not of cytoskeleton tension, suggesting a unique sensitivity of FAs in regulating homeostasis. Theoretical modelling revealed myosin-mediated cytoskeleton contractility and catch-slip-bond-like behaviours in FAs and the cytoskeleton as sufficient and necessary mechanisms for quantitatively recapitulating mechanosensitive rheostasis. Our findings highlight the previously underappreciated physical nature of the mechanical homeostasis of cells. PMID- 27240110 TI - Intracranial subdural hematomas with elevated rivaroxaban concentration and subsequently detected spinal subdural hematoma: A case report. AB - A 79-year-old lean man with a height of 157cm and weight of 42kg (body mass index, 17.2kg/m(2)) receiving rivaroxaban developed an intracranial subdural hematoma and was treated conservatively. Because he had a reduced creatinine clearance of 44mL/min, his dosage of rivaroxaban was reduced from 15 to 10mg daily according to official Japanese prescribing information. However, he developed bilateral intracranial subdural hematomas 2weeks later. Plasma rivaroxaban concentration on anti-factor Xa chromogenic assay was elevated at 301ng/mL, suggesting excessive accumulation. He underwent burr hole drainage and resumed anticoagulation with warfarin. Subsequently, he developed a lumbosacral hematoma. He was treated conservatively and discharged without neurological sequelae. The main cause of the increased concentration of rivaroxaban was believed to be his older age and low body weight. The etiology of the spinal hematoma was suspected to be the migration of intracranial hematoma to the spinal subdural space. PMID- 27240109 TI - Soliton-dependent plasmon reflection at bilayer graphene domain walls. AB - Layer-stacking domain walls in bilayer graphene are emerging as a fascinating one dimensional system that features stacking solitons structurally and quantum valley Hall boundary states electronically. The interactions between electrons in the 2D graphene domains and the one-dimensional domain-wall solitons can lead to further new quantum phenomena. Domain-wall solitons of varied local structures exist along different crystallographic orientations, which can exhibit distinct electrical, mechanical and optical properties. Here we report soliton-dependent 2D graphene plasmon reflection at different 1D domain-wall solitons in bilayer graphene using near-field infrared nanoscopy. We observe various domain-wall structures in mechanically exfoliated graphene bilayers, including network forming triangular lattices, individual straight or bent lines, and even closed circles. The near-field infrared contrast of domain-wall solitons arises from plasmon reflection at domain walls, and exhibits markedly different behaviours at the tensile- and shear-type domain-wall solitons. In addition, the plasmon reflection at domain walls exhibits a peculiar dependence on electrostatic gating. Our study demonstrates the unusual and tunable coupling between 2D graphene plasmons and domain-wall solitons. PMID- 27240111 TI - Effects of exercise intensity on clot microstructure and mechanical properties in healthy individuals. AB - BACKGROUND: Exercise is well established to lead to exercise-induced hypercoagulability, as demonstrated by kinetic coagulation markers. It remains unclear as to whether exercise-induces changes lead in clot development and increased polymerisation. Fractal dimension (df) has been shown to act as a marker of clot microstructure and mechanical properties, and may provide a more meaningful method of determining the relationship between exercise-induced hypercoagulability and potential clot development. METHODS: df was measured in 24 healthy individuals prior to, after 5min of submaximal exercise, following maximal exercise, 45min of passive recovery and following 60min of recovery. Results were compared with conventional markers of coagulation, fibrinolysis and SEM images. RESULTS: Significantly increased df was observed following exercise, returning to resting values following 60min of recovery. The relationship between df and mature clot microstructure was confirmed by SEM: higher df was associated with dense clots formed of smaller fibrin fibres immediately following exercise compared to at rest. Conventional markers of coagulation confirmed findings of previous studies. CONCLUSION: This study demonstrates that df is a sensitive technique which quantifies the structure and properties of blood clots following exercise. In healthy individuals, the haemostatic balance between coagulation and fibrinolysis is maintained in equilibrium following exercise. In individuals with underlying vascular damage who participate in exercise, this equilibrium may be displaced and lead to enhanced clot formation and a prothrombotic state. df may therefore have the potential to not only quantify hypercoagulability, but may also be useful in screening these individuals. PMID- 27240112 TI - Maintenance therapy options for ulcerative colitis. AB - INTRODUCTION: Medical therapy is the cornerstone of the management of ulcerative colitis (UC) and the goal of the treatment is the induction and maintenance of remission. AREAS COVERED: Mesalamine is the first line treatment in patients with mild to moderate UC. Despite having different formulations available, clinically significant differences in pharmacokinetics and exposure to these drugs have not been observed. Evidence supporting the efficacy of azathioprine and mercaptopurine for maintaining remission is UC patients come from both observational cohorts and clinical trials. The main limitation of the treatment with thiopurines is the onset of adverse events that occur in over one-third of patients. Infliximab, adalimumab and golimumab are anti-TNF drugs, which are generally used for more severe or refractory cases. Finally, vedolizumab, a drug directed against the integrins alpha4beta7 has been shown to be effective for the induction and maintenance of remission in moderate-to-severe UC patients. EXPERT OPINION: Several new drugs have enriched the therapeutic armamentarium of UC. Whether the administration of biologics earlier on in the course of the disease would have an impact on the natural history of the disease, avoiding the need for colectomy, remains unknown. PMID- 27240113 TI - Clinical factors and incidence of prolonged fever in neurosurgical patients. AB - AIMS AND OBJECTIVES: To describe the incidence of prolonged fever in patients admitted to the neurosurgery department, and the corresponding risk indicators. BACKGROUND: Prolonged fever was defined as a temperature higher than 38.3 degrees C lasting more than five days. Prolonged fever is a common phenomenon and could lead to worsened outcomes in specific patient groups, especially for those with brain injury. However, the studies on prolonged fever in neurosurgical patients are limited and insufficient. DESIGN: A retrospective observational study. METHODS: Retrospective data were collected from 1 January 2014 to 31 December 2014, at the neurosurgical department of a large teaching hospital. We performed univariate and multivariate analyses to identify independent indicators for prolonged fever vs. short-term fever. RESULTS: Among 2845 patients, prolonged fever occurred in 466 (16%). The older patients were associated with longer duration of mechanical ventilation and hospital stay. It predominantly occurred in patients with subarachnoid haemorrhage (SAH) and traumatic brain injury. Patients receiving antibiotic treatment tended to manifest prolonged fever more frequently. Multivariate analysis revealed that the use of antibiotics, central venous catheter and prolonged mechanical ventilation were independent risk predictors for prolonged fever. Patients diagnosed with brain tumour seemed to be not associated with prolonged fever. CONCLUSIONS: Prolonged fever is the common complication in neurosurgical patients. The risks of prolonged fever in patients are attributed to antibiotic therapy, use of central venous catheter and prolonged mechanical ventilation. Indicators of prolonged fever are helpful for better identification of high-risk patients and fever control. RELEVANCE TO CLINICAL PRACTICE: A better reveal on the epidemiology and predictable factors of prolonged fever in neurosurgical patients will provide a better understanding on those patients who are most at risk, and therefore contribute to fever control and better outcome. PMID- 27240114 TI - Observation of Spontaneous C=C Bond Breaking in the Reaction between Atomic Boron and Ethylene in Solid Neon. AB - A ground-state boron atom inserts into the C=C bond of ethylene to spontaneously form the allene-like compound H2 CBCH2 on annealing in solid neon. This compound can further isomerize to the propyne-like HCBCH3 isomer under UV light excitation. The observation of this unique spontaneous C=C bond insertion reaction is consistent with theoretical predictions that the reaction is thermodynamically exothermic and kinetically facile. This work demonstrates that the stronger C=C bond, rather than the less inert C-H bond, can be broken to form organoboron species from the reaction of a boron atom with ethylene even at cryogenic temperatures. PMID- 27240115 TI - Dynamic lipid landscape of picornavirus replication organelles. AB - Picornavirus infection induces rapid reorganization of the cellular membrane architecture and appearance of novel membranous structures associated with the viral RNA replication and virion assembly-replication organelles. Recent studies significantly advanced our understanding of their lipid composition and cellular mechanisms involved in their development. Picornaviruses activate synthesis of both structural and signaling lipids and reroute cellular cholesterol trafficking pathways to create unique membranous domains favoring viral replication. Rapidly replicating picornaviruses rely on posttranslational activation and/or specific recruitment of cellular proteins rather than on modulation of expression of cellular genes to create favorable membrane microenvironment. At the same time picornaviruses demonstrate remarkable adaptability to changes in the lipid landscape which should be taken into account when developing novel antiviral strategies. PMID- 27240116 TI - Electrochemical C-H/N-H Functionalization for the Synthesis of Highly Functionalized (Aza)indoles. AB - Indoles and azaindoles are among the most important heterocycles because of their prevalence in nature and their broad utility in pharmaceutical industry. Reported herein is an unprecedented noble-metal- and oxidant-free electrochemical method for the coupling of (hetero)arylamines with tethered alkynes to synthesize highly functionalized indoles, as well as the more challenging azaindoles. PMID- 27240117 TI - The role of unregulated care providers in managing heart failure patients in long term care facilities. AB - AIMS AND OBJECTIVES: Heart failure is a complex syndrome in which abnormal heart function results in clinical symptoms and signs of low cardiac output and/or pulmonary or systemic congestion. Heart failure is common among long-term care residents, and is associated with significant morbidity and acute care utilisation. Heart failure guidelines endorse standard therapies, yet long-term care residents are less likely to receive recommended treatments. The objective of this study is to understand the perceptions and potential role of unregulated care providers in contributing to better heart failure management among long-term care residents. DESIGN: Focus group interviews. METHODS: This qualitative study employed focus groups to explore perceptions from 24 unregulated care providers in three Ontario, Canada long-term care homes, about barriers to the optimal management of heart failure. RESULTS: Three overarching concepts emerged characterising unregulated care providers' experiences in caring for residents with heart failure in long-term care: (1) the complexity of providing heart failure care in a long-term care setting, (2) striving for resident-centred decision making and (3) unregulated care providers role enactment nested within an interprofessional team in long-term care. These concepts reflect the complex interplay between individual unregulated care providers and residents, and heart failure-related, socio-cultural and organisational factors that influence heart failure care processes in the long-term care system. CONCLUSIONS: Optimising the management of heart failure in long-term care is contingent on greater engagement of unregulated care providers as active partners in the interprofessional care team. Interventions to improve heart failure management in long-term care must ensure that appropriate education is provided to all long-term care staff, including unregulated care providers, and in a manner that fosters greater and more effective interprofessional collaboration. RELEVANCE TO CLINICAL PRACTICE: Active and collaborative engagement unregulated care providers has the potential to improve the management of heart failure in long-term care residents. PMID- 27240119 TI - Influence of surgical bleeding on the relationship between admission coagulopathy and risk of massive transfusion: lesson from 704 severe trauma patients. AB - BACKGROUND: This study hypothesized that the relationship between early coagulopathy and massive transfusion (MT) in trauma was highly dependent on the presence of surgical bleeding. METHODS: Consecutive severe trauma patients admitted to our institution over a 4-year period were included in this retrospective study. Surgical bleeding was defined as an injury requiring an invasive endovascular or surgical haemostatic procedure. The ability of prothrombin time ratio (PTr) and activated partial thromboplastin time ratio (aPTTr) to predict MT (>=10 units of packed red blood cells during the first 24 h) was determined by ROC curves. The strength of association and interaction between PTr, surgical bleeding and MT was assessed using a logistic regression analysis. RESULTS: Among the 704 patients included (ISS 21.0 +/- 16.2), MT rate was higher in patients with surgical bleeding than in those with no surgical bleeding (47% vs. 5%; P < 0.001). The global performance of PTr and aPTTr to predict MT was only fair in our study population (AUCs 0.83 and 0.81). MT rate was widely higher in the surgical bleeding group whatever the severity of coagulopathy (P < 0.001). PTr was found to be significantly associated with TM [PTr >= 1.5, OR 23.6 (95% CI 13.4-41.7); PTr 1.2-1.5, OR 3.0 (95% CI 1.7-5.3)]. Corresponding ORs were reduced after adjusting for the surgical bleeding: 12.1 (95% CI 6.5-22.5) and 2.1 (95% CI 1.2-4.0), respectively. However, no significant interaction was found regression models. CONCLUSION: The strength of association between MT and coagulation status on admission was found strongly influenced by surgical bleeding. The admission coagulopathy monitoring in trauma patients without considering the surgical bleeding does not allow a reliable determination of MT probability. PMID- 27240118 TI - Contributions to magnetic susceptibility of brain tissue. AB - This review discusses the major contributors to the subtle magnetic properties of brain tissue and how they affect MRI contrast. With the increased availability of high-field scanners, the use of magnetic susceptibility contrast for the study of human brain anatomy and function has increased dramatically. This has not only led to novel applications, but has also improved our understanding of the complex relationship between MRI contrast and magnetic susceptibility. Chief contributors to the magnetic susceptibility of brain tissue have been found to include myelin as well as iron. In the brain, iron exists in various forms with diverse biological roles, many of which are now only starting to be uncovered. An interesting aspect of magnetic susceptibility contrast is its sensitivity to the microscopic distribution of iron and myelin, which provides opportunities to extract information at spatial scales well below MRI resolution. For example, in white matter, the myelin sheath that surrounds the axons can provide tissue contrast that is dependent on the axonal orientation and reflects the relative size of intra- and extra-axonal water compartments. The extraction of such ultrastructural information, together with quantitative information about iron and myelin concentrations, is an active area of research geared towards the characterization of brain structure and function, and their alteration in disease. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27240120 TI - The Anticipated Clinical and Economic Effects of 90-90-90 in South Africa. AB - BACKGROUND: The Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 global treatment target aims to achieve 73% virologic suppression among HIV infected persons worldwide by 2020. OBJECTIVE: To estimate the clinical and economic value of reaching this ambitious goal in South Africa, by using a microsimulation model of HIV detection, disease, and treatment. DESIGN: Modeling of the "current pace" strategy, which simulates existing scale-up efforts and gradual increases in overall virologic suppression from 24% to 36% in 5 years, and the UNAIDS target strategy, which simulates 73% virologic suppression in 5 years. DATA SOURCES: Published estimates and South African survey data on HIV transmission rates (0.16 to 9.03 per 100 person-years), HIV-specific age stratified fertility rates (1.0 to 9.1 per 100 person-years), and costs of care ($11 to $31 per month for antiretroviral therapy and $20 to $157 per month for routine care). TARGET POPULATION: South African HIV-infected population, including incident infections over the next 10 years. PERSPECTIVE: Modified societal perspective, excluding time and productivity costs. TIME HORIZON: 5 and 10 years. INTERVENTION: Aggressive HIV case detection, efficient linkage to care, rapid treatment scale-up, and adherence and retention interventions toward the UNAIDS target strategy. OUTCOME MEASURES: HIV transmissions, deaths, years of life saved, maternal orphans, costs (2014 U.S. dollars), and cost-effectiveness. RESULTS OF BASE-CASE ANALYSIS: Compared with the current pace strategy, over 5 years the UNAIDS target strategy would avert 873 000 HIV transmissions, 1 174 000 deaths, and 726 000 maternal orphans while saving 3 002 000 life-years; over 10 years, it would avert 2 051 000 HIV transmissions, 2 478 000 deaths, and 1 689 000 maternal orphans while saving 13 340 000 life-years. The additional budget required for the UNAIDS target strategy would be $7.965 billion over 5 years and $15.979 billion over 10 years, yielding an incremental cost-effectiveness ratio of $2720 and $1260 per year of life saved, respectively. RESULTS OF SENSITIVITY ANALYSIS: Outcomes generally varied less than 20% from base-case outcomes when key input parameters were varied within plausible ranges. LIMITATION: Several pathways may lead to 73% overall virologic suppression; these were examined in sensitivity analyses. CONCLUSION: Reaching the 90-90-90 HIV suppression target would be costly but very effective and cost-effective in South Africa. Global health policymakers should mobilize the political and economic support to realize this target. PRIMARY FUNDING SOURCE: National Institutes of Health and the Steve and Deborah Gorlin MGH Research Scholars Award. PMID- 27240121 TI - Postoperative Strokes and Intracranial Bleeds in Patients With Atrial Fibrillation: The FibStroke Study. AB - BACKGROUND: Patients with atrial fibrillation (AF) frequently undergo invasive procedures. Optimal perioperative use of oral anticoagulation (OAC) and heparin bridging is not well defined. HYPOTHESIS: Discontinuation of OAC for minor procedures/operations places AF patients at risk for thromboembolism. METHODS: In this study, we assessed perioperative antithrombotic treatment in patients with AF who suffered a postoperative stroke or intracranial bleeding. The FibStroke Study includes AF patients with an ischemic stroke or intracranial bleed identified from the discharge registries of 4 Finnish hospitals. In total, 3632 consecutive patients developed 3252 ischemic strokes and 794 intracranial bleeds. All invasive procedures during the 30 days preceding the stroke or intracranial bleed were identified. RESULTS: A total of 194/3252 (6.0%) ischemic strokes and 23/794 (2.9%) intracranial bleeds were preceded by a procedure. Altogether, 69% of the patients were on OAC prior to index procedure, OAC was interrupted in 81.2% of the procedures preceding a stroke, and heparin bridging was used in 27.8% of interruptions. Of the procedures leading to stroke, 42.3% were low bleeding-risk procedures, and OAC was interrupted in 84.7% of these procedures. The median time from procedure to stroke was 4 days. Heparin bridging was used in 54.5% of OAC interruptions preceding intracranial bleeding and combination of anticoagulation with antiplatelet therapy by 43.5% of patients with postoperative intracranial bleeding. CONCLUSIONS: Perioperative interruption of OAC is common in patients who suffer a postoperative stroke, even in patients with low-bleeding risk procedures. Postoperative intracranial bleeding is frequently preceded by perioperative heparin bridging. PMID- 27240122 TI - Patterned and Specific Attachment of Bacteria on Biohybrid Bacteria-Driven Microswimmers. AB - A surface patterning technique and a specific and strong biotin-streptavidin bonding of bacteria on patterned surfaces are proposed to fabricate Janus particles that are propelled by the attached bacteria. Bacteria-driven Janus microswimmers with diameters larger than 3 MUm show enhanced mean propulsion speed. Such microswimmers could be used for future applications such as targeted drug delivery and environmental remediation. PMID- 27240123 TI - Mapping the nomological network of employee self-determined safety motivation: A preliminary measure in China. AB - The present study introduced a preliminary measure of employee safety motivation based on the definition of self-determination theory from Fleming (2012) research and validated the structure of self-determined safety motivation (SDSM) by surveying 375 employees in a Chinese high-risk organization. First, confirmatory factor analysis (CFA) was used to examine the factor structure of SDSM, and indices of five-factor model CFA met the requirements. Second, a nomological network was examined to provide evidence of the construct validity of SDSM. Beyond construct validity, the analysis also produced some interesting results concerning the relationship between leadership antecedents and safety motivation, and between safety motivation and safety behavior. Autonomous motivation was positively related to transformational leadership, negatively related to abusive supervision, and positively related to safety behavior. Controlled motivation with the exception of introjected regulation was negatively related to transformational leadership, positively related to abusive supervision, and negatively related to safety behavior. The unique role of introjected regulation and future research based on self-determination theory were discussed. PMID- 27240125 TI - Effect evaluation of a road safety education program based on victim testimonials in high schools in Belgium. AB - For several decades policy makers worldwide have experimented with testimonials as a strategy to promote road safety supportive views in a wide variety of target populations such as recidivists and students. In its basic format, a (relative of) a victim or an offender brings a personal testimonial of what it is to experience a traffic accident. The underlying idea is that such a testimonial will emotionally affect participants, thereby stimulating them to cognitively reflect upon their own behavior and responsibility as a road user. Unfortunately, empirical literature on the effectiveness of this strategy is rather scarce and inconsistent. This study investigated the effect of a large-scale program with victim testimonials for high schools in Belgium on five socio-cognitive and behavioral variables drawn from the Theory of Planned Behavior (i.e., attitude, subjective norm, perceived behavioral control, behavioral intention and behavior). Moreover, this study investigated program effects on participants' cognitive and emotional estate and whether this influences the program's impact on socio-cognitive and behavioral variables. Our test sample included 1362 students, who were assigned to a baseline - follow-up group and a post-test - follow-up group. We questioned both groups, a first time (just before or after session attendance) on paper, and a second time (two months after session attendance) online. Results indicate the program had, both immediate and two months after attendance, small to medium positive effects on most socio-cognitive and behavioral variables. However, effects depended on participants' demographic profile, their baseline values on the socio-cognitive and behavioral variables, and the degree to which they were cognitively/emotionally affected by the program. We discuss the practical implications of these findings and formulate recommendations for the development of future interventions based on victim testimonials. PMID- 27240124 TI - Understanding the relationship between safety investment and safety performance of construction projects through agent-based modeling. AB - The construction industry in Hong Kong increased its safety investment by 300% in the past two decades; however, its accident rate has plateaued to around 50% for one decade. Against this backdrop, researchers have found inconclusive results on the causal relationship between safety investment and safety performance. Using agent-based modeling, this study takes an unconventional bottom-up approach to study safety performance on a construction site as an outcome of a complex system defined by interactions among a worksite, individual construction workers, and different safety investments. Instead of focusing on finding the absolute relationship between safety investment and safety performance, this study contributes to providing a practical framework to investigate how different safety investments interacting with different parameters such as human and environmental factors could affect safety performance. As a result, we could identify cost-effective safety investments under different construction scenarios for delivering optimal safety performance. PMID- 27240126 TI - Heterogeneous impacts of gender-interpreted contributing factors on driver injury severities in single-vehicle rollover crashes. AB - In this study, a mixed logit model is developed to identify the heterogeneous impacts of gender-interpreted contributing factors on driver injury severities in single-vehicle rollover crashes. The random parameter of the variables in the mixed logit model, the heterogeneous mean, is elaborated by driver gender-based linear regression models. The model is estimated using crash data in New Mexico from 2010 to 2012. The percentage changes of factors' predicted probabilities are calculated in order to better understand the model specifications. Female drivers are found more likely to experience severe or fatal injuries in rollover crashes than male drivers. However, the probability of male drivers being severely injured is higher than female drivers when the road surface is unpaved. Two other factors with fixed parameters are also found to significantly increase driver injury severities, including Wet and Alcohol Influenced. This study provides a better understanding of contributing factors influencing driver injury severities in rollover crashes as well as their heterogeneous impacts in terms of driver gender. Those results are also helpful to develop appropriate countermeasures and policies to reduce driver injury severities in single-vehicle rollover crashes. PMID- 27240127 TI - Analysis of driver injury severity in single-vehicle crashes on rural and urban roadways. AB - This study analyzes driver injury severities for single-vehicle crashes occurring in rural and urban areas using data collected in New Mexico from 2010 to 2011. Nested logit models and mixed logit models are developed in order to account for the correlation between severity categories (No injury, Possible injury, Visible injury, Incapacitating injury and fatality) and individual heterogeneity among drivers. Various factors, such as crash and environment characteristics, geometric features, and driver behavior are examined in this study. Nested logit model and mixed logit model reveal similar results in terms of identifying contributing factors for driver injury severities. In the analysis of urban crashes, only the nested logit model is presented since no random parameter is found in the mixed logit model. The results indicate that significant differences exist between factors contributing to driver injury severity in single-vehicle crashes in rural and urban areas. There are 5 variables found only significant in the rural model and six significant variables identified only in the urban crash model. These findings can help transportation agencies develop effective policies or appropriate strategies to reduce injury severity resulting from single-vehicle crashes. PMID- 27240128 TI - Injury severity of pedestrians, bicyclists and motorcyclists resulting from crashes with reversing cars. AB - OBJECTIVE: Pedestrians, bicyclists and motorcyclists can suffer serious injury in road traffic crashes. To date, no studies examine the injury severity within this vulnerable cohort following collisions with reversing cars. MATERIAL AND METHODS: Our institution prospectively maintains a database including medical and technical information regarding traffic accidents in our area, including urban and suburban regions. In a retrospective review of this database, the authors describe the injury severity of pedestrians, bicyclists and motorcyclists following traffic crashes involving reversing cars. Injury severity was described using the abbreviated injury scale (AIS) as well as the maximum abbreviated injury scale (MAIS). RESULTS: This study included 234 crashes occurring between 1999 and 2012. The lower extremity was injured most often while also suffering more severe injuries with a median AIS of 1 compared to 0 in all other documented body regions. The upper extremity was injured second most often. AIS ranging from 4 to 6 were infrequent. AIS 3 however, was documented for the legs in 4.3% of patients. MAIS 0, 1, 2, 3, 5 and 9 were found in 1, 164, 46, 14, 1, and 8 patients in the study cohort, respectively. Pedestrians and motorcyclists were seriously injured in 9.1% and 9.6% of cases, respectively. In contrast, no bicyclists suffered serious injuries. As to the zone of impact, most collisions occurred at the rear center of the vehicle (35%) followed by rear left (26%), rear right (20%), side rear (11%), side center (4%) and side front (3%). 204 (87.2%) collisions occurred during the day, 19 (8.1%) at night and 11 (4.7%) at twilight. Speed was similar in crashes involving pedestrians, bicyclists and motorcyclists, being as high as 7.0+/-3.6, 7.0+/-4.0 and 7.9+/-4.2km/h respectively. CONCLUSIONS: This is the first study that analyzes injury severity among these vulnerable road users following collisions with reversing vehicles. The majority of collisions occur at low impact speed during the day. Most injuries resulting from these collisions are not serious, however pedestrians are at greatest risk of severe injury to any body region. The lower extremities suffer the most serious and frequent injuries within this cohort. PMID- 27240129 TI - Aging and orthopedics: how a lifespan development model can inform practice and research. AB - Orthopedic surgical care, like all health care today, is in flux owing to an aging population and to chronic medical conditions leading to an increased number of people with illnesses that need to be managed over the lifespan. The result is an ongoing shift from curing acute illnesses to the management and care of chronic illness and conditions. Theoretical models that provide a useful and feasible vision for the future of health care and health care research are needed. This review discusses how the lifespan development model used in some disciplines within the behavioural sciences can be seen as an extension of the biopsychosocial model. We posit that the lifespan development model provides useful perspectives for both orthopedic care and research. We present key concepts and recommendations, and we discuss how the lifespan development model can contribute to new and evolving perspectives on orthopedic outcomes and to new directions for research. We also offer practical guidelines on how to implement the model in orthopedic practice. PMID- 27240130 TI - Accuracy of the modified Hardinge approach in acetabular positioning. AB - BACKGROUND: The surgical approach chosen for total hip arthroplasty (THA) may affect the positioning of the acetabular component. The purpose of this study was to examine the accuracy in orienting the acetabular component using the modified Hardinge approach. METHODS: We used our institutional arthroplasty database to identify patients with primary, press-fit, hemispherical acetabular components of a metal-on-polyethylene THA performed between 2003 and 2011. Patients with radiographs obtained 1-3 years after the index procedure were included for measurement of anteversion and inclination angles. Acceptable values of anteversion and abduction angles were defined as 15 degrees +/- 10 degrees and 40 degrees +/- 10 degrees , respectively. RESULTS: We identified 1241 patients from the database, and the modified Hardinge approach was used in 1010 of the patients included in our analysis. The acetabular component was anteverted in the acceptable zone in 54.1% of patients. The abduction angle was within the defined range in 79.2% of patients. Combined anteversion and abduction angles within the defined zone were present in 43.6% of patients. CONCLUSION: Consistent with studies examining accuracy from other approaches, our study reveals that the modified Hardinge approach was only moderately accurate in positioning the acetabular component in the acceptable zone. PMID- 27240132 TI - Comparative effectiveness and safety of gastric bypass, sleeve gastrectomy and adjustable gastric banding in a population-based bariatric program: prospective cohort study. AB - BACKGROUND: Bariatric surgery in Canada is primarily delivered within publicly funded specialty clinics. Previous studies have demonstrated that bariatric surgery is superior to intensive medical management for reduction of weight and obesity-related comorbidities. Our objective was to compare the effectiveness and safety of laparoscopic Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (LSG) and adjustable gastric banding (LAGB) in a publicly funded, population-based bariatric treatment program. METHODS: We followed consecutive bariatric surgery patients for 2 years. The primary outcome was weight change (in kilograms). Between-group changes were analyzed using multivariable regression. Last observation-carried-forward imputation was used for missing data. RESULTS: We included 150 consecutive patients (51 RYGB; 51 LSG; 48 LAGB) in our study. At baseline, mean age was 43.5 +/- 9.5 years, 87.3% of patients were women, and preoperative body mass index (BMI) was 46.2 +/- 7.4. Absolute and relative (% of baseline) weight loss at 2 years were 36.6 +/- 19.5 kg (26.1 +/- 12.2%) for RYGB, 21.4 +/- 16.0 kg (16.4 +/- 11.6%) for LSG and 7.0 +/- 9.7 kg (5.8 +/- 7.9%) for LAGB (p < 0.001). Change in BMI was greater for the RYGB (-13.0 +/- 6.6) than both the LSG (-7.6 +/- 5.7) and the LAGB (-2.6 +/- 3.5) groups (p < 0.001). The reduction in diabetes, hypertension and dyslipidemia was greater after RYGB than after LAGB (all p < 0.05). There were no deaths. The anastomotic and staple leakage rate was 1.3%. CONCLUSION: In a publicly funded, population-based bariatric surgery program, RYGB and LSG demonstrated greater weight loss than the LAGB procedure. Bypass resulted in the greatest reduction in obesity-related comorbidities. All procedures were safe. PMID- 27240133 TI - Same-day discharge after unilateral parathyroidectomy is safe. AB - BACKGROUND: Minimally invasive parathyroidectomy (MIP) with intraoperative parathyroid hormone monitoring is the most common surgical approach among endocrine surgeons for primary hyperparathyroidism (PHPT). Overnight hospitalization after MIP represents a drain on resources and may be unnecessary. The aim of this study was to determine the safety of same-day discharge after MIP. METHODS: We performed a retrospective cohort study of patients treated for PHPT between August 2010 and July 2015. Patients were stratified by their length of stay in hospital and compared in terms of postoperative complications. RESULTS: During the study period 154 MIPs were performed. Of these, 101 patients were discharged on the day of their surgery (group 1) and the remaining 53 stayed 1 or more days (group 2). Three patients in group 2 required readmission within 30 days of discharge (p = 0.039). Seven patients in group 1 and 1 patient in group 2 visited the emergency department within 30 days of discharge (p = 0.72). Two patients in group 1 experienced persistent or recurrent PHPT (p = 0.55). Patients in group 2 were older than those in group 1 (69 v. 61 yr, p < 0.001) and had a higher mean American Society of Anesthesiologists classification of physical status (2.66 v. 2.24, p < 0.001). CONCLUSION: Same-day discharge after MIP is a safe practice and saves the cost of an overnight stay in hospital. Same day discharge should be considered for all patients undergoing MIP if there are no clear indications for overnight hospitalization. PMID- 27240131 TI - Diverticulitis in immunosuppressed patients: A fatal outcome requiring a new approach? AB - BACKGROUND: Diagnosis and treatment of diverticulitis in immunosuppressed patients are more challenging than in immunocompetent patients, as maintenance immunosuppressive therapies may mask symptoms or impair the patient's ability to counteract the local and systemic infective sequelae of diverticulitis. The purpose of this study was to compare the in-hospital mortality and morbidity due to diverticulitis in immunosuppressed and immunocompetent patients and identify risk factors for lethal outcomes. METHODS: This retrospective study included consecutive in-patients who received treatment for colonic diverticulitis at our institution between April 2008 and April 2014. Patients were divided into immunocompetent and immunosuppressed groups. Primary end points were mortality and morbidity during treatment. Risk factors for death were evaluated. RESULTS: Of the 227 patients included, 15 (6.6%) were on immunosuppressive therapy for solid organ transplantation, autoimmune disease, or cerebral metastasis. Thirteen of them experienced colonic perforation and showed higher morbidity (p = 0.039). Immunosuppressed patients showed longer stays in hospital (27.6 v. 14.5 d, p = 0.016) and in the intensive care unit (9.8 v. 1.1 d, p < 0.001), a higher rate of emergency operations (66% v. 29.2%, p = 0.004), and higher in-hospital mortality (20% v. 4.7%, p = 0.045). Age, perforated diverticulitis with diffuse peritonitis, emergency operation, C-reactive protein > 20 mg/dL, and immunosuppressive therapy were significant predictors of death. Age (hazard ratio [HR] 2.57, p = 0.008) and emergency operation (HR 3.03, p = 0.003) remained significant after multivariate analysis. CONCLUSION: Morbidity and mortality due to sigmoid diverticulitis is significantly higher in immunosuppressed patients. Early diagnosis and treatment considering elective sigmoid resection for patients with former episodes of diverticulitis who are wait-listed for transplant is crucial to prevent death. PMID- 27240134 TI - The optimal time for surgery in women with serous ovarian cancer. AB - BACKGROUND: Advanced high-grade serous ovarian carcinoma (HGSC) is commonly treated with surgery and chemotherapy. We investigated the survival of patients treated with primary or interval surgery at different times following neoadjuvant chemotherapy. Their survival was compared with that of patients treated with primary cytoreductive surgery and adjuvant chemotherapy. METHODS: Patients with stage III or IV HGSC were included in this retrospective cohort study. Clinical data were obtained from patient records. Patients were divided into 2 groups based on treatment with neoadjuvant chemotherapy and interval cytoreductive surgery (NAC) or with primary cytoreductive surgery and adjuvant chemotherapy (PCS). Study groups were stratified by several clinical variables. RESULTS: We included 334 patients in our study: 156 in the NAC and 178 in the PCS groups. Survival of patients in the NAC group was independent of when they underwent interval cytoreductive surgery following initiation of neoadjuvant chemotherapy (p < 0.001). Optimal surgical cytoreduction had no impact on overall survival in the NAC group (p < 0.001). Optimal cytoreduction (p < 0.001) and platinum sensitivity (p < 0.001) were independent predictors of improved survival in the PCS but not in the NAC group. Patients in the NAC group had significantly worse overall survival than those in the PCS group (31.6 v. 61.3 mo, p < 0.001). CONCLUSION: Women with advanced HGSC who underwent PCS had better survival than those who underwent interval NAC, regardless of the number of cycles of neoadjuvant therapy. Optimal cytoreduction did not provide a survival advantage in the NAC group. PMID- 27240135 TI - Comparison of robotic and laparoscopic colorectal resections with respect to 30 day perioperative morbidity. AB - BACKGROUND: Robotic surgery has emerged as a minimally invasive alternative to traditional laparoscopy. Robotic surgery addresses many of the technical and ergonomic limitations of laparoscopic surgery, but the literature regarding clinical outcomes in colorectal surgery is limited. We sought to compare robotic and laparoscopic colorectal resections with respect to 30-day perioperative outcomes. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was used to identify all patients who underwent robotic or laparoscopic colorectal surgery in 2013. We performed a logistic regression analysis to compare intraoperative variables and 30-day outcomes. RESULTS: There were 8392 patients who underwent laparoscopic colorectal surgery and 472 patients who underwent robotic colorectal surgery. The robotic cohort had a lower incidence of unplanned intraoperative conversion (9.5% v. 13.7%, p = 0.008). There were no significant differences between robotic and laparoscopic surgery with respect to other intraoperative and postoperative outcomes, such as operative duration, length of stay, postoperative ileus, anastomotic leak, venous thromboembolism, wound infection, cardiac complications and pulmonary complications. On multivariable analysis, robotic surgery was protective for unplanned conversion, while male sex, malignancy, Crohn disease and diverticular disease were all associated with open conversion. CONCLUSION: Robotic colorectal surgery has comparable 30-day perioperative morbidity to laparoscopic surgery and may decrease the rate of intraoperative conversion in select patients. PMID- 27240136 TI - Isocyperol, isolated from the rhizomes of Cyperus rotundus, inhibits LPS-induced inflammatory responses via suppression of the NF-kappaB and STAT3 pathways and ROS stress in LPS-stimulated RAW 264.7 cells. AB - The rhizomes of Cyperus rotundus (cyperaceae) have been used in Korean traditional medicines for treating diverse inflammatory diseases. However, little is known about the biological activities of isocyperol, a sesquiterpene isolated from C. rotundus, and their associated molecular mechanisms. In this study, we found that isocyperol significantly inhibited lipopolysaccharide (LPS)-induced production of nitrite oxide (NO) and prostaglandin E2 (PGE2) and suppressed LPS induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the mRNA and protein levels in RAW 264.7 macrophages. In addition, isocyperol downregulated the LPS-induced expression of several proinflammatory cytokines, such as interleukin-1beta (IL-1beta), IL-6, and monocyte chemotactic protein-1 (MCP-1). Isocyperol treatment suppressed the LPS-induced nuclear translocation and transcriptional activation of nuclear factor-kappaB (NF-kappaB) in macrophages. Moreover, the activation of STAT3, another proinflammatory signal, was suppressed by isocyperol in LPS-stimulated RAW 264.7 cells. Isocyperol pretreatment also induced heme oxygenase-1 (HO-1) expression and reduced LPS-stimulated reactive oxygen species (ROS) accumulation in macrophages. Furthermore, isocyperol significantly increased the survival rate and attenuated serum levels of NO, PGE2, and IL-6 in LPS-induced septic shock mouse model. Taken together, these data indicate that isocyperol suppress septic shock through negative regulation of pro-inflammatory factors through inhibition of the NF kappaB and STAT3 pathways and ROS. To our knowledge, this is the first report on the biological activity of isocyperol and its molecular mechanism of action. PMID- 27240138 TI - 3D SERS Imaging Using Chemically Synthesized Highly Symmetric Nanoporous Silver Microparticles. AB - 3D surface-enhanced Raman scattering (SERS) imaging with highly symmetric 3D silver microparticles as a SERS substrate was developed. Although the synthesis method is purely chemical and does not involve lithography, the synthesized nanoporous silver microparticles possess a regular hexapod shape and octahedral symmetry. By using p-aminothiophenol (PATP) as a probe molecule, the 3D enhancement patterns of the particles were shown to be very regular and predictable, resembling the particle shape and exhibiting symmetry. An application to the detection of 3D inhomogeneity in a polymer blend, which relies on the predictable enhancement pattern of the substrate, is presented. 3D SERS imaging using the substrate also provides an improvement in spatial resolution along the Z axis, which is a challenge for Raman measurement in polymers, especially layered polymeric systems. PMID- 27240137 TI - Thymoquinone inhibits inflammation, neoangiogenesis and vascular remodeling in asthma mice. AB - Asthma is a chronic obstructive disease which is characterized by recurring airway inflammation, reversible airway obstruction, airway hyper responsiveness and vascular remodeling. Thymoquinone (TQ), an active ingredient isolated from Nigella sativa, was reported to exhibit anti-inflammation and anti-proliferation of in various cancer cells as well as epithelial cells. The aim of this study was to evaluate the effect of TQ on the inflammation, neoangiogenesis and vascular remodeling induced by Ovalbumin (OVA) in asthma mice in vivo and the anti angiogenesis effects of TQ in VEGF-induced human umbilical vein endothelial cells (HUVECs) in vitro. Our results revealed that TQ inhibited the production of inflammatory factors interleukin-4/-5 (IL-4/-5) by enzyme-linked immunesorbent assay (ELISA). Immunohistochemistry analysis showed that the increase of platelet endothelial cell adhesion molecule-1, which is also known as CD31 and alpha smooth muscle actinalpha (alpha-SMA) expression in asthma mice challenged by OVA was suppressed by TQ. Moreover, TQ suppressed the activation of VEGFR2-PI3K-Akt pathway and up-regulated the expression of Slit glycoprotein-2 (Slit-2) both in vivo and in vitro with the inhibition of tube information in HUVEC cells. Meanwhile immunofluorescence analysis showed that Slit-2 and Roundabout-4 (Robo 4) were co-expressing after TQ treatment in OVA-challenged asthma mice. Our study demonstrates that TQ attenuated the inflammatory reaction by antagonizing IL-4/-5 while the anti-neoangiogenesis effect of TQ is mediated by inhibition of vascular endothelial growth factor (VEGF) expression through VEGFR2/PI3K/Akt signaling pathway, which supports a potential role for TQ in ameliorating asthma. PMID- 27240139 TI - Increased Frequency of Th17 Cells in Children With Mycoplasma pneumoniae Pneumonia. AB - BACKGROUND: Mycoplasma pneumoniae (M. pneumoniae, MP) is recognized globally as a significant cause of primary atypical pneumonia in humans, particularly in children. Overzealous host immune responses are viewed as key mediators of the pathogenesis of M. pneumoniae infection. Although Th17 cells have been identified as key modulators in the clearance of pathogens and induction of autoimmunity caused by excessive immune responses, little is known about the role of Th17 cells in patients with M. pneumoniae infection. METHODS: The percentages of T cells, CD4+ T cells and Th17 cells in children with M. pneumoniae infection were measured by flow cytometry. RESULTS: We documented an increased frequency of Th17 cells in children with M. pneumoniae infection. Furthermore, we found a significantly higher percentage of Th17 cells in M. pneumoniae-infected children with extrapulmonary manifestations, compared with children without extrapulmonary manifestations. In addition, patients who experienced a short course of Mycoplasma pneumoniae pneumonia (MPP) showed an increase in the percentage of Th17 cells. CONCLUSION: Our findings suggest that Th17 cells may be involved in the clearance of M. pneumoniae during an acute infection. Excessive Th17 cell responses may also contribute to the immuno-pathological damage observed during persistent infection. PMID- 27240140 TI - Evaluation of a community-based behavioral weight loss program in Chinese adults: A randomized controlled trial. AB - OBJECTIVE: Weight losses between a group of participants assigned to a weight loss program based in the community [i.e., specifically the methodology used by Weight Watchers (WW)] and a Nutrition Education (NE) control group were compared in this study. METHODS: In this 6-month trial, 300 participants with overweight or obesity were recruited from Beijing city, China, and randomly assigned to the WW or NE group. Weight, waist circumference, and biochemical parameters were assessed at baseline and 6 months. RESULTS: At 6 months, the majority of participants (79% for WW; 89% for NE) completed the study. WW participants lost significantly more weight than the NE group (-4.2 +/- 5.6 kg vs. -0.6 +/- 3.6 kg). More WW participants lost 5% or 10% of their starting weight [>=5%: 52.0% of WW participants vs. 11.3% of NE participants (odds ratio 8.15, 95% CI: 4.43 14.97)]; [>=10%: 26.0% of WW vs. 3.3% of NE participants (odds ratio 9.39, 95% CI: 3.55-24.83)]. In addition, WW participants reduced waist circumference by 3.9 +/- 6.3 cm, while the NE group increased waist circumference by 0.6 +/- 5.5 cm. CONCLUSIONS: The WW program was associated with clinically significant weight loss, demonstrating its potential value as an intervention strategy, based in the community, for the treatment of obesity in China. PMID- 27240141 TI - Microbial safety and overall quality of cantaloupe fresh-cut pieces prepared from whole fruit after wet steam treatment. AB - Fresh-cut cantaloupes have been associated with outbreaks of Salmonellosis. Minimally processed fresh-cut fruits have a limited shelf life because of deterioration caused by spoilage microflora and physiological processes. The objectives of this study were to use a wet steam process to 1) reduce indigenous spoilage microflora and inoculated populations of Salmonella, Escherichia coli O157:H7 and Listeria monocytogenes on the surface of cantaloupes, and 2) reduce the populations counts in cantaloupe fresh-cut pieces after rind removal and cutting. The average inocula of Salmonella, E. coli O157:H7 and Listeria monocytogenes was 10(7)CFU/ml and the populations recovered on the cantaloupe rind surfaces after inoculation averaged 4.5, 4.8 and 4.1logCFU/cm(2), respectively. Whole cantaloupes were treated with a wet steam processing unit for 180s, and the treated melons were stored at 5 degrees C for 29days. Bacterial populations in fresh-cut pieces prepared from treated and control samples stored at 5 and 10 degrees C for up to 12days were determined and changes in color (CIE L*, a*, and b*) due to treatments were measured during storage. Presence and growth of aerobic mesophilic bacteria and Salmonella, E. coli O157:H7 and L. monocytogenes were determined in fresh-cut cantaloupe samples. There were no visual signs of physical damage on all treated cantaloupe surfaces immediately after treatments and during storage. All fresh-cut pieces from treated cantaloupes rind surfaces were negative for bacterial pathogens even after an enrichment process. Steam treatment significantly (p<0.05) changed the color of the fresh-cut pieces. Minimal wet steam treatment of cantaloupes rind surfaces designated for fresh-cut preparation will enhance the microbial safety of fresh cut pieces, by reducing total bacterial populations. This process holds the potential to significantly reduce the incidence of foodborne illness associated with fresh-cut fruits. PMID- 27240142 TI - Cobalt deposition in mineralized bone tissue after metal-on-metal hip resurfacing: Quantitative MU-X-ray-fluorescence analysis of implant material incorporation in periprosthetic tissue. AB - Most resurfacing systems are manufactured from cobalt-chromium alloys with metal on-metal (MoM) bearing couples. Because the quantity of particulate metal and corrosion products which can be released into the periprosthetic milieu is greater in MoM bearings than in metal-on-polyethylene (MoP) bearings, it is hypothesized that the quantity and distribution of debris released by the MoM components induce a compositional change in the periprosthetic bone. To determine the validity of this claim, nondestructive u-X-ray fluorescence analysis was carried out on undecalcified histological samples from 13 femoral heads which had undergone surface replacement. These samples were extracted from the patients after gradient time points due to required revision surgery. Samples from nonintervened femoral heads as well as from a MoP resurfaced implant served as controls. Light microscopy and u-X-ray fluorescence analyses revealed that cobalt debris was found not only in the soft tissue around the prosthesis and the bone marrow, but also in the mineralized bone tissue. Mineralized bone exposed to surface replacements showed significant increases in cobalt concentrations in comparison with control specimens without an implant. A maximum cobalt concentration in mineralized hard tissue of up to 380 ppm was detected as early as 2 years after implantation. Values of this magnitude are not found in implants with a MoP surface bearing until a lifetime of more than 20 years. This study demonstrates that hip resurfacing implants with MoM bearings present a potential long-term health risk due to rapid cobalt ion accumulation in periprosthetic hard tissue. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1855-1862, 2017. PMID- 27240143 TI - Experimental and numerical analysis of B1(+) field and SAR with a new transmit array design for 7T breast MRI. AB - Developing a radiofrequency (RF) coil system that produces a uniform B1(+) field (circularly polarized component of the transverse magnetic field responsible for excitation) and low specific absorption rate (SAR) is critical for high performance ultrahigh field human imaging. In this study, we provide the design of a new eight channel radiofrequency (RF) transmit (Tx) array for breast MRI at 7T. A numerical analysis utilizing an in-house finite difference time domain (FDTD) package was carried out in (1) four breast models, (2) homogeneous spherical model and (3) full body model to calculate the B1(+) intensity (MUT) and homogeneity represented by coefficient of variation (CoV=standard deviation/mean) in the proposed RF array design. The numerical results were compared with that measured in breast phantom (Bphantom) and homogeneous spherical phantom at 7T MRI and showed very good agreement. Average and peak SARs were also calculated in the four breast models and the temperature rises due to the operation of the RF array were also measured in the Bphantom. The proposed RF array; which can operate in a single or multi transmit modes, demonstrates homogeneous RF field excitation with acceptable local/average SAR levels for breast MRI at 7T. PMID- 27240144 TI - High-power (1)H composite pulse decoupling provides artifact free exchange mediated saturation transfer (EST) experiments. AB - Exchange-mediated saturation transfer (EST) provides critical information regarding dynamics of molecules. In typical applications EST is studied by either scanning a wide range of (15)N chemical shift offsets where the applied (15)N irradiation field strength is on the order of hundreds of Hertz or, scanning a narrow range of (15)N chemical shift offsets where the applied (15)N irradiation field-strength is on the order of tens of Hertz during the EST period. The (1)H decoupling during the EST delay is critical as incomplete decoupling causes broadening of the EST profile, which could possibly result in inaccuracies of the extracted kinetic parameters and transverse relaxation rates. Currently two different (1)H decoupling schemes have been employed, intermittently applied 180 degrees pulses and composite-pulse-decoupling (CPD), for situations where a wide range, or narrow range of (15)N chemical shift offsets are scanned, respectively. We show that high-power CPD provides artifact free EST experiments, which can be universally implemented regardless of the offset range or irradiation field strengths. PMID- 27240145 TI - Reverse genetics vaccine seeds for influenza: Proof of concept in the source of PB1 as a determinant factor in virus growth and antigen yield. AB - Growth deficits of reverse genetics vaccine seeds have compromised effective immunization. The impairment has been attributed to sub-optimal protein interactions. Some level of dependence may exist between PB1 and antigenic glycoproteins, however, further research is necessary to clarify the extent to which it can be used in favor of seed production. Our objective was to establish proof of concept on the phenotypic outcome of PB1 source in the PR8: A(H1N1)pdm09 reassortants. Reassortants were generated with the gene constellation of the classical 6:2 PR8: HA, NApdm09 seed prototype and the 5:3 reassortant PR8: HA, NA, PB1pdm09. Viral growth and antigen yield were evaluated 12-60h post infection. The 5:3 reassortant presented statistically significant growth and antigen yield improvements when compared to the 6:2. We believe these findings to be of promising value to vaccine research towards an improvement of reverse genetic seeds, an overall more cost-effective vaccine manufacture and timely delivery. PMID- 27240146 TI - ATP1B3: a virus-induced host factor against EV71 replication by up-regulating the production of type-I interferons. AB - Enterovirus 71 (EV71) infection can cause severe diseases, and is becoming increasingly common in children. In the current study, we carried out yeast two hybrid assays to screen human proteins that could interact with 3A protein of EV71. Human beta3 subunit of Na(+)/K(+)-ATPase (ATP1B3) protein was demonstrated to interact with the 3A protein of EV71. Although 3A protein had no effect on the expression of ATP1B3, EV71 infection resulted in elevated expression of ATP1B3 in RD cell line, both on messenger RNA (mRNA) and protein levels. Interestingly, knockdown of ATP1B3 could significantly increase the replication of EV71, whereas overexpression of ATP1B3 significantly suppressed the replication of EV71 in RD cells. Furthermore, we demonstrated that the expression of ATP1B3 could induce the production of type-I interferons. Our study demonstrated that ATP1B3 inhibit EV71 replication by enhancing the production of type-I interferons, which could act as a potential therapeutic target in EV71 infection. PMID- 27240147 TI - HPV16 E6 regulates annexin 1 (ANXA1) protein expression in cervical carcinoma cell lines. AB - Annexin 1 (ANXA1) is a substrate for E6AP mediated ubiquitylation. It has been hypothesized that HPV 16 E6 protein redirects E6AP away from ANXA1, increasing its stability and possibly contributing to viral pathogenesis. We analyzed ANXA1 expression in HPV-positive and negative cervical carcinoma-derived cells, in cells expressing HPV-16 oncogenes and in cells transduced with shRNA targeting E6AP. We observed that ANXA1 protein expression increased in HPV-16-positive tumor cells, in keratinocytes expressing HPV-16 E6wt (wild-type) or E6/E7 and C33 cells expressing HPV-16 E6wt. ANXA1 protein expression decreased in cells transfected with E6 Dicer-substrate RNAs (DsiRNA) and C33 cells cotransduced with HPV-16 E6wt and E6AP shRNA. Moreover, colony number and proliferation rate decreased in HPV16-positive cells transduced with ANXA1 shRNA. We observed that in cells infected with HPV16, the E6 binds to E6AP to degrade p53 and upregulate ANXA1. We suggest that ANXA1 may play a role in HPV-mediated carcinogenesis. PMID- 27240148 TI - Mechanisms of silver nanoparticle-induced toxicity and important role of autophagy. AB - Safety concerns have been raised over the extensive applications of silver nanoparticles (AgNPs) because nano dimensions make them highly bioactive, being potentially harmful to the exposed humans. Surface physico-chemistry (shape, surface charge, chemical composition, etc.) that mainly dictates nano-bio interactions is relevant for influencing their biocompatibility and toxicity. Although the hazardousness of AgNPs has been demonstrated in vitro and in vivo, mechanistic understanding of the toxicity particularly at the molecular and organismal levels, in addition to oxidative stress and silver ion dissolution, has remained unclear. A growing body of research has elucidated that autophagy, being activated in response to exposure to various nanomaterials, may serve as a cellular defense mechanism against nanotoxicity. Recently, autophagy activation was shown to correlate with AgNPs exposure; however, the subsequent autophagosome lysosome fusion was defective. As autophagy plays a crucial role in selective removal of stress-mediated protein aggregates and injured organelles, AgNPs induced autophagic flux defect may consequently lead to aggravated cytotoxic responses. Furthermore, we suggest that p62 accumulation resulting from defective autophagy may also potentially account for AgNPs cytotoxicity. Intriguingly, AgNPs have been shown to interfere with ubiquitin modifications, either via upregulating levels of enzymes participating in ubiquitination, or through impairing the biological reactivity of ubiquitin (due to formation of AgNPs ubiquitin corona). Ubiquitination both confers selectivity to autophagy as well as modulates stabilization, activation, and trafficking of proteins involved in autophagic clearance pathways. In this regard, we offer a new perspective that interference of AgNPs with ubiquitination may account for AgNPs-induced defective autophagy and cytotoxic effects. PMID- 27240149 TI - Stress in the zoo: Tracking the impact of stress on memory formation over time. AB - Although stress is well known to modulate human memory, precisely how memory formation is altered by a stressful encounter remains unclear. Stress effects on cognition are mainly mediated by the rapidly acting sympathetic nervous system, resulting in the release of catecholamines, and the slower acting hypothalamus pituitary-adrenal axis secreting cortisol, which induces its effects on cognition through fast, non-genomic actions and delayed, genomic actions. Importantly, these different waves of the physiological stress response are thought to dynamically alter neural processing in brain regions important for memory such as the amygdala and the hippocampus. However, the precise time course of stress effects on memory formation is still unclear. To track the development of stress effects on memory over time, we tested individuals who underwent a stressful experience or a control procedure before a 2-h walk through a zoo, while an automatic camera continuously photographed the events they encoded. In a recognition memory test one week later, participants were presented with target photographs of their own zoo tour and lure photographs from an alternate tour. Stressed participants showed better memory for the experimental treatment than control participants, and this memory enhancement for the stressful encounter itself was directly linked to the sympathetic stress response. Moreover, stress enhanced memory for events encoded 41-65min after stressor onset, which was associated with the cortisol stress response, most likely arising from non genomic cortisol actions. However, memory for events encoded long after the stressor, when genomic cortisol actions had most likely developed, remained unchanged. Our findings provide novel insights into how stress effects on memory formation develop over time, depending on the activity of major physiological stress response systems. PMID- 27240150 TI - Adult congenital heart disease: A paradigm of epidemiological change. AB - Increasing survival rates for patients with congenital heart disease (CHD) represent a major achievement of modern medicine. Despite incredible progress been made in diagnosis, follow-up, early treatment and management in adulthood, many patients are faced with long-term complications, such as arrhythmia, thromboembolism, heart failure, pulmonary hypertension, endocarditis and/or the need for reoperation. In parallel, half of the patients are female, most of childbearing age, and, thus warrant specialist reproductive counseling and appropriate obstetric care. It is not surprising therefore, that healthcare utilization has steadily increased for CHD in recent years. Furthermore, cardiology and other medical disciplines are now faced with new challenges, namely the provision of expert care and optimal, lifelong medical surveillance for these patients. PMID- 27240151 TI - Effect of cold spells and their modifiers on cardiovascular disease events: Evidence from two prospective studies. AB - OBJECTIVE: To investigate effects of cold weather spells on incidence of cardiovascular disease (CVD), and potential effect modification of socio demographic, clinical, behavioural and environmental exposures. METHODS: Data from two prospective studies were analysed: the British Regional Heart Study (BRHS), a population-based study of British men aged 60-79years, followed for CVD incidence from 1998-2000 to 2012; and the PROSPER study of men and women aged 70 82 recruited to a trial of pravastatin vs placebo from 1997 to 9 (followed until 2009). Cold spells were defined as at least three consecutive days when daily mean temperature fell below the monthly 10th percentile specific to the closest local weather station. A time-stratified case-crossover approach was used to estimate associations between cold spells and CVD events. RESULTS: 921 of 4252 men from BRHS and 760 of 2519 participants from PROSPER suffered a first CVD event during follow-up. More CVD events were registered in winter in both studies. The risk ratio (RR) associated with cold spells was statistically significant in BRHS (RR=1.86, 95% CI 1.30-2.65, p<0.001), and independent of temperature level: results were similar whether events were fatal or non-fatal. Increased risk was particularly marked in BRHS for ever-smokers (RR of 2.44 vs 0.99 for never-smokers), in moderate/heavy drinkers (RR 2.59 vs 1.41), and during winter months (RR 3.28 vs 1.25). No increased risk was found in PROSPER. CONCLUSIONS: Although CVD risks were higher in winter in both BRHS and PROSPER prospective studies, cold spells increased risk of CVD events, independently of cold temperature, in the BRHS only. PMID- 27240152 TI - Stress-related takotsubo cardiomyopathy despite "optimal" medical therapy. PMID- 27240153 TI - Why is post-partum haemorrhage more common in women with congenital heart disease? AB - OBJECTIVE: To identify the factors associated with an increased post-partum blood loss in women with congenital heart disease (CHD). METHODS: The study was a retrospective cohort study, which included 366 nulliparous women with CHD and a singleton pregnancy cared for in a single tertiary centre (Chelsea and Westminster Hospital) between 1994 and 2014. The women were classified into one of 12 different functional groups and univariate and multivariate regression analysis were used to identify factors associated with increased blood loss at delivery. RESULTS: The average volume of blood loss in women with CHD was twice that expected. Univariate analysis showed that White European women had the lowest blood loss. Women who had been on anticoagulants, had a forceps delivery, emergency Caesarean section or general anaesthesia lost more blood than those having a spontaneous vaginal birth under regional analgesia. Higher CARPREG scores were associated strongly with increased blood loss. Women with a Fontan circulation had the highest blood loss and the difference remained significant after correcting for other significant variables. CONCLUSIONS: Women with CHD are at increased risk of PPH. We have identified several potentially modifiable risk factors that may be targeted to reduce this risk. In addition, women with a Fontan circulation were most prone to PPH, independent of other risk factors, suggesting the existence of lesion-specific abnormalities and the need for extra vigilance in this group of women at the time of birth. PMID- 27240154 TI - Temporal trends in all-cause mortality according to smoking status: Insights from the Global Registry of Acute Coronary Events. PMID- 27240155 TI - Subclinical impairment of lung function is related to mild cardiac dysfunction and manifest heart failure in the general population. AB - BACKGROUND: Lung function impairment has previously been related to heart failure, although no overt cardiovascular or structural heart disease is present. The extent to which pulmonary function is related to subclinical left ventricular impairment in the general population remains to be investigated. METHODS: 15010 individuals from the general population (mean age 55+/-11years, 50.5% men) in the Gutenberg Health Study underwent spirometry, transthoracic echocardiography and biomarker measurement. Forced expiratory volume in 1s (FEV1) and forced vital capacity (FVC) in percent of the predicted value and FEV1/FVC ratio were associated with echocardiographic measures of cardiac structure, systolic and diastolic function, biomarkers of cardiac necrosis (high-sensitive troponin I, hsTnI) and stress (N-terminal pro-B-type natriuretic peptide, Nt-proBNP) and heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF). RESULTS: Percent predicted FEV1 and FVC were significantly associated with hsTnI (P<0.001) and Nt-proBNP (P<0.001). Additionally, FEV1/FVC ratio was significantly related to hsTnI (P=0.0043) and Nt-proBNP (P<0.001). In the multivariable adjusted linear regression analyses strongest associations were observed for percent predicted FEV1 and FVC with LVESD, E/e', SV and EF. FEV1/FVC ratio was significantly related with SV and EF. The three lung function parameters were significantly (P<0.001) associated with HFpEF and HFrEF. Associations remained statistically significant after exclusion of individuals with COPD. CONCLUSIONS: FEV1, FVC and FEV1/FVC ratio were associated with systolic and diastolic function and manifest heart failure. Our observations could show, that subclinical lung function impairment is related to a measurable reduction of left ventricular filling and cardiac output in the general population. PMID- 27240156 TI - Relaxin-2 improves diastolic function of pressure-overloaded rats via phospholamban by activating Akt. AB - BACKGROUND: Relaxin is a peptide hormone which has been demonstrated to be safe and has a therapeutic effect on acute heart failure in clinic trials. However, its effect on diastolic function is still unknown. The aims of the study were to determine whether relaxin could improve the diastolic function in pressure overloaded rat model and to analyze potential mechanisms. METHODS AND RESULTS: In the present study, a pressure-overloaded rat model induced by transaortic constriction (TAC) was established. Four weeks after TAC, echocardiography was performed and then all the rat models were randomly divided into 3 groups: models without intramyocardial injection (TAC), with intramyocardial injection of empty adenoviral vector (TAC+GFP) and adenoviral vector overexpression relaxin-2 gene (TAC+RLN2). A sham group was also included. Twelve days after intramyocardial injection, echocardiography and hemodynamics were carried out to evaluate diastolic function in sham, TAC, TAC+GFP and TAC+RLN2 groups. Then hearts were harvested for subsequent examinations. The results indicated that relaxin-2 had ameliorated diastolic function in the pressure-overloaded rats. Compared with the TAC and TAC+GFP groups, the relaxin-2 gene transfer increased phosphorylation of Akt at both the Ser473 and Thr308 sites. Meanwhile, it increased the Ser16 and Thr17- phosphorylation levels of phospholamban (PLB). Furthermore, SERCA2 activity was enhanced in the TAC+RLN2 group more than in the TAC and TAC+GFP groups. CONCLUSIONS: These results demonstrated that relaxin-2 gene therapy improved diastolic function in pressure-overloaded rats. The potential mechanism may be that relaxin-2 gene transfer enhances SERCA2 activity in hearts by increasing phospholamban phosphorylation through nuclear-targeted Akt phosphorylation. PMID- 27240158 TI - Electrocardiographic and blood pressure effects of energy drinks and Panax ginseng in healthy volunteers: A randomized clinical trial. AB - BACKGROUND: Energy drink usage has been linked to emergency room visits and deaths. The objective of the study is to assess the electrocardiographic and blood pressure effects of energy drinks, Panax ginseng and placebo in healthy individuals. METHODS: This was a randomized, double blinded, placebo controlled, crossover study. Young healthy volunteers with no comorbid conditions consumed 32oz of an energy drink, control drink with 800mg of Panax ginseng or matching placebo-control drink over 45min. Primary endpoints were QTc interval and systolic blood pressure. Secondary endpoints included QT interval, PR interval, QRS duration, heart rate, and diastolic blood pressure. All endpoints were assessed at baseline, 1, 2, 3.5, and 5.5h. RESULTS: A significant increase in QTc interval 2h post energy drink consumption was evident when compared to placebo (3.37+/-10.7ms and -3.19+/-11.8ms respectively; p=0.030). Similarly, systolic blood pressure 2h post energy drink consumption increased when compared to placebo (2.00+/-6.37mmHg and -2.67+/-5.83mmHg respectively; p=0.014). The PR interval significantly reduced over a 2h period post energy drink use in a clinically non-meaningful manner. Heart rate at 2h was not significantly higher in the energy drink group when compared to others. The QT interval, QRS interval and diastolic blood pressure were not impacted at any time point. CONCLUSIONS: Certain energy drinks consumed at a high volume significantly increase the QTc interval and systolic blood pressure by over 6ms and 4mmHg respectively. Panax ginseng does not have a significant impact on ECG or blood pressure parameters. PMID- 27240157 TI - Erythropoietin improves cardiac wasting and outcomes in a rat model of liver cancer cachexia. AB - BACKGROUND: Erythropoietin administration, which is clinically used in cancer patients with cancer-induced anemia, has also potentially beneficial effects on nonhematopoietic organs. We assessed the effects of erythropoietin on cancer cachexia progression and cardiac wasting compared with placebo using the Yoshida hepatoma model. METHODS: Wistar rats were divided in a sham group (n=10) and a tumor-bearing group (n=60). The tumor-bearing group was further randomized to placebo (n=28), 500Unit/kg/day (n=16) or 5000Unit/kg/day of erythropoietin (n=16). Body composition was measured using nuclear magnetic resonance spectroscopy, cardiac function using echocardiography, physical activity using infrared monitoring system. RESULTS: Tumor-bearing rats with high dose erythropoietin led to a significant improvement on survival compared with placebo (hazard ratio: 0.43, 95%CI: 0.20-0.92, p=0.030), though low dose erythropoietin did not reach significance (hazard ratio: 0.46, 95%CI: 0.22-1.02, p=0.056). Loss of body weight, wasting of lean mass, fat mass, and reduced physical activity were ameliorated in rats treated with both low and high doses of erythropoietin (p<0.05, all). Moreover, reduced left ventricular mass and left ventricular systolic function were also ameliorated in rats treated with low and high doses of erythropoietin (p<0.05, respectively). CONCLUSIONS: Overall, the present data support that cardiac wasting induced by cancer cachexia plays an important role which leads to impaired survival, provided that the erythropoietin could be an effective therapeutic approach for cancer cachexia progression and cardiac wasting. PMID- 27240159 TI - Non-toxic lead sulfide nanodots as efficient contrast agents for visualizing gastrointestinal tract. AB - Non-invasive imaging of gastrointestinal (GI) tract using novel but efficient contrast agents is of the most important issues in the diagnosis and prognosis of GI diseases. Here, for the first time, we reported the design and synthesis of biothiol-decorated lead sulfide nanodots, as well as their usages in functional dual-modality imaging of GI tract in vivo. Due to the presence of glutathione on the surface of the nanodots, these well-prepared contrast agents could decrease the unwanted ion leakage, withstand the harsh conditions in GI tract, and avoid the systemic absorption after oral administration. Compared with clinical barium meal and iodine-based contrast agents, these nanodots exhibited much more significant enhancement in contrast efficiency during both 2D X-ray imaging and 3D CT imaging. Different from some conventional invasive imaging modalities, such as gastroscope and enteroscope, non-invasive imaging strategy by using glutathione modified PbS nanodots as contrast agents could reduce the painfulness towards patients, facilitate the imaging procedure, and economize the manipulation period. Moreover, long-term toxicity and bio-distribution of these nanodots after oral administration were evaluated in detail, which indicated their overall safety. Based on our present study, these nanodots could act as admirable contrast agents to integrate X-ray imaging and CT imaging for the direct visualization of GI tract. PMID- 27240160 TI - Controllable synthesis of dual-MOFs nanostructures for pH-responsive artemisinin delivery, magnetic resonance and optical dual-model imaging-guided chemo/photothermal combinational cancer therapy. AB - Theranostic nanoagents which integrate diagnostic and therapeutic moieties into a single platform have attracted broad attention in cancer therapy, however the development of more effective and less toxic diagnostic and therapeutic interventions is still of great urgency. Herein, novel core-shell PB@MIL-100(Fe) dual metal-organic-frameworks (d-MOFs) nanoparticles are fabricated and their combined theranostic effects in vitro and in vivo are investigated. The d-MOFs nanoparticles can serve as a T1-T2 dual-modal magnetic resonance imaging (MRI) contrast and fluorescence optical imaging (FOI) agent due to the existence of inner PB MOFs and outer MIL-100(Fe) MOFs. The artemisinin (a traditional Chinese anticancer medicine) with a high loading content of 848.4 mg/g is released from the d-MOFs upon tumor cellular endocytosis due to the pH-responsive degradation of outer MOFs in low pH lysosomes of tumor cells. Furthermore, the inner PB MOFs can be utilized for photothermal therapy due to its strong absorbance in NIR region. Under the guidance by such dual-modal imaging, in vivo photothermal and chemotherapy is finally carried out, achieving effective tumor ablation in an animal tumor model. Furthermore, histological analysis revealed that the drug delivery system had no obvious effect on the major organs of mice due to the low toxicity of both d-MOFs and artemisinin. The distinctive multimodal imaging capability, excellent synergistic therapy effect through the combined chemo photothermal therapy together with the low toxicity of both d-MOFs and artemisinin endow the theranostic nanoagent a promising next generation of nanomedicine for efficient and safe cancer therapy. PMID- 27240161 TI - Enhanced brain-derived neurotrophic factor delivery by ultrasound and microbubbles promotes white matter repair after stroke. AB - Ultrasound-targeted microbubble destruction (UTMD) has been shown to be a promising tool to deliver proteins to select body areas. This study aimed to analyze whether UTMD was able to deliver brain-derived neurotrophic factor (BDNF) to the brain, enhancing functional recovery and white matter repair, in an animal model of subcortical stroke induced by endothelin (ET)-1. UTMD was used to deliver BDNF to the brain 24 h after stroke. This technique was shown to be safe, given there were no cases of hemorrhagic transformation or blood brain barrier (BBB) leakage. UTMD treatment was associated with increased brain BDNF levels at 4 h after administration. Targeted ultrasound delivery of BDNF improved functional recovery associated with fiber tract connectivity restoration, increasing oligodendrocyte markers and remyelination compared to BDNF alone administration in an experimental animal model of white matter injury. PMID- 27240163 TI - Temporomandibular disorder treatment in a patient wearing removable prostheses: A case report. AB - AIM: The purpose of this intervention was to treat the patient, a 51-year-old woman, who was wearing a maxillary denture and a mandibular bilateral distal extension partial denture (both unfit) and was suffering from temporomandibular disorder (TMD). METHODOLOGY: The treatment suggested was to construct a superior repositioning splint (SRS), and after remission of the symptomatology, fabricate new dentures. RESULTS: The occlusal splint was effective and the symptomatology ceased after about five months of treatment. The new dental prostheses were made and followed up for 10 years with no return of the pain. CONCLUSIONS: SRS and subsequent construction of new dentures after remission of the symptomatology was an effective treatment for TMD in the case described. PMID- 27240164 TI - Calcium channel blockade attenuates abnormal synaptic transmission in the dentate gyrus elicited by entorhinal amyloidopathy. AB - Entorhinal-hippocampal network is one of the earliest circuits which is affected by Alzheimer's disease (AD). There are numerous data providing the evidence of synaptic deficit in the dentate gyrus (DG) of AD animal model. However, there is little known about how entorhinal cortex (EC) amyloidophaty affects each excitatory and/or inhibitory transmission in the early stage of AD. On the other hand, it is believed that calcium dyshomeostasis has a critical role in the etiology of AD. Here, the effect of the EC amyloid pathogenesis on excitatory or inhibitory post synaptic currents (EPSC and IPSC, respectively) in the DG granule cells and then the possible neuroprotective action of L-type calcium channel blockers (CCBs), nimodipine and isradipine, were examined. The amyloid beta (Abeta) 1-42 was injected bilaterally into the EC of male rats and one week later, synaptic currents in the DG granule cells were assessed by whole cell patch clamp. EPSCs were evoked by stimulating the perforant pathway. Voltage clamp recording showed profound decrease of evoked EPSC amplitude and paired pulse facilitation in the DG granule cells of Abeta treated rats. Furthermore, AMPA/NMDA ratio was significantly decreased in the Abeta treated animals. On the other hand, amplitude of IPSC currents was significantly increased in the DG granule cells of these animals. These modifications of synaptic currents were partially reversed by daily intracerebroventricular administration of isradipine or nimodipine. In conclusion, our results suggest that Abeta in the EC triggers decreased excitatory transmission in the DG with substantial decrement in AMPA currents, leading to a prominent activity of inhibitory circuits and increased inhibition of granule cells which may contribute to the development of AD-related neurological deficits in AD and treatment by CCBs could preserve normal synaptic transmission against Abeta toxicity. PMID- 27240162 TI - Non-virally engineered human adipose mesenchymal stem cells produce BMP4, target brain tumors, and extend survival. AB - There is a need for enabling non-viral nanobiotechnology to allow safe and effective gene therapy and cell therapy, which can be utilized to treat devastating diseases such as brain cancer. Human adipose-derived mesenchymal stem cells (hAMSCs) display high anti-glioma tropism and represent a promising delivery vehicle for targeted brain tumor therapy. In this study, we demonstrate that non-viral, biodegradable polymeric nanoparticles (NPs) can be used to engineer hAMSCs with higher efficacy (75% of cells) than leading commercially available reagents and high cell viability. To accomplish this, we engineered a poly(beta-amino ester) (PBAE) polymer structure to transfect hAMSCs with significantly higher efficacy than LipofectamineTM 2000. We then assessed the ability of NP-engineered hAMSCs to deliver bone morphogenetic protein 4 (BMP4), which has been shown to have a novel therapeutic effect by targeting human brain tumor initiating cells (BTIC), a source of cancer recurrence, in a human primary malignant glioma model. We demonstrated that hAMSCs genetically engineered with polymeric nanoparticles containing BMP4 plasmid DNA (BMP4/NP-hAMSCs) secrete BMP4 growth factor while maintaining their multipotency and preserving their migration and invasion capacities. We also showed that this approach can overcome a central challenge for brain therapeutics, overcoming the blood brain barrier, by demonstrating that NP-engineered hAMSCs can migrate to the brain and penetrate the brain tumor after both intranasal and systemic intravenous administration. Critically, athymic rats bearing human primary BTIC-derived tumors and treated intranasally with BMP4/NP-hAMSCs showed significantly improved survival compared to those treated with control GFP/NP-hAMCSs. This study demonstrates that synthetic polymeric nanoparticles are a safe and effective approach for stem cell based cancer-targeting therapies. PMID- 27240165 TI - Secretion of protein disulphide isomerase AGR2 confers tumorigenic properties. AB - The extracellular matrix (ECM) plays an instrumental role in determining the spatial orientation of epithelial polarity and the formation of lumens in glandular tissues during morphogenesis. Here, we show that the Endoplasmic Reticulum (ER)-resident protein anterior gradient-2 (AGR2), a soluble protein disulfide isomerase involved in ER protein folding and quality control, is secreted and interacts with the ECM. Extracellular AGR2 (eAGR2) is a microenvironmental regulator of epithelial tissue architecture, which plays a role in the preneoplastic phenotype and contributes to epithelial tumorigenicity. Indeed, eAGR2, is secreted as a functionally active protein independently of its thioredoxin-like domain (CXXS) and of its ER-retention domain (KTEL), and is sufficient, by itself, to promote the acquisition of invasive and metastatic features. Therefore, we conclude that eAGR2 plays an extracellular role independent of its ER function and we elucidate this gain-of-function as a novel and unexpected critical ECM microenvironmental pro-oncogenic regulator of epithelial morphogenesis and tumorigenesis. PMID- 27240167 TI - Overdiagnosis and overtreatment associated with breast cancer mammography screening: A simulation study with calibration to population-based data. AB - OBJECTIVES: The magnitude of overdiagnosis of breast cancer associated with mammography screening remains controversial because of methodological issues. The objective of this study was to quantify overdiagnosis and overtreatment associated with a population-based screening programme, taking into account lead time and uncertainty concerning baseline incidence of breast cancers. MATERIAL AND METHODS: A simulation model was developed to replicate incidence and detection rates of breast cancer observed in the Isere Departement, France. The parameters of the model were estimated using an approximate Bayesian computation method. RESULTS: For women aged 50-74 years during the 2007-2010 period, overdiagnosis of non-progressive breast cancers accounted for 17.0% (95% credibility interval (CI): 2.5%-35.5%) of all in situ cancers diagnosed, 5.5% (95% CI: 0.8%-9.8%) of all invasive cancers diagnosed, and 20.3% (95% CI: 3.0% 38.9%) of in situ and 13.0% (95% CI: 2.2%-23.3%) of invasive screen detected breast cancers. The estimates of overdiagnosis due to competitive causes of death were 1.0% (95% CI: 0.2%-%1.7) and 1.1% (95% CI: 0.6%-1.7%) for all in situ and invasive cancers diagnosed, respectively, and 1.3% (95% CI: 0.2%-2.0%) and 2.6% (95% CI: 1.4%-4.0%) of all in situ and invasive screen detected breast cancers, respectively. Among 1000 screen-detected cancers in 2010, 155 (95% CI: 27-284), 134 (95% CI: 10-242) and 140 (95% CI: 25-254) women underwent breast conserving surgery, lymph node dissection and radiation therapy for overdiagnosed cancers, respectively. CONCLUSION: Our estimates of overdiagnosis should be balanced against the reduction of breast cancer mortality to assess the value of breast cancer screening programme. PMID- 27240166 TI - Tumor suppression in basal keratinocytes via dual non-cell-autonomous functions of a Na,K-ATPase beta subunit. AB - The molecular pathways underlying tumor suppression are incompletely understood. Here, we identify cooperative non-cell-autonomous functions of a single gene that together provide a novel mechanism of tumor suppression in basal keratinocytes of zebrafish embryos. A loss-of-function mutation in atp1b1a, encoding the beta subunit of a Na,K-ATPase pump, causes edema and epidermal malignancy. Strikingly, basal cell carcinogenesis only occurs when Atp1b1a function is compromised in both the overlying periderm (resulting in compromised epithelial polarity and adhesiveness) and in kidney and heart (resulting in hypotonic stress). Blockade of the ensuing PI3K-AKT-mTORC1-NFkappaB-MMP9 pathway activation in basal cells, as well as systemic isotonicity, prevents malignant transformation. Our results identify hypotonic stress as a (previously unrecognized) contributor to tumor development and establish a novel paradigm of tumor suppression. PMID- 27240168 TI - Clinical significance of fatty liver disease induced by tamoxifen and toremifene in breast cancer patients. AB - BACKGROUND AND AIM: The aim of this study was to identify the effect of selective estrogen receptor modulator (SERM) on non-alcoholic fatty liver disease (NAFLD) in Asian women. METHODS: We retrospectively evaluated fatty liver development and/or serum alanine aminotransferase (ALT) elevation during SERM treatment in 1061 women who were diagnosed and treated with breast cancer in 2005 at Asan Medical Center. RESULTS: 45 of 618 SERM-treated patients with normal ALT at baseline experienced ALT elevation during SERM treatment. Among the 112 SERM treated patients who underwent liver imaging test, fatty liver was observed in 47 and both fatty liver and ALT elevation developed in 16 of 102 SERM-treated patients with normal baseline ALT. The cumulative rates of ALT elevation (10.7 vs. 4.3%; P = 0.002), fatty liver (48.5 vs. 20.9%; P < 0.001), and both fatty liver and ALT elevation (17.7 vs. 7.1%; P = 0.02) at 60 months were significantly higher in the SERM group than non-SERM group. By multivariate analysis, SERM treatment increased the risk of ALT elevation (hazard ratio [HR], 2.20; P = 0.01), fatty liver development (HR, 3.59; P < 0.001), and both fatty liver and ALT elevation (HR, 4.98; P = 0.01). After discontinuation of SERM, elevated serum ALT normalized in 39 (92.9%) and there were no instances of liver-related death or progression to liver cirrhosis in patients who experienced fatty liver or ALT elevation. CONCLUSIONS: Although SERM treatment is significantly associated with NAFLD in Asian women, considering the tolerability and reversibility of NAFLD induced by SERM, it can be continued with liver function monitoring in relevant patients. PMID- 27240169 TI - Effects of locoregional radiotherapy in patients with metastatic breast cancer. AB - OBJECTIVES: This study aims to assess the clinical outcomes of patients with metastatic breast cancer (MBC) who underwent local radiation therapy (RT) for the primary site. MATERIAL AND METHODS: Between 2005 and 2013, we retrospectively evaluated patients with MBC who received breast or chest wall RT with or without regional lymph node irradiation. RESULTS: 2761 patients with breast cancer were treated with RT. Of them, 125 women with stage IV breast carcinoma were included. The median follow-up was 15 months (ranging from 3.8 to 168 months), when 54.7% of the patients had died; local progression was observed in 22.8% of the patients. The mean overall survival (OS) and local progression free survival (LoPFS) were 23.4 +/- 2.4 months and 45.1 +/- 2.9 months, respectively. Three- and five-year overall survival rates were, respectively, 21.2% and 13.3%. Local progression free survival was the same, 67.3%, at three and five years, respectively. Karnofsky Performance Status (KPS) (p = 0.015), number of metastatic sites (p = 0.031), RT dose (p = 0.0001) and hormone therapy (p = 0.0001) were confirmed as independent significant variables correlated with OS. The variables that were independently correlated with LoPFS were the number of previous chemotherapy lines (p = 0.038) and RT dose (p = 0.0001). CONCLUSION: RT of the primary site in patients with MBC is well tolerated. The factors that presented positive impact on survival were good KPS, low disease burden (1-3 metastatic sites), and the use of hormone therapy. PMID- 27240170 TI - Analysis of Duplicated Multiple-Samples Rank Data Using the Mack-Skillings Test. AB - Appropriate analysis for duplicated multiple-samples rank data is needed. This study compared analysis of duplicated rank preference data using the Friedman versus Mack-Skillings tests. Panelists (n = 125) ranked twice 2 orange juice sets: different-samples set (100%, 70%, vs. 40% juice) and similar-samples set (100%, 95%, vs. 90%). These 2 sample sets were designed to get contrasting differences in preference. For each sample set, rank sum data were obtained from (1) averaged rank data of each panelist from the 2 replications (n = 125), (2) rank data of all panelists from each of the 2 separate replications (n = 125 each), (3) jointed rank data of all panelists from the 2 replications (n = 125), and (4) rank data of all panelists pooled from the 2 replications (n = 250); rank data (1), (2), and (4) were separately analyzed by the Friedman test, although those from (3) by the Mack-Skillings test. The effect of sample sizes (n = 10 to 125) was evaluated. For the similar-samples set, higher variations in rank data from the 2 replications were observed; therefore, results of the main effects were more inconsistent among methods and sample sizes. Regardless of analysis methods, the larger the sample size, the higher the chi(2) value, the lower the P value (testing H0 : all samples are not different). Analyzing rank data (2) separately by replication yielded inconsistent conclusions across sample sizes, hence this method is not recommended. The Mack-Skillings test was more sensitive than the Friedman test. Furthermore, it takes into account within-panelist variations and is more appropriate for analyzing duplicated rank data. PMID- 27240171 TI - Do student nurses experience Imposter Phenomenon? An international comparison of Final Year Undergraduate Nursing Students readiness for registration. AB - BACKGROUND: The transition shock or Imposter Phenomena sometimes associated with moving from student to Registered Nurse can lead to feelings of self-doubt and insecurity especially with the increased expectations and responsibilities that registration brings. AIM: The aim of this study was to examine the extent at which imposter phenomenon is evident in four final year nursing student cohorts in Australia, New Zealand and the UK. DESIGN: A survey design. SETTINGS: The study took place at four higher education institutes - two metropolitan campuses and two regional campuses between October 2014 - February 2015 in Australia, New Zealand and the UK. A sample of 223 final year nursing students undertaking nationally accredited nursing programmes were approached. RESULTS: Each cohort exhibited mild to moderate feelings of Imposter Phenomena. A positive weak correlation between imposter phenomena and preparedness for practice was found. The New Zealand cohort scored higher than both the Australian and UK cohorts on both feelings of imposterism and preparedness for practice. CONCLUSIONS: Nursing students possess internalized feelings which suggest their performance and competence once qualified could be compromised. There is some speculation that the respective curriculums may have some bearing on preparing students for registration and beyond. It is recommended that educational programmes designed for this student cohort should be mindful of this internal conflict and potential external hostility. PMID- 27240173 TI - [Psychogenic depression and endogenous process (to the problem of reactive schizophrenia)]. AB - OBJECTIVE: To conduct clinical differentiation of stress-induced conditions in schizophrenia and schizophrenia spectrum disorders according to the concept of so called "Reactive schizophrenia" (J. Berze). MATERIAL AND METHODS: A sample consisted of 40 patients (14 male, 26 female, mean age 38.6+/-12.5. 17 years), including 17 (42%) patients with schizophrenia, 16 (40%) patients with ICD-10 schizotypal disorder and 7 (18%) patients with DSM-V schizotypal personality disorder. RESULTS AND CONCLUSION: All clinical cases were divided into two groups according to the discrepancy of endogenous/psychogenic factor interaction, clinical aspects and disease course. In the first group, the onset of stress induced depression is due to psychogenic provocations of endogenous (schizophreniform) disorders. In the second group, the development of depression is based on the endogenous provocation of psychogenias (an increased affinity to stressful factors associated with the exacerbation of the endogenous process). PMID- 27240174 TI - [Venous thromboembolism in patients with Guillain-Barre syndrome]. AB - OBJECTIVE: To perform an in-depth prospective analysis of the prevalence, risk factors, specific characteristics of venous thromboembolism (VTE) and the dynamics of venous thrombosis during the treatment with low-molecular-weight heparin (LMWH) in patients with different forms and severity of Guillain-Barre syndrome (GBS) admitted to an intensive care unit (ICU). MATERIAL AND METHODS: Prevalence, risk factors and course of VTE were analyzed for the first time in 65 ICU inpatients with various forms and severity of GBS. Neurological status was evaluated at baseline and in dynamics, duplex scanning of veins of the legsin the system of inferior vena cava was performed. RESULTS AND CONCLUSION: Despite the preventive using of LMWH, a half of patients with GBS, regardless of the form of the disease during the progression of neurological symptoms, have VTE (deep vein thrombosis--52%, pulmonary embolism--15%). Significant risk factors include: severe disease course requiring artificial ventilation, bed rest for more than 3 days, infectious complications, the presence of the catheter in the central vein, age over 40 years. Venous thrombosis in the system of inferior vena cava in patients with GBS does not differ from that in other critical illnesses suggesting that this pathological process is universal. Preventive measures for this category of patients is insufficient and requires a search for other prevention strategies. PMID- 27240175 TI - [Mental disorders in patients with HIV infection: systematics and features of development]. AB - OBJECTIVE: To identify and systematize characteristics and patterns of formation and development of mental disorders in HIV-infection. MATERIAL AND METHODS: Two hundred and fifty patients with HIV-infection and 50 injection drug users, aged 18-50 years, were examined. Most of HIV-infected people were aged from 21 to 40 years. In addition to clinical and psychopathological methods, clinical laboratory instrumentation and experimental psychological method were used. RESULTS AND CONCLUSION: Mental disorders in HIV-infected patients include psychogenic-reactive, exogenous organic and personality disorders. The dynamics of these disorders depends on the combined effects of somatogenic, nosogenic and premorbid personality factors. PMID- 27240172 TI - Consider the workhorse: Nonhomologous end-joining in budding yeast. AB - DNA double strand breaks (DSBs) are dangerous sources of genome instability and must be repaired by the cell. Nonhomologous end-joining (NHEJ) is an evolutionarily conserved pathway to repair DSBs by direct ligation of the ends, with no requirement for a homologous template. While NHEJ is the primary DSB repair pathway in mammalian cells, conservation of the core NHEJ factors throughout eukaryotes makes the pathway attractive for study in model organisms. The budding yeast, Saccharomyces cerevisiae, has been used extensively to develop a functional picture of NHEJ. In this review, we will discuss the current understanding of NHEJ in S. cerevisiae. Topics include canonical end-joining, alternative end-joining, and pathway regulation. Particular attention will be paid to the NHEJ mechanism involving core factors, including Yku70/80, Dnl4, Lif1, and Nej1, as well as the various factors implicated in the processing of the broken ends. The relevance of chromatin dynamics to NHEJ will also be discussed. This review illustrates the use of S. cerevisiae as a powerful system to understand the principles of NHEJ, as well as in pioneering the direction of the field. PMID- 27240176 TI - [The efficacy of combination therapy with mexidol and cerebrolysin in chronic cerebral ischemia]. AB - OBJECTIVE: To study the impact of combination therapy with mexidol and cerebrolysin on the clinical status of patients with chronic cerebral ischemia (CCI), II stage, in ambulatory conditions. MATERIAL AND METHODS: The study included 36 patients with CCI, II stage. In addition to basic therapy, patients received two courses of the mexidol/cerebrolysin combination during 6 weeks with 3 month-interval between the courses. The dynamics of subjective complaints of the patients and objective clinical signs was assessed after each course. The content of 13 chemical elements in the hair was determined by atomic-emission method after the treatment. RESULTS AND CONCLUSION: Based on the results of clinical and neurological study, the efficacy of combination therapy with mexidol and cerebrolysin as long-term neuroprotection drugs was shown which manifested a significant reduction in the severity of all major symptoms under the influence of the therapy. PMID- 27240177 TI - [The use of nimesulide in the treatment of acute low back pain]. AB - The objective is to study the efficacy and safety of nimesulide (nemulex) in the treatment of acute low back pain (LBP). The medical documentation of 54 patients with primary syndrome of LBP, which were treated in a polyclinic with nemulex at a dose of 200 mg per day had been studied. The assessment of patients' condition and efficacy and safety of the treatment was conducted based on the information after three visits (1-st, 5-th and 10-th day). The analysis took into account the data of clinical-neurological examination and the assessment of pain intensity at rest and at movement according to the visual analogue scale (VAS) and the severity of Lasegue symptom and limitation of movements in the lumbar spine. Safety of the therapy was evaluated on the basis of accounting of undesirable side reactions and data analysis and physical examination and laboratory testing. Cardiovascular safety was assessed by blood pressure and blood lipid profile on day 10. The use of nemulex at a dose of 200 mg per day resulted in relief of pain and increase of mobility in the lumbar spine on the 5th day of treatment that indicates the effectiveness of anti-inflammatory therapy to restore the previous functional status of patients with LBP. The use of nemulex was accompanied not only by statistically significant analgesic effect (0,78+/-0,14 points alone; 1,12+/-0,18 points when moving by VAS on the 10th day of the treatment) and high security (only 1 of the 54 patients was recorded to have elevation of hepatic transaminases; and 2 patients with dyspepsia without endoscopic changes of gastrointestinal tract). PMID- 27240178 TI - [Cognitive disorders in stroke patients: the possibilities of pharmacological correction]. AB - OBJECTIVE: To determine the efficacy and safety of cellex in treatment of cognitive disorders in acute ischemic stroke (IS). MATERIAL AND METHODS: The study involved 246 patients with acute IS. Patients were randomly divided into two groups depending on the use of cellex or placebo along with basic treatment during 10 days. The dynamics of neuropsychological status was evaluated. RESULTS AND CONCLUSION: In IS patients, treatment with cellex have led to more rapid and marked reduction of mild and moderate cognitive disorders. PMID- 27240179 TI - [Post-stroke cognitive impairment and the possibility of treatment with cellex]. AB - OBJECTIVE: To present neuropsychological characteristics of post-stroke cognitive impairment (PSCI) in acute ischemic stroke (IS) and to assess the efficacy of the drug cellex. MATERIAL AND METHODS: A comprehensive neuropsychological testing battery was administered to 288 patients with acute IS. In addition to basic therapy, 30 patients received cellexin the dosage of 0.1 mg (1 ml) subcutaneously for 10 days, treatment was started in the acute phase. RESULTS AND CONCLUSION: Multifunctional PSCI were revealed in 87% of patients with acute IS. Impairments of attention, regulatory functions, speech and memory were identified in the majority of patients. More than a third of patients had multifunctional nonamnestic PSCI. Monofunctionalnonamnestic PSCI were found in 5.5% of patients. Isolated deficit of memory was observed in 2% of patients. PSCI with the predominance of mixed character were found mostly in elderly patients. In the group of young and middle-aged patients,there was a decrease in isolated speed reduction or regulation of cognitive activity, combined cognitive impairment was detected in every fourth patient. There was a trend towards an increase in the age of patients withPSCI of the mixed character. An analysis of the efficacy of cellex in acute IS has shown that the drug improves cognitive status as well as the state of neurodynamic, regulatory and visuospatial functions. Therefore, cellex is effective in treatment of PSCI in acute IS. PMID- 27240180 TI - [An increase in the efficacy of psychopharmacotherapy of late-onset depressions: combination and substitution of antidepressants]. AB - OBJECTIVE: To comprehensively analyze the possibilities of using the methods of correction of non-effective psychopharmacotherapy of late-onset depressions. MATERIAL AND METHODS: Methods of potentiating, combination and substitution of non-effective psychopharmacotherapy of late-onset depressions were studied. RESULTS AND CONCLUSION: Indications to the use and specific algorithms of substitution and addition of antidepressants in non-effective psychopharmacotherapy of late-onset depressions have been developed. These algorithms of combination therapy suggest the possibilities for choosing the individual combinations of antidepressants. PMID- 27240181 TI - [The efficacy of benzodiazepines and low-potent antipsychotics as adjunctive therapy of somatoform disorders]. AB - OBJECTIVE: To assess the efficacy of monotherapy with sertraline or its combinations with phenazepam or thioridazine in patients with somatoform disorders. MATERIAL AND METHODS: The open study included 65 patients divided into three groups according to the drug used. Clinical condition of the patients was evaluated with CGI and Hamilton scale. The Screening for Somatoform Symptoms 7 was administered as well. RESULTS AND CONCLUSION: During the treatment, a significant decrease in the severity of somatoform disorders was observed in all groups. The more rapid development of therapeutic effect, including the reduction in anxiety symptoms in the sertraline + phenazepam group, was found. There were no significant differences between the sertraline group and the sertraline+ thioridazine group. The differences were identified only during three weeks of treatment while there were no between-group differences in the 4th week. In accordance to these results, the duration of adjunctive therapy with benzodiazepines should be limited in time. PMID- 27240182 TI - [Modeling of hemodynamic changes in the aneurysm of the middle cerebral artery depending on the pathology of the parent artery]. AB - OBJECTIVE: To examine the influence of the parent artery pathology on the local hemodynamics on the level of aneurysm. MATERIAL AND METHODS: Mathematical models of the arteriovenous malformation (AVM) were built on the CT-angiography data of real patients. To simulate the thrombosis, the parent artery and its branches were sequentially turned off in the model 1. In the model 2, the simulation of embolization of AVM was achieved by cutting off the exactly section of the parent artery that was involved in the arteriovenous formation. RESULTS AND CONCLUSION: Model 1 showed that the flow redistribution did not significantly impact on the risk of rupture after the parent artery was turned off and blood pressure was increased in both aneurysms by 3 mm Hg. Model 2, in which the aneurysms were combined with a direct arteriovenous drainage with low peripheral resistance, showed that turning off the parent artery and pathological drainage led to the serious reduction in the venous drainage flow and it's increasing in the parent artery by about 60% that significantly increased the risk of rupture. PMID- 27240183 TI - [The effects of blood serum from schizophrenia patients under olanzapine monotherapy on the ultrastructure of astrocytes in human fetal brain organotypic culture]. AB - OBJECTIVE: To study effects of blood serum (BS) from schizophrenia patients under olanzapine monotherapy on astrocytes in the human fetal brain organotypic culture. MATERIAL AND METHODS: Authors studied the human fetal brain organotypic culture after the application of BS from 20 normals and 33 patients (ICD-10 schizophrenia, paranoid type, F20.02; F20.22) taken before and after 8 and 28 weeks of olanzapine treatment. A qualitative electron microscopic study of glial cells, neurons and neuropil as well as morphometric study of the ultrastructure of astrocytes were performed. RESULTS: Authors found no effects of BS from the patients with schizophrenia on neurons and synaptic contacts. The qualitative and morphometric studies revealed different effects of BS from the patients on the astrocyte ultrastructure before and after olanzapine treatment. The application of BS from untreated schizophrenia patients induced dystrophic alterations of astrocytes, BS from patients who received olanzapine during 8 weeks did not influence the astrocyte ultrastructure. After 28 weeks of olanzapine treatment,a hypertrophy of astrocytes (an increase (r<=0.05) of the area of cells and the number of mitochondria (p=0,015) and unaltered volume density of mitochondria) was found as compared to normal control cultures. CONCLUSION: BS from patients with schizophrenia before and after olanzapine treatment induced opposite types of ultrastructural changes of astrocytes in the human fetal brain organotypic culture. The differences might be due to the previously reported changes of the level of circulating immune complexes and interleukins in blood serum of schizophrenia patients and due to the effects of olanzapine on these parameters. PMID- 27240185 TI - [A case of narcolepsy in adolescent]. AB - A description of the clinical observation of the teenager with narcolepsy is presented. This case demonstrates specific clinical and polysomnographic characteristics of narcolepsy with cataplexy as well as a unique combination of paroxysmal forms of diseases affecting the state of sleep and wakefulness (narcolepsy, epilepsy and other phenomena related to sleep medicine). These forms include sleep-associated eating disorder and restless legs syndrome. The current approaches to treatment of narcolepsy are presented. PMID- 27240184 TI - [The association of the DRD3 gene with Parkinson's disease]. AB - OBJECTIVE: To investigate the association between dopamine receptor DRD3 gene tag single nucleotide polymorphisms (SNPs) and the risk of Parkinson's disease (PD). MATERIAL AND METHODS: One hundred and forty-three patients with PD and 96 healthy individuals from the Russian population were examined. Ten tag SNPs (rs963468, rs2134655, rs9817063, rs324035, rs11721264, rs1800828, rs3773678, rs167770, rs167771, rs7633291) within DRD3 have been genotyped. RESULTS AND CONCLUSION: Associations between 4 polymorphisms (rs11721264, rs3773678, rs167771, rs324035) and PD have been found. Our study confirms the involvement of polymorphic features of dopamine receptors genes in the pathophysiology in PD. PMID- 27240186 TI - [A case of development of a synthetic cannabinoid (Spice) dependency]. PMID- 27240187 TI - [Idiopathic intracranial hypertension]. AB - Idiopathic intracranial hypertension (IIH) is a condition due to high intracranial pressure in the absence of an intracranial mass lesion, venous thrombosis or brain infection. It mostly occurs in young obese females. Currently, the incidence of IIH in obese women is estimated to be 12 per 100,000 people per year. Epidemiological data demonstrate the increase in incidence in this group: 323 cases per 100,000. IIH can cause visual loss in 1-2% of the patients during the year before the diagnosis and beginning of treatment. IIH treatment is a complex multidisciplinary problem that includes a body-mass reduction program, conservative pharmacological treatment, prolonged ophthalmological study and, if necessary, timely neurosurgical treatment. PMID- 27240188 TI - A systematic review of the outcomes of educational interventions relevant to nurses with simultaneous strategies for guideline implementation. AB - AIMS AND OBJECTIVES: To systematically review the literature on the outcomes of educational interventions relevant to nurses with regard to guideline implementation. BACKGROUND: Previous reviews on interventions to implement guidelines have focused on particular clinical problems, but only one included nursing studies. DESIGN: A systematic review based on the procedure of the Centre for Reviews and Dissemination. METHODS: We searched for papers published from 1 January 2008 to 26 February 2015 using the Cochrane, CINAHL and PubMed MEDLINE databases and paper references were searched manually. Quality appraisal was conducted with tools developed by Thomas et al.(Worldviews on Evidence-based Nursing, 1, 2004, 176) and National Heart, Lung, and Blood Institute. Data were analysed with qualitative content analysis and narrative synthesis. RESULTS: The data included 13 studies based on a quasi-experimental study design of 13 different educational interventions, described according to their development and realisation, learning content and teaching and learning methods. Seven interventions were supported by simultaneous strategies, 12 studies reported statistically significant outcomes for the interventions on at least one measurement area and six studies reported improvements in the quality of patient care. Interventions with multi-dimensional content, teaching and learning methods produced several good outcomes. CONCLUSION: Guidelines were implemented in a heterogeneous way and the interventions were delivered once and mainly on a local basis. In the future, we need to test these interventions in different nursing contexts, measure the outcomes on patient care and carry out randomised controlled trials on their effectiveness. It is important to standardise interventions, as this will allow them to be replicated and compared. RELEVANCE TO CLINICAL PRACTICE: Educational interventions to implement guidelines could be beneficial in enhancing nurses' evidence-based decision-making and care practice. The combination of teaching and learning methods proved useful, and educational interventions should be supported with simultaneous strategies. There remains a lack of strong evidence on the subject. PMID- 27240189 TI - Microbial transformation of the anti-diabetic agent corosolic acid by Cunninghamella echinulata. AB - The pentacyclic triterpenoid corosolic acid was metabolized by Cunninghamella echinulata CGMCC 3.2000 to its C-24 aldehyde group metabolite and five other hydroxylated metabolites: madasiatic acid (2), 2alpha, 3beta, 7beta-trihydroxyurs 12-en-28-oic acid (3), 2alpha, 3beta, 15alpha-trihydroxyurs-12-en-28-oic acid (4), 2alpha, 3beta, 6beta, 7beta-tetrahydroxyurs-12-en-28-oic acid (5), 2alpha, 3beta, 7beta, 15alpha-tetrahydroxyurs-12-en-28-oic acid (6), and 2alpha, 3beta,7beta-trihydroxy-24-al-urs-12-en-28-oic acid (7); compounds 3, 5, and 7 were new compounds. The alpha-glucosidase inhibitory effects of the metabolites were also evaluated. PMID- 27240190 TI - 7-Hydroxycoumarin prevents UVB-induced activation of NF-kappaB and subsequent overexpression of matrix metalloproteinases and inflammatory markers in human dermal fibroblast cells. AB - Ultraviolet B (UVB) irradiation alters multiple molecular pathways in the skin, thereby inducing skin damage. Human dermal fibroblasts (HDFa) were subjected to single UVB-irradiation (18mJ/cm(2)) resulting in reactive oxygen species (ROS) generation, oxidative DNA damage and upregulation of nuclear factor kappa B (NF kappaB) expression. Further, it has been observed that there was a significant cytokine production (TNF-alpha and IL-6) in UVB irradiated HDFa cells. Our results show that 7-hydroxycoumarin (7-OHC) prevents UVB-induced activation of NF kappaB thereby subsequently preventing the overexpression of TNF-alpha and IL-6 in HDFa cells. Further, 7-OHC prevents UVB-induced activation of cyclooxygenase-2 (COX-2) expression, an inflammatory mediator in skin cells. Moreover, 7-OHC inhibited mRNA expression pattern of matrix metalloproteinases (MMP-1 and MMP-9) in UVB irradiated skin cells. Furthermore, 7-OHC restored antioxidant status, thereby scavenging the excessively generated ROS; consequently preventing the oxidative DNA damage. It has also been noticed that 7-OHC prevents UVB mediated DNA damage through activation of DNA repair enzymes such as XRCC1 and HOGG1. In this study, we treated HDFa cells with 7-OHC before and after UVB irradiation and we found that pretreatment showed better results when compared to posttreatment. Further, 7-OHC showed 9.8416 sun protection factor (SPF) value and it absorbs photons in the UVB wavelength rage. Thus, it has been concluded that sunscreen property, free radical scavenging potential and prevention of NF-kappaB activation play a role for photoprotective property of 7-OHC. PMID- 27240191 TI - Inflammasome priming increases retinal pigment epithelial cell susceptibility to lipofuscin phototoxicity by changing the cell death mechanism from apoptosis to pyroptosis. AB - Progressive death of retinal pigment epithelium (RPE) cells is a hallmark of age related macular degeneration (AMD), the leading cause of blindness in all developed countries. Photooxidative damage and activation of the NLRP3 inflammasome have been suggested as contributing factors to this process. We investigated the effects of inflammasome activation on oxidative damage-induced RPE cell death. In primary human RPE cells and ARPE-19 cells, lipofuscin accumulated following incubation with oxidatively modified photoreceptor outer segments. Oxidative stress was induced by blue light irradiation (dominant wavelength: 448nm, irradiance: 0.8mW/cm(2), duration: 3 to 6h) of lipofuscin loaded cells and resulted in cell death by apoptosis. Prior inflammasome priming by IL-1alpha or complement activation product C5a altered the cell death mechanism to pyroptosis and resulted in a significant increase of the phototoxic effect. Following IL-1alpha priming, viability 24h after irradiation was reduced in primary RPE cells and ARPE-19 cells from 65.3% and 56.7% to 22.6% (p=0.003) and 5.1% (p=0.0002), respectively. Inflammasome-mediated IL-1beta release occurred only in association with pyroptotic cell lysis. Inflammasome priming by conditioned media of pyroptotic cells likewise increased cell death. Suppression of inflammasome activation by inhibition of caspase-1 or cathepsins B and L significantly reduced cell death in primed cells. In summary, inflammasome priming by IL-1alpha, C5a, or conditioned media of pyroptotic cells increases RPE cell susceptibility to photooxidative damage-mediated cell death and changes the mechanism of induced cell death from apoptosis to pyroptosis. This process may contribute to RPE degeneration in AMD and provide new targets for intervention. PMID- 27240192 TI - The Influence of Prefermentative Addition of Gallic Acid on the Phenolic Composition and Chromatic Characteristics of Cabernet Sauvignon Wines. AB - In this study, the prefermentative addition of gallic acid in Cabernet Sauvignon red winemaking was performed. The influence of gallic acid addition on wine phenolic composition, the ratio of copigmentation, and the color parameters were monitored throughout the winemaking process. The results showed that the prefermentative addition of gallic acid enhanced the extraction of total anthocyanins and the copigmentation effect, producing wines with more darkness, redness, yellowness, and saturation. Moreover, the addition of gallic acid contributed to the concentration of total phenolic acids. However, it had a negative effect on the concentrations of flavonols and flavan-3-ols in the final wines. Thus, the prefermentative addition of gallic acid at appropriate levels might be a promising enological technology to obtain wines with high color quality and aging potential. PMID- 27240194 TI - Environmental determinants of polycystic ovary syndrome. AB - In this review, we summarize existing research on a variety of environmental factors potentially involved in the etiology, prevalence, and modulation of polycystic ovary syndrome (PCOS), and we suggest avenues for future research. The main environmental factors we consider include environmental toxins, diet and nutrition, socioeconomic status, and geography. There is some evidence that environmental toxins play a role in disrupting reproductive health, but there is limited research as to how these toxins may affect the development of PCOS. Although research has also shown that PCOS symptoms are reduced with certain dietary supplements and with weight loss among obese women, additional research is needed to compare various approaches to weight loss, as well as nutritional factors that may play a role in preventing or mitigating the development of PCOS. Limited studies indicate some association of low socioeconomic status with certain PCOS phenotypes, and future research should consider socioeconomic conditions during childhood or adolescence that may be more relevant to the developmental onset of PCOS. Finally, the limited scope of comparable international studies on PCOS needs to be addressed, because global patterns of PCOS are potentially valuable indicators of cultural, environmental, and genetic factors that may contribute to excess risk in certain regions of the world. PMID- 27240193 TI - Antimullerian hormone in relation to tobacco and marijuana use and sources of indoor heating/cooking. AB - OBJECTIVE: To evaluate exposure to tobacco, marijuana, and indoor heating/cooking sources in relation to antimullerian hormone (AMH) levels. DESIGN: Cross sectional analysis in a sample of premenopausal women (n = 913) enrolled in the Sister Study cohort (n = 50,884). SETTING: Not applicable. PATIENT(S): Women, ages 35-54 years at time of enrollment, with an archived serum sample and at least one intact ovary and classified as premenopausal. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Serum AMH (ng/mL) levels ascertained by ultrasensitive ELISA assay. RESULT(S): Lower AMH levels were associated with sources of indoor heating, including burning wood (-36.0%; 95% confidence interval [CI], -55.7%, -7.8%) or artificial fire logs (-45.8%; 95% CI, -67.2%, 10.4%) at least 10 times/year in a residential indoor stove/fireplace. Lower AMH levels were also observed in women who were current smokers of >=20 cigarettes/day relative to nonsmokers (-56.2%; 95% CI, -80.3%, -2.8%) and in women with 10+ years of adult environmental tobacco smoke (ETS) exposure (-31.3%; 95% CI, -51.3%, -3.1%), but no associations were observed for marijuana use. CONCLUSION(S): We confirmed previously reported findings of lower AMH levels in current heavy smokers and also found associations for long-term ETS exposure and indoor burning of wood or artificial fire logs. These findings suggest that combustion by-products from common exposures can have toxic effects on the human ovary. PMID- 27240195 TI - A split horseradish peroxidase for the detection of intercellular protein-protein interactions and sensitive visualization of synapses. AB - Intercellular protein-protein interactions (PPIs) enable communication between cells in diverse biological processes, including cell proliferation, immune responses, infection, and synaptic transmission, but they are challenging to visualize because existing techniques have insufficient sensitivity and/or specificity. Here we report a split horseradish peroxidase (sHRP) as a sensitive and specific tool for the detection of intercellular PPIs. The two sHRP fragments, engineered through screening of 17 cut sites in HRP followed by directed evolution, reconstitute into an active form when driven together by an intercellular PPI, producing bright fluorescence or contrast for electron microscopy. Fusing the sHRP fragments to the proteins neurexin (NRX) and neuroligin (NLG), which bind each other across the synaptic cleft, enabled sensitive visualization of synapses between specific sets of neurons, including two classes of synapses in the mouse visual system. sHRP should be widely applicable to studying mechanisms of communication between a variety of cell types. PMID- 27240196 TI - A bright cyan-excitable orange fluorescent protein facilitates dual-emission microscopy and enhances bioluminescence imaging in vivo. AB - Orange-red fluorescent proteins (FPs) are widely used in biomedical research for multiplexed epifluorescence microscopy with GFP-based probes, but their different excitation requirements make multiplexing with new advanced microscopy methods difficult. Separately, orange-red FPs are useful for deep-tissue imaging in mammals owing to the relative tissue transmissibility of orange-red light, but their dependence on illumination limits their sensitivity as reporters in deep tissues. Here we describe CyOFP1, a bright, engineered, orange-red FP that is excitable by cyan light. We show that CyOFP1 enables single-excitation multiplexed imaging with GFP-based probes in single-photon and two-photon microscopy, including time-lapse imaging in light-sheet systems. CyOFP1 also serves as an efficient acceptor for resonance energy transfer from the highly catalytic blue-emitting luciferase NanoLuc. An optimized fusion of CyOFP1 and NanoLuc, called Antares, functions as a highly sensitive bioluminescent reporter in vivo, producing substantially brighter signals from deep tissues than firefly luciferase and other bioluminescent proteins. PMID- 27240198 TI - Outcome of pleurodesis using different agents in management prolonged air leakage following lung resection. AB - BACKGROUND AND AIMS: Prolonged air leaks (PAL) are a common problem after pulmonary resection. PAL can be a source of significant complications. One of the treatment options is chemical pleurodesis. MATERIAL AND METHODS: The efficiency of three methods of treatment of PAL after lung resection was evaluated. In Iodine_ group aqueous iodine solution (lat.Tinctura Jodi) was applied intrapleurally (30 patients); in Doxycycline_group (34 patients) 200 mg of Doxycyclin was given and in Drainage_group 35 patients were applied Lidocaine solution only. RESULTS: The group investigated was similar with regard to age [F = 0.04, P = 0.96] and the amount of air leakage (approx. 462 mL/min). The shortest drainage time and hospital stay was observed in the Iodine_group [10.57, P < 0.001]. However, this therapy was connected with strongly perceptible chest pain (P < 0.0001]). The number of case of pneumothorax recurrence was low and it was the same was seen in other methods of treatment [F = 0.87, P = 0.42]. Allergic reactions were not observed. The number of episodes of tachycardia, hypotension, dyspnea, pneumonia, subcutaneus empyema, fluid collection, emphysema, pneumothorax recurrence and number of re-thoracotomies were statistically similar in all three methods of treatment. CONCLUSION: Iodine pleurodesis can be considered as one of possible treatment methods of PAL after lung resection as it showed favorable results compared with Doxycycline pleurodesis or drainage alone regarding duration of air leakage, hospitalization and pneumothorax recurrence with only slightly increased pleural pain. PMID- 27240197 TI - An artificial niche preserves the quiescence of muscle stem cells and enhances their therapeutic efficacy. AB - A promising therapeutic strategy for diverse genetic disorders involves transplantation of autologous stem cells that have been genetically corrected ex vivo. A major challenge in such approaches is a loss of stem cell potency during culture. Here we describe an artificial niche for maintaining muscle stem cells (MuSCs) in vitro in a potent, quiescent state. Using a machine learning method, we identified a molecular signature of quiescence and used it to screen for factors that could maintain mouse MuSC quiescence, thus defining a quiescence medium (QM). We also engineered muscle fibers that mimic the native myofiber of the MuSC niche. Mouse MuSCs maintained in QM on engineered fibers showed enhanced potential for engraftment, tissue regeneration and self-renewal after transplantation in mice. An artificial niche adapted to human cells similarly extended the quiescence of human MuSCs in vitro and enhanced their potency in vivo. Our approach for maintaining quiescence may be applicable to stem cells isolated from other tissues. PMID- 27240199 TI - pH-Responsive mineralized nanoparticles as stable nanocarriers for intracellular nitric oxide delivery. AB - We describe a calcium carbonate (CaCO3) mineralization approach to generate pH responsive nanocarriers that can stably load S-nitrosoglutathione (GSNO) and dissolve at acidic endosomes to trigger intracellular release of nitric oxide (NO). GSNO-loaded CaCO3-mineralized nanoparticles (GSNO-MNPs) were prepared by an anionic block copolymer (PEG-Poly(l-aspartic acid))-templated mineralization. Ionic GSNO could be loaded in situ inside the CaCO3 core during the mineralization process. The stability of GSNO shielded within the crystalline CaCO3 core was greatly enhanced. The GSNO-MNPs triggered NO release at endosomal pH and an intracellular ascorbic acid level. Confocal microscopy demonstrated that the GSNO-MNPs could be dissolved at endosomal environments to release GSNO and sequentially generate NO through the GSNO reduction in the cytosol. In vitro cell experiments demonstrated that NO release by the GSNO-MNPs efficiently improved therapeutic activity of doxorubicin (DOX). PMID- 27240200 TI - Now you see, now you don't ... the influence of visual occlusion on racket and ball kinematics in the tennis serve. AB - The serve is considered amongst the most important strokes in tennis. Not surprisingly, the development of a mechanically consistent and proficient serve is paramount. Correspondingly, drills that involve players serving with their eyes closed are thought to promote mechanical consistency. The purpose of this study was therefore to contrast the effect of the removal of visual feedback on ball and racket kinematics in the serve. A 10-camera 500-Hz VICON MX motion analysis system recorded the service actions of eight elite young players as they performed three serves with eyes open and three serves with eyes closed. Removal of vision resulted in considerable differences in both racket and ball kinematics, with players failing to make contact on 16 of 24 serves. Temporally, the preparation phase was significantly shorter with eyes closed. Spatially, the ball was located 6.5 cm further to the right at zenith, and 13 cm higher at impact with eyes closed. These results highlight that the serve is not entirely pre-programmable, and that visual feedback is critical to the spatiotemporal regulation of the serve. In turn, coaches need to be aware of the implications of modifying visual feedback in serve, and ensure that the consequence is congruent with their intent. PMID- 27240201 TI - Modulation of the E. coli rpoH Temperature Sensor with Triptycene-Based Small Molecules. AB - Regulation of the heat shock response (HSR) is essential in all living systems. In E. coli, the HSR is regulated by an alternative sigma factor, sigma(32) , which is encoded by the rpoH gene. The mRNA of rpoH adopts a complex secondary structure that is critical for the proper translation of the sigma(32) protein. At low temperatures, the rpoH gene transcript forms a highly structured mRNA containing several three-way junctions, including a rare perfectly paired three way junction (3WJ). This complex secondary structure serves as a primitive but highly effective strategy for the thermal control of gene expression. In this work, the first small-molecule modulators of the E. coli sigma(32) mRNA temperature sensor are reported. PMID- 27240202 TI - Geospatial estimation of the impact of Deepwater Horizon oil spill on plant oiling along the Louisiana shorelines. AB - Stranded oil covering soil and plant stems in fragile Louisiana marshes was one of the most visible impacts of the 2010 Deepwater Horizon (DWH) oil spill. As part of the assessment of marsh injury after the DWH spill, plant stem oiling was broken into five categories (0%, 0-10%, 10-50%, 50-90%, 90-100%) and used as the independent variable for estimating death of vegetation, accelerated erosion, and other metrics of injury. The length of shoreline falling into each of these stem oiling categories was therefore a key measure of the total extent of marsh injury, and its accurate estimation is the focus of this paper. First, we used geographically-weighted logistic regression (GWR) to explore and model spatially varying relationships between stem oiling field data and secondary information (oiling exposure category) collected during shoreline surveys. We then combined GWR probability estimates with field data using indicator cokriging to predict the probability of exceeding four stem oiling thresholds (0, 10, 50, and 90%) at 50 m intervals along the Louisiana shoreline. Cross-validation using Receiver Operating Characteristic (ROC) Curves demonstrate the greater prediction accuracy of the multivariate geostatistical approach relative to either aspatial regression or indicator kriging that ignores secondary information. PMID- 27240203 TI - Landowner's perception of flood risk and preventive actions in estuarine environment: An empirical investigation. AB - Within Europe, flood and coastal risk management is undergoing a major paradigm shift as it moves from an approach dominated by investment in flood defence and control infrastructure to another one in which non-structural measures are favoured. One research challenge consists in developing a better understanding of local population risk perception and its effects on prevention and preparedness actions in order to improve social acceptability of adaptive flood risk management. Landowners' involvement in wetland management offer benefits beyond the line of their property. Accordingly, the purpose of this study is to achieve an empirical understanding of risk perception and self-protective behaviour among the landowners of the riparian marshes in the Gironde Estuary, in France. Application of the psychometric approach reveals that flood risk perception among landowners can be characterised by three synthetic variables that indicate on the degree of exposure, the sense of control and knowledge of the risk. Examining the relationships between these perceived risk dimensions and landowners' participation in water structures management provides three profiles of self protective behaviour distinguishing "vulnerable", "autonomous", and "passive" individuals. Finally, implications of our findings for the management of flood risk in estuarine environment which is often drained areas are discussed. PMID- 27240204 TI - Reduction of spatial distribution of risk factors for transportation of contaminants released by coal mining activities. AB - It is reported that water-energy nexus composes two of the biggest development and human health challenges. In the present study we presented a Risk Potential Index (RPI) model which encapsulates Source, Vector (Transport), and Target risks for forecasting surface water contamination. The main aim of the model is to identify critical surface water risk zones for an open cast mining environment, taking Jharia Coalfield, India as the study area. The model also helps in feasible sampling design. Based on spatial analysis various risk zones were successfully delineated. Monthly RPI distribution revealed that the risk of surface water contamination was highest during the monsoon months. Surface water samples were analysed to validate the model. A GIS based alternative management option was proposed to reduce surface water contamination risk and observed 96% and 86% decrease in the spatial distribution of very high risk areas for the months June and July respectively. PMID- 27240205 TI - Influence of thermal pretreatment on physical and chemical properties of kitchen waste and the efficiency of anaerobic digestion. AB - The effects of thermal pretreatment at moderate temperatures (70, 80 and 90 degrees C) and high temperatures (120, 140 and 160 degrees C) over heating durations of 10-120 min on the physical and chemical properties of kitchen waste and on anaerobic digestion were investigated. The results show that thermal pretreatment significantly enhances the solubilisation of organic compounds (chemical oxygen demand, crude proteins, crude fats and volatile fatty acids) and their biodegradability during subsequent anaerobic digestion. High temperature and long heating duration are beneficial for the release and reduction of organic compounds, and the efficiency of subsequent anaerobic digestion is improved markedly under these conditions. Moreover, both the methane production rate and methane yield were observed to increase significantly at moderate treatment temperatures when the anaerobic digestion time was longer than 50 h. PMID- 27240206 TI - Border control for stowaway alien species should be prioritised based on variations in establishment debt. AB - Border control is one of the major approaches used by countries to limit the number of organisms introduced as stowaways. However, it is not feasible to inspect all passengers, cargo and vehicles entering a country, and so efforts need to be prioritised. Here we use South Africa as a case study to assess, based on tourism and trade data and climate matching techniques, the number of stowaway species that might be introduced ('colonisation pressure') and the likelihood that once introduced, these organisms will establish ('likelihood of establishment'). These results were used to explore how the number of species that are likely to establish ('establishment debt') varies across donor regions and seasons. A simple theoretical model was then used to compare four strategies for prioritising border control inspections: no prioritisation; based on colonisation pressure; based on likelihood of establishment; and based on both colonisation pressure and likelihood of establishment. Establishment debt was greatest in southern hemisphere spring and autumn when South Africa is climatically similar to northern hemisphere countries with which there are strong, consistent trade and tourism links (i.e. colonisation pressure varied little seasonally, but likelihood of establishment did vary across the seasons). Prioritising inspections based on both colonisation pressure and the likelihood of establishment was clearly the most effective strategy, with this strategy detecting at least 6% more potential invaders than the other strategies. While there are many practical limitations to the implementation of such prioritised inspection strategies, the results highlight the importance of national and regional studies of establishment debt. PMID- 27240207 TI - Evaluation on chemical stability of lead blast furnace (LBF) and imperial smelting furnace (ISF) slags. AB - The leaching behavior of Pb and Zn from lead blast furnace (LBF) and imperial smelting furnace (ISF) slags sampled in the North of France was studied as a function of pHs and under two atmospheres (open air and nitrogen). The leaching of major elements from the slags was monitored as a function of pH (4, 5.5, 7, 8.5 and 10) under both atmospheres for different slag-water interaction times (1 day and 9 days). The leaching results were coupled with a geochemical model; Visual MINTEQ version 3.0, and a detailed morphological and mineralogical analysis was performed on the leached slags by scanning and transmission electron microscopy (SEM and TEM). Significant amounts of Ca, Fe and Zn were released under acidic conditions (pH 4) with a decrease towards the neutral to alkaline conditions (pH 7 and 10) for both LBF and ISF slags. On the other hand, Fe leachability was limited at neutral to alkaline pH for both slags. The concentrations of all elements increased gradually after 216 h compared to initial 24 h of leaching period. The presence of oxygen under open-air atmosphere not only enhanced oxidative weathering but also encouraged formation of secondary oxide and carbonate phases. Formation of carbonates and clay minerals was suggested by Visual MINTEQ which was further confirmed by SEM & TEM. The hydration and partial dissolution of hardystonite, as well as the destabilization of amorphous glassy matrix mainly contributed to the release of major elements, whereas the spinel related oxides were resistant against pH changes and atmospheres within the time frame concerned for both LBF and ISF slags. The total amount of Pb leached out at pH 7 under both atmospheres suggested that both LBF and ISF slags are prone to weathering even at neutral environmental conditions. PMID- 27240208 TI - Landscape character assessment with GIS using map-based indicators and photographs in the relationship between landscape and roads. AB - Planning and monitoring of landscapes cannot be reduced to its outstanding features, but must take into account all its characteristics. In this context, the relationship of landscape with roads is of particular importance, because roads alter the territory's environmental resources but also constitute a resource through which the individual comes into contact with the landscape. The aim of this work is to design a methodology to evaluate both the character and the scenic quality of the landscape as viewed from motorways and to provide measures to assess whether the motorway conveys the character of the landscape of which it forms part. The main contribution of this research consists of assessing landscape character through a novel series of map-based indicators and combining the findings with a photo-based method of assessing visual landscape quality. The method has been applied to a case study around a motorway in Madrid Region (Spain). Landscape character values regarding coherence, complexity, naturalness, visual scale, disturbance, historicity, and ephemera are obtained using Geographic Information Systems. Additionally, the landscape quality results derived using photographs allow the incorporation of the user's perception at a local scale. PMID- 27240209 TI - Evaluating the effectiveness of a water conservation campaign: Combining experimental and field methods. PMID- 27240210 TI - What do preschoolers know about alcohol? Evidence from the electronic Appropriate Beverage Task (eABT). AB - While much is known about alcohol use in adolescence and beyond, factors leading to such behaviors are rooted much earlier in life. To investigate what preschoolers (aged three to six) know about alcohol and adult alcohol use, we developed an electronic version (eABT) of the Appropriate Beverage Task (Zucker, Kincaid, Fitzgerald, & Bingham, 1995). Drawings of adults and children in 11 everyday scenarios and 12 photos of different beverages were shown on a touchscreen computer to 301 three- to six-year-olds (49.5% girls) from 37 preschools and seven nurseries in French-speaking Switzerland. First, the children assigned a beverage to each individual in each drawing, and then were asked if the beverage contained alcohol and if they knew its name. The results revealed that 68.1% correctly classified beer, white wine, red wine and champagne as alcoholic beverages, while 46.4% knew the beverages by name, compared to 83.2% and 73.1% for non-alcoholic beverages. Alcoholic beverages were assigned more often to men (42.2%) than to women (28.7%) or to children (12.7%), and more often to adults at a party (39.4%) than to those playing outdoors (34.7%). In conclusion, children as young as three often have some beverage-specific knowledge. From the age of four onwards, they begin to know that alcoholic beverages contain alcohol. Children aged six and over tend to have some knowledge of adult drinking norms, i.e. who is drinking and in what circumstances. PMID- 27240211 TI - Relationship between negative affect and smoking topography in heavy drinking smokers. AB - Heavy drinking smokers represent a sizeable subgroup of smokers for whom nicotine deprivation and alcohol use increases the urge to smoke in the laboratory and predicts lapses during smoking cessation. The manner in which individuals smoke a cigarette (i.e. smoking topography) provides a reliable index of smoking intensity and reinforcement, yet the effects of affect on smoking topography have not been thoroughly examined in heavy drinking smokers. The current study examined how affect and nicotine deprivation predict smoking behavior as participants (N=27) smoked one cigarette using a smoking topography device after 12-h of nicotine abstinence and after a priming dose of alcohol (target BrAC=0.06g/dl). Primary smoking topography measures were puff volume, velocity, duration, and inter-puff interval (IPI). The effect of nicotine deprivation was measured by the Minnesota Nicotine Withdrawal Scale (MNWS) and the Profile of Mood States (POMS). Measures were obtained at baseline (i.e. 12-h of nicotine abstinence and pre-alcohol) and 30-minutes after alcohol administration (i.e. peak BrAC). Results revealed post-priming negative affect significantly moderated the trajectories of puff volume, puff duration and IPI (p's<0.05) over the course of the cigarette, such that those with greater negative affect had flatter slopes for volume and duration and increasingly infrequent puffs. Our results suggest that baseline and post-priming negative affect following nicotine deprivation alters smoking patterns and increases nicotine exposure throughout a single cigarette. Future studies need to examine differential amounts of nicotine deprivation on response to alcohol and smoking in heavy drinking smokers. PMID- 27240212 TI - Perceived role of motivation and self-efficacy in smoking cessation: A secondary data analysis. AB - BACKGROUND: This secondary analysis tested whether smokers' perceived importance of willpower, ability to quit (i.e., self-efficacy), and use of treatment would prospectively predict occurrence of a quit attempt, duration of abstinence, or use of cessation aids. METHODS: Smokers (n=143) who planned to quit sometime in the next 3months were asked whether, for most smokers, a) willpower is necessary for quitting, b) willpower is sufficient for quitting, c) they could quit anytime, d) they were too addicted to quit, and e) they thought use of aids indicated weakness of character. Smokers then reported quit attempts and abstinence daily for 3months. No treatment was provided. RESULTS: The two willpower beliefs were often endorsed (78% and 60% each); the can quit any time and being too addicted beliefs were endorsed less consistently (12% and 35% each); and the belief that use of aids indicates a weakness was rarely endorsed (8%). The beliefs were only modestly correlated. Those who more strongly endorsed the two willpower beliefs or use of aids as a weakness were less likely to make a quit attempt. None of the constructs predicted duration of quit attempt. Seeing treatment as a weakness predicted less use of treatment. CONCLUSIONS: The large majority of smokers believe willpower is necessary and sufficient for quitting and this belief appears to impede quit attempts. Given this is a post-hoc finding, replication tests are needed. If replicated, clinical and media interventions to combat willpower beliefs may increase quit attempts. PMID- 27240214 TI - Systems medicine in colorectal cancer: from a mathematical model toward a new type of clinical trial. AB - Current colorectal cancer (CRC) treatment guidelines are primarily based on clinical features, such as cancer stage and grade. However, outcomes may be improved using molecular treatment guidelines. Potentially useful biomarkers include driver mutations and somatically inherited alterations, signaling proteins (their expression levels and (post) translational modifications), mRNAs, micro-RNAs and long noncoding RNAs. Moving to an integrated system is potentially very relevant. To implement such an integrated system: we focus on an important region of the signaling network, immediately above the G1-S restriction point, and discuss the reconstruction of a Molecular Interaction Map and interrogating it with a dynamic mathematical model. Extensive model pretraining achieved satisfactory, validated, performance. The model helps to propose future target combination priorities, and restricts drastically the number of drugs to be finally tested at a cellular, in vivo, and clinical-trial level. Our model allows for the inclusion of the unique molecular profiles of each individual patient's tumor. While existing clinical guidelines are well established, dynamic modeling may be used for future targeted combination therapies, which may progressively become part of clinical practice within the near future. WIREs Syst Biol Med 2016, 8:314-336. doi: 10.1002/wsbm.1342 For further resources related to this article, please visit the WIREs website. PMID- 27240215 TI - Olle Hook Lectureship 2015: The World Health Organization's paradigm shift and implementation of the International Classification of Functioning, Disability and Health in rehabilitation. AB - The World Health Organization's (WHO) paradigm shift, implied by the launch of the International Classification of Functioning, Disability and Health (ICF), is inextricably entwined with the emergence of rehabilitation as a key health strategy of the 21st century. To enable health systems to scale up rehabilitation we must spearhead the implementation of the ICF in rehabilitation towards its system-wide implementation in the healthcare system at large. In this essay, based on the Olle Hook lecture 20151, it is argued that the launch of the ICF in 2001 represents a paradigm shift, as it has enabled the WHO to more comprehensively act on its mandate and has guided WHO policies to shape the health system in response to population functioning needs. It is shown that this paradigm shift has important implications for rehabilitation, including its conceptualization and scientific methods. A prerequisite for the system-wide implementation of the ICF in clinical practice, policy, and research, is the availability of practical tools that allow for the universal and standardized description of functioning. Finally, some reflections are presented on how we may foster the system-wide implementation of the ICF by applying approaches from the implementation sciences. PMID- 27240213 TI - Methyltransferase Dnmt3a upregulates HDAC9 to deacetylate the kinase TBK1 for activation of antiviral innate immunity. AB - The DNA methyltransferase Dnmt3a has high expression in terminally differentiated macrophages; however, its role in innate immunity remains unknown. Here we report that deficiency in Dnmt3a selectively impaired the production of type I interferons triggered by pattern-recognition receptors (PRRs), but not that of the proinflammatory cytokines TNF and IL-6. Dnmt3a-deficient mice exhibited enhanced susceptibility to viral challenge. Dnmt3a did not directly regulate the transcription of genes encoding type I interferons; instead, it increased the production of type I interferons through an epigenetic mechanism by maintaining high expression of the histone deacetylase HDAC9. In turn, HDAC9 directly maintained the deacetylation status of the key PRR signaling molecule TBK1 and enhanced its kinase activity. Our data add mechanistic insight into the crosstalk between epigenetic modifications and post-translational modifications in the regulation of PRR signaling and activation of antiviral innate immune responses. PMID- 27240216 TI - Measuring personal and functional changes in prostate cancer survivors: development and validation of the FADE: data from the TROG 03.04 RADAR trial. PMID- 27240217 TI - Effects of different media on the enrichment of low numbers of Shiga toxin producing Escherichia coli in mung bean sprouts and on the development of the sprout microbiome. AB - Sprouted seeds have been implicated in a number of serious outbreaks caused by Salmonella and Shiga toxin-producing Escherichia coli. Sprouts pose a very complex challenge to bacterial pathogen enrichment and detection since they naturally contain high levels of background microflora including members of the Enterobacteriaceae. As such, the currently used method cannot ensure reliable detection of STEC in sprouts. In this study, we compared different media for the enrichment of Enterobacteriaceae in their ability to promote the growth of stressed STEC at 37 degrees C and 42 degrees C. Mung bean sprouts were spiked with low levels of STEC and their growth was recorded over time. In addition, the microbiome of mung bean sprouts was analysed before and after enrichment. Our results indicate that the growth of dry-stressed STEC is comparable in all of the tested enrichment media except for mTSB+Novobiocin and not influenced by the incubation temperature. Low levels of STEC spiked into the sprouts resuspended in media only grew to levels of around 4logcfu/ml during enrichment, which could reduce the probability of detection. Proteobacteria was the dominant phylum detected within the microbiome of non-enriched mung bean sprouts. During enrichment in EE-broth, Proteobacteria remained the most abundant phylum. In contrast, during enrichment in BPW the relative abundance of Proteobacteria decreased whereas Firmicutes increased when compared to the non-enriched mung bean sprout microbiome. The microbiome composition was not significantly influenced by the incubation temperature during enrichment in both BPW and EE broth. This is the first study to examine the microbiome on sprouted mung bean seeds during BPW and EE enrichment and relates the bacterial community composition changes to the enrichment of pathogens. PMID- 27240218 TI - Evolution of sourdough microbiota in spontaneous sourdoughs started with different plant materials. AB - The preparation of sourdough in bakeries may include the use of inocula, e.g. fruits, flowers or rumen cuts to accelerate the process of selection of suitable microorganisms. The aim of this work was to investigate the effect of these inocula on the microbial evolution in sourdoughs. First, the microbiota of nineteen traditional sourdoughs that were initially started with diverse inocula was identified. Second, de novo sourdoughs were started with plant materials and the evolution of sourdough microbiota was investigated by culture, and by high resolution melting curve quantitative PCR (HRM-qPCR). This study developed a new protocol for HRM-qPCR analysis of yeast microbiota in sourdough, and indicates this independent culture method suitable for characterization of yeasts. Microbiota of traditional sourdoughs were largely independent from the use of inoculum, however, Acetobacter spp. were identified only in sourdoughs started with apple flowers or apple pulp. In de novo sourdoughs started with plant materials, microbiota rapidly stabilized, and were characterized by Lactobacillus sanfranciscensis, Lactobacillus plantarum, Lactobacillus graminis, or Lactobacillus rossiae, and Saccharomyces cerevisiae as dominant species. Competition experiments revealed that the ecological fitness of L. plantarum, L. graminis, and L. rossiae in wheat or rye malt sourdoughs was lower when compared to L. sanfranciscensis, demonstrating that their presence in de novo sourdoughs reflects dispersal limitation. In conclusion, establishment of microbiota in de novo sourdoughs is dispersal limited. This study provides scientific support for the artisanal practice to inoculate de novo sourdoughs with flowers, berries, or related plant material. PMID- 27240219 TI - Inactivation of human norovirus and Tulane virus in simple media and fresh whole strawberries by ionizing radiation. AB - Human norovirus (NoV) is a major cause of fresh produce-associated outbreaks and human NoV in irrigation water can potentially lead to viral internalization in fresh produce. Therefore, there is a need to develop novel intervention strategies to target internalized viral pathogens while maintaining fresh produce quality. In this study electron beam (E-beam) and gamma radiation were evaluated for efficacy against a human NoV GII.4 strain and Tulane virus (TV). Virus survival following ionizing radiation treatments was determined using direct quantitative reverse transcriptase PCR (RT-qPCR), the porcine gastric mucin magnetic bead (PGM-MB) binding assay followed by RT-qPCR, and plaque assay. In simple media, a high dose of E-beam treatment was required to completely abolish the receptor binding ability of human NoV (35.3kGy) and TV (19.5-24.1kGy), as assessed using the PGM-MB binding assay. Both human NoV and TV were more susceptible to gamma irradiation than E-beam, requiring 22.4kGy to achieve complete inactivation. In whole strawberries, no human NoV or TV RNA was detected following 28.7kGy of E-beam treatment using the PGM-MB binding assay. Overall, human NoV and TV are highly resistant to ionizing radiation and therefore the technology may not be suitable to eliminate viruses in fresh produce at the currently approved levels. In addition, the PGM-MB binding assay is an improved method to detect viral infectivity compared to direct RT-qPCR. PMID- 27240220 TI - Cellular Assays with a Molecular Endpoint Measured by SAMDI Mass Spectrometry. AB - Cell-based, high-throughput screening (HTS) assays are increasingly important tools used in drug discovery, but frequently rely on readouts of gene expression or phenotypic changes and require development of specialized, labeled reporters. Here a cell-based, label-free assay compatible with HTS is introduced that can report quantitatively on enzyme activities by measuring mass changes of substrates with matrix-assisted laser desorption/ionization mass spectrometry. The assay uses self-assembled monolayers to culture cells on arrays presenting substrates, which serve as reporters for a desired enzyme activity. Each spot of cells is treated with a compound, cultured and lysed, enabling endogenous enzymes to act on the immobilized peptide substrate. It is demonstrated that the assay can measure protein tyrosine phosphatase (PTP) activity from as few as five cells and a screen is described that identifies a compound that reduces PTP activity in cell lysates. This approach offers a valuable addition to the methods available for cell-based screening. PMID- 27240221 TI - Renal cell carcinoma and malignant peritoneal mesothelioma after occupational asbestos exposure: case report. AB - Asbestos is the main causal factor for malignant mesothelioma (MM), a relatively rare and aggressive malignancy. Some epidemiological evidence suggests a role of this agent also in the etiology of renal cell carcinoma (RCC), the most common form of kidney cancer. CASE REPORT: After 7 years of asbestos exposure, a 76-year old asbestos-cement worker came to our notice with left flank pain. Diagnostic imaging disclosed a neoplasm in the upper two thirds of the left kidney, without evidence of metastases. After surgery (nephrectomy with para-aortic lymphadenectomy), histopathology revealed clear cell RCC. One year later, the patient was hospitalized for abdominal pain. Laparoscopy showed diffuse neoplastic infiltration of the peritoneum and liver. Histological and immunohistochemical examination of the bioptic samples led to the diagnosis of biphasic MM. The subject died 2 months later. Autopsy disclosed ascites and diffuse infiltration of the abdominal wall and viscera, without evidence of RCC relapse. CONCLUSIONS: This is the second reported case of association between RCC and peritoneal MM in the scientific literature. Asbestos might be involved in the causation of both malignancies. PMID- 27240222 TI - [In Process Citation]. AB - BACKGROUND: Many authors consider narrative descriptions of injuries gathered by OSH inspectors extremely important in identifying causes, setting priorities and drawing up intervention strategies. Narratives provide additional insight regarding complex behaviour, attitudes and interactions, which help to understand the decision patterns and the context of the injury. Storytelling is an effective way of sharing and remembering information. OBJECTIVE: The main aim was to describe the experience of collecting stories from injury investigation reports, backed up by systematic prevention guidelines, that will improve information sharing by means of a knowledge transfer method based on storytelling. METHODS: OSH operators from Health Units, who were invited to provide the injury stories, were enrolled through educational workshops aimed at selecting the injuries to relate following the sentinel event approach, using an effective style of writing, identifying the key elements of the story and using witnesses' narratives to study in depth the critical points identified during the investigation. RESULTS: 110 OSH operators voluntarily joined the project between 2012 and first half of 2015. 33 injury stories were collected, discussed and published on Dors' website http://www.dors.it/storiedinfortunio. CONCLUSIONS: The results show that prevention and protection measures do indeed benefit from a narrative-based approach, so that health and safety can be viewed in a more comprehensive way by facilitating knowledge improvement and sharing. PMID- 27240223 TI - [In Process Citation]. AB - AIM: To investigate the prevalence of violence towards nurses in a health care structure in the north of Italy. METHOD: An observational cross-sectional study. Data were collected anonymously with a questionnaire developed by Zampieron et al. (2010) on a stratified sample of 198 nurses working in a major Italian Hospital in the Lombardy Region. RESULTS: 43% of the sample (n=85/198) experienced violence in the previous twelve months with a mean of 4 aggressions each. Aggressors were mainly patients (53.3%) or relatives (26.7%), men (63.1%) aged between 36 and 50 years (27.9%). Of the verbal aggressions, one out of four was by a colleague or a superior. The emotional, physical and professional consequences were serious and the result of both physical and verbal violence. Nevertheless, among those who experienced aggressions, 57% did not ask for help and of those who did (43.0%) about 75% asked for help and support from their colleagues. CONCLUSIONS: Violence toward nurses exists and it is commonplace in the workplaces studied, even in the horizontal form. It is important to implement assessment and risk prevention and management measures, via specific training of nurses, and offer support for the victims and an anonymous formal report system guaranteed by the authorities. PMID- 27240224 TI - [In Process Citation]. AB - BACKGROUND: Because of their frequent occurrence, in various situations it may be appropriate to carry out screening of skin disorders in groups of workers. For this purpose the self-administered standardized questionnaires are of great use. Among the best known is the Nordic Occupational Skin Questionnaire (NOSQ-2002), which had not yet been translated and validated in Italian. OBJECTIVES: The aim of the study was to translate the NOSQ-2002 into Italian and validate the resulting Italian version. METHODS: The original English text of the NOSQ-2002 was subjected to the ISPOR task force's procedures for translation and cultural validation of questionnaires in health care. Subsequently, the Italian version was tested on a sample of 52 individuals to assess comprehensibility and reliability through analysis of internal consistency and stability over time and the predictive value of the clinical history through assessment of sensitivity and specificity in 32 subjects. RESULTS: The Italian version of the NOSQ produced proved very true to the original, needing only minor changes. From interviews on the comprehensibility of the questionnaire no significant difficulties in understanding the text were detected. The results of the evaluation of internal consistency (Cronbach's Alpha: 0.88 and 0.97) and stability (K Cohen> 0.81 in 52/57 items) indicated that the Italian version of the NOSQ may be considered reliable for the purposes proposed. There were also excellent sensitivity and specificity results, which were 86% and 89% respectively. CONCLUSIONS: The Italian version of the NOSQ presented here is appropriate for self-administration and is reliable for use in studies on skin diseases in groups of workers. PMID- 27240225 TI - [In Process Citation]. AB - BACKGROUND: Electronic cigarette smoking is spreading among health care professionals. E-cigarette smoke effects on health are not known, especially long term effects. AIM: The aim of this study was to investigate the phenomenon of electronic cigarettes as regards smoking habits, knowledge and opinions of health care professionals. METHODS: A multicentre cross-sectional descriptive study was conducted by administering an online questionnaire to all the health care professionals employed in two hospitals. RESULTS: The population included 800 employees. More than half (66.8%) of respondents believed the e-cigarette is potentially harmful and capable of attracting young people to smoking and 38.8% of respondents believed that it can serve to stop smoking. The male gender was statistically associated with tobacco and e-cigarette smoking (p=0.034). The electronic cigarette was smoked little at the work place. The population studied did not have any specific knowledge about e-cigarettes and asked for specific training; the population knew the ban on the sale of e-cigarettes to underaged and emphasized the importance of specific management guidelines. CONCLUSIONS: The results of the study show the predominantly negative opinion of health professionals concerning the use of electronic cigarette. Moreover, the study results contributed to an improvement of the smoking policies in the hospitals studied. PMID- 27240226 TI - [In Process Citation]. AB - BACKGROUND: Aggressive behaviour of patients and their relatives represent a risk factor for healthcare professionals. OBJECTIVES: The study aimed to explore the context of high risk departments (emergency department, psychiatric department) and of low risk departments (midwifery/paediatrics and outpatients clinic): a) the risk of exposure to various forms of aggression (physical, verbal, threats) by patients and their visitors towards healthcare professionals; b) how the healthcare professionals react to such aggressive events; c) the relationship between verbal aggression and healthcare professional burnout, compared to other work-related stressors. METHODS: The cross-sectional study involved 620 healthcare workers in a hospital in northern Italy (47.7% redemption rate, equivalent to 296 subjects). The data were gathered through a self-report on-line questionnaire. RESULTS: The risk of aggression, regardless of its form, was not dependent on the role of the healthcare professional, while risk was lower for older professionals and for women. The risk index for emergency department health professionals was higher than the index for professionals in the other three areas. Perceived levels of verbal aggression in the midwifery/paediatrics department were similar to those in the psychiatric department. Verbal aggression was found to be linked to the three dimensions of burnout and to a higher contribution to depersonalisation. CONCLUSIONS: the study showed that specific prevention initiatives and health profession support are also needed in clinical departments traditionally considered at low risk. PMID- 27240227 TI - Work-related activities that may contribute to musculoskeletal symptoms among dental students: validation study. AB - BACKGROUND: Dentists are exposed to occupational hazards, such as musculoskeletal disorders, in which symptoms can manifest early in clinical practice. OBJECTIVES: To estimate the reliability and validity of the Portuguese version of the "Questionnaire on work-related activities that may contribute to musculoskeletal symptoms" when applied to dental students. METHODS: 553 Brazilian students participated in the study. The one-factor structure originally proposed was tested through confirmatory factor analysis (CFA) using the indexes c2/df, CFI, GFI, and RMSEA. After observing an inadequate good fit (c2/df=7.140, CFI=0.791, GFI=0.778, RMSEA=0.129), the sample was subdivided into 3 groups and an exploratory factor analysis was conducted (EFA) (n=255). A CFA was then conducted using a subsample (n=113). To test the invariance of the obtained factorial solution, a multi-group analysis was performed using a third sample, independent from the others (n=185). The convergent (AVE) and discriminant (r2) validity were assessed. The composite reliability (CR), Cronbach's alpha coefficient (a), and intra-class correlation coefficient (r) were calculated. RESULTS: In the EFA, 3 factors were extracted: "Repetitiveness," "Working posture," and "External factors" (c2=21895.154; p<0.001; KMO=0.905; l1=6.683; l2=1.464; l3=1.277) that explained 62.82% of the total variance. The three-factor model presented an adequate good fit (n=113 and n=185) (c2/df=2.259; CFI=0.885; GFI=0.833; RMSEA=0.066). The convergent validity was compromised only for "Repetitiveness" (AVE=0.412-0.653). The discriminant validity (r2=0.333-0.428), composite reliability, internal consistency, and reproducibility were adequate for all factors (CR=0.736-0.883; a=0.747-0.876; r=0.729-0.940). CONCLUSION: The questionnaire proved to be reliable and valid for the sample of dentistry students if the three-factor model is used. PMID- 27240228 TI - Integrated Interventions for Improving Total Worker Health: A Panel Report From the National Institutes of Health Pathways to Prevention Workshop: Total Worker Health-What's Work Got to Do With It? AB - This National Institutes of Health (NIH) Pathways to Prevention workshop was cosponsored by the NIH Office of Disease Prevention; National Heart, Lung, and Blood Institute; and National Institute for Occupational Safety and Health of the Centers for Disease Control and Prevention. A multidisciplinary working group developed the agenda, and an evidence-based practice center prepared an evidence report through a contract with the Agency for Healthcare Research and Quality. During the 1.5-day workshop, experts discussed the body of evidence and participants commented during open discussions. After weighing the data from the evidence report, expert presentations, and public comments, an unbiased, independent panel prepared a draft report that identified research gaps and future research priorities. The report was posted on the NIH Office of Disease Prevention Web site for 5 weeks for public comment. This article highlights 8 recommendations critical for advancing the science of integrated interventions to improve the total health of workers. PMID- 27240229 TI - Modeling the efficacy of the extent of surgical resection in the setting of radiation therapy for glioblastoma. AB - Standard therapy for glioblastoma (GBM) includes maximal surgical resection and radiation therapy. While it is established that radiation therapy provides the greatest survival benefit of standard treatment modalities, the impact of the extent of surgical resection (EOR) on patient outcome remains highly controversial. While some studies describe no correlation between EOR and patient survival even up to total resection, others propose either qualitative (partial versus subtotal versus complete resection) or quantitative EOR thresholds, below which there is no correlation with survival. This work uses a mathematical model in the form of a reaction-diffusion partial differential equation to simulate tumor growth and treatment with radiation therapy and surgical resection based on tumor-specific rates of diffusion and proliferation. Simulation of 36 tumors across a wide spectrum of diffusion and proliferation rates suggests that while partial or subtotal resections generally do not provide a survival advantage, complete resection significantly improves patient outcomes. Furthermore, our model predicts a tumor-specific quantitative threshold below which EOR has no effect on patient survival and demonstrates that this threshold increases with tumor aggressiveness, particularly with the rate of proliferation. Thus, this model may serve as an aid for determining both when surgical resection is indicated as well as the surgical margins necessary to provide clinically significant improvements in patient survival. In addition, by assigning relative benefits to radiation and surgical resection based on tumor invasiveness and proliferation, this model confirms that (with the exception of the least aggressive tumors) the survival benefit of radiation therapy exceeds that of surgical resection. PMID- 27240230 TI - Hydrogen production from biomass gasification using biochar as a catalyst/support. AB - Biochar is a promising catalyst/support for biomass gasification. Hydrogen production from biomass steam gasification with biochar or Ni-based biochar has been investigated using a two stage fixed bed reactor. Commercial activated carbon was also studied as a comparison. Catalyst was prepared with an impregnation method and characterized by X-ray diffraction, specific surface and porosity analysis, X-ray fluorescence and scanning electron micrograph. The effects of gasification temperature, steam to biomass ratio, Ni loading and bio char properties on catalyst activity in terms of hydrogen production were explored. The Ni/AC catalyst showed the best performance at gasification temperature of 800 degrees C, S/B=4, Ni loading of 15wt.%. Texture and composition characterization of the catalysts suggested the interaction between volatiles and biochar promoted the reforming of pyrolysis volatiles. Cotton-char supported Ni exhibited the highest activity of H2 production (64.02vol.%, 92.08mgg(-1) biomass) from biomass gasification, while rice-char showed the lowest H2 production. PMID- 27240231 TI - Biodiesel production from municipal secondary sludge. AB - In the present study, feasibility of biodiesel production from freeze dried sewage sludge was studied and its yield was enhanced by optimization of the in situ transesterification conditions (temperature, catalyst and concentration of sludge solids). Optimized conditions (45 degrees C, 5% catalyst and 0.16g/mL sludge solids) resulted in a 20.76+/-0.04% biodiesel yield. The purity of biodiesel was ascertained by GC-MS, FT-IR and NMR ((1)H and (13)C) spectroscopy. The biodiesel profile obtained revealed the predominance of methyl esters of fatty acids such as oleic, palmitic, myristic, stearic, lauric, palmitoleic and linoleic acids indicating potential use of sludge as a biodiesel feedstock. PMID- 27240232 TI - Influence of zeolite and lime as additives on greenhouse gas emissions and maturity evolution during sewage sludge composting. AB - This study aimed to evaluate the role of different amount of zeolite with low dosage of lime amendment on the greenhouse gas (GHGs) emission and maturity during the dewatered fresh sewage sludge (DFSS) composting. The evolution of CO2, CH4, NH3 and N2O and maturity indexes were monitored in five composting mixtures prepared from DFSS mixed with wheat straw, while 10%, 15% and 30% zeolite+1% lime were supplemented (dry weight basis of DFSS) into the composting mass and compared with treatment only 1% lime amended and control without any amendment. The results showed that addition of higher dosage of zeolite+1% lime drastically reduce the GHGs emissions and NH3 loss. Comparison of GHGs emissions and compost quality showed that zeolite amended treatments were superior than control and 1% lime amended treatments. Therefore, DFSS composting with 30% zeolite+1% lime as consortium of additives were found to emit very less amount of GHGs and gave the highest maturity than other treatments. PMID- 27240234 TI - Effect of microbial inoculant or molasses on fermentative quality and aerobic stability of sawdust-based spent mushroom substrate. AB - In the first experiment, the effect of two novel Lactobacillus plantarum strains was studied on the fermentation of spent mushroom substrate (SMS) through 10d of ensiling. Based on lactic acid production and lactic acid bacteria population, L. plantarum KU5 was identified as the best strain for fermentation with a 5-L bag silo. Spent mushroom substrate was ensiled with 0.5% (v/w) L. plantarum KU5 without or with 5% molasses. Silages treated with microbial inoculant and molasses had the lowest pH and the highest fermentative odors. In a second set of experiments similar to the above 5-L silo study, the simultaneous application of L. plantarum KU5 inoculant and molasses to 80-L silos improved fermentability and aerobic stability of SMS silages. For similar treatment using ton-bag silos, aerobic stability decreased and NH3-N content increased dramatically. In conclusion, sawdust-based SMS for animal use was successfully ensiled with L. plantarum KU5 inoculant and molasses. PMID- 27240233 TI - Enhanced phosphorus flux from overlying water to sediment in a bioelectrochemical system. AB - This report proposed a novel technique for the regulation of phosphorus flux based on a bioelectrochemical system. In the simulated water system, a simple in situ sediment microbial fuel cell (SMFC) was constructed. SMFC voltage was increased with time until it was 0.23V. The redox potential of the sediment was increased from -220mV to -178mV during the process. Phosphorus concentration in the water system was decreased from 0.1mg/L to 0.01mg/L, compared with 0.09mg/L in the control. The installation of a SMFC produced an external current and internal circuit, which promoted the transfer of phosphate in overlying water to the sediment, enhanced the microbial oxidation of Fe(2+), and increased the formation of stable phosphorus in sediment. In conclusion, phosphorus flux from the overlying water to sediment was enhanced by SMFC, which has the potential to be used for eutrophication control of water bodies. PMID- 27240235 TI - Start-up and microbial communities of a simultaneous nitrogen removal system for high salinity and high nitrogen organic wastewater via heterotrophic nitrification. AB - In this study, a simultaneous nitrogen removal system for high salinity and high nitrogen organic wastewater was developed in a pressurized biofilm reactor. The result showed that under the air supply rate of 200Lh(-1), salinity of 3.0+/ 0.2%, organic load of 10kgCODm(-3)d(-1) and nitrogen loading of 0.185kgm(-3)d( 1), the reactor started up rapidly and performed stably after 30days operation. Meanwhile, a simultaneous COD and nitrogen removal was achieved in the single stage reactor, with COD, NH4(+)-N and TN removal efficiency of 97%, 99% and 98%, respectively. Denaturing gradient gel electrophoresis profile demonstrated that simultaneous nitrogen removal could be achieved through heterotrophic nitrification-aerobic denitrification, and the pivotal microorganisms were Flavobacterium phragmitis and Paracoccus denitrificans. The microbial community of salt-tolerant halophilic microorganisms was developed successfully. This study can provide a more efficient and feasible solution to treat high salinity organic wastewater. PMID- 27240236 TI - Degradation of synthetic pollutants in real wastewater using laccase encapsulated in core-shell magnetic copper alginate beads. AB - Immobilization of laccase has been highlighted to enhance their stability and reusability in bioremediation. In this study, we provide a novel immobilization technique that is very suitable to real wastewater treatment. A perfect core shell system composing copper alginate for the immobilization of laccase (Lac beads) was produced. Additionally, nFe2O3 was incorporated for the bead recycling through magnetic force. The beads were proven to immobilize 85.5% of total laccase treated and also to be structurally stable in water, acetate buffer, and real wastewater. To test the Lac-beads reactivity, triclosan (TCS) and Remazol Brilliant Blue R (RBBR) were employed. The Lac-beads showed a high percentage of TCS removal (89.6%) after 8h and RBBR decolonization at a range from 54.2% to 75.8% after 4h. Remarkably, the pollutants removal efficacy of the Lac-beads was significantly maintained in real wastewater with the bead recyclability, whereas that of the corresponding free laccase was severely deteriorated. PMID- 27240237 TI - Optimization of ferric chloride concentration and pH to improve both cell growth and flocculation in Chlorella vulgaris cultures. Application to medium reuse in an integrated continuous culture bioprocess. AB - Combined effect of ferric chloride and pH on Chlorella vulgaris growth and flocculation were optimized using DoE. Afterwards, an integrated bioprocess for microalgae cultivation and harvesting conceived as a sole step was run in continuous operation mode. Microalgae concentration in a 2L-photobioreactor was about 0.5gL(-1) and the efficiency of flocculation in the coupled sedimentation tank was about 95%. Dewatered microalgae reached a biomass concentrations increase about 50-fold, whereas it was only about 0.02gL(-1) in the clarified medium. Then, the reuse of the clarified medium recovered was further evaluated. The clarified medium was reused without any further nutrient supplementation, whereas a second round of medium reuse was performed after supplementation of main nutrients (phosphate-sulfate-nitrate), micronutrients and ferric chloride. The medium reuse strategy did not affect cell growth and flocculation. Consequently, the reuse of medium reduces the nutrients requirements and the demand for water, and therefore the production costs should be reduced accordingly. PMID- 27240238 TI - Seasonal variation of chemical composition and biomethane production from the brown seaweed Ascophyllum nodosum. AB - Ascophyllum nodosum, an abundant Irish brown seaweed, shows significant seasonal variation in chemical composition and biogas production. The polyphenol content is shown to be a more important factor in biogas production than ash content. High polyphenol content in summer months adversely affected biogas production; suggesting two potential harvest dates, March and October. A. nodosum harvested in October showed a relatively low level of polyphenols (2% of TS) and ash (23% of volatile solids), and exhibited a specific methane yield of 215LCH4kgVS(-1), which was 44% of theoretical yield. The highest yield per wet weight of 47m(3)CH4t(-1) was achieved in October, which is 2.9 times higher than the lowest value (16m(3)CH4t(-1)), obtained in December. The gross energy yield of A. nodosum based on the optimal biogas production can achieve 116GJha(-1)yr(-1) in October. PMID- 27240239 TI - Simultaneous fermentation of glucose and xylose at elevated temperatures co produces ethanol and xylitol through overexpression of a xylose-specific transporter in engineered Kluyveromyces marxianus. AB - Engineered Kluyveromyces marxianus strains were constructed through over expression of various transporters for simultaneous co-fermentation of glucose and xylose. The glucose was converted into ethanol, whereas xylose was converted into xylitol which has higher value than ethanol. Over-expressing xylose-specific transporter ScGAL2-N376F mutant enabled yeast to co-ferment glucose and xylose and the co-fermentation ability was obviously improved through increasing ScGAL2 N376F expression. The production of glycerol was blocked and acetate production was reduced by disrupting gene KmGPD1. The obtained K. marxianus YZJ119 utilized 120g/L glucose and 60g/L xylose simultaneously and produced 50.10g/L ethanol and 55.88g/L xylitol at 42 degrees C. The yield of xylitol from consumed xylose was over 98% (0.99g/g). Through simultaneous saccharification and co-fermentation at 42 degrees C, YZJ119 produced a maximal concentration of 44.58g/L ethanol and 32.03g/L xylitol or 29.82g/L ethanol and 31.72g/L xylitol, respectively, from detoxified or non-detoxified diluted acid pretreated corncob. PMID- 27240240 TI - Modelling a demand driven biogas system for production of electricity at peak demand and for production of biomethane at other times. AB - Four feedstocks were assessed for use in a demand driven biogas system. Biomethane potential (BMP) assays were conducted for grass silage, food waste, Laminaria digitata and dairy cow slurry. Semi-continuous trials were undertaken for all feedstocks, assessing biogas and biomethane production. Three kinetic models of the semi-continuous trials were compared. A first order model most accurately correlated with gas production in the pulse fed semi-continuous system. This model was developed for production of electricity on demand, and biomethane upgrading. The model examined a theoretical grass silage digester that would produce 435kWe in a continuous fed system. Adaptation to demand driven biogas required 187min to produce sufficient methane to run a 2MWe combined heat and power (CHP) unit for 60min. The upgrading system was dispatched 71min following CHP shutdown. Of the biogas produced 21% was used in the CHP and 79% was used in the upgrading system. PMID- 27240241 TI - Motor cortex excitability in attention-deficit hyperactivity disorder (ADHD): A systematic review and meta-analysis. AB - BACKGROUND: The core characteristic of attention deficit hyperactivity disorder (ADHD) is a persistent pattern of inattention and/or hyperactivity-impulsivity that causes developmental or functional impairment. Observational studies have investigated neurophysiological features in individuals with ADHD using transcranial magnetic stimulation (TMS) to identify which intracortical mechanisms are associated with the symptoms. This systematic review aimed to assess the quality of these studies and present meta-analyses of the available neurophysiological measures. METHODS: This systematic review searched the PubMed, Scopus, Web of Science, with no date restrictions. The methodological quality of observational studies was assessed utilizing the Agency for Healthcare Research and Quality (AHRQ) criteria for observational studies. The analysis of the mean and standard deviation of the neurophysiological measurements was performed using the RevMan software version 5.0 for the meta-analyses of studies. RESULTS: Nine publications that met the inclusion criteria were evaluated. Most of the AHRQ criteria were satisfied, indicating the good quality of the studies. On comparing subjects with ADHD and controls, the forest plot profiles were similar in respect to the resting motor threshold (RMT), and silent period (SP) but a significant difference was found for short intracortical inhibition (SICI). CONCLUSION: This meta-analysis found reduced SICI in individuals with ADHD, when compared with controls. Given the small number of studies, it is important that further studies be conducted for a more robust conclusion to be formed. PMID- 27240242 TI - Micelle co-assembly in surfactant/ionic liquid mixtures. AB - HYPOTHESIS: The phase behavior of amphiphiles is known to depend on their solvent environment. The organic character of ionic liquids suggested the possibility to tune surfactant aggregation, even in the absence of water, by selection of appropriate ionic liquid chemistry. To that end the behavior of the surfactant sodium dodecylsulfate in a chemically similar imidazolium ionic liquid, 1-ethyl-3 methyl imidazolium ethylsulfate, was explored. EXPERIMENTS: The solubility of sodium dodecylsulfate in 1-ethyl-3-methyl imidazolium ethylsulfate was determined, establishing the Krafft temperature. Tensiometry was performed to obtain interfacial properties such as the surface excess and area per molecule. Pulsed-field gradient spin-echo NMR was used to determine the diffusion coefficients of all the major species, including micelles, as a function of surfactant concentration. Importantly, all three methods provided consistent values for the critical micelle concentration. FINDINGS: Analysis of tensiometry data suggests, and is confirmed by NMR results, that the ionic liquid ions are incorporated along with surfactants into micelles, revealing a complex micellization behavior. In light of these findings past studies with ternary mixtures of surfactants, ionic liquids, and water may merit additional scrutiny. Given the large number of ionic liquids, this work suggests opportunities to further control micelle formation and properties. PMID- 27240243 TI - NiCo2S4 nanoparticles anchored on reduced graphene oxide sheets: In-situ synthesis and enhanced capacitive performance. AB - A facile hydrothermal process is developed for the synthesis of NiCo2S4/reduced graphene oxide (RGO) hybrid and NiCo2S4 hollow spheres. The morphology and microstructure are characterized by powder X-ray diffraction (XRD), Raman spectra, transmission electron microscopy (TEM), high-resolution TEM (HRTEM), selected area electron diffraction (SAED), and energy dispersive spectrometry (EDS) mapping. NiCo2S4 nanoparticles with the diameter of about 20-30nm were in situ grown on RGO sheets. NiCo2S4 hollow spheres were obtained with the diameter of about 300-400nm and the width of shell in the range of 30-40nm in the absence of graphene oxide (GO). GO as a substrate material can offer abundant active sites for nucleation of NiCo2S4 and can be reduced to RGO, providing excellent electron transfer path and high conduction, which enable the fast surface redox reaction. Supercapacitor based on NiCo2S4/RGO hybrid shows a high specific capacitance of 1804.7F/g at a current density of 0.5A/g. Due to the high capacitive performance of NiCo2S4/RGO hybrid, the NiCo2S4/RGO//AC asymmetric supercapacitor (ASC) possesses an extended voltage window of 1.5V, high energy density of 24.4Wh/kg at a power density of 750W/kg in 2mol/LKOH electrolyte. NiCo2S4/RGO hybrid can serve as a promising electrode material for high performance supercapacitors. PMID- 27240244 TI - Carbon functionalized mesoporous silica-based gas sensors for indoor volatile organic compounds. AB - Indoor organic gaseous pollution is a global health problem, which seriously threats the health and life of human all over the world. Hence, it is important to fabricate new sensing materials with high sensitivity and efficiency for indoor volatile organic compounds. In this study, a series of ordered mesoporous silica-based nanocomposites with uniform carbon coatings on the internal surface of silica mesopore channels were synthesized through a simple template carbonization strategy. The obtained mesoporous silica-carbon nanocomposites not only possess ordered mesostructures, high surface areas (up to ~759m(2)g(-1)), large and tunable pore sizes (2.6-10.2nm), but also have the improved hydrophobicity and anti-interference capability to environmental humidity. The sensing performances of the mesoporous silica-carbon nanocomposites to volatile organic compounds, such as ethylbenzene, methylbenzene, benzene, methanol, acetone, formaldehyde, dichloromethane and tetrahydrofuran, were systematically investigated. The relationships between the sensing performances and their properties, including mesostructures, surface areas, pore sizes, carbon contents and surface hydrophilic/hydrophobic interactions, have been achieved. The mesoporous silica-carbon nanocomposites with hexagonal mesostructure exhibit outstanding performance at room temperature to benzene and acetone with high responses, short response (2-3s) and recovery (16-19s) time, strong anti interference to environmental humidity, and long-term stability (less than ~5% loss of the frequency shifts after 42days). Therefore, the obtained mesoporous silica-carbon nanocomposites have a hopeful prospect in the field of environmental air quality monitoring. PMID- 27240245 TI - Coatings of active and heat-resistant cobalt-aluminium xerogel catalysts. AB - The application of catalytically coated metallic foams in catalytic processes has a high potential for exothermic catalytic reactions such as CO2 methanation or Fischer-Tropsch synthesis due to good heat conductivity, improved turbulent flow properties and high catalyst efficiencies. But the preparation of homogenous catalyst coats without pore blocking is challenging with conventional wash coating techniques. Here, we report on a stable and additive free colloidal CoAlOOH suspension (sol) for the preparation of catalytically active Co/Al2O3 xerogel catalysts and coatings. Powders with 18wt% Co3O4 prepared from this additive free synthesis route show a catalytic activity in Fischer-Tropsch synthesis and CO2 methanation which is similar to a catalyst prepared by incipient wetness impregnation (IWI) after activating the material under flowing hydrogen at 430 degrees C. Yet, the xerogel catalyst exhibits a much higher thermal stability as compared to the IWI catalyst, as demonstrated in catalytic tests after different heat agings between 430 degrees C and 580 degrees C. It was also found that the addition of polyethylene glycol (PEG) to the sol influences the catalytic properties of the formed xerogels negatively. Only non-reducible cobalt spinels were formed from a CoAlOOH sol with 20wt% PEG. Metallic foams with pores sizes between 450 and 1200MUm were coated with the additive free CoAlOOH sol, which resulted in homogenous xerogel layers. First catalytic tests of the coated metal foams (1200MUm) showed good performance in CO2 methanation. PMID- 27240246 TI - Endoscopic therapy plus beta blocker is still the first choice for prevention of variceal rebleeding? PMID- 27240247 TI - Revisiting the crisis in Freud's libido theory and Abraham's concept of the oral sadistic phase as a way out of it. AB - The now available unabridged correspondence between Freud and Abraham leads to a re-evaluation of the significance of Abraham's work. The author proposes the thesis that clinical observations by Karl Abraham of the ambivalence of object relations and the destructive-sadistic aspects of orality have an important influence on the advancement of psychoanalytical theory. The phantasy problem of the Wolf Man and the question of the pathogenic relevance of early actual, or merely imagined traumata led Freud to doubt the validity of his theory. He attempted repeatedly to solve this problem using libido theory, but failed because of his problematic conception of oral erotics. The pathogenic effect of presymbolic traumatizations cannot be demonstrated scientifically because of the still underdeveloped brain in the early stage of the child's development. Consequently, the important empirical evidence of a scientific neurosis theory could not be provided. A revision of the theory of the instincts thus became necessary. With Abraham's clinical contributions and other pathologic evidence, Freud was, with some reservation, forced to modify his idea of oral erotics by ascribing to it a status of a merely constructed and fictive phase of oral organization. A solution was eventually facilitated via recognition of non-erotic aggression and destruction, thereby opening libido theory to fundamental revisions. Driven by the desire to develop a scientific theory, Freud initially had, in his first theory of the instincts, assumed a strongly causal deterministic view on Psychic Function. His third revision of theory of the instincts, Beyond the Pleasure Principle including the death instinct hypothesis, considered the hermeneutic aspect of psychoanalytic theory, which had previously existed only implicitly in his theory. Further development of the death instinct hypothesis by Melanie Klein and her successors abandoned quantitative-economic and causal-deterministic principles, and instead focused on the practical utility of the psychoanalytic theory. PMID- 27240249 TI - [62-year old woman with itching skin tumor]. PMID- 27240248 TI - New perspectives on the conservative management of osteoradionecrosis of the mandible: A literature review. AB - Over the last decades, several therapeutic options were considered in the treatment of the osteoradionecrosis (ORN) of the mandible, including supportive measures, ultrasound therapy, corticosteroids, hyperbaric oxygen, surgical resection with reconstruction, and, more recently, drugs capable of reversing the fibroatrophic process. Once established, the ORN does not spontaneously disappear and a standard treatment has not yet been defined. The clear clinical effectiveness of hyperbaric oxygen therapy (HBOT) varies according to the literature and there are some economic/logistic issues to be considered; the triplet tocopherol/pentoxifylline/clodronate demands greater evidence from randomized clinical trials and also resilience from the patient, given the long treatment duration and its possible side effects. Controversy around the ideal treatment of the initial stage ORN of the mandible persists. More rigorous randomized prospective trials are essential. The purpose of this article was to review the relevant literature on the physiopathology of ORN of the mandible and discuss the new perspectives of its conservative treatment. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: 1708-1716, 2016. PMID- 27240250 TI - Superporous Poly(ethylene glycol) Diacrylate Cryogel with a Defined Elastic Modulus for Prostate Cancer Cell Research. AB - The physical and mechanical properties of the tumor microenvironment are crucial for the growth, differentiation and migration of cancer cells. However, such microenvironment is not found in the geometric constraints of 2D cell culture systems used in many cancer studies. Prostate cancer research, in particular, suffers from the lack of suitable in vitro models. Here a 3D superporous scaffold is described with thick pore walls in a mechanically stable and robust architecture to support prostate tumor growth. This scaffold is generated from the cryogelation of poly(ethylene glycol) diacrylate to produce a defined elastic modulus for prostate tumor growth. Lymph node carcinoma of the prostate (LNCaP) cells show a linear growth over 21 d as multicellular tumor spheroids in such a scaffold with points of attachments to the walls of the scaffold. These LNCaP cells respond to the growth promoting effects of androgens and demonstrate a characteristic cytoplasmic-nuclear translocation of the androgen receptor and androgen-dependent gene expression. Compared to 2D cell culture, the expression or androgen response of prostate cancer specific genes is greatly enhanced in the LNCaP cells in this system. This scaffold is therefore a powerful tool for prostate cancer studies with unique advantages over 2D cell culture systems. PMID- 27240251 TI - Methods and insights from the characterization of osteoprogenitor cells of bats (Mammalia: Chiroptera). AB - Osteoprogenitor cells contribute to the development and maintenance of skeletal tissues. Bats are unique model taxa whose cellular processes are poorly understood, especially in regards to skeletal biology. Forelimb bones of bats, unlike those of terrestrial mammals, bend during flight and function in controlled deformation. As a first step towards understanding the molecular processes governing deposition of this flexible bone matrix, we provide the first method for isolation and differentiation of cell populations derived from the bone marrow and cortical bone of bats, and compare results with those harvested from C57BL/6J mice. Osteogenic capacity of these cells was assessed via absolute quantitative real-time PCR (qPCR) and through quantification of in vitro mineral deposition. Results indicate the differentiated bone cells of bats display significantly lower gene expression of known osteogenic markers (Runt-related transcription factor (RUNX2), osteocalcin (BGLAP) and osterix (SP7)), and deposit a less-mineralized matrix compared with murine controls. By characterizing the in vitro performance of osteoprogenitor cells throughout differentiation and matrix production, this study lays the ground work for in vitro manipulations of bat stem and osteoprogenitor cells and extends our understanding of the cellular diversity across mammals that occupy different habitats. PMID- 27240252 TI - The mesenchymal transcription factor SNAI-1 instructs human liver specification. AB - Epithelial-mesenchymal transition (EMT) and the mesenchymal-epithelial transition (MET) are processes required for embryo organogenesis. Liver develops from the epithelial foregut endoderm from which the liver progenitors, hepatoblasts, are specified. The migrating hepatoblasts acquire a mesenchymal phenotype to form the liver bud. In mid-gestation, hepatoblasts mature into epithelial structures: the hepatocyte cords and biliary ducts. While EMT has been associated with liver bud formation, nothing is known about its contribution to hepatic specification. We previously established an efficient protocol from human embryonic stem cells (hESC) to generate hepatic cells (Hep cells) resembling the hepatoblasts expressing alpha-fetoprotein (AFP) and albumin (ALB). Here we show that Hep cells express both epithelial (EpCAM and E-cadherin) and mesenchymal (vimentin and SNAI 1) markers. Similar epithelial and mesenchymal hepatoblasts were identified in human and mouse fetal livers, suggesting a conserved interspecies phenotype. Knock-down experiments demonstrated the importance of SNAI-1 in Hep cell hepatic specification. Moreover, ChIP assays revealed direct binding of SNAI-1 in the promoters of AFP and ALB genes consistent with its transcriptional activator function in hepatic specification. Altogether, our hESC-derived Hep cell cultures reveal the dual mesenchymal and epithelial phenotype of hepatoblast-like cells and support the unexpected transcriptional activator role of SNAI-1 in hepatic specification. PMID- 27240254 TI - Plaque stabilizing effects of apolipoprotein A-IV. AB - BACKGROUND AND AIMS: Apolipoprotein (apo) A-IV, the third most abundant HDL associated protein, is atheroprotective and shares similar properties as apoA-I. We have reported previously that apoA-I, the most abundant apolipoprotein in HDL, inhibits plaque disruption in a mouse model. We aimed at examining the effects of apoA-IV on markers of plaque stability in vivo. METHODS: Plaques within brachiocephalic arteries of 16-week old apoE-knockout C57BL/6 mice were examined for changes in composition after 10 weeks on a high-fat diet (HFD). The animals received twice-weekly injections of human lipid-free apoA-IV (1 mg/kg, n = 31) or PBS (n = 32) during the 9th and 10th weeks of the HFD. RESULTS: In the apoA-IV treated mice, there were significantly fewer hemorrhagic plaque disruptions (9/31 vs. 18/32, p < 0.05), thicker fibrous caps, smaller lipid cores, a lower macrophage:SMC ratio, less MMP-9 protein, more collagen, and fewer proliferating cells. In the plaques of mice given apoA-IV, MCP-1, VCAM-1, and inducible NOS were also significantly lower. Based on the percentage of cleaved PARP-positive and TUNEL-positive plaque nuclei, apoA-IV reduced apoptosis. in HMDMs, apoA-IV reduced MMP-9 mRNA expression by half, doubled mRNA levels of TIMP1 and decreased MMP-9 activity. CONCLUSIONS: ApoA-IV treatment is associated with a more stable plaque phenotype and a reduced incidence of acute disruptions in this mouse model. PMID- 27240255 TI - Super-heptazethrene. AB - The challenging synthesis of a laterally extended heptazethrene molecule, the super-heptazethrene derivative SHZ-CF3, is reported. This molecule was prepared using a strategy involving a multiple selective intramolecular Friedel-Crafts alkylation followed by oxidative dehydrogenation. Compound SHZ-CF3 exhibits an open-shell singlet diradical ground state with a much larger diradical character compared with the heptazethrene derivatives. An intermediate dibenzo-terrylene SHZ-2H was also obtained during the synthesis. This study provides a new synthetic method to access large-size quinoidal polycyclic hydrocarbons with unique physical properties. PMID- 27240253 TI - The western-type diet induces anti-HMGB1 autoimmunity in Apoe(-/-) mice. AB - BACKGROUND AND AIMS: Anti-HMGB1 autoimmunity plays a role in systemic lupus erythematosus (SLE). Because SLE increases atherosclerosis, we asked whether the same autoimmunity might play a role in atherogenesis. METHODS: We looked for the induction of HMGB1-specific B and T cell responses by a western-type diet (WTD) in the Apoe(-/-) mouse model of atherosclerosis. We also determined whether modifying the responses modulates atherosclerosis. RESULTS: In the plasma of male Apoe(-/-) mice fed WTD, the level of anti-HMGB1 antibodies (Abs) was detected at ~50 MUg/ml, which was ~6 times higher than that in either Apoe(-/-) mice fed a normal chow or Apoe(+/+) mice fed WTD (p <= 0.0005). The Abs were directed largely toward a novel, dominant epitope of HMGB1 named HMW4; accordingly, compared with chow-fed mice, WTD-fed Apoe(-/-) mice had more activated HMW4 reactive B and T cells (p = 0.005 and p = 0.01, respectively). Compared with mock immunized mice, Apoe(-/-) mice immunized with HMW4 along with an immunogenic adjuvant showed proportional increases in anti-HMW4 IgG and IgM Abs, HMW4 reactive B-1 and B-2 cells, and HMW4-reactive Treg and Teff cells, which was associated with ~30% increase in aortic arch lesions (p <= 0.01) by two methods. In contrast, Apoe(-/-) mice immunized with HMW4 using a tolerogenic adjuvant showed preferential increases in anti-HMW4 IgM (over IgG) Abs, HMW4-reactive B-1 (over B-2) cells, and HMW4-specific Treg (over Teff) cells, which was associated with ~40% decrease in aortic arch lesions (p <= 0.03). CONCLUSIONS: Anti-HMGB1 autoimmunity may potentially play a role in atherogenesis. PMID- 27240256 TI - Data-driven hypothesis weighting increases detection power in genome-scale multiple testing. AB - Hypothesis weighting improves the power of large-scale multiple testing. We describe independent hypothesis weighting (IHW), a method that assigns weights using covariates independent of the P-values under the null hypothesis but informative of each test's power or prior probability of the null hypothesis (http://www.bioconductor.org/packages/IHW). IHW increases power while controlling the false discovery rate and is a practical approach to discovering associations in genomics, high-throughput biology and other large data sets. PMID- 27240258 TI - Cadmium and other elements in tissues from four ungulate species from the Mackenzie Mountain region of the Northwest Territories, Canada. AB - Tissue samples from four ungulate species from the south Mackenzie Mountain region of the Northwest Territories (NT), Canada, were analysed for stable and radioactive elements and (15)N and (13)C stable isotopes. Elevated Cd concentrations in moose (Alces americanus) kidney have been observed in the region and are a health care concern for consumers of traditional foods. This study examined the factors associated with, and potential renal effects from, the accumulation of cadmium, and interactions with other elements in four sympatric ungulate species. Mean renal Cd concentration was highest in moose (48.3mg/kg ww), followed by mountain caribou (Rangifer tarandus caribou) (13.9mg/kg ww) and mountain goat (Oreamnos americanus) (5.78mg/kg ww). No local sources of Cd were evident and the elevated levels in moose are considered to be natural in origin. Conversely, total Hg concentration was significantly higher in mountain caribou kidney (0.21mg/kg ww) than in moose (0.011mg/kg ww). (134)Cs (t1/2=2.1 y) in mountain goat and Dall's sheep (Ovis dalli) muscle is evidence of deposition from the Fukushima reactor accident in 2011. (137)Cs (t1/2=30.2 y) in all four ungulates is primarily a remnant of the nuclear weapons tests of the 1960s. The levels of both nuclides are low and the risk to the animals and people consuming them is negligible. Stable isotope delta(15)N and delta(13)C signatures in muscle showed a separation between the mountain caribou, with a lichen-dominated diet, and moose, which browse shrubs and forbs. Isotope signatures for mountain goat and Dall's sheep showed generalist feeding patterns. Differences in elemental and radionuclide levels between species were attributed to relative levels of metal accumulation in the different food items in the diets of the respective species. Kidneys from each species showed minor histological changes in the proximal tubule and glomerulus, although glomerular changes were rare and all changes were rare in mountain goat kidney. Kidney function was not expected to be affected in any species. Provisional Monthly Intake recommendations from the WHO indicate that Cd in moose organs will continue to be a public health care concern. However, traditional foods continue to be an important nutritional component of northern diets, particularly in consideration of the shift towards store-bought food. PMID- 27240257 TI - Quantitative assessment of fluorescent proteins. AB - The advent of fluorescent proteins (FPs) for genetic labeling of molecules and cells has revolutionized fluorescence microscopy. Genetic manipulations have created a vast array of bright and stable FPs spanning blue to red spectral regions. Common to autofluorescent FPs is their tight beta-barrel structure, which provides the rigidity and chemical environment needed for effectual fluorescence. Despite the common structure, each FP has unique properties. Thus, there is no single 'best' FP for every circumstance, and each FP has advantages and disadvantages. To guide decisions about which FP is right for a given application, we have quantitatively characterized the brightness, photostability, pH stability and monomeric properties of more than 40 FPs to enable straightforward and direct comparison between them. We focus on popular and/or top-performing FPs in each spectral region. PMID- 27240259 TI - The publication rates of abstracts presented at the Turkish Respiratory Society (TUSAD) annual congress: adequate or not? AB - OBJECTIVE: In this study, we aimed to determine the publication status of the abstracts presented at the Turkish Respiratory Society Congress between 2011 and 2014. METHODS: The abstracts were classified according to presentation type (oral presentations, poster discussion, etc.), study type, study design, topic, publication status, time interval between the presentation and the publication date, and the journal in which the article was published. The conversion rate of presentations into full-text articles in peer-reviewed journals were surveyed through Elsevier's Scopus. RESULTS: The total number of abstracts submitted in the congress was 2 009. In terms of study type, the majority of abstracts were case reports (56.4%) and the remainder was original research. Totally, 179 abstracts were published in an indexed journal with an overall publication rate of 8.9%. 18.3% of oral presentations were converted into full-text article. Publication rates according to study types were 14.8% for original researches and 4.4% for case reports. The first three subspecialties with the highest publication rates were "sleep related breathing disorders" (16.9%), "interventional pulmonology" (16.7%) and "pleural diseases" (15.2%). Median publication/acceptance time was 8.0 months (0-38). CONCLUSION: This is the first study evaluating the publication rates of abstracts presented in a respiratory congress. Although the number of presented abstracts in the congress increased year by year, prominently in the case reports, over all conversion rates were decreased. We put forward that encouraging the authors to conduct higher-quality investigations would raise the publication rate as well as improve the scientific quality of congress. PMID- 27240260 TI - Management of unilocular or multilocular cysts more than 5 centimeters in postmenopausal women. AB - OBJECTIVE: To evaluate the malignancy potential of large unilocular and multilocular ovarian cysts in postmenopausal women and to discuss their appropriate management. STUDY DESIGN: This retrospective study included 204 postmenopausal patients who underwent surgery for simple adnexal cysts or cysts with isolated septal structures at the Gynecology and Obstetrics Clinic of Bakirkoy Dr Sadi Konuk Training and Research Hospital. Data obtained from patient and computer records included patient age, follow-up period, ultrasonography reports, surgery information, histopathological evaluation results, and cancer antigen-125 (CA-125) levels at diagnosis and during follow-up. The Kruskal-Wallis test was used to compare three or more groups. The Chi-square test or Fisher's exact test was used to compare qualitative parameters, while relationships between parameters were analyzed by using Spearman's correlation analysis. RESULTS: A total of 236 cysts were identified in 204 postmenopausal women who underwent surgery. The cysts were categorized as having unilocular cyst morphology or complex structures without morphological abnormalities other than septa in 182 (77.1%) and 54 cases (22.9%), respectively. The mean cyst diameter was 6.6+/-3.1cm (range, 2.7-30cm) with diameters >=5cm in 176 cysts (75%). The median cyst volume was 88.5 cm(3) (range, 10-2636; interquartile range: 81) and the mean morphology index was 1.2 (range, 1-6), with 16 cysts (6.8%) >=5. No malignancy or borderline histology was observed in any patient. CONCLUSIONS: Among postmenopausal women, cysts that are unilocular or contain isolated septa, have a low-risk of malignancy even when they are larger than 5cm. Rather than undergoing emergency surgery, these patients may be followed up conservatively with intermittent transvaginal ultrasonography. PMID- 27240261 TI - Biological differences between functionalis and basalis endometria in women with and without adenomyosis. AB - OBJECTIVE: Endometriosis is commonly believed to originate from functionalis endometrium and adenomyosis from basalis endometrium. Due to the lack of enough information, we investigated the biological differences between these two layers of endometrium in women with and without adenomyosis. STUDY DESIGN: This was a case-controlled study with 12 control women and 17 women with adenomyosis undergoing hysterectomy. Full thickness (extending from the endometrium to the myometrium) biopsy specimens were obtained after the hysterectomy. Based on the phases of the menstrual cycle, the expression patterns of estrogen receptor (ER), progesterone receptor (PR), Ki-67, and activated Caspase-3 were analyzed by immunohistochemistry in the functionalis and basalis endometria. Apoptotic cells were evaluated by TdT-mediated dUTP-biotin nick end-labeling (TUNEL) assay. RESULTS: A similar pattern of ER and PR expression was found in the functionalis and basalis endometria during the proliferative phase. In contrast, a significantly lower ER and PR expression was found in the basalis endometria than in the functionalis endometria during the secretory phase and the menstrual phase. This was equally observed in control women and in women with adenomyosis. Except Ki-67 indices, TUNEL-positive cells, and expression of activated Caspase-3 were significantly lower in the basalis endometria than in the functionalis endometria during the secretory phase. CONCLUSION: A significant biological difference was found between the functionalis and the basalis endometria derived from women with adenomyosis. PMID- 27240262 TI - Evaluation of risk factors for the recurrence of ovarian endometriomas. AB - OBJECTIVES: To evaluate the risk factors for the recurrence of ovarian endometrioma after laparoscopic cystectomy. STUDY DESIGN: Reproductive aged patients who underwent laparoscopic ovarian endometriotic cystectomy and with histopathologically confirmed diagnosis of ovarian endometrioma were evaluated retrospectively. Histopathologic specimens were reevaluated and histopathologic characteristics of ovarian endometriotic cysts (thickness of cyst wall, thickness of fibrosis [ToF], thickness of ovarian tissue, the number of follicles per cyst, the depth of penetration [DoP] of endometrial tissue into the cyst wall) were determined. Along the determined histopathologic findings, demographic characteristics (age at surgery, number of pregnancies), clinical symptoms (dysmenorrhea, infertility), intraoperative findings (revised American Society for Reproductive Medicine [rASRM] stage), imaging features (bilaterality, cyst diameter), and biochemical parameters (Ca125, Ca19.9, Ca15.3) were evaluated as possible risk factors for the recurrence of endometrioma. The variables with p<0.2 in univariate analysis were introduced into regression analysis to determine the risk factors for recurrence. RESULTS: There were statistically significant differences in age group (<=35 years and >35 years), the ToF and DoP between patients with recurrence and those with no recurrence. In Cox regression analysis, age <=35 years and DoP were significant risk factors for presence of recurrence. DoP, ToF, preoperative cyst diameters in ultrasonographic examination were inversely correlated with recurrence interval. In multivariate regression analysis, the DoP was found the only significant risk factor for the recurrence interval. 1.2mm of DoP was found as the optimum cut off value for presence of recurrence according to Youden index criteria in ROC curve analyze. The sensitivity (62.9%), specificity (75%) were obtained at the cut off value of 1.2mm for DoP. CONCLUSION: Histopathological features of ovarian endometriotic cyst may have important roles on predicting the recurrence of the endometrioma. Predicting the recurrence risk of particular patient is very important in future management of the disease. Knowing the recurrence risk of an endometrioma will help in deciding the optimal treatment modalities for each individual patient. High risk patients should be offered appropriate treatments according to the clinical status without delay and low risk patients should be protected from overtreatment. PMID- 27240264 TI - Economic analyses are important in health care. PMID- 27240263 TI - Autoimmune polyglandular syndrome type 3 (APS-3) among patients with premature ovarian insufficiency (POI). AB - OBJECTIVES: Autoimmune polyglandular syndrome type 3 - (APS-3), is defined as the coexistence of autoimmune thyroiditis with other non-ovarian autoimmune diseases without primary adrenal insufficiency. Additionally the definition of APS-3 also includes primary ovarian insufficiency (POI) coexistence with autoimmune thyroiditis. The main goal of that study is to assess the prevalence of APS-3 defined as coexistence of autoimmune thyroiditis with POI in population of 46 XX karyotype women with primary ovarian insufficiency (POI). The second goal is to investigate hormonal profile and insulin sensitivity in women with POI and subgroups of women with APS-3 - POI/APS-3(+) and without APS 3 - POI/APS-3(-). MATERIALS AND METHODS: Anthropometric measurements, coexistence of autoimmune diseases, androgens, fasting glucose and insulin, glucose and insulin at 60' and 120' of oral glucose tolerance test (OGTT) and homeostasis model for insulin resistance (HOMA-IR), were determine in 98 patients aged between 18 and 39 with spontaneous 46 XX primary ovarian insufficiency (POI), in 33 POI/APS-3(+), 65 POI/APS-3(-), and 75 healthy controls. RESULTS: Continuous data were summarized by the mean+/-standard deviation (SD), and categorical data by number (percentages). Data were checked for normality using Shapiro-Wilk test, the comparison between groups were performed using non-parametric Mann-Whitney or Kruskall-Wallis test. Pearson's correlation coefficient was used to assess the relationships between parameters. Statistical significance was defined as p values <0.05. Autoimmune thyroid disease (ATD) was presented in 33/98 (33.7%) patients with POI. The groups did not differ significantly in respect to age and body mass index (BMI). Women with POI, POI/APS-3(+) and POI/APS-3(-) showed significantly lower serum androgens in comparison to controls. Additionally women with POI/APS-3(+) showed hyperinsulinemia after 1h of OGTT; No significant differences in serum fasting glucose, insulin and during 2h OGTT between groups were observed. CONCLUSIONS: The prevalence of APS-3 is 33.7% in patients with spontaneous 46 XX primary ovarian insufficiency. Women with POI, POI/APS-3(+) and POI/APS-3(-) feature lower testosterone, androstendione, dehydroepiandrostendione sulphate in comparison to controls. Women with POI/APS-3(+) could have hyperinsulinemia and should be carefully evaluated for metabolic disorders. PMID- 27240265 TI - Alliance rupture and repair processes and therapeutic change in youth with borderline personality disorder. AB - OBJECTIVES: This study aimed to investigate alliance rupture and repair processes in psychotherapy for youth with borderline personality disorder. It sought to examine whether alliance processes differ between treatments, across the phases of therapy, and what associations these processes might have with therapeutic outcomes. DESIGN: The study involves repeated measurement of both process and outcome measures. Hypotheses were addressed using within- and between-subjects analyses. METHODS: Forty-four people, aged 15-24, with a diagnosis of BPD were randomized to receive either 16 sessions of Cognitive Analytic Therapy (CAT) or a supportive treatment known as Befriending. In addition to pre-post outcome assessments, alliance processes were rated using the observer-based Rupture Resolution Rating Scale. RESULTS: Results indicated that CAT and Befriending did not differ in terms of number of ruptures, although CAT was associated with more stages of rupture resolution. Examination of alliance processes across time pointed to increasing ruptures, more frequent confrontation ruptures and increasing rupture resolution, suggesting increased volatility, directness and productivity in the therapeutic process across time. Contrary to hypotheses, there was no consistent link between alliance processes and outcome. However, two specific phases were significant. Early treatment ruptures were associated with poor outcome whereas greater late treatment resolution was associated with better outcomes. CONCLUSIONS: This study suggests that alliance processes can differ across treatments and the phases of therapy in psychotherapy for youth with BPD. Alliance ruptures are more likely to be problematic early in therapy but later in therapy, they appear to be opportunities for therapeutic growth. PRACTITIONER POINTS: Alliance ruptures are more likely than not to occur in any given session with a young person with Borderline Personality Disorder. Early in therapy, withdrawal type ruptures are more frequent, whereas late in therapy, confrontation ruptures are more frequent. Late in therapy, alliance ruptures should be viewed as opportunities for therapeutic change, rather than barriers to good outcomes. PMID- 27240266 TI - Stabilizing a Platinum1 Single-Atom Catalyst on Supported Phosphomolybdic Acid without Compromising Hydrogenation Activity. AB - In coordination chemistry, catalytically active metal complexes in a zero- or low valent state often adopt four-coordinate square-planar or tetrahedral geometry. By applying this principle, we have developed a stable Pt1 single-atom catalyst with a high Pt loading (close to 1 wt %) on phosphomolybdic acid(PMA)-modified active carbon. This was achieved by anchoring Pt on the four-fold hollow sites on PMA. Each Pt atom is stabilized by four oxygen atoms in a distorted square-planar geometry, with Pt slightly protruding from the oxygen planar surface. Pt is positively charged, absorbs hydrogen easily, and exhibits excellent performance in the hydrogenation of nitrobenzene and cyclohexanone. It is likely that the system described here can be extended to a number of stable SACs with superior catalytic activities. PMID- 27240267 TI - A Binuclear 1,1'-Bis(boratabenzene) Complex: Unprecedented Intramolecular Metal Metal Communication through a B-B Bond. AB - We report the synthesis of the first 1,1'-bis(boratabenzene) species by tetrabromodiborane(4)-induced ring-expansion reactions of cobaltocene. Six equivalents of cobaltocene are required as the species plays the dual role of reagent and reductant to yield [{(eta(5) -C5 H5 )Co}2 {MU:eta(6) ,eta(6) -(BC5 H5 )2 }]. The formally dianionic bis(boratabenzene) moiety with a boron-boron single bond can be viewed as a symmetric dimer of the parent boratabenzene anion as well as the first example of a diboron analogue of biphenyl. The solution electrochemistry of the bimetallic complex shows four stepwise redox events, indicating significant intramolecular interaction between the cobalt ions across the 1,1'-bis(boratabenzene) unit. The magnetic properties, as investigated by variable-temperature SQUID magnetometry, reveal weak intramolecular antiferromagnetic interactions. Density functional theory calculations support the experimental results and add insight into the various electronic states of the complex. PMID- 27240268 TI - Quantitative and mixed analyses to identify factors that affect cervical cancer screening uptake among lesbian and bisexual women and transgender men. AB - AIMS AND OBJECTIVES: The purposes of this study were to measure the prevalence of, and identify factors associated with, cervical cancer screening among a sample of lesbian, bisexual and queer women, and transgender men. BACKGROUND: Past research has found that lesbian, bisexual and queer women underuse cervical screening service. Because deficient screening remains the most significant risk factor for cervical cancer, it is essential to understand the differences between routine and nonroutine screeners. DESIGN: A convergent-parallel mixed methods design. METHODS: A convenience sample of 21- to 65-year-old lesbian and bisexual women and transgender men were recruited in the USA from August-December 2014. Quantitative data were collected via a 48-item Internet questionnaire (N = 226), and qualitative data were collected through in-depth telephone interviews (N = 20) and open-ended questions on the Internet questionnaire. RESULTS: Seventy three per cent of the sample was routine cervical screeners. The results showed that a constellation of factors influence the use of cervical cancer screening among lesbian, bisexual and queer women. Some of those factors overlap with the general female population, whereas others are specific to the lesbian, bisexual or queer identity. Routine screeners reported feeling more welcome in the health care setting, while nonroutine screeners reported more discrimination related to their sexual orientation and gender expression. Routine screeners were also more likely to 'out' to their provider. The quantitative and qualitative factors were also compared and contrasted. CONCLUSIONS: Many of the factors identified in this study to influence cervical cancer screening relate to the health care environment and to interactions between the patient and provider. RELEVANCE TO CLINICAL PRACTICE: Nurses should be involved with creating welcoming environments for lesbian, bisexual and queer women and their partners. Moreover, nurses play a large role in patient education and should promote self-care behaviours among lesbian women and transgender men. PMID- 27240269 TI - Differences in communication within the nursing group and with members of other professions at a hospital unit. AB - AIMS AND OBJECTIVES: To investigate what differences exist in nurses' communications with each other as opposed to their communications with members of other healthcare professions. BACKGROUND: Difficulties have been reported related to the introduction of interdisciplinary collaboration in hospitals even when their efficacy has been demonstrated. DESIGN: This paper is a report of a project that was a cross-sectional survey design. METHOD: Nurses and assistant nurses received questionnaires that examined two different components of interdisciplinary collaboration. Using the psychometric method known as Systematizing Person-Group Relations to gather data and for analysis, the method aims to investigate the dominant aspects of the particular work environment by identifying key characteristics of interdisciplinary collaboration. RESULTS: The respondents reported significant differences in six of the 12 factors; high scores on caring, acceptance, engagement and empathy characterised communication with members of their own professional group as low scores on the same factors characterised communication with other healthcare professions. CONCLUSION: Findings in this study suggests that nurses behave in a more loyal, accepting and critical manner when communicating with each other than they do when communicating with members of other healthcare professions. Nurses are more influenced by behaviours characterised by assertiveness and resignation in their communication with members of other healthcare professions. The findings indicate that nurse's experience mixed emotions and behaviours that influence their communications with healthcare personnel from other professions. RELEVANCE TO CLINICAL PRACTICE: Nurses often hold key positions on interdisciplinary collaboration; therefore, they must develop the communicative skills required in this position to be able to improve the quality of patient care in hospitals, related to nurses' experiences and skills. PMID- 27240270 TI - Novel pyrazolopyridine derivatives as potential angiogenesis inhibitors: Synthesis, biological evaluation and transcriptome-based mechanistic analysis. AB - Modified purine derivatives exemplified by pyrazolopyrimidines have emerged as highly selective inhibitors of several angiogenic receptor tyrosine kinases. Herein, we designed and synthesized a new series of substituted pyrazolopyridines and explored their ability to influence crucial pro-angiogenic attributes of endothelial cells. Four of the synthesized compounds, possessing analogous substitution pattern, were found able to inhibit at low micromolar concentrations endothelial cell proliferation, migration and differentiation, constitutively or in response to Vascular Endothelial Growth Factor (VEGF) and to attenuate VEGF induced phosphorylation of VEGF receptor-2 and downstream kinases AKT and ERK1/2. Administration of effective compounds in mice delayed the growth of syngeneic Lewis lung carcinoma transplants and reduced tumor microvessel density, without causing toxicity. Genome-wide microarray and gene ontology analyses of treated endothelial cells revealed derivative 18c as the most efficient modulator of gene expression and "mitotic cell cycle/cell division" along with "cholesterol biosynthesis" as the most significantly altered biological processes. PMID- 27240271 TI - Synthetic strategy and antiviral evaluation of diamide containing heterocycles targeting dengue and yellow fever virus. AB - High-throughput screening of a subset of the CD3 chemical library (Centre for Drug Design and Discovery; KU Leuven) provided us with a lead compound 1, displaying low micromolar potency against dengue virus and yellow fever virus. Within a project aimed at discovering new inhibitors of flaviviruses, substitution of its central imidazole ring led to synthesis of variably substituted pyrazine dicarboxylamides and phthalic diamides, which were evaluated in cell-based assays for cytotoxicity and antiviral activity against the dengue virus (DENV) and yellow fever virus (YFV). Fourteen compounds inhibited DENV replication (EC50 ranging between 0.5 and 3.4 MUM), with compounds 6b and 6d being the most potent inhibitors (EC50 0.5 MUM) with selectivity indices (SI) > 235. Compound 7a likewise exhibited anti-DENV activity with an EC50 of 0.5 MUM and an SI of >235. In addition, good antiviral activity of seven compounds in the series was also noted against the YFV with EC50 values ranging between 0.4 and 3.3 MUM, with compound 6n being the most potent for this series with an EC50 0.4 MUM and a selectivity index of >34. Finally, reversal of one of the central amide bonds as in series 13 proved deleterious to the inhibitory activity. PMID- 27240272 TI - Discovery of in vitro antitubercular agents through in silico ligand-based approaches. AB - The development of new anti-tubercular agents represents a constant challenge mostly due to the insurgency of resistance to the currently available drugs. In this study, a set of 60 molecules were selected by screening the Asinex and the ZINC collections and an in house library by means of in silico ligand-based approaches. Biological assays in Mycobacterium tuberculosis H37Ra ATCC 25177 strain highlighted (+/-)-1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethyl-4-(3,4 dichlorophenyl)piperazine-1-carboxylate (5i) and 3-(4-chlorophenyl)-5-(2,4 dimethylpyrimidin-5-yl)-2-methylpyrazolo[1.5-a]pyrimidin-7(4H)-one (42) as the most potent compounds, having a Minimum Inhibitory Concentration (MIC) of 4 and 2 MUg/mL respectively. These molecules represent a good starting point for further optimization of effective anti-TB agents. PMID- 27240273 TI - Synthesis and optimization of novel allylated mono-carbonyl analogs of curcumin (MACs) act as potent anti-inflammatory agents against LPS-induced acute lung injury (ALI) in rats. AB - A series of novel symmetric and asymmetric allylated mono-carbonyl analogs of curcumin (MACs) were synthesized using an appropriate synthetic route and evaluated experimentally thru the LPS-induced expression of TNF-alpha and IL-6. Most of the obtained compounds exhibited improved water solubility as a hydrochloride salt compared to lead molecule 8f. The most active compound 7a was effective in reducing the Wet/Dry ratio in the lungs and protein concentration in bronchoalveolar lavage fluid. Meanwhile, 7a also inhibited mRNA expression of several inflammatory cytokines, including TNF-alpha, IL-6, IL-1beta, and VCAM-1, in Beas-2B cells after Lipopolysaccharide (LPS) challenge. These results suggest that 7a could be therapeutically beneficial for use as an anti-inflammatory agent in the clinical treatment of acute lung injury (ALI). PMID- 27240274 TI - A critical review of both the synthesis approach and the receptor profile of the 8-chloro-1-(2',4'-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6 tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide and analogue derivatives. AB - 8-Chloro-1-(2',4'-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6 tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide 9a was discovered as potent and selective CB1 antagonist by part of our group few years ago. In particular it was reported to have an affinity towards the CB1 cannabinoid receptor (CB1R), expressed as Ki, of 0.00035 nM. Nevertheless significantly divergent data were reported for the same compound from other laboratories. To unequivocally define the receptor profile of 9a, we have critically reviewed both its synthesis approach and binding data. Here we report that, in contrast to our previously reported data, 9a showed a Ki value for CB1R in the order of nanomolar rather than of fentomolar range. The new determined receptor profile of 9a was also ascertained for analogue derivatives 9b-i, as well as for 12. Moreover, the structural features of the synthesized compounds necessary for CB1R were investigated. Amongst the novel series, effects on CB1R intrinsic activity was highlighted due to the substituents at the position 3 of the pyrazole ring of the 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole scaffold. Although the cannabinoid receptor profile of 9a was reviewed in this work, the relevance of this compound in CB1R antagonist based drug discovery is confirmed. PMID- 27240275 TI - Recent advances in the discovery of heparanase inhibitors as anti-cancer agents. AB - Heparanase, an only endo-beta-d-glucuronidase capable of cleaving heparan sulfate (HS) side chains at specific sites, contributes to remodeling of the extracellular matrix (ECM) and releasing of HS-linked growth factors, cytokines and signaling proteins. In addition, heparanase also plays an indispensable role in tumor angiogenesis, invasion and metastasis, indicating that it is a promising target for the development of antitumor drugs. Recent progress leads to three classes of heparanase inhibitors, including active analogs of endogenous substance, synthetic small molecule compounds and natural products. In this review, following an outline on the heparanase structure and function, an overview of the advancement of heparanase inhibitors as novel and potent anti cancer agents will be given, especially introducing various existing heparanase inhibitors, as well as their inhibitory activities and mechanisms of action. PMID- 27240276 TI - Synthesis, anti-proliferative and genotoxicity studies of 6-chloro-5-(2 substituted-ethyl)-1,3-dihydro-2H-indol-2-ones and 6-chloro-5-(2-chloroethyl)-3 (alkyl/ary-2-ylidene)indolin-2-ones. AB - A series of 6-chloro-5-(2-substituted-ethyl)-1,3-dihydro-2H-indol-2-ones (3a-h) and 6-chloro-5-(2-chloroethyl)-3-(alkyl/aryl-2-ylidene)indolin-2-ones (5i-x) were synthesized. Compounds 3a-e, 5i-l and 5q-r were selected by NIH, USA for in vitro anti-proliferative screening. Based on the impressive growth inhibitory (GI %) effect by the compounds 3a-b and 3e which showed growth inhibition in the range 1.22-76.30%, 2.85-76.03% and 10.98-82.05% respectively at 10(-5) concentration, these compounds were further analyzed for anti-proliferative activity at 5 dose concentration and genotoxicity. PMID- 27240277 TI - Enfuvirtide-PEG conjugate: A potent HIV fusion inhibitor with improved pharmacokinetic properties. AB - Enfuvirtide (ENF) is a clinically used peptide drug for the treatment of HIV infections, but its poor pharmacokinetic profile (T1/2 = 1.5 h in rats) and low aqueous solubility make the therapy expensive and inconvenience. In this study, we present a simple and practical strategy to address these problems by conjugating ENF with polyethylene glycol (PEG). Site-specific attachment of a 2 kDa PEG at the N-terminus of ENF resulted in an ENF-PEG (EP) conjugate with high solubility (>=3 mg/mL) and long half-life in rats (T1/2 = 16.1 h). This conjugate showed similar antiviral activity to ENF against various primary HIV-1 isolates (EC50 = 6-91 nM). Mechanistic studies suggested the sources of the antiviral potency. The conjugate bound to a functional domain of the HIV gp41 protein in a helical conformation with high affinity (Kd = 307 nM), thereby inhibiting the gp41-mediated fusion of viral and host-cell membranes. As PEG conjugation has advanced many bioactive proteins and peptides into clinical applications, the EP conjugate described here represents a potential new treatment for HIV infections that may address the unmet medical needs associated with the current ENF therapy. PMID- 27240278 TI - neo-Clerodane diterpenoids from Scutellaria barbata mediated inhibition of P glycoprotein in MCF-7/ADR cells. AB - Ten new (1-10) and seventeen known (11-27) neo-clerodane diterpenoids substituted with nicotinoyloxyl were isolated from the plant Scutellaria barbata and their structures were established by extensive spectroscopic analysis. Chemoreversal effects of these neo-clerodane diterpenoids on multidrug resistance were evaluated in breast cancer multidrug-resistant MCF-7/ADR cells that overexpress P glycoprotein. Four compounds (11, 14, 16, and 18) exhibited better chemoreversal abilities than the classical P-gp inhibitor verapamil and the most potent compound 11 reduced IC50 value of adriamycin in MCF-7/ADR cells from 58.8 MUM to 1.3 MUM. Mechanistic investigations showed that compound 11 reversed multidrug resistance through suppressing the activity of P-gp and restraining the expression of P-glycoprotein. In the present study, the structure-activity relationships of neo-clerodane diterpenoids were also discussed. PMID- 27240279 TI - Frontal plane comparison between drop jump and vertical jump: implications for the assessment of ACL risk of injury. AB - The potential to use the vertical jump (VJ) to assess both athletic performance and risk of anterior cruciate ligament (ACL) injury could have widespread clinical implications since VJ is broadly used in high school, university, and professional sport settings. Although drop jump (DJ) and VJ observationally exhibit similar lower extremity mechanics, the extent to which VJ can also be used as screening tool for ACL injury risk has not been assessed. This study evaluated whether individuals exhibit similar knee joint frontal plane kinematic and kinetic patterns when performing VJs compared with DJs. Twenty-eight female collegiate athletes performed DJs and VJs. Paired t-tests indicated that peak knee valgus angles did not differ significantly between tasks (p = 0.419); however, peak knee internal adductor moments were significantly larger during the DJ vs. VJ (p < 0.001). Pearson correlations between the DJ and VJ revealed strong correlations for knee valgus angles (r = 0.93, p < 0.001) and for internal knee adductor moments (r = 0.82, p < 0.001). Our results provide grounds for investigating whether frontal plane knee mechanics during VJ can predict ACL injuries and thus can be used as an effective tool for the assessment of risk of ACL injury in female athletes. PMID- 27240280 TI - Social anxiety disorder: a critical overview of neurocognitive research. AB - Social anxiety is a common disorder characterized by a persistent and excessive fear of one or more social or performance situations. Behavioral inhibition is one of the early indicators of social anxiety, which later in life may advance into a certain personality structure (low extraversion and high neuroticism) and the development of maladaptive cognitive biases. While there are several effective psycho- and pharmacotherapy options, a large number of patients benefit insufficiently from these therapies. Brain and neuroendocrine research can help uncover both the biological basis of social anxiety and potentially provide indicators, 'biomarkers,' that may be informative for early disease detection or treatment response, above and beyond self-report data. Several large-scale brain networks related to emotion, motivation, cognitive control, and self-referential processing have been identified, and are affected in social anxiety. Social anxiety is further characterized by increased cortisol response and lower testosterone levels. These neuroendocrine systems are also related to altered connectivity patterns, such as reduced amygdala-prefrontal coupling. Much work is needed however to further elucidate such interactions between neuroendocrine functioning and large-scale brain networks. Despite the great promise of brain research in uncovering the neurobiological basis of social anxiety, several methodological and conceptual issues also need to be considered. WIREs Cogn Sci 2016, 7:218-232. doi: 10.1002/wcs.1390 For further resources related to this article, please visit the WIREs website. PMID- 27240282 TI - Continuous quality improvement in orthopedic surgery: changes and implications with health system funding reform. PMID- 27240281 TI - Microbiome and its impact on gastrointestinal atopy. AB - The prevalence of allergic conditions has continuously increased in the last few decades in Westernized countries. A dysbiotic gut microbiome may play an important role in the development of allergic diseases. Genetic, environmental, and dietary factors may alter the commensal microbiota leading to inflammatory dysregulation of homeostasis. Murine and human studies have begun to elucidate the role of the microbiota in the pathogenesis of atopic diseases including asthma, atopic dermatitis, and food allergies. However, the role of the microbiome in most eosinophilic gastrointestinal diseases (EGIDs) is not yet known. This review provides an overview of what is currently known about the development of tolerance from both molecular and clinical standpoints. We also look at the gut-specific microbiome and its role in atopic conditions with the hope of applying this knowledge to the understanding, prevention, and treatment of EGIDs, particularly EoE. PMID- 27240283 TI - [Amelioration continue de la qualite en chirurgie orthopedique: modifications et repercussions de la reforme du financement du systeme de sante]. PMID- 27240284 TI - Recommendations for surgical safety checklist use in Canadian children's hospitals. AB - BACKGROUND: There is ample evidence that avoidable harm occurs in patients, including children, who undergo surgical procedures. Among a number of harm mitigation strategies, the use of surgical safety checklists (SSC) is now a required organizational practice for accreditation in all North American hospitals. Although much has been written about the effects of SSC on outcomes of adult surgical patients, there is a paucity of literature on the use and role of the SSC as an enabler of safe surgery for children. METHODS: The Pediatric Surgical Chiefs of Canada (PSCC) advocates on behalf of all Canadian children undergoing surgical procedures. We undertook a survey of the use of SSC in Canadian children's hospitals to understand the variability of implementation of the SSC and understand its role as both a measure and driver of patient safety and to make specific recommendations (based on survey results and evidence) for standardized use of the SSC in Canadian children's hospitals. RESULTS: Survey responses were received from all 15 children's hospitals and demonstrated significant variability in how the checklist is executed, how compliance is measured and reported, and whether or not use of the checklist resulted in specific instances of error prevention over a 12-month observation period. There was near unanimous agreement that use of the SSC contributed positively to the safety culture of the operating room. CONCLUSION: Based on the survey results, the PSCC have made 5 recommendations regarding the use of the SSC in Canadian children's hospitals. PMID- 27240285 TI - Temporal trends in the use of diagnostic imaging for inpatients with pancreatic conditions: How much ionizing radiation are we using? AB - BACKGROUND: Low-dose ionizing radiation from medical imaging has been indirectly linked with subsequent cancer and increased costs. Computed tomography (CT) is the gold standard for defining pancreatic anatomy and complications. Our primary goal was to identify the temporal trends associated with diagnostic imaging for inpatients with pancreatic diseases. METHODS: Data were extracted from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample (NIS) database from 2000 to 2008. Pancreas-related ICD-9 diagnostic codes were matched to all relevant imaging modalities. RESULTS: Between 2000 and 2008, a significant increase in admissions (p < 0.001), but decrease in overall imaging procedures (p = 0.032), for all pancreatic disorders was observed. This was primarily a result of a reduction in the number of CT and endoscopic retrograde cholangiopancreatography examinations (i.e., reduced radiation exposure, p = 0.008). A concurrent increase in the number of inpatient magnetic resonance cholangiopancreatography/magnetic resonance imaging performed was observed (p = 0.040). Intraoperative cholangiography and CT remained the dominant imaging modality of choice overall (p = 0.027). CONCLUSION: Inpatients with pancreatic diseases often require diagnostic imaging during their stay. This results in substantial exposure to ionizing radiation. The observed decrease in the use of CT may reflect an improved awareness of potential stochastic risks. PMID- 27240286 TI - Traumatic spinal injuries in children at a single level 1 pediatric trauma centre: report of a 23-year experience. AB - BACKGROUND: With a reported incidence of up to 10% compared to all spinal trauma, spinal injuries in children are less common than in adults. Children can have spine fractures with or without myelopathy, or spinal cord injuries without radiological abnormalities (SCIWORA). METHODS: We retrospectively reviewed the cases of children with spinal injuries treated at a level 1 pediatric trauma centre between 1990 and 2013. RESULTS: A total of 275 children were treated during the study period. The mean age at admission was 12 +/- 4.5 years, and the male:female ratio was 1.4:1. Spinal injuries were more common in children of ages 12-16 years, with most injuries among ages 15-16 years. The top 3 mechanisms of spinal injury were motor vehicle-related trauma (53%), sports (28%) and falls (13%). Myelopathy occurred in 12% and SCIWORA occurred in 6%. The most common spine levels injured were L2-sacrum, followed by O-C2. Associated injuries, including head injuries (29%), and fractures/dislocations (27%) occurred in 55% of children. Overall mortality was 3%. Surgical intervention was required in 14%. CONCLUSION: The creation of a pediatric spinal injury database using this 23-year retrospective review helped identify important clinical concepts; we found that active adolescent boys had the highest risk of spine injury, that noncontiguous spine injuries occured at a rate higher than reported previously and that nonaccidental spine injuries in children are underreported. Our findings also emphasize the importance of maintaining a higher index of suspicion with trauma patients with multiple injuries and of conducting detailed clinical and radiographic examinations of the entire spine in children with a known spinal injury. PMID- 27240287 TI - Clinical importance of bilateral disease in patients with papillary thyroid cancer. AB - ABSTRACT: A cancer-related factor that is not included in papillary thyroid cancer (PTC) prognostic scoring systems is bilaterality. While it may seem that bilaterality should be considered during the management of PTC, its clinical importance has been debated. This controversy exists because the extent of surgery for PTC has not been found to affect survival in low-risk individuals, despite their potential for PTC bilaterality. We sought to determine if PTC bilaterality is a cancer prognosticator based upon its association with known clinical and pathological PTC prognosticators, and MACIS scores. In this article we discuss our findings and their potential clinical implications. PMID- 27240288 TI - GPs with enhanced surgical skills: a questionable solution for remote surgical services. PMID- 27240289 TI - 2016 Trauma Association of Canada Annual Scientific Meeting Abstracts. PMID- 27240290 TI - 2016 Canadian Spine Society Abstracts. PMID- 27240291 TI - 2016 Bethune Round Table Abstracts. PMID- 27240292 TI - 2016 Canadian Society of Surgical Oncology Annual Scientific Meeting Abstracts. PMID- 27240293 TI - Randomized controlled trials of serotonin-norepinephrine reuptake inhibitor in treating major depressive disorder in children and adolescents: a meta-analysis of efficacy and acceptability. AB - New generation antidepressant therapies, including serotonin-norepinephrine reuptake inhibitor (SNRIs), were introduced in the late 1980s; however, few comprehensive studies have compared the benefits and risks of various contemporary treatments for major depressive disorder (MDD) in young patients. A comprehensive literature search of PubMed, Cochrane, Embase, Web of Science, and PsycINFO databases was conducted from 1970 to January 2015. Only clinical trials that randomly assigned one SNRI or placebo to patients aged 7 to 18 years who met the diagnostic criteria for major depressive disorder were included. Treatment success, dropout rate, and suicidal ideation/attempt outcomes were measured. Primary efficacy was determined by pooling the risk ratios (RRs) of treatment response and remission. Acceptability was determined by pooling the RRs of dropouts for all reasons and for adverse effects as well as suicide-risk outcomes. Five trials with a total of 973 patients were included. SNRIs were not significantly more effective than placebo for treatment response but were for remission. The comparison of patients taking SNRIs that dropped out for all reasons and those taking placebo did not reach statistical significance. Significantly more patients taking SNRIs dropped out for adverse effects than those taking placebo. No significant difference was found in suicide-related risk outcomes. SNRI therapy does not display a superior efficacy and is not better tolerated compared to placebo in these young patients. However, duloxetine has a potential beneficial effect for depression in young populations, showing a need for further research. PMID- 27240294 TI - Effect of microRNA-21 on the proliferation of human degenerated nucleus pulposus by targeting programmed cell death 4. AB - This study aims to explore the effect of microRNA-21 (miR-21) on the proliferation of human degenerated nucleus pulposus (NP) by targeting programmed cell death 4 (PDCD4) tumor suppressor. NP tissues were collected from 20 intervertebral disc degeneration (IDD) patients, and from 5 patients with traumatic spine fracture. MiR-21 expressions were tested. NP cells from IDD patients were collected and divided into blank control group, negative control group (transfected with miR-21 negative sequences), miR-21 inhibitor group (transfected with miR-21 inhibitors), miR-21 mimics group (transfected with miR 21 mimics) and PDCD4 siRNA group (transfected with PDCD4 siRNAs). Cell growth was estimated by Cell Counting Kit-8; PDCD4, MMP-2,MMP-9 mRNA expressions were evaluated by qRT-PCR; PDCD4, c-Jun and p-c-Jun expressions were tested using western blot. In IDD patients, the expressions of miR-21 and PDCD4 mRNA were respectively elevated and decreased (both P<0.05). The miR-21 expressions were positively correlated with Pfirrmann grades, but negatively correlated with PDCD4 mRNA (both P<0.001). In miR-21 inhibitor group, cell growth, MMP-2 and MMP-9 mRNA expressions, and p-c-Jun protein expressions were significantly lower, while PDCD4 mRNA and protein expressions were higher than the other groups (all P<0.05). These expressions in the PDCD4 siRNA and miR-21 mimics groups was inverted compared to that in the miR-21 inhibitor group (all P<0.05). MiR-21 could promote the proliferation of human degenerated NP cells by targeting PDCD4, increasing phosphorylation of c-Jun protein, and activating AP-1-dependent transcription of MMPs, indicating that miR-21 may be a crucial biomarker in the pathogenesis of IDD. PMID- 27240295 TI - Characterization of a Polymer-Based, Fully Organic Prosthesis for Implantation into the Subretinal Space of the Rat. AB - Replacement strategies arise as promising approaches in case of inherited retinal dystrophies leading to blindness. A fully organic retinal prosthesis made of conjugated polymers layered onto a silk fibroin substrate is engineered. First, the biophysical and surface properties are characterized; then, the long-term biocompatibility is assessed after implantation of the organic device in the subretinal space of 3-months-old rats for a period of five months. The results indicate a good stability of the subretinal implants over time, with preservation of the physical properties of the polymeric layer and a tight contact with the outer retina. Immunoinflammatory markers detect only a modest tissue reaction to the surgical insult and the foreign body that peaks shortly after surgery and progressively decreases with time to normal levels at five months after implantation. Importantly, the integrity of the polymeric layer in direct contact with the retinal tissue is preserved after five months of implantation. The recovery of the foreign-body tissue reaction is also associated with a normal b wave in the electroretinographic response. The results demonstrate that the device implanted in nondystrophic eyes is well tolerated, highly biocompatible, and suitable as retinal prosthesis in case of photoreceptor degeneration. PMID- 27240297 TI - Colonial cell disaggregation and intracellular microcystin release following chlorination of naturally occurring Microcystis. AB - Colonial cell disaggregation and release of intracellular microcystin were evaluated following chlorine treatment of naturally occurring Microcystis. Microscopic observations of water samples collected from Lake Mead, Nevada, USA, confirmed the presence of colonial Microcystis with cells protected by an outer sheath up to 30 MUm thick. During chlorination, two stages of cell decomposition were observed, stage 1: colonial cell disaggregation, and stage 2: unicellular degradation. Following a [Cl2]0:DOC0 ratio of 0.15 (t = 20 min, pH = 8.2-8.5) in unfiltered Lake Havasu samples, total particle count increased from (1.0 +/- 0.11) * 10(5) to 4.2 * 10(5) particles/mL and fluorescent particle count increased from (1.2 +/- 0.50) * 10(4) to 1.2 * 10(5) particles/mL, illustrating colonial cell disaggregation. Although total and fluorescent particles increased, the concentration of chlorophyll-a (Chl-a) decreased from 81 MUg/L to 72 MUg/L, and continued to decrease at higher [Cl2]0:DOC0 ratios. The preliminary second order rate constant for the reaction between Microcystis and chlorine in natural waters was estimated using either Chl-a (k = 15 M(-1) s(-1)) or fluorescence particle count (k = 38 M(-1) s(-1)) as an indicator of cell damage following colonial disaggregation (i.e., at [Cl2]0:DOC0 ratio >=0.15). Complete release of intracellular microcystin-LR (MC-LR) was observed in both Lake Havasu and Lake Mead samples when applying a [Cl2]0:DOC0 ratio of 0.30 (t = 20 min), which was equivalent to a chlorine exposure of 8 min-mg/L for Lake Havasu samples. With chlorination, DOC increased by 3-18% indicating release of either colony-bound or cell-bound DOC. The results demonstrated the ability of chlorine to disaggregate/inactivate natural Microcystis colonies, and identified oxidation conditions resulting in complete release of intracellular MC-LR. PMID- 27240296 TI - Novel chitosan goethite bionanocomposite beads for arsenic remediation. AB - We report on the synthesis and As adsorption properties of a novel chitosan - iron (oxyhydr)oxide composite material for the remediation of arsenic contaminated water supplies. FE-SEM, Mossbauer spectroscopy, ICP-OES and synchrotron (Bulk XAS, MUXRF) techniques were applied to determine the composition of the new material and investigate the As uptake efficiency and mechanism. The iron (oxyhydr)oxide phase has been identified as a nano-sized goethite, well dispersed in the chitosan matrix, leading to the name 'chitosan goethite bionanocomposite' (CGB). The CGB material is prepared in the form of beads of high density and excellent compression strength; the embedding of the goethite nanoparticles in the chitosan matrix allows for the high adsorption capacity of nanoparticles to be realized. CGB beads remove both As(III) and As(V) efficiently from water, over the pH range 5-9, negating the need for pre oxidation of As(III). Kinetic studies and MUXRF analysis of CGB bead sections show that diffusion-adsorption of As(V) into CGB beads is faster than for As(III). Using CGB beads, synthetic high-arsenic water (0.5 mg-As/L) could be purified to world drinking standard level (<0.01 mg-As/L) using only 1.4 g/L CGB. When considered in combination with the advantages of the low-cost of raw materials required, and facile (green) synthesis route, CGB is a promising material for arsenic remediation, particularly in developing countries, which suffer a diversity of socio-economical-traditional constraints for water purification and sanitation. PMID- 27240298 TI - Study of optical clearing in polarization measurements by Monte Carlo simulations with anisotropic tissue-mimicking models. AB - We conducted Monte Carlo simulations based on anisotropic sclera-mimicking models to examine the polarization features in Mueller matrix polar decomposition (MMPD) parameters during the refractive index matching process, which is one of the major mechanisms of optical clearing. In a preliminary attempt, by changing the parameters of the models, wavelengths, and detection geometries, we demonstrate how the depolarization coefficient and retardance vary during the refractive index matching process and explain the polarization features using the average value and standard deviation of scattering numbers of the detected photons. We also study the depth-resolved polarization features during the gradual progression of the refractive index matching process. The results above indicate that the refractive index matching process increases the depth of polarization measurements and may lead to higher contrast between tissues of different anisotropies in deeper layers. MMPD-derived polarization parameters can characterize the refractive index matching process qualitatively. PMID- 27240299 TI - Development of simultaneous analysis of tryptophan metabolites in serum and gastric juice - an investigation towards establishing a biomarker test for gastric cancer diagnosis. AB - To evaluate changes in tryptophan metabolism and discover diagnostic biomarkers for gastric cancer, a quantitative method was developed for tryptophan and its seven metabolites (indole-3-lactic acid, anthranilic acid, serotonin, nicotinic acid, kynurenic acid, kynurenine and 3-indoxyl sulfate) in both human serum and gastric juice using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Serum and gastric juice were prepared with a simple protein precipitation using aqueous 0.1% formic acid and acetonitrile. As a result, it was found that the kynurenine pathway of tryptophan metabolism was activated in gastric cancer and that the metabolic ratio of kynurenine/tryptophan, which reflects the enzyme activity of indoleamine-2,3-dioxygenase, was associated with the observed metabolic changes. Finally, the investigation of tryptophan metabolites, especially kynurenic acid, in serum and gastric juice might serve as biomarkers for gastric cancer. The findings in this study provide critical information of tryptophan metabolism which can be applied to a serum-based diagnostic test for gastric cancer. PMID- 27240300 TI - Determination of 1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3 in human serum using liquid chromatography with tandem mass spectrometry. AB - Vitamin D plays important roles in skeletal metabolism and many other diseases, including chronic renal failure, hypoparathyroidism, sarcoidosis and rickets. 1alpha,25-dihydroxy vitamin D (1alpha,25(OH)2D), the active form of vitamin D, exhibits an extremely low serum concentration, which makes its quantification very challenging. High performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) is considered to be the "gold standard" for the determination of these chemicals, which are found in low concentrations in the serum, but conventionally, it needs tedious sample pretreatment procedures, such as solid phase extraction and derivatization. Herein, we describe a simple and rapid HPLC MS/MS method for the simultaneous quantification of 1alpha,25-dihydroxy vitamin D3 (1alpha,25(OH)2D3) and 1alpha,25-dihydroxy vitamin D2 (1alpha,25(OH)2D2). The analytes were extracted from the matrix by liquid-liquid extraction, centrifuged to dryness and reconstituted with 75% methanol. Lithium acetate was employed to improve the ionization efficiency of 1alpha,25(OH)2D. The assay was sensitive with a low limit of quantitation of 10.0pg/mL for both 1alpha,25(OH)2D3 and 1alpha,25(OH)2D2 using a 0.5mL sample aliquot. Linearity was obtained over the range of 10.0pg/mL to 500pg/mL. Both the inter-assay and intra-assay precisions were <15%, and the analytical recoveries were within 100+/-5%. The performance evaluation of this assay demonstrated that it was a practical, sensitive and specific method for measuring the serum 1alpha,25(OH)2D3 and 1alpha,25(OH)2D2 concentrations. PMID- 27240301 TI - Identification and quantification of the anti-inflammatory constituents in Pian Tze-Huang by liquid chromatography combined with quadrupole time-of-flight and triple quadrupole mass spectrometry. AB - Both qualitative and quantitative analyses combined with activity evaluation were used for the integrated quality control study of Pien-Tze-Huang (PZH), a precious lozenge used for 460 years in China. In qualitative analysis, a high performance LC-quadrupole time-of-flight MS method was developed for the identification of chemical profiling in PZH. 27 compounds were unambiguously identified by comparing with reference substances, and 12 compounds were tentatively deduced based on their MS data and comparing with literatures. Then the in vitro anti inflammatory activity of 27 compounds were evaluated, and 9 saponins, 11 bile acids, taurine and muscone exhibited significant inhibitory activities on TNF alpha production with IC50 values ranging from 12.34 to 147.24MUM. In quantitative analysis, 21 active compounds, selected as quality control markers, were simultaneously detected in 15 batches of PZH samples by ultra-performance LC triple quadrupole MS. All the analytes were detected within 15min. Satisfactory linearity was achieved with wide linear range and fine determination coefficient (r(2)>0.9990). The respective relative standard deviations of intra- and inter day precisions, repeatability, stability, and recovery were less than 4.32%, 4.94%, 4.78%, 4.87%, and 4.91%. This study established a high sensitive and efficient method for the integrated quality control of PZH, including qualitative and quantitative analyses combined with pharmacological activity evaluation. PMID- 27240302 TI - Quantitative analysis of amino acids and acylcarnitines combined with untargeted metabolomics using ultra-high performance liquid chromatography and quadrupole time-of-flight mass spectrometry. AB - Metabolomics is an "omic" technique being increasingly used in epidemiological and clinical studies. We developed a method combining untargeted metabolomics with the quantitative determination of eight amino acids (AA) and eight acylcarnitines (AC) in plasma using ultra-high pressure liquid chromatography (UHPLC), electrospray ionization (ESI) and quadrupole time-of-flight mass spectrometry (QTOFMS). Separation of metabolites is performed by ion-pair reverse phase UHPLC using a HSS T3 column (2.1*100mm, 100A, 1.8MUm particle size) and formic acid-ammonium acetate-heptafluorobutyric acid in water and formic acid ammonium acetate in methanol as mobile phases. Metabolite identification and quantification are achieved using a QTOFMS operating in ESI-positive and full scan mode along with MS(E) acquisition of fragmentation patterns. Targeted metabolites are quantified using the appropriate labeled standards and include branched-chain AA (leucine, isoleucine, valine), aromatic AA (phenylalanine, tyrosine) as well as acetylcarnitine and propionylcarnitine, which have been identified as biomarkers of future cardiometabolic disease risk. The inter-day precision (relative standard deviation) for the targeted method was <15% for all but one metabolite and accuracy (bias) of amino acids ranged from 0.5% to 13.9% using SRM 1950 as the external standard. Untargeted metabolomics in 30 plasma samples from the general Canadian population revealed 5018 features, of which 48 metabolites were identified using the MZmine 2.19 software including 23 by our in house library that comprises 671 annotated metabolites. SRM 1950 analysis revealed 11,684 features, among which 154 metabolites were identified. Our method is currently applied in several epidemiological studies to better characterize cardiometabolic diseases and identify new biomarkers for disease prevention. PMID- 27240303 TI - Unusual Formation of CoSe@carbon Nanoboxes, which have an Inhomogeneous Shell, for Efficient Lithium Storage. AB - Hybrid hollow nanostructures with tailored shell architectures are attractive for electrochemical energy storage applications. Starting with metal-organic frameworks (MOFs), we demonstrate a facile formation of hybrid nanoboxes with complex shell architecture where a CoSe-enriched inner shell is intimately confined within a carbon-enriched outer shell (denoted as CoSe@carbon nanoboxes). The synthesis is realized through manipulation of the template-engaged reaction between Co-based zeolitic imidazolate framework (ZIF-67) nanocubes and Se powder at elevated temperatures. By virtue of the structural and compositional features, these unique CoSe@carbon nanoboxes manifest excellent lithium-storage performance in terms of high specific capacity, exceptional rate capability, excellent cycling stability, and high initial Coulombic efficiency. PMID- 27240304 TI - Reduced and mutant lysozyme refolding with lipid vesicles. Model study of disulfide impact on equilibria and dynamics. AB - The recovery of secondary structure in disordered, disulfide-reduced hen egg white lysozyme (HEWL) upon interaction with lipid vesicles was studied using circular dichroism (CD), fluorescence and infrared (IR) spectroscopic techniques. Lipid vesicles having negative head groups, such as DMPG, interact with reduced HEWL to induce formation of more helical structure than in native HEWL, but no stable tertiary structure was evident. Changes in tertiary structure, as evidenced by local environment of the tryptophan residues, were monitored by fluorescence. Spectra for oxidized HEWL, reduced HEWL and mutants with no or just one disulfide bond developed variable degrees of increased helicity when added to negatively charged lipid vesicles, mostly depending on packing of tails. When mixed with zwitterionic lipid vesicles, reduced HEWL developed beta-sheet structure with no change in helicity, indicating an altered interaction mechanism. Stopped flow CD and fluorescence dynamics, were fit to multi exponential forms, consistent with refolding to metastable intermediates of increasing helicity for HEWL interacting with lipid vesicles. Formation of an intermediate after rapid interaction of the lipid vesicles and the protein is supported by the correlation of faster steps in CD and fluorescence kinetics, and largely appears driven by electrostatic interaction. In subsequent slower steps, the partially refolded intermediate further alters structure, gaining helicity and modifying tryptophan packing, as driven by hydrophobic interactions. PMID- 27240305 TI - The effect of SCD and LEPR genetic polymorphisms on fat content and composition is maintained throughout fattening in Duroc pigs. AB - The effects of the stearoyl-CoA desaturase (SCD; AY487830:g.2228T>C) and leptin receptor (LEPR; NM_001024587:g.1987C>T) polymorphisms on fat content and fatty acid (FA) composition were investigated throughout fattening. Samples of Longissimus thoracis (LT) and subcutaneous fat (SF) from 214 Duroc barrows were collected from 160days to slaughter age (220days) using a longitudinal design. Results indicated that the positive effect of the T allele at the SCD gene on monounsaturated FA and of the T allele at the LEPR gene on saturated FA are maintained throughout the growing-finishing period, both in LT and SF. In LEPR, however, compositional changes, particularly in SF, are a result of increased fatness. There is very limited evidence of genotype by age interaction, and thus it is concluded that the combined selection for the SCD T and LEPR C alleles is a good strategy to increase the MUFA/SFA ratio regardless of the age at slaughter. PMID- 27240306 TI - Analysis of the interactions of sulfur-containing amino acids in membrane proteins. AB - The interactions of Met and Cys with other amino acid side chains have received little attention, in contrast to aromatic-aromatic, aromatic-aliphatic or/and aliphatic-aliphatic interactions. Precisely, these are the only amino acids that contain a sulfur atom, which is highly polarizable and, thus, likely to participate in strong Van der Waals interactions. Analysis of the interactions present in membrane protein crystal structures, together with the characterization of their strength in small-molecule model systems at the ab initio level, predicts that Met-Met interactions are stronger than Met-Cys ~ Met Phe ~ Cys-Phe interactions, stronger than Phe-Phe ~ Phe-Leu interactions, stronger than the Met-Leu interaction, and stronger than Leu-Leu ~ Cys-Leu interactions. These results show that sulfur-containing amino acids form stronger interactions than aromatic or aliphatic amino acids. Thus, these amino acids may provide additional driving forces for maintaining the 3D structure of membrane proteins and may provide functional specificity. PMID- 27240307 TI - Long-term follow-up of cognitive functions in patients with continuous spike waves during sleep (CSWS). AB - Continuous spike-waves during sleep (CSWS) are associated with several cognitive, neurological, and psychiatric disorders, which sometimes persist after CSWS disappearance. The purpose of this retrospective study was to investigate the correlation between general (clinical and instrumental) and neuropsychological findings in CSWS, to identify variables that predispose patients to a poorer long term neuropsychological outcome. Patients with spikes and waves during sleep with a frequency >=25/min (spikes and waves frequency index - SWFI) were enrolled. There were patients presenting abnormal EEG activity corresponding to the classic CSWS and patients with paroxysmal abnormalities during sleep <85% with SWFI >=25/min that was defined as excessive spike-waves during sleep (ESWS). Clinical and instrumental features and neuropsychological findings during and after the spike and wave active phase period were considered. A statistical analysis was performed utilizing the Spearman correlation test and multivariate analysis. The study included 61 patients; the mean follow-up (i.e., the period between SWFI >=25 first recording and last observation) was 7years and 4months. The SWFI correlated inversely with full and performance IQ during CSWS/ESWS. Longer lasting SWFI >=25 was related to worse results in verbal IQ and performance IQ after CSWS/ESWS disappearance. Other variables may influence the neuropsychological outcome, like age at SWFI >=25 first recording, perinatal distress, pathologic neurologic examination, and antiepileptic drug resistance. This confirms that CSWS/ESWS are a complex pathology and that many variables contribute to its outcome. The SWFI value above all during CSWS/ESWS and long lasting SWFI >=25 after CSWS/ESWS disappearance are the most significant indexes that appear mostly to determine cognitive evolution. This finding underscores the importance of EEG recordings during sleep in children with a developmental disorder, even if seizures are not reported, as well as the importance of using therapy with an early efficacy. PMID- 27240308 TI - Teachers' knowledge about epilepsy in Greece: Information sources and attitudes towards children with epilepsy during school time. AB - AIM: The aim of this study was to explore the sources of information for the educators in Greek primary and secondary schools with regard to epilepsy, first aid to seizures, and pupils' health conditions. METHOD: A semistructured anonymous 52-item questionnaire was sent to 100 public primary and secondary Greek schools from all districts. Two thousand thirty-seven teachers were approached; 446 questionnaires returned. The data were analyzed with SPSS20. Also, 70 head teachers were phone-interviewed with an open-ended unstructured questionnaire. The derived data were analyzed using mixed methodology. RESULTS: Twenty-two percent of the addressed educational community responded to the questionnaire, mostly women (66.6%). More responses came from urban areas (71.5%). The main source for the teachers to obtain information about epilepsy was found to be personal experience (37.75%) and internet (34.93%). Only a small percentage was referred to courses (6.2%). Eighty point three percent of the educators knew what epilepsy is, and 88.1% had the right view about the nature of the illness. However, 92% of the educators replied that they have not had adequate first aid training. Although 80.3% of the teachers believed that the school personnel are aware of the pupils' medical history, 85.48% of the teachers considered that they are informed about the pupils' condition from the parents/carers, and only 5.53% believed that the information came from the family doctor. Ninety-five point seventy percent of the educators declared a wish for further information and training about epilepsy. CONCLUSION: Knowledge and attitudes of the educators towards epilepsy are improved compared with those reported in previous studies conducted in Greece. However, there are still areas of uncertainty which need improvement. The necessity for more information about epilepsy and pupils' medical history along with appropriate training about seizure incidents seems crucial for the Greek educational community. Educational campaigns about epilepsy could improve teachers' knowledge of epilepsy to develop a well-informed and tolerant community. Further research in the field is necessary to provide teachers with accurate information about the illness and the ways to cope with it. PMID- 27240309 TI - Families' experiences of living with pediatric epilepsy: A qualitative systematic review. AB - Living with epilepsy in childhood has implications for the child and their family beyond the physical effects associated with epileptic seizures. Qualitative research has emerged, aiming to deliver a greater depth of understanding of the experiences of living with epilepsy from the perspectives of children with epilepsy, their parents, and their siblings. This review of qualitative research had three aims: first, to synthesize the demographic and epilepsy profiles of research participants in eligible studies in order to provide a clear picture of who are included and excluded when studying families' experiences; second, to present and discuss the methodological concerns and implications of research involving children with epilepsy; and third, to synthesize the findings arising from qualitative research with families in order to identify common themes across all relevant studies to date. Papers published in the English language prior to January 2016 were identified following a search of eight electronic databases: Embase, Psychinfo, Medline, CINAHL, Web of Knowledge, ASSIA, Web of Science, and SCOPUS. Studies were included if they involved a sample of children with epilepsy (up to 18years of age), parents, or siblings of children with epilepsy and used qualitative methods. Twenty-one studies were identified as eligible for inclusion in the review. Findings in relation to the three aims were the following: 1) Researchers were seeking an understanding of children's experiences directly from children rather than by parental proxy. However, children with learning disabilities were often excluded from research, meaning that their views are not being heard. Parental research was predominantly with mothers, and father experiences were not often accessed. There was very little research with siblings. 2) The rationale for and ethical implications of the choice of research methods adopted were not always clear, and not all studies gave adequate attention to the development of appropriate methods for research involving children. 3) Two dominant themes emerged across the studies: normalcy and children's agency. Cutting across many of the challenges that living with epilepsy presented was the desire (by parents and children) for a 'normal' childhood. The studies also highlighted that children have knowledge about their own condition and epilepsy more generally and that they are involved in managing the ways in which they cope with epilepsy, both in terms of seizure prevention and managing their relations with others, particularly peers. Future research should ensure that appropriate design, data collection, and analytic strategies are adopted to facilitate the participation of all family members. Enhancing the quality of the research will, in turn, optimize validity and opportunities for the translation of findings into better health, education, and social practices to improve care for children and their families affected by epilepsy. PMID- 27240310 TI - The effect of hypoxia on thermosensitive poly(N-vinylcaprolactam) hydrogels with tunable mechanical integrity for cartilage tissue engineering. AB - Cartilage repair presents a daunting challenge in tissue engineering applications due to the low oxygen conditions (hypoxia) affiliated in diseased states. Hence, the use of biomaterial scaffolds with unique variability is imperative to treat diseased or damaged cartilage. Thermosensitive hydrogels show promise as injectable materials that can be used as tissue scaffolds for cartilage tissue regeneration. However, uses in clinical applications are limited to due mechanical stability and therapeutic efficacy to treat diseased tissue. In this study, several composite hydrogels containing poly(N-vinylcaprolactam) (PVCL) and methacrylated hyaluronic acid (meHA) were prepared using free radical polymerization to produce PVCL-graft-HA (PVCL-g-HA) and characterized using Fourier transform infrared spectroscopy, nuclear magnetic resonance, and scanning electron microscopy. Lower critical solution temperatures and gelation temperatures were confirmed in the range of 33-34 degrees C and 41-45 degrees C, respectively. Using dynamic sheer rheology, the temperature dependence of elastic (G') and viscous (G") modulus between 25 degrees C and 45 degrees C, revealed that PVCL-g-HA hydrogels at 5% (w/v) concentration exhibited the moduli of 7 Pa (G') to 4 Pa (G"). After 10 days at 1% oxygen, collagen production on PVCL-g-HA hydrogels was 153 +/- 25 MUg/mg (20%) and 106 +/- 18 MUg/mg showing a 10-fold increase compared to meHA controls. These studies show promise in PVCL-g-HA hydrogels for the treatment of diseased or damaged articular cartilage. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1863 1873, 2017. PMID- 27240312 TI - Ambient air pollution and suicide in Tokyo, 2001-2011. AB - BACKGROUND: Some evidence suggests an association may exist between the level of air pollution and suicide mortality. However, this relation has been little studied to date. The current study examined the association in Tokyo, Japan. METHODS: Suicide mortality data for Tokyo for the 11-year period 2001-2011 were obtained together with data on four air pollutants: fine particulate matter (PM2.5), suspended particulate matter (SPM), sulphur dioxide (SO2) and nitrogen dioxide (NO2). A time-stratified case-crossover study design was used to examine the daily association between the level of air pollution and suicide mortality. RESULTS: During the study period there were 29,939 suicide deaths. In stratified analyses an interquartile range (IQR) increase in the same-day concentration of NO2 was linked to increased suicide mortality among those aged under 30 (percentage change: 6.73%, 95% CI: 0.69-13.12%). An IQR increase in PM2.5 and SO2 was associated with a 10.55% (95% CI: 2.05-19.75%) and 11.47% (95% CI: 3.60 19.93%) increase, respectively, in suicide mortality among widowed individuals for mean exposure on the first four days (average lags 0-3). Positive associations were observed for the air pollutants in the summer although associations were reversed in autumn. LIMITATIONS: We relied on monitoring data to approximate individual exposure to air pollutants. CONCLUSIONS: Higher levels of air pollution are associated with increased suicide mortality in some population subgroups in Tokyo. Further research is needed to elucidate the mechanisms linking air pollutants and suicide in this setting. PMID- 27240311 TI - Diagnostic performance of major depression disorder case-finding instruments used among mothers of young children in the United States: A systematic review. AB - INTRODUCTION: Growing recognition of the interrelated negative outcomes associated with major depression disorder (MDD) among mothers and their children has led to renewed public health interest in the early identification and treatment of maternal MDD. Healthcare providers, however, remain unsure of the validity of existing case-finding instruments. We conducted a systematic review to identify the most valid maternal MDD case-finding instrument used in the United States. METHODS: We identified articles reporting the sensitivity and specificity of MDD case-finding instruments based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) by systematically searching through three electronic bibliographic databases, PubMed, PsycINFO, and EMBASE, from 1994 to 2014. Study eligibility and quality were evaluated using the Standards for the Reporting of Diagnostic Accuracy studies and Quality Assessment of Diagnostic Accuracy Studies guidelines respectively. RESULTS: Overall, we retrieved 996 unduplicated articles and selected 74 for full-text review. Of these, 14 articles examining 21 different instruments were included in the systematic review. The 10 item Edinburgh Postnatal Depression Scale and Postpartum Depression Screening Scale had the most stable (lowest variation) and highest diagnostic performance during the antepartum and postpartum periods (sensitivity range: 0.63-0.94 and 0.67-0.95; specificity range: 0.83-0.98 and 0.68-0.97 respectively). Greater variation in diagnostic performance was observed among studies with higher MDD prevalence. LIMITATION: Factors that explain greater variation in instrument diagnostic performance in study populations with higher MDD prevalence were not examined. DISCUSSION: Findings suggest that the diagnostic performance of maternal MDD case-finding instruments is peripartum period-specific. PMID- 27240314 TI - Antibiofilm activity of sandblasted and laser-modified titanium against microorganisms isolated from peri-implantitis lesions. AB - Infections due to biofilm-producing microorganisms are one of the main causes for the failure of dental implants. Increasing efforts have been made in order to develop new strategies to prevent biofilm formation. In this study, the biofilm development on a newly designed laser-modified titanium implant surface was evaluated and compared to that on conventional sandblasted titanium used in implant dentistry. The amount of biofilm produced by Staphylococcus aureus, Pseudomonas aeruginosa and Porphyromonas gingivalis isolated from peri implantitis was assessed by a semi-quantitative spectrophotometric method and by confocal laser scanning microscopy. Results showed a lower biofilm production on laser-modified surface compared to the sandblasted one. In particular, a significantly lower total volume of the biomass was observed on laser-modified surface, while no significant changes in live/dead bacteria percentages were noticed between materials. Modifying the topography of the conventional implant surface with laser ablation could represent a promising approach for inhibiting biofilm formation. PMID- 27240315 TI - Novel Synthesis of Phytosterol Ester from Soybean Sterol and Acetic Anhydride. AB - Phytosterols are important bioactive compounds which have several health benefits including reduction of serum cholesterol and preventing cardiovascular diseases. The most widely used method in the synthesis of its ester analogous form is the use of catalysts and solvents. These methods have been found to present some safety and health concern. In this paper, an alternative method of synthesizing phytosterol ester from soybean sterol and acetic anhydride was investigated. Process parameters such as mole ratio, temperature and time were optimized. The structure and physicochemical properties of phytosterol acetic ester were analyzed. By the use of gas chromatography, the mole ratio of soybean sterol and acetic anhydride needed for optimum esterification rate of 99.4% was 1:1 at 135 degrees C for 1.5 h. FTIR spectra confirmed the formation of phytosterol ester with strong absorption peaks at 1732 and 1250 cm(-1) , which corresponds to the stretching vibration of C=O and C-O-C, respectively. These peaks could be attributed to the formation of ester links which resulted from the reaction between the hydroxyl group of soybean sterol and the carbonyl group of acetic anhydride. This paper provides a better alternative to the synthesis of phytosterol ester without catalyst and solvent residues, which may have potential application in the food, health-care food, and pharmaceutical industries. PMID- 27240316 TI - Quantitative systematic review of multi-professional teamwork and leadership training to optimize patient outcomes in acute hospital settings. AB - AIM: To evaluate the impact of multi-professional teamwork (MPTW) and leadership training interventions on patient outcomes in acute hospital settings. BACKGROUND: Although investigations of teamwork and leadership training in acute hospital settings indicate that such programs can optimize patient outcomes, evidence-based recommendations on the content, duration and frequency of training programs associated with clinical evidence are still absent. DESIGN: Quantitative systematic review. DATA SOURCES: A search was conducted for relevant papers published during the period from 2000-February 2014. REVIEW METHODS: Twelve studies met the inclusion criteria and were appraised for quality and a risk-of bias assessment was conducted. The review used a structured approach for literature search, data evaluation, analysis and presentation. A narrative summary was used to report results. RESULTS: Two MPTW and leadership interventions in stroke units have the greatest impact on patient outcomes in acute hospital settings. The interventions' impact on patient outcomes, explored in the ten remaining studies, is associated with great uncertainty due to several alternative explanations of the findings. CONCLUSION: Research designs that test such interventions must be improved before recommendations on the ultimate program can be made. This can be achieved by strengthening the design, methodology and descriptions of interventions and the use of more consistent patient outcomes. Building a safety culture adjacent to implementing teamwork and leadership training interventions is essential for improving patient outcomes. PMID- 27240317 TI - Empowering self-care ability - a follow-up study of clinical-based perimenopausal women personal health counselling. AB - AIMS AND OBJECTIVES: This study aimed to evaluate the longitudinal effects of a personal counselling intervention for perimenopausal women in northern Taiwan. BACKGROUND: Women face a variety of physical changes during menopause. Counselling intervention could enrich individual health education for menopausal women. DESIGN: Quasi-experimental design. METHODS: The study used one-on-one personal health counselling with a 'menopausal health passport' for perimenopausal women. The Perceived Perimenopausal Disturbances scale, the Practice of Health Behavior scale and the Perceived Uncertainty scale were used to measure the intervention effects. Results were estimated by a Generalized Estimating Equation procedure at one and a half months, three months and six months post intervention. In addition, data regarding perceived health changes were collected qualitatively through interviews in the experimental group at the sixth month. RESULTS: A total of 34 women were included in the experimental group, while 33 were in the control group. Interaction effect results showed that personal health counselling significantly increased the practice of health behaviours at one and a half months and extended to three months post intervention. Additionally, content categories, including 'relief of symptoms', 'establishment of health behaviors', 'interaction with others' and 'consideration from others' were identified in quantitative analysis. CONCLUSIONS: The results suggest that perimenopausal personal health counselling can effectively improve healthy behaviours. This study can also serve as a future reference for effective perimenopausal counselling. RELEVANCE TO CLINICAL PRACTICE: It is crucial to set up personal health counselling for perimenopausal women in clinics and develop information technology systems to support menopausal women in the technological era. PMID- 27240318 TI - Cardiothoracic CT and MRI in adults with tetralogy of Fallot: 11-year experience in a diverse, inner-city population. PMID- 27240319 TI - Evaluation of cystic duct patency: comparison of functional MR cholangiography with gadoxetate disodium and hepatobiliary scintigraphy in suspected acute cholecystitis. AB - PURPOSE: This study aims to compare assessment of cystic duct patency between gadoxetate disodium MRI and hepatobiliary scintigraphy. MATERIALS AND METHODS: We performed a prospective study of patients who underwent gadoxetate disodium MRI within 16 h of scintigraphy. RESULTS: The gallbladder filled on MRI and scintigraphy in 8 patients, none with acute cholecystitis. The mean time to gallbladder filling was 14.6 and 18.9 min for MRI and scintigraphy, respectively. The gallbladder did not fill on both MRI and scintigraphy in 3 patients, all of whom had acute cholecystitis. CONCLUSION: Evaluation of cystic duct patency using gadoxetate disodium MRI is comparable to hepatobiliary scintigraphy. PMID- 27240321 TI - Unexpected Steatotic Liver Lesions. PMID- 27240320 TI - Pten regulates spindle pole movement through Dlg1-mediated recruitment of Eg5 to centrosomes. AB - Phosphatase and tensin homologue (Pten) suppresses neoplastic growth by negatively regulating PI(3)K signalling through its phosphatase activity. To gain insight into the actions of non-catalytic Pten domains in normal physiological processes and tumorigenesis, we engineered mice lacking the PDZ-binding domain (PDZ-BD). Here, we show that the PDZ-BD regulates centrosome movement and that its heterozygous or homozygous deletion promotes aneuploidy and tumour formation. We found that Pten is recruited to pre-mitotic centrosomes in a Plk1-dependent fashion to create a docking site for protein complexes containing the PDZ-domain containing protein Dlg1 (also known as Sap97) and Eg5 (also known as Kif11), a kinesin essential for centrosome movement and bipolar spindle formation. Docking of Dlg1-Eg5 complexes to Pten depended on Eg5 phosphorylation by the Nek9-Nek6 mitotic kinase cascade and Cdk1. PDZ-BD deletion or Dlg1 ablation impaired loading of Eg5 onto centrosomes and spindle pole motility, yielding asymmetrical spindles that are prone to chromosome missegregation. Collectively, these data demonstrate that Pten, through the Dlg1-binding ability of its PDZ-BD, accumulates phosphorylated Eg5 at duplicated centrosomes to establish symmetrical bipolar spindles that properly segregate chromosomes, and suggest that this function contributes to tumour suppression. PMID- 27240322 TI - Rare, Life-Threatening Duodenal Bleeding. PMID- 27240323 TI - Hepatitis C and Numerous Disappearing Hepatic Nodules: No-dule C It, No-dule Don't. PMID- 27240324 TI - Enhanced differentiation of human amniotic fluid-derived stem cells into insulin producing cells in vitro. AB - AIMS/INTRODUCTION: To investigate the ability of human amniotic fluid stem cells (hAFSCs) to differentiate into insulin-producing cells. MATERIALS AND METHODS: hAFSCs were induced to differentiate into pancreatic cells by a multistep protocol. The expressions of pancreas-related genes and proteins, including pancreatic and duodenal homeobox-1, insulin, and glucose transporter 2, were detected by polymerase chain reaction and immunofluorescence. Insulin secreted from differentiated cells was tested by enzyme-linked immunosorbent assay. RESULTS: hAFSCs were successfully isolated from amniotic fluid that expressed the pluripotent markers of embryonic stem cells, such as Oct3/4, and mesenchymal stem cells, such as integrin beta-1 and ecto-5'-nucleotidase. Here, we first obtained the hAFSCs that expressed pluripotent marker stage-specific embryonic antigen 1. Real-time polymerase chain reaction analysis showed that pancreatic and duodenal homeobox-1, paired box gene 4 and paired box gene 6 were expressed in the early phase of induction, and then stably expressed in the differentiated cells. The pancreas-related genes, such as insulin, glucokinase, glucose transporter 2 and Nkx6.1, were expressed in the differentiated cells. Immunofluorescence showed that these differentiated cells co-expressed insulin, C-peptide, and pancreatic and duodenal homeobox-1. Insulin was released in response to glucose stimulation in a manner similar to that of adult human islets. CONCLUSIONS: The present study showed that hAFSCs, under selective culture conditions, could differentiate into islet-like insulin-producing cells, which might be used as a potential source for transplantation in patients with type 1 diabetes mellitus. PMID- 27240325 TI - Short, Enantioselective Total Synthesis of Highly Oxidized Taxanes. AB - In the realm of natural product chemistry, few isolates have risen to the level of fame justifiably accorded to Taxol (1) and its chemical siblings. This report describes the most concise route to date for accessing the highly oxidized members of this family. As representative members of taxanes containing five oxygen atoms, decinnamoyltaxinine E (2) and taxabaccatin III (3), have succumbed to enantioselective total synthesis for the first time in only 18 steps from a simple olefin starting material. The strategy holistically mimics nature's approach (two-phase synthesis) and features a carefully choreographed sequence of stereoselective oxidations and a remarkable redox-isomerization to set the key trans-diol present in 2 and 3. This work lays the critical groundwork necessary to access even higher oxidized taxanes such as 1 in a more practical fashion, thus empowering a medicinal chemistry campaign that is not wedded to semi synthesis. PMID- 27240326 TI - Characterization of New PEEK/HA Composites with 3D HA Network Fabricated by Extrusion Freeforming. AB - Addition of bioactive materials such as calcium phosphates or Bioglass, and incorporation of porosity into polyetheretherketone (PEEK) has been identified as an effective approach to improve bone-implant interfaces and osseointegration of PEEK-based devices. In this paper, a novel production technique based on the extrusion freeforming method is proposed that yields a bioactive PEEK/hydroxyapatite (PEEK/HA) composite with a unique configuration in which the bioactive phase (i.e., HA) distribution is computer-controlled within a PEEK matrix. The 100% interconnectivity of the HA network in the biocomposite confers an advantage over alternative forms of other microstructural configurations. Moreover, the technique can be employed to produce porous PEEK structures with controlled pore size and distribution, facilitating greater cellular infiltration and biological integration of PEEK composites within patient tissue. The results of unconfined, uniaxial compressive tests on these new PEEK/HA biocomposites with 40% HA under both static and cyclic mode were promising, showing the composites possess yield and compressive strength within the range of human cortical bone suitable for load bearing applications. In addition, preliminary evidence supporting initial biological safety of the new technique developed is demonstrated in this paper. Sufficient cell attachment, sustained viability in contact with the sample over a seven-day period, evidence of cell bridging and matrix deposition all confirmed excellent biocompatibility. PMID- 27240327 TI - The Rationale for Insulin Therapy in Alzheimer's Disease. AB - Alzheimer's disease (AD) is the most common form of dementia, with a prevalence that increases with age. By 2050, the worldwide number of patients with AD is projected to reach more than 140 million. The prominent signs of AD are progressive memory loss, accompanied by a gradual decline in cognitive function and premature death. AD is the clinical manifestation of altered proteostasis. The initiating step of altered proteostasis in most AD patients is not known. The progression of AD is accelerated by several chronic disorders, among which the contribution of diabetes to AD is well understood at the cell biology level. The pathological mechanisms of AD and diabetes interact and tend to reinforce each other, thus accelerating cognitive impairment. At present, only symptomatic interventions are available for treating AD. To optimise symptomatic treatment, a personalised therapy approach has been suggested. Intranasal insulin administration seems to open the possibility for a safe, and at least in the short term, effective symptomatic intervention that delays loss of cognition in AD patients. This review summarizes the interactions of AD and diabetes from the cell biology to the patient level and the clinical results of intranasal insulin treatment of cognitive decline in AD. PMID- 27240328 TI - Enantiopure Trisubstituted Tetrahydrofurans with Appendage Diversity: Vinyl Sulfone- and Vinyl Sulfoxide-Modified Furans Derived from Carbohydrates as Synthons for Diversity Oriented Synthesis. AB - Enantiomerically pure 2-substituted-2,5-dihydro-3-(aryl) sulfonyl/sulfinyl furans have been prepared from the easily accessible carbohydrate derivatives. The orientation of the substituents attached at the C-2 position of furans is sufficient to control the diastereoselectivity of the addition of various nucleophiles to the vinyl sulfone/sulfoxide-modified tetrahydrofurans, irrespective of the size of the group. The orientation of the substituents at the C-2 center also suppresses the influence of sulfoxides on the diastereoselectivity of the addition of various nucleophiles. The strategy leads to the creation of appendage diversity, affording a plethora of enantiomerically pure trisubstituted furanics for the first time. PMID- 27240329 TI - Phenolic Profile and Antioxidant Potential of Leaves from Selected Cotoneaster Medik. Species. AB - The antioxidant efficiency of 70% aqueous methanolic extracts from the leaves of twelve selected Cotoneaster Medik. species was evaluated using four complementary in vitro tests based on SET- (single electron transfer) and HAT-type (hydrogen atom transfer) mechanisms (DPPH, FRAP, O2(*-) and H2O2 scavenging assays). The samples exhibited the dose-dependent responses in all assays with activity parameters of EC50 = 18.5-34.5 ug/mL for DPPH; 0.9-3.8 mmol Fe(2+)/g for FRAP; SC50 = 27.7-74.8 ug/mL for O2(*-); and SC50 = 29.0-91.3 ug/mL for H2O2. Significant linear correlations (|r| = 0.76-0.97, p < 0.01) between activity parameters and total contents of phenolics (5.2%-15.4% GAE) and proanthocyanidins (2.1%-15.0% CYE), with weak or no effects for chlorogenic acid isomers (0.69% 2.93%) and total flavonoids (0.28%-1.40%) suggested that among the listed polyphenols, proanthocyanidins are the most important determinants of the tested activity. UHPLC-PDA-ESI-QTOF-MS analyses led to detection of 34 polyphenols, of which 10 B-type procyanidins, 5 caffeoylquinic acids and 14 flavonoids were identified. After cluster analysis of the data matrix, the leaves of Cotoneaster zabelii, C. splendens, C. bullatus, C. divaricatus, C. hjelmqvistii and C. lucidus were selected as the most promising sources of natural antioxidants, exhibiting the highest phenolic levels and antioxidant capacities, and therefore the greatest potential for pharmaceutical applications. PMID- 27240330 TI - Efficient Preparation of Streptochlorin from Marine Streptomyces sp. SYYLWHS-1-4 by Combination of Response Surface Methodology and High-Speed Counter-Current Chromatography. AB - Since first isolated from the lipophilic extract of Streptomyces sp. SF2583, streptochlorin, has attracted a lot of attention because of its various pharmacological properties, such as antibiotic, antiallergic, antitumor, and anti inflammatory activities. For the efficient preparation of streptochlorin from a producing strain Streptomyces sp. SYYLWHS-1-4, we developed a combinative method by using response surface methodology (RSM) and high-speed counter-current chromatography (HSCCC). In the fermentation process, we used RSM to optimize the condition for the efficient accumulation of streptochlorin, and the optimal parameters were: yeast extract 1.889 g/L, soluble starch 8.636 g/L, K2HPO4 0.359 g/L, CaCl2 2.5 g/L, MgSO4 0.625 g/L, marine salt 25 g/L, medium volume 50%, initial pH value 7.0, temperature 27.5 degrees C, which enhanced streptochlorin yield by 17.7-fold. During the purification process, the preparative HSCCC separation was performed using a petroleum ether-ethyl acetate-methanol-water (9:0.8:5:5, v/v/v/v) biphasic solvent system, where 300 mg of crude sample yielded 16.5 mg streptochlorin with over 95% purity as determined by UPLC. Consequently, the combination method provided a feasible strategy for highly effective preparation of streptochlorin, which ensured the supply of large amounts of streptochlorin for in vivo pharmacological assessments or other requirements. PMID- 27240331 TI - Expression of Terpenoid Biosynthetic Genes and Accumulation of Chemical Constituents in Valeriana fauriei. AB - Valeriana fauriei (V. fauriei), which emits a characteristic and unpleasant odor, is important in traditional medicine. In this study, the expression of terpenoid biosynthetic genes was investigated in different organs that were also screened for volatile compounds including valerenic acid and its derivatives. Specific expression patterns from different parts of V. fauriei were observed using quantitative real-time PCR (qRT-PCR). The highest transcript levels of biosynthetic genes involved in mevalonic acid (MVA) and methylerythritol phosphate (MEP) production were found in the stem. Although the amounts of volatile compounds were varied by organ, most of the volatile terpenoids were accumulated in the root. Gas chromatography mass spectrometry (GC-MS) analysis identified 128 volatile compounds, which represented 65.33% to 95.66% of total volatiles. Certain compounds were only found in specific organs. For example, isovalerenic acid and valerenic acid and its derivatives were restricted to the root. Organs with high transcript levels did not necessarily have high levels of the corresponding chemical constituents. According to these results, we hypothesize that translocation may occur between different organs in V. fauriei. PMID- 27240332 TI - Effects of Rhodomyrtus tomentosa Extract on Killing Activity of Human Neutrophils and Membrane Integrity of Enterohaemorrhagic Escherichia coli O157:H7. AB - Enterohaemorrhagic Escherichia coli (E. coli) O157:H7 is one of the most virulent causative agents of foodborne disease. Use of antibiotics for the treatment against E. coli O157:H7 infection leads to hemolytic uremic syndrome. The present study evaluated the potential of ethanolic leaf extract of a medicinal plant, Rhodomyrtus tomentosa in enhancing the killing activity of human neutrophils against E. coli O157:H7. In addition, the effects of the extract on membrane permeability of the organisms were studied. In the killing assay, percentage survival of the bacterial cells after being exposed to human neutrophils in the presence of various concentrations of the extract were determined. At 45 min, percentage survival of E. coli O157:H7 and E. coli ATCC 25922 after treated with neutrophils in the presence of the extract at 125-250 ug/mL was 58.48%-50.28% and 69.13%-35.35%, respectively. Furthermore, upon treatment with R. tomentosa at 250 ug/mL uptake of crystal violet by E. coli O157:H7 and E. coli ATCC 25922 was increased to 40.07% and 36.16%, respectively. Therefore, it is suggested that the extract exhibited dual effects as immunostimulant and membrane permeabilizing agent perhaps resulted in enhancing the killing activity of neutrophils against the organisms. PMID- 27240333 TI - Pharmacokinetic Evaluation of Clozapine in Concomitant Use of Radix Rehmanniae, Fructus Schisandrae, Radix Bupleuri, or Fructus Gardeniae in Rats. AB - Radix Rehmanniae, Fructus Schisandrae, Radix Bupleuri, and Fructus Gardeniae are often used alongside with clozapine (CLZ) for schizophrenia patients in order to reduce side effects and enhance therapeutic efficacy. However, worse outcomes were observed raising concern about a critical issue, herb-drug interactions, which were rarely reported when antipsychotics were included. This study aims to determine whether the concomitant use of these herbal medicines affects the pharmacokinetic characteristics of CLZ in rat models. Rats were given a single or multiple intraperitoneal injections of 10 mg/kg CLZ, either alone or with individual herbal water extracts administered orally. CLZ and its two inactive metabolites, norclozapine and clozapine N-oxide, were determined by high performance liquid chromatography/tandem mass spectrometry. In the acute treatment, the formation of both metabolites was reduced, while no significant change was observed in the CLZ pharmacokinetics for any of the herbal extracts. In the chronic treatment, none of the four herbal extracts significantly influenced the pharmacokinetic parameters of CLZ and its metabolites. Renal and liver functions stayed normal after the 11-day combined use of herbal medicines. Overall, the four herbs had limited interaction effect on CLZ pharmacokinetics in the acute and chronic treatment. Herb-drug interaction includes both pharmacokinetic and pharmacodynamic mechanisms. This result gives us a hint that pharmacodynamic herb-drug interaction, instead of pharmacokinetic types, may exist and need further confirmation. PMID- 27240334 TI - The Chiral Pool in the Pictet-Spengler Reaction for the Synthesis of beta Carbolines. AB - The Pictet-Spengler reaction (PSR) is the reaction of a beta-arylethylamine with an aldehyde or ketone, followed by ring closure to give an aza-heterocycle. When the beta-arylethylamine is tryptamine, the product is a beta-carboline, a widespread skeleton in natural alkaloids. In the natural occurrence, these compounds are generally enantiopure, thus the asymmetric synthesis of these compounds have been attracting the interest of organic chemists. This review aims to give an overview of the asymmetric PSR, in which the chirality arises from optically pure amines or carbonyl compounds both from natural sources and from asymmetric syntheses to assemble the reaction partners. PMID- 27240335 TI - Characterization and Enhanced Antioxidant Activity of the Cysteinyl beta Cyclodextrin-Baicalein Inclusion Complex. AB - Baicalein is a type of flavonoid isolated from the roots of a medicinal plant, Scutellaria baicalensis. Although it has attracted considerable attention due to its antiviral, anti-tumor, and anti-inflammatory activities, its limited aqueous solubility inhibits the clinical application of this flavonoid. The present study aimed to prepare and characterize a host-guest complex in an effort to improve the solubility and antioxidant activity of baicalein. The host molecule is a macrocyclic beta-cyclodextrin (beta-CD) functionalized with cysteine for a synergetic effect. The structure of the synthesized cysteinyl beta-CD was analyzed using nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry. The inclusion complex with baicalein was studied by UV-vis, NMR spectroscopy, scanning electron microscopy, and X-ray powder diffractometry. The formed cysteinyl beta-CD/baicalein inclusion complex efficiently improved the solubility and antioxidant ability of baicalein. Therefore, we suggest that the present cysteinyl beta-CD is a potential host molecule for inclusion complexation and for bioavailability augmentation. PMID- 27240336 TI - Characterization of Active Packaging Films Made from Poly(Lactic Acid)/Poly(Trimethylene Carbonate) Incorporated with Oregano Essential Oil. AB - Antimicromial and antioxidant bioactive films based on poly(lactic acid)/poly(trimenthylene carbonate) films incorporated with different concentrations of oregano essential oil (OEO) were prepared by solvent casting. The antimicrobial, antioxidant, physical, thermal, microstructural, and mechanical properties of the resulting films were examined. Scanning electron microscopy analysis revealed that the cross-section of films became rougher when OEO was incorporated into PLA/PTMC blends. Differential scanning calorimetry analysis indicated that crystallinity of PLA phase decreased by the addition of OEO, but this did not affect the thermal stability of the films. Water vapor permeability of films slightly increased with increasing concentration of OEO. However, active PLA/PTMC/OEO composite films showed adequate barrier properties for food packaging application. The antimicrobial and antioxidant capacities were significantly improved with the incorporation of OEO (p < 0.05). The results demonstrated that an optimal balance between the mechanical, barrier, thermal, antioxidant, and antimicrobial properties of the films was achieved by the incorporation of 9 wt % OEO into PLA/PTMC blends. PMID- 27240337 TI - Inhalable Antitubercular Therapy Mediated by Locust Bean Gum Microparticles. AB - Tuberculosis remains a major global health problem and alternative therapeutic approaches are needed. Considering the high prevalence of lung tuberculosis (80% of cases), the pulmonary delivery of antitubercular drugs in a carrier system capable of reaching the alveoli, being recognised and phagocytosed by alveolar macrophages (mycobacterium hosts), would be a significant improvement to current oral drug regimens. Locust bean gum (LBG) is a polysaccharide composed of galactose and mannose residues, which may favour specific recognition by macrophages and potentiate phagocytosis. LBG microparticles produced by spray drying are reported herein for the first time, incorporating either isoniazid or rifabutin, first-line antitubercular drugs (association efficiencies >82%). Microparticles have adequate theoretical properties for deep lung delivery (aerodynamic diameters between 1.15 and 1.67 MUm). The cytotoxic evaluation in lung epithelial cells (A549 cells) and macrophages (THP-1 cells) revealed a toxic effect from rifabutin-loaded microparticles at the highest concentrations, but we may consider that these were very high comparing with in vivo conditions. LBG microparticles further evidenced strong ability to be captured by macrophages (percentage of phagocytosis >94%). Overall, the obtained data indicated the potential of the proposed system for tuberculosis therapy. PMID- 27240338 TI - Preparative Purification of Anti-Proliferative Diarylheptanoids from Betula platyphylla by High-Speed Counter-Current Chromatography. AB - A simple and rapid method using high-speed counter-current chromatography (HSCCC), along with bioassay-guided fractionation based on the anti-proliferative activity against renal and colon cancer cells, has been developed for the preparative separation of aceroside VIII (1) and platyphylloside (2) from Betula platyphylla. A solvent system composed of ethyl acetate/acetonitrile/water (1:0.1:1, v/v/v) was optimized for the separation. The upper phase was used as the stationary phase, and the lower phase was used as the mobile phase. Among these isolated diarylheptanoids, platyphylloside (2) showed anti-proliferative activity in the COLO205 and KM12 colon cells and renal cancer cell lines A498, U031, as well as in MG63 and MG 63.3 osteosarcoma cells. In addition, it showed dose dependent inhibitory effects in the NCI 60 cell line assay. These results suggest that the diarylheptanoids isolated from B. platyphylla with an efficient HSCCC method could be potential multi-targeted therapeutic agents for cancer. PMID- 27240339 TI - A Theoretical Study of the Hydration of Methane, from the Aqueous Solution to the sI Hydrate-Liquid Water-Gas Coexistence. AB - Monte Carlo and molecular dynamics simulations were done with three recent water models TIP4P/2005 (Transferable Intermolecular Potential with 4 Points/2005), TIP4P/Ice (Transferable Intermolecular Potential with 4 Points/ Ice) and TIP4Q (Transferable Intermolecular Potential with 4 charges) combined with two models for methane: an all-atom one OPLS-AA (Optimal Parametrization for the Liquid State) and a united-atom one (UA); a correction for the C-O interaction was applied to the latter and used in a third set of simulations. The models were validated by comparison to experimental values of the free energy of hydration at 280, 300, 330 and 370 K, all under a pressure of 1 bar, and to the experimental radial distribution functions at 277, 283 and 291 K, under a pressure of 145 bar. Regardless of the combination rules used for sigmaC,O, good agreement was found, except when the correction to the UA model was applied. Thus, further simulations of the sI hydrate were performed with the united-atom model to compare the thermal expansivity to the experiment. A final set of simulations was done with the UA methane model and the three water models, to study the sI hydrate-liquid water-gas coexistence at 80, 230 and 400 bar. The melting temperatures were compared to the experimental values. The results show the need to perform simulations with various different models to attain a reliable and robust molecular image of the systems of interest. PMID- 27240341 TI - Heterogeneous Pathology of Melasma and Its Clinical Implications. AB - Melasma is a commonly acquired hypermelanosis that affects sun-exposed areas of the skin, with frequent facial involvement. Its histologic manifestations are evident in the epidermis, extracellular matrix, and dermis. In addition to epidermal pigmentation, pathologic findings of melasma include extracellular matrix abnormality, especially solar elastosis. The disrupted basement membrane has been described in melasma with variable incidences. In the dermis, an increase in vascularity and an increase in the number of mast cells were observed, indicating that dermal factors have critical roles in the pathogenesis of melasma, despite the fact that melasma is characterized by epidermal hyperpigmentation. This review discusses such histologic characteristics of melasma, with consideration to their implications for melasma treatment. PMID- 27240342 TI - MT1-MMP Inhibits the Activity of Bst-2 via Their Cytoplasmic Domains Dependent Interaction. AB - Bst-2 (bone marrow stromal cell antigen 2) is a type II membrane protein, and it acts as a tetherin to inhibit virion releasing from infectious cells. Membrane type-1 matrix metalloproteinase (MT1-MMP) is a protease. It plays a pivotal role in cellular growth and migration by activating proMMP-2 into active MMP2. Our results here elaborate that MT1-MMP inhibits the tetherin activity of Bst-2 by interacting with Bst-2, and the cytoplasmic domains of both Bst-2 and MT1-MMP play critical roles within this interaction. Based on our experimental data, the assays for virion release and co-immunoprecipitation have clearly demonstrated that the activity of Bst-2 is markedly inhibited by MT1-MMP via their interaction; and both the N-terminal domain of Bst-2 and the C-terminal domain of MT1-MMP are important in the interaction. Immunostaining and Confocal Microscopy assay shows that MT1-MMP interacts with Bst-2 to form granular particles trafficking into cytoplasm from membrane and, finally, results in Bst-2 and MT1 MMP both being inhibited. In addition, mutant experiments elucidate that the N terminal domain of Bst-2 is not only important in relating to the activity of Bst 2 itself, but is important for inhibiting the MT1-MMP/proMMP2/MMP2 pathway. These findings suggest that MT1-MMP is a novel inhibitor of Bst-2 in MT1-MMP expressed cell lines and also indicate that both the N-terminal domain of Bst-2 and the C terminal domain of MT1-MMP are crucial in down-regulation. PMID- 27240343 TI - Metabolic Fingerprinting to Assess the Impact of Salinity on Carotenoid Content in Developing Tomato Fruits. AB - As the presence of health-promoting substances has become a significant aspect of tomato fruit appreciation, this study investigated nutrient solution salinity as a tool to enhance carotenoid accumulation in cherry tomato fruit (Solanum lycopersicum L. cv. Juanita). Hereby, a key objective was to uncover the underlying mechanisms of carotenoid metabolism, moving away from typical black box research strategies. To this end, a greenhouse experiment with five salinity treatments (ranging from 2.0 to 5.0 decisiemens (dS) m(-1)) was carried out and a metabolomic fingerprinting approach was applied to obtain valuable insights on the complicated interactions between salinity treatments, environmental conditions, and the plant's genetic background. Hereby, several hundreds of metabolites were attributed a role in the plant's salinity response (at the fruit level), whereby the overall impact turned out to be highly depending on the developmental stage. In addition, 46 of these metabolites embraced a dual significance as they were ascribed a prominent role in carotenoid metabolism as well. Based on the specific mediating actions of the retained metabolites, it could be determined that altered salinity had only marginal potential to enhance carotenoid accumulation in the concerned tomato fruit cultivar. This study invigorates the usefulness of metabolomics in modern agriculture, for instance in modeling tomato fruit quality. Moreover, the metabolome changes that were caused by the different salinity levels may enclose valuable information towards other salinity-related plant processes as well. PMID- 27240340 TI - The miRacle in Pancreatic Cancer by miRNAs: Tiny Angels or Devils in Disease Progression. AB - Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with increasing incidence and high mortality. Surgical resection is the only potentially curative treatment of patients with PDAC. Because of the late presentation of the disease, about 20 percent of patients are candidates for this treatment. The average survival of resected patients is between 12 and 20 months, with a high probability of relapse. Standard chemo and radiation therapies do not offer significant improvement of the survival of these patients. Furthermore, novel treatment options aimed at targeting oncogenes or growth factors in pancreatic cancer have proved unsuccessful. Thereby, identifying new biomarkers that can detect early stages of this disease is of critical importance. Among these biomarkers, microRNAs (miRNAs) have supplied a profitable recourse and become an attractive focus of research in PDAC. MiRNAs regulate many genes involved in the development of PDAC through mRNA degradation or translation inhibition. The possibility of intervention in the molecular mechanisms of miRNAs regulation could begin a new generation of PDAC therapies. This review summarizes the reports describing miRNAs involvement in cellular processes involving pancreatic carcinogenesis and their utility in diagnosis, survival and therapeutic potential in pancreatic cancer. PMID- 27240344 TI - Targeted Gene Knockin in Porcine Somatic Cells Using CRISPR/Cas Ribonucleoproteins. AB - The pig is an ideal large animal model for genetic engineering applications. A relatively short gestation interval and large litter size makes the pig a conducive model for generating and propagating genetic modifications. The domestic pig also shares close similarity in anatomy, physiology, size, and life expectancy, making it an ideal animal for modeling human diseases. Often, however, the technical difficulties in generating desired genetic modifications such as targeted knockin of short stretches of sequences or transgenes have impeded progress in this field. In this study, we have investigated and compared the relative efficiency of CRISPR/Cas ribonucleoproteins in engineering targeted knockin of pseudo attP sites downstream of a ubiquitously expressed COL1A gene in porcine somatic cells and generated live fetuses by somatic cell nuclear transfer (SCNT). By leveraging these knockin pseudo attP sites, we have demonstrated subsequent phiC31 integrase mediated integration of green fluorescent protein (GFP) transgene into the site. This work for the first time created an optimized protocol for CRISPR/Cas mediated knockin in porcine somatic cells, while simultaneously creating a stable platform for future transgene integration and generating transgenic animals. PMID- 27240345 TI - Cloning, Expression and 3D Structure Prediction of Chitinase from Chitinolyticbacter meiyuanensis SYBC-H1. AB - Two CHI genes from Chitinolyticbacter meiyuanensis SYBC-H1 encoding chitinases were identified and their protein 3D structures were predicted. According to the amino acid sequence alignment, CHI1 gene encoding 166 aa had a structural domain similar to the GH18 type II chitinase, and CHI2 gene encoding 383 aa had the same catalytic domain as the glycoside hydrolase family 19 chitinase. In this study, CHI2 chitinase were expressed in Escherichia coli BL21 cells, and this protein was purified by ammonium sulfate precipitation, DEAE-cellulose, and Sephadex G 100 chromatography. Optimal activity of CHI2 chitinase occurred at a temperature of 40 degrees C and a pH of 6.5. The presence of metal ions Fe(3+), Fe(2+), and Zn(2+) inhibited CHI2 chitinase activity, while Na+ and K+ promoted its activity. Furthermore, the presence of EGTA, EDTA, and beta-mercaptoethanol significantly increased the stability of CHI2 chitinase. The CHI2 chitinase was active with p NP-GlcNAc, with the Km and Vm values of 23.0 umol/L and 9.1 mM/min at a temperature of 37 degrees C, respectively. Additionally, the CHI2 chitinase was characterized as an N-acetyl glucosaminidase based on the hydrolysate from chitin. Overall, our results demonstrated CHI2 chitinase with remarkable biochemical properties is suitable for bioconversion of chitin waste. PMID- 27240346 TI - Fast Modeling of Binding Affinities by Means of Superposing Significant Interaction Rules (SSIR) Method. AB - The Superposing Significant Interaction Rules (SSIR) method is described. It is a general combinatorial and symbolic procedure able to rank compounds belonging to combinatorial analogue series. The procedure generates structure-activity relationship (SAR) models and also serves as an inverse SAR tool. The method is fast and can deal with large databases. SSIR operates from statistical significances calculated from the available library of compounds and according to the previously attached molecular labels of interest or non-interest. The required symbolic codification allows dealing with almost any combinatorial data set, even in a confidential manner, if desired. The application example categorizes molecules as binding or non-binding, and consensus ranking SAR models are generated from training and two distinct cross-validation methods: leave-one out and balanced leave-two-out (BL2O), the latter being suited for the treatment of binary properties. PMID- 27240347 TI - Dendritic-Tumor Fusion Cell-Based Cancer Vaccines. AB - Dendritic cells (DCs) are potent antigen-presenting cells (APCs) that play a critical role in the induction of antitumor immunity. Therefore, various strategies have been developed to deliver tumor-associated antigens (TAAs) to DCs as cancer vaccines. The fusion of DCs and whole tumor cells to generate DC-tumor fusion cells (DC-tumor FCs) is an alternative strategy to treat cancer patients. The cell fusion method allows DCs to be exposed to the broad array of TAAs originally expressed by whole tumor cells. DCs then process TAAs endogenously and present them through major histocompatibility complex (MHC) class I and II pathways in the context of costimulatory molecules, resulting in simultaneous activation of both CD4+ and CD8+ T cells. DC-tumor FCs require optimized enhanced immunogenicity of both DCs and whole tumor cells. In this context, an effective fusion strategy also needs to produce immunogenic DC-tumor FCs. We discuss the potential ability of DC-tumor FCs and the recent progress in improving clinical outcomes by DC-tumor FC-based cancer vaccines. PMID- 27240348 TI - Association of Genetic Polymorphisms of Renin-Angiotensin-Aldosterone System Related Genes with Arterio-Venous Fistula Malfunction in Hemodialysis Patients. AB - Hemodialysis (HD) is the most commonly-used renal replacement therapy for patients with end-stage renal disease worldwide. Arterio-venous fistula (AVF) is the vascular access of choice for HD patients with lowest risk of infection and thrombosis. In addition to environmental factors, genetic factors may also contribute to malfunction of AVF. Previous studies have demonstrated the effect of genotype polymorphisms of angiotensin converting enzyme on vascular access malfunction. We conducted a multicenter, cross-sectional study to evaluate the association between genetic polymorphisms of renin-angiotensin-aldosterone system and AVF malfunction. Totally, 577 patients were enrolled. Their mean age was 60 years old and 53% were male. HD patients with AVF malfunction had longer duration of HD (92.5 +/- 68.1 vs. 61.2 +/- 51.9 months, p < 0.001), lower prevalence of hypertension (44.8% vs. 55.3%, p = 0.025), right-sided (31.8% vs. 18.4%, p = 0.002) and upper arm AVF (26.6% vs. 9.7%, p < 0.001), and higher mean dynamic venous pressure (DVP) (147.8 +/- 28.3 vs. 139.8 +/- 30.0, p = 0.021). In subgroup analysis of different genders, location of AVF and DVP remained significant clinical risk factors of AVF malfunction in univariate and multivariate binary logistic regression in female HD patients. Among male HD patients, univariate binary logistic regression analysis revealed that right-side AVF and upper arm location are two important clinical risk factors. In addition, two single nucleotide polymorphisms (SNPs), rs275653 (Odds ratio 1.90, p = 0.038) and rs1492099 (Odds ratio 2.29, p = 0.017) of angiotensin II receptor 1 (AGTR1), were associated with increased risk of AVF malfunction. After adjustment for age and other clinical factors, minor allele-containing genotype polymorphisms (AA and CA) of rs1492099 still remained to be a significant risk factor of AVF malfunction (Odds ratio 3.63, p = 0.005). In conclusion, we demonstrated that rs1492099, a SNP of AGTR1 gene, could be a potential genetic risk factor of AVF malfunction in male HD patients. PMID- 27240349 TI - Transcriptome and Difference Analysis of Fenpropathrin Resistant Predatory Mite, Neoseiulus barkeri (Hughes). AB - Several fenpropathrin-resistant predatory mites have been reported. However, the molecular mechanism of the resistance remains unknown. In the present study, the Neoseiulus barkeri (N. barkeri) transcriptome was generated using the Illumina sequencing platform, 34,211 unigenes were obtained, and 15,987 were manually annotated. After manual annotation, attentions were attracted to resistance related genes, such as voltage-gated sodium channel (VGSC), cytochrome P450s (P450s), and glutathione S-transferases (GSTs). A polymorphism analysis detected two point mutations (E1233G and S1282G) in the linker region between VGSC domain II and III. In addition, 43 putative P450 genes and 10 putative GST genes were identified from the transcriptome. Among them, two P450 genes, NbCYP4EV2 and NbCYP4EZ1, and four GST genes, NbGSTd01, NbGSTd02, NbGSTd03 and NbGSTm03, were remarkably overexpressed 3.64-46.69-fold in the fenpropathrin resistant strain compared to that in the susceptible strain. These results suggest that fenpropathrin resistance in N. barkeri is a complex biological process involving many genetic changes and provide new insight into the N. barkeri resistance mechanism. PMID- 27240350 TI - Metabolomic Profiling of Bradyrhizobium diazoefficiens-Induced Root Nodules Reveals Both Host Plant-Specific and Developmental Signatures. AB - Bradyrhizobium diazoefficiens is a nitrogen-fixing endosymbiont, which can grow inside root-nodule cells of the agriculturally important soybean and other host plants. Our previous studies described B. diazoefficiens host-specific global expression changes occurring during legume infection at the transcript and protein level. In order to further characterize nodule metabolism, we here determine by flow injection-time-of-flight mass spectrometry analysis the metabolome of (i) nodules and roots from four different B. diazoefficiens host plants; (ii) soybean nodules harvested at different time points during nodule development; and (iii) soybean nodules infected by two strains mutated in key genes for nitrogen fixation, respectively. Ribose (soybean), tartaric acid (mungbean), hydroxybutanoyloxybutanoate (siratro) and catechol (cowpea) were among the metabolites found to be specifically elevated in one of the respective host plants. While the level of C4-dicarboxylic acids decreased during soybean nodule development, we observed an accumulation of trehalose-phosphate at 21 days post infection (dpi). Moreover, nodules from non-nitrogen-fixing bacteroids (nifA and nifH mutants) showed specific metabolic alterations; these were also supported by independent transcriptomics data. The alterations included signs of nitrogen limitation in both mutants, and an increased level of a phytoalexin in nodules induced by the nifA mutant, suggesting that the tissue of these nodules exhibits defense and stress reactions. PMID- 27240351 TI - Serum Galectin-9 and Galectin-3-Binding Protein in Acute Dengue Virus Infection. AB - Dengue fever is a serious threat for public health and induces various inflammatory cytokines and mediators, including galectins and glycoproteins. Diverse immune responses and immunological pathways are induced in different phases of dengue fever progression. However, the status of serum galectins and glycoproteins is not fully determined. The aim of this study was to investigate the serum concentration and potential interaction of soluble galectin-1, galectin 3, galectin-9, galectin-3 binding protein (galectin-3BP), glycoprotein 130 (gp130), and E-, L-, and P-selectin in patients with dengue fever in acute febrile phase. In this study, 317 febrile patients (187 dengue patients, 150 non dengue patients that included 48 patients with bacterial infection and 102 patients with other febrile illness) who presented to the emergency department and 20 healthy controls were enrolled. Our results showed the levels of galectin 9 and galectin-3BP were significantly higher in dengue patients than those in healthy controls. Lower serum levels of galectin-1, galectin-3, and E-, L-, and P selectin in dengue patients were detected compared to bacteria-infected patients, but not to healthy controls. In addition, strong correlation between galectin-9 and galectin-3BP was observed in dengue patients. In summary, our study suggested galectin-9 and galectin-3BP might be critical inflammatory mediators in acute dengue virus infection. PMID- 27240352 TI - Structural Characterization of Heme Environmental Mutants of CgHmuT that Shuttles Heme Molecules to Heme Transporters. AB - Corynebacteria contain a heme uptake system encoded in hmuTUV genes, in which HmuT protein acts as a heme binding protein to transport heme to the cognate transporter HmuUV. The crystal structure of HmuT from Corynebacterium glutamicum (CgHmuT) reveals that heme is accommodated in the central cleft with His141 and Tyr240 as the axial ligands and that Tyr240 forms a hydrogen bond with Arg242. In this work, the crystal structures of H141A, Y240A, and R242A mutants were determined to understand the role of these residues for the heme binding of CgHmuT. Overall and heme environmental structures of these mutants were similar to those of the wild type, suggesting that there is little conformational change in the heme-binding cleft during heme transport reaction with binding and the dissociation of heme. A loss of one axial ligand or the hydrogen bonding interaction with Tyr240 resulted in an increase in the redox potential of the heme for CgHmuT to be reduced by dithionite, though the wild type was not reduced under physiological conditions. These results suggest that the heme environmental structure stabilizes the ferric heme binding in CgHmuT, which will be responsible for efficient heme uptake under aerobic conditions where Corynebacteria grow. PMID- 27240353 TI - The Effect of Hydrofluoric Acid Etching Duration on the Surface Micromorphology, Roughness, and Wettability of Dental Ceramics. AB - The current laboratory study is evaluating the effect of hydrofluoric acid etching duration on the surface characteristics of five silica-based glass ceramics. Changes in the pore pattern, crystal structure, roughness, and wettability were compared and evaluated. Seventy-five rectangularly shaped specimens were cut from each material (IPS e-maxTM, Dentsply CeltraTM, Vita SuprinityTM, Vita mark IITM, and Vita Suprinity FCTM); the sectioned samples were finished, polished, and ultrasonically cleaned. Specimens were randomly assigned into study groups: control (no etching) and four experimental groups (20, 40, 80 and 160 s of etching). The etched surfaces' microstructure including crystal structure, pore pattern, pore depth, and pore width was studied under a scanning electron microscope, and the surface roughness and wettability were analyzed using a non-contact surface profilometer and a contact angle measuring device, respectively. The results were statistically analyzed using one-way analysis of variance (ANOVA) and the post hoc Tukey's test. The results showed a significant change in the pore number, pore pattern, crystal structure, surface roughness, and wettability with increased etching duration. Etching for a short time resulted in small pores, and etching for longer times resulted in wider, irregular grooves. A significant increase in the surface roughness and wettability was observed with an increase in the etching duration. The findings also suggested a strong association between the surface roughness and wettability. PMID- 27240354 TI - The Fundamental Role of NOX Family Proteins in Plant Immunity and Their Regulation. AB - NADPH oxidases (NOXs), also known as respiratory burst oxidase homologs (RBOHs), are the major source of reactive oxygen species (ROS), and are involved in many important processes in plants such as regulation of acclimatory signaling and programmed cell death (PCD). Increasing evidence shows that NOXs play crucial roles in plant immunity and their functions in plant immune responses are not as separate individuals but with other signal molecules such as kinases, Rac/Rop small GTPases and hormones, mediating a series of signal transmissions. In a similar way, NOX-mediated signaling also participates in abiotic stress response of plants. We summarized here the complex role and regulation mechanism of NOXs in mediating plant immune response, and the viewpoint that abiotic stress response of plants may be a kind of special plant immunity is also proposed. PMID- 27240355 TI - Mast Cell Tryptase Contributes to Pancreatic Cancer Growth through Promoting Angiogenesis via Activation of Angiopoietin-1. AB - Pancreatic cancer is a highly lethal malignancy and one of the leading causes of cancer-related death. During the development and progression of cancer, tumor angiogenesis plays a crucial role. A great deal of evidence has revealed that human mast cells (MCs) contributed to tumor angiogenesis through releasing several pro-angiogenetic factors, among which tryptase is one of the most active. However, the role of mast cell tryptase (MCT) in human pancreatic cancer angiogenesis is still not well documented. In this study, we examined the MCT levels in serum from pancreatic cancer patients and evaluated the correlationship of the MCT level and tumor angiogenesis. In addition, the effect of MCT on endothelial cell proliferation and tube formation was investigated both in vitro and in nude mice bearing pancreatic tumor. It was found that MCT contributes to endothelial cell growth and tube formation via up-regulation of angiopoietin-1 expression. Moreover, using the MCT inhibitor nafamostat, tryptase-induced angiogenesis was obviously suppressed both in vitro and in vivo. Our findings suggest that MCT plays an important role in pancreatic cancer angiogenesis and tumor growth via activating the angiopoietin-1 pathway, and tryptase inhibitors may be evaluated as an effective anti-angiogenetic approach in pancreatic cancer therapy. PMID- 27240356 TI - Phenolic Compounds in the Potato and Its Byproducts: An Overview. AB - The potato (Solanum tuberosum L.) is a tuber that is largely used for food and is a source of different bioactive compounds such as starch, dietary fiber, amino acids, minerals, vitamins, and phenolic compounds. Phenolic compounds are synthetized by the potato plant as a protection response from bacteria, fungi, viruses, and insects. Several works showed that these potato compounds exhibited health-promoting effects in humans. However, the use of the potato in the food industry submits this vegetable to different processes that can alter the phenolic content. Moreover, many of these compounds with high bioactivity are located in the potato's skin, and so are eliminated as waste. In this review the most recent articles dealing with phenolic compounds in the potato and potato byproducts, along with the effects of harvesting, post-harvest, and technological processes, have been reviewed. Briefly, the phenolic composition, main extraction, and determination methods have been described. In addition, the "alternative" food uses and healthy properties of potato phenolic compounds have been addressed. PMID- 27240357 TI - Physico-Chemical and Structural Interpretation of Discrete Derivative Indices on N-Tuples Atoms. AB - This report examines the interpretation of the Graph Derivative Indices (GDIs) from three different perspectives (i.e., in structural, steric and electronic terms). It is found that the individual vertex frequencies may be expressed in terms of the geometrical and electronic reactivity of the atoms and bonds, respectively. On the other hand, it is demonstrated that the GDIs are sensitive to progressive structural modifications in terms of: size, ramifications, electronic richness, conjugation effects and molecular symmetry. Moreover, it is observed that the GDIs quantify the interaction capacity among molecules and codify information on the activation entropy. A structure property relationship study reveals that there exists a direct correspondence between the individual frequencies of atoms and Huckel's Free Valence, as well as between the atomic GDIs and the chemical shift in NMR, which collectively validates the theory that these indices codify steric and electronic information of the atoms in a molecule. Taking in consideration the regularity and coherence found in experiments performed with the GDIs, it is possible to say that GDIs possess plausible interpretation in structural and physicochemical terms. PMID- 27240358 TI - Computational Studies of a Mechanism for Binding and Drug Resistance in the Wild Type and Four Mutations of HIV-1 Protease with a GRL-0519 Inhibitor. AB - Drug resistance of mutations in HIV-1 protease (PR) is the most severe challenge to the long-term efficacy of HIV-1 PR inhibitor in highly active antiretroviral therapy. To elucidate the molecular mechanism of drug resistance associated with mutations (D30N, I50V, I54M, and V82A) and inhibitor (GRL-0519) complexes, we have performed five molecular dynamics (MD) simulations and calculated the binding free energies using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method. The ranking of calculated binding free energies is in accordance with the experimental data. The free energy spectra of each residue and inhibitor interaction for all complexes show a similar binding model. Analysis based on the MD trajectories and contribution of each residues show that groups R2 and R3 mainly contribute van der Waals energies, while groups R1 and R4 contribute electrostatic interaction by hydrogen bonds. The drug resistance of D30N can be attributed to the decline in binding affinity of residues 28 and 29. The size of Val50 is smaller than Ile50 causes the residue to move, especially in chain A. The stable hydrophobic core, including the side chain of Ile54 in the wild type (WT) complex, became unstable in I54M because the side chain of Met54 is flexible with two alternative conformations. The binding affinity of Ala82 in V82A decreases relative to Val82 in WT. The present study could provide important guidance for the design of a potent new drug resisting the mutation inhibitors. PMID- 27240360 TI - Computer-Aided Sensor Development Focused on Security Issues. AB - The paper examines intelligent sensor and sensor system development according to the Common Criteria methodology, which is the basic security assurance methodology for IT products and systems. The paper presents how the development process can be supported by software tools, design patterns and knowledge engineering. The automation of this process brings cost-, quality-, and time related advantages, because the most difficult and most laborious activities are software-supported and the design reusability is growing. The paper includes a short introduction to the Common Criteria methodology and its sensor-related applications. In the experimental section the computer-supported and patterns based IT security development process is presented using the example of an intelligent methane detection sensor. This process is supported by an ontology based tool for security modeling and analyses. The verified and justified models are transferred straight to the security target specification representing security requirements for the IT product. The novelty of the paper is to provide a patterns-based and computer-aided methodology for the sensors development with a view to achieving their IT security assurance. The paper summarizes the validation experiment focused on this methodology adapted for the sensors system development, and presents directions of future research. PMID- 27240361 TI - Defining Requirements and Related Methods for Designing Sensorized Garments. AB - Designing smart garments has strong interdisciplinary implications, specifically related to user and technical requirements, but also because of the very different applications they have: medicine, sport and fitness, lifestyle monitoring, workplace and job conditions analysis, etc. This paper aims to discuss some user, textile, and technical issues to be faced in sensorized clothes development. In relation to the user, the main requirements are anthropometric, gender-related, and aesthetical. In terms of these requirements, the user's age, the target application, and fashion trends cannot be ignored, because they determine the compliance with the wearable system. Regarding textile requirements, functional factors-also influencing user comfort-are elasticity and washability, while more technical properties are the stability of the chemical agents' effects for preserving the sensors' efficacy and reliability, and assuring the proper duration of the product for the complete life cycle. From the technical side, the physiological issues are the most important: skin conductance, tolerance, irritation, and the effect of sweat and perspiration are key factors for reliable sensing. Other technical features such as battery size and duration, and the form factor of the sensor collector, should be considered, as they affect aesthetical requirements, which have proven to be crucial, as well as comfort and wearability. PMID- 27240362 TI - X-ray Photon Counting and Two-Color X-ray Imaging Using Indirect Detection. AB - In this paper, we report on the design and performance of a 1 cm2, 90 * 92-pixel image sensor. It is made X-ray sensitive by the use of a scintillator. Its pixels have a charge packet counting circuit topology with two channels, each realizing a different charge packet size threshold and analog domain event counting. Here, the sensor's performance was measured in setups representative of a medical X-ray environment. Further, two-energy-level photon counting performance is demonstrated, and its capabilities and limitations are documented. We then provide an outlook on future improvements. PMID- 27240363 TI - Development of a Tonometric Sensor with a Decoupled Circular Array for Precisely Measuring Radial Artery Pulse. AB - The radial artery pulse is one of the major diagnostic indices used clinically in both Eastern and Western medicine. One of the prominent methods for measuring the radial artery pulse is the piezoresistive sensor array. Independence among channels and an appropriate sensor arrangement are important for effectively assessing the spatial-temporal information of the pulse. This study developed a circular-type seven-channel piezoresistive sensor array using face-down bonding (FDB) as one of the sensor combination methods. The three-layered housing structure that included independent pressure sensor units using the FDB method not only enabled elimination of the crosstalk among channels, but also allowed various array patterns to be created for effective pulse measurement. The sensors were arranged in a circular-type arrangement such that they could estimate the direction of the radial artery and precisely measure the pulse wave. The performance of the fabricated sensor array was validated by evaluating the sensor sensitivity per channel, and the possibility of estimating the blood vessel direction was demonstrated through a radial artery pulse simulator. We expect the proposed sensor to allow accurate extraction of the pulse indices for pulse diagnosis. PMID- 27240359 TI - MicroRNAs: Key Regulators in the Central Nervous System and Their Implication in Neurological Diseases. AB - MicroRNAs (miRNAs) are a class of small, well-conserved noncoding RNAs that regulate gene expression post-transcriptionally. They have been demonstrated to regulate a lot of biological pathways and cellular functions. Many miRNAs are dynamically regulated during central nervous system (CNS) development and are spatially expressed in adult brain indicating their essential roles in neural development and function. In addition, accumulating evidence strongly suggests that dysfunction of miRNAs contributes to neurological diseases. These observations, together with their gene regulation property, implicated miRNAs to be the key regulators in the complex genetic network of the CNS. In this review, we first focus on the ways through which miRNAs exert the regulatory function and how miRNAs are regulated in the CNS. We then summarize recent findings that highlight the versatile roles of miRNAs in normal CNS physiology and their association with several types of neurological diseases. Subsequently we discuss the limitations of miRNAs research based on current studies as well as the potential therapeutic applications and challenges of miRNAs in neurological disorders. We endeavor to provide an updated description of the regulatory roles of miRNAs in normal CNS functions and pathogenesis of neurological diseases. PMID- 27240364 TI - Improving Kinematic Accuracy of Soft Wearable Data Gloves by Optimizing Sensor Locations. AB - Bending sensors enable compact, wearable designs when used for measuring hand configurations in data gloves. While existing data gloves can accurately measure angular displacement of the finger and distal thumb joints, accurate measurement of thumb carpometacarpal (CMC) joint movements remains challenging due to crosstalk between the multi-sensor outputs required to measure the degrees of freedom (DOF). To properly measure CMC-joint configurations, sensor locations that minimize sensor crosstalk must be identified. This paper presents a novel approach to identifying optimal sensor locations. Three-dimensional hand surface data from ten subjects was collected in multiple thumb postures with varied CMC joint flexion and abduction angles. For each posture, scanned CMC-joint contours were used to estimate CMC-joint flexion and abduction angles by varying the positions and orientations of two bending sensors. Optimal sensor locations were estimated by the least squares method, which minimized the difference between the true CMC-joint angles and the joint angle estimates. Finally, the resultant optimal sensor locations were experimentally validated. Placing sensors at the optimal locations, CMC-joint angle measurement accuracies improved (flexion, 2.8 degrees +/- 1.9 degrees ; abduction, 1.9 degrees +/- 1.2 degrees ). The proposed method for improving the accuracy of the sensing system can be extended to other types of soft wearable measurement devices. PMID- 27240365 TI - Real-Time Monitoring System for a Utility-Scale Photovoltaic Power Plant. AB - There is, at present, considerable interest in the storage and dispatchability of photovoltaic (PV) energy, together with the need to manage power flows in real time. This paper presents a new system, PV-on time, which has been developed to supervise the operating mode of a Grid-Connected Utility-Scale PV Power Plant in order to ensure the reliability and continuity of its supply. This system presents an architecture of acquisition devices, including wireless sensors distributed around the plant, which measure the required information. It is also equipped with a high-precision protocol for synchronizing all data acquisition equipment, something that is necessary for correctly establishing relationships among events in the plant. Moreover, a system for monitoring and supervising all of the distributed devices, as well as for the real-time treatment of all the registered information, is presented. Performances were analyzed in a 400 kW transformation center belonging to a 6.1 MW Utility-Scale PV Power Plant. In addition to monitoring the performance of all of the PV plant's components and detecting any failures or deviations in production, this system enables users to control the power quality of the signal injected and the influence of the installation on the distribution grid. PMID- 27240366 TI - A Micro-Platinum Wire Biosensor for Fast and Selective Detection of Alanine Aminotransferase. AB - In this study, a miniaturized biosensor based on permselective polymer layers (overoxidized polypyrrole (Ppy) and Nafion((r))) modified and enzyme (glutamate oxidase (GlutOx)) immobilized micro-platinum wire electrode for the detection of alanine aminotransferase (ALT) was fabricated. The proposed ALT biosensor was measured electrochemically by constant potential amperometry at +0.7 V vs. Ag/AgCl. The ALT biosensor provides fast response time (~5 s) and superior selectivity towards ALT against both negatively and positively charged species (e.g., ascorbic acid (AA) and dopamine (DA), respectively). The detection range of the ALT biosensor is found to be 10-900 U/L which covers the range of normal ALT levels presented in the serum and the detection limit and sensitivity are found to be 8.48 U/L and 0.059 nA/(U/L.mm2) (N = 10), respectively. We also found that one-day storage of the ALT biosensor at -20 degrees C right after the sensor being fabricated can enhance the sensor sensitivity (1.74 times higher than that of the sensor stored at 4 degrees C). The ALT biosensor is stable after eight weeks of storage at -20 degrees C. The sensor was tested in spiked ALT samples (ALT activities: 20, 200, 400, and 900 U/L) and reasonable recoveries (70%~107%) were obtained. PMID- 27240367 TI - GBAS Ionospheric Anomaly Monitoring Based on a Two-Step Approach. AB - As one significant component of space environmental weather, the ionosphere has to be monitored using Global Positioning System (GPS) receivers for the Ground Based Augmentation System (GBAS). This is because an ionospheric anomaly can pose a potential threat for GBAS to support safety-critical services. The traditional code-carrier divergence (CCD) methods, which have been widely used to detect the variants of the ionospheric gradient for GBAS, adopt a linear time-invariant low pass filter to suppress the effect of high frequency noise on the detection of the ionospheric anomaly. However, there is a counterbalance between response time and estimation accuracy due to the fixed time constants. In order to release the limitation, a two-step approach (TSA) is proposed by integrating the cascaded linear time-invariant low-pass filters with the adaptive Kalman filter to detect the ionospheric gradient anomaly. The performance of the proposed method is tested by using simulated and real-world data, respectively. The simulation results show that the TSA can detect ionospheric gradient anomalies quickly, even when the noise is severer. Compared to the traditional CCD methods, the experiments from real-world GPS data indicate that the average estimation accuracy of the ionospheric gradient improves by more than 31.3%, and the average response time to the ionospheric gradient at a rate of 0.018 m/s improves by more than 59.3%, which demonstrates the ability of TSA to detect a small ionospheric gradient more rapidly. PMID- 27240368 TI - Evaluation of a Wobbling Method Applied to Correcting Defective Pixels of CZT Detectors in SPECT Imaging. AB - In this paper, we propose a wobbling method to correct bad pixels in cadmium zinc telluride (CZT) detectors, using information of related images. We build up an automated device that realizes the wobbling correction for small animal Single Photon Emission Computed Tomography (SPECT) imaging. The wobbling correction method is applied to various constellations of defective pixels. The corrected images are compared with the results of conventional interpolation method, and the correction effectiveness is evaluated quantitatively using the factor of peak signal-to-noise ratio (PSNR) and structural similarity (SSIM). In summary, the proposed wobbling method, equipped with the automatic mechanical system, provides a better image quality for correcting defective pixels, which could be used for all pixelated detectors for molecular imaging. PMID- 27240369 TI - Instantaneous Observability of Tightly Coupled SINS/GPS during Maneuvers. AB - The tightly coupled strapdown inertial navigation system (SINS)/global position system (GPS) has been widely used. The system observability determines whether the system state can be estimated by a filter efficiently or not. In this paper, the observability analysis of a two-channel and a three-channel tightly coupled SINS/GPS are performed, respectively, during arbitrary translational maneuvers and angle maneuvers, where the translational maneuver and angle maneuver are modeled. A novel instantaneous observability matrix (IOM) based on a reconstructed psi-angle model is proposed to make the theoretical analysis simpler, which starts from the observability definition directly. Based on the IOM, a series of theoretical analysis are performed. Analysis results show that almost all kinds of translational maneuver and angle maneuver can make a three channel system instantaneously observable, but there is no one translational maneuver or angle maneuver can make a two-channel system instantaneously observable. The system's performance is investigated when the system is not instantaneously observable. A series of simulation studies based on EKF are performed to confirm the analytic conclusions. PMID- 27240370 TI - Embedded Implementation of VHR Satellite Image Segmentation. AB - Processing and analysis of Very High Resolution (VHR) satellite images provide a mass of crucial information, which can be used for urban planning, security issues or environmental monitoring. However, they are computationally expensive and, thus, time consuming, while some of the applications, such as natural disaster monitoring and prevention, require high efficiency performance. Fortunately, parallel computing techniques and embedded systems have made great progress in recent years, and a series of massively parallel image processing devices, such as digital signal processors or Field Programmable Gate Arrays (FPGAs), have been made available to engineers at a very convenient price and demonstrate significant advantages in terms of running-cost, embeddability, power consumption flexibility, etc. In this work, we designed a texture region segmentation method for very high resolution satellite images by using the level set algorithm and the multi-kernel theory in a high-abstraction C environment and realize its register-transfer level implementation with the help of a new proposed high-level synthesis-based design flow. The evaluation experiments demonstrate that the proposed design can produce high quality image segmentation with a significant running-cost advantage. PMID- 27240371 TI - An Automated Comparative Observation System for Sun-Induced Chlorophyll Fluorescence of Vegetation Canopies. AB - Detecting sun-induced chlorophyll fluorescence (SIF) offers a new approach for remote sensing photosynthesis. However, to analyse the response characteristics of SIF under different stress states, a long-term time-series comparative observation of vegetation under different stress states must be carried out at the canopy scale, such that the similarities and differences in SIF change law can be summarized under different time scales. A continuous comparative observation system for vegetation canopy SIF is designed in this study. The system, which is based on a high-resolution spectrometer and an optical multiplexer, can achieve comparative observation of multiple targets. To simultaneously measure the commonly used vegetation index and SIF in the O2-A and O2-B atmospheric absorption bands, the following parameters are used: a spectral range of 475.9 to 862.2 nm, a spectral resolution of approximately 0.9 nm, a spectral sampling interval of approximately 0.4 nm, and the signal-to-noise ratio (SNR) can be as high as 1000:1. To obtain data for both the upward radiance of the vegetation canopy and downward irradiance data with a high SNR in relatively short time intervals, the single-step integration time optimization algorithm is proposed. To optimize the extraction accuracy of SIF, the FluorMOD model is used to simulate sets of data according to the spectral resolution, spectral sampling interval and SNR of the spectrometer in this continuous observation system. These data sets are used to determine the best parameters of Fraunhofer Line Depth (FLD), Three FLD (3FLD) and the spectral fitting method (SFM), and 3FLD and SFM are confirmed to be suitable for extracting SIF from the spectral measurements. This system has been used to observe the SIF values in O2-A and O2-B absorption bands and some commonly used vegetation index from sweet potato and bare land, the result of which shows: (1) the daily variation trend of SIF value of sweet potato leaves is basically same as that of photosynthetically active radiation (PAR); and (2) the bare land is a non-fluorescent emitter, the SIF of which is significantly smaller than that of sweet potato; and (3) analysis result based on the measured data is basically same as that based on simulated data. The above results verified the reliability of the SIF extracted from the measured data and the feasibility of comparatively observing the SIF value and the commonly used vegetation index of multiple vegetation canopy with this continuous observation system. This approach is beneficial for comprehensively analysing the stress response characteristics of vegetation canopies. PMID- 27240372 TI - Molecular Spectrum Capture by Tuning the Chemical Potential of Graphene. AB - Due to its adjustable electronic properties and effective excitation of surface plasmons in the infrared and terahertz frequency range, research on graphene has attracted a great deal of attention. Here, we demonstrate that plasmon modes in graphene-coated dielectric nanowire (GNW) waveguides can be excited by a monolayer graphene ribbon. What is more the transverse resonant frequency spectrum of the GNW can be flexibly tuned by adjusting the chemical potential of graphene, and amplitude of the resonance peak varies linearly with the imaginary part of the analyte permittivity. As a consequence, the GNW works as a probe for capturing the molecular spectrum. Broadband sensing of toluene, ethanol and sulfurous anhydride thin layers is demonstrated by calculating the changes in spectral intensity of the propagating mode and the results show that the intensity spectra correspond exactly to the infrared spectra of these molecules. This may open an effective avenue to design sensors for detecting nanometric-size molecules in the terahertz and infrared regimes. PMID- 27240373 TI - Reputation and Reward: Two Sides of the Same Bitcoin. AB - In Mobile Crowd Sensing (MCS), the power of the crowd, jointly with the sensing capabilities of the smartphones they wear, provides a new paradigm for data sensing. Scenarios involving user behavior or those that rely on user mobility are examples where standard sensor networks may not be suitable, and MCS provides an interesting solution. However, including human participation in sensing tasks presents numerous and unique research challenges. In this paper, we analyze three of the most important: user participation, data sensing quality and user anonymity. We tackle the three as a whole, since all of them are strongly correlated. As a result, we present PaySense, a general framework that incentivizes user participation and provides a mechanism to validate the quality of collected data based on the users' reputation. All such features are performed in a privacy-preserving way by using the Bitcoin cryptocurrency. Rather than a theoretical one, our framework has been implemented, and it is ready to be deployed and complement any existing MCS system. PMID- 27240374 TI - Correction: Abazari, A.M., et al. Modelling the Size Effects on the Mechanical Properties of Micro/Nano Structures. Sensors 2015, 15, 28543-28562. AB - The authors wish to make the following correction to this paper [1]: The article type should be changed from "Review" into "Article".[...]. PMID- 27240375 TI - New Quality Control Algorithm Based on GNSS Sensing Data for a Bridge Health Monitoring System. AB - This research introduces an improvement plan for the reliability of Global Navigation Satellite System (GNSS) positioning solutions. It should be considered the most suitable methodology in terms of the adjustment and positioning of GNSS in order to maximize the utilization of GNSS applications. Though various studies have been conducted with regards to Bridge Health Monitoring System (BHMS) based on GNSS, the outliers which depend on the signal reception environment could not be considered until now. Since these outliers may be connected to GNSS data collected from major bridge members, which can reduce the reliability of a whole monitoring system through the delivery of false information, they should be detected and eliminated in the previous adjustment stage. In this investigation, the Detection, Identification, Adaptation (DIA) technique was applied and implemented through an algorithm. Moreover, it can be directly applied to GNSS data collected from long span cable stayed bridges and most of outliers were efficiently detected and eliminated simultaneously. By these effects, the reliability of GNSS should be enormously improved. Improvement on GNSS positioning accuracy is directly linked to the safety of bridges itself, and at the same time, the reliability of monitoring systems in terms of the system operation can also be increased. PMID- 27240376 TI - Precise Point Positioning Using Triple GNSS Constellations in Various Modes. AB - This paper introduces a new dual-frequency precise point positioning (PPP) model, which combines the observations from three different global navigation satellite system (GNSS) constellations, namely GPS, Galileo, and BeiDou. Combining measurements from different GNSS systems introduces additional biases, including inter-system bias and hardware delays, which require rigorous modelling. Our model is based on the un-differenced and between-satellite single-difference (BSSD) linear combinations. BSSD linear combination cancels out some receiver related biases, including receiver clock error and non-zero initial phase bias of the receiver oscillator. Forming the BSSD linear combination requires a reference satellite, which can be selected from any of the GPS, Galileo, and BeiDou systems. In this paper three BSSD scenarios are tested; each considers a reference satellite from a different GNSS constellation. Natural Resources Canada's GPSPace PPP software is modified to enable a combined GPS, Galileo, and BeiDou PPP solution and to handle the newly introduced biases. A total of four data sets collected at four different IGS stations are processed to verify the developed PPP model. Precise satellite orbit and clock products from the International GNSS Service Multi-GNSS Experiment (IGS-MGEX) network are used to correct the GPS, Galileo, and BeiDou measurements in the post-processing PPP mode. A real-time PPP solution is also obtained, which is referred to as RT-PPP in the sequel, through the use of the IGS real-time service (RTS) for satellite orbit and clock corrections. However, only GPS and Galileo observations are used for the RT-PPP solution, as the RTS-IGS satellite products are not presently available for BeiDou system. All post-processed and real-time PPP solutions are compared with the traditional un-differenced GPS-only counterparts. It is shown that combining the GPS, Galileo, and BeiDou observations in the post-processing mode improves the PPP convergence time by 25% compared with the GPS-only counterpart, regardless of the linear combination used. The use of BSSD linear combination improves the precision of the estimated positioning parameters by about 25% in comparison with the GPS-only PPP solution. Additionally, the solution convergence time is reduced to 10 minutes for the BSSD model, which represents about 50% reduction, in comparison with the GPS-only PPP solution. The GNSS RT-PPP solution, on the other hand, shows a similar convergence time and precision to the GPS-only counterpart. PMID- 27240378 TI - Monitoring Pre-Stressed Composites Using Optical Fibre Sensors. AB - Residual stresses in fibre reinforced composites can give rise to a number of undesired effects such as loss of dimensional stability and premature fracture. Hence, there is significant merit in developing processing techniques to mitigate the development of residual stresses. However, tracking and quantifying the development of these fabrication-induced stresses in real-time using conventional non-destructive techniques is not straightforward. This article reports on the design and evaluation of a technique for manufacturing pre-stressed composite panels from unidirectional E-glass/epoxy prepregs. Here, the magnitude of the applied pre-stress was monitored using an integrated load-cell. The pre-stressing rig was based on a flat-bed design which enabled autoclave-based processing. A method was developed to end-tab the laminated prepregs prior to pre-stressing. The development of process-induced residual strain was monitored in-situ using embedded optical fibre sensors. Surface-mounted electrical resistance strain gauges were used to measure the strain when the composite was unloaded from the pre-stressing rig at room temperature. Four pre-stress levels were applied prior to processing the laminated preforms in an autoclave. The results showed that the application of a pre-stress of 108 MPa to a unidirectional [0]16 E-glass/913 epoxy preform, reduced the residual strain in the composite from -600 uepsilon (conventional processing without pre-stress) to approximately zero. A good correlation was observed between the data obtained from the surface-mounted electrical resistance strain gauge and the embedded optical fibre sensors. In addition to "neutralising" the residual stresses, superior axial orientation of the reinforcement can be obtained from pre-stressed composites. A subsequent publication will highlight the consequences of pres-stressing on fibre alignment, the tensile, flexural, compressive and fatigue performance of unidirectional E glass composites. PMID- 27240377 TI - Towards a Multifunctional Electrochemical Sensing and Niosome Generation Lab-on Chip Platform Based on a Plug-and-Play Concept. AB - In this paper, we present a new modular lab on a chip design for multimodal neurotransmitter (NT) sensing and niosome generation based on a plug-and-play concept. This architecture is a first step toward an automated platform for an automated modulation of neurotransmitter concentration to understand and/or treat neurodegenerative diseases. A modular approach has been adopted in order to handle measurement or drug delivery or both measurement and drug delivery simultaneously. The system is composed of three fully independent modules: three channel peristaltic micropumping system, a three-channel potentiostat and a multi unit microfluidic system composed of pseudo-Y and cross-shape channels containing a miniature electrode array. The system was wirelessly controlled by a computer interface. The system is compact, with all the microfluidic and sensing components packaged in a 5 cm * 4 cm * 4 cm box. Applied to serotonin, a linear calibration curve down to 0.125 mM, with a limit of detection of 31 MU M was collected at unfunctionalized electrodes. Added sensitivity and selectivity was achieved by incorporating functionalized electrodes for dopamine sensing. Electrode functionalization was achieved with gold nanoparticles and using DNA and o-phenylene diamine polymer. The as-configured platform is demonstrated as a central component toward an "intelligent" drug delivery system based on a feedback loop to monitor drug delivery. PMID- 27240379 TI - Indoor Multi-Sensor Acquisition System for Projects on Energy Renovation of Buildings. AB - Energy rehabilitation actions in buildings have become a great economic opportunity for the construction sector. They also constitute a strategic goal in the European Union (EU), given the energy dependence and the compromises with climate change of its member states. About 75% of existing buildings in the EU were built when energy efficiency codes had not been developed. Approximately 75% to 90% of those standing buildings are expected to remain in use in 2050. Significant advances have been achieved in energy analysis, simulation tools, and computer fluid dynamics for building energy evaluation. However, the gap between predictions and real savings might still be improved. Geomatics and computer science disciplines can really help in modelling, inspection, and diagnosis procedures. This paper presents a multi-sensor acquisition system capable of automatically and simultaneously capturing the three-dimensional geometric information, thermographic, optical, and panoramic images, ambient temperature map, relative humidity map, and light level map. The system integrates a navigation system based on a Simultaneous Localization and Mapping (SLAM) approach that allows georeferencing every data to its position in the building. The described equipment optimizes the energy inspection and diagnosis steps and facilitates the energy modelling of the building. PMID- 27240380 TI - Unobtrusive Estimation of Cardiac Contractility and Stroke Volume Changes Using Ballistocardiogram Measurements on a High Bandwidth Force Plate. AB - Unobtrusive and inexpensive technologies for monitoring the cardiovascular health of heart failure (HF) patients outside the clinic can potentially improve their continuity of care by enabling therapies to be adjusted dynamically based on the changing needs of the patients. Specifically, cardiac contractility and stroke volume (SV) are two key aspects of cardiovascular health that change significantly for HF patients as their condition worsens, yet these parameters are typically measured only in hospital/clinical settings, or with implantable sensors. In this work, we demonstrate accurate measurement of cardiac contractility (based on pre-ejection period, PEP, timings) and SV changes in subjects using ballistocardiogram (BCG) signals detected via a high bandwidth force plate. The measurement is unobtrusive, as it simply requires the subject to stand still on the force plate while holding electrodes in the hands for simultaneous electrocardiogram (ECG) detection. Specifically, we aimed to assess whether the high bandwidth force plate can provide accuracy beyond what is achieved using modified weighing scales we have developed in prior studies, based on timing intervals, as well as signal-to-noise ratio (SNR) estimates. Our results indicate that the force plate BCG measurement provides more accurate timing information and allows for better estimation of PEP than the scale BCG (r2 = 0.85 vs. r2 = 0.81) during resting conditions. This correlation is stronger during recovery after exercise due to more significant changes in PEP (r2 = 0.92). The improvement in accuracy can be attributed to the wider bandwidth of the force plate. ?SV (i.e., changes in stroke volume) estimations from the force plate BCG resulted in an average error percentage of 5.3% with a standard deviation of +/-4.2% across all subjects. Finally, SNR calculations showed slightly better SNR in the force plate measurements among all subjects but the small difference confirmed that SNR is limited by motion artifacts rather than instrumentation. PMID- 27240381 TI - Detuned Plasmonic Bragg Grating Sensor Based on a Defect Metal-Insulator-Metal Waveguide. AB - A nanoscale Bragg grating reflector based on the defect metal-insulator-metal (MIM) waveguide is developed and numerically simulated by using the finite element method (FEM). The MIM-based structure promises a highly tunable broad stop-band in transmission spectra. The narrow transmission window is shown to appear in the previous stop-band by changing the certain geometrical parameters. The central wavelengths can be controlled easily by altering the geographical parameters. The development of surface plasmon polarition (SPP) technology in metallic waveguide structures leads to more possibilities of controlling light at deep sub-wavelengths. Its attractive ability of breaking the diffraction limit contributes to the design of optical sensors. PMID- 27240382 TI - A Linked List-Based Algorithm for Blob Detection on Embedded Vision-Based Sensors. AB - Blob detection is a common task in vision-based applications. Most existing algorithms are aimed at execution on general purpose computers; while very few can be adapted to the computing restrictions present in embedded platforms. This paper focuses on the design of an algorithm capable of real-time blob detection that minimizes system memory consumption. The proposed algorithm detects objects in one image scan; it is based on a linked-list data structure tree used to label blobs depending on their shape and node information. An example application showing the results of a blob detection co-processor has been built on a low powered field programmable gate array hardware as a step towards developing a smart video surveillance system. The detection method is intended for general purpose application. As such, several test cases focused on character recognition are also examined. The results obtained present a fair trade-off between accuracy and memory requirements; and prove the validity of the proposed approach for real time implementation on resource-constrained computing platforms. PMID- 27240383 TI - VLC-Based Positioning System for an Indoor Environment Using an Image Sensor and an Accelerometer Sensor. AB - Recently, it is believed that lighting and communication technologies are being replaced by high power LEDs, which are core parts of the visible light communication (VLC) system. In this paper, by taking advantages of VLC, we propose a novel design for an indoor positioning system using LEDs, an image sensor (IS) and an accelerometer sensor (AS) from mobile devices. The proposed algorithm, which provides a high precision indoor position, consists of four LEDs mounted on the ceiling transmitting their own three-dimensional (3D) world coordinates and an IS at an unknown position receiving and demodulating the signals. Based on the 3D world coordinates and the 2D image coordinate of LEDs, the position of the mobile device is determined. Compared to existing algorithms, the proposed algorithm only requires one IS. In addition, by using an AS, the mobile device is allowed to have arbitrary orientation. Last but not least, a mechanism for reducing the image sensor noise is proposed to further improve the accuracy of the positioning algorithm. A simulation is conducted to verify the performance of the proposed algorithm. PMID- 27240384 TI - Metals of Deep Ocean Water Increase the Anti-Adipogenesis Effect of Monascus Fermented Product via Modulating the Monascin and Ankaflavin Production. AB - Deep ocean water (DOW) obtained from a depth of more than 200 m includes abundant nutrients and minerals. DOW was proven to positively increase monascin (MS) and ankaflavin (AK) production and the anti-adipogenesis effect of Monascus-fermented red mold dioscorea (RMD). However, the influences that the major metals in DOW have on Monascus secondary metabolite biosynthesis and anti-adipogenesis remain unknown. Therefore, the major metals in DOW were used as the culture water to produce RMD. The secondary metabolites production and anti-adipogenesis effect of RMD cultured with various individual metal waters were investigated. In the results, the addition of water with Mg, Ca, Zn, and Fe increased MS and AK production and inhibited mycotoxin citrinin (CT). However, the positive influence may be contributed to the regulation of pigment biosynthesis. Furthermore, in the results of cell testing, higher lipogenesis inhibition was seen in the treatments of various ethanol extracts of RMD cultured with water containing Mg, K, Zn, and Fe than in those of RMD cultured with ultra-pure water. In conclusion, various individual metals resulted in different effects on MS and AK productions as well as the anti-adipogenesis effect of RMD, but the specific metals contained in DOW may cause synergistic or comprehensive effects that increase the significantly positive influence. PMID- 27240385 TI - Dissipation and Residues of Dichlorprop-P and Bentazone in Wheat-Field Ecosystem. AB - Dichlorprop-P and bentazone have been widely used in the prevention and control of weeds in wheat field ecosystems. There is a concern that pesticide residues and metabolites remain on or in the wheat. Thus, the study of the determination and monitoring of their residues in wheat has important significance. A rapid, simple and reliable QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) method was modified, developed and validated for the determination of dichlorprop P, bentazone and its metabolites (6-hydroxy-bentazone and 8-hydroxy-bentazone) in wheat (wheat plants, wheat straw and grains of wheat) using high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). The average recoveries of this method ranged from 72.9% to 108.7%, and the limits of quantification (LOQs) were 2.5-12 MUg/kg. The dissipation and final residue of four compounds in three provinces (Shandong, Jiangsu and Heilongjiang) in China were studied. The trial results showed that the half-lives of dichlorprop-P and bentazone were 1.9-2.5 days and 0.5-2.4 days in wheat plants, respectively. The terminal residues in grains of wheat and wheat straw at harvest were all much below the maximum residue limit (MRL) of 0.2 mg/kg for dichlorprop-P and 0.1 mg/kg for bentazone established by the European Union (EU, Regulation No. 396/2005). PMID- 27240386 TI - Change in Environmental Benefits of Urban Land Use and Its Drivers in Chinese Cities, 2000-2010. AB - Driven by rising income and urban population growth, China has experienced rapid urban expansion since the 1980s. Urbanization can have positive effects on the urban environment; however, improvement of urban environment quality, especially its divergence between relatively developed and undeveloped cities in China, is currently a rather rudimentary and subjective issue. This study analyzed urban environmental benefits among China's prefectural cities based on their structure of urban land use in 2000 and 2010. First, we divided 347 prefectural cities into two groups, 81 coastal and capital cities in the relatively developed group (RD) and 266 other prefectural cities in the undeveloped group (RP). Then, we defined three areas of urban environmental benefits, including green infrastructure, industrial upgrade, and environmental management, and developed an assessment index system. Results showed that all prefectural cities saw improvement in urban environmental quality in 2000-2010. Although the RD cities had higher income and more population growth, they had less improvement than the RP cities during the same period. We also found that demographic and urban land agglomeration among RD cities restrained green infrastructure expansion, making green infrastructure unsuitable as a permanent solution to environmental improvement. It is therefore urgent for China to promote balanced improvement among the three areas of urban environmental benefits and between the RD and RP cities through regional differentiation policies. PMID- 27240387 TI - Literature Review of Associations among Attributes of Reported Drinking Water Disease Outbreaks. AB - Waterborne disease outbreaks attributed to various pathogens and drinking water system characteristics have adversely affected public health worldwide throughout recorded history. Data from drinking water disease outbreak (DWDO) reports of widely varying breadth and depth were synthesized to investigate associations between outbreak attributes and human health impacts. Among 1519 outbreaks described in 475 sources identified during review of the primarily peer-reviewed, English language literature, most occurred in the U.S., the U.K. and Canada (in descending order). The outbreaks are most frequently associated with pathogens of unknown etiology, groundwater and untreated systems, and catchment realm associated deficiencies (i.e., contamination events). Relative frequencies of outbreaks by various attributes are comparable with those within other DWDO reviews, with water system size and treatment type likely driving most of the (often statistically-significant at p < 0.05) differences in outbreak frequency, case count and attack rate. Temporal analysis suggests that while implementation of surface (drinking) water management policies is associated with decreased disease burden, further strengthening of related policies is needed to address the remaining burden attributed to catchment and distribution realm-associated deficiencies and to groundwater viral and disinfection-only system outbreaks. PMID- 27240388 TI - Residential Risk Factors for Atopic Dermatitis in 3- to 6-Year Old Children: A Cross-Sectional Study in Shanghai, China. AB - BACKGROUND: Atopic dermatitis (AD) is common among pre-school children in Shanghai. This study aimed to identify the risk factors for childhood AD from the perspectives of home environment, demographics and parents-grandparents' atopic disease. METHODS: A cross-sectional study was conducted in Shanghai in April June, 2010. Preschool children's parents or guardians were invited to participate a questionnaire survey in six districts (two urban and four suburban/rural) and 6624 children were finally recruited (51.3% boys). AD diagnosis was based on the U.K. Working Party's (UKWP) criteria. Adjusted odds ratios (AOR) with 95% confidence intervals (95% CI) were calculated by multiple logistic regression. RESULTS: A total of 8.5% of children ever had AD. Around 10.2% of the mothers had lived in newly renovated/decorated homes (NRDH) during the prenatal period (one year before or during pregnancy) and 9.5% got new home furniture (NHF) during the same period. AD was more common in children when mothers had lived in NRDH homes during the prenatal period (AOR = 1.41; 95% CI 1.03-1.93), the current home had indoor mold (2.00, 1.48-2.70), parents-grandparents' had atopic diseases (3.85, 3.05-4.87), the children had food allergy (3.40, 2.63-4.40) or children lived in urban area (1.52, 1.18-1.96). Associations between AD and NRDH, NHF and indoor molds were only significant in children without parents-grandparents' atopic diseases. There was an interaction effect between parents-grandparents' atopic diseases and NRDH (p < 0.05). CONCLUSIONS: Home renovation/ redecoration, new furniture and indoor mold, urban residency, heredity disposition and food allergy can be risk factors for childhood AD in Shanghai. PMID- 27240389 TI - The Knowledge Base for Achieving the Sustainable Development Goal Targets on Water Supply, Sanitation and Hygiene. AB - Safe drinking water, sanitation, and hygiene (WASH) are fundamental to an improved standard of living. Globally, 91% of households used improved drinking water sources in 2015, while for improved sanitation it is 68%. Wealth disparities are stark, with rural populations, slum dwellers and marginalized groups lagging significantly behind. Service coverage is significantly lower when considering the new water and sanitation targets under the sustainable development goals (SDGs) which aspire to a higher standard of 'safely managed' water and sanitation. Lack of access to WASH can have an economic impact as much as 7% of Gross Domestic Product, not including the social and environmental consequences. Research points to significant health and socio-economic consequences of poor nutritional status, child growth and school performance caused by inadequate WASH. Groundwater over-extraction and pollution of surface water bodies have serious impacts on water resource availability and biodiversity, while climate change exacerbates the health risks of water insecurity. A significant literature documents the beneficial impacts of WASH interventions, and a growing number of impact evaluation studies assess how interventions are optimally financed, implemented and sustained. Many innovations in behavior change and service delivery offer potential for scaling up services to meet the SDGs. PMID- 27240390 TI - Association between Obese Phenotype and Mildly Reduced eGFR among the General Population from Rural Northeast China. AB - Obesity contributes to reduced kidney function; however, whether this is due to obesity itself or the metabolic abnormalities that accompany it is unclear. Besides, most previous studies enrolled participants with moderate or severe stage of chronic kidney disease. In the present study, we aim to investigate the possible relationship between obesity, metabolic abnormalities and mildly reduced estimated glomerular filtration rate (eGFR). A total of 11,127 Chinese participants (age >= 35 years) were enrolled in a survey conducted from January 2012 to August 2013. eGFR 60-90 mL/min/1.73 m2 was defined as mildly reduced eGFR. Obese phenotype was divided into four types: metabolically healthy non obese (MHNO), metabolically healthy obese (MHO), metabolically abnormal non-obese (MANO) and metabolically abnormal obese (MAO). Among all participants, 1941 (17.4%) of them had mildly reduced eGFR (16.7% for men and 18.1% for women, p = 0.025). The prevalence of obese phenotype was 22.5% for MHNO, 9.1% for MHO, 32.1% for MANO and 36.4% for MAO. The prevalence of mildly reduced eGFR was 9.0% among MHNO, 7.0% among MHO, 22.6% among MANO and 20.7% among MAO (p < 0.001). Multivariate logistic regression analysis revealed that obese phenotype did not statically contributed to mildly reduced eGFR (MHO: OR = 1.107, p = 0.662; MANO: OR = 0.800, p = 0.127; MAO: OR = 1.119, p = 0.525). However, gender (OR = 1.475, p < 0.001), aging (OR = 1.283, p < 0.001), dyslipidemia (OR = 1.544, 95%CI: 1.315, 1.814, p < 0.001) and hyperglycemia (OR = 1.247, 95%CI: 1.068, 1.455, p = 0.005) was associated with increased risk of mild reduced eGFR. Among the general population from rural Northeast China, mildly reduced eGFR was associated with metabolic disorders like dyslipidemia and hyperglycemia, but not obesity. PMID- 27240391 TI - Situation of Diabetes and Related Disease Surveillance in Rural Areas of Jilin Province, Northeast China. AB - BACKGROUND: Several studies have investigated the prevalence and awareness of diabetes mellitus (DM) in China, but little is known about the situation of DM in the northeastern rural areas. Our present study investigated the prevalence, awareness and associated characteristics of DM in rural areas of Jilin Province, aiming to suggest more efforts for the prevention and control of DM. METHODS: A multistage stratified random cluster sampling design was used in this cross sectional study which took place in 2012. Data were collected by face-to-face interviews and physical examinations. Rao-Scott Chi-square test, t test and multivariate logistic regression analysis were used. RESULTS: The estimated prevalence of DM in rural areas of Jilin province was 7.2%. DM was positively associated with age, Body mass index (BMI), hypotension, dyslipidemia and was high in participants with a family history of diabetes and those who exercise frequently, but low for high education level and married participants. 69.0% participants with DM were aware of their diabetes status, 88.2% of whom received treatment and 34.4% of whom had received treatment controlled their DM status. CONCLUSIONS: We observed a high prevalence and low awareness status of DM among the rural residents in Jilin Province, but the rate of effective control in those who have received treatment was considerable. The low rate of disease surveillance should draw health authority's attention. PMID- 27240392 TI - A Case of Acute Osteomyelitis: An Update on Diagnosis and Treatment. AB - Osteomyelitis in children is a serious disease in children requiring early diagnosis and treatment to minimize the risk of sequelae. Therefore, it is of primary importance to recognize the signs and symptoms at the onset and to properly use the available diagnostic tools. It is important to maintain a high index of suspicion and be aware of the evolving epidemiology and of the emergence of antibiotic resistant and aggressive strains requiring careful monitoring and targeted therapy. Hereby we present an instructive case and review the literature data on diagnosis and treatment. PMID- 27240393 TI - Investigation and Evaluation of Children's Blood Lead Levels around a Lead Battery Factory and Influencing Factors. AB - Lead pollution incidents have occurred frequently in mainland China, which has caused many lead poisoning incidents. This paper took a battery recycling factory as the subject, and focused on measuring the blood lead levels of environmental samples and all the children living around the factory, and analyzed the relationship between them. We collected blood samples from the surrounding residential area, as well as soil, water, vegetables. The atomic absorption method was applied to measure the lead content in these samples. The basic information of the generation procedure, operation type, habit and personal protect equipment was collected by an occupational hygiene investigation. Blood lead levels in 43.12% of the subjects exceeded 100 MUg/L. The 50th and the 95th percentiles were 89 MUg/L and 232 MUg/L for blood lead levels in children, respectively, and the geometric mean was 94 MUg/L. Children were stratified into groups by age, gender, parents' occupation, distance and direction from the recycling plant. The difference of blood lead levels between groups was significant (p < 0.05). Four risk factors for elevated blood lead levels were found by logistic regression analysis, including younger age, male, shorter distance from the recycling plant, and parents with at least one working in the recycling plant. The rate of excess lead concentration in water was 6.25%, 6.06% in soil and 44.44% in leaf vegetables, which were all higher than the Chinese environment standards. The shorter the distance to the factory, the higher the value of BLL and lead levels in vegetable and environment samples. The lead level in the environmental samples was higher downwind of the recycling plant. PMID- 27240394 TI - Prevalence of Depression among Rural Residents with Diabetes Mellitus: A Cross Sectional Study from Northeast China. AB - Recent economic development in China has resulted in large increases in psychogenic and metabolic diseases. However, few studies have focused on the mental status of rural residents with diabetes. We aimed to investigate the prevalence of depressive symptoms among patients with diabetes to establish the association between depressive symptoms and socio-demographic and clinical factors. We conducted a cross-sectional analysis of 1187 patients with diabetes aged >=35 years from rural Northeast China. Metabolic and anthropometric indicators were measured according to standard methods. Depressive symptoms were defined using the Patient Health Questionnaire-9 (PHQ-9). Five hundred and twenty six residents (44.3%) of the total sample were male and 931 (78.4%) were <65 years old. One hundred and eight residents (8.76%) score >=10 on the PHQ-9 scale. A statistically significant relationship was found between depressive symptoms and female gender, older age (>=65 years), high school or above education level, moderate physical activity, high family income, multiple additional illnesses, current alcohol consumption, and 7-8 h/d sleep duration. Multivariate analysis showed that female gender [odds ratio (OR) = 1.984, p = 0.028], high family income (OR = 0.483 for 5000-20,000 CNY/year, p = 0.011; OR = 0.356 for >2000 CNY/year, p = 0.003), 7-8 h/d sleep duration (OR = 0.453, p = 0.020), and having multiple additional illness (OR = 3.080, p < 0.001) were significantly associated with depressive symptoms. Prevalence of depressive symptoms in our study was high. Female gender and multiple illnesses were risk factors for depression, while long sleep duration and high family income seem to protect against depression among rural residents with diabetes in China. PMID- 27240396 TI - Analysis of the Relationship between Estradiol and Follicle-Stimulating Hormone Concentrations and Polymorphisms of Apolipoprotein E and LeptinGenes in Women Post-Menopause. AB - BACKGROUND: Menopause is the permanent cessation of menstruation due to loss of ovarian follicular activity. A review of the available literature indicates that correlations between the changes that take place in a woman's body after menopause and different genetic variants are still being sought. METHODS: The study was conducted in 252 women who had completed physiological menopause. The women were divided into groups according to the time elapsed since menopause. The total concentrations of estradiol and follicle-stimulating hormone were determined by means of electrochemiluminescence. The apolipoprotein E (APOE) and lepitn (LEP) genotypes were determined by real-time PCR and polymerase chain reaction-restriction fragment length polymorphism, respectively. RESULTS: We observed that people with the APOE3/E3 genotype entered menopause insignificantly later compared to other genotypes. Additionally, in the group of patients with the APOE3/E3 genotypes, differences in the E2 concentration were significantly related to the time since their last menstruation. There is no association found in the literature between these polymorphisms of the LEP gene and hormones. CONCLUSIONS: To date, attempts to formulate a model describing the association between E2 and FSH concentration with the polymorphisms of various genes of menopause in women have not been successful. This relationship is difficult to study because of the number of nongenetic factors. Environmental factors can explain variation in postmenopausal changes in hormone levels. PMID- 27240395 TI - BMI and BMD: The Potential Interplay between Obesity and Bone Fragility. AB - Recent evidence demonstrating an increased fracture risk among obese individuals suggests that adipose tissue may negatively impact bone health, challenging the traditional paradigm of fat mass playing a protective role towards bone health. White adipose tissue, far from being a mere energy depot, is a dynamic tissue actively implicated in metabolic reactions, and in fact secretes several hormones called adipokines and inflammatory factors that may in turn promote bone resorption. More specifically, Visceral Adipose Tissue (VAT) may potentially prove detrimental. It is widely acknowledged that obesity is positively associated to many chronic disorders such as metabolic syndrome, dyslipidemia and type 2 diabetes, conditions that could themselves affect bone health. Although aging is largely known to decrease bone strength, little is yet known on the mechanisms via which obesity and its comorbidities may contribute to such damage. Given the exponentially growing obesity rate in recent years and the increased life expectancy of western countries it appears of utmost importance to timely focus on this topic. PMID- 27240398 TI - Elevation of Fasting Ghrelin in Healthy Human Subjects Consuming a High-Salt Diet: A Novel Mechanism of Obesity? AB - Overweight/obesity is a chronic disease that carries an increased risk of hypertension, diabetes mellitus, and premature death. Several epidemiological studies have demonstrated a clear relationship between salt intake and obesity, but the pathophysiologic mechanisms remain unknown. We hypothesized that ghrelin, which regulates appetite, food intake, and fat deposition, becomes elevated when one consumes a high-salt diet, contributing to the progression of obesity. We, therefore, investigated fasting ghrelin concentrations during a high-salt diet. Thirty-eight non-obese and normotensive subjects (aged 25 to 50 years) were selected from a rural community in Northern China. They were sequentially maintained on a normal diet for three days at baseline, a low-salt diet for seven days (3 g/day, NaCl), then a high-salt diet for seven days (18 g/day). The concentration of plasma ghrelin was measured using an immunoenzyme method (ELISA). High-salt intake significantly increased fasting ghrelin levels, which were higher during the high-salt diet (320.7 +/- 30.6 pg/mL) than during the low salt diet (172.9 +/- 8.9 pg/mL). The comparison of ghrelin levels between the different salt diets was statistically-significantly different (p < 0.01). A positive correlation between 24-h urinary sodium excretion and fasting ghrelin levels was demonstrated. Our data indicate that a high-salt diet elevates fasting ghrelin in healthy human subjects, which may be a novel underlying mechanism of obesity. PMID- 27240397 TI - Impact of Cocoa Consumption on Inflammation Processes-A Critical Review of Randomized Controlled Trials. AB - BACKGROUND: Cocoa flavanols have strong anti-inflammatory properties in vitro. If these also occur in vivo, cocoa consumption may contribute to the prevention or treatment of diseases mediated by chronic inflammation. This critical review judged the evidence for such effects occurring after cocoa consumption. METHODS: A literature search in Medline was performed for randomized controlled trials (RCTs) that investigated the effects of cocoa consumption on inflammatory biomarkers. RESULTS: Thirty-three RCTs were included, along with 9 bolus and 24 regular consumption studies. Acute cocoa consumption decreased adhesion molecules and 4-series leukotrienes in serum, nuclear factor kappaB activation in leukocytes, and the expression of CD62P and CD11b on monocytes and neutrophils. In healthy subjects and in patients with cardiovascular diseases, most regular consumption trials did not find any changes except for a decreased number of endothelial microparticles, but several cellular and humoral inflammation markers decreased in patients suffering from type 2 diabetes and impaired fasting glucose. CONCLUSIONS: Little evidence exists that consumption of cocoa-rich food may reduce inflammation, probably by lowering the activation of monocytes and neutrophils. The efficacy seems to depend on the extent of the basal inflammatory burden. Further well-designed RCTs with inflammation as the primary outcome are needed, focusing on specific markers of leukocyte activation and considering endothelial microparticles as marker of vascular inflammation. PMID- 27240399 TI - Food Group Intakes as Determinants of Iodine Status among US Adult Population. AB - Adequate intake of iodine is essential for proper thyroid function. Although dietary reference intakes for iodine have been established, iodine intake cannot be estimated due to the lack of data on iodine contents in foods. We aimed to determine if food group intakes can predict iodine status assessed by urinary iodine concentration (UIC) from spot urine samples of 5967 US adults in the National Health and Nutrition Examination Survey (NHANES) 2007-2012. From an in person 24-h dietary recall, all foods consumed were aggregated into 12 main food groups using the individual food code of the US Department of Agriculture (USDA); dairy products, meat/poultry, fish/seaweed, eggs, legumes/nuts/seeds, breads, other grain products, fruits, vegetables, fats/oils, sugars/sweets, and beverages. Chi-square test, Spearman correlation, and multiple linear regression analyses were conducted to investigate the predictability of food group intakes in iodine status assessed by UIC. From the multiple linear regressions, the consumption of dairy products, eggs, and breads, and iodine-containing supplement use were positively associated with UIC, whereas beverage consumption was negatively associated with UIC. Among various food group intakes, dairy product intake was the most important determinant of iodine status in both US men and women. Subpopulation groups with a high risk of iodine deficiency may need nutritional education regarding the consumption of dairy products, eggs, and breads to maintain an adequate iodine status. Efforts toward a better understanding of iodine content in each food and a continued monitoring of iodine status within US adults are both warranted. PMID- 27240400 TI - Association between Metabolite Profiles, Metabolic Syndrome and Obesity Status. AB - Underlying mechanisms associated with the development of abnormal metabolic phenotypes among obese individuals are not yet clear. Our aim is to investigate differences in plasma metabolomics profiles between normal weight (NW) and overweight/obese (Ov/Ob) individuals, with or without metabolic syndrome (MetS). Mass spectrometry-based metabolite profiling was used to compare metabolite levels between each group. Three main principal components factors explaining a maximum of variance were retained. Factor 1's (long chain glycerophospholipids) metabolite profile score was higher among Ov/Ob with MetS than among Ov/Ob and NW participants without MetS. This factor was positively correlated to plasma total cholesterol (total-C) and triglyceride levels in the three groups, to high density lipoprotein -cholesterol (HDL-C) among participants without MetS. Factor 2 (amino acids and short to long chain acylcarnitine) was positively correlated to HDL-C and negatively correlated with insulin levels among NW participants. Factor 3's (medium chain acylcarnitines) metabolite profile scores were higher among NW participants than among Ov/Ob with or without MetS. Factor 3 was negatively associated with glucose levels among the Ov/Ob with MetS. Factor 1 seems to be associated with a deteriorated metabolic profile that corresponds to obesity, whereas Factors 2 and 3 seem to be rather associated with a healthy metabolic profile. PMID- 27240401 TI - Complementary Effects of Genetic Variations in LEPR on Body Composition and Soluble Leptin Receptor Concentration after 3-Month Lifestyle Intervention in Prepubertal Obese Children. AB - In obese individuals, weight loss might be affected by variants of the adipokine encoding genes. We verified whether selected functional single nucleotide polymorphisms in LEP, LEPR and ADIPOQ are associated with changes in serum levels of the respective adipokines and weight loss in 100 prepubertal obese (SDS-BMI > 2) Caucasian children undergoing lifestyle intervention. Frequencies of the 2548G > A LEP, Q223R LEPR, K656N LEPR, -11377C > G and -11426A > G ADIPOQ polymorphisms were analyzed by restriction fragment length polymorphism. Serum adipokine and soluble leptin receptor (sOB-R) concentrations were measured using the ELISA method. Among the analyzed polymorphisms, only LEPR polymorphisms were associated with changes of SDS-BMI or sOB-R concentrations in children after therapy. Carriers of the wild-type K665N and at least one minor Q223R allele had the greatest likelihood of losing weight (OR = 5.09, p = 0.006), an increase in sOB-R (ptrend = 0.022) and decrease in SDS-BMI correlated with the decrease of fat mass (p < 0.001). In contrast, carrying of the wild-type Q223R and at least one minor K665N allele were associated with a decrease in sOB-R concentrations and a decrease in SDS-BMI correlated with a decrease in fat-free mass (p = 0.002). We suggest that the combination of different LEPR variants, not a single variant, might determine predisposition to weight loss in the prepubertal period. PMID- 27240402 TI - CD133, Selectively Targeting the Root of Cancer. AB - Cancer stem cells (CSC) are capable of promoting tumor initiation and self renewal, two important hallmarks of carcinoma formation. This population comprises a small percentage of the tumor mass and is highly resistant to chemotherapy, causing the most difficult problem in the field of cancer research, drug refractory relapse. Many CSC markers have been reported. One of the most promising and perhaps least ubiquitous is CD133, a membrane-bound pentaspan glycoprotein that is frequently expressed on CSC. There is evidence that directly targeting CD133 with biological drugs might be the most effective way to eliminate CSC. We have investigated two entirely unrelated, but highly effective approaches for selectively targeting CD133. The first involves using a special anti-CD133 single chain variable fragment (scFv) to deliver a catalytic toxin. The second utilizes this same scFv to deliver components of the immune system. In this review, we discuss the development and current status of these CD133 associated biological agents. Together, they show exceptional promise by specific and efficient CSC elimination. PMID- 27240404 TI - The Regulatory Role of KIBRA and PTPN14 in Hippo Signaling and Beyond. AB - The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. Pivotal effectors of this pathway are YAP/TAZ, transcriptional co-activators whose dysfunction contributes to the development of cancer. Complex networks of intracellular and extracellular signaling pathways that modulate YAP and TAZ activities have recently been identified. Among them, KIBRA and PTPN14 are two evolutionarily-conserved and important YAP/TAZ upstream regulators. They can negatively regulate YAP/TAZ functions separately or in concert. In this review, we summarize the current and emerging regulatory roles of KIBRA and PTPN14 in the Hippo pathway and their functions in cancer. PMID- 27240403 TI - Telomere and Telomerase Therapeutics in Cancer. AB - Telomerase is a reverse transcriptase capable of utilizing an integrated RNA component as a template to add protective tandem telomeric single strand DNA repeats, TTAGGG, to the ends of chromosomes. Telomere dysfunction and telomerase reactivation are observed in approximately 90% of human cancers; hence, telomerase activation plays a unique role as a nearly universal step on the path to malignancy. In the past two decades, multiple telomerase targeting therapeutic strategies have been pursued, including direct telomerase inhibition, telomerase interference, hTERT or hTERC promoter driven therapy, telomere-based approaches, and telomerase vaccines. Many of these strategies have entered clinical development, and some have now advanced to phase III clinical trials. In the coming years, one or more of these new telomerase-targeting drugs may be expected to enter the pharmacopeia of standard care. Here, we briefly review the molecular functions of telomerase in cancer and provide an update about the preclinical and clinical development of telomerase targeting therapeutics. PMID- 27240405 TI - Wool Keratin-Associated Protein Genes in Sheep-A Review. AB - The importance of sheep's wool in making textiles has inspired extensive research into its structure and the underlying genetics since the 1960s. Wool keratin associated proteins (KAPs) are a key structural component of the wool fibre. The characterisation of the genes encoding these proteins has progressed rapidly with advances in the nucleotide and protein sequencing. This review describes our knowledge of ovine KAPs, their categorisation into families, polymorphism in the proteins and genes, the clustering and chromosomal location of the genes, some characteristics of gene expression and some potential effects of the KAPs on wool traits. The extent and nature of genetic variation in wool KAP genes and its association with fibre characteristics, provides an opportunity for the development of gene-markers for selective breeding of sheep to produce better wool with properties highly matched to specific end-uses. PMID- 27240406 TI - Selection and Verification of Candidate Reference Genes for Mature MicroRNA Expression by Quantitative RT-PCR in the Tea Plant (Camellia sinensis). AB - Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) is a rapid and sensitive method for analyzing microRNA (miRNA) expression. However, accurate qRT-PCR results depend on the selection of reliable reference genes as internal positive controls. To date, few studies have identified reliable reference genes for differential expression analysis of miRNAs among tissues, and among experimental conditions in plants. In this study, three miRNAs and four non coding small RNAs (ncRNA) were selected as reference candidates, and the stability of their expression was evaluated among different tissues and under different experimental conditions in the tea plant (Camellia sinensis) using the geNorm and NormFinder programs. It was shown that miR159a was the best single reference gene in the bud to the fifth leaf, 5S rRNA was the most suitable gene in different organs, miR6149 was the most stable gene when the leaves were attacked by Ectropis oblique and U4, miR5368n and miR159a were the best genes when the leaves were treated by methyl jasmonate (MeJA), salicylic acid (SA) and abscisic acid (ABA), respectively. Our results provide suitable reference genes for future investigations on miRNA functions in tea plants. PMID- 27240407 TI - Effects of Low-Temperature Plasma-Sterilization on Mars Analog Soil Samples Mixed with Deinococcus radiodurans. AB - We used Ar plasma-sterilization at a temperature below 80 degrees C to examine its effects on the viability of microorganisms when intermixed with tested soil. Due to a relatively low temperature, this method is not thought to affect the properties of a soil, particularly its organic component, to a significant degree. The method has previously been shown to work well on spacecraft parts. The selected microorganism for this test was Deinococcus radiodurans R1, which is known for its remarkable resistance to radiation effects. Our results showed a reduction in microbial counts after applying a low temperature plasma, but not to a degree suitable for a sterilization of the soil. Even an increase of the treatment duration from 1.5 to 45 min did not achieve satisfying results, but only resulted in in a mean cell reduction rate of 75% compared to the untreated control samples. PMID- 27240408 TI - Limitations and Prospects for Diffusion-Weighted MRI of the Prostate. AB - Diffusion-weighted imaging (DWI) is the most effective component of the modern multi-parametric magnetic resonance imaging (mpMRI) scan for prostate pathology. DWI provides the strongest prediction of cancer volume, and the apparent diffusion coefficient (ADC) correlates moderately with Gleason grade. Notwithstanding the demonstrated cancer assessment value of DWI, the standard measurement and signal analysis methods are based on a model of water diffusion dynamics that is well known to be invalid in human tissue. This review describes the biophysical limitations of the DWI component of the current standard mpMRI protocol and the potential for significantly improved cancer assessment performance based on more sophisticated measurement and signal modeling techniques. PMID- 27240409 TI - Parkinson's Disease: Assay of Phosphorylated alpha-Synuclein in Skin Biopsy for Early Diagnosis and Association with Melanoma. AB - Parkinson's disease (PD) is a degenerative disorder of the central nervous system, in which a small naturally unfolded protein alpha-synuclein plays an essential role. alpha-Synuclein belongs to a synuclein family comprising three members: alpha, beta, and gamma-synucleins associated with neurodegenerative and neoplastic diseases and involved in development. Several studies revealed that alpha-synuclein is present not only in the brain, but also in the skin and other peripheral tissues. This finding open a new approach to PD diagnosis based on the assay of alpha-synuclein from a biological sample of a living patient. Furthermore, PD is associated with an increased risk of skin melanoma. An important posttranslational modification of alpha-synuclein is phosphorylation at serine-129, which may convert the protein into pathological species both in PD and melanoma. Thus, analysis of phosphorylated alpha-synuclein might be an important diagnostic test for both diseases providing additional information about the mechanism of pathology. PMID- 27240410 TI - Prior Binge Ethanol Exposure Potentiates the Microglial Response in a Model of Alcohol-Induced Neurodegeneration. AB - Excessive alcohol consumption results in neurodegeneration which some hypothesize is caused by neuroinflammation. One characteristic of neuroinflammation is microglial activation, but it is now well accepted that microglial activation may be pro- or anti-inflammatory. Recent work indicates that the Majchrowicz model of alcohol-induced neurodegeneration results in anti-inflammatory microglia, while intermittent exposure models with lower doses and blood alcohol levels produce microglia with a pro-inflammatory phenotype. To determine the effect of a repeated binge alcohol exposure, rats received two cycles of the four-day Majchrowicz model. One hemisphere was then used to assess microglia via immunohistochemistry and while the other was used for ELISAs of cytokines and growth factors. A single binge ethanol exposure resulted in low-level of microglial activation; however, a second binge potentiated the microglial response. Specifically, double binge rats had greater OX-42 immunoreactivity, increased ionized calcium-binding adapter molecule 1 (Iba-1+) cells, and upregulated tumor necrosis factor-alpha (TNF-alpha) compared with the single binge ethanol group. These data indicate that prior ethanol exposure potentiates a subsequent microglia response, which suggests that the initial exposure to alcohol primes microglia. In summary, repeated ethanol exposure, independent of other immune modulatory events, potentiates microglial activity. PMID- 27240411 TI - N. meningitidis and TLR Polymorphisms: A Fascinating Immunomodulatory Network. AB - N. meningitidis infections represent a global health problem that can lead to the development of serious permanent sequelae. Although the use of antibiotics and prevention via vaccination have reduced the incidence of meningococcal disease, our understanding regarding N. meningitidis pathogenesis is still limited, especially of those mechanisms responsible for IMD and fulminant or deadly septic shock. These severe clinical presentations occur in a limited number of subjects, whereas about 10% of healthy individuals are estimated to carry the bacteria as a commensal. Since TLR activation is involved in the defense against N. meningitidis, several studies have highlighted the association between host TLR SNPs and a higher susceptibility and severity of N. meningitidis infections. Moreover, TLR SNPs induced variations in immunological responses and in their persistence upon vaccination against meningococcal disease. In the absence of mass vaccination programs, the early identification of risk factors for meningococcal disease would be recommended in order to start immunization strategies and antibiotic treatment in those subjects carrying the risk variants. In addition, it could allow us to identify individuals with a higher risk for severe disease and sequelae in order to develop a personalized healthcare of high risk subjects based on their genomic profile. In this review, we have illustrated important preliminary correlations between TLR variants and meningococcal susceptibility/severity and with vaccine-induced immune responses. PMID- 27240412 TI - Ribosome Assembly as Antimicrobial Target. AB - Many antibiotics target the ribosome and interfere with its translation cycle. Since translation is the source of all cellular proteins including ribosomal proteins, protein synthesis and ribosome assembly are interdependent. As a consequence, the activity of translation inhibitors might indirectly cause defective ribosome assembly. Due to the difficulty in distinguishing between direct and indirect effects, and because assembly is probably a target in its own right, concepts are needed to identify small molecules that directly inhibit ribosome assembly. Here, we summarize the basic facts of ribosome targeting antibiotics. Furthermore, we present an in vivo screening strategy that focuses on ribosome assembly by a direct fluorescence based read-out that aims to identify and characterize small molecules acting as primary assembly inhibitors. PMID- 27240413 TI - The Unicellular State as a Point Source in a Quantum Biological System. AB - A point source is the central and most important point or place for any group of cohering phenomena. Evolutionary development presumes that biological processes are sequentially linked, but neither directed from, nor centralized within, any specific biologic structure or stage. However, such an epigenomic entity exists and its transforming effects can be understood through the obligatory recapitulation of all eukaryotic lifeforms through a zygotic unicellular phase. This requisite biological conjunction can now be properly assessed as the focal point of reconciliation between biology and quantum phenomena, illustrated by deconvoluting complex physiologic traits back to their unicellular origins. PMID- 27240415 TI - NIOSH Response to the NIH Pathways to Prevention Workshop Recommendations. PMID- 27240414 TI - Metabolic Effect of Estrogen Receptor Agonists on Breast Cancer Cells in the Presence or Absence of Carbonic Anhydrase Inhibitors. AB - Metabolic shift is one of the major hallmarks of cancer development. Estrogen receptor (ER) activity has a profound effect on breast cancer cell growth through a number of metabolic changes driven by its effect on transcription of several enzymes, including carbonic anhydrases, Stearoyl-CoA desaturase-1, and oncogenes including HER2. Thus, estrogen receptor activators can be expected to lead to the modulation of cell metabolism in estrogen receptor positive cells. In this work we have investigated the effect of 17beta-estradiol, an ER activator, and ferulic acid, a carbonic anhydrase inhibitor, as well as ER activator, in the absence and in the presence of the carbonic anhydrase inhibitor acetazolamide on the metabolism of MCF7 cells and MCF7 cells, stably transfected to express HER2 (MCF7HER2). Metabolic profiles were studied using 1D and 2D metabolomic Nuclear Magnetic Resonance (NMR) experiments, combined with the identification and quantification of metabolites, and the annotation of the results in the context of biochemical pathways. Overall changes in hydrophilic metabolites were largest following treatment of MCF7 and MC7HER2 cells with 17beta-estradiol. However, the carbonic anhydrase inhibitor acetazolamide had the largest effect on the profile of lipophilic metabolites. PMID- 27240416 TI - Spin-orbit torque switching without an external field using interlayer exchange coupling. AB - Manipulation of the magnetization of a perpendicular ferromagnetic free layer by spin-orbit torque (SOT) is an attractive alternative to spin-transfer torque (STT) in oscillators and switches such as magnetic random-access memory (MRAM) where a high current is passed across an ultrathin tunnel barrier. A small symmetry-breaking bias field is usually needed for deterministic SOT switching but it is impractical to generate the field externally for spintronic applications. Here, we demonstrate robust zero-field SOT switching of a perpendicular CoFe free layer where the symmetry is broken by magnetic coupling to a second in-plane exchange-biased CoFe layer via a nonmagnetic Ru or Pt spacer. The preferred magnetic state of the free layer is determined by the current polarity and the sign of the interlayer exchange coupling (IEC). Our strategy offers a potentially scalable solution to realize bias-field-free switching that can lead to a generation of SOT devices, combining a high storage density and endurance with a low power consumption. PMID- 27240417 TI - Fast spin information transfer between distant quantum dots using individual electrons. AB - Transporting ensembles of electrons over long distances without losing their spin polarization is an important benchmark for spintronic devices. It usually requires injecting and probing spin-polarized electrons in conduction channels using ferromagnetic contacts or optical excitation. In parallel with this development, important efforts have been dedicated to achieving control of nanocircuits at the single-electron level. The detection and coherent manipulation of the spin of a single electron trapped in a quantum dot are now well established. Combined with the recently demonstrated control of the displacement of individual electrons between two distant quantum dots, these achievements allow the possibility of realizing spintronic protocols at the single-electron level. Here, we demonstrate that spin information carried by one or two electrons can be transferred between two quantum dots separated by a distance of 4 MUm with a classical fidelity of 65%. We show that at present it is limited by spin flips occurring during the transfer procedure before and after electron displacement. Being able to encode and control information in the spin degree of freedom of a single electron while it is being transferred over distances of a few micrometres on nanosecond timescales will pave the way towards 'quantum spintronics' devices, which could be used to implement large-scale spin based quantum information processing. PMID- 27240418 TI - Metal nanoparticles in the presence of lipopolysaccharides trigger the onset of metal allergy in mice. AB - Many people suffer from metal allergy, and the recently demonstrated presence of naturally occurring metal nanoparticles in our environment could present a new candidate for inducing metal allergy. Here, we show that mice pretreated with silver nanoparticles (nAg) and lipopolysaccharides, but not with the silver ions that are thought to cause allergies, developed allergic inflammation in response to the silver. nAg-induced acquired immune responses depended on CD4(+) T cells and elicited IL-17A-mediated inflammation, similar to that observed in human metal allergy. Nickel nanoparticles also caused sensitization in the mice, whereas gold and silica nanoparticles, which are minimally ionizable, did not. Quantitative analysis of the silver distribution suggested that small nAg (<=10 nm) transferred to the draining lymph node and released ions more readily than large nAg (>10 nm). These results suggest that metal nanoparticles served as ion carriers to enable metal sensitization. Our data demonstrate a potentially new trigger for metal allergy. PMID- 27240420 TI - A method for the simultaneous quantification of eight metabolites of synthetic pyrethroids in urine of the general population using gas chromatography-tandem mass spectrometry. AB - Synthetic pyrethroids are highly effective, widespread insecticides applied worldwide for different purposes. Among the possible sources of exposure for the general population, pyrethroid residues in food and their prominent use for the conservation of wool carpets or in indoor pest control might play a major role. On the basis of previous works, we have developed and validated a highly sensitive and specific GC/MS/MS-method to simultaneously quantify the metabolites of the most common synthetic pyrethroids in urine, namely cis- and trans-(2,2 dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid (DCCA), cis-(2,2 dibromovinyl)-2,2-dimethylcyclopropanecarboxylic acid (DBCA), 4-fluoro-3 phenoxybenzoic acid (F-PBA), 3-phenoxybenzoic acid (3-PBA) as well as the metabolites cis-3-(2-chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethyl cyclopropanecarboxylic acid (ClF3CA, lambda-cyhalothrin/bifenthrin), 4-chloro alpha-isopropylbenzene acetic acid (CPBA, esfenvalerate), and 2-methyl-3 phenylbenzoic acid (MPB, bifenthrin). After acidic hydrolysis to cleave conjugates in urine, the analytes are subjected to a pH-controlled extraction into n-hexane. After concentration, the analytes are derivatised using MTBSTFA and finally quantified by GC/MS/MS in EI-mode using d6-trans-DCCA and (13)C6-3 PBA as internal standards. The limit of quantification for these metabolites was 0.01 MUg/L urine. Precision within and between series was determined to range between 1.6 and 10.7 % using a native quality control sample as well as a urine sample spiked with 0.3 MUg/L of the analytes. To investigate possible background excretions, we analysed spot urine samples of 38 persons of the general population in a pilot study. cis- and trans-DCCA as well as 3-PBA could be quantified in every urine sample investigated, while MPB and F-PBA could only be detected in two samples. The median levels for excretion of cis-DCCA, trans-DCCA, 3-PBA, ClF3CA, DBCA, CPBA, F-PBA and MPA were 0.08, 0.17, 0.22, 0.04, 0.04, <0.01, <0.01 and < 0.01 MUg/L urine, respectively. The excretion of metabolites revealed excellent correlations between cyclopropane carboxylic acids and 3-PBA. Our method is highly suitable for human biomonitoring of exposures to synthetic pyrethroids in environmental medicine. Remarkable are the high detection rates for the metabolites ClF3CA (90 %) and CPBA (40 %), proving that their parent pyrethroids have entered the market in Germany. PMID- 27240419 TI - Sensitivities to various epidermal growth factor receptor-tyrosine kinase inhibitors of uncommon epidermal growth factor receptor mutations L861Q and S768I: What is the optimal epidermal growth factor receptor-tyrosine kinase inhibitor? AB - Most patients with non-small cell lung cancer (NSCLC) harboring common epidermal growth factor receptor (EGFR) mutations, such as deletions in exon 19 or the L858R mutation in exon 21, respond dramatically to EGFR tyrosine kinase inhibitors (EGFR-TKI), and their sensitivities to various EGFR-TKI have been well characterized. Our previous article showed the in vitro sensitivities of EGFR exon 18 mutations to EGFR-TKI, but little information regarding the sensitivities of other uncommon EGFR mutations is available. First, stable transfectant Ba/F3 cell lines harboring EGFR L858R (Ba/F3-L858R), L861Q (Ba/F3-L861Q) or S768I (Ba/F3-S768I) mutations were created and their drug sensitivities to various EGFR TKI were examined. Both the Ba/F3-L861Q and Ba/F3-S768I cell lines were less sensitive to erlotinib, compared with the Ba/F3-L858R cell line, but their sensitivities to afatinib were similar to that of the Ba/F3-L858R cell line. The Ba/F3-L861Q cell line was similarly sensitive and the Ba/F3-S768I cell line was less sensitive to osimertinib, compared with the Ba/F3-L858R cell line. The results of western blot analyses were consistent with these sensitivities. Next, similar experiments were also performed using the KYSE270 (L861Q) and KYSE 450 (S768I) cell lines, and their results were compatible with those of the transfectant Ba/F3 cell lines. Our findings suggest that NSCLC harboring the EGFR L861Q mutation might be sensitive to afatinib or osimertinib and that NSCLC harboring the EGFR S768I mutation might be sensitive to afatinib. Overall, afatinib might be the optimal EGFR-TKI against these uncommon EGFR mutations. PMID- 27240421 TI - The testing effect for mediator final test cues and related final test cues in online and laboratory experiments. AB - BACKGROUND: The testing effect is the finding that information that is retrieved during learning is more often correctly retrieved on a final test than information that is restudied. According to the semantic mediator hypothesis the testing effect arises because retrieval practice of cue-target pairs (mother child) activates semantically related mediators (father) more than restudying. Hence, the mediator-target (father-child) association should be stronger for retrieved than restudied pairs. Indeed, Carpenter (2011) found a larger testing effect when participants received mediators (father) than when they received target-related words (birth) as final test cues. METHODS: The present study started as an attempt to test an alternative account of Carpenter's results. However, it turned into a series of conceptual (Experiment 1) and direct (Experiment 2 and 3) replications conducted with online samples. The results of these online replications were compared with those of similar existing laboratory experiments through small-scale meta-analyses. RESULTS: The results showed that (1) the magnitude of the raw mediator testing effect advantage is comparable for online and laboratory experiments, (2) in both online and laboratory experiments the magnitude of the raw mediator testing effect advantage is smaller than in Carpenter's original experiment, and (3) the testing effect for related cues varies considerably between online experiments. CONCLUSIONS: The variability in the testing effect for related cues in online experiments could point toward moderators of the related cue short-term testing effect. The raw mediator testing effect advantage is smaller than in Carpenter's original experiment. PMID- 27240422 TI - Modelling the potential impact of a sugar-sweetened beverage tax on stroke mortality, costs and health-adjusted life years in South Africa. AB - BACKGROUND: Stroke poses a growing human and economic burden in South Africa. Excess sugar consumption, especially from sugar-sweetened beverages (SSBs), has been associated with increased obesity and stroke risk. Research shows that price increases for SSBs can influence consumption and modelling evidence suggests that taxing SSBs has the potential to reduce obesity and related diseases. This study estimates the potential impact of an SSB tax on stroke-related mortality, costs and health-adjusted life years in South Africa. METHODS: A proportional multi state life table-based model was constructed in Microsoft Excel (2010). We used consumption data from the 2012 South African National Health and Nutrition Examination Survey, previously published own and cross price elasticities of SSBs and energy balance equations to estimate changes in daily energy intake and BMI arising from increased SSB prices. Stroke relative risk, and prevalent years lived with disability estimates from the Global Burden of Disease Study and modelled disease epidemiology estimates from a previous study, were used to estimate the effect of the BMI changes on the burden of stroke. RESULTS: Our model predicts that an SSB tax may avert approximately 72 000 deaths, 550 000 stroke-related health-adjusted life years and over ZAR5 billion, (USD400 million) in health care costs over 20 years (USD296-576 million). Over 20 years, the number of incident stroke cases may be reduced by approximately 85 000 and prevalent cases by about 13 000. CONCLUSIONS: Fiscal policy has the potential, as part of a multi-faceted approach, to mitigate the growing burden of stroke in South Africa and contribute to the achievement of the target set by the Department of Health to reduce relative premature mortality (less than 60 years) from non-communicable diseases by the year 2020. PMID- 27240423 TI - Positive penicillin allergy testing results: a systematic review and meta analysis of papers published from 2010 through 2015. AB - beta-lactam antibiotics are the most widely used group of antibiotics, given their effectiveness for the most common bacterial pathogens and their relatively low price. Adverse reactions, mainly cutaneous, are often reported to be associated with their use and hence, less effective and usually more costly alternative antibiotics are prescribed. However, it is not clear what is the risk of immediate immune-mediated (i.e. developing within one hour of administration) and potentially life-threatening reactions among those using beta-lactam antibiotic. We conducted a systematic review to assess the prevalence of immediate adverse reactions to beta-lactam antibiotics, specifically penicillin derivatives, in patients with a reported adverse reaction to beta-lactam antibiotics. In addition, we determined the effect of age on the prevalence of immediate reactions. Assessing the true risk of using beta-lactam antibiotics in patients with a reported allergy could prevent physicians from unnecessarily discouraging the use of beta-lactam antibiotics. We conducted a systematic review and a meta-analysis using the PubMed, OVID, and Embase databases of work published in English and in French in the last 5 years. Studies were only eligible if they established the prevalence of immediate penicillin reactions with skin testing or challenges in case of negative skin tests. The meta-analysis was conducted using Stata version 12.0. The prevalence of immediate reactions to penicillin derivatives in patients reporting a beta-lactam hypersensitivity is 1.98% (95%CI; 1.35%, 2.60%) in the pediatric (under 18 years old) group, 7.78% (95%CI; 6.53%, 9.04%) in the adult group, and 2.84% (95%CI; 1.77%, 3.91%) in the combined group, as tested in various studies, using skin tests and oral challenges. The I(2) value ranged between 87.2% and 97.0%. Our results indicate that the prevalence of immediate reactions is higher in adults than in children. However, wide confidence intervals and a large study heterogeneity preclude conclusive estimates. PMID- 27240425 TI - Normative Data for the Spanish Version of the Addenbrooke's Cognitive Examination III. AB - BACKGROUND: Addenbrooke's Cognitive Examination III (ACE-III) is a cognitive test that has been validated for the diagnosis of cognitive disorders. The aim of this study was to provide normative data for the ACE-III for age, education and gender. METHODS: The Spanish version of the ACE-III was administered to a group of 273 healthy subjects in a multicenter study in Spain. Correlation and determination coefficients for age, education and gender were estimated. The overlapping interval strategy and linear regression analyses were used to provide adjusted norms for demographic factors and to explore the potential influence of these factors in the performance of the test. RESULTS: Age and education correlated significantly with the total score and with all the domains. Gender correlated only with the domains of attention and visuospatial skills. Norms for the total score and for cognitive domains (attention, memory, fluency, language, and visuospatial skills) are provided. CONCLUSION: This study confirms the influence of demographic factors (especially age and education) on the performance in the ACE-III and provides normative data for the Spanish version of the ACE-III. PMID- 27240426 TI - Hb Tarrant [alpha126(H9)Asp->Asn; HBA2: c.379G > A (or HBA1)] in a Chinese Family as a Cause of Familial Erythrocytosis. AB - Hb Tarrant [alpha126(H9)Asp->Asn; HBA2: c.379G > A (or HBA1)], is a rare high oxygen affinity hemoglobin (Hb) variant that causes erythrocytosis, previously described in a few Mexican-American families. Here we report the first Chinese family with this Hb variant presenting with unexplained familial erythrocytosis. No evidence of hemolysis was seen. A locally adapted approach to the diagnostic process in clinical laboratories is discussed. Molecular analysis has an important role in confirmation of the diagnosis. Proper identification of this rare but clinically significant Hb variant is helpful for family counseling and will help to guide appropriate management of absolute erythrocytosis. PMID- 27240424 TI - Increase of Positive Net Charge and Conformational Rigidity Enhances the Efficacy of d-Enantiomeric Peptides Designed to Eliminate Cytotoxic Abeta Species. AB - Alzheimer's disease (AD) is a neurodegenerative disorder and the most common type of dementia. Until now, there is no curative therapy available. Previously, we selected the amyloid-beta (Abeta) targeting peptide D3 consisting of 12 d enantiomeric amino acid residues by mirror image phage display as a potential drug candidate for the treatment of AD. In the current approach, we investigated the optimization potential of linear D3 with free C-terminus (D3COOH) by chemical modifications. First, the impact of the net charge was investigated and second, cyclization was introduced which is a well-known tool for the optimization of peptides for enhanced target affinity. Following this strategy, three D3 derivatives in addition to D3COOH were designed: C-terminally amidated linear D3 (D3CONH2), cyclic D3 (cD3), and cyclic D3 with an additional arginine residue (cD3r) to maintain the net charge of linear D3CONH2. These four compounds were compared to each other according to their binding affinities to Abeta(1-42), their efficacy to eliminate cytotoxic oligomers, and consequently their potency to neutralize Abeta(1-42) oligomer induced neurotoxicity. D3CONH2 and cD3r versions with equally increased net charge showed superior properties over D3COOH and cD3, respectively. The cyclic versions showed superior properties compared to their linear version with equal net charge, suggesting cD3r to be the most efficient compound among these four. Indeed, treatment of the transgenic AD mouse model Tg-SwDI with cD3r significantly enhanced spatial memory and cognition of these animals as revealed by water maze performance. Therefore, charge increase and cyclization imply suitable modification steps for an optimization approach of the Abeta targeting compound D3. PMID- 27240427 TI - Clinical Correlates of Reduced Physical Activity in Idiopathic Pulmonary Fibrosis. AB - BACKGROUND: Little is known about the consequences of idiopathic pulmonary fibrosis (IPF) for physical activity (PA). OBJECTIVES: We aimed to investigate levels of PA in IPF and to study associations of PA with lung function, exercise capacity, symptoms, and quality of life. METHODS: In stable patients with IPF we measured PA (steps per day, SPD; physical activity level, PAL; minutes of moderate activity, MMA) by accelerometry (SenseWear Armband) for 1 week. We also assessed lung function (forced vital capacity, FVC; diffusing capacity for carbon monoxide, DLCO); exercise capacity (6-minute walking distance, 6MWD); dyspnea (modified Medical Research Council, mMRC); fatigue (Multidimensional Fatigue Inventory, MFI-20), and generic (12-Item Short Form Survey, SF-12) and health related quality of life (St. George's Respiratory Questionnaire) as further clinical variables. RESULTS: We investigated 48 patients with IPF in two centers (mean age, 67 years; 75% male; 23% on long-term oxygen therapy; mean FVC 75%pred.; mean DLCO 43%pred.; mean 6MWD 355 +/- 140 m; mean SPD 5,017 +/- 3,360). On a bivariate level, all clinical variables were significantly associated with SPD (p < 0.05). The associations of mMRC, MFI-20, SF-12 (physical health), and 6MWD with SPD were independent of impaired lung function (p < 0.05). At multivariate analyses, either 6MWD (total explained variance of the model, total R2: 42%) or MFI-20 (total R2: 39%) were the strongest independent predictors of SPD. CONCLUSION: Fatigue and exercise capacity are strong and independent predictors of PA in patients with IPF, which suggests that both measures should be assessed when the consequences of IPF for PA in daily life are studied. PMID- 27240428 TI - Jasmonoyl-l-isoleucine is required for the production of a flavonoid phytoalexin but not diterpenoid phytoalexins in ultraviolet-irradiated rice leaves. AB - Rice produces low-molecular-weight antimicrobial compounds known as phytoalexins, in response to not only pathogen attack but also abiotic stresses including ultraviolet (UV) irradiation. Rice phytoalexins are composed of diterpenoids and a flavonoid. Recent studies have indicated that endogenous jasmonyl-l-isoleucine (JA-Ile) is not necessarily required for the production of diterpenoid phytoalexins in blast-infected or CuCl2-treated rice leaves. However, JA-Ile is required for the accumulation of the flavonoid phytoalexin, sakuranetin. Here, we investigated the roles of JA-Ile in UV-induced phytoalexin production. We showed that UV-irradiation induces the biosynthesis of JA-Ile and its precursor jasmonic acid. We also showed that rice jasmonate biosynthesis mutants produced diterpenoid phytoalexins but not sakuranetin in response to UV, indicating that JA-Ile is required for the production of sakuranetin but not diterpenoid phytoalexins in UV-irradiated rice leaves. PMID- 27240429 TI - Trajectories of Life Satisfaction After Spinal Cord Injury. AB - OBJECTIVE: To describe individual-level temporal change in life satisfaction after spinal cord injury. DESIGN: Individual growth curve (IGC) analysis of prospectively collected data from the National Institute on Disability, Independent Living, and Rehabilitation Research National Spinal Cord Injury Database (NSCID). SETTING: Multicenter, longitudinal database study. PARTICIPANTS: Participants (N=4846) in the NSCID. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Rasch-transformed Satisfaction With Life Scale scores. RESULTS: Individual-level trajectories reflecting life satisfaction vary extensively and are associated with demographic and injury-related characteristics. Demographic characteristics include race, sex, pre-employment and discharge marital status, and level of education; injury-related factors include days in rehabilitation, neurologic level, age at injury, and injury etiology. Results are displayed graphically by way of a computer-generated interactive tool and represent different trajectories of individual-level changes in life satisfaction. CONCLUSIONS: IGC methodology allows researchers and clinicians to anticipate patient-specific trajectories through use of an automated interactive tool. Projected trajectories hold promise in facilitating planning for inpatient and outpatient services, which could enhance long-term outcomes. PMID- 27240430 TI - Combining Fast-Walking Training and a Step Activity Monitoring Program to Improve Daily Walking Activity After Stroke: A Preliminary Study. AB - OBJECTIVES: To determine preliminary efficacy and to identify baseline characteristics predicting who would benefit most from fast walking training plus a step activity monitoring program (FAST+SAM) compared with fast walking training (FAST) alone in persons with chronic stroke. DESIGN: Randomized controlled trial with blinded assessors. SETTING: Outpatient clinical research laboratory. PARTICIPANTS: Individuals (N=37) >6 months poststroke. INTERVENTIONS: Subjects were assigned to either FAST, which was walking training at their fastest possible speed on the treadmill (30min) and overground 3 times per week for 12 weeks, or FAST+SAM. The step activity monitoring program consisted of daily step monitoring with an activity monitor, goal setting, and identification of barriers to activity and strategies to overcome barriers. MAIN OUTCOME MEASURES: Daily step activity metrics (steps/day [SPD], time walking per day), walking speed, and 6-minute walk test (6MWT) distance. RESULTS: There was a significant effect of time for both groups, with all outcomes improving from pre- to posttraining (all P values <.05). The FAST+SAM was superior to FAST for 6MWT (P=.018), with a larger increase in the FAST+SAM group. The interventions had differential effectiveness based on baseline step activity. Sequential moderated regression models demonstrated that for subjects with baseline levels of step activity and 6MWT distances that were below the mean, the FAST+SAM intervention was more effective than FAST (1715+/-1584 vs 254+/-933 SPD; P<.05 for overall model and DeltaR(2) for SPD and 6MWT). CONCLUSIONS: The addition of a step activity monitoring program to a fast walking training intervention may be most effective in persons with chronic stroke who have initial low levels of walking endurance and activity. Regardless of baseline performance, the FAST+SAM intervention was more effective for improving walking endurance. PMID- 27240431 TI - Intermanual Transfer Effects in Below-Elbow Myoelectric Prosthesis Users. AB - OBJECTIVES: To determine intermanual transfer effects in patients with a below elbow amputation using a myoelectric prosthesis and to establish whether laterality affects these effects. DESIGN: Case-control. SETTING: A standardized setting in a rehabilitation clinic. PARTICIPANTS: A convenience sample (N=44) of experienced myoelectric prosthesis users (n=22) and matched controls (n=22). Controls were matched on sex, age (+/-5y), and hand dominance. INTERVENTIONS: Both the experienced group and the control group performed several tasks using a prosthesis simulator attached to their nonaffected arm. MAIN OUTCOME MEASURES: Movement time, force control, Box and Block test (BBT) scores, and duration of hand opening. RESULTS: Movement times of myoelectric prosthesis users were shorter, and these users had significantly higher BBT scores and shorter hand opening durations than those of controls. No intermanual transfer effects on force control and no laterality effects were found. CONCLUSIONS: Intermanual transfer effects were present in experienced myoelectric prosthesis users with a below-elbow amputation, independent of laterality. These findings support the clinical relevance of intermanual transfer training, which may facilitate persons with an upper limb amputation to start training directly after the amputation. PMID- 27240432 TI - Money Management Activities in Persons With Multiple Sclerosis. AB - OBJECTIVES: To examine whether participants with multiple sclerosis (MS) have more problems in managing finances compared with persons without MS, and to examine the variables that may contribute to these problems. DESIGN: A cross sectional study. SETTING: Nonprofit rehabilitation research institution and the community. PARTICIPANTS: Participants (N=53) comprised adults with MS (n=30) and persons without MS (n=23) who were recruited from a nonprofit rehabilitation research institution and from the community. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants were administered a battery of neuropsychological tests, a money management survey, and a functional test to assess money management skills. RESULTS: Individuals with MS reported and demonstrated more problems managing money than persons without MS. Impaired cognitive functioning was significantly correlated with difficulties in money management. Self-report of functional status (Functional Behavior Profile) was significantly correlated with self-reported money management skills. CONCLUSIONS: To our knowledge, this is the first study to examine money management in MS. Money management is an important activity of daily living that presents problems for individuals with MS. Managing one's own money requires adequate processing speed abilities as well as executive-attentional abilities. Additional studies are needed to explore this area and understand the nature of the problem. PMID- 27240433 TI - Factors Associated With Recurrent Falls in Individuals With Traumatic Spinal Cord Injury: A Multicenter Study. AB - OBJECTIVE: To identify factors associated with recurrent falls in individuals with traumatic spinal cord injury (SCI). DESIGN: Cross-sectional multicenter study. SETTING: Two specialized rehabilitation centers. PARTICIPANTS: Included: individuals with traumatic SCI >=1 year postinjury who were aged >=18 years. Excluded: individuals with motor complete injuries above C5 or below L5. The study sample comprised participants (N=224; 151 wheelchair users, 73 ambulatory; 77% men; mean age +/- SD, 50+/-15y; median time since injury, 15y [range, 1-56y]) who were consecutively recruited at regular follow-up. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Primary outcome was factors associated with recurrent falls (defined as low frequent [0-2] or recurrent [>2]) the previous year. Independent variables were demographic data, wheelchair user or ambulatory, work, health-related quality of life, risk willingness, alcohol consumption, ability to get up from the ground, and exercise habits. RESULTS: Fifty percent reported recurrent falls. In the final multiple logistic regression model, ambulation (odds ratio [OR]=2.67; 95% confidence interval [CI], 1.33-5.37), ability to get up from the ground (OR=2.22; 95% CI, 1.21-4.10), and regular exercise (OR=1.86; 95% CI, 1.05-3.31) were associated with recurrent falls (P<=.05), and with increasing age the OR decreased (OR=.97; 95% CI, .95-.99). CONCLUSIONS: Individuals with SCI should be considered at risk of recurrent falls, and thereby at risk of fall-related injuries. Fall prevention programs should be focused on ambulatory, younger, and more active individuals who had the highest risks for recurrent falls. PMID- 27240434 TI - Test-Retest Reliability and Minimal Detectable Change of the Test of Visual Perceptual Skills-Third Edition in Patients With Stroke. AB - OBJECTIVES: To examine the test-retest reliability, calculate minimal detectable change (MDC), and report internal consistency of the Test of Visual Perceptual Skills-Third Edition (TVPS-3) in patients with stroke. DESIGN: Repeated-measures design (at an interval of 2wk). SETTING: Medical center. PARTICIPANTS: Patients (N=50) with chronic stroke who completed the TVPS-3. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: TVPS-3 that contains 7 subscales, namely, visual discrimination, visual memory, spatial relations, form constancy, sequential memory, visual figure-ground, and visual closure. RESULTS: The intraclass correlation coefficient value of the overall scale was .92 and those of the 7 subscales were .53 to .82. The MDC values of the overall scale and the subscales were 18.1 and 5.4 to 7.1, respectively. The MDC% value of the overall scale was 16.2% (<30%), showing acceptable random measurement error. However, the MDC% values of the subscales were 33.7% to 44.1% (>30%), indicating substantial random measurement errors. The Cronbach alpha of the 7 subscales were .71 to .89, indicating good internal consistency. CONCLUSIONS: Our results showed that the overall scale of the TVPS-3 had satisfactory test-retest reliability. However, the subscales demonstrated insufficient test-retest reliability. Therefore, the subscales should be used cautiously to explain the test results over repeated assessments in patients with stroke. PMID- 27240435 TI - Determination of the Best Parameter for Defining the Hemodynamic Significance of an Iliac Artery Stenosis Detected on Computed Tomography Angiography. AB - PURPOSE: The purpose of this study was to determine the best parameter, derived from computed tomography angiography (CTA) for accurate prediction of a hemodynamically significant stenosis of the common or external iliac artery. METHODS: A retrospective keyword search was performed on the Radiology Information System at our tertiary academic medical centre. Reports from January 2008 to September 2013 were searched using the keywords iliac, stenosis, and pressure. Patients who had both and CTA and a pelvic angiogram with pressure measurements obtained across a potential stenosis were selected. Using 3D postprocessing software (TeraRecon, Foster City, CA), the CTAs were analysed for the following parameters of each lesion: minimum diameter of stenosis, minimum cross-sectional area of stenosis, percent narrowing of vessel diameter, and percent reduction in vessel area. The percent stenosis was calculated in reference to the outer diameter at the point of maximal narrowing and also in reference to a normal segment of vessel more distal to the stenosis. These parameters were then compared with the measured pressure gradient using receiver operating characteristic analysis and the Mann-Whitney U test to determine which best predicted a significant stenosis, defined as a greater than 10% drop in systolic pressure across a lesion. RESULTS: One hundred and two stenoses in 83 patients (26 women, 57 men; 47-88 years old) were identified. Mean diameter of the stenosis was 2.8 mm for significant stenosis compared to 3.8 mm in nonsignificant stenoses (P = .005). Mean minimum area for significant stenoses was 11.8 mm(2) compared to 17.22 mm(2) for nonsignificant stenoses (P = .032) No other variables showed a significant difference between significant and nonsignificant stenoses. A minimum diameter of <=4.0 mm at the level of a stenosis is 92% sensitive and 48% specific for predicting a hemodynamically significant iliac artery stenosis, with a positive predictive value of 88%. CONCLUSIONS: A simple measurement of the minimum diameter of an iliac artery at the level of stenosis is the best predictor of the hemodynamic significance of a stenosis in the common or external iliac artery. PMID- 27240436 TI - Incentives in Rheumatology: the Potential Contribution of Physician Responses to Financial Incentives, Public Reporting, and Treatment Guidelines to Health Care Sustainability. AB - Concerns about the sustainability of current health care expenditure are focusing attention on the cost, quality and value of health care provision. Financial incentives, for example pay-for-performance (P4P), seek to reward quality and value in health care provision. There has long been an expectation that P4P schemes are coming to rheumatology. We review the available evidence about the use of incentives in this setting and provide two emerging examples of P4P schemes which may shape the future of service provision in rheumatology. Currently, there is limited and equivocal evidence in rheumatology about the impact of incentive schemes. However, reporting variation in the quality and provision of rheumatology services has highlighted examples of inefficiencies in the delivery of care. If financial incentives can improve the delivery of timely and appropriate care for rheumatology patients, then they may have an important role to play in the sustainability of health care provision. PMID- 27240438 TI - Proof of concept study: renal sympathetic denervation for treatment of polymorphic premature ventricular complexes. AB - BACKGROUND OR PURPOSE: Polymorphic premature ventricular complexes (PVCs) are very common, appearing most frequently in patients with hypertension, obesity, sleep apnea, and structural heart disease. Sympathetic hyperactivity plays a critical role in the development, maintenance, and aggravation of ventricular arrhythmias. Recently, the relevance of sympathetic activation in patients with ventricular arrhythmias was reported, and this finding suggested a potential role for catheter-based renal sympathetic denervation in reducing the arrhythmic burden. METHODS: We evaluated the effectiveness of the renal sympathetic denervation (RSD) in comparison to antiarrhythmic pharmacologic therapy in reducing polymorphic PVCs refractory to medication therapy and cardiac parameters assessed by 24-h Holter monitoring and cardiac magnetic resonance (CRM), respectively, in patients with structurally normal heart. RESULTS: Thirty-four patients were included in this study, 14 served as control, and 20 were treated with an ablation cardiac catheter with open irrigated tip. RSD was performed by a single operator following the standard technique. All the patients included had polymorphic PVCs and structurally normal heart. Data were obtained at baseline at the 12th month of follow-up (sixth month after RSD or adjustment of antiarrhythmic dosage). In RSD group, we observed a significant decrease in the number of polymorphic PVCs from baseline 36,091 +/- 3327 to 3, 6, 7 (first month after RSD, without drugs), and 12 months (sixth month after RSD, without drugs) of follow-up, 31,009 +/- 3251, 20,411 +/- 3820, 7701 +/- 1549, and 1274 +/- 749, respectively, in all patients, P < 0.0001 to all the comparisons between the mean of each time point with the mean of every other time point. No changes in mean 24 h ABPM and renal function in both groups were observed at 12th month of follow up. However, 24-h Holter mean heart rate decreased in control group at 12th month of follow-up, which did not happen with the RSD group. At the sixth month post RSD in comparison to baseline, a significant reduction in the number of polymorphic PVCs (? = -34,817 +/- 3590, P < 0.0001) was observed, as well as, in CRM parameters such as left ventricular mass/body surface area (? = -5.4 +/- 2.1 g/m2, P < 0.0001) and left ventricular ejection fraction (? = +3.0 +/- 1.8 %, P < 0.0001). In comparison to control group at the same time point, these findings were statistically superior in RSD group (P > 0.05). A significant correlation was found between the Delta number of polymorphic PVCs at the sixth month (r = 0.6723, P = 0.0012) after the RSD and the total number of RSD ablated spots. CONCLUSIONS: Polymorphic PVCs refractory to medication therapy may be modifiable by RSD in patients without structural heart disease. Although encouraging, our data are preliminary and need to be validated in a large population and in long term. PMID- 27240440 TI - A promising marker in early diagnosis of septic acute kidney injury of critically ill patients: urine insulin like growth factor binding protein-7. AB - AIM: An ideal biomarker for early diagnosis of septic acute kidney injury (AKI) should reflect renal stress or damage at initiation point, at cellular level. The aim of this study was to assess the role of a urinary cell cycle arrest marker, insulin-like growth factor-binding protein 7 (IGFBP7) in early diagnosis of septic AKI in adult critical care patients. METHODS: This was a single-center prospective cohort study. Patients without AKI, admitted to a medical intensive care unit (ICU) between January 2010 and March 2013, were included. According to 'sepsis' and 'AKI' development during their ICU stay, they were grouped as 'sepsis-non AKI', 'sepsis-AKI' and 'non-sepsis-non AKI (control)'. Among these groups, urine IGFBP7 was studied and compared with Human ELISA Kit/96 Test/USCNK((r)) first on admission and then on daily collected serial urine samples. RESULTS: A total of 118 patients formed the cohort; 52 in sepsis-non AKI, 43 in sepsis-AKI, 23 in control group. Admission urine IGFBP7 predicted septic AKI development with 72% sensitivity and 70% specificity for a threshold level of 2.5 ng/mL with an area under the receiver operating characteristics curve (AUC) of 0.79 (95% CI: 0.70-0.88). No impact of sepsis was observed on urine IGFBP7 levels in the absence of AKI. In the septic AKI group urine IGFBP7 levels continuously increased up to the day of AKI development and high levels were suspended for 10 days further. CONCLUSION: Admission urine IGFBP7 levels and following its course in ICUs can be used as a promising new biomarker for the early diagnosis of septic AKI development without being affected by sepsis itself. PMID- 27240439 TI - A rapid and efficient method to study the function of crop plant transporters in Arabidopsis. AB - Iron (Fe) is an essential micronutrient for humans. Fe deficiency disease is widespread and has led to extensive studies on the mechanisms of Fe uptake and storage, especially in staple food crops such as rice. However, studies of functionally related genes in rice and other crops are often time and space demanding. Here, we demonstrate that transgenic Arabidopsis suspension culture cells and Arabidopsis plants can be used as an efficient expression system for gain-of-function study of selected transporters, using Fe transporters as a proof of-principle. The vacuolar membrane transporters OsVIT1 and OsVIT2 have been described to be important for iron sequestration, and disruption of these two genes leads to Fe accumulation in rice seeds. In this study, we have taken advantage of the fluorescent-tagged protein GFP-OsVIT1, which functionally complements the Fe hypersensitivity of ccc1 yeast mutant, to generate transgenic Arabidopsis suspension cell lines and plants. GFP-OsVIT1 was shown to localize on the vacuolar membrane using confocal microscopy and immunogold EM. More importantly, the Fe concentration, as well as the concentration of Zn, in the transgenic cell lines and plants were significantly increased compared to that in the WT. Taken together, our study shows that the heterologous expression of rice vacuolar membrane transporter OsVIT1 in Arabidopsis system is functional and effectively enhances iron accumulation, indicating an useful approach for studying other putative transporters of crop plants in this system. PMID- 27240441 TI - Psychiatric disorders and symptoms severity in pre-school children with cow's milk allergy. AB - BACKGROUND: Psychiatric disorders are seen frequently in atopic diseases. The present study aims to evaluate the frequency of psychiatric disorders and the severity of psychiatric symptoms in pre-school children with cow's milk allergy. METHODS: The parents of the pre-school children with cow's milk allergy were interviewed in person and asked to fill out the Early Childhood Inventory-4 form. RESULTS: The cow's milk allergy group included 40 children (27 male, 13 female) with mean age, 44.5+/-14.7 months, and the control group included 41 children (25 male, 16 female) with mean age, 47.6+/-15.2 months. It was established that 65% of the group with cow's milk allergy received at least one psychiatric diagnosis, while 36.6% of the control group received at least one psychiatric diagnosis, with a statistically significant difference (p=0.02). Within the psychiatric disorders, attention deficit hyperactivity disorders (odds ratio: 4.9, 95% CI: 1.472-16.856, p=0.006), oppositional defiant disorder (odds ratio: 5.6, 95% CI: 1.139-28.128, p=0.026), and attachment disorder (odds ratio: 4.8, 95% CI: 1.747 13.506, p=0.004) were found significantly higher compared with the healthy control group. When the groups were compared in terms of psychiatric symptom severity scores, calculated by using the Early Childhood Inventory-4 form, attention deficit hyperactivity disorders severity (p=0.006) and oppositional defiant disorder severity (p=0.037) were found to be higher in the cow's milk allergy group. CONCLUSION: Psychiatric disorders are frequent and severe in pre school children with cow's milk allergy. PMID- 27240442 TI - Increased prevalence of Mycoplasma pneumoniae serological positivity in Chilean young children. AB - BACKGROUND: Mycoplasma pneumoniae is a frequent cause of respiratory infections in school children and adolescents. Epidemiological suspicion is important, since there are no specific symptoms or signs to help in diagnosing infection caused by this agent. OBJECTIVE: To determine the variation in prevalence over the last 10 years of M. pneumoniae IgM seropositivity according to age, particularly in pre schoolers. METHOD: The results of M. pneumoniae IgM serological testing between January 2004 and December 2013 were analysed. Variables such as gender and month and year of sample processing were studied according to age groups (<5, 5-18, 19 50, 51-70 and >70 years of age). RESULTS: Of a total of 20,020 serological samples, 31.9% proved positive for M. pneumoniae. All age groups showed increases in percentage seropositivity over the last 10 years, although the most significant increase corresponded to the 5-18 years group (from 15.8% to 54%), followed by children <5 years of age (from 8.6% to 30%). Seropositivity was significantly higher in women in all age groups, except in those over 50 years of age. CONCLUSION: Children under five years of age were the group with the second highest increase in seropositivity. PMID- 27240443 TI - Oral mite anaphylaxis mimicking acute asthma. PMID- 27240444 TI - Sensitisation to mites and other animal-derived home aeroallergens in children and its concordance as a measure of covariation of sensitisation. AB - BACKGROUND: Sensitisation to home aeroallergens (mites, furry animals and cockroaches) is predominant in patients in our and other areas. Covariation of sensitisation (CS) to these allergens could be due to cross-reactivity or parallel sensitisation. METHODS: Skin prick tests were performed to common and second-line home aeroallergens, shrimp and tropomyosin in 253 paediatric patients seen in our Unit due to chronic respiratory symptoms. CS among the main allergens was analysed by means of Cohen's kappa coefficient of concordance (kappa). RESULTS: House dust mites (HDM) were the main allergens involved in sensitisation, followed by furry animals, pollens, storage mites (SM), moulds and cockroaches. CS was very good between D. pteronyssinus and D. farinae (kappa=0.81), and good between Dermatophagoides and Euroglyphus (kappa=0.71), and decreased markedly to poor (kappa<0.20) between HDM and SM or cockroaches. CS among SM and cockroaches was moderate to fair (kappa=0.21-0.44). CS was good between shrimp and tropomyosin (kappa=0.62), but null between shrimp-tropomyosin and HDM (kappa=0.01-0.02), and poor to fair between shrimp-tropomyosin and SM or cockroaches (kappa=0.06-0.34). CS between cat and dog was moderate (kappa=0.50). CONCLUSIONS: We have shown the usefulness of kappa in exploring CS in a population. In our area, with high sensitisation to HDM and other home allergens, CS is limited for most pairs of allergens, pointing to a lower incidence of cross reactivity than could be expected, especially between HDM and SM or other invertebrates. PMID- 27240445 TI - Ulcers on psoriatic plaques in a patient with advanced Human Immunodeficiency Virus infection. PMID- 27240446 TI - Differential effect of fructose on fat metabolism and clock gene expression in hepatocytes vs. myotubes. AB - In the liver, fructose bypasses the main rate-limiting step of glycolysis at the level of phosphofructokinase, allowing it to act as an unregulated substrate for de novo lipogenesis. It has been reported that consumption of large amounts of fructose increases de novo lipogenesis in the liver. However, the effect of fructose on ectopic deposition of muscle fat has been under dispute. Our aim was to study the effect of fructose on levels of genes and proteins involved in fatty acid oxidation and synthesis in hepatocytes vs. muscle cells. In addition, as fat accumulation leads to disruption of daily rhythms, we tested the effect of fructose treatment on clock gene expression. AML-12 hepatocytes and C2C12 myotubes were treated with fructose or glucose for 2 consecutive 24-h cycles and harvested every 6h. In contrast to glucose, fructose disrupted clock gene rhythms in hepatocytes, but in myotubes, it led to more robust rhythms. Fructose led to low levels of phosphorylated AMP-activated protein kinase (pAMPK) and high levels of LIPIN1 in hepatocytes compared with glucose. In contrast, fructose led to high pAMPK and low LIPIN1 and microsomal triacylglycerol transfer protein (MTTP) levels in myotubes compared with glucose. Analysis of fat content revealed that fructose led to less fat accumulation in myotubes compared to hepatocytes. In summary, fructose shifts metabolism towards fatty acid synthesis and clock disruption in hepatocytes, but not in myotubes. PMID- 27240447 TI - Corrigendum to "Linking the response of endocrine regulated genes to adverse effects on sex differentiation improves comprehension of aromatase inhibition in a Fish Sexual Development Test" [Aquat. Toxicol. 176 (2016) 116-127]. PMID- 27240449 TI - Predictors of Major Morbidity or Mortality After Resection for Esophageal Cancer: A Society of Thoracic Surgeons General Thoracic Surgery Database Risk Adjustment Model. AB - BACKGROUND: The purpose of this analysis was to revise the model for perioperative risk for esophagectomy for cancer utilizing The Society of Thoracic Surgeons General Thoracic Surgery Database to provide enhanced risk stratification and quality improvement measures for contributing centers. METHODS: The Society of Thoracic Surgeons General Thoracic Surgery Database was queried for all patients treated for esophageal cancer with esophagectomy between July 1, 2011, and June 30, 2014. Multivariable risk models for major morbidity, perioperative mortality, and combined morbidity and mortality were created with the inclusion of surgical approach as a risk factor. RESULTS: In all, 4,321 esophagectomies were performed by 164 participating centers. The most common procedures included Ivor Lewis (32.5%), transhiatal (21.7%), minimally invasive esophagectomy, Ivor Lewis type (21.4%), and McKeown (10.0%). Sixty-nine percent of patients received induction therapy. Perioperative mortality (inpatient and 30 day) was 135 of 4,321 (3.4%). Major morbidity occurred in 1,429 patients (33.1%). Major morbidities include unexpected return to operating (15.6%), anastomotic leak (12.9%), reintubation (12.2%), initial ventilation beyond 48 hours (3.5%), pneumonia (12.2%), renal failure (2.0%), and recurrent laryngeal nerve paresis (2.0%). Statistically significant predictors of combined major morbidity or mortality included age more than 65 years, body mass index 35 kg/m(2) or greater, preoperative congestive heart failure, Zubrod score greater than 1, McKeown esophagectomy, current or former smoker, and squamous cell histology. CONCLUSION: Thoracic surgeons participating in The Society of Thoracic Surgeons General Thoracic Surgery Database perform esophagectomy with low morbidity and mortality. McKeown esophagectomy is an independent predictor of combined postoperative morbidity or mortality. Revised predictors for perioperative outcome were identified to facilitate quality improvement processes and hospital comparisons. PMID- 27240448 TI - Reliability and validity of PROMIS measures administered by telephone interview in a longitudinal localized prostate cancer study. AB - PURPOSE: To evaluate the reliability and validity of six PROMIS measures (anxiety, depression, fatigue, pain interference, physical function, and sleep disturbance) telephone-administered to a diverse, population-based cohort of localized prostate cancer patients. METHODS: Newly diagnosed men were enrolled in the North Carolina Prostate Cancer Comparative Effectiveness and Survivorship Study. PROMIS measures were telephone-administered pre-treatment (baseline), and at 3-months and 12-months post-treatment initiation (N = 778). Reliability was evaluated using Cronbach's alpha. Dimensionality was examined with bifactor models and explained common variance (ECV). Ordinal logistic regression models were used to detect potential differential item functioning (DIF) for key demographic groups. Convergent and discriminant validity were assessed by correlations with the legacy instruments Memorial Anxiety Scale for Prostate Cancer and SF-12v2. Known-groups validity was examined by age, race/ethnicity, comorbidity, and treatment. RESULTS: Each PROMIS measure had high Cronbach's alpha values (0.86-0.96) and was sufficiently unidimensional. Floor effects were observed for anxiety, depression, and pain interference measures; ceiling effects were observed for physical function. No DIF was detected. Convergent validity was established with moderate to strong correlations between PROMIS and legacy measures (0.41-0.77) of similar constructs. Discriminant validity was demonstrated with weak correlations between measures of dissimilar domains (-0.20 -0.31). PROMIS measures detected differences across age, race/ethnicity, and comorbidity groups; no differences were found by treatment. CONCLUSIONS: This study provides support for the reliability and construct validity of six PROMIS measures in prostate cancer, as well as the utility of telephone administration for assessing HRQoL in low literacy and hard-to-reach populations. PMID- 27240450 TI - Novel Modifications of a Ventricular Assist Device for Infants and Children. AB - BACKGROUND: A continuous-flow "adult" ventricular assist device (VAD) was modified to support infants and children waiting for heart transplantation. METHODS: A centrifugal VAD, designed to flow at 1.5 to 8 L/min, was used as a bridge to transplantation in pediatric patients. In smaller children and infants, a modified recirculation shunt permitted lower flow ranges. In hypoxic patients, an oxygenator was spliced into the circuit. RESULTS: From 2010 to 2015, the VAD was placed in 13 consecutive patients. Age ranged from 0.9 to 16 years (median, 7 years). Body surface area (BSA) ranged from 0.4 to 2.1 m(2) (median, 0.8 m(2)). Ten patients had a BSA less than 1.0 m(2). Four patients were receiving extracorporeal membrane oxygenation (ECMO) before VAD. Three patients had single ventricle physiology. Five patients had a recirculation shunt and 3 underwent insertion of an oxygenator. Median time on the VAD was 20 days (range, 2-140 days). In patients with a recirculation shunt, mean patient flow was 1.5 L/min (mean flow/BSA, 2.7 L/min/m(2)), with mean total VAD flow of 3.4 L/min. Twelve patients underwent transplantation, and 1 patient underwent VAD explantation. All patients survived and were discharged at a median of 26 days (range, 17-83 days) after transplantation. Three patients experienced major bleeding events. There were 2 cerebrovascular accidents. VAD mortality dropped from 33% (3 of 9) during 2007 to 2010 to 0% (0 of 13) between 2011 and 2015 (p = 0.05). Wait-list mortality dropped from 10% (5 of 52) to 4% (4 of 91) for these periods (p = 0.29). CONCLUSIONS: The centrifugal VAD successfully supported pediatric patients awaiting heart transplantation. The modified recirculation shunt facilitated the successful support of patients in whom optimal flows were substantially lower than those recommended by the manufacturer. The design allows placement of an in line oxygenator. Compared with pulsatile devices, use of this VAD was associated with a trend toward decreased mortality associated with VAD use. PMID- 27240451 TI - Should we lower the age for routine HPV vaccination in the United States? PMID- 27240452 TI - Disentangling the respective roles of the early environment and parental BMI on BMI change across childhood: A counterfactual analysis using the Millennium Cohort Study. AB - This study has two objectives. First, to analyse the respective roles of parental BMI and the wider environment on children's BMI across childhood, using a counterfactual analysis. Second, to determine if the correlations between parents and offspring BMI are partly environmental. We used data on 4437 girls and 4337 boys born in 2000-2001 in the UK and included in the Millennium Cohort Study. Children's BMI was measured at ages 3years, 5years, 7years, and 11years. We described the environment using social class and behaviours within the family. At the age of 3, there was no link between the environment and children's BMI. In contrast, there was a clear link between the environment and BMI slopes between 3 and 11years of age. At the age of 11, we calculated that if all children had the most favourable environment, mean BMI would be reduced by 0.91kg/m(2) (95% CI: 0.57-1.26) for boys and by 1.65kg/m(2) (95% CI: 1.28-2.02) for girls. Associations between parents' and offspring BMI remained unchanged after adjustment for environmental variables. Conversely, the link between the environment and children's BMI is partly reduced after adjustment for parental BMI. This confirms that parental BMI is partly a broad proxy of the environment. We highlighted that if every child's environment was at its most favourable, the mean BMI would be significantly reduced. Thus, the recent rise is likely to be reversible. PMID- 27240453 TI - Myeloid derived suppressor cells and autoimmunity. AB - Myeloid-derived suppressor cells are a heterogeneous group of immature myeloid cells with immunoregulatory function. When activated and expanded, these cells can suppress T cell functions via cell-to cell interactions as well as soluble mediators. Recent studies investigated the involvement of MDSC in autoimmune diseases. Some papers have described beneficial effect of MDSC during the course of autoimmune diseases, and suggest a potential role as a treatment option, while others failed to detect these effects. Their contributions to autoimmune diseases are not fully understood, and many questions and some controversies remain as to the expansion, activation, and inhibitory functions of MDSC. This review aims to summarize current knowledge of MDSC in autoimmune disorders. PMID- 27240454 TI - Using 80 kVp on a 320-row scanner for hepatic multiphasic CT reduces the contrast dose by 50 % in patients at risk for contrast-induced nephropathy. AB - OBJECTIVES: We evaluated the effects of a low contrast material (CM) dose protocol using 80-kVp on the image quality of hepatic multiphasic CT scans acquired on a 320-row CT scanner. METHODS: We scanned 30 patients with renal insufficiency (eGFR < 45 mL/min/1.73 m2) using 80-kVp and a CM dose of 300mgI/kg. Another 30 patients without renal insufficiency (eGFR > 60 mL/min/1.73 m2) were scanned with the conventional 120-kVp protocol and the standard CM dose of 600mgI/kg. Quantitative image quality parameters, i.e. CT attenuation, image noise, and the contrast-to-noise ratio (CNR) were compared and the visual image quality was scored on a four-point scale. The volume CT dose index (CTDIvol) and the size-specific dose estimate (SSDE) recorded with the 80- and the 120-kVp protocols were also compared. RESULTS: Image noise and contrast enhancement were equivalent for the two protocols. There was no significant difference in the CNR of all anatomic sites and in the visual scores for overall image quality. The CTDIvol and SSDE were approximately 25-30 % lower under the 80-kVp protocol. CONCLUSION: Hepatic multiphase CT using 80-kVp on a 320-row CT scanner allowed for a decrease in the CM dose and a reduction in the radiation dose without image quality degradation in patients with renal insufficiency. KEY POINTS: * The 80 kVp CT protocol enabled reduction of contrast dose by 50 % * The 80-kVp CT protocol reduced the radiation dose by 25-33 % * There was no degradation in the image quality of the 80-kVp protocol. PMID- 27240455 TI - From structural biology to designing therapy for inborn errors of metabolism. AB - At the SSIEM Symposium in Istanbul 2010, I presented an overview of protein structural approaches in the study of inborn errors of metabolism (Yue and Oppermann 2011). Five years on, the field is going strong with new protein structures, uncovered catalytic functions and novel chemical matters for metabolic enzymes, setting the stage for the next generation of drug discovery. This article aims to update on recent advances and lessons learnt on inborn errors of metabolism via the protein-centric approach, citing examples of work from my group, collaborators and co-workers that cover diverse pathways of transsulfuration, cobalamin and glycogen metabolism. Taking into consideration that many inborn errors of metabolism result in the loss of enzyme function, this presentation aims to outline three key principles that guide the design of small molecule therapy in this technically challenging field: (1) integrating structural, biochemical and cell-based data to evaluate the wide spectrum of mutation-driven enzyme defects in stability, catalysis and protein-protein interaction; (2) studying multi-domain proteins and multi-protein complexes as examples from nature, to learn how enzymes are activated by small molecules; (3) surveying different regions of the enzyme, away from its active site, that can be targeted for the design of allosteric activators and inhibitors. PMID- 27240456 TI - Antibody Therapies in Cancer. AB - Antibody-based immunotherapy has become a standard treatment for a variety of cancers. Many well-developed antibodies disrupt signaling of various growth factor receptors for the treatment of a number of cancers by targeting surface antigens expressed on tumor cells. In recent years, a new family of antibodies is currently emerging in the clinic, which target immune cells rather than cancer cells. These immune-targeted therapies strive to augment antitumor immune responses by antagonizing immunosuppressive pathways or providing exogenous immune-activating stimuli, which have achieved dramatic results in several cancers. The future of cancer therapies is likely to combine these approaches with other treatments, including conventional therapies, to generate more effective treatments. PMID- 27240457 TI - Biological Response Modifier in Cancer Immunotherapy. AB - Biological response modifiers (BRMs) emerge as a lay of new compounds or approaches used in improving cancer immunotherapy. Evidences highlight that cytokines, Toll-like receptor (TLR) signaling, and noncoding RNAs are of crucial roles in modulating antitumor immune response and cancer-related chronic inflammation, and BRMs based on them have been explored. In particular, besides some cytokines like IFN-alpha and IL-2, several Toll-like receptor (TLR) agonists like BCG, MPL, and imiquimod are also licensed to be used in patients with several malignancies nowadays, and the first artificial small noncoding RNA (microRNA) mimic, MXR34, has entered phase I clinical study against liver cancer, implying their potential application in cancer therapy. According to amounts of original data, this chapter will review the regulatory roles of TLR signaling, some noncoding RNAs, and several key cytokines in cancer and cancer-related immune response, as well as the clinical cases in cancer therapy based on them. PMID- 27240458 TI - Therapeutic Cancer Vaccines. AB - Cancer is one of the major leading death causes of diseases. Prevention and treatment of cancer is an important way to decrease the incidence of tumorigenesis and prolong patients' lives. Subversive achievements on cancer immunotherapy have recently been paid much attention after many failures in basic and clinical researches. Based on deep analysis of genomics and proteomics of tumor antigens, a variety of cancer vaccines targeting tumor antigens have been tested in preclinical and human clinical trials. Many therapeutic cancer vaccines alone or combination with other conventional treatments for cancer obtained spectacular efficacy, indicating the tremendously potential application in clinic. With the illustration of underlying mechanisms of cancer immune regulation, valid, controllable, and persistent cancer vaccines will play important roles in cancer treatment, survival extension and relapse and cancer prevention. This chapter mainly summarizes the recent progresses and developments on cancer vaccine research and clinical application, thus exploring the existing obstacles in cancer vaccine research and promoting the efficacy of cancer vaccine. PMID- 27240459 TI - Adoptive Cellular Therapy (ACT) for Cancer Treatment. AB - Adoptive cellular therapy (ACT) with various lymphocytes or antigen-presenting cells is one stone in the pillar of cancer immunotherapy, which relies on the tumor-specific T cell. The transfusion of bulk T-cell population into patients is an effective treatment for regression of cancer. In this chapter, we summarize the development of various strategies in ACT for cancer immunotherapy and discuss some of the latest progress and obstacles in technical, safety, and even regulatory aspects to translate these technologies to the clinic. ACT is becoming a potentially powerful approach to cancer treatment. Further experiments and clinical trials are needed to optimize this strategy. PMID- 27240460 TI - Oncolytic Immunotherapy for Treatment of Cancer. AB - Immunotherapy entails the treatment of disease by modulation of the immune system. As detailed in the previous chapters, the different modes of achieving immune modulation are many, including the use of small/large molecules, cellular therapy, and radiation. Oncolytic viruses that can specifically attack, replicate within, and destroy tumors represent one of the most promising classes of agents for cancer immunotherapy (recently termed as oncolytic immunotherapy). The notion of oncolytic immunotherapy is considered as the way in which virus-induced tumor cell death (known as immunogenic cancer cell death (ICD)) allows the immune system to recognize tumor cells and provide long-lasting antitumor immunity. Both immune responses toward the virus and ICD together contribute toward successful antitumor efficacy. What is now becoming increasingly clear is that monotherapies, through any of the modalities detailed in this book, are neither sufficient in eradicating tumors nor in providing long-lasting antitumor immune responses and that combination therapies may deliver enhanced efficacy. After the rise of the genetic engineering era, it has been possible to engineer viruses to harbor combination-like characteristics to enhance their potency in cancer immunotherapy. This chapter provides a historical background on oncolytic virotherapy and its future application in cancer immunotherapy, especially as a combination therapy with other treatment modalities. PMID- 27240461 TI - The Neuroprotection of Liraglutide Against Ischaemia-induced Apoptosis through the Activation of the PI3K/AKT and MAPK Pathways. AB - Glucagon-like peptide-1 (GLP-1) is an incretin hormone that increases glucose dependent insulin secretion to reduce the glucose level. Liraglutide, a long acting GLP-1 analogue, has been found to have neuroprotective action in various experimental models. However, the protective mechanisms of liraglutide in ischaemic stroke remain unclear. Here, we demonstrated that liraglutide significantly decreased the infarct volume, improved neurologic deficits, and lowered stress-related hyperglycaemia without causing hypoglycaemia in a rat model of middle cerebral artery occlusion (MCAO). Liraglutide inhibited cell apoptosis by reducing excessive reactive oxygen species (ROS) and improving the function of mitochondria in neurons under oxygen glucose deprivation (OGD) in vitro and MCAO in vivo. Liraglutide up-regulated the phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinases (ERK) and inhibited the phosphorylation of c-jun-NH2-terminal kinase (JNK) and p38. Moreover, the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and/or the ERK inhibitor U0126 counteracted the protective effect of liraglutide. Taken together, these results suggest that liraglutide exerts neuroprotective action against ischaemia induced apoptosis through the reduction of ROS and the activation of the PI3K/AKT and mitogen-activated protein kinase (MAPK) pathways. Therefore, liraglutide has therapeutic potential for patients with ischaemic stroke, especially those with Type 2 diabetes mellitus or stress hyperglycaemia. PMID- 27240462 TI - The unique luminal staining pattern of cytokeratin 5/6 in adenoid cystic carcinoma of the breast may aid in differentiating it from its mimickers. AB - Adenoid cystic carcinoma (AdCC) of the breast is an uncommon but distinct neoplasm composed of a dual cell population polarized around true glandular (luminal) spaces and pseudolumina. The aim of this study was to clarify whether various immunohistochemical markers (CK7, EMA, CD117, p63, calponin, CD10, S100, CK5/6, CK14, vimentin, and type IV collagen) can distinguish between the two cell types in classical AdCC (n = 14) and in collagenous spherulosis (n = 5). The sensitivity and specificity of these 11 markers to distinguish luminal from abluminal cells were evaluated using a curve created by plotting the true positive rate (sensitivity) against the false-positive rate (1 - specificity) at threshold settings of 0, 10, 50, and 70 %. The most sensitive and specific markers for luminal cells in AdCC were CK7 and EMA; those for abluminal cells were type IV collagen, p63, and vimentin. CD10 and S100 did not act as abluminal markers in AdCC. CK5/6, one of the basal/myoepithelial markers, was expressed more frequently in luminal than in abluminal cells of AdCC. Thus, CK5/6 immunostaining resulted in a reverse expression pattern, analogous to what we recently documented in clear cells in mammary adenomyoepithelioma. In conclusion, compared with myoepithelial/abluminal cells of normal breast or collagenous spherulosis, the neoplastic abluminal cells of classical AdCC are characterized by enhanced vimentin and attenuated CD10 and S100. Furthermore, the luminal cells of AdCC show a unique aberrant staining pattern for CK5/6 that may aid in the differential diagnosis. PMID- 27240463 TI - Renal denervation in a patient with unilateral ectopic kidney in the pelvis and refractory hypertension. AB - Ectopic kidney and inherent vascular abnormalities may result in renovascular hypertension. The case we report is peculiar as a left ectopic iliac kidney supplied by a superior and an inferior polar renal arteries was detected in a treatment-resistant hypertensive man. In conclusion, percutaneous renal artery denervation was successfully performed in the right renal artery and in both left accessory renal arteries, obtaining excellent blood pressure decrease at follow up. PMID- 27240464 TI - Identification, synthesis and evaluation of SARS-CoV and MERS-CoV 3C-like protease inhibitors. AB - Severe acute respiratory syndrome (SARS) led to a life-threatening form of atypical pneumonia in late 2002. Following that, Middle East Respiratory Syndrome (MERS-CoV) has recently emerged, killing about 36% of patients infected globally, mainly in Saudi Arabia and South Korea. Based on a scaffold we reported for inhibiting neuraminidase (NA), we synthesized the analogues and identified compounds with low micromolar inhibitory activity against 3CL(pro) of SARS-CoV and MERS-CoV. Docking studies show that a carboxylate present at either R(1) or R(4) destabilizes the oxyanion hole in the 3CL(pro). Interestingly, 3f, 3g and 3m could inhibit both NA and 3CL(pro) and serve as a starting point to develop broad spectrum antiviral agents. PMID- 27240466 TI - Novel approaches to map small molecule-target interactions. AB - The quest for small molecule perturbators of protein function or a given cellular process lies at the heart of chemical biology and pharmaceutical research. Bioactive compounds need to be extensively characterized in the context of the modulated protein(s) or process(es) in living systems to unravel and confirm their mode of action. A crucial step in this workflow is the identification of the molecular targets for these small molecules, for which a generic methodology is lacking. Herein we summarize recently developed approaches for target identification spurred by advances in omics techniques and chemo- and bioinformatics analysis. PMID- 27240465 TI - Synthesis and antimicrobial activity against Pseudomonas aeruginosa of macrocyclic beta-hairpin peptidomimetic antibiotics containing N-methylated amino acids. AB - Antimicrobial resistance among Gram-negative bacteria is a growing problem, fueled by the paucity of new antibiotics that target these microorganisms. One novel family of macrocyclic beta-hairpin-shaped peptidomimetics was recently shown to act specifically against Pseudomonas spp. by a novel mechanism of action, targeting the outer membrane protein LptD, which mediates lipopolysaccharide transport to the cell surface during outer membrane biogenesis. Here we explore the mode of binding of one of these beta-hairpin peptidomimetics to LptD in Pseudomonas aeruginosa, by examining the effects on antimicrobial activity following N-methylation of individual peptide bonds. An N methyl scan of the cyclic peptide revealed that residues on both sides of the beta-hairpin structure at a non-hydrogen bonding position likely mediate hydrogen bonding interactions with the target LptD. Structural analyses by NMR spectroscopy further reinforce the conclusion that the folded beta-hairpin structure of the peptidomimetic is critical for binding to the target LptD. Finally, new NMe analogues with potent activity have been identified, which opens new avenues for optimization in this family of antimicrobial peptides. PMID- 27240467 TI - Synthesis and structure-activity relationships of novel hybrid ferrocenyl compounds based on a bicyclic core skeleton for breast cancer therapy. AB - Breast cancer is the most frequent cancer in women worldwide, and incidence is increasing year by year. Although current selective estrogen receptor modulators (SERMs) have clear advantages in the treatment of hormone-responsive breast cancer, they are ineffective for ER(-). In this study, we describe the design and synthesis of a series of dual-acting estrogen receptor (ER) and histone deacetylase (HDAC) inhibitors with incorporation of the ferrocenyl moiety, leading to novel hybrid ferrocenyl complexes (FcOBHS-HDACis) for breast cancer therapy. It is worth to note that these ferrocenyl conjugates could not only potently inhibit HDACs and the proliferation of ERalpha positive (ER(+)) breast cancer cells (MCF-7), but also show significant antiproliferative effect on ER(-) breast cancer cells (MDA-MB-231). Thus, the FcOBHS-HDACi conjugates represent a novel approach to the development of efficiently dual-acting agents for treatment of breast cancer. PMID- 27240468 TI - Discovery and preliminary structure-activity relationship studies on tecomaquinone I and tectol as novel farnesyltransferase and plasmodial inhibitors. AB - Biological screening of a library of synthesized benzo[c]chromene-7,10-dione natural products against human farnesyltransferase (FTase) has identified tecomaquinone I (IC50 of 0.065+/-0.004MUM) as being one of the more potent natural product inhibitors identified to date. Anti-plasmodial screening of the same library against a drug-resistant strain of Plasmodium falciparum identified the structurally-related dichromenol tectol as a moderately active growth inhibitor with an IC50 3.44+/-0.20MUM. Two novel series of analogues, based on the benzo[c]chromene-7,10-dione scaffold, were subsequently synthesized, with one analogue exhibiting farnesyltransferase inhibitory activity in the low micromolar range. A preliminary structure-activity relationship (SAR) study has identified different structural requirements for anti-malarial activity in comparison to FTase activities for these classes of natural products. Our results identify tecomaquinone I as a novel scaffold from which more potent inhibitors of human and parasitic FTase could be developed. PMID- 27240469 TI - Antiplasmodial activities of gold(I) complexes involving functionalized N heterocyclic carbenes. AB - A series of twenty five molecules, including imidazolium salts functionalized by N-, O- or S-containing groups and their corresponding cationic, neutral or anionic gold(I) complexes were evaluated on Plasmodium falciparum in vitro and then on Vero cells to determine their selectivity. Among them, eight new compounds were synthesized and fully characterized by spectroscopic methods. The X-ray structures of three gold(I) complexes are presented. Except one complex (18), all the cationic gold(I) complexes show potent antiplasmodial activity with IC50 in the micro- and submicromolar range, correlated with their lipophilicity. Structure-activity relationships enable to evidence a lead-complex (21) displaying a good activity (IC50=210nM) close to the value obtained with chloroquine (IC50=514nM) and a weak cytotoxicity. PMID- 27240470 TI - DNA End Resection: Facts and Mechanisms. AB - DNA double-strand breaks (DSBs), which arise following exposure to a number of endogenous and exogenous agents, can be repaired by either the homologous recombination (HR) or non-homologous end-joining (NHEJ) pathways in eukaryotic cells. A vital step in HR repair is DNA end resection, which generates a long 3' single-stranded DNA (ssDNA) tail that can invade the homologous DNA strand. The generation of 3' ssDNA is not only essential for HR repair, but also promotes activation of the ataxia telangiectasia and Rad3-related protein (ATR). Multiple factors, including the MRN/X complex, C-terminal-binding protein interacting protein (CtIP)/Sae2, exonuclease 1 (EXO1), Bloom syndrome protein (BLM)/Sgs1, DNA2 nuclease/helicase, and several chromatin remodelers, cooperate to complete the process of end resection. Here we review the basic machinery involved in DNA end resection in eukaryotic cells. PMID- 27240472 TI - Digit Sucking, Age, Sex, and Socioeconomic Status as Determinants of Oral Hygiene Status and Gingival Health of Children in Suburban Nigeria. AB - BACKGROUND: This study determines prevalence of digit sucking and gingivitis, and association among age, sex, socioeconomic status, presence of digit-sucking habits, oral hygiene status (OHS), and gingivitis among a group of Nigerian children. METHODS: Data of 992 children aged 1 to 12 years recruited through a household survey conducted in Osun State, Nigeria were analyzed. Information on age, sex, socioeconomic status, and history of digit-sucking habits were collected. Children were assessed for OHS and severity of gingivitis using the simplified oral hygiene index and the gingival index, respectively. Predictors of presence of gingivitis and poor oral hygiene were determined using multivariate logistic regression. RESULTS: One (0.2%) and 454 (93.0%) children aged 1 to 5 years had poor oral hygiene and mild gingivitis, respectively. Twenty-two (4.4%) and 361 (72.9%) children aged 6 to 12 years had poor oral hygiene and mild gingivitis, respectively. The odds of having poor oral hygiene (adjusted odds ratio [AOR]: 0.26; 95% confidence interval [CI]: 0.20 to 0.35; P <0.001) and gingivitis (AOR: 0.21; 95% CI: 0.14 to 0.31; P <0.001) was significantly reduced for children aged 1 to 5 years. The odds of having gingivitis was increased in children with low socioeconomic status (AOR: 2.09; 95% CI: 1.32 to 3.31; P = 0.002). There was no significant relationship among sex, digit sucking, OHS, and presence of gingivitis. CONCLUSIONS: A digit-sucking habit did not increase chances of having poor oral hygiene and gingivitis. Increasing age and low socioeconomic status were factors that significantly increased chances of having poor oral hygiene and gingivitis. PMID- 27240473 TI - Elevated MicroRNA-128 in Periodontitis Mitigates Tumor Necrosis Factor-alpha Response via p38 Signaling Pathway in Macrophages. AB - BACKGROUND: Periodontitis is a chronic inflammatory disease resulting from an inflammatory response to subgingival plaque bacteria, including Porphyromonas gingivalis. MicroRNA (miRNA) is a current focus in regulating the inflammatory processes. In this study, the inflammatory miRNA expression in gingival tissues of patients with periodontitis and of healthy individuals is compared, and its role in regulating the inflammatory response is examined. METHODS: Gingival tissues from patients with periodontitis and healthy individuals were collected for miRNA microarray. THP-1 and CA9-22 cells were challenged with P. gingivalis, and miRNA expression was determined by real-time polymerase chain reaction. Target genes for miRNA were predicted using TargetScanHuman database, and miRNA gene expressions were reviewed using public databases. For the functional study, THP-1 cells were transfected with a miRNA-128 mimic, and target gene expression was compared with THP-1 cells challenged with P. gingivalis. For the tolerance test, THP-1 cells transfected with miRNA-128 mimic were treated with phorbol 12 myristate 13-acetate (PMA) or paraformaldehyde (PFA)-fixed Escherichia coli. Tumor necrosis factor (TNF)-alpha production was determined by enzyme-linked immunosorbent assay, and mitogen-activated protein kinase (MAPK) protein phosphorylation was determined by Western blot. RESULTS: Gingival tissues from patients with periodontitis showed increased expression of miRNA-128, miRNA-34a, and miRNA-381 and decreased expression of miRNA-15b, miRNA-211, miRNA-372, and miRNA-656. THP-1 cells and CA9-22 cells challenged with P. gingivalis showed increased miRNA-128 expression. Among the predicted miRNA-128 target genes, several genes that are involved in MAPK signaling pathway showed similar gene expression pattern between P. gingivalis challenge and miRNA-128 mimic transfection. In THP-1 cells transfected with miRNA-128 mimic, TNF-alpha production was lower, and phosphorylation of p38 was inhibited when challenged with PMA or PFA-fixed E. coli. CONCLUSION: miRNA-128 may be involved in mitigating the inflammatory response induced by P. gingivalis in periodontitis. PMID- 27240471 TI - Functions of PARylation in DNA Damage Repair Pathways. AB - Protein poly ADP-ribosylation (PARylation) is a widespread post-translational modification at DNA lesions, which is catalyzed by poly(ADP-ribose) polymerases (PARPs). This modification regulates a number of biological processes including chromatin reorganization, DNA damage response (DDR), transcriptional regulation, apoptosis, and mitosis. PARP1, functioning as a DNA damage sensor, can be activated by DNA lesions, forming PAR chains that serve as a docking platform for DNA repair factors with high biochemical complexity. Here, we highlight molecular insights into PARylation recognition, the expanding role of PARylation in DDR pathways, and the functional interaction between PARylation and ubiquitination, which will offer us a better understanding of the biological roles of this unique post-translational modification. PMID- 27240474 TI - Effects of Atorvastatin on Periodontitis of Rats Subjected to Glucocorticoid Induced Osteoporosis. AB - BACKGROUND: Atorvastatin (ATV) has shown pleiotropic effects on bone tissue, and osteoporosis can aggravate periodontitis. Thus, the effects of ATV on experimental periodontitis (EP) in rats subjected to glucocorticoid-induced osteoporosis (GIOP) was assessed. METHODS: Male Wistar rats were divided into the following groups: 1) naive; 2) EP; 3) GIOP + EP; and 4) ATV. Groups GIOP + EP and ATV received 7 mg/kg dexamethasone intramuscularly once per week for 5 weeks, and the others received saline (SAL). Groups EP, GIOP + EP, and ATV were submitted to EP by ligature around the maxillary left second molars for 11 days. Group ATV received 27 mg/kg ATV orally, and the others received SAL 30 minutes before EP. Periodontium was analyzed by macroscopy, microtomography, and histopathology; by immunohistochemical examination of receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG), wingless (WNT) 10b, dickkopf-related protein 1 (DKK-1), and beta-catenin; and by enzyme-linked immunosorbent assay analysis of myeloperoxidase (MPO), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-8, IL10, reduced glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT). Leukogram, liver and kidney enzymes, and bone-specific alkaline phosphatase (BALP) serum levels were evaluated. RESULTS: ATV decreased bone loss, reduced MPO, TNF-alpha, IL-1beta, IL-6, and IL-8, and increased IL-10, GSH, SOD, and CAT levels. ATV reduced RANKL and DKK-1 and increased OPG, WNT10b, and beta-catenin expressions and BALP activity. CONCLUSION: ATV reduced inflammation, oxidative stress, and bone loss in rats with EP and GIOP, with participation of the WNT signaling pathway. PMID- 27240475 TI - A Novel Regenerative Technique Combining Bone Morphogenetic Protein-2 With Fibroblast Growth Factor-2 for Circumferential Defects in Dog Incisors. AB - BACKGROUND: Periodontal regeneration of incisors is necessary for esthetic recovery. A novel regenerative method combining bone morphogenetic protein (BMP) 2 and fibroblast growth factor (FGF)-2 was developed. The purpose of this study is to evaluate periodontal healing, including root coverage, in circumferential defects of incisors. METHODS: Fifty incisors in five beagles were used. After circumferential defects were surgically created, each group, consisting of ten recipient sites, received: 1) a double layer with FGF-2 (2 MUg)/collagen as inner layer and BMP-2 (4 MUg)/collagen as outer layer (FB-DL group); 2) collagen impregnated with both FGF-2 (2 MUg) and BMP-2 (4 MUg) (FB-M group); 3) BMP-2 (4 MUg)/collagen (B group); 4) FGF-2 (4 MUg)/collagen (F group); or 5) collagen (C group). Dogs were sacrificed 8 weeks post-surgery, and healing was evaluated histologically. RESULTS: The three groups treated with BMP-2 showed enhanced new bone formation compared with control and F groups (P < 0.05). Furthermore, connective tissue attachment with cementum regeneration in the FB-DL group was significantly greater than in FB-M and B groups (P <0.05). Ankylosis in the FB-DL group was significantly less than in FB-M and B groups (P <0.05). Gingival recession was inhibited significantly better in FB-DL and FB-M groups compared with control and B groups. CONCLUSION: These data support development of a double layer method combining BMP-2 and FGF-2 as a therapeutic approach to periodontal regeneration at incisors with horizontal circumferential defects. PMID- 27240476 TI - Externally controlled drug release using a gold nanorod contained composite membrane. AB - Versatile drug delivery devices using nanoporous membranes consisting of gold nanorods and dendrimers have been demonstrated to provide light-triggered on demand pulsatile release from a reservoir containing highly enriched therapeutics for a real patient's needs. The drug release rate is directly correlated with the temperature increase and irradiated energy of a near-IR laser in both static and fluidic devices. This biocompatible platform for on-demand control was further confirmed by in vitro experiments. Interestingly, different responses to stimuli were obtained from each drug in the absence and presence of NIR light, indicating the versatile potential of our on-demand drug delivery system in less-invasive therapies requiring multi-drug delivery strategies. The enhanced delivery system will improve therapeutic efficacy and reduce side effects through regulation of plasma drug profiles. PMID- 27240477 TI - A critical study of the generality of the two step two electron pathway for water splitting by application of a C3N4/MnO2 photocatalyst. AB - A novel C3N4-CDot composite photocatalyst was very recently shown to be highly efficient and very stable in water splitting by solar radiation without using any sacrificial reagent (J. Liu, et al., Science, 2015, 347(6225), 970). This photocatalyst utilizes a two-electron/two-step process in which the production of H2O2 and H2 is photocatalyzed by using C3N4 in the first step and H2O2 is decomposed by using CDots in the second step. The present work is a study on the generality of this approach by application of a C3N4/MnO2 catalyst. This new catalyst indeed splits water by a two step process in a stable way, without any sacrificial agent. It was however found that though the absorbance of the new catalyst in the visible range of 500-600 nm is much larger than that of the C3N4 CDot catalyst, its water splitting efficiency is much lower. These findings add insight into and assist in the further optimization of this new class of photocatalysts to meet the requirements of commercial water splitting systems. PMID- 27240478 TI - Effect of motion on speech recognition. AB - The benefit of spatial separation for talkers in a multi-talker environment is well documented. However, few studies have examined the effect of talker motion on speech recognition. In the current study, we evaluated the effects of (1) motion of the target or distracters, (2) a priori information about the target and distracter spatial configurations, and (3) target and distracter location. In total, seventeen young adults with normal hearing were tested in a large anechoic chamber in two experiments. In Experiment 1, seven stimulus conditions were tested using the Coordinate Response Measure (Bolia et al., 2000) speech corpus, in which subjects were required to report the key words in a target sentence presented simultaneously with two distracter sentences. As in previous studies, there was a significant improvement in key word identification for conditions in which the target and distracters were spatially separated as compared to the co located conditions. In addition, 1) motion of either talker or distracter resulted in improved performance compared to stationary presentation (talker motion yielded significantly better performance than distracter motion) 2) a priori information regarding stimulus configuration was not beneficial, and 3) performance was significantly better with key words at 0 degrees azimuth as compared to -60 degrees (on the listener's left). Experiment 2 included two additional conditions designed to assess whether the benefit of motion observed in Experiment 1 was due to the motion itself or to the fact that the motion conditions introduced small spatial separations in the target and distracter key words. Results showed that small spatial separations (on the order of 5-8 degrees ) resulted in improved performance (relative to co-located key words) whether the sentences were moving or stationary. These results suggest that in the presence of distracting messages, motion of either target or distracters and/or small spatial separation of the key words may be beneficial for sound source segregation and thus for improved speech recognition. PMID- 27240479 TI - Characterization of the nonlinear elastic behavior of chinchilla tympanic membrane using micro-fringe projection. AB - The mechanical properties of an intact, full tympanic membrane (TM) inside the bulla of a fresh chinchilla were measured under quasi-static pressure from -1.0 kPa to 1.0 kPa applied on the TM lateral side. Images of the fringes projected onto the TM were acquired by a digital camera connected to a surgical microscope and analyzed using a phase-shift method to reconstruct the surface topography. The relationship between the applied pressure and the resulting volume displacement was determined and analyzed using a finite element model implementing a hyperelastic 2(nd)-order Ogden model. Through an inverse method, the best-fit model parameters for the TM were determined to allow the simulation results to agree with the experimental data. The nonlinear stress-strain relationship for the TM of a chinchilla was determined up to an equibiaxial tensile strain of 31% experienced by the TM in the experiments. The average Young's modulus of the chinchilla TM from ten bullas was determined as approximately 19 MPa. PMID- 27240481 TI - Enhanced photophysics from self-assembled cyclometalated Ir(iii) complexes in water. AB - Two water-soluble anionic cyclometalated Ir(iii) complexes, Ir(ppy)2BPS [] and Ir(F-mppy)2BPS [] have been synthesized and display clear evidence of self assembly in water. Concentration-induced aggregation enhances the excited-state properties of both complexes, blue-shifting the photoluminescence emission energies as well as increasing the corresponding excited state lifetimes and quantum yields up to a factor of 5. PMID- 27240480 TI - Auditory training improves auditory performance in cochlear implanted children. AB - While the positive benefits of pediatric cochlear implantation on language perception skills are now proven, the heterogeneity of outcomes remains high. The understanding of this heterogeneity and possible strategies to minimize it is of utmost importance. Our scope here is to test the effects of an auditory training strategy, "sound in Hands", using playful tasks grounded on the theoretical and empirical findings of cognitive sciences. Indeed, several basic auditory operations, such as auditory scene analysis (ASA) are not trained in the usual therapeutic interventions in deaf children. However, as they constitute a fundamental basis in auditory cognition, their development should imply general benefit in auditory processing and in turn enhance speech perception. The purpose of the present study was to determine whether cochlear implanted children could improve auditory performances in trained tasks and whether they could develop a transfer of learning to a phonetic discrimination test. MATERIAL AND METHODS: Nineteen prelingually unilateral cochlear implanted children without additional handicap (4-10 year-olds) were recruited. The four main auditory cognitive processing (identification, discrimination, ASA and auditory memory) were stimulated and trained in the Experimental Group (EG) using Sound in Hands. The EG followed 20 training weekly sessions of 30 min and the untrained group was the control group (CG). Two measures were taken for both groups: before training (T1) and after training (T2). RESULTS: EG showed a significant improvement in the identification, discrimination and auditory memory tasks. The improvement in the ASA task did not reach significance. CG did not show any significant improvement in any of the tasks assessed. Most importantly, improvement was visible in the phonetic discrimination test for EG only. Moreover, younger children benefited more from the auditory training program to develop their phonetic abilities compared to older children, supporting the idea that rehabilitative care is most efficient when it takes place early on during childhood. These results are important to pinpoint the auditory deficits in CI children, to gather a better understanding of the links between basic auditory skills and speech perception which will in turn allow more efficient rehabilitative programs. PMID- 27240482 TI - Electrophilic activation of alkynes for enyne cycloisomerization reactions with in situ generated early/late heterobimetallic Pt-Ti catalysts. AB - In situ formation of heterobimetallic Pt-Ti catalysts enables rapid room temperature catalysis in enyne cycloisomerization reactions. The Lewis acidic titanium atom in the ligand framework is shown to be essential for fast catalysis. A range of enyne substrates are efficiently cyclized to carbocycles and heterocycles in high yield. PMID- 27240483 TI - A pyrazolo[1,5-a]pyridine-fused pyrimidine based novel fluorophore and its bioapplication to probing lipid droplets. AB - A new fluorescent core skeleton containing pyrazolo[1,5-a]pyridine-fused pyrimidine, called fluoremidine (FD), was discovered. FD analogues were prepared via a one-pot silver-catalyzed cascade cyclization. An N,N-dimethylamino group at the R(1)- and R(2)-positions plays important roles in controlling fluorescence brightness and emission wavelength. An N-acetyl group at the R(3) position contributes to red shifting of the emission wavelength. FD shows excellent solvatochromism with turn-on fluorescence in the lipophilic environment, which was utilized to design a fluorescent probe, FD13, for visualizing lipid droplets in living cells. PMID- 27240485 TI - Incivility in nursing: from roots to repair. PMID- 27240484 TI - Analysis of tigecycline resistance development in clinical Acinetobacter baumannii isolates through a combined genomic and transcriptomic approach. AB - Tigecycline (Tgc) is considered a last-resort antibiotic for the treatment of multi-drug resistant bacteria. To study Tgc resistance development in the important nosocomial pathogen Acinetobacter baumannii, we adopted six clinical isolates from three patients undergoing antibiotic treatment, and bacterial genomic sequences and seven strand-specific transcriptomes were studied. Interestingly, the Tgc-intermediate 2015ZJAB1 only differed from Tgc-resistant 2015ZJAB2 in an SNP-clustered region including OprD, a sugar-type MFS permease, and a LuxR-type transcriptional regulator. Surprisingly, an almost identical region was found in 2015ZJAB3, which supports the possibility of a homologous recombination event that increased Tgc resistance. Furthermore, comparative transcriptomic analysis identified significantly regulated genes associated with Tgc resistance, which was verified using qRT-PCR. Three enriched COG categories included amino acid transport and metabolism, transcription, and inorganic ion transport and metabolism. KEGG analysis revealed common features under Tgc conditions, including up regulated benzoate degradation and a less active TCA cycle. This may be related to selective antimicrobial pressure in the environment and adaptation by lowering metabolism. This study provides the first report of an in vivo evolutionary process that included a putative homologous recombination event conferring Tgc resistance in clinical A. baumannii isolates in which transcriptome analysis revealed resistance-conferring genes and related metabolism characteristics. PMID- 27240486 TI - Knowledge and attitude (KA) survey regarding infant hearing loss in Karnataka, India. AB - INTRODUCTION: The support provided and the decisions taken by mothers determine the success of Universal Newborn Hearing Screening (UNHS). Attempts at exploring the existing knowledge-attitude among mothers is crucial to create/modify the existing screening programs. The present study attempts to explore the knowledge and attitude toward infant hearing loss (HL) among mothers of newborns in the Indian state of Karnataka. METHOD: A cross-sectional survey was conducted among 219 mothers of newborns in Karnataka, India. The questionnaire was framed from existing literature and consisted of 19 questions assessing knowledge and attitude toward infant HL to be rated on a three-point scale (no, not sure, yes). Descriptive statistics and Cronbach's alpha were used to analyze the data. RESULTS: Mothers exhibited good knowledge of risk factors; noise (70.3%) and ear discharge (54.3%). More than 75% agreed that treatment for HL is available and that these children can attend school. The questions of superstitions and cultural beliefs yielded mixed responses. A large number of mothers expressed desire to have their children tested at birth (84.9%) and were concerned about their children's hearing (87.7%). Yet only 54.3% stated that they would allow their children to wear hearing aids. SUMMARY AND CONCLUSION: The present study is an attempt to understand the knowledge and attitude of mothers toward infant HL in Karnataka and facilitate identification of potential areas of less knowledge as a reference for endeavors of enhancement. It further highlights the need for implementing public awareness programs to improve knowledge and attitude of mothers toward infant HL for better implementation of UNHS. PMID- 27240487 TI - Attention deficit hyperactivity disorder symptoms in children with vocal fold nodules. AB - OBJECTIVES: The aim of this case-control study was to investigate the symptoms of attention-deficit/hyperactivity disorder (ADHD) in children with vocal fold nodules (VNs). METHODS: Study group (SG) included children between 4 and 12 years. As a control group (CG), children between 4 and 12 years without VNs were included in the study. Parents of the participants completed the Conners' Parent Rating Scale-Revised: Short Form (CPRS-RS) which was used to analyze the symptoms of ADHD. RESULTS: Forty-five children (30 boys and 15 girls) with VNs and 45 controls (30 boys and 15 girls) were enrolled in the study. Multivariate analysis of variance revealed that the CPRS-RS Hyperactivity and Oppositional Subscales were significantly higher in the SG than the CG (p < .05), after controlling the effects of age and gender. CONCLUSIONS: Our findings suggest associations between VNs and hyperactivity and oppositional behaviors in children. Clinicians should be aware of ADHD symptoms in children with VNs. PMID- 27240488 TI - Endotracheal tubes and the cricoid: Is there a good fit? AB - BACKGROUND: Choosing an appropriately sized endotracheal tube (ETT) is important in pediatric patients as an inappropriately sized ETT may result in multiple endotracheal intubation attempts or excessive pressure on the tracheal mucosa with the potential for airway damage. Although age-based formulas are generally used with choice of an ETT based on the internal diameter (ID), measurements of the outer diameter (OD) of the ETT would seem to be a more scientific approach to determine the proper size of an ETT. However, the variable OD of the ETT despite the same ID makes the selection of a proper sized ETT more difficult. The current study compares airway dimensions measured using computed tomography (CT) with the OD of ETTs from various manufacturers. METHODS: The outer diameter of commonly used ETTs (12 cuffed and 5 uncuffed) were measured and compared with CT-based cricoid measurements obtained from a previous study involving 130 pediatric patients, ranging in age from 1 month to 10 years. These data were used to determine the likelihood of a clinically acceptable match. RESULTS: The differences of the cricoid dimensions between the 5th and the 95th percentile in each group ranged from a minimum of 2.23mm to a maximum of 6.51mm. Depending on the manufacturer, there was significant variation in the OD of the ETTs with the same ID. These discrepancies, which varied according to manufacturer and were greater with uncuffed as compared to cuffed ETTs, impacted the chances of an acceptable fit with the cricoid diameters. CONCLUSION: When choosing an ETT, age based formulas which use the ID may not be uniformly accurate in ensuring the appropriately-sized ETT given the variation in the OD despite the same ID. These issues further support the use of cuffed ETTs as the variation in fit can be adjusted by inflation of the cuff to provide an adequate tracheal seal. PMID- 27240489 TI - Evaluation of the protective effects of hesperetin against cisplatin-induced ototoxicity in a rat animal model. AB - OBJECTIVES: We aimed to investigate the effects of hesperetin as a flavanon both histopathologically and immunohistochemically on cochlear apoptosis in a rat model of cisplatin-induced ototoxicity (CIO). The evaluation of the effects of hesperetin on cisplatin-induced hearing loss was performed using distortion product otoacoustic emission (DPOAE). METHODS: Twenty-eight wistar albino rats were used in the current study. The rats were randomly divided into four groups with seven rats in each group. Group C was exposed to a single dose of cisplatin (12mg/kg) by intraperitoneal injection. Group CH received intraperitoneally cisplatin (12mg/kg) and hesperetin (20mg/kg). Group H was exposed to hesperetin (20mg/kg) intraperitoneally. The sham group (group S) received normal saline (6cc) intraperitoneally. The measurements of DPOAE and signal-noise ratios (SNR) were performed before the treatment and again on the first and 6 days after administration of the drugs. Rats were sacrificed and cochleae were dissected 10 days after drug administration. The cochlear tissue was assessed in all groups by histopathologic, immunohistochemical and TUNEL assay. In addition, serum oxidative stress markers and antioxidant parameters were analyzed. RESULTS: There was a significant difference between the basal value and the sixth day at frequencies 8.4, 9.6 and 9.96 for group C. We also found a significant difference between the first and sixth day at frequencies 7.2, 8.4, 9.6 and 9.96. On the 6th day, there were significant differences between C and S groups at all frequencies except 2.4. We showed a significant difference between C and H groups at frequencies 4.8, 6.0, 8.4, 9.6 and 9.96. There was also a significant difference between C and CH groups at frequencies 2.4, and 3.6. We found lower levels of oxidants and higher levels of antioxidants in CH group as compared to C group. C group had a significantly greater number of TUNEL-positive cells than did S, H and CH groups. The number of TUNEL-positive cells in CH group was higher than in S and H groups. There was a significant difference between the positive PCNA cells of CH group compared to S and H groups in spiral ganglion and stria vascularis. In addition, there were no positive PCNA cells in C group. CONCLUSIONS: Hesperetin may prevent ototoxicity by increased antioxidant enzymes and reduced oxidant parameters and protected against apoptosis resulting from a proliferation of cochlear cells in CIO. PMID- 27240490 TI - Otofaciocervical syndrome and metachondromatosis in a girl: Presentation of a novel association and remarks on clinical variability of branchial-arch disorders. AB - Otofaciocervical syndrome (OFCS) is a rare disorder characterized by facial, ear, branchial, and musculoskeletal anomalies, along with hearing loss and mild intellectual disability. Clinically, its distinction from branchiootorenal syndrome can be difficult. To date, the coexistence of OFCS and metachondromatosis has not been reported. Here, we describe a sporadic patient with both OFCS and metachondromatosis. This novel association prompts us to do some remarks on the clinical variability of branchial-arch disorders; in fact, our observations are consistent with the highly variable expressivity of OFCS and illustrate the need of a more accurate characterization of these branchial-arch disorders. In the meantime, involvement of clavicles, scapulae and shoulders remains a distinctive feature of OFCS. PMID- 27240492 TI - Protein energy malnutrition associates with different types of hearing impairments in toddlers: Anemia increases cochlear dysfunction. AB - OBJECTIVES: This work aimed to highlight a challenging asymptomatic problem which is early detection of hearing impairment in toddlers with protein energy malnutrition (PEM) as a neuro-cognitive effect of PEM on developing brain in relation to hemoglobin level. METHODS: 100 toddlers, aged 6-24 months, fifty with moderate/severe PEM and fifty healthy children, were included in study. Both TEOAEs and ABR testing were used to assess auditory function. RESULTS: Study reported an association between malnutrition and hearing impairment, 26% of cases had conductive deafness secondary to otitis media with effusion using tympanometry; 84.6% showed type B and 15.4% type C which may suggest developing or resolving otitis media. Their ABR showed 46% mild and 53% moderate impairment. 32% of PEM cases had sensory neural hearing loss and with type (A) tympanometry. Those were assessed using ABR; 58% had mild, 34% moderate and 8% profound impairment. 10% of PEM cases had mixed hearing loss with 50% type B and 50% type C tympanometry and their ABR showed moderate to profound impairment. TEOAEs latencies at different frequencies correlate negatively with hemoglobin level. CONCLUSIONS: Toddlers with moderate/severe PEM had hearing impairments of different types and degrees. Neuro-physiological methods could be early and safe detectors of auditory disorders especially in high-risk toddlers. Anemia increases risk for auditory dysfunction. PMID- 27240491 TI - Hyaluronic acid and upper airway inflammation in pediatric population: A systematic review. AB - BACKGROUND: Inflammatory disease of upper airway in pediatric population represents a social problem for both the pharmaco-economic impact and a burden for the family. To date, the use of topical therapies represents a significant therapeutic progress because they are able to reduce mucosal inflammation and improve tissue healing. Topical Hyaluronic Acid (HA) is a promising molecule that has been recently proposed as adjuvant treatment in the inflammatory disease of the upper aerodigestive tract (UADT) infections. AIMS: The aim of our work was to review the published literature regarding all the potential therapeutic effects of HA in the inflammatory disease of upper airway in pediatric population and evaluate the effectiveness of HA, alone or in combination, in children affected by cystic fibrosis. METHODS: Relevant published studies about use of HA in UADT in pediatrics were searched in Pubmed, Google Scholar, Ovid using various keywords with no limit for the year of publication. Studies based on the use of HA with nasal packing and with invasive administration of HA were excluded. RESULTS: At the end of our selection process, four publications have been included: one of them in children with recurrent upper respiratory tract infections, one of them in children with bacterial acute rhinopharyngitis, two of them in children affected by cystic fibrosis. CONCLUSIONS: Topical administration of HA plays a pivotal role in all the children suffering from UADT inflammatory disease, and positive results are generally observed in children with cystic fibrosis. PMID- 27240493 TI - Managing children with sialorrhoea (drooling): Experience from the first 301 children in our saliva control clinic. AB - OBJECTIVES: Sialorrhoea (drooling) is defined as the involuntary escape of saliva from the mouth. It is considered normal in young children but may cause social problems in older children. Sialorrhoea is frequently seen in children with cerebral palsy, with rates between 10% and 58% and in other neurodevelopmental diseases. Management of these children can be challenging and often requires an individual and stepwise approach. This is a large case series of children managed at the saliva control clinic in Glasgow, Scotland. METHODS: A chart review of all children attending the saliva control clinic between 2006 and June 2012 was performed. This was to ensure that all children would have long term follow up (3 years minimum). Drooling severity was assessed on the child's first attendance at clinic, and at review following a treatment option, using the Teacher Drooling Scale (TDS). RESULTS: The total number of children attending this clinic was 301, of which 274 had adequate records for inclusion in the study. 176 (64%) were male. The mean age was 7.3 (median 5) years. In terms of development 35 (13%) of children were developing normally and 50 (18%) had general developmental delay. There were 105 (38%) children with cerebral palsy. The final management of sialorrhoea in these children was simple reassurance and advice for 34 (12%), speech and language therapy for 62 (23%) anticholinergics in 90 patients (33%), botox for 30 (11%) and surgery for 71 (26%) children. The rate of non-tolerance of anticholinergics is 30%; 90 of the 298 children tried on anticholinergics had side effects leading to the treatment being stopped. The average teachers drooling score was 4.24 before clinic and 1.59 after clinic. Satisfactory results were achieved in 215 (78%) of children. CONCLUSION: Our data illustrates that effective patient management requires all treatment options to be available, including speech therapy, medications, botulinum toxin and surgery. This is one of the larger case series of children attending a saliva control clinic. PMID- 27240495 TI - Mucocele of the hard palate in children. AB - OBJECTIVE: Mucus retention cyst of the hard palate may result from obstruction of the ducts of the minor salivary glands, and it was defined as a mucocele. Although, the disease is not common in the hard palate, it was previously reported by many authors in the soft palate. The aim of our study was to present pediatric patients who were diagnosed to have mucocele of the hard palate, and to evaluate the outcome of the surgical excision of this lesion. METHODS: This is a case series study included 8 pediatric patients who presented with cystic lesions on the hard palate which were removed surgically, and were diagnosed as mucoceles. Preoperative data, surgical procedures, and postoperative outcome were presented. Follow up of patients was performed for at least one year. RESULTS: The swelling was detected as a single isolated lesion, on the side of the hard palate, covered with healthy mucosa, not tender, oval or round in shape, and measuring 0.4 to 1.7cm in its greatest dimension. Computed tomography showed a well defined cavity which was not invading the bone, and not disrupting the muscles of the palate. Histopathological examination confirmed that the lesion was a cavity that is lined with an epithelial layer with pseudoepitheliomatous hyperplasia. No patients developed intraoperative or postoperative complications, and no recurrence was detected in any patient. CONCLUSIONS: Oral mucoceles can develop on the hard palate of the children, the lesions are mucus retention cysts. Complete surgical removal of the lesions with their cystic wall is a good treatment options, it carries no risk of recurrence. PMID- 27240494 TI - Endoscopic bilateral congenital choanal atresia repair of 112 cases, evolving concept and technical experience. AB - OBJECTIVE: This study aims to present 18 years' experience with endoscopic treatment of bilateral congenital choanal atresia as regard to management concept, surgical technique, results, pitfalls, and complications. PATIENTS AND METHODS: A retrospective study including 112 cases of bilateral congenital choanal atresia, treated at Mansoura University Hospital endoscopically in the period from January 1998 to March 2015. As far as we know, this is the largest study group on transnasal endoscopic choanal atresia repair in literature. RESULTS: One hundred and twelve infants (87 females, 25 males) were included in the study. Age at operation ranged between 1 day and 28 days (8.75 days in average), and body weight average was 2.76kg. All patients were diagnosed at birth except 3 infants. In this study, 85 cases were mixed atresia, 25 cases were bony atresia, and only two cases were membranous. In all cases, obliterated choana bone and vomer bone was removed, lateral wall drilling was used in 33 cases. Follow up ranged between 6 months and 18 years (95.6 months in average). The most common complication was restenosis, occurred in 42% (47 cases). Second look procedure was done in 68 cases. The need for second-look evaluation with stent group was 74.5% (62 out of 83 infants), whereas in non-stent group was 20.6% (6 out of 29 infants). CONCLUSION: Endoscopic repair of bilateral choanal atresia is a safe, effective technique with minimal complication. Usage of 30 degree sinuscope permits better visualization and higher accessibility for the surgical instruments. Surgically formed wide single neochoana with removal of all intervening tissue surroundings, and good follow up permit higher success rate without stenting. Advanced learning curve permits tailoring the perfect surgery with minimal tissue injury and better outcome. Post-operative choanal dilatation using esophageal dilators under endoscopic examination decrease the need for stenting and second-look evaluation. PMID- 27240496 TI - Pediatric otitis media in Fiji: Survey findings 2015. AB - OBJECTIVE: Otitis media (OM), as a common infectious disease, is a major cause of hearing impairment among the general population. OM remains a major public health threat in the Pacific islands, but the risks of OM have not been thoroughly explored in this region. The objective of this study is to investigate the prevalence, clinical features, and quality-of-life impacts of OM in Fiji. METHODS: In the medical service trip entitled "Healing and Hope - Taiwan Cathay Heart and Hearing Medical Mission to Fiji" (TCHHMMF), we conducted a cross sectional OM survey study in Suva and Sigatoka areas (Korolevu, Cuvu, and Lomawai) in the summer of 2015. The otitis media - 6 (OM-6) was used to survey the OM-related quality of life. RESULTS: In the 467 pediatric patients (aged 0-18 years old) screened, 13 (2.78%) have acute otitis media (AOM), 37 (7.92%) have otitis media with effusion (OME), and 19 (4.1%) have chronic otitis media (COM). Age (OR 0.53, 95% CI: 0.36-0.77) is a significant predictor of AOM, whereas male gender (OR 2.46, 95% CI: 1.13-5.37), smoke exposure (OR 2.81, 95% CI: 1.01-7.82), and concomitant chronic sinusitis (OR 6.05, 95% CI: 2.31-15.88) are significant predictors of OME. The mean OM-6 item scores are highest in caregiver concerns (3.8), physical suffering (3.7), and hearing loss (3.4) domains. CONCLUSION: OM is an important primary care disease in Fiji that remains under-served. It is critical to educate professionals, parents, and patients to detect and to improve care for OM. PMID- 27240497 TI - Waardenburg syndrome type II in a Chinese patient caused by a novel nonsense mutation in the SOX10 gene. AB - OBJECTIVE: Waardenburg syndrome is a congenital genetic disorder. It is the most common type of syndromic hearing impairment with highly genetic heterogeneity and proved to be related by 6 genes as follows: PAX3, MITF, SNAI2, EDN3, EDNRB and SOX10. This article aims to identify the genetic causes of a Chinese WS child patient. METHODS: A Chinese WS child was collected for clinical data collection by questionnaire survey. DNA samples of proband and his parents were extracted from peripheral blood samples. Six candidate genes were sequenced by the Trusight One sequencing panel on the illumina NextSeq 500 platform. RESULTS: A novel nonsense heterozygous mutation was found in the coding region of exon 2 in the SOX10 gene of proband. The novel nonsense heterozygous mutation could cause the replacement of the 55th lysine codon by stop codon (484T > C, C142R) and further more possibly cause terminating the protein translation in advance. However, both proband's parents had no mutation of genes above mentioned. CONCLUSION: The gene mutation of SOX10 [NM_006941.3 c.163A > T] is a novel nonsense mutation. No record of this mutation has been found in dbSNP, HGMD, 1000 Genomes Project, ClinVar and ESP6500 databases. It meets the condition of PS2 of strong evidence in 2015 ACMG Standards and Guidelines. PMID- 27240498 TI - Examination using modern low dose Multislice-CT (MS-CT) in otorhinolaryngology in a six-week-old baby. AB - A 6-week-old girl suffered from a growing and recurrently bleeding mass of unrecognizable origin, obstructing the left nose. Using low-dose Multislice-CT the exact diagnostic localization could be found within one minute in the sleeping baby without sedation or general anesthesia. The result of this imaging enabled the successful complete microscopic removal of a hemangioma from the left inferior turbinate. Follow-up after 15 months showed normal nasal finds. PMID- 27240499 TI - Epidemiology of otitis media in children from developing countries: A systematic review. AB - OBJECTIVE: This systematic review examined the epidemiology of otitis media (OM) in children <6 years within 90 developing and newly industrialised countries. METHODS: Literature searches (1992-2011), based on MEDLINE, EMBASE, WHO, Index Medicus, country-specific websites, conferences, and the reference lists of included studies, yielded 11,413 records; 59 of 344 studies analysed were included in this review. RESULTS: The majority of the identified studies provided only a single timepoint for OM. In children <6 years of age, OM prevalence was found to be 9.2% in Nigeria, 10% in Egypt, 6.7% in China, 9.2% in India, 9.1% in Iran and 5.1-7.8% in Russia. Few studies examined the etiology of OM and the antibacterial resistance. The most common bacterial pathogens were S. pneumoniae, H. influenzae and S. aureus. A high resistance to penicillin was reported in Nigeria and Turkey. CONCLUSIONS: Despite the variability between the identified studies, this review indicates that OM and its various sub-types remain a significant burden in different settings. However, the heterogeneity of studies and a general lack of reliable data made generalisation very difficult. PMID- 27240500 TI - Identification of a novel mutation in SLC26A4 gene in a Chinese family with enlarged vestibular aqueduct syndrome. AB - OBJECTIVE: To investigate the genetic causes of hearing loss in a two generation Chinese family with enlarged vestibular aqueduct syndrome (EVAS). METHODS: Clinical and genetic evaluations were conducted in a deaf proband and her normal hearing parents. Sanger sequencing analysis of all the 21 exons, the exon-intron boundaries and the promoter in SLC26A4 gene was performed to detect the pathogenic mutations. PCR-restricted fragment length polymorphism (PCR-RFLP) was used to further identify the mutation. Phylogenetic analysis was carried out with multiple sequence alignment using BioEdit software. Three-dimensional (3D) modeling of the human wild-type and mutant SLC26A4 (NP_000432.1) was carried out using I-TASSER (http://zhanglab.ccmb.med.umich.edu/). RESULTS: Clinical examinations showed that the proband suffered from typical features of sensorineural hearing loss with enlarged vestibular aqueduct. A novel nonsense mutation c.2118C>A (p.C706X) in exon 19 was identified in compound heterozygosity with the splice-site mutation c.919-2A>G in the proband by using Sanger sequencing. The mother was a heterozygous carrier of c.919-2A>G in intron 7, while the father was a heterozygous carrier of c.2118C>A. The mutation c.2118C>A was not found in 200 unrelated controls using Sanger sequencing. PCR-RFLP showed the PCR product of the proband was not digested at 2110 by Fau I because of the c.2118C>A mutation. 3D-structure modeling indicated that the mutation c.2118C>A resulted in a truncate Pendrin protein. Protein alignment indicated high conservation of p.C706 residue in healthy Homo, Nomascus, Pan, Macaca, Canis, Sus, Mus, Rattus, Cricetulus and Xenopus. CONCLUSIONS: This study revealed a novel heterozygous mutation c.2118C>A (p.C706X) compound with c.919-2A>G in SLC26A4 gene in a patient with EVAS. PMID- 27240501 TI - Comparative antibacterial activity of topical antiseptic eardrops against methicillin-resistant Staphylococcus aureus and quinolone-resistant Pseudomonas aeruginosa. AB - OBJECTIVE: Aural irrigation using antiseptic solutions can be an effective medical treatment of chronic suppurative otitis media (CSOM) owing to the increasing prevalence of antibiotic-resistant CSOM infections. In the present study, we compared the antimicrobial activities of 100% Burow's solution, 50% Burow's solution, 2% acetic acid, vinegar with water (1:1), and 4% boric acid solution against methicillin-resistant Staphylococcus aureus (MRSA), methicillin susceptible S. aureus (MSSA), quinolone-resistant Pseudomonas aeruginosa (QRPA), and quinolone-susceptible P. aeruginosa (QSPA) in vitro. METHODS: We examined the antimicrobial activities of five antiseptic solutions against MRSA, MSSA, QRPA, and QSPA. The antimicrobial activities of the solutions were calculated as a percentage of the surviving microorganisms by dividing the viable count in each antiseptic solution with that in control. The time (D10 value) required for each of the five solutions to inactivate 90% of the microorganism population was also investigated. RESULTS: Burow's solution exhibited the highest antimicrobial activity and the lowest D10 value against MRSA, MSSA, QRPA, and QSPA, followed by 2% acetic acid, vinegar with water (1:1), and 4% boric acid solution. CONCLUSION: Our results indicate that Burow's solution has the most potent activity against bacteria including antibiotic-resistant strains. Twofold dilution of the solution is recommended to avoid ototoxicity. PMID- 27240502 TI - "Post intubation Laryngeal injuries in a pediatric intensive care unit of tertiary hospital in India: A Fibreoptic endoscopic study". AB - STUDY OBJECTIVES: To identify acute laryngeal injuries among pediatric patients intubated for more than 48hours, and to correlate these injuries with clinical variables. SETTING: Pediatric Intensive Care Unit (PICU) of a tertiary level hospital in India. PATIENTS AND METHODS: Prospective, observational study. Thirty four children meeting the inclusion and exclusion criteria were recruited into the study after obtaining informed consent from the parents. A bedside, flexible, fiberoptic laryngoscopy was done within the first 24hours of extubation. Laryngeal injuries were documented and graded. Individual types of laryngeal injuries were correlated to the duration of intubation, size of the tube, the experience of the intubator and the patient's demographics. A repeat endoscopy was done in the outpatient department, 3-4 weeks after extubation, and findings noted. RESULTS: 97% had acute laryngeal injury, of which 88% were significant. Erythema was the most common form of injury. Duration of intubation, with a mean of 4.5 days, showed a trend towards significance (p=0.06) for association with subglottic narrowing. Laryngeal injuries were similar with both cuffed and uncuffed tubes. Age of the subject, size of the tube and skill level of the intubator did not correlate with the laryngeal injuries. 18% required intervention for post-extubation laryngeal lesions. Three (10%) children had post extubation stridor, and of these, two needed surgical intervention (6%). CONCLUSION: Post-extubation laryngeal injuries are not uncommon. Fiberoptic endoscopy is an inexpensive and cost-effective tool for bedside evaluation of post-intubation status in pediatric larynx. Early diagnosis of post-intubation laryngeal injuries in children can prevent long term sequelae. Hence, post extubation fiberoptic laryngoscopy should be done routinely in pediatric population. PMID- 27240503 TI - Antibiotic resistance in pathogens causing acute otitis media in Finnish children. AB - INTRODUCTION: Microbiology and susceptibility of middle ear pathogens in children change over time and antibiotic resistance is increasing globally. For the clinicians it is important to be up to date about the resistance situation when considering antibiotic treatment in acute otitis media (AOM). In this study we analysed the resistance profile of AOM pathogens in out-patient children in Finland. METHODS AND MATERIALS: A total of 41 culture positive middle ear fluid (MEF) samples were analysed for bacteria and the presence of antibiotic resistant strains. The samples were obtained from children aged six - 39 months who participated in the otitis media trial during one year period. RESULTS: The most common pathogen was Haemophilus influenzae 17 (40%), followed by Streptococcus pneumoniae in 15 (35%) and Moraxella catarrhalis in 8 (19%). Other pathogens were detected in 3 (7%) of cases. Antibiotic resistance or diminished sensitivity was seen in 63% of the detected bacteria and 28% of pathogens produced beta lactamase. CONCLUSIONS: Antibiotic resistant bacterial strains causing AOM have increased in Finland. Nevertheless, most of the pathogens (72%) were sensitive to amoxicillin, which is still recommended as the first line antibiotic in the treatment of AOM. PMID- 27240504 TI - Prevention and management of hearing loss in syndromic craniosynostosis: A case series. AB - OBJECTIVE: To assess the audiological profile in a cohort of children affected by syndromic craniosynostosis. METHODS: Eleven children with Apert syndrome (n=4), Saethre-Chotzen syndrome (n=3), Muenke syndrome (n=2), Crouzon syndrome (n=1) and Pfeiffer syndrome type 1 (n=1) were submitted to a complete audiologic evaluation including otoscopy, pure-tone audiometry, tympanometry and acoustic reflex testing, ABR, otoacustic emissions, temporal bone High Resolution CT (HRCT) scan. The main outcome measures were prevalence, type and severity of hearing loss, prevalence of chronic otitis media, correlation with the time of first surgical correction. RESULTS: Seven of 11 patients (64%) presented hearing loss (HL), conductive in 3/7 patients (43%) and mixed in 4/7 (57%). No patients showed a purely sensorineural HL. All hearing impaired patients displayed middle ear disorders: the patients with conductive HL had otitis media with effusion (OME) and 3/4 patients with mixed HL showed tympanic alterations or cholesteatoma. A bilateral vestibular aqueduct enlargement was detected by HRCT scan in one normal hearing patient. The ABRs resulted normal in all cases. CONCLUSION: Our study confirms the high prevalence of otologic diseases in such patients. In contrast with previous studies, middle ear disorders were responsible for the hearing impairment also in patients with mixed HL due to secondary inner ear damage. These findings restate the necessity of a close audiologic follow-up. We did not detect the specific ABR abnormalities previously reported, possibly because of an early correction of the cranial vault malformations. PMID- 27240505 TI - Evaluating the diagnostic accuracy of Arabic SNAP test for children with hypernasality. AB - Nasometry is a method of measuring the acoustic correlates of resonance through a computer-based instrument called nasometer. High nasalance scores in comparison to normative data suggest hypernasality and/or other nasality disorders, while low scores suggest hyponasality. Normative values of nasalance for Egyptian Arabic speakers were established using the Arabic SNAP (Simplified Nasometric Assessment Procedures) test. OBJECTIVES: to evaluate the diagnostic accuracy of Arabic SNAP test to allow for its use in the differentiation between normal and hypernasal speech in Egyptian Arabic-speaking children. METHODS: Nasalance scores of normal children (n=92) on Arabic SNAP test were compared to those of 30 children with velopharyngeal insufficiency due to cleft palate. Receiver operating characteristic (ROC) curve was used to determine cutoff points with the highest sensitivity and specificity. RESULTS: Statistically significant differences were found between both groups for all items in nasometric evaluation (p<0.05) except for prolonged/m/sound (p>0.05). Cutoff points were determined and certain items were selected for routine nasometric evaluation. CONCLUSION: The Arabic SNAP test is a sensitive and specific tool for evaluation of children with hypernasality and can be used for both diagnosis and follow up of these cases. PMID- 27240506 TI - Results of ossicular chain reconstruction with glass ionomer cement in pediatric patients. AB - OBJECTIVE: The aim of our study was to analyze the hearing results of ossicular chain reconstruction in incus long process defects in pediatric patients. METHODS: This retrospective study included 15 pediatric patients that had incus long process defect due to chronic otitis media or adhesive otitis, and repaired with glass ionomer cement between 2009 and 2015. The audiological tests (air conduction thresholds, bone conduction thresholds, air bone gap) obtained preoperatively and one year after surgery were compared. In addition, preoperative and postoperative air bone gap differences were estimated to determine hearing gain. RESULTS: Mean air conduction and air bone gaps decreased significantly one year after surgery when compared to the preoperative values (p< 0.001 for both). Mean hearing gain was 20.33+/-6.36dB one year after surgery. CONCLUSION: Use of glass ionomer cement to repair incus long process defects is a suitable method that improves hearing in pediatric patients. Further large studies that compare glass ionomer cement ossiculoplasty with other ossicular reconstruction methods are needed. PMID- 27240507 TI - Developmental delay in young children with sleep-disordered breathing before and after tonsil and adenoid surgery. AB - OBJECTIVE: Our objective was to determine the developmental status of young children with sleep-disordered breathing (SDB) as measured by the Ages and Stages Questionnaire (ASQ-3) and to evaluate improvement after treatment. METHODS: The ASQ-3 was completed at entry, 3 months and 6 months after adenotonsillectomy or adenoidectomy. The questionnaire consists of 30 items that assess five domains: communication, gross motor, fine motor, problem solving and personal-social. Domain scores were compared with normative values: abnormal >=2 SDs and borderline >=1 but <2 SDs below the mean. RESULTS: 80 children, mean (SD) age 3.0 (0.94) years, 62.5% male, 77.5% African American, were enrolled. Median (range) apnea-hypopnea index (AHI) was 12.6 (1.4-178.5). At entry, 22 (27.5%) children scored in the abnormal range in at least one developmental area and an additional 23 (28.8%) had at least one borderline score. A generalized linear model including gender, AHI, maternal education and prematurity showed that only prematurity was an independent predictor of at least one abnormal or borderline entry score (likelihood ratio test p < 0.001). Adjusting for covariates and excluding children with a history of prematurity, the prevalence of at least one abnormal or borderline score (based on 112 observations of 70 children) was estimated at 49% (95% CI [37, 62]) at baseline; 34% (95% CI [17, 56]) at 3 months; and 22% (95% CI [10, 41]) at 6 months. Post-hoc pairwise comparison of time points showed the baseline versus 6-month difference to be statistically significant (p = 0.015). CONCLUSIONS: The 27.5% baseline prevalence of abnormal ASQ scores in children with SDB indicates it is a risk factor for developmental delay. Significant improvements in score classifications were found 6 months after surgery. PMID- 27240508 TI - Coblation-assisted closure of persistent tracheocutaneous fistulae. AB - Persistent tracheocutaneous fistulae (PTCFs) are sequelae of long-term tracheostomy tube use, and while many procedures exist to correct this issue, several are invasive and incur risk to the patient. This case study discusses a minimally invasive approach to closure of small PFTFs with a coblator device that may reduce the risks associated with other closure procedures. We demonstrated successful tracheocutaneous fistulae closure after coblation in all 4 patients that the operation was performed. We believe this technique can be considered for patients under select circumstances and can be part of a surgeon's armamentarium for the treatment of small PTCFs. PMID- 27240509 TI - KTP laser assisted endoscopic tissue fibrin glue biocauterization for congenital pyriform sinus fistula in children. AB - OBJECTIVE: This study aims to assess the efficacy of a novel endoscopic management for congenital pyriform sinus fistula (CPSF) using potassium titanyl phosphate (KTP) laser assisted endoscopic tissue fibrin glue biocauterization in children. METHOD: From 2010 to 2014, a total of 5 children with recurrent or acute suppurative thyroiditis or neck abscess secondary to CPSF were enrolled retrospectively in this study. RESULTS: Mean age at the first time of endoscopic biocauterization was 6.2 +/- 0.7 (5-7) years. The barium swallow study detected a fistula in four cases. Endoscopy identified an internal opening at the pyriform sinus in all cases with four on the left side and one on the right side. All patients underwent KTP laser assisted endoscopic tissue fibrin glue biocauterization as treatment for CPSF. Only one case required the second endoscopic procedure due to fluctuation of symptoms. Post-endoscopic follow-up duration of these patients was 24.6 +/- 11.6 (7-36) months. Neither complications nor recurrences were noted during follow-up in all patients. CONCLUSIONS: For children presenting with repeated acute suppurative thyroiditis or neck infections, clinicians should highly suspect the possibility of CPSF. Endoscopy should be performed not only to confirm the diagnosis but also could be served as an initial treatment modality of biocauterization by KTP laser and tissue fibrin glue, which was demonstrated as a less invasive, safe, and effective method in children. PMID- 27240510 TI - Threshold changes of ABR results in toddlers and children. AB - INTRODUCTION: Auditory brainstem response (ABR) is a clinically established method to identify the hearing threshold in young children and is regularly performed after hearing screening has failed. Some studies have shown that, after the first diagnosis of hearing impairment in ABR, further development takes place in a spectrum between progression of hearing loss and, surprisingly, hearing improvement. OBJECTIVE: The aim of this study is to evaluate changes over time of auditory thresholds measured by ABR among young children. MATERIAL AND METHODS: For this retrospective study, 459 auditory brainstem measurements were performed and analyzed between 2010 and 2014. Hearing loss was detected and assessed according to national guidelines. 104 right ears and 101 left ears of 116 children aged between 0 and 3 years with multiple ABR measurements were included. The auditory threshold was identified using click and/or NB-chirp-stimuli in natural sleep or in general anesthesia. The frequency of differences of at least more than 10dB between the measurements was identified. RESULTS: In 37 (35%) measurements of right ears and 38 (38%) of left ears there was an improvement of the auditory threshold of more than 10dB; in 27 of those measurements more than 20dB improvement was found. Deterioration was seen in 12% of the right ears and 10% of the left ears. Only half of the children had stable hearing thresholds in repeated measurements. The time between the measurements was on average 5 months (0 to 31 months). CONCLUSION: Hearing threshold changes are often seen in repeated ABR measurements. Therefore multiple measurements are necessary when ABR yields abnormal. Hearing threshold changes should be taken into account for hearing aid provision. PMID- 27240511 TI - Feeding and reflux in children after mandibular distraction osteogenesis for micrognathia: A systematic review. AB - Mandibular distraction osteogenesis (MDO) is becoming increasingly more commonly used as in neonates and infants with upper airway obstruction secondary to micrognathia. A significant number of these children are dependent on nasoenteric feeding or gastrostomies after birth for adequate nutrition and often suffer from gastro-esophageal reflux (GERD). OBJECTIVE: This analysis is a subset of a larger systematic review. The objective of this study is to determine the effects of MDO on feeding and GERD. DATA SOURCES: The databases searched included PubMed, Embase, Scopus, Web of Knowledge and grey literature sources. STUDY SELECTION: The inclusion criterion included studies in children with clinical evidence of micrognathia/Pierre Robin Sequence (PRS) who have failed conservative treatments, including both syndromic (sMicro) and non-syndromic (iPRS) patients. 21 studies relevant to feeding and 4 studies relevant to GERD outcomes were included. All studies included were case series and case reports. RESULTS: MDO leads to a significant improvement in feeding, with 82% of children feeding exclusively orally after surgery. The overall percentage of children with iPRS who were feeding orally was 93.7% compared with only 72.9% in the sMicro group (p<0.004). A growth decline within the first six weeks after surgery was observed in multiple studies. Overall, out of 70 patients with pre-operative GERD, only four had evidence of GERD after surgery. CONCLUSIONS: Considering the limitations of this systematic review, this study found that successful relief of airway obstruction by MDO leads to improvement of feeding and improvement in symptoms of GERD in children with upper airway obstruction secondary to micrognathia. Clinicians need to be aware of the risk of growth decline in the initial post operative period. PMID- 27240513 TI - The assessment of the impact of anorexia nervosa on the vocal apparatus in adolescent girls - A preliminary report. AB - BACKGROUND: Chronic undernourishment in the course of anorexia nervosa leads to various metabolic and hormonal changes, which translates to the impaired functioning of the majority of systems and internal organs. The impact of eating disorders on the condition of the vocal apparatus has been described in the literature; nevertheless, it concerns mainly bulimia nervosa. OBJECTIVES: assessment of the vocal apparatus in adolescent girls diagnosed with anorexia nervosa from the point of view of possible influence on the function and structure of the larynx, low body mass accompanying anorexia, as well as energy deficiency, hormonal and emotional disturbances. MATERIALS AND METHODS: The research included 41 girls aged 12-19 years, diagnosed with anorexia, who were assessed for the condition of the vocal apparatus, using the perceptual assessment of voice according to GRBAS scale, videolarynostroboscopy, acoustic assessment, and voice self-assessment in Jacobson's VHI scale (voice handicap index). RESULTS: The perceptual assessment of voice using the GRBAS scale revealed that changes in voice were mainly weak, asthenic in nature (70.73%) and there was also the feature of puffing perceived in voice (41.46%). In voice self assessment with the use of VHI, most subjects seemed to point to changes of voice self-perception in emotional subscale (68%). Videolaryngostroboscopy revealed some features of functional disturbances of voice in more than half of subjects, mainly in the form of hyperfunctional dysphonia (31.78%). The maximal phonation time was significantly shorter, in proportion to duration of the primary disease. In the acoustic analysis, the decrease in the basic frequency F0 and narrowing of the voice scale were observed. 55% of older, post-adolescent patients presented with the structure of the larynx that was inappropriate for their age. CONCLUSIONS: These results might indicate that anorexia nervosa could have led to the structural and functional changes in the vocal apparatus. Such disturbances may be explained by the hormonal dysfunctions as well as starvation. Hormonal substitution at the appropriate time might be beneficial for the structure and phonation function of the larynx in girls with AN. PMID- 27240512 TI - Information on co-morbidities collected by history is useful for assigning Otitis Media risk to children. AB - OBJECTIVES: Determine if a 2-Step multivariate analysis of historical symptom/sign data for comorbid diseases can abstract high-level constructs useful in assigning a child's "risk" for different Otitis Media expressions. METHODS: Seventeen items related to the symptom/sign expression of hypothesized Otitis Media comorbidities were collected by history on 141 3-year-old children. Using established criteria, the children were assigned to 1 of 3 groups: Control (no significant past Otitis Media, n=45), Chronic Otitis Media with Effusion (n=45) and Recurrent Acute Otitis Media (n=51). Principal Component Analysis was used to identify factors representing the non-redundant shared information among related items and Discriminant Analysis operating on those factors was used to estimate the best predictor equation for pairwise group assignments. RESULTS: Six multivariate factors representing the assignable comorbidities of frequent colds, nasal allergy, gastroesophageal disease (specific and general), nasal congestion and asthma were identified and explained 81% of the variance in the 17 items. Discriminant Analysis showed that, for the Control-Chronic Otitis Media with Effusion comparison, a combination of 3 factors and, for the Control-Recurrent Acute Otitis Media comparison, a combination of 2 factors had assignment accuracies of 74% and 68%, respectively. For the contrast between the two disease expressions, a 2-factor combination had an assignment accuracy of 61%. CONCLUSION: These results show that this analytic methodology can abstract high level constructs, comorbidities, from low-level data, symptom/sign scores, support a linkage between certain comorbidities and Otitis Media risk and suggest that specific comorbidity combinations contain information relevant to assigning the risk for different Otitis Media expressions. PMID- 27240514 TI - Review of pediatric head and neck pilomatrixoma. AB - INTRODUCTION: Pilomatrixoma is a benign skin tumor, which is commonly found in the head and neck region. It usually presents as an isolated lesion and rarely undergoes malignant transformation. It is not uncommon for these tumors to be misdiagnosed. OBJECTIVE: To review the clinical characteristics of head and neck pilomatrixomas in the pediatric population. METHODS: A systematic review was completed by searching ten databases to identify studies reporting findings on pilomatrixoma in the pediatric population. Eligible articles were independently assessed for quality by two authors. RESULTS: A total of 17 studies met the inclusion criteria totaling 318 pediatric patients. The age of diagnosis ranged from 3 months to 17 years of age. The female to male ratio was 1.65:1. In 14 articles, in which pilomatrixoma was located in the head and neck region, 76 (25%) lesions were found in the neck while 229 (75%) were present in the head region. Three articles exclusively described ophthalmologic pilomatrixoma. Even though pilomatrixoma presents with classical features, the clinical diagnostic accuracy when confronting this lesion averaged 43%. The definitive treatment was surgical excision with a very low recurrence rate. CONCLUSION: Head and neck pilomatrixoma in the pediatric population has a typical presentation with a low clinical diagnostic accuracy. Awareness of this lesion and its clinical appearance can improve its diagnosis. We hereby suggest a management algorithm for suspected pilomatrixoma. PMID- 27240515 TI - Use of the flexible fiber CO2 laser in pediatric transcanal endoscopic middle ear surgery. AB - We describe 4 pediatric patients (age 6-11 years) who underwent transcanal endoscopic ear surgery (TEES) with the assistance of a flexible fiber CO2 laser over a period of 6 months. Three of these individuals suffered from densely adherent cholesteatoma, where the laser permitted one-handed dissection while preserving endoscopic visualization by limiting bleeding. In the fourth patient, TEES ossiculoplasty was performed for a congenital stapes bar, with subsequent hearing improvement. Advantages and disadvantages of the flexible fiber CO2 laser in the setting of TEES are discussed. Use of the flexible fiber CO2 laser was found to expand the TEES toolkit. PMID- 27240516 TI - An exploratory study of visual sequential processing in children with cochlear implants. AB - OBJECTIVE: The objective of the study was to compare visual sequential processing in school-age children with cochlear implants (CIs) and their normal-hearing (NH) peers. Visual sequential processing was examined using both behavioral and an event-related potential (ERP) measures. METHODS: Eighteen children with CIs and nineteen children who had hearing within normal limits (NH) participated in the behavioral study. Subtests from the Test of Visual Perceptual Skills and the Sensory Integration and Praxis Test were administered to all children. ERP measures were collected from five children with CI and five age-matched peers. Peak latencies (N200 and P300) and reaction times for visual sequential processing were compared in these two groups. RESULTS: The findings of the study revealed significant group differences in visual sequential memory and visuo motor sequencing tasks suggesting that children with severe-profound hearing loss may have difficulties in visual sequential tasks. The study also revealed longer P300 latencies and longer reaction times for a visual sequential matching task in children with CI when compared to their NH peers suggesting slower or delayed processing of visual sequential stimuli. CONCLUSIONS: This exploratory study involving behavioral and ERP measures showed that as a group, children with prelingual, severe-profound hearing loss who use CIs have difficulties with visual sequential processing. These findings may have implications for rehabilitation for children with hearing loss in the light of recent evidence that accurate and efficient processing of sequentially presented visual stimuli is important for language and reading outcomes. PMID- 27240517 TI - Pediatric laryngotracheal separation following a go-cart injury. AB - Less than one percent of trauma admission cases are categorized as pediatric neck trauma [13]. Nevertheless, due to an increasingly mobile society, there has been an increasing frequency of pediatric neck trauma with motor vehicle accidents being the most common mechanism of injury [8]. We present a case of laryngotracheal separation from a blunt, clothesline injury to the neck in a pediatric patient. We also review the literature and discuss the benefit of balloon airway dilation and its assistance in the management of laryngeal trauma and its resultant effects. PMID- 27240518 TI - The relationship between cortical auditory evoked potentials (CAEPs) and speech perception in children with Nurotron((r)) cochlear implants during four years of follow-up. AB - OBJECTIVE: The purpose of the current study was to evaluate the relationship between the presence or absence of cortical auditory evoked potentials (CAEPs) to speech stimuli and the performance of speech perception in Chinese pediatric recipients of the Nurotron((r)) cochlear implant (CI).We also wanted to determine how the CAEPs might be used as an indicator for predicting early speech perception and could provide objective evidence for clinical applications of CAEPs. METHODS: 23 pediatric unilateral CI recipients participated in this study. 15 males 8 females, and their ages at implantation ranged from 13 to 68 months, with a mean age of 36 months. CAEPs and Mandarin Early Speech Perception (MESP) tests were used to evaluate the audibility and speech perception of these CI users. The tests were administered at the first, second, third, and fourth year after the CI surgery. RESULTS: All the subjects demonstrated improvements in detection of speech sounds with CI. The percentages of participants who could detect all three stimuli were 26% (6/23) at first year, to 100% (23/23) at the fourth year post-implantation. The percentages of participants who passed the Category 6 of MESP were from 9% (2/23) at first year, to 91% (21/23) at the fourth year post-implantation. Significant correlations (p<0.05) were found between CAEP scores and MESP at the first, second, third year after the CI surgery. The multiple regression equation for prediction of MESP categories from CAEP scores and hearing ages was MESP=1.088+(0.504*CAEP score)+(0.964*hearing ages) (F=72.919, p<0.001, R(2)=0.621). CONCLUSION: The results of this study suggested that aided cortical assessment was a useful tool to evaluate the outcomes of cochlear implantation. Cortical outcomes had a significant positive relationship with the MESP, which predicted the early speech perception of CI recipients. PMID- 27240519 TI - Catecholaminergic neurons in synaptic connections with pre-Botzinger complex neurons in the rostral ventrolateral medulla in normoxic and daily acute intermittent hypoxic rats. AB - The rostral ventrolateral medulla (RVLM) contains cardiovascular-related catecholaminergic neurons and respiratory-related pre-Botzinger complex (pre BotC) neurons, which are intermingled and functionally connected for coordinating cardiorespiratory activities. Daily acute intermittent hypoxia (dAIH) is known to elicit respiratory plasticity. However, it is unclear if the catecholaminergic neurons directly synapse onto pre-BotC neurons, and if the local circuitry exhibits plasticity when exposed to dAIH. The present study was aimed to determine the synaptic phenotypes between dopamine-beta-hydroxylase (DbetaH) immunoreactive (ir) catecholaminergic neurons and neurokinin 1 receptor (NK1R)-ir pre-BotC neurons, and the effect of dAIH on the neuronal network. Immunofluorescence histochemistry was used to reveal immunoreactivities of DbetaH and NK1R in the RVLM of normoxic and dAIH rats. Synaptic phenotypes were examined with double-labeling immunoelectron microscopy. We found that DbetaH immunoreactivity was expressed in somata and processes, some of which were in close apposition to NK1R-ir pre-BotC neurons. DbetaH-ir gold particles were localized to somata, dendrites, and axonal terminals. DbetaH-ir terminals formed asymmetric synapses, and occasionally, symmetric synapses in the pre-BotC, featuring the local circuitry. Of the synapses, 28% in normoxic and 29.6% in dAIH groups were apposed to NK1R-ir dendrites. Significant increases in DbetaH expression and NK1R-ir processes were found in the dAIH group. Moreover, the area and number of processes in close appositions were significantly elevated, strongly suggesting that dAIH induced plasticity with increased connections and interactions between the cardiovascular- and respiratory-related neurons in the local circuitry. In conclusion, asymmetric synapses are predominant in the crosstalk between catecholaminergic and pre-BotC neurons in the RVLM, elaborating excitatory transmission driving the coupling of cardiorespiratory activities. The neural network manifests plasticity in response to dAIH challenge. PMID- 27240521 TI - Lack of CAR impacts neuronal function and cerebrovascular integrity in vivo. AB - Nuclear receptors (NRs) are a group of transcription factors emerging as players in normal and pathological CNS development. Clinically, an association between the constitutive androstane NR (CAR) and cognitive impairment was proposed, however never experimentally investigated. We wished to test the hypothesis that the impact of CAR on neurophysiology and behavior is underlined by cerebrovascular-neuronal modifications. We have used CAR(-/-) C57BL/6 and wild type mice and performed a battery of behavioral tests (recognition, memory, motor coordination, learning and anxiety) as well as longitudinal video electroencephalographic recordings (EEG). Brain cell morphology was assessed using 2-photon or electron microscopy and fluorescent immunohistochemistry. We observed recognition memory impairment and increased anxiety-like behavior in CAR(-/-) mice, while locomotor activity was not affected. Concomitantly to memory deficits, EEG monitoring revealed a decrease in 3.5-7Hz waves during the awake/exploration and sleep periods. Behavioral and EEG abnormalities in CAR(-/-) mice mirrored structural changes, including tortuous fronto-parietal penetrating vessels. At the cellular level we found reduced ZO-1, but not CLDN5, tight junction protein expression in cortical and hippocampal isolated microvessel preparations. Interestingly, the neurotoxin kainic acid, when injected peripherally, provoked a rapid onset of generalized convulsions in CAR(-/-) as compared to WT mice, supporting the hypothesis of vascular permeability. The morphological phenotype of CAR(-/-) mice also included some modifications of GFAP/IBA1 glial cells in the parenchymal or adjacent to collagen-IV(+) or FITC(+) microvessels. Neuronal defects were also observed including increased cortical NEUN(+) cell density, hippocampal granule cell dispersion and increased NPY immunoreactivity in the CA1 region in CAR(-/-) mice. The latter may contribute to the in vivo phenotype. Our results indicate that behavioral and electroencephalographic changes in adult CAR(-/-) mice are concomitant to discrete developmental or structural brain defects. The latter could increase the vulnerability to neurotoxins. The possibility that interfering with nuclear receptors during development could contribute to adulthood brain changes is proposed. PMID- 27240520 TI - Chemoreception and neuroplasticity in respiratory circuits. AB - The respiratory central pattern generator must respond to chemosensory cues to maintain oxygen (O2) and carbon dioxide (CO2) homeostasis in the blood and tissues. To do this, sensorial cells located in the periphery and central nervous system monitor the arterial partial pressure of O2 and CO2 and initiate respiratory and autonomic reflex adjustments in conditions of hypoxia and hypercapnia. In conditions of chronic intermittent hypoxia (CIH), repeated peripheral chemoreceptor input mediated by the nucleus of the solitary tract induces plastic changes in respiratory circuits that alter baseline respiratory and sympathetic motor outputs and result in chemoreflex sensitization, active expiration, and arterial hypertension. Herein, we explored the hypothesis that the CIH-induced neuroplasticity primarily consists of increased excitability of pre-inspiratory/inspiratory neurons in the pre-Botzinger complex. To evaluate this hypothesis and elucidate neural mechanisms for the emergence of active expiration and sympathetic overactivity in CIH-treated animals, we extended a previously developed computational model of the brainstem respiratory-sympathetic network to reproduce experimental data on peripheral and central chemoreflexes post-CIH. The model incorporated neuronal connections between the 2nd-order NTS neurons and peripheral chemoreceptors afferents, the respiratory pattern generator, and sympathetic neurons in the rostral ventrolateral medulla in order to capture key features of sympathetic and respiratory responses to peripheral chemoreflex stimulation. Our model identifies the potential neuronal groups recruited during peripheral chemoreflex stimulation that may be required for the development of inspiratory, expiratory and sympathetic reflex responses. Moreover, our model predicts that pre-inspiratory neurons in the pre-Botzinger complex experience plasticity of channel expression due to excessive excitation during peripheral chemoreflex. Simulations also show that, due to positive interactions between pre-inspiratory neurons in the pre-Botzinger complex and expiratory neurons in the retrotrapezoid nucleus, increased excitability of the former may lead to the emergence of the active expiratory pattern at normal CO2 levels found after CIH exposure. We conclude that neuronal type specific neuroplasticity in the pre-Botzinger complex induced by repetitive episodes of peripheral chemoreceptor activation by hypoxia may contribute to the development of sympathetic over-activity and hypertension. PMID- 27240522 TI - Blocking GluN2B subunits reverses the enhanced seizure susceptibility after prolonged febrile seizures with a wide therapeutic time-window. AB - Febrile seizures (FSs), the most common type of convulsive events in infants, are closely associated with temporal lobe epilepsy (TLE) in adulthood. It is urgent to investigate how FSs promote epileptogenesis and find the potential therapeutic targets. In the present study, we showed that the phosphorylation of GluN2B Tyr1472 gradually reached peak level at 24h after prolonged FSs and remained elevated during 7days thereafter. IL-1beta treatment alone, which in previous study mimicked the effect of prolonged FSs on adult seizure susceptibility, increased GluN2B Tyr1472 phosphorylation. Both IL-1 receptor antagonist (IL-1Ra) and IL-1R1 deletion were sufficient to reverse the prolonged FSs induced hyper phosphorylation of GluN2B Tyr1472. GluN2B antagonist ifenprodil showed a wide therapeutic time-window (3days) to reverse the enhanced seizure susceptibility after prolonged FSs or IL-1beta treatment. Our study demonstrated that GluN2B phosphorylation at Tyr1472 site mediated by the transient increase of IL-1beta was involved in the enhanced adult seizure susceptibility after prolonged FSs, implicating GluN2B-containing NMDAR is a new potential drug target with a wide therapeutic time window to prevent epileptogenesis in patients with infantile FSs. PMID- 27240523 TI - Exogenous NAD(+) decreases oxidative stress and protects H2O2-treated RPE cells against necrotic death through the up-regulation of autophagy. AB - Increased oxidative stress, which can lead to the retinal pigment epithelium (RPE) cell death by inducing ATP depletion and DNA repair, is believed to be a prominent pathology in age-related macular degeneration (AMD). In the present study, we showed that and 0.1 mM nicotinamide adenine dinucleotide (NAD(+)) administration significantly blocked RPE cell death induced by 300 MUM H2O2. Further investigation showed that H2O2 resulted in increased intracellular ROS level, activation of PARP-1 and subsequently necrotic death of RPE cells. Exogenous NAD(+) administration significantly decreased intracellular and intranuclear ROS levels in H2O2-treated RPE cells. In addition, NAD(+) administration to H2O2-treated RPE cells inhibited the activation of PARP-1 and protected the RPE cells against necrotic death. Moreover, exogenous NAD(+) administration up-regulated autophagy in the H2O2-treated RPE cells. Inhibition of autophagy by LY294002 blocked the decrease of intracellular and intranuclear ROS level. Besides, inhibition of autophagy by LY294002 abolished the protection of exogenous NAD(+) against H2O2-induced cell necrotic death. Taken together, our findings indicate that that exogenous NAD(+) administration suppresses H2O2 induced oxidative stress and protects RPE cells against PARP-1 mediated necrotic death through the up-regulation of autophagy. The results suggest that exogenous NAD(+) administration might be potential value for the treatment of AMD. PMID- 27240525 TI - Functionalization of mesoporous materials for lanthanide and actinide extraction. AB - Among the energy sources currently available that could address our insatiable appetite for energy and minimize our CO2 emission, solar, wind, and nuclear energy currently occupy an increasing portion of our energy portfolio. The energy associated with these sources can however only be harnessed after mineral resources containing valuable constituents such as actinides (Ac) and rare earth elements (REEs) are extracted, purified and transformed into components necessary for the conversion of energy into electricity. Unfortunately, the environmental impacts resulting from their manufacture including the generation of undesirable and, sometimes, radioactive wastes and the non-renewable nature of the mineral resources, to name a few, have emerged as challenges that should be addressed by the scientific community. In this perspective, the recent development of functionalized solid materials dedicated to selective elemental separation/pre concentration could provide answers to several of the above-mentioned challenges. This review focuses on recent advances in the field of mesoporous solid-phase (SP) sorbents designed for REEs and Ac liquid-solid extraction. Particular attention will be devoted to silica and carbon sorbents functionalized with commonly known ligands, such as phosphorus or amide-containing functionalities. The extraction performances of these new systems are discussed in terms of sorption capacity and selectivity. In order to support potential industrial applications of the silica and carbon-based sorbents, their main drawbacks and advantages are highlighted and discussed. PMID- 27240524 TI - Angiogenesis-related biomarkers (sFlt-1/PlGF) in placental mesenchymal dysplasia. AB - Determination of the soluble fms-like tyrosine kinase-1 to placental growth factor ratio (sFlt-1/PlGF) in the maternal serum is expected to aid in the monitoring and decision-making process of women at risk for placental dysfunction. We report two cases of placental mesenchymal dysplasia (PMD) with sFlt-1/PlGF correlation. The first case is a dichorionic twin pregnancy with one fetus affected by PMD and Beckwith-Wiedemann syndrome in which a high value of sFlt-1/PlGF was found, coinciding with acute maternal and fetal wellbeing decline at 31 weeks. The second case corresponds to a singleton pregnancy diagnosed of PMD with normal sFlt-1/PlGF and favorable outcome. PMID- 27240526 TI - Narrow QRS Tachycardia with Transition: What Is the Mechanism? AB - A 50-year-old woman underwent radiofrequency catheter ablation of narrow QRS tachycardia that was terminated with intravenous adenosine. Twelve-lead electrocardiogram was normal during sinus rhythm. The electrophysiological study showed normal atriohisian and hisioventricular intervals during sinus rhythm. Atrial burst pacing reproducibly induced two narrow QRS tachycardias. Figure 1 shows spontaneous switch of tachycardia 1 to tachycardia 2. What are the likely mechanisms of the tachycardia and the transition? PMID- 27240527 TI - Effects of ANK3 variation on gray and white matter in bipolar disorder. AB - The single-nucleotide polymorphism rs9804190 in the Ankyrin G (ANK3) gene has been reported in genome-wide association studies to be associated with bipolar disorder (BD). However, the neural system effects of rs9804190 in BD are not known. We investigated associations between rs9804190 and gray and white matter (GM and WM, respectively) structure within a frontotemporal neural system implicated in BD. A total of 187 adolescent and adult European Americans were studied: a group homozygous for the C allele (52 individuals with BD and 56 controls) and a T-carrier group, carrying the high-risk T allele (38 BD and 41 controls). Subjects participated in high-resolution structural magnetic resonance imaging and diffusion tensor imaging (DTI) scanning. Frontotemporal region of interest (ROI) and whole-brain exploratory analyses were conducted. DTI ROI-based analysis revealed a significant diagnosis by genotype interaction within the uncinate fasciculus (P?0.05), with BD subjects carrying the T (risk) allele showing decreased fractional anisotropy compared with other subgroups, independent of age. Genotype effects were not observed in frontotemporal GM volume. These findings support effects of rs9804190 on frontotemporal WM in adolescents and adults with BD and suggest a mechanism contributing to WM pathology in BD. PMID- 27240528 TI - Disrupted habenula function in major depression. AB - The habenula is a small, evolutionarily conserved brain structure that plays a central role in aversive processing and is hypothesised to be hyperactive in depression, contributing to the generation of symptoms such as anhedonia. However, habenula responses during aversive processing have yet to be reported in individuals with major depressive disorder (MDD). Unmedicated and currently depressed MDD patients (N=25, aged 18-52 years) and healthy volunteers (N=25, aged 19-52 years) completed a passive (Pavlovian) conditioning task with appetitive (monetary gain) and aversive (monetary loss and electric shock) outcomes during high-resolution functional magnetic resonance imaging; data were analysed using computational modelling. Arterial spin labelling was used to index resting-state perfusion and high-resolution anatomical images were used to assess habenula volume. In healthy volunteers, habenula activation increased as conditioned stimuli (CSs) became more strongly associated with electric shocks. This pattern was significantly different in MDD subjects, for whom habenula activation decreased significantly with increasing association between CSs and electric shocks. Individual differences in habenula volume were negatively associated with symptoms of anhedonia across both groups. MDD subjects exhibited abnormal negative task-related (phasic) habenula responses during primary aversive conditioning. The direction of this effect is opposite to that predicted by contemporary theoretical accounts of depression based on findings in animal models. We speculate that the negative habenula responses we observed may result in the loss of the capacity to actively avoid negative cues in MDD, which could lead to excessive negative focus. PMID- 27240529 TI - Modeling psychiatric disorders: from genomic findings to cellular phenotypes. AB - Major programs in psychiatric genetics have identified >150 risk loci for psychiatric disorders. These loci converge on a small number of functional pathways, which span conventional diagnostic criteria, suggesting a partly common biology underlying schizophrenia, autism and other psychiatric disorders. Nevertheless, the cellular phenotypes that capture the fundamental features of psychiatric disorders have not yet been determined. Recent advances in genetics and stem cell biology offer new prospects for cell-based modeling of psychiatric disorders. The advent of cell reprogramming and induced pluripotent stem cells (iPSC) provides an opportunity to translate genetic findings into patient specific in vitro models. iPSC technology is less than a decade old but holds great promise for bridging the gaps between patients, genetics and biology. Despite many obvious advantages, iPSC studies still present multiple challenges. In this expert review, we critically review the challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes. PMID- 27240530 TI - Forebrain glutamatergic, but not GABAergic, neurons mediate anxiogenic effects of the glucocorticoid receptor. AB - Anxiety disorders constitute a major disease and social burden worldwide; however, many questions concerning the underlying molecular mechanisms still remain open. Besides the involvement of the major excitatory (glutamate) and inhibitory (gamma aminobutyric acid (GABA)) neurotransmitter circuits in anxiety disorders, the stress system has been directly implicated in the pathophysiology of these complex mental illnesses. The glucocorticoid receptor (GR) is the major receptor for the stress hormone cortisol (corticosterone in rodents) and is widely expressed in excitatory and inhibitory neurons, as well as in glial cells. However, currently it is unknown which of these cell populations mediate GR actions that eventually regulate fear- and anxiety-related behaviors. In order to address this question, we generated mice lacking the receptor specifically in forebrain glutamatergic or GABAergic neurons by breeding GRflox/flox mice to Nex Cre or Dlx5/6-Cre mice, respectively. GR deletion specifically in glutamatergic, but not in GABAergic, neurons induced hypothalamic-pituitary-adrenal axis hyperactivity and reduced fear- and anxiety-related behavior. This was paralleled by reduced GR-dependent electrophysiological responses in the basolateral amygdala (BLA). Importantly, viral-mediated GR deletion additionally showed that fear expression, but not anxiety, is regulated by GRs in glutamatergic neurons of the BLA. This suggests that pathological anxiety likely results from altered GR signaling in glutamatergic circuits of several forebrain regions, while modulation of fear-related behavior can largely be ascribed to GR signaling in glutamatergic neurons of the BLA. Collectively, our results reveal a major contribution of GRs in the brain's key excitatory, but not inhibitory, neurotransmitter system in the regulation of fear and anxiety behaviors, which is crucial to our understanding of the molecular mechanisms underlying anxiety disorders. PMID- 27240532 TI - High-resolution copy number variation analysis of schizophrenia in Japan. AB - Recent schizophrenia (SCZ) studies have reported an increased burden of de novo copy number variants (CNVs) and identified specific high-risk CNVs, although with variable phenotype expressivity. However, the pathogenesis of SCZ has not been fully elucidated. Using array comparative genomic hybridization, we performed a high-resolution genome-wide CNV analysis on a mainly (92%) Japanese population (1699 SCZ cases and 824 controls) and identified 7066 rare CNVs, 70.0% of which were small (<100 kb). Clinically significant CNVs were significantly more frequent in cases than in controls (odds ratio=3.04, P=9.3 * 10-9, 9.0% of cases). We confirmed a significant association of X-chromosome aneuploidies with SCZ and identified 11 de novo CNVs (e.g., MBD5 deletion) in cases. In patients with clinically significant CNVs, 41.7% had a history of congenital/developmental phenotypes, and the rate of treatment resistance was significantly higher (odds ratio=2.79, P=0.0036). We found more severe clinical manifestations in patients with two clinically significant CNVs. Gene set analysis replicated previous findings (e.g., synapse, calcium signaling) and identified novel biological pathways including oxidative stress response, genomic integrity, kinase and small GTPase signaling. Furthermore, involvement of multiple SCZ candidate genes and biological pathways in the pathogenesis of SCZ was suggested in established SCZ associated CNV loci. Our study shows the high genetic heterogeneity of SCZ and its clinical features and raises the possibility that genomic instability is involved in its pathogenesis, which may be related to the increased burden of de novo CNVs and variable expressivity of CNVs. PMID- 27240533 TI - Isolating biomarkers for symptomatic states: considering symptom-substrate chronometry. AB - A long-standing goal of psychopathology research is to develop objective markers of symptomatic states, yet progress has been far slower than expected. Although prior reviews have attributed this state of affairs to diagnostic heterogeneity, symptom comorbidity and phenotypic complexity, little attention has been paid to the implications of intra-individual symptom dynamics and inter-relatedness for biomarker study designs. In this critical review, we consider the impact of short term symptom fluctuations on widely used study designs that regress the 'average level' of a given symptom against biological data collected at a single time point, and summarize findings from ambulatory assessment studies suggesting that such designs may be sub-optimal to detect symptom-substrate relationships. Although such designs have a crucial role in advancing our understanding of biological substrates related to more stable, longer-term changes (for example, gray matter thinning during a depressive episode), they may be less optimal for the detection of symptoms that exhibit high frequency fluctuations, are susceptible to common reporting biases, or may be heavily influenced by the presence of other symptoms. We propose that a greater emphasis on intra individual symptom chronometry may be useful for identifying subgroups of patients with common, proximal pathological indicators. Taken together, these three recent developments in the areas of symptom conceptualization and measurement raise important considerations for future studies attempting to identify reliable biomarkers in psychiatry. PMID- 27240534 TI - Stress-induced structural plasticity of medial amygdala stellate neurons and rapid prevention by a candidate antidepressant. AB - The adult brain is capable of adapting to internal and external stressors by undergoing structural plasticity, and failure to be resilient and preserve normal structure and function is likely to contribute to depression and anxiety disorders. Although the hippocampus has provided the gateway for understanding stress effects on the brain, less is known about the amygdala, a key brain area involved in the neural circuitry of fear and anxiety. Here, in mice more vulnerable to stressors, we demonstrate structural plasticity within the medial and basolateral regions of the amygdala in response to prolonged 21-day chronic restraint stress (CRS). Three days before the end of CRS, treatment with the putative, rapidly acting antidepressant, acetyl-l-carnitine (LAC) in the drinking water opposed the direction of these changes. Behaviorally, the LAC treatment during the last part of CRS enhanced resilience, opposing the effects of CRS, as shown by an increased social interaction and reduced passive behavior in a forced swim test. Furthermore, CRS mice treated with LAC show resilience of the CRS induced structural remodeling of medial amygdala (MeA) stellate neurons. Within the basolateral amygdala (BLA), LAC did not reduce, but slightly enhanced, the CRS-increased length and number of intersections of pyramidal neurons. No structural changes were observed in MeA bipolar neurons, BLA stellate neurons or in lateral amygdala stellate neurons. Our findings identify MeA stellate neurons as an important component in the responses to stress and LAC action and show that LAC can promote structural plasticity of the MeA. This may be useful as a model for increasing resilience to stressors in at-risk populations. PMID- 27240537 TI - Resistive switching behavior of reduced graphene oxide memory cells for low power nonvolatile device application. AB - Graphene Oxide (GO) based low cost flexible electronics and memory cell have recently attracted more attention for the fabrication of emerging electronic devices. As a suitable candidate for resistive random access memory technology, reduced graphene oxide (RGO) can be widely used for non-volatile switching memory applications because of its large surface area, excellent scalability, retention, and endurance properties. We demonstrated that the fabricated metal/RGO/metal memory device exhibited excellent switching characteristics, with on/off ratio of two orders of magnitude and operated threshold switching voltage of less than 1 V. The studies on different cell diameter, thickness, scan voltages and period of time corroborate the reliability of the device as resistive random access memory. The microscopic origin of switching operation is governed by the establishment of conducting filaments due to the interface amorphous layer rupturing and the movement of oxygen in the GO layer. This interesting experimental finding indicates that device made up of thermally reduced GO shows more reliability for its use in next generation electronics devices. PMID- 27240535 TI - A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development. AB - l-type calcium channel (LTCC) antagonists have been used in bipolar disorder for over 30 years, without becoming an established therapeutic approach. Interest in this class of drugs has been rekindled by the discovery that LTCC genes are part of the genetic aetiology of bipolar disorder and related phenotypes. We have therefore conducted a systematic review of LTCC antagonists in the treatment and prophylaxis of bipolar disorder. We identified 23 eligible studies, with six randomised, double-blind, controlled clinical trials, all of which investigated verapamil in acute mania, and finding no evidence that it is effective. Data for other LTCC antagonists (diltiazem, nimodipine, nifedipine, methyoxyverapamil and isradipine) and for other phases of the illness are limited to observational studies, and therefore no robust conclusions can be drawn. Given the increasingly strong evidence for calcium signalling dysfunction in bipolar disorder, the therapeutic candidacy of this class of drugs has become stronger, and hence we also discuss issues relevant to their future development and evaluation. In particular, we consider how genetic, molecular and pharmacological data can be used to improve the selectivity, efficacy and tolerability of LTCC antagonists. We suggest that a renewed focus on LTCCs as targets, and the development of 'brain-selective' LTCC ligands, could be one fruitful approach to innovative pharmacotherapy for bipolar disorder and related phenotypes. PMID- 27240531 TI - Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes. AB - Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts' maps could uncover functionally and clinically related genes. PMID- 27240536 TI - Perspectives of Mexican-origin smokers on healthy eating and physical activity. AB - Key modifiable risk behaviors such as smoking, poor diet and physical inactivity often cluster and may have multiplicative adverse effects on health. This study investigated barriers and facilitators to healthy eating and physical activity (PA) in overweight Mexican-origin smokers to inform the adaptation of an evidence based smoking cessation program into a multiple health behavior change intervention. Five focus groups were conducted with overweight Mexican-origin men (n = 9) and women (n = 21) who smoked. Barriers and facilitators of healthy eating and PA were identified, and gender differences were assessed. Participants expressed some motivation to eat healthfully and identified strategies for doing so, yet many women experienced difficulties related to personal, family and work related circumstances. Barriers to healthy eating among men were related to food preferences and lack of familiarity with fruits and vegetables. Participants performed PA primarily within the context of work and domestic responsibilities. Stress/depressed mood, lack of motivation and concern for physical well-being limited further PA engagement. Routines involving eating, PA and smoking highlight how these behaviors may be intertwined. Findings emphasize the importance of social, structural and cultural contexts and call for additional investigation into how to integrate healthy eating and PA into smoking cessation interventions for overweight Mexican-origin smokers. PMID- 27240538 TI - Paramagnetic effects on the NMR spectra of isotropic bicelles with headgroup modified chelator lipids and metal ions. AB - We characterized the paramagnetic effects of nine metal ions on NMR signals of isotropic bicelles with headgroup-modified lipids. We found that Mn(2+), Gd(3+) and Dy(3+) show evidence for influencing NMR signals on the surface more than inside and on the disc edge, providing distance information in the bilayers. PMID- 27240540 TI - Update on the ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome. AB - Baraitser-Winter cerebrofrontofacial syndrome is caused by heterozygous missense mutations in one of the two ubiquitous cytoplasmic actin-encoding genes ACTB and ACTG1. Recently, we characterized the large cohort of 41 patients presenting with this condition. Our series contained 34 patients with mutations in ACTB and only nine with ACTG1 mutations. Here, we report on seven unrelated patients with six mutations in ACTG1-four novel and two previously reported. Only one of seven patients was clinically diagnosed with this disorder and underwent ACTB/ACTG1 targeted sequencing, four patients were screened as a part of the large lissencephaly cohort and two were tested with exome sequencing. Retrospectively, facial features were compatible with the diagnosis but significantly milder than previously reported in four patients, and non-specific in one. The pattern of malformations of cortical development was highly similar in four of six patients with available MRI images and encompassed frontal predominant pachygyria merging with the posterior predominant band heterotopia. Two remaining patients showed mild involvement consistent with bilaterally simplified gyration over the frontal lobes. Taken together, we expand the clinical spectrum of the ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome demonstrating the mild end of the facial and brain manifestations. (c) 2016 Wiley Periodicals, Inc. PMID- 27240541 TI - Diabetic ketoacidosis, sodium glucose transporter-2 inhibitors and the kidney. AB - Diabetic ketoacidosis is a serious metabolic condition that may occur in patients with either Type 1 or Type 2 diabetes. The accumulation of ketoacids in the serum is a consequence of insulin deficiency and glucagon excess. Sodium Glucose Transporter 2 (SGLT2) inhibitors are novel therapeutic treatments for improving glucose homeostasis in patients with diabetes. Through reductions in glucose reabsorption by the kidney, they lower serum glucose in patients with Type 2 diabetes and they improve glucose control whether used alone or in combination with other therapies. Mechanistically, these drugs increase serum ketoacids and increase glucagon production, which in some individuals, can lead to formation of diabetic ketoacidosis. This review will first focus in how the kidney normally handles ketoacids, and second will discuss how the SGLT2 inhibitors affect the kidney in such a way so as to enhance the risk for development of ketoacidosis in susceptible individuals. PMID- 27240539 TI - Prostaglandin I2 upregulates the expression of anterior pharynx-defective-1alpha and anterior pharynx-defective-1beta in amyloid precursor protein/presenilin 1 transgenic mice. AB - Cyclooxygenase-2 (COX-2) has been recently identified to be involved in the pathogenesis of Alzheimer's disease (AD). Yet, the role of an important COX-2 metabolic product, prostaglandin (PG) I2 , in the pathogenesis of AD remains unknown. Using human- and mouse-derived neuronal cells as well as amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice as model systems, we elucidated the mechanism of anterior pharynx-defective (APH)-1alpha and pharynx defective-1beta induction. In particular, we found that PGI2 production increased during the course of AD development. Then, PGI2 accumulation in neuronal cells activates PKA/CREB and JNK/c-Jun signaling pathways by phosphorylation, which results in APH-1alpha/1beta expression. As PGI2 is an important metabolic by product of COX-2, its suppression by NS398 treatment decreases the expression of APH-1alpha/1beta in neuronal cells and APP/PS1 mice. More importantly, beta amyloid protein (Abeta) oligomers in the cerebrospinal fluid (CSF) of APP/PS1 mice are critical for stimulating the expression of APH-1alpha/1beta, which was blocked by NS398 incubation. Finally, the induction of APH-1alpha/1beta was confirmed in the brains of patients with AD. Thus, these findings not only provide novel insights into the mechanism of PGI2 -induced AD progression but also are instrumental for improving clinical therapies to combat AD. PMID- 27240542 TI - Cyanidin 3-O-beta-glucopyranoside activates peroxisome proliferator-activated receptor-gamma and alleviates cognitive impairment in the APP(swe)/PS1(DeltaE9) mouse model. AB - Alzheimer's disease (AD) is currently one of the most common neurodegenerative disorders worldwide. To date, no cure has been developed for AD, and some disease modifying treatments show side effects and low efficacy. Increasing evidence shows that cyanidin 3-O-beta-glucopyranoside (Cy3G), which is naturally derived from many plants, may provide protection against neurodegenerative diseases including AD; however, its exact role is still unclear. Therefore, we investigated the mechanisms of the effects of Cy3G on beta-amyloid 25-35 (Abeta25 35)-induced SH-SY5Y cell injury and cognitive impairment in the APP(swe)/PS1(DeltaE9) (PAP) mouse model of AD. Furthermore, we aimed to determine the molecular target initiated by Cy3G. The data indicated that Cy3G-mediated neuroprotection involved the inhibition of Abeta25-35 binding to the cell surface and spontaneous aggregation of Abeta25-35 fibrils at the molecular level. Furthermore, in an in vitro study, Abeta25-35-mediated cytotoxicity, which was caused by inducing apoptotic cell death and ROS formation, was also ameliorated by Cy3G intervention. In addition, upregulation of peroxisome proliferator activated receptor-gamma (PPARgamma) protein involved in glucose/lipid metabolism by Cy3G treatment verified that the initiated molecule was Cy3G. In an in vivo study, Cy3G was shown to alleviate cognitive impairment, improve cerebral glucose uptake and decrease fasting blood glucose levels. In conclusion, Cy3G ameliorates amyloid beta peptide-induced injury both in vitro and in vivo through the PPARgamma pathway. Thus, Cy3G has a good safety profile as a potential natural PPARgamma agonist and may be used as an ideal alternative to traditional disease modifying treatments against AD. PMID- 27240543 TI - Knowledge gaps to understanding cardiac macrophage polarization following myocardial infarction. AB - Following myocardial infarction (MI), macrophages coordinate both pro inflammatory and reparative responses of the left ventricle (LV) by reacting to and secreting cytokines, chemokines, and growth factors and by stimulating endothelial cells and fibroblasts to modulate neovascularization and scar formation. Healing of the infarcted LV can be divided into three distinct, but overlapping phases: inflammatory, proliferative, and maturation. Macrophages are involved in all phases. Despite macrophages being a major leukocyte cell type in the post-MI LV, how this cell type regulates LV remodeling over the post-MI time continuum is not completely understood. In this review, we summarize the current literature as a foundation to discuss the major knowledge gaps that remain. Defining the post-MI temporal macrophage phenotypes to establish a classification system is the first step in exploring how macrophage phenotypes are regulated, how temporal stimulation and secretion profiles evolve, and how best to modify stimuli to yield predictable cell responses. This article is part of a Special Issue entitled: The role of post-translational protein modifications on heart and vascular metabolism edited by Jason R.B. Dyck & Jan F.C. Glatz. PMID- 27240546 TI - Highly selective electrodeposition of sub-10 nm crystalline noble metallic nanorods inside vertically aligned multiwall carbon nanotubes. AB - In this paper crystalline noble metallic nanorods including Au and Ag with sub-10 nm diameter, are encapsulated within prealigned and open-ended multiwall carbon nanotubes (MWCNTs) through an electrodeposition method. As the external surface of CNTs has been insulated by the epoxy the CNT channel becomes the only path for the mass transport as well as the nanoreactor for the metal deposition. Highly crystallized Au and Ag2O nanorods parallel to the radial direction of CNTs are confirmed by high-resolution transmission electron microscopy, energy dispersive x-ray spectroscopy and x-ray powder diffraction spectroscopy. The Ag2O nanorods are formed by air oxidation on the Ag metals and show a single crystalline structure with (111) planes. The Au nanorods exhibit a complex crystalline structure including twin-crystal and lattice dislocation with (111) and (200) planes. These crystalline noble metallic nanostructures may have important applications for nanocatalysts for fuel cells as well as nanoelectronic and nanophotonic devices. This method is deemed to benefit the precise deposition of other crystalline nanostructures inside CNTs with a small diameter. PMID- 27240544 TI - Mammalian ataxin-2 modulates translation control at the pre-initiation complex via PI3K/mTOR and is induced by starvation. AB - Ataxin-2 is a cytoplasmic protein, product of the ATXN2 gene, whose deficiency leads to obesity, while its gain-of-function leads to neural atrophy. Ataxin-2 affects RNA homeostasis, but its effects are unclear. Here, immunofluorescence analysis suggested that ataxin-2 associates with 48S pre-initiation components at stress granules in neurons and mouse embryonic fibroblasts, but is not essential for stress granule formation. Coimmunoprecipitation analysis showed associations of ataxin-2 with initiation factors, which were concentrated at monosome fractions of polysome gradients like ataxin-2, unlike its known interactor PABP. Mouse embryonic fibroblasts lacking ataxin-2 showed increased phosphorylation of translation modulators 4E-BP1 and ribosomal protein S6 through the PI3K-mTOR pathways. Indeed, human neuroblastoma cells after trophic deprivation showed a strong induction of ATXN2 transcript via mTOR inhibition. Our results support the notion that ataxin-2 is a nutritional stress-inducible modulator of mRNA translation at the pre-initiation complex. PMID- 27240545 TI - Use of metabolomics and lipidomics to evaluate the hypocholestreolemic effect of Proanthocyanidins from grape seed in a pig model. AB - SCOPE: This work aims to evaluate changes in the fecal metabolomic profile due to grape seed extract (GSE) intake by untargeted and targeted analysis using high resolution mass spectrometry in conjunction with multivariate statistics. METHODS AND RESULTS: An intervention study with six crossbred female pigs was performed. The pigs followed a standard diet for 3 days, then they were fed with a supplemented diet containing 1% (w/w) of MegaNatural(r) Gold grape seed extract for 6 days. Fresh pig fecal samples were collected daily. A combination of untargeted high resolution mass spectrometry, multivariate analysis (PLS-DA), data-dependent MS/MS scan, and accurate mass database matching was used to measure the effect of the treatment on fecal composition. The resultant PLS-DA models showed a good discrimination among classes with great robustness and predictability. A total of 14 metabolites related to the GSE consumption were identified including biliary acid, dicarboxylic fatty acid, cholesterol metabolites, purine metabolites, and eicosanoid metabolites among others. Moreover, targeted metabolomics using GC-MS showed that cholesterol and its metabolites fecal excretion was increased due to the proanthocyanidins from grape seed extract. CONCLUSION: The results show that oligomeric procyanidins from GSE modifies bile acid and steroid excretion, which could exert a hypocholesterolemic effect. PMID- 27240547 TI - Liver disease in patients undergoing head and neck surgery: Incidence and risk for postoperative complications. AB - OBJECTIVES/HYPOTHESIS: Head and neck cancer patients have multiple risk factors for liver disease. However, little is known about the incidence of liver disease or the safety of surgery in these patients. STUDY DESIGN: We conducted a retrospective cohort study using the American College of Surgeons National Surgical Quality Improvement Program from 2005 to 2013. METHODS: We identified patients undergoing head and neck surgery and excluded them if preoperative laboratory data were missing. Patients were classified as having liver disease if their preoperative aspartate aminotransferase-to-platelet ratio index was >= 0.7, and as having advanced liver disease if their Model for End-Stage Liver Disease Sodium score was >= 10. We compared the rate of postoperative complications using multivariable logistic regression. RESULTS: Among 19,138 eligible patients, the incidence of any degree of liver disease was 6.8% for aerodigestive tract surgery and 3.3% for controls. The 30-day mortality rate after major head and neck surgery, which included composite resection; free tissue transfer; and total laryngectomy with advanced, mild, and no liver disease, was 14.6%, 3.0%, and 0.9%, respectively (P < 0.001). For nonmajor surgery, the mortality rate was 3.0%, 0.3%, and 0.3%, respectively (P < 0.001). On multivariable analysis, patients with advanced liver disease experienced a six-fold higher rate of 30-day mortality (odds ratio 6.1; 95% confidence interval, 2.9-12.8). CONCLUSION: There is a high risk to detect liver disease in patients undergoing head and neck surgery of the aerodigestive tract. Those with advanced liver disease are at high risk for perioperative mortality, and this risk should be judiciously considered in medical/surgical decision making and postoperative care. LEVEL OF EVIDENCE: 2c. Laryngoscope, 127:102-109, 2017. PMID- 27240548 TI - Chronic kidney disease-related physical frailty and cognitive impairment: a systemic review. AB - AIM: The objective of this review was to assess chronic kidney disease-related frailty and cognitive impairment, as well as their probable causes, mechanisms and the interventions. METHODS: Studies from 1990 to 2015 were reviewed to evaluate the relationship between chronic kidney disease and physical frailty and cognitive impairment. Of the 1694 studies from the initial search, longitudinal studies (n = 22) with the keywords "Cognitive and CKD" and longitudinal or cross sectional studies (n = 5) with the keywords "Frailty and CKD" were included in final analysis. RESULTS: By pooling current research, we show clear evidence for a relationship between chronic kidney disease and frailty and cognitive impairment in major studies. Vascular disease is likely an important mediator, particularly for cognitive impairment. However, non-vascular factors also play an important role. Many of the other mechanisms that contribute to impaired cognitive function and increased frailty in CKD remain to be elucidated. In limited studies, medication therapy did not obtain the ideal effect. There are limited data on treatment strategies, but addressing the vascular disease risk factors earlier in life might decrease the subsequent burden of frailty and cognitive impairment in this population. Multidimensional interventions, which address both microvascular health and other factors, may have substantial benefits for both the cognitive impairments and physical frailty in this vulnerable population. CONCLUSIONS: Chronic kidney disease is a potential cause of frailty and cognitive impairment. Vascular and non-vascular factors are the possible causes. The mechanism of chronic kidney disease-induced physical frailty and cognitive impairment suggests that multidimensional interventions may be effective therapeutic strategies in the early stage of chronic kidney disease. Geriatr Gerontol Int 2017; 17: 529-544. PMID- 27240549 TI - The half-life and exposure of cefuroxime varied in newborn infants after a Caesarean section. AB - AIM: No information was available on how fast intravenous cefuroxime administered to pregnant women before a Caesarean section was cleared in newborn infants. This study investigated the drug's half-life and the exposure of healthy newborn infants after their mothers received the drug. METHODS: Healthy mothers received a single dose of cefuroxime 15-60 minutes before skin incision. One blood sample was drawn from the umbilical cord, and two blood samples were drawn from the infant after delivery. Total plasma cefuroxime (MUg/mL) was measured using high pressure liquid chromatography. RESULTS: Cefuroxime was given to 22 mothers, including two who had twins. The concentration of cefuroxime varied significantly among infants (p < 0.001), while the rate of decline did not (p = 0.24). The median cefuroxime half-life was 3.5 hours (range 2.9-5.5), which was approximately three times longer than in normal adults and seemed to clear within 24 hours. The median area under the concentration-time curve was 65.0 hour MUg/mL (range 31.7-162.4). CONCLUSION: We found that the cefuroxime half-life after a Caesarean section varied among infants and was longer than in normal adults but cleared within 24 hours. Exposure to cefuroxime in newborn infants may influence the gut microbiota and should be investigated further. PMID- 27240550 TI - Discovery and development of benzo-[1,2,4]-triazolo-[1,4]-oxazepine GPR142 agonists for the treatment of diabetes. AB - A novel series of benzo-[1,2,4]-triazolo-[1,4]-oxazepine GPR142 agonists are described. The series was designed to address the suboptimal PK (pharmacokinetic) and off-target profile of a class of N-aryl-benzo-[1,4]-oxazepine-4-carboxamides, represented by 1, that were identified from a high-throughput screen of the Merck compound collection for GPR142 agonists. This work led to the discovery of 3 phenoxy-benzo-[1,2,4]-triazolo-[1,4]-oxazepine 47, a potent GPR142 agonist with an off-target and PK profile suitable for in vivo studies. This compound and a related analogue 40 were shown to be active in mouse oral glucose tolerance tests (OGTTs). Furthermore, a GPR142 knock-out mouse OGTT study with compound 40 provides evidence that its glucose-lowering effect is mediated by GPR142. PMID- 27240551 TI - Therapeutic effect of tyndallized Lactobacillus rhamnosus IDCC 3201 on atopic dermatitis mediated by down-regulation of immunoglobulin E in NC/Nga mice. AB - The therapeutic effect of oral administration of Lactobacillus rhamnosus IDCC 3201 tyndallizate (RHT3201) on atopic dermatitis (AD)-like skin lesions in NC/Nga mice were investigated. After induction of dermatitis in NC/Nga mice with house dust mite extract, each group was fed RHT3201 with 1 * 10(8) , 1 * 10(9) , or 1 * 10(10) cells orally once a day for 8 weeks. Dermatitis scores and frequency of scratching were improved by oral feeding with RHT3201. In contrast to the control group, RHT3201-fed mice showed significantly down-regulated mast cell numbers and serum immunoglobulin E (IgE) concentrations had significantly less IL4 in their axillary lymph node cells. The therapeutic effect of RHT3201 was found to be dose dependent. These findings indicate that RHT3201 has potential for treating AD. PMID- 27240552 TI - Acylase-containing polyurethane coatings with anti-biofilm activity. AB - Due to the prevalence of biofilm-related infections, which are mediated by bacterial quorum sensing, there is a critical need for materials and coatings that resist biofilm formation. We have developed novel anti-biofilm coatings that disrupt quorum sensing in surface-associated bacteria via the immobilization of acylase in polyurethane films. Specifically, acylase from Aspergillus melleus was covalently immobilized in biomedical grade polyurethane coatings via multipoint covalent immobilization. Coatings containing acylase were enzymatically active and catalyzed the hydrolysis of the quorum sensing (QS) molecules N-butyryl-L homoserine lactone (C4-LHL), N-hexanoyl-L-homoserine lactone (C6-LHL), and N-(3 oxododecanoyl)-L-homoserine lactone (3-oxo-C12-LHL). In biofilm inhibition assays, immobilization of acylase led to an approximately 60% reduction in biofilm formation by Pseudomonas aeruginosa ATCC 10145 and PAO1. Inhibition of biofilm formation was consistent with a reduction in the secretion of pyocyanin, indicating the disruption of quorum sensing as the mechanism of the coating activity. Scanning electron microscopy further showed that acylase-containing coatings contained far fewer bacterial cells than control coatings that lacked acylase. Moreover, acylase-containing coatings retained 90% activity when stored dry at 37 degrees C for 7 days and were more stable than the free enzyme in physiological conditions, including artificial urine. Ultimately, such coatings hold considerable promise for the clinical management of catheter-related infections as well as the prevention of infections in orthopedic applications (i.e., on hip and knee prostheses) and on contact lenses. Biotechnol. Bioeng. 2016;113: 2535-2543. (c) 2016 Wiley Periodicals, Inc. PMID- 27240553 TI - Quantum teleportation from light beams to vibrational states of a macroscopic diamond. AB - With the recent development of optomechanics, the vibration in solids, involving collective motion of trillions of atoms, gradually enters into the realm of quantum control. Here, building on the recent remarkable progress in optical control of motional states of diamonds, we report an experimental demonstration of quantum teleportation from light beams to vibrational states of a macroscopic diamond under ambient conditions. Through quantum process tomography, we demonstrate average teleportation fidelity (90.6+/-1.0)%, clearly exceeding the classical limit of 2/3. The experiment pushes the target of quantum teleportation to the biggest object so far, with interesting implications for optomechanical quantum control and quantum information science. PMID- 27240554 TI - Investigating the timing of origin and evolutionary processes shaping regional species diversity: Insights from simulated data and neotropical butterfly diversification rates. AB - Different diversification scenarios have been proposed to explain the origin of extant biodiversity. However, most existing meta-analyses of time-calibrated phylogenies rely on approaches that do not quantitatively test alternative diversification processes. Here, I highlight the shortcomings of using species divergence ranks, which is a method widely used in meta-analyses. Divergence ranks consist of categorizing cladogenetic events to certain periods of time, typically to either Pleistocene or to pre-Pleistocene ages. This approach has been claimed to shed light on the origin of most extant species and the timing and dynamics of diversification in any biogeographical region. However, interpretations drawn from such method often confound two fundamental questions in macroevolutionary studies, tempo (timing of evolutionary rate shifts) and mode ("how" and "why" of speciation). By using simulated phylogenies under four diversification scenarios, constant-rate, diversity-dependence, high extinction, and high speciation rates in the Pleistocene, I showed that interpretations based on species divergence ranks might have been seriously misleading. Future meta analyses of dated phylogenies need to be aware of the impacts of incomplete taxonomic sampling, tree topology, and divergence time uncertainties, as well as they might be benefited by including quantitative tests of alternative diversification models that acknowledge extinction and diversity dependence. PMID- 27240556 TI - The sclerotic ring of squamates: an evo-devo-eco perspective. AB - The sclerotic ring consists of several bones that form in the sclera of many reptiles. This element has not been well studied in squamates, a diverse order of reptiles with a rich fossil record but debated phylogeny. Squamates inhabit many environments, display a range of behaviours, and have evolved several different body plans. Most importantly, many species have secondarily lost their sclerotic rings. This research investigates the presence of sclerotic rings in squamates and traces the lineage of these bones across evolutionary time. We compiled a database on the presence/absence of the sclerotic ring in extinct and extant squamates and investigated the evolutionary history of the sclerotic ring and how its presence/absence and morphology is correlated with environment and behaviour within this clade. Of the 400 extant species examined (59 families, 214 genera), 69% have a sclerotic ring. Those species that do not are within Serpentes, Amphisbaenia, and Dibamidae. We find that three independent losses of the sclerotic ring in squamates are supported when considering both evolutionary and developmental evidence. We also show that squamate species that lack, or have a reduced, sclerotic ring, are fossorial and headfirst burrowers. Our dataset is the largest squamate dataset with measurements of sclerotic rings, and supports previous findings that size of the ring is related to both environment occupied and behaviour. Specifically, scotopic species tend to have both larger inner and outer sclerotic ring apertures, resulting in a narrower ring of bone than those found in photopic species. Non-fossorial species also have a larger sclerotic ring than fossorial species. This research expands our knowledge of these fascinating bones; with further phylogenetic analyses scleral ossicles could become an extremely useful character trait for inferring the behaviour of fossil squamates. PMID- 27240555 TI - Effects of disturbed sleep on gastrointestinal and somatic pain symptoms in irritable bowel syndrome. AB - BACKGROUND: Sleep disturbances are common, and perhaps are even more prevalent in irritable bowel syndrome (IBS). AIMS: To determine the effect of measured sleep on IBS symptoms the following day, IBS-specific quality of life (IBS-QOL) and non GI pain symptoms. METHODS: IBS patients' sleep patterns were compared to healthy individuals via wrist-mounted actigraphy over 7 days. Daily bowel pain logs (severity, distress; 10-point Likert) stool pattern (Bristol scale) and supporting symptoms (e.g. bloating, urgency; 5-point Likert) were kept. Validated measures, including the GI Symptom Rating Scale-IBS, Visceral Sensitivity Index, Pittsburgh Sleep Quality Index and the IBS-Quality of Life were collected. Mediation analysis explored the relationship between sleep, mood and bowel symptoms. RESULTS: Fifty subjects (38.6 +/- 1.0 years old, 44 female; 24 IBS and 26 healthy controls) completed sleep monitoring. IBS patients slept more hours per day (7.7 +/- 0.2 vs. 7.1 +/- 0.1, P = 0.008), but felt less well-rested. IBS patients demonstrated more waking episodes during sleep (waking episodes; 12.1 vs. 9.3, P < 0.001). Waking episodes predicted worse abdominal pain (P <= 0.01) and GI distress (P < 0.001), but not bowel pattern or accessory IBS symptoms (P > 0.3 for each). Waking episodes negatively correlated with general- and IBS specific QOL in IBS (r = -0.58 and -0.52, P < 0.001 for each). Disturbed sleep effects on abdominal pain were partially explained by mood as an intermediate. CONCLUSIONS: Sleep disturbances are more common in irritable bowel syndrome, and correlate with IBS-related pain, distress and poorer irritable bowel syndrome related quality of life. Disturbed sleep effects extend beyond the bowel, leading to worse mood and greater somatic pain in patients with the irritable bowel syndrome. PMID- 27240558 TI - Optimized Implantation Height of the Edwards SAPIEN 3 Valve to Minimize Pacemaker Implantation After TAVI. AB - AIM: The transcatheter aortic valve SAPIEN 3 aims at reducing paravalvular leakage (PVL). The new design with outer sealing cuff may increase the risk of permanent pacemaker implantation (PPM). The aim of our study was to evaluate the optimal implantation height of the SAPIEN 3. METHODS AND RESULTS: We analysed the correlation between the implantation height of the valve and the need for PPM in 131 patients. The PPM rate for the entire group after TAVI was 18% (n = 24). In patients with a marker distance <2 mm ("low implantation"), the PPM rate was 32%, whereas in patients with a distance >=2 mm ("high implantation"), the rate was only 4.7% (OR of 0.1 (0.03-0.37, P < 0.001)). CONCLUSION: The risk of periprocedural PPM with the Edwards SAPIEN 3 depends on implantation height; it is increased when using conventional implantation techniques. This risk can be minimized below 5% PPM by choosing a higher implantation technique with the central marker 2 mm or more over the annulus plane. PMID- 27240557 TI - Enantiospecific Synthesis and Cytotoxicity Evaluation of Oximidine II Analogues. AB - Analogues of the anticancer natural product oximidine II were prepared and evaluated for cytotoxicity. One analogue of oximidine II that carries a C15 allylic amide side chain as well as two analogues with C15 vinyl sulfone side chains were found to lack cytotoxicity against the cancer cell line SK-Mel-5, thereby confirming the necessity of the C15 enamide side chain of oximidine II for cytotoxicity. Four analogues, designed by comparative molecular similarity index analysis (CoMSIA), that feature a less complex macrolactone scaffold were prepared and tested. The two analogues carrying a C15 vinyl sulfone group and the two analogues with a C15 oximidine II enamide side chain showed weak cytotoxicity against the SK-Mel-5 cell line and other cell lines, indicating that the designed simplified macrocycles cannot replace the oximidine II macrocycle. PMID- 27240559 TI - Implications of fetoplacental mosaicism on cell-free DNA testing: a review of a common biological phenomenon. PMID- 27240560 TI - Consumption of fruits and vegetables associated with other risk behaviors among adolescents in Northeast Brazil. AB - OBJECTIVE: To determine the prevalence of consumption of fruits and vegetables and identify the association with low level of physical activity, exposure to sedentary behavior, consumption of soft drinks and overweight/obesity in adolescents. METHODS: This is a cross-sectional school-based study with a representative sample of 3992 students aged 14-19 years from the state of Sergipe, Brazil. The outcome was low consumption of fruits and vegetables (<5servings/day). Independent variables were: level of physical activity, sedentary behavior, consumption of soft drinks, and overweight/obesity. Global Student Health Survey questionnaire and body mass and height measurements were used, as well as chi-square test and crude and adjusted binary logistic regression. The significance level adopted was 5%. RESULTS: The prevalence of inadequate consumption of fruits and vegetables was high - 88.6% (95%CI=87.6 89.5). Higher likelihood of low consumption of fruits and vegetables was verified among boys who were exposed to sedentary behavior (OR=1.63; 95%CI=1.18-2.24), who consumed soft drinks (OR=3.04; 95%CI=2.10-4.40), with insufficiently physical activity (OR=1.98; 95%CI=1.43-2.73) and girls who consumed soft drinks (OR=1.88; 95%CI=1.43-2.47) and those with overweight/obesity (OR=1.63; 95%CI=1.19-2.23). CONCLUSIONS: There is a need of public policies aimed at encouraging the consumption of healthy foods among adolescents. PMID- 27240561 TI - Triangulating meta-analyses: the example of the serotonin transporter gene, stressful life events and major depression. AB - BACKGROUND: Meta-analysis is intended as a tool for the objective synthesis of evidence across a literature, in order to obtain the best evidence as to whether or not an association or effect is robust. However, as the use of meta-analysis has proliferated it has become increasingly clear that the results of a meta analysis can be critically sensitive to methodological and analytical choices, so that different meta-analyses on the same topic can arrive at quite different conclusions. RESULTS: We demonstrate the variability in results of different meta analyses on the same topic, using the example of the literature on the putative moderating effect of 5-HTTLPR genotype on the association between stressful life events and major depression. We also extend on previous work by including a P curve analysis of studies from this literature, drawn from a previous meta analysis, in an attempt to resolve the discrepant conclusions arrived at by previous meta-analyses. CONCLUSIONS: We highlight the divergent conclusions that can be reached when different methodological and analytical choices are taken, and argue that triangulating evidence using multiple evidence synthesis methods is preferable where possible, and that every effort should be made for meta analyses to be as unbiased as possible (e.g., conducted by methodologists or as part of an adversarial collaboration between authors from opposing camps). PMID- 27240562 TI - A latent trait approach to measuring HIV/AIDS related stigma in healthcare professionals: application of mokken scaling technique. AB - BACKGROUND: The attitudes of healthcare professionals towards HIV positive patients and high risk groups are central to the quality of care and therefore to the management of HIV/AIDS related stigma in health settings. Extant HIV/AIDS stigma scales that measure stigmatising attitudes towards people living with HIV/AIDS have been developed using scaling techniques such as principal component analysis. This approach has resulted in instruments that are often long. Mokken scale analysis is a nonparametric hierarchical scaling technique that can be used to develop unidimensional cumulative scales. This technique is advantageous over the other approaches; as the scales are usually shorter, while retaining acceptable psychometric properties. Moreover, Mokken scales also make no distributional assumptions about the underlying data, other than that the data are capable of being ordered by item and by person. In this study we aimed at developing a precise and concise measure of HIV/AIDS related stigma among health care professionals, using Mokken scale analysis. METHODS: We carried out a cross sectional survey of healthcare students at the Monash University campuses in Malaysia and Australia. The survey consisted of demographic questions and an initial item pool of twenty five potential questions for inclusion in an HIV stigma scale. RESULTS: We analysed the data using the mokken package in the R statistical environment providing a 9-item scale with high reliability, validity and acceptable psychometric properties, measuring and ranking the HIV/AIDS related stigmatising attitudes. CONCLUSION: Mokken scaling procedure not only produced a comprehensive hierarchical scale that could accurately order a person along HIV/AIDS stigmatising attitude, but also demonstrated a unidimensional and reliable measurement tool which could be used in future studies. The principal component analysis confirmed the accuracy of the Mokken scale analysis in correctly detecting the unidimensionality of this scale. We recommend future works to study the generalisability of this scale in a new population. PMID- 27240563 TI - The SCOPE of Hospital Falls: A Systematic Mixed Studies Review. AB - PURPOSE: This systematic mixed studies review on hospital falls is aimed to facilitate proactive decision-making for patient safety during the healthcare facility design. BACKGROUND: Falls were identified by the Centers for Medicare & Medicaid Services as a nonreimbursed hospital-acquired condition (HAC) due to volume and cost, and additional financial penalties were introduced with the 2014 U.S. HAC reduction program. In 2015, the Joint Commission alert identified patient falls as one of the top reported sentinel events, and the Occupational Safety & Health Administration (OSHA) added slips, trips, and falls as a focus for investigators' healthcare inspections. Variations in fall rates at both the hospital and the unit level are indicative of an ongoing challenge. The built environment can act as a barrier or enhancement to achieving the desired results in safety complexity that includes the organization, people, and environment. METHODS: The systematic literature review used Medical Subject Heading terms and key word alternates for hospital falls with searches in MEDLINE, Web of Science, and CINAHL. The search was limited to English-language papers. RESULTS: Following full-text review, 27 papers were included and critically appraised using an evaluation matrix that included a mixed methods appraisal tool. Themes were coded by broad categories of factors for organization (policy/operations), people (caregivers/staff, patients), and the environment (healthcare facility design). Subcategories were developed to define the physical environment and consider the potential interventions in the context of relative stability. CONCLUSIONS: Conditions of hospital falls were identified and evaluated through the literature review. A theoretical model was developed to propose a human factors framework while considering the permanence of solutions. PMID- 27240564 TI - Exploring Environmental Variation in Residential Care Facilities for Older People. AB - OBJECTIVE: The aim of this study was to explore variation in environmental quality in Swedish residential care facilities (RCFs) using the Swedish version of the Sheffield Care Environment Assessment Matrix (S-SCEAM). BACKGROUND: Well designed physical environments can positively impact on health and well-being among older persons with frail health living in RCFs and are essential for supporting person-centered care. However, the evidence base for informing the design of RCFs is weak, partly due to a lack of valid and reliable instruments that could provide important information on the environmental quality. METHODS: Twenty RCFs were purposively sampled from several regions, varying in their building design, year of construction, size, and geographic location. The RCFs were assessed using S-SCEAM and the data were analyzed to examine variation in environmental quality between and within facilities. RESULTS: There was substantial variation in the quality of the physical environment between and within RCFs, reflected in S-SCEAM scores related to specific facility locations and with regard to domains reflecting residents' needs. In general, private apartments and dining areas had high S-SCEAM scores, while gardens had lower scores. Scores on the safety domain were high in the majority of RCFs, whereas scores for cognitive support and privacy were relatively low. CONCLUSIONS: Despite high building standard requirements, the substantial variations regarding environmental quality between and within RCFs indicate the potential for improvements to support the needs of older persons. We conclude that S-SCEAM is a sensitive and unique instrument representing a valuable contribution to evidence based design that can support person-centered care. PMID- 27240565 TI - Simultaneous Determination of Bosentan, Glimepiride, HYBOS and M1 in Rat Plasma by UPLC-MS-MS and its Application to Pharmacokinetic Study. AB - A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS) method for the simultaneous determination of bosentan (BOS), glimepiride (GLP), hydroxyl bosentan (HYBOS) and hydroxyl glimepiride (M1) in rat plasma using one-step protein precipitation was developed and validated. After addition of ambrisentan as an internal standard (IS), protein precipitation by acetonitrile was used in sample preparation. Chromatographic separation was achieved on a Waters ACQUITY UPLC BEH C18 column (2.1 mm * 100 mm, 1.7 MUm particle size, Waters Corp., Milford, MA, USA) and inline 0.2 MUm stainless steel frit filter (Waters Corp.) with acetonitrile-0.1% formic acid as the mobile phase at a flow rate of 0.4 mL/min with gradient elution. The column temperature was maintained at 40 degrees C. Only 4 min was needed for an analytical run. The retention times were ~3.29 min for BOS, 3.56 min for GLP, 1.42 min for HYBOS, 1.53 min for M1 and 3.22 min for IS. Electrospray ionization source was employed and operated in positive-ion mode; multiple reaction monitoring mode was applied to target fragment ions m/z 552 -> 202, m/z 568 -> 202, m/z 491 -> 352, m/z 507 > 352 and m/z 379 -> 347 for BOS, HYBOS, GLP, M1 and IS, respectively. The assay was validated over concentration ranges of 25-5,000 ng/mL (r(2) = 0.9984) for BOS, 1-200 ng/mL (r(2) = 0.9999) for GLP, 0.5-100 ng/mL (r(2) = 0.9999) for HYBOS and 0.1-20 ng/mL (r(2) = 0.9984) for M1. Intra- and interday precision values for replicate quality control samples were within 14.2% for all analytes during the assay validation. Mean quality control accuracy values were within -3.3 to 14.4% of nominal values for all analytes. The mean recoveries of BOS, GLP, HYBOS, M1 and ambrisentan from the plasma exceeded 90.4%. The analytes were stable in rat plasma for at least 2 h at room temperature, 30 days at -40 degrees C and following at least three freeze-thaw cycles (-40 degrees C to room temperature). This method was successfully applied to a pharmacokinetic study of coadministeration of BOS and GLP in rats. PMID- 27240566 TI - Determination of Doxorubicin in Stealth Hyalurionic Acid-Based Nanoparticles in Rat Plasma by the Liquid-Liquid Nanoparticles-Breaking Extraction Method: Application to a Pharmacokinetic Study. AB - An efficient extraction of doxorubicin (Dox) from homemade stealth hyalurionic acid (HA)-based nanoparticles (NPs) in rat plasma could not be performed by previously published methods. Therefore, we attempted to establish the novel NPs breaking and UPLC-MS-MS method for evaluating the pharmacokinetic profiles of the homemade stealth HA NPs in rats. The pretreatment method of plasma samples used the liquid-liquid extraction method with isopropyl alcohol as NPs-breaking and protein-precipitating solvents, and the NPs-breaking efficiency of isopropyl alcohol was as high as 97.2%. The analyte and gliclazide (internal standard) were extracted from plasma samples with isopropyl alcohol and were separated on UPLC BEH C18 with a mobile phase consisting of methanol and water (containing 0.1% formic acid). The method demonstrated good linearity at the concentrations ranging from 5 to 5,000 ng/mL. The intra- and interday relative standard deviations were >10%. Finally, the method was successfully applied to a pharmacokinetic study of homemade stealth HA-based NPs in rats following intravenous administration. PMID- 27240567 TI - Exotic pediculosis and hair-loss syndrome in deer (Odocoileus hemionus) populations in California. AB - Infestation with nonnative, "exotic" lice was first noted in Washington black tailed deer (Odocoileus hemionus columbianus) in 1994 and has since then spread throughout the western United States. In California, infestation with the exotic louse Damalinia (Cervicola) sp. was first detected in black-tailed deer from northern California in 2004, and, in 2009, the exotic louse species Bovicola tibialis and Linognathus africanus were identified on mule deer (Odocoileus hemionus californicus) in central Sierra Nevada in association with a mortality event. Exotic lice have since been detected in various locations throughout the state. We describe the geographic distribution of these exotic lice within California, using data from 520 live-captured and 9 postmortem-sampled, free ranging mule deer examined between 2009 and 2014. Data from live-captured deer were used to assess possible associations between louse infestation and host age, host sex, migratory behavior, season, and blood selenium and serum copper concentrations. Damalinia (Cervicola) sp. and B. tibialis lice were distinctively distributed geographically, with D. (Cervicola) sp. infesting herds in northern and central coastal California, B. tibialis occurring in the central coastal mountains and the Sierra Nevada, and L. africanus occurring only sporadically. Younger age classes and low selenium concentrations were significantly associated with exotic louse infestation, whereas no significant relationship was detected with serum copper levels. Our results show that exotic lice are widespread in California, and younger age classes with low blood selenium concentrations are more likely to be infested with lice than older deer. PMID- 27240568 TI - Confirmation of Elsey virus infection in a Queensland horse with mild neurologic signs. AB - In 2011, a 2-year-old horse in northern Queensland, Australia, was reported to have developed mild neurologic signs, and a blood sample was submitted for laboratory investigation. Virus isolation was performed using the blood sample, and an orbivirus was isolated. This was confirmed to be a strain of Elsey virus (ELSV) after transmission electron microscopy and nucleotide sequencing. The nucleotide sequence was compared with those in GenBank, and had 100% identity with ELSV previously reported from the Northern Territory, Australia. ELSV is taxonomically closely related to Peruvian horse sickness virus. PMID- 27240569 TI - Characterization of spinal cord lesions in cattle and horses with rabies: the importance of correct sampling. AB - Twenty-six cattle and 7 horses were diagnosed with rabies. Samples of brain and spinal cord were processed for hematoxylin and eosin staining and immunohistochemistry (IHC). In addition, refrigerated fragments of brain and spinal cord were tested by direct fluorescent antibody test and intracerebral inoculation in mice. Statistical analyses and Fisher exact test were performed by commercial software. Histologic lesions were observed in the spinal cord in all of the cattle and horses. Inflammatory lesions in horses were moderate at the thoracic, lumbar, and sacral levels, and marked at the lumbar enlargement level. Gitter cells were present in large numbers in the lumbar enlargement region. IHC staining intensity ranged from moderate to strong. Inflammatory lesions in cattle were moderate in all spinal cord sections, and gitter cells were present in small numbers. IHC staining intensity was strong in all spinal cord sections. Only 2 horses exhibited lesions in the brain, which were located mainly in the obex and cerebellum; different from that observed in cattle, which had lesions in 25 cases. Fisher exact test showed that the odds of detecting lesions caused by rabies in horses are 3.5 times higher when spinal cord sections are analyzed, as compared to analysis of brain samples alone. PMID- 27240570 TI - Poisoning of sheep by Vernonia plantaginoides (Less.) Hieron in Uruguay. AB - Vernonia plantaginoides (Less.) Hieron, previously known as Vernonia squarrosa, is a rhizomatous subshrub with purple flowers that is prevalent in the natural grassland of Uruguay, Argentina, and southern Brazil. We report an outbreak of V. plantaginoides (yuyo moro) intoxication in sheep in Treinta y Tres Department, northeastern Uruguay. A total of 54 of 463 (12%) recently weaned lambs died 2-7 days after entering a natural pasture that had been invaded by sprouting V. plantaginoides The first cases were found dead. Affected lambs showed marked jaundice, edema of the face, ears, and eyelids, and severe photodermatitis. At the autopsies of 3 lambs, the carcass was yellow, the liver was enlarged with a marked acinar pattern ("nutmeg liver"), and hemorrhages were observed on serous membranes. Microscopic lesions were characterized by diffuse periacinar hepatocellular necrosis and cholemic nephrosis. Three female lambs were experimentally dosed with the aerial parts of V. plantaginoides collected immediately after the outbreak. The lamb that was dosed once with 40 g/kg body weight died after 36 h with severe hepatic necrosis. The lamb dosed with 20 g/kg daily for 4 days showed clinical signs and microscopic lesions in the liver with multiple apoptotic hepatocytes in the periacinar zone. The third lamb, dosed with 30, 17, and 15 g/kg daily over 3 days, respectively, showed transient clinical signs and a rise in liver enzymes, but recovered, and no lesions were found postmortem. These results demonstrate that V. plantaginoides was responsible for severe field outbreaks of poisoning in sheep in Uruguay. PMID- 27240571 TI - Optimized Chemical Separation and Measurement by TE TIMS Using Carburized Filaments for Uranium Isotope Ratio Measurements Applied to Plutonium Chronometry. AB - An optimized method is described for U/Pu separation and subsequent measurement of the amount contents of uranium isotopes by total evaporation (TE) TIMS with a double filament setup combined with filament carburization for age determination of plutonium samples. The use of carburized filaments improved the signal behavior for total evaporation TIMS measurements of uranium. Elevated uranium ion formation by passive heating during rhenium signal optimization at the start of the total evaporation measurement procedure was found to be a result from byproducts of the separation procedure deposited on the filament. This was avoided using carburized filaments. Hence, loss of sample before the actual TE data acquisition was prevented, and automated measurement sequences could be accomplished. Furthermore, separation of residual plutonium in the separated uranium fraction was achieved directly on the filament by use of the carburized filaments. Although the analytical approach was originally tailored to achieve reliable results only for the (238)Pu/(234)U, (239)Pu/(235)U, and (240)Pu/(236)U chronometers, the optimization of the procedure additionally allowed the use of the (242)Pu/(238)U isotope amount ratio as a highly sensitive indicator for residual uranium present in the sample, which is not of radiogenic origin. The sample preparation method described in this article has been successfully applied for the age determination of CRM NBS 947 and other sulfate and oxide plutonium samples. PMID- 27240572 TI - Structure of Light-Harvesting Aggregates in Individual Chlorosomes. AB - Among all photosynthetic organisms, green bacteria have evolved one of the most efficient light-harvesting antenna, the chlorosome, that contains hundreds of thousands of bacteriochlorophyll molecules, allowing these bacteria to grow photosynthetically by absorbing only a few photons per bacteriochlorophyll molecule per day. In contrast to other photosynthetic light-harvesting antenna systems, for which a protein scaffold imposes the proper positioning of the chromophores with respect to each other, in chlorosomes, this is accomplished solely by self-assembly. This has aroused enormous interest in the structure function relations of these assemblies, as they can serve as blueprints for artificial light harvesting systems. In spite of these efforts, conclusive structural information is not available yet, reflecting the sample heterogeneity inherent to the natural system. Here we combine mutagenesis, polarization resolved single-particle fluorescence-excitation spectroscopy, cryo-electron microscopy, and theoretical modeling to study the chlorosomes of the green sulfur bacterium Chlorobaculum tepidum. We demonstrate that only the combination of these techniques yields unambiguous information on the structure of the bacteriochlorophyll aggregates within the chlorosomes. Moreover, we provide a quantitative estimate of the curvature variation of these aggregates that explains ongoing debates concerning the chlorosome structure. PMID- 27240573 TI - Demographic and behavioral correlates of HIV/STI among Vietnamese female sex workers in southwest China. AB - Previous literature has suggested high rates of HIV/STIs among Chinese FSWs. However, limited data were available regarding HIV-related risks among Vietnamese FSWs - a rapidly increasing, vulnerable population in southwest China. The current study examined the demographic and behavioral factors associated with the infection rates of HIV, syphilis, and Hepatitis C (HCV) among Vietnamese FSWs in Guangxi, China. We conducted a secondary data analysis of a cumulative sample of 1026 Vietnamese FSWs (aged 14-66) recruited over five years (2010-2014) from 35 National Sentinel Surveillance sites in Guangxi. Analyses included Fisher's exact chi-square test, t-test, and binary logistic regression. The overall prevalence of HIV, syphilis, and HCV infections among the cross-border women were 3.2%, 6.9%, and 2.6%, respectively. Multivariate analysis showed that greater lengths of sex work and low paying work venues were significant risk factors for HIV infection; for syphilis infection, older age, drug use experience, and forgoing condom use were significant risk factors; for HCV infection, drug use experience was the only significant risk factor. Our findings suggest that elevated HIV related risks among the Vietnamese FSWs are closely related to their financial disadvantages and that drug use is a prominent risk factor for cross-border women in the sex trade. Furthermore, culturally tailored and linguistically accessible HIV prevention and intervention initiatives that target cross-border FSWs, with a close international collaboration between China and Vietnam, are urgently needed. PMID- 27240574 TI - Bone Formation is Affected by Matrix Advanced Glycation End Products (AGEs) In Vivo. AB - Advanced glycation end products (AGEs) accumulate in bone extracellular matrix as people age. Although previous evidence shows that the accumulation of AGEs in bone matrix may impose significant effects on bone cells, the effect of matrix AGEs on bone formation in vivo is still poorly understood. To address this issue, this study used a unique rat model with autograft implant to investigate the in vivo response of bone formation to matrix AGEs. Fluorochrome biomarkers were sequentially injected into rats to label the dynamic bone formation in the presence of elevated levels of matrix AGEs. After sacrificing animals, dynamic histomorphometry was performed to determine mineral apposition rate (MAR), mineralized surface per bone surface (MS/BS), and bone formation rate (BFR). Finally, nanoindentation tests were performed to assess mechanical properties of newly formed bone tissues. The results showed that MAR, MS/BS, and BFR were significantly reduced in the vicinity of implant cores with high concentration of matrix AGEs, suggesting that bone formation activities by osteoblasts were suppressed in the presence of elevated matrix AGEs. In addition, MAR and BFR were found to be dependent on the surrounding environment of implant cores (i.e., cortical or trabecular tissues). Moreover, MS/BS and BFR were also dependent on how far the implant cores were away from the growth plate. These observations suggest that the effect of matrix AGEs on bone formation is dependent on the biological milieu around the implants. Finally, nanoindentation test results indicated that the indentation modulus and hardness of newly formed bone tissues were not affected by the presence of elevated matrix AGEs. In summary, high concentration of matrix AGEs may slow down the bone formation process in vivo, while imposing little effects on bone mineralization. PMID- 27240585 TI - Predictors of independence in instrumental activities of daily living: Amnestic versus nonamnestic MCI. AB - INTRODUCTION: Individuals with mild cognitive impairment (MCI) demonstrate deficits in instrumental activities of daily living (IADL) that place them at high risk for progression to dementia. The cognitive profiles, IADL deficits, and risk of progression differ between MCI subgroups of amnestic (aMCI) and nonamnestic MCI (naMCI), though many studies of functional impairment have not examined these subgroups separately. This study aims to determine whether common neuropsychological measures, as well as the related concept of patient anosognosia, are associated with IADL functioning differently in aMCI compared to naMCI. METHOD: Seventy-one individuals were identified as naMCI, and 99 individuals were identified as aMCI based on neuropsychological evaluation. Controlling for age, gender, and education, we examined whether performance on neuropsychological tests predicted informant-rated IADL dysfunction. We also investigated the ability of patient awareness, as rated by clinicians and informants, to predict informant-rated IADL dysfunction within MCI subgroups. RESULTS: Better performance in cognitive domains of attention/processing speed and executive functioning predicted IADL independence in aMCI, but not in naMCI. Exploratory analysis with a subset of these individuals revealed that after accounting for an estimate of cerebrovascular burden, better performance in Delayed Memory predicted IADL independence in the naMCI group, but not in the aMCI group. Lastly, informant, but not clinician, ratings of patient awareness predicted IADL independence within the aMCI group only. CONCLUSION: Neuropsychological performance on tests of attention/processing speed and executive functioning may be better able to predict cognitive contributions to IADL dysfunction specifically in aMCI. After controlling for vascular burden, memory deficits may be the earliest cognitive indication of IADL dysfunction in naMCI. These results suggest that executive functions and memory, in addition to patient's awareness of deficits, differentially predict early IADL dysfunction in subgroups of MCI and can be used to formulate patient prognosis and recommendations on a more individualized basis. PMID- 27240586 TI - Cryopreservation of the edible alkalophilic cyanobacterium Arthrospira platensis. AB - Efficient cryopreservation conditions for the edible alkalophilic cyanobacterium Arthrospira (Spirulina) platensis were investigated using a model strain A. platensis NIES-39. As a result, it was found that more than 60% of cells were viable upon thawing, when they had been frozen at a cooling rate of approximately -1 degrees C min(-1) in the presence of 10% (v/v) dimethyl sulfoxide. Further examination with other Arthrospira strains showed that many of them had strain dependent optimal conditions for cryopreservation. For example, the best freezing conditions for A. platensis SAG 21.99 were snap-freezing in liquid nitrogen in the presence of 5% (v/v) dimethyl sulfoxide, while they were slow cooling at approximately -1 degrees C min(-1) in the presence of 10% (v/v) methanol for A. platensis NIES-46, NIES-2308 and UTEX 1926. The variety of successful cryopreservation conditions presented in this study is useful when attempting to cryopreserve various Arthrospira strains. PMID- 27240587 TI - Ring current shifts in (19)F-NMR of membrane proteins. AB - Fluorine-19 NMR markers are attractive reporter groups for use in studies of complex biomacromolecular systems, in particular also for studies of function related conformational equilibria and rate processes in membrane proteins. Advantages of (19)F-NMR probes include high sensitivity of the (19)F chemical shifts to variations in the non-covalent environment. Nonetheless, in studies of G protein-coupled receptors (GPCR) we encountered situations where (19)F chemical shifts were not responsive to conformational changes that had been implicated by other methods. This prompted us to examine possible effects of aromatic ring current fields on the chemical shifts of (19)F-NMR probes used in GPCRs. Analysis of previously reported (19)F-NMR data on the beta2-adrenergic receptor and mammalian rhodopsin showed that all (19)F-labeling sites which manifested conformational changes are located near aromatic residues. Although ring current effects are small when compared to other known non-covalent effects on (19)F chemical shifts, there is thus an indication that their contributions are significant when studying activation processes in GPCRs, since the observed activation-related (19)F-NMR chemical shifts are comparable in size to the calculated ring current shifts. Considering the impact of ring current shifts may thus be helpful in identifying promising indigenous or engineered labeling sites for future (19)F-NMR studies of GPCR activation, and novel information may be obtained on the nature of conformational rearrangements near the (19)F-labels. It will then also be interesting to see if the presently indicated role of ring current shifts in membrane protein studies with (19)F-NMR markers can be substantiated by a more extensive data base resulting from future studies. PMID- 27240588 TI - Variability and conservation of structural domains in divide-and-conquer approaches. AB - The use of protein building blocks for the structure determination of multidomain proteins and protein-protein complexes, also known as the "divide and conquer" approach, is an important strategy for obtaining protein structures. Atomic resolution X-ray or NMR data of the individual domains are combined with lower resolution electron microscopy maps or X-ray data of the full-length protein or the protein complex. Doing so, it is often assumed that the individual domain structures remain invariant in the context of the superstructure. In this work, we show the potentials and limitations of NMR to validate this approach at the example of the dodecameric DnaB helicase from Helicobacter pylori. We investigate how sequentially assigned spectra, as well as unassigned spectral fingerprints can be used to indicate the conservation of individual domains, and also to highlight conformational differences. PMID- 27240589 TI - Hepatic expression of inflammatory genes and microRNAs in pigs with high "cholesteryl ester transfer protein" (CETP) activity. AB - Human obesity and obesity-related diseases (ORD) are growing health problems worldwide and represent a major public health challenge. Most of these diseases are complex conditions, influenced by many genes (including microRNAs) and environmental factors. Many metabolic perturbations are associated with obesity; e.g., low levels of high-density lipoproteins (HDL) are high risk factors of cardiovascular events. A number of genetic, lifestyle, and environmental factors have been shown to contribute to the lowering of HDL-cholesterol. One of these factors is cholesteryl ester transfer protein (CETP) promoting the redistribution of cholesteryl esters, triglycerides, and phospholipids between plasma proteins. Moreover, obesity and ORD are often linked with chronic low-grade inflammation leading to insulin resistance and endothelial and microvascular dysfunctions. The aim of this study was to detect differences in the hepatic expression of genes involved in low-grade inflammation and of obesity- and cholesterol-related microRNAs in two mixed breed populations of pigs (Yorkshire-Gottingen minipig, YM and Duroc-Gottingen minipig, DM) including males and females, with extreme phenotypes for CETP activity levels (designated as CETP-high and CETP-low, respectively). Furthermore, breed and gender differences were also investigated. We found significant difference (P < 0.05) in hepatic expression levels of several mRNAs and microRNAs between the CETP-high and -low groups (C5, IL1RN, IL18, and miR-223-5p); between the two mixed breeds (IL1RAP and miR-140-5p); and between gender (APOA1, IL1RN, and FBLN1). Furthermore, when taking breed into account we show that the transcriptional levels of TNF, miR20a, miR33b, and miR130a differed between the two CETP groups. We conclude that increased CETP activity is accompanied by a modest differential hepatic expression of several microRNAs and inflammatory-related genes. Furthermore, our study demonstrates that when modeling the analysis of expression data, it is important to take gender- and breed-specific effects into account. PMID- 27240591 TI - S100A16 promotes cell proliferation and metastasis via AKT and ERK cell signaling pathways in human prostate cancer. AB - S100A16 is a member of the S100 calcium-binding protein family. It is overexpressed in many types of tumors and associated with proliferation, migration, and invasion; however, its function in human prostate cancer is unresolved. Our objective was to determine its effects and the underlying pathways of S100A16 in prostate cancer tissues and cells. We measured S100A16 expression by quantitative real-time polymerase and Western blotting in eight matched prostate cancer and adjacent normal tissues, and in three prostate cancer cell lines, DU-145, LNCaP, and PC-3, compared to a normal prostate epithelial cell line PrEC. DU-145 cells stably overexpressing S100A16 and PC-3 cells with S100A16 knockdown were established by transfection with S100A16 overexpression plasmid or shRNAs. Invasion, migration, and proliferation were analyzed by transwell assay, wound healing, and colony formation assays, respectively. Western blotting and invasion assays were performed to determine expressions and activation of AKT, ERK, p21, and p27. S100A16 was significantly overexpressed in both prostate cancer tissues and cells lines compared to normal controls (P < 0.05). Overexpression of S100A16 significantly promoted invasion, migration, and proliferation in prostate cancer cells in vitro, whereas silencing S100A16 showed the converse effects (P < 0.05). Furthermore, overexpression of S100A16 activated cell signaling proteins AKT and ERK and downregulated tumor suppressors p21 and p27. Specific inhibitors, LY294002 and PD98059, suppressed activation of AKT and ERK, which attenuated DU-145 cell clone formation and invasion induced by S100A16 overexpression. S100A16 may promote human prostate cancer progression via signaling pathways involving AKT, ERK, p21, and p27 downstream effectors. Our findings suggest that S100A16 may serve as a novel therapeutic or diagnostic target in human prostate cancer. PMID- 27240592 TI - Gene expression profile analysis in response to alpha1,2-fucosyl transferase (FUT1) gene transfection in epithelial ovarian carcinoma cells. AB - The aim of this study was to identify differentially expressed genes (DEGs) in response to alpha1,2-fucosyl transferase (FUT1) gene transfection in epithelial ovarian cancer cells. Human whole-genome oligonucleotide microarrays were used to determine whether gene expression profile may differentiate the epithelial ovarian cell line Caov-3 transfected with FUT1 from the empty plasmid-transfected cells. Quantitative real-time PCR and immunohistochemical staining validated the microarray results. Gene expression profile identified 215 DEGs according to the selection criteria, in which 122 genes were upregulated and 93 genes were downregulated. Gene Ontology (GO) and canonical pathway enrichment analysis were applied, and we found that these DEGs are involved in BioCarta mammalian target of rapamycin (mTOR) pathway, BioCarta eukaryotic translation initiation factor 4 (EIF4) pathway, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in cancer. Interaction network analysis predicted genes participating in the regulatory connection. Highly differential expression of TRIM46, PCF11, BCL6, PTEN, and FUT1 genes was validated by quantitative real-time PCR in two cell line samples. Finally, BCL6 and Lewis Y antigen were validated at the protein level by immunohistochemistry in 103 paraffin-embedded ovarian cancer tissues. The identification of genes in response to FUT1 may provide a theoretical basis for the investigations of the molecular mechanism of ovarian cancer. PMID- 27240590 TI - Caloric restriction: beneficial effects on brain aging and Alzheimer's disease. AB - Dietary interventions such as caloric restriction (CR) extend lifespan and health span. Recent data from animal and human studies indicate that CR slows down the aging process, benefits general health, and improves memory performance. Caloric restriction also retards and slows down the progression of different age-related diseases, such as Alzheimer's disease. However, the specific molecular basis of these effects remains unclear. A better understanding of the pathways underlying these effects could pave the way to novel preventive or therapeutic strategies. In this review, we will discuss the mechanisms and effects of CR on aging and Alzheimer's disease. A potential alternative to CR as a lifestyle modification is the use of CR mimetics. These compounds mimic the biochemical and functional effects of CR without the need to reduce energy intake. We discuss the effect of two of the most investigated mimetics, resveratrol and rapamycin, on aging and their potential as Alzheimer's disease therapeutics. However, additional research will be needed to determine the safety, efficacy, and usability of CR and its mimetics before a general recommendation can be proposed to implement them. PMID- 27240594 TI - Human ROBO1 regulates white matter structure in corpus callosum. AB - The axon guidance receptor, Robo1, controls the pathfinding of callosal axons in mice. To determine whether the orthologous ROBO1 gene is involved in callosal development also in humans, we studied polymorphisms in the ROBO1 gene and variation in the white matter structure in the corpus callosum using both structural magnetic resonance imaging and diffusion tensor magnetic resonance imaging. We found that five polymorphisms in the regulatory region of ROBO1 were associated with white matter density in the posterior part of the corpus callosum pathways. One of the polymorphisms, rs7631357, was also significantly associated with the probability of connections to the parietal cortical regions. Our results demonstrate that human ROBO1 may be involved in the regulation of the structure and connectivity of posterior part of corpus callosum. PMID- 27240593 TI - Repeated ozone exposure exacerbates insulin resistance and activates innate immune response in genetically susceptible mice. AB - BACKGROUND: Inhaled ozone (O3) has been demonstrated as a harmful pollutant and associated with chronic inflammatory diseases such as diabetes and vascular disorders. However, the underlying mechanisms by which O3 mediates harmful effects are poorly understood. OBJECTIVES: To investigate the effect of O3 exposure on glucose intolerance, immune activation and underlying mechanisms in a genetically susceptible mouse model. METHODS: Diabetes-prone KK mice were exposed to filtered air (FA), or O3 (0.5 ppm) for 13 consecutive weekdays (4 h/day). Insulin tolerance test (ITT) was performed following the last exposure. Plasma insulin, adiponectin, and leptin were measured by ELISA. Pathologic changes were examined by H&E and Oil-Red-O staining. Inflammatory responses were detected using flow cytometry and real-time PCR. RESULTS: KK mice exposed to O3 displayed an impaired insulin response. Plasma insulin and leptin levels were reduced in O3 exposed mice. Three-week exposure to O3 induced lung inflammation and increased monocytes/macrophages in both blood and visceral adipose tissue. Inflammatory monocytes/macrophages increased both systemically and locally. CD4 + T cell activation was also enhanced by the exposure of O3 although the relative percentage of CD4 + T cell decreased in blood and adipose tissue. Multiple inflammatory genes including CXCL-11, IFN-gamma, TNFalpha, IL-12, and iNOS were up-regulated in visceral adipose tissue. Furthermore, the expression of oxidative stress-related genes such as Cox4, Cox5a, Scd1, Nrf1, and Nrf2, increased in visceral adipose tissue of O3-exposed mice. CONCLUSIONS: Repeated O3 inhalation induces oxidative stress, adipose inflammation and insulin resistance. PMID- 27240595 TI - Erratum to: Combining the Optimized Yeast Cytosine Deaminase Protein Fragment Complementation Assay and an In Vitro Cdk1 Targeting Assay to Study the Regulation of the gamma-Tubulin Complex. PMID- 27240596 TI - [Genetically modified food and allergies - an update]. AB - Approval by the European Commission is mandatory for placing genetically modified plants as food or feed on the market in member states of the European Union (EU). The approval is preceded by a safety assessment based on the guidance of the European Food Safety Authority EFSA. The assessment of allergenicity of genetically modified plants and their newly expressed proteins is an integral part of this assessment process. Guidance documents for the assessment of allergenicity are currently under revision. For this purpose, an expert workshop was conducted in Brussels on June 17, 2015. There, methodological improvements for the assessment of coeliac disease-causing properties of proteins, as well as the use of complex models for in vitro digestion of proteins were discussed. Using such techniques a refinement of the current, proven system of allergenicity assessment of genetically modified plants can be achieved. PMID- 27240597 TI - [Allergen analysis]. AB - The fundamental requirement when testing for and ensuring compliance with legally required labelling regulations is the reliable analysis of food allergens. This can be carried out by means of either DNA (deoxyribonucleic acid) or protein detection. Protein detection has the advantage of directly detecting the allergenic component and can currently be carried out using immunological (enzyme linked immunosorbent assay [ELISA])/lateral flow devices [LFD]) or mass spectrometry-based techniques. DNA detection is indirect, but allows the presence of food allergens to be validated through the use of another marker. Each method has its pros and cons, which have to be considered on a case-by-case basis. ELISA is quantitative, quick and easy to carry out and has high sensitivity. LFD testing is ideal for industrial applications, as the tests can be carried out on site. Both antibody-based tests may have problems with processed foods and false positive results. Mass-spectrometric techniques show a lot of promise, but are currently still time-consuming and complex to carry out. They also run into problems with processed foods and their degree of sensitivity is matrix and parameter dependent. For these reasons, this technique is only occasionally used. Polymerase chain reaction (PCR) provides the highest specificity and, depending on the target sequence, a very good to good level of sensitivity. Despite the high stability of DNA, PCR is still subject to the influence of processing and matrix related factors. Due to natural variation and production-related changes in the structures relevant in the process of detection, all methods exhibit a relatively high level of uncertainty of measurement. At present, there is no method which provides the absolute correct quantification. However, by means of laboratory-based analyses it is possible to calibrate for the allergen in question and thus be able to make reliable measurements using methods that are already available. PMID- 27240598 TI - The 2015 French guidelines on alcohol misuse, issued in partnership with the European Federation of Addiction Societies: a focus on children and adolescents. PMID- 27240599 TI - Dilatation of the ascending aorta is associated with presence of aortic regurgitation in patients after repair of tetralogy of Fallot. AB - To evaluate the association between aortic morphology and elasticity with aortic regurgitation in surgically corrected of tetralogy of Fallot (TOF) patients. We retrospectively identified 72 consecutive patients with surgically corrected TOF and 27 healthy controls who underwent cardiac MRI evaluation. Velocity-encoded cine MRI was used to quantify degree of aortic regurgitation (AR) in TOF patients. Ascending aorta diameters were measured at standard levels on MRA images. Aortic pulse-wave velocity (PWV) was quantified with MRI. Morphological and functional MRI variables were compared between groups of TOF patients with and without clinically relevant AR and controls. The association between aortic morphology and elasticity with the presence of AR was evaluated using univariate and multivariate logistic regression. The majority of TOF patients had only trace AR. Nine TOF patients (12 %) had an AR fraction higher than 15 %. Indexed aorta diameter at the sinotubular junction (p = 0.007), at the RPA level (p = 0.006), and low left ventricular ejection fraction (LVEF) (p = 0.015) showed the strongest associations with the presence of at least mild AR, which persisted after controlling for age and gender. Increased ascending aorta dimension is associated with AR in patients after repair of TOF. LVEF was also low in the group of patients with relevant AR compared to those without, suggesting even mild to moderate AR may contribute to LV dysfunction in these patients. Enlarged ascending aorta may be an indication for precise quantification of regurgitant fraction with MRI, since symptomatic patients may need aortic valve repair when moderate regurgitation is present. PMID- 27240601 TI - Very early stage left ventricular endocardial dysfunction of patients with hypereosinophilic syndrome. AB - Cardiac involvement in hypereosinophilic syndrome (HES) patients entails significant morbidity and mortality. Left ventricular (LV) endocardial damage is important for the development of cardiac involvement in HES patients. However very early stage LV endocardial damage, such as prior to the first stage of an acute necrotic stage, remains uncertain. We studied 32 HES patients, all with normal conventional echocardiographic findings. Global radial and circumferential strain (GRS and GCS) were determined for each peak global strain curve from the mid-LV short-axis view, and global longitudinal strain (GLS) was averaged each peak global strain curve from standard apical views by means of two-dimensional speckle-tracking method. Thirty-one age-, gender-, LV ejection fraction-matched normal subjects were studied for comparison. GRS and GRS were similar for HES patients and normal controls, but GLS for HES patients was significantly lower than that for normal controls (16.2 +/- 3.3 % vs 19.3 +/- 2.9 %, p < 0.001). Furthermore, receiver operating characteristic curve analysis identified GLS <=17.0 % as the best predictor of LV endocardial dysfunction with a sensitivity of 66 %, specificity of 78 %, and area under the curve of 0.781 (p = 0.0001). In conclusions, LV endocardial dysfunction pre-existed even in HES patients without apparent cardiac involvement. GLS as assessed with the two-dimensional speckle tracking method is a promising tool for the better management of very early stage of HES patients. PMID- 27240600 TI - Pilot study for left ventricular imaging phenotype of patients over 65 years old with heart failure and preserved ejection fraction: the high prevalence of amyloid cardiomyopathy. AB - This study sought to phenotype patients over 65 years old with heart failure and preserved ejection fraction (HFpEF) using clinical available comprehensive cardiovascular imaging modalities. Forty-nine patients with HFpEF and without coronary artery disease underwent clinical evaluation, electrocardiography, echocardiography, cardiac magnetic resonance (CMR) and 99mTc-3,3-diphosphono-1,2 propanodicarboxylic acid scintigraphy (99mTc-DPD). The mean population age was 76 +/- 8 years. Most of the patients (53 %) were NYHA class II. Mean NT-Pro-NBNP level was 1961 +/- 2372 pg/ml. CMR exhibited a hypertrophic cardiomyopathy or infiltrative pattern in 3 (6 %) and 15 (31 %) patients, respectively. In the latter subgroup, 99mTc-DPD was suggestive of transthyretin-related cardiac amyloidosis for nine (18 %) patients, while AL amyloidosis was proven in five patients (10 %) by extracardiac (n = 3, 6 %) or endomyocardial (n = 2, 4 %) biopsies-one patient declined tissue biopsy. Compared to patients with unspecified cardiomyopathy (n = 31), patients with amyloid cardiomyopathy (n = 15 or n = 14/proven) had less hypertension, lower systolic blood pressure and higher NT-pro BNP level. Their electrocardiogram showed lowest QRS voltage and longer QRS duration. Left ventricular (LV) pattern was characterized by a more pronounced LV hypertrophy, a smaller ejection fraction and a decrease of global longitudinal strain associated with an increase of longitudinal strain apical-to basal ratio. In patients over 65 years, HFpEF is a heterogeneous syndrome with at least a 29 % prevalence of amyloid cardiomyopathy. Combined CMR and 99mTc-DPD are helpful imaging tools for accurate phenotyping of patients amenable to histopathological diagnosis or genetic testing, and should be considered for proper management of this population. Further longitudinal investigations are needed to better clarify these preliminary results. PMID- 27240602 TI - Derivation and validation of E/e' ratio as a parameter in the evaluation of left atrial appendage thrombus formation in patients with nonvalvular atrial fibrillation. AB - We sought to determine and prospectively validate, with concomitantly performed transthoracic (TTE) and transesophageal echocardiograms (TEE), a TTE-assessed E/e' threshold that can be useful in predicting left atrial appendage (LAA) thrombus in patients with nonvalvular atrial fibrillation (NVAF). The retrospective derivation cohort was comprised of 297 patients with NVAF with TTE performed within 1 year of TEE. The validation cohort was comprised of 266 prospectively enrolled patients with TTE performed immediately prior to TEE. LAA thrombus was detected by TEE in 6.4 % of patients in both cohorts. Receiver operating characteristic (ROC) analyses demonstrated a good discriminatory capacity of lateral E/e' in predicting LAA thrombus in the derivation cohort (AUC 0.72; CI 0.63-0.82; P = 0.001) which was confirmed in the validation cohort (AUC 0.83; CI 0.75-0.91; P < 0.001). In the derivation cohort, ROC curve point coordinates identified E/e' thresholds of both 9.0 and 8.0 to be associated with 100 % sensitivity, with specificities of 36 and 30 %, respectively. An E/e' threshold of >=8 was selected a priori for prospective validation, and was associated with 100 % sensitivity and 41 % specificity for LAA thrombus, with positive and negative predictive values of 10 and 100 %, respectively, and positive and negative likelihood ratios of 1.69 and 0, respectively. We determined and validated an E/e' threshold of 8 as a highly sensitive and useful parameter that can aid in identifying patients at very low risk for LAA thrombus and potentially obviate the need for a TEE prior to electrophysiology procedures and restoration of sinus rhythm. PMID- 27240604 TI - The burden of atopic dermatitis in US adults: results from the 2013 National Health and Wellness Survey. AB - OBJECTIVES: To characterize comorbidities, health-related quality-of-life (HRQoL), productivity, and healthcare resource use in adults with atopic dermatitis (AD) relative to those without AD, and to evaluate the impact of patient-reported AD severity on these outcomes. METHODS: Data were from the 2013 National Health and Wellness Survey (NHWS), which collected self-reported information on demographics, comorbidities, HRQoL (SF-36v2 Health Survey), productivity (Work Productivity and Impairment questionnaire [WPAI]), and healthcare utilization, which were weighted to the US general population. The AD cohort consisted of subjects who reported that they experienced AD within the past 12 months (n = 428), and the non-AD cohort included all subjects who did not report experiencing AD (n = 74,572); 366 AD subjects self-reported mild (n = 182) or moderate/severe (n = 184) disease. Univariable and multivariable analyses compared characteristics and outcomes between cohorts and between AD severity levels. RESULTS: The AD cohort was younger than non-AD cohort (44.3 vs. 46.6 years; P = 0.0033), and had a higher proportion of females (64.4% vs. 51.8%; P < 0.0001). Relative to the non-AD cohort, the AD cohort had a significantly higher prevalence of atopic conditions including nasal allergies (46.4% vs. 19.8%) and asthma (22.4% vs. 7.9%), and neuropsychiatric conditions such as anxiety (42.5% vs. 21.3%) and depression (37.2% vs. 20.9%) (all P < 0.0001). Units of resource use (healthcare practitioner visits, emergency room, hospitalizations) were higher (all P < 0.05) and HRQoL was poorer (P < 0.0001) with AD. On the WPAI, AD employees reported almost twice as much lost work productivity as non-AD employees (30.0% vs. 16.3%; P < 0.0001). No clear differences in outcomes were observed among patient-reported AD severity categories, except greater impairment of work productivity and daily activities in those with moderate/severe AD relative to mild. CONCLUSIONS: The significant burden associated with AD relative to those without AD suggests an unmet need for more effective management strategies. There also appears to be a need for further characterization of disease severity and its impact on HRQoL. PMID- 27240605 TI - Practices and outcomes of self-treatment with helminths based on physicians' observations. AB - The successful use of helminths as therapeutic agents to resolve inflammatory disease was first recorded 40 years ago. Subsequent work in animal models and in humans has demonstrated that the organisms might effectively treat a wide range of inflammatory diseases, including allergies, autoimmune disorders and inflammation-associated neuropsychiatric disorders. However, available information regarding the therapeutic uses and effects of helminths in humans is limited. This study probes the practices and experiences of individuals 'self treating' with helminths through the eyes of their physicians. Five physicians monitoring more than 700 self-treating patients were interviewed. The results strongly support previous indications that helminth therapy can effectively treat a wide range of allergies, autoimmune conditions and neuropsychiatric disorders, such as major depression and anxiety disorders. Approximately 57% of the self treating patients observed by physicians in the study had autism. Physicians reported that the majority of patients with autism and inflammation-associated co morbidities responded favourably to therapy with either of the two most popular organisms currently used by self-treaters, Hymenolepis diminuta and Trichuris suis. However, approximately 1% of paediatric patients experienced severe gastrointestinal pains with the use of H. diminuta, although the symptoms were resolved with an anti-helminthic drug. Further, exposure to helminths apparently did not affect the impaired comprehension of social situations that is the hallmark of autism. These observations point toward potential starting points for clinical trials, and provide further support for the importance of such trials and for concerted efforts aimed at probing the potential of helminths, and perhaps other biologicals, for therapeutic use. PMID- 27240603 TI - Analysis of compound heterozygotes reveals that the mouse floxed Pax6 (tm1Ued) allele produces abnormal eye phenotypes. AB - Analysis of abnormal phenotypes produced by different types of mutations has been crucial for our understanding of gene function. Some floxed alleles that retain a neomycin-resistance selection cassette (neo cassette) are not equivalent to wild type alleles and provide useful experimental resources. Pax6 is an important developmental gene and the aim of this study was to determine whether the floxed Pax6 (tm1Ued) (Pax6 (fl) ) allele, which has a retained neo cassette, produced any abnormal eye phenotypes that would imply that it differs from the wild-type allele. Homozygous Pax6 (fl/fl) and heterozygous Pax6 (fl/+) mice had no overt qualitative eye abnormalities but morphometric analysis showed that Pax6 (fl/fl) corneas tended be thicker and smaller in diameter. To aid identification of weak effects, we produced compound heterozygotes with the Pax6 (Sey-Neu) (Pax6 (-)) null allele. Pax6 (fl/-) compound heterozygotes had more severe eye abnormalities than Pax6 (+/-) heterozygotes, implying that Pax6 (fl) differs from the wild-type Pax6 (+) allele. Immunohistochemistry showed that the Pax6 (fl/-) corneal epithelium was positive for keratin 19 and negative for keratin 12, indicating that it was abnormally differentiated. This Pax6 (fl) allele provides a useful addition to the existing Pax6 allelic series and this study demonstrates the utility of using compound heterozygotes with null alleles to unmask cryptic effects of floxed alleles. PMID- 27240606 TI - Chicago Spring and ACC.16. PMID- 27240607 TI - Citius, Altius, Fortius: The impact of guide catheter extensions in contemporary percutaneous coronary intervention. PMID- 27240608 TI - Are catheter extension devices one step forward for complex coronary interventions? PMID- 27240609 TI - Wood units . m2 or Wood units/m2: does it matter? PMID- 27240610 TI - The role of protein Z and protein Z-dependent protease inhibitor polymorphisms in the development of prosthetic heart valve thrombosis. PMID- 27240611 TI - Psychological effects of treatment with novel oral anticoagulants in non-valvular atrial fibrillation patients. PMID- 27240612 TI - Author's Reply. PMID- 27240613 TI - Do spontaneous coronary artery dissections always need intervention in patients with no atherosclerosis? PMID- 27240614 TI - Author's Reply. PMID- 27240615 TI - Effects of cardiopulmonary bypass on new-onset atrial fibrillation. PMID- 27240616 TI - Author's Reply. PMID- 27240617 TI - Myocardial infarction in an 11-year-old child with systemic lupus erythematosus. PMID- 27240618 TI - Transcatheter closure of ruptured sinus of valsalva aneurysm using symmetrical perimembraneous VSD device. PMID- 27240619 TI - Partial detachment of tricuspid valve annuloplasty ring detected by three dimensional transesophageal echocardiography. PMID- 27240620 TI - Polarized Airway Epithelial Models for Immunological Co-Culture Studies. AB - Epithelial cells line all cavities and surfaces throughout the body and play a substantial role in maintaining tissue homeostasis. Asthma and other atopic diseases are increasing worldwide and allergic disorders are hypothesized to be a consequence of a combination of dysregulation of the epithelial response towards environmental antigens and genetic susceptibility, resulting in inflammation and T cell-derived immune responses. In vivo animal models have long been used to study immune homeostasis of the airways but are limited by species restriction and lack of exposure to a natural environment of both potential allergens and microflora. Limitations of these models prompt a need to develop new human cell based in vitro models. A variety of co-culture systems for modelling the respiratory epithelium exist and are available to the scientific community. The models have become increasingly sophisticated and specific care needs to be taken with regard to cell types, culture medium and culture models, depending on the aim of the study. Although great strides have been made, there is still a need for further optimization, and optimally also for standardization, in order for in vitro co-culture models to become powerful tools in the discovery of key molecules dictating immunity and/or tolerance, and for understanding the complex interplay that takes place between mucosa, airway epithelium and resident or infiltrating immune cells. This review focuses on current knowledge and the advantages and limitations of the different cell types and culture methods used in co-culture models of the human airways. PMID- 27240621 TI - Agricultural crop exposure and risk of childhood cancer: new findings from a case control study in Spain. AB - BACKGROUND: Childhood cancer is the main cause of disease-related death in children in Spain. Although little is known about the etiology, environmental factors are potential explanations for a fraction of the cases. Previous studies have shown pesticides to be associated with childhood cancer. The difficulty of collecting personal environmental exposure data is an important limitation; this lack of information about pesticides motivates the development of new methods to subrogate this exposure. We developed a crop exposure index based on geographic information to study the relationship between exposure to different types of crops and risk of childhood tumors. METHODS: We conducted a population-based case control study of childhood cancer covering 3350 cases and 20,365 controls in two Spanish regions. We used CORINE Land Cover to obtain data about agricultural land use. We created a 1 km buffer around every child and calculated the percentage of crop surface within the buffer (Global Crop Index) for total crops and for individual types of crops. We fitted mixed multiple unconditional logistic regression models by diagnostic group. RESULTS: We found excess of risk among children living in the proximity of crops. For total crops our results showed excesses of risk for almost all diagnostic groups and increasing risk with increasing crop index value. Analyses by region and individual type of crop also showed excess of risk. CONCLUSION: The results suggest that living in the proximity of cultivated land could be a risk factor for several types of cancer in children. PMID- 27240622 TI - Influence of Host-Plant Surface Chemicals on the Oviposition of the Cereal Stemborer Busseola Fusca. AB - The chemical composition of plant surfaces plays a role in selection of host plants by herbivorous insects. Once the insect reaches the plant, these cues determine host acceptance. Laboratory studies have shown that the stem borer Busseola fusca (Lepidoptera: Noctuidae), an important pest of sorghum and maize in sub-Saharan Africa, is able to differentiate between host and non-host plant species. However, no information is available on the cues used by this insect to seek and accept the host plant. Thus, the role of surface phytochemical stimuli on host selection and oviposition by B. fusca was studied in the laboratory using two host plants, sorghum, Sorghum bicolor, and maize, Zea mays, and one non-host plant, Napier grass, Pennisetum purpureum. The numbers of eggs and egg masses deposited on the three plant species were compared first under no-choice and choice conditions. In both cases, more eggs and egg masses were laid on maize and sorghum than on the non-host. Artificial surrogate stems treated with a water or chloroform surface extract of each plant were then compared with surrogate stems treated with, respectively, water or chloroform as controls, under similar conditions. Surrogate stems treated with plant water extracts did not show an increase in oviposition when compared to controls, indicating that the major compounds in these extracts, i.e., simple sugars and free amino acids, are not significantly responsible for the oviposition preference. By contrast, a chloroform extract of sorghum enhanced oviposition on the surrogate stems compared to the control, while those of maize and Napier grass showed no significant effects. Analysis of the chloroform extract of sorghum showed higher amounts of alpha-amyrin, beta-amyrin, and n-nonacosane compared to those of maize and Napier grass. A blend of the three chemicals significantly increased oviposition compared to the chloroform-treated control, indicating that these compounds are part of the surface chemical signature of the plant responsible for host recognition and oviposition by B. fusca. PMID- 27240623 TI - Carriers of genetic variants in the HNF1A gene are more common among dead opioid addicts than among living addicts. PMID- 27240624 TI - Chronic obstructive pulmonary disease and HIV: are we appropriately screening? AB - Individuals with human immunodeficiency virus (HIV) represent a population that is at a higher risk of developing chronic obstructive pulmonary disease (COPD). In this study, we sought to determine the effects of smoking on respiratory symptoms and diseases among HIV-positive patients and to determine if symptomatic patients are being appropriately screened for COPD. HIV-positive individuals completed a self-administered questionnaire. The effects of smoking on respiratory symptoms and diseases were reported as odds ratios (ORs). The COPD screening criteria were adapted from the Canadian Thoracic Society (CTS) guidelines. Two hundred and forty-seven participants were recruited. The median age was 49 years; 75% were male and 92% were on highly active antiretroviral therapy. Smokers represented 66% of the population. Smoking had a statistically significant effect on respiratory symptoms including wheeze (OR 4.8 [95% confidence interval (CI) 1.6-14.2]), phlegm production (OR 4.9 [95% CI: 2.2 10.5]), cough (OR 7.0 [95% CI: 3.0-16.2]), and dyspnea (OR 7.2 [95% CI: 1.7 31.2]). Smoking had a higher odds of respiratory diseases including COPD (OR 4.9 [95% CI: 1.1-21.9]) and bronchitis (OR 3.8 [95% CI: 1.9-7.7]). Among HIV-positive smokers, 40% met the CTS screening criteria, while only 12% self-reported a diagnosis of COPD. The burden of smoking in the HIV population is significant. HIV-positive smokers are more likely to report both respiratory symptoms and diseases than HIV-positive non-smokers. A discrepancy exists between patients who met the CTS screening criteria and those who were diagnosed with COPD, raising the concern for under-recognition and under-diagnosis of COPD in this population. PMID- 27240625 TI - Dissolved Organic Carbon in the North Atlantic Meridional Overturning Circulation. AB - The quantitative role of the Atlantic Meridional Overturning Circulation (AMOC) in dissolved organic carbon (DOC) export is evaluated by combining DOC measurements with observed water mass transports. In the eastern subpolar North Atlantic, both upper and lower limbs of the AMOC transport high-DOC waters. Deep water formation that connects the two limbs of the AMOC results in a high downward export of non-refractory DOC (197 Tg-C.yr(-1)). Subsequent remineralization in the lower limb of the AMOC, between subpolar and subtropical latitudes, consumes 72% of the DOC exported by the whole Atlantic Ocean. The contribution of DOC to the carbon sequestration in the North Atlantic Ocean (62 Tg-C.yr(-1)) is considerable and represents almost a third of the atmospheric CO2 uptake in the region. PMID- 27240633 TI - Imaging of transfection and intracellular release of intact, non-labeled DNA using fluorescent nanodiamonds. AB - Efficient delivery of stabilized nucleic acids (NAs) into cells and release of the NA payload are crucial points in the transfection process. Here we report on the fabrication of a nanoscopic cellular delivery carrier that is additionally combined with a label-free intracellular sensor device, based on biocompatible fluorescent nanodiamond particles. The sensing function is engineered into nanodiamonds by using nitrogen-vacancy color centers, providing stable non blinking luminescence. The device is used for monitoring NA transfection and the payload release in cells. The unpacking of NAs from a poly(ethyleneimine) terminated nanodiamond surface is monitored using the color shift of nitrogen vacancy centers in the diamond, which serve as a nanoscopic electric charge sensor. The proposed device innovates the strategies for NA imaging and delivery, by providing detection of the intracellular release of non-labeled NAs without affecting cellular processing of the NAs. Our system highlights the potential of nanodiamonds to act not merely as labels but also as non-toxic and non photobleachable fluorescent biosensors reporting complex molecular events. PMID- 27240634 TI - Synthesis, characterization, and reactivity of a side-on manganese(iii)-peroxo complex bearing a pentadentate aminopyridine ligand. AB - A manganese(ii) complex has been prepared with a proline-derived pentadentate ligand (Pro3Py), and it can be converted to a peroxomanganese(iii) complex in the presence of H2O2 and triethylamine. The resulting peroxomanganese(iii) complex was well characterised by UV-vis, EPR and ESI-MS techniques, and the geometric structure was discussed based on DFT calculations. PMID- 27240635 TI - [Erratum to: Does OCT morphology provide indications for prognosis of visual acuity after venous occlusion? : SD-OCT analysis in retinal vein occlusion before and after resolution of initial macular edema]. PMID- 27240636 TI - Dynamic changes of mononuclear phagocytes in circulating, pulmonary alveolar and interstitial compartments in a mouse model of experimental silicosis. AB - CONTEXT: Silicosis is a devastating, irreversible lung fibrosis condition exposed to crystalline silica. The mononuclear phagocyte system plays an important role in the pathogenesis of silicosis. OBJECTIVE: The present study was aimed to explore the dynamic changes of mononuclear phagocytes in circulating, pulmonary alveolar and interstitial compartments in experimental silicosis model. MATERIALS AND METHODS: A mouse model of lung fibrosis was developed with crystalline silica particles (2 mg/40 MUL via oropharyngeal instillation) using male C57BL/6 mice, and were killed on days 1, 3, 7, 14, and 28. The lung inflammation and fibrosis was investigated using hematoxylin-eosin staining and bronchoalveolar lavage fluid (BALF) analysis, Masson's trichrome staining, and immunofluorescence. Circulating monocyte subsets (Ly6C(hi) and Ly6C(lo)), polarization state of BALF derived alveolar macrophages (AMphi) and lung interstitial macrophages (IMphi, derived from enzymatically digested lung tissue) were analyzed by flow cytometry. RESULTS: The percentage of Ly6C(hi) monocytes significantly increased on day 1 after silica exposure, which reached the peak level from day 7 till day 28. Moreover, M2 (alternative activation) AMphi (PI - CD64 + CD206+) was dramatically and progressively increased from day 1 to day 28. A parallel increase in IMphi with M2 polarization (PI-CD64 + CD11b + CD206+) was also observed from day 1 to day 28. CONCLUSION: Our data demonstrate a dynamic view of mononuclear phagocyte change in three compartments after silica challenge, which highlights the remodeling of mononuclear phagocyte system as a potential therapeutic target for silicosis. PMID- 27240638 TI - Investigating the neurodevelopmental mediators of aggression in children with a history of child maltreatment:An exploratory field study. AB - Maltreatment of children is a chronic community problem that increases the risk of future aggression. Despite several decades of research highlighting this relationship, few studies have explored the potential neuropsychological deficits that are likely to mediate it. This exploratory study aimed to examine how child maltreatment may be associated with aggression via impairment in the developing prefrontal-limbic-autonomic pathways that are implicated in neuropsychological models of aggression. Furthermore, it aimed to investigate the relationship between child maltreatment and both reactive and proactive aggression subtypes. To investigate this non-invasively in an at-risk population, children with a documented protective care history (n = 20) and a community control group (n = 30), aged between 6 and 12 years, were compared on measures of cardiovascular functioning, affect regulation and cognitive functioning aligned with this neuropsychological model. Whilst no group differences were found on cardiovascular functioning (i.e., resting heart rate, heart rate reactivity, heart rate variability), the protective care group performed significantly worse on measures of affect regulation and cognitive functioning (i.e., global intelligence, executive functioning, smell identification and social cognition). The relationship between child maltreatment and aggression was mediated by executive dysfunction and affect dysregulation but not global IQ, social cognition or olfactory identification. The results suggest that interventions targeting aggression in maltreated children will benefit from clinical assessment and psychological strategies that address the executive dysfunction and affect dysregulation that has been associated with this clinical outcome. PMID- 27240637 TI - Fasting induces a subcutaneous-to-visceral fat switch mediated by microRNA-149-3p and suppression of PRDM16. AB - Visceral adiposity is strongly associated with metabolic disease risk, whereas subcutaneous adiposity is comparatively benign. However, their relative physiological importance in energy homeostasis remains unclear. Here, we show that after 24-h fasting, the subcutaneous adipose tissue of mice acquires key properties of visceral fat. During this fast-induced 'visceralization', upregulation of miR-149-3p directly targets PR domain containing 16 (PRDM16), a key coregulatory protein required for the 'browning' of white fat. In cultured inguinal preadipocytes, overexpression of miR-149-3p promotes a visceral-like switch during cell differentiation. Mice deficient in miR-149-3p display an increase in whole-body energy expenditure, with enhanced thermogenesis of inguinal fat. However, a visceral-like adipose phenotype is observed in inguinal depots overexpressing miR-149-3p. These results indicate that in addition to the capacity of 'browning' to defend against hypothermia during cold exposure, the subcutaneous adipose depot is also capable of 'whitening' to preserve energy during fasting, presumably to maintain energy balance, via miR-149-3p-mediated regulation of PRDM16. PMID- 27240639 TI - Oxidative stress-mediated selective antimicrobial ability of nano-VO2 against Gram-positive bacteria for environmental and biomedical applications. AB - Vanadium dioxide (VO2) is a unique thermochromic material as a result of its semiconductor-metal transition, holding great promise for energy-saving intelligent windows. Herein, pure nano-VO2 from discrete nanoparticles to continuous films were successfully deposited on quartz glass by controlling the sputtering parameters. It was demonstrated that, for Gram-positive S. aureus and S. epidermidis, the nano-VO2 could effectively disrupt bacteria morphology and membrane integrity, and eventually cause death. By contrast, the nano-VO2 did not exhibit significant toxicity towards Gram-negative E. coli and P. aeruginosa. To our knowledge, this is the first report on a selective antimicrobial effect of nano-VO2 materials on Gram-positive bacteria. Based on the experimental results, a plausible mechanism was proposed for the antimicrobial selectivity, which might originate from the different sensitivity of Gram-positive and Gram-negative bacteria to intracellular reactive oxygen species (ROS) level. Elevated intracellular ROS levels exceed the threshold that bacteria can self-regulate to maintain cellular redox homeostasis and thus cause oxidative stress, which can be alleviated by the intervention of glutathione (GSH) antioxidant. In addition, nano-VO2 did not produce significant cytotoxicity (hemolysis) against human erythrocytes within 12 h. Meanwhile, potential cytotoxicity against HIBEpiC revealed a time- and dose-dependent behavior that might be controlled and balanced by careful design. The findings in the present work may contribute to understanding the antimicrobial behavior of nano-VO2, and to expanding the new applications of VO2-based nanomaterials in environmental and biomedical fields. PMID- 27240641 TI - Length-dependent thermal transport in one-dimensional self-assembly of planar pi conjugated molecules. AB - This work reports a thermal transport study in quasi-one-dimensional organic nanostructures self-assembled from conjugated planar molecules via pi-pi interactions. Thermal resistances of single crystalline copper phthalocyanine (CuPc) and perylenetetracarboxylic diimide (PTCDI) nanoribbons are measured via a suspended thermal bridge method. We experimentally observed the deviation from the linear length dependence for the thermal resistance of single crystalline beta-phase CuPc nanoribbons, indicating possible subdiffusion thermal transport. Interestingly, a gradual transition to the linear length dependence is observed with the increase of the lateral dimensions of CuPc nanoribbons. The measured thermal resistance of single crystalline CuPc nanoribbons shows an increasing trend with temperature. However, the trend of temperature dependence of thermal resistance is reversed after electron irradiation, i.e., decreasing with temperature, indicating that the single crystalline CuPc nanoribbons become 'amorphous'. Similar behavior is also observed for PTCDI nanoribbons after electron irradiation, proving that the electron beam can induce amorphization of single crystalline self-assembled nanostructures of planar pi-conjugated molecules. The measured thermal resistance of the 'amorphous' CuPc nanoribbon demonstrates a roughly linear dependence on the nanoribbon length, suggesting that normal diffusion dominates thermal transport. PMID- 27240640 TI - Pcdh19 Loss-of-Function Increases Neuronal Migration In Vitro but is Dispensable for Brain Development in Mice. AB - Protocadherin 19 (Pcdh19) is an X-linked gene belonging to the protocadherin superfamily, whose members are predominantly expressed in the central nervous system and have been implicated in cell-cell adhesion, axon guidance and dendrite self-avoidance. Heterozygous loss-of-function mutations in humans result in the childhood epilepsy disorder PCDH19 Girls Clustering Epilepsy (PCDH19 GCE) indicating that PCDH19 is required for brain development. However, understanding PCDH19 function in vivo has proven challenging and has not been studied in mammalian models. Here, we validate a murine Pcdh19 null allele in which a beta Geo reporter cassette is expressed under the control of the endogenous promoter. Analysis of beta-Geo reporter activity revealed widespread but restricted expression of PCDH19 in embryonic, postnatal and adult brains. No gross morphological defects were identified in Pcdh19(+/beta-Geo) and Pcdh19(Y/beta Geo) brains and the location of Pcdh19 null cells was normal. However, in vitro migration assays revealed that the motility of Pcdh19 null neurons was significantly elevated, potentially contributing to pathogenesis in patients with PCDH19 mutations. Overall our initial characterization of Pcdh19(+/beta-Geo), Pcdh19(beta-Geo/beta-Geo) and Pcdh19(Y/beta-Geo)mice reveals that despite widespread expression of Pcdh19 in the CNS, and its role in human epilepsy, its function in mice is not essential for brain development. PMID- 27240642 TI - Ruthenium-tris(bipyridine) complexes with multiple redox-active amine substituents: tuning of spin density distribution and deep-red to NIR electrochromism and electrofluorochromism. AB - In response to the application of low electrochemical potentials, ruthenium tris(bipyridine) complexes decorated with multiple electron-rich and redox-active amine substituents show reversible absorption and emission spectral changes in the deep-red to NIR region. The number of amine substituents strongly affects the electrochemical and spectroscopic properties and the spin density distributions of the complex in the one-electron-oxidized state. PMID- 27240643 TI - Demethylation of Methylated Arsenic Species during Generation of Arsanes with Tetrahydridoborate(1-) in Acidic Media. AB - Demethylation during generation of volatile hydrides (HG), i.e. formation of noncorresponding arsanes from monomethylarsonic acid (MAs(V)), dimethylarsinic acid (DMAs(V)), and trimethylarsine oxide (TMAs(V)O) by the reaction of sodium tetrahydridoborate(1-) (THB) with different acids under analytical conditions, was investigated and characterized. Pronounced demethylation of MAs(V), DMAs(V), and TMAs(V)O was found during the reaction of THB with HCl, H2SO4, and HClO4, while HG from CH3COOH or TRIS buffer after prereduction with l-cysteine resulted in the formation of only the corresponding hydrides. In the case of HNO3 formation of corresponding hydrides was preserved for MAs(V) and DMAs(V) but not for TMAs(V)O. The extent of demethylation strongly depends on concentration of the acid and THB. It can be strongly suppressed in HCl medium by partial hydrolysis of THB with optimal concentration of acid before it reacts with MAs(V), DMAs(V), or TMAs(V)O. It appears that the demethylation is due to the action of specific hydrolytic products of THB (most probably by the first and second one). PMID- 27240644 TI - GC Preps: Fast and Easy Extraction of Stable Yeast Genomic DNA. AB - Existing yeast genomic DNA extraction methods are not ideally suited to extensive screening of colonies by PCR, due to being too lengthy, too laborious or yielding poor quality DNA and inconsistent results. We developed the GC prep method as a solution to this problem. Yeast cells from colonies or liquid cultures are lysed by vortex mixing with glass beads and then boiled in the presence of a metal chelating resin. In around 12 minutes, multiple samples can be processed to extract high yields of genomic DNA. These preparations perform as effectively in PCR screening as DNA purified by organic solvent methods, are stable for up to 1 year at room temperature and can be used as the template for PCR amplification of fragments of at least 8 kb. PMID- 27240646 TI - Cytogenetic alterations in human lymphocyte cultures following exposure to ofloxacin. AB - Ofloxacin (OFX), a second-generation of quinolones, is a broad-spectrum flouroquinolone antibiotic used in the treatment of various bacterial infections. In this article, we aimed to investigate the cytotoxic and genotoxic potentials of OFX in cultured human peripheral lymphocytes. The cytotoxicity and genotoxicity of OFX on human peripheral blood lymphocytes were examined in vitro by sister chromatid exchange (SCE), chromosomal aberrations (CAs) and micronucleus (MN) tests. Cultures were treated with 30, 60 and 120 MUg/ml of OFX for 48 h. Dimethylsulfoxide (DMSO) was used as a solvent control. OFX decreased the mitotic index (MI) and nuclear division index (NDI) significantly, especially at higher concentrations (60 and 120 MUg/ml) compared with solvent control. OFX significantly induced CAs at all concentrations and SCEs at higher concentrations (60 and 120 MUg/ml) compared with solvent control. In conclusion, our results indicated that OFX has cytotoxic, cytostatic and genotoxic potential especially at higher concentrations on human peripheral blood lymphocyte cultures under the experimental conditions. PMID- 27240645 TI - Contemporary insights into the pathogenesis and treatment of chronic myeloproliferative neoplasms. AB - This review is based on the deliberations at the 5th John Goldman Colloquium held in Estoril on 2nd October 2015 and the 9th post-ASH International Workshop on chronic myeloid leukemia (CML) and BCR-ABL1-negative myeloproliferative neoplasms (MPN) which took place on the 10th-11th December 2014, immediately following the 56th American Society of Hematology Annual Meeting. It has been updated since and summarizes the most recent advances in the biology and therapy of these diseases, in particular updates of genetics of MPN, novel insights from mouse MPN models, targeting CML stem cells and its niche; clinical advances include updates on JAK2 inhibitors and other therapeutic approaches to BCR-ABL1-negative MPNs, the use of alpha interferons, updates on tyrosine kinase inhibitors (TKI) randomized trials in CML, TKI cessation studies, and optimal monitoring strategies. PMID- 27240653 TI - Correction: An acid-free rechargeable battery based on PbSO4 and spinel LiMn2O4. AB - Correction for 'An acid-free rechargeable battery based on PbSO4 and spinel LiMn2O4' by Yu Liu et al., Chem. Commun., 2014, 50, 13714-13717. PMID- 27240652 TI - High seroprevalence of antibodies against Kaposi's sarcoma-associated herpesvirus (KSHV) among HIV-1-infected children and adolescents in a non-endemic population. AB - Human herpesvirus-8 (HHV-8) is the etiological agent of Kaposi's sarcoma (KS), which primarily affects human immunodeficiency virus (HIV)-infected adults with advanced immunodeficiency. Currently, only limited prevalence data for HHV-8 infection in HIV-infected children living in non-endemic areas are available. This multicenter cross-sectional study was conducted in four university hospitals in Germany specializing in pediatric HIV care. Stored serum specimens obtained from 207 vertically HIV-1-infected children and adolescents were tested for antibodies against lytic and latent HHV-8 antigens. Logistic regression was used to assess independent risk factors associated with HHV-8 seropositivity. The overall HHV-8 seroprevalence was 24.6 % (n = 51/207) without significant differences related to sex, age, or ethnicity. In univariate analysis, HHV-8 seropositivity was significantly associated with a child having being born outside Germany, maternal origin from sub-Saharan Africa, a history of breastfeeding, CDC immunologic category 3, and deferred initiation of antiretroviral therapy (>24 months of age). In multivariate analysis, a child's birth outside Germany was the only significant risk factor for HHV-8 seropositivity (odds ratio 3.98; 95 % confidence interval 1.27-12.42). HHV-8 associated malignancies were uncommon; only one patient had a history of KS. Serum specimen of vertically HIV-infected children and adolescents living in Germany showed a high HHV-8 seroprevalence. These findings suggest that primary HHV-8 infection-a risk factor for KS and other HHV-8-associated malignancies occurs early in life. Thus, management of perinatally HIV-infected children should include testing for HHV-8 coinfection and should consider future risks of HHV-8-associated malignancies. PMID- 27240654 TI - Mechanisms and energetics for N-glycosidic bond cleavage of protonated adenine nucleosides: N3 protonation induces base rotation and enhances N-glycosidic bond stability. AB - Our previous gas-phase infrared multiple photon dissociation action spectroscopy study of protonated 2'-deoxyadenosine and adenosine, [dAdo+H](+) and [Ado+H](+), found that both N3 and N1 protonated conformers are populated with the N3 protonated ground-state conformers predominant in the experiments. Therefore, N glycosidic bond dissociation mechanisms of N3 and N1 protonated [dAdo+H](+) and [Ado+H](+) and the associated quantitative thermochemical values are investigated here using both experimental and theoretical approaches. Threshold collision induced dissociation (TCID) of [dAdo+H](+) and [Ado+H](+) with Xe is studied using guided ion beam tandem mass spectrometry techniques. For both systems, N glycosidic bond cleavage reactions are observed as the major dissociation pathways resulting in production of protonated adenine or elimination of neutral adenine. Electronic structure calculations are performed at the B3LYP/6 311+G(d,p) level of theory to probe the potential energy surfaces (PESs) for N glycosidic bond cleavage of [dAdo+H](+) and [Ado+H](+). Relative energetics of the reactants, transition states, intermediates and products along the PESs for N glycosidic bond cleavage are determined at the B3LYP/6-311+G(2d,2p), B3LYP GD3BJ/6-311+G(2d,2p), and MP2(full)/6-311+G(2d,2p) levels of theory. The predicted N-glycosidic bond dissociation mechanisms for the N3 and N1 protonated species differ. Base rotation of the adenine residue enables formation of a strong N3H(+)O5' hydrogen-bonding interaction that stabilizes the N3 protonated species and its glycosidic bond. Comparison between experiment and theory indicates that the N3 protonated species determine the threshold energies, as excellent agreement between the measured and B3LYP computed activation energies (AEs) and reaction enthalpies (DeltaHrxns) for N-glycosidic bond cleavage of the N3 protonated species is found. PMID- 27240655 TI - How cracks are hot and cool: a burning issue for paper. AB - Material failure is accompanied by important heat exchange, with extremely high temperature - thousands of degrees - reached at crack tips. Such a temperature may subsequently alter the mechanical properties of stressed solids, and finally facilitate their rupture. Thermal runaway weakening processes could indeed explain stick-slip motions and even be responsible for deep earthquakes. Therefore, to better understand catastrophic rupture events, it appears crucial to establish an accurate energy budget of fracture propagation from a clear measure of various energy dissipation sources. In this work, combining analytical calculations and numerical simulations, we directly relate the temperature field around a moving crack tip to the part alpha of mechanical energy converted into heat. By monitoring the slow crack growth in paper sheets using an infrared camera, we measure a significant fraction alpha = 12% +/- 4%. Besides, we show that (self-generated) heat accumulation could weaken our samples by microfiber combustion, and lead to a fast crack/dynamic failure/regime. PMID- 27240656 TI - Sila-fulleranes: promising chemically active fullerene analogs. AB - Density-functional theory (DFT) was applied to investigate the geometry and electronic properties of bare Si60 and H-terminated Si-fullerene. DFT predicts outward sites on a bare Si60 cage. By using pi-orbital axis analysis (POAV), it is shown that these sites result from a strong tendency of silicon atoms to form sp(3) hybridization bonds. Natural bond orbital (NBO) analysis confirms the sp(3) hybridization nature of Si-Si bonds in Si-fulleranes. The quantum confinement effect (QCE) does not affect band gap (BG) so strongly in the size between 1 and 1.7 nm. In contrast, the geometry and symmetry of the cage have a significant influence on the BG. In contrast to their carbon analogs, pentagon rings increase the stability of the cages. Functionalized Si-cages are stable and can be chemically very active. The electronic properties are highly sensitive to the surface chemistry via functionalization with different chemical groups. As a result, BGs and chemical activities of these cages can be drastically tuned through the chemistry of the surface. PMID- 27240657 TI - Brain Stimulation in Addiction. AB - Localized stimulation of the human brain to treat neuropsychiatric disorders has been in place for over 20 years. Although these methods have been used to a greater extent for mood and movement disorders, recent work has explored brain stimulation methods as potential treatments for addiction. The rationale behind stimulation therapy in addiction involves reestablishing normal brain function in target regions in an effort to dampen addictive behaviors. In this review, we present the rationale and studies investigating brain stimulation in addiction, including transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation. Overall, these studies indicate that brain stimulation has an acute effect on craving for drugs and alcohol, but few studies have investigated the effect of brain stimulation on actual drug and alcohol use or relapse. Stimulation therapies may achieve their effect through direct or indirect modulation of brain regions involved in addiction, either acutely or through plastic changes in neuronal transmission. Although these mechanisms are not well understood, further identification of the underlying neurobiology of addiction and rigorous evaluation of brain stimulation methods has the potential for unlocking an effective, long-term treatment of addiction. PMID- 27240658 TI - Nucleus Accumbens Acetylcholine Receptors Modulate Dopamine and Motivation. AB - Environmental reward-predictive cues can motivate reward-seeking behaviors. Although this influence is normally adaptive, it can become maladaptive in disordered states, such as addiction. Dopamine release in the nucleus accumbens core (NAc) is known to mediate the motivational impact of reward-predictive cues, but little is known about how other neuromodulatory systems contribute to cue motivated behavior. Here, we examined the role of the NAc cholinergic receptor system in cue-motivated behavior using a Pavlovian-to-instrumental transfer task designed to assess the motivating influence of a reward-predictive cue over an independently-trained instrumental action. Disruption of NAc muscarinic acetylcholine receptor activity attenuated, whereas blockade of nicotinic receptors augmented cue-induced invigoration of reward seeking. We next examined a potential dopaminergic mechanism for this behavioral effect by combining fast scan cyclic voltammetry with local pharmacological acetylcholine receptor manipulation. The data show evidence of opposing modulation of cue-evoked dopamine release, with muscarinic and nicotinic receptor antagonists causing suppression and augmentation, respectively, consistent with the behavioral effects of these manipulations. In addition to demonstrating cholinergic modulation of naturally-evoked and behaviorally-relevant dopamine signaling, these data suggest that NAc cholinergic receptors may gate the expression of cue motivated behavior through modulation of phasic dopamine release. PMID- 27240659 TI - Incorporating Sex As a Biological Variable in Neuropsychiatric Research: Where Are We Now and Where Should We Be? AB - Understanding the multiplicity of ways in which sex can alter the brain is essential to crafting policies and treatments that are beneficial for all human beings. This is particularly true for the field of neuropsychopharmacology, as many neuropsychiatric disorders exhibit gender bias in the frequency, severity, or response to treatment. The goal of this circumspective is to provide two views on the current state of the art of the relations between sex and the brain, relations that are studied almost exclusively by comparing females and males on specific end points, from gene expression to behavior. We start by suggesting a framework for defining what is being measured and what it means. We suggest that 'sex differences' can be classified on four dimensions: (1) persistent vs transient across the lifespan; (2) context independent vs dependent; (3) dimorphic vs continuous; and (4) a direct vs an indirect consequence of sex. To accurately classify a sex difference along these dimensions, one may need to compare females and males under varied conditions. We next discuss current data on the mechanisms of sexual differentiation of the brain and on sex differences in the brain to conclude that the brain of each male and female is a mosaic of relative masculinization, feminization, and sameness, which theoretically could produce an infinite variety of individuals. We also raise the possibility that sex differences in the brain are canalized, which may act to both enhance and restrain variation between males and females. We end by discussing ways to consider sex when studying neuropsychiatric disorders. PMID- 27240660 TI - Soil fungal community development in a high Arctic glacier foreland follows a directional replacement model, with a mid-successional diversity maximum. AB - Directional replacement and directional non-replacement models are two alternative paradigms for community development in primary successional environments. The first model emphasizes turnover in species between early and late successional niches. The second emphasizes accumulation of additional diversity over time. To test whether the development of soil fungal communities in the foreland of an Arctic glacier conforms to either of these models, we collected samples from the Midtre Lovenbreen Glacier, Svalbard, along a soil successional series spanning >80 years. Soil DNA was extracted, and fungal ITS1 region was amplified and sequenced on an Illumina Miseq. There was a progressive change in community composition in the soil fungal community, with greatest fungal OTU richness in the Mid Stage (50-80 years). A nestedness analysis showed that the Early Stage (20-50 years) and the Late Stage (>80 years) fungal communities were nested within the Mid Stage communities. These results imply that fungal community development in this glacier succession follows a directional replacement model. Soil development processes may initially be important in facilitating arrival of additional fungal species, to give a mid successional diversity maximum that contains both early- and late-successional fungi. Competition may then decrease the overall diversity due to the loss of early successional species. PMID- 27240661 TI - Climate regulation, energy provisioning and water purification: Quantifying ecosystem service delivery of bioenergy willow grown on riparian buffer zones using life cycle assessment. AB - Whilst life cycle assessment (LCA) boundaries are expanded to account for negative indirect consequences of bioenergy such as indirect land use change (ILUC), ecosystem services such as water purification sometimes delivered by perennial bioenergy crops are typically neglected in LCA studies. Consequential LCA was applied to evaluate the significance of nutrient interception and retention on the environmental balance of unfertilised energy willow planted on 50-m riparian buffer strips and drainage filtration zones in the Skane region of Sweden. Excluding possible ILUC effects and considering oil heat substitution, strategically planted filter willow can achieve net global warming potential (GWP) and eutrophication potential (EP) savings of up to 11.9 Mg CO2e and 47 kg PO4e ha-1 year-1, respectively, compared with a GWP saving of 14.8 Mg CO2e ha-1 year-1 and an EP increase of 7 kg PO4e ha-1 year-1 for fertilised willow. Planting willow on appropriate buffer and filter zones throughout Skane could avoid 626 Mg year-1 PO4e nutrient loading to waters. PMID- 27240662 TI - Efficient Immobilization of Porcine Pancreatic alpha-Amylase on Amino Functionalized Magnetite Nanoparticles: Characterization and Stability Evaluation of the Immobilized Enzyme. AB - The potential of the modified magnetic nanoparticles for covalent immobilization of porcine pancreatic alpha-amylase has been investigated. The synthesis and immobilization processes were simple and fast. The co-precipitation method was used for synthesis of magnetic iron oxide (Fe3O4) nanoparticles (NPs) which were subsequently coated with silica through sol-gel reaction. The amino functionalized NPs were prepared by treating silica-coated NPs with 3 aminopropyltriethoxysilane followed by covalent immobilization of alpha-amylase by glutaraldehyde. The optimum enzyme concentration and incubation time for immobilization reaction were 150 mg and 4 h, respectively. Upon this immobilization, the alpha-amylase retained more than 50 % of its initial specific activity. The optimum pH for maximal catalytic activity of the immobilized enzyme was 6.5 at 45 degrees C. The kinetic studies on the immobilized enzyme and its free counterpart revealed an acceptable change of Km and Vmax. The Km values were found as 4 and 2.5 mM for free and immobilized enzymes, respectively. The Vmax values for the free and immobilized enzymes were calculated as 1.75 and 1.03 MUmol mg-1 min-1, in order, when starch was used as the substrate. A quick separation of immobilized amylase from reaction mixture was achieved when a magnetically active support was applied. In comparison to the free enzyme, the immobilized enzyme was thermally stable and was reusable for 9 cycles while retaining 68 % of its initial activity. PMID- 27240664 TI - Highly stereoselective cyclopropanation of diazo Weinreb amides catalyzed by chiral Ru(ii)-Amm-Pheox complexes. AB - The first highly stereoselective cyclopropanation of diazo Weinreb amides with olefins was accomplished using chiral Ru(ii)-Amm-Pheox complex to give the corresponding chiral cyclopropyl Weinreb amides in high yields (up to 99%) with excellent diastereoselectivities (up to 99 : 1 dr) and enantioselectivities (up to 96% ee). PMID- 27240663 TI - Effect of Vanadyl Rosiglitazone, a New Insulin-Mimetic Vanadium Complexes, on Glucose Homeostasis of Diabetic Mice. AB - Diabetes has been cited as the most challenging health problem in the twenty first century. Accordingly, it is urgent to develop a new type of efficient and low-toxic antidiabetic medication. Since vanadium compounds have insulin-mimetic and potential hypoglycemic activities for type 1 and type 2 diabetes, a new trend has been developed using vanadium and organic ligands to form a new compound in order to increase the intestinal absorption and reduce the toxicity of vanadium compound. In the current investigation, a new organic vanadium compounds, vanadyl rosiglitazone, was synthesized and determined by infrared spectra. Vanadyl rosiglitazone and three other organic vanadium compounds were administered to the diabetic mice through oral administration for 5 weeks. The results of mouse model test indicated that vanadyl rosiglitazone could regulate the blood glucose level and relieve the symptoms of polydipsia, polyphagia, polyuria, and weight loss without side effects and was more effective than the other three organic vanadium compounds including vanadyl trehalose, vanadyl metformin, and vanadyl quercetin. The study indicated that vanadyl rosiglitazone presents insulin-mimetic activities, and it will be a good potential candidate for the development of a new type of oral drug for type 2 diabetes. PMID- 27240665 TI - N-acetylcysteine in Cleistanthus collinus Poisoning: A Report of Two Cases in Children. AB - Cleistanthus collinus, also known as Oduvanthalai in Tamil, is the most commonly encountered plant poison in southern India. The leaves are used for poisoning humans (suicide or homicide) and animals (cattle and fish) and as an abortifacient, especially in rural south India. Although this poisoning is commonly reported in adults, data regarding the use of N-acetylcysteine in pediatric poisoning is lacking. We report two previously healthy male siblings of pediatric age group who ingested the liquid extracted from crushed leaves of this plant given to them by their mother as a means of deliberate harm. Both patients developed distal renal tubular acidosis, with hypokalemia. The younger sibling also developed myocardial toxicity. Other significant findings noted include hypocalcemia, hypomagnesemia and elevated liver enzymes. Both patients received supportive care along with N-acetylcysteine infusion, and showed complete recovery within 10 days. PMID- 27240666 TI - Development of the Lupus Interactive Navigator as an Empowering Web-Based eHealth Tool to Facilitate Lupus Management: Users Perspectives on Usability and Acceptability. AB - BACKGROUND: Systemic Lupus Erythematosus (SLE) is a serious, complex, and chronic illness. Similar to most other chronic illness states, there is great interest in helping persons with SLE engage in their disease management. OBJECTIVE: The objectives of this study were to (1) develop the Lupus Interactive Navigator (LIN), a web-based self-management program for persons with SLE, and (2) test the LIN for usability and acceptability. METHODS: The LIN development platform was based on the results of preliminary comprehensive needs assessments and adapted from the Oncology Interactive Navigator, a web-based tool developed for persons with cancer. Medical researchers, writers, designers, and programmers worked with clinical experts and persons with SLE to develop content for the LIN. Usability and acceptability of the LIN was tested on individuals with SLE meeting American College of Rheumatology criteria, who were recruited from five Canadian SLE clinics. Participants were provided with access to the LIN and were asked to use it over a two-week period. Following the testing period, participants were contacted for a 30-minute telephone interview to assess usability and acceptability. RESULTS: The content for the LIN was subdivided into six primary information topics with interview videos featuring rheumatologists, allied health professionals, and persons with SLE. Usability and acceptability of the LIN was tested on 43 females with SLE. Of these, 37 (86%) completed telephone interviews. The average age was 43.6 (SD 15.9) years and disease duration averaged 14.1 (SD 10.8) years. Median time spent on LIN was 16.3 (interquartile range [IQR]:13.7, 53.5) minutes and median number of sessions was 2 (IQR: 1, 3). Overall, Likert ratings (0=strongly disagree; 7=strongly agree) of website usability and content were very high, with 75% scoring >6 out of 7 on all items. All participants agreed that LIN was easy to use, would recommend it to others with SLE, and would refer to it for future questions about SLE. Very high ratings were also given to relevancy, credibility, and usefulness of the information provided. Overall, 73% of the participants rated all topics helpful to very helpful. Participants who reported more prior knowledge about SLE rated items regarding improvement in knowledge and helpfulness relatively lower than persons with less prior knowledge. Most participants commented that the LIN would be very useful to those newly diagnosed with SLE. Minor revisions were recommended. CONCLUSIONS: This study furthers the understanding of the needs in the SLE community and delivers a unique eHealth tool to promote self-management in persons with SLE. The LIN was found to be highly acceptable in content and usability. The information provided on LIN may be most helpful for individuals with less experience with the disease, such as those newly diagnosed, indicating the need to tailor the content for persons with more SLE experience. PMID- 27240668 TI - [Systemic treatments for psoriasis and psoriatic arthritis]. AB - Psoriasis is one of the most common chronic dermatoses. More than 25 % of the affected individuals require effective systemic treatment because of severe symptoms and/or the significantly restricted quality of life. Thanks to intensive research and successful cooperation between academia and the pharmaceutical industry, the options for treating psoriasis have dramatically increased in recent years. Especially targeted therapies give us the opportunity for personalized regimen. This review describes the spectrum of the systemic treatments for psoriasis and psoriatic arthritis and discusses the efficacy, safety, and particular features of the individual substances. PMID- 27240669 TI - [Multiple, black, burning papules on the soles of the feet of a 20-year-old woman]. PMID- 27240667 TI - [Pustular psoriasis]. AB - A number of pustular skin diseases share clinical, pathogenetic, and epidemiological aspects with plaque-type psoriasis, and their classification as a separate clinical entity or as a subtype of psoriasis remains controversial, which is also reflected in the multitude of their names. They include generalized pustular psoriasis with its subtypes, acrodermatitis continua suppurativa (Hallopeau), acute pustulosis palmopantaris, palmoplantar pustular psoriasis, and pustular variants of a mostly TNF-blocker triggered paradoxical psoriasiform dermatitis. In this article, the epidemiology, clinical picture, pathogenesis, genetics, and therapy of these pustular skin diseases are described. PMID- 27240670 TI - A high-molecular-weight, alkaline, and thermostable beta-1,4-xylanase of a subseafloor Microcella alkaliphila. AB - An endo beta-1,4-xylanase (XynE15) from a culture broth of a deep subseafloor microorganism, Microcella alkaliphila JAM-AC0309, was purified to homogeneity. The molecular mass of XynE15 was approximately 150 kDa as judged by SDS-PAGE. The optimal pH and temperature for hydrolysis of xylan were pH 8 and 65 degrees C. The enzyme was stable to incubation for 30 min at up to 75 degrees C, and the half-life at 50 degrees C was 48 h. XynE15 hydrolyzed arabinoxylan, oat spelt xylan, and birchwood xylan well, but not avicel, carboxymethylcellulose, or arabinan. Xylooligosaccharides were hydrolyzed to mainly xylobiose from higher than xylotetraose. The genome sequencing analysis of strain JAM-AC03039 revealed that XynE15 was composed of 1,319 amino acids with one catalytic domain and three carbohydrate-binding domains belonging to glycoside hydrolase (GH) family 10 and carbohydrate-binding module (CBM) family 4, respectively. PMID- 27240671 TI - Hyperthermostable Thermotoga maritima xylanase XYN10B shows high activity at high temperatures in the presence of biomass-dissolving hydrophilic ionic liquids. AB - The gene of Thermotoga maritima GH10 xylanase (TmXYN10B) was synthesised to study the extreme limits of this hyperthermostable enzyme at high temperatures in the presence of biomass-dissolving hydrophilic ionic liquids (ILs). TmXYN10B expressed from Pichia pastoris showed maximal activity at 100 degrees C and retained 92 % of maximal activity at 105 degrees C in a 30-min assay. Although the temperature optimum of activity was lowered by 1-ethyl-3-methylimidazolium acetate ([EMIM]OAc), TmXYN10B retained partial activity in 15-35 % hydrophilic ILs, even at 75-90 degrees C. TmXYN10B retained over 80 % of its activity at 90 degrees C in 15 % [EMIM]OAc and 15-25 % 1-ethyl-3-methylimidazolium dimethylphosphate ([EMIM]DMP) during 22-h reactions. [EMIM]OAc may rigidify the enzyme and lower V max. However, only minor changes in kinetic parameter K m showed that competitive inhibition by [EMIM]OAc of TmXYN10B is minimal. In conclusion, when extended enzymatic reactions under extreme conditions are required, TmXYN10B shows extraordinary potential. PMID- 27240672 TI - Diversity and distribution of cultured endolichenic fungi in the Ny-Alesund Region, Svalbard (High Arctic). AB - Endolichenic fungi within 17 lichen species in the area near Ny-Alesund (Svalbard, High Arctic) were studied by a culture-based method. The 247 fungal isolates were obtained from 2712 lichen thallus segments. The colonization rate of endolichenic fungi ranged from 1.6 to 26.5 %, respectively. These isolates were identified to 40 fungal taxa, including 35 Ascomycota (10 orders), 4 Basidiomycota (3 orders), and 1 unidentified fungus. Thelebolales was the most abundant order, while Sordariales were the most diverse order. The common fungal taxa shared by more than 3 lichen species were Thelebolus microsporus (93 isolates), Coniochaeta hoffmannii (7 isolates), Sarocladium kiliense (33 isolates), Coniochaeta sp. 1 (5 isolates), Coniochaeta sp. 4 (28 isolates), and Coniochaeta sp. 2 (5 isolates). Low Sorenson's similarity coefficients were observed among different lichen species, indicating that host-related factor may shape the endolichenic fungal communities in this region. In addition, no endolichenic fungal taxa were previously found in the Antarctica and Austrian Alps, suggesting endolichenic fungal communities in this region might be also shaped by the Arctic climate. The results demonstrate the existence of specific cultured endolichenic fungal species, which may be suitable objects for further study of their possible functional roles in the lichen thalli. PMID- 27240674 TI - Genetic and genomic dissection of Prolactin revealed potential association with milk production traits in riverine buffalo. AB - Milk yield and quality has been a major selection criterion for genetic improvement in livestock species. Role of Prolactin gene in determining milk quality in terms of protein profile, lactose, lipids and other imperative macromolecules is very important. In this context, genetic profiling of Prolactin gene in riverine buffalo of Pakistan was performed and potential genetic markers were identified illustrating worth of this gene in marker-assisted selection of superior dairy buffaloes. Series of wet and dry lab experimentation was performed starting with genomic DNA isolation from true to breed representatives of indigenous river buffalo (Nili-Ravi). After amplification of coding regions of Prolactin gene, products were eluted and sequenced by Sanger's chain termination method and aligned to get variations in genomic region. A total of 15 novel variations were identified and analyzed statistically for their significance at population level, haplotypes were constructed, and association was estimated. Phylogenetic analysis was performed to evaluate the rate of evolution for Prolactin gene in various mammalian species. Lastly, biological networking for this molecule was predicted to get the bigger pictorial of its functional machinery. Pathway analysis was performed to find its physiological mode of action in milk synthesis. This is a first report toward complete genetic screening of Prolactin gene in Pakistani buffaloes. Results of this study not only provide an insight for potential role of Prolactin gene in milk-producing abilities of buffalo but also suggest new directions for exploration of more genes that may have promising role to enhance future milk production capabilities of river buffalo breeds of Asian region through marker-assisted selection. PMID- 27240673 TI - Efficacy and Safety of the PCSK9 Inhibitor Evolocumab in Patients with Mixed Hyperlipidemia. AB - PURPOSE: Evolocumab significantly reduces low-density lipoprotein-cholesterol (LDL-C); we investigated its effects on LDL-C lowering in patients with mixed hyperlipidemia. METHODS: We compared the efficacy and safety of evolocumab in hypercholesterolemic patients selected from the phase 2 and 3 trials who had fasting triglyceride levels >=1.7 mmol/L (150 mg/dL elevated triglycerides) and <1.7 mmol/L (without elevated triglycerides). Fasting triglyceride level >= 4.5 mmol/L at screening was an exclusion criterion for these studies, but post enrollment triglyceride levels may have exceeded 4.5 mmol/L (400 mg/dL). Efficacy was evaluated in four phase 3 randomized studies (n = 1148) and safety from the phase 2 and 3 studies (n = 2246) and their open-label extension studies (n = 1698). Efficacy analyses were based on 12-week studies, while safety analyses included data from all available studies. Treatment differences were calculated vs. placebo and ezetimibe after pooling dose frequencies. RESULTS: Mean treatment difference in percentage change from baseline in LDL-C for participants with elevated triglycerides and those without elevated triglycerides (mean of weeks 10 and 12) with evolocumab was approximately -67 % vs. placebo and -42 % vs. ezetimibe (all P < 0.001) compared to -65 % vs. placebo and -39 % vs. ezetimibe, [corrected] respectively. Treatment differences for evolocumab vs. placebo and ezetimibe followed a similar pattern for non-high-density lipoprotein (HDL-C) and apolipoprotein B. Evolocumab was well tolerated, with balanced rates of adverse events leading to discontinuation of evolocumab vs. comparator (placebo and/or ezetimibe). CONCLUSION: The significant reductions of atherogenic lipids including LDL-C, non-HDL-C, and apolipoprotein B seen with evolocumab are similar in patients with and without mixed hyperlipidemia. PMID- 27240675 TI - Conspecific Interactions in Adult Laboratory Rodents: Friends or Foes? AB - Interactions between adult conspecifics, including sexual behaviors, affiliation, and aggression are crucial for the well-being, survival, and reproduction of mammals. This holds true for any mammalian species, but certainly for humans: An inability to optimally navigate the social system can have a strong negative impact on physical and mental health. Translational rodent models have been used for decades to unravel the neural pathways and substrates involved in normal and abnormal conspecific interactions. Researchers in the field of translational social neuroscience face a double challenge: Not only do they need to pay considerable attention to the behavioral ecology of their model species or their ancestors, they also have to expect a relatively large variability in behavior and adjust their experimental design accordingly. In this chapter, we will lay out traditional and novel rodent models and paradigms to study sexual, affiliative, and aggressive interactions among adult conspecifics. We will discuss the merits and main findings and briefly consider the most promising novel directions. Finally, we review the modulatory involvement of two major players in mammal social interaction: the central oxytocin and vasopressin system. PMID- 27240677 TI - The Need for Treatment Responsive Translational Biomarkers in Alcoholism Research. AB - Over the past two decades, major advances have been made in the basic neuroscience of alcohol addiction. However, few of these have been translated into clinically useful treatments, which remain limited. In the past decade, psychiatric drug development in general has been stalled, with many preclinically validated mechanisms failing in clinical development. Despite the existence of appealing preclinical models in the area of addictive disorders, drug development for these conditions has been impacted by the exodus of major pharma from psychiatric neuroscience. Here, we discuss translational biomarker strategies that may help turn this tide. Following an approach patterned on an endophenotype approach to complex behavioral traits, we hypothesize that relatively simple biological measures should be sought that can be obtained both in experimental animals and in humans, and that may be responsive to alcoholism medications. These biomarkers have to be tailored to the specific mechanism targeted by candidate medications and may in fact also help identify biologically more homogeneous subpopulations of patients. We introduce as examples alcohol-induced dopamine (DA) release, measures of central glutamate levels, and network connectivity, and discuss our experience to date with these biomarker strategies. PMID- 27240678 TI - Fatty acid profile in the seeds and seed tissues of Paeonia L. species as new oil plant resources. AB - Most common plant oils have little alpha-linolenic acid (C18:3(Delta9,12,15), ALA) and an unhealthy omega6/omega3 ratio. Here, fatty acids (FAs) in the seeds of 11 species of Paeonia L., including 10 tree peony and one herbaceous species, were explored using gas chromatograph-mass spectrometer. Results indicated that all Paeonia had a omega6/omega3 ratio less than 1.0, and high amounts of ALA (26.7-50%), oleic acid (C18:1(Delta9), OA) (20.8-46%) and linoleic acid (C18:2(Delta9,12), LA) (10-38%). ALA was a dominant component in oils of seven subsection Vaginatae species, whereas OA was predominant in two subsection Delavayanae species. LA was a subdominant oil component in P. ostii and P. obovata. Moreover, the FA composition and distribution of embryo (22 FAs), endosperm (14 FAs) and seed coat (6 FAs) in P. ostii, P. rockii and P. ludlowii were first reported. Peony species, particularly P. decomposita and P. rockii, can be excellent plant resources for edible oil because they provide abundant ALA to balance the omega6/omega3 ratio. The differences in the ALA, LA and OA content proportion also make the peony species a good system for detailed investigation of FA biosynthesis pathway and ALA accumulation. PMID- 27240679 TI - The work of negotiating HIV as a chronic condition: a qualitative analysis. AB - Living with human immunodeficiency virus (HIV) in the industrialised world has for over a decade been conceptualised as living with a chronic illness. People living with HIV now are amongst the first to live and age with the virus. Drawing on a qualitative longitudinal study in a low-incidence area in a low-incidence country, this paper investigates the nuanced ways that people negotiate this condition. While it has been argued that HIV is a condition like any other chronic disease, our thematic analysis reveals some similarities and particularities around living with the condition. In comparing themselves to others with the condition, high levels of diversity of experience were identified that extended well beyond length of time from diagnosis. In comparing their illness with other illnesses, the location, for example, of their specialist service within a clinic for those with acute sexually transmitted diseases was identified as problematic. The work involved in maintaining a coherent sense of self in the face of existing and shifting challenges as a result of their infection was a second strong theme. The final theme involved flux and flex work in the ways people sought to gain and maintain control over various aspects of their lives. All of these experiences are mediated by place; that is the experience is not the same as that of those who live where there is a much higher incidence of infection. The work involved in negotiating this condition in low incidence environments deserves more attention, but aspects of these findings are significant in higher incidence contexts as well; in particular, passivity in face of infection as one ages and the potential for medication refusal as a means of maintaining control over life and death. PMID- 27240676 TI - Translational Approaches Targeting Reconsolidation. AB - Maladaptive learned responses and memories contribute to psychiatric disorders that constitute a significant socio-economic burden. Primary treatment methods teach patients to inhibit maladaptive responses, but do not get rid of the memory itself, which explains why many patients experience a return of symptoms even after initially successful treatment. This highlights the need to discover more persistent and robust techniques to diminish maladaptive learned behaviours. One potentially promising approach is to alter the original memory, as opposed to inhibiting it, by targeting memory reconsolidation. Recent research shows that reactivating an old memory results in a period of memory flexibility and requires restorage, or reconsolidation, for the memory to persist. This reconsolidation period allows a window for modification of a specific old memory. Renewal of memory flexibility following reactivation holds great clinical potential as it enables targeting reconsolidation and changing of specific learned responses and memories that contribute to maladaptive mental states and behaviours. Here, we will review translational research on non-human animals, healthy human subjects, and clinical populations aimed at altering memories by targeting reconsolidation using biological treatments (electrical stimulation, noradrenergic antagonists) or behavioural interference (reactivation-extinction paradigm). Both approaches have been used successfully to modify aversive and appetitive memories, yet effectiveness in treating clinical populations has been limited. We will discuss that memory flexibility depends on the type of memory tested and the brain regions that underlie specific types of memory. Further, when and how we can most effectively reactivate a memory and induce flexibility is largely unclear. Finally, the development of drugs that can target reconsolidation and are safe for use in humans would optimize cross-species translations. Increasing the understanding of the mechanism and limitations of memory flexibility upon reactivation should help optimize efficacy of treatments for psychiatric patients. PMID- 27240680 TI - Coping strategies among patients newly diagnosed with diabetes or rheumatoid arthritis at baseline and after 24 months. AB - Patients aged 18-65 years with newly diagnosed diabetes mellitus ( n = 89) or rheumatoid arthritis ( n = 100) were studied by the General Coping Questionnaire at baseline and after 24 months. In total, 34 diabetes mellitus and 46 rheumatoid arthritis patients were diagnosed with psychosocial problems. The use of negative coping strategies, such as protest, isolation, and intrusion, was associated mostly with being classified as having psychosocial problems. With the risk of experiencing a strong impact of the disease at 2 years of follow-up as outcome, intrusion was a significant and independent risk factor, while minimization was a significant and independent protective factor. PMID- 27240681 TI - Advice to patients undergoing stem cell transplant: Content analysis of survivor peer support narratives. AB - Hematopoietic stem cell transplant survivors often share advice with patients undergoing this difficult treatment. We content analyzed narratives written by 59 transplant survivors given the opportunity to share advice with patients. Analyses described categories of advice they shared and evaluated their perceptions of the helpfulness of advice they had received. We found nine advice categories and evidence for variation in their perceived helpfulness, especially for advice to "be your own advocate," "have someone you can rely on," and "think positive." Findings suggest the need to investigate how seemingly innocuous advice can be unhelpful and potentially distressing to some patients. PMID- 27240692 TI - Ultralow power complementary inverter circuits using axially doped p- and n channel Si nanowire field effect transistors. AB - We have successfully synthesized axially doped p- and n-type regions on a single Si nanowire (NW). Diodes and complementary metal-oxide-semiconductor (CMOS) inverter devices using single axial p- and n-channel Si NW field-effect transistors (FETs) were fabricated. We show that the threshold voltages of both p and n-channel Si NW FETs can be lowered to nearly zero by effectively controlling the doping concentration. Because of the high performance of the p- and n-type Si NW channel FETs, especially with regard to the low threshold voltage, the fabricated NW CMOS inverters have a low operating voltage (<3 V) while maintaining a high voltage gain (~6) and ultralow static power dissipation (<=0.3 pW) at an input voltage of +/-3 V. This result offers a viable way for the fabrication of a high-performance high-density logic circuit using a low temperature fabrication process, which makes it suitable for flexible electronics. PMID- 27240693 TI - Should metabolic evaluation be performed in patients with struvite stones? AB - Previous studies suggested that patients with pure struvite calculi rarely have underlying metabolic abnormalities. Therefore, most of these patients do not undergo metabolic studies. We report our experience with these patients and their response to directed medical therapy. Between 1/2005 and 9/2012, 75 patients treated with percutaneous nephrolithotomy for struvite stones were identified. Of these, 7 had pure struvite stones (Group 1), 32 had mixed struvite stones (Group 2), both with metabolic evaluation, and 17 had pure struvite stones without metabolic evaluation (Group 3). The frequency of metabolic abnormalities and stone activity (defined as stone growth or stone-related events) was compared between groups. The median age was 55 years and 64 % were female. No significant difference in race, infection history, family history, stone location or volume existed between groups. Metabolic abnormalities were found in 57 % of Group 1 and 81 % of Group 2 patients. A similar proportion of Group 1 and 2 patients received modification to or continuation of metabolic therapy, whereas no Group 3 patients received any directed therapy. In patients with >6 months follow-up, the stone activity rate between Groups 1 and 2 appeared similar whereas Group 3 trended towards higher stone activity rate. Metabolic abnormalities in pure struvite stone formers appear to be more common than previously reported. Directed medical therapy in these patients may reduce stone activity. The role of metabolic evaluation and directed medical therapy needs reconsideration in patients with pure struvite stones. PMID- 27240694 TI - Synthesis and Characterization of New Fluorinated Tetrazines Displaying a High Fluorescence Yield. AB - Following the case of tetrazines substituted with perfluorinated alkyl chains, separated by two methylene groups from the tetrazine core, a new series of analogous tetrazines, but featuring only one methylene group between the fluorescent core and the perfluorinated chain, have been synthesized, and their photo-physical properties investigated. Their fluorescence quantum yields in acetonitrile are in same range than chloroalkoxytetrazines, which make them interesting candidates for light emission. Surprisingly, the quantum yields are lower with one methylene group, rather than two methylene groups separating the fluorinated chain from the emitting core, in the case of unsymmetrical compounds, while they are superior in the case of symmetrical ones. This unusual observation is discussed in the article. PMID- 27240695 TI - Examining the psychosocial determinants of women's decisions to delay childbearing. AB - STUDY QUESTION: What are the psychosocial determinants of women's intentions to delay childbearing until after 35 years? SUMMARY ANSWER: Attitudes, pressure from important others, perceived self-confidence and anticipated regret all influence the decision-making process of women aged 18-30 years to defer their attempts to conceive their first child until 35+ years. WHAT IS KNOWN ALREADY: Research has consistently demonstrated that, for many women, the decision to delay childbearing can lead to 'unintentional childlessness' due to a failure to consider the impact of age-related fertility decline. A large body of literature has also found strong links between age-related involuntary infertility and negative psychological impacts, including an increased prevalence of anxiety, depression, guilt, stigma and poor mental health. STUDY DESIGN, SIZE, DURATION: The study initially conducted focus groups designed to ascertain important beliefs informing participants' intentions to delay childbearing. A subsequent larger-scale quantitative questionnaire followed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants (n = 358) were female, aged between 18 and 30 years, lived in Australia, identified as being open to the idea of having children, were heterosexual, had not already had children, were not already pregnant, and had not received a diagnosis of medical infertility prior to participating. MAIN RESULTS AND THE ROLE OF CHANCE: Hierarchical multiple regression analyses showed strong support for psychosocial predictors of attitude, pressure from others and perceived self-confidence as predictors of women's intentions to delay childbearing, accounting for 59% of total variance. The extended model that included anticipated regret, accounted for a significant additional 4.4% variance in intention to delay childbearing past the age of 35 years. LIMITATIONS, REASONS FOR CAUTION: Proportionally more participants were younger, Caucasian, and were university students, thus limiting the generalizability of results to the wider Australian community. Future research in this domain is recommended to adopt a prospective design and incorporate a measure of behaviour to investigate the link between intentions to delay childbearing and future fertility behaviour. WIDER IMPLICATIONS OF THE FINDINGS: This research augments our understanding of the decision-making process and key beliefs underlying the decision to delay childbearing. Further efforts are needed to advise young women to investigate their fertility options during the peak of their reproductive years in order to prevent negative psychological consequences associated with unintentional childlessness. STUDY FUNDING/COMPETING INTERESTS: None. PMID- 27240696 TI - The impact of tinnitus upon cognition in adults: A systematic review. AB - OBJECTIVE: To systematically review and analyse experimental outcomes of studies exploring the impact of tinnitus upon cognitive function and their implications for clinical management of invasive tinnitus. DESIGN: A systematic and descriptive review. STUDY SAMPLE: Eighteen studies were identified investigating the impact of tinnitus on cognitive function. RESULTS: The 18 studies evaluated cognitive function using 24 different objective behavioural tests, nine electrophysiological recordings, one oculomotor test, and one self-report questionnaire. The studies spanned 18 years and revealed numerous interactions potentially contributing to the cognitive difficulties frequently reported by people with invasive tinnitus. The studies indicate a clear association between tinnitus and aspects of cognitive function, specifically the executive control of attention. CONCLUSIONS: Tinnitus impairs cognitive function by way of impact upon executive control of attention. Clinical management of patients reporting tinnitus and cognitive difficulties requires an understanding of the reciprocal relationship between tinnitus and cognitive function, with additive effects of anxiety, depression, and somatic cognitive bias. Further study is required to establish the impact of advancing age, hearing loss, anxiety, depression tinnitus duration, and distress upon cognitive function in people with invasive tinnitus. PMID- 27240697 TI - Mining 3D genome structure populations identifies major factors governing the stability of regulatory communities. AB - Three-dimensional (3D) genome structures vary from cell to cell even in an isogenic sample. Unlike protein structures, genome structures are highly plastic, posing a significant challenge for structure-function mapping. Here we report an approach to comprehensively identify 3D chromatin clusters that each occurs frequently across a population of genome structures, either deconvoluted from ensemble-averaged Hi-C data or from a collection of single-cell Hi-C data. Applying our method to a population of genome structures (at the macrodomain resolution) of lymphoblastoid cells, we identify an atlas of stable inter chromosomal chromatin clusters. A large number of these clusters are enriched in binding of specific regulatory factors and are therefore defined as 'Regulatory Communities.' We reveal two major factors, centromere clustering and transcription factor binding, which significantly stabilize such communities. Finally, we show that the regulatory communities differ substantially from cell to cell, indicating that expression variability could be impacted by genome structures. PMID- 27240698 TI - Nailed It: Conservative Management of Penetrating Injury and Potential Infection of a Cardiovascular Implantable Electronic Device. AB - A 47-year-old man with a history of ischemic cardiomyopathy and chronic systolic heart failure presented after he inadvertently shot himself in the left upper chest with a pneumatic nail gun, penetrating his implantable cardioverter defibrillator (ICD) generator. The device was noninterrogable, consistent with device failure. A new ICD was attached to the existing right ventricular lead, which showed no evidence of traumatic damage and normal lead parameters on interrogation. Aggressive debridement and antibiotic irrigation of the ICD pocket was performed and an antibacterial envelope was used. Bacterial culture of the ICD pocket grew Bacillus species. The patient completed a course of at least 14 days of oral clindamycin. At follow-up, there were no signs or symptoms of systemic or local wound infection. PMID- 27240699 TI - Response to Bodin and Grote regarding postdoctoral recruitment in clinical neuropsychology. AB - Bodin and Grote convey their opinion that the field of clinical neuropsychology would be best served by a match system for recruitment into postdoctoral training. We critically review their arguments and offer an alternative point of view. Our view considers the current state of the match system in neuropsychology, incorporates comparisons with other disciplines that rely on a match system, and addresses the role of postdoctoral training and the specialization that takes shape at this level. We make recommendations aimed at promoting greater unity among postdoctoral training programs with the goal of focusing leadership efforts on advancing our shared mission of providing the highest quality training in clinical neuropsychology. PMID- 27240700 TI - Comparison of the incidence of osteoradionecrosis with conventional radiotherapy and intensity-modulated radiotherapy. AB - BACKGROUND: Modern techniques of radiotherapy are supposed to decrease the incidence of osteoradionecrosis of the mandible (ORNM). The purpose of this study was to compare the incidence of ORNM after intensity-modulated radiotherapy (IMRT) in comparison to conventional 3D conformal radiotherapy techniques (conventional RT). METHODS: We conducted a retrospective study of consecutive unselected patients treated in a single institution between 2002 and 2012. To minimize confounding effects, only patients with oropharyngeal carcinoma without surgery of the primary site were included. RESULTS: The cohorts included 145 patients in the conventional RT group and 89 patients in the IMRT group. Total incidence rate of ORNM was similar for both groups with rates of 11% versus 10% (n = 16 for conventional RT and n = 9 for IMRT; p = 1.0). Subanalysis revealed more ORNM in T4 classified lesions with IMRT (p = .007). Analysis of different risk factors showed no statistically significant difference between ORNM and no ORNM patients. CONCLUSION: We found no reduction in ORNM with IMRT. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: 1708-1716, 2016. PMID- 27240701 TI - Effects on the reproductive parameters of two generations of Rattus norvegicus offspring from dams exposed to heptachlor during gestation and lactation. AB - Heptachlor has been targeted for global elimination because of its toxicity and environmental persistence, in accordance with the Stockholm Convention on Persistent Organic Pollutants (POPs). However, there is no regulation of heptachlor use in Mexico, where relatively high levels have been found in maternal breast milk. The aim of this study was to determine the effects of heptachlor on the reproductive system of offspring of two consecutive generations of rats (F1 and F2) from dams orally administered heptachlor during midgestation and lactation. Female offspring were analyzed for different phenotypic, reproductive, and molecular parameters. In the F1 generation, heptachlor treatment induced decreased body weight at weaning, increased female anogenital distance, and delayed vaginal opening. In both generations, serum progesterone levels decreased and estradiol levels remained unchanged, while overexpression of the progesterone receptor was observed in uterine epithelial cells on estrus day. In the F2 generation, expression of the estrogen receptor alpha increased in the glandular epithelium. Finally, heptachlor treatment did not affect apoptosis in the uterine epithelial cells. Overall, the results indicate that heptachlor induced female reproductive alterations when administered to dams during the perinatal period. Accordingly, exposure to heptachlor may represent a risk for the reproductive health of humans. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 856-868, 2017. PMID- 27240703 TI - Chemical consequences of pyrazole orientation in Ru(II) complexes of unsymmetric quinoline-pyrazole ligands. AB - A series of homoleptic Ru(II) complexes including the tris-bidentate complexes of a new bidentate ligand 8-(1-pyrazol)-quinoline (Q1Pz) and bidentate 8-(3-pyrazol) quinoline (Q3PzH), as well as the bis-tridentate complex of bis(quinolinyl)-1,3 pyrazole (DQPz) was studied. Together these complexes explore the orientation of the pyrazole relative to the quinoline. By examining the complexes structurally, photophysically, photochemically, electrochemically, and computationally by DFT and TD-DFT, it is shown that the pyrazole orientation has a significant influence on key properties. In particular, its orientation has noticeable effects on oxidation and reduction potentials, photostability and proton sensitivity, indicating that [Ru(Q3PzH)3](2+) is a particularly good local environment acidity probe candidate. PMID- 27240702 TI - Clinical and radiographic delineation of Bent Bone Dysplasia-FGFR2 type or Bent Bone Dysplasia with Distinctive Clavicles and Angel-shaped Phalanges. AB - Bent Bone Dysplasia-FGFR2 type is a relatively recently described bent bone phenotype with diagnostic clinical, radiographic, and molecular characteristics. Here we report on 11 individuals, including the original four patients plus seven new individuals with three longer-term survivors. The prenatal phenotype included stillbirth, bending of the femora, and a high incidence of polyhydramnios, prematurity, and perinatal death in three of 11 patients in the series. The survivors presented with characteristic radiographic findings that were observed among those with lethality, including bent bones, distinctive (moustache-shaped) small clavicles, angel-shaped metacarpals and phalanges, poor mineralization of the calvarium, and craniosynostosis. Craniofacial abnormalities, hirsutism, hepatic abnormalities, and genitourinary abnormalities were noted as well. Longer term survivors all needed ventilator support. Heterozygosity for mutations in the gene that encodes Fibroblast Growth Factor Receptor 2 (FGFR2) was identified in the nine individuals with available DNA. Description of these patients expands the prenatal and postnatal findings of Bent Bone Dysplasia-FGFR2 type and adds to the phenotypic spectrum among all FGFR2 disorders. (c) 2016 Wiley Periodicals, Inc. PMID- 27240704 TI - Clofarabine as a bridge to hematopoietic stem cell transplant. PMID- 27240705 TI - What factors influence healthy aging? A person-centered approach among older adults in Taiwan. AB - AIM: The present study aimed to identify the health profiles of older adults by using latent class analysis to investigate health heterogeneity and to determine what factors predicted healthy aging among an oldest-old sample cohort that was followed up for 14 years in Taiwan. METHODS: Data were drawn from five waves (carried out in 1993, 1996, 1999, 2003 and 2007) of the Taiwan Longitudinal Study on Aging to examine the changes in health heterogeneity in a nationally representative oldest-old cohort of Taiwanese. Overall, data from a total of 11 145 observations of 3155 older adults were considered. The influential factors predicting health changes were analyzed by using a generalized estimating equation. RESULTS: The results showed that four health profiles were identified among the aging population observed in the Taiwan Longitudinal Study on Aging. With increasing age, the combined effects of the physical functioning, cognitive and emotional health, and comorbidities of older adults significantly impact their health changes. Apart from health deteriorating with age and sex disparities, educational and economic status, health behaviors, and social participation at the individual level were found to be the robust factors in predicting healthy aging. CONCLUSIONS: In considering what factors impact healthy aging, we suggest that a person-centered approach would be useful and critical for policy makers to understand the compositions of health profiles and the influencing factors in view of a life-course perspective. Based on the factors identified as influencing healthy aging at the individual level, it is imperative from a policy-making perspective to maximize opportunities for healthy aging. Geriatr Gerontol Int 2017; 17: 697-707. PMID- 27240706 TI - Identification and characterization of ovary development-related protein EJO1 (Eri s 2) from the ovary of Eriocheir sinensis as a new food allergen. AB - SCOPE: Crab is a major source of shellfish allergens. Most studies have focused on allergens in crab muscle (CM) rather than on allergens in crab ovary (CO). This study aimed to identify potential allergens in CO from Eriocheir sinensis. METHODS AND RESULTS: Dot blot and immunoblotting results revealed the differential reactivity of CM and CO extracts to positive sera from patients allergic to crabs. Four CO proteins showed good specific IgE-binding activities in 2-DE/immunoblotting analysis; mass spectrometry identified the proteins as hemocyanin, vitellogenin, ovary development-related protein EJO1and EJO2. The recently identified allergen EJO1 is named 'Eri s 2' in the World Health Organization and International Union of Immunological Societies (WHO/IUIS) allergen nomenclature database. Recombinant Eri s 2 exhibited good reactivity to positive sera, and pre-incubation with recombinant Eri s 2 abrogated the reactivity of positive sera from two patients to CO in a dose-dependent manner. Moreover, co-incubation of recombinant Eri s 2 with patient basophils dose dependently promoted basophil activation, confirming the biological activity of Eri s 2. CONCLUSION: CO tissue is an important allergen source, and Eri s 2 is a new crab allergen. This study provides insights that will be useful for component resolved diagnostics for crab allergy. PMID- 27240707 TI - Endophytic coming out: the expressorium as a novel fungal structure specialized in outward-directed penetration of the leaf cuticle. PMID- 27240708 TI - Local adaptation or foreign advantage? Effective use of a single-test site common garden to evaluate adaptation across ecological scales. PMID- 27240709 TI - Seeing is believing: cell biology at the plant-microbe interface. PMID- 27240711 TI - Corrigendum. PMID- 27240710 TI - PIN6 auxin transporter at endoplasmic reticulum and plasma membrane mediates auxin homeostasis and organogenesis in Arabidopsis. AB - Plant development mediated by the phytohormone auxin depends on tightly controlled cellular auxin levels at its target tissue that are largely established by intercellular and intracellular auxin transport mediated by PIN auxin transporters. Among the eight members of the Arabidopsis PIN family, PIN6 is the least characterized candidate. In this study we generated functional, fluorescent protein-tagged PIN6 proteins and performed comprehensive analysis of their subcellular localization and also performed a detailed functional characterization of PIN6 and its developmental roles. The localization study of PIN6 revealed a dual localization at the plasma membrane (PM) and endoplasmic reticulum (ER). Transport and metabolic profiling assays in cultured cells and Arabidopsis strongly suggest that PIN6 mediates both auxin transport across the PM and intracellular auxin homeostasis, including the regulation of free auxin and auxin conjugates levels. As evidenced by the loss- and gain-of-function analysis, the complex function of PIN6 in auxin transport and homeostasis is required for auxin distribution during lateral and adventitious root organogenesis and for progression of these developmental processes. These results illustrate a unique position of PIN6 within the family of PIN auxin transporters and further add complexity to the developmentally crucial process of auxin transport. PMID- 27240712 TI - Making Decisions Better: an evaluation of an educational intervention. AB - RATIONALE, AIMS AND OBJECTIVES: Despite the widespread inclusion of consultation skills in undergraduate healthcare curricula, patient-doctor interactions are often an imparting of evidence or information rather than an exchange. Evidence based practice may be further enhanced by increasing explicit understanding of decision-making processes used by healthcare professionals and patients. This exploratory investigation evaluated the impact of an educational intervention on understanding of decision-making processes and practice. The effect of session schedule was assessed to inform the future delivery strategy of such approaches. METHODS: Three groups of primary care health professionals (n = 85) completed questionnaires using Likert scales to assess strength of agreement with decision making statements exploring four themes - Theory, Applied Theory, Practice and Joint Practice - pre-intervention and post-intervention. Responses were analysed, firstly to assess the impact of the intervention on understanding of decision making processes and practice across all participants and then by group to determine the effect of session schedules on outcome measures. RESULTS: Overall agreement with the decision-making statements significantly increased after the learning set (Mean = -0.162, SD = 0.355); t(64) = -3.666, p < 0.001). Multivariate analysis on effect of session schedule only found significant interactions for the theme 'Joint Practice' with group (p < 0.025) and 3-way interaction of Group and Main role. (p < 0.048). No consistent positive impact of longer session schedule was found. CONCLUSION: Participation in the learning sessions significantly improved self-reported understanding of decision-making processes and application to clinical practice. The extended learning sessions did not provide additional benefits over and above 2 half days or 1 whole day learning sessions. PMID- 27240713 TI - Cognition and gait in older people. AB - Cognitive difficulties and gait abnormalities both increase with age. We review normal and pathologic changes in both gait and cognition in older adults. Gait performance in older individuals is linked to specific cognitive changes, in particular in executive function. Structural and functional assays highlight the shared anatomic control of cognitive and gait function, mostly in the prefrontal cortices. Cognitive impairment can be used to predict incident gait difficulties. Changes in gait, especially decreased gait velocity, may be a harbinger of impending cognitive decline. The combination of slow gait and cognitive complaints (the Motoric Cognitive Risk syndrome) is a powerful new clinical tool to identify those at high risk of developing dementia and therefore may be used to target interventions. Evidence is limited, but cognitive training and targeted physical activity may be useful to mitigate or prevent gait and cognitive decline with age. PMID- 27240714 TI - Permselective Ion Transport Across the Nanoscopic Liquid/Liquid Interface Array. AB - Free-standing silica nanochannel membrane (SNM) with perforated channels was utilized to create arrays of nanoscale interfaces between two immiscible electrolyte solutions (nano-ITIES), at which permselective ion transfer and detection were achieved. The SNM consisted of a high density of straight nanochannels with a diameter of 2-3 nm and a length of 70 nm. The silicon wafer coated by 150 nm-thick porous silicon nitride film (p-SiNF) with pores of 5 MUm in-diameter was used to support the SNM in a form of nanochannel-on-micropore. Considering the material surface lipophilicity, the nano-ITIES array was formed at the boundary between SNM and p-SiNF, with a diffusion geometry equivalent to two back-to-back inlaid microdisc interfaces. Thus, the transfer of tetraethylammonium (TEA(+)) across the nano-ITIES array yielded symmetric sigmoidal current responses. In addition, because of the ultrasmall size and negatively charged surface of silica nanochannels, the nano-ITIES displayed obvious size and charge permselectivities. Transfer of ions with a size comparable with or larger than the nanochannel was sterically blocked. Also that of anions with a size smaller than the nanochannels encountered the strong electrostatic repulsion from channel walls, showing obvious dependence on the ionic strength of aqueous solution. The present approach is facile and inexpensive for building a nano-ITIES array with potential applications in ion detection and separation. PMID- 27240715 TI - Oxidation of bisphenol A in water by heat-activated persulfate. AB - The heat-activated persulfate oxidation of bisphenol A (BPA), a representative endocrine disrupting compound, was investigated with respect to the effect of several process variables on degradation rates. The activation temperature appears to be the single most important parameter, i.e. a temperature increase from 40 to 70 degrees C results in an 80-fold rate increase. Regarding initial BPA concentration, the reaction follows a pseudo-first order rate expression, where the kinetic constant decreases from 11.5 10-2 to 3.5 10-2 min-1 when BPA concentration increases from 110 to 440 MUg/L. Reactions in actual water matrices, such as bottled water and secondary treated wastewater, are slower than in pure water since various organic/inorganic water constituents compete with BPA for being oxidized by the reactive oxidizing species; this was confirmed with experiments in pure water spiked with humic acid or bicarbonate. Interestingly though, the presence of chloride seems to promote BPA degradation. Furthermore, degradation is favored at near-neutral pH and increased sodium persulfate (SPS) concentrations. Experiments at an increased BPA concentration of 20 mg/L were performed to identify transformation by-products (TBPs), as well as assess the mineralization and toxicity of the treated samples. Liquid chromatography time-of flight mass spectrometry (LC-TOF-MS) revealed the formation of eleven TBPs of BPA and plausible pathways including hydroxylation, oxidation, cleavage and oligomerization reactions are proposed. Mineralization occurs slower than BPA degradation, while the toxicity to marine bacteria Vibrio fischeri increases during the early stages of the reaction but it progressively decreases thereafter. PMID- 27240716 TI - Redox-induced mobilization of copper, selenium, and zinc in deltaic soils originating from Mississippi (U.S.A.) and Nile (Egypt) River Deltas: A better understanding of biogeochemical processes for safe environmental management. AB - Studies about the mobilization of potentially toxic elements (PTEs) in deltaic soils can be challenging, provide critical information on assessing the potential risk and fate of these elements and for sustainable management of these soils. The impact of redox potential (EH), pH, iron (Fe), manganese (Mn), sulfate (SO42 ), chloride (Cl-), aliphatic dissolved organic carbon (DOC), and aromatic dissolved organic carbon (DAC) on the mobilization of copper (Cu), selenium (Se), and zinc (Zn) was studied in two soils collected from the Nile and Mississippi Rivers deltaic plains focused on increasing our understanding of the fate of these toxic elements. Soils were exposed to a range of redox conditions stepwise from reducing to oxidizing soil conditions using an automated biogeochemical microcosm apparatus. Concentrations of DOC and Fe were high under reducing conditions as compared to oxidizing conditions in both soils. The proportion of DAC in relation to DOC in solution (aromaticity) was high in the Nile Delta soil (NDS) and low in the Mississippi Delta soil (MDS) under oxidizing conditions. Mobilization of Cu was low under reducing conditions in both soils which was likely caused by sulfide precipitation and as a result of reduction of Cu2+ to Cu1+. Mobilization of Se was high under low EH in both soils. Release of Se was positively correlated with DOC, Fe, Mn, and SO42- in the NDS, and with Fe in the MDS. Mobilization of Zn showed negative correlations with EH and pH in the NDS while these correlations were non-significant in the MDS. The release dynamics of dissolved Zn could be governed mainly by the chemistry of Fe and Mn in the NDS and by the chemistry of Mn in the MDS. Our findings suggest that a release of Se and Zn occurs under anaerobic conditions, while aerobic conditions favor the release of Cu in both soils. In conclusion, the release of Cu, Se, and Zn under different reducing and oxidizing conditions in deltaic wetland soils should be taken into account due to increased mobilization and the potential environmental risks associated with food security in utilizing these soils for flooded agricultural and fisheries systems. PMID- 27240718 TI - Gene transcription repression in Clostridium beijerinckii using CRISPR-dCas9. AB - CRISPR-Cas9 has been explored as a powerful tool for genome engineering for many organisms. Meanwhile, dCas9 which lacks endonuclease activity but can still bind to target loci has been engineered for efficient gene transcription repression. Clostridium beijerinckii, an industrially significant species capable of biosolvent production, is generally difficult to metabolically engineer. Recently, we reported our work in developing customized CRISPR-Cas9 system for genome engineering in C. beijerinckii. However, in many cases, gene expression repression (rather than actual DNA mutation) is more desirable for various biotechnological applications. Here, we further demonstrated gene transcription repression in C. beijerinckii using CRISPR-dCas9. A small RNA promoter was employed to drive the expression of the single chimeric guide RNA targeting on the promoter region of amylase gene, while a constitutive thiolase promoter was used to drive Streptococcus pyogenes dCas9 expression. The growth assay on starch agar plates showed qualitatively significant repression of amylase activity in C. beijerinckii transformant with CRISPR-dCas9 compared to the control strain. Further amylase activity quantification demonstrated consistent repression (65 97% through the fermentation process) on the activity in the transformant with CRISPR-dCas9 versus in the control. Our results provided essential references for engineering CRISPR-dCas9 as an effective tool for tunable gene transcription repression in diverse microorganisms. Biotechnol. Bioeng. 2016;113: 2739-2743. (c) 2016 Wiley Periodicals, Inc. PMID- 27240717 TI - Normal tissue complication probability (NTCP) modelling using spatial dose metrics and machine learning methods for severe acute oral mucositis resulting from head and neck radiotherapy. AB - BACKGROUND AND PURPOSE: Severe acute mucositis commonly results from head and neck (chemo)radiotherapy. A predictive model of mucositis could guide clinical decision-making and inform treatment planning. We aimed to generate such a model using spatial dose metrics and machine learning. MATERIALS AND METHODS: Predictive models of severe acute mucositis were generated using radiotherapy dose (dose-volume and spatial dose metrics) and clinical data. Penalised logistic regression, support vector classification and random forest classification (RFC) models were generated and compared. Internal validation was performed (with 100 iteration cross-validation), using multiple metrics, including area under the receiver operating characteristic curve (AUC) and calibration slope, to assess performance. Associations between covariates and severe mucositis were explored using the models. RESULTS: The dose-volume-based models (standard) performed equally to those incorporating spatial information. Discrimination was similar between models, but the RFCstandard had the best calibration. The mean AUC and calibration slope for this model were 0.71 (s.d.=0.09) and 3.9 (s.d.=2.2), respectively. The volumes of oral cavity receiving intermediate and high doses were associated with severe mucositis. CONCLUSIONS: The RFCstandard model performance is modest-to-good, but should be improved, and requires external validation. Reducing the volumes of oral cavity receiving intermediate and high doses may reduce mucositis incidence. PMID- 27240719 TI - The small iron-sulfur protein from the ORP operon binds a [2Fe-2S] cluster. AB - A linear cluster formulated as [S2MoS2CuS2MoS2](3-), a unique heterometallic cluster found in biological systems, was identified in a small monomeric protein (named as Orange Protein). The gene coding for this protein is part of an operon mainly present in strict anaerobic bacteria, which is composed (in its core) by genes coding for the Orange Protein and two ATPase proposed to contain Fe-S clusters. In Desulfovibrio desulfuricans G20, there is an ORF, Dde_3197 that encodes a small protein containing several cysteine residues in its primary sequence. The heterologously produced Dde_3197 aggregates mostly in inclusion bodies and was isolated by unfolding with a chaotropic agent and refolding by dialysis. The refolded protein contained sub-stoichiometric amounts of iron atoms/protein (0.5+/-0.2), but after reconstitution with iron and sulfide, high iron load contents were detected (1.8+/-0.1 or 3.4+/-0.2) using 2- and 4-fold iron excess. The visible absorption spectral features of the iron-sulfur clusters in refolded and reconstituted Dde_3197 are similar and resemble the ones of [2Fe 2S] cluster containing proteins. The refolded and reconstituted [2Fe-2S] Dde_3197 are EPR silent, but after reduction with dithionite, a rhombic signal is observed with gmax=2.00, gmed=1.95 and gmin=1.92, consistent with a one-electron reduction of a [2Fe-2S](2+) cluster into a [2Fe-2S](1+) state, with an electron spin of S=1/2. The data suggests that Dde_3197 can harbor one or two [2Fe-2S] clusters, one being stable and the other labile, with quite identical spectroscopic properties, but stable to oxygen. PMID- 27240720 TI - cis-4-Decenoic and decanoic acids impair mitochondrial energy, redox and Ca(2+) homeostasis and induce mitochondrial permeability transition pore opening in rat brain and liver: Possible implications for the pathogenesis of MCAD deficiency. AB - Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is biochemically characterized by tissue accumulation of octanoic (OA), decanoic (DA) and cis-4 decenoic (cDA) acids, as well as by their carnitine by-products. Untreated patients present episodic encephalopathic crises and biochemical liver alterations, whose pathophysiology is poorly known. We investigated the effects of OA, DA, cDA, octanoylcarnitine (OC) and decanoylcarnitine (DC) on critical mitochondrial functions in rat brain and liver. DA and cDA increased resting respiration and diminished ADP- and CCCP-stimulated respiration and complexes II III and IV activities in both tissues. The data indicate that these compounds behave as uncouplers and metabolic inhibitors of oxidative phosphorylation. Noteworthy, metabolic inhibition was more evident in brain as compared to liver. DA and cDA also markedly decreased mitochondrial membrane potential, NAD(P)H content and Ca(2+) retention capacity in Ca(2+)-loaded brain and liver mitochondria. The reduction of Ca(2+) retention capacity was more pronounced in liver and totally prevented by cyclosporine A and ADP, as well as by ruthenium red, demonstrating the involvement of mitochondrial permeability transition (mPT) and Ca(2+). Furthermore, cDA induced lipid peroxidation in brain and liver mitochondria and increased hydrogen peroxide formation in brain, suggesting the participation of oxidative damage in cDA-induced alterations. Interestingly, OA, OC and DC did not alter the evaluated parameters, implying lower toxicity for these compounds. Our results suggest that DA and cDA, in contrast to OA and medium-chain acylcarnitines, disturb important mitochondrial functions in brain and liver by multiple mechanisms that are possibly involved in the neuropathology and liver alterations observed in MCAD deficiency. PMID- 27240721 TI - Mitochondrial dysfunction associated with nitric oxide pathways in glutamate neurotoxicity. AB - Multiple mechanisms underlying glutamate-induced neurotoxicity have recently been discussed. Likewise, a clear deregulation of the mitochondrial respiratory mechanism has been described in patients with neurodegeneration, oxidative stress, and inflammation. This article highlights nitric oxide, an atypical neurotransmitter synthesized and released on demand by the post-synaptic neurons, and has many important implications for nerve cell survival and differentiation. Consequently, synaptogenesis, synapse elimination, and neurotransmitter release, are nitric oxide-modulated. Interesting, an emergent role of nitric oxide pathways has been discussed as regards neurotoxicity from glutamate-induced apoptosis. These findings suggest that nitric oxide pathways modulation could prevent oxidative damage to neurons through apoptosis inhibition. This review aims to highlight the emergent aspects of nitric oxide-mediated signaling in the brain, and how they can be related to neurotoxicity, as well as the development of neurodegenerative diseases development. PMID- 27240723 TI - Publisher's Note: New Editor-in-Chief appointed. PMID- 27240722 TI - Changing the guards.... PMID- 27240724 TI - Living in the danger zone: Exposure to predators and the evolution of spines and body armor in mammals. AB - Mammals have independently evolved a wide variety of morphological adaptations for use in avoiding death by predation, including spines, quills, dermal plates, and noxious sprays. Although these traits appear to protect their bearer from predatory attack, it is less obvious why some species evolved them and others have not. We investigated the ecological correlates favoring the evolution of specialized defenses in mammals, focusing on conspicuousness to predators due to body size and openness of habitat. We scored species for the degree to which they are protected by spines, quills, dermal plating, and sprays and used phylogenetic comparative analyses to study the morphological and ecological factors that may favor their evolution. We show that medium-sized insectivorous mammals (~800 g to 9 kg) that live in open habitats are more likely to possess one of these defensive traits to reduce predation. Smaller species (<200 g) and those in closed habitats can typically rely on crypsis to avoid predators, and larger species (>10 kg) are less susceptible to predation by most small- to medium-sized predators. We discuss how diet, metabolic rate, and defensive strategy evolve in concert to allow species to exploit this ecomorphological "danger zone" niche. PMID- 27240726 TI - Quality improvement in paediatric inflammatory bowel disease: the Manitoba experience. PMID- 27240725 TI - Heparinized collagen sutures for sustained delivery of PDGF-BB: Delivery profile and effects on tendon-derived cells In-Vitro. AB - Suturing is the standard of repair for lacerated flexor tendons. Past studies focused on delivering growth factors to the repair site by incorporating growth factors to nylon sutures which are commonly used in the repair procedure. However, conjugation of growth factors to nylon or other synthetic sutures is not straightforward. Collagen holds promise as a suture material by way of providing chemical sites for conjugation of growth factors. On the other hand, collagen also needs to be reconstituted as a mechanically robust thread that can be sutured. In this study, we reconstituted collagen solutions as suturable collagen threads by using linear electrochemical compaction. Prolonged release of PDGF-BB (Platelet derived growth factor-BB) was achieved by covalent bonding of heparin to the collagen sutures. Tensile mechanical tests of collagen sutures before and after chemical modification indicated that the strength of sutures following chemical conjugation stages was not compromised. Strength of lacerated tendons sutured with epitendinous collagen sutures (11.2+/-0.7N) converged to that of the standard nylon suture (14.9+/-2.9N). Heparin conjugation of collagen sutures didn't affect viability and proliferation of tendon-derived cells and prolonged the PDGF-BB release up to 15days. Proliferation of cells seeded on PDGF-BB incorporated collagen sutures was about 50% greater than those seeded on plain collagen sutures. Collagen that is released to the media by the cells increased by 120% under the effects of PDGF-BB and collagen production by cells was detectable by histology as of day 21. Addition of PDGF-BB to collagen sutures resulted in a moderate decline in the expression of the tendon-associated markers scleraxis, collagen I, tenomodulin, and COMP; however, expression levels were still greater than the cells seeded on collagen gel. The data indicate that the effects of PDGF-BB on tendon-derived cells mainly occur through increased cell proliferation and that longer term studies are needed to confirm whether this proliferation is outweighs the moderate reduction in the expression of tendon associated genes. STATEMENT OF SIGNIFICANCE: A mechanically robust pure collagen suture was fabricated via linear electrocompaction and conjugated with heparin for prolonged delivery of PDFG-BB. Sustained delivery of the PDGF-BB improved the proliferation of tendon derived cells substantially at the expense of a moderate downregulation of tenogenic markers. The collagen threads were functionally applicable as epitendinous sutures when applied to chicken flexor tendons in vitro. Overall, electrocompacted collagen sutures holds potential to improve repair outcome in flexor tendon surgeries by improving cellularity and collagen production through delivery of the PDGF-BB. The bioinductive suture concept can be applied to deliver other growth factors for a wide-array of applications. PMID- 27240727 TI - Encapsulation of ascorbic acid promotes the reduction of Maillard reaction products in UHT milk. AB - The presence of amino groups and carbonyls renders fortified milk with ascorbic acid particularly susceptible to the reduction of available lysine and to the formation of Maillard reaction products (MRPs), as Nepsilon-(carboxyethyl)-l lysine (CEL), Nepsilon-(carboxymethyl)-l-lysine (CML), Amadori products (APs) and off-flavors. A novel approach was proposed to control the Maillard reaction (MR) in fortified milk: ascorbic acid was encapsulated in a lipid coating and the effects were tested after a lab scale UHT treatment. Encapsulation promoted a delayed release of ascorbic acid and a reduction in the formation of MRPs. Total lysine increased up to 45% in milk with encapsulated ascorbic acid, while reductions in CML, CEL and furosine ranged from 10% to 53% compared with control samples. The effects were also investigated towards the formation of amide-AGEs (advanced glycation end products) by high resolution mass spectrometry (HRMS) revealing that several mechanisms coincide with the MR in the presence of ascorbic acid. PMID- 27240728 TI - Iridium Complexes as a Roadblock for DNA Polymerase during Amplification. AB - Iridium-based metal complexes containing polypyridyl-pyrazine ligands show properties of DNA intercalation. They serve as roadblocks to DNA polymerase activity, thereby inhibiting the polymerization process. Upon the addition of increasing concentrations of these iridium complexes, a rapid polymerase chain reaction (PCR)-based assay reveals the selective inhibition of the DNA polymerization process. This label-free approach to study the inhibition of fundamental cellular processes via physical roadblock can offer an alternative route toward cancer therapy. PMID- 27240729 TI - Cytokine responses to eye spray adjuvants for enhancing vaccine-induced immunity in chickens. AB - Eye spray influenza vaccines for chickens are increasingly available; however, how to enhance cellular and antibody responses to them remains undetermined. Here, eye-drops containing the immune-enhancing adjuvants Pam2CSK4 or polyI:C were assessed in chickens. Application of these TLR agonists to chicken conjunctiva resulted in up-regulation of IL-1beta, but not other cytokines, including IFN and IL-6, in the spleen, lung and Harderian gland. Thus, responses to adjuvant applied to the conjunctival mucosa of chickens differ from those expected from the responses to intra-nasal adjuvants in mammals. Identifying an appropriate delivery route for adjuvants is crucial for evoking immune responses in chickens. PMID- 27240730 TI - Erratum to: Training Lymnaea in the presence of a predator scent results in a long-lasting ability to form enhanced long-term memory. PMID- 27240731 TI - Prospects in the development of natural radioprotective therapeutics with anti cancer properties from the plants of Uttarakhand region of India. AB - Radioprotective agents are substances those reduce the effects of radiation in healthy tissues while maintaining the sensitivity to radiation damage in tumor cells. Due to increased awareness about radioactive substances and their fatal effects on human health, radioprotective agents are now the topic of vivid research. Scavenging of free radicals is the most common mechanism in oncogenesis that plays an important role in protecting tissues from lethal effect of radiation exposure therefore radioprotectors are also good anti-cancer agents. There are numerous studies indicating plant-based therapeutics against cancer and radioprotection. Such plants could be further explored for developing them as promising natural radioprotectors with anti-cancer properties. This review systematically presents information on plants having radioprotective and anti cancer properties. PMID- 27240732 TI - Increased short- and long-term mortality in 8146 hospitalised peptic ulcer patients. AB - BACKGROUND: Incidence and complications of peptic ulcer disease (PUD) have declined, but mortality from peptic ulcer bleeding has remained unchanged. The few recent studies on mortality associated with both uncomplicated and complicated patients with peptic ulcer disease provide contradictory results. AIMS: To evaluate short- and long-term mortality, and the main causes of death in peptic ulcer disease. METHODS: In this retrospective epidemiologic cohort study, register data on 8146 adult patients hospitalised with peptic ulcer disease during 2000-2008 were collected in the capital region of Finland. All were followed in the National Cause of Death Register until the end of 2009. The data were linked with the nationwide Drug Purchase Register of the Finnish Social Insurance Institution. RESULTS: Mean follow-up time was 4.9 years. Overall mortality was substantially increased, standardised mortality ratio 2.53 (95% CI: 2.44-2.63); 3.7% died within 30 days, and 11.8% within 1 year. At 6 months, the survival of patients with perforated or bleeding ulcer was lower compared to those with uncomplicated ulcer; hazard ratios were 2.06 (1.68-2.04) and 1.32 (1.11-1.58), respectively. For perforated duodenal ulcers, both the short- and long-term survival was significantly impaired in women. The main causes of mortality at 1 year were malignancies and cardiovascular diseases. Previous use of statins was associated with significant reduction in all-cause mortality. CONCLUSIONS: One-year mortality in patients hospitalised with peptic ulcer disease remained high with no change. This peptic ulcer disease cohort had a clearly decreased survival rate up to 10 years, especially among women with a perforated duodenal ulcer, most likely explained by poorer survival due to underlying comorbidity. PMID- 27240735 TI - Secondary phases and their influence on the composition of the kesterite phase in CZTS and CZTSe thin films. AB - Secondary phases zinc sulfide/selenide and copper sulfide in Cu2ZnSnS4 (CZTS) and Cu2ZnSnSe4 (CZTSe) thin film samples are investigated by X-ray absorption near edge structure (XANES) analysis at the chalcogen K-edges. Because of the formation of secondary phases the composition of the kesterite phase can deviate significantly from the total sample composition. For a large set of non stoichiometric samples we find that the cation ratios of the kesterite phase never exceed Zn/Sn = 1 even for Zn-rich CZTS and CZTSe, with all excess Zn being contained in secondary phases. For CZTS the cation ratios are found to be additionally constrained by Cu/Sn <= 2, which means that Cu-excess always leads to the formation of CuxS secondary phases. These results give clear bounds on the Cu-rich and Zn-rich sides of the single phase region in polycrystalline CZTS/Se thin films. PMID- 27240733 TI - Light-induced depigmentation in planarians models the pathophysiology of acute porphyrias. AB - Porphyrias are disorders of heme metabolism frequently characterized by extreme photosensitivity. This symptom results from accumulation of porphyrins, tetrapyrrole intermediates in heme biosynthesis that generate reactive oxygen species when exposed to light, in the skin of affected individuals. Here we report that in addition to producing an ommochrome body pigment, the planarian flatworm Schmidtea mediterranea generates porphyrins in its subepithelial pigment cells under physiological conditions, and that this leads to pigment cell loss when animals are exposed to intense visible light. Remarkably, porphyrin biosynthesis and light-induced depigmentation are enhanced by starvation, recapitulating a common feature of some porphyrias - decreased nutrient intake precipitates an acute manifestation of the disease. Our results establish planarians as an experimentally tractable animal model for research into the pathophysiology of acute porphyrias, and potentially for the identification of novel pharmacological interventions capable of alleviating porphyrin-mediated photosensitivity or decoupling dieting and fasting from disease pathogenesis. PMID- 27240734 TI - Evolution-guided functional analyses reveal diverse antiviral specificities encoded by IFIT1 genes in mammals. AB - IFIT (interferon-induced with tetratricopeptide repeats) proteins are critical mediators of mammalian innate antiviral immunity. Mouse IFIT1 selectively inhibits viruses that lack 2'O-methylation of their mRNA 5' caps. Surprisingly, human IFIT1 does not share this antiviral specificity. Here, we resolve this discrepancy by demonstrating that human and mouse IFIT1 have evolved distinct functions using a combination of evolutionary, genetic and virological analyses. First, we show that human IFIT1 and mouse IFIT1 (renamed IFIT1B) are not orthologs, but are paralogs that diverged >100 mya. Second, using a yeast genetic assay, we show that IFIT1 and IFIT1B proteins differ in their ability to be suppressed by a cap 2'O-methyltransferase. Finally, we demonstrate that IFIT1 and IFIT1B have divergent antiviral specificities, including the discovery that only IFIT1 proteins inhibit a virus encoding a cap 2'O-methyltransferase. These functional data, combined with widespread turnover of mammalian IFIT genes, reveal dramatic species-specific differences in IFIT-mediated antiviral repertoires. PMID- 27240737 TI - Anesthetic management in a child with moya-moya disease and sickle cell anemia: Case report. AB - OBJECTIVE: The objective of this case report is to describe the anesthetic management in a child with moya-moya disease and sickle cell anemia provided in a tertiary hospital. CASE: A 6 year-old patient, diagnosed with moya-moya disease and sickle cell anemia, both conditions associated with a greater incidence of intracranial ischemic events, with a history of two strokes of the ischemic subtype, was submitted to general anesthesia for the execution of multiple cranial burr holes in order to produce the neovascularization in poorly perfused regions. There were no complications in the perioperative period and the child was discharged from the hospital on the second postoperative day. CONCLUSION: Although scarcely described in the medical literature, the anesthetic management in a patient with moya-moya disease must ensure the maintenance of cerebral blood flow, normocapnia and the appropriate mean arterial pressure. In a patient with sickle cell disease, an adequate tissue perfusion, adequate oxygenation and hydration and strict pain control are to be primarily expected. The anesthesiologist is expected to know the physiopathology of both conditions to provide the best outcome for these patients. PMID- 27240738 TI - Microporous polyurethane material for size selective heterogeneous catalysis of the Knoevenagel reaction. AB - The first polyurethane material which is microporous (BET surface area of 312 m(2) g(-1)) is prepared by solvothermal synthesis and acts as highly efficient and recyclable heterogeneous catalyst in the Knoevenagel condensation showing size selectivity, and in the Henry reaction showing substrate selectivity under mild reaction conditions. PMID- 27240736 TI - A Microfabricated Platform for Generating Physiologically-Relevant Hepatocyte Zonation. AB - In vitro liver models have been important tools for more than 40 years for academic research and preclinical toxicity screening by the pharmaceutical industry. Hepatocytes, the highly metabolic parenchymal cells of the liver, are efficient at different metabolic chemistries depending on their relative spatial location along the sinusoid from the portal triad to the central vein. Although replicating hepatocyte metabolic zonation is vitally important for physiologically-relevant in vitro liver tissue and organ models, it is most often completely overlooked. Here, we demonstrate the creation of spatially-controlled zonation across multiple hepatocyte metabolism levels through the application of precise concentration gradients of exogenous hormone (insulin and glucagon) and chemical (3-methylcholanthrene) induction agents in a microfluidic device. Observed gradients in glycogen storage via periodic acid-Schiff staining, urea production via carbamoyl phosphatase synthetase I staining, and cell viability after exposure to allyl alcohol and acetaminophen demonstrated the in vitro creation of hepatocyte carbohydrate, nitrogen, alcohol degradation, and drug conjugation metabolic zonation. This type of advanced control system will be crucial for studies evaluating drug metabolism and toxicology using in vitro constructs. PMID- 27240739 TI - Gay and bisexual men's interest in marriage: an Australian perspective. AB - Same-sex marriage is a widely debated issue, including in Australia. This study used an online anonymous survey, with free-text responses, to investigate romantic and sexual relationships among Australian gay and bisexual men. We sought to identify what proportion of such men intended to marry their primary regular partner if marriage was made legally available to same-sex couples in Australia, as well as factors associated with intention or non-intention to marry. Most men in the sample did not intend to marry their primary regular partner. Even among men who considered themselves to be in a 'relationship' with their primary regular partner, less than half intended to marry him. However, many men who would not marry their current primary regular partner agreed that same-sex marriage should be available for gay and bisexual men in Australia. Reasons for intention to marry included a desire for social and legal equality, and ideas about marriage as a rite of passage, an expression of love and the most valued form of relationship in Australia. Those who did not intend to marry their primary regular partner offered a number of reasons, including that the nature of their relationship was incompatible with marriage, and reported a critical position towards marriage as a heteronormative institution. PMID- 27240740 TI - Delayed diastolic recovery and more prevalent psychiatric disorders in Takotsubo cardiomyopathy. PMID- 27240741 TI - Heart transplant coronary artery disease: Multimodality approach in percutaneous intervention. AB - Coronary artery disease is the most important cause of late morbidity and mortality after heart transplantation. It is usually an immunologic phenomenon termed cardiac allograft vasculopathy, but can also be the result of donor transmitted atherosclerosis. Routine surveillance by coronary angiography should be complemented by intracoronary imaging, in order to determine the nature of the coronary lesions, and also by assessment of their functional significance to guide the decision whether to perform percutaneous coronary intervention. We report a case of coronary angiography at five-year follow-up after transplantation, using optical coherence tomography and fractional flow reserve to assess and optimize treatment of coronary disease in this challenging population. PMID- 27240742 TI - Response to the Letter to the Editor "Delayed diastolic recovery and more prevalent psychiatric disorders in Takotsubo cardiomyopathy". PMID- 27240743 TI - "Hot spots" growth on single nanowire controlled by electric charge. AB - "Hot spots" - a kind of highly active site, which are usually composed of some unique units, such as defects, interfaces, catalyst particles or special structures - can determine the performance of nanomaterials. In this paper, we study a model system, i.e. "hot spots" on a single Ag nanowire in the galvanic replacement reaction (GRR), by dark-field microscopy. The research reveals that electric charge can be released by the formation reaction of AgCl, and consequently the electrochemical potential on Ag nanowire drops. The electric charge could induce the reduction of Ag(+) to form the "hot spots" on the nanowire during the GRR. The appearance probability of "hot spots" is almost even along the Ag nanowire, while it is slightly lower near the two ends. The spatial distance between adjacent "hot spots" is also controlled by the charge, and obeys a model based on Boltzmann distribution. In addition, the distance distribution here has an advantage in electron transfer and energy saving. Therefore, it's necessary to consider the functions of electric charge during the synthesis or application of nanomaterials. PMID- 27240744 TI - Polymerization shrinkage kinetics and shrinkage-stress in dental resin composites. AB - OBJECTIVES: To investigate a set of resin-composites and the effect of their composition on polymerization shrinkage strain and strain kinetics, shrinkage stress and the apparent elastic modulus. METHODS: Eighteen commercially available resin-composites were investigated. Three specimens (n=3) were made per material and light-cured with an LED unit (1200mW/cm(2)) for 20s. The bonded-disk method was used to measure the shrinkage strain and Bioman shrinkage stress instrument was used to measure shrinkage stress. The shrinkage strain kinetics at 23 degrees C was monitored for 60min. Maximum strain and stress was evaluated at 60min. The shrinkage strain rate was calculated using numerical differentiation. RESULTS: The shrinkage strain values ranged from 1.83 (0.09) % for Tetric Evoceram (TEC) to 4.68 (0.04) % for Beautifil flow plus (BFP). The shrinkage strain rate ranged from 0.11 (0.01%s(-1)) for Gaenial posterior (GA-P) to 0.59 (0.07) %s(-1) for BFP. Shrinkage stress values ranged from 3.94 (0.40)MPa for TET to 10.45 (0.41)MPa for BFP. The apparent elastic modulus ranged from 153.56 (18.7)MPa for Ever X posterior (EVX) to 277.34 (25.5) MPa for Grandio SO heavy flow (GSO). SIGNIFICANCE: The nature of the monomer system determines the amount of the bulk contraction that occurs during polymerization and the resultant stress. Higher values of shrinkage strain and stress were demonstrated by the investigated flowable materials. The bulk-fill materials showed comparable result when compared to the traditional resin-composites. PMID- 27240746 TI - beta-2-himachalen-6-ol: A novel anticancer sesquiterpene unique to the Lebanese wild carrot. AB - Daucus carota ssp. carota, also known as wild carrot, is a commonly used herb in Lebanese folk medicine to treat several ailments including cancer. Previous studies in our laboratories showed that the Daucus carota oil extract (DCOE) and subsequent fractions exhibit antioxidant, anti-inflammatory and anti-cancer activities. In this study, we report the isolation and identification of the major compound responsible for the anti-cancer activity of DCOE along with the mechanism of action involved. GC-MS and NMR spectroscopy revealed the identity of the major compound as beta-2-himachalen-6-ol, a novel sesquiterpene unique to the Lebanese wild carrot. beta-2-Himachalen-6-ol demonstrated potent anti-cancer activity against B16F-10, Caco-2, MB-MDA-231, A549 and SF-268 cancer cells (IC50 13-4ug/ml; 58-18uM), with SF-268 cells being the most sensitive. The sesquiterpene was shown to induce cell death through apoptosis (flow cytometry), decrease 2D cell motility (wound healing assay) and 3D invasion, as well as increase cell adhesion in SF-268 cells. Additionally, beta-2-himachalen-6-ol showed very low toxicity in mice with an LD50>6000mg/kg body weight. In conclusion, the present data demonstrate that beta-2-himachalen-6-ol is a potential multi-mechanistic chemotherapeutic drug with high potency and safety. PMID- 27240748 TI - Superior Na-ion storage properties of high aspect ratio SnSe nanoplates prepared by a spray pyrolysis process. AB - SnSe nanoplates with thin and uniform morphology are prepared by one-pot spray pyrolysis, and are examined as anode materials for Na-ion batteries. During the spray pyrolysis process, metallic Se and Sn are prepared from SeO2 and SnO2, respectively, under a reducing atmosphere. Metallic Sn and metalloid Se, with melting points of 232 and 221 degrees C, respectively, form a melted Sn-Se mixture, which reacts exothermally to form SnSe nanocrystals. Several of these nanocrystals are grown simultaneously forming a micron-sized powder. Complete elimination of the excess amount of metalloid Se, by forming H2Se gas, results in aggregation-free SnSe nanoplates. The aspect ratio of these nanoplates is as high as 11.3. The discharge capacities for the SnSe nanoplates, prepared from spray solutions containing 100, 400, and 800% of the stoichiometric SeO2 content needed to form SnSe, are 407, 558, and 211 mA h g(-1), respectively, after 50 cycles at a constant current density of 0.3 A g(-1); their capacity retentions calculated from the second cycle onwards are 77, 100, and 60%, respectively. The phase pure SnSe nanoplates with a high aspect ratio show good cycling and rate performances for Na-ion storage. PMID- 27240745 TI - An Improved Method for High Quality Metagenomics DNA Extraction from Human and Environmental Samples. AB - To explore the natural microbial community of any ecosystems by high-resolution molecular approaches including next generation sequencing, it is extremely important to develop a sensitive and reproducible DNA extraction method that facilitate isolation of microbial DNA of sufficient purity and quantity from culturable and uncultured microbial species living in that environment. Proper lysis of heterogeneous community microbial cells without damaging their genomes is a major challenge. In this study, we have developed an improved method for extraction of community DNA from different environmental and human origin samples. We introduced a combination of physical, chemical and mechanical lysis methods for proper lysis of microbial inhabitants. The community microbial DNA was precipitated by using salt and organic solvent. Both the quality and quantity of isolated DNA was compared with the existing methodologies and the supremacy of our method was confirmed. Maximum recovery of genomic DNA in the absence of substantial amount of impurities made the method convenient for nucleic acid extraction. The nucleic acids obtained using this method are suitable for different downstream applications. This improved method has been named as the THSTI method to depict the Institute where the method was developed. PMID- 27240747 TI - Protective effect and potential mechanisms of Wei-Chang-An pill on high-dose 5 fluorouracil-induced intestinal mucositis in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Wei-Chang-An pill (WCA pill), a traditional Chinese pharmaceutical preparation, possessed potential anti-inflammatory advantages and noteworthy gastrointestinal regulations in digestive diseases, which might represent a promising candidate for the treatment of intestinal mucositis (IM) induced by 5-fluorouracil (5-FU). AIM OF THE STUDY: To analyze the bioactive constituents and investigate the effect of methanol extraction from WCA pill (WCA ext) on 5-FU induced IM with underlying mechanisms. MATERIALS AND METHODS: The analysis of serum bioactive constituents after WCA ext administration in rats was carried out by UHPLC-Quadrupole-Time of Flight-Mass Spectrometry. In mice, IM was induced by 5-FU and physical manifestations were measured during the period of drug delivery. Half of mice were assessed with histology, expression of inflammatory cytokines in ileum and plasma via hematoxylin and eosin staining, immunohistochemical staining as well as cytokine enzyme-linked immunosorbent assay test, respectively. Besides, gastric emptying (GE) and gastrointestinal transit (GIT) were further tested in the other half of 5-FU induced mice. RESULTS: Twenty-two compounds were identified or tentatively characterized. IM induced by 5-FU was improved significantly after treatment with WCA ext through reducing the body weight loss, relieving the severe diarrhea, and inhibiting the GE as well as GIT. Further assessments validated that WCA ext promoted the recovery of intestinal mucosa, evaluated the activity of enterocyte proliferation, maintained the integrity of tight junction, and ameliorated the inflammatory disturbances. CONCLUSIONS: These results suggested that WCA ext promoted the restoration of intestinal function in 5-FU-induced IM via regulating multiple sites of actions in intestinal homeostasis. Accordingly, WCA pill might be a promising therapeutic candidate for the prevention of IM during cancer chemotherapy. PMID- 27240749 TI - Screened exchange hybrid density functional for accurate and efficient structures and interaction energies. AB - We extend the recently introduced PBEh-3c global hybrid density functional [S. Grimme et al., J. Chem. Phys., 2015, 143, 054107] by a screened Fock exchange variant based on the Henderson-Janesko-Scuseria exchange hole model. While the excellent performance of the global hybrid is maintained for small covalently bound molecules, its performance for computed condensed phase mass densities is further improved. Most importantly, a speed up of 30 to 50% can be achieved and especially for small orbital energy gap cases, the method is numerically much more robust. The latter point is important for many applications, e.g., for metal organic frameworks, organic semiconductors, or protein structures. This enables an accurate density functional based electronic structure calculation of a full DNA helix structure on a single core desktop computer which is presented as an example in addition to comprehensive benchmark results. PMID- 27240751 TI - Cardiovascular biomechanics in health and disease. PMID- 27240750 TI - Monitoring and probabilistic risk assessment of chlorothalonil residues in vegetables from Shandong province (China). AB - The aims of this study were to investigate the contamination status of chlorothalonil pesticide residues in vegetables from Shandong province, and to assess the potential risk of chlorothalonil to consumers based on vegetable consumption and body weight using an improved non-parameter probabilistic model. The results showed that Young children (8 months-6 years old) were more sensitive than General population(above 1year-old). In general, the health risk of chlorothalonil residues to 2 consumer groups via vegetable exposure was low, and the level of residual chlorothalonil was below the Acute Reference Dose (ARfD). This result would provide useful information for re-evaluating pesticides and for revising the chlorothalonil standard in vegetables. PMID- 27240753 TI - Corrigendum: Computational Approach Towards Exploring Potential Anti-Chikungunya Activity of Selected Flavonoids. PMID- 27240752 TI - Comparison of the properties of membranes produced with alginate and chitosan from mushroom and from shrimp. AB - Dense and porous chitosan-alginate membranes (1:1 in mass) useful as coverages of skin wounds treated through cell therapy were produced using chitosan of different chain sizes from fungal (white mushrooms) and animal (shrimp shells) sources. Porous materials were obtained by adding the surfactant Poloxamer 188 to the formulations. The influence of chitosan type on membranes physicochemical properties and toxicity to fibroblasts was evaluated. Porosity was noticed to be more pronounced in membranes obtained with fungal chitosan and increased with its molecular mass. These formulations showed the highest values of thickness, roughness, opacity, liquid uptake and water vapor permeability. The membranes were not toxic to fibroblasts, but the lowest cytotoxicity values (0.16-0.21%) were observed for membranes prepared with fungal chitosan in the presence of surfactant. In conclusion, it is possible to replace chitosan from animal sources by chitosan of fungal origin to produce membranes with negligible cytotoxicity while maintaining appropriate physicochemical properties. PMID- 27240754 TI - WITHDRAWN: Alterations in the mitochondrial physiology of Biomphalaria glabrata (Mollusca: Gastropoda) after experimental infection by Angiostrongylus cantonensis (Nematoda: Metastongylidae). 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- 27240755 TI - Isolation and characterization of a fatty acid- and retinoid-binding protein from the cereal cyst nematode Heterodera avenae. AB - A gene encoding fatty acid- and retinoid-binding protein was isolated from the cereal cyst nematode Heterodera avenae and the biochemical function of the protein that it encodes was analysed. The full-length cDNA of the Ha-far-1 gene is 827 bp long and includes a 22- nucleotide trans-spliced leader sequence (SL1) at its 5-end. The genomic clone of Ha-far-1 consists of eight exons separated by seven introns, which range in size from 48 to 186 bp. The Ha-far-1 cDNA contains an open reading frame encoding a 191 amino acid protein, with a predicted secretory signal peptide. Sequence analysis showed that Ha-FAR-1 has highest similarity to the Gp-FAR-1 protein from the potato cyst nematode, Globodera pallida and that the protein was grouped with all homologues from other plant parasitic nematodes in a phylogenetic analysis. Fluorescence-based ligand binding analysis confirmed that the recombinant Ha-FAR-1 protein was able to bind fatty acids and retinol. Spatial and temporal expression assays showed that the transcripts of Ha-far-1 accumulated mainly in the hypodermis and that the gene is most highly expressed in third-stage juveniles of H. avenae. Fluorescence immunolocalization showed that the Ha-FAR-1 protein was present on the surface of the infective second-stage juveniles of H. avenae. Nematodes treated with dsRNA corresponding to Ha-far-1 showed significantly reduced reproduction compared to nematodes exposed to dsRNA from a non-endogenous gene, suggesting that Ha-far-1 may be an effective target gene for control of H. avenae using an RNAi strategy. PMID- 27240756 TI - Esophageal surgery in Italy. Criteria to identify the hospital units and the tertiary referral centers entitled to perform it. AB - Esophageal cancer incidence is rapidly increasing in the western countries. Adenocarcinoma has recently become the most frequent subtype because of the changes in lifestyle. As observed for other types of surgery, even for esophageal surgery better results have been observed in centers with high volume of activity. Countries with formal policies of centralization, as Great Britain and The Netherlands, have got lower mortality and longer survival than those obtained before the centralization program introduction and of those countries without centralization programs. However, concerns about accessibility to high volume hospitals for lower level social strata have emerged in different countries. In Italy most of the esophagectomies for cancer are performed in very low volume centers with limited experience. High volume centers with >20 cases/year are few but, even if managing patients with more severe comorbidities have got a lower mortality and a shorter length of stay. The Aim of this paper is to identify the organizational, structural and volume requirements for accreditation of a center as an esophageal surgery center. Special attention must be given to a multidisciplinary approach involving different highly skilled specialists with the creation of a multidisciplinary team and individualized diagnostic and therapeutic pathways. PMID- 27240757 TI - Circadian and ultradian cardiovascular rhythmicity in obese children. AB - Altered circadian and ultradian blood pressure (BP) and heart rate (HR) rhythmicity have been described in diseases with increased cardiovascular risk. We analyzed cardiovascular rhythmicity in obese children. BP and HR rhythmicity was assessed with Fourier analysis from 24-h ambulatory BP measurements in 75 obese children and compared with an age- and gender-matched, lean healthy reference group of 150 subjects. Multivariate regression analysis was applied to identify significant independent factors explaining variability of rhythmicity. Prevalence of 24- and 6-h BP rhythmicity in the obese group was lower (p = 0.03 and p = 0.02), whereas the prevalence of HR rhythmicity was comparable in both groups. Excluding hypertensive participants, the results remained similar. Twenty four-hour BP and HR acrophase were delayed in obese children (p = 0.004, p < 0.0001), 24-h BP amplitude did not differ (p = 0.07), and 24-h HR amplitude was blunted (p = < 0.0001). BP Mesor in the obese group was higher (p = 0.02); HR Mesor did not differ (p = 0.1). Multivariate regression analysis failed to identify a single anthropometric or blood pressure parameter explaining the variability of BP and HR rhythmicity. CONCLUSION: Prevalence and parameters of circadian and ultradian BP and HR rhythmicity in obese children are altered compared to a healthy reference group, independent of preexisting hypertension. WHAT IS KNOWN: * Altered cardiovascular rhythmicity has been described in children with different diseases such as primary hypertension or chronic renal failure. What is New: * This study reveals altered cardiovascular rhythmicity in obese children compared to an age and gender-matched healthy reference group independent from preexisting hypertension. PMID- 27240758 TI - Robert's uterus: modern imaging techniques and ultrasound-guided hysteroscopic treatment without laparoscopy or laparotomy. AB - Robert's uterus is a unique malformation, described as a septate uterus with a non-communicating hemicavity, consisting of a blind uterine horn usually with unilateral hematometra, a contralateral unicornuate uterine cavity and a normally shaped external uterine fundus. The main symptom in affected young women is pelvic pain that becomes intensified near menses. We describe the case of a 22 year-old woman who was referred for diagnostic assessment and treatment of a congenital uterine anomaly. We used three-dimensional sonohysterography with volume-contrast imaging, HDLive rendering mode and automatic volume calculation (SonoHysteroAVC) for the diagnosis, surgical planning and postoperative evaluation. These imaging techniques provided a complete understanding of the internal and external uterine structures, enabling us to perform a minimally invasive hysteroscopic metroplasty, guided by transrectal ultrasound, and therefore avoiding the need for laparotomy/laparoscopy. The outcome of treatment was considered satisfactory; menstruation ceased to be painful and, after two hysteroscopic procedures, the communicating 0.3-cm3 hemicavity was visualized as a 3.6-cm3 normalized uterine cavity using the same imaging techniques. The findings of this case report raise questions about the embryological origin of Robert's uterus, the suitability of current classification systems, and the role of more invasive approaches (laparoscopy/laparotomy) and surgical procedures (horn resection/endometrectomy) that do not aim to improve uterine cavity shape and volume in women with this condition. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 27240759 TI - Heteropoly acids triggered self-assembly of cationic peptides into photo- and electro-chromic gels. AB - A series of cationic peptides with alternating lysines and hydrophobic residues were designed and synthesized. These kinds of short peptides with protonated lysines can complex with anionic heteropoly acids (HPAs) to form a stable gel in water/ethanol mixed solution. Circular dichroism spectroscopy showed that the short peptides adopted a mixed conformation (beta-sheet and random-coil) within the gel matrix. Scanning and transmission electron microscopy revealed that the heteropoly acids, acting as nanosized cross-linkers, first initiated the self assembly of the cationic peptides into spherical nanostructures. Then these nanospheres accumulated with each other through hydrogen bonds and hydrophobic interactions to form large sheet-like assemblies, which further interconnected with each other forming continuous 3D network structures. Fourier-transform infrared spectroscopy showed that the structural integrity of the HPAs was maintained during the gelation process. The resultant hybrid gels showed reversible photo- and elecrtro-chromic properties. X-ray photoelectron spectroscopy revealed that the hybrid gels, capable of persistent and reversible changes of their colour, are attributed to the intervalence charge-transfer transition of the HPAs. Reversible information writing and erasing were demonstrated through a repeated photo-lithograph or electric stimuli without significant loss of the gel performance. PMID- 27240760 TI - New multi-component solid forms of anti-cancer drug Erlotinib: role of auxiliary interactions in determining a preferred conformation. AB - Erlotinib is a BCS (biopharmaceutical classification system) class II drug used for the treatment of non-small cell lung cancer. There is an urgent need to obtain new solid forms of higher solubility to improve the bioavailability of the API (active pharmaceutical ingredient). In this context, cocrystals with urea, succinic acid, and glutaric acid and salts with maleic acid, adipic acid, and saccharin were prepared via wet granulation and solution crystallizations. Crystal structures of the free base (Z' = 2), cocrystals of erlotinib-urea (1:1), erlotinib-succinic acid monohydrate (1:1:1), erlotinib-glutaric acid monohydrate (1:1:1) and salts of erlotinib-adipic acid adipate (1:0.5:0.5) are determined and their hydrogen-bonding patterns are analyzed. Self recognition via the (amine) N H...N (pyridine) hydrogen bond between the API molecules is replaced by several heterosynthons such as acid-pyridine, amide-pyridine and carboxylate-pyridinium in the new binary systems. Auxiliary interactions play an important role in determining the conformation of the API in the crystal. FT-IR spectroscopy is used to distinguish between the salts and cocrystals in the new multi-component systems. The new solid forms are characterized by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) to confirm their unique phase identity. PMID- 27240761 TI - Conformational polymorphs of isobutyl-6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran 3-carboxylate: spectroscopic, structural and DFT approach. AB - The crystal structure of a new crystalline phase, polymorph (II) of isobutyl-6 amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylate, was accurately determined by single-crystal X-ray diffraction analysis providing a clean identification of polymorphic forms. Comparison with a known phase, referred to as polymorph (I), reveals the type of supramolecular assembly. Inter- and intramolecular hydrogen bonding interactions exhibit various supramolecular architectures in crystal packing and these variations confirm well the polymorphism in isobutyl-6-amino-5 cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylate (IAPC) crystal structure. Crystal cohesion is achieved by N-H...N, N-H...O and C-H...H-C interactions, responsible for the formation and strengthening of the supramolecular assembly. The objective of this investigation is to study crystalline forms which can offer enhanced physicochemical properties, and also to recognize the molecular orientations between such forms. The conformational polymorphs of IAPC were compared spectroscopically by FT-IR and FT-Raman. The bulk phases were studied by X-ray powder diffraction patterns. External morphology was investigated using scanning electron microscopic images. The molecular interactions were quantified using Hirshfeld surface and fingerprint analysis. Density functional theory (DFT) computations were used to optimize the structure. The optimized structure is further subjected to an analysis of Mulliken population, natural population and electrostatic potential. PMID- 27240762 TI - Crystal structure and phase transition of thermoelectric SnSe. AB - Tin selenide-based functional materials are extensively studied in the field of optoelectronic, photovoltaic and thermoelectric devices. Specifically, SnSe has been reported to have an ultrahigh thermoelectric figure of merit of 2.6 +/- 0.3 in the high-temperature phase. Here we report the evolution of lattice constants, fractional coordinates, site occupancy factors and atomic displacement factors with temperature by means of high-resolution synchrotron powder X-ray diffraction measured from 100 to 855 K. The structure is shown to be cation defective with a Sn content of 0.982 (4). The anisotropy of the thermal parameters of Sn becomes more pronounced approaching the high-temperature phase transition (~ 810 K). Anharmonic Gram-Charlier parameters have been refined, but data from single crystal diffraction appear to be needed to firmly quantify anharmonic features. Based on modelling of the atomic displacement parameters the Debye temperature is found to be 175 (4) K. Conflicting reports concerning the different coordinate system settings in the low-temperature and high-temperature phases are discussed. It is also shown that the high-temperature Cmcm phase is not pseudo-tetragonal as commonly assumed. PMID- 27240763 TI - Hydrogen bonding at C=Se acceptors in selenoureas, selenoamides and selones. AB - In recent years there has been considerable interest in chalcogen and hydrogen bonding involving Se atoms, but a general understanding of their nature and behaviour has yet to emerge. In the present work, the hydrogen-bonding ability and nature of Se atoms in selenourea derivatives, selenoamides and selones has been explored using analysis of the Cambridge Structural Database and ab initio calculations. In the CSD there are 70 C=Se structures forming hydrogen bonds, all of them selenourea derivatives or selenoamides. Analysis of intramolecular geometries and ab initio partial charges show that this bonding stems from resonance-induced C(delta+)=Se(delta-) dipoles, much like hydrogen bonding to C=S acceptors. C=Se acceptors are in many respects similar to C=S acceptors, with similar vdW-normalized hydrogen-bond lengths and calculated interaction strengths. The similarity between the C=S and C=Se acceptors for hydrogen bonding should inform and guide the use of C=Se in crystal engineering. PMID- 27240764 TI - Supramolecular hydrogen-bonding patterns of co-crystals containing the active pharmaceutical ingredient (API) phloroglucinol and N-heterocycles. AB - The active pharmaceutical ingredient phloroglucinol (PHL) has been taken as an illustrative molecule to explore the intermolecular interactions which can be established with other molecular entities to build PHL pharmaceutical co crystals. The crystal structures of five newly synthesized co-crystals are reported, where PHL is crystallized with N-heterocycles, namely 2-hydroxy-6 methylpyridine (1), 2,4-dimethyl-6-hydroxypyrimidine (2), 4-phenylpyridine (3), 2 hydroxypyridine (4) and 2,3,5,6-tetramethylpyrazine (5). The structural characteristics of these co-crystals, as far as the hydrogen-bonding networks and the crystalline architectures are concerned, are strongly dependent on the chemical features of the coformer molecules, as well as on their size and shape. A detailed analysis of the intermolecular interactions established in all the PHL co-crystals of known structures has allowed the recognition of some regularities in the packing modes that can be useful in the design of new supramolecular adducts forming predictable structural motifs. PMID- 27240765 TI - One-pot green synthesis of biologically relevant novel spiro[indolin-2-one-3,4' pyrano[2,3-c]pyrazoles] and studies on their spectral and X-ray crystallographic behaviors. AB - Syntheses via green route and single-crystal X-ray structural investigations have been carried out for three spiro[indolin-2-one-3,4'-pyrano[2,3-c]pyrazole] derivatives, 6'-amino-2-oxo-3'-propyl-2'H-spiro[indoline-3,4'-pyrano[2,3 c]pyrazole]-5'-carbonitrile dimethyl sulfoxide monosolvate (5a), 6'-amino-5 fluoro-2-oxo-3'-propyl-2'H-spiro[indoline-3,4'-pyrano[2,3-c]pyrazole]-5' carbonitrile dimethyl sulfoxide monosolvate (5b) and methyl 6'-amino-5-cyano-1 methyl-2-oxo-3'-propyl-2'H-spiro[indoline-3,4'-pyrano[2,3-c]pyrazole]-3' carboxylate 0.25 hydrate (5c), respectively. Compounds (5a) and (5b) crystallize in the triclinic space group P?bar 1, whereas compound (5c) crystallizes in the monoclinic space group C2/c. In molecules (5a) and (5b) all the rings are practically flat, while in (5c), the heterocyclic pyran ring adopts a flattened boat conformation. In (5a) and (5b) the cyanide group is oriented in a (-ap) conformation, while the amino group is oriented in a (+ap) conformation with a pyran ring, but in (5c) both the cyanide and amino groups are oriented in a (-ap) conformation with the pyran ring. In the crystal structure of (5a) and (5b), the molecules are linked by an elaborate system of N-H...O and N-H...N hydrogen bonds to generate a zigzag-like construct. In (5c) molecules are linked by N-H...O hydrogen bonds, thereby generating extended chains. The present communication focuses on the detailed and comparative information about spectral behaviors, single-crystal X-ray crystallographic properties and solid-state supramolecular architectures of these synthesized compounds of potential biological interests. PMID- 27240766 TI - Silver(I) coordination polymers assembled from flexible cyclotriphosphazene ligand: structures, topologies and investigation of the counteranion effects. AB - The reactions of a flexible ligand hexakis(3-pyridyloxy)cyclotriphosphazene (HPCP) with a variety of silver(I) salts (AgX; X = NO3(-), PF6(-), ClO4(-), CH3PhSO3(-), BF4(-) and CF3SO3(-)) afforded six silver(I) coordination polymers, namely {[Ag2(HPCP)].(NO3)2.H2O}n (1), {[Ag2(HPCP)(CH3CN)].(PF6)2}n (2), {[Ag2(HPCP)(CH3CN)].(ClO4)2}n (3), [Ag3(HPCP)(CH3PhSO3)3]n (4), [Ag2(HPCP)(CH3CN)(BF4)2]n (5) and {[Ag(HPCP)].(CF3SO3)}n (6). All of the isolated crystalline compounds were structurally determined by X-ray crystallography. Changing the counteranions in the reactions, which were conducted under similar conditions of M/L ratio (1:1), temperature and solvent, resulted in structures with different types of topologies. In complexes (1)-(6), the ligand HPCP shows different coordination modes with Ag(I) ions giving two-dimensional layered structures and three-dimensional frameworks with different topologies. Complex (1) displays a new three-dimensional framework adopting a (3,3,6)-connected 3 nodal net with point symbol {4.6(2)}2{4(2).6(10).8(3)}. Complexes (2) and (3) are isomorphous and have a two-dimensional layered structure showing the same 3,6L60 topology with point symbol {4.2(6)}2{4(8).6(6).8}. Complex (4) is a two dimensional structure incorporating short Ag...Ag argentophilic interactions and has a uninodal 4-connected sql/Shubnikov tetragonal plane net with {4(4).6(2)} topology. Complex (5) exhibits a novel three-dimensional framework and more suprisingly contains twofold interpenetrated honeycomb-like networks, in which the single net has a trinodal (2,3,5)-connected 3-nodal net with point symbol {6(3).8(6).12}{6(3)}{8}. Complex (6) crystallizes in a trigonal crystal system with the space group R?bar 3 and possesses a three-dimensional polymeric structure showing a binodal (4,6)-connected fsh net with the point symbol (4(3).6(3))2.(4(6).6(6).8(3)). The effect of the counteranions on the formation of coordination polymers is discussed in this study. PMID- 27240767 TI - High-pressure studies of three polymorphs of a palladium(II) oxathioether macrocyclic complex. AB - The three reported phases of the mononuclear macrocyclic Pd(II) complex [PdCl2([9]aneS2O)] [(1); [9]aneS2O = 1-oxa-4,7-dithiacyclononane] were each studied up to pressures exceeding 9 GPa using high-pressure single-crystal X-ray diffraction. The alpha- and gamma-phases both exhibit smooth compression of the unit-cell parameters with third-order Birch-Murnaghan bulk moduli of 14.4 (8) and 7.6 (6) GPa, respectively. Between 6.81 and 6.87 GPa beta-[PdCl2([9]aneS2O)] was found to undergo a reversible transition to a phase denoted as beta' and characterized by a tripling of the unit-cell volume. Across the phase transition, rearrangement of the conformation of the bound macrocycle at two of the resulting three unique sites gives rise to an extensively disordered structure. PMID- 27240768 TI - The Z' = 12 superstructure of Lambda-cobalt(III) sepulchrate trinitrate governed by C-H...O hydrogen bonds. AB - Lambda-Cobalt(III) sepulchrate trinitrate crystallizes in P6322 with Z = 2 (Z' = 1/6) at room temperature. Slabs perpendicular to the hexagonal axis comprise molecules Co(sepulchrate) alternating with nitrate groups A and B. Coordinated by six sepulchrate molecules, highly disordered nitrate groups C are accommodated between the slabs. Here we report the fully ordered, low-temperature crystal structure of Co(sep)(NO3)3. It is found to be a high-Z' structure with Z' = 12 of the 12-fold 6a_{h}?times?sqrt{3}b_{h}?times c_{h} superstructure with monoclinic symmetry P21 (c unique). Correlations between structural parameters are effectively removed by refinements within the superspace approach. Superstructure formation is governed by a densification of the packing in conjunction with ordering of nitrate group C, the latter assuming different orientations for each of the Z' = 12 independent copies in the superstructure. The Co(sep) moiety exhibits small structural variations over its 12 independent copies, while orientations of nitrate groups A and B vary less than the orientations of the nitrate group C do. Molecular packing in the superstructure is found to be determined by short C-H...H-C contacts, with H...H distances of 2.2-2.3 A, and by short C-H...O contacts, with H...O distances down to 2.2 A. These contacts presumably represent weak C-H...O hydrogen bonds, but in any case they prevent further densification of the structure and strengthening of weak N-H...O hydrogen bonds with observed H...O distances of 2.4-2.6 A. PMID- 27240769 TI - High-temperature single-crystal X-ray diffraction study of tetragonal and cubic perovskite-type PbTiO3 phases. AB - A high-temperature single-crystal X-ray diffraction study of a synthetic PbTiO3 perovskite was carried out over the wide temperature range 298-928 K. A transition from a tetragonal (P4mm) to a cubic (Pm ?bar 3 m) phase has been revealed near 753 K. In the non-centrosymmetric P4mm symmetry group, the difference in relative displacement between Pb and O along the c-axis is much larger than that between Ti and O. The Pb and Ti cations contribute sufficiently to polarization being shifted in the opposite direction compared with the shift of O atoms. Deviation from the linear changes in Debye-Waller factors and bonding distances in the tetragonal phases can be interpreted as a precursor phenomenon before the phase transition. Disturbance of the temperature factor Ueq for O is observed in the vicinity of the transition point, while Ueq values for Pb and Ti are continuously changing with increasing temperature. The O site includes the clear configurational disorder in the cubic phase. The polar local positional distortions remain in the cubic phase and are regarded as the cause of the paraelectricity. Estimated values of the Debye temperature ThetaD for Pb and Ti are 154 and 467 K in the tetragonal phase and decrease 22% in the high temperature phase. Effective potentials for Pb and Ti change significantly and become soft after the phase transition. PMID- 27240770 TI - Anisotropic compressibility of the coordination polymer emim[Mn(btc)]. AB - The effect of pressure on the crystal structure of a coordination polymer, emim[Mn(II)(btc)] (emim = 1-ethyl,3-methyl imidazolium cation, btc = 1,3,5 benzene-tricarboxylate), was investigated with single-crystal X-ray diffraction. At 4.3 GPa the unit-cell volume had decreased by 14% compared with ambient conditions. The unit-cell contraction is highly anisotropic, with the a- and b axes decreasing by 5.5 and 9.5%, respectively, and the c-axis compressing a mere 0.25% up to 1.7 GPa followed by a 0.2% expansion between 1.7 and 4.3 GPa. The 0.2% increase in length of the c-axis in this interval happens above the quasi hydrostatic limit of the pressure-transmitting medium and therefore it might be a consequence of strain gradients. Under ambient conditions, two MnO6 units are connected by two carboxylate ligands to form dimeric units. On increasing pressure, a non-bonded O atom from a bridging carboxylate group approaches the Mn atom, with the Mn-O distance decreasing from 2.866 (1) A at 0.3 GPa to 2.482 (6) A at 4.3 GPa, increasing the coordination environment of the Mn ion from six- to seven-coordinated. PMID- 27240771 TI - New insight on bismuth cuprates with incommensurate modulated structures. AB - The incommensurate modulated crystal structure of Bi2.27Sr1.73CuO6 + delta (2201) phase [a = 5.3874 (5), b = 5.3869 (4), c = 24.579 (3) A; beta = 90.01 (1) degrees , q = 0.2105 (3)a(*) + 0.538 (4)c(*), Z = 4, the (3 + 1)-dimensional monoclinic A2/a(alpha0gamma) group] has been refined with R = 0.041, wR = 0.052 from X-ray single-crystal data including up to third-order satellite reflections. The same structure has also been considered as incommensurate composite with a2 = 2.437, b2 = 5.387, c2 = 24.614, beta2 = 93.06, q2 = 0.4524a2(*)-0.243c2(*) and the (3 + 1)-dimensional A2/m(alpha0gamma)0s group for the second component. Both approaches give quite similar results. The structure possesses oxygen disorder in the oxygen-rich region of the BiO layer. An extra O atom is determined in the bridging position shifted ~ 0.6 A from BiO towards the SrO layer. Its presence is the cause of the tremendous increase of the bismuth U(11) atomic displacement parameter in ~ 20% of the unit cells (t = -0.05-0.15). Vacancies are determined in the oxygen site of the SrO layer, which may result in the oxygen content variation with annealing at different oxygen pressures. The total refined oxygen content 6.18 (1) corresponds to the results of chemical analysis. PMID- 27240772 TI - Structural analysis of lead magnesium niobate using synchrotron powder X-ray diffraction and the Rietveld method. AB - The room-temperature synchrotron powder X-ray diffraction pattern of the single phase perovskite lead magnesium niobate (PMN) has shown significant broadening in the q range ~ 5-7 A(-1) compared with standard LaB6 synchrotron powder X-ray diffraction data, taken under similar conditions. This broadening/asymmetry lies mainly towards the lower 2theta side of the Bragg peaks. Attempts to fit this data with the paraelectric cubic phase (Pm?bar 3m) and the local rhombohedral phase (R3m) corresponding to polar nanoregions (PNRs) are made using the Rietveld method. Rietveld refinements show that neither cubic (Pm?bar 3m) nor rhombohedral (R3m) symmetry can fit this XRD pattern satisfactorily. The two-phase refinement fits the experimental data satisfactorily and suggests that the weight percentage of the PNRs is approximately 12-16% at room temperature. The unit-cell volume of these rhombohedral PNRs is approximately 0.15% larger than that of the unit cell volume of the paraelectric cubic phase. PMID- 27240773 TI - Structure reinvestigation of alpha-, beta- and gamma-In2S3. AB - Semiconducting indium sulfide (In2S3) has recently attracted considerable attention as a buffer material in the field of thin film photovoltaics. Compared with this growing interest, however, detailed characterizations of the crystal structure of this material are rather scarce and controversial. In order to close this gap, we have carried out a reinvestigation of the crystal structure of this material with an in situ X-ray diffraction study as a function of temperature using monochromatic synchrotron radiation. For the purpose of this study, high quality polycrystalline In2S3 material with nominally stoichiometric composition was synthesized at high temperatures. We found three modifications of In2S3 in the temperature range between 300 and 1300 K, with structural phase transitions at temperatures of 717 K and above 1049 K. By Rietveld refinement we extracted the crystal structure data and the temperature coefficients of the lattice constants for all three phases, including a high-temperature trigonal gamma-In2S3 modification. PMID- 27240774 TI - Local structure in the disordered solid solution of cis- and trans-perinones. AB - The cis- and trans-isomers of the polycyclic aromatic compound perinone, C26H12N4O2, form a solid solution (Vat Red 14). This solid solution is isotypic to the crystal structures of cis-perinone (Pigment Red 194) and trans-perinone (Pigment Orange 34) and exhibits a combined positional and orientational disorder: In the crystal, each molecular position is occupied by either a cis- or trans-perinone molecule, both of which have two possible molecular orientations. The structure of cis-perinone exhibits a twofold orientational disorder, whereas the structure of trans-perinone is ordered. The crystal structure of the solid solution was determined by single-crystal X-ray analysis. Extensive lattice energy minimizations with force-field and DFT-D methods were carried out on combinatorially complete sets of ordered models. For the disordered systems, local structures were calculated, including preferred local arrangements, ordering lengths, and probabilities for the arrangement of neighbouring molecules. The superposition of the atomic positions of all energetically favourable calculated models corresponds well with the experimentally determined crystal structures, explaining not only the atomic positions, but also the site occupancies and anisotropic displacement parameters. PMID- 27240775 TI - Design principles for clinical network-based proteomics. AB - Integrating biological networks with proteomics is a tantalizing option for system-level analysis; for example it can help remove false-positives from proteomics data and improve coverage by detecting false-negatives, as well as resolving inconsistent inter-sample protein expression due to biological heterogeneity. Yet, designing a robust network-based analysis strategy on proteomics data is nontrivial. The issues include dealing with test set bias caused by, for example, inappropriate normalization procedure, devising appropriate benchmarking criteria and formulating statistically robust feature selection techniques. Given the increasing importance of proteomics in contemporary clinical studies, more powerful network-based approaches are needed. We provide some design principles and considerations that can help achieve this, while taking into account the idiosyncrasies of proteomics data. PMID- 27240776 TI - Non-human tools for the evaluation of bitter taste in the design and development of medicines: a systematic review. AB - Taste evaluation is a crucial factor for determining acceptance of medicines by patients. The human taste panel test is the main method used to establish the overall palatability and acceptability of a drug product to a patient towards the end of development. Non-human in vitro and in vivo taste-evaluation tools are very useful for pre-formulation, quality control and screening of formulations. These non-human taste assessment tools can be used to evaluate all aspects of taste quality. The focus of this review is bitterness because it is a key aspect of taste in association with the development of medicines. In this review, recent in vitro (analytical) and in vivo (non-human) tools are described for the assessment of the bitter taste of medicines. Their correlations with human taste data are critically discussed. The potential for their use in early screening of the taste of active pharmaceutical ingredients (APIs) to expedite paediatric formulation development is also considered. PMID- 27240778 TI - Molecular insights into the formation of drug-monoacyl phosphatidylcholine solid dispersions for oral delivery. AB - Phospholipid-based formulations provide a key technology to formulate poorly water-soluble drugs. A recent interest has been in using phospholipids with a high content of monoacyl phosphatidylcholine (monoacyl PC) due to its ability to form mixed micelles of mono- and di-acylphospholipids upon aqueous dispersion. The present work focused on binary drug- monoacyl PC systems (at about equimolar ratio) with respect to screening of solid dispersion feasibility. It was tested whether or not a molecular rule of thumb can predict the desirable absence of drug crystallinity in the products. Subsequently, molecular simulations were performed to gain a better understanding of molecular association between drugs and monoacyl PC. Finally, the glass-forming ability (GFA) of pure drugs was considered with respect to solid dispersion formation. All products were obtained from a solvent-evaporation process and subsequent analysis of potential drug crystallinity was measured with X-ray powder diffraction and differential scanning calorimetry. Molecular simulations were making use of a Monte Carlo algorithm and molecular properties relevant for GFA were calculated. As a result, the dataset of 28 drugs confirmed an earlier proposed empirical rule that enthalpy of fusion and logP were important for solid dispersion formation, while some relevance was also evidenced for drug energies of frontal orbitals. Interestingly, the Monte Carlo simulations revealed several likely associations between drug and phospholipid rather than a well-defined single complex formation. However, drug-excipient interactions were still pivotal, since GFA of pure drug could not predict solid dispersion formation. These findings led to important molecular insights into binary solid dispersions of drug and monoacyl PC, which can guide formulators in early drug product development. PMID- 27240777 TI - Drug combination therapy increases successful drug repositioning. AB - Repositioning of approved drugs has recently gained new momentum for rapid identification and development of new therapeutics for diseases that lack effective drug treatment. Reported repurposing screens have increased dramatically in number in the past five years. However, many newly identified compounds have low potency; this limits their immediate clinical applications because the known, tolerated plasma drug concentrations are lower than the required therapeutic drug concentrations. Drug combinations of two or more compounds with different mechanisms of action are an alternative approach to increase the success rate of drug repositioning. PMID- 27240779 TI - Enzyme-responsive destabilization of stabilized plasmid-lipid nanoparticles as an efficient gene delivery. AB - Stabilized plasmid-lipid particles (SPLPs) have been developed to overcome the low stability issue of cationic liposomes, however, SPLPs that are too stable result in unsatisfactory transfection efficiency. In this article, we prepared enzyme-responsive SPLPs (eSPLPs) composed of 1,2-dioleoyl-3-trimethylammonium propane (DOTAP), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), and mPEG GLFG-K-(C16)2, a PEG lipid with an enzymatically-cleavable linker (glycine phenylalanine-leucine-glycine, GFLG). eSPLPs were successfully prepared with plasmid DNA (pDNA) encapsulation efficiency of over 80%, using the detergent dialysis method. The PEG shell stabilized eSPLPs and maintained a hydrodynamic diameter of around 200nm. Although typical SPLPs were relatively intact in endosomal condition, the PEG shell of eSPLPs was cleaved following the degradation of the GFLG linker by cathepsin B in the endosome. Then, eSPLPs collapsed and induced endosomal disruption triggering the controlled release of the encapsulated pDNA into cytoplasm. Owing to the enzyme-responsive destabilization, eSPLPs showed a 10 to 100-fold higher transfection efficiency than control SPLPs, which was confirmed using luciferase assay. These results suggest that eSPLPs might be promising candidates for practical use as gene delivery systems, with both stability and high transfection efficiency for future in vivo applications. PMID- 27240781 TI - Refractory Cardiogenic Shock During Tramadol Poisoning: A Case Report. AB - Tramadol is a weak opioid analgesic indicated for the treatment of moderate to severe pain. Tramadol intoxication can be lethal, and this drug is frequently involved in voluntary overdose. Classically, tramadol intoxication is associated with neurological and respiratory side effects. In contrast, cardiac effects are poorly documented in the literature. We report a case of severe tramadol intoxication, with plasma concentration 20 times the toxic threshold, complicated by refractory cardiogenic shock, successfully treated by extra corporeal life support (ECLS) with a favorable cardiac outcome and ECLS weaning at day 10. Seizure, clonus, and nonreactive mydriasis were present during 4 days, and complete awakening was delayed to day 15. Poisoning caused by high doses of tramadol can lead to refractory cardiogenic shock, and ECLS can be considered as effective rescue therapy in this context. PMID- 27240780 TI - The Correlation Between 9p21 Chromosome rs4977574 Polymorphism Genotypes and the Development of Coronary Artery Heart Disease. AB - Our aim is to investigate the correlation between 9p21 chromosome rs4977574 polymorphism genotypes and the development of coronary artery heart disease (CHD). Two hundred and eighty-nine patients with angiography-confirmed CHD were recruited as the CHD group, while 338 subjects without CHD symptoms were enrolled as the control group. For all participating subjects, the genotypes of rs4977574 polymorphism were examined by the real-time PCR analysis. Analyses acquired from single-locus technique showed that genotype distribution of rs4977574 polymorphism was significantly different (p = 0.041) between CHD group and the control group. Logistic regression analysis demonstrated that rs4977574 polymorphism in a dominant mode significantly increased (p = 0.038) the risk of CHD, where odds ratio (OR) was 0.71 and the 95 % confidence interval (CI) 0.58 0.97 was applied. 9p21 chromosome rs4977574 polymorphism genotypes are associated with the incidence and development of CHD. The presence of C allele may reduce the risk of CHD. PMID- 27240782 TI - A welcome change in transplantation policy. PMID- 27240783 TI - Raltegravir in second-line ART in resource-limited settings. PMID- 27240784 TI - Time to prioritise the UNAIDS 90-90-90 targets for infants. PMID- 27240785 TI - HIV self-testing to scale up couples and partner testing. PMID- 27240786 TI - Home testing and counselling with linkage to care. PMID- 27240787 TI - Raltegravir in second-line antiretroviral therapy in resource-limited settings (SELECT): a randomised, phase 3, non-inferiority study. AB - BACKGROUND: For second-line antiretroviral therapy, WHO recommends a boosted protease inhibitor plus nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs). However, concerns about toxicity and cross-resistance motivated a search for regimens that do not contain NRTIs. We aimed to assess whether boosted lopinavir plus raltegravir would be non-inferior to boosted lopinavir plus NRTIs for virological suppression in resource-limited settings. METHODS: A5273 was a randomised, open-label, phase 3, non-inferiority study at 15 AIDS Clinical Trials Group (ACTG) research sites in nine resource-limited countries (three sites each in India and South Africa, two each in Malawi and Peru, and one each in Brazil, Kenya, Tanzania, Thailand, and Zimbabwe). Adults with plasma HIV-1 RNA concentrations of at least 1000 copies per mL after at least 24 weeks on a regimen based on a non-NRTI inhibitor were randomly assigned (1:1) to receive oral ritonavir-boosted lopinavir (100 mg ritonavir, 400 mg lopinavir) plus 400 mg raltegravir twice a day (raltegravir group) or to ritonavir-boosted lopinavir plus two or three NRTIs selected from an algorithm (eg, zidovudine after failure with tenofovir and vice versa; NRTI group). Randomised group assignment was done with a computer algorithm concealed to site personnel, and stratified by HIV-1 RNA viral load, CD4 cell count, and intention to use zidovudine, with the groups balanced by each site. The primary endpoint was time to confirmed virological failure (two measurements of HIV-1 RNA viral load >400 copies per mL) at or after week 24 in the intention-to-treat population. Non-inferiority (10% margin) was assessed by comparing the cumulative probability of virological failure by 48 weeks. This trial was registered with ClinicalTrials.gov, NCT01352715. FINDINGS: Between March 13, 2012, and Oct 2, 2013, we randomly assigned 515 participants: 260 to the raltegravir group and 255 to the NRTI group; two participants in the raltegravir group and one in the NRTI group were excluded from analyses because of ineligibility. By the end of follow-up (October, 2014), 96 participants had virological failure (46 in the raltegravir group and 50 in the NRTI group). By 48 weeks, the cumulative probability of virological failure was 10.3% (95% CI 6.5 14.0) in the raltegravir group and 12.4% (8.3-16.5) in the NRTI group, with a weighted difference of -3.4% (-8.4 to 1.5), indicating that raltegravir was non inferior, but not superior, to NRTIs. 62 (24%) participants in the raltegravir group and 81 (32%) in the NRTI group had grade 3 or higher adverse events; 19 (7%) and 29 (11%), respectively, had serious adverse events. Three participants in each group died, all from HIV-related causes. INTERPRETATION: In settings with extensive NRTI resistance but no available resistance testing, our data support WHO's recommendation for ritonavir-boosted lopinavir plus NRTI for second-line antiretroviral therapy. Ritonavir-boosted lopinavir plus raltegravir is an appropriate alternative, especially if NRTI use is limited by toxicity. FUNDING: National Institutes of Health. PMID- 27240788 TI - Early infant HIV diagnosis and entry to HIV care cascade in Thailand: an observational study. AB - BACKGROUND: Early infant diagnosis of HIV is crucial for timely initiation of antiretroviral therapy (ART) in infected children who are at high risk of mortality. Early infant diagnosis with dried blood spot testing was provided by the National AIDS Programme in Thailand from 2007. We report ART initiation and vital status in children with HIV after 7 years of rollout in Thailand. METHODS: Dried blood spot samples were collected from HIV-exposed children in hospitals in Thailand and mailed to the Faculty of Associated Medical Sciences, Chiang Mai University, where HIV DNA was assessed with real-time PCR to establish HIV infection. We linked data from children with an HIV infection to the National AIDS Programme database to ascertain ART and vital status. FINDINGS: Between April 5, 2007, and Oct 1, 2014, 16 046 dried blood spot samples were sent from 8859 children in 364 hospitals in Thailand. Median age at first dried blood spot test was 2.1 (IQR 1.8-2.5) months. Of 7174 (81%) children with two or more samples, 223 (3%) were HIV positive (including five unconfirmed). Of 1685 (19%) children with one sample, 70 (4%) were unconfirmed positive. Of 293 (3%) children who were HIV positive, 220 (75%) registered for HIV care and 170 (58%) initiated ART. Median age at ART initiation decreased from 14.2 months (IQR 10.2-25.6) in 2007 to 6.1 months (4.2-9.2) in 2013, and the number of children initiating ART aged younger than 1 year increased from five (33%) of 15 children initiating ART in 2007 to ten (83%) of 12 initiating ART in 2013. 15 (9%) of 170 children who initiated ART died and 16 (32%) of 50 who had no ART record died. INTERPRETATION: Early infant diagnosis with dried blood spot testing had high uptake in primary care settings. Further improvement of linkage to HIV care is needed to ensure timely treatment of all children with an HIV infection. FUNDING: None. PMID- 27240789 TI - Promoting male partner HIV testing and safer sexual decision making through secondary distribution of self-tests by HIV-negative female sex workers and women receiving antenatal and post-partum care in Kenya: a cohort study. AB - BACKGROUND: Increased uptake of HIV testing by men in sub-Saharan Africa is essential for the success of combination prevention. Self-testing is an emerging approach with high acceptability, but little evidence exists on the best strategies for test distribution. We assessed an approach of providing multiple self-tests to women at high risk of HIV acquisition to promote partner HIV testing and to facilitate safer sexual decision making. METHODS: In this cohort study, HIV-negative women aged 18-39 years were recruited at two sites in Kisumu, Kenya: a health facility with antenatal and post-partum clinics and a drop-in centre for female sex workers. Participants gave informed consent and were instructed on use of oral fluid based rapid HIV tests. Participants enrolled at the health facility received three self-tests and those at the drop-in centre received five self-tests. Structured interviews were conducted with participants at enrolment and over 3 months to determine how self-tests were used. Outcomes included the number of self-tests distributed by participants, the proportion of participants whose sexual partners used a self-test, couples testing, and sexual behaviour after self-testing. FINDINGS: Between Jan 14, 2015, and March 13, 2015, 280 participants were enrolled (61 in antenatal care, 117 in post-partum care, and 102 female sex workers); follow-up interviews were completed for 265 (96%). Most participants with primary sexual partners distributed self-tests to partners: 53 (91%) of 58 participants in antenatal care, 91 (86%) of 106 in post partum care, and 64 (75%) of 85 female sex workers. 82 (81%) of 101 female sex workers distributed more than one self-test to commercial sex clients. Among self tests distributed to and used by primary sexual partners of participants, couples testing occurred in 27 (51%) of 53 in antenatal care, 62 (68%) of 91 from post partum care, and 53 (83%) of 64 female sex workers. Among tests received by primary and non-primary sexual partners, two (4%) of 53 tests from participants in antenatal care, two (2%) of 91 in post-partum care, and 41 (14%) of 298 from female sex workers had positive results. Participants reported sexual intercourse with 235 (62%) of 380 sexual partners who tested HIV-negative, compared with eight (18%) of 45 who tested HIV-positive (p<0.0001); condoms were used in all eight intercourse events after positive results compared with 104 (44%) after of negative results (p<0.0018). Four participants reported intimate partner violence as a result of self-test distribution: two in the post-partum care group and two female sex workers. No other adverse events were reported. INTERPRETATION: Provision of multiple HIV self-tests to women at high risk of HIV infection was successful in promoting HIV testing among their sexual partners and in facilitating safer sexual decisions. This novel strategy warrants further consideration as countries develop self-testing policies and programmes. FUNDING: Bill & Melinda Gates Foundation. PMID- 27240790 TI - Home testing and counselling to reduce HIV incidence in a generalised epidemic setting: a mathematical modelling analysis. AB - BACKGROUND: Home HIV testing and counselling (HTC) achieves high levels of HIV testing and linkage to care. Periodic home HTC, particularly targeted to those with high HIV viral load, might facilitate expansion of antiretroviral therapy (ART) coverage. We used a mathematical model to assess the effect of periodic home HTC programmes on HIV incidence in KwaZulu-Natal, South Africa. METHODS: We developed a dynamic HIV transmission model with parameters, primary cost data, and measures of viral suppression collected from a prospective study of home HTC in KwaZulu-Natal. In our model, we assumed home HTC took place every 5 years with ART initiation for people with CD4 counts of 350 cells per MUL or less. For individuals with CD4 counts of more than 350 cells per MUL, we compared increasing ART coverage for those with 350-500 cells per MUL with initiating treatment for those who have viral loads of more than 10 000 copies per mL. FINDINGS: Maintaining the presently observed level of 36% viral suppression in HIV-positive people, HIV incidence decreases by 33.8% over 10 years. Home HTC every 5 years with linkage to care with ART initiation at CD4 counts of 350 cells per MUL or less reduces HIV incidence by 40.6% over 10 years. Expansion of ART to people with CD4 counts of more than 350 cells per MUL who also have a viral load of 10 000 copies per mL or more decreases HIV incidence by 51.6%, and this was the most cost-effective strategy for prevention of HIV infections at US$2960 per infection averted. Expansion of ART eligibility CD4 counts of 350-500 cells per MUL is cost-effective at $900 per quality-adjusted life-year gained. Following health economic guidelines, expansion of ART use to individuals who have viral loads of more than 10 000 copies per mL among those with CD4 counts of more than 350 cells per MUL was cost-effective to reduce HIV-related morbidity. INTERPRETATION: Our results show that province-wide home HTC every 5 years can be a cost-effective strategy to increase ART coverage and reduce HIV burden. Expanded ART initiation criteria that includes individuals with high viral load will improve the effectiveness of home HTC in linking individuals to ART who are at high risk of transmitting HIV, thereby preventing morbidity and onward transmission. FUNDING: National Institutes of Health. PMID- 27240791 TI - [Anatomy and physiology of the nasolacrimal ducts]. AB - Ophthalmologists and interventional radiologists are not the only professionals for whom diseases of the efferent tear duct system occupy centre stage; this applies also to ENT specialists involving endonasal conservative or surgical treatment. On the basis of current knowledge and taking account of results yielded by own research in recent years and of clinical aspects, we here give an overview of basic knowledge on the anatomy and physiology of the nasolacrimal system. In doing so functional aspects regarding tear transport as well as embryological and pathophysiological issues are integrated. PMID- 27240792 TI - [Concretions and iatrogenic foreign bodies in the lacrimal system : Treatment recommendations]. AB - BACKGROUND: Deposits (dacryoliths or foreign bodies) inside the lacrimal system can cause chronic inflammation and recurrent lacrimal stenosis. Furthermore, dacryoliths can occur due to chronic inflammation. OBJECTIVE: Considering typical clinical courses, the different localizations and surgical options for removing deposits from the lacrimal system are demonstrated. MATERIALS AND METHODS: A retrospective analysis of 1451 lacrimal surgeries in 1131 patients was performed. Fourteen representative lacrimal surgeries of 11 patients were retrospectively analyzed in terms of current complaints, prior surgery, and the performed surgical intervention. In three cases, histologic findings of removed dacryoliths were assessed. The surgical approaches are described using precise photodocumentation. RESULTS: In 220 lacrimal surgeries (15.2 %), dacryoliths were detected. Iatrogenic foreign bodies were found in 0.8 % (n = 12). All chosen patients suffered painful chronic inflammation of the lacrimal system. Localization was either intrasaccular or intracanalicular. In 10 eyes, surgery was performed using a transcanalicular dacryoendoscope, either alone or in combination with another method. An external approach (transcutaneous/transconjunctival) was performed in 4 patients. Regarding the whole study population, dacryoliths were found in 16.9 % (n = 91) of dacryocystorhinostomies, in 14.6 % (n = 77) of dacryoendoscopies, and in 35.6 % (n = 52) of canaliculotomies. CONCLUSION: Foreign bodies and dacryoliths are important differential diagnoses in the treatment of chronic dacryocystitis. Different surgical approaches are possible and should be available for treatment. Patients' history often reports prior lacrimal surgery. PMID- 27240793 TI - [Laryngeal and larynx-associated reflexes]. AB - The laryngeal adductor reflex and the pharyngoglottal closure reflex protect the trachea and lower respiratory tract against the entrance of foreign material. The laryngeal expiration reflex and the cough reflex serve to propel foreign material, which has penetrated in the cranial direction. The inspiration reflex, the sniff reflex, and the swallowing reflex are further larynx-associated reflexes. In patients with dysphagia the laryngeal adductor reflex can be clinically tested with air pulses. The water swallow test serves to show the integrity of the cough reflex. The sniff reflex is useful to test the abduction function of the vocal folds. Future studies should address laryngeal reflexes more specifically, both for a better understanding of these life-supporting mechanisms and to improve diagnostic procedures in patients with impaired laryngeal function. PMID- 27240798 TI - June 2016 message from APIC: APIC 2016: Recognizing high achievement in infection prevention. PMID- 27240794 TI - [Medical examination: Preparation for ENT specialisation : Part 25]. PMID- 27240799 TI - A comparative evaluation of antimicrobial coated versus nonantimicrobial coated peripherally inserted central catheters on associated outcomes: A randomized controlled trial. AB - BACKGROUND: Central line-associated bloodstream infections (CLABSIs) are a common life-threatening risk factor associated with central venous catheters (CVCs). Research has demonstrated benefit in reducing CLABSIs when CVCs coated with antimicrobials are inserted. The impact of chlorhexidine (CHG)-impregnated versus non-CHG peripherally inserted central catheters (PICCs) on risk of CLABSI is unknown. Venous thromboembolism (VTE) is also a complication associated with CVCs. This study compares the impact of both PICC lines on these outcomes. METHODS: Patients in 3 high-risk units were randomly assigned to receive either a CHG-impregnated or non-CHG PICC line. Laboratory data were collected and reviewed daily on all study patients. The PICC dressing site was assessed daily. Medical record documentation was reviewed to determine presence of CLABSI or VTE. RESULTS: There were 167 patients who completed the study. Three patients developed CLABSI (2 in the CHG group, and 1 in the non-CHG group), and 3 patients developed VTE (2 in the non-CHG group, and 1 in the CHG group). No significant relationship was noted between the type of PICC line on development of a CLABSI (P = .61) or VTE (P > .99). A significant difference was noted in moderate bleeding (P <= .001) requiring thrombogenic dressing in the patients who had the CHG PICC line. CONCLUSIONS: No differences were noted in the development of CLABSI and VTE between the CHG and non-CHG groups. PMID- 27240800 TI - Evidence-based practices to increase hand hygiene compliance in health care facilities: An integrated review. AB - BACKGROUND: Hand hygiene (HH) in health care facilities is a key component to reduce pathogen transmission and nosocomial infections. However, most HH interventions (HHI) have not been sustainable. AIMS: This review aims to provide a comprehensive summary of recently published evidence-based HHI designed to improve HH compliance (HHC) that will enable health care providers to make informed choices when allocating limited resources to improve HHC and patient safety. METHODS: The Medline electronic database (using PubMed) was used to identify relevant studies. English language articles that included hand hygiene interventions and related terms combined with health care environments or related terms were included. RESULTS: Seventy-three studies that met the inclusion criteria were summarized. Interventions were categorized as improving awareness with education, facility design, and planning, unit-level protocols and procedures, hospital-wide programs, and multimodal interventions. Past successful HHIs may not be as effective when applied to other health care environments. HH education should be interactive and engaging. Electronic monitoring and reminders should be implemented in phases to ensure cost-effectiveness. To create hospitalwide programs that engage end users, policy makers should draw expertise from interdisciplinary fields. Before implementing the various components of multimodal interventions, health care practitioners should identify and examine HH difficulties unique to their organizations. CONCLUSIONS: Future research should seek to achieve the following: replicate successful HHI in other health care environments, develop reliable HHC monitoring tools, understand caregiver patient-family interactions, examine ways (eg, hospital leadership, financial support, and strategies from public health and infection prevention initiatives) to sustain HHC, and use simulated lab environments to refine study designs. PMID- 27240801 TI - Beyond Access: Characteristics of the Food Environment and Risk of Diabetes. AB - Characteristics of the built environment, including access to unhealthy food outlets, are hypothesized to contribute to type 2 diabetes mellitus (T2D). Swedish nationwide registry data on 4,718,583 adults aged 35-80 years living in 9,353 neighborhoods, each with at least 1 food outlet, were geocoded and linked to commercial registers (e.g., restaurants and grocery stores). Multilevel logistic regression was used to examine the prospective relationship between characteristics of the food environment and T2D from 2005 to 2010. Relative access to health-harming food outlets was associated with greater likelihood of both prevalent and incident T2D in a curvilinear manner, with the highest risk being observed for environments in which one-third of outlets were health harming. Relative to individuals whose food environment did not change, those who moved into areas with more health-harming food outlets had higher odds of developing T2D (odds ratio = 3.67, 95% confidence interval: 2.14, 6.30). Among those who did not move, living in an area that gained relative access to health harming food outlets was also associated with higher odds of T2D (odds ratio = 1.72, 95% confidence interval: 1.27, 2.33). These results suggest that local food environment, including changes that result in greater access to unhealthy food outlets, is associated with T2D. PMID- 27240802 TI - Silencing GTSE-1 expression inhibits proliferation and invasion of hepatocellular carcinoma cells. AB - G2 and S phase-expressed-1 (GTSE1) was recently reported to upregulate in several types of human cancer, based on negatively regulate p53 expression. However, its expression and functional roles in hepatocellular carcinoma (HCC) remain unknown. In this study, GTSE1 was observed to be highly expressed in HCC specimens and cell lines both at messenger RNA (mRNA) and protein levels. Furthermore, high GTSE1 expression was positively associated with tumor size, venous invasion, advanced tumor stage, and short overall survival. Moreover, we generated stable GTSE1 knockdown HCC cell lines to explore the effects of GTSE1 silencing on the growth and invasion of HCC in vitro. In determining the pathway through which GTSE1 regulated cell proliferation and invasion, GTSE1 silencing was found to inhibit AKT phosphorylation and downregulated cell cycle-related protein. In addition, GTSE1 downregulation decreased the growth of xenografts. In conclusion, these results indicated for the first time that overexpression of GTSE1 was involved in the progress of HCC, enhancing proliferation and promoting cell invasion in HCC cells. PMID- 27240803 TI - Computational approaches to find the active binding sites of biological targets against busulfan. AB - Determination of electrophilic and nucleophilic sites of a molecule is the primary task to find the active sites of the lead molecule. In the present study, the active sites of busulfan have been predicted by molecular electrostatic potential surface and Fukui function analysis with the help of dispersion corrected density functional theory. Similarly, the identification of active binding sites of the proteins against lead compound plays a vital role in the field of drug discovery. Rigid and flexible molecular docking approaches are used for this purpose. For rigid docking, Hex 8.0.0 software employing fast Fourier transform (FFT) algorithm has been used. The partial flexible blind docking simulations have been performed with AutoDock 4.2 software; where a Lamarckian genetic algorithm is employed. The results showed that the most electrophilic atoms of busulfan bind with the targets. It is clear from the docking studies that busulfan has inhibition capability toward the targets 12CA and 1BZM. Graphical Abstract Docking of ligand and protein. PMID- 27240805 TI - Immunohistochemical analysis of thymidylate synthase expression in gastric carcinoma: correlation with clinicopathological parameters and survival. AB - The correlation of thymidylate synthase (TS) expression in gastric cancers with tumor histology and prognostic or predictive information remains unclear. Most studies have involved Asian populations, with few conducted in European cohorts. Moreover, all published studies analyze TS expression using semi-quantitative methods. This retrospective study evaluated the association of TS expression in tumor cells with gastric carcinoma histological type, with selected clinicopathological parameters, and with the prognosis of patients who underwent surgical treatment. TS expression was detected using immunochemistry and objectively assessed by computerized image analysis of tumor cells in 100 gastric cancers. We found that high TS expression was significantly more common in intestinal than in diffuse type of gastric cancer according to Lauren classification (P=0.0003); in type I carcinomas compared to type IV according to Goseki classification (P=0.002); and in gastric cancers in men than women (P=0.04). Low TS expression was found more often in carcinomas in the middle and lower third of the stomach than in cancers in the upper third of the stomach (P=0.009 and P=0.001, respectively). In the subgroup of 25 patients without lymph node metastases (stage I+II), high TS expression was associated with better DFS (83% for high TS expression versus 38,5% for low TS expression, P=0.03). The results (1) indicate significant correlation between the Lauren and Goseki histopathological classifications of gastric cancer and TS expression in tumor cells, (2) suggest that high TS expression may be a positive prognostic marker with regard to DFS in patients with gastric cancer without involvement of regional lymph nodes who underwent radical surgical treatment and were not treated with preoperative chemotherapy. Prognostic results need confirmation in larger cohorts. PMID- 27240804 TI - To what extent and why are COPD and Willis-Ekbom disease associated? AB - AIM: Willis-Ekbom disease (RLS/WED) is common in chronic obstructive pulmonary disease (COPD). Patients with RLS/WED have poorer quality of sleep and more fatigue and depressive symptoms. The prevalence of RLS/WED in patients with COPD has been reported to vary between 29.1 and 36.8 %. However, during exacerbation, the prevalence can increase up to 54 %. These rates are higher than those seen in general population. We have not enough knowledge regarding the association between RLS and COPD. In this study, we aimed to determine the frequency of RLS in patients with stable COPD without comorbid conditions. In addition, we also aimed to determine possible related causative factors. METHOD: We included 80 COPD patients without comorbid conditions who presented to our outpatient clinic between April 2013 and September 2013 for RLS/WED evaluation. Three cases that have polyneuropathy and one case that refused undergoing electromyography (EMG) examination were excluded from the study. Demographic data, P-A chest X-rays, pulmonary function tests (PFT), biochemical parameters (including hemogram), and dyspnea scales were evaluated for each patient. In addition, the RLS/WED rating scale and Epworth Sleep Scale (ESS) were applied. Further, each patient diagnosed with RLS/WED underwent a detailed neurological examination (performed by a neurologist) and an EMG examination to rule out polyneuropathy. RESULTS: Out of 76 COPD cases included in our study, 26.3 % (n = 20) were diagnosed with RLS/WED (mean age 60.4 +/- 7.5 years, 20 males). The cases with RLS/WED had significantly lower body mass index (BMI) than cases without RLS/WED (p = 0.009). There were no significant differences between cases with and without RLS/WED with respect to PFT, dyspnea scales, and arterial blood gas values. However, ESS was significantly different (p = 0.016). There were no significant differences in RLS/WED scores and mean hs-CRP levels between COPD stages (p = 0.424; p = 0.518, respectively), while ESS was significantly different (p = 0.016). ESS was significantly higher in stage B COPD than in stages A and D (p = 0.005, p = 0.008, respectively). Based on our model, we found that exacerbations and iron binding capacity (UIBC) were predictive factors for RLS/WED (p < 0.100) CONCLUSION: RLS/WED is a common disease in cases with stable COPD. Despite our hypothesis suggesting that the prevalence of RLS/WED in COPD is related with systemic inflammation, we did not find a significant association between hs-CRP and COPD cases with RLS/WED. However, we did find that UIBC is a predictive factor for the development of RLS/WED. Nonetheless, further studies are needed to understand the relationships between UIBC, low BMI, and the development of RLS/WED in COPD. PMID- 27240806 TI - Non-Invasive Brain Stimulation for Treatment of Focal Hand Dystonia: Update and Future Direction. AB - Focal hand dystonia (FHD) is characterized by excessive and unwanted muscle activation in both the hand and arm resulting in impaired performance in particular tasks. Understanding the pathophysiology of FHD has progressed significantly for several decades and this has led to consideration of other potential therapies such as non-invasive brain stimulation (NIBS). A number of studies have been conducted to develop new therapy for FHD using transcranial magnetic stimulation and transcranial direct current stimulation. In this paper, we review previous studies and describe the potential therapeutic use of NIBS for FHD. We also discuss the future direction of NIBS to treat FHD. PMID- 27240807 TI - Movement Disorders Following Cerebrovascular Lesions: Etiology, Treatment Options and Prognosis. AB - Post-stroke movement disorders are uncommon, but comprise an important part of secondary movement disorders. These exert variable and heterogeneous clinical courses according to the stroke lesion and its temporal relationships. Moreover, the predominant stroke symptoms hinder a proper diagnosis in clinical practice. This article describes the etiology, treatment options and prognosis of post stroke movement disorders. PMID- 27240808 TI - Movement Disorders Following Cerebrovascular Lesion in the Basal Ganglia Circuit. AB - Movement disorders are primarily associated with the basal ganglia and the thalamus; therefore, movement disorders are more frequently manifest after stroke compared with neurological injuries associated with other structures of the brain. Overall clinical features, such as types of movement disorder, the time of onset and prognosis, are similar with movement disorders after stroke in other structures. Dystonia and chorea are commonly occurring post-stroke movement disorders in basal ganglia circuit, and these disorders rarely present with tremor. Rarer movement disorders, including tic, restless leg syndrome, and blepharospasm, can also develop following a stroke. Although the precise mechanisms underlying the pathogenesis of these conditions have not been fully characterized, disruptions in the crosstalk between the inhibitory and excitatory circuits resulting from vascular insult are proposed to be the underlying cause. The GABA (gamma-aminobutyric acid)ergic and dopaminergic systems play key roles in post-stroke movement disorders. This review summarizes movement disorders induced by basal ganglia and thalamic stroke according to the anatomical regions in which they manifest. PMID- 27240809 TI - Movement Disorders Following Cerebrovascular Lesions in Cerebellar Circuits. AB - Cerebellar circuitry is important to controlling and modifying motor activity. It conducts the coordination and correction of errors in muscle contractions during active movements. Therefore, cerebrovascular lesions of the cerebellum or its pathways can cause diverse movement disorders, such as action tremor, Holmes' tremor, palatal tremor, asterixis, and dystonia. The pathophysiology of abnormal movements after stroke remains poorly understood. However, due to the current advances in functional neuroimaging, it has recently been described as changes in functional brain networks. This review describes the clinical features and pathophysiological mechanisms in different types of movement disorders following cerebrovascular lesions in the cerebellar circuits. PMID- 27240810 TI - Cerebrospinal Fluid Amyloid beta1-42, Tau, and Alpha-Synuclein Predict the Heterogeneous Progression of Cognitive Dysfunction in Parkinson's Disease. AB - Parkinson's disease (PD) is a neurodegenerative disease with heterogeneous pathological and clinical features. Cognitive dysfunction, a frequent non-motor complication, is a risk factor for poor prognosis and shows inter-individual variation in its progression. Of the clinical studies performed to identify biomarkers of PD progression, the Parkinson's Progression Markers Initiative (PPMI) study is the largest study that enrolled drug-naive and very early stage PD patients. The baseline characteristics of the PPMI cohort were recently published. The diagnostic utility of cerebrospinal fluid (CSF) biomarkers, including alpha-synuclein (alpha-syn), total tau, phosphorylated tau at Thr181, and amyloid beta1-42, was not satisfactory. However, the baseline data on CSF biomarkers in the PPMI study suggested that the measurement of the CSF biomarkers enables the prediction of future cognitive decline in PD patients, which was consistent with previous studies. To prove the hypothesis that the interaction between Alzheimer's pathology and alpha-syn pathology is important to the progression of cognitive dysfunction in PD, longitudinal observational studies must be followed. In this review, the neuropathological nature of heterogeneous cognitive decline in PD is briefly discussed, followed by a summarized interpretation of baseline CSF biomarkers derived from the data in the PPMI study. The combination of clinical, biochemical, genetic and imaging biomarkers of PD constitutes a feasible strategy to predict the heterogeneous progression of PD. PMID- 27240811 TI - Woodhouse-Sakati Syndrome: Report of the First Tunisian Family with the C2orf37 Gene Mutation. AB - Woodhouse-Sakati syndrome (WSS) is an infrequent autosomal recessive condition characterized by progressive extrapyramidal signs, mental retardation, hypogonadism, alopecia, and diabetes mellitus. This syndrome belongs to a heterogeneous group of inherited neurodegenerative disorders characterized iron accumulation in the brain, and it is caused by mutations of the C2orf37 gene. We report the first Tunisian family with two affected sisters presenting with a phenotype suggestive of WSS. We examined the index patient presenting with movement disorders and mental retardation and then searched for similar cases in her family, which identified a sister with similar signs. We performed a genetic study that confirmed the diagnosis and revealed a c.436delC mutation of the C2orf37 gene. Therefore, WSS is an important consideration in patients presenting with movement disorders and intellectual disability. A high consanguinity contributes to the clustering of such rare autosomal recessive syndromes. PMID- 27240812 TI - Regulatory elements: Putting enhancers into context. PMID- 27240814 TI - Anomalous origin of the left coronary artery from the pulmonary artery in children: diagnostic use of multidetector computed tomography. AB - BACKGROUND: Anomalous origin of the left coronary artery from the pulmonary artery is a rare congenital anomaly. It is important to demonstrate the anomalous origin of the left coronary artery and its course before surgery. OBJECTIVE: To explore the clinical diagnostic use of multidetector CT coronary angiography in detecting anomalous origin of the left coronary artery from the pulmonary artery in children. MATERIALS AND METHODS: Nine children (2 boys, 7 girls) ages 2 months to 9 years with surgically confirmed anomalous origin of the left coronary artery from the pulmonary artery were studied. Clinical data, transthoracic echocardiography and CT coronary angiography images were retrospectively analyzed. RESULTS: Transthoracic echocardiography correctly diagnosed anomalous origin of the left coronary artery from the pulmonary artery in 7 of 9 patients (95% CI: 40-97%). CT coronary angiography revealed the anomalous origin of the left coronary artery in all children (95% CI: 66-100%). In a 4-year-old girl and a 9-year-old girl, CT coronary angiography showed dilation of the right coronary artery and collateral circulation between the right and the left coronary arteries. CONCLUSION: CT coronary angiography is a useful method to show the anomalous origin of the coronary artery in children with anomalous origin of the left coronary artery from the pulmonary artery, especially for patients in whom origin of the left coronary artery cannot be detected by transthoracic echocardiography. PMID- 27240815 TI - Spectroscopic ellipsometry as a complementary tool to characterize coatings on PDMS for CE applications. AB - This paper describes the use of spectroscopic ellipsometry to investigate the adsorption process of model polyelectrolytes (PDDAC and PSS) to thin-films of PDMS. A description of the information collected by ellipsometry as well as complementary information obtained by atomic force microscopy and contact angle measurements is discussed. Upon identification of the driving forces and optimum experimental conditions required for the adsorption, multilayer constructs were fabricated (ranging from 1 to 20 nm in thickness) and used to evaluate their effect on the separation of phenolic compounds by capillary electrophoresis. According to the presented results, polyelectrolyte layers of approximately 10 nm thick provided the best conditions for the separation of the selected phenolic compounds. PMID- 27240813 TI - Lessons from non-canonical splicing. AB - Recent improvements in experimental and computational techniques that are used to study the transcriptome have enabled an unprecedented view of RNA processing, revealing many previously unknown non-canonical splicing events. This includes cryptic events located far from the currently annotated exons and unconventional splicing mechanisms that have important roles in regulating gene expression. These non-canonical splicing events are a major source of newly emerging transcripts during evolution, especially when they involve sequences derived from transposable elements. They are therefore under precise regulation and quality control, which minimizes their potential to disrupt gene expression. We explain how non-canonical splicing can lead to aberrant transcripts that cause many diseases, and also how it can be exploited for new therapeutic strategies. PMID- 27240816 TI - Nutritional Intervention to Improve the Quality of Lunchboxes Among Mexican School Children. AB - In Mexico, the type of foods included in the lunchboxes of school children are unhealthy. The aim of this study was to evaluate the effects of an intervention program to improve the quality of the foods in the lunchboxes. Two schools were randomly selected as the intervention group (IG) and two more as the control group (CG). The evaluation was performed by comparing a food list from 3 days before and 6 months after the intervention. The components of the intervention included: exposure to posters inside and outside the classrooms and the distribution of pamphlets to parents, the pamphlets provided recipes and information about healthy foods. A lunchbox was considered adequate (AL) if it had less than 276 cal, fruits or vegetables, and an item prepared at home; a healthy lunchbox (HL) consisted of fruits or vegetables, water, and it did not have unhealthy foods. At the beginning of the study there were no significant differences in the compliance of AL and HL in both groups. By the end of the study, 19 % of the children in the IG and 10 % of the children in the CG met the criteria of a HL (p = 0.002). The results of this study demonstrate that a simple, 6 month intervention targeting parents improved the quality of the foods in the lunchboxes of second and sixth graders. PMID- 27240819 TI - Amorphous MoSx thin-film-coated carbon fiber paper as a 3D electrode for long cycle life symmetric supercapacitors. AB - Amorphous MoSx thin-film-coated carbon fiber paper as a binder-free 3D electrode was synthesized by a facile hydrothermal method. The maximum specific capacitance of a single electrode was 83.9 mF cm(-2), while it was 41.9 mF cm(-2) for the symmetric device. Up to 600% capacitance retention was observed for 4750 cycles. PMID- 27240818 TI - Categorization and Prediction of Crimes of Passion Based on Attitudes Toward Violence. AB - The present study explored implicit and explicit attitudes toward violence in crimes of passion. Criminals ( n = 96) who had perpetrated crimes of passion and students ( n = 100) participated in this study. Explicit attitudes toward violence were evaluated using the Abnormal Personality Risk Inventory (APRI), and implicit attitude toward violence was evaluated using the Implicit Association Test (IAT). Results indicated that APRI scores of the perpetrators were significantly higher than that of the control group ( p < .05), suggesting that explicit attitudes toward violence could discriminate between the criminals and the control group. There was a significant IAT effect demonstrating a negative implicit attitude toward violence in both the control group and in the criminals ( n = 68); whereas there was a significant IAT effect manifesting a positive implicit attitude toward violence in the criminals ( n = 16) only. These results suggest that combining explicit and implicit attitudes could provide an empirical classification of crimes of passion. PMID- 27240820 TI - Quality of life in patients undergoing orthognathic surgery - A two-centered Swedish study. AB - AIM: Surgical corrections of dentofacial deformities have both physical and psychological impact on quality of life (QoL). The objectives of the present study were to evaluate the impact of oral health related problems on QoL before and after a combination of orthodontic treatment and orthognathic surgery. Additionally, the study aimed to identify correlations between different dentofacial patterns and possible improvements due to treatment. MATERIAL AND METHODS: In a prospective study, we evaluated fifty patients before start of treatment, 6 weeks and 6 months postoperatively. The questionnaires used were: OHIP-14 (Short Form Oral Health Impact Profile), a condition-specific QOL approach (Orthognathic Quality of Life Questionnaires; OQLQ) and a social demographic questionnaire. RESULTS: There was a statistically significant improvement in the OHIP domains from baseline to 6 months follow-up and for the OQLQ, the improvement was significant both at 6 weeks and 6 months in relation to the baseline data. CONCLUSION: Significant improvement of quality of life over time is proved by both OHIP-14 and OQLQ in the present study. Socio-demographic and holistic considerations are important when evaluating treatment outcome after combined orthodontic and orthognatic surgery. However, longer follow-up would be beneficial. PMID- 27240817 TI - Spermatogonial stem cell autotransplantation and germline genomic editing: a future cure for spermatogenic failure and prevention of transmission of genomic diseases. AB - BACKGROUND: Subfertility affects approximately 15% of all couples, and a severe male factor is identified in 17% of these couples. While the etiology of a severe male factor remains largely unknown, prior gonadotoxic treatment and genomic aberrations have been associated with this type of subfertility. Couples with a severe male factor can resort to ICSI, with either ejaculated spermatozoa (in case of oligozoospermia) or surgically retrieved testicular spermatozoa (in case of azoospermia) to generate their own biological children. Currently there is no direct treatment for azoospermia or oligozoospermia. Spermatogonial stem cell (SSC) autotransplantation (SSCT) is a promising novel clinical application currently under development to restore fertility in sterile childhood cancer survivors. Meanwhile, recent advances in genomic editing, especially the clustered regulatory interspaced short palindromic repeats-associated protein 9 (CRISPR-Cas9) system, are likely to enable genomic rectification of human SSCs in the near future. OBJECTIVE AND RATIONALE: The objective of this review is to provide insights into the prospects of the potential clinical application of SSCT with or without genomic editing to cure spermatogenic failure and to prevent transmission of genetic diseases. SEARCH METHODS: We performed a narrative review using the literature available on PubMed not restricted to any publishing year on topics of subfertility, fertility treatments, (molecular regulation of) spermatogenesis and SSCT, inherited (genetic) disorders, prenatal screening methods, genomic editing and germline editing. For germline editing, we focussed on the novel CRISPR-Cas9 system. We included papers written in English only. OUTCOMES: Current techniques allow propagation of human SSCs in vitro, which is indispensable to successful transplantation. This technique is currently being developed in a preclinical setting for childhood cancer survivors who have stored a testis biopsy prior to cancer treatment. Similarly, SSCT could be used to restore fertility in sterile adult cancer survivors. In vitro propagation of SSCs might also be employed to enhance spermatogenesis in oligozoospermic men and in azoospermic men who still have functional SSCs albeit in insufficient numbers. The combination of SSCT with genomic editing techniques could potentially rectify defects in spermatogenesis caused by genomic mutations or, more broadly, prevent transmission of genomic diseases to the offspring. In spite of the promising prospects, SSCT and germline genomic editing are not yet clinically applicable and both techniques require optimization at various levels. WIDER IMPLICATIONS: SSCT with or without genomic editing could potentially be used to restore fertility in cancer survivors to treat couples with a severe male factor and to prevent the paternal transmission of diseases. This will potentially allow these couples to have their own biological children. Technical development is progressing rapidly, and ethical reflection and societal debate on the use of SSCT with or without genomic editing is pressing. PMID- 27240821 TI - Oncological benefit of lateral pelvic lymph node dissection for rectal cancer treated without preoperative chemoradiotherapy: a multicenter retrospective study using propensity score analysis. AB - PURPOSE: We aimed to clarify the prognostic impact of lateral pelvic lymph node (LPN) dissection (LPND) for rectal cancer through a multicenter retrospective study using propensity score analysis. METHODS: A total of 1238 patients with pathological T2-4, M0 rectal cancer who had undergone curative operation between 2007 and 2008 were examined. Majority of the patients (96 %) were treated without preoperative chemoradiotherapy (CRT). Clinical background data of the patients treated with LPND and those treated without LPND were matched using propensity scores, and hazard ratios (HRs) for cancer-specific mortality were compared. RESULTS: LPND was performed more frequently for lower rectal cancers and in patients with more advanced disease, and 29 % of the patients were treated with LPND. After matching background features by propensity scores, LPND did not correlate with improved cancer-specific survival (CSS) among the entire study population [HR, 0.73; 95 % confidence interval (CI) 0.41-1.31; P = 0.28]; however, LPND was correlated with significantly improved CSS in female patients (HR, 0.23; 95 % CI, 0.06-0.89; P = 0.04) but not in male patients (HR, 0.95; 95 % CI, 0.48-1.89; P = 0.89). The results were similar when patients treated with LPND finally diagnosed as pathologically negative for LPN metastasis were compared with those curatively treated without LPND. CONCLUSIONS: It is suggested that the prognostic impact of LPND for rectal cancer treated without CRT might be different between sexes, and LPND should be considered for female rectal cancer patients although they are diagnosed as clinically negative for LPN metastasis. PMID- 27240823 TI - Letter to the Editor on the article "The role of low CRP values in the prediction of the development of acute diverticulitis". PMID- 27240822 TI - Side-to-end vs. straight stapled colorectal anastomosis after low anterior resection: results of randomized clinical trial. AB - AIM: The aim of this study is to compare surgical, functional, physiologic outcomes and QOL after low anterior resection (LAR) with andside-to-end or straight colorectal anastomosis. METHOD: Between 2012 and 2015, 86 patients with mid and low rectal tumors were enrolled into randomized trial. Wexner score, number of defecations, use of antidiarrheal medicine or laxatives, enemas, pads, episodes of nocturnal incontinence, and urgency were recorded. The Fecal Incontinence Quality of Life (FIQL) scale was used for assessment of QOL. Anal manometry and volumetric examination were performed. RESULTS: Six patients were excluded from the study. There was no mortality. The morbidity rate was 6 (14.6 %) for side-to-end vs. 8 (20.0 %) for straight anastomosis (p = 0.57). The median Wexner score was 5 vs. 6 (p = 0.033), 4 vs. 5 (p = 0.006), and 2 vs. 3 (p = 0.1) at 1, 3, and 6 months after stoma reversal, respectively. Side-to-end anastomosis resulted in a fewer mean numbers of bowel movements per day at the same check points of follow-up: 5.8 +/- 0.14 vs. 6.4 +/- 0.15 (p = 0.006), 3.7 +/- 0.1 vs. 4.2 +/- 0.1 (p = 0.003), and 2.5 +/- 0.1 vs. 3.0 +/- 0.10 (p = 0.0002), correspondingly. Maximal tolerated volume was higher for side-to-end anastomosis at 3 and 6 months of follow-up: 152.0 vs. 137.8 cm(3) (p = 0.002) and 180.5 vs. 167.0 cm(3) (p = 0.006), respectively. Better FIQL score was found at 1 and 3 months in the side-to-end group. CONCLUSION: Better functional outcomes and QOL were observed in a short period after stoma closure, but at 6 months of follow up, the only benefit of side-to-end anastomosis was a lower number of bowel movements. PMID- 27240824 TI - Apoplastic H2 O2 plays a critical role in axillary bud outgrowth by altering auxin and cytokinin homeostasis in tomato plants. AB - Although phytohormones such as indole-3-acetic acid (IAA), cytokinin (CK) and strigolactone are important modulators of plant architecture, it remains unclear whether reactive oxygen species are involved in the regulation of phytohormone dependent axillary bud outgrowth in plants. We used diverse techniques, including transcriptional suppression, HPLC-MS, biochemical methodologies and gene transcript analysis to investigate the signaling pathway for apoplastic hydrogen peroxide (H2 O2 )-induced axillary bud outgrowth. Silencing of tomato RESPIRATORY BURST OXIDASE HOMOLOG 1 (RBOH1) and WHITEFLY INDUCED 1 (WFI1), two important genes involved in H2 O2 production in the apoplast, enhanced bud outgrowth, decreased transcript of FZY - a rate-limiting gene in IAA biosynthesis and IAA accumulation in the apex - and increased the transcript of IPT2 involved in CK biosynthesis and CK accumulation in the stem node. These effects were fully abolished by the application of exogenous H2 O2 . Both decapitation and the silencing of FZY promoted bud outgrowth, and downregulated and upregulated the transcripts for IAA3 and IAA15, and IPT2, respectively. However, these effects were not blocked by treatment with exogenous H2 O2 but by napthaleneacetic acid (NAA) treatment. These results suggest that RBOHs-dependent apoplastic H2 O2 promotes IAA biosynthesis in the apex, which, in turn, inhibits CK biosynthesis and subsequent bud outgrowth in tomato plants. PMID- 27240825 TI - Socio-demographic correlates of depression and anxiety among female caregivers living with HIV in rural Uganda. AB - Women living with HIV are at increased risk for psychosocial distress, especially among social and economically disadvantaged women living in rural areas. Little is known about how social support and wealth impacts the mental health of women caring for young children in low- and middle-income countries. The purpose of this paper was to assess demographic, socio-economic, and social support correlates of depression and anxiety in HIV-infected+ female caregivers living in rural Uganda. Depression and anxiety were assessed using the Hopkins Symptom Checklist (HSCL-25), two-domains of social support (family and community) were measured with the adapted Multidimensional Scale for Perceived Social Support, and wealth was measured using a checklist of material possessions and housing quality among 288 women. Multivariable linear regression models assessed the association of depression and anxiety with demographic and social predictors. Sixty-one percent of women reported clinically significant symptoms of depression or anxiety using the standard HSCL-25 cut-off of >1.75. Lower wealth (p = .01) and family support (p = .01) were significantly associated with more depressive symptoms, with greater family support being more protective of depression in the highest wealth group (top 20%) compared to the lowest. More anxiety symptoms were associated with lower wealth (p = .001), lower family support (p = .02), and higher community support (p = .003). Economic and social support factors are important predictors of caregiver mental health in the face of HIV disease in rural Uganda. Findings suggest that interventions should consider ways to increase economic opportunities and strengthen family support for HIV+ caregivers. PMID- 27240826 TI - Weighted gene co-expression network analysis reveals key genes involved in pancreatic ductal adenocarcinoma development. AB - PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy. Up till now, the patient's prognosis remains poor which, among others, is due to the paucity of reliable early diagnostic biomarkers. In the past, candidate diagnostic biomarkers and therapeutic targets have been delineated from genes that were found to be differentially expressed in normal versus tumour samples. Recently, new systems biology approaches have been developed to analyse gene expression data, which may yield new biomarkers. As of yet, the weighted gene co-expression network analysis (WGCNA) tool has not been applied to PDAC microarray-based gene expression data. METHODS: PDAC microarray based gene expression datasets, listed in the Gene Expression Omnibus (GEO) database, were analysed. After pre-processing of the data, we built two final datasets, Normal and PDAC, encompassing 104 and 129 patient samples, respectively. Next, we constructed a weighted gene co-expression network and identified modules of co-expressed genes distinguishing normal from disease conditions. Functional annotations of the genes in these modules were carried out to highlight PDAC-associated molecular pathways and common regulatory mechanisms. Finally, overall survival analyses were carried out to assess the suitability of the genes identified as prognostic biomarkers. RESULTS: Using WGCNA, we identified several key genes that may play important roles in PDAC. These genes are mainly related to either endoplasmic reticulum, mitochondrion or membrane functions, exhibit transferase or hydrolase activities and are involved in biological processes such as lipid metabolism or transmembrane transport. As a validation of the applied method, we found that some of the identified key genes (CEACAM1, MCU, VDAC1, CYCS, C15ORF52, TMEM51, LARP1 and ERLIN2) have previously been reported by others as potential PDAC biomarkers. Using overall survival analyses, we found that several of the newly identified genes may serve as biomarkers to stratify PDAC patients into low- and high-risk groups. CONCLUSIONS: Using this new systems biology approach, we identified several genes that appear to be critical to PDAC development. As such, they may represent potential diagnostic biomarkers as well as therapeutic targets with clinical utility. PMID- 27240827 TI - Multipotent Differentiation of Human Dental Pulp Stem Cells: a Literature Review. AB - The advent of regenerative medicine has brought us the opportunity to regenerate, modify and restore human organs function. Stem cells, a key resource in regenerative medicine, are defined as clonogenic, self-renewing, progenitor cells that can generate into one or more specialized cell types. Stem cells have been classified into three main groups: embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and adult/postnatal stem cells (ASCs). The present review focused the attention on ASCs, which have been identified in many perioral tissues such as dental pulp, periodontal ligament, follicle, gingival, alveolar bone and papilla. Human dental pulp stem cells (hDPSCs) are ectodermal-derived stem cells, originating from migrating neural crest cells and possess mesenchymal stem cell properties. During last decade, hDPSCs have received extensive attention in the field of tissue engineering and regenerative medicine due to their accessibility and ability to differentiate in several cell phenotypes. In this review, we have carefully described the potential of hDPSCs to differentiate into odontoblasts, osteocytes/osteoblasts, adipocytes, chondrocytes and neural cells. PMID- 27240828 TI - Neurobehavioral deficits and brain oxidative stress induced by chronic low dose exposure of persistent organic pollutants mixture in adult female rat. AB - Persistent organic pollutants (POPs) are long-lived organic compounds that are considered one of the major risks to ecosystem and human health. Recently, great concerns are raised about POPs mixtures and its potential toxicity even in low doses of daily human exposure. The brain is mostly targeted by these lipophilic compounds because of its important contain in lipids. So, it would be quite interesting to study the effects of exposure to these mixtures and evaluate their combined toxicity on brain cells. The present study was designed to characterize the cognitive and locomotors deficits and brain areas redox status in rat model. An orally chronic exposure to a representative mixture of POPs composed of endosulfan (2.6 MUg/kg), chlorpyrifos (5.2 MUg/kg), naphthalene (0.023 MUg/kg) and benzopyrane (0.002 MUg/kg); the same mixture with concentration multiplied by 10 and 100 was also tested. Exposed rats have shown a disturbance of memory and a decrease in learning ability concluded by Morris water maze and the open field tests results and anxiolytic behaviour in the test of light/dark box compared to control. Concerning brain redox homeostasis, exposed rats have shown an increased malondialdehyde (MDA) amount and an alteration in glutathione (GSH) levels in both the brain mitochondria and cytosolic fractions of the cerebellum, striatum and hippocampus. These effects were accompanied by a decrease in levels of cytosolic glutathione S-transferase (GST) and a highly significant increase in superoxide dismutase (SOD) and catalase (CAT) activities in both cytosolic and mitochondrial fractions. The current study suggests that environmental exposure to daily even low doses of POPs mixtures through diet induces oxidative stress status in the brain and especially in the mitochondria with important cognitive and locomotor behaviour variations in the rats. PMID- 27240829 TI - Changes in the water quality and bacterial community composition of an alkaline and saline oxbow lake used for temporary reservoir of geothermal waters. AB - Geothermal waters exploited in the southeastern region of Hungary are alkali hydrogen-carbonate type, and beside the high amount of dissolved salt, they contain a variety of aromatic, heteroaromatic, and polyaromatic hydrocarbons. The majority of these geothermal waters used for heating are directed into surface waters following a temporary storage in reservoir lakes. The aim of this study was to gain information about the temporal and spatial changes of the water quality as well as the bacterial community composition of an alkaline and saline oxbow lake operated as reservoir of used geothermal water. On the basis of the water physical and chemical measurements as well as the denaturing gradient gel electrophoresis (DGGE) patterns of the bacterial communities, temporal changes were more pronounced than spatial differences. During the storage periods, the inflow, reservoir water, and sediment samples were characterized with different bacterial community structures in both studied years. The 16S ribosomal RNA (rRNA) gene sequences of the bacterial strains and molecular clones confirmed the differences among the studied habitats. Thermophilic bacteria were most abundant in the geothermal inflow, whereas the water of the reservoir was dominated by cyanobacteria and various anoxygenic phototrophic prokaryotes. In addition, members of several facultative anaerobic denitrifying, obligate anaerobic sulfate reducing and syntrophic bacterial species capable of decomposition of different organic compounds including phenols were revealed from the water and sediment of the reservoir. Most of these alkaliphilic and/or halophilic species may participate in the local nitrogen and sulfur cycles and contribute to the bloom of phototrophs manifesting in a characteristic pink-reddish discoloration of the water of the reservoir. PMID- 27240831 TI - Ellagic acid reduces murine schistosomiasis mansoni immunopathology via up regulation of IL-10 and down-modulation of pro-inflammatory cytokines production. AB - CONTEXT: The main immunopathology in schistosomiasis mansoni consists of a granulomatous inflammatory and fibrosing reaction in the liver and intestine against tissue trapped parasite eggs, which is mediated by CD4(+ )T cells. Ellagic acid (EA), a natural phenolic compound found in fruits and nuts, has potent anti-oxidant and anti-inflammatory properties. OBJECTIVE: The aim of the present study was to evaluate the potential effect of EA in the treatment of murine schistosomiasis mansoni and its induced immunopathology. MATERIALS AND METHODS: Mice were infected, each with 40 Schistosoma mansoni (S. mansoni) cercariae and treated with EA at a total dose of 600 mg/kg body weight. At week eight of infection, mice were sacrificed; worm and egg burden were estimated; hepatic granuloma volume and collagen fibers deposition were evaluated; splenocytes were prepared and cultured in the presence of S. mansoni antigens. RESULTS: EA treatment did not show any significant effect on worm or egg burden. However, hepatic granuloma volume and collagen fibers deposition were largely reduced with EA treatment. EA treatment augmented specific IL-10 production in response to S. mansoni antigenic stimulation. However, specific IL-1beta, IL-4, IL-12, IL-13, IL-17A, TNF-alpha and IFN-gamma production were significantly reduced with ex vivo and in vivo EA treatment. Serum IgM and IgG levels significantly increased, whereas specific IgA and IgE levels did not significantly change with EA treatment. CONCLUSION: EA treatment modulates cellular and humoral immune responses of infected mice and leads to a significant reduction of liver pathology in acute murine schistosomiasis mansoni. PMID- 27240830 TI - Quantitative evaluation of reactive nitrogen emissions with urbanization: a case study in Beijing megacity, China. AB - The rapid increase in anthropogenic nitrogen (N) load in urbanized environment threatens urban sustainability. In this study, we estimated the amount of reactive N (Nr) as an index of N pollution potential caused by human activities, using the megacity of Beijing as a case study. We investigated the temporal changes in Nr emissions in the environment from 2000 to 2012 using a multidisciplinary approach with quantitative evaluation. The Nr emissions presented slightly increasing during study period, and the annual emission was 0.19 Tg N, mainly resulting from fuel combustion. Nevertheless, the Nr output intensity resulting from inhabitants' livelihoods and material production had weakened over the study period. The evaluation results showed that the environmental measures to remove Nr in Beijing were efficient in most years, suggesting that progress in mitigating the growth of the Nr load in this urban environment was significant. Further measures based on N offset are suggested that could help alleviate the environmental pressure resulting from anthropogenic Nr emissions. These could provide theoretical support for the sustainable development of megacities. PMID- 27240832 TI - Genomic profiling and directed ex vivo drug analysis of an unclassifiable myelodysplastic/myeloproliferative neoplasm progressing into acute myeloid leukemia. AB - Myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U) are rare genetically heterogeneous hematologic diseases associated with older age and a poor prognosis. If the disease progresses into acute myeloid leukemia (AML), it is often refractory to treatment. To gain insight into genetic alterations associated with disease progression, whole exome sequencing and single nucleotide polymorphism arrays were used to characterize the bone marrow and blood samples from a 39-year-old woman at MDS/MPN-U diagnosis and at AML progression, in which routine genetic diagnostics had not identified any genetic alterations. The data revealed the presence of a partial tandem duplication of the MLL gene as the only detectable copy number change and 11 non-silent somatic mutations, including DNMT3A R882H and NRAS G13D. All somatic lesions were present both at initial MDS/MPN-U diagnosis and at AML presentation at similar mutant allele frequencies. The patient has since had two extramedullary relapses and is at high risk of a future bone marrow relapse. A directed ex vivo drug sensitivity analysis showed that the patient's AML cells are sensitive to, for example, the MEK inhibitor trametinib and the proteasome inhibitor bortezomib, indicating that she may benefit from treatment with these drugs. (c) 2016 Wiley Periodicals, Inc. PMID- 27240834 TI - Component-Resolved Diagnosis of Peanut Allergy and Its Possible Origins of Sensitization in China. AB - BACKGROUND: Clinical and immunological characteristics of food allergies vary depending on geographic regions. Little is known about peanut allergy in China. The aim of this study was to investigate the peanut sensitization profile in China. METHODS: Thirty-eight participants with immunoglobulin E (IgE)-positive responses to peanuts (peanut-sensitized) were included in our study, and clinical characteristics were evaluated. Total and specific IgE reactivity against peanuts, other plant-derived foods, pollens, and related allergen components were determined. RESULTS: Eighteen patients were symptomatic when exposed to peanuts. The majority of them presented with systemic reactions. More than half of the peanut-sensitized subjects also suffered from mugwort pollinosis and peach allergy. In patients with both peanut and peach allergies, reactions to peanuts were the same as or severer than those to peaches. Positivity rates of IgE response to rAra h 1-3, 8, and 9 in the peanut allergy group were 5.6, 11.1, 5.6, 22.2, and 83.3%, respectively. 66.7% (12/18) of the peanut-allergic patients were monosensitized to rAra h 9. Anti-nArt v 3 [mugwort nonspecific lipid transfer protein (nsLTP)] IgE positivity in the peanut allergy group was significantly higher than that in the asymptomatic peanut-sensitized group. In Ara h 9 (peanut nsLTP)-sensitized patients with mugwort pollinosis, anti-nArt v 3 IgE levels were remarkably higher than anti-rAra h 9 (peanut nsLTP) IgE levels as well as anti Pru p 3 (peach nsLTP) IgE levels. CONCLUSIONS: Ara h 9 was the major allergen of peanut, and Ara h 9 monosensitization was the most common peanut sensitization pattern in our population. Furthermore, there was a strong correlation between peanut sensitization and mugwort pollinosis, as well as peach allergy, in our country. PMID- 27240833 TI - Associations of TNFalpha -308G>A, TNFalpha -238G>A, IL-1alpha -889C>T and IL-10 1082G>A Genetic Polymorphisms with Atopic Diseases: Asthma, Rhinitis and Dermatitis. AB - BACKGROUND: Polymorphisms of cytokine genes are an interesting focus for association studies involving atopic diseases due to their role in immune cell communications during inflammation. The aim of this study was to investigate associations of TNFalpha -308G>A, TNFalpha -238G>A, IL-1alpha -889C>T and IL-10 1082G>A polymorphisms with atopic diseases with adjustment for confounding lifestyle and environmental factors. METHODS: This study was performed on 356 Croatian students. The diagnosis of atopic asthma, atopic rhinitis and atopic dermatitis was based on symptoms reported by the modified International Study of Asthma and Allergies in Childhood questionnaire and a positive skin prick test (SPT) to at least one common inhalatory allergen. Genetic polymorphisms were genotyped using the polymerase chain reaction-based technique. The influence of personal (gender, body mass index, parental history of atopic disease), lifestyle (cigarette smoking, pet ownership) and environmental (urban/rural residency, residency in continental/Mediterranean region) factors reported in the questionnaire was investigated by univariate and multivariate analysis. RESULTS: Compared to the control subjects, univariate analysis showed a significant negative association of the TNFalpha -308G>A polymorphism with atopic asthma, atopic dermatitis, asthma and skin symptoms and positive SPT. These observations were confirmed in a multivariate model only for atopic dermatitis and skin symptoms (atopic dermatitis: OR = 0.27; 95% CI 0.07-1.00; p = 0.050; skin symptoms: OR = 0.29; 95% CI 0.10-0.83; p = 0.021). CONCLUSIONS: The results indicate a protective role of TNFalpha -308G>A genetic polymorphisms regarding atopic dermatitis and skin symptoms even after controlling for personal, lifestyle and environmental factors. Further studies are needed to elucidate the molecular patterns of this association in atopic dermatitis and other chronic inflammatory skin disorders. PMID- 27240835 TI - Genetic Variants of Thymic Stromal Lymphopoietin in Nonsteroidal Anti Inflammatory Drug-Induced Urticaria/Angioedema. AB - BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequent agents involved in hypersensitivity drug reactions, with NSAID-induced urticaria and/or angioedema (NIUA) being the most common entity. Mast cells are key players in NIUA and are activated by thymic stromal lymphopoietin (TSLP). This cytokine functions through recognition by its receptor, composed of IL7Ralpha (interleukin 7 receptor alpha) and TSLPR (TSLP receptor). These genes have been previously associated with other inflammatory diseases. METHODS: We assessed the genetic association between single nucleotide polymorphisms (SNPs) in TSLP, IL7R and TSLPR and NIUA in Spanish individuals, using genotyped and imputed data. A total of 369 unrelated NIUA patients and 580 NSAID-tolerant control subjects were included, and 6 SNPs in TSLP, 6 in IL7R and 3 in TSLPR were genotyped. Further variants were imputed using Mach and the 1,000 Genomes Project (Phase 3) data. Association testing and statistical analyses were performed with Mach2dat and R. RESULTS: A total of 139 SNPs were tested for association following quality control. Two SNPs in TSLP (rs1816678 and rs764917) showed a nominal association (p = 0.033 and 0.024, respectively) with NIUA, although these results were not statistically significant after correcting for multiple comparisons. CONCLUSIONS: Although TSLP, IL7R and TSLPR are important genes involved in the development of the inflammatory response, we found no significant genetic association with NIUA in our population for common SNPs in these genes. PMID- 27240836 TI - Non-IgE-Dependent Hypersensitivity to Rocuronium Reversed by Sugammadex: Report of Three Cases and Hypothesis on the Underlying Mechanism. AB - We present 3 cases of pseudoallergic (anaphylactoid) reactions to perioperatively administered rocuronium, which rapidly resolved after sugammadex injection. Allergological workup showed no evidence for immediate-type hypersensitivity to the drugs used for anesthesia, including rocuronium. However, rocuronium induced an irritative reaction in skin tests in all 3 patients and in 3 healthy individuals. This reaction was specifically suppressed by adding sugammadex at a 1:1 molecular proportion to rocuronium before the skin tests. This observation suggests that the patients suffered from a pseudoallergic reaction, and indicates that sugammadex might act via the inhibition of non-IgE mediated MRGPRX2 (Mas related G-protein-coupled receptor member X2)-triggered mast cell degranulation induced by rocuronium. PMID- 27240837 TI - Seasonal Exacerbation of Asthma Is Frequently Associated with Recurrent Episodes of Acute Urticaria. AB - BACKGROUND: Asthma and urticaria are both partially mediated by an increased release of histamine from highly activated mast cells. They are pathophysiologically different, as mast cell degranulation in these 2 disorders results from different mechanisms. OBJECTIVE: To assess the incidence of urticaria in patients with asthma, and of asthma in patients with chronic spontaneous urticaria (CSU). PATIENTS AND METHODS: Over 1 year of follow-up, asthma patients (n = 110) were assessed for the incidence and characteristics of urticaria, and a link, if it existed, to seasonal exacerbations and the severity of asthma was traced. We also prospectively assessed CSU patients (n = 95) during the same period of time for the incidence of asthma. Healthy individuals (n = 100), serving as a control group, were also assessed. RESULTS: Episodes of urticaria occurred in 26/110 asthma patients (23.6%), but in only 2/100 healthy control subjects (2%) (p < 0.0001). During the 1-year observation period, episodes of urticaria were significantly more frequent in asthma patients with positive skin-prick test reactions (mainly seasonal pollens), and consequently occurred mostly during seasonal asthma exacerbation, i.e. during acute episodes of urticaria. The incidence of asthma in CSU patients was recorded in 10.5% of the group, similar to that in the healthy control population. DISCUSSION: Our study demonstrates, for the first time, that asthma patients frequently develop acute urticaria, mainly during seasonal exacerbations. In contrast, CSU patients do not show an increased incidence of asthma. PMID- 27240838 TI - A case report of hereditary apolipoprotein A-I amyloidosis associated with a novel APOA1 mutation and variable phenotype. AB - Apolipoprotein A-I (apo A-I) amyloidosis is a non-AL, non-AA, and non transthyretin type of amyloidosis associated with mutations in the APOA1 gene inherited in an autosomal dominant fashion. It is a form of systemic amyloidosis, but at presentation, can also mimic localized amyloidosis. The renal presentation generally involves interstitial and medullary deposition of apo A-I amyloid protein. We describe the identification of apo A-I amyloidosis by mass spectrometry in a 52-year old male, with no family history of amyloidosis, presenting with nephrotic syndrome and associated with heterozygosity for a novel APOA1 mutation (c.220 T > A) which encodes the known amyloidogenic Trp50Arg variant. Renal amyloid deposits in this case were confined to the glomeruli alone, and the patient developed progressive renal impairment. One year after diagnosis, the patient had a successful kidney transplant from an unrelated donor. Pathogenic mutations in the APOA1 gene are generally associated with symptoms of amyloidosis. In this family however, genotyping of family members identified several unaffected carriers suggesting a variable disease penetrance, which has not been described before in this form of amyloidosis and has implications when counselling those with APOA1 mutations. PMID- 27240839 TI - Variation of parasitism patterns in bats during hibernation: the effect of host species, resources, health status, and hibernation period. AB - During critical periods of food shortage or variable climatic conditions, the choice of an appropriate host can increase the survival and reproductive performance of parasites. In turn, one of the unique adaptations to periodical food shortages is hibernation, which is often found among insectivorous bat species in the temperate zone. While hibernating, bats are completely defenseless against both predators and ectoparasites, their immune and endocrine systems are diminished, and survival is dependent on the accumulated fat reserves. Differences in the health status or in the rate of consumption of the resources might also explain species-specific differences in ectoparasite abundance, especially between closely related host species, such as the greater mouse-eared bat (Myotis myotis) and the lesser mouse-eared bat (M. blythii) during hibernation. In the present study, the abundance of two ecologically distinct (summer and winter) types of ectoparasites was examined in terms of its influence on the body condition and hemoglobin content of the two host species. The effects of demographic factors, such as host sex and age, were also investigated. Despite a similar pattern of deteriorating body condition and hemoglobin concentration, M. myotis was more parasitized than was M. blythii. The marked decrease in hemoglobin content in first-year females of both host species correlated with the highest parasite load and indicated a risk of anemia. At the intraspecific level, ectoparasite abundance was not correlated with body condition (resources), but it negatively affected hemoglobin content; however, this mostly concerned M. blythii, which had a lower parasite load. Therefore, it can be concluded that interspecific differences in ectoparasite abundance may result from parasites selecting the host species that is less sensitive to their activity. In turn, in summer ectoparasites, the preference for female hosts is probably attributable to the likelihood of reinfection rather than to an effect of host resources or health status. The absence of sex-based preferences in winter ectoparasites could be explained by equal host availability. PMID- 27240840 TI - Development of an Automated Healthcare Kiosk for the Management of Chronic Disease Patients in the Primary Care Setting. AB - An increase in the prevalence of chronic disease has led to a rise in the demand for primary healthcare services in many developed countries. Healthcare technology tools may provide the leverage to alleviate the shortage of primary care providers. Here we describe the development and usage of an automated healthcare kiosk for the management of patients with stable chronic disease in the primary care setting. One-hundred patients with stable chronic disease were recruited from a primary care clinic. They used a kiosk in place of doctors' consultations for two subsequent follow-up visits. Patient and physician satisfaction with kiosk usage were measured on a Likert scale. Kiosk blood pressure measurements and triage decisions were validated and optimized. Patients were assessed if they could use the kiosk independently. Patients and physicians were satisfied with all areas of kiosk usage. Kiosk triage decisions were accurate by the 2nd month of the study. Blood pressure measurements by the kiosk were equivalent to that taken by a nurse (p = 0.30, 0.14). Independent kiosk usage depended on patients' language skills and educational levels. Healthcare kiosks represent an alternative way to manage patients with stable chronic disease. They have the potential to replace physician visits and improve access to primary healthcare. Patients welcome the use of healthcare technology tools, including those with limited literacy and education. Optimization of environmental and patient factors may be required prior to the implementation of kiosk-based technology in the healthcare setting. PMID- 27240841 TI - Evaluation of Digital Compressed Sensing for Real-Time Wireless ECG System with Bluetooth low Energy. AB - In this paper, a wearable and wireless ECG system is firstly designed with Bluetooth Low Energy (BLE). It can detect 3-lead ECG signals and is completely wireless. Secondly the digital Compressed Sensing (CS) is implemented to increase the energy efficiency of wireless ECG sensor. Different sparsifying basis, various compression ratio (CR) and several reconstruction algorithms are simulated and discussed. Finally the reconstruction is done by the android application (App) on smartphone to display the signal in real time. The power efficiency is measured and compared with the system without CS. The optimum satisfying basis built by 3-level decomposed db4 wavelet coefficients, 1-bit Bernoulli random matrix and the most suitable reconstruction algorithm are selected by the simulations and applied on the sensor node and App. The signal is successfully reconstructed and displayed on the App of smartphone. Battery life of sensor node is extended from 55 h to 67 h. The presented wireless ECG system with CS can significantly extend the battery life by 22 %. With the compact characteristic and long term working time, the system provides a feasible solution for the long term homecare utilization. PMID- 27240842 TI - Massive Access Control Aided by Knowledge-Extraction for Co-Existing Periodic and Random Services over Wireless Clinical Networks. AB - The prosperity of e-health is boosted by fast development of medical devices with wireless communications capability such as wearable devices, tiny sensors, monitoring equipments, etc., which are randomly distributed in clinic environments. The drastically-increasing population of such devices imposes new challenges on the limited wireless resources. To relieve this problem, key knowledge needs to be extracted from massive connection attempts dispersed in the air towards efficient access control. In this paper, a hybrid periodic-random massive access (HPRMA) scheme for wireless clinical networks employing ultra narrow band (UNB) techniques is proposed. In particular, the proposed scheme towards accommodating a large population of devices include the following new features. On one hand, it can dynamically adjust the resource allocated for coexisting periodic and random services based on the traffic load learned from signal collision status. On the other hand, the resource allocation within periodic services is thoroughly designed to simultaneously align with the timing requests of differentiated services. Abundant simulation results are also presented to demonstrate the superiority of the proposed HPRMA scheme over baseline schemes including time-division multiple access (TDMA) and random access approach, in terms of channel utilization efficiency, packet drop ratio, etc., for the support of massive devices' services. PMID- 27240843 TI - [E-learning program from the German Society of Rheumatology]. PMID- 27240844 TI - [Osteoporosis]. PMID- 27240845 TI - Characterization, heavy metal content and health risk assessment of urban road dusts from the historic center of the city of Thessaloniki, Greece. AB - In the present study, an investigation of the mineralogy and morphology, the heavy metal content and the health risk of urban road dusts from the second largest city of Greece was conducted. For this reason road dust samples from selected sites within the city core area were collected. No differences were observed in the mineralogy of road dusts coming from different sampling sites, and they were mainly consisted of quartz and calcite, while an elevated amorphous content was detected. Morphologically road dusts presented Ca-rich, Fe-rich and silicates particles with various shapes and sizes. The mean concentrations of Cd, Cr, Cu, Mn, Ni, Pb and Zn in road dust were 1.76, 104.9, 662.3, 336.4, 89.43, 209 and 452.8 MUg g-1, respectively. A series of spatial distribution patterns revealed that the hotspot areas were tended to associate with major road junctions and regions with high traffic. Combination of pollution indexes and statistical analyses (correlation analysis, cluster analysis and principal component analysis) revealed that road dusts have a severe influence by anthropogenic activities. In attempt to identify the source of metals through geostatistical and multivariate statistical analyses, it was concluded as follows: Cr, Cu, Fe and Zn mainly originated from tire/break wear and vehicle abrasions, while Cd, Mn and Pb were mainly related to fuel/oil leakage from automobiles along with oil lubricants and vehicle abrasion. Hazard quotient values for children based on total metal concentrations for the road dust ingestion route were lower than safe level (=1). However, the fact that the Hazard Index value for Pb (0.459) which is a particularly toxic metal, was close to safe level, renders essential further investigation in order to provide more reliable characterizations of potential health risks. PMID- 27240846 TI - Is there a place for a biological mesh in perineal hernia repair? AB - PURPOSE: This study aimed to determine the outcome of perineal hernia repair with a biological mesh after abdominoperineal resection (APR). METHOD: All consecutive patients who underwent perineal hernia repair with a porcine acellular dermal mesh between 2010 and 2014 were included. Follow-up was performed by clinical examination and MRI. RESULTS: Fifteen patients underwent perineal hernia repair after a median of 25 months from APR. Four patients had a concomitant contaminated perineal defect, for which a gluteal fasciocutaneous flap was added in three patients. Wound infection occurred in three patients. After a median follow-up of 17 months (IQR 12-24), a clinically recurrent perineal hernia developed in 7 patients (47 %): 6 of 11 patients after a non-cross-linked mesh and 1 of 4 patients after a cross-linked mesh (p = 0.57). Routine MRI at a median of 17 months revealed a recurrent perineal hernia in 7 of 10 evaluable patients, with clinical confirmation of recurrence in 5 of these 7 patients. No recurrent hernia was observed in the three patients with combined flap reconstruction for contaminated perineal defects. CONCLUSION: A high recurrence rate was observed after biological mesh repair of a perineal hernia following APR. PMID- 27240847 TI - A systematic review of pentacyclic triterpenes and their derivatives as chemotherapeutic agents against tropical parasitic diseases. AB - Parasitic infections are among the leading global public health problems with very high economic and mortality burdens. Unfortunately, the available treatment drugs are beset with side effects and continuous parasite drug resistance is being reported. However, new findings reveal more promising compounds especially of plant origin. Among the promising leads are the pentacyclic triterpenes (PTs) made up of the oleanane, ursane, taraxastane, lupane and hopane types. This paper reviews the literature published from 1985 to date on the in vitro and in vivo anti-parasitic potency of this class of phytochemicals. Of the 191 natural and synthetic PT reported, 85 have shown high anti-parasitic activity against various species belonging to the genera of Plasmodium, Leishmania, Trypanosoma, as well as various genera of Nematoda. Moreover, structural modification especially at carbon 3 (C3) and C27 of the parent backbone of PT has led to improved anti parasitic activity in some cases and loss of activity in others. The potential of this group of compounds as future alternatives in the treatment of parasitic diseases is discussed. It is hoped that the information presented herein will contribute to the full exploration of this promising group of compounds as possible drugs for parasitic diseases. PMID- 27240848 TI - The measurement of the normal thorax using the Haller index methodology at multiple vertebral levels. AB - The Haller index is a ratio of thoracic width and height, measured from an axial CT image and used to describe the internal dimensions of the thoracic cage. Although the Haller index for a normal thorax has been established (Haller et al. 1987; Daunt et al. 2004), this is only at one undefined vertebral level in the thorax. What is not clear is how the Haller index describes the thorax at every vertebral level in the absence of sternal deformity, or how this is affected by age. This paper documents the shape of the thorax using the Haller index calculated from the thoracic width and height at all vertebral levels of the thorax between 8 and 18 years of age. The Haller Index changes with vertebral level, with the largest ratio seen in the most cranial levels of the thorax. Increasing age alters the shape of the thorax, with the most cranial vertebral levels having a greater Haller index over the mid thorax, which does not change. A slight increase is seen in the more caudal vertebral levels. These data highlight that a 'one size fits all' rule for chest width and depth ratio at all ages and all thoracic levels is not appropriate. The normal range for width to height ratio should be based on a patient's age and vertebral level. PMID- 27240849 TI - Neuropsychiatric Adverse Reactions to Mefloquine: a Systematic Comparison of Prescribing and Patient Safety Guidance in the US, UK, Ireland, Australia, New Zealand, and Canada. AB - INTRODUCTION: The antimalarial drug mefloquine (MQ) is associated with neuropsychiatric adverse reactions, some of which may predict the development of more serious effects. Although prescribing guidance in the United States drug label (DL) recommends to discontinue MQ at the onset of neuropsychiatric symptoms, only certain reactions are listed in both the DL and the corresponding patient medication guide with a recommendation to discontinue or to consult a physician should they occur. To identify possible prodromal reactions for which there is complete or partial agreement in prescribing and patient recommendations, a systematic comparison of international drug safety labeling was performed. METHODS: The full text of each DL and medication guide (or equivalent) from six primarily English-speaking countries was reviewed to identify specific reactions with corresponding recommendations in drug safety labeling. Percentage agreement across the countries in corresponding recommendations was determined by MedDRA((r)) high level group term (HLGT). RESULTS: Recommendations were found for reactions in 22 neuropsychiatric HLGTs. Complete or partial international agreement was found for reactions in 11 (50%) HLGTs. CONCLUSION: This analysis suggests opportunities for physicians to improve patient counseling and for international drug regulators to clarify language in MQ safety labeling to reflect national risk-benefit considerations. PMID- 27240850 TI - [Treatment of severely injured patients : Impact of the German Trauma Registry DGU(r)]. AB - The German Trauma Registry DGU(r) started in 1993 as an initiative of five dedicated trauma centers and has evolved significantly since then. Data were obtained at four points of time from the site of the accident until discharge from hospital. In the first year (1993), the registry collected data of 260 patients from 5 hospitals. In 2015 more than 38.000 were included from 640 hospitals.This paper focusses on the impact of the trauma registry on the treatment of severely injured patients. Several authors could show that the data can be used by hospitals for benchmarking. This can help to detect problems in individual hospitals and to find solutions that can be implemented into the process of care and its subsequent reevaluation. Due to structural and process related changes, the time necessary for the management in the emergency room could be reduced significantly. Various scientific analyses of the Trauma Registry DGU(r) data were implemented in the treatment of severely injured patients. In the prehospital treatment, this changed the criteria for intubation and led to a reduction of volume replacement. In the hospital setting, the analysis influenced the radiologic work-up and the treatment of coagulopathy of severely injured patients. Moreover, the risk-adjusted mortality of severely injured patients in Germany could be continuously reduced over the past 20 years. PMID- 27240851 TI - [Transitional fractures : Epiphyseal injuries in adolescence]. AB - The so-called transitional fractures describe articular fractures in adolescents with partial closure of the epiphyseal growth plate. This shows a specific stereotype fracture pattern, which can be differentiated into biplane, triplane I and triplane II fractures depending on the involvement of the metaphysis and the number of fragments. The diagnostics and therapy can differ from fractures where the epiphyseal growth plate is still open. The main focus for surgical treatment is the reconstruction of the articular surface whereas relevant growth disturbances no longer need to be feared when the epiphysis has already begun to close. PMID- 27240852 TI - Changes in cognitive functions and cerebral grey matter and their associations with inflammatory markers, endocrine markers, and APOE genotypes in testicular cancer patients undergoing treatment. AB - Evidence suggests that testicular cancer (TC) and its treatment are associated with cognitive impairment. However, the underlying neural substrate and biological mechanisms are poorly understood. This study aimed to investigate changes in cognition and brain grey matter (GM) morphology in TC patients undergoing treatment, and to explore associations with immune markers, endocrine markers, and genotype. Sixty-five patients with stage I-III TC underwent assessment after surgery but prior to further treatment and again 6 months after. Twenty-two patients received chemotherapy (+CT), while 43 did not (-CT). Assessments included neuropsychological testing, whole-brain magnetic resonance imaging, and blood samples. Twenty-five healthy controls (HCs) underwent neuropsychological testing with a matching time interval. A regression-based approach was used to determine cognitive changes and longitudinal voxel-based morphometry (VBM) was performed to investigate changes in GM density in the TC groups. Compared with the HCs, both TC groups showed higher rates of cognitive decline (p < 0.05). A trend towards greater decline was observed in + CT (63.6 %) compared with -CT patients (39.5 %) (p = 0.07). VBM revealed widespread GM reductions in both TC groups, but a group-by-time interaction analysis revealed prefrontal reductions specific to the + CT group (p = 0.02), which were associated with poorer cognitive performance. Poorer cognitive performance was also associated with an increase in tumor necrosis factor alpha in + CT patients. Furthermore, an interaction effect was found between the APOE epsilon4 genotype and chemotherapy on cognitive performance with epsilon4 carriers performing significantly worse. These findings provide novel evidence of changes in cognition and brain morphology in TC patients undergoing treatment. PMID- 27240853 TI - Effect of ecological restoration and climate change on ecosystems: a case study in the Three-Rivers Headwater Region, China. AB - The Three-Rivers Headwater Region (TRHR) is the headwater of the Yangtze River Basin (YARB), Yellow River Basin (YRB), and Lancang River Basin (LRB); it is known as China's 'Water Tower' owing to its important supply of freshwater. In order to assess ecosystem changes in the TRHR during 2000-2012, we systematically and comprehensively evaluated a combination of model simulation results and actual observational data. The results showed the following: (1) Ecosystem pattern was relatively stable during 2000-2010, with a slight decrease in farmland and desert areas, and a slight increase in grassland and wetland/water body areas. (2) A warmer and wetter climate, and ecological engineering, caused the vegetation cover and productivity to significantly improve. (3) Precipitation was the main controlling factor for streamflow. A significant increase in precipitation during 2000-2012 resulted in an obvious increase in annual and seasonal streamflow. Glacier melting also contributed to the streamflow increase. (4) The total amount of soil conservation increased slightly from 2000 to 2012. The increase in precipitation caused rainfall erosivity to increase, which enhanced the intensity of soil erosion. The decrease in wind speed decreased wind erosion and the frequency of sandstorms. (5) The overall habitat quality in the TRHR was stable between 2000 and 2010, and the spatial pattern exhibited obvious heterogeneity. In some counties that included nature reserves, habitat quality was slightly higher in 2010 than in 2000, which reflected the effectiveness of the ecological restoration. Overall, the aforementioned ecosystem changes are the combined results of ecological restoration and climate change, and they are likely a local and temporary improvement, rather than a comprehensive and fundamental change. Therefore, more investments and efforts are needed to preserve natural ecosystems. PMID- 27240854 TI - Acute pancreatitis: New developments and strategies for the hospitalist. AB - Acute pancreatitis (AP) remains the most common reason for hospital admission of all the gastrointestinal illnesses in the United States. Since the last narrative review in the Journal of Hospital Medicine in 2010, new developments in regard to diagnosis and classification, fluid resuscitation, antibiotic use, nutritional support, and management of complications have helped refine the approach and improve outcomes in this disease. Whereas there is still no proven pharmacologic therapy to specifically combat the inflammatory consequences of AP, recent interventions have led to increased survival, shorter length of stay, and more appropriate transfer criteria for pancreatitis patients. This case-oriented review will highlight these developments and emphasize the primary role of the hospitalist in managing AP over the course of the admission. It will focus on when to coordinate with subspecialists, how to deliver effective yet efficient hospitalized care, and how to optimize appropriate discharge planning. Journal of Hospital Medicine 2016;11:724-729. (c) 2016 Society of Hospital Medicine. PMID- 27240855 TI - Evolution and diversity of floral scent chemistry in the euglossine bee pollinated orchid genus Gongora. AB - * BACKGROUND AND AIMS: Animal-pollinated angiosperms have evolved a variety of signalling mechanisms to attract pollinators. Floral scent is a key component of pollinator attraction, and its chemistry modulates both pollinator behaviour and the formation of plant-pollinator networks. The neotropical orchid genus Gongora exhibits specialized pollinator associations with male orchid bees (Euglossini). Male bees visit orchid flowers to collect volatile chemical compounds that they store in hind-leg pouches to use subsequently during courtship display. Hence, Gongora floral scent compounds simultaneously serve as signalling molecules and pollinator rewards. Furthermore, because floral scent acts as the predominant reproductive isolating barrier among lineages, it has been hypothesized that chemical traits are highly species specific. A comparative analysis of intra- and inter-specific variation of floral scent chemistry was conducted to investigate the evolutionary patterns across the genus. * METHODS: Gas chromatography-mass spectrometry (GC-MS) was used to analyse the floral scent of 78 individuals belonging to 28 different species of Gongora from two of the three major lineages sampled across the neotropical region. Multidimensional scaling and indicator value analyses were implemented to investigate the patterns of chemical diversity within and among taxonomic groups at various geographic scales. Additionally, pollinator observations were conducted on a sympatric community of Gongora orchids exhibiting distinct floral scent phenotypes. * KEY RESULTS: A total of 83 floral volatiles, mainly terpenes and aromatic compounds, were detected. Many of the identified compounds are common across diverse angiosperm families (e.g. cineole, eugenol, beta-ocimene, beta-pinene and terpinen-4-ol), while others are relatively rare outside euglossine bee-pollinated orchid lineages. Additionally, 29 volatiles were identified that are known to attract and elicit collection behaviour in male bees. Floral scent traits were less variable within species than between species, and the analysis revealed exceptional levels of cryptic diversity. Gongora species were divided into 15 fragrance groups based on shared compounds. Fragrance groups indicate that floral scent variation is not predicted by taxonomic rank or biogeographic region. * CONCLUSIONS: Gongora orchids emit a diverse array of scent molecules that are largely species specific, and closely related taxa exhibit qualitatively and quantitatively divergent chemical profiles. It is shown that within a community, Gongora scent chemotypes are correlated with near non-overlapping bee pollinator assemblies. The results lend support to the hypothesis that floral scent traits regulate the architecture of bee pollinator associations. Thus, Gongora provides unique opportunities to examine the interplay between floral traits and pollinator specialization in plant-pollinator mutualisms. PMID- 27240856 TI - Acute exposure to air pollution particulate matter aggravates experimental myocardial infarction in mice by potentiating cytokine secretion from lung macrophages. AB - Clinical, but not experimental evidence has suggested that air pollution particulate matter (PM) aggravates myocardial infarction (MI). Here, we aimed to describe mechanisms and consequences of PM exposure in an experimental model of MI. C57BL/6J mice were challenged with a PM surrogate (Residual Oil Fly Ash, ROFA) by intranasal installation before MI was induced by permanent ligation of the left anterior descending coronary artery. Histological analysis of the myocardium 7 days after MI demonstrated an increase in infarct area and enhanced inflammatory cell recruitment in ROFA-exposed mice. Mechanistically, ROFA exposure increased the levels of the circulating pro-inflammatory cytokines TNF alpha, IL-6, and MCP-1, activated myeloid and endothelial cells, and enhanced leukocyte recruitment to the peritoneal cavity and the vascular endothelium. Notably, these effects on endothelial cells and circulating leukocytes could be reversed by neutralizing anti-TNF-alpha treatment. We identified alveolar macrophages as the primary source of elevated cytokine production after PM exposure. Accordingly, in vivo depletion of alveolar macrophages by intranasal clodronate attenuated inflammation and cell recruitment to infarcted tissue of ROFA-exposed mice. Taken together, our data demonstrate that exposure to environmental PM induces the release of inflammatory cytokines from alveolar macrophages which directly worsens the course of MI in mice. These findings uncover a novel link between air pollution PM exposure and inflammatory pathways, highlighting the importance of environmental factors in cardiovascular disease. PMID- 27240857 TI - Stromal Expression of MicroRNA-21 in Advanced Colorectal Cancer Patients with Distant Metastases. AB - BACKGROUND: The aim of this study was to determine the regional heterogeneity and clinicopathological significance of microRNA-21 (miR-21) in advanced colorectal cancer (CRC) patients with distant metastasis. METHODS: miR-21 expression was investigated by using locked nucleic acid- fluorescence in situ hybridization in the center and periphery of the primary cancer and in distant metastasis from 170 patients with advanced CRC. In addition, alpha-smooth muscle actin and desmin were evaluated to identify cancer-associated fibroblasts (CAFs) by using immunohistochemistry. RESULTS: The miR-21 signal was observed in the cancer stroma. The expression of miR-21 (a score of 1-4) in the center and periphery of the primary cancer and in distant metastasis was observed in specimens from 133 (78.2%), 105 (61.8%), and 91 (53.5%) patients, respectively. miR-21 expression was heterogeneous in advanced CRC. Discordance between miR-21 expression in the center of the primary cancer and either the periphery of the primary cancer or distant metastasis was 31.7% or 44.7%, respectively. miR-21 stromal expression in the periphery of the primary cancer was significantly associated with a better prognosis (p=.004). miR-21 expression was significantly associated with CAFs in the center of the primary cancer (p=.001) and distant metastases (p=.041). CONCLUSIONS: miR-21 expression is observed in cancer stroma related to the CAF quantity and frequently presents regional heterogeneity in CRC. Our findings indicate that the role of miR-21 in predicting prognosis may be controversial but provide a new perspective of miR-21 level measurement in cancer specimens. PMID- 27240858 TI - Fecal diagnostics in combination with serology: best test to establish STEC-HUS. AB - BACKGROUND: In the majority of pediatric patients, the hemolytic-uremic syndrome (HUS) is caused by an infection with Shiga toxin-producing Escherichia coli (STEC), mostly serotype O157. It is important to discriminate between HUS caused by STEC and complement-mediated HUS (atypical HUS) due to differences in treatment and outcome. As STEC and its toxins can only be detected in the patient's stool for a short period of time after disease onset, the infectious agent may go undetected using only fecal diagnostic tests. Serum antibodies to lipopolysaccharide (LPS) of STEC persist for several weeks and may therefore be of added value in the diagnosis of STEC. METHODS: All patients with clinical STEC HUS who were treated at Radboud University Medical Center between 1990 and 2014 were included in this retrospective single-center study. Clinical and diagnostic microbiological data were collected. Immunoglobulin M (IgM) antibodies against LPS of STEC serotype O157 were detected by a serological assay (ELISA). RESULTS: Data from 65 patients weres available for analysis. Fecal diagnostic testing found evidence of an STEC infection in 34/63 patients (54 %). Serological evidence of STEC O157 was obtained in an additional 16 patients. This is an added value of 23 % (p < 0.0001) when the serological antibody assay is used in addition to standard fecal diagnostic tests to confirm the diagnosis STEC-HUS. This added value becomes especially apparent when the tests are performed more than 7 days after the initial manifestation of the gastrointestinal symptoms. CONCLUSIONS: The serological anti-O157 LPS assay clearly makes a positive contribution when used in combination with standard fecal diagnostic tests to diagnose STEC-HUS and should be incorporated in clinical practice. PMID- 27240859 TI - Fluid management of the neurological patient: a concise review. AB - Maintenance fluids in critically ill brain-injured patients are part of routine critical care. Both the amounts of fluid volumes infused and the type and tonicity of maintenance fluids are relevant in understanding the impact of fluids on the pathophysiology of secondary brain injuries in these patients. In this narrative review, current evidence on routine fluid management of critically ill brain-injured patients and use of haemodynamic monitoring is summarized. Pertinent guidelines and consensus statements on fluid management for brain injured patients are highlighted. In general, existing guidelines indicate that fluid management in these neurocritical care patients should be targeted at euvolemia using isotonic fluids. A critical appraisal is made of the available literature regarding the appropriate amount of fluids, haemodynamic monitoring and which types of fluids should be administered or avoided and a practical approach to fluid management is elaborated. Although hypovolemia is bound to contribute to secondary brain injury, some more recent data have emerged indicating the potential risks of fluid overload. However, it is acknowledged that many factors govern the relationship between fluid management and cerebral blood flow and oxygenation and more research seems warranted to optimise fluid management and improve outcomes. PMID- 27240860 TI - Killer cell immunoglobulin-like receptor and human leukocyte antigen gene profiles in a cohort of HIV-infected Mexican Mestizos. AB - Killer cell immunoglobulin-like receptors (KIRs) represent the most polymorphic genes responsible for natural killer cell function, while human leukocyte antigen (HLA) class I molecules define and restrict cytotoxic T lymphocyte responses. Specific KIR, HLA, or KIR-HLA combinations have been implicated in the outcome of human immunodeficiency virus (HIV) disease. The remarkable polymorphism of KIR and HLA genes warrants descriptive gene frequency studies in different populations, as well as their impact on HIV disease progression in different immunogenetic contexts. We report KIR and HLA class I gene profiles of 511 unrelated HIV-infected Mexican Mestizo individuals from 18 states for whom genetic ancestry proportions were assessed. KIR and HLA gene profiles were compared between individuals from the north and central-south regions of the country and between individuals with higher European (EUR) or Amerindian (AMI) genetic ancestry component. A total of 65 KIR genotypes were observed, 11 harboring novel KIR gene combinations. A total of 164 HLA alleles were observed: 43 HLA-A, 87 HLA-B, and 34 HLA-C. Differences in the distribution of 12 HLA alleles were observed between individuals with higher AMI or EUR ancestry components (p < 0.05, q < 0.2). After correcting for genetic ancestry, only individual HLA alleles were associated with HIV disease progression, including a novel association with A*02:06, an Amerindian HLA allele associated with lower CD4+ T cell counts. No KIR effects were significant. Our results highlight the advantages of considering a detailed genetic stratification within populations when studying genetic profiles that could be implicated in disease-association studies. PMID- 27240861 TI - Podoplanin Expression Is Correlated With the Progression of Chronic Discoid Lupus Erythematosus to Lip Squamous Cell Carcinoma. AB - Chronic lip discoid lupus erythematosus (DLE) is a potentially malignant disorder that can develop into lip squamous cell carcinoma (LSCC). Podoplanin is a specific marker for lymphatic endothelial cells and plays a role in cancer progression. The objective of this study was to determine the immunoexpression of podoplanin in samples of patients with DLE and its correlation with the risk of progression to LSCC. In a retrospective study, podoplanin expression was determined using immunohistochemistry in samples from 52 patients with DLE, including 44 patients with untransformed DLE and 8 patients with malignant transformed DLE. Ten samples of normal oral mucosa and 10 samples of LSCC were used as normal and cancer controls, respectively. The results showed that podoplanin expression was observed in 12 of 44 (27.3%) patients with untransformed DLE and in 7 of 8 (87.5%) patients with transformed DLE (P = .002). Podoplanin was not expressed in normal oral mucosa, but it was overexpressed in all of the 10 patients with LSCC. Regression analysis revealed that podoplanin expression was significantly associated with an 18.67-fold increase in the risk of malignant progression (95% confidence interval = 2.07-168.10; P = .009). In summary, podoplanin expression is significantly associated with malignant transformation of DLE into LSCC. Thus, podoplanin expression may identify a subgroup with a high risk of malignant progression of DLE. PMID- 27240862 TI - Cyclin D1 Expression in Ectomesenchymal Chondromyxoid Tumor of the Anterior Tongue. AB - Ectomesenchymal chondromyxoid tumor (ECT) is a rare benign tumor of uncertain lineage, which almost exclusively affects the anterior tongue. Herein, we report 2 cases of ECT occurring in 58- and 56-year-old males on the right and on the left side of the dorsum of the anterior tongue, measuring 18 mm and 10 mm, respectively. Despite positive resection margin in one case, none of the tumors recurred during follow-up of 6 and 5 years. Microscopically, both tumors had lobular architecture with a mixture of solid, microcystic, and chondromyxoid areas. The tumor cells were polygonal or elongated and showed mild atypia in one case. Immunohistochemically, both tumors showed diffuse expression of vimentin and focal positivity of CD10 and of smooth muscle actin. Regarding neural tissue related markers, there was nearly diffuse expression of CD56 and neuron-specific enolase and focal positivity of PGP 9.5 in both cases and variable expression of CD57, synaptophysin, glial fibrillary acidic protein, and S-100 protein. Interestingly, we observed diffuse expression of SOX10 in one case. In both tumors, diffuse strong nuclear expression of cyclin D1 was present, without CCND1/IGH translocation or CCND1 amplification. The EWSR1 gene rearrangement was not detected. To the best of our knowledge, expression of SOX10, which may support neural crest origin of this peculiar lesion, has not been reported in ECT. The significance of strong cyclin D1 expression remains to be further investigated. PMID- 27240863 TI - The vibrational signals that male fiddler crabs (Uca lactea) use to attract females into their burrows. AB - In some fiddler crab species, males emit vibrations from their burrows to mate searching females after they have attracted a female to the burrow entrance using a waving display. Although the vibrations are considered acoustic signals to induce mating, it has not been demonstrated whether the vibrations attract the females into the burrow and, consequently, influence females' mating decisions. We investigated the structures and patterns of the vibrations using a dummy female and demonstrated experimentally a female preference for male vibrations in Uca lactea in the field. The acoustic signals consisted of repetitions of pulses. The dominant frequency of the pulses decreased with male carapace width. The pulse length decreased slightly with an increasing number of vibrational repetitions, and the pulse interval increased with increasing repetitions. These factors imply that the vibrations convey information on male characteristics, such as body size and stamina. In the experiment on female mate choice, the females significantly preferred males with higher pulse repetition rates when they were positioned at the entrance of the burrow, indicating that the females use the male vibrational signals to decide whether to enter the burrow. However, females showed no preference for the vibrations once they were inside a burrow, i.e., whether they decided to copulate, suggesting that the vibrations do not independently affect a female's final decision of mate choice. The vibrations inside the burrow might influence a female's decision by interaction with other male traits such as the burrow structure. PMID- 27240864 TI - Self-reported health status as a predictor of functional decline in a community dwelling elderly population: Nationwide longitudinal survey in Korea. AB - AIM: As the elderly population is increasing, the prediction and prevention of functional decline in older adults are of great concern. The present study aimed to evaluate whether poor self-reported health status (SRHS) could predict functional decline after 2 years in the elderly population. METHODS: Data from the Korean Longitudinal Study of Aging panel, a national representative sample of aging Koreans, were used. Participants of the investigation were the elderly population aged 65 years or more without disability in carrying out activities of daily living (ADL) at baseline. The survey asked respondents about their subjective health status. Setting the respondents who stated their health status as "very good" or "good" as the reference group, multivariable logistic regression analysis was carried out to compare functional decline according to the baseline SRHS. RESULTS: A total of 2824 participants were included in the analysis. Among them, 138 (4.9 %) reported functional decline of at least one of the seven ADL components after 2 years. In multivariable logistic regression analysis, SRHS was significantly associated with subsequent functional decline in respondents who chose "Bad" (odds ratio 3.32, 95% confidence interval 1.71-6.44) or "Very bad" (OR 4.75, 95% CI 2.12-10.66). Furthermore, poorer SRHS was significantly associated with subsequent impairment in each ADL component. Also, SRHS predicted overall subsequent impairment in the instrumental ADL. CONCLUSIONS: SRHS predicted functional decline after 2 years in older adults without baseline disabilities. SRHS can be a good predictor of future functional decline in the elderly population. Geriatr Gerontol Int 2017; 17: 885-892. PMID- 27240865 TI - Optimization of an acetate reduction pathway for producing cellulosic ethanol by engineered yeast. AB - Xylose fermentation by engineered Saccharomyces cerevisiae expressing NADPH linked xylose reductase (XR) and NAD+ -linked xylitol dehydrogenase (XDH) suffers from redox imbalance due to cofactor difference between XR and XDH, especially under anaerobic conditions. We have demonstrated that coupling of an NADH dependent acetate reduction pathway with surplus NADH producing xylose metabolism enabled not only efficient xylose fermentation, but also in situ detoxification of acetate in cellulosic hydrolysate through simultaneous co-utilization of xylose and acetate. In this study, we report the highest ethanol yield from xylose (0.463 g ethanol/g xylose) by engineered yeast with XR and XDH through optimization of the acetate reduction pathway. Specifically, we constructed engineered yeast strains exhibiting various levels of the acetylating acetaldehyde dehydrogenase (AADH) and acetyl-CoA synthetase (ACS) activities. Engineered strains exhibiting higher activities of AADH and ACS consumed more acetate and produced more ethanol from a mixture of 20 g/L of glucose, 80 g/L of xylose, and 8 g/L of acetate. In addition, we performed environmental and genetic perturbations to further improve the acetate consumption. Glucose-pulse feeding to continuously provide ATPs under anaerobic conditions did not affect acetate consumption. Promoter truncation of GPD1 and gene deletion of GPD2 coding for glycerol-3-phosphate dehydrogenase to produce surplus NADH also did not lead to improved acetate consumption. When a cellulosic hydrolysate was used, the optimized yeast strain (SR8A6S3) produced 18.4% more ethanol and 41.3% less glycerol and xylitol with consumption of 4.1 g/L of acetate than a control strain without the acetate reduction pathway. These results suggest that the major limiting factor for enhanced acetate reduction during the xylose fermentation might be the low activities of AADH and ACS, and that the redox imbalance problem of XR/XDH pathway can be exploited for in situ detoxification of acetic acid in cellulosic hydrolysate and increasing ethanol productivity and yield. Biotechnol. Bioeng. 2016;113: 2587-2596. (c) 2016 Wiley Periodicals, Inc. PMID- 27240867 TI - When should we change our clinical practice based on the results of a clinical study? Diagnostic accuracy studies II: the diagnostic accuracy. PMID- 27240866 TI - Effect of rescue breathing by lay rescuers for out-of-hospital cardiac arrest caused by respiratory disease: a nationwide, population-based, propensity score matched study. AB - The importance of respiratory care in cardiopulmonary resuscitation may vary depending on the cause of cardiac arrest. No previous study has investigated the effects of rescue breathing performed by a lay rescuer on the outcomes of patients with out-of-hospital cardiac arrest (OHCA) caused by intrinsic respiratory diseases. The aim of this study was to investigate whether rescue breathing performed by a lay rescuer is associated with outcomes after respiratory disease-related OHCA. In a nationwide, population-based, propensity score-matched study in Japan, among adult patients with OHCA caused by respiratory disease who received bystander cardiopulmonary resuscitation from January 1, 2005 to December 31, 2010, we compared patients with rescue breathing to those without rescue breathing. The primary outcome was neurologically favorable survival 1 month after OHCA. Of the eligible 14,781 patients, 4970 received rescue breathing from a lay rescuer and 9811 did not receive rescue breathing. In a propensity score-matched cohort (4897 vs. 4897 patients), the neurologically favorable survival rate was similar between patients with and without rescue breathing from a lay rescuer [0.9 vs. 0.7 %; OR 1.23 (95 % CI 0.79 1.93)]. Additionally, in subgroup analyses, rescue breathing was not associated with neurological outcome regardless of the type of rescuer [family member: adjusted OR 0.83 (95 % CI 0.39-1.70); or non-family member: adjusted OR 1.91 (95 % CI 0.79-5.35)]. Even among patients with OHCA caused by respiratory disease, rescue breathing performed by a lay rescuer was not associated with neurological outcomes, regardless of the type of lay rescuer. PMID- 27240868 TI - Ever more complex: a new type of organization of reproductive organs in female Dorippe sinica Chen, 1980 (Decapoda: Brachyura: Dorippidae). AB - In this study a new organization of the female reproductive organs of Eubrachyura is presented after using both histology and MRI and MUCT analyses to investigate the morphology and function of the female reproductive organs of Dorippe sinica Chen, 1980. The reproductive organ is composed of two parts: an ectodermal sperm site and a mesodermal ovary. The ectodermal sperm storage site incorporates a concave vagina and a seminal receptacle, which is completely lined by cuticle and is not connected to the ovary. Additionally, a cavernous body is attached to the seminal receptacle. This cavernous body can be interpreted as an important feature in the fertilization process in relation to transporting the spermatozoa out of the lumen of the seminal receptacle. Independently of the seminal receptacle, the ovary is connected to the oviduct via a single opening. The oviduct is lined by an apocrine glandular epithelium. The oviduct and the vagina open directly into the vulva. These new discoveries are compared to the known pattern of eubrachyuran female reproductive systems. PMID- 27240870 TI - Non-cultivated plants present a season-long route of pesticide exposure for honey bees. AB - Recent efforts to evaluate the contribution of neonicotinoid insecticides to worldwide pollinator declines have focused on honey bees and the chronic levels of exposure experienced when foraging on crops grown from neonicotinoid-treated seeds. However, few studies address non-crop plants as a potential route of pollinator exposure to neonicotinoid and other insecticides. Here we show that pollen collected by honey bee foragers in maize- and soybean-dominated landscapes is contaminated throughout the growing season with multiple agricultural pesticides, including the neonicotinoids used as seed treatments. Notably, however, the highest levels of contamination in pollen are pyrethroid insecticides targeting mosquitoes and other nuisance pests. Furthermore, pollen from crop plants represents only a tiny fraction of the total diversity of pollen resources used by honey bees in these landscapes, with the principle sources of pollen originating from non-cultivated plants. These findings provide fundamental information about the foraging habits of honey bees in these landscapes. PMID- 27240871 TI - Steroid Hormone Receptor Coregulators in Endocrine Cancers. AB - Coregulators span a broad and extensive domain in modulating cellular transcriptional activity. Studies have established a dynamic role for such coregulators in various endocrine cancers. Steroid hormone receptors (SHRs) play a pivotal role in such endocrine cancers, and interact abundantly with transcriptional coregulators in altering gene expression. Several families of coregulators have implications in propagating the development, progression and invasion of breast, prostate, and other hormone-responsive cancers. This mini review aims to discuss different classes of coregulators involved in endocrine cancers and highlight unique information regarding each family with relevance to mechanism, intervention, and novel directions being investigated. (c) 2016 IUBMB Life, 68(7):504-515, 2016. PMID- 27240882 TI - Co-ordination behaviour of a novel tristhiourea tripodal ligand; structural variations in a series of transition metal complexes. AB - The co-ordination chemistry of a tristhiourea tris(2-pyridylmethyl)amine ligand () with a series of transition metal ions has been investigated. Crystallographic data show that large metal ions, with no geometrical preferences, such as Mn(ii) and Cd(ii), will form seven co-ordinate monocapped octahedral complexes, while smaller metal ions such as Zn(ii) favour five co-ordinate trigonal bipyramidal structures. In a similar manner to the related bisthiourea complexes, the Ni(ii) complex shows a strong preference for octahedral geometries resulting in the ligand binding asymmetrically. Spectroscopic (IR and NMR), spectrometric (MS) as well as electrochemical data for these complexes are reported. PMID- 27240869 TI - Identifying and Managing Pain in People with Alzheimer's Disease and Other Types of Dementia: A Systematic Review. AB - BACKGROUND AND OBJECTIVE: Pain in patients with Alzheimer's disease is a complex issue; these patients suffer from the common causes of acute and chronic pain, and some also have neuropathic or nociceptive pain. Whatever the mechanism of pain in these patients, their pain will require careful assessment and management, to insure the correct type and level of analgesia is given. The objective of this systematic review was the identification of studies that have investigated the efficacy of different analgesics on pain intensity or pain related behavior during nursing home stay and at the end of life. METHODS: A search using pain, pain treatment, and dementia MESH terms and keywords was conducted (October 15, 2015) in MEDLINE, EMBASE, PsychINFO, CINAHL, and Cochrane libraries. RESULTS: Our search yielded 3138 unique hits, published between 1990 and October 2015. We read titles and abstracts, identified 124 papers for full text evaluation, and included 12 papers to reflect and synthesize the following questions: (1) Which pain assessment tools for people with dementia are responsive to change in pain intensity scores? (2) Which analgesics are efficacy tested by controlled trials including people with dementia living in nursing homes, including at the end of life? (3) Which outcome measures have been used to identify pain, pain behavior, and/or treatment efficacy in people with dementia? CONCLUSION: Despite increased use of analgesics, pain is still prevalent in people with dementia. Validated pain tools are available but not implemented and not fully tested on responsiveness to treatment. Official guidelines for pain assessment and treatment addressing people with dementia living in a nursing home are lacking. The efficacy of analgesic drug use on pain or neuropsychiatric behavior related to dementia has been hardly investigated. PMID- 27240883 TI - Using machine learning to model dose-response relationships. AB - RATIONALE, AIMS AND OBJECTIVES: Establishing the relationship between various doses of an exposure and a response variable is integral to many studies in health care. Linear parametric models, widely used for estimating dose-response relationships, have several limitations. This paper employs the optimal discriminant analysis (ODA) machine-learning algorithm to determine the degree to which exposure dose can be distinguished based on the distribution of the response variable. By framing the dose-response relationship as a classification problem, machine learning can provide the same functionality as conventional models, but can additionally make individual-level predictions, which may be helpful in practical applications like establishing responsiveness to prescribed drug regimens. METHOD: Using data from a study measuring the responses of blood flow in the forearm to the intra-arterial administration of isoproterenol (separately for 9 black and 13 white men, and pooled), we compare the results estimated from a generalized estimating equations (GEE) model with those estimated using ODA. RESULTS: Generalized estimating equations and ODA both identified many statistically significant dose-response relationships, separately by race and for pooled data. Post hoc comparisons between doses indicated ODA (based on exact P values) was consistently more conservative than GEE (based on estimated P values). Compared with ODA, GEE produced twice as many instances of paradoxical confounding (findings from analysis of pooled data that are inconsistent with findings from analyses stratified by race). CONCLUSIONS: Given its unique advantages and greater analytic flexibility, maximum-accuracy machine learning methods like ODA should be considered as the primary analytic approach in dose-response applications. PMID- 27240884 TI - Three-dimensional ruthenium-doped TiO2 sea urchins for enhanced visible-light responsive H2 production. AB - Three-dimensional (3D) monodispersed sea urchin-like Ru-doped rutile TiO2 hierarchical architectures composed of radially aligned, densely-packed TiO2 nanorods have been successfully synthesized via an acid-hydrothermal method at low temperature without the assistance of any structure-directing agent and post annealing treatment. The addition of a minuscule concentration of ruthenium dopants remarkably catalyzes the formation of the 3D urchin structure and drives the enhanced photocatalytic H2 production under visible light irradiation, not possible on undoped and bulk rutile TiO2. Increasing ruthenium doping dosage not only increases the surface area up to 166 m(2) g(-1) but also induces enhanced photoresponse in the regime of visible and near infrared light. The doping introduces defect impurity levels, i.e. oxygen vacancy and under-coordinated Ti(3+), significantly below the conduction band of TiO2, and ruthenium species act as electron donors/acceptors that accelerate the photogenerated hole and electron transfer and efficiently suppress the rapid charge recombination, therefore improving the visible-light-driven activity. PMID- 27240885 TI - Thyroid cancer. AB - Thyroid cancer is the fifth most common cancer in women in the USA, and an estimated over 62 000 new cases occurred in men and women in 2015. The incidence continues to rise worldwide. Differentiated thyroid cancer is the most frequent subtype of thyroid cancer and in most patients the standard treatment (surgery followed by either radioactive iodine or observation) is effective. Patients with other, more rare subtypes of thyroid cancer-medullary and anaplastic-are ideally treated by physicians with experience managing these malignancies. Targeted treatments that are approved for differentiated and medullary thyroid cancers have prolonged progression-free survival, but these drugs are not curative and therefore are reserved for patients with progressive or symptomatic disease. PMID- 27240886 TI - Everyday functioning and cognitive correlates in healthy older adults with subjective cognitive concerns. AB - OBJECTIVE: Few studies have examined functional abilities and complaints in healthy older adults (HOAs) with subjective cognitive concerns (SCC). The aims of this study were to assess everyday functioning in HOAs reporting high and low amounts of SCC and examine cognitive correlates of functional abilities. METHOD: Twenty-six HOAs with high SCC and 25 HOAs with low SCC, as well as their knowledgeable informants, completed the Instrumental Activities of Daily Living Compensation (IADL-C), a questionnaire measure of everyday functioning. RESULTS: After controlling for depression, the high-SCC group self-reported significantly more everyday difficulties on the IADL-C, including all subdomains. Compared to the low-SCC group, informants for the high-SCC group endorsed more difficulties on the IADL-C and specifically the social skills subdomain. For the high-SCC group, poorer self-report of everyday functioning was related to poorer executive functioning and temporal order memory. CONCLUSIONS: These findings indicate that there may be subtle functional changes that occur early in the spectrum of cognitive decline in individuals with high SCC, and these functional changes are evident to informants. Further work is needed to investigate whether individuals with both SCC and functional difficulties are at an even higher risk for progression to mild cognitive impairment. PMID- 27240888 TI - TRPV1-FAAH-COX: The Couples Game in Pain Treatment. AB - Pain is a complex sensation involving the perception and transduction of diverse environmental pain stimuli with cognitive and emotional processing by the central nervous system. It can manifest as acute or chronic pain. Pain is controlled by a series of enzymes and receptors, implicated in a variety of interconnected mechanisms and pathways. In fact, several studies have shown the cannabinoid receptor 1 and the transient receptor potential vanilloid channel 1 to be new players in modulating the sophisticated pain transduction system at the central level. At the peripheral level, the perception of pain involves cyclooxygenases and fatty acid amide hydrolase, as recent studies demonstrate. This Minireview describes the physiological aspects of the receptors and enzymes mentioned above and focuses on the consideration of dual mechanisms as a new therapeutic approach in the treatment of pain. PMID- 27240889 TI - Microfluidic free-flow zone electrophoresis and isotachophoresis using carbon black nano-composite PDMS sidewall membranes. AB - We present a new type of free-flow electrophoresis (FFE) device for performing on chip microfluidic isotachophoresis and zone electrophoresis. FFE is performed using metal gallium electrodes, which are isolated from a main microfluidic flow channel using thin micron-scale polydimethylsiloxane/carbon black (PDMS/CB) composite membranes integrated directly into the sidewalls of the microfluidic channel. The thin membrane allows for field penetration and effective electrophoresis, but serves to prevent bubble generation at the electrodes from electrolysis. We experimentally demonstrate the ability to use this platform to perform on-chip free-flow electrophoretic separation and isotachophoretic concentration. Due to the small size and simple fabrication procedure, this PDMS/CB platform could be used as a part of an on-chip upstream sample preparation toolkit for portable microfluidic diagnostic applications. PMID- 27240890 TI - How to improve the continuing professional development in Korea. PMID- 27240887 TI - Early pancreatic islet fate and maturation is controlled through RBP-Jkappa. AB - Notch signaling is known to control early pancreatic differentiation through Ngn3 repression. In later stages, downstream of Notch, the Presenilins are still required to maintain the endocrine fate allocation. Amongst their multiple targets, it remains unclear which one actually controls the maintenance of the fate of the early islets. Conditional deletions of the Notch effector RBP-Jkappa with lineage tracing in Presenilin-deficient endocrine progenitors, demonstrated that this factor is central to the control of the fate through a non-canonical Notch mechanism. RBP-Jkappa mice exhibit normal islet morphogenesis and function, however, a fraction of the progenitors fails to differentiate and develop into disorganized masses resembling acinar to ductal metaplasia and chronic pancreatitis. A subsequent deletion of RBP-Jkappa in forming beta-cells led to the transdifferentiation into the other endocrine cells types, indicating that this factor still mediates the maintenance of the fate within the endocrine lineage itself. These results highlight the dual importance of Notch signaling for the endocrine lineage. Even after Ngn3 expression, Notch activity is required to maintain both fate and maturation of the Ngn3 progenitors. In a subset of the cells, these alterations of Notch signaling halt their differentiation and leads to acinar to ductal metaplasia. PMID- 27240891 TI - Can disclosure of scoring rubric for basic clinical skills improve objective structured clinical examination? AB - PURPOSE: To determine whether disclosure of scoring rubric for objective basic clinical skills can improve the scores on the objective structured clinical examination (OSCE) in medical students. METHODS: Clinical performance score results of one university medical students (study group, n=345) were compared to those of another university (control group, n=1,847). Both groups took identical OSCE exam. OSCE rubric was not revealed to the study group until they were in the last 2 years of medical school. RESULTS: There was no significant difference between before and after disclosure of rubric. However, history taking and physical examination scores of the study group were lower than those of the control group before the disclosure of rubric. After disclosure of rubric, the scores were either unchanged or slightly increased in the control group. Trend analysis of scores demonstrated that history taking and physical examination scores after the disclosure were significantly increased in the study group for 2 years. CONCLUSION: This study revealed that disclosure of basic clinical skills rubric to medical students could enhance their clinical performance, particularly in history taking and physical examination scores. PMID- 27240892 TI - Identifying weaknesses in undergraduate programs within the context input process product model framework in view of faculty and library staff in 2014. AB - PURPOSE: Objective of this research is to find out weaknesses of undergraduate programs in terms of personnel and financial, organizational management and facilities in view of faculty and library staff, and determining factors that may facilitate program quality-improvement. METHODS: This is a descriptive analytical survey research and from purpose aspect is an application evaluation study that undergraduate groups of selected faculties (Public Health, Nursing and Midwifery, Allied Medical Sciences and Rehabilitation) at Tehran University of Medical Sciences (TUMS) have been surveyed using context input process product model in 2014. Statistical population were consist of three subgroups including department head (n=10), faculty members (n=61), and library staff (n=10) with total population of 81 people. Data collected through three researcher-made questionnaires which were based on Likert scale. The data were then analyzed using descriptive and inferential statistics. RESULTS: Results showed desirable and relatively desirable situation for factors in context, input, process, and product fields except for factors of administration and financial; and research and educational spaces and equipment which were in undesirable situation. CONCLUSION: Based on results, researcher highlighted weaknesses in the undergraduate programs of TUMS in terms of research and educational spaces and facilities, educational curriculum, administration and financial; and recommended some steps in terms of financial, organizational management and communication with graduates in order to improve the quality of this system. PMID- 27240894 TI - Analysis of medical student's book reports on Cronin's The Citadel: would young doctors give up ideals for prestige and wealth? AB - PURPOSE: The purpose of this study is to find what medical students think the reward for their future work should be and whether they would keep their ideals or abandon them for prestige and wealth by analyzing the book reports of Cronin's The Citadel. METHODS: Participants were 50 medical students of junior class. A month before the classroom lecture, the book and digital video disk were provided. Students had discussions in groups of seven and wrote book reports which include answers of three questions. RESULTS: Regarding what should be the reward for the medical doctor, two-thirds of students (66.7%) answered with spiritual compensation, while one-third (33.3%) chose material reward. In the situation presented to Manson, three-fifths (60.0%) answered they would keep their ideals (idealist), while the remaining two-fifths (40.0%) decided they would abandon them. Less than one-third of students (30.0%) answered they would reveal the corruptions of the doctor's society, while two-thirds (64.0%) would not. CONCLUSION: The larger number of idealists who prefer spiritual reward rather than a material reward represents the innocence of youth as in portrayed in The Citadel. PMID- 27240895 TI - Erratum to: The Overt Pronoun Constraint Across Three Dialects of Spanish. PMID- 27240893 TI - Avoiding student infection during a Middle East respiratory syndrome (MERS) outbreak: a single medical school experience. AB - PURPOSE: In outbreaks of infectious disease, medical students are easily overlooked in the management of healthcare personnel protection although they serve in clinical clerkships in hospitals. In the early summer of 2015, Middle East respiratory syndrome (MERS) struck South Korea, and students of Sungkyunkwan University School of Medicine (SKKUSOM) were at risk of contracting the disease. The purpose of this report is to share SKKUSOM's experience against the MERS outbreak and provide suggestions for medical schools to consider in the face of similar challenges. METHODS: Through a process of reflection-on-action, we examined SKKUSOM's efforts to avoid student infection during the MERS outbreak and derived a few practical guidelines that medical schools can adopt to ensure student safety in outbreaks of infectious disease. RESULTS: The school leadership conducted ongoing risk assessment and developed contingency plans to balance student safety and continuity in medical education. They rearranged the clerkships to another hospital and offered distant lectures and tutorials. Five suggestions are extracted for medical schools to consider in infection outbreaks: instant cessation of clinical clerkships; rational decision making on a school closure; use of information technology; constant communication with hospitals; and open communication with faculty, staff, and students. CONCLUSION: Medical schools need to take the initiative and actively seek countermeasures against student infection. It is essential that medical schools keep constant communication with their index hospitals and the involved personnel. In order to assure student learning, medical schools may consider offering distant education with online technology. PMID- 27240896 TI - Stem Tones Pre-activate Suffixes in the Brain. AB - Results from the present event-related potentials (ERP) study show that tones on Swedish word stems can rapidly pre-activate upcoming suffixes, even when the word stem does not carry any lexical meaning. Results also show that listeners are able to rapidly restore suffixes which are replaced with a cough. Accuracy in restoring suffixes correlated positively with the amplitude of an anterior negative ERP elicited by stem tones. This effect is proposed to reflect suffix pre-activation. Suffixes that were cued by an incorrect tone elicited a left anterior negativity and a P600, suggesting that the correct processing of the suffix is crucially tied to the activation of the preceding validly associated tone. PMID- 27240897 TI - Segmentation and tagmosis in Chelicerata. AB - Patterns of segmentation and tagmosis are reviewed for Chelicerata. Depending on the outgroup, chelicerate origins are either among taxa with an anterior tagma of six somites, or taxa in which the appendages of somite I became increasingly raptorial. All Chelicerata have appendage I as a chelate or clasp-knife chelicera. The basic trend has obviously been to consolidate food-gathering and walking limbs as a prosoma and respiratory appendages on the opisthosoma. However, the boundary of the prosoma is debatable in that some taxa have functionally incorporated somite VII and/or its appendages into the prosoma. Euchelicerata can be defined on having plate-like opisthosomal appendages, further modified within Arachnida. Total somite counts for Chelicerata range from a maximum of nineteen in groups like Scorpiones and the extinct Eurypterida down to seven in modern Pycnogonida. Mites may also show reduced somite counts, but reconstructing segmentation in these animals remains challenging. Several innovations relating to tagmosis or the appendages borne on particular somites are summarised here as putative apomorphies of individual higher taxa. We also present our observations within the concept of pseudotagma, whereby the true tagmata - the prosoma and opisthosoma - can be defined on a fundamental change in the limb series while pseudotagmata, such as the cephalosoma/proterosoma, are expressed as divisions in sclerites covering the body without an accompanying change in the appendages. PMID- 27240898 TI - Introduction to special issue of Familial Cancer. PMID- 27240899 TI - Identification of metal species by ESI-MS/MS through release of free metals from the corresponding metal-ligand complexes. AB - Electrospray ionization-mass spectrometry (ESI-MS) is used to analyze metal species in a variety of samples. Here, we describe an application for identifying metal species by tandem mass spectrometry (ESI-MS/MS) with the release of free metals from the corresponding metal-ligand complexes. The MS/MS data were used to elucidate the possible fragmentation pathways of different metal-deoxymugineic acid (-DMA) and metal-nicotianamine (-NA) complexes and select the product ions with highest abundance that may be useful for quantitative multiple reaction monitoring. This method can be used for identifying different metal-ligand complexes, especially for metal species whose mass spectra peaks are clustered close together. Different metal-DMA/NA complexes were simultaneously identified under different physiological pH conditions with this method. We further demonstrated the application of the technique for different plant samples and with different MS instruments. PMID- 27240900 TI - Segmented diffusion-weighted imaging of the prostate: Application to transperineal in-bore 3T MR image-guided targeted biopsy. AB - OBJECTIVE: This study aims to evaluate the applicability of using single-shot and multi-shot segmented diffusion-weighted imaging (DWI) techniques to support biopsy target localization in a cohort of targeted MRI-guided prostate biopsy patients. MATERIALS AND METHODS: Single-shot echo-planar diffusion-weighted imaging (SS-DWI) and multi-shot segmented (MS-DWI) were performed intra procedurally on a 3Tesla system in a total of 35 men, who underwent in-bore prostate biopsy inside the scanner bore. Comparisons between SS-DWI and MS-DWI were performed with (in 16 men) and without (in 19 men) parallel coil acceleration (iPAT) for SS-DWI. Overall image quality and artifacts were scored by a radiologist and scores were compared with the Wilcoxon-Mann-Whitney rank test. Correlation between the presence of air and image quality scores was evaluated with Spearman statistics. To quantify distortion, the anteroposterior prostate dimension was measured in SS and MS b=0 diffusion- and T2-weighted images. Signal-to-noise ratio was estimated in a phantom experiment. Agreement and accuracy of targeting based on retrospective localization of restricted diffusion areas in DWI was evaluated with respect to the targets identified using multi-parametric MRI (mpMRI). RESULTS: Compared to SS-DWI without iPAT, the average image quality score in MS-DWI improved from 2.0 to 3.3 (p<0.005) and the artifact score improved from 2.3 to 1.4 (p<0.005). When iPAT was used in SS-DWI, the average image quality score in MS-DWI improved from 2.6 to 3.3 (p<0.05) and the artifact score improved from 2.1 to 1.4 (p<0.01). Image quality (rho=-0.74, p<0.0005) and artifact scores (rho=0.77, p<0.0005) both showed strong correlation with the presence of air in the rectum for the SS-DWI sequence without iPAT. These correlations remained significant when iPAT was enabled (rho=-0.52, p<0.05 and rho=0.64, p<0.01). For the comparison MS-DWI vs SS-DWI without iPAT, median differences between diffusion- and T2-weighted image gland measurements were 1.1(0.03-10.4)mm and 4.4(0.5-22.7)mm, respectively. In the SS-DWI-iPAT cohort, median gland dimension differences were 2.7(0.4-5.9)mm and 4.2(0.7-8.9)mm, respectively. Out of the total of 89 targets identified in mpMRI, 20 had corresponding restricted diffusion areas in SS-DWI and 28 in MS-DWI. No statistically significant difference was observed between the distances for the targets in the target-concordant SS- and MS-DWI restricted diffusion areas (5.5mm in SS-DWI vs 4.5mm in MS-DWI, p>0.05). CONCLUSIONS: MS-DWI applied to prostate imaging leads to a significant reduction of image distortion in comparison with SS-DWI. There is no sufficient evidence however to suggest that intra-procedural DWI can serve as a replacement for tracking of the targets identified in mpMRI for the purposes of targeted MRI-guided prostate biopsy. PMID- 27240901 TI - Introduction to Clinical Practice Update Committee Articles. PMID- 27240902 TI - Infection Using ERCP Endoscopes. PMID- 27240904 TI - Morphological evolution of lamellar forming polystyrene-block-poly(4 vinylpyridine) copolymers under solvent annealing. AB - In this work, we are reporting a very simple and efficient method to form lamellar structures of symmetric polystyrene-block-poly(4-vinylpyridine) (PS-b P4VP) copolymer thin films with vertically (to the surface plane) orientated lamellae using a solvent annealing approach. The methodology does not require any brush chemistry to engineer a neutral surface and it is the block neutral nature of the film-solvent vapour interface that defines the orientation of the lamellae. The microphase separated structure of two different molecular weight lamellar forming PS-block-P4VP copolymers formed under solvent vapour annealing was monitored using atomic force microscopy (AFM) so as to understand the morphological changes of the films upon different solvent exposure. In particular, the morphology changes from micellar structures to well-defined microphase separated arrangements. The choice of solvent/s (single and dual solvent exposure) and the solvent annealing conditions (temperature, time etc.) has important effects on structural transitions of the films and it was found that a block neutral solvent was required to realize vertically aligned P4VP lamellae. The results of the structural variation of the phase separated nanostructured films through the exposure to ethanol are also described. PMID- 27240903 TI - Efficacy of the Combination of Sofosbuvir, Velpatasvir, and the NS3/4A Protease Inhibitor GS-9857 in Treatment-Naive or Previously Treated Patients With Hepatitis C Virus Genotype 1 or 3 Infections. AB - BACKGROUND & AIMS: We performed a phase 2 trial of the efficacy and safety of 4, 6, and 8 weeks of sofosbuvir, given in combination with the NS5A inhibitor velpatasvir and the NS3/4A protease inhibitor GS-9857, in patients with hepatitis C virus (HCV) infection. METHODS: We enrolled 161 treatment-naive or previously treated patients infected with HCV genotypes 1 or 3 with or without compensated cirrhosis at 2 centers in New Zealand, from September 2014 through March 2015. All patients received sofosbuvir (400 mg) and velpatasvir (100 mg) plus GS-9857 (100 mg) once daily. The primary efficacy end point was sustained virologic response at 12 weeks after therapy (SVR12). The duration of therapy was determined by baseline patient characteristics: 4 or 6 weeks for treatment-naive patients without cirrhosis, 6 weeks for treatment-naive patients with cirrhosis, and 6 or 8 weeks for treatment-experienced patients with or without cirrhosis. RESULTS: Four weeks of sofosbuvir, velpatasvir, and GS-9857 produced an SVR12 in 4 of 15 (27%) treatment-naive patients with HCV genotype 1 without cirrhosis. Six weeks of this combination produced a SVR12 in 14 of 15 (93%) treatment-naive patients with HCV genotype 1 without cirrhosis, in 13 of 15 (87%) treatment-naive genotype 1 patients with cirrhosis, in 15 of 18 (83%) treatment-naive patients with HCV genotype 3 with cirrhosis, and in 20 of 30 (67%) patients with HCV genotype 1 who had failed an all-oral regimen of 2 or more direct-acting antiviral agents. Eight weeks of the drug combination produced an SVR12 in 17 of 17 (100%) patients with HCV genotype 1, in 19 of 19 (100%) patients with HCV genotype 3 and cirrhosis who had failed pegylated interferon plus ribavirin, in 25 of 28 (89%) patients with HCV genotype 1 who had failed protease inhibitor based triple therapy, and in 4 of 4 (100%) patients with HCV genotype 3 who had failed an all-oral regimen of >=2 direct-acting antiviral agents. The most common reported adverse events were headache, nausea, and fatigue. CONCLUSIONS: Eight weeks of treatment with the combination of sofosbuvir, velpatasvir, and GS-9857 produced an SVR12 in most treatment-naive or previously treated patients with HCV genotype 1 or 3 infections, including those with compensated cirrhosis. ClinicalTrials.gov, Number: NCT02202980. PMID- 27240906 TI - The effect of topical lidocaine on muscle artefacts in awake canine electroencephalogram recordings. AB - Muscle artefacts in electroencephalogram recording data interfere with diagnostic accuracy. Lidocaine may reduce these artefacts. The objective of this study was to determine the effect of topical lidocaine on muscle artefacts in unanesthetized canine electroencephalogram (EEG) recording data. Topical 4% lidocaine was applied to each electrode site for six treated dogs prior to subdermal wire electrode placement and compared against historical untreated controls. Twenty-minute recordings began 30 min after lidocaine application. Three epochs (early, middle, and end) were sampled from each recording and scored for muscle artefact incidence and severity by two blinded reviewers. No significant treatment effects on incidence and severity were found. Application of topical lidocaine does not appear to reduce the occurrence of muscle artefacts in canine EEG recordings. PMID- 27240905 TI - Effect of a constant rate infusion of cytosine arabinoside on mortality in dogs with meningoencephalitis of unknown origin. AB - Administration of cytosine arabinoside (CA) by continuous rate infusion (CRI) has pharmacokinetic and pharmacodynamic advantages over traditional intermittent dosing. Whether these advantages translate into clinical efficacy remains unknown. The aim of this study was to assess the efficacy and safety of CRI of CA in dogs with meningoencephalitis of unknown origin (MUO) and to compare outcomes with a group of historical control dogs treated with conventional intermittent subcutaneous (SC) administration of CA; both groups received adjunctive prednisolone. It was hypothesised that a CRI of CA for 24 h at 100 mg/m(2) would improve survival and lesion resolution compared with conventional SC delivery of 50 mg/m(2) every 12 h for 48 h. Eighty dogs with suspected MUO were recruited from consecutive dogs presenting with suspected MUO from 2006 to 2015. All dogs underwent routine clinical evaluation, magnetic resonance imaging of the brain and cerebrospinal fluid analysis. There were 39 dogs in the SC group and 41 dogs in the CRI group; baseline characteristics were similar in both groups. Survival at 3 months was 22/39 (44%) with SC delivery versus 37/41 (90%) with CRI. No dose limiting toxicities were noted for either group. The resolution rate of magnetic resonance imaging and cerebrospinal fluid abnormalities at the 3 month re examination were substantially improved in the CRI group versus the SC group. The CRI regimen produced a survival advantage over the SC route of administration without clinically significant toxicity. These data supports the routine use of CRI at first presentation for the treatment of MUO in dogs. PMID- 27240907 TI - Effect of Parachlamydia acanthamoebae on pulmonary function parameters in a bovine respiratory model. AB - The aim of this study was to evaluate pulmonary dysfunction induced by experimental infection with Parachlamydia acanthamoebae in calves. Intrabronchial inoculation with P. acanthamoebae was performed in 31 calves aged 2-3 months old at two different challenge doses of 10(8) and 10(10) inclusion-forming units (IFU) per animal. Control animals received heat inactivated bacteria. The effects on pulmonary gas exchange were determined by arterial blood gas analysis and haemoximetry during the 7 days post inoculation (DPI). For pulmonary function testing (PFT), impulse oscillometry, capnography, and measurement of O2 uptake were undertaken in spontaneously breathing animals 7 and 3 days before inoculation and were repeated until 10 DPI. In the early phase after challenge (1 3 DPI), mild hypoxaemia occurred, which was accompanied by a significant reduction in both tidal and alveolar volumes (each related to bodyweight, BW). In parallel, expiratory flow rate and specific ventilation (i.e. minute ventilation related to O2 uptake) were significantly increased. Minute and alveolar ventilations (each related to metabolic BW) increased significantly due to higher respiratory rates, lasting until 4 and 5 DPI, respectively. Oxygen uptake was slightly reduced during the first 2 days after challenge, but increased significantly during the recovery phase, from 4 to 8 DPI. No deterioration in respiratory mechanics or acid-base balance was observed. Respiratory infection with 10(10) IFU P. acanthamoebae per calf induced mild respiratory dysfunction, mainly characterised by hypoxaemia. The study's findings do not indicate severe pathophysiological consequences of P. acanthamoebae infection on pulmonary function in the bovine host. PMID- 27240908 TI - New DIVA vaccine for pigs. PMID- 27240910 TI - The holy grail of cartilage defect repair: Crossing species and disciplinary boundaries. PMID- 27240909 TI - Repeated measurements of blood lactate concentration as a prognostic marker in horses with acute colitis evaluated with classification and regression trees (CART) and random forest analysis. AB - The objective of this study was to investigate the prognostic value of single and repeated measurements of blood l-lactate (Lac) and ionised calcium (iCa) concentrations, packed cell volume (PCV) and plasma total protein (TP) concentration in horses with acute colitis. A total of 66 adult horses admitted with acute colitis (<24 h) to a referral hospital in the 2002-2011 period were included. The prognostic value of Lac, iCa, PCV and TP recorded at admission and 6 h post admission was analysed with univariate analysis, logistic regression, classification and regression trees, as well as random forest analysis. Ponies and Icelandic horses made up 59% of the population, whilst the remaining 41% were horses. Blood lactate concentration at admission was the only individual parameter significantly associated with probability of survival to discharge (P < 0.001). In a training sample, a Lac cut-off value of 7 mmol/L had a sensitivity of 0.66 and a specificity of 0.92 in predicting survival. In independent test data, the sensitivity was 0.69 and the specificity was 0.76. At the observed survival rate (38%), the optimal decision tree identified horses as non-survivors when the Lac at admission was >=4.3 mmol/L and the Lac 6 h post admission stayed at >2 mmol/L (sensitivity, 0.72; specificity, 0.8). In conclusion, blood lactate concentration measured at admission and repeated 6 h later aided the prognostic evaluation of horses with acute colitis in this population with a very high mortality rate. This should allow clinicians to give a more reliable prognosis for the horse. PMID- 27240911 TI - Herd-level risk factors for bovine tuberculosis and adoption of related biosecurity measures in Northern Ireland: A case-control study. AB - Bovine tuberculosis (bTB) is a zoonotic disease which is endemic in Northern Ireland. As it has proven difficult to eradicate this disease, partly due to a wildlife reservoir being present in the European badger (Meles meles), a case control study was conducted in a high incidence area in 2010-2011. The aim was to identify risk factors for bTB breakdown relating to cattle and badgers, and to assess the adoption of bTB related biosecurity measures on farms. Face-to-face questionnaires with farmers and surveys of badger setts and farm boundaries were conducted on 117 farms with a recent bTB breakdown (cases) and 75 farms without a recent breakdown (controls). On logistic regression at univariable and multivariable levels, significant risk factors associated with being a case herd included having an accessible badger sett within the farm boundaries in a field grazed in the last year (odds ratio, OR, 4.14; 95% confidence interval, CI, 1.79, 9.55), observation of live badgers (OR 4.14; 95% CI 1.79, 9.55), purchase of beef cattle (OR 4.60; 95% CI 1.61, 13.13), use of contractors to spread slurry (OR 2.83; 95% CI 1.24, 6.49), feeding meal on top of silage (OR 3.55; 95% CI 1.53, 8.23) and feeding magnesium supplement (OR = 3.77; 95% CI 1.39, 10.17). The majority of setts within the farm boundary were stated to be accessible by cattle (77.1%; 95% CI 71.2, 83.0%) and 66.8% (95% CI 63.8, 69.7%) of farm boundaries provided opportunities for nose-to-nose contact between cattle. Adoption of bTB related biosecurity measures, especially with regards to purchasing cattle and badger-related measures, was lower than measures related to disinfection and washing. PMID- 27240912 TI - Natural history of canine paroxysmal movement disorders in Labrador retrievers and Jack Russell terriers. AB - Delineation of the typical disease progression in canine paroxysmal dyskinesia (PD) may assist in evaluating therapeutic agents during clinical trials. Our objective was to establish the natural disease course in a group of dogs diagnosed with PD that received no medication. Fifty-nine dogs (36 Labradors, 23 JRTs) with clinically confirmed PD and a follow-up of >=3 years were retrospectively reviewed. Dogs with PD had a young onset, were triggered by startle or sudden movements, and had a male bias (75%) with the majority being entire sample population. Twenty-one dogs (36%) had at least one event comprising cluster episodes. Episode duration and frequency varied dramatically, even within an individual. Median follow-up was 7 years. No concurrent disease was identified in any dog that was investigated. The natural history was self-limiting with 32% entering remission and an improvement in 75%. Episodes reduced in terms of frequency and duration in Labradors and JRTs respectively. Remission was lower in dogs with cluster episodes than those without. These findings suggest that the diagnostic yield of advanced neuroimaging techniques in dogs with video footage and historical data supporting PD, without neurological deficits, is low. The presence of cluster episodes is of predictive value for the prognosis of canine PD. Future research should be cautious in reporting treatment response for PD without first considering the spontaneous remission rate and improvements in untreated dogs documented in this study. PMID- 27240913 TI - Veterinary oncology: Biology, big data and precision medicine. AB - Despite significant advances in both the understanding and the treatment of cancer, the disease remains one of high mortality and morbidity causes in all species. Increases in survival times in human cancer have increased significantly in the past 25 years but most of these increases have been through small incremental changes. For some cancers, e.g. pancreatic cancer, survival times have not increased significantly in over 100 years. In veterinary oncology, there have been major shifts in the management of cancer in companion animals. Increased availability of specialist centres, coupled with changing attitudes in owners and veterinarians, have meant improvements in veterinary cancer care borne from market pressures and increased awareness and understanding. In this review the changing face of cancer biology over the past 25 years will be examined, and the barriers to clinical progress in veterinary medicine considered. Finally, an optimistic view of the future will be presented with the prospect of greater control over this devastating disease. PMID- 27240914 TI - First impressions: Cytology from the surface of the brain. PMID- 27240915 TI - The effect of imepitoin, a recently developed antiepileptic drug, on thyroid parameters and fat metabolism in healthy Beagle dogs. AB - Since early 2013, imepitoin has been used in most European countries for the management of recurrent single generalised epileptic seizures in dogs with idiopathic epilepsy. It has been reported that imepitoin is as effective as phenobarbital (PB) in controlling seizures in dogs with newly diagnosed idiopathic epilepsy and it has a clinically superior safety profile. As the use of imepitoin gains popularity, its effect on serum thyroid parameters warrants further investigation since long-term PB administration influences thyroid parameters in dogs, which could lead to misinterpretation of laboratory results and incorrect diagnosis of thyroidal illness. A prospective study was conducted to compare the effect of orally administered PB and imepitoin on serum concentrations of total thyroxine (TT4), triiodothyronine, free thyroxine, thyroglobulin autoantibodies, thyroid-stimulating hormone, cholesterol and triglycerides in healthy Beagle dogs. These parameters were determined prior to and at 6, 12 and 18 weeks after antiepileptic drug administration. The starting dose of PB (5 mg/kg PO twice daily; range, 4.4-6.0 mg/kg) was monitored and adjusted to obtain optimal therapeutic serum concentrations (30-35 g/mL). Imepitoin was administered at 30 mg/kg PO twice daily (range, 29.2-35.7 mg/kg). Imepitoin administration did not affect any of the thyroid parameters over an 18 week period. In contrast, serum TT4 concentrations decreased significantly over time in dogs receiving PB (P <0.05). Serum cholesterol concentrations increased significantly over time in dogs in the imepitoin group, but not to the same extent as commonly seen in dogs with primary hypothyroidism. PMID- 27240916 TI - Engineering of a live Salmonella enterica serovar Choleraesuis negative-marker strain that allows serological differentiation between immunised and infected animals. AB - The usefulness of Salmonella vaccine vehicles is limited by the fact that control programmes relying on Salmonella bacteriology and serology cannot differentiate infected animals from vaccinated ones, an ability referred to as DIVA (differentiating infected from vaccinated animals). As a first step towards Salmonella-based DIVA vaccines, the ompA gene was deleted in live attenuated DeltaphoP and DeltarpoS vaccine strains. The ompA gene is present in all Salmonella enterica serovars and it encodes an abundant, highly immunogenic outer membrane protein. The double mutant DeltaphoP DeltaompA and DeltarpoS DeltaompA strains showed similar virulence attenuation, safety and immunogenicity in a mouse model of infection as the parental DeltaphoP and DeltarpoS strains. Sera from mice inoculated with the double mutant strains failed to recognise OmpA in Western blots of outer membrane extracts, whereas the protein was recognised by sera from mice inoculated with wild-type Salmonella or a mixture of double mutant and parental strains. These data suggest that OmpA can be a suitable negative marker for DIVA vaccines. PMID- 27240917 TI - Recovery of stepping and coordination in dogs following acute thoracolumbar intervertebral disc herniations. AB - Prospective data on the recovery of coordination in dogs suffering acute thoracolumbar intervertebral disc herniations (TL-IVDH) are limited. The purpose of this study was to use treadmill based and open field scores (OFS) to quantify recovery of stepping ability and forelimb, hindlimb coordination in the 6 weeks following surgical decompression of dogs with TL-IVDH. Sixty-three dogs were grouped at presentation as grades 3 (non-ambulatory paraparetic), 4 (paraplegic) or 5 (paraplegic without pain sensation) and were evaluated 2, 4, and 6 weeks post-operatively. Stepping scores and Regularity Index (RI), a measure of coordination, were calculated from treadmill walking, and an OFS incorporating supported and unsupported walking was assigned. Outcomes for the three measures were compared between groups and correlation between scoring methods was assessed. Grade 3 and 4 dogs recovered ambulation by 2 weeks, reaching median stepping scores of 96 and 90% by 6 weeks, respectively. Recovery of coordination differed between groups 3 and 4 with median RI scores of 93.9% and 63%, respectively, by 6 weeks. Eight grade 5 dogs failed to recover independent ambulation by 6 weeks. Nine dogs recovered with scores that were significantly worse than the grade 3 and 4 dogs at 6 weeks for stepping score (P < 0.001) and RI (P < 0.001). OFS correlated closely with stepping and RI scores and each group was significantly different using this ordinal scale. In conclusion, recovery of coordination was incomplete in dogs that showed good recovery of stepping. The data generated could be used for clinical trial design. PMID- 27240918 TI - Designing a field trial of an equine grass sickness vaccine: A questionnaire based feasibility study. AB - Without an experimental model of equine grass sickness (EGS), a randomised controlled field trial (RCT) represents the only method of evaluating the efficacy of Clostridium botulinum type C vaccination in preventing naturally occurring disease. Clinical trial feasibility is an important aspect of preliminary work undertaken prior to initiating RCTs, estimating parameters that are important for study design. This cross-sectional study aimed to assess the feasibility of conducting a nationwide RCT of a candidate vaccine for EGS based on responses from a sample of British equine veterinary practices (n = 119/284). Seventy-three percent of practices had attended >=1 EGS case within the preceding 2 years (median four cases), and 51.3% regularly attended recurrently affected premises. Veterinary surgeons had greater confidence diagnosing acute/subacute EGS based solely on history and clinical signs compared to chronic EGS. Ninety one percent of respondents (n = 103/113) considered the proposed RCT to be important/very important to equine veterinary research. Ninety-one percent of respondents (n = 102/112) indicated preparedness to assist in owner recruitment and 92.9% (n = 104/112) indicated willingness to participate in a RCT. The most frequent reasons for practices declining to participate were low incidence of EGS (n = 4), did not believe clients would wish to participate (n = 3) and amount of paperwork/data collection involved (n = 2). There was considerable support amongst participating veterinary practices for a RCT evaluating the efficacy of Clostridium botulinum vaccination for the prevention of EGS in Britain. Substantial proportions of participating practices would be prepared to participate in the RCT and regularly attended EGS-affected premises that would meet trial inclusion criteria. PMID- 27240919 TI - Pathological and immunological features of canine necrotising meningoencephalitis and granulomatous meningoencephalitis. AB - Necrotising meningoencephalitis (NME) and granulomatous meningoencephalitis (GME) are idiopathic inflammatory diseases of the canine central nervous system (CNS). Typical NME occurs predominantly in small breeds of dogs, such as Pug, Maltese and Yorkshire terriers. Although there is no specific breed predisposition to GME, toy and terrier breeds appear to be overrepresented. Recent molecular investigations have identified genetic risk factors for NME in Pug, Maltese and other toy breed dogs; however, details of the pathogenesis of this disease remain to be clarified. NME is characterised pathologically by necrotic lesions with mononuclear cell infiltration in the meninges and perivascular spaces. On the basis of the distribution pattern of major necrotic foci, NME can be divided into cortex dominant and white matter dominant types; the latter is designated necrotising leucoencephalitis (NLE). Lesions in GME are characterised by the accumulation of lymphocytes and macrophages with epithelioid morphology, forming granulomas around blood vessels. Some common genetic factors and/or some additional triggers, such as infection or vaccination, may play a role in the pathogenesis of NME, NLE and GME; however, the host immune responses may define the pathological phenotypes. Different cytokine and chemokine responses are seen in NME, NLE and GME, whilst autoantibodies against astrocytes are detected predominantly in NME. This review focuses on the pathological and immunological characteristics of these canine idiopathic inflammatory CNS disorders. PMID- 27240920 TI - Comparison of in vivo confocal endomicroscopy with other diagnostic modalities to detect intracellular helicobacters. AB - Intracellular colonisation may serve as a protected niche where Helicobacter spp. organisms evade effective treatment. In dogs, non-Helicobacter pylori helicobacters are frequently intracellular. Confocal endomicroscopy allows in vivo gastrointestinal imaging and has aided real-time identification of Helicobacter pylori and other intracellular and mucosally associated bacteria. The objectives of this study were: (1) to determine the utility of confocal endomicroscopy to identify non-Helicobacter pylori-helicobacters compared with other diagnostic modalities, and (2) to assess its ability to identify intracellular organisms. Fourteen clinically healthy dogs underwent standard gastroduodenoscopy followed by confocal endomicroscopy using topical acriflavine. Confocal images were obtained from at least five gastric sites. Endoscopic biopsies were obtained for histopathology, PCR and fluorescence in situ hybridisation (FISH). Methodologies were compared for their ability to determine the presence and spatial distribution of gastric helicobacters in dogs. Confocal endomicroscopy provided high quality images allowing in vivo identification of non-Helicobacter pylori-helicobacters in 13 dogs. Histopathology identified helicobacters in 11 dogs. Organisms were identified within the superficial gastric mucus and within gastric pits, and distribution throughout the stomach was diffuse and multi-focal. Confocal endomicroscopy findings correlated with PCR and FISH post-procedure analysis. Only FISH identified intracellular organisms, which were present in 13/14 dogs. Confocal endomicroscopy provided in vivo histology images and was capable of identifying non-Helicobacter pylori helicobacters during gastroscopy, but was unable to identify intracellular organisms using the current fluorophore protocol. PMID- 27240921 TI - Randomised clinical trial on the effect of a single oral administration of l tryptophan, at three dose rates, on reaction speed, plasma concentration and haemolysis in horses. AB - Tryptophan (TRP) is marketed as a calmative for horses despite reservations about its efficacy. The aim of this study was to measure the effect of oral TRP administration on the reaction speed of horses. Sixty mature horses were used in a two stage randomised, blind, cross-over study, receiving a placebo and an oral dose of TRP (30, 60 or 120 mg/kg body weight), before undergoing a reaction speed test. Blood samples were taken up to 96 h after TRP administration, to identify signs of acute haemolytic anaemia. Plasma TRP concentrations were increased (P <0.001) by the administration of TRP paste. However, TRP had no effect on the reaction speed of horses when startled. There was no evidence of alterations in clinical pathology parameters in 432 blood samples. While the safety of these doses of TRP can be confirmed, there was no evidence to suggest that a single dose of TRP is an effective calmative for horses. PMID- 27240922 TI - Assessment of temporal association of relapse of canine multicentric lymphoma with components of the CHOP protocol: Is cyclophosphamide the weakest link? AB - Combination chemotherapy, using cyclophosphamide, hydroxydaunorubicin, vincristine and prednisolone (CHOP), is the most commonly used treatment for canine lymphoma. Most affected dogs respond during the initial stages of chemotherapy, but many relapse. The aim of this study was to evaluate the relationship between the use of specific chemotherapy drugs and clinical relapse, using the modified Madison-Wisconsin, 25 week chemotherapy protocol. Forty-one of 68 dogs affected with multicentric lymphoma relapsed during the treatment period. Relapse occurred more frequently after the administration of cyclophosphamide (n = 24; P < 0.01), compared with vincristine (n = 9) or doxorubicin (n = 5). Therefore, the therapeutic outcome of traditional CHOP-based chemotherapy might be improved by replacing cyclophosphamide with other cytotoxic drugs. PMID- 27240923 TI - Insulin dysregulation and obesity: You are what you eat. PMID- 27240924 TI - Equine aortic regurgitation: The search for objective repeatable and reproducible indicators of severity. PMID- 27240925 TI - ? PMID- 27240927 TI - Novel CoS2 embedded carbon nanocages by direct sulfurizing metal-organic frameworks for dye-sensitized solar cells. AB - Owing to its excellent electrocatalytic properties, cobalt disulfide (CoS2) is regarded as a promising counter electrode (CE) material for dye-sensitized solar cells (DSSCs). However, hindered by its relatively poor electrical conductivity and chemical instability, it remains a challenge to apply it into high performance DSSCs. In this work, we have developed novel CoS2 embedded carbon nanocages as a CE in DSSCs, using ZIF-67 (zeolitic imidazolate framework 67, Co(mim)2, mim = 2-methylimidolate) as a template. The CoS2 samples sulfurized for different time lengths are prepared through a facile solution process. It is found that the sulfurization time can be optimized to maximize the DSSC efficiency and the DSSC based on the CoS2 embedded carbon nanocages sulfurized for 4 hours exhibits the highest photovoltaic conversion efficiency (PCE) of 8.20%, higher than those of DSSCs consisting of other CoS2 CEs and Pt-based DSSC (7.88%). The significantly improved DSSC PCE is contributed by the synergic effect of inner CoS2 nanoparticles and an amorphous carbon matrix, leading to a CE with high catalytic activity, good electrical conductivity and excellent durability. This study demonstrates that the CE based on inexpensive CoS2 embedded carbon nanocages is a prospective substitute to expensive platinum and provides a new approach for commercializing high-efficiency DSSCs. PMID- 27240926 TI - Prenatal diagnosis of absent pulmonary valve syndrome from first trimester onwards: novel insights into pathophysiology, associated conditions and outcome. AB - OBJECTIVE: To assess the spectrum of associated anomalies, intrauterine course and outcome in fetuses with absent pulmonary valve syndrome (APVS). METHODS: All cases with a prenatal diagnosis of APVS at two centers over a period of 13 years were analyzed retrospectively. APVS was diagnosed in the presence of rudimentary or dysplastic pulmonary valve leaflets with to-and-fro blood flow in the pulmonary trunk on color and pulsed-wave Doppler ultrasound. Data on demographic characteristics, presence of associated conditions, Doppler studies and pregnancy outcome were reviewed. RESULTS: During the study period, 40 cases of APVS were diagnosed prenatally. Thirty-seven (92.5%) cases were associated with tetralogy of Fallot (TOF) and three (7.5%) had an intact ventricular septum. Patency of the ductus arteriosus (DA) was found in 17/37 (45.9%) TOF cases and in all three cases with an intact ventricular septum. Mean gestational age at diagnosis was 19.7 (range, 12-34) weeks with 10 (25.0%) cases (all with TOF) diagnosed in the first trimester. TOF was an isolated finding in 15 (37.5%) cases. Chromosomal anomalies, cardiac defects and extracardiac anomalies were present in 18 (45.0%), four (10.0%) and three (7.5%) cases, respectively. Among the 40 cases, there were 19 (47.5%) terminations of pregnancy, six (15.0%) intrauterine deaths, four (10.0%) neonatal deaths and 11 (27.5%) survivors. Patency of the DA, reversed flow during atrial contraction in the ductus venosus, umbilical artery or fetal middle cerebral artery, and hydrops/increased nuchal translucency thickness were significantly associated with non-survival. All 10 cases diagnosed in the first trimester had a patent DA and abnormal Doppler parameters, eight had hydrops and/or increased nuchal translucency, six were associated with trisomy 13 or 18 and none survived. CONCLUSION: APVS diagnosed in the first trimester is significantly associated with TOF, patency of the DA, abnormal Doppler parameters, lethal trisomies and intrauterine mortality. Cases of APVS with isolated TOF and agenesis of the DA have a better outcome than those with additional anomalies, with > 80% survival. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 27240928 TI - Novel chiral Schiff base/Ti(iv) catalysts for the catalytic asymmetric epoxidation of N-alkenyl sulfonamides. AB - A new method has been developed for the catalytic asymmetric epoxidation of N alkenyl sulfonamides in the presence of a Schiff base derived from hydroquinine and Ti(Oi-Pr)4. This reaction proceeds under mild conditions, providing facile access to chiral epoxy sulfonamides in good yields (up to 95%) with excellent enantioselectivities (up to 97% ee). PMID- 27240929 TI - Variation in serum biomarkers with sex and female hormonal status: implications for clinical tests. AB - Few serum biomarker tests are implemented in clinical practice and recent reports raise concerns about poor reproducibility of biomarker studies. Here, we investigated the potential role of sex and female hormonal status in this widespread irreproducibility. We examined 171 serum proteins and small molecules measured in 1,676 participants from the Netherlands Study of Depression and Anxiety. Concentrations of 96 molecules varied with sex and 66 molecules varied between oral contraceptive pill users, postmenopausal females, and females in the follicular and luteal phases of the menstrual cycle (FDR-adjusted p-value <0.05). Simulations of biomarker studies yielded up to 40% false discoveries when patient and control groups were not matched for sex and up to 41% false discoveries when premenopausal females were not matched for oral contraceptive pill use. High accuracy (over 90%) classification tools were developed to label samples with sex and female hormonal status where this information was not collected. PMID- 27240930 TI - Automated Analysis of Cell Cycle Phase-Specific DNA Damage Reveals Phase-Specific Differences in Cell Sensitivity to Etoposide. AB - The comet assay is one of the most widely used approaches for detecting DNA damage; generally, it provides information on the cell population-averaged level of DNA damage. Here, we present an automatic technique for easy measurement of standard comet characteristics and an annotation of the cell cycle phase of each comet. The approach includes the modified neutral comet assay and a pipeline for CellProfiler software designed to analyze DNA damage-related characteristics and annotate the cell cycle phase of each comet. Using this technique we have performed cell cycle phase-specific analysis of DNA damage induced by the topoisomerase II poison etoposide and have shown that the sensitivity of cells to this drug dramatically differed according to their cell cycle phase. It became evident from our results that the proposed protocol provides important additional information that often remains hidden in a standard comet analysis of an asynchronous cell population. J. Cell. Biochem. 117: 2209-2214, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27240931 TI - Corrigendum: Neuronal activity controls transsynaptic geometry. PMID- 27240932 TI - Composition and function of sourdough microbiota: From ecological theory to bread quality. AB - Sourdough has traditionally been used as leavening agent in artisanal baking. The production of baked and steamed cereal products increasingly employs sourdough as baking improver to achieve improved bread quality, or to obtain "clean label" products. Sourdoughs are maintained in bakeries by continuous propagation; composition and metabolic activity of sourdough microbiota and their impact on bread quality are therefore shaped by processing parameters and fermentation substrates. The diversity of fermentation processes leads to diverse compositions of sourdough microbiota. This communication explores whether concepts in community assembly support an improved understanding of the microbial ecology of sourdough. Community assembly is determined by diversification, drift, dispersal, and selection. Evidence for diversification in sourdoughs is inconclusive. Drift has been shown to shape sourdough microbiota only in specific cases. Increasing knowledge on the primary habitat of sourdough lactobacilli indicates that dispersal (limitation) is an important determinant in sourdoughs that are propagated only for short periods of time. In contrast, selection of adapted organisms mainly determines the microbiota of sourdoughs that are propagated for a long time. Bacterial metabolic traits that determine competitiveness in sourdough fermentation, i.e. effective use of maltose, exopolysaccharide formation from sucrose, the use of electron acceptors by heterofermentative lactic acid bacteria, and acid resistance mediated by arginine and glutamine conversion, also determine bread quality. The concepts in community assembly thus provide a valuable tool to understand the influence of the technology of sourdough fermentation on microbial ecology and on bread quality. PMID- 27240933 TI - Lactobacillus plantarum with broad antifungal activity: A promising approach to increase safety and shelf-life of cereal-based products. AB - Cereal-based fermented products are worldwide diffused staple food resources and cereal-based beverages represent a promising innovative field in the food market. Contamination and development of spoilage filamentous fungi can result in loss of cereal-based food products and it is a critical safety concern due to their potential ability to produce mycotoxins. Lactic Acid Bacteria (LAB) have been proposed as green strategy for the control of the moulds in the food industry due to their ability to produce antifungal metabolites. In this work, eighty-eight Lactobacillus plantarum strains were screened for their antifungal activity against Aspergillus niger, Aspergillus flavus, Fusarium culmorum, Penicillium roqueforti, Penicillium expansum, Penicillium chrysogenum, and Cladosporium spp. The overlayed method was used for a preliminary discrimination of the strains as no, mild and strong inhibitors. L. plantarum isolates that displayed broad antifungal spectrum activity were further screened based on the antifungal properties of their cell-free supernatant (CFS). CFSs from L. plantarum UFG 108 and L. plantarum UFG 121, in reason of their antifungal potential, were characterized and analyzed by HPLC. Results indicated that lactic acid was produced at high concentration during the growth phase, suggesting that this metabolic aptitude, associated with the low pH, contributed to explain the highlighted antifungal phenotype. Production of phenyllactic acid was also observed. Finally, a new oat-based beverage was obtained by fermentation with the strongest antifungal strain L. plantarum UFG 121. This product was submitted or not to a thermal stabilization and artificially contaminated with F. culmorum. Samples containing L. plantarum UFG 121 showed the best biopreservative effects, since that no differences were observed in terms of some qualitative features between not or contaminated samples with F. culmorum. Here we demonstrate, for the first time, the suitability of LAB strains for the fermentation and antifungal biopreservation of oat-based products. PMID- 27240934 TI - Drivers for the establishment and composition of the sourdough lactic acid bacteria biota. AB - The drivers for the establishment and composition of the sourdough microbiota, with particular emphasis on lactic acid bacteria, are reviewed and discussed. More than 60 different species of lactobacilli were identified from sourdoughs, showing the main overlapping between sourdough and human intestine ecosystems. The microbial kinetics during sourdough preparation was described by several studies using various methodological approaches, including culture-dependent and independent (e.g., high throughput sequencing), and metabolite and meta transcriptome analyses. Although the abundant microbial diversity harbored by flours, a succession of dominating and sub-dominating populations of lactic acid bacteria suddenly occurred during sourdough propagation, leading to the progressive assembly of the bacterial community. The contribution of all the potential sources (house microbiota, flour, types of flours and additional ingredients) for contaminating lactic acid bacteria was compared with the aim to find overlapping or specific routes that affect the sourdough microbiota. Once established and mature, pros and cons regarding the stability of the sourdough lactic acid bacteria biota were also reviewed, showing contradictory results, which were mainly dependent on the species/strains. Probably, the future research efforts should be dedicated to decrease the sources/drivers of noticeable variation rather than to full standardization of the process for sourdough preparation and use. PMID- 27240935 TI - 5-Fluorouracil shell-enriched solid lipid nanoparticles (SLN) for effective skin carcinoma treatment. AB - CONTEXT: The effective treatment of skin carcinoma is warranted for targeting the chemotherapeutic agents into tumor cells and avoiding unwanted systemic absorption. OBJECTIVE: This work was dedicated to the purpose of engineering highly penetrating shell-enriched nanoparticles that were loaded with a hydrophilic chemotherapeutic agent, 5-fluorouracil (5-FU). METHODS: Varying ratios of lecithin and poloxamer188 were used to produce shell-enriched nanoparticles by enabling the formation of reversed micelles within this region of the SLN. The localization of 5-FU within the shell region of the SLN, was confirmed using 5-FU nanogold particles as a tracer. SLN were introduced within sodium carboxy methylcellulose hydrogel, and then applied onto the skin of mice bearing Ehrlich's ascites carcinoma. The mice were treated with the gel twice daily for 6 weeks. RESULTS: The transmission electron microscope (TEM) revealed the formation of uniform nanoparticles, which captured reversed micelles within their shell region. The SLNs' had particle size that ranged from 137 +/- 5.5 nm to 800 +/- 53.6, zeta potential of -19.70 +/- 0.40 mV and entrapment efficiency of 47.92 +/- 2.34%. The diffusion of the drug-loaded SLN (269.37 +/- 10.92 MUg/cm2) was doubled when compared with the free drug (122 +/- 3.09 MUg/cm2) when both diffused through a hydrophobic membrane. SLN-treated mice exhibited reduced inflammatory reactions, with reduced degrees of keratosis, in addition to reduced symptoms of angiogenesis compared to 5-FU-treated mice. CONCLUSION: SLN possesses the capacity to be manipulated to entrap and release hydrophilic antitumor drugs with ease. PMID- 27240936 TI - Influence of the analysis technique on estimating hepatic iron content using MRI. AB - PURPOSE: To investigate the effect of the analysis technique on estimating hepatic iron content using MRI. MATERIALS AND METHODS: We evaluated the influences of single-exponential (EXP), bi-exponential (BEXP), and exponential plus-constant (CEXP) models; and pixel-wise (MAP), average (AVG), and median (MED) signal calculation methods on T2* measurement using numerical simulations, calibrated phantoms, and nine patients scanned on 3 Tesla MRI, based on regression, correlation, and t-test statistical analysis. RESULTS: The T2* measurement error varied from 9 to 51% in the numerical simulations (T2*: 5-20 ms), depending on signal-to-noise ratio (SNR; range: 8-233) with significant (P < 0.05) difference between actual and predicted values. The MAP method performed well (error < 10%) at high SNR (>100), but resulted in severe estimation errors at low SNR (<50). The EXP model resulted in significant measurement differences (P < 0.05) compared with all other methods, irrespective of SNR. In vivo T2* values ranged from 3.1 to 53.6 ms, depending on the amount of iron overload and implemented analysis method. The BEXP (range: 3.7-50 ms) and CEXP (range: 3.8 53.6 ms) models, and the AVG (range: 3.2-38.8 ms) and MED (range: 3.1-38.5 ms) methods provided more accurate measurements than the EXP model (range: 3.1-18.3 ms) and MAP (range: 3.8-53.6 ms) method, respectively (P < 0.05). The BEXP and CEXP models provided very similar measurements (P > 0.87). Similarly, the AVG and MED methods provided very similar results (P > 0.97), with slightly better performance of the AVG method. CONCLUSION: Different analysis techniques show different performances based on the fitting model and signal calculation method. Based on this study, the CEXP model and AVG method are recommended due to simpler implementation and less influence by the selected analysis region. J. Magn. Reson. Imaging 2016;44:1448-1455. PMID- 27240937 TI - Developing a framework for implementing intensive care unit diaries: a focused review of the literature. AB - OBJECTIVE: Intensive care unit diaries have been shown to improve post-critical illness recovery, however, prior reports of diary implementation are heterogeneous. We sought to construct a common framework for designing and implementing Intensive Care Unit diaries based on prior studies. REVIEW METHOD USED/DATA SOURCES: We conducted a focused review of the literature regarding intensive care diaries based on a systematic search of several databases. Two reviewers assessed 56 studies and data were abstracted from a total of 25 eligible studies conducted between 1990 and 2014. We identified key information regarding the development, design, and implementation of the journals. We then grouped elements that appeared consistently across these studies within three main categories: (1) diary target populations; (2) diary format and content; and (3) the manner of diary return and follow-up. RESULTS: Most studies were conducted in European countries in adult intensive care units and targeted patients in both medical and surgical units. The timing of diary initiation was based on the elapsed length of stay or duration of mechanical ventilation. We categorised diary format and content as: entry content, authors, use of standardised headings, type of language, initiation, frequency of entries, and physical location of diaries. Diaries were hand written and many studies found that photographs were an essential element in ICU diaries. We categorised the manner of diary return and follow-up. The context in which intensive care unit diaries were returned were felt to be important factors in improving the use of diaries in recovery. CONCLUSIONS: In conclusion, we describe a common framework for the future development of intensive care unit diaries that revolves around the target population for the diaries, their format and content, and the timing of their use. Future studies should address how these elements impact the mechanisms by which intensive are diaries exert beneficial effects. PMID- 27240938 TI - Determination of neutrophil CD64 expression as a prognostic biomarker in patients with community-acquired pneumonia. AB - The expression of CD64 in neutrophils (nCD64) has shown utility in the diagnosis of sepsis. The aim of this study was to assess the usefulness of nCD64 expression to identify patients with community-acquired pneumonia (CAP) at risk of a poor outcome. A prospective study of nCD64 expression (determined by flow cytometry) in patients with CAP was performed. The sensitivity/specificity of nCD64 in predicting poor outcome [defined as intensive care unit (ICU) admission and/or clinical deterioration after arrival at the emergency department] was calculated. Eighty-three adults with CAP were included; 14.5 % had septic shock, 19.3 % required ICU admission, and 10.8 % presented clinical deterioration after admission. The mean of the median fluorescence intensity (MFI) of nCD64 expression was 1140 (+/-1097). Patients with nCD64 expression >=2700 MFI had more clinical deterioration (36.4 vs. 7.2 %, p = 0.015) and more ICU admission (45.5 vs. 14.5 %, p = 0.028). To identify clinical deterioration and ICU admission, nCD64 expression showed a sensitivity of 44.4 and 33.3 % and a specificity of 90.1 and 90.8 %, respectively. The addition of nCD64 expression to the Pneumonia Severity Index and CURB-65 severity scores did not improve the accuracy of predicting these outcomes. Although nCD64 expression is associated with an increased risk of ICU admission or clinical deterioration after admission, its accuracy in predicting these poor outcomes is modest and does not significantly improve the predictive ability of the PSI and CURB-65 severity scores. PMID- 27240939 TI - Parental Characteristics can Explain Why Japanese Women Give Birth to the Smallest Infants in the United States. AB - BACKGROUND: Whether birthweight differences observed between races are due to modifiable factors remains controversial. In the United States, Asian infants weigh less than white infants and Japanese infants weigh the least. METHODS: Using US Natality data, we evaluated 4 132 319 singleton term livebirths to parents of non-Hispanic white or Japanese race/ethnicity from 2009 to 2012. Infants were categorised by parental race/ethnicity (both white, n = 4 116 637; Japanese father/white mother, n = 2377; white father/Japanese mother, n = 7478; both Japanese, n = 5827). We used multivariable regression to sequentially adjust for maternal characteristics to determine to what extent they explained differences in fetal growth due to maternal race/ethnicity. RESULTS: Infants born to Japanese mothers were smaller by 132 (95% CI 101, 122) grams, with higher risk of small for gestational age (relative risk ratio (RRR) 1.56 (95% CI 1.47, 1.65) and lower risk of large for gestational age RRR 0.49, 95% CI 0.44, 0.54), compared to infants of white mothers. Differences in social factors and in maternal age, parity, and gestational age only minimally explained this difference. However, additionally adjusting for maternal height, body mass index and gestational weight gain substantially attenuated this difference to 20 (95% CI 12, 29) grams in birthweight, 0.91 (95% CI 0.86, 0.97) times risk of small for gestational age, and 1.06 (95% CI 0.96, 1.17) times risk of large for gestational age, with the effect similar across strata of paternal race/ethnicity. CONCLUSION: Differences in fetal growth between infants from Japanese and white mothers could be explained by differences in maternal height, pre-pregnancy weight, and gestational weight gain. Fetal growth potential appears to be similar across racial/ethnic groups when parental sizes are similar. PMID- 27240940 TI - Reply to Filippo Alongi, Rosario Mazzola, Sergio Fersino's Letter to the Editor re: Patrick C. Walsh, Nathan Lawrentschuk. Immediate Adjuvant Radiation Therapy Following Radical Prostatectomy Should Not Be Advised for Men with Extraprostatic Extension Who Have Negative Surgical Margins. Eur Urol 2016;69:191-2. PMID- 27240941 TI - Reply to Vincenza Conteduca, Cristian Lolli, and Ugo De Giorgi's Letter to the Editor re: Pasquale Rescigno, David Lorente, Diletta Bianchini, et al. Prostate specific Antigen Decline After 4 Weeks of Treatment with Abiraterone Acetate and Overall Survival in Patients with Metastatic Castration-resistant Prostate Cancer. Eur Urol 2016;70:724-31. PMID- 27240942 TI - Can Adipose-derived Stem Cells Be Used in the Treatment of Urethral Stricture Disease? PMID- 27240943 TI - Application of rifampicin as a chiral selector for enantioresolution of basic drugs using capillary electrophoresis. AB - Rifampicin, a member of rifamycin sub-class of antibiotics which belongs to the naphthalenic ansamycin class of antibiotics, has a characteristic ansa structure, i.e., a ring structure or chromophore spanned by an aliphatic chain. The present work was designed to evaluate its potential as a chiral selector (CS) as its structure consisting of nine stereogenic centers, an aromatic moiety and several functional groups (i.e., one imine, one amide, one acetoxy residue, two aliphatic hydroxyl and three phenolic hydroxyl groups) was expected to instigate multiple enantioselective interactions, namely, hydrogen bonding and inclusion complexation with chiral analytes, and therefore resulting in efficient enantioseparations. Systematic experiments were performed to investigate the effects of concentration of CS, composition of background electrolyte (BGE) and applied voltage on chiral separation. Enantiomers of propranolol and metoprolol were baseline resolved using a BGE consisting of 20mM CS and 50/50 (v/v) iso propanol/phosphate buffer (100mM, pH 7.0) whereas for enantiomers of sertraline, a BGE consisting of 23mM CS and 40/60 (v/v) iso-propanol/phosphate buffer (100mM, pH 7.0) resulted in baseline resolutions. PMID- 27240944 TI - Extensive database of liquid phase diffusion coefficients of some frequently used test molecules in reversed-phase liquid chromatography and hydrophilic interaction liquid chromatography. AB - Diffusion plays an important role in all aspects of band broadening in chromatography. An accurate knowledge of molecular diffusion coefficients in different mobile phases is therefore crucial in fundamental column performance studies. Correlations available in literature, such as the Wilke-Chang equation, can provide good approximations of molecular diffusion under reversed-phase conditions. However, these correlations have been demonstrated to be less accurate for mobile phases containing a large percentage of acetonitrile, as is the case in hydrophilic interaction liquid chromatography. A database of experimentally measured molecular diffusion coefficients of some 45 polar and apolar compounds that are frequently used as test molecules under hydrophilic interaction liquid chromatography and reversed-phase conditions is therefore presented. Special attention is given to diffusion coefficients of polar compounds obtained in large percentages of acetonitrile (>90%). The effect of the buffer concentration (5-10mM ammonium acetate) on the obtained diffusion coefficients is investigated and is demonstrated to mainly influence the molecular diffusion of charged molecules. Diffusion coefficients are measured using the Taylor-Aris method and hence deduced from the peak broadening of a solute when flowing through a long open tube. The validity of the set-up employed for the measurement of the diffusion coefficients is demonstrated by ruling out the occurrence of longitudinal diffusion, secondary flow interactions and extra column effects, while it is also shown that radial equilibration in the 15m long capillary is effective. PMID- 27240945 TI - Nontargeted metabolomic analysis and "commercial-homophyletic" comparison-induced biomarkers verification for the systematic chemical differentiation of five different parts of Panax ginseng. AB - A key segment in authentication of herbal medicines is the establishment of robust biomarkers that embody the intrinsic metabolites difference independent of the growing environment or processing technics. We present a strategy by nontargeted metabolomics and "Commercial-homophyletic" comparison-induced biomarkers verification with new bioinformatic vehicles, to improve the efficiency and reliability in authentication of herbal medicines. The chemical differentiation of five different parts (root, leaf, flower bud, berry, and seed) of Panax ginseng was illustrated as a case study. First, an optimized ultra performance liquid chromatography/quadrupole time-of-flight-MS(E) (UPLC/QTOF MS(E)) approach was established for global metabolites profiling. Second, UNIFITM combined with search of an in-house library was employed to automatically characterize the metabolites. Third, pattern recognition multivariate statistical analysis of the MS(E) data of different parts of commercial and homophyletic samples were separately performed to explore potential biomarkers. Fourth, potential biomarkers deduced from commercial and homophyletic root and leaf samples were cross-compared to infer robust biomarkers. Fifth, discriminating models by artificial neutral network (ANN) were established to identify different parts of P. ginseng. Consequently, 164 compounds were characterized, and 11 robust biomarkers enabling the differentiation among root, leaf, flower bud, and berry, were discovered by removing those structurally unstable and possibly processing-related ones. The ANN models using the robust biomarkers managed to exactly discriminate four different parts and root adulterant with leaf as well. Conclusively, biomarkers verification using homophyletic samples conduces to the discovery of robust biomarkers. The integrated strategy facilitates authentication of herbal medicines in a more efficient and more intelligent manner. PMID- 27240947 TI - A rapid gas chromatographic injection-port derivatization method for the tandem mass spectrometric determination of patulin and 5-hydroxymethylfurfural in fruit juices. AB - A novel method consisting of injection-port derivatization coupled to gas chromatography-tandem mass spectrometry is described. The method allows the rapid assessment of 5-hydroxymethylfurfural (HMF) and patulin content in apple and pear derivatives. The chromatographic separation of the compounds was achieved in a short chromatographic run (12.2min) suitable for routine controls of these compounds in the fruit juice industry. The optimal conditions for the injection port derivatization were at 270 degrees C, 0.5min purge-off, and a 1:2 sample:derivatization reagent ratio (v/v). These conditions represent an important saving in terms of derivatization reagent consumption and sample preparation time. Quality parameters were assessed for the target compounds, giving LOD of 0.7 and 1.6MUg/kg and LOQ of 2 and 5MUg/kg for patulin and HMF, respectively. These values are below the maximum patulin concentration in food products intended for infants and young children. Repeatability (%RSD n=5) was below 12% for both compounds. In addition, the method linearity ranged between 25 and 1000MUg/kg and between 5 and 192MUg/kg for HMF and patulin, respectively. Finally, the method was applied to study HMF and patulin content in various fruit juice samples. PMID- 27240946 TI - Self-disproportionation of enantiomers via achiral gravity-driven column chromatography: A case study of N-acyl-alpha-phenylethylamines. AB - Herein we report a study of the self-disproportionation of enantiomers (SDE) via gravity-driven achiral column chromatography of a series of amides derived from 1 phenylethylamine. We demonstrated that structural and electronic factors of the substituents play an important role in the observed magnitude of the SDE. For the first time, the SDE phenomenon of amides with that of thioamides was compared. We demonstrate that, in sharp contrast to amides, the substitution of the sulphur atom for the oxygen in the acyl group, strongly reduced the observed magnitude of the SDE. These results clearly indicate the importance of the hydrogen bonding for the formation of homo/hetero-chiral association responsible for manifestation of the SDE phenomenon. PMID- 27240948 TI - Formal training in general movement assessment is required to effectively evaluate infants with perinatal asphyxia in outpatient settings. AB - AIM: General movement assessment (GMA) can help to identify children with a high risk of developing neurological dysfunction, such as cerebral palsy, and certified training is provided in this specialism. The aim of this study was to investigate the feasibility and reliability of using video recordings to assess GMA, in a busy Danish outpatient clinic. METHODS: The study comprised 30-term infants born with perinatal asphyxia, who were video recorded at three months. They were assessed by two certified GMA observers and re-assessed two weeks later. Interobserver and intra-observer agreements were analysed using proportional agreement, and nominal kappa statistics were used to calculate 95% confidence intervals (95% CI). RESULTS: We found substantial and almost perfect interobserver and intra-observer reliability. Intra-observer agreement was 0.85 (95% CI: 0.65-1.00; p < 0.0001) and 0.85 (95% CI: 0.62-1.00; p < 0.0001), and interobserver agreement was 0.71 (95% CI: 0.45-0.96; p < 0.0001) at time point one and 0.85 (95% CI: 0.63-1.00; p < 0.0001) two weeks later. All video recordings were completed within our multidisciplinary outpatient clinic without delay. CONCLUSION: This study demonstrated the reliability of the GMA method in a busy multidisciplinary Danish paediatric outpatient setting, when assessors had been formally trained in the method and used it regularly. PMID- 27240949 TI - [Glandular lesions of the uterine cervix: Case 6]. PMID- 27240950 TI - [Glandular lesions of the uterine cervix: Pre-test]. PMID- 27240951 TI - Structural disorder, anisotropic micro-strain and cation vacancies in thermo electric lead chalcogenides. AB - Thermoelectric materials can interconvert heat and electricity, and the extraordinary thermoelectric properties of lead chalcogenides (PbX, X = S, Se, Te) attract immense scientific interest. A key topic is the role of the cation in reaching a very low thermal conductivity necessary for efficient energy conversion. Here we present new structural insights about the deceptively simple rock-salt lead chalcogenides through a comparative multi-temperature synchrotron powder X-ray diffraction study. For the first time, the presence of anisotropic microstrain broadening as well as lead vacancies are quantified for all three compounds. The microstrain implies extended breakage of cubic symmetry as a sign of the incipient ferroelectric nature of PbX. The degree of microstrain is correlated to the transition pressure of a symmetry reducing phase transition, and this trend can be explained by anion mediated s-p hybridization on lead. The observed number of vacancies is greatest for PbS (4-8%), but two samples of PbS show different cation occupancy, and thus sample-dependent vacancies might be the property that unifies conflicting results reported for PbX. Gram-Charlier analysis identifies a local non-spherical distribution of Pb; however, model unbiased maximum entropy analysis indicates that any static displacement of Pb, if present, is less than 0.2 A at 100 K. PMID- 27240952 TI - The MPN domain of Caenorhabditis elegans UfSP modulates both substrate recognition and deufmylation activity. AB - Ubiquitin-fold modifier 1 (Ufm1) specific protease (UfSP) is a novel cysteine protease that activates Ufm1 from its precursor by processing the C-terminus to expose the conserved Gly necessary for substrate conjugation and de-conjugates Ufm1 from the substrate. There are two forms: UfSP1 and UfSP2, the later with an additional domain at the N-terminus. Ufm1 and both the conjugating and deconjugating enzymes are highly conserved. However, in Caenorhabditis elegans there is one UfSP which has extra 136 residues at the N terminus compared to UfSP2. The crystal structure of cUfSP reveals that these additional residues display a MPN fold while the rest of the structure mimics that of UfSP2. The MPN domain does not have the metalloprotease activity found in some MPN-domain containing protein, rather it is required for the recognition and deufmylation of the substrate of cUfSP, UfBP1. In addition, the MPN domain is also required for localization to the endoplasmic reticulum. PMID- 27240953 TI - Anti-arthritic actions of beta-cryptoxanthin against the degradation of articular cartilage in vivo and in vitro. AB - An inverse correlation between the morbidity of rheumatoid arthritis and daily intake of beta-cryptoxanthin has been epidemiologically shown. In this study, we investigated the effects of beta-cryptoxanthin on the metabolism of cartilage extracellular matrix in vivo and in vitro. Oral administration of beta cryptoxanthin (0.1-1 mg/kg) to antigen-induced arthritic rats suppressed the loss of glycosaminoglycans in articular cartilage, which is accompanied by the interference of aggrecanase-mediated degradation of aggrecan. Inhibition of the interleukin 1alpha (IL-1alpha)-induced aggrecan degradation by beta-cryptoxanthin was also observed with porcine articular cartilage explants in culture. beta Cryptoxanthin (1-10 MUM) dose-dependently down-regulated the IL-1alpha-induced gene expression of aggrecanase 1 (ADAMTS-4) and aggrecanase 2 (ADAMTS-5) in cultured human chondrocytes. Moreover, beta-cryptoxanthin was found to augment the gene expression of aggrecan core protein in chondrocytes. These results provide novel evidence that beta-cryptoxanthin exerts anti-arthritic actions and suggest that beta-cryptoxanthin may be useful in blocking the progression of rheumatoid arthritis and osteoarthritis. PMID- 27240954 TI - Inhibition of HCV replication by humanized-single domain transbodies to NS4B. AB - NS4B of hepatitis C virus (HCV) initiates membrane web formation, binds RNA and other HCV proteins for viral replication complex (RC) formation, hydrolyses NTP, and inhibits innate anti-viral immunity. Thus, NS4B is an attractive target of a novel anti-HCV agent. In this study, humanized-nanobodies (VHs/VHHs) that bound to recombinant NS4B were produced by means of phage display technology. The nanobodies were linked molecularly to a cell penetrating peptide, penetratin (PEN), for making them cell penetrable (become transbodies). Human hepatic (Huh7) cells transfected with HCV JFH1-RNA that were treated with transbodies from four Escherichia coli clones (PEN-VHH7, PEN-VHH9, PEN-VH33, and PEN-VH43) had significant reduction of HCV RNA amounts in their culture fluids and intracellularly when compared to the transfected cells treated with control transbody and medium alone. The results were supported by the HCV foci assay. The transbody treated-transfected cells also had upregulation of the studied innate cytokine genes, IRF3, IFNbeta and IL-28b. The transbodies have high potential for testing further as a novel anti-HCV agent, either alone, adjunct of existing anti HCV agents/remedies, or in combination with their cognates specific to other HCV enzymes/proteins. PMID- 27240955 TI - Clathrin-mediated endocytosis is responsible for the lysosomal degradation of dopamine D3 receptor. AB - GRK2-/beta-Arrestin- and PKA-/PKC-mediated desensitization, internalization, and degradation are three representative pathways for regulating G protein-coupled receptors (GPCRs). Compared with GRK2/beta-arrestin-mediated ones, functional relationship among the aforementioned three regulatory processes mediated by PKA/PKC is less clear. Dopamine D3 receptor (D3R), a major target of currently available antipsychotic drugs, is a typical GPCR that selectively undergoes PKC mediated regulation. In the present study, we examined PKC-mediated internalization of D3R in correlation with its roles in desensitization and degradation. Our results showed that the kinase activity of PKCbetaII and the 229th and 257th serine residues of D3R were required for PKC-mediated desensitization, internalization, and degradation of D3R. PMA treatment ubiquitinated D3R and induced its degradation through lysosomal pathway. Blockade of clathrin-mediated internalization inhibited PKC-mediated lysosomal degradation of D3R but did not affect its desensitization. These results suggested that PKC mediated phosphorylation of D3R involved clathrin-mediated internalization, which was important for the lysosomal degradation of D3R. PMID- 27240956 TI - Epigenetic dysregulation of interleukin 8 (CXCL8) hypersecretion in cystic fibrosis airway epithelial cells. AB - Airway epithelial cells in cystic fibrosis (CF) overexpress Interleukin 8 (CXCL8) through poorly defined mechanisms. CXCL8 transcription is dependent on coordinated binding of CCAAT/enhancer binding protein (C/EBP)beta, nuclear factor (NF)-kappaB, and activator protein (AP)-1 to the promoter. Here we show abnormal epigenetic regulation is responsible for CXCL8 overexpression in CF cells. Under basal conditions CF cells had increased bromodomain (Brd)3 and Brd4 recruitment and enhanced NF-kappaB and C/EBPbeta binding to the CXCL8 promoter compared to non-CF cells due to trimethylation of histone H3 at lysine 4 (H3K4me3) and DNA hypomethylation at CpG6. IL-1beta increased NF-kappaB, C/EBPbeta and Brd4 binding. Furthermore, inhibitors of bromodomain and extra-terminal domain family (BET) proteins reduced CXCL8 production in CF cells suggesting a therapeutic target for the BET pathway. PMID- 27240957 TI - A-Raf and C-Raf differentially regulate mechanobiological response of osteoblasts to guide mechanical stress-induced differentiation. AB - Regulation of osteoblast activity by mechanical stress is important for bone remodeling. However, the precise mechanotransduction mechanism that triggers the anabolic reaction of osteoblasts is largely unknown. In this study, we performed RNA interference (RNAi) screening to identify the signaling molecules upstream of ERK, which was responsible for osteogenesis. Of twenty-two mitogen-activated protein kinase (MAPK) kinase kinases (MAP3Ks), we identified A-Raf and C-Raf as upstream MAP3Ks of the mechanical stretch-activated ERK pathway. Subsequently we screened the mechanosensitive cation channel, and identified P2X7 as an upstream molecule of the ERK pathway. Intriguingly, P2X7 functioned as an upstream activator of A-Raf but not of C-Raf. Furthermore, A-Raf contributed to mechanical stretch-induced osteoblast differentiation. In contrast, C-Raf but not A-Raf protected osteoblasts from mechanical stretch-induced apoptosis. These results suggested that A-Raf and C-Raf were involved in mechanobiological osteogenesis in a distinct way: A-Raf was responsible for osteogenesis while C-Raf for anti apoptotic protection and promotion. PMID- 27240959 TI - Ultra-stiff large-area carpets of carbon nanotubes. AB - Herewith, we report the influence of post-synthesis heat treatment (<=2350 degrees C and plasma temperatures) on the crystal structure, defect density, purity, alignment and dispersibility of free-standing large-area (several cm(2)) carpets of ultra-long (several mm) vertically aligned multi-wall carbon nanotubes (VA-MWCNTs). VA-MWCNTs were produced in large quantities (20-30 g per batch) using a semi-scaled-up aerosol-assisted chemical vapour deposition (AACVD) setup. Electron and X-ray diffraction showed that the heat treatment at 2350 degrees C under inert atmosphere purifies, removes residual catalyst particles, and partially aligns adjacent single crystals (crystallites) in polycrystalline MWCNTs. The purification and improvement in the crystallites alignment within the MWCNTs resulted in reduced dispersibility of the VA-MWCNTs in liquid media. High resolution microscopy revealed that the crystallinity is improved in scales of few tens of nanometres while the point defects remain largely unaffected. The heat treatment also had a marked benefit on the mechanical properties of the carpets. For the first time, we report compression moduli as high as 120 MPa for VA-MWCNT carpets, i.e. an order of magnitude higher than previously reported figures. The application of higher temperatures (arc-discharge plasma, >=4000 degrees C) resulted in the formation of a novel graphite-matrix composite reinforced with CVD and arc-discharge-like carbon nanotubes. PMID- 27240958 TI - A rapid chemical odour profiling method for the identification of rhinoceros horns. AB - Illegal poaching causes great harm to species diversity and conservation. A vast amount of money is involved in the trade of illegal or forged animal parts worldwide. In many cases, the suspected animal part is unidentifiable and requires costly and invasive laboratory analysis such as isotopic fingerprinting or DNA testing. The lack of rapid and accurate methods to identify wildlife parts at the point of detection represents a major hindrance in the enforcement and prosecution of wildlife trafficking. The ability of wildlife detector dogs to alert to different wildlife species demonstrates that there is a detectable difference in scent profile of illegally traded animal parts. This difference was exploited to develop a rapid, non-invasive screening method for distinguishing rhinoceros horns of different species. The method involved the collection of volatile organic compounds (VOC) by headspace solid-phase microextraction (HS SPME) and analysis by comprehensive two-dimensional gas chromatography - time-of flight mass spectrometry (GC*GC-TOFMS). It was hypothesised that the use of the specific odour profile as a screening method could separate and differentiate geographic origin or exploit the difference in diets of different species within a family (such as white rhinoceros and black rhinoceros from the Rhinocerotidae family). Known black and white rhinoceros horn samples were analysed using HS SPME-GC*GC-TOFMS and multivariate statistics were applied to identify groupings in the data set. The black rhinoceros horn samples were distinctly different from the white rhinoceros horn samples. This demonstrated that seized rhinoceros horn samples can be identified based on their distinct odour profiles. The chemical odour profiling method has great potential as a rapid and non-invasive screening method in order to combat and track illegal trafficking of wildlife parts. PMID- 27240960 TI - Simplified Frailty Index as a Predictor of Adverse Outcomes in Total Hip and Knee Arthroplasty. AB - BACKGROUND: The modified frailty index (mFI) has been shown to predict adverse outcomes in multiple nonorthopedic surgical specialties. This study aimed to assess whether mFI is a predictor of adverse events in patients undergoing primary total hip arthroplasty (THA) and total knee arthroplasty (TKA). METHODS: Patients who underwent THA and TKA from 2005-2012 were identified in the National Surgical Quality Improvement Program database. mFI was calculated for each patient using 15 variables found in National Surgical Quality Improvement Program. Bivariate and multivariate analyses of postoperative adverse events, including Clavien-Dindo grade IV complications, were performed. RESULTS: A total of 14,583 THA and 25,223 TKA patients were included for analysis. The mean (standard deviation, range) mFIs were 0.083 (0.080, 0-0.55) for THA and 0.097 (0.080, 0-0.64) for TKA cohorts. On bivariate analyses, incidence of Clavien Dindo grade IV complications (cardiac arrest, myocardial infarction, septic shock, pulmonary embolism, postoperative dialysis, reintubation, and prolonged ventilator requirement), hospital-acquired conditions (surgical site infection, venous thromboembolism, and urinary tract infection), any complications, and mortality increased significantly with increase in mFI (P < .0001 for all). Adjusting for demographics, age >= 75, body mass index >=40, American Society of Anesthesiologists class >=4, and nonclean wound status, mFI >=0.45 was shown to be the strongest independent predictor of Clavien-Dindo grade IV complications for both THA and TKA cohorts with odds ratios of 5.140 and 4.183, respectively. CONCLUSION: mFI >=0.45 is an independent predictor of Clavien-Dindo grade IV complications in TKA/THA patients with greater odds ratios than age >75, body mass index >=40, American Society of Anesthesiologists class >=4. mFI should be considered for risk stratifying joint arthroplasty patients preoperatively and perhaps determining immediate postoperative destination. PMID- 27240961 TI - Does Marital Status Impact Outcomes After Total Knee Arthroplasty? AB - BACKGROUND: There is a paucity of research on the relationship between marital status and patient outcomes following total knee arthroplasty (TKA). METHODS: This was a retrospective chart review of patients who underwent TKA by a single surgeon at a university-based orthopedic practice. Data abstracted included age, gender, marital status, body mass index, length of hospital stay, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Oxford Knee Score (OKS). The WOMAC and OKS were administered at the preoperative visit and at approximately 10, 30, 90, and 180 days after TKA. Multivariate analyses with patient-reported outcomes as repeated measures, marital status, day of assessment; and the interaction of marital status and day of assessment as fixed effects; and age, gender, body mass index, and length of hospital stay as covariates were conducted as well as analyses in which preoperative patient reported outcomes were treated as fixed effects. RESULTS: Of 422 patients who underwent TKA during the study period, complete data were available for 249, of whom 124 were married and 125 unmarried. Married patients had significantly higher WOMAC scores than unmarried patients at all postoperative assessments, even after controlling for preoperative scores. Although married patients also had significantly higher postoperative OKS scores than their unmarried peers, differences between groups were attenuated after adjusting for preoperative OKS scores. CONCLUSION: This study found that married patients have better overall outcomes after TKA but yielded conflicting results as to whether the positive effects of marriage are specific to the postoperative period. PMID- 27240962 TI - Quality of Life in Sickle Cell Patients After Cementless Total Hip Arthroplasty. AB - BACKGROUND: Osteonecrosis of femoral head is a serious relentlessly progressive and disabling complication in 20%-50% of sickle cell patients, majority of whom are in their second to third decades. High perioperative medical complications and short survivorship have historically discouraged arthroplasty surgeons in offering total hip arthroplasty to sickle cell patients in their 30s for the fear of inevitable technically demanding revision. In this retrospective study, the primary objective was to assess the impact of early intervention on quality of life (QOL) at midterm follow-up of mean 7.5 years using uncemented porous-coated total hip arthroplasty. The secondary objective of this study was the survival of the prostheses within the same follow-up period and discussion of surgical challenges faced in this cohort of patients. METHODS: A total of 67 (84 hip arthroplasties) sickle cell patients with advance osteonecrosis of femoral head who underwent cementless porous-coated proximal fixation are included in this study. Modified Harris Hip Score, visual analog scale, and QOL assessment criteria are used to assess the outcome. RESULT: Revision surgery was required in 7 patients for aseptic loosening and in 1 patient due to late infection. Visual analog scale improved from average 7 (6-9) to 3 (2-5). Mean Harris Hip Score improved from 46 (32-58) to 81 (74-86). QOL score rose from a mean of 3 (range 1 4) to 7 (range 6-9). In terms of gender, survival in males was 94.30%, whereas in females, it was 88.767%. Revision surgery was required in 7 patients due to aseptic loosening and in 1 patient due to late infection at 7 years. CONCLUSION: We recommend early hip arthroplasty in sickle cell patients, if the hip has reached a stage of irreversible damage and patient's lifestyle is severely compromised to minimize chronic suffering and disability. PMID- 27240963 TI - Madeira-a tourist destination for asthma sufferers. AB - Madeira Island is a famous tourist destination due to its natural and climatic values. Taking into account optimal weather conditions, flora richness and access to various substrates facilitating fungal growth, we hypothesised a very high risk of elevated fungal spore and pollen grain concentrations in the air of Funchal, the capital of Madeira. Concentration levels of the most allergenic taxa were measured from 2003 to 2009, using a 7-day volumetric air sampler, followed by microscopy analysis. Dependence of bioaerosols on the weather conditions and land use were assessed using spatial and statistical tools. Obtained results were re-visited by a comparison with hospital admission data recorded at the Dr. Nelio Mendonca Hospital in Funchal. Our results showed that despite propitious climatic conditions, overall pollen grain and fungal spore concentrations in the air were very low and did not exceed any clinically established threshold values. Pollen and spore peak concentrations also did not match with asthma outbreaks in the winter. Identification of places that are "free" from biological air pollution over the summer, such as Madeira Island, is very important from the allergic point of view. PMID- 27240967 TI - Too little is understood about head and neck cancer by those who make decisions about it. PMID- 27240964 TI - Analysis of measles-related hospitalizations in Tuscany from 2000 to 2014. AB - To evaluate measles incidence and its relevant changes over a 14-year period (2000-2014), we analysed data from the regional hospital discharge database on children and adults hospitalized in Tuscany, Italy. A total of 181 paediatric and 413 adult cases were identified. Despite all the efforts towards regional measles elimination, we observed that the overall measles hospitalization rates for children and adults living in Tuscany globally increased from 0.45 to 0.85/100 000 during the study period (P = 0.001) showing fluctuations due to periodic measles outbreaks. Data stratified by age group showed that the hospitalization rate significantly increased in young adults over the study period, confirming an increase in susceptibility to measles in this subpopulation. Conversely, no statistically significant difference was observed in the hospitalization rate in the other age groups. However, children aged <1 year still exhibit the highest hospitalization rate. Pneumonia represented the most common complication in both the adult and children subsets. No death was reported. Measles still represents a public health problem, and national strategies should be implemented, focusing on emergent susceptible subsets, such as infants and young adults. PMID- 27240968 TI - Analytical and semipreparative chiral separation of cis-itraconazole on cellulose stationary phases by high-performance liquid chromatography. AB - cis-Itraconazole is a chiral antifungal drug administered as a racemate. The knowledge of properties of individual cis-itraconazole stereoisomers is vital information for medicine and biosciences as different stereoisomers of cis itraconazole may possess different affinity to certain biological pathways in the human body. For this purpose, either chiral synthesis of enantiomers or chiral separation of racemate can be used. This paper presents a two-step high performance liquid chromatography approach for the semipreparative isolation of four stereoisomers (two enantiomeric pairs) of itraconazole using polysaccharide stationary phases and volatile organic mobile phases without additives in isocratic mode. The approach used involves the separation of the racemate into three fractions (i.e. two pure stereoisomers and one mixed fraction containing the remaining two stereoisomers) in the first run and consequent separation of the collected mixed fraction in the second one. For this purpose, combination of cellulose tris-(4-methylbenzoate) and cellulose tris-(3,5-dimehylphenylcarbamate) columns with complementary selectivity for cis-itraconazole provided full separation of all four stereoisomers (with purity of each isomer > 97%). The stereoisomers were collected, their optical rotation determined and their identity confirmed based on the results of a previously published study. Pure separated stereoisomers are subjected to further biological studies. PMID- 27240969 TI - Validity of low-efficacy continuous renal replacement therapy in critically ill patients. AB - The 1980s saw the use of continuous arteriovenous hemofiltration whose intensity hemofiltration rate was only 3 or 4 mL kg-1 h-1. With the installation of a blood pump, this dose went up to 8 or 10 mL kg-1 h-1, and continued to increase, reaching about 20 mL kg-1 h-1 by the year 2000. Some studies found that a higher dose could be beneficial, and the world rapidly followed the trend, increasing the dose up to 35 mL kg-1 h-1. Then, two randomized control trials, namely the VA/NIH Acute Renal Failure Trial Network study and the RENAL study, came along in succession which changed the Kidney Disease: Improving Global Outcomes (KDIGO) recommendation to 20 to 25 mL kg-1 h-1. However, no good evidence exists to support this. Our recent multicenter retrospective studies from the JSEPTIC CRRT database show that the Japanese continuous renal replacement therapy dose of (14.3 mL kg-1 h-1) does not seem to have worse outcomes when compared with a higher dose. PMID- 27240970 TI - Is cost a structural barrier preventing men who have sex with men accessing condoms? A systematic review. AB - A systematic review was undertaken to determine whether cost is a structural barrier preventing men who have sex with men (MSM) accessing condoms. Studies were examined from a range of countries where condoms have been distributed free to particular populations and also those where condoms were available at a cost to the individual. The study inclusion criteria were: published between January 1990 and September 2014 inclusive; published in any language, discussed cost as a barrier to condom use, discussed cost barriers to MSM accessing condoms and included a measure of outcome. Articles were systematically extracted from MEDLINE, Embase, PyschINFO and Informat using the five search terms; Male Homosexuality, Access, Cost, Cost and Cost analysis, Condoms. Sixty-four articles were initially identified and 11 included in the final review. The included studies used cost-utility analysis, qualitative, cross-sectional, cohort or randomised control trial design. Large-scale free distribution programmes and smaller targeted programmes showed positive correlations in reducing the burden of disease from HIV and other sexually transmitted infections through eliminating the issue of cost. Decreasing the cost of condoms, and providing them for no cost, appears to increase their utilisation amongst MSM and possibly reduce the burden from HIV and other sexually transmitted infections. Inequality and stigma remain important barriers to MSM accessing and using condoms particularly in the developing world. PMID- 27240971 TI - Discriminating Lipid- from Protein-Calcium Binding To Understand the Interaction between Recoverin and Phosphatidylglycerol Model Membranes. AB - Recoverin is a protein involved in the phototransduction cascade by regulating the activity of rhodopsin kinase through a calcium-dependent binding process at the surface of rod outer segment disk membranes. Understanding how calcium modulates these interactions and how it interacts with anionic lipid membranes is necessary to gain insights into the function of recoverin. In this work, infrared spectroscopy allowed us to show that the availability of calcium to recoverin is modulated by the presence of complexes involving phosphatidylglycerol (PG), which in turn regulates its interactions with this negatively charged lipid. Calcium can indeed be sequestered into strongly bound complexes with PG and is thus sparingly available to recoverin. The thermal stability of recoverin then decreases, which results in weakened interactions with PG. By contrast, when calcium is fully available to recoverin, the protein is thermally stable, indicating that it binds two calcium ions, which results in favorable interactions with negatively charged lipids. Consequently, the protein induces an increase in the chain-melting phase transition temperature of PG, which is indicative of an enhanced lipid chain packing resulting from the peripheral location of the protein. The secondary structure of recoverin is not affected by its interactions with anionic membrane lipids. Similar results have been obtained with saturated and unsaturated anionic lipids. This work shows that the recruitment of recoverin at the surface of anionic lipid membranes is dependent on the availability of calcium. PMID- 27240973 TI - What is the biological reality of gene-environment interaction estimates? An assessment of bias in developmental models. AB - BACKGROUND: Standard models used to test gene-environment interaction (G * E) hypotheses make the causal assumption that there are no unobserved variables that could be biasing the interaction estimate. Whether this assumption can be met in nonexperimental studies is unclear because the interactive biological pathways from genetic polymorphisms and environments to behavior, and the confounders that can be introduced along these pathways, are often not delineated. This is problematic in the context of studies focused on caregiver-child dyads, in which common genes and environments induce gene-environment correlation. To address the impact of sources of bias in G * E models specifically assessing the interaction between child genotype and caregiver behavior, we provide a causal framework that integrates biological and statistical concepts of G * E, and assess the magnitude of bias introduced by various confounding pathways in different causal circumstances. METHODS: A simulation assessed the magnitude of bias introduced by four types of confounding pathways in different causal models. Unadjusted and adjusted statistical models were then applied to the simulated data to assess the efficacy of these procedures to capture unbiased G * E estimates. Finally, the simulation was run under null effects of the genotype to assess the impact of biasing sources on the false-positive rate. RESULTS: Common environmental pathways between caregiver and child inflated G * E estimates and raised the false-positive rate. Evocative effects of the child also inflated G * E estimates. CONCLUSIONS: Gene-environment interaction studies should be approached with consideration to the causal pathways at play and the confounding opportunities along these pathways to facilitate the inclusion of adequate statistical controls and correct inferences from study findings. Bridging biological and statistical concepts of G * E can significantly improve research design and the communication of how a G * E process fits into a broader developmental framework. PMID- 27240972 TI - Organ specificity in the plant circadian system is explained by different light inputs to the shoot and root clocks. AB - Circadian clocks allow the temporal compartmentalization of biological processes. In Arabidopsis, circadian rhythms display organ specificity but the underlying molecular causes have not been identified. We investigated the mechanisms responsible for the similarities and differences between the clocks of mature shoots and roots in constant conditions and in light : dark cycles. We developed an imaging system to monitor clock gene expression in shoots and light- or dark grown roots, modified a recent mathematical model of the Arabidopsis clock and used this to simulate our new data. We showed that the shoot and root circadian clocks have different rhythmic properties (period and amplitude) and respond differently to light quality. The root clock was entrained by direct exposure to low-intensity light, even in antiphase to the illumination of shoots. Differences between the clocks were more pronounced in conditions where light was present than in constant darkness, and persisted in the presence of sucrose. We simulated the data successfully by modifying those parameters of a clock model that are related to light inputs. We conclude that differences and similarities between the shoot and root clocks can largely be explained by organ-specific light inputs. This provides mechanistic insight into the developing field of organ specific clocks. PMID- 27240976 TI - Toward the 'new century' of handedness in biology: In commemoration of the 100th anniversary of the birth of Francis Crick. PMID- 27240974 TI - Dickkopf-1-promoted vasculogenic mimicry in non-small cell lung cancer is associated with EMT and development of a cancer stem-like cell phenotype. AB - To characterize the contributions of Dickkopf-1 (DKK1) towards the induction of vasculogenic mimicry (VM) in non-small cell lung cancer (NSCLC), we evaluated cohorts of primary tumours, performed in vitro functional studies and generated xenograft mouse models. Vasculogenic mimicry was observed in 28 of 205 NSCLC tumours, while DKK1 was detected in 133 cases. Notably, DKK1 was positively associated with VM. Statistical analysis showed that VM and DKK1 were both related to aggressive clinical course and thus were indicators of a poor prognosis. Moreover, expression of epithelial-mesenchymal transition (EMT) related proteins (vimentin, Slug, and Twist), cancer stem-like cell (CSC)-related proteins (nestin and CD44), VM-related proteins (MMP2, MMP9, and vascular endothelial-cadherin), and beta-catenin-nu were all elevated in VM-positive and DKK1-positive tumours, whereas the epithelial marker (E-cadherin) was reduced in the VM-positive and DKK1-positive groups. Non-small cell lung cancer cell lines with overexpressed or silenced DKK1 highlighted its role in the restoration of mesenchymal phenotypes and development of CSC characteristics. Moreover, DKK1 significantly promotes NSCLC tumour cells to migrate, invade and proliferate. In vivo animal studies demonstrated that DKK1 enhances the growth of transplanted human tumours cells, as well as increased VM formation, mesenthymal phenotypes and CSC properties. Our results suggest that DKK1 can promote VM formation via induction of the expression of EMT and CSC-related proteins. As such, we feel that DKK1 may represent a novel target of NSCLC therapy. PMID- 27240975 TI - Proteomic comparisons of venoms of long-term captive and recently wild-caught Eastern brown snakes (Pseudonaja textilis) indicate venom does not change due to captivity. AB - Snake venom is a highly variable phenotypic character, and its variation and rapid evolution are important because of human health implications. Because much snake antivenom is produced from captive animals, understanding the effects of captivity on venom composition is important. Here, we have evaluated toxin profiles from six long-term (LT) captive and six recently wild-caught (RC) eastern brown snakes, Pseudonaja textilis, utilizing gel electrophoresis, HPLC MS, and shotgun proteomics. We identified proteins belonging to the three-finger toxins, group C prothrombin activators, Kunitz-type serine protease inhibitors, and phospholipases A2, among others. Although crude venom HPLC analysis showed LT snakes to be higher in some small molecular weight toxins, presence/absence patterns showed no correlation with time in captivity. Shotgun proteomics indicated the presence of similar toxin families among individuals but with variation in protein species. Although no venom sample contained all the phospholipase A2 subunits that form the textilotoxin, all did contain both prothrombin activator subunits. This study indicates that captivity has limited effects on venom composition, that venom variation is high, and that venom composition may be correlated to geographic distribution. BIOLOGICAL SIGNIFICANCE: Through proteomic comparisons, we show that protein variation within LT and RC groups of snakes (Pseudonaja textilis) is high, thereby resulting in no discernible differences in venom composition between groups. We utilize complementary techniques to characterize the venom proteomes of 12 individual snakes from our study area, and indicate that individuals captured close to one another have more similar venom gel electrophoresis patterns than those captured at more distant locations. These data are important for understanding natural variation in and potential effects of captivity on venom composition. PMID- 27240977 TI - RNA-Seq, and ye shall find: Sexual-stage-specific A-to-I RNA editing in fungi. PMID- 27240979 TI - Human cytomegalovirus-encoded miR-US4-1 promotes cell apoptosis and benefits discharge of infectious virus particles by targeting QARS. AB - Human cytomegalovirus (HCMV) can cause congenital diseases and opportunistic infections in immunocompromised individuals. Its functional proteins and microRNAs (miRNAs) facilitate efficient viral propagation by altering host cell behaviour. Identification of functional target genes of miRNAs is an important step in studies on HCMV pathogenesis. In this study, Glutaminyl-tRNA Synthetase (QARS), which could regulate signal transduction pathways for cellular apoptosis, was identified as a direct target of hcmv-miR-US4-1. Apoptosis assay revealed that as silence of QARS by ectopic expression of hcmv-miR-US4-1 and specific small interference RNA of QARS can promote cell apoptosis in HCMV-infected HELF cells. Moreover, viral growth curve assays showed that hcmv-miR-US4-1 benefits the discharge of infectious virus particles. However, silence of hcmv-miR-US4-1 by its specific inhibitor overturned these effects. These results imply that hcmv miR-US4-1 might have the same effects during HCMV nature infection. In general, hcmv-miR-US4-1 may involve in promoting cell apoptosis and benefiting discharge of infectious virus particles via down-regulation of QARS in HCMV-infected HELF cells. PMID- 27240980 TI - In situ real-time evaluation of radiation-responsive promoters in the extremely radioresistant microbe Deinococcus radiodurans. AB - A third generation promoter probe shuttle vector pKG was constructed, using the green fluorescent protein as a reporter, for in situ evaluation of Deinococcal promoter activity in Escherichia coli or Deinococcus radiodurans. The construct yielded zero background fluorescence in both the organisms, in the absence of promoter sequences. Fifteen Deinococcal promoters, either harbouring Radiation and Desiccation Response Motif (RDRM) or not, were cloned in vector pKG. Only the RDRM-promoter constructs displayed (i) gamma radiation inducible GFP expression in D. radiodurans, following gamma irradiation, (ii) DdrO-mediated repression of GFP expression in heterologous E. coli, or (iii) abolition in GFP induction following gamma irradiation, in pprI mutant of D. radiodurans. Utility of pKG vector for real-time in situ assessment of Deinococcal promoter function was, thus, successfully demonstrated. PMID- 27240978 TI - Host protein Snapin interacts with human cytomegalovirus pUL130 and affects viral DNA replication. AB - The interplay between the host and Human cytomegalovirus (HCMV) plays a pivotal role in the outcome of an infection. HCMV growth in endothelial and epithelial cells requires expression of viral proteins UL128, UL130, and UL131 proteins (UL128-131), of which UL130 is the largest gene and the only one that is not interrupted by introns.Mutation of the C terminus of the UL130 protein causes reduced tropism of endothelial cells (EC). However, very few host factors have been identified that interact with the UL130 protein. In this study, HCMV UL130 protein was shown to directly interact with the human protein Snapin in human embryonic kidney HEK293 cells by Yeast two-hybrid screening, in vitro glutathione S-transferase (GST) pull-down, and co-immunoprecipitation. Additionally, heterologous expression of protein UL130 revealed co-localization with Snapin in the cell membrane and cytoplasm of HEK293 cells using fluorescence confocal microscopy. Furthermore, decreasing the level of Snapin via specific small interfering RNAs decreased the number of viral DNA copies and titer inHCMV infected U373-S cells. Taken together, these results suggest that Snapin, the pUL130 interacting protein, has a role in modulating HCMV DNA synthesis. PMID- 27240982 TI - A conditional Orco requirement in the somatic cyst cells for maintaining spermatids in a tight bundle in Drosophila testis. AB - Odorant receptors (OR) heterodimerizes with the OR co-receptor (Orco), forming specific odorant-gated cation channels, which are key to odor reception at the olfactory sensory neurons (OSN). Mammalian ORs are expressed in many other tissues, including testis. However, their biological implications are yet to be fully ascertained. In the mosquito, Orco is localized along the sperm tail and is indicated to maintain fidelity. Here, we show that orco expresses in Drosophila testis. The levels are higher in the somatic cyst cells. The orco-null mutants are perfectly fertile at 25 degree C. At 28 degree C, the coiled spermatid bundles are severely disrupted. The loss of Orco also disrupts the actin cap, which forms inside the head cyst cell at the rostral ends of the spermatid nuclei after coiling, and plays a key role in preventing the abnormal release of spermatids from the cyst enclosure. Both the defects are rescued by the somatic cyst cell-specific expression of the UAS-orco transgene. These results highlight a novel role of Orco in the somatic tissue during sperm release. PMID- 27240981 TI - Dictyostelium discoideum RabS and Rab2 colocalize with the Golgi and contractile vacuole system and regulate osmoregulation. AB - Small-molecular-weight GTPase Rab2 has been shown to be a resident of pre-Golgi intermediates and is required for protein transport from the ER to the Golgi complex; however, Rab2 has yet to be characterized in Dictyostelium discoideum. DdRabS is a Dictyostelium Rab that is 80 percent homologous to DdRab1 which is required for protein transport between the ER and Golgi. Expression of GFP-tagged DdRab2 and DdRabS proteins showed localization to Golgi membranes and to the contractile vacuole system (CV) in Dictyostelium. Microscopic imaging indicates that the DdRab2 and DdRabS proteins localize at, and are essential for, the proper structure of Golgi membranes and the CV system. Dominant negative (DN) forms show fractionation of Golgi membranes, supporting their role in the structure and function of it. DdRab2 and DdRabS proteins, and their dominant negative and constitutively active (CA) forms, affect osmoregulation of the cells, possibly by the influx and discharge of fluids, which suggests a role in the function of the CV system. This is the first evidence of GTPases being localized to both Golgi membranes and the CV system in Dictyostelium. PMID- 27240983 TI - Silencing of HMGA2 promotes apoptosis and inhibits migration and invasion of prostate cancer cells. AB - The high mobility group protein A2 (HMGA2) has been demonstrated as an architectural transcription factor that is associated with pathogenesis of many malignant cancers; however, its role in prostate cancer cells remains largely unknown. To explore whether HMGA2 participates in the development and progression of prostate cancer, small interfering RNA (siRNA) targeted on human HMGA2 was transfected to suppress the HMGA2 expression in prostate cancer PC3 and DU145 cells, and then the cellular biology changes after decreased the expression of HMGA2 was examined. Our results showed that knockdown of HMGA2 markedly inhibited cell proliferation; this reduced cell proliferation was due to the promotion of cell apoptosis as the Bcl-xl was decreased, whereas Bax was up-regulated. In addition, we found that HMGA2 knockdown resulted in reduction of cell migration and invasion, as well as repressed the expression of matrix metalloproteinases (MMPs) and affected the occurrence of epithelial-mesenchymal transition (EMT) in both cell types. We further found that decreased HMGA2 expression inhibited the transforming growth factor-beta (TGF-beta)/Smad signalling pathway in cancer cells. In conclusion, our data indicated that HMGA2 was associated with apoptosis, migration and invasion of prostate cancer, which might be a promising therapeutic target for prostate cancer. PMID- 27240985 TI - Leptin promoter variant G2548A is associated with serum leptin and HDL-C levels in a case control observational study in association with obesity in a Pakistani cohort. AB - Leptin is a protein hormone synthesized by adipocytes and is involved in the regulation of food intake and energy expenditure. We hypothesized that any change in the promoter sequence can affect the expression of the gene and hence leptin protein levels in the serum. The aim of the current study was to investigate the relationship of such a promoter variant of the leptin gene, G-2548A polymorphism, with obesity and its effect on various anthropometric and metabolic parameters in a Pakistani cohort consisting of 250 obese and 225 non-obese control subjects. Body weight, height, waist circumference (WC), hip circumference (HC) and blood pressure (BP) were measured by standard methods and levels of fasting blood glucose (FBG), total cholesterol, triglycerides, HDLC, LDLC, and leptin were determined. Genotyping was done by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The results showed that the LEP G-2548A polymorphism showed significant association with obesity in Pakistan. In addition, the polymorphism showed association with weight, height, BMI, WC, HDLC and serum leptin levels. The findings suggest that the leptin promoter G-2548A variant may play its part in the progression to obesity by not only affecting the body's fat distribution but also by changing the serum leptin and HDLC levels. PMID- 27240984 TI - Effects of quercetin on predator stress-related hematological and behavioral alterations in pregnant rats and their offspring. AB - This study aims at investigating the effect of a psychogenic stress during gestation on the behaviour and haematological indices in dams as well as on the neonatal haematological status and periadolescent behaviour in their offspring. Moreover, the ability of quercetin, a natural flavonoid, to prevent the stress induced changes was estimated. Pregnant Wistar rats were pretreated with quercetin before the exposure to a predator stress on gestational day 19. Post stress maternal anxiety-like behaviour was assessed with a concomitant haematological analysis. In the offspring, haematological analysis and behavioural testing were performed during the postnatal stage. Our results revealed that predator stress causes an anxiety-like behaviour in dams along with a decrease in erythrocytes, a microcytosis, and a thrombocytosis. Prenatally stressed neonates manifested microcytosis and thrombocytosis with a significant polycythemia. Signs of motor hyperactivity, anxiety-like behaviour, and memory dysfunction were detected at periadolescence. Quercetin pretreatment alleviated the stress-induced behavioural and haematological impairments in dams but failed to attenuate the haematological changes in neonates. A sex-dependent effect of quercetin on behaviour was found at periadolescence. Our findings suggest that, besides a beneficial effect on haematological and behavioural anomalies in traumatized dams, quercetin may lastingly modulate the behaviour of their progeny. PMID- 27240986 TI - Differential expression of carotenoid biosynthetic pathway genes in two contrasting tomato genotypes for lycopene content. AB - Tomato (Solanum lycopersicum L.) is one of the model plant to study carotenoid biosynthesis. In the present study, the fruit carotenoid content were quantified at different developmental stages for two contrasting genotypes, viz. IIHR-249-1 and IIHR-2866 by UPLC. Lycopene content was high in IIHR-249-1 (19.45 mg/100 g fresh weight) compared to IIHR-2866 (1.88 mg/100 g fresh weight) at the ripe stage. qPCR was performed for genes that are involved in the carotenoid biosynthetic pathway to study the difference in lycopene content in fruits of both the genotypes. The expression of Phytoene synthase (PSY) increased by 36 fold and Phytoene desaturase (PDS) increased by 14-fold from immature green stage to ripe stage in IIHR-249-1. The expression of Chloroplast lycopene beta-cyclase (LCY-B) and Chromoplast lycopene beta cyclase (CYC-B) decreased gradually from the initial stage to the ripe stage in IIHR-249-1. IIHR 249-1 showed 3- and 1.8 fold decrease in gene expression for Chloroplast lycopene beta-cyclase (LCY-B) and Chromoplast lycopene beta-cyclase (CYC-B) .The F2 hybrids derived from IIHR 249-1 and IIHR-2866 were analysed at the ripe stage for lycopene content. The gene expression of Chloroplast lycopene beta-cyclase (LCY-B) and Chromoplast lycopene beta-cyclase (CYC-B) in high and low lycopene lines from F2 progenies also showed the decrease in transcript levels of both the genes in high lycopene F2 lines. We wish to suggest that the differential expression of lycopene beta cyclases can be used in marker-assisted breeding. PMID- 27240987 TI - Accelerated processing of solitary and clustered abasic site DNA damage lesions by APE1 in the presence of aqueous extract of Ganoderma lucidum. AB - The stimulatory effect of the aqueous extract of G. lucidum, a basidiomycetes class fungus in the APE1-enzyme-mediated processing of solitary and bistranded clustered abasic sites DNA damages is presented. Abasic sites are considered the most common type of DNA damage lesions. Our study shows enhanced activity of APE1 in the processing of abasic sites in the presence of the polysaccharides fraction of G. lucidum. Remarkable increase in the amount of single-strand breaks (SSBs) and double-strand breaks (DSBs) from solitary and bistranded clustered abasic sites respectively with APE1 in the presence of the extract was found. This trend is maintained when abasic sites in DNA oligomers are exposed to fibroblast cell extracts in the presence of the extract. While DNA conformational alteration is negligible, APE1 enzyme shows characteristic changes in the alpha helix and beta strand ratio after incubation with G. lucidum extract. The enhanced reactivity of APE1 at the molecular level in the presence of G. lucidium is attributed to this effect. This study potentially amplifies the scope of the use of G. lucidum, which was earlier shown to have only reactive oxygen species (ROS) scavenging properties with regards to DNA damage inhibition. PMID- 27240988 TI - (p)ppGpp and the bacterial cell cycle. AB - Genes of the Rel/Spo homolog (RSH) superfamily synthesize and/or hydrolyse the modified nucleotides pppGpp/ ppGpp (collectively referred to as (p)ppGpp) and are prevalent across diverse bacteria and in plant chloroplasts. Bacteria accumulate (p)ppGpp in response to nutrient deprivation (generically called the stringent response) and elicit appropriate adaptive responses mainly through the regulation of transcription. Although at different concentrations (p)ppGpp affect the expression of distinct set of genes, the two well-characterized responses are reduction in expression of the protein synthesis machinery and increase in the expression of genes coding for amino acid biosynthesis. In Escherichia coli, the cellular (p)ppGpp level inversely correlates with the growth rate and increasing its concentration decreases the steady state growth rate in a defined growth medium. Since change in growth rate must be accompanied by changes in cell cycle parameters set through the activities of the DNA replication and cell division apparatus, (p)ppGpp could coordinate protein synthesis (cell mass increase) with these processes. Here we review the role of (p)ppGpp in bacterial cell cycle regulation. PMID- 27240989 TI - The autoregulatory loop: A common mechanism of regulation of key sex determining genes in insects. AB - Sex determination in most insects is structured as a gene cascade, wherein a primary signal is passed through a series of sex-determining genes, culminating in a downstream double-switch known as doublesex that decides the sexual fate of the embryo. From the literature available on sex determination cascades, it becomes apparent that sex determination mechanisms have evolved rapidly. The primary signal that provides the cue to determine the sex of the embryo varies remarkably, not only among taxa, but also within taxa. Furthermore, the upstream key gene in the cascade also varies between species and even among closely related species. The order Insecta alone provides examples of astoundingly complex diversity of upstream key genes in sex determination mechanisms. Besides, unlike key upstream genes, the downstream double-switch gene is alternatively spliced to form functional sex-specific isoforms. This sex-specific splicing is conserved across insect taxa. The genes involved in the sex determination cascade such as Sex-lethal (Sxl) in Drosophila melanogaster, transformer (tra) in many other dipterans, coleopterans and hymenopterans, Feminizer (fem) in Apis mellifera, and IGF-II mRNA-binding protein (Bmimp) in Bombyx mori are reported to be regulated by an autoregulatory positive feedback loop. In this review, by taking examples from various insects, we propose the hypothesis that autoregulatory loop mechanisms of sex determination might be a general strategy. We also discuss the possible reasons for the evolution of autoregulatory loops in sex determination cascades and their impact on binary developmental choices. PMID- 27240990 TI - Bromodomain and extra-terminal (BET) family proteins: New therapeutic targets in major diseases. AB - The bromodomains and extra-terminal domain (BET) family proteins recognize acetylated chromatin through their bromodomains (BDs) and help in regulating gene expression. BDs are chromatin 'readers': by interacting with acetylated lysines on the histone tails, they recruit chromatin-regulating proteins on the promoter region to regulate gene expression and repression. Extensive efforts have been employed by scientific communities worldwide to identify and develop potential inhibitors of BET family BDs to regulate protein expression by inhibiting acetylated histone (H3/H4) interactions. Several small molecule inhibitors have been reported, which not only have high affinity but also have high specificity to BET BDs. These developments make BET family proteins an important therapeutic targets for major diseases such as cancer, neurological disorders, obesity and inflammation. Here, we review and discuss the structural biology of BET family BDs and their applications in major diseases. PMID- 27240992 TI - Suppression of IL-12p40-related regulatory cytokines by suberoylanilide hydroxamic acid an inhibitor of histone deacetylases. AB - Small molecule inhibitors of histone deacetylases (HDACs) are a new class drugs used in clinical trials for the treatment of various malignancies. Emerging evidence suggest that HDAC inhibitors may also have anti-inflammatory properties, although the molecular mechanisms remain poorly defined. Our study investigates the effect of the HDACs inhibitor suberoylanilide hydroxamic acid (SAHA) on the expression of IL-12p40-related cytokines. For this purpose, human peripheral blood mononuclear cells (PBMC) were stimulated with LPS and C3bgp with or without SAHA. IL-12p40, IL-12p35 and IL-23p19 mRNA was determined at 6 h by qRT-PCR. Cytokine levels were determined in culture supernatants at 6 and 24 h, by ELISA. SAHA significantly inhibited IL-12p40 and IL-23p19 mRNA synthesis and did not change IL-12p35 mRNA transcription. Early at 6 h, we detected significantly decreased IL-12p40 and IL-23, but not IL-12p70 protein production in cultures treated with SAHA. Results also showed that the suppression of IL-12p40-related cytokines was clearly defined at 24 h. However, this suppression was less pronounced regarding IL-12p70. The present study showed that SAHA suppressed the gene expression of IL-23p19 stronger than the expression of IL-12p35, as well as the synthesis of IL-23 compared to that of IL-12p70. We suggest that this inhibitory effect of SAHA may be beneficial during treatment of inflammatory and autoimmune diseases mediated by Th17 immune response. PMID- 27240991 TI - ABCG2 inhibition as a therapeutic approach for overcoming multidrug resistance in cancer. AB - Breast cancer resistance protein (BCRP, ABCP or MXR)/ATP-binding cassette subfamily G member 2 (ABCG2) was characterized as a multidrug resistance efflux transporter in 1998. ABCG2 physiologically acts as a part of a selfdefence mechanism for the organism; it enhances eliminating of toxic xenobiotic substances and harmful agents in the intestine, as well as through the blood brain barrier and placenta. ABCG2 recognizes and transports numerous anticancer drugs including conventional chemotherapeutic and new targeted small therapeutic molecules in clinical usage. Development of ABCG2 inhibitors for clinical usage may allow increased penetration of therapeutic agents into sanctuary sites and increases their intestinal absorption. Here we review the mechanisms that modulate MDR mediated by the ABC transporter ABCG2 in normal and cancer cells by different levels including, epigenetic modifications, transcriptional, post transcriptional, translation and post-translational regulation. Some clinical applications of ABCG2 inhibitors are also explained. PMID- 27240993 TI - Classifications of neurogenetic diseases: An increasingly complex problem. AB - Neurodegenerative disorders represent a wide group of diseases affecting the central and/or peripheral nervous system. Many of these disorders were described in the 19th century, but our genetic knowledge of them is recent (over the past 25 years). However, the continual discovery of disease-causing gene mutations has led to difficulties in the classification of these diseases. For this reason, our present proposals for updating and simplifying the classification of some of these conditions (Charcot-Marie-Tooth diseases, distal hereditary motor neuropathies, hereditary sensory and autonomic neuropathies, hereditary spastic ataxias, hereditary spastic paraplegias and hereditary spastic ataxias) are expounded here. PMID- 27240994 TI - Dacomitinib versus erlotinib in patients with EGFR-mutated advanced nonsmall-cell lung cancer (NSCLC): pooled subset analyses from two randomized trials. PMID- 27240995 TI - Positron emission tomography (PET) as a predictive measure in patients with metastatic pancreatic cancer and normal CA19-9 levels at baseline. PMID- 27240996 TI - Age-dependent increase in serum levels of indoxyl sulphate and p-cresol sulphate is not related to their precursors: Tryptophan and tyrosine. AB - AIM: Retention of indoxyl sulphate and p-cresol sulphate is associated with many diseases. The aim of the present study was to examine serum levels of indoxyl sulphate and p-cresol sulphate, the dynamics of their changes according to age, and their precursors. METHODS: The study included 180 healthy individuals aged 20 90 years (n = 180), divided into subgroups by decade (n = 30 in each subgroup) and into subgroups of >=65 years (n = 42) or <65 years (n = 138). Serum indoxyl sulphate and p-cresol sulphate, tryptophan, and tyrosine were measured using high performance liquid chromatography-mass spectrometry. RESULTS: The 70-90 years age group had higher indoxyl sulphate than the 50-59 years age group (P = 0.033). The 70-90 years age group had higher p-cresol sulphate than the 20-29 years (P < 0.001), 30-39 years (P < 0.001), 40-49 years (P = 0.007) and 50-59 years (P = 0.001) age groups; the 60-69 years age group had higher p-cresol sulphate than the 20-29 years (P = 0.043) and 30-39 years (P = 0.011) age groups. Indoxyl sulphate and p-cresol sulphate serum levels were higher in those aged >=65 years. Indoxyl sulphate and p-cresol sulphate serum levels correlated positively with age, but not with tryptophan and tyrosine, respectively. CONCLUSIONS: Healthy aging is associated with indoxyl sulphate and p-cresol sulphate serum level increases, which are not linked to tryptophan and tyrosine serum levels. Geriatr Gerontol Int 2017; 17: 1022-1026. PMID- 27240997 TI - Microwave a.c. conductivity of domain walls in ferroelectric thin films. AB - Ferroelectric domain walls are of great interest as elementary building blocks for future electronic devices due to their intrinsic few-nanometre width, multifunctional properties and field-controlled topology. To realize the electronic functions, domain walls are required to be electrically conducting and addressable non-destructively. However, these properties have been elusive because conducting walls have to be electrically charged, which makes them unstable and uncommon in ferroelectric materials. Here we reveal that spontaneous and recorded domain walls in thin films of lead zirconate and bismuth ferrite exhibit large conductance at microwave frequencies despite being insulating at d.c. We explain this effect by morphological roughening of the walls and local charges induced by disorder with the overall charge neutrality. a.c. conduction is immune to large contact resistance enabling completely non-destructive walls read-out. This demonstrates a technological potential for harnessing a.c. conduction for oxide electronics and other materials with poor d.c. conduction, particularly at the nanoscale. PMID- 27240998 TI - Structural diversity in Ni(II) cluster chemistry: Ni5, Ni6, and {NiNa2}n complexes bearing the Schiff-base ligand N-naphthalidene-2-amino-5-chlorobenzoic acid. AB - The employment of the fluorescent bridging and chelating ligand N-naphthalidene-2 amino-5-chlorobenzoic acid (nacbH2) in Ni(II) cluster chemistry has led to a series of pentanuclear and hexanuclear compounds with different structural motifs, magnetic and optical properties, as well as an interesting 1-D coordination polymer. Synthetic parameters such as the inorganic anion present in the NiX2 starting materials (X = ClO4(-) or Cl(-)), the reaction solvent and the nature of the organic base employed for the deprotonation of nacbH2 were proved to be structure-directing components. Undoubtedly, the reported results demonstrate the rich coordination chemistry of nacbH2 in the presence of Ni(II) metal ions and the ability of this chelate to adopt a variety of different modes, thus fostering the formation of high-nuclearity molecules with many physical properties. PMID- 27240999 TI - Evaluating New Pharmacotherapies for Schizophrenia. PMID- 27241000 TI - A New Modifiable Risk Factor for Schizophrenia? PMID- 27241001 TI - Positron Emission Tomography Studies on Cannabinoid Receptor Type 1 in Schizophrenia. PMID- 27241010 TI - Multitrait aposematic signal in Batesian mimicry. AB - Batesian mimics can parasitize Mullerian mimicry rings mimicking the warning color signal. The evolutionary success of Batesian mimics can increase adding complexity to the signal by behavioral and locomotor mimicry. We investigated three fundamental morphological and locomotor traits in a Neotropical mimicry ring based on Ithomiini butterflies and parasitized by Polythoridae damselflies: wing color, wing shape, and flight style. The study species have wings with a subapical white patch, considered the aposematic signal, and a more apical black patch. The main predators are VS-birds, visually more sensitive to violet than to ultraviolet wavelengths (UVS-birds). The white patches, compared to the black patches, were closer in the bird color space, with higher overlap for VS-birds than for UVS-birds. Using a discriminability index for bird vision, the white patches were more similar between the mimics and the model than the black patches. The wing shape of the mimics was closer to the model in the morphospace, compared to other outgroup damselflies. The wing-beat frequency was similar among mimics and the model, and different from another outgroup damselfly. Multitrait aposematic signals involving morphology and locomotion may favor the evolution of mimicry rings and the success of Batesian mimics by improving signal effectiveness toward predators. PMID- 27241011 TI - Patients' perceptions of implant placement surgery, the post-surgical healing and the transitional implant prostheses: a qualitative study. AB - OBJECTIVES: This study aimed to explore patients' thoughts, feelings about, and experiences of, implant placement surgery (IPS), the post-surgical healing stage and the immediate post-surgical transitional implant prosthesis (TIP) (fixed and removable). METHODS: A qualitative study design was chosen and 38 semi-structured telephone and face-to-face interviews were conducted with 34 patients at different stages of implant treatment. The interviews were transcribed verbatim; the data collection and coding process followed the principles of thematic analysis, which was facilitated through the use of NVivo10. RESULTS: Patients anticipated that surgery would be painful and unpleasant but were prepared to accept this temporary discomfort for the expected benefits of implant treatment. However, a key finding was that patients felt they had overestimated the trauma of surgery but underestimated the discomfort and difficulties of the healing phase. A number of difficulties were also identified with the TIP phase following implant surgery. CONCLUSION: Existing research has tended to focus on the longer term benefits of dental implant treatment. This qualitative study has investigated in-depth patients' perceptions of dental implant surgery, including their experiences related to sedation, and of transitional implant restoration. While patients felt their concerns were overestimated in relation to the implant surgery, they experienced greater morbidity than they expected in the healing phase. Recommendations are made for relatively small changes in care provision which might improve the overall patient experience. Partial dentate patients treated with a fixed transitional prosthesis experienced advantages more quickly than patients with an overdenture. PMID- 27241012 TI - Evolution of resistance to pyrethroid insecticides in Musca domestica. AB - Houseflies, Musca domestica L., are a significant pest because of the numerous diseases they transmit. Control of housefly populations, particularly at animal production facilities, is frequently done using pyrethroid insecticides which kill insects by prolonging the open time of the voltage-sensitive sodium channel (VSSC). Houseflies have evolved resistance to pyrethroids owing to mutations in Vssc and by cytochrome-P450-mediated detoxification. Three Vssc mutations are known: kdr (L1014F), kdr-his (L1014H) and super-kdr (M918T + L1014F). Generally, the levels of resistance conferred by these mutations are kdr-his < kdr < super kdr, but this pattern does not hold for multihalogenated benzyl pyrethroids, for which super-kdr confers less resistance than kdr. P450-mediated resistance can result from overexpression of CYP6D1 or another P450 (unidentified) whose overexpression is linked to autosomes II or V. The initial use of field-stable pyrethroids resulted in different patterns of evolution across the globe, but with time these mutations have become more widespread in their distribution. What is known about the fitness costs of the resistance alleles in the absence of insecticide is discussed, particularly with respect to the current and future utility of pyrethroid insecticides. (c) 2016 Society of Chemical Industry. PMID- 27241013 TI - What's New in 10 Years? A Revised Cardiothoracic Curriculum for Diagnostic Radiology Residency with Goals and Objectives Related to General Competencies. AB - This is a cardiothoracic curriculum document for radiology residents meant to serve not only as a study guide for radiology residents but also as a teaching and curriculum reference for radiology educators and radiology residency program directors. This document represents a revision of a cardiothoracic radiology resident curriculum that was published 10 years ago in Academic Radiology. The sections that have been significantly revised, expanded, or added are (1) lung cancer screening, (2) lung cancer genomic profiling, (3) lung adenocarcinoma revised nomenclature, (4) lung biopsy technique, (5) nonvascular thoracic magnetic resonance, (6) updates to the idiopathic interstitial pneumonias, (7) cardiac computed tomography updates, (8) cardiac magnetic resonance updates, and (9) new and emerging techniques in cardiothoracic imaging. This curriculum was written and endorsed by the Education Committee of the Society of Thoracic Radiology. This curriculum operates in conjunction with the Accreditation Council for Graduate Medical Education (ACGME) milestones project that serves as a framework for semiannual evaluation of resident physicians as they progress through their training in an ACGME-accredited residency or fellowship programs. This cardiothoracic curriculum document is meant to serve not only as a more detailed guide for radiology trainees, educators, and program directors but also complementary to and guided by the ACGME milestones. PMID- 27241014 TI - In vitro ruminal fermentation of treated alfalfa silage using ruminal inocula from high and low feed-efficient lactating cows. AB - AIMS: To assess the effect of two additives on alfalfa silage and on in vitro ruminal fermentation when using ruminal inocula from high feed-efficient (HE) and low feed-efficient (LE) lactating cows. METHODS AND RESULTS: First- and second cut alfalfa was harvested at 40% bloom stage, treated with control (no additive), Lactobacillus plantarum (LP) or formic acid (Formic), ensiled in 1.0 l minisilos, and fermented for 60 days. Fermented alfalfa was incubated in vitro for 24 h using ruminal inoculum from HE and LE lactating cows. The pH was lower in alfalfa silage treated with LP and Formic, and produced lower ammonia-N than did the control. In vitro true dry matter digestibility (IVTDMD) was higher with ruminal inoculum from HE than LE cows, but there was no consistent effect of treated alfalfa on microbial biomass yield and in vitro volatile fatty acids. CONCLUSIONS: The IVTDMD was numerically greater with ruminal inoculum from higher feed-efficient cows although statistical significance was only demonstrated with the first-cut alfalfa. However, treated alfalfa silage did not show the effect expected on in vitro microbial biomass yield. SIGNIFICANCE AND IMPACT OF THE STUDY: The feed efficiency of cows used as a source of ruminal inocula may affect IVTDMD and be a source of variation across in vitro runs. Differences in ruminal fermentation between cows of different feed efficiency could help to explain differences in milk yield and other parameters of dairy cattle performance. PMID- 27241015 TI - Safer scoring? Cryptomarkets, social supply and drug market violence. AB - BACKGROUND: Cryptomarkets are digital platforms that use anonymising software (e.g. Tor) and cryptocurrencies (e.g. Bitcoin) to facilitate trade of goods and services, most notably illicit drugs. Cryptomarkets may reduce systemic violence compared with in-person drug trading because no face-to-face contact is required and disputes can be resolved through a neutral third party. In this paper, we describe the purchasing behaviour of cryptomarket users and then compare the self reported experiences of threats, violence and other drug-market concerns when obtaining drugs from cryptomarkets with obtaining drugs through friends, known dealers and strangers. METHODS: The Global Drug Survey was completed in late 2014 by a self-selected sample who reported accessing drugs through cryptomarkets in the last 12 months (N=3794). RESULTS: Their median age was 22 years and 82% were male. The drug types most commonly obtained through cryptomarkets were MDMA/Ecstasy (55%), cannabis (43%) and LSD (35%). Cryptomarket users reported using a median of 2 sources in addition to cryptomarkets to access drugs, the most common being in-person friendships (74%), in-person dealers (57%) and open markets/strangers (26%). When asked to nominate the main source they would use if cryptomarkets were unavailable, 49% nominated friends, 34% known dealers and 4% strangers. 'Threats to personal safety' (3%) and 'experiencing physical violence' (1%) were less often reported when using cryptomarkets compared with sourcing through friends (14%; 6%), known dealers (24%; 10%) or strangers (35%; 15%). Concerns about drug impurities and law enforcement were reported more often when using the alternative source, while loss of money, waiting too long and not receiving the product were more often reported when using cryptomarkets. CONCLUSION: Cryptomarkets are associated with substantially less threats and violence than alternative market types used by cryptomarket customers, even though a large majority of these alternatives were closed networks where violence should be relatively less common. PMID- 27241016 TI - Implications of placental pathology for disease mechanisms; methods, issues and future approaches. AB - Pathological examination of the placenta is a well-established investigation following delivery in order to investigate the underlying mechanisms of a range of pregnancy related complications. Several recommendations and guidelines are available regarding the indications for such placental testing. The immediate clinical rationale for this process is to identify underlying disease processes which may have an impact on the management of either the infant or the mother in future pregnancies. Additional benefits include improved understanding of the pathophysiological processes of disease and potential medicolegal implications in cases with adverse outcome, including regarding possible timing of lesions. However, interpretation of findings in specific cases remains difficult for several methodological reasons. Future progress requires the use of high quality, well phenotyped tissue collections, with blinded assessment using consensus criteria. In addition, it is likely that novel discovery-based approaches will significantly change the concept of how placental disease is investigated, making tissue sampling even more important across a wide range of pregnancy-related diseases. This will be associated with more stringent conditions for placental evaluation and sampling, including strict definitions of sample site and interval post-delivery, the effects of which will vary depending on the precise assays and methodologies used. PMID- 27241017 TI - Detection of activating MAP2K1 mutations in atypical hairy cell leukemia and hairy cell leukemia variant. PMID- 27241018 TI - Perspective: Targeting the JAK/STAT pathway to fight age-related dysfunction. AB - Senescent cells accumulate in a variety of tissues with aging. They can develop a senescence-associated secretory phenotype (SASP) that entails secretion of inflammatory cytokines, chemokines, proteases, and growth factors. These SASP components can alter the microenvironment within tissues and affect the function of neighboring cells, which can eventually lead to local and systemic dysfunction. The JAK pathway is more highly activate in senescent than non senescent cells. Inhibition of the JAK pathway suppresses the SASP in senescent cells and alleviates age-related tissue dysfunction. Targeting senescent cells could be a promising way to improve healthspan in aged population. PMID- 27241019 TI - Combined therapy using bevacizumab and turmeric ethanolic extract (with absorbable curcumin) exhibited beneficial efficacy in colon cancer mice. AB - Turmeric is commonly used as a medicinal herb and dietary supplement. Its active ingredient, curcumin, has been shown to possess antitumor effects in colorectal cancer patients. However, poor absorption of curcumin in intestine impedes its wide clinical application. Our previous findings showed that the presence of turmerones increased the accumulation of curcumin inside colonic cells. Hence, we hypothesized that curcumin with turmerones or present in turmeric ethanolic extract would augment its anti-tumor activities in tumor-bearing mice. The pharmacokinetics of curcumin in different preparations (containing same amount of curcumin) were studied in mice. The anti-tumor efficacies of curcumin or turmeric extract (with absorbable curcumin) in combination with bevacizumab were further investigated in HT29 colon tumor-bearing mice. Pharmacokinetic results showed that the plasma curcumin level of turmeric extract-fed mice was the highest, suggesting turmeric extract had the best bioavailability of curcumin. Besides, combined turmeric extract plus bevacizumab treatment significantly inhibited the tumor growth. Such inhibitory effects were stronger than those of curcumin plus bevacizumab or bevacizumab alone and were comparable with those of 5 fluorouracil+leucovorin+oxaliplatin (FOLFOX) plus bevacizumab. Notably, there was no observable side effect induced by turmeric extract treatment while significant side effects were found in FOLFOX-treated mice. In conclusion, combination of turmeric extract with bevacizumab possessed potent anti-tumor effects without observable side effects, strongly suggesting the adjuvant use of turmeric extract in colorectal cancer therapy. Our current findings warrant the confirmation regarding the benefits arising from the combined use of bevacizumab and turmeric in colorectal cancer patients in the near future. PMID- 27241021 TI - The effect of water and shampooing on the efficacy of fluralaner spot-on solution against Ixodes ricinus and Ctenocephalides felis infestations in dogs. AB - BACKGROUND: Fluralaner spot-on solution provides immediate and persistent efficacy against tick and flea infestations in dogs and cats for 12-weeks following topical administration. The active ingredient fluralaner is distributed systemically following transdermal absorption. Therefore, this study tested the hypothesis whether water-immersion or shampooing of dogs following administration of fluralaner spot-on solution has an impact on subsequent tick and flea efficacy. METHODS: Thirty-two Beagle dogs were allocated to four study groups of 8 dogs each. On day 0, dogs in the 2 treatment groups received topical administration of fluralaner (BravectoTM spot-on solution) according to label instructions. Dogs in the 2 corresponding control groups remained untreated. On days 3, 21, 49, and 77 dogs in one treatment group and control group were water immersed for 2-5 min, while dogs in the other treatment group and control group were shampooed 6-8 min with a commercial foaming micro-emulsion, unscented product. On days 4, 28, 56, and 84 all dogs were co-infested with 50 +/- 2 female and 10 +/- 2 male Ixodes ricinus and 100 +/- 4 Ctenocephalides felis, with tick and flea removal and counts 48 +/- 2 h post-infestation. Efficacy against ticks and fleas was calculated for each assessment time point. RESULTS: No treatment related adverse event was observed in any of the 16 dogs treated with fluralaner spot-on solution during the study. Efficacy against ticks at each assessment time point was between 99.7 and 100 % in the water-immersed group and between 99.2 and 100 % in the shampooed group. Efficacy against fleas was 100 % at each assessment time point as well in the water-immersed as the shampooed group. Tick and flea reduction in both treatment groups was significant at all assessment time points (p < 0.0001). CONCLUSIONS: Neither water-immersion nor shampooing after single topical administration of fluralaner spot-on solution had an impact on the excellent tick and flea efficacy over the 12-week recommended re-treatment interval. PMID- 27241020 TI - Loganin possesses neuroprotective properties, restores SMN protein and activates protein synthesis positive regulator Akt/mTOR in experimental models of spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease characterized by motor neurons degeneration and muscular atrophy. There is no effective SMA treatment. Loganin is a botanical candidate with anti-inflammatory, anti-oxidant, glucose-lowering and anti-diabetic nephropathy activities. The aim of this study is to investigate the potential protective effects of loganin on SMA using two cellular models, SMN-deficient NSC34 cells and SMA patient fibroblasts, and an animal disease model, SMADelta7 mice. In SMN-deficient NSC34 cells, loganin increased cell viability, neurite length, and expressions of SMN, Gemin2, SMN-Gemin2 complex, p-Akt, p-GSK-3beta, p-CREB, BDNF and Bcl-2. However, both AG1024 (IGF-1 R antagonist) and IGF-1 R siRNA attenuated the protective effects of loganin on SMN level and cell viability in SMN-deficient NSC34 cells. In SMA patient fibroblasts, loganin up-regulated levels of SMN, FL-SMN2, and Gemins, increased numbers of SMN-containing nuclear gems, modulated splicing factors, and up-regulated p-Akt. Furthermore, in the brain, spinal cord and gastrocnemius muscle of SMADelta7 mice, loganin up-regulated the expressions of SMN and p-Akt. Results from righting reflex and hind-limb suspension tests indicated loganin improved muscle strength of SMADelta7 mice; moreover, loganin activated Akt/mTOR signal and inhibited atrogin-1/MuRF-1 signal in gastrocnemius muscle of SMADelta7 mice. Loganin also increased body weight, but the average lifespan of loganin (20mg/kg/day)-treated SMA mice was 16.80+/-0.73 days, while saline-treated SMA mice was 10.91+/-0.96 days. In conclusion, the present results demonstrate that loganin provides benefits to SMA therapeutics via improving SMN restoration, muscle strength and body weight. IGF-1 plays an important role in loganin neuroprotection. Loganin can be therefore a valuable complementary candidate for treatment of neuromuscular diseases via regulation of muscle protein synthesis and neuroprotection. PMID- 27241023 TI - Improvement of in vivo antimicrobial activity of HBcARD peptides by D-arginine replacement. AB - We previously identified a novel antimicrobial peptide with a broad spectrum bactericidal activity from human hepatitis B virus (HBV) core protein (HBc) arginine-rich domain (ARD). We compared the antimicrobial activities of HBcARD peptides from different hepadnaviruses which share similar amino acid sequences. In general, mammalian HBcARD peptides exhibited stronger antimicrobial activity than avian peptides. Using the strategy of D-amino acid substitutions, we improved the antimicrobial efficacy of human HBcARD peptide. This D-HBcARD peptide was much more resistant than L-HBcARD peptide to proteolytic degradation in vitro. Moreover, this D-HBcARD peptide maintained similar minimal bactericidal concentrations (MBC) against tested bacteria, and showed very low hemolytic activity. In the Staphylococcus aureus-infected mouse model, this D-HBcARD peptide was more protective than the L-HBcARD peptide. Repeated treatments with either L- or D-HBcARD peptides induced no significant immunogenicity. New derivatives of HBcARD peptides could serve as alternatives to the conventional antibiotics in clinical medicine in the future. PMID- 27241022 TI - Overexpression of caveolin-1 in inflammatory breast cancer cells enables IBC specific gene delivery and prodrug conversion using histone-targeted polyplexes. AB - Gene therapy platforms offer a variety of potentially effective solutions for development of targeted agents that can be exploited for cancer treatment. The physicochemical properties of nanocarriers can be tuned to enhance their localization in tumors, and cell specificity can also be increased by appropriate selection of gene targets. A relatively underexploited approach to enhance therapeutic selectivity in cancer tissues is the use of nanocarriers whose nuclear targeting and uptake are triggered by the altered expression of specific endomembrane trafficking proteins in cancer cells. Previously, we showed that histone 3 (H3) peptide-targeted DNA polyplexes traffic to the nucleus efficiently through caveolar endocytosis followed by transfer through the Golgi and endoplasmic reticulum (ER). We hypothesized that these polyplexes would exhibit enhanced activity in inflammatory breast cancer (IBC) cells, which overexpress caveolin-1 as part of their invasive phenotype, and we also posited that this targeting effect could be exploited to facilitate IBC-specific transfection and prodrug conversion in the presence of normal breast epithelial cells. Using cellular transfection experiments, function-blocking assays, and confocal imaging in both IBC SUM149 cell monocultures and IBC SUM149 co-cultures with MCF10A normal breast epithelial cells, we found that our H3-targeted polyplexes selectively transfected IBC SUM149 cells at a 4-fold higher level than normal breast epithelial cells. This selectivity and increased transfection were caused by a 2.2-fold overexpression of caveolin-1 in IBC SUM149 cells, which led to increased polyplex trafficking to the nucleus through the Golgi and ER. We also saw similar enhancements in cell selectivity and transfection when cells were transfected with a suicide gene/prodrug combination, as the increased expression of the suicide gene in IBC SUM149 cells led to a 55% decrease in viability in IBC SUM149 cells as compared to a 25% decrease in MCF10A cells. These findings demonstrate that differences in the expression of the endocytic membrane protein caveolin-1 can be exploited for cell-selective gene delivery, and ultimately, these gene-based targeting approaches may be useful in potential treatments for aggressive cancer types. Biotechnol. Bioeng. 2016;113: 2686-2697. (c) 2016 Wiley Periodicals, Inc. PMID- 27241025 TI - Solvent-induced desorption of alkanethiol ligands from Au nanoparticles. AB - Removing surfactants from a colloidal metal nanoparticle surface is necessary for their realistic applications, and how they could be stripped is a subject of active investigation. Here, we report a solvent-induced desorption of dodecanethiol ligands from the gold nanoparticle surface, and traced this desorption process using a combination of in situ X-ray absorption fine structure (XAFS) and Raman spectroscopic techniques. In situ analysis results reveal that the solvent exchange of ethanol with tetrahydrofuran (THF) can effectively remove dodecanethiol ligands while keeping the particle morphology unchanged. Upon increasing the THF/ethanol ratio from 0 : 1 to 5 : 1, the surface coverage of thiol on the Au surface is reduced from 0.47 to 0.07, suggesting the depletion of ligands first from the nanoparticle facet sites, then from the edge sites, while the ligands at the corner sites are intact. This work enriches our knowledge on surfactant removal and may pave the way towards preparing surface-clean nanoparticles for practical applications. PMID- 27241024 TI - Smoothened Agonist Reduces Human Immunodeficiency Virus Type-1-Induced Blood Brain Barrier Breakdown in Humanized Mice. AB - Human Immunodeficiency Virus type-1 (HIV)-associated neurocognitive disorder is characterized by recruitment of activated/infected leukocytes into the CNS via disrupted Blood Brain Barrier (BBB) that contributes to persistent neuro inflammation. In this report, humanized NOD/scid-IL2Rgammac(null) mice were used to establish that impaired Sonic hedgehog (Shh) signaling is associated with loss of BBB function and neurological damage, and that modulating Shh signaling can rescue these detrimental effects. Plasma viral load, p24 levels and CD4(+) T cells were measured as markers of productive HIV infection. These mice also showed impaired exclusion of Evans blue dye from the brain, increased plasma levels of S100B, an astrocytic protein, and down-regulation of tight junction proteins Occludin and Claudin5, collectively indicating BBB dysfunction. Further, brain tissue from HIV(+) mice indicated reduced synaptic density, neuronal atrophy, microglial activation, and astrocytosis. Importantly, reduced expression of Shh and Gli1 was also observed in these mice, demonstrating diminished Shh signaling. Administration of Shh mimetic, smoothened agonist (SAG) restored BBB integrity and also abated the neuropathology in infected mice. Together, our results suggest a neuroprotective role for Shh signaling in the context of HIV infection, underscoring the therapeutic potential of SAG in controlling HAND pathogenesis. PMID- 27241026 TI - Identification of KPNB1 as a Cellular Target of Aminothiazole Derivatives with Anticancer Activity. AB - We found that aminothiazole derivative (E)-N-(5-benzylthiazol-2-yl)-3-(furan-2 yl)acrylamide (1) has strong anticancer activity, and undertook proteomics approaches to identify the target protein of compound 1, importin beta1 (KPNB1). A competitive binding assay using fluorescein-labeled 1 showed that 1 has strong binding affinity for KPNB1 (Kd : ~20 nm). Furthermore, through western blotting assays for KPNB1, KPNA2, EGFR, ErbB2, and STAT3, we confirmed that 1 has inhibitory effects on the importin pathway. KPBN1 appears to be overexpressed in several cancer cells, and siRNA-induced inhibition of KPNB1 shows significant inhibition of cancer cell proliferation, while leaving non-cancerous cells unaffected. Therefore, compound 1 is a promising new lead for the development of KPNB1-targeted anticancer agents. Fluorescein-labeled 1 could be a useful quantitative probe for the development of novel KPNB1 inhibitors. PMID- 27241027 TI - Applying low-molecular weight supramolecular gelators in an environmental setting - self-assembled gels as smart materials for pollutant removal. AB - This review explores supramolecular gels as materials for environmental remediation. These soft materials are formed by self-assembling low-molecular weight building blocks, which can be programmed with molecular-scale information by simple organic synthesis. The resulting gels often have nanoscale 'solid-like' networks which are sample-spanning within a 'liquid-like' solvent phase. There is intimate contact between the solvent and the gel nanostructure, which has a very high effective surface area as a result of its dimensions. As such, these materials have the ability to bring a solid-like phase into contact with liquids in an environmental setting. Such materials can therefore remediate unwanted pollutants from the environment including: immobilisation of oil spills, removal of dyes, extraction of heavy metals or toxic anions, and the detection or removal of chemical weapons. Controlling the interactions between the gel nanofibres and pollutants can lead to selective uptake and extraction. Furthermore, if suitably designed, such materials can be recyclable and environmentally benign, while the responsive and tunable nature of the self-assembled network offers significant advantages over other materials solutions to problems caused by pollution in an environmental setting. PMID- 27241028 TI - Secreted Matrix Metalloproteinase-9 of Proliferating Smooth Muscle Cells as a Trigger for Drug Release from Stent Surface Polymers in Coronary Arteries. AB - Cardiovascular diseases are the leading causes of death in industrialized countries. Atherosclerotic coronary arteries are commonly treated with percutaneous transluminal coronary intervention followed by stent deployment. This treatment has significantly improved the clinical outcome. However, triggered vascular smooth muscle cell (SMC) proliferation leads to in-stent restenosis in bare metal stents. In addition, stent thrombosis is a severe side effect of drug eluting stents due to inhibition of endothelialization. The aim of this study was to develop and test a stent surface polymer, where cytotoxic drugs are covalently conjugated to the surface and released by proteases selectively secreted by proliferating smooth muscle cells. Resting and proliferating human coronary artery smooth muscle cells (HCASMC) and endothelial cells (HCAEC) were screened to identify an enzyme exclusively released by proliferating HCASMC. Expression analyses and enzyme activity assays verified selective and exclusive activity of the matrix metalloproteinase-9 (MMP-9) in proliferating HCASMC. The principle of drug release exclusively triggered by proliferating HCASMC was tested using the biodegradable stent surface polymer poly-l-lactic acid (PLLA) and the MMP-9 cleavable peptide linkers named SRL and AVR. The specific peptide cleavage by MMP-9 was verified by attachment of the model compound fluorescein. Fluorescein release was observed in the presence of MMP-9 secreting HCASMC but not of proliferating HCAEC. Our findings suggest that cytotoxic drug conjugated polymers can be designed to selectively release the attached compound triggered by MMP-9 secreting smooth muscle cells. This novel concept may be beneficial for stent endothelialization thereby reducing the risk of restenosis and thrombosis. PMID- 27241029 TI - Mode-of-action evaluation for the effect of trans fatty acids on low-density lipoprotein cholesterol. AB - The purpose of this work is to systematically consider the data relating to the mode of action (MOA) for the effects of industrially produced trans fatty acid (iTFA) on plasma low-density lipoprotein (LDL) levels. The hypothesized MOA is composed of two key events: increased LDL production and decreased LDL clearance. A substantial database supports this MOA, although the key events are likely to be interdependent, rather than sequential. Both key events are functions of nonlinear biological processes including rate-limited clearance, receptor mediated transcription, and both positive and negative feedback regulation. Each key event was evaluated based on weight-of-evidence analysis and for human relevance. We conclude that the data are inadequate for a detailed dose-response analysis in the context of the evolved Bradford Hill considerations; however, the weight of evidence is strong and the overall shape of the dose-response curves for markers of the key events and the key determinants of those relationships is well understood in many cases and is nonlinear. Feedback controls are responsible for maintaining homeostasis of cholesterol and triglyceride levels and underlie both of the key events, resulting in a less-than-linear or thresholded relationship between TFA and LDL-C. The inconsistencies and gaps in the database are discussed. PMID- 27241030 TI - Regulation of urinary crystal inhibiting proteins and inflammatory genes by lemon peel extract and formulated citrus bioflavonoids on ethylene glycol induced urolithic rats. AB - The objective of this study is to check the regulation of crystal matrix proteins and inflammatory mediators by citrus bioflavonoids (CB) and Lemon peel (LP) extract in hyperoxaluric rats. The animals were divided into six groups with 6 animals each. Group 1: Control, Group 2: Urolithic (Ethylene glycol (EG)-0.75%); Group 3 & 5: Preventive study (EG + CB (20 mg/kg body weight) and LP (100 mg/kg body weight) extract administration from 0th-7th week) respectively; Group 4 & 6: Curative study (EG + CB and LP extract administration from 4th-7th week) respectively by oral administration. Urinary lithogenic factors (Calcium, oxalate, phosphate and citrate) were normalized in CB & LP supplemented rats, while serum parameters revealed the nephroprotective nature of the intervening agents compared to urolithic rats (p < 0.001). Immunoblotting studies showed significantly increased expression of THP, osteopontin and transferrin in kidneys of urolithic rats (p < 0.001), while preventive and curative study showed near normal expression of these proteins. Expression of NF-kappaB, TNF-alpha and IL-6 were raised significantly (p < 0.001), while a very minimal increase in MCP-1 expression was observed in urolithic rats compared to control. Hence, supplementation of CB and LP reduced the crystal promoting factors and provides protection from crystal induced renal damage. PMID- 27241031 TI - Growth of metal-semiconductor core-multishell nanorods with optimized field confinement and nonlinear enhancement. AB - This paper describes a facile method for the synthesis of Au/AuAg/Ag2S/PbS core multishell nanorods with double trapping layers. The synthesis, in sequence, involved deposition of Ag shells onto the surfaces of Au nanorod seeds, formation of AuAg shells by a galvanic replacement reaction, and overgrowth of the Ag2S shells and PbS shells. The resulting core-multishell nanorod possesses an air gap between the Au core and the AuAg shell. Together with the Ag2S shell, the air gap can efficiently trap light, causing strong field confinement and nonlinear enhancement. The as-prepared Au/AuAg/Ag2S/PbS core-multishell nanorods display distinct localized surface plasmon resonance and nonlinear optical properties, demonstrating an effective pathway for maneuvering the optical properties of nanocavities. PMID- 27241032 TI - We are different: the voices of psychiatric advanced practice nurses on the performance of their roles. AB - BACKGROUND: Many studies have affirmed that psychiatric advanced practice nurses (APNs) perform multifaceted roles. However, only a limited amount of research has been conducted on their perceptions of the performance of their roles. AIM: To explore the lived experiences of psychiatric APNs concerning the performance of their roles. DESIGN: Data were collected from individual semi-structured interviews and analysed using the interpretative phenomenological analysis method. METHODS: The study was conducted in a hospital cluster in Hong Kong. Thirteen psychiatric APNs were purposively recruited. RESULTS: Three themes were discerned, namely, 'We are different', 'Who am I?', and 'I am who I am'. CONCLUSIONS: The findings can help psychiatric APNs and nurse administrators to better understand the needs of the role-bearers (APNs) and to develop strategies to support the development of advanced psychiatric nursing practices in Hong Kong and worldwide. PMID- 27241033 TI - Combination of infliximab with thiopurines significantly reduces white cell and neutrophil counts in inflammatory bowel disease patients. AB - BACKGROUND: The effects of thiopurines on white cell count are well documented. OBJECTIVE: We compared the effects of infliximab 5 mg/kg monotherapy and combination of infliximab with thiopurines on the total and differential white cell count (WBC). METHODS: 13 IBD patients treated with infliximab monotherapy and 18 IBD patients treated with a combination of infliximab and thiopurines were included in the study. Using retrospective data, cell counts were examined prior to induction of infliximab, and at 6 weeks and 1 year post-induction. RESULTS: The patients on combination therapy had an absolute WBC at 52 weeks of 5.7 whereas that of patients on Infliximab monotherapy at the same time point was 8.3 with comparable neutrophil count of 3.4 and 5.4. The results showed a significant reduction in white cell count and neutrophils at 6 weeks which persisted at 52 weeks in both groups (p < 0.05) with a greater drop in patients on combination infliximab and thiopurine (p < 0.05) as compared to Infliximab monotherapy. There was no significant change in the lymphocyte count. CONCLUSION: Full blood counts should be closely monitored in all patients starting infliximab therapy, in particular patients receiving concomitant thiopurines. PMID- 27241034 TI - Identification and function analysis of a novel vascular endothelial growth factor, LvVEGF3, in the Pacific whiteleg shrimp Litopenaeus vannamei. AB - VEGF signaling pathway is first discovered in mammals and proved to play important roles in the biological processes of angiogenesis, tumor migration, cell differentiation, apoptosis, host-virus interaction etc. Three members in the VEGF signaling pathway, including LvVEGFR, LvVEGF1 and LvVEGF2 in shrimp have been proved to be related with WSSV infection in our previous studies. Currently, another member of VEGF family, LvVEGF3, was isolated and its function during the WSSV infection of shrimp was studied. The deduced amino acid sequence of LvVEGF3 contained a signal peptide, a typical PDGF/VEGF domain and a cysteine-knot motif (CXCXC). Tissue distribution analysis showed that LvVEGF3 was predominantly expressed in hemocytes. The transcriptional level of LvVEGF3 in hemocytes was apparently up-regulated during WSSV infection. Silencing of LvVEGF3 with double stranded RNA caused a reduction of the cumulative mortality rate of shrimp during WSSV infection. The expression of LvVEGFR was apparently down-regulated after LvVEGF3 silencing and up-regulated after injection of recombinant LvVEGF3 protein, suggesting an interaction between LvVEGF3 and LvVEGFR. Furthermore, the interaction between LvVEGFR and LvVEGF3 was confirmed using the yeast two-hybrid system. The results provided new insights into understanding the role of VEGF signaling pathway during virus infection. PMID- 27241036 TI - A novel polysaccharide isolated from mulberry fruits (Murus alba L.) and its selenide derivative: structural characterization and biological activities. AB - A novel polysaccharide (MFP3P) was isolated from Murus alba L. through the hot water extraction method followed by chromatographic purification. The chemical structure of MFP3P was elucidated by acid hydrolysis, Smith degradation and methylation analysis, along with FT-IR, GC-MS, (1)H and (13)C NMR spectroscopy. Its morphological properties were further characterized by SEM and AFM. The selenide of the polysaccharide (MFP3P-Se) was obtained by the Na2SeO3/BaCl2 method. The antioxidant properties showed that MFP3P-Se exhibited higher peroxy radical-scavenging capacity than MFP3P in vitro. Moreover, MFP3P-Se had more significant hypoglycemic effects than MFP3P through promoting pancreatic cell proliferation and increasing glucose metabolism and insulin secretion. PMID- 27241035 TI - ABO blood groups in relation to breast carcinoma incidence and associated prognostic factors in Moroccan women. AB - The association between blood groups ABO and different types of diseases was established in several previous studies. Our aim was to seek the possible association between the ABO blood group and breast cancer-associated prognostic factors. The Chi-squared analytic test was used to compare phenotypic ABO distribution among Moroccan blood donors and 442 cases of women suffering from breast carcinoma with archived files in Maternity Ward of University Hospital C.H.U Ibn Rochd between 2008 and 2011. High incidence of breast carcinoma was observed in blood type B patients (p < 0.05). Blood type B was associated with breast carcinomas overexpressing human epidermal growth factor receptor HER2 (p < 0.05) and high risk of cancer at age over 70 years (p < 0.001). Blood type A was associated with high risk of cancer among women younger than 35 years old. Blood type A and AB were associated with high incidence of lymph node metastasis (p < 0.05). Multivariate analysis has shown correlation between O blood type and estrogen receptor-positive tumor. Patients with blood group A, B, and AB were more likely to develop aggressive breast carcinoma. Further follow-up studies are necessary to clarify the role of ABH antigens in the progression of breast carcinoma. PMID- 27241037 TI - C9orf72 Hexanucleotide Repeat Analysis in Cases with Pathologically Confirmed Dementia with Lewy Bodies. AB - BACKGROUND: Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia affecting the elderly. The GGGGCC hexanucleotide expansion mutation at the C9orf72 locus has been identified as a major cause of amyotrophic lateral sclerosis and frontotemporal dementia, raising the question of whether this mutation is a factor in DLB. Furthermore, a small number of clinically diagnosed DLB patients have previously been reported to carry the pathologic C9orf72 hexanucleotide repeat expansion. OBJECTIVE: To explore whether the C9orf72 mutation is present in pathologically confirmed DLB patients. METHODS: We screened a cohort of 111 definite DLB cases with extensive Lewy body pathology for the C9orf72 hexanucleotide repeat expansion using the repeat-primed polymerase chain reaction assay. RESULTS: No pathogenic expansions of the C9orf72 hexanucleotide repeat were found, suggesting that there is no causal relationship between C9orf72 and DLB. CONCLUSION: Our data illustrate that C9orf72 screening of clinically diagnosed DLB patients should only be considered in cases with a family history of motor neuron disease or frontotemporal dementia to distinguish between mimic diseases. PMID- 27241039 TI - Sodium chloride's effect on self-assembly of diphenylalanine bilayer. AB - Understanding self-assembling peptides becomes essential in nanotechnology, thereby providing a bottom-up method for fabrication of nanostructures. Diphenylalanine constitutes an outstanding building block that can be assembled into various nanostructures, including two-dimensional bilayers or nanotubes, exhibiting superb mechanical properties. It is known that the effect of the ions is critical in conformational and chemical interactions of bilayers or membranes. In this study, we analyzed the effect of sodium chloride on diphenylalanine bilayer using coarse-grained molecular dynamics simulations, and calculated the bending Young's modulus and the torsional modulus by applying normal modal analysis using an elastic network model. The results showed that sodium chloride dramatically increases the assembling efficiency and stability, thereby promising to allow the precise design and control of the fabrication process and properties of bio-inspired materials. (c) 2016 Wiley Periodicals, Inc. PMID- 27241038 TI - Changing Pattern of Sedative Use in Older Adults: A Population-Based Cohort Study. AB - BACKGROUND: Benzodiazepine medications have well-documented side effects, and their prescription rates in older adults have been declining. Trazodone and quetiapine are medications with sedative properties when used at low doses and are commonly used off-label for sleep or behavioral symptoms in older adults. OBJECTIVE: Our objective was to describe the shifting patterns of sedative prescription in older adults over time by comparing changes in benzodiazepine, trazodone, and quetiapine dispensing between community and long-term care settings. METHODS: We conducted a population-based serial cross-sectional study to compare the patterns of sedative dispensing (specifically, benzodiazepines, trazodone, and quetiapine) to individuals aged >=66 years between 1 January 2002 and 31 March 2013 in Ontario, Canada. We compared rates of use between long-term care and community settings and used linear regression models to characterize the magnitude and direction of the rate of change in sedative use by age, sex, and dementia status. RESULTS: The dispensing of trazodone and quetiapine increased over time, and this coincided with a decrease in benzodiazepine dispensing. This pattern was particularly apparent in the oldest cohort and in those with dementia. Benzodiazepines, trazodone, and quetiapine were associated with high rates of psychotropic polypharmacy. Overall trends were similar in long-term care and the community. CONCLUSIONS: While benzodiazepine prescribing is declining among older adults in Ontario over time, there is a corresponding shift towards low-dose, off-label prescribing of trazodone and quetiapine and psychotropic polypharmacy. These prescribing trends highlight sedative substitution and reinforce the need to confirm efficacy and safety of this practice. PMID- 27241040 TI - Reduction of Cold Ischemia Time and Anastomosis Time Correlates with Lower Delayed Graft Function Rates Following Transplantation of Marginal Kidneys. AB - BACKGROUND In kidney transplantation, the association of cold ischemia time (CIT), anastomosis time (AT), and delayed graft function (DGF) is particularly detrimental in grafts from marginal donors; however, actual cut-off criteria are still debated. MATERIAL AND METHODS Data from patients >65 years (n=193) and patients <65 years (n=1054) transplanted between 2000 and 2010 were retrospectively analyzed regarding the age-dependent impact of ischemia times and DGF. RESULTS Overall death censored graft survival was inferior for ECD/DCD organs. Graft survival was significantly impaired by DGF in younger and older recipients. The multivariate analysis revealed an age-dependent profile of risk factors for DGF. In younger patients, multiple risk factors were identified while in patients >65 years, only CIT and AT were correlated with DGF. Marginal grafts with a CIT<769 min had a comparable outcome to any SCD organ; extended CIT >770 min worsened ECD/DCD survival significantly. Similarly, AT longer than 26 min was associated with a significantly impaired survival of ECD/DCD grafts. In a Cox regression analysis with penalized splines, this increased risk of graft loss was not linear: CIT beyond 800 min and AT beyond 20 min were cut-off values associated with worse outcomes in marginal organs. CONCLUSIONS Thus, risk factors for DGF are age-dependent; keeping ischemia times below these thresholds offers outcome of ECD/DCD organs comparable to SCD organs. PMID- 27241041 TI - Care Challenges in the Bathroom: The Views of Professional Care Providers Working in Clients' Homes. AB - In home care, bathroom activities-particularly bathing and toileting-present a unique set of challenges. In this focus group study, professional home care providers identified factors that increase the danger and difficulty of assisting their clients with bathing and toileting. These included small restrictive spaces, a poor fit between available equipment and the environment, a reliance on manual handling techniques (but insufficient space to use optimal body mechanics), attempts to maintain normalcy, and caring for unsteady and unpredictable clients. Specific elements of each activity that care providers found difficult included multitasking to support client stability while performing care below the waist (dressing/undressing, providing perineal care) and helping clients to lift their legs in and out of a bathtub. Participants did not feel that available assistive devices provided enough assistance to reduce the danger and difficulty of these activities. PMID- 27241042 TI - Fungal Biology: A fungal quorum-sensing system. PMID- 27241043 TI - Bacterial GWAS: not just gilding the lily. PMID- 27241044 TI - Parasite physiology: Trypanosomes chew the fat. PMID- 27241047 TI - Intraoperative tremor in surgeons and trainees. AB - OBJECTIVES: Tremor may be expected to interfere with the performance of fine motor tasks such as surgery. While tremor is readily quantified in inactive subjects, it is more challenging to measure tremor as the subjects perform complex tasks. The objective of this work was to quantify tremor during the performance of a realistic simulated surgery. METHODS: Our novel surgical simulator incorporates a force sensor that allows identification and quantification of the intraoperative effects of tremor on the manipulandum. We have collected preliminary data from trainees and experienced surgeons carrying out multiple simulated anastomoses on silicone vessels, mimicking a procedure such as distal coronary anastomosis. We calculated transient and overall tremor intensity, and tested for a hypothesized 'learning effect'. RESULTS: Several of the recordings of intraoperative force data manifested distinctive features corresponding to substantial oscillation in the range of 8-12 Hz. We attribute this to enhanced physiological tremor. These early results indicate a significant reduction in the transmission of surgeon's tremor to the operative field from the first attempt to later attempts (P = 0.039, standardized effect size = 0.91), which may be associated with increasing confidence. CONCLUSIONS: This new method does not just quantify tremor, but quantifies the transmission of tremor to a manipulandum in the operative field during high-fidelity simulated coronary surgery. This may be used to assess and provide feedback on the performance of trainees and experienced surgeons, along with other fields in which fine motor skills are of vital importance. PMID- 27241045 TI - Plasma beta-amyloid in Alzheimer's disease and vascular disease. AB - Implementation of amyloid biomarkers in clinical practice would be accelerated if such biomarkers could be measured in blood. We analyzed plasma levels of Abeta42 and Abeta40 in a cohort of 719 individuals (the Swedish BioFINDER study), including patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), Alzheimer's disease (AD) dementia and cognitively healthy elderly, using a ultrasensitive immunoassay (Simoa platform). There were weak positive correlations between plasma and cerebrospinal fluid (CSF) levels for both Abeta42 and Abeta40, and negative correlations between plasma Abeta42 and neocortical amyloid deposition (measured with PET). Plasma levels of Abeta42 and Abeta40 were reduced in AD dementia compared with all other diagnostic groups. However, during the preclinical or prodromal AD stages (i.e. in amyloid positive controls, SCD and MCI) plasma concentration of Abeta42 was just moderately decreased whereas Abeta40 levels were unchanged. Higher plasma (but not CSF) levels of Abeta were associated with white matter lesions, cerebral microbleeds, hypertension, diabetes and ischemic heart disease. In summary, plasma Abeta is overtly decreased during the dementia stage of AD indicating that prominent changes in Abeta metabolism occur later in the periphery compared to the brain. Further, increased levels of Abeta in plasma are associated with vascular disease. PMID- 27241048 TI - First-in-man full percutaneous transfemoral valve-in-valve implantations using Edwards SAPIEN 3 prostheses to treat a patient with degenerated mitral and aortic bioprostheses. AB - We report the case of a 64-year old man presenting with pulmonary oedema due to the degeneration of mitral and aortic bioprostheses. Baseline transthoracic and 3D transoesophageal echocardiography showed severe stenotic degeneration of the mitral bioprosthesis (Carpentier-Edwards bioprosthesis n degrees 31), severe intraprosthetic aortic regurgitation (Perimount bioprosthesis n degrees 27), left ventricular dilatation, decreased left ventricular ejection fraction at 50% and pulmonary hypertension. Because of severe comorbidities, the patient was denied redo surgery by the Heart Team (logistic EuroSCORE 2: 23, 85%). Transcatheter transfemoral mitral valve-in-valve implantation was first performed using a 29-mm SAPIEN 3 valve. Two weeks later, aortic valve-in-valve implantation was performed with the same approach using a 26-mm SAPIEN 3 valve. Four months later, the patient remained asymptomatic with good haemodynamic results for both prostheses. This case report illustrates that valve-in-valve implantations using a full percutaneous transfemoral approach may be a valuable alternative to conventional surgery in high-risk patients presenting with concomitant mitral and aortic bioprosthesis dysfunction. PMID- 27241049 TI - Incidence and causes of silent and symptomatic stroke following surgical and transcatheter aortic valve replacement: a comprehensive review. AB - Stroke associated with aortic valve replacement in calcific aortic stenosis, either via transcatheter implantation (TAVR) or via surgical replacement (SAVR), is one of the most devastating complications. However, data concerning the clinical impact and incidence of clinical and silent stroke complicating SAVR and TAVR are varying. This comprehensive review of the literature explores the genuine incidence of neurological events after these procedures. Additionally, potential factors responsible for the discrepancies in stroke rates in the current literature are analysed and a lack of uniform neurological definitions and standardized neurological assessments revealed. Current stroke rates after TAVR show a decline from 7 to 1.7-4.8% in recent studies. Randomized studies comparing TAVR with SAVR yielded initially a significantly higher stroke rate after TAVR procedures as opposed to SAVR. Recently published data showed opposite results with strokes being higher following SAVR. Current data concerning stroke after surgical valve replacement report significantly higher rates of clinical strokes (17%) than previously mentioned in the literature (<=4.9%). Silent cerebral lesions were detected in 68-93% after TAVR and 38-54% after SAVR. A broader application of cerebral protection devices may help to reduce embolic cerebral events. PMID- 27241046 TI - The frontier of RNA metamorphosis and ribosome signature in neocortical development. AB - More than a passive effector of gene expression, mRNA translation (protein synthesis) by the ribosome is a rapidly tunable and dynamic molecular mechanism. Neurodevelopmental disorders are associated with abnormalities in mRNA translation, protein synthesis, and neocortical development; yet, we know little about the molecular mechanisms underlying these abnormalities. Furthermore, our understanding of regulation of the ribosome and mRNA translation during normal brain development is only in its early stages. mRNA translation is emerging as a key driver of the rapid and timed regulation of spatiotemporal gene expression in the developing nervous system, including the neocortex. In this review, we focus on the regulatory role of the ribosome in neocortical development, and construct a current understanding of how ribosomal complex specificity may contribute to the development of the neocortex. We also present a microarray analysis of ribosomal protein-coding mRNAs across the neurogenic phase of neocortical development, in addition to the dynamic enrichment of these mRNAs in actively translating neocortical polysomal ribosomes. Understanding the multivariate control of mRNA translation by ribosomal complex specificity will be critical to reveal the intricate mechanisms of normal brain development and pathologies of neurodevelopmental disorders. PMID- 27241051 TI - The Ross procedure: biomechanical properties of the pulmonary artery according to aortic valve phenotype. AB - OBJECTIVES: The aim of this study is to determine whether patients undergoing the Ross procedure with bicuspid aortic valves have pulmonary artery biomechanical properties different from those with tricuspid valves. METHODS: Thirty-two pulmonary arteries and 20 aortas were obtained from patients undergoing the Ross procedure at the time of surgery, from a cohort of 32 patients. The aortic valve was tricuspid in 5 patients (16%), bicuspid in 18 patients (56%) and unicuspid in 9 patients (28%). Histological analysis and ex vivo equi-biaxial tensile testing completed within 8 hours of surgery were used to evaluate differences in patient groups and between the pulmonary artery and the ascending aorta. RESULTS: There was no difference in thickness among pulmonary arteries when compared according to aortic valve phenotype (P = 0.94). There was no difference in the tensile tissue properties among aortas and pulmonary arteries when compared according to aortic valve phenotype, in either the circumferential or longitudinal axis. When compared according to the main surgical indication, pulmonary artery walls from patients with pure aortic regurgitation were less stiff than their counterparts (aortic regurgitation: 0.055 +/- 0.037 MPa, aortic stenosis: 0.103 +/- 0.051 MPa, mixed disease: 0.110 +/- 0.044 MPa and aortic valve endocarditis: 0.216 +/- 0.033 MPa, P = 0.002). There was no difference in the number of elastic lamellae in pulmonary artery specimens from the three different aortic valve phenotypes, as well as in the aortic specimens. CONCLUSIONS: No significant differences were observed in the biomechanical properties of pulmonary arteries when compared according to aortic valve phenotype. PMID- 27241050 TI - Long-term outcomes after transcatheter aortic valve implantation: the impact of intraoperative tissue Doppler echocardiography. AB - OBJECTIVES: Transcatheter aortic valve implantation improves survival in patients with severe aortic stenosis who are ineligible for surgical valve replacement; however, not all patients benefit from the procedure. We endeavoured to identify these patients using intraoperative echocardiography and hypothesized that intraoperative left ventricular function in response to the acute afterload reduction during the procedure was related to long-term outcomes. METHODS: We prospectively included 64 patients who were scheduled for transcatheter aortic valve implantation and divided them into responders and non-responders based on their left ventricular intraoperative responses to the acute afterload reduction after valve deployment. Responders were defined by increases of >=20% in left ventricular longitudinal peak systolic velocities determined by tissue Doppler echocardiography. All patients were assessed for the following outcomes at 12 months: cardiac mortality, adverse cardiac events, quality of life, New York Heart Association class, N-terminal pro-brain natriuretic peptide (NT-proBNP) and echocardiography. RESULTS: Thirty-five patients (55%) were classified as responders and 29 patients (45%) as non-responders. Compared with responders, non responders had higher risks of death (28 vs 9%, respectively, P = 0.04) and cardiac events (66 vs 26%, respectively, P < 0.01) during the 12-month follow-up. Significant long-term improvements in quality of life, NT-proBNP and left ventricular function were observed only in the responders. Preoperative risk stratification, intraoperative handling, aortic gradient and valve area were similar between groups. CONCLUSIONS: Intraoperative assessment of left ventricular function by tissue Doppler echocardiography predicted long-term outcomes after transcatheter aortic valve implantation. Our results suggest that a preoperative test of myocardial contractile reserve might improve risk stratification and patient selection prior to the procedure. PMID- 27241052 TI - A microscopic model for chemically-powered Janus motors. AB - Very small synthetic motors that make use of chemical reactions to propel themselves in solution hold promise for new applications in the development of new materials, science and medicine. The prospect of such potential applications, along with the fact that systems with many motors or active elements display interesting cooperative phenomena of fundamental interest, has made the study of synthetic motors an active research area. Janus motors, comprising catalytic and noncatalytic hemispheres, figure prominently in experimental and theoretical studies of these systems. While continuum models of Janus motor systems are often used to describe motor dynamics, microscopic models that are able to account for intermolecular interactions, many-body concentration gradients, fluid flows and thermal fluctuations provide a way to explore the dynamical behavior of these complex out-of-equilibrium systems that does not rely on approximations that are often made in continuum theories. The analysis of microscopic models from first principles provides a foundation from which the range of validity and limitations of approximate theories of the dynamics may be assessed. In this paper, a microscopic model for the diffusiophoretic propulsion of Janus motors, where motor interactions with the environment occur only through hard collisions, is constructed, analyzed and compared to theoretical predictions. Microscopic simulations of both single-motor and many-motor systems are carried out to illustrate the results. PMID- 27241054 TI - Endocrine disruption by Bisphenol A, polychlorinated biphenyls and polybrominated diphenyl ether, in zebra fish (Danio rerio) model: an in silico approach. AB - Endocrine disrupting chemicals may induce adverse health effects in humans and wildlife. Recent studies demonstrate that endocrine disrupting chemicals like Bisphenol A (BPA), polychlorinated biphenyls (PCBs) and polybrominated diphenyl ether (PBDE) affect the reproductive characters shared by wide range of creatures including fish. An attempt was made to evaluate the toxicity of these chemicals on the vitellogenin protein of zebra fish (Danio rerio) using in silico approach. The protein structure of zebra fish vitellogenin was predicted using homology modelling, and the stereochemical quality of the model was validated by Ramachandran plot. The 3-D structure of vitellogenin was docked with the aforementioned chemicals that have demonstrated endocrine-disrupting activity. The pair-wise alignments between vitellogenin with phosvitin, lipovitellin-2 and YGP40 obtained by CLUSTALW alignment suggest that the vitellogenin contained lipovitellin-2- phosvitin- and YGP40-related amino acid sequences. Based on the prediction of CASTp and CLUSTALW, BPA and PCB predominantly interacted with lipovitellin-2 site of the protein, while PBDE interacts predominantly with the YGP40 site of the vitellogenin protein. The results indicate that the endocrine disrupting chemicals (BPA, PCB and PBDE) dock with the vitellogenin cleavage sites lipovitellin-2 and YGP40 that play a crucial role in lipid-protein complex formation in the egg yolk. We hypothesize that these chemicals could potentially impair the egg yolk formation and eventually impact the zebra fish population which occupies an important niche among testing models used in drug discovery and related toxicity studies. PMID- 27241053 TI - Supportive Romantic Relationships as Predictors of Resilience Against Early Adolescent Maternal Negativity. AB - Negativity in parent-child relationships during adolescence has been viewed as a risk factor for teens' future personal and interpersonal adjustment. This study examined support from romantic partners and close friends during late adolescence as protective against maternal negativity experienced during early adolescence. A combination of observational, self-report, and peer-report measures were obtained from a community sample of 97 youth (58 % female), their mothers, closest friends, and romantic partners assessed at ages 13, 18, and 20. Moderating effects suggested a protective effect of romantic support against maternal negativity across a variety of psychosocial outcomes, including depressive symptoms, self-worth, social withdrawal, and externalizing behavior. Protective effects were found even after controlling for initial levels of outcome behavior and observed support from close friends throughout adolescence. Receiving support from a romantic partner may provide teens with new, positive ways of coping with adversity and help them avoid more serious distress that may be predicted from maternal negativity when such support is not available. PMID- 27241056 TI - Changes in uterine artery Doppler velocimetry and circulating angiogenic factors in the first half of pregnancies delivering a small-for-gestational-age neonate. AB - OBJECTIVE: To assess the relationship between longitudinal changes in placental Doppler indices and maternal circulating angiogenic factors in the first half of pregnancy and delivery of a small-for-gestational-age (SGA) neonate, and ascertain whether longitudinal evaluation of these variables improves the prediction achieved by second-trimester cross-sectional evaluation. METHODS: From a prospective cohort of unselected singleton pregnancies undergoing first trimester screening for aneuploidy, 138 were included in this study. Of these, 46 were complicated by SGA (delivering after 34 weeks' gestation with a birth weight < 10th centile) and 92 were appropriate-for-gestational-age (AGA) pregnancies, which were included as controls (ratio 1:2). First-to-second trimester longitudinal changes in uterine artery (UtA) Doppler indices and maternal circulating levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were analyzed. RESULTS: Compared with the AGA group, SGA pregnancies had significantly higher UtA impedance in the first (Z-score: 0.46 vs -0.57; P < 0.001) and second (Z-score: 1.71 vs -0.75; P < 0.001) trimesters. Likewise, the sFlt-1/PlGF ratio was significantly higher in SGA than in AGA pregnancies in the first (98.0 vs 67.9; P = 0.01) and early second (22.4 vs 8.8; P < 0.001) trimesters. The predictive performance of the longitudinal changes in UtA Doppler indices for SGA was significantly lower than that of second-trimester cross-sectional values (area under receiver-operating characteristics curve (AUC), 60.8% vs 84.3%; P = 0.0035). The detection rate of SGA, at a 10% false-positive rate (FPR), was 17.7% by longitudinal changes in UtA Doppler and 56.2% by second-trimester cross-sectional UtA Doppler values. Similarly, the predictive performance of the longitudinal changes in PlGF was significantly lower than that of early second-trimester cross-sectional values (AUC, 71.4% vs 76.5%; P = 0.008). The detection rate of SGA at a 10% FPR was 40.6% when screening by longitudinal changes in PlGF and 52.1% when screening by early second-trimester cross-sectional values. CONCLUSIONS: First- and second trimester UtA Doppler velocimetry and maternal circulating angiogenic markers have clinical utility as a cross-sectional assessment for the identification of pregnancies at high risk of delivering a SGA neonate, however, they do not improve prediction when their longitudinal changes are used. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 27241055 TI - Maps created using a new objective procedure (C-NRT) correlate with behavioral, loudness-balanced maps: a study in adult cochlear implant users. AB - In uncooperative patients, electrical compound action potential (ECAP) thresholds are reliable in predicting T-levels, but are not in determining the C-level profile. The present study aims to assess if the C-level profile can be predicted by a new objective procedure (C-NRT) which uses the amplitude growth function (AGF) and is based on the assumption that equal ECAP amplitudes elicit equal loudness percepts. This is a correlational study conducted in five tertiary care referral hospitals with 21 post-lingually deaf adult cochlear implant users. Two maps were created: a behavioral, bitonal balanced (BB) map and an objective map, in which T-levels were the same as in the BB map, and C-levels were obtained with C-NRT. C-NRT consisted of performing the AGF of nine electrodes, and of setting the current level eliciting a 100 MUV ECAP amplitude as C-level in the map. AutoNRT was also measured. Main outcome measures were correlation between behavioral C-profile level, objective C-profile level, behavioral T-profile level and objective T-profile (AutoNRT) level; disyllabic word recognition scores in quiet and in noise conditions (SNR = + 10 and 0) with both maps. A strong correlation was found between behavioral and C-NRT-derived C-levels (mean per electrode correlation: R = 0.862, p < 0.001). C-NRT could predict behavioral C levels with a greater accuracy than AutoNRT. Word recognition was significantly better with BB maps only in the quiet condition (p = 0.002). C-NRT is more accurate than AutoNRT in predicting the C-level profile in adult cochlear implant users. This finding encourages future application in uncooperative patients, especially in very young children. PMID- 27241057 TI - Tuning the basicity of ionic liquids for efficient synthesis of alkylidene carbonates from CO2 at atmospheric pressure. AB - A strategy to achieve the efficient synthesis of alkylidene carbonates from CO2 at atmospheric pressure by tuning the basicity of ionic liquids was developed. Excellent yields were obtained due to basic ionic liquids' dual roles both as absorbents and as activators. The reaction mechanism was investigated through a combination of NMR spectroscopy, controlled experiments and quantum calculations, indicating the importance of a moderate basicity. PMID- 27241058 TI - COMT val158met moderation of dopaminergic drug effects on cognitive function: a critical review. AB - The relationship between dopamine (DA) tone in the prefrontal cortex (PFC) and PFC-dependent cognitive functions (for example, working memory, selective attention, executive function) may be described by an inverted-U-shaped function, in which both excessively high and low DA is associated with impairment. In the PFC, the COMT val158met single nucleotide polymorphism (rs4680) confers differences in catechol-O-methyltransferase (COMT) efficacy and DA tone, and individuals homozygous for the val allele display significantly reduced cortical DA. Many studies have investigated whether val158met genotype moderates the effects of dopaminergic drugs on PFC-dependent cognitive functions. A review of 25 such studies suggests evidence for this pharmacogenetic effect is mixed for stimulants and COMT inhibitors, which have greater effects on D1 receptors, and strong for antipsychotics, which have greater effects on D2 receptors. Overall, COMT val158met genotype represents an enticing target for identifying individuals who are more likely to respond positively to dopaminergic drugs. PMID- 27241059 TI - Genetic epidemiology of pharmacogenetic variants in South East Asian Malays using whole-genome sequences. AB - Expanding the scope of pharmacogenomic research by including multiple global populations is integral to building robust evidence for its clinical translation. Deep whole-genome sequencing of diverse ethnic populations provides a unique opportunity to study rare and common pharmacogenomic markers that often vary in frequency across populations. In this study, we aim to build a diverse map of pharmacogenetic variants in South East Asian (SEA) Malay population using deep whole-genome sequences of 100 healthy SEA Malay individuals. We investigated the allelic diversity of potentially deleterious pharmacogenomic variants in SEA Malay population. Our analysis revealed 227 common and 466 rare potentially functional single nucleotide variants (SNVs) in 437 pharmacogenomic genes involved in drug metabolism, transport and target genes, including 74 novel variants. This study has created one of the most comprehensive maps of pharmacogenetic markers in any population from whole genomes and will hugely benefit pharmacogenomic investigations and drug dosage recommendations in SEA Malays. PMID- 27241060 TI - HLA-B18 as a risk factor of short-term progression to severe liver fibrosis in HIV/HCV co-infected patients with absent or minimal fibrosis: implications for timing of therapy. AB - Our aim was to analyze the influence of HLA-B haplotypes on liver fibrosis progression in HIV/hepatitis C virus (HCV) co-infected patients. Retrospective longitudinal study including HIV/HCV, non-cirrhotic and HCV treatment-naive patients. The main outcome variable was liver fibrosis progression of at least one stage. One hundred and four patients constituted the study population (F0-F1: 62 (59.6%); F2: 22 (21.2%); F3: 20 (19.2%)). During a median follow-up of 54.5 months (IQR: 26.2-77), 45 patients (43.3%) showed an increase in the stage of liver fibrosis (time to event: 29 (IQR: 14-49.5) months). HLA-B18pos patients more frequently had a higher and faster fibrosis progression rate (73.3%; 24 (IQR: 8-29) months) than HLA-B18neg patients (38.2%; 34.5 (IQR: 14.7-51.2) months). This association was also observed in the development of F3-F4 fibrosis among F0-F2 patients (HLA-B18pos: 69.2%; 18 (6.5-37) months vs HLA-B18neg: 28.2%; 37 (IQR: 19-52) months). These results could impact the timing of HCV therapy in F0-F2 patients. PMID- 27241061 TI - Comparing cytochrome P450 pharmacogenetic information available on United States drug labels and European Union Summaries of Product Characteristics. AB - Regulatory agencies are increasing the pharmacogenomic information in their official drug labeling. However, despite the importance of regulatory harmonization, this implementation may not be running in parallel among major agencies. Comparing labeling of medicines approved by different agencies may identify gaps to solve. Our study compared the cytochrome P450 pharmacogenetic information included in the United States (US) Food and Drug Administration (FDA) drug labels and European Union (EU) Summaries of Product Characteristics (SmPCs). US labels presented significantly more specific pharmacogenetic subheadings (51 vs 26%), more prevalence and pharmacokinetic data for each metabolic phenotype (59 vs 25% and 82 vs 48%, respectively) and more applicable information about dose modifications required (25 vs 5%). Approximately 75% of the US labels evaluated scored higher on the overall quality than the analogous EU SmPCs, and this difference was not associated with the time since the EU SmPCs' last review. To enhance harmonization, regulatory agencies should simultaneously introduce the pharmacogenetic information in their drug labeling. PMID- 27241062 TI - Genetic variations in immunomodulatory pathways to predict survival in patients with locoregional gastric cancer. AB - Immunomodulator-targeting therapies are under development in gastric cancer (GC). However, the role of genes modulating anti-tumor immunity in GC remains poorly understood. We investigated the association of variations in genes involved in immunomodulatory pathways with overall survival (OS) in locoregional GC patients. Extracted genomic DNA was analyzed for 35 functional single-nucleotide polymorphisms in genes, PDCD1, CD274, CTLA4, FOXP3, LAG3, ADORA2A, NT5E and IDO1, in 162 Japanese patients as discovery set and 277 US patients as validation set. The C allele of PDCD1 rs10204525 had univariate and multivariable associations with shorter OS in Japanese cohort (P=0.015, P=0.043, respectively). In US cohort the C allele predicted worse OS (P=0.007). Univariate and multivariable analyses revealed IDO1 rs9657182 associated with OS in the Japanese cohort; moreover, the association was confirmed in the US cohort. Genetic predisposition of the host in the immunomodulators may serve as a prognostic biomarker in patients with locoregional GC. PMID- 27241065 TI - Tubular inverse opal scaffolds for biomimetic vessels. AB - There is a clinical need for tissue-engineered blood vessels that can be used to replace or bypass damaged arteries. The success of such grafts depends strongly on their ability to mimic native arteries; however, currently available artificial vessels are restricted by their complex processing, controversial integrity, or uncontrollable cell location and orientation. Here, we present new tubular scaffolds with specific surface microstructures for structural vessel mimicry. The tubular scaffolds are fabricated by rotationally expanding three dimensional tubular inverse opals that are replicated from colloidal crystal templates in capillaries. Because of the ordered porous structure of the inverse opals, the expanded tubular scaffolds are imparted with circumferentially oriented elliptical pattern microstructures on their surfaces. It is demonstrated that these tailored tubular scaffolds can effectively make endothelial cells to form an integrated hollow tubular structure on their inner surface and induce smooth muscle cells to form a circumferential orientation on their outer surface. These features of our tubular scaffolds make them highly promising for the construction of biomimetic blood vessels. PMID- 27241066 TI - Corrigendum: Genetic Variations of NLR family genes in Behcet's Disease. PMID- 27241063 TI - Influence of ABCB1 and ABCG2 polymorphisms on the antiemetic efficacy in patients with cancer receiving cisplatin-based chemotherapy: a TRIPLE pharmacogenomics study. AB - Resistance to antiemetic treatment with 5-hydroxytryptamine-3 receptor antagonist is an issue. This study evaluated the potential roles of ABCB1 and ABCG2 polymorphisms in antiemetic treatment resistance in patients with cancer previously enrolled in a randomized controlled trial. A total of 156 patients were evaluated for their responses to antiemetic therapy and then subdivided into granisetron or palonosetron groups. The genotypes were evaluated for their association with antiemetic efficacy in each treatment groups. Additional risk factors associated with complete response (CR) were examined using a multivariate regression analysis. No significant associations were identified for genetic polymorphisms in the palonosetron group. In the granisetron group, patients with ABCB1 2677TT and 3435TT genotypes had higher proportion of CR. In addition to ABCB1 polymorphisms, gender and cisplatin dose were associated with granisetron response by univariate analysis. Multivariate logistic regression analysis revealed that the ABCB1 3435C>T polymorphism and cisplatin dose were significant predictors of CR. PMID- 27241064 TI - The pharmacogenomics of osteosarcoma. AB - Osteosarcoma (OS), the most common malignant tumor of bone, is presently treated with multidrug neoadjuvant chemotherapy protocols, which allow to cure 60-65% of patients but also induce toxicity events that cannot be predicted or efficiently prevented. The identification and validation of pharmacogenomic biomarkers is, therefore, absolutely warranted to provide the bases for planning personalized treatments with the aim to increase the therapeutic benefits and to avoid or limit unnecessary toxicities. As several targeted therapies against molecular and immunological markers in OS are presently under clinical investigation, it may be speculated that some new agents for innovative treatments may emerge in the next years. However, the real improvement of therapeutic perspectives for OS is strictly connected to the identification of pharmacogenomic biomarkers that may stratify patients in responders or non-responders and identify those individuals with higher susceptibility to treatment-associated toxicity. This review provides an overview of the pharmacogenomic biomarkers identified so far in OS, which appear to be promising candidates for a translation to clinical practice, after further investigation and/or prospective validation. PMID- 27241067 TI - A pilot study to measure dynamic elasticity of the bladder during urodynamics. AB - AIMS: Previous studies using isolated strips of human detrusor muscle identified adjustable preload tension, a novel mechanism that acutely regulates detrusor wall tension. The purpose of this investigation was to develop a method to identify a correlate measure of adjustable preload tension during urodynamics. METHODS: Patients reporting urgency most or all of the time based on ICIq-OAB survey scores were prospectively enrolled in an extended repeat fill-and-empty urodynamics study designed to identify a correlate of adjustable preload tension which we now call "dynamic elasticity." Cystometric capacity was determined during initial fill. Repeat fills to defined percentages of capacity with passive emptying (via syringe aspiration) were performed to strain soften the bladder. A complete fill with active voiding was included to determine whether human bladder exhibits reversible strain softening. RESULTS: Five patients completed the extended urodynamics study. Intravesical pressure (pves ) decreased with subsequent fills and was significantly lower during Fill 3 compared to Fill 1 (P = 0.008), demonstrating strain softening. Active voiding after Fill 3 caused strain softening reversal, with pves in Fill 4 returning to the baseline measured during Fill 1 (P = 0.29). Dynamic elasticity, the urodynamic correlate of adjustable preload tension, was calculated as the amount of strain softening (or its reversal) per %capacity (Deltaaverage pves between fills/Delta%capacity). Dynamic elasticity was lost via repeat passive filling and emptying (strain softening) and regained after active voiding regulated the process (strain softening reversal). CONCLUSIONS: Improved understanding of dynamic elasticity in the human bladder could lead to both improved sub-typing and novel treatments of overactive bladder. Neurourol. Urodynam. 36:1086-1090, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27241068 TI - Nerve injuries of the upper extremity associated with vascular trauma-surgical treatment and outcome. AB - Peripheral nerve injuries are often associated with injuries of adjacent tissue. As a result of anatomic proximity between nerves and vascular structures, there is a high chance of combined injuries of these structures (23 %). The aim of our study is to describe and analyze associated nerve and vascular injuries of the upper extremity in patients treated at the Clinic of Neurosurgery in Belgrade over a 10-year period. This study included 83 patients that received surgical treatment at the Clinic of Neurosurgery in Belgrade after having been diagnosed with upper extremity nerve injury. The study included all patients that satisfied these criteria over a period of 10 years. The patients with associated vascular injuries, 36 of them, were considered our study group, while 47 patients without associated vascular injuries were considered our control group. Finally, we compared treatment outcome between these groups. The final outcome evaluation was performed 2 years after surgical treatment. In our study group, 84.8 % surgical nerve repair was successful (fair, good, and excellent outcome), while in the control group (patients without vascular injury), surgical nerve repair was successful in 87.9 %. The overall satisfactory neurological outcome (M3-M5) was present in 86.6 % of nerve repairs. Our study shows that there is no significant difference between the treatment outcome in patients with associated nerve and vascular injuries and patients with isolated nerve injuries if they are diagnosed in time and treated appropriately. Successful treatment can only be accomplished through a multidisciplinary approach undertaken by a highly qualified medical team. PMID- 27241069 TI - Benefits of Decreased Mortality Risk from Reductions in Primary Mobile Source Fine Particulate Matter: A Limited Data Approach for Urban Areas Worldwide. AB - We developed an approach to estimate the public health benefits resulting from transportation projects or environmental actions that reduce mobile source fine particulate matter (PM2.5 ) in select urban areas worldwide when input data are limited or when a rapid order-of-magnitude assessment is needed. For a given reduction in direct PM2.5 emissions, we can use this approach to quantify (1) the subsequent reduction in ambient primary PM2.5 concentration in the urban area; (2) the public health benefits associated with mortality risk reductions, measured in terms of avoided premature deaths; and (3) the economic value of the reduced mortality risk. To illustrate our approach, we estimated the impact of a 100-metric-ton reduction in primary PM2.5 mobile source emissions in the year 2010 for 42 large, global cities. Our estimates of public health benefits and their economic value varied by city, as did the sensitivity to key assumptions and inputs. The estimated number of premature deaths avoided per 100-metric-ton reduction in PM2.5 emissions ranged from 12 to 202. City-level variability in these estimates was driven by the magnitude of the reduction in ambient PM2.5 concentration, the size of the urban population, and the baseline PM2.5 concentration. The economic value of mortality risk reductions per 100-metric-ton reduction in PM2.5 emissions ranged from $2 million to $328 million in 2010 U.S. dollars. Income per capita was the most important driver of the variability in the economic values across countries. PMID- 27241070 TI - A Meta-analysis on Resting State High-frequency Heart Rate Variability in Bulimia Nervosa. AB - OBJECTIVE: Autonomic nervous system function is altered in eating disorders. We aimed to quantify differences in resting state vagal activity, indexed by high frequency heart rate variability comparing patients with bulimia nervosa (BN) and healthy controls. METHODS: A systematic search of the literature to identify studies eligible for inclusion and meta-analytical methods were applied. Meta regression was used to identify potential covariates. RESULTS: Eight studies reporting measures of resting high-frequency heart rate variability in individuals with BN (n = 137) and controls (n = 190) were included. Random effects meta-analysis revealed a sizeable main effect (Z = 2.22, p = .03; Hedge's g = 0.52, 95% CI [0.06;0.98]) indicating higher resting state vagal activity in individuals with BN. Meta-regression showed that body mass index and medication intake are significant covariates. DISCUSSION: Findings suggest higher vagal activity in BN at rest, particularly in unmedicated samples with lower body mass index. Potential mechanisms underlying these findings and implications for routine clinical care are discussed. Copyright (c) 2016 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 27241071 TI - Characteristics and outcomes of critically ill children following emergency transport by a specialist paediatric transport team. AB - AIM: We compared acute patients admitted to a single paediatric intensive care unit (PICU) following an emergency transfer by a specialist paediatric transport team and by other routes. METHODS: This was a retrospective descriptive register based study of consecutive admissions to a tertiary PICU in Sweden from 1 January 2008 to 31 December 2013. We compared the general characteristics of the cohorts, together with predicted death rates (PDR), PICU mortality, 30-day mortality, PICU length of stay (PICU LOS) and resource use. RESULTS: Of the 3665 nonelective admissions, 221 patients received emergency transport from referring hospitals to the PICU by the specialist paediatric transport team. Their median age was lower (146 versus 482 days), PDR was higher (5.58% versus 1.39%), PICU LOS was longer (4.24 days versus 1.06 days), and they received more PICU-specific therapies. The standardised mortality ratio did not differ between the cohorts, and the PICU mortality was lower than predicted in both groups. The transport distance and mode of transport did not influence survival. CONCLUSION: Children admitted to the PICU following emergency transfers by the specialist paediatric transport team were younger, sicker, received more PICU-specific therapies and had longer PICU LOS than other acutely admitted critically ill patients. This indicates that these transfers were appropriate. PMID- 27241072 TI - Variation in the c-axis conductivity of multi-layer graphene due to H2 exposure. AB - The variation of the c-axis conductivity of a multilayer graphene (MLG) as a function of H2 pressure from vacuum to 20 bar has been investigated. MLG was connected to the electrodes vertically using a wet transfer process. After exposure to H2 gas pressure up to 20 bar, the chemisorption of dissociated atomic hydrogen on MLG affects its electrical and structural properties. The formation of C-H bonds causes a decoupling of graphene layers, and then interferes with charge transfer through the out of plane. As a result, the c-axis conductivity decreases. Furthermore, the electron doping effect and the decoupling of the layers were confirmed using Raman spectroscopy. Hydrogenated carbons induce a defect structure of MLG which results in the expansion of layers. We observed a 43.54% increase in the thickness of the MLG after H2 exposure using atomic force microscopy. PMID- 27241073 TI - Spermatogonial Nature of the Germ Cell Component of Canine Testicular Mixed Germ Cell-Sex Cord Stromal Tumours. AB - The present study has characterized the germ cell component of canine testicular mixed germ cell-sex cord stromal tumours (MGSCTs) by examining the histological nature and histochemical and immunohistochemical features using gonocytic and spermatogonial cellular markers, c-Kit, placental alkaline phosphatase (PLAP), protein gene product 9.5 (PGP9.5), Sal-like protein 4 (SALL4), and the periodic acid-Schiff (PAS) reaction. Histologically, all 45 examples of MGSCTs were classified as spermatocytic seminomas (SSs) and Sertoli cell tumours in combination. The germ cell component of all MGSCTs was negative by PAS staining. Immunohistochemically, PLAP immunoreactivity was lacking in the germ cell component of all MGSCTs, which is not consistent with a gonocytic origin. The germ cell component was positive for PGP9.5 and SALL4 in all MGSCTs and positive for c-Kit in 53% of MGSCTs, which is consistent with the phenotype of spermatogonia. Furthermore, the germ cell component in 71% of MGSCTs had moderate immunoreactivity for SALL4, which is suggestive of a spermatogonial phenotype. Conversely, 29% of cases had a minor population of germ cells showing strong SALL4 immunoreactivity, suggesting a phenotype similar to prespermatogonia. The results suggest that the germ cell component of canine MGSCTs is morphologically classified as SS, with the majority of cases showing the spermatogonial phenotype and some cases containing a small population of prespermatogonia. PMID- 27241074 TI - [Hereditary thrombophilia testing and its therapeutic impact on venous thromboembolism disease: Results from a retrospective single-center study of 162 patients]. AB - INTRODUCTION: Venous thromboembolic disease is a multifactorial, frequently recurrent pathology, whose treatment is based on anticoagulation. As part of the etiological investigation, screening for an inherited thrombophilia is framed by French guidelines published in 2009. The aim of the study is to assess the contribution of inherited thrombophilias testing in common practice. METHOD: This is a retrospective single-center observational study. Over a period of a year, all records of patients who were screened for a hereditary thrombophilia were analyzed. The conformity of the indication of hereditary thrombophilia workup in balance with the guidelines, its completeness and therapeutic impact were studied. RESULTS: Of the 494 records analyzed, 225 were related to venous thromboembolism. Among them, there were 162 pulmonary embolisms or deep vein thrombosis of the lower limbs. In this subgroup, 57 % of records complied with guidelines and 69 % were complete. Thirty-four thrombophilias were highlighted: 4 protein S deficiencies, 1 protein C deficiency, 4 combined deficiencies, 17 factor V Leiden mutations and 8 factor II G20210A mutations. For one patient, hereditary thrombophilia diagnosis had profoundly changed the curative therapeutic approach. CONCLUSION: Adherence to French guidelines remains limited. In clinical practice, diagnosis of hereditary thrombophilia has little impact on the curative therapeutic approach in venous thromboembolic disease. PMID- 27241075 TI - [Paravertebral masses]. PMID- 27241076 TI - [Giant cell aortitis complicated by AA amyloidosis diagnosed with imaging techniques: Report of a case]. AB - INTRODUCTION: AA amyloidosis is a common but severe complication of many chronic inflammatory processes of infectious, autoimmune, or neoplastic origin. It frequently leads to renal damage, often presenting as a nephrotic syndrome. Giant cell arteritis is a common inflammatory arteritis in elderly people, but rarely complicated by AA amyloidosis. CASE REPORT: We report an 87-year-old female who presented with a nephrotic syndrome and a chronic inflammation, in whom the kidney biopsy showed secondary amyloidosis. Etiological investigations concluded an amyloidosis related to giant cell pan-aortitis, whereas there were no typical clinical signs for this diagnosis. Outcome was rapidly unfavourable despite the treatment. CONCLUSION: In case of chronic inflammation of unknown origin in elderly patients, aortitis complicating a giant cell arteritis should be looked for with imaging techniques, as clinical diagnosis of this presentation is difficult, whereas delayed diagnosis exposes to severe or fatal issues. PMID- 27241077 TI - [Antithyroid agents related agranulocytosis: Literature review]. AB - The antithyroid agents (carbimazole, methimazole, thiamazole, propylthiouracil and benzylthiouracile) are the drug class that is associated with a high risk of agranulocytosis. Acute and profound (<0.5*10(9)/L) isolated neutropenia occurring in a subject treated with antithyroid agents should be considered as a drug induced agranulocytosis, until proven otherwise. The clinical spectrum ranges from discovery of acute severe but asymptomatic neutropenia, to isolated fever, localized infections (especially ear, nose and throat, or pulmonary) or septicemia. With an optimal management (discontinuation of antithyroid agents, antibiotics in the presence of fever or a documented infection, or use of hematopoietic growth factor) the current mortality is close to 2%. PMID- 27241078 TI - [Combined heart and kidney transplantation in Fabry's disease: Long-term outcomes in two patients]. AB - INTRODUCTION: Fabry disease is a lysosomal storage disorder linked to an alpha galactosidase A deficiency that can lead to heart and kidney failure. There is little data about the prognosis of patients who undergo a combined heart and kidney transplantation. CASE REPORTS: Two brothers who were diagnosed with Fabry disease after the age of 30 years underwent a combined heart and kidney transplantation at respectively 49 and 42 years of age because of a severe hypertrophic cardiomyopathy with end stage renal failure. They are alive respectively 4 and 9 years after the transplantation. No recurrence of the disease in the transplanted organs has been found. CONCLUSION: Combined heart and kidney transplantation in Fabry disease is an efficient therapy for the cardiomyopathy and kidney failure. Its prognosis can be good when the patients are carefully selected. However, an early diagnosis is critical in order to avoid a procedure associated with a high perioperative mortality. PMID- 27241079 TI - Diminazene aceturate, an angiotensin-converting enzyme II activator, prevents gastric mucosal damage in mice: Role of the angiotensin-(1-7)/Mas receptor axis. AB - The angiotensin (Ang) II converting enzyme (ACE II) pathway has recently been shown to be associated with several beneficial effects in various organisms, including gastroprotection. ACE II is responsible for converting Ang II into an active peptide, Ang-(1-7), which in turn binds the Mas receptor. Recent studies have shown that diminazene aceturate (Dize) a trypanocidal used in animals, activates ACE II. Thus, in this study, we aimed to evaluate the gastroprotective effects of Dize via the ACE II/Ang-(1-7)/Mas receptor pathway against gastric lesions induced by ethanol and acetic acid in mice. The results showed that Dize could promote gastric protection via several mechanisms, including increased levels of antioxidants and anti-inflammatory factors (e.g., decreasing tumor necrosis factor and interleukin-6 expression and reducing myeloperoxidase activity), maturation of collagen fibers, and promotion of re-epithelialization and regeneration of gastric tissue in different injury models. Thus, Dize represents a novel potential gastroprotective agent. PMID- 27241080 TI - [Surveillance of work-related suicide in France: An exploratory study]. AB - BACKGROUND: Despite a large media coverage of the phenomenon, the number of work related suicides is currently unknown in France. There are nevertheless some data available to document this important issue. The aim of this study was to explore the feasibility of an epidemiological surveillance system for work-related suicides designed to quantify and describe work-related suicides mainly according to economic sectors and occupational categories. METHODS: Existing data sources in France were identified and evaluated for their relevance and their potential use in a multi-sources surveillance system. A regional pilot study was performed using the main relevant sources identified to investigate different aspects of the system design. RESULTS: Four major data sources were identified to be used to describe work-related suicides: death certificates, social insurance funds, data collected by the officers of the labor inspectorate and data collected from autopsy reports in forensic departments. The regional pilot study gave an estimate of 28 cases of work-related suicide in two years. CONCLUSION: The findings point out the difficulties involved and the criteria for successful implement of such a system. The study provides some solutions for carrying out this system, the achievement of which will depend upon particular resources and partners' agreements. Recommendations for the next steps have been made based on this work, including possible collaboration with forensic departments, which collect essential data for surveillance. PMID- 27241081 TI - Albumin-coated SPIONs: an experimental and theoretical evaluation of protein conformation, binding affinity and competition with serum proteins. AB - The variety of nanoparticles (NPs) used in biological applications is increasing and the study of their interaction with biological media is becoming more important. Proteins are commonly the first biomolecules that NPs encounter when they interact with biological systems either in vitro or in vivo. Among NPs, super-paramagnetic iron oxide nanoparticles (SPIONs) show great promise for medicine. In this work, we study in detail the formation, composition, and structure of a monolayer of bovine serum albumin (BSA) on SPIONs. We determine, both by molecular simulations and experimentally, that ten molecules of BSA form a monolayer around the outside of the SPIONs and their binding strength to the SPIONs is about 3.5 * 10(-4) M, ten times higher than the adsorption of fetal bovine serum (FBS) on the same SPIONs. We elucidate a strong electrostatic interaction between BSA and the SPIONs, although the secondary structure of the protein is not affected. We present data that supports the strong binding of the BSA monolayer on SPIONs and the properties of the BSA layer as a protein resistant coating. We believe that a complete understanding of the behavior and morphology of BSA-SPIONs and how the protein interacts with SPIONs is crucial for improving NP surface design and expanding the potential applications of SPIONs in nanomedicine. PMID- 27241082 TI - Analysis of mixing conditions and multistage irradiation impact on NOx removal efficiency in the electron beam flue gas treatment process. AB - In the process of electron beam flue gas treatment (EBFGT), most energy is spent on NOx removal. The dose distribution in the reactor is not uniform and the flue gas flow pattern plays an important role in the process efficiency. It was found that proper construction of the reactor may increase the energy efficiency of the process. The impact of the number of irradiation stages and mixing conditions on NOx removal efficiency was investigated for an ideal case and a practical solution was presented and compared with previously known EBFGT reactor constructions. The research was performed by means of computational fluid dynamics methods in combination with empirical Wittig formula. Two versions of dose distribution were taken for calculations. The results of the research show that for an ideal case, application of multistage irradiation and interstage mixing may reduce the energy consumption in the process by up to 39%. On the other side, simulation of reactor construction modification for two-stage irradiation results in 25% energy consumption reduction. The results of presented case study may be applied for improving the existing reactors and proper design of future installations. PMID- 27241083 TI - Doing research drawing on the philosophy of existential hermeneutic phenomenology. PMID- 27241084 TI - Phenomenon of dual- and single-retention behaviors of solutes and its validation by computational simulation in linear programmed temperature gas chromatography. AB - The current theory of programmed temperature gas chromatography considers that solutes are focused by the stationary phase at the column head completely and does not explicitly recognize the different effects of initial temperature (To ) and heating rate (rT ) on the retention time or temperature of a homologue series. In the present study, n-alkanes, 1-alkenes, 1-alkyl alcohols, alkyl benzenes, and fatty acid methyl esters standards were used as model chemicals and were separated on two nonpolar columns, one moderately polar column and one polar column. Effects of To and rT on the retention of nonstationary phase focusing solutes can be explicitly described with isothermal and cubic equation models, respectively. When the solutes were in the stationary phase focusing status, the single-retention behavior of solutes was observed. It is simple, dependent upon rT only and can be well described by the cubic equation model that was visualized through four sequential slope analyses. These observed dual- and single-retention behaviors of solutes were validated by various experimental data, physical properties, and computational simulation. PMID- 27241085 TI - Binge drinking concurrent with anal intercourse and condom use among men who have sex with men. AB - Men who have sex with men (MSM) are the demographic group most severely affected by HIV in the USA. Global association studies have shown that MSM who binge drink are more likely to engage in risky sexual behaviors and day- and event-level analyses have linked binge drinking to sexual risk behavior on specific days and during specific sexual encounters. Despite this strong foundation of research, no studies have examined the association between the frequency of situational binge drinking (i.e., binge drinking concurrent with sexual activity) and aggregated sexual risk over periods of longer duration. We used multivariable logistic regression to assess the relationship between situational binge drinking (i.e., binge drinking concurrent with anal intercourse) and condomless anal intercourse (CAI) and among a cross-sectional sample of 124 MSM in San Francisco, CA. There was a positive relationship between frequency of situational binge drinking and CAI (1-5 times vs. never: adjusted odds ratio = 2.78, 95% CI = 1.01-7.63; 6-10 times vs. never: 6.19, 1.27-30.22; more than 10 times vs. never: 11.88, 1.31 107.60). By filling a methodological gap and complementing existing global and event-level analyses, this positive situational relationship strengthens the evidence linking binge drinking and sexual risk, enhances the comparability of the existing literature, and further suggests that the integration of dual strategies that aim to prevent HIV and reduce binge drinking may be warranted. PMID- 27241086 TI - High dose, high risk? What updated evidence tells us about chemotherapy dosing in early breast cancer. PMID- 27241087 TI - Usefulness of Embolization for Iatrogenic Dural Arteriovenous Fistula Associated with Recurrent Chronic Subdural Hematoma: A Case Report and Literature Review. AB - BACKGROUND: Refractory chronic subdural hematomas due to iatrogenic dural arteriovenous fistulas (dAVFs) are difficult to treat. We report our experience and propose a guideline on basis of a literature review for the usefulness of embolization of middle meningeal artery (MMA) for the treatment of the same. CASE DESCRIPTION: We report a case with right hemiparesis and aphasia 1 month after a fall from a bicycle. Computed tomography scan of the head showed left chronic subdural hematoma, which was evacuated by burr-hole drainage. The postoperative course was complicated by reaccumulation within short period of time. On superselective digital subtraction angiography of MMA, iatrogenic dAVF was found on left side. We embolized successfully it using n-butyl cyanoacrylate after a third irrigation. No reaccumulation found in the postoperative period or at last follow-up. We propose treatment protocol based on our experience and literature review. CONCLUSION: Refractory chronic subdural hematoma with reaccumulation within a short interval should be subjected to digital subtraction angiography of the MMA. Embolization of ipsilateral MMA is safe, effective, and a useful option for the treatment of iatrogenic dAVF and resolution of hematoma. PMID- 27241089 TI - Disposal of Occipital Condyle in Far Lateral Approach for Ventrolateral Foramen Magnum Meningiomas. AB - OBJECTIVE: To investigate the necessity of drilling the occipital condyle in a tailored far lateral approach for resection of ventrolateral foramen magnum meningiomas (FMMs). METHODS: Clinical data of 15 patients with ventrolateral FMMs who underwent surgery during a 6-year period were reviewed retrospectively. RESULTS: A retrocondylar approach was performed in 8 cases (6 above the vertebral artery [VA] and 2 below the VA) in which the dural attachment was surgically accessible with no restriction of the initial part of the V4 segment of the VA, and a partial transcondylar approach was performed in 7 cases on both sides of the VA where the dural attachment associated with the VA auxiliary space was reached by superolateral displacement of the VA by drilling of the condyle. Exposure of the V3 segment of the VA was performed in all patients, but no circumcision of the dural ring along with transposition of the VA was needed. Simpson grade II resection was achieved in all patients. Postoperative complications were encountered in 20% of patients, predominantly associated with cranial nerve impairment. No tumor recurrence was demonstrated during follow-up lasting 7-68 months (mean 29.2 months). CONCLUSIONS: The surgical approach for ventrolateral FMMs varies depending on the location of dural attachment with reference to VA dural entry. Bone removal is warranted in FMMs arising from both sides of the VA to allow superolateral displacement of the VA to some extent, improving surgical accessibility to the hidden VA auxiliary space and achieving a more radical tumor resection. It should be a reasonable alternative to the conventional aggressive VA transposition in cases of ventrolateral FMMs. PMID- 27241088 TI - Secretory Meningiomas: Increased Prevalence of Seizures Secondary to Edema Formation in a Rare Histologic Subtype. AB - OBJECTIVE: Secretory meningioma (SM) is a rare histologic subtype known to cause disproportional peritumoral brain edema. Although meningiomas are defined by slow growth and mostly manifest with benign clinical symptoms, SMs can cause life threatening deterioration. The aim of this study was to characterize the potential pitfalls in treatment of SMs by illustrating their characteristic clinical features. METHODS: We analyzed 69 patients with SM who underwent surgery at our institution and compared them with a matched nonsecretory meningioma cohort. Retrospective data were analyzed for frequency of seizures as the first presenting symptom, maximum corticosteroid use, intensive care unit stay, and hospital stay. In addition, histologic and radiographic data were evaluated for the extent of peritumoral brain edema formation, tumor location, and tumor size and correlated to clinical presentation. RESULTS: Seizures were observed at a significantly higher rate as the first presenting symptom leading to clinical admission in patients with SM (33.3%) compared with the matched nonsecretory meningioma cohort (13%, P = 0.008). In patients with SM, seizures were associated with increased edema formation, whereas seizures in patients with nonsecretory meningioma correlated with tumor size (P = 0.007). The clinically more complicated course in patients with SM was reflected by increased demand for corticosteroids and a prolonged intensive care unit stay (P < 0.001). SM further showed a higher recurrence rate of 35.9% compared with a cohort of 320 World Health Organization grade I meningiomas resected at our institution (P < 0.001). CONCLUSIONS: Our results illustrate the complicated clinical course of this rare histologic meningioma subtype. The increased frequency of seizures may enable raised awareness of clinicians for potential complications and treatment adjustments perioperatively early at clinical admission. PMID- 27241090 TI - Factors Affecting Outcome in Treatment of Chronic Subdural Hematoma in ICU Patients: Impact of Anticoagulation. AB - BACKGROUND: The use of anticoagulants and older age are the main risk factors for chronic subdural hematoma (CSDH). Because the age of the population and use of anticoagulants are increasing, a growing number of CSDH cases is expected. To address this issue, we analyzed the impact of anticoagulants on postsurgical outcome in patients in the intensive care unit (ICU). METHODS: Demographic data, coagulation parameters, surgical details, radiologic appearance of hematoma, Glasgow Coma Scale (GCS) score on admission, and Glasgow Outcome Scale (GOS) score on discharge were retrieved and retrospectively analyzed in 98 patients with CSDH treated in the neurosurgical ICU using correlation coefficient tests and multivariate analysis test. RESULTS: Overall outcome was good (GOS score 4 and 5) in 55.1% of patients. Overall mortality was 9.1%. There was a correlation between GCS score on admission and GOS score. There was no correlation between hematoma thickness/radiologic appearance and impaired coagulation. Disturbance in thrombocyte function (usually resulting from aspirin intake) correlated with improved outcome, whereas warfarin-related coagulopathy correlated with poor recovery. Nevertheless, patients with thrombocytopathy presented with better initial GCS scores. Neither hematoma size nor recurrence rate affected the outcome. CONCLUSIONS: The size of CSDH was not associated with poor outcome and is not necessarily determined by the use of anticoagulants. Coagulopathy does not rule out a good outcome, but the impact of anticoagulation on treatment results in CSDH varies between the main groups of drugs (warfarin vs. antiplatelet drugs). Patients in good neurologic condition on ICU admission have better chances of recovery. PMID- 27241091 TI - Basal Ganglia Germinoma in an Adult. AB - Intracranial germinoma is a rare primary brain cancer, usually located within the midline and mainly affecting Asian pediatric patients. Interestingly, we report here the peculiar case of a young North-African adult patient suffering from a basal ganglia germinoma without the classical ipsilateral cerebral hemiatrophy associated with this location. PMID- 27241092 TI - Alarm Value of Somatosensory Evoked Potential in Idiopathic Scoliosis Surgery. AB - BACKGROUND: Somatosensory evoked potential (SSEP) monitoring is performed to examine postoperative clinical findings when a monitoring event was noted intraoperatively and to ascertain the alarm threshold for intraoperative neural damage. METHODS: The tibial SSEP of both lower limbs was recorded intraoperatively in patients with idiopathic scoliosis. Change of SSEP amplitude as opposed to the baseline was categorized into 4 levels: decrease <40%, decrease of 40%-50%, decrease of 50%-60%, and decrease >60%. Postoperative neurologic function of patients was examined and compared with SSEP data. RESULTS: The baseline amplitude before incision was significantly different from the amplitude after spine exposure. An amplitude reduction of >60% during scoliosis correction procedures was observed in 6 legs, and 4 of them had postoperative deterioration in motor status. As the measure of threshold for alarm, an amplitude reduction of >50% compared with baseline resulted in more false-positive outcomes compared with amplitude attenuation of >60%. CONCLUSIONS: Compared with the traditional SSEP baseline before skin incision, the baseline acquired after spine exposure results in more accurate monitoring. A >60% decrease in SSEP amplitude could be a more suitable alarm threshold. PMID- 27241093 TI - Intermittent Feet Dorsiflexion as a Simple Trick to Improve Cervical Fluoroscopic Visualization. AB - BACKGROUND: Anterior cervical surgery is routinely performed using fluoroscopy. Visualizing the lower cervical levels can be challenging, particularly in obese, muscular, and broad-shouldered patients. We found that grabbing both feet of the patient at the level of the metatarsals and cranially pushing the feet, creating dorsiflexion at the ankle joints, seems to increase the number of fluoroscopically visualized cervical levels. We aimed to measure the average change in fluoroscopically visualized levels when performing this maneuver. METHODS: In 10 consecutive patients undergoing an anterior cervical discectomy and fusion procedure, we counted the number of fluoroscopically visualized cervical levels. Visible cervical levels in lateral fluoroscopic cervical images that were taken with and without the execution of the aforementioned maneuver were counted by 2 blinded observers. RESULTS: Performing this maneuver added on average almost 1 vertebral body height to the fluoroscopic image. The additional number of fluoroscopically visible cervical levels was significantly higher in patients <50 years old but was not affected by sex or body mass index. CONCLUSIONS: We propose a simple, convenient, and effective technique to increase the number of visualized cervical levels on lateral cervical fluoroscopy. This maneuver may have some advantages compared with other commonly used techniques. PMID- 27241094 TI - Measurement of Bone Flap Surface Area and Midline Shift to Predict Overall Survival After Decompressive Craniectomy. AB - BACKGROUND: There is uncertainty about the optimal method for measuring the decompressive craniectomy (DC) surface area and how large the DC should be. METHODS: A radiological technique for measuring the surface area of removed bone flaps in a series of 73 DCs was developed. Preoperative and early postoperative computed tomography scans of each patient were evaluated. Midline shift (MLS) was considered the key factor for successful DC and was assigned to either normal (0 4 mm) or pathological (>=5 mm) ranges. The association between postoperative MLS and patient survival at 12 months was assessed. RESULTS: Measurements of all removed bone flaps yielded a mean surface area of 7759 mm2. The surface area of the removed bone flap did not influence survival (surviving 7643 mm2 vs. deceased 7372 mm2). The only factor associated with survival was reduced postoperative MLS (P < 0.034). Risk of death was 14.4 (3.0-70.1)-fold greater in patients with postoperative shift >=5 mm (P < 0.001). CONCLUSION: The ideal surface area for "large" square bone flaps should result in an MLS of <5 mm. Enlargement of the craniectomy edges should be considered for patients in whom MLS >=5 mm persists according to early postoperative computed tomography scans. PMID- 27241095 TI - Percutaneous Fully Endoscopic Interlaminar Approach to the Filum Terminale: A Cadaveric Study. AB - OBJECTIVE: To investigate the utility, safety, and feasibility of a novel endoscopic technique for the visualization and surgical manipulation of the filum terminale in fresh postmortem adult human cadavers. METHODS: The filums from 18 fresh postmortem adult human cadavers were explored with a percutaneous fully endoscopic interlaminar approach. After the filum was identified and the nerve roots were dissected away from it, the filum was cut. A specimen was sent for histopathologic examination. RESULTS: In 15 of 18 (83%) cadavers, the filum terminale could be visualized. A specimen for histopathologic examination was obtained from 11 of 15 (73%) visualized filums. Histopathologic examination revealed that 2 of them were fatty filums, 7 were normal filums, and 2 were peripheral nerves. CONCLUSIONS: We have described a successful and feasible percutaneous fully endoscopic interlaminar approach to the filum terminale. This technique provides a smaller skin incision, narrow durotomy, and minimal tissue damage. Animal studies are necessary to prove the feasibility and safety of our method before clinical use. PMID- 27241096 TI - Treatment of Recurrent Intracranial Aneurysms After Clipping: A Report of 23 Cases and a Review of the Literature. AB - OBJECTIVE: There are no established treatment strategies for aneurysms that recur after clipping. In this study, we present cases of patients who experienced recurrent aneurysms after clipping and subsequently underwent surgical intervention. METHODS: Between 2004 and 2015, we surgically treated 23 aneurysms that recurred at a previously clipped site. Patient characteristics and clinical history were retrospectively reviewed. RESULTS: Patients included 19 women and 4 men 45-81 years old. Aneurysms recurred 3-31 years (mean, 15.4 years) after the initial operation. For 18 cases, the first clinical presentation was a subarachnoid hemorrhage; aneurysms were incidentally diagnosed in 5 patients. Aneurysm locations were as follows: 9 on the internal carotid artery; 4 on the middle cerebral artery; 7 on the anterior communicating artery; 2 on the distal anterior cerebral artery; and 1 on the basilar artery. The reasons for retreatment included subarachnoid hemorrhage (n = 9) and aneurysm regrowth detected on follow-up examinations (n = 14). Endovascular treatment was performed in 10 cases, and direct surgery was performed in 13 cases (clipping in 8, clipping or trapping with bypass in 5). Various complex vascular reconstructions, including high-flow bypass and intracranial-intracranial in situ bypass, were performed for recurrent aneurysms. CONCLUSIONS: In our experience, coil embolization is a safe and effective procedure for treating recurrent aneurysms. When cases are unsuitable for coil embolization, surgical treatment often requires neurosurgeons not only to overcome the general technical difficulty of reoperative clipping but also to perform challenging vascular reconstruction. PMID- 27241097 TI - Topographic Surgical Anatomy of the Parasylvian Anterior Temporal Artery for Intracranial-Intracranial Bypass. AB - BACKGROUND: The anterior temporal artery (ATA) is an appealing donor artery for intracranial-intracranial bypass procedures. However, its identification may be difficult. Current literature lacks useful landmarks to help identify the ATA at the surface of the sylvian fissure. The objective of this study was to define the topographic anatomy of the cortical segment of the ATA relative to constant landmarks exposed during the pterional approach. METHODS: The temporopolar artery (TPA), ATA, and middle temporal artery (MTA) were examined in 16 cadaveric specimens. The topographic anatomy and key landmarks of the arteries at the sylvian fissure were recorded. The distance between the point of emergence from the sylvian fissure to the lesser sphenoid wing and anterior tip of the temporal lobe was measured. The features of the inferior frontal gyrus relative to each of the arteries at the sylvian fissure were also recorded. RESULTS: The average distances from the lesser sphenoid wing to the TPA, ATA, and MTA were 3.7 mm, 21.2 mm, and 37 mm. The mean distances from the temporal pole were TPA, 14.7 mm; ATA, 32.0 mm; and MTA, 45.4 mm. The differences between the average distances were statistically significant (P < 0.0001). The ATA most frequently faced pars triangularis, whereas the TPA always faced pars orbitalis. The MTA was always found posterior to the junction of pars triangularis and pars opercularis. CONCLUSIONS: This article provides topographic evidence for efficient identification of the ATA in the parasylvian space. The key relationship and landmarks identified in this study may increase efficiency and safety when harvesting the ATA for intracranial-intracranial bypass. PMID- 27241098 TI - A new Subcutaneously Anchored Device for Securing External Cerebrospinal Fluid Catheters: our Preliminary Experience. AB - BACKGROUND: Accidental dislocation or removal is a well-known complication of external cerebrospinal fluid (CSF) drainage in daily clinical practice. At present, no data about the incidence of such complications are available in the scientific literature. SecurAcath (Interrad Medical, Plymouth, Minnesota, USA) is a subcutaneously anchored device recently adopted for securement of central venous catheters, known to be highly effective (and cost-effective) in reducing the risk of catheter dislodgement and/or accidental removal. METHODS: We report our preliminary experience with the use of SecurAcath to secure CSF drainage, either ventricular or spinal, to the skin. RESULTS: SecurAcath was used in 29 consecutive patients (age range: 3 weeks-16 years, median age 6.3 years). In particular, the device was used for 25 ventricular catheters (a patient received 2 catheters in the same procedure for bilateral brain abscess) and 5 spinal drainages. Period in place ranged from 1-4 weeks (median 22 days). No complication related to the use of the device was observed, in particular there was no case of dislocation or accidental removal of the catheter. The removal procedure was extremely easy. The device has proven its utility also in 3 cases requiring an adjustment of the length of the catheter. CONCLUSIONS: In our experience, SecurAcath is a safe and effective device to secure CSF external catheters to the skin, with several relevant advantages: its placement and maintenance are easy; it may stay in place for the entire duration of the catheter; it allows a more complete antisepsis of the exit site, thus reducing local skin complications; it eliminates the risk of suture-related needlestick injuries. PMID- 27241099 TI - Clinical and Anatomic Insights From a Series of Ethmoidal Dural Arteriovenous Fistulas at Barrow Neurological Institute. AB - BACKGROUND: Ethmoidal dural arteriovenous fistulas (dAVFs) have a malignant natural history and an anatomy that make endovascular therapy challenging. Their uniqueness begs for stratified analyses, but this has largely been precluded by their rarity. We sought to summarize the anatomic, presentation, treatment approaches, and clinical outcomes of patients with these lesions. METHODS: We reviewed our prospectively maintained institutional database to identify patients diagnosed with ethmoidal dAVFs from January 1, 2000, to December 31, 2015. We evaluated demographic, presentation, angiographic, treatment, and follow-up data. RESULTS: In total, 27 patients with ethmoidal dAVFs underwent endovascular and/or surgical treatment. Mean patient age was 62 years old and there was a male sex predilection (67% men; 2:1 male-female ratio). All dAVFs exhibited direct cortical venous drainage; venous ectasia was present in 59% of cases. Of the dAVFs, 30% drained posteriorly into the basal vein of Rosenthal or the sylvian veins. Embolization with casting of the draining vein was successful in 2 of 9 cases (22%), including 1 successful transvenous case. There were no clinical or permanent complications from embolization; specifically, no patients experienced visual loss after treatment. Surgical treatment with successful dAVF obliteration was carried out in 24 of 24 patients (100%). One patient declined surgical treatment after attempted endovascular embolization. There were no permanent complications after surgical treatment and no cases of wound infection or cerebrospinal fluid leakage. CONCLUSIONS: Surgical disconnection remains the gold standard in the treatment of ethmoidal dAVFs. Embolization is a consideration for well-selected cases with favorable arterial or venous access anatomy. PMID- 27241101 TI - Distinct subcellular localization of alternative splicing variants of EFA6D, a guanine nucleotide exchange factor for Arf6, in the mouse brain. AB - EFA6D (guanine nucleotide exchange factor for ADP-ribosylation factor 6 [Arf6]D) is also known as EFA6R, Psd3, and HCA67. It is the fourth member of the EFA6 family with guanine nucleotide exchange activity for Arf6, a small guanosine triphosphatase (GTPase) that regulates endosomal trafficking and actin cytoskeleton remodeling. We propose a classification and nomenclature of 10 EFA6D variants deposited in the GenBank database as EFA6D1a, 1b, 1c, 1d, 1s, 2a, 2b, 2c, 2d, and 2s based on the combination of N-terminal and C-terminal insertions. Polymerase chain reaction analysis showed the expression of all EFA6D variants except for variants a and d in the adult mouse brain. Immunoblotting analysis with novel variant-specific antibodies showed the endogenous expression of EFA6D1b, EFA6D1c, and EFA6D1s at the protein level, with the highest expression being EFA6D1s, in the brain. Immunoblotting analysis of forebrain subcellular fractions showed the distinct subcellular distribution of EFA6D1b/c and EFA6D1s. The immunohistochemical analysis revealed distinct but overlapping immunoreactive patterns between EFA6D1b/c and EFA6D1s in the mouse brain. In immunoelectron microscopic analyses of the hippocampal CA3 region, EFA6D1b/c was present predominantly in the mossy fiber axons of dentate granule cells, whereas EFA6D1s was present abundantly in the cell bodies, dendritic shafts, and spines of hippocampal pyramidal cells. These results provide the first anatomical evidence suggesting the functional diversity of EFA6D variants, particularly EFA6D1b/c and EFA6D1s, in neurons. J. Comp. Neurol. 524:2531-2552, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27241100 TI - LIGHT/IFN-gamma triggers beta cells apoptosis via NF-kappaB/Bcl2-dependent mitochondrial pathway. AB - LIGHT recruits and activates naive T cells in the islets at the onset of diabetes. IFN-gamma secreted by activated T lymphocytes is involved in beta cell apoptosis. However, whether LIGHT sensitizes IFNgamma-induced beta cells destruction remains unclear. In this study, we used the murine beta cell line MIN6 and primary islet cells as models for investigating the underlying cellular mechanisms involved in LIGHT/IFNgamma - induced pancreatic beta cell destruction. LIGHT and IFN-gamma synergistically reduced MIN6 and primary islet cells viability; decreased cell viability was due to apoptosis, as demonstrated by a significant increase in Annexin V(+) cell percentage, detected by flow cytometry. In addition to marked increases in cytochrome c release and NF-kappaB activation, the combination of LIGHT and IFN-gamma caused an obvious decrease in expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL, but an increase in expression of the pro-apoptotic proteins Bak and Bax in MIN6 cells. Accordingly, LIGHT deficiency led to a decrease in NF-kappaB activation and Bak expression, and peri insulitis in non-obese diabetes mice. Inhibition of NF-kappaB activation with the specific NF-kappaB inhibitor, PDTC (pyrrolidine dithiocarbamate), reversed Bcl-xL down-regulation and Bax up-regulation, and led to a significant increase in LIGHT and IFN-gamma-treated cell viability. Moreover, cleaved caspase-9, -3, and PARP (poly (ADP-ribose) polymerase) were observed after LIGHT and IFN-gamma treatment. Pretreatment with caspase inhibitors remarkably attenuated LIGHT- and IFNgamma induced cell apoptosis. Taken together, our results indicate that LIGHT signalling pathway combined with IFN-gamma induces beta cells apoptosis via an NF kappaB/Bcl2-dependent mitochondrial pathway. PMID- 27241102 TI - Selective recognition of uranyl ions from bulk of thorium(iv) and lanthanide(iii) ions by tetraalkyl urea: a combined experimental and quantum chemical study. AB - The selective separation of uranyl ions from an aqueous solution is one of the most important criteria for sustainable nuclear energy production. We report herein a known, but unexplored extractant, tetraalkyl urea, which shows supreme selectivity for uranium in the presence of interfering thorium and other lanthanide ions from a nitric acid medium. The structural characterization of the uranyl complex (UO2X2.2L, where X = NO3(-), Cl(-) and Br(-)) by IR, NMR and single crystal X-ray diffraction provides insight into the strong interaction between the uranyl ion and the ligand. The origin of this supreme selectivity for uranyl ions is further supported by electronic structure calculations. Uranyl binding with the extractant is thermodynamically more favourable when compared to thorium and the selectivity is achieved through a combination of electronic and steric effects. PMID- 27241103 TI - Ovarian Cancer in Hereditary Cancer Susceptibility Syndromes. AB - Hereditary breast and ovarian cancer (HBOC) syndrome and Lynch syndrome (LS) are associated with increased risk of developing ovarian carcinoma. Patients with HBOC have a lifetime risk of up to 50% of developing high-grade serous carcinoma of tube or ovary; patients with LS have a 10% lifetime risk of developing endometrioid or clear cell carcinoma of the ovary. Testing all patients with tubo ovarian high-grade serous carcinoma for mutations associated with HBOC syndrome, and all patients presenting with endometrioid or clear cell carcinoma of the ovary for mutations associated with LS can identify patients with undiagnosed underlying hereditary cancer susceptibility syndromes. PMID- 27241104 TI - Lynch Syndrome: Female Genital Tract Cancer Diagnosis and Screening. AB - Lynch syndrome is responsible for approximately 5% of endometrial cancers and 1% of ovarian cancers. The molecular basis for Lynch syndrome is a heritable functional deficiency in the DNA mismatch repair system, typically due to a germline mutation. This review discusses the rationales and relative merits of current Lynch syndrome screening tests for endometrial and ovarian cancers and provides pathologists with an informed algorithmic approach to Lynch syndrome testing in gynecologic cancers. Pitfalls in test interpretation and strategies to resolve discordant test results are presented. The potential role for next generation sequencing panels in future screening efforts is discussed. PMID- 27241105 TI - Small-Cell Carcinoma of the Ovary of Hypercalcemic Type (Malignant Rhabdoid Tumor of the Ovary): A Review with Recent Developments on Pathogenesis. AB - Small-cell carcinoma of the ovary of hypercalcemic type (SCCOHT) is a highly malignant and aggressive tumor and is the most common undifferentiated ovarian malignancy to occur in women younger than 40. SCCOHT is characterized by deleterious germline or somatic mutations in SMARCA4. Given the striking morphologic and molecular similarities between SCCOHT and atypical teratoid/malignant rhabdoid tumor, we propose this should be reflected in a nomenclature change and that SCCOHT be renamed malignant rhabdoid tumor of the ovary. SMARCA4 (BRG1) immunohistochemistry is useful in diagnosis because there is loss of nuclear immunoreactivity in SCCOHT but retention of staining in mimics. PMID- 27241106 TI - Gynecologic Manifestations of the DICER1 Syndrome. AB - Patients with germline DICER1 mutations are at increased risk of developing a wide range of tumors, most of which are relatively rare in the general population. In the gynecologic tract, these include ovarian sex cord-stromal tumors, particularly Sertoli-Leydig cell tumor, and embryonal rhabdomyosarcoma of the cervix. In some cases, these are the sentinel neoplasms. DICER1-associated tumors may have distinctive morphologic appearances that may prompt the pathologist to consider an underlying tumor predisposition syndrome and therefore consideration of genetic evaluation in the patient and her family. PMID- 27241107 TI - Peutz-Jeghers Syndrome: Pathobiology, Pathologic Manifestations, and Suggestions for Recommending Genetic Testing in Pathology Reports. AB - Peutz-Jeghers syndrome (PJS), in most cases, is attributed to mutation in STK11/LKB1 and is clinically characterized by gastrointestinal hamartomatous polyposis, mucocutaneous pigmentation, and predisposition to certain neoplasms. There are currently no recommended gynecologic screening or clinical surveillance guidelines beyond those recommended for the general population; however, cervical cytology samples must be examined with a high level of suspicion for cervical adenocarcinoma. It is considered prudent to note the established association with PJS and recommend referral for genetic counseling. Complete surgical excision after a diagnosis of atypical lobular endocervical glandular hyperplasia is recommended. PMID- 27241108 TI - Gynecologic Manifestations of Less Commonly Encountered Hereditary Syndromes. AB - This review covers gynecologic manifestations that may occur in rare hereditary syndromes. Recent advances in disorders, such as hereditary leiomyomatosis, renal cell carcinoma syndrome and tuberous sclerosis complex, are discussed as well as lesions that occur in von Hippel-Lindau syndrome, nevoid basal cell carcinoma syndrome, Cowden syndrome, Ollier disease/Maffucci syndrome, and Carney complex. Characteristic clinicopathologic features of each of these syndromes are discussed with an emphasis on the key features that enable pathologists to identify patients at highest risk for these diseases. PMID- 27241110 TI - Testing for Hereditary Predisposition in Patients with Gynecologic Cancers, Quo Vadis? AB - Genetic testing for a hereditary predisposition to gynecologic cancers has been available clinically since the 1990s. Since then, knowledge of the hereditary contribution to gynecologic cancers has dramatically increased, especially with respect to ovarian cancer. Although knowledge of the number of gynecologic cancer predisposing genes has increased, the integration of genetic predisposition testing into routine clinical practice has been much slower. This article summarizes the technical and practical aspects of genetic testing in gynecologic cancers, the potential barriers to more widespread access and practice of genetic testing for hereditary predisposition to gynecologic cancers, and the potential solutions to these barriers. PMID- 27241109 TI - Laboratory Assays in Evaluation of Lynch Syndrome in Patients with Endometrial Carcinoma. AB - This article reviews the main tissue testing modalities for Lynch Syndrome in the pathology laboratory, such as immunohistochemistry and PCR based analyses, and discusses their routine application, interpretation pitfalls, and troubleshooting of common technical performance issues. Discrepancies between laboratory and genetic testing may arise, and are examined in the context of the complexity of molecular abnormalities associated with Lynch Syndrome. The merits of targeted versus universal screening in a changing healthcare climate are addressed. In the absence of comprehensive screening programs, specific tumor topography and histological features that may prompt pathologist-initiated molecular tumor testing are outlined. PMID- 27241111 TI - Prophylactic Gynecologic Specimens from Hereditary Cancer Carriers. AB - Hereditary breast ovarian cancer and Lynch/hereditary nonpolyposis colorectal cancer syndrome account for most hereditary gynecologic cancers. In the absence of effective cancer screening and other preventative strategies, risk-reducing surgery in women who are known to be at genetic risk of BRCA-associated or of Lynch syndrome carcinomas is effective in significantly decreasing the lifetime risk of developing malignancy. Reflex genomic testing of high-grade ovarian cancers and reflex immunohistochemistry in endometrial cancers will lead to greater recognition of germline-associated cancers. Approaches to processing surgical specimens, the recognition and classification of cancer precursor lesions, and differentiation from their mimics are discussed. PMID- 27241112 TI - Image Analysis in Surgical Pathology. AB - Digitization of glass slides of surgical pathology samples facilitates a number of value-added capabilities beyond what a pathologist could previously do with a microscope. Image analysis is one of the most fundamental opportunities to leverage the advantages that digital pathology provides. The ability to quantify aspects of a digital image is an extraordinary opportunity to collect data with exquisite accuracy and reliability. In this review, we describe the history of image analysis in pathology and the present state of technology processes as well as examples of research and clinical use. PMID- 27241113 TI - Gynecologic Pathology. PMID- 27241114 TI - Culture-independent characterization of novel psychrophilic magnetotactic cocci from Antarctic marine sediments. AB - Magnetotactic bacteria (MTB) are a heterogeneous group of ubiquitous aquatic microorganisms capable of biomineralizing nano-sized, membrane-bound, magnetic iron-rich mineral particles called magnetosomes. MTB are found in chemically stratified aquatic sediments and/or water columns with a wide range of salinities, moderate to high temperatures, and pH varying from neutral to strongly alkaline. MTB from very cold environments have not been investigated to any great degree and here we characterize MTB from the low temperature Antarctic maritime region. Sediment samples were collected at nine sampling sites within Admiralty Bay, King George Island (62 degrees 23'S 58 degrees 27'W) from 2009 to 2013. Samples from five sites contained MTB and those from two of these sites contained large number of magnetotactic cocci that were studied using electron microscopy and molecular techniques. The magnetotactic cocci contained magnetosomes either arranged as two or four chains or as a disorganized cluster. The crystalline habit and composition of all magnetosomes analyzed with high resolution transmission electron microscopy and energy dispersive X-ray microanalysis were consistent with elongated prismatic crystals of magnetite (Fe3 O4 ). The retrieved 16S rRNA gene sequences from magnetically-enriched magnetotactic cocci clustered into three distinct groups affiliated with the Alphaproteobacteria class of the Proteobacteria. Novel sequences of each phylogenetic cluster were confirmed using fluorescent in situ hybridization. Metagenomic data analysis of magnetically-enriched magnetotactic cocci revealed the presence of mam genes and MTB-specific hypothetical protein coding genes. Sequence homology and phylogenetic analysis indicated that predicted proteins are related to those of cultivated alphaproteobacterial MTB. The consistent and continuous low temperature of the sediment where the magnetotactic cocci are present (always below 1 degrees C) suggests that these MTB from maritime Antarctica are psychrophiles. Moreover, similar morphotypes and 16S gene sequences were retrieved from samples collected from different sites from maritime Antarctica for several years suggesting that these new strains of MTB are indigenous members of Antarctic microbiota. PMID- 27241115 TI - Terminal bacteroid differentiation in the legume-rhizobium symbiosis: nodule specific cysteine-rich peptides and beyond. AB - Contents 411 I. 411 II. 412 III. 412 IV. 413 V. 414 VI. 414 VII. 415 VIII. 415 416 References 416 SUMMARY: Terminal bacteroid differentiation (TBD) is a remarkable case of bacterial cell differentiation that occurs after rhizobia are released intracellularly within plant cells of symbiotic legume organs called nodules. The hallmarks of TBD are cell enlargement, genome amplification and membrane permeabilization. This plant-driven process is governed by a large family of bacteroid-targeted nodule-specific cysteine-rich (NCR) peptides that were until recently thought to be restricted to a specific lineage of the legume family, including the model plant Medicago truncatula. Recently, new plant and bacterial factors involved in TBD have been identified, challenging our view of this phenomenon at mechanistic and evolutionary levels. Here, we review the recent literature and discuss emerging questions about the mechanisms and the role(s) of TBD. PMID- 27241116 TI - Potential role for carbon nanoparticles to guide central neck dissection in patients with papillary thyroid cancer. AB - BACKGROUND: The purpose of this study was to investigate the use and clinical utility of carbon nanoparticles as a lymph node tracer in the central neck lymph node dissection of patients with papillary thyroid cancer. METHODS: One hundred forty consecutive patients were divided into a carbon nanoparticle group (n = 70) and a control group (n = 70). All patients underwent total or near-total thyroidectomy with bilateral central neck dissection. RESULTS: The carbon nanoparticle and control groups had different rates of metastatic lymph nodes (P = .017), total detected numbers of lymph nodes (P = .0001), total numbers of dissected lymph nodes <5 mm (P = .0001), and numbers of metastatic lymph nodes <5 mm (P = .0001). Of the 682 lymph nodes dissected in the carbon nanoparticle group, 579 (85%) were stained black, and of these, 147 (25%) were metastatic lymph nodes. There were 63 metastatic lymph nodes <5 mm among the black-stained metastatic lymph nodes, while there were 12 non-black-stained metastatic lymph nodes <5 mm. Of the total number of metastatic lymph nodes (n = 193), 147 (76%) were stained black. Moreover, pathologic results revealed that 5 accidental parathyroid resections occurred in the carbon nanoparticle group, compared with 14 in the control group (P = .046). CONCLUSION: Carbon nanoparticles might help to detect lymph nodes and increase the number of metastatic lymph nodes visualized and preserved. Therefore, use of carbon nanoparticles may reflect the metastatic condition of the central neck and have the potential to protect parathyroid glands. PMID- 27241117 TI - Breast cancer biology varies by method of detection and may contribute to overdiagnosis. AB - BACKGROUND: Recently, it has been suggested that screening mammography may result in some degree of overdiagnosis (ie, detection of breast cancers that would never become clinically important within the lifespan of the patient). The extent and biology of these overdiagnosed cancers, however, is not well understood, and the effect of newer screening modalities on overdiagnosis is unknown. METHODS: We performed a retrospective review of a prospectively collected database of breast cancers diagnosed at the Yale Breast Center from 2004-2014. The mode of initial presentation was categorized into 5 groups: screening mammogram, screening magnetic resonance imaging, screening ultrasonography, self-detected masses, and physician-detected masses. RESULTS: Compared with cancers presenting with masses, cancers detected by image-based screening were more likely to present with ductal carcinoma-in-situ or T1 cancers (P < .001). In addition to a simple stage shift, however, cancers detected by image-based screening were also more likely to be luminal and low-grade cancers; symptomatic cancers were more likely high-grade and triple-negative (P < .001, respectively). On a multivariate analysis, adjusting for age, race, and tumor size, cancers detected by mammogram, US, and magnetic resonance imaging had greater odds of being luminal (odds ratio 1.8, 95% confidence interval, 1.5-2.3; odds ratio 2.2, 95% confidence interval, 1.1-4.7; and odds ratio 4.7, 95% confidence interval, 2.1-10.6, respectively), and low grade (odds ratio 2.2, 95% confidence interval, 1.6-2.9; odds ratio 4.9, 95% confidence interval, 2.7-8.9; and odds ratio 4.6, 95% confidence interval, 2.6 8.1, respectively) compared with cancers presenting with self-detected masses. CONCLUSION: Screening detects cancers with more indolent biology, potentially contributing to the observed rate of overdiagnosis. With magnetic resonance imaging and US being used more commonly for screening, the rate of overdiagnosis may increase further. PMID- 27241118 TI - Simulator and 2 tools: Validation of performance measures from a novel neurosurgery simulation model using the current Standards framework. AB - BACKGROUND: Ventriculostomy is a common neurosurgical procedure with a relatively steep learning curve. A low-cost, high-fidelity simulator paired with procedure specific performance measures would provide a safe environment to teach ventriculostomy procedural skills. The same validated simulation model could also allow for assessment of trainees' proficiencies with measures that align with Accreditation Council for Graduate Medical Education milestones. This study extends previous work to evaluate validity evidence from the simulator, its newly developed performance assessment, the Ventricolostomy Procedural Assessment Tool, and the Objective Structured Assessment for Technical Skills. METHODS: After Institutional Review Board exemption, performance data were collected from 11 novice and 3 expert neurosurgeons (n = 14). Participants self-reported their ability to perform tasks on the simulator using the Ventricolostomy Procedural Assessment Tool, an 11-item, step-wise instrument with 5-point rating scales ranging from 1 (unable to perform) to 5 (performs easily and smoothly). De identified operative performances were videotaped and independently rated by 3 neurosurgeons, using the Ventricolostomy Procedural Assessment Tool and Objective Structured Assessment for Technical Skills. We evaluated multiple sources of validity evidence (2014 Standards) to examine psychometric quality of the measures and to test our assumption that the tools could discriminate between novice and expert performances adequately. We used a multifacet Rasch model and traditional indices, such as Cronbach alpha, intraclass correlation, and Wilcoxon signed-rank test estimates. RESULTS: Validity evidence relevant to test content and response processes was supported adequately. Evidence of internal structure was supported by high interitem consistency (n = 0.95) and inter-rater agreement for most Ventricolostomy Procedural Assessment Tool items (Intraclass correlation coefficient = [0.00, 0.91]) and all Objective Structured Assessment for Technical Skills items (Intraclass correlation coefficient = [0.80, 0.93]). Overall, novices performed at a lower level than experts on both scales (P < .05), supporting evidence relevant to relationships to other variables. Deeper analysis of novice/expert ratings indicated novices attained lower performances ratings for all Ventricolostomy Procedural Assessment Tool and Objective Structured Assessment for Technical Skills items, but statistical significance was only achieved for the Objective Structured Assessment for Technical Skills items (P < .01). Rater bias estimates were favorable, supporting evidence relevant to consequences of testing. CONCLUSION: Despite a small sample, favorable evidence using current Standards supports the use of the novel simulator and both tools combined for skills training and performance assessment, but challenges (potential threats to validity) should be considered prior to implementation. PMID- 27241119 TI - Commentary on: Clinical practice algorithm for the treatment of cervical hematoma after an endocrine surgical procedure. PMID- 27241120 TI - Prevention of transmission of Babesia canis by Dermacentor reticulatus ticks to dogs after topical administration of fluralaner spot-on solution. AB - BACKGROUND: The preventive effect of fluralaner spot-on solution against transmission of Babesia canis by Dermacentor reticulatus ticks was evaluated. FINDINGS: Sixteen dogs, tested negative for B. canis by polymerase chain reaction (PCR) and immunofluorescence assay test (IFAT), were allocated to two study groups. On day 0, dogs in one group (n = 8) were treated once topically with fluralaner spot-on solution (BravectoTM Spot-on Solution) according to label recommendations and dogs in the control group (n = 8) remained untreated. On days 2, 28, 56, 70 and 84, all dogs were infested with 50 (+/-4) D. reticulatus ticks harbouring B. canis, with tick in situ thumb counts 48 +/- 4 h after each infestation. On day 90, ticks were removed from all dogs and counted. Prior to each infestation, the presence of B. canis in the respective tick batch was confirmed by PCR, and 12-16 % of ticks were found to be infected with B. canis. Efficacy against ticks was 99.5 and 99.3 % on days 4 and 58 after treatment, respectively and 100 % on all other days. Replacement dogs were included for any B. canis infected control dog (in total 19). All control dogs (n = 27) became infected with B. canis, as confirmed by PCR, performed every 7 days, and by IFAT, performed every 14 days after treatment. None of the eight treated dogs became infected with B. canis, as they were tested negative by PCR and IFAT throughout the study until day 112. By comparing infected dogs in the treated group with infected dogs in the untreated control group, a 100 % preventive effect against B. canis transmission was demonstrated. CONCLUSIONS: A single topical administration of fluralaner spot-on solution effectively prevented the transmission of B. canis by infected D. reticulatus ticks over a 12-week period. PMID- 27241122 TI - Prooxidant Activity of Polyphenols, Flavonoids, Anthocyanins and Carotenoids: Updated Review of Mechanisms and Catalyzing Metals. AB - Natural antioxidants, including polyphenols, flavonoids, anthocyanins and carotenoids, play an important role in the treatment and prevention of a large number of diseases. However, studies indicate that natural antioxidants can act as prooxidants, which produce free radicals and cause DNA damage and mutagenesis. The prooxidant activity is typically catalyzed by metals, particularly transition metals such as Fe and Cu, present in biological systems. In this article, we aim to review new in vitro and in vivo evidence of the prooxidant activity of phenolics, flavonoids, anthocyanins and carotenoids. We highlight the role of catalyzing metals, including transition metals, non-transition metals and metalloids, in the prooxidant activity of natural antioxidants. Prooxidant structure-activity relationships of simple phenolics, flavonoids and anthocyanins and the role of cellular antioxidant defense, including endogenous antioxidant compounds and antioxidant enzymes, are also addressed in this review. In addition, we discuss the question, With respect to in vitro evidence of the prooxidant activity of antioxidants, can we translate this activity into biological systems and the human body? Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27241121 TI - Evaluation of the disco-vertebral junction using ultrashort time-to-echo magnetic resonance imaging: inter-reader agreement and association with vertebral endplate lesions. AB - OBJECTIVE: To evaluate ultrashort time to echo (UTE) magnetic resonance (MR) morphology of the cartilaginous endplates (CEP) in cadaveric lumbar spines with bony vertebral endplate (VEP) lesions, to determine inter-reader agreement as well as associations between the CEP morphology and VEP lesions as well as other abnormalities. MATERIALS AND METHODS: MR imaging of cadaveric lumbar spines from 10 donors was performed at 3T using a UTE MR sequence. Two musculoskeletal radiologists identified the location of vertebral endplate lesions in consensus. The morphology of the CEP overlying the lesions and in the adjacent normal regions was assessed individually. A total of 55 vertebral lesions and 55 normal regions were assessed. The presence of osteophytosis, morphological changes of the anterior and posterior longitudinal ligament, and intervertebral disc signal and morphology was also assessed. Agreement between observers was determined using Cohen's kappa analysis, and association between CEP and vertebral endplate lesions was determined using the chi square test. RESULTS: Fifty-five vertebral endplate lesions were identified and the morphology of CEP evaluated by two readers was in substantial agreement with Cohen's kappa of 0.78. The presence of vertebral endplate abnormality was associated with the presence of osteophytes (39 out of 55 levels), altered morphology and signal of the anterior longitudinal ligament (23 out of 55 levels) and intervertebral discs (30 out of 55 levels). CONCLUSION: UTE MRI enables evaluation of the CEP with substantial inter-reader agreement. Abnormal changes of the CEP may facilitate formation of lesions of vertebral endplate over time and are associated with degenerative changes of the lumbar spine. PMID- 27241123 TI - A Colorimetric Microplate Assay for DNA-Binding Activity of His-Tagged MutS Protein. AB - A simple microplate method was designed for rapid testing DNA-binding activity of proteins. The principle of the assay involves binding of tested DNA by his-tagged protein immobilized on a nickel-coated ELISA plate, following colorimetric detection of biotinylated DNA with avidin conjugated to horseradish peroxidase. The method was used to compare DNA mismatch binding activities of MutS proteins from three bacterial species. The assay required relatively low amounts of tested protein (approximately 0.5-10 pmol) and DNA (0.1-10 pmol) and a relatively short time of analysis (up to 60 min). The method is very simple to apply and convenient to test different buffer conditions of DNA-protein binding. Sensitive colorimetric detection enables naked eye observations and quantitation with an ELISA reader. The performance of the assay, which we believe is a distinguishing trait of the method, is based on two strong and specific molecular interactions: binding of a his-tagged protein to a nickel-coated microplate and binding of biotinylated DNA to avidin. In the reported experiments, the solution was used to optimize the conditions for DNA mismatch binding by MutS protein; however, the approach could be implemented to test nucleic acids interactions with any protein of interest. PMID- 27241124 TI - Effects of Psychological and Psychosocial Interventions on Sport Performance: A Meta-Analysis. AB - BACKGROUND: Psychologists are increasingly supporting the quest for performance enhancement in sport and there is a need to evaluate the evidence base underpinning their work. OBJECTIVES: To synthesize the most rigorous available research that has evaluated psychological, social, and psychosocial interventions with sport performers on variables relating to their athletic performance, and to address some of the perplexing issues in the sport psychology intervention literature (e.g., do interventions have a lasting effect on sport performance?). METHODS: Randomized controlled trials were identified through electronic databases, hand-searching volumes of pertinent journals, scrutinizing reference lists of previous reviews, and contacting experts in the evaluation of interventions in this field. Included studies were required to evaluate the effects of psychological, social, or psychosocial interventions on sport performance in athletes when compared to a no-treatment or placebo-controlled treatment comparison group. A random effects meta-analysis calculating the standardized mean difference (Hedges' g), meta-regressions, and trim and fill analyses were conducted. Data were analyzed at post-test and follow-up (ranging from 1 to 4 weeks after the intervention finished) assessments. RESULTS: Psychological and psychosocial interventions were shown to enhance sport performance at post-test (k = 35, n = 997, Hedges' g = 0.57, 95 % CI = 0.22-0.92) and follow-up assessments (k = 8, n = 189, Hedges' g = 1.16, 95 % CI = 0.25 2.08); no social interventions were included or evaluated. Larger effects were found for psychosocial interventions and there was some evidence that effects were greatest in coach-delivered interventions and in samples with a greater proportion of male participants. CONCLUSIONS: Psychological and psychosocial interventions have a moderate positive effect on sport performance, and this effect may last at least a month following the end of the intervention. Future research would benefit from following guidelines for intervention reporting. PMID- 27241125 TI - Relations of Visceral and Abdominal Subcutaneous Adipose Tissue, Body Mass Index, and Waist Circumference to Serum Concentrations of Parameters of Chronic Inflammation. AB - BACKGROUND: Different measures of body fat composition may vary in their relations to parameters of chronic inflammation. METHODS: We assessed the relations of visceral (VAT) and subcutaneous adipose tissue (SAT), BMI, and waist circumference (WC) to serum concentrations of high-sensitive C-reactive protein (hs-CRP), tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), resistin, and adiponectin in 97 healthy adults using multivariate linear regression models, adjusted for age, sex, smoking, physical activity, menopausal status, and use of aspirin or non-steroidal anti-inflammatory drugs (NSAIDs). Parameters of chronic inflammation were mutually adjusted. RESULTS: VAT (beta = 0.34), SAT (beta = 0.43), BMI (beta = 0.40), and WC (beta = 0.47) were all significantly associated with hs-CRP. BMI was additionally inversely related to adiponectin (beta = -0.29). In exploratory subgroup analyses defined by gender, BMI, smoking, and use of aspirin or NSAIDs, VAT was the strongest indicator for increased levels of IL-6, SAT was the most consistent indicator for increased levels of hs-CRP, and BMI was the most consistent indicator for decreased levels of adiponectin. WC showed to be a weak indicator for increased levels of hs-CRP and decreased levels of adiponectin. CONCLUSION: VAT, SAT, BMI, and WC show distinct associations with parameters of chronic inflammation. Whether these differences reflect differential metabolic risks requires clarification by longitudinal studies. PMID- 27241132 TI - An Investigation of the Relationship Between Nurses' Views on Spirituality and Spiritual Care and Their Level of Burnout. AB - PURPOSE: This study aims to evaluate the relationship between nurses' views on spirituality and spiritual care and their level of burnout. METHOD: This cross sectional study used a convenience sample that comprised 118 nurses from one state hospital in eastern Turkey. The data were collected through questionnaires that were filled by the nurses individually, using a sociodemographic characteristics form, the Spirituality and Spiritual Care Rating Scale, and the Maslach Burnout Inventory. RESULTS: A statistically significant relationship was found between subscale scores of Maslach Burnout Inventory and total score of Spirituality and Spiritual Care Rating Scale. With the increase in nurses' spiritual care mean scores, there was an increase in the mean scores of the Emotional Exhaustion, Depersonalization, and Personal Accomplishment subscales. CONCLUSIONS: Nurses' burnout levels increased with the increase in their spirituality and spiritual care mean scores. This situation can be associated with the fact that providing spiritual care increases nurses' workload. Therefore, similar studies are recommended to be conducted with wider groups of participants. PMID- 27241126 TI - Impact of purification conditions and history on A2A adenosine receptor activity: The role of CHAPS and lipids. AB - The adenosine A2A receptor (A2AR) is a much-studied class A G protein-coupled receptor (GPCR). For biophysical studies, A2AR is commonly purified in a detergent mixture of dodecylmaltoside (DDM), 3-(3-cholamidopropyl) dimethylammoniopropane sulfonate (CHAPS), and cholesteryl hemisuccinate (CHS). Here we studied the effects of CHAPS on the ligand binding activity and stability of wild type, full-length human A2AR. We also tested the cholesterol requirement for maintaining the active conformation of the receptor when solubilized in detergent micelles. To this end, the receptor was purified using DDM, DDM/CHAPS, or the short hydrocarbon chain lipid 1,2-dihexanoyl-sn-glycero-3-phosphocholine (DHPC, di-6:0PC). After solubilization in DDM, DDM/CHAPS, or DHPC micelles, although A2AR was found to retain its native-like fold, its binding ability was significantly compromised compared to DDM or DDM/CHAPS with CHS. It therefore appears that although cholesterol is not needed for A2AR to retain a native-like, alpha-helical conformation, it may be a critical component for high affinity ligand binding. Further, this result suggests that the conformational differences between the active and inactive protein may be so subtle that commonly used spectroscopic methods are unable to differentiate between the two forms, highlighting the need for activity measurements. The studies presented in this paper also underline the importance of the protein's purification history; i.e., detergents that interact with the protein during purification affect the ligand binding properties of the receptor in an irreversible manner. PMID- 27241134 TI - Reply to 'Statistical controversies in clinical research: end points other than survival are vital for regulatory approval of anticancer agents' by Saad and Buyse. PMID- 27241133 TI - Prevalence and profile of cognitive impairment in adult glioma: a sensitivity analysis. AB - Cognitive impairment has been reported in 27-83 % of adults with World Health Organization (WHO) grade I-III glioma. However, the few studies in this field used different methods for cognitive assessment. The objective of the present study was to establish the prevalence of cognitive impairment in patients with WHO grade I-III primary brain tumors and determine the effect sizes of a comprehensive battery of tests. This study used a comprehensive neuropsychological battery to examine 27 patients. To control for false positives, prevalence was estimated from the overall neuropsychological score. Size effects were determined using Cohen's d. Cognitive impairment was observed in 51.9 % (95 % CI 33-70.7 %) of the patients; the impairment affected action speed (38.5 %), cognitive (33 %) and behavioral (21.7 %) executive functions, oral expression (29.6 %), episodic memory (29.6 %) and visuoconstructive abilities (19.2 %). The largest effect sizes (d >= 1.645) were observed for the Digit Symbol Substitution test, global hypoactivity, free recall, Stroop time, the Boston Naming test (BNT), the Trail Making test B (TMTB), verbal fluency and the Rey-Osterrieth Complex Figure Test. Four of these scores (global hypoactivity, the Digit Symbol Substitution test, the TMTB perseveration, and the BNT) were combined to make a shortened battery (AUC 0.872; 95 % CI 0.795-0.949). The overall neuropsychological score was the sole factor associated with the functional outcome. Our results suggest that about half of survivors with a grade I-III primary brain tumor suffer from cognitive impairment. Tests with a large effect size should be included in future large-scale studies. PMID- 27241135 TI - Informing Consent for Organ Donation. PMID- 27241136 TI - Time to go global: a consultation on global health competencies for postgraduate doctors. AB - BACKGROUND: Globalisation is having profound impacts on health and healthcare. We solicited the views of a wide range of stakeholders in order to develop core global health competencies for postgraduate doctors. METHODS: Published literature and existing curricula informed writing of seven global health competencies for consultation. A modified policy Delphi involved an online survey and face-to-face and telephone interviews over three rounds. RESULTS: Over 250 stakeholders participated, including doctors, other health professionals, policymakers and members of the public from all continents of the world. Participants indicated that global health competence is essential for postgraduate doctors and other health professionals. Concerns were expressed about overburdening curricula and identifying what is 'essential' for whom. Conflicting perspectives emerged about the importance and relevance of different global health topics. Five core competencies were developed: (1) diversity, human rights and ethics; (2) environmental, social and economic determinants of health; (3) global epidemiology; (4) global health governance; and (5) health systems and health professionals. CONCLUSIONS: Global health can bring important perspectives to postgraduate curricula, enhancing the ability of doctors to provide quality care. These global health competencies require tailoring to meet different trainees' needs and facilitate their incorporation into curricula. Healthcare and global health are ever-changing; therefore, the competencies will need to be regularly reviewed and updated. PMID- 27241137 TI - Th17/Treg-related cytokine imbalance in sulfur mustard exposed and stable chronic obstructive pulmonary (COPD) patients: correlation with disease activity. AB - In this study, we investigated expression changes of Th17/Treg-related cytokine in transbronchial lung biopsy (TBLBs) of sulfur mustard (SM) exposure, stable chronic obstructive pulmonary disease (COPD) patients and also compared it with a healthy control (HC) group. Here, ROR-gammat, FoxP3, and Treg/Th17-related cytokines (IL-10, IL-17A, IL-6, and TGF-beta1) were assessed using a combination of RT-QPCR and ELISA in 11 SM-exposed cases, 9 patients with GOLD stage II COPD diagnosed, and 8 HC. Our results showed that the levels of Foxp3 expression were lower and ROR-gammat expression was higher in SM and COPD patients when compared with HC (all p values were less than 0.001). The relative Foxp3 expressions and Foxp3/ROR-gammat ratio were positively correlated with FEV1 (%) pred (R = 0.682 and R = 0.602, respectively; p <= 0.001). However, the relative ROR-gammat expressions were inversely correlated with FEV1 (%) pred (R= -0.75, p = 0.003) and relative Foxp3 expression (R= -0.704, p = 0.003). The mRNA and protein expression of IL-10 were significantly decreased in SM and COPD patients compared with HC (p < 0.001). An increase of IL-17A (~7.2 fold) and TGF-beta1 (~5.6 fold) are involved in the lung exacerbation of SM and COPD patients. The expression of IL-6 was variable between three groups (p >= 0.05). In addition, an inverse correlation were observed between FEV1 (%) pred and expressions of IL-17A (R= 0.741), IL-6 (R= -0.673) and TGF-beta1 (R= -0.632) (p <= 0.001). Instead, positive correlation was found between IL-10 ratios and FEV1 (%) pred (R = 0.777, p = 0.001). These findings suggest that Treg/Th17-mediated distributions are involved in the progression of chronic lung injury of SM and COPD patients. PMID- 27241138 TI - Childhood apraxia of speech: A survey of praxis and typical speech characteristics. AB - PURPOSE: The purpose of this study was to investigate current knowledge of the diagnosis childhood apraxia of speech (CAS) in Sweden and compare speech characteristics and symptoms to those of earlier survey findings in mainly English-speakers. METHOD: In a web-based questionnaire 178 Swedish speech language pathologists (SLPs) anonymously answered questions about their perception of typical speech characteristics for CAS. They graded own assessment skills and estimated clinical occurrence. RESULTS: The seven top speech characteristics reported as typical for children with CAS were: inconsistent speech production (85%), sequencing difficulties (71%), oro-motor deficits (63%), vowel errors (62%), voicing errors (61%), consonant cluster deletions (54%), and prosodic disturbance (53%). Motor-programming deficits described as lack of automatization of speech movements were perceived by 82%. All listed characteristics were consistent with the American Speech-Language-Hearing Association (ASHA) consensus-based features, Strand's 10-point checklist, and the diagnostic model proposed by Ozanne. The mode for clinical occurrence was 5%. Number of suspected cases of CAS in the clinical caseload was approximately one new patient/year and SLP. CONCLUSIONS: The results support and add to findings from studies of CAS in English-speaking children with similar speech characteristics regarded as typical. Possibly, these findings could contribute to cross-linguistic consensus on CAS characteristics. PMID- 27241139 TI - Shedding light on the dark side of microscopic colitis. PMID- 27241141 TI - A repeat protein-based DNA polymerase inhibitor for an efficient and accurate gene amplification by PCR. AB - A polymerase chain reaction (PCR) using a thermostable DNA polymerase is the most widely applied method in many areas of research, including life sciences, biotechnology, and medical sciences. However, a conventional PCR incurs an amplification of undesired genes mainly owing to non-specifically annealed primers and the formation of a primer-dimer complex. Herein, we present the development of a Taq DNA polymerase-specific repebody, which is a small-sized protein binder composed of leucine rich repeat (LRR) modules, as a thermolabile inhibitor for a precise and accurate gene amplification by PCR. We selected a repebody that specifically binds to the DNA polymerase through a phage display, and increased its affinity to up to 10 nM through a modular evolution approach. The repebody was shown to effectively inhibit DNA polymerase activity at low temperature and undergo thermal denaturation at high temperature, leading to a rapid and full recovery of the polymerase activity, during the initial denaturation step of the PCR. The performance and utility of the repebody was demonstrated through an accurate and efficient amplification of a target gene without nonspecific gene products in both conventional and real-time PCRs. The repebody is expected to be effectively utilized as a thermolabile inhibitor in a PCR. Biotechnol. Bioeng. 2016;113: 2544-2552. (c) 2016 Wiley Periodicals, Inc. PMID- 27241142 TI - [Th17/Treg imbalance mediated by IL-8 in RSV-infected bronchial epithelial cells]. AB - OBJECTIVE: To explore the mechanisms for an increase in susceptibility of asthma induced by respiratory syncytial virus (RSV), to observe the expression of interleukin-8 (IL-8) in human bronchial epithelial cells (HBECs) after RSV infection and to invesigate the regulatory effect of IL-8 on Th17/Treg differentiation.? METHODS: HBECs were divided into a control group and a RSV infected group. The RSVE-infected model of HBECs was established and examined. The expression of IL-8 mRNA was detected by real-time PCR, and the levels of IL-8 were measured by ELISA. Peripheral blood lymphocytes in healthy people were extracted and divided into a control group and an IL-8 treatment group. Based on concentration of IL-8 in RSV-infected HBECs, lymphocytes were treated by a matched concentration of human recombinant IL-8 for 24 h. The distribution of Th17 and Treg subsets in lymphocytes were examined by flow cytometry.? RESULTS: The RSV-infected HBECs model was successfully established. The infected HBECs were still able to split and passage. The RSV could be detected in every passage in the infected cells. Virus particles indicated by bright yellow green fluorescence were seen under fluorescence microscope. Edema of mitochondrias, expansion of endoplasmic reticulum, fissure around nucleus and intracellular virus particles were all observed under electron microscope. The expression IL-8 mRNA were significantly enhanced in the RSV-infected group, and the level of IL-8 in the RSV-infected group was higher than that in the control group (P<0.05). After IL-8 treatment for 24 h, the ratio of Th17 subsets in lymphocytes were dramatically increased compared to the control group (P<0.05), but there was no difference in the ratio of Treg subsets between the 2 groups (P>0.05).? CONCLUSION: Over-secretion of IL-8 by the RSV-infected HBECs may promote the differentiation of Th17 subsets and maintain the Th17/Tred imbalance. PMID- 27241140 TI - Chronic Stress Increases Prefrontal Inhibition: A Mechanism for Stress-Induced Prefrontal Dysfunction. AB - BACKGROUND: Multiple neuropsychiatric disorders, e.g., depression, are linked to imbalances in excitatory and inhibitory neurotransmission and prefrontal cortical dysfunction, and are concomitant with chronic stress. METHODS: We used electrophysiologic (n = 5-6 animals, 21-25 cells/group), neuroanatomic (n = 6 8/group), and behavioral (n = 12/group) techniques to test the hypothesis that chronic stress increases inhibition of medial prefrontal cortex (mPFC) glutamatergic output neurons. RESULTS: Using patch clamp recordings from infralimbic mPFC pyramidal neurons, we found that chronic stress selectively increases the frequency of miniature inhibitory postsynaptic currents with no effect on amplitude, which suggests that chronic stress increases presynaptic gamma-aminobutyric acid release. Elevated gamma-aminobutyric acid release under chronic stress is accompanied by increased inhibitory appositions and terminals onto glutamatergic cells, as assessed by both immunohistochemistry and electron microscopy. Furthermore, chronic stress decreases glucocorticoid receptor immunoreactivity specifically in a subset of inhibitory neurons, which suggests that increased inhibitory tone in the mPFC after chronic stress may be caused by loss of a glucocorticoid receptor-mediated brake on interneuron activity. These neuroanatomic and functional changes are associated with impairment of a prefrontal-mediated behavior. During chronic stress, rats initially make significantly more errors in the delayed spatial win-shift task, an mPFC-mediated behavior, which suggests a diminished impact of the mPFC on decision making. CONCLUSIONS: Taken together, the data suggest that chronic stress increases synaptic inhibition onto prefrontal glutamatergic output neurons, limiting the influence of the prefrontal cortex in control of stress reactivity and behavior. Thus, these data provide a mechanistic link among chronic stress, prefrontal cortical hypofunction, and behavioral dysfunction. PMID- 27241143 TI - [Mechanisms for effect of osthole on inhibiting the growth and invasion of bladder cancer cells]. AB - OBJECTIVE: To investigate the effect of osthole on epidermal growth factor receptor tyrosine kinase (EGFR-TPK), matrix-metalloproteinase-2 (MMP-2), aminopeptidase N (APN) in bladder cancer cell and the underlying mechanism.? METHODS: The T24 cell lines were cultured. The inhibitory effects of osthole on EGFR-TPK, APN and MMP-2 were evaluated by spectrophotometric and MTT assay. The caspase-3 activity and the expression COX-2 and VEGF in T24 were examined. The activity of NF-kappaB was determined by electrophoretic mobility shift assay.? RESULTS: The half inhibition concentrations (IC50) of osthole on EGFR-TPK, APN and MMP-2 were (45.33+/-3.98), (28.21+/-3.23) and (8.11+/-0.54) umol/L, respectively. The growth inhibitory rates for T24 cells were increased in a dose dependent manner (P<0.05). The caspase-3 activities were significantly increased in T24 cells in the osthole group compared with control group, while the expression of angiogenesis related-protein COX-2, VEGF, and NF-kappaB in T24 cells were decreased.? CONCLUSION: Through the inhibitory effect on EGFR-TPK, APN and MMP-2, osthole can decrease COX-2, VEGF and NF-kappaB expression while increase the activity of caspase-3, eventually blocking the growth and invasion of bladder cancer cell. PMID- 27241144 TI - [Effect of hydrogen sulfide on cardiac myosin light chain kinase expression in diabetic rats]. AB - OBJECTIVE: To investigate the effect of hydrogen sulfide (H2S) on cardiac myosin light chain kinase (MLCK) expression in diabetic rats.? METHODS: A total of 32 male SD rats were randomly divided into a normal control group (NC group), a diabetic control group (DM), a NaHS treatment group (DM+NaHS) and a NaHS group (NaHS) (n=8 in each group). Intraperitoneal injection of streptozotocin was utilized to establish Type 1 diabetic rat model. The diabetic rats in the DM+NaHS and NaHS groups were intraperitoneally injected with 28 MUmol/kg NaHS solution. Eight weeks later, the ventricular hemodynamic parameters, the ratio of heart weight/body weight (HW/BW ratio), the levels of lactate dehydrogenase (LDH) and creatine kinase MB isozyme (CK-MB) in serum were determined. The ultrastructures of myocardium were observed under electron microscopy. The expressions of MLCK mRNA and protein level in myocardium were detected by RT-PCR and Western blot, respectively.? RESULTS: Compared with the NC group, there was no significant difference in the various indexes in the NaHS group (all P>0.05). The function of left ventricular contract and relaxation were decreased obviously in diabetic rats, while the HW/BW ratio was increased (all P<0.01). The levels of LDH and CK MB were increased (both P<0.01) in serum, while the levels of MLCK mRNA and protein were decreased significantly (both P<0.01) in myocardial tissues. Compared with the DM group, the left ventricular hemodynamic parameters and myocardial ultrastructure damage were improved in the DM+NaHS group, while the HW/BW ratio was decreased (all P<0.05). The levels of LDH and CK-MB were decreased (both P<0.01), while the levels of MLCK mRNA and protein were increased significantly (both P<0.01).? CONCLUSION: H2S can protect myocardium in diabetic rats, which may be associated with upregulation of cardiac MLCK. PMID- 27241145 TI - Correlation between Helicobacter pylori infection and polymorphism of adiponectin gene promoter?-11391G/A, superoxide dismutase gene in?nonalcoholic fatty liver disease. AB - OBJECTIVE: To investigate the correlation between Helicobacter pylori (H. Pylori) infection and polymorphism of adiponectin gene promoter -11391G/A, extracellular superoxide dismutase (EC-SOD) gene in nonalcoholic fatty liver disease (NAFLD).? METHODS: From June, 2010 to July, 2014, a hospital-based 1:1 matched case-control study was carried out, with 600 cases of NAFLD and 600 healthy people in the First Affiliated Hospital of Xinxiang Medical University. The genetic polymorphisms of adiponectin gene promoter -11391G/A and EC-SOD were analyzed by polymorphism-polymerase chain reaction (PCR) technique in peripheral blood leukocytes of the subjects. 14C-urea breath test (14C-UBT) was used to test 14C disntegration per minute (DPM) for evaluating the infections status of H. Pylori. The synergistic effect between the two mutants and the gene-environment interaction of the genotypes with H. Pylori infection were analyzed.? RESULTS: The frequencies of -11391G/A (AA) and EC-SOD (CG+GG) were 50.67% and 50.33% in NAFLD cases, 23.83% and 24.17% in healthy controls, respectively. Statistical tests showed significantly higher frequencies of -11391G/A (AA) and EC-SOD (CG+GG) in the NAFLD group (-11391G/A: P=0.0051; EC-SOD: P=0.0057). The risk of NAFLD with -11391G/A (AA) was significantly higher than those with 11391G/A(GG+GA) (OR=3.2822, 95% CI 1.9170 to 5.2039). The individuals who carried EC-SOD (CG+GG) had a high risk of NAFLD (OR=3.1800, 95% CI 1.7974 to 5.2391). Combined analysis of the polymorphisms showed that percentage of -11391G/A (AA)/EC-SOD (CG+GG) in the NAFLD group was significantly higher than that in the control groups (25.50% vs 5.83%, P=0.0039). The people who carried with -11391G/A (AA)/EC-SOD (CG+GG) had a high risk of NAFLD (OR=10.3190, 95% CI 8.1869 to 20.5102). The H. Pylori infection rate in the NAFLD group was significantly higher than that in the control group (OR=3.1667, 95% CI 1.9139 to 5.7443, P=0.0062), and statistical analysis suggested a positive correlation between H. Pylori infection and NAFLD with -11391G/A (AA) and EC-SOD (CG+GG) (-11391G/A: gamma=1.8532; EC-SOD: gamma=1.7899).? CONCLUSION: These carriers of -11391G/A(AA) and EC-SOD (CG+GG) genotypes may have a high risk of NAFLD, and the gene genotypes can interact with H. Pylori infection in the pathogenesis of NAFLD. Therefore, effective prevention measures for NAFLD should consider eradicating H. Pylori or regulating gene expression. PMID- 27241146 TI - [Application of Van-Clear and xylene in the detection of cervical hTERC gene by fluorescence in situ hybridization]. AB - OBJECTIVE: To observe the effect of Van-Clear on vamplification of human telomerase RNA component (hTERC) gene in cervical tissues by fluorescence in situ hybridization, and to determine the potential for Van-Clear to replace xylene.? METHODS: A total of 278 specimens of cervix uteri were collected from inpatients of Department of Gynaecology in Boai Hospital of Zhongshan from January to February, 2015, with 81 cases of normal specimens, 68 cases of cervical intraepithelial neoplasia (CIN) I, 57cases of CIN2, 42 cases of CIN3 and 30 cases of cervical invasive cancer. Double samples were collected from the same region. Fluorescence in situ hybridization was applied to detect the changes in the amplification of hTERC gene in 2 groups of specimens from the cervical biopsy.? RESULTS: Differences in the positive expression rate of hTERC gene between the 2 groups of cervical lesions at all levels were not statistically significant (P>0.05).? CONCLUSION: There is no significant difference in the positive rate of hTERC gene expression between the slices made by Van-clear and xylene. As an environmental-friend product, Van-Clear possesses certain value in detection of cervical hTERC gene by fluorescence in situ hybridization. PMID- 27241147 TI - [Pathologic characteristics of bone marrow for ?CD5 positive small B cell lymphoma]. AB - OBJECTIVE: To study the pathologic characteristics of bone marrow for CD5 positive small B cell lymphoma (SBL).? METHODS: The pathologic profiles of 92 patients with CD5 positive SBL were retrospectively analyzed. The morphologic and immunophenotypic features were analyzed by flow cytometry and immunohistochemistry. IgH/CCND1 was examined by fluorescence in situ hybridization (FISH).? RESULTS: A total of 92 patients with CD5 positive SBL were enrolled in this study, including 56 (60.9%) chronic lymphocytic leukemia /small lymphocytic lymphoma (CLL/SLL), 23 (25.0%) mantle cell lymphoma (MCL) and 13 other SBL (14.1%). Among the 13 other cases, 5, 4 and 4 cases were follicular lymphoma (FL), lymphoplasmacytic lymphoma (LPL) and splenic marginal zone lymphoma (SMZL), respectively. The frequency of patterns for bone marrow infiltration was as follow: diffuse pattern (19/92), mixed pattern (15/92), nodular pattern (9/92), interstitial pattern (8/92), and intrasinusodial pattern (2/92). All patients expressed CD19, CD20 and CD5. According to the immunophenotypic score system, all the CLL patients had 4-5 scores, while SMCL and other SBL patients had less than 3 scores. For the other SBL patients, 5 FL expressed CD10, while 3 FL, 1 LPL and 3 SMZL expressed CD23. There was a significant difference in the expression of CD23, sIgM, FMC7, CD11C and CD22 between the CLL and MCL groups (P<0.01). All 23 MCL patients expressed cyclin D1 and showed IgH/CCND1 gene translocation by FISH detection.? CONCLUSION: CD5 positive SBL includes a variety of types of lymphoma. Patterns of bone marrow for CD5 positive SBL are diversity. Immunophenotypic analysis by flow cytometry is essential in the diagnosis and differential diagnosis of CD5 positive SBL, especially for CLL. PMID- 27241148 TI - [Diagnostic value of liver imaging reporting and data system MRI on primary hepatocellular carcinoma]. AB - OBJECTIVE: To evaluate the diagnostic value of liver imaging reporting and classification criteria of data system (LI-RADS) MRI on primary hepatic carcinoma (HCC).? METHODS: The MRI images of 100 patients (72 patients with HCC, 4 with regenerative nodules, 13 with hemangioma, 4 with liver cyst, 3 with Liver abscess, 2 with inflammatory pseudotumor, 1 with hepatic arteriovenous fistula, 1 with Limitations of steatosis) with liver disease were collected in Xiangya Hospital from January, 2014 to January, 2015. All patients were at the risk of HCC. The images were reviewed according to the LI-RADS categorization by American College of Radiology (ACR) under a condition of blindness to the pathological data. The sensitivity, specificity and the area under the ROC curve in the diagnosis of HCC with the LI-RADS categorization were calculated by three associate professors from the Department of Radiology, Xiangya Hospital.? RESULTS: The area under the ROC curve was 0.925 in the 100 patients with HCC. Of the 100 pathologically confirmed patients, 20 cases were LR1 and LR2. However, the post-operation pathological examination showed benign tumor (negative predictive value was 100%). There were 25 HCC in 31 cases of LR3, 27 HCC in 29 cases of LR4 (positive predictive value was 93.1%). All of 20 cases of LR5 were HCC (positive predictive value was 100%). If LR1 and LR2 were considered negative, and LR3, 4, 5 were positive, then the sensitivity, the specificity and the area under the ROC curve was 100%, 71.4% and 0.925, respectively. If LR1, 2 and 3 were considered negative and LR4 and LR5 were positive, the sensitivity, the specificity and the area under the ROC curve was 100%, 90.9% and 0.974, respectively.? CONCLUSION: The MRI LI-RADS categorization is highly sensitive and specific in the diagnosis of HCC, which can improve the diagnostic accuracy. PMID- 27241149 TI - [Effects of cardiac resynchronization therapy on ?time-domain T wave alternans in patients with ?chronic heart failure]. AB - OBJECTIVE: To study the effects of cardiac resynchronization therapy (CRT) with different pacing rates and modes on MTWA.? METHODS: From March, 2012 to October, 2014, 43 patients who received CRT or CRT-D implantation in the first affiliated hospital, Nanjing Medical University were studied. Time-domain MTWA test were assessed following CRT implantation. MTWA was measured at 90 min(-1) and 110 min( 1) by treadmill exercise test with GE CASE 8000 during CRT-on (BIV biventricular) and CRT-off (RA right atrial) pacing modes. The comparsion of MTWA values between different pacing mode and pacing rates were analyzed. According to the heart function classification the patients were divided into 3 groups. The correlation between MTWA and cardiac function was analyzed.? RESULTS: MTWA-AAI was significantly increased compared to MTWA-BIV at the pacing rate of 90 min(-1) [(11.27+/-9.94) uV vs (7.09+/-7.16) uV, P=0.001]. The value of MTWA at pacing rate of 110 min(-1) was nonsignificantly higher than MTWA during AAI pacing [(16.91+/-12.51) uV vs (15.58+/- 10.97) uV, P=0.517]. The value of MTWA at pacing rate of 110 min(-1) was higher than MTWA at pacing rate of 90 min(-1) during AAI or BIV (P<0.05). MTWA-AAI and MTWA-BIV in group of NYHA IV were higher than those in group of NYHA II (P<0.05).? CONCLUSION: Biventricular pacing mode at lower pacing rates can significantly attenuate MTWA. The value of MTWA is associated with the severity of CHF. PMID- 27241150 TI - [Effect of soft tissue thickness of upper lip on lip retraction in orthodontical treated Class II, Division 1 females]. AB - OBJECTIVE: To establish the Chinese Han national criteria for the thickness of upper lip in Chongqing and to investigate the effect of lip thickness on lip retraction in orthodontic treatment.? METHODS: A total of 240 adult patients (male=120, female=120) of Chinese Han nationality aged 18-35 years in Chongqing were treated with cephalograms and measured the thickness of upper lip. We established the Chinese Han national criteria for the thickness of upper lip in Chongqing according to the results. Sixty-eight female patients with Angle II 1 from Department of Orthodontics Stomatological Hospital of Chongqing Medical University were treated with maxillary premolars extraction, and pre- and post treated with lateral cephalograms, then divided into 3 groups according to our criteria: a thin lips group, a normal lips group and a thick lips group. The ratio of the incisors retraction and the upper lip retraction were measured and calculated. The correlation between incisors retraction and the upper lip retraction was analyzed by the Pearson correlation method.? RESULTS: There was statistical significance in the thickness of upper lip between males and females (P<0.01). The ratio of maxillary inscior retraction to the upper lip soft tissue retraction was 1.6:1, 2.2:1 and 2.9:1 in the thin lips group, the normal lips group and the thick lips group, respectively.? CONCLUSION: Gender differences exist in the thickness of upper lip. Upper lip retraction with the incisors was negatively correlated with the soft tissue thickness of the upper lip in females with Angle II 1. PMID- 27241151 TI - [Incidence of long (short) PR interval in electrocardiogram among healthy people in Changsha and its clinical significance]. AB - OBJECTIVE: To analyze the incidence of long (short) PR interval in electrocardiogram among healthy people in Changsha and the clinical significance.? METHODS: Twelve-lead body surface electrocardiogram was taken to measure the heart rates and PR intervals from 4 025 healthy individuals (age range from 6 min after birth to 83 years old) who performed physical examination from Jan, 1993 to Dec, 2012 in the Second Xiangya Hospital, Central South University. Statistics were analyzed by SPSS 16.0.? RESULTS: The total incidence of short PR interval was 19.65% (791/4 025). The age group from birth to 13 years old had a higher incidence than the other age groups (chi2=432, P<0.01). The age groups from 1 month after birth and from 1 month to younger than 1 year-old displayed the highest incidences (43.29% and 44.34%, respectively). The lowest incidences were obtained from the 14-17 year-old, 40-49 year-old and 50-59 year old groups (0.20%, 0.41%, and 0.33%, respectively). The total incidence of long PR intervals was 3.58% (144/4 025). The 1 year-old group had the highest incidence (6.74%), which decreased with the increase of age. The lowest incidence of long PR intervals occurred in the age group from 14-17 years old, which gradually increased after 50 years old. There were no significant differences in long (short) PR intervals between the gender (P>0.05).? CONCLUSION: The incidence of long (short) PR intervals varies in different age groups of healthy people. The incidences of long (short) PR intervals in children before 10 years old are higher than those in adults, especially the short PR intervals, as a result of the heart rate affected by childhood autonomic nervous function and the change in atrial volume with age. Adults have long (short) PR interval should be regularly followed-up to prevent cardiovascular events. PMID- 27241152 TI - [Analysis of relevant factors for recurrence of ovarian endometriosis after conservative laparoscopic surgery]. AB - OBJECTIVE: To analyze relevant factors for recurrence of ovarian endometriosis after conservative surgery.? METHODS: A cohort study was performed on 310 patients who had performed conservative surgery for ovarian endometriosis. All patients underwent clinical interview. The relevant factors included: age at surgery, clinical symptom and signs, medical history, gynecologic examination, preoperative gravidity, complication, adenomyosis, American Society for Reproductive Medicine (ASRM) scores, post-operative drug therapy, post-operative gravidity and so on. The logistic regression analysis was performed to determine the predictive factors for recurrence of endometriosis.? RESULTS: The relevant factors by univariate analysis were determined. The history of endometriosis surgery, history of intrauterine operation, tenderness nodule at cal-de-sal, bilateral endometrioma, multilocular cyst, intraoperative ASRM scores, complication of adenomyosis and operation time were the risk factors; whereas pre and post-operative gravidity, post-operative drug therapy, and age at surgery were the protective factors. Meanwhile, the relevant factors by multivariate analysis were also confirmed. The history of endometriosis surgery, history of intrauterine operation, tenderness nodule at cal-de-sal, bilateral endometrioma, multilocular cyst, and intraoperative ASRM scores were the risk factors; whereas post-operative gravidity, post-operative drug therapy, pre-operative gravidity, and age at surgery were the protective factors.? CONCLUSION: The risk factors for recurrence of ovarian endometriosis are history of endometriosis surgery, history of intrauterine operation, tenderness nodule at cal-de-sal, bilateral endometrioma, multilocular cyst, intraoperative ASRM scores, whereas the protective factors are pre- and post-operative gravidity, post-operative drug therapy and age at surgery. PMID- 27241153 TI - [Logistic regression analysis for factors affecting ?the successful rate of nano carbon in sentinel lymph ?node biopsy]. AB - OBJECTIVE: To explore the factors affecting the successful rate of nano-carbon in sentinel lymph node biopsy.? METHODS: A total of 270 patients with breast cancer, who were treated in First Affilitated Hospital of Henan University of Science and Technology from January 2013 to March 2015, were chosen and given sentinel lymph node biopsy (SLN) with nano-carbon, and the influencial factors were examined by logistic analysis.? RESULTS: Successful rate of biopsy, accuracy, sensitivity and false negative rate was 92.2%, 97.6%, 93.1% and 6.8%, respectively. Age, primary tumor lesions, body mass index, axillary lymph node status, number of SLN and pathological grade were the factors affetcing successful biopsy (all P<0.05), and body mass index, age, and number of SLN were three independent factors affecting the successful rate of biopsy (all P<0.05). The history of biopsy, tumor location, affected sides, injection sites and chemotherapy showed little effect on the successful rate of biopsy (all P> 0.05).? CONCLUSION: Nano-carbon tracer method is a reliable method in sentinel lymph node biopsy. The body mass index, age, and number of lymph node metastasis greatly impact the successful rate of biopsy. PMID- 27241154 TI - Demographic and clinical characteristics and risk factors for Staphylococcal scalded skin syndrome in Hunan. AB - OBJECTIVE: To realize the risk factors, clinical features, and treatments of Staphylococcal scalded skin syndrome (SSSS).? METHODS: The clinical features, laboratory findings, and treatment were retrospectively analyzed in 290 patients from Hunan Children's Hospital.? RESULTS: Of the 290 patients, less than 3 years old children were 76.6%. One hundred and nine patients had induced factors, and 177 patients had elevated white blood cell count. There were 168 patients with SSSS accompanied with fever, 34 patients accompanied with diarrhea, and 58 patients associated with septicemia. Eighty-five patients performed the bacterial cultures of the skin secretions, 21 did the throat swab, and 13 did both of the skin secretions and throat swab. Bacterial culture results showed that 119 samples were positive for Staphylococci. All patients were cured after antimicrobial therapy. The skin lesions were improved in 3.26 d. The mean hospital stay was 6.55 d. Recovery time of the body temperature was 3.48 d in average.? CONCLUSION: SSSS predominates in infants and children under 3 years old, and has tendency to combine with multi-organ symptoms. The early diagnosis and active antimicrobial treatment are the keys of successful treatments. PMID- 27241155 TI - [Construction of a physiological aging scale for healthy people based on a modified Delphi method]. AB - OBJECTIVE: To build a physiological aging scale for healthy people.? METHODS: We collected age-related physiologic items through literature screening and expert interview. Two rounds of Delphi were implemented. The importance, feasibility and the degree of authority for the physiological index system were graded. Using analytic hierarchy process, we determined the weight of dimensions and items.? RESULTS: Using Delphy mothod, 17 physiological and other professional experts offered the results as follow: coefficient of expert authorities Cr was 0.86+/ 0.03, coordination coefficients for the first and second round were 0.264(chi2=229.691, P<0.001) and 0.293(chi2=228.474,P<0.001), respectively. The consistency was good. The aging scale for healthy people included 3 dimensions, namely physical form, feeling movement and functional status. Each dimension had 8 items. The weight coefficients for the 3 dimensions were 0.54, 0.16, and 0.30, respectively. The Cronbach's alpha coefficient of the scale was 0.893, the reliability was 0.796, and the variance of the common factor was 58.17%.? CONCLUSION: The improved Delphi method or physiological aging scale is satisfied, which can provide reference for the evaluation of aging. PMID- 27241157 TI - [Analysis of self-management education on improving the symptoms of female college students with primary dysmenorrhea in Shaoyang]. AB - OBJECTIVE: To explore the effect of self-management education on improving symptoms of female college students with primary dysmenorrhea and the health related quality of life.? METHODS: Female students with primary dysmenorrhea were chosen for the questionnaire in two colleges at Shaoyang. The female students were assigned to an interventional group and a control group. The interventional group (n=195) received self-management education for 6 months, while the control group (n=196) did not receive any intervention. We compared the symptoms scores, VAS, dysmenorrheal degree and health-related quality of life between the 2 groups before and after the intervention. ? RESULTS: After the intervention, the scores of symptoms, VAS and degree of dysmenorrhea were significantly lower than the baseline and the control group (P<0.05), and the physical component summary (PCS), mental component summary (MCS) were significantly improved (P<0.05).? CONCLUSION: Self-management education could effectively improve the symptoms of primary dysmenorrhea and quality of life. PMID- 27241156 TI - [Meta analysis for the anesthesia effect and adverse reactions of etomidate and propofol on ?the painless abortion surgery]. AB - OBJECTIVE: To evaluate the anesthesia effect of etomidate and propofol on painless abortion surgery. ? METHODS: After screening the Cochrane Library, Pubmed, China National Knowledge Infrastructure (CNKI), WANFANG, VIP database, the literatures regarding the anesthesia effect of etomidate and propofol on painless abortion surgery were collected from 1995 to 2014. The randomized controlled trials (RCTs) were selected, the quality evaluation was performed and the data was analyzed by using RevMan5.3 software.? RESULTS: A total of 1 130 patients were included in 9 RCTs. The results of Meta analysis were as follows: the anesthesia induction time in the etomidate group was less than that in propofol group (MD=-0.14, 95% CI -0.24 to -0.04, P=0.004); there were more adverse reactions, such as myoclonus, nausea and vomiting, in the etomidate group compared with the propofol group (P<0.001); the incidence of pain in the etomidate group was less than that in the propofol group (P<0.001); there was no significant difference in the incidence of respiratory depression between the 2 groups (P>0.05); the surgery time, analgesia and duration from withdrawal to the wake-up was not significantly different between the 2 groups (P>0.05). ? CONCLUSION: Etomidate had a shorter anesthesia induction time than propofol in the painless abortion surgery. The incidence of reverse reactions such as myoclonus, nausea and vomiting, was more common in application of etomidate, whereas the incidence of injection pain was more common in the use of propofol group. There was no significant difference in respiratory depression between the 2 drugs. The comprehensive efficacy of propofol is better than etomidate. PMID- 27241158 TI - [A case of complex Crohn's disease with severe complication]. AB - Crohn's disease (CD) is a nonspecific chronic intestinal inflammatory disease with unknown etiology. The course of CD is persistent and recurrent. In the progress, CD can come with many complications such as obstruction, fistula formation, perforation, and hemorrhage. The early diagnosis, treatment, and the time of the surgery for CD pose a big controversy and challenge. There was a female patient diagnosed as Crohn's disease with severe complication in department of Gastroenterology of the Third Xiangya Hospital, Central South University. We reported the diagnosis and treatment on this patient. The choice for the medicine and surgury was discussed. PMID- 27241159 TI - Shared underlying dynamics between heart failure and cancer: autoimmune activation? PMID- 27241160 TI - Aortic intimal separation resulting from manual cardiopulmonary resuscitation completing the spectrum of blunt thoracic aortic injury complicating CPR. AB - Blunt thoracic aortic injury (BTAI) resulting from cardiopulmonary resuscitation (CPR) is rarely reported and most reports are of aortic rupture. Clinical reports have also documented aortic dissection and intramural hematomas with sequential imaging showing the development of these aortic injuries after the administration of CPR, suggesting that non-transmural aortic injury may also result from CPR. We report partial separation of an aortic intimal atheromatous plaque as a component injury in a case with multiple complications of manual CPR. A 74-year-old male presented to the emergency room (ER) with a 2-day history of chest pain. While in the ER, he suffered witnessed cardiac arrest and resuscitative attempts were pursued for 60 min prior to declaring death. At autopsy, there were numerous injuries attributable to CPR, including bilateral rib fractures, sternal fracture, retrosternal and mediastinal hemorrhage, epicardial ecchymoses, and ruptured pericardium. There was a perforated inferior wall myocardial infarct with a large left hemothorax. There was partial separation/laceration of an intimal atheromatous plaque on the anterior wall of the ascending aorta proximal to the origin of the brachiocephalic artery, forming a triangular flap, without associated intramedial dissection or hematoma. There was no thrombus formation, effectively excluding existence of the laceration prior to circulatory arrest. This aortic injury provides pathologic confirmation of non-transmural BTAI definitively sustained during manual CPR. Pathologists and clinicians alike should be cognizant of the possibility of BTAI resulting from CPR, which may manifest the full range of severity from intimal tear through aortic rupture. PMID- 27241161 TI - Biosynthesis of Drug Glucuronide Metabolites in the Budding Yeast Saccharomyces cerevisiae. AB - Glucuronidation is one of the most common pathways in mammals for detoxification and elimination of hydrophobic xenobiotic compounds, including many drugs. Metabolites, however, can form active or toxic compounds, such as acyl glucuronides, and their safety assessment is often needed. The absence of efficient means for in vitro synthesis of correct glucuronide metabolites frequently limits such toxicological analyses. To overcome this hurdle we have developed a new approach, the essence of which is a coexpression system containing a human, or another mammalian UDP-glucuronosyltransferases (UGTs), as well as UDP-glucose-6-dehydrogenase (UGDH), within the budding yeast, Saccharomyces cerevisiae. The system was first tested using resting yeast cells coexpressing UGDH and human UGT1A6, 7-hydroxycoumarin as the substrate, in a reaction medium containing 8% glucose, serving as a source of UDP-glucuronic acid. Glucuronides were readily formed and recovered from the medium. Subsequently, by selecting suitable mammalian UGT enzyme for the coexpression system we could obtain the desired glucuronides of various compounds, including molecules with multiple conjugation sites and acyl glucuronides of several carboxylic acid containing drugs, namely, mefenamic acid, flufenamic acid, and zomepirac. In conclusion, a new and flexible yeast system with mammalian UGTs has been developed that exhibits a capacity for efficient production of various glucuronides, including acyl glucuronides. PMID- 27241162 TI - Graphene ballistic nano-rectifier with very high responsivity. AB - Although graphene has the longest mean free path of carriers of any known electronic material, very few novel devices have been reported to harness this extraordinary property. Here we demonstrate a ballistic nano-rectifier fabricated by creating an asymmetric cross-junction in single-layer graphene sandwiched between boron nitride flakes. A mobility ~200,000 cm(2) V(-1) s(-1) is achieved at room temperature, well beyond that required for ballistic transport. This enables a voltage responsivity as high as 23,000 mV mW(-1) with a low-frequency input signal. Taking advantage of the output channels being orthogonal to the input terminals, the noise is found to be not strongly influenced by the input. Hence, the corresponding noise-equivalent power is as low as 0.64 pW Hz(-1/2). Such performance is even comparable to superconducting bolometers, which however need to operate at cryogenic temperatures. Furthermore, output oscillations are observed at low temperatures, the period of which agrees with the lateral size quantization. PMID- 27241163 TI - Molten fatty acid based microemulsions. AB - We show that ternary mixtures of water (polar phase), myristic acid (MA, apolar phase) and cetyltrimethylammonium bromide (CTAB, cationic surfactant) studied above the melting point of myristic acid allow the preparation of microemulsions without adding a salt or a co-surfactant. The combination of SANS, SAXS/WAXS, DSC, and phase diagram determination allows a complete characterization of the structures and interactions between components in the molten fatty acid based microemulsions. For the different structures characterized (microemulsion, lamellar or hexagonal phases), a similar thermal behaviour is observed for all ternary MA/CTAB/water monophasic samples and for binary MA/CTAB mixtures without water: crystalline myristic acid melts at 52 degrees C, and a thermal transition at 70 degrees C is assigned to the breaking of hydrogen bounds inside the mixed myristic acid/CTAB complex (being the surfactant film in the ternary system). Water determines the film curvature, hence the structures observed at high temperature, but does not influence the thermal behaviour of the ternary system. Myristic acid is partitioned in two "species" that behave independently: pure myristic acid and myristic acid associated with CTAB to form an equimolar complex that plays the role of the surfactant film. We therefore show that myristic acid plays the role of a solvent (oil) and a co-surfactant allowing the fine tuning of the structure of oil and water mixtures. This solvosurfactant behaviour of long chain fatty acid opens the way for new formulations with a complex structure without the addition of any extra compound. PMID- 27241164 TI - The inhibitory kinetics and mechanism of dietary vitamins D3 and B2 on xanthine oxidase. AB - Dietary guidelines to promote health are usually based on the patterns' prediction on disease risk of foods and nutrients. Overactivity of xanthine oxidase (XO) is the underlying cause of gout. Herein, the inhibitory kinetics and mechanism of dietary vitamins D3 and B2 on XO were investigated by multispectroscopic methods and a molecular modeling technique. The results showed that vitamin D3 competitively inhibited XO with an inhibition constant of 26.93 +/- 0.42 MUM by inserting into the active cavity of XO interacting with the surrounding amino acid residues through hydrogen bond and van der Waals forces. Vitamin D3 bound to XO thereby induced the structural compactness of XO which in turn hindered the binding of substrate xanthine to cause the inhibition on XO. Vitamin B2 exhibited a mixed-type inhibition by binding to the vicinity of the active cavity with an inhibition constant of 37.76 +/- 0.87 MUM through hydrophobic interactions and a feeble hydrogen bond, and it induced the unfolding of the XO structure and an increase of the flexible loops (beta-turns and random coils) which might move to cover the active pocket and reduce the binding of the substrate xanthine, and then lead to a lower catalytic activity of the enzyme. In addition, vitamins D3 and B2 showed a synergistic effect on inhibiting the activity of XO in a certain range of concentration. These findings may provide new insights into the inhibitory mechanism of vitamins D3 and B2 on XO and functional research of the vitamins in the supplementary treatment of gout. PMID- 27241165 TI - Chronic exposure to soil salinity in terrestrial species: Does plasticity and underlying physiology differ among specialized ground-dwelling spiders? AB - In salt marshes, the alternation of low and high tides entails rapid shifts of submersion and aerial exposure for terrestrial communities. In these intertidal environments, terrestrial species have to deal with an osmotic loss in body water content and an increase in sodium chloride concentration when salt load increases. In salt marshes, spiders represent an abundant arthropod group, whose physiological ecology in response to variations of soil salinity must be further investigated. In this study, we compared the effect of salinity on the survival and physiology of three species of Lycosidae; two salt marsh species (Arctosa fulvolineata and Pardosa purbeckensis) and one forest species (P. saltans). Spiders were individually exposed at three salinity conditions (00/00, 350/00 and 700/00) and survival, changes in body water content, hemolymph ions (Na(+), Ca(2+), Mg(2+), K(+); ICP-MS technique) and metabolites (mainly amino acids, polyols, sugars; LC and GC techniques) were assessed. The survival of the forest species P. saltans was very quickly hampered at moderate and high salinities. In this spider, variations of hemolymph ions and metabolites revealed a quick loss of physiological homeostasis and a rapid salt-induced dehydration of the specimens. Conversely, high survival durations were measured in the two salt marsh spiders, and more particularly in A. fulvolineata. In both P. purbeckensis and A. fulvolineata, the proportion of Na(+), Ca(2+), Mg(2+), K(+) remained constant at the three experimental conditions. Accumulation of hemolymph Na(+) and amino acids (mainly glutamine and proline) demonstrated stronger osmoregulatory capacities in these salt-marsh resident spiders. To conclude, even if phylogenetically close (belonging to the same, monophyletic, family), we found different physiological capacities to cope with salt load among the three tested spider species. Nevertheless, physiological responses to salinity were highly consistent with the realized ecological niches of the spiders. PMID- 27241166 TI - Debates in Rehabilitation Medicine: A Collaborative Initiative of the European Academy of Rehabilitation Medicine and the Journal of Rehabilitation Medicine & Dear readers and authors of the Journal of Rehabilitation Medicine. AB - No abstract is available. PMID- 27241167 TI - Endorectal MRI for risk classification of localized prostate cancer: Radiographic findings and influence on treatment decisions. AB - PURPOSE: To report the results of endorectal coil magnetic resonance imaging (eMRI) in patients with localized prostate cancer, and how these images influenced radiotherapeutic management. MATERIALS AND METHODS: A total of 122 men with localized adenocarcinoma of the prostate referred to radiation oncology underwent 3-T eMRI between 2010 and 2014, to evaluate candidacy for active surveillance (n = 26) and brachytherapy as monotherapy (n = 47), or to further risk stratify intermediate-risk (n = 29) or high-risk (n = 20) men before external beam radiation therapy. By National Comprehensive Cancer Network classification, men had low-risk (28%), intermediate-risk (55%), or high-risk (17%) disease. Multiparametric MRI sequences included T2-weighted, diffusion weighted imaging, and dynamic contrast-enhanced imaging. Radiographic extracapsular extension, seminal vesicle invasion (rSVI), and pelvic lymph node involvement (LNI) were graded as negative, indeterminate, or positive. A dominant nodule was defined as a nodule>=1.5cm. Changes in management were identified comparing pre-MRI and post-MRI plan of care. RESULTS: The rates of radiographic extracapsular extension, radiographic seminal vesicle invasion, lymph node involvement, and dominant nodule were 39%, 7%, 12%, and 28%, respectively. The eMRI identified measurable disease in most patients with an increasing burden of disease (sextants involved, median nodule size) according to risk category (P<0.01). Changes in management after eMRI occurred in 18%, including 9%, 18%, and 33% of men with low-risk, intermediate-risk, or high-risk disease (P = 0.08), and 12%, 17%, and 22% of men who were candidates for active surveillance, brachytherapy as monotherapy, or external beam radiation therapy (P = 0.48), respectively. CONCLUSION: The eMRI influenced management in a risk-dependent fashion. Further study is required to determine the clinical importance of eMRI findings and to determine whether changes in management can lead to improved clinical outcome. PMID- 27241168 TI - GATA3 immunohistochemical expression in invasive urothelial carcinoma. AB - INTRODUCTION: GATA binding protein 3 (GATA3) is a transcription factor, which belongs to a distinct family of tumor suppressor genes. It is involved in human cancer cell growth and differentiation, and plays an important role in cell proliferation and apoptosis. Although, its expression has been reported in various cancers, there are limited data in genitourinary malignancies. Recent studies found GATA3 to be a sensitive marker for urothelial carcinoma (UC) and associated with prognostic pathologic features. Its level of expression was found to be an independent factor predicting cancer recurrence. METHODS AND MATERIALS: In this article, immunohistochemical evaluation of GATA3 expression in genitourinary malignancies (invasive UC, renal cell carcinoma, and prostatic adenocarcinomas) was performed. RESULTS: GATA3 was positive in 56/79 (70.8%) of invasive UC, and was negative in all renal cell carcinoma and prostatic adenocarcinomas. The pattern of GATA3 staining, when positive, was intensely nuclear within the clusters of malignant cells. No cytoplasmic staining was noted. Negative controls were all negative. High GATA3 expression was associated with larger tumor size in invasive UC (3.19cm vs. 1.65cm, P = 0.01). GATA3 expression did not correlate with other clinicopathologic parameters in UC. CONCLUSIONS: This data suggest that GATA3 is a sensitive marker in confirming invasive UC, and may be helpful in differentiating it from metastatic tumors of renal and prostatic origin. Furthermore, strong GATA3 expression was noted to have an effect on tumor size in patients with UC. PMID- 27241169 TI - YM155, a small molecule inhibitor of survivin expression, sensitizes cancer cells to hypericin-mediated photodynamic therapy. AB - Photodynamic therapy (PDT) represents a rapidly developing alternative treatment for various types of cancers. Although considered highly effective, cancer cells can exploit various mechanisms, including the upregulation of apoptosis inhibitors, to overcome the cytotoxic effect of PDT. Survivin, a member of the inhibitor of apoptosis protein family, is known to play a critical role in cancer progression and therapeutic resistance and therefore represents a potential therapeutic target. The aim of this study was to investigate whether YM155, a small molecule inhibitor of survivin expression, can potentiate the cytotoxic effect of hypericin-mediated PDT (HY-PDT). Accordingly, two cell lines resistant to HY-PDT, HT-29 (colorectal adenocarcinoma) and A549 (lung adenocarcinoma), were treated either with HY-PDT alone or in combination with YM155. The efficacy of different treatment regimens was assessed by MTT assay, flow cytometry analysis of metabolic activity, viability, phosphatidylserine externalisation, mitochondrial membrane potential and caspase-3 activity and immunoblotting for the cleavage of poly (ADP-ribose) polymerase (PARP). Here we show for the first time that the repression of survivin expression by YM155 is effective in sensitizing HT-29 and A549 cells to HY-PDT, as measured by the decrease in cell viability and induction of apoptosis. Combined treatment with hypericin and YM155 led to a more severe dissipation of the mitochondrial membrane potential and caused an increase in caspase-3 activation and subsequent PARP cleavage. Our results demonstrate that the repression of survivin expression by YM155 potentially represents a novel alternative strategy to increase the efficacy of HY-PDT in cancer cells that are otherwise weakly responsive or non-responsive to treatment. PMID- 27241170 TI - Illness perceptions and coping predict post-traumatic stress in caregivers of patients with head and neck cancer. AB - PURPOSE: There is evidence to suggest that caregivers of patients with head and neck cancer (HNC) are susceptible to post-traumatic stress disorder (PTSD) symptoms. The aim of this study was to investigate whether illness perceptions and coping strategies contribute to the development of these symptoms. METHODS: Seventy-eight caregivers completed questionnaires to assess distress, illness perceptions, and coping at diagnosis. Six months later, PTSD symptoms were assessed. Correlation and regression analyses were performed to examine relationships between illness perceptions and coping at diagnosis and PTSD symptoms at 6 months in 48 caregivers. RESULTS: Nineteen percent of caregivers met criteria for estimated PTSD caseness at 6-month follow-up. A regression analysis demonstrated that caregiver perceptions of low treatment benefit and many cancer symptoms, as well as use of avoidant coping techniques, predicted subsequent PTSD. CONCLUSIONS: This preliminary study suggests that caregivers who have perceptions of low benefits from treatment and many patient symptoms, and those using avoidant coping strategies, are at increased risk of experiencing symptoms of PTSD. Psychological interventions that target illness perceptions and coping may help to reduce the prevalence of PTSD in caregivers of patients with HNC. PMID- 27241171 TI - Quantitative analysis of modeled ATP hydrolysis in water by a colorimetric sensor array. AB - Self-assembled colorimetric sensors have been prepared from Zn(II)-DPA-attached phenylboronic acid (.Zn) and catechol-type dyes. The .Zn-dye sensors display selectivity towards oligophosphate over monophosphates. The colorimetric sensor assay (.Zn-dye) is utilized to monitor a model of a metabolic reaction where ATP is hydrolyzed to pyrophosphate (PPi) and AMP. PMID- 27241172 TI - PPP Sliding Window Algorithm and Its Application in Deformation Monitoring. AB - Compared with the double-difference relative positioning method, the precise point positioning (PPP) algorithm can avoid the selection of a static reference station and directly measure the three-dimensional position changes at the observation site and exhibit superiority in a variety of deformation monitoring applications. However, because of the influence of various observing errors, the accuracy of PPP is generally at the cm-dm level, which cannot meet the requirements needed for high precision deformation monitoring. For most of the monitoring applications, the observation stations maintain stationary, which can be provided as a priori constraint information. In this paper, a new PPP algorithm based on a sliding window was proposed to improve the positioning accuracy. Firstly, data from IGS tracking station was processed using both traditional and new PPP algorithm; the results showed that the new algorithm can effectively improve positioning accuracy, especially for the elevation direction. Then, an earthquake simulation platform was used to simulate an earthquake event; the results illustrated that the new algorithm can effectively detect the vibrations change of a reference station during an earthquake. At last, the observed Wenchuan earthquake experimental results showed that the new algorithm was feasible to monitor the real earthquakes and provide early-warning alerts. PMID- 27241173 TI - Spartina alterniflora invasion alters soil microbial community composition and microbial respiration following invasion chronosequence in a coastal wetland of China. AB - The role of exotic plants in regulating soil microbial community structure and activity following invasion chronosequence remains unclear. We investigated soil microbial community structure and microbial respiration following Spartina alterniflora invasion in a chronosequence of 6-, 10-, 17-, and 20-year-old by comparing with bare flat in a coastal wetland of China. S. alterniflora invasion significantly increased soil moisture and salinity, the concentrations of soil water-soluble organic carbon and microbial biomass carbon (MBC), the quantities of total and various types of phospholipid fatty acids (PLFAs), the fungal:bacterial PLFAs ratio and cumulative microbial respiration compared with bare flat. The highest MBC, gram-negative bacterial and saturated straight-chain PLFAs were found in 10-year-old S. alterniflora soil, while the greatest total PLFAs, bacterial and gram-positive bacterial PLFAs were found in 10- and 17-year old S. alterniflora soils. The monounsaturated:branched PLFAs ratio declined, and cumulative microbial respiration on a per-unit-PLFAs increased following S. alterniflora invasion in the chronosequence. Our results suggest that S. alterniflora invasion significantly increased the biomass of soil various microbial groups and microbial respiration compared to bare flat soil by increasing soil available substrate, and modifying soil physiochemical properties. Soil microbial community reached the most enriched condition in the 10-year-old S. alterniflora community. PMID- 27241174 TI - Preclinical Reversal of Atherosclerosis by FDA-Approved Compound that Transforms Cholesterol into an Anti-Inflammatory "Prodrug". AB - Although atherosclerosis is treatable with lipid-lowering drugs, not all patients respond. Hydroxypropyl-beta-cyclodextrin (CD) is an FDA-approved compound for solubilizing, capturing, and delivering lipophilic drugs in humans. Zimmer et al. report that CD mediates regression of atherosclerotic plaques in two mouse models by solubilizing cholesterol crystals (CCs), and promoting metabolism of CCs into water-soluble 27-hydroxycholesterol, which, in turn, activates anti-inflammatory LXR receptor target genes, promotes active and passive efflux of cholesterol from macrophages, and increases metabolic processing of cholesterol. In effect, CD inverts the role of its cargo, cholesterol, from inflammatory to anti inflammatory by converting cholesterol into a "prodrug" that when modified to 27 hydroxycholesterol reduces atherosclerosis. This mechanism defines a new class of pharmaceuticals, "inverters": compounds that cause innate biomolecules to act opposite to their normal function. However, chronic CD treatment in animal models damages auditory cells, which must be addressed before CD can be developed as a systemic drug for atherosclerosis. PMID- 27241175 TI - Centrally administered TNF increases arterial blood pressure independently of nitric oxide synthase. AB - INTRODUCTION: Emerging evidence indicates that increased levels of TNF in the brain are associated with hypertension. Nitric oxide synthase (NOS) is involved in the central control of the cardiovascular system, exerting both pro- and antihypertensive effects. TNF induces hypothalamic synthesis of nitric oxide. AIM: We checked if acutely administered TNF into the cerebral ventricles affects arterial blood pressure, heart rate and baroreflex sensitivity, and whether TNF actions are dependent on NOS in normotensive rats. METHODS: We carried out hemodynamic measurements in 6 groups of freely moving, adult Sprague-Dawley male rats, intracerebroventricularly (ICV) infused with either: 1) saline (5MUl/h); 2) TNF (200ng/5MUl/h); 3) non-selective NO synthase inhibitor - l-NG-Nitroarginine Methyl Ester (l-NAME) (1mg/5MUl/h); 4) TNF together with l-NAME (200ng and 1mg/5MUl/h, respectively); 5) neuronal NO synthase inhibitor - 7-nitroindazole sodium salt (7-NI) (20MUg/10MUl/h); 6) or TNF together with 7-NI (200ng and 20MUg/10MUl/h, respectively). Mean arterial blood pressure (MABP), heart rate (HR) and spontaneous baroreflex sensitivity (sBRS) evaluated by the sequence method were analysed. RESULTS: ICV infusion of TNF caused a significant increase in MABP accompanied by a transient increase in HR, and a decrease in sBRS. ICV infusion of l-NAME increased MABP, but it did not change HR, nor sBRS. ICV infusion of 7-NI did not affect MABP, nor HR, nor sBRS. TNF administered together with l-NAME increased MABP with a transient increase in HR without changes of sBRS. Similarly, ICV infusion of TNF with 7-NI increased MABP without changes in HR and sBRS. CONCLUSIONS: Centrally administered TNF increases MABP and HR and blunts sBRS. The pressor effect of TNF appears to be independent of NOS activity in the brain. Inhibition of nNOS restores sBRS in TNF treated rats. PMID- 27241176 TI - Efficacy of fluralaner spot-on solution against induced infestations with Rhipicephalus sanguineus on dogs. AB - BACKGROUND: The efficacy of fluralaner spot-on solution administered once topically against induced infestations with Rhipicephalus sanguineus was evaluated in dogs over a 12-week post-treatment period. METHODS: Six negative controlled studies were conducted, involving a total of 112 adult dogs (57 mixed breed, 47 Beagles, eight Labradors). In each study, dogs were randomized to two groups of eight to ten dogs each. On day 0, dogs in each treated group were topically administered fluralaner spot-on solution once at a dose of 25 mg/kg body weight, while dogs in each control group were not treated. Two days before treatment, and on days 28, 56 and 84 after treatment, all dogs were infested with approximately 50 unfed, adult Rh. sanguineus ticks (sex ratio 1:1). Ticks were removed and counted on days 2, 30 (4 weeks), 58 (8 weeks), and 86 (12 weeks) after treatment to assess efficacy. RESULTS: Efficacy against ticks 2 days after treatment was 91.1 % (study 1), 98.4 % (study 2), 100 % (study 3), 97.6 % (study 4), 99.6 % (study 5), and 99.8 % (study 6). At all other assessment time points, tick efficacy was 95.4-100 %. Tick reduction in all treatment groups was significant at all assessment time points (P < 0.0001). CONCLUSIONS: A single topical administration of fluralaner spot-on solution provides a high level of therapeutic and persistent efficacy against Rh. sanguineus ticks over the subsequent 12 weeks. PMID- 27241177 TI - Emerging roles of CCN proteins in vascular development and pathology. AB - The CCN family of proteins consists of 6 members (CCN1-CCN6) that share conserved functional domains. These matricellular proteins interact with growth factors, extracellular matrix (ECM) proteins, cell surface integrins and other receptors to promote ECM-intracellular signaling. This signaling leads to propagation of a variety of cellular actions, including adhesion, invasion, migration and proliferation within several cell types, including epithelial, endothelial and smooth muscle cells. Though CCNs share significant homology, the function of each is unique due to distinct and cell specific expression patterns. Thus, their correct spatial and temporal expressions are critical during embryonic development, wound healing, angiogenesis and fibrosis. Disruption of these patterns leads to severe development disorders and contributes to the pathological progression of cancers, vascular diseases and chronic inflammatory diseases such as colitis, rheumatoid arthritis and atherosclerosis. While the effects of CCNs are diverse, this review will focus on the role of CCNs within the vasculature during development and in vascular diseases. PMID- 27241178 TI - Graphitic carbon nitride nanodots: As reductant for the synthesis of silver nanoparticles and its biothiols biosensing application. AB - The graphitic carbon nitride nanodots (g-C3N4-dots) were synthesized by a simple electrochemical "tailoring" process from bulk graphitic carbon nitride (g-C3N4) under alkaline solution for the first time. Compared with the bulk g-C3N4, the novel g-C3N4-dots not only exhibit enhanced fluorescence and excellent dispersion stability in water but also show the reducibility for the reduction of Ag+ to AgNPs at 60 degrees C. The biothiols can bound with Ag+ through formation of biothiol-Ag+ complex to consume the Ag+ and act as capping agent to prevent the growth of AgNPs, which cause the decrease of the absorption peak of the AgNPs. Therefore, an optical sensor was developed for the detection of biothiols based on the change of the plasmon resonance absorption peak of the AgNPs. The proposed method exhibits excellent sensitivity and selectivity to biothiols with low detection limit for cysteine (Cys), homocysteine (Hcy), and glutathione (GSH) with 11.5, 16.1, and 15.5nM, respectively. This method also has been successfully applied for the detection of biothiols in human serum with satisfactory results. PMID- 27241180 TI - Conversion of raw lignocellulosic biomass into branched long-chain alkanes through three tandem steps. AB - Synthesis of branched long-chain alkanes from renewable biomass has attracted intensive interest in recent years, but the feedstock for this synthesis is restricted to platform chemicals. Here, we develop an effective and energy efficient process to convert raw lignocellulosic biomass (e.g., corncob) into branched diesel-range alkanes through three tandem steps for the first time. Furfural and isopropyl levulinate (LA ester) were prepared from hemicellulose and cellulose fractions of corncob in toluene/water biphasic system with added isopropanol, which was followed by double aldol condensation of furfural with LA ester into C15 oxygenates and the final hydrodeoxygenation of C15 oxygenates into branched long-chain alkanes. The core point of this tandem process is the addition of isopropanol in the first step, which enables the spontaneous transfer of levulinic acid (LA) into the toluene phase in the form of LA ester through esterification, resulting in LA ester co-existing with furfural in the same phase, which is the basis for double aldol condensation in the toluene phase. Moreover, the acidic aqueous phase and toluene can be reused and the residues, including lignin and humins in aqueous phase, can be separated and carbonized to porous carbon materials. PMID- 27241179 TI - Role of microRNAs in the Therapeutic Effects of Curcumin in Non-Cancer Diseases. AB - Curcumin is a bioactive polyphenol occurring in the rhizomes of Curcuma longa. It is well-reputed for its chemopreventive and anticancer properties; however, recent evidence has revealed numerous biological and pharmacological effects of curcumin that are relevant to the treatment of non-cancer diseases. Mechanistically, curcumin exerts its pharmacological effects through anti inflammatory and antioxidant mechanisms via interaction with different signaling molecules and transcription factors. In addition, epigenetic modulators such as microRNAs (miRs) have emerged as novel targets of curcumin. Curcumin was found to modulate the expression of several pathogenic miRs in brain, ocular, renal, and liver diseases. The present systematic review was conducted to identify miRs that are regulated by curcumin in non-cancer diseases. PMID- 27241181 TI - Rare Genetic Forms of Obesity: Clinical Approach and Current Treatments in 2016. AB - Obesity results from a synergistic relationship between genes and the environment. The phenotypic expression of genetic factors involved in obesity is variable, allowing to distinguish several clinical pictures of obesity. Monogenic obesity is described as rare and severe early-onset obesity with abnormal feeding behavior and endocrine disorders. This is mainly due to autosomal recessive mutations in genes of the leptin-melanocortin pathway which plays a key role in the hypothalamic control of food intake. Melanocortin 4 receptor(MC4R)-linked obesity is characterized by the variable severity of obesity and no notable additional phenotypes. Mutations in the MC4R gene are involved in 2-3% of obese children and adults; the majority of these are heterozygous. Syndromic obesity is associated with mental retardation, dysmorphic features, and organ-specific developmental abnormalities. Additional genes participating in the development of hypothalamus and central nervous system have been regularly identified. But to date, not all involved genes have been identified so far. New diagnostic tools, such as whole-exome sequencing, will probably help to identify other genes. Managing these patients is challenging. Indeed, specific treatments are available only for specific types of monogenic obesity, such as leptin deficiency. Data on bariatric surgery are limited and controversial. New molecules acting on the leptin-melanocortin pathway are currently being developed. PMID- 27241182 TI - Non-metabolisable insulin glargine does not promote breast cancer growth in a mouse model of type 2 diabetes. AB - AIMS/HYPOTHESIS: Previous epidemiological studies have reported a potential link between insulin analogues and breast cancer; however, a prospective randomised controlled trial showed neutral effects of insulin glargine on cancer risk. Insulin glargine is metabolised in vivo to an M1 metabolite. A question remains whether a subset of individuals with slower rates of glargine metabolism or who are on high doses could, theoretically, have an increased risk of cancer progression if a tumour is already present. In this study, we aimed to determine whether a non-metabolisable form of insulin glargine induced murine breast cancer growth. METHODS: A mouse model of type 2 diabetes (MKR) was used for these studies. MKR mice were injected with two murine mammary cancer cell lines: Mvt-1 cells (derived from MMTV-c-Myc/Vegf tumours) and Met1 cells (derived from MMTV polyoma virus middle T antigen tumours). Mice were treated with 25 U/kg per day of the long-acting insulin analogues, insulin glargine, insulin detemir, insulin degludec or non-metabolisable glargine, or vehicle. RESULTS: No difference in tumour growth was seen in terms of tumour size after insulin glargine, detemir, degludec or vehicle injections. Non-metabolisable glargine did not increase tumour growth compared with insulin glargine or vehicle. Insulin glargine and non metabolisable glargine led to insulin receptor phosphorylation in vivo rather than IGF-1 receptor phosphorylation. CONCLUSIONS/INTERPRETATION: These results demonstrate that in a mouse model of type 2 diabetes, at high concentrations, basal insulin analogues and a non-metabolisable glargine analogue do not promote the progression of breast tumours. PMID- 27241184 TI - Prediction of delivery of small-for-gestational-age neonates and adverse perinatal outcome by fetoplacental Doppler at 37 weeks' gestation. AB - OBJECTIVE: To explore the predictive capacity of fetoplacental Doppler at 37 weeks' gestation in identifying small-for-gestational-age (SGA) neonates, fetal growth restriction (FGR) and adverse perinatal outcome. METHODS: This was a prospective cohort study of low-risk singleton pregnancies undergoing ultrasound assessment at 37 weeks. At study inclusion, biometry for estimated fetal weight (EFW), and fetoplacental Doppler variables (uterine artery pulsatility index (UtA PI), cerebroplacental ratio (CPR) and umbilical vein blood flow (UVBF) normalized by EFW) were measured. SGA was defined as a customized birth weight between the 3rd and 10th centiles, and FGR was defined as a birth weight < 3rd centile, according to local standards. Adverse perinatal outcomes included emergency Cesarean section for non-reassuring fetal status, 5-min Apgar score < 7 and neonatal acidosis at birth. RESULTS: A total of 946 pregnancies were included in the study. Of these, 89 (9.4%) were classified as SGA and 40 (4.2%) as FGR, with an overall rate of adverse perinatal outcome of 4.9%. At a fixed 10% false positive rate (FPR), the detection rate of SGA by EFW, UtA-PI, CPR, UVBF and by a combination of Doppler variables (UtA-PI and CPR) and EFW was 59.2%, 10.5%, 13.7%, 3.2% and 61.0%, respectively. At a fixed 10% FPR, the detection rate of FGR by EFW, UtA-PI, CPR, UVBF and a combination of CPR and EFW centile was 83.3%, 13.9%, 27.8%, 13.9% and 88.6%, respectively. At a fixed 10% FPR, the detection rate of adverse perinatal outcome by EFW, UtA-PI, CPR and UVBF was 19.2%, 9.2%, 23.1% and 16.9%, respectively, while combining EFW with Doppler variables (including CPR and UVBF normalized by EFW) improved the detection rate to nearly 30%. CONCLUSION: In low-risk pregnancies, Doppler evaluation at 37 weeks' gestation did not improve the prediction of SGA and FGR compared with that given by EFW alone, however, combining Doppler variables with EFW improved the prediction of adverse perinatal outcomes given by these parameters alone, although not markedly. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 27241183 TI - Neonatal vitamin D status is not associated with later risk of type 1 diabetes: results from two large Danish population-based studies. AB - AIMS/HYPOTHESIS: The aim of this work was to assess whether neonatal levels of 25 hydroxyvitamin D (25(OH)D) are associated with risk of developing type 1 diabetes before the age of 18 years. METHODS: Two large-scale studies with different designs-a case-cohort and a case-control-were conducted using Danish national register data and biobank material. Weighted Cox regression and conditional logistic regression were used to calculate HRs and ORs, respectively. The concentration of 25(OH)D was assessed from neonatal dried blood spots using highly sensitive liquid chromatography-tandem mass spectrometry. Quintiles of 25(OH)D3 were used in the main analyses. RESULTS: The case-cohort study included 912 type 1 diabetes cases and 2866 individuals without type 1 diabetes born in Denmark between 1981 and 2002 and followed up until the end of 2012. The case control study included 527 matched case-control pairs born between 1981 and 1999 and followed up until May 2004. Both studies found no association between 25(OH)D3 levels and later risk of developing type 1 diabetes. The neonatal total 25(OH)D levels in the studies were low: 46% (case-cohort study) and 51% (case control study) of individuals had 25(OH)D levels <25 nmol/l. CONCLUSIONS/INTERPRETATION: Our two large-scale national studies showed that 25(OH)D3 levels around the time of birth were not associated with later type 1 diabetes risk. Whether higher levels of 25(OH)D3 during pregnancy, acquired by higher doses of supplementation than are recommended today in most countries, could protect the offspring against type 1 diabetes cannot be ruled out by the present studies. PMID- 27241185 TI - Modeling and visualization of the activation wavefront propagation to improve understanding the QRS complex changes indicating left ventricular hypertrophy. AB - Activation wavefront propagation was computed and visualized in a geometrical heart model for pathological cases of reduced velocity of propagation, left ventricular hypertrophy and their combination. Selected parameters of a multiple dipole equivalent heart generator were computed and compared for three heart geometries and several degrees and extents of reduction of propagation velocity. First, the influence of geometrical changes modeling the left ventricular hypertrophy at reference propagation velocity was compared with reduction of the propagation velocity in the reference heart geometry. Reduced propagation velocity yielded similar or greater changes of the magnitude of the (electrical) heart vector representing the activation wavefront than the geometrical changes. Observations of the wavefront propagation with reduced velocity revealed longer presence of a large extent of the wavefront during depolarization which resulted in increased magnitude of the heart vector. The duration of depolarization was significantly prolonged only when the propagation velocity was decreased to 25% of its normal value. Changes of the direction of the maximal heart vector were dependent on the position of the region where the propagation velocity was reduced. Then the combination of the left ventricular hypertrophy and reduced propagation velocity was studied. Such combination enhanced the enlargement of the electrical heart vector and significantly prolonged the duration of depolarization. The influence of reduced activation velocity on the observed parameters was greater than the effect of the enlargement of the left ventricular mass. The presented study showed that intramyocardial conduction disturbances might cause increase of the actual surface area of propagation wavefront leading to changes of the amplitudes of ECG signals comparable with the changes resulting from the left ventricular hypertrophy. Intramyocardial conduction disturbances, as well as the modeled 50% increase of the thickness of the left ventricular wall, did not cause prolongation of the QRS complex out of normal range. Considerable prolongation of the QRS complex duration was observed only for transmural slowing of the propagation velocity to 25% of its reference value in large ventricular areas or for combination of such slowing with the left ventricular hypertrophy. PMID- 27241186 TI - Response to: Murray A. RE: Procedures of limited clinical value in ENT: what effect has there been on operating numbers? PMID- 27241187 TI - Analyzing disparity trends for health care insurance coverage among non-elderly adults in the US: evidence from the Behavioral Risk Factor Surveillance System, 1993-2009. AB - OBJECTIVE: To explore the changing disparities in access to health care insurance in the United States using time-varying coefficient models. DATA: Secondary data from the Behavioral Risk Factor Surveillance System (BRFSS) from 1993 to 2009 was used. STUDY DESIGN: A time-varying coefficient model was constructed using a binary outcome of no enrollment in health insurance plan versus enrolled. The independent variables included age, sex, education, income, work status, race, and number of health conditions. Smooth functions of odds ratios and time were used to produce odds ratio plots. RESULTS: Significant time-varying coefficients were found for all the independent variables with the odds ratio plots showing changing trends except for a constant line for the categories of male, student, and having three health conditions. Some categories showed decreasing disparities, such as the income categories. However, some categories had increasing disparities in health insurance enrollment such as the education and race categories. CONCLUSIONS: As the Affordable Care Act is being gradually implemented, studies are needed to provide baseline information about disparities in access to health insurance, in order to gauge any changes in health insurance access. The use of time-varying coefficient models with BRFSS data can be useful in accomplishing this task. PMID- 27241188 TI - Exploring flavour-producing core microbiota in multispecies solid-state fermentation of traditional Chinese vinegar. AB - Multispecies solid-state fermentation (MSSF), a natural fermentation process driven by reproducible microbiota, is an important technique to produce traditional fermented foods. Flavours, skeleton of fermented foods, was mostly produced by microbiota in food ecosystem. However, the association between microbiota and flavours and flavour-producing core microbiota are still poorly understood. Here, acetic acid fermentation (AAF) of Zhenjiang aromatic vinegar was taken as a typical case of MSSF. The structural and functional dynamics of microbiota during AAF process was determined by metagenomics and favour analyses. The dominant bacteria and fungi were identified as Acetobacter, Lactobacillus, Aspergillus, and Alternaria, respectively. Total 88 flavours including 2 sugars, 9 organic acids, 18 amino acids, and 59 volatile flavours were detected during AAF process. O2PLS-based correlation analysis between microbiota succession and flavours dynamics showed bacteria made more contribution to flavour formation than fungi. Seven genera including Acetobacter, Lactobacillus, Enhydrobacter, Lactococcus, Gluconacetobacer, Bacillus and Staphylococcus were determined as functional core microbiota for production of flavours in Zhenjiang aromatic vinegar, based on their dominance and functionality in microbial community. This study provides a perspective for bridging the gap between the phenotype and genotype of ecological system, and advances our understanding of MSSF mechanisms in Zhenjiang aromatic vinegar. PMID- 27241189 TI - A neural mass model of phase-amplitude coupling. AB - Brain activity shows phase-amplitude coupling between its slow and fast oscillatory components. We study phase-amplitude coupling as recorded at individual sites, using a modified version of the well-known Wendling neural mass model. To the population of fast inhibitory interneurons of this model, we added external modulatory input and dynamic self-feedback. These two modifications together are sufficient to let the inhibitory population serve as a limit-cycle oscillator, with frequency characteristics comparable to the beta and gamma bands. The frequency and power of these oscillations can be tuned through the time constant of the dynamic and modulatory input. Alpha band activity is generated, as is usual in such models, as a result of interactions of pyramidal neurons and a population of slow inhibitory interneurons. The slow inhibitory population activity directly influences the fast oscillations via the synaptic gain between slow and fast inhibitory populations. As a result, the amplitude envelope of the fast oscillation is coupled to the phase of the slow activity; this result is consistent with the notion that phase-amplitude coupling is effectuated by interactions between inhibitory interneurons. PMID- 27241192 TI - Field evaluation of the nematicide fluensulfone for control of the potato cyst nematode Globodera pallida. AB - BACKGROUND: Three field experiments evaluated the performance of the nematicide fluensulfone against the potato cyst nematode Globodera pallida in Shropshire, England. RESULTS: Experiments 1 and 2 showed reduced root infection and lowered multiplication of G. pallida following fluensulfone (Nimitz 15G((r)) ) soil treatments at five rates (1.95, 3.00, 4.05 (full rate), 5.05 and 6.00 kg AI ha( 1) ) and Nimitz 480EC((r)) at the full rate. Experiment 3 demonstrated a positive interaction between the full rate of Nimitz 15G and the potato variety Sante in the reduction of G. pallida. The fluensulfone treatments at the full rate had more consistent effects than the lower rates, and there were no greater effects for the treatments higher than this full rate. Generally, fluensulfone was less efficacious than oxamyl or fosthiazate, which suggests that the treatment may not be reliably integrated within shorter potato rotations. CONCLUSION: The data suggest that fluensulfone soil application could make a useful addition to the few available nematicide treatments for the control of G. pallida rather than be a substitute for these treatments.(c) 2016 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 27241190 TI - Recent Advances in Diverticular Disease. AB - Diverticular disease is common and accounts for substantial health care utilization in the USA. Recent publications in the areas of diverticulosis and diverticular disease have highlighted several notable advances that are now changing practice. Despite colonic diverticula being common, only 1-4 % of individuals with colonic diverticula will develop diverticulitis. After a first occurrence of acute diverticulitis, the risk of recurrence is 20 % at 5 years. Complications most commonly occur with the first occurrence of acute diverticulitis and not with recurrent episodes. After an episode of diverticulitis, many patients continue to experience chronic gastrointestinal symptoms. Prophylactic surgery is an option to reduce the risk of recurrence and its negative impact on quality of life. Importantly, the rationale for surgery is no longer to prevent complications because this risk is low. The review concludes with practical recommendations for patients with diverticulosis and diverticular disease. PMID- 27241191 TI - Obesogen effects after perinatal exposure of 4,4'-sulfonyldiphenol (Bisphenol S) in C57BL/6 mice. AB - Bisphenol A were removed from consumer products and replaced by chemical substitutes such as Bisphenol S (BPS). Based on their structural similarity, BPS may be obesogen like Bisphenol A in mice. Our objective was to determine the impact of BPS on lipid homeostasis in C57Bl/6 mice after perinatal and chronic exposure. Pregnant mice were exposed to BPS via the drinking water (0.2; 1.5; 50MUg/kg bw/d). Treatment began at gestational day 0 and continued in offspring up to 23-weeks old. Then, offspring mice were fed with a standard or high fat diet. The body weight, food consumption, fat mass and energy expenditure were measured. A lipid load test was performed to check the postprandial triglyceridemia. Plasma parameters and mRNA gene expression in adipose tissues were also analysed. BPS induced overweight in male mice offspring fed with a HFD at the two highest doses. There was no change in food intake and energy expenditure. The overweight was correlated to the fat mass, hyperinsulinemia and hyperleptinemia. The plasma triglyceride clearance was significantly increased with BPS and tyloxapol((r)) (triglyceride clearance inhibitor) reversed this phenomenon. BPS induced alteration in mRNA expression of marker genes involved in adipose tissue homeostasis: hormone sensitive lipase, PPARgamma, insulin receptor, SOCS3 and adiponectin. This is the first time that BPS is described as obesogenic at low doses and after perinatal and chronic exposure in male mice. BPS potentiated the obesity induced by a HFD by inducing the lipid storage linked to faster lipid plasma clearance. PMID- 27241193 TI - Outcome of TVT operations in women with low maximum urethral closure pressure. AB - AIMS: (i) To establish whether low maximal urethral closure pressure (MUCP) is associated with a poorer prognosis after TVT-surgery, and if so to establish an MUCP cut-off value for poor outcome. (ii) To characterize the population with a low MUCP. METHODS: Retrospective analysis of data from 6,646 women with stress/mixed urinary incontinence included in the Norwegian Female Incontinence Registry. Postoperative subjective (degree of satisfaction), objective (leakage on stress test) and composite cure according to preoperative MUCP were analyzed in unadjusted and adjusted analysis. Preoperative variables were compared between women having a low or normal MUCP. Non-parametric tests were used on continuous variables and chi2 tests on categorical variables. Logistic regression was used for the adjusted analysis. Level of significance: P < 0.05. RESULTS: An analysis of centiles of preoperative MUCP showed that a cut-off at 20 cm H2 O did best identify women at risk of not being cured. In unadjusted analysis MUCP <=20 cm H2 O (n = 422) was associated with objective (OR: 2.48), subjective (OR: 1.60), and composite failure (OR: 1.95) compared to MUCP >20 cm H2 O. In adjusted analysis MUCP <=20 cm H2 O was associated with neither objective, subjective, nor composite failure. Women with MUCP <20 cm H2 O were preoperatively significantly older, had larger leakage on stress and 24 h pad test, lower mean voided volume and maximum flow rate and higher stress and urge indices. CONCLUSIONS: Women with MUCP <=20 cm H2 O have similar objective, subjective, and composite outcomes after TVT-surgery compared to women with MUCP >20 cm H2 O after adjusting for preoperative variables. Neurourol. Urodynam. 36:1320-1324, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27241194 TI - Neuroprotective Effects of Kukoamine a against Radiation-induced Rat Brain Injury through Inhibition of Oxidative Stress and Neuronal Apoptosis. AB - Radiation-induced brain injury (RIBI) is a prominent side effect of radiotherapy for cranial tumors. Kukoamine A (KuA) has the ability of anti-oxidative stress and anti-apoptosis in vitro. The aim of this study was to investigate whether KuA would prevent the detrimental effect of ionizing radiation on hippocampal neurons. For this study, male Wistar rats were received either sham irradiation or whole brain irradiation (30 Gy single dose of X-rays) followed by the immediate injection of either KuA or vehicle intravenously. The dose of KuA was 5, 10 and 20 mg/kg respectively. The protective effects of KuA were assessed by Nissl staining. The levels of oxidative stress marker and antioxidants activities were assayed by kits. TUNEL staining was performed to detect the level of apoptosis in hippocampal neurons. The expression of apoptosis-related proteins as well as the brain-derived neurophic factor (BDNF) was evaluated by western blot. Whole brain irradiation led to the neuronal abnormality and it was alleviated by KuA. KuA decreased malondialdehyde (MDA) level, increased glutathione (GSH) level, superoxide dismutase (SOD) and catalase (CAT) activities, as well as alleviated neuronal apoptosis by regulating the expression of cleaved caspase-3, cytochrome C, Bax and Bcl-2. Additionally, KuA increased the expression of BDNF. These data indicate that KuA has neuroprotective effects against RIBI through inhibiting neuronal oxidative stress and apoptosis. PMID- 27241196 TI - Synthesis and self-assembly of DNA-chromophore hybrid amphiphiles. AB - DNA based spherical nanostructures are one of the promising nanostructures for several biomedical and biotechnological applications due to their excellent biocompatibility and DNA-directed surface addressability. Herein, we report the synthesis and amphiphilicity-driven self-assembly of two classes of DNA (hydrophilic)-chromophore (hydrophobic) hybrid amphiphiles into spherical nanostructures. A solid-phase "click" chemistry based modular approach is demonstrated for the synthesis of DNA-chromophore amphiphiles. Various spectroscopic and microscopic analyses reveal the self-assembly of the amphiphiles into vesicular and micellar assemblies with the corona made of hydrophilic DNA and the hydrophobic chromophoric unit as the core of the spherical nanostructures. PMID- 27241197 TI - Directional deep brain stimulation of the subthalamic nucleus: A pilot study using a novel neurostimulation device. AB - INTRODUCTION: A novel neurostimulation system allows steering current in horizontal directions by combining segmented leads and multiple independent current control. The aim of this study was to evaluate directional DBS effects on parkinsonian motor features and adverse effects of subthalamic neurostimulation. METHODS: Seven PD patients implanted with the novel directional DBS system for bilateral subthalamic DBS underwent an extended monopolar review session during the first postoperative week, in which current thresholds were determined for rigidity control and stimulation-induced adverse effects using either directional or ring-mode settings. RESULTS: Effect or adverse effect thresholds were modified by directional settings for each of the 14 STN leads. Magnitude of change varied markedly between leads, as did orientation of optimal horizontal current steering. CONCLUSION: Directional current steering through chronically implanted segmented electrodes is feasible, alters adverse effect and efficacy thresholds in a highly individual manner, and expands the therapeutic window in a monopolar review as compared to ring-mode DBS. (c) 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. PMID- 27241195 TI - Genetic variations involved in sudden cardiac death and their associations and interactions. AB - Although the mechanism of sudden cardiac death (SCD) in heart failure is not completely known, genetic variations are known to play key roles in this process. Increasing numbers of mutations and variants are being discovered through genome wide association studies. The genetic variations involved in the mechanisms of SCD have aroused widespread concern. Comprehensive understanding of the genetic variations involved in SCD may help prevent it. To this end, we briefly reviewed the genetic variations involved in SCD and their associations and interactions, and observed that cardiac ion channels are the core molecules involved in this process. Genetic variations involved in cardiac structure, cardiogenesis and development, cell division and differentiation, and DNA replication and transcription are all speculated to be loci involved in SCD. Additionally, the systems involved in neurohumoral regulation as well as substance and energy metabolism are also potentially responsible for susceptibility to SCD. They form an elaborate network and mutually interact with each other to govern the fate of SCD-susceptible individuals. PMID- 27241198 TI - Corrigendum to "Interleukin-30 (IL27p28) alleviates experimental sepsis by modulating cytokine profile in NKT cells". PMID- 27241199 TI - Corrigendum to "Management of the critically ill patients with cirrhosis: A multidisciplinary perspective". PMID- 27241200 TI - The anova to mixed model transition. AB - A transition towards mixed models is underway in science. This transition started up because the requirements for using analyses of variances are often not met and mixed models clearly provide a better framework. Neuroscientists have been slower than others in changing their statistical habits and are now urged to act. PMID- 27241202 TI - Detecting the impact of bank and channel modification on invertebrate communities in Mediterranean temporary streams (Sardinia, SW Italy). AB - We hypothesized that reach-scale, bank and channel modification would impact benthic communities in temporary rivers of Sardinia, when pollution and water abstraction are not relevant. A range of variables were considered, which include both artificial structures/alterations and natural features observed in a stream reach. Multivariate regression trees (MRT) were used to assess the effects of the explanatory variables on invertebrate assemblages and five groups, characterized by different habitat modification and/or features, were recognized. Four node variables determined the splits in the MRT analysis: channel reinforcement, tree related bank and channel habitats, channel modification and bank modification. Continuity of trees in the river corridor diverged among MRT groups and significant differences among groups include presence of alders, extent of channel shading and substrate diversity. Also, the percentage of in-stream organic substrates, in particular CPOM/Xylal, showed highly significant differences among groups. For practical applications, thresholds for the extent of channel reinforcement (40%) and modification (10%) and for bank alteration (~30%) were provided, that can be used to guide the implementation of restoration measures. In moderately altered river reaches, a significant extent of tree related habitats (~5%) can noticeably mitigate the effects of morphological alteration on aquatic invertebrates. The outcomes highlight the importance of riparian zone management as an opportune, achievable prospect in the restoration of Mediterranean temporary streams. The impact of bank and channel modification on ecological status (sensu WFD) was investigated and the tested benthic metrics, especially those based on abundance data, showed legible differences among MRT groups. Finally, bank and channel modification appears to be a potential threat for the conservation of a few Sardo-Corsican endemic species. The introduction of management criteria that openly use information on endemic species seems crucial to reduce the risk of improving overall ecological status while depleting biodiversity. PMID- 27241203 TI - Soil moisture controls on phenology and productivity in a semi-arid critical zone. AB - The Earth's Critical Zone, where physical, chemical and biological systems interact, extends from the top of the canopy to the underlying bedrock. In this study, we investigated soil moisture controls on phenology and productivity of an Acacia woodland in semi-arid central Australia. Situated on an extensive sand plain with negligible runoff and drainage, the carry-over of soil moisture content (theta) in the rhizosphere enabled the delay of phenology and productivity across seasons, until conditions were favourable for transpiration of that water to prevent overheating in the canopy. Storage of soil moisture near the surface (in the top few metres) was promoted by a siliceous hardpan. Pulsed recharge of theta above the hardpan was rapid and depended upon precipitation amount: 150mm storm(-1) resulted in saturation of theta above the hardpan (i.e., formation of a temporary, discontinuous perched aquifer above the hardpan in unconsolidated soil) and immediate carbon uptake by the vegetation. During dry and inter-storm periods, we inferred the presence of hydraulic lift from soil storage above the hardpan to the surface due to (i) regular daily drawdown of theta in the reservoir that accumulates above the hardpan in the absence of drainage and evapotranspiration; (ii) the dimorphic root distribution wherein most roots were found in dry soil near the surface, but with significant root just above the hardpan; and (iii) synchronisation of phenology amongst trees and grasses in the dry season. We propose that hydraulic redistribution provides a small amount of moisture that maintains functioning of the shallow roots during long periods when the surface soil layer was dry, thereby enabling Mulga to maintain physiological activity without diminishing phenological and physiological responses to precipitation when conditions were favourable to promote canopy cooling. PMID- 27241201 TI - Left inferior parietal lobe engagement in social cognition and language. AB - Social cognition and language are two core features of the human species. Despite distributed recruitment of brain regions in each mental capacity, the left parietal lobe (LPL) represents a zone of topographical convergence. The present study quantitatively summarizes hundreds of neuroimaging studies on social cognition and language. Using connectivity-based parcellation on a meta analytically defined volume of interest (VOI), regional coactivation patterns within this VOI allowed identifying distinct subregions. Across parcellation solutions, two clusters emerged consistently in rostro-ventral and caudo-ventral aspects of the parietal VOI. Both clusters were functionally significantly associated with social-cognitive and language processing. In particular, the rostro-ventral cluster was associated with lower-level processing facets, while the caudo-ventral cluster was associated with higher-level processing facets in both mental capacities. Contrarily, in the (less stable) dorsal parietal VOI, all clusters reflected computation of general-purpose processes, such as working memory and matching tasks, that are frequently co-recruited by social or language processes. Our results hence favour a rostro-caudal distinction of lower- versus higher-level processes underlying social cognition and language in the left inferior parietal lobe. PMID- 27241204 TI - Food, water, and fault lines: Remote sensing opportunities for earthquake response management of agricultural water. AB - Earthquakes often cause destructive and unpredictable changes that can affect local hydrology (e.g. groundwater elevation or reduction) and thus disrupt land uses and human activities. Prolific agricultural regions overlie seismically active areas, emphasizing the importance to improve our understanding and monitoring of hydrologic and agricultural systems following a seismic event. A thorough data collection is necessary for adequate post-earthquake crop management response; however, the large spatial extent of earthquake's impact makes challenging the collection of robust data sets for identifying locations and magnitude of these impacts. Observing hydrologic responses to earthquakes is not a novel concept, yet there is a lack of methods and tools for assessing earthquake's impacts upon the regional hydrology and agricultural systems. The objective of this paper is to describe how remote sensing imagery, methods and tools allow detecting crop responses and damage incurred after earthquakes because a change in the regional hydrology. Many remote sensing datasets are long archived with extensive coverage and with well-documented methods to assess plant water relations. We thus connect remote sensing of plant water relations to its utility in agriculture using a post-earthquake agrohydrologic remote sensing (PEARS) framework; specifically in agro-hydrologic relationships associated with recent earthquake events that will lead to improved water management. PMID- 27241205 TI - Evaluation of ammonium adsorption in biochar-fixed beds for treatment of anaerobically digested swine slurry: Experimental optimization and modeling. AB - Fixed-bed column experiments were performed to investigate the effect of influent concentration, flow rate, and adsorbent bed depth on ammonium adsorption from anaerobically digested swine slurry using three types of biochar made from corncobs (MCB), hardwood (WB), and mixed sawdust pellets (MSB). WB performed better than the other two biochar types with a maximum sorption capacity of 67 114mg/g due to its superior surface area and larger pore volume. Ammonium adsorption kinetics and dynamics depended on the influent NH4(+)-N concentration, applied inflow flow rate, and the depth of the fixed bed. Maximum sorption capacities under influent NH4(+)-N concentration of 500mg/L, were identified to be 114.2mg/g, 108.9mg/g, and 24.7mg/g at inflow rate of 15mL/min for WB, MCB, and MSB, respectively. The data shows that using deeper beds and applying lower flow rates could be a better strategy to increase ammonium adsorption in biochar-fixed beds. Moreover, three kinetic models (Thomas, Adams-Bohart (BDST), and Yoon Nelson) were applied to the experimental data to predict breakthrough curves and determine characteristic adsorption parameters for process design. The applied models fitted data in the order: Thomas (R(2)=0.971)>BDST (R(2)=0.960)>Yoon Nelson (R(2)=0.940). It was concluded that ammonium adsorption in biochar-fixed beds could be an effective method for routine cyclic treatment of slurry. However, further effluent polishing is required to meet discharge requirements. PMID- 27241206 TI - Atmospheric PAHs in North China: Spatial distribution and sources. AB - Polycyclic aromatic hydrocarbons (PAHs), formed through incomplete combustion process, have adverse health effects. To investigate spatial distribution and sources of PAHs in North China, PAHs with passive sampling in 90 gridded sites during June to September in 2011 were analyzed. The average concentration of the sum of fifteen PAHs in North China is 220+/-14ng/m(3), with the highest in Shanxi, followed by Shandong and Hebei, and then the Beijing-Tianjin area. Major sources of PAHs are identified for each region of North China, coke process for Shanxi, biomass burning for Hebei and Shandong, and coal combustion for Beijing Tianjin area, respectively. Emission inventory is combined with back trajectory analysis to study the influence of emissions from surrounding areas at receptor sites. Shanxi and Beijing-Tianjin areas are more influenced by sources nearby while regional sources have more impact on Hebei and Shandong areas. Results from this study suggest the areas where local emission should be the major target for control and areas where both local and regional sources should be considered for PAH abatement in North China. PMID- 27241207 TI - Short-term effects of floods on Japanese encephalitis in Nanchong, China, 2007 2012: A time-stratified case-crossover study. AB - This time-stratified case-crossover study aimed to quantify the impact of floods on daily Japanese encephalitis (JE) cases from 2007 to 2012 in Nanchong city of Sichuan Province, China. Using conditional logistic regression analysis, we calculated the odds ratios (ORs) and 95% confidence intervals (CIs) at different lagged days, adjusting for daily average temperature (AT) and daily average relative humidity (ARH). A total of 370 JE cases were notified during the study period, with the median patient age being 4.2years. The seasonal pattern of JE cases clustered in July and August during the study period. Floods were significantly associated with an increased number of JE cases from lag 23 to lag 24, with the strongest lag effect at lag 23 (OR=2.00, 95% CI: 1.14-3.52). Similarly, AT and ARH were positively associated with daily JE cases from lag 0 to lag 8 and from lag 0 to lag 9, respectively. Floods, with AT and ARH, can be used to forecast JE outbreaks in the study area. Based on the results of this study, recommendations include undertaking control measures before the number of cases increases, especially for regions with similar geographic, climatic, and socio-economic conditions as those in the study area. PMID- 27241208 TI - The reporting of adverse events following spinal manipulation in randomized clinical trials-a systematic review. AB - BACKGROUND CONTEXT: Spinal manipulative therapy (SMT) is commonly used to treat spinal disorders. Although clinical practice guidelines recommend the use of SMT in the treatment of neck and back disorders, concerns exist about the nature and incidence of adverse events associated with the intervention. Comprehensive reporting of adverse events in clinical trials could allow for accurate incidence estimates through meta-analysis. However, it is not clear if randomized clinical trials (RCTs) that involve SMT are currently reporting adverse events adequately. PURPOSE: This study aimed to describe the extent of adverse events reporting in published RCTs involving SMT, and to determine whether the quality of reporting has improved since publication of the 2010 Consolidated Standards Of Reporting Trials (CONSORT) statement. STUDY DESIGN: This is a systematic literature review. METHODS: The Physiotherapy Evidence Database (PEDro) and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched for RCTs involving SMT. Domains of interest included classifications of adverse events, completeness of adverse events reporting, nomenclature used to describe the events, methodological quality of the study, and details of the publishing journal. Data were analyzed using descriptive statistics. Frequencies and proportions of trials reporting on each of the specified domains above were calculated. Differences in proportions between pre- and post-CONSORT trials were calculated with 95% confidence intervals using standard methods, and statistical comparisons were analyzed using tests for equality of proportions with continuity correction. There was no funding obtained for this study. The authors declare no conflict of interest. RESULTS: Of 7,398 records identified in the electronic searches, 368 articles were eligible for inclusion in this review. Adverse events were reported in 140 (38.0%) articles. There was a significant increase in the reporting of adverse events post-CONSORT (p=.001). There were two major adverse events reported (0.3%). Only 22 articles (15.7%) reported on adverse events in the abstract. There were no differences in reporting of adverse events post-CONSORT for any of the chosen parameters. CONCLUSIONS: Although there has been an increase in reporting adverse events since the introduction of the 2010 CONSORT guidelines, the current level should be seen as inadequate and unacceptable. We recommend that authors adhere to the CONSORT statement when reporting adverse events associated with RCTs that involve SMT. PMID- 27241209 TI - Optimizing surface characteristics for cell adhesion and proliferation on titanium plasma spray coatings on polyetheretherketone. AB - BACKGROUND: Titanium plasma spray coating on polyetheretherketone (PEEK) is a recent innovation to interbody spacer technology. The inherent hydrophobic properties of standard, uncoated PEEK implants can hamper cell attachment and bone healing during fusion. The addition of titanium coating not only offers initial stability due to increased surface roughness but also long-term stability due to bony ongrowth created from osteoconductive microenvironment on the device surface. The previously established hydrophilic and osteophilic properties of commercially pure titanium (CPTi) can potentially provide an ideal environment promoting cell attachment and bony ongrowth when applied at the end plate level of the fusion site. Because the surface material composition and topography is what seems to directly affect cell adhesion, it is important to determine the ideal titanium coating for the highest effectiveness. PURPOSE: The purpose of the study is to determine whether there is an optimal surface roughness for the titanium coatings and whether different polishing methods have a greater effect than roughness or topography in mediating cell adhesion to the surface. STUDY DESIGN/SETTING: The study was divided into two phases. In Phase 1, the effects of varying surface roughnesses on identical polishing method were compared. In Phase 2, the effect of varying polishing methods was compared on identical surface roughnesses. METHODS: Coating thickness, porosity, and surface roughness were characterized using an optical microscope as per ASTM F 1854 standards. For both phases, PEEK coupons with plasma-sprayed CPTi were used, and human mesenchymal stem cells (hMSCs) at an initial density of 25,000 cells/cm2 were seeded and cultured for 24 hours before fixation in 10% formalin. The cultured hMSCs were visualized by 4',6-diamidino-2-phenylindole (DAPI) staining, a fluorescent stain that binds to the DNA of living cells. Samples were imaged using an environmental scanning electron microscope (eSEM) (Carl Zeiss Microscopy, Thornwood, NY, USA) using a backscattered detector. RESULTS: Image analysis of the CPTi coatings showed uniform and rough surfaces. For Phase 1, roughness was evaluated as fine, medium, and coarse. The eSEM image analysis and cell counting by DAPI demonstrated that hMSCs have a tendency to form stronger adhesion and greater pseudopodia extensions on fine roughness surfaces. Individual hMSCs were seen forming cytoplasmic processes extending across the width of a pore. There was a 4 and 20-fold reduction in adhered hMSCs with an increase to medium and coarse roughnesses, respectively. For Phase 2, studied groups are (1) medium CPTi coating with zirconia polishing, (2) medium CPTi coating with CPTi polishing, and (3) fine CPTi coating with CPTi polishing. The eSEM image analysis and cell counting by DAPI demonstrated that hMSCs have a tendency to form stronger adhesion and greater pseudopodia extensions on Group 3 over the other two groups. There was a twofold reduction in adhered hMSCs on medium roughness relative to fine. No difference in cell adhesion was found between Groups 1 and 2. Individual hMSCs were seen forming cytoplasmic processes extending across the width of a pore. CONCLUSIONS: Previously, it was accepted without much scrutiny that surface coatings were beneficial. This study begins to discover that surface topography directly affects the potential for cells to adhere and proliferate and lead to greater surgical efficacy. PMID- 27241210 TI - Impairment of chemical clearance and mucosal integrity distinguishes hypersensitive esophagus from functional heartburn. AB - BACKGROUND: Hypersensitive esophagus (HE) is defined by endoscopy-negative heartburn with a normal acid exposure time but positive symptom association probability (SAP) and/or symptom index (SI) on impedance-pH monitoring, and proton pump inhibitor (PPI) responsiveness. Functional heartburn (FH) is distinguished by negative SAP/SI and PPI refractoriness. The clinical value of SAP and SI has been questioned. We aimed to investigate whether impairment of chemical clearance and of mucosal integrity, expressed by the postreflux swallow induced peristaltic wave (PSPW) index and the mean nocturnal baseline impedance (MNBI), characterize HE independently of SAP and SI. METHODS: Impedance-pH tracings from PPI-responsive endoscopy-negative patients, 125 with nonerosive reflux disease and 108 with HE, distinguished by an abnormal and a normal acid exposure time, and from 70 patients with FH were retrospectively selected and blindly reviewed. RESULTS: The mean PSPW index and MNBI were significantly lower in nonerosive reflux disease (30 %, 1378 Omega) than in HE (51 %; 2274 Omega) and in both of them as compared with FH (76 %; 3445 Omega) (P = 0.0001). Both the PSPW index (adjusted odds ratio 0.863, P = 0.001) and the MNBI (adjusted odds ratio 0.998, P = 0.001) were independent predictors of HE; with their combined assessment, the area under the curve on receiver operating characteristic analysis was 0.957. SAP and/or SI was positive in 67 of the 108 HE patients (62 %), whereas the PSPW index and/or MNBI was abnormal in 99 of the 108 HE patients (92 %; P < 0.0001). CONCLUSIONS: HE is characterized by impairment of chemical clearance and mucosal integrity, which explains the increased reflux perception. When SAP and SI afford uncertain results, the PSPW index and MNBI should be analyzed. PMID- 27241211 TI - Auditory perceptual restoration and illusory continuity correlates in the human brainstem. AB - When noise obstructs portions of target sounds the auditory system fills in missing information, a phenomenon known as auditory restoration or induction. Previous work in animal models demonstrates that neurons in primary auditory cortex (A1) are capable of restoring occluded target signals suggesting that early auditory cortex is capable of inducing continuity in discontinuous signals (i.e., endogenous restoration). Current consensus is that the neural correlates of auditory induction and perceptual restoration emerge no earlier than A1. Moreover, the neural mechanisms supporting induction in humans are poorly understood. Here, we show that in human listeners, auditory brainstem nuclei support illusory auditory continuity well before engagement of cerebral cortex. We recorded brainstem responses to modulated target tones that did or did not promote illusory auditory percepts. Auditory continuity was manipulated by introducing masking noise or brief temporal interruptions in otherwise continuous tones. We found that auditory brainstem responses paralleled illusory continuity by tagging target sounds even when they were occluded by the auditory scene. Our results reveal (i) a pre-attentive, subcortical origin to a presumed cortical function and (ii) that brainstem signal processing helps partially cancel the negative effects of masking by restoring missing portions of auditory objects that are fragmented in the soundscape. PMID- 27241212 TI - Identification of Preferentially Expressed Antigen of Melanoma as a Potential Tumor Suppressor in Lung Adenocarcinoma. AB - BACKGROUND Preferentially expressed antigen of melanoma (PRAME) is known as a tumor-associated antigen that is altered in a variety of malignancies, including lung cancer. However, the role of PRAME in lung cancer remains unclear. MATERIAL AND METHODS We analyzed the expression of PRAME in human lung adenocarcinomas and studied the function of PRAME using small interfering RNA (siRNA)-induced gene knockdown in lung cancer cell lines PC9 and A549. RESULTS We found that PRAME expression is down-regulated in lung adenocarcinomas. Knockdown of PRAME promoted proliferation and suppressed apoptosis of PC9 and A549 cells. CONCLUSIONS In line with its roles in controlling cell growth, RPAME regulates multiple critical cell growth related genes, including IGF1R oncogene. IGF1R up-regulation contributes to increase of cell growth upon the knockdown of PRAME. Taken together, our results suggest that PRAME has inhibitory roles in lung cancer. PMID- 27241213 TI - Unilateral ultra-brief pulse electroconvulsive therapy for depression in Parkinson's disease. AB - OBJECTIVES: Electroconvulsive therapy (ECT) has demonstrated efficacy in treating core symptoms of Parkinson's disease (PD); however, widespread use of ECT in PD has been limited due to concern over cognitive burden. We investigated the use of a newer ECT technology known to have fewer cognitive side effects (right unilateral [RUL] ultra-brief pulse [UBP]) for the treatment of medically refractory psychiatric dysfunction in PD. MATERIALS AND METHODS: This open-label pilot study included 6 patients who were assessed in the motoric, cognitive, and neuropsychiatric domains prior to and after RUL UBP ECT. Primary endpoints were changes in total score on the HAM-D-17 and GDS-30 rating scales. RESULTS: Patients were found to improve in motoric and psychiatric domains following RUL UBP ECT without cognitive side effects, both immediately following ECT and at 1 month follow-up. CONCLUSIONS: This study demonstrates that RUL UBP ECT is safe, feasible, and potentially efficacious in treating multiple domains of PD, including motor and mood, without clear cognitive side effects. PMID- 27241214 TI - Effects of dredging operations on the demersal fish fauna of a South American tropical-subtropical transition estuary. AB - Changes in the environment and in the composition of fish assemblages in the Paranagua Estuary (South Brazil) were assessed by comparisons made before, during and after dredging operations, in the same months and areas studied in the previous year. Interactions between year and month were observed for salinity. During the dredging year fish total density was 2 individuals m(-2) and with a total biomass of 104 g m(-2) (among 31 species captured). For the same period the year before, 0.3 individuals m(-2) and 3 g m(-2) were captured (38 species). The number of species showed significant time v. month interactions, assuming that fish species composition varied for both year and month. Total mean density and biomass showed significant differences for interaction time v. month, and density and biomass in the dredging month September 2001 in the main channel were scientifically different from other months. Interaction times v. area were significant for Cathorops spixii (increased biomass), Aspistor luniscutis (increased density), Menticirrhus americanus (decreased biomass) and Cynoscion leiarchus (decreased density and biomass). This suggests that during the dredging process there is a change in the structure of the demersal fish assemblage. The impact (damage and mortality) induced by dredging on the macrobenthic animals along the dredge path attracted adults of C. spixii that reached densities 10 times greater than in the year before. On the other hand, sciaenid species practically disappeared. To contribute to the conservation of the estuarine fish fauna, and maintain fisheries production of the Paranagua Estuary and surrounding areas, it is recommended that, dredging should be done from the late rainy season to the early dry season. Decisions must take into account the ecological cycles of socio-economically important fish species and prioritize the safe disposal of dredged spoils. PMID- 27241216 TI - Evolution of brain-body allometry in Lake Tanganyika cichlids. AB - Brain size is strongly associated with body size in all vertebrates. This relationship has been hypothesized to be an important constraint on adaptive brain size evolution. The essential assumption behind this idea is that static (i.e., within species) brain-body allometry has low ability to evolve. However, recent studies have reported mixed support for this view. Here, we examine brain body static allometry in Lake Tanganyika cichlids using a phylogenetic comparative framework. We found considerable variation in the static allometric intercept, which explained the majority of variation in absolute and relative brain size. In contrast, the slope of the brain-body static allometry had relatively low variation, which explained less variation in absolute and relative brain size compared to the intercept and body size. Further examination of the tempo and mode of evolution of static allometric parameters confirmed these observations. Moreover, the estimated evolutionary parameters indicate that the limited observed variation in the static allometric slope could be a result of strong stabilizing selection. Overall, our findings suggest that the brain-body static allometric slope may represent an evolutionary constraint in Lake Tanganyika cichlids. PMID- 27241215 TI - Characterization of gradient echo signal decays in healthy and cancerous prostate at 3T improves with a Gaussian augmentation of the mono-exponential (GAME) model. AB - A biomarker of cancer aggressiveness, such as hypoxia, could substantially impact treatment decisions in the prostate, especially radiation therapy, by balancing treatment morbidity (urinary incontinence, erectile dysfunction, etc.) against mortality. R2 (*) mapping with Mono-Exponential (ME) decay modeling has shown potential for identifying areas of prostate cancer hypoxia at 1.5T. However, Gaussian deviations from ME decay have been observed in other tissues at 3T. The purpose of this study is to assess whether gradient-echo signal decays are better characterized by a standard ME decay model, or a Gaussian Augmentation of the Mono-Exponential (GAME) decay model, in the prostate at 3T. Multi-gradient-echo signals were acquired on 20 consecutive patients with a clinical suspicion of prostate cancer undergoing MR-guided prostate biopsies. Data were fitted with both ME and GAME models. The information contents of these models were compared using Akaike's information criterion (second order, AICC ), in skeletal muscle, the prostate central gland (CG), and peripheral zone (PZ) regions of interest (ROIs). The GAME model had higher information content in 30% of the prostate on average (across all patients and ROIs), covering up to 67% of cancerous PZ ROIs, and up to 100% of cancerous CG ROIs (in individual patients). The higher information content of GAME became more prominent in regions that would be assumed hypoxic using ME alone, reaching 50% of the PZ and 70% of the CG as ME R2 (*) approached 40 s(-1) . R2 (*) mapping may have important applications in MRI; however, information lost due to modeling could mask differences in parameters due to underlying tissue anatomy or physiology. The GAME model improves characterization of signal behavior in the prostate at 3T, and may increase the potential for determining correlates of fit parameters with biomarkers, for example of oxygenation status. PMID- 27241217 TI - New Insights Into Roles of Ubiquitin Modification in Regulating Plastids and Other Endosymbiotic Organelles. AB - Recent findings have revealed important and diverse roles for the ubiquitin modification of proteins in the regulation of endosymbiotic organelles, which include the primary plastids of plants as well as complex plastids: the secondary endosymbiotic organelles of cryptophytes, alveolates, stramenopiles, and haptophytes. Ubiquitin modifications have a variety of potential consequences, both to the modified protein itself and to cellular regulation. The ubiquitin proteasome system (UPS) can target individual proteins for selective degradation by the cytosolic 26S proteasome. Ubiquitin modifications can also signal the removal of whole endosymbiotic organelles, for example, via autophagy as has been well characterized in mitochondria. As plastids must import over 90% of their proteins from the cytosol, the observation that the UPS selectively targets the plastid protein import machinery is particularly significant. In this way, the UPS may influence the development and interconversions of different plastid types, as well as plastid responses to stress, by reconfiguring the organellar proteome. In complex plastids, the Symbiont-derived ERAD-Like Machinery (SELMA) has coopted the protein transport capabilities of the ER-Associated Degradation (ERAD) system, whereby misfolded proteins are retrotranslocated from ER for proteasomal degradation, uncoupling them from proteolysis: SELMA components have been retargeted to the second outermost plastid membrane to mediate protein import. In spite of this wealth of new information, there still remain a large number of unanswered questions and a need to define the roles of ubiquitin modification further in the regulation of plastids. PMID- 27241218 TI - New Insights Into the Role of Ubiquitylation of Proteins. AB - Posttranslational modification of proteins by the addition of ubiquitin and related modifiers has an essential role in cellular processes such as protein degradation and subcellular localization. This impacts on the study of cell and developmental biology in diseases such as cancer, and on the study of protein folding and stability in Alzheimer's disease and other diseases of protein aggregation and misfolding. Recently, there have been many additions to the ubiquitylation literature that have challenged, revised, and expanded our understanding and future directions of this process. Here we present a comprehensive overview of the classical textbook description of protein ubiquitylation and then review the recent literature that has challenged and revised the canonical models of protein ubiquitylation. We discuss the roles of noncanonical ubiquitylation at sites other than lysine residues, unconventional ubiquitylation of mixed and branched polyubiquitin chains, and highlight the role of other structural and posttranslational modifications in ubiquitylation that have been identified in the recent literature. By highlighting the assumptions that have been challenged and revised in the field of protein ubiquitylation, we hope to stimulate further study and questions about this ubiquitous protein modification. PMID- 27241219 TI - Heterogeneity, Cell Biology and Tissue Mechanics of Pseudostratified Epithelia: Coordination of Cell Divisions and Growth in Tightly Packed Tissues. AB - Pseudostratified epithelia (PSE) are tightly packed proliferative tissues that are important precursors of the development of diverse organs in a plethora of species, invertebrate and vertebrate. PSE consist of elongated epithelial cells that are attached to the apical and basal side of the tissue. The nuclei of these cells undergo interkinetic nuclear migration (IKNM) which leads to all mitotic events taking place at the apical surface of the epithelium. In this review, we discuss the intricacies of proliferation in PSE, considering cell biological, as well as the physical aspects. First, we summarize the principles governing the invariability of apical nuclear migration and apical cell division as well as the importance of apical mitoses for tissue proliferation. Then, we focus on the mechanical and structural features of these tissues. Here, we discuss how the overall architecture of pseudostratified tissues changes with increased cell packing. Lastly, we consider possible mechanical cues resulting from these changes and their potential influence on cell proliferation. PMID- 27241220 TI - New Insight Into the Roles of Membrane Microdomains in Physiological Activities of Fungal Cells. AB - The organization of biological membranes into structurally and functionally distinct lateral microdomains is generally accepted. From bacteria to mammals, laterally compartmentalized membranes seem to be a vital attribute of life. The crucial fraction of our current knowledge about the membrane microdomains has been gained from studies on fungi. In this review we summarize the evidence of the microdomain organization of membranes from fungal cells, with accent on their enormous diversity in composition, temporal dynamics, modes of formation, and recognized engagement in the cell physiology. A special emphasis is laid on the fact that in addition to their other biological functions, membrane microdomains also mediate the communication among different membranes within a eukaryotic cell and coordinate their functions. Involvement of fungal membrane microdomains in stress sensing, regulation of lipid homeostasis, and cell differentiation is discussed more in detail. PMID- 27241221 TI - Development and Application of Functionalized Protein Binders in Multicellular Organisms. AB - Protein-protein interactions are crucial for almost all biological processes. Studying such interactions in their native environment is critical but not easy to perform. Recently developed genetically encoded protein binders were shown to function inside living cells. These molecules offer a new, direct way to assess protein function, distribution and dynamics in vivo. A widely used protein binder scaffold are the so-called nanobodies, which are derived from the variable domain of camelid heavy-chain antibodies. Another commonly used scaffold, the DARPins, is based on Ankyrin repeats. In this review, we highlight how these binders can be functionalized in order to study proteins in vivo during the development of multicellular organisms. It is to be anticipated that many more applications for such synthetic protein binders will be developed in the near future. PMID- 27241222 TI - Heparan Sulfate: Biosynthesis, Structure, and Function. AB - Heparan sulfate (HS) proteoglycans (PGs) are ubiquitously expressed on cell surfaces and in the extracellular matrix of most animal tissues, having essential functions in development and homeostasis, as well as playing various roles in disease processes. The functions of HSPGs are mainly dependent on interactions between the HS-side chains with a variety of proteins including cytokines, growth factors, and their receptors. In a given HS polysaccharide, negatively charged sulfate and carboxylate groups are arranged in various types of domains, generated through strictly regulated biosynthetic reactions and with enormous potential for structural variability. The mode of HS-protein interactions is assessed through binding experiments using saccharides of defined composition in vitro, signaling assays in cell models where HS structures are manipulated, and targeted disruption of genes for biosynthetic enzymes in animals (mouse, zebrafish, Drosophila, and Caenorhabditis elegans) followed by phenotype analysis. Whereas some protein ligands appear to require strictly defined HS structure, others bind to variable saccharide domains without apparent dependence on distinct saccharide sequence. These findings raise intriguing questions concerning the functional significance of regulation in HS biosynthesis and the potential for development of therapeutics targeting HS-protein interactions. PMID- 27241223 TI - Functions of Heparan Sulfate Proteoglycans in Development: Insights From Drosophila Models. AB - Heparan sulfate proteoglycans (HSPGs) are a class of carbohydrate-modified proteins involved in key biological processes, including growth factor signaling, cell adhesion, and enzymatic catalysis. HSPGs serve as coreceptors for a number of ligand molecules to regulate their signaling and distribution. These HS dependent factors include fibroblast growth factors, bone morphogenetic proteins, Wnt-related factors, hedgehog, and cytokines. Several classes of HSPGs are evolutionarily conserved from humans to the genetically tractable model organism Drosophila. Sophisticated molecular genetic tools available in Drosophila provide for a powerful system to address unanswered questions regarding in vivo functions of HSPGs. These studies have highlighted the functions of HSPGs in the regulation of significant developmental events, such as morphogen gradient formation, nervous system formation, and the stem cell niche. Drosophila genetics has also established HSPGs as key factors in feedback controls that ensure robustness in developmental systems. PMID- 27241226 TI - Editorial. PMID- 27241224 TI - Synthesis of diaryl ethers with acetylcholinesterase, butyrylcholinesterase and carbonic anhydrase inhibitory actions. AB - A series of diaryl ethers were synthesized and their human (h) carbonic anhydrase (CA) isoenzymes hCA I and II, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) inhibitory actions were investigated. The new compounds were synthesized from the corresponding phenols and bromobenzenes via the Ullmann reaction, by using dipicolinic acid as a copper (I) complexing ligand. hCA I and II were inhibited with Kis in the low nanomolar range of 102.01 127.13 nM against hCA I, and of 73.71-113.40 nM against hCA II, whereas the inhibition constants against AChE were of 15.35-18.34 nM and against BChE in the range of 9.07-22.90 nM. The CA inhibition mechanism with these ethers is unknown, but may be similar to that of aryl methyl ethers investigated earlier by computational approaches. PMID- 27241225 TI - Prospective evaluation of antibiotic treatment for urological procedure in patients presenting with neurogenic bladder. AB - OBJECTIVES: Patients presenting with neurogenic bladder often require urological procedures (urodynamic testing and botulinum toxin injections) and a preventive antibiotic therapy. We aimed to assess the efficacy of this little known strategy in a cohort of patients. PATIENTS AND METHODS: All patients presenting with neurogenic bladder who underwent urological procedure were included in the study. They received an antibiotic therapy in accordance with the urine cytobacteriological examination results. The antibiotic therapy was initiated two days before the procedure and prolonged up until two days after the procedure if the culture was positive. Patients were treated with a single dose of fosfomycin trometamol in case of a negative culture. The main study outcome was the occurrence of urinary tract infection (UTI), defined by a positive urine culture and symptoms, up until 14 days after the procedure. RESULTS: A total of 80 urological procedures were performed. Mean patient age was 47+/-13.1 years (sex ratio 1.22); 59 (73.8%) presented with asymptomatic bacteriuria before the procedure. Nine (11.1%) UTIs were recorded on Day 14, of which one (1.2%) was febrile. Two patients required an additional curative antibiotic therapy. No patient was hospitalized. Overall, 77.8% of UTIs were cured without antibiotic therapy. CONCLUSION: Screening and treating asymptomatic bacteriuria before urological procedures seems unnecessary and vainly exposes this population at high risk of infectious diseases to antibiotic therapies. This data should be confirmed by a randomized clinical trial. PMID- 27241227 TI - Segmentation and additive approach: A reliable technique to study noncovalent interactions of large molecules at the surface of single-wall carbon nanotubes. AB - This investigation explores a new protocol, named Segmentation and Additive approach (SAA), to study exohedral noncovalent functionalization of single-walled carbon nanotubes with large molecules, such as polymers and biomolecules, by segmenting the entire system into smaller units to reduce computational cost. A key criterion of the segmentation process is the preservation of the molecular structure responsible for stabilization of the entire system in smaller segments. Noncovalent interaction of linoleic acid (LA, C18 H32 O2 ), a fatty acid, at the surface of a (10,0) zigzag nanotube is considered for test purposes. Three smaller segmented models have been created from the full (10,0)-LA system and interaction energies were calculated for these models and compared with the full system at different levels of theory, namely omegaB97XD, LDA. The success of this SAA is confirmed as the sum of the interaction energies is in very good agreement with the total interaction energy. Besides reducing computational cost, another merit of SAA is an estimation of the contributions from different sections of the large system to the total interaction energy which can be studied in-depth using a higher level of theory to estimate several properties of each segment. On the negative side, bulk properties, such as HOMO-LUMO (highest occupied molecular orbital - lowest occupied molecular orbital) gap, of the entire system cannot be estimated by adding results from segment models. (c) 2016 Wiley Periodicals, Inc. PMID- 27241228 TI - The relationship between asymmetry, size and unusual venation in honey bees (Apis mellifera). AB - Despite the fact that symmetry is common in nature, it is rarely perfect. Because there is a wide range of phenotypes which differs from the average one, the asymmetry should increase along with deviation. Therefore, the aim of this study was to assess the level of asymmetry in normal individuals as well as in phenodeviants categorized as minor or major based on abnormalities in forewing venation in honey bees. Shape fluctuating asymmetry (FA) was lower in normal individuals and minor phenodeviants compared with major phenodeviants, whereas the former two categories were comparable in drones. In workers and queens, there were not significant differences in FA shape between categories. FA size was significantly lower in normal individuals compared with major phenodeviant drones and higher compared with minor phenodeviant workers. In queens, there were no significant differences between categories. The correlation between FA shape and FA size was significantly positive in drones, and insignificant in workers and queens. Moreover, a considerable level of directional asymmetry was found as the right wing was constantly bigger than the left one. Surprisingly, normal individuals were significantly smaller than minor phenodeviants in queens and drones, and they were comparable with major phenodeviants in all castes. The correlation between wing size and wing asymmetry was negative, indicating that smaller individuals were more asymmetrical. The high proportion of phenodeviants in drones compared with workers and queens confirmed their large variability. Thus, the results of the present study showed that minor phenodeviants were not always intermediate as might have been expected. PMID- 27241229 TI - Host preference and host colonization of the Asian long-horned beetle, Anoplophora glabripennis (Coleoptera Cerambycidae), in Southern Europe. AB - The Asian long-horned beetle (ALB), Anoplophora glabripennis (Motschulsky), is a highly polyphagous invasive pest with a broad range of host species, but showing relevant differences between infestation areas. Host preference and host colonization (female fecundity, egg and larval survival) were assessed in a population in Northern Italy by choice and no-choice experiments conducted in both field and laboratory conditions. During 5 years of field observations, ALB was found to infest seven genera of trees: Acer, Aesculus, Betula, Populus, Prunus, Salix and Ulmus. However, Acer, Betula, Ulmus and Salix resulted to be the preferred hosts corresponding to 97.5% (1112) of the 1140 infested trees. In both laboratory and field trials carried out on these four host genera, no-choice experiments recorded the highest host colonization of A. glabripennis on Acer trees, with the highest number of laid eggs and the lowest egg and larval mortality. Ulmus and Salix showed a lower number of laid eggs during laboratory choice test, but egg and larval mortality had mean values similar to Acer. On the contrary, despite the high number of Betula trees felled during the eradication plan carried out in the infestation area, this tree species showed the lowest beetle suitability in terms of number of laid eggs and insect survival. An overestimation of the number of infested Betula occurring during the tree survey may explain the discordance between high number of infested Betula and low beetle suitability. Instead, the large number of infested Acer recorded in the field was probably due to the high abundance of these trees occurring in parks and gardens within the infestation area and to the low adult dispersal of A. glabripennis. Overall, results from this study confirm that host species affects both beetle colonization and breeding performance. The study shows ALB host preference and host suitability varying between tree species, suggesting an ALB acceptance even of sub-optimal hosts. PMID- 27241230 TI - Chlorpyrifos-induced hormesis in insecticide-resistant and -susceptible Plutella xylostella under normal and high temperatures. AB - Hormesis induced by insecticides at the dosage lower than what ostensibly directly causes death on insects was studied. This paper reports the effects of the in vivo application of varied concentrations of chlorpyrifos (CPF) on Plutella xylostella (DBM). The insecticide concentrations applied included 0.000025-2.5 mg l-1, which are far lower than LC1 (7.2 mg l-1), for the CPF susceptable (Si) DBM, and 250 mg l-1 which is far below LC1 (1286 mg l-1), for the CPF-resistant (Rc) DBM, as well as LC10- and LC50-doses for both strains. Significant hormesis was found with the 'hermetic-CPFs', i.e., 0.0025 mg l-1 for Si DBM and 2.5 mg l-1 for Rc DBM, at the normal or high temperature either in a 24 h or under a long-term treatment. These doses of CPF significantly stimulated the development and increased the fecundity of Si and Rc DBM at 25 degrees C with approximately 23.5-29.8% activity increase on acetylcholinesterase (AChE) and 30.5-91.3% increase on glutathione S-transferases (GSTs) at 25 or 38 degrees C in 4-24 h. The enzymatic activities were significantly reduced by LC50-CPF at 25 degrees C in vivo, but the inhibition was relieved significantly, if the insects were first subjected to a hormetic-CPF pretreatment. It was remarkable that the average rates of enzymatic activity increase were 67.5-76.6% for AChE and 366 546% for GSTs. Consequently, it was concluded that the hormesis on Si and Rc DBM could be induced by CPF doses far below LC1 at normal or high temperature in short- or long-term treatment. These findings might help to improve the current insect control practices in the field. PMID- 27241231 TI - Double Inversion Recovery Magnetic Resonance Imaging in Identifying Focal Cortical Dysplasia. AB - BACKGROUND: Focal cortical dysplasia is commonly recognized in pediatric epilepsy surgery. Despite characteristic radiographic features, focal cortical dysplasia can be subtle on magnetic resonance imaging. Double inversion recovery acquisition suppresses the white matter signal, which may enhance visualization of abnormal features at the gray-white matter interface. We assessed the ability of double inversion recovery to distinguish focal cortical dysplasia from periventricular nodular heterotopia and normal brain. METHODS: Patients with focal cortical dysplasia were identified from our patient database, as was a control group comprising patients with periventricular nodular heterotopia and healthy persons. A senior neuroradiologist reviewed all clinical images and classified them as patients with focal cortical dysplasia (n = 16) or control subjects (periventricular nodular heterotopia, n = 13; normal, n = 20). Four neuroradiologists reviewed the de-identified and randomized double inversion recovery and magnetization prepared rapid acquired gradient echoes (MPRAGE) sequences for each person and scored them as normal, focal cortical dysplasia, or periventricular nodular heterotopia. RESULTS: Among individual reviewers, double inversion recovery showed sensitivity from 50% to 88% and specificity from 67% to 91% in detecting focal cortical dysplasia. The sensitivity was notably higher in reviewers with more clinical experience with the technique. Consensus agreement among the three most experienced reviewers gave a sensitivity of 88% (95% confidence interval [CI], 72% to 97%) and specificity of 88% (95% CI, 62% to 98%) for double inversion recovery and sensitivity of 44% (95% CI, 20% to 70%) and specificity of 100% (95% CI, 89% to 100%) for MPRAGE. CONCLUSIONS: Double inversion recovery is sensitive for detection of focal cortical dysplasia with experienced users, particularly when there is consensus agreement. The use of two clinically available magnetic resonance imaging acquisitions-double inversion recovery and another sequence with high specificity such as MPRAGE-would be complementary in the evaluation of lesional epilepsy. PMID- 27241232 TI - Intravenous Lacosamide in Pediatric Status Epilepticus: An Open-Label Efficacy and Safety Study. AB - INTRODUCTION: Lacosamide is an antiepilepsy drug approved by the Food and Drug Administration for patients aged 17 years and older for partial-onset seizures as monotherapy or adjunctive therapy. We reviewed the use of intravenous lacosamide in children aged less than 17 years with status epilepticus. METHODS: Children who received at least one dose of intravenous lacosamide for status epilepticus at our tertiary care children's hospital from December 2011 to March 2014 were studied. Status epilepticus was defined as continuous seizure activity for longer than 20 minutes or two or more recurrent seizures without regaining baseline level of awareness. Efficacy was defined as seizure freedom or more than 50% reduction of seizures within 24 hours of administering lacosamide. RESULTS: Nine children with a mean age of 5.7 years (range: three months to 16 years) were included. The mean initial or loading dose was 8.7 mg/kg, with seven of nine patients receiving a dose of 10 mg/kg. The average total amount of intravenous lacosamide administered within the initial 24 hours was 13.8 mg/kg. Lacosamide was found to be efficacious in seven of nine (77.8%) patients. Four patients (44.4%) became seizure free. Two patients continued to have status epilepticus within 24 hours of lacosamide administration. Bradycardia was observed in one patient. CONCLUSION: In children with status epilepticus, intravenous lacosamide was efficacious in 78% of the patients and 44% become seizure free. In addition, no significant adverse reactions were observed. An appropriate safe, effective initial, or loading dose may be 10 mg/kg. PMID- 27241233 TI - Electronic Origins of the Variable Efficiency of Room-Temperature Methane Activation by Homo- and Heteronuclear Cluster Oxide Cations [XYO2](+) (X, Y = Al, Si, Mg): Competition between Proton-Coupled Electron Transfer and Hydrogen-Atom Transfer. AB - The reactivity of the homo- and heteronuclear oxide clusters [XYO2](+) (X, Y = Al, Si, Mg) toward methane was studied using Fourier transform ion cyclotron resonance mass spectrometry, in conjunction with high-level quantum mechanical calculations. The most reactive cluster by both experiment and theory is [Al2O2](*+). In its favorable pathway, this cluster abstracts a hydrogen atom by means of proton-coupled electron transfer (PCET) instead of following the conventional hydrogen-atom transfer (HAT) route. This mechanistic choice originates in the strong Lewis acidity of the aluminum site of [Al2O2](*+), which cleaves the C-H bond heterolytically to form an Al-CH3 entity, while the proton is transferred to the bridging oxygen atom of the cluster ion. In addition, a comparison of the reactivity of heteronuclear and homonuclear oxide clusters [XYO2](+) (X, Y = Al, Si, Mg) reveals a striking doping effect by aluminum. Thus, the vacant s-p hybrid orbital on Al acts as an acceptor of the electron pair from methyl anion (CH3(-)) and is therefore eminently important for bringing about thermal methane activation by PCET. For the Al-doped cluster ions, the spin density at an oxygen atom, which is crucial for the HAT mechanism, acts here as a spectator during the course of the PCET mediated C-H bond cleavage. A diagnostic plot of the deformation energy vis-a-vis the barrier shows the different HAT/PCET reactivity map for the entire series. This is a strong connection to the recently discussed mechanism of oxidative coupling of methane on magnesium oxide surfaces proceeding through Grignard-type intermediates. PMID- 27241234 TI - Antinociceptive Effect of Racemic Flurbiprofen and Caffeine Co-Administration in an Arthritic Gout-Type Pain in Rats. AB - Preclinical Research Drug combinations are routinely used in the treatment of pain. In drug associations, adjuvants such as caffeine, are employed with different non-steroidal anti-inflammatories drugs (NSAIDs), however, at present does not exist studies showing the effect of the combination of racemic flurbiprofen (rac-Flur) in association with caffeine. The objective of this work was to evaluate the combination of rac-Flur + caffeine oral in arthritic gout type pain in rats. The antinociceptive effects of the rac-Flur alone and in combination with caffeine were analyzed on a pain-induced functional impairment model in rat. rac-Flur induced a dose-dependent antinociceptive effect and caffeine did not present any effect. The combination of rac-Flur and caffeine achieve a higher percentage of antinociceptive effect compared with the individual administration of rac-Flur. The dose-response curve (DRCs) shows that the combination of rac-Flur (31.6 mg/kg) + caffeine (17.8 mg/kg) exhibited the maximal antinociceptive efficacy (294.0 +/- 21.2 area units), while rac-Flur alone (31.6 mg/kg) showed 207.2 +/- 35.2 au, thus indicating an increase in efficacy (potentiation). Furthermore, the DRCs of the combinations presented a displacement to the left, indicating a change in the potency. Caffeine is able to increase the effect of rac-Flur in the arthritic gout-type pain in rats. Drug Dev Res 77 : 192-198, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27241235 TI - Optimum alcohol concentration for chain elongation in mixed-culture fermentation of cellulosic substrate. AB - Medium-chain fatty acids (MCFA, e.g., caproic, heptanoic, caprylic acid) are more valuable than short-chain fatty acids (SCFA, e.g., acetic, propionic, butyric, valeric acid). SCFAs are major products in methane-inhibited mixed-culture anaerobic fermentation. By feeding ethanol to the fermentor, MCFA formation is enhanced through chain elongation. Microorganisms such as Clostridium kluyveri elongate short-chain acids by combining them with alcohol. Very low ethanol concentration reduces chain elongation rates, whereas very high ethanol concentrations inhibit microorganisms. To maximize MCFA production, different ethanol concentrations were investigated in the mixed-culture fermentation of office paper and chicken manure. At 10 g/L ethanol concentration, 10 g/L MCFA was formed. High ethanol concentrations (above 40 g/L) inhibit microorganisms resulting in no chain elongation. For chain elongation, propanol was found to be more inhibitory than ethanol. The data suggest that MCFA production will increase by continuously extracting MCFA and maintaining 5-10 g/L ethanol concentration by periodic addition. Biotechnol. Bioeng. 2016;113: 2597-2604. (c) 2016 Wiley Periodicals, Inc. PMID- 27241236 TI - Nanocapsules with glycerol monolaurate: Effects on Candida albicans biofilms. AB - Candida albicans does not only occur in the free living planktonic form but also grows in surface-attached biofilm communities. Moreover, these biofilms appear to be the most common lifestyle and are involved in the majority of human Candida infections. Nanoparticles can be used as an alternative to conventional antimicrobial agents and can also act as carriers for antibiotics and other drugs. In view of this, the aim of the study was develop, characterize and verify the anti-biofilm potential of GML Nanocapsules against C. albicans. The GML Nanocapsules showed mean diameter of 193.2 nm, polydispersion index of 0.044, zeta potential of -23.3 mV and pH 6.32. The microdilution assay showed MIC of 15.5 MUg mL(-1) to GML Nanocapsules and 31.25 MUg mL(-1) to GML. The anti-biofilm assay showed the significantly reduction of biomass of C. albicans biofilm treated with GML Nanocapsules while the GML does not exhibit effect. The kinetic assay demonstrated that at 48 h, the GML Nanocapsules reduce 94% of formed biofilm. The positive results suggest the promisor alternative for this public health problem that is biofilm infections. PMID- 27241237 TI - Three-dimensional hierarchical cultivation of human skin cells on bio-adaptive hybrid fibers. AB - The human skin comprises a complex multi-scale layered structure with hierarchical organization of different cells within the extracellular matrix (ECM). This supportive fiber-reinforced structure provides a dynamically changing microenvironment with specific topographical, mechanical and biochemical cell recognition sites to facilitate cell attachment and proliferation. Current advances in developing artificial matrices for cultivation of human cells concentrate on surface functionalizing of biocompatible materials with different biomolecules like growth factors to enhance cell attachment. However, an often neglected aspect for efficient modulation of cell-matrix interactions is posed by the mechanical characteristics of such artificial matrices. To address this issue, we fabricated biocompatible hybrid fibers simulating the complex biomechanical characteristics of native ECM in human skin. Subsequently, we analyzed interactions of such fibers with human skin cells focusing on the identification of key fiber characteristics for optimized cell-matrix interactions. We successfully identified the mediating effect of bio-adaptive elasto-plastic stiffness paired with hydrophilic surface properties as key factors for cell attachment and proliferation, thus elucidating the synergistic role of these parameters to induce cellular responses. Co-cultivation of fibroblasts and keratinocytes on such fiber mats representing the specific cells in dermis and epidermis resulted in a hierarchical organization of dermal and epidermal tissue layers. In addition, terminal differentiation of keratinocytes at the air interface was observed. These findings provide valuable new insights into cell behaviour in three-dimensional structures and cell-material interactions which can be used for rational development of bio-inspired functional materials for advanced biomedical applications. PMID- 27241238 TI - Corneal grafting for the treatment of full-thickness corneal defects in dogs: a review of 50 cases. AB - OBJECTIVE: To describe corneal grafting for the treatment of full-thickness corneal defects in dogs and to determine its effectiveness in preserving vision. METHODS: A review of the medical records of dogs that underwent corneal grafting following corneal perforations (>=3 mm) at the VTH-UAB from 2002 to 2012 was carried out. RESULTS: Fifty dogs of different breed, age and gender were included. Brachycephalic breeds were overrepresented (37/50;74%). All cases were unilateral, with euryblepharon being the most common concurrent ocular abnormality (20/50;40%). Full-thickness penetrating keratoplasties (FTPK) were performed in 21/50 eyes (42%) and lamellar keratoplasties (LK) in 29/50 eyes (58%). Frozen grafts (FroG) were used in 43/50 eyes (86%) and fresh homologous grafts (FreHoG) in 7/50 (14%). Of the former group, 26 were homologous (FroHoG:60%) and 17 heterologous (FroHeG:40%). A combination of topical medication (antibiotics, corticosteroids, cycloplegics, and 0.2% cyclosporine A) and systemic mycophenolate mofetil was administered. Median follow-up time was 200 days. Postsurgical complications included wound dehiscence (6/50;12%) and glaucoma (4/50;8%). Clinical signs of graft rejection were diagnosed as follows: FroHoG (13/26;50%), FroHeG (11/17;65%), FreHoG (4/7;57%), FTPK (12/21;57%), and LK (16/29;55%). Medical treatment successfully controlled graft rejection in 11/28 eyes (39%). Good anatomical outcome was achieved in 86% (43/50), of which 95% (41/43) were visual at last examination, with moderate opacification to complete transparency of the graft present in 48.2%. CONCLUSIONS: Corneal grafting is an effective surgical treatment for full-thickness corneal defects in dogs. If graft rejection is present, additional medical or surgical therapy may be necessary, achieving a highly satisfactory visual outcome. PMID- 27241239 TI - Intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyradiculoneuropathy, a time to start and a time to stop. AB - Intravenous immunoglobulin (IVIg) is often used as preferred treatment in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Several studies highlighted the short-term efficacy of IVIg for CIDP yet many patients need maintenance therapy. Notwithstanding the fact IVIg has been used for over 30 years in CIDP, there is only limited evidence to guide dosage and interval during maintenance treatment. The variation in disease course, lack of biomarkers, and fear of deterioration after stopping IVIg makes long-term treatment challenging. Recent studies suggest a proportion of patients receive unnecessary IVIg maintenance treatment. This review provides an overview of the use of IVIg for CIDP treatment, focusing on evidence for long-term IVIg use. PMID- 27241240 TI - Comparative pharmacokinetics of fluralaner in dogs and cats following single topical or intravenous administration. AB - BACKGROUND: BravectoTM Chewable Tablets for Dogs, containing fluralaner as active ingredient, is an innovative treatment for flea and tick infestations that provides safe, rapid and long acting efficacy after a single oral administration in dogs. Topically applied fluralaner provides similar safe, rapid and long acting efficacy, both in dogs and in cats. The pharmacokinetic profile of fluralaner was evaluated in dogs and in cats following either topical or intravenous administration. METHODS: Twenty four dogs and 24 cats received three different topical doses, with the mid-dose based on the respective minimum recommended dose, and one intravenous dose. Plasma samples were collected for 112 days and fluralaner concentrations were quantified using a validated high performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) method. Pharmacokinetic parameters were calculated using non-compartmental methods. RESULTS: In dogs, fluralaner was readily absorbed from the topical administration site into the skin, subjacent tissues and blood. Fluralaner plasma concentrations showed an apparent plateau between ~ day 7 and 63, with individual tmax seen within this time period. After the plasma plateau, concentrations declined slowly and were quantifiable for more than 12 weeks. In cats, fluralaner was readily systemically absorbed from the topical administration site, reaching maximum concentrations (Cmax) in plasma between 3 and 21 days post administration, after which concentrations declined slowly, and were also quantifiable for more than 12 weeks. Systemic exposure, as shown by Cmax and the area under the concentration versus time curve from time 0 to the last measurable concentration (AUC(0->t)) increased proportionally with dose in both species. Following intravenous administration fluralaner showed a relatively high apparent volume of distribution (Vz), a low plasma clearance (Cl), a long terminal half life (t1/2) and a long mean residence time (MRT); thereby demonstrating a long persistence of fluralaner in both species. CONCLUSIONS: The pharmacokinetic characteristics of fluralaner explain its prolonged activity against fleas and ticks on both dogs and cats after a single topical administration. PMID- 27241242 TI - Acute kidney injury: Zero deaths from AKI by 2025: focus on awareness and therapy. PMID- 27241243 TI - A potential mechanism of dural ossification in ossification of ligamentum flavum. AB - Ossification of the ligamentum flavum (OLF) mostly occurs in the thoracic spine, leading to thoracic spinal stenosis. Surgical treatment is considered as the best option for OLF patients. When the dura mater ossifies, the difficulty of surgery and the risk of complications significantly increase. The cause of dural ossification (DO) is still unknown. Based on the existing research and clinical studies, we propose a potential mechanism of DO in OLF. Firstly, with the progression of OLF, it will compress the dura mater and even the spinal cord. Then, with flexion and extension of spine, relative movement (friction) between the ossified ligamentum flavum and compressed dura mater will lead to local inflammation, subsequently causing dural adhesion. Finally, the adhesion tissue can serve as a pathway for the transportation of osteogenic cytokines (BMP for example) from the ossified ligamentum flavum to the compressed dura mater. Dura will ossify under exposure of these osteogenic cytokines. If this hypothesis is confirmed, it will contribute to the prevention and management of DO. For progressive OLF patients, early surgical treatment before DO should be recommended. PMID- 27241241 TI - The role of neutrophils and NETosis in autoimmune and renal diseases. AB - Systemic autoimmune diseases are a group of disorders characterized by a failure in self-tolerance to a wide variety of autoantigens. In genetically predisposed individuals, these diseases occur as a multistep process in which environmental factors have key roles in the development of abnormal innate and adaptive immune responses. Experimental evidence collected in the past decade suggests that neutrophils - the most abundant type of white blood cell - might have an important role in the pathogenesis of these diseases by contributing to the initiation and perpetuation of immune dysregulation through the formation of neutrophil extracellular traps (NETs), synthesis of proinflammatory cytokines and direct tissue damage. Many of the molecules externalized through NET formation are considered to be key autoantigens and might be involved in the generation of autoimmune responses in predisposed individuals. In several systemic autoimmune diseases, the imbalance between NET formation and degradation might increase the half-life of these lattices, which could enhance the exposure of the immune system to modified autoantigens and increase the capacity for NET-induced organ damage. This Review details the role of neutrophils and NETs in the pathophysiology of systemic autoimmune diseases, including their effect on renal damage, and discusses neutrophil targets as potential novel therapies for these diseases. PMID- 27241244 TI - Possible role of antioxidants and nitric oxide inhibitors against carbon monoxide poisoning: Having a clear conscience because of their potential benefits. AB - Carbon monoxide poisoning is one of the important emergency situations manifested by primarily acute and chronic anoxic central nervous system (CNS) injuries and other organ damages. Current descriptions and therapeutic approaches have been focused on the anoxic pathophysiology. However, this point of view incompletely explains some of the outcomes and needs to be investigated extensively. Considering this, we propose that reactive oxygen species (ROS) including especially nitric oxide (NO) are likely to be a key concept to understand the emergency related to CO poisoning and to discover new therapeutic modalities in CO toxicity. If we consider the hypothesis that ROS is involved greatly in acute and chronic toxic effects of CO on CNS and some other vital organs such as heart, it follows that the antioxidant and anti-NO therapies might give the clinicians more opportunities to prevent deep CNS injury. In support of this, we review the subject in essence and summarize clinical and experimental studies that support a key role of ROS in the explanation of pathophysiology of CO toxicity as well as new treatment modalities after CO poisoning. PMID- 27241245 TI - Dairy products and the French paradox: Could alkaline phosphatases play a role? AB - The French paradox - high saturated fat consumption but low incidence of cardiovascular disease (CVD) and mortality - is still unresolved and continues to be a matter of debate and controversy. Recently, it was hypothesised that the high consumption of dairy products, and especially cheese by the French population might contribute to the explanation of the French paradox, in addition to the "(red) wine" hypothesis. Most notably this would involve milk bioactive peptides and biomolecules from cheese moulds. Here, we support the "dairy products" hypothesis further by proposing the "alkaline phosphatase" hypothesis. First, intestinal alkaline phosphatase (IAP), a potent endogenous anti inflammatory enzyme, is directly stimulated by various components of milk (e.g. casein, calcium, lactose and even fat). This enzyme dephosphorylates and thus detoxifies pro-inflammatory microbial components like lipopolysaccharide, making them unable to trigger inflammatory responses and generate chronic low-grade inflammation leading to insulin resistance, glucose intolerance, type-2 diabetes, metabolic syndrome and obesity, known risk factors for CVD. Various vitamins present in high amounts in dairy products (e.g. vitamins A and D; methyl-donors: folate and vitamin B12), and also fermentation products such as butyrate and propionate found e.g. in cheese, all stimulate intestinal alkaline phosphatase. Second, moulded cheeses like Roquefort contain fungi producing an alkaline phosphatase. Third, milk itself contains a tissue nonspecific isoform of alkaline phosphatase that may function as IAP. Milk alkaline phosphatase is present in raw milk and dairy products increasingly consumed in France. It is deactivated by pasteurization but it can partially reactivate after thermal treatment. Experimental consolidation of the "alkaline phosphatase" hypothesis will require further work including: systematic alkaline phosphatase activity measurements in dairy products, live dairy ferments and intestine of model animals. Furthermore, stool residual IAP, a possible early marker of diabetes, should be assayed in human cohorts. If confirmed, this "alkaline phosphatase" hypothesis will highlight the protective effects of milk alkaline phosphatase and promote the consumption of (microbiologically safe) raw milk and dairy products. Microorganisms secreting alkaline phosphatases may be privileged as ferments in dairy products. PMID- 27241246 TI - Myogenic and metabolic feedback in cerebral autoregulation: Putative involvement of arachidonic acid-dependent pathways. AB - The present paper presents a mechanistic model of cerebral autoregulation, in which the dual effects of the arachidonic acid metabolites 20 hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) on vascular smooth muscle mediate the cerebrovascular adjustments to a change in cerebral perfusion pressure (CPP). 20-HETE signalling in vascular smooth muscle mediates myogenic feedback to changes in vessel wall stretch, which may be modulated by metabolic feedback through EETs released from astrocytes and endothelial cells in response to changes in brain tissue oxygen tension. The metabolic feedback pathway is much faster than 20-HETE-dependent myogenic feedback, and the former thus initiates the cerebral autoregulatory response, while myogenic feedback comprises a relatively slower mechanism that functions to set the basal cerebrovascular tone. Therefore, assessments of dynamic cerebral autoregulation, which may provide information on the response time of the cerebrovasculature, may specifically be used to yield information on metabolic feedback mechanisms, while data based on assessments of static cerebral autoregulation represent the integrated functionality of myogenic and metabolic feedback. PMID- 27241247 TI - Does MeCP2 deficiency in autism confer protection against later development of Alzheimer's disease? A reply to Oberman and Pascual-Leone (2014). AB - Oberman and Pascual-Leone have proposed a novel hypothesis that the hyperplasticity in autism spectrum disorders (ASD) may confer protection against later development of Alzheimer's disease (AD). The author of this correspondence has made the novel proposition elsewhere that exposure to the increasing agricultural air pollutant, nitrous oxide (N2O), may be the primary etiologic factor in driving neurodevelopmental impairment (i.e., ADHD, ASD, etc.) in humans. This correspondence, therefore, merges these heretofore distinct ideas in order to highlight two mechanisms of how gestational exposure to certain environmental pollutants may confer protection against AD. The hyperplasticity undergirding this protection may include limited noradrenergic discharge from locus coeruleus through MeCP2 deficiency (an emerging biomarker in ASD) and a heightened kappa-opioid receptor (KOR) system. While these endogenous dynamics in ASD may exert neural protection against development of AD, long-term pharmacologic intervention that enhances central catecholaminergic activity may disrupt this benefit, and this may be an important follow-up to address in future studies exploring the novel hypothesis from Oberman and Pascual-Leone. PMID- 27241248 TI - Are endogenous cardenolides controlled by atrial natriuretic peptide. AB - Endogenous cardenolides are digoxin-like substances and ouabain-like substances that have been implicated in the pathogenesis of hypertension and mood disorders in clinical and pre-clinical studies. Regulatory signals for endogenous cardenolides are still unknown. These endogenous compounds are believed to be produced by the adrenal gland in the periphery and the hypothalamus in the central nervous system, and constitute part of an hormonal axis that may regulate the catalytic activity of the alpha subunit of Na(+)/K(+)-ATPase. A review of literature suggests that there is great overlap in physiological environments that are associated with either elevations or reductions in the levels of atrial natriuretic peptide (ANP) and endogenous cardenolides. This suggests that these two factors may share a common regulatory signal or perhaps that ANP may be involved in the regulation of endogenous cardenolides. PMID- 27241249 TI - Nicolas Ferry (1741-1764), the court dwarf of King Stanislas, probably suffered from microcephalic osteodysplastic primordial dwarfism type II (MOPD II). PMID- 27241250 TI - Cryogenically salvaged teeth as a potential source for grafting dentoalveolar, periodontal or maxillofacial defects. AB - Bone grafting uses a wide range of materials derived mainly from exogenous sources. Autogenous teeth are often used fresh or fixed with alcohol for later use. Proposed here is a method of using cryogenically preserved autogenous extracted teeth, which could be macerated after thawing. This method avoids the possibility of tissue being denatured by alcohol and preserves intact all calcified structures for optimal bone grafting success. PMID- 27241251 TI - A new era of thoracic oncology? Ex-vivo stereotactic ablative radiosurgery within Ex-vivo Lung Treatment System as a hybrid therapy for unresectable locally advanced pulmonary malignancies. AB - The concept of oligometastases is the medical rationale for a local treatment of a limited number of metastatic tumor manifestations. Patients with pulmonary oligometastases are candidates for surgery or radiotherapy, however there are a number of technical issues that limit treatment. Technical issues relating to radiotherapy include organs at risk of irradiation, chest wall toxicity and decreased precision of tumor targeting because of breathing movements. Technical issues relating to surgery include loss of lung parenchyma and unresectability. We propose the hypothesis that ex-vivo radiosurgery as new hybrid technique in thoracic oncology has the capability to overcome these technical issues and will expand the medical spectrum in thoracic oncology. The proposed - highly complex - technique consists of surgical lung explantation, followed by stereotactic radiotherapy during ex-vivo perfusion followed by surgical re-implantation. PMID- 27241252 TI - Exploring neuroprotective potential of Withania somnifera phytochemicals by inhibition of GluN2B-containing NMDA receptors: An in silico study. AB - N-methyl-d-aspartate receptors (NMDARs) mediated excitotoxicity has been implicated in multi-neurodegenerative diseases. Due to lack of efficacy and adverse effects of NMDA receptor antagonists, search for herbal remedies that may act as therapeutic agents is an active area of research to combat these diseases. Withania somnifera (WS) is being used for centuries as a nerve tonic and Nootropic agents. The present study targets the in silico evaluation of the neuroprotective efficacy of W. somnifera phytochemicals by inhibition of NMDA receptor-mediated excitotoxicity through allosteric inhibition of the GluN2B containing NMDARs. We predict Blood Brain Barrier (BBB) penetration, mutagenicity, drug-likeness and Human Intestinal Absorption properties of 25 WS phytochemicals. Further, molecular docking was performed to know whether these phytochemicals inhibit the GluN2B containing NMDARs or not. The results suggest that Anaferine, Beta-Sitosterol, Withaferin A, Withanolide A, Withanolide B and Withanolide D inhibit GluN2B containing NMDARs through allosteric mode similar to the well-known selective antagonist Ifenprodil. These phytochemicals have potential as an essentially useful oral drug to counter NMDARs mediated excitotoxicity and to treat multi-neurodegenerative diseases. PMID- 27241253 TI - Nanofacilitated synergistic treatment for rheumatoid arthritis: A 'three-pronged' approach. AB - Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease of unidentified etiology that affects the joints and causes pain, swelling, stiffness and redness in the joints. The exact cause of rheumatoid arthritis has not yet been discovered and, consequently, treatment methods have not been optimally effective. It has long been treated with anti-inflammatory and immunosupressants including modern biologics either alone or in combination but all of the drugs have severe life threatening consequences with impaired immune function due to nonspecific targeting. Therefore, a three-pronged approach of local, active and synergistic targeting can be used to optimize delivery of therapeutic agents to reduce toxicity and patient outcome without compromising patient's immunity. PMID- 27241254 TI - Leptin inhibitors from fungal endophytes (LIFEs): Will be novel therapeutic drugs for obesity and its associated immune mediated diseases. AB - Treatment of obesity and its associated immune mediated diseases is challenging due to impaired function of leptin system. Thus leptin is providing an interesting target for therapeutic intervention. Leptin, an adipose tissue derived adipokine, displays a variety of immune functions, and regulate both innate and adaptive immune responses. The increased secretion of leptin (hyperleptinemia) and production of proinflammatory cytokines has been implicated in the pathogenesis of obesity-related immune diseases such as diabetes mellitus, hypertension, atherosclerosis, cancer, systemic lupus erythematosus, rheumatoid arthritis, crohn's disease and multiple sclerosis. These disorders are managed through antibiotics and by cytokines replacement. However, the effectiveness of cytokines coupled to the complexity of the cytokine network leads to severe side effects, which can still occur after careful preclinical evaluation. In addition, synthetic immunotherapeutics carries a degree of risk, is time-consuming and expensive. Hence, the complexity of existing therapy and adverse effects emphasizes the need of an alternative approach for the management of immune dysfunction associated with obesity and its related diseases. For the aforementioned diseases that are related to leptin overabundance, new drugs blocking leptin signaling need to be generated. The research on the discovery of clinically important novel compounds from natural source is expanding due to their safety and no side effect. The fungal endophytes are the microbes that colonize internal tissue of plants without causing negative effects to the host. They produce plethora of substances of potential use to modern medicinal and pharmaceutical industry. The increasing body of evidence associated with application of bioactive metabolites derived from fungal endophytes in diverse disease states merits its use as therapeutic drugs. In particular, the saponins have been extensively proved to modulate the immune system, which has raised a significant interest in their potential as immunomodulators. Thus, our hypothesis is that the saponins derived from fungal endophytes can be explored as clinical applicable leptin inhibitors for treating immune mediated diseases. PMID- 27241255 TI - Suppositional area for the search of bacterial products for anticancer therapy. AB - It is well-known that bacteria can produce compounds which show anticancer effects. In present time, it is impossible to check all bacterial species on their possible production of anticancer compounds (AC) under different conditions. Thus, it is necessary to limit the area for search of bacterial products for the anticancer therapy. We propose that production of AC by bacteria is a part of microbial biological strategy under natural conditions. We propose that bacteria in soils, in water and on plants do not meet human tumors and their AC serve for the competition with eukaryotic organisms. Most probably, an epiphytic growth of bacilli is accompanied with production of compounds inhibiting eukaryotes. According to awaited profit for the AC-producing bacteria, the epiphytic groups of bacilli show inhibition of mycelial fungi which are a natural model of eukaryotic cells. An example of strain isolation and a primary test is presented. PMID- 27241256 TI - Systemic anti-CTLA-4 and intravesical Bacille-Calmette-Guerin therapy in non muscle invasive bladder cancer: Is there a rationale of synergism? AB - Although intravesical instillation of Bacille-Calmette-Guerin (BCG) immunotherapy was approved many decades ago as a first line therapy for intermediate to high risk non-muscle invasive bladder cancer, its long-term efficacy is still arguable as a proportion of up to 30-40% of patients will develop recurrence or progression of their disease. Based on currently available data on the clinical application of checkpoint inhibitors in solid tumors, the mucosa-associated lymphoid tissue seems to be a main target for anti-CTLA-4 antibodies. In this manuscript we hypothesize that the combination of anti-CTLA-4 therapy with BCG might enhance the immune activity in the bladder submucosal tissue, and subsequently, improve oncological outcomes of NMIBC. PMID- 27241257 TI - Human cognition and psychopathology. PMID- 27241258 TI - Targeting the IFN-gamma/CXCL10 pathway in lichen planus. AB - Lichen planus is a chronic inflammatory disease of the skin, mucous membranes and nails. Management of oral involvement, particularly atrophic and erosive lesions, is challenging. Noteworthy, there is a lack of published evidence for treatment. Cell-mediated cytotoxicity is actually regarded as a major mechanism of pathogenesis. The interferon-gamma induced chemokines CXCL10 and CXCL9 are strongly expressed in serum of patients as well as in both skin and mucosal lesions. Therefore the interferon gamma/CXCL10 axis is considered a key process for both progression and maintenance of chronic cytotoxic inflammation. According to these findings, the interferon gamma/CXCL10 axis could be considered a therapeutically attractive target to reverse inflammation. Since interferon gamma signal transduction occurs through JAK 1 and 2, JAK inhibitors could lead to blockade of interferon gamma signaling and downstream CXCL10 expression. PMID- 27241259 TI - Anesthetic effects changeable in habitual drinkers: Mechanistic drug interactions with neuro-active indoleamine-aldehyde condensation products associated with alcoholic beverage consumption. AB - Clinicians often experience the reduced efficacy of general and local anesthetics and anesthesia-related drugs in habitual drinkers and chronic alcoholics. However, the mechanistic background underlying such anesthetic tolerance remains unclear. Biogenic indoleamines condense with alcohol-derived aldehydes during fermentation processes and under physiological conditions to produce neuro-active tetrahydro-beta-carbolines and beta-carbolines, many of which are contained not only in various alcoholic beverages but also in human tissues and body fluids. These indoleamine-aldehyde condensation products are increased in the human body because of their exogenous and endogenous supply enhanced by alcoholic beverage consumption. Since tetrahydro-beta-carbolines and beta-carbolines target receptors, ion channels and neuronal membranes which are common to anesthetic agents, we propose a hypothesis that they may pharmacodynamically interact at GABAA receptors, NMDA receptors, voltage-gated Na(+) channels and membrane lipid bilayers to attenuate anesthetics-induced positive allosteric GABAA receptor modulation, NMDA receptor antagonism, ion channel blockade and neuronal membrane modification, thereby affecting anesthetic efficacy. The condensation products may also cooperatively interact with ethanol that induces adaptive changes and cross-tolerance to anesthetics and with dopamine-aldehyde adducts that act on GABAA receptors and membrane lipids. Because tetrahydro-beta-carbolines and beta carbolines are metabolized to lose or decrease their neuro-activities, induction of the relevant enzymes by habitual drinking could produce an inter-individual difference of drinkers in susceptibility to anesthetic agents. The present hypothesis would also provide a unified framework for different modes of anesthetic action, which are inhibited by neuro-active indoleamine-aldehyde condensation products associated with alcoholic beverage consumption. PMID- 27241261 TI - Tracheal suctioning in ventilatory-associated pneumoniae: Is saline the best choice? PMID- 27241262 TI - The lexeme hypotheses: Their use to generate highly grammatical and completely computerized medical records. AB - INTRODUCTION: Medical records often contain free text created by harried clinicians. Free text often contains errors which make it an unsuitable target for computerized data extraction. The cost of healthcare can be reduced by creating medical records that are fully computerized at their inception. We examine hypotheses that enable us to construct such records. METHODS: We regard the text of the medical record as being an ordered collection of meaningful fragments. The intellectual content (or "lexeme") of each text fragment in the record is considered separately from the language that used to express it. We further consider that each lexeme exists as a combination of a lexeme query (defining the issue being addressed) and a lexeme response to that query. The medical record can then be perceived as a stream of these responses. The responses can be expressed in any style or language, including computer code. Examining medical records in this light gives rise to a number of observations and hypotheses. OBSERVATIONS AND HYPOTHESES: The physical location and nature of the medical episode (which we term "context") determines the general layout of the record. The order that lexeme-queries are addressed in within the record is highly consistent ("coherence"). Issues are only addressed if they are logically called-for by the context or by a previously-selected lexeme response ("predicance"), and only to a needed depth of detail ("level"). We hypothesize that all of the lexeme queries required to write any clinical notes can be stored in a large database ("lexicon") in coherence order, wherein each lexeme query is associated with its own collection of lexeme responses. We hypothesize that the issue a note-writer will need to address next is identifiable purely by using the rules of coherence, level and predicance. TESTING THE HYPOTHESES AND THEIR UTILITY: We have tested these hypotheses with a computer program which repeatedly offers the user a menu of lexeme responses with associated text. On selection, the program issues the text fragment, and its corresponding computer code, to output files. The program then uses coherence, predicance and level to navigate to the next appropriate lexeme query for presentation to the user. The net result is that the user creates a grammatically correct and completely computerized note at the time of its inception. The value of this approach and its practical implementation to create medical records are discussed. In our work so far, the hypotheses appear not to be false, but further testing is needed using a larger lexicon to establish their robustness in actual clinical practice. PMID- 27241260 TI - Colchicine to decrease NLRP3-activated inflammation and improve obesity-related metabolic dysregulation. AB - Obesity is a major risk-factor for the development of insulin resistance, type 2 diabetes, and cardiovascular disease. Circulating molecules associated with obesity, such as saturated fatty acids and cholesterol crystals, stimulate the innate immune system to incite a chronic inflammatory state. Studies in mouse models suggest that suppressing the obesity-induced chronic inflammatory state may prevent or reverse obesity-associated metabolic dysregulation. Human studies, however, have been far less positive, possibly because targeted interventions were too far downstream of the inciting inflammatory events. Recently, it has been shown that, within adipose tissue macrophages, assembly of a multi-protein member of the innate immune system, the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, is essential for the induction of this inflammatory state. Microtubules enable the necessary spatial arrangement of the components of the NLRP3 inflammasome in the cell, leading to its activation and propagation of the inflammatory cascade. Colchicine, a medication classically used for gout, mediates its anti-inflammatory effect by inhibiting tubulin polymerization, and has been shown to attenuate macrophage NLRP3 inflammasome arrangement and activation in vitro and in vivo. Given these findings, we hypothesize that, in at-risk individuals (those with obesity-induced inflammation and metabolic dysregulation), long-term colchicine use will lead to suppression of inflammation and thus cause improvements in insulin sensitivity and other obesity-related metabolic impairments. PMID- 27241263 TI - Intermittent drinking, oxytocin and human health. AB - Looking at a waterhole, it is surprising that so many animals share the same space without visible signs of anxiety or aggression. Although waterholes are the preferred feeding locations of large carnivores, waterholes are shared by all type of herbivores of all sizes and shapes, including elephants. Recent research shows that the homeostatic disturbances leading to the "thirst feeling" not only activate specific substances regulating water and mineral household, but also the "trust and love" hormone oxytocin, while decreasing the production of the typical stress hormone cortisol. People using drugs, seem to be in search for oxytocin, as evidenced in studies with individuals on drugs such as ecstasy and gamma hydroxybyturate. Hot environment, drought and increased sweating also activate specific oxytocin-producing parts of the hypothalamus, just as breastfeeding does in mother and infant. Water homeostasis is the only allostatic system activating trust neuro-anatomy and we suggest that this is due to the fact that all animals depend on water, whereas food type is species specific. Our hypothesis; regulating drinking behaviour through intermittent bulk drinking could increase oxytocin signalling, recover human trust and increase health by down-regulation of stress axis activity and inflammatory activity of the immune system. Intermittent bulk drinking should be defined as water (including tea and coffee) drinking up to a feeling of satiety and regulated by a mild feeling of thirst. This would mean that people would not drink less quantity but less frequently and that's how all animals, but also human newborns behave. It is the latter group, which is probably the only group of humans with a normal fluid homeostasis. PMID- 27241264 TI - Possible relationship between endocrine disrupting chemicals and hormone dependent gynecologic cancers. AB - The effects of the natural and synthetic estrogens have been studied for a long time but the data regarding estrogen related chemicals (endocrine disrupting chemicals, EDCs) and their effects on reproductive system are scarce. EDCs are hormone like agents that are readily present in the environment, which may alter the endocrine system of humans and animals. Approximately 800 chemicals are known or suspected to have the potential to function as EDC. Potential role of EDCs on reproductive disease has gained attention in medical literature in recent years. We hypothesize that exposure to low doses of EDCs in a chronic manner could cause hormone dependent genital cancers including ovarian and endometrial cancer. Long term exposure to low concentrations of EDCs may exert potentiation effect with each other and even with endogenous estrogens and could inhibit enzymes responsible for estrogen metabolism. Exposure time to these EDCs is essential as we have seen from Diethylstilbestrol experience. Dose-response curves of EDCs are also unpredictable. Hence mode of action of EDCs are more complex than previously thought. In the light of these controversies lower doses of EDCs in long term exposure is not harmless. Possibility of this relationship and this hypothesis merit further investigation especially through in vivo studies that could better show the realistic environmental exposure. With the confirmation of our hypothesis, possible EDCs could be identified and eliminated from general use as a public health measure. PMID- 27241265 TI - A biomechanical hypothesis for the pathophysiology of apical lung disease. AB - OBJECTIVE: A hypothesis is presented suggesting that the pathogenesis of apical lung disease is due to progression of subclinical congenital apical bullae in people with low Body Mass Index (BMI), a combination present in 15% of the population, due to high pleural stress levels present in the antero-posteriorly flattened chests of these individuals. DESIGN: The hypothesis was tested for validity in two apical lung pathologies with widespread epidemiological literature, namely tuberculosis (TB) and primary spontaneous pneumothorax (PSP), assessing whether the hypothesis could identify high-risk populations, explain exceptional cases like apical lower lobe disease and confirm predictions. RESULTS: The biomechanical hypothesis can explain the high-risk factors of apical location, age, gender and low-BMI build, as well as the occurrence of disease in the apex of the lower lobe, in both TB and PSP patients. A predicted common pathogenesis for apical lung disease was confirmed by the higher-than-expected incidence of concomitant TB and PSP. CONCLUSION: Pleural stress levels depend on chest wall shape, but are highest in the apex of young males with low BMI, leading to growth of congenital bullae that can eventually limit clearance inhaled material, superinfect or burst. This hypothesis suggests that low-dose computerized tomography may be used to screen for TB eradication. This paper is the first to propose a biomechanical mechanism for all apical lung disease pathophysiology. PMID- 27241266 TI - On the etiology of cardiovascular diseases: A new framework for understanding literature results. AB - The interpretative framework presented here provides a rationale for many well known features of cardiovascular diseases. Prolonged acidemia with high blood levels of free fatty acids is proposed to shape the basic context for formation of fatty acid micelles and vesicles with an acidic core that fuse with the endothelia, disrupt vital cell processes, and initiate atherosclerotic plaque formation. It offers an explanation for the distributed localization of atherosclerotic lesions, and how mild cases of occurrence of fatty acids vesicles formed within the heart and the arteries close to the heart may cause such lesions. It provides a rationale for how acute events, namely heart attacks and strokes, may arise from stormy development of fatty acid vesicles within the heart. Additionally, a process is proposed for clot development from the existing fatty acid vesicles. PMID- 27241267 TI - Could ivabradine challenge be helpful for the diagnosis of intermittent sinoatrial node dysfunction in suspected patients? AB - Sinoatrial node dysfunction (SND) is an important cause of syncope in the elderly. Though the diagnosis can be relatively straightforward in the persistent form of SND, it can be elusive when the dysfunction is intermittent. For intermittent SND, the diagnosis may require prolonged electrocardiographic recordings with an external or internal loop recorder, or an invasive electrophysiologic study. Ivabradine, an If inhibitor that slows sinoatrial discharge rate, is widely used for the treatment of chronic angina or heart failure. Though the drug is contraindicated in patients with known SND as it may exacerbate symptoms, we propose that a simple ivabradine suppression test, followed by a 24-h monitorization of heart rhythm, could be valuable to aid diagnosis of intermittent SND. The test we propose could be used prior to prolonged electrocardiographic monitoring in patients with suspected SND, but both the diagnostic accuracy and the safety should be evaluated with studies prior to implementation. PMID- 27241268 TI - Hydrolytic anaerobic reactor and aerated constructed wetland systems for municipal wastewater treatment - HIGHWET project. AB - The HIGHWET project combines the hydrolytic up-flow sludge bed (HUSB) anaerobic digester and constructed wetlands (CWs) with forced aeration for decreasing the footprint and improving effluent quality. The HIGHWET plant in A Coruna (NW of Spain) treating municipal wastewater consists of a HUSB and four parallel subsurface horizontal flow (HF) CWs. HF1, HF2 and HF3 units are fitted with forced aeration, while the control HF4 is not aerated. All the HF units are provided with effluent recirculation, but different heights of gravel bed (0.8 m in HF1 and HF2, and 0.5 m in HF3 and HF4) are implemented. Besides, a tobermorite enriched material was added in the HF2 unit in order to improve phosphorus removal. The HUSB 76-89% of total suspended solids (TSS) and about 40% of chemical oxygen demand (COD) and biological oxygen demand (BOD). Aerated HF units reached above 96% of TSS, COD and BOD at a surface loading rate of 29-47 g BOD5/m2.d. An aeration regime ranging from 5 h on/3 h off to 3 h on/5 h off was found to be adequate to optimize nitrogen removal, which ranged from 53% to 81%. Average removal rates of 3.4 +/- 0.4 g total nitrogen (TN)/m2.d and 12.8 +/- 3.7 g TN/m3.d were found in the aerated units, being 5.5 and 4.1 times higher than those of the non-aerated system. The tobermorite-enriched HF2 unit showed a distinct higher phosphate (60-67%) and total phosphorus (54%) removal. PMID- 27241269 TI - Strong dependence of fluorescence quenching on the transition metal in layered transition metal dichalcogenide nanoflakes for nucleic acid detection. AB - In recent years, the application of transition metal dichalcogenides for the development of biosensors has been receiving widespread attention from researchers, as demonstrated by the surge in studies present in the field. While different transition metal dichalcogenide materials have been employed for the fabrication of fluorescent biosensors with superior performance, no research has been conducted to draw comparisons across materials containing different transition metals. Herein, the performance of MoS2 and WS2 nanoflakes for the fluorescence detection of nucleic acids is assessed. It is discovered that, at the optimal amount, MoS2 and WS2 nanoflakes exhibit a similar degree of fluorescence quenching, at 75% and 71% respectively. However, MoS2 nanoflakes have better performance in the areas of detection range and selectivity than WS2 nanoflakes. The detection range achieved with MoS2 nanoflakes is 9.60-366 nM while 13.3-143 nM with WS2 nanoflakes. In the context of selectivity, MoS2 nanoflakes display a signal difference of 97.8% between complementary and non complementary DNA targets, whereas WS2 nanoflakes only exhibit 44.3%. Such research is highly beneficial as it delivers vital insights on how the performance of a fluorescent biosensor can be affected by the transition metal present. Furthermore, these insights can assist in the selection of suitable transition metal dichalcogenide materials for utilization in biosensor development. PMID- 27241270 TI - Lack of Evidence for Dual Antiplatelet Therapy after Endovascular Arterial Procedures: A Meta-analysis. AB - INTRODUCTION: Dual antiplatelet therapy (DAPT) has mainly replaced mono antiplatelet therapy (MAPT) and is recommended after arterial endovascular revascularization. The aim of this meta-analysis was to summarize the available evidence for DAPT after endovascular revascularization throughout the arterial system. METHODS: A systematic search was performed in Medline, Embase, and the Cochrane Register. Two reviewers independently performed data extraction and quality assessment using the Cochrane Collaboration risk of bias assessment tool. Included in the search were randomized controlled trials (RCTs) comparing DAPT with MAPT after endovascular procedures for the treatment of coronary, carotid, or peripheral artery disease, reporting at least one clinical outcome. Articles were excluded if patients received anticoagulation in addition to antiplatelet therapy in the post-procedural phase. The primary outcome was restenosis or stent thrombosis, and secondary outcomes were major adverse cardiac events (MACE), target lesion revascularization, cerebrovascular accident or transient ischemic attack, bleeding, and death. Meta-analyses of binary outcomes were performed using the random effects model and described as risk ratios (RRs) and 95% confidence intervals (95% CIs). Chi-square tests were used to test for heterogeneity. RESULTS: Nine articles were included in this study, involving lower limb peripheral arteries (1), carotid arteries (2), and coronary arteries (6). The pooled results of coronary trials showed a RR for restenosis with DAPT of 0.60 (95% CI 0.28-1.31) and for myocardial infarction 0.49 (95% CI 0.12-2.03). In the carotid artery trials the RR for restenosis was 0.22 (95% CI 0.04-1.20) and for peripheral arteries 1.02 (95% CI 0.56-1.82). A meta-analysis of bleeding risk of all the included trials showed a RR of 1.06 (95% CI 0.32-3.52) with DAPT. CONCLUSION: The available evidence comparing DAPT with MAPT after endovascular arterial revascularization is limited and the majority of trials were conducted in the cardiology field. No significant evidence for superiority of DAPT compared with MAPT was found, but there was also no evidence of an increased bleeding risk with DAPT over MAPT. PMID- 27241271 TI - Gastrointestinal Symptoms Increase the Burden of Illness in Dermatitis Herpetiformis: A Prospective Study. AB - Dermatitis herpetiformis (DH) is an extraintestinal manifestation of coeliac disease. The burden of illness in untreated coeliac disease is known to be considerable, but corresponding evidence for DH is lacking. In this study the burden of DH was evaluated prospectively in 52 patients newly diagnosed with DH using a study questionnaire and a validated Psychological General Well-Being (PGWB) questionnaire. The PGWB scores were compared with those of 110 healthy controls. Quality of life was significantly (p < 0.001) lower among patients with DH at the time of diagnosis, but after 1 year on a gluten-free diet their quality of life was at same level as that of the controls. The presence of gastrointestinal symptoms was shown to significantly increase the burden of untreated DH. We conclude that there is a significant burden related to untreated, but not to treated, DH, and the burden is even greater among DH patients with gastrointestinal symptoms. PMID- 27241272 TI - [Consortium for detection and management of lung damage induced by bleomycin]. AB - Bleomycin is a cytotoxic antibiotic and a component of chemotherapy regimens of germ cell tumors and lymphoma. Bleomycin lung injuries occur in 10% of patients, and lead to severe interstitial pneumonia in 3% of patients. Pulmonary toxicity is related to endothelial cells injury induce by free radicals and inflammatory cytokines. Diagnosis of bleomycin-induced lung toxicity is based on the combination of clinical and radiological features, and requires to rule out differential diagnoses including pneumocystis. "Bleomycin-induced pneumonitis" is the most frequent pattern; eosinophilic pneumonitis and organizing pneumonia are rarer. Occurrence of bleomycin lung toxicity requires an immediate and often permanent discontinuation. Treatment is based on steroid. Regular clinical and pulmonary function tests monitoring are mandatory for early detection of bleomycin-induced lung toxicity. PMID- 27241273 TI - Quantification of Multivalent Interactions by Tracking Single Biological Nanoparticle Mobility on a Lipid Membrane. AB - Macromolecular association commonly occurs via dynamic engagement of multiple weak bonds referred to as multivalent interactions. The distribution of the number of bonds, combined with their strong influence on the residence time, makes it very demanding to quantify this type of interaction. To address this challenge in the context of virology, we mimicked the virion association to a cell membrane by attaching lipid vesicles (100 nm diameter) to a supported lipid bilayer via multiple, identical cholesterol-based DNA linker molecules, each mimicking an individual virion-receptor link. Using total internal reflection microscopy to track single attached vesicles combined with a novel filtering approach, we show that histograms of the vesicle diffusion coefficient D exhibit a spectrum of distinct peaks, which are associated with vesicles differing in the number, n, of linking DNA tethers. These peaks are only observed if vesicles with transient changes in n are excluded from the analysis. D is found to be proportional to 1/n, in excellent agreement with the free draining model, allowing to quantify transient changes of n on the single vesicle level and to extract transition rates between individual linking states. Necessary imaging conditions to extend the analysis to multivalent interactions in general are also reported. PMID- 27241274 TI - Enhancement of lomefloxacin Hcl ocular efficacy via niosomal encapsulation: in vitro characterization and in vivo evaluation. AB - The aim of this study is to develop and evaluate niosomal dispersions loaded with the hydrophilic drug; lomefloxacin Hcl (LXN) for the management of ocular bacterial conjunctivitis. LXN-loaded niosomes were prepared by the thin film hydration method following a full factorial formulation design. Two independent variables were evaluated: the type of surfactant (X1) and the surfactant:cholesterol ratio (X2). The dependent variables comprised entrapment efficiency (EE%: Y1), particle size (PS: Y2) and zeta potential (ZP: Y3). The optimum formulation, N-LXN14 (Tw60: CH, 1:1), was spherical in shape and exhibited EE% of 68.41 +/- 0.07, PS of 176.0 +/- 0.98 and ZP of -40.70 +/- 2.20 with a sustained release profile over 8 hours following the Higuchi model. N LXN14 proved good physicochemical stability under refrigeration up to 3 months. Ocular irritancy test showed no signs of ocular toxicity, confirming the safety and suitability for ocular application. Microbiological evaluation of the antibacterial effect of N-LXN14 was conducted using the susceptibility test and through the induction of topical conjunctivitis by Staphylococcus aureus (S. aureus) followed by topical therapy. Susceptibility test manifested significantly higher percent inhibition of S. aureus and higher AUC0-12 h of N-LXN14 (604.59 +/ 0.05) compared to the commercial product (126.25 +/- 0.049). Both clinical observation and colony count of the infected eyes after eight days of treatment demonstrated significant improvement in therapeutic response. The infected eyes were completely healed with eradication of S. aureus. In conclusion, the results showed that LXN niosomal dispersions may serve as a promising superior ocular delivery system in the treatment of bacterial conjunctivitis. PMID- 27241275 TI - A TonB-dependent receptor regulates antifungal HSAF biosynthesis in Lysobacter. AB - Lysobacter species are Gram-negative bacteria that are emerging as new sources of antibiotics, including HSAF (Heat Stable Antifungal Factor), which was identified from L. enzymogenes with a new mode of action. LesR, a LuxR solo, was recently shown to regulate the HSAF biosynthesis via an unidentified mechanism in L. enzymogenes OH11. Here, we used a comparative proteomic approach to identify the LesR targets and found that LesR influenced the expression of 33 proteins belonging to 10 functional groups, with 9 proteins belonging to the TBDR (TonB Dependent Receptor) family. The fundamental role of bacterial TBDR in nutrient uptake motivates us to explore their potential regulation on HSAF biosynthesis which is also modulated by nutrient condition. Six out of 9 TBDR coding genes were individually in-frame deleted. Phenotypic and gene-expression assays showed that TBDR7, whose level was lower in a strain overexpressing lesR, was involved in regulating HSAF yield. TBDR7 was not involved in the growth, but played a vital role in transcribing the key HSAF biosynthetic gene. Taken together, the current lesR-based proteomic study provides the first report that TBDR7 plays a key role in regulating antibiotic (HSAF) biosynthesis, a function which has never been found for TBDRs in bacteria. PMID- 27241276 TI - N-glycan containing a core alpha1,3-fucose residue is required for basipetal auxin transport and gravitropic response in rice (Oryza sativa). AB - In plants, alpha1,3-fucosyltransferase (FucT) catalyzes the transfer of fucose from GDP-fucose to asparagine-linked GlcNAc of the N-glycan core in the medial Golgi. To explore the physiological significance of this processing, we isolated two Oryza sativa (rice) mutants (fuct-1 and fuct-2) with loss of FucT function. Biochemical analyses of the N-glycan structure confirmed that alpha1,3-fucose is missing from the N-glycans of allelic fuct-1 and fuct-2. Compared with the wild type cv Kitaake, fuct-1 displayed a larger tiller angle, shorter internode and panicle lengths, and decreased grain filling as well as an increase in chalky grains with abnormal shape. The mutant allele fuct-2 gave rise to similar developmental abnormalities, although they were milder than those of fuct-1. Restoration of a normal tiller angle in fuct-1 by complementation demonstrated that the phenotype is caused by the loss of FucT function. Both fuct-1 and fuct-2 plants exhibited reduced gravitropic responses. Expression of the genes involved in tiller and leaf angle control was also affected in the mutants. We demonstrate that reduced basipetal auxin transport and low auxin accumulation at the base of the shoot in fuct-1 account for both the reduced gravitropic response and the increased tiller angle. PMID- 27241277 TI - Prodromal myocardial infarction symptoms experienced by women. AB - OBJECTIVES: This integrative review sought to identify studies that describe individual prodromal myocardial infarction (MI) symptoms and clusters of prodromal symptoms in women and to critically examine this body of evidence. BACKGROUND: Studies have suggested that women may experience warning symptoms months prior to MI. METHODS: A comprehensive database search was conducted using multiple search terms in various combinations. A structured literature audit was then conducted. RESULTS: 12 studies were included in the final review, including 10 peer-reviewed journal articles and 2 doctoral dissertations. The review suggests that prodromal myocardial infarction symptoms are prevalent in almost all women prior to MI. The most common prodromal symptom appears to be fatigue, though other symptoms are also prevalent. Further, prodromal symptoms may be useful at predicting myocardial infarction. CONCLUSIONS: Though prodromal MI symptoms experienced by women are prevalent, additional study is required in a larger population of diverse women to fully characterize prodromal MI symptoms in women. PMID- 27241278 TI - Thermally stable J-type phthalocyanine dimers as new non-linear absorbers for low threshold optical limiters. AB - The possibility of developing new advanced optical limiters of laser radiation at 532 nm with low limiting thresholds has been demonstrated on thermally stable phthalocyanine J-type dimeric complexes of Mg, Zn, Cu, Ni, and Co. A new "threshold" model based on radiative transfer phenomena in nonlinear optical media was suggested for the exact definition of nonlinear absorption coefficient beta and optical limiting threshold Ic. This model allows the determination of the optical characteristics of the limiter in the same active material with layers of different thicknesses, as well as the use of different parameters of laser radiation, such as cross-sectional spatial profiles of the laser beam and shapes of the laser pulse over time. The maximum value of the nonlinear absorption coefficient (beta = 360 cm GW(-1)) and the lowest limiting threshold (Ic = 0.03 J cm(-2)) were estimated for a J-type zinc phthalocyanine dimer. PMID- 27241279 TI - Exploring correlation between bone metabolism markers and densitometric traits in extended families from Spain. AB - Osteoporosis is a common multifactorial disorder characterized by low bone mass and reduced bone strength that may cause fragility fractures. In recent years, there have been substantial advancements in the biochemical monitoring of bone metabolism through the measurement of bone turnover markers. Currently, good knowledge of the genetics of such markers has become an indispensable part of osteoporosis research. In this study, we used the Genetic Analysis of Osteoporosis Project to study the genetics of the plasma levels of 12 markers related to bone metabolism and osteoporosis. Plasma phenotypes were determined through biochemical assays and log-transformed values were used together with a set of covariates to model genetic and environmental contributions to phenotypic variation, thus estimating the heritability of each trait. In addition, we studied correlations between the 12 markers and a wide variety of previously described densitometric traits. All of the 12 bone metabolism markers showed significant heritability, ranging from 0.194 for osteocalcin to 0.516 for sclerostin after correcting for covariate effects. Strong genetic correlations were observed between osteocalcin and several bone mineral densitometric traits, a finding with potentially useful diagnostic applications. In addition, suggestive genetic correlations with densitometric traits were observed for leptin and sclerostin. Overall, the few strong and several suggestive genetic correlations point out the existence of a complex underlying genetic architecture for bone metabolism plasma phenotypes and provide a strong motivation for pursuing novel whole-genome gene-mapping strategies. PMID- 27241280 TI - Management of actinic cheilitis using ingenol mebutate gel: A report of seven cases. AB - Actinic cheilitis (AC) can precede the development of squamous cell carcinoma of the lip, a location with high risk of invasiveness and metastasis. We communicate the good results that we obtained when treating seven patients suffering from AC with ingenol mebutate (IM) 0,015% concentration gel on three consecutive days. Three patients achieved complete clearance and four significant improvement. IM is a topical field treatment approved for actinic keratosis. To our knowledge, reported experience in the management of AC with IM is very limited. Local skin responses grade 3 were the main adverse event observed and they resolved in all patients without specific therapy within 1 to 2 weeks. IM is characterized by its rapid clinical effect, its favorable safety profile and its dosing period of only 3 days, shorter than with other field therapies. All these facts make it an attractive new therapy for AC, with need for further study. PMID- 27241281 TI - Long-term excess mortality in Takotsubo syndrome: is it justified to charge Takotsubo for the excess long-term mortality?: Reply. PMID- 27241282 TI - Phosphine-ligated dinitrosyl iron complexes for redox-controlled NO release. AB - Here we present the syntheses and structural, spectroscopic, as well as electrochemical properties of four dinitrosyl iron complexes (DNICs) based on silicon- and carbon-derived di- and tripodal phosphines. Whereas CH3C(CH2PPh2)3 and Ph2Si(CH2PPh2)2 coordinate iron in a eta(2) - binding mode, CH3Si(CH2PPh2)3 undergoes cleavage of one Si-C bond to afford [Fe(NO)2(P(CH3)Ph2)2] at elevated temperatures. The complexes were characterized by IR spectroelectrochemistry as well as UV-vis measurements. The oxidized {Fe(NO)2}(9) compounds were obtained by oxidation with (NH4)2[Ce(NO3)6] and their properties evaluated with Mossbauer and IR spectroscopy. Stability experiments on the complexes suggest that they are capable of releasing their NO-ligands in the oxidized {Fe(NO)2}(9) but not in the reduced {Fe(NO)2}(10) form. A detailed DFT analysis is provided in order to understand the electronic configurations and the complexes' ability to release NO. PMID- 27241283 TI - Experimental test of the no-go theorem for continuous psi-epistemic models. AB - Quantum states are the key mathematical objects in quantum theory; however, there is still much debate concerning what a quantum state truly represents. One such century-old debate is whether a quantum state is ontic or epistemic. Recently, a no-go theorem was proposed, stating that the continuous psi-epistemic models cannot reproduce the measurement statistic of quantum states. Here we experimentally test this theorem with high-dimensional single photon quantum states without additional assumptions except for the fair-sampling assumption. Our experimental results reproduce the prediction of quantum theory and support the no-go theorem. PMID- 27241284 TI - Transciptomic study of mucosal immune, antioxidant and growth related genes and non-specific immune response of common carp (Cyprinus carpio) fed dietary Ferula (Ferula assafoetida). AB - A 8-weeks feeding trial was conducted to examine the effects of different levels (0, 0.5, 1 and 2%) of dietary Ferula (Ferula assafoetida) on expression of antioxidant enzymes (GSR, GPX and GSTA), immune (TNF-alpha, IL1B, IL- 8 and LYZ) and growth (GH, IGF1 and Ghrl) genes as well as cutaneous mucus and serum non specific immune response in common carp. The results revealed Ferula significantly increased antioxidant gene expression (GSR and GSTA) in a dose dependent manner (P < 0.05). The expression of immune growth related genes were significantly higher in Ferula fed fish compared control group (P < 0.05). The effects of Ferula on expression of genes was more pronounced in higher doses. Feeding on Ferula supplemented diet remarkably increased skin mucus lysozyme activity (P < 0.05). However, evaluation of mucus total Ig and protease activity revealed no significant difference between control and treated groups (P > 0.05). Regarding non-specific humoral response, serum total Ig, lysozyme and ACH50 showed no remarkable variation between Ferula fed carps and control group (P > 0.05). These results indicated up-regulation of growth and health related genes in Ferula fed common carp. Further studies using pathogen or stress challenge is required to conclude that transcriptional modulation is beneficial in common carp. PMID- 27241285 TI - Injected phage-displayed-VP28 vaccine reduces shrimp Litopenaeus vannamei mortality by white spot syndrome virus infection. AB - White spot syndrome virus (WSSV) is the most important viral pathogen for the global shrimp industry causing mass mortalities with huge economic losses. Recombinant phages are capable of expressing foreign peptides on viral coat surface and act as antigenic peptide carriers bearing a phage-displayed vaccine. In this study, the full-length VP28 protein of WSSV, widely known as potential vaccine against infection in shrimp, was successfully cloned and expressed on M13 filamentous phage. The functionality and efficacy of this vaccine immunogen was demonstrated through immunoassay and in vivo challenge studies. In ELISA assay phage-displayed VP28 was bind to Litopenaeus vannamei immobilized hemocyte in contrast to wild-type M13 phage. Shrimps were injected with 2 * 10(10) cfu animal(-1) single dose of VP28-M13 and M13 once and 48 h later intramuscularly challenged with WSSV to test the efficacy of the vaccine against the infection. All dead challenged shrimps were PCR WSSV-positive. The accumulative mortality of the vaccinated and challenged shrimp groups was significantly lower (36.67%) than the unvaccinated group (66.67%). Individual phenoloxidase and superoxide dismutase activity was assayed on 8 and 48 h post-vaccination. No significant difference was found in those immunological parameters among groups at any sampled time evaluated. For the first time, phage display technology was used to express a recombinant vaccine for shrimp. The highest percentage of relative survival in vaccinated shrimp (RPS = 44.99%) suggest that the recombinant phage can be used successfully to display and deliver VP28 for farmed marine crustaceans. PMID- 27241287 TI - Enzymatic modification of polysaccharides: Mechanisms, properties, and potential applications: A review. AB - Polysaccharides are natural biopolymers found in almost all living organisms. They are used extensively in various industrial applications, such as food, adhesives, pharmaceuticals, and cosmetics. In many cases, their practical use is limited because of their weak solubility in neutral pH, their unsuitable hydrophilic/hydrophobic balance. In this context, chemical or enzymatic modification of their structure appears as a relevant way, to improve their properties, and thus to enlarge the field of their potential applications. Taking into account the reduction of the input energy and the environmental impact, and due to high specificity and selectivity properties, enzymatic bioprocesses have been investigated as attractive alternatives to toxic and non-specific chemical approaches. This review discusses the methods of enzymatic functionalization of four well-known polysaccharides, chitosan, cellulose, pectin and starch. Particular emphasis was placed on the methods, the reaction types and the enzymes implicated in the modification such as laccases, peroxidases lipases, tyrosinases, and transglutaminases. The impact of functionalization on the properties and the applications of polysaccharide derivatives were described. PMID- 27241286 TI - CXCL1 mediates obesity-associated adipose stromal cell trafficking and function in the tumour microenvironment. AB - White adipose tissue (WAT) overgrowth in obesity is linked with increased aggressiveness of certain cancers. Adipose stromal cells (ASCs) can become mobilized from WAT, recruited by tumours and promote cancer progression. Mechanisms underlying ASC trafficking are unclear. Here we demonstrate that chemokines CXCL1 and CXCL8 chemoattract ASC by signalling through their receptors, CXCR1 and CXCR2, in cell culture models. We further show that obese patients with prostate cancer have increased epithelial CXCL1 expression. Concomitantly, we observe that cells with ASC phenotype are mobilized and infiltrate tumours in obese patients. Using mouse models, we show that the CXCL1 chemokine gradient is required for the obesity-dependent tumour ASC recruitment, vascularization and tumour growth promotion. We demonstrate that alphaSMA expression in ASCs is induced by chemokine signalling and mediates the stimulatory effects of ASCs on endothelial cells. Our data suggest that ASC recruitment to tumours, driven by CXCL1 and CXCL8, promotes prostate cancer progression. PMID- 27241288 TI - Overexpression and secretion of AgaA7 from Pseudoalteromonas hodoensis sp. nov in Bacillus subtilis for the depolymerization of agarose. AB - Interest in agar or agarose-based pharmaceutical products has driven the search for potent agarolytic enzymes. An extracellular beta-agarase (AgaA7) recently isolated from Pseudoalteromonas hodoensis sp. nov was expressed in Bacillus subtilis, which was chosen due to its capability to overproduce and secrete functional enzymes. Phenotypic analysis showed that the engineered B. subtilis secreted a functional AgaA7 when fused with the aprE signal peptide (SP) at the amino-terminus. The maximum agarolytic activity was observed during the late logarithmic phase. To further improve the secretion of AgaA7, an expression library of AgaA7 fused to different naturally occurring B. subtilis SPs was created. The amount of AgaA7 secreted by the clones was compared through activity assay, immuno-blot, and purification via affinity chromatography. Although the aprE SP can readily facilitate the secretion of AgaA7, other SPs such as yqgA, pel, and lipA were relatively more efficient. Among these SPs, lipA was the most efficient in improving the secretion of AgaA7.The use of B. subtilis as host for the expression and secretion of agarolytic and other hydrolytic enzymes can be a useful tool in the field of white biotechnology. PMID- 27241289 TI - Entrapping cross-linked glucose oxidase aggregates within a graphitized mesoporous carbon network for enzymatic biofuel cells. AB - This paper reports a novel method for producing glucose oxidase-nanocomposites by entrapping cross-linked glucose oxidase (GOx) aggregates within a graphitized mesoporous carbon (GMC) network. Entrapment was achieved by utilizing the strong self-aggregation tendency of GMC in aqueous buffer solution to form carbon networks. Using confocal microscopy and TEM, GOx-GMC nanocomposites were visualized. The electrochemical properties of GOx-GMC nanocomposites were studied by means of cyclic voltammograms, chronoamperometric and potentiostatic tests. Results therefrom suggested that the GOx-GMC nanocomposites offer a high electrical conductivity with the maximum electron transfer rate constant estimated at 5.16+/-0.61s(-1). Furthermore, thermally treating the GOx-GMC nanocomposite and GOx aggregates at 60 degrees C for four hours, both samples maintained 99% of their initial activity, while the free GOx were completely deactivated. These performances suggested that our nanocomposite structure offered both improved electrochemical performance and stability by combining the high electrical conductivity offered by the GMC network with the high enzyme loading and stability offered by the cross-linked GOx aggregates. The GOx-GMC nanocomposite's electrochemical activity towards glucose oxidation was also investigated by using an enzymatic biofuel cell without artificial mediators, producing a power density of up to 22.4MUWcm(-2) at 0.24V. PMID- 27241290 TI - Operational stabilities of different chemical derivatives of Novozym 435 in an alcoholysis reaction. AB - Industrial use of Novozym 435 in synthesis of structured lipids and biodiesel via alcoholysis is limited by mass transfer effects of the glycerides through immobilized enzymes and its low operational stability under operation conditions. To better understand this, differently modified Novozym 435 preparations, differing in their surface nature and in their interactions with reactants, have been compared in the alcoholysis of Camelina sativa oil. The three modifications performed have been carried out under conditions where all exposed groups of the enzyme have been modified. These modifications were: 2,4,6-trinitrobenzensulfonic acid (Novo-TNBS), ethylendiamine (Novo-EDA) and polyethylenimine (Novo-PEI). Changes in their operational performance are analyzed in terms of changes detected by scan electron microscopy in the support morphology. The hydrophobic nature of the TNBS accelerates the reaction rate; t-ButOH co-solvent swells the macroporous acrylic particles of Lewatit VP OC 1600 in all biocatalysts, except in the case of Novo-PEI. This co-solvent only increases the maximal conversions obtained at 24h using the modified biocatalysts. t-ButOH reduces enzyme inactivation by alcohol and water. In a co-solvent system, these four biocatalysts remain fully active after 14 consecutive reaction cycles of 24h, but only Novo-TNBS yields maximal conversion before cycle 5. Some deposits on biocatalyst particles could be appreciated during reuses, and TNBS derivatization diminishes the accumulation of product deposits on the catalyst surface. Most particles of commercial Novozym((r)) 435 are broken after operation for 14 reaction cycles. The broken particles are fully active, but they cause problems of blockage in filtration operations and column reactors. The three derivatizations studied make the matrix particles more resistant to rupture. PMID- 27241291 TI - In Search of the E. coli Compounds that Change the Antibiotic Production Pattern of Streptomyces coelicolor During Inter-species Interaction. AB - The aim of this work was to investigate the interaction between E.coli and Streptomyces coelicolor A3 (2) for the increased production of undecylprodigiosin and identify the E. coli actives mediating this inter-species interaction. The antibiotics of interest were the red-pigmented undecylprodigiosin and blue pigmented actinorhodin. Pure cultures of S. coelicolor in a defined medium produced higher concentrations of actinorhodin compared to those of undecylprodigiosin. The latter however, is more important due to its immunosuppressive and antitumor properties. As a strategy to increase undecylprodigiosin production, we added separately, live cells and heat-killed cells of E. coli C600, and the cell-free supernatant of E. coli culture to S. coelicolor cultures in shake flasks. The interaction with live cells of E. coli altered the antibiotic production pattern and undecylprodigiosin production was enhanced by 3.5-fold compared to the pure cultures of S. coelicolor and actinorhodin decreased by 15-fold. The heat-killed cells of E. coli however, had no effect on antibiotic production. In all cases, growth and glucose consumption of S. coelicolor remained almost the same as those observed in the pure culture indicating that the changes in antibiotic production were not due to nutritional stress. Results with cell-free supernatant of E. coli culture indicated that the interaction between S. coelicolor and E. coli was mediated via diffusible molecule(s). Using a set of extraction procedures and agar-well diffusion bioassays, we isolated and preliminarily identified a class of compounds. For the preliminary verification, we added the compound which was the common chemical structural moiety in this class of compounds to the pure S. coelicolor cultures. We observed similar effects on antibiotic production as with the live E. coli cells and their supernatant indicating that this class of compounds secreted by E. coli indeed could act as actives during interspecies interaction and increase the production of undecylprodigiosin. PMID- 27241292 TI - Secretome analysis of Trichoderma reesei and Aspergillus niger cultivated by submerged and sequential fermentation processes: Enzyme production for sugarcane bagasse hydrolysis. AB - Cellulases and hemicellulases from Trichoderma reesei and Aspergillus niger have been shown to be powerful enzymes for biomass conversion to sugars, but the production costs are still relatively high for commercial application. The choice of an effective microbial cultivation process employed for enzyme production is important, since it may affect titers and the profile of protein secretion. We used proteomic analysis to characterize the secretome of T. reesei and A. niger cultivated in submerged and sequential fermentation processes. The information gained was key to understand differences in hydrolysis of steam exploded sugarcane bagasse for enzyme cocktails obtained from two different cultivation processes. The sequential process for cultivating A. niger gave xylanase and beta glucosidase activities 3- and 8-fold higher, respectively, than corresponding activities from the submerged process. A greater protein diversity of critical cellulolytic and hemicellulolytic enzymes were also observed through secretome analyses. These results helped to explain the 3-fold higher yield for hydrolysis of non-washed pretreated bagasse when combined T. reesei and A. niger enzyme extracts from sequential fermentation were used in place of enzymes obtained from submerged fermentation. An enzyme loading of 0.7 FPU cellulase activity/g glucan was surprisingly effective when compared to the 5-15 times more enzyme loadings commonly reported for other cellulose hydrolysis studies. Analyses showed that more than 80% consisted of proteins other than cellulases whose role is important to the hydrolysis of a lignocellulose substrate. Our work combined proteomic analyses and enzymology studies to show that sequential and submerged cultivation methods differently influence both titers and secretion profile of key enzymes required for the hydrolysis of sugarcane bagasse. The higher diversity of feruloyl esterases, xylanases and other auxiliary hemicellulolytic enzymes observed in the enzyme mixtures from the sequential fermentation could be one major reason for the more efficient enzyme hydrolysis that results when using the combined secretomes from A. niger and T. reesei. PMID- 27241293 TI - Effect of ultrasound combined with malic acid on the activity and conformation of mushroom (Agaricus bisporus) polyphenoloxidase. AB - Polyphenoloxidase (PPO) plays an important role in the browning of vegetables, fruits and edible fungi. The effects of ultrasound, malic acid, and their combination on the activity and conformation of mushroom (Agaricus bisporus) PPO were studied. The activity of PPO decreased gradually with the increasing of malic acid concentrations (5-60mM). Neither medium concentrations (10, 20, 30mM) malic acid nor individual ultrasound (25kHz, 55.48W/cm(2)) treatment could remarkably inactivate PPO. However, the inactivation during their combination was more significant than the sum of ultrasound inactivation and malic acid inactivation. The inactivation kinetics of PPO followed a first-order kinetics under the combination of ultrasound and malic acid. The conformation of combination treated PPO was changed, which was reflected in the decrease of alpha helix, increase of beta-sheet contents and disruption of the tertiary structure. Results of molecular microstructure showed that ultrasound broke large molecular groups of PPO into small ones. Moreover, combined treatment disrupted the microstructure of PPO and molecules were connected together. PMID- 27241294 TI - Environmental stress and elicitors enhance taxol production by endophytic strains of Paraconiothyrium variabile and Epicoccum nigrum. AB - This study examined the effect of different elicitors (seven, different concentrations) and environmental factors (water activity (aw), pH) on taxol production by strains of two endophytic fungi, Paraconiothyrium variabile and Epicoccum nigrum, isolated from temperate yew trees. A defined liquid broth medium was modified with elicitors, solute aw depressors at different pH values. For P. variabile, the best elicitor was salicylic acid at 50mg/l which gave a taxol yield of 14.7+/-4.8MUg/l. The study of synergistic effects between elicitor, aw and pH on taxol production showed that the highest yield of taxol (68.9+/-11.9MUg/l) was produced under modified ionic stress of 0.98aw (KCl) at pH 5 when supplemented with 20mg/l of salicylic acid. For E. nigrum, serine was the best elicitor which increased yield significantly (29.6 fold) when KCL was used as the aw depressor (0.98aw) at pH 5.0 with 30mg/l of serine. The maximum taxol yield produced by E. nigrum was 57.1+/-11.8MUg/l. Surface response models were used to build contour maps to determine the conditions for maximum and marginal conditions for taxol yield in relation to the best elicitor and aw, and the best pH for the first time. This will be beneficial for identifying key parameters for improvement of taxol yields by endophytic fungi. PMID- 27241295 TI - Physical and chemical immobilization of choline oxidase onto different porous solid supports: Adsorption studies. AB - This work carries out for the first time the comparison between the physical and chemical immobilization of choline oxidase onto aminated silica-based porous supports. The influence on the immobilization efficiency of concentration, pH, temperature and contact time between the support and choline oxidase, was evaluated. The immobilization efficiency was estimated taking into consideration the choline oxidase activity, which was assessed by using cadmium telluride (CdTe) quantum dots (QDs), obtained by hydrothermal synthesis, as photoluminescent probes. Hydrogen peroxide produced by enzyme activity was capable of quenching CdTe QDs photoluminescence. The magnitude of the PL quenching process was directly related with the enzyme activity. By comparing the chemical process with the physical adsorption, it was observed that the latter provided the highest choline oxidase immobilization. The equilibrium data were analyzed using Langmuir and Freundlich isotherms and kinetic data were fitted to the pseudo-first-order and pseudo-second-order models. Thermodynamic parameters, such as Gibbs free energy and entropy were also calculated. These results will certainly contribute to the development of new sensing schemes for choline, taking into account the growing demand for its quantification in biological samples. PMID- 27241296 TI - LaaA, a novel high-active alkalophilic alpha-amylase from deep-sea bacterium Luteimonas abyssi XH031(T). AB - Alpha-amylase is a kind of broadly used industrial enzymes, most of which have been exploited from terrestrial organism. Comparatively, alpha-amylase from marine environment was largely undeveloped. In this study, a novel alkalophilic alpha-amylase with high activity, Luteimonas abyssi alpha-amylase (LaaA), was cloned from deep-sea bacterium L. abyssi XH031(T) and expressed in Escherichia coli BL21. The gene has a length of 1428bp and encodes 475 amino acids with a 35 residue signal peptide. The specific activity of LaaA reached 8881U/mg at the optimum pH 9.0, which is obvious higher than other reported alpha-amylase. This enzyme can remain active at pH levels ranging from 6.0 to 11.0 and temperatures below 45 degrees C, retaining high activity even at low temperatures (almost 38% residual activity at 10 degrees C). In addition, 1mM Na(+), K(+), and Mn(2+) enhanced the activity of LaaA. To investigate the function of potential active sites, R227G, D229K, E256Q/H, H327V and D328V mutants were generated, and the results suggested that Arg227, Asp229, Glu256 and Asp328 were total conserved and essential for the activity of alpha-amylase LaaA. This study shows that the alpha amylase LaaA is an alkali-tolerant and high-active amylase with strong potential for use in detergent industry. PMID- 27241307 TI - Isolation of Bluetongue Virus 24 from India - An Exotic Serotype to Australasia. AB - Bluetongue (BT) is a viral disease of ruminants and is caused by different serotypes of bluetongue virus (BTV), which is transmitted by several species of Culicoides midges. The disease is endemic in tropical areas, and incursions have been observed in some of the temperate areas. Twenty-seven recognized serotypes of BTV have been reported so far. Some serotype viruses have been shown to circulate in certain geographical areas. BTV-24 has been reported from Africa, the Mediterranean and the Americas, whereas it is exotic to Australasia. Here, we report isolation of BTV-24 from India and show that it has high sequence homology in genome segment 2 with other Western isolates of BTV-24. Entry of this serotype into Australasian region is a cause of concern. PMID- 27241308 TI - Rattlesnake Phospholipase A2 Increases CFTR-Chloride Channel Current and Corrects ?F508CFTR Dysfunction: Impact in Cystic Fibrosis. AB - Deletion of Phe508 in the nucleotide binding domain (?F508-NBD1) of the cystic fibrosis transmembrane regulator (CFTR; a cyclic AMP-regulated chloride channel) is the most frequent mutation associated with cystic fibrosis. This mutation affects the maturation and gating of CFTR protein. The search for new high affinity ligands of CFTR acting as dual modulators (correctors/activators) presents a major challenge in the pharmacology of cystic fibrosis. Snake venoms are a rich source of natural multifunctional proteins, potential binders of ion channels. In this study, we identified the CB subunit of crotoxin from Crotalus durissus terrificus as a new ligand and allosteric modulator of CFTR. We showed that CB interacts with NBD1 of both wild type and ?F508CFTR and increases their chloride channel currents. The potentiating effect of CB on CFTR activity was demonstrated using electrophysiological techniques in Xenopus laevis oocytes, in CFTR-HeLa cells, and ex vivo in mouse colon tissue. The correcting effect of CB was shown by functional rescue of CFTR activity after 24-h DeltaF508CFTR treatments with CB. Moreover, the presence of fully glycosylated CFTR was observed. Molecular docking allowed us to propose a model of the complex involving of the ABCbeta and F1-like ATP-binding subdomains of DeltaF508-NBD1. Hydrogen-deuterium exchange analysis confirmed stabilization in these regions, also showing allosteric stabilization in two other distal regions. Surface plasmon resonance competition studies showed that CB disrupts the ?F508CFTR cytokeratin 8 complex, allowing for the escape of ?F508CFTR from degradation. Therefore CB, as a dual modulator of DeltaF508CFTR, constitutes a template for the development of new anti-CF agents. PMID- 27241309 TI - Structural Basis for Conserved Regulation and Adaptation of the Signal Recognition Particle Targeting Complex. AB - The signal recognition particle (SRP) is a ribonucleoprotein complex with a key role in targeting and insertion of membrane proteins. The two SRP GTPases, SRP54 (Ffh in bacteria) and FtsY (SRalpha in eukaryotes), form the core of the targeting complex (TC) regulating the SRP cycle. The architecture of the TC and its stimulation by RNA has been described for the bacterial SRP system while this information is lacking for other domains of life. Here, we present the crystal structures of the GTPase heterodimers of archaeal (Sulfolobus solfataricus), eukaryotic (Homo sapiens), and chloroplast (Arabidopsis thaliana) SRP systems. The comprehensive structural comparison combined with Brownian dynamics simulations of TC formation allows for the description of the general blueprint and of specific adaptations of the quasi-symmetric heterodimer. Our work defines conserved external nucleotide-binding sites for SRP GTPase activation by RNA. Structural analyses of the GDP-bound, post-hydrolysis states reveal a conserved, magnesium-sensitive switch within the I-box. Overall, we provide a general model for SRP cycle regulation by RNA. PMID- 27241310 TI - Hyperuricemia, Cardiovascular Profile, and Comorbidity in Older Men and Women: The Pro.V.A. Study. AB - Hyperuricemia (HU) is growing worldwide and associates with several medical conditions in the elderly. However, data about older people and possible gender differences are sparse. The aim of this study was to compare HU prevalence rates and association with relevant medical disorders in elderly subjects of both sexes. Pro.V.A. is a survey of 3099 individuals aged 65+, focusing on chronic diseases and disability. Uric acid (UA) levels were dichotomized using 6.0 mg/dL (females) and 7.0 mg/dL (males), and multivariate logistic regression models were used to estimate odds ratios (ORs) between HU and single comorbidity. HU prevalence was 21.5% in females and 15.8% in males. HU was associated with most anthropometric and laboratory variables in women, but not in men. After adjustment for age, body mass index, and renal function, HU was independently associated with the presence of cardiovascular diseases in both sexes. In women, HU was associated with hand osteoarthritis (OR = 1.52; 95%CI: 1.12-2.08) and edentulism (OR = 1.31; 95%CI: 1.01-1.71), while resulted protective for osteoporosis (OR = 0.69; 95%CI: 0.53-0.91). In men, HU was significantly related with knee osteoarthritis (OR = 1.72; 95%CI: 1.06-2.79) and chronic obstructive pulmonary disease (OR = 1.60; 95%CI: 1.04-2.45). The presence of >=4 comorbidities was a stronger determinant of HU in men (OR = 2.54; 95%CI: 1.21 5.37) than in women (ns). Patterns of age-dependent UA increase are markedly different in men and women. HU prevalence is substantial and its association with other diseases is gender specific, connoting a peculiar clinical profile. PMID- 27241311 TI - Exploring ion induced folding of a single-stranded DNA oligomer from molecular simulation studies. AB - One crucial issue in DNA hydration is the effect of salts on its conformational features. This has relevance in biology as cations present in the cellular environment shield the negative charges on the DNA backbone, thereby reducing the repulsive force between them. By screening the negative charges along the backbone, cations stabilize the folded structure of DNA. To study the effect of the added salt on single-stranded DNA (ss-DNA) conformations, we have performed room temperature molecular dynamics simulations of an aqueous solution containing the ss-DNA dodecamer with the 5'-CGCGAATTCGCG-3' sequence in the presence of 0.2, 0.5, and 0.8 M NaCl. Our calculations reveal that in the presence of the salt, the DNA molecule forms more collapsed coil-like conformations due to the screening of negative charges along the backbone. Additionally, we demonstrated that the formation of an octahedral inner-sphere complex by the strongly bound ion plays an important role in the stabilization of such folded conformation of DNA. Importantly, it is found that ion-DNA interactions can also explain the formation of non-sequential base stackings with longer lifetimes. Such non sequential base stackings further stabilize the collapsed coil-like folded form of the DNA oligomer. PMID- 27241312 TI - A stepwise bulk-to-cluster-to-particle transformation toward the efficient synthesis of alkynyl-protected silver nanoclusters. AB - We report herein the efficient synthesis of alkynyl-protected silver nanoclusters in terms of macrocycle-assisted bulk-to-cluster-to-nanoparticle transformation. Different substituted phenylacetylide ligands are applied to stabilize the silver nanoclusters by metal-carbon bonds and meanwhile determine the size of silver nanoclusters. PMID- 27241313 TI - APL1, an altered peptide ligand derived from human heat-shock protein 60, increases the frequency of Tregs and its suppressive capacity against antigen responding effector CD4 + T cells from rheumatoid arthritis patients. AB - Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by a chronic relapsing-remitting joint inflammation. Perturbations in the balance between CD4 + T cells producing IL-17 and CD4 + CD25(high)FoxP3 + Tregs correlate with irreversible bone and cartilage destruction in RA. APL1 is an altered peptide ligand derived from a CD4+ T-cell epitope of human HSP60, an autoantigen expressed in the inflamed synovium, which increases the frequency of CD4 + CD25(high)FoxP3+ Tregs in peripheral blood mononuclear cells from RA patients. The aim of this study was to evaluate the suppressive capacity of Tregs induced by APL1 on proliferation of effector CD4+ T cells using co-culture experiments. Enhanced Treg-mediated suppression was observed in APL1-treated cultures compared with cells cultured only with media. Subsequent analyses using autologous cross over experiments showed that the enhanced Treg suppression in APL1-treated cultures could reflect increased suppressive function of Tregs against APL1 responsive T cells. On the other hand, APL1-treatment had a significant effect reducing IL-17 levels produced by effector CD4+ T cells. Hence, this peptide has the ability to increase the frequency of Tregs and their suppressive properties whereas effector T cells produce less IL-17. Thus, we propose that APL1 therapy could help to ameliorate the pathogenic Th17/Treg balance in RA patients. PMID- 27241314 TI - Factors influencing biochemical recurrence in patients who have received salvage radiotherapy after radical prostatectomy: a systematic review and meta-analysis. AB - Several studies have evaluated the risk factors influencing biochemical recurrence (BCR) of prostate cancer in patients receiving salvage radiotherapy (SRT) for BCR after radical prostatectomy (RP), but the results remain conflicting. In this study, we performed a meta-analysis to resolve this conflict. We searched the following databases: PubMed, Embase, and Web of Science using the following terms in "All fields": "salvage radiation therapy," "salvage IMRT," "S-IMRT," "salvage radiotherapy," "SRT," "radical prostatectomy," "RP," "biochemical recurrence," "BCR," "biochemical relapse." Eleven studies, with a total of 1383 patients, were included in our meta-analysis. Of all the variables, only Gleason score (GS) >=7 (odds ratio [OR]: 3.82; 95% confidence interval [CI]: 2.60-5.64) and pathological tumor (pT) stage >=3a (OR: 1.82; 95% CI: 1.36-2.42) were positively correlated with BCR. However, SRT combined with androgen deprivation therapy (ADT) (OR: 0.63; 95% CI: 0.44-0.90) and radiation therapy (RT) dose >=64 Gy (OR: 0.35; 95% CI: 0.19-0.64) were negatively correlated with BCR. Perineural invasion (OR: 2.64; 95% CI: 1.11-6.26), preoperative prostate specific antigen (PSA) >=10 ng ml-1 (OR: 1.36; 95% CI: 0.94-1.96), positive surgical margin (OR: 0.92; 95% CI: 0.7-1.19), and seminal vesicle involvement (SVI) (OR: 1.09; 95% CI: 0.83-1.43) had no effect on BCR. Our meta-analysis indicated that pT stage, GS, RT dose, and SRT combined with ADT may influence BCR, while preoperative PSA, surgical margin, perineural invasion, and SVI have only a weak effect on BCR. PMID- 27241315 TI - Hospitalised cancer patients' perceptions of individualised nursing care in four European countries. AB - The aim of this study was to describe hospitalised cancer patients' perceptions of individualised care in four European countries and compare these perceptions using the patients' socio-demographic characteristics and the Individualized Care Scale. The patients' socio-demographic characteristics used were: education, age, gender, type of hospital admission, previous hospitalisation and hospital length of stay. The Individualized Care Scale has two parts (1) nurses' support of individuality and (2) patients' receipt of individuality. Data (n = 599) were collected in Cyprus (n = 150), Finland (n = 158), Greece (n = 150) and Sweden (n = 141). Multivariate analysis of variance models were constructed and differences in perceptions of individualised care were analysed using the patients' socio demographic characteristics as covariates. The level of support for individuality and receipt of individualised care was reported as moderate and good respectively. Generally, the highest assessments were made by the Swedish respondents and the lowest by those in Greece. This study revealed some between country differences in patients' perceptions of care individualisation. These differences, for example, conceptual, educational, based in clinical practice or in the health organisation, require further research. Enquiry into the individualised care perceptions of health care providers and the families of cancer patients would also be useful. PMID- 27241316 TI - Surgical intervention during a Can't Intubate Can't Oxygenate (CICO) event: Emergency Front-of-neck Airway (FONA)? PMID- 27241317 TI - Testosterone supplementation and body composition: results from a meta-analysis of observational studies. AB - PURPOSE: The concept of testosterone (T) supplementation (TS) as a new anti obesity medication in men with testosterone deficiency syndrome (TDS) is emerging. Data from placebo-controlled trials are more conflicting. The aim of this study is to systematically review and meta-analyze available observational and register studies reporting data on body composition in studies on TS in TDS. METHODS: An extensive MEDLINE, Embase, and Cochrane search was performed including the following words: "testosterone" and "body composition." All observational studies comparing the effect of TS on body weight and other body composition and metabolic endpoints were considered. RESULTS: Out of 824 retrieved articles, 32 were included in the study enrolling 4513 patients (mean age 51.7 +/- 6.1 years). TS was associated with a time-dependent reduction in body weight and waist circumference (WC). The estimated weight loss and WC reduction at 24 months were -3.50 [-5.21; -1.80] kg and -6.23 [-7.94; -4.76] cm, respectively. TS was also associated with a significant reduction in fat and with an increase in lean mass as well as with a reduction in fasting glycemia and insulin resistance. In addition, an improvement of lipid profile (reduction in total cholesterol as well as of triglyceride levels and an improvement in HDL cholesterol levels) and in both systolic and diastolic blood pressure was observed. CONCLUSIONS: Present data support the view of a positive effect of TS on body composition and on glucose and lipid metabolism. In addition, a significant effect on body weight loss was observed, which should be confirmed by a specifically designed RCT. PMID- 27241318 TI - Increased risk of fracture in patients with bipolar disorder: a nationwide cohort study. AB - OBJECTIVES: Bipolar disorder (BD) is a systemic inflammatory disease, and disrupted bone metabolism due to the inflammatory process can cause fracture. Despite evidence of an association between lower bone mineral density and an increased risk of fracture among patients with depression, schizophrenia, and anorexia nervosa, whether BD is a risk factor for subsequent fracture is unknown. To determine the association between BD and fracture and to examine the risk factors for fracture among patients with BD. METHODS: In this study, we enrolled patients diagnosed with BD from the Taiwan National Health Insurance Research Database. Patients newly diagnosed with BD (ICD-9-CM 296) from 2001 to 2008 were included in the BD cohort, and the date of the initial diagnosis of BD was used as the index date. The comparison cohort, comprising participants without BD, was frequency matched to the BD cohort by age, sex, and index year, and the occurrence of fracture was evaluated in both cohorts. RESULTS: The BD and comparison cohorts were comprised of 47,271 patients with BD and 1,89,084 frequency-matched participants without BD, respectively. The incidence of fracture was higher among patients with BD than among the controls. Cox models showed that BD was an independent risk factor for fracture irrespective of comorbidities [hazard ratio (HR) = 1.79, 95 % confidence interval (CI) = 1.73 1.84, p < .001]. CONCLUSION: Our study showed that patients with BD have a higher risk of subsequent fracture. Additional prospective clinical studies investigating the relationship between BD and fracture are warranted. PMID- 27241319 TI - Clinical Trial Data as Public Goods: Fair Trade and the Virtual Knowledge Bank as a Solution to the Free Rider Problem - A Framework for the Promotion of Innovation by Facilitation of Clinical Trial Data Sharing among Biopharmaceutical Companies in the Era of Omics and Big Data. AB - BACKGROUND: Knowledge in the era of Omics and Big Data has been increasingly conceptualized as a public good. Sharing of de-identified patient data has been advocated as a means to increase confidence and public trust in the results of clinical trials. On the other hand, research has shown that the current research and development model of the biopharmaceutical industry has reached its innovation capacity. In response to that, the biopharmaceutical industry has adopted open innovation practices, with sharing of clinical trial data being among the most interesting ones. However, due to the free rider problem, clinical trial data sharing among biopharmaceutical companies could undermine their innovativeness. METHOD: Based on the theory of public goods, we have developed a commons arrangement and devised a model, which enables secure and fair clinical trial data sharing over a Virtual Knowledge Bank based on a web platform. Our model uses data as a virtual currency and treats knowledge as a club good. RESULTS: Fair sharing of clinical trial data over the Virtual Knowledge Bank has positive effects on the innovation capacity of the biopharmaceutical industry without compromising the intellectual rights, proprietary interests and competitiveness of the latter. CONCLUSION: The Virtual Knowledge Bank is a sustainable and self-expanding model for secure and fair clinical trial data sharing that allows for sharing of clinical trial data, while at the same time it increases the innovation capacity of the biopharmaceutical industry. PMID- 27241320 TI - Analysis of the dynamic co-expression network of heart regeneration in the zebrafish. AB - The zebrafish has the capacity to regenerate its heart after severe injury. While the function of a few genes during this process has been studied, we are far from fully understanding how genes interact to coordinate heart regeneration. To enable systematic insights into this phenomenon, we generated and integrated a dynamic co-expression network of heart regeneration in the zebrafish and linked systems-level properties to the underlying molecular events. Across multiple post injury time points, the network displays topological attributes of biological relevance. We show that regeneration steps are mediated by modules of transcriptionally coordinated genes, and by genes acting as network hubs. We also established direct associations between hubs and validated drivers of heart regeneration with murine and human orthologs. The resulting models and interactive analysis tools are available at http://infused.vital-it.ch. Using a worked example, we demonstrate the usefulness of this unique open resource for hypothesis generation and in silico screening for genes involved in heart regeneration. PMID- 27241330 TI - Sling mobilization in the management of urinary retention after mid-urethral sling surgery. AB - OBJECTIVE: To compare intermittent catheterization, sling mobilization, and sling transection for treatment of urinary retention after mid-urethral sling surgery. METHODS: Data registered in the Norwegian Female Incontinence Registry from 1998 to 2013 were analyzed in this cohort study to compare subjective and objective outcomes after intermittent catheterization, sling mobilization, and sling transection as management of postoperative urinary retention after mid urethral sling surgery. Subjective outcomes were degree of symptom bother and the percentage of women stating "very satisfied" at the postoperative follow-up. The objective outcome was leakage at a cough-jump pad stress test. RESULTS: Intervention due to urinary retention was performed in 585 of 18,772 women (3.1%). Women who had their sling mobilized or had intermittent catheterization, scored better on all postoperative outcomes than those who had their sling transected (P < 0.001). Sling transection was more often needed after intermittent catheterization than after mobilization (P = 0.023). No outcome differences were found between intermittent catheterization only and sling mobilization only. Intention to treat analysis showed that women who underwent sling mobilization as the primary procedure significantly more often had a negative stress test (P = 0.033) and were more often "very satisfied" with the treatment (P = 0.006) than those who were primarily catheterized. CONCLUSIONS: Sling mobilization is a more successful treatment than intermittent catheterization or transection for urinary retention after mid-urethral sling surgery. CLINICAL TRIAL REGISTRATION: Clinical trial registration was not applicable because this study is based on an analysis of anonymous data from The Norwegian Female Incontinence Registry. Neurourol. Urodynam. 36:1091-1096, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27241331 TI - Establishing a standard "Cardiac Arrest Call" telephone number for all hospitals in Europe-2222. PMID- 27241332 TI - The association between timing of tracheal intubation and outcomes of adult in hospital cardiac arrest: A retrospective cohort study. AB - AIM: Resuscitation guidelines indicate the ideal timing of tracheal intubation during in-hospital cardiac arrest (IHCA) has not been adequately studied. METHODS: A retrospective observational study in a single medical centre was conducted that evaluated patients with IHCA between 2006 and 2014. Multivariable logistic regression analysis was used to evaluate associations between independent variables and outcomes. Time to intubation was defined as elapsed time from the first chest compression to the time of completion of endotracheal intubation, tracheostomy, or cricothyroidotomy. RESULTS: A total of 702 patients were included. The mean time to intubation was 8.8min. Ninety-five (13.5%) patients survived to hospital discharge, and 44 (6.3%) patients displayed favourable neurological status at discharge. Time to intubation was shown to be inversely associated with favourable neurological outcome (odds ratio [OR]: 0.86, 95% confidence interval [CI]: 0.80-0.93; p-value <0.001). Delayed time to intubation was noted to be particularly unfavourable for survival outcome in patients with non-shockable rhythms (OR: 0.95, 95% CI: 0.91-0.98; p-value=0.005). Intubation within 8.8min of arrest was demonstrated to be positively associated with both favourable neurological outcome (OR: 7.28, 95% CI: 2.98-20.52; p-value <0.001) and survival to hospital discharge (OR: 2.09, 95% CI: 1.27-3.52; p value=0.004). CONCLUSION: Earlier tracheal intubation during cardiopulmonary resuscitation might be beneficial for clinical outcomes following IHCA. Intubation within 8.8min appears favourable for both neurological and survival outcomes. Nevertheless, this goal should be attempted by clinicians who experienced in intubation to avoid potential complications and harm. PMID- 27241333 TI - Advanced airway management in an anaesthesiologist-staffed Helicopter Emergency Medical Service (HEMS): A retrospective analysis of 1047 out-of-hospital intubations. AB - INTRODUCTION: Airway management in the out-of-hospital emergency setting is challenging. Failed and even prolonged airway management is associated with serious clinical consequences, such as desaturation, bradycardia, airway injuries, or aspiration. The overall success rate of tracheal intubation ranges between 77% and 99%, depending on the level of experience of the provider. Therefore, advanced airway management should only be performed by highly-skilled and experienced providers. METHODS: 9765 patients were treated in the out-of hospital emergency setting by the anaesthesiologist-staffed Helicopter Emergency Medical Services (HEMS) between 2002 and 2014. Patients successfully intubated upon the first attempt were compared to patients who required more than one intubation attempts regarding several potential confounding factors such as age, gender, on-going CPR, NACA Score, initial GCS, prior administration of anaesthetic drugs, neuromuscular blocking agents, and vasopressors. RESULTS: 1573 out of 9765 patients (16.1%) required advanced airway management. 459 patients had already been intubated upon arrival of the HEMS, whereas 1114 patients (11.4%) underwent advanced airway management by the HEMS physician. 67 patients had to be excluded. Data for the remaining 1047 patients (790 males and 257 females) were analyzed further. Primary use of an alternative airway device was reported in 59 patients (5.6%), whereas 988 patients (94.4%) underwent laryngoscopy-guided tracheal intubation. 952 patients (96.4%) could be intubated upon the first attempt and overall intubation success was 99.5% (983 out of 988). CONCLUSION: Our study demonstrates that HEMS physicians performed airway management frequently and that both the first attempt as well as the overall success rate of tracheal intubation was high. Together with the fact that all failed and difficult intubations were successfully recognized and handled and that no surgical airway had to be established, the current study once more underlines the importance of proper training of HEMS care providers regarding airway management. PMID- 27241334 TI - Preoperative prognostic factors for severe diffuse secondary peritonitis: a retrospective study. AB - PURPOSE: The aim of this study was to analyse preoperative risk factors for mortality or intensive care unit admission to describe severe peritonitis. METHODS: This was a single academic centre retrospective study of consecutive adult patients operated for diffuse secondary peritonitis between 2012 and 2013. Patients with appendicitis or cholecystitis were excluded. Independent risk factors were identified using binary and ordinal logistic regression. RESULTS: A total of 223 patients were analysed. Overall 30-day mortality was 14.5 %. Postoperatively, 32.3 % of patients were admitted into the intensive care unit (ICU). Independent risk factors for severe peritonitis were septic shock (odds ratio (OR) 37.94, 95 % confidence interval (CI) 14.52-99.13), chronic kidney insufficiency (OR 5.98 (95 % CI 1.56-22.86), severe sepsis (OR 4.80, 95 % CI 2.10 10.65) and cardiovascular disease (OR 2.58, 95 % CI 1.22-5.47). Patients lacking these factors had no mortality. ICU admission was refused in 24 (10.8 %) patients with 70.8 % mortality. In a subgroup of patients without treatment limitations (n = 190), independent risk factors for weighted outcome of ICU admission or mortality were septic shock (OR 11.89, 95 % CI 4.98-28.40), severe sepsis (OR 5.56, 95 % CI 2.39-12.89), metastatic malignant disease or lymphoma (OR 3.11, 95 % CI 1.34-7.20) and corticosteroid use (OR 2.98, 95 % CI 1.18-7.51). When receiving full level of care, patients with preoperative organ dysfunctions in this subgroup had 8.2 % 30-day mortality. CONCLUSIONS: Preoperative organ dysfunctions, chronic kidney insufficiency and cardiovascular disease are the most important risk factors for severe peritonitis. Without these risk factors, patients had no mortality. PMID- 27241335 TI - Thirteen year follow-up of a cementless femoral stem and a threaded acetabular cup in patients younger than fifty years of age. AB - PURPOSE: Compared to older patients undergoing total hip arthroplasty (THA) younger patients are considered to be more active, thereby exposing the implant to significantly higher loads over a much longer period of time. Additionally, cases of secondary osteoarthritis caused by hip dysplasia, femoral head necrosis or rheumatic diseases are much more frequent than among the average patient population. Therefore, durable implant fixation and low wear rates are extremely important to achieve good long-term implant survival in this group of patients. OBJECTIVE: The aim of this retrospective study was to evaluate the mid- to long term survival of a cementless femoral stem (Zweymuller(r) SL stem) and a threaded cup (Bicon SL(r)) in patients younger than 50 years of age. METHODS: Therefore, a consecutive series of 100 patients (111 hips) aged 50 years or younger (range: 30 to 50 years) was analysed at a mean follow up of 13.5 years. Follow-up assessment included physical examination and radiographic workup. Hip disability osteoarthritis and outcome score (HOOS) and Harris hip score (HHS) were used to evaluate the pre- and post-operative functional outcome, respectively. Patient satisfaction with the surgical result was assessed by standardized questionnaires. RESULTS: The overall survival rate with any revision as endpoint was 96.8 % (95 % CI: 90.5 % to 98.9 %) at ten years. Gender, operation time and the occurence of osteolyses had no influence on joint function or patient satisfaction. We recorded an overall failure rate of 7.4 % (six cases). In four cases (5 %) the prosthesis had to be revised due to aseptic loosening of the cup after 12 years, eight years, 12 years and 11 years, in one case (1.2 %) recurrent luxation led to a revision operation (acetabular cup and head) after three years of primary implantation. In one case an implant failure was recorded (acetabular cup breakage after eight years of implantation). We recorded the occurence of asymptomatic radiolucent lines of the cup in 21 % and of the stem in 35 % in our series. The HOOS was influenced by the presence or abscence of radiolucent lines of the stem. Patients with radiolucent lines of the stem had a median HOOS score of (74 points) compared to those without radiolucent lines (89 points). Other factors, such as "diagnosis led to operation" and "previous operations" had no influence on the HHS and HOOS. CONCLUSION: Our study demonstrates excellent long term survival of cementless femoral stem in combination with a threaded cup in young patients undergoing total hip arthroplasty. PMID- 27241337 TI - Synthesis of furo[3,2-c]coumarin derivatives using visible-light-promoted radical alkyne insertion with bromocoumarins. AB - The synthesis of privileged structures, which are potent drug candidates, is an impetus for drug discovery. The construction of heterocyclic framework furo[3,2 c]coumarins using a visible-light promoted photoredox neutral coupling of 3-bromo 4-hydroxycoumarins with commercially available alkynes has been reported. These reactions can be carried out at room temperature under visible light irradiation with good chemical yields. This work presents 17 furocoumarins, 12 of which are new. Three of the newly synthesized compounds show potent cytotoxicity, and one shows moderate acetylcholinesterase inhibitory activity with IC50 values of 2.16 +/- 0.13 MUM. PMID- 27241336 TI - Treatment and Prognosis of Pulmonary Hypertension in the Left Ventricular Assist Device Patient. AB - This review will discuss the medical management of pulmonary hypertension in patients with left ventricular assist devices. Although much has been written on the management of primary pulmonary hypertension, also called pulmonary arterial hypertension, this review will instead focus on the treatment of pulmonary hypertension secondary to left heart disease. The relevant pharmacotherapy can be divided into medications for treating heart failure, such as diuretics and beta blockers, and medications for treating pulmonary hypertension. We also discuss important preoperative considerations in patients with pulmonary hypertension; the relationships between left ventricular assist devices, pulmonary hemodynamics, and right heart failure; as well as optimal perioperative and long term postoperative medical management of pulmonary hypertension. PMID- 27241338 TI - Appendectomy in mid and later life and risk of Parkinson's disease: A population based study. AB - INTRODUCTION: Pathogenic movement of alpha-synuclein from the gut to the brain in PD has been proposed. The appendix has a relatively high density of alpha synuclein deposition in neurologically healthy individuals. We investigated the incidence of PD after appendectomy. METHODS: Using cause-specific hazards regression models, we compared persons over 35 years of age who had undergone appendectomy with two groups of age- and sex-matched individuals having had: (1) a cholecystectomy and (2) neither procedure. Subsequent diagnoses of PD were identified. RESULTS: Among 42,999 individuals undergoing appendectomy, no difference in risk of PD was identified compared to cholecystectomy (hazard ratio = 1.004; 95% confidence interval: 0.740-1.364). Compared with no procedure, individuals with appendectomy had a higher incidence of PD within 5 years, but no significant difference in risk thereafter. CONCLUSION: In our study, appendectomy in mid or late life does not appear to be associated with a reduced risk of PD. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27241339 TI - Effects of delisting nonprescription combination drugs on health insurance expenditures for pharmaceuticals in Korea. AB - In November 2006, 727 combination drugs in 24 therapeutic classes were delisted in the national formulary in Korea to reduce the country's pharmaceutical expenditure, making these 727 drugs non-reimbursable. This study examines the effects of this delisting on national health insurance expenditures for pharmaceuticals. An interrupted time series analysis was conducted for the period from January 2005 to August 2007 by using administrative claims from Korea's National Health Insurance. The main outcome variable was the total pharmaceutical expenditure measured as a whole and based on the level of health care institutions and therapeutic classes. Comparison between exposure group (delisted drugs) and non-exposure group (listed drugs) were done. No changes in the level of or trend in the total pharmaceutical expenditure were detected. However, the delisting reduced pharmaceutical expenditures in clinics. Delisting effects were also observed according to therapeutic classes of drugs. The results indicate that any delisting should take into account the type of drug. PMID- 27241340 TI - Stockley's drug interactions 11th edition. PMID- 27241341 TI - A systematic review of pharmacists performing obstructive sleep apnea screening services. AB - Background Obstructive sleep apnea (OSA) is a chronic sleep disorder associated with a varying degree of upper airway collapse during sleep. Left untreated, OSA can lead to the development of cardiovascular disease including risk of stroke and increased mortality. Pharmacists are the most accessible and underutilized healthcare resource in the community and can have a significant role in screening patients for OSA. The result may include an expedited referral to the patient's general practitioners or sleep disorder specialists for further diagnostic assessment and therapeutic intervention. Aim of the review The primary aim of this review was to identify the current published evidence of pharmacists providing OSA screening services in a community pharmacy setting. Methods A literature search was conducted to identify evidence of pharmacists providing OSA screening services. The literature search including five databases [PubMed, (1946 January 2015), Cumulative Index of Nursing and Allied Health Literature, International Pharmaceutical Abstracts (1970 to January 2015), Cochrane Database of Systematic Reviews and Google Scholar] with search terms of ("pharmacist or pharmacy") AND ("obstructive sleep apnea") AND ("sleep disorders") AND ("continuous positive airway pressure-CPAP") were used. Articles were limited to English and reported in humans. Results A total of seven publications (four Australia, two Switzerland and one France) were selected and evaluated. Pharmacists utilized validated screening tools in 6/7 (86 %) of clinical studies to assist in the identification of patients with sleep disorders in community pharmacies. A total of 1701 pharmacies encompassing 9177 patients were screened in the clinical studies. Pharmacists were able to identify between 21.4 and 67 % of patients that were at risk for developing OSA or required a referral to a general practitioner or sleep disorder specialist for further diagnostic testing. Conclusion Studies assessing the role of pharmacists performing OSA screening services remains limited due to the small number of studies available and differences in methodological assessment. More qualitative studies including randomized controlled trials are needed to better identify the value of pharmacists providing this novel service. PMID- 27241342 TI - Women's beliefs about medication use during their pregnancy: a UK perspective. AB - Background Previous research has examined the number and extent of medicines taking in pregnant women but not their beliefs and risk perception surrounding their use. Objective To describe beliefs and risk perception associated with medicines use for the treatment of common acute conditions among UK women and explore whether this is related to actual medicines use. Settings Cross sectional, web-based study in the UK. Methods Pregnant women and mothers within 1 year of giving birth were invited to participate in an online cross-sectional questionnaire-based study via a pregnancy website in the UK. Anonymous data were collected from women regarding their use of medicines (both over-the-counter and prescribed) and their beliefs regarding medicines use during pregnancy. Main outcome measures Pregnant women's beliefs about medicines and their relation to pharmacological treatment of acute conditions in pregnancy. Results Pharmacological treatment of conditions in pregnancy ranged from 65.4 % for urinary tract infections (UTIs) to 1.1 % for sleeping problems. Almost three out of ten women avoided using some medications during pregnancy. For heartburn and UTIs, women who did not treat the condition viewed medicines in general as being overused, more harmful and less beneficial, than those who treated the condition. In general, UK pregnant women perceived medicines to be beneficial and slightly overused. Conclusions Women's beliefs about medications impact on treatment of specific conditions in pregnancy such as heartburn and UTIs. Healthcare professionals should explore patient's beliefs regarding medication at the first maternity care visit to promote appropriate medication use in pregnancy. PMID- 27241343 TI - Improvements in the prescribing of antipsychotics in dementia and psychogeriatric units in New Zealand. AB - Background Despite warnings of possible serious events, and reports of little benefit, antipsychotic agents are commonly prescribed in residential care for older people with dementia. A residential care provider (RCP) in New Zealand sought to examine and improve prescribing in some of their facilities. Objective To examine changes following a range of interventions implemented by a RCP to improve the prescribing of antipsychotics. Setting Thirteen dementia and psychogeriatric units in New Zealand managed by a RCP. Method An audit (n = 228 residents) was undertaken in thirteen dementia and psychogeriatric units in New Zealand in July-September 2011. A modified Best Practice Advocacy Centre (bpac(nz)) tool was used to examine antipsychotic prescribing, the administration of "when required" (PRN) antipsychotic doses and antipsychotic-related documentation (e.g. documenting of "target behaviour identified" and "need to monitor for adverse effects"). Prescribing for some central nervous system agents and fractures and fall rates were also examined. Some educational, managerial, environmental, recreational and resident-specific interventions were implemented post-audit. The audit (n = 233) was repeated in July-September 2013. MAIN OUTCOME MEASURES: (1) Number of residents prescribed and administered antipsychotics (2) Documentation of antipsychotic-related information in residents' notes. Results The administration of antipsychotics and prescribing of regular doses (+/-PRN) decreased about a quarter from 2011 to 2013: 50.4-38.2, and 49.1-36.5 % (ORs 0.60, 0.57 respectively, both p < 0.001), and prescribing for any antipsychotic dose (including PRN only) decreased: 60.5-50.6 % (OR 0.67, p = 0.003). Documenting of "target behaviour identified" significantly increased from 54.3 to 71.2 %, (OR 1.99, p = 0.017) and documenting of the "need to monitor for adverse effects" increased non-significantly (30.4-46.6 %, p = 0.098); both falling short of the 90 % goal set by bpac(nz). Benzodiazepine prescribing significantly decreased [39.0-25.8 %, (OR 0.59, p < 0.001)]. Conclusions Following a range of interventions, antipsychotic prescribing, administration and some related documentation improved in dementia and psychogeriatric units in New Zealand. Future studies should aim to identify the most effective of these interventions so they can be considered for implementing in similar settings. PMID- 27241344 TI - Letter: Medication administration via enteral feeding tube. PMID- 27241345 TI - The potential for deprescribing in care home residents with Type 2 diabetes. AB - Background Type 2 diabetes is a common diagnosis in care home residents that is associated with potentially inappropriate prescribing and thus risk of additional suffering. Previous studies found that diabetes medicines can be safely withdrawn in care home residents, encouraging further investigation of the potential for deprescribing amongst these patients. Objectives Describe comorbidities and medicine use in care home residents with Type 2 diabetes; identify number of potentially inappropriate medicines prescribed for these residents using a medicines optimisation tool; assess clinical applicability of the tool. Setting Thirty care homes for older people, East Anglia, UK. Method Data on diagnoses and medicines were extracted from medical records of 826 residents. Potentially inappropriate medicines were identified using the tool 'Optimising Safe and Appropriate Medicines Use'. Twenty percent of results were validated by a care home physician. Main outcome measure Number of potentially inappropriate medicines. Results The 106 residents with Type 2 diabetes had more comorbidities and prescriptions than those without. Over 90 % of residents with Type 2 diabetes had at least one potentially inappropriate medication. The most common was absence of valid indication. The physician unreservedly endorsed 39 % of the suggested deprescribing, and would consider discontinuing all but one of the remaining medicines following access to additional information. Conclusion UK care home residents with Type 2 diabetes had an increased burden of comorbidities and prescriptions. The majority of these patients were prescribed potentially inappropriate medicines. Validation by a care home physician supported the clinical applicability of the medicines optimisation tool. PMID- 27241346 TI - Influencing Perception About Children with Autism and their Parents Using Disclosure Cards. AB - Parents of children with autism often report feeling judged and are increasingly using disclosure cards to reduce negative perceptions. However, no empirical research has been conducted on the effectiveness of these cards. The present study used vignettes of a parent-child interaction in which the child was misbehaving and investigated the efficacy on 160 parents' perceptions. A unique survey was developed with two factors (Maternal Skill Deficit and Negative Reaction) and a single item (Sympathy for Mother). Those who received the disclosure card reported significantly lower Maternal Skill Deficit and Negative Reaction to the Dyad and no difference in Sympathy for the Mother. These results provide preliminary validation for the use of autism disclosure cards in buffering negative judgment. PMID- 27241348 TI - Preliminary Efficacy of Family Implemented TEACCH for Toddlers: Effects on Parents and Their Toddlers with Autism Spectrum Disorder. AB - This study examined the effects of an intervention to support parents and promote skill development in newly diagnosed toddlers with ASD. Participants included 50 children with ASD under 3 and their parents who were randomly assigned to participate in a 6-month intervention, Family Implemented TEACCH for Toddlers (FITT) or 6 months of community services as usual. FITT included 90-min in-home sessions (n = 20) and parent group sessions (n = 4). Results revealed significant treatment effects on parent stress and well-being, with families in the FITT group showing decreased stress and improved well-being over time. While no treatment effects were found for global child measures, there were significant treatment effects on social communication skills. PMID- 27241347 TI - Epidemiology of Injury-Related Emergency Department Visits in the US Among Youth with Autism Spectrum Disorder. AB - Several reports suggest children with autism spectrum disorder (ASD) are more likely to be seen for injury-related ED visits; however, no nationally representative study has examined this question. Using data from the 2008 Nationwide Emergency Department Sample, over a quarter of all visits among those with ASD were related to injury. In the multivariate analyses, the odds of an injury-related visit was 54 % greater among those with ASD compared to youth with intellectual disability (ID), but 48 % less compared to youth without ID or ASD. Compared to all other pediatric injury-visits in the US, visits among children with ASD were more likely to be due to self-inflicted injury and poisoning and were more likely to result in hospitalization (all p < 0.001). PMID- 27241349 TI - Acoustic alterations of ultrasonic vocalization in rat pups induced by perinatal hypothyroidism. AB - Perinatal hypothyroidism causes serious damage to auditory functions that are essential for vocalization development. In rat pups, perinatal hypothyroidism potentially affects the development of ultrasonic vocalization (USV) as a result of hearing deficits. This study examined the effect of perinatal hypothyroidism on the development of USVs in rat pups. Twelve pregnant rats were divided into three groups and treated with the anti-thyroid drug methimazole (MMI) via drinking water, from gestational day 15 to postnatal day (PND) 21. The MMI concentration (w/v) was 0% (control group), 0.01% (low-dose group), or 0.015% (high-dose group). After birth, the pups were individually separated from the dam and littermates on PNDs 5, 10, 15, and 20, and their USVs were recorded for 5min. On PNDs 5 and 10, compared with the control group, the low- and high-dose groups exhibited reductions of both frequency-modulated and downward USVs. On PND 15, however, the low- and high-dose groups displayed increases in number, duration, and amplitude of USVs compared with those in the control group. Lower body weights were observed for the low- and high-dose groups than for the control group. Total thyroxine concentrations in plasma were dose-dependently reduced. The onset of auditory functions appeared on PNDs 11-14. Thus, the rat pups were unable to hear externally produced USVs before PND 11. USVs emitted on PNDs 5 and 10 might have been spontaneous and independent of the pups' own or littermate emitted USVs. The developmental retardation of vocalization-related organs or muscles might underlie the acoustic alterations of USVs on PNDs 5 and 10. The greater number, duration, and amplitude of USVs on PND 15, after which the hearing onset occurred, suggested that the elevation of auditory thresholds occurred as a result of hearing deficits in the low- and high-dose groups. Perinatal hypothyroidism appears to have caused acoustic alterations in the USV development. PMID- 27241350 TI - Methylmercury-induced developmental toxicity is associated with oxidative stress and cofilin phosphorylation. Cellular and human studies. AB - Environmental exposure to methylmercury (MeHg) during development is of concern because it is easily incorporated in children's body both pre- and post-natal, it acts at several levels of neural pathways (mitochondria, cytoskeleton, neurotransmission) and it causes behavioral impairment in child. We evaluated the effects of prolonged exposure to 10-600nM MeHg on primary cultures of mouse cortical (CCN) and of cerebellar granule cells (CGC) during their differentiation period. In addition, it was studied if prenatal MeHg exposure correlated with altered antioxidant defenses and cofilin phosphorylation in human placentas (n=12) from the INMA cohort (Spain). Exposure to MeHg for 9days in vitro (DIV) resulted in protein carbonylation and in cell death at concentrations >=200nM and >=300nM, respectively. Exposure of CCN and CGC to non-cytotoxic MeHg concentrations for 5 DIV induced an early concentration-dependent decrease in cofilin phosphorylation. Furthermore, in both cell types actin was translocated from the cytosol to the mitochondria whereas cofilin translocation was found only in CGC. Translocation of cofilin and actin to mitochondria in CGC occurred from 30nM MeHg onwards. We also found an increased expression of cortactin and LIMK1 mRNA in CGC but not in CCN. All these effects were prevented by the antioxidant probucol. Cofilin phosphorylation was significantly decreased and a trend for decreased activity of glutathione reductase and glutathione peroxidase was found in the fetal side of human placental samples from the highest (20-40MUg/L) MeHg exposed group when compared with the low (<7MUg/L) MeHg-exposed group. In summary, cofilin dephosphorylation and oxidative stress are hallmarks of MeHg exposure in both experimental and human systems. PMID- 27241351 TI - Cardiovascular implantable electronic device function and longevity at autopsy: an underestimated resource. AB - BACKGROUND: The feasibility and safety of postmortem cardiovascular implantable electronic device (CIED; pacemaker or defibrillator) retrieval for reuse has been shown. To date, studies indicate a low yield of reusable postmortem CIEDs (17% 30%). OBJECTIVE: The purpose of this study was to test the hypothesis that a higher rate of reusable CIEDs would be identified upon postmortem retrieval when an institutional protocol for systematic and routine acquisition, interrogation, reprogramming, and manufacturer analysis was used. METHODS: Over a 6-year period, all subjects referred for autopsy underwent concomitant CIED pulse generator retrieval and enrollment in the Johns Hopkins Post-Mortem CIED Registry. CIEDs were interrogated, reprogrammed, and submitted for manufacturer analysis. RESULTS: In total, 84 autopsies had CIEDs (37 pacemakers, 47 implantable cardioverter-defibrillators). CIEDs were implanted 2.84 +/- 2.32 years before death, with 30% implanted <1 year before death. Overall, CIED postmortem longevity was 4.79 +/- 3.41 years, with 56% demonstrating longevity >=4 years (this group had an estimated mean longevity of 7.37 +/- 2.44 years). Manufacturer analyses uncovered 2 falsely triggered elective replacement indication alerts, confirmed 5 correctly triggered elective replacement indication alerts, identified a recalled pacemaker, and verified that a defibrillator had undergone nonprogrammable hard reset. CONCLUSION: When a protocol for systematic and routine postmortem CIED retrieval, interrogation, reprogramming, and analysis was used, we noted that >60% of pacemakers and >50% of defibrillators demonstrated normal functional status with projected longevities >7 years on average. Formation of a national hospital-based "CIED donor network" would facilitate larger scale charitable efforts in underserved countries. PMID- 27241352 TI - Clinical recurrence and electrical pulmonary vein reconnections after second generation cryoballoon ablation. AB - BACKGROUND: Electrical reconnections after pulmonary vein isolation (PVI) are less common after second-generation cryoballoon than radiofrequency ablation. OBJECTIVE: The purpose of this study was to investigate the incidence and characteristics of pulmonary vein (PV) reconnections after second-generation cryoballoon ablation in patients with and those without clinical recurrences. METHODS: Forty patients with paroxysmal atrial fibrillation undergoing second procedures after cryoballoon ablation were enrolled. Twenty-five patients experienced clinical recurrences, and the remaining 15 did not. RESULTS: All 158 PVs were reevaluated a median [25th, 75th percentiles] of 6.0 [4.0-9.0] months after the initial procedure. In total, reconnections were detected in 39 PVs (24.7%) among 25 patients (62.5%). Reconnected PVs included 6 left superior (LS) (15.8%), 7 left inferior (LI) (18.4%), 5 right superior (RS) (12.5%), 20 right inferior (RI) (50.0%), and 1 left common (LC) (50.0%) PV. Reconnected PV potential conduction delays were a median of 112 [76-130], 103 [82-133], 84 [66 96], 68 [49-73], and 204 ms in the LS, LI, RS, RI, and LC PV, respectively. There was no significant difference between those with and those without clinical recurrences with regard to clinical characteristics, procedural results, incidence of reconnections (25/98 vs 14/60, P = .758), and PV conduction delays in each PV. The most common gap location was the RI PV bottom in both groups. Among 5 patients with reconnections of arrhythmogenic PVs (with atrial fibrillation initiation), 2 experienced clinical recurrences, whereas 3 did not. Non-PV foci (with atrial fibrillation initiation) were identified in a second procedures in 10 of 25 patients with clinical recurrences. CONCLUSION: The incidence and characteristics of PV reconnections after second-generation cryoballoon ablation were similar between patients with and those without clinical recurrences. The results should be considered when discussing the optimal dose of cryoballoon applications. PMID- 27241353 TI - Two years outcome in patients with persistent atrial fibrillation after pulmonary vein isolation using the second-generation 28-mm cryoballoon. AB - BACKGROUND: The efficacy of the second-generation cryoballoon (CB) in patients with paroxysmal atrial fibrillation (AF) has been demonstrated previously. Data on the efficacy of CB ablation in patients with persistent AF are sparse. OBJECTIVE: The aim of this study was to evaluate the 2-year success rate of pulmonary vein isolation in patients with persistent AF using the second generation CB. METHODS: Fifty consecutive patients (mean age 64.6 +/- 9.9 years; 19 women [38%]) with persistent AF were included in this analysis. The mean follow-up period was 22 +/- 11 months. All patients were ablated using the second generation 28-mm CB. Isolation of the pulmonary veins was confirmed using a spiral mapping catheter. In all patients, follow-up was obtained using 24-hour Holter monitoring or via interrogation of an implanted loop recorder or pacemaker. RESULTS: The mean left atrial diameter was 43.6 +/- 5.6 mm, the mean CHA2DS2-VASc score was 2.8 +/- 1.5, and the mean HAS-BLED score was 2.1 +/- 1.2. The mean fluoroscopy time was 25.8 +/- 9 minutes, and the mean procedural time was 146.4 +/- 37.8 minutes. After 22 +/- 11 months, the frequency of arrhythmia recurrence was 22 of 50 (44%) in the overall group (paroxysmal AF 6 of 22 [27%]; persistent AF 16 of 22 [73%]). No major complications occurred. Aneurysma spurium not requiring surgical intervention occurred in 1 (2%) patient. No phrenic nerve palsy was observed. CONCLUSION: Two years' results after pulmonary vein isolation using the second-generation CB in patients with persistent AF are promising. The clinical success rate appears to be similar to the reported success rates of radiofrequency ablation for the treatment of persistent AF. PMID- 27241355 TI - Safety and efficacy of starting warfarin after two consecutive platelet count rises in heparin-induced thrombocytopenia. AB - INTRODUCTION: Current guidelines on the treatment of heparin-induced thrombocytopenia (HIT) recommend warfarin initiation when platelet levels recover to 150*10(9)/L or more. However, many patients may not achieve this platelet level or may have slow platelet recovery. The aim of this study is to determine if initiating warfarin when platelets start trending upward instead of at a specific level is safe and effective in patients diagnosed with HIT. MATERIALS AND METHODS: Two groups of patients diagnosed and treated for HIT in a tertiary care hospital were assessed for HIT-related outcomes: 28 patients had warfarin initiated after platelets recovered to 150*10(9)/L or more and 30 patients had warfarin initiated prior to platelet recovery. RESULTS: There was no significant difference between the rate of thrombosis, venous limb gangrene, or limb amputation. Three patients died during the data collection period, all deemed to be unrelated to HIT by independent investigators. The average hospital length of stay was 22.2+/-12.7days and 38.8+/-19.1days for patients who started warfarin at platelets less than 150*10(9)/L and platelets greater than or equal to 150*10(9)/L respectively (P=0.0002). CONCLUSIONS: The data suggests that the absolute platelet level at which warfarin is initiated does not affect the rate of thrombosis or mortality but may shorten overall hospital length of stay and associated costs. Therefore, it may be more important to observe an upward trend in platelets rather than striving to achieve an absolute platelet level before starting warfarin in patients with HIT. PMID- 27241354 TI - Ablating atrial fibrillation: A translational science perspective for clinicians. AB - Although considerable progress has been made in developing ablation approaches to cure atrial fibrillation (AF), outcomes are still suboptimal, especially for persistent and long-lasting persistent AF. In this topical review, we review the arrhythmia mechanisms, both reentrant and nonreentrant, that are potentially relevant to human AF at various stages/settings. We describe arrhythmia mapping techniques used to distinguish between the different mechanisms, with a particular focus on the detection of rotors. We discuss which arrhythmia mechanisms are likely to respond to ablation, and the challenges and prospects for improving upon current ablation strategies to achieve better outcomes. PMID- 27241358 TI - Invasion status of the common carp Cyprinus carpio in inland waters of Argentina. AB - This study documents the presence of Cyprinus carpio in 119 natural environments and 49 artificial habitats in Argentina, showing an exponential increment of invaded locations over time since it was introduced in the nineteenth century. Geographic expansion patterns revealed that since its initial introduction, species records demonstrate an increment in the central portion of the country only after 1970 and subsequent expansion after 1990 to the north, west and south. Using an environmental similarity index it was determined that more than half the country offers good conditions for C. carpio establishment. Environmental factors and anthropogenic impacts are relevant drivers that can account for the current and future distribution of C. carpio in Argentina. PMID- 27241356 TI - Hepatoprotective effects of allyl isothiocyanate against carbon tetrachloride induced hepatotoxicity in rat. AB - We evaluated the hepatoprotective activity of allyl isothiocyanate (AITC) against carbon tetrachloride (CCl4)-induced liver injury in rats. Sprague Dawley rats were orally administered AITC at doses of 5 (AITC 5) and 50 (AITC 50) mg/kg body weight once daily for 3 days, with or without intraperitoneal injection of CCl4. Serum chemistry was assessed for changes in alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The enzyme activities of superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) were examined in liver tissues, while pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF alpha) and interleukin-1 beta (IL-1beta) mRNA expression were analyzed using real time polymerase chain reaction. And heme oxygenase-1 (HO-1) and ionized calcium binding protein-1 (Iba-1) immunoreactivities were evaluated by Western blot analysis and immunohistochemistry, respectively. In serum chemistry, the oral administration of AITC itself did not affect the serum levels of ALT or AST, furthermore pretreatment with AITC 5 and AITC 50 significantly reduced the ALT and AST activity levels that were elevated in CCl4-intoxicated rats. In addition, AITC significantly suppressed the reduction of SOD and CAT, and the elevation of MDA, TNF-alpha mRNA expression, on the other hands, induced the expression of HO 1 compared with those of the vehicle-treated CCl4 group. The histopathological evaluation and Iba-1 immunoreactivity also supported the hepatoprotective effects of AITC against CCl4-induced liver injury. These results suggest that AITC ameliorates oxidative liver injury, possibly through reducing lipid peroxidation, enhancing antioxidant enzymes, and suppressing Kupffer cells and macrophages. PMID- 27241357 TI - Heat shock protein 70 and AMP-activated protein kinase contribute to 17-DMAG dependent protection against heat stroke. AB - Heat shock protein 70 (Hsp70) preconditioning induces thermotolerance, and adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a role in the process of autophagy. Here, we investigated whether 17-dimethylaminoethylamino-17 demethoxy-geldanamycin (17-DMAG) protected against heat stroke (HS) in rats by up regulation of Hsp70 and phosphorylated AMPK (pAMPK). To produce HS, male Sprague Dawley rats were placed in a chamber with an ambient temperature of 42 degrees C. Physiological function (mean arterial pressure, heart rate and core temperature), hepatic and intestinal injury, inflammatory mediators and levels of Hsp70, pAMPK and light chain 3 (LC3B) in hepatic tissue were measured in HS rats or/and rats pre-treated with 17-DMAG. 17-DMAG pre-treatment significantly attenuated hypotension and organ dysfunction induced by HS in rats. The survival time during HS was also prolonged by 17-DMAG treatment. Hsp70 expression was increased, whereas pAMPK levels in the liver were significantly decreased in HS rats. Following pre-treatment with 17-DMAG, Hsp70 protein levels increased further, and pAMPK levels were enhanced. Treatment with an AMPK activator significantly increased the LC3BII/LC3BI ratio as a marker of autophagy in HS rats. Treatment with quercetin significantly suppressed Hsp70 and pAMPK levels and reduced the protective effects of 17-DMAG in HS rats. Both of Hsp70 and AMPK are involved in the 17-DMAG-mediated protection against HS. 17-DMAG may be a promising candidate drug in the clinical setting. PMID- 27241359 TI - Open bilateral interlaminar decompression in lumbar spinal stenosis. PMID- 27241360 TI - High prevalence and increasing incidence of multiple sclerosis in the Norwegian county of Buskerud. AB - OBJECTIVES: The objective was to investigate the incidence of multiple sclerosis (MS) as well as estimate the prevalence as of 1 January 2014 in the southeastern Norwegian county of Buskerud. MATERIALS AND METHODS: All patients with MS living in Buskerud county in Norway between 01 January 2003 and 01 January 2014 were identified. Point prevalence of MS was identified on 01 January 2014. RESULTS: We found a prevalence of 213.8 (95% CI 196.4-231.1) per 100 000. The sex ratio was 2.2:1 with a female prevalence of 293.4 (95% CI 264.7-322.2) per 100 000 and a male prevalence of 134.7 (95% CI 115.3-154.2) per 100 000. About 82% of our MS population had a confirmed relapsing-remitting MS at disease onset, while 16.8% had primary progressive MS. The mean annual incidence between 2003 and 2013 was 11.8 (95% CI 10.6-13.1) per 100 000. CONCLUSION: This study shows a high incidence of MS in Buskerud county in southeastern Norway, and the incidence may still be on the rise. We found a relatively high prevalence of MS in our population, although this does correspond with the recently published national data. Further studies investigating both changes in incidence and possible factors causing the increasing incidence are warranted. PMID- 27241361 TI - Body Hair Transplant by Follicular Unit Extraction: My Experience With 122 Patients. AB - BACKGROUND: Body hair shafts from the beard, trunk, and extremities can be used to treat baldness when patients have inadequate amounts of scalp donor hair, but reports in the literature concerning use of body hair to treat baldness are confined to case reports. OBJECTIVES: This study aimed to assess the outcome of body hair transplanted to bald areas of the scalp in selected patients. METHODS: From 2005 through 2011, 122 patients preselected for adequate body hair had donor hair transplanted from the beard, trunk, and the extremities to the scalp by follicular unit extraction (FUE) by the author at a single center. All patients were emailed surveys to assess surgical outcomes and overall satisfaction. RESULTS: Seventy-nine patients (64.8%) responded with a mean time of 2.9 years between date of last surgery and time of survey. Patients were generally very satisfied with results of their procedure, giving mean scores of at least a 7.8 on a Likert-like scale of 0 to 10 for their healing status, hair growth in recipient areas, and overall satisfaction with their surgeries. These scores were comparable to mean scores provided by patients whose transplants included scalp donor sources. CONCLUSIONS: FUE using body hair can be an effective hair transplantation method for a select patient population of hirsute individuals who suffer from severe baldness or have inadequate scalp donor reserve. LEVEL OF EVIDENCE: 4 Therapeutic. PMID- 27241362 TI - Skin Rejuvenation and Volume Enhancement with the Micro Superficial Enhanced Fluid Fat Injection (M-SEFFI) for Skin Aging of the Periocular and Perioral Regions. AB - BACKGROUND: Adipose-derived stromal and stem cells (ADSC) in autologous fat promises regenerative advantages, and injected into the dermal and subdermal layers, enhances rejuvenation and volume. However, extremely superficial fat injection with current techniques is limited. OBJECTIVES: Efficacy and viability evaluation of fat harvested with extremely small side port (0.3 mm) cannulae without further tissue manipulation for the correction of aging/thin skin in the periocular and perioral regions. METHODS: Micro-superficial enhanced fluid fat injection (M-SEFFI) harvests adipose tissue with a multi-perforated cannula (0.3 mm), and autologous platelet rich plasma (PRP) is added. The tissue is injected into the dermal region of the periocular and perioral zones. Efficacy and viability were evaluated by histological and cell culture analysis. Clinical assessment included retrospective evaluation according to 1 = no effect, 2 = fair effect, 3 = good effect, 4 = excellent effect. RESULTS: Between June 2014 and July 2015, 65 patients (7 men; mean age 49.7 years) were treated with M-SEFFI. No intraoperative complications or visible lumpiness were recorded. Analysis demonstrated mature, viable adipocytes with a strong stromal component. Following PRP addition, there was a greater proliferation noted in the M-SEFFI compared to the SEFFI (0.5 mm). Mean follow-up was 4.1 months. Clinical assessment by surgeons and patients at 1 month was 3.52 and 3.74, and 6 months 3.06 and 2.6 respectively. CONCLUSIONS: M-SEFFI is effective and viable for lump free skin rejuvenation and volume enhancement, through the extraction of smoother ADSC rich, autologous fat tissue that does not require further tissue manipulation, to correct skin aging. LEVEL OF EVIDENCE: 4 Therapeutic. PMID- 27241363 TI - Labia Majora Augmentation with Hyaluronic Acid Filler: Technique and Results. AB - BACKGROUND: External female genitalia lose elasticity and volume with age. In the literature several techniques address the redundancy of the labia minora, but only few reports describe the augmentation of labia majora with fat grafting. At present, no studies describe the augmentation of the labia majora with hyaluronic acid. OBJECTIVES: This study aims to present our technique of infiltration of hyaluronic acid filler, analyzing effectiveness, patient satisfaction, and complications. METHODS: We retrospectively analyzed 54 patients affected by hypotrophy of the labia majora; they were treated with hyaluronic acid filler between November 2010 and December 2014. The Global Aesthetic Improvement Scale (GAIS) filled out by the doctor and the patients was used to evaluate the results 12 months after the infiltration. Complications were recorded. RESULTS: A total of 31 patients affected by mild to moderate labia majora hypotrophy were treated with 19 mg/mL HA filler; 23 patients affected by severe labia majora hypotrophy were treated with 21 mg/mL HA filler. Among the first group of patients, one underwent a second infiltration 6 months later with 19 mg/mL HA filler (maximum 1 mL). A significant improvement (P < .0001) in GAIS score was observed, both in the scores provided by the patients and by the doctor. A greater relative improvement was observed in patients affected by severe hypotrophy. No complications were recorded. CONCLUSIONS: Hyaluronic acid infiltration of the labia majora is able to provide a significant rejuvenation with a simple outpatient procedure. We achieved significant improvements with one infiltration in all cases. The treatment is repeatable, has virtually no complications and it is reversible. LEVEL OF EVIDENCE: 4 Therapeutic. PMID- 27241364 TI - Why Risk Assessment Models are Ineffective in Predicting Venous Thromboembolism in Plastic Surgery Patients. PMID- 27241365 TI - Response to "Why Risk Assessment Models are Ineffective in Predicting Venous Thromboembolism in Plastic Surgery Patients". PMID- 27241366 TI - Preoperative anaemia is associated with increased allogeneic pack red cell transfusion in revision hip and knee joint arthroplasty: a retrospective analysis of 5387 patients over a 10-year period at a single high volume centre. AB - OBJECTIVES: To estimate the prevalence of preoperative World Health Organization (WHO) defined anaemia in patients presenting for revision hip and knee arthroplasty and its association with transfusion of allogeneic packed red blood cells (PRBC). BACKGROUND: Studies have mainly investigated the prevalence of preoperative anaemia in primary and not revision hip and knee joint arthroplasty. METHODS: An analysis of a prospectively collected patient data for 5387 patients having revision hip or knee arthroplasty over a 10-year period at a single high volume centre was conducted. Logistic regression was used to assess whether the presence of WHO defined preoperative anaemia as well as other risk factors were associated with inpatient allogeneic PRBC transfusion. RESULTS: There were 5387 patients assessed of which 3021 (56.01%) patients had revision total hip replacements and 2366 (43.09%) had revision total knee arthroplasty. Of these patients 1956 (36.03%) had preoperative WHO defined anaemia. A total of 2034 (37.08%) patients received at least one unit of allogeneic PRBC during their primary hospital admission. In the final model preoperative WHO defined anaemia was independently associated with allogeneic PRBC transfusion in hip and knee revision surgery OR 4.042 (4.012-4.072 95% CI) CONCLUSIONS: Preoperative anaemia is common in patients presenting for revision hip and knee arthroplasty and independently associated with transfusion of allogeneic PRBC. PMID- 27241367 TI - Evolutionary history shapes patterns of mutualistic benefit in Acacia-rhizobial interactions. AB - The ecological and evolutionary factors that drive the emergence and maintenance of variation in mutualistic benefit (i.e., the benefits provided by one partner to another) in mutualistic symbioses are not well understood. In this study, we evaluated the role that host and symbiont phylogeny might play in determining patterns of mutualistic benefit for interactions among nine species of Acacia and 31 strains of nitrogen-fixing rhizobial bacteria. Using phylogenetic comparative methods we compared patterns of variation in mutualistic benefit (host response to inoculation) to rhizobial phylogenies constructed from housekeeping and symbiosis genes; and a multigene host phylogeny. We found widespread genotype-by genotype variation in patterns of plant growth. A relatively large component of this variation (21-28%) was strongly influenced by the interacting evolutionary histories of both partners, such that phylogenetically similar host species had similar growth responses when inoculated with phylogenetically similar rhizobia. We also found a relatively large nonphylogenetic effect for the average mutualistic benefit provided by rhizobia to plants, such that phylogenetic relatedness did not predict the overall benefit provided by rhizobia across all hosts. We conclude that phylogenetic relatedness should frequently predict patterns of mutualistic benefit in acacia-rhizobial mutualistic interactions; but that some mutualistic traits also evolve independently of the phylogenies. PMID- 27241368 TI - Geographically weighted regression and geostatistical techniques to construct the geogenic radon potential map of the Lazio region: A methodological proposal for the European Atlas of Natural Radiation. AB - In many countries, assessment programmes are carried out to identify areas where people may be exposed to high radon levels. These programmes often involve detailed mapping, followed by spatial interpolation and extrapolation of the results based on the correlation of indoor radon values with other parameters (e.g., lithology, permeability and airborne total gamma radiation) to optimise the radon hazard maps at the municipal and/or regional scale. In the present work, Geographical Weighted Regression and geostatistics are used to estimate the Geogenic Radon Potential (GRP) of the Lazio Region, assuming that the radon risk only depends on the geological and environmental characteristics of the study area. A wide geodatabase has been organised including about 8000 samples of soil gas radon, as well as other proxy variables, such as radium and uranium content of homogeneous geological units, rock permeability, and faults and topography often associated with radon production/migration in the shallow environment. All these data have been processed in a Geographic Information System (GIS) using geospatial analysis and geostatistics to produce base thematic maps in a 1000 m * 1000 m grid format. Global Ordinary Least Squared (OLS) regression and local Geographical Weighted Regression (GWR) have been applied and compared assuming that the relationships between radon activities and the environmental variables are not spatially stationary, but vary locally according to the GRP. The spatial regression model has been elaborated considering soil-gas radon concentrations as the response variable and developing proxy variables as predictors through the use of a training dataset. Then a validation procedure was used to predict soil gas radon values using a test dataset. Finally, the predicted values were interpolated using the kriging algorithm to obtain the GRP map of the Lazio region. The map shows some high GRP areas corresponding to the volcanic terrains (central-northern sector of Lazio region) and to faulted and fractured carbonate rocks (central-southern and eastern sectors of the Lazio region). This typical local variability of autocorrelated phenomena can only be taken into account by using local methods for spatial data analysis. The constructed GRP map can be a useful tool to implement radon policies at both the national and local levels, providing critical data for land use and planning purposes. PMID- 27241369 TI - In vitro activity of dalbavancin against biofilms of staphylococci isolated from prosthetic joint infections. AB - The in vitro activity of dalbavancin was tested against biofilms of 171 staphylococci associated with prosthetic joint infection. Dalbavancin minimum biofilm bactericidal concentration (MBBC) values were: MBBC50 for Staphylococcus aureus and Staphylococcus epidermidis, 1MUg/mL; MBBC90 for S. aureus, 2MUg/mL; MBBC90 for S. epidermidis, 4MUg/mL. PMID- 27241370 TI - Impact of immune status on the clinical characteristics and treatment outcomes of nocardiosis. AB - Nocardiosis occurs in both immunocompromised and immunocompetent patients. We aimed to assess how its characteristics differ depending on patients' immune status. Of a total of 54 patients with culture-proven nocardiosis diagnosed over 13 years, 18 (33%) were immunocompetent. Half of immunocompetent patients had chronic lung disease and were not receiving systemic corticosteroid. There were no significant differences in clinical, radiographic, and microbiologic characteristics, and treatment outcomes according to immune status, except that pulmonary cavitation (47% vs. 8%) and coexisting infections (17% vs. 0%) were more frequent in immunocompromised hosts. Nocardia farcinica, the most commonly identified isolates at the species level (51%), was highly susceptible to trimethoprim-sulfamethoxazole (100%) and highly resistant to ceftriaxone (94%). Nocardiosis should be considered in differential diagnosis of pneumonia, brain abscess, or soft tissue infection that does not respond to conventional antibiotic therapy such as ceftriaxone, regardless of whether the patient is immunocompromised or not. PMID- 27241371 TI - Human infections due to Staphylococcus pseudintermedius, an emerging zoonosis of canine origin: report of 24 cases. AB - BACKGROUND: Staphylococcus pseudintermedius has been recently identified as a novel species within the genus Staphylococcus, and is commonly associated with infections in dogs. Currently, there are few reports of human infections due to this bacterium. OBJECTIVE: To use a population-based approach to describe the characteristics of human S. pseudintermedius infections in a large Canadian healthcare region. METHODS: All adult cases aged >=18 years identified at a large regional laboratory from April 1, 2013 to April 1, 2015 who had at least one positive culture for S. pseudintermedius were retrospectively reviewed. A combination of phenotypic methods, mass spectrometry (i.e., MALDI-TOF), and cpn60 sequencing were used to identify S. pseudintermedius. Chart review was conducted, and cases were analysed descriptively. RESULTS: Twenty-seven isolates of S. pseudintermedius from 24 human cases were included for analysis. 58.3% were male with median age of 61 years (IQR 55-70.5). Most patients [22 (92.1%)] had confirmed contact with dogs at time of infection. S. pseudintermedius was isolated in 18 cases (75.0%) of skin and soft tissue infections (SSTI), and 2 invasive cases (8.3%) including a prosthetic joint and bloodstream infection. The other 4 patients were considered to be colonized (skin - 3; lung - 1). Methicillin resistance was identified in 3 cases with 6 total isolates (22.2%); multi-drug resistance was also demonstrated commonly. CONCLUSION: S. pseudintermedius is most commonly associated with SSTIs in humans. Transmission probably occurs from a pet dog. Species-level identification of S. pseudintermedius is important due to the high prevalence of antibiotic resistance, particularly to methicillin. PMID- 27241373 TI - Management of Hip Pain in Young Adults. AB - The diagnosis and treatment of hip pain in the young adult remains a challenge. Recently, understanding of a few specific hip conditions has improved; most notably femoroacetabular impingement. The differential diagnosis of hip pain has also expanded significantly, offering new challenges and opportunities. Along with the diagnostic dilemma, optimal treatment strategies for many conditions have yet to be proven and are current areas of important inquiry. This article reviews the current research on hip pain in the young adult and presents an overview of diagnostic and management strategies. PMID- 27241372 TI - Miniature bovine pancreatic trypsin inhibitors (m-BPTIs) of the West Nile virus NS2B-NS3 protease. AB - The mosquito-borne West Nile virus (WNV) causes a wide range of symptoms ranging from fever to the often fatal viral encephalitis. To date, no vaccine or drug therapy is available. The trypsin-like WNV NS2B-NS3 protease is deemed a plausible drug target and was shown to be inhibited by bovine pancreatic trypsin inhibitor (BPTI), a 58-residue protein isolated from bovine lung. Herein, we report a protein truncation study that resulted in a novel 14-residue cyclic peptide with equipotent inhibitory activity to native BPTI. We believe our truncation strategy can be further applied in the development of peptide-based inhibitors targeting trypsin-like proteases. PMID- 27241374 TI - Total Hip Arthroplasty Performed Through Direct Anterior Approach Provides Superior Early Outcome: Results of a Randomized, Prospective Study. AB - Studies suggest that total hip arthroplasty (THA) performed through direct anterior (DA) approach has better functional outcomes than other surgical approaches. The immediate to very early outcomes of DA THA are not known. A prospective, randomized study examined the very early outcome of THA performed through DA versus direct lateral approach. The functional outcomes on day 1, day 2, week 6, week 12, 6 months, and 1 year were measured. Patients receiving DA THA had significantly higher functional scores during the early period following surgery. The difference in functional scores leveled out at 6 months. PMID- 27241375 TI - Diagnosis of Periprosthetic Joint Infection Following Hip and Knee Arthroplasty. AB - The diagnosis of periprosthetic joint infection (PJI) following total hip arthroplasty and total knee arthroplasty has been one of the major challenges in orthopedic surgery. As there is no single absolute test for diagnosis of PJI, diagnostic criteria for PJI have been proposed that include using several diagnostic modalities. Focused history, physical examination, plain radiographs, and initial serologic tests should be followed by joint aspiration and synovial analysis. Newer diagnostic techniques, such as alpha-defensin and interleukin-6, hold great promise in the future diagnosis of equivocal infections. PMID- 27241376 TI - Acute Compartment Syndrome. AB - Acute compartment syndrome (ACS) is a well-known pathophysiologic complication of trauma or tissue ischemia. ACS affects the appearance, function, and even the viability of the involved limb, and demands immediate diagnosis and treatment. However, ACS is difficult to diagnose and the only effective treatment is decompressive surgical fasciotomy. The clinical signs and symptoms may easily be attributed to other aspects of the injury, which further complicates the diagnosis. This article highlights the latest information regarding the diagnosis of ACS, how to perform fasciotomies, how to manage fasciotomy wounds, and also reviews complications and outcomes of ACS. PMID- 27241377 TI - Treatment of Hip Dislocations and Associated Injuries: Current State of Care. AB - Hip dislocations, most often caused by motor vehicle accidents or similar high energy trauma, traverse a large subset of distinct injury patterns. Understanding these patterns and their associated injuries allows surgeons to provide optimal care for these patients both in the early and late postinjury periods. Nonoperative care requires surgeons to understand the indications. Surgical care requires the surgeon to understand the benefits and limitations of several surgical approaches. This article presents the current understanding of hip dislocation treatment, focusing on anatomy, injury classifications, nonoperative and operative management, and postinjury care. PMID- 27241378 TI - Management of Pelvic Ring Injuries in Unstable Patients. AB - High-energy pelvic ring injuries can represent life-threatening injuries in the polytraumatized patient, particularly when presenting with hemodynamic instability. These injuries mandate a systematic multidisciplinary approach to evaluation, and timely intervention to address hemorrhage while concomitantly addressing mechanical instability. These pelvic injuries are associated with potentially lethal hemorrhage originating from venous, arterial, and osseous sources. A thorough understanding of anatomy, radiographic findings, and initial physical examination can alert one to the presence of pelvic instability necessitating emergent treatment. The focus is on hemorrhage control, using techniques for skeletal stabilization, angiography, and open procedures to decrease mortality in this high-risk patient population. PMID- 27241379 TI - Pediatric Open Fractures. AB - Open fractures in children are rare and are typically associated with better prognoses compared with their adult equivalents. Regardless, open fractures pose a challenge because of the risk of healing complications and infection, leading to significant morbidity even in the pediatric population. Therefore, the management of pediatric open fractures requires special consideration. This article comprehensively reviews the initial evaluation, classification, treatment, outcomes, and controversies of open fractures in children. PMID- 27241380 TI - Compartment Syndrome in Children. AB - Compartment syndrome in children can present differently than adults. Increased analgesic need should be considered the first sign of evolving compartment syndrome in children. Children with supracondylar humerus fractures, floating elbow injuries, operatively treated forearm fractures, and tibia fractures are at high risk for developing compartment syndrome. Elbow flexion beyond 90 degrees in supracondylar humerus fractures and closed treatment of forearm fractures in floating elbow injuries are associated with increased risk of compartment syndrome. Prompt diagnosis and treatment with fasciotomy in children result in excellent long-term outcomes. PMID- 27241381 TI - Acute Ischemia of the Upper Extremity. AB - Ischemia of the upper extremity is uncommon but can be seen with open or closed trauma. Those dealing with traumatic injury of the upper extremity should be conversant with techniques of vascular surgery and microsurgery to address these injuries when they occur. Closed injury can occur as well, and at times these are best managed nonoperatively. This article discusses the management of both in the acute setting. PMID- 27241382 TI - Acute Carpal Tunnel Syndrome: A Review of Current Literature. AB - Acute carpal tunnel syndrome is a progressive median nerve compression leading to loss of two-point discrimination. Most cases encountered are in the emergency department following wrist trauma and distal radius fractures. Although rare, atraumatic etiologies have been reported and diligent evaluation of these patients should be performed. If missed or neglected, irreversible damage to the median nerve may result. Once diagnosed, emergent carpal tunnel release should be performed. If performed in a timely manner outcomes are excellent, often with complete recovery. PMID- 27241383 TI - Compartment Syndrome of the Hand. AB - Hand compartment syndrome has many etiologies; untreated, it has dire functional consequences. Intracompartmental pressure exceeding capillary filling pressure causes decreased tissue perfusion resulting in progressive ischemic death of compartment contents. Clinical findings can evolve. Serial physical examinations are recommended and, if equivocal, interstitial pressure monitoring is indicated. Definitive management is emergent fasciotomies with incisions designed to decompress the involved hand compartments, which could include the thenar, hypothenar, and interosseous compartments, and the carpal tunnel. Careful wound care, edema management, splinting, and hand therapy are critical. Therapy should start early postoperatively, possibly before wound closure. PMID- 27241384 TI - High-pressure Injection Injuries of the Hand. AB - High-pressure injection hand injuries are often overlooked, with severe complications owing to the acute inflammatory response. Prognosis for depends on the type of material injected, location of injection, involved pressure, and timing to surgical decompression and debridement. Acute management involves broad spectrum antibiotics, tetanus prophylaxis, emergent decompression within 6 hours, and complete removal of the injected material. Most patients have residual sequelae of stiffness, pain, sensation loss, and difficulties in returning to work. The hand surgeon's role is prompt surgical intervention, early postoperative motion, and education of patient and staff regarding short- and long-term expectations. PMID- 27241386 TI - Erratum. PMID- 27241385 TI - Review of Talus Fractures and Surgical Timing. AB - This review article provides an overview of talus fractures. Special attention is given to the clinical literature that evaluates the timing of surgical management for displaced talus fractures. Several series support delayed definitive fixation for talus fractures, suggesting displaced fractures do not necessitate emergent surgical fixation. PMID- 27241387 TI - Orthopedic Urgencies and Emergencies. PMID- 27241388 TI - Development of the Larval Amphibian Growth and Development Assay: Effects of benzophenone-2 exposure in Xenopus laevis from embryo to juvenile. AB - The Larval Amphibian Growth and Development Assay (LAGDA) is a globally harmonized chemical testing guideline developed by the U.S. Environmental Protection Agency in collaboration with Japan's Ministry of Environment to support risk assessment. The assay is employed as a higher tiered approach to evaluate effects of chronic chemical exposure throughout multiple life stages in a model amphibian species, Xenopus laevis. To evaluate the utility of the initial LAGDA design, the assay was performed using a mixed mode of action endocrine disrupting chemical, benzophenone-2 (BP-2). X. laevis embryos were exposed in flow-through conditions to 0, 1.5, 3.0 or 6.0 mg l-1 BP-2 until 2 months post metamorphosis. Overt toxicity was evident throughout the exposure period in the 6.0 mg l-1 treatment due to elevated mortality rates and observed liver and kidney pathologies. Concentration-dependent increases in severity of thyroid follicular cell hypertrophy and hyperplasia occurred in larval tadpoles indicating BP-2-induced impacts on the thyroid axis. Additionally, gonads were impacted in all treatments with some genetic males showing both testis and ovary tissues (1.5 mg l-1 ) and 100% of the genetic males in the 3.0 and 6.0 mg l-1 treatments experiencing complete male-to-female sex reversal. Concentration dependent vitellogenin induction occurred in both genders with associated accumulations of protein in the livers, kidneys and gonads, which was likely vitellogenin and other estrogen-responsive yolk proteins. This is the first study that demonstrates the endocrine effects of this mixed mode of action chemical in an amphibian species and demonstrates the utility of the LAGDA design for supporting chemical risk assessment. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27241389 TI - Lymphatic Embolization for the Treatment of Pelvic Lymphoceles: Preliminary Experience in Five Patients. AB - PURPOSE: To retrospectively assess the outcome of lymphatic embolization in the treatment of pelvic lymphoceles. MATERIALS AND METHODS: From July 2014 to December 2015, a retrospective analysis was performed in 5 consecutive female patients (mean age, 54.6 y; range, 45-65 y) who underwent lymphangiography for the management of symptomatic pelvic lymphoceles that developed after gynecologic surgery. Sclerotherapy had failed in 4 patients. Lymphangiography was performed through an inguinal lymph node to reveal disrupted lymphatic vessels draining into the lymphocele. This inflow vessel was targeted with a fine needle, and N butyl cyanoacrylate (NBCA) was injected. Outcomes and complications were assessed by reviewing electronic medical records and computed tomography (CT). RESULTS: Lymphangiography revealed disrupted lymphatic vessels draining into the lymphocele in all patients. A single inflow vessel was seen in 3 patients and was subsequently embolized. Catheters were successfully removed upon decrease of drainage. Multiple inflow vessels were seen in the remaining 2 patients. Therapeutic effect was anticipated in 1 patient after lymphangiography alone, whereas only the dominant feeding vessel was embolized in the other. The initial procedures failed in both patients, prompting repeat embolization with adjunctive sclerotherapy. Both patients showed improvement and had their catheters removed. Follow-up CT was available in 3 patients. Two patients showed complete regression of lymphoceles, and 1 showed an asymptomatic lymphocele. No procedure-related complications occurred during a mean follow-up period of 35 weeks (range, 2-73 wk). CONCLUSIONS: Lymphatic intervention was technically feasible in treating lymphoceles. However, those with multiple inflow vessels were relatively difficult to treat. PMID- 27241390 TI - Position Statement on Noninvasive Imaging of Peripheral Arterial Disease by the Society of Interventional Radiology and the Canadian Interventional Radiology Association. PMID- 27241391 TI - Clinical Outcomes following Percutaneous Radiofrequency Ablation of Unilateral Aldosterone-Producing Adenoma: Comparison with Adrenalectomy. AB - PURPOSE: To compare adrenal radiofrequency (RF) ablation with adrenalectomy in treating unilateral aldosterone-producing adenoma (APA). MATERIALS AND METHODS: Between April 2008 and September 2013, 44 patients with adrenal venous sampling confirmed (lateralization index >= 4) unilateral APA underwent adrenal RF ablation (12/44 [27%]) or adrenalectomy (32/44 [73%]). Outcomes of adrenal RF ablation (patient age, 51 y +/- 11; 4/12 men) were compared with adrenalectomy (patient age, 50 y +/- 11; 19/32 men). Blood pressure (145/94 mm Hg +/- 19/13 vs 144/89 mm Hg +/- 10/8, P = .92), number of antihypertensives (3.0 +/- 1.3 vs 2.7 +/- 0.89, P = .38), and serum potassium (3.2 mEq/L +/- 0.6 vs 3.5 mEq/L +/- 0.6, P = .65) of patients were similar before treatment. RESULTS: RF ablation and adrenalectomy resulted in normokalemia (RF ablation, 4.2 mEq/L +/- 0.1, P = .0004; adrenalectomy, 4.3 mEq/L +/- 0.6, P < .0001) and normotension (RF ablation, 129/81 mm Hg +/- 11/11, P = .02/P = .001; adrenalectomy, 128/85 mm Hg +/- 13/12, P < .0001/P = .07) in all patients. Proportions of RF ablation and adrenalectomy patients cured of hypertension (2/12 [17%] vs 12/32 [38%], P = .28) or requiring fewer antihypertensives (7/12 [58%] vs 13/32 [40%], P = .29) were similar. RF ablation patients had a shorter length of stay (0.6 d +/- 0.8 [range, 0-2 d] vs 1.7 d +/- 1.4 [range, 0-7 d]; P = .01) and less intraoperative blood loss (1.2 mL +/- 3 vs 40 mL +/-85; P = .01). Procedural complications occurred in 5/32 (15%) adrenalectomy patients (2 major, 3 minor) and in 0/12 RF ablation patients. CONCLUSIONS: RF ablation to treat APA can achieve similar clinical outcomes as adrenalectomy and results in shorter hospital stays. Larger, prospective trials are needed to validate these results. PMID- 27241392 TI - Percutaneous Transhepatic Biliary Stent Implantation for Obstructive Jaundice of Perihilar Cholangiocarcinoma: A Prospective Study on Predictors of Stent Patency and Survival in 92 Patients. AB - PURPOSE: To evaluate prognostic factors for stent patency and survival in patients with perihilar cholangiocarcinoma (pCCA) who underwent percutaneous biliary stent placement. MATERIALS AND METHODS: This prospective study followed 92 consecutive patients with pCCA who underwent metal stent placement between January 2013 and July 2014. Of the total number of patients, 11 had ascites, and 36 had biliary obstruction for > 1 month at the time of stent placement. Cumulative patency and survival rates were assessed with Kaplan-Meier curves, and independent predictors were calculated with Cox regression. A new formula was developed to predict patient survival. RESULTS: Tumor size was significantly associated with stent patency (hazard ratio = 2.425; 95% confidence interval, 1.134-5.168). Independent predictors of survival included lymph node metastasis, intrahepatic mass lesion, cancer antigen 19-9 (CA19-9), ascites, and duration of jaundice. A new equation was developed to assess risk: R = 7 * (duration of biliary obstruction-0 if < 30 d, 1 if > 30 d) + 7 * (CA19-9-0 if < 500, 1 if > 500) + 7 * (ascites-0 if none present, 1 if ascites present) + 10 * (lymph node metastasis-0 if no metastasis, 1 if metastasis present) + 9 (intrahepatic mass lesion-0 if absent, 1 if present). Among patients who developed stent occlusion, patients who underwent recanalization of the occluded stent had longer survival compared with patients who did not undergo recanalization (109 d vs 29 d, P = .001). CONCLUSIONS: Prognostic factors for survival after percutaneous stent placement in patients with pCCA were tumor stage, duration of jaundice, CA19-9, and ascites. Tumor size affected stent patency. Prognosis for patients with reintervention after occlusion of the stent improved. PMID- 27241395 TI - In Memoriam: Josef Rosch, MD April 27, 1925 to January 17, 2016. PMID- 27241397 TI - JVIR Editor's Awards: 2015 Top Papers. PMID- 27241396 TI - A 16-F Sheath with Endobronchial Forceps Improves Reported Retrieval Success of Long-Dwelling "Closed Cell" Inferior Vena Cava Filter Designs. AB - PURPOSE: To report results of a 16-F sheath/endobronchial forceps combination in retrieval of "closed cell" inferior vena cava (IVC) filter designs with prolonged dwell times of >= 60 days. MATERIALS AND METHODS: Forceps retrieval of selected IVC filters using a 16-F 45-cm sheath was performed in 35 patients (25 women and 10 men). Patients presented with filters that were no longer needed without (n = 10) or with (n = 21) prior failed retrieval, caval thrombosis before lysis (n = 3), and back pain (n = 1). Filter designs included 19 Gunther Tulip (54%), 10 Option (29%), and six OptEase (17%). Mean dwell time was 977 days. Imaging characteristics, technical success, fluoroscopy time, and complications were recorded. RESULTS: Filters included 20 tip-embedded, 6 tip-adherent, 4 fractured, and 6 containing thrombus. All were strut and wall-embedded. Initial snare failures occurred in 8 filters because of hook straightening (n = 4), adherent material (n = 2), snare breakage (n = 1), and filter tilt (n = 1). The 16-F sheath/forceps combination was 100% successful in removing filters. In 1 patient, 2 extravascular fragments could not be retrieved. Median fluoroscopy time, excluding 3 extended lysis procedures, was 8 minutes. Minor caval abnormalities, including caval spasm and caval defects, were noted in 17 patients, and filter fracture occurred in 2 patients. No major complications occurred. CONCLUSIONS: A high rate of retrieval for closed cell long-dwelling strut and wall-embedded filters may be achieved using a 16-F sheath/endobronchial forceps combination. PMID- 27241398 TI - Study of praziquantel phytoremediation and transformation and its removal in constructed wetland. AB - Accumulation and/or degradation of Praziquantel (PZQ) in plants were determined using Phragmites australis, both suspension cultures and in vitro cultivated plants. In case of initial PZQ concentration 20mgL-1, 90% was removed from liquid media within 21days. The accumulated PZQ was partly metabolized, twenty one compounds being identified, products of both Phase I and II of detoxification metabolism. Laboratory results were confirmed in real scale using the constructed wetland (CW), where PZQ (500mg in total) was completely removed until the first purification pond. This result offers a promising possibility to use CW for PZQ removal from agricultural as well as domestic waste-waters. PMID- 27241399 TI - Lessons learned from more than two decades of research on emerging contaminants in the environment. AB - In the last twenty years, thousands of research papers covering different aspects of emerging contaminants have been published, ranging from environmental occurrence to treatment and ecological effects. Emerging contaminants are environmental pollutants that have been investigated widely only in the last two decades and include anthropogenic and naturally occurring chemicals such as pharmaceuticals and personal care products and their metabolites, illicit drugs, engineered nanomaterials, and antibiotic resistance genes. The advancement in our knowledge on emerging contaminants has been the result of the appearance of highly sensitive and powerful analytical instrumentation that rapidly developed, allowing identification and trace quantification of unknown contaminants in complex environmental matrices. High efficiency chromatographic separations coupled to high-resolution mass spectrometers have become more common in environmental laboratories and are the pillars of environmental research, increasing our awareness and understanding of the presence of emerging contaminants in the environment, their transformation and fate, and the complex ecological consequences that they pose on exposed biological systems. This introductory paper for the Virtual Thematic Issue on Emerging Contaminants presents a brief literature overview on key research milestones in the area of emerging contaminants, focusing on pharmaceuticals and personal care products and endocrine disrupting compounds, and highlighting selected research papers previously published in the Journal of Hazardous Materials during the period of January 2012 to December 2015. PMID- 27241436 TI - How Acid-Catalyzed Decarboxylation of 2,4-Dimethoxybenzoic Acid Avoids Formation of Protonated CO2. AB - The decarboxylation of 2,4-dimethoxybenzoic acid (1) is accelerated in acidic solutions. The rate of reaction depends upon solution acidity in a manner that is consistent with the formation of the conjugate acid of 1 (RCO2H2(+)), with its higher energy ring-protonated tautomer allowing the requisite C-C bond cleavage. However, this would produce the conjugate acid of CO2, a species that would be too energetic to form. Considerations of mechanisms that fit the observed rate law were supplemented with DFT calculations. Those results indicate that the lowest energy pathway from the ring-protonated reactive intermediate involves early proton transfer from the carboxyl group to water along with C-C bond cleavage, producing 1,3-dimethoxybenzene and CO2 directly. PMID- 27241437 TI - The Effect of Experimental Thyroid Dysfunction on Markers of Oxidative Stress in Rat Pancreas. AB - Preclinical Research The aim of the present study was to evaluate the effects of thyroid dysfunction on markers of oxidative stress in rat pancreas. Hypothyroidism and hyperthyroidism were, respectively, induced in rats via administration of propylthiouracil (PTU) and L-thyroxine sodium salt in drinking water for 45 days. The activities of superoxide dismutase (SOD), catalase (CAT), glutathioen peroxidase (GPx), glutathione reductase (GR), glucose-6-phosphate dehydrogenase (G6PD), xanthine oxidase (XO), and nonenzymatic markers of oxidative stress including malondialdehyde (MDA), protein carbonyl (PC), reduced glutathione (GSH), and total thiols (T-SH) were determined in the rat pancreas. In hyperthyroid rats, pancreatic CAT, SOD, GPx, GR, XO, G6PD activities were increased compared with those in hypothyroid and control groups. There were no differences in activities of antioxidant enzymes between hypothyroid and control rats. Pancreatic MDA and PC in hyperthyroid rats increased compared with hypothyroid and the control animals. Whereas, hyperthyroid rats had decreased levels of tissue GSH and T-SH compared with hypothyroid and the control groups. The findings showed that only GSH level has decreased significantly in the hypothyroid group compared with control groups. In conclusion, our results showed that experimental hyperthyroidism induces oxidative stress in pancreas of rats, but hypothyroidism has no major impact on oxidative stress markers. Drug Dev Res 77 : 199-205, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27241438 TI - Myeloperoxidase-responsive materials for infection detection based on immobilized aminomethoxyphenol. AB - There is a strong need for simple and fast diagnostic tools for the detection of wound infection. Immune system-derived enzymes like myeloperoxidase are efficient biomarkers for wound infection that emerge in the early stage infection process. In this study, 5-amino-2-methoxyphenol was functionalized with alkoxysilane to allow visual detection of MPO on carrier materials, for example, in test strips. Indeed, MPO activity was visually detectable in short time in wound background. Oxidation of the substrate was followed spectrophotometrically and proved via HPLC. LC-ESI TOF and NMR analyses unveiled the reaction mechanism and a dimeric reaction product responsible for the visualization of MPO activity. The substrate specificity and sensitivity toward MPO detection was proved and tests with infected wound fluids were successfully performed. The study demonstrates the suitability of the novel MPO substrate for the detection of wound infection and the covalent immobilization on diagnostic carrier materials. Biotechnol. Bioeng. 2016;113: 2553-2560. (c) 2016 Wiley Periodicals, Inc. PMID- 27241440 TI - A microfluidic flow focusing platform to screen the evolution of crude oil-brine interfacial elasticity. AB - Multiphase fluid flow dynamics dominate processes used to recover the majority of hydrocarbon resources produced by global energy industries. Micromodels have long been used to recapitulate geometric features of these processes, allowing for the phenomenological validation of multiphase porous media transport models. Notably, these platform surrogates typically preserve the complexity of reservoir conditions, preventing the elucidation of underlying physical mechanisms that govern bulk phenomena. Here, we introduce a microfluidic flow focusing platform that allows crude oil to be aged against brines of distinct composition in order to evaluate the pore-level effects of chemically-mediated interfacial properties upon snap-off. Snap-off is a fundamental multiphase flow process that has been shown to be a function of aqueous phase chemistry, which in turn establishes the limits of crude oil recovery during enhanced oil recovery operations. Specifically, this platform was used to evaluate the hypothesis that low salinity brines suppress crude oil snap-off, thus enhancing recovery. This hypothesis was validated and conditions that promote the effect were shown to, unexpectedly, develop over a matter of minutes on the pore scale. Microfluidic snap-off experiments were complemented by finite element fluid dynamics modeling, and further validated against a classical instability framework. PMID- 27241439 TI - Assessing Emotional Suffering in Palliative Care: Use of a Structured Note Template to Improve Documentation. AB - CONTEXT: Documentation of the emotional or psychological needs of seriously ill patients receiving specialty palliative care is endorsed by the "Measuring What Matters" project as a quality performance metric and recommended for use by hospice and palliative care programs for program improvement. OBJECTIVES: The aim of this study was to increase the proportion of inpatient palliative care team encounters in which emotional or psychological needs of patients and family members were documented and to qualitatively enrich the nature of this documentation. METHODS: This is a mixed-methods retrospective study of 200 patient charts reviewed before and after implementation of a structured note template (SmartPhrase) for palliative care encounters. Patterns of documentation of emotional needs pre- and post-implementation were assessed quantitatively and qualitatively using thematic analysis. RESULTS: A total of 158 of 200 pre intervention charts and 185 of 200 post-intervention charts included at least one note from the palliative care team. Documentation of emotional assessment increased after SmartPhrase implementation (63.9% [101 of 158] vs. 74.6% [138 of 185]; P < 0.03). Qualitative analysis revealed a post-intervention reduction in the use of generic phrases ("emotional support provided") and an increase in the breadth and depth of emotion-related documentation. CONCLUSION: A structured note template with a prompt for emotional assessment increases the overall quantity and richness of documentation related to patient and family emotions. However, this documentation remains mostly descriptive. Additional prompting for documentation of recommendations to address identified emotional needs, and the use of screening tools for depression and anxiety, when appropriate, may be necessary for clinically meaningful quality improvements in patient care. PMID- 27241441 TI - A strategy for implementing genomics into nursing practice informed by three behaviour change theories. AB - Genomics is an ever increasing aspect of nursing practice, with focus being directed towards improving health. The authors present an implementation strategy for the incorporation of genomics into nursing practice within the UK, based on three behaviour change theories and the identification of individuals who are likely to provide support for change. Individuals identified as Opinion Leaders and Adopters of genomics illustrate how changes in behaviour might occur among the nursing profession. The core philosophy of the strategy is that genomic nurse Adopters and Opinion Leaders who have direct interaction with their peers in practice will be best placed to highlight the importance of genomics within the nursing role. The strategy discussed in this paper provides scope for continued nursing education and development of genomics within nursing practice on a larger scale. The recommendations might be of particular relevance for senior staff and management. PMID- 27241442 TI - Demographics of tuberculosis of spine and factors affecting neurological improvement in patients suffering from tuberculosis of spine: a retrospective analysis of 312 cases. AB - OBJECTIVES: The purpose of the study was to study demographics of tuberculosis of spine and analyze factors that might affect neurological improvement in such patients. METHODS: Of the 638 suspected cases of spinal tuberculosis, 312 cases with confirmed diagnosis with at least 1-year follow-up were selected for retrospective analysis. Two hundred cases who presented with neurological deficit were further divided into three groups-completely improved, partially improved and no improvement according to American Spinal Injury Association impairment scale (AIS) grading. All continuous variables and categorical variables were compared across groups. RESULTS: A total of 209 (66.99%) patients had typical clinical presentation. A total of 264 (84.62%) had typical magnetic resonance imaging (MRI) presentation. Among 356 involved vertebrae, thoracic levels (T1-10) were most commonly affected in 163 (45.78%) followed by thoracolumbar (T11-L2) vertebrae in 98 (27.52%). In 250 patients (80.12%), disease was restricted to one or two adjoining vertebrae. At presentation, 112 (35.89%) patients were neurologically intact, whereas 97 (31%) were AIS D, 65 (20.83%) were AIS C, 8 (2.5%) were AIS B and 30 (9.61%) were AIS A. On statistical analysis, although three groups of patients with complete improvement, partial improvement and no improvement were similar in age, sex, radiological presentation, and co morbidities and the presence of pulmonary tuberculosis, they were significantly different with regard to the levels of vertebral involvement, AIS grade at presentation, bladder and bowel involvement and its duration. CONCLUSIONS: In management of patients suffering from tuberculosis of spine, levels of vertebral involvement, AIS grade at presentation, bladder and bowel involvement and its duration significantly affect the final neurological improvement. PMID- 27241443 TI - Adapted sport effect on postural control after spinal cord injury. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVE: The aim of this study was to compare trunk muscle activation during anterior and lateral reach in athletic and sedentary individuals with spinal cord injury (SCI) and able-bodied people. SETTINGS: University Hospital-UNICAMP, Campinas, Brazil. METHODS: Individuals with complete traumatic SCI and thoracic neurological level were separated into two groups: sedentary (SSCI: n=10) and physically active (PASCI: n=10). The control group (C: n=10) without SCI was assessed. Trunk muscle activation was recorded during reach and grasp tasks. The significant level was set at P<0.05. RESULTS: The control group showed a highest mean activation for left longissimus muscle during all activities (P<0.05). The PASCI group presented significant highest activation for left iliocostalis muscles during all activities, except in the anterior reach task of 90% maximum reach (anterior reach (AR) 75: P=0.02; right lateral reach (RLR) 75: P=0.03; RLR90: P=0.01). The SSCI group presented highest activation for the left iliocostalis during the right lateral reach task of 75 and 90% maximum reach and right iliocostalis during the anterior reach task of 75% maximum reach (AR75: P=0.007; RLR75: P=0.02; RLR90: P=0.03). A different pattern of muscle activation between the control group and the groups with SCI was observed. CONCLUSION: Our results indicated that sports practice did not affect the trunk muscle activation in people with paraplegia. However, the pattern muscle activation in individuals with SCI is different compared with people without SCI during anterior reach tasks. PMID- 27241444 TI - The impact of pain on spiritual well-being in people with a spinal cord injury. AB - STUDY DESIGN: The study uses a cross-sectional, group comparison, questionnaire based design. OBJECTIVES: To determine whether spinal cord injury and pain have an impact on spiritual well-being and whether there is an association between spiritual well-being and measures of pain and psychological function. SETTING: University teaching hospital in Sydney, New South Wales, Australia. METHODS: Questionnaires evaluating pain, psychological and spiritual well-being were administered to a group of people with a spinal cord injury (n=53) and a group without spinal cord injury (n=37). Spiritual well-being was assessed using the Functional Assessment of Chronic Illness and Therapy - Spirituality Extended Scale (FACIT-Sp-Ex). Pain and psychological function were also assessed using standard, validated measures of pain intensity, pain interference, mood and cognition. RESULTS: Levels of spiritual well-being in people with a spinal cord injury were significantly lower when compared with people without a spinal cord injury. In addition, there was a moderate but significant negative correlation between spiritual well-being and pain intensity. There was also a strong and significant negative correlation between depression and spiritual well-being and a strong and significant positive correlation between spiritual well-being and both pain self-efficacy and satisfaction with life. CONCLUSION: Consequences of a spinal cord injury include increased levels of spiritual distress, which is associated, with higher levels of pain and depression and lower levels of pain self-efficacy and satisfaction with life. These findings indicate the importance of addressing spiritual well-being as an important component in the long-term rehabilitation of any person following spinal cord injury. SPONSORSHIP: This study was supported by grant funding from the Australian and New Zealand College of Anaesthetists, and the National Health and Medical Research Council of Australia. PMID- 27241445 TI - Analysis of prehospital care and emergency room treatment of patients with acute traumatic spinal cord injury: a retrospective cohort study on the implementation of current guidelines. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVES: The aims of the current study were (i) to analyze prehospital and emergency room treatment of patients with acute traumatic spinal cord injury (SCI) and (ii) to analyze whether recommendations given by the current guidelines are implemented. SETTING: German level I trauma center. METHODS: All patients suffering from traumatic SCI who were initially surgically treated in our hospital in the period from January 2008 to December 2013 were included in this study. Available data documented as a standard procedure in our trauma center included patient's demographic and medical information, as well as trauma mechanisms, cause of injury, neurological diagnosis and detailed clinical information about prehospital and early hospital management procedures. Retrospectively, statistical analysis was performed to describe spinal immobilization rates, transportation times and methylprednisolone administration. RESULTS: A total of 133 patients (mean age: 50.5+/-21.2 years) met the inclusion criteria. Immobilization was performed on 69.9% of the patients with traumatic SCI. From 60 patients suffering from cervical traumatic SCI, 47 patients had a cervical collar. Full immobilization was only performed in 34 of these 60 patients. Mean time from accident site to emergency room was 61.3+/-28.7 min. In 25 out of the 133 patients included in the current study, early surgery was not possible because of insufficient circulation and/or increased intracranial pressure. A total of 108 patients could be prepared for early surgery within 322.8+/-254.1 min after the accident. CONCLUSION: The current study shows that recommendations of the current literature and guidelines are mostly followed. PMID- 27241446 TI - Spinal cord injury and Parkinson's disease: a population-based, propensity score matched, longitudinal follow-up study. AB - OBJECTIVES: To investigate whether patients with spinal cord injury (SCI) are at an increased risk of developing Parkinson's disease (PD). STUDY DESIGN: A population-based, propensity score-matched, longitudinal follow-up cohort study. SETTING: The study was conducted using the National Health Insurance (NHI) Research Database. METHODS: A total of 10 125 patients with at least 2 ambulatory visits with a diagnosis of SCI in 2001 were enrolled in the SCI group. The non SCI group comprised 10 125 propensity score-matched patients without SCI. The propensity scores were computed using a logistic regression model that included age, sex, comorbidities and socioeconomic status. The PD-free survival rates of the two groups were estimated using the Kaplan-Meier method. Stratified Cox proportional hazard regression was used to estimate the effect of SCI on subsequent occurrence of PD. RESULTS: During the 3-year follow-up period, 99 subjects in the SCI group and 59 in the non-SCI group developed PD. The hazard ratio of PD for the SCI group compared with the non-SCI group was 1.65 (95% confidence interval 1.16-2.33, P=0.0049). The PD-free survival rate for the SCI group was lower than that for the non-SCI group (P=0.0017). CONCLUSIONS: This study shows that SCI is associated with a subsequent increased risk of PD. Further studies are needed to elucidate the mechanism underlying this association. PMID- 27241447 TI - Spinal cord stimulation. PMID- 27241449 TI - Predicting task performance from upper extremity impairment measures after cervical spinal cord injury. AB - BACKGROUND: Automated sensor-based assessments of upper extremity (UE) function after cervical spinal cord injury (SCI) could provide more detailed tracking of individual recovery profiles than is possible with existing assessments, and optimize the delivery and assessment of new interventions. The design of reliable automated assessments requires identifying the key variables that need to be measured to meaningfully quantify UE function. An unanswered question is to what extent measures of sensorimotor impairment can quantitatively predict performance on functional tasks. OBJECTIVE: The objective was to define the predictive value of impairment measures for concurrent functional task performance in traumatic cervical SCI, as measured by the Graded Redefined Assessment of Strength, Sensibility and Prehension (GRASSP). SETTING: Retrospective analysis. METHODS: A data set of 138 GRASSP assessments was analyzed. The Strength and Sensation modules were used as measures of impairment, whereas the concurrent Prehension Performance module was used as the surrogate measure of function. Classifiers were trained to predict the scores on each of the six individual tasks in the Prehension Performance module. The six scores were added to obtain a total score. RESULTS: The Spearman's rho between predicted and actual total Prehension Performance scores was 0.84. Predictions using both the Strength and Sensation scores were not found to be superior to predictions using the Strength scores alone. CONCLUSIONS: Measures of UE motor impairment are highly predictive of functional task performance after cervical SCI. Automated sensor-based assessments of UE motor function after SCI can rely on measuring only impairment and estimating functional performance accordingly. PMID- 27241448 TI - The contribution of neurophysiology in the diagnosis and management of cervical spondylotic myelopathy: a review. AB - STUDY DESIGN: Topical review of the literature. OBJECTIVE: The objective of this review article was to assess indications and usefulness of various neurophysiological techniques in diagnosis and management of cervical spondylogenic myelopathy (CSM). METHODS: The MEDLINE, accessed by Pubmed and EMBASE electronic databases, was searched using the medical subject headings: 'compressive myelopathy', 'cervical spondylotic myelopathy (CSM)', 'cervical spondylogenic myelopathy', 'motor evoked potentials (MEPs)', 'transcranial magnetic stimulation', 'somatosensory evoked potentials (SEPs)', 'electromyography (EMG)', 'nerve conduction studies (NCS)' and 'cutaneous silent period (CSP)'. RESULTS: SEPs and MEPs recording can usefully supplement clinical examination and neuroimaging findings in assessing the spinal cord injury level and severity. Segmental cervical cord dysfunction can be revealed by an abnormal spinal N13 response, whereas the P14 potential is a reliable marker of dorsal column impairment. MEPs may also help in the differential diagnosis between spinal cord compression and neurodegenerative disorders. SEPs and MEPs are also useful in follow-up evaluation of sensory and motor function during surgical treatment and rehabilitation. EMG and NCS improve the sensitivity of cervical radiculopathy detection and may help rule out peripheral nerve problems that can cause symptoms that are similar to those of CSM. CSP also shows a high sensitivity for detecting CSM. CONCLUSION: Neuroimaging, especially magnetic resonance imaging, represents the procedure of choice for the diagnosis of CSM, but a correct interpretation of morphological findings can be achieved only if they are correlated with functional data. The studies reported in this review highlight the crucial role of the electrophysiological studies in diagnosis and management of CSM. PMID- 27241450 TI - rTMS of the prefrontal cortex has analgesic effects on neuropathic pain in subjects with spinal cord injury. AB - STUDY DESIGN: Repetitive transcranial magnetic stimulation study. OBJECTIVES: The analgesic effects of repetitive transcranial magnetic stimulation (rTMS) in chronic pain have been the focus of several studies. In particular, rTMS of the premotor cortex/dorsolateral prefrontal cortex (PMC/DLPFC) changes pain perception in healthy subjects and has analgesic effects in acute postoperative pain, as well as in fibromyalgia patients. However, its effect on neuropathic pain in patients with traumatic spinal cord injury (SCI) has not been assessed. SETTING: Merano (Italy) and Salzburg (Austria). METHODS: In this study, we performed PMC/DLPFC rTMS in subjects with SCI and neuropathic pain. Twelve subjects with chronic cervical or thoracic SCI were randomized to receive 1250 pulses at 10 Hz rTMS (n=6) or sham rTMS (n=6) treatment for 10 sessions over 2 weeks. The visual analog scale, the sensory and affective pain rating indices of the McGill Pain Questionnaire (MPQ), the Hamilton Depression Rating Scale and the Hamilton Anxiety Rating Scale were used to assed pain and mood at baseline (T0), 1 day after the first week of treatment (T1), 1 day (T2), 1 week (T3) and 1 month (T4) after the last intervention. RESULTS: Subjects who received active rTMS had a statistically significant reduction in pain symptoms in comparison with their baseline pain, whereas sham rTMS participants had a non-significant change in daily pain from their baseline pain. CONCLUSION: The findings of this preliminary study in a small patient sample suggest that rTMS of the PMC/DLPFC may be effective in relieving neuropathic pain in SCI patients. PMID- 27241451 TI - Associations between disability-management self-efficacy, participation and life satisfaction in people with long-standing spinal cord injury. AB - OBJECTIVES: To study disability-management self-efficacy (DMSE) and its correlates in a large sample of Dutch people with long-standing spinal cord injury (SCI). DMSE is the confidence that people with SCI may have in their ability to manage the consequences of their condition with respect to the various domains in their life. Research questions were: (1) What is the level of DMSE in Dutch people with long-standing SCI?; (2) Is DMSE associated with demographic and lesion characteristics?; and (3) Is DMSE associated with participation and life satisfaction if these associations are adjusted for demographic and lesion characteristics and mood? METHODS: Eligible people were identified from all eight rehabilitation centers with a specialty in SCI rehabilitation in the Netherlands (N=261). Data were collected using a self-report questionnaire. DMSE was measured using the University of Washington Self-Efficacy Scale-Short Form (UW-SES-6). Correlation and linear regression analyses were used. RESULTS: Levels of UW-SES-6 scores were largely independent of demographic and lesion characteristics. UW-SES 6 scores were bivariately moderately to strongly associated with mood (0.47), participation (0.39-0.51) and life satisfaction (0.46). In the regression analyses, UW-SES-6 scores still explained a significant amount of variance of participation (standardized beta 0.31-0.33) and life satisfaction (standardized beta 0.21) when controlling for demographic and lesion characteristics and mood, and explained an additional 3.2-8.1% of the variance of participation and life satisfaction. CONCLUSION: DMSE is a psychological resource associated with higher levels of participation and life satisfaction after SCI. The UW-SES-6 is a brief and easy to use measure of this psychological resource. PMID- 27241453 TI - Highly stable and ultrasensitive chlorogenic acid sensor based on metal-organic frameworks/titanium dioxide nanocomposites. AB - Metal-organic frameworks/titanium dioxide (UiO-66-NH2/TiO2) nanocomposites have been prepared by a simple hydrothermal reaction and they exhibit excellent electrocatalytic activity for chlorogenic acid oxidation due to the synergic effect of UiO-66-NH2 and TiO2. Under the optimal conditions, the sensor can be employed in the quantification of chlorogenic acid in the ranges of 0.01-1.0 MUmol L(-1) and 1.0-15 MUmol L(-1) with an ultralow detection limit of 7 nmol L( 1) (S/N = 3). Moreover, UiO-66-NH2/TiO2 nanocomposites demonstrate significant stability in acidic buffer solution and maintain their electrocatalytic activities at least up to 90 cycles. The potential utility was validated by the analysis of coffee and tea samples and good recoveries were obtained from different spiked values. The UiO-66-NH2/TiO2 based sensor with highly sensitive, selective and stable consecutive monitoring of chlorogenic acid is a promising candidate for the construction of highly active electrocatalyst in electrochemical biosensors. PMID- 27241452 TI - An integrative review of standardized clinical evaluation tool utilization in anticholinergic drug trials for neurogenic lower urinary tract dysfunction. AB - STUDY DESIGN: To review prospective and randomized trials studying anticholinergic therapy for neurogenic bladder in SCI to identify whether trials included standardized clinical evaluation tools and reporting measures now recognized to enhance clinical trial data. METHODS: A systematic search via EMBASE, MEDLINE, CENTRAL, CINAHL (Cumulative Index to Nursing and Allied Health Literature), HTA (Health Technology Assessment), CMR (Comprehensive Microbial Resource), HAPI (Health and Psychosocial Instruments) and PsycINFO using the key term spinal cord injury crossed with oxybutynin, tolterodine, darifenacin, solifenacin, fesoterodine, trospium chloride, propiverine, propantheline and anticholinergic(s) for 1946-2015 inclusive. We then collated whether standardized clinical tools, measures and descriptors were used within each study identified: American Spine Injury Association (ASIA) impairment scale; symptom scores validated in SCI; technical methodology for urodynamics/video urodynamics; urinary diaries; and standardized urologic terminology. RESULTS: A total of 1225 entries with 610 unique articles were identified, 14 randomized and 16 prospective studies. In 6/30 the population comprised SCI patients with neurogenic bladder alone; the remainder included mixed neurogenic etiologies. Classification using the ASIA impairment scale was used in <10% of studies; none used symptom scores validated in SCI; <50% reported urodynamic test methodology fully, incorporated urinary diaries or used International Continence Society Standardization Subcommittee urinary tract terminology. CONCLUSION: Integrative review of trials from 1946 to 2015 identified infrequent use of standardized clinical evaluation tools and reporting measures. Data from future trials evaluating therapies for neurogenic bladder would likely be more applicable to specific SCI patients if current standardized classification and descriptors now available were used consistently: for example, the ASIA scale, symptom scores validated in SCI, standardized urodynamic methodology, urinary diaries and urinary tract terminology. Studies recruiting SCI patients exclusively would also provide additional benefit. PMID- 27241454 TI - Production of ethanol from kitchen waste by using flocculating Saccharomyces cerevisiae KF-7. AB - Kitchen waste is rich in carbohydrates and can potentially serve as feedstock for ethanol production. Starch was the primary carbohydrate in kitchen waste obtained from the canteen in the Sichuan University, which was used to evaluate long-term ethanol fermentation performance in this study. The optimal conditions for liquefaction and saccharification of the kitchen waste were as follows: adding alpha-amylase at 0.3 MUL/g glucan for liquefaction at 90 degrees C for 30 min, and adding glucoamylase at 4 MUL/g glucan for saccharification at 50 degrees C. Glucose yield obtained under the optimal conditions was over 80%. Addition of cellulase did not enhance glucose yield, but decreased the viscosity of the saccharified slurry. Repeated-batch presaccharification followed by simultaneous saccharification and fermentation of 20 batches was successfully carried out at an aeration of 0.1 vvm. Ethanol concentration of 43.9-45.0 g/L was achieved, corresponding to ethanol yield and productivity of 88.9-91.2% and 3.3-3.5 g/L/h, respectively, and the CO2/ethanol molar ratio was approximately 1. Continuous PSSF was stably carried out at a dilution rate of <=0.3 h-1. Productivity was 11.5 g/L/h at a dilution rate of 0.3 h-1. Ethanol concentration and yield were 42.0 g/L and 82.8% at a dilution rate of 0.2 h-1, respectively. PMID- 27241455 TI - A multicenter, open-label extension study of velaglucerase alfa in Japanese patients with Gaucher disease: Results after a cumulative treatment period of 24months. AB - Enzyme replacement therapy (ERT) with exogenous glucocerebrosidase is indicated to treat symptomatic Gaucher disease (GD), a rare, inherited metabolic disorder. ERT with velaglucerase alfa, which is produced in a human cell line using gene activation technology, was studied in a 12-month phase III trial in Japanese patients with type 1 or 3 GD who were switched from imiglucerase ERT (n=6); the current, open-label, 12-month extension study was designed to assess longer-term safety and efficacy. Two adult and three pediatric patients (aged <18years) were enrolled into the extension study. Every-other-week intravenous infusions were administered for 63-78weeks at average doses between 51.5 and 60.7units/kg. Three non-serious adverse events were considered related to velaglucerase alfa treatment, but no patient discontinued from the study. Six serious but non-drug related adverse events were reported. No patient tested positive for anti velaglucerase alfa antibodies. Hemoglobin concentrations, platelet counts, and liver and spleen volumes (normalized to body weight) in these patients were generally stable over a cumulative 24-month period from the baseline of the parent trial. The data suggest that velaglucerase alfa was well tolerated and maintained clinical stability in Japanese GD patients over 2years after switching from imiglucerase. ClinicalTrials.gov identifier NCT01842841. PMID- 27241456 TI - Gastric volvulus in children--a diagnostic problem: two case reports. AB - BACKGROUND: Gastric volvulus is a clinically significant cause of acute or recurrent abdominal pain and chronic vomiting in children. Since related clinical symptoms are nonspecific, clinicians often refer to radiologists for a diagnostic evaluation. Early diagnosis is crucial to prevent life-threatening complications of prolonged volvulus, such as intestinal ischemia, infarction, strangulation, necrosis, and perforation that may require immediate surgical treatment. In this report, we describe clinical and radiological criteria for diagnosis of gastric volvulus in children. CASE PRESENTATION: We describe two pediatric clinical cases. A 16-month-old female Caucasian child was admitted to our hospital for recurrent postprandial vomiting episodes, which started at 11 months old, associated with failure to thrive. A 9-month-old term-born baby boy was admitted for chronic, recurrent, postprandial vomiting, which started at 7 months of age, with progressive failure to thrive. A barium study allowed definitive diagnosis of chronic organoaxial gastric volvulus. CONCLUSIONS: Gastric volvulus is an extremely rare disorder in the pediatric population. It can be considered a complex clinical condition with regard to the etiology and the management. A nonoperative approach is advisable in the absence of warning signs. PMID- 27241457 TI - Satisfaction and sustainability: a realist review of decentralized models of perinatal surgery for rural women. AB - INTRODUCTION: This article was developed as part of a larger realist review investigating the viability and efficacy of decentralized models of perinatal surgical services for rural women in the context of recent and ongoing service centralization witnessed in many developed nations. The larger realist review was commissioned by the British Columbia Ministry of Health and Perinatal Services of British Columbia, Canada. Findings from that review are addressed in this article specific to the sustainability of rural perinatal surgical sites and the satisfaction of providers that underpins their recruitment to and retention at such sites. METHODS: A realist method was used in the selection and analysis of literature with the intention to iteratively develop a sophisticated understanding of how perinatal surgical services can best meet the needs of women who live in rural and remote environments. The goal of a realist review is to examine what works for whom under what circumstances and why. The high sensitivity search used language (English) and year (since 1990) limiters in keeping with both a realist and rapid review tradition of using reasoned contextual boundaries. No exclusions were made based on methodology or methodological approach in keeping with a realist review. Databases searched included MEDLINE, PubMed, EBSCO, CINAHL, EBM Reviews, NHS Economic Evaluation Database and PAIS International for literature in December 2013. RESULTS: Database searching produced 103 included academic articles. A further 59 resources were added through pearling and 13 grey literature reports were added on recommendation from the commissioner. A total of 42 of these 175 articles were included in this article as specific to provider satisfaction and service sustainability. Operative perinatal practice was found to be a lynchpin of sustainable primary and surgical services in rural communities. Rural shortages of providers, including challenges with recruitment and retention, were found to be a complex issue, with scope of practice and contextual support as the key factors. Targeted educational programs, exposure to rural practice and living environments, accessible and appropriate continuing medical education, and strong clinical support (including locum coverage and sustainable on-call schedules) were all found to be areas of important consideration in rural service sustainability. CONCLUSIONS: Rural practice was found to be a site to actualize personal goals and values for providers. A broad and challenging scope of practice and the opportunity to participate in community level health improvements were seen as critical to the retention of providers. Without proper support, however, providers reported a feeling of being 'in too deep'. Common themes were a lack of health human resource redundancies, compromised access to specialist support and technology, and a lack of work-life balance. Burnout and attrition in perinatal surgical services threaten to destabilize other aspects of rural community health services, making the need to address sustainability of rural providers urgent. PMID- 27241458 TI - Cost-effectiveness of an 8% Capsaicin Patch in the Treatment of Brachioradial Pruritus and Notalgia Paraesthetica, Two Forms of Neuropathic Pruritus. AB - In brachioradial pruritus and notalgia paraesthetica, the 8% capsaicin patch is a novel and effective, but cost-intense, therapy. Routine data for 44 patients were collected 6 months retrospectively and prospectively to first patch application. The cost to health insurance and the patient, and patient-reported outcomes were analysed (visual analogue scale, numerical rating scale, verbal rating scale for pruritus symptoms, Dermatological Life Quality Index, and Patient Benefit Index). Mean inpatient treatment costs were reduced by ?212.31, and mean outpatient treatment and medication costs by ?100.74 per patient (p.p.). However, these reductions did not offset the high cost of the patch itself (?767.02 p.p.); thus the total cost to health insurance increased by ?453.97 p.p. (p <= 0.01). The additional costs of therapy to the patient decreased by ?441.06, thus the overall cost p.p. remained approximately the same (?3,306.03 vs. ?3,318.94). Capsaicin patch therapy resulted in reduced pruritus, improved quality of life and greater patient benefit, thus long-term cost-efficiency analyses are necessary. PMID- 27241459 TI - Corrigendum to "Aldose reductase inhibition suppresses oxidative stress-induced inflammatory disorders" [Chem. Biol. Interact. (2011) 330-338]. PMID- 27241462 TI - Leaf mass per area, not total leaf area, drives differences in above-ground biomass distribution among woody plant functional types. AB - Here, we aim to understand differences in biomass distribution between major woody plant functional types (PFTs) (deciduous vs evergreen and gymnosperm vs angiosperm) in terms of underlying traits, in particular the leaf mass per area (LMA) and leaf area per unit stem basal area. We used a large compilation of plant biomass and size observations, including observations of 21 084 individuals on 656 species. We used a combination of semiparametric methods and variance partitioning to test the influence of PFT, plant height, LMA, total leaf area, stem basal area and climate on above-ground biomass distribution. The ratio of leaf mass to above-ground woody mass (MF /MS ) varied strongly among PFTs. We found that MF /MS at a given plant height was proportional to LMA across PFTs. As a result, the PFTs did not differ in the amount of leaf area supported per unit above-ground biomass or per unit stem basal area. Climate consistently explained very little additional variation in biomass distribution at a given plant size. Combined, these results demonstrate consistent patterns in above-ground biomass distribution and leaf area relationships among major woody PFTs, which can be used to further constrain global vegetation models. PMID- 27241461 TI - Assessment of polygenic effects links primary open-angle glaucoma and age-related macular degeneration. AB - Primary open-angle glaucoma (POAG) and age-related macular degeneration (AMD) are leading causes of irreversible blindness. Several loci have been mapped using genome-wide association studies. Until very recently, there was no recognized overlap in the genetic contribution to AMD and POAG. At genome-wide significance level, only ABCA1 harbors associations to both diseases. Here, we investigated the genetic architecture of POAG and AMD using genome-wide array data. We estimated the heritability for POAG (h(2)g = 0.42 +/- 0.09) and AMD (h(2)g = 0.71 +/- 0.08). Removing known loci for POAG and AMD decreased the h(2)g estimates to 0.36 and 0.24, respectively. There was evidence for a positive genetic correlation between POAG and AMD (rg = 0.47 +/- 0.25) which remained after removing known loci (rg = 0.64 +/- 0.31). We also found that the genetic correlation between sexes for POAG was likely to be less than 1 (rg = 0.33 +/- 0.24), suggesting that differences of prevalence among genders may be partly due to heritable factors. PMID- 27241460 TI - Slippery signaling: Palmitoylation-dependent control of neuronal kinase localization and activity. AB - Modification of proteins with the lipid palmitate, a process called palmitoylation, is important for the normal function of neuronal cells. However, most attention has focused on how palmitoylation regulates the targeting and trafficking of neurotransmitter receptors and non-enzymatic scaffold proteins. In this review we discuss recent studies that suggest that palmitoylation also plays additional roles in neurons by controlling the localization, interactions and perhaps even the activity of protein kinases that play key roles in physiological neuronal regulation and in neuropathological processes. PMID- 27241463 TI - Running to well-being: A comparative study on the impact of exercise on the physical and mental health of law and psychology students. AB - Research indicates that, in comparison to other university students, law students are at greater risk of experiencing high levels of psychological distress. There is also a large body of literature supporting a general negative association between exercise and stress, anxiety and depression. However, we are not aware of any studies exploring the impact of exercise on the mental health of law students specifically. This article reports evidence of a negative association between exercise and psychological distress in 206 law and psychology students. Compared to psychology students, the law students not only reported greater psychological distress, but, in addition, there was a stronger association between their levels of distress and their levels of exercise. Based on the results of this study, we suggest a simple yet effective way law schools might support the mental health of their students. PMID- 27241464 TI - MD simulation study of direct permeation of a nanoparticle across the cell membrane under an external electric field. AB - Nanoparticles (NPs) have been attracting much attention for biomedical and pharmaceutical applications. In most of the applications, NPs are required to translocate across the cell membrane and to reach the cell cytosol. Experimental studies have reported that by applying an electric field NPs can directly permeate across the cell membrane without the confinement of NPs by endocytic vesicles. However, damage to the cell can often be a concern. Understanding of the mechanism underlying the direct permeation of NPs under an external electric field can greatly contribute to the realization of a technology for the direct delivery of NPs. Here we investigated the permeation of a cationic gold NP across a phospholipid bilayer under an external electric field using a coarse-grained molecular dynamics simulation. When an external electric field that is equal to the membrane breakdown intensity was applied, a typical NP delivery by electroporation was shown: the cationic gold NP directly permeated across a lipid bilayer without membrane wrapping of the NP, while a persistent transmembrane pore was formed. However, when a specific range of the electric field that is lower than the membrane breakdown intensity was applied, a unique permeation pathway was exhibited: the generated transmembrane pore immediately resealed after the direct permeation of NP. Furthermore, we found that the affinity of the NP for the membrane surface is a key for the self-resealing of the pore. Our finding suggests that by applying an electric field in a suitable range NPs can be directly delivered into the cell with less cellular damage. PMID- 27241465 TI - Analysis of the magnetically induced current density of molecules consisting of annelated aromatic and antiaromatic hydrocarbon rings. AB - Magnetically induced current susceptibilities and current pathways have been calculated for molecules consisting of two pentalene groups annelated with a benzene (1) or naphthalene (2) moiety. Current strength susceptibilities have been obtained by numerically integrating separately the diatropic and paratropic contributions to the current flow passing planes through chosen bonds of the molecules. The current density calculations provide novel and unambiguous current pathways for the unusual molecules with annelated aromatic and antiaromatic hydrocarbon moieties. The calculations show that the benzene and naphthalene moieties annelated with two pentalene units as in molecules 1 and 2, respectively, are unexpectedly antiaromatic sustaining only a local paratropic ring current around the ring, whereas a weak diatropic current flows around the C H moiety of the benzene ring. For 1 and 2, the individual five-membered rings of the pentalenes are antiaromatic and a slightly weaker semilocal paratropic current flows around the two pentalene rings. Molecules 1 and 2 do not sustain any net global ring current. The naphthalene moiety of the molecule consisting of a naphthalene annelated with two pentalene units (3) does not sustain any strong ring current that is typical for naphthalene. Instead, half of the diatropic current passing the naphthalene moiety forms a zig-zag pattern along the C-C bonds of the naphthalene moiety that are not shared with the pentalene moieties and one third of the current continues around the whole molecule partially cancelling the very strong paratropic semilocal ring current of the pentalenes. For molecule 3, the pentalene moieties and the individual five-membered rings of the pentalenes are more antiaromatic than for 1 and 2. The calculated current patterns elucidate why the compounds with formally [4n + 2] pi-electrons have unusual aromatic properties violating the Huckel pi-electron count rule. The current density calculations also provide valuable information for interpreting the measured (1)H NMR spectra. PMID- 27241466 TI - Characterization of obesity rates for dermatologic ambulatory office visits to United States physicians. AB - BACKGROUND: Obesity continues to increase in the United States (US) and elsewhere, with a number of published dermatologic associations. The purpose of this study was to characterize obesity among US office visits for dermatologic diseases. METHODS: Data from the 2005 to 2011 National Ambulatory Medical Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey (NHAMCS) were searched for the most common dermatologic diagnoses for which body mass index (BMI) could be classified. RESULTS: For all dermatologic patient visits, 10% were underweight, 36.5% were normal weight, 23.8% were overweight and 29.7% were obese. Increasing age predicted the yearly increased likelihood of obesity (OR 1.02; 95% CI 1.01, 1.02; p < 0.0001). Logistic regression controlling for age, sex, race and dataset found that in addition to age, NHAMCS dermatologic diagnosis patients were more likely to be obese than NAMCS patients (OR 1.22; 95% CI 1.03, 1.45; p = 0.02). Specific diseases were found to have the highest obesity rates, including psoriasis, hidradenitis suppurativa and acanthosis nigricans. CONCLUSION: A large proportion of dermatologic diagnosis patients are obese, and awareness could lead to interventions that may improve their disease and decrease risks of comorbidities. PMID- 27241474 TI - Tailored design of ruthenium molecular catalysts with 2,2'-bypyridine-6,6' dicarboxylate and pyrazole based ligands for water oxidation. AB - With the incorporation of pyrazole and DMSO as axial ligands, a series of tailor designed Ru water oxidation catalysts [Ru(bda)(DMSO)(L)] (H2bda = 2,2'-bypyridine 6,6'-dicarboxylic acid; DMSO = dimethyl sulfoxide; L = pyrazole, A-1; 4-Br-3 methyl pyrazole, B-1) and [Ru(bda)(L)2] (L = pyrazole, A-2; 4-Br-3-methyl pyrazole, B-2) have been generated in situ from their corresponding precursors [Ru(kappa3(O,N,N)-bda)(DMSO)x(L)3-x] which are in a zwitterionic form with an extra pyrazole based ligand in the equatorial position. Formation of the active catalyst has been investigated under pH 1.0 conditions. Electrochemistry and water oxidation activity of these catalysts were investigated. By fine tuning of the catalyst structure, the turnover frequency was increased up to 500 s(-1) and the stability over 6000 turnovers. PMID- 27241473 TI - Rational design of a protein that binds integrin alphavbeta3 outside the ligand binding site. AB - Integrin alphavbeta3 expression is altered in various diseases and has been proposed as a drug target. Here we use a rational design approach to develop a therapeutic protein, which we call ProAgio, that binds to integrin alphavbeta3 outside the classical ligand-binding site. We show ProAgio induces apoptosis of integrin alphavbeta3-expressing cells by recruiting and activating caspase 8 to the cytoplasmic domain of integrin alphavbeta3. ProAgio also has anti-angiogenic activity and strongly inhibits growth of tumour xenografts, but does not affect the established vasculature. Toxicity analyses demonstrate that ProAgio is not toxic to mice. Our study reports a new integrin-targeting agent with a unique mechanism of action, and provides a template for the development of integrin targeting therapeutics. PMID- 27241475 TI - Asymptomatic players with a patellar tendon abnormality do not adapt their landing mechanics when fatigued. AB - This study aimed to explore how asymptomatic athletes with a patellar tendon abnormality (PTA), who are at high risk of developing patellar tendinopathy, alter their landing technique and net patellar tendon loads generated in response to fatigue. Seven asymptomatic players with a PTA performed five successful vertical stop-jump trials before and after a fatigue protocol. Fatigue protocol involved participants repeatedly performing sets of 30 submaximal jump exercises on a sledge apparatus followed by 30 s rest until the task failure criteria were reached. Three-dimensional ground reaction forces, lower limb kinematics and net peak patellar tendon force were recorded during the stop-jump task. No significant between-fatigue condition differences in net patellar tendon loading, or most secondary outcome variables were observed. Only some fatigue changes were seen during the vertical landing phase. Asymptomatic PTA participants did not modify their landing technique or net patellar tendon loading during a stop-jump task in response to fatigue. The lack of between-fatigue condition differences displayed by the asymptomatic PTA participants during both landing phases suggest that these individuals may not be capable of sufficient movement variability in their landing strategies to adapt to fatigue. PMID- 27241476 TI - Outcomes of pediatric identical living-donor liver and hematopoietic stem cell transplantation. AB - Chronic IS is associated with significant morbidity in transplant recipients. Moreover, IS does not prevent chronic graft failure frequently. Allograft immune tolerance in LT can be induced by complete donor chimerism through allogenic HSCT combined with identical LDLT. This approach may exempt patients from chronic lifelong IS. However, it is unclear whether its benefits justify its risks. Here, we present three cases from our institution and analyze seven additional reports of children treated with HSCT/LDLT, all receiving HSCT due to hemato-oncological indications. In eight of 10 cases, donor macrochimerism resulted in allograft tolerance. Nine patients survived. One patient died due to fulminant ADV infection. Further complications were GvHD (n = 3) and bone marrow failure (n = 2). In conclusion, donor-specific allograft tolerance can be achieved by identical-donor HSCT/LDLT. However, at present, this approach should generally be limited to selected indications due to a potentially unfavorable risk-benefit ratio. Novel toxicity-reduced conditioning protocols for HSCT/LDLT in the absence of malignant or non-hepatic disease may prove to be a sufficiently safe approach for inducing graft tolerance in children receiving a LDLT in the future. This concept may reduce the burden of lifelong IS. PMID- 27241477 TI - [In Process Citation]. PMID- 27241478 TI - [In Process Citation]. PMID- 27241479 TI - Explanation of the size dependent in-plane optical resonance of triangular silver nanoprisms. AB - Triangular silver nanoprisms with thicknesses of 3-5 nm and adjustable edge lengths - which can lead to nanoparticles with aspect ratios up to 1 : 50 - are quasi-two-dimensional nanoparticles. Due to high ensemble homogeneities, which are achieved by the application of a microfluid segment based preparation method, the optical properties of the silver nanoprisms can be studied directly in colloidal solution. Investigations of the shift of the longitudinal main absorption peak with varying edge length lead to a semi-empiric model in which inelastic one-photon-one-electron processes are used to explain the found absorption behavior instead of the conventional interpretation of a collective oscillation of the conduction band electrons. Independently of the inserted seed particle volumes or amounts of silver ions, all measurement series follow a linear interrelation between the spectral position of the longitudinal absorption peak and the determined edge length of the nanoprisms, which leads to the derivation of a length constant b0, which in turn can be described within the framework of the model - next to a geometry factor - exclusively by natural constants. The proposed model describes the behavior of quasi-two-dimensional noble metal nanoparticles by a dualism between the assumption of "metallic molecules" and materials with "blurred bandgaps". PMID- 27241480 TI - A Novel Complotype Combination Associates with Age-Related Macular Degeneration and High Complement Activation Levels in vivo. AB - The complement system is the first line of defense against foreign intruders, and deregulation of this system has been described in multiple diseases. In age related macular degeneration (AMD), patients have higher complement activation levels compared to controls. Recently, a combination of three single nucleotide polymorphisms (SNPs) in genes of the complement system, referred to as a complotype, has been described to increase complement activation in vitro. Here we describe a novel complotype composed of CFB (rs4151667)-CFB (rs641153)-CFH (rs800292), which is strongly associated with both AMD disease status (p = 5.84*10(-13)) and complement activation levels in vivo (p = 8.31*10(-9)). The most frequent genotype combination of this complotype was associated with the highest complement activation levels in both patients and controls. These findings are relevant in the context of complement-lowering treatments for AMD that are currently under development. Patients with a genetic predisposition to higher complement activation levels will potentially benefit the most of such treatments. PMID- 27241481 TI - Dynamic causal modeling of touch-evoked potentials in the rubber hand illusion. AB - The neural substrate of bodily ownership can be disclosed by the rubber hand illusion (RHI); namely, the illusory self-attribution of an artificial hand that is induced by synchronous tactile stimulation of the subject's hand that is hidden from view. Previous studies have pointed to the premotor cortex (PMC) as a pivotal area in such illusions. To investigate the effective connectivity between - and within - sensory and premotor areas involved in bodily perceptions, we used dynamic causal modeling of touch-evoked responses in 13 healthy subjects. Each subject's right hand was stroked while viewing their own hand ("REAL"), or an artificial hand presented in an anatomically plausible ("CONGRUENT") or implausible ("INCONGRUENT") position. Bayesian model comparison revealed strong evidence for a differential involvement of the PMC in the generation of touch evoked responses under the three conditions, confirming a crucial role of PMC in bodily self-attribution. In brief, the extrinsic (forward) connection from left occipital cortex to left PMC was stronger for CONGRUENT and INCONGRUENT as compared to REAL, reflecting the augmentation of bottom-up visual input when multisensory integration is challenged. Crucially, intrinsic connectivity in the primary somatosensory cortex (S1) was attenuated in the CONGRUENT condition, during the illusory percept. These findings support predictive coding models of the functional architecture of multisensory integration (and attenuation) in bodily perceptual experience. PMID- 27241482 TI - Imaging brain source extent from EEG/MEG by means of an iteratively reweighted edge sparsity minimization (IRES) strategy. AB - Estimating extended brain sources using EEG/MEG source imaging techniques is challenging. EEG and MEG have excellent temporal resolution at millisecond scale but their spatial resolution is limited due to the volume conduction effect. We have exploited sparse signal processing techniques in this study to impose sparsity on the underlying source and its transformation in other domains (mathematical domains, like spatial gradient). Using an iterative reweighting strategy to penalize locations that are less likely to contain any source, it is shown that the proposed iteratively reweighted edge sparsity minimization (IRES) strategy can provide reasonable information regarding the location and extent of the underlying sources. This approach is unique in the sense that it estimates extended sources without the need of subjectively thresholding the solution. The performance of IRES was evaluated in a series of computer simulations. Different parameters such as source location and signal-to-noise ratio were varied and the estimated results were compared to the targets using metrics such as localization error (LE), area under curve (AUC) and overlap between the estimated and simulated sources. It is shown that IRES provides extended solutions which not only localize the source but also provide estimation for the source extent. The performance of IRES was further tested in epileptic patients undergoing intracranial EEG (iEEG) recording for pre-surgical evaluation. IRES was applied to scalp EEGs during interictal spikes, and results were compared with iEEG and surgical resection outcome in the patients. The pilot clinical study results are promising and demonstrate a good concordance between noninvasive IRES source estimation with iEEG and surgical resection outcomes in the same patients. The proposed algorithm, i.e. IRES, estimates extended source solutions from scalp electromagnetic signals which provide relatively accurate information about the location and extent of the underlying source. PMID- 27241484 TI - Which is the most appropriate strategy for conducting multivariate voxel-based group studies on diffusion tensors? AB - There is a real need in the neuroscience community for efficient tools to compare Diffusion Tensor Magnetic Resonance Imaging across cohorts of subjects. Most studies focus on the comparison of scalar images such as fractional anisotropy or mean diffusivity. Although different statistical frameworks have been proposed to compare the whole diffusion tensor information, they are still seldom used in neuroimaging studies. In this paper, we investigate on both simulated and real data whether there is a real added value of considering the whole tensor information for conducting voxel-based group studies. Then, we compare two statistical tests dedicated to tensor, namely the Cramer test and a tensor-based extension of the General Linear Model (GLM), the latter presenting the advantage to account for covariates. We also evaluate the impact of different metrics (Euclidean, Log-Euclidean and affine-invariant Riemannian metrics) for estimating the GLM parameters. Finally, we address the problem of interpreting the change detection maps obtained by tensor-based methods by proposing a way to characterize each of the detected clusters according to several scalar indices. Our study suggests that if there is no prior assumption about the nature of the expected changes, it is really preferable to use tensor-based rather than scalar based statistical analysis. The Cramer test can advantageously be used when no confounding variable hampers the group comparison, otherwise the GLM should be considered. Finally, the different metrics show similar performance in the real scenario, with a significant computational overhead for the Riemannian framework. PMID- 27241483 TI - Language-related cerebral oscillatory changes are influenced equally by genetic and environmental factors. AB - Twin studies have suggested that there are genetic influences on inter-individual variation in terms of verbal abilities, and candidate genes have been identified by genome-wide association studies. However, the brain activities under genetic influence during linguistic processing remain unclear. In this study, we investigated neuromagnetic activities during a language task in a group of 28 monozygotic (MZ) and 12 dizygotic (DZ) adult twin pairs. We examined the spatio temporal distribution of the event-related desynchronizations (ERDs) in the low gamma band (25-50Hz) using beamformer analyses and time-frequency analyses. Heritability was evaluated by comparing the respective MZ and DZ correlations. The genetic and environmental contributions were then estimated by structural equation modeling (SEM). We found that the peaks of the low gamma ERDs were localized to the left frontal area. The power of low gamma ERDs in this area exhibited higher similarity between MZ twins than that between DZ twins. SEM estimated the genetic contribution as approximately 50%. In addition, these powers were negatively correlated with the behavioral verbal scores. These results improve our understanding of how genetic and environmental factors influence cerebral activities during linguistic processes. PMID- 27241485 TI - Photonic metal-polymer resin nanocomposites with chiral nematic order. AB - Mesoporous resins with chiral nematic order were used as scaffolds to construct novel iridescent metal-polymer composites. Gold, silver and palladium nanoparticles were formed by an in situ reduction reaction. We have investigated the effects of concentration and time on the deposition. As a proof-of-concept, we demonstrate that this process can be extended to patterning photonic resins by inkjet printing. PMID- 27241486 TI - Retinotopic information interacts with category selectivity in human ventral cortex. AB - Until recently, the general consensus with respect to the organization of ventral visual cortex is that early, retinotopic regions are sensitive to the spatial position of the input stimuli whereas later, higher-order regions are sensitive to the category of the input stimuli. Growing recognition of the bidirectional connectivity of the visual system has challenged this view and recent empirical evidence suggests a more interactive and graded system. Here, based on findings from functional MRI in adult observers, in which meridians and category selective regions are localized and their activation sampled, we support this latter perspective by showing that category effects are present in retinotopic cortical areas and spatial position effects are present in higher-order regions. Furthermore, the results indicate that the retinotopic and later areas are functionally connected suggesting a possible mechanism by which these seemingly disparate effects come to be intermixed in both early and later regions of the visual system. PMID- 27241487 TI - Light responsive hybrid nanofibres for on-demand therapeutic drug and cell delivery. AB - Smart materials for on-demand delivery of therapeutically active agents are challenging in pharmaceutical and biomaterials science. In the present study, we report hybrid nanofibres capable of being reversibly controlled to pulsatile deliver both therapeutic drugs and cells on-demand of near-infrared (NIR) light. The nanofibres, fabricated by co-electrospinning of poly (N-isopropylacrylamide), silica-coated gold nanorods and polyhedral oligomeric silsesquinoxanes have, for the first time, demonstrated rapid, reversible large-volume changes of 83% on demand with NIR stimulation, with retained nanofibrous morphology. Combining with the extracellular matrix-mimicking fibrillary properties, the nanofibres achieved accelerated release of model drug or cells on demand with NIR triggering. The release of the model drug doxorubicin demonstrated normal anti-cancer efficacy by reducing the viability of human cervical cancer HeLa cells by 97% in 48 h. In parallel, the fibres allowed model cell NIH3T3 fibroblast entrapment, adhesion, proliferation, differentiation and, upon NIR irradiation, cell release with undisturbed cellular function. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27241488 TI - Pharmacist-patient communication about medication regimen adjustment during Ramadan. AB - OBJECTIVES: During Ramadan, Muslims fast from dawn to sunset while abstaining from food and drink. Although Muslim patients may be aware of their religious exemption from fasting, many patients still choose not to take that exemption and fast. This study examines pharmacists' initiation and timing of communication about medication regimen adjustment (MRA) with patients related to Ramadan. Predictors for initiating this communication with patients were also explored. METHODS: A probability sample of community pharmacists in Alexandria, Egypt was surveyed. The self-administered instrument covered timing and likelihood of initiating discussion about MRA. Using ordered logistic regression, a model was estimated to predict pharmacists' initiation of the conversation on MRA during Ramadan. RESULTS: Ninety-three percent of the 298 approached pharmacists completed surveys. Only 16% of the pharmacists reported that they themselves usually initiated the conversation on MRA. Pharmacists' initiation of these conversations was associated with pharmacists' perceived importance of MRA on pharmacy revenue odds ratio ((OR) = 1.24, CI = 1.03-1.48). Eighty percent of the responding pharmacists reported the MRA conversation for chronic conditions started either 1-3 days before, or during the first week of Ramadan. CONCLUSION: These results suggest considerable pharmacist patient communication gaps regarding medication use during Ramadan. It is especially important for pharmacists and other health professionals to initiate communication with Muslim patients early enough to identify how best to help patients transition safely into and out of Ramadan as they fast. PMID- 27241489 TI - 2,4-D transport and herbicide resistance in weeds. PMID- 27241490 TI - Breaking the rules of Rubisco catalysis. PMID- 27241491 TI - Unwinding JAZ7 - enigma to harmony. PMID- 27241492 TI - Making plant science purposeful and relevant to all. PMID- 27241493 TI - The RICE MINUTE-LIKE1 (RML1) gene, encoding a ribosomal large subunit protein L3B, regulates leaf morphology and plant architecture in rice. AB - Mutations of ribosomal proteins (RPs) are known to cause developmental abnormalities in yeast, mammals, and dicotyledonous plants; however, their effects have not been studied in rice. Here, we identifiy a ribosomal biogenesis mutant, rice minute-like1 (rml1) that displays a minute phenotype as evidenced by retarded growth and defects in the vascular system. We determine that RML1 encodes a ribosome large subunit protein 3B (RPL3B) in rice by means of map-based cloning and genetic complementation. RPL3B is abundantly expressed in all the tissues, whereas RPL3A, another RPL3 gene family member, is expressed at low levels. Notably, the expression level of RPL3A in the rml1 mutant is similar to that in the wild-type, suggesting that RPL3A provides no functional compensation for RPL3B in rml1 plants. Ribosomal profiles show that mutation of RPL3B leads to a significant reduction in free 60S ribosomal subunits and polysomes, indicating a ribosomal insufficiency in the rml1 mutant. Our results demonstrate that the ribosomal protein gene RPL3B is required for maintaining normal leaf morphology and plant architecture in rice through its regulation of ribosome biogenesis. PMID- 27241499 TI - Angioma serpiginosum: A case series of 4 patients. PMID- 27241494 TI - Two shikimate dehydrogenases, VvSDH3 and VvSDH4, are involved in gallic acid biosynthesis in grapevine. AB - In plants, the shikimate pathway provides aromatic amino acids that are used to generate numerous secondary metabolites, including phenolic compounds. In this pathway, shikimate dehydrogenases (SDH) 'classically' catalyse the reversible dehydrogenation of 3-dehydroshikimate to shikimate. The capacity of SDH to produce gallic acid from shikimate pathway metabolites has not been studied in depth. In grapevine berries, gallic acid mainly accumulates as galloylated flavan 3-ols. The four grapevine SDH proteins have been produced in Escherichia coli In vitro, VvSDH1 exhibited the highest 'classical' SDH activity. Two genes, VvSDH3 and VvSDH4, mainly expressed in immature berry tissues in which galloylated flavan-3-ols are accumulated, encoded enzymes with lower 'classical' activity but were able to produce gallic acid in vitro The over-expression of VvSDH3 in hairy roots increased the content of aromatic amino acids and hydroxycinnamates, but had little or no effect on molecules more distant from the shikimate pathway (stilbenoids and flavan-3-ols). In parallel, the contents of gallic acid, beta glucogallin, and galloylated flavan-3-ols were increased, attesting to the influence of this gene on gallic acid metabolism. Phylogenetic analysis from dicotyledon SDHs opens the way for the examination of genes from other plants which accumulate gallic acid-based metabolites. PMID- 27241500 TI - Oleogranulomas of the breast treated with hydroxychloroquine. PMID- 27241501 TI - Adult orbital xanthogranulomatous disease: A case report and brief discussion of the terminology. PMID- 27241502 TI - Squamous cell carcinoma of the nail fold masquerading as pyogenic granuloma. PMID- 27241503 TI - Giant cell arteritis with extensive scalp necrosis: A diagnostic and therapeutic challenge. PMID- 27241504 TI - Multinucleated giant cells in angiolymphoid hyperplasia with eosinophilia. PMID- 27241505 TI - Kimura's disease in an old case of leprosy. PMID- 27241506 TI - Radiation dose and diagnostic image quality associated with iterative reconstruction in coronary CT angiography: A systematic review. AB - The aim of this systematic review is to evaluate the radiation dose reduction achieved using iterative reconstruction (IR) compared to filtered back projection (FBP) in coronary CT angiography (CCTA) and assess the impact on diagnostic image quality. A systematic search of seven electronic databases was performed to identify all studies using a developed keywords strategy. A total of 14 studies met the criteria and were included in a review analysis. The results showed that there was a significant reduction in radiation dose when using IR compared to FBP (P < 0.05). The mean and standard deviation (SD) difference of CTDIvol and dose length-product (DLP) were 14.70 +/- 6.87 mGy and 186 +/- 120 mGy.cm respectively. The mean +/- SD difference of effective dose (ED ) was 2.9 +/- 1.7 mSv with the range from 1.0 to 5.0 mSv. The assessment of diagnostic image quality showed no significant difference (P > 0.05). The mean +/- SD difference of image noise, signal-noise ratio (SNR) and contrast-noise ratio (CNR) were 1.05 +/- 1.29 HU, 0.88 +/- 0.56 and 0.63 +/- 1.83 respectively. The mean +/- SD percentages of overall image quality scores were 71.79 +/- 12.29% (FBP) and 67.31 +/- 22.96% (IR). The mean +/- SD percentages of coronary segment analysis were 95.43 +/- 2.57% (FBP) and 97.19 +/- 2.62% (IR). In conclusion, this review analysis shows that CCTA with the use of IR leads to a significant reduction in radiation dose as compared to the use of FBP. Diagnostic image quality of IR at reduced dose (30 41%) is comparable to FBP at standard dose in the diagnosis of CAD. PMID- 27241507 TI - pH-dependent release of platycodin mitigates its gastrointestinal mucosa irritation after oral administration in rats. AB - The present study aimed to evaluate the gastrointestinal mucosa irritation of three platycodin formulations. Platycodin-loaded core pellets were prepared via extrusion-spheronization method and coated with Eudragit((r)) L100-55 (L100) or Eudragit((r)) S100 (S100) for pH-dependent release. The release of platycodin D from coated pellets exhibited pH dependent release profiles. The pharmacokinetic study in rats showed that Tmax of the coated pellets were prolonged as compared to that of un-coated pellets. The S100-coated pellets possess a lower Cmax and decreased AUC0-24h as compared to the L100-coated and uncoated pellets. Hematoxylin-eosin staining and nuclear factor Kappa B (NF-kappaB) measurement were carried out to observe the gastrointestinal mucosa irritations. The results revealed that the irritations of platycodin on the upper gastrointestinal mucosa are dose-dependent. However, no obvious irritation effect on the gastrointestinal tissues of rats was detected after oral administration of the coated pellets. In addition, the amount of NF-kappaB in the stomach of rats treated with the uncoated pellets was about fivefold higher as compared to that of the coated pellets. In summary, the L100-coated platycodin pellets exhibited higher oral bioavailability and less gastrointestinal mucosa irritations as compared to the other two formulations. PMID- 27241508 TI - Awareness of Influenza and Attitude Toward Influenza Vaccination Among Medical Students. AB - In Poland, influenza vaccination coverage among both the general population and healthcare workers is low. The aim of the study was to evaluate attitudes towards influenza vaccination among final-year medical students compared with first-year students at medical schools in Poland. Students were asked about the last season's influenza vaccination and what the reasons were for having, or not having, the vaccination. The knowledge of influenza was assessed using a 10-point visual analog scale. The study group consisted of 712 medical students, 404 in the first year and 308 in the final year (35 % and 31 % of all students in those years, respectively). Final-year students believed they had a better knowledge of influenza (OR = 3.33; CI95 %: 2.54-4.39). They answered questions about influenza immunizations (OR = 0.59; CI95 %: 0.44-0.78) and vaccination recommendations in pregnant women correctly more frequently (OR = 0.21; CI95 %: 0.16-0.28). The influenza vaccination rate among students in the 2014/2015 season was similar (17.1 % in the first vs. 15.9 % in the final year, NS). Among the final-year students, the reason for not having the vaccination was mainly financial and not any other. We conclude that although medical students' knowledge about influenza increases in the course of study, it did not much affect their unwilling attitude toward vaccination. PMID- 27241509 TI - Heart Rate Variability and Arrhythmic Burden in Pulmonary Hypertension. AB - A growing body of evidence indicates that sudden cardiac death constitutes a major cause of mortality in pulmonary hypertension (PH). As validated method to evaluate cardiac autonomic system dysfunction, alterations in heart rate variability (HRV) are predictive of arrhythmic events, particularly in left ventricular disease. Here, we sought to determine the clinical value of HRV assessment in PH. Sixty-four patients were allocated to different PH-subgroups in this prospectively conducted trial: 25 patients with pulmonary arterial hypertension (PAH), 11 patients with chronic thromboembolic PH (CTEPH), and 28 patients with COPD-induced PH. All patients underwent 24-h Holter electrocardiogram for HRV assessment by time- and frequency-domain analysis. Arrhythmic burden was evaluated by manual analysis and complementary automatic measurement of premature atrial and ventricular contractions. The results were compared to 31 healthy controls. The PAH patients offered a significantly higher mean heart rate (78.6 +/- 10.4 bpm vs. 70.1 +/- 10.3 bpm, p = 0.04), a higher burden of premature ventricular contractions (p < 0.01), and decreases in HRV (SDNN: p < 0.01; SDANN: p < 0.01; very low frequency: p < 0.01; low frequency/high frequency ratio: p < 0.01; total power: p = 0.02). In CTEPH patients, only the amount of premature ventricular contractions differed from controls (p < 0.01), whereas in COPD both premature atrial contraction count and frequency-domain-based HRV manifested significant differences. In conclusion, PAH appears to be primarily affected by HRV alterations and ventricular arrhythmic burden, indicating a high risk for malignant arrhythmic events. PMID- 27241510 TI - Effect of Simulated Microgravity and Lunar Gravity on Human Inspiratory Muscle Function: 'Selena-T' 2015 Study. AB - As a part of the multi-disciplinary "SELENA-T"-2015 Bed Rest Study, we investigated the pattern of inspiratory muscles fatigue in 22 healthy male subjects during incremental exercise test to exhaustion before and after 21 days of hypokinesia evoked by bed rest. Hypokinesia consisted of head-down bed rest (HDBR) at a minus 6 degrees angle, simulating microgravity present on orbiting spacecraft, in 10 subjects. The remaining 12 subjects spent the first 5 days of hypokinesia in HDBR position and the subsequent 16 days in head-up bed rest (HUBR) at a plus 9.6 degrees angle, as a presumed analog of lunar gravity that is six times less than Earth's gravity. Maximal inspiratory pressure (MIP) and electromyograms (EMG) of the diaphragm (D), parasternal (PS), sternocleidomastoid (SCM), and scalene (S) muscles served as indices of inspiratory muscle function. Before both HDBR and HUBR, exercise decreased MIP and centroid frequency (fc) of EMG (D, PS, SCM, and S) power spectrum (p < 0.05). After 3 weeks of HDBR, but not HUBR, inspiratory muscles fatigue was more expressed compared with control (p < 0.05). We conclude that HDBR lowers inspiratory muscles resistance to fatigue during high-intensity exercise while HUBR has no such effect. These changes may limit maximal ventilation and may contribute to exercise intolerance observed after prolonged simulated microgravity. The physiological mechanisms of respiratory muscle dysfunction after HDBR consist primarily of postural effects, and are not due only to hypokinesia. PMID- 27241511 TI - Cardiac Vagal Control and Depressive Symptoms in Response to Negative Emotional Stress. AB - We aimed to study complex cardiovagal control using heart rate variability (HRV), linear and nonlinear analyses at rest and during negative emotional stress in healthy students with varying depressive symptoms. ECG recording in 20 students was performed at baseline, negative emotional stress, and recovery period. The HRV parameters evaluated were the following: RR interval, spectral power in high frequency band (HF-HRV), and symbolic dynamics index 2LV%. The subjects were divided into two groups based on the score of the Beck Depression Inventory (BDI) - normal mood (BDI: 0.6 +/- 0.2) and mild mood disturbance (BDI: 14.3 +/- 1.4). We found significantly lower logHF-HRV during emotional stress in mild mood disturbance compared with normal mood (p = 0.047). No significant differences were found in the remaining parameters. We conclude that negative emotional stress attenuated the cardiovagal control during mood disturbance, which points to discrete abnormalities in the neurocardiac reflex system associated with depressive symptoms. Hampered cardiovagal control could represent a potential pathomechanism leading to depression-linked cardiovascular complications. PMID- 27241512 TI - Thermal Sensitivity and Dimethyl Sulfoxide (DMSO). AB - Dimethyl sulfoxide (DMSO) is commonly used as a solvent for hydrophobic substances, but the compound's innate bioactivity is an area of limited understanding. In this investigation we seek to determine the analgesic potential of DMSO. We addressed the issue by assessing the perception of thermal pain stimulus, using a 55 degrees C hotplate design, in conscious mice. The latency of withdrawal behaviors over a range of incremental accumulative intraperitoneal DMSO doses (0.5-15.5 g/kg) in the same mouse was taken as a measure of thermal endurance. The findings were that the latency, on average, amounted to 15-30 s and it differed inappreciably between the sequential DMSO conditions. Nor was it different from the pre-DMSO control conditions. Thus, DMSO did not influence the cutaneous thermal pain perception. The findings do not lend support to those literature reports that point to the plausible antinociceptive potential of DMSO as one of a plethora of its innate bioactivities. However, the findings concern the mouse's footpad nociceptors which have specific morphology and stimulus transduction pathways, which cannot exclude DMSO's antinociceptive influence on other types of pain or in other types of skin. Complex and as yet unresolved neural mechanisms of perception of cutaneous noxious heat stimulus should be further explored with alternative experimental designs. PMID- 27241513 TI - Content of Asthmagen Natural Rubber Latex Allergens in Commercial Disposable Gloves. AB - The use of natural rubber latex (NRL) gloves in many occupations may lead to latex sensitization, allergic asthma, and skin reactions. Due to their good properties and environmental safety NRL gloves are still being used in the healthcare setting, but also in the food industry, by hairdressers, cleaners, etc. The aim of our study was to assess the protein and NRL allergen content in commercial gloves by different methods, including a new assay. Twenty commercially available NRL gloves were analyzed. Protein extraction was performed according to the international standard ASTM D-5712. Total protein content was measured with a modified Lowry method, NRL content with the CAP Inhibition Assay, the Beezhold ELISA Inhibition Assay, and an innovative ELISA with IgY-antibodies extracted from eggs of NRL-immunized hens (IgY Inhibition Assay). We found a high protein content in a range of 215.0-1304.7 MUg/g in 8 out of the 20 NRL gloves. Seven of the 20 gloves were powdered, four of them with a high protein content. In gloves with high protein content, the immunological tests detected congruently high levels of NRL allergen. We conclude that a high percentage of commercially available NRL gloves still represent a risk for NRL allergy, including asthma. The modified Lowry Method allows to infer on the latex allergen content. PMID- 27241514 TI - [Adolescent idiopathic scoliosis : Guideline for practical application]. AB - Juvenile or adolescent idiopathic scoliosis is a relatively common spinal deformity, with an incidence of more than 1 %. Early diagnosis can lead to successful therapy. In the case of pathological clinical findings, the anteroposterior X-ray of the whole spine leads the way to the correct grading, according to Cobb angle measurement. Depending on the individual risk of progression, brace treatment will be started with a Cobb angle range of 20-25 degrees . Important predictors of therapeutic success are sufficient primary corrective power and patient compliance. COBB angles of 40-50 degrees usually lead to the recommendation for surgery, which is performed as either anterior or posterior spinal fusion in skeletally mature adolescents, depending on the grade of the deformity according to Lenke's classification. To achieve the best possible results, it is recommended that both conservative and surgical treatments are carried out by scoliosis specialists. PMID- 27241515 TI - Fissure Integrity and Volume Reduction in Emphysema: A Retrospective Study. AB - BACKGROUND: One-way endobronchial valves (EBVs) relieve symptoms of emphysema, particularly in patients without collateral ventilation between the target and adjacent lobes. Pretreatment knowledge of fissure integrity could serve as an aid in indicating EBV interventions. OBJECTIVE: This study aimed to investigate the relationship between software-measured lung fissure integrity and clinically relevant lung volume reduction (>=350 ml) in emphysema patients treated with one way EBVs using a lobar exclusion strategy. METHODS: Of 108 patients treated between March 2008 and July 2014, 38 had both baseline and follow-up computed tomography (CT) scans acquired following a specific protocol for quantitative CT analysis and were included in the study (total of 39 treatments, two lungs treated in 1 patient). Outcome measures were fissure integrity measured on baseline CT scans, difference between pre- and postoperative lung volume (considering the lowest measured postoperative volume), and correlation between fissure integrity and volume change. RESULTS: Fissure integrity >=75% correlated with volume reduction >=350 ml (Spearman coefficient: -0.65; p < 0.01). The mean and median volume reductions were 1,223.96 +/- 907.5 ml and 663 ml, respectively, for lungs with fissure integrity >=75% (n = 31). The accuracy of fissure integrity >=75% in predicting a volume reduction was 87.2%. The positive predictive value of fissure integrity >=75% to predict a volume reduction >=350 ml was 83.9%, and it was 70% for fissure integrity 75-90% and 90.5% for fissure integrity >90%. CONCLUSIONS: A target lobe volume reduction using EBVs is possible with lung fissure integrity >=75%. For patients with fissure integrity between 75 and 90%, a further evaluation of interlobar ventilation should be performed. A clinically relevant volume reduction following treatment with EBVs is likely with any level of fissure integrity >90%. PMID- 27241516 TI - Percutaneous Closure of Atrial Septal Defects with Deficient Rims. PMID- 27241518 TI - Total synthesis of cyclomarins A, C and D, marine cyclic peptides with interesting anti-tuberculosis and anti-malaria activities. AB - Cyclomarins are cyclic heptapeptides containing four unusual amino acids. New synthetic protocols toward their synthesis have been developed, leading to the synthesis and biological evaluation of three natural occurring cyclomarins. Interestingly, cyclomarins address two completely different targets: Clp C1, a subunit of the caseinolytic protease of Mycobacterium tuberculosis (MTB), as well as PfAp3Ase of Plasmodium falciparum. Therefore, cyclomarins are interesting lead structures for the development of drugs against tuberculosis and malaria. PMID- 27241517 TI - Electrophysiological correlates of face-evoked person knowledge. AB - Face recognition includes identifying a face as perceptually familiar and recollecting biographical information, or person-knowledge, associated with the face. The majority of studies examining the neural basis of face recognition have confounded these stages by comparing brain responses evoked by novel and perceptually familiar famous faces. Here, we recorded EEG in two tasks in which subjects viewed two sets of faces that were equally perceptually familiar, but which had differing levels of associated person-knowledge. Our results dissociated the effects of person-knowledge from perceptual familiarity. Faces with associated biographical information elicited a larger ~600ms centroparietal positivity in both a passive viewing task in which subjects viewed faces without explicitly responding, and an active question-answering task in which subjects indicated whether or not they knew particular facts about the faces. In the question task only, person-knowledge was associated with a negative ERP difference over right posterior scalp over the 170-450ms interval which appeared again at long latency (>900ms). PMID- 27241519 TI - A radiographic investigation of the relationships between humeral cortical bone thickness, medullary canal width and the supratrochlear aperture (STA). AB - The supratrochlear aperture (STA) is a perforation of the septum between the olecranon and coronoid fossae of the humerus. Bones with STA are prone to supracondylar fractures and are thought to have narrower medullary canals. Our aim was to explore the relationship of the STA with medullary canal width and humeral size. The study employed a case-control research design with approximately equal numbers of individuals with and without STA from South African Whites, Blacks, and the Mixed ethnic group. Radiographs were taken anteroposteriorly using a Lodox Statscan and Image J(r) software was used to acquire measurements from the radiographs. In the proximal diaphysis, the mean medullary canal width was significantly smaller for STA humeri (13.59 vs. 14.72 mm). The same was true for the midshaft (10.21 vs. 10.84 mm) and the distal portion (10.05 vs. 10.63 mm). While STA humeri appeared to have narrower medullary canal dimensions, this was not the case after standardizing for bone size. The smaller medullary canal width reported in the literature for STA bearing humeri is, therefore, due to bone size differences and not STA presence. This is supported by the strong positive correlation between bone size and medullary canal width irrespective of STA status. Thus, the medullary canal width increases with bone size independent of STA status. We, therefore, propose that bone size, and not STA presence, is the major factor to consider when choosing rods for intramedullary fixation. PMID- 27241520 TI - Genomic Characterization of High-Grade Serous Ovarian Cancer: Dissecting Its Molecular Heterogeneity as a Road Towards Effective Therapeutic Strategies. AB - High-grade serous ovarian carcinoma (HGSOC) accounts for the majority of the ovarian cancer deaths, but over the last years little improvement in overall survival has been achieved. HGSOC is a molecularly and clinically heterogeneous disease. At genomic level, it represents a C-class malignancy having frequent gene losses (NF1, RB1, PTEN) and gains (CCNE1, MYC). HGSOC shows a simple mutational profile with TP53 nearly always mutated and with other genes mutated at low frequency. Importantly, 50 % of all HGSOCs have genetic features indicating a homologous recombination (HR) deficiency. HR deficient tumors are highly sensitive to PARP inhibitor anticancer agents, which exhibit synthetic lethality with a defective HR pathway. Transcriptionally, HGSOCs can be grouped into different molecular subtypes with distinct biology and prognosis. Molecular stratification of HGSOC based on these genomic features may result in improved therapeutic strategies. PMID- 27241523 TI - An Adolescent With Fever, Rash, and Altered Mental Status. PMID- 27241521 TI - Protective efficacy and safety of liver stage attenuated malaria parasites. AB - During the clinically silent liver stage of a Plasmodium infection the parasite replicates from a single sporozoite into thousands of merozoites. Infection of humans and rodents with large numbers of sporozoites that arrest their development within the liver can cause sterile protection from subsequent infections. Disruption of genes essential for liver stage development of rodent malaria parasites has yielded a number of attenuated parasite strains. A key question to this end is how increased attenuation relates to vaccine efficacy. Here, we generated rodent malaria parasite lines that arrest during liver stage development and probed the impact of multiple gene deletions on attenuation and protective efficacy. In contrast to P. berghei strain ANKA LISP2(-) or uis3(-) single knockout parasites, which occasionally caused breakthrough infections, the double mutant lacking both genes was completely attenuated even when high numbers of sporozoites were administered. However, different vaccination protocols showed that LISP2(-) parasites protected better than uis3(-) and double mutants. Hence, deletion of several genes can yield increased safety but might come at the cost of protective efficacy. PMID- 27241524 TI - Twelve-week sensor assessment in Parkinson's disease: Impact on quality of life. PMID- 27241525 TI - Respiratory syncytial virus infection in infants in rural Nepal. AB - OBJECTIVES: Respiratory syncytial virus (RSV) pneumonia is a leading cause of infant mortality worldwide. The risk of RSV infection associated with preterm birth is not well-characterized in resource-limited settings. We aimed to obtain precise estimates of risk factors and disease burden of RSV in infants in rural southern Nepal. METHODS: Pregnant women were enrolled, and along with their infants, followed to six months after birth with active weekly home-based surveillance for acute respiratory illness (ARI). Mid-nasal swabs were obtained and tested for RSV by PCR for all illness episodes. Birth outcomes were assessed at a postpartum home visit. RESULTS: 311 (9%) of 3509 infants had an RSV ARI. RSV ARI incidence decreased from 551/1000 person-years in infants born between 28 and 31 weeks to 195/1000 person-years in infants born full-term (p = 0.017). Of 220 infants (71%) evaluated in the health system, 41 (19%) visited a hospital or physician. Of 287 infants with an assessment performed, 203 (71%) had a lower respiratory tract infection. CONCLUSIONS: In a rural south Asian setting with intensive home-based surveillance, RSV caused a significant burden of respiratory illness. Preterm infants had the highest incidence of RSV ARI, and should be considered a priority group for RSV preventive interventions in resource-limited settings. PMID- 27241526 TI - Controlled release of anti-inflammatory peptides from reducible thermosensitive nanoparticles suppresses cartilage inflammation. AB - Characterized by pain, cartilage degradation, and inflammation, osteoarthritis is often treated with anti-inflammatory therapies that provide short-term relief but can have adverse side effects; intra-articular drug delivery systems with controlled release of anti-inflammatory peptides using degradable poly(N isopropylacrylamide) (pNIPAM) nanoparticles could prolong relief and minimize these side effects. Nanoparticles provide a biocompatible drug carrier that can protect encapsulated therapeutics from enzymatic degradation and increase payload delivery upon encountering a degradation stimulus. Here we demonstrate passive targeting of inflamed cartilage ex vivo by uptake of PEGylated pNIPAM nanoparticles with degradable disulfide crosslinks (abbreviated as NGPEGSS) into chondrocytes and subsequent intracellular release of an anti-inflammatory peptide KAFAKLAARLYRKALARQLGVAA (KAFAK). The KAFAK-loaded NGPEGSS treatment reduced ex vivo inflammation to a greater extent compared to its non-degradable counterparts. This study highlights a nanoparticle system that delivers therapeutics intracellularly with improved efficacy by triggered degradation and suppresses inflammation in multiple cell types within an inflamed joint. PMID- 27241527 TI - Synthesis and evaluation of fluorogenic triglycerides as lipase assay substrates. AB - Three racemic fluorogenic triglycerides are synthesized and evaluated as lipase assay substrates. The presented synthesis route goes through a key triglyceride intermediate which can be chemoselectively functionalized with a wide range of different probes. Hence the substrate can be tailor-made for a specific assay, or focus can be on low cost in larger scale for applications in high-throughput screening (HTS) assays. In the specific examples, TG-ED, TG-FD and TG-F2 are assembled with the Edans-Dabcyl or the fluorescein-Dabcyl FRET pair, or relying on fluorescein self-quenching, respectively. Proof-of-concept assays allowed determination of 1st order kinetic parameters (kcat/KM) of 460s(-1)M(-1), 59s( 1)M(-1) and 346s(-1)M(-1), respectively, for the three substrates. Commercially available EnzChek lipase substrate provided 204s(-1)M(-1). Substrate concentration was identified as a critical parameter, with measured reaction rates decreasing at higher concentrations when intermolecular quenching becomes significant. PMID- 27241528 TI - Mental Health Referrals Reduce Recidivism in First-Time Juvenile Offenders, But How Do We Determine Who is Referred? AB - While psychiatric disorders are common among juvenile delinquents, many mental health problems go undetected, increasing the likelihood for persistent difficulties. This is the first known study to examine mental health referral rates and recidivism in the juvenile justice system. In addition to the study, we review juvenile justice mental health screening to improve detection and treatment. Juvenile criminal records in conjunction with behavioral health screenings were analyzed to determine differences in referrals and recidivism among first time offenders. Recidivism rates were significantly lower (p = 0.04) and time to recidivism was significantly longer (p = 0.03) for those referred specifically for mental health services than for those without any referrals, even after adjusting for offense severity. While black youths had a significantly higher recidivism rate (p = 0.02) and a shorter time to recidivism (p = 0.009) than white youths, there was no significant difference between races when referred specifically for mental health services. Among the groups studied, black youths had the most profound positive effect from mental health referrals (p < 0.0001). This study indicates the importance of detecting mental health problems among juvenile delinquents, especially for black offenders. The apparent protective effect of mental health interventions necessitates screening that better identifies underlying psychosocial factors rather than strict reliance upon diagnostic criteria and self-report. Broader or even universal mental health referrals for juvenile offenders could reduce future legal system involvement and costs to society. We review potential reasons that mental health problems go undetected and provide recommendations. PMID- 27241529 TI - Differentially expressed genes in preimplantation human embryos: potential candidate genes for blastocyst formation and implantation. AB - PURPOSE: The aim of this study was to determine which genes and gene pathways are differentially expressed when comparing human blastocysts with cleavage-stage embryos. METHODS: We individually assessed gene expression in preimplantation human embryos at cleavage (n = 3) and blastocyst (n = 3) stages. Gene expression patterns were then validated in publically available datasets and then independently validated in vitro with additional human embryos using TaqMan gene expression assays. Immunolocalization studies were conducted to identify protein expression in intact blastocyst-stage embryos. RESULTS: Compared to cleavage stage embryos, blastocyst-stage embryos differentially expressed 51 genes (p < 0.001), with overrepresentation in amoebiasis pathways and pathways in cancer. Of these 51 genes, 21 were found to be independently validated in a separate, publically available dataset, with a substantial agreement with our initial findings (kappa = 0.8). In an independent set of cleavage- and blastocyst-stage embryos, we validated that six of eight tested genes were differentially expressed (p < 0.05) by RT-qPCR. Immunofluorescence studies documented the presence of two studied proteins in the trophectoderm of blastocyst-stage embryos. CONCLUSIONS: Differentially expressed genes may be implicated in the invasion and proliferation of the early embryo. Our research highlights specific genes that may be further studied for their role in the implantation process and additionally raises questions about localized gene and/or protein expression in the trophectoderm, which could affect protocols for, and interpretation of, trophectoderm biopsies performed in in vitro fertilization cycles. PMID- 27241530 TI - Semen as virus reservoir? PMID- 27241531 TI - SNP array-based analyses of unbalanced embryos as a reference to distinguish between balanced translocation carrier and normal blastocysts. AB - PURPOSE: The purpose of the study is to validate a method that provides the opportunity to distinguish a balanced translocation carrier embryo from a truly normal embryo in parallel with comprehensive chromosome screening (CCS). METHODS: A series of translocation carrier couples that underwent IVF with single nucleotide polymorphism (SNP) array-based CCS on 148 embryos were included. Predictions of balanced or normal status of each embryo were made based upon embryonic SNP genotypes. In one case, microdeletion status was used to designate whether embryos were balanced or normal. In 10 additional cases, conventional karyotyping was performed on newborns in order to establish the true genetic status (balanced or normal) of the original transferred embryo. Finally, implantation potential of balanced or normal embryos was compared. RESULTS: Phasing SNPs using unbalanced embryos allowed accurate prediction of whether transferred embryos were balanced translocation carriers or truly normal in all cases completed to date (100 % concordance with conventional karyotyping of newborns). No difference in implantation potential of balanced or normal embryos was observed. CONCLUSIONS: This study demonstrates the validity of a CCS method capable of distinguishing normal from balanced translocation carrier embryos. The only prerequisite is the availability of parental DNA and an unbalanced IVF embryo, making the method applicable to the majority of carrier couples. In addition, the SNP array platform allows simultaneous CCS for aneuploidy with the same platform and from the same biopsy. Future work will involve prospective predictions to select normal embryos with subsequent karyotyping of the resulting newborns. PMID- 27241532 TI - Comment on: "Intracytoplasmic morphologically selected sperm injection (IMSI) does not improve outcome in patients with two successive IVF-ICSI failures" by Gatimel et al. PMID- 27241534 TI - Progress in the preparation and application of modified biochar for improved contaminant removal from water and wastewater. AB - Modified biochar (BC) is reviewed in its preparation, functionality, applications and regeneration. The nature of precursor materials, preparatory conditions and modification methods are key factors influencing BC properties. Steam activation is unsuitable for improving BC surface functionality compared with chemical modifications. Alkali-treated BC possesses the highest surface functionality. Both alkali modified BC and nanomaterial impregnated BC composites are highly favorable for enhancing the adsorption of different contaminants from wastewater. Acidic treatment provides more oxygenated functional groups on BC surfaces. The Langmuir isotherm model provides the best fit for sorption equilibria of heavy metals and anionic contaminants, while the Freundlich isotherm model is the best fit for emerging contaminants. The pseudo 2(nd) order is the most appropriate model of sorption kinetics for all contaminants. Future research should focus on industry-scale applications and hybrid systems for contaminant removal due to scarcity of data. PMID- 27241533 TI - MiR-16 regulates mouse peritoneal macrophage polarization and affects T-cell activation. AB - MiR-16 is a tumour suppressor that is down-regulated in certain human cancers. However, little is known on its activity in other cell types. In this study, we examined the biological significance and underlying mechanisms of miR-16 on macrophage polarization and subsequent T-cell activation. Mouse peritoneal macrophages were isolated and induced to undergo either M1 polarization with 100 ng/ml of interferon-gamma and 20 ng/ml of lipopolysaccharide, or M2 polarization with 20 ng/ml of interleukin (IL)-4. The identity of polarized macrophages was determined by profiling cell-surface markers by flow cytometry and cytokine production by ELISA. Macrophages were infected with lentivirus-expressing miR-16 to assess the effects of miR-16. Effects on macrophage-T cell interactions were analysed by co-culturing purified CD4(+) T cells with miR-16-expressing peritoneal macrophages, and measuring activation marker CD69 by flow cytometry and cytokine secretion by ELISA. Bioinformatics analysis was applied to search for potential miR-16 targets and understand its underlying mechanisms. MiR-16 induced M1 differentiation of mouse peritoneal macrophages from either the basal M0- or M2-polarized state is indicated by the significant up-regulation of M1 marker CD16/32, repression of M2 marker CD206 and Dectin-1, and increased secretion of M1 cytokine IL-12 and nitric oxide. Consistently, miR-16-expressing macrophages stimulate the activation of purified CD4(+) T cells. Mechanistically, miR-16 significantly down-regulates the expression of PD-L1, a critical immune suppressor that controls macrophage-T cell interaction and T-cell activation. MiR 16 plays an important role in shifting macrophage polarization from M2 to M1 status, and functionally activating CD4(+) T cells. This effect is potentially mediated through the down-regulation of immune suppressor PD-L1. PMID- 27241535 TI - A novel process for low-sulfur biodiesel production from scum waste. AB - Scum is an oil-rich waste from the wastewater treatment plants with a high-sulfur level. In this work, a novel process was developed to convert scum to high quality and low sulfur content biodiesel. A combination of solvent extraction and acid washing as pretreatment was developed to lower the sulfur content in the scum feedstock and hence improve biodiesel conversion yield and quality. Glycerin esterification was then employed to convert free fatty acids to glycerides. Moreover, a new distillation process integrating the traditional reflux distillation and adsorptive desulfurization was developed to further remove sulfur from the crude biodiesel. As a result, 70% of the filtered and dried scum was converted to biodiesel with sulfur content lower than 15ppm. The fatty acid methyl ester profiles showed that the refined biodiesel from the new process exhibited a higher quality and better properties than that from traditional process reported in previous studies. PMID- 27241536 TI - Contact Sensitization in Children: A Retrospective Study of 2,614 Children from a Single Center. AB - BACKGROUND: Contact sensitization in children is more common than previously thought, but few studies have been performed on a large population assessed by the same team. The objective was to evaluate contact sensitization in children with suspected contact dermatitis, the relationship with atopic dermatitis (AD), and the most common allergens. METHODS: The same team patch tested 2,614 children younger than 11 years old with a standard series of 30 allergens. RESULTS: A total of 1220 children (46.7%) developed at least one positive reaction, 606 of which were clinically relevant (49.7%). The most frequent reactions were to nickel sulfate (22.7%), cobalt chloride (11.1%), potassium dichromate (9.9%), neomycin sulfate (5.2%), thimerosal (4.2%), cocamidopropyl betaine (3.4%), and methylchloroisothiazolinone/methylisothiazolinone (3.2%). The prevalence of contact sensitization was similar in children with (47.3%) and without (46.1%) AD. Children with AD had a higher prevalence of positive reactions to potassium dichromate (p < 0.001), Compositae mix (p = 0.01), and disperse blue (p = 0.03). CONCLUSIONS: Contact sensitization is quite common in young children. This study adds some information on the most common contact allergens. A similar prevalence of positive patch test reactions was found in children with and without AD, but children with AD had a greater prevalence of positive patch test reactions to potassium dichromate, Compositae mix, and disperse blue. PMID- 27241537 TI - Are We Giving Optimal Dose of Efavirenz? PMID- 27241538 TI - The Differences Between Interleukin-6 and C-reactive Protein Levels Among Adult Patients of Dengue Infection with and without Plasma Leakage. AB - AIM: to determine the differences in IL-6 and CRP levels among groups of dengue infection patients with and without plasma leakage. METHODS: a cross-sectional study was conducted in adult patients with dengue infection who were treated at Cipto Mangunkusumo and Persahabatan Hospital between 1 March 2014 and 1 April 2015. The study analyzed differences in IL-6 and CRP levels on the 3rd and 5th day of fever in both groups, as well as differences in each group. Interleukin-6 and CRP levels in both groups, was analyzed using unpaired t-test or Mann-Whitney and in each group, the data was subsequently analyzed using paired t-test or Wilcoxon test. RESULTS: the samples of study consisted of 24 subjects with plasma leakage and 20 subjects without plasma leakage. The level of IL-6 for groups with and without plasma leakage for the 3rd and the 5th day of fever were 8.56 (1.85 96.15) vs. 3.80 (1.94-81.93) pg/mL (p=0.069) and 4.30 (1.60-70.28) vs. 2.76 (1.26 11.67) pg/mL (p=0.025), respectively; while for CRP level, there were 10.1 (4.3 36.5) vs 6.8 (3.0-21.6) mg/L (p=0.014) and 5.0 (2.0-20.1) vs 2.9 (0.1-9.9) mg/L (p=0.048). The level of IL-6 on the 3rd and the 5th day of fever in the group with and without plasma leakage were 8.56 (1.85-96.15) vs. 4.30 (1.60-70.28) pg/mL (p=0.037) and 3.80 (1.94-81.93) vs. 2.76 (1.26-11.67) pg/mL (p=0.005). The level of CRP on the 3rd and 5th day of fever in the group with and without plasma leakage were 10.1 (4.3-36.5) vs. 5.0 (2.0-20.1) mg/L (p=0.0001) and 6.8 (0.3 21.6) vs. 2.9 (0.1-9.9) mg/L (p=0.0001). CONCLUSION: there was no difference in IL-6 level on the 3rd day of fever between the two groups; while on the 5th day of fever, the IL-6 level was higher in the group with plasma leakage. The level of CRP on the 3rd and the 5th day of fever were higher in the group with plasma leakage. The levels of IL-6 and CRP on the 3rd day of fever were higher than the levels on the 5th day of fever in both groups. PMID- 27241539 TI - Efavirenz Plasma Concentrations and HIV Viral Load in HIV/AIDS-tuberculosis Infection Patients Treated with Rifampicin. AB - AIM: to determine the effect of a rifampicin-containing tuberculosis regimen on efavirenz plasma concentrations and viral load in HIV/AIDS-Tuberculosis infection patients who received efavirenz-based antiretroviral therapy. METHODS: plasma efavirenz concentrations and HIV viral load were measured in HIV/AIDS patients treated with 600 mg efavirenz-based antiretroviral for 3 to 6 months and in HIV/AIDS-Tuberculosis infection patients treated with similar antiretroviral regimen plus rifampicin-containing antituberculosis in Sulianti Saroso Infectious disease Hospital, Jakarta. Plasma efavirenz concentration in both groups were compared using Mann-Whitney test, while proportion of patients with viral load >40 copy/mL were analyzed with chi-square test. RESULTS: forty five patients (27 with HIV/AIDS and 18 with HIV/AIDS-Tuberculosis infections) were recruited during the period of February to May 2015. The median efavirenz plasma concentration obtained from HIV/AIDS group was 0,680 mg/L(range 0,24 to 5,67 mg/L and that obtained from HIV/AIDS-Tuberculosis group was 0.685 mg/L (0.12 -2.23 mg/L) which was not significantly different statistically. The proportion of patients with viral load 40 copies/mL after 3-6 months of ARV treatment in the HIV/AIDS group was 51.9%, and in the HIV/AIDS-Tuberculosis group was 72.2%, which was not significantly different statistically (Chi Square test, p=0.291). CONCLUSION: plasma efavirenz concentration in HIV/AIDS-tuberculosis patients receiving antiretroviral and rifampicin is not significantly different from that on HIV/AIDS patients without tuberculosis. Proportion of patients with viral load of >40 copy/mL is higher in HIV/AIDS-tuberculosis patients receiving rifampicin compared to HIV/AIDS patients that not receive rifampicin. However, this difference did not reach statistical significance. Confirmatory studies with bigger sample size are needed to clarify the influence of rifampicin on plasma level of efavirenzand and on viral load. PMID- 27241540 TI - Comparison Between End-to-end Anastomosis and Buccal Mucosa Graft in Short Segment Bulbar Urethral Stricture: a Meta-analysis Study. AB - AIM: to compare long term follow-up between end-to-end urethroplasty and bucal mucosal graft for the management of patients with short bulbar urethral stricture. METHODS: we conducted a meta-analysis of cohort studies. Literature research was performed on the MEDLINE, Science Direct, and EMBASE database including studies from 1980 through 2014. The inclusion criteria were patients with short bulbar urethral strictrure (sized 3 cm) undergoing end-to-end anastomosis (EE) and buccal mucosa graft (BMG) with the complication of voiding symptoms and sexual dysfunction 12 months. Pooled risk ratio (RRs) and 95% confidence interval (CIs) were calculated using Mantzel-Haenzel method, while the heterogeneity were determined through I2 value. Data analysis were done using Stata software version 10.0 (StataCorp). RESULTS: We analyze 10 studies in this meta-analysis. Sexual dysfunction following EE and BMG were found in 24.6% (45/183) patients and 9.1% (11/122) patients, respectively (overall RR 2.54; 95% CI: 1,44-4,47; p=0.001). Voiding symptoms following EE and BMG were found in 14% (8/57) patients and 12.5% (7/56) patients, respectively (overall RR 0.77; 95% CI: 0.3-2.0; p=0.591). Furthermore, stricture recurrent following EE and BMG were 8.4% (8/107) and 30% (14/46), respectively (overall RR 0.38; 95% CI: 0.17-0.84; p=0.016). The effectiveness of EE and BMG were found to be equal as both demonstrated few complications. BMG were found to be superior than EE terms of minimal sexual dysfunction complication. On the contrary, EE were found to be superior than BMG in terms of stricture recurence following short bulbar urethral stricture surgery. CONCLUSION: BMG can be considered as the primary treatment rather than EE for managing short urethral stricture cases. PMID- 27241541 TI - Comparison of Asymmetric Dimethylarginine Levels Between Stages Three, Four, and Five Non-dialysis of Chronic Kidney Disease. AB - AIM: to determine the differences of ADMA level between stages 3, 4, and 5 non dialysis of chronic kidney disease (CKD) patients at Outpatient Nephrology Clinic, Dr. Soetomo Hospital. METHODS: a cross-sectional study was conducted on stage 3, 4, and 5 non-dialysis CKD patients at Outpatient Nephrology Clinic, Dr. Soetomo Hospital, Surabaya from January to February 2015. Stages of CKD were determined based on GFR estimation according to 4-variable MDRD formula. Statistical analysis of differences in the levels of ADMA in three subject groups use one-way ANOVA test. RESULTS: seventy-five patients were included in the study. Each group consisted of 25 patients stage 3, 4, and, 5 non-dialysis patients. Mean age of stage 3, stage 4, and stage 5 non-dialysis CKD patients were respectively 57.12 years, 54.80 years and 53.68 years. The mean levels of ADMA in stage 3, stage 4, and 5 were 0.62 (0.11) IU/mL, 0.72 (0.16) IU/mL, and 0.73 (0.18) IU/mL respectively. Analysis of the differences between the groups showed significant differences in ADMA levels (p=0.04), with the highest difference between stage 3 and stage 5. CONCLUSION: comparison of ADMA levels showed significant differences between CKD stages and the level tends to be higher along with increase severity of CKD stages. PMID- 27241542 TI - Antifungal Susceptibility Testing in HIV/AIDS Patients: a Comparison Between Automated Machine and Manual Method. AB - AIM: to evaluate the performance of Vitek2 compact machine (Biomerieux Inc. ver 04.02, France) in reference to manual methods for susceptibility test for Candida resistance among HIV/AIDS patients. METHODS: a comparison study to evaluate Vitek2 compact machine (Biomerieux Inc. ver 04.02, France) in reference to manual methods for susceptibility test for Candida resistance among HIV/AIDS patient was done. Categorical agreement between manual disc diffusion and Vitek2 machine was calculated using predefined criteria. Time to susceptibility result for automated and manual methods were measured. RESULTS: there were 137 Candida isolates comprising eight Candida species with C.albicans and C. glabrata as the first (56.2%) and second (15.3%) most common species, respectively. For fluconazole drug, among the C. albicans, 2.6% was found resistant on manual disc diffusion methods and no resistant was determined by Vitek2 machine; whereas 100% C. krusei was identified as resistant on both methods. Resistant patterns for C. glabrata to fluconazole, voriconazole and amphotericin B were 52.4%, 23.8%, 23.8% vs. 9.5%, 9.5%, 4.8% respectively between manual diffusion disc methods and Vitek2 machine. Time to susceptibility result for automated methods compared to Vitex2 machine was shorter for all Candida species. CONCLUSION: there is a good categorical agreement between manual disc diffusion and Vitek2 machine, except for C. glabrata for measuring the antifungal resistant. Time to susceptibility result for automated methods is shorter for all Candida species. PMID- 27241543 TI - Use of Pleural Fluid Interferon-gamma Enzyme-linked Immunospot Assay in the Diagnosis of Pleural Tuberculosis. AB - AIM: to evaluate the diagnostic value of an interferon-gamma release assay (IGRA) with enzyme-linked immunospot (ELISPOT) method, T-SPOT.TB, in the diagnosis of pleural TB using pleural fluid mononuclear cells (PFMC). METHODS: forty-eight subjects, presumed to have pleural TB with exudative pleural effusion by Light's criteria, dominated by mononuclear cells, had their pleural fluid specimen tested with T-SPOT.TB, Mycobacterial Growth Indicator Tube (MGIT) culture, and adenosine deaminase (ADA) activity. Other causes of pleural effusion such as heart failure, renal failure, hepatic cirrhosis, and malignancy were excluded. RESULTS: the sensitivity, specificity, positive predictive value, and negative predictive value of the IGRA ELISPOT assay using PFMC for the diagnosis of pleural TB were 100%, 88.89%, 97.5%, and 100%, respectively. CONCLUSION: IGRA with ELISPOT method performed on PFMC is useful for a rapid and reliable diagnosis of pleural TB in clinical practice, especially in area with high TB burden. PMID- 27241544 TI - The Ability of Detecting Heart Rate Variability with the Photoplethysmography to Predict Major Adverse Cardiac Event in Acute Coronary Syndrome. AB - AIM: to assess heart rate variability (HRV) measurements using pulse photoplethysmograph (PPG) in predicting major adverse cardiac event (MACE) in acute coronary syndrome (ACS) patients. METHODS: a prospective cohort study was conducted among hospitalized ACS patients. Heart rate variability as predictor was measured by PPG within 48 hours after admission and the incidence of MACE as outcome was identified during ICCU stay. The ability of HRV in predicting MACE during hospitalization was determined by area under ROC curve (AUC) of low frequency (LF), high fequency (HF), and LF/HF ratio parameters. RESULTS: among 75 subjects included in the study, 14 (18.7%) were experienced MACE during hospitalization. HRV parameters of LF and LF/HF ratio have AUC of 0.697 (95% CI, 0.543-0.850) and 0.851 (0.741-0.962), respectively. Using cut-off point of 89.673 ms2, LF had PPV and NPV of 13% and 71%, respectively; while LF/HF ratio of 1.718 had PPV and NPV of 6% and 50%, respectively. CONCLUSION: the HRV parameters of LF and LF/HF ratio are moderate predictors for MACE and predict better ACS patients who will not develop MACE during hospitalization. PMID- 27241545 TI - The Role of Incentive Spirometry in Primary Spontaneous Pneumothorax. AB - Pneumothorax is the presence of air in the pleural space. Its management consists of noninvasive and invasive therapies and it is determined based on clinical manifestations, type and size of pneumothorax. We present a case of a patient with diagnosis of primary spontaneous pneumothorax treated with incentive spirometry (noninvasive therapy). A 20 year old man came to respirology clinic with chief complaint of shortness of breath. He was recently diagnosed with left pneumothorax based on previous chest X-ray in another health care facilities and was advised to undergo tube thoracostomy but he refused the procedure. On physical examination, vital signs were normal. Chest X-ray showed 33% of pneumothorax or 1.2 cm. He was asked to perform incentive spirometry therapy at home. During 12 days of therapy, shortness of breath slowly disappeared and on repeated chest X-ray, it showed minimal pneumothorax in the left upper hemithorax. Noninvasive treatment such as incentive spirometry can be considered in patient with minimal symptoms and no signs of life-threatening respiratory distress. PMID- 27241546 TI - Adult Variant of Self-healing Cutaneous Mucinosis in a Patient with Epilepsy. AB - A 52-year-old woman was admitted with a 3 weeks history of periorbital edema and lips swelling. She developed several subcutaneous firm erythematous papules and nodules on the face, scalp and two indurated plaques on the upper back and left forearm. These lesions grew rapidly. The patient had a positive history of epileptic seizures since childhood. General examination was normal. There was a mild pitting edema on her hands and feet. Laboratory data were within normal limits. Histopathological examination revealed a well circumscribed accumulation of mucin in the dermis. Alcian blue stain was positive. Clinical and histopathological findings followed by spontaneous resolution of the lesions within a period of 4 months was compatible with diagnosis of self-healing cutaneous mucinosis. Herein we report the first case of self-healing cutaneous mucinosis associated with epilepsy. PMID- 27241547 TI - Obstructive Sleep Apnea and Atherosclerosis. AB - Obstructive sleep apnea (OSA) is a sleep respiratory disorder characterized by recurrent episodes of complete or partial airway obstruction, resulting in apneas or hypopneas. OSA could contribute to atherosclerosis through direct and indirect mechanisms. Endothelial dysfunction, sympathetic stimulation, and proinflammatory cytokine modulation caused by OSA play significant role to an atherosclesrotic event. Other risk factors of atherosclerosis like hypertension and diabetes mellitus also associated with OSA. Animal and clinical studies recently showed promising data to prove association between OSA, atherosclerosis, and its risk factors. However, provided data has not showed consistent result. In the future, demand of further research both basic and clinical sciences need to be fulfilled. PMID- 27241548 TI - Chronic Hypoparathyroidism Due to Partial Thyroidectomy with Intracranial Calcification. AB - A 57 year old female came with the complaint of recurrent headache, often fatigue, and sometimes feel numbs and rigid in her extremities, no other symptom was noted. Her body weight is stable and she was in menopausal state. She had a history of partial thyroidectomy 20 years ago and continues thiamazole 2.5 mg with seldom regular consult to physician. From the physical examination, the patient had a scar from thyroid surgery and other organs were in the normal condition. From laboratory examination, there was slight normocytic normochromic anemia (Hb: 10.7 gr/dL), normal fT4: 1.21 ng/dL (0.7-1.48 ng/dL), slightly low Calcium: 8.3 mg/dL (8.5-10.2 mg/dL), others were within normal limit but there was no Phosphorus level data. She was currently on medication: thiamazole 2.5 mg once daily, CaCO3 500 mg once daily, and alfacalcidol 1 mcg once daily, to prevent the rigid and numbness that she felt before. For further investigation, we performed a PTH test with result of hypoparathyroidism with parathyroid hormone 7 pg/mL (15-65 pg/mL) and brain CT-scan with result there was a symmetrical bilateral calcification in radiate corona, frontal lobes, temporal lobes, basal ganglia, thalamic, and dentate nuclei of cerebelli. There was no data about the histopathology examination of the thyroid tumor because the patient did not keep the data. The mechanism of intracranial calcification in hypoparathyroidism, more often seen in pseudohypoparathyroidism than in idiopathic hypoparathyroidism, has not been completely elucidated. It may be related more to the duration of hypocalcaemia and hyperphosphataemia than parathyroid hormone itself. Hyperphosphataemia promotes ectopic calcification in brain tissue in hypoparathyroidism. Intracranial calcification is one of the features of chronic hypocalcemia, and the calcifications typically involve basal ganglia, thalami, and the cerebellum. PMID- 27241549 TI - Endobronchial Valve as Treatment of Emphysema Compared with Standard Medical Care: an Evidence-based Case Report. AB - AIM: to determine the effectiveness of endobronchial valve placement as treatment of emphysema compared to medical care. METHODS: literature searching regarding comparison of endobronchial valve and medical care as treatment of emphysema on PubMed database. The quality of the literatures found was appraised by using critical appraisal sheet from Center of Evidence-Based Medicine, University of Oxford. RESULTS: two randomized controlled trials (RCT) were obtained from literature searching. It was revealed that endobronchial valve placement improved quality of patients with moderate to very severe as compared to medical treatment significantly. However, these significant improvements occurred in patients with high heterogeneity emphysema, complete interlobar fissure, and absence of collateral ventilation. CONCLUSION: endobronchial valve placement was a more effective treatment in patients with high heterogeneity emphysema, complete interlobar fissure, and absence of collateral ventilation. Assessment by using High Resolution CT-scan (HRCT) must be conducted prior to valve placement to determine suitability of this approach in emphysema patients. PMID- 27241550 TI - Nocturnal Hypertension: Neglected Issue in Comprehensive Hypertension Management. AB - The body circardian rhythm affects blood pressure variability at day and night, therefore blood pressure at day and night might be different. Nocturnal hypertension is defined as increase of blood pressure >120/70mmHg at night, which is caused by disturbed circadian rhythm, and associated with higher cardiovascular and cerebrovascular events also mortality in hypertensive patients. Nocturnal hypertension and declining blood pressure pattern, can only be detected by continuous examination for 24 hours, also known as ambulatory blood pressure measurement (ABPM). Chronotherapy, has become a strategy for managing the hypertensive nocturnal patients, by taking hypertensive medication at night to obtain normal blood pressure decrease in accordance with the normal circadian rhythm and, improving blood pressure control. PMID- 27241551 TI - Mercury and methyl mercury in fishes from Bacaja River (Brazilian Amazon): evidence for bioaccumulation and biomagnification. AB - This study assessed total mercury (THg) and methyl mercury (MeHg) concentrations, bioaccumulation and biomagnification of THg through the food web in fishes consumed by indigenous communities of Bacaja River, the largest tributary of the right bank of Xingu River. In total, 496 fish (22 species) were sampled. Nine species had THg concentrations above the limit recommended by the World Health Organisation (0.5 ug g(-1) wet mass), and one exceeded the recommended level for Hg in predatory fishes by Brazilian law (1.0 ug g(-1) ). The average concentration of THg increased significantly with trophic guild (herbivorous to piscivorous) and trophic level, with higher accumulation in fishes with greater total length. Ninety-six per cent of all mercury was methylated. These results suggest that feeding habits determine THg concentrations in fishes and that Hg elimination rate is slow during growth, which allows greater accumulation. These findings show that fishes in the Bacaja River contain high concentrations of THg and MeHg. PMID- 27241553 TI - Yes, circadian rhythms actually do affect almost everything. AB - Circadian rhythms in the level of intracellular Mg appear to be widely conserved phylogenetically, and have the potential to impact nearly all aspects of metabolism. Moreover, the clock regulates the ion channels that generate the rhythm, demonstrating that the whole cell operates as a circadian system. PMID- 27241554 TI - Patterns of drug dependence in a Queensland (Australia) sample of Indigenous and non-Indigenous people who inject drugs. AB - INTRODUCTION AND AIMS: Despite over-representation of Indigenous Australians in sentinel studies of injecting drug use, little is known about relevant patterns of drug use and dependence. This study compares drug dependence and possible contributing factors in Indigenous and non-Indigenous Australians who inject drugs. DESIGN AND METHODS: Respondent-driven sampling was used in major cities and 'peer recruitment' in regional towns of Queensland to obtain a community sample of Indigenous (n = 282) and non-Indigenous (n = 267) injectors. Data are cross sectional. Multinomial models were developed for each group to examine types of dependence on injected drugs (no dependence, methamphetamine-dependent only, opioid-dependent only, dependent on methamphetamine and opioids). RESULTS: Around one-fifth of Indigenous and non-Indigenous injectors were dependent on both methamphetamine and opioids in the previous 12 months. Psychological distress was associated with dual dependence on these drugs for Indigenous [adjusted relative risk (ARR) 4.86, 95% confidence interval (CI) 2.08-11.34] and non-Indigenous (ARR 4.14, 95% CI 1.59-10.78) participants. Unemployment (ARR 8.98, 95% CI 2.25-35.82) and repeated (> once) incarceration as an adult (ARR 3.78, 95% CI 1.43-9.97) were associated with dual dependence for Indigenous participants only. Indigenous participants had high rates of alcohol dependence, except for those dependent on opioids only. DISCUSSION AND CONCLUSIONS: The drug dependence patterns of Indigenous and non-Indigenous people who inject drugs were similar, including the proportions dependent on both methamphetamine and opioids. However, for Indigenous injectors, there was a stronger association between drug dependence and contextual factors such as unemployment and incarceration. Expansion of treatment options and community-level programs may be required. [Smirnov A, Kemp R, Ward J, Henderson S, Williams S, Dev A, Najman J M. Patterns of drug dependence in a Queensland (Australia) sample of Indigenous and non Indigenous people who inject drugs. Drug Alcohol Rev 2016;35:611-619]. PMID- 27241552 TI - RANKL/RANK control Brca1 mutation- . AB - Breast cancer is the most common female cancer, affecting approximately one in eight women during their life-time. Besides environmental triggers and hormones, inherited mutations in the breast cancer 1 (BRCA1) or BRCA2 genes markedly increase the risk for the development of breast cancer. Here, using two different mouse models, we show that genetic inactivation of the key osteoclast differentiation factor RANK in the mammary epithelium markedly delayed onset, reduced incidence, and attenuated progression of Brca1;p53 mutation-driven mammary cancer. Long-term pharmacological inhibition of the RANK ligand RANKL in mice abolished the occurrence of Brca1 mutation-driven pre-neoplastic lesions. Mechanistically, genetic inactivation of Rank or RANKL/RANK blockade impaired proliferation and expansion of both murine Brca1;p53 mutant mammary stem cells and mammary progenitors from human BRCA1 mutation carriers. In addition, genome variations within the RANK locus were significantly associated with risk of developing breast cancer in women with BRCA1 mutations. Thus, RANKL/RANK control progenitor cell expansion and tumorigenesis in inherited breast cancer. These results present a viable strategy for the possible prevention of breast cancer in BRCA1 mutant patients. PMID- 27241555 TI - MicroRNA-146a represses LRP2 translation and leads to cell apoptosis in Alzheimer's disease. AB - MicroRNA regulation of transcript expression has been reported in patients with Alzheimer's disease (AD). Here, we investigate the role of microRNA-146a (miRNA 146a), a brain-enriched miRNA, which is upregulated in AD patients. Through analysis of predicted targets of miRNA-146a, low-density lipoprotein receptor related protein-2 (Lrp2), a member of the LDLR family that is known to play a protective role in AD, was identified. Overexpression of miRNA-146a in SH-SY5Y cells significantly decreased Lrp2 expression, resulting in a reduction of Akt activation and induction of proapoptotic caspase-3, thereby increasing cell apoptosis. Thus, specific miRNA-146a regulation may contribute to AD by downregulating the Lrp2/Akt pathway. PMID- 27241556 TI - Efficacy of petrosectomy in malignant invasion of the temporal bone. AB - We present the outcomes of lateral, subtotal, and total petrosectomies in patients with invasion of the temporal bone by specific primary cancers, with particular emphasis on survival in the advanced stages of disease. We made a retrospective study of 20 consecutive patients (squamous cell carcinoma of the temporal bone, n=11, and primary cancer of the parotid gland with infiltration of the lateral skull base, n=9) treated by total, subtotal, or lateral petrosectomy at the University Department of Otolaryngology, a tertiary referral centre, between June 2006 and December 2010. Fourteen of the 20 patients were alive at the time of analysis, and follow-up ranged from 36-60 months. Six of seven patients whose disease relapsed (4 local and 3 distant metastases) died. The three-year, disease-free survival was 65% and the overall survival 68%. Survival between those with temporal bone and parotid tumours did not differ significantly. The combined group survival was affected by involvement of invaded resection margins (n=6, p=0.03). Involved margins were significant in the development of recurrence (p=0.03). Tumour stage, nodal involvement, type of operation, sex, age, skin involvement, facial palsy, and previous history of disease had no impact on prognosis. There was a significant difference in the survival curves of patients with carcinoma of the temporal bone with and without facial paresis (n=6 compared with n=5; p=0.046). Two of 11 free flaps required revision of the anastomoses, but none was lost. PMID- 27241557 TI - Potential reformatting errors in cone-beam computed tomography for dentoalveolar surgery: a cautionary tale. AB - We describe the removal of a lower second molar tooth in which preoperative cone beam computed tomography (CBCT) showed that the inferior alveolar nerve (IAN) was encased in the distal apex of the root of the tooth. During operation the nerve was found to be entirely separate from the apex of the root and not involved. With the wider use of CBCT in the treatment planning of dentoalveolar surgery, this case represents a cautionary tale to the clinician on reliance on clinical imaging and software in guiding the decision making process. PMID- 27241558 TI - Indications and radiological findings of acute otitis media and its complications. AB - Most cases of acute otitis media resolve with antibiotics and imaging is not required. When treatment fails or a complication is suspected, imaging plays a crucial role. Since the introduction of antibiotic treatment, the complication rate has decreased dramatically. Nevertheless, given the critical clinical relevance of complications, the importance of early diagnosis is vital. Our objective was to review the clinical and radiological features of acute otitis media and its complications. They were classified based on their location, as intratemporal or intracranial. Imaging makes it possible to diagnose the complications of acute otitis media and to institute appropriate treatment. Computed tomography is the initial technique of choice and, in most cases, the ultimate. Magnetic resonance is useful for evaluating the inner ear and when accurate evaluation of disease extent or better characterization of intracranial complications is required. PMID- 27241559 TI - Malignant external otitis in Spain. AB - INTRODUCTION: Malignant external otitis is a necrotizing infection, which extends from the squamous epithelium of the ear canal to the adjacent tissue. The objective of the study was to investigate its incidence and other epidemiological data in Spain, reporting the largest case series to date. METHODS: A descriptive, retrospective study of the Spanish population was carried out using the minimum basic data set (MBDS) based on data of patients admitted to hospitals in the 2008 2013 period. Patients whose diagnosis (principal or secondary) at discharge was encoded as 380.14 (malignant external otitis), according to ICD-9-CM, were included as cases. The Spanish incidence rate was calculated for all its communities and provinces, as well as by season and mortality. RESULTS: A total of 355 patients (302 as principal diagnosis and 53 as secondary) were diagnosed. The incidence rate was 1.30 (95% CI, 1.17 to 1.44) per 106 inhabitants and year, although there were variations among geographical areas. The median age of cases with main diagnosis was 74 years (range 10-95 years). The predominant age group was in patients over 84 years old (19.3 cases per 106 inhabitants and year). The incidence was higher in men and the male-female relative risk was 2.4. Diabetes was present in 74.6% of patients. The diagnosis was predominant in the last quarter of the year. The gross in-hospital mortality rate was 3.7%. CONCLUSIONS: Malignant external otitis is seen mostly among male elderly and diabetic patients. The incidence and mortality rate are low in Spain. PMID- 27241560 TI - The impact of frailty syndrome and risk scores on emergency cholecystectomy patients. AB - PURPOSE: Cholecystectomy, which is one of the most common surgical procedures, is also performed in the emergency setting. A number of risk scores have been introduced in recent studies; moreover, over the last few years literature has focused on surgical patients with frailty syndrome. The aim of the present study is to evaluate whether frailty syndrome and the risk scores are correlated with morbidity, post-operative hospital stay and the ICU admission rate following emergency cholecystectomy. METHODS: Eighty-five consecutive patients of >65 years of age who underwent cholecystectomy were selected from 2306 emergency procedures for inclusion in the present study. The patients were assessed for frailty syndrome and their scores were calculated on the basis of chart review. Univariate analyses were performed to compare severe frailty patients to intermediate frailty and robust patients. ROC and logistic regression analyses were performed with the end-points of morbidity, hospital stay and ICU admission. RESULTS: In addition to having worse ASA, inflammatory and risk values than robust patients, frailty syndrome patients also had higher rates of morbidity and ICU admission and longer hospitalization periods. A logistic regression analysis showed that the P-Possum was independently correlated with morbidity. Frailty and open surgery were independently correlated with longer hospitalization, whereas ICU admission was correlated with worse ASA and P-Possum values. CONCLUSIONS: Frailty syndrome significantly impacts the length of hospitalization in patients undergoing emergency cholecystectomy. Although the ORs were limited, the P-Possum value was independently associated with the outcome. PMID- 27241561 TI - Identification of Mycobacterium tuberculosis leucyl-tRNA synthetase (LeuRS) inhibitors among the derivatives of 5-phenylamino-2H-[1,2,4]triazin-3-one. AB - The increase of antibiotic resistance amongst Mycobacterium tuberculosis strains has become one of the most pressing problems of modern medicine. Therefore, the search of antibiotics against M. tuberculosis with novel mechanisms of action is very important. We have identified inhibitors of M. tuberculosis leucyl-tRNA synthetase (LeuRS) among the derivatives of 5-phenylamino-2H-[1,2,4]triazin-3 one. The most active compounds 5-(5-chloro-2-hydroxy-phenylamino)-6-methyl-2H [1,2,4]triazin-3-one and 5-(5-chloro-2-hydroxy-phenylamino)-2H-[1,2,4]triazin-3 one inhibit M. tuberculosis LeuRS with IC50 of 7.6 MUM and 7.2 MUM, respectively. It was established that the inhibitory activity of compounds against pathogenic LeuRS is 10-fold better, than for human enzyme. PMID- 27241562 TI - Liberatory vertigo: a new prognostic factor for repositioning maneuvers. AB - OBJECTIVE: This study suggests the new concept of liberatory vertigo to facilitate emergency department treatment of benign paroxysmal positional vertigo. METHODS: The present prospective nonrandomized study enrolled 535 patients with typical forms of positional vertigo, who were treated following clinical practice guidelines. We observed the onset of liberatory vertigo during the maneuver as a prognostic factor, and we tested the correlation between that symptom and therapeutic effectiveness. A subjective evaluation of vertigo was made by way of a questionnaire. Data analysis was performed that made use of statistical software. RESULTS: Complete recovery occurred in 287 patients (76.5%) with posterior semicircular canal positional vertigo and in 67 patients (80%) with horizontal semicircular canal positional vertigo; liberatory vertigo occurred in 195 (67.9%) and 59 (88%) of those cases, respectively. Differences in terms of recovery probability resulted regardless of the canal involved. Positive predictive value ranged from 93% to 97%. CONCLUSIONS: In our sample, liberatory vertigo could predict the effectiveness of the maneuver regardless of the canal involved. PMID- 27241563 TI - An irreducible posterolateral knee dislocation: diagnosis, arthroscopic view, and treatment. PMID- 27241564 TI - The effect of surgical consult in the treatment of abdominal pain in older adults in the ED. AB - OBJECTIVE: The objective was to determine whether need for surgical consult contributes to delayed or reduced analgesic administration in older adults presenting to the emergency department with abdominal pain. METHODS: Secondary data analyses from a prospective cohort study consisting of adults >=65 years in age presenting to the emergency department with a chief concern of abdominal pain from November 1, 2012, through October 31, 2014, were performed. Measurements included administration of analgesics, time to administration, type given, and pain score reduction. Covariates for adjusted analyses included age, sex, race/ethnicity, and Emergency Severity Index. RESULTS: A total of 3522 patients were included, of which 281 (8.7%) received any consult. Consult patients were less likely to receive any analgesic medication (53.0%) compared with nonconsult patients (62.5%) (relative risk = 0.80; 95% confidence interval, 0.70-0.91). However, among those patients receiving analgesic medications, there were no differences in likelihood of receiving an opioid, time to administration, or pain score reduction. When analyzing patients who received a surgical consult (n = 154, 4.4%), these associations were notably stronger. Surgical consult patients had a lower rate of analgesic administration (46.8%) compared with nonconsult patients (62.4%) (relative risk = 0.75; 95% confidence interval, 0.63- 0.89). Again, no differences were found in likelihood of receiving any opioid, time to administration, or pain score reduction. CONCLUSION: Need for abdominal surgical consult is associated with decreased administration of analgesics in older patients, possibly indicating a continued need to improve management in this setting. This difference, however, did not impact pain score reductions. PMID- 27241565 TI - Anuria and acute kidney injury: an uncommon case of bilateral synchronous ureteric calculi. PMID- 27241566 TI - Routine tests and automated urinalysis in patients with suspected urinary tract infection at the ED. AB - BACKGROUND: Urinary tract infections (UTIs) are frequently encountered. Diagnostics of UTI (urine dipstick, Gram stain, urine culture) lack proven accuracy and precision in the emergency department. Utility of automated urinalysis shows promise for UTI diagnosis but has not been validated. METHODS: A total of 381 cases presenting with fever and/or clinically suspected UTI were analyzed. Diagnosis was based on clinical presentation, urine culture and/ or blood culture, and successful treatment. Performance of standard diagnostics and automated urinalysis (Sysmex UF-1000i) was analyzed at various cutoff values, and diagnostic algorithms were tested. RESULTS: One hundred forty-three (37.5%) cases were diagnosed with UTI. Sensitivity of urine dipstick nitrite was 32.9% and specificity was 93.7%. Sensitivity of urine dipstick leukocyte esterase (3+) was 80.4% and specificity was 82.8%. Receiver operating characteristic curves of automated bacterial and leukocyte count showed area under the curve of 0.851 and 0.872, respectively. Cutoff values of 133 bacteria/MUL and 48 leukocytes/MUL resulted in >90% sensitivity. Diagnostic values for complicated cases (antibiotics, catheters) were inferior to uncomplicated cases. Algorithms combining dipstick and automated counts did not improve accuracy with the exception of a 5.2% increase in uncomplicated cases (n=247). CONCLUSIONS: Automated leukocyte and bacterial count can be used in the emergency department setting with comparable accuracy compared with standard dipstick analysis with minor improvement when combined. PMID- 27241567 TI - The treatment for maternal supraventricular tachyarrhythmia in pregnant patients in ED practice. PMID- 27241568 TI - Reply to "Dimension reduction: perihematomal edema diameter as a predictive indicator of 30-day mortality of intracranial hematoma". PMID- 27241569 TI - Succinylcholine, rocuronium, and hyperkalemia. PMID- 27241570 TI - Differentiating contrast staining after acute ischemic stroke from hemorrhagic transformation during emergency evaluation. PMID- 27241571 TI - A critical analysis of unplanned ICU transfer within 48 hours from ED admission as a quality measure. AB - HYPOTHESIS: Unplanned intensive care unit (ICU) transfer (UIT) within 48 hours of emergency department (ED) admission increases morbidity and mortality. We hypothesized that a majority of UITs do not have critical interventions (CrIs) and that CrI is associated with worse outcomes. OBJECTIVE: The objective of the study is to characterize all UITs (including patients who died before ICU transfer), the proportion with CrI, and the effect of having CrI on mortality. DESIGN: This is a single-center, retrospective cohort study of UITs within 48 hours from 2008 to 2013 at an urban academic medical center and included patients 18 years or older without advanced directives (ADs). Critical intervention was defined by modified Delphi process. Data included demographics, comorbidities, reasons for UIT, length of stay, CrIs, and mortality. We calculated descriptive statistics with 95% confidence intervals (CIs). RESULTS: A total of 837 (0.76%) of 108 732 floor admissions from the ED had a UIT within 48 hours; 86 admitted patients died before ICU. We excluded 23 ADs, 117 postoperative transfers, 177 planned ICU transfers, and 4 with missing data. Of the 516 remaining, 65% (95% CI, 61%-69%) received a CrI. Unplanned ICU transfer reasons are as follows: 33 medical errors, 90 disease processes not present on arrival, and 393 clinical deteriorations. Mortality was 10.5% (95% CI, 8%-14%), and mean length of stay was 258 hours (95% CI, 233-283) for those with CrI, whereas the mortality was 2.8% (95% CI, 1%-6%) and mean length of stay was 177 hours (95% CI, 157-197) for those without CrI. CONCLUSIONS: Unplanned ICU transfer is rare, and only 65% had a CrI. Those with CrI had increased morbidity and mortality. PMID- 27241572 TI - Activation of autophagy improved the neurologic outcome after cardiopulmonary resuscitation in rats. AB - OBJECTIVE: Recent studies have shown the existence of autophagy in cerebral ischemia; however, there has been no research on the role of autophagy in cerebral injury after cardiopulmonary resuscitation (CPR). This study was conducted to determine the role of autophagy in an animal model of ventricular fibrillation (VF)/CPR. METHODS: Experiment 1: A total of 48 adult Wistar rats were untreated for 7 minutes after induction of VF using an external transthoracic alternating current, and subsequent CPR was performed to observe the existence of autophagy after the return of spontaneous circulation (ROSC). Experiment 2: A total of 72 rats were pretreated with intracerebroventricular injection of physiologic saline (control group), the autophagy inducer (rapamycin group), or the autophagy inhibitor 3-methyladenine (3-methyladenine group) before ROSC to evaluate the contribution of autophagy to neuronal injury after ROSC. RESULTS: The activation of autophagy was attenuated 2 to 4 hours after ROSC, which was related to the activity decrease of 5'-adenosine monophosphate activated protein kinase after ROSC. Rapamycin treatment significantly increased the expressions of LC3-II and Beclin-1 after ROSC, attenuated the activation of caspase-3, promoted neuronal survival and decreased neuronal apoptosis, and improved the neurologic deficit score after CPR. CONCLUSIONS: The activation of autophagy after ROSC offered a remarkable tolerance to VF/CPR ischemic insult and improved the neurologic outcomes. PMID- 27241573 TI - Computational prediction of methylation types of covalently modified lysine and arginine residues in proteins. AB - Protein methylation is an essential posttranslational modification (PTM) mostly occurs at lysine and arginine residues, and regulates a variety of cellular processes. Owing to the rapid progresses in the large-scale identification of methylation sites, the available data set was dramatically expanded, and more attention has been paid on the identification of specific methylation types of modification residues. Here, we briefly summarized the current progresses in computational prediction of methylation sites, which provided an accurate, rapid and efficient approach in contrast with labor-intensive experiments. We collected 5421 methyllysines and methylarginines in 2592 proteins from the literature, and classified most of the sites into different types. Data analyses demonstrated that different types of methylated proteins were preferentially involved in different biological processes and pathways, whereas a unique sequence preference was observed for each type of methylation sites. Thus, we developed a predictor of GPS-MSP, which can predict mono-, di- and tri-methylation types for specific lysines, and mono-, symmetric di- and asymmetrical di-methylation types for specific arginines. We critically evaluated the performance of GPS-MSP, and compared it with other existing tools. The satisfying results exhibited that the classification of methylation sites into different types for training can considerably improve the prediction accuracy. Taken together, we anticipate that our study provides a new lead for future computational analysis of protein methylation, and the prediction of methylation types of covalently modified lysine and arginine residues can generate more useful information for further experimental manipulation. PMID- 27241574 TI - Pluripotent stem cells: An in vitro model for nanotoxicity assessments. AB - The advent of technology has led to an established range of engineered nanoparticles that are used in diverse applications, such as cell-cell interactions, cell-material interactions, medical therapies and the target modulation of cellular processes. The exponential increase in the utilization of nanomaterials and the growing number of associated criticisms has highlighted the potential risks of nanomaterials to human health and the ecosystem. The existing in vivo and in vitro platforms show limitations, with fluctuations being observed in the results of toxicity assessments. Pluripotent stem cells (PSCs) are viable source of cells that are capable of developing into specialized cells of the human body. PSCs can be efficiently used to screen new biomaterials/drugs and are potential candidates for studying impairments of biophysical morphology at both the cellular and tissue levels during interactions with nanomaterials and for diagnosing toxicity. Three-dimensional in vitro models obtained using PSC-derived cells would provide a realistic, patient-specific platform for toxicity assessments and in drug screening applications. The current review focuses on PSCs as an alternative in vitro platform for assessing the hazardous effects of nanomaterials on health systems and highlights the importance of PSC-derived in vitro platforms. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27241576 TI - "Opening the Unopenable": Endovascular Treatment in a Patient with Three Months' Internal Carotid Artery Occlusion and Hemispheric Symptomatic Hypoperfusion. AB - BACKGROUND: Internal carotid artery occlusion (ICAO) is defined as "untouchable" by all specialists; no treatment is indicated because intervention risks (carotid endarterectomy (CEA) or endovascular treatment) are usually much more than benefits.(1,2) We report the case of a patient admitted to our hospital with an atherothrombotic ischemic stroke due to symptomatic acute ICAO, who developed a recurrent stroke with hemispheric hypoperfusion and was treated in the emergency department with ICAO revascularization after 60 days of occlusion finding. CASE DESCRIPTION: D.G., a 62-year-old man, came to our attention for a transient episode of left weakness and hypoesthesia. The electrocardiogram revealed a new diagnosis of atrial fibrillation. CT angiography showed right ICAO; computed tomography and magnetic resonance imaging studies with perfusion imaging revealed a severe hemispheric hypoperfusion. Full anticoagulation therapy was started, and antihypertensive therapy was reduced to help collateral circulation. Some weeks later, the patient was readmitted to the stroke unit for 2 episodes of left-hand weakness. Cerebral angiography confirmed right ICAO from the proximal tract to the siphon. After some days, the patient suffered a femoral hemorrhagic lesion, with active bleeding, and was treated with surgical intervention. On the following day, the patient presented with left hemiplegia with hemianesthesia (National Institutes of Health Stroke Scale score = 14). The patient was treated in the emergency department with a complex endovascular treatment with complete recanalization of ICAO by positioning 3 stents through the intravenous infusion of abciximab. After intensive rehabilitation, at the 3- and 6-month follow-up evaluations, the patient regained autonomy. CONCLUSION: In literature, treatment of chronic ICAO is not indicated. Endovascular recanalization may be beneficial to patients with chronic cerebral hypoperfusion due to ICAO, when all conservative medical therapies have failed. PMID- 27241575 TI - Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy with a Novel NOTCH3 Cys323Trp Mutation Presenting Border-Zone Infarcts: A Case Report and Literature Review. AB - Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary and progressive small-vessel disease caused by NOTCH3 mutations, pathologically characterized by the degeneration of vascular mural cells, white matter changes, and ischemic strokes. Recently, dysautoregulation has received increasing attention regarding the pathogenesis of stroke in CADASIL. Here, we report a CADASIL case with a novel Cys323Trp mutation in the NOTCH3 gene, which suggests a close relationship between hemodynamic factors and clustering of cerebral infarctions in CADASIL. A 47-year-old male patient presented with internal border-zone infarcts in the bilateral hemispheres and was diagnosed with CADASIL by the presence of granular osmiophilic material and the accumulation of the Notch3 extracellular domain around small vessels. A literature review revealed 7 reports of similar CADASIL cases with clustering of cerebral infarctions related to blood pressure fluctuations. Not only large-artery stenosis but also small-vessel pathologies potentiate watershed infarctions, which might be triggered by hemodynamic fluctuation due to cerebral dysautoregulation. PMID- 27241577 TI - Psychiatric Symptoms in Patients with Stroke: A Six-Month Follow-Up Study. PMID- 27241578 TI - The Combination of Clinical Features, Transcranial Doppler, and Alberta Stroke Program Early Computed Tomography Score (Computed Tomography Angiography) in Predicting Outcome in Intravenous Recombinant Tissue Plasminogen Activator Treated Patients. AB - BACKGROUND: Little data exist on using combined baseline clinical neuroimaging and transcranial Doppler (TCD) information in predicting clinical outcome in stroke patients treated with intravenous (IV) thrombolysis. METHODS: Stroke patients received IV recombinant tissue plasminogen activator (rt-PA) and had diagnostic TCD within 3 hours of symptom onset. The TCD result was interpreted using the thrombolysis in brain ischemia (TIBI) flow grading system. Following multiple regression analysis, a grading system was created with 1 point for each of the following: National Institutes of Health Stroke Scale (NIHSS) score of 16 or higher, TIBI score of 1 or lower, and Alberta Stroke Program Early CT Score (ASPECTS) of 6 or lower. The patients' scores were compared to modified Rankin Scale (mRS) scores at 90 days. RESULTS: A total of 349 patients were included. In unvaried analysis, age of 80 years or older (P = .002), an ASPECTS of 6 or lower (P < .001), an NIHSS score of 16 or higher (P < .001), a TIBI score of 1 or lower (P < .001), and a glucose level >= 200 mg/dl (P = .04) were associated with poor outcome (mRS score > 2). In the multiple regression analysis, age of 80 years or older, an ASPECTS of 6 or lower, an NIHSS score of 16 or higher, and hyperglycemia were predictors of poor outcome (P < .05). Based on our scoring system, the patients' odds ratios for poor outcome were 7 (95% confidence interval [CI]: 2-23, P = .003), 8 (95% CI: 3-25, P < .001), and 24 (95% CI: 4 151, P = .001) for scores of 1, 2, and 3, respectively, after adjustment for common stroke risk factors. The mean time to recanalization increased as the score increased (score of 0: 160 +/- 45 minutes versus score of 3: 186 +/- 38 (P = .70). CONCLUSION: A multimodal grading system is useful in predicting outcome in patients treated with IV rt-PA. Those withhigher scores might be candidates for interventional therapy. PMID- 27241579 TI - Acoustic and Perceptual Classification of Within-sample Normal, Intermittently Dysphonic, and Consistently Dysphonic Voice Types. AB - OBJECTIVES: Intermittent dysphonia within an utterance is common, but presents difficulty for both perceptual and objective voice evaluation. This study examined the ability of measures from the within-sample cepstral peak prominence (CPP) distribution to differentiate normal voices from intermittently and consistently dysphonic voices. STUDY DESIGN: Exploratory design. METHODS: Sixty samples of the sentence "We were away a year ago" were classified as normal, intermittently dysphonic, or consistently dysphonic by four judges. Measures of CPP within each sample were obtained, and further analysis with examined CPP distribution variability and patterns of CPP outliers. RESULTS: Whereas the mean CPP was the strongest single discriminator among the three voice types, the normal and intermittent dysphonia groups were not significantly different on CPP distribution skewness and measures of CPP distribution outliers. Both the normal and intermittently dysphonic voices differed significantly from the consistently dysphonic samples on these variables. A combination of measures of the CPP distribution was effective for a linear prediction of percent dysphonia duration for the speech samples (r = 0.825; rho = 0.81). The CPP standard deviation significantly improved the use of the mean CPP in discriminant function analyses and also the classification of the intermittently dysphonic voices. CONCLUSIONS: Auditory-perceptual judgment of dysphonic segments and the typically robust acoustic measurement of mean CPP are both ineffective for classifying intermittently dysphonic voices. However, dysphonia duration may be effectively predicted via measures of the CPP distribution, and acoustic classification of dysphonic voice types via cepstral methods may be improved with an analysis of the CPP distribution across an utterance. PMID- 27241580 TI - Quantitative Study of the Effects of Dehydration on the Viscoelastic Parameters in the Vocal Fold Mucosa. AB - OBJECTIVES: The goal of this study was to quantify the viscoelastic parameters of the vocal fold mucosa at varying dehydration levels. STUDY DESIGN AND METHODS: Healthy canine larynges were obtained postmortem, and the samples were separated from the subglottal wall. The samples were dehydrated in a vacuum dryer. According to the total dehydration time per sample, dehydration levels were divided into four degrees: 0%, 40%, 60%, and 80%. The stepper was set to stretch the sample to a level of 35% strain at the same rate (0.5 mm/s). Data collection was repeated five times under each dehydration condition. The compression resilience, RC% = S'/S*100%, and the hysteresis area were measured according to the stress-strain curves. The varying properties of the samples under different dehydration levels were investigated by fitting the curves. RESULTS: The area of the hysteresis loops observed in the stress-strain curves increased exponentially with dehydration levels, whereas the RC% decreased linearly. For all curves, low strain stages can be explained by Hooke's law (sigma = E0*epsilon). With increasing levels of dehydration, E0 was shown to increase, whereas the linear range was shortened. High-strain stages resembled exponential rather than the linear curves. And the nonlinear stage of the curve became increasingly apparent in the stress-strain curves of increased dehydration levels. CONCLUSIONS: The quantitative results in this study not only provide a numerical reference for future experimental measurements, but also can be used to verify the biphasic model in future studies. PMID- 27241581 TI - Recommendations for the implementation of BRCA testing in the care and treatment pathways of ovarian cancer patients. PMID- 27241582 TI - Topical Anti-Inflammatory and Analgesic Effects of Multiple Applications of S(+) Flurbiprofen Plaster (SFPP) in a Rat Adjuvant-Induced Arthritis Model. AB - Preclinical Research The aim of this study was to evaluate the efficacy of multiple applications of S(+)-flurbiprofen plaster (SFPP), a novel Nonsteroidal anti-inflammatory drug (NSAID) patch, for the alleviation of inflammatory pain and edema in rat adjuvant-induced arthritis (AIA) model as compared to other NSAID patches. The AIA model was induced by the injection of Mycobacterium butyricum and rats were treated with a patch (1.0 cm * 0.88 cm) containing each NSAID (SFP, ketoprofen, loxoprofen, diclofenac, felbinac, flurbiprofen, or indomethacin) applied to the paw for 6 h per day for 5 days. The pain threshold was evaluated using a flexion test of the ankle joint, and the inflamed paw edema was evaluated using a plethysmometer. cyclooxygenase (COX)-1 and COX-2 inhibition was evaluated using human recombinant proteins. Multiple applications of SFPP exerted a significant analgesic effect from the first day of application as compared to the other NSAID patches. In terms of paw edema, SFPP decreased edema from the second day after application, Multiple applications of SFPP were superior to those of other NSAID patches, in terms of the analgesic effect with multiple applications. These results suggest that SFPP may be a beneficial patch for providing analgesic and anti-inflammatory effects clinically. Drug Dev Res 77 : 206-211, 2016. (c) 2016 The Authors Drug Development Research Published by Wiley Periodicals, Inc. PMID- 27241583 TI - Eureka!: What Is Innovation, How Does It Develop, and Who Does It? AB - Innovation is not only central to changes in traditional practice but arguably responsible for humanity's remarkable success at colonizing the earth and diversifying the products, technologies, and systems within it. Surprisingly little is known of how this integral component of behavioral flexibility develops and the factors that are responsible for individual differences therein. This review highlights two primary ways in which the process and development of innovation may be better understood: By emulating the critical advances of animal behavior researchers in examining innovation in nonhuman species and establishing a clearer conceptualization of what is "innovation". A pathway to innovation is suggested and an innovation classification system offered to aid recognition of its appearance and potential cultural contributions. PMID- 27241584 TI - Acrylamide affects proliferation and differentiation of the neural progenitor cell line C17.2 and the neuroblastoma cell line SH-SY5Y. AB - Acrylamide is a well-known neurotoxic compound and people get exposed to the compound by food consumption and environmental pollutants. Since acrylamide crosses the placenta barrier, the fetus is also being exposed resulting in a risk for developmental neurotoxicity. In this study, the neural progenitor cell line C17.2 and the neuroblastoma cell line SH-SY5Y were used to study proliferation and differentiation as alerting indicators for developmental neurotoxicity. For both cell lines, acrylamide reduced the number of viable cells by reducing proliferation and inducing cell death in undifferentiated cells. Acrylamide concentrations starting at 10fM attenuated the differentiation process in SH-SY5Y cells by sustaining cell proliferation and neurite outgrowth was reduced at concentrations from 10pM. Acrylamide significantly reduced the number of neurons starting at 1MUM and altered the ratio between the different phenotypes in differentiating C17.2 cell cultures. Ten micromolar of acrylamide also reduced the expression of the neuronal and astrocyte biomarkers. Although the neurotoxic concentrations in the femtomolar range seem to be specific for the SH-SY5Y cell line, the fact that micromolar concentrations of acrylamide seem to attenuate the differentiation process in both cell lines raises the interest to further investigations on the possible developmental neurotoxicity of acrylamide. PMID- 27241585 TI - High accuracy particle analysis using sheathless microfluidic impedance cytometry. AB - This paper describes a new design of microfluidic impedance cytometer enabling accurate characterization of particles without the need for focusing. The approach uses multiple pairs of electrodes to measure the transit time of particles through the device in two simultaneous different current measurements, a transverse (top to bottom) current and an oblique current. This gives a new metric that can be used to estimate the vertical position of the particle trajectory through the microchannel. This parameter effectively compensates for the non-uniform electric field in the channel that is an unavoidable consequence of the use of planar parallel facing electrodes. The new technique is explained and validated using numerical modelling. Impedance data for 5, 6 and 7 MUm particles are collected and compared with simulations. The method gives excellent coefficient of variation in (electrical) radius of particles of 1% for a sheathless configuration. PMID- 27241586 TI - The relation between histopathological classification and renal outcome, ANCA subtype and treatment regimens in ANCA-associated vasculitis. AB - OBJECTIVES: ANCA-associated vasculitis (AAV) is associated with an increased risk of death and end stage renal disease (ESRD). The aim of this study was to examine the correlation between a histopathological classification and renal outcome and to describe the interaction with ANCA subtype and initial treatment. METHODS: Eighty-seven patients with AAV from 1999-2010 from two centres in Denmark were included in the study and had a 3 year follow-up. Data was collected retrospectively. The renal biopsies were reclassi ed into one of the following groups: crescentic, sclerotic, focal and mixed. RESULTS: Histopathologic groups were not associated with eGFR at three years. Age and baseline eGFR were independent prognostic for eGFR at three years. More patients in the crescentic group than in the mixed and focal groups developed ESRD (33%, 13% and 5% respectively). Patients reaching ESRD had few- er non-affected glomeruli (14 % vs. 34%, p=0.0014) and lower eGFR at baseline (7 vs. 21.7 ml/min/m(2), p<0.0001). At baseline MPO-ANCA positive patients were older, had more sclerotic glomeruli and had a lower eGFR after three years compared to PR3-ANCA positive patients. PR3-ANCA positive patients receiving plasma exchange (PE) improved eGFR more from baseline to three years than those not receiving PE (36 vs. 20 ml/min/m2, p=0.01). CONCLUSIONS: In our cohort most pa- tients in the crescentic group and fewer in the focal group reached ESRD. Age and baseline eGFR are prognostic of renal function after 3 years, as also in the PR3-ANCA positive subgroup initial treatment with PE. PMID- 27241587 TI - Assessment of work limitations and disability in systemic vasculitis. AB - OBJECTIVES: Despite advances in the management of systemic vasculitis (SV), direct consequences of the disease, leading to impairments in physical and mental function can cause disability. The objective of this study was to assess work limitations in SV. METHODS: SV patients were recruited from a tertiary care clinic. Work disabled (WD) was defined as not working, early retirement, or reduced hours at work. Participants who were working at the time of enrolment completed the Work Limitations Questionnaire (WLQ). Other work-related measures were self-reported by questionnaire. Disease outcome measures (Vasculitis Damage Index (VDI), Health Assessment Questionnaire-Disability Index (HAQ) and pain visual analogue score (VAS)) were obtained at time of WLQ. RESULTS: 103 participants were enrolled with mean age 58 (SD17), 60% females, 48% with anti neutrophilic cytoplasmic antibody-associated vasculitis (AAV), 26% with large vessel vasculitis (LVV) and 26% with other types of SV. 22 (21%) were WD secondary to SV, 29 (28%) were working and 52 (51%) subjects were not working for reasons other than SV. SV-related WD subjects were more likely to have a lower level of education (p=0.003) than non-WD subjects. The VDI was higher in SV related WD vs. non-WD subjects: 1.9 (SD 2.7) vs. 2.9 (SD 1.4); p=0.015. 38 subjects were working in some capacity and completed the WLQ; their productivity loss was 8.2% and this was highly correlated with HAQ and pain VAS (rho=0.585 and rho=0.458, respectively). CONCLUSIONS: SV-related work disability occurred in 21% and was associated with lower levels of education, higher disease severity and worse functional outcomes. PMID- 27241588 TI - The type III effector AvrXccB in Xanthomonas campestris pv. campestris targets putative methyltransferases and suppresses innate immunity in Arabidopsis. AB - Xanthomonas campestris pv. campestris (Xcc) causes black rot, one of the most important diseases of brassica crops worldwide. The type III effector inventory plays important roles in the virulence and pathogenicity of the pathogen. However, little is known about the virulence function(s) of the putative type III effector AvrXccB in Xcc. Here, we investigated the immune suppression ability of AvrXccB and the possible underlying mechanisms. AvrXccB was demonstrated to be secreted in a type III secretion system-dependent manner. AvrXccB tagged with green fluorescent protein is localized to the plasma membrane in Arabidopsis, and the putative N-myristoylation motif is essential for its localization. Chemical induced expression of AvrXccB suppresses flg22-triggered callose deposition and the oxidative burst, and promotes the in planta growth of Xcc and Pseudomonas syringae pv. tomato in transgenic Arabidopsis plants. The putative catalytic triad and plasma membrane localization of AvrXccB are required for its immunosuppressive activity. Furthermore, it was demonstrated that AvrXccB interacts with the Arabidopsis S-adenosyl-l-methionine-dependent methyltransferases SAM-MT1 and SAM-MT2. Interestingly, SAM-MT1 is not only self associated, but also associated with SAM-MT2 in vivo. SAM-MT1 and SAM-MT2 expression is significantly induced upon stimulation of microbe-associated molecular patterns and bacterial infection. Collectively, these findings indicate that AvrXccB targets a putative methyltransferase complex and suppresses plant immunity. PMID- 27241589 TI - Symptom management strategies of Jordanian patients following coronary artery bypass grafting surgery. AB - The aim of this study was to explore the symptom management strategies utilized by post coronary artery bypass graft (CABG) patients and its associations with demographic variables. A clear understanding of the use of symptom management strategies following CABG surgery may help nurses in developing educational program and interventions that help patients and their families during recovery period after discharge. A cross-sectional, descriptive design was utilized. A convenience sample of 100 Jordanian patients post CABG surgery selected from five hospitals was surveyed between November 2012 and June 2013 using the Cardiac Symptom Survey. Chi squared analyses were used to examine the associations between the symptoms management strategies and selected demographic variables. Frequency of symptom management strategies utilized by post CABG patients revealed that most frequently employed strategies were use of medications (79%), repositioning (54%) and the rest (45%). Symptom management strategies utilized for poor appetite, sleeping problem and fatigue had significant associations with demographic variables. By providing information about the symptoms expected after surgery and possible ways to manage them, will strengthen the patients psychologically and will make CABG experience within the realm of self-management and coping. PMID- 27241591 TI - A ratiometric fluorescence nanosensor for highly selective and sensitive detection of selenite. AB - The instant and on-site detection of selenium still remains a challenge for environmental monitoring and medical prevention. We herein developed a ratiometric fluorescent nanosensor for accurate and on-site sensing of SeO3(2-) by linking the recognition molecule 3,3'-diaminobenzidine (DAB) onto the surface of carboxyl group modified CdTe@SiO2. The fluorescence of DAB on the surface of silica nanospheres could be selectively and efficiently enhanced by SeO3(2-) through a surface chelating reaction between DAB and SeO3(2-). Thus, in the presence of SeO3(2-), the nanosensor would show two characteristic fluorescence emissions of Se-DAB and CdTe QDs under a single excitation wavelength. The selectivity and the optimal conditions for the detection of SeO3(2-) were carefully investigated. The ratio of F530/F635 linearly increased with increasing SeO3(2-) concentration in the range of 0 to 2.5 MUM and the detection limit reaches as low as 6.68 nM (0.53 ppb). This developed nanosensor has the capability of on-site detection in an aqueous system without any separation step. The Se concentrations in selenium-rich food were detected and the results were consistent with the values determined by ICP-AES. PMID- 27241590 TI - Elastase levels and activity are increased in dystrophic muscle and impair myoblast cell survival, proliferation and differentiation. AB - In Duchenne muscular dystrophy, progressive loss of muscle tissue is accompanied by fibrosis, chronic inflammation and reduced muscle regenerative capacity. Although much is known about the development of fibrosis and chronic inflammation in muscular dystrophy, less is known about how they are mechanistically linked to loss of muscle regenerative capacity. We have developed a proteomics method to discover dystrophy-associated changes in the muscle progenitor cell niche, which identified serine proteases, and especially neutrophil elastase, as candidates. We show that elastase activity is increased in dystrophic (mdx(4cv)) muscle and impairs myoblast survival in culture. While the effect of elastase on C2C12 cell survival correlates with the kinetics of elastase-mediated degradation of the substrate to which the cells adhere, the effect of elastase on satellite cell derived primary myoblast growth and differentiation is substrate-independent and even more dramatic than the effect on C2C12 cells, suggesting a detrimental role for elastase on myogenesis in vivo. Additionally, elastase impairs differentiation of both primary and C2C12 myoblasts into myotubes. Our findings evidence the importance of neutrophil-mediated inflammation in muscular dystrophy and indicate elastase-mediated regulation of myoblast behaviour as a potential mechanism underlying loss of regenerative capacity in dystrophic muscle. PMID- 27241592 TI - Effect of filtration rate on coal-sand dual-media filter performances for microalgae removal. AB - This study tested the efficiency of granular filtration using a bilayer sand filter for microalgae removal from culture dilutions ranging from 10,000 to 17,000 cells/mL. The objective is to evaluate the removal capacity of the filter without chemical coagulation. Two filter media, sand and anthracite, with mean grain sizes of 0.395 and 1.2 mm, respectively, were used in constant-flow-rate experiments (down-flow mode) with suspensions containing Heterocapsa triquetra microalga. The conventional rapid filtration which usually operates at a constant rate of approximately 5 m3/m2 h is compared to high-rate filtration. Two filtration velocities (5 and 10 m/h) were investigated with bed depth of 1100 mm. Average microalgal cell removal rates were 90% at 5 m/h and 68% at 10 m/h. Turbidity removal was more than 71% at 5 m/h but just 57% at 10 m/h. Head losses did not increase significantly, and values measured at process end were 32 mbar at 5 m/h and 78 mbar at 10 m/h. Retention probabilities were calculated from experimental data. A theoretical model was used to evaluate the contributions of the different drivers of microalgae removal. Hypotheses are developed on the understanding of change in the mechanisms of retention as a function of filtration velocity. PMID- 27241593 TI - Outstanding Merit Award for 2015. PMID- 27241598 TI - Projected Savings and Workforce Transformation from Converting Independence at Home to a Medicare Benefit. AB - The Independence at Home (IAH) Demonstration Year 1 results have confirmed earlier studies that showed the ability of home-based primary care (HBPC) to improve care and lower costs for Medicare's frailest beneficiaries. The first year report showed IAH savings of 7.7% for all programs and 17% for the nine of 17 programs that surpassed the 5% mandatory savings threshold. Using these results as applied to the Medicare 5% claims file, the effect of expanding HBPC to the 2.2 million Medicare beneficiaries who are similar to IAH demonstration participants was projected. Total savings ranged from $12 billion to $53 billion depending on the speed and extent of dissemination of HBPC among this IAH-like population. Using a fixed growth rate, as hospitalists experienced in their first decade, 35% coverage would be achieved at the end of 10 years, with total 10-year savings through IAH reaching $37.5 billion and $17.3 billion accruing to the Centers for Medicare and Medicaid Services as a net reduction in overall expenditures, with $12.6 billion from Medicare Parts A and B savings. PMID- 27241599 TI - Non-traumatic hernia of the lateral abdominal wall in a patient infected with the human immunodeficiency virus. AB - Introduction There are several classifications for abdominal hernias, and a non traumatic lateral wall hernia (LAWH) is a rare type. We report the first case of a patient with LAWH infected with the human immunodeficiency virus (HIV). Case History A 53-year-old HIV-infected male presented with an abdominal mass. The patient had a history of treatment with combination antiretroviral therapy. A LAWH was diagnosed based on physical examination and findings of computed tomography. Open mesh repair was undertaken successfully. The patient had no evidence of a recurrent hernia during 11 months of follow-up. Conclusions High intra-abdominal pressure and weak connective tissue can lead to LAWHs. Antiretroviral therapy and lipodystrophy can cause LAWHs in HIV-infected patients. PMID- 27241600 TI - A novel and bespoke absorbable cement restrictor. PMID- 27241601 TI - Traumatic abdominal wall hernia with concealed colonic perforation. AB - Traumatic abdominal wall hernia (TAWH) is a rare clinical entity in terms of aetiology. It occurs following a blunt abdominal injury with energy high enough to cause disruption of the musculoaponeurotic layer but not the elastic skin layer. It is often associated with underlying intra-abdominal injuries, which can be diagnosed either clinically or radiologically. We report a case of TAWH in a young man with associated large bowel transection, which remained undiagnosed in the preoperative period owing to its masked features. He was managed surgically, with no recurrence to date. Considering the high volume of blunt abdominal trauma cases that present to the accident and emergency department, only few cases of TAWH have been reported in the literature. Confusion still exists regarding the timing and mode of management of this condition. PMID- 27241602 TI - Novel technique for tunnelling paediatric cuffed venous catheters. PMID- 27241603 TI - Recurrence after composite repair of a giant hiatus hernia: 'the golf club' deformity is a distinctive clinical and radiological picture. AB - Background Recurrence of a hiatus hernia after cardiopexy repair can obstruct the lower oesophagus but also provide characteristic radiographic images after a barium meal. Case History Two patients with recurrence of a hiatus hernia underwent repeat surgery. Here, we provide and discuss diagnostic imaging, surgical findings and outcome for these male and female patients. Conclusions Repeat surgery is indicated in patients with recurrence of a hiatus hernia after repair. PMID- 27241604 TI - An unusual case of lipoma arborescens. AB - Introduction Lipoma arborescens is a rare condition of the synovial lining. It is particularly uncommon in the bicipitoradial bursae of the elbow. Case Report A 68 year-old woman presented with a 5-month history of anterior elbow pain and swelling causing discomfort. Radiography demonstrated reactive changes of radial tuberosity and magnetic resonance imaging confirmed lipoma arborescens of the bicipitoradial bursa with distal biceps tendinopathy. A bicipital bursa bursectomy and lipoma excision was performed. Gross pathology and histology was consistent with lipoma arborescens. Three months postoperatively, our patient had full range of motion and good strength. Conclusions To our knowledge, this is the first published case report of lipoma arborescens affecting the elbow. Recognising the differential diagnoses of anterior elbow pain and the characteristic imaging is essential for accurate diagnosis. PMID- 27241605 TI - Implantation of the Cochlear Baha((r)) 4 Attract system through a linear incision. PMID- 27241606 TI - Necrotising fasciitis secondary to a colocutaneous fistula. AB - Colocutaneous fistulae secondary to diverticular disease are rare, especially spontaneous fistulae. We report a case of a 74-year-old lady, with no previous history of diverticular disease, presenting with necrotising fasciitis of the anterior abdominal wall in the left iliac fossa, without any other symptoms. Urgent surgery was performed. An initial diagnostic laparoscopy demonstrated a perforated sigmoid diverticulum forming a fistula to the anterior abdominal wall. Following soft tissue debridement, a sigmoid colectomy was performed through a midline laparotomy. Gastrointestinal pathology should be considered as a potential cause of abdominal wall necrotising fasciitis. Our approach of using laparoscopic visualisation to assess for intra-abdominal sources in this context (in the absence of preoperative imaging when imaging could delay treatment) has not been described before. To our knowledge, only two cases of abdominal wall necrotising fasciitis secondary to diverticular disease with a colocutaneous fistula have been reported in the English literature. PMID- 27241607 TI - Rare case of a liposarcoma in the brachial plexus. AB - Introduction A liposarcoma is a rare cancer of connective tissues that resemble fat cells under light microscopy. Case History A 73-year old female patient presented to our tertiary cancer centre with an eight-year history of a large, slow-growing painless mass in the right axilla. Magnetic resonance imaging showed a lipomatous, well-circumscribed mass of dimension 30 * 16 * 10cm extending towards the right clavicle and causing deformation to the right chest wall and right breast. Surgery revealed a large tumour that had stretched all three cords of the brachial plexus. Histopathology was consistent with a diagnosis of a low grade liposarcoma. After a period of neuropraxia, the patient returned to normal activities 4 months after surgery. Conclusions Although extremely rare, low-grade liposarcomas of the brachial plexus should be considered in the differential diagnosis of a slow-growing axillary mass. Referral to a tertiary sarcoma centre is essential for an appropriate diagnosis, adequate treatment, and long-term follow-up. PMID- 27241608 TI - Language translation without expense or delay. PMID- 27241609 TI - Colonic casts: unexpected complications of colonic ischaemia. AB - Introduction Extensive colonic ischaemia can result in passage of a colonic 'cast' (CC) through the rectum. Case Study We report a 69-year-old male who initially underwent surgery to remove a sessile polyp. On postoperative day (POD)15, he was febrile, suffering from diarrhoea, and was treated conservatively. On POD18, the patient returned to our hospital with a CC that presented after defaecation. Computed tomography of the abdomen revealed a CC extending from the descending colon to the anal orifice with presentation of air between the affected colonic wall and the CC. The patient was treated conservatively and discharged on POD20 without complications having passed the CC (~80cm) completely and becoming afebrile. Conclusions In most cases, the cause of CC passage is surgery for colorectal cancer or repair of an abdominal aortic aneurysm. A mild-to-severe presentation is dependent upon the bowel-wall layers affected by ischaemia and which therefore are included in the CC. PMID- 27241610 TI - Giant angiolipoma of the arm in an elderly patient. AB - Introduction Angiolipoma is a histological variant of lipoma and is the most common neoplasm in the trunk and extremities of young adults. It is extremely rare in elderly people, and its size is <=4cm. Few data are available for large angiolipomas. Case History An 86-year-old patient was admitted to our surgical department due to a large mass on his left arm, which was resected. The specimen measured 19.5 * 15 * 10.5cm. Histopathological examination revealed a benign non infiltrating angiolipoma. This is the first report of a giant angiolipoma of the arm reported in an octogenarian patient. Conclusions Giant lipomas of the upper extremities are extremely rare. Resection is associated with cure in most patients, but regular follow-up should be considered. PMID- 27241611 TI - Gallstone ileus in an 'asymptomatic' parastomal hernia. AB - Parastomal hernias are common and often asymptomatic. We report the first known case in which later, acute symptoms developed owing to gallstone ileus in a sac containing both omentum and small bowel. Urgent computed tomography established the diagnosis. PMID- 27241612 TI - A tip for rotation of the limb during ankle fixation. PMID- 27241613 TI - Trethowan retractor technique to aid supination of the wrist during distal radius fracture fixation. PMID- 27241614 TI - CIE-10 and the surgical protocol. PMID- 27241615 TI - Nanoparticle size and combined toxicity of TiO2 and DSLS (surfactant) contribute to lysosomal responses in digestive cells of mussels exposed to TiO2 nanoparticles. AB - The aim of this investigation was to understand the bioaccumulation, cell and tissue distribution and biological effects of disodium laureth sulfosuccinate (DSLS)-stabilised TiO2 nanoparticles (NPs) in marine mussels, Mytilus galloprovincialis. Mussels were exposed in vivo to 0.1, 1 and 10 mg Ti/L either as TiO2 NPs (60 and 180 nm) or bulk TiO2, as well as to DSLS alone. A significant Ti accumulation was observed in mussels exposed to TiO2 NPs, which were localised in endosomes, lysosomes and residual bodies of digestive cells, and in the lumen of digestive tubules, as demonstrated by ultrastructural observations and electron probe X-ray microanalysis. TiO2 NPs of 60 nm were internalised within digestive cell lysosomes to a higher extent than TiO2 NPs of 180 nm, as confirmed by the quantification of black silver deposits after autometallography. The latter were localised mainly forming large aggregates in the lumen of the gut. Consequently, lysosomal membrane stability (LMS) was significantly reduced upon exposure to both TiO2 NPs although more markedly after exposure to TiO2-60 NPs. Exposure to bulk TiO2 and to DSLS also affected the stability of the lysosomal membrane. Thus, effects on the lysosomal membrane depended on the nanoparticle size and on the combined biological effects of TiO2 and DSLS. PMID- 27241616 TI - Fire carbon emissions over maritime southeast Asia in 2015 largest since 1997. AB - In September and October 2015 widespread forest and peatland fires burned over large parts of maritime southeast Asia, most notably Indonesia, releasing large amounts of terrestrially-stored carbon into the atmosphere, primarily in the form of CO2, CO and CH4. With a mean emission rate of 11.3 Tg CO2 per day during Sept Oct 2015, emissions from these fires exceeded the fossil fuel CO2 release rate of the European Union (EU28) (8.9 Tg CO2 per day). Although seasonal fires are a frequent occurrence in the human modified landscapes found in Indonesia, the extent of the 2015 fires was greatly inflated by an extended drought period associated with a strong El Nino. We estimate carbon emissions from the 2015 fires to be the largest seen in maritime southeast Asia since those associated with the record breaking El Nino of 1997. Compared to that event, a much better constrained regional total carbon emission estimate can be made for the 2015 fires through the use of present-day satellite observations of the fire's radiative power output and atmospheric CO concentrations, processed using the modelling and assimilation framework of the Copernicus Atmosphere Monitoring Service (CAMS) and combined with unique in situ smoke measurements made on Kalimantan. PMID- 27241617 TI - The modality effect of ego depletion: Auditory task modality reduces ego depletion. AB - An initial act of self-control that impairs subsequent acts of self-control is called ego depletion. The ego depletion phenomenon has been observed consistently. The modality effect refers to the effect of the presentation modality on the processing of stimuli. The modality effect was also robustly found in a large body of research. However, no study to date has examined the modality effects of ego depletion. This issue was addressed in the current study. In Experiment 1, after all participants completed a handgrip task, one group's participants completed a visual attention regulation task and the other group's participants completed an auditory attention regulation task, and then all participants again completed a handgrip task. The ego depletion phenomenon was observed in both the visual and the auditory attention regulation task. Moreover, participants who completed the visual task performed worse on the handgrip task than participants who completed the auditory task, which indicated that there was high ego depletion in the visual task condition. In Experiment 2, participants completed an initial task that either did or did not deplete self-control resources, and then they completed a second visual or auditory attention control task. The results indicated that depleted participants performed better on the auditory attention control task than the visual attention control task. These findings suggest that altering task modality may reduce ego depletion. PMID- 27241618 TI - On the reproducibility of meta-analyses: six practical recommendations. AB - BACKGROUND: Meta-analyses play an important role in cumulative science by combining information across multiple studies and attempting to provide effect size estimates corrected for publication bias. Research on the reproducibility of meta-analyses reveals that errors are common, and the percentage of effect size calculations that cannot be reproduced is much higher than is desirable. Furthermore, the flexibility in inclusion criteria when performing a meta analysis, combined with the many conflicting conclusions drawn by meta-analyses of the same set of studies performed by different researchers, has led some people to doubt whether meta-analyses can provide objective conclusions. DISCUSSION: The present article highlights the need to improve the reproducibility of meta-analyses to facilitate the identification of errors, allow researchers to examine the impact of subjective choices such as inclusion criteria, and update the meta-analysis after several years. Reproducibility can be improved by applying standardized reporting guidelines and sharing all meta analytic data underlying the meta-analysis, including quotes from articles to specify how effect sizes were calculated. Pre-registration of the research protocol (which can be peer-reviewed using novel 'registered report' formats) can be used to distinguish a-priori analysis plans from data-driven choices, and reduce the amount of criticism after the results are known. The recommendations put forward in this article aim to improve the reproducibility of meta-analyses. In addition, they have the benefit of "future-proofing" meta-analyses by allowing the shared data to be re-analyzed as new theoretical viewpoints emerge or as novel statistical techniques are developed. Adoption of these practices will lead to increased credibility of meta-analytic conclusions, and facilitate cumulative scientific knowledge. PMID- 27241620 TI - Analysing intracellular deformation of polymer capsules using structured illumination microscopy. AB - Understanding the behaviour of therapeutic carriers is important in elucidating their mechanism of action and how they are processed inside cells. Herein we examine the intracellular deformation of layer-by-layer assembled polymer capsules using super-resolution structured illumination microscopy (SIM). Spherical- and cylindrical-shaped capsules were studied in three different cell lines, namely HeLa (human epithelial cell line), RAW264.7 (mouse macrophage cell line) and differentiated THP-1 (human monocyte-derived macrophage cell line). We observed that the deformation of capsules was dependent on cell line, but independent of capsule shape. This suggests that the mechanical forces, which induce capsule deformation during cell uptake, vary between cell lines, indicating that the capsules are exposed to higher mechanical forces in HeLa cells, followed by RAW264.7 and then differentiated THP-1 cells. Our study demonstrates the use of super-resolution SIM in analysing intracellular capsule deformation, offering important insights into the cellular processing of drug carriers in cells and providing fundamental knowledge of intracellular mechanobiology. Furthermore, this study may aid in the design of novel drug carriers that are sensitive to deformation for enhanced drug release properties. PMID- 27241619 TI - Clinical Management of Recurrent Retinopathy of Prematurity after Intravitreal Bevacizumab Monotherapy. AB - PURPOSE: To determine incidence, risk factors, risk period, and characteristics of recurrent retinopathy of prematurity (ROP) treated by intravitreal bevacizumab (IVB) monotherapy. DESIGN: Retrospective case series. PARTICIPANTS: Premature infants with type 1 ROP (subdivided into stage 3+ ROP and aggressive posterior ROP [APROP]) in zone I or zone II posterior who received IVB monotherapy and were followed up for at least 65 weeks adjusted age (AA). METHODS: Retrospective review of infants who demonstrated recurrence of type 1 ROP after IVB monotherapy, including examination of RetCam fundus photographs and fluorescein angiograms. MAIN OUTCOMES MEASURES: Incidence, risk factors, risk period, and characteristics of recurrent ROP. RESULTS: Intravitreal bevacizumab monotherapy in 241 infants (471 eyes) was reviewed. Recurrence incidence was 8.3% (20/241) for infants and 7.2% (34/471) for eyes. Recurrence risk factors of greatest significance were appearance of neovascularization as APROP (P = 0.006), extended duration of hospitalization (P = 0.01), and lower birth weight (P = 0.024). Recurrence risk period was between approximately 45 and 55 weeks AA (90.0% [18/20] for infants and 94.1% [32/34] for eyes), with mean recurrence of 51.2 weeks AA (+/-4.6 weeks; range, 45.7-64.9 weeks) and mean interval of 16.2 weeks (+/-4.4 weeks) between treatments. Recurrence characteristics included plus disease (20/20 infants [100%]) and neovascularization, which appeared at the following sites: stage 3+ ROP with confluent neovascularization recurred both at the advancing edge and at the initial ridge and extraretinal fibrovascular proliferative complex (12/14 infants [85.7%]). However, APROP (6/6 infants [100%]) and stage 3+ ROP with nonconfluent neovascularization (2/14 infants [14.3%]) recurred only at the advancing edge. Also, the anterior extent of retinal vascularization was decreased (mean, 1.76 disc diameters [DD] vs. 4.48 DD), and the rate of retinal vascularization was delayed (mean, 0.11 DD/week vs. 0.23 DD/week) in those with versus without recurrence, respectively. After retreatment with IVB, retinal vascularization proceeded minimally and slowly. CONCLUSIONS: Premature children with severe ROP are being treated successfully with IVB monotherapy. However, recurrence is not uncommon, so vigilant follow-up is necessary to ensure timely re-treatment. Knowledge of recurrence incidence, risk factors, risk period, and characteristics allows for tailored clinical management. PMID- 27241621 TI - The nature of excited states in dipolar donor/fullerene complexes for organic solar cells: evolution with the donor stack size. AB - Electronic delocalization at donor/acceptor (D/A) interfaces can play an important role in photocurrent generation for organic solar cells. Here, we have investigated the nature of local excited and interfacial charge transfer (CT) states in model complexes including one to four anti-parallel stacking dipolar donor (DTDCTB) molecules and one fullerene (C60) molecule by means of density functional theory (DFT) and time-dependent DFT (TDDFT). For all the donor-to acceptor CT states, despite the number of DTDCTB molecules in the complexes, the hole is mainly localized on a single DTDCTB, and moves farther away from C60 for the energy higher level. However, the highest occupied molecular orbitals (HOMOs) and the excitonic states (EX) including the bright and dark EX are delocalized over the whole donor stacks in the complexes. This implies that the formation of ordered DTDCTB arrangements can substantially shorten the exciton diffusion process and facilitate ultrafast charge generation. Interestingly, owing to strong intermolecular Coulomb attraction, the donor-to-donor CT states are situated below the local excited states, but can approach the donor-to-acceptor CT states, indicating a weak role as charge traps. Our work would be helpful for understanding the electronic delocalization effects in organic solar cells. PMID- 27241622 TI - Variation in cash price of the generic medications most prescribed by dermatologists in pharmacies across the United States. AB - BACKGROUND: The United States has the highest drug costs in the world. Consumers complain about large price differences at pharmacies on generic drugs. OBJECTIVE: To evaluate variation in cash prices of generic medications most prescribed in dermatology across different drugstores and states in United States. METHOD: The 11 generic drugs most prescribed by dermatologists according to National Ambulatory Medical Care Survey were assessed. By using Google, the most common used pharmacies in United States were listed, which are located at a random selection of six states. By calling the first available number of each pharmacy in the six states and asking about the generic cash price of the smallest stock size and the most prescribed type, the data were collected. RESULTS: Drug prices varied; the median cumulative price of the 11 medications was highest at Rite Aid ($1226) and lowest at Walmart ($795.34) with 35% difference. The prices at CVS differed by 20% across different states; however, the prices at Walmart, Rite Aid and Walgreens were consistent. New York has the highest and Iowa the lowest prices, especially at CVS, ($1160.79) versus ($931.32). CONCLUSION: There are varieties in the prices for the generic medications in different pharmacies and States. PMID- 27241623 TI - Eugenia dysenterica DC. (Myrtaceae) exerts chemopreventive effects against hexavalent chromium-induced damage in vitro and in vivo. AB - CONTEXT: Eugenia dysenterica DC. (Myrtaceae) has been widely used in the folk medicine and it presents phytochemicals constituents associated to antioxidant properties. OBJECTIVE: The objective of this study was to investigate the protective effects of E. dysenterica leaf hydroalcoholic extract (EDE) in vitro and in vivo using AMJ2-C11 cells and Swiss mice exposed to hexavalent chromium [Cr(VI)], respectively. MATERIALS AND METHODS: AMJ2-C11 cells were pretreated with EDE and exposed to Cr(VI) to evaluate cytotoxicity and the pathways involved in the chemopreventive effects of the extract. Mice were daily pretreated with EDE and then exposed to Cr(VI). Survival analysis, histopathological examination and determination of Cr levels in biological tissues were carried out. RESULTS: In vitro studies showed that pretreatment of the AMJ2-C11 cells with EDE protected against the cytotoxicity and oxidative stress induced by Cr(VI). Consequently, the pretreatment with EDE reduced reactive oxygen species and apoptosis triggered by Cr(VI), probably by a marked antioxidant and chelating activities demonstrated by EDE. Regarding in vivo studies, pretreatment for 10 days with EDE increased survival of the mice exposed to Cr(VI). In addition, EDE prevented liver and kidney pathological damages, in parallel with reduction in chromium levels found in these organs and plasma. EDE also showed a marked antioxidant potential associated with the presence of polyphenols, especially flavonoids and tannins, as confirmed by HPLC-PDA. CONCLUSION: The study showed that EDE protects against Cr(VI)-induced damage in vitro and in vivo supporting further studies for the development of therapeutic products applied to prevent the damage induced by toxic metals, especially Cr(VI). PMID- 27241624 TI - Dirac cone protected by non-symmorphic symmetry and three-dimensional Dirac line node in ZrSiS. AB - Materials harbouring exotic quasiparticles, such as massless Dirac and Weyl fermions, have garnered much attention from physics and material science communities due to their exceptional physical properties such as ultra-high mobility and extremely large magnetoresistances. Here, we show that the highly stable, non-toxic and earth-abundant material, ZrSiS, has an electronic band structure that hosts several Dirac cones that form a Fermi surface with a diamond shaped line of Dirac nodes. We also show that the square Si lattice in ZrSiS is an excellent template for realizing new types of two-dimensional Dirac cones recently predicted by Young and Kane. Finally, we find that the energy range of the linearly dispersed bands is as high as 2 eV above and below the Fermi level; much larger than of other known Dirac materials. This makes ZrSiS a very promising candidate to study Dirac electrons, as well as the properties of lines of Dirac nodes. PMID- 27241625 TI - Chromophore-labelled, luminescent platinum complexes: syntheses, structures, and spectroscopic properties. AB - Ligands based upon 4-carboxamide-2-phenylquinoline derivatives have been synthesised with solubilising octyl hydrocarbon chains and tethered aromatic chromophores to give naphthyl (), anthracenyl () and pyrenyl () ligand variants, together with a non-chromophoric analogue () for comparison. (1)H NMR spectroscopic studies of the ligands showed that two non-interchangeable isomers exist for and while only one isomer exists for and . Supporting DFT calculations on suggest that the two isomers may be closely isoenergetic with a relatively high barrier to exchange of ca. 100 kJ mol(-1). These new ligands were cyclometalated with Pt(ii) to give complexes [Pt()(acac)] (acac = acetylacetonate). The spectroscopically characterised complexes were studied using multinuclear NMR spectroscopy including (195)Pt{(1)H} NMR studies which revealed deltaPtca. -2785 ppm for [Pt()(acac)]. X-ray crystallographic studies were undertaken on [Pt()(acac)] and [Pt()(acac)], each showing the weakly distorted square planar geometry at Pt(ii); the structure of [Pt()(acac)] showed evidence for intermolecular Pt-Pt interactions. The UV-vis. absorption studies show that the spectral profiles for [Pt()(acac)] are a composite of the organic chromophore centred bands and a broad (1)MLCT (5d -> pi*) band (ca. 440 nm) associated with the complex. Luminescence studies showed that complexes [Pt()(acac)] are dual emissive with fluorescence characteristic of the tethered fluorophore and long-lived phosphorescence attributed to (3)MLCT emission. In the case of the pyrenyl derivative, [Pt()(acac)], the close energetic matching of the (3)MLCT and (3)LCpyr excited states led to an elongation of the (3)MLCT emission lifetime (tau = 42 MUs) under degassed solvent conditions, suggestive of energy transfer processes between the two states. PMID- 27241626 TI - Effect of the starting and turning performances on the subsequent swimming parameters of elite swimmers. AB - In the present research, we examined the effect of the starting and turning performances on the subsequent swimming parameters by (1) comparing the starting and turning velocities with the swimming parameters on the emersion and mid-pool segments and (2) by relating the individual behaviour of swimmers during the start and turns with subsequent behaviour on each swimming lap. One hundred and twelve 100 m performances on the FINA 2013 World Swimming Championships were analysed by an image-processing system (InThePool 2.0(r)). At the point of the start emersion, the swimming parameters of the 100-m elite swimmers were substantially greater than the mid-pool parameters, except on the breaststroke races. On the other hand, no diminution in the swimming parameters was observed between the turn emersion and the mid-pool swimming, except on the butterfly and backstroke male races. Changes on the surface swimming kinematics were not generally related to the starting or turning parameters, although male swimmers who develop faster starts seem to achieve faster velocities at emersion. Race analysts should be aware of a transfer of momentum when swimmers emerge from underwater with implications on the subsequent swimming kinematics, especially for male swimmers who employ underwater undulatory techniques. PMID- 27241627 TI - Spectroscopic observation of nitrogen anions N(-) in solid matrices. AB - Analysis of old and recent experiments on thermoluminescence of cryocrystals and nanoclusters of N2, Ne, Ar, and Kr containing stabilized nitrogen atoms, suggests that the so-called gamma-line may correspond to the bound-bound transition (1)D (3)P of nitrogen anions N(-) formed in solids by the association of delocalized electrons and metastable nitrogen atoms N((2)D). The recent observations of the gamma-line were accompanied by simultaneous luminescence of metastable nitrogen N((2)D) atoms and exoelectron emission. The fine structure of the gamma-line at 793 nm has been experimentally observed and investigated for the first time. PMID- 27241628 TI - Corrigendum: The Inhibition of the Rayleigh-Taylor Instability by Rotation. PMID- 27241630 TI - A MOF-derived Co-CoO@N-doped porous carbon for efficient tandem catalysis: dehydrogenation of ammonia borane and hydrogenation of nitro compounds. AB - The one-step pyrolysis of a zeolite-type metal-organic framework, Co(2 methylimidazole)2 (ZIF-67), produces an N-doped porous carbon incorporating well dispersed Co/CoO nanoparticles, which exhibit excellent catalytic activity, chemoselectivity and magnetic recyclability for the tandem dehydrogenation of ammonia borane and hydrogenation of nitro compounds at room temperature. PMID- 27241629 TI - Phylogeographic and population genetic analyses reveal multiple species of Boa and independent origins of insular dwarfism. AB - Boa is a Neotropical genus of snakes historically recognized as monotypic despite its expansive distribution. The distinct morphological traits and color patterns exhibited by these snakes, together with the wide diversity of ecosystems they inhabit, collectively suggest that the genus may represent multiple species. Morphological variation within Boa also includes instances of dwarfism observed in multiple offshore island populations. Despite this substantial diversity, the systematics of the genus Boa has received little attention until very recently. In this study we examined the genetic structure and phylogenetic relationships of Boa populations using mitochondrial sequences and genome-wide SNP data obtained from RADseq. We analyzed these data at multiple geographic scales using a combination of phylogenetic inference (including coalescent-based species delimitation) and population genetic analyses. We identified extensive population structure across the range of the genus Boa and multiple lines of evidence for three widely-distributed clades roughly corresponding with the three primary land masses of the Western Hemisphere. We also find both mitochondrial and nuclear support for independent origins and parallel evolution of dwarfism on offshore island clusters in Belize and Cayos Cochinos Menor, Honduras. PMID- 27241631 TI - l-Carnitine improves cognitive and renal functions in a rat model of chronic kidney disease. AB - Over the past decade, the prevalence of chronic kidney disease (CKD) has reached epidemic proportions. The search for novel pharmacological treatment for CKD has become an area of intensive clinical research. l-Carnitine, considered as the "gatekeeper" responsible for admitting long chain fatty acids into cell mitochondria. l-Carnitine synthesis and turnover are regulated mainly by the kidney and its levels inversely correlate with serum creatinine of normal subjects and CKD patients. Previous studies showed that l-carnitine administration to elderly people is improving and preserving cognitive function. As yet, there are no clinical intervention studies that investigated the effect of l-carnitine administration on cognitive impairment evidenced in CKD patients. Thus, we aimed to investigate the effects of l-carnitine treatment on renal function and on the cognitive performance in a rat model of progressive CKD. To assess the role of l-carnitine on CKD condition, we estimated the renal function and cognitive abilities in a CKD rat model. We found that all CKD animals exhibited renal function deterioration, as indicated by elevated serum creatinine, BUN, and ample histopathological abnormalities. l-Carnitine treatment of CKD rats significantly reduced serum creatinine and BUN, attenuated renal hypertrophy and decreased renal tissue damage. In addition, in the two way shuttle avoidance learning, CKD animals showed cognitive impairment which recovered by the administration of l-carnitine. We conclude that in a rat model of CKD, l-carnitine administration significantly improved cognitive and renal functions. PMID- 27241632 TI - Gender features and estrous cycle variations of nocturnal behavior of mice after a single exposure to light at night. AB - Light at night alters behavior and cognitive performances in rodents, the variations of which in gender and stages of reproductive cycle in females are elusive. Young mice habituated in light:dark (12:12h) cycle were given a single exposure of light (100lx) at early night for one hour duration followed by experimentations in open field (closed wall with circular big arena), elevated plus maze and square habituated field for memory performance using novel object recognition task. Light effects were compared with results found during without light conditions. Proestrous females appeared to have greater locomotor activity, less anxiety and better memory performance compared to the diestrous females at night without light exposure. The status of locomotor activity, anxiety and memory performance of male mice at night without light exposure appeared to be comparable to females where the stage of estrous cycle is important to characterize the nocturnal behavior of male mice. Light maximally affected proestrous females with decrease in locomotor activity, increase in anxiety and failure of memory performance. Male and diestrous female mice performed memory performance without alteration of locomotor activity and anxiety after exposure to light where males performed better memory performance with greater locomotor activity and more anxiety compared to that of diestrous females. The present study characterizes the mice nocturnal behavior with and without a single exposure to light stimuli with its gender features and estrous cycle variation. In addition, the study indicates an association of memory performance with locomotor activity and anxiety in mice nocturnal behavior. PMID- 27241633 TI - Physical activity counteracts the influence of mental work on blood pressure in healthy children. PMID- 27241634 TI - Structural propensities of kinase family proteins from a Potts model of residue co-variation. AB - Understanding the conformational propensities of proteins is key to solving many problems in structural biology and biophysics. The co-variation of pairs of mutations contained in multiple sequence alignments of protein families can be used to build a Potts Hamiltonian model of the sequence patterns which accurately predicts structural contacts. This observation paves the way to develop deeper connections between evolutionary fitness landscapes of entire protein families and the corresponding free energy landscapes which determine the conformational propensities of individual proteins. Using statistical energies determined from the Potts model and an alignment of 2896 PDB structures, we predict the propensity for particular kinase family proteins to assume a "DFG-out" conformation implicated in the susceptibility of some kinases to type-II inhibitors, and validate the predictions by comparison with the observed structural propensities of the corresponding proteins and experimental binding affinity data. We decompose the statistical energies to investigate which interactions contribute the most to the conformational preference for particular sequences and the corresponding proteins. We find that interactions involving the activation loop and the C-helix and HRD motif are primarily responsible for stabilizing the DFG-in state. This work illustrates how structural free energy landscapes and fitness landscapes of proteins can be used in an integrated way, and in the context of kinase family proteins, can potentially impact therapeutic design strategies. PMID- 27241635 TI - Unite all the services against childhood tuberculosis. PMID- 27241636 TI - Challenges in the use of intraosseous access. PMID- 27241637 TI - Is fat mass & obesity-associated (FTO) gene master regulator of obesity ? PMID- 27241638 TI - Stem cells to replace or regenerate the diabetic pancreas: Huge potential & existing hurdles. AB - Various stem cell sources are being explored to treat diabetes since the proof-of concept for cell therapy was laid down by transplanting cadaveric islets as a part of Edmonton protocol in 2000. Human embryonic stem (hES) cells derived pancreatic progenitors have got US-FDA approval to be used in clinical trials to treat type 1 diabetes mellitus (T1DM). However, these progenitors more closely resemble their foetal counterparts and thus whether they will provide long-term regeneration of adult human pancreas remains to be demonstrated. In addition to lifestyle changes and administration of insulin sensitizers, regeneration of islets from endogenous pancreatic stem cells may benefit T2DM patients. The true identity of pancreatic stem cells, whether these exist or not, whether regeneration involves reduplication of existing islets or ductal epithelial cells transdifferentiate, remains a highly controversial area. We have recently demonstrated that a novel population of very small embryonic-like stem cells (VSELs) is involved during regeneration of adult mouse pancreas after partial pancreatectomy. VSELs (pluripotent stem cells in adult organs) should be appreciated as an alternative for regenerative medicine as these are autologous (thus immune rejection issues do not exist) with no associated risk of teratoma formation. T2DM is a result of VSELs dysfunction with age and uncontrolled proliferation of VSELs possibly results in pancreatic cancer. Extensive brainstorming and financial support are required to exploit the potential of endogenous VSELs to regenerate the pancreas in a patient with diabetes. PMID- 27241639 TI - Feasibility study of a novel intraosseous device in adult human cadavers. AB - BACKGROUND & OBJECTIVES: Intraosseous (IO) access is an alternative to difficult intravenous (iv) access during emergency clinical situations. Existing IO solutions are expensive, require power supply and trained manpower; limiting their use in resource constrained settings. To address these limitations, a novel IO device has been developed. The objectives of this study were to evaluate functionality and safety of this device in adult human cadavers. METHODS: The ability of the IO device to penetrate the proximal and/or distal tibia was evaluated in three adult cadavers. Subjective parameters of loss of resistance, stable needle hold, easy needle withdrawal and any damage to the device were evaluated during the study. The insertion time was the objective parameter measured. Four sets of radiographs per insertion confirmed the position of the needle and identified complications. RESULTS: A single physician performed 12 IO access procedures using the same device. Penetration of proximal and/or distal tibia was achieved in all instances. It was successful in the first attempt in eight (66.7%) and during second attempt in the remaining. The mean time to insertion was 4.1 +/- 3.1 sec. Appropriate insertion of needle in the intra medullary space of bone was confirmed with radiological examination in 10 (83.3%) insertions. In two occasions after penetrating the cortical layer of bone, the device overshot the intra-medullary space, as detected by radiological examination. Device got bent during insertion in one instance. There was no evidence of needle breakage or bone fracture. The needle could be withdrawn effortlessly in all instances. INTERPRETATION & CONCLUSIONS: The novel IO device could successfully penetrate the adult cadaver bones in most cases. Further studies are needed to confirm these results on a large sample. PMID- 27241640 TI - Association between rs9930506 polymorphism of the fat mass & obesity-associated (FTO) gene & onset of obesity in Polish adults. AB - BACKGROUND & OBJECTIVES: The fat mass and obesity-associated (FTO) gene is known to be associated with obesity. However, no data are available on the relation between FTO rs9930506 polymorphism and obesity in Polish population. The aim of this study was to evaluate an association between rs9930506 variants of the FTO gene and obesity in Polish adults. METHODS: The study group consisted of 442 adults, aged 33.9 +/-12.7 yr, with mean BMI 27.2 +/- 5.4 kg/m2. The following variables were determined for each subject: fasting blood glucose, total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides. Real-time PCR was used to detect the A/G alleles of the rs9939506 polymorphism in the FTO gene. An association between the rs9930506 polymorphism and obesity was determined using codominant, dominant, and recessive models. The odds ratio (OR) was calculated to determine the risk of obesity associated with this polymorphism. RESULTS: It was observed that the presence of FTO rs9939506 G allele was associated with increased risk for obesity and this association was found significant in both recessive (OR = 1.72, P = 0.014) and co-dominant (OR = 1.36, P = 0.031) models of inheritance. The FTO rs9939506 GG homozygotes had a significantly higher BMI than those with other genotypes. INTERPRETATION & CONCLUSIONS: This study shows that FTO rs9939506 GG genotype is related to higher BMI and is associated with obesity in Polish adults. PMID- 27241641 TI - Serum levels of phosphorylated heat shock protein 27 (pHSP27) are associated with bone mineral density in pre- & postmenopausal women: A pilot study. AB - BACKGROUND & OBJECTIVES: Phosphorylated heat shock protein 27 (pHSP27) has been implicated in the pathogenesis of osteoporosis. oxidative stress and proinflammatory cytokines, which are known to be involved in aetiology of osteoporosis, can trigger HSP27 phosphorylation. Since pHSP27 is present in circulation, it was hypothesized that serum pHSP27 would be elevated in low bone mineral density (BMD) condition and might serve as an indicator of osteoporosis/osteopenia. Hence, the aim of this study was to examine serum levels of pHSP27 in relation with BMD in pre- and postmenopausal women. METHODS: Premenopausal (30 to 40 yr) and postmenopausal (50 to 60 yr) women having either low BMD (osteopenia/osteoporosis) or high BMD were selected (n=80) from a prospective cohort (n=200). Serum levels of pHSP27; along with levels of oestradiol, malondialdehyde, total antioxidant capacity, interleukin (IL)-1, IL 6, tumour necrosis factor - alpha, (TNF-alpha), c-telopeptide fragments of collagen type I (CTX-1) and osteocalcin were estimated. RESULTS: The serum levels of pHSP27 were significantly elevated in low BMD groups in premenopausal and postmenopausal categories (p<0.05). It also exhibited a significant odds ratio (OR) to differentiate between low and high BMD in both premenopausal (OR=1.734, p=0.013) and postmenopausal (OR=1.463, p=0.042) categories. Additionally, area under the curve to predict low BMD was non-significantly higher for pHSP27 than CTX-1 in premenopausal and postmenopausal categories. INTERPRETATION & CONCLUSIONS: This study highlights a novel relation between serum pHSP27 and BMD in Indian women however, these findings need to be confirmed in larger studies. PMID- 27241642 TI - Spared nerve injury model to study orofacial pain. AB - BACKGROUND & OBJECTIVES: There are many difficulties in generating and testing orofacial pain in animal models. Thus, only a few and limited models that mimic the human condition are available. The aim of the present research was to develop a new model of trigeminal pain by using a spared nerve injury (SNI) surgical approach in the rat face (SNI-face). METHODS: Under anaesthesia, a small incision was made in the infraorbital region of adult male Wistar rats. Three of the main infraorbital nerve branches were tightly ligated and a 2 mm segment distal to the ligation was resected. Control rats were sham-operated by exposing the nerves. Chemical hyperalgesia was evaluated 15 days after the surgery by analyzing the time spent in face grooming activity and the number of head withdrawals in response to the orofacial formalin test. RESULTS: SNI-face rats presented a significant increase of the formalin-induced pain-related behaviours evaluated both in the acute and tonic phases (expected biphasic pattern), in comparison to sham controls. INTERPRETATION & CONCLUSIONS: The SNI-face model in the rat appears to be a valid approach to evaluate experimental trigeminal pain. Ongoing studies will test the usefulness of this model to evaluate therapeutic strategies for the treatment of orofacial pain. PMID- 27241643 TI - Extracellular matrix protein 1 gene (ECM1) mutations in nine Iranian families with lipoid proteinosis. AB - BACKGROUND & OBJECTIVES: Lipoid proteinosis (LP) is an autosomal recessive disease. Clinical characteristics of this disease are hoarse voice, scarring of the skin, brain calcifications, and eyelid papules (moniliform blepharosis). Mutations in the ECM1 gene on 1q21.2 are responsible for this disease. This study was conducted to investigate the mutation spectrum of ECM1 gene in nine Iranian families having at least one LP patient diagnosed clinically. METHODS: The entire ECM1 gene was screened using PCR and direct sequencing in nine Iranian families with 12 suspected LP patients who were referred to the clinic, along with their parents and siblings. Thirty healthy individuals were included as controls. RESULTS: In only one patient a homozygous G>A transition at nucleotide c.806 in exon 7 was detected. A G>A substitution at nucleotide 1243 in exon 8 that changes glycine (GGT) to serine (AGT) was observed in most of our patients. Furthermore, in one patient there was a change in the sequence of intron 8, the A>T transition in nucleotide 4307. In addition, in two cases (one patient and one healthy mother with affected child) there was a C (4249) deletion in intron 8. INTERPRETATION & CONCLUSIONS: Our results indicate that although mutation in ECM1gene is responsible for lipoid proteinosis, it is likely that this is not the only gene causing this disease and probably other genes may be involved in the pathogenesis of the LP disease. PMID- 27241644 TI - Evaluation of epidermal growth factor receptor mutations based on mutation specific immunohistochemistry in non-small cell lung cancer: A preliminary study. AB - BACKGROUND & OBJECTIVES: Studies have shown that immunohistochemical (IHC) staining using epidermal growth factor receptor (EGFR) mutation specific antibodies, is an easy and cost-effective, screening method compared with molecular techniques. The purpose of present study was to assess the percentage positivity of IHC using EGFR mutation specific antibodies in lung biopsy samples from patients with primary lung adenocarcinoma (ADC). METHODS: Two hundred and six biopsies of primary lung ADC were subjected to EGFR mutation specific antibodies against del E746-A750 and L858R. Detection of EGFR mutation done by high resolution melting analysis (HRM) was used as gold standard. A concordance was established between molecular and IHC results. Frequency of IHC positivity was assessed. RESULTS: Of the 206 patients, 129 were male and 77 were female patients, with a mean age of 54.1 yr. Fifty five (26.6%) patients (36 men; 19 women) showed positivity for IHC of del E746-A750 (33) and L858R (22). HRM results were available in 14 patients which showed EGFR mutations in correspondence with del E746-750 or L858R in 64.2 per cent cases. Positive cases on HRM were further confirmed by DNA sequencing and fragment analysis. Three patients showed exon[20] variation. Two cases were negative for mutation. The genotype of del E746-750 mutation was more common than L858R. A concordance was established between molecular mutation and IHC in 85.7 per cent cases. INTERPRETATION & CONCLUSIONS: In this preliminary study from India mutation specific IHC was used for assessment of mutation status of EGFR. Although the number tested was small, a good concordance was observed between molecular EGFR mutation and IHC expression. IHC methodology is a potentially useful tool to guide clinicians for personalized treatment in lung ADC, especially where facilities for molecular analysis are not readily available and for use in small biopsies where material is scant for molecular tests. PMID- 27241645 TI - Prevalence of alpha-thalassaemia genotypes in pregnant women in northern Thailand. AB - BACKGROUND & OBJECTIVES: Alpha-thalassaemias are genetic disorders with high prevalence in northern Thailand. However, common genotypes and current data on the prevalence of alpha-thalassaemias have not been reported in this region. Therefore, the objective of the present study was to determine the prevalence of alpha-thalassaemia genotypes in pregnant women in northern Thailand. METHODS: Genomic DNA was extracted from blood samples of pregnant women who came to Maharaj Nakorn Chiang Mai University Hospital during July 2009 to 2010. The common deletion and point mutation genotypes of alpha-thalassaemia were evaluated by gap- polymerase chain reaction (PCR) and PCR with restriction fragment length polymorphism (RFLP). RESULTS: Genotypes of 638 pregnant women were: 409 samples (64.11%) being normal subjects (alphaalpha/alphaalpha) and 229 samples (35.89%) with alpha-thalassaemias. these 229 samples could be classified into deletional HbH disease (--SEA/-alpha3.7) for 18 samples (2.82%); heterozygous alpha0 thalassaemia --SEA type (--SEA/alphaalpha)) for 78 (12.23%); heterozygous alpha+ thalassaemia - alpha3.7 type (-alpha3.7/alphaalpha) for 99 (15.52%); homozygous alpha+-thalassaemia - alpha3.7 type (-alpha3.7/- alpha3.7) for five (0.78%); heterozygous alpha+-thalassaemia - alpha4.2 type (-alpha4.2/alphaalpha) for two (0.31%); and heterozygous HbCS (alphaCSalpha/alphaalpha) for 27 (4.23%) cases. INTERPRETATION & CONCLUSIONS: The prevalence of alpha-thalassaemias in pregnant women in northern Thailand was high. This finding supports the implementation of the prevention and control of this common genetic disorder by screening for alpha thalassaemia genotypes. PMID- 27241646 TI - Comparison of body composition in persons with epilepsy on conventional & new antiepileptic drugs. AB - BACKGROUND & OBJECTIVES: Certain antiepileptic drugs (AEDs) such as valproic acid (VPA) are known to affect body weight, and lipid profile. However, evidences regarding effects of AEDs on the body composition are deficient. This cross sectional study compared the body composition and lipid profile among patients with epilepsy on newer and conventional AEDs. METHODS: The patients with epilepsy (n=109) on treatment with conventional and newer AEDs (levetiracetam, lamotrigine and clobazam) for > 6 months were enrolled. Of these, 70 were on monotherapy: levetiracetam (n=12), VPA (n=16), carbamazepine (n=20) and phenytoin (n=22) and the remaining on polytherapy. Their body composition [body fat mass, lean dry mass (LDM), total body water (TBW), intracellular water (ICW), extracellular water (ECW) and basal metabolic rate (BMR) was estimated and biochemical parameters were assessed. RESULTS: Levetiracetam group had no significant difference with VPA, carbamazepine, phenytoin and control groups, except low LDM (17.8+/-2.4) than VPA groups (20.2+/-2.7, p<0.05). In comparison with control, AEDs monotherapy groups had no significant difference, except higher LDM and ECW in VPA group. Among groups based on conventional and newer AEDs, there was no significant difference in body composition parameters except for higher LDM (as % of BW) in conventional AEDs only treated group than control (p<0.01). INTERPRETATION & CONCLUSIONS: The alterations observed in body composition with valproic acid in contrast to other AEDs like levetiracetam, carbamazepine and phenytoin could affect treatment response in epilepsy especially in subjects with already altered body composition status like obese and thin frail patients, which needs to be established by prospective studies (CTRI/2013/05/003701). PMID- 27241647 TI - Demographic profile, host, disease & viral predictive factors of response in patients with chronic hepatitis C virus infection at a tertiary care hospital in north India. AB - BACKGROUND & OBJECTIVES: Standard of care for chronic hepatitis C (CHC) in India is peginterferon and ribavirin (RBV). The response to treatment in real life stetting is unclear. The objectives of this study were to evaluate the demographic profile and assess the virological response and predictors of response in CHC patients. METHODS: Consecutive patients with CHC were included in this study. Detailed clinical history, risk factors, and predictive factors of response were noted. Patients were treated with peginterferon alpha2b (1.5 ug/kg/wk) and RBV (12 mg/kg/day) for 6 to 18 months based on response. RESULTS: A total of 211 patients were included in the analysis, mean age 40.6+/-12.3 yr, 144 (68%) were males and 71 (34%) had compensated cirrhosis. Commonest risk factor for acquiring CHC was previous transfusion and surgery (51%). Genotype 3 (72%) was most common followed by genotype 1 (23%). Overall sustained virologic response (SVR) was 64 per cent [95% CI 57.1%-70.4%]. The SVR was 66.5 per cent [95% CI 58.34-73.89%] for genotype 3 and 61.2 per cent [95% CI 46.23 to 74.80%] for genotype 1. Non-cirrhotics had better SVR rates compared to cirrhotics (76 vs 41%, p<0.001). On multivariate analysis, BMI >=23 kg/m2, HOMA-IR >=2, compliance (<=80%), and fibrosis >2 were predictors of low SVR. INTERPRETATION & CONCLUSIONS: Genotype 3 was the commonest HCV genotype. The commonest source of infection was previous transfusion and surgery. SVR rates for genotypes 3 were better than genotype 1 patients. Predictors of non-response were high BMI, insulin resistance, significant fibrosis and inadequate compliance. PMID- 27241648 TI - A study on pre-XDR & XDR tuberculosis & their prevalent genotypes in clinical isolates of Mycobacterium tuberculosis in north India. AB - BACKGROUND & OBJECTIVES: Pre-extensively drug resistant (pre-XDR) and extensively drug resistant tuberculosis (XDR-TB) have been areas of growing concern, and are posing threat to global efforts of TB control. The present study was planned to study the presence of pre-XDR and XDR Mycobacterium tuberculosis and their genotypes in clinical isolates obtained from previously treated cases of pulmonary TB. METHODS: A total of 219 isolates obtained from previously treated cases of pulmonary TB were subjected to first-line (streptomycin, isoniazid, rifampicin and ethambutol) and second-line (ofloxacin, kanamycin, capreomycin and amikacin) drug susceptibility testing on solid Lowenstein-Jensen medium by proportion method. Genotyping was done for pre-XDR and XDR-TB isolates using 12 loci Mycobacterial Interspersed Repetitive Units-Variable Number Tandem Repeats (MIRU-VNTR). RESULTS: Multi-drug resistance was observed in 39.7 per cent (87/219) isolates. pre-XDR and XDR M. tuberculosis isolates amongst 87 multi-drug resistant (MDR) TB isolates were 43 (49.4%) and 10 (11.4%), respectively. Two most dominant genotypes among pre-XDR and XDR M. tuberculosis isolates were Beijing and Delhi/CAS types. INTERPRETATION & CONCLUSIONS: Resistance to second line anti-tubercular drugs should be routinely assessed in areas endemic for TB. Similar genotype patterns were seen in pre-XDR and XDR-TB isolates. Beijing and Delhi/CAS were predominant genotypes. PMID- 27241649 TI - High burden of hepatitis C & HIV co-infection among people who inject drugs in Manipur, Northeast India. AB - BACKGROUND & OBJECTIVES: It is well documented that the Northeast state of Manipur in India has been dealing with the dual problems of injecting drug use and HIV for the last two decades, but the hepatitis C problem has not been so well characterized. The aim of this study was to assess the prevalence of hepatitis C virus (HCV) infection and HCV/HIV co-infection among people who inject drugs (PWID) in Manipur, and identify factors associated with infection. METHODS: Data were obtained from the Integrated Behavioural and Biological Assessment (2009-2010), a cross-sectional survey among 821 male PWID in two districts of Manipur (Churachandpur and Bishnupur). Information about drug use, sexual and injecting risk behaviours, and exposure to interventions was obtained, and biological specimens tested for HIV and HCV. Logistic regression analyses identified factors associated with HCV infection and HCV/HIV co-infection. RESULTS: HCV prevalence was 74 per cent (91% Churachandpur, 56% Bishnupur), and HCV/HIV co-infection was 29 per cent (38% Churachandpur, 21% Bishnupur). Among the 31 per cent of HIV positive PWID, 95 per cent were co-infected. HCV infection was associated with district, longer duration of injecting, injecting at least once daily, generally injecting with a used needle and syringe, and having had an HIV test. HCV/HIV co-infection was associated with district, older age, being employed, being widowed/divorced, longer duration of injecting, and feeling at risk of HIV infection. INTERPRETATION & CONCLUSIONS: The HCV/HIV co-infection among PWID in Manipur was very high, highlighting the urgent need for effective prevention, diagnosis and treatment. PMID- 27241650 TI - Emergence of vanA gene among vancomycin-resistant enterococci in a tertiary care hospital of North - East India. AB - BACKGROUND & OBJECTIVES: Vancomycin-resistant enterococci (VRE) have become one of the most challenging nosocomial pathogens with the rapid spread of the multi drug resistant strain with limited therapeutic options. It is a matter of concern due to its ability to transfer vancomycin resistant gene to other organisms. The present study was undertaken to determine the emergence of vancomycin-resistant enterococci and the vanA gene among the isolates in a tertiary care hospital of North-East India. METHODS: A total of 67 consecutive enterococcal isolates from different clinical samples were collected and identified by using the standard methods. Antibiogram was done by disk diffusion method and VRE was screened by the disk diffusion and vancomycin supplement agar dilution method. The minimum inhibitory concentration (MIC) value for vancomycin was determined by E-test. The VRE isolates were analyzed by PCR for vanA gene. RESULTS: A total of 54 (81%) Enterococcus faecalis and 13 (19%) E. faecium were detected among the clinical isolates and 16 (24%) were VRE. The VRE isolates were multidrug resistant and linezolid resistance was also found to be in three. MIC range to vancomycin was 16-32 ug/ml among the VRE. The vanA gene was found in nine of 16 VRE isolates. INTERPRETATION & CONCLUSIONS: Emergence of VRE and presence of vanA in a tertiary care hospital setting in North-East India indicate toward a need for implementing infection control policies and active surveillance. PMID- 27241651 TI - Methicillin resistance & inducible clindamycin resistance in Staphylococcus aureus. AB - BACKGROUND & OBJECTIVES: Methicillin resistant Staphylococcus aureus (MRSA) isolates with inducible clindamycin resistance (iCR) are resistant to erythromycin and sensitive to clindamycin on routine testing and inducible clindamycin resistance can only be identified by D-test. This study was aimed to detect methicillin resistance and iCR among S. aureus isolates, effectiveness of some commonly used antibiotics and correlation between methicillin resistance and iCR. METHODS: The present cross-sectional study included 46 S. aureus isolates subjected to Kirby-Bauer's disk diffusion method for antibiotic susceptibility testing (AST) to estimate MRSA and resistance to some commonly used antibiotics. D-test was employed to detect iCR. RESULTS: Eleven of the 46 (23.9%) isolates tested were MRSA. Overall, 19 (41.3%) isolates showed of iCR. Vancomycin and linezolid were found to be 100 per cent effective. A positive Karl-Pearson's coefficient of correlation (0.89) between methicillin resistance and iCR was obtained. INTERPRETATION & CONCLUSIONS: Detection of iCR is important for the use of clindamycin in MRSA infections. Methicillin resistance and iCR appear to be clinically unrelated. PMID- 27241652 TI - Staphylococcal Cassette Chromosome mec (SCCmec) typing of clinical isolates of coagulase-negative staphylocci (CoNS) from a tertiary care hospital in New Delhi, India. PMID- 27241653 TI - Methicillin resistant Staphylococcus aureus (MRSA) in Malwa region of Punjab (North-West India). PMID- 27241654 TI - Wiser to prevent childhood obesity. PMID- 27241655 TI - Authors' response. PMID- 27241656 TI - Prevalence of hypertension & prehypertension among school children. PMID- 27241657 TI - Authors' response. PMID- 27241658 TI - Turner like dysmorphia as presenting feature of Type-II Mayer-Rokitansky-Kuster Hauser syndrome. PMID- 27241659 TI - Plexiform neurofibromatosis type 1. PMID- 27241660 TI - Dr Vasanthapuram Kumaraswami (1950-2016). PMID- 27241661 TI - Volume changes with stereotactic body radiation therapy in early lung cancer: Time trends and outcomes. AB - INTRODUCTION: Tumour response during stereotactic body radiotherapy (SBRT) could be heterogeneous and the pattern of response may be used as an early predictor for outcome. METHODS: Twenty-two consecutive patients with early lung cancer (ELC), treated with SBRT, were evaluated retrospectively for their gross tumour volume (GTV) changes during radiation therapy (RT). Kilo-voltage computed tomography scans (KVCTs) were acquired before every fraction and GTV was contoured manually on a total of 152 datasets. Tumour volume changes were noted with every fraction. The overall survival (OS), locoregional recurrence free survival (LRFS) and distant metastasis free survival (DMFS) were computed using the Kaplan-Meier method and comparisons were made using log-rank test. RESULTS: Of the 22 patients, six had T1 tumours and 16 had T2 tumours. Median GTV was 40.6 cc (range 7.3-140.2 cc) on CT1 (KVCT at first fraction) and 33.3 cc (range 4.1 83.4 cc) on CTlast (KVCT at last fraction), suggesting a 17.9% median volume reduction at RT completion. Increase in tumour volume was noted in 18 (81.8%) patients at some point during RT. In the mid-treatment scan, 12 (54.5%) patients had higher tumour volumes than in CT1, however, only six (27.3%) patient's GTV remained larger compared to the baseline at the end of treatment. The median follow-up was 12.4 months. The OS, LRFS and DMFS rate at 12 and 18 months were 86.4%, 88.2%, 62% and 64.8%, 75.6% and 37.2% respectively. Tumours that regressed in volume by >17.9% (median volume reduction at RT completion) had significantly worse OS and LRFS compared to those that regressed <17.9% (P = 0.03 and 0.01 respectively). CONCLUSION: Gross tumour volume undergoes significant changes during SBRT. Early regression in tumour volume may be used as a predictor of poor LRFS and OS. PMID- 27241662 TI - Parents' Experiences and Wishes at End of Life in Children with Spinal Muscular Atrophy Types I and II. AB - OBJECTIVE: To explore experiences and wishes of bereaved parents concerning end of-life care for their child with severe spinal muscular atrophy. STUDY DESIGN: A follow-up survey was conducted in 2013 on parents of deceased Swedish children who were born between 2000 and 2010 and later diagnosed with spinal muscular atrophy type I or II (n = 48). The questions used in this study covered location of death (LoD), support from health care staff, and parents' wishes and concerns about their child's end-of-life care. RESULTS: One-half of those who had wishes about LoD (16/32) wanted their child to die at home, rather than at the hospital. All of those who wanted the child to die at the hospital had their wishes fulfilled. Among those who wanted the child to die at home, 10 of 16 got their wish. Among parents who talked with a physician about how they wanted their child to pass away (n = 26), all but 2 had their wishes fulfilled. Thirty-six parents (75%) reported that their child had siblings: 12 reported that the sibling was too young for professional psychological support, and only 4 of the remaining 24 siblings received such support after the death of their brother or sister. CONCLUSIONS: Parents' communication with the physician about their wishes and concerns regarding their child's end-of-life care and preferred LoD contributed to their wishes being fulfilled. The wish of hospital death was fulfilled more often than the wish of home deaths. A vast majority of siblings did not receive psychological support after death of their brother or sister. PMID- 27241663 TI - [Not Available]. PMID- 27241664 TI - Total synthesis of desoxycyclomarin C and the cyclomarazines A and B. AB - Removing the beta-hydroxy group from the prenylated tryptophan moiety of cyclomarins simplifies the synthesis of these interesting natural products significantly, without having a noteworthy effect on the anti-tuberculosis activity of the cyclomarins. In contrast, cyclomarazines did not show biological activity. PMID- 27241665 TI - The asialoglycoprotein receptor suppresses the metastasis of hepatocellular carcinoma via LASS2-mediated inhibition of V-ATPase activity. AB - The asialoglycoprotein receptor (ASGR), which is expressed mainly in hepatocytes, is downregulated in poorly differentiated hepatocellular carcinoma (HCC). Here we investigated the role of ASGR1 in HCC metastasis as well as the possible underlying molecular mechanisms. We found that ASGR1 was downregulated in HCC tissue compared with adjacent non-tumorous liver tissue and that lower ASGR1 expression was associated with higher TNM stage and poorer prognosis in HCC patients. ASGR1 overexpression inhibited hepatoma cell migration and invasion in vitro and in vivo, while ASGR1 knockdown had the opposite effects. Furthermore, ASGR1 interacted directly with human longevity assurance homolog 2 of yeast LAG1 (LASS2). Knockdown of LASS2 attenuated the inhibitory effects of ASGR1 on hepatoma cell migration and invasion in vitro. ASGR1 decreased V-ATPase activity in hepatoma cells, and this was reversed by LASS2 knockdown. Finally, HCC patients with low LASS2 levels had poor prognosis, while those with high ASGR1 and LASS2 levels had better prognosis. Thus, ASGR1 may act as a potential metastasis suppressor in HCC, and the combination of ASGR1 and LASS2 may help predict the prognosis of HCC patients. PMID- 27241666 TI - Big Data and machine learning in radiation oncology: State of the art and future prospects. AB - Precision medicine relies on an increasing amount of heterogeneous data. Advances in radiation oncology, through the use of CT Scan, dosimetry and imaging performed before each fraction, have generated a considerable flow of data that needs to be integrated. In the same time, Electronic Health Records now provide phenotypic profiles of large cohorts of patients that could be correlated to this information. In this review, we describe methods that could be used to create integrative predictive models in radiation oncology. Potential uses of machine learning methods such as support vector machine, artificial neural networks, and deep learning are also discussed. PMID- 27241667 TI - Growth hormone receptor antagonism suppresses tumour regrowth after radiotherapy in an endometrial cancer xenograft model. AB - Human GH expression is associated with poor survival outcomes for endometrial cancer patients, enhanced oncogenicity of endometrial cancer cells and reduced sensitivity to ionising radiation in vitro, suggesting that GH is a potential target for anticancer therapy. However, whether GH receptor inhibition sensitises to radiotherapy in vivo has not been tested. In the current study, we evaluated whether the GH receptor antagonist, pegvisomant (Pfizer), sensitises to radiotherapy in vivo in an endometrial tumour xenograft model. Subcutaneous administration of pegvisomant (20 or 100 mg/kg/day, s.c.) reduced serum IGF1 levels by 23% and 68%, respectively, compared to vehicle treated controls. RL95-2 xenografts grown in immunodeficient NIH-III mice were treated with vehicle or pegvisomant (100 mg/kg/day), with or without fractionated gamma radiation (10 * 2.5 Gy over 5 days). When combined with radiation, pegvisomant significantly increased the median time tumours took to reach 3* the pre-radiation treatment volume (49 days versus 72 days; p = 0.001). Immunohistochemistry studies demonstrated that 100 mg/kg pegvisomant every second day was sufficient to abrogate MAP Kinase signalling throughout the tumour. In addition, treatment with pegvisomant increased hypoxic regions in irradiated tumours, as determined by immunohistochemical detection of pimonidazole adducts, and decreased the area of CD31 labelling in unirradiated tumours, suggesting an anti-vascular effect. Pegvisomant did not affect intratumoral staining for HIF1alpha, VEGF-A, CD11b, or phospho-EGFR. Our results suggest that blockade of the human GH receptor may improve the response of GH and/or IGF1-responsive endometrial tumours to radiation. PMID- 27241668 TI - Erratum. PMID- 27241670 TI - A Prospective Randomized Study Comparing Manual and Wall Suction in the Performance of Bronchoalveolar Lavage. AB - BACKGROUND: Bronchoalveolar lavage (BAL) may be performed using a hand-held syringe or wall suction. OBJECTIVES: The aim was to study BAL volume and diagnostic yields based on BAL technique. METHODS: A total of 220 consecutive patients undergoing BAL at our center were included. Manual aspiration was performed in 115 patients (group 1), and wall suction (<50 mm Hg of negative pressure) was used in 105 patients (group 2). All bronchoscopies were performed under conscious sedation applying topical anesthesia with lidocaine. Three 50-ml sterile saline aliquots were instilled in all patients. RESULTS: The mean total amount of fluid recovered was 67 +/- 20 ml in group 1 and 55 +/- 22 ml in group 2 (p < 0.001). More patients in the manual aspiration group met American Thoracic Society criteria (recovery of >=30% of instilled fluid) for an optimal BAL (81 vs. 59%; p < 0.001). The quantity of recovered fluid was also related to BAL location (p < 0.001) and radiologic findings (p = 0.002). Forty-eight (22%) BALs were diagnostic (23 in group 1 and 25 in group 2), including 37 positive bacterial cultures, 6 positive stains for Pneumocystis, and 5 cases of malignancy. No statistically significant difference in diagnostic yield was observed between the two groups. A BAL diagnosis was more likely in patients with certain radiologic (p = 0.033) and endoscopic findings (p = 0.001). When taking into account all bronchoscopic techniques performed during the procedure (e.g. biopsies, brushing, etc.), bronchoscopy was diagnostic in 37% of patients. CONCLUSIONS: Manual aspiration is superior to wall suction during BAL yielding a larger quantity of aspirate. Diagnostic yields are similar for both techniques. PMID- 27241669 TI - Clinical characteristics and risk factors of postoperative pneumonia after hip fracture surgery: a prospective cohort study. AB - In this study, we attempt to determine the clinical characteristic and risk factors of postoperative pneumonia (POP) after hip fracture surgery in a well defined hip fracture cohort. We find that intrinsic factors as well as major clinical interventions were all important risk factors of POP. INTRODUCTION: Postoperative pneumonia (POP) is one of the major complications following hip fractures surgery. However, the risk factors of POP are not well studied in hip fracture cohorts. We attempt to determine the clinical characteristic and risk factors of POP after hip fracture surgery in a well-defined hip fracture cohort. METHODS: Datasets from a prospective hip fracture cohort study with a 2-year follow-up period, from 2000 to 2011, were reanalyzed for characteristics of POP. Multivariate Cox proportional regression was used to evaluate the association between the incidence of POP and all-cause mortality. Multivariate logistic regression was used to screen for potential risk factors of POP by analyzing demographic factors, comorbidities, major clinical interventions, and hematological parameters. RESULTS: In 1429 patients who underwent hip surgery, the incidence of POP was 4.9 % (n = 70). All-cause mortality of patients with POP was significantly higher than that of patients without POP at 30 days (hazard ratio (HR) 3.05, 95 % confidence intervals (CI) 1.88-4.94), 1 year (HR 1.87, 95 % CI 1.41-2.48), and 2 years (HR 1.57, 95 % CI 1.23-1.99) postoperatively. Multivariate logistic regression showed that intrinsic factors (advanced age, anemia, diabetes, prior stroke, number of comorbidities, ASA score >=III, and some laboratory biomarkers) as well as major clinical interventions were all significant risk factors for POP. CONCLUSION: Intrinsic factors and major clinical interventions were all important risk factors of POP in patients after hip fracture surgery. Targeted preventive measures to mitigate the above risk factors may help in reducing the incidence of POP. PMID- 27241671 TI - In situ Effect of Chewing Gum with and without CPP-ACP on Enamel Surface Hardness Subsequent to ex vivo Acid Challenge. AB - The erosion-protective effect of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) is controversial. This study aimed to investigate the ability of CPP-ACP chewing gum to prevent a single event of erosive demineralization in situ. Bovine enamel blocks (n = 120) were randomly assigned to 3 phases according to the baseline surface hardness: phase I (PI) - chewing gum with CPP-ACP, phase II (PII) - chewing gum without CPP-ACP, and control phase (PIII) - salivary effect without stimulation (no gum). Nineteen volunteers participated in this study during 3 crossover phases of 2 h. In PI and PII, the volunteers wore intraoral palatal appliances for 120 min and chewed a unit of the corresponding chewing gum for the final 30 min. In the control phase the volunteers wore the appliance for 2 h, without chewing gum. Immediately after intraoral use, the appliances were extraorally immersed in a cola drink for 5 min to promote erosive demineralization. The percentage of surface hardness loss was calculated. The data were analyzed by ANOVA models and Tukey's test. Lower enamel hardness loss was found after the use of chewing gum with CPP-ACP (PI: 32.7%) and without CPP ACP (PII: 33.5%) compared to the salivary effect without stimulation (PIII: 39.8%) (p < 0.05). There was no difference between PI and PII (p > 0.05). The results suggest that the use of chewing gum immediately before an erosive demineralization can diminish enamel hardness loss. However, the presence of CPP ACP in the chewing gum cannot enhance this protective effect. PMID- 27241672 TI - Middle age has a significant impact on gene expression during skin wound healing in male mice. AB - The vast majority of research on the impact of age on skin wound healing (WH) compares old animals to young ones. The middle age is often ignored in biogerontological research despite the fact that many functions that decline in an age-dependent manner have starting points in mid-life. With this in mind, we examined gene expression patterns during skin WH in late middle-aged versus young adult male mice, using the head and back punch models. The rationale behind this study was that the impact of age would first be detectable at the transcriptional level. We pinpointed several pathways which were over-activated in the middle aged mice, both in the intact skin and during WH. Among them were various metabolic, immune-inflammatory and growth-promoting pathways. These transcriptional changes were much more pronounced in the head than in the back. In summary, the middle age has a significant impact on gene expression in intact and healing skin. It seems that the head punch model is more sensitive to the effect of age than the back model, and we suggest that it should be more widely applied in aging research on wound healing. PMID- 27241673 TI - The harder you run, the longer (and smoother) the road: exercise, muscle and ageing. PMID- 27241674 TI - Neurobiological effects of repeated radiofrequency exposures in male senescent rats. AB - The increasing use of mobile phones by aging people raises issues about the effects of radiofrequency electromagnetic fields (RF-EMF) on the aging central nervous system. Here, we tested if mobile phone RF-EMF exposures could exacerbate senescence-typical neurobiological deficits. Thus, aged (22-24 months) and young (4-6 months) adult male rats were subjected to head RF-EMF exposures (900 MHz, specific absorption rate (SAR) of 6 W/kg, 45 min/day for 1 month in restraint rockets). To assess senescence-typical neurobiological deficits, spatial memory, emotional memory, anxiety-related behavior, locomotor activity, interleukins (IL) 1beta and 6, glial fibrillary acidic protein and corticosterone were measured. Aged rats presented deficits in spatial learning, exploration, anxiety-related behaviors, and increased hippocampal ILs and cortical IL-1beta. Results showed that senescence-typical neurobiological deficits were not modified by RF-EMF exposures. RF-EMF-exposed rats (young and aged adults pooled) had decreased anxiety-related behaviors in the elevated plus maze. This study which is the first to assess RF-EMF exposures during late aging did not support the hypothesis of a specific cerebral vulnerability to RF-EMF during senescence. More investigations using longer RF-EMF exposures should be performed to conclude regarding the inoffensiveness of RF-EMF exposures. PMID- 27241676 TI - Seriously overestimated prognostic value of baseline and interim FDG-PET in diffuse large B cell lymphoma. PMID- 27241677 TI - Interleukin-17A Contributes to the Control of Streptococcus pyogenes Colonization and Inflammation of the Female Genital Tract. AB - Postpartum women are at increased risk of developing puerperal sepsis caused by group A Streptococcus (GAS). Specific GAS serotypes, including M1 and M28, are more commonly associated with puerperal sepsis. However, the mechanisms of GAS genital tract infection are not well understood. We utilized a murine genital tract carriage model to demonstrate that M1 and M28 GAS colonization triggers TNF alpha, IL-1beta, and IL-17A production in the female genital tract. GAS-induced IL-17A significantly influences streptococcal carriage and alters local inflammatory responses in two genetically distinct inbred strains of mice. An absence of IL-17A or the IL-1 receptor was associated with reduced neutrophil recruitment to the site of infection; and clearance of GAS was significantly attenuated in IL-17A(-/-) mice and Rag1(-/-) mice (that lack mature lymphocytes) but not in mice deficient for the IL-1 receptor. Together, these findings support a role for IL-17A in contributing to the control of streptococcal mucosal colonization and provide new insight into the inflammatory mediators regulating host-pathogen interactions in the female genital tract. PMID- 27241679 TI - Patients with lung cancer: Are electronic cigarettes harmful or useful? AB - E-cigarettes remain controversial because the scientific evidence of short term and long term effects on tolerance and the health value of a switch from tobacco to e-cigarettes is contested and controversial. Nevertheless the quality of e cigarettes and e-liquids has improved. The main ingredients, propylene glycol, vegetable glycerine and nicotine are pharmaceutical-grade quality in most e liquids. Flavors are almost all food grade. The high quality of ingredients has decreased the presence of impurities in e-liquids. The emissions of e-cigarettes do not contain solid particles or carbon monoxide. Nitrosamine content is at least one hundred times lower than in tobacco smoke. E-cigarette emissions in normal use do not contain any harmful constituents at significant levels except nicotine. UK public health authorities have stated that e-cigarette use is likely to be at least 95% less toxic than cigarette use. There are benefits from having a well-regulated legal market. In countries where e-liquid containing nicotine is not allowed, "do-it-yourself" liquids are common and have handling risks and may sometimes contain toxic impurities. Though e-cigarettes should never be assumed safe products for non-smokers, for smokers, the e-cigarette is at least 20 times less dangerous than the cigarette. Tobacco cessation specialists in countries where nicotine containing e-cigarettes are available increasingly provide counselling for e-cigarette use to stop smoking or to reduce smoking at the request of patients. Based on current knowledge, for patients with lung or other forms of cancer who would otherwise continue to smoke, e-cigarettes offer an alternative way to quit smoking while they undergo medical treatment. PMID- 27241678 TI - Hajdu-Cheney Syndrome, a Disease Associated with NOTCH2 Mutations. AB - Notch plays an important function in skeletal homeostasis, osteoblastogenesis, and osteoclastogenesis. Hajdu-Cheney syndrome (HCS) is a rare disease associated with mutations in NOTCH2 leading to the translation of a truncated NOTCH2 stable protein. As a consequence, a gain-of-NOTCH2 function is manifested. HCS is inherited as an autosomal dominant disease although sporadic cases exist. HCS is characterized by craniofacial developmental defects, including platybasia and wormian bones, osteoporosis with fractures, and acro-osteolysis. Subjects may suffer severe neurological complications, and HCS presents with cardiovascular defects and polycystic kidneys. An experimental mouse model harboring a HCSNotch2 mutation exhibits osteopenia secondary to enhanced bone resorption suggesting this as a possible mechanism for the skeletal disease. If the same mechanisms were operational in humans, anti-resorptive therapy could correct the bone loss, but not necessarily the acro-osteolysis. In conclusion, HCS is a devastating disease associated with a gain-of-NOTCH2 function resulting in diverse clinical manifestations. PMID- 27241680 TI - Erratum to "Expression of Mina53, a novel c-Myc target gene, is a favorable prognostic marker in early stage lung cancer" [Lung Cancer 69/2 (2010) 232-238]. PMID- 27241681 TI - Effects of Smoking Status on Device Survival Among Individuals Undergoing Artificial Urinary Sphincter Placement. AB - Smoking is an established risk factor for wound complications. There is limited data on the impact of smoking on artificial urinary sphincter (AUS) outcomes. Thus, the aim of this study was to assess AUS device survival outcomes based on smoking status. From 1985 to 2014, 1,270 patients underwent AUS placement with 728 having smoking status available for review. Smoking status was categorized as never, prior, and active smokers. Kaplan-Meier analysis was performed to evaluate differences in survival, including overall device and erosion/infection-free survival. Hazard regression analysis was utilized to determine the association between smoking and device outcomes. Of the 728 patients in the study, 401 had a history of smoking with 41 active smokers and 360 never smokers at the time of AUS implant. When compared with nonsmokers, past smokers had a higher rate of hypertension and prior transient ischemic attack. Clinical comorbidities were similar between nonsmokers and active smokers. On univariate analysis, patient age, history of transient ischemic attack, diabetes, and coronary artery disease were significantly associated with infection/erosion rate, but prior or active smoking statuses were not. Likewise, when comparing smokers (past or active) with lifelong nonsmokers, there was no significant difference in 1- and 5-year overall device survival. There was no evidence for adverse AUS outcomes in current or past smokers compared with nonsmokers. Given the established risk of perioperative complications secondary to smoking, the recommendation should still be to counsel patients to quit prior to undergoing AUS placement. External validation of these findings is needed. PMID- 27241682 TI - Factor VIII chromogenic assays can be used for potency labeling and postadministration monitoring of N8-GP. AB - Essentials Chromogenic assays may be less variable than one-stage clot assays for measuring modified factor VIII. Chromogenic assays were evaluated for N8-GP potency labeling and postadministration monitoring. There was no significant difference between chromogenic assay kits for measuring N8-GP potency. Postadministration monitoring of N8-GP was comparable to turoctocog alfa for all kits tested. SUMMARY: Background Factor VIII activity ( FVIII: C) is commonly measured using one-stage activated partial thromboplastin time (aPTT)-based clot assays. Chromogenic assays are, however, an alternative, and potency assessment in Europe is performed using chromogenic assays. One-stage clot assays are in general associated with high variability, and modified FVIII products may add to this variability. FVIII chromogenic assays may be less affected. Objectives To evaluate available chromogenic assay kits for potency labeling of polyethylene glycol-glycoconjugated turoctocog alfa (turoctocog alfa pegol [N8-GP]) and to evaluate selected chromogenic kits for postadministration monitoring of N8-GP using turoctocog alfa (Novoeight((r)) ) as comparator. Methods Six FVIII chromogenic assay kits were adapted to the European Pharmacopeia guidelines for potency labeling, including assessment of time to 50% FX activation. Four kits were adapted for postadministration monitoring using an ACL((r)) TOP 500 analyzer. Severe hemophilia A plasma was spiked with N8-GP or turoctocog alfa to simulate postadministration samples. The World Health Organization (WHO) 8th International Standard (IS) FVIII concentrate was used as calibrator throughout. In addition, a plasma calibrator was used for postadministration samples. Results When measuring N8-GP potency, no significant difference using a 1% significance level was observed between kits. In simulated postadministration samples, all test kits were highly accurate and precise, except at low concentrations, with no significant difference between FVIII: C (P > 0.05) measured using the different calibrators. However, values obtained using the WHO 8th IS were closer to labeled values. Conclusions Chromogenic assay kits tested measured consistent FVIII: C for N8-GP potency and showed comparable results for N8-GP and turoctocog alfa in simulated postadministration samples. PMID- 27241683 TI - Institutional Context of Family Eldercare in Mexico and the United States. PMID- 27241684 TI - Apolipoprotein E gene polymorphism and the risk of subarachnoid hemorrhage: a meta-analysis of case-control studies. AB - BACKGROUND: Studies investigating the association between the apolipoprotein E gene (APOE) polymorphism and the risk of subarachnoid hemorrhage (SAH) have reported inconsistent results. So we performed a meta-analysis to estimate the association between APOE polymorphism and SAH susceptibility. METHODS: Relevant studies published before 5 November 2015 were identified by searching PubMed, Embase, EBSCO, and ISI web of knowledge. The strength of relationship between the APOE gene and SAH susceptibility was assessed using odds ratio (OR) and corresponding 95 % confidence interval (95 % CI). RESULTS: A total number of six case-control studies including 638 SAH cases and 2,341 controls were identified. No association was found in dominant model or allele contrast genetic model (epsilon4 dominant model: OR = 1.06, 95 % CI = 0.91-1.25; epsilon3 dominant model: OR = 0.99, 95 % CI = 0.97-1.01; epsilon2 dominant model: OR = 0.99, 95 % CI = 0.78-1.25; epsilon4 versus epsilon3: OR = 1.14, 95 % CI = 0.96-1.35; epsilon4 versus epsilon2: OR = 1.07, 95 % CI = 0.90-1.28; epsilon3 versus epsilon2: OR = 1.00, 95 % CI = 0.96-1.04) for APOE polymorphism and SAH susceptibility. In the subgroup analyzed that was stratified by ethnicity, increased risk of SAH was found in Asian subjects when epsilon4 allele compared with epsilon3 allele (epsilon4 vs epsilon3, OR = 1.55, 95 % CI = 1.07-2.52). CONCLUSIONS: Our meta-analysis suggested that there is no association between APOE polymorphism and SAH risk for overall population. Due to several limitations in the present study, well-designed epidemiological studies with large sample size among different ethnicities should be performed in the future. PMID- 27241685 TI - Electromyographic evidence in support of a knock-in mouse model of DYT1 Dystonia. AB - INTRODUCTION: DYT1 dystonia is an autosomal-dominant movement disorder characterized by abnormal, often repetitive, movements and postures. Its hallmark feature is sustained or intermittent contractions of muscles involving co contractions of antagonist muscle pairs. The symptoms are relieved with the anticholinergic drug trihexyphenidyl. The primary mutation is a trinucleotide deletion (DeltaGAG) in DYT1/TOR1A, which codes for torsinA. Previous studies showed that (1) heterozygous Dyt1 DeltaGAG knock-in mice, which have an analogous mutation in the endogenous gene, exhibit motor deficits and altered corticostriatal synaptic plasticity in the brain and (2) these deficits can be rescued by trihexyphenidyl. However, brain imaging studies suggest that the Dyt1 knock-in mouse models nonmanifesting mutation carriers of DYT1 dystonia. The aim of this work was to examine the hallmark features of DYT1 dystonia in the Dyt1 knock-in mice by analyzing muscular activities. METHODS: Wireless telemetry devices with biopotential channels were implanted to the bicep and the rectus femori muscles in Dyt1 knock-in mice, and muscular activities were recorded before and after trihexyphenidyl administration. RESULTS: (1) Consistent with DYT1 dystonia patients, Dyt1 knock-in mice showed sustained contractions and co contractions of the antagonistic bicep femoris and rectus femoris. (2) The abnormal muscle contractions were normalized by trihexyphenidyl. CONCLUSION: The results suggest that the motor deficits in Dyt1 knock-in mice are likely produced by abnormal muscle contractions, and Dyt1 knock-in mice can potentially be used as a manifesting disease model to study pathophysiology and develop novel therapeutics. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27241686 TI - A novel GJA1 mutation identified by whole exome sequencing in a Chinese family with autosomal dominant syndactyly. PMID- 27241687 TI - Study protocol for a randomized clinical trial of a fatherhood intervention for African American non-resident fathers: Can we improve father and child outcomes? AB - PURPOSE: African American (AA) fathers who live apart from their children face multiple obstacles to consistent and positive involvement with their children. Consequently, significant numbers of children are bereft of their father's positive involvement. Intervention research that is explicitly focused on promoting the positive involvement of non-resident AA fathers with their young children is limited. The purpose of this article is to describe the study protocol of a randomized trial (RCT) designed to test the Building Bridges to Fatherhood program against a financial literacy comparison condition; and discuss early implementation challenges. METHODS: Fathers (n=180) are recruited to attend 10 group meetings, reimbursed for transportation, given dinner and activity vouchers for spending time with their child, and incentivized with a $40 gift card at each data collection time point. Mothers are incentivized ($40 gift card) at data collection and must be amenable to father child interaction. Intervention targets include father psychological well-being, parenting competence, communication, problem-solving ability; father-mother relationship quality; and child behavioral and emotional/social development. RESULTS: To date, 57 fathers have been randomized to study condition. Recruitment has been influenced by father and mother hesitancy and the logistics of reaching and maintaining contact with participants. Strategies to surmount challenges to father and mother recruitment and engagement have been developed. CONCLUSIONS: The prospective benefits of positive father involvement to children, fathers and families outweigh the challenges associated with community-based intervention research. The findings from this RCT can inform the body of knowledge on engaging AA non resident fathers in culturally relevant fatherhood programming. PMID- 27241688 TI - Improved immune response to an attenuated pseudorabies virus vaccine by ginseng stem-leaf saponins (GSLS) in combination with thimerosal (TS). AB - Vaccination using attenuated vaccines remains an important method to control animal infectious diseases. The present study evaluated ginseng stem-leaf saponins (GSLS) and thimerosal (TS) for their adjuvant effect on an attenuated pseudorabies virus (aPrV) vaccine in mice. Compared to the group immunized with aPrV alone, the co-inoculation of GSLS and/or TS induced a higher antibody response. Particularly, when administered together with GSLS-TS, the aPrV vaccine provoked a higher serum gB-specific antibody, IgG1 and IgG2a levels, lymphocyte proliferative responses, as well as production of cytokines (IFN-gamma, IL-12, IL 5 and IL-10) from lymphocytes, and more importantly provided an enhanced cytotoxicity of NK cells and protection against virulent field pseudorabies virus challenge. Additionally, the increased expression of miR-132, miR-146a, miR-147 and miR-155 was found in murine macrophages cultured with GSLS and/or TS. These data suggest that GSLS-TS as adjuvant improve the efficacy of aPrV vaccine in mouse model and have potential for the development of attenuated viral vaccines. PMID- 27241689 TI - Identification of entry inhibitors of Ebola virus pseudotyped vectors from a myxobacterial compound library. AB - Myxobacteria produce secondary metabolites many of which were described to have various biological effects including anti-fungal, anti-bacterial and anti-viral activity. The majority of these metabolites are novel scaffolds with unique modes of-action and hence might be potential leads for drug discovery. Here, we tested a myxobacterial natural product library for compounds with inhibitory activity against Ebola virus (EBOV). The assay was performed with a surrogate system using Ebola envelope glycoprotein (GP) pseudotyped lentiviral vectors. EBOV specificity was proven by counter-screening with vesicular stomatitis virus G protein pseudotyped vectors. Two compounds were identified that preferentially inhibited EBOV GP mediated cell entry: Chondramides that act on the actin skeleton but might be too toxic and noricumazole A, a potassium channel inhibitor, which might constitute a novel pathway to inhibit Ebola virus cell entry. PMID- 27241690 TI - Synthesis, crystal structures, molecular docking, and in vitro biological activities of transition metals with 4-(2,3-dichlorophenyl)piperazine-1 carboxylic acid. AB - Four novel mononuclear complexes, [Cd(L)2.2H2O] (1), [Ni(L)2.2H2O] (2) [Cu(L)2.H2O] (3), and [Zn(L)2.2H2O] (4) (CCDC numbers: 1444630-1444633 for complexes 1-4) (HL=4-(2,3-dichlorophenyl)piperazine-1-carboxylic acid) were synthesized, and have been characterized by IR spectroscopy, elemental analysis, and X-ray crystallography. Molecular docking study preliminarily revealed that complex 1 had potential telomerase inhibitory activity. In accordance with the result of calculation, in vitro tests of the inhibitory activities of complex 1 against telomerase showed complex 1 (IC50=8.17+/-0.91MUM) had better inhibitory activities, while complexes 2, 3 and 4 showed no inhibitory activities. Antiproliferative activity in human cancer cell line HepG2 was further determined by MTT assays. The IC50 value (6.5+/-0.2MUM) for the complex 1 having good inhibitory activity against HepG2 was at the same micromolar concentrations with cis-platinum (2.2+/-1.2MUM). While the IC50 value for the metal-free ligand, complex 2, 3 and 4 was more than 100MUM. These results indicated that telomerase was potentially an anticancer drug target and showed that complex 1 was a potent inhibitor of human telomerase as well as an antiproliferative compound. PMID- 27241691 TI - Novel 5-substituted-2-anilinoquinolines with 3-(morpholino or 4-methylpiperazin-1 yl)propoxy moiety as broad spectrum antiproliferative agents: Synthesis, cell based assays and kinase screening. AB - A series of new 2-anilinoquinolines possessing 3-(morpholino or 4-methylpiperazin 1-yl)propoxy moiety at C5 of quinoline has been designed and synthesized as potential anticancer agents. Their antiproliferative activities were evaluated against a panel of 60 cancer cell lines at NCI and compared with gefitinib as a reference compound. Most of the tested compounds displayed potent and broad spectrum antiproliferative activities. Compounds 7d, 7f and 7g showed strong inhibitory and lethal effects at 10MUM concentration. Moreover, they manifested superior potencies and efficacies than gefitinib across the most tested cell lines. Compound 7d, with 4-chloro-3-trifluoromethylphenyl group, proved to be the most potent and efficacious derivative in this series, with mean GI50 and TGI values of 1.62MUM and 3.47MUM, respectively. Kinase screening of 7d against a panel of 47 oncogenic kinases revealed its selective inhibitory effect (96% inhibition) towards TrkA kinase. Furthermore, the most potent compounds showed low cytotoxic effects against HFF-1 normal cell line. PMID- 27241693 TI - Antimycobacterial activity of new N(1)-[1-[1-aryl-3-[4-(1H-imidazol-1-yl)phenyl] 3-oxo]propyl]-pyridine-2-carboxamidrazone derivatives. AB - N(1)-[1-[1-aryl-3-[4-(1H-imidazol-1-yl)phenyl]-3-oxo]propyl]-pyridine-2 carboxamidrazone derivatives were design, synthesized and tested for their in vitro antimycobacterial activity. The new compounds showed a moderate antimycobacterial activity against the tested strain of Mycobacterium tuberculosis H37Ra and a significant antimycobacterial activity against several mycobacteria other than tuberculosis strains. PMID- 27241692 TI - Coumarin carboxylic acids as monocarboxylate transporter 1 inhibitors: In vitro and in vivo studies as potential anticancer agents. AB - Novel N,N-dialkyl carboxy coumarins have been synthesized as potential anticancer agents via inhibition of monocarboxylate transporter 1 (MCT1). These coumarin carboxylic acids have been evaluated for their in vitro MCT1 inhibition, MTT cancer cell viability, bidirectional Caco-2 cell permeability, and stability in human and liver microsomes. These results indicate that one of the lead candidate compounds 4a has good absorption, metabolic stability, and a low drug efflux ratio. Systemic toxicity studies with lead compound 4a in healthy mice demonstrate that this inhibitor is well tolerated based on zero animal mortality and normal body weight gains compared to the control group. In vivo tumor growth inhibition studies in mice show that the candidate compound 4a exhibits significant single agent activity in MCT1 expressing GL261-luc2 syngraft model but doesn't show significant activity in MCT4 expressing MDA-MB-231 xenograft model, indicating the selectivity of 4a for MCT1 expressing tumors. PMID- 27241694 TI - Robust analysis of secondary phenotypes in case-control genetic association studies. AB - The case-control study is a common design for assessing the association between genetic exposures and a disease phenotype. Though association with a given (case control) phenotype is always of primary interest, there is often considerable interest in assessing relationships between genetic exposures and other (secondary) phenotypes. However, the case-control sample represents a biased sample from the general population. As a result, if this sampling framework is not correctly taken into account, analyses estimating the effect of exposures on secondary phenotypes can be biased leading to incorrect inference. In this paper, we address this problem and propose a general approach for estimating and testing the population effect of a genetic variant on a secondary phenotype. Our approach is based on inverse probability weighted estimating equations, where the weights depend on genotype and the secondary phenotype. We show that, though slightly less efficient than a full likelihood-based analysis when the likelihood is correctly specified, it is substantially more robust to model misspecification, and can out-perform likelihood-based analysis, both in terms of validity and power, when the model is misspecified. We illustrate our approach with an application to a case-control study extracted from the Framingham Heart Study. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27241695 TI - Mechanisms of homeostatic plasticity in the excitatory synapse. AB - Brain development, sensory information processing, and learning and memory processes depend on Hebbian forms of synaptic plasticity, and on the remodeling and pruning of synaptic connections. Neurons in networks implicated in these processes carry out their functions while facing constant perturbation; homeostatic responses are therefore required to maintain neuronal activity within functional ranges for proper brain function. Here, we will review in vitro and in vivo studies demonstrating that several mechanisms underlie homeostatic plasticity of excitatory synapses, and identifying participant molecular players. Emerging evidence suggests a link between disrupted homeostatic synaptic plasticity and neuropsychiatric and neurologic disorders. Hebbian forms of synaptic plasticity, such as long-term potentiation (LTP), induce long-lasting changes in synaptic strength, which can be destabilizing and drive activity to saturation. Conversely, homeostatic plasticity operates to compensate for prolonged activity changes, stabilizing neuronal firing within a dynamic physiological range. We review mechanisms underlying homeostatic plasticity, and address how neurons integrate distinct forms of plasticity for proper brain function. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases". PMID- 27241696 TI - [Modern Lipid therapy today and tomorrow: anti-PCSK9 : A magic bullet concept following Paul Ehrlich]. PMID- 27241697 TI - The majority of murine gammadelta T cells at the maternal-fetal interface in pregnancy produce IL-17. AB - Compared with lymphoid tissues, the immune cell compartment at mucosal sites is enriched with T cells bearing the gammadelta T-cell receptor (TCR). The female reproductive tract, along with the placenta and uterine decidua during pregnancy, are populated by gammadelta T cells predominantly expressing the invariant Vgamma6(+)Vdelta1(+) receptor. Surprisingly little is understood about the function of these cells. We found that the majority of gammadelta T cells in the non-pregnant uterus, pregnant uterus, decidua and placenta of mice express the transcription factor RORgammat and produce interleukin-17 (IL-17). In contrast, IFNgamma-producing gammadelta T cells were markedly reduced in gestational tissues compared with uterine-draining lymph nodes and spleen. Both uterine resident invariant Vgamma6(+) and Vgamma4(+) gammadelta T cells which are more typically found in lymphoid tissues and circulating blood, were found to express IL-17. Vgamma4(+) gammadelta T cells were particularly enriched in the placenta, suggesting a pregnancy-specific recruitment or expansion of these cells. A small increase in IL-17-producing gammadelta T cells was observed in allogeneic compared with syngeneic pregnancy, suggesting a contribution to regulating the maternal response to paternally-derived alloantigens. However, their high proportions also in non-pregnant uteri and gestational tissues of syngeneic pregnancy imply a role in the prevention of intrauterine infection or quality control of fetal development. These data suggest the need for a more rigorous evaluation of the role of IL-17 in sustaining normal pregnancy, particularly as emerging data points to a pathogenic role for IL-17 in pre-eclampsia, pre-term birth, miscarriage and maternal immune activation-induced behavioral abnormalities in offspring. PMID- 27241698 TI - The exceptionally high reactivity of Cys 621 is critical for electrophilic activation of the sensory nerve ion channel TRPA1. AB - Activation of the sensory nerve ion channel TRPA1 by electrophiles is the key mechanism that initiates nociceptive signaling, and leads to defensive reflexes and avoidance behaviors, during oxidative stress in mammals. TRPA1 is rapidly activated by subtoxic levels of electrophiles, but it is unclear how TRPA1 outcompetes cellular antioxidants that protect cytosolic proteins from electrophiles. Here, using physiologically relevant exposures, we demonstrate that electrophiles react with cysteine residues on mammalian TRPA1 at rates that exceed the reactivity of typical cysteines by 6,000-fold and that also exceed the reactivity of antioxidant enzymes. We show that TRPA1 possesses a complex reactive cysteine profile in which C621 is necessary for electrophile-induced binding and activation. Modeling of deprotonation energies suggests that K620 contributes to C621 reactivity and mutation of K620 alone greatly reduces the effect of electrophiles on TRPA1. Nevertheless, binding of electrophiles to C621 is not sufficient for activation, which also depends on the function of another reactive cysteine (C665). Together, our results demonstrate that TRPA1 acts as an effective electrophilic sensor because of the exceptionally high reactivity of C621. PMID- 27241699 TI - Electrophysiological characterization of the archaeal transporter NCX_Mj using solid supported membrane technology. AB - Sodium-calcium exchangers (NCXs) are membrane transporters that play an important role in Ca(2+) homeostasis and Ca(2+) signaling. The recent crystal structure of NCX_Mj, a member of the NCX family from the archaebacterium Methanococcus jannaschii, provided insight into the atomistic details of sodium-calcium exchange. Here, we extend these findings by providing detailed functional data on purified NCX_Mj using solid supported membrane (SSM)-based electrophysiology, a powerful but unexploited tool for functional studies of electrogenic transporter proteins. We show that NCX_Mj is highly selective for Na(+), whereas Ca(2+) can be replaced by Mg(2+) and Sr(2+) and that NCX_Mj can be inhibited by divalent ions, particularly Cd(2+) By directly comparing the apparent affinities of Na(+) and Ca(2+) for NCX_Mj with those for human NCX1, we show excellent agreement, indicating a strong functional similarity between NCX_Mj and its eukaryotic isoforms. We also provide detailed instructions to facilitate the adaption of this method to other electrogenic transporter proteins. Our findings demonstrate that NCX_Mj can serve as a model for the NCX family and highlight several possible applications for SSM-based electrophysiology. PMID- 27241701 TI - Aortic Valve Replacement: The Era of Transcatheter Therapies. PMID- 27241700 TI - Polymodal activation of the TREK-2 K2P channel produces structurally distinct open states. AB - The TREK subfamily of two-pore domain (K2P) K(+) channels exhibit polymodal gating by a wide range of physical and chemical stimuli. Crystal structures now exist for these channels in two main states referred to as the "up" and "down" conformations. However, recent studies have resulted in contradictory and mutually exclusive conclusions about the functional (i.e., conductive) status of these two conformations. To address this problem, we have used the state dependent TREK-2 inhibitor norfluoxetine that can only bind to the down state, thereby allowing us to distinguish between these two conformations when activated by different stimuli. Our results reconcile these previously contradictory gating models by demonstrating that activation by pressure, temperature, voltage, and pH produce more than one structurally distinct open state and reveal that channel activation does not simply involve switching between the up and down conformations. These results also highlight the diversity of structural mechanisms that K2P channels use to integrate polymodal gating signals. PMID- 27241702 TI - Dedicated CTO-PCI Centres: 'If you Build it they will Come'. PMID- 27241703 TI - Gammopathy at first sight. PMID- 27241704 TI - Biosimilars in rheumatology: understanding the rigor of their development. AB - This article examines the current landscape of biosimilar development in rheumatology. As misperceptions about biosimilars exist regarding their comparability to the reference products for clinical use, we review the development paradigm with the goal of improving rheumatologists' understanding of the rigor with which biosimilars are developed. With an emphasis on European Union and US markets, it gives an overview of some of the challenges and issues related to biosimilar development that need to be considered by rheumatologists in this increasingly growing therapeutic space. PMID- 27241705 TI - Genotyping of relapsing polychondritis identified novel susceptibility HLA alleles and distinct genetic characteristics from other rheumatic diseases. AB - OBJECTIVE: To uncover the genetic background of relapsing polychondritis (RPC), a rare autoimmune disease with unknown mechanisms characterized by systemic inflammation of the cartilage, to deepen our understanding of the pathophysiology of RPC and show its distinct genetic characteristics from other rheumatic diseases. METHODS: A total of 102 patients with RPC and 1000 healthy subjects were recruited for a two-staged genetic association study and genotyped for six HLA classical loci. Haplotype association tests were also performed. The associations of amino acid (AA) residues and positions with susceptibility to RPC were analysed. Frequencies of representative susceptibility HLA alleles to other rheumatic diseases in RPC were also analysed. RESULTS: HLA-DRB1*16:02, HLA DQB1*05:02 and HLA-B*67:01, which are in linkage disequilibrium with each other, were associated with RPC (P = 1.9 * 10(-6), 1.4 * 10(-5) and 0.00024, respectively). AA residue at position 57 in HLA-DQB1, the most significant position in type I diabetes mellitus, showed the strongest association among AA residues. HLA-DR4, a known susceptibility allele in Germans, showed a trend of susceptibility association without significance (P = 0.067). No associations were observed between the three alleles and clinical phenotypes. Representative susceptibility HLA alleles to RA, SLE, Behcet disease and Takayasu arteritis did not show enrichment in RPC in spite of sufficient statistical power. CONCLUSIONS: HLA-DRB1*16:02, HLA-DQB1*05:02 and HLA-B*67:01, in linkage disequilibrium with each other, are associated with susceptibility to RPC Importance of HLA-class II loci in RPC susceptibility is suggested. RPC is considered a genetically distinct disease from other rheumatic diseases. PMID- 27241706 TI - Calcinosis in systemic sclerosis: subsets, distribution and complications. AB - OBJECTIVE: To retrospectively analyse the features of calcinosis in a cohort of SSc patients. METHODS: Charts of SSc patients attending the Ulcer Unit of the Rheumatology Department, University of Florence and presenting a clinical suspicion of calcinosis were considered in the study. Data on clinical history, including recent skin changes, and clinical examination of all areas with suspected calcinosis, radiological imaging of the calcinotic area, demographics and SSc-related organ involvement and pain measured by a visual analogue scale were recorded. RESULTS: In 52 of 112 SSc patients, a total of 316 calcinoses were recorded and were divided into visible and palpable {154 [47.4%], clustered according to their macroscopic features as mousse [49 (31.8%)] and stone [: 105 (68.2%)]} and non-visible but palpable {: 162 [52.6%]: net [5 (3%)], plate [22 (13.8%)] and stone [135 (83.2%)]}. The X-ray-based classification of all calcinoses, both visible and non-visible, was as follows: stone, 289 (91.4%); net, 12 (3.8%) and plate, 15 (4.8%). Skin ulcers complicated 154 of 316 calcinoses (48.7%). Mousse calcinosis was associated with pulmonary arterial hypertension, the stone subset was suggestive of pulmonary involvement and justified further investigation and the net subset was the slowest to heal. CONCLUSION: Our data indicate that calcinosis may be classified in SSc as mousse, stone, net and plate according to its clinical and X-ray features. This classification awaits validation for a possible use in clinical practice and to support early treatment and prevention of complications. PMID- 27241707 TI - Arrhythmogenic effect of androgens on the rat heart. AB - In most species androgens shorten the cardiac action potential and reduce the risk of afterdepolarizations. Despite the central role of the rat model in physiological studies, the effects of androgens on the rat heart are still inconclusive. We therefore performed electrophysiological studies on the perfused rat right ventricular free wall. We found a correlation between androgenic activity and a propensity to generate ventricular ectopic action potentials. We also found that the testosterone treatment increased action potential duration at 90 % of repolarization (APD90), while androgenic inhibition increased the time to peak and decreased APD90. We observed that the voltage-gated potassium channel Kv4.3 and the bi-directional membrane ion transporter NCX in the rat myocardium were regulated by androgenic hormones. One possible explanation for these findings is that due to the expression of specific ion channels in the rat myocardium, the action potential response to its hormonal background is different from those described in other experimental models. Our results indicate that androgenic control of NCX expression plays a key role in determining arrhythmogenicity in the rat heart. PMID- 27241708 TI - Adjunctive therapies for Kawasaki disease. AB - Kawasaki disease (KD) is the most common cause of acquired heart disease in children in developed countries.(1,2) The primary goal of treatment is to prevent coronary artery aneurysms (CAA). Between 10 and 20% of KD patients are resistant to treatment with intravenous immunoglobulin (IVIG) and have an almost nine-fold increased risk of developing CAA.(3) In addition, approximately 80-90% of patients who go on to develop CAA have abnormal coronary artery dimensions on their first echocardiogram and can therefore be identified as high-risk patients. These two subsets of KD patients are candidates for adjunctive therapy, in addition to IVIG. Understanding the mechanism of action of IVIG may provide insight into IVIG resistance and guidance for choosing adjunctive therapies in KD. Therapeutic options in the treatment of refractory KD and patients with early CAA include additional IVIG, glucocorticoids, tumor necrosis factor inhibitors, calcineurin inhibitors and interleukin-1 (IL-1) blockers.(3-10) Animal studies suggest that the anti-inflammatory properties of statins may also be beneficial in blocking CAA progression.(6) It is unlikely that these therapies will be studied in large, randomized controlled trials in the future due to required sample size and funding constraints. Thus, data from the research laboratory may be helpful in guiding selection of the most promising adjunctive therapies. PMID- 27241709 TI - Lorcaserin and CP-809101 reduce motor impulsivity and reinstatement of food seeking behavior in male rats: Implications for understanding the anti-obesity property of 5-HT2C receptor agonists. AB - RATIONALE: The 5-HT2C receptor agonist lorcaserin (Belviq(r)) has been approved by the FDA for the treatment of obesity. Impulsivity is a contributory feature of some eating disorders. OBJECTIVE: Experiments investigated the effect of lorcaserin and the highly selective 5-HT2C agonist CP-809101 on measures of impulsivity and on reinstatement of food-seeking behaviour, a model of dietary relapse. The effect of both drugs on 22-h deprivation-induced feeding was also examined, as was the effect of prefeeding in each impulsivity test. RESULTS: Lorcaserin (0.3-0.6 mg/kg SC) and CP-809101 (0.6-1 mg/kg SC) reduced premature responding in rats trained on the 5-CSRTT and improved accuracy in a Go-NoGo task by reducing false alarms. At equivalent doses, both drugs also reduced reinstatement for food-seeking behaviour. Neither drug altered impulsive choice measured in a delay-discounting task. Lorcaserin (1-3 mg/kg SC) and CP-809101 (3 6 mg/kg SC) reduced deprivation-induced feeding but only at higher doses. CONCLUSIONS: These results suggest that in addition to previously reported effects on satiety and reward, altered impulse control may represent a contributory factor to the anti-obesity property of 5-HT2C receptor agonists. Lorcaserin may promote weight loss by improving adherence to dietary regimens in individuals otherwise prone to relapse and may be beneficial in cases where obesity is associated with eating disorders tied to impulsive traits, such as binge eating disorder. PMID- 27241712 TI - Treatment of Warts in Children: An Update. AB - Warts are among the most common skin infections in children. Although numerous treatment options are available, none are completely effective in a single session. Treatment is particularly complicated in children, not only because certain treatments are poorly tolerated, but also because parents frequently have unrealistic expectations. In this article, we offer an update on the treatments available for warts, focusing specifically on pediatric patients. We do not discuss treatments for oral and anogenital warts. PMID- 27241710 TI - Levodopa impairs probabilistic reversal learning in healthy young adults. AB - RATIONALE: Dopaminergic therapy improves some cognitive functions and worsens others in patients with Parkinson's disease (PD). These paradoxical effects are explained by the dopamine overdose hypothesis, which proposes that effects of dopaminergic therapy on a cognitive function is determined by the baseline dopamine levels in brain regions mediating that function. OBJECTIVES: We directly tested this prevalent hypothesis, evaluating the effects of levodopa on stimulus reward learning in healthy young adults, who presumably have optimal baseline dopamine levels and dopamine regulation. METHODS: Twenty-six healthy, young adults completed a probabilistic reversal learning task in a randomized, double blind, placebo-controlled, crossover design. Participants completed one session on levodopa 100 mg/carbidopa 25 mg and another session on placebo. RESULTS: We found that levodopa impaired reversal learning relative to placebo. Further analyses revealed that levodopa impaired learning from both punishment and reward. CONCLUSIONS: Exogenous dopamine impairs stimulus-reward learning, independent of PD pathology and prior to sensitization through repeated exposure, in healthy adults with normal cognition and baseline dopamine function. Our findings support the dopamine overdose hypothesis and caution clinicians about detrimental effects of levodopa in all clinical populations (e.g., early PD, restless leg syndrome) regardless of baseline cognitive and dopaminergic system function. PMID- 27241711 TI - Genetic predisposition of six well-defined polymorphisms in HMGB1/RAGE pathway to breast cancer in a large Han Chinese population. AB - Breast cancer constitutes an enormous burden in China. A strong familial clustering of breast cancer suggests a genetic component in its carcinogenesis. To examine the genetic predisposition of high mobility group box-1/receptor for advanced glycation end products (HMGB1/RAGE) pathway to breast cancer, we genotyped six well-defined polymorphisms in this pathway among 524 breast cancer patients and 518 cancer-free controls from Heilongjiang province, China. There were no deviations from Hardy-Weinberg equilibrium for all polymorphisms. In single-locus analysis, the frequency of rs1800624 polymorphism mutant A allele in RAGE gene was significantly higher in patients than in controls (24.52% versus 19.50%, P = 0.006), with the carriers of rs1800624-A allele being 1.51 times more likely to develop breast cancer relative to those with rs1800624-GG genotype after adjustment (95% confidence interval or CI: 1.17-1.94, P = 0.001). In HMGB1 gene, haplotype analysis did not reveal any significance, while in RAGE gene, haplotypes C-T-A and C-A-G (alleles in order of rs1800625, rs18006024, rs2070600) were significantly associated with an increased risk of breast cancer (adjusted OR = 2.72 and 10.35; 95% CI: 1.20-6.18 and 1.58-67.80; P = 0.017 and 0.015 respectively). In further genetic score analysis, per unit and quartile increments of unfavourable alleles were significantly associated with an increased risk of breast cancer after adjustment (odds ratio or OR = 1.20 and 1.26; 95% CI: 1.09-1.32 and 1.12-1.42; P < 0.001 and <0.001 respectively). Our findings altogether demonstrate a significant association between RAGE gene rs1800624 polymorphism and breast cancer risk, and more importantly a cumulative impact of multiple risk associated polymorphisms in HMGB1/RAGE pathway on breast carcinogenesis. PMID- 27241714 TI - Baptisia Poisoning: Consideration on the Botanical Variety. PMID- 27241715 TI - Localized Hyperlucency in an Acutely Dyspneic Patient: Always a Pneumothorax? AB - BACKGROUND: Every emergency physician encounters acutely dyspneic patients with localized hyperlucency on chest x-ray study. Although most commonly due to pneumothorax, alternative diagnosis in selected cases with atypical features includes bullae and cystic lesions, especially in childhood. Presence of atypical radiology shouId alert an emergency physician to rule out any alternative diagnosis. Computed tomography is usually diagnostic in such cases and a double wall sign on computed tomography aids to distinguish between pneumothorax and bullous disease. CASE REPORT: A 60-year-old male presented with sudden increase in dyspnea and a localized hyperlucency on chest x-ray study. A review of his medical records and evaluation of atypical radiology by computed tomography revealed increase in size of bulla to be the cause for distress rather than a pneumothorax. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Every emergency physician encountering acutely dyspneic patients should be aware of these potential mimickers of pneumothorax and ways to distinguish them to avoid inadvertent tube thoracostomy and possible complications. PMID- 27241713 TI - Fat-specific Dicer deficiency accelerates aging and mitigates several effects of dietary restriction in mice. AB - Aging increases the risk of type 2 diabetes, and this can be prevented by dietary restriction (DR). We have previously shown that DR inhibits the downregulation of miRNAs and their processing enzymes - mainly Dicer - that occurs with aging in mouse white adipose tissue (WAT). Here we used fat-specific Dicer knockout mice (AdicerKO) to understand the contributions of adipose tissue Dicer to the metabolic effects of aging and DR. Metabolomic data uncovered a clear distinction between the serum metabolite profiles of Lox control and AdicerKO mice, with a notable elevation of branched-chain amino acids (BCAA) in AdicerKO. These profiles were associated with reduced oxidative metabolism and increased lactate in WAT of AdicerKO mice and were accompanied by structural and functional changes in mitochondria, particularly under DR. AdicerKO mice displayed increased mTORC1 activation in WAT and skeletal muscle, where Dicer expression is not affected. This was accompanied by accelerated age-associated insulin resistance and premature mortality. Moreover, DR-induced insulin sensitivity was abrogated in AdicerKO mice. This was reverted by rapamycin injection, demonstrating that insulin resistance in AdicerKO mice is caused by mTORC1 hyperactivation. Our study evidences a DR-modulated role for WAT Dicer in controlling metabolism and insulin resistance. PMID- 27241716 TI - A cell-surface-anchored ratiometric i-motif sensor for extracellular pH detection. AB - A FRET-based sensor is anchored on the cell surface through streptavidin-biotin interactions. Due to the excellent properties of the pH-sensitive i-motif structure, the sensor can detect extracellular pH with high sensitivity and excellent reversibility. PMID- 27241717 TI - Climate change and biological invasions: evidence, expectations, and response options. AB - A changing climate may directly or indirectly influence biological invasions by altering the likelihood of introduction or establishment, as well as modifying the geographic range, environmental impacts, economic costs or management of alien species. A comprehensive assessment of empirical and theoretical evidence identified how each of these processes is likely to be shaped by climate change for alien plants, animals and pathogens in terrestrial, freshwater and marine environments of Great Britain. The strongest contemporary evidence for the potential role of climate change in the establishment of new alien species is for terrestrial arthropods, as a result of their ectothermic physiology, often high dispersal rate and their strong association with trade as well as commensal relationships with human environments. By contrast, there is little empirical support for higher temperatures increasing the rate of alien plant establishment due to the stronger effects of residence time and propagule pressure. The magnitude of any direct climate effect on the number of new alien species will be small relative to human-assisted introductions driven by socioeconomic factors. Casual alien species (sleepers) whose population persistence is limited by climate are expected to exhibit greater rates of establishment under climate change assuming that propagule pressure remains at least at current levels. Surveillance and management targeting sleeper pests and diseases may be the most cost-effective option to reduce future impacts under climate change. Most established alien species will increase their distribution range in Great Britain over the next century. However, such range increases are very likely be the result of natural expansion of populations that have yet to reach equilibrium with their environment, rather than a direct consequence of climate change. To assess the potential realised range of alien species will require a spatially explicit approach that not only integrates bioclimatic suitability and population level demographic rates but also simulation of landscape-level processes (e.g. dispersal, land-use change, host/habitat distribution, non-climatic edaphic constraints). In terms of invasive alien species that have known economic or biodiversity impacts, the taxa that are likely to be the most responsive are plant pathogens and insect pests of agricultural crops. However, the extent to which climate adaptation strategies lead to new crops, altered rotations, and different farming practices (e.g. irrigation, fertilization) will all shape the potential agricultural impacts of alien species. The greatest uncertainty in the effects of climate change on biological invasions exists with identifying the future character of new species introductions and predicting ecosystem impacts. Two complementary strategies may work under these conditions of high uncertainty: (i) prioritise ecosystems in terms of their perceived vulnerability to climate change and prevent ingress or expansion of alien species therein that may exacerbate problems; (ii) target those ecosystem already threatened by alien species and implement management to prevent the situation deteriorating under climate change. PMID- 27241718 TI - Histone H3 acetylation in the postmortem Parkinson's disease primary motor cortex. AB - Although the role of epigenetics in Parkinson's disease (PD) has not been extensively studied, alpha-synuclein, the main component of Lewy bodies, decreased histone H3 acetylation. Here, we determined if there were histone acetylation changes in the primary motor cortex which, according to the Braak model, is one of the last brain regions affected in PD. Net histone H3 acetylation, histone H3 lysine 9 (H3K9), histone H3 lysine 14 (H3K14), histone H3 lysine 18 (H3K18), and histone H3 lysine 23 (H3K23) acetylation was assessed in the primary motor cortex of those affected and unaffected by PD. There was net increase in histone H3 acetylation due to increased H3K14 and H3K18 acetylation. There was a decrease in H3K9 acetylation. No between-groups difference was detected in H3K23 acetylation. Relationships between Unified Lewy Body Staging scores and histone H3 acetylation and substantia nigra depigmentation scores and histone H3 acetylation were observed. No relationships were detected between postmortem interval and histone H3 acetylation and expired age and histone H3 acetylation. These correlational data support the notion that the histone H3 acetylation changes observed here are not due to the postmortem interval or aging. Instead, they are due to PD and/or factors that covary with PD. The data suggest enhanced gene transcription in the primary motor cortex of the PD brain due to increase H3K14 and H3K18 acetylation. This effect is partially offset by a decreased H3K9 acetylation, which might repress gene transcription. PMID- 27241719 TI - Mutant SOD1 accumulation in sensory neurons does not associate with endoplasmic reticulum stress features: Implications for differential vulnerability of sensory and motor neurons to SOD1 toxicity. AB - Mutations in Cu/Zn-superoxide dismutase (SOD1) cause familial amyotrophic lateral sclerosis (ALS). Previous papers showed that mutant SOD1 accumulates and undergoes misfolding in motor neurons and that the specific interaction of mutant SOD1 with derlin-1 leads to endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). Because evidence shows that mutant SOD1 expression also damages sensory neurons, we hypothesized that, similarly to motor neurons, the sensory neurons of ALS mouse model SOD1(G93A) accumulate mutant/misfolded SOD1 and suffer from ER stress and UPR activation. Our results reveal that SOD1(G93A) sensory neurons accumulate mutant/misfolded SOD1 but, surprisingly, do not suffer from ER stress and UPR activation. Moreover, the sensory neurons do not express detectable levels of the SOD1 interactor derlin-1. These results suggest a potential molecular mechanism underlying the differential vulnerability of motor and sensory neurons to mutant SOD1 toxicity. PMID- 27241720 TI - An apoE-derived mimic peptide, COG1410, alleviates early brain injury via reducing apoptosis and neuroinflammation in a mouse model of subarachnoid hemorrhage. AB - This study investigated the neuroprotective effects of COG1410, an apoliporotein E (apoE)-derived mimic peptide, against early brain injury (EBI) after subarachnoid hemorrhage (SAH). SAH was induced in C57BL/6J mice (n=68) by endovascular perforation. Mice received intravenous injection of COG1410 (2mg/kg) or equal volume of vehicle (saline). The mortality rate, neurological score, rotarod latencies, cell apoptosis, microglial activation, pro-inflammatory cytokines production and protein levels of apoptotic and inflammatory markers were assessed at 24h after sham operation or SAH. Results showed that COG1410 alleviated the neurological deficits associated with SAH. Compared with vehicle treatment group, the number of apoptotic cells and activated microglia decreased significantly in the COG1410 treated group. COG1410 enhanced Akt activation and suppressed caspase-3 cleavage. The imbalance of Bax and Bcl-2 induced by SAH was regulated by COG1410. Additionally, COG1410 attenuated cytokines production of IL 1beta, IL-6 and TNF-alpha and suppressed the activation of JNK/c-Jun and NF kappaB. Taken together, COG1410 protected against EBI via reducing apoptosis and neuroinflammation, through mechanisms that involve the regulation of apoptotic signaling and microglial activation. COG1410 is a potential neuroprotective agent for SAH treatment. PMID- 27241721 TI - The effect of cyclin-dependent kinases inhibitor treatment on experimental herpes simplex encephalitis mice. AB - Herpes simplex encephalitis(HSE) is the most common and serious viral encephalitis in humans. There is a lack of effective medication to date for HSE. A better understanding of the mediators of tissue damage is essential for finding new targets for therapeutic intervention. In this project, we explored the effect of cyclin-dependent kinases inhibitor olomoucine treatment on experimental HSE mice. The following results were obtained: (1) olomoucine increased survival in HSE mice; (2) olomoucine inhibited microglial activation and reduced HSV-1 induced cytokines release; (3) olomoucine prevented neural cells apoptosis and attenuated brain tissue pathological changes following HSV-1 infection; (4) olomoucine reduced brain edema and improved neurological function in HSE. Overall, olomoucine can induce a blunted inflammatory response, maintain the blood vessel wall intact, improve neurological function and increase survival in HSE mice. PMID- 27241722 TI - Part 2-The firings of many neurons and their density; the neural network its connections and field of firings. AB - This paper is concerned with the firing of many neurons and the synthesis of these firings to develop functions and their transforms which relate chemical and electrical phenomena to the physical world. The density of such functions in the most general spaces that we encounter allows us to use linear combinations of them to approximate arbitrarily close to any phenomenon we encounter, imagine or think about. Absence of the technology needed to represent all the senses and the mathematical difficulty of making geometric representations of functions of a complex and of more general division algebra variables make it difficult to validate the mathematical outcome of this approach to neural firings. But we think that this problem will be solved in the not-too-distant future when at least the senses of smell, taste and touch would have been so mathematized that it is possible to instill these qualities in robots in some fashion. PMID- 27241723 TI - Preclinical safety study of a recombinant Streptococcus pyogenes vaccine formulated with aluminum adjuvant. AB - A recombinant vaccine composed of a fusion protein formulated with aluminum hydroxide adjuvant is under development for protection against diseases caused by Streptococcus pyogenes. The safety and local reactogenicity of the vaccine was assessed by a comprehensive series of clinical, pathologic and immunologic tests in preclinical experiments. Outbred mice received three intramuscular injections of 1/5th of the human dose (0.1 ml) and rabbits received two injections of the full human dose. Control groups received adjuvant or protein antigen. The vaccine did not cause clinical evidence of systemic toxicity in mice or rabbits. There was a transient increase of peripheral blood neutrophils after the third vaccination of mice. In addition, the concentration of acute phase proteins serum amyloid A and haptoglobin was significantly increased 1 day after injection of the vaccine in mice. There was mild transient swelling and erythema of the injection site in both mice and rabbits. Treatment-related pathology was limited to inflammation at the injection site and accumulation of adjuvant-containing macrophages in the draining lymph nodes. In conclusion, the absence of clinical toxicity in two animal species suggest that the vaccine is safe for use in a phase I human clinical trial. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27241724 TI - Controlled attenuation parameter for the detection of hepatic steatosis in patients with chronic hepatitis B. AB - BACKGROUND: Controlled attenuation parameter (CAP) is a non-invasive method for diagnosing liver steatosis based on vibration-controlled transient elastography. The primary objective of this study was to assess CAP performance and determine the cut-off values for the diagnosis of hepatic steatosis in patients with chronic hepatitis B (CHB) using liver biopsy as a gold standard. The second objective was to apply the cut-off values found in the first cohort to a larger cohort to compare the performance of CAP and ultrasonography. METHODS: Overall, 189 patients with CHB who underwent liver biopsy and CAP detection and 1707 patients with CHB and CAP who underwent abdominal ultrasonography were prospectively enrolled. The performance of CAP for evaluating hepatic steatosis compared with liver biopsy was calculated using the area under the receiver operating characteristic curve (AUROC). RESULTS: In the 189 patients who underwent liver biopsy, the cut-offs for the CAP with steatosis S >= 1, S >= 2 and S >= 3 were 222 dB/m, 247 dB/m and 274 dB/m, respectively, and the AUROC were 0.88 (95% confidence interval [CI] = 0.82-0.95), 0.92 (95% CI = 0.87-0.97) and 0.94 (95% CI = 0.90-0.99), respectively. After applying the cut-offs above to the 1707 patients, it was found that CAP had a good concordance with abdominal ultrasonography with steatosis grade > S2. On multivariate analysis, body mass index (p < 0.001), triglyceride level (p < 0.001) and fasting glucose level (p = 0.001) were independent risk factors of CAP. CONCLUSIONS: CAP had high diagnostic performance for evaluating hepatic steatosis in patients with CHB and had a good concordance with abdominal ultrasonography. PMID- 27241725 TI - Development of a Database of the Fluoride Content of Selected Drinks and Foods in the UK. AB - It is important to monitor systemic fluoride (F) intake from foods, drinks and inadvertent toothpaste ingestion in order to minimise the risk of dental fluorosis while maximising caries prevention. In the UK, an F database containing the F content of commercially available foods and drinks was compiled from 518 products analysed using an acid-diffusion method and F-ion-selective electrode. The individual products analysed ranged from <0.01 ug F/100 g for butter/margarine (miscellaneous foods group) to 1,054.20 ug F/100 g for canned sardines (fish group). These findings, along with the wide range of F contents found within the food groups, highlight the need for comprehensive F content labelling of food and drink products. PMID- 27241726 TI - A new application of the phase-field method for understanding the mechanisms of nuclear architecture reorganization. AB - Specific features of nuclear architecture are important for the functional organization of the nucleus, and chromatin consists of two forms, heterochromatin and euchromatin. Conventional nuclear architecture is observed when heterochromatin is enriched at nuclear periphery, and it represents the primary structure in the majority of eukaryotic cells, including the rod cells of diurnal mammals. In contrast to this, inverted nuclear architecture is observed when the heterochromatin is distributed at the center of the nucleus, which occurs in the rod cells of nocturnal mammals. The inverted architecture found in the rod cells of the adult mouse is formed through the reorganization of conventional architecture during terminal differentiation. Although a previous experimental approach has demonstrated the relationship between these two nuclear architecture types at the molecular level, the mechanisms underlying long-range reorganization processes remain unknown. The details of nuclear structures and their spatial and temporal dynamics remain to be elucidated. Therefore, a comprehensive approach, using mathematical modeling, is required, in order to address these questions. Here, we propose a new mathematical approach to the understanding of nuclear architecture dynamics using the phase-field method. We successfully recreated the process of nuclear architecture reorganization, and showed that it is robustly induced by physical features, independent of a specific genotype. Our study demonstrates the potential of phase-field method application in the life science fields. PMID- 27241727 TI - Phase transition on the convergence rate of parameter estimation under an Ornstein-Uhlenbeck diffusion on a tree. AB - Diffusion processes on trees are commonly used in evolutionary biology to model the joint distribution of continuous traits, such as body mass, across species. Estimating the parameters of such processes from tip values presents challenges because of the intrinsic correlation between the observations produced by the shared evolutionary history, thus violating the standard independence assumption of large-sample theory. For instance (Ho and Ane, Ann Stat 41:957-981, 2013) recently proved that the mean (also known in this context as selection optimum) of an Ornstein-Uhlenbeck process on a tree cannot be estimated consistently from an increasing number of tip observations if the tree height is bounded. Here, using a fruitful connection to the so-called reconstruction problem in probability theory, we study the convergence rate of parameter estimation in the unbounded height case. For the mean of the process, we provide a necessary and sufficient condition for the consistency of the maximum likelihood estimator (MLE) and establish a phase transition on its convergence rate in terms of the growth of the tree. In particular we show that a loss of [Formula: see text] consistency (i.e., the variance of the MLE becomes [Formula: see text], where n is the number of tips) occurs when the tree growth is larger than a threshold related to the phase transition of the reconstruction problem. For the covariance parameters, we give a novel, efficient estimation method which achieves [Formula: see text]-consistency under natural assumptions on the tree. Our theoretical results provide practical suggestions for the design of comparative data collection. PMID- 27241729 TI - Systems medicine approaches for peptide array-based protein kinase profiling: progress and prospects. AB - INTRODUCTION: Pharmacological manipulation of signalling pathways is becoming an increasingly important avenue for the rational clinical management of disease but is hampered by a lack of technologies that allow the generation of comprehensive descriptions of cellular signalling. AREAS COVERED: Herein, the authors discuss the potential of peptide array-based kinome profiling for evaluating cellular signalling in the context of drug discovery. Expert commentary: Genomic and proteomic approaches have been of significant value to our elucidation of the molecular mechanisms that govern physiology. However, an equally, if not more important goal, is to define those proteins that participate in signalling pathways that ultimately control cell fate, especially kinases. Traditional genetic and biochemical approaches can certainly provide answers here, but for technical and practical reasons, are typically pursued one gene or pathway at a time. A more comprehensive approach is one in which peptide arrays of kinase specific substrates are incubated with cell lysates and (33)P-ATP generating comprehensive descriptions, or where arrays are interrogated with phosphospecific antibodies. Both approaches allow analysis of cellular signalling without a priori assumptions to possibly influenced pathways. PMID- 27241730 TI - Liquid structure of dibutyl sulfoxide. AB - We present experimental (X-ray diffraction) data on the structure of liquid dibutyl sulfoxide at 320 K and rationalise the data by means of molecular dynamics simulations. Not unexpectedly, DBSO bearing a strong dipolar moiety and two medium length, apolar butyl chains, this compound was characterised by a distinct degree of polar vs. apolar structural differentiation at the nm spatial scale, which was fingerprinted by a low Q peak in its X-ray diffraction pattern. Similar to, but to a larger extent than its shorter chain family members (such as DMSO), DBSO was also characterised by an enhanced dipole-dipole correlation, which was responsible for a moderate Kirkwood correlation factor as well as for the self-association detected in this compound. We show, however, that the supposedly relevant hydrogen bonding correlations between oxygen and the butyl chain hydrogens are of a limited extent only, and only in the case of alpha hydrogens is an appreciable indication of the existence of such an interaction found, albeit this turned out to be a mere consequence of the strong dipole dipole correlation. PMID- 27241728 TI - Graphene-based microfluidics for serial crystallography. AB - Microfluidic strategies to enable the growth and subsequent serial crystallographic analysis of micro-crystals have the potential to facilitate both structural characterization and dynamic structural studies of protein targets that have been resistant to single-crystal strategies. However, adapting microfluidic crystallization platforms for micro-crystallography requires a dramatic decrease in the overall device thickness. We report a robust strategy for the straightforward incorporation of single-layer graphene into ultra-thin microfluidic devices. This architecture allows for a total material thickness of only ~1 MUm, facilitating on-chip X-ray diffraction analysis while creating a sample environment that is stable against significant water loss over several weeks. We demonstrate excellent signal-to-noise in our X-ray diffraction measurements using a 1.5 MUs polychromatic X-ray exposure, and validate our approach via on-chip structure determination using hen egg white lysozyme (HEWL) as a model system. Although this work is focused on the use of graphene for protein crystallography, we anticipate that this technology should find utility in a wide range of both X-ray and other lab on a chip applications. PMID- 27241731 TI - The carbon bonus of organic nitrogen enhances nitrogen use efficiency of plants. AB - The importance of organic nitrogen (N) for plant nutrition and productivity is increasingly being recognized. Here we show that it is not only the availability in the soil that matters, but also the effects on plant growth. The chemical form of N taken up, whether inorganic (such as nitrate) or organic (such as amino acids), may significantly influence plant shoot and root growth, and nitrogen use efficiency (NUE). We analysed these effects by synthesizing results from multiple laboratory experiments on small seedlings (Arabidopsis, poplar, pine and spruce) based on a tractable plant growth model. A key point is that the carbon cost of assimilating organic N into proteins is lower than that of inorganic N, mainly because of its carbon content. This carbon bonus makes it more beneficial for plants to take up organic than inorganic N, even when its availability to the roots is much lower - up to 70% lower for Arabidopsis seedlings. At equal growth rate, root:shoot ratio was up to three times higher and nitrogen productivity up to 20% higher for organic than inorganic N, which both are factors that may contribute to higher NUE in crop production. PMID- 27241732 TI - Surveillance of antibiotic susceptibility in a Swedish Burn Center 1994-2012. AB - Patients with burn trauma are at risk for infections caused by antibiotic resistant bacteria (ABR) with subsequent increase in morbidity and mortality. As part of the Swedish strategic program against antibiotic resistance in intensive care (ICU-Strama), we have surveyed the distribution of species and ABR in isolates from patients admitted to a Swedish burn center at Linkoping University Hospital from 1994 through 2012. In an international comparison Strama has been successful in reducing the antibiotic consumption among animals and humans in primary care. The aim of this study was to investigate the antibiotic consumption pressure and resistance rates in a Swedish burn unit. METHODS: Microbiology data, total body surface area (TBSA), patient days, and mortality were collected from a hospital database for all patients admitted to the Burn Center at the University Hospital of Linkoping from April 1994 through December 2012. RESULTS: A total of 1570 patients were admitted with a mean annual admission rate of 83 patients (range: 57-152). 15,006 microbiology cultures (approximately 10 per patient) were collected during the study period and of these 4531 were positive (approximately 3 per patient). The annual mean total body surface area (TBSA) was 13.4% (range 9.5-18.5) with an annual mortality rate of 5.4% (range 1-8%). The MRSA incidence was 1.7% (15/866) which corresponds to an MRSA incidence of 0.34/1000 admission days (TAD). Corresponding figures were for Escherichia coli resistant to 3(rd) generation cephalosporins (ESBL phenotype) 8% (13/170) and 0.3/TAD, Klebsiella spp. ESBL phenotype 5% (6/134) and 0.14/TAD, carbapenem resistant Pseudomonas aeruginosa 26% (56/209) and 1.28/TAD, and carbapenem resistant Acinetobacter spp. 3% (2/64) and 0.04/TAD. CONCLUSIONS: Our results show a sustained low risk for MRSA and high, although not increasing, risk for carbapenem resistant P. aeruginosa. PMID- 27241734 TI - Distinctive Drug-resistant Mutation Profiles and Interpretations of HIV-1 Proviral DNA Revealed by Deep Sequencing in Reverse Transcriptase. AB - OBJECTIVE: To investigate distinctive features in drug-resistant mutations (DRMs) and interpretations for reverse transcriptase inhibitors (RTIs) between proviral DNA and paired viral RNA in HIV-1-infected patients. METHODS: Forty-three HIV-1 infected individuals receiving first-line antiretroviral therapy were recruited to participate in a multicenter AIDS Cohort Study in Anhui and Henan Provinces in China in 2004. Drug resistance genotyping was performed by bulk sequencing and deep sequencing on the plasma and whole blood of 77 samples, respectively. Drug resistance interpretation was compared between viral RNA and paired proviral DNA. RESULTS: Compared with bulk sequencing, deep sequencing could detect more DRMs and samples with DRMs in both viral RNA and proviral DNA. The mutations M184I and M230I were more prevalent in proviral DNA than in viral RNA (Fisher's exact test, P<0.05). Considering 'majority resistant variants', 15 samples (19.48%) showed differences in drug resistance interpretation between viral RNA and proviral DNA, and 5 of these samples with different DRMs between proviral DNA and paired viral RNA showed a higher level of drug resistance to the first-line drugs. Considering 'minority resistant variants', 22 samples (28.57%) were associated with a higher level of drug resistance to the tested RTIs for proviral DNA when compared with paired viral RNA. CONCLUSION: Compared with viral RNA, the distinctive information of DRMs and drug resistance interpretations for proviral DNA could be obtained by deep sequencing, which could provide more detailed and precise information for drug resistance monitoring and the rational design of optimal antiretroviral therapy regimens. PMID- 27241733 TI - BK channels in microglia are required for morphine-induced hyperalgesia. AB - Although morphine is a gold standard medication, long-term opioid use is associated with serious side effects, such as morphine-induced hyperalgesia (MIH) and anti-nociceptive tolerance. Microglia-to-neuron signalling is critically involved in pain hypersensitivity. However, molecules that control microglial cellular state under chronic morphine treatment remain unknown. Here we show that the microglia-specific subtype of Ca(2+)-activated K(+) (BK) channel is responsible for generation of MIH and anti-nociceptive tolerance. We find that, after chronic morphine administration, an increase in arachidonic acid levels through the MU-opioid receptors leads to the sole activation of microglial BK channels in the spinal cord. Silencing BK channel auxiliary beta3 subunit significantly attenuates the generation of MIH and anti-nociceptive tolerance, and increases neurotransmission after chronic morphine administration. Therefore, microglia-specific BK channels contribute to the generation of MIH and anti nociceptive tolerance. PMID- 27241735 TI - Comparison of Two Molecular Assays For Detecting Smear Negative Pulmonary Tuberculosis. AB - OBJECTIVE: To compare the performance of MTBDRplus V2 and Xpert MTB/RIF for detecting smear negative pulmonary tuberculosis (PTB). METHODS: Clinical PTB suspects were enrolled consecutively in Anhui Chest Hospital and Xi'an Chest Hospital from January to December in 2014. The sputum samples of smear negative PTB suspects were collected and decontaminated. The sediment was used to conduct MTBDRplus V2, Xpert MTB/RIF and drug susceptibility test (DST). All the samples with discrepant drug susceptibility result between molecular methods and phenotypic method were confirmed by DNA sequencing. RESULTS: A total of 1973 cases were enrolled in this study. The detection rates of Mycobacterium tuberculosis complex (MTBC) by MTBDRplus V2 and Xpert MTB/RIF were 27.67% and 27.98%, respectively. When setting MGIT culture result as a gold standard, the sensitivity and specificity of MTBDRplus V2 were 86.74% and 93.84%, and the sensitivity and specificity of Xpert MTB/RIF were 86.55% and 93.43%, respectively. For the detection of the resistance to rifampin, the sensitivity and specificity of MTBDRplus V2 were 94.34% and 96.62%, and the sensitivity and specificity of Xpert MTB/RIF were 88.68% and 95.96%, respectively. For the detection of the resistance to isoniazid, the sensitivity and specificity of MTBDRplus V2 were 77.38% and 98.02%, respectively. CONCLUSION: MTBDRplus V2 and Xpert MTB/RIF can be used to detect MTBC in smear negative samples with satisfactory performance. PMID- 27241736 TI - Longitudinal Changes in Liver Aminotransferases Predict Metabolic Syndrome in Chinese Patients with Nonviral Hepatitis. AB - OBJECTIVE: This study explored the correlation of longitudinal changes in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels with the incidence of metabolic syndrome (Mets) based on a dynamic health examination cohort. METHODS: A Mets-free dynamic cohort involving 4541 participants who underwent at least three health examinations from 2006 to 2011 was included in the study. Mets was defined according to the Chinese Medical Association Diabetes Branch definition that included hypertension, obesity, hyperlipidemia, and hyperglycemia. Generalized estimating equation (GEE) model was used to analyze multivariate relative risk (RR) of repeated observations of ALT and AST in quartiles for Mets or its components according to gender. RESULTS: In all, 826 Mets cases were reported. Adjustment of relevant parameters indicated that time varying changes in ALT and AST levels were positively associated with the incidence of Mets in a dose-response manner. Positive association between high ALT levels and fatty liver was much stronger than that between high AST levels and fatty liver, particularly in male participants. These associations were consistently observed in the following subgroups: participants with ALT and AST levels of <40 U/L, participants with of <25 kg/m2, and participants with non fatty liver. Furthermore, participants with 2 Mets components at baseline showed lower multivariate adjusted RRs of ALT and AST for Mets than participants with 0 1 Mets component. CONCLUSION: These results suggested that elevated serum ALT and AST levels were early biomarkers of Mets or its components. PMID- 27241737 TI - Effects of Parental Dietary Exposure to GM Rice TT51 on the Male Reproductive System of Rat Offspring. AB - OBJECTIVE: To evaluate the health effects of parental dietary exposure to GM rice TT51 on the male reproductive system of rat off spring. METHODS: Rice-based diets, containing 60% ordinary grocery rice, MingHui63, or TT51 by weight, were given to parental rats (15 males/30 females each group) for 70 days prior mating and throughout pregnancy and lactation. After weaning, eight male offspring rats were randomly selected at each group and fed with diets correspondent to their parents' for 70 days. The effects of exposure to TT51 on male reproductive system of offspring rats were assessed through sperm parameters, testicular function enzyme activities, serum hormones (FSH, LH, and testosterone levels), testis histopathological examination, and the relative expression levels of selected genes along the hypothalamic-pituitary- testicular (HPT) axis. RESULTS: No significant differences were observed in body weight, food intake, organ/body weights, serum hormone, sperm parameters, testis function enzyme ACP, LDH, and SDH activities, testis histopathological changes, and relative mRNA expression levels of GnRH-R, FSH-R, LH-R, and AR along the HPT axis. CONCLUSION: The results of this study demonstrate that parental dietary exposure to TT51 reveals no significant differences on the reproductive system of male offspring rats compared with MingHui63 and control. PMID- 27241738 TI - Prevention of H2O2 Induced Oxidative Damages of Rat Testis by Thymus algeriensis. AB - OBJECTIVE: We evaluate the effects of Thymus algeriensis (TEO) against hydrogen peroxide (H2O2) toxicity on body and testis weight, testis sperm count, testis lipid peroxidation, and antioxidant enzyme activities in rats. METHODS: Rats were treated with low (LD) and high dose (HD) of H2O2 (0.1 and 1 mmol/L) in the presence or absence of TEO (150 mg/kg). RESULTS: The results exhibited a significant decrease in body weight and testis weight, in total sperm number decrease (P<0.05), sperm motility and percentage of sperm viability, leading to complete arrest, in sperm flagellar beat frequency by the gavage of 1 mmol/L H2O2 compared to controls. The administration of H2O2 resulted in a significant reduction in testis GSH, GPx, CAT, SOD, and GST activity and significant increase (P<0.05) in MDA concentration compared with the untreated control animals. TEO pre-treatment protected testis from the H2O2 generated oxidative stress. These results were confirmed by histological architecture examinations. CONCLUSION: H2O2 has the ability to alter the sperm function, characteristics and development of testis. However, TEO is an efficient natural agent, which can prevent the testis from H2O2-induced oxidative damage in rats. PMID- 27241739 TI - Norovirus Infection and Histo-blood Group Antigens in Children Hospitalized with Diarrhea in Lulong and Chenzhou in China. AB - Norovirus (NoV) is a pathogen that commonly causes viral diarrhea in children. Studies indicate that NoV recognizes human histo-blood group antigens (HBGAs) as cell attachment factors. In order to explore the correlation between of NoV infection and HBGAs, a cross-sectional study was conducted in children less than five years old who were hospitalized with diarrhea in two areas of China between November 2014 and February 2015. Of the paired stool and saliva samples taken from 424 children, NoV was detected in 24 (6%) children, with viral genotypes GII.3 (n=5), GII.4 (n=14), GII.12 (n=1), and GII.17 (n=4). All of the individuals having NoV infection were either secretors (Lea-b+/Lex-y+) or partial secretors (Lea+b+/Lex+y+) except one GII.3 infection of a non-secretor (Lea+b-/Lex+y-). These results suggest that secretor positive is associated with NoV infection, although non-secretors are not absolutely protected from NoV infection. PMID- 27241740 TI - Prevalence and Predictors of Hypertension in the Labor Force Population in China: Results from a Cross-sectional Survey in Xinjiang Uygur Autonomous Region. AB - The objective of this study was to examine the prevalence of hypertension and identify its contributory factors in the labor force population in Karamay. A total of 2819 adults (55.9% male adults) were interviewed and examined. The overall crude prevalence of hypertension was 32.4%. Among 914 hypertensive patients, 34.8% were aware of their diagnosis, 22.1% received treatment, and 5.6% achieved blood pressure control. Hypertension was significantly correlated with age, overweight/obesity, central obesity, diabetes, and dyslipidemia in both men and women. In addition, less education, alcohol consumption, and less walking were risk factors for men. Effective hypertension prevention and control programs are urgently needed to decrease the burden of hypertension in this region. PMID- 27241741 TI - Toxic Effects of Tetrabromobisphenol A on Thyroid Hormones in SD Rats and the Derived-reference Dose. AB - The present study determined the thyroid hormone interference of tetrabromobisphenol A (TBBPA) in Sprague-Dawley (SD) rats, and the derived reference dose (RfD) of different endpoint effects on mammals based on experimental results and data collection. Based on repeated exposure toxicity tests on mammals and extensive research, the present study used BMDS240 Software to derive a benchmark dose, and analyzed the accuracy and uncertainty, and similarity with other studies. Test results on triiodothyronine (T3), thyroxine (T4), and thyroid stimulating hormone (TSH) demonstrated that all the indicators presented a non-monotonous dose-effect relationship clearly, except TSH in male rats exposed to 0-1000 mg/kg BW per day. Therefore, RfDs were derived from different critical effects. In summary, RfD for mammals in the present study was found to be 0.6 mg/kg per day. PMID- 27241742 TI - The Main Biological Hazards in Animal Biosafety Level 2 Facilities and Strategies for Control. AB - Concern about the biological hazards involved in microbiological research, especially research involving laboratory animals, has increased in recent years. Working in an animal biosafety level 2 facility (ABSL-2), commonly used for research on infectious diseases, poses various biological hazards. Here, the regulations and standards related to laboratory biosafety in China are introduced, the potential biological hazards present in ABSL-2 facilities are analyzed, and a series of strategies to control the hazards are presented. PMID- 27241743 TI - Exposure Assessment of Sb2O3 in PET Food Contact Materials. AB - This study was conducted to do exposure assessment of the possible migration of antimony trioxide (Sb2O3) from Polyethylene terephthalate (PET) food contact materials (FCM). Consumption Factor (CF) and Food-type Distribution Factor (fT) were calculated from survey data with reference to the US FDA method. The most conservative migration conditions were obtained by testing Sb migration from PET FCM based on the Chinese national standard of GB/T 5009.101-2003[1]. Migration levels of Sb from PET FCM were tested and migration levels of Sb2O3 were obtained through molecular weight conversion between Sb and Sb2O3. Exposure assessment of Sb2O3 was undertaken. The Chinese Estimated Daily Intake (EDI) of Sb2O3 resulted from PET FCM was 90.7 ng p-1d-1. PMID- 27241744 TI - Enhancing growth and non-specific immunity of grass carp and Nile tilapia by incorporating Chinese herbs (Astragalus membranaceus and Lycium barbarum) into food waste based pellets. AB - The effects of Astragalus membranaceus and Lycium barbarum on the growth performance and non-specific immunity of grass carp and Nile tilapia were studied. Herb extracts of Chinese medicinal herbs (2 g kg-1 or 20 g kg-1) were incorporated into food waste based fish feed pellets. Fish growth and selected non-specific immune parameters of grass carp and Nile tilapia were studied in two separate feeding trials. Both grass carp and Nile tilapia fed diets of feed pellets containing 2 g kg-1Lycium barbarum extract achieved the best relative weight gain, feed conversion ratio, specific growth rate and protein efficiency ratio among all experimental diets. Fish fed with diets containing 2 g kg-1Lycium barbarum also resulted in significantly higher total immunoglobin, bactericidal activity and anti-protease activity; and also a lower mortality when challenged with pathogenic bacteria. On the other hand, both fish species fed with diets containing 20 g kg-1 of Astragalus membranaceus and 20 g kg-1Lycium barbarum, resulted in significantly impaired weight gain. In addition, incorporation of 2 g kg-1Lycium barbarum extract would be a more suitable dose for both fish species, in terms of achieving better feed conversion ratio, specific growth rate, protein digestibility, and improved non-specific immune parameters. Based on this study, it can be concluded that waste based feed pellets incorporated with Chinese medicinal herb extracts have the ability to enhance growth and immunity of fish. Therefore, the use of Chinese medicinal herbs in aquaculture should be encouraged, in order to replace certain antibiotics known to impose environmental and health effects through the discharge of aquaculture effluents. PMID- 27241745 TI - Warming increases nutrient mobilization and gaseous nitrogen removal from sediments across cascade reservoirs. AB - Increases in water temperature, as a result of climate change, may influence biogeochemical cycles, sediment-water fluxes and consequently environmental sustainability. Effects of rising temperature on dynamics of nitrate, nitrite, ammonium, dissolved inorganic nitrogen (DIN), dissolved reactive phosphorus (DRP), dissolved organic carbon (DOC) and gaseous nitrogen (N2 and N2O) were examined in a subtropical river (the Jiulong River, southeast China) by microcosm experiments. Slurry sediments and overlying water were collected from three continuous cascade reservoirs, and laboratory incubations were performed at four temperature gradients (5 degrees C, 15 degrees C, 25 degrees C and 35 degrees C). Results indicated: (1) warming considerably increased sediment ammonium, DIN and DOC fluxes to overlying water; (2) warming increased retention of nitrate, and to a lesser extent, nitrite, corresponding to increases in N2 and N2O emission; (3) DRP was retained but released from Fe/Al-P enriched sediments at high temperature (35 degrees C) due to enhanced coupled transformation of carbon and nitrogen with oxygen deficiency. Using relationships between sediment fluxes and temperature, a projected 2.3 degrees C-warming in future would increase ammonium flux from sediment by 7.0%-16.8%, while increasing nitrate flux into sediment by 8.9%-28.6%. Moreover, substrates (e.g., grain size, carbon availability) influenced nutrient delivery and cycling across cascade reservoirs. This study highlights that warming would increase bioreactive nutrient (i.e., ammonium and phosphate) mobilization with limited gaseous N removal from sediments, consequently deteriorating water quality and increasing eutrophication with future climate change. PMID- 27241746 TI - Myelodysplastic Syndrome Occurring in a Patient with Gorlin Syndrome. AB - We report a case of myelodysplastic syndrome (MDS) occurring in an African American boy with Gorlin syndrome with a novel PTCH1 mutation. Before developing MDS, the patient had been treated with chemotherapy and radiation for a medulloblastoma. He received a bone marrow transplant for the MDS and eventually died of treatment complications. Secondary hematologic malignancies are a known complication of certain chemotherapeutics, although whether a patient with Gorlin syndrome has a greater propensity for the development of such malignancies is unclear. PMID- 27241747 TI - Self-Injection Locking of a Vortex Spin Torque Oscillator by Delayed Feedback. AB - The self-synchronization of spin torque oscillators is investigated experimentally by re-injecting its radiofrequency (rf) current after a certain delay time. We demonstrate that the integrated power and spectral linewidth are improved for optimal delays. Moreover by varying the phase difference between the emitted power and the re-injected one, we find a clear oscillatory dependence on the phase difference with a 2pi periodicity of the frequency of the oscillator as well as its power and linewidth. Such periodical behavior within the self injection regime is well described by the general model of nonlinear auto oscillators including not only a delayed rf current but also all spin torque forces responsible for the self-synchronization. Our results reveal new approaches for controlling the non-autonomous dynamics of spin torque oscillators, a key issue for rf spintronics applications as well as for the development of neuro-inspired spin-torque oscillators based devices. PMID- 27241748 TI - RNA Imaging with Multiplexed Error-Robust Fluorescence In Situ Hybridization (MERFISH). AB - Quantitative measurements of both the copy number and spatial distribution of large fractions of the transcriptome in single cells could revolutionize our understanding of a variety of cellular and tissue behaviors in both healthy and diseased states. Single-molecule fluorescence in situ hybridization (smFISH)-an approach where individual RNAs are labeled with fluorescent probes and imaged in their native cellular and tissue context-provides both the copy number and spatial context of RNAs but has been limited in the number of RNA species that can be measured simultaneously. Here, we describe multiplexed error-robust fluorescence in situ hybridization (MERFISH), a massively parallelized form of smFISH that can image and identify hundreds to thousands of different RNA species simultaneously with high accuracy in individual cells in their native spatial context. We provide detailed protocols on all aspects of MERFISH, including probe design, data collection, and data analysis to allow interested laboratories to perform MERFISH measurements themselves. PMID- 27241749 TI - Imaging Single mRNA Dynamics in Live Neurons and Brains. AB - RNA is a key player in the process of gene expression. Whereas fluorescence in situ hybridization allows single mRNA imaging in fixed cells, the MS2-GFP labeling technique enables the observation of mRNA dynamics in living cells. Recently, two genetically engineered mouse models have been developed for the application of the MS2-GFP system in live animals. First, the Actb-MBS mouse was generated by knocking in 24 repeats of the MS2 stem-loop sequence in the 3' untranslated region of the beta-actin gene. Second, the MCP mouse was made to express the NLS-HA-MCP-GFP transgene in all cell types. By crossing Actb-MBS and MCP mice, a double homozygous mouse line, MCP*MBS, was established to visualize endogenous beta-actin mRNA labeled with multiple green fluorescent proteins. By imaging hippocampal neurons or brain slices from MCP*MBS mice, the dynamics of mRNA, such as transcription, transport, and localization, can be studied at single mRNA resolution. In this chapter, we explain the basics of MCP*MBS mice and describe methods for utilizing these animals. PMID- 27241750 TI - Monitoring of RNA Dynamics in Living Cells Using PUM-HD and Fluorescent Protein Reconstitution Technique. AB - Fluorescence live-cell RNA imaging to monitor the intracellular localization and dynamics of the target RNA is a challenging subject. One of the difficulties to achieve this is to establish a precise method to enable a fluorescent labeling to the target RNA in living cells. Technologies to reduce the background fluorescence and to detect the RNA with high sensitivity are also necessary to visualize and analyze the intracellular localization and dynamic of the target RNA precisely. Especially in monitoring single-molecule motion, a special setup of a microscope system is required. Such technical problems make the live-cell RNA imaging to be a difficult subject. We recently developed a methodology to label and to visualize a target RNA in living cells with low background fluorescence by using a probe that is based on an RNA-binding protein domain PUM HD (pumilio homology domain) and a fluorescent protein reconstitution method. A noteworthy property of PUM-HD to apply RNA probes is that this protein domain can be modified to recognize a particular 8-base RNA sequence by inducing tailor-made designed mutagenesis. The fluorescent protein reconstitution method allows us to detect the target RNA with high signal-to-noise ratio. Using the probe based on PUM-HD, a fluorescent protein reconstitution method, and a homebuilt fluorescent microscope system, we succeeded in single-molecule observation of a target RNA in living cells. In this chapter, the techniques to establish the probe and to observe the motion of single-molecule RNA are described. PMID- 27241752 TI - In Vivo RNA Visualization in Plants Using MS2 Tagging. AB - Intracellular trafficking and asymmetric localization of RNA molecules within cells are a prevalent process across phyla involved in developmental control and signaling and thus in the determination of cell fate. In addition to intracellular localization, plants support the trafficking of RNA molecules also between cells through plasmodesmata (PD), which has important roles in the cell to-cell and systemic communication during plant growth and development. Viruses have developed strategies to exploit the underlying plant RNA transport mechanisms for the cell-to-cell and systemic dissemination of infection. In vivo RNA visualization methods have revolutionized the study of RNA dynamics in living cells. However, their application in plants is still in its infancy. To gain insights into the RNA transport mechanisms in plants, we study the localization and transport of Tobacco mosaic virus RNA using MS2 tagging. This technique involves the tagging of the RNA of interest with repeats of an RNA stem-loop (SL) that is derived from the origin of assembly of the bacteriophage MS2 and recruits the MS2 coat protein (MCP). Thus, expression of MCP fused to a fluorescent marker allows the specific visualization of the SL-carrying RNA. Here we describe a detailed protocol for Agrobacterium tumefaciens-mediated transient expression and in vivo visualization of MS2-tagged mRNAs in Nicotiana benthamiana leaves. PMID- 27241751 TI - Applications of Hairpin DNA-Functionalized Gold Nanoparticles for Imaging mRNA in Living Cells. AB - Molecular imaging agents are useful for imaging molecular processes in living systems in order to elucidate the function of molecular mediators in health and disease. Here, we demonstrate a technique for the synthesis, characterization, and application of hairpin DNA-functionalized gold nanoparticles (hAuNPs) as fluorescent hybridization probes for imaging mRNA expression and spatiotemporal dynamics in living cells. These imaging probes feature gold colloids linked to fluorophores via engineered oligonucleotides to resemble a molecular beacon in which the gold colloid serves as the fluorescence quencher in a fluorescence resonance energy transfer system. Target-specific hybridization of the hairpin oligonucleotide enables fluorescence de-quenching and subsequent emission with high signal to noise ratios. hAuNPs exhibit high specificity without adverse toxicity or the need for transfection reagents. Furthermore, tunability of hAuNP emission profiles by selection of spectrally distinct fluorophores enables multiplexed mRNA imaging applications. Therefore, hAuNPs are promising tools for imaging gene expression in living cells. As a representative application of this technology, we discuss the design and applications of hAuNP targeted against distinct matrix metalloproteinase enzymes for the multiplexed detection of mRNA expression in live breast cancer cells using flow cytometry and fluorescence microscopy. PMID- 27241753 TI - TRICK: A Single-Molecule Method for Imaging the First Round of Translation in Living Cells and Animals. AB - The life of an mRNA is dynamic within a cell. The development of quantitative fluorescent microscopy techniques to image single molecules of RNA has allowed many aspects of the mRNA lifecycle to be directly observed in living cells. Recent advances in live-cell multicolor RNA imaging, however, have now made it possible to investigate RNA metabolism in greater detail. In this chapter, we present an overview of the design and implementation of the translating RNA imaging by coat protein knockoff RNA biosensor, which allows untranslated mRNAs to be distinguished from ones that have undergone a round of translation. The methods required for establishing this system in mammalian cell lines and Drosophila melanogaster oocytes are described here, but the principles may be applied to any experimental system. PMID- 27241754 TI - Fluctuation Analysis: Dissecting Transcriptional Kinetics with Signal Theory. AB - Recent live-cell microscopy techniques now allow the visualization in multiple colors of RNAs as they are transcribed on genes of interest. Following the number of nascent RNAs over time at a single locus reveals complex fluctuations originating from the underlying transcriptional kinetics. We present here a technique based on concepts from signal theory-called fluctuation analysis-to analyze and interpret multicolor transcriptional time traces and extract the temporal signatures of the underlying mechanisms. The principle is to generate, from the time traces, a set of functions called correlation functions. We explain how to compute these functions practically from a set of experimental traces and how to interpret them through different theoretical and computational means. We also present the major difficulties and pitfalls one might encounter with this technique. This approach is capable of extracting mechanistic information hidden in transcriptional fluctuations at multiple timescales and has broad applications for understanding transcriptional kinetics. PMID- 27241755 TI - IMAGEtags: Quantifying mRNA Transcription in Real Time with Multiaptamer Reporters. AB - Cell communications are essential to the organization, development, and maintenance of multicellular organisms. Much of this communication involves changes in RNA transcription and is dynamic. Most methods for studying transcription require interrupting the continuity of cellular function by sacrificing the communicating cells and capturing gene expression information by periodic sampling of individual cells or the population. The IMAGEtag technology to quantify RNA levels in living cells, demonstrated here in yeast, allows individual cells to be tracked over time as they respond to different environmental cues. IMAGEtags are short RNAs consisting of strings of a variable number of tandem aptamers that bind small-molecule ligands. The aptamer strings can vary in length and in configuration of aptamer constituents, such as to contain multiples of the same aptamer or two or more different aptamers that alternate in their occurrence. A minimum effective length is about five aptamers. The maximum length is undefined. The small-molecule ligands are enabled for imaging as fluorophore conjugates. For each IMAGEtag, two fluorophore conjugates are provided, which are FRET pairs. When a cell expresses an RNA containing an IMAGEtag sequence, the aptamers bind their ligands and bring the fluorophores into sufficiently close proximity to allow FRET. The background fluorescence of both fluorophores is minimal in the FRET channel. These features endow IMAGEtags with the sensitivity to report on mRNA expression levels in living cells. PMID- 27241756 TI - A Method for Expressing and Imaging Abundant, Stable, Circular RNAs In Vivo Using tRNA Splicing. AB - Recent improvements in high-throughput sequencing technologies underscore the pervasiveness of circular RNA (circRNA) expression in animal cells. CircRNAs are distinct from their linear counterparts because they lack the 5' caps and 3' tails that typically help determine the cellular fate of a transcript. However, due to the lack of free ends, circRNAs are impervious to exonucleases and thus can evade normal RNA turnover mechanisms. Most circRNAs are derived from protein coding pre-mRNAs, via a mechanism called "back-splicing." Existing methods of circRNA expression thus typically involve genes that have been engineered to contain sequence elements that promote back-splicing. We recently uncovered an anciently conserved mechanism of RNA circularization in metazoans that involves splicing of tRNA introns. This splicing mechanism is completely independent from that of pre-mRNAs. In this chapter, we detail an orthogonal method that involves splicing of intron-containing tRNAs in order to produce circRNAs in vivo. We utilize fluorescence-based RNA reporters to characterize the expression, localization, and stability of these so-called tRNA intronic circular RNAs. Because tRNA biogenesis is essential for all cellular life, this method provides a means to express ultrastable, high-copy, circRNA effectors in a wide variety of metazoan cell types. PMID- 27241757 TI - RNA-ID, a Powerful Tool for Identifying and Characterizing Regulatory Sequences. AB - The identification and analysis of sequences that regulate gene expression is critical because regulated gene expression underlies biology. RNA-ID is an efficient and sensitive method to discover and investigate regulatory sequences in the yeast Saccharomyces cerevisiae, using fluorescence-based assays to detect green fluorescent protein (GFP) relative to a red fluorescent protein (RFP) control in individual cells. Putative regulatory sequences can be inserted either in-frame or upstream of a superfolder GFP fusion protein whose expression, like that of RFP, is driven by the bidirectional GAL1,10 promoter. In this chapter, we describe the methodology to identify and study cis-regulatory sequences in the RNA-ID system, explaining features and variations of the RNA-ID reporter, as well as some applications of this system. We describe in detail the methods to analyze a single regulatory sequence, from construction of a single GFP variant to assay of variants by flow cytometry, as well as modifications required to screen libraries of different strains simultaneously. We also describe subsequent analyses of regulatory sequences. PMID- 27241758 TI - Fluorescent Protein-Based Quantification of Alternative Splicing of a Target Cassette Exon in Mammalian Cells. AB - Alternative splicing is an important mechanism of regulation of gene expression and expansion of proteome complexity. Recently we developed a new fluorescence reporter for quantitative analysis of alternative splicing of a target cassette exon in live cells (Gurskaya et al., 2012). It consists of a specially designed minigene encoding red and green fluorescent proteins (Katushka and TagGFP2) and a fragment of the target gene between them. Skipping or inclusion of the alternative exon induces a frameshift; ie, alternative exon length must not be a multiple of 3. Finally, red and green fluorescence intensities of cells expressing this reporter are used to estimate the percentage of alternative (exon skipped) and normal (exon-retained) transcripts. Here, we provide a detailed description of design and application of the fluorescence reporter of a target alternative exon splicing in mammalian cell lines. PMID- 27241759 TI - IRAS: High-Throughput Identification of Novel Alternative Splicing Regulators. AB - Alternative splicing is a fundamental regulatory process of gene expression. Defects in alternative splicing can lead to various diseases, and modification of disease-causing splicing events presents great therapeutic promise. Splicing outcome is commonly affected by extracellular stimuli and signaling cascades that converge on RNA-binding splicing regulators. These trans-acting factors recognize cis-elements in pre-mRNA transcripts to affect spliceosome assembly and splice site choices. Identification of these splicing regulators and/or upstream modulators has been difficult and traditionally done by piecemeal. High throughput screening strategies to find multiple regulators of exon splicing have great potential to accelerate the discovery process, but typically confront low sensitivity and low specificity of screening assays. Here we describe a unique screening strategy, IRAS (identifying regulators of alternative splicing), using a pair of dual-output minigene reporters to allow for sensitive detection of exon splicing changes. Each dual-output reporter produces green fluorescent protein (GFP) and red fluorescent protein (RFP) fluorescent signals to assay the two spliced isoforms exclusively. The two complementary minigene reporters alter GFP/RFP output ratios in the opposite direction in response to splicing change. Applying IRAS in cell-based high-throughput screens allows sensitive and specific identification of splicing regulators and modulators for any alternative exons of interest. In comparison to previous high-throughput screening methods, IRAS substantially enhances the specificity of the screening assay. This strategy significantly eliminates false positives without sacrificing sensitive identification of true regulators of splicing. PMID- 27241760 TI - Analysis of Nonsense-Mediated mRNA Decay at the Single-Cell Level Using Two Fluorescent Proteins. AB - Nonsense-mediated mRNA decay (NMD) is an evolutionarily conserved mechanism of specific degradation of transcripts with a premature stop codon. NMD eliminates aberrant mRNAs arising from mutations, alternative splicing, and other events in cells. In addition, many normal transcripts undergo NMD. Recent studies demonstrated that NMD activity is specifically regulated and that NMD can play a role of global regulator of gene expression. Recently, we developed dual-color fluorescent protein-based reporters for quantification of NMD activity using fluorescence microscopy and flow cytometry (Pereverzev, Gurskaya, et al., 2015). Due to ratiometric fluorescence response, these reporters make it possible to assess NMD activity in live cells at the single-cell level and to reveal otherwise hidden heterogeneity of cells in respect of NMD activity. Here we provide a detailed description of applications of the NMD reporters in mammalian cell lines. PMID- 27241762 TI - Preface. PMID- 27241761 TI - Developing Fluorogenic Riboswitches for Imaging Metabolite Concentration Dynamics in Bacterial Cells. AB - Genetically encoded small-molecule sensors are important tools for revealing the dynamics of metabolites and other small molecules in live cells over time. We recently developed RNA-based sensors that exhibit fluorescence in proportion to a small-molecule ligand. One class of these RNA-based sensors are termed Spinach riboswitches. These are RNAs that are based on naturally occurring riboswitches, but have been fused to the Spinach aptamer. The resulting RNA is a fluorogenic riboswitch, producing fluorescence upon binding the cognate small-molecule analyte. Here, we describe how to design and optimize these sensors by adjusting critical sequence elements, guided by structural insights from the Spinach aptamer. We provide a stepwise procedure to characterize sensors in vitro and to express sensors in bacteria for live-cell imaging of metabolites. Spinach riboswitch sensors offer a simple method for fluorescence measurement of a wide range of metabolites for which riboswitches exist, including nucleotides and their derivatives, amino acids, cofactors, cations, and anions. PMID- 27241763 TI - Basketball lay-up - foot loading characteristics and the number of trials necessary to obtain stable plantar pressure variables. AB - This study aimed (1) to profile the plantar loading characteristics when performing the basketball lay-up in a realistic setting and (2) to determine the number of trials necessary to establish a stable mean for plantar loading variables during the lay-up. Thirteen university male basketball players [age: 23.0 (1.4) years, height: 1.75 (0.05) m, mass: 68.4 (8.6) kg] performed ten successful basketball lay-ups from a stationary position. Plantar loading variables were recorded using the Novel Pedar-X in-shoe system. Loading variables including peak force, peak pressure, and pressure-time integral were extracted from eight foot regions. Performance stability of plantar loading variables during the take-off and landing steps were assessed using the sequential averaging technique and intra-class correlation coefficient (ICC). High plantar loadings were experienced at the heel during the take-off steps, and both the heel and forefoot regions upon landing. The sequential estimation technique revealed a five-eight trial range to achieve a stable mean across all plantar loading variables, whereas ICC analysis was insensitive to inter-trial differences of repeated lay-up performances. Future studies and performance evaluation protocols on plantar loading during basketball lay-ups should include at least eight trials to ensure that the measurements obtained are sufficiently stable. PMID- 27241764 TI - Curcumin inhibits hyperlipidemia and hepatic fat accumulation in high-fructose fed male Wistar rats. AB - CONTEXT: Curcumin, an active principal of Curcuma longa Linn. (Zingiberaceae), has potent antioxidant and anti-inflammatory properties. OBJECTIVES: This study investigated the effects of curcumin on hyperlipidemia and hepatic steatosis in high-fructose-fed Wistar rats. MATERIALS AND METHODS: Forty male Wistar rats were divided into four groups with 10 rats in each. Two groups were fed with standard rodent diet and the other two with 60% high-fructose diet for 10 weeks. Curcumin (200 mg/kg body weight) was administered along with the diets simultaneously to each of the aforementioned diet groups. After 10 weeks of experiment, blood samples were collected from tail vein. Liver, adipose and epididymal tissues were collected after sacrifice of the animals and stored for further analyses. RESULTS: Administration of curcumin reduced body weight (280.6 +/- 7.4 g), liver weight (2.5 +/- 0.2 g/100 g BW), adipose weight (1.4 +/- 0.3 g/100 g BW), plasma levels of TAG (86.1 +/- 13.5 mg/dL), VLDL-C (17.2 +/- 2.7 mg/dL), lipid ratios and increased HDL-C (28.4 +/- 4.5 mg/dL) in fructose-fed rats. Curcumin supplementation significantly lowered TAG content and decreased the protein expression of LXR-alpha (43%) and SREBP1c (59%) in the liver. Furthermore, curcumin suppressed the expression of lipogenic enzymes, ACLY (95%), ACC (50%) and FAS (77%) in rats fed with high-fructose diet. No significant change was found in the expression of PPAR-alpha. DISCUSSION AND CONCLUSION: Curcumin prevented the high-fructose induced hyperlipidemia and hepatic steatosis. PMID- 27241765 TI - A potential role for N-acetylcysteine in the management of methamphetamine dependence. AB - Methamphetamine dependence is a growing problem in Australia and globally. Currently, there are no approved pharmacotherapy options for the management of methamphetamine dependence. N-acetylcysteine is one potential pharmacotherapy option. It has received growing attention as a therapy for managing addictions because of its capacity to restore homeostasis to brain glutamate systems disrupted in addiction and thereby reduce craving and the risk of relapse. N acetylcysteine also has antioxidant properties that protect against methamphetamine-induced toxicity and it may therefore assist in the management of the neuropsychiatric and neurocognitive effects of methamphetamine. This commentary overviews the actions of N-acetylcysteine and evidence for its efficacy in treating addiction with a particular focus on its potential utility for methamphetamine dependence. We conclude that the preliminary evidence indicates a need for full-scale trials to definitively establish whether N acetylcysteine has a therapeutic benefit and the nature of this benefit, for managing methamphetamine dependence. [McKetin R, Dean O, Baker A. L, Carter G, Turner A, Kelly P. J, Berk M. A potential role for N-acetylcysteine in the management of methamphetamine dependence. Drug Alcohol Rev 2017;36:153-159]. PMID- 27241766 TI - Residual Mitral Regurgitation Elicited by Right Ventricular Pacing After Mitral Valve Repair. PMID- 27241767 TI - The Effects of On-Pump and Off-Pump Coronary Artery Bypass Surgery on Metabolic Profiles in the Early Postoperative Period. AB - OBJECTIVE: Hyperlactatemia and base deficit (BD) are markers of adverse outcome after cardiac surgery, and their derangement can be influenced by the use of extracorporeal circulation. The authors hypothesized a better postoperative metabolic profile in off-pump coronary artery bypass grafting (OPCABG) compared with "on-pump" coronary artery bypass grafting (ONCABG). DESIGN: This was a retrospective study, with consecutive data collected for 1 year from electronic medical records. SETTING: Cardiothoracic intensive care unit at a tertiary university hospital. PARTICIPANTS: The study comprised 339 patients who underwent elective coronary artery bypass grafting (ONCABG [n = 215], OPCABG [n = 124]). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The metabolic (arterial lactatemia, pH, and BD) and hemodynamic (inotropic/vasopressor support) parameters of OPCABG and ONCABG patients were compared at 7 predefined time points (intensive care admission and the 1st, 3rd, 6th, 12th, 18th, and 24th postoperative hours). For each output of interest, mixed-effects linear regression models were used (with time as random-effect to allow for clustering of repeated measures) and adjusted for a predetermined set of covariates. Arterial lactatemia and pH were comparable at all time points; BD was worse in the ONCABG group overall (p = 0.01) and at most time points (except at the 1st and 24th postoperative hours). For the whole period, inotropic support was more common in ONCABG patients (p<0.05), whereas vasopressor use was more frequent in the OPCABG group (p< 0.05). CONCLUSIONS: Improved postoperative BD values were demonstrated in the OPCABG group, although pH and lactatemia were similar between groups. Inotropic support was less common in the OPCABG group at the expense of more frequent vasopressor support. PMID- 27241768 TI - The Sievers Classification of the Bicuspid Aortic Valve for the Perioperative Echocardiographer: The Importance of Valve Phenotype for Aortic Valve Repair in the Era of the Functional Aortic Annulus. PMID- 27241769 TI - Corrigendum: Generation of a monoclonal antibody recognizing the CEACAM glycan structure and inhibiting adhesion using cancer tissue-originated spheroid as an antigen. PMID- 27241770 TI - ANZSGM ANNUAL SCIENTIFIC MEETING 2016: 1-3 June 2016, Cairns Convention Centre, Queensland. PMID- 27241771 TI - Welcome Message. PMID- 27241772 TI - Prizes. PMID- 27241773 TI - Committee Structure. PMID- 27241774 TI - The Australian and New Zealand Society for Geriatric Medicine Annual Scientific Meeting 2016, "The AGEnder Paradox", 1-3 June 2016, Cairns Convention Centre, Queensland, Australia. PMID- 27241775 TI - [Not Available]. PMID- 27241776 TI - [Treatment of acute and chronic right ventricular failure]. AB - Acute or chronic right ventricular failure is an often misdiagnosed cause of cardiopulmonary insufficiency. In addition to clinical symptoms or laboratory testing, echocardiography and invasive hemodynamic measurement by means of right heart catheterization are essential for diagnosis and treatment control. In case of acute right ventricular failure, adequate symptomatic treatment of the life threatening situation is important. Main issues are maintenance of coronary artery perfusion pressure and myocardial oxygen delivery as well as reduction of right ventricular afterload. In persistent right ventricular failure extracorporeal or intracorporeal assist devices are increasingly used as bridging or destination therapy. On a long-term basis, the targeted therapy of the underlying disease is crucial. PMID- 27241777 TI - [Acute liver failure]. AB - Acute liver failure (ALF) is a rare condition with fatal outcome. Characteristic is rapid onset of liver damage without preexisting liver diseases, including hepatic encephalopathy and coagulopathy. Early and correct diagnosis is essential for further management of patients, since diagnosis impacts therapy choice. Survival of patients with ALF has improved dramatically due to advances in critical care medicine and the use of liver transplantation. PMID- 27241779 TI - Novel zirconium complexes with constrained cyclic beta-enaminoketonato ligands: improved catalytic capability toward ethylene polymerization. AB - Novel Zr(iv) and Hf(iv) complexes bearing two constrained bulky beta enaminoketonato ligands {[ArN[double bond, length as m-dash]CH C8H3(CH2)n(R)O]2MBn2, M = Zr or Hf; n = 1, 2 or 3; R = H or C6H5; Ar = C6H5 or C6F5} were synthesized and clearly characterized. X-ray crystal structure analysis reveals that these complexes adopt a distorted octahedral geometry. Compared with non-constrained analogues, the Zr(iv) complexes with a cyclic skeleton exhibited high catalytic activities (up to 16.4 kgPE mmolZr(-1) h(-1)) toward ethylene polymerization at ambient pressure and elevated temperatures. Moreover, the catalytic properties of these complexes could be governed exquisitely by appropriate variation of the N-aryl substituents and the size of the benzocyclane. The Zr(iv) complexes bearing a non-fluorinated N-aryl group yielded oligomers, while the fluorinated analogues bearing a five-membered or six membered cyclane group produced high molecular weight polyethylenes (33.4-306 kg mol(-1)) under similar conditions on account of the suppression effects on beta-H elimination. The Zr(iv) complexes are more active toward ethylene polymerization than the Hf(iv) analogues, and the resulting polymers exhibited higher molecular weight and narrower molecular weight distribution. PMID- 27241778 TI - [Hepatorenal syndrome in decompensated cirrhosis : A special form of acute renal failure]. AB - Renal failure is a serious complication in patients with advanced cirrhosis. It occurs in about 20 % of patients hospitalized with cirrhosis. In about 70 % it is caused by prerenal failure, and in 30 % it is due to intrarenal causes. In about 70 % of patients with rperenal failure, renal function can be restored with fluid replacement, but the remaining 30 % are unresponsive to volume expansion. Minor increase in serum creatinine have been shown to be clinically relevant and can adversely affect survival. Therefore early efforts should be made to avoid precipitation of renal failure.Hepatorenal syndrome (HRS) is a fully reversible impairment of renal function in patients with cirrhosis unresponsive to volume expansion characterized by an acute progressive decrease in kidney function (serumcreatinin > 1,5 mg/dl) - type 1 HRS, whereas type 2 HRS features a decrease in kidney function over a long time, mostly in patients with refractory ascites. Therapy with vasoconstrictors like terlipressin to reverse splanchnic vasodilation, together with albumin is effective in 30-50 % of patients with HRS 1 and improves survival. The only effective longterm therapy is livertransplantation. An improvement of kidney fuction before transplantation is associated with a better outcome and posttransplant kidney function. PMID- 27241780 TI - Propionibacterium acnes biofilm - A sanctuary for Staphylococcus aureus? AB - The purpose of this study was to measure the effect of combined culture of Propionibacterium acnes and Staphylococcus aureus on biofilm formation under different oxygen concentrations. We measured planktonic growth and biofilm formation of P. acnes and S. aureus alone and together under aerobic and anaerobic conditions. Both P. acnes and S. aureus grew under anaerobic conditions. When grown under anaerobic conditions, P. acnes with or without S. aureus formed a denser biomass biofilm than did S. aureus alone. Viable S. aureus was recovered from a16-day old combined P. acnes and S. aureus biofilm, but not a monomicrobial S. aureus biofilm. PMID- 27241782 TI - Corrigendum to "Formulation and characterization of self-nanoemulsifying drug delivery systems containing monoacyl phosphatidylcholine" [Int. J. Pharm. 502 (1 2) (2016) 151-160]. PMID- 27241781 TI - Bile acid sensitivity and in vivo virulence of clinical Clostridium difficile isolates. AB - Clostridium difficile is an anaerobic bacterium that causes diarrheal illnesses. Disease onset is linked with exposure to oral antibiotics and consequent depletion of secondary bile acids. Here we investigate the relationship between in vitro secondary bile acid tolerance and in vivo disease scores of diverse C. difficile strains in mice. PMID- 27241783 TI - The clinical utility of next-generation sequencing in the neonatal intensive care unit. PMID- 27241784 TI - Heel-stick calcinosis cutis. PMID- 27241785 TI - Discussing death with the living. PMID- 27241787 TI - Dairy research: "Real" science or marketing? PMID- 27241786 TI - Next-generation sequencing for diagnosis of rare diseases in the neonatal intensive care unit. AB - BACKGROUND: Rare diseases often present in the first days and weeks of life and may require complex management in the setting of a neonatal intensive care unit (NICU). Exhaustive consultations and traditional genetic or metabolic investigations are costly and often fail to arrive at a final diagnosis when no recognizable syndrome is suspected. For this pilot project, we assessed the feasibility of next-generation sequencing as a tool to improve the diagnosis of rare diseases in newborns in the NICU. METHODS: We retrospectively identified and prospectively recruited newborns and infants admitted to the NICU of the Children's Hospital of Eastern Ontario and the Ottawa Hospital, General Campus, who had been referred to the medical genetics or metabolics inpatient consult service and had features suggesting an underlying genetic or metabolic condition. DNA from the newborns and parents was enriched for a panel of clinically relevant genes and sequenced on a MiSeq sequencing platform (Illumina Inc.). The data were interpreted with a standard informatics pipeline and reported to care providers, who assessed the importance of genotype-phenotype correlations. RESULTS: Of 20 newborns studied, 8 received a diagnosis on the basis of next-generation sequencing (diagnostic rate 40%). The diagnoses were renal tubular dysgenesis, SCN1A-related encephalopathy syndrome, myotubular myopathy, FTO deficiency syndrome, cranioectodermal dysplasia, congenital myasthenic syndrome, autosomal dominant intellectual disability syndrome type 7 and Denys-Drash syndrome. INTERPRETATION: This pilot study highlighted the potential of next-generation sequencing to deliver molecular diagnoses rapidly with a high success rate. With broader use, this approach has the potential to alter health care delivery in the NICU. PMID- 27241788 TI - Residents focus on fatigue management. PMID- 27241789 TI - Effectiveness of direct and non-direct auditory stimulation on coma arousal after traumatic brain injury. AB - The aim of this study was to evaluate the effect of direct and non-direct auditory stimulation on arousal in coma patients with severe traumatic brain injury and to compare the effects of direct vs. non-direct auditory stimulation. A crossover intervention study design was used. Nine participants who were comatose after a severe traumatic brain injury underwent direct and non-direct auditory stimulation. Direct auditory stimulation requires a higher level of interpersonal interaction between the patient and stimuli such as voices of family members, orientation by a nurse or family member and familiar music. In contrast, non-direct auditory stimuli were characterized as more general, less familiar, less interactive, indirect and not lively such as general music and TV sounds. Participants received both direct and non-direct auditory stimulation in randomized order for 15 minutes. Recovery of consciousness was measured with the Glasgow Coma Scale (GCS) and Sensory Stimulation Assessment Measure (SSAM). The Friedman test with post hoc analysis by Wilcoxon's signed-rank test comparisons was used for data analysis. Patients who received both direct and non-direct auditory stimulation exhibited significantly increased GCS (p = 0.008) and SSAM scores (p = 0.008) over baseline. The improvement in SSAM scores after direct auditory stimulation was significantly greater than that after non-direct auditory stimulation (p = 0.021), but there was no statistically significant difference in GCS scores (p = 0.139). Auditory stimulation, in particular direct auditory stimulation, might be useful for improving the recovery of consciousness and increasing the arousal of comatose patients. The SSAM is more useful for detecting subtle changes from stimulation intervention than the GCS. PMID- 27241790 TI - A Fluid Mass-Dependent Headache in History of Brain Dermoid Cyst Resection: A Case Report. PMID- 27241792 TI - Quantification of selected volatile organic compounds in human urine by gas chromatography selective reagent ionization time of flight mass spectrometry (GC SRI-TOF-MS) coupled with head-space solid-phase microextraction (HS-SPME). AB - Selective reagent ionization time of flight mass spectrometry with NO(+) as the reagent ion (SRI-TOF-MS(NO(+))) in conjunction with gas chromatography (GC) and head-space solid-phase microextraction (HS-SPME) was used to determine selected volatile organic compounds in human urine. A total of 16 volatiles exhibiting high incidence rates were quantified in the urine of 19 healthy volunteers. Amongst them there were ten ketones (acetone, 2-butanone, 3-methyl-2-butanone, 2 pentanone, 3-methyl-2-pentanone, 4-methyl-2-pentanone, 2-hexanone, 3-hexanone, 2 heptanone, and 4-heptanone), three volatile sulphur compounds (dimethyl sulfide, allyl methyl sulfide, and methyl propyl sulfide), and three heterocyclic compounds (furan, 2-methylfuran, 3-methylfuran). The concentrations of the species under study varied between 0.55 nmol L(-1) (0.05 nmol mmol(-1)creatinine) for allyl methyl sulfide and 11.6 MUmol L(-1) (1.54 MUmol mmol(-1)creatinine) for acetone considering medians. Limits of detection (LODs) ranged from 0.08 nmol L( 1) for allyl methyl sulfide to 1.0 nmol L(-1) for acetone and furan (with RSDs ranging from 5 to 9%). The presented experimental setup assists both real-time and GC analyses of volatile organic compounds, which can be performed consecutively using the same analytical system. Such an approach supports the novel concept of hybrid volatolomics, an approach which combines VOC profiles obtained from two or more body fluids to improve and complement the chemical information on the physiological status of an individual. PMID- 27241791 TI - Natural antisense transcription from a comparative perspective. AB - Natural antisense transcripts (NATs) can interfere with the expression of complementary sense transcripts with exquisite specificity. We have previously cloned NATs of Slc34a loci (encoding Na-phosphate transporters) from fish and mouse. Here we report the cloning of a human SLC34A1-related NAT that represents an alternatively spliced PFN3 transcript (Profilin3). The transcript is predominantly expressed in testis. Phylogenetic comparison suggests two distinct mechanisms producing Slc34a-related NATs: Alternative splicing of a transcript from a protein coding downstream gene (Pfn3, human/mouse) and transcription from the bi-directional promoter (Rbpja, zebrafish). Expression analysis suggested independent regulation of the complementary Slc34a mRNAs. Analysis of randomly selected bi-directionally transcribed human/mouse loci revealed limited phylogenetic conservation and independent regulation of NATs. They were reduced on X chromosomes and clustered in regions that escape inactivation. Locus structure and expression pattern suggest a NATs-associated regulatory mechanisms in testis unrelated to the physiological role of the sense transcript encoded protein. PMID- 27241793 TI - Hearing Tests on Mobile Devices: Evaluation of the Reference Sound Level by Means of Biological Calibration. AB - BACKGROUND: Hearing tests carried out in home setting by means of mobile devices require previous calibration of the reference sound level. Mobile devices with bundled headphones create a possibility of applying the predefined level for a particular model as an alternative to calibrating each device separately. OBJECTIVE: The objective of this study was to determine the reference sound level for sets composed of a mobile device and bundled headphones. METHODS: Reference sound levels for Android-based mobile devices were determined using an open access mobile phone app by means of biological calibration, that is, in relation to the normal-hearing threshold. The examinations were conducted in 2 groups: an uncontrolled and a controlled one. In the uncontrolled group, the fully automated self-measurements were carried out in home conditions by 18- to 35-year-old subjects, without prior hearing problems, recruited online. Calibration was conducted as a preliminary step in preparation for further examination. In the controlled group, audiologist-assisted examinations were performed in a sound booth, on normal-hearing subjects verified through pure-tone audiometry, recruited offline from among the workers and patients of the clinic. In both the groups, the reference sound levels were determined on a subject's mobile device using the Bekesy audiometry. The reference sound levels were compared between the groups. Intramodel and intermodel analyses were carried out as well. RESULTS: In the uncontrolled group, 8988 calibrations were conducted on 8620 different devices representing 2040 models. In the controlled group, 158 calibrations (test and retest) were conducted on 79 devices representing 50 models. Result analysis was performed for 10 most frequently used models in both the groups. The difference in reference sound levels between uncontrolled and controlled groups was 1.50 dB (SD 4.42). The mean SD of the reference sound level determined for devices within the same model was 4.03 dB (95% CI 3.93-4.11). Statistically significant differences were found across models. CONCLUSIONS: Reference sound levels determined in the uncontrolled group are comparable to the values obtained in the controlled group. This validates the use of biological calibration in the uncontrolled group for determining the predefined reference sound level for new devices. Moreover, due to a relatively small deviation of the reference sound level for devices of the same model, it is feasible to conduct hearing screening on devices calibrated with the predefined reference sound level. PMID- 27241795 TI - Understanding cold bias: Variable response of skeletal Sr/Ca to seawater pCO2 in acclimated massive Porites corals. AB - Coral skeletal Sr/Ca is a palaeothermometer commonly used to produce high resolution seasonal sea surface temperature (SST) records and to investigate the amplitude and frequency of ENSO and interdecadal climate events. The proxy relationship is typically calibrated by matching seasonal SST and skeletal Sr/Ca maxima and minima in modern corals. Applying these calibrations to fossil corals assumes that the temperature sensitivity of skeletal Sr/Ca is conserved, despite substantial changes in seawater carbonate chemistry between the modern and glacial ocean. We present Sr/Ca analyses of 3 genotypes of massive Porites spp. corals (the genus most commonly used for palaeoclimate reconstruction), cultured under seawater pCO2 reflecting modern, future (year 2100) and last glacial maximum (LGM) conditions. Skeletal Sr/Ca is indistinguishable between duplicate colonies of the same genotype cultured under the same conditions, but varies significantly in response to seawater pCO2 in two genotypes of Porites lutea, whilst Porites murrayensis is unaffected. Within P. lutea, the response is not systematic: skeletal Sr/Ca increases significantly (by 2-4%) at high seawater pCO2 relative to modern in both genotypes, and also increases significantly (by 4%) at low seawater pCO2 in one genotype. This magnitude of variation equates to errors in reconstructed SST of up to -5 degrees C. PMID- 27241796 TI - Measurement of protein size in concentrated solutions by small angle X-ray scattering. AB - By simulations on the distance distribution function (DDF) derived from small angle X-ray scattering (SAXS) theoretical data of a dense monodisperse system, we found a quantitative mathematical correlation between the apparent size of a spherically symmetric (or nearly spherically symmetric) homogenous particle and the concentration of the solution. SAXS experiments on protein solutions of human hemoglobin and horse myoglobin validated the correlation. This gives a new method to determine, from the SAXS DDF, the size of spherically symmetric (or nearly spherically symmetric) particles of a dense monodisperse system, specifically for protein solutions with interference effects. PMID- 27241794 TI - Detection and treatment of atherosclerosis using nanoparticles. AB - Atherosclerosis is the key pathogenesis of cardiovascular disease, which is a silent killer and a leading cause of death in the United States. Atherosclerosis starts with the adhesion of inflammatory monocytes on the activated endothelial cells in response to inflammatory stimuli. These monocytes can further migrate into the intimal layer of the blood vessel where they differentiate into macrophages, which take up oxidized low-density lipoproteins and release inflammatory factors to amplify the local inflammatory response. After accumulation of cholesterol, the lipid-laden macrophages are transformed into foam cells, the hallmark of the early stage of atherosclerosis. Foam cells can die from apoptosis or necrosis, and the intracellular lipid is deposed in the artery wall forming lesions. The angiogenesis for nurturing cells is enhanced during lesion development. Proteases released from macrophages, foam cells, and other cells degrade the fibrous cap of the lesion, resulting in rupture of the lesion and subsequent thrombus formation. Thrombi can block blood circulation, which represents a major cause of acute heart events and stroke. There are generally no symptoms in the early stages of atherosclerosis. Current detection techniques cannot easily, safely, and effectively detect the lesions in the early stages, nor can they characterize the lesion features such as the vulnerability. While the available therapeutic modalities cannot target specific molecules, cells, and processes in the lesions, nanoparticles appear to have a promising potential in improving atherosclerosis detection and treatment via targeting the intimal macrophages, foam cells, endothelial cells, angiogenesis, proteolysis, apoptosis, and thrombosis. Indeed, many nanoparticles have been developed in improving blood lipid profile and decreasing inflammatory response for enhancing therapeutic efficacy of drugs and decreasing their side effects. WIREs Nanomed Nanobiotechnol 2017, 9:e1412. doi: 10.1002/wnan.1412 For further resources related to this article, please visit the WIREs website. PMID- 27241798 TI - Prevalence and risk behaviour for human immunodeficiency virus 1 infection in Marajo Island, Northern Brazil. AB - BACKGROUND: Human immunodeficiency virus 1 (HIV-1) infection is a global public health problem, but, so far, there is no published information regarding the epidemiology of HIV-1 in Marajo Archipelago (Para, Brazil). AIM: The present study reports the occurrence of infection by HIV-1 in four municipalities of the Marajo Island, Para, Brazil. SUBJECTS AND METHODS: A total of 1877 samples were collected from volunteer blood donors (1296 women and 551 men) living in the municipalities of Anajas, Chaves, Portel and Sao Sebastiao da Boa Vista. Information about risk behaviour assessment was obtained from a questionnaire. Plasma samples were tested for the presence of anti-HIV antibodies using serological tests. The infection was confirmed by nucleic acid amplification assays. RESULTS: Twelve samples were seropositive for HIV by ELISA. Western blot analysis showed four positive samples, eight indeterminate patterns and one found to be negative. Molecular analysis revealed three positive samples. Risk factors for HIV-1 infection included absence of condoms during sexual intercourse (41.3%, Sao Sebastiao da Boa Vista), use of illicit drugs (5.8%, Anajas) and early initiation of sexual activities, from 10-15 years (30.7%). CONCLUSION: Although the study indicates a low HIV-1 prevalence in Marajo Island, some factors may increase the risk for HIV-1 and these include early sexual initiation, unprotected sexual intercourse and the use of illicit drugs. PMID- 27241799 TI - Gastric Electrical Stimulation Is an Option for Patients with Refractory Cyclic Vomiting Syndrome. AB - Background/Aims: Cyclic vomiting syndrome (CVS) is a disabling migraine variant manifesting as severe episodes of nausea and vomiting and often refractory to many therapies. Gastric electrical stimulation (GES), which can reduce nausea and vomiting in gastroparesis, may provide symptomatic relief for drug-refractory CVS. This study assessed the utility GES in reducing the symptoms of CVS and improving the quality of life. Methods: A one-year, non-randomized, clinical study was conducted. Eleven consecutive patients with drug refractory, cyclic vomiting syndrome based on Rome III criteria and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN), underwent treatment with temporary GES (Temp GES) and permanent GES (Perm GES). Post treatment follow up was done up to one year after permanent gastric electrical stimulation therapy. Results: Total symptom score decreased by 68% and 40% after temporary and permanent GES therapies, respectively. Hospital admission events significantly decreased to 1.50 (+/- 1.00) events from 9.14 (+/- 7.21) annual admissions prior to treatment with permanent GES. Vomiting episodes fell by 83% post Temp GES and 69% after Perm GES treatments. Mucosal electrogram values also changed after temporary stimulation. Conclusions: In a small group of drug refractory CVS patients, treatments with temporary and permanent GES significantly reduced the severity of gastrointestinal symptoms and frequency of hospital admissions. PMID- 27241797 TI - Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status. AB - In humans, the A1 (T) allele of the dopamine (DA) D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) TaqIA (rs1800497) single nucleotide polymorphism has been associated with reduced striatal DA D2/D3 receptor (D2/D3R) availability. However, radioligands used to estimate D2/D3R are displaceable by endogenous DA and are nonselective for D2R, leaving the relationship between TaqIA genotype and D2R specific binding uncertain. Using the positron emission tomography (PET) radioligand, (N-[(11) C]methyl)benperidol ([(11) C]NMB), which is highly selective for D2R over D3R and is not displaceable by endogenous DA, the current study examined whether DRD2/ANKK1 TaqIA genotype predicts D2R specific binding in two independent samples. Sample 1 (n = 39) was composed of obese and nonobese adults; sample 2 (n = 18) was composed of healthy controls, unmedicated individuals with schizophrenia, and siblings of individuals with schizophrenia. Across both samples, A1 allele carriers (A1+) had 5 to 12% less striatal D2R specific binding relative to individuals homozygous for the A2 allele (A1-), regardless of body mass index or diagnostic group. This reduction is comparable to previous PET studies of D2/D3R availability (10-14%). The pooled effect size for the difference in total striatal D2R binding between A1+ and A1- was large (0.84). In summary, in line with studies using displaceable D2/D3R radioligands, our results indicate that DRD2/ANKK1 TaqIA allele status predicts striatal D2R specific binding as measured by D2R-selective [(11) C]NMB. These findings support the hypothesis that DRD2/ANKK1 TaqIA allele status may modify D2R, perhaps conferring risk for certain disease states. PMID- 27241800 TI - Superconducting magnetic separation of phosphate using freshly formed hydrous ferric oxide sols. AB - Paramagnetic materials, such as ferric hydroxides, which are cost-effective and highly-efficient, have been little studied in relation to the magnetic separation process. In this study, freshly formed hydrous ferric oxide (HFO) sols were used to remove aqueous phosphate, followed by superconducting magnetic separation. The magnetization of HFO was determined to be 5.7 emu/g in 5.0 T. The particle size distributions ranged from 1 to 80 MUm. Ferrihydrite was the primary mineral phase according to XRD analysis. Dissolved P (DP) was first adsorbed on HFO, and second, the P-containing HFO were separated by high gradient superconducting magnetic separation (HGSMS) to remove the Total P (TP). To obtain a P concentration of <0.05 mg/l in the effluent, 0.3, 1.0 and 1.3 g/l HFO were added to 2.5, 5 and 10 mg/l P solutions. The capacity of the HGSMS canister for capturing P-adsorbed HFO depends on the magnetic intensity and flow rate. In the 5.0 T HGSMS at a 1.0 cm/s flow rate, there were 75 column volumes in a single HGSMS cycle. The P concentration increased by 37.5 times after regeneration. Approximately 170 mg/l TP was measured in the backwash water. PMID- 27241801 TI - A high performance flexible all solid state supercapacitor based on the MnO2 sphere coated macro/mesoporous Ni/C electrode and ionic conducting electrolyte. AB - A high contact resistance between the active materials and the current collector, a low ionic conductivity of the gel electrolyte, and an impenetrable electrode structure are the three major barriers which greatly limit the capacitance of MnO2 in solid state supercapacitors. As a potential solution to these problems, in this work we report a novel electrode for solid state supercapacitors, based on a ternary system composed of hierarchical MnO2 spheres as the active material, macroporous Ni foam as gel penetrable skeletons and an ordered mesoporous carbon (OMC) membrane as the charge-transport accelerating layer. By employing butyl-3 methylimidazolium chloride (BMIMCl) modified gels as the ionic conducting electrolyte, the utilization efficiency of MnO2 on the specific capacitance was enhanced up to 88% of the theoretical value, delivering a volumetric capacitance of 81 F cm(-3), which is the highest value among MnO2 based solid state supercapacitors. Moreover, such a flexible device exhibits exceptional volumetric energy and power density (6.6 Wh L(-1) and 549 W L(-1), based on the whole device volume) combined with a small capacity loss of 8.5% after 6000 cycles under twisting. These encouraging findings unambiguously overcome the energy bottleneck of MnO2 in solid state supercapacitors, and open up a new application of macro/mesoporous materials in flexible devices. PMID- 27241802 TI - Correction. PMID- 27241803 TI - Consumption of dairy in teenagers with and without acne. AB - BACKGROUND: Recent literature has implicated dairy as having a potential acne inducing effect. OBJECTIVES: The aim of this study was to investigate the link between dairy consumption and acne in teenagers. We tested the hypothesis that teenagers with facial acne consume more dairy than those without acne. METHODS: A case-control study was conducted among 225 participants, ages 14 to 19 years, with either moderate acne or no acne. Moderate acne was determined by a dermatologist using the Global Acne Assessment Scale. Participants who met inclusion criteria then completed up to three 24-hour diet recall interviews using the Nutrition Data System for Research software and food and nutrient intake were compared between groups. RESULTS: The amount of low-fat/skim milk consumed by participants with acne with significantly higher (P = .01) than those with no acne. No significant difference was found among total dairy intake, saturated fat or trans-fat, or glycemic load. No significant difference was found for total energy intake or body mass index. LIMITATIONS: Limitations include self report of diet and portion size, and association does not determine causation. CONCLUSIONS: Consumption of low-fat/skim milk, but not full-fat milk, was positively associated with acne. PMID- 27241804 TI - Eruptive nevi associated with medications (ENAMs). AB - Eruptive melanocytic nevi have been reported in association with severe blistering diseases, renal transplantation, malignancy, AIDS, and medications. Eruptive nevi associated with medications have been reported with increasing frequency. Of particular interest are eruptive nevi associated with medications developing in association with biologic therapies, which we anticipate will continue to become more common as use of these medications continues to increase. We searched the databases PubMed/MEDLINE, Cochrane, and Cumulative Index to Nursing and Allied Health Literature for associated medications using the terms "eruptive nevi," "melanocytic + medications," and "nevi + medications" for relevant articles. We report the summary of our findings, which were used in defining what constitutes an eruptive nevi associated with medication and developing a classification system by medication type. PMID- 27241805 TI - Theory of diffusion-influenced reactions in complex geometries. AB - Chemical transformations involving the diffusion of reactants and subsequent chemical fixation steps are generally termed "diffusion-influenced reactions" (DIR). Virtually all biochemical processes in living media can be counted among them, together with those occurring in an ever-growing number of emerging nano technologies. The role of the environment's geometry (obstacles, compartmentalization) and distributed reactivity (competitive reactants, traps) is key in modulating the rate constants of DIRs, and is therefore a prime design parameter. Yet, it is a formidable challenge to build a comprehensive theory that is able to describe the environment's "reactive geometry". Here we show that such a theory can be built by unfolding this many-body problem through addition theorems for special functions. Our method is powerful and general and allows one to study a given DIR reaction occurring in arbitrary "reactive landscapes", made of multiple spherical boundaries of given size and reactivity. Importantly, ready to-use analytical formulas can be derived easily in most cases. PMID- 27241806 TI - An evaluation of transcriptome-based exon capture for frog phylogenomics across multiple scales of divergence (Class: Amphibia, Order: Anura). AB - Custom sequence capture experiments are becoming an efficient approach for gathering large sets of orthologous markers in nonmodel organisms. Transcriptome based exon capture utilizes transcript sequences to design capture probes, typically using a reference genome to identify intron-exon boundaries to exclude shorter exons (<200 bp). Here, we test directly using transcript sequences for probe design, which are often composed of multiple exons of varying lengths. Using 1260 orthologous transcripts, we conducted sequence captures across multiple phylogenetic scales for frogs, including outgroups ~100 Myr divergent from the ingroup. We recovered a large phylogenomic data set consisting of sequence alignments for 1047 of the 1260 transcriptome-based loci (~561 000 bp) and a large quantity of highly variable regions flanking the exons in transcripts (~70 000 bp), the latter improving substantially by only including ingroup species (~797 000 bp). We recovered both shorter (<100 bp) and longer exons (>200 bp), with no major reduction in coverage towards the ends of exons. We observed significant differences in the performance of blocking oligos for target enrichment and nontarget depletion during captures, and differences in PCR duplication rates resulting from the number of individuals pooled for capture reactions. We explicitly tested the effects of phylogenetic distance on capture sensitivity, specificity, and missing data, and provide a baseline estimate of expectations for these metrics based on a priori knowledge of nuclear pairwise differences among samples. We provide recommendations for transcriptome-based exon capture design based on our results, cost estimates and offer multiple pipelines for data assembly and analysis. PMID- 27241807 TI - Assessing the reliability of microscopy and rapid diagnostic tests in malaria diagnosis in areas with varying parasite density among older children and adult patients in Nigeria. AB - BACKGROUND: Current malaria control strategies are based on early diagnosis and appropriate treatment of malaria cases. The study aimed at comparing the performance of blood film microscopy and rapid diagnostic test (RDT) in Plasmodium falciparum detection in patients >=6 years of age. MATERIALS AND METHODS: A total of 154 consecutive pyretic patients aged 6-62 years were enrolled, sampled, and tested for malaria using RDT (first response) and microscopy by Giemsa staining. Genomic DNA was extracted after saponin hemolysis and nested polymerase chain reaction (PCR) was used to detect Plasmodium falciparum. The endpoints were sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: Of the 154 patients, 80 (51.9%) had fever of >=37.5 degrees C. 106 (68.8%) were positive by First response(r) , 132 (85.7%) by microscopy, and 121 (78.6%) by PCR. The sensitivity, specificity, PPV, and NPV of first response compared to microscopic method were 82.2%, 100.0%, 100.0%, and 34.3%, respectively, while it was 75.4%, 75.0%, 95.3%, and 31.2%, respectively, when compared to PCR. The sensitivity, specificity, PPV, and NPV of the microscopic method compared to PCR were 92.3%, 50.0%, 90.91%, and 54.5%, respectively. There was a significant difference in the performance of RDT and film microscopy methods (P <= 0.05). CONCLUSION: Microscopy performed better and is more reliable than first response (RDT) in areas with low parasite density among patients >=6 years of age. Rapid diagnostic tests could be useful in aareas with high parasite density as an alternative to smear microscopy. PMID- 27241808 TI - Accessing completeness of pregnancy, delivery, and death registration by Accredited Social Health Activists [ASHA] in an innovative mHealth project in the tribal areas of Gujarat: A cross-sectional study. AB - BACKGROUND: The Innovative Mobile-phone Technology for Community Health Operation (ImTeCHO) is a mobile-phone application that helps Accredited Social Health Activists (ASHAs) in complete registration through the strategies employed during implementation that is linking ASHAs' incentives to digital records, regular feedback, onsite data entry, and demand generation among beneficiaries. OBJECTIVE: To determine the proportion of pregnancies, deliveries, and infant deaths (events) being registered through the ImTeCHO application against actual number of events in a random sample of villages. MATERIALS AND METHODS: Five representative villages were randomly selected from the ImTeCHO project area in the tribal areas of Gujarat, India to obtain the required sample of 98 recently delivered women. A household survey was done in the entire villages to enumerate each family and create a line-listing of events since January 2014; the line listing was compared with list of women registered through the ImTeCHO application. The proportion of events being registered through the ImTeCHO application was compared against the actual number of events to find sensitivity of the ImTeCHO application. RESULT: A total of 844 families were found during household enumeration. Out of actual line-listing of pregnancies (N = 39), deliveries (N = 102), and infant deaths (N = 5) found during household enumeration, 38 (97.43%), 101 (99.01%), and 5 (100%) were registered by ASHAs through the ImTeCHO application. CONCLUSION: The use of mobile-phone technology and strategies applied during the ImTeCHO implementation should be upscaled to supplement efforts to improve the completeness of registration. PMID- 27241809 TI - Mixed method approach for determining factors associated with late presentation to HIV/AIDS care in southern India. AB - BACKGROUND: Early diagnosis and treatment of human Immunodeficiency virus (HIV) is not only beneficial for the people living with HIV/acquired immunodeficiency syndrome (AIDS) (PLHA) but for the public and society as well. The study was aimed to identify the factors associated with late presentation to HIV/AIDS care. MATERIALS AND METHODS: A facility-based unmatched case-control (1:1) study along with in-depth qualitative assessment was conducted at an ART Plus center at a district hospital, Udupi, southern India. A sample of 320 HIV patients (160 cases and 160 controls) was selected randomly between February and July 2014. Information regarding the patients were collected using an interviewer administered semi-structured questionnaire. The qualitative component was assessed by in-depth interviews of 4 health professionals and 12 HIV-positive patients who were late for HIV care. The quantitative data were analyzed using Statistical Package for the Social Sciences (SPSS) version 15.0. The technique of thematic analysis was adopted for the analysis of qualitative data. RESULTS: HIV positive individuals who lived with families [odds ratio (OR) = 5.11], the patients having non-AIDS comorbidities [OR= 2.19, 95% confidence interval (CI): 1.09-4.40], the patients who perceived fear of losing family [OR = 5.00, 95% CI: 2.17-11.49], the patients who perceived fear that their status will be ruined in the community [OR= 2.00, 95% CI: 1.01-3.97], the patients who perceived fear of side effects of ART medications [OR = 4.3, 95% CI: 2.65-11.33], the patients who perceived fear of losing confidentiality [OR = 4.94, 95% CI: 2.54-9.59], the patients those who lack information available on government services [OR = 4.12, 95% CI: 2.127-8.005], and the patients who consumed alcohol [OR= 3.52, 95% CI: 1.83-6.77] were found to be independently associated with the late presentation to HIV/AIDS care after adjusting for all known confounders in a multivariable analysis. The qualitative summary showed that the perceived HIV stigma, inadequate health education, lack of awareness on available government services, psychological problems, alcohol use, asymptomatic conditions, and financial problems are major barriers to access care early for the late presenters. CONCLUSION: The identified factors can be utilized for the formulation of policies and interventions by promoting early diagnoses and addressing special concerns such as stigma, disclosure, health education, and awareness. PMID- 27241810 TI - Severity and pattern of bone mineral loss in endocrine causes of osteoporosis as compared to age-related bone mineral loss. AB - BACKGROUND: Data are scant on bone health in endocrinopathies from India. This study evaluated bone mineral density (BMD) loss in endocrinopathies [Graves' disease (GD), type 1 diabetes mellitus (T1DM), hypogonadotrophic hypogonadism (HypoH), hypergonadotropic hypogonadism (HyperH), hypopituitarism, primary hyperparathyroidism (PHPT)] as compared to age-related BMD loss [postmenopausal osteoporosis (PMO), andropause]. MATERIALS AND METHODS: Retrospective audit of records of patients >30 years age attending a bone clinic from August 2014 to January 2016 was done. RESULTS: Five-hundred and seven records were screened, out of which 420 (females:male = 294:126) were analyzed. A significantly higher occurrence of vitamin D deficiency and insufficiency was noted in T1DM (89.09%), HyperH (85%), and HypoH (79.59%) compared to age-related BMD loss (60.02%; P < 0.001). The occurrence of osteoporosis among females and males was 55.41% and 53.97%, respectively, and of osteopenia among females and males was 28.91% and 32.54%, respectively. In females, osteoporosis was significantly higher in T1DM (92%), HyperH (85%), and HypoH (59.26%) compared to PMO (49.34%; P < 0.001). Z score at LS, TF, NOF, and greater trochanter (GT) was consistently lowest in T1DM women. Among men, osteoporosis was significantly higher in T1DM (76.67%) and HypoH (54.55%) compared to andropause (45.45%; P = 0.001). Z score at LS, TF, NOF, GT, and TR was consistently lowest in T1DM men. In GD, the burden of osteoporosis was similar to PMO and andropause. BMD difference among the study groups was not significantly different after adjusting for body mass index (BMI) and vitamin D. CONCLUSION: Low bone mass is extremely common in endocrinopathies, warranting routine screening and intervention. Concomitant vitamin D deficiency compounds the problem. Calcium and vitamin D supplementations may improve bone health in this setting. PMID- 27241811 TI - Treatment of Intramyometrial Pregnancy by In Situ Injection of Methotrexate. AB - Intramyometrial ectopic pregnancies are rare, and various management modalities have been described. We report a patient with intramyometrial pregnancy who was successfully treated by in situ injection of methotrexate (MTX) after the failure of 2 intramuscular injections of MTX. We emphasize the difficult management of intramyometrial pregnancy and show that in situ MTX injection may be indicated for this particular type of ectopic pregnancy. PMID- 27241812 TI - Angiopoietin-2 mediates thrombin-induced monocyte adhesion and endothelial permeability. AB - Essentials Mechanism of thrombin-induced inflammation is not fully understood. Thrombin induced monocyte adhesion and barrier loss require Angiopoietin-2 (Ang 2). Ang-2 mediates vessel leakage and monocyte adhesion through SHP-2/p38MAPK pathway. Calcium dependent SHP2/p38MAPK activation regulates Ang-2 expression through a feedback loop. SUMMARY: Background Thrombin imparts an inflammatory phenotype to the endothelium by promoting increased monocyte adhesion and vascular permeability. However, the molecular players that govern these events are incompletely understood. Objective The aim of this study was to determine whether Angiopoietin-2 (Ang-2) has a role, if any, in regulating inflammatory signals initiated by thrombin. Methods Assessment of vascular leakage by Miles assay was performed by intra-dermal injection on the foot paw. Surface levels of intercellular adhesion molecule-1 (ICAM-1) were determined by flow cytometry. Overexpression, knockdown and phosphorylation of proteins were determined by Western blotting. Results In time-course experiments, thrombin-stimulated Ang-2 up-regulation, peaked prior to the expression of adhesion molecule ICAM-1 in human umbilical vein-derived endothelial cells (HUVECs). Knockdown of Ang-2 blocked both thrombin-induced monocyte adhesion and ICAM-1 expression. In addition, Ang-2(-/-) mice displayed defective vascular leakage when treated with thrombin. Introducing Ang-2 protein in Ang-2(-/-) mice failed to recover a wild type phenotype. Mechanistically, Ang-2 appears to regulate the thrombin-activated calcium spike that is required for tyrosine phosphatase SHP2 and p38 MAPK activation. Further, down-regulation of SHP2 attenuated both thrombin-induced Ang 2 expression and monocyte adhesion. Down-regulation of the adaptor protein Gab1, a co-activator of SHP2, as well as overexpression of the Gab1 mutant incapable of interacting with SHP2 (YFGab1), inhibited thrombin-mediated effects, including downstream activation of p38 MAPK, which in turn was required for Ang-2 expression. Conclusions The data establish an essential role of the Gab1/SHP2/p38MAPK signaling pathway and Ang-2 in regulating thrombin-induced monocyte adhesion and vascular leakage. PMID- 27241813 TI - Synthesis and biological evaluation of acylated oligorhamnoside derivatives structurally related to mezzettiaside-6 with cytotoxic activity. AB - Two partially acylated oligorhamnoside derivatives 1 and 2 structurally related to the natural product mezzettiaside-6 were synthesized via a '2 + 1 + 1' convergent strategy. The bioassay results showed that the introduction of the acetyl groups to the 2-position of the terminal l-rhamnose was helpful to improve in vitro cytotoxicity. Compound 1 showed both extensive in vitro cytotoxicity in tumor cell lines and potential antimultidrug resistance capability. Preliminary mechanistic studies demonstrated that compound 1 could inhibit cell growth by inducing apoptosis, arresting cell cycle progression at the S phase in K562 cells. PMID- 27241814 TI - Vogt-Koyanagi-Harada disease. AB - Vogt-Koyanagi-Harada disease, a severe bilateral granulomatous intraocular inflammation associated with serous retinal detachments, disk edema, and vitritis, with eventual development of a sunset glow fundus, is an autoimmune inflammatory condition mediated by T cells that target melanocytes in individuals susceptible to the disease. Vogt-Koyanagi-Harada disease presents clinically in 4 different phases: prodromal, uveitic, convalescent, and recurrent, with extraocular manifestations including headache, meningismus, hearing loss, poliosis, and vitiligo, to varying degrees. There have been considerable advances in imaging modalities resulting in earlier diagnosis and improved understanding of this disease. Ocular coherence tomography has replaced other imaging modalities in the diagnosis of acute and chronic Vogt-Koyanagi-Harada disease by revealing exudative detachments of the retina in the acute stage, along with choroidal thickening and demonstrating choroidal thinning in the chronic stage. Treatment of this disease is initially with corticosteroids, with a transition to immunomodulatory drugs for long-term control. Patients with Vogt-Koyanagi-Harada disease can have good final outcomes if treated promptly and aggressively and thus avoid complications such as sunset glow fundus, cataracts, glaucoma, subretinal fibrosis, and choroidal neovascularization. PMID- 27241815 TI - Three measures of explained variation for correlated survival data under the proportional hazards mixed-effects model. AB - Measures of explained variation are useful in scientific research, as they quantify the amount of variation in an outcome variable of interest that is explained by one or more other variables. We develop such measures for correlated survival data, under the proportional hazards mixed-effects model. Because different approaches have been studied in the literature outside the classical linear regression model, we investigate three measures R(2) , Rres2, and rho(2) that quantify three different population coefficients. We show that although the three population measures are not the same, they reflect similar amounts of variation explained by the predictors. Among the three measures, we show that R(2) , which is the simplest to compute, is also consistent for the first population measure under the usual asymptotic scenario when the number of clusters tends to infinity. The other two measures, on the other hand, all require that in addition the cluster sizes be large. We study the properties of the measures both analytically and through simulation studies. We illustrate their different usage on a multi-center clinical trial and a recurrent events data set. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27241817 TI - An electric generator using living Torpedo electric organs controlled by fluid pressure-based alternative nervous systems. AB - Direct electric power generation using biological functions have become a research focus due to their low cost and cleanliness. Unlike major approaches using glucose fuels or microbial fuel cells (MFCs), we present a generation method with intrinsically high energy conversion efficiency and generation with arbitrary timing using living electric organs of Torpedo (electric rays) which are serially integrated electrocytes converting ATP into electric energy. We developed alternative nervous systems using fluid pressure to stimulate electrocytes by a neurotransmitter, acetylcholine (Ach), and demonstrated electric generation. Maximum voltage and current were 1.5 V and 0.64 mA, respectively, with a duration time of a few seconds. We also demonstrated energy accumulation in a capacitor. The current was far larger than that using general cells other than electrocytes (~pA level). The generation ability was confirmed against repetitive cycles and also after preservation for 1 day. This is the first step toward ATP-based energy harvesting devices. PMID- 27241819 TI - LC of high to moderately polar basic drugs in urine with water and detergent, and direct injection. AB - BACKGROUND: Micellar LC was first proposed as a 'green' mode using mobile phases of water and surfactant. However, in most procedures a small amount of organic solvent is required to decrease the retention to convenient values. Results & methodology: Mixed micellar mobile phases prepared with both cationic (sodium dodecyl sulphate) and nonionic surfactant (Brij-35) modulate the retention of high to moderately polar basic drugs to practical times, eliminating the need of organic solvent. While the mobile phase is continuously recycled through the system, the stationary phase performance is maintained after repetitive injection of the samples. DISCUSSION & CONCLUSION: Through an extensive validation, the approach is shown to be appropriate to determine these drugs in urine samples without previous pretreatment. PMID- 27241818 TI - Group III/IV muscle afferents limit the intramuscular metabolic perturbation during whole body exercise in humans. AB - KEY POINTS: The purpose of this study was to determine the role of group III/IV muscle afferents in limiting the endurance exercise-induced metabolic perturbation assayed in muscle biopsy samples taken from locomotor muscle. Lumbar intrathecal fentanyl was used to attenuate the central projection of MU-opioid receptor-sensitive locomotor muscle afferents during a 5 km cycling time trial. The findings suggest that the central projection of group III/IV muscle afferent feedback constrains voluntary neural 'drive' to working locomotor muscle and limits the exercise-induced intramuscular metabolic perturbation. Therefore, the CNS might regulate the degree of metabolic perturbation within locomotor muscle and thereby limit peripheral fatigue. It appears that the group III/IV muscle afferents are an important neural link in this regulatory mechanism, which probably serves to protect locomotor muscle from the potentially severe functional impairment as a consequence of severe intramuscular metabolic disturbance. ABSTRACT: To investigate the role of metabo- and mechanosensitive group III/IV muscle afferents in limiting the intramuscular metabolic perturbation during whole body endurance exercise, eight subjects performed 5 km cycling time trials under control conditions (CTRL) and with lumbar intrathecal fentanyl impairing lower limb muscle afferent feedback (FENT). Vastus lateralis muscle biopsies were obtained before and immediately after exercise. Motoneuronal output was estimated through vastus lateralis surface electromyography (EMG). Exercise-induced changes in intramuscular metabolites were determined using liquid and gas chromatography-mass spectrometry. Quadriceps fatigue was quantified by pre- to post-exercise changes in potentiated quadriceps twitch torque (DeltaQTsingle ) evoked by electrical femoral nerve stimulation. Although motoneuronal output was 21 +/- 12% higher during FENT compared to CTRL (P < 0.05), time to complete the time trial was similar (~8.8 min). Compared to CTRL, power output during FENT was 10 +/- 4% higher in the first half of the time trial, but 11 +/- 5% lower in the second half (both P < 0.01). The exercise induced increase in intramuscular inorganic phosphate, H(+) , adenosine diphosphate, lactate and phosphocreatine depletion was 55 +/- 30, 62 +/- 18, 129 +/- 63, 47 +/- 14 (P < 0.001) and 27 +/- 14% (P < 0.01) greater in FENT than CTRL. DeltaQTsingle was greater following FENT than CTRL (-52 +/- 2 vs -31 +/- 1%, P < 0.001) and this difference was positively correlated with the difference in inorganic phosphate (r(2) = 0.79; P < 0.01) and H(+) (r(2) = 0.92; P < 0.01). In conclusion, during whole body exercise, group III/IV muscle afferents provide feedback to the CNS which, in turn, constrains motoneuronal output to the active skeletal muscle. This regulatory mechanism limits the exercise-induced intramuscular metabolic perturbation, preventing an abnormal homeostatic challenge and excessive peripheral fatigue. PMID- 27241820 TI - Applications and challenges in using LC-MS/MS assays for quantitative doping analysis. AB - LC-MS/MS is useful for qualitative and quantitative analysis of 'doped' biological samples from athletes. LC-MS/MS-based assays at low-mass resolution allow fast and sensitive screening and quantification of targeted analytes that are based on preselected diagnostic precursor-product ion pairs. Whereas LC coupled with high-resolution/high-accuracy MS can be used for identification and quantification, both have advantages and challenges for routine analysis. Here, we review the literature regarding various quantification methods for measuring prohibited substances in athletes as they pertain to World Anti-Doping Agency regulations. PMID- 27241821 TI - Laryngeal and phrenic nerve involvement in a patient with hereditary neuropathy with liability to pressure palsies (HNPP). AB - Lower cranial and phrenic nerve involvement is exceptional in hereditary neuropathy with liability to pressure palsies (HNPP). Here we report the occurrence of reversible laryngeal and phrenic nerve involvement in a patient with HNPP. The patient recalled several episodes of reversible weakness and numbness of his feet and hands since the age of 30 years. His medical history was uneventful, apart from chronic obstructive pulmonary disease (COPD). At age 44, following severe weight loss, he presented with progressive dysphonia and hoarseness. EMG of cricoarytenoid and thyroarytenoid muscles and laryngeal fibroscopy confirmed vocal cord paralysis. These speech disturbances gradually regressed. Two years later, he reported rapidly worsening dyspnea. Electroneurography showed increased distal latency of the right phrenic nerve and diaphragm ultrasonography documented reduced right hemi-diaphragm excursion. Six months later and after optimization of CODP treatment, his respiratory function had improved and both phrenic nerve conduction and diaphragm excursion were completely restored. We hypothesize that chronic cough and nerve stretching in the context of CODP, together with severe weight loss, may have triggered the nerve paralysis in this patient. Our report highlights the need for optimal management of comorbidities such as CODP as well as careful control of weight in HNPP patients to avoid potentially harmful complications. PMID- 27241822 TI - Describing nutrition in spinal muscular atrophy: A systematic review. AB - Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease of variable severity. Progressive muscle wasting and impairment in functional ability in SMA have a profound influence on nutritional outcomes. This systematic review summarises the existing evidence on nutrition in SMA. The search strategy was conducted across five databases in August 2014, and updated in March 2016, using key terms relating to growth, nutrition requirements, dietary intake and nutrition management. Studies were selected for inclusion using a two pass method, and data systematically extracted using standardised forms. Thirty-nine studies met eligibility criteria. Body composition is abnormal in patients with SMA, and feeding and swallowing issues are prevalent among sufferers of SMA types I and II. Nutritional management practices vary internationally. There is a paucity of literature regarding nutrition requirements in SMA, although it appears that energy expenditure may be reduced. Children with SMA require individualised nutritional management in order to address their growth and nutrition requirements. There is an urgent need for larger, coordinated, prospective intervention studies of nutrition in SMA. PMID- 27241823 TI - Race and Color: Two Sides of One Story? Development of Biases in Categorical Perception. AB - Categorical perception is a phenomenon that leads people to group stimuli into categories instead of perceiving their natural continua. This article reviews the literature of two biases connected with categorical perception: categorical color perception and the other-race effect. Although these two phenomena concern distant targets (colors and faces) and imply different biases (one attentional, one mnemonic), they share at least three commonalities. First, they both involve the chunking of continuous dimensions into categories. Second, adult categories are shaped by cultural processes. Third, infants' discrimination performance seems universal and guided by perception. In this article, it is proposed to look for a common developmental mechanism that clarifies the shift from a perceptual to a sociocognitive knowledge of the environment. New perspectives are discussed. PMID- 27241824 TI - A Bipartisan Approach to Better Care and Smarter Spending for Elderly Adults with Advanced Chronic Illness. PMID- 27241825 TI - Cochlear implantation in Pendred syndrome and non-syndromic enlarged vestibular aqueduct - clinical challenges, surgical results, and complications. AB - OBJECTIVE: To explore specific clinical issues, surgical results, and complications of 80 cochlear implantations (CI) in 55 patients with Pendred syndrome (PS) or non-syndromic enlarged vestibular aqueduct (NSEVA). BACKGROUND: Previous studies have focused either on unselected case series or on populations with mixed cochlear malformations. PS/NSEVA accounts for up to 10% of congenital SNHL, rendering this a large group of cochlear implant candidates. The abnormal inner ear anatomy of these patients may be associated with a lower surgical success rate and a higher rate of complications. STUDY DESIGN: Retrospective review of patients' medical records and CT/MRI. SETTING: Tertiary referral center. MATERIALS AND METHODS: The medical records and CT/MRI images of 55 PS/NSEVA patients receiving 80 cochlear implantations from 1982-2014 were reviewed. Demographic data, surgical results, intra-operative incidents, and post operative complications were retrieved. RESULTS: Complications occurred in 36% of implantations; 5% hereof major complications. Gushing/oozing from the cochleostoma occurred in 10% of implantations and was related to transient, but not prolonged post-operative vertigo. CONCLUSION: Intra-operative risks of gushing/oozing and post-operative vertigo are the primary clinical issues in PS/NSEVA patients regarding CI. Nonetheless, the surgical success rate is high and the major complication rate is low; similar to studies of unselected series of CI recipients. PMID- 27241826 TI - Ammonia as an efficient catalyst for decomposition of carbonic acid: a quantum chemical investigation. AB - Electronic structure calculations using M06-2X, MP2 and CCSD(T) methods have been employed to show ammonia as an efficient catalyst for decomposition of carbonic acid. The results predict that ammonia can catalyze the reaction as both a monomer and dimer, the latter being more efficient as it makes the reaction nearly barrierless. It has been shown that monomeric ammonia makes the process significantly faster compared with the water monomer (the rate constant being 10(4) to 10(5) times higher) as well as the water dimer (10-20 times faster). Dimeric ammonia has been shown to be a better catalyst than its monomeric counterpart (the rate constant being 10(3) to 10(4) times higher). Its efficiency as a catalyst was found to be close to that of formic acid. Owing to the fact that ammonia is present in the Earth's atmosphere at a significant trace level, it is expected to play a nontrivial, if not pivotal, role in atmospheric chemistry as a catalyst. PMID- 27241827 TI - Turning the corner in fertility: high DNA integrity of boundary-following sperm. AB - We present a passive microfluidic sperm selection strategy that collects motile sperm based on their preference to follow boundaries and turn corners. Clinical assessment of selected human sperm from the device revealed a strong correlation between high DNA integrity and the tendency for sperm to follow boundaries. Human sperm with preference to follow boundaries on the left- or right-hand sides have higher (>51%) DNA integrity than straight swimmers and significantly higher (>67%) DNA integrity than sperm in raw semen. Boundary following behaviour offers a strategy to selecting sperm with the highest DNA integrity to improve the success rate of assisted reproduction. PMID- 27241828 TI - Evaluation of five commercial methods for the extraction and purification of DNA from human faecal samples for downstream molecular detection of the enteric protozoan parasites Cryptosporidium spp., Giardia duodenalis, and Entamoeba spp. AB - High quality, pure DNA is required for ensuring reliable and reproducible results in molecular diagnosis applications. A number of in-house and commercial methods are available for the extraction and purification of genomic DNA from faecal material, each one offering a specific combination of performance, cost effectiveness, and easiness of use that should be conveniently evaluated in function of the pathogen of interest. In this comparative study the marketed kits QIAamp DNA stool mini (Qiagen), SpeedTools DNA extraction (Biotools), DNAExtract VK (Vacunek), PowerFecal DNA isolation (MoBio), and Wizard magnetic DNA purification system (Promega Corporation) were assessed for their efficacy in obtaining DNA of the most relevant enteric protozoan parasites associated to gastrointestinal disease globally. A panel of 113 stool specimens of clinically confirmed patients with cryptosporidiosis (n=29), giardiasis (n=47) and amoebiasis by Entamoeba histolytica (n=3) or E. dispar (n=10) and apparently healthy subjects (n=24) were used for this purpose. Stool samples were aliquoted in five sub-samples and individually processed by each extraction method evaluated. Purified DNA samples were subsequently tested in PCR-based assays routinely used in our laboratory. The five compared methods yielded amplifiable amounts of DNA of the pathogens tested, although performance differences were observed among them depending on the parasite and the infection burden. Methods combining chemical, enzymatic and/or mechanical lysis procedures at temperatures of at least 56 degrees C were proven more efficient for the release of DNA from Cryptosporidium oocysts. PMID- 27241829 TI - Expression and purification of rhIL-10-RGD from Escherichia coli as a potential wound healing agent. AB - Various protocols for recombinant Interleukin-10 (IL-10) purification in wound healing have been reported previously. However, the therapeutic effect was not obvious. Thus, it is of great importance to find new and effective approaches for therapy. In this study, we propose that IL-10 and Arginine-Glycine-Aspartic (RGD) peptide would be a valuable therapeutic for wound healing. To explore a high efficiency and cost-effective approach for the production of IL-10 and RGD peptide with bioactivity, a synthetic gene was cloned into a recombinant pTWIN1 vector. As a consequence, rhIL-10-RGD and the pH-induced self-cleavable Ssp DnaB mini-intein as a fusion protein was highly expressed by IPTG induction in Escherichia coli Rosetta without extra residues in a bioreactor. After Ni affinity chromatographic purification, rhIL-10-RGD was released by the Ssp DnaB intein-mediated self-cleavage that is triggered by pH shift. SDS-PAGE and silver staining showed a major band with an estimated molecular mass of 19.3kDa. Cell proliferation assay confirmed its potent proliferation activity on MC/9 murine mast cells. In conclusion, we report a novel strategy to produce rhIL-10-RGD mediated by the pH-induced self-cleavable Ssp DnaB mini-intein, and show that rhIL-10-RGD could play an effective role in wound healing of BALB/c mice. PMID- 27241830 TI - Patient-provider discussions about lung cancer screening pre- and post guidelines: Health Information National Trends Survey (HINTS). AB - OBJECTIVE: In 2013, the USPSTF issued a Grade B recommendation that long-term current and former smokers receive lung cancer screening. Shared decision-making is important for individuals considering screening, and patient-provider discussions an essential component of the process. We examined prevalence and predictors of lung cancer screening discussions pre- and post-USPSTF guidelines. METHODS: Data were obtained from two cycles of the Health Information National Trends Survey (2012; 2014). The analyzed sample comprised screening-eligible current and former smokers with no personal history of lung cancer (n=746 in 2012; n=795 in 2014). Descriptive and multiple logistic regression analyses were conducted; patient-reported discussion about lung cancer screening with provider was the outcome of interest. RESULTS: Contrary to expectations, patient-provider discussions about lung cancer screening were more prevalent pre-guideline, but overall patient-provider discussions were low in both years (17% in 2012; 10% in 2014). Current smokers were more likely to have had a discussion than former smokers. Significant predictors of patient-provider discussions included family history of cancer and having healthcare coverage. CONCLUSIONS: The prevalence of patient-provider discussions about lung cancer screening is suboptimal. PRACTICE IMPLICATIONS: There is a critical need for patient and provider education about shared decision-making and its importance in cancer screening decisions. PMID- 27241831 TI - ENRICH: A promising oncology nurse training program to implement ASCO clinical practice guidelines on fertility for AYA cancer patients. AB - OBJECTIVE: We describe the impact of ENRICH (Educating Nurses about Reproductive Issues in Cancer Healthcare), a web-based communication-skill-building curriculum for oncology nurses regarding AYA fertility and other reproductive health issues. METHODS: Participants completed an 8-week course that incorporated didactic content, case studies, and interactive learning. Each learner completed a pre- and post-test assessing knowledge and a 6-month follow-up survey assessing learner behaviors and institutional changes. RESULTS: Out of 77 participants, the majority (72%) scored higher on the post-test. Fifty-four participants completed the follow-up survey: 41% reviewed current institutional practices, 20% formed a committee, and 37% gathered patient materials or financial resources (22%). Participants also reported new policies (30%), in-service education (37%), new patient education materials (26%), a patient navigator role (28%), and workplace collaborations with reproductive specialists (46%). CONCLUSION: ENRICH improved nurses' knowledge and involvement in activities addressing fertility needs of oncology patients. Our study provides a readily accessible model to prepare oncology nurses to integrate American Society of Clinical Oncology guidelines and improve Quality Oncology Practice Initiative measures related to fertility. PRACTICE IMPLICATIONS: Nurses will be better prepared to discuss important survivorship issues related to fertility and reproductive health, leading to improved quality of life outcomes for AYAs. PMID- 27241832 TI - Enhanced copper-mediated (18)F-fluorination of aryl boronic esters provides eight radiotracers for PET applications. AB - [(18)F]FMTEB, [(18)F]FPEB, [(18)F]flumazenil, [(18)F]DAA1106, [(18)F]MFBG, [(18)F]FDOPA, [(18)F]FMT and [(18)F]FDA are prepared from the corresponding arylboronic esters and [(18)F]KF/K222 in the presence of Cu(OTf)2py4. The method was successfully applied using three radiosynthetic platforms, and up to 26 GBq of non-carrier added starting activity of (18)F-fluoride. PMID- 27241834 TI - Using the PyMOL application to reinforce visual understanding of protein structure. AB - Visualization of chemical concepts can be challenging for many students. This is arguably a critical skill for beginning students of biochemistry to develop, since new information is often presented visually in the form of textbook figures. It is recommended that visual literacy be explicitly taught in the classroom rather than assuming that students will develop this skill on their own. The activity described here is designed to assist students in their development of understanding of basic representations of protein three dimensional structure as well as various types of ligands (small molecules, ions) through the use of the iPad application PyMOL. It has been used as a laboratory exercise but can also be used in a typical 50-minute class period with a portion of the activity assigned as homework. (c) 2016 by The International Union of Biochemistry and Molecular Biology, 44(5):433-437, 2016. PMID- 27241833 TI - Missing heritability of complex diseases: Enlightenment by genetic variants from intermediate phenotypes. AB - Diseases of complex origin have a component of quantitative genetics that contributes to their susceptibility and phenotypic variability. However, after several studies, a major part of the genetic component of complex phenotypes has still not been found, a situation known as "missing heritability." Although there have been many hypotheses put forward to explain the reasons for the missing heritability, its definitive causes remain unknown. Complex diseases are caused by multiple intermediate phenotypes involved in their pathogenesis and, very often, each one of these intermediate phenotypes also has a component of quantitative inheritance. Here we propose that at least part of the missing heritability can be explained by the genetic component of intermediate phenotypes that is not detectable at the level of the main complex trait. At the same time, the identification of the genetic component of intermediate phenotypes provides an opportunity to identify part of the missing heritability of complex diseases. PMID- 27241835 TI - Effect of Low-Frame Invasive Coronary Angiography on Radiation and Image Quality. AB - Invasive coronary angiography (ICA) uses harmful x-ray energy. To date, there are no studies evaluating the effect of performing ICA at lower than the standard 15 frames per second (f/s) on radiation dose and image quality. In this study, we investigated the effect of performing ICAs at 7.5 f/s as opposed to the standard 15 f/s on radiation exposure and image quality. Thirty-nine patients referred for ICA for clinical indications were assigned to have their ICA performed at 7.5 f/s or 15 f/s in a 2:1 ratio, respectively. All studies were performed by one experienced operator in the same laboratory. Magnification, table height, collimation, number of images, and specific angles for image acquisition were kept constant to account for these variables that also effect radiation. Studies performed at 7.5 f/s had significantly less radiation exposure than those performed at 15 f/s (252.2 mGy vs 433.7 mGy, p <0.01). In addition, radiation per unit time was also significantly reduced in the 7.5 f/s versus the 15 f/s group (140.0 mGy/min vs 254.7 mGy/min, p <0.01). Image quality was evaluated by an experienced operator blinded to the goals of the study; allstudies were graded as good to excellent. In conclusion, performing ICA at 7.5 f/s versus 15 f/s significantly reduces x-ray exposure without compromising image quality. The results of this single-center study warrant a larger randomized clinical trial. PMID- 27241836 TI - Effect of Aspirin Supplementation on Hemostatic Responses in Firefighters Aged 40 to 60 Years. AB - Sudden cardiovascular events account for approximately 45% to 50% of all duty related deaths among firefighters and a disproportionate number of these fatalities occur after strenuous fire suppression activities. The purpose of this study was to evaluate the effect of acute and chronic aspirin supplementation on hemostatic function before and after live firefighting activities in older firefighters. A double-blind, crossover design included 4 treatments: a 2-week aspirin/placebo treatment ("chronic") and a single prefirefighting aspirin/placebo treatment ("acute"). Hemostatic function was assessed in 24 male firefighters (mean age = 48.2 +/- 5.9 years) immediately before and after 18 minutes of live-fire firefighting activity. An acute bout of firefighting activity significantly decreased platelet aggregation time and decreased activated partial thromboplastin time. Compared with placebo, acute aspirin supplementation resulted in a significant increase in epinephrine closure time, which was further augmented by chronic supplementation. Aspirin supplementation had no effect on coagulatory or fibrinolytic factors. Our findings suggest that an acute bout of firefighting leads to increased coagulatory potential in older firefighters. In conclusion, aspirin supplementation had an antiplatelet effect that decreased platelet aggregability at rest and after an acute bout of firefighting compared with placebo. PMID- 27241837 TI - Effect of Cardiac Resynchronization Therapy on Left Atrial Size and Function as Expressed by Speckle Tracking 2-Dimensional Strain. AB - Changes in left atrial (LA) strain in patients treated with cardiac resynchronization therapy (CRT) remain not entirely explored. We prospectively evaluated long-term changes in LA size and function and their relation with left ventricular (LV) reverse remodeling and noninvasive hemodynamic variables in patients treated with CRT by 2-dimensional speckle tracking echocardiography. Thirty patients (62 +/- 11 years, 63% men) underwent 2-dimensional speckle tracking echocardiography before implant and after 12 months. LA area, global and regional LA strains, LV ejection fraction (LVEF) and longitudinal strain, mitral regurgitation (MR), and diastolic variables were evaluated. At 12 months, CRT responders (60%) exhibited an increase in LA strain (11.4 +/- 6.5% vs 16.5 +/- 7.9%, p <0.001) and a reduction in LA area (p = 0.002), which were associated with an improvement in MR, E/E' ratio, LVEF, and LV longitudinal strain. In nonresponders, a worsening in LA strain (11.4 +/- 6.8% vs 8.7 +/- 4.6%, p = 0.017) and LA area (p = 0.002) occurred in parallel with an increase in E/E', whereas LVEF and LV longitudinal strain were unchanged. In conclusion, over long term follow-up, LA size and strain improved in CRT responders, while worsening in nonresponders. Changes in LV function, filling pressures, and MR seem to be related to LA reverse remodeling, giving a feedback loop. PMID- 27241838 TI - Independent Link Between Levels of Proprotein Convertase Subtilisin/Kexin Type 9 and FABP4 in a General Population Without Medication. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to and degrades the low-density lipoprotein (LDL) receptor, leading to hypercholesterolemia and cardiovascular risk. Fatty acid binding protein 4 (FABP4/adipocyte FABP/aP2) is secreted from adipocytes in association with lipolysis, and circulating FABP4 has been reported to act as an adipokine for the development of insulin resistance and atherosclerosis. Elevated serum FABP4 level is associated with obesity, insulin resistance, dyslipidemia, and atherosclerosis. In this study, we examined the association between circulating levels of FABP4 and PCSK9 in a general population. A total of 265 subjects (male/female: 98/167) who were not on medication were recruited from subjects of the Tanno-Sobetsu Study, and concentrations of FABP4 and PCSK9 were measured. The level of FABP4, but not that of PCSK9, showed a gender difference, being higher in women than in men. FABP4 level was independently associated with gender, adiposity, renal dysfunction, and levels of cholesterol and PCSK9. There was a significant and gender-different correlation between PCSK9 level and age: negatively in men (r = -0.250, p = 0.013) and positively in women (r = 0.183, p = 0.018). After adjustment of age, gender, and LDL cholesterol level, PCSK9 level was positively and independently correlated with FABP4 concentration. In conclusion, PCSK9 level is differentially regulated by gender during aging. Circulating FABP4 is independently associated with the PCSK9 level, suggesting that elevation of FABP4 level as an adipokine leads to dyslipidemia through increased PCSK9 level and subsequent degradation of the LDL receptor. PMID- 27241840 TI - Predictable Superiority of Everolimus-Eluting Stent Over Paclitaxel-Eluting Balloon in Patients With In-Stent Restenosis. PMID- 27241839 TI - Effect of Left Ventricular Systolic Dysfunction on Response to Warfarin. AB - Candidates for chronic warfarin therapy often have co-morbid conditions, such as heart failure, with reduced left ventricular ejection fraction. Previous reports have demonstrated an increased risk of over-anticoagulation due to reduced warfarin dose requirement in patients with decompensated heart failure. However, the influence of left ventricular systolic dysfunction (LVSD), defined as left ventricular ejection fraction <40%, on warfarin response has not been evaluated. Here, we assess the influence of LVSD on warfarin dose, anticoagulation control (percent time in target range), and risk of over-anticoagulation (international normalized ratio >4) and major hemorrhage. Of the 1,354 patients included in this prospective cohort study, 214 patients (16%) had LVSD. Patients with LVSD required 11% lower warfarin dose compared with those without LVSD (p <0.001) using multivariate linear regression analyses. Using multivariate Cox proportional hazards model, patients with LVSD experienced similar levels of anticoagulation control (percent time in target range: 51% vs 53% p = 0.15), risk of over-anticoagulation (international normalized ratio >4; hazard ratio 1.01, 95% confidence interval 0.82 to 1.25; p = 0.91), and risk of major hemorrhage (hazard ratio 1.11; 95% confidence interval 0.70 to 1.74; p = 0.66). Addition of LVSD variable in the model increased the variability explained from 35% to 36% for warfarin dose prediction. In conclusion, our results demonstrate that patients with LVSD require lower doses of warfarin. Whether warfarin dosing algorithms incorporating LVSD in determining initial doses improves outcomes needs to be evaluated. PMID- 27241842 TI - Recent developments in the diagnosis of avian influenza. AB - The diagnosis of influenza A virus infections in poultry or wild birds is difficult due to variations in the pathogenicity of the viruses in different avian hosts and also the antigenic and genetic diversity of the virus, particularly the recent H5 highly pathogenic avian influenza viruses. A classical standard laboratory technique is virus isolation prior to subtyping and pathotyping. This diagnostic technique is crucial for further virological analyses, particularly during an initial outbreak; however, delays in diagnosis have thwarted effective disease control in recent years. Recent developments in molecular biological techniques provide an accelerated diagnosis. Such technologies, which include real-time reverse transcriptase PCR, isothermal nucleic acid amplification, next-generation sequencing and immunochromatography, contribute to simpler and more rapid diagnosis. The advantages of each of these diagnostic techniques should be considered for effective control of avian influenza. PMID- 27241841 TI - miR-134 inhibits non-small cell lung cancer growth by targeting the epidermal growth factor receptor. AB - The epidermal growth factor receptor (EGFR) is frequently activated in a wide range of solid tumours and represents an important therapeutic target. MicroRNAs (miRNAs) have recently been recognized as a rational and potential modality for anti-EGFR therapies. However, more EGFR-targeting miRNAs need to be explored. In this study, we identified a novel EGFR-targeting miRNA, miRNA-134 (miR-134), in non-small-cell lung cancer (NSCLC) cell lines. Luciferase assays confirmed that EGFR is a direct target of miR-134. In addition, the overexpression of miR-134 inhibited EGFR-related signaling and suppressed NSCLC cells proliferation by inducing cell cycle arrest and/or apoptosis, suggesting that miR-134 functions as a tumour suppressor in NSCLC. Further mechanistic investigation including RNAi and rescue experiments suggested that the down-regulation of EGFR by miR-134 partially contributes to the antiproliferative role of miR-134. Last, in vivo experiments demonstrated that miR-134 suppressed tumour growth of A549 xenograft in nude mice. Taken together, our findings suggest that miR-134 inhibits non small cell lung cancer growth by targeting the EGFR. PMID- 27241843 TI - Grasping physical exercise through recreational running and non-representational theory: a case study from Sofia, Bulgaria. AB - To become and maintain being physically active encompasses more than purely mindful and rational decision-making. Physical activity requires theoretical methodological approaches that provide more subtle understandings of the variety of contextual factors. Nettleton and Green have recently argued persuasively for the need for the sociology of public health to embrace social practices. It is also necessary to think about the spaces, affects and technologies of engagement in physical exercise. This article examines the practices of recreational runners in Sofia, the capital of Bulgaria. The article has three aims; (i) to draw attention to the promise of non-representational theory as an additive for health research and the contextual factors of health practices, (ii) to examine recreational runner's practices and techniques of engagement in light of non representational theory, and (iii) to highlight how interventions in Sofia and beyond can incorporate elements of non-representational theory into their strategies for improved public health. In drawing attention to the promise of non representational theory and social practices this article concludes by emphasising their importance for public health interventions in physical activity strategies. PMID- 27241844 TI - HER2-Targeted Polyinosine/Polycytosine Therapy Inhibits Tumor Growth and Modulates the Tumor Immune Microenvironment. AB - The development of targeted therapies that affect multiple signaling pathways and stimulate antitumor immunity is greatly needed. About 20% of patients with breast cancer overexpress HER2. Small molecules and antibodies targeting HER2 convey some survival benefits; however, patients with advanced disease succumb to the disease under these treatment regimens, possibly because HER2 is not completely necessary for the survival of the targeted cancer cells. In the present study, we show that a polyinosine/polycytosine (pIC) HER2-homing chemical vector induced the demise of HER2-overexpressing breast cancer cells, including trastuzumab resistant cells. Targeting pIC to the tumor evoked a number of cell-killing mechanisms, as well as strong bystander effects. These bystander mechanisms included type I IFN induction, immune cell recruitment, and activation. The HER2 targeted pIC strongly inhibited the growth of HER2-overexpressing tumors in immunocompetent mice. The data presented here could open additional avenues in the treatment of HER2-positive breast cancer. Cancer Immunol Res; 4(8); 688-97. (c)2016 AACR. PMID- 27241846 TI - Hydration of proteins and nucleic acids: Advances in experiment and theory. A review. AB - BACKGROUND: Most biological processes involve water, and the interactions of biomolecules with water affect their structure, function and dynamics. SCOPE OF REVIEW: This review summarizes the current knowledge of protein and nucleic acid interactions with water, with a special focus on the biomolecular hydration layer. Recent developments in both experimental and computational methods that can be applied to the study of hydration structure and dynamics are reviewed, including software tools for the prediction and characterization of hydration layer properties. MAJOR CONCLUSIONS: In the last decade, important advances have been made in our understanding of the factors that determine how biomolecules and their aqueous environment influence each other. Both experimental and computational methods contributed to the gradually emerging consensus picture of biomolecular hydration. GENERAL SIGNIFICANCE: An improved knowledge of the structural and thermodynamic properties of the hydration layer will enable a detailed understanding of the various biological processes in which it is involved, with implications for a wide range of applications, including protein structure prediction and structure-based drug design. PMID- 27241845 TI - Antitumor Efficacy of Radiation plus Immunotherapy Depends upon Dendritic Cell Activation of Effector CD8+ T Cells. AB - Tumor cells dying after cytotoxic therapy are a potential source of antigen for T cell priming. Antigen-presenting cells (APC) can cross-present MHC I-restricted peptides after the uptake of dying cells. Depending on the nature of the surrounding environmental signals, APCs then orchestrate a spectrum of responses ranging from immune activation to inhibition. Previously, we had demonstrated that combining radiation with either agonistic monoclonal antibody (mAb) to CD40 or a systemically administered TLR7 agonist could enhance CD8 T-cell-dependent protection against syngeneic murine lymphoma models. However, it remains unknown how individual APC populations affect this antitumor immune response. Using APC depletion models, we now show that dendritic cells (DC), but not macrophages or B cells, were responsible for the generation of long-term immunologic protection following combination therapy with radiotherapy and either agonistic CD40 mAb or systemic TLR7 agonist therapy. Novel immunotherapeutic approaches that augment antigen uptake and presentation by DCs may further enhance the generation of therapeutic antitumor immune responses, leading to improved outcomes after radiotherapy. Cancer Immunol Res; 4(7); 621-30. (c)2016 AACR. PMID- 27241847 TI - Unification of [FeFe]-hydrogenases into three structural and functional groups. AB - BACKGROUND: [FeFe]-hydrogenases (Hyd) are structurally diverse enzymes that catalyze the reversible oxidation of hydrogen (H2). Recent biochemical data demonstrate new functional roles for these enzymes, including those that function in electron bifurcation where an exergonic reaction is coupled with an endergonic reaction to drive the reversible oxidation/production of H2. METHODS: To identify the structural determinants that underpin differences in enzyme functionality, a total of 714 homologous sequences of the catalytic subunit, HydA, were compiled. Bioinformatics approaches informed by biochemical data were then used to characterize differences in inferred quaternary structure, HydA active site protein environment, accessory iron-sulfur clusters in HydA, and regulatory proteins encoded in HydA gene neighborhoods. RESULTS: HydA homologs were clustered into one of three classification groups, Group 1 (G1), Group 2 (G2), and Group 3 (G3). G1 enzymes were predicted to be monomeric while those in G2 and G3 were predicted to be multimeric and include HydB, HydC (G2/G3) and HydD (G3) subunits. Variation in the HydA active site and accessory iron-sulfur clusters did not vary by group type. Group-specific regulatory genes were identified in the gene neighborhoods of both G2 and G3 Hyd. Analyses of purified G2 and G3 enzymes by mass spectrometry strongly suggest that they are post-translationally modified by phosphorylation. CONCLUSIONS: These results suggest that bifurcation capability is dictated primarily by the presence of both HydB and HydC in Hyd complexes, rather than by variation in HydA. GENERAL SIGNIFICANCE: This classification scheme provides a framework for future biochemical and mutagenesis studies to elucidate the functional role of Hyd enzymes. PMID- 27241850 TI - The Effect of Radial Head Hemiarthroplasty Geometry on Proximal Radioulnar Joint Contact Mechanics. AB - PURPOSE: To compare the joint contact area and peak contact stress of different radial head (RH) hemiarthroplasty articular profiles for the proximal radioulnar joint (PRUJ) to the native radial head with the hypothesis that the side radius and side angle closest to the native mating ulnar articular profile would provide the best contact mechanics. METHODS: Finite element models generated from the computed tomography geometry of 14 native elbows (73 +/- 17.5 years) were subjected to 12 different RH profiles having varying side radii (flat [r = infinity mm], 16.25, 8.12, and 4.50 mm) and side angles (0 degrees , 5 degrees , and 10 degrees ) under a constant compressive 20-N medial load. Contact areas and peak contact stresses were computed and compared with the native joint. RESULTS: On average, RH implants significantly reduced PRUJ contact area by 55% +/- 16% and increased peak contact stress by 337% +/- 241% compared with the native RH. The prosthesis side radius had significant effects on both contact area and stress, but side angle did not. The 16.25-mm radii produced the largest contact areas, and the 4.50-mm radius model generated the smallest contact areas. As the side radius was decreased, peak contact stress was reduced as the contact migrated toward the center of the native ulnar articulation, although the 8.12-mm radius achieved the lowest peak contact stress. CONCLUSIONS: Whereas RH hemiarthroplasty side radius can affect both contact area and peak contact stress, the magnitude of the effect on contact area is relatively small compared with that of the peak contact stress. Furthermore, although a flat RH side profile with a side angle of 5 degrees more closely matched the side profile of the native ulnas used in the present study, the optimal profile was found to be a smaller radius of 8.12 mm. CLINICAL RELEVANCE: Optimizing PRUJ contact mechanics after metallic RH hemiarthroplasty may contribute to better clinical outcomes by reducing the potential for native cartilage degeneration. PMID- 27241848 TI - Enzyme-specific differences in mannose phosphorylation between GlcNAc-1 phosphotransferase alphabeta and gamma subunit deficient zebrafish support cathepsin proteases as early mediators of mucolipidosis pathology. AB - Targeting soluble acid hydrolases to lysosomes requires the addition of mannose 6 phosphate residues on their N-glycans. This process is initiated by GlcNAc-1 phosphotransferase, a multi-subunit enzyme encoded by the GNPTAB and GNPTG genes. The GNPTAB gene products (the alpha and beta subunits) are responsible for recognition and catalysis of hydrolases whereas the GNPTG gene product (the gamma subunit) enhances mannose phosphorylation of a subset of hydrolases. Here we identify and characterize a zebrafish gnptg insertional mutant and show that loss of the gamma subunit reduces mannose phosphorylation on a subset glycosidases but does not affect modification of several cathepsin proteases. We further show that glycosidases, but not cathepsins, are hypersecreted from gnptg(-/-) embryonic cells, as evidenced by reduced intracellular activity and increased circulating serum activity. The gnptg(-/-) embryos lack the gross morphological or craniofacial phenotypes shown in gnptab-deficient morphant embryos to result from altered cathepsin activity. Despite the lack of overt phenotypes, decreased fertilization and embryo survival were noted in mutants, suggesting that gnptg associated deposition of mannose 6-phosphate modified hydrolases into oocytes is important for early embryonic development. Collectively, these findings demonstrate that loss of the zebrafish GlcNAc-1-phosphotransferase gamma subunit causes enzyme-specific effects on mannose phosphorylation. The finding that cathepsins are normally modified in gnptg(-/-) embryos is consistent with data from gnptab-deficient zebrafish suggesting these proteases are the key mediators of acute pathogenesis. This work also establishes a valuable new model that can be used to probe the functional relevance of GNPTG mutations in the context of a whole animal. PMID- 27241852 TI - Neonatal Alopecia Due to Birth Trauma: Case Report and Trichoscopic Findings. AB - A 4-day-old boy was referred for evaluation of an oval patch of occipital alopecia associated with caput succedaneum and ipsilateral eyelid ecchymoses. Based on the history of a prolonged, difficult labor with vacuum-assisted delivery, the diagnosis of neonatal alopecia associated with birth trauma was made. Trichoscopy showed purple dots corresponding to blood extravasation and follicular ostia. We also review the trichoscopic differential diagnosis of focal neonatal alopecia. PMID- 27241851 TI - Attosecond nanoscale near-field sampling. AB - The promise of ultrafast light-field-driven electronic nanocircuits has stimulated the development of the new research field of attosecond nanophysics. An essential prerequisite for advancing this new area is the ability to characterize optical near fields from light interaction with nanostructures, with sub-cycle resolution. Here we experimentally demonstrate attosecond near-field retrieval for a tapered gold nanowire. By comparison of the results to those obtained from noble gas experiments and trajectory simulations, the spectral response of the nanotaper near field arising from laser excitation can be extracted. PMID- 27241853 TI - Continuous Dialysis Therapies: Core Curriculum 2016. PMID- 27241849 TI - A novel mosquito ubiquitin targets viral envelope protein for degradation and reduces virion production during dengue virus infection. AB - BACKGROUND: Dengue virus (DENV) is a mosquito-borne flavivirus that causes significant human disease and mortality in the tropics and subtropics. By examining the effects of virus infection on gene expression, and interactions between virus and vector, new targets for prevention of infection and novel treatments may be identified in mosquitoes. We previously performed a microarray analysis of the Aedes aegypti transcriptome during infection with DENV and found that mosquito ubiquitin protein Ub3881 (AAEL003881) was specifically and highly down-regulated. Ubiquitin proteins have multiple functions in insects, including marking proteins for proteasomal degradation, regulating apoptosis and mediating innate immune signaling. METHODS: We used qRT-PCR to quantify gene expression and infection, and RNAi to reduce Ub3881 expression. Mosquitoes were infected with DENV through blood feeding. We transfected DENV protein expression constructs to examine the effect of Ub3881 on protein degradation. We used site-directed mutagenesis and transfection to determine what amino acids are involved in Ub3881 mediated protein degradation. Immunofluorescence, Co-immunoprecipitation and Western blotting were used to examine protein interactions and co-localization. RESULTS: The overexpression of Ub3881, but not related ubiquitin proteins, decreased DENV infection in mosquito cells and live Ae. aegypti. The Ub3881 protein was demonstrated to be involved in DENV envelope protein degradation and reduce the number of infectious virions released. CONCLUSIONS: We conclude that Ub3881 has several antiviral functions in the mosquito, including specific viral protein degradation. GENERAL SIGNIFICANCE: Our data highlights Ub3881 as a target for future DENV prevention strategies in the mosquito transmission vector. PMID- 27241854 TI - Pemetrexed-Induced Nephrogenic Diabetes Insipidus. AB - Pemetrexed is an approved antimetabolite agent, now widely used for treating locally advanced or metastatic nonsquamous non-small cell lung cancer. Although no electrolyte abnormalities are described in the prescribing information for this drug, several case reports have noted nephrogenic diabetes insipidus with associated acute kidney injury. We present a case of nephrogenic diabetes insipidus without severely reduced kidney function and propose a mechanism for the isolated finding. Severe hypernatremia can lead to encephalopathy and osmotic demyelination, and our report highlights the importance of careful monitoring of electrolytes and kidney function in patients with lung cancer receiving pemetrexed. PMID- 27241856 TI - Side-sloped surfaces substantially affect lower limb running kinematics. AB - Running on side-sloped surfaces is a common obstacle in the environment; however, how and to what extent the lower extremity kinematics adapt is not well known. The purpose of this study was to determine the effects of side-sloped surfaces on three-dimensional kinematics of hip, knee, and ankle during stance phase of running. Ten healthy adult males ran barefoot along an inclinable runway in level (0 degrees ) and side-sloped (10 degrees up-slope and down-slope inclinations, respectively) configurations. Right hip, knee, and ankle angles along with their time of occurrence were analysed using repeated measures MANOVA. Up-slope hip was more adducted (p = 0.015) and internally rotated (p = 0.030). Knee had greater external rotations during side-sloped running at heel-strike (p = 0.005), while at toe-off, it rotated externally and internally during up-slope and down-slope running, respectively (p = 0.001). Down-slope ankle had greatest plantar flexion (p = 0.001). Up-slope ankle had greatest eversion compared with down-slope (p = 0.043), while it was more externally rotated (p = 0.030). These motion patterns are necessary to adjust the lower extremity length during side-sloped running. Timing differences in the kinematic events of hip adduction and external rotation, and ankle eversion were observed (p = 0.006). Knowledge on these alterations is a valuable tool in adopting strategies to enhance performance while preventing injury. PMID- 27241855 TI - Mitogenomics of southern hemisphere blue mussels (Bivalvia: Pteriomorphia): Insights into the evolutionary characteristics of the Mytilus edulis complex. AB - Marine blue mussels (Mytilus spp.) are widespread species that exhibit an antitropical distribution with five species occurring in the Northern Hemisphere (M. trossulus, M. edulis, M. galloprovincialis, M. californianus and M. coruscus) and three in the Southern Hemisphere (M. galloprovincialis, M. chilensis and M. platensis). Species limits in this group remain controversial, in particular for those forms that live in South America. Here we investigated structural characteristics of marine mussels mitogenomes, based on published F mtDNA sequences of Northern Hemisphere species and two newly sequenced South American genomes, one from the Atlantic M. platensis and another from the Pacific M. chilensis. These mitogenomes exhibited similar architecture to those of other genomes of Mytilus, including the presence of the Atp8 gene, which is missing in most of the other bivalves. Our evolutionary analysis of mitochondrial genes indicates that purifying selection is the predominant force shaping the evolution of the coding genes. Results of our phylogenetic analyses supported the monophyly of Pteriomorphia and fully resolved the phylogenetic relationships among its five orders. Finally, the low genetic divergence of specimens assigned to M. chilensis and M. platensis suggests that these South American marine mussels represent conspecific variants rather than distinct species. PMID- 27241857 TI - 5th Georgian Bay International Conference on Bioinorganic Chemistry. PMID- 27241858 TI - ASIC2a-dependent increase of ASIC3 surface expression enhances the sustained component of the currents. AB - Acid-sensing ion channels (ASICs) are proton-gated cation channels widely expressed in the nervous system. Proton sensing by ASICs has been known to mediate pain, mechanosensation, taste transduction, learning and memory, and fear. In this study, we investigated the differential subcellular localization of ASIC2a and ASIC3 in heterologous expression systems. While ASIC2a targeted the cell surface itself, ASIC3 was mostly accumulated in the ER with partial expression in the plasma membrane. However, when ASIC3 was co-expressed with ASIC2a, its surface expression was markedly increased. By using bimolecular fluorescence complementation (BiFC) assay, we confirmed the heteromeric association between ASIC2a and ASIC3 subunits. In addition, we observed that the ASIC2a-dependent surface trafficking of ASIC3 remarkably enhanced the sustained component of the currents. Our study demonstrates that ASIC2a can increase the membrane conductance sensitivity to protons by facilitating the surface expression of ASIC3 through herteromeric assembly. [BMB Reports 2016; 49(10): 542 547]. PMID- 27241859 TI - Long-term outcome of the cheek advancement flap, a report of 41 cases. AB - BACKGROUND: Due to incidental occurrence of ectropion as a late complication of cheek advancement flaps, this study investigated the long-term effects of these flaps for post-Mohs' reconstruction of the cheek aesthetic. METHODS: All the patients who underwent a cheek advancement flap in the Catharina Hospital Eindhoven between January 2006 and January 2013 where included and assessed by means of a retrospective chart review and a survey about the long-term outcome and patient satisfaction. RESULTS: A retrospective chart review was performed on all 54 eligible patients, and 41 (76%) of these patients participated in the study. The mean follow-up was 3.5 years (SD = 2.0, range = 1-7 years). Early complications were ectropion (6%), infection (2%), dog-ears (1%), haematoma (4%), and distal tip necrosis (2%). Late outcome and complications were sensory neuropathies (41%), late ectropion (7%), hypopigmentation of scars (29%), contractures (27%), and abnormal hair distribution (17%). Patients rated their reconstruction as good or excellent in 87% of cases. CONCLUSIONS: The cheek advancement flap is a suitable technique for reconstruction of large cheek skin defects after excision of skin malignancies. However, patients should be informed that long-term complications, including ectropion, can occur. Additional follow up might lead to an early detection of these late effects. PMID- 27241860 TI - The prevalence of QT prolongation in a population of patients with substance use disorders. AB - INTRODUCTION AND AIMS: Drug induced QT prolongation occurs in patients with substance use disorders from prescription medications that prolong the QT, such as methadone. Knowing the prevalence of QT prolongation in this population is important for prescribers. This study aimed to investigate the prevalence of QT prolongation in patients with current substance use disorders. DESIGN AND METHODS: We undertook a retrospective review of electrocardiograms (ECG) from patients with substance use disorders from an urban general hospital with a large drug and alcohol service and toxicology unit. ECGs were taken from patients seen by the alcohol and drug unit over three years. The QT interval was measured manually on each ECG and defined as abnormal if above the line on the QT nomogram. The QT was also heart rate corrected using Fridericia's formula (QTcF) to investigate associated factors. RESULTS: Nine of 446 (2.0%; 95% confidence interval 1.0-3.9%) patients had an ECG with a prolonged QT interval. Three were prescribed methadone for opiate dependence (80, 90 and 125 mg daily), one also with hypokalemia; one prescribed escitalopram with hypokalaemia/hypomagnesaemia; three more with hypokalaemia alone. Only two patients had a prolonged QT with no identifiable cause. There was no association between QTcF and sex (P = 0.34), but there was a statistically significant association with age (Pearson R = 0.19, 95% confidence interval 0.10-0.28, P < 0.0001). DISCUSSION AND CONCLUSIONS: QT prolongation is rare in patients with substance use disorders and is most likely similar to the general population once cases related to methadone use and electrolyte abnormalities are excluded. [Scott AJ, Dunlop AJ, Brown A, Craig S. The prevalence of QT prolongation in a population of patients with substance use disorders. Drug Alcohol Rev 2017;36:239-244]. PMID- 27241861 TI - Right ventricular concentric hypertrophy and clinical worsening in idiopathic pulmonary arterial hypertension. AB - BACKGROUND: Because the pathophysiology of idiopathic pulmonary arterial hypertension (IPAH) is an afterload mismatch, wall stress represents the most important feature affecting the overloaded right ventricle (RV). Thus, the RV mass/volume (M/V) ratio may reflect more adequately the suitability of the remodeling pattern in minimizing RV wall stress compared with the lone RV volume. This study investigated the prognostic effect of the RV M/V ratio in IPAH. METHODS: Enrolled in our center were 74 therapy-naive IPAH patients who were prospectively monitored for the presence of clinical worsening (CW). Baseline evaluation included clinical, hemodynamic, and echocardiographic parameters. Cardiac magnetic resonance was used for RV M/V ratio determination. RESULTS: During 541 +/- 283 days of follow-up, 31 of 74 patients (42%) presented with CW. Actuarial rates of CW were 14%, 28%, and 46%, at 6, 12, and 24 months, respectively. The RV M/V ratio significantly improved the power of the prognostic model based on traditional clinical, hemodynamic, and imaging parameters (area under the curve: 0.74 vs 0.66, respectively; p = 0.01). When the cutoff values of the RV M/V ratio and cardiac index (CI) derived from receiver operating characteristic curve analysis were combined, patients with a low RV M/V ratio/low CI, low RV M/V ratio/high CI, and high RV M/V ratio/low CI showed a 28.8, 8.8, and 6.1 increase in the hazard ratio, respectively, compared with high RV M/V ratio/high CI patients (p = 0.0001). CONCLUSIONS: The RV M/V ratio is an independent predictor of prognosis in IPAH and may allow clinicians to better stratify patients with normal CI, identifying at an early stage those patients at higher risk of right heart failure development before hemodynamic instability appears. PMID- 27241862 TI - Metagenomic sequencing reveals the relationship between microbiota composition and quality of Chinese Rice Wine. AB - Chinese Rice Wine (CRW) is a common alcoholic beverage in China. To investigate the influence of microbial composition on the quality of CRW, high throughput sequencing was performed for 110 wine samples on bacterial 16S rRNA gene and fungal Internal Transcribed Spacer II (ITS2). Bioinformatic analyses demonstrated that the quality of yeast starter and final wine correlated with microbial taxonomic composition, which was exemplified by our finding that wine spoilage resulted from a high proportion of genus Lactobacillus. Subsequently, based on Lactobacillus abundance of an early stage, a model was constructed to predict final wine quality. In addition, three batches of 20 representative wine samples selected from a pool of 110 samples were further analyzed in metagenomics. The results revealed that wine spoilage was due to rapid growth of Lactobacillus brevis at the early stage of fermentation. Gene functional analysis indicated the importance of some pathways such as synthesis of biotin, malolactic fermentation and production of short-chain fatty acid. These results led to a conclusion that metabolisms of microbes influence the wine quality. Thus, nurturing of beneficial microbes and inhibition of undesired ones are both important for the mechanized brewery. PMID- 27241863 TI - Development and validation of the Humanitarian Aid Difficulty Scale for Japanese healthcare workers. AB - Few studies have investigated deployment-related experiences of healthcare workers dispatched for medical humanitarian aid or attempted to assess their difficult living and working environments. This is the first study to develop and validate a scale to measure these kinds of difficulties, in 264 Japanese healthcare workers. The Humanitarian Aid Difficulty Scale was developed in three stages. First, an item pool was generated based on literature and expert reviews. The scale was then tested in a pilot study. Reliability and validity were identified through exploratory and confirmatory factor analysis and Cronbach's alpha. The scale consisted of 23 items across five factors based on exploratory factor analysis (cooperation, health status, infrastructure, culture and customs, and supplies and equipment). The total variance explained was 60.7%. Reliability of the five factors was acceptable and validity was supported by confirmatory factor analysis. Cronbach's alpha for the scale was 0.87. The scale may enable evaluation of the level of difficulty of the living and working environments of Japanese healthcare workers in medical humanitarian aid who are at a greater risk of distress. PMID- 27241864 TI - Amide bond cleavage initiated by coordination with transition metal ions and tuned by an auxiliary ligand. AB - The reaction of ligand , N,N-bis(pyridin-2-ylmethyl)acetamide, with five transition metal salts, FeCl3.6H2O, CuCl2.2H2O, Cu(ClO4)2.6H2O, ZnCl2 and K2PtCl4/KI, produced five metal complexes, [(MU-O)(FeClL')(FeCl3)] (), [CuLCl2] (), [CuBPA(ClO4)(CHCN)] ClO4 (), [ZnLCl2] () and [PtLI2] (), where = 1-(2,4,5 tri(pyridin-2-yl)-3-(pyridin-2-ylmethyl)imidazolidin-1-yl)ethanone which formed in situ, and BPA = bis(pyridin-2-ylmethyl)amine. The ligand and complexes were characterized by a variety of spectroscopic techniques including X-ray single crystal diffraction where applicable. Depending on the metal ion and auxiliary ligand of the complex, the acetyl group of the ligand could be either intact or cleaved. When ferric chloride hexahydrate was used, the deacetylation proceeded even further and a novel heterocyclic compound () was formed in situ. A possible mechanism was proposed for the formation of the heterocyclic compound found in complex . Our results indicate that to cleave effectively an amide bond, it is essential for a metal centre to bind to the amide bond and the metal centre is of sufficient Lewis acidity. PMID- 27241865 TI - Geriatric hip fracture management: keys to providing a successful program. AB - BACKGROUND: Hip fractures are a common event in older adults and are associated with significant morbidity, mortality and costs. This review examines the necessary elements required to implement a successful geriatric fracture program and identifies some of the barriers faced when implementing a successful program. INTERVENTION: The Geriatric Fracture Center (GFC) is a treatment model that standardizes the approach to the geriatric fracture patient. It is based on five principles: surgical fracture management; early operative intervention; medical co-management with geriatricians; patient-centered, standard order sets to employ best practices; and early discharge planning with a focus on early functional rehabilitation. Implementing a geriatric fracture program begins with an assessment of the hospital's data on hip fractures and standard care metrics such as length of stay, complications, time to surgery, readmission rates and costs. Business planning is essential along with the medical planning process. CONCLUSION: To successfully develop and implement such a program, strong physician leadership is necessary to articulate both a short- and long-term plan for implementation. Good communication is essential-those organizing a geriatric fracture program must be able to implement standardized plans of care working with all members of the healthcare team and must also be able to foster relationships both within the hospital and with other institutions in the community. Finally, a program of continual quality improvement must be undertaken to ensure that performance outcomes are improving patient care. PMID- 27241866 TI - Dual-energy CT with iodine quantification in distinguishing between bland and neoplastic portal vein thrombosis in patients with hepatocellular carcinoma. AB - AIM: To investigate the diagnostic accuracy of dual-energy multidetector computed tomography (MDCT) with iodine quantification compared to conventional enhancement measurements in distinguishing bland from neoplastic portal vein thrombosis in patients with hepatocellular carcinoma. MATERIAL AND METHODS: Thirty-four patients (26 men, eight women; mean age, 62 years) with hepatocellular carcinoma and portal vein thrombosis underwent contrast-enhanced dual-energy MDCT during the late hepatic arterial phase for the assessment of portal thrombosis (bland, n=21; neoplastic, n=13). Datasets were analysed separately by two different readers. Interobserver correlation and variability were calculated and compared with the Bland-Altman method. Diagnostic accuracy of conventional enhancement measurements and iodine quantification was calculated by setting either histopathology (n=7) or a reference standard based on MDCT imaging criteria and thrombus evolutionary characteristics compared to a previous MDCT examination (n=27). For iodine quantification threshold determination receiver operating characteristic (ROC) curves were drawn. p-Values <0.05 were considered significant. RESULTS: For conventional enhancement measurements and iodine quantification interobserver correlation was 98% and 96%. Enhancement measurement resulted in a sensitivity of 92.3%, specificity of 85.7%, positive predictive value (PPV) of 80%, and negative predictive value (NPV) of 94.7%. An iodine concentration of 0.9 mg/ml optimised discrimination between neoplastic and bland thrombi (area under the ROC [AUC] 0.993) resulting in a sensitivity of 100%, specificity of 95.2%, PPV of 92.9%, and NPV of 100%. The overall diagnostic accuracy of iodine quantification (97%) was significantly better than conventional enhancement measurements (88.2%; p<0.001). CONCLUSION: Compared to conventional enhancement measurements, iodine quantification improves the characterisation of portal vein thrombi during the late hepatic arterial phase in patients with hepatocellular carcinoma. PMID- 27241867 TI - Work related stress, burnout, job satisfaction and general health of nurses: A follow-up study. AB - Nurses experience high levels of work related stress and burnout as well as low job satisfaction and poor general health owing to the nature of their work. This paper seeks to provide a better understanding of the nature of relationships between work related stress, burnout, job satisfaction and general health of nurses over one year. This study involved a longitudinal design. Two hundred and seventy seven nurses from four hospitals completed a follow up survey consisting of five questionnaires. Data were collected between 2013 and 2014. The data were analysed using generalized estimation equation analysis. Lack of support was associated with burnout, patient care was associated with job satisfaction and staff issues were associated with general health of nurses. Burnout is more strongly related to job satisfaction than general health. The findings of this study could inform evidence based policy and practice through interventions aimed at improving job satisfaction and reducing the impact of burnout on general health of nurses. PMID- 27241868 TI - Intravascular Ultrasound-Guided Mesenteric Stenting in Patients with Advanced Chronic Kidney Disease. AB - Endovascular treatment of chronic mesenteric ischemia in patients with impaired renal function or allergy to contrast media is a challenging procedure because angiography requires iodinated contrast media for accurate diagnosis and interventional procedures. Superior mesenteric artery stenting without contrast angiography is described in an 81-year-old woman with cardiovascular disease and chronic kidney disease (CKD) stage 5. Balloon angioplasty and stent placement were performed successfully using intravascular ultrasound, pressure wire, surface ultrasound, and fluoroscopy. Intervention without contrast media has wide applicability to patients with advanced CKD and/or those with allergy to iodinated contrast media. PMID- 27241869 TI - Barrier Patch Implantation during Redo Surgery for Varicose Vein Recurrences in the Groin: 1-Year Results. AB - BACKGROUND: Rerecurrences after redo surgery for recurrent varicose veins in the groin are a common problem. The present report looks at the efficacy of an additional barrier patch implantation in reducing these rerecurrences. METHODS: A retrospective review of a prospectively collected database was conducted. This included 67 patients with 86 legs who underwent redo-groin surgery for symptomatic recurrences. In addition, a polytetrafluoroethylene-barrier patch was placed at the former saphenofemoral junction. All patients had undergone ligation and stripping of the great saphenous vein a mean of 13.9 years earlier. All patients were examined by duplex ultrasound before and 1 year after the procedure. RESULTS: Perioperatively, minor complications occurred in 5.8% of cases, the groin infection rate was 2.4%. In 85 of 86 legs, the duplex follow-up examination was performed after 1 year. This revealed an overall rerecurrence rate of 12%, of which only 2.4% were caused by recurrent neovascularization in the groin bypassing the barrier patch. The remaining 9.6% were caused by different sites of reflux (pelvic veins and perforators). CONCLUSIONS: Redo-groin surgery with additional barrier patch implantation seems to be a safe and effective way to prevent rerecurrences in the groin. In our experience, it provided very promising 1-year results with a very low rate of recurrent neovascularization. PMID- 27241870 TI - Knowledge of the Nigerian Code of Health Research Ethics Among Biomedical Researchers in Southern Nigeria. AB - Responsibility for protection of research participants from harm and exploitation rests on Research Ethics Committees and principal investigators. The Nigerian National Code of Health Research Ethics defines responsibilities of stakeholders in research so its knowledge among researchers will likely aid ethical conduct of research. The levels of awareness and knowledge of the Code among biomedical researchers in southern Nigerian research institutions was assessed. Four institutions were selected using a stratified random sampling technique. Research participants were selected by purposive sampling and completed a pre-tested structured questionnaire. A total of 102 biomedical researchers completed the questionnaires. Thirty percent of the participants were aware of the National Code though 64% had attended at least one training seminar in research ethics. Twenty-five percent had a fairly acceptable knowledge (scores 50%-74%) and 10% had excellent knowledge of the code (score >=75%). Ninety-five percent expressed intentions to learn more about the National Code and agreed that it is highly relevant to the ethical conduct of research. Awareness and knowledge of the Code were found to be very limited among biomedical researchers in southern Nigeria. There is need to improve awareness and knowledge through ethics seminars and training. Use of existing Nigeria-specific online training resources is also encouraged. PMID- 27241871 TI - Community Partnered Research Ethics Training in Practice: A Collaborative Approach to Certification. AB - This report describes the development and implementation of a tailored research ethics training for academic investigators and community research partners (CRP). The Community Partnered Research Ethics Training (CPRET) and Certification is a free and publicly available model and resource created by a university and community partnership to ensure that traditional and non-traditional research partners may study, define, and apply principles of human subjects' research. To date, seven academic and 34 CRP teams have used this highly interactive, engaging, educational, and relationship building process to learn human subjects' research and be certified by the University of Pittsburgh Institutional Review Board (IRB). This accessible, flexible, and engaging research ethics training process serves as a vehicle to strengthen community and academic partnerships to conduct ethical and culturally sensitive research. PMID- 27241872 TI - Research Ethics Committees and Participatory Action Research With Young People: The Politics of Voice. AB - Participatory action research (PAR) is a methodological approach that seeks to maximize the participation of people whose lives it researches. It is underpinned by an ethical concern to research "with" people, rather than "on" people. However, this ethical approach to research is often, paradoxically, problematized by universities' research ethics committees (RECs). This article explores one site of tension between PAR and RECs-the requirement for anonymity for below 18 year-olds. It explores this tension by exploring a case study of a peer-to-peer research project undertaken by young women in East London, and using our own experiences and perspectives, it argues that anonymity can be unjust, disempowering, and unnecessary, and can reduce "pride." Without wanting to develop specific recommendations, given the limited scope of our case study, this article uses firsthand experiences to add weight to the broader discussions calling for a critical rethink of REC guidelines. PMID- 27241873 TI - Parental Estimation of Their Child's Increased Type 1 Diabetes Risk During the First 2 Years of Participation in an International Observational Study: Results From the TEDDY study. AB - This study assessed mothers' and fathers' perception of their child's risk of getting type 1 diabetes (T1D) during the first 2 years of their participation in The Environmental Determinants of Diabetes in the Young (TEDDY) study. TEDDY parents were informed of their child's increased genetic risk for T1D at study inception. Parent perception of the child's risk was assessed at 3, 6, 15, and 27 months of age. In families with no history of T1D, underestimation of the child's T1D risk was common in mothers (>38%) and more so in fathers (>50%). The analyses indicated that parental education, country of residence, family history of T1D, household crowding, ethnic minority status, and beliefs that the child's T1D risk can be reduced were factors associated with parental risk perception accuracy. Even when given extensive information about their child's T1D risk, parents often fail to accurately grasp the information provided. This is particularly true for fathers, families from low socioeconomic backgrounds, and those with no family history of T1D. It is important to develop improved tools for risk communication tailored to individual family needs. PMID- 27241875 TI - Recent topics on single-molecule fluctuation analysis using blinking in surface enhanced resonance Raman scattering: clarification by the electromagnetic mechanism. AB - Surface-enhanced Raman scattering (SERS) spectroscopy has become an ultrasensitive tool for clarifying molecular functions on plasmonic metal nanoparticles (NPs). SERS has been used for in situ probing of detailed behaviors of few or single molecules (SMs) at plasmonic NP junctions. SM SERS signals are commonly observed with temporal and spectral changes known as "blinking", which are related to various physical and chemical interactions between molecules and NP junctions. These temporal and spectral changes simultaneously take place, therefore resulting in serious complexities in interpretations of the SM SERS results. Dual contributions of Raman enhancement mechanisms in SERS (i.e., electromagnetic (EM) and chemical enhancements) also make interpretations more difficult. To resolve these issues and reduce the degree of complexities in SM SERS analyses, the present review is focused on the recent studies of probing SM behaviors using SERS exclusively within the framework of the EM mechanism. The EM mechanism is briefly introduced, and several recent topics on SM SERS blinking analysis are discussed in light of the EM mechanism. This review will provide a basis for clarification of complex SERS fluctuations of various molecules. PMID- 27241874 TI - New-Onset Headache in Patients With Autoimmune Encephalitis Is Associated With anti-NMDA-Receptor Antibodies. AB - OBJECTIVE: We tested the hypotheses (i) that autoimmune encephalitis is associated with new-onset headache, and (ii) that the occurrence of headache is associated with the presence of anti-N-methyl-D-aspartate (NMDA)-receptor antibodies. BACKGROUND: Autoimmune encephalitis presents with cognitive dysfunction as well as neuro-psychiatric symptoms. Its pathophysiology might involve antibody-mediated dysfunction of the glutamatergic system as indicated by the presence of anti-NMDA-receptor antibodies in some patients. METHODS: In this cross-sectional study, patients with autoimmune encephalitis were assessed with a standardized interview for previous headache and headache associated with autoimmune encephalitis. Headache was classified according to the International Classification of Headache Disorders, second edition. Clinical and paraclinical findings were correlated with the occurrence of headache. RESULTS: Of 40 patients with autoimmune encephalitis, 19 did not have a history of headache. Of those, nine suffered from encephalitis-associated headache. Seven of these nine had anti NMDA-receptor antibodies in contrast to only two among the remaining 10 patients without new-onset headache (P = .023, odds ratio: 14, 95% confidence interval: 1.5; 127). In most patients headache occurred in attacks on more than 15 days/month, was severe, and of short duration (less than 4 hours). International Headache Society criteria for migraine were met in three patients. CONCLUSIONS: New-onset headache is a relevant symptom in patients with autoimmune encephalitis who have no history of previous headache, especially in the subgroup with anti NMDA-receptor antibodies. This indicates a thorough investigation for secondary headaches including anti-NMDA-R antibodies for patients with new-onset headache and neuropsychiatric findings. Glutamatergic dysfunction might be important for the generation of head pain but may only occasionally be sufficient to trigger migraine-like attacks in nonmigraineurs. PMID- 27241876 TI - Acceptability, Feasibility, and Cost of Telemedicine for Nonacute Headaches: A Randomized Study Comparing Video and Traditional Consultations. AB - BACKGROUND: The feasibility of telemedicine in diagnosing and treating nonacute headaches, such as primary headaches (migraine and tension-type) and medication overuse headaches has not been previously investigated. By eliminating the need of travel to specialists, telemedicine may offer significant time and money savings. OBJECTIVES: Our objective was to estimate the acceptance of telemedicine and investigate the feasibility and cost savings of telemedicine consultations in diagnosing and treating nonacute headaches. METHODS: From September 2012 to March 2015, nonacute headache patients from Northern Norway who were referred to neurologists through an electronic application system were consecutively screened and randomized to participate in either telemedicine or traditional specialist visits. All patients were consulted by two neurologists at the neurological department in Tromso University Hospital. Feasibility outcomes were compared between telemedicine and traditional groups. Baseline characteristics and costs were then compared between rural and urban patients. Travel costs were calculated by using the probabilistic method of the Norwegian traveling agency: the cheapest means of public transport for each study participant. Loss of pay was calculated based on the Norwegian full-time employee's average salary: < 3.5 hours=a half day's salary, > 3.5 hours spent on travel and consultation=one day's salary. Distance and time spent on travel were estimated by using Google Maps. RESULTS: Of 557 headache patients screened, 479 were found eligible and 402 accepted telemedicine participation (83.9%, 402/479) and were included in the final analyses. Of these, 202 received traditional specialist consultations and 200 received telemedicine. All patients in the telemedicine group were satisfied with the video quality, and 198 (99%, 198/200) were satisfied with the sound quality. The baseline characteristics as well as headache diagnostics and follow-up appointments, and the investigation, advice, and prescription practices were not statistically different between the two randomized groups. In addition, telemedicine consultations were shorter than traditional visits (38.8 vs 43.7 min, P<.001). The travel cost per rural individual (292/402, 73%) was ?249, and estimated lost income was ?234 per visit. The travel cost in the urban area (110/402, 27%) was ?6, and estimated lost income was ?117 per visit. The median traveling distance for rural patients was 526 km (range 1892 km), and the median traveling time was 7.8 hours (range 27.3 hours). Rural patients had a longer waiting time than urban patients (64 vs 47 days, P=.001), and fewer women were referred from rural areas (P=.04). Rural women reported higher pain scores than urban women (P=.005). CONCLUSION: Our study shows that telemedicine is an accepted, feasible, time-saving, and cost-saving alternative to traditional specialist consultations for nonacute headaches. TRIAL REGISTRATION: Clinicaltrials.gov NCT02270177; http://clinicaltrials.gov/ct2/show/NCT02270177 (Archived by WebCite at http://www.webcitation.org/6hmoHGo9Q). PMID- 27241878 TI - Brain structure, executive function and appetitive traits in adolescent obesity. AB - BACKGROUND: Children with obesity show differences in brain structure, executive function and appetitive traits when compared with lean peers. Little is known on the relationship between brain structure and these traits. OBJECTIVES: To investigate the relationship between differences in brain structure and executive function and appetitive traits, in obese and lean adolescents. METHODS: MRI was used to measure cortical thickness and subcortical volumes. Executive function was measured by a Stop Signal-and a Choice Delay Task. Appetitive traits were measured using the Child Eating Behaviour Questionnaire. RESULTS: Adolescents with obesity had greater volumes of the pallidum; 1.78 mL (SE 0.03, p=0.014), when compared with controls; 1.65 mL (SE 0.02). In the group with obesity, greater pallidum volume was positively associated with the ability to delay reward in the Choice Delay Task (p=0.012). CONCLUSION: The association between pallidum volumes and Choice Delay Task in obese adolescents supports the hypothesis that the pallidum plays an important role in executive dysfunction in obese children. PMID- 27241877 TI - Formulation optimization of Docetaxel loaded self-emulsifying drug delivery system to enhance bioavailability and anti-tumor activity. AB - Poor bioavailability of Docetaxel (DCT) arising due to its low aqueous solubility and permeability limits its clinical utility. The aim of the present study was to develop DCT loaded self-emulsified drug delivery systems (D-SEDDS) and evaluate its potential ability to improve the oral bioavailability and therapeutic efficacy of DCT. D-SEDDS were characterized for their in vitro antitumor activity, in situ single pass intestinal perfusion (SPIP), bioavailability, chylomicron flow blocking study and bio-distribution profile. The D-SEDDS were prepared using Capryol 90, Vitamin E TPGS, Gelucire 44/14 and Transcutol HP with a ratio of 32.7/29.4/8.3/29.6 using D-Optimal Mixture Design. The solubility of DCT was improved upto 50 mg/mL. The oral bioavailability of the D-SEDDS in rats (21.84 +/- 3.12%) was increased by 3.19 fold than orally administered Taxotere (6.85 +/- 1.82%). The enhanced bioavailability was probably due to increase in solubility and permeability. In SPIP, effective permeability of D-SEDDS was significantly higher than Taxotere. D-SEDDS showed 25 fold more in vitro cytotoxic activity compared to free DCT. Chylomicron flow blocking study and tissue distribution demonstrated the intestinal lymphatic transport of D-SEDDS and higher retention in tumor than Taxotere. The data suggests that D-SEDDS showed desired stability, enhanced oral bioavailability and in vitro antitumor efficacy. PMID- 27241879 TI - Under pressure: Investigating marine resource-based livelihoods in Jakarta Bay and the Thousand Islands. AB - Jakarta Bay, next to the Jakarta Metropolitan Area with around 30 million inhabitants, is facing extreme pollution. Although local coral reefs are degraded and marine resources heavily exploited, they provide livelihoods for millions of people. This study investigates anthropogenic pressures on local fisheries resources and associated livelihoods. Questionnaire surveys were conducted in 15 coastal communities (10 coastal neighborhoods in Jakarta Bay on the mainland and 5 of the offshore Thousand Islands). The most economically valuable species were Caesio cuning (Redbelly yellowtail fusilier) on the islands and Rastrelliger kanagurta (Indian mackerel) on the mainland. Over 80% of all interviewed fishermen regarded the current state of marine resources as declining, mainly due to pollution and overexploitation. While perceptions of declining resources were equally high on the islands and the mainland, pollution was listed as the principal cause of degradation significantly more on the mainland. Findings are discussed in the context of coastal livelihood vulnerability. PMID- 27241880 TI - A theoretical model to estimate the oil burial depth on sandy beaches: A new oil spill management tool. AB - In oiled sandy beaches, unrecovered fuel can be buried up to several metres. This study proposes a theoretical approach to oil burial estimation along the intertidal area. First, our results revealed the existence of two main patterns in seasonal beach profile behaviour. Type A is characterized by intertidal slopes of time-constant steepness which advance/recede parallel to themselves in response to changing wave conditions. Type B is characterized by slopes of time varying steepness which intersect at a given point in the intertidal area. This finding has a direct influence on the definition of oil depth. Type A pattern exhibits oil burial along the entire intertidal area following decreasing wave energy, while the type B pattern combines burial in high intertidal and exhumation in mid and/or low intertidal zones, depending on the position of the intersection point. These outcomes should be incorporated as key tools in future oil spill management programs. PMID- 27241881 TI - Development of a solid-phase extraction system modified for preconcentration of emerging contaminants in large sample volumes from rivers of the lagoon system in the city of Rio de Janeiro, Brazil. AB - A single method modified for monitoring of emerging contaminants in river water was developed for large sample volumes. Water samples from rivers of the lagoon system in the city of Rio de Janeiro (Brazil) were analyzed by the SPE-HPLC-MS TOF analytical method. Acetaminophen was detected in four rivers in the concentration range of 0.09MUgL(-1) to 0.14MUgL(-1). Salicylic acid was also found in the four rivers in the concentration range of 1.65MUgL(-1) to 4.81MUgL( 1). Bisphenol-A was detected in all rivers in the concentration range of 1.37MUgL(-1) to 39.86MUgL(-1). Diclofenac was found in only one river, with concentration of 0.22MUgL(-1). The levels of emerging organic pollutants in the water samples of the Jacarepagua hydrographical basin are significant. The compounds are not routinely monitored and present potential risks to environmental health. PMID- 27241882 TI - A lesbian, gay, bisexual and transgender dedicated inpatient psychiatric unit in rural New England: a descriptive analysis in demographics, service utilisation and needs. AB - AIMS AND OBJECTIVES: To develop an understanding of lesbian-, gay-, bisexual-, transgender-specific mental health and substance abuse needs in rural populations and to improve data about sexual orientation and gender identity. BACKGROUND: Existing literature on mental health needs for lesbian, gay, bisexual and transgender populations has continued to reveal higher levels of need. Research has also demonstrated that few mental health providers have expertise or comfort in treating lesbian, gay, bisexual and transgender clients. DESIGN: Descriptive correlational study. METHODS: A sample (n = 456) of patient records admitted to a rural lesbian, gay, bisexual and transgender inpatient psychiatric clinic over 12 months were examined using descriptive statistics. Patient zip code information was used to determine the levels of rurality. Chi-square analysis was used to determine relationships between sexual orientation, rural/urban distinctions and concomitant drug use. RESULTS: Unexpectedly, those who identified as heterosexual were significantly more likely to concomitantly abuse alcohol and heroin than those who identified as lesbian, gay, bisexual and transgender. Patients residing in small or isolated rural areas were more likely to abuse alcohol or synthetics than those residing in urban or micropolitan areas. CONCLUSIONS: Results of this study concerning substance abuse among lesbian, gay, bisexual and transgender individuals are not reflective of prior studies. LGBT patients did not demonstrate a higher proportion of substance abuse compared with those identifying as heterosexual. Increased substance abuse among those from rural isolated areas does support prior studies. The context of gathering demographic information on sexual orientation was thought by staff to increase the number of those identifying as heterosexual. RELEVANCE TO CLINICAL PRACTICE: Context in which sensitive questions are asked may affect the accuracy of demographic data. Lack of information regarding patients' sexual orientation or gender identity may impact perceived need for culturally competent care. Results suggest the need for efforts to provide training for mental health specialists in rural areas to provide sensitive care. PMID- 27241883 TI - Determination of Urine Albumin by New Simple High-Performance Liquid Chromatography Method. AB - BACKGROUND: A simple high-performance liquid chromatography (HPLC) method was developed for the determination of albumin in patients' urine samples without coeluting proteins and was compared with the immunoturbidimetric determination of albumin. Urine albumin is important biomarker in diabetic patients, but part of it is immuno-nonreactive. METHODS: Albumin was determined by high-performance liquid chromatography (HPLC), UV detection at 280 nm, Zorbax 300SB-C3 column. Immunoturbidimetric analysis was performed using commercial kit on automatic biochemistry analyzer COBAS INTEGRA(r) 400, Roche Diagnostics GmbH, Manheim, Germany. RESULTS: The HLPC method was fully validated. No significant interference with other proteins (transferrin, alpha-1-acid glycoprotein, alpha-1 antichymotrypsin, antitrypsin, hemopexin) was found. The results from 301 urine samples were compared with immunochemical determination. We found a statistically significant difference between these methods (P = 0.0001, Mann-Whitney test). CONCLUSION: New simple HPLC method was developed for the determination of urine albumin without coeluting proteins. Our data indicate that the HPLC method is highly specific and more sensitive than immunoturbidimetry. PMID- 27241884 TI - A frontal external ventricular drain causing a third cranial nerve palsy. AB - This 47-year-old gentleman presented with acute hydrocephalus secondary to a colloid cyst. Bilateral external ventricular drains (EVDs) were inserted. The patient developed a third nerve palsy during post-operative period - cranial imaging demonstrated the tip of an EVD in this vicinity. The palsy recovered completely on slight withdrawal of the EVD. PMID- 27241885 TI - A size, shape and concentration controlled self-assembling structure with host guest recognition at the liquid-solid interface studied by STM. AB - In the present investigation, we reported the fabrication of host networks formed by two newly prepared phenanthrene-butadiynylene macrocycles (PBMs) at the liquid solid interface. Size, shape and concentration controlled experiments have been performed to investigate the PBMs/coronene (COR) host-guest system with the structural polymorphism phenomenon. Initially, PBM1 could form a regular linear network structure and PBM2 form a well-ordered nanoporous network structure. When the COR molecules were introduced, the self-assembled structure of PBM1 remained unchanged, while COR could be entrapped into the cavities of the PBM2 nanoporous network, and the co-assembly of the PBM2/COR host-guest systems underwent a structural transformation with the increase of concentration of COR. Scanning tunneling microscopy (STM) measurements and density functional theory (DFT) calculations are utilized to reveal the formation mechanism of the molecular nanoarrays controlled by the solution concentration. PMID- 27241886 TI - SRT contributes significantly to sludge reduction in the OSA-based activated sludge process. AB - Though activated sludge systems have contributed significantly to the control of hygiene of our society, the wastewater treatment generates large amount of excess sludge. The oxic-settling-anaerobic (OSA)-based biological processes have been shown to be promising approaches for sludge reduction during wastewater treatment. However, the sludge reduction mechanism is still unclear. Four conditions were examined to clarify the sludge reduction mechanism in the OSA based process. Sludge retention time (SRT) was the main 'contributor' to sludge reduction. The sludge reduction percentage of the process with side hydrolysis and acidification was 42%, with the contribution by long SRT of 33%, energy uncoupling of 7.7%, and hydrolysis/acidification of 1.1%. In addition, the sludge reduction in the OSA-based process had no obvious impact on the efficiency of nutrient removal. The clarified mechanism for sludge reduction in the OSA-based process could provide valuable clue for future system optimization. PMID- 27241887 TI - Frequency of Alcohol Use Among Injured Adult Patients Presenting to a Ghanaian Emergency Department. AB - STUDY OBJECTIVE: Injuries are the cause of almost 6 million deaths annually worldwide, with 15% to 20% alcohol associated. The frequency of alcohol associated injury varies among countries and is unknown in Ghana. We determined the frequency of positive alcohol test results among injured adults in a Ghanaian emergency department (ED). METHODS: This is a cross-sectional chart review of consecutive injured patients aged 18 years or older presenting to the Komfo Anokye Teaching Hospital ED for care within 8 hours of injury. Patients were tested for presence of alcohol with a breathalyzer or a saliva alcohol test. Patients were excluded if they had minor injuries resulting in referral to a separate outpatient clinic, or death before admission. Alcohol test results, subject, and injury characteristics were collected. Proportions with 95% confidence intervals were calculated. RESULTS: Injured adult patients (2,488) presented to the ED from November 2014 to April 2015, with 1,085 subjects (43%) included in this study. Three hundred eighty-two subjects (35%; 95% confidence interval 32% to 38%) tested alcohol positive. Forty-two percent of men (320/756), 40% of subjects aged 25 to 44 years (253/626), 42% of drivers (66/156), 42% of pedestrians (85/204), 49% of assault victims (82/166), 40% of those seriously injured (124/311), and 53% of subjects who died in the ED (8/15) had positive results for presence of alcohol. CONCLUSION: The frequency of alcohol-associated injury was 35% among tested subjects in this Ghanaian tertiary care hospital ED. These findings have implications for health policy-, ED- and legislative-based interventions, and acute care. PMID- 27241888 TI - Revealing nanoscale optical properties and morphology in perfluoropentacene films by confocal and tip-enhanced near-field optical microscopy and spectroscopy. AB - Combining high resolution optical microscopy and spectroscopy, we propose a novel, generally applicable and highly sensitive method for determining the local morphology in organic semiconductor thin films (e.g. perfluoropentacene (PFP)). An azimuthally or radially polarized doughnut mode (APDM or RPDM) laser beam is focused by a high numerical aperture parabolic-mirror to excite a diffraction limited volume of the PFP film with an electric field polarized either exclusively in-plane or dominantly out-of-plane (relative to the substrate). We find two distinct morphologies of thin PFP films: molecular aggregates and crystalline terraces. The well-defined dipole emission patterns observed from the molecular aggregates strongly suggest the presence of localized excitations. For both laser modes, we observe that for the PFP aggregates, the photoluminescence (PL) emission from the main electronic transition is blue-shifted by about 10 meV, as compared to that from the molecular terraces. For the C-C bending modes, the B3g at 1581 cm(-1) (nu1) and the Ag at 1316 cm(-1) (nu0), we observe a decrease of the intensity ratio (Inu1/Inu0) from 0.6 (terrace) to 0.15 (aggregate). Furthermore, the intensity ratios (IAPDM/IRPDM) of nu1 excited by different polarizations increase from 0.12 (terrace) to 0.73 (aggregate). These results indicate that the PFP molecules orient rather parallel to the substrate in the aggregates, whilst more upright in the terraces. Benefiting from the nanometer scale optical resolution offered by the tip-enhanced near-field optical method, we observe clear optical contrasts between the molecular aggregate and the terrace as well as individual layers within a terrace. Tip-enhanced optical spectra locally taken from the molecular terrace and the aggregate show similar blue-shift of the main PL peak and change in the Raman intensity with different polarizations as from the far-field assemble-measurements, which further confirms the different molecular orientations in these two morphologies. PMID- 27241889 TI - Oral administration of recombinant Mycobacterium smegmatis expressing a tripeptide construct derived from endogenous and microbial antigens prevents atherosclerosis in ApoE(-/-) mice. AB - INTRODUCTION: Immunotherapy by inducing oral tolerance to atherogenic self antigens is gaining importance as an alternative treatment modality for atherosclerosis. The use of live bacterial vectors to express the recombinant antigen in vivo will obviate the need for large-scale purification of recombinant protein and may also augment the efficacy of oral tolerance induction. AIM: The objective of the study was to explore the use of recombinant Mycobacterium smegmatis as a live vector for oral delivery of antigens to induce immune tolerance. METHOD AND RESULTS: We developed a M. smegmatis vector to secrete a recombinant tripeptide construct (AHC; peptides from Apolipoprotein B, Heat-shock protein 60 and Chlamydia pneumoniae outer membrane protein) expressed in a dendroaspin protein scaffold in pJH154 background. Immune response and oral tolerance to the cloned peptides were studied in C57/BL6 mice. The efficacy of this live vaccine to control atherosclerosis was studied in ApoE(-/-) knockout mice in C57/BL6 background. Oral administration of M. smegmatis secreting the cloned AHC antigen was found to induce tolerance to cloned protein and reduce the development of atherosclerosis by 24.0% compared to control. Protection against atherosclerosis was associated with increase in expression of regulatory T cell associated markers including CTLA4 (1.8-fold), Foxp3 (2.6-fold), TGF-beta (2.8 fold), IL10 (2.9-fold), and reduction in lipids, macrophage infiltration, and expression of inflammatory mediators in aorta. CONCLUSIONS: Our results suggest that M. smegmatis can be developed as an oral carrier of recombinant proteins to treat inflammatory autoimmune diseases. PMID- 27241890 TI - Association between domestic water hardness, chlorine, and atopic dermatitis risk in early life: A population-based cross-sectional study. AB - BACKGROUND: Domestic water hardness and chlorine have been suggested as important risk factors for atopic dermatitis (AD). OBJECTIVE: We sought to examine the link between domestic water calcium carbonate (CaCO3) and chlorine concentrations, skin barrier dysfunction (increased transepidermal water loss), and AD in infancy. METHODS: We recruited 1303 three-month-old infants from the general population and gathered data on domestic water CaCO3 (in milligrams per liter) and chlorine (Cl2; in milligrams per liter) concentrations from local water suppliers. At enrollment, infants were examined for AD and screened for filaggrin (FLG) skin barrier gene mutation status. Transepidermal water loss was measured on unaffected forearm skin. RESULTS: CaCO3 and chlorine levels were strongly correlated. A hybrid variable of greater than and less than median levels of CaCO3 and total chlorine was constructed: a baseline group of low CaCO3/low total chlorine (CaL/ClL), high CaCO3/low total chlorine (CaH/ClL), low CaCO3/high total chlorine (CaL/ClH) and high CaCO3/high total chlorine (CaH/ClH). Visible AD was more common in all 3 groups versus the baseline group: adjusted odds ratio (AOR) of 1.87 (95% CI, 1.25-2.80; P = .002) for the CaH/ClL group, AOR of 1.46 (95% CI, 0.97-2.21; P = .07) for the CaL/ClH, and AOR of 1.61 (95% CI, 1.09-2.38; P = .02) for the CaH/ClH group. The effect estimates were greater in children carrying FLG mutations, but formal interaction testing between water quality groups and filaggrin status was not statistically significant. CONCLUSIONS: High domestic water CaCO3 levels are associated with an increased risk of AD in infancy. The influence of increased total chlorine levels remains uncertain. An intervention trial is required to see whether installation of a domestic device to decrease CaCO3 levels around the time of birth can reduce this risk. PMID- 27241891 TI - Effect of stem cell source on long-term chimerism and event-free survival in children with primary immunodeficiency disorders after fludarabine and melphalan conditioning regimen. AB - BACKGROUND: Reduced-intensity conditioning (RIC) regimens are increasingly being used in the transplantation of patients with primary immunodeficiency disorders (PIDs), but there are no large studies looking at long-term lineage-specific chimerism. OBJECTIVES: We sought to analyze long-term chimerism and event-free survival in children undergoing transplantation for PIDs using RIC with fludarabine and melphalan (Flu/Melph) and to study the effect of donor type and stem cell source. METHODS: One hundred forty-two children underwent transplantation with RIC by using Flu/Melph and for PIDs by using bone marrow (n = 93) or peripheral blood stem cells (PBSCs; n = 49). Donors were matched unrelated donors (n = 72), mismatched unrelated donors (n = 37), matched sibling donors (n = 14), matched family donors (n = 12), and mismatched family donors (n = 7). RESULTS: Overall survival at a median follow-up of 7.5 years was 78%, irrespective of stem cell source or donor type. When bone marrow was used as the stem cell source, 26% of patients ended up with very low levels of donor chimerism (<10% donor), especially in the myeloid lineage. Event-free survival in this group was significantly lower compared with that in the rest of the group (25% vs 70%, P < .001). With the use of PBSCs, more than 90% of patients achieved complete donor chimerism or high-level mixed chimerism (>50% donor chimerism) in all lineages. CONCLUSIONS: On the basis of our experience, we would suggest that PBSCs should be the stem cell source of choice in children with PIDs undergoing transplantation with Flu/Melph RIC from a matched donor source. This is most likely to ensure sustained high-level donor chimerism. PMID- 27241892 TI - Spatio-temporal expression of Sox genes in murine palatogenesis. AB - Members of the Sox gene family play critical roles in many biological processes including organogenesis. We carried out comparative in situ hybridisation analysis of seventeen Sox genes (Sox1-14, 17, 18 and 21) during murine palatogenesis from initiation to fusion of the palatal shelves above the dorsal side of the tongue. At palatal shelf initiation (E12.5), the localized expression of six Sox genes (Sox2, 5, 6, 9, 12 and 13) was observed in the shelves, whereas Sox4 and Sox11 showed ubiquitious expression. During the down-growth of palatal shelves (E13.5), Sox4, Sox5, and Sox9 exhibited restricted expression to the interior side of the palatal shelves facing the tongue. Following elevation of the palatal shelves (E14.5), Sox2, Sox11 and Sox21 expression was present in the midline epithelial seam. We thus identify dynamic spatio-temporal expression of Sox gene family during the process of palatogenesis. PMID- 27241894 TI - Membranes under shear stress: visualization of non-equilibrium domain patterns and domain fusion in a microfluidic device. AB - In this study we investigate the effect of shear force on lipid membranes induced by external fluid flow. We use giant unilamellar vesicles (GUVs) as simple cell models and chose a ternary lipid mixture that exhibits liquid-ordered and liquid disordered domains. These domains are stained with different dyes to allow visualization of changes within the membrane after the application of flow. A microfluidic device served as a valuable platform to immobilize the vesicles and apply shear forces of a defined strength. Moreover, integration of valves allowed us to stop the flow instantaneously and visualize the relaxing domain patterns by means of high-resolution fluorescence microscopy. We observed the formation of transient, non-deterministic patterns of the formerly round domains during application of flow. When the flow is stopped, round domains are formed again on a time scale of ms to s. At longer time scales of several seconds to minutes, the domains fuse into larger domains until they reach equilibrium. These processes are accelerated with increasing temperature and vesicles with budding domains do not fuse unless the temperature is elevated. Our results show the strong effect of the flow on the lipid membrane and we believe that this phenomenon plays a crucial role in the processes of mechanotransduction in living cells. PMID- 27241893 TI - Serum Bicarbonate and Structural and Functional Cardiac Abnormalities in Chronic Kidney Disease - A Report from the Chronic Renal Insufficiency Cohort Study. AB - BACKGROUND: Heart failure (HF) is a frequent occurrence in chronic kidney disease (CKD) patients and predicts poor survival. Serum bicarbonate is associated with increased rates of HF in CKD; however, the mechanisms leading to this association are incompletely understood. This study aims to assess whether serum bicarbonate is independently associated with structural and functional cardiac abnormalities in CKD. METHODS: The association between serum bicarbonate and left ventricular (LV) hypertrophy (LVH), LV mass indexed to height2.7, LV geometry, ejection fraction (EF) and diastolic dysfunction was assessed in 3,483 participants without NYHA class III/IV HF, enrolled in the Chronic Renal Insufficiency Cohort study. RESULTS: The mean estimated glomerular filtration rate was 42.5 +/- 17 ml/min/1.73 m2. The overall prevalence of LVH was 51.2%, with 57.8, 50.9 and 47.7% for bicarbonate categories <22, 22-26 and >26 mmol/l, respectively. Participants with low bicarbonate were more likely to have LVH and abnormal LV geometry (OR 1.32; 95% CI 1.07-1.64, and OR 1.57; 95% CI 1.14-2.16, respectively). However, the association was not statistically significant after adjustment for demographics, traditional cardiovascular risk factors, medications and kidney function (OR 1.07; 95% CI 0.66-1.72, and OR 1.27; 95% CI 0.64-2.51, respectively). No association was found between bicarbonate and systolic or diastolic dysfunction. During follow-up, no significant changes in LV mass or EF were observed in any bicarbonate strata. CONCLUSIONS: In a large CKD study, serum bicarbonate was associated with LV mass and concentric LVH; however, this association was attenuated after adjustment for clinical factors suggesting that the observed cardiac effects are mediated through yet unknown mechanisms. PMID- 27241895 TI - Synthetic osmotic dilators with adjunctive misoprostol for same-day dilation and evacuation: a randomized controlled trial. AB - OBJECTIVE: This study aims to evaluate buccal misoprostol as an adjunct to synthetic osmotic dilators for same-day dilation and evacuation (D&E). STUDY DESIGN: A randomized, double-blinded, placebo-controlled trial of women 16 0/7 to 20 6/7 weeks gestation desiring D&E was used. Participants received synthetic osmotic cervical dilators (Dilapan-S(r)) at least 4 h prior to D&E and were randomized to 400mcg buccal misoprostol or placebo 3 h preoperatively, stratified by gestational age. The primary outcome was operative time with 36 participants needed to detect a 4-min difference (two-sided alpha=0.05, 80% power). Secondary outcomes included total procedure time, patient and provider acceptability, baseline cervical dilation and complications. RESULTS: Twenty-nine women were enrolled (misoprostol n=14, placebo n=15) and mean operative time was similar between the groups (11.1 vs. 13.5 min, respectively, p=.17). Complications were nonsignificantly more common for participants >=19 weeks compared to <19 weeks (22% vs. 9%, p=.62) and those who received placebo compared to misoprostol (27% vs. 7%, p=.33). Two serious adverse events in the placebo group prompted early study closure for safety and futility. Placebo participants had longer overall procedure times (24 vs. 18 min, p=.03) and less cramping preoperatively (p<.01) but similar results for other secondary outcomes compared to those receiving misoprostol. Women strongly preferred same-day cervical preparation (98%). CONCLUSIONS: Adjunctive buccal misoprostol may not decrease operative times but may decrease complications when combined with synthetic osmotic dilators for cervical preparation for same-day D&E procedures. IMPLICATIONS: Although the trial was halted early and underpowered to make conclusions about the primary outcome, complication frequency and type warrant caution for use of synthetic osmotic dilators alone for cervical preparation for same-day D&E at >=19 weeks gestation. PMID- 27241896 TI - Mifepristone by prescription: not quite a reality in the Northern Territory of Australia. PMID- 27241897 TI - Postpartum uptake of contraception in rural northern Malawi: A prospective study. AB - OBJECTIVES: Cross-sectional estimates of contraceptive use do not provide understanding of time to postpartum uptake. This paper uses a range of Malawian data sources: a prospective study to explore time to uptake of contraception and a cross-sectional survey to assess whether sexually active postpartum women whose fecundity has returned use contraception, and whether abstaining/amenorrheic women report using contraception. STUDY DESIGN: A demographic surveillance site (DSS) in Malawi was used to identify 7393 women aged 15-49 years eligible for a 1 year prospective study of contraception using provider-recorded data on patient held records (2012-2013). This provided a reliable record of time to uptake of postpartum contraception. The average timing of resumption of sexual activities after postpartum abstinence and return of menses was estimated from a population based sexual behaviour survey in the DSS (2010-2011). RESULTS: Of 4678 women recruited to the prospective contraception study, 442 delivered an infant during the observation period. Of these, 28.4% used modern contraception within 6 months of delivery. However, at 6-9 months after delivery, only 28.0% women had started menstruation and resumed sexual activities; of these, 77.6% used contraception. Amongst abstaining/amenorrheic women, a quarter reported contraceptive use. CONCLUSIONS: The low uptake of postpartum contraception is likely due to many women abstaining and/or experiencing amenorrhea. Self-reports of contraceptive use amongst abstaining/amenorrheic women bring into question the quality of cross sectional surveys and demonstrate that contraceptive use by women at low risk of pregnancy could contribute to the Malawi paradox of high contraceptive use and high fertility. Given relatively low risk of pregnancy in the postpartum period in this context, a focus on long-acting/permanent methods may be more effective to avert unintended pregnancies. IMPLICATIONS: There has been increasing interest in the utility of postpartum contraceptive programmes to assist women to space births. Our findings suggest that, although uptake of contraception is low, this is partly due to postpartum abstinence and amenorrhea. Provision of long acting/permanent methods will be more effective for women after delivery. PMID- 27241898 TI - The role of training in effective simulated self-injection of subcutaneous depot medroxyprogesterone acetate: observations from a usability study. AB - OBJECTIVES: The need for quarterly clinic visits is a barrier to use of subcutaneous depot medroxyprogesterone acetate (DMPA-SC) contraception. The ability to self-inject at home may enhance method acceptance. Since efficacy depends on proper administration, we evaluated whether women could correctly perform simulated injections of DMPA-SC in a UnijectTM injection system using printed Instructions for Use (IFU), with and without hands-on training. STUDY DESIGN: Adult female volunteers (N=120) injected DMPA-SC into a rubber trainer at two visits, 3 months apart. Women were randomly assigned to receive hands-on training before the first injection or no training. The primary outcome was the proportion of women who successfully operated the injection system. An attempt was defined as successful if the participant correctly performed all critical steps in the injection procedure (getting ready, selecting an injection area, preparing the injector, mixing the medicine, activating the injector, injecting the dose) and expelled the dose without unexpected interruption. The success rate at month 3 was considered the primary endpoint. A one-sided 95% confidence limit >80% was used to declare the delivery system and IFU "fit for purpose." RESULTS: With training, the success rate (one-sided 95% confidence limit) was 90.0% (81.8%) at day 1 and 96.7% (90.4%) at month 3; without training, rates were 76.7% (66.7%) and 88.3% (79.8%), respectively. The trained (96.4%) and untrained (92.2%) groups successfully completed injecting into the trainer at first injection, the final critical step of the injection procedure, despite the fact that about one third of participants considered expelling depot medroxyprogesterone acetate (one component of this step) to be difficult. CONCLUSION: Most participants understood the IFU and successfully operated the injection system. Initial hands-on training improved success rates at both visits. For women interested in self-injection, providers should review all steps of the IFU, provide a demonstration, supervise initial injection(s) and ensure that the patient is aware of future injection dates. The potential for self injection to improve adherence should be studied. IMPLICATIONS: After initial training, women performed simulated self-injections of DMPA-SC in the Uniject system proficiently using printed instructions. Women who are motivated and demonstrate competent injection technique during training can be relied upon to self-inject correctly at home. DMPA-SC users not suitable for self-injection should continue receiving injections at the clinic. PMID- 27241899 TI - Modeling and optimization of antibacterial activity of the chitosan-based hydrogel films using central composite design. AB - In the present study, hydrogel films composed of chitosan-poly(vinyl alcohol) gelatin-thyme honey were successfully prepared by casting method, and their anti bacterial properties were modeled and optimized. Antibacterial properties of the prepared films were analyzed by applying agar diffusion method. Staphylococcus aureus and Pseudomonas aeruginosa were tested as Gram-positive and Gram-negative bacteria, respectively. In order to obtain the composition of the film with maximum inhibition zone against both above-mentioned bacterial strains, the experiments were designed using response surface methodology based on five-level central composite design with four parameters, including concentrations of chitosan, poly(vinyl alcohol), gelatin, and honey. The results indicated that the prepared samples had good antibacterial activities against these two studied bacteria strains. Response surface method is conducted to develop mathematical models for process responses. Variance analysis on the experimental data shows that inhibition zone can be predicted effectively with quadratic models. In addition, swelling properties and rate of water vapor transmission of the prepared hydrogel films were studied. Due to the successful results, this hydrogel film has an excellent potential to be explored further as a wound healing material. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2544-2553, 2016. PMID- 27241900 TI - Inferring the demographic history from DNA sequences: An importance sampling approach based on non-homogeneous processes. AB - In Ait Kaci Azzou et al. (2015) we introduced an Importance Sampling (IS) approach for estimating the demographic history of a sample of DNA sequences, the skywis plot. More precisely, we proposed a new nonparametric estimate of a population size that changes over time. We showed on simulated data that the skywis plot can work well in typical situations where the effective population size does not undergo very steep changes. In this paper, we introduce an iterative procedure which extends the previous method and gives good estimates under such rapid variations. In the iterative calibrated skywis plot we approximate the effective population size by a piecewise constant function, whose values are re-estimated at each step. These piecewise constant functions are used to generate the waiting times of non homogeneous Poisson processes related to a coalescent process with mutation under a variable population size model. Moreover, the present IS procedure is based on a modified version of the Stephens and Donnelly (2000) proposal distribution. Finally, we apply the iterative calibrated skywis plot method to a simulated data set from a rapidly expanding exponential model, and we show that the method based on this new IS strategy correctly reconstructs the demographic history. PMID- 27241902 TI - A conditional estimating equation approach for recurrent event data with additional longitudinal information. AB - Recurrent event data are quite common in biomedical and epidemiological studies. A significant portion of these data also contain additional longitudinal information on surrogate markers. Previous studies have shown that popular methods using a Cox model with longitudinal outcomes as time-dependent covariates may lead to biased results, especially when longitudinal outcomes are measured with error. Hence, it is important to incorporate longitudinal information into the analysis properly. To achieve this, we model the correlation between longitudinal and recurrent event processes using latent random effect terms. We then propose a two-stage conditional estimating equation approach to model the rate function of recurrent event process conditioned on the observed longitudinal information. The performance of our proposed approach is evaluated through simulation. We also apply the approach to analyze cocaine addiction data collected by the University of Connecticut Health Center. The data include recurrent event information on cocaine relapse and longitudinal cocaine craving scores. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27241904 TI - A highly soluble, non-phototoxic, non-fluorescent blebbistatin derivative. AB - Blebbistatin is a commonly used molecular tool for the specific inhibition of various myosin II isoforms both in vitro and in vivo. Despite its popularity, the use of blebbistatin is hindered by its poor water-solubility (below 10 micromolar in aqueous buffer) and blue-light sensitivity, resulting in the photoconversion of the molecule, causing severe cellular phototoxicity in addition to its cytotoxicity. Furthermore, blebbistatin forms insoluble aggregates in water-based media above 10 micromolar with extremely high fluorescence and also high adherence to different types of surfaces, which biases its experimental usage. Here, we report a highly soluble (440 micromolar in aqueous buffer), non fluorescent and photostable C15 amino-substituted derivative of blebbistatin, called para-aminoblebbistatin. Importantly, it is neither photo- nor cytotoxic, as demonstrated on HeLa cells and zebrafish embryos. Additionally, para aminoblebbistatin bears similar myosin II inhibitory properties to blebbistatin or para-nitroblebbistatin (not to be confused with the C7 substituted nitroblebbistatin), tested on rabbit skeletal muscle myosin S1 and on M2 and HeLa cells. Due to its drastically improved solubility and photochemical feature, as well as lack of photo- or cytotoxicity, para-aminoblebbistatin may become a feasible replacement for blebbistatin, especially at applications when high concentrations of the inhibitor or blue light irradiation is required. PMID- 27241905 TI - Determination of Bifidobacterium and Lactobacillus in breast milk of healthy women by digital PCR. AB - Breast milk is one of the most important sources of postnatal microbes. Quantitative real-time polymerase chain reaction (qRT-PCR) is currently used for the quantitative analysis of bacterial 16S rRNA genes in breast milk. However, this method relies on the use of standard curves and is imprecise when quantitating target DNA of low abundance. In contrast, droplet digital PCR (DD PCR) provides an absolute quantitation without the need for calibration curves. A comparison between DD-PCR and qRT-PCR was conducted for the quantitation of Bifidobacterium and Lactobacillus 16S RNA genes in human breast milk, and the impacts of selected maternal factors were studied on the composition of these two bacteria in breast milk. From this study, DD-PCR reported between 0-34,460 16S rRNA gene copies of Bifidobacterium genera and between 1,108-634,000 16S rRNA gene copies of Lactobacillus genera in 1 ml breast milk. The 16S rRNA gene copy number of Lactobacillus genera was much greater than that of Bifidobacterium genera in breast milk. DD-PCR showed a 10-fold lower limit of quantitation as compared to qRT-PCR. A higher correlation and agreement was observed between qRT PCR and DD-PCR in Lactobacillus quantitation as compared to Bifidobacterium quantitation. Based on our DD-PCR quantitation, a low abundance of Bifidobacterium bacteria in breast milk was correlated to higher pre-pregnancy body mass index (BMI). However, no significant difference was observed for these two bacteria in breast milk between mothers who had vaginal deliveries and caesarean deliveries. This study suggests that DD-PCR is a better tool to quantitate the bacterial load of breast milk compared to the conventional qRT-PCR method. The number of breast milk Bifidobacterium bacteria is influenced by maternal pre-pregnancy BMI. PMID- 27241906 TI - Efficacy of probiotics as an adjuvant agent in eradication of Helicobacter pylori infection and associated side effects. AB - The intestinal tract is a host to various types of bacteria that are essential to health. Interactions between intestinal bacteria, i.e. the normal microbiota of the host's intestine, have been a subject of intensive research, as they may influence disease cycles. Recent studies of selected probiotic species and their therapeutic benefits have suggested a potential efficacy in treatment of several gastrointestinal illnesses, including Helicobacter pylori infection. The increasing evidence from these clinical studies supports the promising role of probiotics in improving the treatment of H. pylori by increasing eradication rates as well as decreasing the adverse effects of current medication therapy. However, many unsolved questions remain which require high quality trials on specific probiotic strains in the future. The main part of this review will focus on the effects of supplementary probiotic products during standard triple H. pylori therapy. PMID- 27241907 TI - Why biological anthropologists should identify as anthropologists: The meaning of membership in the AAA and the AAAS. PMID- 27241908 TI - Six1 is required for mouse dental follicle cell and human periodontal ligament derived cell proliferation. AB - The periodontal ligament (PDL) is a connective tissue that attaches the tooth cementum to the alveolar bone and is derived from dental follicle cells (DFCs). The DFCs form fibroblasts, osteoblasts, cementoblasts, and PDL stem cells (PDLSCs). We previously reported homeobox transcription factor Six1 expression in mouse DFCs. However, the role of Six1 in periodontal tissue development is largely unknown. In this study, we analyzed SIX1 expression in mouse periodontal tissue cells during postnatal development and adulthood. We also addressed the role of SIX1 in mouse periodontium development and in human cultured PDL-derived cells (PDLCs). In mouse development, SIX1 production was abundant in DFCs and PDL cells by 2 weeks, but it was greatly diminished in the PDL at 4 weeks and in adults. Although the SIX1-positive cell distribution was sparse in the adult PDL, SIX1-positive cells were observed with low expression levels. We used 5-ethynyl 2'-deoxyuridine (EdU) for cell labeling to reveal numerous EdU/SIX1-double positive cells at 2 weeks; however, a few EdU-positive cells remained at 4 weeks. The proportion of DFCs that incorporated EdU was significantly lower in Six1 deficient mice compared with wild-type mice at E18.5. In human PDLCs, SIX1 was intensely expressed, and SIX1-knockdown using siRNA reduced proliferating PDLCs. Our results suggest that SIX1 is a key proliferation regulator in mouse DFCs and human PDLCs, which provides novel insight into Six family gene function in mammals. PMID- 27241909 TI - Printing of stretchable silk membranes for strain measurements. AB - Quantifying the deformation of biological tissues under mechanical loading is crucial to understand its biomechanical response in physiological conditions and important for designing materials and treatments for biomedical applications. However, strain measurements for biological tissues subjected to large deformations and humid environments are challenging for conventional methods due to several limitations such as strain range, boundary conditions, surface bonding and biocompatibility. Here we propose the use of silk solutions and printing to synthesize prototype strain gauges for large strain measurements in biological tissues. The study shows that silk-based strain gauges can be stretched up to 1300% without failure, which is more than two orders of magnitude larger than conventional strain gauges, and the mechanics can be tuned by adjusting ion content. We demonstrate that the printing approach can accurately provide well bonded fluorescent features on the silk membranes using designs which can accurately measure strain in the membrane. The results show that these new strain gauges measure large deformations in the materials by eliminating the effects of sliding from the boundaries, making the measurements more accurate than direct outputs from tensile machines. PMID- 27241910 TI - Num1 anchors mitochondria to the plasma membrane via two domains with different lipid binding specificities. AB - The mitochondria-ER cortex anchor (MECA) is required for proper mitochondrial distribution and functions by tethering mitochondria to the plasma membrane. The core component of MECA is the multidomain protein Num1, which assembles into clusters at the cell cortex. We show Num1 adopts an extended, polarized conformation. Its N-terminal coiled-coil domain (Num1CC) is proximal to mitochondria, and the C-terminal pleckstrin homology domain is associated with the plasma membrane. We find that Num1CC interacts directly with phospholipid membranes and displays a strong preference for the mitochondria-specific phospholipid cardiolipin. This direct membrane interaction is critical for MECA function. Thus, mitochondrial anchoring is mediated by a protein that interacts directly with two different membranes through lipid-specific binding domains, suggesting a general mechanism for interorganelle tethering. PMID- 27241911 TI - In vivo confinement promotes collective migration of neural crest cells. AB - Collective cell migration is fundamental throughout development and in many diseases. Spatial confinement using micropatterns has been shown to promote collective cell migration in vitro, but its effect in vivo remains unclear. Combining computational and experimental approaches, we show that the in vivo collective migration of neural crest cells (NCCs) depends on such confinement. We demonstrate that confinement may be imposed by the spatiotemporal distribution of a nonpermissive substrate provided by versican, an extracellular matrix molecule previously proposed to have contrasting roles: barrier or promoter of NCC migration. We resolve the controversy by demonstrating that versican works as an inhibitor of NCC migration and also acts as a guiding cue by forming exclusionary boundaries. Our model predicts an optimal number of cells in a given confinement width to allow for directional migration. This optimum coincides with the width of neural crest migratory streams analyzed across different species, proposing an explanation for the highly conserved nature of NCC streams during development. PMID- 27241912 TI - Nuclear bodies: Built to boost. AB - The classic archetypal function of nuclear bodies is to accelerate specific reactions within their crowded space. In this issue, Tatomer et al. (2016. J. Cell Biol http://dx.doi.org/10.1083/jcb.201504043) provide the first direct evidence that the histone locus body acts to concentrate key factors required for the proper processing of histone pre-mRNAs. PMID- 27241913 TI - MICOS and phospholipid transfer by Ups2-Mdm35 organize membrane lipid synthesis in mitochondria. AB - Mitochondria exert critical functions in cellular lipid metabolism and promote the synthesis of major constituents of cellular membranes, such as phosphatidylethanolamine (PE) and phosphatidylcholine. Here, we demonstrate that the phosphatidylserine decarboxylase Psd1, located in the inner mitochondrial membrane, promotes mitochondrial PE synthesis via two pathways. First, Ups2-Mdm35 complexes (SLMO2-TRIAP1 in humans) serve as phosphatidylserine (PS)-specific lipid transfer proteins in the mitochondrial intermembrane space, allowing formation of PE by Psd1 in the inner membrane. Second, Psd1 decarboxylates PS in the outer membrane in trans, independently of PS transfer by Ups2-Mdm35. This latter pathway requires close apposition between both mitochondrial membranes and the mitochondrial contact site and cristae organizing system (MICOS). In MICOS deficient cells, limiting PS transfer by Ups2-Mdm35 and reducing mitochondrial PE accumulation preserves mitochondrial respiration and cristae formation. These results link mitochondrial PE metabolism to MICOS, combining functions in protein and lipid homeostasis to preserve mitochondrial structure and function. PMID- 27241914 TI - T cell activation requires force generation. AB - Triggering of the T cell receptor (TCR) integrates both binding kinetics and mechanical forces. To understand the contribution of the T cell cytoskeleton to these forces, we triggered T cells using a novel application of atomic force microscopy (AFM). We presented antigenic stimulation using the AFM cantilever while simultaneously imaging with optical microscopy and measuring forces on the cantilever. T cells respond forcefully to antigen after calcium flux. All forces and calcium responses were abrogated upon treatment with an F-actin inhibitor. When we emulated the forces of the T cell using the AFM cantilever, even these actin-inhibited T cells became activated. Purely mechanical stimulation was not sufficient; the exogenous forces had to couple through the TCR. These studies suggest a mechanical-chemical feedback loop in which TCR-triggered T cells generate forceful contacts with antigen-presenting cells to improve access to antigen. PMID- 27241915 TI - Postnatal telomere dysfunction induces cardiomyocyte cell-cycle arrest through p21 activation. AB - The molecular mechanisms that drive mammalian cardiomyocytes out of the cell cycle soon after birth remain largely unknown. Here, we identify telomere dysfunction as a critical physiological signal for cardiomyocyte cell-cycle arrest. We show that telomerase activity and cardiomyocyte telomere length decrease sharply in wild-type mouse hearts after birth, resulting in cardiomyocytes with dysfunctional telomeres and anaphase bridges and positive for the cell-cycle arrest protein p21. We further show that premature telomere dysfunction pushes cardiomyocytes out of the cell cycle. Cardiomyocytes from telomerase-deficient mice with dysfunctional telomeres (G3 Terc(-/-)) show precocious development of anaphase-bridge formation, p21 up-regulation, and binucleation. In line with these findings, the cardiomyocyte proliferative response after cardiac injury was lost in G3 Terc(-/-) newborns but rescued in G3 Terc(-/-)/p21(-/-) mice. These results reveal telomere dysfunction as a crucial signal for cardiomyocyte cell-cycle arrest after birth and suggest interventions to augment the regeneration capacity of mammalian hearts. PMID- 27241917 TI - Food safety regulations in Australia and New Zealand Food Standards. PMID- 27241918 TI - Wireless rotating disk electrode (wRDE) for assessing heterogeneous water oxidation catalysts (WOCs). AB - A novel method for assessing the activity of a powdered water oxidation catalyst (WOC) is described, utilising an easily-prepared wireless rotating disc electrode of the WOC, thereby allowing its activity to be probed, via the observed kinetics of water oxidation by Ce(iv) ions, and so provide invaluable electrochemical information. PMID- 27241916 TI - Concentrating pre-mRNA processing factors in the histone locus body facilitates efficient histone mRNA biogenesis. AB - The histone locus body (HLB) assembles at replication-dependent histone genes and concentrates factors required for histone messenger RNA (mRNA) biosynthesis. FLASH (Flice-associated huge protein) and U7 small nuclear RNP (snRNP) are HLB components that participate in 3' processing of the nonpolyadenylated histone mRNAs by recruiting the endonuclease CPSF-73 to histone pre-mRNA. Using transgenes to complement a FLASH mutant, we show that distinct domains of FLASH involved in U7 snRNP binding, histone pre-mRNA cleavage, and HLB localization are all required for proper FLASH function in vivo. By genetically manipulating HLB composition using mutations in FLASH, mutations in the HLB assembly factor Mxc, or depletion of the variant histone H2aV, we find that failure to concentrate FLASH and/or U7 snRNP in the HLB impairs histone pre-mRNA processing. This failure results in accumulation of small amounts of polyadenylated histone mRNA and nascent read-through transcripts at the histone locus. Thus, the HLB concentrates FLASH and U7 snRNP, promoting efficient histone mRNA biosynthesis and coupling 3' end processing with transcription termination. PMID- 27241919 TI - The charge states of Au on gold-substituted Ce1-xO2(111) surfaces with multiple oxygen vacancies. AB - The surface structures and the charge on Au for a gold atom adsorbed on the cerium vacancy of the (111) surface of CeO2 in the presence of oxygen vacancies are investigated via density functional theory calculations. Without oxygen vacancies, the Au atom adsorbed on a Ce vacancy of CeO2(111) is highly positively charged. By systematically exploring oxygen vacancy configurations, it is found that not only does the Au charge have a trend of decreasing when the number of oxygen vacancies increases, but this charge also can be significantly changed by adjusting the locations of the oxygen vacancies without altering the vacancy number. Consequently, by arranging the oxygen vacancy configuration, the Au can exist in both positive and negative states in the case of three oxygen vacancies. Detailed analyses show that the variation in the Au charge with oxygen vacancies can be attributed to the distribution of the leftover electrons after the oxygen vacancies were created, which, in turn, depends on the vacancy number and locations of the vacancies. These results suggest a potential method to adjust the oxidation states of Au atoms absorbed on ceria. In addition, the implications of the findings for experimental results are also discussed. PMID- 27241920 TI - Hydrops of the organ of Corti. AB - OBJECTIVES: The authors would like to confirm a fluid pathway from the scala tympani to the organ of Corti, and to observe its morphological changes. METHODS: A staining solution for succinic dehydrogenase was perfused with phenazine methosulfate in the scala tympani of living guinea pigs (n = 5) under deep anesthesia. After fixation, the cochleas were eventually embedded in epon. Sections were observed under a light microscope. RESULTS: Blue-stained tissue is indicative of the pathway taken by the solution. The staining solution entered the organ of Corti through Hensen-Deiters' slit. The slit widened and Hensen's cells were pushed laterally. A new space was formed medial to Hensen's cells. Cortilymphatic hydrops developed. CONCLUSION: The Hensen-Deiters' slit is a pathway of a certain staining solution from the scala tympani to inside the organ of Corti of the guinea pig. The influx of the fluid pushes Hensen's cells laterally and upward, resulting in a formation of hydrops of the organ of Corti or cortilymphatic hydrops. The hydrops is observed in animals with experimental perilymphatic fistula and with viral labyrinthitis. At the end stage of the hydrops, only the surface of the organ of Corti remains as a thin layer without any cellular elements. PMID- 27241921 TI - Differences in prognosis of Siewert II and III oesophagogastric junction cancers are determined by the baseline tumour staging but not its anatomical location. AB - BACKGROUND: The anatomical Siewert classification for adenocarcinoma of the oesophagogastric junction (OGJ) was dictated by the potential differences in tumour epidemiology and pathology. However, there are some uncertainties whether the distinction of true carcinoma of the cardia (type II) and subcardial gastric cancer (type III) is of clinical value. METHODS: Using a multicentre data set, we studied 243 patients with OGJ adenocarcinomas who underwent gastric resections between 1998 and 2008. Postoperative complications and long-term survival were compared to evaluate the potential differences in clinically relevant outcomes. RESULTS: A group of 109 patients with Siewert type II and 134 with Siewert type III OGJ adenocarcinoma was identified. Both groups showed similar baseline characteristics, including clinical symptoms and duration of diagnostic delay. However, the prevalence of node-negative cancers and superficial (T1-T2) lesions was significantly higher among type II tumours, i.e. 42% vs 21% (P = 0.003) and 43% vs 20% (P = 0.045), respectively. Morbidity and mortality rates were 25% and 3.7%, respectively, but types and incidence of postoperative complications were not affected by the anatomical location of the tumour. The overall median survival was significantly longer for Siewert type II tumours (42 vs 16 months; P < 0.001). However, only patients' age >70 years, depth of tumour infiltration, lymph node metastases, distant metastases, and radical resection were identified as independent prognostic factors using the Cox proportional hazards model. CONCLUSION: The topographic-anatomic sub-classification of OGJ adenocarcinomas does not correspond to relevant differences in clinical parameters of safety and efficacy of surgical treatment. PMID- 27241922 TI - Radical hysterectomy after chemoradiation in FIGO stage III cervical cancer patients versus chemoradiation and brachytherapy: Complications and 3-years survival. AB - BACKGROUND: To compare patterns and rates of early and late complications, and survival outcome in FIGO stage III cervical cancer patients underwent to radical hysterectomy after chemo-radiation (CT-RT) vs. chemo-radiation alone. METHODS: Between May 1996 and April 2013 150 FIGO stage III cervical cancer patients were treated. We divide patients according to type of treatment: 77 were submitted to standard treatment (Group A), and 73 to completion hysterectomy after chemo radiation (Group B). RESULTS: The baseline characteristics of the 2 groups were superimposable. We observed lower intra-operative and treatment-related early urinary and gastro-intestinal complications in Group B with respect to Group A (p < 0.001). Vascular complications were registered only in Group B (p < 0.001). We found a significantly higher rate of local recurrences in the Group A than in the Group B (p < 0.002). We registered 29 deaths in the Group A and 22 in the Group B (p = 0.021). The 3-years disease-free survival rate in the Group A and in the Group B was 62.9% and 68.3%, respectively (p = 0.686), and the 3-years overall survival rate in the Group A and in the Group B was 63.2% and 67.7%, respectively (p = 0.675). CONCLUSIONS: This study confirms that radical hysterectomy after CT RT is an effective therapeutic approach for advanced cervical cancer. Further prospective and randomized studies should be performed in order to solve the question about the standard approach, and how the different pattern of complication could impact on the quality of life. PMID- 27241923 TI - Salvage surgery in patients with recurrent or residual squamous cell carcinoma of the anus. AB - INTRODUCTION: Anal squamous cell cancers are uncommon, and primary treatment is radical chemoradiotherapy. The role of radical surgery is in salvage of patients with residual and recurrent disease. The primary aim of the study is to determine how often such salvage surgery is required, while the secondary aim is to determine which features indicate salvage surgery may be required and to determine the outcome of salvage surgery. METHODS: A prospective database was analysed of all patients with anal cancer over an 18 year period (Dec 1996-Jan 2015). The records of patients requiring salvage surgery were reviewed. RESULTS: 203 Patients were identified with anal cancers, of which 180 had squamous cell anal carcinoma. 112 Female (median age 59.4, range 33-92) 68 male (median age 63.8 range 36-87). Of these 27 patients (15%) required salvage surgery. 23 Patients had a R0 resection. 18 Patients had an extended resection (16 R0) while 9 had a routine APR (7 R0). The 30-day post-operative mortality rate was 0%. The overall 5 year survival was 78%, not significantly different from those not requiring salvage surgery (p = 0.23). Age, gender, AJCC stage, T stage, radiation therapy alone, were not predicators of the need for salvage surgery. CONCLUSIONS: Salvage surgery is uncommonly required. Extended surgery beyond routine APR is often required to obtain an R0 resection. Excellent patient survival can be achieved in highly selected cases. There were no identifiable clinical predictors of those needing salvage surgery, and consideration should be given to explore molecular and genetic factors. PMID- 27241924 TI - The European Organization for Research and Treatment for Cancer (EORTC) strategy for quality assurance in surgical clinical research: Assessment of the past and moving towards the future. AB - AIMS: Quality assurance (QA) in a surgical trial must be planned and implemented from study development to completion. Elements of quality must be consistently described in a protocols, case report forms (CRFs) and reported in publications. The purpose of this review was to evaluate the most common surgical parameters and how consistently they were described in EORTC study documents where surgery was included. This was the preliminary step in mapping out the challenges of developing a surgical QA strategy in EORTC. METHODS: A systematic review of EORTC surgical protocols from 1980 to 2013 was performed. Two independent reviewers selected and reviewed the protocols. Data extraction was done using a questionnaire developed by EORTC QA committee. The results were compared across the time period. RESULTS: The most common quality parameters described in protocols were surgical technique, definition of resectability, surgical margins and methods of assessing adverse events using the Common Terminology Criteria for Adverse Event (CTCAE). However, these were not consistently reported in publications. A general improvement in the method of protocol development was observed since year 2000 after standardization measures by EORTC. A new surgical chapter template has been proposed. CONCLUSION: There is a need to consistently define and report surgical parameters from protocol development to publication as a first step to QA. A standard surgical chapter in the EORTC protocol template can help address this need. A framework to consistently implement QA for future surgical trials is needed and the rationale for this is described in this review. PMID- 27241925 TI - Should total gastrectomy and total colectomy be considered for selected patients with severe tumor burden of pseudomyxoma peritonei in cytoreductive surgery? AB - BACKGROUND: This study aims to evaluate the safety and efficacy of cytoreductive surgery (CRS) including total gastrectomy and total colectomy in selected pseudomyxoma peritonei (PMP) patients with entire stomach and colon covered by mucinous tumor. METHODS: A total of 48 patients received this extensive treatment between January 2006 and January 2014. The main focus of this study was survival after CRS as well as perioperative morbidity and mortality. RESULTS: Twenty-eight patients were male, and median age was 52.5 years. Median peritoneal cancer index was 33. Complete cytoreduction was achieved in all 48 patients, and 26 patients received hyperthermic intraperitoneal chemotherapy (HIPEC). Until last follow-up, the estimated median survival after CRS was 54.0 months (95% CI 36.5-71.6 months). The 1-, 2-, 3-, and 5-year survival rates were 91.7%, 81.3%, 70.1%, and 48.6%, respectively. Histology was significantly associated with survival (P = 0.020). The median disease-free survival was 32.0 (95% CI 25.7-38.3) months. HIPEC (P = 0.048) and histology (P = 0.002) was significantly associated with disease-free survival after CRS. Overall Grade 3-5 complications occurred in 18 (37.5%) patients with mortality of 2.1%. For patients who received surgery over 6 months, they could gradually have an acceptable quality-of-life similar as other patients receiving ordinary CRS and HIPEC. CONCLUSION: CRS including total gastrectomy and total colectomy can be performed in experienced specialized institutions as a feasible option to achieve complete cytoreduction with acceptable safety in selected PMP patients with stomach and colon covered by mucinous tumor. Perioperative management should be carried out cautiously to decrease and avoid complications. PMID- 27241927 TI - The E. coli DNA Replication Fork. AB - DNA replication in Escherichia coli initiates at oriC, the origin of replication and proceeds bidirectionally, resulting in two replication forks that travel in opposite directions from the origin. Here, we focus on events at the replication fork. The replication machinery (or replisome), first assembled on both forks at oriC, contains the DnaB helicase for strand separation, and the DNA polymerase III holoenzyme (Pol III HE) for DNA synthesis. DnaB interacts transiently with the DnaG primase for RNA priming on both strands. The Pol III HE is made up of three subassemblies: (i) the alphaEtheta core polymerase complex that is present in two (or three) copies to simultaneously copy both DNA strands, (ii) the beta2 sliding clamp that interacts with the core polymerase to ensure its processivity, and (iii) the seven-subunit clamp loader complex that loads beta2 onto primer template junctions and interacts with the alpha polymerase subunit of the core and the DnaB helicase to organize the two (or three) core polymerases. Here, we review the structures of the enzymatic components of replisomes, and the protein protein and protein-DNA interactions that ensure they remain intact while undergoing substantial dynamic changes as they function to copy both the leading and lagging strands simultaneously during coordinated replication. PMID- 27241928 TI - The Replication System of Bacteriophage T7. AB - The replication system of bacteriophage T7 is remarkable in that the 40,000 nucleotide genome is replicated over 100-fold in a matter of minutes. In order to accomplish this feat T7 has evolved an efficient and economical process for the replication of its DNA. The T7 replisome provides a model system to study DNA replication. Four proteins are sufficient for reconstitution of the functional replication complex, yet the assembled replisome recapitulates all the key features of more complex prokaryotic and eukaryotic systems. In this review, we describe chemical mechanisms employed by individual proteins at the replication fork. Integration of structural, biochemical, and single-molecule data reveals a compelling view on how a nearly 1-MDa molecular machine acts as a unit to synthetize the two antiparallel DNA strands in a coordinated fashion. PMID- 27241929 TI - Protein-Primed Replication of Bacteriophage Phi29 DNA. AB - The requirement of DNA polymerases for a 3'-hydroxyl (3'-OH) group to prime DNA synthesis raised the question about how the ends of linear chromosomes could be replicated. Among the strategies that have evolved to handle the end replication problem, a group of linear phages and eukaryotic and archaeal viruses, among others, make use of a protein (terminal protein, TP) that primes DNA synthesis from the end of their genomes. The replicative DNA polymerase recognizes the OH group of a specific residue in the TP to initiate replication that is guided by an internal 3' nucleotide of the template strand. By a sliding-back mechanism or variants of it the terminal nucleotide(s) is(are) recovered and the TP becomes covalently attached to the genome ends. Bacillus subtilis phage phi29 is the organism in which such a mechanism has been studied more extensively, having allowed to lay the foundations of the so-called protein-primed replication mechanism. Here we focus on the main biochemical and structural features of the two main proteins responsible for the protein-primed initiation step: the DNA polymerase and the TP. Thus, we will discuss the structural determinants of the DNA polymerase responsible for its ability to use sequentially a TP and a DNA as primers, as well as for its inherent capacity to couple high processive synthesis to strand displacement. On the other hand, we will review how TP primes initiation followed by a transition step for further DNA-primed replication by the same polymerase molecule. Finally, we will review how replication is compartmentalized in vivo. PMID- 27241930 TI - Archaeal DNA Replication Origins and Recruitment of the MCM Replicative Helicase. AB - DNA replication is fundamental to the propagation of all life on the planet. Remarkably, given the central importance for this process, two distinct core cellular DNA replication machineries have evolved. One is found in the bacterial domain of life and the other is present in Archaea and Eukarya. The archaeal machinery represents a simplified and presumably ancestral form of the eukaryotic DNA replication apparatus. As such, archaeal replication proteins have been studied extensively as models for their eukaryal counterparts. In addition, a number of archaea have been developed as model organisms. Accordingly, there has been a considerable increase in our knowledge of how archaeal chromosomes are replicated. It has become apparent that the majority of archaeal cells replicate their genomes from multiple origins per chromosome. Thus, at both organizational and mechanistic levels, archaeal DNA replication resembles that of eukarya. In this chapter, we will describe recent advances in our understanding of the basis of archaeal origin definition and how the archaeal initiator proteins recruit the replicative helicase to origins. PMID- 27241926 TI - Replication Initiation in Bacteria. AB - The initiation of chromosomal DNA replication starts at a replication origin, which in bacteria is a discrete locus that contains DNA sequence motifs recognized by an initiator protein whose role is to assemble the replication fork machinery at this site. In bacteria with a single chromosome, DnaA is the initiator and is highly conserved in all bacteria. As an adenine nucleotide binding protein, DnaA bound to ATP is active in the assembly of a DnaA oligomer onto these sites. Other proteins modulate DnaA oligomerization via their interaction with the N-terminal region of DnaA. Following the DnaA-dependent unwinding of an AT-rich region within the replication origin, DnaA then mediates the binding of DnaB, the replicative DNA helicase, in a complex with DnaC to form an intermediate named the prepriming complex. In the formation of this intermediate, the helicase is loaded onto the unwound region within the replication origin. As DnaC bound to DnaB inhibits its activity as a DNA helicase, DnaC must dissociate to activate DnaB. Apparently, the interaction of DnaB with primase (DnaG) and primer formation leads to the release of DnaC from DnaB, which is coordinated with or followed by translocation of DnaB to the junction of the replication fork. There, DnaB is able to coordinate its activity as a DNA helicase with the cellular replicase, DNA polymerase III holoenzyme, which uses the primers made by primase for leading strand DNA synthesis. PMID- 27241931 TI - The Eukaryotic Replication Machine. AB - The cellular replicating machine, or "replisome," is composed of numerous different proteins. The core replication proteins in all cell types include a helicase, primase, DNA polymerases, sliding clamp, clamp loader, and single strand binding (SSB) protein. The core eukaryotic replisome proteins evolved independently from those of bacteria and thus have distinct architectures and mechanisms of action. The core replisome proteins of the eukaryote include: an 11 subunit CMG helicase, DNA polymerase alpha-primase, leading strand DNA polymerase epsilon, lagging strand DNA polymerase delta, PCNA clamp, RFC clamp loader, and the RPA SSB protein. There are numerous other proteins that travel with eukaryotic replication forks, some of which are known to be involved in checkpoint regulation or nucleosome handling, but most have unknown functions and no bacterial analogue. Recent studies have revealed many structural and functional insights into replisome action. Also, the first structure of a replisome from any cell type has been elucidated for a eukaryote, consisting of 20 distinct proteins, with quite unexpected results. This review summarizes the current state of knowledge of the eukaryotic core replisome proteins, their structure, individual functions, and how they are organized at the replication fork as a machine. PMID- 27241932 TI - The Many Roles of PCNA in Eukaryotic DNA Replication. AB - Proliferating cell nuclear antigen (PCNA) plays critical roles in many aspects of DNA replication and replication-associated processes, including translesion synthesis, error-free damage bypass, break-induced replication, mismatch repair, and chromatin assembly. Since its discovery, our view of PCNA has evolved from a replication accessory factor to the hub protein in a large protein-protein interaction network that organizes and orchestrates many of the key events at the replication fork. We begin this review article with an overview of the structure and function of PCNA. We discuss the ways its many interacting partners bind and how these interactions are regulated by posttranslational modifications such as ubiquitylation and sumoylation. We then explore the many roles of PCNA in normal DNA replication and in replication-coupled DNA damage tolerance and repair processes. We conclude by considering how PCNA can interact physically with so many binding partners to carry out its numerous roles. We propose that there is a large, dynamic network of linked PCNA molecules at and around the replication fork. This network would serve to increase the local concentration of all the proteins necessary for DNA replication and replication-associated processes and to regulate their various activities. PMID- 27241935 TI - Preface. PMID- 27241936 TI - Letter: the emergence of multi-drug resistant spontaneous bacterial peritonitis: a new challenge for the hepatologist? PMID- 27241933 TI - Animal Mitochondrial DNA Replication. AB - Recent advances in the field of mitochondrial DNA (mtDNA) replication highlight the diversity of both the mechanisms utilized and the structural and functional organization of the proteins at mtDNA replication fork, despite the relative simplicity of the animal mtDNA genome. DNA polymerase gamma, mtDNA helicase and mitochondrial single-stranded DNA-binding protein-the key replisome proteins, have evolved distinct structural features and biochemical properties. These appear to be correlated with mtDNA genomic features in different metazoan taxa and with their modes of DNA replication, although substantial integrative research is warranted to establish firmly these links. To date, several modes of mtDNA replication have been described for animals: rolling circle, theta, strand displacement, and RITOLS/bootlace. Resolution of a continuing controversy relevant to mtDNA replication in mammals/vertebrates will have a direct impact on the mechanistic interpretation of mtDNA-related human diseases. Here we review these subjects, integrating earlier and recent data to provide a perspective on the major challenges for future research. PMID- 27241934 TI - Fidelity of Nucleotide Incorporation by the RNA-Dependent RNA Polymerase from Poliovirus. AB - Using poliovirus (PV) and its RNA-dependent RNA polymerase (RdRp) as our primary model system, we have advanced knowledge fundamental to the chemistry and fidelity of nucleotide addition by nucleic acid polymerase. Two fidelity checkpoints exist prior to nucleotide addition. The first toggles the enzyme between a nucleotide binding-occluded state and a nucleotide binding-competent state. The second represents an ensemble of conformational states of conserved structural motifs that permits retention of the incoming nucleotide in a state competent for phosphoryl transfer long enough for chemistry to occur. Nucleophilic attack of the alpha-phosphorous atom of the incoming nucleotide produces a pentavalent transition state, collapse of which is facilitated by protonation of the pyrophosphate leaving group by a general acid. All of the relevant conformational states of the enzyme are controlled by a network of interacting residues that permits remote-site residues to control active-site function. The current state of the art for PV RdRp enzymology is such that mechanisms governing fidelity of this enzyme can now be targeted genetically and chemically for development of attenuated viruses and antiviral agents, respectively. Application of the knowledge obtained with the PV RdRp to the development of vaccines and antivirals for emerging RNA viruses represents an important goal for the future. PMID- 27241937 TI - Clinical features of the systolic anterior motion of the mitral valve among patients without hypertrophic cardiomyopathy. AB - BACKGROUND: The prevalence and clinical features of the systolic anterior motion of the mitral valve (SAM) without hypertrophic cardiomyopathy (HCM) have not been studied well. METHODS: Records of 9180 sequential patients who underwent echocardiography at Tokyo Women's Medical University Hospital were reviewed. SAM patients were divided into those with HCM (HCM; n=60, 68%) and those without HCM (non-HCM; n=28, 32%). To assess SAM morphology, non-HCM patients were divided into the valvular and chordal groups. RESULTS: The prevalence of non-HCM SAM was 0.3%. Non-HCM patients showed older age (65.7+/-15.0 years vs. 56.9+/-16.8 years, p=0.02), higher prevalence of sigmoid septum (75% vs. 50%, p=0.03), and lower left ventricular outflow tract pressure gradient (LVOT-PG) (27+/-31mmHg vs. 43+/ 41mmHg, p=0.03) than HCM patients. However, 8 of 28 non-HCM patients showed a LVOT-PG >30mmHg. Valvular SAM showed higher dyspnea prevalence (29% vs. 0%, p=0.04), higher LVOT-PG (39+/-36mmHg vs. 6+/-2mmHg, p<0.001), longer anterior mitral leaflet (28+/-2mm vs. 26+/-3mm, p=0.04) and more pronounced mitral regurgitation than chordal SAM. CONCLUSION: Non-HCM SAM prevalence was 0.3% in the Japanese population. Non-HCM SAM correlated with older age, sigmoid septum, and a lower LVOT-PG compared with HCM SAM. Among non-HCM SAM, valvular SAM showed a significant symptom, higher LVOT-PG, and more pronounced mitral regurgitation than chordal SAM. PMID- 27241938 TI - Targeting change: Assessing a faculty learning community focused on increasing statistics content in life science curricula. AB - Transformation of research in all biological fields necessitates the design, analysis and, interpretation of large data sets. Preparing students with the requisite skills in experimental design, statistical analysis, and interpretation, and mathematical reasoning will require both curricular reform and faculty who are willing and able to integrate mathematical and statistical concepts into their life science courses. A new Faculty Learning Community (FLC) was constituted each year for four years to assist in the transformation of the life sciences curriculum and faculty at a large, Midwestern research university. Participants were interviewed after participation and surveyed before and after participation to assess the impact of the FLC on their attitudes toward teaching, perceived pedagogical skills, and planned teaching practice. Overall, the FLC had a meaningful positive impact on participants' attitudes toward teaching, knowledge about teaching, and perceived pedagogical skills. Interestingly, confidence for viewing the classroom as a site for research about teaching declined. Implications for the creation and development of FLCs for science faculty are discussed. (c) 2016 by The International Union of Biochemistry and Molecular Biology, 44(6):517-525, 2016. PMID- 27241939 TI - Effects of poloxamer 407-induced hyperlipidemia on hepatic multidrug resistance protein 2 (Mrp2/Abcc2) and the pharmacokinetics of mycophenolic acid in rats. AB - Hepatic multidrug resistance-associated protein 2 (Mrp2) is responsible for the majority of the biliary elimination of endogenous and exogenous substances, therefore it is important to evaluate possible functional changes in Mrp2 activity under conditions of hyperlipidemia (HL). Thus, the present study assessed the protein expression and transporting activity of hepatic Mrp2 based on the in vivo biliary excretion of phenolsulfonphthalein (PSP) as a model anionic substrate for Mrp2 in poloxamer 407-induced hyperlipidemic rats (HL rats) and compared these values with those for control rats. The pharmacokinetics of mycophenolic acid (MPA) and mycophenolic acid-7-O-glucuronide (MPAG) were evaluated after the intravenous (5 mg/kg) and oral (10 mg/kg) administration of MPA to control and HL rats. In HL rats, the protein expression of hepatic Mrp2 and its biliary transporting activity exhibited significant reductions (by 24.3% and 24.6%, respectively) in the absence of a change in bile flow rate. Unexpectedly, HL and control rats showed comparable biliary excretion rates of MPAG due to the counter effects of the reduced expression and activity of Mrp2 and a 484% increase in the free fraction of MPAG in HL rats. The estimated biliary clearance value of free MPAG in HL rats was considerably slower (by 77.1%) than that in control rats. Although significant pharmacokinetic changes in total MPA and MPAG levels were not observed in HL rats, there was a marked increase in free MPA and MPAG levels. Clinically relevant pharmacokinetic changes in subjects with HL that are related to MRP2 could not be ruled out. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27241940 TI - Combining Computed Tomography-Based Bone Density Assessment with FRAX Screening in Men with Prostate Cancer. AB - To investigate the addition of a computed tomography (CT)-based method of osteoporosis screening to FRAX without bone mineral density (BMD) fracture risk assessment in men undergoing radiotherapy for prostate cancer, we reviewed the records of all patients with localized prostate cancer treated with external beam radiotherapy at our institution between 2001 and 2012. The 10-yr probability of hip fracture was calculated using the FRAX algorithm without BMD. The CT attenuation of the L5 trabecular bone (L5CT) was assessed by contouring the trabecular bone on a single CT slice at the level of the midvertebral body and by averaging the Hounsfield units (HU) of all included voxels. L5CT values of 105 and 130 HU were used as screening thresholds. The clinical characteristics of additional patients identified by each L5CT screening threshold value were compared to patients whose estimated 10-yr risk of hip fracture was 3% or greater by FRAX without BMD. A total of 609 patients treated between 2001 and 2012 had CT scans available for review and complete clinical information allowing for FRAX without BMD risk calculation. Seventy-four (12.2%) patients had an estimated 10 yr risk of hip fracture of 3% or greater. An additional 22 (3.6%) and 71 (11.6%) patients were identified by CT screening when thresholds L5CT = 105 HU and L5CT = 130 HU were used, respectively. Compared to the group of patients identified by FRAX without BMD, the additional patients identified by CT screening at each L5CT threshold level tended to be younger and heavier, and were more likely to be African-American or treated without androgen deprivation therapy. These results suggest that the addition of CT-based screening to FRAX without BMD risk assessment identifies additional men with different underlying clinical characteristics who may be at risk for osteoporosis and may benefit from pharmacological therapy to increase BMD and reduce fracture risk. PMID- 27241941 TI - An experimental model for studies on delayed tooth replantation and ankylosis in rabbits. AB - AIM: To develop an experimental in vivo model to study dentoalveolar ankylosis and osseous replacement resorption after delayed replantation. MATERIALS AND METHODS: The maxillary right incisors of eight rabbits were extracted and replanted, while the maxillary left incisors served as controls. A special technique for extraction was used, luxating the incisor laterally prior to extraction. Extra-oral root canal treatment was performed. In four of the eight replanted teeth, periodontal ligament was removed using gauze. All teeth were replanted after one-hour dry storage. A horizontal line was drilled on the labial enamel surface of the incisors to enable registration of possible subsequent infraposition. The rabbits were sacrificed after 1 week or 4 weeks, respectively. Percussion test of the teeth was carried out and infraposition was registered. Histological processing and evaluation were performed. RESULTS: Percussion sound was normal after 1 week and high in the 4 week group; infraposition was noted in all replanted teeth in the 4-week group. Fusion between the bone and dentin was seen in some areas on the root already after 1 week, but there was little or no osseous replacement. Larger areas of ankylosis were seen in the 4-week group although not significant, but deeper progressive osseous replacement was noted in this group. There was no significant difference in ankylosis with regard to periodontal ligament removal or not. Pulp and periodontal tissues were normal in all control teeth. CONCLUSION: The rabbit tooth model may be useful for experimental in-vivo studies on delayed replantation, subsequent ankylosis, osseous replacement and infraposition. PMID- 27241942 TI - Protective effect of lithium chloride against hypoglycemia-induced apoptosis in neuronal PC12 cell. AB - Hypoglycemia is defined by an arbitrary plasma glucose level lower than 3.9mmol/L and is a most common and feared adverse effect of treatment of diabetes mellitus. Emerging evidences demonstrated that hypoglycemia could induce enhanced apoptosis. Lithium chloride (LiCl), a FDA approved drug clinically used for treatment of bipolar disorders, is recently proven having neuroprotection against various stresses in the cellular and animal models of neural disorders. Here, we have established a hypoglycemia model in vitro and assessed the neuroprotective efficacy of LiCl against hypoglycemia-induced apoptosis and the underlying cellular and molecular mechanisms. Our studies showed that LiCl protects against hypoglycemia-induced neurotoxicity in vitro. Exposure to hypoglycemia results in enhanced apoptosis and the underlying cellular and molecular mechanisms involved inhibition of the canonical Wnt signaling pathway by decreasing wnt3a levels, beta-catenin levels and increasing GSK-3beta levels, which was confirmed by the use of Wnt-specific activator LiCl. Hypoglycemia-induced apoptosis were significantly reversed by LiCl, leading to increased cell survival. LiCl also alters the expression/levels of the Wnt pathway genes/proteins, which were reduced due to exposed to hypoglycemia. Overall, our results conclude that LiCl provides neuroprotection against hypoglycemia-induced apoptosis via activation of the canonical Wnt signaling pathway. PMID- 27241943 TI - The complex STATes of astrocyte reactivity: How are they controlled by the JAK STAT3 pathway? AB - Astrocytes play multiple important roles in brain physiology. In pathological conditions, they become reactive, which is characterized by morphological changes and upregulation of intermediate filament proteins. Besides these descriptive hallmarks, astrocyte reactivity involves significant transcriptional and functional changes that are far from being fully understood. Most importantly, astrocyte reactivity seems to encompass multiple states, each having a specific influence on surrounding cells and disease progression. These diverse functional states of reactivity must be regulated by subtle signaling networks. Many signaling cascades have been associated with astrocyte reactivity, but among them, the JAK-STAT3 pathway is emerging as a central regulator. In this review, we aim (i) to show that the JAK-STAT3 pathway plays a key role in the control of astrocyte reactivity, (ii) to illustrate that STAT3 is a pleiotropic molecule operating multiple functions in reactive astrocytes, and (iii) to suggest that each specific functional state of reactivity is governed by complex molecular interactions within astrocytes, which converge on STAT3. More research is needed to precisely identify the signaling networks controlling the diverse states of astrocyte reactivity. Only then, we will be able to precisely delineate the therapeutic potential of reactive astrocytes in each neurological disease context. PMID- 27241944 TI - Altered brain morphology and functional connectivity reflect a vulnerable affective state after cumulative multigenerational stress in rats. AB - Prenatal stress is a risk factor for abnormal neuroanatomical, cognitive, behavioral and mental health outcomes with potentially transgenerational consequences. Females in general seem more resilient to the effects of prenatal stress than males. Here, we examined if repeated stress across generations may diminish stress resiliency and cumulatively enhance the susceptibility for adverse health outcomes in females. Pregnant female rats of three successive generations were exposed to stress from gestational days 12-18 to generate multigenerational prenatal stress (MPS) in the maternal lineage. Stress response was measured by plasma corticosterone levels and open-field exploration in each generation. Neuromorphological consequences of MPS were investigated in the F3 generation using in vivo manganese-enhanced magnetic resonance imaging (MEMRI), T2-relaxometry, and cytoarchitectonics in relation to candidate gene expression involved in brain plasticity and mental health. Each additional generation of prenatal stress incrementally elevated hypothalamic-pituitary-adrenal axis activation, anxiety-like and aversive behaviors in adult female offspring. Elevated stress responses in the MPS F3 generation were accompanied by reduced neural density in prefrontal cortex, hippocampus and whole brain along with altered brain activation patterns in in vivo MEMRI. MPS increased ephrin receptor A5 (Epha5), neuronal growth regulator (Negr1) and synaptosomal-associated protein 25 (Snap25) gene expression and reduced fibroblast growth factor 12 (Fgf12) in prefrontal cortex. These genes regulate neuronal maturation, arborization and synaptic plasticity and may explain altered brain cytoarchitectonics and connectivity. These findings emphasize that recurrent stress across generations may cumulatively increase stress vulnerability and the risk of adverse health outcomes through perinatal programing in females. PMID- 27241945 TI - Investigating the Role of Alpha and Beta Rhythms in Functional Motor Networks. AB - It is recognized that lower electroencephalography (EEG) frequencies correspond to distributed brain activity over larger spatial regions than higher frequencies and are associated with coordination. In motor processes it has been suggested that this is not always the case. Our objective was to explore this contradiction. In our study, seven healthy subjects performed four motor tasks (execution and imagery of right hand and foot) under EEG recording. Two cortical source models were defined, model "A" with 16 regions of interest (ROIs) and model "B" with 20 ROIs over the sensorimotor cortex. Functional connectivity was calculated by Directed Transfer Function for alpha and beta rhythm networks. Four graph properties were calculated for each network: characteristic path length (CPL), clustering coefficient (CC), density (D) and small-world-ness (SW). Different network modules and in-degrees of nodes were also calculated and depicted in connectivity maps. Analysis of variance was used to determine statistical significance of observed differences in the network properties between tasks, between rhythms and between ROI models. Consistently on both models, CPL and CC were lower and D was higher in beta rhythm networks. No statistically significant difference was observed for SW between rhythms or for any property between tasks on any model. Comparing the models we observed lower CPL for both rhythms, lower CC in alpha and higher CC in beta when the number of ROIs increased. Also, denser networks with higher SW were correlated with higher number of ROIs. We propose a non-exclusive model where alpha rhythm uses greater wiring costs to engage in local information progression while beta rhythm coordinates the neurophysiological processes in sensorimotor tasks. PMID- 27241946 TI - Efficient entanglement distillation without quantum memory. AB - Entanglement distribution between distant parties is an essential component to most quantum communication protocols. Unfortunately, decoherence effects such as phase noise in optical fibres are known to demolish entanglement. Iterative (multistep) entanglement distillation protocols have long been proposed to overcome decoherence, but their probabilistic nature makes them inefficient since the success probability decays exponentially with the number of steps. Quantum memories have been contemplated to make entanglement distillation practical, but suitable quantum memories are not realised to date. Here, we present the theory for an efficient iterative entanglement distillation protocol without quantum memories and provide a proof-of-principle experimental demonstration. The scheme is applied to phase-diffused two-mode-squeezed states and proven to distil entanglement for up to three iteration steps. The data are indistinguishable from those that an efficient scheme using quantum memories would produce. Since our protocol includes the final measurement it is particularly promising for enhancing continuous-variable quantum key distribution. PMID- 27241948 TI - Impaired Left and Right Ventricular Systolic and Diastolic Function in Response to Exercise in Patients with Diastolic Dysfunction. AB - BACKGROUND: Diastolic dysfunction (DD) is associated with exercise intolerance. To evaluate mechanisms of exercise intolerance in patients with DD, we performed bicycle stress echocardiography. METHOD AND RESULTS: Doppler measurements were performed at baseline, during exercise and recovery in 26 patients (58 +/- 11 years) with DD and normal left ventricular ejection fraction and 6 normal controls (53 +/- 5 years). Compared to controls, patients achieved similar target heart rates but lower METs (5.5 +/- 2 vs. 9.8 +/- 3, P < 0.01) and a higher peak pulmonary artery pressure (PAP) at peak exercise (50 +/- 13 vs. 32 +/- 7 mmHg, P < 0.01) despite similar PAP at rest and similar mean blood pressure at peak exercise (110.4 +/- 18.0 vs. 106.9 +/- 11.4 mmHg, P = NS). In patients versus controls, mitral E/E' was similar at baseline (10 +/- 3 vs. 8 +/- 1.3, P = NS) but higher at recovery (11 +/- 2 vs. 7 +/- 2, P < 0.05), % mitral filling time was shorter at baseline, onset, and peak exercise, whereas % LV and RV ejection time was similar to controls throughout exercise. Compared to controls, lateral mitral annular S' (11.8 +/- 2.5 cm/sec vs. 14.9 +/- 1.9 cm/sec, P < 0.02) and tricuspid annular S' (14.8 +/- 4.1 cm/sec vs. 19.4 +/- 4.0 cm/sec, P < 0.05) were lower at peak exercise in patients. CONCLUSION: Diastolic filling time is reduced at rest and stress while LV ejection time increases normally during exercise in DD. There is a reduced systolic reserve in LV and RV during exercise in DD. These mechanisms contribute to exercise intolerance and elevation of left atrial and PAP in patients with DD. PMID- 27241950 TI - Effects of a combined inversion and plantarflexion surface on knee and hip kinematics during landing. AB - Although landing in a plantarflexion and inversion position is a well-known characteristic of lateral ankle sprains, the associated kinematics of the knee and hip is largely unknown. Therefore, the purpose of this study was to examine the changes in knee and hip kinematics during landings on an altered landing surface of combined plantarflexion and inversion. Participants performed five drop landings from 30 cm onto a trapdoor platform in three different conditions: flat landing surface, 25 degrees inversion, or a combined 25 degrees plantarflexion and 25 degrees inversion. Kinematic data were collected using a seven camera motion capture system. A 2 * 3 (leg * surface) repeated measures ANOVA was used for statistical analysis. The combined surface showed decreased knee and hip flexion range of motion (ROM) and increased knee abduction ROM (p < 0.05). The altered landing surface creates a stiff landing pattern where reductions in sagittal plane motion are transferred to the frontal plane, resulting in increased knee abduction. A stiff landing pattern is frequently related to increased risk of anterior cruciate ligament injury. It may be beneficial for athletes at risk to train for alternate methods of increasing their sagittal plane motion of the knee and hip with active knee or trunk flexion. PMID- 27241949 TI - Lanthanum induced B-to-Z transition in self-assembled Y-shaped branched DNA structure. AB - Controlled conversion of right-handed B-DNA to left-handed Z-DNA is one of the greatest conformational transitions in biology. Recently, the B-Z transition has been explored from nanotechnological points of view and used as the driving machinery of many nanomechanical devices. Using a combination of CD spectroscopy, fluorescence spectroscopy, and PAGE, we demonstrate that low concentration of lanthanum chloride can mediate B-to-Z transition in self-assembled Y-shaped branched DNA (bDNA) structure. The transition is sensitive to the sequence and structure of the bDNA. Thermal melting and competitive dye binding experiments suggest that La(3+) ions are loaded to the major and minor grooves of DNA and stabilize the Z-conformation. Our studies also show that EDTA and EtBr play an active role in reversing the transition from Z-to-B DNA. PMID- 27241951 TI - The Strengths and Difficulties Questionnaire (SDQ) for preschool children-a Swedish validation. AB - BACKGROUND: In Sweden, 80-90% of children aged 1-5 years attend preschool, and that environment is well suited to identify behaviours that may be signs of mental health problems. The Strengths and Difficulties Questionnaire (SDQ) is a well-known short and structured instrument measuring child behaviours that indicate mental health problems well suited for preschool use. AIM: To investigate whether SDQ is a reliable and valid instrument for identifying behavioural problems in children aged 1-3 years and 4-5 years in a Swedish population, as rated by preschool teachers. METHODS: Preschools situated in different sized municipalities in Sweden participated. The preschool teacher rated each individual child. Concurrent validity was tested using the Child Teacher Report Form (C-TRF) and Child Engagement Questionnaire (CEQ). Exploratory factor analysis was conducted for age groups, 1-3 years and 4-5 years. RESULTS: The preschool teachers considered most of the SDQ items relevant and possible to rate. For the children aged 1-3 years, the subscales 'Hyperactivity' (Cronbach alpha = 0.84, split half = 0.73) and 'Conduct' (Cronbach alpha = 0.76, split half = 0.80) were considered to be valid. For the age group 4-5 years, the whole original SDQ scale, 4-factor solution was used and showed reasonable validity (Cronbach alpha = 0.83, split half = 0.87). CONCLUSION: SDQ can be used in a preschool setting by preschool teachers as a valid instrument for identifying externalizing behavioural problems (hyperactivity and conduct problems) in young children. CLINICAL IMPLICATIONS: SDQ could be used to identify preschool children at high-risk for mental health problems later in life. PMID- 27241952 TI - Zika, more reasons for concern. PMID- 27241953 TI - Species composition and habitat characterization of mosquito (Diptera: Culicidae) larvae in semi-urban areas of Dhaka, Bangladesh. AB - Mosquito larvae are purely aquatic and develop in water bodies, the type of which is more or less specific to each species. Therefore, a study was carried out to identify the habitat characters of different mosquito species along with their species composition in semi-urban area of Dhaka in Bangladesh during the month of May and June 2012. A total of 6088 mosquito larvae belonging to 12 species (Aedes aegypti, Aedes albopictus, Anopheles barbirostris, Anopheles peditaeniatus, Anopheles vagus, Culex gelidus, Culex hutchinsoni, Culex quinquefasciatus, Culex tritaeniorhynchus, Mansonia annulifera, Mansonia uniformis, and Toxorhynchites splendens) under 5 genera were collected from 14 different types of habitats. Culex quinquefsciatus was the dominant (21.7/500 ml) species followed by Cx. tritaeniorhynchus (10.53/500 ml). Dissolved oxygen and chlorophyll a were the preeminent predictors for the abundance of all collected mosquito larvae except Ae. aegypti. Water temperature was positively associated with the breeding of An. vagus (r = 0.421, p = <0.001), An. barbirostris (r = 0.489, p = <0.001) and An. peditaeniatus (r = 0.375, p = <0.001). Water depth, distance from nearest house, emergent plant coverage, and alkalinity were found as the basis of larval abundance. Every Culex species and Tx. splendens (r = 0.359, p = 0.001) were found positively associated with chemical oxygen demand, while Mn. annulifera showed negative association (r = -0.115, p = 0.0297). This study also highlighted that various physicochemical factors affect the presence or abundance of mosquito larvae. PMID- 27241954 TI - Characteristics of and factors associated with dengue vector breeding sites in the City of Colombo, Sri Lanka. AB - INTRODUCTION: Dengue has emerged as a major public health problem in Sri Lanka. Vector control at community level is a frequent and widespread strategy for dengue control. The aim of the study was to assess Aedes mosquito breeding sites and the prevention practices of community members in a heavily urbanized part of Colombo. METHODS: A cross-sectional entomological survey was conducted from April to June 2013 in 1469 premises located in a subdistrict of the City of Colombo. Types of breeding sites and, where found, their infestation with larvae or pupae were recorded. Furthermore, a questionnaire was administered to the occupants of these premises to record current practices of dengue vector control. RESULTS: The surveyed premises consisted of 1341 residential premises and 110 non-residential premises (11 schools, 99 work or public sites), 5 open lands, and 13 non specified. In these 1469 premises, 15447 potential breeding sites suitable to host larvae of pupae were found; of these sites18.0% contained water. Among the 2775 potential breeding sites that contained water, 452 (16.3%) were positive for larvae and/or pupae. Schools were associated with the proportionally highest number of breeding sites; 85 out of 133 (63.9%) breeding sites were positive for larvae and/or pupae in schools compared with 338 out of 2288 (14.8%) in residential premises. The odds ratio (OR) for schools and work or public sites for being infested with larvae and/or pupae was 2.77 (95% CI 1.58, 4.86), when compared to residential premises. Occupants of 80.8% of the residential premises, 54.5% of the schools and 67.7% of the work or public sites reported using preventive measures. The main prevention practices were coverage of containers and elimination of mosquito breeding places. Occupants of residential premises were much more likely to practice preventive measures than were those of non residential premises (OR 2.23; 1.49, 3.36). CONCLUSION: Schools and working sites were associated with the highest numbers of breeding sites and lacked preventive measures for vector control. In addition to pursuing vector control measures at residential level, public health strategies should be expanded in schools and work places. PMID- 27241955 TI - Death from liver disease in a cohort of injecting opioid users in a Swedish city in relation to registration for opioid substitution therapy. AB - INTRODUCTION AND AIMS: Injecting opioid users are at elevated risk of death. Although liver disease (especially hepatitis C) is common, its impact on mortality is low in active injectors. Because opioid substitution therapy (OST) reduces the risk of death from directly drug related causes, we hypothesised that the proportion of liver-related deaths would increase in subjects receiving OST. We investigated liver-related mortality in a cohort of injecting opioid users attending a needle exchange program (NEP) in a Swedish city in relation to OST exposure. DESIGN AND METHODS: Participants enrolled in the NEP between 1987 and 2011 with available national identity numbers, and registered use of opioids, were included. Linkage based on national identity numbers was performed with national registers for death, emigration and prescription of OST. Participants were categorised as non-OST recipients until the registered date of first OST prescription, and hence as OST recipients. Hazard ratios were calculated by Cox regression for overall and liver-related mortality in relation to OST, with OST as a time-dependent variable. RESULTS: Among 4494 NEP participants, 1488 opioid users were identified; 711/1488 had been prescribed OST. During a follow-up period of 15 546 person-years 368 deaths occurred. Sixteen deaths were caused by liver disease; 10 of these occurred in OST recipients. The risk of liver-related death was significantly increased in OST receiving participants (hazard ratio 3.08, 95% confidence interval [1.09, 8.68], P = 0.03). CONCLUSIONS: Liver related mortality among opioid users was significantly elevated in OST recipients, showing the long-term importance of chronic liver disease in this population. [Jerkeman A, Hakansson A, Rylance R, Wagner P, Alanko Blome M, Bjorkman P. Death from liver disease in a cohort of injecting opioid users in a Swedish city in relation to registration for opioid substitution therapy. Drug Alcohol Rev 2017;36:424-431]. PMID- 27241956 TI - Identifying structures of continuously-varying weighted networks. AB - Identifying network structures from dynamical observations is a fundamental problem currently pervading scientific research on complex systems, as understanding and modeling the structure of a complex network will lead to greater knowledge of its evolutionary mechanisms and to a better understanding of its functional behaviors. Usually, one needs to identify a network's structure through a limited number of observations. Particularly, couplings of many real world networks are sparse and continuously varying with time. In this study, a new framework is developed via optimization for identifying structures of continuously-varying weighted networks formed by sparsely-connected dynamical systems. Furthermore, a regularization technique is employed to increase the numerical stability of the parameter estimation algorithm. Three numerical examples are provided to illustrate the feasibility and effectiveness of the proposed identification method. In comparison with other existing techniques, the main advantages of our method include its ability to identify structures of continuously-varying weighted networks in addition to static ones, as well as its requirement of a relatively small number of observations. The proposed method has a potential applicability to a variety of evolving complex dynamical networks. PMID- 27241957 TI - OFF-ON-OFF Dual Emission at Visible and UV Wavelengths from Carbazole Functionalized beta-Diketonate Europium(III) Complex. AB - This work demonstrates dual emission "OFF-ON-OFF" switching at visible and UV wavelengths of a carbazole functionalized beta-diketone (LH) by a simple change of a europium(III) ion (Eu(3+)) concentration in the submicromolar concentration range. In the presence of 0.25 equiv of Eu(3+) (5 MUM), LH forms a luminescent 4:1 complex ([Eu(3+)(L(-))4](-)) exhibiting dual emission at 357 and 613 nm resulting from the local excitation of the carbazole ring and ligand-sensitized luminescence from the Eu(3+)-beta-diketonate unit, respectively. The 4:1 complex begins to convert into a 2:1 complex ([Eu(3+)(L(-))2](+)) via a 3:1 complex [Eu(3+)(L(-))3] above a molar ratio ([Eu(3+)]/[LH]) of 0.25, which provides the opportunity for binding of solvent methanol molecules to the vacant site of the Eu(3+) ion in the complex ([Eu(3+)(L(-))2(MeOH)n](+)). The OH oscillators of coordinated methanol molecules facilitate the nonradiative pathway of the Eu(3+) emission; hence the emission at 613 nm almost disappears above the 0.50 equivalent of Eu(3+) (11 MUM), while the UV emission at 357 nm remains mostly constant over the whole concentration range. PMID- 27241958 TI - Ethnicity as an independent predictive factor for the results of computed tomography pulmonary angiography and ultrasonography of the lower limbs. AB - BACKGROUND: Asians, Pacific Islanders and Maori have significantly lower rates of venous thromboembolism (VTE) compared to Europeans, but its clinic implication regarding diagnosis and prevention is unclear. AIMS: To investigate if ethnicity affects the yield of computed tomography pulmonary angiography (CTPA) and ultrasonography of the lower limbs. METHODS: Data previously collected for 523 patients from another study were used to analyse the effect of ethnicity on the results of CTPA; 1587 consecutive ultrasonography of lower limbs was retrospectively analysed according to ethnicity. The Wells score was retrospectively calculated to determine the pretest probability of VTE. RESULTS: The positive rates of CTPA were 23.3% for European patients and 9.3% for non European patients. The rate ratio was 2.50 (confidence interval [CI] 1.27-4.95). European patients were 2.5 times more likely to have a positive scan result than non-Europeans, given same pretest probability. There was a larger difference among patients with low and moderate pretest probability with a rate ratio of 4.27 (CI 1.62-11.3). The positive rates of ultrasound scans (USS) among European patients were 16.6 and 9.0% for non-European patients. Rate ratio was 1.85 (CI 1.27-4.95). The difference was also more significant amongst patients with low and moderate pretest probability. The rate ratio was 2.31 (CI 1.38-3.86) for European patients compared to non-European patients. CONCLUSION: Given the same pretest probability according to the Wells score, European patients had significantly higher positive rates of CTPA and ultrasonography of the lower limbs than non-European patients. Further prospective studies are required to confirm our findings and establish an appropriate pretest assessment tool for non European patients. PMID- 27241959 TI - Compact film fabrication of porous coordination polymer Co3[Co(CN)6]2 and its reversible vapochromic behavior. AB - Films of Prussian blue analogue (PBA) Co3[Co(CN)6]2 were fabricated on porous alpha-alumina, ITO glass, silicon wafer and non-woven fabric substrates via a facile self-assembly method, and were characterized using infrared spectroscopy, X-ray powder diffraction and scanning electron microscope techniques. The films composed of truncated cube-shaped PBA particles are highly oriented with a preferred (100) plane on the glossy and smooth surfaces of ITO glass and silicon wafer, but crystallographically isotropic on the rough surface of porous alpha alumina and non-woven fabric substrates. Compact films were achieved on porous alpha-alumina and surface-functionalized ITO glass. Reversible solvatochromism/vapochromism was discovered and investigated for the powdered and thin-film PBA samples. Such peculiar solvatochromism/vapochromism is related to the process of the adsorbed solvent molecules replacing the coordinated water molecules in octahedral Co(2+)-(N)4(H2O)2. The change of the Co(2+) ion's coordination atmosphere leads to the variation of crystal field strength, as a result, the d-d transitions within the Co(2+) ions are altered to give rise to a color change. PMID- 27241960 TI - Miro GTPase controls mitochondrial behavior affecting stress tolerance and virulence of a fungal insect pathogen. AB - Miro homologues are small mitochondrial Rho GTPases belonging to the Ras superfamily across organisms and are generally unexplored in filamentous fungi. Here we identified a Miro orthologue (bMiro) in Beauveria bassiana, a filamentous fungal insect pathogen as a classic biological control agent of insect pests. This orthologue was proven to anchor on mitochondrial outer membrane in a manner depending completely upon a short C-terminal transmembrane domain. As a result of bmiro deletion, mitochondria in hyphal cells were largely aggregated, and their mass and mobility were reduced, accompanied with a remarkable decrease in ATP content but little change in mitochondrial morphology. The deletion mutant became 42%, 37%, 19% and 10% more tolerant to Ca(2+), Mn(2+), Zn(2+) and Mg(2+) than wild-type, respectively, during cultivation in a minimal medium under normal conditions. The deletion mutant also showed mild defects in conidial germination, vegetative growth, thermotolerance, UV-B resistance and virulence despite null response to oxidative and osmotic stresses. All these phenotypic changes were restored by targeted gene complementation. Our results indicate that bMiro can control mitochondrial distribution and movement required for the transport of ATP form energy and metal ions and contributes significantly to the fungal potential against insect pests through the control. PMID- 27241961 TI - Case of catatonia associated with paliperidone. PMID- 27241962 TI - Update of Thyroid Developmental Genes. AB - Thyroid dysgenesis (TD) is the most common cause of congenital hypothyroidism in iodine-sufficient regions and includes a spectrum of developmental anomalies. The genetic components of TD are complex. Although a sporadic disease, advances in developmental biology have revealed monogenetic forms of TD. Inheritance is not based on a simple Mendelian pattern and additional genetic elements might contribute to the phenotypic spectrum. This article summarizes the key steps of normal thyroid development and provides an update on responsible genes and underlying mechanisms of TD. Up-to-date technologies in genetics and biology will allow us to advance in our knowledge of TD. PMID- 27241963 TI - Thyroid Imaging in Infants. AB - Congenital hypothyroidism is the most common preventable cause of mental retardation. It is important to know the cause of each patient's thyroid dysfunction to foresee the course of therapy and outcomes. Imaging methods, such as ultrasound and thyroid scan, help determine the anatomy and function of the thyroid gland. Although thyroid scan is considered superior in detecting ectopic thyroid tissue, ultrasound is able to detect the presence of thyroid tissue not otherwise visualized in 15% of patients. PMID- 27241964 TI - Prenatal Diagnosis of Congenital Adrenal Hyperplasia. AB - Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency is a monogenic disorder of adrenal steroidogenesis. To prevent genital ambiguity, in girls, prenatal dexamethasone treatment is administered early in the first trimester. Prenatal genetic diagnosis of CAH and fetal sex determination identify affected female fetuses at risk for genital virilization. Advancements in prenatal diagnosis are owing to improved understanding of the genetic basis of CAH and improved technology. Cloning of the CYP21A2 gene ushered in molecular genetic analysis as the current standard of care. Noninvasive prenatal diagnosis allows for targeted treatment and avoids unnecessary treatment of males and unaffected females. PMID- 27241965 TI - Growth and Metabolism in Children Born Small for Gestational Age. AB - Most children born SGA show spontaneous catch-up growth to a normal weight and height above -2 SDS; however, 10% remain short. GH treatment improves adult height and has positive effects on body composition, blood pressure and serum lipids. At 6.5 years after stopping GH treatment, body composition, blood pressure, and lipid levels are similar to untreated short SGA adults indicating that GH-induced catch-up in height has no unfavorable effects on metabolic health. GH-induced reduction in insulin sensitivity is reversible after stopping GH. It remains to be elucidated how metabolic health develops when these subjects become older. PMID- 27241966 TI - Endocrine Dysfunction in X-Linked Adrenoleukodystrophy. AB - X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene and leads to an elevation of very-long-chain fatty acids (VLCFA). The accumulation of the VLCFA and the associated oxidative stress can present with a spectrum of significant neurologic disease, adrenal insufficiency, and testicular dysfunction in males with ABCD1 gene mutations. Much of the published literature for X-ALD has focused on the associated devastating progressive neurologic conditions. The purpose of this review is to summarize the concerns for endocrine dysfunction associated with X-ALD and provide guidance for monitoring and management of adrenal insufficiency. PMID- 27241967 TI - Diagnosis and Clinical Genetics of Cushing Syndrome in Pediatrics. AB - Endogenous Cushing syndrome (CS) in pediatrics is rare; it may be caused by tumors that produce corticotropin in the pituitary gland or elsewhere, tumors that produce corticotropin-releasing hormone anywhere, and adrenocortical masses that produce cortisol. Adrenocortical cancer is a rare cause of CS in children but should be excluded first. CS in children is often caused by germline or somatic mutations with implications for patient prognosis and for their families. CS should be recognized early in children; otherwise, it can lead to significant morbidity and mortality. Patients with suspected CS should be referred to specialized clinical centers for workup. PMID- 27241968 TI - Polycystic Ovary Syndrome in Adolescents. AB - Polycystic ovary syndrome (PCOS) is a familial heterogeneous disorder affecting 6% to 10% of reproductive-age women. The use of criteria developed for adult women is problematic for the adolescent girl because the clinical features associated with PCOS are normal pubertal events. The recent consensus statement on PCOS in adolescents stated that hyperandrogenism and oligomenorrhea need to persist for at least 2 years to consider the diagnosis of PCOS. Although insulin resistance, hyperinsulinism, and obesity are often associated with PCOS, these features are not considered valid diagnostic criteria. Recent genomewide association studies implicate genetic loci involved in the hypothalamic-pituitary ovarian axis. PMID- 27241969 TI - Genetic Techniques in the Evaluation of Short Stature. AB - Normal growth is a complex dynamic process dependent on the coordination of multiple factors including genetics, nutrition and hormones that are all working in balance. This chapter will review selected features of commonly utilized genetic techniques such as chromosomal analysis, microarray analysis, targeted gene screening and whole exome sequencing that are being used to identify genes influencing growth. As genetic technologies continue to improve and become more accessible many of these techniques will help to provide a better understanding of mechanisms underlying abnormal growth and will eventually lead to novel management approaches for abnormal growth. PMID- 27241970 TI - Thyroid Cancer in Pediatrics. AB - Well differentiated thyroid cancer (DTC) in children is characterized by a high rate of response to treatment and low disease-specific mortality. Treatment of children with DTC has evolved toward a greater reliance on evaluation and monitoring with serial serum thyroglobulin measurements and ultrasound examinations. Radioiodine therapy is recommended for thyroid remnant ablation in high-risk patients, treatment of demonstrated radioiodine-avid local-regional disease not amenable to surgical resection, or distant radioiodine-avid metastatic disease. Sufficient time should be given for benefits of radioiodine therapy to be realized, with follow-up monitoring. Re-treatment with radioiodine can be deferred until progression of significant disease manifests. PMID- 27241971 TI - Cardiovascular Risk in Growth Hormone Deficiency: Beneficial Effects of Growth Hormone Replacement Therapy. AB - Growth hormone deficiency (GHD) in adulthood is associated with an increased risk of developing adverse cardiovascular events and with reduced life expectancy. Cardiovascular and metabolic abnormalities have so far been evaluated only in a small number of children with GHD and adolescents. In this article we review these abnormalities and their underlying mechanisms and discuss the beneficial effect of growth hormone treatment in subjects with GHD. PMID- 27241972 TI - Bariatric Surgery in Youth. AB - Bariatric surgery provides a clinically effective and cost-effective means of achieving sustained weight reduction and management of associated comorbidities and has been met with increasing enthusiasm for application in obese youth. Following trends seen among obese adults, carefully selected obese youth are now undergoing bariatric surgical procedures with excellent short-term and intermediate-term outcomes. Although long-term data are not yet available, the results thus far hold great promise in the management of this population. PMID- 27241974 TI - Advances in Imaging of the Pediatric Pituitary Gland. AB - High-resolution MRI of the pediatric sella can help identity or confirm clinical abnormalities, assess pituitary gland size and structure, and reveal acquired lesions. This article reviews contemporary techniques for imaging of the sella and associated structures in this population. Strengths and weaknesses of conventional imaging are discussed, as are techniques that can enhance yield. Some new and emerging technologies are discussed, including MR elastography, perfusion imaging, spectroscopy, and diffusion-weighted and diffusion-tensor imaging. It is expected that this overview will provide insight as to where pediatric sella imaging is currently and where it may head in the future. PMID- 27241975 TI - Racial and Ethnic Disparities in the Incidence, Treatment, and Outcomes of Youth with Type 1 Diabetes. AB - Type 1 diabetes mellitus (T1DM) is the third most common chronic childhood disease in the United States. As more Hispanic and non-Hispanic black children are diagnosed with T1DM, racial and ethnic disparities in the treatment and outcomes of T1DM are increasing. This article reviews the increasing incidence and prevalence of T1DM in non-Hispanic white, non-Hispanic black, and Hispanic children. In addition, the racial and ethnic disparities in diabetes treatment, such as blood glucose monitoring, insulin therapy, and continuous glucose monitoring, and outcomes, including glycemic control, diabetic ketoacidosis, severe hypoglycemia, retinopathy, nephropathy, neuropathy, and diabetes-related mortality, are highlighted. PMID- 27241973 TI - Update on Bone Health in Pediatric Chronic Disease. AB - Children and adolescents with chronic disease are predisposed to impaired bone health. Pediatric illness, including type 1 diabetes mellitus, celiac disease, and cystic fibrosis, have significant risk of low bone mineralization and fracture due to underlying inflammation, malabsorption, lack of physical activity, and delayed puberty. Dual-energy x-ray absorptiometry is the primary imaging method to assess bone health in this population. The purpose of this review is to update readers about the assessment and management of bone health in children with common pediatric chronic illnesses and review recent advances in the prevention and treatment of impaired bone health. PMID- 27241976 TI - Gender Incongruity in Children With and Without Disorders of Sexual Differentiation. AB - Access to the Internet and recent major media coverage has contributed to an increased societal awareness of the variations of gender identity. There are two sets of clinical guidelines primarily used by practitioners who care for transgender adolescents and adults. Although these guidelines have been tremendously helpful for the management of transgender adolescents, those working in the field recognize the limitations of firm recommendations with a population that is so heterogeneous. This article will summarize current recommendations for the management of children and adolescents with gender incongruence and suggest ways in which we might vary from the current guidelines. PMID- 27241977 TI - Pediatric Endocrinology. PMID- 27241978 TI - Focus on Pediatric Endocrinology: Time to Revisit Some Established Challenges and Explore New Ones. PMID- 27241979 TI - One phase or two, and Buridan's paradox. PMID- 27241980 TI - Concerns about combining samples. PMID- 27241981 TI - Authors' response. PMID- 27241982 TI - Rapid palatal expansion, with and without alternating constriction. PMID- 27241983 TI - Authors' response. PMID- 27241984 TI - Authors' response. PMID- 27241985 TI - Match program. PMID- 27241986 TI - Genetic causes vs guidance theory for palatal displacement of canines. PMID- 27241987 TI - Reconsidering "The inappropriateness of conventional cephalometrics". AB - Of all the articles on cephalometrics this journal has published over the last half-century, the one most cited across the scientific literature is the 1979 lecture "The inappropriateness of conventional cephalometrics" by Robert Moyers and me. But the durable salience of this article is perplexing, as its critique was misdirected (it should have been aimed at the craniometrics of the early twentieth century, not merely the roentgenographic extension used in the orthodontic clinic) and its proposed remedies have all failed to establish themselves as methods of any broad utility. When problems highlighted by Moyers and me have been resolved at all, the innovations that resolved them owe to tools very different from those suggested in our article and imported from fields quite a bit farther from biometrics than we expected back in 1979. One of these tools was the creation de novo of a new abstract mathematical construction, statistical shape space, in the 1980s and 1990s; another was a flexible and intuitive new graphic, the thin-plate spline, for meaningfully and suggestively visualizing a wide variety of biological findings in these spaces. On the other hand, many of the complaints Moyers and I enunciated back in 1979, especially those stemming from the disarticulation of morphometrics from the explanatory styles and purposes of clinical medicine, remain unanswered even today. The present essay, a retrospective historical meditation, reviews the context of the 1979 publication, its major themes, and its relevance today. This essay is dedicated to the memory of Robert E. Moyers on the 100th anniversary of the American Journal of Orthodontics and Dentofacial Orthopedics. PMID- 27241988 TI - Evolution of imaging and management systems in orthodontics. AB - Orthodontists have long been among the most progressive of the dental specialists, quick to embrace new technologies for enhancing clinical efficiencies and practice workflow. Orthodontic software innovations, whether for imaging and clinical applications or for managing the business side of a practice, have led the consistent need for more powerful computing requirements for more than 4 decades. This article recounts the history of how computers and orthodontic software have been used in America from their nascence to today and provides an outlook for the future. PMID- 27241990 TI - Do you believe in magic? PMID- 27241991 TI - Comparative assessment of fluoride varnish and fluoride film for remineralization of postorthodontic white spot lesions in adolescents and adults over a 6-month period: A single-center, randomized controlled clinical trial. AB - INTRODUCTION: The objective of this 3-arm parallel randomized trial was to evaluate the effects of a fluoride varnish and a fluoride film on the remineralization of white spot lesions around orthodontic brackets after orthodontic treatment. METHODS: Patients who had recently completed orthodontic treatment were randomly assigned to the varnish, film, and control groups. Eligibility criteria included age of 12 to 25 years, good general health, and at least 1 maxillary anterior tooth with a white spot lesion. The primary outcome was the decrease in the lesion volume of each patient after 6 months of treatment; fluorescence loss and area were the secondary outcome measures. Randomization was accomplished according to a computer-generated randomization schedule, and allocation concealment was achieved with nontransparent concealed envelopes. Blinding was applicable for the treatments only. The test groups received fluoride varnish or film treatment once a month for 6 months, and the control group received a placebo treatment. All patients received oral hygiene education and were required to use fluoride toothpaste daily. Quantitative light induced fluorescence images were taken at baseline and at the 3-month and 6-month follow-ups. A mixed-effects linear model was used to analyze quantitative light induced fluorescence parameters with confounders integrated into the model. RESULT: Two hundred forty patients (mean age, 16.9 years; range, 12-25 years) with 597 teeth with a white spot lesion were randomized 1:1:1 to the varnish, film, and control groups. Baseline demographics were similar between groups, and 29 patients were lost to follow-up. The primary analysis was carried out on a per protocol basis involving 72 patients in the control group, 69 patients in the varnish group, and 70 patients in the film group who completed the study. The product of fluorescence loss and lesion area values were statistically associated with time (estimate, -4.58; 95% confidence interval [CI], -5.84 to -3.31; P <0.0001), and a significant decrease in the product of fluorescence loss and lesion area was observed in all groups after 6 months with each treatment. The interaction between group and time in the statistical analysis indicated that the product of fluorescence loss and lesion area values of the 3 groups followed different trends over time. Further pair-wise comparisons showed that the decreases in the 2 test groups were significantly greater than those in the control group (varnish vs control: estimate, -11.83; 95% CI, -15.39 to -8.26; P <0.0001; film vs control, estimate: -7.72; 95% CI, -11.34 to 4.10; P <0.0001) in the analysis for 6 months. In addition, the decrease in the varnish group was significantly greater than that in the film group (estimate, 4.11; 95% CI, 0.48 to 7.73; P = 0.0266) in the analysis for 6 months. No serious adverse effects associated with the use of the tested varnish, film, or placebo occurred. CONCLUSIONS: After removal of the orthodontic brackets, some natural remineralization of white spot lesions occurred, and daily use of fluoride toothpaste may be helpful for this process. However, not all patients experienced this remineralization, and treatment with fluoride varnish or fluoride film induced greater remineralization of white spot lesions. In addition, our results suggest that fluoride varnish may be slightly more effective than fluoride film. However, further similar clinical trials with more patients are needed to definitively determine which fluoride treatment is most effective. REGISTRATION: This trial was registered on the Chinese Clinical Trial Register, number ChiCTR TRC-13003764. PROTOCOL: The details of the trial protocol are posted online at: http://apps.who.int/trialsearch/Trial.aspx?TrialID=ChiCTR-TRC-13003764. PMID- 27241992 TI - Adverse effects of lingual and buccal orthodontic techniques: A systematic review and meta-analysis. AB - INTRODUCTION: The aim of this systematic review was to assess the prevalence of adverse effects associated with lingual and buccal fixed orthodontic techniques. METHODS: Two authors searched the PubMed, EMBASE, Cochrane Library, and LILACS databases up to October 2014. Agreement between the authors was quantified by the Cohen kappa statistic. The following variables were analyzed: pain, caries, eating and speech difficulties, and oral hygiene. The Newcastle-Ottawa scale was used to assess risk of bias in nonrandomized studies, and the Cochrane Collaboration's tool for assessing risk of bias was used for randomized controlled trials. RESULTS: Eight articles were included in this systematic review. Meta-analysis showed a statistically greater risk of pain of the tongue (odds ratio [OR], 28.32; 95% confidence interval [95% CI], 8.60-93.28; P <0.001), cheeks (OR, 0.087; 95% CI, 0.036-0.213; P <0.0010), and lips (OR, 0.13; 95% CI, 0.04-0.39; P <0.001), as well as for the variables of speech difficulties (OR, 9.39; 95% CI, 3.78-23.33; P <0.001) and oral hygiene (OR, 3.49; 95% CI, 1.02 11.95; P = 0.047) with lingual orthodontics. However, no statistical difference was found with respect to eating difficulties (OR, 3.74; 95% CI, 0.86-16.28; P = 0.079) and caries (OR, 1.15; 95% CI, 0.17-7.69; P = 0.814 [Streptococcus mutans] and OR, 0.67; 95% CI, 0.20-2.23; P = 0.515 [Lactobacillus]). CONCLUSIONS: This systematic review suggests that patients wearing lingual appliances have more pain, speech difficulties, and problems in maintaining adequate oral hygiene, although no differences for eating and caries risk were identified. Further prospective studies involving larger sample sizes and longer follow-up periods are needed to confirm these results. PMID- 27241993 TI - Evaluation of maxillary arch dimensional and inclination changes with self ligating and conventional brackets using broad archwires. AB - INTRODUCTION: Our objective was to comparatively evaluate different bracket types (conventional, active self-ligating, and passive self-ligating) combined with broad archwires in terms of maxillary dental arch widths and molar inclinations. METHODS: Forty-six patients aged 13 to 17 years with moderate maxillary and mandibular crowding and a Class I malocclusion were included in this prospective clinical trial. The primary outcome measures were changes in maxillary arch width dimensions and molar inclinations. The secondary outcome measures were changes in maxillary and mandibular incisor inclinations. Group I included 15 patients (mean age, 14.4 +/- 1.5 years) treated with 0.022-in active self-ligating brackets. Group II included 15 patients (mean age, 14.4 +/- 1.6 years) treated with 0.022 in Roth prescription conventional brackets. Group III was a retrospective group of 16 patients (mean age, 14.8 +/- 1.0 years) previously treated with 0.022-in passive self-ligating brackets. Each participant underwent alignment with the standard Damon archwire sequence. Whereas the differences among groups were evaluated by 1-way analysis of variance or Kruskal-Wallis tests, the paired samples t test was applied for intragroup comparisons. For all possible multiple comparisons, the Bonferroni correction was applied to control for type I error. RESULTS: The maxillary intercanine, interpremolar, and intermolar widths were significantly greater after treatment in each bracket group. However, when the levels of expansion achieved among the 3 groups were compared, no significant difference was found. Although all posteroanterior cephalometric variables showed significant changes during treatment in all groups, these changes were not significant among the groups. A statistically significant labial proclination of the teeth was seen in each group. CONCLUSIONS: No differences in maxillary arch dimensional changes or molar and incisor inclination changes were found in conventional and active and passive self-ligating brackets used with broad archwires. PMID- 27241994 TI - Nonlinear dependency of tooth movement on force system directions. AB - INTRODUCTION: Moment-to-force ratios (M:F) define the type of tooth movement. Typically, the relationship between M:F and tooth movement has been analyzed in a single plane. Here, to improve the 3-dimensional tooth movement theory, we tested the hypothesis that the mathematical relationships between M:F and tooth movement are distinct, depending on force system directions. METHODS: A finite element model of a maxillary first premolar, scaled to average tooth dimensions, was constructed based on a cone-beam computed tomography scan. We conducted finite element analyses of the M:F and tooth movement relationships, represented by the projected axis of rotation in each plane, for 510 different loads. RESULTS: We confirmed that a hyperbolic equation relates the distance and M:F; however, the constant of proportionality ("k") varied nonlinearly with the force direction. With a force applied parallel to the tooth's long axis, "k" was 12 times higher than with a force parallel to the mesiodistal direction and 7 times higher than with a force parallel to the buccolingual direction. CONCLUSIONS: The M:F influence on tooth movement depends on load directions. It is an incomplete parameter to describe the quality of an orthodontic load system if it is not associated with force and moment directions. PMID- 27241995 TI - Anterior open-bite treatment with bonded vs conventional lingual spurs: A comparative study. AB - INTRODUCTION: The purpose of this study was to compare the isolated effects of bonded and conventional spurs on the craniofacial and dentoalveolar complexes of patients in the mixed dentition with anterior open bite. METHODS: The sample included 68 subjects with anterior open bite and Class I malocclusion. Group 1 comprised 20 patients treated with bonded lingual spurs with a mean initial age of 9.31 years (SD, 1.17). Group 2 consisted of 21 patients treated with conventional lingual spurs with a mean initial age of 9.22 years (SD, 1.62). The control group (group 3) consisted of 27 untreated subjects. One-way analysis of variance tests followed by Tukey tests were used for intergroup cephalometric comparisons. After 1 month of treatment, patient acceptance of the spurs was evaluated with a questionnaire. RESULTS: There were significantly greater overbite increases in the experimental groups than in the control group. The group with bonded lingual spurs showed significantly better acceptance than did the group with conventional lingual spurs during chewing and eating. CONCLUSIONS: The 2 appliances resulted in similar overbite increases during early open-bite treatment. After a week or less of treatment, 92.5% of the children had adjusted to the spurs. PMID- 27241996 TI - Long-term stability of rapid palatal expansion in the mixed dentition vs the permanent dentition. AB - INTRODUCTION: Palatal expansion has been a popular and proven technique for transverse discrepancies used in orthodontics for decades. The short-term effectiveness of the technique is understood, yet questions remain regarding the long-term stability, with much debate surrounding the optimum treatment timing to initiate expansion for the most beneficial and stable results, especially with regard to mixed dentition treatment. The purpose of this study was to determine the long-term stability of palatal expansion performed in the mixed dentition vs the permanent dentition. METHODS: Fifty-four subjects were grouped as follows: 24 in the mixed dentition and 30 in the permanent dentition at the start of treatment. All patients had been treated with the Haas type of palatal expansion appliance followed by nonextraction fixed edgewise mechanics. Digitized dental casts were evaluated at 3 times: before treatment (T1), after treatment (T2), and at the long-term retention (T3). Intermolar widths were computed by subtracting measurements between time points, and comparisons between the groups were made to determine expansion and stability differences. RESULTS: Significant intermolar width increases were observed from T1 to T2 with significant relapses from T2 to T3, and an overall net gain remained at T3 in each group. No significant differences were found for relapse between the mixed and permanent dentitions. CONCLUSIONS: There are no differences for the long-term intermolar width stability in patients treated with palatal expansion in the mixed dentition vs the permanent dentition. PMID- 27241997 TI - Esthetic evaluation of lip position in silhouette with respect to profile divergence. AB - INTRODUCTION: The aim of this study was to determine the preferred lip position in silhouette profiles with different amounts of divergence. METHODS: A normal profile was constructed based on normal values and was altered using software (Photoshop CS, version 8.0; Adobe Systems, San Jose, Calif) to produce a series of 15 profiles in 3 sets (straight, anterior, and posterior divergent). Each set consisted of 5 photographs with different lip positions from -4 mm to +4 mm in 2 mm increments. We asked 240 people in 5 panels (79 senior dental students, 26 orthodontists, 27 maxillofacial surgeons, 27 prosthodontists, and 81 laypeople) to rate the profiles. Mann-Whitney and Kruskal-Wallis tests, and intraclass correlation coefficients were used to analyze the data. RESULTS: In the anterior and posterior divergent profiles, most groups tended to prefer the original lip positions for both the male and female profiles. In the straight divergent profile, the results were scattered and inconsistent in the different groups. In the posterior divergent profile, the orthodontists and the surgeons selected the 4-mm lip retrusion as the least attractive, and other groups selected the 4-mm lip protrusion as the least attractive. In the anterior and straight divergent profiles, all groups were unanimous in the selection of the 4-mm lip protrusion as the least attractive images. Significant differences were found between the raters in the rankings of some images. No significant difference was found between the male and female raters in the rankings of the profile images. CONCLUSIONS: It is important to establish a normal lip position, especially for a patient with an anterior or a posterior divergent profile. Posterior divergent patients should be treated cautiously so that excessive lip retrusion does not result. PMID- 27241998 TI - Herbst appliance anchored to miniscrews with 2 types of ligation: Effectiveness in skeletal Class II treatment. AB - INTRODUCTION: The aim of this study was to evaluate the effectiveness of the treatment of skeletal Class II malocclusions with an acrylic splint Herbst appliance anchored to miniscrews with 2 types of ligation. METHODS: Sixty patients (mean age, 11.6 years; SD, 1.9) with a bilateral Angle Class II Division 1 malocclusion were retrospectively selected and divided into 3 homogeneous and balanced groups on the basis of the Herbst anchorage used: without anchorage, miniscrews with elastic chains, and miniscrews with metallic ligatures. A cephalometric sagittal occlusion analysis merged with mandibular incisor proclination and skeletal divergence was carried out before and after treatment. To compare the absolute variations within and among the groups, we performed the 1-sample t test for repeated measures and 1-way analysis of variance, respectively. RESULTS: Overjet was reduced similarly in all groups (P <0.05). The mandibular bone base length increased in the group with elastic chains only (P = 0.001). The change in the distance between Point A and pogonion showed the most reduction in the group with elastic chains (P <0.05). Incisive flaring was more pronounced in the group with no anchorage than in the group with elastic chains (P <0.001) and the group with metallic ligatures (P = 0.003). CONCLUSIONS: Anchorage to miniscrews with elastic chains increases the orthopedic effect of the acrylic splint Herbst appliance. It has been confirmed that skeletal anchorage reduces incisor flaring. PMID- 27241999 TI - Effect of minocycline on induced glial activation by experimental tooth movement. AB - INTRODUCTION: Orthodontic tooth movement causes pain to a patient. Glial cells are nonneuronal cells in the central nervous system and are implicated in various types of pain. In this study, we assessed glial activation responses after experimental tooth movement using immunocytochemical detection of anti-CD11b (OX42) and glial fibrillary acidic protein immunoreactivity to illustrate the microglial and astrocytes response, respectively. In addition, the effect of minocycline in reducing pain during tooth movement was also investigated. METHODS: Fifty-five Sprague Dawley rats with and without administration of minocycline after 1, 3, 5, 7, and 14 days (n = 5, for each) of tooth movement were used. Immunohistochemistry for microglia (OX42) and astrocyte (glial fibrillary acidic protein) were performed at the medullary dorsal horn (trigeminal subnucleus caudalis). Three-dimensional quantitative analysis was performed with a confocal fluorescence microscope and a software program. RESULTS: There was a significant increase in the OX42 and glial fibrillary acidic protein immunoreactivity in response to tooth movement in the medullary dorsal horn. Furthermore, systematic administration of minocycline, a selective inhibitor of microglial activation, significantly attenuated the nociceptive c Fos expression in the medullary dorsal horn that was induced by experimental tooth movement. CONCLUSIONS: These data indicate the possible importance of microglial activation in the development of orthodontic pain. This is also the first report on the systematic application of minocycline. PMID- 27242000 TI - Nonsurgical treatment of an adult with an open bite and large lower anterior facial height with edgewise appliances and temporary anchorage devices. AB - A woman was referred to the orthodontic clinic for treatment. She was diagnosed with a skeletal Class II malocclusion, a steep mandibular plane, and an anterior open bite. Conventional orthodontic treatment was considered to correct the maxillary protrusion and anterior open bite, but the patient also requested improvement of her facial esthetics. We therefore decided that nonsurgical treatment consisting of 4 premolar extractions combined with temporary anchorage devices was indicated. Satisfactory improvement of the overjet and overbite, and proper functional occlusion were obtained, resulting in a Class I molar relationship. Active treatment was completed in 2 years 10 months, and the result remained stable at 2 years 6 months after debonding. PMID- 27242001 TI - Orthodontic treatment of a patient with severe crowding and unilateral fracture of the mandibular condyle. AB - A 15-year-old girl who had a unilateral condylar fracture with severe crowding in both arches was treated with 4 premolar extractions followed by orthodontic therapy with a temporary skeletal anchorage device in the maxillary arch. The total active treatment time was 21 months. Her occlusion was significantly improved by orthodontic treatment, and the range of condylar movement was also improved. Posttreatment records after 30 months showed excellent results with a good stable occlusion. The remodeling process of the condyle was confirmed with cone-beam computed tomography images. PMID- 27242002 TI - Long-term stability of maxillary group distalization with interradicular miniscrews in a patient with a Class II Division 2 malocclusion. AB - We successfully treated a Class II Division 2 patient with maxillary group distalization using interradicular miniscrews. A woman, aged 28 years 11 months, had a convex profile and an excessive overjet caused by a skeletal Class II jaw base relationship. After leveling and alignment, titanium miniscrews were obliquely implanted between the maxillary second premolar and first molar. To distalize the maxillary dentition, nickel-titanium closing coil springs with a 2 N load were placed between the screws and the hooks on the archwire. After 28 months of active orthodontic treatment, a proper facial profile and an acceptable occlusion were achieved with a 4-mm distalization of the maxillary dentition. The resultant occlusion was stable throughout a 5-year retention period. Interradicular miniscrews were useful to distalize the maxillary dentition for correcting a Class II malocclusion. This new strategy, group distalization with miniscrews, can make the treatment simpler with greater predictability. PMID- 27242003 TI - Eruption of an impacted canine in an adenomatid odontogenic tumor treated with combined orthodontic and surgical therapy. AB - An adenomatoid odontogenic tumor is an uncommon asymptomatic lesion that is often misdiagnosed as a dentigerous cyst. It originates from the odontogenic epithelium. Enucleation and curettage is the usual treatment of choice. Marsupialization may be attempted instead of extraction of the impacted tooth, since it provides an opportunity for tooth eruption. This case report is the first to report on the eruption of an impacted canine in an adenomatoid odontogenic tumor treated with combined orthodontics and marsupialization. The impacted canine erupted uneventfully, with no evidence of recurrence 3 years after the treatment. PMID- 27242005 TI - Ulterior motives. PMID- 27242004 TI - Three-dimensional imaging for indirect-direct bonding. AB - The aim of this article is to introduce a new concept of bracket positioning with special consideration to root axes. Cone-beam computed tomography imaging and computer-aided manufacturing were used to produce stereolithographic trays for indirect-direct bonding. PMID- 27242006 TI - Analysis of variance to linear regression. PMID- 27242007 TI - Application of a loop-mediated isothermal amplification (LAMP) assay for molecular identification of Trueperella pyogenes isolated from various origins. AB - In the present study 28 Trueperella pyogenes strains isolated from various origins could successfully be identified with a newly designed loop-mediated isothermal amplification (LAMP) assay based on gene cpn60 encoding chaperonin. No cross reaction could be observed with control strains representing four species of genus Trueperella and seven species of closely related genus Arcanobacterium. The present cpn60 LAMP assay might allow a reliable and low cost identification of T. pyogenes also in laboratories with less specified equipment. PMID- 27242009 TI - What Biology Can't Do. PMID- 27242008 TI - A dual PCR-based sequencing approach for the identification and discrimination of Echinococcus and Taenia taxa. AB - Reliable and rapid molecular tools for the genetic identification and differentiation of Echinococcus species and/or genotypes are crucial for studying spatial and temporal transmission dynamics. Here, we describe a novel dual PCR targeting regions in the small (rrnS) and large (rrnL) subunits of mitochondrial ribosomal RNA (rRNA) genes, which enables (i) the specific identification of species and genotypes of Echinococcus (rrnS + L-PCR) and/or (ii) the identification of a range of taeniid cestodes, including different species of Echinococcus, Taenia and some others (17 species of diphyllidean helminths). This dual PCR approach was highly sensitive, with an analytical detection limit of 1 pg for genomic DNA of Echinococcus. Using concatenated sequence data derived from the two gene markers (1225 bp), we identified five unique and geographically informative single nucleotide polymorphisms (SNPs) that allowed genotypes (G1 and G3) of Echinococcus granulosus sensu stricto to be distinguished, and 25 SNPs that allowed differentiation within Echinococcus canadensis (G6/7/8/10). In conclusion, we propose that this dual PCR-based sequencing approach can be used for molecular epidemiological studies of Echinococcus and other taeniid cestodes. PMID- 27242010 TI - Oral care in a neonatal intensive care unit. AB - OBJECTIVE: Compare the oral colonization profile of premature infants admitted at NICU before and after doing oral care routine with sterile water versus no intervention. METHODS: It was a randomized clinical trial composed of 37 premature infants admitted at the Neonatal Intensive Care Unit (NICU) with a birth weight (BW) <1500 g. They were distributed in two groups: the study group (SG) with 15 patients who received an oral hygiene with sterile water; and a control group (CG) (no intervention) formed by 22 patients. Primary outcome was oral colonization profile before and after doing oral care. RESULT: In the study group, the number of patients colonized by the Gram-positive bacteria at the beginning of the study was 53% versus 40% at the end (p=0.10). For Gram negative, 40% at the study's beginning versus 60% at the end (p=0.18). In the control group, the number of colonized patients for the Gram-positive bacteria at the onset of the study was 54.5% versus 32% patients at the end (p=0.24). For Gram negative, 32% patients at the start of the study versus 77% at the end (p = 0.003). CONCLUSION: There is a significant increase of the Gram-negative flora in those patients without oral care. PMID- 27242011 TI - Contributors to the emerging investigators issue. PMID- 27242012 TI - Community Structure of a Mental Health Internet Support Group: Modularity in User Thread Participation. AB - BACKGROUND: Little is known about the community structure of mental health Internet support groups, quantitatively. A greater understanding of the factors, which lead to user interaction, is needed to explain the design information of these services and future research concerning their utility. OBJECTIVE: A study was conducted to determine the characteristics of users associated with the subgroup community structure of an Internet support group for mental health issues. METHODS: A social network analysis of the Internet support group BlueBoard (blueboard.anu.edu.au) was performed to determine the modularity of the community using the Louvain method. Demographic characteristics age, gender, residential location, type of user (consumer, carer, or other), registration date, and posting frequency in subforums (depression, generalized anxiety, social anxiety, panic disorder, bipolar disorder, obsessive compulsive disorder, borderline personality disorder, eating disorders, carers, general (eg, "chit chat"), and suggestions box) of the BlueBoard users were assessed as potential predictors of the resulting subgroup structure. RESULTS: The analysis of modularity identified five main subgroups in the BlueBoard community. Registration date was found to be the largest contributor to the modularity outcome as observed by multinomial logistic regression. The addition of this variable to the final model containing all other factors improved its classification accuracy by 46.3%, that is, from 37.9% to 84.2%. Further investigation of this variable revealed that the most active and central users registered significantly earlier than the median registration time in each group. CONCLUSIONS: The five subgroups resembled five generations of BlueBoard in distinct eras that transcended discussion about different mental health issues. This finding may be due to the activity of highly engaged and central users who communicate with many other users. Future research should seek to determine the generalizability of this finding and investigate the role that highly active and central users may play in the formation of this phenomenon. PMID- 27242014 TI - Cutaneous Recording and Stimulation of Muscles Using Organic Electronic Textiles. AB - Electronic textiles are an emerging field providing novel and non-intrusive solutions for healthcare. Conducting polymer-coated textiles enable a new generation of fully organic surface electrodes for electrophysiological evaluations. Textile electrodes are able to assess high quality muscular monitoring and to perform transcutaneous electrical stimulation. PMID- 27242013 TI - Treatment of Rats with Apocynin Has Considerable Inhibitory Effects on Arylamine N-Acetyltransferase Activity in the Liver. AB - The effect of apocynin on the activity of arylamine N-acetyltransferases (NATs) in excised liver samples was examined using eighteen Sprague-Dawley rats. Three groups of six animals each were fed a normal diet alone or a treatment of 50 or 100 mg/kg/day of apocynin via gavages for eight (8) weeks. Chronic in vivo administration of apocynin led to significant (p < 0.001) reduction of in vitro liver NAT activity up to 93% as compared with untreated rats (18.80 +/- 2.10 MUmols p-anisidine/min/MUg liver protein). In vitro exposure of untreated liver homogenates to apocynin led to a dose-dependent inhibition of NAT activity with IC50 = 0.69 +/- 0.02 mM. In silico modelling of apocynin tautomers and radical species into human NAT crystal structures supported the hypothesis that thiol functionalities in NAT enzymes may be crucial in apocynin binding. The involvement of human NAT enzymes in different pathological conditions, such as cancer, has encouraged the research for selective NAT inhibitors in both humans and animal models with possible chemopreventive properties. PMID- 27242016 TI - Biomarkers, old and new: for sleep, sleepiness, circadian phase and much more.... PMID- 27242015 TI - [Placental atherosclerosis and markers of endothelial dysfunction in infants born to mothers with gestational diabetes]. AB - BACKGROUND AND OBJECTIVE: The pathophysiology of gestational diabetes itself causes hyperstimulation of adipose tissue and of the placenta cells increasing the production of inflammatory cytokines, which cause changes in the tissues exposed such as the placenta and foetus. Therefore, the objective of this study was to compare metabolic markers and endothelial dysfunction in umbilical cord blood, as well as to determine the presence of atherosclerosis in the placentas of newborn infants of patients with gestational diabetes and in patients with normally progressing pregnancies. PATIENTS AND METHOD: An analytical cross sectional study was carried out in 84 patients, obtaining data such as age, smoking and weight gain in pregnancy; the gestational age of the newborns was determined by Capurro, and their weight and destination subsequent to birth, the placentas were also collected in order to look for atherosclerosis through histological studies and glucose, insulin, VLDL-C, HDL-C, triglycerides, cholesterol, fibrinogen, PCR and markers of endothelial dysfunction (adiponectin, VCAM-1, ICAM-1 and IL-6) were determined in blood samples obtained from the umbilical cord. RESULTS: Placental atherosclerosis presented in 28.94% of the group with gestational diabetes compared to 10.52% of the group with normally progressing pregnancies (P=.044); differences were found in glucose, cholesterol, triglycerides, fibrinogen, HOMA-IR, PCR-us, HDL-C, not in VLDL-C. Twenty-one point five percent of the newborns of the gestational diabetes patients required hospitalization, against 5.2% in the control group, CONCLUSIONS: Pregnancies that involve diabetes have higher proportion of atherosclerosis, hospitalization of the newborn, insulin resistance, as well as elevation of markers associated with inflammation and endothelial dysfunction in umbilical cord blood. PMID- 27242018 TI - Percutaneous Closure of Paravalvular Leaks: A Systematic Review. AB - Paravalvular leak (PVL) is an uncommon yet serious complication associated with the implantation of mechanical or bioprosthetic surgical valves and more recently recognized with transcatheter aortic valves implantation (TAVI). A significant number of patients will present with symptoms of congestive heart failure or haemolytic anaemia due to PVL and need further surgical or percutaneous treatment. Until recently, surgery has been the only available therapy for the treatment of clinically significant PVLs despite the significant morbidity and mortality associated with re-operation. Percutaneous treatment of PVLs has emerged as a safe and less invasive alternative, with low complication rates and high technical and clinical success rates. However, it is a complex procedure, which needs to be performed by an experienced team of interventional cardiologists and echocardiographers. This review discusses the current understanding of PVLs, including the utility of imaging techniques in PVL diagnosis and treatment, and the principles, outcomes and complications of transcatheter therapy of PVLs. PMID- 27242017 TI - Association of the cystatin C/creatinine ratio with the renally cleared hormones parathyroid hormone (PTH) and brain natriuretic peptide (BNP) in primary care patients: a cross-sectional study. AB - The ratio of cystatin C to creatinine (cysC/crea) is regarded as a marker of glomerular filtration quality and predicts mortality. It has been hypothesized that increased mortality may be mediated by the retention of biologically active substances due to shrinking glomerular pores. The present study investigated whether cysC/crea is independently associated with the levels of two renally cleared hormones, which have been linked to increased mortality. We conducted a multicenter, cross-sectional study with a random selection of general practitioners (GPs) from all GP offices in seven Swiss cantons. Markers of glomerular filtration quality were investigated together with estimated glomerular filtration rate (eGFR), albuminuria and urinary neutrophil gelatinase associated lipocalin (uNGAL) as well as two renally cleared low-molecular-weight protein hormones (i.e. BNP and PTH), Morbidity was assessed with the Charlson Comorbidity Index (CCI). A total of 1000 patients (433 males; mean age 57 +/- 17 years) were included. There was a significant univariate association of BNP (r = 0.36, p < 0.001) and PTH (r = 0.18, p < 0.001) with cysC/crea. An adjusted model that accounted for kidney function (eGFR), altered glomerular structure (albuminuria), renal stress (uNGAL), and CCI showed that BNP and PTH were independently associated with cysC/crea as well as with the ratio of cystatin C based to creatinine-based eGFR. In conclusion, in primary care patients, BNP and PTH are independently associated both with markers of glomerular filtration quality and eGFR regardless of structural kidney damage or renal stress. These findings offer an explanation, how altered glomerular filtration quality could contribute to increased mortality. PMID- 27242019 TI - Effects of para-substituents of styrene derivatives on their chemical reactivity on platinum nanoparticle surfaces. AB - Stable platinum nanoparticles were successfully prepared by the self-assembly of para-substituted styrene derivatives onto the platinum surfaces as a result of platinum-catalyzed dehydrogenation and transformation of the vinyl groups to the acetylene ones, forming platinum-vinylidene/-acetylide interfacial bonds. Transmission electron microscopic measurements showed that the nanoparticles were well dispersed without apparent aggregation, suggesting sufficient protection of the nanoparticles by the organic capping ligands, and the average core diameter was estimated to be 2.0 +/- 0.3 nm, 1.3 +/- 0.2 nm, and 1.1 +/- 0.2 nm for the nanoparticles capped with 4-tert-butylstyrene, 4-methoxystyrene, and 4 (trifluoromethyl)styrene, respectively, as a result of the decreasing rate of dehydrogenation with the increasing Taft (polar) constant of the para substituents. Importantly, the resulting nanoparticles exhibited unique photoluminescence, where an increase of the Hammett constant of the para substituents corresponded to a blue-shift of the photoluminescence emission, suggesting an enlargement of the HOMO-LUMO band gap of the nanoparticle-bound acetylene moieties. Furthermore, the resulting nanoparticles exhibited apparent electrocatalytic activity towards oxygen reduction in acidic media, with the best performance among the series of samples observed with the 4-tert-butylstyrene capped nanoparticles due to an optimal combination of the nanoparticle core size and ligand effects on the bonding interactions between platinum and oxygen species. PMID- 27242020 TI - Low-temperature co-pyrolysis behaviours and kinetics of oily sludge: effect of agricultural biomass. AB - Pyrolysis is potentially an effective treatment of oily sludge for oil recovery, and its kinetics and efficiency are expected to be affected by additives. In the present study, the pyrolysis parameters, including heating rate, final pyrolysis temperature, and pyrolysis time of oily sludge in the presence of agricultural biomass, apricot shell, were systematically explored. As a result, maximum oil recovery is achieved when optimizing the pyrolysis conditionas15 K/min, 723 K, and 3 h for heating rate, final pyrolysis temperature, and pyrolysis time, respectively. Thermogravimetric experiments of oily sludge samples in the presence of various biomasses conducted with non-isothermal temperature programmes suggest that the pyrolysis process contains three stages, and the main decomposition reaction occurs in the range of 400-740 K. Taking Flynn-Wall-Ozawa analysis of the derivative thermogravimetry and thermogravimetry results, the activation energy (Ea) values for the pyrolysis of oily sludge in the presence and absence of apricot shell were derived to be 35.21 and 39.40 kJ mol-1, respectively. The present work supports that the presence of biomass promotes the pyrolysis of oily sludge, implying its great potential as addictive in the industrial pyrolysis of oily sludge. PMID- 27242021 TI - HoLEP turns 20. Not yet? PMID- 27242022 TI - Effects of Healthy Life Practice Education on Reported Health Behaviors Among Fourth-Grade Elementary School Students in South Korea. AB - The purpose of this study was to test the effects of healthy life practice (HLP) education on reported health behaviors, including health promotion, disease prevention, and safety among fourth-grade elementary school students. A quasi experimental, pretest/posttest design was used. The 101 recruited participants from two schools were assigned to the intervention group (n = 51) that received 10 health education sessions and the control group (n = 50) that did not receive the intervention. Significant differences in health behaviors were observed between the two groups (t = 2.563, p = .012), specifically for disease prevention (t = 2.178, p = .032) and safety (t = 2.711, p = .008). However, no significant between-group differences were observed in health promotion (t = .270, p = .788). Educational interventions aimed at changing HLP-related health behaviors may be effective for elementary schoolchildren. PMID- 27242023 TI - Single-particle to single-particle transformation of an active type organic MU tubular homo-structure photonic resonator into a passive type hetero-structure resonator. AB - Self-assembled hexagonal organic submicrotubes, upon electronic excitation with an UV laser, display an active type polarized whispering gallery mode (WGM) resonance in the visible (Vis) range (400-600 nm). Due to the photonic cavity effect the tubes show fluorescence (FL) signal intensity 5* greater than the corresponding powder state. Furthermore, the same tubes, which are passive to a visible laser, produce yellow-orange emitting carbonaceous lumps when burnt with an intense laser beam (42 mW) forming a chemically binary heterogeneous structure. The hetero-structure upon excitation with a visible laser at the passive tubular part showed emission in the Vis-Near infrared (NIR) range (500 800 nm) with WGMs thus producing a passive/active type hetero-structure photonic resonator. PMID- 27242024 TI - Thermally stable and efficient polymer solar cells based on a novel donor acceptor copolymer. AB - We report high photovoltaic performance of a novel donor-acceptor (D-A) conjugated polymer poly[2,6[4,8-bis(2-ethyl-hexyl)benzo[1,2-b;4,5-b']dithiophene co-2,5-thiophene-co-4,7[5,6-bis-octyloxy-benzo[1,2,5]thiadiazole]-co-2,5 thiophene] (PBDTTBTZT) in bulk heterojunctions with [6,6]-phenyl-C71-butyric acid methyl ester (PC70BM). A power conversion efficiency (PCE) of more than 7% is obtained for optimized charge-extracting electrodes. Upon application of thermal stress via annealing, a superior thermal stability is demonstrated as compared to poly[N-9"-hepta-decanyl-2,7-carbazole-alt-5,5-(4',7'-di-2-thienyl-2',1',3' benzothiadiazole)] (PCDTBT). PMID- 27242025 TI - Proton pump inhibitors use and change in bone mineral density. AB - OBJECTIVE: Limited data are available reporting the effect of proton pump inhibitor (PPI) use on changes in bone mineral density (BMD). The aim of this study was to investigate the relationship between PPI use and BMD. METHODS: The current cross-sectional study included 80 patients (31 male and 49 female) aged 20-45 years old without history of hip fracture with a follow-up of at least 2 years. The study was carried out in 40 daily PPI users and 40 PPI non-users. Femur and posterior-anterior spine BMD were quantified by dual-energy X-ray absorptiometry in all participants. The relationship between use of PPI and BMD was tested by multivariate linear regression analysis adjusted for age, sex, BMI and serum vitamin D levels. RESULTS: Our study demonstrated that mean femoral T scores were significant between PPI and non-user groups (-0.44 +/- 1.11 vs. +0.19 +/- 0.95, P = 0.007). In addition, the frequency of femoral osteoporosis and osteopenia in the exposed group was significantly more in the control group (P = 0.04). Mean femoral Z-scores, lumbar spine T-score and lumbar spine Z-score were not statistically different between PPI and non-user groups. The linear regression analysis revealed that there was no association between PPI and non users, and lumbar spine T-score. CONCLUSION: Overall, the results of this study showed that PPI use in subjects without risk factors of osteoporosis determined by the femoral T-score compared with the control group was associated with increased risk of developing osteoporosis and osteopenia in the femur bones. PMID- 27242026 TI - From DNA damage to functional changes of the trabecular meshwork in aging and glaucoma. AB - Glaucoma is a degenerative disease of the eye. Both the anterior and posterior segments of the eye are affected, extensive damage being detectable in the trabecular meshwork and the inner retina-central visual pathway complex. Oxidative stress is claimed to be mainly responsible for molecular damage in the anterior chamber. Indeed, oxidation harms the trabecular meshwork, leading eventually to endothelial cell decay, tissue malfunction, subclinical inflammation, changes in the extracellular matrix and cytoskeleton, altered motility, reduced outflow facility and (ultimately) increased IOP. Moreover, free radicals are involved in aging and can be produced in the brain (as well as in the eye) as a result of ischemia, leading to oxidation of the surrounding neurons. Glaucoma-related cell death occurs by means of apoptosis, and apoptosis is triggered by oxidative stress via (a) mitochondrial damage, (b) inflammation, (c) endothelial dysregulation and dysfunction, and (d) hypoxia. The proteomics of the aqueous humor is significantly altered in glaucoma as a result of oxidation induced trabecular damage. Those proteins whose aqueous humor levels are increased in glaucoma are biomarkers of trabecular meshwork impairment. Their diffusion from the anterior to the posterior segment of the eye may be relevant in the cascade of events triggering apoptosis in the inner retinal layers, including the ganglion cells. PMID- 27242027 TI - Mapping the Dynamic Network Interactions Underpinning Cognition: A cTBS-fMRI Study of the Flexible Adaptive Neural System for Semantics. AB - Higher cognitive function reflects the interaction of a network of multiple brain regions. Previous investigations have plotted out these networks using functional or structural connectivity approaches. While these map the topography of the regions involved, they do not explore the key aspect of this neuroscience principle-namely that the regions interact in a dynamic fashion. Here, we achieved this aim with respect to semantic memory. Although converging evidence implicates the anterior temporal lobes (ATLs), bilaterally, as a crucial component in semantic representation, the underlying neural interplay between the ATLs remains unclear. By combining continuous theta-burst stimulation (cTBS) with functional magnetic resonance imaging (fMRI), we perturbed the left ventrolateral ATL (vATL) and investigated acute changes in neural activity and effective connectivity of the semantic system. cTBS resulted in decreased activity at the target region and compensatory, increased activity at the contralateral vATL. In addition, there were task-specific increases in effective connectivity between the vATLs, reflecting an increased facilitatory intrinsic connectivity from the right to left vATL. Our results suggest that semantic representation is founded on a flexible, adaptive bilateral neural system and reveals an adaptive plasticity-based mechanism that might support functional recovery after unilateral damage in neurological patients. PMID- 27242029 TI - Contour Integration over Time: Psychophysical and fMRI Evidence. AB - The brain integrates discrete but collinear stimuli to perceive global contours. Previous contour integration (CI) studies mainly focus on integration over space, and CI is attributed to either V1 long-range connections or contour processing in high-visual areas that top-down modulate V1 responses. Here, we show that CI also occurs over time in a design that minimizes the roles of V1 long-range interactions. We use tilted contours embedded in random orientation noise and moving horizontally behind a fixed vertical slit. Individual contour elements traveling up/down within the slit would be encoded over time by parallel, rather than aligned, V1 neurons. However, we find robust contour detection even when the slit permits only one viewable contour element. Similar to CI over space, CI over time also obeys the rule of collinearity. fMRI evidence shows that while CI over space engages visual areas as early as V1, CI over time mainly engages higher dorsal and ventral visual areas involved in shape processing, as well as posterior parietal regions involved in visual memory that can represent the orientation of temporally integrated contours. These results suggest at least partially dissociable mechanisms for implementing the Gestalt rule of continuity in CI over space and time. PMID- 27242030 TI - Spiral formation at the microscale by MU-pyro-electrospinning. AB - Spiral shapes occur frequently in nature as in the case of snail shells or the cochlea - the auditory portion of the inner ear. They also inspire many technological devices that take advantage of this geometry. Here we show that MU pyro-electrospinning is able to control whipping instabilities in order to form spiralling fibres (down to 300 nm thick) directly on a support with true microscale regularity. The results show that polymer concentration plays a key role in producing reliable and long spirals. We investigate the cell response to these spiral templates that, thanks to their true regularity, would be useful for developing innovative cochlea regeneration scaffolds. PMID- 27242028 TI - Persistence of Amygdala-Hippocampal Connectivity and Multi-Voxel Correlation Structures During Awake Rest After Fear Learning Predicts Long-Term Expression of Fear. AB - After encoding, memories undergo a process of consolidation that determines long term retention. For conditioned fear, animal models postulate that consolidation involves reactivations of neuronal assemblies supporting fear learning during postlearning "offline" periods. However, no human studies to date have investigated such processes, particularly in relation to long-term expression of fear. We tested 24 participants using functional MRI on 2 consecutive days in a fear conditioning paradigm involving 1 habituation block, 2 acquisition blocks, and 2 extinction blocks on day 1, and 2 re-extinction blocks on day 2. Conditioning blocks were preceded and followed by 4.5-min rest blocks. Strength of spontaneous recovery of fear on day 2 served as a measure of long-term expression of fear. Amygdala connectivity primarily with hippocampus increased progressively during postacquisition and postextinction rest on day 1. Intraregional multi-voxel correlation structures within amygdala and hippocampus sampled during a block of differential fear conditioning furthermore persisted after fear learning. Critically, both these main findings were stronger in participants who exhibited spontaneous recovery 24 h later. Our findings indicate that neural circuits activated during fear conditioning exhibit persistent postlearning activity that may be functionally relevant in promoting consolidation of the fear memory. PMID- 27242031 TI - Effect of ultra-fast mild hypothermia using total liquid ventilation on hemodynamics and respiratory mechanics. AB - Ultra-fast cooling for mild therapeutic hypothermia (MTH) has several potential applications, including prevention of post-cardiac arrest syndrome. Ultra-fast MTH by total liquid ventilation (TLV) entails the sudden filling of the lungs with a cold perfluorocarbon liquid and its subsequent use to perform TLV. The present physiological study was aimed at assessing whether pulmonary and systemic hemodynamics as well as lung mechanics are significantly altered during this procedure. Pulmonary and systemic arterial pressures, cardiac output as well as airway resistance and respiratory system compliance were measured during ultra fast MTH by TLV followed by rewarming and normothermia in six healthy juvenile lambs. Results show that none of the studied variables were altered upon varying the perfluorocarbon temperature from 12 to 41 degrees C. It is concluded that ultra-fast MTH by TLV does not have any deleterious effect on hemodynamics or lung mechanics in healthy juvenile lambs. PMID- 27242032 TI - URS DataBase: universe of RNA structures and their motifs. AB - The Universe of RNA Structures DataBase (URSDB) stores information obtained from all RNA-containing PDB entries (2935 entries in October 2015). The content of the database is updated regularly. The database consists of 51 tables containing indexed data on various elements of the RNA structures. The database provides a web interface allowing user to select a subset of structures with desired features and to obtain various statistical data for a selected subset of structures or for all structures. In particular, one can easily obtain statistics on geometric parameters of base pairs, on structural motifs (stems, loops, etc.) or on different types of pseudoknots. The user can also view and get information on an individual structure or its selected parts, e.g. RNA-protein hydrogen bonds. URSDB employs a new original definition of loops in RNA structures. That definition fits both pseudoknot-free and pseudoknotted secondary structures and coincides with the classical definition in case of pseudoknot-free structures. To our knowledge, URSDB is the first database supporting searches based on topological classification of pseudoknots and on extended loop classification.Database URL: http://server3.lpm.org.ru/urs/. PMID- 27242033 TI - gEVE: a genome-based endogenous viral element database provides comprehensive viral protein-coding sequences in mammalian genomes. AB - In mammals, approximately 10% of genome sequences correspond to endogenous viral elements (EVEs), which are derived from ancient viral infections of germ cells. Although most EVEs have been inactivated, some open reading frames (ORFs) of EVEs obtained functions in the hosts. However, EVE ORFs usually remain unannotated in the genomes, and no databases are available for EVE ORFs. To investigate the function and evolution of EVEs in mammalian genomes, we developed EVE ORF databases for 20 genomes of 19 mammalian species. A total of 736,771 non overlapping EVE ORFs were identified and archived in a database named gEVE (http://geve.med.u-tokai.ac.jp). The gEVE database provides nucleotide and amino acid sequences, genomic loci and functional annotations of EVE ORFs for all 20 genomes. In analyzing RNA-seq data with the gEVE database, we successfully identified the expressed EVE genes, suggesting that the gEVE database facilitates studies of the genomic analyses of various mammalian species.Database URL: http://geve.med.u-tokai.ac.jp. PMID- 27242034 TI - Abasy Atlas: a comprehensive inventory of systems, global network properties and systems-level elements across bacteria. AB - The availability of databases electronically encoding curated regulatory networks and of high-throughput technologies and methods to discover regulatory interactions provides an invaluable source of data to understand the principles underpinning the organization and evolution of these networks responsible for cellular regulation. Nevertheless, data on these sources never goes beyond the regulon level despite the fact that regulatory networks are complex hierarchical modular structures still challenging our understanding. This brings the necessity for an inventory of systems across a large range of organisms, a key step to rendering feasible comparative systems biology approaches. In this work, we take the first step towards a global understanding of the regulatory networks organization by making a cartography of the functional architectures of diverse bacteria. Abasy ( A: cross- BA: cteria SY: stems) Atlas provides a comprehensive inventory of annotated functional systems, global network properties and systems level elements (global regulators, modular genes shaping functional systems, basal machinery genes and intermodular genes) predicted by the natural decomposition approach for reconstructed and meta-curated regulatory networks across a large range of bacteria, including pathogenically and biotechnologically relevant organisms. The meta-curation of regulatory datasets provides the most complete and reliable set of regulatory interactions currently available, which can even be projected into subsets by considering the force or weight of evidence supporting them or the systems that they belong to. Besides, Abasy Atlas provides data enabling large-scale comparative systems biology studies aimed at understanding the common principles and particular lifestyle adaptions of systems across bacteria. Abasy Atlas contains systems and system-level elements for 50 regulatory networks comprising 78 649 regulatory interactions covering 42 bacteria in nine taxa, containing 3708 regulons and 1776 systems. All this brings together a large corpus of data that will surely inspire studies to generate hypothesis regarding the principles governing the evolution and organization of systems and the functional architectures controlling them.Database URL: http://abasy.ccg.unam.mx. PMID- 27242035 TI - MET network in PubMed: a text-mined network visualization and curation system. AB - Metastasis is the dissemination of a cancer/tumor from one organ to another, and it is the most dangerous stage during cancer progression, causing more than 90% of cancer deaths. Improving the understanding of the complicated cellular mechanisms underlying metastasis requires investigations of the signaling pathways. To this end, we developed a METastasis (MET) network visualization and curation tool to assist metastasis researchers retrieve network information of interest while browsing through the large volume of studies in PubMed. MET can recognize relations among genes, cancers, tissues and organs of metastasis mentioned in the literature through text-mining techniques, and then produce a visualization of all mined relations in a metastasis network. To facilitate the curation process, MET is developed as a browser extension that allows curators to review and edit concepts and relations related to metastasis directly in PubMed. PubMed users can also view the metastatic networks integrated from the large collection of research papers directly through MET. For the BioCreative 2015 interactive track (IAT), a curation task was proposed to curate metastatic networks among PubMed abstracts. Six curators participated in the proposed task and a post-IAT task, curating 963 unique metastatic relations from 174 PubMed abstracts using MET.Database URL: http://btm.tmu.edu.tw/metastasisway. PMID- 27242036 TI - CoopTFD: a repository for predicted yeast cooperative transcription factor pairs. AB - In eukaryotic cells, transcriptional regulation of gene expression is usually accomplished by cooperative Transcription Factors (TFs). Therefore, knowing cooperative TFs is helpful for uncovering the mechanisms of transcriptional regulation. In yeast, many cooperative TF pairs have been predicted by various algorithms in the literature. However, until now, there is still no database which collects the predicted yeast cooperative TFs from existing algorithms. This prompts us to construct Cooperative Transcription Factors Database (CoopTFD), which has a comprehensive collection of 2622 predicted cooperative TF pairs (PCTFPs) in yeast from 17 existing algorithms. For each PCTFP, our database also provides five types of validation information: (i) the algorithms which predict this PCTFP, (ii) the publications which experimentally show that this PCTFP has physical or genetic interactions, (iii) the publications which experimentally study the biological roles of both TFs of this PCTFP, (iv) the common Gene Ontology (GO) terms of this PCTFP and (v) the common target genes of this PCTFP. Based on the provided validation information, users can judge the biological plausibility of a PCTFP of interest. We believe that CoopTFD will be a valuable resource for yeast biologists to study the combinatorial regulation of gene expression controlled by cooperative TFs.Database URL: http://cosbi.ee.ncku.edu.tw/CoopTFD/ or http://cosbi2.ee.ncku.edu.tw/CoopTFD/. PMID- 27242038 TI - GESDB: a platform of simulation resources for genetic epidemiology studies. AB - Computer simulations are routinely conducted to evaluate new statistical methods, to compare the properties among different methods, and to mimic the observed data in genetic epidemiology studies. Conducting simulation studies can become a complicated task as several challenges can occur, such as the selection of an appropriate simulation tool and the specification of parameters in the simulation model. Although abundant simulated data have been generated for human genetic research, currently there is no public database designed specifically as a repository for these simulated data. With the lack of such a database, for similar studies, similar simulations may have been repeated, which resulted in redundant work. Thus, we created an online platform, the Genetic Epidemiology Simulation Database (GESDB), for simulation data sharing and discussion of simulation techniques for genetic epidemiology studies. GESDB consists of a database for storing simulation scripts, simulated data and documentation from published articles as well as a discussion forum, which provides a platform for discussion of the simulated data and exchanging simulation ideas. Moreover, summary statistics such as the simulation tools that are most commonly used and datasets that are most frequently downloaded are provided. The statistics will be informative for researchers to choose an appropriate simulation tool or select a common dataset for method comparisons. GESDB can be accessed at http://gesdb.nhri.org.twDatabase URL: http://gesdb.nhri.org.tw. PMID- 27242037 TI - ArthropodaCyc: a CycADS powered collection of BioCyc databases to analyse and compare metabolism of arthropods. AB - Arthropods interact with humans at different levels with highly beneficial roles (e.g. as pollinators), as well as with a negative impact for example as vectors of human or animal diseases, or as agricultural pests. Several arthropod genomes are available at present and many others will be sequenced in the near future in the context of the i5K initiative, offering opportunities for reconstructing, modelling and comparing their metabolic networks. In-depth analysis of these genomic data through metabolism reconstruction is expected to contribute to a better understanding of the biology of arthropods, thereby allowing the development of new strategies to control harmful species. In this context, we present here ArthropodaCyc, a dedicated BioCyc collection of databases using the Cyc annotation database system (CycADS), allowing researchers to perform reliable metabolism comparisons of fully sequenced arthropods genomes. Since the annotation quality is a key factor when performing such global genome comparisons, all proteins from the genomes included in the ArthropodaCyc database were re-annotated using several annotation tools and orthology information. All functional/domain annotation results and their sources were integrated in the databases for user access. Currently, ArthropodaCyc offers a centralized repository of metabolic pathways, protein sequence domains, Gene Ontology annotations as well as evolutionary information for 28 arthropod species. Such database collection allows metabolism analysis both with integrated tools and through extraction of data in formats suitable for systems biology studies.Database URL: http://arthropodacyc.cycadsys.org/. PMID- 27242039 TI - Aflatoxin B1 induced upregulation of protein arginine methyltransferase 5 in human cell lines. AB - The exposure of naturally occurring mycotoxins affects human health and play a vital role in cancer initiation and progression. Aflatoxin B1 is a difuranocoumarin mycotoxin, classified as a group I carcinogen. The present study was conducted to assess the effect of aflatoxin B1 on epigenetic regulatory proteins. The protein arginine methyltransferase 5 expression was induced upon aflatoxin B1 treatment in a dose and time dependent manner. Further global arginine methylation was also increased in the same manner. This is the first report showing the induction of epigenetic regulatory protein, protein arginine methyltransferase 5 upon aflatoxin B1 treatment. Further study is required to establish the detailed pathway of PRMT5 induction. PMID- 27242040 TI - Nomenclatural instability in the venomous snakes of the Bothrops complex: Implications in toxinology and public health. AB - Since nomenclature is intended to reflect the evolutionary history of organisms, advances in our understanding of historical relationships may lead to changes in classification, and thus potentially in taxonomic instability. An unstable nomenclature for medically important animals like venomous snakes is of concern, and its implications in venom/antivenom research and snakebite treatment have been extensively discussed since the 90's. The taxonomy of the pitvipers of the Bothrops complex has been historically problematic and different genus-level rearrangements were proposed to rectify the long-standing paraphyly of the group. Here we review the toxinological literature on the Bothrops complex to estimate the impact of recent proposals of classification in non-systematic research. This assessment revealed moderate levels of nomenclatural instability in the last five years, and the recurrence of some practices discussed in previous studies regarding the use of classifications and the information provided about the origin of venom samples. We briefly comment on a few examples and the implications of different proposals of classifications for the Bothrops complex. The aim of this review is to contribute to the reduction of adverse effects of current taxonomic instability in a group of medical importance in the Americas. PMID- 27242041 TI - p38 MAPK is involved in human neutrophil chemotaxis induced by L-amino acid oxidase from Calloselasma rhodosthoma. AB - The action of LAAO, an L-amino acid oxidase isolated from Calloselasma rhodosthoma snake venom, on isolated human neutrophil function was investigated. Cr-LAAO showed no toxicity on neutrophils. Cr-LAAO in its native form induced the neutrophil chemotaxis, suggesting that its primary structure is essential for stimulation the cell. p38 MAPK and PI3K have a role as signaling pathways of CR LAAO induced chemotaxis. This toxin also induced the production of hydrogen peroxide and stimulated phagocytosis in neutrophils. Furthermore, Cr-LAAO was able to stimulate neutrophils to release IL-6, IL-8, MPO, LTB4 and PGE2. Together, the data showed that the Cr-LAAO triggers relevant proinflammatory events. PMID- 27242042 TI - Insights into the potential of picoplanktonic marine cyanobacteria strains for cancer therapies - Cytotoxic mechanisms against the RKO colon cancer cell line. AB - PURPOSE: In this work, we analysed the potential of picoplanktonic marine cyanobacteria strains as a source of anticancer compounds by elucidating the cytotoxic mechanisms of an ethyl acetate fraction of Cyanobium sp. (LEGE06113) and the Synechocystis salina (LEGE06155) on the RKO colon adenocarcinoma cell line. METHODS: Cytotoxicity was analysed by MTT. Effects on cells were evaluated by mRNA expression of cell cycle and apoptotic genes, flow cytometry (cell cycle), qualitative and quantitative fluorescence microscopy (apoptosis), and quantitative proteomics. RESULTS: IC50 values were 27.01 and 8.03 MUg/ml for Cyanobium sp., and 37.71 and 17.17 MUg/ml for Synechocystis salina, after 24 h and 48 h, respectively. Exposure to the Cyanobium sp. fraction increased 2.5 fold BCL-2 mRNA expression (p < 0.05), and altered proteins (13, p < 0.05) belonged to apoptosis (PSMA5, PSMA7, TPT1, UBE2K), cell cycle (EIF4E, PCNA), cellular metabolism (AHSG, GLO1, ATP5H, HSP90AB1, NME1, HNRNPC) and cell structure (KRT10). Exposure to the Synechocystis salina fraction decreased 2fold CCNB1 mRNA expression (p < 0.05). Accordingly, flow cytometry demonstrated a decrease of cells in the G0/G1 and S phase (p < 0.05), indicating a cell cycle arrest at the G2/M transition. Fluorescence microscopy confirmed a higher level of apoptosis compared to the solvent control group (p < 0.01). Altered proteins (6, p < 0.05) belonged to apoptosis (HSPD1, UBE2K), protein metabolism (PKM, PDIA3) and cell structure (KRT10, KRT1). CONCLUSION: Since induction of cytotoxicity is a very broad parameter, the study demonstrates the potential of picocyanobacteria to produce bioactive compounds that target cancer cells via different molecular mechanisms. PMID- 27242043 TI - Taming C-terminal peptides of Staphylococcus aureus leukotoxin M for B-cell response: Implication in improved subclinical bovine mastitis diagnosis and protective efficacy in vitro. AB - Leukotoxin M/F'-PV (LukM/F'-PV) produced by bovine mastitis causing Staphylococcus aureus structurally comprises three domains, the beta-sandwich, rim and stem domain. The rim and stem domains interacting with target cell membrane lipid rafts contributes to the virulent trait of the toxin. In the present study, two facts were hypothesized that neutralization of these domains will ebb LukM/F'-PV leukotoxicity. Secondly, the neutralizing antibodies can improve the leukotoxin detection sensitivity in bovine mastitis milk samples. The in silico mapping of S. aureus LukM C-termini comprising these domains predicted seven linear B-cell antigenic epitopes. The immune response of C-terminal truncated recombinant peptides rCtM19 (19 kDa; near carboxy-terminal) having four epitopes and rCtM15 (15 kDa; C-terminal) with three epitopes were evaluated for their diagnostic and neutralization potential. Anti-rCtM19 and anti-rCtM15 antibodies with enhanced immunogenicity had the most striking outcome in IgG ELISA for detecting native determinants of leukotoxin. For the obtained ELISA values, ROC curve inferred a cut-off score of >0.102 OD405. The assay sensitivity in the range of 90-96% along with 100% specificity and AUC of 0.93-0.98 categorized subclinical and clinical from healthy bovine milk samples. As observed through in vitro neutralization and LDH assays, C-terminus specific antibodies (1:42 titer) deactivating leukotoxicity abolished LukM from interacting with lipid bilayer and LukF for forming pores on bovine neutrophil membrane. As a proof of concept, it was proved that peptide antibodies can be a more specific serodiagnostic and passive therapeutic molecules. PMID- 27242044 TI - Biocompatible polyhydroxyalkanoates/bacterial cellulose composites: Preparation, characterization, and in vitro evaluation. AB - Biocompatible composites play a critical role as scaffolds in tissue engineering. Novel biocomposites made from poly(3-hydroxybutyrate) (PHB), polyhydroxyalkanoate (PHA) and bacterial cellulose (BC) in different concentrations were prepared by solution casting and their thermal and mechanical behavior as well as biocompatibility was characterized. BC addition increased the thermal stability of the polymer matrix as evidenced by thermogravimetric analysis. The crystallinity of PHB and the crystallization temperature decreased with the addition of BC and PHA, thus increasing the processing window. BC in small concentration determined an increase in the mechanical properties due to a concerted action of PHA and filler. Good cells attachment and proliferation were observed for all the biocomposites. By the addition of PHA (more hydrophobic than the matrix) and various amounts of BC (highly hydrophilic), surface properties and cell attachment can be controlled. Cytocompatibility studies using L929 cell line revealed that this material is suitable for biomedical applications. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2576-2584, 2016. PMID- 27242046 TI - Cerebral Metabolism in Head Trauma1. PMID- 27242045 TI - Outcomes of intracytoplasmic sperm injection in oligozoospermic men with Y chromosome AZFb or AZFc microdeletions. AB - We investigated whether the presence of Y chromosome azoospermia factor (AZF) microdeletions impacts upon the outcomes of intracytoplasmic sperm injection (ICSI) using fresh ejaculated spermatozoa. Sixteen oligozoospermia patients with Y chromosome AZFb or AZFc microdeletions and undergoing ICSI cycles between March 2013 and November 2014 were studied. Twenty-six infertile men with normal Y chromosomes and also undergoing IVF/ICSI in the same time period were used as controls. A retrospective case-control study approach was used. Among the 16 cases, 12 (75%, 12/16) had deletions of AZFc markers (sY152, sY254 and sY255), one (6.25%, 1/16) had a deletion of sY152, and two (12.5%, 2/16) had deletions of sY152, sY254, sY255 and sY157. AZFb microdeletions were found in one patient (6.25%, 1/16). There were no significant differences between groups for cleaved embryo rate, high-grade embryo rate, blastocyst formation rate, embryo implantation rate, clinical pregnancy rate and delivery rate. The clinical outcomes of ICSI for oligozoospermic patients with Y chromosome AZF microdeletion are comparable to those of infertile patients with normal Y chromosomes. Our findings indicate that ICSI should be offered to patients with an AZFc deletion and that oligozoospermia patients with AZFb microdeletions are likely to father children. PMID- 27242047 TI - Cerebral Blood Flow and Metabolism after Intracranial Trauma. PMID- 27242048 TI - Posttraumatic Hemispheric Contusion and Laceration. PMID- 27242049 TI - Severity of Brain Damage - Altered Consciousness and Other Indicators. PMID- 27242050 TI - Computer Tomography in Head Injury. PMID- 27242051 TI - Acute Traumatic Intracranial Hematomas. PMID- 27242053 TI - Post-Traumatic Epilepsy. PMID- 27242052 TI - Nonsurgical Management of Severe Head Injuries. PMID- 27242054 TI - The Importance of Rehabilitation Programs in the Prevention and Alleviation of Head Injury Sequelae. PMID- 27242057 TI - Corrigendum: Velocity distribution in active particles systems. PMID- 27242058 TI - Direct observation of the actin filament by tip-scan atomic force microscopy. AB - Actin filaments, the actin-myosin complex and the actin-tropomyosin complex were observed by a tip-scan atomic force microscope (AFM), which was recently developed by Olympus as the AFM part of a correlative microscope. This newly developed AFM uses cantilevers of similar size as stage-scan AFMs to improve substantially the spatial and temporal resolution. Such an approach has previously never been possible by a tip-scan system, in which a cantilever moves in the x, y and z directions. We evaluated the performance of this developed tip scan AFM by observing the molecular structure of actin filaments and the actin tropomyosin complex. In the image of the actin filament, the molecular interval of the actin subunits (~5.5 nm) was clearly observed as stripes. From the shape of the stripes, the polarity of the actin filament was directly determined and the results were consistent with the polarity determined by myosin binding. In the image of the actin-tropomyosin complex, each tropomyosin molecule (~2 nm in diameter) on the actin filament was directly observed without averaging images of different molecules. Each tropomyosin molecule on the actin filament has never been directly observed by AFM or electron microscopy. Thus, our developed tip scan AFM offers significant potential in observing purified proteins and cellular structures at nanometer resolution. Current results represent an important step in the development of a new correlative microscope to observe nm-order structures at an acceptable frame rate (~10 s/frame) by AFM at the position indicated by the fluorescent dye observed under a light microscope. PMID- 27242061 TI - Prevalence of obesity in paediatric psoriasis and its impact on disease severity and progression. AB - BACKGROUND/OBJECTIVES: The current literature suggests there is a possible connection between paediatric psoriasis and obesity. However, there is a paucity of research on the influence of increased adiposity on the severity of paediatric psoriasis and disease progression. We aimed to compare the prevalence of being overweight or obese in paediatric psoriasis patients and controls and assess the potential impact of being overweight/obese on disease severity and progression of disease. METHODS: This multicentre prospective case-control study included 289 psoriasis patients (aged < 18 years) treated and followed up by one of the four university hospitals in Turkey. The control group consisted of 151 consecutive age-matched and sex-matched children who lacked a personal or family history of psoriasis. The participants' characteristics, psoriasis-related parametres (e.g., initial subtype, psoriasis area and severity index, presence of psoriatic arthritis) and body mass index were determined. RESULTS: The difference between the prevalence of being overweight/obese among psoriatics (28%) and the control group (19%) was significant (P = 0.024). Being overweight/obese had no significant impact on disease severity and unresponsiveness to topical treatment. Within a median follow-up time of 12 months, 23% of our patients with localised disease at disease onset progressed to generalised disease. The impact of being overweight/obese on disease progression was found to be non-significant; however, disease duration was found to have a significant impact on disease progression (P = 0.026). CONCLUSIONS: Although it is not associated with disease severity and course, increased bodyweight may be a health problem for psoriatic children. PMID- 27242060 TI - Alcohol use predicts elevation in inflammatory marker soluble CD14 in men living with HIV. AB - Independently, HIV infection and heavy alcohol use increase microbial translocation (MT) of gut products into systemic circulation. MT and consequent immune response have been linked to chronic inflammation and a host of negative health outcomes in individuals living with HIV. However, previous research has not systematically investigated the immune correlates of heavy drinking specifically within the HIV-positive population. This pilot study investigated MT and immune activation as a function of alcohol use in 21 HIV-positive men who met NIAAA criteria for heavy drinking. Participants averaged 46.7 +/- 8.5 (mean +/- standard deviation) years of age, 12.2 +/- 9.2 years since HIV diagnosis, 337 +/- 158 CD4 nadir, and 643 +/- 245 current CD4 count. All participants were virologically suppressed on antiretroviral therapy. Data on alcohol use and immune function were collected at baseline and three-month follow-up. Plasma concentrations of markers of MT and immune activation (lipopolysaccharide (LPS), soluble CD14 (sCD14), endotoxin core antibody immunoglobulin M (EndoCAb)) were measured using enzyme-linked immunosorbent assays. Generalized estimating equation models tested alcohol use variables as predictors of LPS, sCD14, and EndoCAb levels. Greater quantity and frequency of drinking significantly predicted higher sCD14 levels (p's < .01). Conversely, longer duration of abstinence from alcohol significantly predicted lower sCD14 levels (p < .001). These results remained significant after controlling for age, HIV duration, smoking status, current CD4 count, CD4 nadir, and antiretroviral drug type. In addition, participants with >=50% relative reduction in drinks per week showed a significant decrease (p < .05) in sCD14 from baseline to three-month follow-up. This pilot study provides preliminary evidence that heavy drinking may increase a key inflammatory marker in HIV-infected individuals with suppressed infection. PMID- 27242062 TI - Rapid tumor growth with glial differentiation of central neurocytoma after stereotactic radiosurgery. AB - Although stereotactic radiosurgery (SRS) is effective for central neurocytoma (CN), the long-term outcome of SRS remains unclear. We present a case of recurrent CN that was diagnosed 10years after surgical resection and consecutive stereotactic radiotherapy. The patient was treated with SRS for the recurrent tumor, but underwent two-staged surgery once again due to rapid tumor growth. Histological features of the recurrent tumor were consistent with the diagnosis of CN. However, an increased Ki-67 proliferation index (3.4%), aberrant angiogenesis and glial differentiation of the tumor cells were observed, which were not identified in the initial CN. In addition, vascular endothelial growth factor (VEGF) and VEGF receptor were highly expressed in the recurrent tumor cells, as well as in the vascular endothelial cells. Our case suggests that malignant transition with aberrant angiogenesis and glial differentiation may be attributable to SRS. PMID- 27242063 TI - Epidemiology of inpatient stay in Parkinson's disease in the United States: Insights from the Nationwide Inpatient Sample. AB - The total number of people living with Parkinson's disease (PD) worldwide is expected to double by 2030. The risk factors for emergency department visits in PD patients have been described before, however, there is limited data on inpatient hospitalizations of PD patients. We derived our study cohort from the Nationwide Inpatient Sample (NIS) database from 2002-2011. The NIS is a stratified 20% sample of discharges from all U.S. hospitals. We extracted causes of hospitalization using International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) codes and calculated inpatient mortality, length of stay and cost. Further, the significance of trends over 10 years was assessed. A total of 3,015,645 (weighted) admissions of PD patients were documented from 2002-2011. Pneumonia, urinary tract infection (UTI), septicemia and aspiration pneumonitis were the most common causes of admission, of which incidence of sepsis and UTI was trending up. Of all causes, 3.9% of the admissions resulted in inpatient mortality. Inpatient mortality for PD patients decreased from 4.9% in 2002 to 3.3% in 2011 (p<0.001). The median length of stay has also steadily declined from 3.6days in 2002 to 2.3days in 2011. However, the inflation-adjusted cost of care has been steadily rising, from $22,250 per hospitalization in 2002 to $37,942 in 2011. We conclude that the epidemiology of inpatient admissions in PD has changed significantly over the last decade. Our study underscores the need for future, in-depth prospective studies to explore this changing disease spectrum to design preventive measures and targeted interventions. PMID- 27242064 TI - High density 3D printed microfluidic valves, pumps, and multiplexers. AB - In this paper we demonstrate that 3D printing with a digital light processor stereolithographic (DLP-SLA) 3D printer can be used to create high density microfluidic devices with active components such as valves and pumps. Leveraging our previous work on optical formulation of inexpensive resins (RSC Adv., 2015, 5, 106621), we demonstrate valves with only 10% of the volume of our original 3D printed valves (Biomicrofluidics, 2015, 9, 016501), which were already the smallest that have been reported. Moreover, we show that incorporation of a thermal initiator in the resin formulation along with a post-print bake can dramatically improve the durability of 3D printed valves up to 1 million actuations. Using two valves and a valve-like displacement chamber (DC), we also create compact 3D printed pumps. With 5-phase actuation and a 15 ms phase interval, we obtain pump flow rates as high as 40 MUL min(-1). We also characterize maximum pump back pressure (i.e., maximum pressure the pump can work against), maximum flow rate (flow rate when there is zero back pressure), and flow rate as a function of the height of the pump outlet. We further demonstrate combining 5 valves and one DC to create a 3-to-2 multiplexer with integrated pump. In addition to serial multiplexing, we also show that the device can operate as a mixer. Importantly, we illustrate the rapid fabrication and test cycles that 3D printing makes possible by implementing a new multiplexer design to improve mixing, and fabricate and test it within one day. PMID- 27242065 TI - Intravenous immunoglobulin in paediatric neurology: safety, adherence to guidelines, and long-term outcome. AB - AIM: Intravenous immunoglobulin (IVIG) is an expensive therapy used in immunodeficiency and autoimmune disorders. Increasing demands and consequent shortages result in a need for usage to conform to guidelines. METHOD: We retrospectively evaluated IVIG use for neuroimmunological indications and adherence to existing guidelines in a major Australian paediatric hospital between 2000 and 2014. RESULTS: One-hundred and ninety-six children (96 male, 100 female; mean age at disease onset 6y 5mo [range 3mo-15y 10mo], mean age at first IVIG dose 7y 2mo [range 3mo-16y 5mo]) received IVIG for neuroimmunological indications during the study period (28.1% had Guillain-Barre syndrome), representing 15.5% of all hospital indications. In total, 1669 IVIG courses were administered (total 57 221g, median 78g/patient, range 12-5748g). The highest median numbers of courses were in chronic inflammatory demyelinating polyneuropathies, opsoclonus-myoclonus ataxia syndrome, suspected immune-mediated epilepsies, and Rasmussen's encephalitis. Adverse reactions occurred in 25.5% of patients, but these were mostly minor. Outcome at follow-up was best in anti-N methyl-d-aspartate receptor (anti-NMDAR) encephalitis, Guillain-Barre syndrome, and myasthenia gravis, and worst in Rasmussen's encephalitis and epilepsies. The total cost of IVIG was US$2 595 907 (median $3538/patient, range $544-260 766). Of patients receiving IVIG, 45.4% to 57.1% were given the therapy for 'weak' indications or indications 'not listed' in international guidelines. Some entities commonly treated with IVIG in current practice, such as anti-NMDAR encephalitis and transverse myelitis, are not listed in most guidelines. INTERPRETATION: Our study demonstrates that IVIG is generally well tolerated but expensive, and discloses discrepancies between guidelines and clinical practice in paediatric neurology, suggesting both the need for greater adherence to current recommendations, and for recommendations to be updated to accommodate emerging indications. PMID- 27242066 TI - Mixed-linker approach in designing porous zirconium-based metal-organic frameworks with high hydrogen storage capacity. AB - Three highly porous Zr(iv)-based metal-organic frameworks, UBMOF-8, UBMOF-9, and UBMOF-31, were synthesized by using 2,2'-diamino-4,4'-stilbenedicarboxylic acid, 4,4'-stilbenedicarboxylic acid, and combination of both linkers, respectively. The mixed-linker UBMOF-31 showed excellent hydrogen uptake of 4.9 wt% and high selectivity for adsorption of CO2 over N2 with high thermal stability and moderate water stability with permanent porosity and surface area of 2552 m(2) g( 1). PMID- 27242067 TI - Using poverty of speech as a case study to explore the overlap between negative symptoms and cognitive dysfunction. AB - BACKGROUND: Negative symptoms and cognitive impairment are both regarded as important prognostic markers in schizophrenia. Although these two domains are viewed as distinct and separable, conceptual overlap exists. We sought to illustrate this overlap using speech deficits among patients with schizophrenia. METHOD: Reductions in verbal output were rated by a clinician following an interview, and these ratings were taken to represent negative symptoms (i.e., alogia). Patients were also asked to recount words from specific categories in a standardized manner, and the number of words was recorded as per standard protocol for verbal fluency tests. These scores were taken to represent cognitive impairment. The cross-sectional and longitudinal relationships between these two variables were then examined. RESULTS: Patients with more severe alogia produced significantly less words on the verbal fluency tests. This relationship was stronger than that observed with other negative symptoms, and also held after controlling for a number of sociodemographic and clinical variables (e.g., severity of illness). Prospective increases in the number of words produced during the verbal fluency test were associated with improvements in clinical alogia ratings, a longitudinal relationship that was not observed with other negative symptoms. CONCLUSIONS: Some negative symptoms are conceptually related and therefore not fully distinct from cognitive impairments. Here, we demonstrate that clinical ratings of alogia and words produced during a cognitive test are tapping into a similar construct. Whether a specific deficit is classified as a negative versus cognitive symptom may be matter of semantics rather than reflective of divisible underlying processes. PMID- 27242068 TI - Approaching anger in schizophrenia: What an implicit task tells you that self report does not. AB - Motivational deficits are important determinants of impaired social functioning in schizophrenia, yet we know very little about their precise nature. One influential model of motivation distinguishes between approach and avoidance neurobiological systems that impact the tendency to approach rewarding and avoid threatening stimuli. The current study evaluated approach and avoidance motivational tendencies using both implicit and explicit measures. One-hundred and sixteen individuals with schizophrenia and 73 healthy controls completed the implicit Approach Avoidance Task (AAT) which provides a reaction time-based measure of approach and avoidance tendencies for happy and angry faces, and the Behavioral Inhibition/Behavioral Activation System Scale (BIS/BAS), a self-report measure of approach and avoidance tendencies. The patient sample was re administered the AAT four weeks later to evaluate re-test reliability. At baseline, patients showed a significant tendency to approach (rather than avoid) angry faces on the AAT. This same pattern was replicated at the follow-up assessment. In contrast, on the BIS/BAS, patients reported significantly elevated BIS scores, reflecting increased avoidance of aversive, anxiety-inducing stimuli. Results suggest a discrepancy between patients' implicit behavioral tendency to approach angry faces and their self-reported avoidance of aversive stimuli. PMID- 27242069 TI - Primary and persistent negative symptoms: Concepts, assessments and neurobiological bases. AB - Primary and persistent negative symptoms (PPNS) represent an unmet need in the care of people with schizophrenia. They have an unfavourable impact on real-life functioning and do not respond to available treatments. Underlying etiopathogenetic mechanisms of PPNS are still unknown. The presence of primary and enduring negative symptoms characterizes deficit schizophrenia (DS), proposed as a separate disease entity with respect to non-deficit schizophrenia (NDS). More recently, to reduce the heterogeneity of negative symptoms by using criteria easily applicable in the context of clinical trials, the concept of persistent negative symptoms (PNS) was developed. Both PNS and DS constructs include enduring negative symptoms (at least 6months for PNS and 12months for DS) that do not respond to available treatments. PNS exclude secondary negative symptoms based on a cross-sectional evaluation of severity thresholds on commonly used rating scales for positive symptoms, depression and extrapyramidal side effects; the DS diagnosis, instead, excludes all potential sources of secondary negative symptoms based on a clinical longitudinal assessment. In this paper we review the evolution of concepts and assessment modalities relevant to PPNS, data on prevalence of DS and PNS, as well as studies on clinical, neuropsychological, brain imaging electrophysiological and psychosocial functioning aspects of DS and PNS. PMID- 27242070 TI - Vocal fold motion outcome based on excellent prognosis with laryngeal electromyography. AB - OBJECTIVES/HYPOTHESIS: As laryngeal electromyography (LEMG) becomes more refined, accurate predictions of vocal fold motion recovery are possible. Focus has been on outcomes for patients with poor prognosis for vocal fold motion recovery. Limited information is available regarding the expected rate of purposeful vocal fold motion recovery when there is good to normal motor recruitment, no signs of denervation, and no signs of synkinetic activity with LEMG, termed excellent prognosis. The objective of this study is to determine the rate of vocal fold motion recovery with excellent prognosis findings on LEMG after acute recurrent laryngeal nerve injury. STUDY DESIGN: Retrospective review. METHODS: Patients undergoing a standardized LEMG protocol, consisting of qualitative (evaluation of motor recruitment, motor unit configuration, detection of fibrillations, presence of synkinesis) and quantitative (turns analysis) measurements were evaluated for purposeful vocal-fold motion recovery, calculated after at least 6 months since onset of injury. RESULTS: Twenty-three patients who underwent LEMG for acute vocal fold paralysis met the inclusion criteria of excellent prognosis. Eighteen patients (78.3%) recovered vocal fold motion, as determined by flexible laryngoscopy. CONCLUSION: Nearly 80% of patients determined to have excellent prognosis for vocal fold motion recovery experienced return of vocal fold motion. This information will help clinicians not only counsel their patients on expectations but will also help guide treatment. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:2310-2314, 2016. PMID- 27242071 TI - Social identity change in response to discrimination. AB - This study investigated the conditions under which discrimination can lead to social identity changes among members of a minority group. Both positive and negative relations between perceptions of discrimination and social identity have previously been reported. To explain the conflicting results and understand the complex reality of members of stigmatized groups, we argue that group-based emotions (e.g., group-based dissatisfaction) and ambiguity of discrimination cues (i.e., overt vs. ambiguous) need to be considered. We hypothesized that perceptions of discrimination would play a moderating role between group-based dissatisfaction and social identity change in a context of ambiguous, but not of overt, discrimination. The sample was comprised of 151 Arab Muslims living in the province of Quebec. Participants read fictitious newspaper articles portraying either overt (n = 76) or ambiguous (n = 75) discrimination towards in-group members. Results revealed that for participants in the overt discrimination condition, only group-based dissatisfaction was positively associated with social identity change. In contrast, for the participants in the ambiguous discrimination condition, those who perceived little discrimination and felt low group-based dissatisfaction reported a decrease in social identity. However, those who perceived low group discrimination and felt high group-based dissatisfaction reported a positive social identity change. PMID- 27242072 TI - Analysis of gene functions in Maize chlorotic mottle virus. AB - Gene functions of strains of Maize chlorotic mottle virus, which comprises the monotypic genus Machlomovirus, have not been previously identified. In this study mutagenesis of the seven genes encoded in maize chlorotic mottle virus (MCMV) showed that the genes with positional and sequence similarity to their homologs in viruses of related tombusvirid genera had similar functions. p50 and its readthrough protein p111 are the only proteins required for replication in maize protoplasts, and they function at a low level in trans. Two movement proteins, p7a and p7b, and coat protein, encoded on subgenomic RNA1, are required for cell to-cell movement in maize, and p7a and p7b function in trans. A unique protein, p31, expressed as a readthrough extension of p7a, is required for efficient systemic infection. The 5' proximal MCMV gene encodes a unique 32kDa protein that is not required for replication or movement. Transcripts lacking p32 expression accumulate to about 1/3 the level of wild type transcripts in protoplasts and produce delayed, mild infections in maize plants. Additional studies on p32, p31 and the unique amino-terminal region of p50 are needed to further characterize the life cycle of this unique tombusvirid. PMID- 27242073 TI - An experimental ovine Theileriosis: The effect of Theileria lestoquardi infection on cardiovascular system in sheep. AB - The malignant ovine theileriosis is caused by Theileria lestoquardi, which is highly pathogenic in sheep. Theileriosis involves different organs in ruminants, but the effect of the disease on the cardiovascular system is unclear. To understand the pathogenesis of T. lestoquardi on the cardiovascular system, Baluchi breed sheep were infected with the mentioned parasite by releasing unfed adults of Hyalomma anatolicum anatolicum, which were infected with T. lestoquardi. The infected sheep were clinically examined on days 0, 2, 5, 7, 10, 12, 14, 17, and 21, and the blood samples were collected for biochemical parameters measurement. At termination of the experiment, the infected sheep were euthanized and pathological examinations of heart tissue were conducted. During experimental infection of sheep with T. lestoquardi, activities of cardiac troponin I (cTnI), lactate dehydrogenase, and aspartate aminotransferase, were significantly increased (P?0.05), while a conspicuous decrease (P?0.05) was observed in creatine phosphokinase activities. Alterations made in biochemical factors almost coincided with the presence of piroplasm in the blood and schizont in lymph nodes. Maximum and minimum of parasitemia in the sheep stood between 3.3% and 0.28%, respectively. In addition, electrocardiography revealed sinus tachycardia, sinus arrhythmia, sino-atrial block and ST-elevation, atrial premature beat, and alteration in QRS and in T waves' amplitude. Heart histopathological examination showed hyperemia, infiltration of mononuclear inflammatory cells into interstitial tissue, endocarditis, and focal necrosis of cardiac muscle cells. In addition, in one of the sheep, definite occurrence of infarction was observed. The results indicate that T. lestoquardi infection has devastating pathological impacts on the cardiovascular system of sheep. Furthermore, measurement of the cTnI amount is a useful biochemical factor for diagnosis and for better understanding of the severity and progression of the disease and its effects on cardiac tissue. PMID- 27242074 TI - Addendum. PMID- 27242076 TI - Letter: the emergence of multi-drug resistant spontaneous bacterial peritonitis: a new challenge for the hepatologist? Authors' reply. PMID- 27242075 TI - T-bet promotes the accumulation of encephalitogenic Th17 cells in the CNS. AB - T-bet enhances the encephalitogenicity of myelin-reactive CD4+ T cells, however its mechanism of action is unknown. In this study we show that T-bet confers a competitive advantage for the accumulation of IL-23 conditioned Th17 effector cells in the central nervous system (CNS). Impaired migration of T-bet deficient Th17 cells to the CNS is associated with altered expression of adhesion molecules and chemokine receptors on their cell surface. Our data suggest that therapeutic targeting of T-bet in individuals with Th17-mediated autoimmune demyelinating disease may inhibit inflammatory infiltration of the CNS and, hence, clinical exacerbations. PMID- 27242077 TI - An organosilane self-assembled monolayer incorporated into polymer solar cells enabling interfacial coherence to improve charge transport. AB - The reproducible silylation of titanium oxide (TiO2) with small molecular (dichloromethyl) dimethylchlorosilane (DCS) as the cathode buffer layer was developed to improve electron extraction. Through incorporating the DCS capping layer into polymer solar cells (PSCs), the interfacial coherence of devices could be enhanced, leading to a shift in nanocrystallite size and a smaller internal charge transport resistance. Furthermore, a TiO2/DCS combined interfacial layer could serve as both an exciton dissociation center and a charge transfer channel, which results in a reduction in the energy barrier and electron loss, improving hole-blocking and surface-state passivation in the TiO2 interfacial layer. The Kelvin probe measurements demonstrate that the employment of the DCS nanolayer decreases conduction band energy of TiO2via forming a dipole layer at the interface of TiO2 and the DCS nanolayer, which tunes the work-function of the device and ulteriorly enhances charge carrier transfer between the electrode and the active layer. As a result, the photocurrent and the fill factor of the PSCs are both increased, resulting in an increased power conversion efficiency (PCE) of 6.959%. PMID- 27242078 TI - Estrogen-induced neuroprotective and anti-inflammatory effects are dependent on the brain areas of middle-aged female rats. AB - BACKGROUND: Reproductive aging in females is characterized by fluctuations and precipitous decline in estrogen levels, which may lead to reduction in cognitive function and age-associated neurodegenerative disorders. The nature of estrogen mediated neuronal plasticity is unknown during reproductive aging. We hypothesize that estrogen treatment of early middle-aged ovariectomized rats may exert specific effects in the brain by modulating signaling pathways regulating metabolic enzymes, inflammatory markers, antioxidant status, cholinergic function and survival signals. PURPOSE: To investigate the mechanisms of estrogen-induced effects on neuroprotection and neuroinflammation through the involvement of intracellular signaling pathways in brain areas of ovariectomized (OVX) middle aged (MA) female rats. METHODS: Ovariectomized early MA female Sprague-Dawley rats (n=8/group) were implanted with 17beta-estradiol (E2) 30-day release pellets (0.6MUg and 300MUg). At the end of the treatment period, frontal cortex (FC), striatum (STR), medial basal hypothalamus (MBH), and hippocampus (HP) were isolated and examined for the expression of tyrosine hydroxylase (p-TH), nerve growth factor (NGF), p-NF-kappaB (p50 and p65)and p-ERK, p-CREB, p-Akt, and activities of cholinesterases and antioxidant enzymes, key regulatory enzymes of metabolic pathways, and nitric oxide production. RESULTS: E2 enhanced p-TH expression in FC and HP, reduced NGF expression in HP, and suppressed p-NF-kappaB expression in FC and STR. It also increased the expression of molecular markers (p-ERK, p-CREB and p-Akt), and nitric oxide production in various brain areas, while differentially regulating the activities of metabolic enzymes and cholinesterases. CONCLUSION: Estrogen modulates the neural and inflammatory factors, and intracellular markers depending on the brain areas that may influence differential remodeling of neuronal circuitry which can be used to develop therapeutic strategies in cognitive impairment and neurodegenerative disorders in aging. PMID- 27242079 TI - Use of Electronic Cigarettes Among Cancer Survivors in the U.S. AB - INTRODUCTION: The population-level patterns of electronic cigarette (e-cigarette) use among cancer survivors in the U.S. are unknown. The objective of this study was to examine the prevalence and correlates of e-cigarette use among cancer survivors in a nationally representative sample. METHODS: A cross-sectional analysis was conducted of the 2014 National Health Interview Survey of the U.S. non-institutionalized civilian population. The main study outcomes were the prevalence and correlates of ever and current e-cigarette use among adults with self-reported history of cancer, excluding non-melanoma skin cancer (N=2,695). Multivariable logistic regression analyses examined whether e-cigarette use differed by cigarette smoking status and demographic subgroups. The analyses were performed in 2015. RESULTS: The prevalence of e-cigarette use among adult cancer survivors was lower than the general population: 2.8% of cancer survivors reported currently using e-cigarettes and an additional 6.3% had previously used e-cigarettes but were not currently using them. Use of e-cigarettes was most common among cancer survivors who currently smoked cigarettes: 34.3% of current smokers were ever e-cigarette users and 15.6% were current e-cigarette users, compared with former smokers (2.7% ever and 1.4% current e-cigarette users) and never smokers (small sample/estimates unavailable). CONCLUSIONS: E-cigarettes are not part of current evidence-based smoking-cessation strategies. However, the finding that cancer survivors who currently smoke cigarettes are more likely to use e-cigarettes highlights the importance of addressing e-cigarette use in patient-provider communications around tobacco cessation. PMID- 27242080 TI - Continued Importance of Sexually Transmitted Disease Clinics in the Era of the Affordable Care Act. AB - INTRODUCTION: Following the 2014 expansions of Medicaid and private health insurance through the Affordable Care Act, municipal sexually transmitted disease (STD) clinics-which have historically served predominantly uninsured patients have been threatened with budget cuts nationwide. This study was conducted to evaluate the impact of the insurance expansions on the demand for STD clinic services. METHODS: The proportion of total incident sexually transmitted infections in Baltimore City that were diagnosed at STD clinics was compared between 2013 and 2014, and a multivariate analysis was conducted to determine factors associated with diagnosis at an STD clinic. Analyses were conducted in July 2015. RESULTS: There was no change in the overall proportion of sexually transmitted infection diagnoses made at STD clinics from 2013 to 2014 (relative rate, 1.03; 95% CI=0.95, 1.11). Hispanic ethnicity, black race, male sex, and age >24 years were associated with an increased likelihood of STD clinic utilization (p<0.0001). CONCLUSIONS: Despite the Affordable Care Act's insurance expansion measures, the demand for STD clinics remained stable. These safety net clinics serve patients likely to face barriers to accessing traditional health care and their preservation should remain a priority. PMID- 27242082 TI - The North Karelia Project: The Spark That Ignited the Flame! PMID- 27242081 TI - Colorectal Cancer Screening in Vulnerable Patients: Promoting Informed and Shared Decisions. AB - INTRODUCTION: Low-income, low-literacy, limited English-proficient populations have low colorectal cancer (CRC) screening rates and experience poor patient provider communication and decision-making processes around screening. The purpose of this study was to test the effect of a CRC screening decision aid on screening-related communication and decision making in primary care visits. STUDY DESIGN: RCT with data collected from patients at baseline and immediately after the provider encounter. SETTING/PARTICIPANTS: Patients aged 50-75 years, due for CRC screening, were recruited from two safety net clinics in North Carolina and New Mexico (data collection, January 2014-September 2015; analysis, 2015). INTERVENTION: Participants viewed a CRC screening decision aid or a food safety (control) video immediately before their provider encounter. MAIN OUTCOME MEASURES: CRC screening-related knowledge, discussion, intent, test preferences, and test ordering. RESULTS: The study population (N=262) had a mean age of 58.3 years and was 66% female, 61% Latino, 17% non-Latino black, and 16% non-Latino white. Among Latino participants, 71% preferred Spanish. Compared with controls, intervention participants had greater screening-related knowledge (on average 4.6 vs 2.8 of six knowledge items correct, adjusted difference [AD]=1.8, 95% CI=1.5, 2.1) and were more likely to report screening discussion (71.0% vs 45.0%, AD=26.1%, 95% CI=14.3%, 38.0%) and high screening intent (93.1% vs 84.7%, AD=9.0%, 95% CI=2.0%, 16.0%). Intervention participants were more likely to indicate a specific screening test preference (93.1% vs 68.0%, AD=26.5%, 95% CI=17.2%, 35.8%) and to report having a test ordered (56.5% vs 32.1%, AD=25.8%, 95% CI=14.4%, 37.2%). CONCLUSIONS: Viewing a CRC screening decision aid before a primary care encounter improves knowledge and shared decision making around screening in a racially, ethnically, and linguistically diverse safety net clinic population. TRIAL REGISTRATION: This study is registered at www.clinicaltrials.gov NCT02054598. PMID- 27242083 TI - Background, Principles, Implementation, and General Experiences of the North Karelia Project. AB - The extremely high mortality of cardiovascular diseases in the 1960s in Finland, particularly in the Eastern Province of North Karelia and especially that of coronary heart disease in men, caused great concern among the local population. Action to reduce the problem was demanded in a petition signed in 1971 by the representatives of the population. In response, the North Karelia Project was launched in 1972 to carry out a comprehensive preventive project, first only in North Karelia as a national pilot (1972 to 1977), and thereafter continuing in North Karelia but at the same time transferring the experiences to a national level. The intervention was based on the at-that-time relatively new scientific information on the main causal risk factors. A comprehensive population-based intervention was carried out, aiming especially at the reduction of the high levels of serum cholesterol, blood pressure, and tobacco use, emphasizing general dietary changes and smoking reduction. A comprehensive monitoring and evaluation program was designed and implemented to learn from the experience in preparation for national and international use. Presented here are the background, principles, and general experiences of this project, which has made major contributions both to the contemporary public health work for the prevention and control of heart disease and noncommunicable diseases and for research in the area. PMID- 27242084 TI - Changes in Serum Cholesterol and Diet in North Karelia and All Finland. AB - Finland in the 1960s, and especially North Karelia in the eastern part of the country, had the highest cardiovascular mortality in the world. The classical cardiovascular risk factors were all common, but serum cholesterol level was extremely high because of the very high intake of saturated fats, mainly from dairy products. The North Karelia Project was started as a comprehensive preventive program to reduce serum cholesterol levels by reducing the intake of saturated fats and increasing the intake of polyunsaturated fats in the whole population. Cross-sectional population surveys were done in North Karelia and nearby Kuopio province every 5 years starting in 1972. After 1982, surveys were started in 2 other areas. Blood cholesterol was measured from serum samples, and diet was assessed by a questionnaire in all surveys-since 1982 by 3-day food record, since 1997 by 24-hour recall, and since 2002 by 48-hour recall. Between 1972 and 2012, the population in North Karelia reduced serum cholesterol from 6.92 mmol/l to 5.46 mmol/l (21%) in men and from 6.81 mmol/l to 5.37 mmol/l (21%) in women. In men, serum cholesterol level reduced more in North Karelia than in the reference province of Kuopio during the first 5 years from 1972 to 1977. Since that time, changes in serum cholesterol level have been very similar in different parts of the country. Saturated fats were reduced from 20% of energy intake to 12% in 2007 but increased from 2007 to 2012 to 14%. In conclusion, serum cholesterol reduction by dietary changes is feasible on the population level but requires active work and large-scale cooperation between all the meaningful sectors in the society. PMID- 27242085 TI - Tobacco Control: From North Karelia to the National Level. AB - After World War II, smoking among men was very common in Finland, and especially in North Karelia, contributing to the high rates of cardiovascular diseases and cancer. Thus, the North Karelia Project, from its very start in 1972, took reduction in smoking as one of its main targets. After 1977, the project actively contributed to national tobacco control work, including comprehensive legislation and many other activities. Smoking in North Karelia declined initially much more than in the rest of Finland, but thereafter there has been a steady national decline, resulting in a prevalence of daily smoking among adults of approximately 15% and contributing to the big reduction in the rates of heart disease and tobacco-related cancers, especially among men. PMID- 27242086 TI - Blood Pressure, Sodium Intake, and Hypertension Control: Lessons From the North Karelia Project. AB - From the very beginning of the North Karelia Project, prevention, detection, and control of hypertension were included as key aims in the project. An intensive hypertension prevention and control program was established in North Karelia in 1972 that included community-based activities to reduce blood pressure levels in the entire population, detect people with hypertension, improve their treatment, establish standard diagnostic and therapeutic methods, and to monitor blood pressure levels, control of hypertension, and the performance of the health care. After the first 5 years of the project, most of these activities were also implemented on the national level. In late 1970s, work to reduce the salt intake was started, and substantial reductions have taken place in salt intake in the Finnish population. Remarkable improvements have been seen both in blood pressure levels and in treatment and control of hypertension in North Karelia and in the whole of Finland. Between 1972 and 2012 in North Karelia, the mean systolic blood pressure among 30- to 59-year-old men has decreased from 149 mm Hg to 135 mm Hg and among women from 153 mm Hg to 129 mm Hg. The decreases in mean diastolic blood pressure have been from 92 mm Hg to 84 mm Hg among men and from 92 mm Hg to 79 mm Hg among women. PMID- 27242087 TI - Changes in CVD Incidence and Mortality Rates, and Life Expectancy: North Karelia and National. AB - During the last 40 years, Finland has experienced a remarkable decline in coronary heart disease and stroke mortality. The latest coronary heart disease mortality figures in the working-age population are <20% of the top figures in the early 1970s. Equal declines can be seen in men and in women, and the improvement extends to elderly populations as well. However, due to the very high historic levels, Finland still continues to have clearly higher cardiovascular mortality than, for example, the Mediterranean countries. Parallel to the decline in cardiovascular mortality, the life expectancy of Finns has increased by 11.6 years in men and by 9.2 years in women. The probability for a 30-year-old man to die of cardiovascular disease has dropped from about 30% in 1970 to 7% in 2013, and for a 30-year-old woman, the corresponding probability has dropped from 13% to about 2%. PMID- 27242088 TI - 40-Year CHD Mortality Trends and the Role of Risk Factors in Mortality Decline: The North Karelia Project Experience. AB - In the 1960s and early 1970s, coronary heart disease (CHD) mortality in Finland was the highest in the world, and within Finland, mortality was particularly high in the eastern part of the country. The North Karelia Project, the first large community-based cardiovascular diseases prevention program was established in 1972 to reduce the extremely high CHD mortality through behavioral change and reduction of the main cardiovascular disease risk factors among the whole population of North Karelia, the easternmost province of Finland. During the 40 year period from 1972 to 2012, smoking prevalence, serum total cholesterol, and systolic blood pressure declined markedly, except a small increase in serum cholesterol levels between 2007 and 2012. From the early 1970s to 2012, CHD mortality decreased by 82% (from 643 to 118 per 100,000) among working-age (35 to 64 years) men. Among working-age women, the decline was 84% (from 114 to 17 per 100,000). During the first 10 years, changes in these 3 target risk factors explained nearly all of the observed mortality reduction. Since the mid-1980s, the observed reduction in mortality has been larger than the predicted reduction. In the early 1970s, premature CHD mortality (35 to 74 years) was about 37% higher among Eastern Finnish men and 23% higher among Eastern Finnish women, compared with men and women in Southwestern Finland. During the last 40 years, premature CHD mortality declined markedly in both areas, but the decline was larger in Eastern Finland and the mortality gap between the two areas nearly disappeared. PMID- 27242089 TI - Predicting Coronary Heart Disease and Stroke: The FINRISK Calculator. AB - The FINRISK risk calculator predicts 10-year risk for coronary heart disease, stroke incidence, and their combination. The model is based on 10-year cohort follow-up from 3 different cohorts in 1982, 1987, and 1992 from a random population sample in 3 areas in Finland. Coronary heart disease, stroke, and their combination are predicted by smoking, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, diabetes, and family history. The Internet-based calculator is commonly used in Finland in health services to assess the need for hypertension and hypercholesterolemia treatment and is used also in patients' counseling. PMID- 27242090 TI - WHO MONICA Project and its Connections to the North Karelia Project. AB - The World Health Organization's MONICA (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease) Project was established after the increase in mortality from coronary heart disease had turned to a decline in some countries. Its objective was to measure the trends in cardiovascular mortality and coronary heart disease and cerebrovascular disease morbidity, and to assess the extent to which these trends were related to changes in known risk factors and health care measured at the same time in defined populations in different countries. Thirty-one centers in 21 countries carried out the monitoring over a period of 10 years in the 1980s and 1990s. The project provided information on disease rates, risk factors, and treatment for the first time in most of the study populations. The results answered some of the initial questions and opened new questions on the complexity of the associations between disease trends and their determinants. MONICA had a major impact in training cardiovascular epidemiologists and in creating measurement standards for international use. PMID- 27242091 TI - Following in the Footsteps of the North Karelia Project: Prevention of Type 2 Diabetes. AB - The prevalence as well as actual number of people with type 2 diabetes has been increasing in Finland during the past decades, in parallel with an increase in overweight and obesity. Besides obesity, population aging is among the main drivers of increasing numbers of diabetic patients. Type 2 diabetes brings along complications, most importantly cardiovascular diseases, and increasing type 2 diabetes prevalence has also been suggested to lead to a new upward turn in cardiovascular diseases. Therefore, it is important to implement activities to prevent type 2 diabetes. We present the trial evidence for the prevention of type 2 diabetes with emphasis on the Finnish Diabetes Prevention Study findings. Furthermore, we discuss the practical implementation of screening of individuals for high type 2 diabetes risk and prevention of type 2 diabetes in Finland at the population level and describe how they have contributed to European level initiatives. PMID- 27242092 TI - Genetic and Environmental Contributions to Cardiovascular Risk: Lessons From North Karelia and FINRISK. AB - Systematic collection of DNA samples started in FINRISK during the 1992 survey and has continued in all surveys since then. At the moment, FINRISK has DNA, careful phenotyping at baseline, and prospective follow-up for incident disease for about 34,000 participants. These data have been used for genome-wide association studies by contributing to numerous large international consortia, mainly focused on cardiovascular diseases and their risk factors. In parallel, genomic data from FINRISK have been used for cardiovascular risk estimation, and our constantly improving knowledge of cardiovascular disease risk variants generates promising prospects in this field. The isolated nature of the Finnish population and recent bottlenecks in our population history, particularly in eastern Finland, provide certain advantages for sequencing studies. The power to detect low-frequency variants is stronger in isolated populations, like those in eastern Finland, than in more admixed populations. Together with country-wide and reliable electronic health records, this provides a resource that is currently widely utilized in whole exome and whole genome sequencing studies. PMID- 27242093 TI - From Heart Health to Brain Health: Legacy of the North Karelia Project for Dementia Research. AB - Cognitive impairment is very common in advanced age, with dementia representing the main cause of disability in older adults. Over the past 20 years, several modifiable risk factors have been identified for dementia and Alzheimer's disease (AD), and many of them are shared with cardiovascular diseases. Given that the pathologic changes leading to dementia may start decades before dementia is diagnosed, it is crucial to adopt a life course approach when investigating risk factors for dementia. The CAIDE (Cardiovascular Risk Factors, Aging and Dementia) study is one of the first and still very few existing observational studies to have investigated the role of midlife risk factors for the subsequent development of dementia and AD in late life. The CAIDE study is built on the North Karelia Project, enabling risk factor assessment 20 to 30 years before the dementia diagnosis. The CAIDE study has revealed that late-life dementia and AD are heterogeneous and multifactorial disorders, suggesting that multidomain interventions targeting several risk factors simultaneously may be needed for optimal preventive effects. The FINGER (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) study is the first large long-term multidomain lifestyle intervention showing effect on prevention of cognitive impairment in at-risk elderly people. The study is conducted within the existing framework and builds on multidisciplinary prevention expertise following the North Karelia Project and CAIDE study. The FINGER study will, together with the ongoing multinational preventive initiatives, pave the way for pragmatic prevention programs and integrated interventions to facilitate healthy brain aging. This paper summarizes major findings on risk and protective factors for dementia and AD, and reviews key aspects and future directions in preventative strategies. PMID- 27242094 TI - Contribution of the North Karelia Project to International Work in CVD and NCD Prevention and Health Promotion. AB - During the decades after the start of the North Karelia Project in 1971, cardiovascular diseases and related noncommunicable diseases have emerged as the greatest global public health burden. The prevention and control of these diseases have thus become a major challenge and target for global public health, as emphasized by the Political Declaration of the United Nations (UN) General Assembly in 2011. The experiences and results of the North Karelia Project have accordingly received much international attention and have in many ways contributed to the international work in the area, including the strategies and programs of the World Health Organization. The experience of the Project shows the great potential of population-based prevention of cardiovascular diseases and other noncommunicable diseases and that influencing lifestyles related to heart health with comprehensive health promotion and national policies is the cost effective and sustainable way to improve contemporary public health. PMID- 27242095 TI - From Framingham and Bethesda to North Karelia and Back: Turning Prevention and Population Science Discoveries into Heart Health. PMID- 27242096 TI - Correction. PMID- 27242097 TI - Dry-cured ham tissue characterization by fast field cycling NMR relaxometry and quantitative magnetization transfer. AB - Fast field cycling (FFC) and quantitative magnetization transfer (qMT) NMR methods are two powerful tools in NMR analysis of biological tissues. The qMT method is well established in biomedical NMR applications, while the FFC method is often used in investigations of molecular dynamics on which longitudinal NMR relaxation times of the investigated material critically depend. Despite their proven analytical potential, these two methods were rarely used in NMR studies of food, especially when combined together. In our study, we demonstrate the feasibility of a combined FFC/qMT-NMR approach for the fast and nondestructive characterization of dry-curing ham tissues differing by protein content. The characterization is based on quantifying the pure quadrupolar peak area (area under the quadrupolar contribution of dispersion curve obtained by FFC-NMR) and the restricted magnetization pool size (obtained by qMT-NMR). Both quantities correlate well with concentration of partially immobilized, nitrogen-containing and proton magnetization exchanging muscle proteins. Therefore, these two quantities could serve as potential markers for dry-curing process monitoring. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27242098 TI - Aurora-A recruitment and centrosomal maturation are regulated by a Golgi activated pool of Src during G2. AB - The Golgi apparatus is composed of stacks of cisternae laterally connected by tubules to form a ribbon-like structure. At the onset of mitosis, the Golgi ribbon is broken down into discrete stacks, which then undergo further fragmentation. This ribbon cleavage is required for G2/M transition, which thus indicates that a 'Golgi mitotic checkpoint' couples Golgi inheritance with cell cycle transition. We previously showed that the Golgi-checkpoint regulates the centrosomal recruitment of the mitotic kinase Aurora-A; however, how the Golgi unlinking regulates this recruitment was unknown. Here we show that, in G2, Aurora-A recruitment is promoted by activated Src at the Golgi. Our data provide evidence that Src and Aurora-A interact upon Golgi ribbon fragmentation; Src phosphorylates Aurora-A at tyrosine 148 and this specific phosphorylation is required for Aurora-A localization at the centrosomes. This process, pivotal for centrosome maturation, is a fundamental prerequisite for proper spindle formation and chromosome segregation. PMID- 27242099 TI - Ring-Shaped Microlanes and Chemical Barriers as a Platform for Probing Single Cell Migration. AB - Quantification and discrimination of pharmaceutical and disease-related effects on cell migration requires detailed characterization of single-cell motility. In this context, micropatterned substrates that constrain cells within defined geometries facilitate quantitative readout of locomotion. Here, we study quasi one-dimensional cell migration in ring-shaped microlanes. We observe bimodal behavior in form of alternating states of directional migration (run state) and reorientation (rest state). Both states show exponential lifetime distributions with characteristic persistence times, which, together with the cell velocity in the run state, provide a set of parameters that succinctly describe cell motion. By introducing PEGylated barriers of different widths into the lane, we extend this description by quantifying the effects of abrupt changes in substrate chemistry on migrating cells. The transit probability decreases exponentially as a function of barrier width, thus specifying a characteristic penetration depth of the leading lamellipodia. Applying this fingerprint-like characterization of cell motion, we compare different cell lines, and demonstrate that the cancer drug candidate salinomycin affects transit probability and resting time, but not run time or run velocity. Hence, the presented assay allows to assess multiple migration-related parameters, permits detailed characterization of cell motility, and has potential applications in cell biology and advanced drug screening. PMID- 27242100 TI - [Indoor air pollution by fine particulate matter in the homes of newborns]. AB - INTRODUCTION: Air pollution by particulate matter (PM) is a major public health problem. In Chile, the study has focused on outdoor air and PM10, rather than indoor air and PM2.5. Because newborns and infants spend most of their time at home, it is necessary to evaluate the exposure to indoor air pollution in this susceptible population. OBJECTIVE: To determine concentration of PM2.5 in the homes of newborns and identify the emission sources of the pollutants. PATIENTS AND METHOD: The PM2.5 concentration ([PM2.5]) was collected over a 24hour period in 207 households. Baseline sociodemographic information and environmental factors (heating, ventilation, smoking and house cleaning), were collected. RESULTS: The median [PM2.5] was 107.5MUg/m3. Family history of asthma was associated with lower [PM2.5] (P=.0495). Homes without heating showed a lower median [PM2.5], 58.6MUg/m3, while those using firewood, kerosene, and electricity ranged between 112.5 and 114.9, and coal users' homes reached 162.9MUg/m3. Wood using homes had significant differences (P=.0164) in median [PM2.5] whether the stove had complete combustion (98.2MUg/m3) vs. incomplete (112.6MUg/m3), or a salamander stove (140.6MUg/m3). Cigarette smoking was reported in 8.7% of the households, but was not associated with the [PM2.5]. Ventilation was associated with a higher median [PM2.5] (120.6 vs. 99.1MUg/m3, P=.0039). CONCLUSION: We found homes with high [PM2.5]. Residential wood consumption was almost universal, and it is associated with the [PM2.5]. Natural ventilation increased MP2.5, probably due to infiltration from outside. PMID- 27242101 TI - Incidence of crown fracture and risk factors in the primary dentition: a prospective longitudinal study. AB - BACKGROUND/AIM: Few studies have assessed the incidence and risk factors to crown fractures in preschool children. The aim of this study was to estimate the incidence of crown fracture in the primary dentition over a 1-year follow-up period, identify risk factors, and test the hypothesis that children with previous crown fracture are more prone to experience further cases of crown fracture independently of other risk factors. MATERIALS AND METHODS: This study was developed in two phases: cross-sectional and prospective longitudinal study. The cross-sectional study was carried out 261 preschool children. The prospective longitudinal study was carried out 194 children allocated to two groups: exposed group (children with prior exposure to crown fracture) and non-exposed group (children without prior exposure). On both occasions, children were examined for the diagnosis of crown fracture and evaluation of lip coverage and overjet. The parents were interviewed with regard to the socioeconomic indicators. New cases of crown fracture were identified based on the comparison of the two examinations. Data analysis involved Pearson's chi-square test, McNemar's test, and Poisson regression with robust variance. RESULTS: Among the 261 children who participated in the cross-sectional study, 194 were re-examined (65 in the exposed group and 129 in the non-exposed group). The overall incidence of crown fracture was 55.7% (n = 108). The difference in percentage of increased risk of crown fracture in exposed and non-exposed groups was 13.4%. A greater incidence of crown fracture was found in the exposed group (64.6%; P < 0,001). The children exposed (RR: 1.30; 95% CI: 1.01-1.67) had a greater risk of developing new cases of crown fracture in comparison with the non-exposed group. CONCLUSION: The incidence of crown fracture was high and children with previous crown fracture had a greater risk of suffering new cases of crown fracture during the 1-year follow-up period. PMID- 27242102 TI - Perceived unmet need and barriers to care amongst street-involved people who use illicit drugs. AB - INTRODUCTION AND AIMS: Research on perceived unmet need for care for mental health and substance use problems focuses on general populations to the detriment of hidden populations. This study describes prevalence and correlates of perceived unmet need for care in a community-based sample of street-involved people who use illicit drugs and identifies barriers to care. DESIGN AND METHODS: A sample of 320 street-involved people who use drugs participated in a structured, interviewer-assisted survey in Edmonton, Canada. The survey included the Perceived Need for Care Questionnaire, which assessed unmet need for care for mental health and substance use problems across seven service types. Logistic regression examined the associations between perceived unmet need, extent of socioeconomic marginalisation and problem severity. Barriers underlying unmet service needs were also examined. RESULTS: Most (82%) participants reported unmet need for one or more services during the past year. Odds of reporting one or more unmet needs were elevated amongst participants reporting substantial housing instability (adjusted odds ratio = 2.37; 95% confidence interval 1.19-4.28) and amongst participants meeting criteria for drug dependence (adjusted odds ratio = 1.22; 95% confidence interval 1.03-1.50), even after adjustment for sociodemographic covariates. Structural, rather than motivational barriers were the most commonly reported reasons underlying unmet service needs. DISCUSSION AND CONCLUSION: Street-involved people who use drugs experience very high rates of perceived unmet need for care for mental health and substance use problems. General population studies on perceived unmet need are insufficient for understanding needs and barriers to care in hidden populations.[Hyshka E, Anderson JT, Wild TC. Perceived unmet need and barriers to care amongst street involved people who use illicit drugs. Drug Alcohol Rev 2017;36:295-304]. PMID- 27242103 TI - Shedding (infrared) light on the septic brain. PMID- 27242104 TI - Effect of diabetes and pre-hospital blood glucose level on survival and recovery after out-of-hospital cardiac arrest. AB - OBJECTIVE: Diabetes mellitus and blood glucose level (BGL) are emerging as important prognosticators of outcome in critically ill patients. We evaluated the effect of diabetes and pre-hospital BGL on survival to hospital discharge and on 12-month functional recovery after out-of-hospital cardiac arrest (OHCA). DESIGN, SETTING AND PARTICIPANTS: We performed a retrospective analysis of data from a statewide cardiac arrest registry in Victoria, Australia. We included 11 873 adult patients who had had an OHCA of presumed cardiac aetiology between 1 January 2007 and 30 June 2015. Of these, 2438 (20.5%) had documented diabetes. MAIN OUTCOME MEASURES: Survival to hospital discharge and 12-month functional recovery, measured using the Extended Glasgow Outcome Scale. RESULTS: Crude survival to hospital discharge differed among patients with and without diabetes (6.8% v 13.4%; P < 0.001). Diabetes significantly reduced the odds of survival to hospital discharge for patients presenting with a shockable rhythm (adjusted odds ratio [OR], 0.57; 95% CI, 0.38-0.86; P = 0.007) and reduced the odds of good 12 month functional recovery for patients discharged alive (OR, 0.57; 95% CI, 0.35 0.95; P = 0.03). In contrast, a mild-to-moderate elevation of pre-hospital BGL (8.0- 15.9 mmol/L) was present in 695 of 1319 patients with available data (52.7%) and was associated with improved survival and functional recovery outcomes, which were independent of diabetes status. CONCLUSIONS: Diabetes affects at least one in five patients who have had an OHCA and is associated with poorer survival and 12-month functional recovery after OHCA. In comparison, an elevated pre-hospital BGL is common in the peri-arrest period and may be associated with improved outcomes. PMID- 27242105 TI - Changes in intravenous fluid use patterns in Australia and New Zealand: evidence of research translating into practice. AB - OBJECTIVES: To describe changes in the use of intravenous (IV) fluid by quantity and type in different regions of Australia and New Zealand. DESIGN, SETTING AND PARTICIPANTS: We conducted a retrospective ecological study examining regional and temporal trends in IV fluid consumption across Australia and New Zealand over the periods 2012-2013 and 2013- 2014, using national proprietary sales data as a surrogate for consumption, and demographic data from the public domain. RESULTS: More than 13.3 million litres of IV fluid were consumed in Australia and New Zealand in 2012-2013, and more than 13.9 million litres in 2013-2014, with colloid solutions accounting for < 2%. There was marked regional variation in consumption of fluids, by volumes and proportions used, when standardised to overall Australian and New Zealand values. There was no significant change in the overall volume of crystalloid solutions consumed but there was a significant decrease (9%; P = 0.02) in the ratio of unbalanced to balanced crystalloid solutions consumed. Consumption of all forms of colloid solutions decreased, with a 12% reduction overall (P = 0.02), primarily driven by a 67% reduction in the consumption of hydroxyethyl starch (HES) solutions. CONCLUSIONS: The amount and type of IV fluid use, as determined by fluid sales, is highly variable across Australia and New Zealand. However, overall use of balanced crystalloid solutions is increasing and the use of HES has decreased dramatically. PMID- 27242106 TI - Maintenance fluid practices in intensive care units in Australia and New Zealand. AB - BACKGROUND: Administration of maintenance fluid is common practice in the intensive care unit, contributing to daily fluid and sodium intake and balance. Despite this, there is little evidence to describe clinical practices relating to its administration to ICU patients. METHODS: We conducted a prospective, observational, point-prevalence study in 49 Australian and New Zealand ICUs in 2014. We aimed to document the type and volume of maintenance fluid administered to ICU patients, and to describe additional fluid received. We also assessed changes in maintenance fluid administration practices compared with our similar study conducted in 2011. RESULTS: Of 645 patients enrolled, 399 (62%) received maintenance fluid on the study day. A median volume of 630 mL (interquartile range [IQR], 272-1250 mL) was delivered, accounting for a median of 35% (IQR, 16% 56%) of total daily administered fluids. This was in addition to other fluids administered as fluid resuscitation, drug infusions and boluses, flushes and enteral or parenteral feeds, as well as oral intake. 0.9% saline was the most commonly used maintenance fluid (36%), followed by balanced salt solutions (30%). Compared with data from 2011, there has been a decrease in the median volume of maintenance fluid administered (2011, 860 mL [IQR, 360- 1533 mL]; 2014, 630 mL [IQR, 287-1328 mL]; P = 0.01), although the proportion of patients receiving maintenance fluid remains unchanged. There has been no change in the types of fluids most commonly used for maintenance, but the use of balanced salt solutions has increased (2011, 24%; 2014, 30%; P = 0.01). CONCLUSION: Administration of maintenance fluids to patients in Australian and New Zealand ICUs is common. Although the volume being delivered has decreased, maintenance fluids contribute over one-third of daily total fluid administration. PMID- 27242107 TI - Is impaired cerebrovascular autoregulation associated with outcome in patients admitted to the ICU with early septic shock? AB - OBJECTIVE: To investigate the correlation between early changes in cerebrovascular autoregulation (CVAR) and neurological outcome and mortality in patients admitted to the intensive care unit with septic shock. DESIGN, SETTING AND PARTICIPANTS: A prospective observational study in a tertiary, university affiliated ICU, of 28 patients with septic shock (median age, 66 years; interquartile range [IQR], 56-74 years), with a median APACHE III score of 86 (IQR, 55-119). MAIN OUTCOME MEASURES: We used the correlation in time between cerebral tissue oxygenation (measured with near infrared spectroscopy) and mean arterial pressure to determine the tissue oxygenation reactivity index (TOx) as a measure of CVAR. Low TOx represents intact CVAR and high TOx represents impaired CVAR. We performed the measurements in the first 3 days after admission to the ICU. Survival and neurological outcomes, measured using the modified Rankin Scale and the Cerebral Performance Category scale, were censored 3 months later. RESULTS: All survivors of septic shock had a good neurological outcome. The TOx for Days 1-3 was higher (P < 0.001) in non-survivors (median, 0.04 [IQR, 0.12- 0.24]) compared with survivors (median, -0.02 [IQR, -0.13 to 0.05]). The TOx was independently associated with survival at 3 months (odds ratio, 0.13 [95% CI, 0.01-0.69]; P < 0.05) using logistic regression analysis. CONCLUSIONS: CVAR is impaired early in septic shock and is independently associated with mortality at 3-month follow-up. Information based on bedside monitoring of CVAR in the ICU could form a valuable adjunct to guide haemodynamic optimisation in patients with septic shock. PMID- 27242108 TI - A prospective observational study of the effect of critical illness on ultrastructural and microscopic morphology of duodenal mucosa. AB - OBJECTIVE: Disturbed intestinal barrier function due to 'leaky' tight junctions may cause secondary sepsis via paracellular translocation across the gut wall. Our objective was to describe the effects of critical illness on duodenal morphology and ultrastructure. DESIGN, SETTING AND PARTICIPANTS: Prospective observational study of 12 mechanically ventilated critically ill patients in an intensive care unit and 15 control participants in an outpatient endoscopy suite. INTERVENTION: We took six endoscopic biopsy samples of the duodenum from each participant for analysis by electron and light microscopy. MAIN OUTCOME MEASURES: Our primary outcome was tight junction morphology, examined with electron microscopy. Secondary outcomes were microvillus length and density, vascular endothelium morphology and mitochondrial density and morphology, examined with electron microscopy, and morphology examined with light microscopy. RESULTS: We observed no abnormalities of tight junction ultrastructure in either group. There was a tendency towards shorter microvilli in the critically ill group: mean length in critically ill patients, 1.17 um (interquartile range [IQR], 1.05-1.60 um) v mean length in control patients, 1.58 um (IQR, 1.30-1.72 um); P = 0.07. There was a tendency towards less dense microvilli in the critically ill group: mean density in critically ill patients, 7.29 microvilli/um (IQR, 6.83-8.05 microvilli/um) v mean density in control patients, 8.23 microvilli/um (IQR, 7.34 9.11 microvilli/um); P = 0.07. Vascular endothelium appeared normal in all critically ill patients and abnormal in one control participant. Abnormal mitochondrial morphology was noted in one critically ill patient and one control participant, and no differences were seen in mitochondrial density. Using light microscopy, we saw more apoptotic cells in the critically ill patients (P = 0.018), but villus height, crypt depth and lymphocyte density were normal. CONCLUSIONS: We did not detect any morphological abnormalities of duodenal tight junctions in critically ill patients. Our results should be interpreted with caution because of the small sample population, but our observations challenge the concept that paracellular translocation facilitates secondary sepsis. PMID- 27242109 TI - Knowledge of the law about withholding or withdrawing life-sustaining treatment by intensivists and other specialists. AB - OBJECTIVE: Decisions about withholding or withdrawing life-sustaining treatment (WWLST) from adults who lack capacity are an integral part of intensive care (IC) practice. We compare the knowledge, attitudes and practice of intensivists in relation to the law about WWLST with six other specialties most often involved in end-of-life care. DESIGN, SETTING AND PARTICIPANTS: We used a cross-sectional postal survey of medical specialists in the three most populous Australian states, and analysed responses from 867 medical specialists from the seven specialties most likely to be involved in WWLST decisions in the acute-care setting (emergency, geriatric, palliative, renal and respiratory medicine, medical oncology and IC). MAIN OUTCOME MEASURES: Attitudes to, and knowledge and practice of, the law relating to end-of-life care. RESULTS: Of 2702 surveys sent to eligible practitioners, 867 completed questionnaires were returned. There was an overall response rate of 32% and an IC response rate also of 32% (125/388). Intensivists performed better than average in legal knowledge but important knowledge gaps remain. Intensivists had a more negative attitude to the role of law in this area than other specialty groups but reported being seen as a leading source of information about legal issues by other medical specialists and nurses. Intensivists also reported being the specialists most frequently making decisions about end-of-life treatment. CONCLUSIONS: Improved legal knowledge and open engagement with the law can help manage the risk of harm to patients and protect intensivists from liability. IC guidelines and continuing professional development are important strategies to address these issues. PMID- 27242110 TI - Bedside lung ultrasound, mobile radiography and physical examination: a comparative analysis of diagnostic tools in the critically ill. AB - OBJECTIVE: To compare lung ultrasonography (LUS), chest xray (CXR) and physical examination (Ex) for the detection of pathological abnormalities in the lungs of critically ill patients. DESIGN, SETTING AND PARTICIPANTS: A prospective cohort study of 145 patients in the intensive care unit of a tertiary teaching hospital who were undergoing echocardiography for a clinical indication. MAIN OUTCOME MEASURES: Each patient was independently assessed by Ex, CXR and LUS on the same day. Examiners were asked to comment on the presence or absence and severity of pleural effusion, lung consolidation and alveolar interstitial syndrome (AIS). Independent expert examiners performed the LUS and an independent radiologist reported on the CXR. RESULTS: Ex, CXR and LUS were in fair agreement with each other in detecting a pulmonary abnormality (CXR v LUS, kappa = 0.31; CXR v Ex, kappa = 0.29; LUS v Ex, kappa = 0.22). LUS detected more abnormalities than did CXR (16.2%; chi(2) = 64.1; P < 0.001) or Ex (23.5%; chi(2) = 121.9; P < 0.001). CXR detected more pleural effusions than LUS (9.3%; chi(2) = 7.6; kappa = 0.39), but LUS detected more pleural effusions than Ex (22.8%; chi(2) = 36.4; kappa = 0.18). There was no significant difference in the performance of LUS and CXR in quantifying the size of a pleural effusion (Z = -1.2; P = 0.23). Ex underestimated size compared with CXR or LUS. LUS detected more consolidation than CXR (17%; chi(2) = 115.9; P < 0.001) and Ex (16.2%; chi(2) = 90.3; P < 0.001). We saw no difference in performance between CXR and Ex in detecting lung consolidation (0.9%; chi(2) = 0.51; P < 0.48). LUS detected more cases of AIS than CXR (5.5%; chi(2) = 7.9; P = 0.005) and Ex (13%; chi(2) = 25.8; P < 0.001). CONCLUSIONS: There was only fair-to-moderate agreement between LUS, CXR and Ex in detecting pulmonary abnormalities, including pleural effusion, lung consolidation and AIS. The higher rate of detection from LUS, combined with its ease of use and increasing accessibility, makes for a powerful diagnostic tool in the ICU. PMID- 27242111 TI - Female specialists in intensive care medicine: job satisfaction, challenges and work-life balance. AB - OBJECTIVE: Women are under-represented in the intensive care medicine (ICM) specialist workforce. I aimed to better understand the challenges these women face so they can be considered in the training and support of ICM specialists. DESIGN AND PARTICIPANTS: All female Fellows of the College of Intensive Care Medicine (CICM) of Australia and New Zealand were surveyed using an online questionnaire. The study was approved by the Cabrini Human Research Ethics Committee. Thirty respondents with children volunteered to complete a second questionnaire. MAIN OUTCOME MEASURES: I surveyed demographic and workforce data and women's experiences in the ICM specialist workforce in the first survey, and experiences with child-rearing in the second survey. RESULTS: The response rate was 80.3% (127/158). The median age bracket was 40-45 years, and 118 respondents were practising ICM, 85 full-time in a tertiary intensive care unit. Eighteen were ICU directors and 23 were CICM-appointed supervisors of training. Sixty-five women were mothers, and 70% returned to full-time work after their maternity leave. Child care was most commonly undertaken by family members or a nanny. Overall, 81% were satisfied with their experiences, but 37% felt they had been disadvantaged because of their sex. Fewer women with leadership roles felt disadvantaged. Their major challenges included the on-call work affecting child rearing and family life, sexism in the workplace and difficulties with academic advancement. CONCLUSION: The participation and satisfaction rates of women working in the ICM specialist workforce are encouraging. Although challenges exist, women contemplating a career in ICM should see it as achievable and rewarding. PMID- 27242112 TI - Preclinical research in critical care--the Australasian perspective. PMID- 27242113 TI - Arteriovenous blood gas agreement in intensive care patients with varying levels of circulatory compromise. PMID- 27242114 TI - Arteriovenous blood gas agreement in intensive care patients with varying levels of circulatory compromise. PMID- 27242115 TI - Success of intraosseous access procedure in simulated adult resuscitation. PMID- 27242116 TI - Prevalence of gestational diabetes and risk of complications before and after initiation of a general systematic two-step screening strategy in Germany (2012 2014). AB - AIMS: Information on the prevalence of gestational diabetes mellitus is scarce on national and international level. On July 1st, 2013, a general two-step screening was implemented in Germany harmonizing gestational diabetes diagnoses. We aim to provide prevalence estimates for gestational diabetes and pregnancy-related complications for the large region of North Rhine for the 12 months before and after introduction of the general screening. METHODS: Routine care data covering all outpatient diagnoses of more than 150,000 pregnancies per 12-month period in women aged 15-55 years was used to determine cases of gestational diabetes. Gestational diabetes diagnosis and pregnancy-related complications were assessed according to the International Statistical Classification of Diseases and Related Health Problems (ICD-10). Relative Risks for pregnancy-related complications were calculated in pregnancies with and without gestational diabetes. RESULTS: Before the screening, diagnosis of gestational diabetes was made in 6.02% of pregnancies and in 6.81% after this date (other types of diabetes mellitus: 1.67% and 1.76% respectively). The prevalence of GDM increased with age and was highest at age 36 40 years (8.45%). The relative increase in prevalence after introduction of the screening was highest in the age group<=25 years (24.9%). The frequency of pregnancy-related complications such as hypertension, pre-eclampsia, cesarean section was increased in pregnancies with gestational diabetes in comparison to those without independent of observation period. CONCLUSIONS: We found a high prevalence of gestational diabetes, which has relatively increased by 13.12% after the introduction of the general screening. PMID- 27242117 TI - How are metabolic control targets of patients with Type 1 diabetes mellitus achieved in daily practice in the area with high diabetes prevalence? AB - AIMS: We assessed the prevalence of Type 1 diabetes mellitus and determined how the targets established in the guidelines for patients with Type 1 diabetes mellitus were achieved in clinical practice in North Karelia, Finland. METHODS: All adult Type 1 diabetes mellitus patients (n=1075) were identified from the regional electronic patient database. The data for HbA1c and LDL cholesterol measurements during the years 2013 and 2014 were obtained from medical records. RESULTS: The prevalence of Type 1 diabetes mellitus in the adult population in North Karelia was 0.8%, which is among the highest worldwide. HbA1c and LDL cholesterol were measured in 93% and 90% of participants, respectively. Nineteen percent of patients reached the HbA1c target of <7.0% (53mmol/mol) and 45% attained LDL cholesterol <2.5mmol/l. Overall, 26% of patients over 60 years old with diabetes achieved glycaemic control targets compared with 13-16% of younger patients with diabetes. CONCLUSIONS: Glycaemic control was in line with the recommendations in only one-fifth of Type 1 diabetes mellitus patients and less than half of them had LDL cholesterol levels within the target range. Interestingly, older Type 1 diabetes mellitus patients met the glycaemic control target more often than younger patients with diabetes. The targets established for patients with Type 1 diabetes mellitus are not achieved satisfactorily in daily practice. PMID- 27242118 TI - Relationship between glycated albumin and glycated hemoglobin according to glucose tolerance status: A multicenter study. AB - AIMS: To determine the relationship between glycated albumin (GA) and glycated hemoglobin (HbA1c) and to explore the association of glycated albumin/glycated hemoglobin (GA/HbA1c) ratio with glucose indices in Chinese subjects with varying glucose tolerance status. METHODS: This hospital-based, cross-sectional study involved 953 participants without known diabetes from 11 centers in China. Oral glucose tolerance test (OGTT) was used to identify three groups of subjects: normal glucose regulation (n=194), impaired glucose regulation (n=303) and newly diagnosed type 2 diabetes group (n=456). The GA, HbA1c and GA/HbA1c ratio were tested. RESULTS: GA was positively correlated with HbA1c (r=0.832, P<0.001). After correcting for age, sex and BMI, the correlations remained significant (r=0.824, P<0.001). Linear regression analysis estimated that a 1% increase of HbA1c was associated with a 2.84% increase of GA (GA=2.843*HbA1c-0.203; R(2)=0.692, P<0.001). GA would be 18.3 (16.7-19.9)% and 19.7 (18.0-21.4)% with HbA1c of 6.5% (48mmol/mol) and 7.0% (53mmol/mol). The mean GA/HbA1c ratio was 2.81+/-0.38, and it significantly increased with the presence of glucose intolerance (all, P<0.05). In the total study population, GA/HbA1c was correlated with BMI, glucose levels and 30-min insulin during OGTT, the homeostatic model assessment of beta-cell function (HOMA-beta), and DeltaI30/DeltaG30 (all, P<0.05). Increased glucose at 30min (standardized beta=0.221, P<0.001), and decreased BMI (standardized beta=-0.114, P=0.008) were associated with elevated GA/HbA1c ratio by multiple linear regression (adjusted R(2)=0.045). CONCLUSIONS: The relationship between GA and HbA1c was strong. The GA/HbA1c ratio was related to acute postprandial glucose fluctuation and BMI level. PMID- 27242119 TI - Risk factors for hypoglycemia in patients with type 2 diabetes, hospitalized in internal medicine wards: Findings from the FADOI-DIAMOND study. AB - AIMS: Hypoglycemia is a potential risk in the management of patients suffering from type 2 diabetes (T2DM) and hospitalized in internal medicine units (IMUs). The aim of this analysis was to evaluate incidence of hypoglycemia and related risk factors in a group of patients admitted to IMUs. METHODS: We used the FADOI DIAMOND study carried out in 53 Italian IMUs. The DIAMOND design included two cross-sectional surveys interspersed with an educational program. In both phases each center reviewed the charts of the last 30 hospitalized patients with known T2DM (n=3167), including information about hypoglycemia during hospital stay. The association between occurrence of hypoglycemia and potential predictors was evaluated by means of a multivariable logistic regression analysis. RESULTS: A total of 385 symptomatic hypoglycemic events were observed (rate=12%). Advanced age, cognitive dysfunction, and nephropathy were associated with hypoglycemia. Hypoglycemia occurred in 19.4% of patients treated according to the insulin sliding-scale method versus 11.4% of patients treated with basal bolus (p<0.01). More patients with hypoglycemia received sulfonylureas versus the no-hypoglycemia group (28.3% versus 20.6%, p<0.001). Significantly longer length of hospital stay and increased in-hospital mortality were found in the group with hypoglycemia compared with the no-hypoglycemia group (12.7+/-10.9 versus 9.6+/-6.5 days; 8.8% versus 4.8%, p<0.01). CONCLUSIONS: Hypoglycemia in hospitalized patients with diabetes is associated with increased length of hospitalization and in-hospital mortality. Identification of patients at increased risk of hypoglycemia may be important for optimally adapting treatment and patient management. PMID- 27242120 TI - Trend of antihyperglycaemic therapy and glycaemic control in 184,864 adults with type 1 or 2 diabetes between 2002 and 2014: Analysis of real-life data from the DPV registry from Germany and Austria. AB - AIMS: To analyse time trends of antihyperglycaemic therapy and glycaemic control in adult subjects with type 1, or type 2 diabetes between 2002 and 2014 in Germany/Austria. METHODS: 184,864 adults with diabetes (35,144 type 1 diabetes (T1D), 149,720 type 2 diabetes (T2D)) from the DPV-database documented between 2002 and 2014 were included. Regression models were applied for antihyperglycaemic therapy in T2D (non-pharmacological, OADs only, insulin+/ OADs), insulin therapy in T1D (CT, ICT, CSII) and T2D (BOT, SIT, CT, ICT, CSII), for the use of insulin analogues, and for glycaemic control (HbA1C, severe hypoglycaemia), adjusting for confounders sex, age, and diabetes duration. RESULTS: In T1D, CT (2002:19.7%; 2014:16.0%) and ICT (2002:66.8%; 2014:52.4%) decreased, while CSII increased from 13.5% to 31.5%. In T2D, non-pharmacological treatment became less frequent (2002:36.0%, 2014:21.8%), the use of OADs (2002:19.3%, 2014:28.9%) and insulin+/-OADs (2002:44.6%, 2014:49.4%) increased. BOT increased from 7.9% to 18.9%, SIT decreased from 12.0% to 8.3%. ICT slightly increased (2002:44.0%, 2014:45.3%), CT decreased (2002:35.8%, 2014:27.2%). Insulin analogues were used more frequently in T1D (rapid-acting:2002:46.8%, 2014:84.8%; long-acting:2002:26.0%, 2014:54.8%) and in T2D (rapid acting:2002:26.0%, 2014:43.5%; long-acting:2002:13.7%, 2014:53.6%). Until 2011, HbA1C increased in T1D and T2D, but then decreased again. High variability in the rate of hypoglycaemia was observed. CONCLUSIONS: This observational study indicates an increased use of insulin pumps in T1D. In T2D, non-pharmacological therapy decreased, and insulin therapy, particular as BOT, rose. An increase in the use of rapid- and long-acting insulin analogues was present in both patient groups. Time trend was less clear in glycaemic control. PMID- 27242121 TI - Zinc supplementation for improving glucose handling in pre-diabetes: A double blind randomized placebo controlled pilot study. AB - AIMS: There are a number of studies showing that zinc supplementation may improve glucose handling in people with established diabetes. We sought to investigate whether this zinc-dependent improvement in glucose handling could potentially be harnessed to prevent the progression of pre-diabetes to diabetes. In this double blind randomized placebo-controlled trial, we determined participants' fasting blood glucose levels, (FBG) and Homeostasis Model Assessment (HOMA) parameters (beta cell function, insulin sensitivity and insulin resistance) at baseline and after 6 months of zinc supplementation. METHODS: The Bangladesh Institute of Health Sciences Hospital (BIHS) (Mirpur, Dhaka, Bangladesh) database was used to identify 224 patients with prediabetes, of whom 55 met the inclusion criteria and agreed to participate. The participants were randomized either to the intervention or control group using block randomization. The groups received either 30mg zinc sulphate dispersible tablet or placebo, once daily for six months. RESULTS: After six months, the intervention group significantly improved their FBG concentration compared to the placebo group (5.37+/-0.20mmol/L vs 5.69+/-0.26, p<0.001) as well as compared to their own baseline (5.37+/ 0.20mmol/L vs 5.8+/-0.09, p<0.001). Beta cell function, insulin sensitivity and insulin resistance all showed a statistically significant improvement as well. CONCLUSION: To our knowledge this is the first trial to show an improvement in glucose handling using HOMA parameters in participants with prediabetes. Larger randomized controlled trials are warranted to confirm these findings and to explore clinical endpoints. PMID- 27242122 TI - Glycemic control and fracture risk in elderly patients with diabetes. AB - AIMS: Elderly patients with diabetes are at increased fracture risk. Although long exposure to hyperglycemia may increase fracture risk via adverse effects on bone metabolism, tight glycemic control may increase risk via trauma subsequent to hypoglycemia. We tested the prospective relationship between glycemic control and fracture risk in 10,572 elderly patients (age >=65) with diabetes. METHODS: Geriatric patients with diabetes were drawn from Vanderbilt University Medical Center's Electronic Health Record. Baseline was defined as age at first HbA1c after the latter of age 65 or ICD 9 code for diabetes. Cox analysis was used to test the relationship of updated mean HbA1c (average HbA1c over follow-up) with time to first fracture since baseline. HbA1c was categorized as follows: <6.5% [<48mmol/mol]; 6.5-6.9% [48-52mmol/mol]; 7-7.9% [53-63mmol/mol]; 8-8.9% [64-74 mmol-mol]; >=9% [>=75mmol/mol]. The number of BMI measurements was used as a surrogate for relative frequency of outpatient visits, i.e. patient-provider contacts. RESULTS: During follow-up, there were 949 fracture events. HbA1c demonstrated a cubic relationship with fracture risk (p<0.05). In analyses accounting for age, sex, race, and number of BMI measures (a surrogate for patient-provider interaction), compared to an HbA1c of 7-7.9%, HRs (95% CIs) were: HbA1c<6.5% HR=0.97 (0.82-1.14), 6.5-6.9% HR=0.80 (0.66-0.97), 8-8.9% HR=1.13 (0.92-1.40), >=9% HR=1.19 (0.93-1.54). CONCLUSIONS: An HbA1c of 6.5-6.9% is associated with the lowest risk of fracture in elderly patients with diabetes. Risk associated with an HbA1c >=9% may be a marker of infrequent patient-provider interaction. PMID- 27242123 TI - 25-Hydroxyvitamin D and glycemic control: A cross-sectional study of children and adolescents with type 1 diabetes. AB - AIM: The objective of this study was to describe the vitamin D status of children and adolescents with type 1 diabetes and to evaluate whether levels of 25 hydroxyvitamin D are significantly associated with HbA1c in this population. METHODS: 197 children and adolescents from a diabetes center in a children's hospital were recruited during regular follow up visit. Non-fasting blood samples were collected to measure 25-hydroxyvitamin D and blood glucose levels. HbA1c and other key variables were abstracted from patients' medical records. RESULTS: Of the 197 children and adolescents, more than half were adolescents, males, and Caucasian. 23% were overweight, while 13% were obese. Mean HbA1c was 8.6+/-1.4% (70+/-15.3mmol/mol). 40.6% of patients had 25-hydroxyvitamin D levels <=50nmol/L; 49.2% had 25-hydroxyvitamin D levels between 51 and 75nmol/L and 10.2% had 25 hydroxyvitamin D levels >75nmol/L. The bivariate relationship between 25 hydroxyvitamin D and HbA1c almost reached statistical significance (P=0.057), while no significance was established in the multivariate model. CONCLUSIONS: To the best of our knowledge this is the first study that has been adequately powered to examine the association between 25-hydroxyvitamin D and HbA1c in children and adolescents with T1DM. This study demonstrated the high prevalence of patients with low levels of 25-hydroxyvitamin D specifically in healthy weight and Caucasian children and adolescents with T1DM. These data suggest the need for monitoring of 25-hydroxyvitamin D in all youth with T1DM. PMID- 27242124 TI - Comparative risk of severe hypoglycemia among concomitant users of thiazolidinedione antidiabetic agents and antihyperlipidemics. AB - We conducted high-dimensional propensity score-adjusted cohort studies to examine whether thiazolidinedione use with a statin or fibrate was associated with an increased risk of severe hypoglycemia. We found that concomitant therapy with a thiazolidinedione+fibrate was associated with a generally delayed increased risk of severe hypoglycemia. PMID- 27242125 TI - Associations of serum anti-ganglioside antibodies and inflammatory markers in diabetic peripheral neuropathy. AB - AIMS: To investigate the associations between inflammatory markers, serum anti ganglioside antibodies (anti-GS-ab), serum plasminogen activator inhibitor-1 (PAI 1), tumor necrosis factor-alpha (TNF-alpha), C-reactive protein (CRP), and diabetic peripheral neuropathy (DPN). METHODS: Study subjects were divided into three groups: normal group (N group) with 101 healthy individuals; diabetes mellitus without peripheral neuropathy group (DM group) with 87 patients; and DPN group with 178 cases. American Nicolet Viking IV electromyography was applied to detect nerve conduction velocity; enzyme linked immunosorbent assay was used to determine the levels of anti-GS-IgG-ab, PAI-1, and TNF-alpha; and immunoturbidimetry was employed to measure CRP levels. RESULTS: Motor nerve conduction velocity and sensory nerve conduction velocity in the DNC group were significantly lower than in the N and DM groups (all P<0.05). Pairwise comparisons among diabetic peripheral neuropathy clinical (DPNC) levels were statistically significant (P<0.05), and the level of anti-GS-ab was positively correlated with DPNC. There were statistically significant differences in PAI-1, TNF-alpha, and CRP levels between the DPN group and DM and N groups (both P<0.05). Pairwise comparisons of PAI-1, TNF-alpha, and CRP levels among DPNC levels showed no statistical significance in volumes (P>0.05), and the concentration of anti-GS-IgM-ab was in significant positive correlated with PAI 1, TNF-alpha, and CRP levels. CONCLUSION: Anti-GS-ab and inflammatory markers such as PAI-1, TNF-alpha, and CRP were associated with DPN and can be used as important indicators for the prediction and early diagnosis of DPN. PMID- 27242126 TI - Serum levels of immunoglobulins in an adult population and their relationship with type 2 diabetes. AB - OBJECTIVE: Some studies have found patients with diabetes had an impaired humoral immune response. Immunoglobulins provide key information on the humoral immune status. But few population-based studies comprehensively estimated the serum immunoglobulins concentration in type 2 diabetes (T2D). So we design a cross sectional study to investigate the relationships between immunoglobulin levels and prevalence of T2D in a large-scale adult population. METHODS: A cross sectional assessment was performed in 10,691 participants living in Tianjin, China. Type 2 diabetes was defined in accordance with the criteria of the world health organization, and serum levels of immunoglobulins were determined by the immunonephelometric technique. Adjusted logistic models were used to assess relationships between the quintiles of immunoglobulins concentration and the prevalence of T2D. RESULTS: In this study, the prevalence of T2D was 11.7%, and the means (standard deviation) of immunoglobulins (IgG, IgE, IgM, IgA) were 1192.3 (241.1)mg/dL, 92.3 (234.6)IU/mL, 104.8 (55.8)mg/dL, 234.1 (96.2)mg/dL, respectively. The adjusted odds ratio (95% confidence interval) of T2D for the highest immunoglobulins (IgG, IgE, IgM, IgA) quintile, when compared to the lowest quintile were 0.64 (0.52, 0.78), 1.00 (0.81, 1.22), 0.77 (0.62, 0.95) and 1.57 (1.29, 1.92), respectively. CONCLUSIONS: Decreased IgG and IgM, and increased IgA levels were independently related to the prevalence of T2D among the adult population. Our findings indicate that the immunoglobulins might useful predictive factors for T2D in the general adult population. Further studies are needed to explore the causality and exact mechanisms of immunoglobulins in T2D. PMID- 27242128 TI - Q&A: Five questions on the 2015 IDF Diabetes Atlas. PMID- 27242127 TI - Overweight adolescents with type 2 diabetes have significantly higher lipoprotein abnormalities than those with type 1 diabetes. AB - AIM: Diabetes-associated glucoregulatory derangements may precipitate atherogenesis in childhood and CVD risk, particularly with obesity. We aimed to delineate lipoprotein profile differences between children with type 1 and 2 diabetes who are overweight/obese. METHODS: Data were obtained from electronic medical records of patients >=85th BMI percentile with type 1 (n=159) and type 2 (n=77) diabetes, ages 12-19y. Group differences were evaluated by correlations and general linear modeling analysis, adjusting for BMI, HbA1c, and diabetes duration. RESULTS: There were no group differences in TC, LDL, or non-HDL. Fewer subjects with type 1 diabetes had low HDL (17 vs. 30%; P<0.05). While no difference in HbA1c level was observed between groups, HbA1c was positively correlated with TC (P<=0.0001), LDL (P<=0.0001), non-HDL (P<=0.0001), ApoB100 (P<=0.0001), and LDL pattern B (P<=0.0001). In adjusted models, apoB100 (85.4 vs. 91.3mg/dl; P<0.05) and incidence of LDL pattern B (21 vs. 42%; P<0.01) were lower in subjects with type 1 diabetes. BMI was inversely correlated with HDL, HDL-2 and HDL-3 (all P<=0.0001). The correlation of BMI with HDL-2 and HDL-3 were attenuated when evaluating subjects by diabetes type. CONCLUSIONS: Despite having no difference in absolute LDL levels, children with type 2 diabetes were more likely to have small, dense LDL particle pattern, higher apo B100 and lower total HDL, HDL-2, and HDL-3 fractions. Furthermore, poor glycemic control was associated with abnormal lipoprotein profiles in patients with both type 1 and 2 diabetes. PMID- 27242130 TI - Heart valve health, disease, replacement, and repair: a 25-year cardiovascular pathology perspective. AB - The past several decades have witnessed major advances in the understanding of the structure, function, and biology of native valves and the pathobiology and clinical management of valvular heart disease. These improvements have enabled earlier and more precise diagnosis, assessment of the proper timing of surgical and interventional procedures, improved prosthetic and biologic valve replacements and repairs, recognition of postoperative complications and their management, and the introduction of minimally invasive approaches that have enabled definitive and durable treatment for patients who were previously considered inoperable. This review summarizes the current state of our understanding of the mechanisms of heart valve health and disease arrived at through innovative research on the cell and molecular biology of valves, clinical and pathological features of the most frequent intrinsic structural diseases that affect the valves, and the status and pathological considerations in the technological advances in valvular surgery and interventions. The contributions of many cardiovascular pathologists and other scientists, engineers, and clinicians are emphasized, and potentially fruitful areas for research are highlighted. PMID- 27242129 TI - Hyperosmotic stress memory in Arabidopsis is mediated by distinct epigenetically labile sites in the genome and is restricted in the male germline by DNA glycosylase activity. AB - Inducible epigenetic changes in eukaryotes are believed to enable rapid adaptation to environmental fluctuations. We have found distinct regions of the Arabidopsis genome that are susceptible to DNA (de)methylation in response to hyperosmotic stress. The stress-induced epigenetic changes are associated with conditionally heritable adaptive phenotypic stress responses. However, these stress responses are primarily transmitted to the next generation through the female lineage due to widespread DNA glycosylase activity in the male germline, and extensively reset in the absence of stress. Using the CNI1/ATL31 locus as an example, we demonstrate that epigenetically targeted sequences function as distantly-acting control elements of antisense long non-coding RNAs, which in turn regulate targeted gene expression in response to stress. Collectively, our findings reveal that plants use a highly dynamic maternal 'short-term stress memory' with which to respond to adverse external conditions. This transient memory relies on the DNA methylation machinery and associated transcriptional changes to extend the phenotypic plasticity accessible to the immediate offspring. PMID- 27242132 TI - Modular co-culture engineering, a new approach for metabolic engineering. AB - With the development of metabolic engineering, employment of a selected microbial host for accommodation of a designed biosynthetic pathway to produce a target compound has achieved tremendous success in the past several decades. Yet, increasing requirements for sophisticated microbial biosynthesis call for establishment and application of more advanced metabolic engineering methodologies. Recently, important progress has been made towards employing more than one engineered microbial strains to constitute synthetic co-cultures and modularizing the biosynthetic labor between the co-culture members in order to improve bioproduction performance. This emerging approach, referred to as modular co-culture engineering in this review, presents a valuable opportunity for expanding the scope of the broad field of metabolic engineering. We highlight representative research accomplishments using this approach, especially those utilizing metabolic engineering tools for microbial co-culture manipulation. Key benefits and major challenges associated with modular co-culture engineering are also presented and discussed. PMID- 27242133 TI - Magnetic frustration in a hexaazatrinaphthylene-bridged trimetallic dysprosium single-molecule magnet. AB - The synthesis, structure and magnetic properties of the HAN-bridged tri dysprosium complex [{(thd)3Dy}3HAN] (1) are described. The complex is an SMM that shows two relaxation processes owing to the presence of two geometrically distinct Dy3+ sites in 1. Ab initio calculations reveal that the magnetic ground state of 1 is characterized by magnetic frustration. PMID- 27242131 TI - Bioengineered kidney tubules efficiently excrete uremic toxins. AB - The development of a biotechnological platform for the removal of waste products (e.g. uremic toxins), often bound to proteins in plasma, is a prerequisite to improve current treatment modalities for patients suffering from end stage renal disease (ESRD). Here, we present a newly designed bioengineered renal tubule capable of active uremic toxin secretion through the concerted action of essential renal transporters, viz. organic anion transporter-1 (OAT1), breast cancer resistance protein (BCRP) and multidrug resistance protein-4 (MRP4). Three dimensional cell monolayer formation of human conditionally immortalized proximal tubule epithelial cells (ciPTEC) on biofunctionalized hollow fibers with maintained barrier function was demonstrated. Using a tailor made flow system, the secretory clearance of human serum albumin-bound uremic toxins, indoxyl sulfate and kynurenic acid, as well as albumin reabsorption across the renal tubule was confirmed. These functional bioengineered renal tubules are promising entities in renal replacement therapies and regenerative medicine, as well as in drug development programs. PMID- 27242134 TI - Fibromyalgia onset has a high impact on work ability in Australians. AB - BACKGROUND: Although the disabling effects of fibromyalgia (FM) are well recognised, there are no published data regarding the impact of FM on work ability in Australians. The impact of the development of FM symptoms on ability to work in Australians was explored in a pilot survey project. METHOD: Members of the Fibromyalgia Support Network of Western Australia were invited to undertake an anonymous online survey. Information was gathered regarding demographics, symptom onset, the timing of diagnosis, employment status and changes in the ability to work. RESULTS: Two hundred and eighty-seven responses were analysed. Of the respondents, 90.6% were female, with a mean age of 51.1 +/- 10.6 years and had experienced symptoms between 2 and 20 years; 52.8% were diagnosed less than 5 years previously. Of the participants, 54.2% were working full time and 21.5% working part time at symptom onset; however, only 15.6% were currently working full time, with 44.8% not currently working at all. Because of FM, 24.3% stopped and 32.6% reduced paid work directly within 5 years of symptom development, with 15.3% ceasing and an additional 17.4% reducing work because of symptoms before diagnosis. Due to FM symptoms, 35.1% currently received financial support because they were unable to work. While 24.3% reported FM medication increased their ability to work, 20.8% reported it reduced their ability to work. CONCLUSION: A community pilot survey of Australians with FM indicates a high impact on work ability. This occurs from symptom onset and often before diagnosis. Early diagnosis and intervention may provide a window of opportunity to prevent work disability in FM. PMID- 27242135 TI - Update in lung cancer: epilogue to a modern review series. PMID- 27242136 TI - A water splitting system using an organo-photocathode and titanium dioxide photoanode capable of bias-free H2 and O2 evolution. AB - This study examined a water-splitting system comprising a TiO2 photoanode and an organo-photocathode consisting of a p-n bilayer. Stoichiometric decomposition of water into H2 and O2 successfully occurred at bias voltages lower than the theoretical value (i.e. 1.23 V). Compared to the conventional TiO2 and Pt systems, the proposed water-splitting system demonstrated water splitting without any externally applied bias. PMID- 27242137 TI - Inactivation of glutamate racemase (MurI) eliminates virulence in Streptococcus mutans. AB - Inhibition of enzymes required for bacterial cell wall synthesis is often lethal or leads to virulence defects. Glutamate racemase (MurI), an essential enzyme in peptidoglycan biosynthesis, has been an attractive target for therapeutic interventions. Streptococcus mutans, one of the many etiological factors of dental caries, possesses a series of virulence factors associated with cariogenicity. However, little is known regarding the mechanism by which MurI influences pathogenesis of S. mutans. In this work, a stable mutant of S. mutans deficient in glutamate racemase (S. mutans FW1718) was constructed to investigate the impact of murI inactivation on cariogenic virulence in S. mutans UA159. Microscopy revealed that the murI mutant exhibited an enlarged cell size, longer cell chains, diminished cell?cell aggregation, and altered cell surface ultrastructure compared with the wild-type. Characterization of this mutant revealed that murI deficiency weakened acidogenicity, aciduricity, and biofilm formation ability of S. mutans (P<0.05). Real-time quantitative polymerase chain reaction (qRT-PCR) analysis demonstrated that the deletion of murI reduced the expression of the acidogenesis-related gene ldh by 44-fold (P<0.0001). The expression levels of the gene coding for surface protein antigen P (spaP) and the acid-tolerance related gene (atpD) were down-regulated by 99% (P<0.0001). Expression of comE, comD, gtfB and gtfC, genes related to biofilm formation, were down-regulated 8-, 43-, 85- and 298-fold in the murI mutant compared with the wild-type (P<0.0001), respectively. Taken together, the current study provides the first evidence that MurI deficiency adversely affects S. mutans virulence properties, making MurI a potential target for controlling dental caries. PMID- 27242138 TI - Isolation and characterization of a new Bacillus thuringiensis strain with a promising toxicity against Lepidopteran pests. AB - Insecticides derived from Bacillus thuringiensis are gaining worldwide importance as environmentally desirable alternatives to chemicals for the control of pests in public health and agriculture. Isolation and characterization of new strains with higher and broader spectrum of activity is an ever growing field. In the present work, a novel Tunisian B. thuringiensis isolate named BLB459 was characterized and electrophoresis assay showed that among a collection of 200 B. thuringiensis strains, the plasmid profile of BLB459 was distinctive. SmaI-PFGE typing confirmed the uniqueness of the DNA pattern of this strain, compared with BUPM95 and HD1 reference strains. PCR and sequencing assays revealed that BLB459 harbored three cry genes (cry30, cry40 and cry54) corresponding to the obtained molecular sizes in the protein pattern. Interestingly, PCR-RFLP assay demonstrated the originality of the BLB459 cry30-type gene compared to the other published cry30 genes. Insecticidal bioassays showed that BLB459 spore-crystal suspension was highly toxic to both Ephestia kuehniella and Spodoptera littoralis with LC50 values of about 64 (53-75) and 80 (69-91) MUg of toxin cm(-2), respectively, comparing with that of the commercial strain HD1 used as reference. Important histopathological effects of BLB459 delta-endotoxins on the two tested larvae midguts were detected, traduced by the vacuolization of the apical cells, the damage of microvilli, and the disruption of epithelial cells. These results proved that BLB459 strain could be of a great interest for lepidopteran biocontrol. PMID- 27242139 TI - GH10 XynA is the main xylanase identified in the crude enzymatic extract of Paenibacillus sp. A59 when grown on xylan or lignocellulosic biomass. AB - A novel bacterial isolate with polysaccharides degrading activity was identified as Paenibacillus sp., and named Paenibacillus sp. A59. Even though it is a strict mesophile, optimal xylanase activity of the crude enzymatic extract was achieved between 50 degrees C and 70 degrees C and more than 60% of the activity was retained after incubation for 48h at 50 degrees C, indicating thermotolerance of the enzymes involved. The extract was also active on pre-treated sugarcane residue (SCR) and wheat straw, releasing xylobiose and xylose as the main products, therefore confirming its predominantly xylanolytic activity. By zymograms and mass spectrometry of crude enzymatic extracts of xylan or SCR cultures, a 32kDa GH10 beta- 1,4- endoxylanase with xylanase and no CMCase activity was identified. We named this enzyme XynA and it was the only xylanase identified under both conditions assayed, suggesting that it is a good candidate for recombinant expression and evaluation in hemicelluloses deconstruction applications. Also, a protein with two S-layer homology domains (SLH) and a large uncharacterized C-terminal domain as well as an ABC substrate binding protein were identified in crude extracts of SCR cultures. We propose that Paenibacillus sp. A59 uses a system similar to anaerobic and other Gram positive bacteria, with SLH-domain proteins anchoring polysaccharide-degrading enzymes close to the membrane and the substrate binding protein assisting translocation of simple sugars to the cell interior. PMID- 27242140 TI - Large-scale gene expression profiling reveals physiological response to deletion of chaperone dnaKJ in Escherichia coli. AB - Chaperone DnaK and its co-chaperone DnaJ plays various essential roles such as in assisting in the folding of nascent peptides, preventing protein aggregation and maintaining cellular protein homeostasis. Global transcriptional changes in vivo associated with deletion of dnaKJ were monitored using DNA microarray to elucidate the role of DnaKJ at the transcriptional level. Microarray profiling and bioinformatics analysis revealed that a few chaperone and protease genes, stress-related genes and genes involved in the tricarboxylic acid cycle and oxidative phosphorylation were up-regulated, whereas various transporter genes, pentose phosphate pathway and transcriptional regulation related genes were down regulated. This study is the first to systematically analyze the alterations at the transcriptional level in vivo in deletion of dnaKJ. Fatty acid methyl esters analysis indicated that the amount of unsaturated fatty acid sharply increased and subcellular location prediction analysis showed a marked decrease in transcription of inner-membrane protein genes, which might have triggered the development of aberrant cell shape and susceptibility for some antibiotics in the DeltadnaKJ strain. PMID- 27242141 TI - Wheat seeds harbour bacterial endophytes with potential as plant growth promoters and biocontrol agents of Fusarium graminearum. AB - The role of endophytic communities of seeds is still poorly characterised. The purpose of this work was to survey the presence of bacterial endophytes in the seeds of a commercial wheat cultivar widely sown in Argentina and to look for plant growth promotion features and biocontrol abilities against Fusarium graminearum among them. Six isolates were obtained from wheat seeds following a culture-dependent protocol. Four isolates were assignated to Paenibacillus genus according to their 16S rRNA sequencing. The only gammaproteobacteria isolated, presumably an Enterobactereaceae of Pantoea genus, was particularly active as IAA and siderophore producer, and also solubilised phosphate and was the only one that grew on N-free medium. Several of these isolates demonstrated ability to restrain F. graminearum growth on dual culture and in a bioassay using barley and wheat kernels. An outstanding ability to form biofilm on an inert surface was corroborated for those Paenibacillus which displayed greater biocontrol of F. graminearum, and the inoculation with one of these isolates in combination with the Pantoea isolate resulted in greater chlorophyll content in barley seedlings. Our results show a significant ecological potential of some components of the wheat seed endophytic community. PMID- 27242142 TI - The effect of berberine hydrochloride on Enterococcus faecalis biofilm formation and dispersion in vitro. AB - Enterococcus faecalis (E. faecalis) is one of the major causes of biofilm infections. Berberine hydrochloride (BBH) has diverse pharmacological effects; however, the effects and mechanisms of BBH on E. faecalis biofilm formation and dispersion have not been reported. In this study, 99 clinical isolates from the urine samples of patients with urinary tract infections (UTIs) were collected and identified. Ten strains of E. faecalis with biofilm formation ability were studied. BBH inhibited E. faecalis biofilm formation and promoted the biofilm dispersion of E. faecalis. In addition, sortase A and esp expression levels were elevated during early E. faecalis biofilm development, whereas BBH significantly reduced their expression levels. The results of this study indicated that BBH effectively prevents biofilm formation and promotes biofilm dispersion in E. faecalis, most likely by inhibiting the expressions of sortase A and esp. PMID- 27242143 TI - Discovering novel enzymes by functional screening of plurigenomic libraries from alga-associated Flavobacteriia and Gammaproteobacteria. AB - Alga-associated microorganisms, in the context of their numerous interactions with the host and the complexity of the marine environment, are known to produce diverse hydrolytic enzymes with original biochemistry. We recently isolated several macroalgal-polysaccharide-degrading bacteria from the surface of the brown alga Ascophyllum nodosum. These active isolates belong to two classes: the Flavobacteriia and the Gammaproteobacteria. In the present study, we constructed two "plurigenomic" (with multiple bacterial genomes) libraries with the 5 most interesting isolates (regarding their phylogeny and their enzymatic activities) of each class (Fv and Gm libraries). Both libraries were screened for diverse hydrolytic activities. Five activities, out of the 48 previously identified in the natural polysaccharolytic isolates, were recovered by functional screening: a xylanase (GmXyl7), a beta-glucosidase (GmBg1), an esterase (GmEst7) and two iota carrageenases (Fvi2.5 and Gmi1.3). We discuss here the potential role of the used host-cell, the average DNA insert-sizes and the used restriction enzymes on the divergent screening yields obtained for both libraries and get deeper inside the "great screen anomaly". Interestingly, the discovered esterase probably stands for a novel family of homoserine o-acetyltransferase-like-esterases, while the two iota-carrageenases represent new members of the poorly known GH82 family (containing only 19 proteins since its description in 2000). These original results demonstrate the efficiency of our uncommon "plurigenomic" library approach and the underexplored potential of alga-associated cultivable microbiota for the identification of novel and algal-specific enzymes. PMID- 27242144 TI - Cellulolytic potential of probiotic Bacillus Subtilis AMS6 isolated from traditional fermented soybean (Churpi): An in-vitro study with regards to application as an animal feed additive. AB - The aim of the present study is to evaluate the probiotic attributes of Bacillus subtilis AMS6 isolated from fermented soybean (Churpi). This isolate exhibited tolerance to low pH (pH 2.0) and bile salt (0.3%), capability to autoaggregate and coaggregate. AMS6 also showed highest antibacterial activity against the pathogenic indicator strain Salmonella enterica typhimurium (MTCC 1252) and susceptibility towards different antibiotics tested. The isolate was effective in inhibiting the adherence of food borne pathogens to Caco-2 epithelial cell lines, and was also found to be non-hemolytic which further strengthen the candidature of the isolate as a potential probiotic. Further studies revealed B. subtilis AMS6 showed cellulolytic activity (0.54+/-0.05 filter paper units mL(-1)) at 37 degrees C. The isolate was found to hydrolyze carboxymethyl cellulose, filter paper and maize (Zea mays) straw. The maize straw digestion was confirmed by scanning electron microscopy studies. The isolate was able to degrade filter paper within 96h of incubation. A full length cellulase gene of AMS6 was amplified using degenerate primers consisting of 1499 nucleotides. The ORF encoded for a protein of 499 amino acids residues with a predicted molecular mass of 55.04kDa. The amino acids sequence consisted of a glycosyl hydrolase family 5 domain at N-terminal; Glycosyl hydrolase catalytic core and a CBM-3 cellulose binding domain at its C terminal. The study suggests potential probiotic B. subtilis AMS6 as a promising candidate envisaging its application as an animal feed additive for enhanced fiber digestion and gut health of animal. PMID- 27242145 TI - Diversity, ecological distribution and biotechnological potential of Actinobacteria inhabiting seamounts and non-seamounts in the Tyrrhenian Sea. AB - In the present study, the ecological distribution of marine Actinobacteria isolated from seamount and non-seamount stations in the Tyrrhenian Sea was investigated. A collection of 110 isolates was analyzed by Automated Ribosomal Intergenic Spacer Analysis (ARISA) and 16S rRNA gene sequencing of representatives for each ARISA haplotype (n=49). Phylogenetic analysis of 16S rRNA sequences showed a wide diversity of marine isolates and clustered the strains into 11 different genera, Janibacter, Rhodococcus, Arthrobacter, Kocuria, Dietzia, Curtobacterium, Micrococcus, Citricoccus, Brevibacterium, Brachybacterium and Nocardioides. Interestingly, Janibacter limosus was the most encountered species particularly in seamounts stations, suggesting that it represents an endemic species of this particular ecosystem. The application of BOX-PCR fingerprinting on J. limosus sub-collection (n=22), allowed their separation into seven distinct BOX-genotypes suggesting a high intraspecific microdiversity among the collection. Furthermore, by screening the biotechnological potential of selected actinobacterial strains, J. limosus was shown to exhibit the most important biosurfactant activity. Our overall data indicates that Janibacter is a major and active component of seamounts in the Tyrrhenian Sea adapted to low nutrient ecological niche. PMID- 27242146 TI - Functions of Saccharomyces cerevisiae Ecm27p, a putative Na(+)/Ca(2+) exchanger, in calcium homeostasis, carbohydrate storage and cell cycle reentry from the quiescent phase. AB - The quiescent phase of the cell cycle is of fundamental importance for fungi, yet our understanding of this phase of the cycle is much less well understood than the mitotic cell cycle. We found that the ECM27 gene, which encodes a Na(+)/Ca(2+) exchanger, is responsible for influx of calcium from the extracellular space and release from intracellular stores during membrane stress. Wild type cells increase total Ca(2+) in quiescence but cells lacking ECM27 gene fail to do so and are defective in cell cycle reentry from the quiescent phase. ecm27Delta cells are also defective in maintaining trehalose levels throughout this phase. Addition of high levels of CaCl2 to the growth medium can increase total cellular calcium in ecm27Delta cells during quiescence and can also restore trehalose levels as well as partially restore ability of cells to reenter the mitotic cell cycle. ecm27Delta cells also have altered glycogen levels in exponentially growing cells. Our results show that Ecm27p and Ca(2+) play roles in maintaining a high level of trehalose in quiescent cells, which in turn is important in the ability of cells to rapidly return to proliferation. PMID- 27242147 TI - The effect of mutation in the clpX gene on the synthesis of N-acyl-homoserine lactones and other properties of Burkholderia cenocepacia 370. AB - In order to study the regulation of N-acyl-homoserine lactones synthesis (AHLs, the signal molecules of Quorum Sensing regulation) in Burkholderia cenocepacia strain 370 we obtained mutants with increased AHL production. One of the mutants, named BC-B6, was obtained by TnMod-RKm(r) plasposon mutagenesis. The plasposon insertion was located within the clpX gene encoding the ATPase subunit ClpX of the ClpXP protease. The mutation reduced bacterial virulence in mice intranasal infection. The results of proteomic analysis demonstrated that the expression of at least 19 proteins differed not less than 2-fold between the parental and mutant strains. 18 of the proteins were upregulated in the mutant, and one protein was downregulated. The proteins included those that involved in protein synthesis and modification, in energy production, in general metabolism, in transport and regulation. To check the effect of the clpX mutation on the AHL synthesis, a mutant with inactivated clpX gene (BC-clpX:Km(r)) was constructed by gene replacement method. This mutant also exhibited increased AHLs production. A swarming motility of both mutants was reduced compared to the original strain. Thus, the obtained results show that the clpX gene was involved in the regulation of AHL production and a number of cellular processes in B. cenocepacia 370. PMID- 27242148 TI - Powered by light: Phototrophy and photosynthesis in prokaryotes and its evolution. AB - Photosynthesis is a complex metabolic process enabling photosynthetic organisms to use solar energy for the reduction of carbon dioxide into biomass. This ancient pathway has revolutionized life on Earth. The most important event was the development of oxygenic photosynthesis. It had a tremendous impact on the Earth's geochemistry and the evolution of living beings, as the rise of atmospheric molecular oxygen enabled the development of a highly efficient aerobic metabolism, which later led to the evolution of complex multicellular organisms. The mechanism of photosynthesis has been the subject of intensive research and a great body of data has been accumulated. However, the evolution of this process is not fully understood, and the development of photosynthesis in prokaryota in particular remains an unresolved question. This review is devoted to the occurrence and main features of phototrophy and photosynthesis in prokaryotes. Hypotheses concerning the origin and spread of photosynthetic traits in bacteria are also discussed. PMID- 27242149 TI - Characterization and antimicrobial potential of extremely halophilic archaea isolated from hypersaline environments of the Algerian Sahara. AB - Halophilic archaea were isolated from different chotts and sebkha, dry salt lakes and salt flat respectively, of the Algerian Sahara and characterized using phenotypic and phylogenetic approaches. From 102 extremely halophilic strains isolated, forty three were selected and studied. These strains were also screened for their antagonistic potential and the production of hydrolytic enzymes. Sequencing of the 16S rRNA genes and phylogenetic analysis allowed the identification of 10 archaeal genera within the class Halobacteria: Natrinema (13 strains), Natrialba (12 strains), Haloarcula (4 strains), Halopiger (4 strains), Haloterrigena (3 strains), Halorubrum (2 strains), Halostagnicola (2 strains), Natronococcus, Halogeometricum and Haloferax (1 strain each). The most common producers of antimicrobial compounds belong to the genus Natrinema while the most hydrolytic isolates, with combined production of several enzymes, belong to the genus Natrialba. The strain affiliated to Halopiger djelfamassilliensis was found to produce some substances of interest (halocins, anti-Candida, enzymes). After partial purification and characterization of one of the strains Natrinema gari QI1, we found similarities between the antimicrobial compound and the halocin C8. Therefore, the gene encoding halocin C8 was amplified and sequenced. PMID- 27242150 TI - A cost effective cultivation medium for biocalcification of Bacillus pasteurii KCTC 3558 and its effect on cement cubes properties. AB - Application of carbonate precipitation induced by Bacillus pasteurii for improving some properties of cement has been reported. However, it is not yet successful in commercial scale due to the high cost of cultivation medium. This is the first report on the application of effluent from chicken manure bio-gas plant, a high protein content agricultural waste, as an alternative growth medium for carbonate precipitation by B. pasteurii KCTC3558. Urease activity of B. pasteurii KCTC3558 cultured in chicken manure effluent medium and other three standard media were examined using phenate method. The highest urease production was achieved in chicken manure effluent medium (16.756Umg(-1) protein). Cost per liter of chicken manure effluent medium is up to 88.2% lower than other standard media. The most effective cultivation media was selected for carbonate precipitation study in cement cubes. Water absorption, voids, apparent density and compressive strength of cement cubes were measured according to the ASTM standard. The correlation between the increasing density and compressive strength of bacterial added cement cube was evident. The density of bacterial cement cube is 5.1% higher than control while the compressive strength of cement mixed with bacterial cells in chicken manure effluent medium increases up to 30.2% compared with control. SEM and XRD analysis also found the crystalline phase of calcium carbonate within bacterial cement which confirmed that the increasing density and compressive strength were resulted from bacterial carbonate precipitation. This study indicated that the effluent from chicken manure bio-gas plant could be used as an alternative cost effective culture medium for cultivation and biocalcification of B. pasteurii KCTC3558 in cement. PMID- 27242151 TI - The antibacterial activity and action mechanism of emodin from Polygonum cuspidatum against Haemophilus parasuis in vitro. AB - Haemophilus parasuis is the causative agent of Glasser's disease, which leads to serious economic loss to the swine industry. Although antibiotics are widely used to control infections, outbreaks of this disease repeatedly happen. In this study, emodin from Polygonum cuspidatum showed potent inhibitory effect against H. parasuis. The minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) values of emodin were 32 and 64MUg/mL, respectively. The antibacterial kinetic curves indicated the antibacterial activity of emodin was in a concentration-dependent manner. Cell membrane permeability and flow cytometry assays proved that emodin could destroy cell membrane integrity and increase membrane permeability, and fluorescence spectra assay indicated emodin has influenced conformation of membrane protein. Under transmission electron microscopy, serious lesions of H. parasuis exposed to emodin (64MUg/mL) were found, including irregular cell shape, plasmolysis, ruptured cell wall and membrane and cytoplasmic vacuolation. These results suggested that emodin could be used as candidate for treating Glasser's disease. PMID- 27242152 TI - Roles of two RyhB paralogs in the physiology of Salmonella enterica. AB - Salmonella has evolved complicated regulatory systems to regulate the expression of virulence determinants that are acquired by horizontal gene transfer in response to various environmental niches. Among these, small RNA (sRNA)-mediated regulation exhibits unique features, distinct from those of protein factor mediated regulation, which may provide benefits for a pathogen coping with the complex stress conditions encountered during host infection. Specifically, iron acquisition by this pathogenic bacterium is important for cellular processes such as energy metabolism and DNA replication. Many studies on the role of RyhB sRNA have begun to unveil the essential nature of iron acquisition in allowing the organism to persist and develop pathogenicity. The Salmonella genome encodes two RyhB paralogs, RyhB-1 and RyhB-2, which are known to act singularly or together on target expression. Based on the mechanism of Escherichia coli RyhB function, this review proposes a possible model to show how two Salmonella RyhB paralogs regulate the level of target mRNAs by sensing environmental inputs or conditions. This review also describes the involvement of Salmonella RyhBs in diverse functions including nitrate homeostasis, adaptive system to oxidative stress, and intracellular survival. Thus, the two Salmonella RyhBs play a critical role in the regulation of gene expression that appears to be essential for persistence and pathogenesis of Salmonella spp. PMID- 27242153 TI - Diaporthe endophytica and D. terebinthifolii from medicinal plants for biological control of Phyllosticta citricarpa. AB - The citrus industry is severely affected by citrus black spot (CBS), a disease caused by the pathogen Phyllosticta citricarpa. This disease causes loss of production, decrease in the market price of the fruit, and reduction in its export to the European Union. Currently, CBS disease is being treated in orchards with various pesticides and fungicides every year. One alternative to CBS disease control without harming the environment is the use of microorganisms for biological control. Diaporthe endophytica and D. terebinthifolii, isolated from the medicinal plants Maytenus ilicifolia and Schinus terebinthifolius have an inhibitory effect against P. citricarpa in vitro and in detached fruits. Moreover, D. endophytica and D. terebinthifolii were transformed by Agrobacterium tumefaciens for in vivo studies. The transformants retained the ability to control of phytopathogenic fungus P. citricarpa after transformation process. Furthermore, D. endophytica and D. terebinthifolii were able to infect and colonize citrus plants, which is confirmed by reisolation of transformants from inoculated and uninoculated leaves. Light microscopic analysis showed fungus mycelium colonizing intercellular region and oil glands of citrus, suggesting that these two new species are capable of colonizing citrus plants, in addition to controlling the pathogen P. citricarpa. PMID- 27242155 TI - The effect of nanoparticle packing on capacitive electrode performance. AB - Nanoparticles pack together to form macro-scale electrodes in various types of devices, and thus, optimization of the nanoparticle packing is a prerequisite for the realization of a desirable device performance. In this work, we provide in depth insight into the effect of nanoparticle packing on the performance of nanoparticle-based electrodes by combining experimental and computational findings. As a model system, polypyrrole nanospheres of three different diameters were used to construct pseudocapacitive electrodes, and the performance of the electrodes was examined at various nanosphere diameter ratios and mixed weight fractions. Two numerical algorithms are proposed to simulate the random packing of the nanospheres on the electrode. The binary nanospheres exhibited diverse, complicated packing behaviors compared with the monophasic packing of each nanosphere species. The packing of the two nanosphere species with lower diameter ratios at an optimized composition could lead to more dense packing of the nanospheres, which in turn could contribute to better device performance. The dense packing of the nanospheres would provide more efficient transport pathways for ions because of the reduced inter-nanosphere pore size and enlarged surface area for charge storage. Ultimately, it is anticipated that our approach can be widely used to define the concept of "the best nanoparticle packing" for desirable device performance. PMID- 27242154 TI - Childhood Abuse, Intimate Partner Violence and Risk of Migraine Among Pregnant Women: An Epidemiologic Study. AB - OBJECTIVE: To examine the independent and joint associations of childhood abuse and intimate partner violence with migraine among pregnant women. BACKGROUND: Childhood abuse and intimate partner violence have each been associated with migraine headaches in previous studies, but these associations have not been explored among pregnant women. METHODS: A cross-sectional study was conducted among a cohort of 2970 pregnant women attending prenatal clinics in Lima, Peru. History of childhood abuse (ie, physical or sexual abuse) was assessed using the Childhood Physical and Sexual Abuse Questionnaire. Intimate partner violence (IPV) was assessed using the World Health Organization questionnaire. Migraine classification (including migraine and probable migraine) was based on International Classification of Headache Disorders (ICHD)-III beta criteria. Multivariable logistic regression analyses were performed to estimate odd ratios (OR) and 95% confidence intervals (95% CI). RESULTS: The prevalence of any migraine was 33.5% while approximately 70% of participants reported a history of childhood abuse and 36.7% a history of IPV. Women with a history of any childhood abuse had a 38% increased odds of any migraine compared to women with no history of childhood abuse (OR = 1.38; 95% CI 1.15-1.64). The odds of migraine increased with increasing numbers of experienced childhood abuse events (Ptrend < .001). Additionally, after adjusting for confounders women with a history of IPV had a 43% increased odds of any migraine as compared to women without intimate partner violence (OR = 1.43; 95%CI 1.02-2.02). Women with a joint positive history of childhood abuse and IPV, as compared with the reference group, had a 88% increased odds of migraine (aOR = 1.88, 95%CI: 1.51-2.35). CONCLUSION: Childhood abuse and IPV are associated with increased odds of migraine in pregnant women. Our findings highlight the importance of screening for abuse among pregnant migraineurs to help guide treatment strategies. PMID- 27242156 TI - Historical analysis of experience with small bowel capsule endoscopy in a spanish tertiary hospital. AB - INTRODUCTION: Capsule endoscopy was approved by the FDA in 2001. Gastrointestinal bleeding and inflammatory bowel disease are the main indications. It has been available in our hospital since 2004. METHODS: We retrospectively analysed data from patients who underwent small bowel capsule endoscopy in our hospital from October 2004 to April 2015. Indications were divided into: Obscure gastrointestinal bleeding (occult and overt), inflammatory bowel disease, and other indications. Findings were divided into: Vascular lesions, inflammatory lesions, other lesions, normal studies, and inconclusive studies. RESULTS: A total of 1027 out of 1291 small bowel studies were included. Mean patient age was 56.45 years; 471 were men and 556 women. The most common lesion observed was angiectasia, as an isolated finding or associated with other lesions. Findings were significant in up to 80% of studies when the indication was gastrointestinal bleeding, but in only 50% of studies in inflammatory bowel disease. Diagnostic yield was low in the group "other indications". No major complications were reported. DISCUSSION: Small bowel capsule endoscopy has high diagnostic yield in patients with gastrointestinal bleeding, but yield is lower in patients with inflammatory bowel disease. CONCLUSIONS: Our experience shows that capsule endoscopy is a safe and useful tool for the diagnosis of small bowel disease. The diagnostic yield of the technique in inflammatory bowel disease must be improved. PMID- 27242157 TI - Bacteraemia due to non-toxigenic Vibrio cholerae: The risks of eating seafood in a cirrhotic patient. PMID- 27242158 TI - First case report of oesophageal actinomycosis in a patient with active eosinophilic oesophagitis. PMID- 27242159 TI - Medical and surgical management of patients with enterocutaneous fistula and intestinal failure: The case for specialised functional units. PMID- 27242160 TI - Endoscopic alternative to buried bumper syndrome secondary to Duodopa(r) pump treatment. PMID- 27242161 TI - Cystic duct remnant syndrome as a cause of post-cholecystectomy syndrome. PMID- 27242162 TI - Mobile Phone Apps for Preventing Cancer Through Educational and Behavioral Interventions: State of the Art and Remaining Challenges. AB - BACKGROUND: Rapid developments in technology have encouraged the use of mobile phones in smoking cessation, promoting healthy diet, nutrition, and physical activity, sun safety, and cancer screening. Although many apps relating to the prevention of cancer and other chronic diseases are available from major mobile phone platforms, relatively few have been tested in research studies to determine their efficacy. OBJECTIVE: In this paper, we discuss issues related to the development and testing of new apps for preventing cancer through smoking cessation, sun safety, and other healthy behaviors, including key methodologic issues and outstanding challenges. METHODS: An exploratory literature review was conducted using bibliographic searches in PubMed and CINAHL with relevant search terms (eg, smartphones, smoking cessation, cancer prevention, cancer screening, and carcinogens) to identify papers published in English through October 2015. RESULTS: Only 4 randomized controlled trials of the use of mobile phone apps for smoking cessation and 2 trials of apps for sun safety were identified, indicating that it is premature to conduct a systematic search and meta-analysis of the published literature on this topic. CONCLUSIONS: Future studies should utilize randomized controlled trial research designs, larger sample sizes, and longer study periods to better establish the cancer prevention and control capabilities of mobile phone apps. In developing new and refined apps for cancer prevention and control, both health literacy and eHealth literacy should be taken into account. There is a need for culturally appropriate, tailored health messages to increase knowledge and awareness of health behaviors such as smoking cessation, cancer screening, and sun safety. Mobile phone apps are likely to be a useful and low-cost intervention for preventing cancer through behavioral changes. PMID- 27242163 TI - Optic nerve injury upregulates retinoic acid signaling in the adult frog visual system. AB - Retinoic acid (RA) is important during development, in neuronal plasticity, and also in peripheral nervous system regeneration. Here we use the frog visual system as a model to investigate the changes in RA signaling that take place after axonal injury to the central nervous system. Immunocytochemistry was used to localize different components of RA signaling within sections of the retina and optic tectum, namely, the synthetic enzyme retinaldehyde dehydrogenase (RALDH), the RA binding proteins CRABPI and II, the retinoic acid receptors RARalpha, beta and gamma, and finally the catabolic enzyme CYP26A1. The levels of these proteins were quantified in extracts of retina and tectum using Western blotting. Animals were studied at 1 week, 3 weeks and 6 weeks after optic nerve transection. At the latter time point the RGC axons were re-entering the optic tectum. All the components of RA signaling were present at low to moderate levels in retinas and tecta of control, unoperated animals. In retina, soon after optic nerve injury there was a large increase in RALDH, some increase in the CRABPs, and a large increase in RGC RARbeta and (expression. These increases continued as the RGC axons were regenerating, with the addition of later RARalpha expression at 6 weeks. At no stage did CYP26A1 expression significantly change. In the tectum the levels of RALDH increased after axotomy and during regrowth of axons (3 weeks), then decreased at 6 weeks, at which time the levels of CYP26A1 increased. Axotomy did not cause an immediate increase in tectal RAR levels but RARalpha and RARbeta increased after 3 weeks and RARgamma only after 6 weeks. These results are consistent with RA signaling playing an important role in the survival and regeneration of frog RGCs. PMID- 27242164 TI - Combined IL-21-primed polyclonal CTL plus CTLA4 blockade controls refractory metastatic melanoma in a patient. AB - Adoptive transfer of peripheral blood-derived, melanoma-reactive CD8(+) cytotoxic T lymphocytes (CTLs) alone is generally insufficient to eliminate bulky tumors. Similarly, monotherapy with anti-CTLA4 infrequently yields sustained remissions in patients with metastatic melanoma. We postulated that a bolus of enhanced IL 21-primed polyclonal antigen-specific CTL combined with CTLA4 blockade might boost antitumor efficacy. In this first-in-human case study, the combination successfully led to a durable complete remission (CR) in a patient whose disease was refractory to both monoclonal CTL and anti-CTLA4. Long-term persistence and sustained anti-tumor activity of transferred CTL, as well as responses to nontargeted antigens, confirmed mutually beneficial effects of the combined treatment. In this first-in-human study, Chapuis et al. demonstrate that the combination of adoptive cellular therapy with CTLA4 blockade induces long-term remission in a melanoma patient resistant to both modalities administered serially and individually. PMID- 27242165 TI - Early onset combined immunodeficiency and autoimmunity in patients with loss-of function mutation in LAT. AB - The adapter protein linker for activation of T cells (LAT) is a critical signaling hub connecting T cell antigen receptor triggering to downstream T cell responses. In this study, we describe the first kindred with defective LAT signaling caused by a homozygous mutation in exon 5, leading to a premature stop codon deleting most of the cytoplasmic tail of LAT, including the critical tyrosine residues for signal propagation. The three patients presented from early childhood with combined immunodeficiency and severe autoimmune disease. Unlike in the mouse counterpart, reduced numbers of T cells were present in the patients. Despite the reported nonredundant role of LAT in Ca(2+) mobilization, residual T cells were able to induce Ca(2+) influx and nuclear factor (NF) kappaB signaling, whereas extracellular signal-regulated kinase (ERK) signaling was completely abolished. This is the first report of a LAT-related disease in humans, manifesting by a progressive combined immune deficiency with severe autoimmune disease. PMID- 27242166 TI - Human T cell responses to Japanese encephalitis virus in health and disease. AB - Japanese encephalitis (JE) virus (JEV) is an important cause of encephalitis in children of South and Southeast Asia. However, the majority of individuals exposed to JEV only develop mild symptoms associated with long-lasting adaptive immunity. The related flavivirus dengue virus (DENV) cocirculates in many JEV endemic areas, and clinical data suggest cross-protection between DENV and JEV. To address the role of T cell responses in protection against JEV, we conducted the first full-breadth analysis of the human memory T cell response using a synthetic peptide library. Ex vivo interferon-gamma (IFN-gamma) responses to JEV in healthy JEV-exposed donors were mostly CD8(+) and targeted nonstructural (NS) proteins, whereas IFN-gamma responses in recovered JE patients were mostly CD4(+) and targeted structural proteins and the secreted protein NS1. Among patients, a high quality, polyfunctional CD4(+) T cell response was associated with complete recovery from JE. T cell responses from healthy donors showed a high degree of cross-reactivity to DENV that was less apparent in recovered JE patients despite equal exposure. These data reveal divergent functional CD4(+) and CD8(+) T cell responses linked to different clinical outcomes of JEV infection, associated with distinct targeting and broad flavivirus cross-reactivity including epitopes from DENV, West Nile, and Zika virus. PMID- 27242168 TI - Editorial. PMID- 27242170 TI - Effect on Clinical Restenosis of an Ultra-Thin-Strut Bare Metal Cobalt-Chromium Stent Versus a Thin-Strut Stainless Steel Stent. AB - OBJECTIVES: To prospectively compare the impact of ultrathin-strut cobalt chromium (Cro-Co) bare metal stent (BMS) versus thin-strut stainless steel (SS) BMS on clinically driven target lesion revascularization (TLR). BACKGROUND: Stent characteristics are an important determinant of restenosis. Thinner strut Cro-Co BMS is associated with a reduction of neointimal formation compared to SS BMS. The advantages of Cro-Co BMS in a real-world population is not clear. METHODS: Patients undergoing percutaneous coronary intervention (PCI) with BMS for any reason were enrolled. Patient with multi-vessel PCI, multi-lesions PCI, PCI of unprotected left main and coronary grafts were not excluded. They were divided in two groups according to stent type: Cro-Co or SS group. The primary endpoint was clinically driven TLR at follow-up. RESULTS: A total of 383 patients were enrolled: 222 in SS and 161 in Cro-Co group. During the follow-up, Cro-Co patients had a significantly lower occurrence of TLR compared to SS patients (1.9% vs 8.6%, P = 0.006). There were no significant differences for the composite endpoint of death, myocardial infarct, and stroke (4.9% in Cro-Co group vs 9.5% in SS group, P = 0.119). At multivariate analysis, the variables that were predictors of TLR were: use of SS stent (OR 4.43, P = 0.019) and diabetes (OR 2.84, P = 0.025). CONCLUSIONS: Ultra-thin strut Cro-Co BMS is associated with a significant reduction of clinically driven TLR in all comers population with any type of coronary disease complexity. (J Interven Cardiol 2016;29:300-310). PMID- 27242167 TI - Increased expression of AT-1/SLC33A1 causes an autistic-like phenotype in mice by affecting dendritic branching and spine formation. AB - The import of acetyl-CoA into the lumen of the endoplasmic reticulum (ER) by AT 1/SLC33A1 regulates Nepsilon-lysine acetylation of ER-resident and -transiting proteins. Specifically, lysine acetylation within the ER appears to influence the efficiency of the secretory pathway by affecting ER-mediated quality control. Mutations or duplications in AT-1/SLC33A1 have been linked to diseases such as familial spastic paraplegia, developmental delay with premature death, and autism spectrum disorder with intellectual disability. In this study, we generated an AT 1 Tg mouse model that selectively overexpresses human AT-1 in neurons. These animals demonstrate cognitive deficits, autistic-like social behavior, aberrations in synaptic plasticity, an increased number of dendritic spines and branches, and widespread proteomic changes. We also found that AT-1 activity regulates acetyl-CoA flux, causing epigenetic modulation of the histone epitope H3K27 and mitochondrial adaptation. In conclusion, our results indicate that increased expression of AT-1 can cause an autistic-like phenotype by affecting key neuronal metabolic pathways. PMID- 27242169 TI - Response surface optimization of bioremediation of Acid black 52 (Cr complex dye) using Aspergillus tamarii. AB - Bioremediation of the Cr complex dye (Acid black 52) was performed in batch and continuous modes using growing Aspergillus tamarii. The removal of Cu which may be present as an impurity was 100% at 100 mg/L initial dye concentration. The removal of color and Cr decreased from 87% to 4% and from 92% to 8%, respectively, by increasing dye concentration from 100 to 5000 mg/L in batch mode. The removal of color and Cr increased from 27% to 67.8% and from 32% to 72%, respectively, with increasing hydraulic retention time from 28 to 220 h at 100 mg/L dye concentration in continuous mode. For optimization of color removal using response surface methodology (RSM) the ranges of parameters were kept at dye concentration: 200-500 mg/L; pH: 4-6 and time: 35-50 hours. Maximum color removal suggested by the model was 85.6809% at initial dye concentration 200 mg/L, pH 5.25 and time 50 h. The validation experiments in batch and continuous modes were conducted at the optimum conditions as suggested by the RSM model. The theoretical and experimental responses of color removal were in close agreement in batch mode. The scanning electron microscopy, energy dispersive X-ray analysis, transmission electron microscopy and gas chromatography-mass spectroscopy analyses indicated biosorption and biodegradation of dye. PMID- 27242171 TI - Sleep-wake profiles predict longitudinal changes in manic symptoms and memory in young people with mood disorders. AB - Mood disorders are characterized by disabling symptoms and cognitive difficulties which may vary in intensity throughout the course of the illness. Sleep-wake cycles and circadian rhythms influence emotional regulation and cognitive functions. However, the relationships between the sleep-wake disturbances experienced commonly by people with mood disorders and the longitudinal changes in their clinical and cognitive profile are not well characterized. This study investigated associations between initial sleep-wake patterns and longitudinal changes in mood symptoms and cognitive functions in 50 young people (aged 13-33 years) with depression or bipolar disorder. Data were based on actigraphy monitoring conducted over approximately 2 weeks and clinical and neuropsychological assessment. As part of a longitudinal cohort study, these assessments were repeated after a mean follow-up interval of 18.9 months. No significant differences in longitudinal clinical changes were found between the participants with depression and those with bipolar disorder. Lower sleep efficiency was predictive of longitudinal worsening in manic symptoms (P = 0.007). Shorter total sleep time (P = 0.043) and poorer circadian rhythmicity (P = 0.045) were predictive of worsening in verbal memory. These findings suggest that some sleep-wake and circadian disturbances in young people with mood disorders may be associated with less favourable longitudinal outcomes, notably for subsequent manic symptoms and memory difficulties. PMID- 27242172 TI - Importance of Plasmonic Heating on Visible Light Driven Photocatalysis of Gold Nanoparticle Decorated Zinc Oxide Nanorods. AB - Herein we explore the role of localized plasmonic heat generated by resonantly excited gold (Au) NPs on visible light driven photocatalysis process. Au NPs are deposited on the surface of vertically aligned zinc oxide nanorods (ZnO NRs). The localized heat generated by Au NPs under 532 nm continuous laser excitation (SPR excitation) was experimentally probed using Raman spectroscopy by following the phonon modes of ZnO. Under the resonant excitation the temperature at the surface of the Au-ZnO NRs reaches up to about 300 degrees C, resulting in almost 6 times higher apparent quantum yield (AQY) for photocatalytic degradation of methylene blue (MB) compared to the bare ZnO NRs. Under solar light irradiation the Au-ZnO NRs demonstrated visible light photocatalytic activity twice that of what was achieved with bare ZnO NRs, while significantly reduced the activation energy required for the photocatalytic reactions allowing the reactions to occur at a faster rate. PMID- 27242173 TI - Tailoring ruthenium exposure to enhance the performance of fcc platinum@ruthenium core-shell electrocatalysts in the oxygen evolution reaction. AB - The catalytic properties of noble metal nanocrystals are a function of their size, structure, and surface composition. In particular, achieving high activity without sacrificing stability is essential for designing commercially viable catalysts. A major challenge in designing state-of-the-art Ru-based catalysts for the oxygen evolution reaction (OER), which is a key step in water splitting, is the poor stability and surface tailorability of these catalysts. In this study, we designed rapidly synthesizable size-controlled, morphology-selective, and surface-tailored platinum-ruthenium core-shell (Pt@Ru) and alloy (PtRu) nanocatalysts in a scalable continuous-flow reactor. These core-shell nanoparticles with atomically precise shells were produced in a single synthetic step with carbon monoxide as the reducing agent. By varying the metal precursor concentration, a dendritic or layer-by-layer ruthenium shell can be grown. The synthesized Pt@Ru and PtRu nanoparticles exhibit noticeably higher electrocatalytic activity in the OER compared to that of pure Pt and Ru nanoparticles. Promisingly, Pt@Ru nanocrystals with a ~2-3 atomic layer Ru cuboctahedral shell surpass conventional Ru nanoparticles in terms of both durability and activity. PMID- 27242174 TI - Open-access microcavities for chemical sensing. AB - The recent development of open-access optical microcavities opens up a number of intriguing possibilities in the realm of chemical sensing. We provide an overview of the different possible sensing modalities, with examples of refractive index sensing, optical absorption measurements, and optical tracking and trapping of nanoparticles. The extremely small mode volumes within an optical microcavity allow very small numbers of molecules to be probed: our current best detection limits for refractive index and absorption sensing are around 10(5) and 10(2) molecules, respectively, with scope for further improvements in the future. PMID- 27242175 TI - Obesity-related health status is a better predictor of pregnancy with fertility treatment than body mass index: a prospective study. AB - This study assessed whether an obesity-related health status instrument (Edmonton obesity scoring system - EOSS) or body mass index (BMI) better predicted pregnancy rates in overweight women undergoing fertility treatments. A prospective cohort study was conducted on patients with a BMI >= 25 kg m(-2) undergoing a fertility treatment cycle (ovulation induction, superovulation, or in vitro fertilization). Obesity-related health status including blood pressure, blood work, health history, and functional assessment were assessed. A total of 101 patients were included in the study with an average age of 36.3 +/- 4.2 years and a mean BMI of 31.8 +/- 5.2 kg m(-2) . EOSS was found to be statistically predictive of pregnancy rate/cycle (OR 0.51, 95% CI 0.27-0.94; P = 0.03), whereas BMI was not (OR 0.95, 95% CI 0.86-1.05). A similar trend was seen for clinical pregnancy rate/cycle started. However, the association between clinical pregnancy rates and EOSS or BMI did not reach statistical significance (OR 0.53, P = 0.06 and OR 0.98, P = 0.62 respectively). Our results demonstrated that EOSS better predicted pregnancy rates after fertility treatments than BMI. In fact, for every EOSS stage increased by one unit, the odds of pregnancy were approximately halved. A multi-centre study powered for live birth is warranted to establish effective pre-fertility management of overweight women. PMID- 27242176 TI - Immunotherapy using inhibin antiserum enhanced the efficacy of equine chorionic gonadotropin on superovulation in major inbred and outbred mice strains. AB - Improvement of the superovulation technique will help to enhance the efficiency of embryo and animal production. Blocking inhibin using inhibin antiserum (IAS) is known to promote follicular development by increasing the level of FSH. Previously, we reported that coadministration of IAS and eCG produced more than 100 oocytes from a single female C57BL/6 mouse at 4 weeks old. The oocytes derived from the IAS + eCG (IASe) treatment were able to fertilize and develop normally into offspring. In this study, we examined the effect of IASe treatment on the numbers of ovulated oocytes in major inbred (A/J, BALB/cByJ, C3HeJ, DBA/2J, and FVB/NJ) and outbred (CD1) mice strains at 4 weeks old. We confirmed the fertilization and developmental ability of the IASe-derived oocytes. IASe treatment ovulated 1.5 to 3.2 times higher numbers of oocytes than eCG treatment alone. The fertilization rate of IASe-derived oocytes was similar to that of eCG derived oocytes. In vitro and in vivo developmental rates of the embryos derived from IASe were similar to the rates of embryos derived from eCG. We have shown that superovulation by IASe is very effective in obtaining high numbers of ovulated oocytes from small numbers of oocyte donor in a number of mice strains. The superovulation technique will contribute to the archiving of cryopreserved embryos of genetically engineered mice using small numbers of donors and has the potential to produce more live animals for rederivation of the archived mouse lines in mouse repositories. PMID- 27242177 TI - Validation of a noninvasive diagnostic tool to verify neuter status in dogs: The urinary FSH to creatinine ratio. AB - Determining the presence of functional gonadal tissue in dogs can be challenging, especially in bitches during anestrus or not known to have been ovariectomized, or in male dogs with nonscrotal testes. Furthermore, in male dogs treated with deslorelin, a slow-release GnRH agonist implant for reversible chemical castration, the verification of complete downregulation of the hypothalamic pituitary-gonadal (HPG) axis can be difficult, especially if pretreatment parameters such as the size of the testes or prostate gland are not available. The aims of this study were to validate an immunoradiometric assay for measurement of FSH in canine urine, to determine if the urinary FSH to creatinine ratio can be used to verify the neuter status in bitches and male dogs, as an alternative to the plasma FSH concentration, and to determine if downregulation of the HPG axis is achieved in male dogs during deslorelin treatment. Recovery of added canine FSH and serial dilutions of urine reported that the immunoradiometric assay measures urinary FSH concentration accurately and with high precision. Plasma FSH concentrations (the mean of two samples, taken 40 minutes apart) and the urinary FSH to creatinine ratio were determined before gonadectomy and 140 days (median, range 121-225 days) and 206 days (median, range 158-294 days) after gonadectomy of 13 bitches and five male dogs, respectively, and in 13 male dogs before and 132 days (median, range 117-174 days) after administration of a deslorelin implant. In both bitches and male dogs, the plasma FSH concentration and the urinary FSH to creatinine ratio were significantly higher after gonadectomy, with no overlapping of their ranges. Receiver operating characteristic analysis of the urinary FSH to creatinine ratio revealed a cut-off value of 2.9 in bitches and 6.5 in males to verify the presence or absence of functional gonadal tissue. In male dogs treated with deslorelin, the plasma FSH concentrations and urinary FSH to creatinine ratios were significantly lower after administration of the implant, but their ranges overlapped. We conclude that the urinary FSH to creatinine ratio can be used to verify the neuter status of bitches and male dogs. However, it cannot be used for the assessment of complete downregulation of the HPG axis after administration of a deslorelin implant. The urinary FSH to creatinine ratio is preferable over the plasma FSH concentration because it involves only one sample that can be collected relatively easy and noninvasively. PMID- 27242178 TI - Mitochondrial oxygen consumption is a unique indicator of stallion spermatozoal health and varies with cryopreservation media. AB - Mitochondrial oxygen consumption is a sensitive indicator of spermatozoal health in the context of cryopreservation. We investigated oxygen consumption of equine sperm mitochondria during incubation in four commercially available sperm cryopreservation extenders: modified INRA 96, BotuCrio, EZ Freezin-"LE" and "MFR5", in addition to several other parameters including motility, reactive oxygen species (ROS) production and viability. All experimental endpoints, with the exception of average path velocity, were affected significantly by freezing extender type after freezing and thawing. Sperm in INRA 96 had the lowest average progressive motility after thawing (24 +/- 4.8%, P < 0.05). Sperm in EZ Freezin "LE" had the highest post thaw viability (79 +/- 3.1%, P < 0.05) and lowest post thaw ROS production (13 +/- 2.4%), but sperm in BotuCrio had the highest maximal oxygen consumption levels, while also demonstrating similar ROS production and viability. This difference would not have been detected using conventional sperm analytical methods. In addition, sperm in BotuCrio had the highest average total motility (49 +/- 7.4%), progressive motility (41 +/- 6.4%), and velocity (VAP, 90 +/- 3.6 MUm/s) indicating that this medium preserved mitochondrial function optimally after cryopreservation. Mitochondrial oxygen consumption was positively correlated with traditional measures of sperm function including motility and viability (r = 0.62 and r = 0.49, respectively, P < 0.05), thus making it a sensitive method for determining cryopreservation success and mitochondrial function in stallion sperm. PMID- 27242179 TI - Use of peripheral blood for production of buffalo (Bubalus bubalis) embryos by handmade cloning. AB - Buffalo embryos were produced by handmade cloning using peripheral blood-derived lymphocytes as donor cells. Although the blastocyst rate was lower (P < 0.01) for lymphocyte- than control skin fibroblast-derived embryos (6.6 +/- 0.84% vs. 31.15 +/- 2.97%), the total cell number (152.6 +/- 23.06 vs. 160.1 +/- 13.25) and apoptotic index (6.54 +/- 0.95 vs. 8.45 +/- 1.32) were similar. The global level of H3K9ac was higher (P < 0.05) in lymphocyte- than that in skin-derived blastocysts; whereas in IVF blastocysts, the level was not significantly different from the two cloned groups. The level of H3K27me3 was similar among the three groups. The expression level of DNMT1, DNMT3a, HDAC1, and IGF-1R was higher (P < 0.01) in lymphocytes than that in skin fibroblasts. The expression level of CDX2 was higher (P < 0.05) than that of DNMT3a, IGF-1R, OCT4, and NANOG was lower (P < 0.05) in lymphocyte-derived than in IVF blastocysts; that of DNMT1 and HDAC1 was similar in the two groups. The expression level of all these genes, except that of NANOG, was lower (P < 0.05) in lymphocyte- than in skin fibroblast derived blastocysts. It is concluded that, peripheral blood-derived lymphocytes can be used for producing handmade cloning embryos in bubaline buffaloes. PMID- 27242180 TI - In vitro fertilization using frozen-thawed feline epididymal spermatozoa from corpus and cauda regions. AB - Epididymal sperm preservation offers a potential for rescuing genetic material from endangered or valuable animals after injury or death. Spermatozoa from corpus, as well as from cauda, have the capability to be motile and to undergo capacitation and can thus potentially be preserved for assisted reproductive technologies. In the present study, feline frozen-thawed epididymal spermatozoa from corpus and cauda regions were investigated for their ability to fertilize homologous oocytes and further embryo development in vitro. Epididymal spermatozoa from corpus and cauda of seven cats were cryopreserved and used for IVF. Cumulus-oocyte complexes (n = 419) were obtained from female cats after routine spaying. Frozen-thawed corpus epididymal spermatozoa showed similar properties of acrosome integrity, membrane integrity, and chromatin integrity as frozen-thawed spermatozoa from cauda except corpus spermatozoa showed lower motility (P < 0.05). The fertilizing capacity of frozen-thawed corpus epididymal spermatozoa was confirmed by similar number of embryos developing to the two- and four-cell stages compared with sperm from cauda (32.03% vs. 33.33%). However, oocytes fertilized with corpus spermatozoa had lower potential to develop to the blastocyst stage (6.79%) and had lower cell numbers compared to oocytes fertilized with cauda spermatozoa (14.08%). In conclusion, spermatozoa from corpus epididymis had a similar capability to fertilize homologous oocytes in vitro as sperm from cauda but resulted in fewer embryos developing to the blastocyst stage compared to spermatozoa from the cauda. PMID- 27242181 TI - Hematocrit changes in healthy periparturient bitches that underwent elective cesarean section. AB - Hematocrits were measured before each of 406 cesarean sections performed on 324 bitches at term and again after crystalloid fluid therapy administered at 35 mL/kg over 11/2-2 hours starting from induction. The mean hematocrit was 44.2% (95% confidence interval [CI] 43.8%-44.6%) before cesarean section and 37.8% (95% CI 37.3%-38.2%) after cesarean section and fluid therapy, with a mean decrease of 6.4% points (95% CI 6.1%-6.7%) over all 406 cesarean sections. These results provide the clinician with clear guidelines of the normal expected ranges of hematocrits in bitches before and after cesarean section. Results of this study show that bitches have hematocrits at term that are at the lower end of the normal reference ranges for nonpregnant dogs and that there is no true anemia of pregnancy. It is therefore suggested that if late term bitches present with anemia, other causes besides pregnancy should be considered. PMID- 27242183 TI - Exploring the dynamics of phase separation in colloid-polymer mixtures with long range attraction. AB - We have studied the kinetics of phase separation and gel formation in a low dispersity colloid - non-adsorbing polymer system with long range attraction using small-angle light scattering. This system exhibits two-phase and three phase coexistence of gas, liquid and crystal phases when the strength of attraction is between 2 and 4kBT and gel phases when the strength of attraction is increased. For those samples that undergo macroscopic phase separation, whether to gas-crystal, gas-liquid or gas-liquid-crystal coexistence, we observe dynamic scaling of the structure factor and growth of a characteristic length scale that behaves as expected for phase separation in fluids. In samples that gel, the power law associated with the growth of the dominant length scale is not equal to 1/3, but appears to depend mainly on the strength of attraction, decreasing from 1/3 for samples near the coexistence region to 1/27 at 8kBT, over a wide range of colloid and polymer concentrations. PMID- 27242182 TI - Cytosine methylation of sperm DNA in horse semen after cryopreservation. AB - Semen processing may contribute to epigenetic changes in spermatozoa. We have therefore addressed changes in sperm DNA cytosine methylation induced by cryopreservation of stallion semen. The relative amount of 5-methylcytosine relative to the genomic cytosine content of sperm DNA was analyzed by ELISA. In experiment 1, raw semen (n = 6 stallions, one ejaculate each) was shock-frozen. Postthaw semen motility and membrane integrity were completely absent, whereas DNA methylation was similar in raw (0.4 +/- 0.2%) and shock-frozen (0.3 +/- 0.1%) semen (not significant). In experiment 2, three ejaculates per stallion (n = 6) were included. Semen quality and DNA methylation was assessed before addition of the freezing extender and after freezing-thawing with either Ghent (G) or BotuCrio (BC) extender. Semen motility, morphology, and membrane integrity were significantly reduced by cryopreservation but not influenced by the extender (e.g., total motility: G 69.5 +/- 2.0, BC 68.4 +/- 2.2%; P < 0.001 vs. centrifugation). Cryopreservation significantly (P < 0.01) increased the level of DNA methylation (before freezing 0.6 +/- 0.1%, postthaw G 6.4 +/- 3.7, BC 4.4 +/- 1.5%; P < 0.01), but no differences between the freezing extenders were seen. The level of DNA methylation was not correlated to semen motility, morphology, or membrane integrity. The results demonstrate that semen processing for cryopreservation increases the DNA methylation level in stallion semen. We conclude that assessment of sperm DNA methylation allows for evaluation of an additional parameter characterizing semen quality. The lower fertility rates of mares after insemination with frozen-thawed semen may at least in part be explained by cytosine methylation of sperm-DNA induced by the cryopreservation procedure. PMID- 27242184 TI - Promoting Occupational Safety and Health for Cambodian Entertainment Sector Workers. AB - Cambodia has developed booming textile, garment, tourism, and entertainment service industries since the mid-1990s. The 2007 global financial crisis pushed many garment workers, who lost their jobs, into the entertainment sector. Entertainment workers are typically engaged informally by their employers and are subjected to long working hours, sexual harassment, and violence. Many who sell beverages are forced into excessive alcohol consumption as part of their work. Many are also expected by their employers and clients to provide sexual services. To address unsafe and unhealthy working conditions for these workers, an innovative occupational safety and health regulation was adopted in 2014. This first-of-its-kind occupational safety and health regulation was developed jointly by the Cambodian Ministry of Labour and Vocational Training and employers' and workers' organizations in the entertainment sector. The implementation of this regulation can also be a viable contribution of occupational safety and health to HIV interventions for these workers. PMID- 27242186 TI - Immunotherapy for gynecologic cancers. PMID- 27242187 TI - Ecosystem services, environmental stressors, and decision making: How far have we got? PMID- 27242185 TI - The 11beta-hydroxysteroid dehydrogenase type 1 inhibitor protects against the insulin resistance and hepatic steatosis in db/db mice. AB - Glucocorticoids (GCs) metabolism is regulated by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). When GCs are present in excess, they can impair glucose-dependent insulin sensitivity. We have previously synthesized several curcumin analogues, of which four compounds were selective inhibitors of 11beta-HSD1. Here, we present data supporting that the 11beta-hydroxysteroid dehydrogenase type 1 inhibitor (H8) inhibits insulin resistance and ameliorates hepatic steatosis in db/db mice. We compared glucose and lipid metabolism in db/db mice with or without administration of H8, which significantly decreased fasting blood glucose levels and protected against insulin resistance and hepatic steatosis compared to when glucose and lipid metabolism were measured following curcumin administration. The hepatic enzyme was reduced significantly in the plasma samples from db/db mice which were treated with H8. Serum corticosterone (active) levels, which are regulated by 11beta-HSD1 were reduced when mice received H8. H8 administration suppressed phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6-pase) expression, which are related to gluconeogenesis and enhanced glucose transporter 4 (GLUT4) protein content in liver. Treatment with H8 improved obesity and metabolic disorders, such as insulin resistance and hepatic steatosis by suppressing activity of 11beta-HSD1, suggesting that H8 might be a beneficial drug for the treatment of obesity and Type-2 diabetes (T2D). PMID- 27242188 TI - Meta-analysis: effectiveness of forced-air warming for prevention of perioperative hypothermia in surgical patients. AB - AIM: The aim of this study was to evaluate the effectiveness of forced-air warming for preventing perioperative hypothermia. BACKGROUND: Perioperative hypothermia commonly occurs in patients receiving anaesthesia during surgeries. However, the effectiveness of warming systems requires verification. DESIGN: Systematic review incorporating meta-analysis. DATA SOURCES: We searched OVID, PubMed, Cochrane Library, Medline, CINAHL, CETD and CEPS databases (2001-2015) for randomized controlled trials published in English and Chinese. Outcome measures of interests were body temperature and thermal comfort. REVIEW METHODS: Cochrane methods, Quality of evidence (GRADE) assessments and Jadad Quality Score were used. RESULTS: Twenty-nine trials (1875 patients) met inclusion criteria, including seven trials (502 patients) related to thermal comfort. Results showed that: (1) forced-air warming was more effective than passive insulation and circulating-water mattresses; (2) there was no statistically significant difference among forced-air warming, resistive heating blankets, radiant warming systems and circulating-water garments; and (3) that thermal comfort provided by forced-air warming was superior to that of passive insulation, resistive heating blankets and radiant warming systems, but inferior to that of circulating-water mattresses. CONCLUSIONS: Forced-air warming prevents perioperative hypothermia more effectively than passive insulation and circulating-water mattresses, whereas there is no statistically significant difference in its effectiveness compared with circulating-water garments, resistive heating blankets and radiant warming systems. PMID- 27242189 TI - Corrigendum: Detection of DNA viruses in prostate cancer. PMID- 27242190 TI - A multifunctional lanthanide metal-organic framework supported by Keggin type polyoxometalates. AB - A neodymium metal-organic framework with 1D nanotubular channels incorporating Keggin type [SiWWO38](3-) has been synthesized by utilizing pyridine-2,5 dicarboxylic acid as an organic ligand. It represents an unusual polyoxometalate templated framework with the multifunctionality of magnetism, near-infrared luminescence and the selective adsorption of Rhodamine B dye molecules. PMID- 27242191 TI - Clinical Utility of Preimplantation Homograft Cultures in Patients Undergoing Congenital Cardiac Surgery. AB - Institutional practice at our hospital (Boston Children's Hospital) is to culture homografts before implantation during congenital cardiac surgery. Over a 4-year period, 5% (73 of 1376) of these cultures were positive, but the results had minimal clinical impact. Our experience demonstrates that there is limited utility in preimplantation cultures of cardiac homografts. PMID- 27242192 TI - First case of drug eruption due to ipragliflozin: Case report and review of the literature. AB - Ipragliflozin is a new drug for the treatment of diabetes mellitus. Its action of sodium-glucose cotransporter 2 (SGLT2) inhibition induces glucosuria and decreases blood glucose levels. We report the first case of ipragliflozin-related eczematous drug eruption and a review of the past literature on drug eruptions caused by SGLT2 inhibitors. PMID- 27242193 TI - The Diverse Structures and Functions of Surfactant Proteins. AB - Surface tension at liquid-air interfaces is a major barrier that needs to be surmounted by a wide range of organisms; surfactant and interfacially active proteins have evolved for this purpose. Although these proteins are essential for a variety of biological processes, our understanding of how they elicit their function has been limited. However, with the recent determination of high resolution 3D structures of several examples, we have gained insight into the distinct shapes and mechanisms that have evolved to confer interfacial activity. It is now a matter of harnessing this information, and these systems, for biotechnological purposes. PMID- 27242194 TI - Blind Evaluation of Hybrid Protein Structure Analysis Methods based on Cross Linking. AB - Hybrid methods combine experimental data and computational modeling to analyze protein structures that are elusive to structure determination. To spur the development of hybrid methods, we propose to test them in the context of the CASP experiment and would like to invite experimental groups to participate in this initiative. PMID- 27242195 TI - Osteopenia of the hip joint in cerebral palsy - does this affect hip stability? PMID- 27242196 TI - pH-regulated metal-ligand switching in the HM loop of ATP7A: a new paradigm for metal transfer chemistry. AB - Cuproproteins such as PHM and DBM mature in late endosomal vesicles of the mammalian secretory pathway where changes in vesicle pH are employed for sorting and post-translational processing. Colocation with the P1B-type ATPase ATP7A suggests that the latter is the source of copper and supports a mechanism where selectivity in metal transfer is achieved by spatial colocation of partner proteins in their specific organelles or vesicles. In previous work we have suggested that a lumenal loop sequence located between trans-membrane helices TM1 and TM2 of the ATPase, and containing five histidines and four methionines, acts as an organelle-specific chaperone for metallation of the cuproproteins. The hypothesis posits that the pH of the vesicle regulates copper ligation and loop conformation via a mechanism which involves His to Met ligand switching induced by histidine protonation. Here we report the effect of pH on the HM loop copper coordination using X-ray absorption spectroscopy (XAS), and show via selenium substitution of the Met residues that the HM loop undergoes similar conformational switching to that found earlier for its partner PHM. We hypothesize that in the absence of specific chaperones, HM motifs provide a template for building a flexible, pH-sensitive transfer site whose structure and function can be regulated to accommodate the different active site structural elements and pH environments of its partner proteins. PMID- 27242198 TI - The role of disulfide-bridge on the activities of H-shape gemini-like cationic lipid based siRNA delivery. AB - In our previous study, a H-shape gemini-like cationic lipid (ssGLCL, formerly named as CLD), composed of two hydrophilic lysine heads and two hydrophobic oleyl alcohol tails with a bridge of the redox-active disulfide-bond, had been synthesized and used as a nanocarrier for delivering small interfering RNAs (siRNAs) into cells. In order to further elucidate the role of disulfide (-S-S-) bridge on the activity of ssGLCL based siRNA delivery, a comparable ccGLCL bridged with a non-reducible carbon-carbon bond was synthesized and used as control in this study. Both two H-shape GLCL molecules could individually self assemble into cationic nanoparticles in water phase and complex with negatively charged siRNA into nanoplexes with particle size of ~200nm and zeta potential of ~ +30mV, and exhibit effective siRNA delivery both in vitro and in vivo. Investigation of internalization pathway displayed that both ssGLCL/siRNA and ccGLCL/siRNA nanoplexes were predominantly internalized into MCF-7 cells by the clathrin-mediated endocytosis pattern. Although a lower cellular uptake of siRNA was found in the human breast cancer MCF-7 cells, the ssGLCL/siRNA nanoplexes could exhibit similar or even stronger down-regulation effects on the targeted EGFR mRNA and protein in MCF-7 cells when compared to the ccGLCL/siRNA nanoplexes. Furthermore, mechanistic study showed that the enhanced down regulation effects of ssGLCL/siRNA nanoplexes on targeted mRNA and protein were probably attributed to the increased release of siRNA from lysosomes to cytoplasm following the cleavage of redox-active disulfide-bridge in ssGLCL. Therefore, we believed that the redox-active H-shape ssGLCL could be a potential nanocarrier towards improving siRNA delivery. PMID- 27242197 TI - Deficiency in the anti-aging gene Klotho promotes aortic valve fibrosis through AMPKalpha-mediated activation of RUNX2. AB - Fibrotic aortic valve disease (FAVD) is an important cause of aortic stenosis, yet currently there is no effective treatment for FAVD due to its unknown etiology. The purpose of this study was to investigate whether deficiency in the anti-aging Klotho gene (KL) promotes high-fat-diet-induced FAVD and to explore the underlying molecular mechanism. Heterozygous Klotho-deficient (KL(+/-) ) mice and WT littermates were fed with a high-fat diet (HFD) or normal diet for 13 weeks, followed by treatment with the AMPKalpha activator (AICAR) for an additional 2 weeks. A HFD caused a greater increase in collagen levels in the aortic valves of KL(+/-) mice than of WT mice, indicating that Klotho deficiency promotes HFD-induced aortic valve fibrosis (AVF). AMPKalpha activity (pAMPKalpha) was decreased, while protein expression of collagen I and RUNX2 was increased in the aortic valves of KL(+/-) mice fed with a HFD. Treatment with AICAR markedly attenuated HFD-induced AVF in KL(+/-) mice. AICAR not only abolished the downregulation of pAMPKalpha but also eliminated the upregulation of collagen I and RUNX2 in the aortic valves of KL(+/-) mice fed with HFD. In cultured porcine aortic valve interstitial cells, Klotho-deficient serum plus cholesterol increased RUNX2 and collagen I protein expression, which were attenuated by activation of AMPKalpha by AICAR. Interestingly, silencing of RUNX2 abolished the stimulatory effect of Klotho deficiency on cholesterol-induced upregulation of matrix proteins, including collagen I and osteocalcin. In conclusion, Klotho gene deficiency promotes HFD-induced fibrosis in aortic valves, likely through the AMPKalpha-RUNX2 pathway. PMID- 27242199 TI - Quercetin-loaded freeze-dried nanomicelles: Improving absorption and anti-glioma efficiency in vitro and in vivo. AB - To improve its poor aqueous solubility and stability, the potential chemopreventive agent quercetin was encapsulated in freeze-dried polymeric micelles by a thin film hydration and vacuum freeze-drying process before being used for glioma chemotherapy. The micelle characteristics, release profile, cellular uptake, intracellular drug concentration, transport across the blood brain barrier, and antitumor efficiency in vivo were investigated. Results showed that the particle size of quercetin-loaded freeze-dried nanomicelles (QUE-FD-NMs) ranged from 20 to 80nm, with an efficiently sustained release profile. Increased intracellular uptake into Caco-2 cells with low cytotoxicity, efficient penetration of BBB, and powerful cytotoxicity on C6 glioma cells were observed. QUE-FD-NMs accumulated in tumor-bearing brain tissues and exhibited significant antitumor effects in vivo, which significantly benefited the survival of glioma bearing mice. These findings suggest that freeze-drying micelles loaded with quercetin is a promising drug delivery method for glioma therapy. PMID- 27242200 TI - Contemporary outcomes of sickle cell disease in pregnancy. AB - BACKGROUND: Data regarding pregnancy outcomes in sickle cell disease are conflicting. Previous studies are limited by small sample size, narrow geographic area, and a wide range of resource availability. OBJECTIVE: The purpose of this study was to examine the association between maternal sickle cell disease and adverse pregnancy outcomes in a contemporary North American cohort. STUDY DESIGN: We performed a retrospective cohort study of 2,027,323 women with singleton pregnancies delivered in California from 2005-2008. Deliveries at <24 or >42 6/7 weeks of gestation were excluded. Women with sickle cell disease were compared with control subjects. Maternal outcomes of interest included preeclampsia, preterm delivery, placental abruption, oligohydramnios, and cesarean delivery; neonatal outcomes included small for gestational age, anomalies, stillbirth, neonatal death, and infant death. RESULTS: The prevalence of sickle cell disease was 0.017%. Compared with control subjects, women with sickle cell disease were more likely to have limited prenatal care (7.4 vs 3.8%; P=.001), underlying chronic hypertension (2.3% vs 1.1%; P=.038), and fetal anomalies (14.0 vs 6.4%; P<.001). The increased odds of fetal anomalies persisted after adjustment for multiple confounders (odds ratio, 1.73; 95% confidence interval, 1.26-2.38). Women with sickle cell disease also had higher odds of severe preeclampsia (odds ratio, 3.75; 95% confidence interval, 2.21-6.38), preterm delivery (odds ratio, 2.50; 95% confidence interval, 1.93-3.21), small for gestational age (odds ratio, 1.96; 95% confidence interval, 1.18-3.25), and cesarean delivery (odds ratio, 1.93; 95% confidence interval, 1.40-2.67). CONCLUSION: Women with sickle cell disease are at high risk of maternal and neonatal morbidity. Low rates of fetal and neonatal death may reflect improved antenatal surveillance and management as compared with previous studies. The association between sickle cell disease and fetal anomalies warrants further investigation. PMID- 27242201 TI - Lateral asymmetric decubitus position for the rotation of occipito-posterior positions: multicenter randomized controlled trial EVADELA. AB - BACKGROUND: Fetal occiput posterior positions are associated with poorer maternal outcomes than occiput anterior positions. Although methods that include instrumental and manual rotation can be used at the end of labor to promote the rotation of the fetal head, various maternal postures may also be performed from the beginning of labor in occiput posterior position. Such postures might facilitate flexion of the fetal head and favor its rotation into an occiput anterior position. OBJECTIVE: The purpose of this study was to determine whether a lateral asymmetric decubitus posture facilitates the rotation of fetal occiput posterior into occiput anterior positions. STUDY DESIGN: Evaluation of Decubitus Lateral Asymmetric posture was a multicenter randomized controlled trial that included 322 women from May 2013 through December 2014. Study participants were women who labored with ruptured membranes and a term fetus that was confirmed by ultrasound imaging to be in cephalic posterior position. Women who were assigned to the intervention group were asked to lie in a lateral asymmetric decubitus posture on the side opposite that of the fetal spine during the first hour and encouraged to maintain this position for as long as possible during the first stage of labor. In the control group, women adopted a dorsal recumbent posture during the first hour after random assignment. The primary outcome was occiput anterior position at 1 hour after random assignment. Secondary outcomes were occiput anterior position at complete dilation, mode of delivery, speed of dilation during the active first stage, maternal pain, and women's satisfaction. RESULTS: One hundred sixty women were assigned to the intervention group, and 162 women were assigned to the control group. One hour after random assignment, the rates of occiput anterior position did not differ between the intervention and control groups (21.9% vs 21.6%, respectively; P=.887). Occiput anterior rates did not differ between groups at complete dilation (43.7% vs 43.2%, respectively; P=.565) or at birth (83.1% vs 86.4%, respectively; P=.436). Finally, the groups did not differ significantly for cesarean delivery rates (18.1% among women in lateral asymmetric decubitus and 14.2% among control subjects (P=0.608) or for speed of cervical dilation during the active first stage of labor (P=.684), pain assessment (P=.705), or women's satisfaction (P=.326). No maternal or neonatal adverse effect that was associated with either posture was observed. CONCLUSION: Lateral asymmetric decubitus position on the side opposite that of the fetal spine did not facilitate rotation of fetal head. Nevertheless, other maternal positions may be effective in promoting fetal head rotation. Further research is needed; posturing during labor, nonetheless, should remain a woman's active choice. PMID- 27242202 TI - Reply. PMID- 27242203 TI - The impact of mode of delivery on infant neurologic outcomes in myelomeningocele. AB - BACKGROUND: Controversy exists regarding the optimal route of delivery for fetuses who are diagnosed prenatally with myelomeningocele. Current recommendations are based partly on antiquated studies with questionable methods. All studies that have been published to date suffer from nonstandardized outcome measures, selection bias, and small sample size. The larger studies are >15 years old. OBJECTIVE: The purpose of this study was to provide information for evidence based decision-making regarding the impact of route of delivery on motor outcomes for pediatric patients with prenatally were diagnosed myelomeningocele in a well defined retrospective cohort. STUDY DESIGN: Medical records were reviewed retrospectively for all neonates who had been diagnosed with a myelomeningocele at birth from 1995-2015 within the University of Pittsburgh Medical Center system, as identified through the Children's Hospital of Pittsburgh Neurosurgery Department operative database. Records were matched with maternal records with the use of the Center for Assistance in Research that used eRecord. Data from 72 maternal-neonatal pairs were analyzed for multiple variables. The primary outcome measure was the difference between the functional and anatomic motor levels in the child at the age of 2 years, stratified by mode of delivery and presence or absence of labor. The sample size necessary to detect a difference between the groups with power of 0.8 and significance of .05 was calculated to be 52 subjects total (26 per group). RESULTS: Functional levels were slightly better than predicted by anatomic levels for all pediatric patient groups, regardless of mode of delivery or presence of labor. Anatomic levels were slightly lower (better), and defects were smaller for those infants who underwent vaginal delivery or a trial of labor, likely attributable to selection bias. Attempts to correct for this selection bias did not change the results. No other outcomes that were analyzed were associated significantly with mode of delivery or presence of labor. CONCLUSION: No benefit to motor function from delivery by cesarean section or avoidance of labor was demonstrated statistically in this mother-infant cohort. PMID- 27242204 TI - Effect of surgery on ovarian reserve in women with endometriomas, endometriosis and controls. AB - BACKGROUND: Many women who experience endometriosis and endometriomas also encounter problems with fertility. OBJECTIVE: The purpose of this study was to determine the impact of surgical excision of endometriosis and endometriomas compared with control subjects on ovarian reserve. STUDY DESIGN: This was a prospective cohort study of 116 women aged 18-43 years with pelvic pain and/or infertility who underwent surgical treatment of suspected endometriosis (n=58) or endometriomas (n=58). Based on surgical findings, the suspected endometriosis group was further separated into those with evidence of peritoneal disease (n=29) and those with no evidence of endometriosis (n=29). Ovarian reserve was measured by anti-Mullerian hormone and compared before surgery and at 1 month and 6 months after surgery. RESULTS: Baseline anti-Mullerian hormone values were significantly lower in the endometrioma vs negative laparoscopy group (1.8 ng/mL [95% confidence interval, 1.2-2.4 ng/mL] vs 3.2 ng/mL [95% confidence interval, 2.0 4.4 ng/mL]; P<.02), but the peritoneal endometriosis group was not significantly different than either of these groups. Only patients with endometriomas had a significant decline in ovarian reserve at 1 month (-48%; 95% confidence interval, -54 to -18%; P<.01; mean anti-Mullerian hormone baseline value, 1.77-1.12 ng/mL at 1 month). Six months after surgery, anti-Mullerian hormone values continued to be depressed from baseline but were no longer significantly different. The rate of anti-Mullerian hormone decline was correlated positively with baseline preoperative anti-Mullerian hormone values and the size of endometrioma that was removed. Those with bilateral endometriomas (n=19) had a significantly greater rate of decline (53.0% [95% confidence interval, 35.4-70.5%] vs 17.5% [95% confidence interval, 3.2-31.8%]; P=.002). CONCLUSION: At baseline, patients with endometriomas had significantly lower anti-Mullerian hormone values compared with women without endometriosis. Surgical excision of endometriomas appears to have temporary detrimental effects on ovarian reserve. PMID- 27242205 TI - The endocrine disrupting chemicals as possible stillbirth contributors. PMID- 27242206 TI - New therapeutic approaches in rheumatoid arthritis. AB - The treatment of rheumatoid arthritis (RA) has changed dramatically over the past two decades. The combination of better insights into the pathophysiological and immunological mechanisms of RA and the possibilities offered by biotechnology led to the development and introduction into clinical practice of a new class of antirheumatic biologic therapies, which along with earlier and more aggressive treatment contributed to dramatically better outcomes for patients with RA. To date, nine biologic agents have been approved for the treatment for RA, and a first Janus kinase (JAK) inhibitor has also been approved in the United States and various other countries in the world (but not by the European Medicines Agency [EMA]). Many additional molecules with distinct mechanisms of action are currently being tested in laboratories and in clinical trials. In addition, considerable improvements have been made in the optimal use of all these agents through treatment strategies such as treating-to-target, induction-maintenance, and dose individualization. PMID- 27242207 TI - [Hepatic hydrothorax]. AB - Hydrothorax liver is defined by the presence of pleural effusion greater than 500mL secondary to portal hypertension in cirrhotic patients. Poor tolerance of hepatic hydrothorax makes the therapeutic management of these fragile patients and is associated with iatrogenic complications. The mechanism of hydrothorax formation cirrhosis is due to a unidirectional transfer of the abdominal ascites through the diaphragmatic gaps (that were identified macroscopically and microscopically) in the pleural cavity. The treatment of hepatic hydrothorax is determined by the possibility or not of liver transplantation. In some patients, anastomosis portocaval transjugular (TIPS) may however be sufficient. PMID- 27242208 TI - Therapeutic innovations in endocrine diseases - Part 1: New medical treatments for chronic excess of endogenous cortisol (Cushing's syndrome). AB - Diverse hormonal, antisecretory, antitumoural or immunomodulatory therapeutic innovations act for broadening the management scope of adrenal, pituitary and endocrine tumours. PMID- 27242209 TI - [Not Available]. AB - The use of rituximab in Graves' orbitopathy is appealing but its exact role in the therapeutic arsenal remains to be clarified, and its safety profile also needs to be confirmed on a larger scale. PMID- 27242210 TI - Therapeutic innovations in endocrine diseases - Part 4 : Pasireotide: Long-acting release somatostatin analogue. AB - Pasireotide, the latest long-acting release somatostatin analogue, is distributed more widely to the various somatostatin receptors, which theoretically increases its strength and broadens its scope. Does this reflect genuine therapeutic progress? Or rather does its reduced specificity cause too many adverse reactions to make it a significant therapeutic achievement? PMID- 27242211 TI - Therapeutic innovations in endocrine diseases - part 3 : temozolomide and future therapeutics for aggressive pituitary tumors and carcinomas. AB - Pituitary tumors are the most frequent intracranial tumor and classically considered as benign. However, clinical evidence and recent advances in pathological and molecular analyses suggest that these tumors should be considered as more than a simple endocrine disorder. Descriptions of aggressive pituitary tumors and pituitary carcinomas have increased notably over the last decade following the first report on the successful treatment of pituitary carcinomas using temozolomide. This alkylating agent, widely used to treat glioblastoma, is now the first-line treatment for pituitary tumors resistant to conventional therapies. However, only 40 to 50% of pituitary tumors are sensitive to this treatment. Here, we review results of temozolomide treatment in this indication and discuss the interest of different prognostic markers and perspectives for new therapeutics. PMID- 27242212 TI - [Cross-border evaluation of needs for training in therapeutic education of the patient for the management in type 2 diabetes and obesity: Survey by method of nominal group with healthcare professionals]. AB - INTRODUCTION: The design of continuous training programs in therapeutic patient education (ETP) should be inspired by needs shown by the professionals concerned in terms of mobilization or acquisition of skills in this domain. The objective of this study is to analyze needs expressed by healthcare professionals (HP) involved in patients' management presenting a type 2 diabetes (T2D) and/or obesity and to compare them with the existing recommendations. METHODS: One hundred and five PS (general practitioners, dietitians and nurses) of 3 frontier regions of French-speaking European countries (France, Belgium and Grand duchy of Luxembourg) were questioned in 12 monodisciplinary groups according to the technique of the nominal group. Needs expressed by the participants were classified in the categories of the reference table of skills to dispense TPE (National Institute for Health Prevention and Education [INPES], 2013). RESULTS/DISCUSSION: Among needs expressed by HP, 52 % of the votes targeted relational skills, 10 % of the skills relative to the biomedical techniques, 20 % of the skills relative to the educational techniques and 11 %, those of organization and the coordination. Seven percent of the proposals were out of the categories of the INPES. Results do not allow to establish profiles of skills according to the studied region or profession. The recognition of the TPE by the French legislation does not seem to influence in a major way the data. CONCLUSION: The needs expressed by PS in the context of this study are focused on the relation HP/patient that is the heart of the TPE. It would however be necessary to raise awareness among HP in the acquisition of the other skills which concern in particular the animation of group, the interprofessional coordination, the consideration of the environment or more generally the procedures. PMID- 27242213 TI - Future treatments for Sjogren's syndrome. AB - Primary Sjogren's syndrome (pSS) is a systemic multiorgan autoimmune disease that runs a chronic progressive course. The recently developed treat-to-target paradigm involves identifying and targeting the molecular mechanisms that underlie disease manifestations in individual patients. This review discusses the immunopathology of pSS and the treatment approaches currently under investigation. To date, only symptomatic treatments are available for pSS, and only a few of the potential new treatment strategies have been evaluated. Among them, B-cell depletion is the most extensively investigated, although the data remain insufficient to support use in everyday practice. Specific patient subgroups likely to benefit from B-cell depletion may be identified in the future. Improved knowledge about the pathophysiology of pSS, the development of validated endpoints for evaluating treatment effects, and the currently unmet treatment needs of patients with pSS are now strong incentives for pharmaceutical firms to embark on randomized controlled trials. PMID- 27242214 TI - Safety of transoral surgery for oropharyngeal malignancies: An analysis of the ACS NSQIP. AB - OBJECTIVES/HYPOTHESIS: Minimally invasive transoral surgical approaches for the resection of oropharyngeal tumors offer unique opportunities to achieve oncologically sound results while reducing treatment-related morbidity. The objective of this study is to characterize the mortality and complication rates of transoral oncologic resections in a large, prospective, de-identified national dataset from multiple hospitals. STUDY DESIGN: Retrospective, multi-institutional cohort study of 305 patients. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) datasets were accessed and examined for adult patients who underwent transoral surgical resection of oropharyngeal cancers during the years 2010 through 2013. Patient demographics, postoperative complications, and 30-day mortality were evaluated. RESULTS: A total of 305 patients in the 2010 to 2013 ACS NSQIP datasets met study criteria. For the 18 postoperative complications that we assessed, 24 of 305 patients developed 37 complications, representing a complication rate of 7.9%. Among all patients, the 30-day mortality rate was 0.7%, representing two patient deaths. The presence of preoperative dyspnea, hypertension requiring medication, and an American Society of Anesthesiologists classification of 3 or 4 were significantly associated with extended hospital length of stay (LOS) (> 4 days). On multivariate analysis, hypertension was the only factor that was marginally significant with a longer LOS (odds ratio = 1.74, P = 0.057). CONCLUSION: Transoral resection of properly selected oropharyngeal tumors is safe, with low 30-day morbidity and mortality. A greater understanding of the risk factors for complications following transoral surgery may improve patient selection and safety. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:2484-2491, 2016. PMID- 27242216 TI - Five new 5,11-epoxyguaiane sesquiterpenes in agarwood "Qi-Nan" from Aquilaria sinensis. PMID- 27242215 TI - Chronic Gestational Exposure to Ethanol Leads to Enduring Aberrances in Cortical Form and Function in the Medial Prefrontal Cortex. AB - BACKGROUND: Exposure to ethanol (EtOH) in utero alters the disposition of tangentially migrating GABAergic interneurons in the fetal brain. The medial ganglionic eminence (MGE) gives rise to a large portion of cortical GABAergic interneurons, including the parvalbumin-expressing interneurons that shape and contribute to inhibitory/excitatory (I/E) balance of the intracortical circuit. Here, we investigated in the mouse medial prefrontal cortex (mPFC) the hypothesis that low levels of maternal EtOH consumption from closure of the neural tube embryonic day (E) 9.5 until birth result in an enduring interneuronopathy. METHODS: Pregnant mice were subjected to a 2% w/w EtOH consumption regimen starting at neural tube closure and ending at parturition. Neurogenesis in the MGE was assessed by 5-bromo-2-deoxyuridine (BrdU) immunofluorescence at E12.5. The count and distribution of parvalbumin-expressing interneurons were determined in adult animals, and patch clamp electrophysiology was performed to determine GABAergic function and I/E balance. Open-field behavior in adult mice was assessed to determine whether the EtOH-exposed cohort displayed a lasting alteration in exploratory behavior. RESULTS: In embryos exposed to EtOH in utero, we found increased BrdU labeling in the MGE, pointing to increased neurogenesis. Adult mice prenatally exposed to EtOH were hyperactive, and this was associated with an increase in parvalbumin-expressing GABAergic interneurons in the mPFC. In addition, prenatal EtOH exposure altered the balance between spontaneous inhibitory and excitatory synaptic input and attenuated GABAergic tone in layer V mPFC pyramidal neurons in juvenile mice. CONCLUSIONS: These findings underscore that altered migration of GABAergic interneurons contributes to the EtOH-induced aberration of cortical development and that these effects persist into adulthood as altered cortical form and function. PMID- 27242217 TI - Anticancer activities of proanthocyanidins from the plant Urceola huaitingii and their synergistic effects in combination with chemotherapeutics. AB - Phytochemical investigation of the stem of Urceola huaitingii resulted in the isolation of nine proanthocyanidins (1-9), including a new compound (9). Their chemical structures were determined by UV, (HR) ESI-MS, 1D-, 2D-NMR, and CD spectra in combination with chemical derivatization. Determination of the absolute configuration of proanthocyanidins were discussed, which suggested that positive Deltaepsilon values at 245nm can be applied to determine the absolute configuration of them. In addition, anticancer activities of proanthocyanidins (1 9) and their synergistic anticancer effects in combination with chemotherapeutics were evaluated. The results showed that some proanthocyanidins, especially compound 7 possessing two doubly interflavonoid linkages, exhibited significant synergistic anticancer effects with some chemotherapeutics in multiple cancer cell lines. PMID- 27242218 TI - A short-duration restrictive diet reduces visceral adiposity in the morbidly obese surgical patient. AB - BACKGROUND: This study aims to determine if visceral obesity can be reduced after a brief preoperative diet in obese patients. METHODS: Forty morbidly obese patients were placed on a 1,000 kCal per day diet for 14 days before bariatric surgery. Patients had weight measurements and an abdominal ultrasound performed on days 1 and 14. The ultrasound measured visceral obesity using the distance between the abdominal muscle and the aorta, the fat thickness of the perinephric space, and the distance between the abdominal muscle and splenic vein. Mesenteric fat burden was calculated and compared. RESULTS: Thirty-eight patients (95%) lost weight on the diet, with a mean loss of 5.2 lbs. Twenty-five patients (63%) had a reduction in mesenteric fat. The average visceral obesity lost was 7.76 cm3 or 3% of the visceral adiposity of the average obese patient (250 cm3). CONCLUSIONS: A short preoperative calorie restricting diet is well tolerated and results in a reduction in visceral obesity. PMID- 27242219 TI - Benchmarking hospital outcomes for improvement of care in Medicare elective colon surgery. AB - BACKGROUND: Risk-adjusted outcomes are essential for hospitals to benchmark care improvement. METHODS: We used the Medicare Limited Data Set for 2010 to 2012 to create risk models in elective colon surgery for the adverse outcomes (AOs) of inpatient deaths, prolonged length-of-stay outliers, 90-day post-discharge deaths without readmission, and 90-day relevant readmissions. Risk models permitted the prediction of AOs for each hospital and the design of hospital-specific standard deviations (SDs) to define performance from observed values. Risk-adjusted AO rates were computed for hospital comparisons. RESULTS: In all, 1,903 hospitals with 129,861 patients were studied. Overall AO rate was 27.8%; 84 hospitals had AO performance that was 2 SDs poorer than average and 66 were 2 SDs better. The top performing decile of hospitals had a risk-adjusted AO rate of 15.8%, whereas the lowest performing hospital's rate was 39.4%. CONCLUSIONS: Benchmarking risk adjusted AOs identifies the opportunity for care improvement in elective colon surgery in Medicare patients. PMID- 27242220 TI - Association of plasma cytokines with radiological recovery in pulmonary tuberculosis patients. AB - OBJECTIVE/BACKGROUND: The characterization of tuberculosis (TB) patients as slow or fast responders post anti-TB treatment has always been a matter of tremendous interest as slow responders are most likely to relapse and/or develop complications. Pulmonary tissue healing as assessed with radiology is the only available tool for tissue recovery but is not predictive at intake. The objective of the current study was to assess biomarkers associated with fast and slow recovery in TB patients at recruitment. METHODS: Pulmonary TB patients (N=15) were assessed for radiological recovery serially in parallel with clinical signs and symptoms, hematological parameters, and plasma cytokines at 0months, 6months, 12months, and 24months. On the basis of differential radiological healing, patients were characterized into slow (>12months), intermediate (<12months), and fast (<6months) responders. RESULTS: Baseline plasma cytokines (interleukin [IL] 2, -4, -6, -10, tumor necrosis factor-alpha, and interferon-gamma) were determined using cytometric bead array. IL-2 and -4 were able to accurately differentiate slow and fast responders into two distinct clusters using hierarchal clustering analysis. Compared with fast responders, slow responders showed significantly high IL-2 and -4 at baseline (p=.001 Mann-Whitney U test). CONCLUSION: In-depth analysis of cytokines and its association with radiological recovery in TB patients may be useful in monitoring TB patients postchemotherapy for both clinicians and TB control program. PMID- 27242221 TI - Selection of phage-displayed human antibody fragments specific for CD1b presenting the Mycobacterium tuberculosis glycolipid Ac2SGL. AB - OBJECTIVE/BACKGROUND: The development of new tools capable of targeting Mycobacterium tuberculosis (Mtb)-infected cells have potential applications in diagnosis, treatment, and prevention of tuberculosis. In Mtb-infected cells, CD1b molecules present Mtb lipids to the immune system (Mtb lipid-CD1b complexes). Because of the lack of CD1b polymorphism, specific Mtb lipid-CD1b complexes could be considered as universal Mtb infection markers. 2-Stearoyl-3 hydroxyphthioceranoyl-2'-sulfate-alpha-alpha'-d-trehalose (Ac2SGL) is specific for Mtb, and is not present in other mycobacterial species. The CD1b-Ac2SGL complexes are expressed on the surface of human cells infected with Mtb. The aim of this study was to generate ligands capable of binding these CD1b-Ac2SGL complexes. METHODS: A synthetic human scFv phage antibody library was used to select phage-displayed antibody fragments that recognized CD1b-Ac2SGL using CD1b transfected THP-1 cells loaded with Ac2SGL. RESULTS: One clone, D11-a single, light-variable domain (kappa) antibody (dAbkappa11)-showed high relative binding to the Ac2SGL-CD1b complex. CONCLUSION: A ligand recognizing the Ac2SGL-CD1b complex was obtained, which is a potential candidate to be further tested for diagnostic and therapeutic applications. PMID- 27242222 TI - A cross-sectional study about knowledge and attitudes toward multidrug-resistant and extensively drug-resistant tuberculosis in a high-burden drug-resistant country. AB - OBJECTIVE/BACKGROUND: Tuberculosis (TB) is a leading cause of death worldwide, with new threats of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. Pakistan is the fifth highest among high-burden TB countries and the fourth highest among high-burden drug-resistant-TB countries. Pakistan is the sixth most populous country in the world, and Pakistani youth is the highest population group in Pakistan and second in the world. This study was aimed at assessing the understanding, awareness, and mindset of university students toward TB, MDR TB, and XDR TB in Lahore. METHODS: A cross-sectional questionnaire-based study was performed on 1137 individuals from three major public-sector universities in Lahore, Pakistan. Information regarding their knowledge and attitude toward MDR and XDR TB was gathered using a structured questionnaire. Data collected was analyzed using SPSS version 20. RESULTS: Male (531) and female (606) students were asked about different aspects of MDR and XDR TB. Although 80.47% students had good knowledge about simple TB, a very small fraction had awareness and appropriate knowledge about MDR/XDR-TB. Considering TB as a stigma, only 9.3% students disclosed that they had household TB contact. Only 25% students knew about XDR TB. CONCLUSION: Our results indicated that a small fraction of people knew the exact definition and treatment duration of MDR TB and XDR TB in our society. There is a need to increase the awareness and knowledge status of university students about MDR and XDR TB. PMID- 27242223 TI - Mycobacterium leprae specific genomic target in the promoter region of probable 4 alpha-glucanotransferase (ML1545) gene with potential sensitivity for polymerase chain reaction based diagnosis of leprosy. AB - With the absence of an effective diagnostic tool for leprosy, cases with negative bacteriological index and limited clinical manifestations often pose diagnostic challenges. In this study, we investigated the utility of a novel Mycobacterium leprae specific 112-bp DNA sequence in the promoter region of probable 4-alpha glucanotransferase (pseudogene, ML1545) for polymerase chain reaction (PCR) based diagnosis of leprosy in comparison to that of the RLEP gene. DNA was extracted from slit skin scrapings of 180 newly diagnosed untreated leprosy cases that were classified as per Ridley Jopling classifications and bacteriological index (BI). Primers were designed using Primer Blast 3.0 and PCR was performed with annealing temperatures of 61 degrees C for ML1545 and 58 degrees C for the RLEP gene using conventional gradient PCR. The results indicated a significant increase in PCR positivity of ML1545 when compared to RLEP across the study groups (164/180 [91.11%] were positive for ML1545 whereas 114/180 (63.33%) were positive for RLEP [p<.0001, z=6.3]). Among 58 leprosy cases with negative BI, 28 (48.28%) were positive for RLEP and 48 (82.76%) were positive for ML1545 (p=.0001, z=3.8). Of the 42 borderline tuberculoid leprosy cases, 23 (54.76%) were positive for RLEP whereas 37 (88.09%) were positive for ML1545 (p<.0001, z=3.9). Increase in PCR positivity for ML1545 was also noted in lepromatous leprosy and BI-positive groups. ML1545 can be a potential gene target for PCR-based diagnosis of leprosy especially in cases where clinical manifestations were minimal. PMID- 27242224 TI - Genotyping of mutations detected with GeneXpert. AB - OBJECTIVE/BACKGROUND: Tuberculosis remains an important cause of mortality worldwide. Previous tuberculosis treatment is a strong determinant of multi-drug resistant tuberculosis. The study objective was to describe the mutations detected of Mycobacterium tuberculosis (MTB) complex clinical strains screened with GeneXpert isolated from previously treated patients in Cote d'Ivoire. METHODS: Sputum collected and decontaminated by the n-acetyl-l-cysteine method was used to perform Ziehl-Neelsen staining, GeneXpert MTB/rifampicin, and culture on Lowenstein-Jensen medium. Drug susceptibility testing (DST) for first-line drugs was performed in a Bactec 960 Automated System. After strain identification by antigen MPT64 detection, DNA extraction, and genotyping with MTBDRplus assay was performed and interpreted. The strains muted in rpoB without a specific protein identified and were sequenced. RESULTS: Mutant sequences were detected in 60 sputum samples with GeneXpert MTB/rifampicin of which 55 were confirmed multi drug resistant MTB strains after DST. The most frequent mutations responsible for rifampin resistance were detected with MTBDRplus assay for 49 (81.7%) clinical strains, while sequencing was required for 11 (18.3%). H526Q mutation, L533P, and D516V associated respectively with L533P, A532A, and S522L, and were observed for three relapse cases. For these cases, GeneXpert and sequencing results were concordant. Discrepancies between GeneXpert and mycobacteria growth indicator tube-DST for rifampin were observed for three strains, on which D516Y, H526C, and L533P were identified. CONCLUSION: In the setting of a high prevalence of drug resistance, characterization of the genetic basis of MTB strains resistant to rifampin could be screened first with MTBDRplus. PMID- 27242225 TI - Use of RODAC plates to measure containment of Mycobacterium tuberculosis in a Class IIB biosafety cabinet during routine operations. AB - OBJECTIVE/BACKGROUND: Guidelines for the manipulation of Mycobacterium tuberculosis (MTB) cultures require a Biosafety Level 3 (BSL-3) infrastructure and accompanying code of conduct. In this study, we aimed to validate and apply detection methods for viable mycobacteria from surfaces in a BSL-3 MTB laboratory. METHODS: We evaluated phenotypic (Replicate Organism Detection and Counting [RODAC] plates) and molecular (propidium monoazide [PMA]-based polymerase chain reaction [PCR]) approaches for the detection of viable mycobacteria, as well as the effect of 70% ethanol applied for 5min for disinfection against mycobacteria. For validation of the method, recovery of serial dilutions of Mycobacterium bovis bacillus Calmette-Guerin from glass slides was measured. Subsequently, we stamped surfaces in and around the biosafety cabinet (BSC) after different technicians had manipulated high bacterial load suspensions for routine drug-susceptibility testing in a Class II BSC. RESULTS: RODAC stamping could detect as few as three bacteria on slides stamped either 5min or 60min after inoculation. PMA-based PCR, tested in parallel, did not pass validation. Mycobacteria were still detected after 5-min disinfection with ethanol 70%. In the BSL-3, from 201 RODAC-stamped surfaces, MTB was detected in four: three inside a BSC-on a tube cap and on an operator's gloves-and one outside, on an operator's gown. CONCLUSION: RODAC plates detect mycobacteria at low numbers of microorganisms. In addition, this method allowed us to show that 70% ethanol does not reliably kill mycobacteria when applied for 5min to a dried surface, and that MTB bacilli may arrive outside a Class II BSC during routine practice, although the route could not be documented. PMID- 27242226 TI - Expression profile of Rab5, Rab7, tryptophan aspartate-containing coat protein, leprae lipoarabinomannan, and phenolic glycolipid-1 on the failure of the phagolysosome process in macrophages of leprosy patients as a viability marker of Mycobacterium leprae. AB - OBJECTIVE/BACKGROUND: Phagolysosome process in macrophage of leprosy patients' is important in the early phase of eliminating Mycobacterium leprae invasion. This study was to clarify the involvement of Rab5, Rab7, and trytophan aspartate containing coat protein (TACO) from host macrophage and leprae lipoarabinomannan (Lep-LAM) and phenolic glycolipid-1 (PGL-1) from M. leprae cell wall as the reflection of phagolysosome process in relation to 16 subunit ribosomal RNA (16S rRNA) M. leprae as a marker of viability of M. leprae. METHODS: Using a cross sectional design study, skin biopsies were obtained from 47 newly diagnosed, untreated leprosy at Dr Soetomo Hospital, Surabaya, Indonesia. RNA isolation and complementary DNA synthesis were performed. Samples were divided into two groups: 16S rRNA M. leprae-positive and 16S rRNA M. leprae-negative. The expressions of Rab5, Rab7, TACO, Lep-LAM, and PGL-1 were assessed with an immunohistochemistry technique. RESULT: Using Mann-Whitney U analysis, a significant difference in the expression profile of Rab5, Rab7, Lep-LAM, and PGL-1 was found (p<.05), but there was no significant difference of TACO between the two groups (p>.05). Spearman analysis revealed that there was a significant correlation between the score of Rab5, Rab7, Lep-LAM, and PGL-1 and the score of 16S rRNA M. leprae (p<.05). CONCLUSION: In M. leprae infection, Rab5, Rab7, and Lep-LAM play important roles in the failure of phagolysosome process via a membrane trafficking pathway, while PGL-1 plays a role via blocking lysosomal activities. These inventions might be used for the development of an early diagnostic device in the future. PMID- 27242227 TI - Determining treatment outcome of smear-positive pulmonary tuberculosis cases in Afar Regional State, Ethiopia: A retrospective facility based study. AB - OBJECTIVE/BACKGROUND: The World Health Organization (WHO) declared tuberculosis (TB) as a global public health emergency and recommended directly observed treatment, short-course (DOTS) as a standard strategy to control the disease. In Ethiopia the strategy was started in 1992 as a pilot in the Arsi and Bale zone, Oromia Region. The DOTS strategy has been subsequently scaled up in the country and implemented at a national level reaching better coverage, although there are recognizable variations from region to region and district to district. The aim of this study was to assess the impact of the DOTS strategy on smear-positive pulmonary TB case findings and their treatment outcomes in the Afar Regional State, Ethiopia, from 2003 to 2012 and from 2002 to 2011, respectively. METHODS: A health facility-based retrospective study was conducted. Data were collected and reported on a quarterly basis using the WHO reporting format for TB case findings and their treatment outcomes from all DOTS-implementing health facilities in all zones of the region to the Federal Ministry of Health. RESULTS: A total of 34,894 of TB cases had been registered in the period from 2003 to 2012. Out of these, 11,595 (33.2%) were smear-positive pulmonary TB, 13,859 (39.7%) smear-negative pulmonary TB, and 9838 (28.2%) extrapulmonary TB. The case detection rate (CDR) of smear-positive pulmonary TB had increased from 18.3% to 37.2%, with the average value being 32% (standard deviation=6.8) from the total TB cases to its peak of 39% in 2008. The treatment success rate (TSR) had an average value of 86.2% from 2002 to 2011 with its peak value being 96.5% in 2007. Moreover, the average values of treatment defaulter and treatment failure rate were 2.9% and 2.7%, respectively. CONCLUSION: The implementation for the DOTS strategy in the area improved the CDR of smear-positive TB, although it is unacceptably lower than the recommended WHO target of 70%. Additionally, the WHO target of 85% for TSR had already been achieved in the region. However, continued efforts should be in place to increase the CDR and maintain the high TSR registered. PMID- 27242228 TI - Impact of industrial structure and soil exposure on the regional variations in pulmonary nontuberculous mycobacterial disease prevalence. AB - OBJECTIVE/BACKGROUND: The prevalence of pulmonary nontuberculous mycobacterial (pNTM) disease, including Mycobacterium avium complex (MAC), varies widely according to geographic region. However, the factors that influence regional variations in pNTM disease prevalence remain unknown. This study was undertaken to examine whether environmental or occupational factors or host traits could influence regional variations in pNTM disease prevalence. METHODS: We collected laboratory data on pulmonary tuberculosis (pTB) and pNTM from two hospitals in the West Harima area of Japan and five hospitals in Kyoto City, Japan from 2012 to 2013. We estimated microbiological pNTM disease prevalence by multiplying all pTB cases in each area with the ratio of pNTM cases and pTB cases at the survey hospitals in each area. We administered a standardized questionnaire to 52 patients and 120 patients with pulmonary MAC (pMAC) disease at Ako City Hospital and Kyoto University Hospital, respectively. RESULTS: The estimated prevalence of microbiological pNTM disease in the West Harima area (85.4/100,000 population years) was significantly higher than that observed in Kyoto City (23.6/100,000 population-years; p<.001). According to multiple logistic regression analysis, in Ako City Hospital, primary (activities directly related to natural resources) and secondary industries (construction, mining, and manufacturing primary industry produce; odds ratio [OR]=4.79; 95% confidence interval [CI]=1.49-14.0; p=.007) and soil exposure (OR=13.6; 95% CI=4.94-45.26; p<.001) were associated with pMAC disease. CONCLUSION: Environmental factors, both industrial structures associated with occupational dust and environmental soil exposure, could influence the regional variations in pNTM disease prevalence. PMID- 27242229 TI - The pros and cons of the QuantiFERON test for the diagnosis of tuberculosis, prediction of disease progression, and treatment monitoring. AB - OBJECTIVE/BACKGROUND: Tuberculosis (TB) is a re-emerging disease with the advent of human immunodeficiency virus/AIDS infections. Discovered in 1959, diagnosed by various approaches and treated with antibiotics, the treatment of TB infection still poses public health concerns. Many cases of resistance and cross-resistance are observed. Diagnosis by culture, which is considered as the standard method, takes too long (20-30days) and is not suitable for extrapulmonary TB. QuantiFERON test, which is an indirect immunoassay based on blood, was developed. Much hope was placed in this new approach because it is based on blood, and many research teams have used it. We discuss the results of these different research groups who have used QuantiFERON for diagnosis, prediction of disease progression, or monitoring patients during the treatment of TB. METHODS: Articles published in PubMed and documents published on Google were searched with the keywords: diagnosis and TB and QuantiFERON; TB and QuantiFERON and therapeutic monitoring; interferon-gamma release assay; disease progression. These articles were read and analyzed. RESULTS: The results were controversial with regards to using the QuantiFERON test for the diagnosis of TB according to the study population (ethnic group, bacillus Calmette-Guerin vaccine use) and according to the state of the immune system of the people studied (human immunodeficiency virus immunosuppression in cancer medication, hypertension). Also, research findings were controversial with regards to using QuantiFERON for monitoring TB patients on anti-TB medications. Also, the predictive positive value for the progression to TB among immigrant close contacts of both interferon-gamma release assays was not better than that of the tuberculin skin test. CONCLUSION: The QuantiFERON has advantages and limitations depending on the type of population studied. Recommendations are made to improve the sensitivity and specificity and to differentiate between latent and active TB by adding other specific proteins in the Mycobacterium tuberculosis antigen cocktail. PMID- 27242230 TI - Drug resistance-conferring mutations in Mycobacterium tuberculosis from pulmonary tuberculosis patients in Southwest Ethiopia. AB - OBJECTIVE/BACKGROUND: The nature and frequency of mutations in rifampicin (RIF) and isoniazid (INH) resistant Mycobacterium tuberculosis isolates vary considerably according to geographic locations. However, information regarding specific mutational patterns in Ethiopia remains limited. METHODS: A cross sectional prospective study was carried out among confirmed pulmonary tuberculosis cases in Southwest Ethiopia. Mutations associated with RIF and INH resistances were studied using GenoType MTBDRplus line probe assay in 112 M. tuberculosis isolates. Culture (MGIT960) and identification tests were performed at the Mycobacteriology Research Center of Jimma University, Jimma, Ethiopia. RESULTS: Mutations conferring resistance to INH, RIF, and multidrug resistance were detected in 36.6% (41/112), 30.4% (34/112), and 27.7% (31/112) of M. tuberculosis isolates respectively. Among 34 RIF-resistant isolates, 82.4% (28/34) had rpoB gene mutations at S531L, 2.9% (1/34) at H526D, and 14.7% (5/34) had mutations only at wild type probes. Of 41 INH-resistant strains, 87.8% (36/41) had mutations in the katG gene at Ser315Thr1 and 9.8% (4/41) had mutations in the inhA gene at C15T. Mutations in inhA promoter region were strongly associated with INH monoresistance. CONCLUSION: A high rate of drug resistance was commonly observed among failure cases. The most frequent gene mutations associated with the resistance to INH and RIF were observed in the codon 315 of the katG gene and codon 531 of the rpoB gene, respectively. Further studies on mutations in different geographic regions using DNA sequencing techniques are warranted to improve the kit by including more specific mutation probes in the kit. PMID- 27242231 TI - Anti-mycobacterial activity of polyketides from Penicillium sp. endophyte isolated from Garcinia nobilis against Mycobacteriumsmegmatis. AB - OBJECTIVE/BACKGROUND: According to estimates by the World Health Organization, there were 9.6 million new tuberculosis (TB) cases in 2014: 5.4 million among men, 3.2 million among women, and 1.0 million among children. There were also 1.5 million TB deaths. Although there are potent anti-TB molecules, the misuse of these drugs in addition to inconsistent or partial treatment have led to the development of multidrug-resistant TB and extensively drug-resistant TB. It is established that plants harbor microorganisms, collectively known as endophytes, which also produce metabolites. Exploring the as-yet untapped natural products from the endophytes increases the chances of finding novel and active compounds. The present study was aimed to investigate the antimycobacterial activity of the crude extract and compounds isolated from Penicillium sp. endophyte associated with Garcinia nobilis against Mycobacterium smegmatis. METHODS: Liquid culture obtained from the fermentation of Penicillium sp. was extracted using ethylacetate and the liquid chromatography-mass spectrometry monitored fractionation of crude extracts yielded six compounds. Their structures were elucidated with spectroscopic analyses including two-dimensional nuclear magnetic resonance, high resolution mass spectrometry by dereplication using Antibase, and by comparison to literature data. All compounds and the crude extract from the liquid medium were evaluated for their antimycobacterial activity against M. smegmatis. RESULTS: In this study, the activity of penialidins A-C (1-3), citromycetin (4), p-hydroxy phenyl glyoxalaldoxime (5), and Brefeldin A (6) were tested against nonpathogenic M. smegmatis. Penialidin C was the most active compound with a minimum inhibitory concentration of 15.6MUg/mL. CONCLUSION: Isolated compounds from Penicillium sp. harbored in G. nobilis exhibited promising antimycobacterial activity against M. smegmatis thus supporting the immensity of the potential of antimycobacterial drug discovery from endophytes from medicinal plants. Penialidin C could further be investigated for antimycobacterial drug development. PMID- 27242232 TI - Limonia acidissima L. leaf mediated synthesis of zinc oxide nanoparticles: A potent tool against Mycobacterium tuberculosis. AB - OBJECTIVE/BACKGROUND: The present investigation was undertaken to synthesize zinc oxide nanoparticles using Limonia acidissima L. and to test their efficacy against the growth of Mycobacterium tuberculosis. METHODS: The formation of zinc oxide nanoparticles was confirmed with UV-visible spectrophotometry. Fourier transform infrared spectroscopy shows the presence of bio-molecules involved in the stabilization of zinc oxide nanoparticles. The shape and size was confirmed with atomic force microscope, X-ray diffraction, and high resolution transmission electron microscope. These nanoparticles were tested for their effect on the growth of M. tuberculosis through the microplate alamar blue assay technique. RESULTS: The UV-visible data reveal that an absorbance peak at 374nm confirms formation of zinc oxide nanoparticles and they are spherical in shape with sizes between 12nm and 53nm. These nanoparticles control the growth of M. tuberculosis at 12.5MUg/mL. CONCLUSION: Phytosynthesis of zinc oxide nanoparticles is a green, eco-friendly technology because it is inexpensive and pollution free. In the present investigation, based on our results we conclude that the aqueous extract of leaves of L. acidissima can be used for the synthesis of zinc oxide nanoparticles. These nanoparticles control the growth of M. tuberculosis and this was confirmed with the microplate alamar blue method. The potential of biogenic zinc oxide nanoparticles may be harnessed as a novel medicine ingredient to combat tuberculosis disease. PMID- 27242233 TI - Magnitude and treatment outcomes of pulmonary tuberculosis patients in a poor urban slum of Abia State, Nigeria. AB - OBJECTIVE/BACKGROUND: Tuberculosis (TB) remains one of the deadliest infectious diseases worldwide, with a disproportionate number of those affected living in slum areas. We assessed the magnitude of pulmonary cases among tuberculosis patients in an urban slum in southeast Nigeria, their demographic and clinical characteristics and any associations with treatment outcomes. METHODS: A retrospective cohort study of patients registered under the National TB Programme (NTP) from 1 January to 31 December 2012 was carried out. Data were extracted from TB treatment cards and registers. RESULTS: Of 647 new TB patients registered, 555 (85.8%) were pulmonary TB (PTB) with a mean age of 34.5years, and a male/female ratio of 1.3. Among these, 468 (84.3%) were smear-positive, while 87 (15.7%) were smear-negative cases. Twenty-one (3.8%) were children younger than 15years old. TB/HIV co-infection rate was 16.9%; 57.4% received antiretroviral therapy (ART) and 88.3% received cotrimoxazole preventive therapy (CPT). Female patients were significantly younger compared to male patients (p=0.003), had higher proportions of smear-negative TB (p=0.001) and HIV-positive status (p?0.001). Treatment success rate was 88.5% among smear-positive patients and 79.3% among smear-negative patients. More patients with smear-negative TB were lost to follow up compared with smear-positive TB patients (p<0.02). HIV co infection was associated with unfavourable treatment outcomes (OR 0.2, CI 0.1 0.4, p?0.001). Among them, those who received ART had better outcomes. CONCLUSIONS: The study revealed high proportion of PTB, mostly smear-positive TB with HIV-associated outcomes and underlines the need to ensure early TB diagnosis and improved access to HIV care for HIV co-infected patients in this setting. PMID- 27242234 TI - Increased detection of smear-negative pulmonary tuberculosis by GeneXpert MTB/RIF(r) assay after bleach concentration. AB - OBJECTIVE/BACKGROUND: The GeneXpert MTB/RIF assay (Xpert) was endorsed as the initial diagnostic tool in people suspected of human immunodeficiency virus associated or drug-resistant tuberculosis (TB). However, information regarding the performance of Xpert for diagnosing smear-negative TB in high burden settings remains limited. We evaluated the diagnostic accuracy of Xpert and the impact of bleach concentration on the performance of Xpert using smear-negative sputum samples from human immunodeficiency virus-negative patients. METHODS: One spot and one morning smear-negative sputum samples per patient were examined using Xpert and culture at the Mycobacteriology Research Center of Jimma University, Ethiopia. The sputum culture on both Lowenstein-Jensen and/or Mycobacteria Growth Indicator Tube was the gold-standard. RESULTS: Of 185 smear-negative presumptive pulmonary TB cases, 19 (10.3%) had culture-proven TB. The sensitivity of Xpert on spot and morning sputum was similar (63.2%). Testing two specimens per patient insignificantly increased the sensitivity of Xpert. Bleach concentration and pelleting improved the sensitivity of Xpert over unprocessed sputum in paired samples (73.8% vs. 63.2%) without affecting the specificity (95%). Bleach concentration and pelleting allowed an additional seven cases of TB (missed on the first and second direct Xperts) to be detected, five of which were from culture-negative cases. CONCLUSION: Testing of a single sputum sample by Xpert can reach reasonable sensitivity and results would be available on the same day, avoiding loss of patients and treatment delay. The sensitivity of Xpert was improved after bleach concentration and pelleting, although its added value needs further study on a larger scale. PMID- 27242235 TI - Chronic oozing skin lesions in children: Possible tuberculosis? Two case reports. AB - Cutaneous tuberculosis is frequently misleading and challenging, as it mimics a wide differential diagnosis. Here, we present two pediatric cases with chronic multiple ulcerating nodules. Proper history, physical examination, and histopathological analysis are included in the workup of suspected skin tuberculosis. Diagnosis was confirmed by positive culture for mycobacteria. PMID- 27242236 TI - Treatment of severe refractory erythema nodosum leprosum with tumor necrosis factor inhibitor Etanercept. AB - Erythema nodosum leprosum (ENL) is a common complication of lepromatous leprosy. Some patients unresponsive to conventional, first-line therapeutics develop recurrent, recalcitrant ENL. Here, we report a case of severe refractory ENL that was successfully treated with Etanercept. Biologics may be considered as therapeutic alternatives in management of severe, recalcitrant ENL. PMID- 27242237 TI - High prevalence of multidrug-resistant tuberculosis among patients with rifampicin resistance using GeneXpert Mycobacterium tuberculosis/rifampicin in Ghana. AB - OBJECTIVE/BACKGROUND: Drug-resistant strains of tuberculosis (TB) represent a major threat to global TB control. In low- and middle-income countries, resource constraints make it difficult to identify and monitor cases of resistance using drug susceptibility testing and culture. Molecular assays such as the GeneXpert Mycobacterium tuberculosis/rifampicin may prove to be a cost-effective solution to this problem in these settings. The objective of this study is to evaluate the use of GeneXpert in the diagnosis of pulmonary TB since it was introduced into two tertiary hospitals in Ghana in 2013. METHODS: A 2-year retrospective audit of clinical cases involving patients who presented with clinically suspected TB or documented TB not improving on standard therapy and had samples sent for GeneXpert testing. RESULTS: GeneXpert identified 169 cases of TB, including 17 cases of rifampicin-resistant TB. Of the seven cases with final culture and drug susceptibility testing results, six demonstrated further drug resistance and five of these were multidrug-resistant TB. CONCLUSION: These findings call for a scale up of TB control in Ghana and provide evidence that the expansion of GeneXpert may be an optimal means to improve case finding and guide treatment of drug resistant TB in this setting. PMID- 27242238 TI - Tuberculous ventriculitis: A rare complication of central nervous system tuberculosis. AB - Tuberculous ventriculitis is an inflammatory infection of the ventricular system of the brain, and is caused by Mycobacterium tuberculosis. We herein present the case of an immunocompromised patient with brain tuberculomas who developed ventriculitis during treatment. The patient was successfully treated with a high dose of steroid, long-term antituberculosis drugs, and aggressive supportive care. PMID- 27242239 TI - Pulmonary aspergilloma: An evasive disease. AB - Aspergillomas are often misdiagnosed as tuberculosis (TB) in developing countries where the prevalence of TB is high, hemoptysis is often equated with TB, and most patients are diagnosed clinically. This report describes the case of a patient being treated for smear-negative TB who presented with hemoptysis and was found to have an aspergilloma. PMID- 27242240 TI - Methylobacterium spp. as an indicator for the presence or absence of Mycobacterium spp. AB - OBJECTIVE/BACKGROUND: A published survey of bacteria in showerhead biofilm samples revealed that Methylobacterium spp. and Mycobacterium spp. seldom coexisted in biofilms. METHODS: To confirm that information, biofilm samples were collected from household plumbing of Mycobacterium avium patients and Methylobacterium spp. and M. avium numbers were measured by direct colony counts. RESULTS: The results demonstrated that if Methylobacterium spp. were present, Mycobacterium spp. were absent, and the opposite. CONCLUSION: The data demonstrate that microbial populations in biofilms can influence the presence or absence of opportunistic premise plumbing pathogens and, thereby, increase the range of strategies to reduce exposure to waterborne pathogens. Finally, by assessing for the visual presence of methylobacteria as pink pigmentation on showers and shower curtains, homeowners and managers of hospitals and other buildings can quickly determine whether a premise plumbing biofilm sample has mycobacteria with a high degree of assurance. PMID- 27242241 TI - An unusual outbreak of nontuberculous mycobacteria in hospital respiratory wards: Association with nontuberculous mycobacterial colonization of hospital water supply network. AB - The incidence and prevalence of pulmonary nontuberculous mycobacterial (NTM) infection is increasing worldwide arousing concerns that NTM infection may become a serious health challenge. We recently observed a significant increase of NTM positive sputa samples from patients referred to respiratory disease wards of a large tertiary hospital in Rome. A survey to identify possible NTM contamination revealed a massive presence of NTM in the hospital water supply network. After decontamination procedures, NTM presence dropped both in water pipelines and sputa samples. We believe that this observation should encourage water network surveys for NTM contamination and prompt decontamination procedures should be considered to reduce this potential source of infection. PMID- 27242242 TI - The principle of conformational signaling. AB - Signal transduction is the primary process by which cells respond to changes in their physical and chemical environments. Cellular response is initiated through a signaling protein (a receptor), which interacts with the "signal", most often a novel molecule outside or inside the cell. The mechanism of activation of the receptor is a conformational change and/or covalent modification, which then sets in motion a signaling pathway, i.e. a cascade of modification and binding events that relay and amplify the message to eventually alter the state of the cell. In reflection of this general perception, concepts such as the "second messenger" and the "phosphorylation cascade" dominate our views of signal transduction. The idea I advocate here is that the non-covalent change in protein conformation itself might serve as the initial or intermittent "signal" in the cascade, and it is often the primary event being recognized and interpreted by downstream receptor(s). This signaling principle is intertwined with many other cellular regulatory concepts, such as (pathway) allostery, conformational spread, induced folding/unfolding, conformational memory, the hierarchical assembly of complexes, and the action of regulatory chaperones and prions. By elaborating on many examples and also recent advances in experimental methodology, I show that conformational signaling, although thus far underappreciated, is a general and robust signaling principle that most of the time operates in close interplay with covalent signals in the cell. PMID- 27242243 TI - Giant right inguinal hernia. PMID- 27242244 TI - Life course outcomes for women with different alcohol consumption trajectories: A population-based longitudinal study. AB - INTRODUCTION AND AIMS: Relatively little is known about the consequences for women of sustained higher levels of alcohol consumption. We examine three outcomes (marital relationship, reproductive health and well-being) for women with different alcohol consumption trajectories over 21 years. DESIGN AND METHODS: Data were from a prospective cohort study in Brisbane, Queensland (n = 3337). Group-based trajectory modeling measured women's alcohol consumption trajectories spanning 21 years. Outcomes were measured using a self-report questionnaire at the 27-year follow-up. RESULTS: Four trajectories of women's alcohol consumption were identified: abstaining, low-stable drinkers, moderate escalating drinkers and heavy-escalating drinkers. Abstaining predicts positive outcomes measured at the 27-year follow-up such as being married, never having a divorce, never having multiple partners, and fewer pregnancy terminations. Moderate and heavy-escalating trajectories predict being unmarried, having multiple partners, having fewer children, having a termination of a previous pregnancy, and reporting lower levels of well-being at the 27-year follow-up. DISCUSSION AND CONCLUSIONS: The escalating-trajectory group is of particular interest as membership of this group is associated with a wide range of adverse life course outcomes by the 27-year follow-up. The consequences of moderate and heavy-escalating alcohol trajectories in a community sample of women whose pattern of alcohol consumption do not reach clinical criteria of problem drinking have not previously been described. Women with these sustained patterns of alcohol consumption are an appropriate target group for intervention programs. programs. [TranNT, Clavarino A,WilliamsGM,Najman JM. Life course outcomes for women with different alcohol consumption trajectories: A population-based longitudinal study. Drug Alcohol Rev 2016;35:763-771]. PMID- 27242245 TI - Evaluation of laser phototherapy (lambda 780 nm) after dental replantation in rats. AB - BACKGROUND/AIM: Tooth replantation is the treatment of choice in cases of avulsion although the outcomes are variable. The teeth can be lost due to external root resorption. The aim of this study was to histologically assess of the effect of laser phototherapy (lambda780 nm) on replanted teeth in rats. MATERIAL AND METHODS: Sixty Wistar Albinus rats had their maxillary right incisors extracted and were then divided into four groups: G1-absence of storage medium; G2-milk as storage medium; G3-milk as storage medium followed by a laser irradiation of the root surfaces and entrance of the alveolus (lambda = 780 nm; P = 70 mW; CW; DE = 21 J/cm2 ); G4-milk as storage medium, laser irradiation as in G3 before replantation. After this procedure, laser irradiation was performed on the buccal and palatal mucosa (8.4 J/cm2 per session) every 48 h for 15 days. The animals were euthanized 15, 30, and 60 days after replantation. RESULTS: The histological results showed that after 15 days, G4 exhibited intense chronic inflammation with the presence of clastic cells and moderate external inflammatory root resorption (P < 0.05) when compared with G3, in which these outcomes were not observed. At the 30th day, G1, G2, and G4 showed chronic inflammation varying from discrete to moderate, as well as intense external inflammatory root resorption. G3 remained without any inflammation and external inflammatory root resorption up to the 60th day. CONCLUSIONS: The use of laser phototherapy on the root surface and at the entrance of the alveolus prior to replantation had a positive biomodulative effect on alveolar repair after tooth replantation in rats. PMID- 27242247 TI - "Dr. Google": The quality and limitations of on-line information and its impact on the doctor-patient relationship. PMID- 27242246 TI - Autopsy case of pulmonary artery sarcoma forming aneurysm without FDG uptake. PMID- 27242248 TI - Calcified atherosclerosis of the pulmonary trunk, stenosis of the main pulmonary arteries, and post-stenotic dilation of segmental pulmonary arteries in a patient with Alagille syndrome. PMID- 27242249 TI - Radiological diagnosis of pulmonary tumor thrombotic microangiopathy: A non bronchial cause of "tree-in-bud" pattern on computed tomography. PMID- 27242251 TI - The State of Salt: How state-based initiatives can drive national action on salt reduction in Australia. PMID- 27242250 TI - Single-dose rituximab in refractory lupus nephritis. AB - BACKGROUND: Off-label use of rituximab in lupus nephritis is reported to be beneficial. While the optimal dose is unknown, the regimen of four intravenous doses of 375 mg/m(2) is commonly employed, despite expense and potential side effects. AIM: To investigate the response to single-dose rituximab, added to standard corticosteroids plus additional immunosuppressive agent, in refractory lupus nephritis. METHODS: Consecutive consenting patients with refractory lupus nephritis despite steroids plus either cyclophosphamide, mycophenolate or azathioprine were enrolled in this ethics-approved, open-label, prospective study. After baseline assessment, patients received one intravenous infusion of 375 mg/m(2) rituximab. Clinical, biochemical and serological (DsDNA, complement) responses to this dose were analysed. Complete renal response (CR) was defined as normalisation of creatinine, albumin, proteinuria and urinary RBCs and partial response (PR) as >=50% improvement in at least one parameter, without deterioration in others. B-cell depletion was defined as peripheral CD19 lymphocyte count <=0.05 * 10(9) /L. RESULTS: Fourteen patients were enrolled in the study. All were B-cell-depleted until 8 months post-dose. Eleven patients (79%) responded (2CR, 9PR) at a median time of 5 months, with a 6-month probability of renal response of 43%. Five patients (45%) relapsed at a median time of 17 months. DsDNA titres decreased in 69%. Side-effects were minimal. CONCLUSIONS: Single-dose rituximab is effective in relapsed/refractory lupus nephritis. Longevity of B-cell depletion with single-dose rituximab is similar to that of four doses with potentially fewer side-effects. PMID- 27242252 TI - From strength to strength: the next step for ANZJPH. PMID- 27242253 TI - Little change in tobacco imagery on New Zealand television: 10 years on. AB - OBJECTIVES: To examine changes in the frequency and contexts of tobacco imagery on New Zealand television since 2004. METHODS: A content analysis of 73 hours of prime time evening television in 2014, including programs, advertisements and trailers, was coded for tobacco imagery. Imagery was defined as being either neutral/pro-tobacco or anti-tobacco. RESULTS: Of the 93 programs coded, 29% had at least one scene with tobacco imagery. Of the 71 scenes with tobacco imagery, 59 were judged as showing neutral/pro-tobacco imagery, while 12 showed anti tobacco imagery. No significant change in the number of programs containing tobacco imagery, or the type of imagery, was found since 2004, but there were fewer scenes that contained imagery. CONCLUSIONS: There has been little change in the amount of tobacco imagery over the past decade. Given the potential for tobacco imagery to promote smoking among young people while reinforcing the habit among those who are trying to quit, action needs to be taken. IMPLICATIONS: More could be done to counterbalance pro-tobacco imagery by promoting the Quitline and anti-tobacco media campaigns, and encouraging producers of local TV programs to consider the depiction of tobacco imagery in a way that reflects declining tobacco use. PMID- 27242254 TI - Predictors of sunburn among a NZ urban population in a cross-sectional survey series (1999 to 2006). PMID- 27242255 TI - Geographies of Health and Development. PMID- 27242256 TI - Health measurement scales: a practical guide to their development and use (5th edition). PMID- 27242257 TI - Food & Nutrition Throughout Life. PMID- 27242258 TI - Unsafe Abortion and Women's Health: Change and Liberalization. PMID- 27242259 TI - Male Sex Work & Society. PMID- 27242260 TI - Socialize your patient engagement strategy. PMID- 27242261 TI - Genomics and the Reimagining of Personalized Medicine. PMID- 27242262 TI - Editorial overview: The cell nucleus: Plastic, elastic and fantastic. PMID- 27242263 TI - Frailty in elderly people with chronic kidney disease. AB - In recent years, the concept of frailty as a "state of pre-disability" has been widely accepted by those involved in the care of the elderly. Its importance lies not only in its high prevalence - more than 25% in people over 85 years of age - but it is also considered an independent risk factor of disability, institutionalisation and mortality amongst the elderly. The study of renal function is relevant in patients with major comorbidities. Studies have shown a significant association between chronic kidney disease and the development of adverse clinical outcomes such as heart disease, heart failure, end-stage renal disease, increased susceptibility to infections and greater functional impairment. Frailty can be reversed, which is why a study of frailty in patients with chronic kidney disease is of particular interest. This article aims to describe the association between ageing, frailty and chronic kidney disease in light of the most recent and relevant scientific publications. PMID- 27242264 TI - Creating a hyperpolarised pseudo singlet state through polarisation transfer from parahydrogen under SABRE. AB - The creation of magnetic states that have long lifetimes has been the subject of intense investigation, in part because of their potential to survive the time taken to travel from the point of injection in a patient to the point where a clinically diagnostic MRI trace is collected. We show here that it is possible to harness the signal amplification by reversible exchange (SABRE) process to create such states in a hyperpolarised form that improves their detectability in seconds without the need for any chemical change by reference to the model substrate 2 aminothiazole. We achieve this by transferring Zeeman derived polarisation that is 1500 times larger than that normally available at 400 MHz with greater than 90% efficiency into the new state, which in this case has a 27 second lifetime. PMID- 27242265 TI - Characteristics of Schistosoma japonicum infection induced IFN-gamma and IL-4 co expressing plasticity Th cells. AB - Schistosoma japonicum infection can induce granulomatous inflammation and cause tissue damage in the mouse liver. The cytokine secretion profile of T helper (Th) cells depends on both the nature of the activating stimulus and the local microenvironment (e.g. cytokines and other soluble factors). In the present study, we found an accumulation of large numbers of IFN-gamma(+) IL-4(+) CD4(+) T cells in mouse livers. This IFN-gamma(+) IL-4(+) cell population increased from 0.68 +/- 0.57% in uninfected mice to 7.05 +/- 3.0% by week 4 following infection and to 9.6 +/- 5.28% by week 6, before decreasing to 6.3 +/- 5.9% by week 8 in CD4 T cells. Moreover, IFN-gamma(+) IL-4(+) Th cells were also found in mouse spleen and mesenteric lymph nodes 6 weeks after infection. The majority of the IFN-gamma(+) IL-4(+) Th cells were thought to be related to a state of immune activation, and some were memory T cells. Moreover, we found that these S. japonicum infection-induced IFN-gamma(+) IL-4(+) cells could express interleukin 2 (IL-2), IL-9, IL-17 and high IL-10 levels at 6 weeks after S. japonicum infection. Taken together, our data suggest the existence of a population of IFN gamma(+) IL-4(+) plasticity effector/memory Th cells following S. japonicum infection in C57BL/6 mice. PMID- 27242266 TI - Artemisinin conferred ERK mediated neuroprotection to PC12 cells and cortical neurons exposed to sodium nitroprusside-induced oxidative insult. AB - The production of nitric oxide (NO) is one of the primary mediators of ischemic damage, glutamate neurotoxicity and neurodegeneration and therefore inhibition of NO-induced neurotoxicity may be considered a therapeutic target for reducing neuronal cell death (neuroprotection). In this study, artemisinin, a well-known anti-malaria drug was found to suppress sodium nitroprusside (SNP, a nitric oxide donor)-induced cell death in the PC12 cells and brain primary cortical neuronal cultures. Pretreatment of PC12 cells with artemisinin significantly suppressed SNP-induced cell death by decreasing the extent of oxidation, preventing the decline of mitochondrial membrane potential, restoring abnormal changes in nuclear morphology and reducing lactate dehydrogenase release and inhibiting caspase 3/7 activities. Western blotting analysis revealed that artemisinin was able to activate extracellular regulated protein kinases (ERK) pathway. Furthermore, the ERK inhibitor PD98059 blocked the neuroprotective effect of artemisinin whereas the PI3K inhibitor LY294002 had no effect. Cumulatively these findings support the notion that artemisinin confers neuroprotection from SNP induce neuronal cell death insult, a phenomenon coincidentally related to activation of ERK phosphorylation. This SNP-induced oxidative insult in PC12 cell culture model may be useful to investigate molecular mechanisms of NO-induced neurotoxicity and drug-induced neuroprotection, and to generate novel therapeutic concepts for ischemic disease treatment. PMID- 27242267 TI - beta-Lapachone increases phase II antioxidant enzyme expression via NQO1 AMPK/PI3K-Nrf2/ARE signaling in rat primary astrocytes. AB - beta-Lapachone (beta-LAP) is a naturally occurring quinine that exerts a number of pharmacological actions including antibacterial, antifungal, antimalarial, and antitumor activities. In the present study, we investigated whether beta-LAP has an antioxidant effect in rat primary astrocytes. beta-LAP suppressed intracellular reactive oxygen species (ROS) production induced by hydrogen peroxide and inhibited astroglial cell death. It also increased astrocytic expression of phase II antioxidant enzymes such as heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), manganese superoxide dismutase (MnSOD), and catalase. Further mechanistic studies revealed that beta-LAP activated AMPK and Akt, and pretreatment of cells with an AMPK inhibitor (compound C) or PI3K/Akt inhibitor (LY294002) suppressed beta-LAP-induced antioxidant enzyme expression by inhibiting Nrf2/antioxidant response element (ARE) signaling. Compound C also decreased Akt phosphorylation, suggesting that AMPK is upstream of PI3K/Akt. Furthermore, the AMPK activator 5-aminoimidazole-4-carboxamide 1 beta-d-ribofuranoside mimicked the effect of beta-LAP by increasing Akt phosphorylation and ARE-mediated transcription, suggesting that AMPK plays a pivotal role in beta-LAP-mediated antioxidant enzyme expression. Because beta-LAP effects are usually associated with NQO1 activity, we examined the effect of NQO1 knockdown on antioxidant enzyme expression. Small interfering RNA (siRNA) specific for NQO1 inhibited beta-LAP-induced AMPK/Akt phosphorylation and downstream antioxidant enzyme expression. Collectively, the results suggest that beta-LAP increases antioxidant enzyme gene expression in astrocytes by modulating NQO1-AMPK/PI3K-Nrf2/ARE signaling. PMID- 27242270 TI - Charge-state dynamics in electrostatic force spectroscopy. AB - We present a numerical model that allows us to study the response of an oscillating probe in electrostatic force spectroscopy to charge switching in quantum dots at various time scales. The model provides more insight into the behavior of frequency shift and dissipated energy under different scanning conditions when measuring a temporarily charged quantum dot on a surface. Namely, we analyze the dependence of the frequency shift, the dissipated energy, and their fluctuations on the resonance frequency of the tip and on the electron tunneling rates across the tip-quantum dot and quantum dot-sample junctions. We discuss two complementary approaches to simulating the charge dynamics, a stochastic and a deterministic one. In addition, we derive analytic formulas valid for small amplitudes, describing relations between the frequency shift, dissipated energy, and the characteristic rates driving the charging and discharging processes. PMID- 27242269 TI - The chemical biology of protein hydropersulfides: Studies of a possible protective function of biological hydropersulfide generation. AB - The recent discovery of significant hydropersulfide (RSSH) levels in mammalian tissues, fluids and cells has led to numerous questions regarding their possible physiological function. Cysteine hydropersulfides have been found in free cysteine, small molecule peptides as well as in proteins. Based on their chemical properties and likely cellular conditions associated with their biosynthesis, it has been proposed that they can serve a protective function. That is, hydropersulfide formation on critical thiols may protect them from irreversible oxidative or electrophilic inactivation. As a prelude to understanding the possible roles and functions of hydropersulfides in biological systems, this study utilizes primarily chemical experiments to delineate the possible mechanistic chemistry associated with cellular protection. Thus, the ability of hydropersulfides to protect against irreversible electrophilic and oxidative modification was examined. The results herein indicate that hydropersulfides are very reactive towards oxidants and electrophiles and are modified readily. However, reduction of these oxidized/modified species is facile generating the corresponding thiol, consistent with the idea that hydropersulfides can serve a protective function for thiol proteins. PMID- 27242271 TI - 'Life in the age of screens': parent perspectives on a 24-h no screen-time challenge. AB - Screens have become ubiquitous in modern society. Their use frequently underlies sedentary behaviour, a well-established determinant of obesity. As part of a family oriented clinic offering a 2-year lifestyle program for obese children and youth, we explored parents' experiences with a 24-h no screen-time challenge, an intervention designed to raise awareness of screen-time habits and to help families develop strategies to limit their use. In total, 15 parents representing 13 families participated. A focus group with nine parents and six phone interviews with those who could not join in person were conducted. Interviews were transcribed verbatim and analysed qualitatively. Key elements to successful completion of the 24-h no screen-time challenge emerged, namely: clear rules about permitted activities during the 24-h period; togetherness, i.e. involving all family members in the challenge; and busyness, i.e. planning a full schedule in order to avoid idleness and preclude the temptation to use screens. Our findings suggest that practitioners aiming to increase awareness of screen-time or to limit their use may be more likely to succeed if they include all family members, offer concrete alternatives to screen-based activities and provide tailored strategies to manage discretionary time. PMID- 27242268 TI - Redox biology and the interface between bioenergetics, autophagy and circadian control of metabolism. AB - Understanding molecular mechanisms that underlie the recent emergence of metabolic diseases such as diabetes and heart failure has revealed the need for a multi-disciplinary research integrating the key metabolic pathways which change the susceptibility to environmental or pathologic stress. At the physiological level these include the circadian control of metabolism which aligns metabolism with temporal demand. The mitochondria play an important role in integrating the redox signals and metabolic flux in response to the changing activities associated with chronobiology, exercise and diet. At the molecular level this involves dynamic post-translational modifications regulating transcription, metabolism and autophagy. In this review we will discuss different examples of mechanisms which link these processes together. An important pathway capable of linking signaling to metabolism is the post-translational modification of proteins by O-linked N-acetylglucosamine (O-GlcNAc). This is a nutrient regulated protein modification that plays an important role in impaired cellular stress responses. Circadian clocks have also emerged as critical regulators of numerous cardiometabolic processes, including glucose/lipid homeostasis, hormone secretion, redox status and cardiovascular function. Central to these pathways are the response of autophagy, bioenergetics to oxidative stress, regulated by Keap1/Nrf2 and mechanisms of metabolic control. The extension of these ideas to the emerging concept of bioenergetic health will be discussed. PMID- 27242272 TI - Impact of continuous positive airway pressure (CPAP) on quality of life in patients with obstructive sleep apnea (OSA). AB - Obstructive sleep apnea is a chronic illness with increasing prevalence. In addition to associated cardiovascular comorbidities, obstructive sleep apnea syndrome has been linked to poor quality of life, occupational accidents, and motor vehicle crashes secondary to excessive daytime sleepiness. Although continuous positive airway pressure is the gold standard for sleep apnea treatment, its effects on quality of life are not well defined. In the current study we investigated the effects of treatment on quality of life using the data from the Apnea Positive Pressure Long-term Efficacy Study (APPLES), a randomized controlled trial of continuous positive airway pressure (CPAP) versus sham CPAP. The Calgary Sleep Apnea Quality of Life Index (SAQLI) was used to assess quality of life. Overall we found no significant improvement in quality of life among sleep apnea patients after CPAP treatment. However, after stratifying by OSA severity, it was found that long-term improvement in quality of life might occur with the use of CPAP in people with severe and possibly moderate sleep apnea, and no demonstrable improvement in quality of life was noted among participants with mild obstructive sleep apnea. PMID- 27242273 TI - Results From the International Drug Coated Balloon Registry for the Treatment of Bifurcations. Can a Bifurcation Be Treated Without Stents? AB - OBJECTIVES: This observational study assessed the 9-month clinical outcomes in patients with coronary bifurcation lesions suitable for drug-coated balloon (DCB) angioplasty. It was the intention to use DCB's without additional stenting (DCB only strategy) in selected patients for this chosen strategy. Bail-out main branch (MB) and/or side branch (SB) stenting, however, were permissible when flow limiting dissections or excessive recoil occurred. BACKGROUND: A multitude of interventional strategies have been studied to treat bifurcation lesions. With the availability of DCB angioplasty, investigators have been using this interventional tool with the optional implantation of bare metal stents (BMS). METHODS: This study is an international, prospective, multicenter registry enrolling patients with coronary bifurcation lesions including a side branch >=2 mm in diameter. Patients with stable angina and documented ischemia or selected forms of unstable angina due to a culprit bifurcation lesion of any Medina classification type were recruited. The primary endpoint was clinically driven target-lesion revascularization (TLR) at 9 months. Secondary endpoints included 9 month major adverse cardiac events (death, myocardial infarction, or TLR), technical success, in-hospital outcomes and vessel thrombosis rates. RESULTS: A total 127 patients 66.1 +/- 10.1 years of age were enrolled. Demographic characteristics were 80.3% (102/127) male gender, 31.5% (40/127) diabetes, 91.3% (116/127) hypertension, 7.1% (9/127) ST-elevation myocardial infarction (STEMI), and 9.4% (12/127) non ST-elevation myocardial infarction (NSTEMI). The 130 lesions were treated with 184 DCB's and 64 BMS. In 53.8% (70/130) of all lesions the DCB-only strategy could be used while 34.6% (45/130) of lesions had at least 1 stent (BMS) in the main branch, 8.5% (11/130) had at least 1 stent in the side branch and 3.1% (4/130) needed at least 1 stent in the main and side branch. 94.5% patients (121/127) were available for follow-up after 9.8 +/- 2.0 months. The TLR rate was 4.6% in the absence of any thrombotic events in the treated vessels whereas the 9-month MACE rate was 6.2%. CONCLUSION: This observational study suggests that the DCB-only strategy is safe and effective to treat selected bifurcations while benefiting from a shortened dual antiplatelet therapy (DAPT). PMID- 27242274 TI - The adaptor protein alpha-syntrophin regulates adipocyte lipid droplet growth. AB - The scaffold protein alpha-syntrophin (SNTA) regulates lipolysis indicating a role in lipid homeostasis. Adipocytes are the main lipid storage cells in the body, and here, the function of SNTA has been analyzed in 3T3-L1 cells. SNTA is expressed in preadipocytes and is induced early during adipogenesis. Knock-down of SNTA in preadipocytes increases their proliferation. Proteins which are induced during adipogenesis like adiponectin and caveolin-1, and the inflammatory cytokine IL-6 are at normal levels in the mature cells differentiated from preadipocytes with low SNTA. This suggests that SNTA does neither affect differentiation nor inflammation. Expression of proteins with a role in cholesterol and triglyceride homeostasis is unchanged. Consequently, basal and epinephrine induced lipolysis as well as insulin stimulated phosphorylation of Akt and ERK1/2 are normal. Importantly, adipocytes with low SNTA form smaller lipid droplets and store less triglycerides. Stearoyl-CoA reductase and MnSOD are reduced upon SNTA knock-down but do not contribute to lower lipid levels. Oleate uptake is even increased in cells with SNTA knock-down. In summary, current data show that SNTA is involved in the expansion of lipid droplets independent of adipogenesis. Enhanced preadipocyte proliferation and capacity to store surplus fatty acids may protect adipocytes with low SNTA from lipotoxicity in obesity. PMID- 27242275 TI - A study of the treatment of cutaneous fungal infection in animal model using photoactivated composite of methylene blue and gold nanoparticle. AB - BACKGROUND: Onychomycosis is a widespread public health problem, in which T. rubrum and T. mentagrophytes is the commenest causative organisms. Current medical therapy has many drawbacks and side effects. Methylene blue (m.b) photodynamic therapy (pdt) proved efficacy but with lengthy sessions. OBJECTIVES: Optimizing methylene blue photodynamic therapy by combination of methylene blue photosensitizer and gold nanoparticles (aunps) in a composite as gold nanoparticles are efficient delivery systems and efficient enhancers of photosensitizers for antifungal photodynamic therapy. MATERIALS AND METHODS: Eighty newzealand rabbit (Oryctolagus cuniculus) were used and categorized in eight equal groups as follows; healthy and infection control, composite photodynamic therapy and five comparative groups. Photodynamic therapy was initiated at day three to five post inoculation, for four sessions forty eight hours apart. Each group divided and light exposure at two fluencies; 80J and 100J. All groups were investigated macroscopically and microscopically (histopathology and scanning electron microscope) also flowcytometry assessment for cell death and X-ray analysis for gold nanoparticles accumulation in brain and liver tissues were determined. RESULTS: Recovery from infection approaching 96% in gold nanoparticles+light group, around 40% in methylene blue photodynamic therapy and 34% in composite photodynamic therapy. The observed findings confirmed by apparent decrease of apoptosis, however small amounts of gold nanoparticles detected in brain and liver. CONCLUSION: Light stimulated gold nanoparticles is a promising tool in treatment of onychomycosis. PMID- 27242276 TI - Developing a model of limited-access nicotine consumption in C57Bl/6J mice. AB - Although United States smoking rates have been on the decline over the past few decades, cigarette smoking still poses a critical health and economic threat. Very few treatment options for smoking exist, and many of them do not lead to long-term abstinence. Preclinical models are necessary for understanding the effects of nicotine and developing treatments. Current self-administration models of nicotine intake may require surgical procedures and often result in low levels of intake. Further, they do not lend themselves to investigating treatments. The current study sought to develop a limited-access model of nicotine intake using the Drinking-in-the-Dark paradigm, which results in high levels of binge-like ethanol consumption that can be pharmacologically manipulated. The present study found that mice will consume nicotine under a range of parameters. Intakes under the preferred condition of 0.14mg/ml nicotine in 0.2% saccharin reached over 6mg/kg in two hours and were reduced by an injection of R(+)-baclofen. Mecamylamine did not significantly affect nicotine consumption. As nicotine and ethanol are often co-abused, nicotine intake was also tested in the presence of ethanol. When presented in the same bottle, mice altered nicotine intake under various concentrations to maintain consistent levels of ethanol intake. When nicotine and ethanol were presented in separate bottles, mice greatly reduced their nicotine intake while maintaining ethanol intake. In conclusion, these studies characterize a novel model of limited-access nicotine intake that can be pharmacologically manipulated. PMID- 27242277 TI - Gonadal mosaicism for ACTA1 gene masquerading as autosomal recessive nemaline myopathy. PMID- 27242278 TI - Development of research discourses: a conceptual map. AB - AIM: The aim of this study was to discuss: (1) how methodologies are constructed and perpetuated in the context of research paradigms; (2) what exactly constitutes a paradigm; (3) how the proposed conceptual map of discourse development provides a new and original method for understanding knowledge production. BACKGROUND: In nursing research, methodologies are constructed by several external and internal contextually driven influences. Our focus is on how two methodological paradigms - evidence-based practice and mixed methods - continue to impact and be impacted by patterns of knowledge production. DESIGN: Discussion paper. DATA SOURCES: This discussion is based on our own experiences and supported by literature and theory using examples from the two paradigms to illustrate how discourses are developed, perpetuated and deconstructed and how these have specific impacts on qualitative nursing research. IMPLICATIONS FOR NURSING: The conceptual map should be used to cultivate an awareness in practitioners, researchers and policy makers of how discourses surrounding research evidence and research practices are generated. This level of awareness will facilitate critical reflection on how certain practices assume dominance, potentially leading to hegemony in nursing research, practice and scholarship. CONCLUSION: This research offers a critical examination of the meaning of paradigms and a meta-perspective on the production and practice of methodologies using a conceptual map of discourse development as a heuristic device. We anticipate that these examples will encourage debate and discussion on how methodologies and paradigms are perpetuated in academia and the impact this has on nursing knowledge. PMID- 27242279 TI - Corrigendum: Spin-orbit coupling enhanced superconductivity in Bi-rich compounds ABi3 (A = Sr and Ba). PMID- 27242280 TI - Mirror Neurons and Mirror-Touch Synesthesia. AB - Since mirror neurons were introduced to the neuroscientific community more than 20 years ago, they have become an elegant and intuitive account for different cognitive mechanisms (e.g., empathy, goal understanding) and conditions (e.g., autism spectrum disorders). Recently, mirror neurons were suggested to be the mechanism underlying a specific type of synesthesia. Mirror-touch synesthesia is a phenomenon in which individuals experience somatosensory sensations when seeing someone else being touched. Appealing as it is, careful delineation is required when applying this mechanism. Using the mirror-touch synesthesia case, we put forward theoretical and methodological issues that should be addressed before relying on the mirror-neurons account. PMID- 27242281 TI - Effects of tibial rotation on Ober's test and patellar tracking. AB - BACKGROUND: The purpose of this study was to investigate the effects of tibial position on ITB flexibility and patellar position. METHODS: A total of 31 asymptomatic subjects (21 males, 10 females) were recruited for this investigation. Adduction angle was measured by Ober's test, and PCD was measured by ultrasonography in three different tibial rotation conditions: N, IR, and ER. RESULTS: Repeated measures ANOVA revealed a significant difference in adduction angle and PCD among three different tibial positions (P<0.05). Adduction angle was significantly greater in the N tibial position than in ER (P<0.05). The PCD was significantly greater in N position than in IR (P<0.05). However, the PCD was significantly smaller in IR compared with the N position (P<0.05). CONCLUSIONS: These findings support that tibial rotation influences the flexibility of ITB and patellar positions. Therefore, excessive tibial rotation can cause inappropriate patellar positions that eventually lead to knee injury. Therapists should consider tibial rotation when measuring adduction angles because tibial rotation can change Ober's test results and contribute to the consistency of ITB length measurements. LEVEL OF EVIDENCE: Level IV. PMID- 27242282 TI - Psychological traits regarding competitiveness are related to the incidence of anterior cruciate ligament injury in high school female athletes. AB - BACKGROUND: The purpose of this study was to investigate the relationship between psychological competitive ability and the incidence of noncontact ACL injuries among high school female athletes. METHODS: A three-year prospective cohort study was conducted using 300 15-year-old high school female athletes with no previous injuries or symptoms in their lower limbs (106 handball players and 194 basketball players). At baseline, their psychological competitive abilities were assessed using a self-administered questionnaire-the Diagnostic Inventory of Psychological Competitive Ability (DIPCA.3). After the baseline examination was performed at high school entry, all players were prospectively followed for 36months to document any subsequent incidence of ACL injury, according to their coaches. An unpaired t-test with Welch's correction was performed to compare the differences in the psychological competitive abilities between the injured and uninjured players. RESULTS: Of the 300 players, 25 (8.3%) experienced a noncontact ACL injury during the three-year observation period. The injured players had significantly higher total DIPCA.3 scores for psychological competitive ability than the uninjured players (169.9+/-18.8 vs. 159.2+/-21.6, P=.036). Additionally, the injured players had significantly higher scores than the uninjured players in the following categories: aggressiveness, volition for self-realization, volition for winning, judgment, and cooperation. However, no significant differences were observed in patience, self-control, ability to relax, concentration, confidence, decision, and predictive ability. CONCLUSIONS: High psychological competitive ability was associated with the incidence of noncontact ACL injuries in high school female athletes. LEVEL OF EVIDENCE: Level II (prospective cohort study). PMID- 27242283 TI - Favorable femoral component rotation achieved in severe varus deformity by using the gap-balancing technique. AB - BACKGROUND: In a group of patients with severe varus deformity, this study used the gap-balancing technique and evaluated component rotation by using postoperative CT scans in order to determine whether a favorable axis could be achieved. METHODS: Thirty-one patients (34 knees) with varus deformity of >15 degrees , and 31 age-matched and sex-matched patients (36 knees) with varus deformity of <=15 degrees were enrolled. The transepicondylar axis and three degrees of external rotation off the posterior femoral condylar axis were lined out intraoperatively to compare measurements relative to the gap-balancing axis. Joint line elevations were determined, and the femoral component rotation was evaluated on postoperative CT scans. RESULTS: Most of the study patients required stripping the capsule off the posteromedial distal femur and release of the medial collateral ligament. The difference in tibial joint line elevation was not significantly different (P=0.134). The two groups did not differ significantly in terms of the transepicondylar axis relative to the gap-balancing axis (P=0.166), the three degrees of external rotation off the posterior femoral condylar axis relative to the gap-balancing axis (P=0.913), the posterior condylar angles (P=0.218), and the prevalence of cases with a variation of <=+/-3 degrees in all alignment measurements. Comparable clinical outcomes were determined. CONCLUSIONS: When the gap-balancing technique was used in the patients with severe varus deformity of >15 degrees , over-release of the medial collateral ligament was avoided when tight posteromedial structures had been corrected first, and favorable femoral component rotations were achieved. PMID- 27242284 TI - Relationships between the center of pressure and the movements of the ankle and knee joints during the stance phase in patients with severe medial knee osteoarthritis. AB - BACKGROUND: The knee joint movement during the stance phase is affected by altered ankle movement and the center of pressure (COP). However the relationships between changes in the center of pressure (COP) and the altered kinematics and kinetics of the ankle and knee joints in patients with osteoarthritis (OA) of the knee are not well understood. The purpose of this study was to determine the relationships between changes in the COP and the altered kinematic and kinetic variables in ankle and knee joints during the stance phase in patients with medial knee OA. METHODS: Fourteen patients with knee OA (21 knees) and healthy subjects were assessed by gait analysis using an eight-camera motion analysis system to record forward and lateral shifts in the COP and the angle and net internal moments of the knee and ankle joint. Spearman rank-correlation coefficients were used to determine the relationship between these results. RESULTS: In knees with medial OA, lateral shifts in the COP were correlated with knee flexion angle. Lateral shifts in the COP were correlated with the second peak of the knee extensor moment and correlated with the knee abductor moment. CONCLUSIONS: In patients with medial knee OA, lateral shifts in the COP were negatively correlated with the kinematic and kinetic variables in the sagittal plane of the knee joints. Controlling such lateral shifts in the COP may thus be an effective intervention for mechanical loads on the knee during the stance phase in patients with knee OA. PMID- 27242285 TI - Experience-dependent changes in the development of face preferences in infant rhesus monkeys. AB - It is well known that early experience shapes the development of visual perception for faces in humans. However, the effect of experience on the development of social attention in non-human primates is unknown. In two studies, we examined the effect of cumulative social experience on developmental changes in attention to the faces of unfamiliar conspecifics or heterospecifics, and mom versus an unfamiliar female. From birth, infant rhesus monkeys preferred to look at conspecific compared to heterospecific faces, but this pattern reversed over time. In contrast, no consistent differences were found for attention to mom's face compared to an unfamiliar female. These results suggest differential roles of social experience in shaping the development of face preferences in infant monkeys. Results have important implications for establishing normative trajectories for the development of face preferences in an animal model of human social behavior. PMID- 27242286 TI - [Safety of long-term nicotine use: An ongoing debate]. AB - INTRODUCTION: Long-term nicotine use has been proposed as a risk-reduction strategy in smokers unwilling or unable to quit. However, its safety remains debated. METHODS: Analysis of publications identified in PubMed, Toxibase, Google Scholar and in the Food and Drug Administration, and French National Authority for Health websites. RESULTS: Nicotine seems to be implicated in the genesis of atherosclerosis. It could be a cancer precursor, could be implicated in cancer proliferation and angiogenesis, in apoptosis reduction, and may be genotoxic. New studies are warranted for more complete assessment of the risk-benefit balance. CONCLUSION: It is difficult to affirm the safety of long term nicotine use. The risk-benefit balance should be assessed in terms of a risk-reduction strategy, as in other domains, notably illicit drug use. PMID- 27242287 TI - Effects of 7-day repeated treatment with the 5-HT2A inverse agonist/antagonist pimavanserin on methamphetamine vs. food choice in male rhesus monkeys. AB - BACKGROUND: Preclinical drug vs. food choice is an emerging group of drug self administration procedures that have shown predictive validity to clinical drug addiction. Emerging data suggest that serotonin (5-HT)2A receptors modulate mesolimbic dopamine function, such that 5-HT2A antagonists blunt the abuse related neurochemical effects of monoamine transporter substrates, such as amphetamine or methamphetamine. Whether subchronic 5-HT2A antagonist treatment attenuates methamphetamine reinforcement in any preclinical drug self administration procedure is unknown. The study aim was therefore to determine 7 day treatment effects with the 5-HT2A inverse agonist/antagonist pimavanserin on methamphetamine vs. food choice in monkeys. METHODS: Behavior was maintained under a concurrent schedule of food delivery (1g pellets, fixed-ratio 100 schedule) and intravenous methamphetamine injections (0-0.32 mg/kg/injection, fixed-ratio 10 schedule) in male rhesus monkeys (n=3). Methamphetamine choice dose-effect functions were determined daily before and during 7-day repeated pimavanserin (1.0-10mg/kg/day, intramuscular) treatment periods. RESULTS: Under control conditions, increasing methamphetamine doses resulted in a corresponding increase in methamphetamine vs. food choice. Repeated pimavanserin administration failed to attenuate methamphetamine choice and produce a reciprocal increase in food choice in any monkey up to doses (3.2-10mg/kg) that suppressed rates of operant responding primarily during components where behavior was maintained by food pellets. CONCLUSIONS: Repeated 5-HT2A receptor inverse agonist/antagonist treatment did not attenuate methamphetamine reinforcement under a concurrent schedule of intravenous methamphetamine and food presentation in nonhuman primates. Overall, these results do not support the therapeutic potential of 5 HT2A inverse agonists/antagonists as candidate medications for methamphetamine addiction. PMID- 27242288 TI - The longitudinal associations between substance use, crime, and social risk among emerging adults: A longitudinal within and between-person latent variables analysis. AB - BACKGROUND: The reciprocal relationship between crime and substance use is well known. However, when examining this relationship, no study to date has disaggregated between- and within-person effects, which represents a more methodologically sound and developmentally-appropriate analytic approach. Further, few studies have considered the role of social risk (e.g., deviant peers, high-risk living situations) in the aforementioned relationship. We examined these associations in a group of individuals with heightened vulnerability to substance use, crime and social risk: emerging adults (aged 18 25 years) in substance use treatment. METHODS: Participants were 3479 emerging adults who had entered treatment. We used auto-regressive latent growth models with structured residuals (ALT-SR) to examine the within-person cross-lagged association between crime and substance use and whether social risk contributed to this association. A taxonomy of nested models was used to determine the structural form of the data, within-person cross-lagged associations, and between person associations. RESULTS: In contrast to the extant literature on cross lagged relations between crime and substance use, we found little evidence of such relations once between- and within-person relations were plausibly disaggregated. Yet, our results indicated that within-person increases in social risk were predictive of subsequent increases in crime and substance use. Post-hoc analyses revealed a mediation effect of social risk between crime and substance use. CONCLUSIONS: Findings suggest the need to re-think the association between crime and substance use among emerging adults. Individuals that remain connected to high-risk social environments after finishing treatment may represent a group that could use more specialized, tailored treatments. PMID- 27242290 TI - Modelling of stiffness degradation due to cracking in laminates subjected to multi-axial loading. AB - The paper presents an analytical approach to predicting the effect of intra- and interlaminar cracking on residual stiffness properties of the laminate, which can be used in the post-initial failure analysis, taking full account of damage mode interaction. The approach is based on a two-dimensional shear lag stress analysis and the equivalent constraint model of the laminate with multiple damaged plies. The application of the approach to predicting degraded stiffness properties of multidirectional laminates under multi-axial loading is demonstrated on cross-ply glass/epoxy and carbon/epoxy laminates with transverse and longitudinal matrix cracks and crack-induced transverse and longitudinal delaminations. This article is part of the themed issue 'Multiscale modelling of the structural integrity of composite materials'. PMID- 27242289 TI - Dietary supplementation with fish oil prevents high fat diet-induced enhancement of sensitivity to the locomotor stimulating effects of cocaine in adolescent female rats. AB - BACKGROUND: Eating a diet high in fat can lead to obesity, chronic metabolic disease, and increased inflammation in both the central and peripheral nervous systems. Dietary supplements that are high in omega-3 polyunsaturated fatty acids can reduce or prevent these negative health consequences in rats. Eating high fat chow also increases the sensitivity of rats to behavioral effects of drugs acting on dopamine systems (e.g., cocaine), and this effect is greatest in adolescent females. METHODS: The present experiment tested the hypothesis that dietary supplementation with fish oil prevents high fat chow induced increases in sensitivity to cocaine in adolescent female rats. Female Sprague-Dawley rats (post-natal day 25-27) ate standard laboratory chow (5.7% fat), high fat chow (34.4% fat), or high fat chow supplemented with fish oil (20% w/w). Cocaine dose dependently (1-17.8mg/kg) increased locomotion and induced sensitization across 6 weeks of once-weekly testing in all rats; however, these effects were greatest in rats eating high fat chow. RESULTS: Dietary supplementation with fish oil prevented enhanced locomotion and sensitization in rats eating high fat chow. There were no differences in inflammatory markers in plasma or the hypothalamus among dietary conditions. CONCLUSIONS: These results demonstrate that dietary supplementation with fish oil can prevent high fat diet-induced sensitization to cocaine, but they fail to support the view that these effects are due to changes in proinflammatory cytokines. These data add to a growing literature on the relationship between diet and drug abuse and extend the potential health benefits of fish oil to stimulant drug abuse prevention. PMID- 27242291 TI - A comparison of different approaches for imaging cracks in composites by X-ray microtomography. AB - X-ray computed tomography (CT) has emerged as a key imaging tool in the characterization of materials, allowing three-dimensional visualization of an object non-destructively as well as enabling the monitoring of damage accumulation over time through time-lapse imaging. However, small defects and cracks can be difficult to detect, particularly in composite materials where low contrast, plate-like geometries of large area can compromise detectability. Here, we investigate a number of strategies aimed at increasing the capability of X-ray CT to detect composite damage such as transverse ply cracking and delamination, looking specifically at a woven glass fibre-reinforced three-dimensional composite. High-resolution region of interest (ROI) scanning, in situ loading, phase contrast and contrast agents are examined systematically as strategies for improving the defect detectability. Spatial resolution, contrast, signal-to-noise ratio, full width at half maximum, user friendliness and measurement time are all considered. Taken together, the results suggest that high-resolution ROI scanning combined with the increased contrast resulting from staining give the highest defect detectability. This article is part of the themed issue 'Multiscale modelling of the structural integrity of composite materials'. PMID- 27242292 TI - Internal instability as a possible failure mechanism for layered composites. AB - This paper revisits a three-dimensional analytical approach to study internal instability in layered composites, when the behaviour of each component of the material is described by the three-dimensional equations of solid mechanics. It shows the development of a unified computational procedure for numerical realization of the three-dimensional analytical method as applied to various constitutive equations of the layers and fibres, and different loading schemes (uniaxial or biaxial loading). The paper also contains many examples of calculation of critical controlled parameters for particular composites as well as analysis of different buckling modes. The results of this method can be used as a benchmark for simplified models. This article is part of the themed issue 'Multiscale modelling of the structural integrity of composite materials'. PMID- 27242293 TI - Structural integrity of engineering composite materials: a cracking good yarn. AB - Predicting precisely where a crack will develop in a material under stress and exactly when in time catastrophic fracture of the component will occur is one the oldest unsolved mysteries in the design and building of large-scale engineering structures. Where human life depends upon engineering ingenuity, the burden of testing to prove a 'fracture safe design' is immense. Fitness considerations for long-life implementation of large composite structures include understanding phenomena such as impact, fatigue, creep and stress corrosion cracking that affect reliability, life expectancy and durability of structure. Structural integrity analysis treats the design, the materials used, and figures out how best components and parts can be joined, and takes service duty into account. However, there are conflicting aims in the complete design process of designing simultaneously for high efficiency and safety assurance throughout an economically viable lifetime with an acceptable level of risk. This article is part of the themed issue 'Multiscale modelling of the structural integrity of composite materials'. PMID- 27242294 TI - Damage and failure modelling of hybrid three-dimensional textile composites: a mesh objective multi-scale approach. AB - This paper is concerned with predicting the progressive damage and failure of multi-layered hybrid textile composites subjected to uniaxial tensile loading, using a novel two-scale computational mechanics framework. These composites include three-dimensional woven textile composites (3DWTCs) with glass, carbon and Kevlar fibre tows. Progressive damage and failure of 3DWTCs at different length scales are captured in the present model by using a macroscale finite element (FE) analysis at the representative unit cell (RUC) level, while a closed form micromechanics analysis is implemented simultaneously at the subscale level using material properties of the constituents (fibre and matrix) as input. The N layers concentric cylinder (NCYL) model (Zhang and Waas 2014 Acta Mech. 225, 1391 1417; Patel et al. submitted Acta Mech.) to compute local stress, srain and displacement fields in the fibre and matrix is used at the subscale. The 2-CYL fibre-matrix concentric cylinder model is extended to fibre and (N-1) matrix layers, keeping the volume fraction constant, and hence is called the NCYL model where the matrix damage can be captured locally within each discrete layer of the matrix volume. The influence of matrix microdamage at the subscale causes progressive degradation of fibre tow stiffness and matrix stiffness at the macroscale. The global RUC stiffness matrix remains positive definite, until the strain softening response resulting from different failure modes (such as fibre tow breakage, tow splitting in the transverse direction due to matrix cracking inside tow and surrounding matrix tensile failure outside of fibre tows) are initiated. At this stage, the macroscopic post-peak softening response is modelled using the mesh objective smeared crack approach (Rots et al. 1985 HERON 30, 1-48; Heinrich and Waas 2012 53rd AIAA/ASME/ASCE/AHS/ASC Structures, Structural Dynamics and Materials Conference, Honolulu, HI, 23-26 April 2012 AIAA 2012-1537). Manufacturing-induced geometric imperfections are included in the simulation, where the FE mesh of the unit cell is generated directly from micro computed tomography (MCT) real data using a code Simpleware Results from multi scale analysis for both an idealized perfect geometry and one that includes geometric imperfections are compared with experimental results (Pankow et al. 2012 53rd AIAA/ASME/ASCE/AHS/ASC Structures, Structural Dynamics and Materials Conference, Honolulu, HI, 23-26 April 2012 AIAA 2012-1572). This article is part of the themed issue 'Multiscale modelling of the structural integrity of composite materials'. PMID- 27242295 TI - Fibre break failure processes in unidirectional composites: evaluation of critical damage states. AB - Earlier work which successfully modelled the kinetics of fibre breakage in unidirectional composites under monotonic tensile loading has been extended to quantify the kinetics of fibre failure during both monotonic and sustained tensile loading. In both cases, failure was seen to occur when a critical density of large clusters (more than 16 fibres are broken within the representative volume element) of fibre breaks developed. However, in monotonic loading failure occurred very quickly after the first development of these large clusters, whereas under sustained loading the composite could accommodate greater levels of large clusters because of the lower applied load. This article is part of the themed issue 'Multiscale modelling of the structural integrity of composite materials'. PMID- 27242296 TI - Hierarchical analysis of the degradation of fibre-reinforced polymers under the presence of void imperfections. AB - The subject of this work is the investigation of the influence of voids on the mechanical properties of fibre-reinforced polymers (FRPs) under compression loading. To specify the damage accumulation of FRPs in the presence of voids, the complex three-dimensional structure of the composite including voids was analysed and a reduced mechanical model composite was derived. The hierarchical analysis of the model composite on a micro-scale level implies the description of the stress and strain behaviour of the matrix using the photoelasticity technique and digital image correlation technology. These studies are presented along with an analytical examination of the stability of a single fibre. As a result of the experimental and analytical studies, the stiffness of the matrix and fibre as well as their bonding, the initial fibre orientation and the fibre diameter have the highest impact on the failure initiation. All these facts lead to a premature fibre-matrix debonding with ongoing loss of stability of the fibre and followed by kink-band formation. Additional studies on the meso-scale of transparent glass FRPs including a unique void showed that the experiments carried out on the model composites could be transferred to real composites. This article is part of the themed issue 'Multiscale modelling of the structural integrity of composite materials'. PMID- 27242297 TI - Multiscale characterization and representation of composite materials during processing. AB - Given the importance of residual stresses and dimensional changes in composites manufacturing, process simulation has been the focus of many studies in recent years. Consequently, various constitutive models and simulation approaches have been developed and implemented for composites process simulation. In this paper, various constitutive models, ranging from elastic to nonlinear viscoelastic; and simulation approaches ranging from separated flow/solid phases to multiscale integrated phases are presented and their applicability for process simulation is discussed. Attention has been paid to practical aspects of the problem where the complexity of the model coupled with the complexity and size scaling of the structure increases the characterization and simulation costs. Two specific approaches and their application are presented in detail: the pseudo-viscoelastic cure hardening instantaneously linear elastic (CHILE) and linear viscoelastic (VE). It is shown that CHILE can predict the residual stress formation in simple cure cycles such as the one-hold cycle for HEXCEL AS4/8552 where the material does not devitrify during processing. It is also shown that using this simple approach, the cure cycle can be modified to lower the residual stress level and therefore increase the mechanical performance of the composite laminate. For a more complex cure cycle where the material is devitrified during a post-cure, it is shown that a more complex model such as VE is required. This article is part of the themed issue 'Multiscale modelling of the structural integrity of composite materials'. PMID- 27242298 TI - From matrix nano- and micro-phase tougheners to composite macro-properties. AB - In this paper, firstly, the morphology and toughness of a range of bulk epoxy polymers, which incorporate a second phase of well-dispersed silica nanoparticles and/or rubber microparticles, have been determined. Secondly, the macro properties of natural-fibre reinforced-plastic (NFRP) composites based upon these epoxy polymers have been ascertained, using (i) unidirectional flax fibres or (ii) regenerated-cellulose fibres in the architecture of a plain-woven fabric. Thirdly, the toughening mechanisms which are induced in these materials by the presence of the silica nanoparticles, the rubber microparticles and the natural fibres have been identified. Finally, the values of the toughness of the bulk epoxy polymers and corresponding NFRPs have been quantitatively modelled. The increased toughness recorded for the bulk epoxy polymer due to the presence of the silica nanoparticles and/or rubber microparticles was indeed typically transferred to the NFRP composites when using such epoxies as the matrices for the fibres. Thus, the important role that may be played by modifications to the epoxy matrices in order to increase the toughness of the composites was very clearly demonstrated by these results. However, notwithstanding, the toughening mechanisms induced by the fibres were essentially responsible for the very high toughnesses of the NFRP composites, compared with the bulk epoxy polymers. The modelling studies successfully predicted the values of toughness of the bulk epoxy polymers and of the NFRP composites. These studies also quantified the extent to which each toughening mechanism, induced by the second-phase nano- and microparticles and the natural fibres, contributed to the overall values of toughness of the materials. This article is part of the themed issue 'Multiscale modelling of the structural integrity of composite materials'. PMID- 27242299 TI - Use of microfasteners to produce damage tolerant composite structures. AB - The paper concerns the mechanical performance of continuous fibre/thermosetting polymer matrix composites reinforced in the through-thickness direction with fibrous or metallic rods or threads in order to mitigate against low delamination resistance. Specific illustrations of the effects of microfasteners in reducing delamination crack growth are made for Z-pinned and tufted composites. Response to loading in such 'structured materials' is subject to multiple parameters defining their in-plane and out-of-plane properties. Single microfastener mechanical tests are well suited to establish the crack bridging laws under a range of loading modes, from simple delamination crack opening to shear, and provide the basis for predicting the corresponding response of microfastener arrays, within a given material environment. The fundamental experiments on microfasteners can be used to derive analytical expressions to describe the crack bridging behaviour in a general sense, to cover all possible loadings. These expressions can be built into cohesive element constitutive laws in a finite element framework for modelling the effects of microfastener arrays on the out-of plane mechanical response of reinforced structural elements, including the effects of known manufacturing imperfections. Such predictive behaviour can then be used to assess structural integrity under complex loading, as part of the component design process. This article is part of the themed issue 'Multiscale modelling of the structural integrity of composite materials'. PMID- 27242301 TI - Multiscale modelling of the structural integrity of composite materials. PMID- 27242300 TI - Modelling the development of defects during composite reinforcements and prepreg forming. AB - Defects in composite materials are created during manufacture to a large extent. To avoid them as much as possible, it is important that process simulations model the onset and the development of these defects. It is then possible to determine the manufacturing conditions that lead to the absence or to the controlled presence of such defects. Three types of defects that may appear during textile composite reinforcement or prepreg forming are analysed and modelled in this paper. Wrinkling is one of the most common flaws that occur during textile composite reinforcement forming processes. The influence of the different rigidities of the textile reinforcement is studied. The concept of 'locking angle' is questioned. A second type of unusual behaviour of fibrous composite reinforcements that can be seen as a flaw during their forming process is the onset of peculiar 'transition zones' that are directly related to the bending stiffness of the fibres. The 'transition zones' are due to the bending stiffness of fibres. The standard continuum mechanics of Cauchy is not sufficient to model these defects. A second gradient approach is presented that allows one to account for such unusual behaviours and to master their onset and development during forming process simulations. Finally, the large slippages that may occur during a preform forming are discussed and simulated with meso finite-element models used for macroscopic forming. This article is part of the themed issue 'Multiscale modelling of the structural integrity of composite materials'. PMID- 27242302 TI - Prediction of failure in notched carbon-fibre-reinforced-polymer laminates under multi-axial loading. AB - A damage-based finite-element model is used to predict the fracture behaviour of centre-notched quasi-isotropic carbon-fibre-reinforced-polymer laminates under multi-axial loading. Damage within each ply is associated with fibre tension, fibre compression, matrix tension and matrix compression. Inter-ply delamination is modelled by cohesive interfaces using a traction-separation law. Failure envelopes for a notch and a circular hole are predicted for in-plane multi-axial loading and are in good agreement with the observed failure envelopes from a parallel experimental study. The ply-by-ply (and inter-ply) damage evolution and the critical mechanisms of ultimate failure also agree with the observed damage evolution. It is demonstrated that accurate predictions of notched compressive strength are obtained upon employing the band broadening stress for microbuckling, highlighting the importance of this damage mode in compression. This article is part of the themed issue 'Multiscale modelling of the structural integrity of composite materials'. PMID- 27242303 TI - Augmented finite-element method for arbitrary cracking and crack interaction in solids under thermo-mechanical loadings. AB - In this paper, a thermal-mechanical augmented finite-element method (TM-AFEM) has been proposed, implemented and validated for steady-state and transient, coupled thermal-mechanical analyses of complex materials with explicit consideration of arbitrary evolving cracks. The method permits the derivation of explicit, fully condensed thermal-mechanical equilibrium equations which are of mathematical exactness in the piece-wise linear sense. The method has been implemented with a 4-node quadrilateral two-dimensional (2D) element and a 4-node tetrahedron three dimensional (3D) element. It has been demonstrated, through several numerical examples that the new TM-AFEM can provide significantly improved numerical accuracy and efficiency when dealing with crack propagation problems in 2D and 3D solids under coupled thermal-mechanical loading conditions. This article is part of the themed issue 'Multiscale modelling of the structural integrity of composite materials'. PMID- 27242304 TI - Environmental degradation of composites for marine structures: new materials and new applications. AB - This paper describes the influence of seawater ageing on composites used in a range of marine structures, from boats to tidal turbines. Accounting for environmental degradation is an essential element in the multi-scale modelling of composite materials but it requires reliable test data input. The traditional approach to account for ageing effects, based on testing samples after immersion for different periods, is evolving towards coupled studies involving strong interactions between water diffusion and mechanical loading. These can provide a more realistic estimation of long-term behaviour but still require some form of acceleration if useful data, for 20 year lifetimes or more, are to be obtained in a reasonable time. In order to validate extrapolations from short to long times, it is essential to understand the degradation mechanisms, so both physico chemical and mechanical test data are required. Examples of results from some current studies on more environmentally friendly materials including bio-sourced composites will be described first. Then a case study for renewable marine energy applications will be discussed. In both cases, studies were performed first on coupons at the material level, then during structural testing and analysis of large components, in order to evaluate their long-term behaviour. This article is part of the themed issue 'Multiscale modelling of the structural integrity of composite materials'. PMID- 27242305 TI - The role of interlayer adhesion in graphene oxide upon its reinforcement of nanocomposites. AB - Graphene oxide (GO) has become a well-established reinforcement for polymer-based nanocomposites. It provides stronger interfacial interaction with the matrix when compared with that of graphene, but its intrinsic stiffness and strength are somewhat compromised because of the presence of functional groups damaging the graphene lattice and increasing its thickness, and its tendency to adopt a crumpled structure. Although the micromechanics of graphene reinforcement in nanocomposites has been studied widely, the corresponding micromechanics investigations on GO have not been undertaken in such detail. In this work, it is shown that the deformation micromechanics of GO can be followed using Raman spectroscopy and the observed behaviour can be analysed with continuum mechanics. Furthermore, it is shown that the reinforcement efficiency of GO is independent of its number of layers and stacking configurations, indicating that it is not necessary to ensure a high degree of exfoliation of GO in the polymer matrix. It also demonstrates the possibility of increasing the concentration of GO in nanocomposites without sacrificing mechanical reinforcement efficiency. This article is part of the themed issue 'Multiscale modelling of the structural integrity of composite materials'. PMID- 27242306 TI - Strength and toughness of structural fibres for composite material reinforcement. AB - The characterization of the strength and fracture toughness of three common structural fibres, E-glass, AS4 carbon and Kevlar KM2, is presented in this work. The notched specimens were prepared by means of selective carving of individual fibres by means of the focused ion beam. A straight-fronted edge notch was introduced in a plane perpendicular to the fibre axis, with the relative notch depth being a0/D~0.1 and the notch radius at the tip approximately 50 nm. The selection of the appropriate beam current during milling operations was performed to avoid to as much as possible any microstructural changes owing to ion impingement. Both notched and un-notched fibres were submitted to uniaxial tensile tests up to failure. The strength of the un-notched fibres was characterized in terms of the Weibull statistics, whereas the residual strength of the notched fibres was used to determine their apparent toughness. To this end, the stress intensity factor of a fronted edge crack was computed by means of the finite-element method for different crack lengths. The experimental results agreed with those reported in the literature for polyacrylonitrile-based carbon fibres obtained by using similar techniques. After mechanical testing, the fracture surface of the fibres was analysed to ascertain the failure mechanisms. It was found that AS4 carbon and E-glass fibres presented the lower toughness with fracture surfaces perpendicular to the fibre axis, emanating from the notch tip. The fractured region of Kevlar KM2 fibres extended along the fibre and showed large permanent deformation, which explains their higher degree of toughness when compared with carbon and glass fibres. This article is part of the themed issue 'Multiscale modelling of the structural integrity of composite materials'. PMID- 27242307 TI - Physical modelling of failure in composites. AB - Structural integrity of composite materials is governed by failure mechanisms that initiate at the scale of the microstructure. The local stress fields evolve with the progression of the failure mechanisms. Within the full span from initiation to criticality of the failure mechanisms, the governing length scales in a fibre-reinforced composite change from the fibre size to the characteristic fibre-architecture sizes, and eventually to a structural size, depending on the composite configuration and structural geometry as well as the imposed loading environment. Thus, a physical modelling of failure in composites must necessarily be of multi-scale nature, although not always with the same hierarchy for each failure mode. With this background, the paper examines the currently available main composite failure theories to assess their ability to capture the essential features of failure. A case is made for an alternative in the form of physical modelling and its skeleton is constructed based on physical observations and systematic analysis of the basic failure modes and associated stress fields and energy balances. This article is part of the themed issue 'Multiscale modelling of the structural integrity of composite materials'. PMID- 27242308 TI - Multi-scale damage modelling in a ceramic matrix composite using a finite-element microstructure meshfree methodology. AB - The problem of multi-scale modelling of damage development in a SiC ceramic fibre reinforced SiC matrix ceramic composite tube is addressed, with the objective of demonstrating the ability of the finite-element microstructure meshfree (FEMME) model to introduce important aspects of the microstructure into a larger scale model of the component. These are particularly the location, orientation and geometry of significant porosity and the load-carrying capability and quasi brittle failure behaviour of the fibre tows. The FEMME model uses finite-element and cellular automata layers, connected by a meshfree layer, to efficiently couple the damage in the microstructure with the strain field at the component level. Comparison is made with experimental observations of damage development in an axially loaded composite tube, studied by X-ray computed tomography and digital volume correlation. Recommendations are made for further development of the model to achieve greater fidelity to the microstructure. This article is part of the themed issue 'Multiscale modelling of the structural integrity of composite materials'. PMID- 27242309 TI - Summary and concluding remarks. PMID- 27242310 TI - Dedication: Prof. Tony Kelly CBE FRS (1929-2014). PMID- 27242311 TI - Dynamic damage in carbon-fibre composites. AB - The Taylor test is used to determine damage evolution in carbon-fibre composites across a range of strain rates. The hierarchy of damage across the scales is key in determining the suite of operating mechanisms and high-speed diagnostics are used to determine states during dynamic loading. Experiments record the test response as a function of the orientation of the cylinder cut from the engineered multi-ply composite with high-speed photography and post-mortem target examination. The ensuing damage occurs during the shock compression phase but three other tensile loading modes operate during the test and these are explored. Experiment has shown that ply orientations respond to two components of release; longitudinal and radial as well as the hoop stresses generated in inelastic flow at the impact surface. The test is a discriminant not only of damage thresholds but of local failure modes and their kinetics. This article is part of the themed issue 'Multiscale modelling of the structural integrity of composite materials'. PMID- 27242312 TI - Influence of mannitol concentration on the physicochemical, mechanical and pharmaceutical properties of lyophilised mannitol. AB - Mannitol is a pharmaceutical excipient that is receiving increased popularity in solid dosage forms. The aim of this study was to provide comparative evaluation on the effect of mannitol concentration on the physicochemical, mechanical, and pharmaceutical properties of lyophilised mannitol. The results showed that the physicochemical, mechanical and pharmaceutical properties of lyophilised mannitol powders are strong functions of mannitol concentration. By decreasing mannitol concentration, the true density, bulk density, cohesivity, flowability, netcharge to-mass ratio, and relative degree of crystallinity of LM were decreased, whereas the breakability, size distribution, and size homogeneity of lyophilised mannitol particles were increased. The mechanical properties of lyophilised mannitol tablets improved with decreasing mannitol concentration. The use of lyophilised mannitol has profoundly improved the dissolution rate of indomethacin from tablets in comparison to commercial mannitol. This improvement exhibited an increasing trend with decreasing mannitol concentration. In conclusion, mannitols lyophilised from lower concentrations are more desirable in tableting than mannitols from higher concentrations due to their better mechanical and dissolution properties. PMID- 27242313 TI - Preliminary characterization of dexamethasone-loaded cross-linked hyaluronic acid films for topical ocular therapy. AB - The aim of this work was to design and characterize cross-linked hyaluronic acid (HA)-itaconic acid (IT) films loaded with dexamethasone sodium phosphate salt (DEX) for topical therapy of inflammatory ocular surface diseases. Films were chemically cross-linked with polyethylene glycol diglycidyl ether (PEGDE), then physical and mechanical characterization by stress-strain, X-ray diffraction, X ray fluorescence spectrometry and swelling assays was conducted. A sequential in vitro therapeutic efficacy model was designed to assess changes in interleukin (IL)-6 production in an inflamed human corneal epithelial (HCE) cell line after film exposure. Changes in cell proliferation after film exposure were assessed using the alamarBlue((r)) proliferation assay. Experimental findings showed desirable mechanical properties and in vitro efficacy to reduce cell inflammation. A moderately decreased proliferation rate was induced in HCE cells by DEX-loaded films, compared to commercial DEX eye drops. These results suggest that DEX and HA have opposite effects. The sequential in vitro therapeutic efficacy model arises as an efficient tool to study drug release from delivery systems by indirect measurement of a biological response. PMID- 27242314 TI - In vivo residence duration of human growth hormone loaded in nanogels comprising cinnamoyl alginate, cinnamoyl Pluronic F127 and cinnamoyl poly(ethylene glycol). AB - Cinnamoyl alginate, cinnamoyl Pluronic F127 and cinnamoyl poly(ethylene glycol) were self-assembled into nanogel in aqueous phase. The size of nanogel was 100nm 200nm on TEM photos. When 1ml of human growth hormone (hGH) solution (5mg/ml, pH3.0) was mixed with 4ml of the nanogel suspension (37.5mg/ml, pH3.0), 100% of hGH was loaded in the nanogels (corresponding to specific loading of 3.33% (w hGH/w nanogel)). In the in vivo pharmacokinetics study, the substantial blood level of hGH was maintained during the entire experiment period (two weeks) after one-time injection of hGH-loaded nanogel at 0.5mg hGH/kg body weight, and the area under curve (AUC) obtained with the one-time injection of hGH-loaded nanogel was higher than AUC obtained with daily injections of free hGH at 0.05mg hGH/kg for 7days. In the in vivo pharmacodynamics study, the blood level of insulin-like growth factor (IGF-1) increased in 2h and it was maintained during the entire experiment period (two weeks) after one-time injection of hGH-loaded nanogel at 0.5mg hGH/kg body weight. The in vivo fluorescence images of mice injected with rhodamine B isothiocyanate-labelled nanogel suspension showed fluorescence intensity up to 96h after intravenous injection, indicating that the in vivo residence time of the nanogel was greater than 96h. PMID- 27242315 TI - Resurrection of response-guided therapy for sofosbuvir combination therapies. PMID- 27242316 TI - Sustained virologic response to interferon-free therapies ameliorates HCV-induced portal hypertension. AB - BACKGROUND & AIMS: We aimed to investigate the impact of sustained virologic response (SVR) to interferon (IFN)-free therapies on portal hypertension in patients with paired hepatic venous pressure gradient (HVPG) measurements. METHODS: One hundred and four patients with portal hypertension (HVPG ?6mmHg) who underwent HVPG and liver stiffness measurement before IFN-free therapy (baseline [BL]) were retrospectively studied. Among 100 patients who achieved SVR, 60 patients underwent HVPG and transient elastography (TE) after antiviral therapy (follow-up [FU]). RESULTS: SVR to IFN-free therapies significantly decreased HVPG across all BL HVPG strata: 6-9mmHg (BL: 7.37+/-0.28 vs. FU: 5.11+/-0.38mmHg; 2.26+/-0.42mmHg; p<0.001), 10-15mmHg (BL: 12.2+/-0.4 vs. FU: 8.91+/-0.62mmHg; 3.29+/-0.59mmHg; p<0.001) and ?16mmHg (BL: 19.4+/-0.73 vs. FU: 17.1+/-1.21mmHg; 2.3+/-0.89mmHg; p=0.018). In the subgroup of patients with BL HVPG of 6-9mmHg, HVPG normalized (<6mmHg) in 63% (12/19) of patients, while no patient progressed to ?10mmHg. Among patients with BL HVPG ?10mmHg, a clinically relevant HVPG decrease ?10% was observed in 63% (26/41); 24% (10/41) had a FU HVPG <10mmHg. Patients with Child-Pugh stage B were less likely to have a HVPG decrease (hazard ratio [HR]: 0.103; 95% confidence interval [CI]: 0.02-0.514; p=0.006), when compared to Child-Pugh A patients. In the subgroup of patients with BL CSPH, the relative change in liver stiffness (per %; HR: 0.972; 95% CI: 0.945-0.999; p=0.044) was a predictor of a HVPG decrease ?10%. The area under the receiver operating characteristic curve for the diagnosis of FU CSPH by FU liver stiffness was 0.931 (95% CI: 0.865-0.997). CONCLUSIONS: SVR to IFN-free therapies might ameliorate portal hypertension across all BL HVPG strata. However, changes in HVPG seemed to be more heterogeneous among patients with BL HVPG of ?16mmHg and a HVPG decrease was less likely in patients with more advanced liver dysfunction. TE might be useful for the non-invasive evaluation of portal hypertension after SVR. LAY SUMMARY: We investigated the impact of curing hepatitis C using novel interferon-free treatments on portal hypertension, which drives the development of liver-related complications and mortality. Cure of hepatitis C decreased portal pressure, but a decrease was less likely among patients with more pronounced hepatic dysfunction. Transient elastography, which is commonly used for the non-invasive staging of liver disease, might identify patients without clinically significant portal hypertension after successful treatment. PMID- 27242317 TI - Cranberry (poly)phenol metabolites correlate with improvements in vascular function: A double-blind, randomized, controlled, dose-response, crossover study. AB - SCOPE: Cranberries are rich in potentially bioactive (poly)phenols. The aim of this paper was to investigate whether cranberry juice intake can improve vascular function in healthy men in a dose- and time-dependent manner, and to understand which of the circulating (poly)phenol metabolites correlate with vascular effects. METHODS AND RESULTS: A double-blind randomized controlled crossover trial was conducted in ten healthy males. Flow-mediated dilation (FMD), blood pressure, pulse wave velocity and augmentation index were investigated at baseline, 1, 2, 4, 6, and 8 h post-consumption of cranberry juices containing 409, 787, 1238, 1534, and 1910 mg of total cranberry (poly)phenols (TP), and a control drink. Plasma (poly)phenol metabolites were analyzed by UPLC-Q-TOF MS using authentic standards. We observed dose-dependent increases in FMD at 1, 2, 4, 6, and 8 h with a peak at 4 h and maximal effects with juice containing 1238 mg TP. A total of 60 metabolites were quantified in plasma after cranberry consumption. Twelve (poly)phenol metabolites significantly correlated with the increases in FMD, including ferulic and caffeic acid sulfates, quercetin-3-O-beta D-glucuronide and a gamma-valerolactone sulfate. CONCLUSION: (Poly)phenols in cranberry juice can improve vascular function in healthy males and this is linked to the presence of specific newly identified plasma metabolites. PMID- 27242318 TI - Clonal spread of blaOXA-72-carrying Acinetobacter baumannii sequence type 512 in Taiwan. AB - This is the first report to show an insidious outbreak of armA- and blaOXA-72 carrying Acinetobacter baumannii sequence type 512 (ST512) at a study hospital in northern Taiwan. Multilocus sequence typing revealed that this was a ST512 clone. All of the isolates with ST512 carried a novel 12,056-bp repGR2 in combination with a repGR12-type plasmid. This plasmid, designated pAB-ML, had one copy of the blaOXA-72 gene that was flanked by XerC/XerD-like sites and conferred resistance to carbapenems. PMID- 27242319 TI - Development of a vestibular schwannoma xenograft zebrafish model for in vivo antitumor drug screening. AB - OBJECTIVES/HYPOTHESIS: The development of a simple, reliable, and cost-effective animal model greatly facilitates disease treatment. We aimed to establish a rapid, simple, and reproducible live zebrafish vestibular schwannoma xenograft model for antitumor drug screening. METHODS: We optimized each of the following conditions for tumor cell xenografts in zebrafish larvae: larval stage, incubation temperature, and injected cell number. We used NF2-/-mouse Schwann (SC4) cells and generated mCherry fluorescent protein-expressing cells prior to injection into zebrafish larvae. SC4 cells were counted using a fluorescence microscope, suspended in 10% fetal bovine serum, and injected into the center of the yolk sac using a microinjection system. The injected embryos were transferred to E3 medium (for zebrafish embryos), and subsequent tumor formation was observed by fluorescence microscopy over a 5-day period. To validate our model, xenografted embryos were transferred into 6-well plates (5 embryos per well) and treated with everolimus, a known antitumor drug. RESULTS: mCherry fluorescent protein-expressing SC4 cells were successfully grafted into the yolk sacs of zebrafish embryos without any immunosuppressant treatment. At 2 days postinjection, the xenografted cells had grown into tumor masses. The optimal speed of tumor formation depended on the larval stage (30 hpf), incubation temperature (31 degrees C), and injected cell number (200 cells). In preliminary tests, everolimus treatment yielded a > 20% reduction in the number of SC4 cells in the yolk. CONCLUSION: Our in vivo model has the potential to greatly facilitate vestibular schwannoma treatment because of its speed, simplicity, reproducibility, and amenability to live imaging. LEVEL OF EVIDENCE: NA Laryngoscope, 126:E409-E415, 2016. PMID- 27242320 TI - New reference centiles for boys' height, weight and body mass index used voice break as the marker of biological age. AB - AIM: We aimed to develop the first references for body height, body weight and body mass index (BMI) for boys based on the individual developmental tempo with respect to their voice break status. METHODS: We re-analysed data from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS study) on body height, body weight and body mass index based on the voice break, or mutation, in 3956 boys aged 10-17 years. We used the LMS method to construct smoothed references centiles for the studied variables in premutational, mutational and postmutational boys. RESULTS: Body height, body weight and BMI differed significantly (p < 0.001) between the different stages of voice break. On average, boys were 5.9 cm taller, 5.8 kg heavier and had a 0.7 kg/m2 higher BMI with every higher stage of voice break. Currently used growth references for chronological age in comparison with maturity-related references led to an average of 5.4% of boys being falsely classified as overweight. CONCLUSION: These newly developed growth references allowed convenient classifications of underweight and overweight or obese boys with respect to their voice break status. They should be added to currently used references centiles for the body mass index to avoid misclassifying boys' weight. PMID- 27242321 TI - [New therapeutic era in heart failure with reduced ejection fraction: Which population of French patients is concerned?]. AB - A new class of cardiovascular drugs, angiotensin receptor neprilysin inhibitors, has shown its efficacy in the PARADIGM-HF study in replacement of renin angiotensin blockers in symptomatic heart failure patients with reduced ejection fraction, and already treated according to the recommendations. Recent French epidemiological data in the literature allow assessing the number of French patients who could be concerned by the new treatment in taking account the different parameters from the PARADIGM-HF study. PMID- 27242322 TI - [Anticoagulation use in older patients with atrial fibrillation in a cardio geriatric unit]. AB - OBJECTIVE: Older people with atrial fibrillation (AF) have an increased embolic risk but they are less frequently treated with anticoagulants. We wanted to assess our current practice in a specialized service. PATIENTS AND METHODS: Prospective observational study including all patients older than 75 years admitted during 3 months in a cardio-geriatric unit. Patients' embolic risk (CHADS2 score), hemorrhagic risk (HAS-BLED score), anti-thrombotic treatment at arrival and any modification afterwards, were analyzed. RESULTS: Thirty-four patients were included (mean age: 85 years). AF was known in 28 patients, of whom 20 were under anticoagulant therapy at their admission (10 fluindione, 9 warfarine, 1 dabigatran), 4 received aspirin and 4 no anti-thrombotic treatment. Only the treatment of one of these patients was modified, replacing aspirin by warfarin. AF was newly diagnosed in 6 patients, of whom anticoagulation were initiated in 4 patients (3 warfarine, 1 fluindione). Finally, 9 patients (26%) left the hospital without anticoagulant treatment. Reasons given by their attending doctors were: advanced dementia (4 patients), estimated excessive hemorrhagic risk (4), and estimated low embolic risk (1). There was a clear trend to initiate anticoagulation more frequently in patients with a newly diagnosed AF (P=0.09) CONCLUSIONS: A substantial proportion of older patients with AF do not receive anticoagulant therapy, even after having been admitted to a specialized service. Advanced dementia and hemorrhagic risk are the reasons most frequently given for that. PMID- 27242323 TI - MicroRNA-182 aggravates cerebral ischemia injury by targeting inhibitory member of the ASPP family (iASPP). AB - Ischemic stroke is one of the leading causes of death and disability globally and has been regarded as a major public health problem. MicroRNA 182 (miR-182) plays important roles in cellular differentiation, cell growth, cell apoptosis and metastasis. However, the role of miR-182 in the cerebral ischemia injury has never been investigated. In the present study, we demonstrate a crucial role of miR-182 in down-regulating inhibitory member of the ASPP family (iASPP) expression and promoting cerebral ischemia injury. MiR-182 also promotes NO and 3 NT production, and Caspase3 expression, while reduces SOD and MnSOD activities. Furthermore, the amplified cerebral ischemia injury induced by miR-182 is aggravated by inhibition of iASPP. In conclusion, miR-182 plays an aggressive role in the cerebral ischemia injury, and this is associated with inhibited iASPP expression. PMID- 27242324 TI - Role of SERCA and the sarcoplasmic reticulum calcium content on calcium waves propagation in rat ventricular myocytes. AB - In Ca(2+)-overloaded ventricular myocytes, SERCA is crucial to steadily achieve the critical sarcoplasmic reticulum (SR) Ca(2+) level to trigger and sustain Ca(2+) waves, that propagate at constant rate (vwave). High luminal Ca(2+) sensitizes RyR2, thereby increasing Ca(2+) sparks frequency, and the larger RyR2 mediated SR Ca(2+) flux (dF/dt) sequentially activates adjacent RyR2 clusters. Recently, it was proposed that rapid SERCA Ca(2+) reuptake, ahead of the wave front, further sensitizes RyR2, increasing vwave. Nevertheless, this is controversial because rapid cytosolic Ca(2+) removal could instead impair RyR2 activation. We assessed whether rapid SR Ca(2+) uptake enhances vwave by changing SERCA activity (?Decay) over a large range (~175%). We used normal (Ctrl) and hyperthyroid rat (HT; reduced phospholamban by ~80%) myocytes treated with thapsigargin or isoproterenol (ISO). We found that vwave and dF/dt had a non linear dependency with ?Decay, while Ca(2+) waves amplitude was largely unaffected. Furthermore, SR Ca(2+) also showed a non-linear dependency with ?Decay, however, the relationships vwave vs. SR Ca(2+) and vwave vs. dF/dt were linear, suggesting that high steady state SR Ca(2+) determines vwave, while rapid SERCA Ca(2+) uptake does not. Finally, ISO did not increase vwave in HT cells, therefore, ISO-enhanced vwave in Ctrl depended on high SR Ca(2+). PMID- 27242325 TI - Simvastatin inhibits CD44 fragmentation in chondrocytes. AB - In human osteoarthritic chondrocytes, the hyaluronan receptor CD44 undergoes proteolytic cleavage at the cell surface. CD44 cleavage is thought to require transit of CD44 into cholesterol-rich lipid rafts. The purpose of this study was to investigate whether statins exert a protective effect on articular chondrocytes due to diminution of cholesterol. Three model systems of chondrocytes were examined including human HCS-2/8 chondrosarcoma cells, human osteoarthritic chondrocytes and normal bovine articular chondrocytes. Treatment with IL-1beta + Oncostatin M resulted in a substantial increase in CD44 fragmentation in each of the three chondrocyte models. Pre-incubation with simvastatin prior to treatment with IL-1beta + Oncostatin M decreased the level of CD44 fragmentation, decreased the proportion of CD44 that transits into the lipid raft fractions, decreased ADAM10 activity and diminished the interaction between CD44 and ADAM10. In HCS-2/8 cells and bovine articular chondrocytes, fragmentation of CD44 was blocked by the knockdown of ADAM10. Inhibition of CD44 fragmentation by simvastatin also resulted in improved retention of pericellular matrix. Addition of cholesterol and farnesyl-pyrophosphate reversed the protective effects of simvastatin. Thus, the addition of simvastatin exerts positive effects on chondrocytes including reduced CD44 fragmentation and enhanced the retention of pericellular matrix. PMID- 27242327 TI - Will Zika return to the 'Old World'? PMID- 27242326 TI - Immunohistochemical study of hepatic fibropoiesis associated with canine visceral leishmaniasis. AB - Hepatic fibropoiesis has been confirmed in canine visceral leishmaniasis. In fibrotic disease, hepatic stellate cells (HSC) play an important role in fibropoiesis, undergoing activation by TGF-beta to acquire characteristics of myofibroblasts. These cells show extensive capacity for proliferation, motility, contractility, collagen synthesis and extracellular matrix component synthesis. The aim of this work was to identify markers of HSC activation in 10 symptomatic and 10 asymptomatic dogs naturally infected with Leishmania (Leishmania) infantum. Eight uninfected dogs were used as controls. Alpha-actin (alpha-SMA), vimentin and cytokeratin were investigated by immunohistochemistry as HSC markers. The cytokine TGF-beta in tissue was also evaluated by immunohistochemistry. All infected dogs showed higher numbers of reticular fibres than controls. Fibropoiesis found in infected dogs was always associated with the presence of parasites and chronic granulomatous hepatitis. Positive correlation was found among fibropoiesis, parasite tissue load and expression of alpha-SMA. There was no correlation between fibropoiesis, vimentin and cytokeratin markers. The expression of cytokine TGF-beta was higher in infected dogs than in controls, but not significantly different between symptomatic and asymptomatic dogs. These results confirm previous work describing the intense hepatic fibropoiesis in dogs naturally infected with Leishmania infantum, but now associated them with overexpression of TGF-beta, where alpha-SMA may be a superior marker for activated HSC cells in CVL. PMID- 27242328 TI - Is there a benefit of proximal locking screws in osteoporotic distal radius fractures? - A biomechanical study. AB - INTRODUCTION: The distal radial fracture is a common fracture and frequently seen in geriatric patients. During the last years, volar plating has become a popular treatment option. While the application of locking screws at the distal fragment is widely accepted, there is no evidence for their use at the radial shaft. MATERIALS AND METHODS: In six osteoporotic pairs of matched human cadaver radii an extra-articular model creating an AO 23-A2.1 fracture was employed. Osteosynthesis were performed using the APTUS 2.5 Adaptive TriLock Distal Radius System (Medartis AG) with locking (LS) or non-locking screws (NLS) for proximal fixation. Biomechanical testing was performed in a staircase fashion: starting with 50 cycles at 200N, the load was continuously increased by 50N every 80 cycles up to a maximum force of 400N. Finally, load to failure was analyzed with failure defined as sudden loss of force measured (20%) or major deformation of the radii (10mm). RESULTS: At 200N, 250N, 300N, 400N and load to failure, the NLS group showed a higher degree of elastic modulus. In contrast, the LS group showed higher elastic modulus at 350N. Maximum force was higher in the LS group without reaching statistical significance. Reasons for loss of fixation were longitudinal shaft fractures, horizontal peri-implant fractures and distal cutting out. No difference was seen between the two groups concerning the development of the above mentioned complications. CONCLUSION: Our study did not show biomechanical superiority for distal radius fracture fixation by using locking screws in the proximal holes in an osteoporotic cadaver study. At load to failure, longitudinal shaft fractures and peri-implant fractures seemed to be a more relevant problem rather than failure of the proximal fixation. PMID- 27242329 TI - Dynamic contrast-enhanced ultrasound (CEUS) after open and minimally invasive locked plating of proximal humerus fractures. AB - INTRODUCTION: Closed reduction and locked plate fixation of proximal humerus fractures with the minimally invasive deltoid-splitting approach intends to minimize soft tissue damage although axillary nerve injury has been reported. The aim of this study was to assess the deltoid muscle perfusion with dynamic contrast-enhanced ultrasound (CEUS) as novel technique and evaluate its relation to the functional and neurologic outcome after open (ORIF) and minimally invasive (MIPO) fracture fixation. PATIENTS AND METHODS: 50 patients, 30 with deltopectoral ORIF and 20 with deltoid-splitting MIPO approach were examined 6-49 months after surgery. Only patients with a healthy, contralateral shoulder were selected. Shoulder function, satisfaction as well as psychosocial outcome were assessed with established scores (Constant, DASH, Simple Shoulder Test, ASES, SF 12). Electromyography (EMG) of the deltoid muscle was performed to determine axillary nerve damage. Ultrasound of both shoulders included CEUS and Power Doppler after deltoid muscle activation via active abduction for two minutes. RESULTS: None of the examinations and scores showed significant differences between ORIF and MIPO patients, the psychosocial outcome was similar. The fracture types were equally distributed in both groups. The normalized Constant Score was 76.3+/-18.6 in the ORIF and 81.6+/-16.1 in the MIPO group (p=0.373). Deltoid muscle perfusion in CEUS and Power Doppler revealed no differences between both approaches. EMG excluded functionally relevant axillary nerve injuries. Compared with the contralateral shoulder, Constant- and ASES-Scores (p<=0.001 for both ORIF and MIPO) as well as the deltoid CEUS perfusion (ORIF p=0.035; MIPO p=0.030) were significantly worse for both approaches. CONCLUSIONS: Convincing consensus of functional, ultrasonographic and neurologic examinations demonstrated comparable outcomes after deltopectoral and deltoid-splitting approach. The quantification of the deltoid muscle perfusion with CEUS indicates that the proclaimed benefits of the MIPO approach on soft tissue might not be as great as expected. PMID- 27242330 TI - New classification focusing on the relationship between the attachment of the iliofemoral ligament and the course of the fracture line for intertrochanteric fractures. AB - PURPOSE: There are various types of intertrochanteric fractures that are unstable pertrochanteric fractures of the hip. The aim of this study was to develop a systematic and comprehensive classification of intertrochanteric fractures. MATERIALS AND METHODS: This study enrolled 74 patients with intertrochanteric fractures treated by us between 2012 and 2015. The fractures were classified using 3D-CT images taken immediately after the fractures occurred based on the course of the lateral fracture line (LFL) that extends through the lateral femoral cortex distal to the vastus ridge of the greater trochanter in the intertrochanteric area. Furthermore, the presence or absence of additional typical fractures was also studied. Then, 4 orthopedic specialists examined the 3D-CT images of 20 patients randomly selected from the 74 patients to evaluate both the inter-rater and intra-rater agreement levels. RESULTS: Intertrochanteric fractures were classified into three types according to the LFL patterns. Type I (41.9%), the Lateral Wall Pattern, has a LFL that extends towards the lateral fiber bundle attachment area of the iliofemoral ligament. Type II (24.3%), the Transverse Pattern, has a LFL that extends towards the medial bundle attachment area. Type III (33.8%), the Reverse Oblique Pattern, has a LFL that extends between the lateral and medial fiber bundle area of the iliofemoral ligament. Each type showed characteristic displacement and was associated with various combinations of typical fractures (fracture across the intertrochanteric line, posteromedial fragment, including the lesser trochanter, posterolateral fragment posterior to the femoral greater trochanter, and banana-shaped big fragment, including both the greater trochanter and the lesser trochanter). The mean kappa values for the interobserver and intraobserver agreement levels were 0.77 (0.70 0.85) and 0.76 (0.70-0.85), respectively, which were considered substantial agreement levels. CONCLUSION: We believe our new classification is a useful communication tool for medical professionals in the diagnosis of fractures. PMID- 27242331 TI - Reconstruction of Monteggia-like proximal ulna fractures using different fixation devices: A biomechanical study. AB - BACKGROUND: Comminuted proximal ulna fractures are rare and reconstruction of these fractures is discussed controversially. The aim of this study was to test three currently available plate devices in a standardized comminuted four-part fracture model created in proximal ulna sawbones. MATERIAL AND METHODS: A standardized four-part fracture of the proximal ulna was created in 80 sawbones. Reconstruction was performed by five experienced test surgeons according to a standardized reconstruction protocol. Each surgeon reconstructed 4 fractures with a 3.5mm eight-hole reconstruction plate, 4 fractures with seven-hole third tubular double plates and 4 fractures with a 3.5mm anatomical seven-hole locked angle proximal ulna plate. 4 more fractures were reconstructed with simple K wires as a reference construct for further experiments. Outcome measurements were time for reconstruction, quality of reconstruction and stability of the reconstruction. Stability testing was done in 90 degrees and 30 degrees flexion of the elbow. Testing in 30 degrees flexion was done to test the anteroposterior stability regarding the fixed coronoid process. RESULTS: Time for reconstruction was significantly less for K-wire fixation than for the plate devices. Time for reconstruction plating and locked angle plating was significantly lower than for double plating (p<0.005). Quality of reduction did not differ between the three plate systems (p<0.05). K-wire fixation showed the best quality of reduction (p<0.005). In 90 degrees of elbow flexion the anatomic locked angle olecranon plate showed a significantly higher stability compared to the other devices. Furthermore the tubular double plating was significantly more stable than reconstruction plating or K-wire fixation (p<0.05). In anteroposterior loading at 30 degrees , the stability did not differ between the 4 different fixation techniques (p>0.05). For all devices the testing in 30 degrees flexion showed a significantly higher rigidity compared to 90 degrees flexion. CONCLUSION: The locked angle plate system showed the highest stability in 90 degrees of elbow flexion. Each implant was more stable in 30 degrees flexion than in 90 degrees flexion. Testing of the anterior stability of the elbow did not show any differences between the different implants. Because of the superior stability of this device, we conclude that locked angle plating should be preferred for reconstruction of monteggia like complex proximal ulna fractures. PMID- 27242334 TI - As-prepared MoS2 quantum dot as a facile fluorescent probe for long-term tracing of live cells. AB - Recently, the newly emerged two-dimensional nanomaterials, layered transition metal dichalcogenide (e.g. MoS2) nanosheets, have drawn tremendous attentions due to their extraordinary electronic and optical properties, and MoS2 quantum dots (MoS2 QDs) with lateral sizes less than 10 nm have been found to be highly luminescent. In the present study, a facile approach for large-scale preparation of MoS2 QDs by Na intercalation reaction without using any toxic organic reagents is proposed. MoS2 QDs were carefully characterized by various techniques including transmission electron microscopy, atomic force microscopy, dynamic light scattering, spectroscopy, in vitro cytotoxicology, and capillary electrophoresis. The as-prepared MoS2 QDs were strongly fluorescent, highly photo stable, low in cytotoxicity, and readily reactive to thiols. These inherent properties of MoS2 QDs make them excellent fluorescent probes for long-term live cell tracing. The results of live cells imaging indicated that MoS2 QD stained cells remained highly fluorescent after long-term culture, and could be easily traced from other co-cultured cell lines. PMID- 27242332 TI - Thalamocortical functional connectivity and behavioral disruptions in neonates with prenatal cocaine exposure. AB - Prenatal cocaine exposure (PCE) affects neurobehavioral development, however, disentangling direct drug-related mechanisms from contextual effects (e.g., socioeconomic status) has proven challenging in humans. The effects of environmental confounds are minimal immediately after birth thus we aimed to delineate neurobehavioral correlates of PCE in a large cohort of neonates (2 6weeks of age, N=152) with and without drug exposure using resting state functional magnetic resonance imaging (rsfMRI) and developmental assessments at 3months with the Bayley Scales of Infant & Toddler Development, 3rd edition. The cohort included healthy controls and neonates with similar poly-drug exposure+/ cocaine. We focused on the thalamus given its critical importance in early brain development and its unique positioning in the dopamine system. Our results revealed PCE-related hyper-connectivity between the thalamus and frontal regions and a drug-common hypo-connective signature between the thalamus and motor related regions. PCE-specific neonatal thalamo-frontal connectivity was inversely related to cognitive and fine motor scores and thalamo-motor connectivity showed a positive relationship with composite (gross plus fine) motor scores. Finally, cocaine by selective-serotonin-reuptake-inhibitor (SSRI) interactions were detected, suggesting the combined use of these drugs during pregnancy could have additional consequences on fetal development. Overall, our findings provide the first delineation of PCE-related disruptions of thalamocortical functional connectivity, neurobehavioral correlations, and drug-drug interactions during infancy. PMID- 27242333 TI - Dietary inflammatory index and prostate cancer survival. AB - Systemic inflammatory status has been reported to impact survival of prostate cancer (PCa) patients; however, evidence is lacking on whether the inflammatory potential of diet can influence prognosis of PCa patients. To investigate the association between a dietary inflammatory index (DII) and PCa survival, we conducted a retrospective cohort study including 726 men with PCa originally enrolled, between 1995 and 2002, in an Italian case-control study. Information on diet and Gleason score was collected at PCa diagnosis. DII was derived from a food frequency questionnaire using a validated algorithm. Adjusted hazard ratios (HRs) of death with 95% confidence intervals (CIs) were estimated using a Fine Gray model. DII scores were not significantly associated with all-cause mortality of PCa patients (HR highest vs. lowest DII tertile = 1.25; 95% CI: 0.86-1.83). However, considerable heterogeneity emerged according to Gleason score (p < 0.01): no associations emerged among men with Gleason score 2-6 PCa; whereas, among patients with Gleason score 7-10 PCa, DII was directly associated with both all-cause and PCa-specific mortality (HR highest vs. lowest DII tertile: 2.78; 95% CI: 1.41-5.48; and 4.01; 95% CI: 1.25-12.86; respectively). Among patients with Gleason score 7-10 PCa, ten-year all-cause survival probabilities were 58% (95% CI: 47-67%) for highest and 78% (95% CI: 67-86%) for lowest DII tertile. Study findings support the hypothesis that diet, through its inflammatory potential, may influence the prognosis of patients with more aggressive PCa. Dietary interventions aimed at decreasing inflammation may be considered to improve survival of men with PCa. PMID- 27242336 TI - Fitting the data from embryo implantation prediction: Learning from label proportions. AB - Machine learning techniques have been previously used to assist clinicians to select embryos for human-assisted reproduction. This work aims to show how an appropriate modeling of the problem can contribute to improve machine learning techniques for embryo selection. In this study, a dataset of 330 consecutive cycles (and associated embryos) carried out by the Unit of Assisted Reproduction of the Hospital Donostia (Spain) throughout 18 months has been analyzed. The problem of the embryo selection has been modeled by a novel weakly supervised paradigm, learning from label proportions, which considers all the available data, including embryos whose fate cannot be certainly established. Furthermore, all the collected features, describing cycles and embryos, have been considered in a multi-variate data analysis. Our integral solution has been successfully tested. Experimental results show that the proposed technique consistently outperforms an equivalent approach based on standard supervised classification. Embryos in this study were selected for transference according to the criteria of the Spanish Association for Reproduction Biology Studies. Obtained classification models outperform these criteria, specifically reordering medium-quality embryos. PMID- 27242335 TI - Non-thermal Plasma Exposure Rapidly Attenuates Bacterial AHL-Dependent Quorum Sensing and Virulence. AB - The antimicrobial activity of atmospheric pressure non-thermal plasma has been exhaustively characterised, however elucidation of the interactions between biomolecules produced and utilised by bacteria and short plasma exposures are required for optimisation and clinical translation of cold plasma technology. This study characterizes the effects of non-thermal plasma exposure on acyl homoserine lactone (AHL)-dependent quorum sensing (QS). Plasma exposure of AHLs reduced the ability of such molecules to elicit a QS response in bacterial reporter strains in a dose-dependent manner. Short exposures (30-60 s) produce of a series of secondary compounds capable of eliciting a QS response, followed by the complete loss of AHL-dependent signalling following longer exposures. UPLC-MS analysis confirmed the time-dependent degradation of AHL molecules and their conversion into a series of by-products. FT-IR analysis of plasma-exposed AHLs highlighted the appearance of an OH group. In vivo assessment of the exposure of AHLs to plasma was examined using a standard in vivo model. Lettuce leaves injected with the rhlI/lasI mutant PAO-MW1 alongside plasma treated N-butyryl homoserine lactone and n-(3-oxo-dodecanoyl)-homoserine lactone, exhibited marked attenuation of virulence. This study highlights the capacity of atmospheric pressure non-thermal plasma to modify and degrade AHL autoinducers thereby attenuating QS-dependent virulence in P. aeruginosa. PMID- 27242337 TI - Enhancement of the antimicrobial activity and selectivity of GNU7 against Gram negative bacteria by fusion with LPS-targeting peptide. AB - Antimicrobial peptides (AMPs) provide a potential source of new antimicrobial therapeutics for the treatment of multidrug-resistant pathogens. To develop Gram negative selective AMPs that can inhibit the effects of lipopolysaccharide (LPS) induced sepsis, we added various rationally designed LPS-targeting peptides [amino acids 28-34 of lactoferrin (Lf28-34), amino acids 84-99 of bactericidal/permeability increasing protein (BPI84-99), and de novo peptide (Syn)] to the potent AMP, GNU7 (RLLRPLLQLLKQKLR). Compared to our original starting peptide GNU7, hybrid peptides had an 8- to 32-fold improvement in antimicrobial activity against Gram-negative bacteria, such as Escherichia coli and Salmonella typhimurium. Among them, Syn-GNU7 showed the strongest LPS-binding and -neutralizing activities, thus allowing it to selectively eliminate Gram negative bacteria from within mixed cultures. Our results suggest that LPS targeting peptides would be useful to increase the antimicrobial activity and selectivity of other AMPs against Gram-negative bacteria. PMID- 27242338 TI - Radiation therapy for nasopharyngeal carcinoma: the predictive value of interim survival assessment. AB - Pretreatment characteristics are suggested as predictive and/or prognostic factors for nasopharyngeal carcinoma (NPC); however, individual tumor radiosensitivities have previously not been considered. As boost planning is recommended for NPC, we performed interim assessments of magnetic resonance (MR) images for boost planning and retrospectively evaluated their predictive value for the survival of NPC patients. Radiation therapy via elective nodal irradiation (median dose: 39.6 Gy) with/without chemotherapy was used to treat 63 NPC patients. Boost irradiation (median total dose: 70 Gy) was performed based on the interim assessment. The largest lymph node (LN) was measured on MR images acquired at the time of interim assessment. The site of first failure was local in 8 (12.7%), regional in 7 (11.1%), and distant in 12 patients (19.0%). All 7 patients with regional failure harbored LNs >=15 mm at interim assessment. We divided the 63 patients into two groups based on LN size [large (>=15 mm), n = 10 and small (<15 mm), n = 53]. Univariate analysis showed that 5-year overall survival (OS) and cause-specific survival (CSS) rates for large LNs were significantly lower than for small LNs (OS: 12.5% vs 70.5%, P < 0.001 and CSS: 25.0% vs 80.0%, P < 0.001). Multivariate analysis showed that large LNs were a significantly unfavorable factor for both OS (hazard ratio = 4.543, P = 0.002) and CSS (hazard ratio = 6.020, P = 0.001). The results suggest that LN size at interim assessment could predict survival in NPC patients. PMID- 27242339 TI - A novel Nrf2 activator from microbial transformation inhibits radiation-induced dermatitis in mice. AB - Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcriptional factor that regulates many antioxidants, and we have recently succeeded in obtaining a novel Nrf2 activator, RS9, from microbial transformation. RS9 is categorized as a triterpenoid, and well-known triterpenoids such as RTA 402 (bardoxolone methyl) and RTA 408 have been tested in clinical trials. RTA 408 lotion is currently being tested in patients at risk for radiation dermatitis. This prompted us to study the profiles of RS9 in the skin. All the above triterpenoids increased the level of an Nrf2-targeted gene, NADPH:quinone oxidoreductase-1, in normal human epidermal keratinocytes. Among them, the activity of RS9 was prominent; furthermore, the cellular toxicity was less compared with RTA compounds. BALB/c mice were irradiated with 30 Gy/day on Day 0, and compounds were topically applied on the back once daily from Day 1 to Day 30. Dermatitis scores peaked on Day 18, with a score of 2.6 in vehicle-treated mice, and topical applications of 0.1% RTA 402, RTA 408 and RS9 reduced the scores to 1.8, 2.0 and 1.4, respectively. Moreover, the percentage of animals with scores >=2 was analyzed, and 0.1% RS9 suppressed the percentage from 100% to 47%. These results imply that RS9 has potential efficacy for treating radiation dermatitis. PMID- 27242340 TI - PU-H71, a novel Hsp90 inhibitor, as a potential cancer-specific sensitizer to carbon-ion beam therapy. AB - PU-H71, a heat shock protein 90 (Hsp90) inhibitor, has yielded therapeutic efficacy in many preclinical models and is currently in clinical trials. Carbon ion radiotherapy (CIRT) has provided successful tumor control; however, there is still room for improvement, particularly in terms of tumor-specific radiosensitization. The Hsp90 inhibitor PU-H71 has been shown to sensitize tumor cells to X-ray radiation. A murine osteosarcoma cell line (LM8) and a normal human fibroblast cell line (AG01522) were treated with PU-H71 before X-ray, 14- or 50-keV/um carbon-ion beam (C-ion) irradiation. Cell survival and protein expression were evaluated with colony formation and western blot, respectively. Treatment with PU-H71 alone was shown to be non-toxic to both cell lines; however, PU-H71 was shown to significantly sensitize LM8 cells to not only X-ray, but also to C-ion irradiation, while only a minimal sensitizing effect was observed in AG01522 cells. PU-H71 treatment was found to suppress the protein expression levels of Rad51 and Ku70, which are associated with the homologous recombination pathway and the non-homologous end-joining pathway of double-strand break repair. The findings reported here suggest that PU-H71 could be a promising radiosensitizer for CIRT. PMID- 27242341 TI - Dosimetric comparison of carbon ion and X-ray radiotherapy for Stage IIIA non small cell lung cancer. AB - The present study compared the dose-volume histograms of patients with Stage IIIA non-small cell lung cancer (NSCLC) treated with carbon ion radiotherapy with those of patients treated with X-ray radiotherapy. Patients with Stage IIIA NSCLC (n = 10 patients for each approach) were enrolled. Both radiotherapy plans were calculated with the same targets and organs at risk on the same CT. The treatment plan for the prophylactic lymph node and primary tumor (PTV1) delivered 40 Gy for X-ray radiotherapy and 40 Gy (relative biological effectiveness; RBE) for carbon ion radiotherapy. The total doses for the primary tumor and clinically positive lymph nodes (PTV2) were 60 Gy for X-ray radiotherapy and 60 Gy (RBE) for carbon ion radiotherapy. The homogeneity indexes for PTV1 and PTV2 were superior for carbon ion radiotherapy in comparison with X-ray radiotherapy (PTV1, 0.57 vs 0.65, P = 0.009; PTV2, 0.07 vs 0.16, P = 0.005). The normal lung mean dose, V5, V10 and V20 for carbon ion radiotherapy were 7.7 Gy (RBE), 21.4%, 19.7% and 17.0%, respectively, whereas the corresponding doses for X-ray radiotherapy were 11.9 Gy, 34.9%, 26.6% and 20.8%, respectively. Maximum spinal cord dose, esophageal maximum dose and V50, and bone V10, V30 and V50 were lower with carbon ion radiotherapy than with X-ray radiotherapy. The present study indicates that carbon ion radiotherapy provides a more homogeneous target dose and a lower dose to organs at risk than X-ray radiotherapy for Stage IIIA non-small cell lung cancer. PMID- 27242343 TI - Letters to the Editor. PMID- 27242344 TI - Evaluation of Effective Dose from CT Scans for Overweight and Obese Adult Patients Using the VirtualDose Software. AB - This paper evaluates effective dose (ED) of overweight and obese patients who undergo body computed tomography (CT) examinations. ED calculations were based on tissue weight factors in the International Commission on Radiological Protection Publication 103 (ICRP 103). ED per unit dose length product (DLP) are reported as a function of the tube voltage, body mass index (BMI) of patient. The VirtualDose software was used to calculate ED for male and female obese phantoms representing normal weight, overweight, obese 1, obese 2 and obese 3 patients. Five anatomic regions (chest, abdomen, pelvis, abdomen/pelvis and chest/abdomen/pelvis) were investigated for each phantom. The conversion factors were computed from the DLP, and then compared with data previously reported by other groups. It was observed that tube voltage and BMI are the major factors that influence conversion factors of obese patients, and that ED computed using ICRP 103 tissue weight factors were 24% higher for a CT chest examination and 21% lower for a CT pelvis examination than the ED using ICRP 60 factors. For body CT scans, increasing the tube voltage from 80 to 140 kVp would increase the conversion factors by as much as 19-54% depending on the patient's BMI. Conversion factor of female patients was ~7% higher than the factors of male patients. DLP and conversion factors were used to estimate ED, where conversion factors depended on tube voltage, sex, BMI and tissue weight factors. With increasing number of obese individuals, using size dependence conversion factors will improve accuracy, in estimating patient radiation dose. PMID- 27242342 TI - Revisiting the health effects of psychological stress-its influence on susceptibility to ionizing radiation: a mini-review. AB - Both psychological stress (PS) and ionizing radiation (IR) cause varied detrimental effects on humans. There has been no direct evidence so far showing PS alone could cause cancer; however, long-lasting PS may affect our overall health and ability to cope with cancer. Due to their living conditions and occupations, some people may encounter concurrent exposure to both PS and IR to a high extent. In addition to possible health effects resulting directly from exposure to IR on these people, fear of IR exposure is also a cause of PS. The question of whether PS would influence susceptibility to IR, radiocarcinogenesis in particular, is of great concern by both the academic world and the public. Recently, investigations using animal PS models demonstrated that PS could modulate susceptibility to IR, causing increased susceptibility to radiocarcinogenesis in Trp53-heterozygous mice, hematological toxicity in peripheral blood and elevated chromosome aberration (dicentrics) frequency in splenocytes of Trp53-wild-type mice. To actively reduce health risk from exposure to IR, further studies are needed to cumulate more evidence and provide insights into the mechanisms underlying the alterations in susceptibility due to PS modulation. This mini-review gives a general overview of the significance of PS effects on humans and experimental animals, with a special focus on summarizing the latest weight-of-evidence approaches to radiobiological studies on PS-induced alterations in susceptibility in experimental animal models. The susceptibility being investigated is mainly in the context of the impact of the modulatory effect of PS on radiocarcinogenesis; we seek to improve understanding of the combined effects of exposure to both PS and IR in order to facilitate, via active intervention, strategies for radiation risk reduction. PMID- 27242345 TI - A flexible organic resistance memory device for wearable biomedical applications. AB - Parylene is a Food and Drug Administration (FDA)-approved material which can be safely used within the human body and it is also offers chemically inert and flexible merits. Here, we present a flexible parylene-based organic resistive random access memory (RRAM) device suitable for wearable biomedical application. The proposed device is fabricated through standard lithography and pattern processes at room temperature, exhibiting the feasibility of integration with CMOS circuits. This organic RRAM device offers a high storage window (>10(4)), superior retention ability and immunity to disturbing. In addition, brilliant mechanical and electrical stabilities of this device are demonstrated when under harsh bending (bending cycle >500, bending radius <10 mm). Finally, the underlying mechanism for resistance switching of this kind of device is discussed, and metallic conducting filament formation and annihilation related to oxidization/redox of Al and Al anions migrating in the parylene layer can be attributed to resistance switching in this device. These advantages reveal the significant potential of parylene-based flexible RRAM devices for wearable biomedical applications. PMID- 27242347 TI - Lithography-free shell-substrate isolation for core-shell GaAs nanowires. AB - A facile and scalable lithography-free technique(5) for the rapid construction of GaAs core-shell nanowires incorporating shell isolation from the substrate is reported. The process is based on interrupting NW growth and applying a thin spin on-glass (SOG) layer to the base of the NWs and resuming core-shell NW growth. NW growth occurred in an atmospheric pressure metalorganic vapour phase epitaxy (MOVPE) system with gold nanoparticles used as catalysts for the vapour-liquid solid growth. It is shown that NW axial core growth and radial shell growth can be resumed after interruption and even exposure to air. The SOG residues and native oxide layer that forms on the NW surface are shown to prevent or perturb resumption of epitaxial NW growth if not removed. Both HF etching and in situ annealing of the air-exposed NWs in the MOVPE were shown to remove the SOG residues and native oxide layer. While both procedures are shown capable of removing the native oxide and enabling resumption of epitaxial NW growth, in situ annealing produced the best results and allowed construction of pristine core shell NWs. No growth occurred on SOG and it was observed that axial NW growth was more rapid when a SOG layer covered the substrate. The fabricated p-core/n-shell NWs exhibited diode behaviour upon electrical testing. The isolation of the NW shells from the substrate was confirmed by scanning electron microscopy and electrical measurements. The crystal quality of the regrown core-shell NWs was verified with a high resolution transmission electron microscope. The reported technique potentially provides a pathway using MOVPE for scalable and high throughput production of shell-substrate isolated core-shell NWs on an industrial scale. PMID- 27242346 TI - Fibroblast recruitment as a tool for ovarian cancer detection and targeted therapy. AB - Metastatic ovarian cancer, the most lethal of gynecologic malignancies, is typically managed by debulking surgery, followed by chemotherapy. However, despite significant efforts, survival rate remains low. We have previously demonstrated, in mouse models, a specific systemic homing of labeled fibroblasts to solid ovarian tumors. Here, we demonstrate the feasibility of utilizing this specific homing of genetically modified fibroblasts for detection and targeted therapy of orthotopic metastatic ovarian carcinoma model in immune-deficient mice. Using an in vivo metastatic mouse model for ovarian cancer, we demonstrated that fibroblasts expressing fluorescent reporters injected intra-peritoneally, were specifically recruited to peritoneal tumor nodules (resulting in 93-100% co localization). We further used fibroblasts over expressing the soluble receptor variant of VEGFR1 (s-Flt1). Mice bearing tumors were injected weekly with either control or s-Flt1 expressing fibroblasts. Injection of s-Flt1 expressing fibroblasts resulted in a significant reduction in the ascites volume, reduced vascularization of adherent metastases, and improved overall survival. Using fluorescently labeled fibroblasts for tumor detection with readily available intra-operative fluorescence imaging tools may be useful for tumor staging and directing biopsies or surgical efforts during exploratory or debulking surgery. Fibroblasts may serve as a beacon pointing to the otherwise invisible metastases in the peritoneal cavity of ovarian cancer patients. Utilizing the recruited fibroblasts also for targeted delivery of anti angiogenic or antitumor molecules may aid in controlling tumor progression. Thus, these results suggest a novel approach for targeting ovarian tumor metastases for both tumor detection and therapy. PMID- 27242349 TI - Pneumocystis jirovecii Pneumonia in the Non-HIV-Infected Population. AB - OBJECTIVE: Summarize data on the pathophysiology, treatment, and prevention options for non-AIDS immunocompromised patients who have Pneumocystis jirovecii pneumonia (PJP); review the epidemiology of patients presenting with PJP; and discuss the first and second-line pharmacological options for treatment and prophylaxis of PJP in this population. DATA SOURCES: MEDLINE (1989-February 2016) searched. Terms searched included combinations of Pneumocystis jirovecii, Pneumocystis carinii, non-HIV, infected, patients, prevention, prophylaxis, Bactrim, treatment, AIDS, opportunistic, immunocompromised, cancer, and pathophysiology STUDY SELECTION AND DATA EXTRACTION: Articles included had the most relevant information on PJP pathophysiology, and first-/second-line treatment and prophylactic options. Inclusion criteria were met and evaluated with 43 sources. DATA SYNTHESIS: P jirovecii has a complicated life-cycle; it seeks to find compromised immune systems in order to replicate, causing life threatening complications. With immunosuppressive medications coming to market for immunomodulating diseases, PJP has become a prevalent opportunistic infection in the non-HIV population. CD4+ lymphocyte count <200 cells/uL is the primary risk factor for PJP presentation in these patients. With data from clinical trials, trimethoprim/sulfamethoxazole (TMP/SMX) has become the primary treatment and prophylaxis of PJP in the non-HIV population, although second-line options are available. CONCLUSION: PJP is a health problem that may result in an increased concern as more immunomodulating medications to treat various disease states are developed. Patients on these drugs or those with immunosuppressive diseases should have their CD4+ count monitored. Health care providers should continue to use TMP/SMX as the primary option in non-HIV, immunocompromised patients for treatment and prophylaxis of PJP. PMID- 27242348 TI - Genome-Wide Association Studies Suggest Limited Immune Gene Enrichment in Schizophrenia Compared to 5 Autoimmune Diseases. AB - There has been intense debate over the immunological basis of schizophrenia, and the potential utility of adjunct immunotherapies. The major histocompatibility complex is consistently the most powerful region of association in genome-wide association studies (GWASs) of schizophrenia and has been interpreted as strong genetic evidence supporting the immune hypothesis. However, global pathway analyses provide inconsistent evidence of immune involvement in schizophrenia, and it remains unclear whether genetic data support an immune etiology per se. Here we empirically test the hypothesis that variation in immune genes contributes to schizophrenia. We show that there is no enrichment of immune loci outside of the MHC region in the largest genetic study of schizophrenia conducted to date, in contrast to 5 diseases of known immune origin. Among 108 regions of the genome previously associated with schizophrenia, we identify 6 immune candidates (DPP4, HSPD1, EGR1, CLU, ESAM, NFATC3) encoding proteins with alternative, nonimmune roles in the brain. While our findings do not refute evidence that has accumulated in support of the immune hypothesis, they suggest that genetically mediated alterations in immune function may not play a major role in schizophrenia susceptibility. Instead, there may be a role for pleiotropic effects of a small number of immune genes that also regulate brain development and plasticity. Whether immune alterations drive schizophrenia progression is an important question to be addressed by future research, especially in light of the growing interest in applying immunotherapies in schizophrenia. PMID- 27242350 TI - Effects of Rosuvastatin Versus Atorvastatin, Alone or in Combination, on Lipoprotein (a). AB - BACKGROUND: There are little evidences about the therapeutic efficacy of different lipid-lowering agents in the reduction of elevated lipoprotein(a) [Lp(a)]. OBJECTIVE: testing the effect of different lipid-lowering agents on elevated Lp(a). METHODS: prospective interventional study performed in patients with CAD, or high CAD risk, with Lp(a), >50 mg/dL. Lp(a), total cholesterol (C), HDL-C, LDL-C, triglycerides (TGs), apolipoprotein (Apo) A1, Apo B, enzymes of myocyte and hepatic injury were comparatively analyzed between 4 lipid-lowering strategies: rosuvastatin (R group) 40 mg, atorvastatin (A group) 80 mg, atorvastatin 40 mg add-on micronized fenofibrate (A+F group), and atorvastatin 40 mg add-on 1 g extended-release niacin (A+ERN group). Comparison was made for their therapeutic efficacy on Lp(a), and safety. RESULTS: 87 patients with mean Lp(a) 94.6 +/- 39.6 mg/dL were analyzed. Groups: 25 patients in the R, 22 in the A, 20 in the A+F and 20 in A+ERN group. Significant reduction in all lipid fractions in all treatment groups was reported after 6 months. The average reduction of Lp(a) was 15.9 +/- 21.0 mg/dL, with: 18.2 +/- 24.8 (P = 0.001) in the R group, 17.3 +/- 10.4 (P = 0.001) in A+F, 19.5 +/- 10.9 (P = 0.001) in A+ERN and the lowest in the A group (11.24 +/- 22.91, P = 0.032). No adverse effects were observed in any of the treatment groups. CONCLUSIONS: When compared with atorvastatin, it seems that rosuvastatin can achieve more significant decrease of Lp(a).The efficacy of the second one can be increased by adding fibrate or ERN. PMID- 27242351 TI - MitraClip and surgery should not compete. PMID- 27242352 TI - Watershed of veno-arterial extracorporeal life support. PMID- 27242353 TI - Re: Preoperative intra-aortic counterpulsation in high-risk patients undergoing cardiac surgery: a meta-analysis of randomized controlled trials. PMID- 27242354 TI - The JUPITER registry: 1-year results of transapical aortic valve implantation using a second-generation transcatheter heart valve in patients with aortic stenosis. AB - OBJECTIVES: Transcatheter aortic valve replacement (TAVR) is an established therapy for patients with aortic stenosis (AS) at high surgical risk. The JenaValveTM is a second-generation, self-expanding transcatheter heart valve (THV), implanted through transapical access (TA). During stent deployment, a specific 'clipping-mechanism' engages native aortic valve cusps for fixation. We present 1-year outcomes of the JUPITER registry, a post-market registry of the JenaValve for TA-TAVR. METHODS: The JUPITER registry is a prospective, multicentre, uncontrolled and observational European study to evaluate the long term safety and effectiveness of the Conformite Europeenne-marked JenaValve THV. A total of 180 patients with AS were enrolled between 2012 and 2014. End-points were adjudicated in accordance with the valve academic research consortium document no. 1 definitions. RESULTS: The mean age was 80.4 +/- 5.9 years and the mean logistic European system for cardiac operative risk evaluation I 21.2 +/- 14.7%. The procedure was successful in 95.0% (171/180), implantation of a second THV (valve-in-valve) was performed in 2.2% (4/180) and conversion to surgical aortic valve replacement (SAVR) was necessary in 2.8% (5/180). No annular rupture or coronary ostia obstruction occurred. Two patients required SAVR after the day of index procedure (1.1%). All-cause mortality at 30 days was 11.1% (20/180), being cardiovascular in 7.2% (13/180). A major stroke occurred in 1.1% (2/180) at 30 days, no additional major strokes were observed during 1 year. All-cause mortality after 30 days was 13.1% (21/160) and combined efficacy at 1 year was 80.8% (122/151). At 1-year follow-up, no patient presented with more than moderate paravalvular leakage, while 2 patients (3.2%) showed moderate, 12 (19.0%) mild and 49 (82.4%) trace/none paravalvular regurgitation. CONCLUSIONS: In a high-risk cohort of patients undergoing TA-TAVR for AS, the use of the JenaValve THV is safe and effective. In patients at higher risk for coronary ostia obstruction, annular rupture or with limited aortic valve calcification, the JenaValve might be preferable for implantation due to its clipping-mechanism engaging native aortic valve cusps for fixation with reduced radial forces of the self-expanding stent. PMID- 27242355 TI - Surgical decision-making in aortic prosthetic valve endocarditis: the influence of electrocardiogram-gated computed tomography. AB - OBJECTIVES: The aim of this study was to investigate the value of electrocardiogram (ECG)-gated computed tomography (CT) in the surgical decision making and preoperative evaluation in patients with aortic prosthetic valve endocarditis (PVE). METHODS: Sixty-eight prosthetic valves in 67 patients with aortic PVE were prospectively evaluated with ECG-gated CT and transoesophageal echocardiography (TEE). Imaging findings considered indications for surgery were as follows: (i) abscess/pseudoaneurysm formation; (ii) prosthetic valve dehiscence; (iii) valve destruction with valvular regurgitation; (iv) large vegetations (>1.5 cm). The coronary arteries were evaluated with ECG-gated CT. Clinical data including surgical reports and mortality data were collected. RESULTS: Fifty-eight of 68 cases had indication for surgery based on imaging findings (ECG-gated CT/TEE). In 8 of these cases (14%), there was indication for surgery based on CT but not on TEE findings (all had perivalvular pseudoaneurysms). In 11 cases (19%), there was indication for surgery based on TEE but not on CT findings [non-drained abscess (n = 5), prosthetic valve dehiscence (n = 4), large vegetation (n = 1), valve destruction (n = 1)]. In 31 of 32 patients with indication for preoperative coronary angiography, ECG-gated CT coronary angiography was diagnostic. In 1 patient, ECG-gated CT coronary angiography was inconclusive and invasive coronary angiography was performed. CONCLUSIONS: In patients with aortic PVE, ECG-gated CT provides additional information over TEE regarding perivalvular extension of infection, which can influence surgical decision-making. Furthermore, ECG-gated CT provides a non invasive coronary angiogram and can in most cases replace invasive coronary angiography in the preoperative evaluation. PMID- 27242356 TI - Non-intubated video-assisted thoracic surgery: the final frontier? PMID- 27242357 TI - Continuous paravertebral block for post-cardiothoracic surgery analgesia: a systematic review and meta-analysis. AB - A continuous paravertebral block is used when pain relief is required beyond the duration of a single-injection paravertebral block. Surgical procedures requiring an incision into the pleural cavity are some of the most painful procedures postoperatively and, if not managed appropriately, can lead to chronic pain. The current gold standard for post-cardiothoracic surgery pain management is epidural analgesia, which has contraindications, a failure rate of up to 12% and risk of complications such as epidural abscess and spinal haematoma. This systematic review and meta-analysis aimed to investigate the use of a continuous paravertebral block for post-cardiothoracic surgery analgesia. Randomized controlled trials evaluating the continuous paravertebral block against epidural analgesia, wound infiltration, placebo or standard care (intravenous opioids) for post-cardiothoracic surgery analgesia were considered for inclusion in the systematic review. PubMed, EMBASE, The Cochrane Library and the University of York Centre for Reviews and Dissemination databases were searched from inception to 15 September 2014. Risk of bias and generalizability were assessed using a modified Downs and Black checklist. A meta-analysis was conducted on suitable studies comparing the continuous paravertebral nerve block with epidural anaesthesia, with fixed-effects models being used to pool the effects. Twenty three randomized controlled trials with 1120 participants were included. The continuous paravertebral block was associated with a significant improvement in incidence of nausea and vomiting (odds ratio = 0.29, 95% confidence interval = [0.16, 0.56]), hypotension (odds ratio = 0.16, 95% confidence interval = [0.06, 0.41]) and urinary retention (odds ratio = 0.22, 95% confidence interval = [0.09, 0.52]) compared with the epidural block. No statistically significant difference in pain relief was reported. The continuous paravertebral block has equivalent analgesic effects to epidural analgesia, wound infiltration and standard care, but is associated with a lower incidence of nausea and vomiting, hypotension and urinary retention than epidural analgesia. PMID- 27242358 TI - Re: Low-flow lower body perfusion for spinal protection in a frozen elephant trunk simulation model. PMID- 27242359 TI - Uniportal video-assisted thoracic surgery: a call for better evidence, not just more evidence. PMID- 27242360 TI - Reporting surgeon-specific outcome data: panacea for everything? PMID- 27242361 TI - Reply to Yang. PMID- 27242362 TI - Donor lung assessment using selective pulmonary vein gases. AB - OBJECTIVES: Standard donor lung assessment relies on imaging, challenge gases and subjective interpretation of bronchoscopic findings, palpation and visual assessment. Central gases may not accurately represent true quality of the lungs. We report our experience using selective pulmonary vein gases to corroborate the subjective judgement. METHODS: Starting, January 2012, donor lungs have been assessed by intraoperative bronchoscopy, palpation and visual judgement of lung collapse upon temporary disconnection from ventilator, central gases from the aorta and selective pulmonary vein gases. Partial pressure of oxygen (pO2) <300 mmHg on FiO2 of 1.0 was considered low. The results of the chest X-ray and last pO2 in the intensive care unit were also collected. Post-transplant primary graft dysfunction and survival were monitored. RESULTS: To date, 259 consecutive brain dead donors have been assessed and 157 transplants performed. Last pO2 in the intensive care unit was poorly correlated with intraoperative central pO2 (Spearman's rank correlation rs = 0.29). Right inferior pulmonary vein pO2 was associated (Mann-Whitney, P < 0.001) with findings at bronchoscopy [clean: median pO2 443 mmHg (25th-75th percentile range 349-512) and purulent: 264 mmHg (178 408)]; palpation [good: 463 mmHg (401-517) and poor: 264 mmHg (158-434)] and visual assessment of lung collapse [good lung collapse: 429 mmHg (320-501) and poor lung collapse: 205 mmHg (118-348)]. Left inferior pulmonary pO2 was associated (P < 0.001) with findings at bronchoscopy [clean: 419 mmHg (371-504) and purulent: 254 mmHg (206-367)]; palpation [good: 444 mmHg (400-517) and poor 282 mmHg (211-419)] and visual assessment of lung collapse [good: 420 mmHg (349 496) and poor: 246 mmHg (129-330)]. At 72 h, pulmonary graft dysfunction 2 was in 21/157 (13%) and pulmonary graft dysfunction 3 in 17/157 (11%). Ninety-day and 1 year mortalities were 6/157 (4%) and 13/157 (8%), respectively. CONCLUSIONS: Selective pulmonary vein gases provide corroborative objective support to the findings at bronchoscopy, palpation and visual assessment. Central gases do not always reflect true function of the lungs, having high false-positive rate towards the individual lower lobe gas exchange. Objective measures of donor lung function may optimize donor surgeon assessment, allowing for low pulmonary graft dysfunction rates and low 90-day and 1-year mortality. PMID- 27242363 TI - WRNIP1 protects stalled forks from degradation and promotes fork restart after replication stress. AB - Accurate handling of stalled replication forks is crucial for the maintenance of genome stability. RAD51 defends stalled replication forks from nucleolytic attack, which otherwise can threaten genome stability. However, the identity of other factors that can collaborate with RAD51 in this task is poorly elucidated. Here, we establish that human Werner helicase interacting protein 1 (WRNIP1) is localized to stalled replication forks and cooperates with RAD51 to safeguard fork integrity. We show that WRNIP1 is directly involved in preventing uncontrolled MRE11-mediated degradation of stalled replication forks by promoting RAD51 stabilization on ssDNA We further demonstrate that replication fork protection does not require the ATPase activity of WRNIP1 that is however essential to achieve the recovery of perturbed replication forks. Loss of WRNIP1 or its catalytic activity causes extensive DNA damage and chromosomal aberrations. Intriguingly, downregulation of the anti-recombinase FBH1 can compensate for loss of WRNIP1 activity, since it attenuates replication fork degradation and chromosomal aberrations in WRNIP1-deficient cells. Therefore, these findings unveil a unique role for WRNIP1 as a replication fork-protective factor in maintaining genome stability. PMID- 27242364 TI - miRNAFold: a web server for fast miRNA precursor prediction in genomes. AB - Computational methods are required for prediction of non-coding RNAs (ncRNAs), which are involved in many biological processes, especially at post transcriptional level. Among these ncRNAs, miRNAs have been largely studied and biologists need efficient and fast tools for their identification. In particular, ab initio methods are usually required when predicting novel miRNAs. Here we present a web server dedicated for miRNA precursors identification at a large scale in genomes. It is based on an algorithm called miRNAFold that allows predicting miRNA hairpin structures quickly with high sensitivity. miRNAFold is implemented as a web server with an intuitive and user-friendly interface, as well as a standalone version. The web server is freely available at: http://EvryRNA.ibisc.univ-evry.fr/miRNAFold. PMID- 27242365 TI - Middle Cranial Fossa Dehiscence as an Incidental Finding on CT. AB - OBJECTIVES: This retrospective chart review demonstrates that the prevalence of middle cranial fossa (MCF) dehiscence on computed tomography (CT) scans increases with age. METHODS: High-resolution temporal bone CT scans, which had been obtained for any otologic complaint, were reviewed independent of all clinical history. Scans showing soft tissue, fluid, trauma, or previous operations were excluded. The CTs from 183 patients (296 ears) were reviewed, blinded for age and body mass index (BMI). The MCF floor was divided into 7 regions and systematically inspected. Ages and BMIs of the patients were subsequently extracted from the medical record. RESULTS: Logistic regression analysis confirmed increasing MCF dehiscence with age (P < .05, odds ratio [OR] = 1.07, R = .584). Over all ages (range, 1-88 years; average, 38.5), 32% of MCF floors were dehiscent at any 1 site. For age 60 and over, 55% were dehiscent. The most common sites of MCF dehisence were directly above the malleus head and above the additus ad antrum (35% and 28%, respectively). Superior canal dehiscence (SCD) was seen in 7% of all patients and only in the context of MCF dehiscence. The prevalence of MCF dehiscence increased with age when patients were analyzed by BMI <25, BMI = 25-30, and BMI >30 (P < .003, P < .04, P = .03). CONCLUSION: The increase of middle cranial fossa dehiscence with respect to age is statistically significant. Over all ages, approximately 32% of ears show dehiscence. Over 60 years, approximately 55% show dehiscence. The odds of having dehiscence double with a 10 year difference in age. The most common sites along the MCF floor are in the epitympanum over the malleus head and the additus ad antrum. There was a statistically significant increase in MCF dehiscence with age when patients with equivalent BMIs are compared. PMID- 27242367 TI - Challenges in the rural family doctor system in Iran in 2013-14: a qualitative approach. AB - BACKGROUND: Family doctor is a medical specialization that provides families and people of all ages, genders and diseases with comprehensive ongoing health services. OBJECTIVE: The present study wasconducted to describe challenges in the rural family physician program from the perspective of family physician program directors and family doctors in Iran using a qualitative approach. METHODS: We conducted interviews with 13 family physician program directors and 8 family doctors selected through purposive snowball sampling. The initial in-depth unstructured interviews were reviewed and transformed into semi-structured ones. The data obtained were analyzed in ATLAS.ti using the conceptual framework method. RESULTS: Nine main concepts (comprehensive planning, medical insurance system, compensation for services, performance evaluation, welfare facilities, recruiting and retaining a workforce, information system, culture-building and financing) and 27 subgroups emerged from the analysis of the data. CONCLUSION: The main challenges in the family physician program include cultural, economic and environmental factors and work conditions. The implementation of this program can be improved through building a community culture and exercising minor and major modifications. PMID- 27242366 TI - Phenotype of a Belgian Family With 6p25 Deletion Syndrome. AB - BACKGROUND: The 6p25 deletion syndrome is one of the many syndromes with both hearing impairment as well as vision impairment. However, the audiometric characteristics and radiological findings of patients with 6p25 deletions are only scarcely described in literature. This study focused on characterizing the audiometric and radiological features of a Belgian family with a chromosome 6p25 deletion. OBJECTIVE: To evaluate the hearing impairment, audiometric testing and radiological examination of the temporal bones in 3 family members with a 3.4 Mb deletion in chromosome band 6p25. RESULTS: All 3 family members demonstrated slowly progressive sensorineural or mixed hearing impairment. Radiologic examination revealed thickened and sclerotic stapes in all patients and a minor internal partition type II of the cochlea in 2 patients. CONCLUSION: There is a significant phenotypic variability within and among families with the 6p25 deletion syndrome. A thorough genotype-phenotype correlation is difficult because of the small number of affected patients and the limited clinical data available. More clinical data of families with 6p25 deletions need to be published in order to create a reliable and precise phenotypic characterization. However, our findings can facilitate counseling of hearing impairment caused by 6p25 deletions. PMID- 27242369 TI - Risk and Protective Factors Affecting Sexual Risk Behavior Among School-Aged Adolescents in Fiji, Kiribati, Samoa, and Vanuatu. AB - There are limited studies on the prevalence and correlates of sexual risk behavior among adolescents in Pacific Island countries. In order to inform public sexual and reproductive health interventions, the aim of this study was to assess the prevalence and correlates of various sexual risk behaviors among in-school adolescents in 4 Pacific Island countries using data from the Global School-Based Health Survey. In a cross-sectional study, 6792 school-going adolescents (49.7% boys and 50.3% girls; 13-16 years old) from Fiji, Kiribati, Samoa, and Vanuatu were surveyed with a self-administered questionnaire. Overall, 18.9% of students reported to ever had sex (ranging from 12.9% in Vanuatu to 57.5% in Samoa), and of those sexually active, 38.0% had an early sexual debut (<14 years), 38.1% had 2 or more sexual partners during their lifetime, 39.5% had not used a condom at last sex, 50.9% had not used birth control at last sex, and 77.8% engaged in sexually risky behavior using a composite measure. Multivariate logistic regression found that male sex, older age, tobacco use, alcohol use, mental distress, having no close friends, and truancy were associated with several of 5 or all 5 sexual risk behaviors. Sexual and reproductive health promotion programs are indicated to address the high risk of sexually transmitted infection, HIV, and pregnancy in this adolescent population. PMID- 27242368 TI - Extended versus standard azathioprine maintenance therapy in newly diagnosed proteinase-3 anti-neutrophil cytoplasmic antibody-associated vasculitis patients who remain cytoplasmic anti-neutrophil cytoplasmic antibody-positive after induction of remission: a randomized clinical trial. AB - BACKGROUND: Cytoplasmic anti-neutrophil cytoplasmic antibody (C-ANCA) positivity at remission has been associated with an increased relapse rate in patients with proteinase 3 anti-neutrophil cytoplasmic antibody-associated vasculitis (PR3-AAV) after a switch to azathioprine maintenance therapy. We therefore hypothesized that extended azathioprine maintenance therapy could reduce the incidence of relapse in this setting. METHODS: Patients newly diagnosed with PR3-AAV at 12 centres in The Netherlands during 2003-11 who received a standardized induction regimen consisting of oral cyclophosphamide and corticosteroids were enrolled (n = 131). Patients were randomized to standard or extended azathioprine maintenance therapy when C-ANCA was positive at the time of stable remission. Standard maintenance treatment consisted of azathioprine (1.5-2.0 mg/kg) until 1 year after diagnosis and subsequent tapering to 25 mg every 3 months. Extended azathioprine maintenance therapy (1.5-2.0 mg/kg) was continued until 4 years after diagnosis and tapered thereafter. The primary endpoint was relapse-free survival at 4 years after diagnosis. RESULTS: In patients with PR3-AAV who were C ANCA positive at the time of stable remission, relapse-free survival at 4 years after diagnosis did not differ significantly between standard azathioprine (n = 24) and extended azathioprine (n = 21) maintenance therapy (P = 0.40). There was also no significant difference in relapse-free survival between patients receiving standard azathioprine (n = 106) versus extended azathioprine maintenance therapy (n = 21; P = 0.94). In addition, there was no difference in the relapse rate between patients with PR3-AAV who were C-ANCA positive (n = 45) at the time of remission versus patients who became C-ANCA negative at the time of remission (n = 82; P = 0.62). CONCLUSIONS: This randomized trial suggests that extended azathioprine maintenance therapy has only a limited effect on the prevention of relapse in patients with PR3-AAV at 4 years after diagnosis. Moreover, positive C-ANCA status at stable remission was not associated with an increased rate of relapse. TRIAL REGISTRATION: ClinicalTrials.gov NCT 00128895. PMID- 27242370 TI - Functional characterization of a soybean growth stimulator Bradyrhizobium sp. strain SR-6 showing acylhomoserine lactone production. AB - A soybean nodule endophytic bacterium Bradyrhizobium sp. strain SR-6 was characterized for production of acyl homoserine lactones (AHLs) as quorum sensing molecules. Mass spectrometry analysis of AHLs revealed the presence of C6-HSL, 3OH-C6-HSL, C8-HSL, C10-HSL, 3oxoC10-HSL, 3oxo-C12-HSL and 3OH-C12-HSL which are significantly different from those reported earlier in soybean symbionts. Purified AHL extracts significantly improved wheat and soybean seedling growth and root hair development along with increased soybean nodulation under axenic conditions. A positive correlation was observed among in vivo nitrogenase and catalase enzyme activities of the strain SR-6. Transmission electron microscopic analysis showed the cytochemical localization of catalase activity within the bacteroids, specifically attached to the peribacteroidal membrane. Root and nodule colonization proved rhizosphere competence of SR-6. The inoculation of SR 6 resulted in increased shoot length (13%), plant dry matter (50%), grain weight (16%), seed yield (20%) and N-uptake (14%) as compared to non-inoculated soybean plants. The symbiotic bacterium SR-6 has potential to improve soybean growth and yield in sub-humid climate of Azad Jammu and Kashmir region of Pakistan. The production and mass spectrometric profiling of AHLs as well as in vivo cytochemical localization of catalase enzyme activity in soybean Bradyrhizobium sp. have never been reported earlier elsewhere before our these investigations. PMID- 27242372 TI - Association between vascular access creation and deceleration of estimated glomerular filtration rate decline in late-stage chronic kidney disease patients transitioning to end-stage renal disease. AB - Background: Prior studies have suggested that arteriovenous fistula (AVF) or graft (AVG) creation may be associated with slowing of estimated glomerular filtration rate (eGFR) decline. It is unclear if this is attributable to the physiological benefits of a mature access on systemic circulation versus confounding factors. Methods: We examined a nationwide cohort of 3026 US veterans with advanced chronic kidney disease (CKD) transitioning to dialysis between 2007 and 2011 who had a pre-dialysis AVF/AVG and had at least three outpatient eGFR measurements both before and after AVF/AVG creation. Slopes of eGFR were estimated using mixed-effects models adjusted for fixed and time-dependent confounders, and compared separately for the pre- and post-AVF/AVG period overall and in patients stratified by AVF/AVG maturation. In all, 3514 patients without AVF/AVG who started dialysis with a catheter served as comparators, using an arbitrary 6-month index date before dialysis initiation to assess change in eGFR slopes. Results: Of the 3026 patients with AVF/AVG (mean age 67 years, 98% male, 75% diabetic), 71% had a mature AVF/AVG at dialysis initiation. eGFR decline accelerated in the last 6 months prior to dialysis in patients with a catheter (median, from -6.0 to -16.3 mL/min/1.73 m2/year, P < 0.001), while a significant deceleration of eGFR decline was seen after vascular access creation in those with AVF/AVG (median, from -5.6 to -4.1 mL/min/1.73 m2/year, P < 0.001). Findings were independent of AVF/AVG maturation status and were robust in adjusted models. Conclusions: The creation of pre-dialysis AVF/AVG appears to be associated with eGFR slope deceleration and, consequently, may delay the onset of dialysis initiation in advanced CKD patients. PMID- 27242373 TI - Urinary soluble CD163 level reflects glomerular inflammation in human lupus nephritis. AB - BACKGROUND: In addition to classically activated macrophages that have effector roles in tissue injury, alternatively activated M2 macrophages are involved in the resolution of inflammation in animal models of kidney disease. To clarify the clinical relevance of macrophage phenotypes in human glomerular diseases, we evaluated the renal accumulation of macrophages and plasma and urine levels of CD163, an M2 marker, in lupus nephritis (LN) patients. METHODS: Kidney biopsies and plasma and urine samples were obtained from LN patients who underwent renal biopsy between 2008 and 2012. CD163+, CD68+ and CD204+ cells were counted in paraffin-embedded and frozen sections. LN histological activity was evaluated semiquantitatively using the biopsy activity index. Plasma and urinary soluble CD163 (sCD163) concentrations were also measured and evaluated for their significance as potential LN biomarkers. RESULTS: Immunohistological analysis of glomeruli from LN patients revealed that >60% of CD68+ macrophages had merged with CD163+ cells. The increased number of glomerular CD163+ macrophages was correlated with LN severity, as determined by the biopsy active index (r = 0.635). Urinary (u-) sCD163 level was strongly correlated with glomerular CD163+ cell counts and histological disease score as well as urinary monocyte chemoattractant protein 1 levels (r = 0.638 and 0.592, respectively). Furthermore, the u-sCD163 level was higher in patients with active LN than in those with other diseases. CONCLUSIONS: Glomerular CD163+ macrophages are the predominant phenotype in the kidneys of lupus patients. These findings indicate that the u-sCD163 level can serve as a biomarker for macrophage-dependent glomerular inflammation in human LN. PMID- 27242374 TI - Microbial detoxification in the gut of a specialist avian herbivore, the Greater Sage-Grouse. AB - One function of the gut microbiota gaining recent attention, especially in herbivorous mammals and insects, is the metabolism of plant secondary metabolites (PSMs). We investigated whether this function exists within the gut communities of a specialist avian herbivore. We sequenced the cecal metagenome of the Greater Sage-Grouse (Centrocercus urophasianus), which specializes on chemically defended sagebrush (Artemisia spp.). We predicted that the cecal metagenome of the sage grouse would be enriched in genes associated with the metabolism of PSMs when compared to the metagenome of the domestic chicken. We found that representation of microbial genes associated with 'xenobiotic degradation and metabolism' was 3 fold higher in the sage-grouse cecal metagenomes when compared to that of the domestic chicken. Further, we identified a complete metabolic pathway for the degradation of phenol to pyruvate, which was not detected in the metagenomes of the domestic chicken, bovine rumen or 14 species of mammalian herbivores. Evidence of monoterpene degradation (a major class of PSMs in sagebrush) was less definitive, although we did detect genes for several enzymes associated with this process. Overall, our results suggest that the gut microbiota of specialist avian herbivores plays a similar role to the microbiota of mammalian and insect herbivores in degrading PSMs. PMID- 27242375 TI - In vitro activity of levofloxacin against planktonic and biofilm Stenotrophomonas maltophilia lifestyles under conditions relevant to pulmonary infection in cystic fibrosis, and relationship with SmeDEF multidrug efflux pump expression. AB - The activity of levofloxacin against planktonic and biofilm Stenotrophomonas maltophilia cells and the role played by the multidrug efflux pump SmeDEF were evaluated under conditions relevant to the cystic fibrosis (CF) lung. MIC, MBC and MBEC of levofloxacin were assessed, against five CF strains, under 'standard' (CLSI-recommended) and 'CF-like' (pH 6.8, 5% CO2, in a synthetic CF sputum) conditions. Levofloxacin was tested against biofilms at concentrations (10, 50 and 100 MUg mL(-1)) corresponding to achievable serum levels and sputum levels by aerosolisation. smeD expression was evaluated, under both conditions, in planktonic and biofilm cells by RT-PCR. The bactericidal effect of levofloxacin was decreased, in three out of five strains tested, under 'CF-like' conditions (MBC: 2-4 vs 8-16 MUg mL(-1), under 'standard' and 'CF-like' conditions, respectively). Biofilm was intrinsically resistant to levofloxacin, regardless of conditions tested (MBECs >= 100 MUg mL(-1) for all strains). Only under 'CF-like' conditions, smeD expression increased during planktonic-to-biofilm transition, and in biofilm cells compared to stationary planktonic cells. Our findings confirmed that S. maltophilia biofilm is intrinsically resistant to therapeutic concentrations of levofloxacin. Under conditions relevant to CF, smeD overexpression could contribute to levofloxacin resistance. Further studies are warranted to define the clinical relevance of our findings. PMID- 27242371 TI - Regulation of polar auxin transport by protein and lipid kinases. AB - The directional transport of auxin, known as polar auxin transport (PAT), allows asymmetric distribution of this hormone in different cells and tissues. This system creates local auxin maxima, minima, and gradients that are instrumental in both organ initiation and shape determination. As such, PAT is crucial for all aspects of plant development but also for environmental interaction, notably in shaping plant architecture to its environment. Cell to cell auxin transport is mediated by a network of auxin carriers that are regulated at the transcriptional and post-translational levels. Here we review our current knowledge on some aspects of the 'non-genomic' regulation of auxin transport, placing an emphasis on how phosphorylation by protein and lipid kinases controls the polarity, intracellular trafficking, stability, and activity of auxin carriers. We describe the role of several AGC kinases, including PINOID, D6PK, and the blue light photoreceptor phot1, in phosphorylating auxin carriers from the PIN and ABCB families. We also highlight the function of some receptor-like kinases (RLKs) and two-component histidine kinase receptors in PAT, noting that there are probably RLKs involved in co-ordinating auxin distribution yet to be discovered. In addition, we describe the emerging role of phospholipid phosphorylation in polarity establishment and intracellular trafficking of PIN proteins. We outline these various phosphorylation mechanisms in the context of primary and lateral root development, leaf cell shape acquisition, as well as root gravitropism and shoot phototropism. PMID- 27242377 TI - Toward consensus on self-management support: the international chronic condition self-management support framework. AB - Self-management support (SMS) initiatives have been hampered by insufficient attention to underserved and disadvantaged populations, a lack of integration between health, personal and social domains, over emphasis on individual responsibility and insufficient attention to ethical issues. This paper describes a SMS framework that provides guidance in developing comprehensive and coordinated approaches to SMS that may address these gaps and provides direction for decision makers in developing and implementing SMS initiatives in key areas at local levels. The framework was developed by researchers, policy-makers, practitioners and consumers from 5 English-speaking countries and reviewed by 203 individuals in 16 countries using an e-survey process. While developments in SMS will inevitably reflect local and regional contexts and needs, the strategic framework provides an emerging consensus on how we need to move SMS conceptualization, planning and development forward. The framework provides definitions of self-management (SM) and SMS, a collective vision, eight guiding principles and seven strategic directions. The framework combines important and relevant SM issues into a strategic document that provides potential value to the SMS field by helping decision-makers plan SMS initiatives that reflect local and regional needs and by catalyzing and expanding our thinking about the SMS field in relation to system thinking; shared responsibility; health equity and ethical issues. The framework was developed with the understanding that our knowledge and experience of SMS is continually evolving and that it should be modified and adapted as more evidence is available, and approaches in SMS advance. PMID- 27242378 TI - Antileishmanial Activity of Date (Phoenix dactylifera L) Fruit and Pit Extracts In Vitro. AB - Leishmaniasis is considered as a major public health problem worldwide. Current drugs in treatment of leishmaniasis have some limitations; thus, the current study was aimed to assess the methanolic extracts of pit and fruit of Phoenix dactylifera against Leishmania major promastigotes. L major promastigotes were cultured in RPMI 1640 and incubated at 25 degrees C +/- 1 degrees C for 24, 48, and 72 hours. For obtaining the IC50 (half maximal inhibitory concentration) value, MTT assay was employed. Furthermore, promastigotes were examined in terms of morphology under light microscope. About 48 hours after treatment, IC50s were estimated 23 MUg/mL and 500 mg/mL for methanolic extracts of pit and fruit of P dactylifera, respectively. Both extracts exhibited a dose and time-dependent antileishmanial activity against L major parasites. Also, some visible morphological changes were seen. This finding revealed both date fruit and pit, are effective against L major promastigotes. Further studies should be designed in future based on apoptosis induction in vitro and in vivo. PMID- 27242376 TI - The oncolytic virus DeltaPK has multimodal anti-tumor activity. AB - Oncolytic viruses (OVs) are an emerging cancer therapeutic, with a near complete absence of serious adverse effects. However, clinical efficacy is relatively modest, related to poor tumor penetration, failure to lyse cancer stem cells (CSCs) and blockade of immunogenic cell death by the immunosuppressive tumor microenvironment. To overcome such limitations, we developed an OV (known as DeltaPK) with multimodal anti-tumor activity. DeltaPK has potent anti-tumor activity both in melanoma cell lines and xenograft animal models, associated with virus replication and the induction of multiple independent programmed cell death pathways. It lyses CSCs through autophagy modulation and it reverses the immunosuppressive tumor microenvironment by altering the balance of cytokines secreted by the tumor cells. This includes decreased tumor cell secretion of the immunosuppressive and procancerous cytokines IL-10 and IL-18 and concomitant increased secretion of the proinflammatory cytokines TNF-alpha, GM-CSF, IL-6 and IL-1beta. DeltaPK also upregulates the NKG2D ligand, MICA expressed by cytotoxic NK and T cells, and downregulates the negative immune checkpoint regulator cytotoxic T-lymphocyte antigen-4 (CTLA-4). DeltaPK is well tolerated in human patients in whom it also alters the Th1/Th2 balance. Further studies are designed to elucidate the role of these contributions in different tumor types. PMID- 27242379 TI - Influence of Office Systems on Pediatric Vaccination Rates. AB - This study seeks to better understand the impact of practice-level factors on up to-date (UTD) rates in children. We compared practice-level vaccination rates for 54 practices to survey data regarding office practices for staffing, vaccine delivery, reminder-recall, and quality improvement. Vaccination rates at 24 and 35 months were analyzed using t tests, analysis of variance, and linear regression. Private practices and those using standing orders had higher UTD rates at 24 months ( P = .01; P = .03), but not at 35 months. Having a pediatrician in the office was associated with higher UTD rates at both 24 and 35 months ( P < .01). Participating in a network and taking walk-in patients were associated with lower UTD rates ( P = .03; P = .03). As the percentage of publicly insured patients decreases, the UTD rate rises at 24 and 35 months ( r = -0.43, P = .001; r = -0.037, P = .007). Reported use of reminder recall-systems, night/evening hours, and taking walk-in patients were not associated with increased UTD rates. PMID- 27242380 TI - Cerebellitis as an atypical manifestation of scrub typhus. PMID- 27242381 TI - IV thrombolysis in very severe and severe ischemic stroke: Results from the SITS ISTR Registry. PMID- 27242383 TI - Antibiotic-associated encephalopathy. PMID- 27242382 TI - Pearls & Oy-sters: Hemicrania epileptica: Unfolding the mystery of an unremitting migraine. PMID- 27242384 TI - Use of amyloid-PET to determine cutpoints for CSF markers: A multicenter study. PMID- 27242385 TI - Mystery Case: Parkinsonism in a diabetic uremic patient. PMID- 27242386 TI - Journal Club: Effect of comorbidity on mortality in multiple sclerosis. PMID- 27242387 TI - Eating seafood and cognitive decline in older adults. PMID- 27242388 TI - LOCAL INDEPENDENCE FEATURE SCREENING FOR NONPARAMETRIC AND SEMIPARAMETRIC MODELS BY MARGINAL EMPIRICAL LIKELIHOOD. AB - We consider an independence feature screening technique for identifying explanatory variables that locally contribute to the response variable in high dimensional regression analysis. Without requiring a specific parametric form of the underlying data model, our approach accommodates a wide spectrum of nonparametric and semiparametric model families. To detect the local contributions of explanatory variables, our approach constructs empirical likelihood locally in conjunction with marginal nonparametric regressions. Since our approach actually requires no estimation, it is advantageous in scenarios such as the single-index models where even specification and identification of a marginal model is an issue. By automatically incorporating the level of variation of the nonparametric regression and directly assessing the strength of data evidence supporting local contribution from each explanatory variable, our approach provides a unique perspective for solving feature screening problems. Theoretical analysis shows that our approach can handle data dimensionality growing exponentially with the sample size. With extensive theoretical illustrations and numerical examples, we show that the local independence screening approach performs promisingly. PMID- 27242389 TI - The Relationship between Betatrophin Levels in Blood and T2DM: A Systematic Review and Meta-Analysis. AB - BACKGROUND: In order to clarify previous ambiguous research conclusions, a meta analysis was made to investigate the relationship between betatrophin levels in blood and type 2 diabetes mellitus (T2DM). METHODS: We have searched all the English and Chinese references regarding the relationship between betatrophin and diabetes in database both manually and online. Strict criteria have been established to include and exclude articles, with Mean and Standard Deviation as statistics to evaluate strength of association. We have chosen either fixed- or random effect model according to heterogeneity inspection results and used Begg's test and Egger's test to analyze publication bias. RESULTS: A total of 11 studies were included in this meta-analysis. Meta-analysis indicated a significant association between betatrophin and T2DM (Mean: 329.46; 95% confidence interval: 182.51 to 476.42, P < 0.0001). However, in the subgroup analysis, there was no significant statistic between betatrophin concentration and T2DM within Caucasian population (Mean: 98.40; 95% confidence interval: -1585.08 to 1781.88, P = 0.91). CONCLUSIONS: Such relationship may suggest preference for association between betatrophin and T2DM in different population. PMID- 27242390 TI - China's marriage squeeze: A decomposition into age and sex structure. AB - Most recent studies of marriage patterns in China have emphasized the male-biased sex ratio but have largely neglected age structure as a factor in China's male marriage squeeze. In this paper we develop an index we call "spousal sex ratio" (SSR) to measure the marriage squeeze, and a method of decomposing the proportion of male surplus into age and sex structure effects within a small spousal age difference interval. We project that China's marriage market will be confronted with a relatively severe male squeeze. For the decomposition of the cohort aged 30, from 2010 to 2020 age structure will be dominant, while from 2020 through 2034 the contribution of age structure will gradually decrease and that of sex structure will increase. From then on, sex structure will be dominant. The index and decomposition, concentrated on a specific female birth cohort, can distinguish spousal competition for single cohorts which may be covered by a summary index for the whole marriage market; these can also be used for consecutive cohorts to reflect the situation of the whole marriage market. PMID- 27242391 TI - Graphene as a signal amplifier for preparation of ultrasensitive electrochemical biosensors. AB - Early diagnostics of diseases performed with minimal money and time consumption has become achievable due to recent advances in development of biosensors. These devices use biorecognition elements for selective interaction with an analyte and signal readout is obtained via different types of transducers. Operational characteristics of biosensors have been reported to improve substantially, when a diverse range of nanomaterials was employed. This review presents construction of electrochemical biosensors based on graphene, atomically thin 2D carbon crystals, which is currently intensively studied nanomaterial. The most attractive directions of graphene applications in biosensor preparation are discussed here including novel detection and amplification schemes exploiting graphene's unique electrochemical, physical and chemical properties. The future of graphene-based biosensors is most likely bright, but there is still a lot of work to do to fulfill high expectations. PMID- 27242393 TI - Interactive Effects of Psychosocial Stress and Early Pubertal Timing on Youth Depression and Anxiety: Contextual Amplification in Family and Peer Environments. AB - While off-time pubertal development has emerged as a potential risk factor for both symptoms of depression and anxiety in youth, the literature is mixed and inconsistent as to (1) how early versus late pubertal timing confers risk for both boys and girls, (2) if the conferred risk is distinct between symptoms of anxiety and depression, and (3) under what social contexts (e.g., family environment, peer relationships) off-time pubertal development may emerge as a potent risk factor for these symptoms. The present study examined the impact of perceived pubertal timing on symptoms of anxiety and depression in two distinct psychosocial contexts: parent's perceptions of their own harsh parenting and parent's perceptions of their child's peer problems. The sample consisted of 412 parents (M = 38.6 years old, SD = 7.8, 60.4% mothers) of children between the ages of eight and seventeen (M = 12.13, SD = 2.97, 45.4% girls). All constructs were assessed by parent reports. Linear multiple regression analyses revealed that the interaction between earlier pubertal timing and greater peer problems was significantly related to higher youth depressive and anxiety symptoms. The interaction between earlier pubertal timing and greater harsh discipline was significantly related to higher youth anxiety but not depressive symptoms. Youth gender did not qualify findings. Results suggest that the contextual amplification process of early pubertal timing may occur in both high stress family and peer environments and impact both girls and boys. PMID- 27242394 TI - Bequest Motives of older people in Rural China: From the Perspective of Intergenerational Support. AB - China, a society long characterized by traditional Confucianism and the practice of filial piety, is undergoing dramatic socioeconomic development and erosion of traditions. In this rapidly changing context, the motives behind rural parental bequests have not been well studied. This paper draws on a survey conducted in rural Anhui province of China and uses hierarchical linear models (HLM) to examine whether three kinds of support from children are associated with older parents' bequest motives. We find that while instrumental support accords with an exchange model of motivation, financial transfer is consistent with an altruistic motivation for parental bequest plans. Offspring gender is strongly associated with parental planning of bequests, when only sons are considered; family division is a strong correlate of parents' bequest plan and reflects exchange motivation. These findings have important implications for research on traditional culture and an evolving social security system. PMID- 27242392 TI - Chemokines and Heart Disease: A Network Connecting Cardiovascular Biology to Immune and Autonomic Nervous Systems. AB - Among the chemokines discovered to date, nineteen are presently considered to be relevant in heart disease and are involved in all stages of cardiovascular response to injury. Chemokines are interesting as biomarkers to predict risk of cardiovascular events in apparently healthy people and as possible therapeutic targets. Moreover, they could have a role as mediators of crosstalk between immune and cardiovascular system, since they seem to act as a "working-network" in deep linkage with the autonomic nervous system. In this paper we will describe the single chemokines more involved in heart diseases; then we will present a comprehensive perspective of them as a complex network connecting the cardiovascular system to both the immune and the autonomic nervous systems. Finally, some recent evidences indicating chemokines as a possible new tool to predict cardiovascular risk will be described. PMID- 27242395 TI - An Efficient and Reliable Statistical Method for Estimating Functional Connectivity in Large Scale Brain Networks Using Partial Correlation. AB - Currently, network-oriented analysis of fMRI data has become an important tool for understanding brain organization and brain networks. Among the range of network modeling methods, partial correlation has shown great promises in accurately detecting true brain network connections. However, the application of partial correlation in investigating brain connectivity, especially in large scale brain networks, has been limited so far due to the technical challenges in its estimation. In this paper, we propose an efficient and reliable statistical method for estimating partial correlation in large-scale brain network modeling. Our method derives partial correlation based on the precision matrix estimated via Constrained L1-minimization Approach (CLIME), which is a recently developed statistical method that is more efficient and demonstrates better performance than the existing methods. To help select an appropriate tuning parameter for sparsity control in the network estimation, we propose a new Dens-based selection method that provides a more informative and flexible tool to allow the users to select the tuning parameter based on the desired sparsity level. Another appealing feature of the Dens-based method is that it is much faster than the existing methods, which provides an important advantage in neuroimaging applications. Simulation studies show that the Dens-based method demonstrates comparable or better performance with respect to the existing methods in network estimation. We applied the proposed partial correlation method to investigate resting state functional connectivity using rs-fMRI data from the Philadelphia Neurodevelopmental Cohort (PNC) study. Our results show that partial correlation analysis removed considerable between-module marginal connections identified by full correlation analysis, suggesting these connections were likely caused by global effects or common connection to other nodes. Based on partial correlation, we find that the most significant direct connections are between homologous brain locations in the left and right hemisphere. When comparing partial correlation derived under different sparse tuning parameters, an important finding is that the sparse regularization has more shrinkage effects on negative functional connections than on positive connections, which supports previous findings that many of the negative brain connections are due to non-neurophysiological effects. An R package "DensParcorr" can be downloaded from CRAN for implementing the proposed statistical methods. PMID- 27242397 TI - Simple Cortical and Thalamic Neuron Models for Digital Arithmetic Circuit Implementation. AB - Trade-off between reproducibility of neuronal activities and computational efficiency is one of crucial subjects in computational neuroscience and neuromorphic engineering. A wide variety of neuronal models have been studied from different viewpoints. The digital spiking silicon neuron (DSSN) model is a qualitative model that focuses on efficient implementation by digital arithmetic circuits. We expanded the DSSN model and found appropriate parameter sets with which it reproduces the dynamical behaviors of the ionic-conductance models of four classes of cortical and thalamic neurons. We first developed a four-variable model by reducing the number of variables in the ionic-conductance models and elucidated its mathematical structures using bifurcation analysis. Then, expanded DSSN models were constructed that reproduce these mathematical structures and capture the characteristic behavior of each neuron class. We confirmed that statistics of the neuronal spike sequences are similar in the DSSN and the ionic conductance models. Computational cost of the DSSN model is larger than that of the recent sophisticated Integrate-and-Fire-based models, but smaller than the ionic-conductance models. This model is intended to provide another meeting point for above trade-off that satisfies the demand for large-scale neuronal network simulation with closer-to-biology models. PMID- 27242396 TI - Processing Complex Sounds Passing through the Rostral Brainstem: The New Early Filter Model. AB - The rostral brainstem receives both "bottom-up" input from the ascending auditory system and "top-down" descending corticofugal connections. Speech information passing through the inferior colliculus of elderly listeners reflects the periodicity envelope of a speech syllable. This information arguably also reflects a composite of temporal-fine-structure (TFS) information from the higher frequency vowel harmonics of that repeated syllable. The amplitude of those higher frequency harmonics, bearing even higher frequency TFS information, correlates positively with the word recognition ability of elderly listeners under reverberatory conditions. Also relevant is that working memory capacity (WMC), which is subject to age-related decline, constrains the processing of sounds at the level of the brainstem. Turning to the effects of a visually presented sensory or memory load on auditory processes, there is a load-dependent reduction of that processing, as manifest in the auditory brainstem responses (ABR) evoked by to-be-ignored clicks. Wave V decreases in amplitude with increases in the visually presented memory load. A visually presented sensory load also produces a load-dependent reduction of a slightly different sort: The sensory load of visually presented information limits the disruptive effects of background sound upon working memory performance. A new early filter model is thus advanced whereby systems within the frontal lobe (affected by sensory or memory load) cholinergically influence top-down corticofugal connections. Those corticofugal connections constrain the processing of complex sounds such as speech at the level of the brainstem. Selective attention thereby limits the distracting effects of background sound entering the higher auditory system via the inferior colliculus. Processing TFS in the brainstem relates to perception of speech under adverse conditions. Attentional selectivity is crucial when the signal heard is degraded or masked: e.g., speech in noise, speech in reverberatory environments. The assumptions of a new early filter model are consistent with these findings: A subcortical early filter, with a predictive selectivity based on acoustical (linguistic) context and foreknowledge, is under cholinergic top-down control. A prefrontal capacity limitation constrains this top-down control as is guided by the cholinergic processing of contextual information in working memory. PMID- 27242398 TI - Neuropathological Mechanisms of Seizures in Autism Spectrum Disorder. AB - This manuscript reviews biological abnormalities shared by autism spectrum disorder (ASD) and epilepsy. Two neuropathological findings are shared by ASD and epilepsy: abnormalities in minicolumn architecture and gamma-aminobutyric acid (GABA) neurotransmission. The peripheral neuropil, which is the region that contains the inhibition circuits of the minicolumns, has been found to be decreased in the post-mortem ASD brain. ASD and epilepsy are associated with inhibitory GABA neurotransmission abnormalities including reduced GABAA and GABAB subunit expression. These abnormalities can elevate the excitation-to-inhibition balance, resulting in hyperexcitablity of the cortex and, in turn, increase the risk of seizures. Medical abnormalities associated with both epilepsy and ASD are discussed. These include specific genetic syndromes, specific metabolic disorders including disorders of energy metabolism and GABA and glutamate neurotransmission, mineral and vitamin deficiencies, heavy metal exposures and immune dysfunction. Many of these medical abnormalities can result in an elevation of the excitatory-to-inhibitory balance. Fragile X is linked to dysfunction of the mGluR5 receptor and Fragile X, Angelman and Rett syndromes are linked to a reduction in GABAA receptor expression. Defects in energy metabolism can reduce GABA interneuron function. Both pyridoxine dependent seizures and succinic semialdehyde dehydrogenase deficiency cause GABA deficiencies while urea cycle defects and phenylketonuria cause abnormalities in glutamate neurotransmission. Mineral deficiencies can cause glutamate and GABA neurotransmission abnormalities and heavy metals can cause mitochondrial dysfunction which disrupts GABA metabolism. Thus, both ASD and epilepsy are associated with similar abnormalities that may alter the excitatory-to-inhibitory balance of the cortex. These parallels may explain the high prevalence of epilepsy in ASD and the elevated prevalence of ASD features in individuals with epilepsy. PMID- 27242400 TI - Adult Olfactory Bulb Interneuron Phenotypes Identified by Targeting Embryonic and Postnatal Neural Progenitors. AB - Neurons are generated during embryonic development and in adulthood, although adult neurogenesis is restricted to two main brain regions, the hippocampus and olfactory bulb. The subventricular zone (SVZ) of the lateral ventricles generates neural stem/progenitor cells that continually provide the olfactory bulb (OB) with new granule or periglomerular neurons, cells that arrive from the SVZ via the rostral migratory stream. The continued neurogenesis and the adequate integration of these newly generated interneurons is essential to maintain homeostasis in the olfactory bulb, where the differentiation of these cells into specific neural cell types is strongly influenced by temporal cues. Therefore, identifying the critical features that control the generation of adult OB interneurons at either pre- or post-natal stages is important to understand the dynamic contribution of neural stem cells. Here, we used in utero and neonatal SVZ electroporation along with a transposase-mediated stable integration plasmid, in order to track interneurons and glial lineages in the OB. These plasmids are valuable tools to study the development of OB interneurons from embryonic and post-natal SVZ progenitors. Accordingly, we examined the location and identity of the adult progeny of embryonic and post-natally transfected progenitors by examining neurochemical markers in the adult OB. These data reveal the different cell types in the olfactory bulb that are generated in function of age and different electroporation conditions. PMID- 27242402 TI - The Temple University Hospital EEG Data Corpus. PMID- 27242403 TI - Major Superficial White Matter Abnormalities in Huntington's Disease. AB - BACKGROUND: The late myelinating superficial white matter at the juncture of the cortical gray and white matter comprising the intracortical myelin and short range association fibers has not received attention in Huntington's disease. It is an area of the brain that is late myelinating and is sensitive to both normal aging and neurodegenerative disease effects. Therefore, it may be sensitive to Huntington's disease processes. METHODS: Structural MRI data from 25 Pre symptomatic subjects, 24 Huntington's disease patients and 49 healthy controls was run through a cortical pattern-matching program. The surface corresponding to the white matter directly below the cortical gray matter was then extracted. Individual subject's Diffusion Tensor Imaging (DTI) data was aligned to their structural MRI data. Diffusivity values along the white matter surface were then sampled at each vertex point. DTI measures with high spatial resolution across the superficial white matter surface were then analyzed with the General Linear Model to test for the effects of disease. RESULTS: There was an overall increase in the axial and radial diffusivity across much of the superficial white matter (p < 0.001) in Pre-symptomatic subjects compared to controls. In Huntington's disease patients increased diffusivity covered essentially the whole brain (p < 0.001). Changes are correlated with genotype (CAG repeat number) and disease burden (p < 0.001). CONCLUSIONS: This study showed broad abnormalities in superficial white matter even before symptoms are present in Huntington's disease. Since, the superficial white matter has a unique microstructure and function these abnormalities suggest it plays an important role in the disease. PMID- 27242399 TI - The Enemy within: Innate Surveillance-Mediated Cell Death, the Common Mechanism of Neurodegenerative Disease. AB - Neurodegenerative diseases comprise an array of progressive neurological disorders all characterized by the selective death of neurons in the central nervous system. Although, rare (familial) and common (sporadic) forms can occur for the same disease, it is unclear whether this reflects several distinct pathogenic pathways or the convergence of different causes into a common form of nerve cell death. Remarkably, neurodegenerative diseases are increasingly found to be accompanied by activation of the innate immune surveillance system normally associated with pathogen recognition and response. Innate surveillance is the cell's quality control system for the purpose of detecting such danger signals and responding in an appropriate manner. Innate surveillance is an "intelligent system," in that the manner of response is relevant to the magnitude and duration of the threat. If possible, the threat is dealt with within the cell in which it is detected, by degrading the danger signal(s) and restoring homeostasis. If this is not successful then an inflammatory response is instigated that is aimed at restricting the spread of the threat by elevating degradative pathways, sensitizing neighboring cells, and recruiting specialized cell types to the site. If the danger signal persists, then the ultimate response can include not only the programmed cell death of the original cell, but the contents of this dead cell can also bring about the death of adjacent sensitized cells. These responses are clearly aimed at destroying the ability of the detected pathogen to propagate and spread. Innate surveillance comprises intracellular, extracellular, non-cell autonomous and systemic processes. Recent studies have revealed how multiple steps in these processes involve proteins that, through their mutation, have been linked to many familial forms of neurodegenerative disease. This suggests that individuals harboring these mutations may have an amplified response to innate mediated damage in neural tissues, and renders innate surveillance mediated cell death a plausible common pathogenic pathway responsible for neurodegenerative diseases, in both familial and sporadic forms. Here we have assembled evidence in favor of the hypothesis that neurodegenerative disease is the cumulative result of chronic activation of the innate surveillance pathway, triggered by endogenous or environmental danger or damage associated molecular patterns in a progressively expanding cascade of inflammation, tissue damage and cell death. PMID- 27242401 TI - Variants in Adjacent Oxytocin/Vasopressin Gene Region and Associations with ASD Diagnosis and Other Autism Related Endophenotypes. AB - BACKGROUND: There has been increasing interest in oxytocin (peptide: OT, gene: OXT) as a treatment pathway for neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). Neurodevelopmental disorders affect functional, social, and intellectual abilities. With advances in molecular biology, research has connected multiple gene regions to the clinical presentation of ASD. Studies have also shown that the neuropeptide hormones OT and arginine vasopressin (AVP) influence mammalian social and territorial behaviors and may have treatment potential for neurodevelopmental disorders. Published data examining molecular and phenotypic variation in ASD, such as cognitive abilities, are limited. Since most studies have focused on the receptors in the OT-AVP system, we investigated genetic variation within peptide genes for association with phenotypic ASD features that help identify subgroups within the spectrum. METHODS: In this study, TDT analysis was carried out utilizing FBAT in 207 probands (156 trios) and a European Ancestry (EA) subsample (108 trios).The evolutionarily related and adjacent genes of OXT and AVP were studied for associations between the tagged single nucleotide polymorphisms and ASD diagnosis, social abilities, restrictive and repetitive behaviors, and IQ for cognitive abilities. Additionally, relationships with whole blood serotonin (WB5HT) were explored because of the developmental relationships connecting plasma levels of OT and WB5HT within ASD. RESULTS: RESULTS indicate significant association between OXT rs6084258 (p = 0.001) and ASD. Associations with several endophenotypes were also noted: OXT rs6133010 was associated with IQ (full scale IQ, p = 0.008; nonverbal IQ, p = 0.010, verbal IQ, p = 0.006); and OXT rs4813625 and OXT rs877172 were associated with WB5HT levels (EA, p = 0.027 and p = 0.033, respectively). Additionally, we measured plasma OT (pOT) levels in a subsample (N = 54). RESULTS show the three polymorphisms, OXT rs6084258, OXT rs11697250, and OXT rs877172, have significant association with pOT (EA, p = 0.011, p = 0.010, and p = 0.002, respectively). CONCLUSIONS: These findings suggest that SNPs near OXT and AVP are associated with diagnosis of ASD, social behaviors, restricted and repetitive behaviors, IQ, pOT, and WB5HT. Future studies need to replicate these findings and examine gene interactions in other neurodevelopmental disorders. Mechanisms of action may influence early social and cognitive development that may or may not be limited to ASD diagnosis. PMID- 27242404 TI - Prediction of STN-DBS Electrode Implantation Track in Parkinson's Disease by Using Local Field Potentials. AB - Optimal electrophysiological placement of the DBS electrode may lead to better long term clinical outcomes. Inter-subject anatomical variability and limitations in stereotaxic neuroimaging increase the complexity of physiological mapping performed in the operating room. Microelectrode single unit neuronal recording remains the most common intraoperative mapping technique, but requires significant expertise and is fraught by potential technical difficulties including robust measurement of the signal. In contrast, local field potentials (LFPs), owing to their oscillatory and robust nature and being more correlated with the disease symptoms, can overcome these technical issues. Therefore, we hypothesized that multiple spectral features extracted from microelectrode recorded LFPs could be used to automate the identification of the optimal track and the STN localization. In this regard, we recorded LFPs from microelectrodes in three tracks from 22 patients during DBS electrode implantation surgery at different depths and aimed to predict the track selected by the neurosurgeon based on the interpretation of single unit recordings. A least mean square (LMS) algorithm was used to de-correlate LFPs in each track, in order to remove common activity between channels and increase their spatial specificity. Subband power in the beta band (11-32 Hz) and high frequency range (200-450 Hz) were extracted from the de-correlated LFP data and used as features. A linear discriminant analysis (LDA) method was applied both for the localization of the dorsal border of STN and the prediction of the optimal track. By fusing the information from these low and high frequency bands, the dorsal border of STN was localized with a root mean square (RMS) error of 1.22 mm. The prediction accuracy for the optimal track was 80%. Individual beta band (11-32 Hz) and the range of high frequency oscillations (200-450 Hz) provided prediction accuracies of 72 and 68% respectively. The best prediction result obtained with monopolar LFP data was 68%. These results establish the initial evidence that LFPs can be strategically fused with computational intelligence in the operating room for STN localization and the selection of the track for chronic DBS electrode implantation. PMID- 27242406 TI - Motor Alterations Induced by Chronic 4-Aminopyridine Infusion in the Spinal Cord In vivo: Role of Glutamate and GABA Receptors. AB - Motor neuron (MN) degeneration is the pathological hallmark of MN diseases, a group of neurodegenerative disorders clinically manifested as muscle fasciculations and hyperreflexia, followed by paralysis, respiratory failure, and death. Ample evidence supports a role of glutamate-mediated excitotoxicity in motor death. In previous work we showed that stimulation of glutamate release from nerve endings by perfusion of the K(+)-channel blocker 4-aminopyridine (4 AP) in the rat hippocampus induces seizures and neurodegeneration, and that AMPA infusion in the spinal cord produces paralysis and MN death. On these bases, in this work we have tested the effect of the chronic infusion of 4-AP in the spinal cord, using implanted osmotic minipumps, on motor activity and on MN survival, and the mechanisms underlying this effect. 4-AP produced muscle fasciculations and motor deficits assessed in two motor tests, which start 2-3 h after the implant, which ameliorated spontaneously within 6-7 days, but no neurodegeneration. These effects were prevented by both AMPA and NMDA receptors blockers. The role of GABAA receptors was also explored, and we found that chronic infusion of bicuculline induced moderate MN degeneration and enhanced the hyperexcitation produced by 4-AP. Unexpectedly, the GABAAR agonist muscimol also induced motor deficits and failed to prevent the MN death induced by AMPA. We conclude that motor alterations induced by chronic 4-AP infusion in the spinal cord in vivo is due to ionotropic glutamate receptor overactivation and that blockade of GABAergic neurotransmission induces MN death under chronic conditions. These results shed light on the role of glutamatergic and GABAergic neurotransmission in the regulation of MN excitability in the spinal cord. PMID- 27242405 TI - Effects of Aging and Adult-Onset Hearing Loss on Cortical Auditory Regions. AB - Hearing loss is a common feature in human aging. It has been argued that dysfunctions in central processing are important contributing factors to hearing loss during older age. Aging also has well documented consequences for neural structure and function, but it is not clear how these effects interact with those that arise as a consequence of hearing loss. This paper reviews the effects of aging and adult-onset hearing loss in the structure and function of cortical auditory regions. The evidence reviewed suggests that aging and hearing loss result in atrophy of cortical auditory regions and stronger engagement of networks involved in the detection of salient events, adaptive control and re allocation of attention. These cortical mechanisms are engaged during listening in effortful conditions in normal hearing individuals. Therefore, as a consequence of aging and hearing loss, all listening becomes effortful and cognitive load is constantly high, reducing the amount of available cognitive resources. This constant effortful listening and reduced cognitive spare capacity could be what accelerates cognitive decline in older adults with hearing loss. PMID- 27242408 TI - Endocannabinoid Mediates Excitatory Synaptic Function of beta-Neurexins. Commentary: beta-Neurexins Control Neural Circuits by Regulating Synaptic Endocannabinoid Signaling. PMID- 27242409 TI - Altered Brain Network in Amyotrophic Lateral Sclerosis: A Resting Graph Theory Based Network Study at Voxel-Wise Level. AB - Amyotrophic lateral sclerosis (ALS) is a rare degenerative disorder characterized by loss of upper and lower motor neurons. Neuroimaging has provided noticeable evidence that ALS is a complex disease, and shown that anatomical and functional lesions extend beyond precentral cortices and corticospinal tracts, to include the corpus callosum; frontal, sensory, and premotor cortices; thalamus; and midbrain. The aim of this study is to investigate graph theory-based functional network abnormalities at voxel-wise level in ALS patients on a whole brain scale. Forty-three ALS patients and 44 age- and sex-matched healthy volunteers were enrolled. The voxel-wise network degree centrality (DC), a commonly employed graph-based measure of network organization, was used to characterize the alteration of whole brain functional network. Compared with the controls, the ALS patients showed significant increase of DC in the left cerebellum posterior lobes, bilateral cerebellum crus, bilateral occipital poles, right orbital frontal lobe, and bilateral prefrontal lobes; significant decrease of DC in the bilateral primary motor cortex, bilateral sensory motor region, right prefrontal lobe, left bilateral precuneus, bilateral lateral temporal lobes, left cingulate cortex, and bilateral visual processing cortex. The DC's z-scores of right inferior occipital gyrus were significant negative correlated with the ALSFRS-r scores. Our findings confirm that the regions with abnormal network DC in ALS patients were located in multiple brain regions including primary motor, somatosensory and extra-motor areas, supporting the concept that ALS is a multisystem disorder. Specifically, our study found that DC in the visual areas was altered and ALS patients with higher DC in right inferior occipital gyrus have more severity of disease. The result demonstrated that the altered DC value in this region can probably be used to assess severity of ALS. PMID- 27242410 TI - A Model of Synaptic Reconsolidation. AB - Reconsolidation of memories has mostly been studied at the behavioral and molecular level. Here, we put forward a simple extension of existing computational models of synaptic consolidation to capture hippocampal slice experiments that have been interpreted as reconsolidation at the synaptic level. The model implements reconsolidation through stabilization of consolidated synapses by stabilizing entities combined with an activity-dependent reservoir of stabilizing entities that are immune to protein synthesis inhibition (PSI). We derive a reduced version of our model to explore the conditions under which synaptic reconsolidation does or does not occur, often referred to as the boundary conditions of reconsolidation. We find that our computational model of synaptic reconsolidation displays complex boundary conditions. Our results suggest that a limited resource of hypothetical stabilizing molecules or complexes, which may be implemented by protein phosphorylation or different receptor subtypes, can underlie the phenomenon of synaptic reconsolidation. PMID- 27242407 TI - From Linkage Studies to Epigenetics: What We Know and What We Need to Know in the Neurobiology of Schizophrenia. AB - Schizophrenia is a complex psychiatric disorder characterized by the presence of positive, negative, and cognitive symptoms that lacks a unifying neuropathology. In the present paper, we will review the current understanding of molecular dysregulation in schizophrenia, including genetic and epigenetic studies. In relation to the latter, basic research suggests that normal cognition is regulated by epigenetic mechanisms and its dysfunction occurs upon epigenetic misregulation, providing new insights into missing heritability of complex psychiatric diseases, referring to the discrepancy between epidemiological heritability and the proportion of phenotypic variation explained by DNA sequence difference. In schizophrenia the absence of consistently replicated genetic effects together with evidence for lasting changes in gene expression after environmental exposures suggest a role of epigenetic mechanisms. In this review we will focus on epigenetic modifications as a key mechanism through which environmental factors interact with individual's genetic constitution to affect risk of psychotic conditions throughout life. PMID- 27242411 TI - Altered Morphologies and Functions of the Olfactory Bulb and Hippocampus Induced by miR-30c. AB - Adult neurogenesis is considered to contribute to a certain degree of plasticity for the brain. However, the effects of adult-born neurons on the brain are still largely unknown. Here, we specifically altered the expression of miR-30c in the subventricular zone (SVZ) and dentate gyrus (DG) by stereotaxic injection with their respective up- and down-regulated lentiviruses. Results showed an increased level of miR-30c enhanced adult neurogenesis by prompting cell-cycles of stem cells, whereas down-regulated miR-30c led to the opposite results. When these effects of miR-30c lasted for 3 months, we detected significant morphological changes in the olfactory bulb (OB) and lineage alteration in the hippocampus. Tests of olfactory sensitivity and associative and spatial memory showed that a certain amount of adult-born neurons are essential for the normal functions of the OB and hippocampus, but there also exist redundant newborn neurons that do not further improve the functioning of these areas. Our study revealed the interactions between miRNA, adult neurogenesis, brain morphology and function, and this provides a novel insight into understanding the role of newborn neurons in the adult brain. PMID- 27242412 TI - An Event-Based Solution to the Perspective-n-Point Problem. AB - The goal of the Perspective-n-Point problem (PnP) is to find the relative pose between an object and a camera from a set of n pairings between 3D points and their corresponding 2D projections on the focal plane. Current state of the art solutions, designed to operate on images, rely on computationally expensive minimization techniques. For the first time, this work introduces an event-based PnP algorithm designed to work on the output of a neuromorphic event-based vision sensor. The problem is formulated here as a least-squares minimization problem, where the error function is updated with every incoming event. The optimal translation is then computed in closed form, while the desired rotation is given by the evolution of a virtual mechanical system whose energy is proven to be equal to the error function. This allows for a simple yet robust solution of the problem, showing how event-based vision can simplify computer vision tasks. The approach takes full advantage of the high temporal resolution of the sensor, as the estimated pose is incrementally updated with every incoming event. Two approaches are proposed: the Full and the Efficient methods. These two methods are compared against a state of the art PnP algorithm both on synthetic and on real data, producing similar accuracy in addition of being faster. PMID- 27242413 TI - Literature Review on Needs of Upper Limb Prosthesis Users. AB - The loss of one hand can significantly affect the level of autonomy and the capability of performing daily living, working and social activities. The current prosthetic solutions contribute in a poor way to overcome these problems due to limitations in the interfaces adopted for controlling the prosthesis and to the lack of force or tactile feedback, thus limiting hand grasp capabilities. This paper presents a literature review on needs analysis of upper limb prosthesis users, and points out the main critical aspects of the current prosthetic solutions, in terms of users satisfaction and activities of daily living they would like to perform with the prosthetic device. The ultimate goal is to provide design inputs in the prosthetic field and, contemporary, increase user satisfaction rates and reduce device abandonment. A list of requirements for upper limb prostheses is proposed, grounded on the performed analysis on user needs. It wants to (i) provide guidelines for improving the level of acceptability and usefulness of the prosthesis, by accounting for hand functional and technical aspects; (ii) propose a control architecture of PNS-based prosthetic systems able to satisfy the analyzed user wishes; (iii) provide hints for improving the quality of the methods (e.g., questionnaires) adopted for understanding the user satisfaction with their prostheses. PMID- 27242414 TI - Melodic Priming of Motor Sequence Performance: The Role of the Dorsal Premotor Cortex. AB - The purpose of this study was to determine whether exposure to specific auditory sequences leads to the induction of new motor memories and to investigate the role of the dorsal premotor cortex (dPMC) in this crossmodal learning process. Fifty-two young healthy non-musicians were familiarized with the sound to key press mapping on a computer keyboard and tested on their baseline motor performance. Each participant received subsequently either continuous theta burst stimulation (cTBS) or sham stimulation over the dPMC and was then asked to remember a 12-note melody without moving. For half of the participants, the contour of the melody memorized was congruent to a subsequently performed, but never practiced, finger movement sequence (Congruent group). For the other half, the melody memorized was incongruent to the subsequent finger movement sequence (Incongruent group). Hearing a congruent melody led to significantly faster performance of a motor sequence immediately thereafter compared to hearing an incongruent melody. In addition, cTBS speeded up motor performance in both groups, possibly by relieving motor consolidation from interference by the declarative melody memorization task. Our findings substantiate recent evidence that exposure to a movement-related tone sequence can induce specific, crossmodal encoding of a movement sequence representation. They further suggest that cTBS over the dPMC may enhance early offline procedural motor skill consolidation in cognitive states where motor consolidation would normally be disturbed by concurrent declarative memory processes. These findings may contribute to a better understanding of auditory-motor system interactions and have implications for the development of new motor rehabilitation approaches using sound and non invasive brain stimulation as neuromodulatory tools. PMID- 27242415 TI - Developing Brain Vital Signs: Initial Framework for Monitoring Brain Function Changes Over Time. AB - Clinical assessment of brain function relies heavily on indirect behavior-based tests. Unfortunately, behavior-based assessments are subjective and therefore susceptible to several confounding factors. Event-related brain potentials (ERPs), derived from electroencephalography (EEG), are often used to provide objective, physiological measures of brain function. Historically, ERPs have been characterized extensively within research settings, with limited but growing clinical applications. Over the past 20 years, we have developed clinical ERP applications for the evaluation of functional status following serious injury and/or disease. This work has identified an important gap: the need for a clinically accessible framework to evaluate ERP measures. Crucially, this enables baseline measures before brain dysfunction occurs, and might enable the routine collection of brain function metrics in the future much like blood pressure measures today. Here, we propose such a framework for extracting specific ERPs as potential "brain vital signs." This framework enabled the translation/transformation of complex ERP data into accessible metrics of brain function for wider clinical utilization. To formalize the framework, three essential ERPs were selected as initial indicators: (1) the auditory N100 (Auditory sensation); (2) the auditory oddball P300 (Basic attention); and (3) the auditory speech processing N400 (Cognitive processing). First step validation was conducted on healthy younger and older adults (age range: 22-82 years). Results confirmed specific ERPs at the individual level (86.81-98.96%), verified predictable age-related differences (P300 latency delays in older adults, p < 0.05), and demonstrated successful linear transformation into the proposed brain vital sign (BVS) framework (basic attention latency sub-component of BVS framework reflects delays in older adults, p < 0.05). The findings represent an initial critical step in developing, extracting, and characterizing ERPs as vital signs, critical for subsequent evaluation of dysfunction in conditions like concussion and/or dementia. PMID- 27242416 TI - Leaky Integrate-and-Fire Neuron Circuit Based on Floating-Gate Integrator. AB - The artificial spiking neural network (SNN) is promising and has been brought to the notice of the theoretical neuroscience and neuromorphic engineering research communities. In this light, we propose a new type of artificial spiking neuron based on leaky integrate-and-fire (LIF) behavior. A distinctive feature of the proposed FG-LIF neuron is the use of a floating-gate (FG) integrator rather than a capacitor-based one. The relaxation time of the charge on the FG relies mainly on the tunnel barrier profile, e.g., barrier height and thickness (rather than the area). This opens up the possibility of large-scale integration of neurons. The circuit simulation results offered biologically plausible spiking activity (<100 Hz) with a capacitor of merely 6 fF, which is hosted in an FG metal-oxide semiconductor field-effect transistor. The FG-LIF neuron also has the advantage of low operation power (<30 pW/spike). Finally, the proposed circuit was subject to possible types of noise, e.g., thermal noise and burst noise. The simulation results indicated remarkable distributional features of interspike intervals that are fitted to Gamma distribution functions, similar to biological neurons in the neocortex. PMID- 27242417 TI - Commentary: Oxygen regulation of breathing through an olfactory receptor activated by lactate. PMID- 27242418 TI - Editorial: Synaptic Plasticity for Neuromorphic Systems. PMID- 27242419 TI - Commentary: Visual Fixation in Human Newborns Correlates with Extensive White Matter Networks and Predicts Long-Term Neurocognitive Development. PMID- 27242420 TI - Modulation of Auditory Spatial Attention by Angry Prosody: An fMRI Auditory Dot Probe Study. AB - Emotional stimuli have been shown to modulate attentional orienting through signals sent by subcortical brain regions that modulate visual perception at early stages of processing. Fewer studies, however, have investigated a similar effect of emotional stimuli on attentional orienting in the auditory domain together with an investigation of brain regions underlying such attentional modulation, which is the general aim of the present study. Therefore, we used an original auditory dot-probe paradigm involving simultaneously presented neutral and angry non-speech vocal utterances lateralized to either the left or the right auditory space, immediately followed by a short and lateralized single sine wave tone presented in the same (valid trial) or in the opposite space as the preceding angry voice (invalid trial). Behavioral results showed an expected facilitation effect for target detection during valid trials while functional data showed greater activation in the middle and posterior superior temporal sulci (STS) and in the medial frontal cortex for valid vs. invalid trials. The use of reaction time facilitation [absolute value of the Z-score of valid (invalid+neutral)] as a group covariate extended enhanced activity in the amygdalae, auditory thalamus, and visual cortex. Taken together, our results suggest the involvement of a large and distributed network of regions among which the STS, thalamus, and amygdala are crucial for the decoding of angry prosody, as well as for orienting and maintaining attention within an auditory space that was previously primed by a vocal emotional event. PMID- 27242421 TI - Cell-Type Dependent Effect of Surface-Patterned Microdot Arrays on Neuronal Growth. AB - Surface micropatterns have been widely used as chemical cues to control the microenvironment of cultured neurons, particularly for neurobiological assays and neurochip designs. However, the cell-type dependency on the interactions between neurons and underlying micropatterns has been rarely investigated despite the inherent differences in the morphology of neuronal types. In this study, we used surface-printed microdot arrays to investigate the effect of the same micropatterns on the growth of mouse spinal interneuron, mouse hippocampal neurons, and rat hippocampal neurons. While mouse hippocampal neurons showed no significantly different growth on control and patterned substrates, we found the microdot arrays had different effects on early neuronal growth depending on the cell type; spinal interneurons tended to grow faster in length, whereas hippocampal neurons tended to form more axon collateral branches in response to the microdot arrays. Although there was a similar trend in the neurite length and branch number of both neurons changed across the microdot arrays with the expanded range of size and spacing, the dominant responses of each neuron, neurite elongation of mouse spinal interneurons and branching augmentation of rat hippocampal neurons were still preserved. Therefore, our results demonstrate that the same design of micropatterns could cause different neuronal growth results, raising an intriguing issue of considering cell types in neural interface designs. PMID- 27242422 TI - Prenatal and Newborn Immunoglobulin Levels from Mother-Child Pairs and Risk of Autism Spectrum Disorders. AB - BACKGROUND: An etiological role for immune factors operating during early brain development in children with autism spectrum disorders (ASD) has not yet been established. A major obstacle has been the lack of early biologic specimens that can be linked to later diagnosis. In a prior study, we found lower risk of ASD associated with higher levels of maternally-derived total IgG and Toxoplasmosis gondii (Toxo) IgG in newborn blood spot specimens from children later diagnosed with ASD compared to population controls. METHODS: We obtained maternal mid gestational serum specimens and newborn screening blood spots from the California Genetics Disease Screening Program (GDSP) for linked mother-baby pairs for 84 children with ASD and 49 children with developmental delay but not ASD (DD) identified from California Department of Developmental Services records and for 159 population controls sampled from birth certificates.Immunoglobulin levels in maternal and newborn specimens were measured by solid phase immunoassays and analyzed in logistic regression models for total IgG, total IgM, and Toxo IgG, and, for maternal specimens only, Toxo IgM. Correlations between maternal and newborn ranked values were evaluated. RESULTS: In both maternal and newborn specimens, we found significantly lower risk of ASD associated with higher levels of Toxo IgG. In addition, point estimates for all comparisons were < 1.0 suggesting an overall pattern of lower immunoglobulin levels associated with higher ASD risk but most did not reach statistical significance. We did not find differences in maternal or newborn specimens comparing children with DD to controls. DISCUSSION: These results are consistent with evidence from our prior study and other published reports indicating that immune factors during early neurodevelopment may be etiologically relevant to ASD. Lowered immunoglobulin levels may represent suboptimal function of the maternal immune system or reduced maternal exposure to common infectious agents. CONCLUSION: Patterns seen in these selected immunoglobulins may provide clues to mechanisms of early abnormalities in neurodevelopment contributing to ASD. We recommend further study of immunoglobulin profiles in larger samples of linked mother-baby pairs to evaluate possible etiologic relevance. PMID- 27242423 TI - Parcellation of the Healthy Neonatal Brain into 107 Regions Using Atlas Propagation through Intermediate Time Points in Childhood. AB - Neuroimage analysis pipelines rely on parcellated atlases generated from healthy individuals to provide anatomic context to structural and diffusion MRI data. Atlases constructed using adult data introduce bias into studies of early brain development. We aimed to create a neonatal brain atlas of healthy subjects that can be applied to multi-modal MRI data. Structural and diffusion 3T MRI scans were acquired soon after birth from 33 typically developing neonates born at term (mean postmenstrual age at birth 39(+5) weeks, range 37(+2)-41(+6)). An adult brain atlas (SRI24/TZO) was propagated to the neonatal data using temporal registration via childhood templates with dense temporal samples (NIH Pediatric Database), with the final atlas (Edinburgh Neonatal Atlas, ENA33) constructed using the Symmetric Group Normalization (SyGN) method. After this step, the computed final transformations were applied to T2-weighted data, and fractional anisotropy, mean diffusivity, and tissue segmentations to provide a multi-modal atlas with 107 anatomical regions; a symmetric version was also created to facilitate studies of laterality. Volumes of each region of interest were measured to provide reference data from normal subjects. Because this atlas is generated from step-wise propagation of adult labels through intermediate time points in childhood, it may serve as a useful starting point for modeling brain growth during development. PMID- 27242424 TI - Working Memory Load Affects Processing Time in Spoken Word Recognition: Evidence from Eye-Movements. AB - In daily life, speech perception is usually accompanied by other tasks that tap into working memory capacity. However, the role of working memory on speech processing is not clear. The goal of this study was to examine how working memory load affects the timeline for spoken word recognition in ideal listening conditions. We used the "visual world" eye-tracking paradigm. The task consisted of spoken instructions referring to one of four objects depicted on a computer monitor (e.g., "point at the candle"). Half of the trials presented a phonological competitor to the target word that either overlapped in the initial syllable (onset) or at the last syllable (offset). Eye movements captured listeners' ability to differentiate the target noun from its depicted phonological competitor (e.g., candy or sandal). We manipulated working memory load by using a digit pre-load task, where participants had to retain either one (low-load) or four (high-load) spoken digits for the duration of a spoken word recognition trial. The data show that the high-load condition delayed real-time target discrimination. Specifically, a four-digit load was sufficient to delay the point of discrimination between the spoken target word and its phonological competitor. Our results emphasize the important role working memory plays in speech perception, even when performed by young adults in ideal listening conditions. PMID- 27242425 TI - Activin Signaling in the Pathogenesis and Therapy of Neuropsychiatric Diseases. AB - Activins are members of the transforming growth factor beta (TGFbeta) family and serve as multifunctional regulatory proteins in many tissues and organs. In the brain, activin A, which is formed by two disulfide-linked betaA subunits, is recognized as the predominant player in activin signaling. Over the last years, considerable progress has been made in elucidating novel and unexpected functions of activin in the normal and diseased brain and in deciphering the underlying molecular mechanisms. Initially identified as a neurotrophic and protective factor during development and in several forms of acute injury, the scope of effects of activin A in the adult central nervous system (CNS) has been considerably broadened by now. Here, we will highlight recent findings that bear significance for a better understanding of the pathogenesis of various neuropsychiatric diseases and might hold promise for novel therapeutic strategies. While the basal level of activin A in the adult brain is low, significant short-term up-regulation occurs in response to increased neuronal activity. In fact, brief exposure to an enriched environment (EE) is already sufficient to considerably strengthen activin signaling. Enhancement of this pathway tunes the performance of glutamatergic and GABAergic synapses in a fashion that impacts on cognitive functions and affective behavior, counteracts death-inducing signals through extrasynaptic NMDA receptors (NMDARs), and stimulates adult neurogenesis in the hippocampus. We will discuss how impaired activin signaling is involved in anxiety disorders, depression, drug dependence, and neurodegenerative diseases such as Alzheimer's and Parkinson's, and how reinforcement of activin signaling might be exploited for therapeutic interventions. PMID- 27242427 TI - Retraction: Molecular structure and target recognition of neuronal calcium sensor proteins. AB - [This retracts the article on p. 10 in vol. 5, PMID: 22363261.]. PMID- 27242426 TI - LRRK2 Regulates Voltage-Gated Calcium Channel Function. AB - Voltage-gated Ca(2+) (CaV) channels enable Ca(2+) influx in response to membrane depolarization. CaV2.1 channels are localized to the presynaptic membrane of many types of neurons where they are involved in triggering neurotransmitter release. Several signaling proteins have been identified as important CaV2.1 regulators including protein kinases, G-proteins and Ca(2+) binding proteins. Recently, we discovered that leucine rich repeat kinase 2 (LRRK2), a protein associated with inherited Parkinson's disease, interacts with specific synaptic proteins and influences synaptic transmission. Since synaptic proteins functionally interact with CaV2.1 channels and synaptic transmission is triggered by Ca(2+) entry via CaV2.1, we investigated whether LRRK2 could impact CaV2.1 channel function. CaV2.1 channel properties were measured using whole cell patch clamp electrophysiology in HEK293 cells transfected with CaV2.1 subunits and various LRRK2 constructs. Our results demonstrate that both wild type (wt) LRRK2 and the G2019S LRRK2 mutant caused a significant increase in whole cell Ca(2+) current density compared to cells expressing only the CaV2.1 channel complex. In addition, LRRK2 expression caused a significant hyperpolarizing shift in voltage dependent activation while having no significant effect on inactivation properties. These functional changes in CaV2.1 activity are likely due to a direct action of LRRK2 as we detected a physical interaction between LRRK2 and the beta3 CaV channel subunit via coimmunoprecipitation. Furthermore, effects on CaV2.1 channel function are dependent on LRRK2 kinase activity as these could be reversed via treatment with a LRRK2 inhibitor. Interestingly, LRRK2 also augmented endogenous voltage-gated Ca(2+) channel function in PC12 cells suggesting other CaV channels could also be regulated by LRRK2. Overall, our findings support a novel physiological role for LRRK2 in regulating CaV2.1 function that could have implications for how mutations in LRRK2 contribute to Parkinson's disease pathophysiology. PMID- 27242428 TI - Corrigendum: Morphogenetic and Histogenetic Roles of the Temporal-Spatial Organization of Cell Proliferation in the Vertebrate Corticogenesis as Revealed by Inter-specific Analyses of the Optic Tectum Cortex Development. AB - [This corrects the article on p. 67 in vol. 10, PMID: 27013978.]. PMID- 27242429 TI - Brain State-Dependent Closed-Loop Modulation of Paired Associative Stimulation Controlled by Sensorimotor Desynchronization. AB - BACKGROUND: Pairing peripheral electrical stimulation (ES) and transcranial magnetic stimulation (TMS) increases corticospinal excitability when applied with a specific temporal pattern. When the two stimulation techniques are applied separately, motor imagery (MI)-related oscillatory modulation amplifies both ES related cortical effects-sensorimotor event-related desynchronization (ERD), and TMS-induced peripheral responses-motor-evoked potentials (MEP). However, the influence of brain self-regulation on the associative pairing of these stimulation techniques is still unclear. OBJECTIVE: The aim of this pilot study was to investigate the effects of MI-related ERD during associative ES and TMS on subsequent corticospinal excitability. METHOD: The paired application of functional electrical stimulation (FES) of the extensor digitorum communis (EDC) muscle and subsequent single-pulse TMS (110% resting motor threshold (RMT)) of the contralateral primary motor cortex (M1) was controlled by beta-band (16-22 Hz) ERD during MI of finger extension and applied within a brain-machine interface environment in six healthy subjects. Neural correlates were probed by acquiring the stimulus-response curve (SRC) of both MEP peak-to-peak amplitude and area under the curve (AUC) before and after the intervention. RESULT: The application of approximately 150 pairs of associative FES and TMS resulted in a significant increase of MEP amplitudes and AUC, indicating that the induced increase of corticospinal excitability was mediated by the recruitment of additional neuronal pools. MEP increases were brain state-dependent and correlated with beta-band ERD, but not with the background EDC muscle activity; this finding was independent of the FES intensity applied. CONCLUSION: These results could be relevant for developing closed-loop therapeutic approaches such as the application of brain state-dependent, paired associative stimulation (PAS) in the context of neurorehabilitation. PMID- 27242430 TI - Soluble RAGE Treatment Delays Progression of Amyotrophic Lateral Sclerosis in SOD1 Mice. AB - The etiology of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder characterized by progressive muscle weakness and spasticity, remains largely unknown. Approximately 5-10% of cases are familial, and of those, 15-20% are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Mutations of the SOD1 gene interrupt cellular homeostasis and contribute to cellular toxicity evoked by the presence of altered SOD1, along with other toxic species, such as advanced glycation end products (AGEs). AGEs trigger activation of their chief cell surface receptor, RAGE (receptor for advanced glycation end products), and induce RAGE-dependent cellular stress and inflammation in neurons, thereby affecting their function and leading to apoptosis. Here, we show for the first time that the expression of RAGE is higher in the SOD1 transgenic mouse model of ALS vs. wild-type mouse spinal cord. We tested whether pharmacological blockade of RAGE may delay the onset and progression of disease in this mouse model. Our findings reveal that treatment of SOD1 transgenic mice with soluble RAGE (sRAGE), a natural competitor of RAGE that sequesters RAGE ligands and blocks their interaction with cell surface RAGE, significantly delays the progression of ALS and prolongs life span compared to vehicle treatment. We demonstrate that in sRAGE-treated SOD1 transgenic animals at the final stage of the disease, a significantly higher number of neurons and lower number of astrocytes is detectable in the spinal cord. We conclude that RAGE antagonism may provide a novel therapeutic strategy for ALS intervention. PMID- 27242431 TI - NSC-34 Motor Neuron-Like Cells Are Unsuitable as Experimental Model for Glutamate Mediated Excitotoxicity. AB - Glutamate-induced excitotoxicity is a major contributor to motor neuron degeneration in the pathogenesis of amyotrophic lateral sclerosis (ALS). The spinal cord * Neuroblastoma hybrid cell line (NSC-34) is often used as a bona fide cellular model to investigate the physiopathological mechanisms of ALS. However, the physiological response of NSC-34 to glutamate remains insufficiently described. In this study, we evaluated the relevance of differentiated NSC-34 (NSC-34D) as an in vitro model for glutamate excitotoxicity studies. NSC-34D showed morphological and physiological properties of motor neuron-like cells and expressed glutamate receptor subunits GluA1-4, GluN1 and GluN2A/D. Despite these diverse characteristics, no specific effect of glutamate was observed on cultured NSC-34D survival and morphology, in contrast to what has been described in primary culture of motor neurons (MN). Moreover, a small non sustained increase in the concentration of intracellular calcium was observed in NSC-34D after exposure to glutamate compared to primary MN. Our findings, together with the inability to obtain cultures containing only differentiated cells, suggest that the motor neuron-like NSC-34 cell line is not a suitable in vitro model to study glutamate-induced excitotoxicity. We suggest that the use of primary cultures of MN is more suitable than NSC-34 cell line to explore the pathogenesis of glutamate-mediated excitotoxicity at the cellular level in ALS and other motor neuron diseases. PMID- 27242433 TI - Immature Responses to GABA in Fragile X Neurons Derived from Human Embryonic Stem Cells. AB - Fragile X Syndrome (FXS) is the most common form of inherited cognitive disability. However, functional deficiencies in FX neurons have been described so far almost exclusively in animal models. In a recent study we found several functional deficits in FX neurons differentiated in-vitro from human embryonic stem cells (hESCs), including their inability to fire repetitive action potentials, and their lack of synaptic activity. Here, we investigated the responses of such neurons to pulse application of the neurotransmitter GABA. We found two distinct types of responses to GABA and sensitivity to the GABA-A receptor antagonist bicuculline; type 1 (mature) characterized by non desensitized responses to GABA as well as a high sensitivity to bicuculline, and type 2 (immature) which are desensitized to GABA and insensitive to bicuculline. Type 1 responses were age-dependent and dominant in mature WT neurons. In contrast, FX neurons expressed primarily type 2 phenotype. Expression analysis of GABA-A receptor subunits demonstrated that this bias in human FX neurons was associated with a significant alteration in the expression pattern of the GABA-A receptor subunits alpha2 and beta2. Our results indicate that FMRP may play a role in the development of the GABAergic synapse during neurogenesis. This is the first demonstration of the lack of a mature response to GABA in human FX neurons and may explain the inappropriate synaptic functions in FXS. PMID- 27242432 TI - Astrocytes in Oligodendrocyte Lineage Development and White Matter Pathology. AB - White matter is primarily composed of myelin and myelinated axons. Structural and functional completeness of myelin is critical for the reliable and efficient transmission of information. White matter injury has been associated with the development of many demyelinating diseases. Despite a variety of scientific advances aimed at promoting re-myelination, their benefit has proven at best to be marginal. Research suggests that the failure of the re-myelination process may be the result of an unfavorable microenvironment. Astrocytes, are the most ample and diverse type of glial cells in central nervous system (CNS) which display multiple functions for the cells of the oligodendrocytes lineage. As such, much attention has recently been drawn to astrocyte function in terms of white matter myelin repair. They are different in white matter from those in gray matter in specific regards to development, morphology, location, protein expression and other supportive functions. During the process of demyelination and re myelination, the functions of astrocytes are dynamic in that they are able to change functions in accordance to different time points, triggers or reactive pathways resulting in vastly different biologic effects. They have pivotal effects on oligodendrocytes and other cell types in the oligodendrocyte lineage by serving as an energy supplier, a participant of immunological and inflammatory functions, a source of trophic factors and iron and a sustainer of homeostasis. Astrocytic impairment has been shown to be directly linked to the development of neuromyelities optica (NMO). In addition, astroctyes have also been implicated in other white matter conditions such as psychiatric disorders and neurodegenerative diseases such as Alzheimer's disease (AD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Inhibiting specifically detrimental signaling pathways in astrocytes while preserving their beneficial functions may be a promising approach for remyelination strategies. As such, the ability to manipulate astrocyte function represents a novel therapeutic approach that can repair the damaged myelin that is known to occur in a variety of white matter related disorders. PMID- 27242435 TI - Dynamics of Mitochondrial Transport in Axons. AB - The polarized structure and long neurites of neurons pose a unique challenge for proper mitochondrial distribution. It is widely accepted that mitochondria move from the cell body to axon ends and vice versa; however, we have found that mitochondria originating from the axon ends moving in the retrograde direction never reach to the cell body, and only a limited number of mitochondria moving in the anterograde direction from the cell body arrive at the axon ends of mouse hippocampal neurons. Furthermore, we have derived a mathematical formula using the Fokker-Planck equation to characterize features of mitochondrial transport, and the equation could determine altered mitochondrial transport in axons overexpressing parkin. Our analysis will provide new insights into the dynamics of mitochondrial transport in axons of normal and unhealthy neurons. PMID- 27242434 TI - New Insights into Reelin-Mediated Signaling Pathways. AB - Reelin, a multifunctional extracellular protein that is important for mammalian brain development and function, is secreted by different cell types in the prenatal or postnatal brain. The spatiotemporal regulation of Reelin expression and distribution during development relates to its multifaceted function in the brain. Prenatally Reelin controls neuronal radial migration and proper positioning in cortical layers, whereas postnatally Reelin promotes neuronal maturation, synaptic formation and plasticity. The molecular mechanisms underlying the distinct biological functions of Reelin during and after brain development involve unique and overlapping signaling pathways that are activated following Reelin binding to its cell surface receptors. Distinct Reelin ligand isoforms, such as the full-length protein or fragments generated by proteolytic cleavage differentially affect the activity of downstream signaling pathways. In this review, we discuss recent advances in our understanding of the signaling transduction pathways activated by Reelin that regulate different aspects of brain development and function. A core signaling machinery, including ApoER2/VLDLR receptors, Src/Fyn kinases, and the adaptor protein Dab1, participates in all known aspects of Reelin biology. However, distinct downstream mechanisms, such as the Crk/Rap1 pathway and cell adhesion molecules, play crucial roles in the control of neuronal migration, whereas the PI3K/Akt/mTOR pathway appears to be more important for dendrite and spine development. Finally, the NMDA receptor (NMDAR) and an unidentified receptor contribute to the activation of the MEK/Erk1/2 pathway leading to the upregulation of genes involved in synaptic plasticity and learning. This knowledge may provide new insight into neurodevelopmental or neurodegenerative disorders that are associated with Reelin dysfunction. PMID- 27242436 TI - The Differential DRP1 Phosphorylation and Mitochondrial Dynamics in the Regional Specific Astroglial Death Induced by Status Epilepticus. AB - The response and susceptibility to astroglial degenerations are relevant to the distinctive properties of astrocytes in a hemodynamic-independent manner following status epilepticus (SE). Since impaired mitochondrial fission plays an important role in mitosis, apoptosis and programmed necrosis, we investigated whether the unique pattern of mitochondrial dynamics is involved in the characteristics of astroglial death induced by SE. In the present study, SE induced astroglial apoptosis in the molecular layer of the dentate gyrus, accompanied by decreased mitochondrial length. In contrast, clasmatodendritic (autophagic) astrocytes in the CA1 region showed mitochondrial elongation induced by SE. Mdivi-1 (an inhibitor of mitochondrial fission) effectively attenuated astroglial apoptosis, but WY14643 (an enhancer of mitochondrial fission) aggravated it. In addition, Mdivi-1 accelerated clasmatodendritic changes in astrocytes. These regional specific mitochondrial dynamics in astrocytes were closely correlated with dynamin-related protein 1 (DRP1; a mitochondrial fission protein) phosphorylation, not optic atrophy 1 (OPA1; a mitochondrial fusion protein) expression. To the best of our knowledge, the present data demonstrate for the first time the novel role of DRP1-mediated mitochondrial fission in astroglial loss. Thus, the present findings suggest that the differential astroglial mitochondrial dynamics may participate in the distinct characteristics of astroglial death induced by SE. PMID- 27242437 TI - Astrocyte-Secreted Factors Selectively Alter Neural Stem and Progenitor Cell Proliferation in the Fragile X Mouse. AB - An increasing body of evidence indicates that astrocytes contribute to the governance and fine tuning of stem and progenitor cell production during brain development. The effect of astrocyte function in cell production in neurodevelopmental disorders is unknown. We used the Neural Colony Forming Cell assay to determine the effect of astrocyte conditioned media (ACM) on the generation of neurospheres originating from either progenitor cells or functional stem cells in the knock out (KO) Fragile X mouse model. ACM from both normal and Fmr1-KO mice generated higher percentages of smaller neurospheres indicative of restricted proliferation of the progenitor cell population in Fmr1-KO brains. Wild type (WT) neurospheres, but not KO neurospheres, showed enhanced responses to ACM from the Fmr1-KO mice. In particular, Fmr1-KO ACM increased the percentage of large neurospheres generated, representative of spheres produced from neural stem cells. We also used 2D DIGE to initiate identification of the astrocyte secreted proteins with differential expression between Fmr1-KO and WT cortices and hippocampi. The results further support the critical role of astrocytes in governing neural cell production in brain development and point to significant alterations in neural cell proliferation due to astrocyte secreted factors from the Fragile X brain. HIGHLIGHTS: * We studied the proliferation of neural stem and progenitor cells in Fragile X.* We examined the role of astrocyte-secreted factors in neural precursor cell biology.* Astrocyte-secreted factors with differential expression in Fragile X identified. PMID- 27242438 TI - Intersubunit Concerted Cooperative and cis-Type Mechanisms Modulate Allosteric Gating in Two-Pore-Domain Potassium Channel TREK-2. AB - In response to diverse stimuli, two-pore-domain potassium channel TREK-2 regulates cellular excitability, and hence plays a key role in mediating neuropathic pain, mood disorders and ischemia through. Although more and more input modalities are found to achieve their modulations via acting on the channel, the potential role of subunit interaction in these modulations remains to be explored. In the current study, the deletion (lack of proximal C-terminus, DeltapCt) or point mutation (G312A) was introduced into TREK-2 subunits to limit K(+) conductance and used to report subunit stoichiometry. The constructs were then combined with wild type (WT) subunit to produce concatenated dimers with defined composition, and the gating kinetics of these channels to 2 Aminoethoxydiphenyl borate (2-APB) and extracellular pH (pHo) were characterized. Our results show that combination of WT and DeltapCt/G312A subunits reserves similar gating properties to that of WT dimmers, suggesting that the WT subunit exerts dominant and positive effects on the mutated one, and thus the two subunits controls channel gating via a concerted cooperative manner. Further introduction of DeltapCt into the latter subunit of heterodimeric channel G312A WT or G312A-G312A attenuated their sensitivity to 2-APB and pHo alkalization, implicating that these signals were transduced by a cis-type mechanism. Together, our findings elucidate the mechanisms for how the two subunits control the pore gating of TREK-2, in which both intersubunit concerted cooperative and cis-type manners modulate the allosteric regulations induced by 2-APB and pHo alkalization. PMID- 27242439 TI - Low-Dose Endothelial-Monocyte-Activating Polypeptide-II Induced Autophagy by Down Regulating miR-20a in U-87 and U-251 Glioma Cells. AB - Preliminary studies have shown that endothelial-monocyte-activating polypeptide II (EMAP-II) induces autophagy and inhibits the viability of glioma cells via an unknown molecular mechanism. This study explored the possible mechanisms associated with EMAP-II-induced autophagy in glioma cells by regulation of the expression of microRNA-20a (miR-20a). EMAP-II effectively inhibited the viability, migration and invasion of human U-87 and U-251 glioma cells. EMAP-II also up-regulated the expression level of autophagy biomarker microtubule associated protein one light chain 3 (LC3)-II/I, autophagy related gene ATG7 and ATG5, but down-regulated autophagy substrate P62/SQSTM1 protein expression. The expression levels of miR-20a decreased significantly after U-87 and U-251 cells were treated with EMAP-II. MiR-20a overexpression partly reversed the EMAP-II induced up-regulation of LC3-II/I and down-regulation of P62/SQSTM1. MiR-20a had a negative regulatory effect on the expression of the proteins ATG7 and ATG5; which were also targets of miR-20a, as detected by a dual-luciferase reporter assay. In addition, both EMAP-II and miR-20a inhibition significantly reduced the viability, migration and invasion of U-87 and U-251 cells, and their combination showed a synergistic effect. Furthermore, nude mice carrying silencing-expressed miR-20a combined with EMAP-II treatment produced the smallest tumors and the highest survival. In summary, low-dose EMAP-II increased expression levels of ATG5 and ATG7 via down-regulation of the expression of miR-20a. This activated the autophagy pathway, thereby significantly inhibiting the viability, migration and invasion of U-87 and U-251 glioma cells. The combined treatment of EMAP-II with a miR-20a inhibitor showed a synergistic effect against glioma. PMID- 27242440 TI - Central Role of Maladapted Astrocytic Plasticity in Ischemic Brain Edema Formation. AB - Brain edema formation and the ensuing brain damages are the major cause of high mortality and long term disability following the occurrence of ischemic stroke. In this process, oxygen and glucose deprivation and the resulting reperfusion injury play primary roles. In response to the ischemic insult, the neurovascular unit experiences both intracellular and extracellular edemas, associated with maladapted astrocytic plasticity. The astrocytic plasticity includes both morphological and functional plasticity. The former involves a reactive gliosis and the subsequent glial retraction. It relates to the capacity of astrocytes to buffer changes in extracellular chemical levels, particularly K(+) and glutamate, as well as the integrity of the blood-brain barrier (BBB). The latter involves the expression and activity of a series of ion and water transport proteins. These molecules are grouped together around glial fibrillary acidic protein (GFAP) and water channel protein aquaporin 4 (AQP4) to form functional networks, regulate hydromineral balance across cell membranes and maintain the integrity of the BBB. Intense ischemic challenges can disrupt these capacities of astrocytes and result in their maladaptation. The maladapted astrocytic plasticity in ischemic stroke cannot only disrupt the hydromineral homeostasis across astrocyte membrane and the BBB, but also leads to disorders of the whole neurovascular unit. This review focuses on how the maladapted astrocytic plasticity in ischemic stroke plays the central role in the brain edema formation. PMID- 27242441 TI - Anti-GAD65 Containing Cerebrospinal Fluid Does not Alter GABAergic Transmission. AB - Glutamic acid decarboxylase of 65 kDa (GAD65) antibodies have been reported in a variety of neurological disorders such as stiff-person syndrome (SPS), sporadic ataxia and some cases of epilepsy. Since the target is believed to be the cytoplasmic enzyme GAD65, the key enzyme of gamma-aminobutyric acid (GABA) synthesis, the pathophysiological role of these antibodies is poorly understood. Here, we stereotactically injected human cerebrospinal fluid (CSF) containing GAD65-antibodies into the hippocampus of rats in vivo and then prepared hippocampal slices 1-2 days after post-operative recovery. We characterized both evoked and spontaneous GABAergic transmission in vitro using sharp microelectrode and patch-clamp recordings in CA1 neurons. Intracellular recordings with sharp microelectrodes from CA1 neurons showed that evoked GABAAR- or GABABR-mediated inhibitory postsynaptic potentials (IPSP) remained unaltered in anti-GAD65 tissue. These results were confirmed with patch-clamp recordings showing no difference in evoked gabazine-sensitive inhibitory postsynaptic currents (IPSCs). In addition, spontaneous IPSCs also showed no difference between anti-GAD65 tissue and controls with respect to the mean frequency, the mean amplitude and the sIPSC distribution. In conclusion, stereotactic injection of GAD65-antibodies into the hippocampus leaves evoked and spontaneous GABAergic synaptic transmission intact. Hence, dysfunction of the inhibitory GABAergic system does not appear to be the major mechanism of epileptogenicity in this disease. PMID- 27242442 TI - Persistent Gliosis Interferes with Neurogenesis in Organotypic Hippocampal Slice Cultures. AB - Neurogenesis in the adult hippocampus has become an intensively investigated research topic, as it is essential for proper hippocampal function and considered to bear therapeutic potential for the replacement of pathologically lost neurons. On the other hand, neurogenesis itself is frequently affected by CNS insults. To identify processes leading to the disturbance of neurogenesis, we made use of organotypic hippocampal slice cultures (OHSC), which, for unknown reasons, lose their neurogenic potential during cultivation. In the present study, we show by BrdU/Prox1 double-immunostaining that the generation of new granule cells drops by 90% during the first week of cultivation. Monitoring neurogenesis dynamically in OHSC from POMC-eGFP mice, in which immature granule cells are endogenously labeled, revealed a gradual decay of the eGFP signal, reaching 10% of initial values within 7 days of cultivation. Accordingly, reverse transcription quantitative polymerase chain reaction analysis showed the downregulation of the neurogenesis-related genes doublecortin and Hes5, a crucial target of the stem cell-maintaining Notch signaling pathway. In parallel, we demonstrate a strong and long-lasting activation of astrocytes and microglial cells, both, morphologically and on the level of gene expression. Enhancement of astroglial activation by treating OHSC with ciliary neurotrophic factor accelerated the loss of neurogenesis, whereas treatment with indomethacin or an antagonist of the purinergic P2Y12 receptor exhibited potent protective effects on the neurogenic outcome. Therefore, we conclude that OHSC rapidly lose their neurogenic capacity due to persistent inflammatory processes taking place after the slice preparation. As inflammation is also considered to affect neurogenesis in many CNS pathologies, OHSC appear as a useful tool to study this interplay and its molecular basis. Furthermore, we propose that modification of glial activation might bear the therapeutic potential of enabling neurogenesis under neuropathological conditions. PMID- 27242443 TI - ATP Released by Injured Neurons Activates Schwann Cells. AB - Injured nerve terminals of neuromuscular junctions (NMJs) can regenerate. This remarkable and complex response is governed by molecular signals that are exchanged among the cellular components of this synapse: motor axon nerve terminal (MAT), perisynaptic Schwann cells (PSCs), and muscle fiber. The nature of signals that govern MAT regeneration is ill-known. In the present study the spider toxin alpha-latrotoxin has been used as tool to investigate the mechanisms underlying peripheral neuroregeneration. Indeed this neurotoxin induces an acute, specific, localized and fully reversible damage of the presynaptic nerve terminal, and its action mimics the cascade of events that leads to nerve terminal degeneration in injured patients and in many neurodegenerative conditions. Here we provide evidence of an early release by degenerating neurons of adenosine triphosphate as alarm messenger, that contributes to the activation of a series of intracellular pathways within Schwann cells that are crucial for nerve regeneration: Ca(2+), cAMP, ERK1/2, and CREB. These results contribute to define the cross-talk taking place among degenerating nerve terminals and PSCs, involved in the functional recovery of the NMJ. PMID- 27242444 TI - Calcium Imaging of Basal Forebrain Activity during Innate and Learned Behaviors. AB - The basal forebrain (BF) plays crucial roles in arousal, attention, and memory, and its impairment is associated with a variety of cognitive deficits. The BF consists of cholinergic, GABAergic, and glutamatergic neurons. Electrical or optogenetic stimulation of BF cholinergic neurons enhances cortical processing and behavioral performance, but the natural activity of these cells during behavior is only beginning to be characterized. Even less is known about GABAergic and glutamatergic neurons. Here, we performed microendoscopic calcium imaging of BF neurons as mice engaged in spontaneous behaviors in their home cages (innate) or performed a go/no-go auditory discrimination task (learned). Cholinergic neurons were consistently excited during movement, including running and licking, but GABAergic and glutamatergic neurons exhibited diverse responses. All cell types were activated by overt punishment, either inside or outside of the discrimination task. These findings reveal functional similarities and distinctions between BF cell types during both spontaneous and task-related behaviors. PMID- 27242445 TI - Push-Pull Receptive Field Organization and Synaptic Depression: Mechanisms for Reliably Encoding Naturalistic Stimuli in V1. AB - Neurons in the primary visual cortex are known for responding vigorously but with high variability to classical stimuli such as drifting bars or gratings. By contrast, natural scenes are encoded more efficiently by sparse and temporal precise spiking responses. We used a conductance-based model of the visual system in higher mammals to investigate how two specific features of the thalamo cortical pathway, namely push-pull receptive field organization and fast synaptic depression, can contribute to this contextual reshaping of V1 responses. By comparing cortical dynamics evoked respectively by natural vs. artificial stimuli in a comprehensive parametric space analysis, we demonstrate that the reliability and sparseness of the spiking responses during natural vision is not a mere consequence of the increased bandwidth in the sensory input spectrum. Rather, it results from the combined impacts of fast synaptic depression and push-pull inhibition, the later acting for natural scenes as a form of "effective" feed forward inhibition as demonstrated in other sensory systems. Thus, the combination of feedforward-like inhibition with fast thalamo-cortical synaptic depression by simple cells receiving a direct structured input from thalamus composes a generic computational mechanism for generating a sparse and reliable encoding of natural sensory events. PMID- 27242446 TI - Glutamatergic Retinal Waves. AB - Spontaneous activity patterns propagate through many parts of the developing nervous system and shape the wiring of emerging circuits. Prior to vision, waves of activity originating in the retina propagate through the lateral geniculate nucleus (LGN) of the thalamus to primary visual cortex (V1). Retinal waves have been shown to instruct the wiring of ganglion cell axons in LGN and of thalamocortical axons in V1 via correlation-based plasticity rules. Across species, retinal waves mature in three stereotypic stages (I-III), in which distinct circuit mechanisms give rise to unique activity patterns that serve specific functions in visual system refinement. Here, I review insights into the patterns, mechanisms, and functions of stage III retinal waves, which rely on glutamatergic signaling. As glutamatergic waves spread across the retina, neighboring ganglion cells with opposite light responses (ON vs. OFF) are activated sequentially. Recent studies identified lateral excitatory networks in the inner retina that generate and propagate glutamatergic waves, and vertical inhibitory networks that desynchronize the activity of ON and OFF cells in the wavefront. Stage III wave activity patterns may help segregate axons of ON and OFF ganglion cells in the LGN, and could contribute to the emergence of orientation selectivity in V1. PMID- 27242448 TI - Reg-2, A Downstream Signaling Protein in the Ciliary Neurotrophic Factor Survival Pathway, Alleviates Experimental Autoimmune Encephalomyelitis. AB - Ciliary neurotrophic factor (CNTF), originally described as a neurocytokine that could support the survival of neurons, has been recently found to alleviate demyelination, prevent axon loss, and improve functional recovery in a rat model of acute experimental autoimmune encephalomyelitis (EAE). However, poor penetration into the brain parenchyma and unfavorable side effects limit the utility of CNTF. Here, we evaluated the therapeutic potential of a protein downstream of CNTF, regeneration gene protein 2 (Reg-2). Using multiple morphological, molecular biology, and electrophysiological methods to assess neuroinflammation, axonal loss, demyelination, and functional impairment, we observed that Reg-2 and CNTF exert similar effects in the acute phase of EAE. Both treatments attenuated axonal loss and demyelination, improved neuronal survival, and produced functional improvement. With a smaller molecular weight and improved penetration into the brain parenchyma, Reg-2 may be a useful substitute for CNTF therapy in EAE and multiple sclerosis (MS). PMID- 27242447 TI - A Lack of Correlation between Brain-Derived Neurotrophic Factor Serum Level and Verbal Memory Performance in Healthy Polish Population. AB - Brain derived neurotrophic factor (BDNF) is considered to be connected with memory and learning through the processes of long term synaptic potentiation and synaptic plasticity. The aim of the study was to examine the relationship between precursor BDNF (proBNDF) and mature BDNF (mBDNF) serum levels and performance on Rey Auditory-Verbal Learning Test (RAVLT) in 150 healthy volunteers. In addition, we have verified the relationships between serum concentration of both forms of BDNF and RAVLT with sociodemographic and lifestyle factors.We found no strong evidence for the correlation of proBDNF and mBDNF serum levels with performance on RAVLT in healthy Polish population in early and middle adulthood. We observed the mBDNF serum concentration to be higher in women compared with men. Moreover, we revealed higher mBDNF level to be connected with lower body mass index (BMI). In turn, the results of RAVLT correlated with sociodemographic and lifestyle factors, such as: age, education, gender, BMI and smoking. PMID- 27242450 TI - Verification of the Cross Immunoreactivity of A60, a Mouse Monoclonal Antibody against Neuronal Nuclear Protein. AB - A60, the mouse monoclonal antibody against the neuronal nuclear protein (NeuN), is the most widely used neuronal marker in neuroscience research and neuropathological assays. Previous studies identified fragments of A60 immunoprecipitated protein as Synapsin I (Syn I), suggesting the antibody will demonstrate cross immunoreactivity. However, the likelihood of cross reactivity has never been verified by immunohistochemical techniques. Using our established tissue processing and immunofluorescent staining protocols, we found that A60 consistently labeled mossy fiber terminals in hippocampal area CA3. These A60 positive mossy fiber terminals could also be labeled by Syn I antibody. After treating brain slices with saponin in order to better preserve various membrane and/or vesicular proteins for immunostaining, we observed that A60 could also label additional synapses in various brain areas. Therefore, we used A60 together with a rabbit monoclonal NeuN antibody to confirm the existence of this cross reactivity. We showed that the putative band positive for A60 and Syn I could not be detected by the rabbit anti-NeuN in Western blotting. As efficient as Millipore A60 to recognize neuronal nuclei, the rabbit NeuN antibody demonstrated no labeling of synaptic structures in immunofluorescent staining. The present study successfully verified the cross reactivity present in immunohistochemistry, cautioning that A60 may not be the ideal biomarker to verify neuronal identity due to its cross immunoreactivity. In contrast, the rabbit monoclonal NeuN antibody used in this study may be a better candidate to substitute for A60. PMID- 27242449 TI - New Insights in Trigeminal Anatomy: A Double Orofacial Tract for Nociceptive Input. AB - Orofacial pain in patients relies on the anatomical pathways that conduct nociceptive information, originating from the periphery towards the trigeminal sensory nucleus complex (TSNC) and finally, to the thalami and the somatosensorical cortical regions. The anatomy and function of the so-called trigeminothalamic tracts have been investigated before. In these animal-based studies from the previous century, the intracerebral pathways were mapped using different retro- and anterograde tracing methods. We review the literature on the trigeminothalamic tracts focusing on these animal tracer studies. Subsequently, we related the observations of these studies to clinical findings using fMRI trials. The intracerebral trigeminal pathways can be subdivided into three pathways: a ventral (contralateral) and dorsal (mainly ipsilateral) trigeminothalamic tract and the intranuclear pathway. Based on the reviewed evidence we hypothesize the co-existence of an ipsilateral nociceptive conduction tract to the cerebral cortex and we translate evidence from animal-based research to the human anatomy. Our hypothesis differs from the classical idea that orofacial pain arises only from nociceptive information via the contralateral, ventral trigeminothalamic pathway. Better understanding of the histology, anatomy and connectivity of the trigeminal fibers could contribute to the discovery of a more effective pain treatment in patients suffering from various orofacial pain syndromes. PMID- 27242451 TI - Altered Amygdala Development and Fear Processing in Prematurely Born Infants. AB - CONTEXT: Prematurely born children have a high risk of developmental and behavioral disabilities. Cerebral abnormalities at term age have been clearly linked with later behavior alterations, but existing studies did not focus on the amygdala. Moreover, studies of early amygdala development after premature birth in humans are scarce. OBJECTIVE: To compare amygdala volumes in very preterm infants at term equivalent age (TEA) and term born infants, and to relate premature infants' amygdala volumes with their performance on the Laboratory Temperament Assessment Battery (Lab-TAB) fear episode at 12 months. PARTICIPANTS: Eighty one infants born between 2008 and 2014 at the University Hospitals of Geneva and Lausanne, taking part in longitudinal and functional imaging studies, who had undergone a magnetic resonance imaging (MRI) scan at TEA enabling manual amygdala delineation. OUTCOMES: Amygdala volumes assessed by manual segmentation of MRI scans; volumes of cortical and subcortical gray matter, white matter and cerebrospinal fluid (CSF) automatically segmented in 66 infants; scores for the Lab-TAB fear episode for 42 premature infants at 12 months. RESULTS: Amygdala volumes were smaller in preterm infants at TEA than term infants (mean difference 138.03 mm(3), p < 0.001), and overall right amygdala volumes were larger than left amygdala volumes (mean difference 36.88 mm(3), p < 0.001). White matter volumes were significantly smaller (p < 0.001) and CSF volumes significantly larger (p < 0.001) in preterm than in term born infants, while cortical and subcortical gray matter volumes were not significantly different between groups. Amygdala volumes showed significant correlation with the intensity of the escape response to a fearsome toy (rs = 0.38, p = 0.013), and were larger in infants showing an escape response compared to the infants showing no escape response (mean difference 120.97 mm(3), p = 0.005). Amygdala volumes were not significantly correlated with the intensity of facial fear, distress vocalizations, bodily fear and positive motor activity in the fear episode. CONCLUSION: Our results indicate that premature birth is associated with a reduction in amygdala volumes and white matter volumes at TEA, suggesting that altered amygdala development might be linked to alterations in white matter connectivity reported in premature infants. Moreover, our data suggests that such alterations might affect infants' fear-processing capabilities. PMID- 27242452 TI - A State Space Model for Spatial Updating of Remembered Visual Targets during Eye Movements. AB - In the oculomotor system, spatial updating is the ability to aim a saccade toward a remembered visual target position despite intervening eye movements. Although this has been the subject of extensive experimental investigation, there is still no unifying theoretical framework to explain the neural mechanism for this phenomenon, and how it influences visual signals in the brain. Here, we propose a unified state-space model (SSM) to account for the dynamics of spatial updating during two types of eye movement; saccades and smooth pursuit. Our proposed model is a non-linear SSM and implemented through a recurrent radial-basis-function neural network in a dual Extended Kalman filter (EKF) structure. The model parameters and internal states (remembered target position) are estimated sequentially using the EKF method. The proposed model replicates two fundamental experimental observations: continuous gaze-centered updating of visual memory related activity during smooth pursuit, and predictive remapping of visual memory activity before and during saccades. Moreover, our model makes the new prediction that, when uncertainty of input signals is incorporated in the model, neural population activity and receptive fields expand just before and during saccades. These results suggest that visual remapping and motor updating are part of a common visuomotor mechanism, and that subjective perceptual constancy arises in part from training the visual system on motor tasks. PMID- 27242453 TI - Spatiotemporal Dynamics of Cortical Representations during and after Stimulus Presentation. AB - Visual perception is a spatiotemporally complex process. In this study, we investigated cortical dynamics during and after stimulus presentation. We observed that visual category information related to the difference between faces and objects became apparent in the occipital lobe after 63 ms. Within the next 110 ms, activation spread out to include the temporal lobe before returning to residing mainly in the occipital lobe again. After stimulus offset, a peak in information was observed, comparable to the peak after stimulus onset. Moreover, similar processes, albeit not identical, seemed to underlie both peaks. Information about the categorical identity of the stimulus remained present until 677 ms after stimulus offset, during which period the stimulus had to be retained in working memory. Activation patterns initially resembled those observed during stimulus presentation. After about 200 ms, however, this representation changed and class-specific activity became more equally distributed over the four lobes. These results show that, although there are common processes underlying stimulus representation both during and after stimulus presentation, these representations change depending on the specific stage of perception and maintenance. PMID- 27242455 TI - Functional MRI Representational Similarity Analysis Reveals a Dissociation between Discriminative and Relative Location Information in the Human Visual System. AB - Neural responses in visual cortex are governed by a topographic mapping from retinal locations to cortical responses. Moreover, at the voxel population level early visual cortex (EVC) activity enables accurate decoding of stimuli locations. However, in many cases information enabling one to discriminate between locations (i.e., discriminative information) may be less relevant than information regarding the relative location of two objects (i.e., relative information). For example, when planning to grab a cup, determining whether the cup is located at the same retinal location as the hand is hardly relevant, whereas the location of the cup relative to the hand is crucial for performing the action. We have previously used multivariate pattern analysis techniques to measure discriminative location information, and found the highest levels in EVC, in line with other studies. Here we show, using representational similarity analysis, that availability of discriminative information in fMRI activation patterns does not entail availability of relative information. Specifically, we find that relative location information can be reliably extracted from activity patterns in posterior intraparietal sulcus (pIPS), but not from EVC, where we find the spatial representation to be warped. We further show that this variability in relative information levels between regions can be explained by a computational model based on an array of receptive fields. Moreover, when the model's receptive fields are extended to include inhibitory surround regions, the model can account for the spatial warping in EVC. These results demonstrate how size and shape properties of receptive fields in human visual cortex contribute to the transformation of discriminative spatial representations into relative spatial representations along the visual stream. PMID- 27242454 TI - Disruption of Network Synchrony and Cognitive Dysfunction After Traumatic Brain Injury. AB - Traumatic brain injury (TBI) is a heterogeneous disorder with many factors contributing to a spectrum of severity, leading to cognitive dysfunction that may last for many years after injury. Injury to axons in the white matter, which are preferentially vulnerable to biomechanical forces, is prevalent in many TBIs. Unlike focal injury to a discrete brain region, axonal injury is fundamentally an injury to the substrate by which networks of the brain communicate with one another. The brain is envisioned as a series of dynamic, interconnected networks that communicate via long axonal conduits termed the "connectome". Ensembles of neurons communicate via these pathways and encode information within and between brain regions in ways that are timing dependent. Our central hypothesis is that traumatic injury to axons may disrupt the exquisite timing of neuronal communication within and between brain networks, and that this may underlie aspects of post-TBI cognitive dysfunction. With a better understanding of how highly interconnected networks of neurons communicate with one another in important cognitive regions such as the limbic system, and how disruption of this communication occurs during injury, we can identify new therapeutic targets to restore lost function. This requires the tools of systems neuroscience, including electrophysiological analysis of ensemble neuronal activity and circuitry changes in awake animals after TBI, as well as computational modeling of the effects of TBI on these networks. As more is revealed about how inter-regional neuronal interactions are disrupted, treatments directly targeting these dysfunctional pathways using neuromodulation can be developed. PMID- 27242457 TI - The Neurobiology of Cannabis Use Disorders: A Call for Evidence. PMID- 27242458 TI - Comparison of Burrowing and Stimuli-Evoked Pain Behaviors as End-Points in Rat Models of Inflammatory Pain and Peripheral Neuropathic Pain. AB - Establishment and validation of ethologically-relevant, non-evoked behavioral end points as surrogate measures of spontaneous pain in rodent pain models has been proposed as a means to improve preclinical to clinical research translation in the pain field. Here, we compared the utility of burrowing behavior with hypersensitivity to applied mechanical stimuli for pain assessment in rat models of chronic inflammatory and peripheral neuropathic pain. Briefly, groups of male Sprague-Dawley rats were habituated to the burrowing environment and trained over a 5-day period. Rats that burrowed <= 450 g of gravel on any 2 days of the individual training phase were excluded from the study. The remaining rats received either a unilateral intraplantar injection of Freund's complete adjuvant (FCA) or saline, or underwent unilateral chronic constriction injury (CCI) of the sciatic nerve- or sham-surgery. Baseline burrowing behavior and evoked pain behaviors were assessed prior to model induction, and twice-weekly until study completion on day 14. For FCA- and CCI-rats, but not the corresponding groups of sham-rats, evoked mechanical hypersensitivity developed in a temporal manner in the ipsilateral hindpaws. Although burrowing behavior also decreased in a temporal manner for both FCA-and CCI- rats, there was considerable inter-animal variability. By contrast, mechanical hyperalgesia and mechanical allodynia in the ipsilateral hindpaws of FCA- and CCI-rats respectively, exhibited minimal inter animal variability. Our data collectively show that burrowing behavior is altered in rodent models of chronic inflammatory pain and peripheral neuropathic pain. However, large group sizes are needed to ensure studies are adequately powered due to considerable inter-animal variability. PMID- 27242456 TI - Top-Down Dysregulation-From ADHD to Emotional Instability. AB - Deficient cognitive top-down executive control has long been hypothesized to underlie inattention and impulsivity in attention-deficit/hyperactivity disorder (ADHD). However, top-down cognitive dysfunction explains a modest proportion of the ADHD phenotype whereas the salience of emotional dysregulation is being noted increasingly. Together, these two types of dysfunction have the potential to account for more of the phenotypic variance in patients diagnosed with ADHD. We develop this idea and suggest that top-down dysregulation constitutes a gradient extending from mostly non-emotional top-down control processes (i.e., "cool" executive functions) to mainly emotional regulatory processes (including "hot" executive functions). While ADHD has been classically linked primarily to the former, conditions involving emotional instability such as borderline and antisocial personality disorder are closer to the other. In this model, emotional subtypes of ADHD are located at intermediate levels of this gradient. Neuroanatomically, gradations in "cool" processing appear to be related to prefrontal dysfunction involving dorsolateral prefrontal cortex (dlPFC) and caudal anterior cingulate cortex (cACC), while "hot" processing entails orbitofrontal cortex and rostral anterior cingulate cortex (rACC). A similar distinction between systems related to non-emotional and emotional processing appears to hold for the basal ganglia (BG) and the neuromodulatory effects of the dopamine system. Overall we suggest that these two systems could be divided according to whether they process non-emotional information related to the exteroceptive environment (associated with "cool" regulatory circuits) or emotional information related to the interoceptive environment (associated with "hot" regulatory circuits). We propose that this framework can integrate ADHD, emotional traits in ADHD, borderline and antisocial personality disorder into a related cluster of mental conditions. PMID- 27242459 TI - Retrieval and Reconsolidation Accounts of Fear Extinction. AB - Extinction is the primary mode for the treatment of anxiety disorders. However, extinction memories are prone to relapse. For example, fear is likely to return when a prolonged time period intervenes between extinction and a subsequent encounter with the fear-provoking stimulus (spontaneous recovery). Therefore there is considerable interest in the development of procedures that strengthen extinction and to prevent such recovery of fear. We contrasted two procedures in rats that have been reported to cause such deepened extinction. One where extinction begins before the initial consolidation of fear memory begins (immediate extinction) and another where extinction begins after a brief exposure to the consolidated fear stimulus. The latter is thought to open a period of memory vulnerability similar to that which occurs during initial consolidation (reconsolidation update). We also included a standard extinction treatment and a control procedure that reversed the brief exposure and extinction phases. Spontaneous recovery was only found with the standard extinction treatment. In a separate experiment we tested fear shortly after extinction (i.e., within 6 h). All extinction procedures, except reconsolidation update reduced fear at this short-term test. The findings suggest that strengthened extinction can result from alteration in both retrieval and consolidation processes. PMID- 27242460 TI - Distinct Types of Feeding Related Neurons in Mouse Hypothalamus. AB - The last two decades of research provided evidence for a substantial heterogeneity among feeding-related neurons (FRNs) in the hypothalamus. However, it remains unclear how FRNs differ in their firing patterns during food intake. Here, we investigated the relationship between the activity of neurons in mouse hypothalamus and their feeding behavior. Using tetrode-based in vivo recording technique, we identified various firing patterns of hypothalamic FRNs, which, after the initiation of food intake, can be sorted into four types: sharp increase (type I), slow increase (type II), sharp decrease (type III), and sustained decrease (type IV) of firing rates. The feeding-related firing response of FRNs was rigidly related to the duration of food intake and, to a less extent, associated with the type of food. The majority of these FRNs responded to glucose and leptin and exhibited electrophysiological characteristics of putative GABAergic neurons. In conclusion, our study demonstrated the diversity of neurons in the complex hypothalamic network coordinating food intake. PMID- 27242461 TI - Walking while Performing Working Memory Tasks Changes the Prefrontal Cortex Hemodynamic Activations and Gait Kinematics. AB - BACKGROUND: Increasing evidence suggests that walking while performing a concurrent task negatively influences gait performance. However, it remains unclear how higher-level cognitive processes and coordination of limb movements are altered in challenging walking environments. This study investigated the influence of cognitive task complexity and walking road condition on the neutral correlates of executive function and postural control in dual-task walking. METHODS: Twenty-four healthy young adults completed a series of overground walks with three walking road conditions (wide, narrow, with obstacles) with and without the concurrent n-back working memory tasks of two complexity levels (1 back and 3-back). Prefrontal brain activation was assessed by functional near infrared spectroscopy. A three-dimensional motion analysis system was used simultaneously to measure gait performance and lower-extremity kinematics. Repeated measures analysis of variance were performed to examine the differences between the conditions. RESULTS: In comparison with standing still, participants showed lower n-back task accuracy while walking, with the worst performance from the road with obstacles. Spatiotemporal gait parameters, lower-extremity joint movements, and the relative changes in oxygenated hemoglobin (HbO) concentration levels were all significantly different across the task complexity and walking path conditions. While dual-tasking participants were found to flex their hips and knees less, leading to a slower gait speed, longer stride time, shorter step length, and greater gait variability than during normal walking. For narrow-road walking, smaller ankle dorsiflexion and larger hip flexion were observed, along with a reduced gait speed. Obstacle negotiation was mainly characterized by increased gait variability than other conditions. HbO levels appeared to be lower during dual-task walking than normal walking. Compared to wide and obstacle conditions, walking on the narrow road was found to elicit a smaller decrement in HbO levels. CONCLUSION: The current study provided direct evidence that, in young adults, neural correlates of executive function and dynamic postural control tend to be altered in response to the cognitive load imposed by the walking environment and the concurrent task during ambulation. A shift of brain activation patterns between functionally connected networks may occur when facing challenging cognitive-motor interaction. PMID- 27242462 TI - The Mechanosensory Lateral Line System Mediates Activation of Socially-Relevant Brain Regions during Territorial Interactions. AB - Animals use multiple senses during social interactions and must integrate this information in the brain to make context-dependent behavioral decisions. For fishes, the largest group of vertebrates, the mechanosensory lateral line system provides crucial hydrodynamic information for survival behaviors, but little is known about its function in social communication. Our previous work using the African cichlid fish, Astatotilapia burtoni, provided the first empirical evidence that fish use their lateral line system to detect water movements from conspecifics for mutual assessment and behavioral choices. It is unknown, however, where this socially-relevant mechanosensory information is processed in the brain to elicit adaptive behavioral responses. To examine for the first time in any fish species which brain regions receive contextual mechanosensory information, we quantified expression of the immediate early gene cfos as a proxy for neural activation in sensory and socially-relevant brain nuclei from lateral line-intact and -ablated fish following territorial interactions. Our in situ hybridization results indicate that in addition to known lateral line processing regions, socially-relevant mechanosensory information is processed in the ATn (ventromedial hypothalamus homolog), Dl (putative hippocampus homolog), and Vs (putative medial extended amygdala homolog). In addition, we identified a functional network within the conserved social decision-making network (SDMN) whose co-activity corresponds with mutual assessment and behavioral choice. Lateral line-intact and -ablated fight winners had different patterns of co activity of these function networks and group identity could be determined solely by activation patterns, indicating the importance of mechanoreception to co activity of the SDMN. These data show for the first time that the mechanosensory lateral line system provides relevant information to conserved decision-making centers of the brain during territorial interactions to mediate crucial behavioral choices such as whether or not to engage in a territorial fight. To our knowledge, this is also the first evidence of a subpallial nucleus receiving mechanosensory input, providing important information for elucidating homologies of decision-making circuits across vertebrates. These novel results highlight the importance of considering multimodal sensory input in mediating context appropriate behaviors that will provide broad insights on the evolution of decision-making networks across all taxa. PMID- 27242463 TI - Concerted Gene Expression of Hippocampal Steroid Receptors during Spatial Learning in Male Wistar Rats: A Correlation Analysis. AB - Adrenal and gonadal steroid receptor activities are significantly involved and interact in the regulation of learning, memory and stress. Thus, a coordinated expression of steroid receptor genes during a learning task can be expected. Although coexpression of steroid receptors in response to behavioral tasks has been reported the correlative connection is unclear. According to the inverted U shape model of the impact of stress upon learning and memory we hypothesized that glucocorticoid (GR) receptor expression should be correlated to corticosterone levels in a linear or higher order manner. Other cognition modulating steroid receptors like estrogen receptors (ER) should be correlated to GR receptors in a quadratic manner, which describes a parabola and thus a U-shaped connection. Therefore, we performed a correlational meta-analyis of data of a previous study (Meyer and Korz, 2013a) of steroid receptor gene expressions during spatial learning, which provides a sufficient data basis in order to perform such correlational connections. In that study male rats of different ages were trained in a spatial holeboard or remained untrained and the hippocampal gene expression of different steroid receptors as well as serum corticosterone levels were measured. Expressions of mineralocorticoid (MR) and GR receptors were positively and linearly correlated with blood serum corticosterone levels in spatially trained but not in untrained animals. Training induced a cubic (best fit) relationship between mRNA levels of estrogen receptor alpha (ERalpha) and androgen receptor (AR) with MR mRNA. GR gene expression was linearly correlated with MR expression under both conditions. ERalpha m RNA levels were negatively and linearily and MR and GR gene expressions were cubicely correlated with reference memory errors (RME). Due to only three age classes correlations with age could not be performed. The findings support the U-shape theory of steroid receptor interaction, however the cubic fit suggest a more complex situation, which mechanisms may be revealed in further studies. PMID- 27242464 TI - Differential Kinetics in Alteration and Recovery of Cognitive Processes from a Chronic Sleep Restriction in Young Healthy Men. AB - Chronic sleep restriction (CSR) induces neurobehavioral deficits in young and healthy people with a morning failure of sustained attention process. Testing both the kinetic of failure and recovery of different cognitive processes (i.e., attention, executive) under CSR and their potential links with subject's capacities (stay awake, baseline performance, age) and with some biological markers of stress and anabolism would be useful in order to understand the role of sleep debt on human behavior. Twelve healthy subjects spent 14 days in laboratory with 2 baseline days (B1 and B2, 8 h TIB) followed by 7 days of sleep restriction (SR1-SR7, 4 h TIB), 3 sleep recovery days (R1-R3, 8 h TIB) and two more ones 8 days later (R12-R13). Subjective sleepiness (KSS), maintenance of wakefulness latencies (MWT) were evaluated four times a day (10:00, 12:00 a.m. and 2:00, 4:00 p.m.) and cognitive tests were realized at morning (8:30 a.m.) and evening (6:30 p.m.) sessions during B2, SR1, SR4, SR7, R2, R3 and R13. Saliva (B2, SR7, R2, R13) and blood (B1, SR6, R1, R12) samples were collected in the morning. Cognitive processes were differently impaired and recovered with a more rapid kinetic for sustained attention process. Besides, a significant time of day effect was only evidenced for sustained attention failures that seemed to be related to subject's age and their morning capacity to stay awake. Executive processes were equally disturbed/recovered during the day and this failure/recovery process seemed to be mainly related to baseline subject's performance and to their capacity to stay awake. Morning concentrations of testosterone, cortisol and alpha-amylase were significantly decreased at SR6-SR7, but were either and respectively early (R1), tardily (after R2) and not at all (R13) recovered. All these results suggest a differential deleterious and restorative effect of CSR on cognition through biological changes of the stress pathway and subject's capacity (ClinicalTrials-NCT01989741). PMID- 27242466 TI - Prediction of Mortality Based on Facial Characteristics. AB - Recent studies have shown that characteristics of the face contain a wealth of information about health, age and chronic clinical conditions. Such studies involve objective measurement of facial features correlated with historical health information. But some individuals also claim to be adept at gauging mortality based on a glance at a person's photograph. To test this claim, we invited 12 such individuals to see if they could determine if a person was alive or dead based solely on a brief examination of facial photographs. All photos used in the experiment were transformed into a uniform gray scale and then counterbalanced across eight categories: gender, age, gaze direction, glasses, head position, smile, hair color, and image resolution. Participants examined 404 photographs displayed on a computer monitor, one photo at a time, each shown for a maximum of 8 s. Half of the individuals in the photos were deceased, and half were alive at the time the experiment was conducted. Participants were asked to press a button if they thought the person in a photo was living or deceased. Overall mean accuracy on this task was 53.8%, where 50% was expected by chance (p < 0.004, two-tail). Statistically significant accuracy was independently obtained in 5 of the 12 participants. We also collected 32-channel electrophysiological recordings and observed a robust difference between images of deceased individuals correctly vs. incorrectly classified in the early event related potential (ERP) at 100 ms post-stimulus onset. Our results support claims of individuals who report that some as-yet unknown features of the face predict mortality. The results are also compatible with claims about clairvoyance warrants further investigation. PMID- 27242465 TI - Eye Movements during Auditory Attention Predict Individual Differences in Dorsal Attention Network Activity. AB - The neural mechanisms supporting auditory attention are not fully understood. A dorsal frontoparietal network of brain regions is thought to mediate the spatial orienting of attention across all sensory modalities. Key parts of this network, the frontal eye fields (FEF) and the superior parietal lobes (SPL), contain retinotopic maps and elicit saccades when stimulated. This suggests that their recruitment during auditory attention might reflect crossmodal oculomotor processes; however this has not been confirmed experimentally. Here we investigate whether task-evoked eye movements during an auditory task can predict the magnitude of activity within the dorsal frontoparietal network. A spatial and non-spatial listening task was used with on-line eye-tracking and functional magnetic resonance imaging (fMRI). No visual stimuli or cues were used. The auditory task elicited systematic eye movements, with saccade rate and gaze position predicting attentional engagement and the cued sound location, respectively. Activity associated with these separate aspects of evoked eye movements dissociated between the SPL and FEF. However these observed eye movements could not account for all the activation in the frontoparietal network. Our results suggest that the recruitment of the SPL and FEF during attentive listening reflects, at least partly, overt crossmodal oculomotor processes during non-visual attention. Further work is needed to establish whether the network's remaining contribution to auditory attention is through covert crossmodal processes, or is directly involved in the manipulation of auditory information. PMID- 27242467 TI - Proposing Metrics for Benchmarking Novel EEG Technologies Towards Real-World Measurements. AB - Recent advances in electroencephalographic (EEG) acquisition allow for recordings using wet and dry sensors during whole-body motion. The large variety of commercially available EEG systems contrasts with the lack of established methods for objectively describing their performance during whole-body motion. Therefore, the aim of this study was to introduce methods for benchmarking the suitability of new EEG technologies for that context. Subjects performed an auditory oddball task using three different EEG systems (Biosemi wet-BSM, Cognionics Wet-Cwet, Conionics Dry-Cdry). Nine subjects performed the oddball task while seated and walking on a treadmill. We calculated EEG epoch rejection rate, pre-stimulus noise (PSN), signal-to-noise ratio (SNR) and EEG amplitude variance across the P300 event window (CVERP) from a subset of 12 channels common to all systems. We also calculated test-retest reliability and the subject's level of comfort while using each system. Our results showed that using the traditional 75 MUV rejection threshold BSM and Cwet epoch rejection rates are ~25% and ~47% in the seated and walking conditions respectively. However, this threshold rejects ~63% of epochs for Cdry in the seated condition and excludes 100% of epochs for the majority of subjects during walking. BSM showed predominantly no statistical differences between seated and walking condition for all metrics, whereas Cwet showed increases in PSN and CVERP, as well as reduced SNR in the walking condition. Data quality from Cdry in seated conditions were predominantly inferior in comparison to the wet systems. Test-retest reliability was mostly moderate/good for these variables, especially in seated conditions. In addition, subjects felt less discomfort and were motivated for longer recording periods while using wet EEG systems in comparison to the dry system. The proposed method was successful in identifying differences across systems that are mostly caused by motion-related artifacts and usability issues. We conclude that the extraction of the selected metrics from an auditory oddball paradigm may be used as a benchmark method for testing the performance of different EEG systems in mobile conditions. Moreover dry EEG systems may need substantial improvements to meet the quality standards of wet electrodes. PMID- 27242468 TI - Commentary: The Role of the Parietal Cortex in the Representation of Task-Reward Associations. PMID- 27242470 TI - Spontaneous Fluctuations in Sensory Processing Predict Within-Subject Reaction Time Variability. AB - When engaged in a repetitive task our performance fluctuates from trial-to-trial. In particular, inter-trial reaction time variability has been the subject of considerable research. It has been claimed to be a strong biomarker of attention deficits, increases with frontal dysfunction, and predicts age-related cognitive decline. Thus, rather than being just a consequence of noise in the system, it appears to be under the control of a mechanism that breaks down under certain pathological conditions. Although the underlying mechanism is still an open question, consensual hypotheses are emerging regarding the neural correlates of reaction time inter-trial intra-individual variability. Sensory processing, in particular, has been shown to covary with reaction time, yet the spatio-temporal profile of the moment-to-moment variability in sensory processing is still poorly characterized. The goal of this study was to characterize the intra-individual variability in the time course of single-trial visual evoked potentials and its relationship with inter-trial reaction time variability. For this, we chose to take advantage of the high temporal resolution of the electroencephalogram (EEG) acquired while participants were engaged in a 2-choice reaction time task. We studied the link between single trial event-related potentials (ERPs) and reaction time using two different analyses: (1) time point by time point correlation analyses thereby identifying time windows of interest; and (2) correlation analyses between single trial measures of peak latency and amplitude and reaction time. To improve extraction of single trial ERP measures related with activation of the visual cortex, we used an independent component analysis (ICA) procedure. Our ERP analysis revealed a relationship between the N1 visual evoked potential and reaction time. The earliest time point presenting a significant correlation of its respective amplitude with reaction time occurred 175 ms after stimulus onset, just after the onset of the N1 peak. Interestingly, single trial N1 latency correlated significantly with reaction time, while N1 amplitude did not. In conclusion, our findings suggest that inter-trial variability in the timing of extrastriate visual processing contributes to reaction time variability. PMID- 27242469 TI - tDCS of the Cerebellum: Where Do We Stand in 2016? Technical Issues and Critical Review of the Literature. AB - Transcranial Direct Current Stimulation (tDCS) is an up-and-coming electrical neurostimulation technique increasingly used both in healthy subjects and in selected groups of patients. Due to the high density of neurons in the cerebellum, its peculiar anatomical organization with the cortex lying superficially below the skull and its diffuse connections with motor and associative areas of the cerebrum, the cerebellum is becoming a major target for neuromodulation of the cerebellocerebral networks. We discuss the recent studies based on cerebellar tDCS with a focus on the numerous technical and open issues which remain to be solved. Our current knowledge of the physiological impacts of tDCS on cerebellar circuitry is criticized. We provide a comparison with transcranial Alternating Current Stimulation (tACS), another promising transcranial electrical neurostimulation technique. Although both tDCS and tACS are becoming established techniques to modulate the cerebellocerebral networks, it is surprising that their impacts on cerebellar disorders remains unclear. A major reason is that the literature lacks large trials with a double-blind, sham controlled, and cross-over experimental design in cerebellar patients. PMID- 27242471 TI - Futurist Art: Motion and Aesthetics As a Function of Title. AB - Very often the titles of Futurist paintings contain words denoting movement in order to satisfy their artistic poetic focused on motion and velocity. The aim of the present study is to investigate the reported dynamism and aesthetic quality of several Futurist artworks as a function of their title. Ten Futurist artworks with a movement-related word in the title were selected for this study. The titles were manipulated, resulting in four conditions for each painting: the "original title" with the movement word; an "increased" title in which an adjective was added in order to intensify the sense of dynamism; a "decreased" title, in which the movement word was eliminated; no title. Participants evaluated the movement suggested by each painting in the four different title conditions, rated their beauty and reported how much they liked the work. Results showed that the manipulation of the title had an effect on the reported movement: compared to the others, paintings presented with the "original" and with the "increased" title received significant higher movement scores. Of interest, beauty did not differ across conditions, but liking was higher for the conditions with more movement. Lastly, positive correlations between the quantity of perceived movement and aesthetic evaluation were found. From the present results it can be concluded that Futurists attributed much relevance to the titles of their artworks in order to effectively increase the expression of the movement represented. PMID- 27242472 TI - Computer Enabled Neuroplasticity Treatment: A Clinical Trial of a Novel Design for Neurofeedback Therapy in Adult ADHD. AB - BACKGROUND: We report a randomized controlled clinical trial of neurofeedback therapy intervention for ADHD/ADD in adults. We focus on internal mechanics of neurofeedback learning, to elucidate the primary role of cortical self-regulation in neurofeedback. We report initial results; more extensive analysis will follow. METHODS: Trial has two phases: intervention and follow-up. The intervention consisted of neurofeedback treatment, including intake and outtake measurements, using a waiting-list control group. Treatment involved ~40 h-long sessions 2-5 times per week. Training involved either theta/beta or sensorimotor-rhythm regimes, adapted by adding a novel "inverse-training" condition to promote self regulation. Follow-up (ongoing) will consist of self-report and executive function tests. SETTING: Intake and outtake measurements were conducted at University of Helsinki. Treatment was administered at partner clinic Mental Capital Care, Helsinki. RANDOMIZATION: We randomly allocated half the sample then adaptively allocated the remainder to minimize baseline differences in prognostic variables. BLINDING: Waiting-list control design meant trial was not blinded. PARTICIPANTS: Fifty-four adult Finnish participants (mean age 36 years; 29 females) were recruited after screening by psychiatric review. Forty-four had ADHD diagnoses, 10 had ADD. MEASUREMENTS: Symptoms were assessed by computerized attention test (T.O.V.A.) and self-report scales, at intake and outtake. Performance during neurofeedback trials was recorded. RESULTS: PARTICIPANTS were recruited and completed intake measurements during summer 2012, before assignment to treatment and control, September 2012. Outtake measurements ran April-August 2013. After dropouts, 23 treatment and 21 waiting-list participants remained for analysis. Initial analysis showed that, compared to waiting-list control, neurofeedback promoted improvement of self-reported ADHD symptoms, but did not show transfer of learning to T.O.V.A. Comprehensive analysis will be reported elsewhere. TRIAL REGISTRATION: "Computer Enabled Neuroplasticity Treatment (CENT)," ISRCTN13915109. PMID- 27242473 TI - Polarity-Specific Cortical Effects of Transcranial Direct Current Stimulation in Primary Somatosensory Cortex of Healthy Humans. AB - Transcranial direct current stimulation (tDCS) is a non-invasive stimulation method that has been shown to modulate the excitability of the motor and visual cortices in human subjects in a polarity dependent manner in previous studies. The aim of our study was to investigate whether anodal and cathodal tDCS can also be used to modulate the excitability of the human primary somatosensory cortex (S1). We measured paired-pulse suppression (PPS) of somatosensory evoked potentials in 36 right-handed volunteers before and after anodal, cathodal, or sham stimulation over the right non-dominant S1. Paired-pulse stimulation of the median nerve was performed at the dominant and non-dominant hand. After anodal tDCS, PPS was reduced in the ipsilateral S1 compared to sham stimulation, indicating an excitatory effect of anodal tDCS. In contrast, PPS in the stimulated left hemisphere was increased after cathodal tDCS, indicating an inhibitory effect of cathodal tDCS. Sham stimulation induced no pre-post differences. Thus, tDCS can be used to modulate the excitability of S1 in polarity-dependent manner, which can be assessed by PPS. An interesting topic for further studies could be the investigation of direct correlations between sensory changes and excitability changes induced by tDCS. PMID- 27242474 TI - Integrative Processing of Touch and Affect in Social Perception: An fMRI Study. AB - Social perception commonly employs multiple sources of information. The present study aimed at investigating the integrative processing of affective social signals. Task-related and task-free functional magnetic resonance imaging was performed in 26 healthy adult participants during a social perception task concerning dynamic visual stimuli simultaneously depicting facial expressions of emotion and tactile sensations that could be either congruent or incongruent. Confounding effects due to affective valence, inhibitory top-down influences, cross-modal integration, and conflict processing were minimized. The results showed that the perception of congruent, compared to incongruent stimuli, elicited enhanced neural activity in a set of brain regions including left amygdala, bilateral posterior cingulate cortex (PCC), and left superior parietal cortex. These congruency effects did not differ as a function of emotion or sensation. A complementary task-related functional interaction analysis preliminarily suggested that amygdala activity depended on previous processing stages in fusiform gyrus and PCC. The findings provide support for the integrative processing of social information about others' feelings from manifold bodily sources (sensory-affective information) in amygdala and PCC. Given that the congruent stimuli were also judged as being more self-related and more familiar in terms of personal experience in an independent sample of participants, we speculate that such integrative processing might be mediated by the linking of external stimuli with self-experience. Finally, the prediction of task-related responses in amygdala by intrinsic functional connectivity between amygdala and PCC during a task-free state implies a neuro-functional basis for an individual predisposition for the integrative processing of social stimulus content. PMID- 27242475 TI - Aesthetic Responses to Exact Fractals Driven by Physical Complexity. AB - Fractals are physically complex due to their repetition of patterns at multiple size scales. Whereas the statistical characteristics of the patterns repeat for fractals found in natural objects, computers can generate patterns that repeat exactly. Are these exact fractals processed differently, visually and aesthetically, than their statistical counterparts? We investigated the human aesthetic response to the complexity of exact fractals by manipulating fractal dimensionality, symmetry, recursion, and the number of segments in the generator. Across two studies, a variety of fractal patterns were visually presented to human participants to determine the typical response to exact fractals. In the first study, we found that preference ratings for exact midpoint displacement fractals can be described by a linear trend with preference increasing as fractal dimension increases. For the majority of individuals, preference increased with dimension. We replicated these results for other exact fractal patterns in a second study. In the second study, we also tested the effects of symmetry and recursion by presenting asymmetric dragon fractals, symmetric dragon fractals, and Sierpinski carpets and Koch snowflakes, which have radial and mirror symmetry. We found a strong interaction among recursion, symmetry and fractal dimension. Specifically, at low levels of recursion, the presence of symmetry was enough to drive high preference ratings for patterns with moderate to high levels of fractal dimension. Most individuals required a much higher level of recursion to recover this level of preference in a pattern that lacked mirror or radial symmetry, while others were less discriminating. This suggests that exact fractals are processed differently than their statistical counterparts. We propose a set of four factors that influence complexity and preference judgments in fractals that may extend to other patterns: fractal dimension, recursion, symmetry and the number of segments in a pattern. Conceptualizations such as Berlyne's and Redies' theories of aesthetics also provide a suitable framework for interpretation of our data with respect to the individual differences that we detect. Future studies that incorporate physiological methods to measure the human aesthetic response to exact fractal patterns would further elucidate our responses to such timeless patterns. PMID- 27242477 TI - High-Performance Bioinstrumentation for Real-Time Neuroelectrochemical Traumatic Brain Injury Monitoring. AB - Traumatic brain injury (TBI) has been identified as an important cause of death and severe disability in all age groups and particularly in children and young adults. Central to TBIs devastation is a delayed secondary injury that occurs in 30-40% of TBI patients each year, while they are in the hospital Intensive Care Unit (ICU). Secondary injuries reduce survival rate after TBI and usually occur within 7 days post-injury. State-of-art monitoring of secondary brain injuries benefits from the acquisition of high-quality and time-aligned electrical data i.e., ElectroCorticoGraphy (ECoG) recorded by means of strip electrodes placed on the brains surface, and neurochemical data obtained via rapid sampling microdialysis and microfluidics-based biosensors measuring brain tissue levels of glucose, lactate and potassium. This article progresses the field of multi-modal monitoring of the injured human brain by presenting the design and realization of a new, compact, medical-grade amperometry, potentiometry and ECoG recording bioinstrumentation. Our combined TBI instrument enables the high-precision, real time neuroelectrochemical monitoring of TBI patients, who have undergone craniotomy neurosurgery and are treated sedated in the ICU. Electrical and neurochemical test measurements are presented, confirming the high-performance of the reported TBI bioinstrumentation. PMID- 27242476 TI - Studying Autism Spectrum Disorder with Structural and Diffusion Magnetic Resonance Imaging: A Survey. AB - Magnetic resonance imaging (MRI) modalities have emerged as powerful means that facilitate non-invasive clinical diagnostics of various diseases and abnormalities since their inception in the 1980s. Multiple MRI modalities, such as different types of the sMRI and DTI, have been employed to investigate facets of ASD in order to better understand this complex syndrome. This paper reviews recent applications of structural magnetic resonance imaging (sMRI) and diffusion tensor imaging (DTI), to study autism spectrum disorder (ASD). Main reported findings are sometimes contradictory due to different age ranges, hardware protocols, population types, numbers of participants, and image analysis parameters. The primary anatomical structures, such as amygdalae, cerebrum, and cerebellum, associated with clinical-pathological correlates of ASD are highlighted through successive life stages, from infancy to adulthood. This survey demonstrates the absence of consistent pathology in the brains of autistic children and lack of research investigations in patients under 2 years of age in the literature. The known publications also emphasize advances in data acquisition and analysis, as well as significance of multimodal approaches that combine resting-state, task-evoked, and sMRI measures. Initial results obtained with the sMRI and DTI show good promise toward the early and non-invasive ASD diagnostics. PMID- 27242478 TI - Reduced Volume of the Arcuate Fasciculus in Adults with High-Functioning Autism Spectrum Conditions. AB - Atypical language is a fundamental feature of autism spectrum conditions (ASC), but few studies have examined the structural integrity of the arcuate fasciculus, the major white matter tract connecting frontal and temporal language regions, which is usually implicated as the main transfer route used in processing linguistic information by the brain. Abnormalities in the arcuate have been reported in young children with ASC, mostly in low-functioning or non-verbal individuals, but little is known regarding the structural properties of the arcuate in adults with ASC or, in particular, in individuals with ASC who have intact language, such as those with high-functioning autism or Asperger syndrome. We used probabilistic tractography of diffusion-weighted imaging to isolate and scrutinize the arcuate in a mixed-gender sample of 18 high-functioning adults with ASC (17 Asperger syndrome) and 14 age- and IQ-matched typically developing controls. Arcuate volume was significantly reduced bilaterally with clearest differences in the right hemisphere. This finding remained significant in an analysis of all male participants alone. Volumetric reduction in the arcuate was significantly correlated with the severity of autistic symptoms as measured by the Autism-Spectrum Quotient. These data reveal that structural differences are present even in high-functioning adults with ASC, who presented with no clinically manifest language deficits and had no reported developmental language delay. Arcuate structural integrity may be useful as an index of ASC severity and thus as a predictor and biomarker for ASC. Implications for future research are discussed. PMID- 27242479 TI - The Left Fusiform Gyrus is a Critical Region Contributing to the Core Behavioral Profile of Semantic Dementia. AB - Given that extensive cerebral regions are co-atrophic in semantic dementia (SD), it is not yet known which critical regions (SD-semantic-critical regions) are really responsible for the semantic deficits of SD. To identify the SD-semantic critical regions, we explored the relationship between the degree of cerebral atrophy in the whole brain and the severity of semantic deficits in 19 individuals with SD. We found that the gray matter volumes (GMVs) of two regions [left fusiform gyrus (lFFG) and left parahippocampal gyrus (lPHG)] significantly correlated with the semantic scores of patients with SD. Importantly, the effects of the lFFG remained significant after controlling for the GMVs of the lPHG. Moreover, the effects of the region could not be accounted for by the total GMV, general cognitive ability, laterality of brain atrophy, or control task performance. We further observed that each atrophic portion of the lFFG along the anterior-posterior axis might dedicate to the loss of semantic functions in SD. These results reveal that the lFFG could be a critical region contributing to the semantic deficits of SD. PMID- 27242480 TI - Into the Wild: Neuroergonomic Differentiation of Hand-Held and Augmented Reality Wearable Displays during Outdoor Navigation with Functional Near Infrared Spectroscopy. AB - Highly mobile computing devices promise to improve quality of life, productivity, and performance. Increased situation awareness and reduced mental workload are two potential means by which this can be accomplished. However, it is difficult to measure these concepts in the "wild". We employed ultra-portable battery operated and wireless functional near infrared spectroscopy (fNIRS) to non invasively measure hemodynamic changes in the brain's Prefrontal cortex (PFC). Measurements were taken during navigation of a college campus with either a hand held display, or an Augmented reality wearable display (ARWD). Hemodynamic measures were also paired with secondary tasks of visual perception and auditory working memory to provide behavioral assessment of situation awareness and mental workload. Navigating with an augmented reality wearable display produced the least workload during the auditory working memory task, and a trend for improved situation awareness in our measures of prefrontal hemodynamics. The hemodynamics associated with errors were also different between the two devices. Errors with an augmented reality wearable display were associated with increased prefrontal activity and the opposite was observed for the hand-held display. This suggests that the cognitive mechanisms underlying errors between the two devices differ. These findings show fNIRS is a valuable tool for assessing new technology in ecologically valid settings and that ARWDs offer benefits with regards to mental workload while navigating, and potentially superior situation awareness with improved display design. PMID- 27242481 TI - Reading Aloud and Solving Simple Arithmetic Calculation Intervention (Learning Therapy) Improves Inhibition, Verbal Episodic Memory, Focus Attention and Processing Speed in Healthy Elderly People: Evidence from a Randomized Controlled Trial. AB - BACKGROUND: Previous reports have described that simple cognitive training using reading aloud and solving simple arithmetic calculations, so-called "learning therapy", can improve executive functions and processing speed in the older adults. Nevertheless, it is not well-known whether learning therapy improve a wide range of cognitive functions or not. We investigated the beneficial effects of learning therapy on various cognitive functions in healthy older adults. METHODS: We used a single-blinded intervention with two groups (learning therapy group: LT and waiting list control group: WL). Sixty-four elderly were randomly assigned to LT or WL. In LT, participants performed reading Japanese aloud and solving simple calculations training tasks for 6 months. WL did not participate in the intervention. We measured several cognitive functions before and after 6 months intervention periods. RESULTS: Compared to WL, results revealed that LT improved inhibition performance in executive functions (Stroop: LT (Mean = 3.88) vs. WL (Mean = 1.22), adjusted p = 0.013 and reverse Stroop LT (Mean = 3.22) vs. WL (Mean = 1.59), adjusted p = 0.015), verbal episodic memory (Logical Memory (LM): LT (Mean = 4.59) vs. WL (Mean = 2.47), adjusted p = 0.015), focus attention (D-CAT: LT (Mean = 2.09) vs. WL (Mean = -0.59), adjusted p = 0.010) and processing speed compared to the WL control group (digit symbol coding: LT (Mean = 5.00) vs. WL (Mean = 1.13), adjusted p = 0.015 and Symbol Search (SS): LT (Mean = 3.47) vs. WL (Mean = 1.81), adjusted p = 0.014). DISCUSSION: This randomized controlled trial (RCT) can be showed the benefit of LT on inhibition of executive functions, verbal episodic memory, focus attention and processing speed in healthy elderly people. Our results were discussed under overlapping hypothesis. PMID- 27242482 TI - Muscle Relaxation of the Foot Reduces Corticospinal Excitability of Hand Muscles and Enhances Intracortical Inhibition. AB - The object of this study was to clarify the effects of foot muscle relaxation on activity in the primary motor cortex (M1) of the hand area. Subjects were asked to volitionally relax the right foot from sustained contraction of either the dorsiflexor (tibialis anterior; TA relaxation) or plantarflexor (soleus; SOL relaxation) in response to an auditory stimulus. Single- and paired-pulse transcranial magnetic stimulation (TMS) was delivered to the hand area of the left M1 at different time intervals before and after the onset of TA or SOL relaxation. Motor evoked potentials (MEPs) were recorded from the right extensor carpi radialis (ECR) and flexor carpi radialis (FCR). MEP amplitudes of ECR and FCR caused by single-pulse TMS temporarily decreased after TA and SOL relaxation onset, respectively, as compared with those of the resting control. Furthermore, short-interval intracortical inhibition (SICI) of ECR evaluated with paired-pulse TMS temporarily increased after TA relaxation onset. Our findings indicate that muscle relaxation of the dorsiflexor reduced corticospinal excitability of the ipsilateral hand muscles. This is most likely caused by an increase in intracortical inhibition. PMID- 27242483 TI - Exploring Neuro-Physiological Correlates of Drivers' Mental Fatigue Caused by Sleep Deprivation Using Simultaneous EEG, ECG, and fNIRS Data. AB - Investigations of the neuro-physiological correlates of mental loads, or states, have attracted significant attention recently, as it is particularly important to evaluate mental fatigue in drivers operating a motor vehicle. In this research, we collected multimodal EEG/ECG/EOG and fNIRS data simultaneously to develop algorithms to explore neuro-physiological correlates of drivers' mental states. Each subject performed simulated driving under two different conditions (well rested and sleep-deprived) on different days. During the experiment, we used 68 electrodes for EEG/ECG/EOG and 8 channels for fNIRS recordings. We extracted the prominent features of each modality to distinguish between the well-rested and sleep-deprived conditions, and all multimodal features, except EOG, were combined to quantify mental fatigue during driving. Finally, a novel driving condition level (DCL) was proposed that distinguished clearly between the features of well rested and sleep-deprived conditions. This proposed DCL measure may be applicable to real-time monitoring of the mental states of vehicle drivers. Further, the combination of methods based on each classifier yielded substantial improvements in the classification accuracy between these two conditions. PMID- 27242484 TI - Predicting Treatment Outcomes from Prefrontal Cortex Activation for Self-Harming Patients with Borderline Personality Disorder: A Preliminary Study. AB - Self-harm is a potentially lethal symptom of borderline personality disorder (BPD) that often improves with dialectical behavior therapy (DBT). While DBT is effective for reducing self-harm in many patients with BPD, a small but significant number of patients either does not improve in treatment or ends treatment prematurely. Accordingly, it is crucial to identify factors that may prospectively predict which patients are most likely to benefit from and remain in treatment. In the present preliminary study, 29 actively self-harming patients with BPD completed brain-imaging procedures probing activation of the prefrontal cortex (PFC) during impulse control prior to beginning DBT and after 7 months of treatment. Patients that reduced their frequency of self-harm the most over treatment displayed lower levels of neural activation in the bilateral dorsolateral prefrontal cortex (DLPFC) prior to beginning treatment, and they showed the greatest increases in activity within this region after 7 months of treatment. Prior to starting DBT, treatment non-completers demonstrated greater activation than treatment-completers in the medial PFC and right inferior frontal gyrus. Reductions in self-harm over the treatment period were associated with increases in activity in right DLPFC even after accounting for improvements in depression, mania, and BPD symptom severity. These findings suggest that pre treatment patterns of activation in the PFC underlying impulse control may be prospectively associated with improvements in self-harm and treatment attrition for patients with BPD treated with DBT. PMID- 27242485 TI - Concentration: The Neural Underpinnings of How Cognitive Load Shields Against Distraction. AB - Whether cognitive load-and other aspects of task difficulty-increases or decreases distractibility is subject of much debate in contemporary psychology. One camp argues that cognitive load usurps executive resources, which otherwise could be used for attentional control, and therefore cognitive load increases distraction. The other camp argues that cognitive load demands high levels of concentration (focal-task engagement), which suppresses peripheral processing and therefore decreases distraction. In this article, we employed an functional magnetic resonance imaging (fMRI) protocol to explore whether higher cognitive load in a visually-presented task suppresses task-irrelevant auditory processing in cortical and subcortical areas. The results show that selectively attending to an auditory stimulus facilitates its neural processing in the auditory cortex, and switching the locus-of-attention to the visual modality decreases the neural response in the auditory cortex. When the cognitive load of the task presented in the visual modality increases, the neural response to the auditory stimulus is further suppressed, along with increased activity in networks related to effortful attention. Taken together, the results suggest that higher cognitive load decreases peripheral processing of task-irrelevant information-which decreases distractibility-as a side effect of the increased activity in a focused attention network. PMID- 27242486 TI - Evaluation of an Adaptive Game that Uses EEG Measures Validated during the Design Process as Inputs to a Biocybernetic Loop. AB - Biocybernetic adaptation is a form of physiological computing whereby real-time data streaming from the brain and body is used by a negative control loop to adapt the user interface. This article describes the development of an adaptive game system that is designed to maximize player engagement by utilizing changes in real-time electroencephalography (EEG) to adjust the level of game demand. The research consists of four main stages: (1) the development of a conceptual framework upon which to model the interaction between person and system; (2) the validation of the psychophysiological inference underpinning the loop; (3) the construction of a working prototype; and (4) an evaluation of the adaptive game. Two studies are reported. The first demonstrates the sensitivity of EEG power in the (frontal) theta and (parietal) alpha bands to changing levels of game demand. These variables were then reformulated within the working biocybernetic control loop designed to maximize player engagement. The second study evaluated the performance of an adaptive game of Tetris with respect to system behavior and user experience. Important issues for the design and evaluation of closed-loop interfaces are discussed. PMID- 27242487 TI - Relationship between Speech Production and Perception in People Who Stutter. AB - Speech production difficulties are apparent in people who stutter (PWS). PWS also have difficulties in speech perception compared to controls. It is unclear whether the speech perception difficulties in PWS are independent of, or related to, their speech production difficulties. To investigate this issue, functional MRI data were collected on 13 PWS and 13 controls whilst the participants performed a speech production task and a speech perception task. PWS performed poorer than controls in the perception task and the poorer performance was associated with a functional activity difference in the left anterior insula (part of the speech motor area) compared to controls. PWS also showed a functional activity difference in this and the surrounding area [left inferior frontal cortex (IFC)/anterior insula] in the production task compared to controls. Conjunction analysis showed that the functional activity differences between PWS and controls in the left IFC/anterior insula coincided across the perception and production tasks. Furthermore, Granger Causality Analysis on the resting-state fMRI data of the participants showed that the causal connection from the left IFC/anterior insula to an area in the left primary auditory cortex (Heschl's gyrus) differed significantly between PWS and controls. The strength of this connection correlated significantly with performance in the perception task. These results suggest that speech perception difficulties in PWS are associated with anomalous functional activity in the speech motor area, and the altered functional connectivity from this area to the auditory area plays a role in the speech perception difficulties of PWS. PMID- 27242489 TI - Brain Atrophy as a Measure of Neuroprotective Drug Effects in Multiple Sclerosis: Influence of Inflammation. PMID- 27242488 TI - Visual Space Constructed by Saccade Motor Maps. AB - How visual space is represented in the brain is an open question in neuroscience. Embodiment theories propose that spatial perception is structured by neural motor maps. Especially, maps which code the targets for saccadic eye movements contain a precise representation of external space. In this review article, we examine how modifications in saccade maps are accompanied by changes in visual space perception. Saccade adaptation, a method which systematically modifies saccade amplitudes, alters the localization of visual objects in space. We illustrate how information about saccade amplitudes is transferred from the cerebellum (CB) to the frontal eye field (FEF). We argue that changes in visual localization after adaptation of saccade maps provide evidence for a shared representation of visual and motor space. PMID- 27242490 TI - How Plantar Exteroceptive Efficiency Modulates Postural and Oculomotor Control: Inter-Individual Variability. AB - In a previous experiment, we showed that among young and healthy subjects, thin plantar inserts improve postural control and modify vergence amplitudes. In this experiment, however, significant inter-individual variability was observed. We hypothesize that its origin could be attributed to a different reliance upon feet cutaneous afferents. In order to test this hypothesis, we re-analyzed the data relative to 31 young (age 25.7 +/- 3.8) and healthy subjects who participated in the first experiment after having classified them into two groups depending on their Plantar Quotient (PQ = Surface area of CoPfoam/Surface area of CoPfirm ground * 100). Foam decreases the information arising from the feet, normally resulting in a PQ > 100. Hence, the PQ provides information on the weight of plantar cutaneous afferents used in postural control. Twelve people were Plantar Independent Subjects, as indicated by a PQ < 100. These individuals did not behave like the Normal Plantar Quotient Subjects: they were almost insensitive to the plantar stimulations in terms of postural control and totally insensitive in terms of oculomotor control. We conclude that the inter-individual variability observed in our first experiment is explained by the subjects' degree of plantar reliance. We propose that plantar independence is a dysfunctional situation revealing inefficiency in plantar cutaneous afferents. The latter could be due to a latent somatosensory dysfunction generating a noise which prevents the CNS from correctly processing and using feet somatosensory afferents both for balance and vergence control: Plantar Irritating Stimulus. Considering the non-noxious nature and prevalence of this phenomenon, these results can be of great interest to researchers and clinicians who attempt to trigger postural or oculomotor responses through mechanical stimulation of the foot sole. PMID- 27242491 TI - Systemizers Are Better Code-Breakers: Self-Reported Systemizing Predicts Code Breaking Performance in Expert Hackers and Naive Participants. AB - Studies on hacking have typically focused on motivational aspects and general personality traits of the individuals who engage in hacking; little systematic research has been conducted on predispositions that may be associated not only with the choice to pursue a hacking career but also with performance in either naive or expert populations. Here, we test the hypotheses that two traits that are typically enhanced in autism spectrum disorders-attention to detail and systemizing-may be positively related to both the choice of pursuing a career in information security and skilled performance in a prototypical hacking task (i.e., crypto-analysis or code-breaking). A group of naive participants and of ethical hackers completed the Autism Spectrum Quotient, including an attention to detail scale, and the Systemizing Quotient (Baron-Cohen et al., 2001, 2003). They were also tested with behavioral tasks involving code-breaking and a control task involving security X-ray image interpretation. Hackers reported significantly higher systemizing and attention to detail than non-hackers. We found a positive relation between self-reported systemizing (but not attention to detail) and code breaking skills in both hackers and non-hackers, whereas attention to detail (but not systemizing) was related with performance in the X-ray screening task in both groups, as previously reported with naive participants (Rusconi et al., 2015). We discuss the theoretical and translational implications of our findings. PMID- 27242492 TI - Modulation of the Default Mode Network in First-Episode, Drug-Naive Major Depressive Disorder via Acupuncture at Baihui (GV20) Acupoint. AB - BACKGROUND: Previous neuroimaging studies have revealed that acupuncture modulates the default mode network (DMN) in healthy subjects and patients with certain disorder. However, few studies have been performed to investigate whether or not acupuncture might modulate the DMN in patients with major depressive disorder (MDD). Thereby, the aim of the present study was to assess alterations of the DMN induced by acupuncture stimulation in patients with first-episode, drug-naive MDD. MATERIALS AND METHODS: Twenty nine patients with first-episode, drug-naive MDD and 29 healthy subjects were enrolled in this study. All the healthy subjects underwent 6-min resting-state functional magnetic resonance imaging (R-fMRI) scan. While patients underwent acupuncture stimulation for 20 min electro-acupuncture stimulation (EAS) at Baihui acupoint (GV20) and two 6-min R-fMRI scans before and after EAS. Based on the precuneus/posterior cingulate cortex (PC/PCC) as the seed region, functional connectivity (FC) method was adopted to examine abnormal DMN in patients by comparing with healthy subjects and to evaluate the influence of EAS on intrinsic connectivity within the DMN in patients with MDD. RESULTS: Compared to healthy subjects, MDD patients had abnormal DMN. Moreover, results showed that EAS at GV20 induced increased FC between the PC/PCC and bilateral anterior cingulate cortex (ACC), and decreased FC between the PC/PCC and left middle prefrontal cortex, left angualr gyrus and bilateral hippocampus/parahippocampus (HIPP/paraHIPP) in patients with MDD, which were the main brain regions showing significant differences between the patients and healthy subjects. CONCLUSION: Our findings provide imaging evidence to support that GV20-related acupuncture stimulation may modulate the DMN in patients with first-episode, drug-naive MDD. This study may partly interpret the neural mechanisms of acupuncture at GV20 which is used to treat patients with MDD in clinical. PMID- 27242493 TI - From Capture to Inhibition: How does Irrelevant Information Influence Visual Search? Evidence from a Spatial Cuing Paradigm. AB - Even though information is spatially and temporally irrelevant, it can influence the processing of subsequent information. The present study used a spatial cuing paradigm to investigate the origins of this persisting influence by means of event-related potentials (ERPs) of the EEG. An irrelevant color cue that was either contingent (color search) or non-contingent (shape search) on attentional sets was presented prior to a target array with different stimulus-onset asynchronies (SOA; 200, 400, 800 ms). Behavioral results indicated that color cues captured attention only when they shared target-defining properties. These same-location effects persisted over time but were pronounced when cue and target array were presented in close succession. N2 posterior contralateral (N2pc) showed that the color cue generally drew attention, but was strongest in the contingent condition. A subsequently emerging contralateral posterior positivity referred to the irrelevant cue (i.e., distractor positivity, Pd) was unaffected by the attentional set and therefore interpreted as an inhibitory process required to enable a re-direction of the attentional focus. Contralateral delay activity (CDA) was only observable in the contingent condition, indicating the transfer of spatial information into working memory and thus providing an explanation for the same-location effect for longer SOAs. Inhibition of this irrelevant information was reflected by a second contralateral positivity triggered through target presentation. The results suggest that distracting information is actively maintained when it resembles a sought-after object. However, two independent attentional processes are at work to compensate for attentional distraction: the timely inhibition of attentional capture and the active inhibition of mental representation of irrelevant information. PMID- 27242494 TI - Modulation of Auditory Responses to Speech vs. Nonspeech Stimuli during Speech Movement Planning. AB - Previously, we showed that the N100 amplitude in long latency auditory evoked potentials (LLAEPs) elicited by pure tone probe stimuli is modulated when the stimuli are delivered during speech movement planning as compared with no speaking control conditions. Given that we probed the auditory system only with pure tones, it remained unknown whether the nature and magnitude of this pre speech auditory modulation depends on the type of auditory stimulus. Thus, here, we asked whether the effect of speech movement planning on auditory processing varies depending on the type of auditory stimulus. In an experiment with nine adult subjects, we recorded LLAEPs that were elicited by either pure tones or speech syllables when these stimuli were presented prior to speech onset in a delayed-response speaking condition vs. a silent reading control condition. Results showed no statistically significant difference in pre-speech modulation of the N100 amplitude (early stages of auditory processing) for the speech stimuli as compared with the nonspeech stimuli. However, the amplitude of the P200 component (later stages of auditory processing) showed a statistically significant pre-speech modulation that was specific to the speech stimuli only. Hence, the overall results from this study indicate that, immediately prior to speech onset, modulation of the auditory system has a general effect on early processing stages but a speech-specific effect on later processing stages. This finding is consistent with the hypothesis that pre-speech auditory modulation may play a role in priming the auditory system for its role in monitoring auditory feedback during speech production. PMID- 27242495 TI - Combining Partial Directed Coherence and Graph Theory to Analyse Effective Brain Networks of Different Mental Tasks. AB - PURPOSE: The aim of this study is to qualify the network properties of the brain networks between two different mental tasks (play task or rest task) in a healthy population. METHODS AND MATERIALS: EEG signals were recorded from 19 healthy subjects when performing different mental tasks. Partial directed coherence (PDC) analysis, based on Granger causality (GC), was used to assess the effective brain networks during the different mental tasks. Moreover, the network measures, including degree, degree distribution, local and global efficiency in delta, theta, alpha, and beta rhythms were calculated and analyzed. RESULTS: The local efficiency is higher in the beta frequency and lower in the theta frequency during play task whereas the global efficiency is higher in the theta frequency and lower in the beta frequency in the rest task. SIGNIFICANCE: This study reveals the network measures during different mental states and efficiency measures may be used as characteristic quantities for improvement in attentional performance. PMID- 27242496 TI - Slowing of Hippocampal Activity Correlates with Cognitive Decline in Early Onset Alzheimer's Disease. An MEG Study with Virtual Electrodes. AB - Pathology in Alzheimer's disease (AD) starts in the entorhinal cortex and hippocampus. Because of their deep location, activity from these areas is difficult to record with conventional electro- or magnetoencephalography (EEG/MEG). The purpose of this study was to explore hippocampal activity in AD patients and healthy controls using "virtual MEG electrodes". We used resting state MEG recordings from 27 early onset AD patients [age 60.6 +/- 5.4, 12 females, mini-mental state examination (MMSE) range: 19-28] and 26 cognitively healthy age- and gender-matched controls (age 61.8 +/- 5.5, 14 females). Activity was reconstructed using beamformer-based virtual electrodes for 78 cortical regions and 6 hippocampal regions. Group differences in peak frequency and relative power in six frequency bands were identified using permutation testing. For the patients, spearman correlations between the MMSE scores and peak frequency or relative power were calculated. Moreover, receiver operator characteristic curves were plotted to estimate the diagnostic accuracy. We found a lower hippocampal peak frequency in AD compared to controls, which, in the patients, correlated positively with MMSE [r(25) = 0.61; p < 0.01] whereas hippocampal relative theta power correlated negatively with MMSE [r(25) = -0.54; p < 0.01]. Cortical peak frequency was also lower in AD in association areas. Furthermore, cortical peak frequency correlated positively with MMSE [r(25) = 0.43; p < 0.05]. In line with this finding, relative theta power was higher in AD across the cortex, and relative alpha and beta power was lower in more circumscribed areas. The average cortical relative theta power was the best discriminator between AD and controls (sensitivity 82%; specificity 81%). Using beamformer-based virtual electrodes, we were able to detect hippocampal activity in AD. In AD, this hippocampal activity is slowed, and correlates better with cognition than the (slowed) activity in cortical areas. On the other hand, the average cortical relative power in the theta band was shown to be the best diagnostic discriminator. We postulate that this novel approach using virtual electrodes can be used in future research to quantify functional interactions between the hippocampi and cortical areas. PMID- 27242497 TI - Art expertise modulates the emotional response to modern art, especially abstract: an ERP investigation. AB - Art is one of life's great joys, whether it is beautiful, ugly, sublime or shocking. Aesthetic responses to visual art involve sensory, cognitive and visceral processes. Neuroimaging studies have yielded a wealth of information regarding aesthetic appreciation and beauty using visual art as stimuli, but few have considered the effect of expertise on visual and visceral responses. To study the time course of visual, cognitive and emotional processes in response to visual art we investigated the event-related potentials (ERPs) elicited whilst viewing and rating the visceral affect of three categories of visual art. Two groups, artists and non-artists viewed representational, abstract and indeterminate 20th century art. Early components, particularly the N1, related to attention and effort, and the P2, linked to higher order visual processing, was enhanced for artists when compared to non-artists. This effect was present for all types of art, but further enhanced for abstract art (AA), which was rated as having lowest visceral affect by the non-artists. The later, slow wave processes (500-1000 ms), associated with arousal and sustained attention, also show clear differences between the two groups in response to both type of art and visceral affect. AA increased arousal and sustained attention in artists, whilst it decreased in non-artists. These results suggest that aesthetic response to visual art is affected by both expertise and semantic content. PMID- 27242499 TI - Burst Firing Enhances Neural Output Correlation. AB - Neurons communicate and transmit information predominantly through spikes. Given that experimentally observed neural spike trains in a variety of brain areas can be highly correlated, it is important to investigate how neurons process correlated inputs. Most previous work in this area studied the problem of correlation transfer analytically by making significant simplifications on neural dynamics. Temporal correlation between inputs that arises from synaptic filtering, for instance, is often ignored when assuming that an input spike can at most generate one output spike. Through numerical simulations of a pair of leaky integrate-and-fire (LIF) neurons receiving correlated inputs, we demonstrate that neurons in the presence of synaptic filtering by slow synapses exhibit strong output correlations. We then show that burst firing plays a central role in enhancing output correlations, which can explain the above mentioned observation because synaptic filtering induces bursting. The observed changes of correlations are mostly on a long time scale. Our results suggest that other features affecting the prevalence of neural burst firing in biological neurons, e.g., adaptive spiking mechanisms, may play an important role in modulating the overall level of correlations in neural networks. PMID- 27242498 TI - The effects of anodal-tDCS on corticospinal excitability enhancement and its after-effects: conventional vs. unihemispheric concurrent dual-site stimulation. AB - Previous researchers have approved the ability of anodal transcranial direct current stimulation (a-tDCS) of the primary motor cortex (M1) to enhance corticospinal excitability (CSE). The primary aim of the current study was to investigate the effect of concurrent stimulation of M1 and a functionally connected cortical site of M1 on CSE modulation. This new technique is called unihemispheric concurrent dual-site a-tDCS (a-tDCSUHCDS). The secondary aim was to investigate the mechanisms underlying the efficacy of this new approach in healthy individuals. In a randomized crossover study, 12 healthy right-handed volunteers received a-tDCS under five conditions: a-tDCS of M1, a-tDCSUHCDS of M1 dorsolateral prefrontal cortex (DLPFC), a-tDCSUHCDS of M1-primary sensory cortex (S1), a-tDCSUHCDS of M1-primary visual cortex (V1), and sham a-tDCSUHCDS. Peak-to peak amplitude of transcranial magnetic stimulation (TMS) induced MEPs, short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were assessed before and four times after each condition. A-tDCSUHCDS conditions induced larger MEPs than conventional a-tDCS. The level of M1 CSE was significantly higher following a-tDCSUHCDS of M1-DLPFC than other a-tDCSUHCDS conditions (p < 0.001), and lasted for over 24 h. The paired-pulse TMS results after a-tDCS of M1-DLPFC showed significant facilitatory increase and inhibitory change. A-tDCSUHCDS of M1-DLPFC increases M1 CSE twofold that of conventional a tDCS. A-tDCSUHCDS of M1-DLPFC enhances the activity of glutamergic mechanisms for at least 24 h. Such long-lasting M1 CSE enhancement induced by a-tDCSUHCDS of M1 DLPFC could be a valuable finding in clinical scenarios such as learning, motor performance, or pain management. The present study has been registered on the Australian New Zealand Clinical Trial at http://www.anzctr.org.au/ with registry number of ACTRN12614000817640. PMID- 27242500 TI - Anti-kindling Induced by Two-Stage Coordinated Reset Stimulation with Weak Onset Intensity. AB - Abnormal neuronal synchrony plays an important role in a number of brain diseases. To specifically counteract abnormal neuronal synchrony by desynchronization, Coordinated Reset (CR) stimulation, a spatiotemporally patterned stimulation technique, was designed with computational means. In neuronal networks with spike timing-dependent plasticity CR stimulation causes a decrease of synaptic weights and finally anti-kindling, i.e., unlearning of abnormally strong synaptic connectivity and abnormal neuronal synchrony. Long lasting desynchronizing aftereffects of CR stimulation have been verified in pre clinical and clinical proof of concept studies. In general, for different neuromodulation approaches, both invasive and non-invasive, it is desirable to enable effective stimulation at reduced stimulation intensities, thereby avoiding side effects. For the first time, we here present a two-stage CR stimulation protocol, where two qualitatively different types of CR stimulation are delivered one after another, and the first stage comes at a particularly weak stimulation intensity. Numerical simulations show that a two-stage CR stimulation can induce the same degree of anti-kindling as a single-stage CR stimulation with intermediate stimulation intensity. This stimulation approach might be clinically beneficial in patients suffering from brain diseases characterized by abnormal neuronal synchrony where a first treatment stage should be performed at particularly weak stimulation intensities in order to avoid side effects. This might, e.g., be relevant in the context of acoustic CR stimulation in tinnitus patients with hyperacusis or in the case of electrical deep brain CR stimulation with sub-optimally positioned leads or side effects caused by stimulation of the target itself. We discuss how to apply our method in first in man and proof of concept studies. PMID- 27242501 TI - Placebo Analgesia Changes Alpha Oscillations Induced by Tonic Muscle Pain: EEG Frequency Analysis Including Data during Pain Evaluation. AB - Placebo exhibits beneficial effects on pain perception in human experimental studies. Most of these studies demonstrate that placebo significantly decreased neural activities in pain modulatory brain regions and pain-evoked potentials. This study examined placebo analgesia-related effects on spontaneous brain oscillations. We examined placebo effects on four order-fixed 20-min conditions in two sessions: isotonic saline-induced control conditions (with/without placebo) followed by hypertonic saline-induced tonic muscle pain conditions (with/without placebo) in 19 subjects using continuous electroencephalography (EEG) recording. Placebo treatment exerted significant analgesic effects in 14 placebo responders, as subjective intensity of pain perception decreased. Frequency analyses were performed on whole continuous EEG data, data during pain perception rating and data after rating. The results in the first two cases revealed that placebo induced significant increases and a trend toward significant increases in the amplitude of alpha oscillation during tonic muscle pain compared to control conditions in frontal-central regions of the brain, respectively. Placebo-induced decreases in the subjective intensity of pain perception significantly and positively correlated with the increases in the amplitude of alpha oscillations during pain conditions. In conclusion, the modulation effect of placebo treatment was captured when the pain perception evaluating period was included. The strong correlation between the placebo effect on reported pain perception and alpha amplitude suggest that alpha oscillations in frontal-central regions serve as a cortical oscillatory basis of the placebo effect on tonic muscle pain. These results provide important evidence for the investigation of objective indicators of the placebo effect. PMID- 27242502 TI - Novel Modeling of Task vs. Rest Brain State Predictability Using a Dynamic Time Warping Spectrum: Comparisons and Contrasts with Other Standard Measures of Brain Dynamics. AB - Dynamic time warping, or DTW, is a powerful and domain-general sequence alignment method for computing a similarity measure. Such dynamic programming-based techniques like DTW are now the backbone and driver of most bioinformatics methods and discoveries. In neuroscience it has had far less use, though this has begun to change. We wanted to explore new ways of applying DTW, not simply as a measure with which to cluster or compare similarity between features but in a conceptually different way. We have used DTW to provide a more interpretable spectral description of the data, compared to standard approaches such as the Fourier and related transforms. The DTW approach and standard discrete Fourier transform (DFT) are assessed against benchmark measures of neural dynamics. These include EEG microstates, EEG avalanches, and the sum squared error (SSE) from a multilayer perceptron (MLP) prediction of the EEG time series, and simultaneously acquired FMRI BOLD signal. We explored the relationships between these variables of interest in an EEG-FMRI dataset acquired during a standard cognitive task, which allowed us to explore how DTW differentially performs in different task settings. We found that despite strong correlations between DTW and DFT-spectra, DTW was a better predictor for almost every measure of brain dynamics. Using these DTW measures, we show that predictability is almost always higher in task than in rest states, which is consistent to other theoretical and empirical findings, providing additional evidence for the utility of the DTW approach. PMID- 27242503 TI - Building the Ferretome. AB - Databases of structural connections of the mammalian brain, such as CoCoMac (cocomac.g-node.org) or BAMS (https://bams1.org), are valuable resources for the analysis of brain connectivity and the modeling of brain dynamics in species such as the non-human primate or the rodent, and have also contributed to the computational modeling of the human brain. Another animal model that is widely used in electrophysiological or developmental studies is the ferret; however, no systematic compilation of brain connectivity is currently available for this species. Thus, we have started developing a database of anatomical connections and architectonic features of the ferret brain, the Ferret(connect)ome, www.Ferretome.org. The Ferretome database has adapted essential features of the CoCoMac methodology and legacy, such as the CoCoMac data model. This data model was simplified and extended in order to accommodate new data modalities that were not represented previously, such as the cytoarchitecture of brain areas. The Ferretome uses a semantic parcellation of brain regions as well as a logical brain map transformation algorithm (objective relational transformation, ORT). The ORT algorithm was also adopted for the transformation of architecture data. The database is being developed in MySQL and has been populated with literature reports on tract-tracing observations in the ferret brain using a custom-designed web interface that allows efficient and validated simultaneous input and proofreading by multiple curators. The database is equipped with a non-specialist web interface. This interface can be extended to produce connectivity matrices in several formats, including a graphical representation superimposed on established ferret brain maps. An important feature of the Ferretome database is the possibility to trace back entries in connectivity matrices to the original studies archived in the system. Currently, the Ferretome contains 50 reports on connections comprising 20 injection reports with more than 150 labeled source and target areas, the majority reflecting connectivity of subcortical nuclei and 15 descriptions of regional brain architecture. We hope that the Ferretome database will become a useful resource for neuroinformatics and neural modeling, and will support studies of the ferret brain as well as facilitate advances in comparative studies of mesoscopic brain connectivity. PMID- 27242504 TI - Concepts and Relations in Neurally Inspired In Situ Concept-Based Computing. AB - In situ concept-based computing is based on the notion that conceptual representations in the human brain are "in situ." In this way, they are grounded in perception and action. Examples are neuronal assemblies, whose connection structures develop over time and are distributed over different brain areas. In situ concepts representations cannot be copied or duplicated because that will disrupt their connection structure, and thus the meaning of these concepts. Higher-level cognitive processes, as found in language and reasoning, can be performed with in situ concepts by embedding them in specialized neurally inspired "blackboards." The interactions between the in situ concepts and the blackboards form the basis for in situ concept computing architectures. In these architectures, memory (concepts) and processing are interwoven, in contrast with the separation between memory and processing found in Von Neumann architectures. Because the further development of Von Neumann computing (more, faster, yet power limited) is questionable, in situ concept computing might be an alternative for concept-based computing. In situ concept computing will be illustrated with a recently developed BABI reasoning task. Neurorobotics can play an important role in the development of in situ concept computing because of the development of in situ concept representations derived in scenarios as needed for reasoning tasks. Neurorobotics would also benefit from power limited and in situ concept computing. PMID- 27242505 TI - Molecular Machines Determining the Fate of Endocytosed Synaptic Vesicles in Nerve Terminals. AB - The cycle of a synaptic vesicle (SV) within the nerve terminal is a step-by-step journey with the final goal of ensuring the proper synaptic strength under changing environmental conditions. The SV cycle is a precisely regulated membrane traffic event in cells and, because of this, a plethora of membrane-bound and cytosolic proteins are devoted to assist SVs in each step of the journey. The cycling fate of endocytosed SVs determines both the availability for subsequent rounds of release and the lifetime of SVs in the terminal and is therefore crucial for synaptic function and plasticity. Molecular players that determine the destiny of SVs in nerve terminals after a round of exo-endocytosis are largely unknown. Here we review the functional role in SV fate of phosphorylation/dephosphorylation of SV proteins and of small GTPases acting on membrane trafficking at the synapse, as they are emerging as key molecules in determining the recycling route of SVs within the nerve terminal. In particular, we focus on: (i) the cyclin-dependent kinase-5 (cdk5) and calcineurin (CN) control of the recycling pool of SVs; (ii) the role of small GTPases of the Rab and ADP-ribosylation factor (Arf) families in defining the route followed by SV in their nerve terminal cycle. These regulatory proteins together with their synaptic regulators and effectors, are molecular nanomachines mediating homeostatic responses in synaptic plasticity and potential targets of drugs modulating the efficiency of synaptic transmission. PMID- 27242506 TI - Discriminative Learning for Alzheimer's Disease Diagnosis via Canonical Correlation Analysis and Multimodal Fusion. AB - To address the challenging task of diagnosing neurodegenerative brain disease, such as Alzheimer's disease (AD) and mild cognitive impairment (MCI), we propose a novel method using discriminative feature learning and canonical correlation analysis (CCA) in this paper. Specifically, multimodal features and their CCA projections are concatenated together to represent each subject, and hence both individual and shared information of AD disease are captured. A discriminative learning with multilayer feature hierarchy is designed to further improve performance. Also, hybrid representation is proposed to maximally explore data from multiple modalities. A novel normalization method is devised to tackle the intra- and inter-subject variations from the multimodal data. Based on our extensive experiments, our method achieves an accuracy of 96.93% [AD vs. normal control (NC)], 86.57 % (MCI vs. NC), and 82.75% [MCI converter (MCI-C) vs. MCI non-converter (MCI-NC)], respectively, which outperforms the state-of-the-art methods in the literature. PMID- 27242507 TI - Impact of Exercise and Education in Adults of Lubbock, Texas: Implications for Better Lifestyle. AB - The objective of our study was to evaluate the exercise and educational intervention in the city of Lubbock via GET FiT Lubbock (GFL) program. The GFL program was designed to increase exercise and educational opportunities, which positively impact health risk factors in Lubbock residents. The GFL program design included the recruitment of subjects to participate on a team that consisted of four individuals, each subject tracked their exercise minutes, and their educational session attendance. The tracking of exercise and educational sessions was done on the GFL website. Biometric testing was conducted pre- and post- intervention. The program was located within the Lubbock community in places that were close to their place of residence. The intervention included walking and educational sessions, including goal setting lectures, nutrition information, and exercise demonstrations. Study participants, included male and female adults who tracked their exercise time and educational sessions. Exercise minutes and educational session attendance were self-reported. Our data analysis revealed that significant difference was found between pre- and post- intervention measures, including weight, body mass index (BMI), high-density lipoprotein (HDL). Significant difference was found for weight, BMI, and HDL in females. Based on these findings, we conclude that the intervention showed positive effects on exercise and lifestyle. PMID- 27242508 TI - Small Changes, But Huge Impact? The Right Anterior Insula's Loss of Connection Strength during the Transition of Old to Very Old Age. AB - A major contribution to our understanding of the aging brain comes either from studies comparing young with older adults or from studies investigating pathological aging and using the healthy aging older adults as control group. In consequence, we know relatively well, what distinguishes young from old brains or pathological aging from healthy but that does not mean that we really understand the structural and functional transformations characterizing the healthy aging brain. By analyzing task-free fMRI data from a large cross-sectional sample of 186 older adults (mean age = 70.4, 97 female), we aimed to elucidate age-related changes in the intrinsically active functional architecture of the brain in our study group covering an age range from 65 to 85 years. First, we conducted an intrinsic connectivity contrast analysis (ICC) in order to detect the brain regions whose degree of connectedness was significantly correlated with increasing age. Secondly, using connectivity analyses we investigated how the clusters highlighted by the ICC analysis functionally related to the other major resting-state networks. The most important finding was the right anterior insula's loss of connectedness in the older participants of the study group because of the region's causal role in the switching from the task-negative to the task-positive state of the brain. Further, we found a higher functional dedifferentiation of two of the brain's major intrinsic connectivity networks, the DMN, and the cingulo-opercular network, caused by a reduction of functional connection strength, especially in the frontal regions. At last, we showed that all these age-related changes have the potential to impair older adult's performance of working memory tasks. PMID- 27242509 TI - Isolation and Molecular Profiling of Primary Mouse Retinal Ganglion Cells: Comparison of Phenotypes from Healthy and Glaucomatous Retinas. AB - Loss of functional retinal ganglion cells (RGC) is an element of retinal degeneration that is poorly understood. This is in part due to the lack of a reliable and validated protocol for the isolation of primary RGCs. Here we optimize a feasible, reproducible, standardized flow cytometry-based protocol for the isolation and enrichment of homogeneous RGC with the Thy1.2(hi)CD48(neg)CD15(neg)CD57(neg) surface phenotype. A three-step validation process was performed by: (1) genomic profiling of 25-genes associated with retinal cells; (2) intracellular labeling of homogeneous sorted cells for the intracellular RGC-markers SNCG, brain-specific homeobox/POU domain protein 3A (BRN3A), TUJ1, and RNA-binding protein with multiple splicing (RBPMS); and (3) by applying the methodology on RGC from a mouse model with elevated intraocular pressure (IOP) and optic nerve damage. Use of primary RGC cultures will allow for future careful assessment of important cell specific pathways in RGC to provide mechanistic insights into the declining of visual acuity in aged populations and those suffering from retinal neurodegenerative diseases. PMID- 27242510 TI - The Busier the Better: Greater Busyness Is Associated with Better Cognition. AB - Sustained engagement in mentally challenging activities has been shown to improve memory in older adults. We hypothesized that a busy schedule would be a proxy for an engaged lifestyle and would facilitate cognition. Here, we examined the relationship between busyness and cognition in adults aged 50-89. Participants (N = 330) from the Dallas Lifespan Brain Study (DLBS) completed a cognitive battery and the Martin and Park Environmental Demands Questionnaire (MPED), an assessment of busyness. Results revealed that greater busyness was associated with better processing speed, working memory, episodic memory, reasoning, and crystallized knowledge. Hierarchical regressions also showed that, after controlling for age and education, busyness accounted for significant additional variance in all cognitive constructs-especially episodic memory. Finally, an interaction between age and busyness was not present while predicting cognitive performance, suggesting that busyness was similarly beneficial in adults aged 50-89. Although correlational, these data demonstrate that living a busy lifestyle is associated with better cognition. PMID- 27242511 TI - An Event-Related Potential Investigation of the Effects of Age on Alerting, Orienting, and Executive Function. AB - The present study compared young and older adults on behavioral and neural correlates of three attentional networks (alerting, orienting, and executive control). Nineteen young and 16 older neurologically-healthy adults completed the Attention Network Test (ANT) while behavioral data (reaction time and error rates) and 64-channel event-related potentials (ERPs) were acquired. Significant age-related RT differences were observed across all three networks; however, after controlling for generalized slowing, only the alerting network remained significantly reduced in older compared with young adults. ERP data revealed that alerting cues led to enhanced posterior N1 responses for subsequent attentional targets in young adults, but this effect was weakened in older adults. As a result, it appears that older adults did not benefit fully from alerting cues, and their lack of subsequent attentional enhancements may compromise their ability to be as responsive and flexible as their younger counterparts. N1 alerting deficits were associated with several key neuropsychological tests of attention that were difficult for older adults. Orienting and executive attention networks were largely similar between groups. Taken together, older adults demonstrated behavioral and neural alterations in alerting, however, they appeared to compensate for this reduction, as they did not significantly differ in their abilities to use spatially informative cues to aid performance (e.g., orienting), or successfully resolve response conflict (e.g., executive control). These results have important implications for understanding the mechanisms of age related changes in attentional networks. PMID- 27242512 TI - Age-Related Differences in the Modulation of Small-World Brain Networks during a Go/NoGo Task. AB - Although inter-regional phase synchrony of neural oscillations has been proposed as a plausible mechanism for response control, little is known about the possible effects due to normal aging. We recorded multi-channel electroencephalography (EEG) from healthy younger and older adults in a Go/NoGo task, and examined the aging effects on synchronous brain networks with graph theoretical analysis. We found that in both age groups, brain networks in theta, alpha or beta band for either response execution (Go) or response inhibition (NoGo) condition showed prominent small-world property. Furthermore, small-world property of brain networks showed significant differences between different task conditions. Further analyses of node degree suggested that frontal-central theta band phase synchrony was enhanced during response inhibition, whereas during response execution, increased phase synchrony was observed in beta band over central parietal regions. More interestingly, these task-related modulations on brain networks were well preserved and even more robust in older adults compared with younger adults. Taken together, our findings not only suggest that response control involves synchronous brain networks in functionally-distinct frequency bands, but also indicate an increase in the recruitment of brain network resources due to normal aging. PMID- 27242514 TI - EPA/DHA and Vitamin A Supplementation Improves Spatial Memory and Alleviates the Age-related Decrease in Hippocampal RXRgamma and Kinase Expression in Rats. AB - Studies suggest that eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and vitamin A are critical to delay aged-related cognitive decline. These nutrients regulate gene expression in the brain by binding to nuclear receptors such as the retinoid X receptors (RXRs) and the retinoic acid receptors (RARs). Moreover, EPA/DHA and retinoids activate notably kinase signaling pathways such as AKT or MAPK, which includes ERK1/2. This suggests that these nutrients may modulate brain function in a similar way. Therefore, we investigated in middle-aged rats the behavioral and molecular effects of supplementations with EPA/DHA and vitamin A alone or combined. 18-month-old rats exhibited reference and working memory deficits in the Morris water maze, associated with a decrease in serum vitamin A and hippocampal EPA/DHA contents. RARalpha, RXRbeta, and RXRgamma mRNA expression and CAMKII, AKT, ERK1/2 expression were decreased in the hippocampus of middle aged rats. A combined EPA/DHA and vitamin A supplementation had a beneficial additive effect on reference memory but not in working memory in middle-aged rats, associated with an alleviation of the age-related decrease in RXRgamma, CAMKII, AKT, and ERK1 expression in the hippocampus. This study provides a new combined nutritional strategy to delay brain aging. PMID- 27242515 TI - Attentional Control of Gait and Falls: Is Cholinergic Dysfunction a Common Substrate in the Elderly and Parkinson's Disease? AB - The aim of this study was to address whether deficits in the central cholinergic activity may contribute to the increased difficulty to allocate attention during gait in the elderly with heightened risk of falls. We recruited 50 participants with a history of two or more falls (33 patients with Parkinson's Disease and 17 older adults) and 14 non-fallers age-matched adults. Cholinergic activity was estimated by means of short latency afferent inhibition (SAI), a transcranial magnetic stimulation (TMS) technique that assesses an inhibitory circuit in the sensorimotor cortex and is regarded as a global marker of cholinergic function in the brain. Increased difficulty to allocate attention during gait was evaluated by measuring gait performance under single and dual-task conditions. Global cognition was also assessed. Results showed that SAI was reduced in patients with PD than in the older adults (fallers and non-fallers) and in older adults fallers with respect to non-fallers. Reduction in SAI indicates less inhibition i.e., less cholinergic activity. Gait speed was reduced in the dual task gait compared to normal gait only in our faller population and changes in gait speed under dual task significantly correlated with the mean value of SAI. This association remained significant after adjusting for cognitive status. These findings suggest that central cholinergic activity may be a predictor of change in gait characteristics under dual tasking in older adults and PD fallers independently of cognitive status. PMID- 27242513 TI - Cognitive Aging and Time Perception: Roles of Bayesian Optimization and Degeneracy. AB - This review outlines the basic psychological and neurobiological processes associated with age-related distortions in timing and time perception in the hundredths of milliseconds-to-minutes range. The difficulty in separating indirect effects of impairments in attention and memory from direct effects on timing mechanisms is addressed. The main premise is that normal aging is commonly associated with increased noise and temporal uncertainty as a result of impairments in attention and memory as well as the possible reduction in the accuracy and precision of a central timing mechanism supported by dopamine glutamate interactions in cortico-striatal circuits. Pertinent to these findings, potential interventions that may reduce the likelihood of observing age-related declines in timing are discussed. Bayesian optimization models are able to account for the adaptive changes observed in time perception by assuming that older adults are more likely to base their temporal judgments on statistical inferences derived from multiple trials than on a single trial's clock reading, which is more susceptible to distortion. We propose that the timing functions assigned to the age-sensitive fronto-striatal network can be subserved by other neural networks typically associated with finely-tuned perceptuo-motor adjustments, through degeneracy principles (different structures serving a common function). PMID- 27242516 TI - Impact of Mild Head Injury on Neuropsychological Performance in Healthy Older Adults: Longitudinal Assessment in the AIBL Cohort. AB - Traumatic brain injury (TBI) is suggested to be a significant risk factor for dementia. However, little research has been conducted into long-term neuropsychological outcomes after head trauma. Participants from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing (AIBL) who had recovered after sustaining a mild TBI involving loss of consciousness more than 5 years previously were compared with matched controls across a 3-year period. Bayesian nested-domain modeling was used to estimate the effect of TBI on neuropsychological performance. There was no evidence for a chronic effect of mild TBI on any neuropsychological domain compared to controls. Within the TBI group, there was some evidence suggesting that the age that the head trauma occurred and the duration of unconsciousness were modulators of episodic memory. However, these findings were not robust. Taken together, these findings indicate that adults who have sustained a TBI resulting in loss of consciousness, but who recover to a healthy level of cognitive functioning, do not experience frank deficits in cognitive ability. PMID- 27242517 TI - Commentary: Modulation of Prepulse Inhibition and Startle Reflex by Emotions: A Comparison between Young and Older Adults. PMID- 27242518 TI - Glycines from the APP GXXXG/GXXXA Transmembrane Motifs Promote Formation of Pathogenic Abeta Oligomers in Cells. AB - Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by progressive cognitive decline leading to dementia. The amyloid precursor protein (APP) is a ubiquitous type I transmembrane (TM) protein sequentially processed to generate the beta-amyloid peptide (Abeta), the major constituent of senile plaques that are typical AD lesions. There is a growing body of evidence that soluble Abeta oligomers correlate with clinical symptoms associated with the disease. The Abeta sequence begins in the extracellular juxtamembrane region of APP and includes roughly half of the TM domain. This region contains GXXXG and GXXXA motifs, which are critical for both TM protein interactions and fibrillogenic properties of peptides derived from TM alpha helices. Glycine-to-leucine mutations of these motifs were previously shown to affect APP processing and Abeta production in cells. However, the detailed contribution of these motifs to APP dimerization, their relation to processing, and the conformational changes they can induce within Abeta species remains undefined. Here, we describe highly resistant Abeta42 oligomers that are produced in cellular membrane compartments. They are formed in cells by processing of the APP amyloidogenic C-terminal fragment (C99), or by direct expression of a peptide corresponding to Abeta42, but not to Abeta40. By a point-mutation approach, we demonstrate that glycine-to-leucine mutations in the G(29)XXXG(33) and G(38)XXXA(42) motifs dramatically affect the Abeta oligomerization process. G33 and G38 in these motifs are specifically involved in Abeta oligomerization; the G33L mutation strongly promotes oligomerization, while G38L blocks it with a dominant effect on G33 residue modification. Finally, we report that the secreted Abeta42 oligomers display pathological properties consistent with their suggested role in AD, but do not induce toxicity in survival assays with neuronal cells. Exposure of neurons to these Abeta42 oligomers dramatically affects neuronal differentiation and, consequently, neuronal network maturation. PMID- 27242520 TI - Commentary: Older adults can improve compensatory stepping with repeated postural perturbations. PMID- 27242519 TI - Age-Related Changes in BOLD Activation Pattern in Phonemic Fluency Paradigm: An Investigation of Activation, Functional Connectivity and Psychophysiological Interactions. AB - Healthy aging is associated with decline of cognitive functions. However, even before those declines become noticeable, the neural architecture underlying those mechanisms has undergone considerable restructuring and reorganization. During performance of a cognitive task, not only have the task-relevant networks demonstrated reorganization with aging, which occurs primarily by recruitment of additional areas to preserve performance, but the task-irrelevant network of the "default-mode" network (DMN), which is normally deactivated during task performance, has also consistently shown reduction of this deactivation with aging. Here, we revisited those age-related changes in task-relevant (i.e., language system) and task-irrelevant (i.e., DMN) systems with a language production paradigm in terms of task-induced activation/deactivation, functional connectivity, and context-dependent correlations between the two systems. Our task fMRI data demonstrated a late increase in cortical recruitment in terms of extent of activation, only observable in our older healthy adult group, when compared to the younger healthy adult group, with recruitment of the contralateral hemisphere, but also other regions from the network previously underutilized. Our middle-aged individuals, when compared to the younger healthy adult group, presented lower levels of activation intensity and connectivity strength, with no recruitment of additional regions, possibly reflecting an initial, uncompensated, network decline. In contrast, the DMN presented a gradual decrease in deactivation intensity and deactivation extent (i.e., low in the middle-aged, and lower in the old) and similar gradual reduction of functional connectivity within the network, with no compensation. The patterns of age related changes in the task-relevant system and DMN are incongruent with the previously suggested notion of anti-correlation of the two systems. The context dependent correlation by psycho-physiological interaction (PPI) analysis demonstrated an independence of these two systems, with the onset of task not influencing the correlation between the two systems. Our results suggest that the language network and the DMN may be non-dependent systems, potentially correlated through the re-allocation of cortical resources, and that aging may affect those two systems differently. PMID- 27242521 TI - Abnormal Changes of Brain Cortical Anatomy and the Association with Plasma MicroRNA107 Level in Amnestic Mild Cognitive Impairment. AB - MicroRNA107 (Mir107) has been thought to relate to the brain structure phenotype of Alzheimer's disease. In this study, we evaluated the cortical anatomy in amnestic mild cognitive impairment (aMCI) and the relation between cortical anatomy and plasma levels of Mir107 and beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1). Twenty aMCI (20 aMCI) and 24 cognitively normal control (NC) subjects were recruited, and T1-weighted MR images were acquired. Cortical anatomical measurements, including cortical thickness (CT), surface area (SA), and local gyrification index (LGI), were assessed. Quantitative RT-PCR was used to examine plasma expression of Mir107, BACE1 mRNA. Thinner cortex was found in aMCI in areas associated with episodic memory and language, but with thicker cortex in other areas. SA decreased in aMCI in the areas associated with working memory and emotion. LGI showed a significant reduction in aMCI in the areas involved in language function. Changes in Mir107 and BACE1 messenger RNA plasma expression were correlated with changes in CT and SA. We found alterations in key left brain regions associated with memory, language, and emotion in aMCI that were significantly correlated with plasma expression of Mir107 and BACE1 mRNA. This combination study of brain anatomical alterations and gene information may shed lights on our understanding of the pathology of AD. CLINICAL TRIAL REGISTRATION: http://www.ClinicalTrials.gov, identifier NCT01819545. PMID- 27242524 TI - Economic Evaluation in Stratified Medicine: Methodological Issues and Challenges. AB - BACKGROUND: Stratified Medicine (SM) is becoming a practical reality with the targeting of medicines by using a biomarker or genetic-based diagnostic to identify the eligible patient sub-population. Like any healthcare intervention, SM interventions have costs and consequences that must be considered by reimbursement authorities with limited resources. Methodological standards and guidelines exist for economic evaluations in clinical pharmacology and are an important component for health technology assessments (HTAs) in many countries. However, these guidelines have initially been developed for traditional pharmaceuticals and not for complex interventions with multiple components. This raises the issue as to whether these guidelines are adequate to SM interventions or whether new specific guidance and methodology is needed to avoid inconsistencies and contradictory findings when assessing economic value in SM. OBJECTIVE: This article describes specific methodological challenges when conducting health economic (HE) evaluations for SM interventions and outlines potential modifications necessary to existing evaluation guidelines /principles that would promote consistent economic evaluations for SM. RESULTS/CONCLUSIONS: Specific methodological aspects for SM comprise considerations on the choice of comparator, measuring effectiveness and outcomes, appropriate modeling structure and the scope of sensitivity analyses. Although current HE methodology can be applied for SM, greater complexity requires further methodology development and modifications in the guidelines. PMID- 27242522 TI - Transcription Profile of Aging and Cognition-Related Genes in the Medial Prefrontal Cortex. AB - Cognitive function depends on transcription; however, there is little information linking altered gene expression to impaired prefrontal cortex function during aging. Young and aged F344 rats were characterized on attentional set shift and spatial memory tasks. Transcriptional differences associated with age and cognition were examined using RNA sequencing to construct transcriptomic profiles for the medial prefrontal cortex (mPFC), white matter, and region CA1 of the hippocampus. The results indicate regional differences in vulnerability to aging. Age-related gene expression in the mPFC was similar to, though less robust than, changes in the dorsolateral PFC of aging humans suggesting that aging processes may be similar. Importantly, the pattern of transcription associated with aging did not predict cognitive decline. Rather, increased mPFC expression of genes involved in regulation of transcription, including transcription factors that regulate the strength of excitatory and inhibitory inputs, and neural activity related immediate-early genes was observed in aged animals that exhibit delayed set shift behavior. The specificity of impairment on a mPFC-dependent task, associated with a particular mPFC transcriptional profile indicates that impaired executive function involves altered transcriptional regulation and neural activity/plasticity processes that are distinct from that described for impaired hippocampal function. PMID- 27242525 TI - beta-Adrenoceptor-mediated Relaxation of Urinary Bladder Muscle in beta2 Adrenoceptor Knockout Mice. AB - BACKGROUND AND OBJECTIVE: In order to characterize the beta-adrenoceptor (AR) subtypes involved in agonist-stimulated relaxation of murine urinary bladder we studied the effects of (-)-isoprenaline and CL 316,243 on tonic contraction and spontaneous contractions in detrusor strips of wild-type (WT) and beta2-AR knockout (beta2-AR KO) mice. MATERIALS AND METHODS: Urinary bladders were isolated from male WT and beta2-AR KO mice. beta-AR subtype expression was determined with quantitative real-time PCR. Intact muscle strips pre-contracted with KCl (40 mM) were exposed to cumulatively increasing concentrations of (-) isoprenaline or beta3-AR agonist CL 316,243 in the presence and absence of the subtype-selective beta-AR blockers CGP 20712A (beta1-ARs), ICI 118,551 (beta2 ARs), and L748,337 (beta3-ARs). RESULTS: Quantitative real-time PCR confirmed lack of beta2-AR expression in bladder tissue from beta2-AR KO mice. In isolated detrusor strips, pre-contraction with KCl increased basal tone and enhanced spontaneous activity significantly more in beta2-AR KO than in WT. (-) Isoprenaline relaxed tonic tension and attenuated spontaneous activity with similar potency, but the concentrations required were two orders of magnitude higher in beta2-AR KO than WT. The concentration-response curves (CRCs) for relaxation were not affected by CGP 20712A (300 nM), but were shifted to the right by ICI 118,551 (50 nM) and L748,337 (10 MUM). The -logEC50 values for (-) isoprenaline in WT and beta2-AR KO tissue were 7.98 and 6.00, respectively, suggesting a large receptor reserve of beta2-AR. (-)-CL 316,243 relaxed detrusor and attenuated spontaneous contractions from WT and beta2-AR KO mice with a potency corresponding to the drug's affinity for beta3-AR. L743,337 shifted the CRCs to the right. CONCLUSION: Our findings in beta2-AR KO mice suggest that there is a large receptor reserve for beta2-AR in WT mice so that this beta-AR subtype will mediate relaxation of tone and attenuation of spontaneous activity under physiological conditions. Nevertheless, upon removal of this reserve, beta3 AR can also mediate murine detrusor relaxation. PMID- 27242523 TI - A Review of Sleep and Its Disorders in Patients with Parkinson's Disease in Relation to Various Brain Structures. AB - Sleep is an indispensable normal physiology of the human body fundamental for healthy functioning. It has been observed that Parkinson's disease (PD) not only exhibits motor symptoms, but also non-motor symptoms such as metabolic irregularities, altered olfaction, cardiovascular dysfunction, gastrointestinal complications and especially sleep disorders which is the focus of this review. A good understanding and knowledge of the different brain structures involved and how they function in the development of sleep disorders should be well comprehended in order to treat and alleviate these symptoms and enhance quality of life for PD patients. Therefore it is vital that the normal functioning of the body in relation to sleep is well understood before proceeding on to the pathophysiology of PD correlating to its symptoms. Suitable treatment can then be administered toward enhancing the quality of life of these patients, perhaps even discovering the cause for this disease. PMID- 27242526 TI - E2F4 Promotes Neuronal Regeneration and Functional Recovery after Spinal Cord Injury in Zebrafish. AB - Mammals exhibit poor recovery after spinal cord injury (SCI), whereas non mammalian vertebrates exhibit significant spontaneous recovery after SCI. The mechanisms underlying this difference have not been fully elucidated; therefore, the purpose of this study was to investigate these mechanisms. Using comparative transcriptome analysis, we demonstrated that genes related to cell cycle were significantly enriched in the genes specifically dysregulated in zebrafish SCI. Most of the cell cycle-related genes dysregulated in zebrafish SCI were down regulated, possibly through activation of e2f4. Using a larval zebrafish model of SCI, we demonstrated that the recovery of locomotive function and neuronal regeneration after SCI were significantly inhibited in zebrafish treated with an E2F4 inhibitor. These results suggest that activation of e2f4 after SCI may be responsible, at least in part, for the significant recovery in zebrafish. This provides novel insight into the lack of recovery after SCI in mammals and informs potential therapeutic strategies. PMID- 27242527 TI - Rifaximin Improves Clostridium difficile Toxin A-Induced Toxicity in Caco-2 Cells by the PXR-Dependent TLR4/MyD88/NF-kappaB Pathway. AB - BACKGROUND: Clostridium difficile infections (CDIs) caused by Clostridium difficile toxin A (TcdA) lead to severe ulceration, inflammation and bleeding of the colon, and are difficult to treat. AIM: The study aimed to evaluate the effect of rifaximin on TcdA-induced apoptosis in intestinal epithelial cells and investigate the role of PXR in its mechanism of action. METHODS: Caco-2 cells were incubated with TcdA and treated with rifaximin (0.1-10 MUM) with or without ketoconazole (10 MUM). The transepithelial electrical resistance (TEER) and viability of the treated cells was determined. Also, the expression of zona occludens-1 (ZO-1), toll-like receptor 4 (TLR4), Bcl-2-associated X protein (Bax), transforming growth factor-beta-activated kinase-1 (TAK1), myeloid differentiation factor 88 (MyD88), and nuclear factor-kappaB (NF-kappaB) was determined. RESULTS: Rifaximin treatment (0.1, 1.0, and 10 MUM) caused a significant and concentration-dependent increase in the TEER of Caco-2 cells (360, 480, and 680% vs. TcdA treatment) 24 h after the treatment and improved their viability (61, 79, and 105%). Treatment also concentration-dependently decreased the expression of Bax protein (-29, -65, and -77%) and increased the expression of ZO-1 (25, 54, and 87%) and occludin (71, 114, and 262%) versus TcdA treatment. The expression of TLR4 (-33, -50, and -75%), MyD88 (-29, -60, and 81%) and TAK1 (-37, -63, and -79%) were also reduced with rifaximin versus TcdA treatment. Ketoconazole treatment inhibited these effects. CONCLUSION: Rifaximin improved TcdA-induced toxicity in Caco-2 cells by the PXR-dependent TLR4/MyD88/NF kappaB pathway mechanism, and may be useful in the treatment of CDIs. PMID- 27242529 TI - Impact of Bep or Carboplatin Chemotherapy on Testicular Function and Sperm Nucleus of Subjects with Testicular Germ Cell Tumor. AB - Young males have testicular germ cells tumors (TGCT) as the most common malignancy and its incidence is increasing in several countries. Besides unilateral orchiectomy (UO), the treatment of TGCT may include surveillance, radiotherapy, or chemotherapy (CT), basing on tumor histology and stage of disease. It is well known that both radio and CT may have negative effects on testicular function, affecting spermatogenesis, and sex hormones. Many reports investigated these aspects in patients treated with bleomycin, etoposide, and cisplatin (BEP), after UO. In contrast no data are available on the side effects of carboplatin treatment in these patients. We included in this study 212 consecutive subjects who undergone to sperm banking at our Andrology and Human Reproduction Unit after UO for TGCT. Hundred subjects were further treated with one or more BEP cycles (BEP-group), 54 with carboplatin (CARB group), and 58 were just surveilled (S-group). All patients were evaluated for seminal parameters, sperm aneuploidy, sperm DNA, sex hormones, volume of the residual testis at baseline (T0) and after 12 (T1) and 24 months (T2) from UO or end of CT. Seminal parameters, sperm aneuploidies, DNA status, gonadic hormones, and testicular volume at baseline were not different between groups. At T1, we observed a significant reduction of sperm concentration and sperm count in the BEP group versus baseline and versus both Carb and S-group. A significant increase of sperm aneuploidies was present at T1 in the BEP group. Similarly, the same group at 1 had altered sperm DNA integrity and fragmentation compared with baseline, S-group and Carb group. These alterations were persistent after 2 years from the end of BEP treatment. Despite a slight improvement at T2, the BEP group had still higher percentages of sperm aneuploidies than other groups. No impairment of sperm aneuploidies and DNA status were observed in the Carb group both after 1 and 2 years from the end of treatment. Despite preliminary, these data demonstrate that in selected patients with TGCTs CT with carboplatin represents a therapeutic option that that seems to not affect sex hormones, spermatogenesis, and sperm nucleus. PMID- 27242530 TI - Very Early PSA Response to Abiraterone in mCRPC Patients: A Novel Prognostic Factor Predicting Overall Survival. AB - BACKGROUND: Abiraterone Acetate (AA) is approved for the treatment of mCRPC after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated and for treatment of mCRPC progressed during or after docetaxel-based chemotherapy regimen. The aim of this study is to evaluate the role of early PSA decline for detection of therapy success or failure in mCRPC patients treated with AA in post chemotherapy setting. PATIENTS AND METHODS: We retrospectively evaluated 87 patients with mCRPC treated with AA. Serum PSA levels were evaluated after 15, 90 days and then monthly. The PSA flare phenomenon was evaluated, according to a confirmation value at least 1 week apart. The primary endpoint was to demonstrate that an early PSA decline correlates with a longer progression free survival (PFS) and overall survival (OS). The secondary endpoind was to demonstrate a correlation between better outcome and demographic and clinical patient characteristics. RESULTS: We have collected data of 87 patients between Sep 2011 and Sep 2014. Early PSA response (>=50% from baseline at 15 days) was found in 56% evaluated patients and confirmed in 29 patients after 90 days. The median PFS was 5.5 months (4.6-6.5) and the median OS was 17.1 months (8.8-25.2). In early responders patients (PSA RR >= 50% at 15 days), we found a significant statistical advantage in terms of PFS at 1 year, HR 0.28, 95%CI 0.12-0.65, p = 0.003, and OS, HR 0.21 95% CI 0.06 0.72, p = 0.01. The results in PFS at 1 years and OS reached statistical significance also in the evaluation at 90 days. CONCLUSION: A significant proportion (78.6%) of patients achieved a rapid response in terms of PSA decline. Early PSA RR (>=50% at 15 days after start of AA) can provide clinically meaningful information and can be considered a surrogate of longer PFS and OS. PMID- 27242531 TI - SIRT Is Required for EDP-Mediated Protective Responses toward Hypoxia Reoxygenation Injury in Cardiac Cells. AB - Hypoxia-reoxygenation (H/R) injury is known to cause extensive injury to cardiac myocardium promoting development of cardiac dysfunction. Despite the vast number of studies dedicated to studying H/R injury, the molecular mechanisms behind it are multiple, complex, and remain very poorly understood, which makes development of novel pharmacological agents challenging. Docosahexaenoic acid (DHA, 22:6n3) is an n - 3 polyunsaturated fatty acid obtained from dietary sources, which produces numerous effects including regulation of cell survival and death mechanisms. The beneficial effects of DHA toward the cardiovascular system are well documented but the relative role of DHA or one of its more potent metabolites is unresolved. Emerging evidence indicates that cytochrome P450 (CYP) epoxygenase metabolites of DHA, epoxydocosapentaenoic acids (EDPs), have more potent biological activity than DHA in cardiac cells. In this study we examined whether EDPs protect HL-1 cardiac cells from H/R injury. Our observations demonstrate that treatment with 19,20-EDP protected HL-1 cardiac cells from H/R damage through a mechanism(s) protecting and enhancing mitochondrial quality. EDP treatment increased the relative rates of mitobiogenesis and mitochondrial respiration in control and H/R exposed cardiac cells. The observed EDP protective response toward H/R injury involved SIRT1-dependent pathways. PMID- 27242528 TI - Therapeutic Approaches to Genetic Ion Channelopathies and Perspectives in Drug Discovery. AB - In the human genome more than 400 genes encode ion channels, which are transmembrane proteins mediating ion fluxes across membranes. Being expressed in all cell types, they are involved in almost all physiological processes, including sense perception, neurotransmission, muscle contraction, secretion, immune response, cell proliferation, and differentiation. Due to the widespread tissue distribution of ion channels and their physiological functions, mutations in genes encoding ion channel subunits, or their interacting proteins, are responsible for inherited ion channelopathies. These diseases can range from common to very rare disorders and their severity can be mild, disabling, or life threatening. In spite of this, ion channels are the primary target of only about 5% of the marketed drugs suggesting their potential in drug discovery. The current review summarizes the therapeutic management of the principal ion channelopathies of central and peripheral nervous system, heart, kidney, bone, skeletal muscle and pancreas, resulting from mutations in calcium, sodium, potassium, and chloride ion channels. For most channelopathies the therapy is mainly empirical and symptomatic, often limited by lack of efficacy and tolerability for a significant number of patients. Other channelopathies can exploit ion channel targeted drugs, such as marketed sodium channel blockers. Developing new and more specific therapeutic approaches is therefore required. To this aim, a major advancement in the pharmacotherapy of channelopathies has been the discovery that ion channel mutations lead to change in biophysics that can in turn specifically modify the sensitivity to drugs: this opens the way to a pharmacogenetics strategy, allowing the development of a personalized therapy with increased efficacy and reduced side effects. In addition, the identification of disease modifiers in ion channelopathies appears an alternative strategy to discover novel druggable targets. PMID- 27242532 TI - EP300 Protects from Light-Induced Retinopathy in Zebrafish. AB - Exposure of rhodopsin to bright white light can induce photoreceptor cell damage and degeneration. However, a comprehensive understanding of the mechanisms underlying light-induced retinopathy remains elusive. In this study, we performed comparative transcriptome analysis of three rodent models of light-induced retinopathy, and we identified 37 genes that are dysregulated in all three models. Gene ontology analysis revealed that this gene set is significantly associated with a cytokine signaling axis composed of signal transducer and activator of transcription 1 and 3 (STAT1/3), interleukin 6 signal transducer (IL6ST), and oncostatin M receptor (OSMR). Furthermore, the analysis suggested that the histone acetyltransferase EP300 may be a key upstream regulator of the STAT1/3-IL6ST/OSMR axis. To examine the role of EP300 directly, we developed a larval zebrafish model of light-induced retinopathy. Using this model, we demonstrated that pharmacological inhibition of EP300 significantly increased retinal cell apoptosis, decreased photoreceptor cell outer segments, and increased proliferation of putative Muller cells upon exposure to intense light. These results suggest that EP300 may protect photoreceptor cells from light induced damage and that activation of EP300 may be a novel therapeutic approach for the treatment of retinal degenerative diseases. PMID- 27242533 TI - The Mechanism by Which Safflower Yellow Decreases Body Fat Mass and Improves Insulin Sensitivity in HFD-Induced Obese Mice. AB - OBJECTIVES: Safflower yellow (SY) is the main effective ingredient of Carthamus tinctorius L. It has been reported that SY plays an important role in anti inflammation, anti-platelet aggregation, and inhibiting thrombus formation. In present study, we try to investigate the effects of SY on body weight, body fat mass, insulin sensitivity in high fat diet (HFD)-induced obese mice. METHODS: HFD induced obese male ICR mice were intraperitoneally injected with SY (120 mg kg( 1)) daily. Eight weeks later, intraperitoneal insulin tolerance test (IPITT), and intraperitoneal glucose tolerance test (IPGTT) were performed, and body weight, body fat mass, serum insulin levels were measured. The expression of glucose and lipid metabolic related genes in white adipose tissue (WAT) were determined by RT qPCR and western blot technologies. RESULTS: The administration obese mice with SY significantly reduced the body fat mass of HFD-induced obese mice (P < 0.05). IPITT test showed that the insulin sensitivity of SY treated obese mice were evidently improved. The mRNA levels of insulin signaling pathway related genes including insulin receptor substrate 1(IRS1), PKB protein kinase (AKT), glycogen synthase kinase 3beta (GSK3beta) and forkhead box protein O1(FOXO1) in mesenteric WAT of SY treated mice were significantly increased to 1.9- , 2.8- , 3.3- , and 5.9-folds of that in HFD-induced control obese mice, respectively (P < 0.05). The protein levels of AKT and GSK3beta were also significantly increased to 3.0 and 5.2-folds of that in HFD-induced control obese mice, respectively (P < 0.05). Meanwhile, both the mRNA and protein levels of peroxisome proliferator-activated receptorgamma coactivator 1alpha (PGC1alpha) in inguinal subcutaneous WAT of SY group were notably increased to 2.5 and 3.0-folds of that in HFD-induced control obese mice (P < 0.05). CONCLUSIONS: SY significantly reduce the body fat mass, fasting blood glucose and increase insulin sensitivity of HFD-induced obese mice. The possible mechanism is to promote the browning of subcutaneous WAT and activate the IRS1/AKT/GSK3beta pathway in visceral WAT. Our study provides an important experimental evidence for developing SY as a potential anti-obesity and anti-diabetic drug. PMID- 27242535 TI - Varanoid Tooth Eruption and Implantation Modes in a Late Cretaceous Mosasaur. AB - Erupting teeth are some of the oldest witnesses of developmental processes in the vertebrate fossil record and provide an important resource for vertebrate cladistics. Here, we have examined a mosasaur jaw fragment from central Texas using ultrathin ground section histology and 3D tomographic imaging to assess features critical for the cladistic placement of mosasaurs among varanoids vs. snakes: (i) the orientation of replacement teeth compared to the major tooth axis, (ii) the occurrence of resorption pits, and (iii) the mode of tooth implantation/attachment to the tooth bearing element (TBE). The replacement tooth studied here developed in an inclined position slightly distal of the deciduous parent tooth, similar to another varanoid squamate, the Gila monster Heloderma suspectum. Ground sections and tomographs also demonstrated that the replacement tooth attachment apparatus was entirely intact and that there was no evidence of mechanical deformation. Sections and tomographs further illustrated that the replacement tooth was located within a bony crypt and the inclination of the crypt matched the inclination of the replacement tooth. These preparations also revealed the presence of a resorption pit within the boundaries of the deciduous tooth that surrounded the developing replacement tooth. This finding suggests that developing mosasaur teeth developed within the walls of resorption pits similar to varanoid tooth germs and unlike developing snake teeth which are surrounded by fibrous connective tissue integuments. Finally, mosasaurs featured pseudo-thecodont tooth implantation with teeth anchored within a socket of mineralized tissue by means of a mineralized periodontal ligament. Together, these data indicate that the moderate inclination of the erupting mosasaur tooth studied here is neither a result of postmortem displacement nor a character representative of snakes, but rather a shared character between Mosasaurs and other varanoids such as Heloderma. In conjunction with the presence of resorption pits and the evidence for pseudothecodont tooth implantation, the tooth eruption and implantation characters described in the present study either place mosasaurs among the varanoids or suggest convergent evolution mechanisms between both clades, with mosasaurs evolving somewhat independently from a common varanoid ancestor. PMID- 27242534 TI - Group II Metabotropic Glutamate Receptors as Targets for Novel Antipsychotic Drugs. AB - Schizophrenia is a chronic psychiatric disorder which substantially impairs patients' quality of life. Despite the extensive research in this field, the pathophysiology and etiology of schizophrenia remain unknown. Different neurotransmitter systems and functional networks have been found to be affected in the brain of patients with schizophrenia. In this context, postmortem brain studies as well as genetic assays have suggested alterations in Group II metabotropic glutamate receptors (mGluRs) in schizophrenia. Despite many years of drug research, several needs in the treatment of schizophrenia have not been addressed sufficiently. In fact, only 5-10% of patients with schizophrenia successfully achieve a full recovery after treatment. In recent years mGluRs have turned up as novel targets for the design of new antipsychotic medications for schizophrenia. Concretely, Group II mGluRs are of particular interest due to their regulatory role in neurotransmission modulating glutamatergic activity in brain synapses. Preclinical studies have demonstrated that orthosteric Group II mGluR agonists exhibit antipsychotic-like properties in animal models of schizophrenia. However, when these compounds have been tested in human clinical studies with schizophrenic patients results have been inconclusive. Nevertheless, it has been recently suggested that this apparent lack of efficacy in schizophrenic patients may be related to previous exposure to atypical antipsychotics. Moreover, the role of the functional heterocomplex formed by 5 HT2A and mGlu2 receptors in the clinical response to Group II mGluR agonists is currently under study. PMID- 27242536 TI - Assessment of the Brain's Macro- and Micro-Circulatory Blood Flow Responses to CO2 via Transfer Function Analysis. AB - OBJECTIVES: At present, there is no standard bedside method for assessing cerebral autoregulation (CA) with high temporal resolution. We combined the two methods most commonly used for this purpose, transcranial Doppler sonography (TCD, macro-circulation level), and near-infrared spectroscopy (NIRS, micro circulation level), in an attempt to identify the most promising approach. METHODS: In eight healthy subjects (5 women; mean age, 38 +/- 10 years), CA disturbance was achieved by adding carbon dioxide (CO2) to the breathing air. We simultaneously recorded end-tidal CO2 (ETCO2), blood pressure (BP; non-invasively at the fingertip), and cerebral blood flow velocity (CBFV) in both middle cerebral arteries using TCD and determined oxygenated and deoxygenated hemoglobin levels using NIRS. For the analysis, we used transfer function calculations in the low-frequency band (0.07-0.15 Hz) to compare BP-CBFV, BP-oxygenated hemoglobin (OxHb), BP-tissue oxygenation index (TOI), CBFV-OxHb, and CBFV-TOI. RESULTS: ETCO2 increased from 37 +/- 2 to 44 +/- 3 mmHg. The CO2-induced CBFV increase significantly correlated with the OxHb increase (R (2) = 0.526, p < 0.001). Compared with baseline, the mean CO2 administration phase shift (in radians) significantly increased (p < 0.005) from -0.67 +/- 0.20 to -0.51 +/- 0.25 in the BP-CBFV system, and decreased from 1.21 +/- 0.81 to -0.05 +/- 0.91 in the CBFV-OxHb system, and from 0.94 +/- 1.22 to -0.24 +/- 1.0 in the CBFV-TOI system; no change was observed for BP-OxHb (0.38 +/- 1.17 to 0.41 +/- 1.42). Gain changed significantly only in the BP-CBFV system. The correlation between the ETCO2 change and phase change was higher in the CBFV-OxHb system [r = -0.60; 95% confidence interval (CI): -0.16, -0.84; p < 0.01] than in the BP-CBFV system (r = 0.52; 95% CI: 0.03, 0.08; p < 0.05). CONCLUSION: The transfer function characterizes the blood flow transition from macro- to micro-circulation by time delay only. The CBFV-OxHb system response with a broader phase shift distribution offers the prospect of a more detailed grading of CA responses. Whether this is of clinical relevance needs further studies in different patient populations. PMID- 27242537 TI - Contributions of Central Command and Muscle Feedback to Sympathetic Nerve Activity in Contracting Human Skeletal Muscle. AB - During voluntary contractions, muscle sympathetic nerve activity (MSNA) to contracting muscles increases in proportion to force but the underlying mechanisms are not clear. To shed light on these mechanisms, particularly the influences of central command and muscle afferent feedback, the present study tested the hypothesis that MSNA is greater during voluntary compared with electrically-evoked contractions. Seven male subjects performed a series of 1-min isometric dorsiflexion contractions (left leg) separated by 2-min rest periods, alternating between voluntary and electrically-evoked contractions at similar forces (5-10% of maximum). MSNA was recorded continuously (microneurography) from the left peroneal nerve and quantified from cardiac-synchronized, negative-going spikes in the neurogram. Compared with pre-contraction values, MSNA increased by 51 +/- 34% (P < 0.01) during voluntary contractions but did not change significantly during electrically-evoked contractions (-8 +/- 12%, P > 0.05). MSNA analyzed at 15-s intervals revealed that this effect of voluntary contraction appeared 15-30 s after contraction onset (P < 0.01), remained elevated until the end of contraction, and disappeared within 15 s after contraction. These findings suggest that central command, and not feedback from contracting muscle, is the primary mechanism responsible for the increase in MSNA to contracting muscle. The time-course of MSNA suggests that there is a longer delay in the onset of this effect compared with its cessation after contraction. PMID- 27242538 TI - Effects of Resistance Training in Youth Athletes on Muscular Fitness and Athletic Performance: A Conceptual Model for Long-Term Athlete Development. AB - During the stages of long-term athlete development (LTAD), resistance training (RT) is an important means for (i) stimulating athletic development, (ii) tolerating the demands of long-term training and competition, and (iii) inducing long-term health promoting effects that are robust over time and track into adulthood. However, there is a gap in the literature with regards to optimal RT methods during LTAD and how RT is linked to biological age. Thus, the aims of this scoping review were (i) to describe and discuss the effects of RT on muscular fitness and athletic performance in youth athletes, (ii) to introduce a conceptual model on how to appropriately implement different types of RT within LTAD stages, and (iii) to identify research gaps from the existing literature by deducing implications for future research. In general, RT produced small-to moderate effects on muscular fitness and athletic performance in youth athletes with muscular strength showing the largest improvement. Free weight, complex, and plyometric training appear to be well-suited to improve muscular fitness and athletic performance. In addition, balance training appears to be an important preparatory (facilitating) training program during all stages of LTAD but particularly during the early stages. As youth athletes become more mature, specificity, and intensity of RT methods increase. This scoping review identified research gaps that are summarized in the following and that should be addressed in future studies: (i) to elucidate the influence of gender and biological age on the adaptive potential following RT in youth athletes (especially in females), (ii) to describe RT protocols in more detail (i.e., always report stress and strain-based parameters), and (iii) to examine neuromuscular and tendomuscular adaptations following RT in youth athletes. PMID- 27242539 TI - Coupling Developmental Physiology, Photoperiod, and Temperature to Model Phenology and Dynamics of an Invasive Heteropteran, Halyomorpha halys. AB - We developed an agent-based stochastic model expressing stage-specific phenology and population dynamics for an insect species across geographic regions. We used the invasive pentatomid, Halyomorpha halys, as the model organism because gaps in knowledge exist regarding its developmental physiology, it is expanding its global distribution, and it is of significant economic importance. Model predictions were compared against field observations over 3 years, and the parameter set that enables the largest population growth was applied to eight locations over 10 years, capturing the variation in temperature and photoperiod profiles of significant horticultural crop production that could be affected by H. halys in the US. As a species that overwinters as adults, critical photoperiod significantly impacted H. halys seasonality and population size through its influence on diapause termination and induction, and this may impact other insects with similar life-histories. Photoperiod and temperature interactions influenced life stage synchrony among years, resulting in an order of magnitude difference, for occurrence of key life stages. At all locations, there was a high degree of overlap among life stages and generation. Although all populations produced F2 adults and thus could be characterized as bivoltine, the size and relative contribution of each generation to the total, or overwintering, adult population also varied dramatically. In about half of the years in two locations (Geneva, NY and Salem, OR), F1 adults comprised half or more of the adult population at the end of the year. Yearly degree-day accumulation was a significant covariate influencing variation in population growth, and average maximum adult population size varied by 10-fold among locations. Average final population growth was positive (Asheville, NC, Homestead, FL, Davis, CA) or marginal (Geneva, NY, Bridgeton, NJ, Salem, OR, Riverside, CA), but was negative in one location (Wenatchee WA) due to cooler temperatures coupled with timing of vitellogenesis of F2 adults. Years of the highest population growth in the mid Atlantic site coincided with years of highest crop damage reports. We discuss these results with respect to assumptions and critical knowledge gaps, the ability to realistically model phenology of species with strongly overlapping life stage and which diapause as adults. PMID- 27242540 TI - NADPH Oxidase-Derived ROS Induced by Chronic Intermittent Hypoxia Mediates Hypersensitivity of Lung Vagal C Fibers in Rats. AB - Obstructive sleep apnea (OSA), manifested by exposure to chronic intermittent hypoxia (CIH) and excess production of reactive oxygen species (ROS) in the airways, is associated with hyperreactive airway diseases. ROS, particularly when created by NADPH oxidase, are known to sensitize lung vagal C fibers (LVCFs), which may contribute to airway hypersensitivity pathogenesis. We investigated whether CIH augments the reflex and afferent responses of LVCFs to chemical stimulants and the roles of ROS and NADPH oxidase in such airway hypersensitivity. Rats were exposed to room air (RA) or CIH with/without daily treatment with MnTMPyP (a superoxide anion scavenger), apocynin (an NADPH oxidase inhibitor), or vehicle. At 16 h after their last exposure, intravenous capsaicin, adenosine, or alpha,beta-methylene-ATP evoked an augmented apneic response in anesthetized rats with 14-days CIH exposure, compared to anesthetized rats with 14-days RA exposure. The augmented apneic responses to these LVCF stimulants were abolished by bilateral vagotomy or perivagal capsaicin treatment, which block LVCFs neural conduction and were significantly suppressed by treatment with MnTMPyP or apocynin, but not vehicle. Electrophysiological studies revealed that 14-days CIH exposure potentiated the responses of LVCFs to these stimulants. This effect was inhibited by treatment with MnTMPyP or apocynin treatment and was not seen in rats who received 7-days of CIH exposure. Biochemical analysis indicated that 14-days CIH exposure increased both lung lipid peroxidation, which is indicative of oxidative stress, and expression of the p47(phox) subunit in the membrane fraction of lung tissue, which is an index of NADPH oxidase activation. The former was prevented by treatment with either MnTMPyP or apocynin, while the later was prevented by treatment with apocynin only. These results suggest that 14-days CIH exposure sensitizes LVCFs in rats, leading to an exaggerated reflex and afferent responses to stimulants and that this sensitization is mediated via ROS generated by NADPH oxidase. PMID- 27242541 TI - ATP Sensitive Potassium Channels in the Skeletal Muscle Function: Involvement of the KCNJ11(Kir6.2) Gene in the Determination of Mechanical Warner Bratzer Shear Force. AB - The ATP-sensitive K(+)-channels (KATP) are distributed in the tissues coupling metabolism with K(+) ions efflux. KATP subunits are encoded by KCNJ8 (Kir6.1), KCNJ11 (Kir6.2), ABCC8 (SUR1), and ABCC9 (SUR2) genes, alternative RNA splicing give rise to SUR variants that confer distinct physiological properties on the channel. An high expression/activity of the sarco-KATP channel is observed in various rat fast-twitch muscles, characterized by elevated muscle strength, while a low expression/activity is observed in the slow-twitch muscles characterized by reduced strength and frailty. Down-regulation of the KATP subunits of fast-twitch fibers is found in conditions characterized by weakness and frailty. KCNJ11 gene knockout mice have reduced glycogen, lean phenotype, lower body fat, and weakness. KATP channel is also a sensor of muscle atrophy. The KCNJ11 gene is located on BTA15, close to a QTL for meat tenderness, it has also a role in glycogen storage, a key mechanism of the postmortem transformation of muscle into meat. The role of KCNJ11 gene in muscle function may underlie an effect of KCNJ11 genotypes on meat tenderness, as recently reported. The fiber phenotype and genotype are important in livestock production science. Quantitative traits including meat production and quality are influenced both by environment and genes. Molecular markers can play an important role in the genetic improvement of animals through breeding strategies. Many factors influence the muscle Warner Bratzler shear force including breed, age, feeding, the biochemical, and functional parameters. The role of KCNJ11gene and related genes on muscle tenderness will be discussed in the present review. PMID- 27242542 TI - The Inositide Signaling Pathway As a Target for Treating Gastric Cancer and Colorectal Cancer. AB - Gastric cancer and colorectal cancer are the leading cause of cancer mortality and have a dismal prognosis. The introduction of biological agents to treat these cancers has resulted in improved outcomes, and combination chemotherapy with targeted agents and conventional chemotherapeutic agents is regarded as standard therapy. Additional newly clarified mechanisms of oncogenesis and resistance to targeted agents require the development of new biologic agents. Aberrant activation of the inositide signaling pathway by a loss of function PTEN mutation or gain of function mutation/amplification of PIK3CA is an oncogenic mechanism in gastric cancer and colorectal cancer. Clinical trials with biologic agents that target the inositide signaling pathway are being performed to further improve treatment outcomes of patients with advanced gastric cancer and metastatic colorectal cancer (CRC). In this review we summarize the inositide signaling pathway, the targeted agents that inhibit abnormal activation of this signaling pathway and the clinical trials currently being performed in patients with advanced or metastatic gastric cancer and metastatic CRC using these targeted agents. PMID- 27242543 TI - Regulation of Differentiation by Calcium-Sensing Receptor in Normal and Tumoral Developing Nervous System. AB - During normal development of the nervous system (NS), neural progenitor cells (NPCs) produce specialized populations of neurons and glial cells upon cell fate restriction and terminal differentiation. These sequential processes require the dynamic regulation of thousands of genes. The calcium-sensing receptor (CaSR) is temporally and spatially regulated in both neurons and glial cells during development of the NS. In particular, CaSR expression and function have been shown to play a significant role during differentiation of NPCs toward the oligodendrocyte lineage and also in maturation of cerebellar granule cell precursors (GCPs). Moreover, CaSR regulates axonal and dendritic growth in both central and peripheral nervous systems (PNSs), a process necessary for proper construction of mature neuronal networks. On the other hand, several lines of evidence support a role for CaSR in promotion of cell differentiation and inhibition of proliferation in neuroblastoma, a tumor arising from precursor cells of developing PNS. Thus, among the variety of NS functions in which the CaSR participates, this mini-review focuses on its role in differentiation of normal and tumoral cells. Current knowledge of the mechanisms responsible for CaSR regulation and function in these contexts is also discussed, together with the therapeutic opportunities provided by CaSR allosteric modulators. PMID- 27242544 TI - Gene Expression Changes during the Gummosis Development of Peach Shoots in Response to Lasiodiplodia theobromae Infection Using RNA-Seq. AB - Lasiodiplodia theobromae is a causal agent of peach (Prunus persica L.) tree gummosis, a serious disease affecting peach cultivation and production. However, the molecular mechanism underlying the pathogenesis remains unclear. RNA-Seq was performed to investigate gene expression in peach shoots inoculated or mock inoculated with L. theobromae. A total of 20772 genes were detected in eight samples; 4231, 3750, 3453, and 3612 differentially expressed genes were identified at 12, 24, 48, and 60 h after inoculation, respectively. Furthermore, 920 differentially co-expressed genes (515 upregulated and 405 downregulated) were found, respectively. Gene ontology annotation revealed that phenylpropanoid biosynthesis and metabolism, uridine diphosphate-glucosyltransferase activity, and photosynthesis were the most differentially regulated processes during gummosis development. Significant differences were also found in the expression of genes involved in glycometabolism and in ethylene and jasmonic acid biosynthesis and signaling. These data illustrate the dynamic changes in gene expression in the inoculated peach shoots at the transcriptome level. Overall, gene expression in defense response and glycometabolism might result in the gummosis of peach trees induced by L. theobromae. PMID- 27242546 TI - A Statistical Method and Tool to Account for Indirect Calorimetry Differential Measurement Error in a Single-Subject Analysis. AB - Indirect calorimetry and oxygen consumption (VO2) are accepted tools in human physiology research. It has been shown that indirect calorimetry systems exhibit differential measurement error, where the error of a device is systematically different depending on the volume of gas flow. Moreover, systems commonly report multiple decimal places of precision, giving the clinician a false sense of device accuracy. The purpose of this manuscript is to demonstrate the use of a novel statistical tool which models the reliability of two specific indirect calorimetry systems, Douglas bag and Parvomedics 2400 TrueOne, as univariate normal distributions and implements the distribution overlapping coefficient to determine the likelihood that two VO2 measures are the same. A command line implementation of the tool is available for the R programming language as well as a web-based graphical user interface (GUI). This tool is valuable for clinicians performing a single-subject analysis as well as researchers interested in determining if their observed differences exceed the error of the device. PMID- 27242545 TI - Aging Reduces L-Type Calcium Channel Current and the Vasodilatory Response of Small Mesenteric Arteries to Calcium Channel Blockers. AB - Calcium channel blockers (CCBs) are widely used to treat cardiovascular disease (CVD) including hypertension. As aging is an independent risk factor for CVD, the use of CCBs increases with increasing age. Hence, this study was designed to evaluate the effect of aging on the sensitivity of small mesenteric arteries to L type voltage-gated calcium channel (LTCC) blockers and also to investigate whether there was a concomitant change in calcium current density. Third order mesenteric arteries from male F344 rats, aged 2.5-3 months (young) and 22-26 months (old) were mounted on wire myograph to measure the tension during isometric contraction. Arteries were contracted with 100 mM KCl and were then relaxed in a cumulative concentration-response dependent manner with nifedipine (0.1 nM-1 MUM), verapamil (0.1 nM-10 MUM), or diltiazem (0.1 nM-10 MUM). Relaxation-concentration response curves produced by cumulative concentrations of three different CCBs in arteries of old rats were shifted to the right with statistically significant IC50s. pIC50 +/- s.e.m: (8.37 +/- 0.06 vs. 8.04 +/- 0.05, 7.40 +/- 0.07 vs. 6.81 +/- 0.04, and 6.58 +/- 0.07 vs. 6.34 +/- 0.06) in young vs. old. It was observed that the maximal contractions induced by phenylephrine and reversed by sodium nitroprusside were not different between young and old groups. However, Bay K 8644 (1 MUM) increased resting tension by 23 +/- 4.8% in young arteries and 4.7 +/- 1.6% in old arteries. LTCC current density were also significantly lower in old arteries (-2.77 +/- 0.45 pA/pF) compared to young arteries (-4.5 +/- 0.40 pA/pF); with similar steady-state activation and inactivation curves. Parallel to this reduction, the expression of Cav1.2 protein was reduced by 57 +/- 5% in arteries from old rats compared to those from young rats. In conclusion, our results suggest that aging reduces the response of small mesenteric arteries to the vasodilatory effect of the CCBs and this may be due to, at least in part, reduced current density of LTCC. PMID- 27242547 TI - Skeletal Muscle, but not Cardiovascular Function, Is Altered in a Mouse Model of Autosomal Recessive Hypophosphatemic Rickets. AB - Autosomal recessive hypophosphatemic rickets (ARHR) is a heritable disorder characterized by hypophosphatemia, osteomalacia, and poor bone development. ARHR results from inactivating mutations in the DMP1 gene with the human phenotype being recapitulated in the Dmp1 null mouse model which displays elevated plasma fibroblast growth factor 23. While the bone phenotype has been well characterized, it is not known what effects ARHR may also have on skeletal, cardiac, or vascular smooth muscle function, which is critical to understand in order to treat patients suffering from this condition. In this study, the extensor digitorum longus (EDL-fast-twitch muscle), soleus (SOL-slow-twitch muscle), heart, and aorta were removed from Dmp1 null mice and ex-vivo functional tests were simultaneously performed in collaboration by three different laboratories. Dmp1 null EDL and SOL muscles produced less force than wildtype muscles after normalization for physiological cross sectional area of the muscles. Both EDL and SOL muscles from Dmp1 null mice also produced less force after the addition of caffeine (which releases calcium from the sarcoplasmic reticulum) which may indicate problems in excitation contraction coupling in these mice. While the body weights of the Dmp1 null were smaller than wildtype, the heart weight to body weight ratio was higher. However, there were no differences in pathological hypertrophic gene expression compared to wildtype and maximal force of contraction was not different indicating that there may not be cardiac pathology under the tested conditions. We did observe a decrease in the rate of force development generated by cardiac muscle in the Dmp1 null which may be related to some of the deficits observed in skeletal muscle. There were no differences observed in aortic contractions induced by PGF2alpha or 5-HT or in endothelium-mediated acetylcholine-induced relaxations or endothelium-independent sodium nitroprusside-induced relaxations. In summary, these results indicate that there are deficiencies in both fast twitch and slow twitch muscle fiber type contractions in this model of ARHR, while there was less of a phenotype observed in cardiac muscle, and no differences observed in aortic function. These results may help explain skeletal muscle weakness reported by some patients with osteomalacia and need to be further investigated. PMID- 27242548 TI - Interactive Effects of Dorsomedial Hypothalamic Nucleus and Time-Restricted Feeding on Fractal Motor Activity Regulation. AB - One evolutionary adaptation in motor activity control of animals is the anticipation of food that drives foraging under natural conditions and is mimicked in laboratory with daily scheduled food availability. Food anticipation is characterized by increased activity a few hours before the feeding period. Here we report that 2-h food availability during the normal inactive phase of rats not only increases activity levels before the feeding period but also alters the temporal organization of motor activity fluctuations over a wide range of time scales from minutes up to 24 h. We demonstrate this multiscale alteration by assessing fractal patterns in motor activity fluctuations-similar fluctuation structure at different time scales-that are robust in intact animals with ad libitum food access but are disrupted under food restriction. In addition, we show that fractal activity patterns in rats with ad libitum food access are also perturbed by lesion of the dorsomedial hypothalamic (DMH)-a neural node that is involved in food anticipatory behavior. Instead of further disrupting fractal regulation, food restriction restores the disrupted fractal patterns in these animals after the DMH lesion despite the persistence of the 24-h rhythms. This compensatory effect of food restriction is more clearly pronounced in the same animals after the additional lesion of the suprachiasmatic nucleus (SCN)-the central master clock in the circadian system that generates and orchestrates circadian rhythms in behavior and physiological functions in synchrony with day night cycles. Moreover, all observed influences of food restriction persist even when data during the food anticipatory and feeding period are excluded. These results indicate that food restriction impacts dynamics of motor activity at different time scales across the entire circadian/daily cycle, which is likely caused by the competition between the food-induced time cue and the light entrained circadian rhythm of the SCN. The differential impacts of food restriction on fractal activity control in intact and DMH-lesioned animals suggest that the DMH plays a crucial role in integrating these different time cues to the circadian network for multiscale regulation of motor activity. PMID- 27242549 TI - Anguillicola crassus Infection Significantly Affects the Silvering Related Modifications in Steady State mRNA Levels in Gas Gland Tissue of the European Eel. AB - Using Illumina sequencing, transcriptional changes occurring during silvering in swimbladder tissue of the European eel have been analyzed by comparison of yellow and silver eel tissue samples. Functional annotation analysis based on GO terms revealed significant expression changes in a number of genes related to the extracellular matrix, important for the control of gas permeability of the swimbladder, and to reactive oxygen species (ROS) defense, important to cope with ROS generated under hyperbaric oxygen partial pressures. Focusing on swimbladder tissue metabolism, levels of several mRNA species encoding glucose transport proteins were several-fold higher in silver eels, while enzymes of the glycolytic pathway were not affected. The significantly higher steady state level of a transcript encoding for membrane bound carbonic anhydrase, however, suggested that CO2 production in the pentose phosphate shunt and diffusion of CO2 was of particular importance in silver eel swimbladder. In addition, the mRNA level of a large number of genes related to immune response and to sexual maturation was significantly modified in the silver eel swimbladder. The modification of several processes related to protein metabolism and transport, cell cycle, and apoptosis suggested that these changes in swimbladder metabolism and permeability were achieved by increasing cell turn-over. The impact of an infection of the swimbladder with the nematode Anguillicola crassus has been assessed by comparing these expression changes with expression changes observed between uninfected yellow eel swimbladder tissue and infected silver eel swimbladder tissue. In contrast to uninfected silver eel swimbladder tissue, in infected tissue the mRNA level of several glycolytic enzymes was significantly elevated, and with respect to extracellular matrix, several mucin genes were many-fold higher in their mRNA level. Modification of many immune related genes and of the functional categories "response to DNA damage stimulus" and "cellular response to stress" illustrated the damaging effect of the nematode infection. This study has identified a range of cellular processes in the swimbladder of silver eels that appear to be altered by nematode infection. These altered cellular processes could contribute to detrimental changes in swimbladder function that, in turn, may lead to impairment of spawning migration. PMID- 27242550 TI - Mitochondrial Ultrastructure and Glucose Signaling Pathways Attributed to the Kv1.3 Ion Channel. AB - Gene-targeted deletion of the potassium channel Kv1.3 (Kv1.3(-/-)) results in "Super-smeller" mice with a sensory phenotype that includes an increased olfactory ability linked to changes in olfactory circuitry, increased abundance of olfactory cilia, and increased expression of odorant receptors and the G protein, Golf. Kv1.3(-/-) mice also have a metabolic phenotype including lower body weight and decreased adiposity, increased total energy expenditure (TEE), increased locomotor activity, and resistance to both diet- and genetic-induced obesity. We explored two cellular aspects to elucidate the mechanism by which loss of Kv1.3 channel in the olfactory bulb (OB) may enhance glucose utilization and metabolic rate. First, using in situ hybridization we find that Kv1.3 and the insulin-dependent glucose transporter type 4 (GLUT4) are co-localized to the mitral cell layer of the OB. Disruption of Kv1.3 conduction via construction of a pore mutation (W386F Kv1.3) was sufficient to independently translocate GLUT4 to the plasma membrane in HEK 293 cells. Because olfactory sensory perception and the maintenance of action potential (AP) firing frequency by mitral cells of the OB is highly energy demanding and Kv1.3 is also expressed in mitochondria, we next explored the structure of this organelle in mitral cells. We challenged wildtype (WT) and Kv1.3(-/-) male mice with a moderately high-fat diet (MHF, 31.8 % kcal fat) for 4 months and then examined OB ultrastructure using transmission electron microscopy. In WT mice, mitochondria were significantly enlarged following diet-induced obesity (DIO) and there were fewer mitochondria, likely due to mitophagy. Interestingly, mitochondria were significantly smaller in Kv1.3(-/-) mice compared with that of WT mice. Similar to their metabolic resistance to DIO, the Kv1.3(-/-) mice had unchanged mitochondria in terms of cross sectional area and abundance following a challenge with modified diet. We are very interested to understand how targeted disruption of the Kv1.3 channel in the OB can modify TEE. Our study demonstrates that Kv1.3 regulates mitochondrial structure and alters glucose utilization; two important metabolic changes that could drive whole system changes in metabolism initiated at the OB. PMID- 27242551 TI - The Impact of a Cognitive-Behavioral Therapy on Event-Related Potentials in Patients with Tic Disorders or Body-Focused Repetitive Behaviors. AB - CONTEXT: Tic disorders (TD) are characterized by the presence of non-voluntary contractions of functionally related groups of skeletal muscles in one or multiple body parts. Patients with body-focused repetitive behaviors (BFRB) present frequent and repetitive behaviors, such as nail biting or hair pulling. TD and BFRB can be treated with a cognitive-behavioral therapy (CBT) that regulates the excessive amount of sensorimotor activation and muscular tension. Our CBT, which is called the cognitive-psychophysiological (CoPs) model, targets motor execution and inhibition, and it was reported to modify brain activity in TD. However, psychophysiological effects of therapy are still poorly understood in TD and BFRB patients. Our goals were to compare the event-related potentials (ERP) of TD and BFRB patients to control participants and to investigate the effects of the CoPs therapy on the P200, N200, and P300 components during a motor and a non-motor oddball task. METHOD: Event-related potential components were compared in 26 TD patients, 27 BFRB patients, and 27 control participants. ERP were obtained from 63 EEG electrodes during two oddball tasks. In the non-motor task, participants had to count rare stimuli. In the motor task, participants had to respond with a left and right button press for rare and frequent stimuli, respectively. ERP measures were recorded before and after therapy in both patient groups. RESULTS: CoPs therapy improved symptoms similarly in both clinical groups. Before therapy, TD and BFRB patients had reduced P300 oddball effect during the non-motor task, in comparison with controls participants. An increase in the P300 oddball effect was observed posttherapy. This increase was distributed over the whole cortex in BFRB patients, but localized in the parietal area in TD patients. DISCUSSION: These results suggest a modification of neural processes following CoPs therapy in TD and BFRB patients. CoPs therapy seems to impact patients' attentional processes and context updating capacities in working memory (i.e., P300 component). Our results are consistent with a possible role of the prefrontal cortex and corpus callosum in mediating interhemispheric interference in TD. PMID- 27242553 TI - Editorial: Endophenotypes for Schizophrenia and Mood Disorders: Implications from Genetic, Biochemical, Cognitive, Behavioral, and Neuroimaging Studies. PMID- 27242554 TI - Tic Frequency Decreases during Short-term Psychosocial Stress - An Experimental Study on Children with Tic Disorders. AB - It has been suggested that psychosocial stress influences situational fluctuations of tic frequency. However, evidence from experimental studies is lacking. The current study investigated the effects of the Trier Social Stress Test (TSST-C) on tic frequency in 31 children and adolescents with tic disorders. A relaxation and a concentration situation served as control conditions. Patients were asked either to suppress their tics or to "tic freely." Physiological measures of stress were measured throughout the experiment. The TSST-C elicited a clear stress response with elevated levels of saliva cortisol, increased heart rate, and a larger number of skin conductance responses. During relaxation and concentration, the instruction to suppress tics reduced the number of tics, whereas during stress, the number of tics was low, regardless of the given instruction. Our study suggests that the stress might result in a situational decrease of tic frequency. PMID- 27242552 TI - Effect of Pharmacological Interventions on the Fronto-Cingulo-Parietal Cognitive Control Network in Psychiatric Disorders: A Transdiagnostic Systematic Review of fMRI Studies. AB - Executive function deficits, such as working memory, decision-making, and attention problems, are a common feature of several psychiatric disorders for which no satisfactory treatment exists. Here, we transdiagnostically investigate the effects of pharmacological interventions (other than methylphenidate) on the fronto-cingulo-parietal cognitive control network, in order to identify functional brain markers for future procognitive pharmacological interventions. Twenty-nine manuscripts investigated the effect of pharmacological treatment on executive function-related brain correlates in psychotic disorders (n = 11), depression (n = 4), bipolar disorder (n = 4), ADHD (n = 4), OCD (n = 2), smoking dependence (n = 2), alcohol dependence (n = 1), and pathological gambling (n = 1). In terms of impact on the fronto-cingulo-parietal network, the preliminary evidence for catechol-O-methyl-transferase inhibitors, nicotinic receptor agonists, and atomoxetine was relatively consistent, the data for atypical antipsychotics and anticonvulsants moderate, and interpretation of the data for antidepressants was hampered by the employed study designs. Increased activity in task-relevant areas and decreased activity in task-irrelevant areas were the most common transdiagnostic effects of pharmacological treatment. These markers showed good positive and moderate negative predictive value. It is concluded that fronto cingulo-parietal activity changes can serve as a marker for future procognitive interventions. Future recommendations include the use of randomized double-blind designs and selective cholinergic and glutamatergic compounds. PMID- 27242555 TI - The Chaos of Combat: An Overview of Challenges in Military Mild Traumatic Brain Injury Research. AB - Mild traumatic brain injury (mTBI), or concussion, is among the most common injuries affecting Veterans of recent combat deployments. Military mTBI differs from civilian mTBI in fundamental ways that make assessment and diagnosis difficult, including a reliance on retrospective self-report and the potential influence of comorbid psychopathology. These unique features and their implications for research and clinical practice are summarized, and neuroimaging studies are discussed in the context of these complicating factors. PMID- 27242556 TI - Interneurons: Role in Maintaining and Restoring Synaptic Plasticity. PMID- 27242558 TI - Observed Workplace Incivility toward Women, Perceptions of Interpersonal Injustice, and Observer Occupational Well-Being: Differential Effects for Gender of the Observer. AB - The present study examined perceptions of interpersonal injustice as a mediator of the relationship between observed incivility toward women at work and employees' occupational well-being. We also examined gender of the observer as a moderator of these mediational relationships. Using online survey data from 1702 (51% women; 92% White) employees, results showed that perceptions of injustice partially mediated the relationship between observed incivility toward women and job satisfaction, turnover intentions, and organizational trust. Men reported greater perceptions of injustice than did women the more they observed the uncivil treatment of women at work, and the indirect effects of observed incivility toward women on well-being were stronger for men compared to women. Observed incivility toward women also had direct relationships with the occupational well-being outcomes over and above the impact mediated through injustice, particularly for women. Specifically, observing incivility toward female coworkers directly related to lowered job satisfaction and perceptions of safety for female bystanders. In addition, although both male and female bystanders reported heightened turnover intentions and lowered trust in the organization with higher levels of observed incivility toward women, these relationships were stronger for female than male observers. Our findings both replicate and extend past research on vicarious workplace incivility toward women. PMID- 27242557 TI - The Genetic Basis of Cognitive Impairment and Dementia in Parkinson's Disease. AB - Cognitive dysfunction is a common feature of Parkinson's disease (PD) with mild cognitive impairment affecting around a quarter of patients in the early stages of their disease, and approximately half developing dementia by 10 years from diagnosis. However, the pattern of cognitive impairments and their speed of evolution vary markedly between individuals. While some of this variability may relate to extrinsic factors and comorbidities, inherited genetic heterogeneity is also known to play an important role. A number of common genetic variants have been identified, which contribute to cognitive function in PD, including variants in catechol-O-methyltransferase, microtubule-associated protein tau, and apolipoprotein E. Furthermore, rarer mutations in glucocerebrosidase and alpha synuclein and are strongly associated with dementia risk in PD. This review explores the functional impact of these variants on cognition in PD and discusses how such genotype-phenotype associations provide a window into the mechanistic basis of cognitive heterogeneity in this disorder. This has consequent implications for the development of much more targeted therapeutic strategies for cognitive symptoms in PD. PMID- 27242559 TI - Comparison of Estimation Procedures for Multilevel AR(1) Models. AB - To estimate a time series model for multiple individuals, a multilevel model may be used. In this paper we compare two estimation methods for the autocorrelation in Multilevel AR(1) models, namely Maximum Likelihood Estimation (MLE) and Bayesian Markov Chain Monte Carlo. Furthermore, we examine the difference between modeling fixed and random individual parameters. To this end, we perform a simulation study with a fully crossed design, in which we vary the length of the time series (10 or 25), the number of individuals per sample (10 or 25), the mean of the autocorrelation (-0.6 to 0.6 inclusive, in steps of 0.3) and the standard deviation of the autocorrelation (0.25 or 0.40). We found that the random estimators of the population autocorrelation show less bias and higher power, compared to the fixed estimators. As expected, the random estimators profit strongly from a higher number of individuals, while this effect is small for the fixed estimators. The fixed estimators profit slightly more from a higher number of time points than the random estimators. When possible, random estimation is preferred to fixed estimation. The difference between MLE and Bayesian estimation is nearly negligible. The Bayesian estimation shows a smaller bias, but MLE shows a smaller variability (i.e., standard deviation of the parameter estimates). Finally, better results are found for a higher number of individuals and time points, and for a lower individual variability of the autocorrelation. The effect of the size of the autocorrelation differs between outcome measures. PMID- 27242560 TI - Reactance to Transgressors: Why Authorities Deliver Harsher Penalties When the Social Context Elicits Expectations of Leniency. AB - This paper combines experimental and field data to examine how authorities with discretion over how rules are enforced penalize transgressors when the social context of the transgression elicits expectations of leniency. Specifically, we test how transgressors are punished when it is their birthday: a day that triggers expectations of lenient treatment. First, in three scenario studies we explore individuals' intuitions about how they would behave and expect to be treated if they transgressed on their birthdays, as well as how they would imagine penalizing a birthday transgressor. Second, using more than 134,000 arrest records for drunk driving in Washington State, we establish that police officers penalize drivers more harshly when it is their birthday. Then, in a lab experiment in which we grant participants discretion over enforcing the rules of an essay-writing contest, we test psychological reactance toward transgressors who make their birthday salient, even subtly, as the mechanism behind this increased stringency. We rule out several alternative explanations for this effect, including public safety concerns, negative affect and overcompensation for bias. We conclude with a discussion of the theoretical and practical implications of our findings for the literatures on punishment, rule-breaking, and legal transgressions. PMID- 27242561 TI - Corrigendum: Where am I? Who am I? The Relation Between Spatial Cognition, Social Cognition, and Individual Differences in the Built Environment. AB - [This corrects the article on p. 64 in vol. 7, PMID: 26903893.]. PMID- 27242562 TI - Not Only Clinical Efficacy in Psychological Treatments: Clinical Psychology Must Promote Cost-Benefit, Cost-Effectiveness, and Cost-Utility Analysis. PMID- 27242563 TI - Psychometric Properties of the Theory of Mind Assessment Scale in a Sample of Adolescents and Adults. AB - This research aimed at the evaluation of the psychometric properties of the Theory of Mind Assessment Scale (Th.o.m.a.s.). Th.o.m.a.s. is a semi-structured interview meant to evaluate a person's Theory of Mind (ToM). It is composed of several questions organized in four scales, each focusing on one of the areas of knowledge in which such faculty may manifest itself: Scale A (I-Me) investigates first-order first-person ToM; Scale B (Other-Self) investigates third-person ToM from an allocentric perspective; Scale C (I-Other) again investigates third person ToM, but from an egocentric perspective; and Scale D (Other-Me) investigates second-order ToM. The psychometric proprieties of Th.o.m.a.s. were evaluated in a sample of 156 healthy persons: 80 preadolescent and adolescent (aged 11-17 years, 42 females) and 76 adults (aged from 20 to 67 years, 35 females). Th.o.m.a.s. scores show good inter-rater agreement and internal consistency; the scores increase with age. Evidence of criterion validity was found as Scale B scores were correlated with those of an independent instrument for the evaluation of ToM, the Strange Stories task. Confirmatory factor analysis (CFA) showed good fit of the four-factors theoretical model to the data, although the four factors were highly correlated. For each of the four scales, Rasch analyses showed that, with few exceptions, items fitted the Partial credit model and their functioning was invariant for gender and age. The results of this study, along with those of previous researches with clinical samples, show that Th.o.m.a.s. is a promising instrument to assess ToM in different populations. PMID- 27242564 TI - Only Behavioral But Not Self-Report Measures of Speech Perception Correlate with Cognitive Abilities. AB - Good speech perception and communication skills in everyday life are crucial for participation and well-being, and are therefore an overarching aim of auditory rehabilitation. Both behavioral and self-report measures can be used to assess these skills. However, correlations between behavioral and self-report speech perception measures are often low. One possible explanation is that there is a mismatch between the specific situations used in the assessment of these skills in each method, and a more careful matching across situations might improve consistency of results. The role that cognition plays in specific speech situations may also be important for understanding communication, as speech perception tests vary in their cognitive demands. In this study, the role of executive function, working memory (WM) and attention in behavioral and self report measures of speech perception was investigated. Thirty existing hearing aid users with mild-to-moderate hearing loss aged between 50 and 74 years completed a behavioral test battery with speech perception tests ranging from phoneme discrimination in modulated noise (easy) to words in multi-talker babble (medium) and keyword perception in a carrier sentence against a distractor voice (difficult). In addition, a self-report measure of aided communication, residual disability from the Glasgow Hearing Aid Benefit Profile, was obtained. Correlations between speech perception tests and self-report measures were higher when specific speech situations across both were matched. Cognition correlated with behavioral speech perception test results but not with self-report. Only the most difficult speech perception test, keyword perception in a carrier sentence with a competing distractor voice, engaged executive functions in addition to WM. In conclusion, any relationship between behavioral and self-report speech perception is not mediated by a shared correlation with cognition. PMID- 27242565 TI - Mindful Reading: Mindfulness Meditation Helps Keep Readers with Dyslexia and ADHD on the Lexical Track. AB - This study explored the effects of a Mindfulness-Based Stress Reduction (MBSR) intervention on reading, attention, and psychological well-being among people with developmental dyslexia and/or attention deficits. Various types of dyslexia exist, characterized by different error types. We examined a question that has not been tested so far: which types of errors (and dyslexias) are affected by MBSR training. To do so, we tested, using an extensive battery of reading tests, whether each participant had dyslexia, and which errors types s/he makes, and then compared the rate of each error type before and after the MBSR workshop. We used a similar approach to attention disorders: we evaluated the participants' sustained, selective, executive, and orienting of attention to assess whether they had attention-disorders, and if so, which functions were impaired. We then evaluated the effect of MBSR on each of the attention functions. Psychological measures including mindfulness, stress, reflection and rumination, lifesatisfaction, depression, anxiety, and sleep-disturbances were also evaluated. Nineteen Hebrew-readers completed a 2-month mindfulness workshop. The results showed that whereas reading errors of letter-migrations within and between words and vowelletter errors did not decrease following the workshop, most participants made fewer reading errors in general following the workshop, with a significant reduction of 19% from their original number of errors. This decrease mainly resulted from a decrease in errors that occur due to reading via the sublexical rather than the lexical route. It seems, therefore, that mindfulness helped reading by keeping the readers on the lexical route. This improvement in reading probably resulted from improved sustained attention: the reduction in sublexical reading was significant for the dyslexic participants who also had attention deficits, and there were significant correlations between reduced reading errors and decreases in impulsivity. Following the meditation workshop, the rate of commission errors decreased, indicating decreased impulsivity, and the variation in RTs in the CPT task decreased, indicating improved sustained attention. Significant improvements were obtained in participants' mindfulness, perceived-stress, rumination, depression, state anxiety, and sleep-disturbances. Correlations were also obtained between reading improvement and increased mindfulness following the workshop. Thus, whereas mindfulness training did not affect specific types of errors and did not improve dyslexia, it did affect the reading of adults with developmental dyslexia and ADHD, by helping them to stay on the straight path of the lexical route while reading. Thus, the reading improvement induced by mindfulness sheds light on the intricate relation between attention and reading. Mindfulness reduced impulsivity and improved sustained attention, and this, in turn, improved reading of adults with developmental dyslexia and ADHD, by helping them to read via the straight path of the lexical route. PMID- 27242566 TI - Visibility Is Not Equivalent to Confidence in a Low Contrast Orientation Discrimination Task. AB - In several visual tasks, participants report that they feel confident about discrimination responses at a level of stimulation at which they would report not seeing the stimulus. How general and reliable is this effect? We compared subjective reports of discrimination confidence and subjective reports of visibility in an orientation discrimination task with varying stimulus contrast. Participants applied more liberal criteria for subjective reports of discrimination confidence than for visibility. While reports of discrimination confidence were more efficient in predicting trial accuracy than reports of visibility, only reports of visibility but not confidence were associated with stimulus contrast in incorrect trials. It is argued that the distinction between discrimination confidence and visibility can be reconciled with both the partial awareness hypothesis and higher order thought theory. We suggest that consciousness research would benefit from differentiating between subjective reports of visibility and confidence. PMID- 27242567 TI - Exploring Environmental Factors in Nursing Workplaces That Promote Psychological Resilience: Constructing a Unified Theoretical Model. AB - Building nurses' resilience to complex and stressful practice environments is necessary to keep skilled nurses in the workplace and ensuring safe patient care. A unified theoretical framework titled Health Services Workplace Environmental Resilience Model (HSWERM), is presented to explain the environmental factors in the workplace that promote nurses' resilience. The framework builds on a previously-published theoretical model of individual resilience, which identified the key constructs of psychological resilience as self-efficacy, coping and mindfulness, but did not examine environmental factors in the workplace that promote nurses' resilience. This unified theoretical framework was developed using a literary synthesis drawing on data from international studies and literature reviews on the nursing workforce in hospitals. The most frequent workplace environmental factors were identified, extracted and clustered in alignment with key constructs for psychological resilience. Six major organizational concepts emerged that related to a positive resilience-building workplace and formed the foundation of the theoretical model. Three concepts related to nursing staff support (professional, practice, personal) and three related to nursing staff development (professional, practice, personal) within the workplace environment. The unified theoretical model incorporates these concepts within the workplace context, linking to the nurse, and then impacting on personal resilience and workplace outcomes, and its use has the potential to increase staff retention and quality of patient care. PMID- 27242568 TI - EEG Oscillation Evidences of Enhanced Susceptibility to Emotional Stimuli during Adolescence. AB - BACKGROUND: Our recent event-related potential (ERP) study showed that adolescents are more emotionally sensitive to negative events compared to adults, regardless of the valence strength of the events. The current work aimed to confirm this age-related difference in response to emotional stimuli of diverse intensities by examining Electroencephalography (EEG) oscillatory power in time frequency analysis. METHODS: Time-frequency analyses were performed on the EEG data recorded for highly negative (HN), moderately negative (MN) and Neutral pictures in 20 adolescents and 20 adults during a covert emotional task. The results showed a significant age by emotion interaction effect in the theta and beta oscillatory power during the 500-600 ms post stimulus. RESULTS: Adolescents showed significantly less pronounced theta synchronization (ERS, 5.5-7.5 Hz) for HN stimuli, and larger beta desynchronization (ERD; 18-20 Hz) for both HN and MN stimuli, in comparison with neutral stimuli. By contrast, adults exhibited no significant emotion effects in theta and beta frequency bands. In addition, the analysis of the alpha spectral power (10.5-12 Hz; 850-950 ms) showed a main effect of emotion, while the emotion by age interaction was not significant. Irrespective of adolescents or adults, HN and MN stimuli elicited enhanced alpha suppression compared to Neutral stimuli, while the alpha power was similar across HN and MN conditions. CONCLUSIONS: These results confirmed prior findings that adolescents are more sensitive to emotionally negative stimuli compared to adults, regardless of emotion intensity, possibly due to the developing prefrontal control system during adolescence. PMID- 27242569 TI - How Age and Linguistic Competence Affect Memory for Heard Information. AB - The short-term memory performance of a group of younger adults, for whom English was a second language (young EL2 listeners), was compared to that of younger and older adults for whom English was their first language (EL1 listeners). To-be remembered words were presented in noise and in quiet. When presented in noise, the listening situation was adjusted to ensure that the likelihood of recognizing the individual words was comparable for all groups. Previous studies which used the same paradigm found memory performance of older EL1 adults on this paired associate task to be poorer than that of their younger EL1 counterparts both in quiet and in a background of babble. The purpose of the present study was to investigate whether the less well-established semantic and linguistic skills of EL2 listeners would also lead to memory deficits even after equating for word recognition as was done for the younger and older EL1 listeners. No significant differences in memory performance were found between young EL1 and EL2 listeners after equating for word recognition, indicating that the EL2 listeners' poorer semantic and linguistic skills had little effect on their ability to memorize and recall paired associates. This result is consistent with the hypothesis that age related declines in memory are primarily due to age-related declines in higher order processes supporting stream segregation and episodic memory. Such declines are likely to increase the load on higher-order (possibly limited) cognitive processes supporting memory. The problems that these results pose for the comprehension of spoken language in these three groups are discussed. PMID- 27242570 TI - Plant Studies May Lead Us to Rethink the Concept of Behavior. PMID- 27242571 TI - Phonetic Encoding of Coda Voicing Contrast under Different Focus Conditions in L1 vs. L2 English. AB - This study investigated how coda voicing contrast in English would be phonetically encoded in the temporal vs. spectral dimension of the preceding vowel (in vowel duration vs. F1/F2) by Korean L2 speakers of English, and how their L2 phonetic encoding pattern would be compared to that of native English speakers. Crucially, these questions were explored by taking into account the phonetics-prosody interface, testing effects of prominence by comparing target segments in three focus conditions (phonological focus, lexical focus, and no focus). Results showed that Korean speakers utilized the temporal dimension (vowel duration) to encode coda voicing contrast, but failed to use the spectral dimension (F1/F2), reflecting their native language experience-i.e., with a more sparsely populated vowel space in Korean, they are less sensitive to small changes in the spectral dimension, and hence fine-grained spectral cues in English are not readily accessible. Results also showed that along the temporal dimension, both the L1 and L2 speakers hyperarticulated coda voicing contrast under prominence (when phonologically or lexically focused), but hypoarticulated it in the non-prominent condition. This indicates that low-level phonetic realization and high-order information structure interact in a communicatively efficient way, regardless of the speakers' native language background. The Korean speakers, however, used the temporal phonetic space differently from the way the native speakers did, especially showing less reduction in the no focus condition. This was also attributable to their native language experience-i.e., the Korean speakers' use of temporal dimension is constrained in a way that is not detrimental to the preservation of coda voicing contrast, given that they failed to add additional cues along the spectral dimension. The results imply that the L2 phonetic system can be more fully illuminated through an investigation of the phonetics-prosody interface in connection with the L2 speakers' native language experience. PMID- 27242572 TI - Threat to Freedom and the Detrimental Effect of Avoidance Goal Frames: Reactance as a Mediating Variable. AB - Two experiments examined how individuals respond to a restriction presented within an approach versus an avoidance frame. In Study 1, working on a problem solving task, participants were initially free to choose their strategy, but for a second task were told to change their strategy. The message to change was embedded in either an approach or avoidance frame. When confronted with an avoidance compared to an approach frame, the participants' reactance toward the request was greater and, in turn, led to impaired performance. The role of reactance as a response to threat to freedom was explicitly examined in Study 2, in which participants evaluated a potential change in policy affecting their program of study herein explicitly varying whether a restriction was present or absent and whether the message was embedded in an approach versus avoidance frame. When communicated with an avoidance frame and as a restriction, participants showed the highest resistance in terms of reactance, message agreement and evaluation of the communicator. The difference in agreement with the change was mediated by reactance only when a restriction was present. Overall, avoidance goal frames were associated with more resistance to change on different levels of experience (reactance, performance, and person perception). Reactance mediated the effect of goal frame on other outcomes only when a restriction was present. PMID- 27242573 TI - The Shame and Guilt Scales of the Test of Self-Conscious Affect-Adolescent (TOSCA A): Psychometric Properties for Responses from Children, and Measurement Invariance Across Children and Adolescents. AB - This study examined various psychometric properties of the items comprising the shame and guilt scales of the Test of Self-Conscious Affect-Adolescent (TOSCA-A) in a group children between 8 and 11 years of age. A total of 699 children (367 females and 332 males) completed these scales, and also measures of depression and empathy. Confirmatory factor analysis (CFA) provided support for an oblique two-factor model, with the originally proposed shame and guilt items comprising shame and guilt factors, respectively. There was good internal consistency reliability for the shame and guilt scales, with omega coefficient values of 0.77 and 0.81 for shame and guilt, respectively. Also, shame correlated with depression symptoms positively (0.34, p < 0.001) and had no relation with empathy (-0.07, ns). Guilt correlated with depression symptoms negatively (-0.28, p < 0.001), and with empathy positively (0.13. p < 0.05). Thus there was support for the convergent and discriminant validity of the shame and guilt factors. Multiple group CFA comparing this group of children with a separate group of adolescents (320 females and 242 males), based on the chi-square difference test, supported full metric invariance, the intercept invariance of 17 of the 30 shame and guilt items, and higher latent mean scores among children for both shame and guilt. The non-equivalency for intercepts and mean scores were of small effect sizes. Comparisons based on the difference in root mean squared error of approximation values supported full measurement invariance and no group difference for latent mean scores. The findings in the current study support the use of the TOSCA-A in children and the valid comparison of scores between children and adolescents, thereby opening up the possibility of evaluating change in the TOSCA-A shame and guilt factors over these developmental age groups. PMID- 27242574 TI - Risky Decisions in a Lottery Task Are Associated with an Increase of Cocaine Use. AB - Cocaine use disorder is associated with maladaptive decision-making behavior, which strongly contributes to the harmful consequences of chronic drug use. Prior research has shown that cocaine users exhibit impaired neuropsychological test performances, particularly with regard to attention, learning, and memory but also in executive functions such as decision-making and impulse control. However, to what extent cocaine users show impaired decision-making under risk without feedback has not yet been investigated systematically. Therefore, to examine risk taking behavior, 31 chronic cocaine users and 26 stimulant-naive healthy controls who were part of the Zurich Cocaine Cognition Study, performed the Randomized Lottery Task (RALT) with winning lotteries consisting of an uncertain and a certain prospect. Results revealed that risky decisions were associated with male sex, increased cocaine use in the past year, higher cocaine concentrations in the hair, and younger age. In addition, higher levels of cocaine in the hair and cumulative lifetime consumption were associated with risky decisions, whereas potentially confounding factors including cognition and psychiatric symptoms had no significant effect. Taken together, our results indicate that cocaine users who increased their consumption over a period of 1 year show deficits in the processing of risky information accompanied with increased risk-taking. Future research should analyse whether risky decisions could potentially serve as a prognostic marker for cocaine use disorder. PMID- 27242575 TI - Bilingual Object Naming: A Connectionist Model. AB - Patterns of object naming often differ between languages, but bilingual speakers develop convergent naming patterns in their two languages that are distinct from those of monolingual speakers of each language. This convergence appears to reflect interactions between lexical representations for the two languages. In this study, we developed a self-organizing connectionist model to simulate semantic convergence in the bilingual lexicon and investigate the mechanisms underlying this semantic convergence. We examined the similarity of patterns in the simulated data to empirical data from past research, and we identified how semantic convergence was manifested in the simulated bilingual lexical knowledge. Furthermore, we created impaired models in which components of the network were removed so as to examine the importance of the relevant components on bilingual object naming. Our results demonstrate that connections between two languages' lexicons can be established through the simultaneous activations of related words in the two languages. These connections between languages allow the outputs of their lexicons to become more similar, that is, to converge. Our model provides a basis for future computational studies of how various input variables may affect bilingual naming patterns. PMID- 27242576 TI - Music Memory Following Short-term Practice and Its Relationship with the Sight reading Abilities of Professional Pianists. AB - This study investigated the relationship between the ability to sight-read and the ability to memorize a score using a behavioral experiment. By measuring the amount of memorization following short-term practice, we examined whether better sight-readers not only estimate forthcoming notes but also memorize musical structures and phrases with more practice. Eleven pianists performed the music first by sight-reading. After a 20-minute practice, the participants were asked to perform from memory without any advance notice. The number of mistakes was used as an index of performance. There were no correlations in the numbers of mistakes between sight-reading and memory trial performance. Some pianists memorized almost the entire score, while others hardly remembered it despite demonstrating almost completely accurate performance just before memory trial performance. However, judging from the participants' responses to a questionnaire regarding their practice strategies, we found auditory memory was helpful for memorizing music following short-term practice. PMID- 27242577 TI - Processing Coordinate Subject-Verb Agreement in L1 and L2 Greek. AB - The present study examines the processing of subject-verb (SV) number agreement with coordinate subjects in pre-verbal and post-verbal positions in Greek. Greek is a language with morphological number marked on nominal and verbal elements. Coordinate SV agreement, however, is special in Greek as it is sensitive to the coordinate subject's position: when pre-verbal, the verb is marked for plural while when post-verbal the verb can be in the singular. We conducted two experiments, an acceptability judgment task with adult monolinguals as a pre study (Experiment 1) and a self-paced reading task as the main study (Experiment 2) in order to obtain acceptance as well as processing data. Forty adult monolingual speakers of Greek participated in Experiment 1 and a hundred and forty one in Experiment 2. Seventy one children participated in Experiment 2: 30 Albanian-Greek sequential bilingual children and 41 Greek monolingual children aged 10-12 years. The adult data in Experiment 1 establish the difference in acceptability between singular VPs in SV and VS constructions reaffirming our hypothesis. Meanwhile, the adult data in Experiment 2 show that plural verbs accelerate processing regardless of subject position. The child online data show that sequential bilingual children have longer reading times (RTs) compared to the age-matched monolingual control group. However, both child groups follow a similar processing pattern in both pre-verbal and post-verbal constructions showing longer RTs immediately after a singular verb when the subject was pre verbal indicating a grammaticality effect. In the post-verbal coordinate subject sentences, both child groups showed longer RTs on the first subject following the plural verb due to the temporary number mismatch between the verb and the first subject. This effect was resolved in monolingual children but was still present at the end of the sentence for bilingual children indicating difficulties to reanalyze and integrate information. Taken together, these findings demonstrate that (a) 10-12 year-old sequential bilingual children are sensitive to number agreement in SV coordinate constructions parsing sentences in the same way as monolingual children even though their vocabulary abilities are lower than that of age-matched monolingual peers and (b) bilinguals are slower in processing overall. PMID- 27242578 TI - Commentary: Fairness is intuitive. PMID- 27242579 TI - Decreased Empathic Responses to the 'Lucky Guy' in Love: The Effect of Intrasexual Competition. AB - People have a greater desire to date highly attractive partners, which induces intrasexual competition between same-sex individuals. The present study used functional magnetic resonance imaging to explore whether and how intrasexual competition modulates pain empathy for a same-sex rival and the underlying neural mechanism. Participants were scanned while processing the pain of a same-sex 'lucky guy' who had an attractive partner and one with a plain partner. The results revealed that participants reported lower pain intensity for the lucky guy. Neurally, reduced pain-related activations in anterior insula and anterior mid-cingulate cortex and increased activations in right superior frontal gyrus (SFG) and medial prefrontal gyrus (MPFC) were found for the lucky guy compared to the one with a plain partner. Right SFG and MPFC activations could predict participants' subsequent pain intensity ratings for the lucky guy. These findings suggest intrasexual competition can modulate normal empathic responses. PMID- 27242580 TI - The Speech-to-Song Illusion Is Reduced in Speakers of Tonal (vs. Non-Tonal) Languages. AB - The speech-to-song illusion has attracted interest as a probe of the perceptual interface between language and music. One might anticipate differential speech-to song effects in tonal vs. non-tonal languages, since these language classes differ importantly in the linguistic value they assign to tones. Here we addressed this issue for the first time in a cohort of 20 healthy younger adults whose native language was either tonal (Thai, Mandarin) or non-tonal (German, Italian) and all of whom were also fluent in English. All participants were assessed using a protocol designed to induce the speech-to-song illusion on speech excerpts presented in each of the five study languages. Over the combined participant group, there was evidence of a speech-to-song illusion effect for all language stimuli and the extent to which individual participants rated stimuli as "song-like" at baseline was significantly positively correlated with the strength of the speech-to-song effect. However, tonal and non-tonal language stimuli elicited comparable speech-to-song effects and no acoustic language parameter was found to predict the effect. Examining the effect of the listener's native language, tonal language native speakers experienced significantly weaker speech to-song effects than non-tonal native speakers across languages. Both non-tonal native language and inability to understand the stimulus language significantly predicted the speech-to-song illusion. These findings together suggest that relative propensity to perceive prosodic structures as inherently linguistic vs. musical may modulate the speech-to-song illusion. PMID- 27242581 TI - Emotional Exhaustion and Job Satisfaction in Airport Security Officers - Work Family Conflict as Mediator in the Job Demands-Resources Model. AB - The growing threat of terrorism has increased the importance of aviation security and the work of airport security officers (screeners). Nonetheless, airport security research has yet to focus on emotional exhaustion and job satisfaction as major determinants of screeners' job performance. The present study bridges this research gap by applying the job demands-resources (JD-R) model and using work-family conflict (WFC) as an intervening variable to study relationships between work characteristics (workload and supervisor support), emotional exhaustion, and job satisfaction in 1,127 screeners at a European airport. Results of structural equation modeling revealed that (a) supervisor support as a major job resource predicted job satisfaction among screeners; (b) workload as a major job demand predicted their emotional exhaustion; and (c) WFC proved to be a promising extension to the JD-R model that partially mediated the impact of supervisor support and workload on job satisfaction and emotional exhaustion. Theoretical and practical implications are discussed. PMID- 27242582 TI - Incremental Validity and Informant Effect from a Multi-Method Perspective: Assessing Relations between Parental Acceptance and Children's Behavioral Problems. AB - This study examines the relationships between perceived parental acceptance and children's behavioral problems (externalizing and internalizing) from a multi informant perspective. Using mothers, fathers, and children as sources of information, we explore the informant effect and incremental validity. The sample was composed of 681 participants (227 children, 227 fathers, and 227 mothers). Children's (40% boys) ages ranged from 9 to 17 years (M = 12.52, SD = 1.81). Parents and children completed both the Parental Acceptance Rejection/Control Questionnaire (PARQ/Control) and the check list of the Achenbach System of Empirically Based Assessment (ASEBA). Statistical analyses were based on the correlated uniqueness multitrait-multimethod matrix (model MTMM) by structural equations and different hierarchical regression analyses. Results showed a significant informant effect and a different incremental validity related to which combination of sources was considered. A multi-informant perspective rather than a single one increased the predictive value. Our results suggest that mother father or child-father combinations seem to be the best way to optimize the multi informant method in order to predict children's behavioral problems based on perceived parental acceptance. PMID- 27242583 TI - Counterfactual Reasoning in Non-psychotic First-Degree Relatives of People with Schizophrenia. AB - Counterfactual thinking (CFT) is a type of conditional reasoning that enables the generation of mental simulations of alternatives to past factual events. Previous research has found this cognitive feature to be disrupted in schizophrenia (Hooker et al., 2000; Contreras et al., 2016). At the same time, the study of cognitive deficits in unaffected relatives of people with schizophrenia has significantly increased, supporting its potential endophenotypic role in this disorder. Using an exploratory approach, the current study examined CFT for the first time in a sample of non-psychotic first-degree relatives of schizophrenia patients (N = 43), in comparison with schizophrenia patients (N = 54) and healthy controls (N = 44). A series of tests that assessed the "causal order effect" in CFT and the ability to generate counterfactual thoughts and counterfactually derive inferences using the Counterfactual Inference Test was completed. Associations with variables of basic and social cognition, levels of schizotypy and psychotic-like experiences in addition to clinical and socio-demographic characteristics were also explored. Findings showed that first-degree relatives generated a lower number of counterfactual thoughts than controls, and were more adept at counterfactually deriving inferences, specifically in the scenarios related to regret and to judgments of avoidance in an unusual situation. No other significant results were found. These preliminary findings suggest that non psychotic first-degree relatives of schizophrenia patients show a subtle disruption of global counterfactual thinking compared with what is normally expected in the general population. Due to the potential impact of such deficits, new treatments targeting CFT improvement might be considered in future management strategies. PMID- 27242584 TI - Limits on Monolingualism? A Comparison of Monolingual and Bilingual Infants' Abilities to Integrate Lexical Tone in Novel Word Learning. AB - To construct their first lexicon, infants must determine the relationship between native phonological variation and the meanings of words. This process is arguably more complex for bilingual learners who are often confronted with phonological conflict: phonological variation that is lexically relevant in one language may be lexically irrelevant in the other. In a series of four experiments, the present study investigated English-Mandarin bilingual infants' abilities to negotiate phonological conflict introduced by learning both a tone and a non-tone language. In a novel word learning task, bilingual children were tested on their sensitivity to tone variation in English and Mandarin contexts. Their abilities to interpret tone variation in a language-dependent manner were compared to those of monolingual Mandarin learning infants. Results demonstrated that at 12-13 months, bilingual infants demonstrated the ability to bind tone to word meanings in Mandarin, but to disregard tone variation when learning new words in English. In contrast, monolingual learners of Mandarin did not show evidence of integrating tones into word meanings in Mandarin at the same age even though they were learning a tone language. However, a tone discrimination paradigm confirmed that monolingual Mandarin learning infants were able to tell these tones apart at 12-13 months under a different set of conditions. Later, at 17-18 months, monolingual Mandarin learners were able to bind tone variation to word meanings when learning new words. Our findings are discussed in terms of cognitive adaptations associated with bilingualism that may ease the negotiation of phonological conflict and facilitate precocious uptake of certain properties of each language. PMID- 27242585 TI - Investor Behavior and Flow-through Capability in the US Stock Market. AB - This paper analyzes investor behavior depending on the flow-through capability (FTC) in the US stock market, because investors seek protection from inflation rate changes, and the FTC (a firm's ability to transmit inflation shocks to the prices of its products and services) is a key factor in investment decisions. Our estimates of the FTC of firms listed on the US stock exchange at the sector level are significantly different among industries, and we demonstrate a direct relationship between changes in stock prices (at the sector level) and FTC. These results would be relevant because they have important implications on investor behavior. PMID- 27242586 TI - The Effects of Meaning and Emotional Content of a Sentence on the Kinematics of a Successive Motor Sequence Mimiking the Feeding of a Conspecific. AB - AIM: Do the emotional content and meaning of sentences affect the kinematics of successive motor sequences? MATERIAL AND METHODS: Participants observed video clips of an actor pronouncing sentences expressing positive or negative emotions and meanings (related to happiness or anger in Experiment 1 and food admiration or food disgust in Experiment 2). Then, they reached-to-grasp and placed a sugar lump on the actor's mouth. Participants acted in response to sentences whose content could convey (1) emotion (i.e., face expression and prosody) and meaning, (2) meaning alone, or (3) emotion alone. Within each condition, the kinematic effects of sentences expressing positive and negative emotions were compared. Stimuli (positive for food admiration and negative for food disgust), conveyed either by emotion or meaning affected similarly the kinematics of both grasp and reach. RESULTS: In Experiment 1, the kinematics did not vary between positive and negative sentences either when the content was expressed by both emotion and meaning, or meaning alone. In contrast, in the case of sole emotion, sentences with positive valence made faster the approach of the conspecific. In Experiment 2, the valence of emotions (positive for food admiration and negative for food disgust) affected the kinematics of both grasp and reach, independently of the modality. DISCUSSION: The lack of an effect of meaning in Experiment 1 could be due to the weak relevance of sentence meaning with respect to the motor sequence goal (feeding). Experiment 2 demonstrated that, indeed, this was the case, because when the meaning and the consequent emotion were related to the sequence goal, they affected the kinematics. In contrast, the sole emotion activated approach or avoidance toward the actor according to positive and negative valence. The data suggest a behavioral dissociation between effects of emotion and meaning. PMID- 27242587 TI - Grades, Student Satisfaction and Retention in Online and Face-to-Face Introductory Psychology Units: A Test of Equivalency Theory. AB - There has been a recent rapid growth in the number of psychology courses offered online through institutions of higher education. The American Psychological Association has highlighted the importance of ensuring the effectiveness of online psychology courses (Halonen et al., 2013). Despite this, there have been inconsistent findings regarding student grades, satisfaction, and retention in online psychology units. Equivalency Theory (Simonson, 1999; Simonson et al., 1999) posits that online and classroom-based learners will attain equivalent learning outcomes when equivalent learning experiences are provided. We present a study of an online introductory psychology unit designed to provide equivalent learning experiences to the pre-existing face-to-face version of the unit. Using quasi-experimental methods, academic performance, student feedback, and retention data from 866 Australian undergraduate psychology students were examined to assess whether the online unit developed to provide equivalent learning experiences produced comparable outcomes to the 'traditional' unit delivered face to-face. Student grades did not significantly differ between modes of delivery, except for a group-work based assessment where online students performed more poorly. Student satisfaction was generally high in both modes of the unit, with group-work the key source of dissatisfaction in the online unit. The results provide partial support for Equivalency Theory. The group-work based assessment did not provide an equivalent learning experience for students in the online unit highlighting the need for further research to determine effective methods of engaging students in online group activities. Consistent with previous research, retention rates were significantly lower in the online unit, indicating the need to develop effective strategies to increase online retention rates. While this study demonstrates successes in presenting students with an equivalent learning experience, we recommend that future research investigate means of successfully facilitating collaborative group-work assessment, and to explore contributing factors to actual student retention in online units beyond that of non-equivalent learning experiences. PMID- 27242588 TI - Sampling Participants' Experience in Laboratory Experiments: Complementary Challenges for More Complete Data Collection. AB - Speelman and McGann's (2013) examination of the uncritical way in which the mean is often used in psychological research raises questions both about the average's reliability and its validity. In the present paper, we argue that interrogating the validity of the mean involves, amongst other things, a better understanding of the person's experiences, the meaning of their actions, at the time that the behavior of interest is carried out. Recently emerging approaches within Psychology and Cognitive Science have argued strongly that experience should play a more central role in our examination of behavioral data, but the relationship between experience and behavior remains very poorly understood. We outline some of the history of the science on this fraught relationship, as well as arguing that contemporary methods for studying experience fall into one of two categories. "Wide" approaches tend to incorporate naturalistic behavior settings, but sacrifice accuracy and reliability in behavioral measurement. "Narrow" approaches maintain controlled measurement of behavior, but involve too specific a sampling of experience, which obscures crucial temporal characteristics. We therefore argue for a novel, mid-range sampling technique, that extends Hurlburt's descriptive experience sampling, and adapts it for the controlled setting of the laboratory. This controlled descriptive experience sampling may be an appropriate tool to help calibrate both the mean and the meaning of an experimental situation with one another. PMID- 27242589 TI - Cue-induced Behavioral and Neural Changes among Excessive Internet Gamers and Possible Application of Cue Exposure Therapy to Internet Gaming Disorder. AB - Internet gaming disorder (IGD) may lead to many negative consequences in everyday life, yet there is currently no effective treatment for IGD. Cue-reactivity paradigm is commonly used to evaluate craving for substance, food, and gambling; cue exposure therapy (CET) is applied to treating substance use disorders (SUDs) and some other psychological disorders such as pathological gambling (PG). However, no study has explored CET's application to the treatment of IGD except two articles having implied that cues' exposure may have therapeutic effect on IGD. This paper reviews studies on cue-induced behavioral and neural changes in excessive Internet gamers, indicating that behavioral and neural mechanisms of IGD mostly overlap with those of SUD. The CET's effects in the treatment of SUDs and PG are also reviewed. We finally propose an optimized CET paradigm, which future studies should consider and investigate as a probable treatment of IGD. PMID- 27242590 TI - The Insensitive Ruins It All: Compositional and Compilational Influences of Social Sensitivity on Collective Intelligence in Groups. AB - A group's collective intelligence reflects its capacity to perform well across a variety of cognitive tasks and it transcends the individual intelligence of its members. Previous research shows that group members' social sensitivity is a potential antecedent of collective intelligence, yet it is still unclear whether individual or group-level indices are responsible for the positive association between social sensitivity and collective intelligence. In a comprehensive manner, we test the extent to which both compositional (lowest and highest individual score) and compilational aspects (emergent group level) of social sensitivity are associated with collective intelligence. This study has implications for research that explores groups as information processors, and for group design as it indicates how a group should be composed with respect to social sensitivity if the group is to reach high levels of collective intelligence. Our empirical results indicate that collectively intelligent groups are those in which the least socially sensitive group member has a rather high score on social sensitivity. Differently stated, (socially sensitive) group members cannot compensate for the lack of social sensitivity of the other group members. PMID- 27242591 TI - Affect and Subsequent Physical Activity: An Ambulatory Assessment Study Examining the Affect-Activity Association in a Real-Life Context. AB - Traditionally, cognitive, motivational, and volitional determinants have been used to explain and predict health behaviors such as physical activity. Recently, the role of affect in influencing and regulating health behaviors received more attention. Affects as internal cues may automatically activate unconscious processes of behavior regulation. The aim of our study was to examine the association between affect and physical activity in daily life. In addition, we studied the influence of the habit of being physically active on this relationship. An ambulatory assessment study in 89 persons (33.7% male, 25 to 65 years, M = 45.2, SD = 8.1) was conducted. Affect was assessed in the afternoon on 5 weekdays using smartphones. Physical activity was measured continuously objectively using accelerometers and subjectively using smartphones in the evening. Habit strength was assessed at the beginning of the diary period. The outcomes were objectively and subjectively measured moderate-to-vigorous physical activity (MVPA) performed after work. Multilevel regression models were used to analyze the association between affect and after work MVPA. In addition, the cross-level interaction of habit strength and affect on after work MVPA was tested. Positive affect was positively related to objectively measured and self reported after work MVPA: the greater the positive affect the more time persons subsequently spent on MVPA. An inverse relationship was found for negative affect: the greater the negative affect the less time persons spent on MVPA. The cross-level interaction effect was significant only for objectively measured MVPA. A strong habit seems to strengthen both the positive influence of positive affect and the negative influence of negative affect. The results of this study confirm previous results and indicate that affect plays an important role for the regulation of physical activity behavior in daily life. The results for positive affect were consistent. However, in contrast to previous reports of no or an inverse association, negative affect decreased subsequent MVPA. These inconsistencies may be-in part-explained by the different measurements of affect in our and other studies. Therefore, further research is warranted to gain more insight into the association between affect and physical activity. PMID- 27242593 TI - Relative Age Effects in Mathematics and Reading: Investigating the Generalizability across Students, Time and Classes. AB - A child's age in comparison to the age of her or his classmates (relative age) has been found to be an influential factor on academic achievement, particularly but not exclusively at the beginning of formal schooling. However, few studies have focused on the generalizability of relative age effects. To close this gap, the present study analyzes the generalizability across students with and without immigrant backgrounds, across three student cohorts that entered school under a changing law of school enrollment, and across classes. To this end, we capitalized on representative large-scale data sets from three student cohorts attending public schools in Berlin, the capital of Germany. We analyzed the data using a multilevel framework. Our results for the overall student sample indicate relative age effects for reading and mathematics in favor of the relatively older students in Grade 2 that become somewhat smaller in size in Grade 3. By Grade 8, relative age effects had vanished in reading and had even reversed in favor of the relatively young in mathematics. Furthermore, relative age effects were not found to be systematically different among students with and without immigrant backgrounds, student cohorts, or across classes. Taken together, these results empirically underscore the broad generalizability of the findings as found for the overall student population and replicate the pattern of findings on relative effects as identified by the majority of previous studies. PMID- 27242592 TI - The Bilingual Disadvantage in Speech Understanding in Noise Is Likely a Frequency Effect Related to Reduced Language Exposure. AB - The present study sought to explain why bilingual speakers are disadvantaged relative to monolingual speakers when it comes to speech understanding in noise. Exemplar models of the mental lexicon hold that each encounter with a word leaves a memory trace in long-term memory. Words that we encounter frequently will be associated with richer phonetic representations in memory and therefore recognized faster and more accurately than less frequently encountered words. Because bilinguals are exposed to each of their languages less often than monolinguals by virtue of speaking two languages, they encounter all words less frequently and may therefore have poorer phonetic representations of all words compared to monolinguals. In the present study, vocabulary size was taken as an estimate for language exposure and the prediction was made that both vocabulary size and word frequency would be associated with recognition accuracy for words presented in noise. Forty-eight early Spanish-English bilingual and 53 monolingual English young adults were tested on speech understanding in noise (SUN) ability, English oral verbal ability, verbal working memory (WM), and auditory attention. Results showed that, as a group, monolinguals recognized significantly more words than bilinguals. However, this effect was attenuated by language proficiency; higher proficiency was associated with higher accuracy on the SUN test in both groups. This suggests that greater language exposure is associated with better SUN. Word frequency modulated recognition accuracy and the difference between groups was largest for low frequency words, suggesting that the bilinguals' insufficient exposure to these words hampered recognition. The effect of WM was not significant, likely because of its large shared variance with language proficiency. The effect of auditory attention was small but significant. These results are discussed within the Ease of Language Understanding model (Ronnberg et al., 2013), which provides a framework for explaining individual differences in SUN. PMID- 27242594 TI - Secondary School Students' LLL Competencies, and Their Relation with Classroom Structure and Achievement. AB - There is a strong urge to foster lifelong learning (LLL) competencies with its key components - motivation and self-regulated learning - from early on in the education system. School in general is presently not considered to be successful in systematically imparting motivation and self-regulated learning strategies. There is strong evidence that decisive motivational determinants decrease the longer students stay in school. At present, the central sources of information about the situation in Austria are international monitoring studies, which only examine selected aspects of specific target groups, and their interpretability concerning mean values is constricted due to cultural differences. Thus, it is important to conduct additional and more differentiated national surveys of the actual state. This is why this study aimed at answering the following questions: (1) how well are Austrian students equipped for the future, in terms of their lifelong learning competencies, (2) can perceived classroom structure predict students' LLL, and (3) is there a correlation of students' LLL with their achievement in the school subjects math and German language. 5366 students (52.1% female) from 36 Austrian schools took part in the online-questionnaire (mean age 15.35 years, SD = 2.45), which measured their perceived LLL competencies in the subjects math and German language, their perceived classroom structure and their achievement. Results showed that the great majority of Austrian students - independent from domain and sex - know and are able to apply cognitive as well as metacognitive learning strategies. With regard to motivation the picture is less satisfactory: whilst students' self-efficacy is not the problem, there is a lack of interest in the school subjects and they often report to follow performance approach goals. Classroom structure positively predicted students' goals, interest, self-efficacy and learning strategies. Self-efficacy, performance approach goals, meta-cognitive and deep learning strategies in turn predicted achievement positively, and performance avoidance goals negatively. PMID- 27242595 TI - Deployment of Attention on Handshakes. AB - Understanding the social structures between objects, organizing, and selecting them accordingly, is fundamental to social cognition. We report an example that demonstrates the object association learned from social interactions could impact visual attention. Particularly, when two hands approach each other to perform a handshake, they tend to be attended to as a unit because of the cooperative relationship exhibited in the action: even a cue presented on a non-target hand may facilitate a response to the targets that appear on the non-cued hand (Experiment 1), indicating that attentional shift between two hands was facilitated; furthermore, the response to a target on one hand is significantly impaired by a distractor on the other hand (Experiment 2), implying that it is difficult to selectively confine attention to a single hand. These effects were dependent on the existence of the hands when cue and target appeared (Experiment 3); neither perceptual familiarity, or physical fit can explain all the attention effects (Experiment 4). These results have bearings on the perceptual root of social cognition. PMID- 27242596 TI - A New Tool to Measure Malevolent Creativity: The Malevolent Creativity Behavior Scale. AB - The present study developed the malevolent creativity behavior scale (MCBS), which contains 13 items and was designed to measure individuals' malevolent creativity through the behavior of daily lives. A total of 958 participants from different regions of China completed the MCBS in an online fashion. Cronbach's alpha coefficient, using the 908 MCBSs with entirely complete data, indicated that the MCBS had satisfactory reliability. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) revealed that the MCBS had 3 dimensions: hurting people, lying, and playing tricks. MCBS scores were positively correlated with individuals' aggression, openness, extraversion, and scores on the Runco Ideational Behavior Scale (RIBS). MCBS scores also predicted individuals' malevolent creativity performances when solving realistic, open-ended problems. The MCBS has a simple response medium and scoring procedure. This, along with the adequate psychometric properties uncovered here, indicates that it is a useful tool for research on malevolent creativity. Given that the MCBS contains a relatively small number of categories and items, further research could expand the categories of items and develop and test more items. Moreover, it would be useful to test MCBS's reliability and validity with other criteria. Perhaps future research could obtain actual MC data from criminal or other unambiguously malevolent samples. PMID- 27242597 TI - Comparison of Measures of Ability in Adolescents with Intellectual Disability. AB - Finding the most appropriate intelligence test for adolescents with Intellectual Disability (ID) is challenging given their limited language, attention, perceptual, and motor skills and ability to stay on task. The study compared performance of 23 adolescents with ID on the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV), one of the most widely used intelligence tests, and three non-verbal IQ tests, the Raven's Colored Progressive Matrices (RCPM), the Test of Non-verbal Intelligence-Fourth Edition and the Wechsler Non verbal test of Ability. Results showed that the WISC-IV Full Scale IQ raw and scaled scores were highly correlated with total scores from the three non-verbal tests, although the correlations were higher for raw scores, suggesting they may lead to better understanding of within group differences and what individuals with ID can do at the time of assessment. All participants attempted more questions on the non-verbal tests than the verbal. A preliminary analysis showed that adolescents with ID without ASD (n = 15) achieved higher scores overall than those presenting with ID+ASD (n = 8). Our findings support the view that short non-verbal tests are more likely to give a similar IQ result as obtained from the WISC-IV. In terms of the time to administer and the stress for participants, they are more appropriate for assessing adolescents with ID. PMID- 27242598 TI - Brazilian Normative Data on Letter and Category Fluency Tasks: Effects of Gender, Age, and Geopolitical Region. AB - Verbal fluency is a basic function of language that refers to the ability to produce fluent speech. Despite being an essentially linguistic function, its measurements are also used to evaluate executive aspects of verbal behavior. Performance in verbal fluency (VF) tasks varies according to age, education, and cognitive development. Neurodevelopmental disorders that affect the functioning of frontal areas tend to cause lower performance in VF tasks. Despite the relative consensus that has been reached in terms of the use of VF tasks for the diagnosis of dyslexia and attention-deficit/hyperactivity disorder, few studies have considered regional variations in Brazil. The present study sought to provide normative data on VF tasks in children by considering gender, age, education, and geopolitical region of origin with auxiliary purposes in neuropsychological diagnosis of disorders that occur with executive changes The study included 298 participants, 7-10 years of age of both genders, who performed three letter fluency tasks and three category fluency tasks. The data were subjected to correlational and variance analyses, with age and gender as factors. No effect of gender on the children's performance was found. However, significant differences between age groups were observed, with better performance in letter tasks in older children and better performance in letter tasks compared with category tasks. Significant regional differences in performance on the letter VF task were observed. These results reinforce the importance of regional normative data in countries with high regional cultural variations, such as Brazil. PMID- 27242599 TI - Varied Practice in Laparoscopy Training: Beneficial Learning Stimulation or Cognitive Overload? AB - Determining the optimal design for surgical skills training is an ongoing research endeavor. In education literature, varied practice is listed as a positive intervention to improve acquisition of knowledge and motor skills. In the current study we tested the effectiveness of a varied practice intervention during laparoscopy training. Twenty-four trainees (control group) without prior experience received a 3 weeks laparoscopic skills training utilizing four basic and one advanced training task. Twenty-eight trainees (experimental group) received the same training with a random training task schedule, more frequent task switching and inverted viewing conditions on the four basic training tasks, but not the advanced task. Results showed inferior performance of the experimental group on the four basic laparoscopy tasks during training, at the end of training and at a 2 months retention session. We assume the inverted viewing conditions have led to the deterioration of learning in the experimental group because no significant differences were found between groups on the only task that had not been practiced under inverted viewing conditions; the advanced laparoscopic task. Potential moderating effects of inter-task similarity, task complexity, and trainee characteristics are discussed. PMID- 27242600 TI - Positive Psychology Interventions Addressing Pleasure, Engagement, Meaning, Positive Relationships, and Accomplishment Increase Well-Being and Ameliorate Depressive Symptoms: A Randomized, Placebo-Controlled Online Study. AB - Seligman (2002) suggested three paths to well-being, the pursuit of pleasure, the pursuit of meaning, and the pursuit of engagement, later adding two more, positive relationships and accomplishment, in his 2011 version. The contribution of these new components to well-being has yet to be addressed. In an online positive psychology intervention study, we randomly assigned 1624 adults aged 18 78 (M = 46.13; 79.2% women) to seven conditions. Participants wrote down three things they related to either one of the five components of Seligman's Well-Being theory (Conditions 1-5), all of the five components (Condition 6) or early childhood memories (placebo control condition). We assessed happiness (AHI) and depression (CES-D) before and after the intervention, and 1-, 3-, and 6 months afterwards. Additionally, we considered moderation effects of well-being levels at baseline. Results confirmed that all interventions were effective in increasing happiness and most ameliorated depressive symptoms. The interventions worked best for those in the middle-range of the well-being continuum. We conclude that interventions based on pleasure, engagement, meaning, positive relationships, and accomplishment are effective strategies for increasing well being and ameliorating depressive symptoms and that positive psychology interventions are most effective for those people in the middle range of the well being continuum. PMID- 27242602 TI - "Having to Shift Everything We've Learned to the Side": Expanding Research Methods Taught in Psychology to Incorporate Qualitative Methods. AB - In Australia the tradition of conducting quantitative psychological research within a positivist framework has been challenged, with calls made for the inclusion of the full range of qualitative and quantitative methodologies within the undergraduate psychology curriculum. Despite this, the undergraduate psychology curriculum in most Australian universities retains a strong focus on teaching quantitative research methods. Limited research has examined attitudes toward qualitative research held by undergraduate psychology students taught within a positivist framework, and whether these attitudes are malleable and can be changed through teaching qualitative methodologies. Previous research has suggested that students from strong quantitative backgrounds experience some cognitive dissonance and greater difficulties in learning qualitative methods. In this article we examine 3rd year undergraduate psychology students' attitudes to qualitative research prior to commencing and upon completion of a qualitative research unit. All students had previously completed two 13 weeks units of study in quantitative research methods. At Time 1, 63 students (84.1% female) completed online surveys comprising attitudinal measures. Key themes to emerge from student comments were that qualitative research was seen as an alternative approach, representing a paradigmatic shift that was construed by some students advantageous for meeting future professional and educative goals. Quantitative measures of attitudes to qualitative research were associated with general attitudes toward research, and psychology-specific epistemological beliefs. Changes in attitudes following completion of the qualitative research methods unit were in the hypothesized direction, but non-significant (small effect sizes). The findings increase our understanding of psychology students' attitudes toward qualitative research and inform our recommendations for teaching research methods within the undergraduate psychology curriculum. PMID- 27242601 TI - Intense, Passionate, Romantic Love: A Natural Addiction? How the Fields That Investigate Romance and Substance Abuse Can Inform Each Other. AB - Individuals in the early stage of intense romantic love show many symptoms of substance and non-substance or behavioral addictions, including euphoria, craving, tolerance, emotional and physical dependence, withdrawal and relapse. We have proposed that romantic love is a natural (and often positive) addiction that evolved from mammalian antecedents by 4 million years ago as a survival mechanism to encourage hominin pair-bonding and reproduction, seen cross-culturally today in Homo sapiens. Brain scanning studies using functional magnetic resonance imaging support this view: feelings of intense romantic love engage regions of the brain's "reward system," specifically dopamine-rich regions, including the ventral tegmental area, also activated during drug and/or behavioral addiction. Thus, because the experience of romantic love shares reward pathways with a range of substance and behavioral addictions, it may influence the drug and/or behavioral addiction response. Indeed, a study of overnight abstinent smokers has shown that feelings of intense romantic love attenuate brain activity associated with cigarette cue-reactivity. Could socially rewarding experiences be therapeutic for drug and/or behavioral addictions? We suggest that "self expanding" experiences like romance and expanding one's knowledge, experience and self-perception, may also affect drug and/or behavioral addiction behaviors. Further, because feelings of romantic love can progress into feelings of calm attachment, and because attachment engages more plastic forebrain regions, there is a rationale for therapies that may help substance and/or behavioral addiction by promoting activation of these forebrain systems through long-term, calm, positive attachments to others, including group therapies. Addiction is considered a negative (harmful) disorder that appears in a population subset; while romantic love is often a positive (as well as negative) state experienced by almost all humans. Thus, researchers have not categorized romantic love as a chemical or behavioral addiction. But by embracing data on romantic love, it's classification as an evolved, natural, often positive but also powerfully negative addiction, and its neural similarity to many substance and non-substance addictive states, clinicians may develop more effective therapeutic approaches to alleviate a range of the addictions, including heartbreak-an almost universal human experience that can trigger stalking, clinical depression, suicide, homicide, and other crimes of passion. PMID- 27242603 TI - Parent Scaffolding of Young Children When Engaged with Mobile Technology. AB - Shared parent-child experiences while engaged with an iPad(TM) were examined to determine if and then how parents interact with their children when using mobile digital devices. In total, 104 parent-child dyads participated in an observation session where parent-child interactions using the touchscreen tablet device were video recorded in order to observe first-hand the supports and exchanges between parent and child (age range 46.21-75.9 months). Results indicate that parents provide a great deal of support to their children while interacting with the touchscreen tablet device including verbal, emotional-verbal, physical and emotional-physical supports. The types of support offered did not differ as a function of parent gender or experience with mobile devices (users versus non users). Overall, parents rated their own experience engaging with the touchscreen tablet and that of their child's positively. Additional survey measures assessed parents' perceptions of their child's technology use and attitudes regarding optimal ages and conditions for introducing and using technology. Most parents indicated a preference for very early introduction to mobile technologies. Implications of these findings are discussed. PMID- 27242604 TI - A Values-Affirmation Intervention Does Not Benefit Negatively Stereotyped Immigrant Students in the Netherlands. AB - Previous research showed that a values-affirmation intervention can help reduce the achievement gap between African American and European American students in the US. In the present study, it was examined if these results would generalize to ethnic minority students in a country outside the US, namely the Netherlands, where there is also an achievement gap between native and ethnic minority students. This type of intervention was tested in two separate studies, the first among first-year pre-vocational students (n = 361, 84% ethnic minority), and the second among sixth grade students (n = 290, 96% ethnic minority). Most minority participants had a Turkish-Dutch or Moroccan-Dutch immigrant background. In the second study, a third condition was added to the original paradigm, in which students elaborated on either their affirmation- or a control exercise with the help of a teaching assistant. We also examined whether values affirmation affected the level of problem behavior of negatively stereotyped ethnic minority youth. Contrary to what was expected, multilevel analyses revealed that the intervention had no effect on the school achievement or the problem behavior of the ethnic minority students. Possible explanations for these findings, mainly related to contextual and cultural differences between the Netherlands and the US, are discussed. PMID- 27242605 TI - On Cooperative Behavior in Distributed Teams: The Influence of Organizational Design, Media Richness, Social Interaction, and Interaction Adaptation. AB - Self-interest vs. cooperation is a fundamental dilemma in animal behavior as well as in human and organizational behavior. In organizations, how to get people to cooperate despite or in conjunction with their self-interest is fundamental to the achievement of a common goal. While both organizational designs and social interactions have been found to further cooperation in organizations, some of the literature has received contradictory support, just as very little research, if any, has examined their joint effects in distributed organizations, where communication is usually achieved via different communication media. This paper reviews the extant literature and offers a set of hypotheses to integrate current theories and explanations. Further, it discusses how future research should examine the joint effects of media, incentives, and social interactions. PMID- 27242607 TI - Innovation in education. Commentary: Teaching statistics using dance and movement and a case for neuroscience in mathematics education. PMID- 27242606 TI - Emotional Actions Are Coded via Two Mechanisms: With and without Identity Representation. AB - Accurate perception of an individual's identity and emotion derived from their actions and behavior is essential for successful social functioning. Here we determined the role of identity in the representation of emotional whole-body actions using visual adaptation paradigms. Participants adapted to actors performing different whole-body actions in a happy and sad fashion. Following adaptation subsequent neutral actions appeared to convey the opposite emotion. We demonstrate two different emotional action aftereffects showing distinctive adaptation characteristics. For one short-lived aftereffect, adaptation to the emotion expressed by an individual resulted in biases in the perception of the expression of emotion by other individuals, indicating an identity-independent representation of emotional actions. A second, longer lasting, aftereffect was observed where adaptation to the emotion expressed by an individual resulted in longer-term biases in the perception of the expressions of emotion only by the same individual; this indicated an additional identity-dependent representation of emotional actions. Together, the presence of these two aftereffects indicates the existence of two mechanisms for coding emotional actions, only one of which takes into account the actor's identity. The results that we observe might parallel processing of emotion from face and voice. PMID- 27242608 TI - Consequences of Misspecifying Levels of Variance in Cross-Classified Longitudinal Data Structures. AB - The purpose of this study was to determine if modeling school and classroom effects was necessary in estimating passage reading growth across elementary grades. Longitudinal data from 8367 students in 2989 classrooms in 202 Reading First schools were used in this study and were obtained from the Progress Monitoring and Reporting Network maintained by the Florida Center for Reading Research. Oral reading fluency (ORF) was assessed four times per school year. Five growth models with varying levels of data (student, classroom, and school) were estimated in order to determine which structures were necessary to correctly partition variance and accurately estimate standard errors for growth parameters. Because the results illustrate that not modeling higher-level clustering inflated lower-level variance estimates and in some cases led to biased standard errors, the authors recommend the practice of including classroom cross-classification and school nesting when predicting longitudinal student outcomes. PMID- 27242609 TI - Correlation between Patent Foramen Ovale, Cerebral "Lesions" and Neuropsychometric Testing in Experienced Sports Divers: Does Diving Damage the Brain? AB - SCUBA diving exposes divers to decompression sickness (DCS). There has been considerable debate whether divers with a Patent Foramen Ovale of the heart have a higher risk of DCS because of the possible right-to-left shunt of venous decompression bubbles into the arterial circulation. Symptomatic neurological DCS has been shown to cause permanent damage to brain and spinal cord tissue; it has been suggested that divers with PFO may be at higher risk of developing subclinical brain lesions because of repeated asymptomatic embolization of decompression-induced nitrogen bubbles. These studies however suffer from several methodological flaws, including self-selection bias. We recruited 200 volunteer divers from a recreational diving population who had never suffered from DCS; we then randomly selected 50 of those for further investigation. The selected divers underwent brain Magnetic Resonance Imaging to detect asymptomatic brain lesions, contrast trans-oesophageal echocardiography for PFO, and extensive neuro psychometric testing. Neuro-psychometry results were compared with a control group of normal subjects and a separate control group for subjects exposed to neurotoxic solvents. Forty two divers underwent all the tests and are included in this report. Grade 2 Patent Foramen Ovale was found in 16 (38%) of the divers; brain Unidentified Bright Objects (UBO's) were found in 5 (11.9%). There was no association between PFO and the presence of UBO's (P = 0.693) or their size (p = 0.5) in divers. Neuropsychometric testing in divers was significantly worse from controls in two tests, Digit Span Backwards (DSB; p < 0.05) and Symbol-Digit Substitution (SDS; p < 0.01). Compared to subjects exposed to neurotoxic solvents, divers scored similar on DSB and SDS tests, but significantly better on the Simple Reaction Time (REA) and Hand-Eye Coordination (EYE) tests. There was no correlation between PFO, number of UBO's and any of the neuro-psychometric tests. We conclude that for uneventful recreational diving, PFO does not appear to influence the presence of UBO's. Diving by itself seems to cause some decrease of short-term memory and higher cognitive function, including visual-motor skills; this resembles some of the effects of nitrogen narcosis and we suggest that this may be a prolonged effect of diving. PMID- 27242610 TI - Differences in Sequential Eye Movement Behavior between Taiwanese and American Viewers. AB - Knowledge of how information is sought in the visual world is useful for predicting and simulating human behavior. Taiwanese participants and American participants were instructed to judge the facial expression of a focal face that was flanked horizontally by other faces while their eye movements were monitored. The Taiwanese participants distributed their eye fixations more widely than American participants, started to look away from the focal face earlier than American participants, and spent a higher percentage of time looking at the flanking faces. Eye movement transition matrices also provided evidence that Taiwanese participants continually, and systematically shifted gaze between focal and flanking faces. Eye movement patterns were less systematic and less prevalent in American participants. This suggests that both cultures utilized different attention allocation strategies. The results highlight the importance of determining sequential eye movement statistics in cross-cultural research on the utilization of visual context. PMID- 27242611 TI - Visualizing Similarity of Appearance by Arrangement of Cards. AB - This study proposes a novel method to extract the configuration of the psychological space by directly measuring subjects' similarity rating without computational work. Although multidimensional scaling (MDS) is well-known as a conventional method for extracting the psychological space, the method requires many pairwise evaluations. The times taken for evaluations increase in proportion to the square of the number of objects in MDS. The proposed method asks subjects to arrange cards on a poster sheet according to the degree of similarity of the objects. To compare the performance of the proposed method with the conventional one, we developed similarity maps of typefaces through the proposed method and through non-metric MDS. We calculated the trace correlation coefficient among all combinations of the configuration for both methods to evaluate the degree of similarity in the obtained configurations. The threshold value of trace correlation coefficient for statistically discriminating similar configuration was decided based on random data. The ratio of the trace correlation coefficient exceeding the threshold value was 62.0% so that the configurations of the typefaces obtained by the proposed method closely resembled those obtained by non metric MDS. The required duration for the proposed method was approximately one third of the non-metric MDS's duration. In addition, all distances between objects in all the data for both methods were calculated. The frequency for the short distance in the proposed method was lower than that of the non-metric MDS so that a relatively small difference was likely to be emphasized among objects in the configuration by the proposed method. The card arrangement method we here propose, thus serves as a easier and time-saving tool to obtain psychological structures in the fields related to similarity of appearance. PMID- 27242612 TI - Disruption of Foveal Space Impairs Discrimination of Peripheral Objects. AB - Visual space is retinotopically mapped such that peripheral objects are processed in a cortical region outside the region that represents central vision. Despite this well-known fact, neuroimaging studies have found information about peripheral objects in the foveal confluence, the cortical region representing the fovea. Further, this information is behaviorally relevant: disrupting the foveal confluence using transcranial magnetic stimulation impairs discrimination of peripheral objects at time-points consistent with a disruption of feedback. If the foveal confluence receives feedback of information about peripheral objects to boost vision, there should be behavioral consequences of this phenomenon. Here, we tested the effect of foveal distractors at different stimulus onset asynchronies (SOAs) on discrimination of peripheral targets. Participants performed a discrimination task on target objects presented in the periphery while fixating centrally. A visual distractor presented at the fovea ~100 ms after presentation of the targets disrupted performance more than a central distractor presented at other SOAs. This was specific to a central distractor; a peripheral distractor at the same time point did not have the same effect. These results are consistent with the claim that foveal retinotopic cortex is recruited for extra-foveal perception. This study describes a new paradigm for investigating the nature of the foveal feedback phenomenon and demonstrates the importance of this feedback in peripheral vision. PMID- 27242613 TI - Understanding the Reasons behind Anticipated Regret for Missing Regular Physical Activity. AB - Anticipated affective reactions to missing physical activity (PA), often labeled anticipated regret, has reliable evidence as a predictor of PA intention and behavior independent of other standard social cognitive constructs. Despite this evidence, the sources of regret are understudied and may come from many different reasons. The purpose of this study was to theme the reasons for why people responded to anticipated regret over missing regular PA for 2 weeks. Participants were a random sample of 120 university students who were primed on the public health definition of PA, completed measures of regret, and were asked to list their reasons for regret. Ninety-five percent of participants expressed that they would regret not being active and gave a total of 357 reasons. The dominant theme (n = 247; 69%) was a missed opportunity to obtain the benefits of PA, followed by shame/guilt for not being able to follow-through with one's goals or self categorized role (n = 99; 28%) with a final theme of perceived pressure from others (n = 11; 3%). From a practical perspective, the diversity of these reasons suggest that more clarity on the source of regret should be present in assessment, while building from both attitude and identity theories may help understand how regret motivates PA in future intervention. PMID- 27242614 TI - Behavioral Advantages of the First-Person Perspective Model for Imitation. AB - Visuomotor information may be better conveyed through a first-person perspective than through a third-person perspective. However, few reports have shown a clear behavioral advantage of the first-person perspective because of the confounding factor of spatial stimulus-response compatibility. Most imitation studies have utilized visuospatial imitation tasks in which participants use the same body part as that used by the model, identified by its spatial position (i.e., the response action is predefined). In such studies, visuomotor information conveyed by the model does not appear to facilitate imitative behavior. We hypothesized that the use of the first-person perspective would facilitate more efficient imitative behavior than a third-person perspective when participants are asked to choose and reproduce an action identical to that of the model rather than to select the same body part; this task requires the analysis of both visual and motor information from the model rather than a simple assessment of spatial information. To test this hypothesis, we asked 15 participants to observe a model from two perspectives (first-person and third-person) with left or right hand laterality and to lift their index finger with an identical movement type (extension or flexion) as quickly as possible. Response latencies were shorter and fewer errors were made in trials using the first-person perspective than in those using the third-person perspective, regardless of whether the model used the right or left hand. These findings suggest that visuomotor information from the first-person perspective, without confounding effects of spatial information, facilitates efficient imitative behavior. PMID- 27242615 TI - Phonotactic Constraints Are Activated across Languages in Bilinguals. AB - During spoken language comprehension, auditory input activates a bilingual's two languages in parallel based on phonological representations that are shared across languages. However, it is unclear whether bilinguals access phonotactic constraints from the non-target language during target language processing. For example, in Spanish, words with s+ consonant onsets cannot exist, and phonotactic constraints call for epenthesis (addition of a vowel, e.g., stable/estable). Native Spanish speakers may produce English words such as estudy ("study") with epenthesis, suggesting that these bilinguals apply Spanish phonotactic constraints when speaking English. The present study is the first to examine whether bilinguals access Spanish phonotactic constraints during English comprehension. In an English cross-modal priming lexical decision task, Spanish English bilinguals and English monolinguals heard English cognate and non-cognate primes containing s+ consonant onsets or controls without s+ onsets, followed by a lexical decision on visual targets with the /e/ phonotactic constraint or controls without /e/. Results revealed that bilinguals were faster to respond to /es/ non-word targets preceded by s+ cognate primes and /es/ and /e/ non-word targets preceded by s+ non-cognate primes, confirming that English primes containing s+ onsets activated Spanish phonotactic constraints. These findings are discussed within current accounts of parallel activation of two languages during bilingual spoken language comprehension, which may be expanded to include activation of phonotactic constraints from the irrelevant language. PMID- 27242616 TI - Perceived Work Conditions and Turnover Intentions: The Mediating Role of Meaning of Work. AB - Perceived working conditions lead to various negative outcomes for employee behaviors, including turnover intentions. Although potential mediators for these relationships were previously identified, the importance of meaning of work has not yet been investigated. This study examines the role of this psychological resource as a mediator for the relationships between perceived working conditions and turnover intentions in a sample of 336 French workers from different job contexts. Results show that adverse working conditions were positively and significantly associated with turnover intentions. Meaning of work is negatively related to both perceived working conditions and turnover intentions. Mediation analyses for meaning of work demonstrated indirect effects of several adverse working conditions on turnover intentions. The role of meaning of work as a psychological resource for employees facing adverse working conditions is discussed, especially regarding its implications for research and practice within organizational contexts. PMID- 27242618 TI - Corrigendum: Bifactor analysis and construct validity of the Five Facet Mindfulness Questionnaire (FFMQ) in non-clinical Spanish samples. AB - [This corrects the article on p. 404 in vol. 6, PMID: 25914664.]. PMID- 27242617 TI - Brain Oscillatory Correlates of Altered Executive Functioning in Positive and Negative Symptomatic Schizophrenia Patients and Healthy Controls. AB - Working Memory and executive functioning deficits are core characteristics of patients suffering from schizophrenia. Electrophysiological research indicates that altered patterns of neural oscillatory mechanisms underpinning executive functioning are associated with the psychiatric disorder. Such brain oscillatory changes have been found in local amplitude differences at gamma and theta frequencies in task-specific cortical areas. Moreover, interregional interactions are also disrupted as signified by decreased phase coherence of fronto-posterior theta activity in schizophrenia patients. However, schizophrenia is not a one dimensional psychiatric disorder but has various forms and expressions. A common distinction is between positive and negative symptomatology but most patients have both negative and positive symptoms to some extent. Here, we examined three groups-healthy controls, predominantly negative, and predominantly positive symptomatic schizophrenia patients-when performing a working memory task with increasing cognitive demand and increasing need for executive control. We analyzed brain oscillatory activity in the three groups separately and investigated how predominant symptomatology might explain differences in brain oscillatory patterns. Our results indicate that differences in task specific fronto-posterior network activity (i.e., executive control network) expressed by interregional phase synchronization are able to account for working memory dysfunctions between groups. Local changes in the theta and gamma frequency range also show differences between patients and healthy controls, and more importantly, between the two patient groups. We conclude that differences in oscillatory brain activation patterns related to executive processing can be an indicator for positive and negative symptomatology in schizophrenia. Furthermore, changes in cognitive and especially executive functioning in patients are expressed by alterations in a task-specific fronto-posterior connectivity even in the absence of behavioral impairment. PMID- 27242619 TI - A Two-Factor Model Better Explains Heterogeneity in Negative Symptoms: Evidence from the Positive and Negative Syndrome Scale. AB - Acknowledging separable factors underlying negative symptoms may lead to better understanding and treatment of negative symptoms in individuals with schizophrenia. The current study aimed to test whether the negative symptoms factor (NSF) of the Positive and Negative Syndrome Scale (PANSS) would be better represented by expressive and experiential deficit factors, rather than by a single factor model, using confirmatory factor analysis (CFA). Two hundred and twenty individuals with schizophrenia spectrum disorders completed the PANSS; subsamples additionally completed the Brief Negative Symptom Scale (BNSS) and the Motivation and Pleasure Scale-Self-Report (MAP-SR). CFA results indicated that the two-factor model fit the data better than the one-factor model; however, latent variables were closely correlated. The two-factor model's fit was significantly improved by accounting for correlated residuals between N2 (emotional withdrawal) and N6 (lack of spontaneity and flow of conversation), and between N4 (passive social withdrawal) and G16 (active social avoidance), possibly reflecting common method variance. The two NSF factors exhibited differential patterns of correlation with subdomains of the BNSS and MAP-SR. These results suggest that the PANSS NSF would be better represented by a two factor model than by a single-factor one, and support the two-factor model's adequate criterion-related validity. Common method variance among several items may be a potential source of measurement error under a two-factor model of the PANSS NSF. PMID- 27242620 TI - Commentary: Weighty data: importance information influences estimated weight of digital information storage devices. PMID- 27242621 TI - Different Loci of Semantic Interference in Picture Naming vs. Word-Picture Matching Tasks. AB - Naming pictures and matching words to pictures belonging to the same semantic category impairs performance relative to when stimuli come from different semantic categories (i.e., semantic interference). Despite similar semantic interference phenomena in both picture naming and word-picture matching tasks, the locus of interference has been attributed to different levels of the language system - lexical in naming and semantic in word-picture matching. Although both tasks involve access to shared semantic representations, the extent to which interference originates and/or has its locus at a shared level remains unclear, as these effects are often investigated in isolation. We manipulated semantic context in cyclical picture naming and word-picture matching tasks, and tested whether factors tapping semantic-level (generalization of interference to novel category items) and lexical-level processes (interactions with lexical frequency) affected the magnitude of interference, while also assessing whether interference occurs at a shared processing level(s) (transfer of interference across tasks). We found that semantic interference in naming was sensitive to both semantic- and lexical-level processes (i.e., larger interference for novel vs. old and low- vs. high-frequency stimuli), consistent with a semantically mediated lexical locus. Interference in word-picture matching exhibited stable interference for old and novel stimuli and did not interact with lexical frequency. Further, interference transferred from word-picture matching to naming. Together, these experiments provide evidence to suggest that semantic interference in both tasks originates at a shared processing stage (presumably at the semantic level), but that it exerts its effect at different loci when naming pictures vs. matching words to pictures. PMID- 27242622 TI - Evidence for a Global Sampling Process in Extraction of Summary Statistics of Item Sizes in a Set. AB - Several studies have shown that our visual system may construct a "summary statistical representation" over groups of visual objects. Although there is a general understanding that human observers can accurately represent sets of a variety of features, many questions on how summary statistics, such as an average, are computed remain unanswered. This study investigated sampling properties of visual information used by human observers to extract two types of summary statistics of item sets, average and variance. We presented three models of ideal observers to extract the summary statistics: a global sampling model without sampling noise, global sampling model with sampling noise, and limited sampling model. We compared the performance of an ideal observer of each model with that of human observers using statistical efficiency analysis. Results suggest that summary statistics of items in a set may be computed without representing individual items, which makes it possible to discard the limited sampling account. Moreover, the extraction of summary statistics may not necessarily require the representation of individual objects with focused attention when the sets of items are larger than 4. PMID- 27242623 TI - Brain Activity toward Gaming-Related Cues in Internet Gaming Disorder during an Addiction Stroop Task. AB - BACKGROUND AND AIMS: Attentional bias for drug-related stimuli is a key characteristic for drug addiction. Characterizing the relationship between attentional bias and brain reactivity to Internet gaming-related stimuli may help in identifying the neural substrates that critical to Internet gaming disorder (IGD). METHODS: 19 IGD and 21 healthy control (HC) subjects were scanned with functional magnetic resonance imaging while they were performing an addiction Stroop task. RESULTS: Compared with HC group, IGD subjects showed higher activations when facing Internet gaming-related stimuli in regions including the inferior parietal lobule, the middle occipital gyrus and the dorsolateral prefrontal cortex. These brain areas were thought to be involved in selective attention, visual processing, working memory and cognitive control. DISCUSSION AND CONCLUSIONS: The results demonstrated that compared with HC group, IGD subjects show impairment in both visual and cognitive control ability while dealing with gaming-related words. This finding might be helpful in understanding the underlying neural basis of IGD. PMID- 27242624 TI - Making Sense of Infant Familiarity and Novelty Responses to Words at Lexical Onset. AB - This study suggests that familiarity and novelty preferences in infant experimental tasks can in some instances be interpreted together as a single indicator of language advance. We provide evidence to support this idea based on our use of the auditory headturn preference paradigm to record responses to words likely to be either familiar or unfamiliar to infants. Fifty-nine 10-month-old infants were tested. The task elicited mixed preferences: familiarity (longer average looks to the words likely to be familiar to the infants), novelty (longer average looks to the words likely to be unfamiliar) and no-preference (similar length of looks to both type of words). The infants who exhibited either a familiarity or a novelty response were more advanced on independent indices of phonetic advance than the infants who showed no preference. In addition, infants exhibiting novelty responses were more lexically advanced than either the infants who exhibited familiarity or those who showed no-preference. The results provide partial support for Hunter and Ames' (1988) developmental model of attention in infancy and suggest caution when interpreting studies indexed to chronological age. PMID- 27242627 TI - Process vs. Processor Accounts of Stage Models: A Cautionary Tale. Commentary: Seeing changes: How familiarity alters our perception of change. PMID- 27242625 TI - Developmental Trajectories in Primary Schoolchildren Using n-Back Task. AB - BACKGROUND: Neuropsychological instruments to assess cognitive trajectories during childhood in epidemiological studies are needed. This would improve neurodevelopment characterization in order to identify its potential determinants. We aimed to study whether repeated measures of n-back, a working memory task, detect developmental trajectories in schoolchildren during a 1-year follow-up. METHODS: We administered the n-back task to 2897 healthy children aged 7-11 years old from 39 schools in Barcelona (Spain). The task consisted of 2 levels of complexity or loads (2- and 3-back) and 2 different stimuli (numbers and words). Participants performed the task four times from January 2012 to March 2013. To study the trajectories during the follow-up, we performed linear mixed effects models including school, individual and age as random effects. RESULTS: We observed improvements related to age in n-back outcomes d', HRT and accuracy, as well as reduced cognitive growth at older ages in d' and HRT. Greater improvements in performance were observed at younger ages, in 2-back, in verbal rather than numerical stimuli and in girls compared to boys. Boys responded faster at baseline, while girls showed increased growth in 2-back numbers. Children with ADHD (Attention Deficit and Hyperactivity Disorder) symptoms (15% of boys and 6% of girls) had a lower working memory at baseline, but they showed similar cognitive growth trajectories in numbers variants of the task, as compared to children without ADHD symptoms. However, the age-related improvement in response speed was not observed in children with ADHD symptoms. CONCLUSIONS: Changes in n-back outcomes reflected developmental trajectories in 1-year follow up. The present results suggest that the repeated administration of this task can be used to study the factors that may alter the cognitive development during childhood. PMID- 27242626 TI - How to Modify (Implicit) Evaluations of Fear-Related Stimuli: Effects of Feature Specific Attention Allocation. AB - We demonstrate that feature-specific attention allocation influences the way in which repeated exposure modulates implicit and explicit evaluations toward fear related stimuli. During an exposure procedure, participants were encouraged to assign selective attention either to the evaluative meaning (i.e., Evaluative Condition) or a non-evaluative, semantic feature (i.e., Semantic Condition) of fear-related stimuli. The influence of the exposure procedure was captured by means of a measure of implicit evaluation, explicit evaluative ratings, and a measure of automatic approach/avoidance tendencies. As predicted, the implicit measure of evaluation revealed a reduced expression of evaluations in the Semantic Condition as compared to the Evaluative Condition. Moreover, this effect generalized toward novel objects that were never presented during the exposure procedure. The explicit measure of evaluation mimicked this effect, although it failed to reach conventional levels of statistical significance. No effects were found in terms of automatic approach/avoidance tendencies. Potential implications for the treatment of anxiety disorders are discussed. PMID- 27242628 TI - Joint Action of a Pair of Rowers in a Race: Shared Experiences of Effectiveness Are Shaped by Interpersonal Mechanical States. AB - The purpose of this study was to understand how a single pair of expert individual rowers experienced their crew functioning in natural conditions when asked to practice a joint movement for the first time. To fulfill this objective, we conducted a field study of interpersonal coordination that combined phenomenological and mechanical data from a coxless pair activity, to analyze the dynamics of the (inter)subjective experience compared with the dynamics of the team coordination. Using an enactivist approach to social couplings, these heterogeneous data were combined to explore the salience (and accuracy) of individuals' shared experiences of their joint action. First, we determined how each rower experienced the continuous crew functioning states (e.g., feelings of the boat's glide). Second, the phenomenological data helped us to build several categories of oar strokes (i.e., cycles), experienced by the rowers as either detrimentally or effectively performed strokes. Third, the mechanical signatures that correlated with each phenomenological category were tracked at various level of organization (i.e., individual-, interpersonal-, and boat-levels). The results indicated that (a) the two rowers did not pay attention to their joint action during most of the cycles, (b) some cycles were simultaneously lived as a salient, meaningful experience of either a detrimental (n = 15 cycles) or an effective (n = 18 cycles) joint action, and (c) the mechanical signatures diverged across the delineated phenomenological categories, suggesting that the way in which the cycles were experienced emerged from the variance in some mechanical parameters (i.e., differences in peak force level and mean force). Notably, the mechanical measures that helped to explain differences within the phenomenological categories were found at the interpersonal level of analysis, thus suggesting an intentional inter-personal mode of regulation of their joint action. This result is further challenged and discussed in light of extra personal regulation processes that might concurrently explain why participants did not make an extensive salient experience of their joint action. We conclude that attempts to combine phenomenological and mechanical data should be pursued to continue the research on how individuals regulate the effectiveness of their joint actions' dynamics. PMID- 27242629 TI - Physical Activity in the School Setting: Cognitive Performance Is Not Affected by Three Different Types of Acute Exercise. AB - Recent studies indicate that a single bout of physical exercise can have immediate positive effects on cognitive performance of children and adolescents. However, the type of exercise that affects cognitive performance the most in young adolescents is not fully understood. Therefore, this controlled study examined the acute effects of three types of 12-min classroom-based exercise sessions on information processing speed and selective attention. The three conditions consisted of aerobic, coordination, and strength exercises, respectively. In particular, this study focused on the feasibility and efficiency of introducing short bouts of exercise in the classroom. One hundred and ninety five students (5th and 6th grade; 10-13 years old) participated in a double baseline within-subjects design, with students acting as their own control. Exercise type was randomly assigned to each class and acted as between-subject factor. Before and immediately after both the control and the exercise session, students performed two cognitive tests that measured information processing speed (Letter Digit Substitution Test) and selective attention (d2 Test of Attention). The results revealed that exercising at low to moderate intensity does not have an effect on the cognitive parameters tested in young adolescents. Furthermore, there were no differential effects of exercise type. The results of this study are discussed in terms of the caution which should be taken when conducting exercise sessions in a classroom setting aimed at improving cognitive performance. PMID- 27242630 TI - Performance of Motor Sequences in Children at Heightened vs. Low Risk for ASD: A Longitudinal Study from 18 to 36 Months of Age. AB - Recent research shows that motor difficulties are a prominent component of the behavioral profile of autism spectrum disorder (ASD) and are also apparent from early in development in infants who have an older sibling with ASD (High Risk; HR). Delays have been reported for HR infants who do and who do not receive an eventual diagnosis of ASD. A growing body of prospective studies has focused on the emergence of early motor skills primarily during the first year of life. To date, however, relatively little work has examined motor skills in the second and third years. Thus, the present research was designed to investigate motor performance in object transport tasks longitudinally in HR and LR (Low Risk) children between the ages of 18 and 36 months. Participants (15 HR children and 14 LR children) were observed at 18, 24, and 36 months. Children completed two motor tasks, the Ball Task and the Block Task, each of which included two conditions that varied in terms of the precision demands of the goal action. Kinematic data were acquired via two magneto inertial sensors worn on each wrist. In the Block Task, HR children reached more slowly (i.e., mean acceleration was lower) compared to LR children. This finding is in line with growing evidence of early delays in fine motor skills in HR children and suggests that vulnerabilities in motor performance may persist into the preschool years in children at risk for ASD. PMID- 27242631 TI - Editorial: Improving Working Memory in Learning and Intellectual Disabilities. PMID- 27242633 TI - Heterogeneous Motives in the Trust Game: A Tale of Two Roles. AB - Trustful and trustworthy behaviors have important externalities for the society. But what exactly drives people to behave in a trustful and trustworthy manner? Building on research suggesting that individuals' social preferences might be a common factor informing both behaviors, we study the impact of a set of different motives on individuals' choices in a dual-role Trust Game (TG). We employ data from a large-scale representative experiment (N = 774), where all subjects played both roles of a binary TG with real monetary incentives. Subjects' social motives were inferred using their decisions in a Dictator Game and a dual-role Ultimatum Game. Next to self-interest and strategic motives we consider preferences for altruism, spitefulness, egalitarianism, and efficiency. We demonstrate that there exists considerable heterogeneity in motives in the TG. Most importantly, among individuals who choose to trust as trustors, social motives can differ dramatically as there is a non-negligible proportion of them who seem to act out of (strategic) self-interest whereas others are driven more by efficiency considerations. Subjects' elicited trustworthiness, however, can be used to infer such motivations: while the former are not trustworthy as trustees, the latter are. We discuss that research on trust can benefit from adding the second player's choice in TG designs. PMID- 27242632 TI - The Social Effect of "Being Imitated" in Children with Autism Spectrum Disorder. AB - There is evidence that "being imitated" has social effects, and that the imitation of the child's actions may be used as a strategy to promote social engagement in children with autism spectrum disorder (ASD). The observation of someone that imitates us recruits, indeed, neural areas involved in social cognition. We reviewed studies exploring the behavioral consequences of "being imitated" in children with ASD. We aimed at assessing what are the social skills targeted by this strategy, and the factors that may improve the response. The "being imitated" strategy improves social gazes, proximal social behaviors, and play skills, particularly in children with low developmental level, and also when the strategy is implemented by children's mothers. The "being imitated" may be used as a tool in early intervention to improve social skills, helping to assess the effects of intervention at both behavioral and neural level. PMID- 27242634 TI - Metacognitions Are Associated with Subjective Memory Problems in Individuals on Sick Leave due to Chronic Fatigue. AB - BACKGROUND: Subjective cognitive impairments are frequent, but poorly understood in patients with chronic fatigue. We hypothesized that maladaptive metacognitive beliefs at baseline were associated with baseline subjective cognitive impairments, that they predict subjective cognitive impairments at treatment termination, and that a reduction in maladaptive metacognitive beliefs was associated with less subjective cognitive impairments at treatment termination, independent of changes in fatigue, pain, insomnia, depression, and anxiety. METHODS: In this non-controlled study, patients (n = 137) on sick leave due to chronic fatigue received a 3.5-week inpatient RTW rehabilitation program. Of these patients 69 (50.4%) was referred with a ICPC-2 diagnosis of chronic fatigue. Patients completed questionnaires about metacognitive beliefs, somatic complaints, psychological complaints, and cognitive impairments before and after treatment. To test the hypotheses we performed paired t-tests of change, as well as seven hierarchical linear regressions. RESULTS: RESULTS showed that baseline maladaptive metacognitive beliefs were significantly associated with subjective cognitive impairments at baseline, controlling for symptoms. Score on baseline metacognitive beliefs did not predict impairments post-treatment. Testing specific maladaptive beliefs, pre-treatment scores on cognitive confidence were associated with subjective cognitive impairments both pre and post-treatment, controlling for symptoms. Post-treatment metacognitive beliefs and post-treatment cognitive confidence were associated with post-treatment subjective cognitive impairments, controlling for pre-treatment impairments and pre-treatment metacognitive beliefs, as well as pre and post-scores on symptom measures. CONCLUSION: This study reports associations between maladaptive metacognitive beliefs and subjective cognitive impairments in patients with chronic fatigue. Targeting metacognitive beliefs could prove an effective therapeutic intervention for subjective cognitive impairments in these patients. PMID- 27242635 TI - Can Birds Perceive Rhythmic Patterns? A Review and Experiments on a Songbird and a Parrot Species. AB - While humans can easily entrain their behavior with the beat in music, this ability is rare among animals. Yet, comparative studies in non-human species are needed if we want to understand how and why this ability evolved. Entrainment requires two abilities: (1) recognizing the regularity in the auditory stimulus and (2) the ability to adjust the own motor output to the perceived pattern. It has been suggested that beat perception and entrainment are linked to the ability for vocal learning. The presence of some bird species showing beat induction, and also the existence of vocal learning as well as vocal non-learning bird taxa, make them relevant models for comparative research on rhythm perception and its link to vocal learning. Also, some bird vocalizations show strong regularity in rhythmic structure, suggesting that birds might perceive rhythmic structures. In this paper we review the available experimental evidence for the perception of regularity and rhythms by birds, like the ability to distinguish regular from irregular stimuli over tempo transformations and report data from new experiments. While some species show a limited ability to detect regularity, most evidence suggests that birds attend primarily to absolute and not relative timing of patterns and to local features of stimuli. We conclude that, apart from some large parrot species, there is limited evidence for beat and regularity perception among birds and that the link to vocal learning is unclear. We next report the new experiments in which zebra finches and budgerigars (both vocal learners) were first trained to distinguish a regular from an irregular pattern of beats and then tested on various tempo transformations of these stimuli. The results showed that both species reduced the discrimination after tempo transformations. This suggests that, as was found in earlier studies, they attended mainly to local temporal features of the stimuli, and not to their overall regularity. However, some individuals of both species showed an additional sensitivity to the more global pattern if some local features were left unchanged. Altogether our study indicates both between and within species variation, in which birds attend to a mixture of local and to global rhythmic features. PMID- 27242636 TI - Self-Reported Stickiness of Mind-Wandering Affects Task Performance. AB - When asked to perform a certain task, we typically spend a decent amount of time thinking thoughts unrelated to that task-a phenomenon referred to as "mind wandering." It is thought that this mind-wandering is driven at least in part by our unfinished goals and concerns. Previous studies have shown that just after presenting a participant with their own concerns, their reports of task-unrelated thinking increased somewhat. However, effects of these concerns on task performance were somewhat inconsistent. In this study we take the opposite approach, and examine whether task performance depends on the self-reported thought content. Specifically, a particularly intriguing aspect of mind-wandering that has hitherto received little attention is the difficulty of disengaging from it, in other words, the "stickiness" of the thoughts. While presenting participants with their own concerns was not associated with clear effects on task performance, we showed that the reports of off-task thinking and variability of response times increased with the amount of self-reported stickiness of thoughts. This suggests that the stickiness of mind-wandering is a relevant variable, and participants are able to meaningfully report on it. PMID- 27242637 TI - Reward Promotes Self-Face Processing: An Event-Related Potential Study. AB - The present study adopted a reward-priming paradigm to investigate whether and how monetary reward cues affected self-face processing. Event-related potentials were recorded during judgments of head orientation of target faces (self, friend, and stranger), with performance associated with a monetary reward. The results showed self-faces elicited larger N2 mean amplitudes than other-faces, and mean N2 amplitudes increased after monetary reward as compared with no reward cue. Moreover, an interaction effect between cue type and face type was observed for the P3 component, suggesting that both self-faces and friend-faces elicited larger P3 mean amplitudes than stranger-faces after no reward cue, with no significant difference between self-faces and friend-faces under this condition. However, self-faces elicited larger P3 mean amplitudes than friend-faces when monetary reward cues were provided. Interestingly, the enhancement of reward on friend-faces processing was observed at late positive potentials (LPP; 450-600 ms), suggesting that the LPP difference between friend-faces and stranger-faces was enhanced with monetary reward cues. Thus, we found that the enhancement effect of reward on self-relevant processing occurred at the later stages, but not at the early stage. These findings suggest that the activation of the reward expectations can enhance self-face processing, yielding a robust and sustained modulation over their overlapped brain areas where reward and self-relevant processing mechanisms may operate together. PMID- 27242638 TI - Commentary: Effects of psilocybin on time perception and temporal control of behavior in humans. PMID- 27242639 TI - Analyzing Big Data in Psychology: A Split/Analyze/Meta-Analyze Approach. AB - Big data is a field that has traditionally been dominated by disciplines such as computer science and business, where mainly data-driven analyses have been performed. Psychology, a discipline in which a strong emphasis is placed on behavioral theories and empirical research, has the potential to contribute greatly to the big data movement. However, one challenge to psychologists-and probably the most crucial one-is that most researchers may not have the necessary programming and computational skills to analyze big data. In this study we argue that psychologists can also conduct big data research and that, rather than trying to acquire new programming and computational skills, they should focus on their strengths, such as performing psychometric analyses and testing theories using multivariate analyses to explain phenomena. We propose a split/analyze/meta analyze approach that allows psychologists to easily analyze big data. Two real datasets are used to demonstrate the proposed procedures in R. A new research agenda related to the analysis of big data in psychology is outlined at the end of the study. PMID- 27242640 TI - Commentary: Mindfulness training for reducing anger, anxiety, and depression in fibromyalgia patients. PMID- 27242641 TI - The 2 * 2 Standpoints Model of Achievement Goals. AB - In the present research, we proposed and tested a 2 * 2 standpoints model of achievement goals grounded in the development-demonstration and approach avoidance distinctions. Three empirical studies are presented. Study 1 provided evidence supporting the structure and psychometric properties of a newly developed measure of the goals of the 2 * 2 standpoints model. Study 2 documented the predictive utility of these goal constructs for intrinsic motivation: development-approach and development-avoidance goals were positive predictors, and demonstration-avoidance goals were a negative predictor of intrinsic motivation. Study 3 documented the predictive utility of these goal constructs for performance attainment: Demonstration-approach goals were a positive predictor and demonstration-avoidance goals were a negative predictor of exam performance. The conceptual and empirical contributions of the present research were discussed within the broader context of existing achievement goal theory and research. PMID- 27242643 TI - Momentary Affective States Are Associated with Momentary Volume, Prospective Trends, and Fluctuation of Daily Physical Activity. AB - Several interventions aiming to enhance physical activity in everyday life showed mixed effects. Affective constructs are thought to potentially support health behavior change. However, little is known about within-subject associations between momentary affect and subsequent physical activity in everyday life. This study analyzed the extent to which three dimensions of affective states (valence, calmness, and energetic arousal) were associated with different components of daily activity trajectories. Sixty-five undergraduates' students (Age: M = 24.6; SD = 3.2; females: 57%) participated in this study. Physical activity was assessed objectively through accelerometers during 24 h. Affective states assessments were conducted randomly every 45 min using an e-diary with a six-item mood scale that was especially designed for ambulatory assessment. We conducted three-level multi-level analyses to investigate the extent to which momentary affect accounted for momentary volume, prospective trends, and stability vs. fluctuation of physical activity in everyday life. All three affect dimensions were significantly associated with momentary activity volumes and prospective trends over 45 min periods. Physical activity didn't fluctuate freely, but featured significant autocorrelation across repeated measurements, suggesting some stability of physical activity across 5-min assessments. After adjusting for the autoregressive structure in physical activity assessments, only energetic arousal remained a significant predictor. Feeling energized and awake was associated with an increased momentary volume of activity and initially smaller but gradually growing decreases in subsequent activity within the subsequent 45 min. Although not related to trends in physical activity, higher valence predicted lower stability in physical activity across subsequent 45 min, suggesting more short-term fluctuations in daily activity the more participants reported positive affective valence. The current analyses afford interesting insight into within-subject associations between momentary affect and activity trajectories in everyday life. Energetic arousal emerged as the only meaningful predictor of physical activity in daily life after adjusting for autoregression. A significant effect of valence on short-term activity fluctuations might indicate that activity interventions would benefit from taking into account enhancement of positive affective valence in everyday life. Moments of enhanced valence may scaffold attempts helping inactive people to get started with daily activities and overcome periods of inactivity in everyday life. PMID- 27242642 TI - On the Origin of Interoception. AB - Over the course of a century, the meaning of interoception has changed from the restrictive to the inclusive. In its inclusive sense, it bears relevance to every individual via its link to emotion, decision making, time-perception, health, pain, and various other areas of life. While the label for the perception of the body state changes over time, the need for an overarching concept remains. Many aspects can make any particular interoceptive sensation unique and distinct from any other interoceptive sensation. This can range from the sense of agency, to the physical cause of a sensation, the ontogenetic origin, the efferent innervation, and afferent pathways of the tissue involved amongst others. In its overarching meaning, interoception primarily is a product of the central nervous system, a construct based on an integration of various sources, not per se including afferent information. This paper proposes a definition of interoception as based on subjective experience, and pleas for the use of specific vocabulary in addressing the many aspects that contribute to it. PMID- 27242645 TI - Editorial: Sub- and Supra-Second Timing: Brain, Learning and Development. PMID- 27242644 TI - Response: Commentary: Why sprint interval training is inappropriate for a largely sedentary population. PMID- 27242646 TI - BOiS-Berlin Object in Scene Database: Controlled Photographic Images for Visual Search Experiments with Quantified Contextual Priors. PMID- 27242647 TI - Individual Differences in Aesthetic Ability: The Case for an Aesthetic Quotient. PMID- 27242648 TI - Arguments from Developmental Order. AB - In this article, I investigate a special type of argument regarding the role of development in theorizing about psychological processes and cognitive capacities. Among the issues that developmental psychologists study, discovering the ontogenetic trajectory of mechanisms or capacities underpinning our cognitive functions ranks highly. The order in which functions are developed or capacities are acquired is a matter of debate between competing psychological theories, and also philosophical conceptions of the mind - getting the role and the significance of the different steps in this order right could be seen as an important virtue of such theories. Thus, a special kind of strategy in arguments between competing philosophical or psychological theories is using developmental order in arguing for or against a given psychological claim. In this article, I will introduce an analysis of arguments from developmental order, which come in two general types: arguments emphasizing the importance of the early cognitive processes and arguments emphasizing the late cognitive processes. I will discuss their role in one of the central tools for evaluating scientific theories, namely in making inferences to the best explanation. I will argue that appeal to developmental order is, by itself, an insufficient criterion for theory choice and has to be part of an argument based on other core explanatory or empirical virtues. I will end by proposing a more concerted study of philosophical issues concerning (cognitive) development, and I will present some topics that also pertain to a full-fledged 'philosophy of development.' PMID- 27242649 TI - Social Anxiety, Stress Type, and Conformity among Adolescents. AB - Social anxiety and stress type can influence strong conformity among adolescents; however, the interaction between them is not clear. In this study, 152 adolescents were recruited and assigned one of two conditions: an interaction and a judgment condition. In the interaction condition, adolescents with high social anxiety (HSA) were less likely to conform when completing a modified Asch task, compared to adolescents who had low social anxiety. In the judgment condition, adolescents with HSA were more likely to conform to the opinions from the unanimous majority. The results suggest that adolescents with HSA may show different styles of strong conformity with the change of stress type. We believe that socially anxious adolescents avoid potential social situations with weaker conformity, while avoiding negative evaluations from others with stronger conformity. These findings contribute to a better understanding of the social dysfunctions among adolescents with HSA and provide a new direction for clinical interventions. PMID- 27242650 TI - Editorial: Components of the Language-Ready Brain. PMID- 27242651 TI - The Ecology of Withdrawal. Commentary: The NEET and Hikikomori spectrum: Assessing the risks and consequences of becoming culturally marginalized. PMID- 27242653 TI - Leucine-Rich Glioma Inactivated-1 and Voltage-Gated Potassium Channel Autoimmune Encephalitis Associated with Ischemic Stroke: A Case Report. AB - Autoimmune encephalitis is associated with a wide variety of antibodies and clinical presentations. Voltage-gated potassium channel (VGKC) antibodies are a cause of autoimmune non-paraneoplastic encephalitis characterized by memory impairment, psychiatric symptoms, and seizures. We present a case of VGKC encephalitis likely preceding an ischemic stroke. Reports of autoimmune encephalitis associated with ischemic stroke are rare. Several hypotheses linking these two disease processes are proposed. PMID- 27242652 TI - Idiopathic Inflammatory Myopathies: Clinical Approach and Management. AB - Idiopathic inflammatory myopathies (IIM) are a group of chronic, autoimmune conditions affecting primarily the proximal muscles. The most common types are dermatomyositis (DM), polymyositis (PM), necrotizing autoimmune myopathy (NAM), and sporadic inclusion body myositis (sIBM). Patients typically present with sub acute to chronic onset of proximal weakness manifested by difficulty with rising from a chair, climbing stairs, lifting objects, and combing hair. They are uniquely identified by their clinical presentation consisting of muscular and extramuscular manifestations. Laboratory investigations, including increased serum creatine kinase (CK) and myositis specific antibodies (MSA) may help in differentiating clinical phenotype and to confirm the diagnosis. However, muscle biopsy remains the gold standard for diagnosis. These disorders are potentially treatable with proper diagnosis and initiation of therapy. Goals of treatment are to eliminate inflammation, restore muscle performance, reduce morbidity, and improve quality of life. This review aims to provide a basic diagnostic approach to patients with suspected IIM, summarize current therapeutic strategies, and provide an insight into future prospective therapies. PMID- 27242654 TI - BDNF Genotype Interacts with Motor Function to Influence Rehabilitation Responsiveness Poststroke. AB - BACKGROUND: Persistent motor impairment is common but highly heterogeneous poststroke. Genetic polymorphisms, including those identified on the brain derived neurotrophic factor (BDNF) and apolipoprotein E (APOE) genes, may contribute to this variability by limiting the capacity for use-dependent neuroplasticity, and hence rehabilitation responsiveness. OBJECTIVE: To determine whether BDNF and APOE genotypes influence motor improvement facilitated by poststroke upper-limb rehabilitation. METHODS: BDNF-Val66Met and APOE isoform genotypes were determined using leukocyte DNA for 55 community-dwelling patients 2-123 months poststroke. All patients completed a dose-matched upper-limb rehabilitation program of either Wii-based Movement Therapy or Constraint-induced Movement Therapy. Upper-limb motor function was assessed pre- and post-therapy using a suite of functional measures. RESULTS: Motor function improved for all patients post-therapy, with no difference between therapy groups. In the pooled data, there was no significant effect of BDNF or APOE genotype on motor function at baseline, or following the intervention. However, a significant interaction between the level of residual motor function and BDNF genotype was identified (p = 0.029), whereby post-therapy improvement was significantly less for Met allele carriers with moderate and high, but not low motor function. There was no significant association between APOE genotype and therapy outcomes. CONCLUSION: This study identified a novel interaction between the BDNF-Val66Met polymorphism, motor-function status, and the magnitude of improvement with rehabilitation in chronic stroke. This polymorphism does not preclude, but may reduce, the magnitude of motor improvement with therapy, particularly for patients with higher, but not lower residual motor function. BDNF genotype should be considered in the design and interpretation of clinical trials. PMID- 27242655 TI - Temporal Profile of Cerebrovascular Reactivity Impairment, Gray Matter Volumes, and Persistent Symptoms after Mild Traumatic Head Injury. AB - OBJECTIVE: Increased awareness around neurocognitive deficits after mild traumatic brain injury (mTBI) has progressed the search for objective, diagnostic, and monitoring tools, yet imaging biomarkers for mTBI and recovery are not established in clinical use. It has been suggested that mTBI impairs cerebrovascular reactivity (CVR) to CO2, which could be related to post concussive syndrome (PCS). We investigate CVR evolution after mTBI using blood oxygen-level dependent (BOLD) magnetic resonance imaging (MRI) and possible correlation with PCS. METHODS: A prospective cohort of 25 mTBI patients and 18 matched controls underwent BOLD MRI CVR measurements. A subset of 19 mTBI patients underwent follow-up testing. Visits took place at a mean of 63 and 180 days after injury. Symptoms were assessed with the Sport Concussion Assessment Tool 2 (SCAT2). Symptoms, CVR and brain volume [gray matter (GM), white matter (WM), and whole brain (WB)], age, and sex, were examined between groups and longitudinally within traumatic brain injury (TBI) patients. RESULTS: Traumatic brain injury participants were 72% males, mean age being 42.7 years. Control participants were 61% with mean age of 38.7 years. SCAT2 scores tended to improve among those mTBI patients with follow-up visits (p = 0.07); however, they did not tend to recover to scores of the healthy controls. Brain volumes were not statistically different between groups at the first visit (WM p = 0.71; GM p = 0.36). In mTBI patients, there was a reduction in GM volume between visits 1 and 2 (p = 0.0046). Although mean CVR indexes were similar (WM p = 0.27; GM p = 0.36; and WB p = 0.35), the correlation between SCAT2 and CVR was negative in controls (WM-r = -0.59; p = 0.010; GM-r = -0.56; p = 0.016; brain-r = -0.58; p = 0.012) and weaker and positive in mTBI (brain-r = 0.4; p = 0.046; GM-r = 0.4; p = 0.048). SCAT2 correlated with GM volume (r = 0.5215, p = 0.0075) in mTBI but not in controls (r = 0.2945, p = 0.2355). CONCLUSION: There is a correlation between lower GM CVR indexes and lower performance on SCAT2 in patients with mTBI, which seems to be associated with more symptoms. This correlation seems to persist well beyond 120 days. mTBI may lead to a decrease in GM volume in these patients. PMID- 27242657 TI - Distribution and Coexistence of Myoclonus and Dystonia as Clinical Predictors of SGCE Mutation Status: A Pilot Study. AB - INTRODUCTION: Myoclonus-dystonia (M-D) is a young onset movement disorder typically involving myoclonus and dystonia of the upper body. A proportion of the cases are caused by mutations to the autosomal dominantly inherited, maternally imprinted, epsilon-sarcoglycan gene (SGCE). Despite several sets of diagnostic criteria, identification of patients most likely to have an SGCE mutation remains difficult. METHODS: Forty consecutive patients meeting pre-existing diagnostic clinical criteria for M-D underwent a standardized clinical examination (20 SGCE mutation positive and 20 negative). Each video was reviewed and systematically scored by two assessors blinded to mutation status. In addition, the presence and coexistence of myoclonus and dystonia was recorded in four body regions (neck, arms, legs, and trunk) at rest and with action. RESULTS: Thirty-nine patients were included in the study (one case was excluded owing to insufficient video footage). Based on previously proposed diagnostic criteria, patients were subdivided into 24 "definite," 5 "probable," and 10 "possible" M-D. Motor symptom severity was higher in the SGCE mutation-negative group. Myoclonus and dystonia were most commonly observed in the neck and upper limbs of both groups. Truncal dystonia with action was significantly seen more in the mutation-negative group (p < 0.05). Coexistence of myoclonus and dystonia in the same body part with action was more commonly seen in the mutation-negative cohort (p < 0.05). CONCLUSION: Truncal action dystonia and coexistence of myoclonus and dystonia in the same body part with action might suggest the presence of an alternative mutation in patients with M-D. PMID- 27242656 TI - A Personalized Approach to Parkinson's Disease Patients Based on Founder Mutation Analysis. AB - While the phenotype of Parkinson disease (PD) is heterogeneous, treatment approaches are mostly uniform. Personalized medicine aims to treat diseases with targeted therapies based on cumulative variables, including genotype. We believe that sufficient evidence has accumulated to warrant the initiation of personalized medicine in PD based on subjects genotype and provide examples for our reasoning from observations of GBA and LRRK2 mutations carriers. While PD patients who carry the G2019S mutation in the LRRK2 gene seem to develop relatively mild disease with more frequent postural instability gait disturbance phenotype, carriers of mutations in the GBA gene tend to have an early onset, rapidly deteriorating disease, with more pronounced cognitive and autonomic impairments. These characteristics have significant implications for treatment and outcome and should be addressed from an early stage in the attempt to improve the patient's quality of life. PMID- 27242658 TI - Neuromyelitis Optica Spectrum Disorder with Tumefactive Demyelination mimicking Multiple Sclerosis: A Rare Case. AB - Neuromyelitis optica spectrum disorder (NMOSD) is a diverse condition which not only encompasses isolated longitudinally extensive transverse myelitis (LETM) and optic neuritis but also includes area postrema syndrome, acute brainstem syndrome, symptomatic narcolepsy or acute diencephalic clinical syndrome, and symptomatic cerebral syndrome. Imaging may reveal periependymal lesions surrounding the ventricular system or involvement of corticospinal tracts, area postrema, diencephalon, and corpus callosum. Rarely, there may be hemispheric tumefactive lesions that enhance in a "Cloud-like" fashion on gadolinium injection unlike in tumefactive multiple sclerosis where there is incomplete ring enhancement. Here, we present a case of aquaporin-4 positive relapsing NMOSD who presented to us with recurrent episodes of paraparesis with LETM and tumefactive lesions of brain on imaging, which enhanced in an incomplete ring like pattern resembling multiple sclerosis. PMID- 27242659 TI - Artistic Skills Recovery and Compensation in Visual Artists after Stroke. AB - BACKGROUND: Art is a characteristic of mankind, which requires superior central nervous processing and integration of motor functions with visual information. At the present time, a significant amount of information related to neurobiological basis of artistic creation has been derived from neuro-radiological cognitive studies, which have revealed that subsequent to tissue destruction, the artists continue to create art. The current study aims to review the most important cases of visual artists with stroke and to discuss artistic skills recovery and compensation as well as artistic style after stroke. METHODS: The role of various central nervous system regions in artistic creation was reviewed on the basis of previously published functional studies. Our PubMed search (1995-2015) has identified 10 famous artists with right cerebral stroke as well as 5 with left cerebral stroke who survived and continued to create art after stroke. As the artists included in this review lived at various times during the twentieth century and in different countries, clinical information related to their case was limited. However, it appears that artistic skills recovery and compensation appear within days after stroke. Some of the artists would subsequently change their artistic style. All these elements have been evaluated within the context of specific clinical cases. CONCLUSION: The poststroke artistic skills recovery and compensation with development of a new style or the opposite, regaining the previous prestroke style, represents a significant element of clinical importance in medical rehabilitation as well as neuroesthetics, which requires further evaluation. At the present time, the molecular mechanisms of artistic creation are poorly understood, and more standardized clinical and experimental studies are needed. PMID- 27242660 TI - Meta-analysis of Vascular Imaging Features to Predict Outcome Following Intravenous rtPA for Acute Ischemic Stroke. AB - BACKGROUND: The present review investigated which findings in vascular imaging techniques can be used to predict clinical outcome and the risk of symptomatic intracerebral hemorrhage (sICH) in patients who underwent intravenous thrombolytic treatment. METHODS: Publications were searched, and the inclusion criteria were as follows: (1) published manuscripts, (2) patients with acute ischemic stroke managed with intravenous recombinant tissue plasminogen activator (rtPA), and (3) availability of imaging assessment to determine vessel patency or the regulation of cerebral blood flow prior to, during, and/or after thrombolytic treatment. Clinical outcomes were divided into neurological outcome [National Institutes of Health Stroke Scale (NIHSS) within 7 days] and functional outcome (modified Rankin score in 2-3 months). sICH was defined as rtPA-related intracerebral bleeding associated with any worsening of NIHSS. RESULTS: Thirty nine articles were selected. Recanalization was associated with improved neurological and functional outcomes (OR = 7.83; 95% CI, 3.71-16.53; p < 0.001 and OR = 11.12; 95% CI, 5.85-21.14; p < 0.001, respectively). Both tandem internal carotid artery/middle cerebral artery (ICA/MCA) occlusions and isolated ICA occlusion had worse functional outcome than isolated MCA occlusion (OR = 0.26, 95% CI, 0.12-0.52; p < 0.001 and OR = 0.24, 95% CI, 0.07-0.77; p = 0.016, respectively). Reocclusion was associated with neurological deterioration (OR = 6.48, 95% CI, 3.64-11.56; p < 0.001), and early recanalization was associated with lower odds of sICH (OR = 0.36, 95% CI, 0.18-0.70; p = 0.003). CONCLUSION: Brain circulation data before, during, and after thrombolysis may be useful for predicting the clinical outcome. Cerebral arterial recanalization, presence and site of occlusion, and reocclusion are all important in predicting the clinical outcome. PMID- 27242662 TI - Editorial: Mechanisms of Innate Neuroprotection. PMID- 27242661 TI - The Cerebellum and SIDS: Disordered Breathing in a Mouse Model of Developmental Cerebellar Purkinje Cell Loss during Recovery from Hypercarbia. AB - The cerebellum assists coordination of somatomotor, respiratory, and autonomic actions. Purkinje cell alterations or loss appear in sudden infant death and sudden death in epilepsy victims, possibly contributing to the fatal event. We evaluated breathing patterns in 12 wild-type (WT) and Lurcher mutant mice with 100% developmental cerebellar Purkinje cell loss under baseline (room air), and recovery from hypercapnia, a concern in sudden death events. Six mutant and six WT mice were exposed to 4-min blocks of increasing CO2 (2, 4, 6, and 8%), separated by 4-min recovery intervals in room air. Breath-by-breath patterns, including depth of breathing and end-expiratory pause (EEP) durations during recovery, were recorded. No baseline genotypic differences emerged. However, during recovery, EEP durations significantly lengthened in mutants, compared to WT mice, following the relatively low levels of CO2 exposure. Additionally, mutant mice exhibited signs of post-sigh disordered breathing during recovery following each exposure. Developmental cerebellar Purkinje cell loss significantly affects compensatory breathing patterns following mild CO2 exposure, possibly by inhibiting recovery from elevated CO2. These data implicate cerebellar Purkinje cells in the ability to recover from hypercarbia, suggesting that neuropathologic changes or loss of these cells contribute to inadequate ventilatory recovery to increased environmental CO2. Multiple disorders, including sudden infant death syndrome (SIDS) and sudden unexpected death in epilepsy (SUDEP), appear to involve both cardiorespiratory failure and loss or injury to cerebellar Purkinje cells; the findings support the concept that such neuropathology may precede and exert a prominent role in these fatal events. PMID- 27242663 TI - Comparative Effect of ACTH and Related Peptides on Proliferation and Growth of Rat Adrenal Gland. AB - Pro-opiomelanocortin (POMC) is a polypeptide precursor known to yield biologically active peptides related to a range of functions. These active peptides include the adrenocorticotropic hormone (ACTH), which is essential for maintenance of adrenal growth and steroidogenesis, and the alpha-melanocyte stimulation hormone, which plays a key role in energy homeostasis. However, the role of the highly conserved N-terminal region of POMC peptide fragments has begun to be unraveled only recently. Here, we review the cascade of events involved in regulation of proliferation and growth of murine adrenal cortex triggered by ACTH and other POMC-derived peptides. Key findings regarding signaling pathways and modulation of genes and proteins required for the regulation of adrenal growth are summarized. We have outlined the known mechanisms as well as future challenges for research on the regulation of adrenal proliferation and growth triggered by these peptides. PMID- 27242664 TI - The Potential of ACTH in the Genesis of Primary Aldosteronism. AB - Aldosterone is a homeostatic hormone, rising in volume depletion, sodium deficiency, and potassium loading, in response to angiotensin11 and elevation of plasma potassium. Pathophysiologically, in primary aldosteronism (PA) aldosterone levels are inappropriate for the patient's sodium and potassium status, and thus outside the normal feedback loop. ACTH is equivalent with A11 and [K(+)] in elevating aldosterone: its effects differ from those of the other secretagogues in four ways. First, it is not sustained; second, it raises aldosterone and cortisol secretion with equal potency; third, it is outside the normal feedback loops, reflecting the epithelial action of aldosterone; and finally its possible role in driving inappropriate aldosterone secretion (aka PA) is not widely recognized. Thirty years ago, it was shown that on a fixed sodium intake of 175 meq/day 36 of 100 unselected hypertensives, in whom PA has been excluded on contemporary criteria, had 24 h urinary aldosterone levels above the upper limit of normotensive controls. More recently, the dexamethasone enhanced fludrocortisone suppression test (FDST) showed 29% of unselected hypertensives to have plasma aldosterone concentrations above the upper limit of normotensive controls. In subjects negative for PA on the FDST, 27% were extremely hyper responsive to ultra-low dose ACTH infusion; the remaining 73% showed minimal aldosterone elevation, as did normotensive controls: all three groups had negligible cortisol responses. On treadmill testing, no differences were found between groups in (minimally altered) ACTH and cortisol levels: hyper-responders to ultra-low ACTH, however, showed a major elevation in PAC. The implications of these studies, when validated, are substantial for PA, in that approximately half of hypertensive patients appear to show inappropriate aldosterone levels for their sodium status. The physiological role(s) of ACTH as an acute aldosterone secretagogue, and the mechanisms whereby its continuous secretion is curtailed, remain to be established. PMID- 27242665 TI - Editorial: Trends in Neuroendocrinology. PMID- 27242666 TI - ACTH Regulation of Adrenal SR-B1. AB - The adrenal gland is one of the prominent sites for steroid hormone synthesis. Lipoprotein-derived cholesterol esters (CEs) delivered via SR-B1 constitute the dominant source of cholesterol for steroidogenesis, particularly in rodents. Adrenocorticotropic hormone (ACTH) stimulates steroidogenesis through downstream actions on multiple components involved in steroidogenesis. Both acute and chronic ACTH treatments can modulate SR-B1 function, including its transcription, posttranscriptional stability, phosphorylation and dimerization status, as well as the interaction with other protein partners, all of which result in changes in the ability of SR-B1 to mediate HDL-CE uptake and the supply of cholesterol for conversion to steroids. Here, we provide a review of the recent findings on the regulation of adrenal SR-B1 function by ACTH. PMID- 27242668 TI - Editorial: Molecular Mechanism of Neuronal Dysfunction in the Diabetic Brain. PMID- 27242667 TI - T-Type Calcium Channel: A Privileged Gate for Calcium Entry and Control of Adrenal Steroidogenesis. AB - Intracellular calcium plays a crucial role in modulating a variety of functions such as muscle contraction, hormone secretion, gene expression, or cell growth. Calcium signaling has been however shown to be more complex than initially thought. Indeed, it is confined within cell microdomains, and different calcium channels are associated with different functions, as shown by various channelopathies. Sporadic mutations on voltage-operated L-type calcium channels in adrenal glomerulosa cells have been shown recently to be the second most prevalent genetic abnormalities present in human aldosterone-producing adenoma. The observed modification of the threshold of activation of the mutated channels not only provides an explanation for this gain of function but also reminds us on the importance of maintaining adequate electrophysiological characteristics to make channels able to exert specific cellular functions. Indeed, the contribution to steroid production of the various calcium channels expressed in adrenocortical cells is not equal, and the reason has been investigated for a long time. Given the very negative resting potential of these cells, and the small membrane depolarization induced by their physiological agonists, low threshold T-type calcium channels are particularly well suited for responding under these conditions and conveying calcium into the cell, at the right place for controlling steroidogenesis. In contrast, high threshold L-type channels are normally activated by much stronger cell depolarizations. The fact that dihydropyridine calcium antagonists, specific for L-type channels, are poorly efficient for reducing aldosterone secretion either in vivo or in vitro, strongly supports the view that these two types of channels differently affect steroid biosynthesis. Whether a similar analysis is transposable to fasciculata cells and cortisol secretion is one of the questions addressed in the present review. No similar mutations on L-type or T-type channels have been described yet to affect cortisol secretion or to be linked to the development of Cushing syndrome, but several evidences suggest that the function of T channels is also crucial in fasciculata cells. Putative molecular mechanisms and cellular structural organization making T channels a privileged entry for the "steroidogenic calcium" are also discussed. PMID- 27242669 TI - Which Is the Ideal Treatment for Benign Diffuse and Multinodular Non-Toxic Goiters? AB - Patients with large benign goiters often present local compressive symptoms that require surgical treatment, including dysphagia, neck tightness, and airway obstruction. In contrast, patients with such goiters who remain asymptomatic may be observed after exclusion of malignancy. The use of levothyroxine (LT4) to reduce the volume of the goiter is still a controversial treatment for large goiters, and the optimal surgical procedure for multinodular goiter is still debatable. Radioiodine is a safe and effective treatment option when used alone or in combination with recombinant human TSH. This review discusses current therapeutic options to treat diffuse and multinodular non-toxic benign goiters. PMID- 27242670 TI - Rapid, Multiplexed Characterization of Shiga Toxin-Producing Escherichia coli (STEC) Isolates Using Suspension Array Technology. AB - Molecular methods have emerged as the most reliable techniques to detect and characterize pathogenic Escherichia coli. These molecular techniques include conventional single analyte and multiplex PCR, PCR followed by microarray detection, pulsed-field gel electrophoresis (PFGE), and whole genome sequencing. The choice of methods used depends upon the specific needs of the particular study. One versatile method involves detecting serogroup-specific markers by hybridization or binding to encoded microbeads in a suspension array. This molecular serotyping method has been developed and adopted for investigating E. coli outbreaks. The major advantages of this technique are the ability to simultaneously serotype E. coli and detect the presence of virulence and pathogenicity markers. Here, we describe the development of a family of multiplex molecular serotyping methods for Shiga toxin-producing E. coli, compare their performance to traditional serotyping methods, and discuss the cost-benefit balance of these methods in the context of various food safety objectives. PMID- 27242671 TI - Fecal Carriage of Staphylococcus aureus in the Hospital and Community Setting: A Systematic Review. AB - BACKGROUND AND RATIONALE: Staphylococcus aureus fecal carriage has been identified as a potential source for nosocomial transmission and a risk factor for disease development. This systematic review determined the overall S. aureus [including methicillin susceptible and resistant S. aureus (MSSA and MRSA)] fecal carriage rates within the community and healthcare settings. METHODOLOGY: Peer reviewed articles indexed in Medline, Scopus, Academic Search Premier, Africa Wide Information, CINAHL, and Web of Science were identified using applicable and controlled vocabulary through to 11 November 2015. Eligible studies were ascertained by three independent reviewers. Random-effects meta-analyses of proportions were performed to determine S. aureus, MSSA and MRSA fecal carriage rates reported by eligible studies. RESULTS: Twenty six studies were included in this review. The pooled estimates for S. aureus, MSSA and MRSA fecal carriage were 26% (95% confidence interval (CI): 16.8-36.3%), 86% (95% confidence interval (CI): 65.9-97.9%) and 10% (95% CI: 0.7-27.0%), respectively. Fecal S. aureus carriage rates increased on average from 10 to 65% during the first 8 weeks of life, followed by an average carriage rate of 64% at 6 months and 46% at 1 year of life. Genotyping techniques were employed mainly in studies conducted in developed countries and comprised largely of gel-based techniques. Six studies reported on the role of S. aureus fecal strains in diarrhea (n = 2) and the risk for acquiring infections (n = 4). Eight of the 26 studies included in this review performed antibiotic susceptibility testing of S. aureus fecal isolates. CONCLUSION: This study provides evidence that screening for S. aureus fecal carriage, at least in populations at high risk, could be an effective measure for the prevention of S. aureus transmission and infection in the healthcare and community setting. More well-structured studies need to be conducted and sequence based genotyping techniques should be employed for the comparison of isolates on a global scale in both developing and developed countries. PMID- 27242672 TI - Bovine Teat Microbiome Analysis Revealed Reduced Alpha Diversity and Significant Changes in Taxonomic Profiles in Quarters with a History of Mastitis. AB - Mastitis is a mammary gland inflammatory disease often due to bacterial infections. Like many other infections, it used to be considered as a host pathogen interaction driven by host and bacterial determinants. Until now, the involvement of the bovine mammary gland microbiota in the host-pathogen interaction has been poorly investigated, and mainly during the infectious episode. In this study, the bovine teat microbiome was investigated in 31 quarters corresponding to 27 animals, which were all free of inflammation at sampling time but which had different histories regarding mastitis: from no episode of mastitis on all the previous lactations (Healthy quarter, Hq) to one or several clinical mastitis events (Mastitic quarter, Mq). Several quarters whose status was unclear (possible history of subclinical mastitis) were classified as NDq. Total bacterial DNA was extracted from foremilk samples and swab samples of the teat canal. Taxonomic profiles were determined by pyrosequencing on 16s amplicons of the V3-4 region. Hq quarters showed a higher diversity compared to Mq ones (Shannon index: ~8 and 6, respectively). Clustering of the quarters based on their bacterial composition made it possible to separate Mq and Hq quarters into two separate clusters (C1 and C2, respectively). Discriminant analysis of taxonomic profiles between these clusters revealed several differences and allowed the identification of taxonomic markers in relation to mastitis history. C2 quarters were associated with a higher proportion of the Clostridia class (including genera such as Ruminococcus, Oscillospira, Roseburia, Dorea, etc.), the Bacteroidetes phylum (Prevotella, Bacteroides, Paludibacter, etc.), and the Bifidobacteriales order (Bifidobacterium), whereas C1 quarters showed a higher proportion of the Bacilli class (Staphylococcus) and Chlamydiia class. These results indicate that microbiota is altered in udders which have already developed mastitis, even far from the infectious episode. Microbiome alteration may have resulted from the infection itself and or the associated antibiotic treatment. Alternatively, differences in microbiome composition in udders with a history of mastitis may have occurred prior to the infection and even contributed to infection development. Further investigations on the dynamics of mammary gland microbiota will help to elucidate the contribution of this endogenous microbiota to the mammary gland health. PMID- 27242673 TI - Sample Processing Impacts the Viability and Cultivability of the Sponge Microbiome. AB - Sponges host complex microbial communities of recognized ecological and biotechnological importance. Extensive cultivation efforts have been made to isolate sponge bacteria, but most still elude cultivation. To identify the bottlenecks of sponge bacterial cultivation, we combined high-throughput 16S rRNA gene sequencing with a variety of cultivation media and incubation conditions. We aimed to determine the extent to which sample processing and cultivation conditions can impact bacterial viability and recovery in culture. We isolated 325 sponge bacteria from six specimens of Cymbastela concentrica and three specimens of Scopalina sp. These isolates were distributed over 37 different genera and 47 operational taxonomic units (defined at 97% 16S rRNA gene sequence identity). The cultivable bacterial community was highly specific to its sponge host and different media compositions yielded distinct microbial isolates. Around 97% of the isolates could be detected in the original sponge and represented a large but highly variable proportion (0.5-92% total abundance, depending on sponge species) of viable bacteria obtained after sample processing, as determined by propidium monoazide selective DNA modification of compromised cells. Our results show that the most abundant viable bacteria are also the most predominant groups found in cultivation, reflecting, to some extent, the relative abundances of the viable bacterial community, rather than the overall community estimated by direct molecular approaches. Cultivation is therefore shaped not only by the growth conditions provided, but also by the different cell viabilities of the bacteria that constitute the cultivation inoculum. These observations highlight the need to perform experiments to assess each method of sample processing for its accurate representation of the actual in situ bacterial community and its yield of viable cells. PMID- 27242674 TI - Photoconversion and Fluorescence Properties of a Red/Green-Type Cyanobacteriochrome AM1_C0023g2 That Binds Not Only Phycocyanobilin But Also Biliverdin. AB - Cyanobacteriochromes (CBCRs) are distantly related to the red/far-red responsive phytochromes. Red/green-type CBCRs are widely distributed among various cyanobacteria. The red/green-type CBCRs covalently bind phycocyanobilin (PCB) and show red/green reversible photoconversion. Recent studies revealed that some red/green-type CBCRs from chlorophyll d-bearing cyanobacterium Acaryochloris marina covalently bind not only PCB but also biliverdin (BV). The BV-binding CBCRs show far-red/orange reversible photoconversion. Here, we identified another CBCR (AM1_C0023g2) from A. marina that also covalently binds not only PCB but also BV with high binding efficiencies, although BV chromophore is unstable in the presence of urea. Replacement of Ser334 with Gly resulted in significant improvement in the yield of the BV-binding holoprotein, thereby ensuring that the mutant protein is a fine platform for future development of optogenetic switches. We also succeeded in detecting near-infrared fluorescence from mammalian cells harboring PCB-binding AM1_C0023g2 whose fluorescence quantum yield is 3.0%. Here the PCB-binding holoprotein is shown as a platform for future development of fluorescent probes. PMID- 27242675 TI - Biofilm-Forming Capacity in Biogenic Amine-Producing Bacteria Isolated from Dairy Products. AB - Biofilms on the surface of food industry equipment are reservoirs of potentially food-contaminating bacteria-both spoilage and pathogenic. However, the capacity of biogenic amine (BA)-producers to form biofilms has remained largely unexamined. BAs are low molecular weight, biologically active compounds that in food can reach concentrations high enough to be a toxicological hazard. Fermented foods, especially some types of cheese, accumulate the highest BA concentrations of all. The present work examines the biofilm-forming capacity of 56 BA-producing strains belonging to three genera and 10 species (12 Enterococcus faecalis, 6 Enterococcus faecium, 6 Enterococcus durans, 1 Enterococcus hirae, 12 Lactococcus lactis, 7 Lactobacillus vaginalis, 2 Lactobacillus curvatus, 2 Lactobacillus brevis, 1 Lactobacillus reuteri, and 7 Lactobacillus parabuchneri), all isolated from dairy products. Strains of all the tested species - except for L. vaginalis were able to produce biofilms on polystyrene and adhered to stainless steel. However, the biomass produced in biofilms was strain-dependent. These results suggest that biofilms may provide a route via which fermented foods can become contaminated by BA-producing microorganisms. PMID- 27242676 TI - Intestinal Microbiota of Broiler Chickens As Affected by Litter Management Regimens. AB - Poultry litter is a mixture of bedding materials and enteric bacteria excreted by chickens, and it is typically reused for multiple growth cycles in commercial broiler production. Thus, bacteria can be transmitted from one growth cycle to the next via litter. However, it remains poorly understood how litter reuse affects development and composition of chicken gut microbiota. In this study, the effect of litter reuse on the microbiota in litter and in chicken gut was investigated using 2 litter management regimens: fresh vs. reused litter. Samples of ileal mucosa and cecal digesta were collected from young chicks (10 days of age) and mature birds (35 days of age). Based on analysis using DGGE and pyrosequencing of bacterial 16S rRNA gene amplicons, the microbiota of both the ileal mucosa and the cecal contents was affected by both litter management regimen and age of birds. Faecalibacterium, Oscillospira, Butyricicoccus, and one unclassified candidate genus closely related to Ruminococcus were most predominant in the cecal samples, while Lactobacillus was predominant in the ileal samples at both ages and in the cecal samples collected at day 10. At days 10 and 35, 8 and 3 genera, respectively, in the cecal luminal microbiota differed significantly in relative abundance between the 2 litter management regimens. Compared to the fresh litter, reused litter increased predominance of halotolerant/alkaliphilic bacteria and Faecalibacterium prausnitzii, a butyrate producing gut bacterium. This study suggests that litter management regimens affect the chicken GI microbiota, which may impact the host nutritional status and intestinal health. PMID- 27242677 TI - Tricking Arthrinium malaysianum into Producing Industrially Important Enzymes Under 2-Deoxy D-Glucose Treatment. AB - This study catalogs production of industrially important enzymes and changes in transcript expression caused by 2-deoxy D-glucose (2-DG) treatment in Arthrinium malaysianum cultures. Carbon Catabolite Repression (CCR) induced by 2-DG in this species is cAMP independent unlike many other organisms. Higher levels of secreted endoglucanase (EG), beta-glucosidase (BGL), beta-xylosidase (BXL), and filter paper activity assay (FPase) enzymes under 2-DG treatment can be exploited for commercial purposes. An integrated RNA sequencing and quantitative proteomic analysis was performed to investigate the cellular response to 2-DG in A. malaysianum. Analysis of RNASeq data under 2-DG treated and control condition reveals that 56% of the unigenes do not have any known similarity to proteins in non-redundant database. Gene Ontology IDs were assigned to 36% of the transcripts (13260) and about 5207 (14%) were mapped to Kyoto Encyclopedia of Genes and Genomes pathway (KEGG). About 1711 genes encoding 2691 transcripts were differentially expressed in treated vs. control samples. Out of the 2691 differentially expressed transcripts, only 582 have any known function. The most up regulated genes belonged to Pentose Phosphate Pathways and carbohydrate degradation class as expected. In addition, genes involved in protein folding, binding, catalytic activity, DNA repair, and secondary metabolites were up regulated under 2-DG treatment. Whereas genes encoding glycosylation pathways, growth, nutrient reservoir activity was repressed. Gene ontology analysis of the differentially expressed genes indicates metabolic process (35%) is the pre dominant class followed by carbohydrate degradation (11%), protein folding, and trafficking (6.2%) and transport (5.3%) classes. Unlike other organisms, conventional unfolded protein response (UPR) was not activated in either control or treated conditions. Major enzymes secreted by A. malaysianum are those degrading plant polysaccharides, the most dominant ones being beta-glucosidase, as demonstrated by the 2D gel analysis. A set of 7 differentially expressed mRNAs were validated by qPCR. Transmission electron microscopy analyses demonstrated that the 2-DG treated cell walls of hyphae showed significant differences in the cell-wall thickness. Overall 2-DG treatment in A. malaysianum induced secretion of large amount of commercially viable enzymes compared to other known species. PMID- 27242678 TI - Hospital Acquired Pneumonia Due to Achromobacter spp. in a Geriatric Ward in China: Clinical Characteristic, Genome Variability, Biofilm Production, Antibiotic Resistance and Integron in Isolated Strains. AB - BACKGROUND: Hospital-acquired pneumonia (HAP) due to Achromobacter has become a substantial concern in recent years. However, HAP due to Achromobacter in the elderly is rare. METHODS: A retrospective analysis was performed on 15 elderly patients with HAP due to Achromobacter spp., in which the sequence types (STs), integrons, biofilm production and antibiotic resistance of the Achromobacter spp. were examined. RESULTS: The mean age of the 15 elderly patients was 88.8 +/- 5.4 years. All patients had at least three underlying diseases and catheters. Clinical outcomes improved in 10 of the 15 patients after antibiotic and/or mechanical ventilation treatment, but three patients had chronic infections lasting more than 1 year. The mortality rate was 33.3% (5/15). All strains were resistant to aminoglycosides, aztreonam, nitrofurantoin, and third- and fourth generation cephalosporins (except ceftazidime and cefoperazone). Six new STs were detected. The most frequent ST was ST306. ST5 was identified in two separate buildings of the hospital. ST313 showed higher MIC in cephalosporins, quinolones and carbapenems, which should be more closely considered in clinical practice. All strains produced biofilm and had integron I and blaOXA-114-like . The main type was blaOXA-114q . The variable region of integron I was different among strains, and the resistance gene of the aminoglycosides was most commonly inserted in integron I. Additionally, blaPSE-1 was first reported in this isolate. CONCLUSION: Achromobacter spp. infection often occurs in severely ill elders with underlying diseases. The variable region of integrons differs, suggesting that Achromobacter spp. is a reservoir of various resistance genes. PMID- 27242679 TI - Unscrambling Cyanobacteria Community Dynamics Related to Environmental Factors. AB - Future climate scenarios in the Baltic Sea project an increase of cyanobacterial bloom frequency and duration, attributed to eutrophication and climate change. Some cyanobacteria can be toxic and their impact on ecosystem services is relevant for a sustainable sea. Yet, there is limited understanding of the mechanisms regulating cyanobacterial diversity and biogeography. Here we unravel successional patterns and changes in cyanobacterial community structure using a 2 year monthly time- series during the productive season in a 100 km coastal offshore transect using microscopy and high-throughput sequencing of 16S rRNA gene fragments. A total of 565 cyanobacterial OTUs were found, of which 231 where filamentous/colonial and 334 picocyanobacterial. Spatial differences in community structure between coastal and offshore waters were minor. An "epidemic population structure" (dominance of asingle cluster) was found for Aphanizomenon/Dolichospermum within the filamentous/colonial cyanobacterial community. In summer, this clusters imultaneously occurred with opportunistic clusters/OTUs, e.g., Nodularia spumigena and Pseudanabaena. Picocyanobacteria, Synechococcus/Cyanobium, formeda consistent but highly diverse group. Overall, the potential drivers structuring summer cyanobacterial communities were temperature and salinity. However, the different responses to environmental factors among and within genera suggest high niche specificity for individual OTUs. The recruitment and occurrence of potentially toxic filamentous/colonial clusters was likely related to disturbance such as mixing events and short-term shifts in salinity, and not solely dependent on increasing temperature and nitrogen-limiting conditions. Nutrients did not explain further the changes in cyanobacterial community composition. Novel occurrence patterns were identified as a strong seasonal succession revealing a tight coupling between the emergence of opportunistic picocynobacteria and the bloom offilamentous/colonialclusters. These findings highlight that if environmental conditions can partially explain the presence of opportunistic picocyanobacteria, microbial and trophic interactions with filamentous/colonial cyanobacteria should also be considered as potential shaping factors for single-celled communities. Regional climate change scenarios in the Baltic Sea predict environmental shifts leading to higher temperature and lower salinity; conditions identified here as favorable for opportunistic filamentous/colonial cyanobacteria. Altogether, the diversity and complexity of cyanobacterial communities reported here is far greater than previously known, emphasizing the importance of microbial interactions between filamentous and picocyanobacteria in the context of environmental disturbances. PMID- 27242680 TI - Predicting the Responses of Soil Nitrite-Oxidizers to Multi-Factorial Global Change: A Trait-Based Approach. AB - Soil microbial diversity is huge and a few grams of soil contain more bacterial taxa than there are bird species on Earth. This high diversity often makes predicting the responses of soil bacteria to environmental change intractable and restricts our capacity to predict the responses of soil functions to global change. Here, using a long-term field experiment in a California grassland, we studied the main and interactive effects of three global change factors (increased atmospheric CO2 concentration, precipitation and nitrogen addition, and all their factorial combinations, based on global change scenarios for central California) on the potential activity, abundance and dominant taxa of soil nitrite-oxidizing bacteria (NOB). Using a trait-based model, we then tested whether categorizing NOB into a few functional groups unified by physiological traits enables understanding and predicting how soil NOB respond to global environmental change. Contrasted responses to global change treatments were observed between three main NOB functional types. In particular, putatively mixotrophic Nitrobacter, rare under most treatments, became dominant under the 'High CO2+Nitrogen+Precipitation' treatment. The mechanistic trait-based model, which simulated ecological niches of NOB types consistent with previous ecophysiological reports, helped predicting the observed effects of global change on NOB and elucidating the underlying biotic and abiotic controls. Our results are a starting point for representing the overwhelming diversity of soil bacteria by a few functional types that can be incorporated into models of terrestrial ecosystems and biogeochemical processes. PMID- 27242681 TI - Transcriptome Analysis of Scrippsiella trochoidea CCMP 3099 Reveals Physiological Changes Related to Nitrate Depletion. AB - Dinoflagellates are a major component of marine phytoplankton and many species are recognized for their ability to produce harmful algal blooms (HABs). Scrippsiella trochoidea is a non-toxic, marine dinoflagellate that can be found in both cold and tropic waters where it is known to produce "red tide" events. Little is known about the genomic makeup of S. trochoidea and a transcriptome study was conducted to shed light on the biochemical and physiological adaptations related to nutrient depletion. Cultures were grown under N and P limiting conditions and transcriptomes were generated via RNAseq technology. De novo assembly reconstructed 107,415 putative transcripts of which only 41% could be annotated. No significant transcriptomic response was observed in response to initial P depletion, however, a strong transcriptional response to N depletion was detected. Among the down-regulated pathways were those for glutamine/glutamate metabolism as well as urea and nitrate/nitrite transporters. Transcripts for ammonia transporters displayed both up- and down-regulation, perhaps related to a shift to higher affinity transporters. Genes for the utilization of DON compounds were up-regulated. These included transcripts for amino acids transporters, polyamine oxidase, and extracellular proteinase and peptidases. N depletion also triggered down regulation of transcripts related to the production of Photosystems I & II and related proteins. These data are consistent with a metabolic strategy that conserves N while maximizing sustained metabolism by emphasizing the relative contribution of organic N sources. Surprisingly, the transcriptome also contained transcripts potentially related to secondary metabolite production, including a homolog to the Short Isoform Saxitoxin gene (sxtA) from Alexandrium fundyense, which was significantly up regulated under N-depletion. A total of 113 unique hits to Sxt genes, covering 17 of the 34 genes found in C. raciborskii were detected, indicating that S. trochoidea has previously unrecognized potential for the production of secondary metabolites with potential toxicity. PMID- 27242682 TI - Genomic-Based Restriction Enzyme Selection for Specific Detection of Piscirickettsia salmonis by 16S rDNA PCR-RFLP. AB - The gram negative facultative bacterium P. salmonis is the etiological agent of Salmonid Rickettsial Septicaemia (SRS), a severe disease that causes important economic losses in the global salmon farmer industry. Despite efforts to control this disease, the high frequency of new epizootic events indicate that the vaccine and antibiotics treatments have limited effectiveness, therefore the preventive and diagnostic approaches must be improved. A comparison of several methodologies for SRS diagnostic indicate differences in their specificity and its capacity to detect other bacteria coexisting with P. salmonis in culture media (contamination) and fish samples (coinfection), aspects relevant for research, vaccine development and clinical diagnostic. By computer-simulation analyses, we identified a group of restriction enzymes that generate unique P. salmonis 16S rDNA band patterns, distinguishable from all other bacteria. From this information, we designed and developed a PCR-RFLP (Polymerase Chain Reaction Restriction Fragment Length Polymorphism) assay, which was validated using 16S rDNA universal primers and restriction enzyme PmaCI for the amplification and digestion, respectively. Experimental validation was performed by comparing the restriction pattern of P. salmonis with the restriction patterns generated by bacteria that cohabit with P. salmonis (fish bacterial isolates and culture media contaminants). Our results indicate that the restriction enzyme selection pipeline was suitable to design a more specific, sensible, faster and cheaper assay than the currently used P. salmonis detection methodologies. PMID- 27242683 TI - A Network of Paralogous Stress Response Transcription Factors in the Human Pathogen Candida glabrata. AB - The yeast Candida glabrata has become the second cause of systemic candidemia in humans. However, relatively few genome-wide studies have been conducted in this organism and our knowledge of its transcriptional regulatory network is quite limited. In the present work, we combined genome-wide chromatin immunoprecipitation (ChIP-seq), transcriptome analyses, and DNA binding motif predictions to describe the regulatory interactions of the seven Yap (Yeast AP1) transcription factors of C. glabrata. We described a transcriptional network containing 255 regulatory interactions and 309 potential target genes. We predicted with high confidence the preferred DNA binding sites for 5 of the 7 CgYaps and showed a strong conservation of the Yap DNA binding properties between S. cerevisiae and C. glabrata. We provided reliable functional annotation for 3 of the 7 Yaps and identified for Yap1 and Yap5 a core regulon which is conserved in S. cerevisiae, C. glabrata, and C. albicans. We uncovered new roles for CgYap7 in the regulation of iron-sulfur cluster biogenesis, for CgYap1 in the regulation of heme biosynthesis and for CgYap5 in the repression of GRX4 in response to iron starvation. These transcription factors define an interconnected transcriptional network at the cross-roads between redox homeostasis, oxygen consumption, and iron metabolism. PMID- 27242684 TI - Selection of the N-Acylhomoserine Lactone-Degrading Bacterium Alteromonas stellipolaris PQQ-42 and of Its Potential for Biocontrol in Aquaculture. AB - The production of virulence factors by many pathogenic microorganisms depends on the intercellular communication system called quorum sensing, which involves the production and release of signal molecules known as autoinducers. Based on this, new-therapeutic strategies have emerged for the treatment of a variety of infections, such as the enzymatic degradation of signaling molecules, known as quorum quenching (QQ). In this study, we present the screening of QQ activity amongst 450 strains isolated from a bivalve hatchery in Granada (Spain), and the selection of the strain PQQ-42, which degrades a wide range of N-acylhomoserine lactones (AHLs). The selected strain, identified as Alteromonas stellipolaris, degraded the accumulation of AHLs and reduced the production of protease and chitinase and swimming motility of a Vibrio species in co-cultivation experiments in vitro. In the bio-control experiment, strain PQQ-42 significantly reduced the pathogenicity of Vibrio mediterranei VibC-Oc-097 upon the coral Oculina patagonica showing a lower degree of tissue damage (29.25 +/- 14.63%) in its presence, compared to when the coral was infected with V. mediterranei VibC-Oc 097 alone (77.53 +/- 13.22%). Our results suggest that this AHL-degrading bacterium may have biotechnological applications in aquaculture. PMID- 27242685 TI - Iron Transformation Pathways and Redox Micro-Environments in Seafloor Sulfide Mineral Deposits: Spatially Resolved Fe XAS and delta(57/54)Fe Observations. AB - Hydrothermal sulfide chimneys located along the global system of oceanic spreading centers are habitats for microbial life during active venting. Hydrothermally extinct, or inactive, sulfide deposits also host microbial communities at globally distributed sites. The main goal of this study is to describe Fe transformation pathways, through precipitation and oxidation reduction (redox) reactions, and examine transformation products for signatures of biological activity using Fe mineralogy and stable isotope approaches. The study includes active and inactive sulfides from the East Pacific Rise 9 degrees 50'N vent field. First, the mineralogy of Fe(III)-bearing precipitates is investigated using microprobe X-ray absorption spectroscopy (MUXAS) and X-ray diffraction (MUXRD). Second, laser-ablation (LA) and micro-drilling (MD) are used to obtain spatially-resolved Fe stable isotope analysis by multicollector inductively coupled plasma-mass spectrometry (MC-ICP-MS). Eight Fe-bearing minerals representing three mineralogical classes are present in the samples: oxyhydroxides, secondary phyllosilicates, and sulfides. For Fe oxyhydroxides within chimney walls and layers of Si-rich material, enrichments in both heavy and light Fe isotopes relative to pyrite are observed, yielding a range of delta(57)Fe values up to 60/00. Overall, several pathways for Fe transformation are observed. Pathway 1 is characterized by precipitation of primary sulfide minerals from Fe(II)aq-rich fluids in zones of mixing between vent fluids and seawater. Pathway 2 is also consistent with zones of mixing but involves precipitation of sulfide minerals from Fe(II)aq generated by Fe(III) reduction. Pathway 3 is direct oxidation of Fe(II) aq from hydrothermal fluids to form Fe(III) precipitates. Finally, Pathway 4 involves oxidative alteration of pre existing sulfide minerals to form Fe(III). The Fe mineralogy and isotope data do not support or refute a unique biological role in sulfide alteration. The findings reveal a dynamic range of Fe transformation pathways consistent with a continuum of micro-environments having variable redox conditions. These micro environments likely support redox cycling of Fe and S and are consistent with culture-dependent and -independent assessments of microbial physiology and genetic diversity of hydrothermal sulfide deposits. PMID- 27242686 TI - Performance of 16s rDNA Primer Pairs in the Study of Rhizosphere and Endosphere Bacterial Microbiomes in Metabarcoding Studies. AB - Next-generation sequencing technologies have revolutionized the methods for studying microbial ecology by enabling high-resolution community profiling. However, the use of these technologies in unraveling the plant microbiome remains challenging. Many bacterial 16S rDNA primer pairs also exhibit high affinity for non-target DNA such as plastid (mostly chloroplast) DNA and mitochondrial DNA. Therefore, we experimentally tested a series of commonly used primers for the analysis of plant-associated bacterial communities using 454 pyrosequencing. We evaluated the performance of all selected primer pairs in the study of the bacterial microbiomes present in the rhizosphere soil, root, stem and leaf endosphere of field-grown poplar trees (Populus tremula * Populus alba) based on (a) co-amplification of non-target DNA, (b) low amplification efficiency for pure chloroplast DNA (real-time PCR), (c) high retrieval of bacterial 16S rDNA, (d) high operational taxonomic unit (OTU) richness and Inverse Simpson diversity and (e) taxonomic assignment of reads. Results indicate that experimental evaluation of primers provide valuable information that could contribute in the selection of suitable primer pairs for 16S rDNA metabarcoding studies in plant-microbiota research. Furthermore, we show that primer pair 799F-1391R outperforms all other primer pairs in our study in the elimination of non-target DNA and retrieval of bacterial OTUs. PMID- 27242688 TI - Phylogenetic Analysis of the Bifidobacterium Genus Using Glycolysis Enzyme Sequences. AB - Bifidobacteria are important members of the human gastrointestinal tract that promote the establishment of a healthy microbial consortium in the gut of infants. Recent studies have established that the Bifidobacterium genus is a polymorphic phylogenetic clade, which encompasses a diversity of species and subspecies that encode a broad range of proteins implicated in complex and non digestible carbohydrate uptake and catabolism, ranging from human breast milk oligosaccharides, to plant fibers. Recent genomic studies have created a need to properly place Bifidobacterium species in a phylogenetic tree. Current approaches, based on core-genome analyses come at the cost of intensive sequencing and demanding analytical processes. Here, we propose a typing method based on sequences of glycolysis genes and the proteins they encode, to provide insights into diversity, typing, and phylogeny in this complex and broad genus. We show that glycolysis genes occur broadly in these genomes, to encode the machinery necessary for the biochemical spine of the cell, and provide a robust phylogenetic marker. Furthermore, glycolytic sequences-based trees are congruent with both the classical 16S rRNA phylogeny, and core genome-based strain clustering. Furthermore, these glycolysis markers can also be used to provide insights into the adaptive evolution of this genus, especially with regards to trends toward a high GC content. This streamlined method may open new avenues for phylogenetic studies on a broad scale, given the widespread occurrence of the glycolysis pathway in bacteria, and the diversity of the sequences they encode. PMID- 27242687 TI - Type II Toxin-Antitoxin Distribution and Adaptive Aspects on Xanthomonas Genomes: Focus on Xanthomonas citri. AB - Prokaryotic toxin-antitoxin (TA) systems were first described as being designed to prevent plasmid loss in bacteria. However, with the increase in prokaryotic genome sequencing, recently many TAs have been found in bacterial chromosomes, having other biological functions, such as environmental stress response. To date, only few studies have focused on TA systems in phytopathogens, and their possible impact on the bacterial fitness. This may be especially important for pathogens like Xanthomonas spp., which live epiphytically before entering the host. In this study, we looked for TA systems in the genomes of 10 Xanthomonas strains. We verified that citrus-infecting pathovars have, on average, 50% more TAs than other Xanthomonas spp. and no genome harbors classical toxins such as MqsR, RelB, and HicA. Only one TA system (PIN_VapC-FitB-like/SpoVT_AbrB) was conserved among the Xanthomonas genomes, suggesting adaptive aspects concerning its broad occurrence. We also detected a trend of toxin gene loss in this genus, while the antitoxin gene was preferably maintained. This study discovers the quantitative and qualitative differences among the type II TA systems present in Xanthomonas spp., especially concerning the citrus-infecting strains. In addition, the antitoxin retention in the genomes is possibly related with the resistance mechanism of further TA infections as an anti-addiction system or might also be involved in regulation of certain specific genes. PMID- 27242689 TI - Quantification of Slackia and Eggerthella spp. in Human Feces and Adhesion of Representatives Strains to Caco-2 Cells. AB - Eggerthella and Slackia spp. are gut associated bacteria that have been suggested to play roles in host lipid and xenobiotic metabolism. A quantitative PCR method for the selective enumeration of bacteria belonging to either the genus Eggerthella or Slackia was developed in order to establish the numbers of these bacteria occurring in human feces. The primers developed for selective amplification of these genera were tested first in conventional PCR to test for their specificity. Representative species of Eggerthella and Slackia, as well as closely related genera of the Coriobacteriia, were included in the investigation. The selected primers were shown to be capable of specific amplification of species of the genera Eggerthella and Slackia, but not all species of the genera may be amplified by the respective primers. Their use in qPCR experiments to assess the levels of Slackia equolifaciens and Eggerthella lenta in the feces of 19 human volunteers showed they occurred at mean counts of 7 * 10(5) and 3.1 * 10(5) CFU/g for Eggerthella spp. and Slackia spp., respectively. Electron microscopy investigations showed that while E. lenta cells exhibited slender and very regular shaped rods, Slackia cells showed a remarkably pleomorphic phenotype. Both species did not appear to have fimbriae or pili. Some S. equolifaciens cells showed a characteristic "ribbon" of presumably extracellular material around the cells, particularly at the areas of cell division. The two species also differed markedly in their adhesion behavior to Caco-2 cells in cell culture, as E. lenta DSMZ 15644 showed a high adhesion capacity of 74.2% adherence of the bacterial cells added to Caco-2 cells, while S. equolifaciens DSM 24851(T) on the other hand showed only low adhesion capability, as 6.1% of bacterial cells remained bound. Speculatively, this may imply that the ecological compartments where these bacteria reside in the gut may be different, i.e., E. lenta may be associated more with the gut wall, while Slackia may be free living in the lumen. PMID- 27242690 TI - Quorum Sensing Inhibiting Activity of Streptomyces coelicoflavus Isolated from Soil. AB - Quorum sensing (QS) systems communicate bacterial population and stimulate microbial pathogenesis through signaling molecules. Inhibition of QS signals potentially suppresses microbial infections. Antimicrobial properties of Streptomyces have been extensively studied, however, less is known about quorum sensing inhibitory (QSI) activities of Streptomyces. This study explored the QSI potential of Streptomyces isolated from soil. Sixty-five bacterial isolates were purified from soil samples with morphological characteristics of Streptomyces. The three isolates: S6, S12, and S17, exhibited QSI effect by screening with the reporter, Chromobacterium violaceum. Isolate S17 was identified as Streptomyces coelicoflavus by sequencing of the hypervariable regions (V1-V6) of 16S rRNA and was assigned gene bank number KJ855087. The QSI effect of the cell-free supernatant of isolate S17 was not abolished by proteinase K indicating the non enzymatic activity of QSI components of S17. Three major compounds were isolated and identified, using spectroscopic techniques (1D, 2D NMR, and Mass spectrometry), as behenic acid (docosanoic acid), borrelidin, and 1H-pyrrole-2 carboxylic acid. 1H-pyrrole-2-carboxylic acid inhibited QS and related virulence factors of Pseudomonas aeruginosa PAO1 including; elastase, protease, and pyocyanin without affecting Pseudomonas viability. At the molecular level, 1H pyrrole-2-carboxylic acid suppressed the expression of QS genes (lasI, lasR, lasA, lasB, rhlI, rhlR, pqsA, and pqsR). Moreover, QSI activity of S17 was assessed under different growth conditions and ISP2 medium supplemented with glucose 0.4% w/v and adjusted at pH 7, showed the highest QSI action. In conclusion, 1H-pyrrole-2-carboxylic acid, one of the major metabolites of Streptomyces isolate S17, inhibited QS and virulence determinants of P. aeruginosa PAO1. The findings of the study open the scope to exploit the in vivo efficacy of this active molecule as anti-pathogenic and anti-virulence of P. aeruginosa. PMID- 27242692 TI - Editorial: Wired for Life. PMID- 27242691 TI - Molecular Characterization and Meta-Analysis of Gut Microbial Communities Illustrate Enrichment of Prevotella and Megasphaera in Indian Subjects. AB - The gut microbiome has varied impact on the wellbeing of humans. It is influenced by different factors such as age, dietary habits, socio-economic status, geographic location, and genetic makeup of individuals. For devising microbiome based therapies, it is crucial to identify population specific features of the gut microbiome. Indian population is one of the most ethnically, culturally, and geographically diverse, but the gut microbiome features remain largely unknown. The present study describes gut microbial communities of healthy Indian subjects and compares it with the microbiota from other populations. Based on large differences in alpha diversity indices, abundance of 11 bacterial phyla and individual specific OTUs, we report inter-individual variations in gut microbial communities of these subjects. While the gut microbiome of Indians is different from that of Americans, it shared high similarity to individuals from the Indian subcontinent i.e., Bangladeshi. Distinctive feature of Indian gut microbiota is the predominance of genus Prevotella and Megasphaera. Further, when compared with other non-human primates, it appears that Indians share more OTUs with omnivorous mammals. Our metagenomic imputation indicates higher potential for glycan biosynthesis and xenobiotic metabolism in these subjects. Our study indicates urgent need of identification of population specific microbiome biomarkers of Indian subpopulations to have more holistic view of the Indian gut microbiome and its health implications. PMID- 27242693 TI - Microbial Terroir in Chilean Valleys: Diversity of Non-conventional Yeast. AB - In this study, the presence of non-conventional yeast associated with vineyards located between latitudes 30 degrees S and 36 degrees S was examined, including the valleys of Limari, Casablanca, Maipo, Colchagua, Maule, and Itata. The microbial fingerprinting in each valley was examined based on the specific quantification of yeast of enological interest. Grape-berries were sampled to evaluate the presence and load of non-conventional yeast with enological potential, such as Metschnikowia, Hanseniaspora, Torulaspora, Debaryomyces, Meyerozyma, and Rhodotorula. These yeasts were present in all vineyards studied but with varying loads depending on the valley sampled. No identical fingerprints were observed; however, similarities and differences could be observed among the microbial profiles of each valley. A co-variation in the loads of Metschnikowia and Hanseniaspora with latitude was observed, showing high loads in the Casablanca and Itata valleys, which was coincident with the higher relative humidity or rainfall of those areas. Non-conventional yeasts were also isolated and identified after sequencing molecular markers. Potentially good aromatic properties were also screened among the isolates, resulting in the selection of mostly Metschnikowia and Hanseniaspora isolates. Finally, our results suggest that microbial terroir might be affected by climatic conditions such as relative humidity and rainfall, especially impacting the load of non-conventional yeast. In this study, the microbial fingerprint for yeast in Chilean vineyards is reported for the first time revealing an opportunity to study the contribution of this assembly of microorganisms to the final product. PMID- 27242694 TI - Bacillus cereus AR156 Extracellular Polysaccharides Served as a Novel Micro associated Molecular Pattern to Induced Systemic Immunity to Pst DC3000 in Arabidopsis. AB - Non-host resistance (NHR) is a broad-spectrum plant defense. Upon colonizing on the surface on the root or leaves of non-host species, pathogens initial encounter preform and induce defense response in plant, such as induced hypersensitive response, PAMPs triggered immunity (PTI), and effector triggered immunity (ETI). The ability of plants to develop an induced systemic response (ISR) in reaction to the colonization by non-pathogenic rhizobacterium depends on interactions between host plants and the colonizing rhizobacterium, and the ISR also can be defined as a NHR. However, how the colonization signal is and how systemic resistance to pathogens is developed is still unclear. In this study, we demonstrated that the extracellular polysaccharides (EPSs) of Bacillus cereus AR156 could act as novel microbe-associated molecular patterns (MAMPs) and function in the early perception status of the ISR of B. cereus AR156. The results revealed that B. cereus AR156 EPS could induce systemic resistance to Pst DC3000 in Arabidopsis. Cellular defense response markers such as hydrogen peroxide accumulation, callose deposition, and defense-associated enzyme were induced upon challenge inoculation in the leaves primed by EPS. Moreover, the defense-related genes PR1, PR2, and PR5 and mitogen-activated kinases (MAPK) cascade marker gene MPK6 were concurrently expressed in the leaves of EPS-treated plants and induced higher resistance to Pst DC3000 in Col-0 than that in the jar1 or etr1 mutants. The protection was absent in the NahG transgenic plants and npr1 mutant, suggesting an activation of the salicylic acid (SA)- and the MAPK dependent signaling pathways with NPR1-dependent by B. cereus AR156 EPS. In conclusion, B. cereus AR156 EPS play an important role in MAMP perception during the process of rhizobacteria-triggered NHR. This study is the first to illustrate how AR156 induces systemic resistance to Pst DC3000 in Arabidopsis. It also provides the first explanation of how plants perceive colonization of non pathogenic bacteria and how rhizobacteria trigger ISR to plant pathogens. PMID- 27242695 TI - Identification of Free-Living and Particle-Associated Microbial Communities Present in Hadal Regions of the Mariana Trench. AB - Relatively few studies have described the microbial populations present in ultra deep hadal environments, largely as a result of difficulties associated with sampling. Here we report Illumina-tag V6 16S rRNA sequence-based analyses of the free-living and particle-associated microbial communities recovered from locations within two of the deepest hadal sites on Earth, the Challenger Deep (10,918 meters below surface-mbs) and the Sirena Deep (10,667 mbs) within the Mariana Trench, as well as one control site (Ulithi Atoll, 761 mbs). Seawater samples were collected using an autonomous lander positioned ~1 m above the seafloor. The bacterial populations within the Mariana Trench bottom water samples were dissimilar to other deep-sea microbial communities, though with overlap with those of diffuse flow hydrothermal vents and deep-subsurface locations. Distinct particle-associated and free-living bacterial communities were found to exist. The hadal bacterial populations were also markedly different from one another, indicating the likelihood of different chemical conditions at the two sites. In contrast to the bacteria, the hadal archaeal communities were more similar to other less deep datasets and to each other due to an abundance of cosmopolitan deep-sea taxa. The hadal communities were enriched in 34 bacterial and 4 archaeal operational taxonomic units (OTUs) including members of the Gammaproteobacteria, Epsilonproteobacteria, Marinimicrobia, Cyanobacteria, Deltaproteobacteria, Gemmatimonadetes, Atribacteria, Spirochaetes, and Euryarchaeota. Sequences matching cultivated piezophiles were notably enriched in the Challenger Deep, especially within the particle-associated fraction, and were found in higher abundances than in other hadal studies, where they were either far less prevalent or missing. Our results indicate the importance of heterotrophy, sulfur-cycling, and methane and hydrogen utilization within the bottom waters of the deeper regions of the Mariana Trench, and highlight novel community features of these extreme habitats. PMID- 27242696 TI - Superimposed Pristine Limestone Aquifers with Marked Hydrochemical Differences Exhibit Distinct Fungal Communities. AB - Fungi are one important group of eukaryotic microorganisms in a diverse range of ecosystems, but their diversity in groundwater ecosystems is largely unknown. We used DNA-based pyro-tag sequencing of the fungal internal transcribed spacer (ITS) rDNA gene to investigate the presence and community structure of fungi at different sampling sites of two superimposed limestone aquifers ranging from 8.5 to 84 m depth in the newly established Hainich Critical Zone Exploratory (Hainich CZE). We detected a diversity of fungal OTUs in groundwater samples of all sampling sites. The relative percentage abundance of Basidiomycota was higher in the upper aquifer assemblage, whilst Ascomycota dominated the lower one. In parallel to differences in the hydrochemistry we found distinct fungal communities at all sampling sites. Classification into functional groups revealed an overwhelming majority of saprotrophs. Finding taxa common to all analyzed groundwater sites, point to a groundwater specific fungal microbiome. The presence of different functional groups and, in particular plant and cattle pathogens that are not typical of subsurface habitats, suggests links between the surface and subsurface biogeosphere due to rapid transportation across the fracture networks typical of karstic regions during recharge episodes. However, further studies including sampling series extended in both time and space are necessary to confirm this hypothesis. PMID- 27242697 TI - Mathematical Models of Tuberculosis Reactivation and Relapse. AB - The natural history of human infection with Mycobacterium tuberculosis (Mtb) is highly variable, as is the response to treatment of active tuberculosis. There is presently no direct means to identify individuals in whom Mtb infection has been eradicated, whether by a bactericidal immune response or sterilizing antimicrobial chemotherapy. Mathematical models can assist in such circumstances by measuring or predicting events that cannot be directly observed. The 3 models discussed in this review illustrate instances in which mathematical models were used to identify individuals with innate resistance to Mtb infection, determine the etiologic mechanism of tuberculosis in patients treated with tumor necrosis factor blockers, and predict the risk of relapse in persons undergoing tuberculosis treatment. These examples illustrate the power of various types of mathematic models to increase knowledge and thereby inform interventions in the present global tuberculosis epidemic. PMID- 27242698 TI - The Oenological Potential of Hanseniaspora uvarum in Simultaneous and Sequential Co-fermentation with Saccharomyces cerevisiae for Industrial Wine Production. AB - In oenology, the utilization of mixed starter cultures composed by Saccharomyces and non-Saccharomyces yeasts is an approach of growing importance for winemakers in order to enhance sensory quality and complexity of the final product without compromising the general quality and safety of the oenological products. In fact, several non-Saccharomyces yeasts are already commercialized as oenological starter cultures to be used in combination with Saccharomyces cerevisiae, while several others are the subject of various studies to evaluate their application. Our aim, in this study was to assess, for the first time, the oenological potential of H. uvarum in mixed cultures (co-inoculation) and sequential inoculation with S. cerevisiae for industrial wine production. Three previously characterized H. uvarum strains were separately used as multi-starter together with an autochthonous S. cerevisiae starter culture in lab-scale micro vinification trials. On the basis of microbial development, fermentation kinetics and secondary compounds formation, the strain H. uvarum ITEM8795 was further selected and it was co- and sequentially inoculated, jointly with the S. cerevisiae starter, in a pilot scale wine production. The fermentation course and the quality of final product indicated that the co-inoculation was the better performing modality of inoculum. The above results were finally validated by performing an industrial scale vinification The mixed starter was able to successfully dominate the different stages of the fermentation process and the H. uvarum strain ITEM8795 contributed to increasing the wine organoleptic quality and to simultaneously reduce the volatile acidity. At the best of our knowledge, the present report is the first study regarding the utilization of a selected H. uvarum strain in multi-starter inoculation with S. cerevisiae for the industrial production of a wine. In addition, we demonstrated, at an industrial scale, the importance of non-Saccharomyces in the design of tailored starter cultures for typical wines. PMID- 27242699 TI - QnrS1- and Aac(6')-Ib-cr-Producing Escherichia coli among Isolates from Animals of Different Sources: Susceptibility and Genomic Characterization. AB - Salmonella enterica and Escherichia coli can inhabit humans and animals from multiple origins. These bacteria are often associated with gastroenteritis in animals, being a frequent cause of resistant zoonotic infections. In fact, bacteria from animals can be transmitted to humans through the food chain and direct contact. In this study, we aimed to assess the antibiotic susceptibility of a collection of S. enterica and E. coli recovered from animals of different sources, performing a genomic comparison of the plasmid-mediated quinolone resistance (PMQR)-producing isolates detected. Antibiotic susceptibility testing revealed a high number of non-wild-type isolates for fluoroquinolones among S. enterica recovered from poultry isolates. In turn, the frequency of non-wild-type E. coli to nalidixic acid and ciprofloxacin was higher in food-producing animals than in companion or zoo animals. Globally, we detected two qnrS1 and two aac(6') Ib-cr in E. coli isolates recovered from animals of different origins. The genomic characterization of QnrS1-producing E. coli showed high genomic similarity (O86:H12 and ST2297), although they have been recovered from a healthy turtle dove from a Zoo Park, and from a dog showing symptoms of infection. The qnrS1 gene was encoded in a IncN plasmid, also carrying bla TEM-1-containing Tn3. Isolates harboring aac(6')-Ib-cr were detected in two captive bottlenose dolphins, within a time span of two years. The additional antibiotic resistance genes of the two aac(6')-Ib-cr-positive isolates (bla OXA-1, bla TEM-1,bla CTX-M 15, catB3, aac(3)-IIa, and tetA) were enclosed in IncFIA plasmids that differed in a single transposase and 60 single nucleotide variants. The isolates could be assigned to the same genetic sublineage-ST131 fimH30-Rx (O25:H4), confirming clonal spread. PMQR-producing isolates were associated with symptomatic and asymptomatic hosts, which highlight the aptitude of E. coli to act as silent vehicles, allowing the accumulation of antibiotic resistance genes, mobile genetic elements and other relevant pathogenicity determinants. Continuous monitoring of health and sick animals toward the presence of PMQR should be strongly encouraged in order to restrain the clonal spread of these antibiotic resistant strains. PMID- 27242700 TI - Increased Prevalence of Human Polyomavirus JC Viruria in Chronic Inflammatory Rheumatic Diseases Patients in Treatment with Anti-TNF alpha: A 18 Month Follow Up Study. AB - Chronic inflammatory rheumatic diseases (CIRDs) are immune-mediated pathologies involving joints. To date, TNFalpha-blocking agents administration is the most promising therapy, although these treatments are associated with an increased Polyomavirus JC (JCPyV) reactivation, the etiological agent of the Progressive Multifocal Leukoencephalopathy (PML). The aim of this study was the recruitment and the analysis of a CIRDs cohort in order to investigate a possible correlation between JCPyV presence and the influence of anti-TNF-alpha agents on viral loads. Blood and urine samples were collected from 34 CIRDs subjects prior the first anti-TNF-alpha infusion (T0) and after 3 (T3), 6 (T6), 12 (T12), and 18 (T18) months. Results showed persistent JC viruria significantly higher than JC viremia throughout the 18 month follow-up study (p = 0.002). In JCPyV positive samples, the non-coding control region (NCCR) was analyzed. Results evidenced archetypal structures (type II-S) in all isolates with the exception of a sequence isolated from a plasma sample, that corresponds to the type II-R found in PML subjects. Finally, the viral protein 1 (VP1) genotyping was performed and results showed the prevalence of the European genotypes 1A, 1B, and 4. Since only few studies have been carried out to understand whether there is a PML risk in CIRDs population infected by JCPyV, this study contributes to enrich literature insight on JCPyV biology in this cluster. Further investigations are necessary in order to recognize the real impact of biologics on JCPyV life cycle and to identify possible and specific viral variants related to increased virulence in CIRDs patients. PMID- 27242702 TI - Chronic Chagas' Disease: Targeting the Interleukin-2 Axis and Regulatory T Cells in a Condition for Which There Is No Treatment. PMID- 27242701 TI - Metabolic Network Modeling of Microbial Interactions in Natural and Engineered Environmental Systems. AB - We review approaches to characterize metabolic interactions within microbial communities using Stoichiometric Metabolic Network (SMN) models for applications in environmental and industrial biotechnology. SMN models are computational tools used to evaluate the metabolic engineering potential of various organisms. They have successfully been applied to design and optimize the microbial production of antibiotics, alcohols and amino acids by single strains. To date however, such models have been rarely applied to analyze and control the metabolism of more complex microbial communities. This is largely attributed to the diversity of microbial community functions, metabolisms, and interactions. Here, we firstly review different types of microbial interaction and describe their relevance for natural and engineered environmental processes. Next, we provide a general description of the essential methods of the SMN modeling workflow including the steps of network reconstruction, simulation through Flux Balance Analysis (FBA), experimental data gathering, and model calibration. Then we broadly describe and compare four approaches to model microbial interactions using metabolic networks, i.e., (i) lumped networks, (ii) compartment per guild networks, (iii) bi-level optimization simulations, and (iv) dynamic-SMN methods. These approaches can be used to integrate and analyze diverse microbial physiology, ecology and molecular community data. All of them (except the lumped approach) are suitable for incorporating species abundance data but so far they have been used only to model simple communities of two to eight different species. Interactions based on substrate exchange and competition can be directly modeled using the above approaches. However, interactions based on metabolic feedbacks, such as product inhibition and synthropy require extensions to current models, incorporating gene regulation and compounding accumulation mechanisms. SMN models of microbial interactions can be used to analyze complex "omics" data and to infer and optimize metabolic processes. Thereby, SMN models are suitable to capitalize on advances in high-throughput molecular and metabolic data generation. SMN models are starting to be applied to describe microbial interactions during wastewater treatment, in-situ bioremediation, microalgae blooms methanogenic fermentation, and bioplastic production. Despite their current challenges, we envisage that SMN models have future potential for the design and development of novel growth media, biochemical pathways and synthetic microbial associations. PMID- 27242703 TI - Strategies for Human Tumor Virus Discoveries: From Microscopic Observation to Digital Transcriptome Subtraction. AB - Over 20% of human cancers worldwide are associated with infectious agents, including viruses, bacteria, and parasites. Various methods have been used to identify human tumor viruses, including electron microscopic observations of viral particles, immunologic screening, cDNA library screening, nucleic acid hybridization, consensus PCR, viral DNA array chip, and representational difference analysis. With the Human Genome Project, a large amount of genetic information from humans and other organisms has accumulated over the last decade. Utilizing the available genetic databases, Feng et al. (2007) developed digital transcriptome subtraction (DTS), an in silico method to sequentially subtract human sequences from tissue or cellular transcriptome, and discovered Merkel cell polyomavirus (MCV) from Merkel cell carcinoma. Here, we review the background and methods underlying the human tumor virus discoveries and explain how DTS was developed and used for the discovery of MCV. PMID- 27242704 TI - Phosphorylation Modulates Catalytic Activity of Mycobacterial Sirtuins. AB - Sirtuins are NAD(+)-dependent deacetylases involved in the regulation of diverse cellular processes and are conserved throughout phylogeny. Here we report about in vitro transphosphorylation of the only NAD(+)-dependent deacetylase (mDAC) present in the genome of Mycobacterium tuberculosis by eukaryotic-type Ser/Thr kinases, particularly PknA. The phosphorylated mDAC displayed decreased deacetylase activity compared to its unphosphorylated counterpart. Mass spectrometric study identified seven phosphosites in mDAC; however, mutational analysis highlighted major contribution of Thr-214 for phosphorylation of the protein. In concordance to this observation, variants of mDAC substituting Thr 214 with either Ala (phospho-ablated) or Glu (phosphomimic) exhibited significantly reduced deacetylase activity suggesting phosphorylation mediated control of enzymatic activity. To assess the role of phosphorylation towards functionality of mDAC, we opted for a sirtuin knock-out strain of Escherichia coli (Deltadac), where interference of endogenous mycobacterial kinases could be excluded. The Deltadac strain in nutrient deprived acetate medium exhibited compromised growth and complementation with mDAC reversed this phenotype. The phospho-ablated or phosphomimic variant, on the other hand, was unable to restore the functionality of mDAC indicating the role of phosphorylation per se in the process. We further over-expressed mDAC or mDAC-T214A as His-tagged protein in M. smegmatis, where endogenous eukaryotic-type Ser/Thr kinases are present. Anti phosphothreonine antibody recognized both mDAC and mDAC-T214A proteins in western blotting. However, the extent of phosphorylation as adjudged by scanning the band intensity, was significantly low in the mutant protein (mDAC-T214A) compared to that of the wild-type (mDAC). Furthermore, expression of PknA in the mDAC complemented Deltadac strain was able to phosphorylate M. tuberculosis sirtuin. The growth profile of this culture in acetate medium was slow compared to that transformed with only vector. On the other hand, use of a kinase dead variant, PknA-K42N instead of PknA, did not display such behavior, which again supported phosphorylation mediated control of mDAC protein. Thus, our results ostensibly render evidence for cross-talk between two distinct post-translational modifications, phosphorylation and deacetylation, in any bacteria. Bioinformatic analysis further indicated conservation of Thr-214 among different mDAC orthologs, thereby arguing the event as mycobacteria specific. PMID- 27242705 TI - Deep Subsurface Life from North Pond: Enrichment, Isolation, Characterization and Genomes of Heterotrophic Bacteria. AB - Studies of subsurface microorganisms have yielded few environmentally relevant isolates for laboratory studies. In order to address this lack of cultivated microorganisms, we initiated several enrichments on sediment and underlying basalt samples from North Pond, a sediment basin ringed by basalt outcrops underlying an oligotrophic water-column west of the Mid-Atlantic Ridge at 22 degrees N. In contrast to anoxic enrichments, growth was observed in aerobic, heterotrophic enrichments from sediment of IODP Hole U1382B at 4 and 68 m below seafloor (mbsf). These sediment depths, respectively, correspond to the fringes of oxygen penetration from overlying seawater in the top of the sediment column and upward migration of oxygen from oxic seawater from the basalt aquifer below the sediment. Here we report the enrichment, isolation, initial characterization and genomes of three isolated aerobic heterotrophs from North Pond sediments; an Arthrobacter species from 4 mbsf, and Paracoccus and Pseudomonas species from 68 mbsf. These cultivated bacteria are represented in the amplicon 16S rRNA gene libraries created from whole sediments, albeit at low (up to 2%) relative abundance. We provide genomic evidence from our isolates demonstrating that the Arthrobacter and Pseudomonas isolates have the potential to respire nitrate and oxygen, though dissimilatory nitrate reduction could not be confirmed in laboratory cultures. The cultures from this study represent members of abundant phyla, as determined by amplicon sequencing of environmental DNA extracts, and allow for further studies into geochemical factors impacting life in the deep subsurface. PMID- 27242706 TI - Diversity of Pico- to Mesoplankton along the 2000 km Salinity Gradient of the Baltic Sea. AB - Microbial plankton form the productive base of both marine and freshwater ecosystems and are key drivers of global biogeochemical cycles of carbon and nutrients. Plankton diversity is immense with representations from all major phyla within the three domains of life. So far, plankton monitoring has mainly been based on microscopic identification, which has limited sensitivity and reproducibility, not least because of the numerical majority of plankton being unidentifiable under the light microscope. High-throughput sequencing of taxonomic marker genes offers a means to identify taxa inaccessible by traditional methods; thus, recent studies have unveiled an extensive previously unknown diversity of plankton. Here, we conducted ultra-deep Illumina sequencing (average 10(5) sequences/sample) of rRNA gene amplicons of surface water eukaryotic and bacterial plankton communities sampled in summer along a 2000 km transect following the salinity gradient of the Baltic Sea. Community composition was strongly correlated with salinity for both bacterial and eukaryotic plankton assemblages, highlighting the importance of salinity for structuring the biodiversity within this ecosystem. In contrast, no clear trends in alpha diversity for bacterial or eukaryotic communities could be detected along the transect. The distribution of major planktonic taxa followed expected patterns as observed in monitoring programs, but groups novel to the Baltic Sea were also identified, such as relatives to the coccolithophore Emiliana huxleyi detected in the northern Baltic Sea. This study provides the first ultra-deep sequencing based survey on eukaryotic and bacterial plankton biogeography in the Baltic Sea. PMID- 27242707 TI - Horizontal Acquisition of a Multidrug-Resistance Module (R-type ASSuT) Is Responsible for the Monophasic Phenotype in a Widespread Clone of Salmonella Serovar 4,[5],12:i:. AB - Salmonella enterica serovar 4,[5],12:i:- is a monophasic variant of S. Typhimurium incapable of expressing the second-phase flagellar antigen (fljAB operon), and it is recognized to be one of the most prevalent serovars causing human infections. A clonal lineage characterized by phage type DT193, PulseNet PFGE profile STYMXB.0131 and multidrug resistance to ampicillin, streptomycin, sulphonamides and tetracycline (R-type ASSuT) is commonly circulating in Europe. In this study we determined the deletions affecting the fljAB operon and the resistance region responsible for the R-type ASSuT in a strain of Salmonella enterica serovar 4,5,12:i:- DT193/STYMXB.0131, through an approach based on PCRs and Southern blot hybridization of genomic DNA. Using a set of nine specific PCRs, the prevalence of the resistance region was assessed in a collection of 144 S. enterica serovar 4,[5],12:i:-/ASSuT/STYMXB.0131 strains isolated from Germany, Switzerland and Italy. A 28 kb-region is embedded between the loci STM2759 and iroB, replacing the DNA located in between, including the fljAB operon. It encompasses the genes bla TEM-1, strA-strB, sul2 and tet(B) responsible for the R type ASSuT together with genes involved in plasmid replication and orfs of unknown function characteristically located on IncH1 plasmids. Its location and internal structure is fairly conserved in S. enterica serovar 4,[5],12:i: /ASSuT/STYMXB.0131 strains regardless of the isolation source or country. Hence, in the S. enterica serovar 4,[5],12:i:-/ASSuT/STYMXB.0131 clonal lineage widespread in Germany, Switzerland and Italy, a resistance region derived from IncH1 plasmids has replaced the chromosomal region encoding the second flagellar phase and is an example of the stabilization of new plasmid-derived genetic material due to integration into the bacterial chromosome. PMID- 27242708 TI - Antimicrobial Activity of Tulsi (Ocimum tenuiflorum) Essential Oil and Their Major Constituents against Three Species of Bacteria. AB - In recent years scientists worldwide have realized that the effective life span of any antimicrobial agent is limited, due to increasing development of resistance by microorganisms. Consequently, numerous studies have been conducted to find new alternative sources of antimicrobial agents, especially from plants. The aims of this project were to examine the antimicrobial properties of essential oils distilled from Australian-grown Ocimum tenuiflorum (Tulsi), to quantify the volatile components present in flower spikes, leaves and the essential oil, and to investigate the compounds responsible for any activity. Broth micro-dilution was used to determine the minimum inhibitory concentration (MIC) of Tulsi essential oil against selected microbial pathogens. The oils, at concentrations of 4.5 and 2.25% completely inhibited the growth of Staphylococcus aureus (including MRSA) and Escherichia coli, while the same concentrations only partly inhibited the growth of Pseudomonas aeruginosa. Of 54 compounds identified in Tulsi leaves, flower spikes, or essential oil, three are proposed to be responsible for this activity; camphor, eucalyptol and eugenol. Since S. aureus (including MRSA), P. aeruginosa and E. coli are major pathogens causing skin and soft tissue infections, Tulsi essential oil could be a valuable topical antimicrobial agent for management of skin infections caused by these organisms. PMID- 27242709 TI - Dynamics of Actin Cables in Polarized Growth of the Filamentous Fungus Aspergillus nidulans. AB - Highly polarized growth of filamentous fungi requires a continuous supply of proteins and lipids to the hyphal tip. This transport is managed by vesicle trafficking via the actin and microtubule cytoskeletons and their associated motor proteins. Particularly, actin cables originating from the hyphal tip are essential for hyphal growth. Although, specific marker proteins have been developed to visualize actin cables in filamentous fungi, the exact organization and dynamics of actin cables has remained elusive. Here, we observed actin cables using tropomyosin (TpmA) and Lifeact fused to fluorescent proteins in living Aspergillus nidulans hyphae and studied the dynamics and regulation. GFP tagged TpmA visualized dynamic actin cables formed from the hyphal tip with cycles of elongation and shrinkage. The elongation and shrinkage rates of actin cables were similar and approximately 0.6 MUm/s. Comparison of actin markers revealed that high concentrations of Lifeact reduced actin dynamics. Simultaneous visualization of actin cables and microtubules suggests temporally and spatially coordinated polymerization and depolymerization between the two cytoskeletons. Our results provide new insights into the molecular mechanism of ordered polarized growth regulated by actin cables and microtubules. PMID- 27242710 TI - Aspergillus fumigatus-Related Species in Clinical Practice. AB - Aspergillus fumigatus is the main etiologic agent of invasive aspergillosis (IA). Other Aspergillus species belonging to the section Fumigati (A. fumigatus complex) may occasionally be the cause of IA. These strains are often misidentified, as they cannot be distinguished from A. fumigatus by conventional morphological analysis and sequencing methods. This lack of recognition may have important consequences as these A. fumigatus-related species often display some level of intrinsic resistance to azoles and other antifungal drugs. A. lentulus, A. udagawae, A. viridinutans, and A. thermomutatus (Neosartorya pseudofischeri) have been associated with refractory cases of IA. Microbiologists should be able to suspect the presence of these cryptic species behind a putative A. fumigatus isolate on the basis of some simple characteristics, such as defect in sporulation and/or unusual antifungal susceptibility profile. However, definitive species identification requires specific sequencing analyses of the beta-tubulin or calmodulin genes, which are not available in most laboratories. Multiplex PCR assays or matrix-assisted laser desorption ionization - time-of-flight mass spectrometry (MALDI-TOF MS) gave promising results for rapid and accurate distinction between A. fumigatus and other Aspergillus spp. of the section Fumigati in clinical practice. Improved diagnostic procedures and antifungal susceptibility testing may be helpful for the early detection and management of these particular IA cases. PMID- 27242711 TI - Carolacton Treatment Causes Delocalization of the Cell Division Proteins PknB and DivIVa in Streptococcus mutans in vivo. AB - The small inhibitory molecule Carolacton has been shown to cause chain formation and bulging in Streptococci, suggesting a defect in cell division, but it is not known how cell division is impaired on a molecular level. Fluorescent fusion proteins have successfully been applied to visualize protein localization and dynamics in vivo and have revolutionized our understanding of cell wall growth, cell division, chromosome replication and segregation. However, in Streptococci the required vectors are largely lacking. We constructed vectors for chromosomal integration and inducible expression of fluorescent fusion proteins based on GFP+ in S. mutans. Their applicability was verified using four proteins with known localization in the cell. We then determined the effect of Carolacton on the subcellular localization of GFP+ fusions of the cell division protein DivIVa and the serine-threonine protein kinase PknB. Carolacton caused a significant delocalization of these proteins from midcell, in accordance with a previous study demonstrating the Carolacton insensitive phenotype of a pknB deletion strain. Carolacton treated cells displayed an elongated phenotype, increased septum formation and a severe defect in daughter cell separation. GFP+ fusions of two hypothetical proteins (SMU_503 and SMU_609), that had previously been shown to be the most strongly upregulated genes after Carolacton treatment, were found to be localized at the septum in midcell, indicating their role in cell division. These findings highlight the importance of PknB as a key regulator of cell division in streptococci and indicate a profound impact of Carolacton on the coordination between peripheral and septal cell wall growth. The established vector system represents a novel tool to study essential steps of cellular metabolism. PMID- 27242712 TI - An In Vitro Model for Oral Mixed Biofilms of Candida albicans and Streptococcus gordonii in Synthetic Saliva. AB - As a member of the normal human oral microbiota, the fungus Candida albicans is often found in association with Streptococcus gordonii, a member of dental plaque forming bacteria. Evidence suggests that S. gordonii serves as a facilitator of C. albicans adherence to dental tissues, which represents a clinically relevant problem, particularly for immunocompromised individuals that could subsequently develop fungal infections. In this study we describe the development of a relatively simple and economical in vitro model that allows for the growth of mixed bacterial/fungal biofilms in 96-well microtiter plates. We have applied this method to test and compare the growth characteristics of single and dual species biofilms in traditional microbiological media versus a synthetic saliva medium (basal medium mucin, BMM) that more closely resembles physiological conditions within the oral cavity. Results indicated a synergistic effect for the formation of biofilms when both microorganisms were seeded together under all conditions tested. The structural and architectural features of the resulting biofilms were further characterized using scanning electron microscopy and confocal scanning laser microscopy. We also performed drug susceptibility assays against single and mixed species biofilms using commonly used antifungals and antibacterial antibiotics, both in monotherapy and in combination therapy, for a direct comparison of resistance against antimicrobial treatment. As expected, mixed species biofilms displayed higher levels of resistance to antimicrobial treatment at every dose tested in both traditional media and BMM synthetic saliva, as compared to single-species biofilms. PMID- 27242713 TI - The rnc Gene Promotes Exopolysaccharide Synthesis and Represses the vicRKX Gene Expressions via MicroRNA-Size Small RNAs in Streptococcus mutans. AB - Dental caries is a biofilm-dependent disease that largely relies on the ability of Streptococcus mutans to synthesize exopolysaccharides. Although the rnc gene is suggested to be involved in virulence mechanisms in many other bacteria, the information regarding it in S. mutans is very limited. Here, using deletion or overexpression mutant assay, we demonstrated that rnc in S. mutans significantly positively regulated exopolysaccharide synthesis and further altered biofilm formation. Meanwhile, the cariogenecity of S. mutans was decreased by deletion of rnc in a specific pathogen-free (SPF) rat model. Interestingly, analyzing the expression at mRNA level, we found the downstream vic locus was repressed by rnc in S. mutans. Using deep sequencing and bioinformatics analysis, for the first time, three putative microRNA-size small RNAs (msRNAs) targeting vicRKX were predicted in S. mutans. The expression levels of these msRNAs were negatively correlated with vicRKX but positively correlated with rnc, indicating rnc probably repressed vicRKX expression through msRNAs at the post-transcriptional level. In all, the results present that rnc has a potential role in the regulation of exopolysaccharide synthesis and can affect vicRKX expressions via post-transcriptional repression in S. mutans. This study provides an alternative avenue for further research aimed at preventing caries. PMID- 27242714 TI - Pseudomonas aeruginosa Exhibits Deficient Biofilm Formation in the Absence of Class II and III Ribonucleotide Reductases Due to Hindered Anaerobic Growth. AB - Chronic lung infections by the ubiquitous and extremely adaptable opportunistic pathogen Pseudomonas aeruginosa correlate with the formation of a biofilm, where bacteria grow in association with an extracellular matrix and display a wide range of changes in gene expression and metabolism. This leads to increased resistance to physical stress and antibiotic therapies, while enhancing cell-to cell communication. Oxygen diffusion through the complex biofilm structure generates an oxygen concentration gradient, leading to the appearance of anaerobic microenvironments. Ribonucleotide reductases (RNRs) are a family of highly sophisticated enzymes responsible for the synthesis of the deoxyribonucleotides, and they constitute the only de novo pathway for the formation of the building blocks needed for DNA synthesis and repair. P. aeruginosa is one of the few bacteria encoding all three known RNR classes (Ia, II, and III). Class Ia RNRs are oxygen dependent, class II are oxygen independent, and class III are oxygen sensitive. A tight control of RNR activity is essential for anaerobic growth and therefore for biofilm development. In this work we explored the role of the different RNR classes in biofilm formation under aerobic and anaerobic initial conditions and using static and continuous-flow biofilm models. We demonstrated the importance of class II and III RNR for proper cell division in biofilm development and maturation. We also determined that these classes are transcriptionally induced during biofilm formation and under anaerobic conditions. The molecular mechanism of their anaerobic regulation was also studied, finding that the Anr/Dnr system is responsible for class II RNR induction. These data can be integrated with previous knowledge about biofilms in a model where these structures are understood as a set of layers determined by oxygen concentration and contain cells with different RNR expression profiles, bringing us a step closer to the understanding of this complex growth pattern, essential for P. aeruginosa chronic infections. PMID- 27242715 TI - Metagenomic Analysis of the Rumen Microbiome of Steers with Wheat-Induced Frothy Bloat. AB - Frothy bloat is a serious metabolic disorder that affects stocker cattle grazing hard red winter wheat forage in the Southern Great Plains causing reduced performance, morbidity, and mortality. We hypothesize that a microbial dysbiosis develops in the rumen microbiome of stocker cattle when grazing on high quality winter wheat pasture that predisposes them to frothy bloat risk. In this study, rumen contents were harvested from six cannulated steers grazing hard red winter wheat (three with bloat score "2" and three with bloat score "0"), extracted for genomic DNA and subjected to 16S rDNA and shotgun sequencing on 454/Roche platform. Approximately 1.5 million reads were sequenced, assembled and assigned for phylogenetic and functional annotations. Bacteria predominated up to 84% of the sequences while archaea contributed to nearly 5% of the sequences. The abundance of archaea was higher in bloated animals (P < 0.05) and dominated by Methanobrevibacter. Predominant bacterial phyla were Firmicutes (65%), Actinobacteria (13%), Bacteroidetes (10%), and Proteobacteria (6%) across all samples. Genera from Firmicutes such as Clostridium, Eubacterium, and Butyrivibrio increased (P < 0.05) while Prevotella from Bacteroidetes decreased in bloated samples. Co-occurrence analysis revealed syntrophic associations between bacteria and archaea in non-bloated samples, however; such interactions faded in bloated samples. Functional annotations of assembled reads to Subsystems database revealed the abundance of several metabolic pathways, with carbohydrate and protein metabolism well represented. Assignment of contigs to CaZy database revealed a greater diversity of Glycosyl Hydrolases dominated by oligosaccharide breaking enzymes (>70%) in non-bloated samples. However, the abundance and diversity of CaZymes were greatly reduced in bloated samples indicating the disruption of carbohydrate metabolism. We conclude that mild to moderate frothy bloat results from tradeoffs both within and between microbial domains due to greater competition for substrates that are of limited availability as a result of biofilm formation. PMID- 27242716 TI - The Ability of Microbial Community of Lake Baikal Bottom Sediments Associated with Gas Discharge to Carry Out the Transformation of Organic Matter under Thermobaric Conditions. AB - The ability to compare the composition and metabolic potential of microbial communities inhabiting the subsurface sediment in geographically distinct locations is one of the keys to understanding the evolution and function of the subsurface biosphere. Prospective areas for study of the subsurface biosphere are the sites of hydrocarbon discharges on the bottom of the Lake Baikal rift, where ascending fluxes of gas-saturated fluids and oil from deep layers of bottom sediments seep into near-surface sediment. The samples of surface sediments collected in the area of the Posolskaya Bank methane seep were cultured for 17 months under thermobaric conditions (80 degrees C, 5 MPa) with the addition of complementary organic substrate, and a different composition for the gas phase. After incubation, the presence of intact cells of microorganisms, organic matter transformation and the formation of oil biomarkers was confirmed in the samples, with the addition of Baikal diatom alga Synedra acus detritus, and gas mixture CH4:H2:CO2. Taxonomic assignment of the 16S rRNA sequence data indicates that the predominant sequences in the enrichment were Sphingomonas (55.3%), Solirubrobacter (27.5%) and Arthrobacter (16.6%). At the same time, in heat killed sediment and in sediment without any additional substrates, which were cultivated in a CH4 atmosphere, no geochemical changes were detected, nor the presence of intact cells and 16S rRNA sequences of Bacteria and Archaea. This data may suggest that the decomposition of organic matter under culturing conditions could be performed by microorganisms from low-temperature sediment layers. One possible explanation of this phenomenon is migration of the representatives of the deep thermophilic community through fault zones in the near surface sediment layers, together with gas-bearing fluids. PMID- 27242717 TI - Pandoraea pnomenusa Isolated from an Australian Patient with Cystic Fibrosis. AB - Pandoraea species are considered as emerging pathogens in people with cystic fibrosis (CF). The contribution of these organisms to disease progression in CF patients is not fully understood owing in large measure to the scant reports in clinical and research literature describing their colonization of CF patients and their associated virulence determinants. In an effort to increase awareness and evidence for Pandoraea spp. infection in people with CF, and to stimulate research aimed at unraveling the pathogenic properties of Pandoraea, we report a case of a 26-year-old Australian (Tasmanian) man with CF who was chronically infected with Pandoraea pnomenusa for at least one year prior to his death from respiratory failure. In addition, we describe for the first time evidence suggesting that this bacterium is a facultative anaerobe and report on the availability of a whole genome sequence for this organism. To the best of our knowledge, this report represents only the second clinical case study of P. pnomenusa infection in the world, and the first in an Australian CF patient. PMID- 27242718 TI - Epidemiology of Mycoplasma pneumoniae Infections in Japan and Therapeutic Strategies for Macrolide-Resistant M. pneumoniae. AB - Pneumonia caused by Mycoplasma pneumoniae (M. pneumoniae pneumonia) is a major cause of community-acquired pneumonia worldwide. The surveillance of M. pneumoniae pneumonia is important for etiological and epidemiological studies of acute respiratory infections. In Japan, nation-wide surveillance of M. pneumoniae pneumonia has been conducted as a part of the National Epidemiological Surveillance of Infectious Diseases (NESID) program. This surveillance started in 1981, and significant increases in the numbers of M. pneumoniae pneumonia patients were noted in 1984, 1988, 2006, 2010, 2011, 2012, and 2015. The epidemics in 2011 and 2012 were particularly widespread and motivated researchers to conduct detailed epidemiological studies, including genotyping and drug resistance analyses of M. pneumoniae isolates. The genotyping studies based on the p1 gene sequence suggested that the p1 gene type 1 lineage has been dominant in Japan since 2003, including the epidemic period during 2011-2012. However, more detailed p1 typing analysis is required to determine whether the type 2 lineages become more relevant after the dominance of the type 1 lineage. There has been extensive research interest in implications of the p1 gene types on the epidemiology of M. pneumoniae infections. Serological characterizations of sera from patients have provided a glimpse into these associations, showing the presence of type specific antibody in the patient sera. Another important epidemiological issue of M. pneumoniae pneumonia is the emergence of macrolide resistant M. pneumoniae (MRMP). MRMPs were noted among clinical isolates in Japan after 2000. At present, the isolation rate of MRMPs from pediatric patients is estimated at 50-90% in Japan, depending on the specific location. In view of the situation, Japanese societies have issued guiding principles for treating M. pneumoniae pneumonia. In these guiding principles, macrolides are still recommended as the first-line drug, however, if the fever does not subside in 48 72 h from first-line drug administration, a change of antibiotics to second-line drugs is recommended. PMID- 27242720 TI - Correlation between Radiological and Pathological Findings in Patients with Mycoplasma pneumoniae Pneumonia. AB - Studies focused on the pathological-radiological correlation of human Mycoplasma (M) pneumoniae pneumonia have rarely been reported. Therefore, we extensively reviewed the literature regarding pathological and radiological studies of Mycoplasma pneumonia, and compared findings between open lung biopsy specimen and computed tomography (CT). Major three correlations were summarized. (1) Peribronchial and perivascular cuffing characterized by mononuclear cells infiltration was correlated with bronchovascular bundles thickening on CT, which was the most common finding of this pneumonia. (2) Cellular bronchitis in the small airways accompanied with exudates or granulation tissue in the lumen revealed as centrilobular nodules on CT. (3) Neutrophils and exudates in the alveolar lumen radiologically demonstrated as air-space consolidation or ground glass opacities. In M. pulmonis-infected mice model, pathologic patterns are strikingly different according to host cell-mediated immunity (CMI) levels; treatment with interleukin-2 lead to marked cellular bronchitis in the small airways and treatment with prednisolone or cyclosporin-A lead to neutrophils and exudates in the alveolar lumen. Patients with centrilobular nodules predominant radiologic pattern have a high level of CMI, measuring by tuberculin skin test. From these findings, up-regulation of host CMI could change radiological pattern to centrilobular nodules predominant, on the other hand down-regulation of host CMI would change radiological pattern to ground-glass opacity and consolidation. It was suggested the pathological features of M. pneumoniae pneumonia may be altered by the level of host CMI. PMID- 27242719 TI - Gas Fermentation-A Flexible Platform for Commercial Scale Production of Low Carbon-Fuels and Chemicals from Waste and Renewable Feedstocks. AB - There is an immediate need to drastically reduce the emissions associated with global fossil fuel consumption in order to limit climate change. However, carbon based materials, chemicals, and transportation fuels are predominantly made from fossil sources and currently there is no alternative source available to adequately displace them. Gas-fermenting microorganisms that fix carbon dioxide (CO2) and carbon monoxide (CO) can break this dependence as they are capable of converting gaseous carbon to fuels and chemicals. As such, the technology can utilize a wide range of feedstocks including gasified organic matter of any sort (e.g., municipal solid waste, industrial waste, biomass, and agricultural waste residues) or industrial off-gases (e.g., from steel mills or processing plants). Gas fermentation has matured to the point that large-scale production of ethanol from gas has been demonstrated by two companies. This review gives an overview of the gas fermentation process, focusing specifically on anaerobic acetogens. Applications of synthetic biology and coupling gas fermentation to additional processes are discussed in detail. Both of these strategies, demonstrated at bench-scale, have abundant potential to rapidly expand the commercial product spectrum of gas fermentation and further improve efficiencies and yields. PMID- 27242721 TI - How to Optimize the Use of Blood Cultures for the Diagnosis of Bloodstream Infections? A State-of-the Art. AB - Bloodstream infection (BSI) is a major cause of death in developed countries and the detection of microorganisms is essential in managing patients. Despite major progress has been made to improve identification of microorganisms, blood culture (BC) remains the gold standard and the first line tool for detecting BSIs. Consensus guidelines are available to ensure optimal BSI procedures, but BC practices often deviate from the recommendations. This review provides an update on clinical and technical issues related to blood collection and to BC performance, with a special focus on the blood sample strategy to optimize the sensitivity and specificity of BCs. PMID- 27242722 TI - Modulation of Cell Sialoglycophenotype: A Stylish Mechanism Adopted by Trypanosoma cruzi to Ensure Its Persistence in the Infected Host. AB - Trypanosoma cruzi, the etiological agent of Chagas disease exhibits multiple mechanisms to guarantee its establishment and persistence in the infected host. It has been well demonstrated that T. cruzi is not able to synthesize sialic acids (Sia). To acquire the monosaccharide, the parasite makes use of a multifunctional enzyme called trans-sialidase (Tc-TS). Since this enzyme has no analogous in the vertebrate host, it has been used as a target in drug therapy development. Tc-TS preferentially catalyzes the transfer of Sia from the host glycoconjugates to the terminal beta-galactopyranosyl residues of mucin-like molecules present on the parasite's cell surface. Alternatively, the enzyme can sialylate/re-sialylate glycoconjugates expressed on the surface of host cells. Since its discovery, several studies have shown that T. cruzi employs the Tc-TS activity to modulate the host cell sialoglycophenotype, thus favoring its perpetuation in the infected vertebrate. In this review, we summarize the dynamic of host/parasite sialoglycophenotype modulation, highlighting its role in the subversion of host immune response in order to promote the establishment of persistent chronic infection. PMID- 27242723 TI - Segregation of the Anodic Microbial Communities in a Microbial Fuel Cell Cascade. AB - Metabolic interactions within microbial communities are essential for the efficient degradation of complex organic compounds, and underpin natural phenomena driven by microorganisms, such as the recycling of carbon-, nitrogen-, and sulfur-containing molecules. These metabolic interactions ultimately determine the function, activity and stability of the community, and therefore their understanding would be essential to steer processes where microbial communities are involved. This is exploited in the design of microbial fuel cells (MFCs), bioelectrochemical devices that convert the chemical energy present in substrates into electrical energy through the metabolic activity of microorganisms, either single species or communities. In this work, we analyzed the evolution of the microbial community structure in a cascade of MFCs inoculated with an anaerobic microbial community and continuously fed with a complex medium. The analysis of the composition of the anodic communities revealed the establishment of different communities in the anodes of the hydraulically connected MFCs, with a decrease in the abundance of fermentative taxa and a concurrent increase in respiratory taxa along the cascade. The analysis of the metabolites in the anodic suspension showed a metabolic shift between the first and last MFC, confirming the segregation of the anodic communities. Those results suggest a metabolic interaction mechanism between the predominant fermentative bacteria at the first stages of the cascade and the anaerobic respiratory electrogenic population in the latter stages, which is reflected in the observed increase in power output. We show that our experimental system represents an ideal platform for optimization of processes where the degradation of complex substrates is involved, as well as a potential tool for the study of metabolic interactions in complex microbial communities. PMID- 27242724 TI - Induction of Subacute Ruminal Acidosis Affects the Ruminal Microbiome and Epithelium. AB - Subacute ruminal acidosis (SARA) negatively impacts the dairy industry by decreasing dry matter intake, milk production, profitability, and increasing culling rate and death loss. Six ruminally cannulated, lactating Holstein cows were used in a replicated incomplete Latin square design to determine the effects of SARA induction on the ruminal microbiome and epithelium. Experimental periods were 10 days with days 1-3 for ad libitum intake of control diet, followed by 50% feed restriction on day 4, and ad libitum access on day 5 to the basal diet or the basal diet with an additional 10% of a 50:50 wheat/barley pellet. Based on subsequent ruminal pH, cows were grouped (SARA grouping; SG) as Non-SARA or SARA based on time <5.6 pH (0 and 3.4 h, respectively). Ruminal samples were collected on days 1 and 6 of each period prior to feeding and separated into liquid and solid fractions. Microbial DNA was extracted for bacterial analysis using 16S rRNA gene paired-end sequencing on the MiSeq Illumina platform and quantitative PCR (qPCR). Ruminal epithelium biopsies were taken on days 1 and 6 before feeding. Quantitative RT-PCR was used to determine gene expression in rumen epithelium. Bray-Curtis similarity indicated samples within the liquid fraction separated by day and coincided with an increased relative abundance of genera Prevotella, Ruminococcus, Streptococcus, and Lactobacillus on day 6 (P < 0.06). Although Firmicutes was the predominant phyla in the solid fraction, a SG * day interaction (P < 0.01) indicated a decrease on day 6 for SARA cows. In contrast, phylum Bacteroidetes increased on day 6 (P < 0.01) for SARA cows driven by greater genera Prevotella and YRC22 (P < 0.01). Streptococcus bovis and Succinivibrio dextrinosolvens populations tended to increase on day 6 but were not affected by SG. In ruminal epithelium, CLDN1 and CLDN4 expression increased on day 6 (P < 0.03) 24 h after SARA induction and a tendency for a SG * day interaction (P < 0.10) was observed for CLDN4. Overall, results indicate more rapid adaptation to an induced bout of SARA in the solid fraction ruminal microbiome compared with ruminal epithelium. PMID- 27242725 TI - Unearthing the Ecology of Soil Microorganisms Using a High Resolution DNA-SIP Approach to Explore Cellulose and Xylose Metabolism in Soil. AB - We explored microbial contributions to decomposition using a sophisticated approach to DNA Stable Isotope Probing (SIP). Our experiment evaluated the dynamics and ecological characteristics of functionally defined microbial groups that metabolize labile and structural C in soils. We added to soil a complex amendment representing plant derived organic matter substituted with either (13)C xylose or (13)C-cellulose to represent labile and structural C pools derived from abundant components of plant biomass. We found evidence for (13)C-incorporation into DNA from (13)C-xylose and (13)C-cellulose in 49 and 63 operational taxonomic units (OTUs), respectively. The types of microorganisms that assimilated (13)C in the (13)C-xylose treatment changed over time being predominantly Firmicutes at day 1 followed by Bacteroidetes at day 3 and then Actinobacteria at day 7. These (13)C-labeling dynamics suggest labile C traveled through different trophic levels. In contrast, microorganisms generally metabolized cellulose-C after 14 days and did not change to the same extent in phylogenetic composition over time. Microorganisms that metabolized cellulose-C belonged to poorly characterized but cosmopolitan soil lineages including Verrucomicrobia, Chloroflexi, and Planctomycetes. PMID- 27242726 TI - Evasion and Immuno-Endocrine Regulation in Parasite Infection: Two Sides of the Same Coin in Chagas Disease? AB - Chagas disease is a serious illness caused by the protozoan parasite Trypanosoma cruzi. Nearly 30% of chronically infected people develop cardiac, digestive, or mixed alterations, suggesting a broad range of host-parasite interactions that finally impact upon chronic disease outcome. The ability of T. cruzi to persist and cause pathology seems to depend on diverse factors like T. cruzi strains, the infective load and the route of infection, presence of virulence factors, the parasite capacity to avoid protective immune response, the strength and type of host defense mechanisms and the genetic background of the host. The host-parasite interaction is subject to a constant neuro-endocrine regulation that is thought to influence the adaptive immune system, and as the infection proceeds it can lead to a broad range of outcomes, ranging from pathogen elimination to its continued persistence in the host. In this context, T. cruzi evasion strategies and host defense mechanisms can be envisioned as two sides of the same coin, influencing parasite persistence and different outcomes observed in Chagas disease. Understanding how T. cruzi evade host's innate and adaptive immune response will provide important clues to better dissect mechanisms underlying the pathophysiology of Chagas disease. PMID- 27242727 TI - Activation of Immune and Defense Responses in the Intestinal Mucosa by Outer Membrane Vesicles of Commensal and Probiotic Escherichia coli Strains. AB - The influence of microbiota in human health is well-known. Imbalances in microbiome structure have been linked to several diseases. Modulation of microbiota composition through probiotic therapy is an attempt to harness the beneficial effects of commensal microbiota. Although, there is wide knowledge of the responses induced by gut microbiota, the microbial factors that mediate these effects are not well-known. Gram-negative bacteria release outer membrane vesicles (OMVs) as a secretion mechanism of microbial factors, which have an important role in intercellular communication. Here, we investigated whether OMVs from the probiotic Escherichia coli strain Nissle 1917 (EcN) or the commensal E. coli strain ECOR12 trigger immune responses in various cellular models: (i) peripheral blood mononuclear cells (PBMCs) as a model of intestinal barrier disruption, (ii) apical stimulation of Caco-2/PMBCs co-culture as a model of intact intestinal mucosa, and (iii) colonic mucosa explants as an ex vivo model. Stimulations with bacterial lysates were also performed. Whereas, both OMVs and lysates activated expression and secretion of several cytokines and chemokines in PBMCs, only OMVs induced basolateral secretion and mRNA upregulation of these mediators in the co-culture model. We provide evidence that OMVs are internalized in polarized Caco-2 cells. The activated epithelial cells elicit a response in the underlying immunocompetent cells. The OMVs effects were corroborated in the ex vivo model. This experimental study shows that OMVs are an effective strategy used by beneficial gut bacteria to communicate with and modulate host responses, activating signaling events through the intestinal epithelial barrier. PMID- 27242728 TI - Bacterial Cell-Cell Communication in the Host via RRNPP Peptide-Binding Regulators. AB - Human microbiomes are composed of complex and dense bacterial consortia. In these environments, bacteria are able to react quickly to change by coordinating their gene expression at the population level via small signaling molecules. In Gram positive bacteria, cell-cell communication is mostly mediated by peptides that are released into the extracellular environment. Cell-cell communication based on these peptides is especially widespread in the group Firmicutes, in which they regulate a wide array of biological processes, including functions related to host-microbe interactions. Among the different agents of communication, the RRNPP family of cytoplasmic transcriptional regulators, together with their cognate re internalized signaling peptides, represents a group of emerging importance. RRNPP members that have been studied so far are found mainly in species of bacilli, streptococci, and enterococci. These bacteria are characterized as both human commensal and pathogenic, and share different niches in the human body with other microorganisms. The goal of this mini-review is to present the current state of research on the biological relevance of RRNPP mechanisms in the context of the host, highlighting their specific roles in commensalism or virulence. PMID- 27242729 TI - High Level Secretion of Laccase (LccH) from a Newly Isolated White-Rot Basidiomycete, Hexagonia hirta MSF2. AB - Newer and novel laccases attract considerable attention due to its promising and valuable multiple applications in biotech industry. This present investigation documents, for the first time, on high level extracellular secretion of laccase (LccH) in newly isolated wood-degrading basidiomycete Hexagonia hirta MSF2. LccH was optimally active at 40 degrees C in citrate phosphate buffer with a pH of 3.4. Optimized Cu(2+) in glucose yeast extract (GY) medium enhanced the LccH production by H. hirta to 1944.44 U.ml(-1). A further increment in LccH activity of 5671.30 U.ml(-1) was achieved by the addition of a phenolic inducer, 2,5 Xylidine. Zymogram and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis of LccH revealed that LccH is a monomer with a molecular mass of 66 kDa. MALDI-TOF-MS based peptide mass fingerprinting and comparative modeling of the amino acid sequence of LccH showed that it was closer to Trametes sp. AH28-2 (PDB: 3KW7) with 48% identity, 95% coverage, 0.011 alignment score and RMSD of 0.497A. Crude LccH delignified lignocellulosic biomass such as wood and corncob, to a level of 28.6 and 16.5%, respectively. Such high level secretion, thermal and solvent stability of LccH make H. hirta a potential candidate not only for LccH production and biodelignification but also generation of lignin derived aromatic feed stock chemicals for industrial and environmental applications. PMID- 27242730 TI - De novo Transcriptome Analysis of Rhizoctonia solani AG1 IA Strain Early Invasion in Zoysia japonica Root. AB - Zoysia japonica brown spot was caused by necrotrophic fungus Rhizoctonia solani invasion, which led to severe financial loss in city lawn and golf ground maintenance. However, little was known about the molecular mechanism of R. solani pathogenicity in Z. japonica. In this study we examined early stage interaction between R. solani AG1 IA strain and Z. japonica cultivar "Zenith" root by cell ultra-structure analysis, pathogenesis-related proteins assay and transcriptome analysis to explore molecular clues for AG1 IA strain pathogenicity in Z. japonica. No obvious cell structure damage was found in infected roots and most pathogenesis-related protein activities showedg a downward trend especially in 36 h post inoculation, which exhibits AG1 IA strain stealthy invasion characteristic. According to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) database classification, most DEGs in infected "Zenith" roots dynamically changed especially in three aspects, signal transduction, gene translation, and protein synthesis. Total 3422 unigenes of "Zenith" root were predicted into 14 kinds of resistance (R) gene class. Potential fungal resistance related unigenes of "Zenith" root were involved in ligin biosynthesis, phytoalexin synthesis, oxidative burst, wax biosynthesis, while two down regulated unigenes encoding leucine-rich repeat receptor protein kinase and subtilisin-like protease might be important for host-derived signal perception to AG1 IA strain invasion. According to Pathogen Host Interaction (PHI) database annotation, 1508 unigenes of AG1 IA strain were predicted and classified into 37 known pathogen species, in addition, unigenes encoding virulence, signaling, host stress tolerance, and potential effector were also predicted. This research uncovered transcriptional profiling during the early phase interaction between R. solani AG1 IA strain and Z. japonica, and will greatly help identify key pathogenicity of AG1 IA strain. PMID- 27242731 TI - Studying the Mechanism of Plasmopara viticola RxLR Effectors on Suppressing Plant Immunity. AB - The RxLR effector family, produced by oomycete pathogens, may manipulate host physiological and biochemical events inside host cells. A group of putative RxLR effectors from Plasmopara viticola have been recently identified by RNA-Seq analysis in our lab. However, their roles in pathogenesis are poorly understood. In this study, we attempted to characterize 23 PvRxLR effector candidates identified from a P. viticola isolate "ZJ-1-1." During host infection stages, expression patterns of the effector genes were varied and could be categorized into four different groups. By using transient expression assays in Nicotiana benthamiana, we found that 17 of these effector candidates fully suppressed programmed cell death elicited by a range of cell death-inducing proteins, including BAX, INF1, PsCRN63, PsojNIP, PvRxLR16 and R3a/Avr3a. We also discovered that all these PvRxLRs could target the plant cell nucleus, except for PvRxLR55 that localized to the membrane. Furthermore, we identified a single effector, PvRxLR28, that showed the highest expression level at 6 hpi. Functional analysis revealed that PvRxLR28 could significantly enhance susceptibilities of grapevine and tobacco to pathogens. These results suggest that most P. viticola effectors tested in this study may act as broad suppressors of cell death to manipulate immunity in plant. PMID- 27242732 TI - Organic Nitrogen-Driven Stimulation of Arbuscular Mycorrhizal Fungal Hyphae Correlates with Abundance of Ammonia Oxidizers. AB - Large fraction of mineral nutrients in natural soil environments is recycled from complex and heterogeneously distributed organic sources. These sources are explored by both roots and associated mycorrhizal fungi. However, the mechanisms behind the responses of arbuscular mycorrhizal (AM) hyphal networks to soil organic patches of different qualities remain little understood. Therefore, we conducted a multiple-choice experiment examining hyphal responses to different soil patches within the root-free zone by two AM fungal species (Rhizophagus irregularis and Claroideoglomus claroideum) associated with Medicago truncatula, a legume forming nitrogen-fixing root nodules. Hyphal colonization of the patches was assessed microscopically and by quantitative real-time PCR (qPCR) using AM taxon-specific markers, and the prokaryotic and fungal communities in the patches (pooled per organic amendment treatment) were profiled by 454-amplicon sequencing. Specific qPCR markers were then designed and used to quantify the abundance of prokaryotic taxa showing the strongest correlation with the pattern of AM hyphal proliferation in the organic patches as per the 454-sequencing. The hyphal density of both AM fungi increased due to nitrogen (N)-containing organic amendments (i.e., chitin, DNA, albumin, and clover biomass), while no responses as compared to the non-amended soil patch were recorded for cellulose, phytate, or inorganic phosphate amendments. Abundances of several prokaryotes, including Nitrosospira sp. (an ammonium oxidizer) and an unknown prokaryote with affiliation to Acanthamoeba endosymbiont, which were frequently recorded in the 454-sequencing profiles, correlated positively with the hyphal responses of R. irregularis to the soil amendments. Strong correlation between abundance of these two prokaryotes and the hyphal responses to organic soil amendments by both AM fungi was then confirmed by qPCR analyses using all individual replicate patch samples. Further research is warranted to ascertain the causality of these correlations and particularly which direct roles (if any) do these prokaryotes play in the observed AM hyphal responses to organic N amendment, organic N utilization by the AM fungus and its (N-unlimited) host plant. Further, possible trophic dependencies between the different players in the AM hyphosphere needs to be elucidated upon decomposing the organic N sources. PMID- 27242733 TI - Tracking Strains in the Microbiome: Insights from Metagenomics and Models. AB - Transmission usually refers to the movement of pathogenic organisms. Yet, commensal microbes that inhabit the human body also move between individuals and environments. Surprisingly little is known about the transmission of these endogenous microbes, despite increasing realizations of their importance for human health. The health impacts arising from the transmission of commensal bacteria range widely, from the prevention of autoimmune disorders to the spread of antibiotic resistance genes. Despite this importance, there are outstanding basic questions: what is the fraction of the microbiome that is transmissible? What are the primary mechanisms of transmission? Which organisms are the most highly transmissible? Higher resolution genomic data is required to accurately link microbial sources (such as environmental reservoirs or other individuals) with sinks (such as a single person's microbiome). New computational advances enable strain-level resolution of organisms from shotgun metagenomic data, allowing the transmission of strains to be followed over time and after discrete exposure events. Here, we highlight the latest techniques that reveal strain level resolution from raw metagenomic reads and new studies that are tracking strains across people and environments. We also propose how models of pathogenic transmission may be applied to study the movement of commensals between microbial communities. PMID- 27242734 TI - The Common Gut Microbe Eubacterium hallii also Contributes to Intestinal Propionate Formation. AB - Eubacterium hallii is considered an important microbe in regard to intestinal metabolic balance due to its ability to utilize glucose and the fermentation intermediates acetate and lactate, to form butyrate and hydrogen. Recently, we observed that E. hallii is capable of metabolizing glycerol to 3 hydroxypropionaldehyde (3-HPA, reuterin) with reported antimicrobial properties. The key enzyme for glycerol to 3-HPA conversion is the cobalamin-dependent glycerol/diol dehydratase PduCDE which also utilizes 1,2-propanediol (1,2-PD) to form propionate. Therefore our primary goal was to investigate glycerol to 3-HPA metabolism and 1,2-PD utilization by E. hallii along with its ability to produce cobalamin. We also investigated the relative abundance of E. hallii in stool of adults using 16S rRNA and pduCDE based gene screening to determine the contribution of E. hallii to intestinal propionate formation. We found that E. hallii utilizes glycerol to produce up to 9 mM 3-HPA but did not further metabolize 3-HPA to 1,3-propanediol. Utilization of 1,2-PD in the presence and absence of glucose led to the formation of propanal, propanol and propionate. E. hallii formed cobalamin and was detected in stool of 74% of adults using 16S rRNA gene as marker gene (n = 325). Relative abundance of the E. hallii 16S rRNA gene ranged from 0 to 0.59% with a mean relative abundance of 0.044%. E. hallii PduCDE was detected in 63 to 81% of the metagenomes depending on which subunit was investigated beside other taxons such as Ruminococcus obeum, R. gnavus, Flavonifractor plautii, Intestinimonas butyriciproducens, and Veillonella spp. In conclusion, we identified E. hallii as a common gut microbe with the ability to convert glycerol to 3-HPA, a step that requires the production of cobalamin, and to utilize 1,2-PD to form propionate. Our results along with its ability to use a broad range of substrates point at E. hallii as a key species within the intestinal trophic chain with the potential to highly impact the metabolic balance as well as the gut microbiota/host homeostasis by the formation of different short chain fatty acids. PMID- 27242735 TI - Biological Control of Lettuce Drop and Host Plant Colonization by Rhizospheric and Endophytic Streptomycetes. AB - Lettuce drop, caused by the soil borne pathogen Sclerotinia sclerotiorum, is one of the most common and serious diseases of lettuce worldwide. Increased concerns about the side effects of chemical pesticides have resulted in greater interest in developing biocontrol strategies against S. sclerotiorum. However, relatively little is known about the mechanisms of Streptomyces spp. as biological control agents against S. sclerotiorum on lettuce. Two Streptomyces isolates, S. exfoliatus FT05W and S. cyaneus ZEA17I, inhibit mycelial growth of Sclerotinia sclerotiorum by more than 75% in vitro. We evaluated their biocontrol activity against S. sclerotiorum in vivo, and compared them to Streptomyces lydicus WYEC 108, isolated from Actinovate(r). When Streptomyces spp. (10(6) CFU/mL) were applied to S. sclerotiorum inoculated substrate in a growth chamber 1 week prior lettuce sowing, they significantly reduced the risk of lettuce drop disease, compared to the inoculated control. Interestingly, under field conditions, S. exfoliatus FT05W and S. cyaneus ZEA17I protected lettuce from drop by 40 and 10% respectively, whereas S. lydicus WYEC 108 did not show any protection. We further labeled S. exfoliatus FT05W and S. cyaneus ZEA17I with the enhanced GFP (EGFP) marker to investigate their rhizosphere competence and ability to colonize lettuce roots using confocal laser scanning microscopy (CLSM). The abundant colonization of young lettuce seedlings by both strains demonstrated Streptomyces' capability to interact with the host from early stages of seed germination and root development. Moreover, the two strains were detected also on 2-week-old roots, indicating their potential of long-term interactions with lettuce. Additionally, scanning electron microscopy (SEM) observations showed EGFP-S. exfoliatus FT05W endophytic colonization of lettuce root cortex tissues. Finally, we determined its viability and persistence in the rhizosphere and endorhiza up to 3 weeks by quantifying its concentration in these compartments. Based on these results we conclude that S. exfoliatus FT05W has high potential to be exploited in agriculture for managing soil borne diseases barely controlled by available plant protection products. PMID- 27242737 TI - High Primary Production Contrasts with Intense Carbon Emission in a Eutrophic Tropical Reservoir. AB - Recent studies from temperate lakes indicate that eutrophic systems tend to emit less carbon dioxide (CO2) and bury more organic carbon (OC) than oligotrophic ones, rendering them CO2 sinks in some cases. However, the scarcity of data from tropical systems is critical for a complete understanding of the interplay between eutrophication and aquatic carbon (C) fluxes in warm waters. We test the hypothesis that a warm eutrophic system is a source of both CO2 and CH4 to the atmosphere, and that atmospheric emissions are larger than the burial of OC in sediments. This hypothesis was based on the following assumptions: (i) OC mineralization rates are high in warm water systems, so that water column CO2 production overrides the high C uptake by primary producers, and (ii) increasing trophic status creates favorable conditions for CH4 production. We measured water air and sediment-water CO2 fluxes, CH4 diffusion, ebullition and oxidation, net ecosystem production (NEP) and sediment OC burial during the dry season in a eutrophic reservoir in the semiarid northeastern Brazil. The reservoir was stratified during daytime and mixed during nighttime. In spite of the high rates of primary production (4858 +/- 934 mg C m(-2) d(-1)), net heterotrophy was prevalent due to high ecosystem respiration (5209 +/- 992 mg C m(-2) d(-1)). Consequently, the reservoir was a source of atmospheric CO2 (518 +/- 182 mg C m( 2) d(-1)). In addition, the reservoir was a source of ebullitive (17 +/- 10 mg C m(-2) d(-1)) and diffusive CH4 (11 +/- 6 mg C m(-2) d(-1)). OC sedimentation was high (1162 mg C m(-2) d(-1)), but our results suggest that the majority of it is mineralized to CO2 (722 +/- 182 mg C m(-2) d(-1)) rather than buried as OC (440 mg C m(-2) d(-1)). Although temporally resolved data would render our findings more conclusive, our results suggest that despite being a primary production and OC burial hotspot, the tropical eutrophic system studied here was a stronger CO2 and CH4 source than a C sink, mainly because of high rates of OC mineralization in the water column and sediments. PMID- 27242736 TI - Bioactive Molecules Released From Cells Infected with the Human Cytomegalovirus. AB - Following primary infection in humans, the human cytomegalovirus (HCMV) persists in a latent state throughout the host's lifetime despite a strong and efficient immune response. If the host experiences some form of immune dysregulation, such as immunosuppression or immunodeficiency, HCMV reactivates, thereby emerging from latency. Thus, in the absence of effective functional immune responses, as occurs in immunocompromised or immunoimmature individuals, both HCMV primary infections and reactivations from latency can cause significant morbidity and mortality. However, even in immunocompetent hosts, HCMV represents a relevant risk factor for the development of several chronic inflammatory diseases and certain forms of neoplasia. HCMV infection may shift between the lytic and latent state, regulated by a delicate and intricate balance between virus-mediated immunomodulation and host immune defenses. Indeed, HCMV is a master in manipulating innate and adaptive host defense pathways, and a large portion of its genome is devoted to encoding immunomodulatory proteins; such proteins may thus represent important virulence determinants. However, the pathogenesis of HCMV-related diseases is strengthened by the activities of bioactive molecules, of both viral and cellular origin, that are secreted from infected cells and collectively named as the secretome. Here, we review the state of knowledge on the composition and functions of HCMV-derived secretomes. In lytic infections of fibroblasts and different types of endothelial cells, the majority of HCMV-induced secreted proteins act in a paracrine fashion to stimulate the generation of an inflammatory microenvironment around infected cells; this may lead to vascular inflammation and angiogenesis that, in turn, foster HCMV replication and its dissemination through host tissues. Conversely, the HCMV secretome derived from latently infected hematopoietic progenitor cells induces an immunosuppressive extracellular environment that interferes with immune recognition and elimination of latently infected cells, thereby promoting viral persistence. Characterization of the composition and biological activities of HCMV secretomes from different types of infected cells will lay the foundation for future advances in our knowledge about the pathogenesis HCMV diseases and may provide targets for the development of novel antiviral intervention strategies. PMID- 27242738 TI - Probiotic Bacillus cereus Strains, a Potential Risk for Public Health in China. AB - Bacillus cereus is an important cause of foodborne infectious disease and food poisoning. However, B. cereus has also been used as a probiotic in human medicine and livestock production, with low standards of safety assessment. In this study, we evaluated the safety of 15 commercial probiotic B. cereus preparations from China in terms of mislabeling, toxin production, and transferable antimicrobial resistance. Most preparations were incorrectly labeled, as they contained additional bacterial species; one product did not contain viable B. cereus at all. In total, 18 B. cereus group strains-specifically B. cereus and Bacillus thuringiensis-were isolated. Enterotoxin genes nhe, hbl, and cytK1, as well as the ces-gene were assessed by PCR. Enterotoxin production and cytotoxicity were confirmed by ELISA and cell culture assays, respectively. All isolated B. cereus group strains produced the enterotoxin Nhe; 15 strains additionally produced Hbl. Antimicrobial resistance was assessed by microdilution; resistance genes were detected by PCR and further characterized by sequencing, transformation and conjugation assays. Nearly half of the strains harbored the antimicrobial resistance gene tet(45). In one strain, tet(45) was situated on a mobile genetic element-encoding a site-specific recombination mechanism-and was transferable to Staphylococcus aureus and Bacillus subtilis by electro-transformation. In view of the wide and uncontrolled use of these products, stricter regulations for safety assessment, including determination of virulence factors and transferable antimicrobial resistance genes, are urgently needed. PMID- 27242739 TI - Mycobacterium tuberculosis Co-operonic PE32/PPE65 Proteins Alter Host Immune Responses by Hampering Th1 Response. AB - PE/PPE genes, present in cluster with ESAT-6 like genes, are suspected to have a role in antigenic variation and virulence of Mycobacterium tuberculosis. Their roles in immune evasion and immune modulation of host are also well documented. We present evidence that PE32/PPE65 present within the RD8 region are co operonic, co-transcribed, and co-translated, and play role in modulating host immune responses. Experiments with macrophage cell lines revealed that this protein complex suppresses pro-inflammatory cytokines such as TNF-alpha and IL-6 whereas also inducing high expression of anti-inflammatory IL-10. Immunization of mice with these recombinant proteins dampens an effective Th1 response as evident from reduced frequency of IFN-gamma and IL-2 producing CD4(+) and CD8(+) T cells. IgG sub-typing from serum of immunized mice revealed high levels of IgG1 when compared with IgG2a and IgG2b. Further IgG1/IgG2a ratio clearly demonstrated that the protein complex manipulates the host immune response favorable to the pathogen. Our results demonstrate that the co-transcribed and co-translated PE32 and PPE65 antigens are involved specifically in modulating anti-mycobacterial host immune response by hampering Th1 response. PMID- 27242740 TI - Dual Identification and Analysis of Differentially Expressed Transcripts of Porcine PK-15 Cells and Toxoplasma gondii during in vitro Infection. AB - Toxoplasma gondii is responsible for causing toxoplasmosis, one of the most prevalent zoonotic parasitoses worldwide. The mechanisms that mediate T. gondii infection of pigs (the most common source of human infection) and renal tissues are still unknown. To identify the critical alterations that take place in the transcriptome of both porcine kidney (PK-15) cells and T. gondii following infection, infected cell samples were collected at 1, 3, 6, 9, 12, 18, and 24 h post infection and RNA-Seq data were acquired using Illumina Deep Sequencing. Differential Expression of Genes (DEGs) analysis was performed to study the concomitant gene-specific temporal patterns of induction of mRNA expression of PK 15 cells and T. gondii. High sequence coverage enabled us to thoroughly characterize T. gondii transcriptome and identify the activated molecular pathways in host cells. More than 6G clean bases/sample, including >40 million clean reads were obtained. These were aligned to the reference genome of T. gondii and wild boar (Sus scrofa). DEGs involved in metabolic activities of T. gondii showed time-dependent down-regulation. However, DEGs involved in immune or disease related pathways of PK-15 cells peaked at 6 h PI, and were highly enriched as evidenced by KEGG analysis. Protein-protein interaction analysis revealed that TGME49_120110 (PCNA), TGME49_049180 (DHFR-TS), TGME49_055320, and TGME49_002300 (ITPase) are the four hub genes with most interactions with T. gondii at the onset of infection. These results reveal altered profiles of gene expressed by PK-15 cells and T. gondii during infection and provide the groundwork for future virulence studies to uncover the mechanisms of T. gondii interaction with porcine renal tissue by functional analysis of these DEGs. PMID- 27242741 TI - In situ Dynamics of O2, pH, Light, and Photosynthesis in Ikaite Tufa Columns (Ikka Fjord, Greenland)-A Unique Microbial Habitat. AB - The Ikka Fjord (SW Greenland) harbors a unique microbial habitat in the form of several hundred submarine tufa columns composed of ikaite, a special hexahydrate form of calcium carbonate that precipitates when alkaline phosphate- and carbonate-enriched spring water seeping out of the sea floor meets cold seawater. While several unique heterotrophic microbes have been isolated from the tufa columns, the microbial activity, and the boundary conditions for microbial growth in ikaite have remained unexplored. We present the first detailed in situ characterization of the physico-chemical microenvironment and activity of oxygenic phototrophs thriving within the ikaite columns. In situ underwater microsensor measurements of pH, temperature, and irradiance in the porous ikaite crystal matrix, revealed an extreme microenvironment characterized by low temperatures, strong light attenuation, and gradients of pH changing from pH 9 at the outer column surface to above pH 10 over the first 1-2 cm of the ikaite. This outer layer of the freshly deposited ikaite matrix contained densely pigmented yellow and green zones harboring a diverse phototrophic community dominated by diatoms and cyanobacteria, respectively, as shown by amplicon sequencing. In situ O2 measurements, as well as underwater variable chlorophyll fluorescence measurements of photosynthetic activity, demonstrated high levels of oxygenic photosynthesis in this extreme gradient environment with strong irradiance-driven O2 dynamics ranging from anoxia to hyperoxic conditions in the ikaite matrix, albeit the local formation of gas bubbles buffered the day-night dynamics of O2 in the tufa columns. The microbial phototrophs in the ikaite matrix are embedded in exopolymers forming endolithic biofilms that may interact with mineral formation and cementing of ikaite crystals. PMID- 27242742 TI - Polyphosphate Kinase Mediates Antibiotic Tolerance in Extraintestinal Pathogenic Escherichia coli PCN033. AB - Extraintestinal pathogenic Escherichia coli (ExPEC) causes a variety of acute infections in its hosts, and multidrug-resistant strains present significant challenges to public health and animal husbandry. Therefore, it is necessary to explore new drug targets to control E. coli epidemics. Previous studies have reported that ppk mutants of Burkholderia pseudomallei and Mycobacterium tuberculosis are more susceptible than the wild types (WTs) to stress. Therefore, we investigated the stress response to antibiotics mediated by polyphosphate kinase (PPK) in ExPEC strain PCN033. We observed that planktonic cells of a ppk knockout strain (Deltappk) were more susceptible to antibiotics than was WT. However, biofilm-grown Deltappk cells showed similar susceptibility to that of the WT and were more tolerant than the planktonic cells. During the planktonic lifestyle, the expression of genes involved in antibiotic tolerance (including resistance-conferring genes, and antibiotic influx, and efflux genes) did not change in the Deltappk mutant without antibiotic treatment. However, the resistance-conferring gene bla and efflux genes were upregulated more in the WT than in the Deltappk mutant by treatment with tazobactam. After treatment with gentamycin, the efflux genes and influx genes were upregulated and downregulated, respectively, more in the WT than in the Deltappk mutant. The expression of genes involved in biofilm regulation also changed after treatment with tazobactam or gentamycin, and which is consistent with the results of the biofilm formation. Together, these observations indicate that PPK is important for the antibiotic stress response during the planktonic growth of ExPEC and might be a potential drug target in bacteria. PMID- 27242744 TI - The Resistance of Vibrio cholerae O1 El Tor Strains to the Typing Phage 919TP, a Member of K139 Phage Family. AB - Bacteriophage 919TP is a temperate phage of Vibrio cholerae serogroup O1 El Tor and is used as a subtyping phage in the phage-biotyping scheme in cholera surveillance in China. In this study, sequencing of the 919TP genome showed that it belonged to the Vibrio phage K139 family. The mechanisms conferring resistance to 919TP infection of El Tor strains were explored to help understand the subtyping basis of phage 919TP and mutations related to 919TP resistance. Among the test strains resistant to phage 919TP, most contained the temperate 919TP phage genome, which facilitated superinfection exclusion to 919TP. Our data suggested that this immunity to Vibrio phage 919TP occurred after absorption of the phage onto the bacteria. Other strains contained LPS receptor synthesis gene mutations that disable adsorption of phage 919TP. Several strains resistant to 919TP infection possessed unknown resistance mechanisms, since they did not contain LPS receptor mutations or temperate K139 phage genome. Further research is required to elucidate the phage infection steps involved in the resistance of these strains to phage infection. PMID- 27242743 TI - Cyanide Toxicity to Burkholderia cenocepacia Is Modulated by Polymicrobial Communities and Environmental Factors. AB - Microbes within polymicrobial communities can establish positive and negative interactions that have the potential to influence the overall behavior of the community. Pseudomonas aeruginosa and species of the Burkholderia cepacia complex (Bcc) can co-exist in the lower airways, however several studies have shown that P. aeruginosa can effectively kill the Bcc in vitro, for which hydrogen cyanide (HCN) was recently proposed to play a critical role. Here we show that modification of the environment (i.e., culture medium), long-term genetic adaptation of P. aeruginosa to the cystic fibrosis (CF) lung, or the addition of another bacterial species to the community can alter the sensitivity of Burkholderia cenocepacia to P. aeruginosa toxins. We specifically demonstrate that undefined rich media leads to higher susceptibility of B. cenocepacia to P. aeruginosa toxins like cyanide as compared to a synthetic medium (SCFM), that mimics the CF lung nutritional content. Overall, our study shows that the polymicrobial environment can have profound effects on negative interactions mediated by P. aeruginosa against B. cenocepacia. In fact, evolved P. aeruginosa or the presence of other species such as Staphylococcus aureus can directly abolish the direct competition mediated by cyanide and consequently maintaining a higher level of species diversity within the community. PMID- 27242745 TI - Editorial: Antifungal Drug Discovery: New Theories and New Therapies. PMID- 27242746 TI - Osmotic Stress Confers Enhanced Cell Integrity to Hydrostatic Pressure but Impairs Growth in Alcanivorax borkumensis SK2. AB - Alcanivorax is a hydrocarbonoclastic genus dominating oil spills worldwide. While its presence has been detected in oil-polluted seawaters, marine sediment and salt marshes under ambient pressure, its presence in deep-sea oil-contaminated environments is negligible. Recent laboratory studies highlighted the piezosensitive nature of some Alcanivorax species, whose growth yields are highly impacted by mild hydrostatic pressures (HPs). In the present study, osmotic stress was used as a tool to increase HP resistance in the type strain Alcanivorax borkumensis SK2. Control cultures grown under standard conditions of salinity and osmotic pressure with respect to seawater (35.6 ppt or 1136 mOsm kg( 1), respectively) were compared with cultures subjected to hypo- and hyperosmosis (330 and 1720 mOsm kg(-1), or 18 and 62 ppt in salinity, equivalent to brackish and brine waters, respectively), under atmospheric or increased HP (0.1 and 10 MPa). Osmotic stress had a remarkably positive impact on cell metabolic activity in terms of CO2 production (thus, oil bioremediation) and O2 respiration under hyperosmosis, as acclimation to high salinity enhanced cell activity under 10 MPa by a factor of 10. Both osmotic shocks significantly enhanced cell protection by reducing membrane damage under HP, with cell integrities close to 100% under hyposmosis. The latter was likely due to intracellular water-reclamation as no trace of the piezolyte ectoine was found, contrary to hyperosmosis. Notably, ectoine production was equivalent at 0.1 MPa in hyperosmosis-acclimated cells and at 10 MPa under isosmotic conditions. While stimulating cell metabolism and enhancing cell integrity, osmotic stress had always a negative impact on culture growth and performance. No net growth was observed during 4-days incubation tests, and CO2:O2 ratios and pH values indicated that culture performance in terms of hydrocarbon degradation was lowered by the effects of osmotic stress alone or combined with increased HP. These findings confirm the piezosensitive nature of A. borkumensis, which lacks proper resistance mechanisms to improve its metabolic efficiency under increased HP, thus explaining its limited role in oil polluted deep-sea environments. PMID- 27242747 TI - Experimental Warming Decreases the Average Size and Nucleic Acid Content of Marine Bacterial Communities. AB - Organism size reduction with increasing temperature has been suggested as a universal response to global warming. Since genome size is usually correlated to cell size, reduction of genome size in unicells could be a parallel outcome of warming at ecological and evolutionary time scales. In this study, the short-term response of cell size and nucleic acid content of coastal marine prokaryotic communities to temperature was studied over a full annual cycle at a NE Atlantic temperate site. We used flow cytometry and experimental warming incubations, spanning a 6 degrees C range, to analyze the hypothesized reduction with temperature in the size of the widespread flow cytometric bacterial groups of high and low nucleic acid content (HNA and LNA bacteria, respectively). Our results showed decreases in size in response to experimental warming, which were more marked in 0.8 MUm pre-filtered treatment rather than in the whole community treatment, thus excluding the role of protistan grazers in our findings. Interestingly, a significant effect of temperature on reducing the average nucleic acid content (NAC) of prokaryotic cells in the communities was also observed. Cell size and nucleic acid decrease with temperature were correlated, showing a common mean decrease of 0.4% per degrees C. The usually larger HNA bacteria consistently showed a greater reduction in cell and NAC compared with their LNA counterparts, especially during the spring phytoplankton bloom period associated to maximum bacterial growth rates in response to nutrient availability. Our results show that the already smallest planktonic microbes, yet with key roles in global biogeochemical cycling, are likely undergoing important structural shrinkage in response to rising temperatures. PMID- 27242748 TI - MAP Kinase Hog1 Regulates Metabolic Changes Induced by Hyperosmotic Stress. PMID- 27242749 TI - Comparative Resistance of Bacterial Foodborne Pathogens to Non-thermal Technologies for Food Preservation. AB - In this paper the resistance of bacterial foodborne pathogens to manosonication (MS), pulsed electric fields (PEFs), high hydrostatic pressure (HHP), and UV light (UV) is reviewed and compared. The influence of different factors on the resistance of bacterial foodborne pathogens to these technologies is also compared and discussed. Only results obtained under harmonized experimental conditions have been considered. This has allowed us to establish meaningful comparisons and draw significant conclusions. Among the six microorganisms here considered, Staphyloccocus aureus is the most resistant foodborne pathogen to MS and HHP and Listeria monocytogenes to UV. The target microorganism of PEF would change depending on the treatment medium pH. Thus, L. monocytogenes is the most PEF resistant microorganism at neutral pH but Gram-negatives (Escherichia coli, Salmonella spp., Cronobacter sakazakii, Campylobacter jejuni) would display a similar or even higher resistance at acidic pH. It should be noted that, in acidic products, the baroresistance of some E. coli strains would be comparable to that of S. aureus. The factors affecting the resistance of bacterial foodborne pathogens, as well as the magnitude of the effect, varied depending on the technology considered. Inter- and intra-specific differences in microbial resistance to PEF and HHP are much greater than to MS and UV. Similarly, both the pH and aw of the treatment medium highly condition microbial resistance to PEF and HHP but no to MS or UV. Growth phase also drastically affected bacterial HHP resistance. Regarding UV, the optical properties of the medium are, by far, the most influential factor affecting its lethal efficacy. Finally, increasing treatment temperature leads to a significant increase in lethality of the four technologies, what opens the possibility of the development of combined processes including heat. The appearance of sublethally damaged cells following PEF and HHP treatments could also be exploited in order to design combined processes. Further work would be required in order to fully elucidate the mechanisms of action of these technologies and to exhaustively characterize the influence of all the factors acting before, during, and after treatment. This would be very useful in the areas of process optimization and combined process design. PMID- 27242750 TI - Mutational Studies of Putative Biosynthetic Genes for the Cyanobacterial Sunscreen Scytonemin in Nostoc punctiforme ATCC 29133. AB - The heterocyclic indole-alkaloid scytonemin is a sunscreen found exclusively among cyanobacteria. An 18-gene cluster is responsible for scytonemin production in Nostoc punctiforme ATCC 29133. The upstream genes scyABCDEF in the cluster are proposed to be responsible for scytonemin biosynthesis from aromatic amino acid substrates. In vitro studies of ScyA, ScyB, and ScyC proved that these enzymes indeed catalyze initial pathway reactions. Here we characterize the role of ScyD, ScyE, and ScyF, which were logically predicted to be responsible for late biosynthetic steps, in the biological context of N. punctiforme. In-frame deletion mutants of each were constructed (DeltascyD, DeltascyE, and DeltascyF) and their phenotypes studied. Expectedly, DeltascyE presents a scytoneminless phenotype, but no accumulation of the predicted intermediaries. Surprisingly, DeltascyD retains scytonemin production, implying that it is not required for biosynthesis. Indeed, scyD presents an interesting evolutionary paradox: it likely originated in a duplication event from scyE, and unlike other genes in the operon, it has not been subjected to purifying selection. This would suggest that it is a pseudogene, and yet scyD is highly conserved in the scytonemin operon of cyanobacteria. DeltascyF also retains scytonemin production, albeit exhibiting a reduction of the production yield compared with the wild-type. This indicates that ScyF is not essential but may play an adjuvant role for scytonemin synthesis. Altogether, our findings suggest that these downstream genes are not responsible, as expected, for the late steps of scytonemin synthesis and we must look for those functions elsewhere. These findings are particularly important for biotechnological production of this sunscreen through heterologous expression of its genes in more tractable organisms. PMID- 27242751 TI - Chironomids' Relationship with Aeromonas Species. AB - Chironomids (Diptera: Chironomidae), also known as non-biting midges, are one of the most abundant groups of insects in aquatic habitats. They undergo a complete metamorphosis of four life stages of which three are aquatic (egg, larva, and pupa), and the adult emerges into the air. Chironomids serve as a natural reservoir of Aeromonas and Vibrio cholerae species. Here, we review existing knowledge about the mutual relations between Aeromonas species and chironomids. Using 454-pyrosequencing of the 16S rRNA gene, we found that the prevalence of Aeromonas species in the insects' egg masses and larvae was 1.6 and 3.3% of the insects' endogenous microbiota, respectively. Aeromonas abundance per egg mass remained stable during a 6-month period of bacterial monitoring. Different Aeromonas species were isolated and some demonstrated the ability to degrade the insect's egg masses and to prevent eggs hatching. Chitinase was identified as the enzyme responsible for the egg mass degradation. Different Aeromonas species isolated from chironomids demonstrated the potential to protect their host from toxic metals. Aeromonas is a causative agent of fish infections. Fish are frequently recorded as feeding on chironomids. Thus, fish might be infected with Aeromonas species via chironomid consumption. Aeromonas strains are also responsible for causing gastroenteritis and wound infections in humans. Different virulence genes were identified in Aeromonas species isolated from chironomids. Chironomids may infest drinking water reservoirs, hence be the source of pathogenic Aeromonas strains in drinking water. Chironomids and Aeromonas species have a complicated mutual relationship. PMID- 27242752 TI - A Terpene Synthase Is Involved in the Synthesis of the Volatile Organic Compound Sodorifen of Serratia plymuthica 4Rx13. AB - Bacteria release a plethora of volatile organic compounds, including compounds with extraordinary structures. Sodorifen (IUPAC name: 1,2,4,5,6,7,8-heptamethyl-3 methylenebicyclo[3.2.1]oct-6-ene) is a recently identified and unusual volatile hydrocarbon that is emitted by the rhizobacterium Serratia plymuthica 4R*13. Sodorifen comprises a bicyclic ring structure solely consisting of carbon and hydrogen atoms, where every carbon atom of the skeleton is substituted with either a methyl or a methylene group. This unusual feature of sodorifen made a prediction of its biosynthetic origin very difficult and so far its biosynthesis is unknown. To unravel the biosynthetic pathway we performed genome and transcriptome analyses to identify candidate genes. One knockout mutant (SOD_c20750) showed the desired negative sodorifen phenotype. Here it was shown for the first time that this gene is indispensable for the synthesis of sodorifen and strongly supports the hypothesis that sodorifen descends from the terpene metabolism. SOD_c20750 is the first bacterial terpene cyclase isolated from Serratia spp. and Enterobacteriales. Homology modeling revealed a 3D structure, which exhibits a functional role of amino acids for intermediate cation stabilization (W325) and putative proton acception (Y332). Moreover, the size and hydrophobicity of the active site strongly indicates that indeed the enzyme may catalyze the unusual compound sodorifen. PMID- 27242753 TI - Effect of Bifidobacterium upon Clostridium difficile Growth and Toxicity When Co cultured in Different Prebiotic Substrates. AB - The intestinal overgrowth of Clostridium difficile, often after disturbance of the gut microbiota by antibiotic treatment, leads to C. difficile infection (CDI) which manifestation ranges from mild diarrhea to life-threatening conditions. The increasing CDI incidence, not only in compromised subjects but also in traditionally considered low-risk populations, together with the frequent relapses of the disease, has attracted the interest for prevention/therapeutic options. Among these, probiotics, prebiotics, or synbiotics constitute a promising approach. In this study we determined the potential of selected Bifidobacterium strains for the inhibition of C. difficile growth and toxicity in different carbon sources. We conducted co-cultures of the toxigenic strain C. difficile LMG21717 with four Bifidobacterium strains (Bifidobacterium longum IPLA20022, Bifidobacterium breve IPLA20006, Bifidobacterium bifidum IPLA20015, and Bifidobacterium animalis subsp. lactis Bb12) in the presence of various prebiotic substrates (Inulin, Synergy, and Actilight) or glucose, and compared the results with those obtained for the corresponding mono-cultures. C. difficile and bifidobacteria levels were quantified by qPCR; the pH and the production of short chain fatty acids was also determined. Moreover, supernatants of the cultures were collected to evaluate their toxicity using a recently developed model. Results showed that co-culture with B. longum IPLA20022 and B. breve IPLA20006 in the presence of short-chain fructooligosaccharides, but not of Inulin, as carbon source significantly reduced the growth of the pathogen. With the sole exception of B. animalis Bb12, whose growth was enhanced, the presence of C. difficile did not show major effects upon the growth of the bifidobacteria. In accordance with the growth data, B. longum and B. breve were the strains showing higher reduction in the toxicity of the co-culture supernatants. PMID- 27242754 TI - Backup Expression of the PhaP2 Phasin Compensates for phaP1 Deletion in Herbaspirillum seropedicae, Maintaining Fitness and PHB Accumulation. AB - Phasins are important proteins controlling poly-3-hydroxybutyrate (PHB) granules formation, their number into the cell and stability. The genome sequencing of the endophytic and diazotrophic bacterium Herbaspirillum seropedicae SmR1 revealed two homologous phasin genes. To verify the role of the phasins on PHB accumulation in the parental strain H. seropedicae SmR1, isogenic strains defective in the expression of phaP1, phaP2 or both genes were obtained by gene deletion and characterized in this work. Despite of the high sequence similarity between PhaP1 and PhaP2, PhaP1 is the major phasin in H. seropedicae, since its deletion reduced PHB accumulation by ~50% in comparison to the parental and DeltaphaP2. Upon deletion of phaP1, the expression of phaP2 was sixfold enhanced in the DeltaphaP1 strain. The responsive backup expression of phaP2 partially rescued the DeltaphaP1 mutant, maintaining about 50% of the parental PHB level. The double mutant DeltaphaP1.2 did not accumulate PHB in any growth stage and showed a severe reduction of growth when glucose was the carbon source, a clear demonstration of negative impact in the fitness. The co-occurrence of phaP1 and phaP2 homologous in bacteria relatives of H. seropedicae, including other endophytes, indicates that the mechanism of phasin compensation by phaP2 expression may be operating in other organisms, showing that PHB metabolism is a key factor to adaptation and efficiency of endophytic bacteria. PMID- 27242755 TI - Chicken Anti-Campylobacter Vaccine - Comparison of Various Carriers and Routes of Immunization. AB - Campylobacter spp, especially the species Campylobacter jejuni, are important human enteropathogens responsible for millions of cases of gastro-intestinal disease worldwide every year. C. jejuni is a zoonotic pathogen, and poultry meat that has been contaminated by microorganisms is recognized as a key source of human infections. Although numerous strategies have been developed and experimentally checked to generate chicken vaccines, the results have so far had limited success. In this study, we explored the potential use of non-live carriers of Campylobacter antigen to combat Campylobacter in poultry. First, we assessed the effectiveness of immunization with orally or subcutaneously delivered Gram-positive Enhancer Matrix (GEM) particles carrying two Campylobacter antigens: CjaA and CjaD. These two immunization routes using GEMs as the vector did not protect against Campylobacter colonization. Thus, we next assessed the efficacy of in ovo immunization using various delivery systems: GEM particles and liposomes. The hybrid protein rCjaAD, which is CjaA presenting CjaD epitopes on its surface, was employed as a model antigen. We found that rCjaAD administered in ovo at embryonic development day 18 by both delivery systems resulted in significant levels of protection after challenge with a heterologous C. jejuni strain. In practice, in ovo chicken vaccination is used by the poultry industry to protect birds against several viral diseases. Our work showed that this means of delivery is also efficacious with respect to commensal bacteria such as Campylobacter. In this study, we evaluated the protection after one dose of vaccine given in ovo. We speculate that the level of protection may be increased by a post-hatch booster of orally delivered antigens. PMID- 27242756 TI - Trichoderma viride Laccase Plays a Crucial Role in Defense Mechanism against Antagonistic Organisms. AB - Fungal laccases are involved in a variety of physiological functions such as delignification, morphogenesis, and parasitism. In addition to these functions, we suggest that fungal laccases are involved in defense mechanisms. When the laccase secreting Trichoderma viride was grown in the presence of a range of microorganisms including bacteria and fungi, laccase secretion was enhanced in response to antagonistic organisms alone. In addition, growth of antagonistic microbes was restricted by the secreting fungi. Besides, our study for the first time shows the inability of the secreting fungi (T. viride) to compete with antagonistic organism when laccase activity is inhibited, further emphasizing its involvement in rendering a survival advantage to the secreting organism. When laccase inhibitor was added to the media, the zone of inhibition exerted by the antagonist organism was more pronounced and consequently growth of T. viride was significantly restricted. Based on these observations we accentuate that, laccase plays an important role in defense mechanism and provides endurance to the organism when encountered with an antagonistic organism in its surrounding. PMID- 27242757 TI - A Drug Combination Screen Identifies Drugs Active against Amoxicillin-Induced Round Bodies of In Vitro Borrelia burgdorferi Persisters from an FDA Drug Library. AB - Although currently recommended antibiotics for Lyme disease such as doxycycline or amoxicillin cure the majority of the patients, about 10-20% of patients treated for Lyme disease may experience lingering symptoms including fatigue, pain, or joint and muscle aches. Under experimental stress conditions such as starvation or antibiotic exposure, Borrelia burgdorferi can develop round body forms, which are a type of persister bacteria that appear resistant in vitro to customary first-line antibiotics for Lyme disease. To identify more effective drugs with activity against the round body form of B. burgdorferi, we established a round body persister model induced by exposure to amoxicillin (50 MUg/ml) and then screened the Food and Drug Administration drug library consisting of 1581 drug compounds and also 22 drug combinations using the SYBR Green I/propidium iodide viability assay. We identified 23 drug candidates that have higher activity against the round bodies of B. burgdorferi than either amoxicillin or doxycycline. Eleven individual drugs scored better than metronidazole and tinidazole which have been previously described to be active against round bodies. In this amoxicillin-induced round body model, some drug candidates such as daptomycin and clofazimine also displayed enhanced activity which was similar to a previous screen against stationary phase B. burgdorferi persisters not exposure to amoxicillin. Additional candidate drugs active against round bodies identified include artemisinin, ciprofloxacin, nifuroxime, fosfomycin, chlortetracycline, sulfacetamide, sulfamethoxypyridazine and sulfathiozole. Two triple drug combinations had the highest activity against amoxicillin-induced round bodies and stationary phase B. burgdorferi persisters: artemisinin/cefoperazone/doxycycline and sulfachlorpyridazine/daptomycin/doxycycline. These findings confirm and extend previous findings that certain drug combinations have superior activity against B. burgdorferi persisters in vitro, even when pre-treated with amoxicillin. These findings may have implications for improved treatment of Lyme disease. PMID- 27242758 TI - Proteomic Analysis of a Novel Bacillus Jumbo Phage Revealing Glycoside Hydrolase As Structural Component. AB - Tailed phages with genomes of larger than 200 kbp are classified as Jumbo phages and exhibited extremely high uncharted diversity. The genomic annotation of Jumbo phage is often disappointing because most of the predicted proteins, including structural proteins, failed to make good hits to the sequences in the databases. In this study, 23 proteins of a novel Bacillus Jumbo phage, vB_BpuM_BpSp, were identified as phage structural proteins by the structural proteome analysis, including 14 proteins of unknown function, 5 proteins with predicted function as structural proteins, a glycoside hydrolase, a Holliday junction resolvase, a RNA polymerase beta-subunit, and a host-coding portal protein, which might be hijacked from the host strain during phage virion assembly. The glycoside hydrolase (Gp255) was identified as phage virion component and was found to interact with the phage baseplate protein. Gp255 shows specific lytic activity against the phage host strain GR8 and has high temperature tolerance. In situ peptidoglycan-hydrolyzing activities analysis revealed that the expressed Gp255 and phage structural proteome exhibited glycoside hydrolysis activity against the tested GR8 cell extracts. This study identified the first functional individual structural glycoside hydrolase in phage virion. The presence of activated glycoside hydrolase in phage virions might facilitate the injection of the phage genome during infection by forming pores on the bacterial cell wall. PMID- 27242759 TI - Effects of Incubation Conditions on Cr(VI) Reduction by c-type Cytochromes in Intact Shewanella oneidensis MR-1 Cells. AB - It is widely recognized that the outer membrane c-type cytochromes (OM c-Cyts) of metal-reducing bacteria play a key role in microbial metal reduction processes. However, the in situ redox status of OM c-Cyts during microbial metal reduction processes remain poorly understood. In this study, diffuse-transmission UV/Vis spectroscopy is used to investigate the in situ spectral reaction of Cr(VI) reduction by c-Cyts in intact Shewanella oneidensis MR-1 cells under different incubation conditions. The reduced c-Cyts decreased transiently at the beginning and then recovered gradually over time. The Cr(VI) reduction rates decreased with increasing initial Cr(VI) concentrations, and Cr(III) was identified as a reduced product. The presence of Cr(III) substantially inhibited Cr(VI) reduction and the recovery of reduced c-Cyts, indicating that Cr(III) might inhibit cell growth. Cr(VI) reduction rates increased with increasing cell density. The highest Cr(VI) reduction rate and fastest recovery of c-Cyts were obtained at pH 7.0 and 30 degrees C, with sodium lactate serving as an electron donor. The presence of O2 strongly inhibited Cr(VI) reduction, suggesting that O2 might compete with Cr(VI) as an electron acceptor in cells. This study provides a case of directly examining in vivo reaction properties of an outer-membrane enzyme during microbial metal reduction processes under non-invasive physiological conditions. PMID- 27242760 TI - Drug Resistance Mechanisms in Bacteria Causing Sexually Transmitted Diseases and Associated with Vaginosis. AB - Here, we review sexually transmitted diseases (STDs) caused by pathogenic bacteria and vaginal infections which result from an overgrowth of opportunistic bacterial microflora. First, we describe the STDs, the corresponding pathogens and the antimicrobials used for their treatment. In addition to the well-known diseases caused by single pathogens (i.e., syphilis, gonococcal infections, and chlamydiosis), we consider polymicrobial reproductive tract infections (especially those that are difficult to effectively clinically manage). Then, we summarize the biochemical mechanisms that lead to antimicrobial resistance and the most recent data on the emergence of drug resistance in STD pathogens and bacteria associated with vaginosis. A large amount of research performed in the last 10-15 years has shed light on the enormous diversity of mechanisms of resistance developed by bacteria. A detailed understanding of the mechanisms of antimicrobials action and the emergence of resistance is necessary to modify existing drugs and to develop new ones directed against new targets. PMID- 27242761 TI - Cobalamin Protection against Oxidative Stress in the Acidophilic Iron-oxidizing Bacterium Leptospirillum Group II CF-1. AB - Members of the genus Leptospirillum are aerobic iron-oxidizing bacteria belonging to the phylum Nitrospira. They are important members of microbial communities that catalyze the biomining of sulfidic ores, thereby solubilizing metal ions. These microorganisms live under extremely acidic and metal-loaded environments and thus must tolerate high concentrations of reactive oxygen species (ROS). Cobalamin (vitamin B12) is a cobalt-containing tetrapyrrole cofactor involved in intramolecular rearrangement reactions and has recently been suggested to be an intracellular antioxidant. In this work, we investigated the effect of the exogenous addition of cobalamin on oxidative stress parameters in Leptospirillum group II strain CF-1. Our results revealed that the external supplementation of cobalamin reduces the levels of intracellular ROSs and the damage to biomolecules, and also stimulates the growth and survival of cells exposed to oxidative stress exerted by ferric ion, hydrogen peroxide, chromate and diamide. Furthermore, exposure of strain CF-1 to oxidative stress elicitors resulted in the transcriptional activation of the cbiA gene encoding CbiA of the cobalamin biosynthetic pathway. Altogether, these data suggest that cobalamin plays an important role in redox protection of Leptospirillum strain CF-1, supporting survival of this microorganism under extremely oxidative environmental conditions. Understanding the mechanisms underlying the protective effect of cobalamin against oxidative stress may help to develop strategies to make biomining processes more effective. PMID- 27242762 TI - Aurelia aurita Ephyrae Reshape a Coastal Microbial Community. AB - Over the last two decades, increasing attention has been paid to the impact of jellyfish blooms on marine communities. Aurelia aurita is one of the most studied of the Scyphozoans, and several studies have been carried out to describe its role as a top-down controller within the classical food web. However, little data are available to define the effects of these jellyfish on microbial communities. The aims of this study were to describe the predation impact of A. aurita ephyrae on a natural microplanktonic assemblage, and to determine any reshaping effects on the prokaryote community composition and functioning. Surface coastal water was used to set up a 24-h grazing experiment in microcosms. Samples were collected to determine the variations in prey biomass, heterotrophic carbon production (HCP), extracellular leucine aminopeptidase activity, and grazing pressure. A next-generation sequencing technique was used to investigate biodiversity shifts within the prokaryote and protist communities through the small subunit rRNA tag approach. This study shows that A. aurita ephyrae were responsible for large decreases in the abundances of the more motile microplankton groups, such as tintinnids, Dinophyceae, and aloricate ciliates. Bacillariophyceae and Mediophyceae showed smaller reductions. No evidence of selective predation emerged in the analysis of the community diversity down to the family level. The heterotrophic prokaryote biomass increased significantly (by up to 45%), in parallel with increases in HCP and leucine aminopeptidase activity (40%). Significant modifications were detected in prokaryotic community composition. Some classes of Gammaproteobacteria and Flavobacteriia showed higher relative abundances when exposed to A. aurita ephyrae, while there was a net decrease for Alphaproteobacteria. Overall, this study provides new insight into the effects of A. aurita on microbial communities, underlining their selective predation toward the more motile groups of microplankton and their impact on prokaryotic assemblages, by favoring blooms of copiotrophic taxa. PMID- 27242763 TI - Candida albicans Induces Metabolic Reprogramming in Human NK Cells and Responds to Perforin with a Zinc Depletion Response. AB - As part of the innate immune system, natural killer (NK) cells are directly involved in the response to fungal infections. Perforin has been identified as the major effector molecule acting against many fungal pathogens. While several studies have shown that perforin mediated fungicidal effects can contribute to fungal clearance, neither the activation of NK cells by fungal pathogens nor the effects of perforin on fungal cells are well-understood. In a dual approach, we have studied the global gene expression pattern of primary and cytokine activated NK cells after co-incubation with Candida albicans and the transcriptomic adaptation of C. albicans to perforin exposure. NK cells responded to the fungal pathogen with an up-regulation of genes involved in immune signaling and release of cytokines. Furthermore, we observed a pronounced increase of genes involved in glycolysis and glycolysis inhibitor 2-deoxy-D-glucose impaired C. albicans induced NK cell activation. This strongly indicates that metabolic adaptation is a major part of the NK cell response to C. albicans infections. In the fungal pathogen, perforin induced a strong up-regulation of several fungal genes involved in the zinc depletion response, such as PRA1 and ZRT1. These data suggest that fungal zinc homeostasis is linked to the reaction to perforin secreted by NK cells. However, deletion mutants in PRA1 and ZRT1 did not show altered susceptibility to perforin. PMID- 27242765 TI - Snapshot of a Bacterial Microbiome Shift during the Early Symptoms of a Massive Sponge Die-Off in the Western Mediterranean. AB - Ocean warming is affecting marine benthic ecosystems through mass mortality events that involve marine invertebrates, in particular bivalves, corals, and sponges. Among these events, extensive die-offs of Ircinia fasciculata sponges have been recurrently reported in western Mediterranean. The goal of our study was to test whether the temperature-related mass sponge die-offs were associated with or preceded by an early unbalanced bacterial microbiome in the sponge tissues. We took advantage of the early detection of disease and compared the microbiomes of healthy vs. early diseased I. fasciculata tissues. Our results showed a microbiome shift in early diseased tissues. The abundance of Gammaproteobacteria and Acidobacteria increased and that of Deltaproteobacteria decreased in diseased vs. healthy tissues. The change in community composition was also noticeable at the operational taxonomic unit (OTU) level. Diseased tissues contained more bacterial sequences previously identified in injured or stressed sponges and corals than healthy tissues. Bacterial diversity increased significantly in diseased tissues, which contained a higher number of low abundance OTUs. Our results do not support the hypothesis of one particular pathogen, whether a Vibrio or any other bacteria, triggering the Northwestern Mediterranean mass mortalities of I. fasciculata. Our data rather suggest an early disruption of the bacterial microbiome balance in healthy sponges through a shift in OTU abundances, and the purported consequent decline of the sponge fitness and resistance to infections. Opportunistic bacteria could colonize the sponge tissues, taking benefit of the sponge weakness, before one or more virulent pathogens might proliferate ending in the mass sponge die-off. PMID- 27242764 TI - Genome-Wide Transcriptional Profiling Reveals Two Distinct Outcomes in Central Nervous System Infections of Rabies Virus. AB - Rabies remains a major public health concern in many developing countries. The precise neuropathogenesis of rabies is unknown, though it is hypothesized to be due to neuronal death or dysfunction. Mice that received intranasal inoculation of an attenuated rabies virus (RABV) strain HEP-Flury exhibited subtle clinical signs, and eventually recovered, which is different from the fatal encephalitis caused by the virulent RABV strain CVS-11. To understand the neuropathogenesis of rabies and the mechanisms of viral clearance, we applied RNA sequencing (RNA-Seq) to compare the brain transcriptomes of normal mice vs. HEP-Flury or CVS-11 intranasally inoculated mice. Our results revealed that both RABV strains altered positively and negatively the expression levels of many host genes, including genes associated with innate and adaptive immunity, inflammation and cell death. It is found that HEP-Flury infection can activate the innate immunity earlier through the RIG-I/MDA-5 signaling, and the innate immunity pre-activated by HEP Flury or Newcastle disease virus (NDV) infection can effectively prevent the CVS 11 to invade central nervous system (CNS), but fails to clear the CVS-11 after its entry into the CNS. In addition, following CVS-11 infection, genes implicated in cell adhesion, blood vessel morphogenesis and coagulation were mainly up regulated, while the genes involved in synaptic transmission and ion transport were significantly down-regulated. On the other hand, several genes involved in the MHC class II-mediated antigen presentation pathway were activated to a greater extent after the HEP-Flury infection as compared with the CVS-11 infection suggesting that the collaboration of CD4(+) T cells and MHC class II mediated antigen presentation is critical for the clearance of attenuated RABV from the CNS. The differentially regulated genes reported here are likely to include potential therapeutic targets for expanding the post-exposure treatment window for RABV infection. PMID- 27242766 TI - Multiplex, Rapid, and Sensitive Isothermal Detection of Nucleic-Acid Sequence by Endonuclease Restriction-Mediated Real-Time Multiple Cross Displacement Amplification. AB - We have devised a novel isothermal amplification technology, termed endonuclease restriction-mediated real-time multiple cross displacement amplification (ET MCDA), which facilitated multiplex, rapid, specific and sensitive detection of nucleic-acid sequences at a constant temperature. The ET-MCDA integrated multiple cross displacement amplification strategy, restriction endonuclease cleavage and real-time fluorescence detection technique. In the ET-MCDA system, the functional cross primer E-CP1 or E-CP2 was constructed by adding a short sequence at the 5' end of CP1 or CP2, respectively, and the new E-CP1 or E-CP2 primer was labeled at the 5' end with a fluorophore and in the middle with a dark quencher. The restriction endonuclease Nb.BsrDI specifically recognized the short sequence and digested the newly synthesized double-stranded terminal sequences (5' end short sequences and their complementary sequences), which released the quenching, resulting on a gain of fluorescence signal. Thus, the ET-MCDA allowed real-time detection of single or multiple targets in only a single reaction, and the positive results were observed in as short as 12 min, detecting down to 3.125 fg of genomic DNA per tube. Moreover, the analytical specificity and the practical application of the ET-MCDA were also successfully evaluated in this study. Here, we provided the details on the novel ET-MCDA technique and expounded the basic ET MCDA amplification mechanism. PMID- 27242767 TI - New Reassortant H5N6 Highly Pathogenic Avian Influenza Viruses in Southern China, 2014. AB - New reassortant H5N6 highly pathogenic avian influenza viruses (AIVs) were isolated from apparently healthy domestic ducks in Southern China in 2014. Our results show that the viruses grew efficiently in eggs and replicated systemically in chickens. They were completely lethal in chicken (100% mortality), and the mean death time was 6 to 7 days post-inoculation. The viruses could transmit in chickens by naive contact. BLAST analysis revealed that their HA gene was most closely related to A/wild duck/Shangdong/628/2011 (H5N1), and their NA genes were most closely related to A/swine/Guangdong/K6/2010 (H6N6). The other genes had the highest identity with A/wild duck/Fujian/1/2011(H5N1). The results of phylogenetic analysis showed that their HA genes clustered into clade 2.3.4.4 of the H5N1 viruses and all genes derived from H5 were Mix-like or H6 like viruses. Thus, the new H5N6 viruses were reassortmented of H5N1 and H6N6 virus. Therefore, the circulation of the new H5N6 AIVs may become a threat to poultry and human health. PMID- 27242768 TI - Isolation and Characterization of Electrochemically Active Subsurface Delftia and Azonexus Species. AB - Continental subsurface environments can present significant energetic challenges to the resident microorganisms. While these environments are geologically diverse, potentially allowing energy harvesting by microorganisms that catalyze redox reactions, many of the abundant electron donors and acceptors are insoluble and therefore not directly bioavailable. Extracellular electron transfer (EET) is a metabolic strategy that microorganisms can deploy to meet the challenges of interacting with redox-active surfaces. Though mechanistically characterized in a few metal-reducing bacteria, the role, extent, and diversity of EET in subsurface ecosystems remains unclear. Since this process can be mimicked on electrode surfaces, it opens the door to electrochemical techniques to enrich for and quantify the activities of environmental microorganisms in situ. Here, we report the electrochemical enrichment of microorganisms from a deep fractured-rock aquifer in Death Valley, CA, USA. In experiments performed in mesocosms containing a synthetic medium based on aquifer chemistry, four working electrodes (WEs) were poised at different redox potentials (272, 373, 472, 572 mV vs. SHE) to serve as electron acceptors, resulting in anodic currents coupled to the oxidation of acetate during enrichment. The anodes were dominated by Betaproteobacteria from the families Comamonadaceae and Rhodocyclaceae. A representative of each dominant family was subsequently isolated from electrode associated biomass. The EET abilities of the isolated Delftia strain (designated WE1-13) and Azonexus strain (designated WE2-4) were confirmed in electrochemical reactors using WEs poised at 522 mV vs. SHE. The rise in anodic current upon inoculation was correlated with a modest increase in total protein content. Both genera have been previously observed in mixed communities of microbial fuel cell enrichments, but this is the first direct measurement of their electrochemical activity. While alternate metabolisms (e.g., nitrate reduction) by these organisms were previously known, our observations suggest that additional 'hidden' interactions with external electron acceptors are also possible. Electrochemical approaches are well positioned to dissect such extracellular interactions that may be prevalent in the subsurface. PMID- 27242769 TI - New Insights into the Genetic Diversity of Clostridium botulinum Group III through Extensive Genome Exploration. AB - Animal botulism is caused by group III Clostridium botulinum strains producing type C and D toxins, or their chimeric forms C/D and D/C. Animal botulism is considered an emerging disease in Europe, notably in poultry production. Before our study, 14 genomes from different countries were available in the public database, but none were from France. In order to investigate the genetic relationship of French strains with different geographical areas and find new potential typing targets, 17 strains of C. botulinum group III were sequenced (16 from France and one from New Caledonia). Fourteen were type C/D strains isolated from chickens, ducks, guinea fowl and turkeys and three were type D/C strains isolated from cattle. The New Caledonian strain was a type D/C strain. Whole genome sequence analysis showed the French strains to be closely related to European strains from C. botulinum group III lineages Ia and Ib. The investigation of CRISPR sequences as genetic targets for differentiating strains in group III proved to be irrelevant for type C/D due to a deficient CRISPR/Cas mechanism, but not for type D/C. Conversely, the extrachromosomal elements of type C/D strains could be used to generate a genetic ID card. The highest level of discrimination was achieved with SNP core phylogeny, which allowed differentiation up to strain level and provide the most relevant information for genetic epidemiology studies and discrimination. PMID- 27242770 TI - Pika Population Density Is Associated with the Composition and Diversity of Gut Microbiota. AB - Host population density is positively associated with the strength of social interactions or the frequency of physical contacts, and thus potentially influences microbial transmission among individuals. However, the relationship between host density and gut microbiota remains unknown. Here, we characterized the gut microbiota of plateau pikas (Ochotona curzoniae) in wild experimental fields with different host population densities. The abundance of some gut microbes significantly correlated with host density, such as Ruminococcaceae, Lachnospiraceae, and Staphylococcaceae. Intriguingly, host density was positively correlated with alpha diversity (Shannon diversity and observed species) of gut microbial communities. The inter-individual gut microbiota within high-density groups were more similar to each other than those of low-density groups. Host density significantly explained the variations in the gut microbiota, even after controlling sex, weight, diet and geographical locations. Based on the PICRUSt metagenome prediction, positive correlations were observed between host density and the relative abundances of 12 gene functions involved in cellular processes, environmental information processing and metabolism. These results indicate the importance of host density as a factor in shaping gut microbial composition and diversity in plateau pikas, and may further help us understand the social transmission of gut microbiota. PMID- 27242771 TI - The Chromatin of Candida albicans Pericentromeres Bears Features of Both Euchromatin and Heterochromatin. AB - Centromeres, sites of kinetochore assembly, are important for chromosome stability and integrity. Most eukaryotes have regional centromeres epigenetically specified by the presence of the histone H3 variant CENP-A. CENP-A chromatin is often surrounded by pericentromeric regions packaged into transcriptionally silent heterochromatin. Candida albicans, the most common human fungal pathogen, possesses small regional centromeres assembled into CENP-A chromatin. The chromatin state of C. albicans pericentromeric regions is unknown. Here, for the first time, we address this question. We find that C. albicans pericentromeres are assembled into an intermediate chromatin state bearing features of both euchromatin and heterochromatin. Pericentromeric chromatin is associated with nucleosomes that are highly acetylated, as found in euchromatic regions of the genome; and hypomethylated on H3K4, as found in heterochromatin. This intermediate chromatin state is inhibitory to transcription and partially represses expression of proximal genes and inserted marker genes. Our analysis identifies a new chromatin state associated with pericentromeric regions. PMID- 27242773 TI - C239S Mutation in the beta-Tubulin of Phytophthora sojae Confers Resistance to Zoxamide. AB - Zoxamide is the sole beta-tubulin inhibitor registered for the control of oomycete pathogens. The current study investigated the activity of zoxamide against Phytophthora sojae and baseline sensitivity was established with a mean EC50 of 0.048 MUg/ml. The data is critical for monitoring changes in zoxamide sensitivity in the field. Three stable resistant mutants with a high resistance level were obtained by selection on zoxamide amended media. Although the development of resistance occurred at a low frequency, there were no apparent fitness penalty in the acquired mutants in terms of growth rate, sporulation, germination and pathogenicity. Based on the biological profiles and low mutagenesis rate, the resistance risk of P. sojae to zoxamide can be estimated as low to medium. Further investigation revealed all the zoxamide-resistant mutants had a point mutation of C239S in their beta-tubulin. Zoxamide also exhibited high activity against most species from the genus Pythium in which only Pythium aphanidermatum was found naturally resistant to zoxamide and harboring the natural point mutation S239 in the beta-tubulin. Back-transformation in P. sojae with the mutated allele (S239) confirmed the C239S mutation can induce resistance to zoxamide, and the resistance level was positively related to the expression level of the mutated gene. In contrast, the overexpression of the wild type gene was unable to cause zoxamide resistance. It is the first report on the resistance molecular mechanism of zoxamide in oomycetes. Based on our study, C239 is supposed to be a key target site of zoxamide, which distinguishes zoxamide from benzimidazoles and accounts for its low resistance risk. The result can provide advice on the design of new beta-tubulin inhibitors in future. PMID- 27242772 TI - Synergistic and Additive Effect of Oregano Essential Oil and Biological Silver Nanoparticles against Multidrug-Resistant Bacterial Strains. AB - Bacterial resistance to conventional antibiotics has become a clinical and public health problem, making therapeutic decisions more challenging. Plant compounds and nanodrugs have been proposed as potential antimicrobial alternatives. Studies have shown that oregano (Origanum vulgare) essential oil (OEO) and silver nanoparticles have potent antibacterial activity, also against multidrug resistant strains; however, the strong organoleptic characteristics of OEO and the development of resistance to these metal nanoparticles can limit their use. This study evaluated the antibacterial effect of a two-drug combination of biologically synthesized silver nanoparticles (bio-AgNP), produced by Fusarium oxysporum, and OEO against Gram-positive and Gram-negative bacteria, including multidrug-resistant strains. OEO and bio-AgNP showed bactericidal effects against all 17 strains tested, with minimal inhibitory concentrations (MIC) ranging from 0.298 to 1.193 mg/mL and 62.5 to 250 MUM, respectively. Time-kill curves indicated that OEO acted rapidly (within 10 min), while the metallic nanoparticles took 4 h to kill Gram-negative bacteria and 24 h to kill Gram positive bacteria. The combination of the two compounds resulted in a synergistic or additive effect, reducing their MIC values and reducing the time of action compared to bio-AgNP used alone, i.e., 20 min for Gram-negative bacteria and 7 h for Gram-positive bacteria. Scanning electron microscopy (SEM) revealed similar morphological alterations in Staphylococcus aureus (non-methicillin-resistant S. aureus, non-MRSA) cells exposed to three different treatments (OEO, bio-AgNP and combination of the two), which appeared cell surface blebbing. Individual and combined treatments showed reduction in cell density and decrease in exopolysaccharide matrix compared to untreated bacterial cells. It indicated that this composition have an antimicrobial activity against S. aureus by disrupting cells. Both compounds showed very low hemolytic activity, especially at MIC levels. This study describes for the first time the synergistic and additive interaction between OEO and bio-AgNP produced by F. oxysporum against multidrug resistant bacteria, such as MRSA, and beta-lactamase- and carbapenemase-producing Escherichia coli and Acinetobacter baumannii strains. These results indicated that this combination can be an alternative in the control of infections with few or no treatment options. PMID- 27242774 TI - A Rapid Molecular Test for Determining Yersinia pestis Susceptibility to Ciprofloxacin by the Quantification of Differentially Expressed Marker Genes. AB - Standard antimicrobial susceptibility tests used to determine bacterial susceptibility to antibiotics are growth dependent and time consuming. The long incubation time required for standard tests may render susceptibility results irrelevant, particularly for patients infected with lethal bacteria that are slow growing on agar but progress rapidly in vivo, such as Yersinia pestis. Here, we present an alternative approach for the rapid determination of antimicrobial susceptibility, based on the quantification of the changes in the expression levels of specific marker genes following exposure to growth-inhibiting concentrations of the antibiotic, using Y. pestis and ciprofloxacin as a model. The marker genes were identified by transcriptomic DNA microarray analysis of the virulent Y. pestis Kimberley53 strain after exposure to specific concentrations of ciprofloxacin for various time periods. We identified several marker genes that were induced following exposure to growth-inhibitory concentrations of ciprofloxacin, and we confirmed the marker expression profiles at additional ciprofloxacin concentrations using quantitative RT-PCR. Eleven candidate marker transcripts were identified, of which four mRNA markers were selected for a rapid quantitative RT-PCR susceptibility test that correctly determined the Minimal Inhibitory Concentration (MIC) values and the categories of susceptibility of several Y. pestis strains and isolates harboring various ciprofloxacin MIC values. The novel molecular susceptibility test requires just 2 h of antibiotic exposure in a 7-h overall test time, in contrast to the 24 h of antibiotic exposure required for a standard microdilution test. PMID- 27242775 TI - Recovery and Growth Potential of Listeria monocytogenes in Temperature Abused Milkshakes Prepared from Naturally Contaminated Ice Cream Linked to a Listeriosis Outbreak. AB - The recovery and growth potential of Listeria monocytogenes was evaluated in three flavors of milkshakes (vanilla, strawberry, and chocolate) that were prepared from naturally contaminated ice cream linked to a listeriosis outbreak in the U.S. in 2015, and were subsequently held at room temperature for 14 h. The average lag phase duration of L. monocytogenes was 9.05 h; the average generation time was 1.67 h; and the average population level increase per sample at 14 h was 1.14 log CFU/g. Milkshake flavors did not significantly affect these parameters. The average lag phase duration of L. monocytogenes in milkshakes with initial contamination levels <= 3 CFU/g (9.50 h) was significantly longer (P < 0.01) than that with initial contamination levels > 3 CFU/g (8.60 h). The results highlight the value of using samples that are contaminated with very low levels of L. monocytogenes for recovery and growth evaluations. The behavior of L. monocytogenes populations in milkshakes prepared from naturally contaminated ice cream linked to the listeriosis outbreak should be taken into account when performing risk based analysis using this outbreak as a case study. PMID- 27242776 TI - Six Novel O Genotypes from Shiga Toxin-Producing Escherichia coli. AB - Serotyping is one of the typing techniques used to classify strains within the same species. O-serogroup diversification shows a strong association with the genetic diversity of O-antigen biosynthesis genes. In a previous study, based on the O-antigen biosynthesis gene cluster (O-AGC) sequences of 184 known Escherichia coli O serogroups (from O1 to O187), we developed a comprehensive and practical molecular O serogrouping (O genotyping) platform using a polymerase chain reaction (PCR) method, named E. coli O-genotyping PCR. Although, the validation assay using the PCR system showed that most of the tested strains were successfully classified into one of the O genotypes, it was impossible to classify 6.1% (35/575) of the strains, suggesting the presence of novel O genotypes. In this study, we conducted sequence analysis of O-AGCs from O genotype untypeable Shiga toxin-producing E. coli (STEC) strains and identified six novel O genotypes; OgN1, OgN8, OgN9, OgN10, OgN12 and OgN31, with unique wzx and/or wzy O-antigen processing gene sequences. Additionally, to identify these novel O-genotypes, we designed specific PCR primers. A screen of O genotypes using O-genotype untypeable strains showed 13 STEC strains were classified into five novel O genotypes. The O genotyping at the molecular level of the O-AGC would aid in the characterization of E. coli isolates and will assist future studies in STEC epidemiology and phylogeny. PMID- 27242777 TI - Implementation of Whole Genome Sequencing (WGS) for Identification and Characterization of Shiga Toxin-Producing Escherichia coli (STEC) in the United States. AB - Shiga toxin-producing Escherichia coli (STEC) is an important foodborne pathogen capable of causing severe disease in humans. Rapid and accurate identification and characterization techniques are essential during outbreak investigations. Current methods for characterization of STEC are expensive and time-consuming. With the advent of rapid and cheap whole genome sequencing (WGS) benchtop sequencers, the potential exists to replace traditional workflows with WGS. The aim of this study was to validate tools to do reference identification and characterization from WGS for STEC in a single workflow within an easy to use commercially available software platform. Publically available serotype, virulence, and antimicrobial resistance databases were downloaded from the Center for Genomic Epidemiology (CGE) (www.genomicepidemiology.org) and integrated into a genotyping plug-in with in silico PCR tools to confirm some of the virulence genes detected from WGS data. Additionally, down sampling experiments on the WGS sequence data were performed to determine a threshold for sequence coverage needed to accurately predict serotype and virulence genes using the established workflow. The serotype database was tested on a total of 228 genomes and correctly predicted from WGS for 96.1% of O serogroups and 96.5% of H serogroups identified by conventional testing techniques. A total of 59 genomes were evaluated to determine the threshold of coverage to detect the different WGS targets, 40 were evaluated for serotype and virulence gene detection and 19 for the stx gene subtypes. For serotype, 95% of the O and 100% of the H serogroups were detected at > 40x and >= 30x coverage, respectively. For virulence targets and stx gene subtypes, nearly all genes were detected at > 40x, though some targets were 100% detectable from genomes with coverage >=20x. The resistance detection tool was 97% concordant with phenotypic testing results. With isolates sequenced to > 40x coverage, the different databases accurately predicted serotype, virulence, and resistance from WGS data, providing a fast and cheaper alternative to conventional typing techniques. PMID- 27242778 TI - Commentary: Clinical utilization of genomics data produced by the international Pseudomonas aeruginosa consortium. PMID- 27242779 TI - Mathematical Model Reveals the Role of Memory CD8 T Cell Populations in Recall Responses to Influenza. AB - The current influenza vaccine provides narrow protection against the strains included in the vaccine, and needs to be reformulated every few years in response to the constantly evolving new strains. Novel approaches are directed toward developing vaccines that provide broader protection by targeting B and T cell epitopes that are conserved between different strains of the virus. In this paper, we focus on developing mathematical models to explore the CD8 T cell responses to influenza, how they can be boosted, and the conditions under which they contribute to protection. Our models suggest that the interplay between spatial heterogeneity (with the virus infecting the respiratory tract and the immune response being generated in the secondary lymphoid organs) and T cell differentiation (with proliferation occurring in the lymphoid organs giving rise to a subpopulation of resident T cells in the respiratory tract) is the key to understand the dynamics of protection afforded by the CD8 T cell response to influenza. Our results suggest that the time lag for the generation of resident T cells in the respiratory tract and their rate of decay following infection are the key factors that limit the efficacy of CD8 T cell responses. The models predict that an increase in the level of central memory T cells leads to a gradual decrease in the viral load, and, in contrast, there is a sharper protection threshold for the relationship between the size of the population of resident T cells and protection. The models also suggest that repeated natural influenza infections cause the number of central memory CD8 T cells and the peak number of resident memory CD8 T cells to reach their plateaus, and while the former is maintained, the latter decays with time since the most recent infection. PMID- 27242780 TI - Coupling of HIV-1 Antigen to the Selective Autophagy Receptor SQSTM1/p62 Promotes T-Cell-Mediated Immunity. AB - Vaccines aiming to promote T-cell-mediated immune responses have so far showed limited efficacy, and there is a need for novel strategies. Studies indicate that autophagy plays an inherent role in antigen processing and presentation for CD4(+) and CD8(+) T cells. Here, we report a novel vaccine strategy based on fusion of antigen to the selective autophagy receptor sequestosome 1 (SQSTM1)/p62. We hypothesized that redirection of vaccine antigen from proteasomal degradation into the autophagy pathway would increase the generation of antigen-specific T cells. A hybrid vaccine construct was designed in which the antigen is fused to the C-terminus of p62, a signaling hub, and a receptor that naturally delivers ubiquitinated cargo for autophagic degradation. Fusion of the human immunodeficiency virus-1 antigen Gagp24 to p62 resulted in efficient antigen delivery into the autophagy pathway. Intradermal immunization of mice revealed that, in comparison to Gagp24 delivered alone, fusion to p62 enhanced the number of Gagp24-specific interferon-gamma-producing T cells, including CD8(+) T cells. The strategy may also have the potential to modulate the antigenic peptide repertoire. Because p62 and autophagy are highly conserved between species, we anticipate this strategy to be a candidate for the development of T-cell-based vaccines in humans. PMID- 27242781 TI - Suppressors of Cytokine Signaling in Sickness and in Health of Pancreatic beta Cells. AB - Suppressors of cytokine signaling (SOCS) are a family of eight proteins that negatively regulate Janus kinase and signal transducers and activators of transcription signaling in cells that utilize this pathway to respond to extracellular stimuli. SOCS are best known for attenuating cytokine signaling in the immune system. However, they are also expressed in many other cell types, including pancreatic beta-cells, where there is considerable interest in harnessing SOCS molecules to prevent cytokine-mediated apoptosis during diabetes and allogeneic transplantation. Apart from their potential as therapeutic targets, SOCS molecules play a central role for regulating important functions in beta-cells, including growth, glucose sensing, and insulin secretion. This review will discuss SOCS proteins as central regulators for diverse cellular processes important for normal beta-cell function as well as their protective anti apoptotic effects during beta-cell stress. PMID- 27242784 TI - Immune Complexes in Juvenile Idiopathic Arthritis. AB - Juvenile idiopathic arthritis (JIA) reflects a group of clinically heterogeneous, autoimmune disorders in children characterized by chronic arthritis and hallmarked by elevated levels of circulating immune complexes (CICs) and associated complement activation by-products in their sera. Immune complexes (ICs) have been detected in patients' sera with JIA utilizing a variety of methods, including the anti-human IgM affinity column, C1q solid-phase assay, polyethylene glycol precipitation, Staphylococcal Protein A separation method, anti-C1q/C3 affinity columns, and FcgammaRIII affinity method. As many as 75% of JIA patients have had IC detected in their sera. The CIC proteome in JIA patients has been examined to elucidate disease-associated proteins that are expressed in active disease. Evaluation of these ICs has shown the presence of multiple peptide fragments by SDS-PAGE and 2-DE. Subsequently, all isotypes of rheumatoid factor (RF), isotypes of anti-cyclic citrullinated peptide (CCP) antibodies, IgG, C1q, C4, C3, and the membrane attack complex (MAC) were detected in these IC. Complement activation and levels of IC correlate with disease activity in JIA, indicating their role in the pathophysiology of the disease. This review will summarize the existing literature and discuss the role of possible protein modification that participates in the generation of the immune response. We will address the possible role of these events in the development of ectopic germinal centers that become the secondary site of plasma cell development in JIA. We will further address possible therapeutic modalities that could be instituted as a result of the information gathered by the presence of ICs in JIA. PMID- 27242785 TI - CD4(+) T-Cell-Independent Secondary Immune Responses to Pneumocystis Pneumonia. AB - Pneumocystis pneumonia is a major cause of morbidity and mortality among immunocompromised patients, especially in the context of HIV/AIDS. In the murine model of Pneumocystis pneumonia, CD4(+) T-cells are required for clearance of a primary infection of Pneumocystis, but not the memory recall response. We hypothesized that the memory recall response in the absence of CD4(+) T-cells is mediated by a robust memory humoral response, CD8(+) T-cells, and IgG-mediated phagocytosis by alveolar macrophages. To investigate the role of CD8(+) T-cells and alveolar macrophages in the immune memory response to Pneumocystis, mice previously challenged with Pneumocystis were depleted of CD8(+) T-cells or alveolar macrophages prior to re-infection. Mice depleted of CD4(+) T-cells prior to secondary challenge cleared Pneumocystis infection within 48 h identical to immunocompetent mice during a secondary memory recall response. However, loss of CD8(+) T-cells or macrophages prior to the memory recall response significantly impaired Pneumocystis clearance. Specifically, mice depleted of CD8(+) T-cells or alveolar macrophages had significantly higher fungal burden in the lungs. Furthermore, loss of alveolar macrophages significantly skewed the lung CD8(+) T cell response toward a terminally differentiated effector memory population and increased the percentage of IFN-gamma(+) CD8(+) T-cells. Finally, Pneumocystis infected animals produced significantly more bone marrow plasma cells and Pneumocystis-specific IgG significantly increased macrophage-mediated killing of Pneumocystis in vitro. These data suggest that secondary immune memory responses to Pneumocystis are mediated, in part, by CD8(+) T-cells, alveolar macrophages, and the production of Pneumocystis-specific IgG. PMID- 27242782 TI - Immune Response of Amebiasis and Immune Evasion by Entamoeba histolytica. AB - Entamoeba histolytica is a protozoan parasite and the causative agent of amebiasis. It is estimated approximately 1% of humans are infected with E. histolytica, resulting in an estimate of 100,000 deaths annually. Clinical manifestations of amebic infection range widely from asymptomatic to severe symptoms, including dysentery and extra-intestinal abscesses. Like other infectious diseases, it is assumed that only ~20% of infected individuals develop symptoms, and genetic factors of both the parasite and humans as well as the environmental factors, e.g., microbiota, determine outcome of infection. There are multiple essential steps in amebic infection: degradation of and invasion into the mucosal layer, adherence to the intestinal epithelium, invasion into the tissues, and dissemination to other organs. While the mechanisms of invasion and destruction of the host tissues by the amebae during infection have been elucidated at the molecular levels, it remains largely uncharacterized how the parasite survive in the host by evading and attacking host immune system. Recently, the strategies for immune evasion by the parasite have been unraveled, including immunomodulation to suppress IFN-gamma production, elimination of immune cells and soluble immune mediators, and metabolic alterations against reactive oxygen and nitrogen species to fend off the attack from immune system. In this review, we summarized the latest knowledge on immune reaction and immune evasion during amebiasis. PMID- 27242783 TI - Signaling in Effector Lymphocytes: Insights toward Safer Immunotherapy. AB - Receptors on T and NK cells systematically propagate highly complex signaling cascades that direct immune effector functions, leading to protective immunity. While extensive studies have delineated hundreds of signaling events that take place upon receptor engagement, the precise molecular mechanism that differentially regulates the induction or repression of a unique effector function is yet to be fully defined. Such knowledge can potentiate the tailoring of signal transductions and transform cancer immunotherapies. Targeted manipulations of signaling cascades can augment one effector function such as antitumor cytotoxicity while contain the overt generation of pro-inflammatory cytokines that contribute to treatment-related toxicity such as "cytokine storm" and "cytokine-release syndrome" or lead to autoimmune diseases. Here, we summarize how individual signaling molecules or nodes may be optimally targeted to permit selective ablation of toxic immune side effects. PMID- 27242786 TI - A New Biological Feature of Natural Killer Cells: The Recognition of Solid Tumor Derived Cancer Stem Cells. AB - Natural killer (NK) cells are classified as a member of the innate lymphoid cells (ILCs) group 1. ILCs have been recently identified and grouped on the basis of their phenotypical and functional characteristics. They are effectors of innate immunity and are involved in secondary lymphoid organ generation and tissue remodeling. NK cells are powerful cytotoxic lymphocytes able to recognize and eliminate tumor- and virus-infected cells by limiting their spread and tissue damage. The recognition of tumor cells is mediated by both activating and inhibitory receptors. While in hematological malignancies the role played by NK cells is widely known, their role in recognizing solid tumors remains unclear. Recently, tumor cell populations have been divided into two compartments: cancer initiating cells (CICs) or cancer stem cells (CSCs) and senescent tumor cells. Here, CSC will be used. CSCs are a small subset of malignant cells with stem-like properties that are involved in tumor maintenance and recurrence due to their ability to survive to traditional therapies; they are, moreover, poorly recognized by T lymphocytes. Recent data showed that NK cells recognize in vitro cancer-initiating cells derived from colon cancer, glioblastoma, and melanoma. However, more in vivo studies are urgently required to fully understand whether these new antitumor NK cells with cytotoxic capability may be considered in the design of new immunotherapeutic interventions. PMID- 27242787 TI - mTOR Regulation of Lymphoid Cells in Immunity to Pathogens. AB - Immunity to pathogens exists as a fine balance between promoting activation and expansion of effector cells, while simultaneously limiting normal and aberrant responses. These seemingly opposing functions are kept in check by immune regulators. The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that senses nutrient availability and, in turn, regulates cell metabolism, growth, and survival accordingly. mTOR plays a pivotal role in facilitating immune defense against invading pathogens by regulating the differentiation, activation, and effector functions of lymphoid cells. Here, we focus on the emerging and sometimes contradictory roles of mTOR in orchestrating lymphoid cell mediated host immune responses to pathogens. A thorough understanding of how mTOR impacts lymphoid cells in pathogen defense will provide the necessary base for developing therapeutic interventions for infectious diseases. PMID- 27242788 TI - Host Intracellular Signaling Events and Pro-inflammatory Cytokine Production in African Trypanosomiasis. AB - Pathogens, such as bacteria, viruses, and parasites, possess specific molecules or proteins that are recognized by several host innate immune receptors, leading to the activation of several intracellular signaling molecules and pathways. The magnitude and quality of these events significantly affect the outcome of infection. African trypanosomes, including Trypanosoma congolense, are capable of manipulating the host immune response, including the activity of macrophages, which are the key immune cells that contribute to the immunopathogenesis of African trypanosomiasis. Although it is known that immune hyperactivation and excessive pro-inflammatory cytokine production are the hallmarks of African trypanosomiasis, the mechanisms through which these events are triggered are poorly defined. However, it is known that macrophages may play a significant role in these processes, because phagocytosis of trypanosomes by macrophages initiates intracellular signal transduction cascades that lead to the release of pro inflammatory cytokines and alteration in cell function. This review highlights recent progress in our understanding of the innate immune receptors, signaling pathways, and transcription factors involved in T. congolense-induced pro inflammatory cytokine production in macrophages. It will reveal the existence of complex signaling events through which the parasite modulates the host immune response, thus identifying novel targets that could aid in designing strategies to effectively control the disease. PMID- 27242789 TI - Disruption of a Regulatory Network Consisting of Neutrophils and Platelets Fosters Persisting Inflammation in Rheumatic Diseases. AB - A network of cellular interactions that involve blood leukocytes and platelets maintains vessel homeostasis. It plays a critical role in the response to invading microbes by recruiting intravascular immunity and through the generation of neutrophil extracellular traps (NETs) and immunothrombosis. Moreover, it enables immune cells to respond to remote chemoattractants by crossing the endothelial barrier and reaching sites of infection. Once the network operating under physiological conditions is disrupted, the reciprocal activation of cells in the blood and the vessel walls determines the vascular remodeling via inflammatory signals delivered to stem/progenitor cells. A deregulated leukocyte/mural cell interaction is an early critical event in the natural history of systemic inflammation. Despite intense efforts, the signals that initiate and sustain the immune-mediated vessel injury, or those that enforce the often-prolonged phases of clinical quiescence in patients with vasculitis, have only been partially elucidated. Here, we discuss recent evidence that implicates the prototypic damage-associated molecular pattern/alarmin, the high mobility group box 1 (HMGB1) protein in systemic vasculitis and in the vascular inflammation associated with systemic sclerosis. HMGB1 could represent a player in the pathogenesis of rheumatic diseases and an attractive target for molecular interventions. PMID- 27242790 TI - Modulation of Chemokine Responses: Synergy and Cooperativity. AB - Chemokine biology is mediated by more complex interactions than simple monomolecular ligand-receptor interactions, as chemokines can form higher order quaternary structures, which can also be formed after binding to glycosaminoglycans (GAGs) on endothelial cells, and their receptors are found as dimers and/or oligomers at the cell surface. Due to the complexity of the chemokine binding and signaling system, several mechanisms have been proposed to provide an explanation for the synergy observed between chemokines in leukocyte migration. Pioneering studies on interactions between different chemokines have revealed that they can act as antagonists, or synergize with other chemokines. The synergism can occur at different levels, involving either two chemokine receptors triggered simultaneously or sequentially exposed to their agonists, or the activation of one type of chemokine receptor triggered by chemokine heterocomplexes. In addition to the several chemokines that, by forming a heterocomplex with chemokine receptor agonists, act as enhancers of molecules of the same family, we have recently identified HMGB1, an endogenous damage associated molecular patterns (DAMPs) molecule, as an enhancer of the activity of CXCL12. It is now evident that synergism between chemokines is crucial at the very early stage of inflammation. In addition, the low-affinity interaction with GAGs has recently been shown to induce cooperativity allowing synergy or inhibition of activity by displacement of other ligands. PMID- 27242792 TI - Strategies for Monitoring Outcomes in HIV-Exposed Uninfected Children in the United Kingdom. AB - Surveillance of pregnancies in women living with HIV is carried out on a national basis in the United Kingdom (UK) through the National Study of HIV in Pregnancy and Childhood. There are currently around 1100-1200 HIV-exposed uninfected (HEU) infants born every year in the UK, where vertical transmission of HIV now occurs in fewer than 5 in every 1000 pregnancies. By the end of 2014, there was a cumulative total of more than 15,000 HEU children with any combination antiretroviral therapy (cART) exposure and more than 5000 with cART exposure from conception in the UK. HEU infants are increasingly being exposed to newer antiretroviral drugs for which less is known regarding both short- and long-term safety. In this commentary, we describe the approaches that have been taken to explore health outcomes in HEU children born in the UK. This includes the Children exposed to AntiRetroviral Therapy (CHART) Study, which was a consented follow-up study carried out in 2002-2005 of HEU children born in 1996-2004. The CHART Study showed that 4% of HEU children enrolled had a major health or development problem in early childhood; this was within expected UK norms, but the study was limited by small numbers and short-term follow-up. However, the problems with recruitment and retention that were encountered within the CHART Study demonstrated that comprehensive, clinic-based follow-up was not a feasible approach for long-term assessment of HEU children in the UK. We describe an alternative approach developed to monitor some aspects of their long-term health, involving the "flagging" of HEU infants for death and cancer registration with the UK Office for National Statistics. Some of the ethical concerns regarding investigation of long-term outcomes of in utero and perinatal exposure to antiretrovirals, including those relating to consent and confidentiality, are also discussed. PMID- 27242791 TI - A T Cell View of the Bone Marrow. AB - The majority of T cells present in the bone marrow (BM) represent an activated/memory phenotype and most of these, if not all, are circulating T cells. Their lodging in the BM keeps them activated, turning the BM microenvironment into a "memory reservoir." This article will focus on how T cell activation in the BM results in both direct and indirect effects on the hematopoiesis. The hematopoietic stem cell niche will be presented, with its main components and organization, along with the role played by T lymphocytes in basal and pathologic conditions and their effect on the bone remodeling process. Also discussed herein will be how "normal" bone mass peak is achieved only in the presence of an intact adaptive immune system, with T and B cells playing critical roles in this process. Our main hypothesis is that the partnership between T cells and cells of the BM microenvironment orchestrates numerous processes regulating immunity, hematopoiesis, and bone remodeling. PMID- 27242793 TI - Phosphatidylinositol 4-Phosphate 5-Kinases in the Regulation of T Cell Activation. AB - Phosphatidylinositol 4,5-biphosphate kinases (PIP5Ks) are critical regulators of T cell activation being the main enzymes involved in the synthesis of phosphatidylinositol 4,5-biphosphate (PIP2). PIP2 is indeed a pivotal regulator of the actin cytoskeleton, thus controlling T cell polarization and migration, stable adhesion to antigen-presenting cells, spatial organization of the immunological synapse, and co-stimulation. Moreover, PIP2 also serves as a precursor for the second messengers inositol triphosphate, diacylglycerol, and phosphatidylinositol 3,4,5-triphosphate, which are essential for the activation of signaling pathways regulating cytokine production, cell cycle progression, survival, metabolism, and differentiation. Here, we discuss the impact of PIP5Ks on several T lymphocyte functions with a specific focus on the role of CD28 co stimulation in PIP5K compartimentalization and activation. PMID- 27242794 TI - Modulation of Innate Immune Mechanisms to Enhance Leishmania Vaccine-Induced Immunity: Role of Coinhibitory Molecules. AB - No licensed human vaccines are currently available against any parasitic disease including leishmaniasis. Several antileishmanial vaccine formulations have been tested in various animal models, including genetically modified live-attenuated parasite vaccines. Experimental infection studies have shown that Leishmania parasites utilize a broad range of strategies to undermine effector properties of host phagocytic cells, i.e., dendritic cells (DCs) and macrophages (MPhi). Furthermore, Leishmania parasites have evolved strategies to actively inhibit TH1 polarizing functions of DCs and to condition the infected MPhi toward anti inflammatory/alternative/M2 phenotype. The altered phenotype of phagocytic cells is characterized by decreased production of antimicrobial reactive oxygen, nitrogen molecules, and pro-inflammatory cytokines, such as IFN-gamma, IL-12, and TNF-alpha. These early events limit the activation of TH1-effector cells and set the stage for pathogenesis. Furthermore, this early control of innate immunity by the virulent parasites results in substantial alteration in the adaptive immunity characterized by reduced proliferation of CD4(+) and CD8(+) T cells and TH2 biased immunity that results in production of anti-inflammatory cytokines, such as TGF-beta, and IL-10. More recent studies have also documented the induction of coinhibitory ligands, such as CTLA-4, PD-L1, CD200, and Tim-3, that induce exhaustion and/or non-proliferation in antigen-experienced T cells. Most of these studies focus on viral infections in chronic phase, thus limiting the direct application of these results to parasitic infections and much less to parasitic vaccines. However, these studies suggest that vaccine-induced protective immunity can be modulated using strategies that enhance the costimulation that might reduce the threshold necessary for T cell activation and conversely by strategies that reduce or block inhibitory molecules, such as PD-L1 and CD200. In this review, we will focus on the polarization of antigen-presenting cells and subsequent role of costimulatory and coinhibitory molecules in mediating vaccine induced immunity using live-attenuated Leishmania parasites as specific examples. PMID- 27242795 TI - NK Cells and Other Innate Lymphoid Cells in Hematopoietic Stem Cell Transplantation. AB - Natural killer (NK) cells play a major role in the T-cell depleted haploidentical hematopoietic stem cell transplantation (haplo-HSCT) to cure high-risk leukemias. NK cells belong to the expanding family of innate lymphoid cells (ILCs). At variance with NK cells, the other ILC populations (ILC1/2/3) are non-cytolytic, while they secrete different patterns of cytokines. ILCs provide host defenses against viruses, bacteria, and parasites, drive lymphoid organogenesis, and contribute to tissue remodeling. In haplo-HSCT patients, the extensive T-cell depletion is required to prevent graft-versus-host disease (GvHD) but increases risks of developing a wide range of life-threatening infections. However, these patients may rely on innate defenses that are reconstituted more rapidly than the adaptive ones. In this context, ILCs may represent important players in the early phases following transplantation. They may contribute to tissue homeostasis/remodeling and lymphoid tissue reconstitution. While the reconstitution of NK cell repertoire and its role in haplo-HSCT have been largely investigated, little information is available on ILCs. Of note, CD34(+) cells isolated from different sources of HSC may differentiate in vitro toward various ILC subsets. Moreover, cytokines released from leukemia blasts (e.g., IL-1beta) may alter the proportions of NK cells and ILC3, suggesting the possibility that leukemia may skew the ILC repertoire. Further studies are required to define the timing of ILC development and their potential protective role after HSCT. PMID- 27242796 TI - Imaging Axonal Degeneration and Repair in Preclinical Animal Models of Multiple Sclerosis. AB - Multiple sclerosis (MS) is a central nervous system (CNS) disease characterized by chronic neuroinflammation, demyelination, and axonal damage. Infiltration of activated lymphocytes and myeloid cells are thought to be primarily responsible for white matter damage and axonopathy. Over time, this neurologic damage manifests clinically as debilitating motor and cognitive symptoms. Existing MS therapies focus on symptom relief and delay of disease progression through reduction of neuroinflammation. However, long-term strategies to remyelinate, protect, or regenerate axons have remained elusive, posing a challenge to treating progressive forms of MS. Preclinical mouse models and techniques, such as immunohistochemistry, flow cytometry, and genomic and proteomic analysis have provided advances in our understanding of discrete time-points of pathology following disease induction. More recently, in vivo and in situ two-photon (2P) microscopy has made it possible to visualize continuous real-time cellular behavior and structural changes occurring within the CNS during neuropathology. Research utilizing 2P imaging to study axonopathy in neuroinflammatory demyelinating disease has focused on five areas: (1) axonal morphologic changes, (2) organelle transport and health, (3) relationship to inflammation, (4) neuronal excitotoxicity, and (5) regenerative therapies. 2P imaging may also be used to identify novel therapeutic targets via identification and clarification of dynamic cellular and molecular mechanisms of axonal regeneration and remyelination. Here, we review tools that have made 2P accessible for imaging neuropathologies and advances in our understanding of axonal degeneration and repair in preclinical models of demyelinating diseases. PMID- 27242797 TI - Functional Mechanisms of Treg in the Context of HIV Infection and the Janus Face of Immune Suppression. AB - Regulatory T cells (Tregs) play an important role in infections, by modulating host immune responses and avoiding the overreactive immunity that in the case of human immunodeficiency virus (HIV) infection leads to a marked erosion and deregulation of the entire immune system. Therefore, the suppressive function of Treg in HIV-infected patients is critical because of their implication on preventing the immune hyperactivation, even though it could also have a detrimental effect by suppressing HIV-specific immune responses. In recent years, several studies have shown that HIV-1 can directly infect Treg, disturbing their phenotype and suppressive capacity via different mechanisms. These effects include Foxp3 and CD25 downregulation, and the impairment of suppressive capacity. This review describes the functional mechanisms of Treg to modulate immune activation during HIV infection, and how such control is no longer fine tune orchestrated once Treg itself get infected. We will review the current knowledge about the HIV effects on the Treg cytokine expression, on pathways implying the participation of different ectoenzymes (i.e., CD39/CD73 axis), transcription factors (ICER), and lastly on cyclic adenosine monophosphate (cAMP), one of the keystones in Treg-suppressive function. To define which are the HIV effects upon these regulatory mechanisms is crucial not only for the comprehension of immune deregulation in HIV-infected patients but also for the correct understanding of the role of Tregs in HIV infection. PMID- 27242799 TI - Microenvironmental Control of High-Speed Interstitial T Cell Migration in the Lymph Node. AB - T cells are highly concentrated in the lymph node (LN) paracortex, which serves an important role in triggering adoptive immune responses. Live imaging using two photon laser scanning microscopy revealed vigorous and non-directional T cell migration within this area at average velocity of more than 10 MUm/min. Active interstitial T cell movement is considered to be crucial for scanning large numbers of dendritic cells (DCs) to find rare cognate antigens. However, the mechanism by which T cells achieve such high-speed movement in a densely packed, dynamic tissue environment is not fully understood. Several new findings suggest that fibroblastic reticular cells (FRCs) and DCs control T cell movement in a multilateral manner. Chemokines and lysophosphatidic acid produced by FRCs cooperatively promote the migration, while DCs facilitate LFA-1-dependent motility via expression of ICAM-1. Furthermore, the highly dense and confined microenvironment likely plays a key role in anchorage-independent motility. We propose that T cells dynamically switch between two motility modes; anchorage dependent and -independent manners. Unique tissue microenvironment and characteristic migration modality of T cells cooperatively generate high-speed interstitial movement in the LN. PMID- 27242798 TI - Breaking Free of Control: How Conventional T Cells Overcome Regulatory T Cell Suppression. AB - Conventional T (Tcon) cells are crucial in shaping the immune response, whether it is protection against a pathogen, a cytotoxic attack on tumor cells, or an unwanted response to self-antigens in the context of autoimmunity. In each of these immune settings, regulatory T cells (Tregs) can potentially exert control over the Tcon cell response, resulting in either suppression or activation of the Tcon cells. Under physiological conditions, Tcon cells are able to transiently overcome Treg-imposed restraints to mount a protective response against an infectious threat, achieving clonal expansion, differentiation, and effector function. However, evidence has accumulated in recent years to suggest that Tcon cell resistance to Treg-mediated suppression centrally contributes to the pathogenesis of autoimmune disease. Tipping the balance too far in the other direction, cancerous tumors utilize Tregs to establish an overly suppressive microenvironment, preventing antitumor Tcon cell responses. Given the wide ranging clinical importance of the Tcon/Treg interaction, this review aims to provide a better understanding of what determines whether a Tcon cell is susceptible to Treg-mediated suppression and how perturbations to this finely tuned balance play a role in pathological conditions. Here, we focus in detail on the complex array of factors that confer Tcon cells with resistance to Treg suppression, which we have divided into two categories: (1) extracellular factor mediated signaling and (2) intracellular signaling molecules. Further, we explore the therapeutic implications of manipulating the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway, which is proposed to be the convergence point of signaling pathways that mediate Tcon resistance to suppression. Finally, we address important unresolved questions on the timing and location of acquisition of resistance, and the stability of the "Treg-resistant" phenotype. PMID- 27242801 TI - The Zebrafish Breathes New Life into the Study of Tuberculosis. AB - Tuberculosis (TB) is a global health emergency. Up to one-third of the world's population is infected with Mycobacterium tuberculosis, and the pathogen continues to kill 1.5 million people annually. Currently, the means for preventing, diagnosing, and treating TB are unsatisfactory. One of the main reasons for the poor progress in TB research has been a lack of good animal models to study the latency, dormancy, and reactivation of the disease. Although sophisticated in vitro and in silico methods suitable for TB research are constantly being developed, they cannot reproduce the complete vertebrate immune system and its interplay with pathogens and vaccines. However, the zebrafish has recently emerged as a useful alternative to more traditional models, such as mice, rabbits, guinea pigs, and non-human primates, for studying the complex pathophysiology of a mycobacterial infection. The model is based on the similarity between Mycobacterium marinum - a natural fish pathogen - and M. tuberculosis. In both zebrafish larvae and adult fish, an infection with M. marinum leads to the formation of macrophage aggregates and granulomas, which resemble the M. tuberculosis infections in humans. In this review, we will summarize the current status of the zebrafish model in TB research and highlight the advantages of using zebrafish to dissect mycobacterial virulence strategies as well as the host immune responses elicited against them. In addition, we will discuss the possibilities of using the adult zebrafish model for studying latency, dormancy, and reactivation in a mycobacterial infection. PMID- 27242802 TI - The PHACS SMARTT Study: Assessment of the Safety of In Utero Exposure to Antiretroviral Drugs. AB - The Surveillance Monitoring for ART Toxicities (SMARTT) cohort of the Pediatric HIV/AIDS Cohort Study includes over 3,500 HIV-exposed but uninfected infants and children at 22 sites in the US, including Puerto Rico. The goal of the study is to determine the safety of in utero exposure to antiretrovirals (ARVs) and to estimate the incidence of adverse events. Domains being assessed include metabolic, growth and development, cardiac, neurological, neurodevelopmental (ND), behavior, language, and hearing. SMARTT employs an innovative trigger-based design as an efficient means to identify and evaluate adverse events. Participants who met a predefined clinical or laboratory threshold (trigger) undergo additional evaluations to define their case status. After adjusting for birth cohort and other factors, there was no significant increase in the likelihood of meeting overall case status (case in any domain) with exposure to combination ARVs (cARVs), any ARV class, or any specific ARV. However, several individual ARVs were significantly associated with case status in individual domains, including zidovudine for a metabolic case, first trimester stavudine for a language case, and didanosine plus stavudine for a ND case. We found an increased rate of preterm birth with first trimester exposure to protease inhibitor-based cARV. Although there was no overall increase in congenital anomalies with first trimester cARV, a significant increase was seen with exposure to atazanavir, ritonavir, and didanosine plus stavudine. Tenofovir exposure was associated with significantly lower mean whole-body bone mineral content in the newborn period and a lower length and head circumference at 1 year of age. With ND testing at 1 year of age, specific ARVs (atazanavir, ritonavir boosted lopinavir, nelfinavir, and tenofovir) were associated with lower performance, although all groups were within the normal range. No ARVs or classes were associated with lower performance between 5 and 13 years of age. Atazanavir and saquinavir exposure were associated with late language emergence at 1 year, but not at 2 years of age. The results of the SMARTT study are generally reassuring, with little evidence for serious adverse events resulting from in utero ARV exposure. However, several findings of concern warrant further evaluation, and new ARVs used in pregnancy need to be evaluated. PMID- 27242800 TI - Heterosubtypic T-Cell Immunity to Influenza in Humans: Challenges for Universal T Cell Influenza Vaccines. AB - Influenza A virus (IAV) remains a significant global health issue causing annual epidemics, pandemics, and sporadic human infections with highly pathogenic avian or swine influenza viruses. Current inactivated and live vaccines are the mainstay of the public health response to influenza, although vaccine efficacy is lower against antigenically distinct viral strains. The first pandemic of the twenty-first century underlined the urgent need to develop new vaccines capable of protecting against a broad range of influenza strains. Such "universal" influenza vaccines are based on the idea of heterosubtypic immunity, wherein immune responses to epitopes conserved across IAV strains can confer protection against subsequent infection and disease. T-cells recognizing conserved antigens are a key contributor in reducing viral load and limiting disease severity during heterosubtypic infection in animal models. Recent studies undertaken during the 2009 H1N1 pandemic provided key insights into the role of cross-reactive T-cells in mediating heterosubtypic protection in humans. This review focuses on human influenza to discuss the epidemiological observations that underpin cross protective immunity, the role of T-cells as key players in mediating heterosubtypic immunity including recent data from natural history cohort studies and the ongoing clinical development of T-cell-inducing universal influenza vaccines. The challenges and knowledge gaps for developing vaccines to generate long-lived protective T-cell responses is discussed. PMID- 27242804 TI - A Targeted Management of the Nutrient Solution in a Soilless Tomato Crop According to Plant Needs. AB - The adoption of closed soilless systems is useful in minimizing the environmental impact of the greenhouse crops. Instead, a significant problem in closed soilless systems is represented by the accumulation of ions in the recycled nutrient solution (NS), in particular the unabsorbed or poorly absorbed ones. To overcome such problem, we: (1) studied the effect of several values of the electrical conductivity (EC) of NS in a NFT (Nutrient Film Technique) system on a cherry type tomato crop, and (2) define a NS (called recovery solution), based on the concept of "uptake concentration" and transpiration-biomass ratio, that fits the real needs of the plant with respect to water and nutrients. Three levels of EC set point (SP), above which the NS was completely replaced (SP5, SP7.5, and SP10 for the EC limit of 5, 7.5, and 10 dS m(-1), respectively), were established. The SP10 treatment yield was not different from other treatments, and it allowed a better quality of the berries (for dry matter and total soluble solids) and higher environmental sustainability due to a lower discharge of total nutrients into the environment (37 and 59% with respect to SP7.5 and SP5, respectively). The recovery solution used in the second trial allowed a more punctual NS management, by adapting to the real needs of the crop. Moreover, it allowed a lesser amount of water and nutrients to be discharged into the environment and a better use of brackish water, due to a more accurate management of the EC of the NS. The targeted management, based on transpiration-biomass ratio, indicates that, in some stages of the plant cycle, the NS used can be diluted, in order to save water and nutrients. With such management a closed cycle can be realized without affecting the yield, but improving the quality of the tomato berries. PMID- 27242803 TI - Selection and Validation of Housekeeping Genes as Reference for Gene Expression Studies in Pigeonpea (Cajanus cajan) under Heat and Salt Stress Conditions. AB - To identify stable housekeeping genes as a reference for expression analysis under heat and salt stress conditions in pigeonpea, the relative expression variation for 10 commonly used housekeeping genes (EF1alpha, UBQ10, GAPDH, 18Sr RNA, 25Sr RNA, TUB6, ACT1, IF4alpha, UBC, and HSP90) was studied in root, stem, and leaves tissues of Asha (ICPL 87119), a leading pigeonpea variety. Three statistical algorithms geNorm, NormFinder, and BestKeeper were used to define the stability of candidate genes. Under heat stress, UBC, HSP90, and GAPDH were found to be the most stable reference genes. In the case of salinity stress, GAPDH followed by UBC and HSP90 were identified to be the most stable reference genes. Subsequently, the above identified genes were validated using qRT-PCR based gene expression analysis of two universal stress-resposive genes namely uspA and uspB. The relative quantification of these two genes varied according to the internal controls (most stable, least stable, and combination of most stable and least stable housekeeping genes) and thus confirmed the choice as well as validation of internal controls in such experiments. The identified and validated housekeeping genes will facilitate gene expression studies under heat and salt stress conditions in pigeonpea. PMID- 27242805 TI - High-Throughput Growth Prediction for Lactuca sativa L. Seedlings Using Chlorophyll Fluorescence in a Plant Factory with Artificial Lighting. AB - Poorly grown plants that result from differences in individuals lead to large profit losses for plant factories that use large electric power sources for cultivation. Thus, identifying and culling the low-grade plants at an early stage, using so-called seedlings diagnosis technology, plays an important role in avoiding large losses in plant factories. In this study, we developed a high throughput diagnosis system using the measurement of chlorophyll fluorescence (CF) in a commercial large-scale plant factory, which produces about 5000 lettuce plants every day. At an early stage (6 days after sowing), a CF image of 7200 seedlings was captured every 4 h on the final greening day by a high-sensitivity CCD camera and an automatic transferring machine, and biological indices were extracted. Using machine learning, plant growth can be predicted with a high degree of accuracy based on biological indices including leaf size, amount of CF, and circadian rhythms in CF. Growth prediction was improved by addition of temporal information on CF. The present data also provide new insights into the relationships between growth and temporal information regulated by the inherent biological clock. PMID- 27242806 TI - Applications of 2-deoxy-2-fluoro-D-glucose (FDG) in Plant Imaging: Past, Present, and Future. AB - The aim of this review article is to explore and establish the current status of 2-deoxy-2-fluoro-D-glucose (FDG) applications in plant imaging. In the present article, we review the previous literature on its experimental merits to formulate a consistent and inclusive picture of FDG applications in plant-imaging research. 2-deoxy-2-fluoro-D-glucose is a [(18)F]fluorine-labeled glucose analog in which C-2 hydroxyl group has been replaced by a positron-emitting [(18)F] radioisotope. As FDG is a positron-emitting radiotracer, it could be used in in vivo imaging studies. FDG mimics glucose chemically and structurally. Its uptake and distribution are found to be similar to those of glucose in animal models. FDG is commonly used as a radiotracer for glucose in medical diagnostics and in vivo animal imaging studies but rarely in plant imaging. Tsuji et al. (2002) first reported FDG uptake and distribution in tomato plants. Later, Hattori et al. (2008) described FDG translocation in intact sorghum plants and suggested that it could be used as a tracer for photoassimilate translocation in plants. These findings raised interest among other plant scientists, which has resulted in a recent surge of articles involving the use of FDG as a tracer in plants. There have been seven studies describing FDG-imaging applications in plants. These studies describe FDG applications ranging from monitoring radiotracer translocation to analyzing solute transport, root uptake, photoassimilate tracing, carbon allocation, and glycoside biosynthesis. Fatangare et al. (2015) recently characterized FDG metabolism in plants; such knowledge is crucial to understanding and validating the application of FDG in plant imaging research. Recent FDG studies significantly advance our understanding of FDG translocation and metabolism in plants but also raise new questions. Here, we take a look at all the previous results to form a comprehensive picture of FDG translocation, metabolism, and applications in plants. In conclusion, we summarize current knowledge, discuss possible implications and limitations of previous studies, point to open questions in the field, and comment on the outlook for FDG applications in plant imaging. PMID- 27242808 TI - De novo Taproot Transcriptome Sequencing and Analysis of Major Genes Involved in Sucrose Metabolism in Radish (Raphanus sativus L.). AB - Radish (Raphanus sativus L.) is an important annual or biennial root vegetable crop. The fleshy taproot comprises the main edible portion of the plant with high nutrition and medical value. Molecular biology study of radish begun rather later, and lacks sufficient transcriptomic and genomic data in pubic databases for understanding of the molecular mechanism during the radish taproot formation. To develop a comprehensive overview of the 'NAU-YH' root transcriptome, a cDNA library, prepared from three equally mixed RNA of taproots at different developmental stages including pre-cortex splitting stage, cortex splitting stage, and expanding stage was sequenced using high-throughput Illumina RNA sequencing. From approximately 51 million clean reads, a total of 70,168 unigenes with a total length of 50.28 Mb, an average length of 717 bp and a N50 of 994 bp were obtained. In total, 63,991 (about 91.20% of the assembled unigenes) unigenes were successfully annotated in five public databases including NR, GO, COG, KEGG, and Nt. GO analysis revealed that the majority of these unigenes were predominately involved in basic physiological and metabolic processes, catalytic, binding, and cellular process. In addition, a total of 103 unigenes encoding eight enzymes involved in the sucrose metabolism related pathways were also identified by KEGG pathway analysis. Sucrose synthase (29 unigenes), invertase (17 unigenes), sucrose-phosphate synthase (16 unigenes), fructokinase (17 unigenes), and hexokinase (11 unigenes) ranked top five in these eight key enzymes. From which, two genes (RsSuSy1, RsSPS1) were validated by T-A cloning and sequenced, while the expression of six unigenes were profiled with RT-qPCR analysis. These results would be served as an important public reference platform to identify the related key genes during taproot thickening and facilitate the dissection of molecular mechanisms underlying taproot formation in radish. PMID- 27242809 TI - Kinetic Modeling of Sunflower Grain Filling and Fatty Acid Biosynthesis. AB - Grain growth and oil biosynthesis are complex processes that involve various enzymes placed in different sub-cellular compartments of the grain. In order to understand the mechanisms controlling grain weight and composition, we need mathematical models capable of simulating the dynamic behavior of the main components of the grain during the grain filling stage. In this paper, we present a non-structured mechanistic kinetic model developed for sunflower grains. The model was first calibrated for sunflower hybrid ACA855. The calibrated model was able to predict the theoretical amount of carbohydrate equivalents allocated to the grain, grain growth and the dynamics of the oil and non-oil fraction, while considering maintenance requirements and leaf senescence. Incorporating into the model the serial-parallel nature of fatty acid biosynthesis permitted a good representation of the kinetics of palmitic, stearic, oleic, and linoleic acids production. A sensitivity analysis showed that the relative influence of input parameters changed along grain development. Grain growth was mostly affected by the specific growth parameter (MU') while fatty acid composition strongly depended on their own maximum specific rate parameters. The model was successfully applied to two additional hybrids (MG2 and DK3820). The proposed model can be the first building block toward the development of a more sophisticated model, capable of predicting the effects of environmental conditions on grain weight and composition, in a comprehensive and quantitative way. PMID- 27242810 TI - Sunflower Resistance to Broomrape (Orobanche cumana) Is Controlled by Specific QTLs for Different Parasitism Stages. AB - Orobanche cumana (sunflower broomrape) is an obligatory and non-photosynthetic root parasitic plant that specifically infects the sunflower. It is located in Europe and in Asia, where it can cause yield losses of over 80%. More aggressive races have evolved, mainly around the Black Sea, and broomrape can rapidly spread to new areas. Breeding for resistance seems to be the most efficient and sustainable approach to control broomrape infestation. In our study, we used a population of 101 recombinant inbred lines (RILs), derived from a cross between the two lines HA89 and LR1 (a line derived from an interspecific cross with Helianthus debilis). Rhizotrons, pots and field experiments were used to characterize all RILs for their resistance to O. cumana race F parasitism at three post vascular connection life stages: (i) early attachment of the parasite to the sunflower roots, (ii) young tubercle and (iii) shoot emergence. In addition, RIL resistance to race G at young tubercle development stage was evaluated in pots. The entire population was genotyped, and QTLs were mapped. Different QTLs were identified for each race (F from Spain and G from Turkey) and for the three stages of broomrape development. The results indicate that there are several quantitative resistance mechanisms controlling the infection by O. cumana that can be used in sunflower breeding. PMID- 27242807 TI - Tuning of Redox Regulatory Mechanisms, Reactive Oxygen Species and Redox Homeostasis under Salinity Stress. AB - Soil salinity is a crucial environmental constraint which limits biomass production at many sites on a global scale. Saline growth conditions cause osmotic and ionic imbalances, oxidative stress and perturb metabolism, e.g., the photosynthetic electron flow. The plant ability to tolerate salinity is determined by multiple biochemical and physiological mechanisms protecting cell functions, in particular by regulating proper water relations and maintaining ion homeostasis. Redox homeostasis is a fundamental cell property. Its regulation includes control of reactive oxygen species (ROS) generation, sensing deviation from and readjustment of the cellular redox state. All these redox related functions have been recognized as decisive factors in salinity acclimation and adaptation. This review focuses on the core response of plants to overcome the challenges of salinity stress through regulation of ROS generation and detoxification systems and to maintain redox homeostasis. Emphasis is given to the role of NADH oxidase (RBOH), alternative oxidase (AOX), the plastid terminal oxidase (PTOX) and the malate valve with the malate dehydrogenase isoforms under salt stress. Overwhelming evidence assigns an essential auxiliary function of ROS and redox homeostasis to salinity acclimation of plants. PMID- 27242811 TI - Jasmonic Acid Modulates the Physio-Biochemical Attributes, Antioxidant Enzyme Activity, and Gene Expression in Glycine max under Nickel Toxicity. AB - In present study, we evaluated the effects of Jasmonic acid (JA) on physio biochemical attributes, antioxidant enzyme activity, and gene expression in soybean (Glycine max L.) plants subjected to nickel (Ni) stress. Ni stress decreases the shoot and root length and chlorophyll content by 37.23, 38.31, and 39.21%, respectively, over the control. However, application of JA was found to improve the chlorophyll content and length of shoot and root of Ni-fed seedlings. Plants supplemented with JA restores the chlorophyll fluorescence, which was disturbed by Ni stress. The present study demonstrated increase in proline, glycinebetaine, total protein, and total soluble sugar (TSS) by 33.09, 51.26, 22.58, and 49.15%, respectively, under Ni toxicity over the control. Addition of JA to Ni stressed plants further enhanced the above parameters. Ni stress increases hydrogen peroxide (H2O2) by 68.49%, lipid peroxidation (MDA) by 50.57% and NADPH oxidase by 50.92% over the control. Supplementation of JA minimizes the accumulation of H2O2, MDA, and NADPH oxidase, which helps in stabilization of biomolecules. The activities of superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and ascorbate peroxidase (APX) increases by 40.04, 28.22, 48.53, and 56.79%, respectively, over the control in Ni treated seedlings and further enhancement in the antioxidant activity was observed by the application of JA. Ni treated soybean seedlings showed increase in expression of Fe-SOD by 77.62, CAT by 15.25, POD by 58.33, and APX by 80.58% over the control. Nevertheless, application of JA further enhanced the expression of the above genes in the present study. Our results signified that Ni stress caused negative impacts on soybean seedlings, but, co-application of JA facilitate the seedlings to combat the detrimental effects of Ni through enhanced osmolytes, activity of antioxidant enzymes and gene expression. PMID- 27242812 TI - Clarification on Host Range of Didymella pinodes the Causal Agent of Pea Ascochyta Blight. AB - Didymella pinodes is the principal causal agent of ascochyta blight, one of the most important fungal diseases of pea (Pisum sativum) worldwide. Understanding its host specificity has crucial implications in epidemiology and management; however, this has not been clearly delineated yet. In this study we attempt to clarify the host range of D. pinodes and to compare it with that of other close Didymella spp. D. pinodes was very virulent on pea accessions, although differences in virulence were identified among isolates. On the contrary, studied isolates of D. fabae, D. rabiei, and D. lentil showed a reduced ability to infect pea not causing macroscopically visible symptoms on any of the pea accessions tested. D. pinodes isolates were also infective to some extend on almost all species tested including species such as Hedysarum coronarium, Lathyrus sativus, Lupinus albus, Medicago spp., Trifolium spp., Trigonella foenum-graecum, and Vicia articulata which were not mentioned before as hosts of D. pinodes. On the contrary, D. lentil and D. rabiei were more specific, infecting only lentil and chickpea, respectively. D. fabae was intermediate, infecting mainly faba bean, but also slightly other species such as Glycine max, Phaseolus vulgaris, Trifolium spp., Vicia sativa, and V. articulata. DNA sequence analysis of the nuclear ribosomal internal transcribed spacer region (ITS) was performed to confirm identity of the isolates studies and to determine phylogenetic relationship among the Didymella species, revealing the presence of two clearly distinct clades. Clade one was represented by two supported subclusters including D. fabae isolates as well as D. rabiei with D. lentil isolates. Clade two was the largest and included all the D. pinodes isolates as well as Phoma medicaginis var. pinodella. Genetic distance between D. pinodes and the other Didymella spp. isolates was not correlated with overall differences in pathogenicity. Based on evidences presented here, D. pinodes is not specialized on pea and its host range is larger than that of D. fabae, D. lentil, and D. rabiei. This has relevant implications in epidemiology and control as these species might act as alternative hosts for D. pinodes. PMID- 27242813 TI - Biological Implications in Cassava for the Production of Amylose-Free Starch: Impact on Root Yield and Related Traits. AB - Cassava (Manihot esculenta, Crantz) is an important food security crop, but it is becoming an important raw material for different industrial applications. Cassava is the second most important source of starch worldwide. Novel starch properties are of interest to the starch industry, and one them is the recently identified amylose-free (waxy) cassava starch. Waxy mutants have been found in different crops and have been often associated with a yield penalty. There are ongoing efforts to develop commercial cassava varieties with amylose-free starch. However, little information is available regarding the biological and agronomic implications of starch mutations in cassava, nor in other root and tuber crops. In this study, siblings from eight full-sib families, segregating for the waxy trait, were used to determine if the mutation has implications for yield, dry matter content (DMC) and harvest index in cassava. A total of 87 waxy and 87 wild type starch genotypes from the eight families were used in the study. The only significant effect of starch type was on DMC (p < 0.01), with waxy clones having a 0.8% lower content than their wild type counterparts. There was no effect of starch type on fresh root yield (FRY), adjusted FRY and harvest index. It is not clear if lower DMC is a pleiotropic effect of the waxy starch mutation or else the result of linked genes introgressed along with the mutation. It is expected that commercial waxy cassava varieties will have competitive FRYs but special efforts will be required to attain adequate DMCs. This study contributes to the limited knowledge available of the impact of starch mutations on the agronomic performance of root and tuber crops. PMID- 27242815 TI - Development of a Worldwide Consortium on Evolutionary Participatory Breeding in Quinoa. AB - Chenopodium quinoa is gaining global importance due to its excellent protein quality and tolerance of abiotic stresses. The last 60 years have seen major strides in the expansion of quinoa crop production and experimentation. Quinoa's wide genetic diversity has led to its agronomic versatility and adaptation to different soil types, particularly saline soils, and environments with extremely variable conditions in terms of humidity, altitude, and temperature. The potential of quinoa to contribute to global food security was recognized in 2013 in the declaration of the International Year of Quinoa (IYQ). Promoting the use of improved homogeneous quinoa varieties standardized to comply with applicable norms on seeds or suited to intensified conventional agriculture farming systems may not generate the necessary resilience needed to respond to current and future global challenges. Maintaining and increasing quinoa biodiversity is imperative, as the dynamics of the global expansion of quinoa may constitute a threat to farmers if the spread is generated with a narrow genetic base. In this article, we propose that the method of evolutionary participatory breeding could be a useful tool to develop new quinoa genetic material in cooperation with farmers. We introduce preliminary results on quinoa population development with farmers in the Pacific Northwest region of the USA. We conclude that a global collaborative network on quinoa (GCN-Quinoa) could be the baseline for participatory plant breeding programs originating in developing or developed countries to meet the needs of farmers across a diversity of agronomic systems and a wide range of physical environments. PMID- 27242814 TI - Trait Acclimation Mitigates Mortality Risks of Tropical Canopy Trees under Global Warming. AB - There is a heated debate about the effect of global change on tropical forests. Many scientists predict large-scale tree mortality while others point to mitigating roles of CO2 fertilization and - the notoriously unknown - physiological trait acclimation of trees. In this opinion article we provided a first quantification of the potential of trait acclimation to mitigate the negative effects of warming on tropical canopy tree growth and survival. We applied a physiological tree growth model that incorporates trait acclimation through an optimization approach. Our model estimated the maximum effect of acclimation when trees optimize traits that are strongly plastic on a week to annual time scale (leaf photosynthetic capacity, total leaf area, stem sapwood area) to maximize carbon gain. We simulated tree carbon gain for temperatures (25 35 degrees C) and ambient CO2 concentrations (390-800 ppm) predicted for the 21st century. Full trait acclimation increased simulated carbon gain by up to 10-20% and the maximum tolerated temperature by up to 2 degrees C, thus reducing risks of tree death under predicted warming. Functional trait acclimation may thus increase the resilience of tropical trees to warming, but cannot prevent tree death during extremely hot and dry years at current CO2 levels. We call for incorporating trait acclimation in field and experimental studies of plant functional traits, and in models that predict responses of tropical forests to climate change. PMID- 27242816 TI - Calcium Supplementation Improves Na(+)/K(+) Ratio, Antioxidant Defense and Glyoxalase Systems in Salt-Stressed Rice Seedlings. AB - The present study investigates the regulatory role of exogenous calcium (Ca) in developing salt stress tolerance in rice seedlings. Hydroponically grown 13-day old rice (Oryza sativa L. cv. BRRI dhan47) seedlings were exposed to 200 mM NaCl alone and combined with 2 mM CaCl2 and 2 mM ethylene glycol tetraacetic acid (EGTA, a Ca scavenger) for 3 days. The salt stress caused growth inhibition, chlorosis and water shortage in the rice seedlings. The salt-induced stress disrupted ion homeostasis through Na(+) influx and K(+) efflux, and decreased other mineral nutrient uptake. Salt stress caused oxidative stress in seedlings through lipid peroxidation, loss of plasma membrane integrity, higher reactive oxygen species (ROS) production and methylglyoxal (MG) formation. The salt stressed seedlings supplemented with exogenous Ca recovered from water loss, chlorosis and growth inhibition. Calcium supplementation in the salt-stressed rice seedlings improved ion homeostasis by inhibition of Na(+) influx and K(+) leakage. Exogenous Ca also improved ROS and MG detoxification by improving the antioxidant defense and glyoxalase systems, respectively. On the other hand, applying EGTA along with salt and Ca again negatively affected the seedlings as EGTA negated Ca activity. It confirms that, the positive responses in salt stressed rice seedlings to exogenous Ca were for Ca mediated improvement of ion homeostasis, antioxidant defense and glyoxalase system. PMID- 27242817 TI - A Pragmatic Approach to Getting Published: 35 Tips for Early Career Researchers. AB - It is trite to say "publish or perish," yet many early career researchers are often at a loss on how to best get their work published. With strong competition and many manuscripts submitted, it is difficult to convince editors and reviewers to opt for acceptance. A pragmatic approach to publishing may increase one's odds of success. Here, we - a group of postdocs in the field of plant science - present specific recommendations for early career scientists on advanced levels. We cannot provide a recipe-like set of instructions with success guaranteed, but we come from a broad background in plant science, with experience publishing in a number of journals of varying topics and impact factors. We provide tips, tricks, and tools for collaboration, journal selection, and achieving acceptance. PMID- 27242818 TI - Regulation of the Regulators: Post-Translational Modifications, Subcellular, and Spatiotemporal Distribution of Plant 14-3-3 Proteins. AB - 14-3-3 proteins bind to and modulate the activity of phosphorylated proteins that regulate a variety of metabolic processes in eukaryotes. Multiple 14-3-3 isoforms are expressed in most organisms and display redundancy in both sequence and function. Plants contain the largest number of 14-3-3 isoforms. For example, Arabidopsis thaliana contains thirteen 14-3-3 genes, each of which is expressed. Interest in the plant 14-3-3 field has swelled over the past decade, largely due to the vast number of possibilities for 14-3-3 metabolic regulation. As the field progresses, it is essential to understand these proteins' activities at both the spatiotemporal and subcellular levels. This review summarizes current knowledge of 14-3-3 proteins in plants, including 14-3-3 interactions, regulatory functions, isoform specificity, and post-translational modifications. We begin with a historical overview and structural analysis of 14-3-3 proteins, which describes the basic principles of 14-3-3 function, and then discuss interactions and regulatory effects of plant 14-3-3 proteins in specific tissues and subcellular compartments. We conclude with a summary of 14-3-3 phosphorylation and current knowledge of the functional effects of this modification in plants. PMID- 27242819 TI - Heterologous Overexpression of Poplar SnRK2 Genes Enhanced Salt Stress Tolerance in Arabidopsis thaliana. AB - Subfamily 2 of SNF1-related protein kinase (SnRK2) plays important roles in plant abiotic stress responses as a global positive regulator of abscisic acid signaling. In the genome of the model tree Populus trichocarpa, 12 SnRK2 genes have been identified, and some are upregulated by abiotic stresses. In this study, we heterologously overexpressed the PtSnRK2 genes in Arabidopsis thaliana and found that overexpression of PtSnRK2.5 and PtSnRK2.7 genes enhanced stress tolerance. In the PtSnRK2.5 and PtSnRK2.7 overexpressors, chlorophyll content, and root elongation were maintained under salt stress conditions, leading to higher survival rates under salt stress compared with those in the wild type. Transcriptomic analysis revealed that PtSnRK2.7 overexpression affected stress related metabolic genes, including lipid metabolism and flavonoid metabolism, even under normal growth conditions. However, the stress response genes reported to be upregulated in Arabidopsis SRK2C/SnRK2.6 and wheat SnRK2.8 overexpressors were not changed by PtSnRK2.7 overexpression. Furthermore, PtSnRK2.7 overexpression widely and largely influenced the transcriptome in response to salt stress; genes related to transport activity, including anion transport related genes, were characteristically upregulated, and a variety of metabolic genes were specifically downregulated. We also found that the salt stress response genes were greatly upregulated in the PtSnRK2.7 overexpressor. Taken together, poplar subclass 2 PtSnRK2 genes can modulate salt stress tolerance in Arabidopsis, through the activation of cellular signaling pathways in a different manner from that by herbal subclass 2 SnRK2 genes. PMID- 27242821 TI - Brassinosteroid Ameliorates Zinc Oxide Nanoparticles-Induced Oxidative Stress by Improving Antioxidant Potential and Redox Homeostasis in Tomato Seedling. AB - In the last few decades use of metal-based nanoparticles (MNPs) has been increased significantly that eventually contaminating agricultural land and limiting crop production worldwide. Moreover, contamination of food chain with MNPs has appeared as a matter of public concern due to risk of potential health hazard. Brassinosteroid has been shown to play a critical role in alleviating heavy metal stress; however, its function in relieving zinc oxide nanoparticles (ZnO NPs)-induced phytotoxicity remains unknown. In this study, we investigated the potential role of 24-epibrassinolide (BR) in mitigating ZnO NPs-induced toxicity in tomato seedlings. Seedling growth, biomass production, and root activity gradually decreased, but Zn accumulation increased with increasing ZnO NPs concentration (10-100 mg/L) in growth media (1/2 MS). The augmentation of BR (5 nM) in media significantly ameliorated 50 mg/L ZnO NPs-induced growth inhibition. Visualization of hydrogen peroxide (H2O2), and quantification of H2O2 and malondialdehyde (MDA) in tomato roots confirmed that ZnO NPs induced an oxidative stress. However, combined treatment with BR and ZnO NPs remarkably reduced concentration of H2O2 and MDA as compared with ZnO NPs only treatment, indicating that BR supplementation substantially reduced oxidative stress. Furthermore, the activities of key antioxidant enzymes such as superoxide dismutase (SOD), catalase, ascorbate peroxidase and glutathione reductase were increased by combined treatment of BR and ZnO NPs compared with ZnO NPs only treatment. BR also increased reduced glutathione (GSH), but decreased oxidized glutathione (GSSG)] and thus improved cellular redox homeostasis by increasing GSH:GSSG ratio. The changes in relative transcript abundance of corresponding antioxidant genes such as Cu/Zn SOD, CAT1, GSH1, and GR1 were in accordance with the changes in those antioxidants under different treatments. More importantly, combined application of BR and ZnO NPs significantly decreased Zn content in both shoot and root of tomato seedlings as compared with ZnO NPs alone. Taken together, this study, for the first time, showed that BR could not only improve plant tolerance to ZnO NPs but also reduce the excess zinc content in tomato seedlings. Such a finding may have potential implication in safe vegetable production in the MNPs-polluted areas. PMID- 27242820 TI - Holophytochrome-Interacting Proteins in Physcomitrella: Putative Actors in Phytochrome Cytoplasmic Signaling. AB - Phytochromes are the principle photoreceptors in light-regulated plant development, primarily acting via translocation of the light-activated photoreceptor into the nucleus and subsequent gene regulation. However, several independent lines of evidence indicate unambiguously that an additional cytoplasmic signaling mechanism must exist. Directional responses in filament tip cells of the moss Physcomitrella patens are steered by phy4 which has been shown to interact physically with the blue light receptor phototropin at the plasma membrane. This complex might perceive and transduce vectorial information leading to cytoskeleton reorganization and finally a directional growth response. We developed yeast two-hybrid procedures using photochemically functional, full length phy4 as bait in Physcomitrella cDNA library screens and growth assays under different light conditions, revealing Pfr-dependent interactions possibly associated with phytochrome cytoplasmic signaling. Candidate proteins were then expressed in planta with fluorescent protein tags to determine their intracellular localization in darkness and red light. Of 14 candidates, 12 were confirmed to interact with phy4 in planta using bimolecular fluorescence complementation. We also used database information to study their expression patterns relative to those of phy4. We discuss the likely functional characteristics of these holophytochrome-interacting proteins (HIP's) and their possible roles in signaling. PMID- 27242822 TI - Overexpression of Thiamin Biosynthesis Genes in Rice Increases Leaf and Unpolished Grain Thiamin Content But Not Resistance to Xanthomonas oryzae pv. oryzae. AB - Thiamin diphosphate (ThDP), also known as vitamin B1, serves as an enzymatic cofactor in glucose metabolism, the Krebs cycle, and branched-chain amino acid biosynthesis in all living organisms. Unlike plants and microorganisms, humans are not able to synthesize ThDP de novo and must obtain it from their diet. Staple crops such as rice are poor sources of thiamin. Hence, populations that mainly consume rice commonly suffer thiamin deficiency. In addition to thiamin's nutritional function, studies in rice have shown that some thiamin biosynthesis genes are involved in resistance to Xanthomonas oryzae, which causes a serious disease in rice fields. This study shows that overexpression of two thiamin biosynthesis genes, 4-methyl-5-beta-hydroxyethylthiazole phosphate synthase and 4 amino-2-methyl-5-hydroxymethylpyrimidine phosphate synthase, involved in the first steps of the thiazole and pyrimidine synthesis branches, respectively, increased thiamin content up to fivefold in unpolished seeds that retain the bran. However, thiamin levels in polished seeds with removed bran were similar to those found in polished control seeds. Plants with higher accumulation of thiamin did not show enhanced resistance to X. oryzae. These results indicate that stacking of two traits can enhance thiamin accumulation in rice unpolished grain. We discuss potential roadblocks that prevent thiamin accumulation in the endosperm. PMID- 27242824 TI - Genetic Screening for Arabidopsis Mutants Defective in STA1 Regulation under Thermal Stress Implicates the Existence of Regulators of Its Specific Expression, and the Genetic Interactions in the Stress Signaling Pathways. AB - To cope with environmental stresses, plants have developed various stress tolerance mechanisms that involve the induction of many stress responsive genes through stress-specific and common signaling pathways. Stress-specific/common transcription factors, rather than general basal factors, were considered important in this stress tolerance. The Arabidopsis STABILIZED1 (STA1) gene encodes a putative pre-mRNA splicing factor that is similar to the human U5 snRNP associated 102-kDa protein and the yeast pre-mRNA splicing factors, PRP1p and Prp6p. As pre-mRNA splicing is a necessary process for proper gene expression in eukaryotes, STA1 is expected to be constantly functional in all conditions. Interestingly, STA1 expression is induced by temperature stresses, and STA1 recessive mutation (sta1-1) resulted in temperature stress-specific hypersensitivity. This suggests STA1's stress specific function in addition to its presumed "housekeeping" role. In order to establish the genetic system to understand the regulation of STA1 expression in temperature stresses, we generated a bioluminescent Arabidopsis plant harboring the STA1 promoter fused to the firefly luciferase coding sequence (STA1p-LUC). Through genetic analysis, the bioluminescent Arabidopsis homozygous for one-copy STA1p-LUC was isolated and characterized. In this STA1p-LUC line, the expression patterns of STA1p-LUC were similar to those of the endogenous STA1 gene under cold and heat stresses. The STA1p-LUC line was then chemically mutagenized and screened to isolate the genetic loci of STA1 regulators under cold or heat stresses. Mutants with altered STA1p-LUC luminescence were identified and further confirmed through luminescence imaging in the next generation and analysis of endogenous STA1 expression. The categorization of STA1p-LUC deregulated mutants implicated the existence of cold or heat stress-specific as well as common genetic regulators for STA1 expression. Interestingly, some mutants showed opposite-directional deregulation of STA1 expression depending on the type of thermal stress, suggesting that the loci may represent important switch factors which determine the direction of signaling pathways for STA1 expression in response to temperature. PMID- 27242826 TI - The Global Expansion of Quinoa: Trends and Limits. AB - Quinoa (Chenopodium quinoa Willd.) was first domesticated in Andean countries over 7000 years ago. Following the Spanish conquest, quinoa was rejected as "Indian food." After centuries of neglect, the potential of quinoa was rediscovered during the second half of the 20th century. Since then, the number of countries importing quinoa increased, with new producers appearing on the map and quinoa now being cultivated in areas outside the Andean countries. The geographical increase in distribution of quinoa has highlighted the difficulty of access to quality seed, which is a key factor for testing the crop outside the Andes. In this context, research partnerships have helped promote the exchange of quinoa germplasm and have allowed trials to be undertaken in non-traditional areas of cultivation. The number of countries growing the crop has increased rapidly from eight in 1980, to 40 in 2010, and to 75 in 2014. A further 20 countries have sown quinoa for the first time in 2015. In this paper, we analyze this trend and discuss the limits of quinoa's expansion. As commercial production of quinoa is expected to develop, changes in international regulatory frameworks on genetic resources are needed in order to facilitate plant breeding for the most adaptive varieties for each region. PMID- 27242825 TI - Public Availability of a Genotyped Segregating Population May Foster Marker Assisted Breeding (MAB) and Quantitative Trait Loci (QTL) Discovery: An Example Using Strawberry. AB - Much of the cost associated with marker discovery for marker assisted breeding (MAB) can be eliminated if a diverse, segregating population is generated, genotyped, and made available to the global breeding community. Herein, we present an example of a hybrid, wild-derived family of the octoploid strawberry that can be used by other breeding programs to economically find and tag useful genes for MAB. A pseudo test cross population between two wild species of Fragaria virginiana and F. chiloensis (FVC 11) was generated and evaluated for a set of phenotypic traits. A total of 106 individuals in the FVC 11 were genotyped for 29,251 single nucleotide polymorphisms (SNPs) utilizing a commercially available, genome-wide scanning platform (Affymetrix Axiom IStraw90(TW)). The marker trait associations were deduced using TASSEL software. The FVC 11 population segregating for daughters per mother, inflorescence number, inflorescence height, crown production, flower number, fruit size, yield, internal color, soluble solids, fruit firmness, and plant vigor. Coefficients of variations ranged from 10% for fruit firmness to 68% for daughters per mother, indicating an underlying quantitative inheritance for each trait. A total of 2,474 SNPs were found to be polymorphic in FVC 11 and strong marker trait associations were observed for vigor, daughters per mother, yield and fruit weight. These data indicate that FVC 11 can be used as a reference population for quantitative trait loci detection and subsequent MAB across different breeding programs and geographical locations. PMID- 27242827 TI - The qTSN4 Effect on Flag Leaf Size, Photosynthesis and Panicle Size, Benefits to Plant Grain Production in Rice, Depending on Light Availability. AB - Increasing rice yield potential is essential to secure world food supply. The quantitative trait locus qTSN4 was reported to achieve yield increases by enhancing both source and sink capacity. Three greenhouse experiments and one field experiment in the Philippines were conducted to study near-isogenic lines (NILs) in two genetic backgrounds, subjected to treatments with restricted light resources through shading (greenhouse) or population density (field and greenhouse). A consistent promotion of flag leaf width, leaf area and panicle size in terms of spikelet number was observed in the presence of qTSN4, regardless of environment. However, grain production per plant was enhanced only in one greenhouse experiment. An in-depth study demonstrated that increased flag leaf size in the presence of qTSN4 was associated with increased photosynthetic rates, along with lower SLA and greater N content per leaf weight and per area. This was emphasized under low light situation as the qTSN4-NILs did not express shade acclimation traits in contrast with the recipient varieties. The authors conclude that qTSN4 is a promising subject for further physiological studies, particularly under limited radiation. However, the QTL alone may not be a reliable source of increased yield potential because its effects at the plant and population scale are prone to genotype * environment interactions and the increased panicle size is compensated by the adaptive plasticity of other morphological traits. PMID- 27242823 TI - The Use of Advanced Mass Spectrometry to Dissect the Life-Cycle of Photosystem II. AB - Photosystem II (PSII) is a photosynthetic membrane-protein complex that undergoes an intricate, tightly regulated cycle of assembly, damage, and repair. The available crystal structures of cyanobacterial PSII are an essential foundation for understanding PSII function, but nonetheless provide a snapshot only of the active complex. To study aspects of the entire PSII life-cycle, mass spectrometry (MS) has emerged as a powerful tool that can be used in conjunction with biochemical techniques. In this article, we present the MS-based approaches that are used to study PSII composition, dynamics, and structure, and review the information about the PSII life-cycle that has been gained by these methods. This information includes the composition of PSII subcomplexes, discovery of accessory PSII proteins, identification of post-translational modifications and quantification of their changes under various conditions, determination of the binding site of proteins not observed in PSII crystal structures, conformational changes that underlie PSII functions, and identification of water and oxygen channels within PSII. We conclude with an outlook for the opportunity of future MS contributions to PSII research. PMID- 27242828 TI - Isolation and Characterization of Two Persimmon Xyloglucan Endotransglycosylase/Hydrolase (XTH) Genes That Have Divergent Functions in Cell Wall Modification and Fruit Postharvest Softening. AB - Fruit cell wall modification is the primary factor affecting fruit softening. Xyloglucan endotransglycosylase/hydrolase (XTH), a cell wall-modifying enzyme, is involved in fruit softening. In this study, two novel XTH genes (DkXTH6 and DkXTH7) were identified from persimmon fruit. Transcriptional profiles of both of the two genes were analyzed in different tissues of persimmon, and in response to multiple hormonal and environmental treatments [gibberellic acid (GA3), abscisic acid (ABA), propylene, and low temperature]. Expression of DkXTH6 was positively up-regulated during ethylene production and by propylene and ABA treatments, and suppressed by GA3 and cold treatment. In contrast, DkXTH7 exhibited its highest transcript levels in GA3-treated fruit and cold-treated fruit, which had higher fruit firmness. We found that DkXTH6 protein was localized in cell wall by its signal peptide, while cytoplasmic DkXTH7 protein contained no signal peptide. When expressed in vitro, the recombinant proteins of both DkXTH6 and DkXTH7 exhibited strict xyloglucan endotransglycosylase (XET) activity but no xyloglucan endohydrolase (XEH) activity. The recombinant protein of DkXTH6 showed a higher affinity with small acceptor molecules than the recombinant DkXTH7. Taken together with their opposing expression patterns and subcellular localizations, these results suggested that DkXTH6 might take part in cell wall restructuring and DkXTH7 was likely to be involved in cell wall assembly, indicating their special roles in persimmon fruit softening. PMID- 27242829 TI - Analysis of Cryptic, Systemic Botrytis Infections in Symptomless Hosts. AB - Botrytis species are generally considered to be aggressive, necrotrophic plant pathogens. By contrast to this general perception, however, Botrytis species could frequently be isolated from the interior of multiple tissues in apparently healthy hosts of many species. Infection frequencies reached 50% of samples or more, but were commonly less, and cryptic infections were rare or absent in some plant species. Prevalence varied substantially from year to year and from tissue to tissue, but some host species routinely had high prevalence. The same genotype was found to occur throughout a host, representing mycelial spread. Botrytis cinerea and Botrytis pseudocinerea are the species that most commonly occur as cryptic infections, but phylogenetically distant isolates of Botrytis were also detected, one of which does not correspond to previously described species. Sporulation and visible damage occurred only when infected tissues were stressed, or became mature or senescent. There was no evidence of cryptic infection having a deleterious effect on growth of the host, and prevalence was probably greater in plants grown in high light conditions. Isolates from cryptic infections were often capable of causing disease (to varying extents) when spore suspensions were inoculated onto their own host as well as on distinct host species, arguing against co-adaptation between cryptic isolates and their hosts. These data collectively suggest that several Botrytis species, including the most notorious pathogenic species, exist frequently in cryptic form to an extent that has thus far largely been neglected, and do not need to cause disease on healthy hosts in order to complete their life-cycles. PMID- 27242830 TI - The Thiol Reductase Activity of YUCCA6 Mediates Delayed Leaf Senescence by Regulating Genes Involved in Auxin Redistribution. AB - Auxin, a phytohormone that affects almost every aspect of plant growth and development, is biosynthesized from tryptophan via the tryptamine, indole-3 acetamide, indole-3-pyruvic acid, and indole-3-acetaldoxime pathways. YUCCAs (YUCs), flavin monooxygenase enzymes, catalyze the conversion of indole-3-pyruvic acid (IPA) to the auxin (indole acetic acid). Arabidopsis thaliana YUC6 also exhibits thiol-reductase and chaperone activity in vitro; these activities require the highly conserved Cys-85 and are essential for scavenging of toxic reactive oxygen species (ROS) in the drought tolerance response. Here, we examined whether the YUC6 thiol reductase activity also participates in the delay in senescence observed in YUC6-overexpressing (YUC6-OX) plants. YUC6 overexpression delays leaf senescence in natural and dark-induced senescence conditions by reducing the expression of SENESCENCE-ASSOCIATED GENE 12 (SAG12). ROS accumulation normally occurs during senescence, but was not observed in the leaves of YUC6-OX plants; however, ROS accumulation was observed in YUC6-OX(C85S) plants, which overexpress a mutant YUC6 that lacks thiol reductase activity. We also found that YUC6-OX plants, but not YUC6-OX(C85S) plants, show upregulation of three genes encoding NADPH-dependent thioredoxin reductases (NTRA, NTRB, and NTRC), and GAMMA-GLUTAMYLCYSTEINE SYNTHETASE 1 (GSH1), encoding an enzyme involved in redox signaling. We further determined that excess ROS accumulation caused by methyl viologen treatment or decreased glutathione levels caused by buthionine sulfoximine treatment can decrease the levels of auxin efflux proteins such as PIN2-4. The expression of PINs is also reduced in YUC6-OX plants. These findings suggest that the thiol reductase activity of YUC6 may play an essential role in delaying senescence via the activation of genes involved in redox signaling and auxin availability. PMID- 27242831 TI - Characterization of Rice Homeobox Genes, OsHOX22 and OsHOX24, and Over-expression of OsHOX24 in Transgenic Arabidopsis Suggest Their Role in Abiotic Stress Response. AB - Homeobox transcription factors are well known regulators of plant growth and development. In this study, we carried out functional analysis of two candidate stress-responsive HD-ZIP I class homeobox genes from rice, OsHOX22, and OsHOX24. These genes were highly up-regulated under various abiotic stress conditions at different stages of rice development, including seedling, mature and reproductive stages. The transcript levels of these genes were enhanced significantly in the presence of plant hormones, including abscisic acid (ABA), auxin, salicylic acid, and gibberellic acid. The recombinant full-length and truncated homeobox proteins were found to be localized in the nucleus. Electrophoretic mobility shift assay established the binding of these homeobox proteins with specific DNA sequences, AH1 (CAAT(A/T)ATTG) and AH2 (CAAT(C/G)ATTG). Transactivation assays in yeast revealed the transcriptional activation potential of full-length OsHOX22 and OsHOX24 proteins. Homo- and hetero-dimerization capabilities of these proteins have also been demonstrated. Further, we identified putative novel interacting proteins of OsHOX22 and OsHOX24 via yeast-two hybrid analysis. Over-expression of OsHOX24 imparted higher sensitivity to stress hormone, ABA, and abiotic stresses in the transgenic Arabidopsis plants as revealed by various physiological and phenotypic assays. Microarray analysis revealed differential expression of several stress-responsive genes in transgenic lines as compared to wild-type. Many of these genes were found to be involved in transcriptional regulation and various metabolic pathways. Altogether, our results suggest the possible role of OsHOX22/OsHOX24 homeobox proteins as negative regulators in abiotic stress responses. PMID- 27242833 TI - Brassinosteroids and Response of Plants to Heavy Metals Action. AB - Brassinosteroids (BRs) are a widespread group of plant hormones. These phytohormones play a crucial role in the regulation of growth and development of various plant species, and they demonstrate high biological activity. BRs are considered to demonstrate protective activity in the plants exposed to various stresses. Due to rapid industrialization and urbanization, heavy metals have become one of the most important plant stressors. In plants, accumulation of heavy metals beyond the critical levels leads to oxidative stress. However, BRs may inhibit the degradation of lipids, resulted from the overproduction of reactive oxygen species under stress conditions, and increase the activity of antioxidants. They also have the ability to promote phytochelatins synthesis. PMID- 27242832 TI - Identification of Two bZIP Transcription Factors Interacting with the Promoter of Soybean Rubisco Activase Gene (GmRCAalpha). AB - Rubisco activase (RCA), a key photosynthetic protein, catalyses the activation of Rubisco and thus plays an important role in photosynthesis. Although the RCA gene has been characterized in a variety of species, the molecular mechanism regulating its transcription remains unclear. Our previous studies on RCA gene expression in soybean suggested that expression of this gene is regulated by trans-acting factors. In the present study, we verified activity of the GmRCAalpha promoter in both soybean and Arabidopsis and used a yeast one-hybrid (Y1H) system for screening a leaf cDNA expression library to identify transcription factors (TFs) interacting with the GmRCAalpha promoter. Four basic leucine zipper (bZIP) TFs, GmbZIP04g, GmbZIP07g, GmbZIP1, and GmbZIP71, were isolated, and GmbZIP04g and GmbZIP07g were confirmed as able to bind to a 21-nt G box-containing sequence. Additionally, the expression patterns of GmbZIP04g, GmbZIp07g, and GmRCAalpha were analyzed in response to abiotic stresses and during a 24-h period. Our study will help to advance elucidation of the network regulating GmRCAalpha transcription. PMID- 27242835 TI - Plant Genetic Background Increasing the Efficiency and Durability of Major Resistance Genes to Root-knot Nematodes Can Be Resolved into a Few Resistance QTLs. AB - With the banning of most chemical nematicides, the control of root-knot nematodes (RKNs) in vegetable crops is now based essentially on the deployment of single, major resistance genes (R-genes). However, these genes are rare and their efficacy is threatened by the capacity of RKNs to adapt. In pepper, several dominant R-genes are effective against RKNs, and their efficacy and durability have been shown to be greater in a partially resistant genetic background. However, the genetic determinants of this partial resistance were unknown. Here, a quantitative trait loci (QTL) analysis was performed on the F2:3 population from the cross between Yolo Wonder, an accession considered partially resistant or resistant, depending on the RKN species, and Doux Long des Landes, a susceptible cultivar. A genetic linkage map was constructed from 130 F2 individuals, and the 130 F3 families were tested for resistance to the three main RKN species, Meloidogyne incognita, M. arenaria, and M. javanica. For the first time in the pepper-RKN pathosystem, four major QTLs were identified and mapped to two clusters. The cluster on chromosome P1 includes three tightly linked QTLs with specific effects against individual RKN species. The fourth QTL, providing specific resistance to M. javanica, mapped to pepper chromosome P9, which is known to carry multiple NBS-LRR repeats, together with major R-genes for resistance to nematodes and other pathogens. The newly discovered cluster on chromosome P1 has a broad spectrum of action with major additive effects on resistance. These data highlight the role of host QTLs involved in plant-RKN interactions and provide innovative potential for the breeding of new pepper cultivars or rootstocks combining quantitative resistance and major R-genes, to increase both the efficacy and durability of RKN control by resistance genes. PMID- 27242834 TI - Decreased Polysaccharide Feruloylation Compromises Plant Cell Wall Integrity and Increases Susceptibility to Necrotrophic Fungal Pathogens. AB - The complexity of cell wall composition and structure determines the strength, flexibility, and function of the primary cell wall in plants. However, the contribution of the various components to cell wall integrity (CWI) and function remains unclear. Modifications of cell wall composition can induce plant responses known as CWI control. In this study, we used transgenic expression of the fungal feruloyl esterase AnFAE to examine the effect of post-synthetic modification of Arabidopsis and Brachypodium cell walls. Transgenic Arabidopsis plants expressing AnFAE showed a significant reduction of monomeric ferulic acid, decreased amounts of wall-associated extensins, and increased susceptibility to Botrytis cinerea, compared with wild type. Transgenic Brachypodium showed reductions in monomeric and dimeric ferulic acids and increased susceptibility to Bipolaris sorokiniana. Upon infection, transgenic Arabidopsis and Brachypodium plants also showed increased expression of several defense-related genes compared with wild type. These results demonstrate a role, in both monocot and dicot plants, of polysaccharide feruloylation in plant CWI, which contributes to plant resistance to necrotrophic pathogens. PMID- 27242837 TI - Identification of Striga hermonthica-Resistant Upland Rice Varieties in Sudan and Their Resistance Phenotypes. AB - Rice has become a major staple cereal in sub-Saharan Africa. Currently, upland rice cultivation is expanding particularly in rainfed areas where the root parasitic weed Striga hermonthica, a major constraint to cereal production, is endemic. Laboratory, pot, and semi-controlled open air experiments were performed to evaluate resistance of selected rice varieties in Sudan to a resident S. hermonthica population. In the laboratory, 27 varieties were screened for post attachment resistance using the rhizotron technique. Varieties displaying high post-attachment resistance, Umgar, NERICA5, and NERICA13 together with NERICA4, NERICA18, and Nipponbare, a lowland rice variety, were further evaluated for performance and Striga resistance in pot and semi-controlled open air experiments and for germination inducing activity in a laboratory. In addition, comparative studies on reaction of Umgar, Kosti1 and Kosti2, released varieties for commercial production in Sudan, to the parasite were performed in two pot experiments. In the pot experiments Umgar and NERICA5, consistently, sustained the lowest Striga emergence (<2.2 Striga plants per pot), while NERICA13 and NERICA4 supported 1.8-5.7 and 8.7-16.4 Striga plants per pot, respectively. In an artificially Striga-infested field, number of emergent Striga plants per 10 rice hills, at harvest, was 2.0, 2.0, 4.8, 13.5, 13.3, and 18.3 on Umgar, NERICA5, NERICA13, NERICA4, NERICA18, and Nipponbare, respectively. Striga had no adverse effects on total above-ground parts and panicle dry weight in Umgar and NERICA5. Germination-inducing activity of root exudates, at 14 days after sowing onward, was markedly lower for Umgar than for NERICA5, NERICA13, NERICA4, and NERICA18. Based on these findings, Umgar has both pre and post-attachment resistance to a resident Striga population in Sudan. Kosti1 and Kosti2 did not exhibit Striga resistance at the same level as Umgar. Further the resistance of NERICA5, a variety reported to be endowed with a broad spectrum resistance to Striga species and ecotypes, at least to one resident Striga population in Sudan was clearly indicated. PMID- 27242836 TI - VESPUCCI: Exploring Patterns of Gene Expression in Grapevine. AB - Large-scale transcriptional studies aim to decipher the dynamic cellular responses to a stimulus, like different environmental conditions. In the era of high-throughput omics biology, the most used technologies for these purposes are microarray and RNA-Seq, whose data are usually required to be deposited in public repositories upon publication. Such repositories have the enormous potential to provide a comprehensive view of how different experimental conditions lead to expression changes, by comparing gene expression across all possible measured conditions. Unfortunately, this task is greatly impaired by differences among experimental platforms that make direct comparisons difficult. In this paper, we present the Vitis Expression Studies Platform Using COLOMBOS Compendia Instances (VESPUCCI), a gene expression compendium for grapevine which was built by adapting an approach originally developed for bacteria, and show how it can be used to investigate complex gene expression patterns. We integrated nearly all publicly available microarray and RNA-Seq expression data: 1608 gene expression samples from 10 different technological platforms. Each sample has been manually annotated using a controlled vocabulary developed ad hoc to ensure both human readability and computational tractability. Expression data in the compendium can be visually explored using several tools provided by the web interface or can be programmatically accessed using the REST interface. VESPUCCI is freely accessible at http://vespucci.colombos.fmach.it. PMID- 27242838 TI - The Over-expression of the Plastidial Transglutaminase from Maize in Arabidopsis Increases the Activation Threshold of Photoprotection. AB - Plastidial transglutaminase is one of the most promising enzymes in chloroplast bioenergetics due to its link with polyamine pathways and the cross talk with signals such as Ca(2+) and GTP. Here, we show the effect of the increase of transglutaminase activity in Arabidopsis by using genetic transformation techniques. These lines fulfill their biological cycle normally (normal growth in soil, production of viable seeds) and show a relatively mild increase in transglutaminase activity (127%). These overexpressors of transglutaminase (OE TGase) have an extended stroma thylakoid network (71% higher number of PSIIbeta centers), similar chlorophyll content (-4%), higher linear electron flow (+13%), and higher threshold of photoprotection activation (~100%). On the other hand OE TGase showed a reduced maximum photochemistry of PSII (-6.5%), a smaller antenna per photosystem II (-25%), a lower photoprotective "energization" quenching or qE (-77% at 490 MUmol photons m(-2) s(-1)) due to a higher threshold of qE activation and slightly lower light induced proton motive force (-17%). The role of the polyamines and of the transglutaminase in the regulation of chemiosmosis and photoprotection in chloroplasts is discussed. PMID- 27242839 TI - Different Gene Expression Patterns between Leaves and Flowers in Lonicera japonica Revealed by Transcriptome Analysis. AB - The perennial and evergreen twining vine, Lonicera japonica is an important herbal medicine with great economic value. However, gene expression information for flowers and leaves of L. japonica remains elusive, which greatly impedes functional genomics research on this species. In this study, transcriptome profiles from leaves and flowers of L. japonica were examined using next generation sequencing technology. A total of 239.41 million clean reads were used for de novo assembly with Trinity software, which generated 150,523 unigenes with N50 containing 947 bp. All the unigenes were annotated using Nr, SwissProt, COGs (Clusters of Orthologous Groups), GO (Gene Ontology), and KEGG (Kyoto Encyclopedia of Genes and Genomes) databases. A total of 35,327 differentially expressed genes (DEGs, P <= 0.05) between leaves and flowers were detected. Among them, a total of 6602 DEGs were assigned with important biological processes including "Metabolic process," "Response to stimulus," "Cellular process," and etc. KEGG analysis showed that three possible enzymes involved in the biosynthesis of chlorogenic acid were up-regulated in flowers. Furthermore, the TF-based regulation network in L. japonica identified three differentially expressed transcription factors between leaves and flowers, suggesting distinct regulatory roles in L. japonica. Taken together, this study has provided a global picture of differential gene expression patterns between leaves and flowers in L japonica, providing a useful genomic resource that can also be used for functional genomics research on L. japonica in the future. PMID- 27242840 TI - Isolation and Characterization of Three New Monoterpene Synthases from Artemisia annua. AB - Artemisia annua, an annual herb used in traditional Chinese medicine, produces a wealth of monoterpenes and sesquiterpenes, including the well-known sesquiterpene lactone artemisinin, an active ingredient in the treatment for malaria. Here we report three new monoterpene synthases of A. annua. From a glandular trichome cDNA library, monoterpene synthases of AaTPS2, AaTPS5, and AaTPS6, were isolated and characterized. The recombinant proteins of AaTPS5 and AaTPS6 produced multiple products with camphene and 1,8-cineole as major products, respectively, and AaTPS2 produced a single product, beta-myrcene. Although both Mg(2+) and Mn(2+) were able to support their catalytic activities, altered product spectrum was observed in the presence of Mn(2+) for AaTPS2 and AaTPS5. Analysis of extracts of aerial tissues and root of A. annua with gas chromatography-mass spectrometry detected more than 20 monoterpenes, of which the three enzymes constituted more than 1/3 of the total. Mechanical wounding induced the expression of all three monoterpene synthase genes, and transcript levels of AaTPS5 and AaTPS6 were also elevated after treatments with phytohormones of methyl jasmonate, salicylic acid, and gibberellin, suggesting a role of these monoterpene synthases in plant-environment interactions. The three new monoterpene synthases reported here further our understanding of molecular basis of monoterpene biosynthesis and regulation in plant. PMID- 27242841 TI - Production of alpha-Amylase by Aspergillus terreus NCFT 4269.10 Using Pearl Millet and Its Structural Characterization. AB - In this investigation, Aspergillus terreus NCFT4269.10 was employed in liquid static surface (LSSF) and solid state (SSF) fermentation to assess the optimal conditions for alpha-amylase biosynthesis. One-variable-at-a-time approach (quasi optimum protocol) was primarily used to investigate the effect of each parameter on production of amylase. The maximum amylase production was achieved using pearl millet (PM) as substrate by SSF (19.19 +/- 0.9 Ug(-1)) and also in presence of 1 mM magnesium sulfate, 0.025% (w/v) gibberellic acid, and 30 mg/100 ml (w/v) of vitamin E (~60-fold higher production of amylase) with the initial medium pH of 7.0 and incubation at 30 degrees C for 96 h. In addition, maltose, gelatin and isoleucine also influenced the alpha-amylase production. Amylase was purified to homogeneity with molecular mass around 15.3 kDa. The enzyme comprised of a typical secondary structure containing alpha-helix (12.2%), beta-pleated sheet (23.6%), and beta-turn (27.4%). Exploitation of PM for alpha-amylase production with better downstream makes it the unique enzyme for various biotechnological applications. PMID- 27242843 TI - Molecular and Functional Characterization of a Wheat B2 Protein Imparting Adverse Temperature Tolerance and Influencing Plant Growth. AB - Genomic attempts were undertaken to elucidate the plant developmental responses to heat stress, and to characterize the roles of B2 protein in mediating those responses. A wheat expressed sequence tag for B2 protein was identified which was cloned and characterized to assess its functional relevance causing plant growth and development during stress adaptation. Here, we show that wheat B2 protein is highly expressed in root and shoot tissues as well as in developing seed tissues under high temperature stress conditions. Morphological studies of transgenic Arabidopsis overexpressing gene encoding wheat B2 protein and Deltab2 mutant plants were studied at major developmental stages. The stunted growth phenotype of mutant plants, together with hypocotyl and root elongation analysis of transgenic plants showed that B2 protein exhibits a crucial role in plant growth and development. Additional physiological analyses highlights the role of B2 protein in increased tolerance to heat and cold stresses by maintaining high chlorophyll content, strong activity of photosystem II and less membrane damage of overexpression transgenics as compared with the wild-type. Furthermore, the constitutive overexpression of TaB2 in Arabidopsis resulted in ABA hypersensitivity. Taken together, these studies suggest a novel perspectives of B2 protein in plant development and in mediating the thermal stress tolerance. PMID- 27242844 TI - Gibberellin Deficiency Confers Both Lodging and Drought Tolerance in Small Cereals. AB - Tef [Eragrostis tef (Zucc.) Trotter] and finger millet [Eleusine coracana Gaertn] are staple cereal crops in Africa and Asia with several desirable agronomic and nutritional properties. Tef is becoming a life-style crop as it is gluten-free while finger millet has a low glycemic index which makes it an ideal food for diabetic patients. However, both tef and finger millet have extremely low grain yields mainly due to moisture scarcity and susceptibility of the plants to lodging. In this study, the effects of gibberellic acid (GA) inhibitors particularly paclobutrazol (PBZ) on diverse physiological and yield-related parameters were investigated and compared to GA mutants in rice (Oryza sativa L.). The application of PBZ to tef and finger millet significantly reduced the plant height and increased lodging tolerance. Remarkably, PBZ also enhanced the tolerance of both tef and finger millet to moisture deficit. Under moisture scarcity, tef plants treated with PBZ did not exhibit drought-related symptoms and their stomatal conductance was unaltered, leading to higher shoot biomass and grain yield. Semi-dwarf rice mutants altered in GA biosynthesis, were also shown to have improved tolerance to dehydration. The combination of traits (drought tolerance, lodging tolerance and increased yield) that we found in plants with altered GA pathway is of importance to breeders who would otherwise rely on extensive crossing to introgress each trait individually. The key role played by PBZ in the tolerance to both lodging and drought calls for further studies using mutants in the GA biosynthesis pathway in order to obtain candidate lines which can be incorporated into crop-breeding programs to create lodging tolerant and climate-smart crops. PMID- 27242842 TI - Expression of a Codon-Optimized dsdA Gene in Tobacco Plastids and Rice Nucleus Confers D-Serine Tolerance. AB - D-serine is toxic to plants. D-serine ammonia lyase, which is encoded by the dsdA gene, can attenuate this toxicity with high specificity. In the present study, we explored the function of codon-optimized dsdA with tobacco plastids and rice nuclear transformation system. It was shown that dsdA gene was site-specifically integrated into the tobacco plastid genome and displayed a high level of expression. Genetic analysis of the progenies showed that dsdA gene is maternally inherited and confers sufficient D-serine resistance in tobacco. The effective screening concentrations of D-serine for seed germination, callus regeneration and foliar spray were 10, 30, and 75 mM, respectively. In addition, calluses from homozygous transgenic rice lines also showed significant tolerance to D-serine (up to 75 mM). Our study proves the feasibility of using dsdA gene as a selectable marker in both plastid and nuclear transformation systems. PMID- 27242845 TI - Regulation of Plant Growth, Photosynthesis, Antioxidation and Osmosis by an Arbuscular Mycorrhizal Fungus in Watermelon Seedlings under Well-Watered and Drought Conditions. AB - Drought stress has become an increasingly serious environmental issue that influences the growth and production of watermelon. Previous studies found that arbuscular mycorrhizal (AM) colonization improved the fruit yield and water use efficiency (WUE) of watermelon grown under water stress; however, the exact mechanisms remain unknown. In this study, the effects of Glomus versiforme symbiosis on the growth, physio-biochemical attributes, and stress-responsive gene expressions of watermelon seedlings grown under well-watered and drought conditions were investigated. The results showed that AM colonization did not significantly influence the shoot growth of watermelon seedlings under well watered conditions but did promote root development irrespective of water treatment. Drought stress decreased the leaf relative water content and chlorophyll concentration, but to a lesser extent in the AM plants. Compared with the non-mycorrhizal seedlings, mycorrhizal plants had higher non-photochemical quenching values, which reduced the chloroplast ultrastructural damage in the mesophyll cells and thus maintained higher photosynthetic efficiency. Moreover, AM inoculation led to significant enhancements in the enzyme activities and gene expressions of superoxide dismutase, catalase, ascorbate peroxidase, glutathione reductase, and monodehydroascorbate reductase in watermelon leaves upon drought imposition. Consequently, AM plants exhibited lower accumulation of MDA, H2O2 and [Formula: see text] compared with non-mycorrhizal plants. Under drought stress, the soluble sugar and proline contents were significantly increased, and further enhancements were observed by pre-treating the drought-stressed plants with AM. Taken together, our findings indicate that mycorrhizal colonization enhances watermelon drought tolerance through a stronger root system, greater protection of photosynthetic apparatus, a more efficient antioxidant system and improved osmoregulation. This study contributes to advances in the knowledge of AM-induced drought tolerance. PMID- 27242846 TI - Physiological and Biochemical Responses in Two Ornamental Shrubs to Drought Stress. AB - Drought stress is one of the most important abiotic stress limiting the plant survival and growth in the Mediterranean environment. In this work, two species typically grown in Mediterranean areas with different drought responses were used. Two shrubs, with slow (Photinia * fraseri Dress 'Red Robin') or fast (Eugenia uniflora L. 'Etna Fire') adaptation ability to drought, were subjected to three water regimes: well-watered (WW), moderate (MD), and severe (SD) drought stress conditions for 30 days. Net photosynthetic rate, stomatal conductance, maximum quantum efficiency of PSII photochemistry (Fv/Fm), relative water content (RWC), chlorophyll content, proline, malondialdehyde (MDA), and antioxidant enzyme activities (superoxide dismutase, catalase, and peroxidase) were measured. Results showed that RWC and proline were higher in Eugenia than in Photinia, demonstrating the greater tolerance of the latter to the water stress. The drought stress levels applied did not compromise photosynthetic efficiency through stomatal regulation, while a reduction of Fv/Fm ratio was observed at the end of the experimental period. MDA significantly increased after 30 days in both species. The antioxidant enzyme activities showed different responses to water stress conditions. In both species, the water stress scores showed positive, while proline content showed negative correlations with all physiological parameters. PMID- 27242847 TI - Physical Methods for Seed Invigoration: Advantages and Challenges in Seed Technology. AB - In the context of seed technology, the use of physical methods for increasing plant production offers advantages over conventional treatments based on chemical substances. The effects of physical invigoration treatments in seeds can be now addressed at multiple levels, ranging from morpho-structural aspects to changes in gene expression and protein or metabolite accumulation. Among the physical methods available, "magneto-priming" and irradiation with microwaves (MWs) or ionizing radiations (IRs) are the most promising pre-sowing seed treatments. "Magneto-priming" is based on the application of magnetic fields and described as an eco-friendly, cheap, non-invasive technique with proved beneficial effects on seed germination, vigor and crop yield. IRs, as gamma-rays and X-rays, have been widely regarded as a powerful tool in agricultural sciences and food technology. Gamma-rays delivered at low dose have showed to enhance germination percentage and seedling establishment, acting as an actual 'priming' treatment. Different biological effects have been observed in seeds subjected to MWs and X-rays but knowledge about their impact as seed invigoration agent or stimulatory effects on germination need to be further extended. Ultraviolet (UV) radiations, namely UV-A and UV-C have shown to stimulate positive impacts on seed health, germination, and seedling vigor. For all mentioned physical treatments, extensive fundamental and applied research is still needed to define the optimal dose, exposition time, genotype- and environment-dependent irradiation conditions. Electron paramagnetic resonance has an enormous potential in seed technology not fully explored to monitor seed invigoration treatments and/or identifying the best suitable irradiation dose or time-point to stop the treatment. The present manuscript describes the use of physical methods for seed invigoration, while providing a critical discussion on the constraints and advantages. The future perspectives related to the use of these approaches to address the need of seed technologists, producers and trade markers will be also highlighted. PMID- 27242849 TI - Strain of Synechocystis PCC 6803 with Aberrant Assembly of Photosystem II Contains Tandem Duplication of a Large Chromosomal Region. AB - Cyanobacterium Synechocystis PCC 6803 represents a favored model organism for photosynthetic studies. Its easy transformability allowed construction of a vast number of Synechocystis mutants including many photosynthetically incompetent ones. However, it became clear that there is already a spectrum of Synechocystis "wild-type" substrains with apparently different phenotypes. Here, we analyzed organization of photosynthetic membrane complexes in a standard motile Pasteur collection strain termed PCC and two non-motile glucose-tolerant substrains (named here GT-P and GT-W) previously used as genetic backgrounds for construction of many photosynthetic site directed mutants. Although, both the GT P and GT-W strains were derived from the same strain constructed and described by Williams in 1988, only GT-P was similar in pigmentation and in the compositions of Photosystem II (PSII) and Photosystem I (PSI) complexes to PCC. In contrast, GT-W contained much more carotenoids but significantly less chlorophyll (Chl), which was reflected by lower level of dimeric PSII and especially trimeric PSI. We found that GT-W was deficient in Chl biosynthesis and contained unusually high level of unassembled D1-D2 reaction center, CP47 and especially CP43. Another specific feature of GT-W was a several fold increase in the level of the Ycf39 Hlip complex previously postulated to participate in the recycling of Chl molecules. Genome re-sequencing revealed that the phenotype of GT-W is related to the tandem duplication of a large region of the chromosome that contains 100 genes including ones encoding D1, Psb28, and other PSII-related proteins as well as Mg-protoporphyrin methylester cyclase (Cycl). Interestingly, the duplication was completely eliminated after keeping GT-W cells on agar plates under photoautotrophic conditions for several months. The GT-W strain without a duplication showed no obvious defects in PSII assembly and resembled the GT-P substrain. Although, we do not exactly know how the duplication affected the GT-W phenotype, we hypothesize that changed stoichiometry of protein components of PSII and Chl biosynthetic machinery encoded by the duplicated region impaired proper assembly and functioning of these multi-subunit complexes. The study also emphasizes the crucial importance of a proper control strain for evaluating Synechocystis mutants. PMID- 27242848 TI - The Roles of Organic Acids in C4 Photosynthesis. AB - Organic acids are involved in numerous metabolic pathways in all plants. The finding that some plants, known as C4 plants, have four-carbon dicarboxylic acids as the first product of carbon fixation showed these organic acids play essential roles as photosynthetic intermediates. Oxaloacetate (OAA), malate, and aspartate (Asp) are substrates for the C4 acid cycle that underpins the CO2 concentrating mechanism of C4 photosynthesis. In this cycle, OAA is the immediate, short-lived, product of the initial CO2 fixation step in C4 leaf mesophyll cells. The malate and Asp, resulting from the rapid conversion of OAA, are the organic acids delivered to the sites of carbon reduction in the bundle-sheath cells of the leaf, where they are decarboxylated, with the released CO2 used to make carbohydrates. The three-carbon organic acids resulting from the decarboxylation reactions are returned to the mesophyll cells where they are used to regenerate the CO2 acceptor pool. NADP-malic enzyme-type, NAD-malic enzyme-type, and phosphoenolpyruvate carboxykinase-type C4 plants were identified, based on the most abundant decarboxylating enzyme in the leaf tissue. The genes encoding these C4 pathway-associated decarboxylases were co-opted from ancestral C3 plant genes during the evolution of C4 photosynthesis. Malate was recognized as the major organic acid transferred in NADP-malic enzyme-type C4 species, while Asp fills this role in NAD-malic enzyme-type and phosphoenolpyruvate carboxykinase-type plants. However, accumulating evidence indicates that many C4 plants use a combination of organic acids and decarboxylases during CO2 fixation, and the C4 type categories are not rigid. The ability to transfer multiple organic acid species and utilize different decarboxylases has been suggested to give C4 plants advantages in changing and stressful environments, as well as during development, by facilitating the balance of energy between the two cell types involved in the C4 pathway of CO2 assimilation. The results of recent empirical and modeling studies support this suggestion and indicate that a combination of transferred organic acids and decarboxylases is beneficial to C4 plants in different light environments. PMID- 27242850 TI - Inter-Species Comparative Analysis of Components of Soluble Sugar Concentration in Fleshy Fruits. AB - The soluble sugar concentration of fleshy fruit is a key determinant of fleshy fruit quality. It affects directly the sweetness of fresh fruits and indirectly the properties of processed products (e.g., alcohol content in wine). Despite considerable divergence among species, soluble sugar accumulation in a fruit results from the complex interplay of three main processes, namely sugar import, sugar metabolism, and water dilution. Therefore, inter-species comparison would help to identify common and/or species-specific modes of regulation in sugar accumulation. For this purpose, a process-based mathematical framework was used to compare soluble sugar accumulation in three fruits: grape, tomato, and peach. Representative datasets covering the time course of sugar accumulation during fruit development were collected. They encompassed 104 combinations of species (3), genotypes (30), and growing conditions (19 years and 16 nutrient and environmental treatments). At maturity, grape showed the highest soluble sugar concentrations (16.5-26.3 g/100 g FW), followed by peach (2.2 to 20 g/100 g FW) and tomato (1.4 to 5 g/100 g FW). Main processes determining soluble sugar concentration were decomposed into sugar importation, metabolism, and water dilution with the process-based analysis. Different regulation modes of soluble sugar concentration were then identified, showing either import-based, dilution based, or import and dilution dual-based. Firstly, the higher soluble sugar concentration in grape than in tomato is a result of higher sugar importation. Secondly, the higher soluble sugar concentration in grape than in peach is due to a lower water dilution. The third mode of regulation is more complicated than the first two, with differences both in sugar importation and water dilution (grape vs. cherry tomato; cherry tomato vs. peach; peach vs. tomato). On the other hand, carbon utilization for synthesis of non-soluble sugar compounds (namely metabolism) was conserved among the three fruit species. These distinct modes appear to be quite species-specific, but the intensity of the effect may significantly vary depending on the genotype and management practices. These results provide novel insights into the drivers of differences in soluble sugar concentration among fleshy fruits. PMID- 27242851 TI - Identification of Novel Components of the Unfolded Protein Response in Arabidopsis. AB - Unfavorable environmental and developmental conditions may cause disturbances in protein folding in the endoplasmic reticulum (ER) that are recognized and counteracted by components of the Unfolded Protein Response (UPR) signaling pathways. The early cellular responses include transcriptional changes to increase the folding and processing capacity of the ER. In this study, we systematically screened a collection of inducible transgenic Arabidopsis plants expressing a library of transcription factors for resistance toward UPR-inducing chemicals. We identified 23 candidate genes that may function as novel regulators of the UPR and of which only three genes (bZIP10, TBF1, and NF-YB3) were previously associated with the UPR. The putative role of identified candidate genes in the UPR signaling is supported by favorable expression patterns in both developmental and stress transcriptional analyses. We demonstrated that WRKY75 is a genuine regulator of the ER-stress cellular responses as its expression was found to be directly responding to ER stress-inducing chemicals. In addition, transgenic Arabidopsis plants expressing WRKY75 showed resistance toward salt stress, connecting abiotic and ER-stress responses. PMID- 27242852 TI - Vascular Sap Proteomics: Providing Insight into Long-Distance Signaling during Stress. AB - The plant vascular system, composed of the xylem and phloem, is important for the transport of water, mineral nutrients, and photosynthate throughout the plant body. The vasculature is also the primary means by which developmental and stress signals move from one organ to another. Due to practical and technological limitations, proteomics analysis of xylem and phloem sap has been understudied in comparison to accessible sample types such as leaves and roots. However, recent advances in sample collection techniques and mass spectrometry technology are making it possible to comprehensively analyze vascular sap proteomes. In this mini-review, we discuss the emerging field of vascular sap proteomics, with a focus on recent comparative studies to identify vascular proteins that may play roles in long-distance signaling and other processes during stress responses in plants. PMID- 27242853 TI - Tissue- and Cell-Specific Cytokinin Activity in Populus * canescens Monitored by ARR5::GUS Reporter Lines in Summer and Winter. AB - Cytokinins play an important role in vascular development. But knowledge on the cellular localization of this growth hormone in the stem and other organs of woody plants is lacking. The main focus of this study was to investigate the occurrence and cellular localization of active cytokinins in leaves, roots, and along the stem of Populus * canescens and to find out how the pattern is changed between summer and winter. An ARR5::GUS reporter construct was used to monitor distribution of active cytokinins in different tissues of transgenic poplar lines. Three transgenic lines tested under outdoor conditions showed no influence of ARR5::GUS reporter construct on the growth performance compared with the wild type, but one line lost the reporter activity. ARR5::GUS activity indicated changes in the tissue- and cell type-specific pattern of cytokinin activity during dormancy compared with the growth phase. ARR5::GUS activity, which was present in the root tips in the growing season, disappeared in winter. In the stem apex ground tissue, ARR5::GUS activity was higher in winter than in summer. Immature leaves from tissue-culture grown plants showed inducible ARR5::GUS activity. Leaf primordia in summer showed ARR5::GUS activity, but not the expanded leaves of outdoor plants or leaf primordia in winter. In stem cross sections, the most prominent ARR5::GUS activity was detected in the cortex region and in the rays of bark in summer and in winter. In the cambial zone the ARR5::GUS activity was more pronounced in the dormant than in growth phase. The pith and the ray cells adjacent to the vessels also displayed ARR5::GUS activity. In silico analyses of the tissue-specific expression patterns of the whole PtRR type-A family of poplar showed that PtRR10, the closest ortholog to the Arabidopsis ARR5 gene, was usually the most highly expressed gene in all tissues. In conclusion, gene expression and tissue-localization indicate high activity of cytokinins not only in summer, but also in winter. The presence of the signal in meristematic tissues supports their role in meristem maintenance. The reporter lines will be useful to study the involvement of cytokinins in acclimation of poplar growth to stress. PMID- 27242854 TI - Use of BABA and INA As Activators of a Primed State in the Common Bean (Phaseolus vulgaris L.). AB - To survive in adverse conditions, plants have evolved complex mechanisms that "prime" their defense system to respond and adapt to stresses. Their competence to respond to such stresses fundamentally depends on its capacity to modulate the transcriptome rapidly and specifically. Thus, chromatin dynamics is a mechanism linked to transcriptional regulation and enhanced defense in plants. For example, in Arabidopsis, priming of the SA-dependent defense pathway is linked to histone lysine methylation. Such modifications could create a memory of the primary infection that is associated with an amplified gene response upon exposure to a second stress-stimulus. In addition, the priming status of a plant for induced resistance can be inherited to its offspring. However, analyses on the molecular mechanisms of generational and transgenerational priming in the common bean (Phaseolus vulagris L.), an economically important crop, are absent. Here, we provide evidence that resistance to P. syringae pv. phaseolicola infection was induced in the common bean with the synthetic priming activators BABA and INA. Resistance was assessed by evaluating symptom appearance, pathogen accumulation, changes in gene expression of defense genes, as well as changes in the H3K4me3 and H3K36me3 marks at the promoter-exon regions of defense-associated genes. We conclude that defense priming in the common bean occurred in response to BABA and INA and that these synthetic activators primed distinct genes for enhanced disease resistance. We hope that an understanding of the molecular changes leading to defense priming and pathogen resistance will provide valuable knowledge for producing disease-resistant crop varieties by exposing parental plants to priming activators, as well as to the development of novel plant protection chemicals that stimulate the plant's inherent disease resistance mechanisms. PMID- 27242855 TI - Enhancing Neoplasm Expression in Field Pea (Pisum sativum) via Intercropping and Its Significance to Pea Weevil (Bruchus pisorum) Management. AB - Neoplasm formation, a non-meristematic tissue growth on young field pea (Pisum sativum L.) pods is triggered in the absence of UV light and/or in response to oviposition by pea weevil (Bruchus pisorum L.). This trait is expressed in some genotypes [neoplastic (Np) genotypes] of P. sativum and has the capacity to obstruct pea weevil larval entry into developing seeds. In the present study, 26% of the tested accessions depicted the trait when grown under greenhouse conditions. However, UV light inhibits full expression of this trait and subsequently it is inconspicuous at the field level. In order to investigate UV light impact on the expression of neoplasm, particular Np genotypes were subjected to UV lamp light exposure in the greenhouse and sunlight at the field level. Under these different growing conditions, the highest mean percentage of Np pods was in the control chamber in the greenhouse (36%) whereas in single and double UV lamp chambers, the percentage dropped to 10 and 15%, respectively. Furthermore, when the same Np genotypes were grown in the field, the percentage of Np pods dropped significantly (7%). In order to enhance Np expression at the field level, intercropping of Np genotypes with sorghum was investigated. As result, the percentage of Np pods was threefold in intercropped Np genotypes as compared to those without intercropping. Therefore, intercropping Np genotypes with other crops such as sorghum and maize can facilitate neoplasm formation, which in turn can minimize the success rate of pea weevil larvae entry into developing seeds. Greenhouse artificial infestation experiments showed that pea weevil damage in Np genotypes is lower in comparison to wild type genotypes. Therefore, promoting Np formation under field conditions via intercropping can serve as part of an integrated pea weevil management strategy especially for small scale farming systems. PMID- 27242856 TI - On the Developmental and Environmental Regulation of Secondary Metabolism in Vaccinium spp. Berries. AB - Secondary metabolites have important defense and signaling roles, and they contribute to the overall quality of developing and ripening fruits. Blueberries, bilberries, cranberries, and other Vaccinium berries are fleshy berry fruits recognized for the high levels of bioactive compounds, especially anthocyanin pigments. Besides anthocyanins and other products of the phenylpropanoid and flavonoid pathways, these berries also contain other metabolites of interest, such as carotenoid derivatives, vitamins and flavor compounds. Recently, new information has been achieved on the mechanisms related with developmental, environmental, and genetic factors involved in the regulation of secondary metabolism in Vaccinium fruits. Especially light conditions and temperature are demonstrated to have a prominent role on the composition of phenolic compounds. The present review focuses on the studies on mechanisms associated with the regulation of key secondary metabolites, mainly phenolic compounds, in Vaccinium berries. The advances in the research concerning biosynthesis of phenolic compounds in Vaccinium species, including specific studies with mutant genotypes in addition to controlled and field experiments on the genotype * environment (G*E) interaction, are discussed. The recently published Vaccinium transcriptome and genome databases provide new tools for the studies on the metabolic routes. PMID- 27242857 TI - New Insight into Quinoa Seed Quality under Salinity: Changes in Proteomic and Amino Acid Profiles, Phenolic Content, and Antioxidant Activity of Protein Extracts. AB - Quinoa (Chenopodium quinoa Willd) is an ancient Andean seed-producing crop well known for its exceptional nutritional properties and resistance to adverse environmental conditions, such as salinity and drought. Seed storage proteins, amino acid composition, and bioactive compounds play a crucial role in determining the nutritional value of quinoa. Seeds harvested from three Chilean landraces of quinoa, one belonging to the salares ecotype (R49) and two to the coastal-lowlands ecotype, VI-1 and Villarrica (VR), exposed to two levels of salinity (100 and 300 mM NaCl) were used to conduct a sequential extraction of storage proteins in order to obtain fractions enriched in albumins/globulins, 11S globulin and in prolamin-like proteins. The composition of the resulting protein fractions was analyzed by one- and two-dimensional polyacrylamide gel electrophoresis. Results confirmed a high polymorphism in seed storage proteins; the two most representative genotype-specific bands of the albumin/globulin fraction were the 30- and 32-kDa bands, while the 11S globulin showed genotype specific polymorphism for the 40- and 42-kDa bands. Spot analysis by mass spectrometry followed by in silico analyses were conducted to identify the proteins whose expression changed most significantly in response to salinity in VR. Proteins belonging to several functional categories (i.e., stress protein, metabolism, and storage) were affected by salinity. Other nutritional and functional properties, namely amino acid profiles, total polyphenol (TPC) and flavonoid (TFC) contents, and antioxidant activity (AA) of protein extracts were also analyzed. With the exception of Ala and Met in R49, all amino acids derived from protein hydrolysis were diminished in seeds from salt-treated plants, especially in landrace VI-1. By contrast, several free amino acids were unchanged or increased by salinity in R49 as compared with VR and VI-1, suggesting a greater tolerance in the salares landrace. VR had the highest TPC and AA under non-saline conditions. Salinity increased TPC in all three landraces, with the strongest increase occurring in R49, and enhanced radical scavenging capacity in R49 and VR. Overall, results show that salinity deeply altered the seed proteome and amino acid profiles and, in general, increased the concentration of bioactive molecules and AA of protein extracts in a genotype-dependent manner. PMID- 27242860 TI - Phenology, Canopy Aging and Seasonal Carbon Balance as Related to Delayed Winter Pruning of Vitis vinifera L. cv. Sangiovese Grapevines. AB - Manipulating or shifting annual grapevine growing cycle to offset limitations imposed by global warming is a must today, and delayed winter pruning is a tool to achieve it. However, no information is available about its physiological background, especially in relation to modifications in canopy phenology, demography and seasonal carbon budget. Mechanistic hypothesis underlying this work was that very late winter pruning (LWP) can achieve significant postponement of phenological stages so that ripening might occur in a cooler period and, concurrently, ripening potential can be improved due to higher efficiency and prolonged longevity of the canopy. Variability in the dynamics of the annual cycle was created in mature potted cv. Sangiovese grapevines subjected to either standard winter pruning (SWP) or late and very late winter pruning (LWP, VLWP) performed when apical shoots on the unpruned canes were at the stage of 2 and 7 unfolded leaves. Vegetative growth, phenology and canopy net CO2 exchange (NCER) were followed throughout the season. Despite LWP and VLWP induced a bud-burst delay of 17 and 31 days vs. SWP, the delay was fully offset at harvest for LWP and was reduced to 6 days in VLWP. LWP showed notably higher canopy efficiency as shorter time needed to reach maximum NCER/leaf area (22 days vs. 34 in SWP), highest maximum NCER/leaf area (+37% as compared to SWP) and higher NCER/leaf area rates from veraison to end of season. As a result, seasonal cumulated carbon in LWP was 17% higher than SWP. A negative functional relationship was also established between amount of leaf area removed at winter pruning and yield per vine and berry number per cluster. Although retarded winter pruning was not able to postpone late-season phenological stages under the warm conditions of this study, it showed a remarkable potential to limit yield while improving grape quality, thereby fostering the hypothesis that it could be used to replace time consuming and costly cluster thinning. This preliminary study indicates that proper winter pruning date should be timed so as not to exceed the stage of two unfolded leaves. PMID- 27242858 TI - Elevated-CO2 Response of Stomata and Its Dependence on Environmental Factors. AB - Stomata control the flow of gases between plants and the atmosphere. This review is centered on stomatal responses to elevated CO2 concentration and considers other key environmental factors and underlying mechanisms at multiple levels. First, an outline of general responses in stomatal conductance under elevated CO2 is presented. Second, stomatal density response, its development, and the trade off with leaf growth under elevated CO2 conditions are depicted. Third, the molecular mechanism regulating guard cell movement at elevated CO2 is suggested. Finally, the interactive effects of elevated CO2 with other factors critical to stomatal behavior are reviewed. It may be useful to better understand how stomata respond to elevated CO2 levels while considering other key environmental factors and mechanisms, including molecular mechanism, biochemical processes, and ecophysiological regulation. This understanding may provide profound new insights into how plants cope with climate change. PMID- 27242859 TI - Identification of Rapeseed MicroRNAs Involved in Early Stage Seed Germination under Salt and Drought Stresses. AB - Drought and salinity are severe and wide-ranging abiotic stresses that substantially affect crop germination, development and productivity, and seed germination is the first critical step in plant growth and development. To comprehensively investigate small-RNA targets and improve our understanding of miRNA-mediated post-transcriptional regulation networks during Brassica napus seed imbibition under drought and salt stresses, we constructed three small-RNA libraries from B. napus variety ZS11 embryos exposed to salt (200 mM NaCl, denoted "S"), drought (200 g L(-1) PEG-6000, denoted "D"), and distilled water (denoted "CK") during imbibition and sequenced them using an Illumina Genome Analyzer. A total of 11,528,557, 12,080,081, and 12,315,608 raw reads were obtained from the CK, D, and S libraries, respectively. Further analysis identified 85 known miRNAs belonging to 31 miRNA families and 882 novel miRNAs among the three libraries. Comparison of the D and CK libraries revealed significant down-regulation of six miRNA families, miR156, miR169, miR860, miR399, miR171, and miR395, whereas only miR172 was significantly up-regulated. In contrast, comparison of the S library with the CK library showed significant down-regulation of only two miRNA families: miRNA393 and miRNA399. Putative targets for 336, 376, and 340 novel miRNAs were successfully predicted in the CK, D, and S libraries, respectively, and 271 miRNA families and 20 target gene families [including disease resistance protein (DIRP), drought-responsive family protein (DRRP), early responsive to dehydration stress protein (ERD), stress responsive alpha-beta barrel domain protein (SRAP), and salt tolerance homolog2 (STH2)] were confirmed as being core miRNAs and genes involved in the seed imbibition response to salt and drought stresses. The sequencing results were partially validated by quantitative RT-PCR for both conserved and novel miRNAs as well as the predicted target genes. Our data suggest that diverse and complex miRNAs are involved in seed imbibition, indicating that miRNAs are involved in plant hormone regulation, and may play important roles during seed germination under salt- or drought-stress conditions. PMID- 27242861 TI - Effective Use of Water and Increased Dry Matter Partitioned to Grain Contribute to Yield of Common Bean Improved for Drought Resistance. AB - Common bean (Phaseolus vulgaris L.) is the most important food legume in the diet of poor people in the tropics. Drought causes severe yield loss in this crop. Identification of traits associated with drought resistance contributes to improving the process of generating bean genotypes adapted to these conditions. Field studies were conducted at the International Center for Tropical Agriculture (CIAT), Palmira, Colombia, to determine the relationship between grain yield and different parameters such as effective use of water (EUW), canopy biomass, and dry partitioning indices (pod partitioning index, harvest index, and pod harvest index) in elite lines selected for drought resistance over the past decade. Carbon isotope discrimination (CID) was used for estimation of water use efficiency (WUE). The main objectives were: (i) to identify specific morpho physiological traits that contribute to improved resistance to drought in lines developed over several cycles of breeding and that could be useful as selection criteria in breeding; and (ii) to identify genotypes with desirable traits that could serve as parents in the corresponding breeding programs. A set of 36 bean genotypes belonging to the Middle American gene pool were evaluated under field conditions with two levels of water supply (irrigated and drought) over two seasons. Eight bean lines (NCB 280, NCB 226, SEN 56, SCR 2, SCR 16, SMC 141, RCB 593, and BFS 67) were identified as resistant to drought stress. Resistance to terminal drought stress was positively associated with EUW combined with increased dry matter partitioned to pod and seed production and negatively associated with days to flowering and days to physiological maturity. Differences in genotypic response were observed between grain CID and grain yield under irrigated and drought stress. Based on phenotypic differences in CID, leaf stomatal conductance, canopy biomass, and grain yield under drought stress, the lines tested were classified into two groups, water savers and water spenders. Pod harvest index could be a useful selection criterion in breeding programs to select for drought resistance in common bean. PMID- 27242862 TI - Understanding the Impacts of Soil, Climate, and Farming Practices on Soil Organic Carbon Sequestration: A Simulation Study in Australia. AB - Carbon sequestration in agricultural soils has the capacity to mitigate greenhouse gas emissions, as well as to improve soil biological, physical, and chemical properties. The review of literature pertaining to soil organic carbon (SOC) dynamics within Australian grain farming systems does not enable us to conclude on the best farming practices to increase or maintain SOC for a specific combination of soil and climate. This study aimed to further explore the complex interactions of soil, climate, and farming practices on SOC. We undertook a modeling study with the Agricultural Production Systems sIMulator modeling framework, by combining contrasting Australian soils, climates, and farming practices (crop rotations, and management within rotations, such as fertilization, tillage, and residue management) in a factorial design. This design resulted in the transposition of contrasting soils and climates in our simulations, giving soil-climate combinations that do not occur in the study area to help provide insights into the importance of the climate constraints on SOC. We statistically analyzed the model's outputs to determinate the relative contributions of soil parameters, climate, and farming practices on SOC. The initial SOC content had the largest impact on the value of SOC, followed by the climate and the fertilization practices. These factors explained 66, 18, and 15% of SOC variations, respectively, after 80 years of constant farming practices in the simulation. Tillage and stubble management had the lowest impacts on SOC. This study highlighted the possible negative impact on SOC of a chickpea phase in a wheat-chickpea rotation and the potential positive impact of a cover crop in a sub-tropical climate (QLD, Australia) on SOC. It also showed the complexities in managing to achieve increased SOC, while simultaneously aiming to minimize nitrous oxide (N2O) emissions and nitrate leaching in farming systems. The transposition of contrasting soils and climates in our simulations revealed the importance of the climate constraints on SOC. PMID- 27242863 TI - Functional Plant Types Drive Plant Interactions in a Mediterranean Mountain Range. AB - Shrubs have positive (facilitation) and negative (competition) effects on understory plants, the net interaction effect being modulated by abiotic conditions. Overall shrubs influence to great extent the structure of plant communities where they have significant presence. Interactions in a plant community are quite diverse but little is known about their variability and effects at community level. Here we checked the effects of co-occurring shrub species from different functional types on a focal understory species, determining mechanisms driving interaction outcome, and tested whether effects measured on the focal species were a proxy for effects measured at the community level. Growth, physiological, and reproductive traits of Euphorbia nicaeensis, our focal species, were recorded on individuals growing in association with four dominant shrub species and in adjacent open areas. We also recorded community composition and environmental conditions in each microhabitat. Shrubs provided environmental conditions for plant growth, which contrasted with open areas, including moister soil, greater N content, higher air temperatures, and lower radiation. Shrub-associated individuals showed lower reproductive effort and greater allocation to growth, while most physiological traits remained unaffected. Euphorbia individuals were bigger and had more leaf N under N-fixing than under non-fixing species. Soil moisture was also higher under N-fixing shrubs; therefore soil conditions in the understory may counter reduced light conditions. There was a significant effect of species identity and functional types in the outcome of plant interactions with consistent effects at individual and community levels. The contrasting allocation strategies to reproduction and growth in Euphorbia plants, either associated or not with shrubs, showed high phenotypic plasticity and evidence its ability to cope with contrasting environmental conditions. PMID- 27242864 TI - Eco-Physiological Responses of Dominant Species to Watering in a Natural Grassland Community on the Semi-Arid Loess Plateau of China. AB - Altered precipitation regimes significantly affect ecosystem structure and function in arid and semi-arid regions. In order to investigate effects of precipitation changes on natural grassland community in the semi-arid Loess Plateau, the current research examined eco-physiological characteristics of two co-dominant species (i.e., Bothriochloa ischaemum and Lespedeza davurica) and community composition following two watering instances (i.e., precipitation pulses, July and August, 2011, respectively) in a natural grassland community. Results showed that the photosynthetic rate, transpiration rate, stomatal conductance and intercellular CO2 concentration rapidly increased on the first to third day following watering in both species, and both months. Under watering treatments, the maximum net photosynthetic rates appeared on the second to third day after watering, which increased 30-80% in B. ischaemum and 40-50% in L. davurica compared with non-watering treatments, respectively. Leaf water use efficiency kept stable or initially decreased in both species under watering treatments. Watering in July produced more promoting effects on grass photosynthesis than in August, particularly in B. ischaemum. Community above ground biomass at the end of the growing season increased after watering, although no significant changes in species diversity were observed. Our results indicated that timing and magnitude of watering could significantly affect plant eco-physiological processes, and there were species-specific responses in B. ischaemum and L. davurica. Pulsed watering increased community productivity, while did not significantly alter community composition after one growing season. The outcomes of this study highlight eco-physiological traits in dominant species may playing important roles in reshaping community composition under altered precipitation regimes. PMID- 27242865 TI - Metabolite Profiling of Italian Tomato Landraces with Different Fruit Types. AB - Increased interest toward traditional tomato varieties is fueled by the need to rescue desirable organoleptic traits and to improve the quality of fresh and processed tomatoes in the market. In addition, the phenotypic and genetic variation preserved in tomato landraces represents a means to understand the genetic basis of traits related to health and organoleptic aspects and improve them in modern varieties. To establish a framework for this approach, we studied the content of several metabolites in a panel of Italian tomato landraces categorized into three broad fruit type classes (flattened/ribbed, pear/oxheart, round/elongate). Three modern hybrids, corresponding to the three fruit shape typologies, were included as reference. Red ripe fruits were morphologically characterized and biochemically analyzed for their content in glycoalkaloids, phenols, amino acids, and Amadori products. The round/elongate types showed a higher content in glycoalkaloids, whereas flattened types had higher levels of phenolic compounds. Flattened tomatoes were also rich in total amino acids and in particular in glutamic acid. Multivariate analysis of amino acid content clearly separated the three classes of fruit types. Making allowance of the very low number of genotypes, phenotype-marker relationships were analyzed after retrieving single nucleotide polymorphisms (SNPs) among the landraces available in the literature. Sixty-six markers were significantly associated with the studied traits. The positions of several of these SNPs showed correspondence with already described genomic regions and QTLs supporting the reliability of the association. Overall the data indicated that significant changes in quality related metabolites occur depending on the genetic background in traditional tomato germplasm, frequently according to specific fruit shape categories. Such a variability is suitable to harness association mapping for metabolic quality traits using this germplasm as an experimental population, paving the way for investigating their genetic/molecular basis, and facilitating breeding for quality-related compounds in tomato fruits. PMID- 27242866 TI - Exploitation of Diversity within Crops-the Key to Disease Tolerance? AB - Tolerance, defined as the ability of a crop to maintain yield in the presence of disease, is a difficult characteristic to measure, and its component traits are generally undefined. It has been studied as a characteristic of plant genotypes grown singly or in monoculture crop stands. However, it is similarly valid as a characteristic of ecosystems, or mixtures / inter-cropping in crops and this paper seeks to evaluate theoretical and practical aspects of tolerance in this context. Focusing on cereals and fungal pathogens, consideration is given to the process of yield formation, the impact of disease on yield, and how tolerance might be assessed in monocultures. Variation in tolerance traits in monocultures and how such plants might interact in mixtures is considered; specifically the expression of tolerance in mixtures and how plants with contrasting tolerance traits in monocultures combine. Having focused on disease, further consideration is given to the impact of and on other microbial species in the crop environment. Finally the practical approaches that could be adopted to identify and assess the main traits responsible for expressing tolerance are addressed. These focus on the dynamic nature of plant-plant and plant-microbe interactions particularly in response to both biotic and abiotic stress out with the range of optimal or normal crop evaluation environments. It is proposed that by using more extreme factor parameter values in mixed crop evaluation environments the key traits affecting tolerance will be identified. PMID- 27242867 TI - A Novel Remote Sensing Approach for Prediction of Maize Yield Under Different Conditions of Nitrogen Fertilization. AB - Maize crop production is constrained worldwide by nitrogen (N) availability and particularly in poor tropical and subtropical soils. The development of affordable high-throughput crop monitoring and phenotyping techniques is key to improving maize cultivation under low-N fertilization. In this study several vegetation indices (VIs) derived from Red-Green-Blue (RGB) digital images at the leaf and canopy levels are proposed as low-cost tools for plant breeding and fertilization management. They were compared with the performance of the normalized difference vegetation index (NDVI) measured at ground level and from an aerial platform, as well as with leaf chlorophyll content (LCC) and other leaf composition and structural parameters at flowering stage. A set of 10 hybrids grown under five different nitrogen regimes and adequate water conditions were tested at the CIMMYT station of Harare (Zimbabwe). Grain yield and leaf N concentration across N fertilization levels were strongly predicted by most of these RGB indices (with R (2)~ 0.7), outperforming the prediction power of the NDVI and LCC. RGB indices also outperformed the NDVI when assessing genotypic differences in grain yield and leaf N concentration within a given level of N fertilization. The best predictor of leaf N concentration across the five N regimes was LCC but its performance within N treatments was inefficient. The leaf traits evaluated also seemed inefficient as phenotyping parameters. It is concluded that the adoption of RGB-based phenotyping techniques may significantly contribute to the progress of plant breeding and the appropriate management of fertilization. PMID- 27242868 TI - Characterization of Genome-Wide Variation in Four-Row Wax, a Waxy Maize Landrace with a Reduced Kernel Row Phenotype. AB - In southwest China, some maize landraces have long been isolated geographically, and have phenotypes that differ from those of widely grown cultivars. These landraces may harbor rich genetic variation responsible for those phenotypes. Four-row Wax is one such landrace, with four rows of kernels on the cob. We resequenced the genome of Four-row Wax, obtaining 50.46 Gb sequence at 21.87* coverage, then identified and characterized 3,252,194 SNPs, 213,181 short InDels (1-5 bp) and 39,631 structural variations (greater than 5 bp). Of those, 312,511 (9.6%) SNPs were novel compared to the most detailed haplotype map (HapMap) SNP database of maize. Characterization of variations in reported kernel row number (KRN) related genes and KRN QTL regions revealed potential causal mutations in fea2, td1, kn1, and te1. Genome-wide comparisons revealed abundant genetic variations in Four-row Wax, which may be associated with environmental adaptation. The sequence and SNP variations described here enrich genetic resources of maize, and provide guidance into study of seed numbers for crop yield improvement. PMID- 27242869 TI - Crystal Structure of Hyp-1, a Hypericum perforatum PR-10 Protein, in Complex with Melatonin. AB - Hyp-1, a PR-10-fold protein from Hypericum perforatum, was crystallized in complex with melatonin (MEL). The structure confirms the conserved protein fold and the presence of three unusual ligand binding sites, two of which are internal chambers (1,2), while the third one (3) is formed as an invagination of the protein surface. The MEL ligand in site 1 is well defined while that in site 3 seems to be rotating between the side chains of Lys33 and Tyr150 that act as a molecular vise. The patch of electron density in site 2 does not allow unambiguous modeling of a melatonin molecule but suggests a possible presence of its degradation product. This pattern of ligand occupation is reproducible in repeated crystallization/structure determination experiments. Although the binding of melatonin by Hyp-1 does not appear to be very strong (for example, MEL cannot displace the artificial fluorescence probe ANS), it is strong enough to suggest a physiological role of this interaction. For example, trans-zeatin, which is a common ligand of PR-10 proteins, does not overcompete melatonin for binding to Hyp-1 as it does not affect the crystallization process of the Hyp 1/MEL complex, and among a number of potential natural mediators tested, melatonin was the only one to form a crystalline complex with Hyp-1 with the use of standard crystallization screens. Hyp-1 is the second protein in the Protein Data Bank for which melatonin binding has been demonstrated crystallographically, the first one being human quinone reductase. PMID- 27242870 TI - Trade-Offs between Economic and Environmental Impacts of Introducing Legumes into Cropping Systems. AB - Europe's agriculture is highly specialized, dependent on external inputs and responsible for negative environmental impacts. Legume crops are grown on less than 2% of the arable land and more than 70% of the demand for protein feed supplement is imported from overseas. The integration of legumes into cropping systems has the potential to contribute to the transition to a more resource efficient agriculture and reduce the current protein deficit. Legume crops influence the production of other crops in the rotation making it difficult to evaluate the overall agronomic effects of legumes in cropping systems. A novel assessment framework was developed and applied in five case study regions across Europe with the objective of evaluating trade-offs between economic and environmental effects of integrating legumes into cropping systems. Legumes resulted in positive and negative impacts when integrated into various cropping systems across the case studies. On average, cropping systems with legumes reduced nitrous oxide emissions by 18 and 33% and N fertilizer use by 24 and 38% in arable and forage systems, respectively, compared to systems without legumes. Nitrate leaching was similar with and without legumes in arable systems and reduced by 22% in forage systems. However, grain legumes reduced gross margins in 3 of 5 regions. Forage legumes increased gross margins in 3 of 3 regions. Among the cropping systems with legumes, systems could be identified that had both relatively high economic returns and positive environmental impacts. Thus, increasing the cultivation of legumes could lead to economic competitive cropping systems and positive environmental impacts, but achieving this aim requires the development of novel management strategies informed by the involvement of advisors and farmers. PMID- 27242872 TI - Germination Stage Oxygen Deficiency (GSOD): An Emerging Stress in the Era of Changing Trends in Climate and Rice Cultivation Practice. PMID- 27242871 TI - The Alcohol Dehydrogenase Gene Family in Melon (Cucumis melo L.): Bioinformatic Analysis and Expression Patterns. AB - Alcohol dehydrogenases (ADH), encoded by multigene family in plants, play a critical role in plant growth, development, adaptation, fruit ripening and aroma production. Thirteen ADH genes were identified in melon genome, including 12 ADHs and one formaldehyde dehydrogenease (FDH), designated CmADH1-12 and CmFDH1, in which CmADH1 and CmADH2 have been isolated in Cantaloupe. ADH genes shared a lower identity with each other at the protein level and had different intron-exon structure at nucleotide level. No typical signal peptides were found in all CmADHs, and CmADH proteins might locate in the cytoplasm. The phylogenetic tree revealed that 13 ADH genes were divided into three groups respectively, namely long-, medium-, and short-chain ADH subfamily, and CmADH1,3-11, which belongs to the medium-chain ADH subfamily, fell into six medium-chain ADH subgroups. CmADH12 may belong to the long-chain ADH subfamily, while CmFDH1 may be a Class III ADH and serve as an ancestral ADH in melon. Expression profiling revealed that CmADH1, CmADH2, CmADH10 and CmFDH1 were moderately or strongly expressed in different vegetative tissues and fruit at medium and late developmental stages, while CmADH8 and CmADH12 were highly expressed in fruit after 20 days. CmADH3 showed preferential expression in young tissues. CmADH4 only had slight expression in root. Promoter analysis revealed several motifs of CmADH genes involved in the gene expression modulated by various hormones, and the response pattern of CmADH genes to ABA, IAA and ethylene were different. These CmADHs were divided into ethylene-sensitive and -insensitive groups, and the functions of CmADHs were discussed. PMID- 27242874 TI - A Bistable Switch Mechanism for Stem Cell Domain Nucleation in the Shoot Apical Meristem. PMID- 27242873 TI - Candidate Genes Involved in the Biosynthesis of Triterpenoid Saponins in Platycodon grandiflorum Identified by Transcriptome Analysis. AB - BACKGROUND: Platycodon grandiflorum is the only species in the genus Platycodon of the family Campanulaceae, which has been traditionally used as a medicinal plant for its lung-heat-clearing, antitussive, and expectorant properties in China, Japanese, and Korean. Oleanane-type triterpenoid saponins were the main chemical components of P. grandiflorum and platycodin D was the abundant and main bioactive component, but little is known about their biosynthesis in plants. Hence, P. grandiflorum is an ideal medicinal plant for studying the biosynthesis of Oleanane-type saponins. In addition, the genomic information of this important herbal plant is unavailable. PRINCIPAL FINDINGS: A total of 58,580,566 clean reads were obtained, which were assembled into 34,053 unigenes, with an average length of 936 bp and N50 of 1,661 bp by analyzing the transcriptome data of P. grandiflorum. Among these 34,053 unigenes, 22,409 unigenes (65.80%) were annotated based on the information available from public databases, including Nr, NCBI, Swiss-Prot, KOG, and KEGG. Furthermore, 21 candidate cytochrome P450 genes and 17 candidate UDP-glycosyltransferase genes most likely involved in triterpenoid saponins biosynthesis pathway were discovered from the transcriptome sequencing of P. grandiflorum. In addition, 10,626 SSRs were identified based on the transcriptome data, which would provide abundant candidates of molecular markers for genetic diversity and genetic map for this medicinal plant. CONCLUSION: The genomic data obtained from P. grandiflorum, especially the identification of putative genes involved in triterpenoid saponins biosynthesis pathway, will facilitate our understanding of the biosynthesis of triterpenoid saponins at molecular level. PMID- 27242876 TI - Phenotyping of Eggplant Wild Relatives and Interspecific Hybrids with Conventional and Phenomics Descriptors Provides Insight for Their Potential Utilization in Breeding. AB - Eggplant (Solanum melongena) is related to a large number of wild species that are a source of variation for breeding programmes, in particular for traits related to adaptation to climate change. However, wild species remain largely unexploited for eggplant breeding. Detailed phenotypic characterization of wild species and their hybrids with eggplant may allow identifying promising wild species and information on the genetic control and heterosis of relevant traits. We characterizated six eggplant accessions, 21 accessions of 12 wild species (the only primary genepool species S. insanum and 11 secondary genepool species) and 45 interspecific hybrids of eggplant with wild species (18 with S. insanum and 27 with secondary genepool species) using 27 conventional morphological descriptors and 20 fruit morphometric descriptors obtained with the phenomics tool Tomato Analyzer. Significant differences were observed among cultivated, wild and interspecific hybrid groups for 18 conventional and 18 Tomato Analyzer descriptors, with hybrids generally having intermediate values. Wild species were generally more variable than cultivated accessions and interspecific hybrids displayed intermediate ranges of variation and coefficient of variation (CV) values, except for fruit shape traits in which the latter were the most variable. The multivariate principal components analysis (PCA) reveals a clear separation of wild species and cultivated accessions. Interspecific hybrids with S. insanum plotted closer to cultivated eggplant, while hybrids with secondary genepool species generally clustered together with wild species. Many differences were observed among wild species for traits of agronomic interest, which allowed identifying species of greatest potential interest for eggplant breeding. Heterosis values were positive for most vigor-related traits, while for fruit size values were close to zero for hybrids with S. incanum and highly negative for hybrids with secondary genepool species. Our results allowed the identification of potentially interesting wild species and interspecific hybrids for introgression breeding in eggplant. This is an important step for broadening the genetic base of eggplant and for breeding for adaptation to climate change in this crop. PMID- 27242875 TI - Comparative Transcriptional Profiling of Melatonin Synthesis and Catabolic Genes Indicates the Possible Role of Melatonin in Developmental and Stress Responses in Rice. AB - As a well-known animal hormone, melatonin (N-acetyl-5-methoxytryptamine) is also involved in multiple plant biological processes, especially in various stress responses. Rice is one of the most important crops, and melatonin is taken in by many people everyday from rice. However, the transcriptional profiling of melatonin-related genes in rice is largely unknown. In this study, the expression patterns of 11 melatonin related genes in rice in different periods, tissues, in response to different treatments were synthetically analyzed using published microarray data. These results suggest that the melatonin-related genes may play important and dual roles in rice developmental stages. We highlight the commonly regulation of rice melatonin-related genes by abscisic acid (ABA), jasmonic acid (JA), various abiotic stresses and pathogen infection, indicating the possible role of these genes in multiple stress responses and underlying crosstalks of plant hormones, especially ABA and JA. Taken together, this study may provide insight into the association among melatonin biosynthesis and catabolic pathway, plant development and stress responses in rice. The profile analysis identified candidate genes for further functional characterization in circadian rhythm and specific stress responses. PMID- 27242877 TI - Abiotic Stress Tolerance of Charophyte Green Algae: New Challenges for Omics Techniques. AB - Charophyte green algae are a paraphyletic group of freshwater and terrestrial green algae, comprising the classes of Chlorokybophyceae, Coleochaetophyceae, Klebsormidiophyceae, Zygnematophyceae, Mesostigmatophyceae, and Charo- phyceae. Zygnematophyceae (Conjugating green algae) are considered to be closest algal relatives to land plants (Embryophyta). Therefore, they are ideal model organisms for studying stress tolerance mechanisms connected with transition to land, one of the most important events in plant evolution and the Earth's history. In Zygnematophyceae, but also in Coleochaetophyceae, Chlorokybophyceae, and Klebsormidiophyceae terrestrial members are found which are frequently exposed to naturally occurring abiotic stress scenarios like desiccation, freezing and high photosynthetic active (PAR) as well as ultraviolet (UV) irradiation. Here, we summarize current knowledge about various stress tolerance mechanisms including insight provided by pioneer transcriptomic and proteomic studies. While formation of dormant spores is a typical strategy of freshwater classes, true terrestrial groups are stress tolerant in vegetative state. Aggregation of cells, flexible cell walls, mucilage production and accumulation of osmotically active compounds are the most common desiccation tolerance strategies. In addition, high photophysiological plasticity and accumulation of UV-screening compounds are important protective mechanisms in conditions with high irradiation. Now a shift from classical chemical analysis to next-generation genome sequencing, gene reconstruction and annotation, genome-scale molecular analysis using omics technologies followed by computer-assisted analysis will give new insights in a systems biology approach. For example, changes in transcriptome and role of phytohormone signaling in Klebsormidium during desiccation were recently described. Application of these modern approaches will deeply enhance our understanding of stress reactions in an unbiased non-targeted view in an evolutionary context. PMID- 27242878 TI - Validation of Reference Genes for Relative Quantitative Gene Expression Studies in Cassava (Manihot esculenta Crantz) by Using Quantitative Real-Time PCR. AB - Reverse transcription quantitative real-time polymerase chain reaction (real-time PCR, also referred to as quantitative RT-PCR or RT-qPCR) is a highly sensitive and high-throughput method used to study gene expression. Despite the numerous advantages of RT-qPCR, its accuracy is strongly influenced by the stability of internal reference genes used for normalizations. To date, few studies on the identification of reference genes have been performed on cassava (Manihot esculenta Crantz). Therefore, we selected 26 candidate reference genes mainly via the three following channels: reference genes used in previous studies on cassava, the orthologs of the most stable Arabidopsis genes, and the sequences obtained from 32 cassava transcriptome sequence data. Then, we employed ABI 7900 HT and SYBR Green PCR mix to assess the expression of these genes in 21 materials obtained from various cassava samples under different developmental and environmental conditions. The stability of gene expression was analyzed using two statistical algorithms, namely geNorm and NormFinder. geNorm software suggests the combination of cassava4.1_017977 and cassava4.1_006391 as sufficient reference genes for major cassava samples, the union of cassava4.1_014335 and cassava4.1_006884 as best choice for drought stressed samples, and the association of cassava4.1_012496 and cassava4.1_006391 as optimal choice for normally grown samples. NormFinder software recommends cassava4.1_006884 or cassava4.1_006776 as superior reference for qPCR analysis of different materials and organs of drought stressed or normally grown cassava, respectively. Results provide an important resource for cassava reference genes under specific conditions. The limitations of these findings were also discussed. Furthermore, we suggested some strategies that may be used to select candidate reference genes. PMID- 27242879 TI - Editorial: Abiotic Stress Signaling in Plants: Functional Genomic Intervention. PMID- 27242880 TI - The Imprint of Extreme Climate Events in Century-Long Time Series of Wood Anatomical Traits in High-Elevation Conifers. AB - Extreme climate events are of key importance for forest ecosystems. However, both the inherent infrequency, stochasticity and multiplicity of extreme climate events, and the array of biological responses, challenges investigations. To cope with the long life cycle of trees and the paucity of the extreme events themselves, our inferences should be based on long-term observations. In this context, tree rings and the related xylem anatomical traits represent promising sources of information, due to the wide time perspective and quality of the information they can provide. Here we test, on two high-elevation conifers (Larix decidua and Picea abies sampled at 2100 m a.s.l. in the Eastern Alps), the associations among temperature extremes during the growing season and xylem anatomical traits, specifically the number of cells per ring (CN), cell wall thickness (CWT), and cell diameter (CD). To better track the effect of extreme events over the growing season, tree rings were partitioned in 10 sectors. Climate variability has been reconstructed, for 1800-2011 at monthly resolution and for 1926-2011 at daily resolution, by exploiting the excellent availability of very long and high quality instrumental records available for the surrounding area, and taking into account the relationship between meteorological variables and site topographical settings. Summer temperature influenced anatomical traits of both species, and tree-ring anatomical profiles resulted as being associated to temperature extremes. Most of the extreme values in anatomical traits occurred with warm (positive extremes) or cold (negative) conditions. However, 0-34% of occurrences did not match a temperature extreme event. Specifically, CWT and CN extremes were more clearly associated to climate than CD, which presented a bias to track cold extremes. Dendroanatomical analysis, coupled to high-quality daily resolved climate records, seems a promising approach to study the effects of extreme events on trees, but further investigations are needed to improve our comprehension of the critical role of such elusive events in forest ecosystems. PMID- 27242881 TI - Variability in Seed Traits in a Collection of Cannabis sativa L. Genotypes. AB - The seed of Cannabis sativa L. is an expanding source of proteins and oil for both humans and animals. In this study, the proximate composition of a collection of hemp cultivars and accessions of different geographical origins grown under the same conditions for 1 year was analyzed in order to identify potential accessions to improve hemp cultivars. Fatty acids, tocopherols, and antinutritional components, as well as concentrations of crude protein and oil were quantified. The seed oil concentrations varied between 285 and 360 g kg(-1) dry seed (DS), while crude protein ranged between 316 and 356 g kg(-1) dry matter (DM). The seed oil was mainly composed of unsaturated fatty acids and, as expected, the dominant fatty acids were linoleic and alpha-linolenic acid. A high variability among the cultivars and accessions was also detected for polyphenolic content which ranged from 5.88 to 10.63 g kg(-1) DM, cv. Felina was the richest, whereas cv. Finola had the lowest polyphenolic content. Regarding antinutritional compounds in seed, a high variability was detected among all genotypes analyzed and phytic acid was particularly abundant (ranging between 43 and 75 g kg(-1) DM). In conclusion, our results reveal noticeable differences among hemp seed genotypes for antinutritional components, oil and protein content. Collectively, this study suggests that the hemp seed is an interesting product in terms of protein, oil and antioxidant molecules but a reduction of phytic acid would be desirable for both humans and monogastric animals. The high variability detected among the different genotypes indicates that an improvement of hemp seed might be possible by conventional and/or molecular breeding. PMID- 27242883 TI - Does the Genotype Have a Significant Effect on the Formation of Intra-Annual Density Fluctuations? A Case Study Using Larix decidua from Northern Poland. AB - Intra-annual density fluctuations (IADFs) can imprint environmental conditions within the growing season and most of the research on IADFs has been focused on their climatic signal. However, to our knowledge, the genetic influence on the frequency and type of IADFs has not been evaluated. To understand if the genotype can affect the formation of IADFs we have used a common garden experiment using eight families of Larix decidua established in two neighboring forest stands in northern Poland. Four types of IADFs were identified using X-ray density profiles: latewood-like cells within earlywood (IADF-type E), latewood-like cells in the transition from early- to latewood (IADF type E+), earlywood-like cells within latewood (IADF-type L), and earlywood-like cells in the border zone between the previous and present annual ring (IADF-type L+). The influence of explanatory variables i.e., families, sites, and years on identified density fluctuations was analyzed using generalized estimating equations (GEE). We hypothesized that trees from different families will differ in terms of frequency and type of IADFs because each family will react to precipitation and temperature in a different way, depending on the origin of those trees. The most frequent fluctuation was E+ and L types on both sites. The most important factors in the formation of IADFs were the site and year, the last one reflecting the variable climatic conditions, with no significant effect of the family. However, the relation between the formation of IADFs and selected climate parameters was different between families. Although, our results did not give a significant effect of the genotype on the formation of IADFs, the different sensitivity to climatic parameters among different families indicate that there is a genetic influence. PMID- 27242882 TI - Overexpression of Cotton GhMPK11 Decreases Disease Resistance through the Gibberellin Signaling Pathway in Transgenic Nicotiana benthamiana. AB - Many changes in development, growth, hormone activity and environmental stimuli responses are mediated by mitogen-activated protein kinase (MAPK) cascades. However, in plants, studies on MAPKs have mainly focused on MPK3, MPK4 and MPK6. Here, a novel group B MAPK gene, GhMPK11, was isolated from cotton (Gossypium hirsutum L.) and characterized. Both promoter and expression pattern analyses revealed that GhMPK11 is involved in defense responses and signaling pathways. GhMPK11 overexpression in Nicotiana benthamiana plants could increase gibberellin 3 (GA3) content through the regulation of GA-related genes. Interestingly, either GhMPK11 overexpression or exogenous GA3 treatment in N. benthamiana plants could enhance the susceptibility of these plants to the infectious pathogens Ralstonia solanacearum and Rhizoctonia solani. Moreover, reactive oxygen species (ROS) accumulation was increased after pathogen infiltration due to the increased expression of ROS-related gene respiratory burst oxidative homologs (RbohB) and the decreased expression or activity of ROS detoxification enzymes regulated by GA3, such as superoxide dismutases (SODs), peroxidases (PODs), catalase (CAT) and glutathione S-transferase (GST). Taken together, these results suggest that GhMPK11 overexpression could enhance the susceptibility of tobacco to pathogen infection through the GA3 signaling pathway via down-regulation of ROS detoxification enzymes. PMID- 27242884 TI - Highly Abundant Small Interfering RNAs Derived from a Satellite RNA Contribute to Symptom Attenuation by Binding Helper Virus-Encoded RNA Silencing Suppressors. PMID- 27242885 TI - Protein Bodies in Leaves Exchange Contents through the Endoplasmic Reticulum. AB - Protein bodies (PBs) are organelles found in seeds whose main function is the storage of proteins that are used during germination for sustaining growth. PBs can also be induced to form in leaves when foreign proteins are produced at high levels in the endoplasmic reticulum (ER) and when fused to one of three tags: Zera(r), elastin-like polypeptides (ELP), or hydrophobin-I (HFBI). In this study, we investigate the differences between ELP, HFBI and Zera PB formation, packing, and communication. Our results confirm the ER origin of all three fusion-tag induced PBs. We show that secretory pathway proteins can be sequestered into all types of PBs but with different patterns, and that different fusion tags can target a specific protein to different PBs. Zera PBs are mobile and dependent on actomyosin motility similar to ELP and HFBI PBs. We show in vivo trafficking of proteins between PBs using GFP photoconversion. We also show that protein trafficking between ELP or HFBI PBs is faster and proteins travel further when compared to Zera PBs. Our results indicate that fusion-tag-induced PBs do not represent terminally stored cytosolic organelles, but that they form in, and remain part of the ER, and dynamically communicate with each other via the ER. We hypothesize that the previously documented PB mobility along the actin cytoskeleton is associated with ER movement rather than independent streaming of detached organelles. PMID- 27242886 TI - Ethylene Antagonizes Salt-Induced Growth Retardation and Cell Death Process via Transcriptional Controlling of Ethylene-, BAG- and Senescence-Associated Genes in Arabidopsis. AB - The existing question whether ethylene is involved in the modulation of salt induced cell death to mediate plant salt tolerance is important for understanding the salt tolerance mechanisms. Here, we employed Arabidopsis plants to study the possible role of ethylene in salt-induced growth inhibition and programmed cell death (PCD) profiles. The root length, DNA ladder and cell death indicated by Evan's blue detection were measured by compared to the control or salt-stressed seedlings. Secondly, the protoplasts isolated from plant leaves and dyed with Annexin V-FITC were subjected to flow cytometric (FCM) assay. Our results showed that ethylene works effectively in seedling protoplasts, antagonizing salt included root retardation and restraining cell death both in seedlings or protoplasts. Due to salinity, the entire or partial insensitivity of ethylene signaling resulted in an elevated levels of cell death in ein2-5 and ein3-1 plants and the event were amended in ctr1-1 plants after salt treatment. The subsequent experiment with exogenous ACC further corroborated that ethylene could modulate salt-induced PCD process actively. Plant Bcl-2-associated athanogene (BAG) family genes are recently identified to play an extensive role in plant PCD processes ranging from growth, development to stress responses and even cell death. Our result showed that salinity alone significantly suppressed the transcripts of BAG6, BAG7 and addition of ACC in the saline solution could obviously re-activate BAG6 and BAG7 expressions, which might play a key role to inhibit the salt-induced cell death. In summary, our research implies that ethylene and salinity antagonistically control BAG family-, ethylene-, and senescence-related genes to alleviate the salt-induced cell death. PMID- 27242887 TI - Metabolic Consequences of Infection of Grapevine (Vitis vinifera L.) cv. "Modra frankinja" with Flavescence Doree Phytoplasma. AB - Flavescence doree, caused by the quarantine phytoplasma FDp, represents the most devastating of the grapevine yellows diseases in Europe. In an integrated study we have explored the FDp-grapevine interaction in infected grapevines of cv. "Modra frankinja" under natural conditions in the vineyard. In FDp-infected leaf vein-enriched tissues, the seasonal transcriptional profiles of 14 genes selected from various metabolic pathways showed an FDp-specific plant response compared to other grapevine yellows and uncovered a new association of the SWEET17a vacuolar transporter of fructose with pathogens. Non-targeted metabolome analysis from leaf vein-enriched tissues identified 22 significantly changed compounds with increased levels during infection. Several metabolites corroborated the gene expression study. Detailed investigation of the dynamics of carbohydrate metabolism revealed significant accumulation of sucrose and starch in the mesophyll of FDp-infected leaves, as well as significant up-regulation of genes involved in their biosynthesis. In addition, infected leaves had high activities of ADP-glucose pyrophosphorylase and, more significantly, sucrose synthase. The data support the conclusion that FDp infection inhibits phloem transport, resulting in accumulation of carbohydrates and secondary metabolites that provoke a source-sink transition and defense response status. PMID- 27242888 TI - The Use of DREADDs to Deconstruct Behavior. AB - A central goal in understanding brain function is to link specific cell populations to behavioral outputs. In recent years, the selective targeting of specific neural circuits has been made possible with the development of new experimental approaches, including chemogenetics. This technique allows for the control of molecularly defined subsets of cells through engineered G protein coupled receptors (GPCRs), which have the ability to activate or silence neuronal firing. Through chemogenetics, neural circuits are being linked to behavioral outputs at an unprecedented rate. Further, the coupling of chemogenetics with imaging techniques to monitor neural activity in freely moving animals now makes it possible to deconstruct the complex whole-brain networks that are fundamental to behavioral states. In this review, we highlight a specific chemogenetic application known as DREADDs (designer receptors exclusively activated by designer drugs). DREADDs are used ubiquitously to modulate GPCR activity in vivo and have been widely applied in the basic sciences, particularly in the field of behavioral neuroscience. Here, we focus on the impact and utility of DREADD technology in dissecting the neural circuitry of various behaviors including memory, cognition, reward, feeding, anxiety and pain. By using DREADDs to monitor the electrophysiological, biochemical, and behavioral outputs of specific neuronal types, researchers can better understand the links between brain activity and behavior. Additionally, DREADDs are useful in studying the pathogenesis of disease and may ultimately have therapeutic potential. PMID- 27242890 TI - Recursive Indirect-Paths Modularity (RIP-M) for Detecting Community Structure in RNA-Seq Co-expression Networks. AB - Clusters of genes in co-expression networks are commonly used as functional units for gene set enrichment detection and increasingly as features (attribute construction) for statistical inference and sample classification. One of the practical challenges of clustering for these purposes is to identify an optimal partition of the network where the individual clusters are neither too large, prohibiting interpretation, nor too small, precluding general inference. Newman Modularity is a spectral clustering algorithm that automatically finds the number of clusters, but for many biological networks the cluster sizes are suboptimal. In this work, we generalize Newman Modularity to incorporate information from indirect paths in RNA-Seq co-expression networks. We implement a merge-and-split algorithm that allows the user to constrain the range of cluster sizes: large enough to capture genes in relevant pathways, yet small enough to resolve distinct functions. We investigate the properties of our recursive indirect pathways modularity (RIP-M) and compare it with other clustering methods using simulated co-expression networks and RNA-seq data from an influenza vaccine response study. RIP-M had higher cluster assignment accuracy than Newman Modularity for finding clusters in simulated co-expression networks for all scenarios, and RIP-M had comparable accuracy to Weighted Gene Correlation Network Analysis (WGCNA). RIP-M was more accurate than WGCNA for modest hard thresholds and comparable for high, while WGCNA was slightly more accurate for soft thresholds. In the vaccine study data, RIP-M and WGCNA enriched for a comparable number of immunologically relevant pathways. PMID- 27242889 TI - Engineered Swine Models of Cancer. AB - Over the past decade, the technology to engineer genetically modified swine has seen many advancements, and because their physiology is remarkably similar to that of humans, swine models of cancer may be extremely valuable for preclinical safety studies as well as toxicity testing of pharmaceuticals prior to the start of human clinical trials. Hence, the benefits of using swine as a large animal model in cancer research and the potential applications and future opportunities of utilizing pigs in cancer modeling are immense. In this review, we discuss how pigs have been and can be used as a biomedical models for cancer research, with an emphasis on current technologies. We have focused on applications of precision genetics that can provide models that mimic human cancer predisposition syndromes. In particular, we describe the advantages of targeted gene-editing using custom endonucleases, specifically TALENs and CRISPRs, and transposon systems, to make novel pig models of cancer with broad preclinical applications. PMID- 27242891 TI - Human Germline Interventions-Think First. PMID- 27242893 TI - Single Molecule Analysis of Laser Localized Interstrand Crosslinks. AB - DNA interstrand crosslinks (ICLs) block unwinding of the double helix, and have always been regarded as major challenges to replication and transcription. Compounds that form these lesions are very toxic and are frequently used in cancer chemotherapy. We have developed two strategies, both based on immunofluorescence (IF), for studying cellular responses to ICLs. The basis of each is psoralen, a photoactive (by long wave ultraviolet light, UVA) DNA crosslinking agent, to which we have linked an antigen tag. In the one approach, we have taken advantage of DNA fiber and immuno-quantum dot technologies for visualizing the encounter of replication forks with ICLs induced by exposure to UVA lamps. In the other, psoralen ICLs are introduced into nuclei in live cells in regions of interest defined by a UVA laser. The antigen tag can be displayed by conventional IF, as can the recruitment and accumulation of DNA damage response proteins to the laser localized ICLs. However, substantial difference between the technologies creates considerable uncertainty as to whether conclusions from one approach are applicable to those of the other. In this report, we have employed the fiber/quantum dot methodology to determine lesion density and spacing on individual DNA molecules carrying laser localized ICLs. We have performed the same measurements on DNA fibers with ICLs induced by exposure of psoralen to UVA lamps. Remarkably, we find little difference in the adduct distribution on fibers prepared from cells exposed to the different treatment protocols. Furthermore, there is considerable similarity in patterns of replication in the vicinity of the ICLs introduced by the two techniques. PMID- 27242892 TI - Regulation of the Telomerase Reverse Transcriptase Subunit through Epigenetic Mechanisms. AB - Chromosome-shortening is characteristic of normal cells, and is known as the end replication problem. Telomerase is the enzyme responsible for extending the ends of the chromosomes in de novo synthesis, and occurs in germ cells as well as most malignant cancers. There are three subunits of telomerase: human telomerase RNA (hTERC), human telomerase associated protein (hTEP1), or dyskerin, and human telomerase reverse transcriptase (hTERT). hTERC and hTEP1 are constitutively expressed, so the enzymatic activity of telomerase is dependent on the transcription of hTERT. DNA methylation, histone methylation, and histone acetylation are basic epigenetic regulations involved in the expression of hTERT. Non-coding RNA can also serve as a form of epigenetic control of hTERT. This epigenetic-based regulation of hTERT is important in providing a mechanism for reversibility of hTERT control in various biological states. These include embryonic down-regulation of hTERT contributing to aging and the upregulation of hTERT playing a critical role in over 90% of cancers. Normal human somatic cells have a non-methylated/hypomethylated CpG island within the hTERT promoter region, while telomerase-positive cells paradoxically have at least a partially methylated promoter region that is opposite to the normal roles of DNA methylation. Histone acetylation of H3K9 within the promoter region is associated with an open chromatin state such that transcription machinery has the space to form. Histone methylation of hTERT has varied control of the gene, however. Mono- and dimethylation of H3K9 within the promoter region indicate silent euchromatin, while a trimethylated H3K9 enhances gene transcription. Non-coding RNAs can target epigenetic-modifying enzymes, as well as transcription factors involved in the control of hTERT. An epigenetics diet that can affect the epigenome of cancer cells is a recent fascination that has received much attention. By combining portions of this diet with epigenome-altering treatments, it is possible to selectively regulate the epigenetic control of hTERT and its expression. PMID- 27242894 TI - TP53 Mutation Spectrum in Smokers and Never Smoking Lung Cancer Patients. AB - BACKGROUND: TP53 mutations are among the most common mutations found in lung cancers, identified as an independent prognostic factor in many types of cancers. The purpose of this study was to investigate the frequency and prognostic impact of TP53 mutations in never-smokers and in different histological subtypes of lung cancer. METHODS: We analyzed tumor tissue from 394 non-small cell carcinomas including adenocarcinomas (n = 229), squamous cell carcinomas (n = 112), large cell carcinomas (n = 30), and others (n = 23) for mutations in TP53 by the use of Sanger sequencing (n = 394) and next generation sequencing (n = 100). RESULTS: TP53 mutations were identified in 47.2% of the samples, with the highest frequency (65%) of mutations among squamous cell carcinomas. Among never-smokers, 36% carried a TP53 mutation, identified as a significant independent negative prognostic factor in this subgroup. For large cell carcinomas, a significantly prolonged progression free survival was found for those carrying a TP53 mutation. In addition, the frequency of frameshift mutations was doubled in squamous cell carcinomas (20.3%) compared to adenocarcinomas (9.1%). CONCLUSION: TP53 mutation patterns differ between the histological subgroups of lung cancers, and are also influenced by smoking history. This indicates that the histological subtypes in lung cancer are genetically different, and that smoking-induced TP53 mutations may have a different biological impact than TP53 mutations occurring in never smokers. PMID- 27242896 TI - Fine-Mapping of 18q21.1 Locus Identifies Single Nucleotide Polymorphisms Associated with Nonsyndromic Cleft Lip with or without Cleft Palate. AB - Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common congenital birth defects. NSCL/P is a complex multifactorial disease caused by interactions between multiple environmental and genetic factors. However, the causal single nucleotide polymorphism (SNP) signature profile underlying the risk of familial NSCL/P still remains unknown. We previously reported a 5.7-Mb genomic region on chromosome 18q21.1 locus that potentially contributes to autosomal dominant, low-penetrance inheritance of NSCL/P. In the current study, we performed exome sequencing on 12 familial genomes (six affected individuals, two obligate carriers, and four seemingly unaffected individuals) of a six-generation family to identify candidate SNPs associated with NSCL/P risk. Subsequently, targeted bidirectional DNA re-sequencing of polymerase chain reaction (PCR)-amplified high-risk regions of MYO5B gene and sequenom iPLEX genotpying of 29 candidate SNPs were performed on a larger set of 33 members of this NSCL/P family (10 affected + 4 obligate carriers + 19 unaffected relatives) to find SNPs significantly associated with NSCL/P trait. SNP vs. NSCL/P association analysis showed the MYO5B SNP rs183559995 GA genotype had an odds ratio of 18.09 (95% Confidence Interval = 1.86-176.34; gender-adjusted P = 0.0019) compared to the reference GG genotype. Additionally, the following SNPs were also found significantly associated with NSCL/P risk: rs1450425 (LOXHD1), rs6507992 (SKA1), rs78950893 (SMAD7), rs8097060, rs17713847 (SCARNA17), rs6507872 (CTIF), rs8091995 (CTIF), and rs17715416 (MYO5B). We could thus identify mutations in several genes as key candidate SNPs associated with the risk of NSCL/P in this large multi-generation family. PMID- 27242897 TI - Editorial: Grappling with the Multifaceted World of the DNA Damage Response. PMID- 27242898 TI - Risk of Dumping Syndrome after Sleeve Gastrectomy and Roux-en-Y Gastric Bypass: Early Results of a Multicentre Prospective Study. AB - Background. Bariatric surgery is an important field of surgery. An important complication of bariatric surgery is dumping syndrome (DS). Aims. To evaluate the incidence of DS in patients undergoing bariatric surgery. Methods. 541 patients included from 5 nutrition and bariatric centers in France underwent either LSG or LRYGB. They were evaluated at 1 month (M1) and 6 months (M6) postoperatively by an interview and completion of a dumping syndrome questionnaire. Results. 268 patients underwent LSG (Group A) and 273 underwent LRYGB. From the LRYGB patients 229 had mechanical gastrojejunoanal anastomosis with 30 mm linear stapler (Group B) and 44 had manual (hand sewn) 15 mm gastrojejunal anastomosis (Group C). Overall incidence of DS was 8.5% at M1 and M6. In LSG group (Group A), only 4 patients (1.49%) reported episodes of DS at M1 and 3 (1.12%) at M6. In Group B, 41 patients (17.90%) reported episodes of DS at M1 and 43 (18.78%) at M6. Group C experienced one case (2.27%) of DS at M1 and none (0%) at M6. Conclusions. Patients undergoing LRYGB, especially with larger gastrojejunal anastomosis, are more prone to developing DS following surgery than patients undergoing LSG or LRYGB with calibrated manual anastomosis. PMID- 27242899 TI - Human Papilloma Virus Infection in Patients with Male Accessory Gland Infection: Usefulness of the Ultrasound Evaluation. AB - This study evaluated the ultrasound (US) features of 20 patients with MAGI and concomitant papilloma virus (HPV) infection compared to 20 patients with microbial (presence of Chlamydia trachomatis alone) MAGI and 20 patients with amicrobial (inflammatory) MAGI. Patients with HPV infection showed significantly (p < 0.05) higher total prostate, seminal vesicles, and epididymal US signs (18.0 +/- 2.0) compared to the other 2 groups (12.0 +/- 4.0 versus 10.0 +/- 3.0, resp.). In addition, patients with MAGI and HPV had a higher prevalence of complicated forms of MAGI [prostatovesiculitis (PV) and prostate-vesiculo epididymitis (PVE)] and a higher frequency of the fibrosclerotic variant compared to the other groups (70.0 +/- 10.0% versus 48.0 +/- 5.0% versus 15.0 +/- 10.0%). Moreover, HPV infected patients had a higher number of US criteria suggestive for MAGI in the periurethral region of the prostate compared to the other groups. In particular, the patients showed a higher ratio between periurethral and lobar US criteria distribution (5.0 versus 0.5). Finally, the seminal fluid concentration of CD45pos leukocytes (2.0 +/- 0.2 versus 1.3 +/- 0.3 versus 1.0 +/- 0.3 mil/mL) was significantly higher and sperm progressive motility was significantly lower in these patients compared to other groups. PMID- 27242895 TI - Functions of Ubiquitin and SUMO in DNA Replication and Replication Stress. AB - Complete and faithful duplication of its entire genetic material is one of the essential prerequisites for a proliferating cell to maintain genome stability. Yet, during replication DNA is particularly vulnerable to insults. On the one hand, lesions in replicating DNA frequently cause a stalling of the replication machinery, as most DNA polymerases cannot cope with defective templates. This situation is aggravated by the fact that strand separation in preparation for DNA synthesis prevents common repair mechanisms relying on strand complementarity, such as base and nucleotide excision repair, from working properly. On the other hand, the replication process itself subjects the DNA to a series of hazardous transformations, ranging from the exposure of single-stranded DNA to topological contortions and the generation of nicks and fragments, which all bear the risk of inducing genomic instability. Dealing with these problems requires rapid and flexible responses, for which posttranslational protein modifications that act independently of protein synthesis are particularly well suited. Hence, it is not surprising that members of the ubiquitin family, particularly ubiquitin itself and SUMO, feature prominently in controlling many of the defensive and restorative measures involved in the protection of DNA during replication. In this review we will discuss the contributions of ubiquitin and SUMO to genome maintenance specifically as they relate to DNA replication. We will consider cases where the modifiers act during regular, i.e., unperturbed stages of replication, such as initiation, fork progression, and termination, but also give an account of their functions in dealing with lesions, replication stalling and fork collapse. PMID- 27242901 TI - ATP Bioluminometers Analysis on the Surfaces of Removable Orthodontic Aligners after the Use of Different Cleaning Methods. AB - Purpose. The aim was to quantify the bacteria concentration on the surface of orthodontic clear aligners using three different cleaning methods. Furthermore the objective was to validate the efficacy of the bioluminometer in assessing the bacteria concentration. Materials and Methods. Twenty subjects (six males and fourteen females) undergoing orthodontic therapy with clear aligners (Invisalign(r) Align Technology, Santa Clara, California) were enrolled in this study. The observation time was of six weeks. The patients were instructed to use different cleaning methods (water, brushing with toothpaste, and brushing with toothpaste and use of sodium carbonate and sulphate tablet). At the end of each phase a microbiological analysis was performed using the bioluminometer. Results. The highest bacteria concentration was found on aligners cleaned using only water (583 relative light units); a value of 189 relative light units was found on aligners cleaned with brushing and toothpaste. The lowest bacteria concentration was recorded on aligners cleaned with brushing and toothpaste and the use of sodium carbonate and sulfate tablet. Conclusions. The mechanical removal of the bacterial biofilm proved to be effective with brushing and toothpaste. The best results in terms of bacteria concentration were achieved adding the use of sodium carbonate and sulfate tablet. PMID- 27242902 TI - Liposomal Systems as Nanocarriers for the Antiviral Agent Ivermectin. AB - RNA virus infections can lead to the onset of severe diseases such as fever with haemorrhage, multiorgan failure, and mortality. The emergence and reemergence of RNA viruses continue to pose a significant public health threat worldwide with particular attention to the increasing incidence of flaviviruses, among others Dengue, West Nile Virus, and Yellow Fever viruses. Development of new and potent antivirals is thus urgently needed. Ivermectin, an already known antihelminthic drug, has shown potent effects in vitro on Flavivirus helicase, with EC50 values in the subnanomolar range for Yellow Fever and submicromolar EC50 for Dengue Fever, Japanese encephalitis, and tick-borne encephalitis viruses. However ivermectin is hampered in its application by pharmacokinetic problems (little solubility and high cytotoxicity). To overcome such problems we engineered different compositions of liposomes as ivermectin carriers characterizing and testing them on several cell lines for cytotoxicity. The engineered liposomes were less cytotoxic than ivermectin alone and they showed a significant increase of the antiviral activity in all the Dengue stains tested (1, 2, and S221). In the current study ivermectin is confirmed to be an effective potential antiviral and liposomes, as drug carriers, are shown to modulate the drug activity. All together the results represent a promising starting point for future improvement of ivermectin as antiviral and its delivery. PMID- 27242900 TI - Curcumin and Resveratrol as Promising Natural Remedies with Nanomedicine Approach for the Effective Treatment of Triple Negative Breast Cancer. AB - Researchers have made considerable progress in last few decades in understanding mechanisms underlying pathogenesis of breast cancer, its phenotypes, its molecular and genetic changes, its physiology, and its prognosis. This has allowed us to identify specific targets and design appropriate chemical entities for effective treatment of most breast cancer phenotypes, resulting in increased patient survivability. Unfortunately, these strategies have been largely ineffective in the treatment of triple negative breast cancer (TNBC). Hormonal receptors lacking render the conventional breast cancer drugs redundant, forcing scientists to identify novel targets for treatment of TNBC. Two natural compounds, curcumin and resveratrol, have been widely reported to have anticancer properties. In vitro and in vivo studies show promising results, though their effectiveness in clinical settings has been less than satisfactory, owing to their feeble pharmacokinetics. Here we discuss these naturally occurring compounds, their mechanism as anticancer agents, their shortcomings in translational research, and possible methodology to improve their pharmacokinetics/pharmacodynamics with advanced drug delivery systems. PMID- 27242903 TI - In Vitro Evaluation of Bacterial Leakage at Implant-Abutment Connection: An 11 Degree Morse Taper Compared to a Butt Joint Connection. AB - Background and Aim. The geometry of implant-abutment interface (IAI) affects the risk of bacterial leakage and invasion into the internal parts of the implant. The aim of this study was to compare the bacterial leakage of an 11-degree Morse taper IAI with that of a butt joint connection. Materials and Methods. Two implants systems were tested (n = 10 per group): CSM (submerged) and TBR (connect). The deepest inner parts of the implants were inoculated with 2 MUL of Streptococcus mutans suspension with a concentration of 108 CFU/mL. The abutments were tightened on the implants. The specimens were stored in the incubator at a temperature of 37 degrees C for 14 days and the penetration of the bacterium in the surrounding area was determined by the observation of the solution turbidity and comparison with control specimens. Kaplan-Meier survival curve was traced for the estimation of bacterial leakage and the results between two groups of implants were statistically analyzed by chi-square test. Results. No case of the implant system with the internal conical connection design revealed bacterial leakage in 14 days and no turbidity of the solution was reported for it. In the system with butt joint implant-abutment connection, 1 case showed leakage on the third day, 1 case on the eighth day, and 5 cases on the 13th day. In total, 7 (70%) cases showed bacterial leakage in this system. Significant differences were found between the two groups of implants based on the incidence of bacterial leakage (p < 0.05). Conclusion. The 11-degree Morse taper demonstrated better resistance to microbial leakage than butt joint connection. PMID- 27242905 TI - Effect of Chromatin-Remodeling Agents in Hepatic Differentiation of Rat Bone Marrow-Derived Mesenchymal Stem Cells In Vitro and In Vivo. AB - Epigenetic events, including covalent histone modifications and DNA methylation, play fundamental roles in the determination of lineage-specific gene expression and cell fates. The aim of this study was to determine whether the DNA methyltransferase inhibitor (DNMTi) 5-aza-2'-deoxycytidine (5-aza-dC) and the histone deacetylase inhibitor (HDACi) trichostatin A (TSA) promote the hepatic differentiation of rat bone marrow-derived mesenchymal stem cells (rBM-MSCs) and their therapeutic effect on liver damage. 1 MUM TSA and 20 MUM 5-aza-dC were added to standard hepatogenic medium especially at differentiation and maturation steps and their potential function on hepatic differentiation in vitro and in vivo was determined. Exposure of rBM-MSCs to 1 MUM TSA at both the differentiation and maturation steps considerably improved hepatic differentiation. TSA enhanced the development of the hepatocyte shape, promoted the chronological expression of hepatocyte-specific markers, and improved hepatic functions. In contrast, treatment of rBM-MSCs with 20 MUM 5-aza-dC alone or in combination with TSA was ineffective in improving hepatic differentiation in vitro. TSA and/or 5-aza-dC derived hepatocytes-like cells failed to improve the therapeutic potential in liver damage. We conclude that HDACis enhance hepatic differentiation in a time-dependent manner, while DNMTis do not induce the hepatic differentiation of rBM-MSCs in vitro. Their in vivo function needs further investigation. PMID- 27242904 TI - Bioceramic-Based Root Canal Sealers: A Review. AB - Bioceramic-based root canal sealers are considered to be an advantageous technology in endodontics. The aim of this review was to consider laboratory experiments and clinical studies of these sealers. An extensive search of the endodontic literature was made to identify publications related to bioceramic based root canal sealers. The outcome of laboratory and clinical studies on the biological and physical properties of bioceramic-based sealers along with comparative studies with other sealers was assessed. Several studies were evaluated covering different properties of bioceramic-based sealers including physical properties, biocompatibility, sealing ability, adhesion, solubility, and antibacterial efficacy. Bioceramic-based sealers were found to be biocompatible and comparable to other commercial sealers. The clinical outcomes associated with the use of bioceramic-based root canal sealers are not established in the literature. PMID- 27242907 TI - Timing of Caffeine Therapy and Neonatal Outcomes in Preterm Infants: A Retrospective Study. AB - Background. Caffeine is widely used to treat apnea of prematurity. Here, we evaluated the efficacy of early caffeine (1-2 DOL) in decreasing the incidence of adverse neonatal outcomes. Methods. A retrospective cohort was used to compare the neonatal morbidity of 150 preterm neonates with gestational age <=29 weeks. Infants were divided into 3 groups based on the initiation timing of caffeine therapy; (1) early caffeine (1-2 DOL), (2) late caffeine (3-7 DOL), and (3) very late caffeine (>=8 DOL). Results. The neonatal outcomes of early caffeine were comparable with those of the late caffeine group. Moreover, when comparing the neonatal morbidity of the very late caffeine group with that of the early caffeine group, multivariable logistic regression analyses were performed. We found that the timing of caffeine did not influence the risk of BPD (OR, 0.393; CI, 0.126-1.223; p = 0.107), but birthweight did (OR, 0.996; CI, 0.993-0.999; p = 0.018) in these infants. Conclusion. Neonatal outcomes of preterm infants were comparable whether caffeine was administered early or late in the first 7 DOL. The risk of BPD in infants receiving caffeine after 8 DOL was irrespective of delayed treatment with caffeine. Our results clearly demonstrate the need for further studies before caffeine prophylaxis can be universally recommended. PMID- 27242906 TI - Genetic Engineering of Mesenchymal Stem Cells to Induce Their Migration and Survival. AB - Mesenchymal stem cells (MSCs) are very attractive for regenerative medicine due to their relatively easy derivation and broad range of differentiation capabilities, either naturally or induced through cell engineering. However, efficient methods of delivery to diseased tissues and the long-term survival of grafted cells still need improvement. Here, we review genetic engineering approaches designed to enhance the migratory capacities of MSCs, as well as extend their survival after transplantation by the modulation of prosurvival approaches, including prevention of senescence and apoptosis. We highlight some of the latest examples that explore these pivotal points, which have great relevance in cell-based therapies. PMID- 27242908 TI - The Impact of General Strike on Government Healthcare Delivery in Kerala State in India. AB - General strike (also known as hartal) is used as a mode of protest by organizations and political parties in India. It is generally thought that hartals negatively impact the healthcare delivery in a society. We used the Right to Information Act to obtain data from government health centers in Kerala state in India for four hartal days (H-day) and two control days (A-day and B-day) for each H-day, from sixteen health centers including 6 Community Health Center (CHC), 6 Secondary Health Center (SHC), and 4 Tertiary Health Center (THC). Data on emergency room visits was available for six HCs. 15 HCs had a statistically significant decrease in the number of outpatient visits on H-day. There was no difference in the number of outpatient visits between the two control days (A and B) in 15 HCs, suggesting the lack of a posthartal surge in visits. Median decrease in outpatient visits in CHCs, SHCs, and THCs was 50.4%, 59.5%, and 47.4%, respectively. Hartal did not impact the number of emergency room visits in 6 out of 7 health centers assessed. Our study identified a significant harmful impact on government healthcare delivery due to hartals in Kerala. These findings have major public health implications. PMID- 27242909 TI - More Than Needles: The Importance of Explanations and Self-Care Advice in Treating Primary Dysmenorrhea with Acupuncture. AB - Background. Primary dysmenorrhea is a common gynaecological condition. Traditional Chinese medicine (TCM) acupuncturists commonly treat primary dysmenorrhea and dispense specific self-care advice for this condition. The impact of self-care advice on primary dysmenorrhea is unknown. Methods. 19 TCM acupuncture practitioners from New Zealand or Australia and 12 New Zealand women who had recently undergone acupuncture treatment for primary dysmenorrhea as part of a randomised controlled trial participated in this qualitative, pragmatic study. Focus groups and semistructured interviews were used to collect data. These were recorded, transcribed, and analysed using thematic analysis. Results. The overarching theme was that an acupuncture treatment consisted of "more than needles" for both practitioners and participants. Practitioners and participants both discussed the partnership they engaged in during treatment, based on openness and trust. Women felt that the TCM self-care advice was related to positive outcomes for their dysmenorrhea and increased their feelings of control over their menstrual symptoms. Conclusions. Most of the women in this study found improved symptom control and reduced pain. A contributing factor for these improvements may be an increased internal health locus of control and an increase in self-efficacy resulting from the self-care advice given during the clinical trial. PMID- 27242910 TI - Prior to Conception: The Role of an Acupuncture Protocol in Improving Women's Reproductive Functioning Assessed by a Pilot Pragmatic Randomised Controlled Trial. AB - The global average of couples with fertility problems is 9%. Assisted reproductive technologies are often inaccessible. Evidence points to acupuncture offering an opportunity to promote natural fertility. This study asked whether providing a multiphasic fertility acupuncture protocol to women with sub/infertility would increase their awareness of fertility and achieve normalisation of their menstrual cycle compared with a lifestyle control. In a pragmatic randomised controlled trial sub/infertile women were offered an intervention of acupuncture and lifestyle modification or lifestyle modification only. There was a statistically significant increase in fertility awareness in the acupuncture group (86.4%, 19) compared to 40% (n = 8) of the lifestyle only participants (Relative Risk (RR) 2.38, 95% confidence interval (CI) of 1.25, 4.50), with an adjusted p value of 0.011. Changes in menstrual regularity were not statistically significant. There was no statistical difference in the pregnancy rate with seven women (adjusted p = 0.992) achieving pregnancy during the course of the study intervention. Those receiving the acupuncture conceived within an average of 5.5 weeks compared to 10.67 weeks for the lifestyle only group (p = 0.422). The acupuncture protocol tested influenced women who received it compared to women who used lifestyle modification alone: their fertility awareness and wellbeing increased, and those who conceived did so in half the time. PMID- 27242912 TI - Antcin K, a Triterpenoid Compound from Antrodia camphorata, Displays Antidiabetic and Antihyperlipidemic Effects via Glucose Transporter 4 and AMP-Activated Protein Kinase Phosphorylation in Muscles. AB - The purpose of this study was to screen firstly the potential effects of antcin K (AnK), the main constituent of the fruiting body of Antrodia camphorata, in vitro and further evaluate the activities and mechanisms in high-fat-diet- (HFD-) induced mice. Following 8-week HFD-induction, mice were treated with AnK, fenofibrate (Feno), metformin (Metf), or vehicle for 4 weeks afterward. In C2C12 myotube cells, the membrane GLUT4 and phospho-Akt expressions were higher in insulin and AnK-treated groups than in the control group. It was observed that AnK-treated mice significantly lowered blood glucose, triglyceride, total cholesterol, and leptin levels in AnK-treated groups. Of interest, AnK at 40 mg/kg/day dosage displayed both antihyperglycemic effect comparable to Metf (300 mg/kg/day) and antihypertriglyceridemic effect comparable to Feno (250 mg/kg/day). The combination of significantly increased skeletal muscular membrane expression levels of glucose transporter 4 (GLUT4) but decreased hepatic glucose 6-phosphatase (G6 Pase) mRNA levels by AnK thus contributed to a decrease in blood glucose levels. Furthermore, AnK enhanced phosphorylation of AMP-activated protein kinase (phospho-AMPK) expressions in the muscle and liver. Moreover, AnK treatment exhibited inhibition of hepatic fatty acid synthase (FAS) but enhancement of fatty acid oxidation peroxisome proliferator-activated receptor alpha (PPARalpha) expression coincident with reduced sterol response element binding protein-1c (SREBP-1c) mRNA levels in the liver may contribute to decreased plasma triglycerides, hepatic steatosis, and total cholesterol levels. The present findings indicate that AnK displays an advantageous therapeutic potential for the management of type 2 diabetes and hyperlipidemia. PMID- 27242913 TI - Ovatodiolide of Anisomeles indica Exerts the Anticancer Potential on Pancreatic Cancer Cell Lines through STAT3 and NF-kappaB Regulation. AB - Pancreatic cancer is the eighth leading cause of cancer death worldwide. Patients with pancreatic cancer are normally diagnosed at an advanced stage and present poor survival rate. Ovatodiolide (OV), a bioactive macrocyclic diterpenoid isolated from Anisomeles indica, showed cytotoxicity effects in pancreatic cancer cells by inhibiting cell proliferation and inducing apoptosis. Moreover, not only were cell adhesion and invasion markedly suppressed in a dose-dependent manner, but the mRNA expression of matrix metalloproteinase-9 (MMP-9) and focal adhesion kinase (FAK) was also significantly decreased. Western blot analysis indicated that OV potently suppressed the phosphorylation of STAT-3 and its upstream kinase including ERK1/2, P38, and AKT Ser473. Meanwhile, OV inactivated the nuclear factor kappa B (NF-kappaB) by inhibiting IkappaB kinase (IKK alpha/beta) activation and the subsequent suppression of inhibitor of kappa B (IkappaB) phosphorylation. These results demonstrated that OV could potentially inhibit Mia PaCa2 cancer cells proliferation and induce apoptosis through modulation of NF kappaB and STAT3 pathway. Moreover, OV suppressed cell invasiveness and interfered with cell-matrix adhesion in Mia-PaCa2 cancer cells by reducing MMP-9 and FAK transcription through suppressing NF-kappaB and STAT3 pathway. Taken together, our findings reveal a new therapeutic and antimetastatic potential of ovatodiolide for pancreatic cancer remedy. PMID- 27242911 TI - The Status of the Quality Control in Acupuncture-Neuroimaging Studies. AB - Using neuroimaging techniques to explore the central mechanism of acupuncture gains increasing attention, but the quality control of acupuncture-neuroimaging study remains to be improved. We searched the PubMed Database during 1995 to 2014. The original English articles with neuroimaging scan performed on human beings were included. The data involved quality control including the author, sample size, characteristics of the participant, neuroimaging technology, and acupuncture intervention were extracted and analyzed. The rigorous inclusion and exclusion criteria are important guaranty for the participants' homogeneity. The standard operation process of acupuncture and the stricter requirement for acupuncturist play significant role in quality control. More attention should be paid to the quality control in future studies to improve the reproducibility and reliability of the acupuncture-neuroimaging studies. PMID- 27242915 TI - A Comparative Randomized Controlled Clinical Trial on the Effectiveness, Safety, and Tolerability of a Homeopathic Medicinal Product in Children with Sleep Disorders and Restlessness. AB - A prospective, multicenter, randomized, open-label, controlled clinical trial was performed to evaluate the effectiveness and safety of the homeopathic product ZinCyp-3-02 in children with sleep disorders for >= one month compared to glycine. Children <= six years old received either ZinCyp-3-02 (N = 89) or comparator glycine (N = 90). After treatment for 28 days, total sleep-disorder associated complaints severity scores decreased in both groups from median 7.0 (out of maximum 11.0) points to 2.0 (ZinCyp-3-02) and 4.0 (glycine) points, respectively, with overall higher odds of showing improvement for ZinCyp-3-02 (odds ratio: 4.45 (95% CI: 2.77-7.14), p < 0.0001, POM overall treatment related effect). Absence of individual complaints (time to sleep onset, difficulties maintaining sleep, sleep duration, troubled sleep (somniloquism), physical inactivity after awakening, restlessness for unknown reason, and sleep disorders frequency) at study end were significantly higher with ZinCyp-3-02 (all p values < 0.05). More children with ZinCyp-3-02 were totally free of complaints (p = 0.0258). Treatment effectiveness (p < 0.0001) and satisfaction assessments (p < 0.0001) were more favorable for ZinCyp-3-02. Few nonserious adverse drug reactions were reported (ZinCyp-3-02: N = 2, glycine: N = 1) and both treatments were well tolerated. Treatment with the homeopathic product ZinCyp-3-02 was found to be safe and superior to the comparator glycine in the treatment of sleep disorders in children. PMID- 27242914 TI - Chinese Herbs Interfering with Cancer Reprogramming Metabolism. AB - Emerging evidence promotes a reassessment of metabolic reprogramming regulation in cancer research. Although there exists a long history of Chinese herbs applied in cancer treatment, few reports have addressed the effects of Chinese herbal components on metabolic reprogramming, which is a central cancer hallmark involved in the slowing or prevention of chemoresistance in cancer cells. In this review, we have focused on four core elements altered by metabolic reprogramming in cancer cells. These include glucose transport, glycolysis, mitochondrial oxidative phosphorylation, and fatty acid synthesis. With this focus, we have summarized recent advances in metabolic reprogramming of cancer cells in response to specific Chinese herbal components. We propose that exploring Chinese herbal interference in cancer metabolic reprogramming might identify new therapeutic targets for cancer and more ways in which to approach metabolism-related diseases. PMID- 27242916 TI - Semantic Signature: Comparative Interpretation of Gene Expression on a Semantic Space. AB - Background. Interpretation of microarray data remains challenging because biological meaning should be extracted from enormous numeric matrices and be presented explicitly. Moreover, huge public repositories of microarray dataset are ready to be exploited for comparative analysis. This study aimed to provide a platform where essential implication of a microarray experiment could be visually expressed and various microarray datasets could be intuitively compared. Results. On the semantic space, gene sets from Molecular Signature Database (MSigDB) were plotted as landmarks and their relative distances were calculated by Lin's semantic similarity measure. By formal concept analysis, a microarray dataset was transformed into a concept lattice with gene clusters as objects and Gene Ontology terms as attributes. Concepts of a lattice were located on the semantic space reflecting semantic distance from landmarks and edges between concepts were drawn; consequently, a specific geographic pattern could be observed from a microarray dataset. We termed a distinctive geography shared by microarray datasets of the same category as "semantic signature." Conclusions. "Semantic space," a map of biological entities, could serve as a universal platform for comparative microarray analysis. When microarray data were displayed on the semantic space as concept lattices, "semantic signature," characteristic geography for a microarray experiment, could be discovered. PMID- 27242918 TI - Iodine in commercial edible iodized salts and assessment of iodine exposure in Sri Lanka. AB - BACKGROUND: Iodine is an essential micronutrient used by the thyroid gland in the production of thyroid hormones. Both excessive and insufficient iodine intakes can cause thyroid diseases thus harmful to the human body. Inadequate iodine intake by human body causes Iodine Deficiency Disorders (IDD) and hypothyroidism. Excessive iodine intake causes Iodine Induced Hyperthyroidism (IIH). Universal Salt Iodization (USI) is the most effective way of preventing IDD. This study determined the concentrations of iodine species in commercial edible salt products, the stability of iodine at different conditions and iodine exposure at the consumer level. METHODS: The iodine contents of six commercial edible iodized salts were determined qualitatively and quantitatively for both iodide and iodate. Thereafter, the first three products of highest iodine contents, the stability of iodide at exposed to air and heat was measured after 24 hours. Risk assessment of exposure was done at four levels considering the WHO estimation. RESULTS: Results revealed that all of the salt products have excess iodine that is above the fortification level of 15-30 mg kg(-1) level in Sri Lanka. Iodide stability was reduced at the average percentages of 13.1, 10.7 and 11.3. The iodate loss percentages were 0, 5.7 and 0 at open air. The iodide loss percentages at the temperature of 50 degrees C were 4.6, 7.8 and 8.6 while at 100 degrees C, loss percentages were 11.1, 11.4 and 15.9 for the same salt products. The iodine exposure at lower consumption during cooking ranged 244.4 432.2 MUg/day while 325.9-576.3 MUg/day for medium consumption, 407.4-720.4 MUg/day for moderate high salt consumptions and 488.8-864.4 MUg/day for high salt consumptions. As a total 95.8 % cases can cause IIH and only 4.1 % of them can provide optimal iodine nutrition in a population. Iodine exposure without cooking ranged 305.5-540.3 MUg/day for low salt consumption, 407.4-720.4 MUg/day for medium consumption and 509.2-900.5 MUg/day for moderate high consumption and 611.1-1080.6 MUg/day for high salt consumptions. CONCLUSIONS: All of the incidents (100 %) of consumption without cooking at the household level can cause excessive iodine intake and IIH in a population. PMID- 27242917 TI - (Z)-5-(2,4-Dihydroxybenzylidene)thiazolidine-2,4-dione Prevents UVB-Induced Melanogenesis and Wrinkle Formation through Suppressing Oxidative Stress in HRM-2 Hairless Mice. AB - Background. Uncontrolled melanogenesis and wrinkle formation are an indication of photoaging. Our previous studies demonstrated that (Z)-5-(2,4 dihydroxybenzylidene)thiazolidine-2,4-dione (MHY498) inhibited tyrosinase activity and melanogenesis in vitro. Objective. To examine in vivo effects of MHY498 as an antiaging compound on UVB-induced melanogenesis and wrinkle formation, we topically applied MHY498 on dorsal skin of HRM-2 hairless mice. Methods. Using histological analysis, we evaluated effects of MHY498 on melanogenesis and wrinkle formation after UVB exposure. In addition, related molecular signaling pathways were examined using western blotting, fluorometric assay, and enzyme-linked immunosorbent assay. Results. MHY498 suppressed UVB induced melanogenesis by inhibiting phosphorylation of CREB and translocation of MITF protein into the nucleus, which are key factors for tyrosinase expression. Consistently, tyrosinase protein levels were notably reduced in the dorsal skin of the hairless mice by MHY498 treatment. Furthermore, MHY498 inhibited UVB induced wrinkle formation and collagen fiber destruction by increasing type 1 procollagen concentration and decreasing protein expression levels of MMPs, which play an essential role in collagen fiber degradation. As a mechanism, MHY498 notably ameliorated UVB-induced oxidative stress and NF-kappaB activation in the dermal skin of the hairless mice. Conclusion. Our study suggests that MHY498 can be used as a therapeutic or cosmetic agent for preventing uncontrolled melanogenesis and wrinkle formation. PMID- 27242919 TI - Association of Common Variants in eNOS Gene with Primary Open Angle Glaucoma: A Meta-Analysis. AB - Purpose. To clarify the association of endothelial nitric oxide synthase (eNOS) polymorphisms and primary open angle glaucoma (POAG). Methods. After a systematic literature search in the MEDLINE, EMBASE, and ISI Web of Science databases, all relevant studies evaluating the association between the polymorphisms (rs2070744 and rs1799983) of eNOS gene and POAG were screened and included. The pooled odds ratios (ORs) and the 95% confidence interval (CI) of each single-nucleotide polymorphism (SNP) in five genetic models were estimated using fixed-effect model if I (2) < 50% in the test for heterogeneity; otherwise the random-effects model was used. Results. Thirty-one records were obtained, with five being suitable for meta-analysis. The overall results showed that both TT genotype in rs2070744 and GG genotype in rs1799983 are associated with decreased risk of POAG susceptibility. Stratified analysis based on ethnicity showed that the association of rs2070744 with POAG remained only in Caucasians. Results of subgroup analysis by sex indicated association between both polymorphisms and POAG in female group, but not in male group. Conclusions. TT genotype and/or T allele in rs2070744, as well as GG genotype and/or G-allele in rs1799983, was associated with decreased risk for POAG overall and in female group. PMID- 27242920 TI - Propolis, a Constituent of Honey, Inhibits the Development of Sugar Cataracts and High-Glucose-Induced Reactive Oxygen Species in Rat Lenses. AB - Purpose. This study investigated the effects of oral propolis on the progression of galactose-induced sugar cataracts in rats and the in vitro effects of propolis on high-glucose-induced reactive oxygen species (ROS) and cell death in cultured rat lens cells (RLECs). Methods. Galactose-fed rats and RLECs cultured in high glucose (55 mM) medium were treated with propolis or vehicle control. Relative lens opacity was assessed by densitometry and changes in lens morphology by histochemical analysis. Intracellular ROS levels and cell viability were measured. Results. Oral administration of propolis significantly inhibited the onset and progression of cataract in 15% and 25% of galactose-fed rats, respectively. RLECs cultured with high glucose showed a significant increase in ROS expression with reduced cell viability. Treatment of these RLECs with 5 and 50 MUg/mL propolis cultured significantly reduced ROS levels and increased cell viability, indicating that the antioxidant activity of propolis protected cells against ROS-induced damage. Conclusion. Propolis significantly inhibited the onset and progression of sugar cataract in rats and mitigated high-glucose induced ROS production and cell death. These effects may be associated with the ability of propolis to inhibit hyperglycemia-evoked oxidative or osmotic stress induced cellular insults. PMID- 27242921 TI - In Vivo and Cadaver Studies of the Canalicular/Lacrimal Sac Mucosal Folds. AB - Purpose. The study aimed to investigate canalicular/lacrimal sac mucosal folds (CLS-MFs) in vivo and in cadavers in order to explore their functional roles in the lacrimal drainage system. Method. The observations of CLS-MFs in vivo were performed on 16 patients with chronic dacryocystitis after undergoing an endonasal endoscopic dacryocystorhinostomy (EE-DCR). The lacrimal sacs and common canaliculi of 19 adult cadavers were dissected. The opening/closing of an orifice and mucosal fold was recorded. All of the specimens were subjected to a histological examination. Results. The upper and lower lacrimal canaliculi in all of the samples united to form a common canaliculus that opened to the lacrimal sac. CLS-MFs were observed in 10 of the 16 patients (62.5%) and 9 of the 19 cadavers (47.4%). The orifices or mucosal folds could be opened or closed when related muscles contracted or relaxed. Histological sections showed a mucosal fold at one side of an orifice. Conclusion. Common canaliculus is the most common type that the canaliculus opens to lacrimal sac. CLS-MFs exist in a certain ratio that can be opened/closed with the movement of the orifices. They may be involved in the drainage of tears or the pathogenesis of acute dacryocystitis or lacrimal sac mucocele. PMID- 27242922 TI - Racial Differences in Serum Adipokine and Insulin Levels in a Matched Osteoarthritis Sample: A Pilot Study. AB - BACKGROUND: In an attempt to correlate biomarkers with disease, serum-based biomarkers often are compared between individuals with osteoarthritis (OA) and control subjects. However, variable results have been reported. Some studies have suggested an association between certain adipokines and insulin and OA. We know that there are racial differences in OA prevalence and incidence, and from general population-based studies, those of Asian race consistently demonstrate a unique adipokine/insulin serum concentration profile as compared to Caucasians. Whether similar racial differences exist within OA samples is unknown and may have implications for selecting appropriate controls in comparative studies. METHODS: Serum levels of adipokines, leptin, and adiponectin, along with insulin, were determined by ELISA in patients scheduled for total hip or knee replacement surgery for OA. Fifteen Asian patients were matched 1 : 1 on age (+/-2 years), gender, body mass index (+/-1.5 kg/m(2)), and surgical joint with Caucasian patients. Differences in serum concentrations were tested using paired t-tests. RESULTS: Serum leptin and insulin levels were significantly higher in Asians compared to Caucasians (p < 0.05). While serum adiponectin levels were lower among Asians, the difference did not reach statistical significance (p = 0.12). CONCLUSION: Findings from this work suggest that when studying serum biomarker concentrations in OA versus controls, race may be an important factor to consider. Our findings warrant confirmation in larger studies. PMID- 27242923 TI - Treatment of Dermatological Conditions Associated with HIV/AIDS: The Scarcity of Guidance on a Global Scale. AB - Background. Skin diseases associated with Human Immunodeficiency Virus (HIV) infection are associated with significant morbidity and mortality. In resource limited settings, nondermatologists and lay health care providers on the front line of HIV care provide much of the treatment for these conditions. Objective. To evaluate guidelines for treatment of HIV-related skin conditions and assess their accessibility, comprehensiveness, and quality of evidence employed. Methods. A review was undertaken of all national and society guidelines which included treatment information on the ten highest burden HIV-related skin conditions. The search strategy included gray and peer-reviewed literature. Results. Of 430 potential guidelines, 86 met inclusion criteria, and only 2 were written specifically to address HIV-related skin diseases as a whole. Treatment information for HIV-related skin conditions was embedded within guidelines written for other purposes, primarily HIV/AIDs treatment guidelines (49%). Development of guidelines relied either partially or completely on expert opinion (62%). Only 16% of guidelines used gradation of evidence quality and these were primarily from high-income countries (p = 0.001). Limitations. Due to the nature of gray literature, not all guidelines may have been identified. Conclusion. This review highlights the need for evidence-based summary guidelines that address treatment for HIV-related skin conditions in an accessible format. PMID- 27242924 TI - Immunocompromised Children with Severe Adenoviral Respiratory Infection. AB - Purpose. To investigate the impact of severe respiratory adenoviral infection on morbidity and case fatality in immunocompromised children. Methods. Combined retrospective-prospective cohort study of patients admitted to the intensive care unit (ICU) in four children's hospitals with severe adenoviral respiratory infection and an immunocompromised state between August 2009 and October 2013. We performed a secondary case control analysis, matching our cohort 1 : 1 by age and severity of illness score with immunocompetent patients also with severe respiratory adenoviral infection. Results. Nineteen immunocompromised patients were included in our analysis. Eleven patients (58%) did not survive to hospital discharge. Case fatality was associated with cause of immunocompromised state (p = 0.015), multiple organ dysfunction syndrome (p = 0.001), requirement of renal replacement therapy (p = 0.01), ICU admission severity of illness score (p = 0.011), and treatment with cidofovir (p = 0.005). Immunocompromised patients were more likely than matched controls to have multiple organ dysfunction syndrome (p = 0.01), require renal replacement therapy (p = 0.02), and not survive to hospital discharge (p = 0.004). One year after infection, 43% of immunocompromised survivors required chronic mechanical ventilator support. Conclusions. There is substantial case fatality as well as short- and long-term morbidity associated with severe adenoviral respiratory infection in immunocompromised children. PMID- 27242925 TI - The Efficacy of Interdisciplinary Rehabilitation for Improving Function in People with Chronic Pain. AB - Objective. To examine the efficacy of interdisciplinary rehabilitation for improving function in people with chronic pain. Design. Retrospective Chart Review. Setting. The Pain Rehabilitation Center (PRC) at a medical center. Participants. Individuals admitted to the PRC. Interventions. The PRC operates a 3-week outpatient program that utilizes an interdisciplinary approach to treat people with chronic pain. The main treatment elements include physical therapy, occupational therapy, cognitive behavioral therapy (CBT), and medication management. Physical therapy groups focus on moderate exercise despite symptoms. Occupational therapists teach moderation, time management, and activity modification. CBT groups, led by a pain psychologist, address the psychosocial comorbidities of chronic pain. Medical staff oversee the tapering of opiate analgesics and other symptom targeted treatments. This integrated approach is indicated when conventional treatments have been ineffective. Outcome Measures. The objective outcome was the 6-minute walk test (6 mWT) distance. The subjective outcomes were performance (COPM-PER) and satisfaction (COPM-SAT) as measured by the Canadian Occupational Performance Measure (COPM). Results. Average 6 mWT distances improved by 39% from 375 m to 523 m. Average COPM-PER scores increased from 3.4 to 7.5. Average COPM-SAT scores increased from 2.4 to 7.5. Conclusions. Comprehensive interdisciplinary outpatient rehabilitation can significantly improve function in people with chronic pain. PMID- 27242926 TI - Evaluation of Clinical Alvarado Scoring System and CT Criteria in the Diagnosis of Acute Appendicitis. AB - Aim. The aim was to evaluate the clinical Alvarado scoring system and computed tomography (CT) criteria for the diagnosis of acute appendicitis. Material and Methods. 117 patients with acute abdominal pain who underwent abdominal CT were enrolled in this retrospective study. Patient demographics, clinical Alvarado scoring, CT images, and pathologic results of the patients were evaluated. Results. 39 of the 53 patients who were operated on had pathologically proven acute appendicitis. CT criteria of appendiceal diameter, presence of periappendiceal inflammation, fluid, appendicolith, and white blood cell (WBC) count were significantly correlated with the inflammation of the appendix. The best cut-off value for appendiceal diameter was 6.5 mm. The correlation between appendiceal diameter and WBC count was 80% (P = 0.01 < 0.05). The correlation between appendiceal diameter and Alvarado score was 78.7% (P = 0.01 < 0.05). Conclusion. Presence of CT criteria of appendiceal diameter above 6.5 mm, periappendiceal inflammation, fluid, and appendicolith should prompt the diagnosis of acute appendicitis. Since patients with acute appendicitis may not always show the typical signs and symptoms, CT is a helpful imaging modality for patients with relatively low Alvarado score and leukocytosis and when physical examination is confusing. PMID- 27242927 TI - Effect of pH, Temperature, and Chemicals on the Endoglucanases and beta Glucosidases from the Thermophilic Fungus Myceliophthora heterothallica F.2.1.4. Obtained by Solid-State and Submerged Cultivation. AB - This work reports endoglucanase and beta-glucosidase production by the thermophilic fungus Myceliophthora heterothallica in solid-state (SSC) and submerged (SmC) cultivation. Wheat bran and sugarcane bagasse were used for SSC and cardboard for SmC. Highest endoglucanase production in SSC occurred after 192 hours: 1,170.6 +/- 0.8 U/g, and in SmC after 168 hours: 2,642 +/- 561 U/g. The endoglucanases and beta-glucosidases produced by both cultivation systems showed slight differences concerning their optimal pH and temperature. The number of endoglucanases was also different: six isoforms in SSC and ten in SmC. Endoglucanase activity remained above 50% after incubation between pH 3.0 and 9.0 for 24 h for both cultivation systems. The effect of several chemicals displayed variation between SSC and SmC isoenzymes. Manganese activated the enzymes from SmC but inhibited those from SSC. For beta-glucosidases, maximum production on SmC was 244 +/- 48 U/g after 168 hours using cardboard as carbon source. In SSC maximum production reached 10.9 +/- 0.3 U/g after 240 h with 1 : 1 wheat bran and sugarcane bagasse. Manganese exerted a significant activation on SSC beta glucosidases, and glucose inhibited the enzymes from both cultivation systems. FeCl3 exerted the strongest inhibition for endoglucanases and beta-glucosidases. PMID- 27242928 TI - Bilateral Chondroepitrochlearis Muscle: Case Report, Phylogenetic Analysis, and Clinical Significance. AB - Anomalous muscular variants of pectoralis major have been reported on several occasions in the medical literature. Among them, chondroepitrochlearis is one of the rarest. Therefore, this study aims to provide a comprehensive description of its anatomy and subsequent clinical significance, along with its phylogenetic importance in pectoral muscle evolution with regard to primate posture. The authors suggest a more appropriate name to better reflect its proximal attachment to the costochondral junction and distal attachment to the epicondyle of humerus, as "chondroepicondylaris"; in addition, we suggest a new theory of phylogenetic significance to explain the twisting of pectoralis major tendon in primates that may have occurred with their adoption to bipedalism and arboreal lifestyle. Finally, the clinical significance of this aberrant muscle is elaborated as a cause of potential neurovascular entrapment and as a possible hurdle during axillary surgeries (i.e., mastectomy). PMID- 27242929 TI - The Use of Adenovirus Dodecahedron in the Delivery of an Enzymatic Activity in the Cell. AB - Penton-dodecahedron (Pt-Dd) derived from adenovirus type 3 is a symmetric complex of pentameric penton base plus fiber which can be produced in the baculovirus system at a high concentration. The size of Pt-Dd is smaller than the virus, but this virus-like particle (VLP) has the major proteins recognized by specific receptors on the surface of almost all types of cell. In this study, by direct observation with fluorescence microscopy on a fixed and living cell, the intracellular trafficking and localization of Pt-Dd labeled with fluorescence dyes in the cytoplasm of HeLa Tub-GFP showed a rapid internalization characteristic. Subsequently, the linkage of horseradish peroxidase (HRP) with Pt Dd as the vector demonstrated an efficient system to deliver this enzyme into the cell without interfering its enzymatic activity as shown by biochemical and cellular experiments. These results were supported by additional studies using Bs Dd or free form of the HRP used as the control. Overall, this study strengthens the potential role of Pt-Dd as an alternative vector for delivering therapeutic agents. PMID- 27242930 TI - Auricular Acupuncture and Cognitive Behavioural Therapy for Insomnia: A Randomised Controlled Study. AB - Objective. The most effective nonpharmacological treatment for insomnia disorder is cognitive behavioural therapy-insomnia (CBT-i). However CBT-i may not suit everyone. Auricular acupuncture (AA) is a complementary treatment. Studies show that it may alleviate insomnia symptoms. The aim of this randomised controlled study was to compare treatment effects of AA with CBT-i and evaluate symptoms of insomnia severity, anxiety, and depression. Method. Fifty-nine participants, mean age 60.5 years (SD 9.4), with insomnia disorder were randomised to group treatment with AA or CBT-i. Self-report questionnaires, the Insomnia Severity Index (ISI), Dysfunctional Beliefs and Attitudes about Sleep scale (DBAS-16), Epworth Sleepiness Scale (ESS), and Hospital Anxiety and Depression scale (HAD), were collected at baseline, after treatment, and at 6-month follow-up. A series of linear mixed models were performed to examine treatment effect over time between and within the groups. Results. Significant between-group improvements were seen in favour of CBT-i in ISI after treatment and at the 6-month follow-up and in DBAS-16 after treatment. Both groups showed significant within-group postintervention improvements in ISI, and these changes were maintained six months later. The CBT-i group also showed a significant reduction in DBAS-16 after treatment and six months later. Conclusions. Compared to CBT-i, AA, as offered in this study, cannot be considered an effective stand-alone treatment for insomnia disorder. The trial is registered with ClinicalTrials.gov NCT01765959. PMID- 27242932 TI - Transcranial Alternating Current and Random Noise Stimulation: Possible Mechanisms. AB - Background. Transcranial alternating current stimulation (tACS) is a relatively recent method suited to noninvasively modulate brain oscillations. Technically the method is similar but not identical to transcranial direct current stimulation (tDCS). While decades of research in animals and humans has revealed the main physiological mechanisms of tDCS, less is known about the physiological mechanisms of tACS. Method. Here, we review recent interdisciplinary research that has furthered our understanding of how tACS affects brain oscillations and by what means transcranial random noise stimulation (tRNS) that is a special form of tACS can modulate cortical functions. Results. Animal experiments have demonstrated in what way neurons react to invasively and transcranially applied alternating currents. Such findings are further supported by neural network simulations and knowledge from physics on entraining physical oscillators in the human brain. As a result, fine-grained models of the human skull and brain allow the prediction of the exact pattern of current flow during tDCS and tACS. Finally, recent studies on human physiology and behavior complete the picture of noninvasive modulation of brain oscillations. Conclusion. In future, the methods may be applicable in therapy of neurological and psychiatric disorders that are due to malfunctioning brain oscillations. PMID- 27242934 TI - A Case of Spontaneous Multivessel Coronary Artery Spasm That Underwent Stent Implantation Accompanying ST Segment Elevation on Inferior Electrocardiographic Leads. AB - Coronary artery spasm is usually defined as a focal constriction of a coronary artery segment, which is reversible, and causes myocardial ischaemia by restricting coronary blood flow. A coronary spasm may rarely compromise all three epicardial arteries simultaneously. We present a case of severe coronary spasm afflicting all coronary arteries accompanying an ST segment elevation in leads D2 D3 and aVF. PMID- 27242931 TI - Radiation-Induced Growth Retardation and Microstructural and Metabolite Abnormalities in the Hippocampus. AB - Cranial radiotherapy (CRT) increases survival in pediatric brain-tumor patients but can cause deleterious effects. This study evaluates the acute and long-term impact of CRT delivered during childhood/adolescence on the brain and body using a rodent model. Rats received CRT, either 4 Gy fractions * 5 d (fractionated) or a cumulative dose of 20 Gy (single dose) at 28 d of age. Animals were euthanized 1 d, 5 d, or 3.5 mo after CRT. The 3.5 mo group was imaged prior to euthanasia. At 3.5 mo, we observed significant growth retardation in irradiated animals, versus controls, and the effects of single dose on brain and body weights were more severe than fractionated. Acutely single dose significantly reduced body weight but increased brain weight, whereas fractionation significantly reduced brain but not body weights, versus controls. CRT suppressed cell proliferation in the hippocampal subgranular zone acutely. Fractional anisotropy (FA) in the fimbria was significantly lower in the single dose versus controls. Hippocampal metabolite levels were significantly altered in the single dose animals, reflecting a heightened state of inflammation that was absent in the fractionated. Our findings indicate that despite the differences in severity between the doses they both demonstrated an effect on cell proliferation and growth retardation, important factors in pediatric CRT. PMID- 27242933 TI - Synaptic Cell Adhesion Molecules in Alzheimer's Disease. AB - Alzheimer's disease (AD) is a neurodegenerative brain disorder associated with the loss of synapses between neurons in the brain. Synaptic cell adhesion molecules are cell surface glycoproteins which are expressed at the synaptic plasma membranes of neurons. These proteins play key roles in formation and maintenance of synapses and regulation of synaptic plasticity. Genetic studies and biochemical analysis of the human brain tissue, cerebrospinal fluid, and sera from AD patients indicate that levels and function of synaptic cell adhesion molecules are affected in AD. Synaptic cell adhesion molecules interact with Abeta, a peptide accumulating in AD brains, which affects their expression and synaptic localization. Synaptic cell adhesion molecules also regulate the production of Abeta via interaction with the key enzymes involved in Abeta formation. Abeta-dependent changes in synaptic adhesion affect the function and integrity of synapses suggesting that alterations in synaptic adhesion play key roles in the disruption of neuronal networks in AD. PMID- 27242935 TI - Thoracic Stent Graft Implantation for Aortic Coarctation with Patent Ductus Arteriosus via Retroperitoneal Iliac Approach in the Presence of Small Sized Femoral Artery. AB - Endovascular stent graft implantation is a favorable method for complex aortic coarctation accompanied by patent ductus arteriosus. Herein, an 18-year-old woman with complex aortic coarctation and patent ductus arteriosus was successfully treated by endovascular thoracic stent graft via retroperitoneal approach. The reason for retroperitoneal iliac approach was small sized common femoral arteries which were not suitable for stent graft passage. This case is the first aortic coarctation plus patent ductus arteriosus case described in the literature which is treated by endovascular thoracic stent graft via retroperitoneal approach. PMID- 27242936 TI - Cerebral Malaria: An Unusual Cause of Central Diabetes Insipidus. AB - Central diabetes insipidus is an uncommon feature of malaria. A previously healthy 72-year-old man presented with fever, rigors, and altered mental status after a recent trip to Liberia, a country known for endemic falciparum malaria. Investigations confirmed plasmodium falciparum parasitemia. Within one week after admission, the serum sodium rose to 166 mEq/L and the urine output increased to 7 liters/day. Other labs were notable for a high serum osmolality, low urine osmolality, and low urine specific gravity. The hypernatremia did not respond to hypotonic fluids. Diabetes insipidus was suspected and parenteral desmopressin was started with a prompt decrease in urinary output and improvement in mental status. Additional testing showed normal anterior pituitary hormones. The desmopressin was eventually tapered off with complete resolution of symptoms. Central diabetes insipidus occurred likely as a result of obstruction of the neurohypophyseal microvasculature. Other endocrinopathies that have been reported with malaria include hyponatremia, adrenal insufficiency, hypothyroidism, hypocalcemia, hypophosphatemia, hyper-, and hypoglycemia, but none manifested in our patient. Though diabetes insipidus is a rare complication of malaria, clinicians need to be aware of this manifestation, as failure to do so may lead to fatality particularly if the patient is dehydrated. PMID- 27242937 TI - High-Grade Glioma of the Ventrolateral Medulla in an Adult: Case Presentation and Discussion of Surgical Considerations. AB - Background. High-grade gliomas of the brainstem are rare in adults and are particularly rare in the anterolateral medulla. We describe an illustrative case and discuss the diagnostic and treatment issues associated with a tumor in this location, including differential diagnosis, anatomical considerations for options for surgical management, multimodality treatment, and prognosis. Case Description. A 69-year-old woman presented with a 3-week history of progressive right lower extremity weakness. She underwent an open biopsy via a far lateral approach with partial condylectomy, which revealed a glioblastoma. Concurrent temozolomide and radiation were completed; however, she elected to stop her chemotherapy after 5.5 weeks of treatment. She succumbed to her disease 11 months after diagnosis. Conclusions. Biopsy can be performed relatively safely to provide definitive diagnosis to guide treatment, but long-term prognosis is poor. PMID- 27242938 TI - Imaging Evidence for Cerebral Hyperperfusion Syndrome after Intravenous Tissue Plasminogen Activator for Acute Ischemic Stroke. AB - Background. Cerebral hyperperfusion syndrome (CHS), a rare complication after cerebral revascularization, is a well-described phenomenon after carotid endarterectomy or carotid artery stenting. However, the imaging evidence of CHS after intravenous tissue plasminogen activator (iv tPA) for acute ischemic stroke (AIS) has not been reported. Case Report. Four patients were determined to have manifestations of CHS with clinical deterioration after treatment with iv tPA, including one patient who developed seizure, one patient who had a deviation of the eyes toward lesion with worsened mental status, and two patients who developed worsened hemiparesis. In all four patients, postthrombolysis head CT examinations were negative for hemorrhage; CT angiogram showed patent cervical and intracranial arterial vasculature; CT perfusion imaging revealed hyperperfusion with increased relative cerebral blood flow and relative cerebral blood volume and decreased mean transit time along with decreased time to peak in the clinically related artery territory. Vascular dilation was also noted in three of these four cases. Conclusions. CHS should be considered in patients with clinical deterioration after iv tPA and imaging negative for hemorrhage. Cerebral angiogram and perfusion studies can be useful in diagnosing CHS thereby helping with further management. PMID- 27242939 TI - Primary Umbilical Endometriosis: Unusual and Rare Clinical Presentation. AB - Primary umbilical endometriosis is a rare disorder and is defined as the presence of ectopic endometrial tissue within the umbilicus. A patient with painful mass in the umbilicus during menstrual period is studied in this paper. The possibility of subcutaneous endometriosis should be considered when an umbilical mass is detected despite the absence of previous surgery. In this case, urachal cancer, urachal remnant, umbilical endometriosis, and its malignant transformation were among the diseases considered in the differential diagnosis. Complete excision and histology are necessary to obtain a definitive diagnosis and optimal treatment for umbilical subcutaneous endometriosis. PMID- 27242940 TI - Acute Achilles Paratendinopathy following Major Injury of the Crural Fascia in a Professional Soccer Player: A Possible Correlation? AB - Background. The anatomy and mechanical properties of the Crural Fascia (CF), the ubiquitous connective tissue of the posterior region of the leg, have recently been investigated. The most important findings are that (i) the CF may suffer structural damage from indirect trauma, (ii) structural changes of the CF may affect the biomechanics of tissues connected to it, causing myofascial pain syndromes, and (iii) the CF is in anatomical continuity with the Achilles paratenon. Consistent with these points, the authors hypothesize that the onset of acute Achilles paratendinopathy may be related to histological and biomechanical changes of the CF. Case Presentation. A professional male football player suffered an isolated injury of the CF, interposed between the soleus and medial gastrocnemius (an atypical site of injury) with structural connective integrity of the muscles. After participating in the first official match, two and a half months after the trauma, he has unexpectedly demonstrated the clinical picture of acute Achilles paratendinopathy in the previously injured limb. Conclusions. Analysis of this case suggests that the acute Achilles paratendinopathy may be a muscle injury complication from indirect trauma of the calf muscle, if a frank and extensive involvement of the CF were to be ascertained. PMID- 27242941 TI - A Case of Spontaneous Osteonecrosis of the Knee with Early and Simultaneous Involvement of the Medial Femoral Condyle and Medial Tibial Plateau. AB - Spontaneous osteonecrosis of the knee (SPONK) usually involves a single condyle, most often the medial femoral condyle (MFC). Involvement of the medial tibial plateau (MTP) is less common, occurring in about 2% of knees with SPONK. Early onset SPONK on the ipsilateral side of the medial compartment is very rare, with, to our knowledge, only four cases reported to date. We describe a very rare case of SPONK with early simultaneous development in the MFC and MTP. Serial plain radiographs and magnetic resonance imaging showed that SPONK in both condyles followed a similar progressive course. The pathological findings in these lesions were similar to those observed in subchondral insufficiency fractures. PMID- 27242942 TI - Solitary Myofibroma of the Bladder Trigone in a 3-Month-Old Patient: First Case Report. AB - Visceral solitary myofibromas are uncommon in childhood. We report a case of a solitary asymptomatic visceral myofibroma of the bladder trigone occurring in a 3 month-old boy. Once malignancies were ruled out by cystoscopy, radical excision was performed in order to avoid any potential impairment of bladder dynamic. Postoperative course was uneventful and patient was discharged on day 3 after surgery. After 36 months of follow-up, the patient is toilet-trained and remains well; bladder function is normal. PMID- 27242943 TI - Concomitant Guillain Barre Syndrome and Transverse Myelitis as Initial Neuropsychiatric Manifestation in a Case of Lupus: A Diagnostic Quandary. AB - Neuropsychiatric manifestations of systemic lupus erythematosus are varied. Presently nineteen in number, they are classified as whether affecting the central or the peripheral compartments of the nervous system. Its diagnosis however remains difficult, more so when two or more of the syndromes are found concomitantly in the same patient and when they occur in absence of the more classical rash, serositis, and haematological manifestations. We present a case of lupus where myelopathy as well as demyelination existed simultaneously as the initial neurologic manifestation. PMID- 27242944 TI - Pneumatosis Intestinalis Associated with Juvenile Dermatomyositis. AB - We herein report a case of pneumatosis intestinalis (PI), a condition characterized by the presence of gas within the wall of the digestive tract, associated with juvenile dermatomyositis (JDM). A 16-year-old girl, diagnosed with JDM at the age of 10, presented with abdominal pain and distention. She developed PI based on radiological findings that also included a dilated large intestine, extraluminal gas, and secondary diaphragmatic elevation. She was observed with medical therapy including bowel rest and hyperbaric oxygen therapy. However, she ultimately developed a strangulated obstruction 5 years after presentation with PI and large intestine resection and colostomy were performed emergently. PMID- 27242945 TI - Voltammetric Determination of Flunixin on Molecularly Imprinted Polypyrrole Modified Glassy Carbon Electrode. AB - A novel electrochemical sensing approach, based on electropolymerization of a molecularly imprinted polypyrrole (MIPpy) film onto a glassy carbon electrode (GCE) surface, was developed for the detection of flunixin (FXN). The sensing conditions and the performance of the constructed sensor were assessed by cyclic, differential pulse and (DPV) square wave voltammetry (SWV). The sensor exhibited high sensitivity, with linear responses in the range of 5.0 to 50.0 uM with detection limits of 1.5 and 1.0 uM for DPV and SWV, respectively. In addition, the sensor showed high selectivity towards FXN in comparison to other interferents. The sensor was successfully utilized for the direct determination of FXN in buffalo raw milk samples. PMID- 27242946 TI - Short Wavelength Cone Opsin Is Not Expressed in the Retina of Arboreal African Pangolin (Manis tricuspis). AB - This paper reports a study of cone photoreceptors present in the retina of Manis tricuspis. Specifically, the LWS (L-) opsin expressed in longwave-sensitive cones and SWS1 (S-) opsin shortwave-sensitive cones were targeted. Vertical sections revealed reactivity to a cone marker, peanut agglutinin (PNA), and to an LWS antibody, but not to an SWS1 antibody. This suggests that the Manis tricuspis visual system is not able to discriminate shorter wavelengths from longer wavelengths because the short wavelength cones are not expressed in their retina. PMID- 27242947 TI - Sociodemographic and Obstetric Characteristics of Anaemic Pregnant Women Attending Antenatal Clinic in Bolgatanga Regional Hospital. AB - The study determined the sociodemographic and obstetric characteristics of pregnant women which contribute to the risk of developing anaemia. A cross sectional study was conducted among 400 pregnant women attending their first antenatal visit at the Bolgatanga Regional Hospital Antenatal Clinic. Anaemia was significantly associated (p < 0.05) with younger maternal age, parity, gravidity, trimester of pregnancy, and source of drinking water. Multivariate logistic regression identified the following factors with adjusted odds ratios (aOR) and 95% confidence intervals (CI): unemployment (aOR = 4.76 (CI: 2.26-11.33); p < 0.0001), rural dwelling (aOR = 3.10 (CI: 2.16-4.91); p = 0.0071), primigravida (aOR = 2.13 (CI: 1.34-3.18); p = 0.0201), nulliparity (aOR = 1.92 (CI: 1.23 2.86); p = 0.0231), first antenatal visit at second trimester (aOR = 1.71 (CI: 1.33-3.12); p = 0.0149) and first antenatal visit at third trimester (aOR = 2.73 (CI: 1.24-4.35); p = 0.0017), drinking from well and boreholes (aOR = 2.78 (CI: 2.27-5.21); p < 0.0001), and the presence of domestic livestock (aOR = 2.15 (CI: 1.33-3.68); p = 0.0019). This study has shown the various sociodemographic and obstetric factors which significantly contribute to anaemia in pregnancy. PMID- 27242948 TI - Micropropagation, Micromorphological Studies, and In Vitro Flowering in Rungia pectinata L. AB - A tissue culture protocol was developed for an important medicinal plant Rungia pectinata L. in the present study. Nodal shoots were used as explants and surface sterilized with 0.1% HgCl2 solution. Murashige and Skoog (MS) medium was used to establish the cultures of R. pectinata. The bud break was reported on MS medium supplemented with 1.0 mg L(-1) 6-benzylaminopurine (BAP). About 98% response was observed with this media combination and maximum 3.2 shoots per explant with 4.3 cm length were recorded. The shoots were further multiplied using MS medium augmented with 0.5 mg L(-1) each of BAP and kinetin (Kin) + 0.1 mg L(-1) indole-3 acetic acid (IAA). Maximum 13.2 shoots per explant with 5.2 cm length were observed. All the shoots were rooted (4.9 roots per shoot with 3.5 cm length) on half strength MS medium fortified with 2.0 mg L(-1) indole-3 butyric acid (IBA). In vitro flowering was induced from the shoots on half strength MS medium supplemented with same concentrations and combinations of growth regulators used for shoot multiplication under 12/12 hr light/dark photoperiod. The plantlets were hardened in the greenhouse for two months and finally transferred to the field. The foliar micromorphological studies revealed the developmental changes in stomata, vein density, and trichomes during the culture of shoots under in vitro conditions. PMID- 27242949 TI - Solo Sonographically Guided PCNL under Spinal Anesthesia: Defining Predictors of Success. AB - Aim. Sonography has been brought in percutaneous nephrolithotripsy (PCNL) as an adjunct to or substitute for X-ray to restrict radiation exposure. This study was designed to investigate the possible predictors for the success of the solo sonographically guided PCNL. Methods. 148 consecutive cases were prospectively enrolled. All steps of PCNL were performed solely with sonography guidance under spinal anesthesia. Residual stones were evaluated the day after surgery using sonography and plain radiography. Results. The mean age was 46 +/- 15 years; 40% of kidneys had hydronephrosis. The mean stone burden was 504 +/- 350 mm(2). The mean duration of surgery was 43 +/- 21 minutes. The early stone-free rate was 92% in inferior or middle calyceal stones, 89.5% in single pelvic stones, 81.5% in partial staghorn stones, and 61.9% in staghorn stones. The mean residual stone size was 13 +/- 8 mm. Logistic regression showed that a lower age and a larger stone burden significantly predicted positive residual stones. Fifteen percent of patients presented with grade I or II and six percent showed grade III complication based on Clavien classification. There was no cases of organ injury or death. Conclusion. Solo ultrasonographically guided PCNL under spinal anesthesia is feasible with an acceptable stone-free rate and complication rate. PMID- 27242950 TI - Managing Sleep Disturbances in Cirrhosis. AB - Sleep disturbances, particularly daytime sleepiness and insomnia, are common problems reported by patients suffering from liver cirrhosis. Poor sleep negatively impacts patients' quality of life and cognitive functions and increases mortality. Although sleep disturbances can be an early sign of hepatic encephalopathy (HE), many patients without HE still complain of poor quality sleep. The pathophysiology of these disturbances is not fully understood but is believed to be linked to impaired hepatic melatonin metabolism. This paper provides an overview for the clinician of common comorbidities contributing to poor sleep in patients with liver disease, mainly restless leg syndrome and obstructive sleep apnea. It discusses nondrug and pharmacologic treatment options in these patients, such as the use of light therapy and histamine (H1) blockers. PMID- 27242951 TI - Office-based Management of Recurrent Respiratory Papilloma. AB - This review will highlight the indications and benefits of office-based therapy for recurrent respiratory papillomatosis (RRP) and discuss the utilization of photo-dynamic lasers and adjuvant medical therapy in office-based settings. Office-based management of RRP allows for more timely interventions, is preferred by the majority of patients, and negates the risk of general anesthesia. Current literature argues for the utilization of KTP laser over CO2 laser for office based treatment of RRP. Medical therapies for RRP are limited, but agents such as bevacizumab are promising and have been shown to reduce disease burden. Medical therapies that can induce disease remission are still needed. Office-based procedures save time and healthcare expenses compared to like procedures in the operating room. However, the increased frequency for office-based procedures predicts similar overall healthcare costs for office-based and OR laser excision of RRP. Office-based management of RRP is a feasible and well-tolerated strategy in appropriately selected patients with adequate local anesthesia. PMID- 27242952 TI - The Relationship Context for Sexual Activity and its Associations with Romantic Cognitions among Emerging Adults. AB - Few studies have examined the associations of sexual activity with romantic cognitions, particularly longitudinally. We used a multi-analytic approach to examine the longitudinal, between-person, and within-person associations between sexual activity and romantic cognitions. We distinguished among sexual activity with four different types of partners-romantic partners, friends, acquaintances, and friends with benefits. An ethnically/racially representative sample of 185 participants (94 males & 91 females) completed questionnaires when they were 2.5, 4, and 5.5 years out of high school. Frequent sexual activity with a romantic partner was associated with positive romantic cognitions, including less avoidant and anxious relational styles, greater romantic life satisfaction, and romantic appeal. Frequent sexual activity with various nonromantic partners was often associated with more negative romantic cognitions, including avoidant styles, lower romantic life satisfaction, and lower romantic appeal. Few longitudinal effects were found. Findings contribute to a developmental task theory concepualization of sexual behavior. PMID- 27242954 TI - Computer-Aided Image Analysis and Fractal Synthesis in the Quantitative Evaluation of Tumor Aggressiveness in Prostate Carcinomas. AB - The subjective evaluation of tumor aggressiveness is a cornerstone of the contemporary tumor pathology. A large intra- and interobserver variability is a known limiting factor of this approach. This fundamental weakness influences the statistical deterministic models of progression risk assessment. It is unlikely that the recent modification of tumor grading according to Gleason criteria for prostate carcinoma will cause a qualitative change and improve significantly the accuracy. The Gleason system does not allow the identification of low aggressive carcinomas by some precise criteria. The ontological dichotomy implies the application of an objective, quantitative approach for the evaluation of tumor aggressiveness as an alternative. That novel approach must be developed and validated in a manner that is independent of the results of any subjective evaluation. For example, computer-aided image analysis can provide information about geometry of the spatial distribution of cancer cell nuclei. A series of the interrelated complexity measures characterizes unequivocally the complex tumor images. Using those measures, carcinomas can be classified into the classes of equivalence and compared with each other. Furthermore, those measures define the quantitative criteria for the identification of low- and high-aggressive prostate carcinomas, the information that the subjective approach is not able to provide. The co-application of those complexity measures in cluster analysis leads to the conclusion that either the subjective or objective classification of tumor aggressiveness for prostate carcinomas should comprise maximal three grades (or classes). Finally, this set of the global fractal dimensions enables a look into dynamics of the underlying cellular system of interacting cells and the reconstruction of the temporal-spatial attractor based on the Taken's embedding theorem. Both computer-aided image analysis and the subsequent fractal synthesis could be performed effectively using the standardized software implemented on the world internet platform. This platform should help to verify the quantitative criteria for the identification of indolent prostate cancers or highly aggressive cancers as well as to test the improved statistical models for progression risk assessment within a single prospective study. PMID- 27242953 TI - Turning-Off Signaling by Siglecs, Selectins, and Galectins: Chemical Inhibition of Glycan-Dependent Interactions in Cancer. AB - Aberrant glycosylation, a common feature associated with malignancy, has been implicated in important events during cancer progression. Our understanding of the role of glycans in cancer has grown exponentially in the last few years, concurrent with important advances in glycomics and glycoproteomic technologies, paving the way for the validation of a number of glycan structures as potential glycobiomarkers. However, the molecular bases underlying cancer-associated glycan modifications are still far from understood. Glycans exhibit a natural heterogeneity, crucial for their diverse functional roles as specific carriers of biologically relevant information. This information is decoded by families of proteins named lectins, including sialic acid-binding immunoglobulin (Ig)-like lectins (siglecs), C-type lectin receptors (CLRs), and galectins. Siglecs are primarily expressed on the surface of immune cells and differentially control innate and adaptive immune responses. Among CLRs, selectins are a family of cell adhesion molecules that mediate interactions between cancer cells and platelets, leukocytes, and endothelial cells, thus facilitating tumor cell invasion and metastasis. Galectins, a family of soluble proteins that bind beta-galactoside containing glycans, have been implicated in diverse events associated with cancer biology such as apoptosis, homotypic cell aggregation, angiogenesis, cell migration, and tumor-immune escape. Consequently, individual members of these lectin families have become promising targets for the design of novel anticancer therapies. During the past decade, a number of inhibitors of lectin-glycan interactions have been developed including small-molecule inhibitors, multivalent saccharide ligands, and more recently peptides and peptidomimetics have offered alternatives for tackling tumor progression. In this article, we review the current status of the discovery and development of chemical lectin inhibitors and discuss novel strategies to limit cancer progression by targeting lectin-glycan interactions. PMID- 27242956 TI - The FLUKA Code: An Accurate Simulation Tool for Particle Therapy. AB - Monte Carlo (MC) codes are increasingly spreading in the hadrontherapy community due to their detailed description of radiation transport and interaction with matter. The suitability of a MC code for application to hadrontherapy demands accurate and reliable physical models capable of handling all components of the expected radiation field. This becomes extremely important for correctly performing not only physical but also biologically based dose calculations, especially in cases where ions heavier than protons are involved. In addition, accurate prediction of emerging secondary radiation is of utmost importance in innovative areas of research aiming at in vivo treatment verification. This contribution will address the recent developments of the FLUKA MC code and its practical applications in this field. Refinements of the FLUKA nuclear models in the therapeutic energy interval lead to an improved description of the mixed radiation field as shown in the presented benchmarks against experimental data with both (4)He and (12)C ion beams. Accurate description of ionization energy losses and of particle scattering and interactions lead to the excellent agreement of calculated depth-dose profiles with those measured at leading European hadron therapy centers, both with proton and ion beams. In order to support the application of FLUKA in hospital-based environments, Flair, the FLUKA graphical interface, has been enhanced with the capability of translating CT DICOM images into voxel-based computational phantoms in a fast and well structured way. The interface is capable of importing also radiotherapy treatment data described in DICOM RT standard. In addition, the interface is equipped with an intuitive PET scanner geometry generator and automatic recording of coincidence events. Clinically, similar cases will be presented both in terms of absorbed dose and biological dose calculations describing the various available features. PMID- 27242957 TI - Radiation Therapy after Radical Prostatectomy: Implications for Clinicians. AB - Depending on the pathological findings, up to 60% of prostate cancer patients who undergo radical prostatectomy (RP) will develop biochemical relapse and require further local treatment. Radiotherapy (RT) immediately after RP may potentially eradicate any residual localized microscopic disease in the prostate bed, and it is associated with improved biochemical, clinical progression-free survival, and overall survival in patients with high-risk pathological features according to published randomized trials. Offering immediate adjuvant RT to all men with high risk pathological factors we are over-treating around 50% of patients who would anyway be cancer-free, exposing them to unnecessary toxicity and adding costs to the health-care system. The current dilemma is, thus, whether to deliver adjuvant immediate RT solely on the basis of high-risk pathology, but in the absence of measurable prostate-specific antigen, or whether early salvage radiotherapy would yield equivalent outcomes. Randomized trials are ongoing to definitely answer this question. Retrospective analyses suggest that there is a dose-response favoring doses >70 Gy to the prostate bed. The evidence regarding the role of androgen deprivation therapy is emerging, and ongoing randomized trials are underway. PMID- 27242958 TI - Reducing Overtreatment in Gynecologic Oncology: The Case for Less in Endometrial and Ovarian Cancer. AB - A growing awareness of the harms of overtreatment in cancer care has reached physicians, patients, health policy makers, and medical researchers. Overtreatment exposes patients to the risk of adverse events from procedures or medications that were not necessary. This review examines common practices in gynecologic malignancies that are unlikely to produce direct benefit to patients with these malignancies, but are likely to produce harms. Specifically, we will explore the utility of lymphadenectomy and adjuvant radiation for women with early-stage endometrial cancer; and screening for recurrence and continuous chemotherapy for advanced-stage ovarian cancer patients. PMID- 27242955 TI - Anti-Cancer Stem-like Cell Compounds in Clinical Development - An Overview and Critical Appraisal. AB - Cancer stem-like cells (CSC) represent a subpopulation of tumor cells with elevated tumor-initiating potential. Upon differentiation, they replenish the bulk of the tumor cell population. Enhanced tumor-forming capacity, resistance to antitumor drugs, and metastasis-forming potential are the hallmark traits of CSCs. Given these properties, it is not surprising that CSCs have become a therapeutic target of prime interest in drug discovery. In fact, over the last few years, an enormous number of articles describing compounds endowed with anti CSC activities have been published. In the meanwhile, several of these compounds and also approaches that are not based on the use of pharmacologically active compounds (e.g., vaccination, radiotherapy) have progressed into clinical studies. This article gives an overview of these compounds, proposes a tentative classification, and describes their biological properties and their developmental stage. Eventually, we discuss the optimal clinical setting for these compounds, the need for biomarkers allowing patient selection, the redundancy of CSC signaling pathways and the utility of employing combinations of anti-CSC compounds and the therapeutic limitations posed by the plasticity of CSCs. PMID- 27242959 TI - Ovarian Cancer and BRCA1/2 Testing: Opportunities to Improve Clinical Care and Disease Prevention. AB - Without prevention or screening options available, ovarian cancer is the most lethal malignancy of the female reproductive tract. High-grade serous ovarian cancer (HGSOC) is the most common histologic subtype, and the role of germline BRCA1/2 mutation in predisposition and prognosis is established. Given the targeted treatment opportunities with PARP inhibitors, a predictive role for BRCA1/2 mutation has emerged. Despite recommendations to provide BRCA1/2 testing to all women with histologically confirmed HGSOC, uniform implementation remains challenging. The opportunity to review and revise genetic screening and testing practices will identify opportunities, where universal adoption of BRCA1/2 mutation testing will impact and improve treatment of women with ovarian cancer. Improving education and awareness of genetic testing for women with cancer, as well as the broader general community, will help focus much-needed attention on opportunities to advance prevention and screening programs in ovarian cancer. This is imperative not only for women with cancer and those at risk of developing cancer but also for their first-degree relatives. In addition, BRCA1/2 testing may have direct implications for patients with other types of cancers, many of which are now being found to have BRCA1/2 involvement. PMID- 27242961 TI - Editorial: Novel Targets and Targeting Technologies to Modulate Tumor Microenvironment. PMID- 27242960 TI - Alternate Service Delivery Models in Cancer Genetic Counseling: A Mini-Review. AB - Demand for cancer genetic counseling has grown rapidly in recent years as germline genomic information has become increasingly incorporated into cancer care, and the field has entered the public consciousness through high-profile celebrity publications. Increased demand and existing variability in the availability of trained cancer genetics clinicians place a priority on developing and evaluating alternate service delivery models for genetic counseling. This mini-review summarizes the state of science regarding service delivery models, such as telephone counseling, telegenetics, and group counseling. Research on comparative effectiveness of these models in traditional individual, in-person genetic counseling has been promising for improving access to care in a manner acceptable to patients. Yet, it has not fully evaluated the short- and long-term patient- and system-level outcomes that will help answer the question of whether these models achieve the same beneficial psychosocial and behavioral outcomes as traditional cancer genetic counseling. We propose a research agenda focused on comparative effectiveness of available service delivery models and how to match models to patients and practice settings. Only through this rigorous research can clinicians and systems find the optimal balance of clinical quality, ready and secure access to care, and financial sustainability. Such research will be integral to achieving the promise of genomic medicine in oncology. PMID- 27242962 TI - Acute Urinary Morbidity Following Stereotactic Body Radiation Therapy for Prostate Cancer with Prophylactic Alpha-Adrenergic Antagonist and Urethral Dose Reduction. AB - BACKGROUND: Stereotactic body radiation therapy (SBRT) delivers high doses of radiation to the prostate while minimizing radiation to the adjacent critical organs. Large fraction sizes may increase urinary morbidity due to unavoidable treatment of the prostatic urethra. This study reports rates of acute urinary morbidity following SBRT for localized prostate cancer with prophylactic alpha adrenergic antagonist utilization and urethral dose reduction (UDR). METHODS: From April 2013 to September 2014, 102 patients with clinically localized prostate cancer were treated with robotic SBRT to a total dose of 35-36.25 Gy in five fractions. UDR was employed to limit the maximum point dose of the prostatic urethra to 40 Gy. Prophylactic alpha-adrenergic antagonists were initiated 5 days prior to SBRT and continued until resolution of urinary symptoms. Quality of life (QoL) was assessed before and after treatment using the American Urological Association Symptom Score (AUA) and the Expanded Prostate Cancer Index Composite 26 (EPIC-26). Clinical significance was assessed using a minimally important difference (MID) of one half SD change from baseline. RESULTS: One hundred two patients underwent definitive prostate SBRT with UDR and were followed for 3 months. No patient experienced acute urinary retention requiring catheterization. A mean baseline AUA symptom score of 9.06 significantly increased to 11.83 1-week post-SBRT (p = 0.0024) and 11.84 1-month post-SBRT (p = 0.0023) but returned to baseline by 3 months. A mean baseline EPIC-26 irritative/obstructive score of 87.7 decreased to 74.1 1-week post-SBRT (p < 0.0001) and 77.8 1-month post-SBRT (p < 0.0001) but returned to baseline at 3 months. EPIC-26 irritative/obstructive score changes were clinically significant, exceeding the MID of 6.0. At baseline, 8.9% of men described their urinary function as a moderate to big problem, and that proportion increased to 37.6% 1 week following completion of SBRT before returning to baseline by 3 months. CONCLUSION: Stereotactic body radiation therapy for localized prostate cancer with utilization of prophylactic alpha adrenergic antagonist and UDR was well tolerated as determined by acute urinary function and bother, and symptoms were comparable to those observed following conventionally fractionated external beam radiation therapy (EBRT). Longer follow up is required to assess long-term toxicity and efficacy following SBRT with UDR. PMID- 27242963 TI - The Hypothetical Rabbit. PMID- 27242964 TI - Cross Talk between Cancer and Mesenchymal Stem Cells through Extracellular Vesicles Carrying Nucleic Acids. AB - Extracellular vesicles (EVs) are considered to be a novel complex mechanism of cell communication within the tumor microenvironment. EVs may act as vehicles for transcription factors and nucleic acids inducing epigenetic changes in recipient cells. Since tumor EVs may be present in patient biological fluids, it is important to investigate their function and molecular mechanisms of action. It has been shown that tumor cells release EVs, which are capable of regulating cell apoptosis, proliferation, invasion, and epithelial-mesenchymal transition, as well as to suppress activity of immune cells, to enhance angiogenesis, and to prepare a favorable microenvironment for metastasis. On the other hand, EVs derived from stromal cells, such as mesenchymal stem cells (MSCs), may influence the phenotype of tumor cells through reciprocal cross talk greatly influenced by the transcription factors and nucleic acids they carry. In particular, non-coding RNAs (ncRNAs), including microRNAs and long ncRNAs, have recently been identified as the main candidates for the phenotypic changes induced in the recipient cells by EVs. ncRNAs, which are important regulators of mRNA and protein expression, can function either as tumor suppressors or as oncogenes, depending on their targets. Herein, we have attempted to revise actual evidence reported in the literature on the role of EVs in tumor biology with particular regard to the cross talk of ncRNAs between cancer cells and MSCs. PMID- 27242965 TI - Potential of Diffusion-Weighted Imaging in the Characterization of Malignant, Benign, and Healthy Breast Tissues and Molecular Subtypes of Breast Cancer. AB - The role of apparent diffusion coefficient (ADC) in the diagnosis of breast cancer and its association with molecular biomarkers was investigated in 259 patients with breast cancer, 67 with benign pathology, and 54 healthy volunteers using diffusion-weighted imaging (DWI) at 1.5 T. In 59 breast cancer patients, dynamic contrast-enhanced MRI (DCEMRI) was also acquired. Mean ADC of malignant lesions was significantly lower (1.02 +/- 0.17 * 10(-3) mm(2)/s) compared to benign (1.57 +/- 0.26 * 10(-3) mm(2)/s) and healthy (1.78 +/- 0.13 * 10(-3) mm(2)/s) breast tissues. A cutoff ADC value of 1.23 * 10(-3) mm(2)/s (sensitivity 92.5%; specificity 91.1%; area under the curve 0.96) to differentiate malignant from benign diseases was arrived by receiver operating curve analysis. In 10/59 breast cancer patients, indeterminate DCE curve was seen, while their ADC value was indicative of malignancy, implying the potential of the addition of DWI in increasing the specificity of DCEMRI data. Further, the association of ADC with tumor volume, stage, hormonal receptors [estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor (HER2)], and menopausal status was investigated. A significant difference was seen in tumor volume between breast cancer patients of stages IIA and IIIA, IIB and IIIA, and IIB and III (B + C), respectively (P < 0.05). Patients with early breast cancer (n = 52) had significantly lower ADC and tumor volume than those with locally advanced breast cancer (n = 207). No association was found in ADC and tumor volume with the menopausal status. Breast cancers with ER-, PR-, and triple-negative (TN) status showed a significantly larger tumor volume compared to ER+, PR+, and non-triple negative (nTN) cancers, respectively. Also, TN tumors showed a significantly higher ADC compared to ER+, PR+, and nTN cancers. Patients with ER- and TN cancers were younger than those with ER+ and nTN cancers. The present study demonstrated that ADC may increase the diagnostic specificity of DCEMRI and be useful for treatment management in clinical setting. Additionally, it provides an insight into characterization of molecular types of breast cancer and may serve as an indicator of metabolic reprograming underlying tumor proliferation. PMID- 27242966 TI - Galectin-3 Determines Tumor Cell Adaptive Strategies in Stressed Tumor Microenvironments. AB - Galectin-3 is a member of the beta-galactoside-binding lectin family, whose expression is often dysregulated in cancers. While galectin-3 is usually an intracellular protein found in the nucleus and in the cytoplasm, under certain conditions, galectin-3 can be secreted by an yet unknown mechanism. Under stressing conditions (e.g., hypoxia and nutrient deprivation) galectin-3 is upregulated, through the activity of transcription factors, such as HIF-1alpha and NF-kappaB. Here, we review evidence that indicates a positive role for galectin-3 in MAPK family signal transduction, leading to cell proliferation and cell survival. Galectin-3 serves as a scaffold protein, which favors the spatial organization of signaling proteins as K-RAS. Upon secretion, extracellular galectin-3 interacts with a variety of cell surface glycoproteins, such as growth factor receptors, integrins, cadherins, and members of the Notch family, among other glycoproteins, besides different extracellular matrix molecules. Through its ability to oligomerize, galectin-3 forms lectin lattices that act as scaffolds that sustain the spatial organization of signaling receptors on the cell surface, dictating its maintenance on the plasma membrane or their endocytosis. Galectin-3 induces tumor cell, endothelial cell, and leukocyte migration, favoring either the exit of tumor cells from a stressed microenvironment or the entry of endothelial cells and leukocytes, such as monocytes/macrophages into the tumor organoid. Therefore, galectin-3 plays homeostatic roles in tumors, as (i) it favors tumor cell adaptation for survival in stressed conditions; (ii) upon secretion, galectin-3 induces tumor cell detachment and migration; and (iii) it attracts monocyte/macrophage and endothelial cells to the tumor mass, inducing both directly and indirectly the process of angiogenesis. The two latter activities are potentially targetable, and specific interventions may be designed to counteract the protumoral role of extracellular galectin-3. PMID- 27242967 TI - Stereotactic Accelerated Partial Breast Irradiation for Early-Stage Breast Cancer: Rationale, Feasibility, and Early Experience Using the CyberKnife Radiosurgery Delivery Platform. AB - PURPOSE: The efficacy of accelerated partial breast irradiation (APBI) utilizing brachytherapy or conventional external beam radiation has been studied in early stage breast cancer treated with breast-conserving surgery. Data regarding stereotactic treatment approaches are emerging. The CyberKnife linear accelerator enables excellent dose conformality to target structures while adjusting for target and patient motion. We report our institutional experience on the technical feasibility and rationale for stereotactic accelerated partial breast irradiation (SAPBI) delivery using the CyberKnife radiosurgery system. METHODS: Ten patients completed CyberKnife SAPBI (CK-SAPBI) in 2013 at Georgetown University Hospital. Four gold fiducials were implanted around the lumpectomy cavity prior to treatment under ultrasound guidance. The synchrony system tracked intrafraction motion of the fiducials. The clinical target volume was defined on contrast enhanced CT scans using surgical clips and post-operative changes. A 5 mm expansion was added to create the planning treatment volume (PTV). A total dose of 30 Gy was delivered to the PTV in five consecutive fractions. Target and critical structure doses were assessed as per the National Surgical Adjuvant Breast and Bowel Project B-39 study. RESULTS: At least three fiducials were tracked in 100% of cases. The Mean treated PTV was 70 cm(3) and the mean prescription isodose line was 80%. Mean dose to target volumes and constraints are as follows: 100% of the PTV received the prescription dose (PTV30). The volume of the ipsilateral breast receiving 30 Gy (V30) and above 15 Gy (V > 15) was 14 and 31%, respectively. The ipsilateral lung volume receiving 9 Gy (V9) was 3%, and the contralateral lung volume receiving 1.5 Gy (V1.5) was 8%. For left sided breast cancers, the volume of heart receiving 1.5 Gy (V1.5) was 31%. Maximum skin dose was 36 Gy. At a median follow-up of 1.3 years, all patients have experienced excellent/good breast cosmesis outcomes, and no breast events have been recorded. CONCLUSION: CyberKnife stereotactic accelerated partial breast irradiation is an appealing technique for partial breast irradiation offering improvements over existing APBI techniques. Our early findings indicate that CK-SAPBI delivered in five daily fractions is feasible, well tolerated, and is a reliable platform for delivering APBI. PMID- 27242968 TI - Haemophilus haemolyticus Interaction with Host Cells Is Different to Nontypeable Haemophilus influenzae and Prevents NTHi Association with Epithelial Cells. AB - Nontypeable Haemophilus influenzae (NTHi) is an opportunistic pathogen that resides in the upper respiratory tract and contributes to a significant burden of respiratory related diseases in children and adults. Haemophilus haemolyticus is a respiratory tract commensal that can be misidentified as NTHi due to high levels of genetic relatedness. There are reports of invasive disease from H. haemolyticus, which further blurs the species boundary with NTHi. To investigate differences in pathogenicity between these species, we optimized an in vitro epithelial cell model to compare the interaction of 10 H. haemolyticus strains with 4 NTHi and 4 H. influenzae-like haemophili. There was inter- and intra species variability but overall, H. haemolyticus had reduced capacity to attach to and invade nasopharyngeal and bronchoalveolar epithelial cell lines (D562 and A549) within 3 h when compared with NTHi. H. haemolyticus was cytotoxic to both cell lines at 24 h, whereas NTHi was not. Nasopharyngeal epithelium challenged with some H. haemolyticus strains released high levels of inflammatory mediators IL-6 and IL-8, whereas NTHi did not elicit an inflammatory response despite higher levels of cell association and invasion. Furthermore, peripheral blood mononuclear cells stimulated with H. haemolyticus or NTHi released similar and high levels of IL-6, IL-8, IL-10, IL-1beta, and TNFalpha when compared with unstimulated cells but only NTHi elicited an IFNgamma response. Due to the relatedness of H. haemolyticus and NTHi, we hypothesized that H. haemolyticus may compete with NTHi for colonization of the respiratory tract. We observed that in vitro pre-treatment of epithelial cells with H. haemolyticus significantly reduced NTHi attachment, suggesting interference or competition between the two species is possible and warrants further investigation. In conclusion, H. haemolyticus interacts differently with host cells compared to NTHi, with different immunostimulatory and cytotoxic properties. This study provides an in vitro model for further investigation into the pathogenesis of Haemophilus species and the foundation for exploring whether H. haemolyticus can be used to prevent NTHi disease. PMID- 27242970 TI - Intramacrophage Survival for Extracellular Bacterial Pathogens: MgtC As a Key Adaptive Factor. PMID- 27242969 TI - Identification of Secreted Exoproteome Fingerprints of Highly-Virulent and Non Virulent Staphylococcus aureus Strains. AB - Staphylococcus aureus is a commensal inhabitant of skin and mucous membranes in nose vestibule but also an important opportunistic pathogen of humans and livestock. The extracellular proteome as a whole constitutes its major virulence determinant; however, the involvement of particular proteins is still relatively poorly understood. In this study, we compared the extracellular proteomes of poultry-derived S. aureus strains exhibiting a virulent (VIR) and non-virulent (NVIR) phenotype in a chicken embryo experimental infection model with the aim to identify proteomic signatures associated with the particular phenotypes. Despite significant heterogeneity within the analyzed proteomes, we identified alpha haemolysin and bifunctional autolysin as indicators of virulence, whereas glutamylendopeptidase production was characteristic for non-virulent strains. Staphopain C (StpC) was identified in both the VIR and NVIR proteomes and the latter fact contradicted previous findings suggesting its involvement in virulence. By supplementing NVIR, StpC-negative strains with StpC, and comparing the virulence of parental and supplemented strains, we demonstrated that staphopain C alone does not affect staphylococcal virulence in a chicken embryo model. PMID- 27242971 TI - Autophagy-Related Proteins Target Ubiquitin-Free Mycobacterial Compartment to Promote Killing in Macrophages. AB - Autophagy is a lysosomal degradative process that plays essential functions in innate immunity, particularly, in the clearance of intracellular bacteria such as Mycobacterium tuberculosis. The molecular mechanisms involved in autophagy activation and targeting of mycobacteria, in innate immune responses of macrophages, are only partially characterized. Autophagy targets pathogenic M. tuberculosis via a cytosolic DNA recognition- and an ubiquitin-dependent pathway. In this report, we show that non-pathogenic M. smegmatis induces a robust autophagic response in THP-1 macrophages with an up regulation of several autophagy-related genes. Autophagy activation relies in part on recognition of mycobacteria by Toll-like receptor 2 (TLR2). Notably, LC3 targeting of M. smegmatis does not rely on membrane damage, ubiquitination, or autophagy receptor recruitment. Lastly, M. smegmatis promotes recruitment of several autophagy proteins, which are required for mycobacterial killing. In conclusion, our study uncovered an alternative autophagic pathway triggered by mycobacteria which involves cell surface recognition but not bacterial ubiquitination. PMID- 27242972 TI - Circadian Control of Antibacterial Immunity: Findings from Animal Models. AB - Most of the biological functions, including the immune system, are linked to circadian rhythms in living organisms. Changes occurring to biological parameters as the result of these circadian rhythms can therefore affect the outcome of a disease. For decades, model organisms have proven to be a great tool to understanding biological mechanisms such as circadian cycle and immunity. In this review, we created an inventory of the use of model organisms in order to decipher the relation between circadian rhythms and antibacterial immunity. PMID- 27242973 TI - Surface Proteins and Pneumolysin of Encapsulated and Nonencapsulated Streptococcus pneumoniae Mediate Virulence in a Chinchilla Model of Otitis Media. AB - Streptococcus pneumoniae infections result in a range of human diseases and are responsible for almost one million deaths annually. Pneumococcal disease is mediated in part through surface structures and an anti-phagocytic capsule. Recent studies have shown that nonencapsulated S. pneumoniae (NESp) make up a significant portion of the pneumococcal population and are able to cause disease. NESp lack some common surface proteins expressed by encapsulated pneumococci, but express surface proteins unique to NESp. A chinchilla model of otitis media (OM) was used to determine the effect various pneumococcal mutations have on pathogenesis in both NESp and encapsulated pneumococci. Epithelial cell adhesion and invasion assays were used to examine the effects in relation to deletion of intrinsic genes or expression of novel genes. A mouse model of colonization was also utilized for comparison of various pneumococcal mutants. It was determined that pneumococcal surface protein K (PspK) and pneumolysin (Ply) affect NESp middle ear pathogenesis, but only PspK affected epithelial cell adhesion. Experiments in an OM model were done with encapsulated strains testing the importance of native virulence factors and treatment of OM. First, a triple deletion of the common virulence factors PspA, PspC, and Ply, (DeltaPAC), from an encapsulated background abolished virulence in an OM model while a PspC mutant had detectable, but reduced amounts of recoverable bacteria compared to wildtype. Next, treatment of OM was effective when starting antibiotic treatment within 24 h with resolution by 48 h post-treatment. Expression of NESp-specific virulence factor PspK in an encapsulated strain has not been previously studied, and we showed significantly increased adhesion and invasion of human epithelial cells by pneumococci. Murine colonization was not significantly increased when an encapsulated strain expressed PspK, but colonization was increased when a capsule mutant expressed PspK. The ability of PspK expression to increase colonization in a capsule mutant despite no increase in adhesion can be attributed to other functions of PspK, such as sIgA binding or immune modulation. OM is a substantial economic burden, thus a better understanding of both encapsulated pneumococcal pathogenesis and the emerging pathogen NESp is necessary for effective prevention and treatment. PMID- 27242975 TI - Novel Psychological Formulation and Treatment of "Tic Attacks" in Tourette Syndrome. AB - One important, but underreported, phenomenon in Tourette syndrome (TS) is the occurrence of "tic attacks." These episodes have been described at conferences as sudden bouts of tics and/or functional tic-like movements, lasting from 15 min to several hours. They have also been described by patients in online TS communities. To date, there are no reports of tic attacks in the literature. The aim of this article is to stimulate discussion and inform clinical practices by describing the clinical presentation of 12 children (mean age 11 years and 3 months; SD = 2 years and 4 months) with TS and tic attacks, with a detailed case report for one case (13-year-old male). These children commonly present acutely to casualty departments and undergo unnecessary medical investigations. Interestingly, all children reported comorbid anxiety, with worries about the tics themselves and an increased internal focus of attention on tics once the attacks had started. In keeping with other children, the index case reported a strong internal focus of attention, with a relationship between physiological sensations/tic urges, worries about having tic attacks, and behavioral responses (e.g., body scanning, situational avoidance, and other responses). In our experience, the attacks reduce with psychological therapy, for example, the index case attended 13 sessions of therapy that included metacognitive and attention training techniques, as well as cognitive-behavioral strategies. Following treatment, an improvement was seen across a range of measures assessing tics, mood, anxiety, and quality of life. Thus, psychological techniques used to treat anxiety disorders are effective at supporting a reduction in tic attacks through modifying attention, worry processes, and negative beliefs. It is hypothesized that an attentional style of threat monitoring, difficulties tolerating internal sensory urges, cognitive misattributions, and maladaptive coping strategies contribute to the onset and maintenance of tic attacks. These cases provide support for the view that tic attacks are triggered and maintained by psychological factors, thereby challenging the view that tic attacks merely reflect extended bouts of tics. As such, we propose that the movements seen in tic attacks may resemble a combination of tics and functional neurological movements, with tic attacks reflecting episodes of panic and anxiety for individuals with TS. PMID- 27242974 TI - F. novicida-Infected A. castellanii Does Not Enhance Bacterial Virulence in Mice. AB - Francisella tularensis is a facultative intracellular bacterium that causes tularemia in humans and animals. Epidemiology of tularemia worldwide is often associated with water-borne transmission, which includes mosquitoes and amoebae as the potential host reservoirs of the bacteria in water environment. In vitro studies showed intracellular replication of F. tularensis within Acanthamoeba castellanii and Hartmanella vermiformis cells. While infection of amoeba by Legionella pneumophila has been shown to enhance infectivity of L. pneumophila the role of F. tularensis-infected protozoa in the pathogenesis of tularemia is not known. We used 6 h coculture of A. castellanii and F. novicida for investigation of the effect of inhaled amoeba on the pathogenesis of tularemia on in vivo model. Balb/c mice were infected intratracheally with F. novicida or with F. novicida-infected A. castellanii. Surprisingly, infection with F. novicida infected A. castellanii did not lead to bronchopneumonia in Balb/c mice, and Francisella did not disseminate into the liver and spleen. Upon inhalation, F. novicida infects a variety of host cells, though neutrophils are the predominant cells early during infection in the lung infiltrates of pulmonary tularemia. The numbers of neutrophils in the lungs of Balb/c mice were significantly lower in the infection of mice with F. novicida-infected A. castellanii in comparison to group of mice infected only with F. novicida. These results demonstrate that following inoculation of mice with F. novicida-infected A. castellanii, mice did not develop tularemia. PMID- 27242976 TI - Hemophagocytic Lymphohistiocytosis in Children: Pathogenesis and Treatment. AB - Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder in children that is characterized by persistent fever, splenomegaly with cytopenia, hypertriglyceridemia, and hypofibrinogenemia. Increased levels of various cytokines and soluble interleukin-2 receptor are biological markers of HLH. HLH can be classified into two major forms: primary and secondary. Familial hemophagocytic lymphohistiocytosis (FHL), a type of primary HLH, is an autosomal recessive disorder that typically occurs in infancy and can be classified into five different subtypes (FHL types 1-5). In Japan, >80% of patients with FHL have either PRF1 (FHL type 2) or UNC13D (FHL type 3) defects. FHL is considered to be a disorder of T-cell function because the activity of NK cells or cytotoxic T lymphocytes as target cells is usually impaired. Moreover, Epstein-Barr virus associated HLH (EBV-HLH) is considered a major subtype of secondary HLH. Any genetic background could have an effect on the pathogenesis of secondary HLH because EBV-HLH is considered to be particularly prevalent in Asian countries. For primary HLH, hematopoietic stem cell transplantation is the only accepted curative therapy, although cord blood transplantation with a reduced-conditioning regimen has been used with superior outcomes. For secondary HLH, including EBV HLH, immunochemotherapy based on the HLH-2004 protocol has been used. In the near future, the entire mechanism of HLH should be clarified to establish less toxic therapies, including cell therapy and gene targeting therapy. PMID- 27242977 TI - Should CAH in Females Be Classified as DSD? AB - Great controversies and misunderstandings have developed around the relatively recently coined term disorders of sex development (DSD). In this article, we question the wisdom of including XX individuals with congenital adrenal hyperplasia (CAH) in the DSD category and develop arguments against it based on the published literature on the subject. It is clear that females with CAH assigned the female gender before 24 months of age and properly managed retain the female gender identity regardless of the Prader grade. Females with CAH and low Prader grades have the potential for a normal sexual and reproductive life. Those with greater degrees of prenatal androgen exposure (Prader grades IV and V) raised as females also identify themselves as females but experience more male like behavior in childhood, have a greater rate of homosexuality, and have greater difficulty with vaginal penetration and maintaining pregnancies. Improvement in surgical techniques, better endocrinological, psychological, and surgical follow-up may lessen these problems in the future. Given the fact that the term DSD includes many conditions with problematic gender identity and conflicts with the gender assigned at birth, it may be appropriate to exclude females with CAH from the DSD classification. PMID- 27242978 TI - The Functional Role of PRC2 in Early T-cell Precursor Acute Lymphoblastic Leukemia (ETP-ALL) - Mechanisms and Opportunities. AB - Early T-Cell precursor acute lymphoblastic leukemia (ETP-ALL) is a relatively newly identified subset of T-lineage ALL. There are conflicting results regarding prognosis, and the genetic basis of this condition is variable. Here, we summarize the current status of the field and discuss the role of mutations in the Polycomb Repressive Complex 2 frequently identified in ETP-ALL patients. PMID- 27242979 TI - Quality of Life of Children with Cystic Periventricular Leukomalacia - A Prospective Analysis with the Child Health Questionnaire-Parent Form 50. AB - OBJECTIVE: Cystic periventricular leukomalacia (PVL) is associated with moderate to severe physical and mental handicaps in preterm infants. We hypothesized whether or not those handicaps were associated with a poorer quality of life (QOL) of affected children and their families compared to matched controls. PATIENTS AND METHODS: All children with the diagnosis PVL collected from a local database of the Division of Neonatology of the Medical University of Graz, Austria, and born between 1997 and 2008 were included in the study group. Preterm infants matched for gestational age, birth weight, year of birth, and gender without PVL served as controls. Selected perinatal data and neurological outcome were documented. The interview of the parents was conducted using the Child Health Questionnaire-Parent Form 50 (CHQ-PF50), German version. The CHQ-PF50 consists of 50 items divided over 11 multi-item scales and 2 single-item questions. RESULTS: The CHQ-PF50 was answered by 21 parents of the study (26%) and 44 of the control (39%) group. Cases were diagnosed as having developmental delay, dystonia, strabismus, central visual impairment, seizures, and cerebral palsy (81 vs. 7%, p < 0.001) more common than controls. Analysis of the CHQ-PF 50 revealed significantly poorer results for cases regarding physical health (physical functioning: p < 0.001, physical social limitations: p < 0.001, and physical summary score: p < 0.001). Several psychosocial categories (behavior, mental health, and self-esteem) and the psychosocial summary score did not differ between groups. Only two categories (parental impact concerning time p = 0.004 and family activities: p = 0.026) revealed significantly poorer results in the cases as it was for the global category for health (p = 0.009). CONCLUSION: Children with PVL had an overall poorer QOL regarding physical aspects. However, PVL was not generally associated with a poorer QOL regarding psychosocial aspects. PMID- 27242981 TI - Deep Retraction Pockets, Endometriosis, and Quality of Life. AB - OBJECTIVE: The purpose of this study was to examine if deep retraction pockets (DRPs) in the posterior cul-de-sac and uterosacral ligaments could be a manifestation of endometriosis and if excision of these pockets improves pain symptoms and quality of life. STUDY DESIGN: Prospective cohort study Canadian Task Force Classification, II-3. MATERIALS AND METHODS: Preoperative data, operative data, and follow-up data were collected prospectively at the Center for Endometriosis at Saint Louis University, a referral center for the surgical management of endometriosis. RESULTS: The 107 consecutive patients who presented with preoperative deep dyspareunia were included in the study, and the median postoperative follow-up was 13 months. Endometriosis was confirmed histologically in any location excised in 88/107 (82.2%) of the women, and 31 DRPs were excised from 25 women with DRPs in the posterior cul-de-sac or uterosacral ligaments, of which 15/31 (48.4%) had endometriosis. Of the 10 DRPs without visible surface lesions, 3 (30.0%) had endometriosis on histology. Pain symptoms and quality of life significantly improved after excision surgery, whether or not DRPs were present. Women who had endometriosis in their DRP also had significant improvement in deep dyspareunia and chronic pelvic pain and quality of life. Results did not differ when patients who took postoperative hormonal suppression were removed from the analyses. CONCLUSION: Patients had significantly improved pain symptoms and quality of life after excision surgery, whether or not DRPs were present. This study demonstrated that a DRP may be a manifestation of endometriosis (even with a clear surface of the pocket), so that DRPs should be excised to achieve optimal excision of endometriosis. PMID- 27242980 TI - Relevant Outcomes in Pediatric Acute Respiratory Distress Syndrome Studies. AB - Despite distinct epidemiology and outcomes, pediatric acute respiratory distress syndrome (PARDS) is often managed based on evidence extrapolated from treatment of adults. The impact of non-pulmonary processes on mortality as well as the lower mortality rate compared to adults with acute respiratory distress syndrome (ARDS) renders the utilization of short-term mortality as a primary outcome measure for interventional studies problematic. However, data regarding alternatives to mortality are profoundly understudied, and proposed alternatives, such as ventilator-free days, may be themselves subject to hidden biases. Given the neuropsychiatric and functional impairment in adult survivors of ARDS, characterization of these morbidities in children with PARDS is of paramount importance. The purpose of this review is to frame these challenges in the context of the existing pediatric literature, and using adult ARDS as a guide, suggest potential clinically relevant outcomes that deserve further investigation. The goal is to identify important areas of study in order to better define clinical practice and facilitate future interventional trials in PARDS. PMID- 27242982 TI - Commentary: Help-Seeking Patterns and Attitudes to Treatment amongst Men Who Attempted Suicide. PMID- 27242983 TI - Does Pedestrian Danger Mediate the Relationship between Local Walkability and Active Travel to Work? AB - BACKGROUND: Environmental and policy factors play an important role in influencing people's lifestyles, physical activity (PA), and risks for developing obesity. Research suggests that more walkable communities are needed to sustain lifelong PA behavior, but there is a need to determine what local built environment features facilitate making being active the easy choice. PURPOSE: This county-level study examined the association between local walkability (walkability and traffic calming scales), pedestrian danger, and the percent of adults who used active transport to work. METHODS: Built environment and PA outcome measures were constructed for the 496 most populous counties representing 74% of the U.S. population. Geographic information system-based walkability scales were constructed and include a census of roads located within the counties using 2011 Navteq data. The pedestrian danger index (PDI) includes data collected from the Fatality Analysis Reporting System 2009-2011, and measures the likelihood of a pedestrian being hit and killed by a vehicle. Four continuous outcome measures were constructed using 2009-2013 American Community Survey county-level 5-year estimates. The measures represent the percentage of workers living in a county who worked away from home and (1) walked to work; (2) biked to work; (3) took public transit; and (4) used any form of active transport. Linear regression and mediation analyses were conducted to examine the association between walkability, PDI, and active transport. Models accounted for clustering within state with robust SEs, and controlled for median household income, families with children in poverty, race, ethnicity, urbanicity, and region. RESULTS: The walkability scale was significantly negatively associated with the PDI (beta = -0.06, 95% CI = -0.111, -0.002). In all models, the PDI was significantly negatively associated with all active travel-related outcomes at the p < 0.01 level. The walkability scale was positively associated with all four outcomes at the p < 0.01 level. Results showed that the significant positive relationship between local walkability and the four active transport outcome measures was partially mediated by the PDI. We found no association between traffic calming, the PDI, and the active transport outcomes. CONCLUSION: Results from this study show that, at the county-level, walkability is associated with active travel, and this association is partially mediated by an index of pedestrian safety. PMID- 27242984 TI - Corrigendum: Electronic medication monitoring-informed counseling to improve adherence to combination anti-retroviral therapy and virologic treatment outcomes: a meta-analysis. AB - [This corrects the article on p. 139 in vol. 3, PMID: 26042212.]. PMID- 27242986 TI - Editorial: Emergent Public Health Issues in the US-Mexico Border Region. PMID- 27242985 TI - Toxicological Risks of Agrochemical Spray Adjuvants: Organosilicone Surfactants May Not Be Safe. AB - Agrochemical risk assessment that takes into account only pesticide active ingredients without the spray adjuvants commonly used in their application will miss important toxicity outcomes detrimental to non-target species, including humans. Lack of disclosure of adjuvant and formulation ingredients coupled with a lack of adequate analytical methods constrains the assessment of total chemical load on beneficial organisms and the environment. Adjuvants generally enhance the pesticidal efficacy and inadvertently the non-target effects of the active ingredient. Spray adjuvants are largely assumed to be biologically inert and are not registered by the USA EPA, leaving their regulation and monitoring to individual states. Organosilicone surfactants are the most potent adjuvants and super-penetrants available to growers. Based on the data for agrochemical applications to almonds from California Department of Pesticide Regulation, there has been increasing use of adjuvants, particularly organosilicone surfactants, during bloom when two-thirds of USA honey bee colonies are present. Increased tank mixing of these with ergosterol biosynthesis inhibitors and other fungicides and with insect growth regulator insecticides may be associated with recent USA honey bee declines. This database archives every application of a spray tank adjuvant with detail that is unprecedented globally. Organosilicone surfactants are good stand alone pesticides, toxic to bees, and are also present in drug and personal care products, particularly shampoos, and thus represent an important component of the chemical landscape to which pollinators and humans are exposed. This mini review is the first to possibly link spray adjuvant use with declining health of honey bee populations. PMID- 27242987 TI - Narrative Methods and Sociocultural Linguistic Approaches in Facilitating In depth Understanding of HIV Disclosure in a Cohort of Women and Men in Cape Town, South Africa. AB - The South African National Department of Health has rapidly extended free public sector antiretroviral treatment for people living with HIV from 2007. Approximately 6 million people are living with HIV in South Africa, with 3.1 million currently on treatment. HIV disclosure stigma has been reduced in high prevalence, generalized epidemic settings, but some remains, including in research interviews. This paper documents the unexpected reactions of people living with HIV to interviewers. It highlights shifts over time from discussing daily events with researchers to later expressing distress and then relief at having an uninvolved, sympathetic person with whom to discuss HIV disclosure. While there are commonalities, women and men had gendered responses to interviewers. These are apparent in men's uncharacteristic emotional responses and women's shyness in revealing gendered aspects of HIV acquisition. Both women and men expressed stress at not being allowed or able to fulfill dominant expected masculine or feminine roles. The findings underline the role of research interviewers in study participants confiding and fully expressing their feelings. This greater confidence occurred in follow-up interviews with researchers in busy health facilities, where time of health-care providers is limited. It underlines the methodological value of narrative inquiries with research cohorts. These allowed richer data than cross-sectional interviews. They shaped the questions asked and the process of interview. They revealed participants' increasing level of agency in expressing feelings that they find important. This research contributes to highlighting pivotal, relational aspects in research between empathetic, experienced researchers and study participants and how participant researcher relationships progress over time. It highlights ethical dilemmas in roles of researchers as opposed to counselors, raising questions of possible blurring of lines between research and service roles. This requires further research exploration. It additionally underscores the importance of "care for the carer." Furthermore, it emphasizes that cultural sensitivity to language involves more than merely speaking the words in a language. Culture, humor, dialects, conceptual issues, wordplay, common sense, and respectful attitudes to other languages, resonates. PMID- 27242988 TI - Scientists and Civil Society Must Move Together toward a New Science. PMID- 27242989 TI - Webcams, Crowdsourcing, and Enhanced Crosswalks: Developing a Novel Method to Analyze Active Transportation. AB - INTRODUCTION: Active transportation opportunities and infrastructure are an important component of a community's design, livability, and health. Features of the built environment influence active transportation, but objective study of the natural experiment effects of built environment improvements on active transportation is challenging. The purpose of this study was to develop and present a novel method of active transportation research using webcams and crowdsourcing, and to determine if crosswalk enhancement was associated with changes in active transportation rates, including across a variety of weather conditions. METHODS: The 20,529 publicly available webcam images from two street intersections in Washington, DC, USA were used to examine the impact of an improved crosswalk on active transportation. A crowdsource, Amazon Mechanical Turk, annotated image data. Temperature data were collected from the National Oceanic and Atmospheric Administration, and precipitation data were annotated from images by trained research assistants. RESULTS: Summary analyses demonstrated slight, bi-directional differences in the percent of images with pedestrians and bicyclists captured before and after the enhancement of the crosswalks. Chi-square analyses revealed these changes were not significant. In general, pedestrian presence increased in images captured during moderate temperatures compared to images captured during hot or cold temperatures. Chi square analyses indicated the crosswalk improvement may have encouraged walking and biking in uncomfortable outdoor conditions (P < 0.5). CONCLUSION: The methods employed provide an objective, cost-effective alternative to traditional means of examining the effects of built environment changes on active transportation. The use of webcams to collect active transportation data has applications for community policymakers, planners, and health professionals. Future research will work to validate this method in a variety of settings as well as across different built environment and community policy initiatives. PMID- 27242990 TI - Comparison of Working Conditions and Prevalence of Musculoskeletal Symptoms among Dairy Farmers in Southern Sweden over a 25-Year Period. AB - Working conditions and the prevalence of perceived musculoskeletal symptoms (MSSs) among dairy farmers in 2013 were monitored by repeating a mail survey of dairy workers in Scania, southern Sweden, using the same method for collecting data on MSSs and working conditions employed in previous surveys conducted in 1988 and 2002. All dairy enterprises in Scania (total 419) were sent two copies of a questionnaire. One or more responses were received from 232 enterprises (55.4%), of which those from 247 dairy farmers (75% men and 25% women) in 199 enterprises are included in this study. The farmers had increased their weekly working hours in 2013 compared with 2002 (males [Formula: see text]; females [Formula: see text]). Each male milked on average 30 cows in 1988, 44 cows in 2002, and 86 cows in 2013. The corresponding numbers milked by female farmers were 29, 60, and 102, respectively. In 1988, almost all farmers used tethered systems, while in 2013, 54.4% of male and 66.1% of female farmers instead worked with loose-housing systems. Of the farmers who used loose-housing systems, 50.7% had a robotic milking system. In 2013, 79.0% of male and 88.5% of female farmers reported MSSs on some occasion, especially in the lower back, shoulders, and knees for men, and in the shoulders, lower back, and wrists/hands for women. However, there was no statistical change compared with the frequency of MSSs in 2002. In 2013, there was a tendency for younger dairy farmers (<=35 years) to report MSSs, especially in the shoulders, elbows, lower back, and feet, more frequently than younger farmers in 2002. The males who worked with robot milking systems in 2013 indicated less discomfort in the shoulders than men who worked with other systems. The corresponding females indicated fewer problems in the lower back in 2013. Various aspects of milking system design and technology have been improved to reduce the workload and prevent MSSs in dairy farmers. Nevertheless, more improvements are needed to make the milking process more attractive and reduce health problems, especially in younger farmers currently working with milking and in new recruits. PMID- 27242991 TI - Effect of Financially Punished Audit and Feedback in a Pediatric Setting in China, within an Antimicrobial Stewardship Program, and as Part of an International Accreditation Process. AB - BACKGROUND: Prior authorization, audit and feedback, and pay for performance are the three core "active" strategies of antimicrobial stewardship program (ASP), yet little is known about the individual or combined benefits of such programs, particularly in a pediatric setting. OBJECTIVES: The aim of this study was to compare these core ASP strategies and determine the incremental effect of financially punished audit and feedback. METHODS: During the journey to the Joint Commission International accreditation, a tertiary pediatric medical center performed two different hospital-wide stewardship interventions in succession. The first stage without formalized ASPs served as pre-intervention period, January 2011 to April 2011. The ASP used prior authorization alone during the first-intervention period, May 2011 to September 2011. In October 2011, financially punished audit and feedback was introduced, marking the start of the second-intervention period, October 2011 to November 2012. We compared the differences of the change in monthly average use of antibiotics and expenditure on antibiotics before and after the ASP changes by using interrupted time series via dynamic regression. The main end points included the proportions of antibiotic prescriptions and expenditure on antibacterial relative to all medications. RESULTS: Before the second-intervention period, neither the proportion of antibiotic prescriptions nor the proportion of expenditure on antibiotics declined significantly in both ambulatory and inpatient settings. However, after the introduction of financially punished audit and feedback, the proportion of both antibiotic prescriptions (beta = -6.269, P < 0.001, and reduction = 59.4% for outpatients; beta = -1.235, P < 0.001, and reduction = 19.8% for inpatients) and expenditure on antibiotics (beta = -7.777, P < 0.001, and reduction = 46.7% for outpatients; beta = -4.933, P = 0.001, and reduction = 16.3% for inpatients) dropped immediately. CONCLUSION: The combination of more than one core strategies (prior authorization, audit and feedback, and pay for performance) will be more effective than one strategy alone. PMID- 27242992 TI - Race and Urbanity Alter the Protective Effect of Education but not Income on Mortality. AB - BACKGROUND: Although the effects of socioeconomic status (SES) on mortality are well established, these effects may vary based on contextual factors such as race and place. Using 25-year follow-up data of a nationally representative sample of adults in the U.S., this study had two aims: (1) to explore separate, additive, and multiplicative effects of race and place (urbanity) on mortality and (2) to test the effects of education and income on all-cause mortality based on race and place. METHODS: The Americans' Changing Lives (ACL) Study followed Whites and Blacks 25 years and older from 1986 until 2011. The focal predictors were baseline SES (education and income) collected in 1986. The main outcome was time until death due to all causes from 1986 until 2011. Age, gender, behaviors (smoking and exercise), and health (chronic medical conditions, self-rated health, and depressive symptoms) at baseline were potential confounders. A series of survey Cox proportional hazard models were used to test protective effects of education and income on mortality based on race and urbanity. RESULTS: Race and place had separate but not additive or multiplicative effects on mortality. Higher education and income were protective against all-cause mortality in the pooled sample. Race and urbanity significantly interacted with baseline education but not income on all-cause mortality, suggesting that the protective effect of education but not income depend on race and place. While the protective effect of education were fully explained by baseline health status, the effect of income remained significant beyond health. CONCLUSION: In the U.S., the health return associated with education depends on race and place. This finding suggests that populations differently benefit from SES resources, particularly education. Differential effect of education on employment and health care may explain the different protective effect of education based on race and place. Findings support the "diminishing returns" hypothesis for Blacks. PMID- 27242993 TI - Label-Free Proteomics Assisted by Affinity Enrichment for Elucidating the Chemical Reactivity of the Liver Mitochondrial Proteome toward Adduction by the Lipid Electrophile 4-hydroxy-2-nonenal (HNE). AB - The analysis of oxidative stress-induced post-translational modifications remains challenging due to the chemical diversity of these modifications, the possibility of the presence of positional isomers and the low stoichiometry of the modified proteins present in a cell or tissue proteome. Alcoholic liver disease (ALD) is a multifactorial disease in which mitochondrial dysfunction and oxidative stress have been identified as being critically involved in the progression of the disease from steatosis to cirrhosis. Ethanol metabolism leads to increased levels of reactive oxygen species (ROS), glutathione depletion and lipid peroxidation. Posttranslational modification of proteins by electrophilic products of lipid peroxidation has been associated with governing redox-associated signaling mechanisms, but also as contributing to protein dysfunction leading to organelle and liver injury. In particular the prototypical alpha,beta-unsaturated aldehyde, 4-hydroxy-2-nonenal (HNE), has been extensively studied as marker of increased oxidative stress in hepatocytes. In this study, we combined a LC-MS label-free quantification method and affinity enrichment to assess the dose-dependent insult by HNE on the proteome of rat liver mitochondria. We used a carbonyl-selective probe, the ARP probe, to label HNE-protein adducts and to perform affinity capture at the protein level. Using LC-MS to obtain protein abundance estimates, a list of protein targets was obtained with increasing concentration of HNE used in the exposure studies. In parallel, we performed affinity capture at the peptide level to acquire site-specific information. Examining the concentration dependence of the protein modifications, we observed distinct reactivity profiles for HNE-protein adduction. Pathway analysis indicated that proteins associated with metabolic processes, including amino acid, fatty acid, and glyoxylate and dicarboxylate metabolism, bile acid synthesis and TCA cycle, showed enhanced reactivity to HNE adduction. Whereas, proteins associated with oxidative phosphorylation displayed retardation toward HNE adduction. We provide a list of 31 protein targets with a total of 61 modification sites that may guide future targeted LC-MS assays to monitor disease progression and/or intervention in preclinical models of ALD and possibly other liver diseases with an oxidative stress component. PMID- 27242994 TI - Small-Molecule Binding Aptamers: Selection Strategies, Characterization, and Applications. AB - Aptamers are single-stranded, synthetic oligonucleotides that fold into 3 dimensional shapes capable of binding non-covalently with high affinity and specificity to a target molecule. They are generated via an in vitro process known as the Systematic Evolution of Ligands by EXponential enrichment, from which candidates are screened and characterized, and then used in various applications. These applications range from therapeutic uses to biosensors for target detection. Aptamers for small molecule targets such as toxins, antibiotics, molecular markers, drugs, and heavy metals will be the focus of this review. Their accurate detection is needed for the protection and wellbeing of humans and animals. However, the small molecular weights of these targets, including the drastic size difference between the target and the oligonucleotides, make it challenging to select, characterize, and apply aptamers for their detection. Thus, recent (since 2012) notable advances in small molecule aptamers, which have overcome some of these challenges, are presented here, while defining challenges that still exist are discussed. PMID- 27242995 TI - Improved Tracking and Resolution of Bacteria in Holographic Microscopy Using Dye and Fluorescent Protein Labeling. AB - Digital holographic microscopy (DHM) is an emerging imaging technique that permits instantaneous capture of a relatively large sample volume. However, large volumes usually come at the expense of lower spatial resolution, and the technique has rarely been used with prokaryotic cells due to their small size and low contrast. In this paper we demonstrate the use of a Mach-Zehnder dual-beam instrument for imaging of labeled and unlabeled bacteria and microalgae. Spatial resolution of 0.3 MUm is achieved, providing a sampling of several pixels across a typical prokaryotic cell. Both cellular motility and morphology are readily recorded. The use of dyes provides both amplitude and phase contrast improvement and is of use to identify cells in dense samples. PMID- 27242997 TI - Better Resolved Low Frequency Dispersions by the Apt Use of Kramers-Kronig Relations, Differential Operators, and All-In-1 Modeling. AB - The dielectric spectra of colloidal systems often contain a typical low frequency dispersion, which usually remains unnoticed, because of the presence of strong conduction losses. The KK relations offer a means for converting epsilon' into epsilon" data. This allows us to calculate conduction free epsilon" spectra in which the l.f. dispersion will show up undisturbed. This interconversion can be done on line with a moving frame of logarithmically spaced epsilon' data. The coefficients of the conversion frames were obtained by kernel matching and by using symbolic differential operators. Logarithmic derivatives and differences of epsilon' and epsilon" provide another option for conduction free data analysis. These difference-based functions actually derived from approximations to the distribution function, have the additional advantage of improving the resolution power of dielectric studies. A high resolution is important because of the rich relaxation structure of colloidal suspensions. The development of all-in-1 modeling facilitates the conduction free and high resolution data analysis. This mathematical tool allows the apart-together fitting of multiple data and multiple model functions. It proved also useful to go around the KK conversion altogether. This was achieved by the combined approximating epsilon' and epsilon" data with a complex rational fractional power function. The all-in-1 minimization turned out to be also highly useful for the dielectric modeling of a suspension with the complex dipolar coefficient. It guarantees a secure correction for the electrode polarization, so that the modeling with the help of the differences epsilon' and epsilon" can zoom in on the genuine colloidal relaxations. PMID- 27242996 TI - Links between Human LINE-1 Retrotransposons and Hepatitis Virus-Related Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) accounts for approximately 80% of liver cancers, the third most frequent cause of cancer mortality. The most prevalent risk factors for HCC are infections by hepatitis B or hepatitis C virus. Findings suggest that hepatitis virus-related HCC might be a cancer in which LINE-1 retrotransposon, often termed L1, activity plays a potential role. Firstly, hepatitis viruses can suppress host defense factors that also control L1 mobilization. Secondly, many recent studies also have indicated that hypomethylation of L1 affects the prognosis of HCC patients. Thirdly, endogenous L1 retrotransposition was demonstrated to activate oncogenic pathways in HCC. Fourthly, several L1 chimeric transcripts with host or viral genes are found in hepatitis virus-related HCC. Such lines of evidence suggest a linkage between L1 retrotransposons and hepatitis virus-related HCC. Here, I briefly summarize current understandings of the association between hepatitis virus-related HCC and L1. Then, I discuss potential mechanisms of how hepatitis viruses drive the development of HCC via L1 retrotransposons. An increased understanding of the contribution of L1 to hepatitis virus-related HCC may provide unique insights related to the development of novel therapeutics for this disease. PMID- 27242998 TI - Functional Dissection of the Bipartite Active Site of the Class I Coenzyme A (CoA)-Transferase Succinyl-CoA:Acetate CoA-Transferase. AB - Coenzyme A (CoA)-transferases catalyze the reversible transfer of CoA from acyl CoA thioesters to free carboxylates. Class I CoA-transferases produce acylglutamyl anhydride intermediates that undergo attack by CoA thiolate on either the internal or external carbonyl carbon atoms, forming distinct tetrahedral intermediates <3 A apart. In this study, crystal structures of succinyl-CoA:acetate CoA-transferase (AarC) from Acetobacter aceti are used to examine how the Asn347 carboxamide stabilizes the internal oxyanion intermediate. A structure of the active mutant AarC-N347A bound to CoA revealed both solvent replacement of the missing contact and displacement of the adjacent Glu294, indicating that Asn347 both polarizes and orients the essential glutamate. AarC was crystallized with the nonhydrolyzable acetyl-CoA (AcCoA) analog dethiaacetyl CoA (1a) in an attempt to trap a closed enzyme complex containing a stable analog of the external oxyanion intermediate. One active site contained an acetylglutamyl anhydride adduct and truncated 1a, an unexpected result hinting at an unprecedented cleavage of the ketone moiety in 1a. Solution studies confirmed that 1a decomposition is accompanied by production of near-stoichiometric acetate, in a process that seems to depend on microbial contamination but not AarC. A crystal structure of AarC bound to the postulated 1a truncation product (2a) showed complete closure of one active site per dimer but no acetylglutamyl anhydride, even with acetate added. These findings suggest that an activated acetyl donor forms during 1a decomposition; a working hypothesis involving ketone oxidation is offered. The ability of 2a to induce full active site closure furthermore suggests that it subverts a system used to impede inappropriate active site closure on unacylated CoA. PMID- 27243000 TI - Stability of a Tick-Borne Flavivirus in Milk. AB - The tick-borne flaviviruses (TBFV) occur worldwide and the tick-borne encephalitis virus (TBEV) members of the group often cause severe, debilitating neurological disease in humans. Although the primary route of infection is through the bite of an infected tick, alimentary infection through the consumption of TBEV-contaminated dairy products is also well-documented and is responsible for some disease in endemic areas. Experimental infection of goats, cattle, and sheep with TBEV shows that the virus can be excreted in the milk of infected animals. Additionally, the virus remains infectious after exposure to low pH levels, similar to those found in the stomach. To evaluate the survival of virus in milk, we studied the stability of the BSL-2 TBFV, Langat virus, in unpasteurized goat milk over time and after different thermal treatments. Virus was stable in milk maintained under refrigeration conditions; however, there was a marked reduction in virus titer after incubation at room temperature. High temperature, short time pasteurization protocols completely inactivated the virus. Interestingly, simulation of a typical thermal regime utilized for cheese did not completely inactivate the virus in milk. These findings stress the importance of proper milk handling and pasteurization processes in areas endemic for TBEV. PMID- 27243001 TI - Human Mesenchymal Stem Cell Morphology and Migration on Microtextured Titanium. AB - The implant used in spinal fusion procedures is an essential component to achieving successful arthrodesis. At the cellular level, the implant impacts healing and fusion through a series of steps: first, mesenchymal stem cells (MSCs) need to adhere and proliferate to cover the implant; second, the MSCs must differentiate into osteoblasts; third, the osteoid matrix produced by the osteoblasts needs to generate new bone tissue, thoroughly integrating the implant with the vertebrate above and below. Previous research has demonstrated that microtextured titanium is advantageous over smooth titanium and PEEK implants for both promoting osteogenic differentiation and integrating with host bone tissue; however, no investigation to date has examined the early morphology and migration of MSCs on these surfaces. This study details cell spreading and morphology changes over 24 h, rate and directionality of migration 6-18 h post-seeding, differentiation markers at 10 days, and the long-term morphology of MSCs at 7 days, on microtextured, acid-etched titanium (endoskeleton), smooth titanium, and smooth PEEK surfaces. The results demonstrate that in all metrics, the two titanium surfaces outperformed the PEEK surface. Furthermore, the rough acid etched titanium surface presented the most favorable overall results, demonstrating the random migration needed to efficiently cover a surface in addition to morphologies consistent with osteoblasts and preosteoblasts. PMID- 27242999 TI - Mesenchymal Stem Cell Fate: Applying Biomaterials for Control of Stem Cell Behavior. AB - The materials pipeline for biomaterials and tissue engineering applications is under continuous development. Specifically, there is great interest in the use of designed materials in the stem cell arena as materials can be used to manipulate the cells providing control of behavior. This is important as the ability to "engineer" complexity and subsequent in vitro growth of tissues and organs is a key objective for tissue engineers. This review will describe the nature of the materials strategies, both static and dynamic, and their influence specifically on mesenchymal stem cell fate. PMID- 27243002 TI - Efficient Synergistic Single-Cell Genome Assembly. AB - As the vast majority of all microbes are unculturable, single-cell sequencing has become a significant method to gain insight into microbial physiology. Single cell sequencing methods, currently powered by multiple displacement genome amplification (MDA), have passed important milestones such as finishing and closing the genome of a prokaryote. However, the quality and reliability of genome assemblies from single cells are still unsatisfactory due to uneven coverage depth and the absence of scattered chunks of the genome in the final collection of reads caused by MDA bias. In this work, our new algorithm Hybrid De novo Assembler (HyDA) demonstrates the power of coassembly of multiple single cell genomic data sets through significant improvement of the assembly quality in terms of predicted functional elements and length statistics. Coassemblies contain significantly more base pairs and protein coding genes, cover more subsystems, and consist of longer contigs compared to individual assemblies by the same algorithm as well as state-of-the-art single-cell assemblers SPAdes and IDBA-UD. Hybrid De novo Assembler (HyDA) is also able to avoid chimeric assemblies by detecting and separating shared and exclusive pieces of sequence for input data sets. By replacing one deep single-cell sequencing experiment with a few single-cell sequencing experiments of lower depth, the coassembly method can hedge against the risk of failure and loss of the sample, without significantly increasing sequencing cost. Application of the single-cell coassembler HyDA to the study of three uncultured members of an alkane-degrading methanogenic community validated the usefulness of the coassembly concept. HyDA is open source and publicly available at http://chitsazlab.org/software.html, and the raw reads are available at http://chitsazlab.org/research.html. PMID- 27243003 TI - Membrane Tethering Complexes in the Endosomal System. AB - Vesicles that are generated by endocytic events at the plasma membrane are destined to early endosomes. A prerequisite for proper fusion is the tethering of two membrane entities. Tethering of vesicles to early endosomes is mediated by the class C core vacuole/endosome tethering (CORVET) complex, while fusion of late endosomes with lysosomes depends on the homotypic fusion and vacuole protein sorting (HOPS) complex. Recycling through the trans-Golgi network (TGN) and to the plasma membrane is facilitated by the Golgi associated retrograde protein (GARP) and endosome-associated recycling protein (EARP) complexes, respectively. However, there are other tethering functions in the endosomal system as there are multiple pathways through which proteins can be delivered from endosomes to either the TGN or the plasma membrane. Furthermore, proteins that may be part of novel tethering complexes have been recently identified. Thus, it is likely that more tethering factors exist. In this review, I will provide an overview of different tethering complexes of the endosomal system and discuss how they may provide specificity in membrane traffic. PMID- 27243004 TI - N-Terminal Ile-Orn- and Trp-Orn-Motif Repeats Enhance Membrane Interaction and Increase the Antimicrobial Activity of Apidaecins against Pseudomonas aeruginosa. AB - The Gram-negative bacterium Pseudomonas aeruginosa is a life-threatening nosocomial pathogen due to its generally low susceptibility toward antibiotics. Furthermore, many strains have acquired resistance mechanisms requiring new antimicrobials with novel mechanisms to enhance treatment options. Proline-rich antimicrobial peptides, such as the apidaecin analog Api137, are highly efficient against various Enterobacteriaceae infections in mice, but less active against P. aeruginosa in vitro. Here, we extended our recent work by optimizing lead peptides Api755 (gu-OIORPVYOPRPRPPHPRL-OH; gu = N,N,N',N'-tetramethylguanidino, O = L-ornithine) and Api760 (gu-OWORPVYOPRPRPPHPRL-OH) by incorporation of Ile-Orn- and Trp-Orn-motifs, respectively. Api795 (gu-O(IO)2RPVYOPRPRPPHPRL-OH) and Api794 (gu-O(WO)3RPVYOPRPRPPHPRL-OH) were highly active against P. aeruginosa with minimal inhibitory concentrations of 8-16 and 8-32 MUg/mL against Escherichia coli and Klebsiella pneumoniae. Assessed using a quartz crystal microbalance, these peptides inserted into a membrane layer and the surface activity increased gradually from Api137, over Api795, to Api794. This mode of action was confirmed by transmission electron microscopy indicating some membrane damage only at the high peptide concentrations. Api794 and Api795 were highly stable against serum proteases (half-life times >5 h) and non-hemolytic to human erythrocytes at peptide concentrations of 0.6 g/L. At this concentration, Api795 reduced the cell viability of HeLa cells only slightly, whereas the IC50 of Api794 was 0.23 +/- 0.09 g/L. Confocal fluorescence microscopy revealed no colocalization of 5(6) carboxyfluorescein-labeled Api794 or Api795 with the mitochondria, excluding interactions with the mitochondrial membrane. Interestingly, Api795 was localized in endosomes, whereas Api794 was present in endosomes and the cytosol. This was verified using flow cytometry showing a 50% higher uptake of Api794 in HeLa cells compared with Api795. The uptake was reduced for both peptides by 50 and 80%, respectively, after inhibiting endocytotic uptake with dynasore. In summary, Api794 and Api795 were highly active against P. aeruginosa in vitro. Both peptides passed across the bacterial membrane efficiently, most likely then disturbing the ribosome assembly, and resulting in further intracellular damage. Api795 with its IOIO-motif, which was particularly active and only slightly toxic in vitro, appears to represent a promising third generation lead compound for the development of novel antibiotics against P. aeruginosa. PMID- 27243005 TI - Customized Steady-State Constraints for Parameter Estimation in Non-Linear Ordinary Differential Equation Models. AB - Ordinary differential equation models have become a wide-spread approach to analyze dynamical systems and understand underlying mechanisms. Model parameters are often unknown and have to be estimated from experimental data, e.g., by maximum-likelihood estimation. In particular, models of biological systems contain a large number of parameters. To reduce the dimensionality of the parameter space, steady-state information is incorporated in the parameter estimation process. For non-linear models, analytical steady-state calculation typically leads to higher-order polynomial equations for which no closed-form solutions can be obtained. This can be circumvented by solving the steady-state equations for kinetic parameters, which results in a linear equation system with comparatively simple solutions. At the same time multiplicity of steady-state solutions is avoided, which otherwise is problematic for optimization. When solved for kinetic parameters, however, steady-state constraints tend to become negative for particular model specifications, thus, generating new types of optimization problems. Here, we present an algorithm based on graph theory that derives non-negative, analytical steady-state expressions by stepwise removal of cyclic dependencies between dynamical variables. The algorithm avoids multiple steady-state solutions by construction. We show that our method is applicable to most common classes of biochemical reaction networks containing inhibition terms, mass-action and Hill-type kinetic equations. Comparing the performance of parameter estimation for different analytical and numerical methods of incorporating steady-state information, we show that our approach is especially well-tailored to guarantee a high success rate of optimization. PMID- 27243006 TI - The Secret Life of Tethers: The Role of Tethering Factors in SNARE Complex Regulation. AB - Trafficking in eukaryotic cells is a tightly regulated process to ensure correct cargo delivery to the proper destination organelle or plasma membrane. In this review, we focus on how the vesicle fusion machinery, the SNARE complex, is regulated by the interplay of the multisubunit tethering complexes (MTC) with the SNAREs and Sec1/Munc18 (SM) proteins. Although these factors are used in different stages of membrane trafficking, e.g., Golgi to plasma membrane transport vs. vacuolar fusion, and in a variety of diverse eukaryotic cell types, many commonalities between their functions are being revealed. We explore the various protein-protein interactions and findings from functional reconstitution studies in order to highlight both their common features and the differences in their modes of regulation. These studies serve as a starting point for mechanistic explorations in other systems. PMID- 27243007 TI - Tetraspanins and Transmembrane Adaptor Proteins As Plasma Membrane Organizers Mast Cell Case. AB - The plasma membrane contains diverse and specialized membrane domains, which include tetraspanin-enriched domains (TEMs) and transmembrane adaptor protein (TRAP)-enriched domains. Recent biophysical, microscopic, and functional studies indicated that TEMs and TRAP-enriched domains are involved in compartmentalization of physicochemical events of such important processes as immunoreceptor signal transduction and chemotaxis. Moreover, there is evidence of a cross-talk between TEMs and TRAP-enriched domains. In this review we discuss the presence and function of such domains and their crosstalk using mast cells as a model. The combined data based on analysis of selected mast cell-expressed tetraspanins [cluster of differentiation (CD)9, CD53, CD63, CD81, CD151)] or TRAPs [linker for activation of T cells (LAT), non-T cell activation linker (NTAL), and phosphoprotein associated with glycosphingolipid-enriched membrane microdomains (PAG)] using knockout mice or specific antibodies point to a diversity within these two families and bring evidence of the important roles of these molecules in signaling events. An example of this diversity is physical separation of two TRAPs, LAT and NTAL, which are in many aspects similar but show plasma membrane location in different microdomains in both non-activated and activated cells. Although our understanding of TEMs and TRAP-enriched domains is far from complete, pharmaceutical applications of the knowledge about these domains are under way. PMID- 27243008 TI - Coat/Tether Interactions-Exception or Rule? AB - Coat complexes are important for cargo selection and vesicle formation. Recent evidence suggests that they may also be involved in vesicle targeting. Tethering factors, which form an initial bridge between vesicles and the target membrane, may bind to coat complexes. In this review, we ask whether these coat/tether interactions share some common mechanisms, or whether they are special adaptations to the needs of very specific transport steps. We compare recent findings in two multisubunit tethering complexes, the Dsl1 complex and the HOPS complex, and put them into context with the TRAPP I complex as a prominent example for coat/tether interactions. We explore where coat/tether interactions are found, compare their function and structure, and comment on a possible evolution from a common ancestor of coats and tethers. PMID- 27243009 TI - New Trends in Aryl Hydrocarbon Receptor Biology. AB - Traditionally considered as a critical intermediate in the toxic and carcinogenic response to dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD), the Aryl hydrocarbon/Dioxin receptor (AhR) has proven to be also an important regulator of cell physiology and organ homeostasis. AhR has become an interesting and actual area of research mainly boosted by a significant number of recent studies analyzing its contribution to the proper functioning of the immune, hepatic, cardiovascular, vascular and reproductive systems. At the cellular level, AhR establishes functional interactions with signaling pathways governing cell proliferation and cell cycle, cell morphology, cell adhesion and cell migration. Two exciting new aspects in AhR biology deal with its implication in the control of cell differentiation and its more than likely involvement in cell pluripotency and stemness. In fact, it is possible that AhR could help modulate the balance between differentiation and pluripotency in normal and transformed tumor cells. At the molecular level, AhR regulates an increasingly large array of physiologically relevant genes either by traditional transcription-dependent mechanisms or by unforeseen processes involving genomic insulators, chromatin dynamics and the transcription of mobile genetic elements. AhR is also closely related to epigenetics, not only from the point of view of target gene expression but also with respect to its own regulation by promoter methylation. It is reasonable to consider that deregulation of these many functions could have a causative role, or at least contribute to, human disease. Consequently, several laboratories have proposed that AhR could be a valuable tool as diagnostic marker and/or therapeutic target in human pathologies. An additional point of interest is the possibility of regulating AhR activity by endogenous non-toxic low weight molecules agonist or antagonist molecules that could be present or included in the diet. In this review, we will address these molecular and functional features of AhR biology within physiological and pathological contexts. PMID- 27243010 TI - Tethering Complexes in the Arabidopsis Endomembrane System. AB - Targeting of endomembrane transport containers is of the utmost importance for proper land plant growth and development. Given the immobility of plant cells, localized membrane vesicle secretion and recycling are amongst the main processes guiding proper cell, tissue and whole plant morphogenesis. Cell wall biogenesis and modification are dependent on vectorial membrane traffic, not only during normal development, but also in stress responses and in plant defense against pathogens and/or symbiosis. It is surprising how little we know about these processes in plants, from small GTPase regulation to the tethering complexes that act as their effectors. Tethering factors are single proteins or protein complexes mediating first contact between the target membrane and arriving membrane vesicles. In this review we focus on the tethering complexes of the best studied plant model-Arabidopsis thaliana. Genome-based predictions indicate the presence of all major tethering complexes in plants that are known from a hypothetical last eukaryotic common ancestor (LECA). The evolutionary multiplication of paralogs of plant tethering complex subunits has produced the massively expanded EXO70 family, indicating a subfunctionalization of the terminal exocytosis machinery in land plants. Interpretation of loss of function (LOF) mutant phenotypes has to consider that related, yet clearly functionally specific complexes often share some common core subunits. It is therefore impossible to conclude with clarity which version of the complex is responsible for the phenotypic deviations observed. Experimental interest in the analysis of plant tethering complexes is growing and we hope to contribute with this review by attracting even more attention to this fascinating field of plant cell biology. PMID- 27243012 TI - Quantitative Evaluation of Therapeutic Response by FDG-PET-CT in Metastatic Breast Cancer. AB - PURPOSE: To assess the therapeutic response for metastatic breast cancer with (18)F-FDG position emission tomography (PET), this retrospective study aims to compare the performance of six different metabolic metrics with PERCIST, PERCIST with optimal thresholds, and an image-based parametric approach. METHODS: Thirty six metastatic breast cancer patients underwent 128 PET scans and 123 lesions were identified. In a per-lesion and per-patient analysis, the performance of six metrics: maximum standardized uptake value (SUVmax), SUVpeak, standardized added metabolic activity (SAM), SUVmean, metabolic volume (MV), total lesion glycolysis (TLG), and a parametric approach (SULTAN) were determined and compared to the gold standard (defined by clinical assessment and biological and conventional imaging according RECIST 1.1). The evaluation was performed using PERCIST thresholds (for per-patient analysis only) and optimal thresholds (determined by the Youden criterion from the receiver operating characteristic curves). RESULTS: In the per-lesion analysis, 210 pairs of lesion evolutions were studied. Using the optimal thresholds, SUVmax, SUVpeak, SUVmean, SAM, and TLG were significantly correlated with the gold standard. SUVmax, SUVpeak, and SUVmean reached the best sensitivity (91, 88, and 83%, respectively), specificity (93, 95, and 97%, respectively), and negative predictive value (NPV, 90, 88, and 83%, respectively). For the per--patient analysis, 79 pairs of PET were studied. The optimal thresholds compared to the PERCIST threshold did not improve performance for SUVmax, SUVpeak, and SUVmean. Only SUVmax, SUVpeak, SUVmean, and TLG were correlated with the gold standard. SULTAN also performed equally: 83% sensitivity, 88% specificity, and NPV 86%. CONCLUSION: This study showed that SUVmax and SUVpeak were the best parameters for PET evaluation of metastatic breast cancer lesions. Parametric imaging is helpful in evaluating serial studies. PMID- 27243011 TI - Regenerative Capacity of Macrophages for Remyelination. AB - White matter injury, consisting of loss of axons, myelin, and oligodendrocytes, is common in many neurological disorders and is believed to underlie several motor and sensory deficits. Remyelination is the process in which the insulative myelin sheath is restored to axons, thereby facilitating recovery from functional loss. Remyelination proceeds with oligodendrocyte precursor cells (OPCs) that differentiate into oligodendrocytes to synthesize the new myelin sheath after demyelination. This process is influenced by several factors, including trophic factors, inhibitory molecules in the lesion microenvironment, age of the subject, as well as the inflammatory response. Currently studied strategies that enhance remyelination consist of pharmacological approaches that directly induce OPC differentiation or using agents to neutralize the inhibitory microenvironment. Another strategy is to harness a reparative inflammatory response. This response, coordinated by central nervous system resident microglia and peripherally-derived infiltrating macrophages, has been shown to be important in the remyelination process. These innate immune cells perform important functions in remyelination, including the proteolysis and phagocytosis of inhibitory molecules present in the lesion microenvironment, the provision of trophic and metabolic factors to OPCs, in addition to iron handling capacity. Additionally, an initial pro-inflammatory phase followed by a regulatory/anti-inflammatory phase has been shown to be important for OPC proliferation and differentiation, respectively. This review will discuss the beneficial roles of macrophages/microglia in remyelination and discuss therapeutic strategies to obtain the optimal regenerative macrophage phenotype for enhanced remyelination. PMID- 27243013 TI - Editorial: "How to Improve Cord Blood Transplantation: By Enhancing Cell Counts or Engraftment?". PMID- 27243015 TI - Drivers of Phosphorus Uptake by Barley Following Secondary Resource Application. AB - Minable rock phosphate is a finite resource. Replacing mineral phosphorus (P) fertilizer with P-rich secondary resources is one way to manage P more efficiently, but the importance of physicochemical and microbial soil processes induced by secondary resources for plant P uptake is still poorly understood. Using radioactive-labeling techniques, the fertilization effects of dairy manure, fish sludge, meat bone meal, and wood ash were studied as P uptake by barley after 44 days and compared with those of water-soluble mineral P (MinP) and an unfertilized control (NoP) in a pot experiment with an agricultural soil containing little available P at two soil pH levels, approximately pH 5.3 (unlimed soil) and pH 6.2 (limed soil). In a parallel incubation experiment, the effects of the secondary resources on physicochemical and microbial soil processes were studied. The results showed that the relative agronomic efficiency compared with MinP decreased in the order: manure >=fish sludge >=wood ash >=meat bone meal. The solubility of inorganic P in secondary resources was the main driver for P uptake by barley (Hordeum vulgare). The effects of secondary resources on physicochemical and microbial soil processes were of little overall importance. Application of organic carbon with manure resulted in microbial P immobilization and decreased uptake by barley of P derived from the soil. On both soils, P uptake by barley was best explained by a positive linear relationship with the H2O + NaHCO3-soluble inorganic P fraction in fertilizers or by a linear negative relationship with the HCl-soluble inorganic P fraction in fertilizers. PMID- 27243016 TI - Endoscopic-Assisted Linea Alba Reconstruction plus Mesh Augmentation for Treatment of Umbilical and/or Epigastric Hernias and Rectus Abdominis Diastasis - Early Results. AB - INTRODUCTION: Symptomatic umbilical and/or epigastric hernias are often seen concomitantly with rectus abdominis diastasis (RAD), and suture repair of such defects has a high recurrence rate. In the literature, there are reports of both endoscopic and open techniques for repair of symptomatic umbilical and/or epigastric hernias in association with RAD. This paper now reports on the early results of a hybrid technique used for reconstruction of the linea alba and mesh augmentation [endoscopic-assisted linea alba reconstruction plus mesh augmentation (ELAR plus)]. MATERIALS AND METHODS: Between 15 June 2015 and 31 January 2016, 40 patients with symptomatic umbilical and/or epigastric hernia and concomitant RAD underwent reconstruction of the linea alba using a hybrid technique involving a small umbilical incision and the use of video-endoscopic equipment. The patients comprised 29 men and 11 women with a mean age of 53.6 years and mean BMI of 32.6. The mean operating time was 120 min. The mesh had a mean longitudinal extension of 18.6 cm and transverse extension of 9.1 cm. RESULTS: Thirty-day follow-up results are available for all patients. Thirty seven out of 40 patients (92.5%) experienced no postoperative complication. Two cases of discrete impaired umbilical wound healing and one seroma were successfully managed with conservative treatment. On 30-day follow-up, 3 out of 40 patients (7.5%) complained of intermittent pain on exertion, and 2 out of 40 patients (5%) still took painkillers when required. CONCLUSION: ELAR plus is a novel minimally invasive procedure for repair of symptomatic umbilical and/or epigastric hernias with concomitant RAD. Reconstruction of the linea alba via a minimally invasive access route is able to restore the normal anatomy of the abdominal wall. PMID- 27243014 TI - Aberrant Pulmonary Vascular Growth and Remodeling in Bronchopulmonary Dysplasia. AB - In contrast to many other organs, a significant portion of lung development occurs after birth during alveolarization, thus rendering the lung highly susceptible to injuries that may disrupt this developmental process. Premature birth heightens this susceptibility, with many premature infants developing the chronic lung disease, bronchopulmonary dysplasia (BPD), a disease characterized by arrested alveolarization. Over the past decade, tremendous progress has been made in the elucidation of mechanisms that promote postnatal lung development, including extensive data suggesting that impaired pulmonary angiogenesis contributes to the pathogenesis of BPD. Moreover, in addition to impaired vascular growth, patients with BPD also frequently demonstrate alterations in pulmonary vascular remodeling and tone, increasing the risk for persistent hypoxemia and the development of pulmonary hypertension. In this review, an overview of normal lung development will be presented, and the pathologic features of arrested development observed in BPD will be described, with a specific emphasis on the pulmonary vascular abnormalities. Key pathways that promote normal pulmonary vascular development will be reviewed, and the experimental and clinical evidence demonstrating alterations of these essential pathways in BPD summarized. PMID- 27243017 TI - Prophylactic Resorbable Synthetic Mesh to Prevent Wound Dehiscence and Incisional Hernia in High High-risk Laparotomy: A Pilot Study of Using TIGR Matrix Mesh. AB - BACKGROUND: Wound dehiscence and incisional hernia are potentially serious complications following abdominal surgery, especially if performed through a midline incision. Although prophylactic reinforcement with on-lay mesh has been shown to reduce this risk, a permanent mesh carries the risk of seroma formation, infection, and persistent pain. The aim of this study was to assess the safety of a reabsorbable on-lay mesh to reinforce the midline suture in patients with high risk for wound dehiscence or incisional hernia. METHOD: Sixteen patients with three or more risk factors for wound dehiscence or incisional hernia were included. A TIGR((r)) Matrix mesh, composed of a mixture of 40% copolymer fibers of polyglycolide, polylactide, and polytrimethylene carbonate and 60% copolymer fibers of polylactide and polytrimethylene carbonate, was placed on the aponeurosis with an overlap of five on either side and fixated with continuous monofilament polydioxanone suture. All postoperative complications were registered at clinical follow-up. RESULTS: Mean follow-up was 9 months. One patient developed a seroma that needed drainage and antibiotic treatment. One patient had a wound infection that needed antibiotic treatment. There was no complication requiring a reoperation. No wound dehiscence or incisional hernia was seen. CONCLUSION: On-lay placement of TIGR((r)) Matrix is safe and may provide a feasible way of reinforcing the suture line in patients with high risk for postoperative wound dehiscence or incisional hernia. Larger samples are required, however, if one is to draw any conclusion regarding the safety and effectiveness of this technique. PMID- 27243019 TI - Does the Intestinal Microbiota Explain Differences in the Epidemiology of Liver Disease between East and West? AB - Changes in bacterial communities are associated with the pathogenesis of many diseases including inflammatory bowel disease and liver disease. Dysbiosis can induce intestinal inflammation resulting in increased intestinal permeability and bacterial translocation. The majority of chronic liver diseases are associated with bacterial translocation resulting in or enhancing an inflammatory response in the liver. Intestinal inflammation and a dysfunctional intestinal barrier are not sufficient to cause liver disease in the absence of an additional liver insult. In this article, the authors summarize differences in intestinal microbiota composition between Eastern and Western countries. The authors specifically discuss whether differences in microbiota composition could explain the epidemiological differences in liver disease found in Asia and Europe/the USA. PMID- 27243018 TI - Historical and Current Concepts of Fibrillogenesis and In vivo Amyloidogenesis: Implications of Amyloid Tissue Targeting. AB - Historical and current concepts of in vitro fibrillogenesis are considered in the light of disorders in which amyloid is deposited at anatomic sites remote from the site of synthesis of the corresponding precursor protein. These clinical conditions set constraints on the interpretation of information derived from in vitro fibrillogenesis studies. They suggest that in addition to kinetic and thermodynamic factors identified in vitro, fibrillogenesis in vivo is determined by site specific factors most of which have yet to be identified. PMID- 27243021 TI - Lung-Centered Open Heart Surgery: A Call for a Paradigm Change. PMID- 27243020 TI - Cytomegalovirus Colitis, Cytomegalovirus Hepatitis and Systemic Cytomegalovirus Infection: Common Features and Differences. AB - Cytomegalovirus (CMV) is a ubiquitous human herpes virus, which, after often asymptomatic primary infection, establishes a lifelong latent infection that can periodically be reactivated in both immunocompetent and immunosuppressed carriers. Whereas the diagnostic approach in case of a suspicion of CMV reactivation is well defined, the indication for antiviral therapy can often only be made in the context of an extent of organ involvement, the immune status, and comorbidities of the patient. This article reviews the epidemiology, diagnosis, and therapy of CMV reactivation with a focus on inflammatory bowel diseases and potentially different diagnostic and therapeutic approaches in Asia and the Western world. PMID- 27243022 TI - Feasibility for Measuring Transverse Area Ratios and Asymmetry of Lumbosacral Region Paraspinal Muscles in Working Dogs Using Computed Tomography. AB - OBJECTIVES: Describe computed tomographic (CT) anatomy of canine lumbosacral (LS) paraspinal muscles, a method for measuring paraspinal muscle transverse area ratios and asymmetry using CT, and application of this method in a small sample of working dogs with versus without LS pain. METHODS: Published anatomy references and atlases were reviewed and discrepancies were resolved by examination of anatomic specimens and multiplanar reformatted images to describe transverse CT anatomy of LS region paraspinal muscles. Sixteen Belgian malinois military working dogs were retrospectively recruited and assigned to LS pain positive versus negative groups based on medical record entries. A single observer unaware of dog group measured CT transverse areas of paraspinal muscles and adjacent vertebral bodies, in triplicate, for L5-S1 vertebral locations. A statistician compared muscle transverse area ratios and asymmetry at each vertebral location between groups. RESULTS: The relative coefficient of variation for triplicate CT area measurements averaged 2.15% (N = 16). Multifidus lumborum (L6-7), psoas/iliopsoas (L5-6, L6-7), and sacrocaudalis dorsalis lateralis (L6-7, L7-S1) transverse area ratios were significantly smaller in dogs with LS pain (n = 11) versus without LS pain (n = 5) (p <= 0.05). Muscle asymmetry values were not significantly greater in dogs with versus without LS pain. CLINICAL RELEVANCE: Computed tomographic morphometry of LS region paraspinal muscles is a feasible objective method for use in future evidence-based research studies in working dogs. Potential future research applications include determining whether decreased paraspinal muscle area ratios and/or increased paraspinal muscle asymmetry could be used as markers for preclinical LS pain in stoic dogs or risk factors for other injuries in high performance canine athletes, or determining whether core muscle strengthening exercise prescriptions for dogs with LS pain have an effect on paraspinal muscle area ratios and asymmetry. PMID- 27243023 TI - Behavioral Ecology of Captive Species: Using Bibliographic Information to Assess Pet Suitability of Mammal Species. AB - Which mammal species are suitable to be kept as pet? For answering this question many factors have to be considered. Animals have many adaptations to their natural environment in which they have evolved that may cause adaptation problems and/or risks in captivity. Problems may be visible in behavior, welfare, health, and/or human-animal interaction, resulting, for example, in stereotypies, disease, and fear. A framework is developed in which bibliographic information of mammal species from the wild and captive environment is collected and assessed by three teams of animal scientists. Oneliners from literature about behavioral ecology, health, and welfare and human-animal relationship of 90 mammal species are collected by team 1 in a database and strength of behavioral needs and risks is assessed by team 2. Based on summaries of those strengths the suitability of the mammal species is assessed by team 3. Involvement of stakeholders for supplying bibliographic information and assessments was propagated. Combining the individual and subjective assessments of the scientists using statistical methods makes the final assessment of a rank order of suitability as pet of those species less biased and more objective. The framework is dynamic and produces an initial rank ordered list of the pet suitability of 90 mammal species, methods to add new mammal species to the list or remove animals from the list and a method to incorporate stakeholder assessments. A model is developed that allows for provisional classification of pet suitability. Periodical update of the pet suitability framework is expected to produce an updated list with increased reliability and accuracy. Furthermore, the framework could be further developed to assess the pet suitability of additional species of other animal groups, e.g., birds, reptiles, and amphibians. PMID- 27243024 TI - Detection of Pulpal Blood Flow In Vivo with Pulse Oximetry in Dogs. AB - OBJECTIVE: The aim of the present study was to investigate the ability of pulse oximetry to detect blood flow within the canine tooth of dogs. MATERIALS AND METHODS: Dogs aged 18-138 months presenting for oral treatment and meeting the inclusion criteria underwent pulse oximetry evaluation of at least one canine tooth. Oxygen saturation (SpO2) and pulse rate values were acquired from vital canine teeth of 38 clinical patients (representing 40 total teeth) with a handheld pulse oximeter and compared to a control area. SpO2 values from the tooth and control area were recorded every 5 s for three 60-s intervals. The sensors were repositioned after each 60-s interval. RESULTS: The vital teeth consistently recorded SpO2 values significantly lower than the control area. The mean vital tooth SpO2 was 85.9% (median = 87%; SD = 8.6), and the mean control area SpO2 was 97.7% (median = 98%; SD = 1.8). An age-related significant difference was noted in vital tooth SpO2 values. CONCLUSION: In conclusion, the present data support the possible use of pulse oximetry to detect blood flow in canine teeth. However, there was no significant correlation between SpO2 values in the vital tooth and in the control areas. Additionally, the results were not definitive, and validation of the modality with additional studies of non-vital canine teeth is needed before clinical use can be recommended. PMID- 27243025 TI - Lameness Affects Cow Feeding But Not Rumination Behavior as Characterized from Sensor Data. AB - Using automatic sensor data, this is the first study to characterize individual cow feeding and rumination behavior simultaneously as affected by lameness. A group of mixed-parity, lactating Holstein cows were loose-housed with free access to 24 cubicles and 12 automatic feed stations. Cows were milked three times/day. Fresh feed was delivered once daily. During 24 days with effectively 22 days of data, 13,908 feed station visits and 7,697 rumination events obtained from neck mounted accelerometers on 16 cows were analyzed. During the same period, cows were locomotion scored on four occasions and categorized as lame (n = 9) or not lame (n = 7) throughout the study. Rumination time, number of rumination events, feeding time, feeding frequency, feeding rate, feed intake, and milk yield were calculated per day, and coefficients of variation were used to estimate variation between and within cows. Based on daily sums, using each characteristic as response, the effects of lameness and stage of lactation were tested in a mixed model. With rumination time as response, each of the four feeding characteristics, milk yield, and lameness were tested in a second mixed model. On a visit basis, effects of feeding duration, lameness, and milk yield on feed intake were tested in a third mixed model. Overall, intra-individual variation was <15% and inter-individual variation was up to 50%. Lameness introduced more inter-individual variation in feeding characteristics (26-50%) compared to non lame cows (17-29%). Lameness decreased daily feeding time and daily feeding frequency, but increased daily feeding rate. Interestingly, lameness did not affect daily rumination behaviors, fresh matter intake, or milk yield. On a visit basis, a high feeding rate was associated with a higher feed intake, a relationship that was exacerbated in the lame cows. In conclusion, cows can be characterized in particular by their feeding behavior, and lame cows differ from their non-lame pen-mates in terms of fewer feed station visits, faster eating, less time spent feeding, and more variable feeding behavior. Further, daily rumination time was slightly negatively associated with feeding rate, a relationship which calls for more research to quantify rumination efficiency relative to feeding rate. PMID- 27243026 TI - Time to Loss of Consciousness and Its Relation to Behavior in Slaughter Pigs during Stunning with 80 or 95% Carbon Dioxide. AB - Exposure to CO2 at high concentration is a much debated stunning method in pigs. Pigs respond aversively to high concentrations of CO2, and there is uncertainty about what behaviors occur before and after loss of consciousness. The aim was to assess timing of unconsciousness in pigs during exposure to high concentrations of CO2 based on changes in electroencephalogram (EEG) activity and the relation with the behaviors sniffing, retreat and escape attempts, lateral head movements, jumping, muscular contractions, loss of posture, and gasping. Pigs (108 +/- 9 kg) were randomly assigned to 80% CO2 (80C, n = 24) or 95% CO2 (95C, n = 24). The time at which the gondola started descending into the well pre-filled with 80C or 95C was marked as T = 0. The CO2 exposure lasted 346 s after which the corneal reflex and breathing were assessed for 1 min. Visual assessment of changes in the amplitude and frequency of EEG traces after T = 0 was used to determine loss of consciousness. Time to loss of consciousness was longer in 80C pigs (47 +/- 6 s) than in 95C pigs (33 +/- 7 s). Time to an iso-electric EEG was similar in 80C pigs (75 +/- 23 s) and 95C pigs (64 +/- 32 s). When pigs descended into the well, the earlier entry of 95C pigs into high CO2 atmosphere rather than the concentration of CO2 by itself affected the latency of behavioral responses and decreasing brain activity. During exposure to the gas, 80C and 95C pigs exhibited sniffing, retreat attempts, lateral head movements, jumping, and gasping before loss of consciousness. 95C pigs exhibited all these behaviors on average earlier than 80C pigs after T = 0. But the interval between onset of these behaviors and loss of consciousness and the duration of these behaviors, except gasping, was similar for both treatments. Loss of posture was on average observed in both groups 10 s before EEG-based loss of consciousness. Furthermore, 88% of 80C pigs and 94% of 95C pigs demonstrated muscular contractions before loss of consciousness. The findings provide little reason to conclude on a behavioral basis that these atmospheres are greatly different in their impact on pig welfare. PMID- 27243027 TI - Recent Advances in Measurement and Dietary Mitigation of Enteric Methane Emissions in Ruminants. AB - Methane (CH4) emission, which is mainly produced during normal fermentation of feeds by the rumen microorganisms, represents a major contributor to the greenhouse gas (GHG) emissions. Several enteric CH4 mitigation technologies have been explored recently. A number of new techniques have also been developed and existing techniques have been improved in order to evaluate CH4 mitigation technologies and prepare an inventory of GHG emissions precisely. The aim of this review is to discuss different CH4 measuring and mitigation technologies, which have been recently developed. Respiration chamber technique is still considered as a gold standard technique due to its greater precision and reproducibility in CH4 measurements. With the adoption of recent recommendations for improving the technique, the SF6 method can be used with a high level of precision similar to the chamber technique. Short-term measurement techniques of CH4 measurements generally invite considerable within- and between-animal variations. Among the short-term measuring techniques, Greenfeed and methane hood systems are likely more suitable for evaluation of CH4 mitigation studies, if measurements could be obtained at different times of the day relative to the diurnal cycle of the CH4 production. Carbon dioxide and CH4 ratio, sniffer, and other short-term breath analysis techniques are more suitable for on farm screening of large number of animals to generate the data of low CH4-producing animals for genetic selection purposes. Different indirect measuring techniques are also investigated in recent years. Several new dietary CH4 mitigation technologies have been explored, but only a few of them are practical and cost-effective. Future research should be directed toward both the medium- and long-term mitigation strategies, which could be utilized on farms to accomplish substantial reductions of CH4 emissions and to profitably reduce carbon footprint of livestock production systems. This review presents recent developments and critical analysis on different measurements and dietary mitigation of enteric CH4 emissions technologies. PMID- 27243029 TI - Adaptive Neuromorphic Circuit for Stereoscopic Disparity Using Ocular Dominance Map. AB - Stereopsis or depth perception is a critical aspect of information processing in the brain and is computed from the positional shift or disparity between the images seen by the two eyes. Various algorithms and their hardware implementation that compute disparity in real time have been proposed; however, most of them compute disparity through complex mathematical calculations that are difficult to realize in hardware and are biologically unrealistic. The brain presumably uses simpler methods to extract depth information from the environment and hence newer methodologies that could perform stereopsis with brain like elegance need to be explored. This paper proposes an innovative aVLSI design that leverages the columnar organization of ocular dominance in the brain and uses time-staggered Winner Take All (ts-WTA) to adaptively create disparity tuned cells. Physiological findings support the presence of disparity cells in the visual cortex and show that these cells surface as a result of binocular stimulation received after birth. Therefore, creating in hardware cells that can learn different disparities with experience not only is novel but also is biologically more realistic. These disparity cells, when allowed to interact diffusively on a larger scale, can be used to adaptively create stable topological disparity maps in silicon. PMID- 27243028 TI - The Pathogenesis of Foot-and-Mouth Disease in Pigs. AB - The greatest proportion of foot-and-mouth disease (FMD) clinical research has been dedicated to elucidating pathogenesis and enhancing vaccine protection in cattle with less efforts invested in studies specific to pigs. However, accumulated evidence from FMD outbreaks and experimental investigations suggest that critical components of FMD pathogenesis, immunology, and vaccinology cannot be extrapolated from investigations performed in cattle to explain or to predict outcomes of infection or vaccination in pigs. Furthermore, it has been shown that failure to account for these differences may have substantial consequences when FMD outbreaks occur in areas with dense pig populations. Recent experimental studies have confirmed some aspects of conventional wisdom by demonstrating that pigs are more susceptible to FMD virus (FMDV) infection via exposure of the upper gastrointestinal tract (oropharynx) than through inhalation of virus. The infection spreads rapidly within groups of pigs that are housed together, although efficiency of transmission may vary depending on virus strain and exposure intensity. Multiple investigations have demonstrated that physical separation of pigs is sufficient to prevent virus transmission under experimental conditions. Detailed pathogenesis studies have recently demonstrated that specialized epithelium within porcine oropharyngeal tonsils constitute the primary infection sites following simulated natural virus exposure. Furthermore, epithelium of the tonsil of the soft palate supports substantial virus replication during the clinical phase of infection, thus providing large amounts of virus that can be shed into the environment. Due to massive amplification and shedding of virus, acutely infected pigs constitute a considerable source of contagion. FMDV infection results in modulation of several components of the host immune response. The infection is ultimately cleared in association with a strong humoral response and, in contrast to ruminants, there is no subclinical persistence of FMDV in pigs. The aim of this review is to provide an overview of knowledge gained from experimental investigations of FMD pathogenesis, transmission, and host response in pigs. Details of the temporo-anatomic progression of infection are discussed in relation to specific pathogenesis events and the likelihood of transmission. Additionally, relevant aspects of the host immune response are discussed within contexts of conventional and novel intervention strategies of vaccination and immunomodulation. PMID- 27243030 TI - Demographic and Clinical Features of Endometrial Polyps in Patients with Endometriosis. AB - Aims. To compare the clinical features of endometrial polyps (EPs) between patients with endometriosis (EM) (EM group) and without EM (non-EM group). Methods and Results. Seventy-six cases in the EM group and 133 cases in the non EM group underwent laparotomy or hysteroscopy and laparoscopy; later, it was confirmed that the results by pathology from July 2002 to April 2008 in the Department of Gynecology and Obstetrics at the First Affiliated Hospital of Sun Yat-sen University. The recurrence of EPs was followed up after the surgery until 2013. The following parameters were assessed: age, gravidity, parity, infertility, and menstrual cycle changes, as well as polyps diameters, locations, number, association with the revised American Fertility Society (r-AFS) classification, and their recurrence. On review, 76 EPs cases of EM group histologically resembled EPs but the majority of EPs with EM occurred in primary infertility cases and in fewer pregnancy rate women who had stable and smaller EPs without association with the AFS stage. The recurrence rate of EPs in EM group was higher than that in non-EM group. Conclusion. It is important to identify whether infertile patients with EM are also having EPs. Removing any coexisting EPs via hysteroscopy would be clinically helpful in treating endometriosis-related infertility in these patients. PMID- 27243031 TI - Amlodipine Ameliorates Ischemia-Induced Neovascularization in Diabetic Rats through Endothelial Progenitor Cell Mobilization. AB - Objectives. We investigated whether amlodipine could improve angiogenic responses in a diabetic rat model of acute myocardial infarction (AMI) through improving bone marrow endothelial progenitor cell (EPC) mobilization, in the same way as angiotensin converting enzyme inhibitors. Methods. After induction of AMI by coronary artery ligation, diabetic rats were randomly assigned to receive perindopril (2 mgkg(-1) day(-1)), amlodipine (2.5 mgkg(-1) day(-1)), or vehicle by gavage (n = 20 per group). Circulating EPC counts before ligation and on days 1, 3, 5, 7, 14, and 28 after AMI were measured in each group. Microvessel density, cardiac function, and cardiac remodeling were assessed 4 weeks after treatment. The signaling pathway related to EPC mobilization was also measured. Results. Circulating EPC count in amlodipine- and perindopril-treated rats peaked at day 7, to an obvious higher level than the control group peak which was reached earlier (at day 5). Rats treated with amlodipine showed improved postischemia neovascularization and cardiac function, together with reduced cardiac remodeling, decreased interstitial fibrosis, and cardiomyocyte apoptosis. Amlodipine treatment also increased cardiac SDF-1/CXCR4 expression and gave rise to activation of VEGF/Akt/eNOS signaling in bone marrow. Conclusions. Amlodipine promotes neovascularization by improving EPC mobilization from bone marrow in diabetic rats after AMI, and activation of VEGF/Akt/eNOS signaling may in part contribute to this. PMID- 27243032 TI - The Use of Protein-Protein Interactions for the Analysis of the Associations between PM2.5 and Some Diseases. AB - Nowadays, pollution levels are rapidly increasing all over the world. One of the most important pollutants is PM2.5. It is known that the pollution environment may cause several problems, such as greenhouse effect and acid rain. Among them, the most important problem is that pollutants can induce a number of serious diseases. Some studies have reported that PM2.5 is an important etiologic factor for lung cancer. In this study, we extensively investigate the associations between PM2.5 and 22 disease classes recommended by Goh et al., such as respiratory diseases, cardiovascular diseases, and gastrointestinal diseases. The protein-protein interactions were used to measure the linkage between disease genes and genes that have been reported to be modulated by PM2.5. The results suggest that some diseases, such as diseases related to ear, nose, and throat and gastrointestinal, nutritional, renal, and cardiovascular diseases, are influenced by PM2.5 and some evidences were provided to confirm our results. For example, a total of 18 genes related to cardiovascular diseases are identified to be closely related to PM2.5, and cardiovascular disease relevant gene DSP is significantly related to PM2.5 gene JUP. PMID- 27243033 TI - Reducing the Cost of the Diagnostic Odyssey in Early Onset Epileptic Encephalopathies. AB - Whole exome sequencing (WES) has revolutionized the way we think about and diagnose epileptic encephalopathies. Multiple recent review articles discuss the benefits of WES and suggest various algorithms to follow for determining the etiology of epileptic encephalopathies. Incorporation of WES in these algorithms is leading to the discovery of new genetic diagnoses of early onset epileptic encephalopathies (EOEEs) at a rapid rate; however, WES is not yet a universally utilized diagnostic tool. Clinical WES may be underutilized due to provider discomfort in ordering the test or perceived costliness. At our hospital WES is not routinely performed for patients with EOEE due to limited insurance reimbursement. In fact for any patient with noncommercial insurance (Medicaid) the institution does not allow sending out WES as this is not "established"/"proven to be highly useful and cost effective"/"approved test" in patients with epilepsy. Recently, we performed WES on four patients from three families and identified novel mutations in known epilepsy genes in all four cases. These patients had State Medicaid as their insurance carrier and were followed up for several years for EOEE while being worked up using the traditional/approved testing methods. Following a recently proposed diagnostic pathway, we analyzed the cost savings (US dollars) that could be accrued if WES was performed earlier in the diagnostic odyssey. This is the first publication that addresses the dollar cost of traditional testing in EOEE as performed in these four cases versus WES and the potential cost savings. PMID- 27243034 TI - Vagal Reactions during Cryoballoon-Based Pulmonary Vein Isolation: A Clue for Autonomic Nervous System Modulation? AB - Although paroxysmal atrial fibrillation (AF) is known to be initiated by rapid firing of pulmonary veins (PV) and non-PV triggers, the crucial role of cardiac autonomic nervous system (ANS) in the initiation and maintenance of AF has long been appreciated in both experimental and clinical studies. The cardiac intrinsic ANS is composed of ganglionated plexi (GPs), located close to the left atrium pulmonary vein junctions and a vast network of interconnecting neurons. Ablation strategies aiming for complete PV isolation (PVI) remain the cornerstone of AF ablation procedures. However, several observational studies and few randomized studies have suggested that GP ablation, as an adjunctive strategy, might achieve better clinical outcomes in patients undergoing radiofrequency-based PVI for both paroxysmal and nonparoxysmal AF. In these patients, vagal reactions (VR) such as vagally mediated bradycardia or asystole are thought to reflect intrinsic cardiac ANS modulation and/or denervation. Vagal reactions occurring during cryoballoon- (CB-) based PVI have been previously reported; however, little is known on resulting ANS modulation and/or prevalence and significance of vagal reactions during PVI with the CB technique. We conducted a review of prevalence, putative mechanisms, and significance of VR during CB-based PVI. PMID- 27243035 TI - A 12-Week Vigorous Exercise Protocol in a Healthy Group of Persons over 65: Study of Physical Function by means of the Senior Fitness Test. AB - The aim of this study was to assess the effects of vigorous exercise on functional abilities by means of a Senior Fitness Test (SFT) in a group of elderly adults. Twenty healthy and inactive people performed vigorous exercise (VE: 12 men and 8 women, aged 69.6 +/- 3.9 years). At the beginning of the study (T0) and after 3 months (T1), each subject's functional ability was tested for muscular strength, agility, cardiovascular fitness, flexibility, and balance. The VE was designed with continuous and interval exercise involving large muscle activities. Functional exercises were performed between 60% and 84% of heart rate reserve (HRR) for a duration of 65 minutes. Five out of the 6 SFTs performed were found significantly improved: Chair Stand (T0 12.4 +/- 2.4, T1 13.5 +/- 2.6, p < 0.01), Arm Curl (T0 14.2 +/- 3.6, T1 16.6 +/- 3.6, p < 0.01), 2 min step (T0 98.2 +/- 15.7, T1 108.9 +/- 16.2, p < 0.01), Chair Sit-and-Reach (T0 -9.9 +/- 7.7 cm, T1 1.7 +/- 6.3 cm, p < 0.01), and Back Scratch (T0 -15.8 +/- 10.9 cm, T1 -8.4 +/- 13.1 cm, p < 0.01). Our results suggest that a high intensity protocol and functional exercises can improve functional mobility and muscle endurance in those over 65 years of age. SFTs are an effective method for assessing improvements in the functional capacity of elderly adults. PMID- 27243036 TI - 2-Methoxyestradiol Alleviates Experimental Autoimmune Uveitis by Inhibiting Lymphocytes Proliferation and T Cell Differentiation. AB - Purpose. To investigate the effect of 2-Methoxyestradiol (2ME2) on experimental autoimmune uveitis (EAU) and the mechanism. Method. C57BL/6 male mice were used to establish the EAU model. 2ME2 was abdominal administrated in D0-D13, D0-D6, and D7-D13 and control group was given vehicle from D0-D13. At D14, pathological severity was scored. Lymphocyte reaction was measured using MTT assay. T cell differentiation in draining lymph nodes and eye-infiltrating cells was tested by flow cytometry. Proinflammatory cytokines production from lymphocytes was determined by ELISA. Result. The disease scores from 2ME2 D0-D13, 2ME2 D0-D6, 2ME2 D7-D13, and vehicle groups were 0.20 +/- 0.12, 1.42 +/- 0.24, 2.25 +/- 0.32, and 2.42 +/- 0.24. Cells from all 2ME2 treated groups responded weaker than control (p < 0.05). The inhibitory effect of 2ME2 on lymphocyte proliferation attenuated from 2ME2 D0-D13 to 2ME2 D0-D6 and to 2ME2 D7-D13 groups (p < 0.05). 2ME2 treated mice developed fewer Th1 and Th17 cells both in draining lymph nodes and in eyes than control (p < 0.05). Lymphocytes from 2ME2 group secreted less IFN-gamma and IL-17A than those from control (p < 0.05). Conclusion. 2ME2 ameliorated EAU progression and presented a better effect at priming phase. The possible mechanism could be the inhibitory impact on IRBP specific lymphocyte proliferation and Th1 and Th17 cell differentiation. PMID- 27243037 TI - Feline Coronavirus 3c Protein: A Candidate for a Virulence Marker? AB - Feline infectious peritonitis virus (FIPV) is highly virulent and responsible for the highly fatal disease feline infectious peritonitis (FIP), whereas feline enteric coronavirus (FECV) is widespread among the feline population and typically causes asymptomatic infections. Some candidates for genetic markers capable of differentiating these two pathotypes of a unique virus (feline coronavirus) have been proposed by several studies. In the present survey, in order to search for markers that can differentiate FECV and FIPV, several clones of the 3a-c, E, and M genes were sequenced from samples obtained from cats with or without FIP. All genes showed genetic diversity and suggested the presence of FCoV mutant spectrum capable of producing a virulent pathotype in an individual specific way. In addition, all the feline coronavirus FIPV strains demonstrated a truncated 3c protein, and the 3c gene was the only observed pathotypic marker for FCoVs, showing that 3c gene is a candidate marker for the distinction between the two pathotypes when the mutant spectrum is taken into account. PMID- 27243038 TI - Evaluation of Multiple Immunoassay Technology Platforms to Select the Anti-Drug Antibody Assay Exhibiting the Most Appropriate Drug and Target Tolerance. AB - The aim of this study was, at the assay development stage and thus with an appropriate degree of rigor, to select the most appropriate technology platform and sample pretreatment procedure for a clinical ADA assay. Thus, ELISA, MSD, Gyrolab, and AlphaLISA immunoassay platforms were evaluated in association with target depletion and acid dissociation sample pretreatment steps. An acid dissociation step successfully improved the drug tolerance for all 4 technology platforms and the required drug tolerance was achieved with the Gyrolab and MSD platforms. The target tolerance was shown to be better for the ELISA format, where an acid dissociation treatment step alone was sufficient to achieve the desired target tolerance. However, inclusion of a target depletion step in conjunction with the acid treatment raised the target tolerance to the desired level for all of the technologies. A higher sensitivity was observed for the MSD and Gyrolab assays and the ELISA, MSD, and Gyrolab all displayed acceptable interdonor variability. This study highlights the usefulness of evaluating the performance of different assay platforms at an early stage in the assay development process to aid in the selection of the best fit-for-purpose technology platform and sample pretreatment steps. PMID- 27243040 TI - Assessment of the Economic Structure of Brazilian Agribusiness. AB - This paper presents an economic assessment of Brazilian agribusiness and its relationship with other economic sectors. It was found that, in 2011, agribusiness had a share of 18.45% (basic prices) and 19.77% (market prices) of Brazilian GDP. The tax burden of agribusiness (20.68%) was higher than that of other sectors (13.59%), despite agribusiness being a major contributor to the generation of foreign exchange, employment, and essential products, such as food. Brazilian agribusiness is a major employer, responsible for 29.39% of national employment. However, its average income is lower than in the other sectors of the Brazilian economy. Finally, agribusiness was found to be the biggest generator of foreign exchange, with a positive balance of trade. It was possible to conclude that agribusiness forms a strong link between agriculture and livestock, industry, and services in other economic sectors. For this reason, it can be said that the development of agribusiness is highly relevant to the process of Brazilian economic development and is therefore important to the progress of economic policies. PMID- 27243041 TI - Electronic structures of intermolecular hydrogen bond contacts with solute in aqueous solution: glycine as a working prototype. AB - The intermolecular hydrogen bond (H-bond) interactions play vital roles in many biological systems. Despite continued interest, the nature of their electronic structures has remained elusive. Based on the unique features of aqueous solution, a simple model depicting the H-bond electronic states by orbital hybridizations is developed. The model is demonstrated by reproducing the experimental IR data and yielding favorable solute-solvent interactions for the prototype glycine. The H-bond state for solute H, O and N atoms is found to be characterized by sp(1), sp(2), and sp(3) hybridizations, respectively. The model provides a new way for probing the intricate solute-solvent contacts. PMID- 27243039 TI - Clinical Relevance of HLA Gene Variants in HBV Infection. AB - Host gene variants may influence the natural history of hepatitis B virus (HBV) infection. The human leukocyte antigen (HLA) system, the major histocompatibility complex (MHC) in humans, is one of the most important host factors that are correlated with the clinical course of HBV infection. Genome-wide association studies (GWASs) have shown that single nucleotide polymorphisms (SNPs) near certain HLA gene loci are strongly associated with not only persistent HBV infection but also spontaneous HBV clearance and seroconversion, disease progression, and the development of liver cirrhosis and HBV-related hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB). These variations also influence the efficacy of interferon (IFN) and nucleot(s)ide analogue (NA) treatment and response to HBV vaccines. Meanwhile, discrepant conclusions were reached with different patient cohorts. It is therefore essential to identify the associations of specific HLA allele variants with disease progression and viral clearance in chronic HBV infection among different ethnic populations. A better understanding of HLA polymorphism relevance in HBV infection outcome would enable us to elucidate the roles of HLA SNPs in the pathogenesis and clearance of HBV in different areas and ethnic groups, to improve strategies for the prevention and treatment of chronic HBV infection. PMID- 27243042 TI - Active chemisorption sites in functionalized ionic liquids for carbon capture. AB - Development of novel technologies for the efficient and reversible capture of CO2 is highly desired. In the last decade, CO2 capture using ionic liquids has attracted intensive attention from both academia and industry, and has been recognized as a very promising technology. Recently, a new approach has been developed for highly efficient capture of CO2 by site-containing ionic liquids through chemical interaction. This perspective review focuses on the recent advances in the chemical absorption of CO2 using site-containing ionic liquids, such as amino-based ionic liquids, azolate ionic liquids, phenolate ionic liquids, dual-functionalized ionic liquids, pyridine-containing ionic liquids and so on. Other site-containing liquid absorbents such as amine-based solutions, switchable solvents, and functionalized ionic liquid-amine blends are also investigated. Strategies have been discussed for how to activate the existent reactive sites and develop novel reactive sites by physical and chemical methods to enhance CO2 absorption capacity and reduce absorption enthalpy. The carbon capture mechanisms of these site-containing liquid absorbents are also presented. Particular attention has been paid to the latest progress in CO2 capture in multiple-site interactions by amino-free anion-functionalized ionic liquids. In the last section, future directions and prospects for carbon capture by site containing ionic liquids are outlined. PMID- 27243043 TI - Professor Yechezkiel Stein, MD 1926-2015: A physician, educator and a pioneer in lipid and atherosclerosis research. PMID- 27243044 TI - Education: Degrees of success. PMID- 27243045 TI - Response. PMID- 27243046 TI - Response. PMID- 27243047 TI - Response. PMID- 27243048 TI - Response. PMID- 27243049 TI - Long-term Follow-up Results from PET/CT Surveillance after Surgical Resection of Lung Adenocarcinoma Manifesting as Ground-glass Opacity: Notice of Retraction. PMID- 27243050 TI - Everything you ever wanted to know about Policy Advisory Council. PMID- 27243051 TI - Inflammation, guts and STEAM. PMID- 27243052 TI - AVA strategy 2021. PMID- 27243053 TI - Animal welfare teaching portal. PMID- 27243054 TI - New mechanism of resistance in a last-resort antibiotic. PMID- 27243055 TI - Pinery bushfire. PMID- 27243056 TI - The debate over penalty rates gets complicated. PMID- 27243057 TI - Underinsurance: a simple term with potentially disastrous consequences. PMID- 27243058 TI - CSU scholarship in honour of Dr Sandy Sutherland. PMID- 27243059 TI - Request for Notice of Resolutions for the Annual General Meeting of The Australian Veterinary Association Ltd. PMID- 27243060 TI - Rupert Woods: keeping watch over wildlife. PMID- 27243061 TI - British profession creates its own Vet Futures. PMID- 27243062 TI - Exploring veterinary hospitals in Kent, UK. PMID- 27243063 TI - Saving rhinos. PMID- 27243064 TI - The veterinary profession's disgrace. PMID- 27243065 TI - The veterinary profession's disgrace--Reply. PMID- 27243066 TI - Mental health = whole health. PMID- 27243067 TI - Safety Culture Proven to Improve Quality, Must be Monitored and Measured. PMID- 27243068 TI - Study Shows Safety Culture Affects Hospital Quality. PMID- 27243069 TI - Quality and Safety Promoted by Disclosing Errors to All Staff. PMID- 27243070 TI - Hospital Explains Errors with Duplicate Dose, Clonidine. PMID- 27243071 TI - Strategies for Recruiting Peer Review Physicians. PMID- 27243072 TI - Senior Patients: Unique Expectations, Needs. PMID- 27243073 TI - Quality Reporting Costs $15 Billion Annually. PMID- 27243074 TI - Overview and Summary: Emotional Health: Strategies for Nurses. PMID- 27243076 TI - [Ethics in scientific original papers review]. PMID- 27243075 TI - Reply to DB Shennan. PMID- 27243077 TI - [Not Available]. PMID- 27243078 TI - [Arteriovenous fistula (AVF) of the kidney in a patient with Cowden's syndrome]. PMID- 27243079 TI - [Renal injury grade IV: laceration and secondary urinoma. Conservative management]. PMID- 27243080 TI - Editorial comment. PMID- 27243081 TI - Author reply. PMID- 27243082 TI - Editorial comment. PMID- 27243083 TI - Author reply. PMID- 27243084 TI - Editorial comment. PMID- 27243085 TI - Author reply. PMID- 27243086 TI - Editorial comment. PMID- 27243087 TI - Editorial comment. PMID- 27243088 TI - Editorial comment. PMID- 27243089 TI - Editorial comment. PMID- 27243090 TI - Author reply. PMID- 27243091 TI - Chest X-ray quiz (Question). PMID- 27243092 TI - Improving databases for human variation. PMID- 27243093 TI - Driving out malaria. PMID- 27243094 TI - Simple tools for difficult imaging. PMID- 27243095 TI - Watching proteins fold on the ribosome. PMID- 27243096 TI - Taking a stab at neuronal heterogeneity. PMID- 27243097 TI - The condition-dependent proteome. PMID- 27243098 TI - Evaluation of [(89)Zr]-Oxalate as a PET Tracer in Inflammation, Tumor, and Rheumatoid Arthritis Models. AB - To obtain an additional pharmacological agent for the diagnosis of inflammation, we investigated the medical use of (89)Zr-oxalate as a positron emission tomography (PET) probe for the in vivo imaging of inflammation and compared its efficacy to that of 2-deoxy-2-[(18)F]fluoro-d-glucose ([(18)F]FDG) and sodium [(18)F]fluoride. (89)Zr-oxalate exhibited observable higher uptake in a macrophage cell line than in tumor cells. The inflammatory lesions and tumors were clearly visualized by PET imaging and autoradiography using (89)Zr-oxalate. Compared to [(18)F]FDG and sodium [(18)F]fluoride, (89)Zr-oxalate demonstrated a high selectivity index to the tumor at an early time point after injection and to inflammation at a delayed time point after injection (24 h). Through histological examination, large numbers of macrophages and neutrophils were observed in the tumor lesions with the highest (89)Zr-oxalate uptake. In a rheumatoid arthritis (RA) mouse model, (89)Zr-oxalate demonstrated a high level of accumulation in inflammatory lesions. (89)Zr-oxalate is a new strategic tool for tumor imaging and inflammatory processes. PMID- 27243099 TI - Cardiovascular Responses to Sexual Activity in Able-Bodied Individuals and Those Living with Spinal Cord Injury. AB - Sexuality is an integral part of the human experience and persists in health and disability. The cardiovascular system is crucial to sexual function and can be affected profoundly by spinal cord injury (SCI). The effects of sexual activity on the cardiovascular system in SCI have not been summarized and compared with sexual activity in able-bodied individuals. A keyword search of Embase, PubMed, and Medline was conducted. From 471 retrieved studies for able-bodied individuals, 11 were included that met the strict criteria of medically uncomplicated participants. In the SCI literature, 117 studies were screened, with 18 meeting criteria. In able-bodied persons, sexual activity resulted in modest increases in systolic blood pressure peaking at orgasm (males of 163 mm Hg and females of 142 mm Hg) and returning to baseline shortly afterward. In persons with SCI, results varied from minimal changes to significant elevations in systolic blood pressure because of episodes of autonomic dysreflexia, especially in those with high thoracic and cervical lesions. Peak systolic blood pressure in these individuals was measured to be as high as 325 mm Hg. In the SCI population, more intense stimuli (including penile vibrostimulation and electroejaculation) tended to result in a greater increase in systolic blood pressure compared with self-stimulation. Studies that used continuous versus intermittent monitoring were more likely to report greater changes in systolic blood pressure. In able bodied persons, sexual activity results in modest increases in blood pressure. In those with SCI, intense stimulation and higher injury levels result in a higher likelihood of autonomic dysreflexia and elevated blood pressure. Because of rapid changes in blood pressure, continuous monitoring is more advantageous than intermittent measurement, because the latter may miss peak values. PMID- 27243100 TI - Protein-Poly(amino acid) Nanocore-Shell Mediated Synthesis of Branched Gold Nanostructures for Computed Tomographic Imaging and Photothermal Therapy of Cancer. AB - Anisotropic noble metal nanoparticles especially branched gold nanoparticles with a large absorption cross-section and high molar extinction coefficient have promising applications in biomedical field. However, sophisticated and cumbersome methodologies of synthesis along with toxic precursors pose serious concern for its use. Herein, we report the synthesis of branched gold nanostructures from protein (albumin) nanoparticles by a simple reduction method. Albumin nanoparticles were synthesized by a modified desolvation technique with poly-l arginine (cationic poly amino acid) substituting the conventional toxic cross linker, glutaraldehyde. In silico molecular docking was carried out to study the interaction of poly-l-arginine with albumin which revealed its binding to Pocket 1B of the A-chain of albumin. The poly-l-arginine-albumin core-shell nanoparticles of ~100 nm in size served as a base for attachment of gold ions and its reduction to form 140 nm sized branched gold nanostructures conjugated with glutathione. These gold nanostructures exhibited near-infrared absorption lambdamax at 800 nm with extreme compatibility toward non cancerous (NIH 3T3), oral epithelial carcinoma (KB) cell lines, and human blood (red blood cells, platelets, and coagulation mechanisms) even up to a high concentration of 250 MUg/mL. These structures demonstrated superior computed tomographic (CT) contrast ability and marked photothermal cytotoxicity on KB cells. This study reports for the first time a method to develop blood and cell compatible branched gold nanostructures from protein nanoparticles as a dual CT diagnostic and photothermal therapeutic agent. PMID- 27243101 TI - Reciprocal influences among family processes and toddlers' sleep problems. AB - The current study examined bidirectional relations between children's sleep problems and parents' relationship satisfaction, coparental cooperation, and global family functioning in a sample of 249 families with 2-3-year-old children. Mothers and fathers were assessed across 5 waves with 2-month lags; the target children (53% female) were 2.8 years old (SD = .62) at baseline. Results of lagged path analyses indicated that children's sleep problems were reciprocally related to lower relationship satisfaction for mothers after accounting for covariates; however, for fathers, only relationship satisfaction predicted residual decreases in children's sleep problems 2 months later. Coparental cooperation also demonstrated reciprocal predictive links with fewer children's sleep problems in mothers; no such effect was found for fathers. Finally, for fathers, family functioning predicted residual decreases in children's sleep problems 2 months later across the 5 waves of the study. Findings build on a growing body of literature addressing reciprocal links between toddlers' sleep problems and adaptive family processes and highlight the importance of examining children's sleep within the context of the larger family system. (PsycINFO Database Record PMID- 27243102 TI - Validation and modification of a diagnostic scoring system to predict microscopic colitis. AB - OBJECTIVE: Many patients with diarrhoea undergo colonoscopy. If this is macroscopically normal, random biopsies are obtained to rule out microscopic colitis (MC), but most patients have functional disease. Accurate predictors of MC could avoid the need to take biopsies in a substantial proportion of patients, saving money for the health service. We validated a previously described diagnostic scoring system for MC, and incorporated further variables to assess whether this improved performance. MATERIAL AND METHODS: Consecutive adults with loose stools undergoing colonoscopy in Leeds, UK were included. Demographic and symptom data were collected prospectively. The diagnostic scoring system described previously was applied. In addition, the incorporation of further variables, including drugs associated with MC, number of stools, nocturnal passage of stools, and duration of loose stools, into the scoring system was assessed. Sensitivities, specificities, and positive and negative predictive values were calculated. RESULTS: Among 242 patients (mean age 51.0 years, 163 (67.4%) female), 26 (10.7%) of whom had MC, a cut off of >=4 on the original scoring system had a sensitivity of 92.3% and specificity of 35.2%. Nocturnal passage of stools and duration of loose stools <6 months were significant predictors of MC. Incorporating these variables in a new scoring system with a cut off of >=6 identified MC with 95.7% sensitivity and 46.0% specificity. CONCLUSIONS: Incorporating nocturnal passage of stools and duration of loose stools into the scoring system may improve ability to predict MC, and avoid random colonic biopsies in a greater proportion of patients with loose stools. PMID- 27243103 TI - Achieving Ultrafast Hole Transfer at the Monolayer MoS2 and CH3NH3PbI3 Perovskite Interface by Defect Engineering. AB - The performance of a photovoltaic device is strongly dependent on the light harvesting properties of the absorber layer as well as the charge separation at the donor/acceptor interfaces. Atomically thin two-dimensional transition metal dichalcogenides (2-D TMDCs) exhibit strong light-matter interaction, large optical conductivity, and high electron mobility; thus they can be highly promising materials for next-generation ultrathin solar cells and optoelectronics. However, the short optical absorption path inherent in such atomically thin layers limits practical applications. A heterostructure geometry comprising 2-D TMDCs (e.g., MoS2) and a strongly absorbing material with long electron-hole diffusion lengths such as methylammonium lead halide perovskites (CH3NH3PbI3) may overcome this constraint to some extent, provided the charge transfer at the heterostructure interface is not hampered by their band offsets. Herein, we demonstrate that the intrinsic band offset at the CH3NH3PbI3/MoS2 interface can be overcome by creating sulfur vacancies in MoS2 using a mild plasma treatment; ultrafast hole transfer from CH3NH3PbI3 to MoS2 occurs within 320 fs with 83% efficiency following photoexcitation. Importantly, our work highlights the feasibility of applying defect-engineered 2-D TMDCs as charge extraction layers in perovskite-based optoelectronic devices. PMID- 27243104 TI - Theoretical Investigation on the Substituent Effect of Halogen Atoms at the C8 Position of Adenine: Relative Stability, Vibrational Frequencies, and Raman Spectra of Tautomers. AB - We have theoretically investigated the substituent effect of adenine at the C8 position with a substituent X = H, F, Cl, and Br by using the density functional theory (DFT) at the B3LYP/6-311+G(d, p) level. The aim is to study the substituent effect of halogen atoms on the relative stability, vibrational frequencies, and solvation effect of tautomers. Our calculated results show that for substituted adenine molecules the N9H8X tautomer to be the most stable structure in gas phase at the present theoretical level. Here N9H8X denotes the hydrogen atom binds to the N9 position of imidazole ring and X denotes H, F, Cl, and Br atoms. The influence of the induced attraction of the fluorine substituent is significantly larger than chlorine and bromine ones. The halogen substituent effect has a significant influence on changes of vibrational frequencies and Raman intensities. PMID- 27243105 TI - Unveiling the Role of Co in Improving the High-Rate Capability and Cycling Performance of Layered Na0.7Mn0.7Ni0.3-xCoxO2 Cathode Materials for Sodium-Ion Batteries. AB - Co substitution has been extensively used to improve the electrochemical performances of cathode materials for sodium-ion batteries (SIBs), but the role of Co has not been well understood. Herein, we have comprehensively investigated the effects of Co substitution for Ni on the structure and electrochemical performances of Na0.7Mn0.7Ni0.3-xCoxO2 (x = 0, 0.1, 0.3) as cathode materials for SIBs. In comparison with the Co-free sample, the high-rate capability and cycle performance have been greatly improved by the substitution of Co, and some new insights into the role of Co have been proposed for the first time. With the substitution of Co(3+) for Ni(2+) the lattice parameter a decreases; however, c increases, and the d-spacing of the sodium-ion diffusion layer has been enlarged, which enhances the diffusion coefficient of the sodium ion and the high-rate capability of cathode materials. In addition, Co substitution shortens the bond lengths of TM-O (TM = transition metal) and O-O due to the smaller size of Co(3+) than Ni(2+), which accounts for the decreased thickness and volume of the TMO6 octahedron. The contraction of TM-O and O-O bond lengths and the shrinkage of the TMO6 octahedron improve the structure stability and the cycle performance. Last but not least, the aliovalent substitution of Co(3+) for Ni(2+) can improve the electronic conductivity during the electrochemical reaction, which is also favorable to enhance the high-rate performance. This study not only unveils the role of Co in improving the high-rate capability and the cycle stability of layered Na0.7Mn0.7Ni0.3-xCoxO2 cathode materials but also offers some new insights into designing high performance cathode materials for SIBs. PMID- 27243106 TI - Pathological Hyaluronan Matrices in Cystic Fibrosis Airways and Secretions. AB - Hyaluronan (HA) has been used in treatment of cystic fibrosis (CF) via a nebulizer and has demonstrated success in clinical outcomes. HA is an important glycosaminoglycan that is cross-linked by heavy chains (HCs) from inter-alpha inhibitor during inflammation. HC cross-linked HA (HC-HA) becomes significantly more adhesive for leukocytes than non-cross-linked HA, which can enhance inflammation. Our studies tested the hypothesis that HC-HA is present in CF airways and that altered ratios of HC-HA to its degradation into relatively lower molecular weight HA contribute to the pathophysiology of chronic inflammation in CF. We evaluated the distribution, levels, and size of HC-HA within CF, healthy, and diseased control lung, bronchus, and sputum tissues by histological and biochemical approaches. HC-HA was significantly elevated in CF, with deposits around the pulmonary vasculature, airway submucosa, and in the stroma of the submucosal glands. The increased infiltration of leukocyte populations correlated with the distribution of HC-HA matrices in the airways. Elevated lung tissue HC HA correlated with decreased HA levels in CF mucus and sputum compared with controls, suggesting that aberrant degradation and cross-linking of HA in lung tissue is a unique feature of CF. The accumulation and degradation of proinflammatory HC-HA in CF lung tissue suggests that aberrant HA catabolism and cross-linking may contribute to chronic inflammation in airway tissues and affect mucus viscosity in CF airways. PMID- 27243107 TI - Effect of Structure on Transport Properties (Viscosity, Ionic Conductivity, and Self-Diffusion Coefficient) of Aprotic Heterocyclic Anion (AHA) Room Temperature Ionic Liquids. 2. Variation of Alkyl Chain Length in the Phosphonium Cation. AB - A series of room-temperature ionic liquids (ILs) composed of triethyl(alkyl)phosphonium cations paired with three different aprotic heterocyclic anions (AHAs) (alkyl = butyl ([P2224](+)) and octyl ([P2228](+))) were prepared to investigate the effect of cationic alkyl chain length on transport properties. The transport properties and density of these ILs were measured from 283.15 to 343.15 K at ambient pressure. The dependence of the transport properties (viscosity, ionic conductivity, diffusivity, and molar conductivity) on temperature can be described by the Vogel-Fulcher-Tamman (VFT) equation. The ratio of the molar conductivity obtained from the molar concentration and ionic conductivity measurements to that calculated from self diffusion coefficients (measured by pulsed gradient spin-echo nuclear magnetic resonance spectroscopy) using the Nernst-Einstein equation was used to quantify the ionicity of these ILs. The molar conductivity ratio decreases with increasing number of carbon atoms in the alkyl chain, indicating that the reduced Coulombic interactions resulting from lower density are more than balanced by the increased van der Waals interactions between the alkyl chains. The results of this study may provide insight into the design of ILs with enhanced dynamics that may be suitable as electrolytes in lithium ion batteries and other electrochemical applications. PMID- 27243108 TI - High-Resolution Distance Dependence Study of Surface-Enhanced Raman Scattering Enabled by Atomic Layer Deposition. AB - We present a high-resolution distance dependence study of surface-enhanced Raman scattering (SERS) enabled by atomic layer deposition (ALD) at 55 and 100 degrees C. ALD is used to deposit monolayers of Al2O3 on bare silver film over nanospheres (AgFONs) and AgFONs functionalized with self-assembled monolayers. Operando SERS is used to measure the intensities of the Al-CH3 and C-H stretches from trimethylaluminum (TMA) as a function of distance from the AgFON surface. This study clearly demonstrates that SERS on AgFON substrates displays both a short- and long-range nanometer scale distance dependence. Excellent agreement is obtained between these experiments and theory that incorporates both short-range and long-range terms. This is a high-resolution operando SERS distance dependence study performed in one integrated experiment using ALD Al2O3 as the spacer layer and Raman label simultaneously. The long-range SERS distance dependence should make it possible to detect chemisorbed surface species located as far as ~3 nm from the AgFON substrate and will provide new insight into the surface chemistry of ALD and catalytic reactions. PMID- 27243109 TI - Mercury Export from Mainland China to Adjacent Seas and Its Influence on the Marine Mercury Balance. AB - Exports from mainland China are a significant source of mercury (Hg) in the adjacent seas (Bohai Sea, Yellow Sea, East China Sea, and South China Sea) near China. A total of 240 +/- 23 Mg was contributed in 2012 (30% from natural sources and 70% from anthropogenic sources), including Hg from rivers, industrial wastewater, domestic sewage, groundwater, nonpoint sources, and coastal erosion. Among the various sources, the Hg from rivers amounts to 160 +/- 21 Mg and plays a dominant role. The Hg that is exported from mainland China increased from 1984 to 2013; the contributions from rivers, industrial wastewater, domestic sewage and groundwater increased, and the contributions from nonpoint sources and coastal erosion remained stable. A box model is constructed to simulate the mass balance of Hg in these seas and quantify the sources, sinks and Hg biogeochemical cycle in the seas. In total, 160 Mg of Hg was transported to the Pacific Ocean and other oceans from these seas through oceanic currents in 2012, which could have negative impacts on the marine ecosystem. A prediction of the changes in Hg exportation through 2030 shows that the impacts of terrestrial export might worsen without effective pollution reduction measures and that the Hg load in these seas will increase, especially in the seawater of the Bohai Sea, Yellow Sea, and East China Sea and in the sea margin sediments of the Bohai Sea and East China Sea. PMID- 27243110 TI - Engagement in mental health treatment following primary care mental health integration contact. AB - Although the majority of mental health conditions are treated in primary care, treatment provided in this setting is often inadequate. In response to this problem, integrated mental health programs were created to enhance direct patient care and increase support for primary care providers. Data on the efficacy of these programs have suggested improved access, treatment outcomes, and patient satisfaction. However, infrequently examined is how interaction with integrated mental health providers impacts completion of referrals to specialty mental health (SMH) programs for patients whose treatment needs are too severe to treat in primary care alone. The current study examined referral acceptance rates among a veteran population at a large Midwest Veterans Affairs (VA) medical center. Results found that completion rates to SMH following integrated mental health contact (87.1%) were higher than published comparisons (32% in 1 study). It was found that a large proportion of these veterans maintained continued attendance to SMH treatment at 1- and 6-month follow-up (88.9% and 71.9%, respectively). Finally, data also suggest that only a small amount of contact (5 or more minutes) was needed to significantly increase the likelihood of SMH referral success but was not related to improved continued attendance in treatment at follow-up intervals. Clinical implications and suggestions for future research are discussed. (PsycINFO Database Record PMID- 27243111 TI - Effectiveness of a self-administered intervention for criminal thinking: Taking a Chance on Change. AB - The current study tested the effectiveness of a self-administered, cognitive behavioral intervention targeting criminal thinking for inmates in segregated housing: Taking a Chance on Change (TCC). Participants included 273 inmates in segregated housing at state correctional institutions. Reductions in criminal thinking, as assessed by the Psychological Inventory of Criminal Styles Simplified Version, were found in the general criminal thinking score as well as the proactive and reactive composite scores. Examination of demographic predictors of change (i.e., age, years of education, length of sentence) revealed older and more educated participants decreased in criminal thinking more than younger and less educated participants. For a subset of 48 inmates, completion of TCC was associated with significant reduction of disciplinary infractions. Reductions in reactive criminal thinking predicted reductions in disciplinary infractions. Although further research is needed to determine the effectiveness of TCC in reducing recidivism, the reductions in criminal thinking and disordered conduct suggest this is a promising intervention and mode of treatment delivery. By utilizing self-directed study at an accessible reading level, the intervention is uniquely suited to a correctional setting where staff and monetary resources are limited and security and operational issues limit the feasibility of traditional cognitive-behavioral group treatment. (PsycINFO Database Record PMID- 27243112 TI - The impact of diabetes mellitus and other comorbidities on hematopoietic stem cell collection and hematologic recovery post-transplantation. PMID- 27243113 TI - The Effect of the CYP1A1*2A Allele on Colorectal Cancer Susceptibility in a British Population. AB - AIM: Colorectal cancer (CRC) is a major health problem despite recent improvements in overall survival rates. Genetic polymorphisms affecting carcinogen biotransformation or DNA repair play pivotal roles in the carcinogenesis process. CYP1A1*2A (6235 T/C, rs4646903, MspI) is thought to be associated with an increased risk of CRC because of its role in metabolic activation of polycyclic aromatic hydrocarbons; however, the results of previous studies are conflicting. In this study, a possible association between the CYP1A1*2A allele and CRC and the effect of cigarette smoking on this risk were examined in a British population. MATERIAL AND METHODS: A prospective case control study including 200 cases and 254 age-and-sex-matched controls was conducted with British participants from the north-east of England. Genotyping of the CYP1A1*2A allele was performed using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: CYP1A1*2A was not associated with CRC development (OR = 1.566; 95% confidence interval [CI] = 0.90-2.73; p = 0.12). However, it was observed that C allele-carrying individuals who had smoked within the past 5 years had a significant risk of CRC (OR = 2.28; 95% CI = 1.07-4.86; p = 0.043). CONCLUSION: These data are of interest in understanding CRC etiology and identifying an individual's risk of developing CRC. However, a full evaluation of an association between CYP1A1*2A and cancer susceptibility in Europeans is difficult and will require a larger number of participants. PMID- 27243114 TI - Synthesis, Electronic Structure, and Reactivity Studies of a 4-Coordinate Square Planar Germanium(IV) Cation. AB - A tetra-coordinate, square planar germanium(IV) cation [(TPFC)Ge](+) (TPFC = tris(pentafluorophenyl)corrole) was synthesized quantitatively by the reaction of (TPFC)Ge-H with [Ph3C](+)[B(C6F5)4](-). The highly reactive [(TPFC)Ge](+) cation reacted with benzene to form phenyl complex (TPFC)Ge-C6H5 through an electrophilic pathway. The key intermediate, a sigma-type germylium-benzene adduct, [(TPFC)Ge(eta(1)-C6H6)](+), was isolated and characterized by single crystal X-ray diffraction. Deprotonation of [(TPFC)Ge(eta(1)-C6H6)](+) cation led to the formation of (TPFC)Ge-C6H5. [(TPFC)Ge](+) also reacted with ethylene and cyclopropane in benzene at room temperature to form (TPFC)Ge-CH2CH2C6H5 and (TPFC)Ge-CH2CH2CH2C6H5, respectively. The observed electrophilic reactivity is ascribed to the highly exposed cationic germanium center with novel frontier orbitals comprising two vacant sp-hybridized orbitals that are not conjugated to pi-system. The three electron-withdrawing pentafluorophenyl groups on the corrole ligand also enhance the electrophilicity of the cationic germanium corrole. PMID- 27243116 TI - Protein-Mineral Interactions: Molecular Dynamics Simulations Capture Importance of Variations in Mineral Surface Composition and Structure. AB - Molecular dynamics simulations, conventional and metadynamics, were performed to determine the interaction of model protein Gb1 over kaolinite (001), Na(+) montmorillonite (001), Ca(2+)-montmorillonite (001), goethite (100), and Na(+) birnessite (001) mineral surfaces. Gb1, a small (56 residue) protein with a well characterized solution-state nuclear magnetic resonance (NMR) structure and having alpha-helix, 4-fold beta-sheet, and hydrophobic core features, is used as a model protein to study protein soil mineral interactions and gain insights on structural changes and potential degradation of protein. From our simulations, we observe little change to the hydrated Gb1 structure over the kaolinite, montmorillonite, and goethite surfaces relative to its solvated structure without these mineral surfaces present. Over the Na(+)-birnessite basal surface, however, the Gb1 structure is highly disturbed as a result of interaction with this birnessite surface. Unraveling of the Gb1 beta-sheet at specific turns and a partial unraveling of the alpha-helix is observed over birnessite, which suggests specific vulnerable residue sites for oxidation or hydrolysis possibly leading to fragmentation. PMID- 27243115 TI - Esophageal and anorectal involvement in systemic sclerosis: a systematic assessment with high resolution manometry. AB - OBJECTIVES: In systemic sclerosis (SSc), esophageal and anorectal involvements are frequent and often associated with each other. In clinical practice, esophageal explorations are often prescribed, while anorectal explorations are rarely proposed and therefore, under-recognised. However, it is well documented in the literature that early detection of anorectal dysfunction could delay and/or prevent the onset of symptoms such as fecal incontinence (FI). The main objective was the systematic evaluation and detection of esophageal and anorectal involvements in SSc patients. METHODS: In this monocentric retrospective study, all patients with SSc addressed in the Department of Functional Digestive Explorations, North Hospital, Marseille for esophageal and anorectal explorations were included. Self-Questionnaires, evaluating the symptoms and quality of life, were filled by patients during their visit. Explorations were performed on the same day: high resolution esophageal manometry (EHRM), 3 Dimensional high resolution anorectal manometry (3DHRARM) and endo anal sonography (EUS). RESULTS: 44 patients (41 women), mean age 59.8+/-12 years, were included. With regard to the symptoms, 45.5% of patients had gastro-esophageal reflux disease (GERD), 66.9% dysphagia, 65.9% constipation and 77.3% FI. The incidence of esophageal dismotility was 65.9%, anorectal and both upper and lower dysfunction were 43.2%. More than 89% patients with abnormal explorations (EHRM, 3DHRARM or both) were symptomatic. Duration of SSc and altered quality of life was correlated with the severity of digestive involvement. CONCLUSIONS: Anorectal dysfunction appears to be closely linked to esophageal involvement in SSc. Their routine screening is undoubtedly essential to limit the occurrence of severe symptoms such as FI. PMID- 27243131 TI - Scalp Basal Cell Carcinoma: Review of 2,202 Cases. AB - BACKGROUND: Increases in the incidence of basal cell carcinoma (BCC) in women, younger age groups and in aggressive scalp subtypes in younger women have been reported. OBJECTIVE: To describe lesion and patient characteristics in scalp BCC. MATERIALS AND METHODS: Retrospective audit of scalp BCCs from 3 pathology laboratories in Adelaide, South Australia, January 2009-December 2013. RESULTS: Scalp BCC was 2.6% of all BCC. Of 2,202 patients with scalp BCC, 62% were male and 78% were >60 years. Histologic subtypes included nodular (55%), mixed (30%), and superficial (8%). The concordance between biopsy and excision was 83% for division into nonaggressive and aggressive subtypes. The incomplete excision rate was 16%. Aggressive subtypes were larger and had perineural invasion (PNI) in 8.5% and incomplete excision in 26%. CONCLUSION: Basal cell carcinoma on the scalp was less common. Men and the elderly had the majority of cases, with no predilection for women, including aggressive histologic subtypes in younger women. Aggressive subtypes were associated with increased size, incomplete excision, and PNI. A preliminary biopsy assisted division into aggressive and nonaggressive histologic subtypes. Incomplete excision rates were higher and increased in aggressive histologic subtypes and PNI. Mohs surgery or wider margins are suggested in these cases. PMID- 27243132 TI - Successful Treatment of Acquired Balanic Lymphangiectasia Following Circumcision Using 2,940-nm Erbium-Doped Yttrium Aluminium Garnet Laser. PMID- 27243133 TI - Neodymium-Doped Yttrium Aluminium Garnet Laser Treatment of Pediatric Venous Malformation in the Oral Cavity. AB - BACKGROUND: Treatment of venous malformations in the orofacial region remains a challenge. Laser therapy is an alternative treatment in inoperable cases. OBJECTIVE: To retrospectively evaluate the effectiveness and complications associated with neodymium-doped yttrium aluminium garnet (Nd:YAG) laser treatment of oral venous malformations. MATERIALS AND METHODS: A total of 10 children (mean age: 7.3 years; range: 10 months-15 years) with oral venous malformation were treated with Nd:YAG laser during 2005 to 2013. Clinical improvement, including degree of color lightening and size reduction, and treatment complications, including dyspigmentation, textural change, and scarring were evaluated. RESULTS: Color clearing of 51% to 75% and >75% was seen in 25% and 45% of patients, respectively. Size reduction of 25% to 50%, 51% to 75%, and >75% was observed in 30%, 15%, and 45% of patients, respectively. Mild and moderate scarring was observed in 15% and 5% of cases, respectively. CONCLUSION: Nd:YAG laser is a promising alternative treatment in pediatric patients with inoperable venous malformations in the oral cavity. Mild to moderate scarring was the most common complication. PMID- 27243134 TI - Hydrochlorothiazide Use and Skin Cancer: A Mohs Surgeon's Concern. PMID- 27243135 TI - A Shot of Alcohol May be the Answer to Persistent Pyogenic Granulomas. PMID- 27243136 TI - Association Between Insulin Resistance and Bone Structure in Nondiabetic Postmenopausal Women. AB - CONTEXT: The clinical consequences of insulin resistance and hyperinsulinemia on bone remain largely unknown. OBJECTIVE: The objective of the study was to evaluate the effect of insulin resistance on peripheral bone geometry, volumetric bone mineral density (vBMD), bone microarchitecture, and estimated bone strength. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study included 146 postmenopausal, nondiabetic Caucasian women (mean age 60.3 +/- 2.7 y) who were participating in the Study of Women's Health Across the Nation. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: High-resolution peripheral quantitative computed tomography was used to assess bone density and microstructure at the distal radius and tibia. Fasting insulin and glucose were measured and insulin resistance was estimated using homeostasis model assessment of insulin resistance (HOMA-IR), with higher values indicating greater insulin resistance. RESULTS: There was a negative association between HOMA-IR and bone size and a positive association between HOMA-IR and total vBMD, trabecular vBMD, trabecular thickness, and cortical thickness at the radius and tibia. These relationships remained, even after adjusting for body weight and other potential covariates (eg, time since menopause, cigarette smoking, physical activity, prior use of osteoporosis medications or glucocorticoids). CONCLUSIONS: In nondiabetic, postmenopausal women, insulin resistance was associated with smaller bone size, greater volumetric bone mineral density, and generally favorable bone microarchitecture at weight-bearing and nonweight-bearing skeletal sites. These associations were independent of body weight and other potential covariates, suggesting that hyperinsulinemia directly affects bone structure independent of obesity and may explain, in part, the higher trabecular bone density and favorable trabecular microarchitecture seen in individuals with type 2 diabetes mellitus. PMID- 27243137 TI - Spontaneous Cerebrospinal Fluid Leak With Venous Engorgement Mimicking a Contrast Enhancing Cervical Mass. PMID- 27243138 TI - Seeded preparation of ultrathin FeS2 nanosheets from Fe3O4 nanoparticles. AB - FeS2 nanomaterials with two-dimensional features hold great promise for electrochemical and photovoltaic applications. However, the preparation of ultrathin FeS2 nanosheets is still challenging because of the lack of a tailor made approach. In this work, FeS2 nanosheets with a thickness of 2.1 nm are prepared through a Fe3O4-seeded approach. Uniform Fe3O4 nanoparticles are foremost synthesized via the standard method in organic media. The injection of a S solution leads to the replacement of O in Fe3O4 through anion-exchange, which generates (110) facet-enriched FeS2 nuclei. The subsequent (110) facet-mediated oriented attachment and fusion of FeS2 nuclei produce ultrathin FeS2 nanosheets. As catalysts in the hydrogen evolution reaction, FeS2 nanosheets exhibit good electrochemical activity. PMID- 27243139 TI - See-and-Treat Loop Electrosurgical Excision Procedure for High-Grade Cervical Cytology: Are We Overtreating? AB - OBJECTIVES: To report the overtreatment rate for see-and-treat versus 3-step conventional strategy (cervical cytology, colposcopic biopsies, then LEEP) for patients with high-grade squamous intraepithelial lesion (HSIL) cytology. Our second aim was to identify risk factors for overtreatment. METHODS: We included 178 women with HSIL cytology from our university-based colposcopy clinic who underwent LEEP between 2007 and 2014. Overtreatment was defined as cervical intraepithelial neoplasia (CIN) 1 or less on LEEP specimen. Differences between treatment groups were compared using chi-square test, 2-sample t test, or Mann Whitney rank-sum test as appropriate. RESULTS: CIN2+ was found in 69 (80%) of women in the see-and-treat group and 69 (75%) of the conventional management group (P = 0.093), with overtreatment in 17 (20%) and 23 (25%, P = 0.403), respectively. Women who underwent see-and-treat (n = 86) were older (mean age, 36 vs 31 years; P = 0.007), and a greater proportion completed childbearing (30% vs 13%, P = 0.024). There were no differences in top hat excision; however, a higher proportion of the see-and-treat group had CIN2+ in endocervical samples (54% vs 27%, P = 0.047). Overtreatment, regardless of management strategy, was associated with age at time of LEEP, where older women were more likely to be overtreated (median age, 37 vs 32 years, respectively; OR, 1.04; 95% CI, 1.01-1.08; P = 0.011). CONCLUSIONS: A see-and-treat strategy minimizes risk of loss to follow-up with a similar overtreatment rate compared with conventional management. With CIN2+ in some three-fourths of women with HSIL, a see-and-treat should be favored especially when adherence to follow-up is questionable. PMID- 27243140 TI - See-and-Treat for High-Grade Cytology: Do Young Women Have Different Rates of High-Grade Histology? AB - OBJECTIVE: To compare rates of cervical intraepithelial neoplasia grade 3 or greater (CIN3+) between women aged 21 to 24 and women aged 25 or older undergoing a see-and-treat strategy for high-grade squamous intraepithelial lesion (HSIL) cytology. METHODS: In this retrospective cohort study, women treated with a see and-treat loop electrosurgical excisional procedure (LEEP) for HSIL cytology at our university-based colposcopy clinic between 2008 and 2013 were identified. Data collected included age, race, parity, smoking status, method of contraception, history of abnormal cytology, HIV status, and LEEP histology. Cohorts were compared using Pearson chi-squared test of association and Fisher exact test. RESULTS: Three hundred sixty-nine women were included in this analysis. The mean age was 30 (SD, 7.2; range, 21-56). Ninety-seven women (26.3%) were 21 to 24 years old. The rate of CIN3 in all women undergoing a see-and-treat LEEP for HSIL cytology was 65.9% (95% CI, 60.8-70.5). The rate of CIN 2 was 15.2% (95% CI, 11.9-19.2). Three women (1.1%) had invasive carcinoma. There was no difference in risk of CIN3+ in the young women compared with women aged 25 years or older (RR, 1.37; 95% CI, 0.92-2.02). Within this see-and-treat population, there was no correlation between presence of CIN3+ and race, smoking, contraception, or HIV status. CONCLUSIONS: Most women undergoing see-and-treat for HSIL cytology will have CIN3 on final histology. In this large cohort, women aged 21 to 24 did not have lower rates of CIN3 compared with women aged 25 and older, suggesting that see-and-treat is still a valid treatment option for the prevention of invasive disease in young women. PMID- 27243141 TI - Biomarkers for Cervical Cancer Prevention Programs: The Long and Winding Road From Discovery to Clinical Use. PMID- 27243142 TI - Chronic Cervicitis: Presenting Features and Response to Therapy. AB - OBJECTIVES: Chronic nongonococcal nonchlamydial cervicitis is a condition of unknown etiology. Data about treatment options are limited. Our goal was to review a single center's experience in managing women with chronic NGNCC. METHODS: We evaluated all encounters at a tertiary care center with ICD-9 code for cervicitis between April 2008 and March 2014. Cases were defined by having two of the following 3 diagnostic criteria: mucopurulent discharge noted by (1) patient or (2) practitioner, and (3) cervical bleeding upon gentle probing. All women had negative nucleic acid amplification testing for Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis. Information regarding patient demographics, symptoms, findings, treatment, and outcomes were analyzed. Cure was defined as resolution of patient-specific diagnostic criteria. RESULTS: Sixty-one women were identified. The mean age was 31 years; 73.7% were white, and 59% were nulliparous. The mean duration of symptoms was 25.2 months. Initially, all 61 patients received one of 3 antibiotic treatments. The cure rate after initial antibiotic treatment was 65.6%. Nineteen patients required at least one further treatment. Additional treatments included secondary antibiotics, hormonal treatments, vaginal hydrocortisone, silver nitrate, cryotherapy, and loop excision electrosurgical procedure. Cure rates were as follows: 57.9% with antibiotics, 50% with hormone treatment, 0% with hydrocortisone, 100% with silver nitrate, 0% with cryotherapy, and 100% with loop electrosurgical excisional procedure. Of the initial 61 women, 93.4% were eventually cured. CONCLUSIONS: Nongonococcal nonchlamydial cervicitis is a condition that can cause unremitting symptoms. Most patients will respond to antibiotics, although other treatments including surgery may be necessary. PMID- 27243143 TI - The Use of the Colposcopically Directed Punch Biopsy in Clinical Practice: A Survey of British Society of Colposcopy and Cervical Pathology (BSCCP)-Accredited Colposcopists. AB - OBJECTIVES: The colposcopically directed punch biopsy has been an integral component of colposcopic practice. In light of the changing landscape of the cervical screening programme, a study was conducted to investigate the current practice of British Society of Colposcopy and Cervical Pathology-accredited colposcopists on technique and rationale for performing a punch biopsy. MATERIALS AND METHODS: A web-based questionnaire survey was e-mailed to all British Society of Colposcopy and Cervical Pathology-accredited colposcopists. Questions included selection criteria for performing a punch biopsy, number of biopsies, and technique. Results were analyzed by specialty, experience, and workload. RESULTS: A total of 749 colposcopists responded, 50.2% of the 1,493 total. The respondents were obstetrician and gynecologists (42.9%), gynecologists/oncologists (33.6%), and nurse colposcopists (19.8%). Most colposcopists (78.3%) had more than 5-year colposcopy experience and saw in excess of 11 new cases (73.4%) of abnormal cervical cytology/month. Most colposcopists (56%) aimed to take 2 biopsies to diagnose cervical intraepithelial neoplasia, and very few (16.2%) reported routinely taking random biopsies from normal areas of cervix. Looking at the trends in management in the case scenarios, there was a lower threshold for performing punch biopsy before large loop excision of the transformation zone in younger (age, <25 years) or nulliparous women versus older women (age, >40 years; p < .05). Colposcopists were more likely to take biopsies in women with low-grade cytology/colposcopic findings (71.2%, always or most of the times) as compared with high-grade cytology/colposcopic findings (40.3%, never or rarely). CONCLUSIONS: Colposcopically directed punch biopsy is routinely used by colposcopists; however, techniques, number of biopsies taken, and rationale for performing a biopsy vary greatly between colposcopists. PMID- 27243145 TI - The Enhancement on Proton Conductivity of Stable Polyoxometalate-Based Coordination Polymers by the Synergistic Effect of MultiProton Units. AB - Two novel polyoxometalate (POM)-based coordination polymers, namely, [Co(bpz)(Hbpz)][Co(SO4 )0.5 (H2 O)2 (bpz)]4 [PMo(VI) 8 Mo(V) 4 V(IV) 4 O42 ]?13 H2 O (NENU-530) and [Ni2 (bpz)(Hbpz)3 (H2 O)2 ][PMo(VI) 8 Mo(V) 4 V(IV) 4 O44 ]?8 H2 O (NENU-531) (H2 bpz=3,3',5,5'-tetramethyl-4,4'-bipyrazole), were isolated by hydrothermal methods, which represented 3D networks constructed by POM units, the protonated ligand and sulfate group. In contrast with most POM-based coordination polymers, these two compounds exhibit exceptional excellent chemical and thermal stability. More importantly, NENU-530 shows a high proton conductivity of 1.5*10( 3) S cm(-1) at 75 degrees C and 98 % RH, which is one order of magnitude higher than that of NENU-531. Furthermore, structural analysis and functional measurement successfully demonstrated that the introduction of sulfate group is favorable for proton conductivity. Herein, the syntheses, crystal structures, proton conductivity, and the relationship between structure and property are presented. PMID- 27243146 TI - Dielectric polarization transients in biological tissue moving in a static magnetic field. AB - Movement of a body in a static magnetic field gives rise to the Lorentz force that induces in the medium both electric currents and dielectric polarization. It is usually assumed that the conductivity of biological tissues is sufficiently high in order to neglect dielectric phenomenon arising from non-equilibrium of polarization charges. However, the permittivity of biological tissues is extremely high and the relaxation time of free charges is relatively low. In this study, we examined the effect of dielectric polarization on the electric field (EF) induced by human movements in a strong magnetic field (MF). Analytic equations for brain and bone equivalent spheres translating and rotating in a uniform MF were derived from Maxwell equations. Several examples were computed by using Fast Fourier Transform to examine transient dielectric effects in a time domain. The results showed that dielectric polarization transients do arise, but in the case of homogeneous medium, they are vanishingly small. In contrast, the local dielectric transients are not vanishingly small in heterogeneous medium. However, due to limited acceleration and deceleration of normal human movements, the transients are relatively small, at maximum a few dozen percent of the EF induced by the change of the magnetic flux. Taking into account the high uncertainty in numerical simulation, the dielectric transients can be neglected in the case of biological materials but not in the case of many non-biological materials of low conductivity. Bioelectromagnetics. 37:409-422, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27243144 TI - Excess HB-EGF, which promotes VEGF signaling, leads to hydrocephalus. AB - Heparin binding epidermal growth factor-like growth factor (HB-EGF) is an angiogenic factor mediating radial migration of the developing forebrain, while vascular endothelial growth factor (VEGF) is known to influence rostral migratory stream in rodents. Cell migratory defects have been identified in animal models of hydrocephalus; however, the relationship between HB-EGF and hydrocephalus is unclear. We show that mice overexpressing human HB-EGF with beta-galactosidase reporter exhibit an elevated VEGF, localization of beta-galactosidase outside the subventricular zone (SVZ), subarachnoid hemorrhage, and ventriculomegaly. In Wistar polycystic kidney rats with hydrocephalus, alteration of migratory trajectory is detected. Furthermore, VEGF infusions into the rats result in ventriculomegaly with an increase of SVZ neuroblast in rostral migratory stream, whereas VEGF ligand inhibition prevents it. Our results support the idea that excess HB-EGF leads to a significant elevation of VEGF and ventricular dilatation. These data suggest a potential pathophysiological mechanism that elevated HB-EGF can elicit VEGF induction and hydrocephalus. PMID- 27243147 TI - An array of individually addressable micro-needles for mapping pH distributions. AB - This work describes the preparation of an array of individually addressable pH sensitive microneedles which are sensitized by electrodepositing iridium oxide. The impact of the deposition potential, storage conditions and interferents on the sensor characteristics such as slope, offset, intra- and inter-batch reproducibility is investigated. The device may be a useful tool for carrying out direct pH measurements of soft and heterogeneous samples such as tissues and organs. For example, we demonstrated that the microneedle array can be employed for real-time mapping of the cardiac pH distribution during cycles of global ischemia and reperfusion. PMID- 27243149 TI - Leptospirosis in Tasmanian Devils ( Sarcophilus harrisii ) in Tasmania, 2008-12. AB - In 2014, we performed a diagnostic study of leptospirosis in Tasmanian devil ( Sarcophilus harrisii ) samples collected between 2008 and 2012 from wild and captive animals. Tasmanian devil populations have been declining because of a facial tumor disease since the 1990s, with ongoing investigations examining potential causative agents. Identifying other causative pathogens that may contribute additively to their decline is important to preserve current and future populations. We tested 81 Tasmanian devil serum samples and two tissue samples using PCR, microscopic agglutination test (MAT), and microsphere immunoassay (MIA). We found evidence of leptospirosis in Tasmanian devil populations across a wide geographic range of Tasmania. Antibodies to serovars in the serogroup Javanica, which are not considered endemic to Australia, were identified in 10 Tasmanian devils using MAT. We also identified serovar Celledoni serologically using the immunoglobulin G MIA and detected Leptospira in one sample using PCR. PMID- 27243150 TI - Antibody Prevalence and Isolation of Viable Toxoplasma gondii from Raptors in the Southeastern USA. AB - Raptors are good indicators of the prevalence of Toxoplasma gondii in the environment because they prey on small mammals and birds. These prey species are a major source of infection in domestic cats ( Felis catus ), which shed the environmentally resistant oocysts. We assessed T. gondii infection in 281 opportunistically available raptors at a rehabilitation facility between 2012 and 2014. Antibodies to T. gondii were assayed by a modified agglutination test (cutoff 1:25) and found in serum of 22/71 Red-tailed Hawks ( Buteo jamaicensis ), 25/54 Barred Owls ( Strix varia ), 9/41 Red-shouldered Hawks ( Buteo lineatus ), 13/28 Great Horned Owls ( Bubo virginianus ), 6/20 Broad-winged Hawks ( Buteo platypterus ), 2/16 Eastern Screech Owls (Megascops asio), 12/13 Bald Eagles ( Haliaeetus leucocephalus ), 6/12 Cooper's Hawks ( Accipiter cooperii ), 1/8 Black Vultures ( Coragyps atratus ), and 1/1 Golden Eagle ( Aquila chrysaetos ). Antibodies were not detected in 5 Barn Owls ( Tyto alba ), 3 American Kestrels ( Falco sparverius ), 1 Mississippi Kite ( Ictinia mississippiensis ), and 1 Osprey ( Pandion haliaetus ). Viable T. gondii was isolated from the tissues of 1 antibody-positive Barred Owl and identified as a strain having type II alleles at all 10 loci tested, except one (ToxoDB polymerase chain reaction-restriction fragment length polymorphism genotype 3). Type II strain is the most common strain in the US. Results of this study indicate a high prevalence of T. gondii in some raptor species and the first reported genotyping from a Barred Owl. PMID- 27243151 TI - Causes of Admission for Raptors to the Tafira Wildlife Rehabilitation Center, Gran Canaria Island, Spain: 2003-13. AB - We report the causes of morbidity of 2,458 free-living raptors admitted to the Tafira Wildlife Rehabilitation Center on Gran Canaria Island, Spain, during 2003 13. The seasonal cumulative incidences were investigated while considering estimates of the wild populations in the region. These methods were used as a more accurate approach to assess the potential ecologic impact of different causes of morbidity. The most frequently admitted species were the Eurasian Kestrel ( Falco tinnunculus ; 53.0%), the Eurasian Long-eared Owl ( Asio otus canariensis; 28.1%), the Canary Islands Common Buzzard ( Buteo buteo insularum; 8.0%), and the Eurasian Barn Owl ( Tyto alba ; 4.4%). The most frequent causes of admission were trauma (33.8%), orphaned-young birds (21.7%), unknown (18.4%), and metabolic/nutritional disease (11.1%). Local morbidity caused by glue trapping and entanglement in burr bristlegrass (Setaria adhaerens) had prevalences of 5.0% and 1.8%, respectively. The highest number of admissions during the breeding and nonbreeding seasons was observed for the Eurasian Barn Owl and the Barbary Falcon ( Falco pelegrinoides ), respectively, mainly due to trauma of unknown origin. PMID- 27243152 TI - Arterial pH and Blood Lactate Levels of Anesthetized Mongolian Khulan ( Equus hemionus hemionus) in the Mongolian Gobi Correlate with Induction Time. AB - Research and conservation of wide-ranging wild equids in most cases necessitate capture and handling of individuals. For free-roaming Mongolian khulan ( Equus hemionus hemionus), also known as the khulan, capture involves a strenuous, high speed chase, and physiologic responses have yet to be elucidated. We analyzed sequential arterial blood gas (ABG) samples as a proxy for respiratory and metabolic status of khulan during capture-related anesthesia. We recorded precise chase and induction times and monitored vital parameters and ABG from free ranging khulan during anesthesia performed for GPS collaring. At the initiation of anesthesia, animals had ABG values similar to those recorded for thoroughbred horses ( Equus caballus ) after maximal exercise. Longer induction times resulted in higher arterial pH (P<0.001) and lower blood lactate (P<0.002). This trend of improvement continued over the course of anesthesia. The most important factor explaining pH and lactate was the time that elapsed between cessation of the chase and obtaining the first ABG sample, which, under field conditions, is tightly linked to induction time. All animals recovered uneventfully. Our data show that khulan recover and shift their metabolic status back toward expected normal values during opioid-based field anesthesia. PMID- 27243153 TI - Identification of Avian Paramyxovirus Serotype-1 in Wild Birds in the USA. AB - In the US, sampling for avian paramyxovirus serotype-1 (APMV-1) is generally conducted when morbidity or mortality events occur involving certain families of wild birds known to be affected by the virus, such as cormorants (Family Phalacrocoracidae), pigeons, doves (Family Columbidae), or pelicans (Family Pelecanidae). To quantify the prevalence of APMV-1 in apparently healthy wild birds and to determine its geographic distribution, we collected swab and serum samples from >3,500 wild birds, representing eight orders from 1 January 2013 to 30 September 2013. Antibody prevalence was highest in wild birds of Order Suliformes (44.9%), followed by Pelecaniformes (24.4%), Anseriformes (22.7%), and Columbiformes (11.7%), with a relatively high occurrence of virulent viruses in Columbiformes (100% of virulent viruses isolated). As expected, viral shedding was comparatively much lower, and positives were only identified in Orders Accipitriformes (1.4%), Columbiformes (1.0%), Anseriformes (0.8%), and Charadriiformes (0.4%). We also demonstrate circulating virulent APMV-1 viruses of genotype VI in apparently healthy Rock Pigeons ( Columba livia ) from March through September in three states. PMID- 27243154 TI - Detection of Hepatozoon felis in Ticks Collected from Free-Ranging Amur Tigers ( Panthera tigris altaica), Russian Far East, 2002-12. AB - We collected 69 ticks from nine, free-ranging Amur tigers ( Panthera tigris altaica) between 2002 and 2011 and investigated them for tick-borne pathogens. DNA was extracted using alkaline digestion and PCR was performed to detect apicomplexan organisms. Partial 18S rDNA amplification products were obtained from 14 ticks from four tigers, of which 13 yielded unambiguous nucleotide sequence data. Comparative sequence analysis revealed all 13 partial 18S rDNA sequences were most similar to those belonging to strains of Hepatozoon felis (>564/572 base-pair identity, >99% sequence similarity). Although this tick-borne protozoon pathogen has been detected in wild felids from many parts of the world, this is the first record from the Russian Far East. PMID- 27243155 TI - Use of Acoustic Transmitter-Equipped Remote Sedation to Aid in Tracking and Capture of Entangled California Sea Lions (Zalophus californianus). AB - Free-ranging California sea lions ( Zalophus californianus ) with marine debris entanglements were darted with a combination of medetomidine, butorphanol, and midazolam by using acoustic transmitter-equipped darts. Of the 15 animals sedated, 13 (87%) reentered the water and were tracked by using a unidirectional hydrophone. Sea lions that entered the water continued to surface and breathe postsedation. There were three mortalities (20%) during the course of this study due to the following: suspected drowning caused by entrapment under a dock, overdose due to inaccurate weight estimation, and trauma caused by a dart puncturing the animal's abdomen. The drug combination, new dart design, and tracking techniques allowed for successful remote sedation and capture of California sea lions in high-risk situations and improved our ability to determine the final outcome for all cases. These methods allow targeting and capture of individual animals, while minimizing disturbance to other animals. PMID- 27243156 TI - Ivermectin: A Reflection on Simplicity (Nobel Lecture). AB - Parasitic diseases including river blindness and lymphatic filariasis affect hundreds of millions of people annually. The discovery of the drug ivermectin has provided humankind with a powerful new means to combat these severe diseases. To a very large extent the drug was brought about by "simple" science. PMID- 27243206 TI - A Case of Ventricular Arrhythmia: When the Right Isn't Right. PMID- 27243157 TI - Changing ideas about others' intentions: updating prior expectations tunes activity in the human motor system. AB - Predicting intentions from observing another agent's behaviours is often thought to depend on motor resonance - i.e., the motor system's response to a perceived movement by the activation of its stored motor counterpart, but observers might also rely on prior expectations, especially when actions take place in perceptually uncertain situations. Here we assessed motor resonance during an action prediction task using transcranial magnetic stimulation to probe corticospinal excitability (CSE) and report that experimentally-induced updates in observers' prior expectations modulate CSE when predictions are made under situations of perceptual uncertainty. We show that prior expectations are updated on the basis of both biomechanical and probabilistic prior information and that the magnitude of the CSE modulation observed across participants is explained by the magnitude of change in their prior expectations. These findings provide the first evidence that when observers predict others' intentions, motor resonance mechanisms adapt to changes in their prior expectations. We propose that this adaptive adjustment might reflect a regulatory control mechanism that shares some similarities with that observed during action selection. Such a mechanism could help arbitrate the competition between biomechanical and probabilistic prior information when appropriate for prediction. PMID- 27243208 TI - SignalPlant: an open signal processing software platform. AB - The growing technical standard of acquisition systems allows the acquisition of large records, often reaching gigabytes or more in size as is the case with whole day electroencephalograph (EEG) recordings, for example. Although current 64-bit software for signal processing is able to process (e.g. filter, analyze, etc) such data, visual inspection and labeling will probably suffer from rather long latency during the rendering of large portions of recorded signals. For this reason, we have developed SignalPlant-a stand-alone application for signal inspection, labeling and processing. The main motivation was to supply investigators with a tool allowing fast and interactive work with large multichannel records produced by EEG, electrocardiograph and similar devices. The rendering latency was compared with EEGLAB and proves significantly faster when displaying an image from a large number of samples (e.g. 163-times faster for 75 * 10(6) samples). The presented SignalPlant software is available free and does not depend on any other computation software. Furthermore, it can be extended with plugins by third parties ensuring its adaptability to future research tasks and new data formats. PMID- 27243207 TI - Genome-culture coevolution promotes rapid divergence of killer whale ecotypes. AB - Analysing population genomic data from killer whale ecotypes, which we estimate have globally radiated within less than 250,000 years, we show that genetic structuring including the segregation of potentially functional alleles is associated with socially inherited ecological niche. Reconstruction of ancestral demographic history revealed bottlenecks during founder events, likely promoting ecological divergence and genetic drift resulting in a wide range of genome-wide differentiation between pairs of allopatric and sympatric ecotypes. Functional enrichment analyses provided evidence for regional genomic divergence associated with habitat, dietary preferences and post-zygotic reproductive isolation. Our findings are consistent with expansion of small founder groups into novel niches by an initial plastic behavioural response, perpetuated by social learning imposing an altered natural selection regime. The study constitutes an important step towards an understanding of the complex interaction between demographic history, culture, ecological adaptation and evolution at the genomic level. PMID- 27243209 TI - Evaluation of sensitivity of TaqMan RT-PCR for rubella virus detection in clinical specimens. AB - BACKGROUND: An easy and reliable assay for detection of the rubella virus is required to strengthen rubella surveillance. Although a TaqMan RT-PCR assay for detection of the rubella virus has been established in Japan, its utility for diagnostic purposes has not been tested. OBJECTIVES: To allow introduction of the TaqMan RT-PCR into the rubella surveillance system in Japan, the sensitivity of the assay was determined using representative strains for all genotypes and clinical specimens. STUDY DESIGN: The detection limits of the method for individual genotypes were examined using viral RNA extracted from 13 representative strains. The assay was also tested at 10 prefectural laboratories in Japan, designated as local reference laboratories for measles and rubella, to allow nationwide application of the assay. RESULTS: The detection limits and amplification efficiencies of the assay were similar among all the representative strains of the 13 genotypes. The TaqMan RT-PCR could detect approximately 90% of throat swab and urine samples taken up to 5days of illness. These samples were determined positive by a highly sensitive nested RT-PCR. CONCLUSIONS: The TaqMan RT-PCR could detect at least 10 pfu of rubella virus. Although the sensitivity was somewhat lower than that of the conventional nested RT-PCR, the TaqMan RT-PCR could be more practical to routine tests for rubella laboratory diagnosis and detection in view of the rapid response and reducing risks of contamination. PMID- 27243210 TI - Hepatitis E virus infection in the HIV-positive patient. AB - Hepatitis E virus (HEV) is a RNA virus that can cause hepatitis. In immunocompetent individuals, infection with HEV usually leads to asymptomatic seroconversion. However, in immunosuppressed patients, such as transplant recipients, HEV can develop into a chronic infection. Studies regarding the seroprevalence and clinical implications of HEV in patients infected with the human immunodeficiency virus (HIV) are conflicting. Levels of CD4 count in blood seem to be the most widely associated risk factor, while other factors such as meat consumption or proximity to animals are less clearly associated with HEV infection. Progression to chronicity, as well as extrahepatic manifestations of HEV seem rare in HIV, and the implications of HEV in liver disease progression are poorly understood in the HIV-infected. In this review we describe the epidemiology, risk factors, and clinical implications of HEV infection in individuals infected with HIV. PMID- 27243211 TI - Ductal carcinoma in situ: How much is too much? PMID- 27243213 TI - Complementary and Alternative Medicine Use Among Patients With Cancer: A Challenge in the Oncologist-Patient Relationship. PMID- 27243212 TI - The regulation of TIM-3 transcription in T cells involves c-Jun binding but not CpG methylation at the TIM-3 promoter. AB - Tim-3 is an immunomodulatory protein that is expressed constitutively on monocytes but is induced in activated T cells. The mechanisms involved in the regulation of TIM-3 transcription are poorly understood. In the present study, we investigated whether methylation of the TIM-3 promoter is involved in regulatingTIM-3 transcription in T cells, and identified a transcription factor that regulates TIM-3 transcription by associating with the TIM-3 minimal promoter region. Pyrosequencing of the TIM-3 promoter up to -1440bp revealed 11 hypermethylated CpG sites and 4 hypomethylated CpG sites in human CD4(+) T cells as well as in CD11b(+) cells. Dimethylation of histone H3 lysine 4 (H3K4), a mark of transcriptional activation, was predominantly found in the proximal TIM-3 promoter -954 to -34bp region, whereas trimethylation of H3K9 and H3K27, which are markers of transcriptional suppression, were mostly observed in the distal promoter -1549 to -1048bp region in human CD4(+) T cells and CD11b(+) cells. However, no change in the methylation status of CpG sites and the histone H3 in the TIM-3 promoter was found during induction of TIM-3 transcription in T cells. Finally, AP-1 involvement in TIM-3 transcription was shown in relation with the TIM-3 minimal promoter -146 to +144bp region. The present study defines the minimal TIM-3 promoter region and demonstrates its interaction with c-Jun during TIM-3 transcription in CD4(+) T cells. PMID- 27243214 TI - Normal stress-only myocardial single photon emission computed tomography predicts good outcome in patients with coronary artery stenoses between 40 and 70. AB - OBJECTIVE: Normal stress myocardial single photon emission computed tomography (SPECT) usually indicates good physiologic function of all coronary lesions, and also indicates a good outcome. We hypothesize that it can still predict good outcome in patients with coronary stenoses between 40 and 70%. METHODS: A group of patients who underwent stress myocardial SPECT after coronary angiography were consecutively recruited in our center. Patients were eligible if they had one or more coronary stenoses between 40 and 70%. Patients with coronary stenoses greater than 50% diameter of left main or greater than 70% diameter of nonleft main epicardial vessels, and left ventricular ejection fraction less than 50% were excluded. The outcome was defined as major adverse events, including cardiac death, nonfatal myocardial infarction, and revascularization. Patients' survival curves were constructed accorded to the method of Kaplan and Meier and compared using the log-rank test. RESULTS: A study cohort of 77 patients was enrolled. According to the summed stress score, 43 patients were assigned to the perfusion defect group and 34 patients were assigned to the perfusion normal group. The follow-up duration was 6.4+/-0.3 years. In the perfusion normal group, only one of 34 (2.9%) patients developed major adverse events. In the perfusion defect group, six of 43 (14%) developed major adverse events, P-value of 0.041. CONCLUSION: It is safe to defer a percutaneous coronary intervention in patients with coronary stenoses between 40 and 70% and normal stress myocardial SPECT. PMID- 27243215 TI - Performance of 177Lu-DOTATATE-based peptide receptor radionuclide therapy in metastatic gastroenteropancreatic neuroendocrine tumor: a multiparametric response evaluation correlating with primary tumor site, tumor proliferation index, and dual tracer imaging characteristics. AB - OBJECTIVES: To assess the performance of Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in metastatic gastroenteropancreatic neuroendocrine tumor (GEP-NET) and correlate it with primary tumor site, tumor proliferation index, and dual tracer imaging characteristics. MATERIALS AND METHODS: Fifty patients (M : F 33 : 17, age: 26-71 years) with histopathologically confirmed metastatic/inoperable NETs who had undergone at least three cycles of PRRT with Lu-DOTATATE were included in the analysis. As part of the pretreatment evaluation, they underwent either Tc-HYNIC TOC (n=40)/Ga-DOTATATE PET (n=10) or fluorine-18-fluorodeoxyglucose (F-FDG) PET-computed tomography (CT). Response was assessed after three and five cycles PRRT on the basis of three parameters: (a) symptomatic and subjective scale, (b) biochemical tumor marker level, and (c) objective imaging (F-FDG/Ga DOTATATE PET/CT, Tc-HYNIC TOC, ceCT), and was categorized using predefined criteria (detailed in methods). Stable disease on imaging assessment with response on symptomatic or biochemical tumor marker scales or both were included in the responder group. RESULTS: The study population was broadly classified into (a) metastatic GEP-NET with known primary (n=43 i.e. 86%), which was further subclassified according to the site of primary and (b) those with unknown primary (n=7 i.e. 14%). Symptomatic response: 96% of patients showed a symptomatic response or improvement in health-related quality of life, irrespective of tumor proliferation index, dual tracer imaging characteristics, and response or progression of disease in the scan. Biochemical tumor marker response: 83% of scan responders showed a decrease, 10% showed a stable value, and 7% showed an increase in tumor marker levels. Among the scan nonresponders, 67% patients showed a corresponding increase in the tumor marker level, 22% patient showed a decrease, whereas 11% showed stable values. Scan response: 31 out of total 50 patients (62%) showed a partial scan response with either a decrease in the number of somatostatin receptor (SSTR)-positive lesions or metabolic activity in F-FDG/Ga-DOTATATE PET-CT or both, 10 patients (20%) showed stable disease, and nine patients (18%) showed progressive disease. The higher objective partial scan response documented can be explained by the introduction of the F-FDG-PET/CT parameter as a determinant criterion. Among the responders category (n=41), 32 (78.04%) showed discordance between F-FDG-PET/CT based and SSTR-based imaging, whereas eight out of nine patients with nonresponse category (88.89%) showed concordance between SSTR-based imaging and F-FDG-PET/CT. Conversely, 32 of 33 patients (96.97%) with SSTR/F-FDG discordance and nine out of 17 (52.94%) with concordance were finally classified as responders, whereas the remaining, that is, 1/33 (3.03%) in the 'discordant' category and 8/17 (47.06%) with imaging concordance were classified as nonresponders, respectively. CONCLUSION: Our data show that high pretherapy F-FDG maximum standardized uptake values were associated with increased chances of treatment refractoriness in GEP NETs. However, symptomatic improvement was observed in most cases irrespective of grade and F-FDG uptake. High pretherapy F-FDG maximum standardized uptake value in both low-grade and high-grade NET predicted a poor outcome and was associated with disease progression. Introduction of F-FDG-PET/CT parameter as a determinant of response classification increases the percentage of objective scan responders among patients with grades I and II GEP-NETs as F-FDG activity was observed to decrease before SSTR-based imaging and more frequently compared with the latter. PMID- 27243216 TI - LPS/TLR4 Signaling Enhances TGF-beta Response Through Downregulating BAMBI During Prostatic Hyperplasia. AB - Compelling evidence suggests that benign prostatic hyperplasia (BPH) development involves accumulation of mesenchymal-like cells derived from the prostatic epithelium by epithelial-mesenchymal transition (EMT). Transforming growth factor (TGF)-beta induces EMT phenotypes with low E-cadherin and high vimentin expression in prostatic epithelial cells. Here we report that LPS/TLR4 signalling induces down-regulation of the bone morphogenic protein and activin membrane bound inhibitor (BAMBI), which enhances TGF-beta signalling in the EMT process during prostatic hyperplasia. Additionally, we found that the mean TLR4 staining score was significantly higher in BPH tissues with inflammation compared with BPH tissues without inflammation (5.13 +/- 1.21 and 2.96 +/- 0.73, respectively; P < 0.001). Moreover, patients with inflammatory infiltrate were more likely to have a higher age (P = 0.020), BMI (P = 0.026), prostate volume (P = 0.024), total IPSS score (P = 0.009) and IPSS-S (P < 0.001). Pearson's correlation coefficient and multiple regression analyses demonstrated that TLR4 mRNA expression level was significantly positively associated with age, BMI, serum PSA levels, urgency and nocturia subscores of IPSS in the inflammatory group. These findings provide new insights into the TLR4-amplified EMT process and the association between TLR4 levels and storage LUTS, suggesting chronic inflammation as vital to the pathogenesis of BPH. PMID- 27243217 TI - A Phytophthora sojae effector PsCRN63 forms homo-/hetero-dimers to suppress plant immunity via an inverted association manner. AB - Oomycete pathogens produce a large number of effectors to promote infection. Their mode of action are largely unknown. Here we show that a Phytophthora sojae effector, PsCRN63, suppresses flg22-induced expression of FRK1 gene, a molecular marker in pathogen-associated molecular patterns (PAMP)-triggered immunity (PTI). However, PsCRN63 does not suppress upstream signaling events including flg22 induced MAPK activation and BIK1 phosphorylation, indicating that it acts downstream of MAPK cascades. The PsCRN63-transgenic Arabidopsis plants showed increased susceptibility to bacterial pathogen Pseudomonas syringae pathovar tomato (Pst) DC3000 and oomycete pathogen Phytophthora capsici. The callose deposition were suppressed in PsCRN63-transgenic plants compared with the wild type control plants. Genes involved in PTI were also down-regulated in PsCRN63 transgenic plants. Interestingly, we found that PsCRN63 forms an dimer that is mediated by inter-molecular interactions between N-terminal and C-terminal domains in an inverted association manner. Furthermore, the N-terminal and C terminal domains required for the dimerization are widely conserved among CRN effectors, suggesting that homo-/hetero-dimerization of Phytophthora CRN effectors is required to exert biological functions. Indeed, the dimerization was required for PTI suppression and cell death-induction activities of PsCRN63. PMID- 27243219 TI - Prenatal Antidepressant Use and Risk of Autism Spectrum Disorders in Children. PMID- 27243218 TI - Immunometabolic Status during the Peripartum Period Is Enhanced with Supplemental Zn, Mn, and Cu from Amino Acid Complexes and Co from Co Glucoheptonate. AB - The peripartum (or transition) period is the most-critical phase in the productive life of lactating dairy cows and optimal supply of trace minerals through more bioavailable forms could minimize the negative effects associated with this phase. Twenty Holstein cows received a common prepartal diet and postpartal diet. Both diets were partially supplemented with an inorganic (INO) mix of Zn, Mn, and Cu to supply 35, 45, and 6 ppm, respectively, of the diet dry matter (DM). Cows were assigned to treatments in a randomized completed block design, receiving an daily oral bolus with INO or organic trace minerals (AAC) Zn, Mn, Cu, and Co to achieve 75, 65, 11, and 1 ppm supplemental, respectively, in the diet DM. Liver tissue and blood samples were collected throughout the experiment. The lower glutamic-oxaloacetic transaminase concentration after 15 days in milk in AAC cows indicate lower hepatic cell damage. The concentration of cholesterol and albumin increased, while IL-6 decreased over time in AAC cows compared with INO indicating a lower degree of inflammation and better liver function. Although the acute-phase protein ceruloplasmin tended to be lower in AAC cows and corresponded with the reduction in the inflammatory status, the tendency for greater serum amyloid A concentration in AAC indicated an inconsistent response on acute-phase proteins. Oxygen radical absorbance capacity increased over time in AAC cows. Furthermore, the concentrations of nitric oxide, nitrite, nitrate, and the ferric reducing ability of plasma decreased with AAC indicating a lower oxidative stress status. The expression of IL10 and ALB in liver tissue was greater overall in AAC cows reinforcing the anti-inflammatory response detected in plasma. The greater overall expression of PCK1 in AAC cows indicated a greater gluconeogenic capacity, and partly explained the greater milk production response over time. Overall, feeding organic trace minerals as complexed with amino acids during the transition period improved liver function and decreased inflammation and oxidative stress. PMID- 27243221 TI - Computational Fluid Dynamics Analysis of the Fossil Crinoid Encrinus liliiformis (Echinodermata: Crinoidea). AB - Crinoids, members of the phylum Echinodermata, are passive suspension feeders and catch plankton without producing an active feeding current. Today, the stalked forms are known only from deep water habitats, where flow conditions are rather constant and feeding velocities relatively low. For feeding, they form a characteristic parabolic filtration fan with their arms recurved backwards into the current. The fossil record, in contrast, provides a large number of stalked crinoids that lived in shallow water settings, with more rapidly changing flow velocities and directions compared to the deep sea habitat of extant crinoids. In addition, some of the fossil representatives were possibly not as flexible as today's crinoids and for those forms alternative feeding positions were assumed. One of these fossil crinoids is Encrinus liliiformis, which lived during the middle Triassic Muschelkalk in Central Europe. The presented project investigates different feeding postures using Computational Fluid Dynamics to analyze flow patterns forming around the crown of E. liliiformis, including experimental validation by Particle Image Velocimetry. The study comprises the analysis of different flow directions, velocities, as well as crown orientations. Results show that inflow from lateral and oral leads to direct transport of plankton particles into the crown and onto the oral surface. With current coming from the "rear" (aboral) side of the crinoid, the conical opening of the crown produces a backward oriented flow in its wake that transports particles into the crown. The results suggest that a conical feeding position may have been less dependent on stable flow conditions compared to the parabolic filtration fan. It is thus assumed that the conical feeding posture of E. liliiformis was suitable for feeding under dynamically changing flow conditions typical for the shallow marine setting of the Upper Muschelkalk. PMID- 27243222 TI - Do Farmers Using Conventional and Non-Conventional Systems of Agriculture Have Different Perceptions of the Diversity of Wild Birds? Implications for Conservation. AB - Farmers' perceptions of birds' interactions with agricultural production systems are fundamental to species conservation efforts. In the present study, we evaluated the perceptions of birds held by farmers who engage in conventional and non-conventional agricultural production processes and the implications of potential differences in these perceptions on species conservation. To accomplish this, data were collected using questionnaires, semi-structured interviews, and other complementary sources of information gathered from 191 farmers in northeastern Brazil. Although some similarities were identified among the farmers in their perceptions and local ecological knowledge (LEK) of birds, differences existed between the conventional and non-conventional farmers in their attitudes toward, conflicts with, and usage of bird species. Compared to the conventional farmers, the non-conventional farmers could identify more bird species, possessed more favorable attitudes toward birds, and engaged in practices more beneficial to the conservation of avifauna. The perceptions that were identified were related to the type of agriculture practiced, and such perceptions may affect the conservation of bird species. Therefore, the adoption of certain agricultural practices has important implications for conservation. Our results indicate the need for investment in public policies, programs and actions that account for farmers' knowledge and perceptions. Such investments will contribute to the development and adoption of practices supporting wild bird conservation in agricultural areas. PMID- 27243223 TI - Use of an Improved Matching Algorithm to Select Scaffolds for Enzyme Design Based on a Complex Active Site Model. AB - Active site preorganization helps native enzymes electrostatically stabilize the transition state better than the ground state for their primary substrates and achieve significant rate enhancement. In this report, we hypothesize that a complex active site model for active site preorganization modeling should help to create preorganized active site design and afford higher starting activities towards target reactions. Our matching algorithm ProdaMatch was improved by invoking effective pruning strategies and the native active sites for ten scaffolds in a benchmark test set were reproduced. The root-mean squared deviations between the matched transition states and those in the crystal structures were < 1.0 A for the ten scaffolds, and the repacking calculation results showed that 91% of the hydrogen bonds within the active sites are recovered, indicating that the active sites can be preorganized based on the predicted positions of transition states. The application of the complex active site model for de novo enzyme design was evaluated by scaffold selection using a classic catalytic triad motif for the hydrolysis of p-nitrophenyl acetate. Eighty scaffolds were identified from a scaffold library with 1,491 proteins and four scaffolds were native esterase. Furthermore, enzyme design for complicated substrates was investigated for the hydrolysis of cephalexin using scaffold selection based on two different catalytic motifs. Only three scaffolds were identified from the scaffold library by virtue of the classic catalytic triad based motif. In contrast, 40 scaffolds were identified using a more flexible, but still preorganized catalytic motif, where one scaffold corresponded to the alpha amino acid ester hydrolase that catalyzes the hydrolysis and synthesis of cephalexin. Thus, the complex active site modeling approach for de novo enzyme design with the aid of the improved ProdaMatch program is a promising approach for the creation of active sites with high catalytic efficiencies towards target reactions. PMID- 27243229 TI - Disease-specific impairment of the quality of life in adult patients with chronic spontaneous urticaria. AB - BACKGROUND/AIMS: Chronic urticaria (CU) is a common skin disorder characterized by wheals and pruritus lasting more than 6 weeks. Due to its long duration and changeable symptoms, the quality of life (QOL) of patients with CU can be impaired substantially. We evaluated the CU-QOL, a previously validated CU specific QOL measure, and investigated factors influencing QOL in chronic spontaneous urticaria (CSU) patients. METHODS: A hospital-based cross-sectional study was performed on 390 adult patients diagnosed with CSU from March 2009 to December 2012 at the Allergy and Clinical Immunology Clinic at Ajou University Hospital. The CU-QOL questionnaire, urticaria activity score (UAS), combined angioedema, and serum total immunoglobulin E (IgE) levels were investigated. RESULTS: The average CU-QOL score obtained from the questionnaire was 70.6 (of 100 points). The CU-QOL scores correlated significantly with the UAS, particularly with the 15-point UAS (UAS-15; coefficient -0.532, p < 0.01) rather than the 6-point UAS (-0.502, p < 0.01). The patients presenting with angioedema and urticaria had poorer scores in the urticaria symptom domain than those with urticaria alone (37.4 vs. 46.9, p = 0.004). Log-transformed serum total IgE levels correlated significantly with CU-QOL (-0.131, p < 0.05). Multivariate regression models indicated that severe CU (UAS-15 score >= 13), log (total IgE), and the presence of angioedema were significant predictors of impaired CU-QOL (< 85 points). CONCLUSIONS: CU has a substantial negative impact on QOL. The assessment of UAS-15, total IgE, and the presence of angioedema can be useful to predict QOL of the patients with CSU. PMID- 27243230 TI - Clinical efficacy of serum lipase subtype analysis for the differential diagnosis of pancreatic and non-pancreatic lipase elevation. AB - BACKGROUND/AIMS: Non-pancreatic elevations of serum lipase have been reported, and differential diagnosis is necessary for clinical practice. This study aimed to evaluate the clinical efficacy of serum lipase subtype analysis for the differential diagnosis of pancreatic and non-pancreatic lipase elevation. METHODS: Patients who were referred for the serum lipase elevation were prospectively enrolled. Clinical findings and serum lipase subtypes were analyzed and compared by dividing the patients into pancreatitis and non-pancreatitis groups. RESULTS: A total of 34 patients (12 pancreatitis vs. 22 non-pancreatitis cases) were enrolled. In univariate analysis, the fraction of pancreatic lipase (FPL) in the total amount of serum lipase subtypes was statistically higher in patients with pancreatitis ([median, 0.004; interquartile range [IQR], 0.003 to 0.011] vs. [median, 0.002; IQR, 0.001 to 0.004], p = 0.04). Based on receiver operating characteristic curve analysis for the prediction of acute pancreatitis, FPL was the most valuable predictor (area under the receiver-operating characteristic curve [AUROC], 0.72; 95% confidence interval [CI], 0.54 to 0.86; sensitivity, 83.3%; specificity, 63.6%; positive predictive value, 55.6%; negative predictive value, 97.5%). In multivariate analysis, a cut-off value higher than 0.0027 for the FPL was associated with acute pancreatitis (odds ratio, 8.3; 95% CI, 1.3 to 51.7; p = 0.02). CONCLUSIONS: The results did not support that serum lipase subtype analysis could replace standard lipase measurement for the diagnosis of acute pancreatitis. However, the test demonstrated adequate sensitivity for use in triage or as an add-on test for serum lipase elevation. PMID- 27243232 TI - Nondisclosure of Financial Interest in Clinical Practice Guideline Development: An Intractable Problem? AB - In a Perspective linked to Stelfox and colleagues, Hilda Bastian discusses the challenges of improving transparency and management of financial conflicts of interest among committees that develop guidelines for medical practice. PMID- 27243231 TI - Antioxidant Activities of 4-Methylumbelliferone Derivatives. AB - The synthesis of derivatives of 4-Methylumbelliferone (4-MUs), which are structurally interesting antioxidants, was performed in this study. The modification of 4-Methylumbelliferone (4-MU) by different reaction steps was performed to yield the target compounds, the 4-MUs. The 4-MUs were characterized by different spectroscopic techniques (Fourier transform infrared; FT-IR and Nuclear magnetic resonance; NMR) and micro-elemental analysis (CHNS). The in vitro antioxidant activity of the 4-MUs was evaluated in terms of their free radical scavenging activities against 2,2-diphenyl-1-picrylhydrazyl (DPPH), Nitric oxide radical scavenging activity assay, chelating activity and their (FRAP) ferric-reducing antioxidant power, which were compared with a standard antioxidant. Our results reveal that the 4-MUs exhibit excellent radical scavenging activities. The antioxidant mechanisms of the 4-MUs were also studied. Density Function Theory (DFT)-based quantum chemical studies were performed with the basis set at 3-21G. Molecular models of the synthesized compounds were studied to understand the antioxidant activity. The electron levels, namely HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital), for these synthesized antioxidants were also studied. PMID- 27243233 TI - Granulomatous-lymphocytic interstitial lung disease as the first manifestation of common variable immunodeficiency. AB - Common variable immunodeficiency (CVID) is one of the most common primary immunodeficiencies, which is characterized by reduced serum immunoglobulin levels and B-lymphocyte dysfunction. There are many clinical manifestations of this disease, the most common of which are recurrent respiratory tract infections. Among the most recently recognized autoimmune manifestation of CVID is a disease described as granulomatous-lymphocytic interstitial lung disease (GLILD), where CVID coexists with a small airway lymphoproliferative disorder, mimicking follicular bronchiolitis, or lymphocytic interstitial pneumonitis (LIP) on histology specimens. We herein describe the clinical and radiological features of GLILD in a 55-year-old woman where the diagnosis of CVID was actively pursued and eventually confirmed after her lung biopsy showed characteristic features of GLILD. The patient had dramatic response to treatment with IVIG and corticosteroids for 3 months followed by Mycophenolate mofetil for maintenance therapy. PMID- 27243234 TI - The risk of cataract in relation to metal arc welding. AB - OBJECTIVES: There are indications that solar ultraviolet radiation (UVR) increases the risk of cataract, but there is only circumstantial evidence that metal welding, an important occupational source of UVR exposure, is a risk factor. The objective of this study is to unravel if metal welding increases the risk of cataract. METHOD: We compared the risk of being diagnosed with cataract from 1987-2012 in a historic cohort of 4288 male metal arc welders against a reference group comprised of Danish skilled and unskilled male workers with similar age distribution. For the welders' cohort, information on welding was collected from questionnaires and, for both cohorts, information about cataract diagnosis and operation was gathered from Danish national registers. Using Cox regression analysis, the hazard ratio (HR) for cataract diagnosis and/or operation was calculated in the follow-up period adjusted for baseline data regarding age, diabetes, and social group. RESULTS: There were 266 welders and 29 007 referents with a diagnosis and/or operation for cataract. The unadjusted HR for cataract comparing ever-welders with referents was 1.07 [95% confidence interval (95% CI) 0.95-1.21] and the adjusted HR was 1.08 (95% CI 0.95-1.22). Age and diabetes were as expected strong risk factors. CONCLUSION: We found no increased risk of developing cataract among Danish metal welders who worked with arc welding from 1950-1985. This may be attributed to the effectiveness of personal safety equipment. PMID- 27243236 TI - Alterations and correlations of the gut microbiome, metabolism and immunity in patients with primary biliary cirrhosis. AB - We selected 42 early-stage primary biliary cirrhosis (PBC) patients and 30 healthy controls (HC). Metagenomic sequencing of the 16S rRNA gene was used to characterize the fecal microbiome. UPLC-MS/MS assaying of small molecules was used to characterize the metabolomes of the serum, urine and feces. Liquid chip assaying of serum cytokines was used to characterize the immune profiles. The gut of PBC patients were depleted of some potentially beneficial bacteria, such as Acidobacteria, Lachnobacterium sp., Bacteroides eggerthii and Ruminococcus bromii, but were enriched in some bacterial taxa containing opportunistic pathogens, such as gamma-Proteobacteria, Enterobacteriaceae, Neisseriaceae, Spirochaetaceae, Veillonella, Streptococcus, Klebsiella, Actinobacillus pleuropneumoniae, Anaeroglobus geminatus, Enterobacter asburiae, Haemophilus parainfluenzae, Megasphaera micronuciformis and Paraprevotella clara. Several altered gut bacterial taxa exhibited potential interactions with PBC through their associations with altered metabolism, immunity and liver function indicators, such as those of Klebsiella with IL-2A and Neisseriaceae with urinary indoleacrylate. Many gut bacteria, such as some members of Bacteroides, were altered in their associations with the immunity and metabolism of PBC patients, although their relative abundances were unchanged. Consequently, the gut microbiome is altered and may be critical for the onset or development of PBC by interacting with metabolism and immunity. PMID- 27243235 TI - Multi-Compartmentalisation in the MAPK Signalling Pathway Contributes to the Emergence of Oscillatory Behaviour and to Ultrasensitivity. AB - Signal transduction through the Mitogen Activated Protein Kinase (MAPK) pathways is evolutionarily highly conserved. Many cells use these pathways to interpret changes to their environment and respond accordingly. The pathways are central to triggering diverse cellular responses such as survival, apoptosis, differentiation and proliferation. Though the interactions between the different MAPK pathways are complex, nevertheless, they maintain a high level of fidelity and specificity to the original signal. There are numerous theories explaining how fidelity and specificity arise within this complex context; spatio-temporal regulation of the pathways and feedback loops are thought to be very important. This paper presents an agent based computational model addressing multi compartmentalisation and how this influences the dynamics of MAPK cascade activation. The model suggests that multi-compartmentalisation coupled with periodic MAPK kinase (MAPKK) activation may be critical factors for the emergence of oscillation and ultrasensitivity in the system. Finally, the model also establishes a link between the spatial arrangements of the cascade components and temporal activation mechanisms, and how both contribute to fidelity and specificity of MAPK mediated signalling. PMID- 27243237 TI - Feeding Behavior of Subadult Sixgill Sharks (Hexanchus griseus) at a Bait Station. AB - This is the first in-situ study of feeding behaviors exhibited by bluntnose sixgill sharks. Bait was placed beneath the Seattle Aquarium pier situated on the waterfront in Elliott Bay, Puget Sound, Washington at 20m of water depth. Cameras and lights were placed around the bait box to record sixgill shark presence and behavior while feeding. Analysis of feeding behavior revealed that sixgills utilize a bite comparable to many other elasmobranchs and aquatic vertebrates, have the ability to protrude their upper jaw, change their feeding behavior based on the situation, and employ sawing and lateral tearing during manipulation. The versatility of their feeding mechanism and the ability of sixgills to change their capture and food manipulation behaviors may have contributed to the species' worldwide distribution and evolutionary success. PMID- 27243239 TI - Use of direct behavior ratings to collect functional assessment data. AB - The purpose of this investigation was to evaluate the utility of Direct Behavior Rating Single Item Scale (DBR-SIS) methodology in collecting functional behavior assessment data. Specific questions of interest pertained to the evaluation of the accuracy of brief DBR-SIS ratings of behavioral consequences and determination of the type of training necessary to support such accuracy. Undergraduate student participants (N = 213; 62.0% male; 62.4% White) viewed video clips of students in a classroom setting, and then rated both disruptive behavior and 4 consequences of that behavior (i.e., adult attention, peer attention, escape/avoidance, and access to tangibles/activities). Results indicated training with performance feedback was necessary to support the generation of accurate disruptive behavior and consequence ratings. Participants receiving such support outperformed students in training-only, pretest-posttest, and posttest-only groups for disruptive behavior and all 4 DBR-SIS consequence targets. Future directions for research and implications for practice are discussed, including how teacher ratings may be collected along with other forms of assessment (e.g., progress monitoring) within an efficient Tier 2 assessment model. (PsycINFO Database Record PMID- 27243238 TI - Concurrent radiotherapy and intrathecal methotrexate for treating leptomeningeal metastasis from solid tumors with adverse prognostic factors: A prospective and single-arm study. AB - The prognosis of leptomeningeal metastasis (LM) from solid tumors is extremely poor, especially for patients with adverse prognostic factors. In this phase II clinical trial, we evaluated the efficacy and safety of intrathecal chemotherapy (IC) combined with concomitant involved-field radiotherapy (IF-RT) for treating LM from solid tumors with adverse prognostic factors. Fifty-nine patients with LM from various solid tumors were enrolled between May 2010 and December 2014. Concurrent therapy consisted of concomitant IC (methotrexate 12.5-15 mg and dexamethasone 5 mg, weekly) and IF-RT (whole brain and/or spinal canal RT, 40 Gy/20f). For patients with low Karnofsky performance status (KPS) score and radiotherapy intolerance, induction IC (1-3 times) was given before concurrent therapy. Thirty-eight patients (64.4%) received subsequent treatments. All patients were followed up at least 6 months after LM diagnosis or until death. Primary endpoint evaluated was clinical response rate. Secondary endpoints were overall survival (OS) and safety. The pathological types included lung cancer (n = 42), breast cancer (n = 11) and others (n = 6). Median KPS score was 40 (range 20-70). Fifty-one patients (86.4%) completed concurrent therapy. The overall response rate was 86.4% (51/59). OS ranged from 0.4 to 36.7 months (median 6.5 months), and 1-year-survival rate was 21.3%. Treatment-related adverse events mainly included acute meningitis, chronic-delayed encephalopathy, radiculitis, myelosuppression and mucositis. Twelve patients (20.3%) had grade III-V toxic reactions. We concluded that IC combined with concomitant IF-RT, with significant efficacy and acceptable toxicity, may be an optimal therapeutic option for treatment of LM from solid tumors with adverse prognostic factors. LM, in which cancer cells spread to membranes enveloping the brain and spinal cord, is a devastating complication of solid cancers. Existing LM therapies center on IC. In this prospective clinical study, the authors combined intrathecal methotrexate with involved-field radiotherapy in a concomitant regimen, showing that the approach can potentially improve quality of life for patients with adverse prognostic factors. Concurrent radiotherapy-bolstered IC by contributing to prolonged remission of neurological symptoms and increasing OS. The findings suggest that the concomitant regimen could be an optimal treatment option for LM. PMID- 27243240 TI - Understanding immigrants, schooling, and school psychology: Contemporary science and practice. AB - Immigration into the United States is a particularly salient topic of current contemporary educational, social, and political discussions. The school-related needs of immigrant children and youth can be well served by rigorous research and effective school psychology preservice training and preparation. This overview highlights key definitions, demographic statistics, and current resources related to immigration in U.S. society. This special topic section on understanding immigrants, schooling, and school psychology features articles relevant to this important topic. We conclude with a call for this effort to serve as a springboard for future discussions, scholarship, and school psychology training in preparing practitioners for serving children who are immigrants. (PsycINFO Database Record PMID- 27243241 TI - Demography and early academic skills of students from immigrant families: The kindergarten class of 2011. AB - Children from immigrant families are one of the fastest growing and most diverse groups in America's schools. This study provides a demographic portrait of immigrant children who entered kindergarten in 2010 and describes patterns and predictors of early educational outcomes of students from immigrant families. A nationally representative sample of 13,530 students who participated in the Early Childhood Longitudinal Study-Kindergarten Class of 2010-11 was analyzed. Descriptive statistics were used to estimate the sociodemographic characteristics of this population. Regression was used to examine the relations between nativity, child characteristics, and family characteristics to reading and mathematics skills in kindergarten. Approximately 27% of kindergartners in the class of 2011 came from immigrant families. These students were more racially, linguistically, and socioeconomically diverse than students from U.S.-born parents. Educational outcomes varied by parents' region of origin. Children's early academic skills were significantly related to parent's region of origin, but these relations were attenuated when child health, language, family structure, and socioeconomic status were accounted for. These results indicate the importance of considering parent nativity when examining the outcomes and needs of students from immigrant families. Because of the diversity of characteristics and outcomes of children of immigrants, researchers should consider the implications of nativity for students' experiences and needs. (PsycINFO Database Record PMID- 27243242 TI - Newcomer immigrant adolescents: A mixed-methods examination of family stressors and school outcomes. AB - Family stressors predict negative psychological outcomes for immigrant adolescents, yet little is known about how such stressors interact to predict school outcomes. The purpose of this study was to explore the interactive role of family stressors on school outcomes for newcomer adolescent immigrants. Using a convergent parallel mixed-methods design, we used quantitative methods to explore interactions between family separation, acculturative family conflict, and family life events to predict 2 school outcomes, academic achievement (via grade point average [GPA]), and externalizing problems (student- and teacher-reported). The sample included 189 newcomer immigrant public high school students from 34 countries of origin. Quantitative measures included the Multicultural Events Scale for Adolescents, Family Conflicts Scale, and the Achenbach System of Empirically Based Assessment (ASEBA). Qualitative data were collected through a semi-structured interview. Quantitative results found that more family life events were associated with lower GPA, but this association was weaker for participants who had been separated from their parents. More family conflict was associated with more externalizing symptoms (both youth- and teacher-reported). However, the association between family conflict and teacher-reported externalizing symptoms was found only among participants reporting a greater than average number of life events. Qualitative results show that separation from extended family networks was among the most stressful of experiences, and demonstrate the highly complex nature of each family stressor domain. At a time when immigration is rapidly changing our school system, a better understanding of early risk factors for new immigrants can help teachers, administrators, and mental health practitioners to identify students with greatest need to foster behavioral, academic, and emotional well-being. (PsycINFO Database Record PMID- 27243243 TI - Association of acculturative stress, Islamic practices, and internalizing symptoms among Arab American adolescents. AB - Although the numbers of Arab American immigrant youth in schools is increasing, there is little understanding of their mental health and the sociocultural factors that might influence it. This study examined the relationship between 2 sociocultural factors (i.e., acculturative stress and religious practices) and internalizing symptoms in first- and second-generation Muslim Arab American adolescents. Adolescents (n = 88) ages 11 to 18 completed measures related to acculturative stress, religious practices, internalizing symptoms, and general demographic information. Results of multiple regression analyses found that acculturative stress significantly predicted internalizing symptoms. Gender was found to moderate this association. No differences in the reported acculturative stress and internalizing symptoms were found between youth of different generational status (i.e., first- vs. second-generation). Finally, adolescents' organizational religious practices, but not their private religious practices, were found to be associated with lower acculturative stress. Implications are discussed related to how school psychologists can provide culturally responsive services to this population. (PsycINFO Database Record PMID- 27243244 TI - Factor structure and differential item functioning of the BASC-2 BESS Spanish Language Parent Form. AB - Given the steady increase of students from diverse backgrounds in the U.S. educational system, in particular immigrant and Latino students, it is important to consider how to best support all students within our schools. The present study focuses on the Behavior Assessment System for Children-Second Edition (BASC 2) Behavioral and Emotional Screening System (BESS) Parent Spanish form, which is a promising assessment tool for those who are interested in screening for behavioral and emotional risk among Spanish-speaking populations. The present study included 725 students of Latino descent in Grades K-6 in an urban school district and their parents or legal guardians, who served as the informants. All parents completed the BESS language form (English or Spanish) of their choice. A confirmatory factor analysis (CFA) supported a 4-factor structure (Externalizing, Internalizing, Inattention, and Adaptive Skills) similar to that of the BESS Parent English form: chi2(77) = 248.06, p < .001; CFI = 0.903; TLI = 0.940. However, differential item functioning (DIF) analyses revealed 5 items (16.7%) demonstrated significant levels of DIF, with 4 of the 5 being easier to endorse in English. This study provides preliminary evidence of partial invariance of the BESS Parent across language forms. Although some evidence of invariance across language forms at the structural and item levels exists, more research is necessary to determine whether the DIF found in the present study results in any perceptible test bias. (PsycINFO Database Record PMID- 27243245 TI - Discouraging partnerships? Teachers' perspectives on immigration-related barriers to family-school collaboration. AB - This study investigates barriers to facilitating family-school partnerships with immigrant families as identified by teachers in an urban school district with high rates of immigration. Participants consisted of 18 elementary teachers who identified predominantly as Hispanic (38.9%) or non-Hispanic White (33.3%), were frequently bilingual (55.6%), and were mostly female (94.4%) with an average age of 36.5 years. Participants engaged in focus group interviews that were transcribed and open-coded. Barriers to engagement for immigrant families fell into 3 broad areas: language and culture, family resources, and families' undocumented status. Many teachers attributed the barriers preventing parental collaboration to school policies (94.4%) and ineffective communication strategies (83.3%). Teachers also identified barriers as emanating from the families themselves, including families not attending school functions (88.9%) and being unresponsive to school-initiated communication (72.2%). Teachers noted that many families lacked resources necessary for school engagement (88.9%) and were hesitant to become engaged with schools due to required screening procedures (55.6%). Overall, numerous barriers to effective family engagement were identified, several of which are directly related to immigration and residency status. Given the strong evidence suggesting that family engagement in education mediates risk for children of recent immigrants, strategies to foster meaningful engagement for all families are desperately needed (Naughton, 2004). Roles for school psychologists to facilitate effective family-school partnerships are discussed. (PsycINFO Database Record PMID- 27243246 TI - Investigation of social cognitive career theory for minority recruitment in school psychology. AB - School psychology trainers have historically struggled to adequately increase the number of professionals from diverse backgrounds. An increase in diverse providers is important in meeting the needs of a burgeoning racial/ethnic minority student population. Previous research suggests that minority undergraduate psychology students have less knowledge and exposure to school psychology than for counseling and clinical psychology, and that students with greater exposure or knowledge of school psychology reported significantly greater choice intentions for school psychology. The purpose of this study is to test the applicability of the Social Cognitive Career Theory (SCCT; Lent, Brown, & Hackett, 1994) in explaining minority undergraduate psychology students' choice intentions for school psychology. This study is an analysis of existing data and is based on a national sample of 283 minority undergraduate psychology students. All instruments used in this study were found to have internal consistency ranging from .83 to .91. Students' learning experiences, self-efficacy, outcome expectations, and choice intentions for school psychology were evaluated by way of a mediator analysis. Results from a path analysis suggest that outcome expectations mediated the relationship between exposure and choice intentions for school psychology. Implications for minority recruitment practices are discussed. (PsycINFO Database Record PMID- 27243266 TI - Functionalized Surfaces with Tailored Wettability Determine Influenza A Infectivity. AB - Surfaces contaminated with pathogenic microorganisms contribute to their transmission and spreading. The development of "active surfaces" that can reduce or eliminate this contamination necessitates a detailed understanding of the molecular mechanisms of interactions between the surfaces and the microorganisms. Few studies have shown that, among the different surface characteristics, the wetting properties play an important role in reducing virus infectivity. Here, we systematically tailored the wetting characteristics of flat and nanostructured glass surfaces by functionalizing them with alkyl- and fluoro-silanes. We studied the effects of these functionalized surfaces on the infectivity of Influenza A viruses using a number of experimental and computational methods including real time fluorescence microscopy and molecular dynamics simulations. Overall, we show that surfaces that are simultaneously hydrophobic and oleophilic are more efficient in deactivating enveloped viruses. Our results suggest that the deactivation mechanism likely involves disruption of the viral membrane upon its contact with the alkyl chains. Moreover, enhancing these specific wetting characteristics by surface nanostructuring led to an increased deactivation of viruses. These combined features make these substrates highly promising for applications in hospitals and similar infrastructures where antiviral surfaces can be crucial. PMID- 27243267 TI - Blood-Brain Barrier Leakage in Patients with Early Alzheimer Disease. AB - Purpose To investigate whether the blood-brain barrier (BBB) leaks blood circulating substances in patients with early forms of Alzheimer disease (AD), and if so, to examine the extent and pattern of leakage. Materials and Methods This study was approved by the local medical ethical committees of the Maastricht University Medical Center and Leiden University Medical Center, and written informed consent was obtained from all subjects. For this pilot study, 16 patients with early AD and 17 healthy age-matched control subjects underwent dynamic contrast material-enhanced magnetic resonance (MR) imaging sequence with dual time resolution for 25 minutes. The Patlak graphical approach was used to quantify the BBB leakage rate and local blood plasma volume. Subsequent histogram analysis was used to determine the volume fraction of the leaking brain tissue. Differences were assessed with linear regression analysis, adjusted for confounding variables. Results The BBB leakage rate was significantly higher in patients compared with that in control subjects in the total gray matter (P < .05) and cortex (P = .03). Patients had a significantly higher volume fraction of the leaking brain tissue in the gray matter (P = .004), normal-appearing white matter (P < .04), deep gray matter (P = .01), and cortex (P = .004). When all subjects were considered, scores on the Mini-Mental State Examination decreased significantly with increasing leakage in the deep gray matter (P = .007) and cortex (P < .05). Conclusion The results of this study showed global BBB leakage in patients with early AD that is associated with cognitive decline. A compromised BBB may be part of a cascade of pathologic events that eventually lead to cognitive decline and dementia. (c)RSNA, 2016 Online supplemental material is available for this article. PMID- 27243268 TI - Encapsulation of Zwitterionic Au Nanocrystals into Liposomes by Reverse Phase Evaporation Method: Influence of the Surface Charge. AB - Since both liposomes and nanoparticles have shown great potential in application for clinical diagnostics and therapeutics, the perfect combination of the two materials is appealing for further improving the theranostic effect. Therefore, fabrication of liposomes loaded with nanoparticles in a controllable manner is desirable. Detection of various factors affecting encapsulation needs to be assigned. Here, we use zwitterionic Au nanoparticles (Au+/-NPs) coated with a mixture of 11-mercaptoundecanoic acid and N,N,N-trimethyl(11-mercaptoundecyl) ammonium chloride to study their encapsulation behavior by reversed phase evaporation (REV) method. To produce a reverse emulsion, an organic solution of dipalmitoylphosphatidylcholine (DPPC) and 1,2-dioleoyl-sn-glycero-3 phosphoethanolamine-N-[methoxy(poly(ethylene glycol))-2000] (ammonium salt) (PEG2000-DOPE) is mixed with an aqueous Au+/-NP colloidal solution under sonication. The pH of the colloidal solution controls the surface charge of the Au+/-NPs and then tunes the interactions between Au+/-NPs and phospholipids. At lower pH, the positive surface charges favor Au+/-NP transfer into the organic phase and consequently prevent their encapsulation into liposomes. The efficiency in encapsulation is markedly improved by increasing the pH of the Au+/-NP colloidal solution. The highest efficiency is obtained at a pH value slightly larger than the isoelectric point. Further pH increase induces a decrease in encapsulation efficiency. This is due to increase of the repulsive forces between Au+/-NPs and phospholipids indicating that both the nature (positive or negative) and the amount of surface charge are key parameters in the encapsulation efficiency. We also find that the increase in Au+/-NP concentration favors the encapsulation process. PMID- 27243269 TI - Developing standardised treatment for adults with myositis and different phenotypes: an international survey of current prescribing preferences. AB - OBJECTIVES: The evidence base for treatment of the idiopathic inflammatory myopathies is extremely limited. The rarity and heterogeneity of these diseases has hampered the development of good quality clinical trials and while a range of immunomodulatory treatments are commonly used in clinical practice, as yet there are no clear guidelines directing their use. We aimed to establish current prescribing regimens used to treat adults with myositis internationally. METHODS: An electronic survey based on different clinical scenarios was distributed internationally to clinicians involved in the treatment of patients with myositis. Participants were asked to select their first-line treatment preferences in each situation. A multinomial regression analysis was used to assess the influence of clinical scenario, respondent expertise and country of origin on first-line treatment choice. RESULTS: 107 survey responses were received. 57% of respondents considered themselves an expert in myositis and the majority of respondents were rheumatologists although responses from other specialities were also received. Pharmacological treatment with steroids and additional immunotherapy was the preference in most scenarios. First-line immunosuppressant choice was significantly influenced by the clinical scenario, the expertise of the treating physician and country of practice. Azathioprine, methotrexate and mycophenolate mofetil were the most commonly chosen agents. CONCLUSIONS: In the absence of available evidence, clinical experience and expert consensus often forms the basis of treatment guidelines. These results suggest that an international consensus approach would be possible in myositis and would overcome an urgent, yet unmet need for patients suffering with this difficult disease. PMID- 27243271 TI - New Insights into Mechanism of Molybdenum(VI)-Dioxo Complex Catalyzed Hydrosilylation of Carbonyls: An Alternative Model for Activating Si-H Bond. AB - Recently, a series of oxo/nitrido-Re(V)/Mo(VI)/Ru(VI)/Mn(V) complexes were demonstrated to be efficient catalysts in activating silanes and catalyzing hydrosilylations of unsaturated organic substrates. In the present study, the high-valent molybdenum(VI)-dioxo complex MoO2Cl2 catalyzed hydrosilylations of carbonyls was reinvestigated using density functional theory method. Previous experimental and theoretical investigations suggested a [2 + 2] addition pathway for MoO2Cl2 catalyzed hydrosilylations of ketones. In the present study, we propose an ionic outer-sphere mechanistic pathway to be the most favorable pathway. The key step in the ionic outer-sphere pathway is oxygen atom of C?O bonds nucleophilically attacking the silicon atom in an eta(1)-silane molybdenum adduct. The Si-H bond is then cleaved heterolytically. This process features a novel SN2@Si transition state, which then generates a loosely bound ion pair: anionic molybdenum hydride paired with silylcarbenium ion ([MoO2Cl2H](-) [SiR3(OCR'R")](+)) in solvent. The last step is silylcarbenium ion abstracting the hydride on molybdenum hydride to yield silyl ether. The calculated activation free energy barrier of the rate-determing step was 24.1 kcal/mol for diphenylketone (PhC?OPh) and silane of PhMe2SiH. Furthermore, the ionic outer sphere pathway is calculated to be ~10.0 kcal/mol lower than the previously proposed [2 + 2] addition pathway for a variety of silanes and aldehyde/ketone substrates. This preference arises from stronger electrophilicity of the high valent molybdenum(VI) metal center toward a hydride. Here, we emphasize MoO2Cl2 behaves similar to Lewis acidic trispentafluorophenyl borane B(C6F5)3 in activating Si-H bond. PMID- 27243270 TI - Enzymatic Regulation of Self-Assembling Peptide A9K2 Nanostructures and Hydrogelation with Highly Selective Antibacterial Activities. AB - Hydrogels offer great potential for many biomedical and technological applications. For clinical uses, hydrogels that act as scaffold materials for cell culture, regenerative medicine, and drug delivery are required to have bactericidal properties. The amphiphilic peptide A9K2 was designed to effectively inhibit bacterial growth via a mechanism of membrane permeabilization. The present study demonstrated that addition of fetal bovine serum (FBS) or plasma amine oxidase (PAO) induced a sol-gel transition in A9K2 aqueous solutions. The transformation of A9K2 molecules catalyzed by lysyl oxidase (LO) in FBS or PAO accounted for the hydrogelation. Importantly, the enzymatic A9K2 hydrogel displayed high antibacterial ability against both Gram-negative and Gram-positive bacterial strains while showing extremely low mammalian cell cytotoxicity, thus demonstrating good biocompatibility. Under established coculture conditions, the peptide hydrogel showed excellent selectivity by favoring the adherence and spreading of mammalian cells, while killing pathogenic bacteria, thus avoiding bacterial contamination. These advantages endow the enzymatic A9K2 hydrogel with great potential for biomedical applications. PMID- 27243272 TI - Kekule.js: An Open Source JavaScript Chemoinformatics Toolkit. AB - Kekule.js is an open-source, object-oriented JavaScript toolkit for chemoinformatics. It provides methods for many common tasks in molecular informatics, including chemical data input/output (I/O), two- and three dimensional (2D/3D) rendering of chemical structure, stereo identification, ring perception, structure comparison, and substructure search. Encapsulated widgets to display and edit chemical structures directly in web context are also supplied. Developed with web standards, the toolkit is ideal for building chemoinformatics applications over the Internet. Moreover, it is highly platform independent and can also be used in desktop or mobile environments. Some initial applications, such as plugins for inputting chemical structures on the web and uses in chemistry education, have been developed based on the toolkit. PMID- 27243273 TI - Coeliac disease in the elderly in a tertiary centre. AB - INTRODUCTION AND AIMS: Coeliac disease (CD) was believed to be a childhood disease while it can affect any age. AIM: to evaluate the prevalence of CD in elderly population, recording the main clinical features of this group respect to young patients. METHODS: We retrospectively analysed the prevalence of CD in an elderly population from 1970 to 2015. We divided patients into three age-groups (group A: 18-34 years; group B: 35-64 years; group C: >=65 years) and compared them regarding baseline anthropometric and serological variables, clinical features at diagnosis, diagnostic mode, associated autoimmune diseases, and CD related neoplastic complications. RESULTS: We made 2812 CD diagnoses in adults: 2.5% of them were >=65 years at diagnosis. When comparing the three groups, we found no differences in sex, haemoglobin, serum iron, albumin, and anti-tissue transglutaminase (anti-tTG) (p = NS) while as expected, we found higher values of cholesterol, glycaemia, and triglycerides in older patients (p < 0.0001). Elderly had a higher risk of being diagnosed with malabsorption symptoms compared to younger patients (OR 2.20, 95%CI 1.3-3.74). No difference in the risk of autoimmune CD-related diseases was seen among groups. Furthermore, we observed 16 neoplastic complications, 13 of them happened in the patients diagnosed with CD aged 35-64 years. The number of CD diagnoses increased over time, particularly in elderly. CONCLUSION: CD diagnosis in elderly population is quite uncommon although not rare. Elderly CD patients have a higher risk of being diagnosed with malabsorption symptoms than younger patients but without increased risk of autoimmune and neoplastic complications. PMID- 27243274 TI - Density Functional Study for Homodendrimers and Amphiphilic Dendrimers. AB - The conformation of homodendrimers and amphiphilic dendrimers in various solvents is studied using classical density functional theory (DFT), in which the excluded volume effects are treated explicitly. For homodendrimers in an athermal solvent, DFT results predict a remarkable fold-back behavior for the outer generation of segments, supporting the dense-core model. A coil-to-globule transition is observed for homodendrimers in a poor solvent. The size of the dendrimers, characterized by the radius of gyration, ?Rg?, is found to follow the scaling relationship, ?Rg? ~ N(nu), where N is the total number of segments of the dendrimers. For amphiphilic dendrimers, DFT results show that chemical modification in the outermost generation is an effective method to drive the ends toward the periphery of the dendrimers. In particular, a conformation with a hollow interior structure could be formed for amphiphilic dendrimers with longer end spacers in a selective solvent. The resulting unimolecular micelles with a hollow core and dense shell could serve as a unique candidate for encapsulation applications, such as sustained-drug-release nanocontainers. PMID- 27243275 TI - Potential anti-leukemic activity of iron chelation after allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia. PMID- 27243276 TI - Understanding Initiation with Triethylboron and Oxygen: The Differences between Low-Oxygen and High-Oxygen Regimes. AB - A unified kinetic theory for both initiation and autoxidation reactions of Et3B and O2 is put forth, and then divided into low-oxygen and high-oxygen experimental regimes for application of Et3B/O2 as an initiating system. In the low-oxygen regime, only long, efficient chains can be initiated. In the high oxygen regime, less efficient chains can be initiated but they must compete with autoxidation. We apply the analysis along with new experimental results to show why AIBN and Et3B/O2 give different stereochemical results in hydrostannation reactions of propargyl silyl ethers. Counterintuitively, AIBN is the better initiator, initiating both the rapid chain hydrostannation and the subsequent slow E/Z isomerization. AIBN gives the thermodynamic results. Et3B/O2 is the poorer initiator, initiating only the hydrostannation and not the isomerization. Et3B gives the kinetic result. We further apply the analysis to understand recent results in Et3B/water reductions. PMID- 27243277 TI - Molecular Reorientation Dynamics Govern the Glass Transitions of the Amorphous Ices. AB - The glass transitions of low-density amorphous ice (LDA) and high-density amorphous ice (HDA) are the topic of controversial discussions. Understanding their exact nature may be the key to explaining the anomalies of liquid water but has also got implications in the general context of polyamorphism, the occurrence of multiple amorphous forms of the same material. We first show that the glass transition of hydrogen-disordered ice VI is associated with the kinetic unfreezing of molecular reorientation dynamics by measuring the calorimetric responses of the corresponding H2O, H2(18)O, and D2O materials in combination with X-ray diffraction. Well-relaxed LDA and HDA show identical isotopic-response patterns in calorimetry as ice VI, and we conclude that the glass transitions of the amorphous ices are also governed by molecular reorientation processes. This "reorientation scenario" seems to resolve the previously conflicting viewpoints and is consistent with the fragile-to-strong transition from water to the amorphous ices. PMID- 27243278 TI - Efficacy and Tolerability of Pegylated Interferon and Ribavirin in Combination with Simeprevir to Treat Hepatitis C Virus Infections After Living Donor Liver Transplantation. AB - Pegylated interferon and ribavirin plus simeprevir therapy (simeprevir-based triple therapy) has been recently introduced, providing excellent results for nontransplant patients with hepatitis C virus (HCV) infection. However, there are limited data available on its effect on liver transplant recipients. In the present study, we evaluated the efficacy and tolerability of simeprevir-based triple therapy in liver transplant recipients. We treated 9 liver transplant recipients for genotype 1b HCV reinfection with simeprevir-based triple therapy. The efficacy and adverse effects were evaluated until 24 weeks after therapy. All recipients continued immunosuppressive therapy at the same dose as that before therapy induction. Seven of the 9 recipients (77.8%) achieved sustained virological response at 24 weeks. Two recipients (22.2%) experienced viral breakthrough (BT) at 12 and 16 weeks; NS3 HCV mutations conferring resistance to simeprevir were detected in both these patients after BT. Anemia was the most common adverse effect, requiring ribavirin dose reduction and blood transfusion. However, all recipients, except those with BT, completed the 24-week therapy. No recipient experienced cellular rejection during therapy. In conclusion, simeprevir-based triple therapy exhibited high efficacy and tolerability in liver transplant recipients with genotype 1b HCV reinfection. PMID- 27243279 TI - Improving the Diagnosis of Legionella Pneumonia within a Healthcare System through a Systematic Consultation and Testing Program. AB - RATIONALE: Legionella testing is not recommended for all patients with pneumonia, but rather for particular patient subgroups. As a result, the overall incidence of Legionella pneumonia may be underestimated. OBJECTIVES: To determine the incidence of Legionella pneumonia in a veteran population in an endemic area after introduction of a systematic infectious diseases consultation and testing program. METHODS: In response to a 2011-2012 outbreak, the VA Pittsburgh Healthcare System mandated infectious diseases consultations and testing for Legionella by urine antigen and sputum culture in all patients with pneumonia. MEASUREMENTS AND MAIN RESULTS: Between January 2013 and December 2015, 1,579 cases of pneumonia were identified. The incidence of pneumonia was 788/100,000 veterans per year, including 352/100,000 veterans per year and 436/100,000 veterans per year with community-associated pneumonia (CAP) and health care associated pneumonia, respectively. Ninety-eight percent of patients with suspected pneumonia were tested for Legionella by at least one method. Legionella accounted for 1% of pneumonia cases (n = 16), including 1.7% (12/706) and 0.6% (4/873) of CAP and health care-associated pneumonia, respectively. The yearly incidences of Legionella pneumonia and Legionella CAP were 7.99 and 5.99/100,000 veterans, respectively. The sensitivities of urine antigen and sputum culture were 81% and 60%, respectively; the specificity of urine antigen was >99.97%. Urine antigen testing and Legionella cultures increased by 65% and 330%, respectively, after introduction of our program. CONCLUSIONS: Systematic testing of veterans in an endemic area revealed a higher incidence of Legionella pneumonia and CAP than previously reported. Widespread urine antigen testing was not limited by false positivity. PMID- 27243280 TI - In reply - on the toxicity of ibogaine. PMID- 27243329 TI - The Unrestricted Black-Box Complexity of Jump Functions. AB - We analyze the unrestricted black-box complexity of the Jump function classes for different jump sizes. For upper bounds, we present three algorithms for small, medium, and extreme jump sizes. We prove a matrix lower bound theorem which is capable of giving better lower bounds than the classic information theory approach. Using this theorem, we prove lower bounds that almost match the upper bounds. For the case of extreme jump functions, which apart from the optimum reveal only the middle fitness value(s), we use an additional lower bound argument to show that any black-box algorithm does not gain significant insight about the problem instance from the first [Formula: see text] fitness evaluations. This, together with our upper bound, shows that the black-box complexity of extreme jump functions is [Formula: see text]. PMID- 27243330 TI - Avian Hemosporidian Parasite Lineages in Four Species of Free-ranging Migratory Waterbirds from Mongolia, 2008. AB - Avian hemosporidian parasites have been detected in Asia, but little information is known about the hemosporidian parasite lineages that circulate in waterbirds that migrate along the East Asian and Central Asian migratory flyways to breed in Mongolia. To gather baseline data on hemosporidian parasite presence in Mongolian waterbirds, 151 blood-spot samples (81 hatch year [HY] and 70 after hatch year [AHY]) from Bar-headed Goose (Anser indicus), Ruddy Shelduck (Tadorna ferruginea), Great Cormorant ( Phalacrocorax carbo ), and Mongolian Gull (Larus mongolicus) were screened for three genera of apicomplexan parasites, Plasmodium, Haemoproteus, and Leucocytozoon, using nested PCR. Of these, 17 samples (11%, 95% confidence interval: 7.1-17.4%), representing all four species, were positive. We identified 10 species (six Plasmodium, one Haemoproteus, and three Leucocytozoon) through mitochondrial DNA sequencing of the cytochrome b gene and BLAST analysis. One lineage shared 100% nucleotide identity to a hemosporidian parasite lineage that has been previously identified as Plasmodium relictum (SGS1). Six lineages were found in AHY birds and five in HY birds, the latter confirming that infection with some of the identified hemosporidian parasites occurred on the breeding grounds. Our data provide important baseline information on hemosporidian parasite lineages found in AHY waterbirds that breed and migrate through Mongolia as well as in HY offspring. PMID- 27243331 TI - Hematology, Serum Chemistry, and Early Hematologic Changes in Free-Ranging South American Fur Seals ( Arctocephalus australis ) at Guafo Island, Chilean Patagonia. AB - The establishment of clinical pathology baseline data is critical to evaluate temporal and spatial changes in marine mammal groups. Despite increased availability of studies on hematology and biochemistry of marine mammals, reference ranges are lacking for many populations, especially among fur seal species. During the austral summers of 2014 and 2015, we evaluated basic hematologic and biochemical parameters in clinically healthy, physically restrained South American fur seal ( Arctocephalus australis ) lactating females and 2-mo-old pups. We also assessed the temporal variation of hematology parameters on the pups during their first 2 mo of life. Reference ranges of lactating females were similar to those previously reported in other fur seal species. In the case of pups, reference ranges are similar to values previously reported in sea lion species. As expected, most biochemical and hematologic values differ significantly between adult females and pups. As in other otariids, South American fur seals pups are born with higher values of total red blood cells, hemoglobin, and packed cell volume, and lower numbers of total leukocytes, neutrophils, lymphocytes, and eosinophils. To the best of our knowledge, data on hematology reference values for South American fur seals has not been previously reported and is useful for continued health monitoring of this species, as well as for comparisons with other otariid groups. PMID- 27243332 TI - Cryptococcus gattii Type VGIIa Infection in Harbor Seals ( Phoca vitulina ) in British Columbia, Canada. AB - Cryptococcosis has been reported in marine mammals in the northeastern Pacific with increasing frequency in the last 15 yr. Although a variety of cetaceans have been diagnosed with cryptococcosis, Cryptococcus gattii has not been reported in pinnipeds. We document C. gattii VGIIa in a harbor seal ( Phoca vitulina ) pup and in an unrelated adult. Both animals were presented to Vancouver Aquarium's Marine Mammal Rescue Centre (VAMMRC) with generalized weakness, dehydration, respiratory compromise, minimally responsive mentation, and suboptimal body condition. Necropsy and histopathology findings were consistent in both animals and featured generalized lymphadenopathy, bronchopneumonia, and meningoencephalitis with intralesional yeast and fungemia. Cryptococcal serum antigen titers were >=1,024 in both animals. Fungal culture of lung and lymph nodes confirmed C. gattii . Exposure was likely via inhalation prior to presentation to VAMMRC, and C. gattii infection was the proximate cause of death. This report expands the range of susceptible host species as C. gattii continues to emerge as a pathogen of concern in marine mammals in the northeastern Pacific. PMID- 27243333 TI - Resistivity of Rotated Graphite-Graphene Contacts. AB - Robust electrical contact of bulk conductors to two-dimensional (2D) material, such as graphene, is critical to the use of these 2D materials in practical electronic devices. Typical metallic contacts to graphene, whether edge or areal, yield a resistivity of no better than 100 Omega MUm but are typically >10 kOmega MUm. In this Letter, we employ single-crystal graphite for the bulk contact to graphene instead of conventional metals. The graphite contacts exhibit a transfer length up to four-times longer than in conventional metallic contacts. Furthermore, we are able to drive the contact resistivity to as little as 6.6 Omega MUm(2) by tuning the relative orientation of the graphite and graphene crystals. We find that the contact resistivity exhibits a 60 degrees periodicity corresponding to crystal symmetry with additional sharp decreases around 22 degrees and 39 degrees , which are among the commensurate angles of twisted bilayer graphene. PMID- 27243334 TI - Design Defines the Effects of Nanoceria at a Low Dose on Soil Microbiota and the Potentiation of Impacts by the Canola Plant. AB - Soils act as nanoceria sinks via agricultural spreading and surface waters. Canola plants were grown for one month in soil spiked with nanoceria (1 mg.kg( 1)). To define the role of nanomaterials design on environmental impacts, we studied nanoceria with different sizes (3.5 or 31 nm) and coating (citrate). We measured microbial activities involved in C, N, and P cycling in the rhizosphere and unplanted soil. Bacterial community structure was analyzed in unplanted soil, rhizosphere, and plant roots by 454-pyrosequencing of the 16S rRNA gene. This revealed an impact gradient dependent on nanomaterials design, ranging from decreased microbial enzymatic activities in planted soil to alterations in bacterial community structure in roots. Particle size/aggregation was a key parameter in modulating nanoceria effects on root communities. Citrate coating lowered the impact on microbial enzymatic activities but triggered variability in the bacterial community structure near the plant root. Some nanoceria favored taxa whose closest relatives are hydrocarbon-degrading bacteria and disadvantaged taxa frequently associated in consortia with disease-suppressive activity toward plant pathogens. This work provides a basis to determine outcomes of nanoceria in soil, at a dose close to predicted environmental concentrations, and to design them to minimize these impacts. PMID- 27243335 TI - Capsaicin-Coated Silver Nanoparticles Inhibit Amyloid Fibril Formation of Serum Albumin. AB - We have synthesized capsaicin-coated silver nanoparticles (AgNPs(Cap)) and have tested their anti-amyloid activity, considering serum albumin (BSA) as a model protein. We found that amyloid formation of BSA was strongly suppressed in the presence of AgNPs(Cap). However, isolated capsaicin and uncapped control nanoparticles did not show such an inhibition effect. Bioinformatics analysis reveals CH-pi and H-bonding interactions between capsaicin and BSA in the formation of the protein-ligand complex. These results suggest the significance of surface functionalization of nanoparticles with capsaicin, which probably allows capsaicin to effectively interact with the key residues of the amyloidogenic core of BSA. PMID- 27243336 TI - Review of metastable states in heavy nuclei. AB - The structure of nuclear isomeric states is reviewed in the context of their role in contemporary nuclear physics research. Emphasis is given to high-spin isomers in heavy nuclei, with [Formula: see text]. The possibility to exploit isomers to study some of the most exotic nuclei is a recurring theme. In spherical nuclei, the role of octupole collectivity is discussed in detail, while in deformed nuclei the limitations of the K quantum number are addressed. Isomer targets and isomer beams are considered, along with applications related to energy storage, astrophysics, medicine, and experimental advances. PMID- 27243337 TI - Residual Hearing Outcomes After Cochlear Implant Surgery Using Ultra-flexible 28 mm Electrodes. AB - OBJECTIVE: To evaluate the preservation of low frequency residual hearing after cochlear implant surgery using an electrode for atraumatic implantation and complete cochlear stimulation. STUDY DESIGN: Retrospective clinical record study. SETTING: Tertiary referral center. PATIENTS: Fifty-six patients with functional deafness who had undergone cochlear implant surgery and received a Flex electrode (MED-EL GmbH, Innsbruck, Austria) between 2011 and 2014. INTERVENTION: Audiometric testing was performed before surgery and at the time of initial fitting. MAIN OUTCOME MEASURE: Change in low frequency residual hearing measured by pure tone audiometry. RESULTS: Preoperative hearing was relatively poor. After surgery low frequency residual hearing was partially preserved in most cases, however there was a significant hearing loss at all frequencies compared with the preoperative state. In only 23% of all cases complete hearing preservation was observed. CONCLUSION: Despite the use of a flexible electrode, complete preservation of low frequency residual hearing can only be achieved in a minority of patients. The use of a full insertion electrode of 28 mm in patients with poor preoperative thresholds does not allow for usable additional hearing at present. PMID- 27243338 TI - Circulating tissue factor in humans. PMID- 27243339 TI - Determinants of C-reactive protein concentrations in pregnant women with type 1 diabetes. PMID- 27243340 TI - Mineralocortoid receptor antagonists, sleep apnea, and resistant hypertension: a consolidated relationship. PMID- 27243341 TI - Serum soluble CD40L concentration depending on the stage of multiple myeloma and its correlation with selected angiogenic cytokines. AB - INTRODUCTION Little is known about the CD40L-CD40 pathway in hematologic malignancies, especially in multiple myeloma (MM). OBJECTIVES The aim of the current study was to evaluate serum soluble CD40 ligand (sCD40L) concentrations in patients with newly diagnosed MM prior to treatment at different stages of disease, compared with healthy controls. To assess the clinical significance of sCD40L, we assessed correlations between the levels of sCD40L and those of angiogenic cytokines: interleukin 6 (IL-6), soluble receptor of IL-6 (sIL-6R), tumor necrosis factor alpha (TNF-alpha), soluble vascular cell adhesion molecule 1 (sVCAM-1), and platelet-derived growth factor AB (PDGF-AB), as well as with well-established biomarkers of MM activity (lactate dehydrogenase activity and percentage of bone marrow plasma cells) and with a marker of platelet activation (beta-thromboglobulin). PATIENTS AND METHODS The study group consisted of 41 patients with newly diagnosed MM; the control group consisted of 30 healthy subjects. The level of sCD40L was determined using an enzyme-linked immunosorbent assay. RESULTS The level of sCD40L was significantly higher in patients with MM than in controls and increased with the stage of the disease. Moreover, it significantly correlated with the levels of IL-6, sIL-6R, sVCAM-1, PDGF-AB, as well as the levels of MM activity markers and beta-thromboglobulin. CONCLUSIONS Our findings indicate that increased serum sCD40L levels may be related to angiogenesis in patients with MM. This protein has potential clinical usefulness in MM and may be considered as an additional prognostic marker. The correlation of sCD40L with beta-thromboglobulin may indicate that in patients with MM sCD40L derives from activated platelets. PMID- 27243342 TI - Extrinsic blood coagulation pathway and risk factors for thrombotic events in patients with essential thrombocythemia. AB - INTRODUCTION The clinical course of essential thrombocythemia (ET) is varied, and some patients do not exhibit any clinical signs of the disease at the time of diagnosis. The most frequent complications that occur during the course of ET are hemostasis abnormalities manifesting as hemorrhagic or thrombotic events. The mechanism of thrombotic events in patients with ET is complex and not fully understood. OBJECTIVES The aim of the study was to evaluate the concentration and activity of tissue factor (TF) and tissue factor pathway inhibitor (TFPI), depending on the most important risk factors of thrombotic complications (age >60 years, history of thrombotic episodes, presence or absence of the JAK2 V617F mutation, and increased leukocyte count). PATIENTS AND METHODS The study group included 113 patients with diagnosed ET, and the control group, 30 healthy volunteers matched for age and sex. The concentration and activity of TF and TFPI were measured using enzyme-linked immunosorbent assays. RESULTS Patients with ET had a significantly higher activity and concentration of TF and increased activity of TFPI, as compared with controls. The analysis of the studied parameters in relation to risk factors revealed that patients with ET with a history of thrombotic events had a significantly higher concentration of TF, and patients with the JAK2 V617F mutation had a lower TFPI activity, as compared with patients without the mutation. CONCLUSIONS Our study showed that in patients with ET who have a history of thrombosis or the JAK2 V617F mutation, the enhanced risk of thrombosis may result from an increased TF concentration or decreased TFPI activity. PMID- 27243343 TI - Management of patients with atrial fibrillation and chronic kidney disease in light of the latest guidelines. AB - Atrial fibrillation (AF) frequently occurs in patients with chronic kidney disease (CKD), and the rate reaches even 30% in patients with end-stage renal disease (ESRD). Patients with AF and CKD have a significantly higher risk of thrombotic complications, particularly ischemic stroke, and at the same time, a higher bleeding risk (proportionally to the grade of renal failure). In addition, AF and CKD share a number of comorbidities and risk factors, which results in increased mortality rates. Moreover, disturbances in hemostasis are common complications of kidney disease. Their occurrence and severity correlate with worsening renal function, including ESRD. At present, the incidence of bleeding is declining, while thrombotic complications have become the predominant cause of mortality. Prophylactic antithrombotic treatment reduces the rate of stroke and other thrombotic complications. Vitamin K antagonists (VKAs) have long been used in anticoagulant therapy, and more recently, non-vitamin K oral anticoagulants (NOACs) have been introduced, which are direct thrombin inhibitors. NOACs are a valuable anticoagulant option in this group of patients as long as a summary of product characteristics is followed. They are at least as effective as warfarin, while being safer, especially when it comes to intracranial hemorrhage. Renal function should be evaluated before initiation of NOACs and reevaluated when clinically indicated. Importantly, disturbances in hemostasis in patients with CKD and ESRD may lead to unexpected complications, such as extensive bleeding. If anticoagulation is administered to patients on dialysis, effects of an individual dialysis modality as well as interactions with other drugs given (eg, heparin) should be considered. PMID- 27243344 TI - Unresectable heart neuroblastoma in an adult: a natural follow-up. PMID- 27243345 TI - Coexistence of 2 malignant urogenital neoplasms: a testicular seminoma and adenocarcinoma of the prostate gland in a patient 1 year after kidney transplantation. PMID- 27243346 TI - Is Disuse Osteopenia a Favorable Prognostic Sign After Femoral Neck Fracture? AB - OBJECTIVES: Avascular necrosis (AVN) of the femoral head is a devastating complication following fixation of femoral neck fractures in younger adults. In this study, we investigate the prognostic utility of disuse osteopenia. DESIGN: Retrospective study. SETTING: Three academic Level 1 trauma centers. PATIENTS: One hundred twenty patients younger than 60 years treated for a femoral neck fracture. INTERVENTION: N/A. MAIN OUTCOME MEASURES: The presence of sclerosis or osteopenia, compared to the contralateral femoral head, was measured 6 weeks from injury both subjectively and using a novel radiographic measure, the relative density ratio (RDR). The outcome measure was radiographic development of AVN. RESULTS: The presence of relative sclerosis was associated with AVN and overall treatment failure. Patients with subjective relative sclerosis had a 12.6 (95% confidence interval, 2.9-61.3; P < 0.001) times higher odds of developing AVN. Multiple logistic regression showed that for every 0.10 increase in the RDR, there was a 5.2 increase in the odds (95% confidence interval, 2.1-26.9; P = 0.009) of developing AVN. Patients with an RDR of >=1.2 have an 80% probability of AVN, whereas those with an RDR <=0.8 have a <1% probability of developing AVN. CONCLUSIONS: Disuse osteopenia detected on 6-week radiographs is a favorable prognostic sign following fixation of femoral neck fractures. Patients who have relative sclerosis of the femoral head at 6-week follow-up are at a higher risk of developing AVN. LEVEL OF EVIDENCE: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 27243347 TI - Objective Metric of Energy Absorbed in Tibial Plateau Fractures Corresponds Well to Clinician Assessment of Fracture Severity. AB - OBJECTIVES: Determine the agreement between subjective assessments of fracture severity and an objective computed tomography (CT)-based metric of fracture energy in tibial plateau fractures. METHODS: Six fellowship-trained orthopaedic trauma surgeons independently rank-ordered 20 tibial plateau fractures in terms of severity based on anteroposterior and lateral knee radiographs. A CT-based image analysis methodology was used to quantify the fracture energy, and agreement between the surgeons' severity rankings and the fracture energy metric was tested by computing their concordance, a statistical measure that estimates the probability that any 2 cases would be ranked with the same ordering by 2 different raters or methods. RESULTS: Concordance between the 6 orthopaedic surgeons ranged from 82% to 93%, and concordance between surgeon severity rankings and the computed fracture energy ranged from 73% to 78%. CONCLUSIONS: There is a high level of agreement between experienced surgeons in their assessments of tibial plateau fracture severity, and a slightly lower agreement between the surgeon assessments and an objective CT-based metric of fracture energy. Taken together, these results suggest that experienced surgeons share a similar understanding of what makes a tibial plateau fracture more or less severe, and an objective CT-based metric of fracture energy captures much but not all of that information. Further research is ongoing to characterize the relationship between surgeon assessments of severity, fracture energy, and the eventual clinical outcomes for patients with fractures of the tibial plateau. PMID- 27243348 TI - Rim Plating of Posterolateral Fracture Fragments (PLFs) Through a Modified Anterolateral Approach in Tibial Plateau Fractures. AB - Posterolateral fracture fragments in tibial plateau fractures have proven to be particularly difficult to reduce and adequately repair internally through anterior or anterolateral approaches, although they are safer. Posterior and posterolateral approaches offer a direct approach for the reduction and fixation of plates, but they have several limitations. Here, we have proposed a modified anterolateral approach, which ensures a safe and effective technique for the reduction and fixation of posterolateral fracture fragments, aided by our innovative rim plate. PMID- 27243349 TI - Compliance and Subjective Patient Responses to Eyelid Hygiene. AB - OBJECTIVES: Lid hygiene is a commonly prescribed first-line therapy in patients with lid margin disease, yet compliance with therapy is not well characterized. The goals of this study were to assess patient compliance with lid hygiene and evaluate which factors predict a favorable symptomatic response to treatment. METHODS: This was a cross-sectional study of patients seen in the Miami Veterans Affairs eye clinic between August and December 2014. An evaluation was performed to assess dry eye symptoms and lid margin signs. All patients were then instructed to perform warm compresses and lid scrubs. A follow-up phone survey assessed compliance and subjective therapeutic response 6 weeks later. RESULTS: Two hundred seven of 211 (98%) patients (94% male, 60% white) completed the survey. Of the 207 patients, 188 (91%) completed the follow-up survey. Compliance with therapy was reported in 104 patients (55%); 66 reported complete improvement, 30 partial improvement, and 8 no improvement in symptoms. Patients who self-reported dry eye symptoms at first visit (n=86, 74%) were more likely to be compliant with lid hygiene than those who did not report symptoms (n=18, 25%) (P<0.0005). The only factor associated with poorer response to lid hygiene was longer time of self-reported dry eye symptoms. None of the other signs studied, including the presence of skin rosacea and lid margin telangiectasia, were associated with a differential response to lid hygiene. CONCLUSIONS: Patients with dry eye symptoms were moderately compliant with lid hygiene, and patients who performed the routine noted improvement in symptoms. PMID- 27243350 TI - Predicting Short-term Performance of Multifocal Contact Lenses. AB - OBJECTIVE: To investigate if initial multifocal contact lens (MFCL) performance predicts short-term dispensing performance. METHODS: A retrospective analysis of 55 participants (Px) in a masked, crossover, clinical trial, using ACUVUE OASYS for Presbyopia and AIR OPTIX AQUA Multifocal. Subjective questionnaires were administered at the following instances: initial fitting, two take home questionnaires (THQ) completed between days 2 and 4 and at assessment, >=5 days after fitting. Questionnaires included vision clarity and lack of ghosting at distance, intermediate and near at day/night time points rated on a 1 to 10 (1 step, 10 most favorable) rating scale. Vision stability, vision while driving, overall vision satisfaction, willingness to purchase and comfort, as well as acuity-based measures were also collected. RESULTS: There were no statistical differences in comfort and vision at all distances, in vision stability or driving at either time points between THQ and assessment (P>0.05). However, there was a statistical decline in subjective overall vision satisfaction and comfort between fitting and assessment visits (P<0.001). Willingness to purchase remained the same at fitting and assessment in 68% of Px, whereas only 4% of Px converted to a positive willingness to purchase at assessment. The majority of acuity-based measures remained constant between fitting and assessment visits. CONCLUSION: Initial performance at fitting was not able to predict short-term performance of MFCL. Subjective measures peaked at fitting and declined thereafter whereas acuity-based measures remained constant. Utility of subjective rating tools may aid practitioners to gauge success of MFCL. PMID- 27243351 TI - Transscleral Suture-Fixated Versus Intrascleral Haptic-Fixated Intraocular Lens: A Comparative Study. AB - PURPOSE: To compare the clinical outcomes between sutured transscleral-fixated and intrascleral haptic-fixated posterior chamber intraocular lens (IOL). SETTING: Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi. DESIGN: A comparative case series. METHODS: Forty eyes of 40 patients were included; 20 in each group. Patients in group 1 underwent sutured transscleral-fixated IOL and those in group 2 underwent intrascleral haptic-fixated IOL augmented by fibrin glue. Parameters evaluated were uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA), intraocular pressure (IOP), central macular thickness (CMT), IOL tilt on ultrasound biomicroscopy (UBM), and pseudophakodonesis on slitlamp and UBM. RESULTS: The most common cause of aphakia was complicated cataract surgery (50%). The mean preoperative UCVA in logarithm of minimum angle of resolution (logMAR) was 1.59+/-0.24 and 1.63+/-0.26 in group 1 and 2, respectively (P=0.45). There was significant improvement in UCVA in both groups (P=0.001) at 6 months (group 1: 0.33+/-0.17; group 2: 0.22+/-0.10); the improvement being greater in group 2 (P<0.05). Mean percentage endothelial cell loss and IOP change were comparable. Mean CMT (MUm) was 250.95+/-23.98 and 225.85+/-21.13 in group 1 and 2, respectively (P=0.009). Pseudophakodonesis was more in group 1 as assessed on slitlamp (P=0.037) and as assessed on UBM (P=0.046). Macular edema was the most common complication seen more in group 1. CONCLUSIONS: Intrascleral haptic fixated IOL provides more stable fixation, better visual outcome, and lesser complication in comparison with sutured transscleral-fixated IOL. PMID- 27243352 TI - Diquafosol Ophthalmic Solution Increases Pre- and Postlens Tear Film During Contact Lens Wear in Rabbit Eyes. AB - OBJECTIVES: To investigate the behavior of prelens tear film (PLTF) and postlens tear film (PoLTF) after the instillation of diquafosol using an experimental rabbit model of eyes with contact lens. METHODS: Cross-sectional, anterior segment optical coherence tomographic images of the inferior midperipheral cornea were obtained at baseline and at 5, 15, 30, 60, 90, and 120 min after the instillation of 3% diquafosol ophthalmic solution in 10 Japanese white rabbits wearing contact lenses. From the obtained images, the areas of the PLTF and PoLTF were calculated. Both artificial tear solution and 0.1% sodium hyaluronate ophthalmic solution were used for comparison. RESULTS: Significant fluid accumulation in both the PLTF and PoLTF was observed after diquafosol instillation, whereas no fluid accumulation was visible after the instillation of artificial tear or sodium hyaluronate. The increase in PLTF area after diquafosol instillation was significantly higher (P<0.01) at 15 and 30 min than that after the instillation of artificial tear or sodium hyaluronate. The increase in PoLTF area up to 60 min after the instillation of diquafosol was significantly higher (P<0.01) than that after the instillation of either of the other two drugs. CONCLUSIONS: Instillation of 3% diquafosol ophthalmic solution increases PLTF and PoLTF in rabbit eyes with contact lenses. Diquafosol has potential as a treatment option for contact lens-related dry eye. PMID- 27243353 TI - Safety and Efficacy of an Artificial Tear Containing 0.3% Hyaluronic Acid in the Management of Moderate-to-Severe Dry Eye Disease. AB - PURPOSE: To evaluate the safety and efficacy of a new 0.3% hyaluronic acid artificial tear compared with 0.9% saline solution (0.9% NaCl) in moderate-to severe dry eye patients after 1 month's use. METHODS: A total of 16 patients with moderate-to-severe dry eye were included in this crossover study. After a 1-week washout period, patients used the experimental (Visaid 0.3%) or control solution (0.9% NaCl), selected randomly, applying three to eight drops daily for a month. After another washout period, patients used the other solution in the same way. Percentage of change (DeltaY) was calculated and analyzed for (1) safety variables: visual acuity, intraocular pressure, and ophthalmoscopy evaluation; (2) efficacy variable: Ocular Surface Disease Index (OSDI) questionnaire; and (3) secondary variables: biomicroscopy findings, fluorescein corneal staining, lissamine green conjunctival staining, tear breakup time (TBUT), contrast sensitivity, Schirmer test, and subject satisfaction. RESULTS: There were no significant differences in the safety parameters for either solution. After using Visaid 0.3%, patients showed significant improvements in OSDI score (DeltaY: 9.66%+/-10.90), tarsal hyperemia (DeltaY: -16.67%+/-27.89), corneal staining extension (DeltaY: -34.90%+/-42.41), TBUT (DeltaY: 13.98%+/-26.19), and subjective satisfaction (DeltaY: 38.06%+/-47.06). When using 0.9% NaCl, Schirmer test results were significantly worse (DeltaY: -11.47%+/-19.27). A significant difference between the 2 solutions was found in TBUT (DeltaY: 13.98%+/-26.19 vs. 10.15%+/-42.34, respectively; P=0.0214). CONCLUSION: Visaid 0.3% is a safe product with some benefits over 0.9% NaCl in reducing ocular symptoms and improving some ocular signs in patients with moderate-to-severe dry eye. PMID- 27243354 TI - Short-Term Effects of Overnight Orthokeratology on Corneal Sub-basal Nerve Plexus Morphology and Corneal Sensitivity. AB - OBJECTIVE: To assess the effects of a short period of orthokeratology (OK) on corneal sub-basal nerve plexus (SBNP) morphology and corneal sensitivity. METHODS: Measurements were made in 56 right eyes of 56 subjects with low-to moderate myopia who wore 2 OK lens designs (Group CRT: HDS 100 Paragon CRT, n=35; Group SF: Seefree; n=21) for a period of 1 month and in 15 right eyes of noncontact lens wearers as controls. The variables determined in each participant were corneal sensitivity using a Cochet-Bonnet esthesiometer and 12 SBNP variables determined on laser scanning confocal microscopy images using 3 different software packages. Correlation between SBNP architecture and corneal sensitivity was also examined. RESULTS: Few changes were observed over the 1 month period in the variables examined in the OK treatment and control groups. However, significant reductions were detected over time in the number of nerves in the central cornea in the groups CRT (P=0.029) and SF (P=0.043) and in central corneal sensitivity in CRT (P=0.047) along with significant increases in central and midperipheral corneal Langerhans cell counts in SF (P=0.001 and 0.048, respectively). CONCLUSIONS: This study provides useful data to better understand the anatomical changes induced by OK in corneal SBNP. The different response observed to the 2 OK lens designs requires further investigation. PMID- 27243355 TI - Evaluation of Corneal Biomechanics After Excimer Laser Corneal Refractive Surgery in High Myopic Patients Using Dynamic Scheimpflug Technology. AB - OBJECTIVE: To compare the effect of femtosecond-assisted thin flap laser-assisted in situ keratomileusis (FS-LASIK) and photorefractive keratectomy with mitomycin C (PRK-MMC) in highly myopic patients (>7.0 D [D]) on corneal biomechanical parameters. METHODS: In this prospective comparative interventional case series, 60 patients (30 patients in each group) with a manifest refractive spherical equivalent (MRSE) greater than 7.0 D were enrolled. Corvis ST parameters were measured before and at 3 and 6 months postoperatively. RESULTS: Preoperatively, mean MRSE was -8.65+/-1.51 D in FS-LASIK and -8.04+/-1.70 D in PRK-MMC groups (P=0.149), and corneal thickness was 570.67+/-36.79 MUm and 507.12+/-32.55 MUm, respectively (P<0.001). At 6 months, both groups showed significantly higher applanation (A) 2 time and A2-velocity (P<0.05 in both), whereas intraocular pressure (IOP), corrected IOP, A1 time, A1-velocity, and radius at highest concavity were significantly reduced (P<0.05 in all). In the FS-LASIK group, there was a significant increase in deformation amplitude (DA) (P=0.001), and significant decreases in A2-length (P=0.004). Peak distance increased in the PRK MMC group (P=0.029). At 6 months, after controlling for fellow eye correlations and preoperative corneal thickness between the two groups, decreases in IOP, A1 time, A2-length and radius, and the increase in DA was greater in FS-LASIK. CONCLUSION: This study demonstrated significant changes in Corvis ST ocular biomechanical metrics after both PRK-MMC and FS-LASIK in high myopic patients, indicating the significant effect of excimer laser refractive surgery on corneal biomechanical properties. However, changes that occur with FS-LASIK are more significant than with PRK-MMC. Further randomized studies are needed to better characterize the pattern of biomechanical changes associated with each type of surgery. PMID- 27243356 TI - Patient-Reported Wearing Experience From Hydrogel Daily Disposable Wearers Older Than 40 Years From the TEMPO Registry. AB - OBJECTIVES: To describe the patient-reported wearing experience over time among wearers of hydrogel daily disposable (HydDD) contact lenses (CLs) in the TruEye and Moist Performance Overview (TEMPO) Registry (NCT01467557). METHODS: Registered wearers older than 40 years who were recently fit with 1-DAY ACUVUE MOIST HydDDs completed self-administered questionnaires four times during a year long Registry. Overall opinion of CLs, replacement schedules, Contact Lens Dry Eye Questionnaire (CLDEQ-8), and compliance were queried. Data were analyzed with analysis of variance and signed rank tests. RESULTS: A total of 86 subjects (24% men, age 50.2+/-7.1 years) completed the Registry. Approximately 76% were new to daily disposable lenses, and 8% were neophytes. Overall opinion of CLs improved significantly after refitting with HydDDs (baseline 57% excellent/very good vs. 69%-79% at follow-ups, P<0.05 all vs. baseline). Changing to HydDDs maintained average and comfortable wear time (P>0.05), and it did significantly improve CLDEQ-8 scores at all follow-ups (baseline, 11.2+/-7.3 vs. 2 weeks, 7.8+/-5.8, P<0.0001; 4 months, 8.6+/-6.5, P=0.0006; 12 months, 9.3+/-6.5, P=0.01). Self assessment of compliance was excellent/very good for 80% at baseline, and improved to 92% to 98% at follow-ups (P<0.0001). More than 90% never slept in their HydDDs, although compliance to daily replacement diminished from 2-week to 4-month surveys (93% vs. 84%, P=0.007). CONCLUSIONS: After refitting with HydDDs, older wearers reported significantly higher overall opinions of their lenses, better CLDEQ-8 symptom scores, and most were compliant with proper daily disposable lens use. Diminishing daily replacement rates from 2 weeks to 4 months indicate a need to reinforce that recommendation. Wearers of HydDD CLs older than 40 years experienced many benefits from refitting with these daily disposable lenses. PMID- 27243357 TI - A Possible Association Between Dry Eye Symptoms and Body Fat: A Prospective, Cross-Sectional Preliminary Study. AB - OBJECTIVES: To examine the relationship between dry eye symptoms and adiposity in a population study. METHODS: A prospective cross-sectional single-visit preliminary study was designed to sample ocular symptoms and indices of adiposity in the general adult population. Patients recruited from the UNSW optometry clinic, the university campus and surrounding community, and overseas were invited to complete a survey composed of the short form Dry Eye Questionnaire (SFDEQ) (Dry Eye Questionnaire-5 or Contact Lens Dry Eye Questionnaire-8) and the Ocular Comfort Index (OCI) via hardcopy or online. Participants self-measured their weight, height, waist circumference (WC), and body fat % (optional). Associations between measures of adiposity (Body mass index [BMI], WC, and body fat %) and ocular symptoms scores (SFDEQ and OCI) were determined using Spearman correlation coefficients. Group differences were compared using independent t test. RESULTS: Three hundred and five participants including 52 contact lens wearers completed the study and 78 of them measured body fat %. There was a moderate correlation between body fat % and dry eye symptoms (SFDEQ r=0.34, P=0.003; OCI r=0.32, P=0.004). The interaction between body fat % and gender, wear of contact lenses, and older age were shown to be significant predictors of less ocular comfort in multivariate analysis (F(3,74)=12.13, P<0.001). CONCLUSIONS: An association between adiposity measured by body fat % and symptoms of dry eye was demonstrated in the general adult population. Confirmation of these findings in a large study is required. PMID- 27243358 TI - Transformation between divacancy defects induced by an energy pulse in graphene. AB - The mutual transformations among the four typical divacancy defects induced by a high-energy pulse were studied via molecular dynamics simulation. Our study revealed all six possible mutual transformations and found that defects transformed by absorbing energy to overcome the energy barrier with bonding, debonding, and bond rotations. The reversibility of defect transformations was also investigated by potential energy analysis. The energy difference was found to greatly influence the transformation reversibility. The direct transformation path was irreversible if the energy difference was too large. We also studied the correlation between the transformation probability and the input energy. It was found that the transformation probability had a local maxima at an optimal input energy. The introduction of defects and their structural evolutions are important for tailoring the exceptional properties and thereby performances of graphene based devices, such as nanoporous membranes for the filtration and desalination of water. PMID- 27243359 TI - A dual-emitting 4d-4f nanocrystalline metal-organic framework as a self calibrating luminescent sensor for indoor formaldehyde pollution. AB - A dual-emissive 4d-4f Ag(i)-Eu(iii) functionalized MOF nanocomposite was fabricated and utilized as a self-calibrating luminescent nanoprobe for detecting indoor formaldehyde (FA). The implantation of Ag(+) ions can tune the dual emissive characters of the material. FA can interact with the Ag(+) ions and induce opposite luminescence behaviors of the two emitters in the singular molecular material, thus realizing its recognition. This nanoprobe for FA exhibits many merits, such as excellent selectivity, high sensitivity with a detection limit of 51 ppb, fast response, room-temperature testing ability, easy preparation and low cost. This is the first example of a MOF-implicated self calibrated sensor for indoor FA detection. PMID- 27243360 TI - Offenders in emerging adulthood: School maladjustment, childhood adversities, and prediction of aggressive antisocial behaviors. AB - Early psychosocial adversities and maladjustment, such as childhood maltreatment and school adjustment problems, have been linked to an increased risk of aggressive antisocial behaviors. Yet, clinical studies of subjects at the highest risk of persistence in such behaviors are rare, especially during the life changing transition years of emerging adulthood. This study describes early predictors of aggressive antisocial behaviors in a large, nationally representative cohort of Swedish, male violent offenders in emerging adulthood (age range = 18-25 years; N = 270). First, data on psychosocial background characteristics and aggressive antisocial behaviors (including age at onset) are provided. Second, early predictors of aggressive antisocial behaviors are tested in bivariate and multivariate interactive models. The offenders demonstrated a diversity of early onset adversities and disruptive behaviors, in line with established risk factors for subsequent criminality and adverse outcomes in a variety of life domains. Severe school adjustment problems, especially bullying others and early onset truancy, were important and interrelated predictors of aggressive antisocial behaviors over the lifetime, whereas childhood adversities such as parental substance or alcohol abuse and repeated exposure to violence at home during childhood were interrelated predictors of aggressive antisocial behaviors, albeit with less statistical importance. The findings stress the importance of early identification of individuals in the risk zone of developing severe and persistent aggressive antisocial behaviors and of early preventive interventions directed toward families with high-risk profiles. The findings also provide initial guidelines on which psychosocial background risk factors that need to be considered first-hand in early interventions. (PsycINFO Database Record PMID- 27243361 TI - Can expert testimony sensitize jurors to variations in confession evidence? AB - Confession evidence can be extremely damaging in the courtroom; jurors are more willing to convict based on the presence of a confession than eyewitness evidence and character testimony (Kassin & Neumann, 1997). To date, no research has examined whether jurors notice variations in confession evidence based on whether the confession is consistent or inconsistent with the crime evidence (a likely low quality confession). In Study 1, mock jurors read a trial summary in which a suspect's confession was consistent or inconsistent with other case facts. Jurors were marginally more likely to convict if the confession and case facts were consistent than if they were not, but did not view the confession differently based on the consistency of the confession and case facts. In Study 2, we varied whether an expert testified about the consistency of the confession and case facts. Jurors who reported for jury duty did not render different trial decisions or view the confession differently based on the consistency of the confession and case facts or the presence of the expert testimony. We expanded the design in Study 3 to vary the content of the confession in addition to the case facts. Jurors used the consistency of the confession and case facts in making decisions, and expert testimony sensitized jurors to variations in the content of confession evidence on the verdict measure. Findings suggest jurors notice variations in confession evidence and expert testimony shows promise for educating jurors about characteristics of confessions. (PsycINFO Database Record PMID- 27243362 TI - Adversarial allegiance: The devil is in the evidence details, not just on the witness stand. AB - This study examined the potential influence of adversarial allegiance on expert testimony in a simulated child sexual abuse case. A national sample of 100 witness suggestibility experts reviewed a police interview of an alleged 5-year old female victim. Retaining party (prosecution, defense) and interview suggestibility (low, high) varied across experts. Experts were very willing to testify, but more so for the prosecution than the defense when interview suggestibility was low and vice versa when interview suggestibility was high. Experts' anticipated testimony focused more on prodefense aspects of the police interview and child's memory overall (negativity bias), but favored retaining party only when interview suggestibility was low. Prosecution-retained experts shifted their focus from prodefense aspects of the case in the high suggestibility interview to proprosecution aspects in the low suggestibility interview; defense experts did not. Blind raters' perceptions of expert focus mirrored those findings. Despite an initial bias toward retaining party, experts' evaluations of child victim accuracy and police interview quality were lower in the high versus low interview suggestibility condition only. Our data suggest that adversarial allegiance exists, that it can (but not always) influence how experts process evidence, and that it may be more likely in cases involving evidence that is not blatantly flawed. Defense experts may evaluate this type of evidence more negatively than prosecution experts because of negativity bias and positive testing strategies associated with confirmation bias. (PsycINFO Database Record PMID- 27243366 TI - Maternal Smoking Among Women With and Without Use of Assisted Reproductive Technologies. AB - OBJECTIVE: To estimate smoking prevalence during the year before pregnancy and during pregnancy and adverse outcomes among women who delivered infants with and without assisted reproductive technology (ART) using linked birth certificates (BC) and National ART Surveillance System (NASS) data. METHODS: Data were analyzed for 384,390 women and 392,248 infants born in Massachusetts and Michigan during 2008-2009. Maternal smoking prevalence was estimated using smoking indicated from BC by ART status. For ART users, to evaluate underreporting, prepregnancy smoking was estimated from BC, NASS, or both sources. Effect of prenatal smoking on preterm and mean birthweight (term only) for singleton infants were examined by ART status. RESULTS: Maternal smoking prevalence estimates were significantly lower for ART users than nonusers (prepregnancy = 3.2% vs. 16.7%; prenatal = 1.0% vs. 11.1%, p < 0.05). When combining smoking information from BC and NASS, prepregnancy smoking prevalence estimates for ART users could be as high as 4.4% to 6.1%. Adverse effects of smoking on infant outcomes in ART pregnancies were consistent with the effects seen in non-ART pregnancies, specifically decline in infant birthweight and increase in preterm delivery, although association between smoking and preterm was not significant. CONCLUSION: A low, but substantial proportion of ART users smoked before and during pregnancy. As ART users are highly motivated to get pregnant, it should be clearly communicated that smoking can decrease fertility and adversely affect pregnancy outcomes. Continued efforts are needed to encourage smoking cessation and maintain tobacco abstinence among all women of reproductive age. PMID- 27243368 TI - The origin, evolution and signatures of primordial magnetic fields. AB - The universe is magnetized on all scales probed so far. On the largest scales, galaxies and galaxy clusters host magnetic fields at the micro Gauss level coherent on scales up to ten kpc. Recent observational evidence suggests that even the intergalactic medium in voids could host a weak ~ 10(-16) Gauss magnetic field, coherent on Mpc scales. An intriguing possibility is that these observed magnetic fields are a relic from the early universe, albeit one which has been subsequently amplified and maintained by a dynamo in collapsed objects. We review here the origin, evolution and signatures of primordial magnetic fields. After a brief summary of magnetohydrodynamics in the expanding universe, we turn to magnetic field generation during inflation and phase transitions. We trace the linear and nonlinear evolution of the generated primordial fields through the radiation era, including viscous effects. Sensitive observational signatures of primordial magnetic fields on the cosmic microwave background, including current constraints from Planck, are discussed. After recombination, primordial magnetic fields could strongly influence structure formation, especially on dwarf galaxy scales. The resulting signatures on reionization, the redshifted 21 cm line, weak lensing and the Lyman-alpha forest are outlined. Constraints from radio and gamma-ray astronomy are summarized. Astrophysical batteries and the role of dynamos in reshaping the primordial field are briefly considered. The review ends with some final thoughts on primordial magnetic fields. PMID- 27243367 TI - Wolbachia infections in natural Anopheles populations affect egg laying and negatively correlate with Plasmodium development. AB - The maternally inherited alpha-proteobacterium Wolbachia has been proposed as a tool to block transmission of devastating mosquito-borne infectious diseases like dengue and malaria. Here we study the reproductive manipulations induced by a recently identified Wolbachia strain that stably infects natural mosquito populations of a major malaria vector, Anopheles coluzzii, in Burkina Faso. We determine that these infections significantly accelerate egg laying but do not induce cytoplasmic incompatibility or sex-ratio distortion, two parasitic reproductive phenotypes that facilitate the spread of other Wolbachia strains within insect hosts. Analysis of 221 blood-fed A. coluzzii females collected from houses shows a negative correlation between the presence of Plasmodium parasites and Wolbachia infection. A mathematical model incorporating these results predicts that infection with these endosymbionts may reduce malaria prevalence in human populations. These data suggest that Wolbachia may be an important player in malaria transmission dynamics in Sub-Saharan Africa. PMID- 27243370 TI - Monitoring drug-lipid membrane interactions via a molecular rotor probe. AB - Molecular rotors are fluorescent molecules with a viscosity-sensitive fluorescence quantum yield that are often used to measure viscosity changes in biological membranes. Herein, we report the use of a lipophilic molecular rotor probe to monitor the interactions between the local anesthetic tetracaine (TTC) and small unilamellar vesicles (SUVs) in a label-free manner. The probe was developed by modifying the fluorescent molecular rotor CCVJ with an amphiphilic anchor group that enables adequate integration of the rotor group into the hydrophobic core of lipid bilayers. The temperature-dependent profile of the quantum yield of the probe clearly exhibited the subtransition, pretransition and main phase transition of the lipid bilayers as drastic changes in the activation energies. The temperature-TTC phase diagrams were determined based on an Arrhenius fitting. The results show that TTC has a significant chain ordering effect on liquid-crystalline phase lipids compared to solid-gel phase lipids, especially subgel phase lipids. A TTC-induced interdigitated gel (LbetaI) phase appeared at the pretransition temperature. The LbetaI phase spread both its ends in a TTC-dependent fashion, and the low-temperature end merged to the subtransition at a TTC concentration of 25 mM. Adding cholesterol (CHOL) to the SUVs stabilizes the LbetaI phase and reduces the insertion of TTC into the bilayers. The paper demonstrates that our method is highly sensitive to the microenvironment of the lipid membrane, providing a facile and efficient new tool to study drug-membrane interactions. Also, molecular rotors may potentially be exploited as screen probes for drug development and analysis. PMID- 27243369 TI - Expanding the geriatric mental health workforce through utilization of non licensed providers. AB - OBJECTIVES: We evaluate policy and practice strategies for bolstering the geriatric mental healthcare workforce and describe costs and considerations of implementing one approach. METHOD: Narrative overview of the literature and policy retrieved from searches of databases, hand searches, and authoritative texts. We identified three proposed strategies to increase the geriatric mental healthcare workforce: (1) production of more geriatric mental health providers; (2) team-based care; and (3) non-licensed providers. We evaluate each in terms of challenges and potential and provide estimates of costs, policy, and practice considerations for training, employing, and supervising non-licensed mental health providers. RESULTS: Use of non-licensed providers is key to reforms needed to allow a more older adults to access necessary mental healthcare. Licensed and non-licensed providers have achieved similar improvements for generalized anxiety disorder among patients, although non-licensed providers did so at a lower cost. CONCLUSION: Supervised non-licensed providers can extend the reach of licensed providers for specific mental health conditions, resulting in lower costs and increased number of patients treated. Although several barriers to implementation exist, policy and infrastructure changes that may support this type of care delivery model are emerging from reforms in financing and associated delivery initiatives created by the Affordable Care Act. PMID- 27243371 TI - Metabolic Patterns in Chronic Multiple Sclerosis Lesions and Normal-appearing White Matter: Intraindividual Comparison by Using 2D MR Spectroscopic Imaging. AB - Purpose To perform a direct metabolic comparison of chronic lesions and diffusely injured normal-appearing white matter (NAWM) in multiple sclerosis (MS). Materials and Methods In this institutional review board-approved study, with the written informed consent of all patients, two-dimensional magnetic resonance spectroscopic imaging data in 46 patients with relapsing-remitting MS (median disease duration, 0.8 year) were analyzed by using the spectral quantification tool LCModel. Metabolic patterns were evaluated for non-gadolinium-enhancing chronic lesions and the corresponding contralateral NAWM. The sensitivity of the method was assessed by reproducing the known metabolic differences between cortical gray matter (GM) and NAWM. In addition to individual spectra, averaged spectra were calculated by accumulating free induction decays over all subjects to yield an increased signal-to-noise ratio (SNR), and in turn, to allow improved curve fitting as demonstrated by lower error bounds for low-concentration metabolites. Metabolite concentrations were statistically tested for intraindividual differences (paired t tests) to avoid effects resulting from variations in disease severity or treatment. Results Differences between the metabolite concentrations in the NAWM and the cortical GM were highly significant (P < .001), demonstrating the reliability of the spectral analysis used here. The spectral patterns of the individual and averaged spectra of chronic lesions and NAWM were qualitatively very similar at visual inspection. Furthermore, in the quantitative comparison, the estimated metabolite concentrations showed only slight differences (P > .07). Owing to increased SNRs in the averaged spectra compared with individual spectra (eg, for chronic lesions, 63 vs 28.4 +/- 4.1), it was possible to reliably (Cramer-Rao lower bound [CRLB], <20%) estimate scyllo inositol levels with a CRLB of 14%. Conclusion These findings revealed that NAWM exhibits the same metabolic changes as chronic white matter lesions, even very early in the disease course, further supporting the view that such lesions may not be as relevant as widely assumed. (c) RSNA, 2016. PMID- 27243372 TI - Interventions for lowering plasma homocysteine levels in dialysis patients. AB - BACKGROUND: People with end-stage kidney disease (ESKD) have high rates of cardiovascular events. Randomised controlled trials (RCTs) of homocysteine lowering therapies have not shown reductions in cardiovascular event rates in the general population. However, people with kidney disease have higher levels of homocysteine and may have different mechanisms of cardiovascular disease. We performed a systematic review of the effect of homocysteine-lowering therapies in people with ESKD. OBJECTIVES: To evaluate the benefits and harms of established homocysteine lowering therapy (folic acid, vitamin B6, vitamin B12) on all-cause mortality and cardiovascular event rates in patients with ESKD. SEARCH METHODS: We searched Cochrane Kidney and Transplant's Specialised Register to 25 January 2016 through contact with the Information Specialist using search terms relevant to this review. SELECTION CRITERIA: Studies conducted in people with ESKD that reported at least 100 patient-years of follow-up and assessed the effect of therapies that are known to have homocysteine-lowering properties were included. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data using a standardised form. The primary outcome was cardiovascular mortality. Secondary outcomes included all-cause mortality, incident cardiovascular disease (fatal and nonfatal myocardial infarction and coronary revascularisation), cerebrovascular disease (stroke and cerebrovascular revascularisation), peripheral vascular disease (lower limb amputation), venous thromboembolic disease (deep vein thrombosis and pulmonary embolism), thrombosis of dialysis access, and adverse events. The effects of homocysteine-lowering therapies on outcomes were assessed with meta-analyses using random-effects models. Prespecified subgroup and sensitivity analyses were conducted. MAIN RESULTS: We included six studies that reported data on 2452 participants with ESKD. Interventions investigated were folic acid with or without other vitamins (vitamin B6, vitamin B12). Participants' mean age was 48 to 65 years, and proportions of male participants ranged from 50% to 98%.Homocysteine-lowering therapy probably leads to little or no effect on cardiovascular mortality (4 studies, 1186 participants: RR 0.93, 95% CI 0.70 to 1.22). There was no evidence of heterogeneity among the included studies (I2 = 0%). Homocysteine-lowering therapy had little or no effect on all cause mortality or any other of this review's secondary outcomes. All prespecified subgroup and sensitivity analyses demonstrated little or no difference. Reported adverse events were mild and there was no increase in the incidence of adverse events from homocysteine-lowering therapies (3 studies, 1248 participants: RR 1.12, 95% CI 0.51 to 2.47; I(2) = 0%). Overall, studies were assessed as being at low risk of bias and there was no evidence of publication bias. AUTHORS' CONCLUSIONS: Homocysteine-lowering therapies were not found to reduce mortality (cardiovascular and all-cause) or cardiovascular events among people with ESKD. PMID- 27243373 TI - Clinical outcomes after assisted reproductive technology in twin pregnancies: chorionicity-based comparison. AB - The chorionicity-based evaluation of the perinatal risk in twin pregnancies after assisted reproductive technology (ART) is lacking. A retrospective review was performed of all twin pregnancies monitored prenatally and delivered at our hospital between 2010 and 2014. Chorionicity was diagnosed by ultrasound examination at first trimester and confirmed by postnatal pathology. Pregnancy and perinatal outcomes were prospectively recorded. Adjusted odds ratios (aOR) with 95% confidence intervals (CI) were calculated in a logistic regression model. A total of 1153 twin pregnancies were analyzed. The occurrence of preterm premature rupture of membranes (PPROM) was 3 times as frequent in monochorionic diamniotic (MCDA) twin pregnancies after ART as in those spontaneous counterparts (aOR 3.0; 95%CI 1.1-3.2). The prevalence of intrahepatic cholestasis of pregnancies (ICP) was significantly higher in dichorionic diamniotic (DCDA) twin pregnancies following ART compared to spontaneous DCDA pregnancies (aOR 3.3; 95%CI 1.3-5.6). Perinatal outcomes did not differ between two conception methods, either in MCDA or DCDA twin pregnancies. Based on differentiation of chorionicity, ART is associated with the increased risk of PPROM in MCDA twin pregnancies and with a higher rate of ICP in DCDA twin gestations. ART does not increase adversity of perinatal outcomes in twin pregnancies. PMID- 27243374 TI - Preparation of Carbon Nanotube/TiO2 Mesoporous Hybrid Photoanode with Iron Pyrite (FeS2) Thin Films Counter Electrodes for Dye-Sensitized Solar Cell. AB - Multi-walled carbon nanotube (MWCNT)/TiO2 mesoporous networks can be employed as a new alternative photoanode in dye-sensitized solar cells (DSSCs). By using the MWCNT/TiO2 mesoporous as photoanodes in DSSC, we demonstrate that the MWCNT/TiO2 mesoporous photoanode is promising alternative to standard FTO/TiO2 mesoporous based DSSC due to larger specific surface area and high electrochemical activity. We also show that iron pyrite (FeS2) thin films can be used as an efficient counter electrode (CE), an alternative to the conventional high cost Pt based CE. We are able to synthesis FeS2 nanostructures utilizing a very cheap and easy hydrothermal growth route. MWCNT/TiO2 mesoporous based DSSCs with FeS2 CE achieved a high solar conversion efficiency of 7.27% under 100 mW cm(-2) (AM 1.5G 1-Sun) simulated solar irradiance which is considerably (slightly) higher than that of A-CNT/TiO2 mesoporous based DSSCs with Pt CE. Outstanding performance of the FeS2 CE makes it a very promising choice among the various CE materials used in the conventional DSSC and it is expected to be used more often to achieve higher photon-to-electron conversion efficiencies. PMID- 27243375 TI - A Conductive Hybridization Matrix of RuO2 Two-Dimensional Nanosheets: A Hybrid Type Photocatalyst. AB - A universal methodology to efficiently improve the photocatalyst performance of semiconductors was developed by employing exfoliated RuO2 two-dimensional nanosheets as a conducting hybridization matrix. The hybridization with a RuO2 nanosheet is easily achieved by crystal growth or electrostatically derived anchoring of semiconductor nanocrystals on the RuO2 nanosheet. An enhanced chemical interaction of inorganic semiconductor with hydrophilic RuO2 nanosheet is fairly effective in optimizing their photocatalytic activity and photostability by the enhancement of charge separation and charge mobility. The RuO2 -containing nanohybrids show much better photocatalyst functionalities than do the graphene-containing ones. The present study clearly demonstrates that hydrophilic RuO2 nanosheets are superior hybridization matrices, over the widely used hydrophobic graphene nanosheets, for exploring new efficient hybrid-type photocatalysts. PMID- 27243376 TI - Transition-Selective Pulses in Zero-Field Nuclear Magnetic Resonance. AB - We use low-amplitude, ultralow frequency pulses to drive nuclear spin transitions in zero and ultralow magnetic fields. In analogy to high-field NMR, a range of sophisticated experiments becomes available as these allow narrow-band excitation. As a first demonstration, pulses with excitation bandwidths 0.5-5 Hz are used for population redistribution, selective excitation, and coherence filtration. These methods are helpful when interpreting zero- and ultralow-field NMR spectra that contain a large number of transitions. PMID- 27243377 TI - Experimental GVD engineering in slow light slot photonic crystal waveguides. AB - The use in silicon photonics of the new optical materials developed in soft matter science (e.g. polymers, liquids) is delicate because their low refractive index weakens the confinement of light and prevents an efficient control of the dispersion properties through the geometry. We experimentally demonstrate that such materials can be incorporated in 700 MUm long slot photonic crystal waveguides, and hence can benefit from both slow-light field enhancement effect and slot-induced ultra-small effective areas. Additionally, we show that their dispersion can be engineered from anomalous to normal regions, along with the presence of multiple zero group velocity dispersion (ZGVD) points exhibiting Normalized Delay Bandwidth Product as high as 0.156. The reported results provide experimental evidence for an accurate control of the dispersion properties of fillable periodical slotted structures in silicon photonics, which is of direct interest for on-chip all-optical data treatment using nonlinear optical effects in hybrid-on-silicon technologies. PMID- 27243378 TI - Thermal Transport in Silicon Nanowires at High Temperature up to 700 K. AB - Thermal transport in silicon nanowires has captured the attention of scientists for understanding phonon transport at the nanoscale, and the thermoelectric figure-of-merit (ZT) reported in rough nanowires has inspired engineers to develop cost-effective waste heat recovery systems. Thermoelectric generators composed of silicon target high-temperature applications due to improved efficiency beyond 550 K. However, there have been no studies of thermal transport in silicon nanowires beyond room temperature. High-temperature measurements also enable studies of unanswered questions regarding the impact of surface boundaries and varying mode contributions as the highest vibrational modes are activated (Debye temperature of silicon is 645 K). Here, we develop a technique to investigate thermal transport in nanowires up to 700 K. Our thermal conductivity measurements on smooth silicon nanowires show the classical diameter dependence from 40 to 120 nm. In conjunction with Boltzmann transport equation, we also probe an increasing contribution of high-frequency phonons (optical phonons) in smooth silicon nanowires as the diameter decreases and the temperature increases. Thermal conductivity of rough silicon nanowires is significantly reduced throughout the temperature range, demonstrating a potential for efficient thermoelectric generation (e.g., ZT = 1 at 700 K). PMID- 27243379 TI - Radical-Radical Cyclization Cascades of Barbiturates Triggered by Electron Transfer Reduction of Amide-Type Carbonyls. AB - Radical-radical cyclization cascades, triggered by single-electron transfer to amide-type carbonyls by SmI2-H2O, convert simple achiral barbiturates in one step to hemiaminal- or enamine-containing tricyclic scaffolds containing up to five contiguous stereocenters (including quaternary stereocenters). Furthermore, we describe the surprising beneficial effect of LiBr on the most challenging of the radical-radical cyclization cascades. An alternative fragmentation-radical cyclization sequence of related substrates allows access to bicyclic uracil derivatives. The radical-radical cyclization process constitutes the first example of a radical cascade involving ET reduction of the amide carbonyl. Products of the cascade can be readily manipulated to give highly unusual and medicinally relevant bi- and tricyclic barbiturates. PMID- 27243380 TI - Ultrafast Electron Transfer Kinetics in the LM Dimer of Bacterial Photosynthetic Reaction Center from Rhodobacter sphaeroides. AB - It has become increasingly clear that dynamics plays a major role in the function of many protein systems. One system that has proven particularly facile for studying the effects of dynamics on protein-mediated chemistry is the bacterial photosynthetic reaction center from Rhodobacter sphaeroides. Previous experimental and computational analysis have suggested that the dynamics of the protein matrix surrounding the primary quinone acceptor, QA, may be particularly important in electron transfer involving this cofactor. One can substantially increase the flexibility of this region by removing one of the reaction center subunits, the H-subunit. Even with this large change in structure, photoinduced electron transfer to the quinone still takes place. To evaluate the effect of H subunit removal on electron transfer to QA, we have compared the kinetics of electron transfer and associated spectral evolution for the LM dimer with that of the intact reaction center complex on picosecond to millisecond time scales. The transient absorption spectra associated with all measured electron transfer reactions are similar, with the exception of a broadening in the QX transition and a blue-shift in the QY transition bands of the special pair of bacteriochlorophylls (P) in the LM dimer. The kinetics of the electron transfer reactions not involving quinones are unaffected. There is, however, a 4-fold decrease in the electron transfer rate from the reduced bacteriopheophytin to QA in the LM dimer compared to the intact reaction center and a similar decrease in the recombination rate of the resulting charge-separated state (P(+)QA(-)). These results are consistent with the concept that the removal of the H-subunit results in increased flexibility in the region around the quinone and an associated shift in the reorganization energy associated with charge separation and recombination. PMID- 27243382 TI - Inceased frequency of psoriasis in the families of the children with familial Mediterranean fever. PMID- 27243381 TI - Impact of hypofractionated and standard fractionated chemoradiation before pancreatoduodenectomy for pancreatic ductal adenocarcinoma. AB - BACKGROUND: Previous studies have suggested that preoperative chemoradiation (CRT) is associated with an improved margin-negative resection rate among patients who undergo pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC). However, the optimal preoperative regimen has not been established. METHODS: All patients with PDAC who received chemotherapy and/or CRT followed by PD between 1999 and 2014 were retrospectively reviewed. The effects of 2 external-beam radiation regimens-a standard course of 50.4 Gy in 28 fractions and a hypofractionated course of 30 Gy in 10 fractions-were compared. Differences in clinicopathologic characteristics, locoregional recurrence (LR), and overall survival (OS) were assessed. RESULTS: Among 472 patients who received preoperative therapy, 224 (47.5%) received 30 Gy, 221 (46.8%) received 50.4 Gy, and 27 (5.7%) received chemotherapy alone. Patients who received 50.4 Gy were more likely to have advanced-stage disease and to have received induction and postoperative chemotherapy, but there was no difference in the R1 margin status, treatment effect, LR, or OS between the 2 radiation groups (all P values > .05). Patients who received preoperative CRT had a lower rate of LR than patients who received preoperative chemotherapy alone (P < .01). In a multivariate Cox proportional hazards analysis, 50.4 Gy was associated with OS and LR similar to those associated with 30 Gy, whereas the absence of preoperative radiation was associated with a higher rate of LR (odds ratio, 2.21; 95% confidence interval, 1.04-4.70) and similar OS. CONCLUSIONS: Preoperative hypofractionated CRT was associated with similar local control and OS in comparison with standard CRT in patients undergoing PD for PDAC. The use of chemotherapy alone without CRT was associated with poorer local control but similar survival. Cancer 2016. (c) 2016 American Cancer Society. Cancer 2016;122:2671-2679. (c) 2016 American Cancer Society. PMID- 27243383 TI - The Statistical Value of Raw Fluorescence Signal in Luminex xMAP Based Multiplex Immunoassays. AB - Tissue samples (plasma, saliva, serum or urine) from 169 patients classified as either normal or having one of seven possible diseases are analysed across three 96-well plates for the presences of 37 analytes using cytokine inflammation multiplexed immunoassay panels. Censoring for concentration data caused problems for analysis of the low abundant analytes. Using fluorescence analysis over concentration based analysis allowed analysis of these low abundant analytes. Mixed-effects analysis on the resulting fluorescence and concentration responses reveals a combination of censoring and mapping the fluorescence responses to concentration values, through a 5PL curve, changed observed analyte concentrations. Simulation verifies this, by showing a dependence on the mean florescence response and its distribution on the observed analyte concentration levels. Differences from normality, in the fluorescence responses, can lead to differences in concentration estimates and unreliable probabilities for treatment effects. It is seen that when fluorescence responses are normally distributed, probabilities of treatment effects for fluorescence based t-tests has greater statistical power than the same probabilities from concentration based t-tests. We add evidence that the fluorescence response, unlike concentration values, doesn't require censoring and we show with respect to differential analysis on the fluorescence responses that background correction is not required. PMID- 27243384 TI - Refined Sulfur Nanoparticles Immobilized in Metal-Organic Polyhedron as Stable Cathodes for Li-S Battery. AB - The lithium-sulfur (Li-S) battery presents a promising rechargeable energy storage technology for the increasing energy demand in a worldwide range. However, current main challenges in Li-S battery are structural degradation and instability of the solid-electrolyte interphase caused by the dissolution of polysulfides during cycling, resulting in the corrosion and loss of active materials. Herein, we developed novel hybrids by employing metal-organic polyhedron (MOP) encapsulated PVP-functionalized sulfur nanoparticles (S@MOP), where the active sulfur component was efficiently encapsulated within the core of MOP and PVP as a surfactant was helpful to stabilize the sulfur nanoparticles and control the size and shape of corresponding hybrids during their syntheses. The amount of sulfur embedded into MOP could be controlled according to requirements. By using the S@MOP hybrids as cathodes, an obvious enhancement in the performance of Li-S battery was achieved, including high specific capacity with good cycling stability. The MOP encapsulation could enhance the utilization efficiency of sulfur. Importantly, the structure of the S@MOP hybrids was very stable, and they could last for almost 1000 cycles as cathodes in Li-S battery. Such high performance has rarely been obtained using metal-organic framework systems. The present approach opens up a promising route for further applications of MOP as host materials in electrochemical and energy storage fields. PMID- 27243385 TI - Protein, enzyme and carbohydrate quantification using smartphone through colorimetric digitization technique. AB - In this paper the utilization of smartphone as a detection platform for colorimetric quantification of biological macromolecules has been demonstrated. Using V-channel of HSV color space, the quantification of BSA protein, catalase enzyme and carbohydrate (using D-glucose) have been successfully investigated. A custom designed android application has been developed for estimating the total concentration of biological macromolecules. The results have been compared with that of a standard spectrophotometer which is generally used for colorimetric quantification in laboratory settings by measuring its absorbance at a specific wavelength. The results obtained with the designed sensor is found to be similar when compared with the spectrophotometer data. The designed sensor is low cost, robust and we envision that it could promote diverse fields of bio-analytical investigations. Schematic illustration of the smartphone sensing mechanism for colorimetric analysis of biomolecular samples. PMID- 27243386 TI - Predicting the apparent viscosity and yield stress of mixtures of primary, secondary and anaerobically digested sewage sludge: Simulating anaerobic digesters. AB - Predicting the flow behaviour, most notably, the apparent viscosity and yield stress of sludge mixtures inside the anaerobic digester is essential because it helps optimize the mixing system in digesters. This paper investigates the rheology of sludge mixtures as a function of digested sludge volume fraction. Sludge mixtures exhibited non-Newtonian, shear thinning, yield stress behaviour. The apparent viscosity and yield stress of sludge mixtures prepared at the same total solids concentration was influenced by the interactions within the digested sludge and increased with the volume fraction of digested sludge - highlighted using shear compliance and shear modulus of sludge mixtures. However, when a thickened primary - secondary sludge mixture was mixed with dilute digested sludge, the apparent viscosity and yield stress decreased with increasing the volume fraction of digested sludge. This was caused by the dilution effect leading to a reduction in the hydrodynamic and non-hydrodynamic interactions when dilute digested sludge was added. Correlations were developed to predict the apparent viscosity and yield stress of the mixtures as a function of the digested sludge volume fraction and total solids concentration of the mixtures. The parameters of correlations can be estimated using pH of sludge. The shear and complex modulus were also modelled and they followed an exponential relationship with increasing digested sludge volume fraction. PMID- 27243387 TI - Elimination of micropollutants and transformation products from a wastewater treatment plant effluent through pilot scale ozonation followed by various activated carbon and biological filters. AB - Conventional wastewater treatment plants are ineffective in removing a broad range of micropollutants, resulting in the release of these compounds into the aquatic environment, including natural drinking water resources. Ozonation is a suitable treatment process for micropollutant removal, although, currently, little is known about the formation, behavior, and removal of transformation products (TP) formed during ozonation. We investigated the elimination of 30 selected micropollutants (pharmaceuticals, X-ray contrast media, industrial chemicals, and TP) by biological treatment coupled with ozonation and, subsequently, in parallel with two biological filters (BF) or granular activated carbon (GAC) filters. The selected micropollutants were removed to very different extents during the conventional biological wastewater treatment process. Ozonation (specific ozone consumption: 0.87 +/- 0.29 gO3 gDOC(-1), hydraulic retention time: 17 +/- 3 min) eliminated a large number of the investigated micropollutants. Although 11 micropollutants could still be detected after ozonation, most of these were eliminated in subsequent GAC filtration at bed volumes (BV) of approximately 25,000 m(3) m(-3). In contrast, no additional removal of micropollutants was achieved in the BF. Ozonation of the analgesic tramadol led to the formation of tramadol-N-oxide that is effectively eliminated by GAC filters, but not by BF. For the antiviral drug acyclovir, the formation of carboxy-acyclovir was observed during activated sludge treatment, with an average concentration of 3.4 +/- 1.4 MUg L(-1) detected in effluent samples. Subsequent ozonation resulted in the complete elimination of carboxy-acyclovir and led to the formation of N-(4-carbamoyl-2-imino-5-oxo imidazolidin)-formamido-N methoxyacetetic acid (COFA; average concentration: 2.6 +/- 1.0 MUg L(-1)). Neither the BF nor the GAC filters were able to remove COFA. These results highlight the importance of considering TP in the evaluation of advanced wastewater treatment processes. The results further indicate that post-treatment of ozonated wastewater with GAC filtration seems to be more suitable than BF, due to the sorption of formed TP to the activated carbon. PMID- 27243388 TI - Ethnicity is an independent predictor of IVF-ICSI outcome: a study of 5,549 cycles in Spain and India. AB - AIM: To determine the role of ethnicity on IVF/ICSI outcomes between Indian and white Caucasian women. SETTINGS AND DESIGN: Retrospective cohort study. MATERIALS AND METHODS: White Caucasian and Indian women undergoing IVF/ICSI treatment cycles. Total 5549 self, non-donor, fresh IVF cycles conducted from January 2014 to March 2015, out of which, 4227 were white Caucasian and 1322 were Indian. Data were collected on baseline characteristics, IVF cycle parameters and outcomes. Ongoing pregnancy rate (OPR) was measured as main outcome. RESULTS: Indian women differed significantly from white Caucasian women in baseline characteristics like age (30.6 +/- 0.2 versus 37.6 +/- 0.1 years; p < 0.001), BMI (22.3 +/- 0.2 versus 26.6 +/- 1.0 kg/m2; p < 0.05), duration of infertility (6.9 +/- 3.0 versus 2.5 +/- 0.1 years; p < 0.001) and antral follicle count (AFC) (8.9 +/- 0.4 versus 7.5 +/- 0.2; p < 0.001). Indian women had lower implantation rate (30.1% versus 39.6%: p < 0.001) and OPR (35.1% versus 41.7%: p < 0.001) compared with white Caucasian women. Regression analysis proved independent effect of ethnicity on OPR (OR 0.944; 95% CI 0.928-0.961: p < 0.001) Conclusions: OPR was significantly lower among Indian ethnic group following IVF/ICSI suggest that ethnicity, like age, is a major and an independent predictor of IVF outcome. PMID- 27243412 TI - Novel regimens prior to autologous stem cell transplantation for the management of adults with relapsed/refractory non-Hodgkin lymphoma and Hodgkin lymphoma: alternatives to BEAM conditioning. AB - High-dose therapy (HDT) followed by autologous stem cell transplant (ASCT) is the standard treatment for relapsed or refractory non-Hodgkin and Hodgkin lymphoma. Until recently, carmustine, etoposide, cytarabine and melphalan (BEAM) was the most commonly used conditioning regimen in this setting, given its acceptable efficacy and tolerability. Despite reasonable success with BEAM, carmustine is associated with a number of acute and late toxicities. Moreover, recent supply and cost issues for this agent have created an urgent need for alternative conditioning regimens. As such, etoposide and melphalan (VP16/MEL) or busulfan, cyclophosphamide, and etoposide (BuCyE) are currently being used with limited success. A number of novel conditioning regimens that replace carmustine with other agents are under investigation, which may provide effective alternatives to BEAM. In considering novel agents to replace carmustine, bendamustine may provide the best alternative, as demonstrated by the results of a number of phase II, multicenter, controlled studies. PMID- 27243413 TI - Morphology Control of Metal-Organic Frameworks Based on Paddle-Wheel Units on Ion Doped Polymer Substrate Using an Interfacial Growth Approach. AB - A three-dimensional metal-organic framework (MOF) consisting of pillared square grid nets based on paddle-wheel units was synthesized by interfacial self assembly of the frameworks on a metal-ion-doped polymer substrate. Although this type of Cu-based MOF is typically synthesized by a two-step solvothermal method, the utilization of a metal-ion-doped polymer substrate as a metal source for the framework allowed for the one-pot growth of MOF crystals on the substrate. The morphology of the obtained MOF crystals could be controlled from tetragonal to elongated tetragonal with different aspect ratios by changing the concentrations of the dicarboxylate layer ligands and diamine pillar ligands. The present approach provides a new route for the design and synthesis of MOF crystals and thin films for future applications such as gas membranes, catalysts, and electronic devices. PMID- 27243414 TI - Postdischarge Care of Pediatric Traumatic Brain Injury in Argentina: A Multicenter Randomized Controlled Trial. AB - OBJECTIVE: To develop, in partnership with families of children with traumatic brain injury, a postdischarge intervention that is effective, simple, and sustainable. DESIGN: Randomized Controlled Trial. SETTING: Seven Level 1 Pediatric Trauma Centers in Argentina. PATIENTS: Persons less than 19 years of age admitted to one of the study hospitals with a diagnosis of severe, moderate, or complicated mild traumatic brain injury and were discharged alive. INTERVENTIONS: Patients were randomly assigned to either the intervention or standard care group. A specially trained Community Resource Coordinator was assigned to each family in the intervention group. We hypothesized that children with severe, moderate, and complicated mild traumatic brain injury who received the intervention would have significantly better functional outcomes at 6 months post discharge than those who received standard care. We further hypothesized that there would be a direct correlation between patient outcome and measures of family function. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was a composite measured at 6 months post injury. There were 308 patients included in the study (61% men). Forty-four percent sustained a complicated mild traumatic brain injury, 18% moderate, and 38% severe. Sixty-five percent of the patients were 8 years old or younger, and over 70% were transported to the hospital without ambulance assistance. There was no significant difference between groups on the primary outcome measure. There was a statistically significant correlation between the primary outcome measure and the scores on the Family Impact Module of the Pediatric Quality of Life Inventory (rho = 0.57; p < 0.0001). Children with better outcomes lived with families reporting better function at 6 months post injury. CONCLUSIONS: Although no significant effect of the intervention was demonstrated, this study represents the first conducted in Latin America that documents the complete course of treatment for pediatric patients with traumatic brain injury spanning hospital transport through hospital care and into the postdischarge setting. PMID- 27243416 TI - Activating Hospitalized Older Patients to Confront the Epidemic of Low Mobility. PMID- 27243417 TI - Synthesis, Optical Properties, and Sensing Applications of Gold Nanodots. AB - In this Personal Account, we briefly address our journey in developing photoluminescent nanomaterials for sensing purposes, with a focus on gold nanodots (Au NDs). Their synthetic strategies, optical properties, and sensing applications are emphasized. The Au NDs can be simply prepared from the etching of small-sized Au nanoparticles (<3 nm in diameter) by thiol compounds such as 11 mercaptoundecanoic acid under alkaline conditions. This simple approach allows the preparation of various functional Au NDs by choosing different thiol compounds as etching agents. Since the optical properties of Au NDs are highly dependent on the core and shell of each Au ND, the selection of etching reagents is important. Over the years we have developed various sensing systems using Au NDs for the detection of metal ions, anions, and proteins, based on analyte induced photoluminescence quenching/enhancement of Au NDs as a result of changes in their oxidation state, shell composition, and structure. PMID- 27243415 TI - Variation in Anticonvulsant Selection and Electroencephalographic Monitoring Following Severe Traumatic Brain Injury in Children-Understanding Resource Availability in Sites Participating in a Comparative Effectiveness Study. AB - OBJECTIVES: Early posttraumatic seizures may contribute to worsened outcomes after traumatic brain injury. Evidence to guide the evaluation and management of early posttraumatic seizures in children is limited. We undertook a survey of current practices of continuous electroencephalographic monitoring, seizure prophylaxis, and the management of early posttraumatic seizures to provide essential information for trial design and the development of posttraumatic seizure management pathways. DESIGN: Surveys were sent to site principal investigators at all 43 sites participating in the Approaches and Decisions in Acute Pediatric TBI trial at the time of the survey. Surveys consisted of 12 questions addressing strategies to 1) implement continuous electroencephalographic monitoring, 2) posttraumatic seizure prophylaxis, 3) treat acute posttraumatic seizures, 4) treat status epilepticus and refractory status epilepticus, and 5) monitor antiseizure drug levels. SETTING: Institutions comprised a mixture of free-standing children's hospitals and university medical centers across the United States and Europe. SUBJECTS: Site principal investigators of the Approaches and Decisions in Acute Pediatric TBI trial. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Continuous electroencephalographic monitoring was available in the PICU in the overwhelming majority of clinical sites (98%); however, the plans to operationalize such monitoring for children varied considerably. A similar majority of sites report that administration of prophylactic antiseizure medications is anticipated in children (93%); yet, a minority reports that a specified protocol for treatment of posttraumatic seizures is in place (43%). Reported medication choices varied substantially between sites, but the majority of sites reported pentobarbital for refractory status epilepticus (81%). The presence of treatment protocols for seizure prophylaxis, early posttraumatic seizures, posttraumatic status epilepticus, and refractory status epilepticus was associated with decreased reported medications (all p < 0.05). CONCLUSIONS: This study reports the current management practices for early posttraumatic seizures in select academic centers after pediatric severe traumatic brain injury. The substantial variation in continuous electroencephalographic monitoring implementation, choice of seizure prophylaxis medications, and management of early posttraumatic seizures across institutions was reported, signifying the areas of clinical uncertainty that will help provide focused design of clinical trials. Although sites with treatment protocols reported a decreased number of medications for the scenarios described, completion of the Approaches and Decisions in Acute Pediatric TBI trial will be able to determine if these protocols lead to decreased variability in medication administration in children at the clinical sites. PMID- 27243418 TI - Minor salivary glands function is decreased in hyposalivation-related diseases. AB - OBJECTIVES: The aim of this cross-sectional study was to investigate the relationship between minor salivary gland (MSG) flow rates and oral dryness degrees in patients with xerostomia induced by primary Sjogren's syndrome (pSS), IgG4-related sialadenitis (IgG4-RS), radiation therapy-induced dry mouth (RTDM), or Steven-Johnson syndrome (SJS). DESIGN: 160 patients with pSS, IgG4-RS, RTDM, or SJS and their age- and sex-matched healthy control subjects were enrolled. The whole saliva flow rates and MSG flow rates were measured in four locations, including the upper labial, lower labial, buccal, and palatal mucosae. The degree of oral dryness was assessed in patient groups using the summated xerostomia inventory (SXI). RESULTS: The flow rates of whole saliva and most MSGs in patient groups were significantly lower than the flow rates in healthy control groups (P<0.05). The mean relative percentage of decrease in saliva flow rates was smaller in MSGs than in whole saliva in patient groups (P<0.05), indicating that these disorders have less impact on MSGs. Among the four MSG locations (the upper labial, lower labial, buccal, and palatal), buccal glands showed the highest flow rates in patient groups (P<0.05). SXI scores were significantly higher in pSS and RTDM patients than in IgG4-RS and SJS patients (P<0.05). The degree of xerostomia varied among different patient groups (P<0.05) and there was no clear correlation between MSG flow rates and SXI scores (P>0.05). CONCLUSIONS: MSG function is significantly reduced in pSS, RTDM, IgG4-RS, and SJS patients, but this reduction is more pronounced in the major salivary glands. PMID- 27243419 TI - Impact of multiple sclerosis on employment and use of job-retention strategies: The situation in France in 2015. AB - OBJECTIVE: The main objective of this survey of persons with multiple sclerosis was to describe their employment situation. Secondary objectives were to ascertain when and how multiple sclerosis symptoms first impact employment per se and what strategies persons with multiple sclerosis use to cope with their employment problems. METHODS: A retrospective survey was conducted to collect data from persons with multiple sclerosis aged 18 years and over, using a computer-assisted web tool. RESULTS: A total of 941 respondents were working at the time of multiple sclerosis diagnosis or had worked subsequently. Median time since diagnosis was 10 years. Multiple sclerosis had an impact on employment for 74.3% of respondents. The overall employment rate at the time of the survey was 68.1%; 27.2% had discontinued their occupational activity for a multiple sclerosis-related reason. Median time from diagnosis to multiple sclerosis related cessation of occupational activity was 24.0 years (95% confidence interval (CI) 21.7-26.3 years). Respondents were poorly aware of available tools designed to assist them in retaining employment. CONCLUSION: This study highlights the importance of early intervention by the occupational medicine physician in order to favour job retention and use of available tools by all workers with MS and not only those with a recognized status as a disabled worker. PMID- 27243420 TI - alpha1,2-Fucosyllactose Does Not Improve Intestinal Function or Prevent Escherichia coli F18 Diarrhea in Newborn Pigs. AB - OBJECTIVES: Infectious diarrhea, a leading cause of morbidity and deaths, is less prevalent in breastfed infants compared with infants fed infant formula. The dominant human milk oligosaccharide (HMO), alpha-1,2-fucosyllactose (2'-FL), has structural homology to bacterial adhesion sites in the intestine and may in part explain the protective effects of human milk. We hypothesized that 2'-FL prevents diarrhea via competitive inhibition of pathogen adhesion in a pig model for sensitive newborn infants. METHODS: Intestinal cell studies were coupled with studies on cesarean-delivered newborn pigs (n = 24) without (control) or with inoculation of enterotoxigenic Escherichia coli F18 (7.5 * 10/day for 8 days) fed either no (F18) or 10 g/L 2'-FL (2FL-F18). RESULTS: In vitro studies revealed decreased pathogen adhesion to intestinal epithelial cells with 2'-FL (5 g/L; P < 0.001). F18 pigs showed more diarrhea than control pigs (P < 0.01). Administration of 2'-FL to F18 pigs failed to prevent diarrhea, although the relative weight loss tended to be reduced (-19 vs -124 g/kg, P = 0.12), higher villi were observed in the distal small intestine (P < 0.05), and a trend toward increased proportion of mucosa and activities of some brush border enzymes in the proximal small intestine. In situ abundance of alpha-1,2-fucose and E coli was similar between groups, whereas sequencing showed higher abundance of Enterobacteriaceae in F18, Enterococcus in control and Lachnospiraceae in 2FL-F18 pigs. CONCLUSIONS: 2'-FL inhibited in vitro adhesion of E coli F18 to epithelial cells, but had limited effects on diarrhea and mucosal health in newborn pigs challenged with E coli F18. PMID- 27243421 TI - Predictors of Pouchitis After Ileal Pouch-Anal Anastomosis in Children. AB - OBJECTIVES: Predictive factors for the development of pouchitis after ileal pouch anal anastomosis (IPAA) in children have not been well studied. In this retrospective study, the incidence and risk factors that predict pouchitis in children with IPAA will be identified. METHODS: The records of patients who underwent IPAA surgery at Children's Hospital of Wisconsin between January 2000 and December 2013 were reviewed retrospectively. Patients with clinical, endoscopic, and histological findings consistent with pouchitis were identified. The groups of patients with and without pouchitis or chronic pouchitis were compared to determine which demographic, pathological, or disease characteristics may serve as predictive factors for the development of pouchitis or chronic pouchitis. RESULTS: Out of a total of 60 patients who underwent IPAA, preoperative diagnosis was ulcerative colitis (UC) in 43 and familial adenomatous polyposis (FAP) in 17. Pouchitis was identified in 24 (56%) patients with UC and 2 (12%) patients with FAP. Subgroup analysis of patients with UC revealed that chronic pouchitis occurred in 15 (35%) patients. The median follow-up period from construction of the IPAA was 35 months (range 4.59-104.26 months). The study analysis revealed that a higher Pediatric Ulcerative Colitis Activity Index score at the time of diagnosis was a significant predictive factor for both pouchitis (P = 0.001) and chronic pouchitis (P = 0.02). CONCLUSIONS: Patients with UC and a higher PUCAI score at the time of diagnosis have a higher risk for developing pouchitis. PMID- 27243422 TI - Clearance of Hepatitis C Virus After Fixed-Dose Combination Ledipasvir/Sofosbuvir in an Adolescent Female With Decompensated Cirrhosis. AB - Currently the only Food and Drug Administration-approved treatment for children with chronic hepatitis C virus is pegylated interferon with ribavirin, which is associated with significant adverse effects and low sustained virologic response rates. In this report, we discuss the use of ledipasvir/sofosbuvir to treat an adolescent with cirrhosis secondary to chronic hepatitis C virus. PMID- 27243423 TI - Associated Factors for Antegrade Continence Enemas for Refractory Constipation and Fecal Incontinence. AB - OBJECTIVE: Determine clinical and manometric parameters associated with success of antegrade continence enemas (ACEs) administered via cecostomy in the treatment of constipation and fecal overflow incontinence. METHODS: We performed a retrospective review of clinical symptoms and manometry (colonic and anorectal) before cecostomy in 40 pediatric patients (20 males, 20 females). The mean age at time of follow-up was 9.5 +/- 4.4 years with a mean follow-up time of 12.2 +/- 10.9 months. Clinical outcomes were defined as good, if subjects had >3 bowel movements per week, <2 episodes of soiling per week, and absence of pain at the time of follow-up after cecostomy. RESULTS: Before cecostomy, the mean duration of constipation and/or fecal incontinence was 7.7 +/- 4.4 years, mean number of BMs was 1.5 +/- 0.9 per week, and soiling episodes 4.12 +/- 3.5 per week; 24 (60%) patients had abdominal pain. At follow-up 30 out of 40 patients had a good outcome, and 10 had a poor outcome; with a difference in the number of weekly BM of 5.7 +/- 2.2 versus 1.5 +/- 0.9, P < 0.001, and soiling episodes (0.4 +/- 1.5 vs 4 +/- 3.1, P < 0.001). There was no difference in the duration of symptoms between groups. Obesity was more common in the poor-outcome group, 60% versus 21% (P = 0.01). Abdominal pain was more common in the poor-outcome group, 100% versus 47% (P = 0.003). Normal colonic manometry was associated with good outcome, whereas absence of high-amplitude propagating contraction (HAPC) in any part of the colon was associated with poor outcome. No other differences in colonic manometry were observed between the good- and poor-outcome groups with the exception of a trend toward decreased number of sigmoid HAPCs in the poor-outcome group (P = 0.07). No differences were observed in anorectal manometry measurements between good- and poor-outcome groups with the exception of an observable increased baseline resting pressure in the poor outcome (P = 0.05). CONCLUSIONS: Obesity and abdominal pain tend to be associated with poor outcomes after cecostomy for refractory constipation. Normal colonic and anorectal manometry were associated with good outcome. Absence of HAPC in any part of the colon, and increased baseline resting pressure of the anal canal were more associated with poor outcome. No other specific differences in either colonic or anorectal manometric parameters were observed in patients with good versus poor outcomes with cecostomy. Large prospective studies potentially combining other diagnostic modalities such as colonic transit studies are needed to determine the optimal tests to predict successful outcomes from cecostomy. PMID- 27243425 TI - A Tribute to Home Health Aides Everywhere. PMID- 27243424 TI - Physiotherapy and Occupational Therapy and Mild to Moderate Parkinson Disease. PMID- 27243427 TI - Parkinson Disease. AB - Parkinson disease (PD) is a progressive neurodegenerative disease that affects one million people in the United States. This article reviews the etiology and pathophysiology of PD, risk factors, clinical manifestations, diagnostic criteria, and treatment of this common disease. Implications for home care clinicians are included. PMID- 27243428 TI - Integrating a Student Pharmacist Into the Home Healthcare Setting. AB - Patients in a transition of care are highly susceptible to health and medication errors. In many situations, patients are eager to go home and providers are expected to discharge quickly. It is in this time of documented vulnerability that an increase in adverse effects related to poor health literacy, medication usage, and a lack of documentation occurs. Through the collaboration of Vanderbilt Home Care Services, Inc., and Belmont University College of Pharmacy, pharmacy students are utilized in a capacity that integrates pharmacy students into the home healthcare team to ease transitions of care and reduce medication related problems in patients. Students work alongside home healthcare clinicians in both the field and the office to benefit patients the most by allowing each healthcare discipline to focus on what it does best. PMID- 27243429 TI - Chronic Pain in Older African American Grandparent Caregivers. AB - African American grandparent caregiving is increasing, and evidence shows that grandparent caregiving influences health and its management. As older adults age, their potential of experiencing chronic pain increases, and this is profound given that physiological research shows that African Americans, aside from aging, may have a predisposition for developing chronic pain. Research shows older African Americans experience significant chronic pain, but few have discussed the implications of managing chronic pain in older African Americans who have added parental responsibility. Many older African Americans receive home healthcare services and there is a unique role for home healthcare clinicians in caring for this vulnerable population. This article discusses the impact of pain on caregiving, challenges in pain management, and practice and policy implications to assist home healthcare clinicians maintain the safety and protection of both the older grandparent and grandchildren. PMID- 27243430 TI - Indicators of Job Satisfaction of Home Healthcare Nurses in the San Francisco Bay Area of California. AB - The purpose of this study was to identify the factors that provide job satisfaction for home healthcare nurses and to determine if the nurses' educational level makes a difference in job satisfaction. Data were collected using Ellenbecker's (2004) 21-item Home Healthcare Nurses Job Satisfaction Scale. The study results indicated the majority of this population of home healthcare nurses was satisfied on all items, except in having the power to change agency policy. Educational level made no significant difference in job satisfaction. Recommendations include encouraging agencies to include clinicians in policy decision-making and management of patient care. Nursing education programs should ensure nurses graduate with the skills necessary for policy development and to make decisions that positively impact patient care. PMID- 27243431 TI - Visiting Nursing. AB - The following is a reprint from the October 1900 issue of The American Journal of Nursing. PMID- 27243432 TI - Glargine U-100 (Basaglar(r)): A Follow-On Insulin. PMID- 27243433 TI - Providing Unused Medications at Discharge; Dosing Error With Tasigna. PMID- 27243434 TI - Reducing the Risk of Infection When Using a Bath Basin. PMID- 27243435 TI - A Day in the Life of a Home Health Aide/Health Coach. PMID- 27243436 TI - Injured Employees. PMID- 27243437 TI - Providers' Rights When Patients Are Abusive. PMID- 27243438 TI - Primary Home Care: The Foundation of Quality. PMID- 27243440 TI - Parkinson Disease. PMID- 27243439 TI - Respecting and Supporting Home Health Aides. PMID- 27243441 TI - Ischemia detection from morphological QRS angle changes. AB - In this paper, an ischemia detector is presented based on the analysis of QRS derived angles. The detector has been developed by modeling ischemic effects on the QRS angles as a gradual change with a certain transition time and assuming a Laplacian additive modeling error contaminating the angle series. Both standard and non-standard leads were used for analysis. Non-standard leads were obtained by applying the PCA technique over specific lead subsets to represent different potential locations of the ischemic zone. The performance of the proposed detector was tested over a population of 79 patients undergoing percutaneous coronary intervention in one of the major coronary arteries (LAD (n = 25), RCA (n = 16) and LCX (n = 38)). The best detection performance, obtained for standard ECG leads, was achieved in the LAD group with values of sensitivity and specificity of [Formula: see text], [Formula: see text], followed by the RCA group with [Formula: see text], Sp = 94.4 and the LCX group with [Formula: see text], [Formula: see text], notably outperforming detection based on the ST series in all cases, with the same detector structure. The timing of the detected ischemic events ranged from 30 s up to 150 s (mean = 66.8 s) following the start of occlusion. We conclude that changes in the QRS angles can be used to detect acute myocardial ischemia. PMID- 27243442 TI - Expression of homeobox genes in the mouse olfactory epithelium. AB - Homeobox genes constitute a large family of genes widely studied because of their role in the establishment of the body pattern. However, they are also involved in many other events during development and adulthood. The main olfactory epithelium (MOE) is an excellent model to study neurogenesis in the adult nervous system. Analyses of homeobox genes during development show that some of these genes are involved in the formation and establishment of cell diversity in the MOE. Moreover, the mechanisms of expression of odorant receptors (ORs) constitute one of the biggest enigmas in the field. Analyses of OR promoters revealed the presence of homeodomain binding sites in their sequences. Here we characterize the expression patterns of a set of 49 homeobox genes in the MOE with in situ hybridization. We found that seven of them (Dlx3, Dlx5, Dlx6, Msx1, Meis1, Isl1, and Pitx1) are zonally expressed. The homeobox gene Emx1 is expressed in three guanylate cyclase(+) populations, two located in the MOE and the third one in an olfactory subsystem known as Gruneberg ganglion located at the entrance of the nasal cavity. The homeobox gene Tshz1 is expressed in a unique patchy pattern across the MOE. Our findings provide new insights to guide functional studies that aim to understand the complexity of transcription factor expression and gene regulation in the MOE. J. Comp. Neurol. 524:2713-2739, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27243443 TI - Determinants of urinary concentrations of dialkyl phosphates among pregnant women in Canada - Results from the MIREC study. AB - Organophosphate (OP) insecticides are commonly used in agriculture. Their use decreased in recent years as they were gradually replaced by other pesticides, but some OPs are still among the insecticides most used in Canada. Exposure to elevated levels of OPs during pregnancy has been associated with adverse birth outcomes and poorer neurodevelopment in children. The objective of the present study was to examine the relationship between the concentrations of OP pesticides urinary dialkyl phosphate (DAP) metabolites and various factors that are potential sources of exposure or determinants of DAP levels. In the Maternal Infant Research on Environmental Chemicals (MIREC) Study, six DAPs were measured in 1st trimester urine samples of 1884 pregnant women living in Canada. They were grouped into sums of dimethyl alkyl phosphates (DMAP) and diethyl alkyl phosphates (DEAP) for statistical analysis. We found that 93% of women had at least one DAP detected in their urine. Geometric means (GM) of specific gravity corrected levels for urine dilution were 59 (95% CI 56-62) and 21 (95% CI 20-22) nmol/L for DMAP and DEAP, respectively. The following characteristics were significantly associated with higher urinary concentrations of DMAP or DEAP: higher education, nulliparous, normal pre-pregnancy body mass index, non-smoker, not fasting at sampling, winter season at sampling, and early and late day collection times. Dietary items that were significantly related with higher urinary concentrations included higher intake of citrus fruits, apple juice, sweet peppers, tomatoes, beans and dry peas, soy and rice beverages, whole grain bread, white wine and green and herbal teas. This study indicates that exposure to these compounds is quasi-ubiquitous. The factors associated with greater DAP levels identified here could be useful to regulatory agencies for risk analysis and management. However, some exposure misclassification might occur due to the single DAP measurement available, and to the presence of preformed DAPs in the environment. PMID- 27243444 TI - The Role of Posterior Longitudinal Ligament in Cervical Disc Replacement: An Ovine Cadaveric Biomechanical Analysis. AB - BACKGROUND Cervical disc replacement (CDR) has been widely used to restore and maintain mobility and function of the treated and adjacent motion segments. Posterior longitudinal ligament (PLL) resection has been shown to be efficient in anterior cervical decompression and fusion. However, less is known about the biomechanical effect of PLL removal versus preservation in cervical disc arthroplasty. MATERIAL AND METHODS Three motion segments of 24 ovine cervical spines (C2-C5) were evaluated in a robotic spine system with axial compressive loads of 50 N. These cervical spines were divided in three groups according to the following conditions: (1) intact spine, (2) C3/C4 CDR with the Prestige LP prosthesis and PLL preservation, and (3) C3/C4 CDR with the Prestige LP prosthesis and PLL removal. The ranges of motion (ROMs) were recorded and analyzed in each group. RESULTS The C3/C4 ROM in group 3 (CDR with PLL removed) increased significantly in flexion-extension and axial rotation compared with group 1 (intact spine). Moreover, in flexion-extension, the mean total ROM was significantly larger in group 3 than in group 1. All the ROM observed in group 2 (CDR with PLL preserved) did not significantly differ from the ROM observed in group 1. CONCLUSIONS Compared with intact spines, CDR with PLL removal partly increased ROM. Moreover, the ROM in CDR with PLL preservation did not significantly differ from the ROM observed in intact spines. The PLL appears to contribute to the balance and stability of the cervical spine and should thus be preserved in cervical disc replacement provided that the posterior longitudinal ligament is not degenerative and the compression can be removed without PLL takedown. PMID- 27243445 TI - Effects of 3G cell phone exposure on the structure and function of the human cytochrome P450 reductase. AB - Cell phones increase exposure to radiofrequency (RF) electromagnetic fields (EMFs). Whether EMFs exert specific effects on biological systems remains debatable. This study investigated the effect of cell phone exposure on the structure and function of human NADPH-cytochrome P450 reductase (CPR). CPR plays a key role in the electron transfer to cytochrome P450, which takes part in a wide range of oxidative metabolic reactions in various organisms from microbes to humans. Human CPR was exposed for 60min to 1966-MHz RF inside a transverse electromagnetic cell (TEM-cell) placed in an incubator. The specific absorption rate (SAR) was 5W.kg(-1). Conformation changes have been detected through fluorescent spectroscopy of flavin and tryptophan residues, and investigated through circular dichroism, dynamic light scattering and microelectrophoresis. These showed that CPR was narrowed. By using cytochrome C reductase activity to assess the electron flux through the CPR, the Michaelis Menten constant (Km) and the maximum initial velocity (Vmax) decreased by 22% as compared with controls. This change was due to small changes in the tertiary and secondary structures of the protein at 37 degrees C. The relevance of these findings to an actual RF exposure scenario demands further biochemical and in-vivo confirmation. PMID- 27243446 TI - Microbial community dynamics in continuous microbial fuel cells fed with synthetic wastewater and pig slurry. AB - Two-chambered microbial fuel cells (MFCs) operating with synthetic wastewater and pig slurry were assessed. Additionally, the use of 2-bromoethanesulfonate (BES Inh) was studied. The synthetic wastewater-fed MFC (MFCSW) showed a maximum power density (PDmax) of 2138mWm(-3), and the addition of BES-Inh (10mM) did not show any improvement in its performance (PDmax=2078mWm(-3)). When pig slurry was used as feed (MFCPS), PDmax increased up to 5623mWm(-3). The microbial community composition was affected by the type of substrate used. While, Pseudomonadaceae and Clostridiaceae were the most representative families within the acetate-based medium, Flavobacteriaceae, Chitinophagaceae, Comamonadaceae and Nitrosomonadaceae were predominant when pig slurry was used as feed. Otherwise, only the Eubacterial microbial community composition was strongly modified when adding BES Inh, thus leading to an enrichment of the Bacteroidetes phylum. Oppositely, the Archaeal community was less affected by the addition of BES-Inh, and Methanosarcina sp., arose as the predominant family in both situations. Despite all the differences in microbial communities, 6 operational taxonomic units (OTUs) belonging to Bacteroidetes (Porphyromonadaceae and Marinilabiaceae) and Firmicutes (Clostridiales) were found to be common to both MFCs, also for different contents of COD and N-NH4(+), and therefore could be considered as the bioanode core microbiome. PMID- 27243447 TI - Direct electric current treatment modifies mitochondrial function and lipid body content in the A549 cancer cell line. AB - Electrochemical therapy (EChT) entails treatment of solid tumors with direct electric current (DC). This work evaluated the specific effects of anodic flow generated by DC on biochemical and metabolic features of the A549 human lung cancer cell line. Apoptosis was evaluated on the basis of caspase-3 activity and mitochondrial transmembrane potential dissipation. Cell morphology was analyzed using transmission electron microscopy, and lipid droplets were studied through morphometric analysis and X-ray qualitative elemental microanalysis. High resolution respirometry was used to assess mitochondrial respiratory parameters. Results indicated A549 viability decreased in a dose-dependent manner with a prominent drop between 18 and 24h after treatment (p<0.001), together with a two fold increase in caspase-3 activity. AF-treatment induced a significantly increase (p<0.01) in the cell number with disrupted mitochondrial transmembrane potential. Furthermore, treated cells demonstrated important ultrastructural mitochondria damage and a three-fold increase in the cytoplasmic lipid bodies' number, quantified by morphometrical analyses. Conversely, 24h after treatment, the cells presented a two-fold increase of residual oxygen consumption, accounting for 45.3% of basal oxygen consumption. These results show remarkable alterations promoted by anodic flow on human lung cancer cells which are possibly involved with the antitumoral effects of EChT. PMID- 27243448 TI - Assessing fit of alternative unidimensional polytomous IRT models using posterior predictive model checking. AB - This article explored the application of the posterior predictive model checking (PPMC) method in assessing fit for unidimensional polytomous item response theory (IRT) models, specifically the divide-by-total models (e.g., the generalized partial credit model). Previous research has primarily focused on using PPMC in model checking for unidimensional and multidimensional IRT models for dichotomous data, and has paid little attention to polytomous models. A Monte Carlo simulation was conducted to investigate the performance of PPMC in detecting different sources of misfit for the partial credit model family. Results showed that the PPMC method, in combination with appropriate discrepancy measures, had adequate power in detecting different sources of misfit for the partial credit model family. Global odds ratio and item total correlation exhibited specific patterns in detecting the absence of the slope parameter, whereas Yen's Q1 was found to be promising in the detection of misfit caused by the constant category intersection parameter constraint across items. (PsycINFO Database Record PMID- 27243449 TI - Nature-Derived Aloe Vera Gel Blended Silk Fibroin Film Scaffolds for Cornea Endothelial Cell Regeneration and Transplantation. AB - The goal of this study was to fabricate an appropriate replacement for cadaveric corneas to overcome a shortage of cadaveric corneas for transplantation. In this study, we fabricated transparent ultrathin film scaffolds with nature-derived aloe vera (AV) gel and silk fibroin (SF) for corneal endothelial cells (CECs). The scaffolds were subjected to analysis of transparency and contact angle using field emission scanning electron microscopy (FESEM) and Fourier transform infrared spectroscopy to determine their physical and chemical properties. FESEM images revealed that the critical morphology of CECs was formed on the AV gel in the blend with SF rather than in the scaffold with SF alone. The cell proliferation, phenotype, and specific gene marker expressions for CECs were determined by MTT assays, immunofluorescence, and reverse transcription polymerase chain reactions. Incorporation of a small amount of AV gel increased the cell viability and maintained its functions well. The scaffolds were easily handled for transplantation into rabbit eyes with small incisions and examined by their transparency after transplantation and histological staining. The scaffolds attached to the surface of the corneal stroma and integrated with surrounding corneal tissue without a significant inflammatory reaction. These results indicate that AV blended SF film scaffolds might be a suitable substitute for alternative corneal grafts for transplantation. PMID- 27243450 TI - Efficient separation of transition metals from rare earths by an undiluted phosphonium thiocyanate ionic liquid. AB - The ionic liquid trihexyl(tetradecyl)phosphonium thiocyanate has been used for the extraction of the transition metal ions Co(ii), Ni(ii), Zn(ii), and the rare earth ions La(iii), Sm(iii) and Eu(iii) from aqueous solutions containing nitrate or chloride salts. The transition metal ions showed a high affinity for the ionic liquid phase and were efficiently extracted, while the extraction efficiency of the rare-earth ions was low. This difference in extraction behavior enabled separation of the pairs Co(ii)/Sm(iii), Ni(ii)/La(iii) and Zn(ii)/Eu(iii). These separations are relevant for the recycling of rare earths and transition metals from samarium cobalt permanent magnets, nickel metal hydride batteries and lamp phosphors, respectively. The extraction of metal ions from a chloride or nitrate solution with a thiocyanate ionic liquid is an example of "split-anion extraction", where different anions are present in the aqueous and ionic liquid phase. Close to 100% loading was possible for Co(ii) and Zn(ii) up to a concentration of 40 g L(-1) of the transition metal salt in the initial aqueous feed solution, whereas the extraction efficiency for Ni(ii) gradually decreased with increase in the initial feed concentration. Stripping of Co(ii), Zn(ii) and Ni(ii) from the loaded ionic liquid phase was possible by a 15 wt% NH3 solution. The ionic liquid could reused after extraction and stripping. PMID- 27243451 TI - The vocal repertoire of Tibetan macaques (Macaca thibetana): A quantitative classification. AB - Vocal repertoires are basic and essential components for describing vocal communication in animals. Studying the entire suite of vocal signals aids investigations on the variation of acoustic structure across social contexts, comparisons on the complexity of communication systems across taxa, and in exploration of the evolutionary origins of species-specific vocalizations. Here, we describe the vocal repertoire of the largest species in the macaque genus, Macaca thibetana. We extracted thirty acoustic parameters from call recordings. Post hoc validation through quantitative analyses of the a priori repertoire classified eleven call types: coo, squawk, squeal, noisy scream, growl, bark, compound squeak, leap coo, weeping, modulated tonal scream, and pant. In comparison to the rest of the genus, Tibetan macaques uttered a wider array of vocalizations in the context of copulations. Previous reports did not include modulated tonal screams and pants during harassment of copulatory dyads. Furthermore, in comparison to the rest of the genus, Tibetan macaque females emit acoustically distinct copulation calls. The vocal repertoire of Tibetan macaques contributes to the literature on the emergence of species-specific calls in the genus Macaca with potential insights from social, reproductive, and ecological comparisons across species. Am. J. Primatol. 78:937-949, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27243452 TI - Facile and environmentally friendly synthesis of ultrathin nickel hydroxide nanosheets with excellent supercapacitor performances. AB - In this article, we report a facile and environmentally friendly glutamic acid assisted hydrothermal strategy for the preparation of ultrathin two-dimensional (2D) beta-Ni(OH)2 nanosheets with a thickness of about 2 nm, which exhibit a maximum specific capacitance of 2537.4 F g(-1) at a current density of 1 A g(-1), even at 10 A g(-1), the specific capacitance is still maintained at 2290.0 F g( 1) with 77.6% retention after 3000 cycles. PMID- 27243453 TI - Treatment of Renal Cell Cancer With Programmed Cell Death 1 Blockade: How Much Is Enough? PMID- 27243454 TI - Stimulus Specificity of Brain-Computer Interfaces Based on Code Modulation Visual Evoked Potentials. AB - A brain-computer interface (BCI) based on code modulated visual evoked potentials (c-VEP) is among the fastest BCIs that have ever been reported, but it has not yet been given a thorough study. In this study, a pseudorandom binary M sequence and its time lag sequences are utilized for modulation of different stimuli and template matching is adopted as the method for target recognition. Five experiments were devised to investigate the effect of stimulus specificity on target recognition and we made an effort to find the optimal stimulus parameters for size, color and proximity of the stimuli, length of modulation sequence and its lag between two adjacent stimuli. By changing the values of these parameters and measuring classification accuracy of the c-VEP BCI, an optimal value of each parameter can be attained. Experimental results of ten subjects showed that stimulus size of visual angle 3.8 degrees , white, spatial proximity of visual angle 4.8 degrees center to center apart, modulation sequence of length 63 bits and the lag of 4 bits between adjacent stimuli yield individually superior performance. These findings provide a basis for determining stimulus presentation of a high-performance c-VEP based BCI system. PMID- 27243455 TI - Diversity and Distribution Patterns of Cetaceans in the Subtropical Southwestern Atlantic Outer Continental Shelf and Slope. AB - Temporal and spatial patterns of cetacean diversity and distribution were investigated through eight ship-based surveys carried out during spring and autumn between 2009 and 2014 on the outer continental shelf (~150m) and slope (1500m) off southeastern and southern Brazil (~23 degrees S to ~34 degrees S). The survey area was divided into southeast and south areas according to their oceanographic characteristics. Twenty-one species were observed in 503 sightings. The overall number of species was similar between the two areas, though it was higher in the spring in the south area. Five species were dominant and diversity varied more seasonally than spatially. ANOVA and kernel analyses showed that overall cetacean densities were higher in spring compared to autumn. Physeter macrocephalus, the most frequent species, concentrated throughout the south area at depths over 1000m in both seasons. Despite the overlapped occurrence at a broader scale, small delphinids presented latitudinal and in-offshore gradients as well as seasonal variation in distribution patterns, which could indicate habitat partitioning between some species. Delphinus delphis was only recorded in the south and its density decreased in areas where the presence of Stenella frontalis increased, mainly beyond the 250m isobath. Densities of S. longirostris and S. attenuata increased in lower latitudes and beyond the shelf break. The large delphinids Tursiops truncatus and Globicephala melas formed mixed groups in many occasions and were observed along the study area around depths of 500m. Grampus griseus was twice as frequent in the south area and densities increased in waters deeper than 600m. As expected, densities of both small and large migratory whales were higher during spring, over the continental slope, in the southeast area. The results presented here provided strong evidence on the importance of the outer continental shelf and slope to a diverse community of cetaceans occurring in the subtropical Southwestern Atlantic. PMID- 27243456 TI - Chronic Vitamin D Intoxication in Captive Iberian Lynx (Lynx pardinus). AB - To document the biochemical and pathologic features of vitamin D intoxication in lynx and to characterize mineral metabolism in healthy lynx, blood samples were obtained from 40 captive lynx that had been receiving excessive (approximately 30 times the recommended dose) vitamin D3 in the diet, and from 29 healthy free ranging lynx. Tissue samples (kidney, stomach, lung, heart and aorta) were collected from 13 captive lynx that died as a result of renal disease and from 3 controls. Vitamin D intoxication resulted in renal failure in most lynx (n = 28), and widespread extraskeletal calcification was most severe in the kidneys and less prominent in cardiovascular tissues. Blood minerals and calciotropic hormones in healthy lynx were similar to values reported in domestic cats except for calcitriol which was higher in healthy lynx. Changes in mineral metabolism after vitamin D intoxication included hypercalcemia (12.0 +/- 0.3 mg/dL), hyperphosphatemia (6.3 +/- 0.4 mg/dL), increased plasma calcidiol (381.5 +/- 28.2 ng/mL) and decreased plasma parathyroid hormone (1.2 +/- 0.7 pg/mL). Hypercalcemia and, particularly, hyperphosphatemia were of lower magnitude that what has been previously reported in the course of vitamin D intoxication in other species. However, extraskeletal calcifications were severe. The data suggest that lynx are sensitive to excessive vitamin D and extreme care should be taken when supplementing this vitamin in captive lynx diets. PMID- 27243457 TI - Hypothetical Rectal Microbicide Acceptability and Factors Influencing It among Men Who Have Sex with Men in Tianjin, China. AB - OBJECTIVES: To measure potential acceptability of rectal microbicides and to explore factors likely to affect their acceptability among men who have sex with men (MSM). METHODS: Cross-sectional and retrospective surveys were conducted in this study. A questionnaire and a scale were used to measure the acceptability score for physical and functional characteristics of hypothetical rectal microbicides. We also evaluated the involvement of other factors such as sexual behaviors, social context, etc. RESULTS: MSMs we interviewed showed a high acceptability to rectal microbicides, indicated by the mean acceptability score of 2.92 (SD, 0.54, scale of 1-4). The results also suggested that microbicides were preferred in a cream form that can moisten and lubricate the rectum, prevent HIV infection and go unnoticed by their partners. Multivariate analysis showed that the microbicides acceptability varied significantly by education level (beta = 0.135; P = 0.028), having casual partners (beta = 0.174; P = 0.007), frequency of lubricant use (beta = 0.134; P = 0.031), history of HIV test (beta = 0.129; P = 0.036), willingness to use lubricant (beta = 0.126; P = 0.045), locus of control by partners regarding STI infection (beta = 0.168; P = 0.009). CONCLUSIONS: A positive response to rectal microbicides among MSMs was found in our study, suggesting that rectal microbicides might have a potential market in MSMs and they might play an important role in HIV/STIs prevention as a supplement. Further studies may be considered to combine the acceptability study with clinical research together to understand the true feelings of MSMs when they use the products. PMID- 27243458 TI - Examining daily variability in willingness to drink in relation to underage young adult alcohol use. AB - A key component of the Prototype Willingness Model is willingness, which reflects an openness to opportunity to perform a behavior in situations that are conducive to that behavior. Willingness has traditionally been tested using global, hypothetical assessments, and has not been examined at the daily level. We expected to find within-person variability in willingness to drink, such that on days with greater willingness, individuals would report greater drinking. A national sample (N=288) of young adults aged 18 to 20 (31.60% female) completed a Web-based survey that was comprised of measures of drinking and sexual behavior, including the Timeline Follow-Back (Sobell & Sobell, 1992). Findings show daily variability in willingness to drink (ICC=0.54), which suggests that there are substantial differences from day-to-day in this drinking-related cognition. Participants drank more on days when individuals also reported feeling more willing to drink than their own average level across the two weeks. Daily process level mechanisms allow greater insight into factors contributing to increased risk in-the-moment, which may point to targets for interventions aimed at improving adolescents' and young adults' abilities to make healthier choices in moments when they may be at greater risk for engaging in risky behaviors. PMID- 27243459 TI - Disruption of Splenic Lymphoid Tissue and Plasmacytosis in Canine Visceral Leishmaniasis: Changes in Homing and Survival of Plasma Cells. AB - Visceral leishmaniasis (VL) is a disease caused by Leishmania infantum, which is transmitted by phlebotomine sandflies. Dogs are the main urban reservoir of this parasite and the disease presents similar characteristics in both humans and dogs. In this paper, we investigated the potential pathways involved in plasma cell replacement of normal cell populations in the spleen, with respect to disease severity in dogs from an endemic area for visceral leishmaniasis. To this end, canine spleen samples were grouped into three categories: TYPE1SC- (non infected dogs or without active infection with organized white pulp), TYPE1SC+ (infected dogs with organized white pulp) or TYPE3SC+ (infected animals with disorganized white pulp). We analyzed the distribution of different plasma cell isotypes (IgA, IgG and IgM) in the spleen. The expression of cytokines and chemokines involved in plasma cell homing and survival were assessed by real time RT-PCR. Polyclonal B cell activation and hypergammaglobulinemia were also evaluated. The proportion of animals with moderate or intense plasmacytosis was higher in the TYPE3SC+ group than in the other groups (Fisher test, P<0.05). This was mainly due to a higher density of IgG+ plasma cells in the red pulp of this group. The albumin/globulin ratio was lower in the TYPE3SC+ animals than in the TYPE1SC- or TYPE1SC+ animals, which evidences VL-associated dysproteinemia. Interestingly, TYPE3SC+ animals showed increased expression of the BAFF and APRIL cytokines, as well as chemokine CXCL12. Aberrant expression of BAFF, APRIL and CXCL12, together with amplified extrafollicular B cell activation, lead to plasma cell homing and the extended survival of these cells in the splenic red pulp compartment. These changes in the distribution of immunocompetent cells in the spleen may contribute to the progression of VL, and impair the spleen's ability to protect against blood borne pathogens. PMID- 27243461 TI - A Revolution in Treatment for Hepatitis C Infection: Mitigating the Budgetary Impact. AB - In a Perspective accompanying Hill and colleagues, Elliot Marseille and James Kahn compare the history of pricing and availability of ART for HIV with that of the new HCV drugs and discuss strategies for providing treatment in LMIC even in the face of high costs. PMID- 27243460 TI - Characterization and Transferable Utility of Microsatellite Markers in the Wild and Cultivated Arachis Species. AB - Microsatellite or simple sequence repeat (SSR) is one of the most widely distributed molecular markers that have been widely utilized to assess genetic diversity and genetic mapping for important traits in plants. However, the understanding of microsatellite characteristics in Arachis species and the currently available amount of high-quality SSR markers remain limited. In this study, we identified 16,435 genome survey sequences SSRs (GSS-SSRs) and 40,199 expressed sequence tag SSRs (EST-SSRs) in Arachis hypogaea and its wild relative species using the publicly available sequence data. The GSS-SSRs had a density of 159.9-239.8 SSRs/Mb for wild Arachis and 1,015.8 SSR/Mb for cultivated Arachis, whereas the EST-SSRs had the density of 173.5-384.4 SSR/Mb and 250.9 SSRs/Mb for wild and cultivated Arachis, respectively. The trinucleotide SSRs were predominant across Arachis species, except that the dinucleotide accounted for most in A. hypogaea GSSs. From Arachis GSS-SSR and EST-SSR sequences, we developed 2,589 novel SSR markers that showed a high polymorphism in six diverse A. hypogaea accessions. A genetic linkage map that contained 540 novel SSR loci and 105 anchor SSR loci was constructed by case of a recombinant inbred lines F6 population. A subset of 82 randomly selected SSR markers were used to screen 39 wild and 22 cultivated Arachis accessions, which revealed a high transferability of the novel SSRs across Arachis species. Our results provided informative clues to investigate microsatellite patterns across A. hypogaea and its wild relative species and potentially facilitate the germplasm evaluation and gene mapping in Arachis species. PMID- 27243462 TI - Are Worry and Rumination Specific Pathways Linking Neuroticism and Symptoms of Anxiety and Depression in Patients with Generalized Anxiety Disorder, Major Depressive Disorder and Mixed Anxiety-Depressive Disorder? AB - This study examines the relationships between neuroticism (higher-order vulnerability factor), the cognitive styles of worry, brooding and reflection (second-order vulnerability factors) and symptoms of anxiety and depression in three groups of patients: patients with Generalized Anxiety Disorder (GAD), with Major Depressive Disorder (MDD) and with Mixed Anxiety-Depressive Disorder (MADD). One hundred and thirty four patients completed a battery of questionnaires including measures of neuroticism, worry, rumination (brooding and reflection), anxiety and depression. Multiple mediation analyses indicate that worry may act as a mediating mechanism linking neuroticism and anxiety symptoms in the three diagnostic groups, whereas brooding-rumination may play a mediating role between neuroticism and depressive symptoms in patients with MDD and MADD and, with less certainty, in patients with GAD. Overall, our findings suggest that neuroticism may increase the risk of anxious and depressive symptoms via specific links involving either worry or brooding, respectively, and that both worry and brooding may operate in the three groups examined, irrespectively of whether anxiety or depression are the main emotions or whether they coexist without any clear predominance; consequently, we hypothesize the existence of "specific transdiagnostic" mechanisms. PMID- 27243463 TI - Fluorescent Lipid Nanoparticles as Biomembrane Models for Exploring Emerging Contaminant Bioavailability Supported by Density Functional Theory Calculations. AB - Experimental sensing schemes and thermodynamic in-silico studies are combined holistically in this manuscript so as to give new insights into the bioavailability of environmental contaminants via permeation across lipid nanoparticles (liposomes) as a mimicry of biological membranes. Using Prodan and Laurdan as fluorescent membrane probes, phosphatidylcholine-based unilamellar liposomes are harnessed to investigate membranotropic effects of alkyl esters of p-hydroxybenzoic acid and triclosan in vitro on the basis of steady-state fluorescence anisotropy, light scattering, and generalized polarization measurements. The feasibility of the analytical responses to ascertain differences in temperature-dependent contaminant bioavailability is investigated in detail. High level density functional theory (DFT) calculations (RI-BP86 D3/def2-SVP) have been resorted to investigate noncovalent 1:1 complexes of the fluorescent probes and emerging contaminants with dipalmitoylphosphatidylcholine, as a minimalist model of a lipid nanoparticle, to evaluate both the interaction energies and the geometries of the complexes. This information can be related to the degree of penetration of the guest across the lipid bilayer. Our experimental results supported by in-silico DFT calculations and ecotoxicological data let us to conclude that simple analytical measurements of liposomal changes in lipid packaging, permeability, and fluidity are appropriate to foresee the potential bioavailability and toxicity of emerging contaminants. PMID- 27243465 TI - Catalytic Iodination of the Aliphatic C-F Bond by YbI3(THF)3: Mechanistic Insight and Synthetic Utility. AB - A facile iodination protocol of unactivated alkyl fluorides using catalytic amounts of YbI3(THF)3 in the presence of iodotrimethylsilane as a stoichiometric fluoride trapping agent is presented. (1)H NMR spectroscopy demonstrates a two step catalytic cycle where TMSI regenerates active YbI3(THF)3. Finally, the catalytic reaction is extended into a one-pot procedure to demonstrate a potential application of the method. Overall, the findings present a distinct strategy for C-F bond transformations in the presence of catalytic YbI3(THF)3. PMID- 27243464 TI - Pattern of Imaging after Lung Cancer Resection. 1992-2005. AB - RATIONALE: Imaging intensity after lung cancer resection performed with curative intent is unknown. OBJECTIVES: To describe the pattern and trends in the use of computed tomography (CT) and positron emission tomography (PET) scans in patients after resection of early-stage lung cancer. METHODS: Retrospective analysis of the linked Surveillance, Epidemiology and End Results (SEER)-Medicare database. Subjects included 8,621 Medicare beneficiaries (age, >=66 yr) who underwent lung cancer resection with curative intent between 1992 and 2005. A surveillance CT or PET examination was defined as CT or PET imaging performed in an outpatient setting on patients who did not undergo chest radiography in the preceding 30 days. MEASUREMENTS AND MAIN RESULTS: Overall, imaging use was higher within the first 2 years versus Years 3-5 after surgical resection. Use of surveillance CT scans increased sharply from 13.7 to 57.3% of those diagnosed in 1996-1997 and 2004-2005, respectively. PET scan use increased threefold, from 6.2% in 2000-2001 to 19.6% in 2004-2005. In multivariable analyses, we observed a 32% increase in the odds of undergoing surveillance CT or PET imaging for every year of diagnosis between 1998 and 2005. There was no substantial decline in the odds of having a surveillance CT or PET scan during each successive follow-up period, suggesting no change in the intensity of surveillance over the first 5 years after surgical resection. The proportion of surveillance CT imaging performed at freestanding imaging centers increased from 18.0% in 1998-1999 to 30.6% in 2004-2005. CONCLUSIONS: The use of CT and PET imaging for surveillance after curative-intent surgical resection of early-stage lung cancer increased sharply in the United States between 1997-1998 and 2005. In the absence of evidence demonstrating favorable outcomes, this practice was likely driven by prevailing expert opinion embedded in clinical practice guidelines made available during that time. Research is clearly needed to determine the role and optimal approach to surveillance thoracic imaging after surgical resection of lung cancer. PMID- 27243466 TI - Three new isobenzofuranone derivatives from the fruiting bodies of Hericium erinaceus. AB - Three new isobenzofuranone derivatives erinaceolactones D-F (1-3), together with four known ones (4-7), were isolated from the fruiting bodies of Hericium erinaceus. Their structures were determined on the basis of comprehensive spectroscopic analyses including UV, 1D, 2D NMR and HR-TOF-MS. The absolute configuration of erinaceolactone D (1) and erinaceolactone E (2) were assigned by comparing their specific rotation with those of analogs in literatures. The four known compounds were isomers with each other and were isolated simultaneously for the first time. PMID- 27243467 TI - Evolutionary determinants of polycystic ovary syndrome: part 2. AB - Polycystic ovary syndrome (PCOS) is a prehistoric complex genetic trait, perhaps dating back at least 50,000 years. The disorder also represents an evolutionary paradox, demonstrating clear reproductive disadvantages (i.e., lack of evolutionary fitness), albeit persisting tens of thousands of years. Here we examine possible explanations for this paradox. We evaluate a variety of possible benefits accruing to women in ancestral populations who possessed this trait, including considerations of whether dramatic changes in environment and lifestyle from the ancestral past to the contemporary present have altered the selection dynamics operating on the trait. Putative benefits include metabolic functioning, immune system dynamics, patterns of child-rearing and mothering, reproductive longevity, in utero or childhood survival, and musculoskeletal advantages. However, there is limited evidence that the persistence and relative homogeneity in the prevalence of PCOS can be accounted for by direct positive selection. Rather, PCOS evolution has likely been driven by nonadaptive evolutionary mechanisms, including genetic drift due to a serial founder effect and population balance due to sexually antagonistic selection. Ultimately, insights into the evolutionary origins of PCOS will emerge through the study not only of unique characteristics of affected individuals and their environments butalso through a broad consideration of the potential adaptive and beneficial aspects of vulnerability to the disorder, importantly including examination of populations whose fertility, disease load, and diet resemble those of ancestral humans. PMID- 27243468 TI - Prenatal Antidepressant Use and Risk of Autism Spectrum Disorders in Children. PMID- 27243469 TI - The Carboxyl Terminus of Eremomycin Facilitates Binding to the Non-d-Ala-d-Ala Segment of the Peptidoglycan Pentapeptide Stem. AB - Glycopeptide antibiotics inhibit cell wall biosynthesis in Gram-positive bacteria by targeting the peptidoglycan (PG) pentapeptide stem structure (l-Ala-d-iso-Gln l-Lys-d-Ala-d-Ala). Structures of the glycopeptide complexed with a PG stem mimic have shown that the d-Ala-d-Ala segment is the primary drug binding site; however, biochemical evidence suggests that the glycopeptide-PG interaction involves more than d-Ala-d-Ala binding. Interactions of the glycopeptide with the non-d-Ala-d-Ala segment of the PG stem were investigated using solid-state nuclear magnetic resonance (NMR). LCTA-1421, a double (15)N-enriched eremomycin derivative with a C-terminal [(15)N]amide and [(15)N]Asn amide, was complexed with whole cells of Staphylococcus aureus grown in a defined medium containing l [3-(13)C]Ala and d-[1-(13)C]Ala in the presence of alanine racemase inhibitor alaphosphin. (13)C{(15)N} and (15)N{(13)C} rotational-echo double-resonance (REDOR) NMR measurements determined the (13)C-(15)N internuclear distances between the [(15)N]Asn amide of LCTA-1421 and the (13)C atoms of the bound d-[1 (13)C]Ala-d-[1-(13)C]Ala to be 5.1 and 4.8 A, respectively. These measurements also determined the distance from the C-terminal [(15)N]amide of LCTA-1421 to the l-[3-(13)C]Ala of PG to be 3.5 A. The measured REDOR distance constraints position the C-terminus of the glycopeptide in the proximity of the l-Ala of the PG, suggesting that the C-terminus of the glycopeptide interacts near the l-Ala segment of the PG stem. In vivo REDOR measurements provided structural insight into how C-terminally modified glycopeptide antibiotics operate. PMID- 27243470 TI - PCR: the price of infidelity. PMID- 27243471 TI - Expansion microscopy passes its first test. PMID- 27243472 TI - Redesigning CLIP for efficiency, accuracy and speed. PMID- 27243473 TI - On the toxicity of ibogaine. PMID- 27243474 TI - High Rates of Herpes Simplex Virus Type 2 Infection in Homeless Women: Informing Public Health Strategies. AB - BACKGROUND: Homeless and unstably housed women living in an urban setting are at risk for sexually transmitted diseases, yet the seroprevalence and correlates of herpes simplex virus type 2 (HSV-2) specific to impoverished women are poorly understood. MATERIALS AND METHODS: Between April and October 2010, we conducted a cross-sectional analysis of sociodemographic, structural, and behavioral factors associated with prevalent HSV-2 infection (recent and historical infections) within a community-recruited cohort of homeless and unstably housed women. Logistic regression modeling was used to identify independent sociobehavioral correlates of HSV-2 infection. RESULTS: Among 213 women (114 HIV positive and 99 HIV negative), the median age was 49, 48% were African American, and 63% had completed high school. HSV-2 seroprevalence was 88%, and only 17% of infected women were aware of their infection. In adjusted analysis, odds of HSV-2 infection were significantly higher for those reporting at-risk drinking (adjusted odds ratio [AOR] = 7.04; 95% confidence interval [CI] = 1.59, 67.91), heterosexual orientation (AOR = 4.56; 95% CI = 1.81, 11.69), and for those who were HIV positive (AOR = 3.64; 95% CI = 1.43, 10.30). Odds of HSV-2 infection decreased as current income increased (AOR for each $500 monthly increase = 0.90; 95% CI = 0.78, 0.997). CONCLUSIONS: There is an extremely high seroprevalence of HSV-2 infection among homeless and unstably housed women, and most are unaware of their HSV-2 status. Screening all unstably housed women for HSV-2 infection, with additional counseling for sexual risk and alcohol use, may lead to the identification of more infections and be a first step in reducing additional disease transmission. PMID- 27243475 TI - Enhanced Fluorescence Turn-on Imaging of Hypochlorous Acid in Living Immune and Cancer Cells. AB - Two closely related phenyl selenyl based boron-dipyrromethene (BODIPY) turn-on fluorescent probes for the detection of hypochlorous acid (HOCl) were synthesized for studies in chemical biology; emission intensity is modulated by a photoinduced electron-transfer (PET) process. Probe 2 intrinsically shows a negligible background signal; however, after reaction with HOCl, chemical oxidation of selenium forecloses the PET process, which evokes a significant increase in fluorescence intensity. The fluorescence intensity of probes 1 and 2 with HOCl involves an ~18 and ~50-fold enhancement compared with the respective responses from other reactive oxygen/nitrogen species (ROS/RNS) and low detection limits (30.9 nm for 1 and 4.5 nm for 2). Both probes show a very fast response with HOCl; emission intensity reached a maximum within 1 s. These probes show high selectivity for HOCl, as confirmed by confocal microscopy imaging when testing with RAW264.7 and MCF-7 cells. PMID- 27243476 TI - Physical Activity Self-Efficacy and Fitness: Family Environment Relationship Correlates and Self-Esteem as a Mediator among Adolescents Who Are Overweight or Obese. AB - BACKGROUND: Little is known regarding how dimensions of the family social environment relate to fitness levels and physical activity self-efficacy (PASE) among adolescents who are overweight or obese and whether these relationships are mediated by self-esteem. METHODS: Potential associations were evaluated between relationship subdomains (cohesion, conflict, expressivity) of the Family Environment Scale (FES), self-esteem (Rosenberg Self-Esteem Scale, RSES), and PASE and fitness, using recovery heart rate [RHR, beats per minute (bpm)] from a 3-minute submaximal step test at baseline. Participants were 108 adolescents who were overweight or obese and were seeking weight-loss treatment as part of the Healthy Kids, Healthy Weight 12-week multidisciplinary pediatric weight management program. Structural equation modeling (SEM) was used to simultaneously evaluate paths between these variables and test for mediation. RESULTS: In multivariable models, higher FES cohesion (beta = -2.18, s.e. = 0.98; p = 0.02), expressivity (beta = -1.97, s.e. = 0.99; p < 0.05), and PASE (beta = -0.64, s.e. = 0.33; p < 0.05) scores were associated with lower RHR, which represents higher fitness. Furthermore, higher FES conflict scores were associated with lower RSES scores (beta = -0.83, s.e. = 0.29; p < 0.01), and FES conflict (beta = -0.63, s.e. = 0.22; p < 0.01) and RSES (beta = 0.33, s.e. = 0.07; p < 0.01) were associated with PASE scores. In a good-fitting multivariate SEM [Comparative Fit Index (CFI) = 1.00; Standardized Root Mean Square Residual (SRMR) = 0.02; Tucker Lewis index (TLI) = 1.22; Root Mean Squared Error of Approximation (RMSEA) <0.01], RSES mediated the relationship between FES conflict and PASE (sum of indirect paths: beta = -0.30, s.e. = 0.11; p < 0.01) scores. CONCLUSIONS: Our results highlight the importance of the relationship domain of the family environment on self-esteem, PASE, and physical fitness in adolescents who are overweight or obese. PMID- 27243477 TI - Chronic activation of NPFFR2 stimulates the stress-related depressive behaviors through HPA axis modulation. AB - Neuropeptide FF (NPFF) is a morphine-modulating peptide that regulates the analgesic effect of opioids, and also controls food consumption and cardiovascular function through its interaction with two cognate receptors, NPFFR1 and NPFFR2. In the present study, we explore a novel modulatory role for NPFF-NPFFR2 in stress-related depressive behaviors. In a mouse model of chronic mild stress (CMS)-induced depression, the expression of NPFF significantly increased in the hypothalamus, hippocampus, medial prefrontal cortex (mPFC) and amygdala. In addition, transgenic (Tg) mice over-expressing NPFFR2 displayed clear depression and anxiety-like behaviors with hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis, reduced expression of glucocorticoid receptor (GR) and neurogenesis in the hippocampus. Furthermore, acute treatment of NPFFR2 agonists in wild-type (WT) mice enhanced the activity of the HPA axis, and chronic administration resulted in depressive and anxiety-like behaviors. Chronic stimulation of NPFFR2 also decreased the expression of hippocampal GR and led to persistent activation of the HPA axis. Strikingly, bilateral intra paraventricular nucleus (PVN) injection of NPFFR2 shRNA predominately inhibits the depressive-like behavior in CMS-exposed mice. Antidepressants, fluoxetine and ketamine, effectively relieved the depressive behaviors of NPFFR2-Tg mice. We speculate that persistent NPFFR2 activation, in particular in the hypothalamus, up-regulates the HPA axis and results in long-lasting increases in circulating corticosterone (CORT), consequently damaging hippocampal function. This novel role of NPFFR2 in regulating the HPA axis and hippocampal function provides a new avenue for combating depression and anxiety-like disorder. PMID- 27243549 TI - Early Gastric Cancers: Is CT Surveillance Necessary after Curative Endoscopic Submucosal Resection for Cancers That Meet the Expanded Criteria? AB - Purpose To determine the yield of follow-up abdominopelvic computed tomography (CT) in detecting extragastric recurrence after curative endoscopic submucosal dissection (ESD) for early gastric cancers (EGCs) that meet the expanded criteria. Materials and Methods Institutional review board approval was obtained for this retrospective study, and the requirement to obtain informed consent was waived. Patients who underwent curative ESD for EGCs that met the expanded criteria between November 2005 and December 2009 and who underwent post-ESD CT and endoscopy were included. The final cohort comprised 415 EGCs in 404 patients (261 EGCs in 251 patients met the conventional criteria, and 154 EGCs in 153 patients met the expanded criteria). The primary outcome was post-ESD CT discovery of extragastric recurrence (ie, lymph node or distant metastasis) not detected with endoscopy. The mean radiation dose from each CT examination was calculated. The incidence of gastric recurrence detected with endoscopy and/or CT was also analyzed. The cumulative incidence of gastric recurrence during the post ESD follow-up period was analyzed with the Kaplan-Meier method. Results From a total of 2182 post-ESD CT examinations, extragastric recurrence (lymph node metastasis) was detected in only two patients (one with EGC that met conventional criteria and one with EGC that met expanded criteria). The mean (+/-standard deviation) volume CT dose index, dose-length product, and size-specific dose estimate per CT examination was 28.95 mGy +/- 8.44, 876.80 mGy . cm +/- 161.86, and 43.78 mGy +/- 11.54, respectively. From a total of 3262 post-ESD endoscopic examinations, 41 gastric recurrences were detected (11 local recurrences and five synchronous and 25 metachronous gastric cancers). Among them, eight gastric recurrences were also detected with CT. The cumulative incidences of gastric recurrence 1, 3, and 5 years after ESD were 1.7% (two of 404 patients), 3.2% (13 of 404 patients), and 7.4% (30 of 404 patients), respectively. Conclusion When EGC meets the expanded criteria, surveillance CT after curative ESD rarely depicts extragastric recurrence during 5-year post-ESD follow-up. (c) RSNA, 2016 Online supplemental material is available for this article. PMID- 27243550 TI - Fabrication of Chemically Tunable, Hierarchically Branched Polymeric Nanostructures by Multi-branched Anodic Aluminum Oxide Templates. AB - In this paper, a template-assisted replication method is demonstrated for the fabrication of hierarchically branched polymeric nanostructures composed of post modifiable poly(pentafluorophenyl acrylate). Anodic aluminum oxide templates with various shapes of hierarchically branched pores are fabricated by an asymmetric two-step anodization process. The hierarchical polymeric nanostructures are obtained by infiltration of pentafluorophenyl acrylate with a cross-linker and photoinitiator, followed by polymerization and selective removal of the template. Furthermore, the nanostructures containing reactive pentafluorophenyl ester are modified with spiropyran amine via post-polymerization modification to fabricate ultraviolet-responsive nanostructures. This method can be readily extended to other amines and offers a generalized strategy for controlling functionality and wettability of surfaces. PMID- 27243551 TI - Recent Progress in Aptamer-Based Functional Probes for Bioanalysis and Biomedicine. AB - Nucleic acid aptamers are short synthetic DNA or RNA sequences that can bind to a wide range of targets with high affinity and specificity. In recent years, aptamers have attracted increasing research interest due to their unique features of high binding affinity and specificity, small size, excellent chemical stability, easy chemical synthesis, facile modification, and minimal immunogenicity. These properties make aptamers ideal recognition ligands for bioanalysis, disease diagnosis, and cancer therapy. This review highlights the recent progress in aptamer selection and the latest applications of aptamer-based functional probes in the fields of bioanalysis and biomedicine. PMID- 27243552 TI - Differential effects of Cytomegalovirus carriage on the immune phenotype of middle-aged males and females. AB - The elderly population is more susceptible to infections as a result of an altered immune response, commonly referred to as immunosenescence. Cytomegalovirus (CMV)-infection associated changes in blood lymphocytes are known to impact this process, but the interaction with gender remains unclear. Therefore, we analysed the effects and interaction of gender and CMV on the absolute numbers of a comprehensive set of naive and memory T- and B-cell subsets in people between 50 and 65 years of age. Enumeration and characterisation of lymphocyte subsets by flow cytometry was performed on fresh whole blood samples from 255 middle-aged persons. CMV-IgG serostatus was determined by ELISA. Gender was a major factor affecting immune cell numbers. CMV infection was mainly associated with an expansion of late-differentiated T-cell subsets. CMV+ males carried lower numbers of total CD4+, CD4+ central memory (CM) and follicular helper T-cells than females and CMV- males. Moreover, CMV+ males had significantly lower numbers of regulatory T (Treg)-cells and memory B-cells than CMV+ females. We here demonstrate an interaction between the effects of CMV infection and gender on T- and B-cells in middle-aged individuals. These differential effects on adaptive immunity between males and females may have implications for vaccination strategies at middle-age. PMID- 27243553 TI - Comparative effectiveness of surgical and nonsurgical therapy for advanced laryngeal cancer. AB - BACKGROUND: The treatment of patients with advanced stage laryngeal cancer includes surgery or concurrent chemoradiation (CRT). Although CRT has become more common in recent years, to the authors' knowledge, the effectiveness of complete CRT in improving survival over surgery has not been studied. METHODS: The authors examined patients in the Surveillance, Epidemiology, and End Results (SEER) Medicare claims-linked data set with locoregional laryngeal cancer who were diagnosed between 1997 and 2007. Multivariate Cox proportional hazard analyses were conducted to compare overall and cause-specific 5-year survival rates between treatment modalities, adjusting for patient sociodemographic and clinical characteristics. A propensity score-matched subcohort also was used to compare survival. RESULTS: Of the 3212 patients in the study cohort, 42% underwent surgery and 18% underwent CRT. Only approximately one-quarter of patients who were treated with CRT completed the courses. In adjusted analyses, the authors were unable to reject the null hypothesis of no difference in 5-year all-cause or cause-specific mortality risk between patients treated with surgery and patients undergoing complete CRT (hazards ratio, 1.25 [95% confidence interval, 0.91-1.71; P = .16] and hazard ratio, 1.41 [95% confidence interval, 0.9-2.2; P = .14], respectively). Older age, not currently married, Medicaid eligibility, and prior cancer history were found to be associated with a higher risk of mortality (P<.05). CONCLUSIONS: Patients with advanced laryngeal cancer who underwent complete CRT were found to have overall and cause-specific survival rates similar to those of patients undergoing surgery. However, a substantial percentage of patients who initiated CRT did not complete the course. Although CRT provides organ preservation, the benefits and trade-offs of CRT and total laryngectomy should be discussed fully with patients. The importance of completing the full course of CRT should be emphasized. Cancer 2016. (c) 2016 American Cancer Society. Cancer 2016;122:2845-2856. (c) 2016 American Cancer Society. PMID- 27243564 TI - Synthesis of S-Aryl Phosphorothioates by Copper-Catalyzed Phosphorothiolation of Diaryliodonium and Arenediazonium Salts. AB - Green methods for the synthesis of S-aryl phosphorothioates have been developed based on copper-catalyzed multicomponent reactions involving diaryliodonium/arenediazonium salts, elemental sulfur, and R2P(O)H compounds. Most target products are obtained with these two methods in good to high yields at room temperature. These transformations allow the direct formation P-S and C-S bonds in one reaction. PMID- 27243554 TI - Signal transduction pathways activated by insulin-like peptide 5 at the relaxin family peptide RXFP4 receptor. AB - BACKGROUND AND PURPOSE: Insulin-like peptide 5 (INSL5) is a two-chain, three disulfide-bonded peptide of the insulin/relaxin superfamily, uniquely expressed in enteroendocrine L-cells of the colon. It is the cognate ligand of relaxin family peptide RXFP4 receptor that is mainly expressed in the colorectum and enteric nervous system. This study identifies new signalling pathways activated by INSL5 acting on RXFP4 receptors. EXPERIMENTAL APPROACH: INSL5/RXFP4 receptor signalling was investigated using AlphaScreen(r) proximity assays. Recruitment of Galphai/o proteins by RXFP4 receptors was determined by rescue of Pertussis toxin (PTX)-inhibited cAMP and ERK1/2 responses following transient transfection of PTX insensitive Galphai/o C351I mutants. Cell proliferation was studied with bromodeoxyuridine. RXFP4 receptor interactions with beta-arrestins, GPCR kinase 2 (GRK2), KRas and Rab5a was assessed with real-time BRET. Gene expression was investigated using real-time quantitative PCR. Insulin release was measured using HTRF and intracellular Ca2+ flux monitored in a Flexstation(r) using Fluo-4-AM. KEY RESULTS: INSL5 inhibited forskolin-stimulated cAMP accumulation and increased phosphorylation of ERK1/2, p38MAPK, Akt Ser473 , Akt Thr308 and S6 ribosomal protein. cAMP and ERK1/2 responses were abolished by PTX and rescued by mGalphaoA , mGalphaoB and mGalphai2 and to a lesser extent mGalphai1 and mGalphai3 . RXFP4 receptors interacted with GRK2 and beta-arrestins, moved towards Rab5a and away from KRas, indicating internalisation following receptor activation. INSL5 inhibited glucose-stimulated insulin secretion and Ca2+ mobilisation in MIN6 insulinoma cells and forskolin-stimulated cAMP accumulation in NCI-H716 enteroendocrine cells. CONCLUSIONS AND IMPLICATIONS: Knowledge of signalling pathways activated by INSL5 at RXFP4 receptors is essential for understanding the biological roles of this novel gut hormone. LINKED ARTICLES: This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc. PMID- 27243565 TI - Climatic change controls productivity variation in global grasslands. AB - Detection and identification of the impacts of climate change on ecosystems have been core issues in climate change research in recent years. In this study, we compared average annual values of the normalized difference vegetation index (NDVI) with theoretical net primary productivity (NPP) values based on temperature and precipitation to determine the effect of historic climate change on global grassland productivity from 1982 to 2011. Comparison of trends in actual productivity (NDVI) with climate-induced potential productivity showed that the trends in average productivity in nearly 40% of global grassland areas have been significantly affected by climate change. The contribution of climate change to variability in grassland productivity was 15.2-71.2% during 1982-2011. Climate change contributed significantly to long-term trends in grassland productivity mainly in North America, central Eurasia, central Africa, and Oceania; these regions will be more sensitive to future climate change impacts. The impacts of climate change on variability in grassland productivity were greater in the Western Hemisphere than the Eastern Hemisphere. Confirmation of the observed trends requires long-term controlled experiments and multi-model ensembles to reduce uncertainties and explain mechanisms. PMID- 27243566 TI - The Crystal Structure of the YknZ Extracellular Domain of ABC Transporter YknWXYZ from Bacillus amyloliquefaciens. AB - Bacillus possesses the peptide toxin Sporulation-Delaying Protein (SDP), which can kill cells within a biofilm to support continued growth, thereby delaying the onset of biofilm sporulation. The four-component transporter YknWXYZ acts as a major SDP efflux pump to protect cells against the endogenous SDP toxin, for which YknYZ is a non-canonical ATP-binding cassette (ABC)-type transporter. YknYZ consists of the following two components: (1) an individual protein (YknY) and (2) a respective permease (YknZ). To date, the crystal structure, molecular function, and mechanism of action of the integral membrane protein YknZ remain to be elucidated. In this study, to characterize the structural and biochemical roles of YknZ in the functional assembly of YknWXYZ, we predicted and overexpressed the YknZ extracellular domain. We determined the crystal structure of B. amyloliquefaciens YknZ at a resolution of 2.0 A. The structure revealed that the YknZ extracellular region exhibits significant structural similarity with the MacB periplasmic domain, which is a non-canonical ABC-type transporter in the tripartite macrolide-specific efflux pump in Gram-negative bacteria. We also found that the YknZ extracellular domain can directly bind to an extracellular component of YknX. This structural and biochemical study provides insights into the assembly of YknWXYZ, which may be relevant to understanding cannibalistic peptide toxin resistance in Bacillus and controlling bacterial growth. PMID- 27243567 TI - Residual sleep disturbances following PTSD treatment in active duty military personnel. AB - OBJECTIVE: Sleep disturbances, including nightmares and insomnia, are frequently reported symptoms of posttraumatic stress disorder (PTSD). Insomnia is one of the most common symptoms to persist after evidence-based PTSD treatment. The purpose of this study was to examine the prevalence of sleep disturbances in a sample of active duty military personnel before and after receiving therapy for PTSD in a clinical trial and to explore the associations of insomnia and nightmares with PTSD diagnosis after treatment. METHOD: Sleep parameters were evaluated with the PTSD Checklist in 108 active duty U.S. Army soldiers who had completed at least one deployment in support of the wars in Iraq and Afghanistan and who participated in a randomized clinical trial comparing Group Cognitive Processing Therapy-Cognitive Only Version with Group Present-Centered Therapy. RESULTS: Insomnia was the most frequently reported symptom before and after treatment, with 92% reporting insomnia at baseline and 74%-80% reporting insomnia at follow up. Nightmares were reported by 69% at baseline and by 49%-55% at follow-up. Among participants who no longer met criteria for PTSD following treatment, 57% continued to report insomnia, but only 13% continued to report nightmares. At baseline, 54% were taking sleep medications, but sleep medication use did not affect the overall results. CONCLUSIONS: Insomnia was found to be one of the most prevalent and persistent problems among service members receiving PTSD treatment. Nightmares were relatively more positively responsive to treatment. For some service members with PTSD, the addition of specific treatments targeting insomnia and/or nightmares may be indicated. (PsycINFO Database Record PMID- 27243568 TI - Resilience in Palestinian adolescents living in Gaza. AB - : [Correction Notice: An Erratum for this article was reported in Vol 9(1) of Psychological Trauma: Theory, Research, Practice, and Policy (see record 2016 36102-001). There were grammatical errors to the Method section of the abstract and the Method subsection Participants. Corrected versions are provided.] Objective: The pathogenic impact of ongoing political conflict on children and adolescents has been well-documented in the literature. The present study, by contrast, examined the factors that support adolescent health and utilized a salutogenic model to examine prevalence of depression and anxiety and predictors of resilience in a group of adolescents attending secondary school in Gaza. METHOD: There were 335 Palestinian adolescents (n = 335) enrolled in 11th and 12th grades in secondary schools in Gaza refugee camps completed the Beck Depression Inventory, the Beck Anxiety Inventory, and self-report measures assessing coping skills, self-regulation, optimism, parenting style, family sense of coherence, national identity, ethnic identity, and other demographic variables. RESULTS: Participants with stronger national identity, stronger family sense of coherence, greater self-regulation, and more optimism reported less depressive and anxious symptoms. In a logistic regression analysis, significant predictors of resilience (minimal to no anxiety and depression, n = 135) were age, optimism, family sense of coherence, ethnic identity, self-regulation, and coping skills. CONCLUSION: These findings indicate that older age, optimism, perception of family seeing the world as comprehensible, manageable, and meaningful, stronger Arab ethnic identity, greater self-regulation and stronger coping skills promote adolescent adaptation and health. Salutogenesis frames information about how resilient youth living in high threat environments may respond to preventative community-based behavioral health interventions as well as treatment of depression, anxiety, and other psychological distress among adolescents living with ongoing violence. (PsycINFO Database Record PMID- 27243569 TI - Trauma symptoms in a diverse population of sexually abused children. AB - OBJECTIVE: The role of ethnicity, age, and gender in studies of sexually abused children has been overlooked. Yet, studies have found that African American and Latino sexually abused children suffer from more severe symptoms at treatment presentation and longer lasting effects than Caucasian children. Furthermore, evidence suggests that age and gender impact symptoms resulting from sexual abuse. This study focused on examining demographic differences in trauma symptoms and posttreatment data in an urban, ethnically diverse population of sexually abused children. METHOD: The sample was selected from archival data of 176 children who ranged from the ages of 8 to 16. Therapists administered the Trauma Symptom Checklist for Children (TSCC) at pretreatment and posttreatment. RESULTS: Symptom scores were significantly lower for 41 children who completed 3 months of trauma-focused cognitive-behavioral therapy (TF-CBT) on all TSCC scales except Sexual Concerns, Dissociation, and Overt Dissociation. For the entire sample, mean symptom scores for Sexual Preoccupation were significantly higher for African American children compared to Latino and Caucasian children. Older children had significantly higher scores on scales for Anxiety, Depression, Anger, Posttraumatic Stress, Dissociation, and Sexual Distress. Sexual Distress scale scores were significantly higher among females. CONCLUSION: Findings indicate that trauma symptoms significantly improved after 3 months of TF-CBT. Trauma symptoms differed for children by ethnic group, age, and gender. Identifying factors that impact symptomatology is critical to providing effective, culturally competent treatment for ethnic minority children who are child sexual abuse victims. (PsycINFO Database Record PMID- 27243570 TI - The role of oxytocin in empathy in PTSD. AB - OBJECTIVE: Although impairments in social skills are common in posttraumatic stress disorder (PTSD), only a handful of studies have investigated the empathic abilities of patients with PTSD. The first aim of this study was to characterize emotional and cognitive empathy deficits among patients with PTSD. Furthermore, intranasal oxytocin (OT) has been reported as possibly improving emotional empathy, and it has recently been suggested that patients with PTSD may suffer from abnormal functioning of the oxytocinergic system. Therefore, the second aim of this study was to investigate whether intranasal OT may enhance empathic abilities in these patients. METHOD: Using a randomized, double-blind, placebo controlled crossover design, we administered 24 International Units of oxytocin and placebo at a 1-week interval to 32 patients with PTSD and to 30 matched healthy controls and then measured participants' emotional and cognitive empathy. RESULTS: Patients with PTSD exhibited deficits in both emotional and cognitive empathy, and these deficits were associated with the severity of their PTSD symptoms. The administration of OT did not improve empathic abilities in our sample, although it did tend to selectively enhance the ability of men with PTSD to recognize body motions of anger. CONCLUSIONS: These results indicate that patients with PTSD have deficits in both emotional and cognitive empathic abilities and that their empathic difficulties may underlie their impairments in social and interpersonal skills. (PsycINFO Database Record PMID- 27243571 TI - Impulsivity facets' predictive relations with DSM-5 PTSD symptom clusters. AB - OBJECTIVE: Posttraumatic stress disorder (PTSD) has a well-established theoretical and empirical relation with impulsivity. Prior research has not used a multidimensional approach for measuring both PTSD and impulsivity constructs when assessing their relationship. METHOD: The current study assessed the unique relationship of impulsivity facets on PTSD symptom clusters among a nonclinical sample of 412 trauma-exposed adults. RESULTS: Linear regression analyses revealed that impulsivity facets best accounted for PTSD's arousal symptoms. The negative urgency facet of impulsivity was most predictive, because it was associated with all of PTSD's symptom clusters. Sensation seeking did not predict PTSD's intrusion symptoms, but did predict the other symptom clusters of PTSD. Lack of perseverance only predicted intrusion symptoms, while lack of premeditation only predicted PTSD's mood/cognition symptoms. CONCLUSIONS: Results extend theoretical and empirical research on the impulsivity-PTSD relationship, suggesting that impulsivity facets may serve as both risk and protective factors for PTSD symptoms. (PsycINFO Database Record PMID- 27243572 TI - Workplace belongingness, distress, and resilience in emergency service workers. AB - OBJECTIVE: Ambulance personnel provide emergency medical services to the community, often attending to highly challenging and traumatic scenes in complex and chaotic circumstances. Currently, the assessment of predictors of psychological well-being remains limited. The current study investigated whether workplace belongingness was significant in predicting psychological distress as well as the presence of resilience in ambulance personnel while controlling for more routinely examined factors. METHOD: Australian ambulance officers (N = 740) completed a survey battery including the Kessler 10, Brief Resilience Scale, and Psychological Sense of Organizational Membership scale. RESULTS: Controlling for more commonly examined factors such as severity of trauma exposure and length of service, hierarchical multiple regression analyses demonstrated that workplace belongingness was significantly associated with reduced distress levels and enhanced resilience levels. CONCLUSIONS: Results suggest that strategies to enhance a sense of workplace belongingness in emergency service organizations could promote the well-being of emergency workers despite routine exposure to potentially traumatic events. (PsycINFO Database Record PMID- 27243573 TI - Trajectories of daily PTSD symptoms in recent traumatic injury victims. AB - OBJECTIVE: Prior research has identified different PTSD symptom (PTSS) trajectories over months and years posttrauma that warrant different levels of clinical attention. Earlier identification of at-risk trauma victims can facilitate efficient and appropriate intervention efforts. METHOD: Using latent class growth analysis, we examined daily PTSS trajectories beginning 6 weeks postinjury in 68 injury victims. Resulting classes were compared on key characteristics at 6 and 21 weeks postinjury. RESULTS: Three trajectories were identified: a nonreactive class (67.8%) with low initial symptom levels that remained low, a moderate-stable class (27.9%) with elevated symptom levels that remained constant, and a severe-increasing class (4.4%) with high symptom levels that increased. CONCLUSIONS: High-risk injury victims can be identified by their daily PTSS, allowing for early identification of those at risk for elevated distress and in greater need for intervention. (PsycINFO Database Record PMID- 27243575 TI - The process of desistance among core ex-gang members. AB - Research has established robust links between gang membership, delinquency, violence and victimization. Yet studies examining the process of gang desistance in general and that of core gang members in particular, are quite rare. The current study aims to identify factors associated with desistance of core gang members as well as describe the nature of the process that these "formers" have undergone. Thirty-nine core ex-gang members (80% males and 20% females) from the San Francisco Bay area and Los Angeles, with an average length of 11.6-years gang membership, were interviewed regarding their involvement in the gang and the desistance process. A systematic qualitative analysis based on grounded theory methodology was mainly utilized. We found that the decision to leave the gang is a result of a combination of push (e.g., personal and vicarious victimization, burnout of gang lifestyle, disillusionment by the gang) and pull (e.g., parenthood, family responsibilities, religious and cultural awakening) factors that evolved over time. Push factors were more dominant in this domain. We also found that while male core ex-gang members tended to leave the gang more frequently because of push factors, female ex-gang members were more inclined to desist due to pull factors. Our analysis also showed that core gang members shared a general pattern of the desistance process comprising of the following 5 stages: triggering, contemplation, exploration, exiting and maintenance. Based on these results, we outlined stage-specific recommendations for agents of societal change to help in facilitating the desistance of core gang members. (PsycINFO Database Record PMID- 27243574 TI - Implementation of Symptom Protocols for Nurses Providing Telephone-Based Cancer Symptom Management: A Comparative Case Study. AB - BACKGROUND: The pan-Canadian Oncology Symptom Triage and Remote Support (COSTaRS) team developed 13 evidence-informed protocols for symptom management. AIM: To build an effective and sustainable approach for implementing the COSTaRS protocols for nurses providing telephone-based symptom support to cancer patients. METHODS: A comparative case study was guided by the Knowledge to Action Framework. Three cases were created for three Canadian oncology programs that have nurses providing telephone support. Teams of researchers and knowledge users: (a) assessed barriers and facilitators influencing protocol use, (b) adapted protocols for local use, (c) intervened to address barriers, (d) monitored use, and (e) assessed barriers and facilitators influencing sustained use. Analysis was within and across cases. RESULTS: At baseline, >85% nurses rated protocols positively but barriers were identified (64-80% needed training). Patients and families identified similar barriers and thought protocols would enhance consistency among nurses teaching self-management. Twenty-two COSTaRS workshops reached 85% to 97% of targeted nurses (N = 119). Nurses felt more confident with symptom management and using the COSTaRS protocols (p < .01). Protocol adaptations addressed barriers (e.g., health records approval, creating pocket versions, distributing with telephone messages). Chart audits revealed that protocols used were documented for 11% to 47% of patient calls. Sustained use requires organizational alignment and ongoing leadership support. LINKING EVIDENCE TO ACTION: Protocol uptake was similar to trials that have evaluated tailored interventions to improve professional practice by overcoming identified barriers. Collaborating with knowledge users facilitated interpretation of findings, aided protocol adaptation, and supported implementation. Protocol implementation in nursing requires a tailored approach. A multifaceted intervention approach increased nurses' use of evidence-informed protocols during telephone calls with patients about symptoms. Training and other interventions improved nurses' confidence with using COSTaRS protocols and their uptake was evident in some documented telephone calls. Protocols could be adapted for use by patients and nurses globally. PMID- 27243576 TI - Obsessive-compulsive disorder in African American children and adolescents: Risks, resiliency, and barriers to treatment. AB - Obsessive-compulsive disorder (OCD) is a serious condition that remains understudied in ethnoracial minority populations. The presence of OCD and the individual, familial, and cultural factors that influence this condition can interfere with healthy development and cause lifelong disability. To date, there has not been a single published research article focused on OCD in African American youth. Ethnic and racial minorities with OCD are underrepresented or altogether absent from treatment centers and research studies, although evidence suggests that OCD may be particularly persistent in these populations. This article reviews risk factors, protective factors, and barriers to treatment in African American children and adolescents with OCD. This review conceptualizes cultural differences in symptomology, low income, reduced access to care, racism, and mental health stigma, as risk factors. Also discussed are the roles of family factors in the development and maintenance of the disorder, including family accommodations, conflictual family communication, and parenting styles. Potential protective factors are also examined, including a positive ethnic identity, social support, present-centered time orientation, and religious communities. Implications of findings are discussed. There is an urgent need for research to understand the needs of African American children and adolescents with OCD. (PsycINFO Database Record PMID- 27243577 TI - Understory herb layer exerts strong controls on soil microbial communities in subtropical plantations. AB - The patterns and drivers of soil microbial communities in forest plantations remain inadequate although they have been extensively studied in natural forest and grassland ecosystems. In this study, using data from 12 subtropical plantation sites, we found that the overstory tree biomass and tree cover increased with increasing plantation age. However, there was a decline in the aboveground biomass and species richness of the understory herbs as plantation age increased. Biomass of all microbial community groups (i.e. fungi, bacteria, arbuscular mycorrhizal fungi, and actinomycete) decreased with increasing plantation age; however, the biomass ratio of fungi to bacteria did not change with increasing plantation age. Variation in most microbial community groups was mainly explained by the understory herb (i.e. herb biomass and herb species richness) and overstory trees (i.e. tree biomass and tree cover), while soils (i.e. soil moisture, soil organic carbon, and soil pH) explained a relative low percentage of the variation. Our results demonstrate that the understory herb layer exerts strong controls on soil microbial community in subtropical plantations. These findings suggest that maintenance of plantation health may need to consider the management of understory herb in order to increase the potential of plantation ecosystems as fast-response carbon sinks. PMID- 27243578 TI - Physiotherapy and Occupational Therapy and Mild to Moderate Parkinson Disease. PMID- 27243580 TI - Mapping of Primary Instructional Methods and Teaching Techniques for Regularly Scheduled, Formal Teaching Sessions in an Anesthesia Residency Program. AB - In this study, we examined the regularly scheduled, formal teaching sessions in a single anesthesiology residency program to (1) map the most common primary instructional methods, (2) map the use of 10 known teaching techniques, and (3) assess if residents scored sessions that incorporated active learning as higher quality than sessions with little or no verbal interaction between teacher and learner. A modified Delphi process was used to identify useful teaching techniques. A representative sample of each of the formal teaching session types was mapped, and residents anonymously completed a 5-question written survey rating the session. The most common primary instructional methods were computer slides-based classroom lectures (66%), workshops (15%), simulations (5%), and journal club (5%). The number of teaching techniques used per formal teaching session averaged 5.31 (SD, 1.92; median, 5; range, 0-9). Clinical applicability (85%) and attention grabbers (85%) were the 2 most common teaching techniques. Thirty-eight percent of the sessions defined learning objectives, and one-third of sessions engaged in active learning. The overall survey response rate equaled 42%, and passive sessions had a mean score of 8.44 (range, 5-10; median, 9; SD, 1.2) compared with a mean score of 8.63 (range, 5-10; median, 9; SD, 1.1) for active sessions (P = 0.63). Slides-based classroom lectures were the most common instructional method, and faculty used an average of 5 known teaching techniques per formal teaching session. The overall education scores of the sessions as rated by the residents were high. PMID- 27243579 TI - Stress and Sucrose Intake Modulate Neuronal Activity in the Anterior Hypothalamic Area in Rats. AB - The anterior hypothalamic area (AHA) is an important integrative relay structure for a variety of autonomic, endocrine, and behavioral responses including feeding behavior and response to stress. However, changes in the activity of the AHA neurons during stress and feeding in freely moving rats are not clear. The present study investigated the firing rate and burst activity of neurons in the central nucleus of the AHA (cAHA) during sucrose intake in non-stressful conditions and after acute stress in freely behaving rats. Rats were implanted with micro-electrodes into the cAHA, and extracellular multi-unit activity was recorded during 1-h access to 10% sucrose in non-stressful conditions or after acute foot shock stress. Acute stress significantly reduced sucrose intake, total sucrose lick number, and lick frequency in licking clusters, and increased inter lick intervals. At the cluster start (CS) of sucrose licking, the cAHA neurons increased (CS-excited, 20% of the recorded neurons), decreased (CS-inhibited, 42% of the neurons) or did not change (CS-nonresponsive, 38% of the neurons) their firing rate. Stress resulted in a significant increase in the firing rate of the CS-inhibited neurons by decreasing inter-spike intervals within the burst firing of these neurons. This increase in the stress-induced firing rate of the CS inhibited neurons was accompanied by a disruption of the correlation between the firing rate of CS-inhibited and CS-nonresponsive neurons that was observed in non stressful conditions. Stress did not affect the firing rate of the CS-excited and CS-nonresponsive neurons. However, stress changed the pattern of burst firing of the CS-excited and CS-nonresponsive neurons by decreasing and increasing the burst number in the CS-excited and CS-nonresponsive neurons, respectively. These results suggest that the cAHA neurons integrate the signals related to stress and intake of palatable food and play a role in the stress- and eating-related circuitry. PMID- 27243581 TI - Posttranscatheter Aortic Valve Replacement Ventricular Septal Defect During Transfemoral Edwards SAPIEN Valve Implantation. AB - Transcatheter aortic valve replacement (TAVR) is gaining favor as a treatment for aortic stenosis in patients at high risk for the open surgical approach. The following is a report of a 95-year-old woman with severe aortic stenosis who presented for TAVR with an Edwards SAPIEN valve. Her medical history included pacemaker-dependent complete heart block and a recent episode of congestive heart failure secondary to a non-ST segment elevation myocardial infarction. The TAVR was performed successfully through an open left femoral artery approach, and the patient was found to have a new perimembranous ventricular septal defect identified postoperatively. PMID- 27243582 TI - Development and validation of a UHPLC-MS/MS method for simultaneous quantitation the plasma concentration of Sabarubicin and its alcohol metabolite M3 in Chinese small cell lung cancer patients. AB - To support a novel anthracycline agent - Sabarubicin's pharmacokinetics study in Chinese small cell lung cancer patients, a rapid, sensitive, and high throughput ultra-performance liquid chromatography tandem mass spectrometry method using Doxorubicin hydrochloride as internal standard (IS) was developed and validated for simultaneously quantifying Sabarubicin and its alcohol metabolite M3 in human plasma. Plasma samples were pre-extracted with n-hexane to remove hydrophobic interferences and the target compounds were extracted into a 1ml mixture of chloroform and isopropanol (1:1, v/v) and separated on an ACQUITY UPLC BEH Shield RP18 (100mm*2.1mm, 1.7MUm) column with gradient mobile phase composed of acetonitrile and water containing 0.1% formic acid. Detection was performed by electrospray ionization in the positive ionization mode under multiple reaction monitoring of the transitions at m/z 644->130 for Sabarubicin, m/z 646->333.2 for M3, and m/z 544->360 for IS. For Sabarubicin and M3, calibration curves over 2 400ng/ml and 0.5-100ng/ml could achieve excellent linearity respectively(r>0.99). Intra- and inter-day precisions were 1.5%-9.1% and 2.2%-12.8%, and accuracy were 9.6% to 0.7% and -4.8% to 5.9% for Sabarubicin and M3 respectively at four concentration levels. The mean recovery for Sabarubicin was 62.4%, 71.9% for M3, and 58.8% for IS. This method was completely validated and successfully applied in the pharmacokinetics study of Sabarubicin and M3 in Chinese small cell lung cancer patients. PMID- 27243583 TI - 1,2,3-Triazole-Functionalized Polysulfone Synthesis through Microwave-Assisted Copper-Catalyzed Click Chemistry: A Highly Proton Conducting High Temperature Membrane. AB - Microwave heating holds all the aces regarding development of effective and environmentally friendly methods to perform chemical transformations. Coupling the benefits of microwave-enhanced chemistry with highly reliable copper catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry paves the way for a rapid and efficient synthesis procedure to afford high performance thermoplastic materials. We describe herein fast and high yielding synthesis of 1,2,3-triazole functionalized polysulfone through microwave-assisted CuAAC as well as explore their potential as phosphoric acid doped polymer electrolyte membranes (PEM) for high temperature PEM fuel cells. Polymers with various degrees of substitution of the side-chain functionality of 1,4-substituted 1,2,3-triazole with alkyl and aryl pendant structures are prepared by sequential chloromethylation, azidation, and microwave-assisted CuAAC using a range of alkynes (1-pentyne, 1-nonyne, and phenylacetylene). The completeness of reaction at each step and the purity of the clicked polymers were confirmed by (1)H-(13)C NMR, DOSY-NMR and FTIR-ATR spectroscopies. The thermal and thermochemical properties of the modified polymers were characterized by differential scanning calorimetry and thermogravimetric analysis coupled with mass spectroscopy (TG-MS), respectively. TG-MS analysis demonstrated that the commencement of the thermal degradation takes place with the decomposition of the triazole ring while its substituents have critical influence on the initiation temperature. Polysulfone functionalized with 4-phenyl-1,2,3-triazole demonstrates significantly higher Tg, Td, and elastic modulus than the ones bearing 4-propyl-1,2,3-triazole and 4-heptyl-1,2,3 triazole groups. After doping with phosphoric acid, the functionalized polymers with acid doping level of 5 show promising performance with high proton conductivity in anhydrous conditions (in the range of 27-35 mS/cm) and satisfactorily high elastic modulus (in the range of 332-349 MPa). PMID- 27243584 TI - Investigation of optical attenuation imaging using optical coherence tomography for monitoring of scars undergoing fractional laser treatment. AB - We demonstrate the use of the near-infrared attenuation coefficient, measured using optical coherence tomography (OCT), in longitudinal assessment of hypertrophic burn scars undergoing fractional laser treatment. The measurement method incorporates blood vessel detection by speckle decorrelation and masking, and a robust regression estimator to produce 2D en face parametric images of the attenuation coefficient of the dermis. Through reliable co-location of the field of view across pre- and post-treatment imaging sessions, the study was able to quantify changes in the attenuation coefficient of the dermis over a period of ~20 weeks in seven patients. Minimal variation was observed in the mean attenuation coefficient of normal skin and control (untreated) mature scars, as expected. However, a significant decrease (13 +/- 5%, mean +/- standard deviation) was observed in the treated mature scars, resulting in a greater distinction from normal skin in response to localized damage from the laser treatment. By contrast, we observed an increase in the mean attenuation coefficient of treated (31 +/- 27%) and control (27 +/- 20%) immature scars, with numerical values incrementally approaching normal skin as the healing progressed. This pilot study supports conducting a more extensive investigation of OCT attenuation imaging for quantitative longitudinal monitoring of scars. En face 2D OCT attenuation coefficient map of a treated immature scar derived from the pre treatment (top) and the post-treatment (bottom) scans. (Vasculature (black) is masked out.) The scale bars are 0.5 mm. PMID- 27243585 TI - Impact of cement dust pollution on Cedrela fissilis Vell. (Meliaceae): A potential bioindicator species. AB - Considering the impacts caused to vegetation in the vicinity of cement factories, the aim of this study was to evaluate the impacts of cement dust on the structural organization and physiological/biochemical traits of Cedrela fissilis leaflets, a woody species native to tropical America. Plants were exposed to 2.5 or 5 mg cm-2 cement dust applied to the leaf surface, to the soil or simultaneously to the leaf surface and the soil.. Leaves of shoot-treated plants exhibited chlorosis, marginal and inter veins necrosis, diminished thickness, epidermal cells less turgid, cellular collapse, obstructed stomata, senescence, rolling and some abscission. In few cases, individual death was recorded. Cement dust-treated plants also presented decreased amount of photosynthetic pigments and iron (Fe) and increase in calcium (Ca) levels. The cement crust formed in leaves surface blocked from 30 to 50% of the incoming light and reduced the stomatal conductance and the potential quantum yield of photosystem II. Control or soil-treated plants did not exhibit morphophysiological changes throughout the experiment. The activity of superoxide dismutase, catalase and ascorbate peroxidase increased in leaves of plants upon treatment with 2.5 mg cm(-2) cement dust, independent of the site application. Overall, these results indicate that C. fissilis is highly sensitive to cement dust at the initial stage of development. PMID- 27243586 TI - Landfill leachate sludge use as soil additive prior and after electrocoagulation treatment: A cytological assessment using CHO-k1 cells. AB - Electrocoagulation has recently attracted attention as a potential technique for treating toxic effluents due to its versatility and environmental compatibility, generating a residue chemically suitable to be used as a soil additive. In the present study, landfill leachate sludge hazardous effects were investigated prior and after electrocoagulation process using in vitro assays with the mammalian cells CHO-k1. An integrated strategy for risk assessment was used to correctly estimate the possible adverse landfill leachate sludge effects on human health and ecosystem. Electrocoagulation process proved to be an effective treatment due to possibility to improve effluent adverse characteristics and produce sludge with potential to be used as soil additive. Despite low cytoxicity, the residue presented genotoxic and mutagenic effects, indicating a capacity to induce genetic damages, probably due to induction of polyploidization process in cells. The observed effects demand an improvement of waste management methods for reduce negative risks of landfill leachate sludge application. PMID- 27243587 TI - When Less Is Better, but Physicians Are Afraid Not to Intervene. PMID- 27243588 TI - Overexpression of c-myc is associated with adverse clinical features and worse overall survival in multiple myeloma. AB - The role of c-myc in multiple myeloma (MM) is controversial. We conducted a retrospective study of 117 patients with MM diagnosed between 2004 and 2010 at Herlev Hospital. Immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) were performed on tissue microarrays (TMAs) made from diagnostic bone marrow aspirates. Clinical data were obtained from the Danish Multiple Myeloma Database (DMMD). Overexpression of c-myc was found in 40% of patients. MYC translocation was found in 10% of patients. Overexpression of c-myc was not associated with MYC translocation. Overexpression of c-myc was associated with hypercalcemia (p = 0.02) and extramedullary myeloma (p < 0.01). Overexpression of c-myc was associated with shorter overall survival (OS) by multivariable analysis of the entire patient cohort [HR 1.92 (1.06-3.45), p = 0.03] and univariable analysis of high-dose-therapy (HDT)-ineligible patients [HR 2.01 (1.05-3.86), p = 0.04]. Further studies of c-myc overexpression in larger cohorts of patients with MM are warranted. PMID- 27243589 TI - Regulating the effects of GPR21, a novel target for type 2 diabetes. AB - Type 2 diabetes is a chronic metabolic disorder primarily caused by insulin resistance to which obesity is a major contributor. Expression levels of an orphan G protein-coupled receptor (GPCR), GPR21, demonstrated a trend towards a significant increase in the epididymal fat pads of wild type high fat high sugar (HFHS)-fed mice. To gain further insight into the potential role this novel target may play in the development of obesity-associated type 2 diabetes, the signalling capabilities of the receptor were investigated. Overexpression studies in HEK293T cells revealed GPR21 to be a constitutively active receptor, which couples to Galphaq type G proteins leading to the activation of mitogen activated protein kinases (MAPKs). Overexpression of GPR21 in vitro also markedly attenuated insulin signalling. Interestingly, the effect of GPR21 on the MAPKs and insulin signalling was reduced in the presence of serum, inferring the possibility of a native inhibitory ligand. Homology modelling and ligand docking studies led to the identification of a novel compound that inhibited GPR21 activity. Its effects offer potential as an anti-diabetic pharmacological strategy as it was found to counteract the influence of GPR21 on the insulin signalling pathway. PMID- 27243590 TI - Validation of a Simple 0 to 10 Numerical Score (IBD-10) of Patient-reported Inflammatory Bowel Disease Activity for Routine Clinical Use. AB - BACKGROUND: Various physician- and patient-reported instruments exist for quantification of disease activity in inflammatory bowel diseases (IBD) but none are widely used in routine clinical practice. A simple patient-reported outcome measure might help inform clinical decision making. We evaluated a patient reported 0 to 10 score of IBD activity (IBD-10) by correlation with conventional multicomponent activity indices. METHODS: A single-center prospective cross sectional study was conducted in ambulant patients with IBD. Patients were asked to verbally rate the control of Crohn's disease (CD) or ulcerative colitis (UC) on a numerical scale from 0 to 10, with 10 indicating perfect control. Disease activity was assessed using Harvey-Bradshaw index for CD and simple clinical colitis activity index for UC. RESULTS: A total of 405 patients were included, of whom 209 (52%) had CD and 196 (48%) had UC. The median age was 41 (interquartile range, 27-55) years. IBD-10 correlated well with Harvey-Bradshaw Index (rs = 0.69, P < 0.001) and simple clinical colitis activity index (rs = -0.79, P < 0.001). An IBD-10 score of >=7 predicted remission (defined by Harvey-Bradshaw index/simple clinical colitis activity index) with 90% sensitivity (95% confidence interval [CI], 86-94) and 75% specificity (95% CI, 67-82). The discriminatory ability of IBD-10 for remission was better for UC (area under the receiver operating characteristic curve, 0.93; 95% CI, 0.89-0.97) than for CD (area under the receiver operating characteristic curve, 0.86; 95% CI, 0.81-0.91; P = 0.035). An IBD-10 score of <7 correlated with treatment escalation. CONCLUSIONS: The IBD-10 score correlates well with more complex clinical activity indices. Correlation was less strong for CD than for UC, possibly reflecting a weaker link in CD between stool frequency and the patient perspective of disease activity. The IBD-10 score could readily be used in routine clinical practice. PMID- 27243592 TI - Analysis and Interpretation of the Human Microbiome. AB - Microbiome research has experienced an unprecedented level of growth over the last decade. This is largely due to revolutionary developments in, and accessibility to, DNA sequencing technologies that have enabled laboratories with even modest budgets to undertake projects. Study of the human microbiome in particular has seen a surge in interest, and although a lot of time and money has been focused on health and disease, the clinical interpretation of these data and the ability of clinicians to understand these studies in the context of disease are less straightforward. Conditions such as inflammatory bowel disease, asthma, and cancer have seen a huge increase in research focused on the role of microbiome in disease pathogenesis, but the ability of clinicians to appraise and use these data is largely lacking. The purpose of this article is to provide an introduction for clinicians and nonclinicians wishing to learn about and engage in microbiome research. It details the background of microbiome research and discusses the process of generating 16S rRNA sequencing data, the most commonly used method for microbiome analysis. We discuss the interpretation of results in a clinical context, commonly used metrics for analysis and discuss future impact and direction for microbiome research. The meteoric rise of genomic medicine to the brink of routine clinical use should be seen as a blueprint for the microbiome; the ability for physicians to understand and interpret these data is vital to this growth and aiding clinicians (and researchers) to participate in further microbiome research. PMID- 27243591 TI - Interleukin-27 as a Novel Therapy for Inflammatory Bowel Disease: A Critical Review of the Literature. AB - Inflammatory bowel disease (IBD) is an inflammatory disorder of the intestine that affects an estimated 329 per 100,000 people in the United States and is increasing in incidence within a number of cultures worldwide. Likely due to its incompletely understood pathophysiology and etiology, the standard treatments for IBD are only efficacious in subsets of patients and often do not induce lasting remission. As a result, novel therapies are needed. The success of anti-tumor necrosis factor-alpha treatment in a subset of patients with IBD demonstrated that therapy targeting a single cytokine could be efficacious in IBD, and clinical trials investigating the blockade of a variety of cytokines have commenced. Interleukin (IL) 27 is a relatively recently discovered type I cytokine with established roles in infectious disease, autoimmunity, and cancer in a variety of organs. IL-27 was identified as a candidate gene for IBD, and a number of studies in mouse models of IBD have demonstrated that IL-27 therapy is protective. However, in contrast to these investigations, genetic deletion of the IL-27 receptor has been shown to be protective in some mouse models of IBD. The purpose of this review is to highlight the recent literature investigating the role of IL-27 in IBD and to discuss the possible explanations for the sometimes conflicting results of these studies. Evidence supporting IL-27 therapy as a treatment for IBD will also be discussed. PMID- 27243593 TI - An Antibody Against Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) Dampens Proinflammatory Cytokine Secretion by Lamina Propria Cells from Patients with IBD. AB - BACKGROUND: Triggering receptor expressed on myeloid cells 1 (TREM-1) is a potent amplifier of inflammation. Recently, the antimicrobial peptide PGLYRP-1 was shown to be the ligand of TREM-1. Here, the ability of an anti-TREM-1 antibody to dampen the release of proinflammatory cytokines by colon lamina propria cells (LPCs) from patients with IBD was investigated and correlated with PGLYRP-1 levels. METHODS: Biopsies from patients with ulcerative colitis (UC, n = 45) or Crohn's disease (CD, n = 26) were compared with those from individuals undergoing colonoscopy for other reasons (n = 17). TREM-1 expression was analyzed on myeloid cells by flow cytometry. Cell culture experiments with LPCs were used to analyze PGLYRP-1 and inflammatory cytokine levels and assess the effect of anti-TREM-1 on cytokine secretion. RESULTS: The frequency of TREM-1-expressing neutrophils and recruited macrophages was higher in inflamed than in noninflamed biopsies. The PGLYRP-1 level in inflamed tissue was higher than in noninflamed tissue; it was produced primarily by neutrophils, and its level correlated with the secretion of proinflammatory cytokines. Secretion of myeloperoxidase, tumor necrosis factor alpha, interleukin-1beta, and interleukin-8 by LPCs stimulated with the potent TREM-1 agonist consisting of PGLYRP-1 complexed with peptidoglycan was reduced in the presence of anti-TREM-1. Moreover, a blocking effect of anti-TREM-1 was apparent when LPCs from a subset of inflamed individuals with elevated PGLYRP-1 were stimulated with killed bacteria. CONCLUSIONS: An anti-TREM-1 antibody can dampen secretion of proinflammatory cytokines in inflamed patients with elevated PGLYRP-1. Moreover, PGLYRP-1 + myeloperoxidase is a potential biomarker for predicting the effect of anti-TREM-1 therapy. PMID- 27243594 TI - Profiles of Lamina Propria T Helper Cell Subsets Discriminate Between Ulcerative Colitis and Crohn's Disease. AB - BACKGROUND: Distinction between 2 forms of inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease (CD), can be challenging. Aberrant mucosal immunity suggests that CD is a T helper type 1 cell (Th1)-driven disease, whereas UC as Th2-driven response. However, whether this paradigm truly distinguishes CD from UC is controversial. We aimed to clarify the discriminating potential of lamina propria Th subsets in patients with IBD. METHODS: Biopsies from 79 patients with IBD and 20 healthy controls were collected for Th subsets analysis (Th1:interferon gamma [IFN-gamma], T-bet; Th2:interleukin 13 [IL-13], Gata3; Th17:IL-17, RORgammat; Treg:FoxP3). The receiver-operating characteristic curves were constructed to assess the discriminating ability by calculating the area under the receiver-operating characteristic curve. The equation with the highest area under the receiver-operating characteristic curve was applied to newly diagnosed patients to evaluate discriminating ability. RESULTS: Patients with CD showed increased IFN-gamma or T-bet cells and decreased IL-13 or Gata3 cells compared with UC. A discriminant equation composed of 4 markers (IFN-gamma, T-bet, IL-13, and Gata3) yielded the highest area under the receiver-operating characteristic curve. In 36 established CD or UC, the sensitivity, specificity, positive and negative predictive probabilities were 92.6%, 55.6%, 86.2%, and 71.4% and in 14 newly diagnosed patients were 100.0%, 42.9%, 63.6%, and 100.0%. Furthermore, Gata3 cells were increased in tumor necrosis factor inhibitor therapy nonresponders compared with responders in CD. IFN-gamma cells were directly and inversely proportional to disease activity in patients with CD and UC, respectively. CONCLUSIONS: The Th1/Th2 paradigm can distinguish CD from UC and may be further associated with response to tumor necrosis factor inhibitor in CD and disease activity in patients with IBD. PMID- 27243595 TI - Role of Monocytes and Intestinal Macrophages in Crohn's Disease and Ulcerative Colitis. AB - Monocytes and macrophages are part of the body's first line of defence, eliminating pathogens by phagocytosis or by releasing a broad array of inflammatory mediators, such as cytokines, chemokines, and proteases. In humans, 3 subsets of monocytes are described in blood with seemingly different functions, the classical (CD14CD16) monocytes, the intermediate (CD14CD16) monocytes, and the nonclassical (CD14CD16) monocytes. In the intestine, macrophages can be divided into resident and inflammatory macrophages that are distinguished by low and high expression of CD14, respectively. However, the roles and function of the 3 monocyte subsets in health and disease are not fully understood. In this review, we describe what is known about the origin of human intestinal macrophages and their blood monocytic counterparts and many of their numerous distinct mechanisms influencing the intestinal immune system. PMID- 27243596 TI - Monodisperse Uni- and Multicompartment Liposomes. AB - Liposomes are self-assembled phospholipid vesicles with great potential in fields ranging from targeted drug delivery to artificial cells. The formation of liposomes using microfluidic techniques has seen considerable progress, but the liposomes formation process itself has not been studied in great detail. As a result, high throughput, high-yielding routes to monodisperse liposomes with multiple compartments have not been demonstrated. Here, we report on a surfactant assisted microfluidic route to uniform, single bilayer liposomes, ranging from 25 to 190 MUm, and with or without multiple inner compartments. The key of our method is the precise control over the developing interfacial energies of complex W/O/W emulsion systems during liposome formation, which is achieved via an additional surfactant in the outer water phase. The liposomes consist of single bilayers, as demonstrated by nanopore formation experiments and confocal fluorescence microscopy, and they can act as compartments for cell-free gene expression. The microfluidic technique can be expanded to create liposomes with a multitude of coupled compartments, opening routes to networks of multistep microreactors. PMID- 27243597 TI - Primary hyperparathyroidism in pregnancy: a case series and literature review. AB - Primary Hyperparathyroidism (PHP) in pregnancy constitutes a serious danger to mother and fetus. The diagnosis of PHP in pregnancy presents a challenge, and PHP commonly goes unidentified and untreated in pregnancy. We present four case reports about patients having PHP, which is very rare condition in pregnancy and their treatment modalities. Three patients, not to be controlled biochemically, denied the parathyroidectomy operation although they are informed about the details of their disease. They are followed up with medical therapy. The first one had no maternal or fetal complications, the second one acquired nephrolithiasis crisis in the last trimester and the third one gave birth to a premature baby who succumbed to tetany. The fourth patient who underwent parathyroidectomy operation in the second trimester had no maternal or fetal complications. PHP in pregnancy is a preventable cause of fetal and maternal mortality and morbidity. Thus, suspecting from PHP during the pregnancy and early diagnosis is critically important in terms of maternal and fetal wellness. PMID- 27243598 TI - Physical exercise, sickness absence and subjective employability: An 8-year longitudinal observational study among musculoskeletal patients. AB - OBJECTIVE: Physical exercise recommendations become particularly effective when embedded into medical rehabilitation. However, little is known about long-term behaviour maintenance and its effect on sickness absence and subjective employability. The current longitudinal observational study investigated self reported physical exercise, sickness absence and subjective employability over a period of 8 years. SUBJECTS: A total of 601 (T0) outpatients (mean age 45.14 years; standard deviation 10.73 years, age range 18-65 years) with different orthopaedic disorders were recruited during their 3-week medical rehabilitation in Germany. Of these, 61.7% (n = 371) were female. Follow-ups were carried out at 6 months (T1, n = 495), 12 months (T2, n = 340), 3 years (T3, n = 296) and 8 years (T4, n = 142) after baseline. METHODS: Patient characteristics, exercise status, social-cognitive variables, sickness absence and subjective employability were obtained via self-report questionnaires. SPSS hierarchical regression models were used for data analysis, controlling for baseline measures and sociodemographic variables. RESULTS: Physical exercise status 6 months after rehabilitation treatment (T1) predicted sickness absence at 12 months (T2). Inactive people were 3.28 times more likely to be on sick leave at T2. In addition, physical exercise at T1 predicted subjective employability 12 months (T2) and 3 years (T3) later. Those who met the recommendations to be physically active for at least 40 min a week were more likely to feel able to work. CONCLUSION: Exercise appears to play an important role in reducing sickness absence and subjective employability and should be promoted within and after rehabilitation treatment. PMID- 27243599 TI - Regression models for near-infrared measurement of subcutaneous adipose tissue thickness. AB - Obesity is often associated with the risks of diabetes and cardiovascular disease, and there is a need to measure subcutaneous adipose tissue (SAT) thickness for acquiring the distribution of body fat. The present study aimed to develop and evaluate different model-based methods for SAT thickness measurement using an SATmeter developed in our laboratory. Near-infrared signals backscattered from the body surfaces from 40 subjects at 20 body sites each were recorded. Linear regression (LR) and support vector regression (SVR) models were established to predict SAT thickness on different body sites. The measurement accuracy was evaluated by ultrasound, and compared with results from a mechanical skinfold caliper (MSC) and a body composition balance monitor (BCBM). The results showed that both LR- and SVR-based measurement produced better accuracy than MSC and BCBM. It was also concluded that by using regression models specifically designed for certain parts of human body, higher measurement accuracy could be achieved than using a general model for the whole body. Our results demonstrated that the SATmeter is a feasible method, which can be applied at home and in the community due to its portability and convenience. PMID- 27243600 TI - Of Poisons and Antidotes in Polypropylene Catalysis. AB - Quenched-flow studies of MgCl2 -supported Ziegler-Natta catalysts were combined for the first time with (13) C NMR fingerprinting of the nascent polymer and conclusively proved that, depending on the catalyst formulation, propene polymerization can be slowed down significantly by the occurrence of the few regiodefects (2,1 monomer insertions), changing active sites into dormant sites. Catalysts modified with ethylbenzoate show little dormancy. The more industrially relevant phthalate based catalysts, instead, are highly dormant and require the presence of H2 to counteract the deleterious effect of this self-poisoning on productivity and stereoselectivity. PMID- 27243601 TI - Claustral afferents of superior parietal areas PEc and PE in the macaque. AB - The exposed surface of the primate superior parietal cortex includes two cytoarchitectonically defined areas, the PEc and PE. In the present study we describe the distribution of neurons projecting from the claustrum to these areas. Retrograde neuronal tracers were injected by direct visualization of regions of interest, and the location of injection sites was reconstructed relative to cytoarchitectural borders. For comparison, the patterns of claustral label that resulted from injections involving neighboring cytoarchitectonic areas were analyzed. We found that the claustral territories sending projections to areas PE and PEc partially overlapped zones previously shown to form projections to the posterior parietal, somatosensory, visual, and motor cortex. The projection zones to the PE and PEc overlapped extensively, and consisted of multiple patches separated by label-free zones. Most of the labeled neurons were located in the posterior-ventral part of the claustrum. Area PE received additional inputs from a posterior-dorsal part of the claustrum, which has been previously reported to project to the somatosensory cortex, while the PEc receives additional input from an anterior-ventral region of the claustrum, which has been reported to project to the visual association cortex. These observations reflect the known functional properties of the PE and PEc, with the former containing neurons that are predominantly involved in somatosensory processing, and the latter including both somatosensory and visual neurons. The present results suggest that the claustrum projections may help coordinate the activity of an extensive neural circuit involved in sensory and motor processing for movement execution. J. Comp. Neurol. 525:1475-1488, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27243602 TI - Targeted modification of organic components of municipal solid waste by short term pre-aeration and its enhancement on anaerobic degradation in simulated landfill bioreactors. AB - Pre-aeration is effective on regulating subsequent anaerobic degradation of municipal solid waste (MSW) with high organic fractions during landfilling. The strength of pre-aeration should be optimized to intentionally remove some easily biodegradable fractions while conserve bio-methane potential as much as possible. This study investigates the evolution of organic components in MSW during 2 14days pre-aeration process and its impacts on subsequent anaerobic degradation in simulated landfill bioreactors. Results showed that a 6-day pre-aeration enabled to develop a thermophilic stage, which significantly accelerated biodegradation of organics except lignocelluloses, with removal rates of 42.8%, 76.7% and 25.1% for proteins, carbohydrates and lipids, respectively. Particularly, ammonia from accelerated ammonification in the thermophilic stage neutralized VFAs generated from anaerobic landfilling. As a result, the MSW with 6-day pre-aeration obtained the highest methane yield 123.4NL/kg dry matter. Therefore, it is recommended to interrupt pre-aeration before its cooling stage to switch to anaerobic landfilling. PMID- 27243603 TI - Deeper insight into the structure of the anaerobic digestion microbial community; the biogas microbiome database is expanded with 157 new genomes. AB - This research aimed to better characterize the biogas microbiome by means of high throughput metagenomic sequencing and to elucidate the core microbial consortium existing in biogas reactors independently from the operational conditions. Assembly of shotgun reads followed by an established binning strategy resulted in the highest, up to now, extraction of microbial genomes involved in biogas producing systems. From the 236 extracted genome bins, it was remarkably found that the vast majority of them could only be characterized at high taxonomic levels. This result confirms that the biogas microbiome is comprised by a consortium of unknown species. A comparative analysis between the genome bins of the current study and those extracted from a previous metagenomic assembly demonstrated a similar phylogenetic distribution of the main taxa. Finally, this analysis led to the identification of a subset of common microbes that could be considered as the core essential group in biogas production. PMID- 27243604 TI - Improving microalgal growth with small bubbles in a raceway pond with swing gas aerators. AB - A novel swing gas aerator was developed to generate small bubbles for improving the mass transfer coefficient and microalgal growth rate in a raceway pond. A high-speed photography system (HSP) was used to measure the bubble diameter and generation time, and online precise dissolved oxygen probes and pH probes were used to measure the mass transfer coefficient and mixing time. Bubble generation time and diameter decreased by 21% and 9%, respectively, when rubber gas aerators were swung in the microalgae solution. When water pump power and gas aeration rate increased in a raceway pond with swing gas aerators and oscillating baffles (SGAOB), bubble generation time and diameter decreased but solution velocity and mass transfer coefficient increased. The mass transfer coefficient increased by 25% and the solution velocity increased by 11% when SGAOB was used, and the microalgal biomass yield increased by 18%. PMID- 27243605 TI - Improving pollutants removal by microalgae Chlorella PY-ZU1 with 15% CO2 from undiluted anaerobic digestion effluent of food wastes with ozonation pretreatment. AB - In order to purify various pollutants (3108mg COD/L, 2120mg NH3-N/L) in the undiluted anaerobic digestion effluent of food wastes (UADEFW), ozonation pretreatment was employed to improve pollutants removal by microalgae mutant Chlorella PY-ZU1 with 15% CO2. Ozonation pretreatment broke CC bonds and benzene rings of refractory organics such as unsaturated fatty acids and phenols in UADEFW and degraded them into low-molecular-weight organics such as methanoic acid and methanal, but excessive ozone induced the accumulation of toxic by products. The microalgal growth rate and biomass yield markedly increased to the peaks of 456mg/L/d and 4.3g/L, respectively, when the UADEFW was pretreated with 2mg-O3/mg-C of ozone. The removal efficiencies of NH3-N, TP and COD reached 99%, 99% and 68%, respectively. The lipid and carbohydrate contents of microalgal biomass increased because of the relative lack of nitrogen when microalgae was cultured with 15% CO2 to purify the UADEFW with ozonation pretreatment. PMID- 27243606 TI - Co-combustion of peanut hull and coal blends: Artificial neural networks modeling, particle swarm optimization and Monte Carlo simulation. AB - Co-combustion of coal and peanut hull (PH) were investigated using artificial neural networks (ANN), particle swarm optimization, and Monte Carlo simulation as a function of blend ratio, heating rate, and temperature. The best prediction was reached by ANN61 multi-layer perception model with a R(2) of 0.99994. Blend ratio of 90 to 10 (PH to coal, wt%), temperature of 305 degrees C, and heating rate of 49 degrees Cmin(-1) were determined as the optimum input values and yield of 87.4% was obtained under PSO optimized conditions. The validation experiments resulted in yields of 87.5%+/-0.2 after three replications. Monte Carlo simulations were used for the probabilistic assessments of stochastic variability and uncertainty associated with explanatory variables of co-combustion process. PMID- 27243608 TI - Structural Evolution of Co-Based Metal Organic Frameworks in Pyrolysis for Synthesis of Core-Shells on Nanosheets: Co@CoOx@Carbon-rGO Composites for Enhanced Hydrogen Generation Activity. AB - In this article, Co-based metal organic frameworks (MOFs) with two shapes were used as pyrolysis precursor to synthesize multilayer core-shells composites loaded on reduced graphene oxide (rGO) sheets. The core-shell structures were obtained by the formation of cores from metal ions and carbon shells from carbonization of ligands. Controllable oxidation of Co cores to CoOx shells generated multilayer core-shell structures anchored onto the surface of rGO sheets. The N-doped composites were obtained by adding poly vinylpyrrolidone. The multilayer core-shells composites exhibited superior catalytic activity toward hydrogen generation compared to their single layer counterparts. By using the N doped multilayer composites, high hydrogen generation specific rate of 5560 mL min(-1) gCo(-1) was achieved at room temperature. The rGO sheets in composites improved their structure stability. These catalysts exhibited high stability after used five cycling. This synergistic strategy proposes simple, efficient, and versatile blue-prints for the fabrication of rGO composites from MOFs-based precursors. PMID- 27243607 TI - Association Between Complementary and Alternative Medicine Use and Breast Cancer Chemotherapy Initiation: The Breast Cancer Quality of Care (BQUAL) Study. AB - IMPORTANCE: Not all women initiate clinically indicated breast cancer adjuvant treatment. It is important for clinicians to identify women at risk for noninitiation. OBJECTIVE: To determine whether complementary and alternative medicine (CAM) use is associated with decreased breast cancer chemotherapy initiation. DESIGN, SETTING, AND PARTICIPANTS: In this multisite prospective cohort study (the Breast Cancer Quality of Care [BQUAL] study) designed to examine predictors of breast cancer treatment initiation and adherence, 685 women younger than 70 years with nonmetastatic invasive breast cancer were recruited from Columbia University Medical Center, Kaiser Permanente Northern California, and Henry Ford Health System and enrolled between May 2006 and July 31, 2010. Overall, 306 patients (45%) were clinically indicated to receive chemotherapy per National Comprehensive Cancer Network guidelines. Participants were followed for up to 12 months. EXPOSURES: Baseline interviews assessed current use of 5 CAM modalities (vitamins and/or minerals, herbs and/or botanicals, other natural products, mind-body self-practice, mind-body practitioner-based practice). CAM use definitions included any use, dietary supplement use, mind-body use, and a CAM index summing the 5 modalities. MAIN OUTCOMES AND MEASURES: Chemotherapy initiation was assessed via self-report up to 12 months after baseline. Multivariable logistic regression models examined a priori hypotheses testing whether CAM use was associated with chemotherapy initiation, adjusting for demographic and clinical covariates, and delineating groups by age and chemotherapy indication. RESULTS: A cohort of 685 women younger than 70 years (mean age, 59 years; median age, 59 years) with nonmetastatic invasive breast cancer were recruited and followed for up to 12 months to examine predictors of breast cancer treatment initiation. Baseline CAM use was reported by 598 women (87%). Chemotherapy was initiated by 272 women (89%) for whom chemotherapy was indicated, compared with 135 women (36%) for whom chemotherapy was discretionary. Among women for whom chemotherapy was indicated, dietary supplement users and women with high CAM index scores were less likely than nonusers to initiate chemotherapy (odds ratio [OR], 0.16; 95% CI, 0.03-0.51; and OR per unit, 0.64; 95% CI, 0.46-0.87, respectively). Use of mind-body practices was not related to chemotherapy initiation (OR, 1.45; 95% CI, 0.57-3.59). There was no association between CAM use and chemotherapy initiation among women for whom chemotherapy was discretionary. CONCLUSIONS AND RELEVANCE: CAM use was high among patients with early-stage breast cancer enrolled in a multisite prospective cohort study. Current dietary supplement use and higher number of CAM modalities used but not mind-body practices were associated with decreased initiation of clinically indicated chemotherapy. Oncologists should consider discussing CAM with their patients during the chemotherapy decision-making process. PMID- 27243609 TI - Boston Children's Hospital orthopedic surgery program. PMID- 27243610 TI - Extreme femoral valgus and patella dislocation following lateral plate fixation of a pediatric femur fracture. AB - A 15-year-old boy presented with a 35 degrees femoral valgus deformity, leg length discrepancy, painful retained hardware, and a lateral dislocation of the patella 4 years after undergoing lateral plate fixation of a distal femur fracture. Femoral valgus is a possible complication of lateral plate fixation in up to 30% of pediatric distal femur fractures. With this patient's unusual combination of deformities as an example, we suggest early hardware removal after fracture union to prevent the development of deformity. If plate removal is not chosen, then continued close monitoring of the patient is necessary until skeletal maturity. PMID- 27243611 TI - Short-term Music Training Enhances Complex, Distributed Neural Communication during Music and Linguistic Tasks. AB - Musical training is frequently associated with benefits to linguistic abilities, and recent focus has been placed on possible benefits of bilingualism to lifelong executive functions; however, the neural mechanisms for such effects are unclear. The aim of this study was to gain better understanding of the whole-brain functional effects of music and second-language training that could support such previously observed cognitive transfer effects. We conducted a 28-day longitudinal study of monolingual English-speaking 4- to 6-year-old children randomly selected to receive daily music or French language training, excluding weekends. Children completed passive EEG music note and French vowel auditory oddball detection tasks before and after training. Brain signal complexity was measured on source waveforms at multiple temporal scales as an index of neural information processing and network communication load. Comparing pretraining with posttraining, musical training was associated with increased EEG complexity at coarse temporal scales during the music and French vowel tasks in widely distributed cortical regions. Conversely, very minimal decreases in complexity at fine scales and trends toward coarse-scale increases were displayed after French training during the tasks. Spectral analysis failed to distinguish between training types and found overall theta (3.5-7.5 Hz) power increases after all training forms, with spatially fewer decreases in power at higher frequencies (>10 Hz). These findings demonstrate that musical training increased diversity of brain network states to support domain-specific music skill acquisition and music to-language transfer effects. PMID- 27243612 TI - Eye Gaze Behavior at Turn Transition: How Aphasic Patients Process Speakers' Turns during Video Observation. AB - The human turn-taking system regulates the smooth and precise exchange of speaking turns during face-to-face interaction. Recent studies investigated the processing of ongoing turns during conversation by measuring the eye movements of noninvolved observers. The findings suggest that humans shift their gaze in anticipation to the next speaker before the start of the next turn. Moreover, there is evidence that the ability to timely detect turn transitions mainly relies on the lexico-syntactic content provided by the conversation. Consequently, patients with aphasia, who often experience deficits in both semantic and syntactic processing, might encounter difficulties to detect and timely shift their gaze at turn transitions. To test this assumption, we presented video vignettes of natural conversations to aphasic patients and healthy controls, while their eye movements were measured. The frequency and latency of event-related gaze shifts, with respect to the end of the current turn in the videos, were compared between the two groups. Our results suggest that, compared with healthy controls, aphasic patients have a reduced probability to shift their gaze at turn transitions but do not show significantly increased gaze shift latencies. In healthy controls, but not in aphasic patients, the probability to shift the gaze at turn transition was increased when the video content of the current turn had a higher lexico-syntactic complexity. Furthermore, the results from voxel-based lesion symptom mapping indicate that the association between lexico-syntactic complexity and gaze shift latency in aphasic patients is predicted by brain lesions located in the posterior branch of the left arcuate fasciculus. Higher lexico-syntactic processing demands seem to lead to a reduced gaze shift probability in aphasic patients. This finding may represent missed opportunities for patients to place their contributions during everyday conversation. PMID- 27243613 TI - Integration Processes Compared: Cortical Differences for Consistency Evaluation and Passive Comprehension in Local and Global Coherence. AB - This research studies the neural systems underlying two integration processes that take place during natural discourse comprehension: consistency evaluation and passive comprehension. Evaluation was operationalized with a consistency judgment task and passive comprehension with a passive listening task. Using fMRI, the experiment examined the integration of incoming sentences with more recent, local context and with more distal, global context in these two tasks. The stimuli were stories in which we manipulated the consistency of the endings with the local context and the relevance of the global context for the integration of the endings. A whole-brain analysis revealed several differences between the two tasks. Two networks previously associated with semantic processing and attention orienting showed more activation during the judgment than the passive listening task. A network previously associated with episodic memory retrieval and construction of mental scenes showed greater activity when global context was relevant, but only during the judgment task. This suggests that evaluation, more than passive listening, triggers the reinstantiation of global context and the construction of a rich mental model for the story. Finally, a network previously linked to fluent updating of a knowledge base showed greater activity for locally consistent endings than inconsistent ones, but only during passive listening, suggesting a mode of comprehension that relies on a local scope approach to language processing. Taken together, these results show that consistency evaluation and passive comprehension weigh differently on distal and local information and are implemented, in part, by different brain networks. PMID- 27243614 TI - Memory-reliant Post-error Slowing Is Associated with Successful Learning and Fronto-occipital Activity. AB - Negative feedback after an action in a cognitive task can lead to devaluing that action on future trials as well as to more cautious responding when encountering that same choice again. These phenomena have been explored in the past by reinforcement learning theories and cognitive control accounts, respectively. Yet, how cognitive control interacts with value updating to give rise to adequate adaptations under uncertainty is less clear. In this fMRI study, we investigated cognitive control-based behavioral adjustments during a probabilistic reinforcement learning task and studied their influence on performance in a later test phase in which the learned value of items is tested. We provide support for the idea that functionally relevant and memory-reliant behavioral adjustments in the form of post-error slowing during reinforcement learning are associated with test performance. Adjusting response speed after negative feedback was correlated with BOLD activity in right inferior frontal gyrus and bilateral middle occipital cortex during the event of receiving the feedback. Bilateral middle occipital cortex activity overlapped partly with activity reflecting feedback deviance from expectations as measured by unsigned prediction error. These results suggest that cognitive control and feature processing cortical regions interact to implement feedback-congruent adaptations beneficial to learning. PMID- 27243615 TI - Voluntary Saccadic Eye Movements Ride the Attentional Rhythm. AB - Visual perception seems continuous, but recent evidence suggests that the underlying perceptual mechanisms are in fact periodic-particularly visual attention. Because visual attention is closely linked to the preparation of saccadic eye movements, the question arises how periodic attentional processes interact with the preparation and execution of voluntary saccades. In two experiments, human observers made voluntary saccades between two placeholders, monitoring each one for the presentation of a threshold-level target. Detection performance was evaluated as a function of latency with respect to saccade landing. The time course of detection performance revealed oscillations at around 4 Hz both before the saccade at the saccade origin and after the saccade at the saccade destination. Furthermore, oscillations before and after the saccade were in phase, meaning that the saccade did not disrupt or reset the ongoing attentional rhythm. Instead, it seems that voluntary saccades are executed as part of an ongoing attentional rhythm, with the eyes in flight during the troughs of the attentional wave. This finding for the first time demonstrates that periodic attentional mechanisms affect not only perception but also overt motor behavior. PMID- 27243616 TI - Neural Measures Reveal Implicit Learning during Language Processing. AB - Language input is highly variable; phonological, lexical, and syntactic features vary systematically across different speakers, geographic regions, and social contexts. Previous evidence shows that language users are sensitive to these contextual changes and that they can rapidly adapt to local regularities. For example, listeners quickly adjust to accented speech, facilitating comprehension. It has been proposed that this type of adaptation is a form of implicit learning. This study examined a similar type of adaptation, syntactic adaptation, to address two issues: (1) whether language comprehenders are sensitive to a subtle probabilistic contingency between an extraneous feature (font color) and syntactic structure and (2) whether this sensitivity should be attributed to implicit learning. Participants read a large set of sentences, 40% of which were garden-path sentences containing temporary syntactic ambiguities. Critically, but unbeknownst to participants, font color probabilistically predicted the presence of a garden-path structure, with 75% of garden-path sentences (and 25% of normative sentences) appearing in a given font color. ERPs were recorded during sentence processing. Almost all participants indicated no conscious awareness of the relationship between font color and sentence structure. Nonetheless, after sufficient time to learn this relationship, ERPs time-locked to the point of syntactic ambiguity resolution in garden-path sentences differed significantly as a function of font color. End-of-sentence grammaticality judgments were also influenced by font color, suggesting that a match between font color and sentence structure increased processing fluency. Overall, these findings indicate that participants can implicitly detect subtle co-occurrences between physical features of sentences and abstract, syntactic properties, supporting the notion that implicit learning mechanisms are generally operative during online language processing. PMID- 27243617 TI - Temporal Binding and Segmentation in Visual Search: A Computational Neuroscience Analysis. AB - Human visual search operates not only over space but also over time, as old items remain in the visual field and new items appear. Preview search (where one set of distractors appears before the onset of a second set) has been used as a paradigm to study search over time and space [Watson, D. G., & Humphreys, G. W. Visual marking: Prioritizing selection for new objects by top-down attentional inhibition of old objects. Psychological Review, 104, 90-122, 1997], with participants showing efficient search when old distractors can be ignored and new targets prioritized. The benefits of preview search are lost, however, if a temporal gap is introduced between a first presentation of the old items and the re-presentation of all the items in the search display [Kunar, M. A., Humphreys, G. W., & Smith, K. J. History matters: The preview benefit in search is not onset capture. Psychological Science, 14, 181-185, 2003a], consistent with the old items being bound by temporal onset to the new stimuli. This effect of temporal binding can be eliminated if the old items reappear briefly before the new items, indicating also a role for the memory of the old items. Here we simulate these effects of temporal coding in search using the spiking search over time and space model [Mavritsaki, E., Heinke, D., Allen, H., Deco, G., & Humphreys, G. W. Bridging the gap between physiology and behavior: Evidence from the sSoTS model of human visual attention. Psychological Review, 118, 3-41, 2011]. We show that a form of temporal binding by new onsets has to be introduced to the model to simulate the effects of a temporal gap, but that effects of the memory of the old item can stem from continued neural suppression across a temporal gap. We also show that the model can capture the effects of brain lesion on preview search under the different temporal conditions. The study provides a proof-of-principle analysis that neural suppression and temporal binding can be sufficient to account for human search over time and space. PMID- 27243618 TI - Designing P-Chirogenic 1,2-Diphosphinobenzenes at Both P-Centers Using P(III) Phosphinites. AB - A new enantiodivergent synthesis of P-chirogenic 1,2-diphosphinobenzenes (DP*B) bearing the chirality on one or both phosphorus centers is reported using aryne chemistry. The principle is based on successive reactions of 1,2-dibromobenzene with sec-phosphide boranes, then DABCO to remove the borane, and finally with chlorophosphines or P(III)-chirogenic phosphinites. The efficiency of this synthesis was demonstrated by the stereoselective preparation of (S,S)-1,2-bis(o anisylphenylphosphino)benzene. A comparison of DIPAMP and homochiral DP*B ligands in asymmetric Rh- or Pd-catalyzed reactions was reported. PMID- 27243619 TI - Empirically supported psychosocial interventions for bipolar disorder: Current state of the research. AB - OBJECTIVES: Bipolar disorder requires psychiatric medications, but even guideline concordant treatment fails to bring many patients to remission or keep them euthymic. To address this gap, researchers have developed adjunctive psychotherapies. The purpose of this paper is to critically review the evidence for the efficacy of manualized psychosocial interventions for bipolar disorder. METHODS: We conducted a search of the literature to examine recent (2007 present), randomized controlled studies of the following psychotherapy interventions for bipolar disorder: psychoeducation (PE), cognitive behavioral therapy (CBT), interpersonal and social rhythm therapy (IPSRT), dialectical behavior therapy (DBT), mindfulness-based cognitive therapy (MBCT), and family therapies such as family focused therapy (FFT). RESULTS: All of the psychotherapy interventions appear to be effective in reducing depressive symptoms. Psychoeducation and CBT are associated with increased time to mood episode relapse or recurrence. MBCT has demonstrated a particular effectiveness in improving depressive and anxiety symptoms. Online psychotherapy interventions, programs combining one or more psychotherapy interventions, and targeted interventions centering on particular symptoms have been the focus of recent, randomized controlled studies in bipolar disorder. CONCLUSIONS: Psychotherapy interventions for the treatment of bipolar disorder have substantial evidence for efficacy. The next challenge will to disseminate these psychotherapies into the community. PMID- 27243620 TI - Tunneled Indwelling Pleural Catheters for Refractory Pleural Effusions after Solid Organ Transplant. A Case-Control Study. AB - RATIONALE: The use of tunneled indwelling pleural catheters for management of refractory pleural effusions continues to increase. Pleural space infections are among the most common and serious complication of the procedure. The risk may be higher in patients receiving immunosuppressive medications. OBJECTIVES: The aim of this study was to assess the risk of infections complicating placement of a tunneled indwelling pleural catheter in patients who have received a solid organ transplant. METHODS: Electronic medical records were retrospectively reviewed to identify patients with prior solid organ transplant who subsequently underwent placement of a tunneled intrapleural catheter. We selected a matched sample of comparison patients without solid organ transplant who underwent the same procedure during the study period. Detailed chart abstraction was performed to compare baseline clinical information with procedure outcomes in both groups. MEASUREMENTS AND MAIN RESULTS: Nineteen study patients underwent kidney, liver, lung, or heart transplant. Another 55 patients were included in the nontransplant comparison group. Transplant patients were taking a mean of 2.4 (range, 1-4) immunosuppressive medications. In transplant patients, the intrapleural catheter remained in place for a median of 95 days (interquartile range, 58-256 d). Two of the 19 transplant patients (16.9% 90-day Kaplan-Meier estimate) and 4 of the 55 control patients (11.0% weighted 90-day Kaplan-Meier estimate) developed a major infectious complication (not significant). There were no deaths attributed to intrapleural catheter placement in either group. CONCLUSIONS: In a series of 19 patients with solid organ transplantation taking daily immunosuppressive medications who underwent placement of a tunneled intrapleural catheter, we report an 11% rate of major infectious complications over the lifetime of the catheter in the transplant group with no significant difference in 90-day estimated risk of complication between transplant and nontransplant comparison group. PMID- 27243622 TI - Correction: Development of an Agent-Based Model (ABM) to Simulate the Immune System and Integration of a Regression Method to Estimate the Key ABM Parameters by Fitting the Experimental Data. AB - [This corrects the article DOI: 10.1371/journal.pone.0141295.]. PMID- 27243621 TI - Xenotransfusion of anemic cats with blood compatibility issues: pre- and posttransfusion laboratory diagnostic and crossmatching studies. AB - BACKGROUND: Finding compatible feline blood donors can be challenging. Canine blood has been occasionally used when compatible feline blood was not available in emergency situations. OBJECTIVES: The study goals were to describe the effects of xenotransfusion in 2 anemic cats receiving canine blood because of discordant blood types and acute transfusion reaction, respectively, and to report in vitro heterotyping and crossmatching results between canine and feline blood samples. MATERIAL AND METHODS: Blood samples from patients and other cats and dogs were typed, crossmatched, and assessed for alloantibodies using gel, card, and immunochromatographic strip techniques. RESULTS: Cat 1 was found to have type AB blood. Cat 2, which experienced an acute transfusion reaction, had type A blood. Neither had detectable alloantibodies against feline RBC. Both cats transiently improved after transfusion with canine blood; however, acute intravascular hemolysis occurred and the PCV rapidly declined. Blood typing post xenotransfusion with DEA 1 strips revealed a positive control band that was absent in feline blood, thus allowing for the identification of transfused canine RBC. Longitudinal assessment revealed that canine RBC could no longer be detected 4 days after xenotransfusion. Major crossmatching (feline plasma with canine RBC) resulted in both positive and negative reactions, depending on the cat. Minor crossmatching results showed mostly incompatibility. CONCLUSION: While both cats survived xenotransfusion, the positive control band on the DEA 1 strip revealed that transfused canine RBC were short-lived and intravascular hemolysis occurred. Crossmatch results between cats and dogs showed varied incompatibilities and may not predict transfusion reactions. PMID- 27243623 TI - Coarctation of the aorta: are genes relevant? AB - In a busy clinic, it is easy to overlook genetic aspects of congenital heart disease. The complexity of genetic influence on disease makes it difficult to provide clear, accurate advice about recurrence risks and genetics to individual patients. This is particularly true of coarctation of the aorta, which appears sporadic in the majority of cases. We will see that in fact, genetics can play an important role in coarctation. We will review the current state of knowledge about the genetics of coarctation, encompassing syndromic and non-syndromic presentations, and consider the implications for clinical practice. PMID- 27243624 TI - Modern management of adult coarctation: transcatheter and surgical options. AB - Coarctation of the aorta (CoA), a juxtaductal obstructive lesion in the descending aorta and commonly associated with hypoplasia of the aortic arch occurs in 5-8% of patients with congenital heart disease. Since the initial surgical corrections in the 1950, surgical and transcatheter options have constantly evolved. Nowadays, transcatheter options are widely accepted as the initial treatment of choice in adults presenting with native or recurrent CoA. Surgical techniques are mainly reserved for patients with complex aortic arch anatomy such as extended arch hypoplasia or stenosis or para-CoA aneurysm formation. Extended aneurysms can be covered by conformable stents but stent implantation may require preparative vascular surgery. Complex re-CoA my best be treated by an ascending to descending bypass conduit. The following review aims to describe current endovascular and surgical practice pointing out modern developments and their limitations. PMID- 27243625 TI - Regional Effects of Agricultural Conservation Practices on Nutrient Transport in the Upper Mississippi River Basin. AB - Despite progress in the implementation of conservation practices, related improvements in water quality have been challenging to measure in larger river systems. In this paper we quantify these downstream effects by applying the empirical U.S. Geological Survey water-quality model SPARROW to investigate whether spatial differences in conservation intensity were statistically correlated with variations in nutrient loads. In contrast to other forms of water quality data analysis, the application of SPARROW controls for confounding factors such as hydrologic variability, multiple sources and environmental processes. A measure of conservation intensity was derived from the USDA-CEAP regional assessment of the Upper Mississippi River and used as an explanatory variable in a model of the Upper Midwest. The spatial pattern of conservation intensity was negatively correlated (p = 0.003) with the total nitrogen loads in streams in the basin. Total phosphorus loads were weakly negatively correlated with conservation (p = 0.25). Regional nitrogen reductions were estimated to range from 5 to 34% and phosphorus reductions from 1 to 10% in major river basins of the Upper Mississippi region. The statistical associations between conservation and nutrient loads are consistent with hydrological and biogeochemical processes such as denitrification. The results provide empirical evidence at the regional scale that conservation practices have had a larger statistically detectable effect on nitrogen than on phosphorus loadings in streams and rivers of the Upper Mississippi Basin. PMID- 27243626 TI - Morphometry of Concepcion Bank: Evidence of Geological and Biological Processes on a Large Volcanic Seamount of the Canary Islands Seamount Province. AB - Concepcion Bank is the largest seamount in the Canary Islands Seamount Province (CISP), an oceanic area off NW Africa including 16 main seamounts, the Canaries archipelago and the Selvagens subarchipelago. The Bank is located 90 km northeast of Lanzarote Island and has been identified as a candidate Marine Protected Area (MPA) to be included in the Natura 2000 network. A compilation of complementary datasets consisting of multibeam bathymetry, TOPAS seismic reflection profiles, side scan sonar sonographs, Remotely Operated Vehicle video records and seafloor samples allowed describing in detail and ground truthing the submarine landforms and bioconstructions exhibited by the bank. The Concepcion Bank presently rises up to 2,433 m above the adjacent seafloor and exhibits two main domains: an extensive summit plateau and steep flanks. The sub-round summit plateau is 50km by 45 km and ranges from 158 to 1,485 m depth. The steep flanks that bound it descend to depths ranging between 1,700 and 2,500 m and define a seamount base that is 66km by 53 km. This morphology is the result of constructive and erosive processes involving different time scales, volumes of material and rates of change. The volcanic emplacement phase probably lasted 25-30 million years and was likely responsible for most of the 2,730 km3 of material that presently form the seamount. Subsequently, marine abrasion and, possibly, subaerial erosion modulated by global sea level oscillations, levelled the formerly emerging seamount summit plateau, in particular its shallower (<400 m), flatter (<0.5 degrees ) eastern half. Subsidence associated to the crustal cooling that followed the emplacement phase further contributed the current depth range of the seamount. The deeper and steeper (2.3 degrees ) western half of Concepcion Bank may result from tectonic tilting normal to a NNE-SSW fracture line. This fracture may still be expressed on the seafloor surface at some scarps detected on the seamount's summit. Sediment waves and cold-water coral (CWC) mounds on the bank summit plateau are the youngest features contributing to its final shaping, and may be indicative of internal wave effects. Numerous submarine canyons generally less than 10 km in length are incised on the bank's flanks. The most developed, hierarchized canyon system runs southwest of the bank, where it merges with other canyons coming from the southern bulges attached to some sections of the seamount flanks. These bulges are postulated as having an intrusive origin, as no major headwall landslide scars have been detected and their role as deposition areas for the submarine canyons seems to be minor. The results presented document how geological processes in the past and recent to subrecent oceanographic conditions and associated active processes determined the current physiography, morphology and sedimentary patterns of Concepcion Bank, including the development and decline of CWC mounds The setting of the seamount in the regional crustal structure is also discussed. PMID- 27243627 TI - Social Structure and Genetic Distance Mediate Nestmate Recognition and Aggressiveness in the Facultative Polygynous Ant Pheidole pallidula. AB - In social insects, the evolutionary stability of cooperation depends on the privileged relationships between individuals of the social group, which is facilitated by the recognition of relatives. Nestmate recognition is based on genetically determined cues and/or environmentally derived chemical components present on the cuticle of individuals. Here, we studied nestmate recognition in the ant Pheidole pallidula, a species where both single-queen (monogyne) and multiple-queen (polygyne) colonies co-occur in the same population. We combined geographical, genetic and chemical analyses to disentangle the factors influencing the level of intraspecific aggressiveness. We show that encounters between workers from neighbouring colonies (i.e., nests less than 5 m away) are on average less aggressive than those between workers from more distant colonies. Aggressive behaviour is associated with the level of genetic difference: workers from monogyne colonies are more aggressive than workers from polygyne colonies, and the intensity of aggressiveness is positively associated with the genetic distance between colonies. Since the genetic distance is correlated with the spatial distance between pairs of colonies, the lower level of aggression toward neighbours may result from their higher relatedness. In contrast, the analysis of overall cuticular hydrocarbon profiles shows that aggressive behaviour is associated neither with the chemical diversity of colonies, nor with the chemical distances between them. When considering methyl-branched alkanes only, however, chemical distances differed between monogyne and polygyne colonies and were significantly associated with aggressiveness. Altogether, these results show that the social structure of colonies and the genetic distances between colonies are two major factors influencing the intensity of agonistic behaviours in the ant P. pallidula. PMID- 27243628 TI - Effect of Surface Modifications of Ti40Zr10Cu38Pd12 Bulk Metallic Glass and Ti 6Al-4V Alloy on Human Osteoblasts In Vitro Biocompatibility. AB - The use of biocompatible materials, including bulk metallic glasses (BMGs), for tissue regeneration and transplantation is increasing. The good mechanical and corrosion properties of Ti40Zr10Cu38Pd12 BMG and its previously described biocompatibility makes it a potential candidate for medical applications. However, it is known that surface properties like topography might play an important role in regulating cell adhesion, proliferation and differentiation. Thus, in the present study, Ti40Zr10Cu38Pd12 BMG and Ti6-Al-4V alloy were surface modified electrochemically (nanomesh) or physically (microscratched) to investigate the effect of material topography on human osteoblasts cells (Saos-2) adhesion, proliferation and differentiation. For comparative purposes, the effect of mirror-like polished surfaces was also studied. Electrochemical treatments led to a highly interconnected hierarchical porous structure rich in oxides, which have been described to improve corrosion resistance, whereas microscratched surfaces showed a groove pattern with parallel trenches. Cell viability was higher than 96% for the three topographies tested and for both alloy compositions. In all cases, cells were able to adhere, proliferate and differentiate on the alloys, hence indicating that surface topography plays a minor role on these processes, although a clear cell orientation was observed on microscratched surfaces. Overall, our results provide further evidence that Ti40Zr10Cu38Pd12 BMG is an excellent candidate, in the present two topographies, for bone repair purposes. PMID- 27243629 TI - Prices, Costs, and Affordability of New Medicines for Hepatitis C in 30 Countries: An Economic Analysis. AB - INTRODUCTION: New hepatitis C virus (HCV) medicines have markedly improved treatment efficacy and regimen tolerability. However, their high prices have limited access, prompting wide debate about fair and affordable prices. This study systematically compared the price and affordability of sofosbuvir and ledipasvir/sofosbuvir across 30 countries to assess affordability to health systems and patients. METHODS AND FINDINGS: Published 2015 ex-factory prices for a 12-wk course of treatment were provided by the Pharma Price Information (PPI) service of the Austrian public health institute Gesundheit Osterreich GmbH or were obtained from national government or drug reimbursement authorities and recent press releases, where necessary. Prices in Organisation for Economic Co operation and Development (OECD) member countries and select low- and middle income countries were converted to US dollars using period average exchange rates and were adjusted for purchasing power parity (PPP). We analysed prices compared to national economic performance and estimated market size and the cost of these drugs in terms of countries' annual total pharmaceutical expenditure (TPE) and in terms of the duration of time an individual would need to work to pay for treatment out of pocket. Patient affordability was calculated using 2014 OECD average annual wages, supplemented with International Labour Organization median wage data where necessary. All data were compiled between 17 July 2015 and 25 January 2016. For the base case analysis, we assumed a 23% rebate/discount on the published price in all countries, except for countries with special pricing arrangements or generic licensing agreements. The median nominal ex-factory price of a 12-wk course of sofosbuvir across 26 OECD countries was US$42,017, ranging from US$37,729 in Japan to US$64,680 in the US. Central and Eastern European countries had higher PPP-adjusted prices than other countries: prices of sofosbuvir in Poland and Turkey (PPP$101,063 and PPP$70,331) and of ledipasvir/sofosbuvir in Poland (PPP$118,754) were at least 1.09 and 1.63 times higher, respectively than in the US (PPP$64,680 and PPP$72,765). Based on PPP adjusted TPE and without the cost of ribavirin and other treatment costs, treating the entire HCV viraemic population with these regimens at the PPP adjusted prices with a 23% price reduction would amount to at least one-tenth of current TPE across the countries included in this study, ranging from 10.5% of TPE in the Netherlands to 190.5% of TPE in Poland. In 12 countries, the price of a course of sofosbuvir without other costs was equivalent to 1 y or more of the average annual wage of individuals, ranging from 0.21 y in Egypt to 5.28 y in Turkey. This analysis relies on the accuracy of price information and infection prevalence estimates. It does not include the costs of diagnostic testing, supplementary treatments, treatment for patients with reinfection or cirrhosis, or associated health service costs. CONCLUSIONS: Current prices of these medicines are variable and unaffordable globally. These prices threaten the sustainability of health systems in many countries and prevent large-scale provision of treatment. Stakeholders should implement a fairer pricing framework to deliver lower prices that take account of affordability. Without lower prices, countries are unlikely to be able to increase investment to minimise the burden of hepatitis C. PMID- 27243630 TI - Engaging Terminally Ill Patients in End of Life Talk: How Experienced Palliative Medicine Doctors Navigate the Dilemma of Promoting Discussions about Dying. AB - OBJECTIVE: To examine how palliative medicine doctors engage patients in end-of life (hereon, EoL) talk. To examine whether the practice of "eliciting and responding to cues", which has been widely advocated in the EoL care literature, promotes EoL talk. DESIGN: Conversation analysis of video- and audio-recorded consultations. PARTICIPANTS: Unselected terminally ill patients and their companions in consultation with experienced palliative medicine doctors. SETTING: Outpatient clinic, day therapy clinic, and inpatient unit of a single English hospice. RESULTS: Doctors most commonly promoted EoL talk through open elaboration solicitations; these created opportunities for patients to introduce then later further articulate-EoL considerations in such a way that doctors did not overtly ask about EoL matters. Importantly, the wording of elaboration solicitations avoided assuming that patients had EoL concerns. If a patient responded to open elaboration solicitations without introducing EoL considerations, doctors sometimes pursued EoL talk by switching to a less participatory and more presumptive type of solicitation, which suggested the patient might have EoL concerns. These more overt solicitations were used only later in consultations, which indicates that doctors give precedence to patients volunteering EoL considerations, and offer them opportunities to take the lead in initiating EoL talk. There is evidence that doctors treat elaboration of patients' talk as a resource for engaging them in EoL conversations. However, there are limitations associated with labelling that talk as "cues" as is common in EoL communication contexts. We examine these limitations and propose "possible EoL considerations" as a descriptively more accurate term. CONCLUSIONS: Through communicating-via open elaboration solicitations-in ways that create opportunities for patients to volunteer EoL considerations, doctors navigate a core dilemma in promoting EoL talk: giving patients opportunities to choose whether to engage in conversations about EoL whilst being sensitive to their communication needs, preferences and state of readiness for such dialogue. PMID- 27243632 TI - Prenatal Antidepressant Use and Risk of Autism Spectrum Disorders in Children. PMID- 27243631 TI - Synthesis of pogostone by one-step. AB - Pogostone, isolated from Pogostemon cablin, has many biological activities such as potential antibacterial, anticandida, and antifungal. Traditional extraction leads to low output of PO about 17.6 mg/kg from Herba Pogostemonis. The previous literature had reported a synthetic study and the yield had reached 4.48% with strictly controlled reaction conditions. The two methods above cannot meet the large demand of PO; we report a new synthesis method. 4-hydroxy-6-methyl-2-pyrone (1) was added in toluene, with the existence of acylation catalyst 4 dimethylaminopyridine (DMAP), 4-methylvaleric acid (2), and condensing agent dicyclohexylcarbodiimide (DCC), PO was synthesized after the combination of 3 carbon of (1) with 1-OH of (2) in the acylation reaction. The purity had reached 98%, determined by HPLC. The structure was confirmed by spectroscopic methods including infrared, electron ionization mass spectrometry, and nuclear magnetic resonance spectroscopy. PO was totally synthesized in one step including cyclization, with total yield of 27.2%. PMID- 27243633 TI - Multiple White Plaques in the Body of the Stomach in a Patient Undergoing Hemodialysis. PMID- 27243634 TI - Reply. PMID- 27243635 TI - Integrin alphaEbeta7 in Inflammatory Bowel Disease: Friend or Foe? PMID- 27243636 TI - An Incidentally Discovered Abdominal Mass During Physical Examination. PMID- 27243637 TI - Reply. PMID- 27243638 TI - Roux-en-Y Gastric Bypass and Intestinal Glucose Handling: A Salty Sweet Operation. PMID- 27243639 TI - Reply. PMID- 27243640 TI - A Hazard of Outdoor Grilling. PMID- 27243641 TI - The METEOR Trial: The Burial of Methotrexate in Ulcerative Colitis? PMID- 27243642 TI - Mutation of Aryl Binding Pocket Residues Results in an Unexpected Activity Switch in an Oryza sativa Tyrosine Aminomutase. PMID- 27243643 TI - Arabidopsis callose synthases CalS1/8 regulate plasmodesmal permeability during stress. AB - Plants need to cope with biotic and abiotic stress through well-coordinated cell to-cell communication to survive as sedentary organisms. Environmental challenges such as wounding, low temperature, oxidative states and pathogen infection are known to affect the symplasmic molecular exchange between plant cells determined by plasmodesmal permeability. However, the signalling pathways and mechanisms by which different environmental stressors affect plasmodesmal permeability are not well understood. Here we show that regulating callose accumulation at plasmodesmal channels is a common strategy to alter plasmodesmal permeability under both pathogen infection and mechanical wounding stress. We have identified Arabidopsis callose synthase 1 (CalS1) and CalS8 as key genes involved in this process, and have integrated these new players into both known and novel signalling pathways that control responses to biotic and abiotic stress. Our studies provide experimental data that indicate the presence of specialized pathways tuned to respond to particular stressors, and new insights into how plants regulate plasmodesmata in response to environmental assaults. PMID- 27243644 TI - Mother-plant-mediated pumping of zinc into the developing seed. AB - Insufficient intake of zinc and iron from a cereal-based diet is one of the causes of 'hidden hunger' (micronutrient deficiency), which affects some two billion people(1,2). Identifying a limiting factor in the molecular mechanism of zinc loading into seeds is an important step towards determining the genetic basis for variation of grain micronutrient content and developing breeding strategies to improve this trait(3). Nutrients are translocated to developing seeds at a rate that is regulated by transport processes in source leaves, in the phloem vascular pathway, and at seed sinks. Nutrients are released from a symplasmic maternal seed domain into the seed apoplasm surrounding the endosperm and embryo by poorly understood membrane transport processes(4-6). Plants are unique among eukaryotes in having specific P1B-ATPase pumps for the cellular export of zinc(7). In Arabidopsis, we show that two zinc transporting P1B-ATPases actively export zinc from the mother plant to the filial tissues. Mutant plants that lack both zinc pumps accumulate zinc in the seed coat and consequently have vastly reduced amounts of zinc inside the seed. Blockage of zinc transport was observed at both high and low external zinc supplies. The phenotype was determined by the mother plant and is thus due to a lack of zinc pump activity in the seed coat and not in the filial tissues. The finding that P1B-ATPases are one of the limiting factors controlling the amount of zinc inside a seed is an important step towards combating nutritional zinc deficiency worldwide. PMID- 27243645 TI - C4 photosynthesis boosts growth by altering physiology, allocation and size. AB - C4 photosynthesis is a complex set of leaf anatomical and biochemical adaptations that have evolved more than 60 times to boost carbon uptake compared with the ancestral C3 photosynthetic type(1-3). Although C4 photosynthesis has the potential to drive faster growth rates(4,5), experiments directly comparing C3 and C4 plants have not shown consistent effects(1,6,7). This is problematic because differential growth is a crucial element of ecological theory(8,9) explaining C4 savannah responses to global change(10,11), and research to increase C3 crop productivity by introducing C4 photosynthesis(12). Here, we resolve this long-standing issue by comparing growth across 382 grass species, accounting for ecological diversity and evolutionary history. C4 photosynthesis causes a 19-88% daily growth enhancement. Unexpectedly, during the critical seedling establishment stage, this enhancement is driven largely by a high ratio of leaf area to mass, rather than fast growth per unit leaf area. C4 leaves have less dense tissues, allowing more leaves to be produced for the same carbon cost. Consequently, C4 plants invest more in roots than C3 species. Our data demonstrate a general suite of functional trait divergences between C3 and C4 species, which simultaneously drive faster growth and greater investment in water and nutrient acquisition, with important ecological and agronomic implications. PMID- 27243646 TI - The phosphorus cost of agricultural intensification in the tropics. AB - Agricultural intensification in the tropics is one way to meet rising global food demand in coming decades(1,2). Although this strategy can potentially spare land from conversion to agriculture(3), it relies on large material inputs. Here we quantify one such material cost, the phosphorus fertilizer required to intensify global crop production atop phosphorus-fixing soils and achieve yields similar to productive temperate agriculture. Phosphorus-fixing soils occur mainly in the tropics, and render added phosphorus less available to crops(4,5). We estimate that intensification of the 8-12% of global croplands overlying phosphorus-fixing soils in 2005 would require 1-4 Tg P yr(-1) to overcome phosphorus fixation, equivalent to 8-25% of global inorganic phosphorus fertilizer consumption that year. This imposed phosphorus 'tax' is in addition to phosphorus added to soils and subsequently harvested in crops, and doubles (2-7 Tg P yr(-1)) for scenarios of cropland extent in 2050(6). Our estimates are informed by local-, state- and national-scale investigations in Brazil, where, more than any other tropical country, low-yielding agriculture has been replaced by intensive production. In the 11 major Brazilian agricultural states, the surplus of added inorganic fertilizer phosphorus retained by soils post harvest is strongly correlated with the fraction of cropland overlying phosphorus-fixing soils (r(2) = 0.84, p < 0.001). Our interviews with 49 farmers in the Brazilian state of Mato Grosso, which produces 8% of the world's soybeans mostly on phosphorus-fixing soils, suggest this phosphorus surplus is required even after three decades of high phosphorus inputs. Our findings in Brazil highlight the need for better understanding of long-term soil phosphorus fixation elsewhere in the tropics. Strategies beyond liming, which is currently widespread in Brazil, are needed to reduce phosphorus retention by phosphorus-fixing soils to better manage the Earth's finite phosphate rock supplies and move towards more sustainable agricultural production. PMID- 27243647 TI - The nature of self-regulation in photosynthetic light-harvesting antenna. AB - The photosynthetic apparatus of green plants is well known for its extremely high efficiency that allows them to operate under dim light conditions. On the other hand, intense sunlight may result in overexcitation of the light-harvesting antenna and the formation of reactive compounds capable of 'burning out' the whole photosynthetic unit. Non-photochemical quenching is a self-regulatory mechanism utilized by green plants on a molecular level that allows them to safely dissipate the detrimental excess excitation energy as heat. Although it is believed to take place in the plant's major light-harvesting complexes (LHC) II, there is still no consensus regarding its molecular nature. To get more insight into its physical origin, we performed high-resolution time-resolved fluorescence measurements of LHCII trimers and their aggregates across a wide temperature range. Based on simulations of the excitation energy transfer in the LHCII aggregate, we associate the red-emitting state, having fluorescence maximum at ~700 nm, with the partial mixing of excitonic and chlorophyll-chlorophyll charge transfer states. On the other hand, the quenched state has a totally different nature and is related to the incoherent excitation transfer to the short-lived carotenoid excited states. Our results also show that the required level of photoprotection in vivo can be achieved by a very subtle change in the number of LHCIIs switched to the quenched state. PMID- 27243648 TI - Arabidopsis AGO3 predominantly recruits 24-nt small RNAs to regulate epigenetic silencing. AB - Argonaute (AGO) proteins recruit 21-24-nucleotide (nt) small RNAs (sRNAs) to constitute RNA-induced silencing complexes (RISCs) to regulate gene expression at transcriptional or posttranscriptional levels(1-3). Arabidopsis encodes nine functional AGO proteins. These proteins are classified into three clusters, AGO1/5/10, AGO2/3/7 and AGO4/6/9, based on their sequence similarity, functional redundancy, as well as species and features of AGO-bound sRNAs(4-7). Although most Arabidopsis AGO proteins have been studied well, AGO3-bound sRNAs and their basic function remain unknown. Here we observed that AGO3 could not complement the signature function of AGO2, the closest genetic paralog of AGO3, in host antiviral defence. We also found, surprisingly, that AGO3 predominantly bound 24 nt sRNAs with 5'-terminal adenine. The spectrum of AGO3-associated sRNAs was different from those bound to AGO2, further indicating their functional divergence. By contrast, approximately 30% of AGO3-bound 24-nt sRNAs overlapped with those bound to AGO4, and over 60% of AGO3-associated 24-nt sRNA-enriched loci were identical to those of AGO4. Moreover, the redundancy of AGO3- and AGO4 bound sRNAs is much more than that of AGO6- and AGO4-recruited sRNAs. In addition, expression of AGO3 driven by the AGO4 promoter partially complemented AGO4 function and rescued a DNA methylation defect in the ago4-1 background. Together, our results indicated that AGO3, similarly to AGO4, is a component in the epigenetic pathway. PMID- 27243649 TI - Nonsense-mediated mRNA decay modulates FLM-dependent thermosensory flowering response in Arabidopsis. AB - Increasing global temperatures have an impact on flowering, and the underlying mechanisms are just beginning to be unravelled(1,2). Elevated temperatures can induce flowering, and different mechanisms that involve either activation or de repression of FLOWERING LOCUS T (FT) by transcription factor PHYTOCHROME INTERACTING FACTOR 4 (PIF4) or the FLOWERING LOCUS M (FLM)-SHORT VEGETATIVE PHASE (SVP) complex, respectively, have been suggested to be involved(3-6). Thermosensitivity in flowering has been mapped to FLM(5), which encodes a floral repressor(7,8). FLM undergoes alternative splicing(8) and it has been suggested that temperature-dependent alternative splicing leads to differential accumulation of the FLM-beta and FLM-delta transcripts, encoding proteins with antagonistic effects, and that their ratio determines floral transition(4). Here we show that high temperatures downregulate FLM expression by alternative splicing coupled with nonsense-mediated mRNA decay (AS-NMD). We identify thermosensitive splice sites in FLM and show that the primary effect of temperature is explained by an increase in NMD target transcripts. We also show that flm is epistatic to pif4, which suggests that most of the PIF4 effects are FLM dependent. Our findings suggest a model in which the loss of the floral repressor FLM occurs through mRNA degradation in response to elevated temperatures, signifying a role for AS-NMD in conferring environmental responses in plants. PMID- 27243650 TI - Extrafloral nectar secretion from wounds of Solanum dulcamara. AB - Plants usually close wounds rapidly to prevent infections and the loss of valuable resources such as assimilates(1). However, herbivore-inflicted wounds on the bittersweet nightshade Solanum dulcamara appear not to close completely and produce sugary wound secretions visible as droplets. Many plants across the plant kingdom secrete sugary nectar from extrafloral nectaries(2) to attract natural enemies of herbivores for indirect defence(3,4). As ants forage on wound edges of S. dulcamara in the field, we hypothesized that wound secretions are a form of extrafloral nectar (EFN). We show that, unlike EFN from known nectaries, wound secretions are neither associated with any specific structure nor restricted to certain locations. However, similar to EFN, they are jasmonate-inducible and the plant controls their chemical composition. Wound secretions are attractive for ants, and application of wound secretion mimics increases ant attraction and reduces herbivory on S. dulcamara plants in a natural population. In greenhouse experiments, we reveal that ants can defend S. dulcamara from two of its native herbivores, slugs and flea beetle larvae. Since nectar is defined by its ecological function as a sugary secretion involved in interactions with animals(5), such 'plant bleeding' could be a primitive mode of nectar secretion exemplifying an evolutionary origin of structured extrafloral nectaries. PMID- 27243652 TI - RNA interference: A dark horse in the AGO stable. PMID- 27243653 TI - Micronutrients: Supplementing seeds with zinc. PMID- 27243651 TI - Unique cell-type-specific patterns of DNA methylation in the root meristem. AB - DNA methylation is an epigenetic modification that differs between plant organs and tissues, but the extent of variation between cell types is not known. Here, we report single-base-resolution whole-genome DNA methylomes, mRNA transcriptomes and small RNA transcriptomes for six cell populations covering the major cell types of the Arabidopsis root meristem. We identify widespread cell-type-specific patterns of DNA methylation, especially in the CHH sequence context, where H is A, C or T. The genome of the columella root cap is the most highly methylated Arabidopsis cell characterized so far. It is hypermethylated within transposable elements (TEs), accompanied by increased abundance of transcripts encoding RNA directed DNA methylation (RdDM) pathway components and 24-nt small RNAs (smRNAs). The absence of the nucleosome remodeller DECREASED DNA METHYLATION 1 (DDM1), required for maintenance of DNA methylation, and low abundance of histone transcripts involved in heterochromatin formation suggests that a loss of heterochromatin may occur in the columella, thus allowing access of RdDM factors to the whole genome, and producing an excess of 24-nt smRNAs in this tissue. Together, these maps provide new insights into the epigenomic diversity that exists between distinct plant somatic cell types. PMID- 27243654 TI - Epigenetics: Cell-type methylomes in the root. PMID- 27243655 TI - Reply to 'Misconceptions on the application of biological market theory to the mycorrhizal symbiosis'. PMID- 27243656 TI - Misconceptions on the application of biological market theory to the mycorrhizal symbiosis. PMID- 27243657 TI - Protecting medicine's wild pharmacy. PMID- 27243658 TI - How scalable is sustainable intensification? PMID- 27243659 TI - Immunity: RALF to the rescue. PMID- 27243660 TI - Maize genetics: Backyard biodiversity. PMID- 27243662 TI - RNA silencing: Machinery in algae. PMID- 27243661 TI - Systematics: Blind dating. PMID- 27243663 TI - Artists of discovery. PMID- 27243664 TI - Cross-reactivity features of deoxynivalenol (DON)-targeted immunoaffinity columns aiming to achieve simultaneous analysis of DON and major conjugates in cereal samples. AB - Immunoaffinity columns (IACs) are a well-established tool in the determination of regulated mycotoxins in food and feed commodities. However, they also have the potential to become attractive pre-concentration and clean-up materials for the determination of masked (also called modified) mycotoxins, which have been recognised as important contributors to the toxicological hazard deriving from fungal spoilage of goods. However, the information available in the literature concerning the cross-reactivity of DON-IACs against the major conjugates (DON-3 G, 15-AcDON and 3-AcDON) is incomplete and often contradictory. We have carried out a detailed characterisation of the cross-reactivity of the four main IACs brands against DON and its conjugates as well as an assessment of the competition among the analytes. Only one IAC enabled the simultaneous analysis of all relevant DON forms while two missed 15-AcDON and the fourth one missed DON-3-G and 3-AcDON. In the case of the multivalent IAC, the analytes modified at the C-3 position compete for the antibody binding with preference for 3-AcDON (less spatially hindered) while DON-3-G has the more-hindered access to the active sites. Taking into consideration the levels of DON conjugates existing in real samples, the cross-reactivity of one DON-IAC allows a quantitative analysis of all of these analytes. Important but rather neglected aspects such as the continuous supply of IACs with identical characteristics, and of columns which are strictly blank, are also addressed in this paper. PMID- 27243665 TI - Robot-Assisted Simultaneous Bilateral Radical Inguinal Lymphadenectomy Along with Robotic Bilateral Pelvic Lymphadenectomy: A Feasibility Study. AB - INTRODUCTION: To report the surgical technique, procedure outcomes, and feasibility of robot-assisted simultaneous bilateral radical inguinal with bilateral pelvic lymphadenectomy. MATERIALS AND METHODS: Three consecutive patients of penile and urethral carcinoma with palpable inguinal lymphadenopathy who underwent robot-assisted simultaneous bilateral radical inguinal with bilateral pelvic lymphadenectomy in our institution from May 2013 to October 2015 were included in the study. Surgical technique is described and feasibility of the procedure is assessed. RESULTS: Three patients aged 58, 76, and 35 years underwent robot-assisted simultaneous bilateral radical inguinal with bilateral pelvic lymphadenectomy with a mean operative duration of 453.33 minutes (range 420-490 minutes). Average blood loss was 66.66 mL (range 50-80 mL) and mean time to removal of last drain was 44.66 days (range 28-72 days). Mean lymph node yield in left inguinal region, right inguinal region, left pelvic region, and right pelvic region was 18, 14.6, 13.3, and 16.6, respectively. The perioperative period was uneventful. No skin flap-related complications were seen. One patient suffered lymphocele postoperatively, which was managed successfully with needle aspiration. One patient developed lung metastasis in follow-up and none of them had local recurrence. CONCLUSION: Robot-assisted simultaneous bilateral radical inguinal with bilateral pelvic lymphadenectomy is feasible, safe, and may result in decreased morbidity compared to conventional open lymphadenectomy. PMID- 27243666 TI - Altered conscious state as a presentation of the syndrome of transient headache and neurological deficits with cerebrospinal fluid lymphocytosis (HaNDL syndrome) in a paediatric patient. PMID- 27243667 TI - Primary Cleft Lip and Palate Repair in Assam, India: Does Preoperative Anthropometric Analysis Help Identify Patients With Increased Surgical Risk in a Clinically Prescreened Population? AB - OBJECTIVE: To compare anthropometric z-scores with incidence of post-operative complications for patients undergoing primary cleft lip or palate repair. DESIGN: This was a retrospective observational analysis of patients from a surgical center in Assam, India, and includes a cohort from a single surgical mission completed before the opening of the center. SETTING: Patients included in the study underwent surgery during an Operation Smile mission before the opening of Operation Smile's Guwahati Comprehensive Cleft Care Center in Guwahati, India. The remaining cohort received treatment at the center. All patients received preoperative assessment and screening; surgery; and postoperative care, education, and follow-up. PATIENTS, PARTICIPANTS: Our sample size included 1941 patients and consisted of all patients with complete information in the database who returned for follow-up after receiving primary cleft lip repair or primary cleft palate repair between January 2011 and April 2013. INTERVENTIONS: Preoperative anthropometric measurements. MAIN OUTCOME MEASURE(S): Postoperative complications. RESULTS: Anthropometric z-scores were not a significant predictor of adverse surgical outcomes in the group analyzed. Palate surgery had increased risk of complication versus lip repair, with an overall odds ratio of 5.66 (P < .001) for all patients aged 3 to 228 months. CONCLUSIONS: Anthropometric z-scores were not correlated with increased risk of surgical complications, possibly because patients were well screened for malnutrition before surgery at this center. Primary palate repair is associated with an approximate fivefold increased risk of developing postoperative complication(s) compared with primary lip repair. PMID- 27243668 TI - A Novel Interferon Regulatory Factor 6 Mutation in an Asian Family With Van der Woude Syndrome. AB - Van der Woude syndrome (VWS) is a rare autosomal dominant genetic disorder characterized by orofacial clefting and lip pits. Mutations in the transcription factor interferon regulatory factor 6 gene (IRF6) have been identified in individuals with VWS. We performed direct sequencing of the gene for molecular investigation of a proband with Bangladeshi-Malay ancestry. A novel transition mutation (c.113T>C), which resulted in an amino acid substitution (p.Ile38Thr) in the deoxyribonucleic acid-binding domain was detected. Testing of family members showed that the mutation segregated with the VWS phenotype for members of her immediate family. Although there is some phenotypic variability, all of the affected members are of the female gender. PMID- 27243669 TI - Early Craniofacial Defects in Zebrafish That Have Reduced Function of a Wnt Interacting Extracellular Matrix Protein, Tinagl1. AB - OBJECTIVE: Tinagl1 has a weak genetic association with craniosynostosis, but its functions in cartilage and bone development are unknown. Knockdown of Tinagl1 in zebrafish embryos allowed an initial characterization of its potential effects on craniofacial cartilage development and a test of whether these effects could involve Wnt signaling. RESULTS: Tinagl1 knockdown resulted in dose-dependent reductions and defects in ventral pharyngeal arch cartilages as well as the ethmoid plate, a zebrafish correlate to the palate. These defects could be correlated to reduced numbers of cranial neural crest cells in the pharyngeal arches and could be reproduced with comanipulation of Tinagl1 and Wnt3a by morpholino-based knockdown. CONCLUSIONS: These results suggest that Tinagl1 is required early in the proliferation or migration of cranial neural crest cells and that its effects are mediated via Wnt3a signaling. Because Wnt3a is among the Wnts that contribute to nonsyndromic cleft lip and cleft palate in mouse and man, further investigation of Tinagl1 may help to elucidate mechanisms underlying these disorders. PMID- 27243670 TI - Arsenate toxicity and metabolism in the halotolerant microalga Dunaliella salina under various phosphate regimes. AB - Microalgae play an important role in arsenic (As) biogeochemical cycles as they are capable of accumulating and metabolizing this metalloid efficiently. This study aimed to investigate the toxicity, accumulation and transformation of arsenate (As(v)) in Dunaliella salina, an exceptionally halotolerant microalga, under various phosphate (PO4(3-)) regimes. The results of the 72-h toxicity test showed that D. salina was tolerant to As(v). In addition, the toxicity of As(v) was mitigated by an increased PO4(3-) supply. D. salina resisted the adverse effects of As(v) through the suppression of As uptake, enhancement of As reduction, methylation in the cell and excretion from the cell. Our study revealed that D. salina reduced As(v) toxicity using different strategies, i.e., reduction of As uptake upon acute As stress (24 h) and increase of As efflux following chronic As exposure (9 day). Moreover, PO4(3-) strongly affected the adsorption, uptake and transformation of As(v) in D. salina. As(v) reduction, DMA production and As excretion were enhanced under P-limited conditions (0.112 mg L( 1)) or upon higher As(v) exposure (1120 MUg L(-1)). Furthermore, PO4(3-) had a significant influence on the As removal ability of D. salina. A high As removal efficiency (>95.6%) was observed in the 5-day cultures at an initial As concentration of 11.2 MUg L(-1) and PO4(3-) of 0.112 and 1.12 mg L(-1). However, only 10.9% of total As was removed under 11.2 mg L(-1) PO4(3-) after 9 days of incubation. The findings of this study illustrate the pivotal roles of extracellular PO4(3-) in As(v) toxicity and metabolism, and the results may be relevant for future research on the minimization of As contamination in algal products as well as on the enhancement of As removal from the environment. PMID- 27243749 TI - Simulated Microgravity and Low-Dose/Low-Dose-Rate Radiation Induces Oxidative Damage in the Mouse Brain. AB - Microgravity and radiation are stressors unique to the spaceflight environment that can have an impact on the central nervous system (CNS). These stressors could potentially lead to significant health risks to astronauts, both acutely during the course of a mission or chronically, leading to long-term, post-mission decrements in quality of life. The CNS is sensitive to oxidative injury due to high concentrations of oxidizable, unsaturated lipids and low levels of antioxidant defenses. The purpose of this study was to evaluate oxidative damage in the brain cortex and hippocampus in a ground-based model for spaceflight, which includes prolonged unloading and low-dose radiation. Whole-body low dose/low-dose-rate (LDR) gamma radiation using (57)Co plates (0.04 Gy at 0.01 cGy/h) was delivered to 6 months old, mature, female C57BL/6 mice (n = 4-6/group) to simulate the radiation component. Anti-orthostatic tail suspension was used to model the unloading, fluid shift and physiological stress aspects of the microgravity component. Mice were hindlimb suspended and/or irradiated for 21 days. Brains were isolated 7 days or 9 months after irradiation and hindlimb unloading (HLU) for characterization of oxidative stress markers and microvessel changes. The level of 4-hydroxynonenal (4-HNE) protein, an oxidative specific marker for lipid peroxidation, was significantly elevated in the cortex and hippocampus after LDR + HLU compared to controls (P < 0.05). The combination group also had the highest level of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) expression compared to controls (P < 0.05). There was a significant decrease in superoxide dismutase (SOD) expression in the animals that received HLU only or combined LDR + HLU compared to control (P < 0.05). In addition, 9 months after LDR and HLU exposure, microvessel densities were the lowest in the combination group, compared to age-matched controls in the cortex (P < 0.05). Our data provide the first evidence that prolonged exposure to simulated microgravity and LDR radiation is associated with increased oxidative stress biomarkers that may increase the likelihood of brain injury and reduced antioxidant defense. NOX2-containing nicotinamide adenosine dinucleotide phosphate (NADPH oxidase) may contribute to spaceflight environment-induced oxidative stress. PMID- 27243750 TI - Per-Substituted [8]Circulene and Its Non-Planar Fragments: Synthesis, Structural Analysis, and Properties. AB - The syntheses, structures, and physical properties of a full series of benzannulated tetraphenylenes are reported. The palladium-catalyzed annulation of tetraiodo-substituted 2,3,6,7,10,11,14,15-octamethyltetraphenylene with insufficient di(4-anisyl)ethyne yielded a mixture of per-substituted [8]circulene and its non-planar fragments, including mono-, para-di-, ortho-di-, and triannulated products. Their structures were unambiguously verified by X-ray crystallography. Successive benzannulations significantly affect the molecular geometries, dynamic behaviors, and physical properties of the compounds. In this series of compounds, [8]circulene is the most strained one, as reflected by the significant deplanarization of the phenanthrene moieties (ca. 63 degrees in the bay region) and the fact that it has the highest strain energy (120.6 kcal mol( 1) ). The dynamic behaviors of these compounds were examined both experimentally and theoretically. The ring flipping of per-substituted [8]circulene is confirmed to proceed through pseudorotation with a barrier of around 21 kcal mol(-1) , whereas its non-planar fragments require much more energy for the ring inversion. The photophysical and electrochemical properties of the investigated compounds depend strongly on the extent of efficient pi conjugation. The successive benzannulations red-shift both the absorption and the emission bands, and reduce the first oxidation potential. PMID- 27243751 TI - Copper-Catalyzed Tandem Decyclization-Cyclization Reaction of N-Alkynyl-3 hydroxyisoindolin-1-ones Generated from N-Alkynyl Phthalimides: Selective Synthesis of ortho-(2-Oxazolyl)phenyl Ketones. AB - Selective carbophilic monoaddition on N-alkynyl phthalimides was performed with organometallic reagents to afford 3-substituted N-alkynyl-3-hydroxyisoindolin-1 ones (alpha-hydroxy ynamides) as a new subgroup of ynamides. Owing to the alkynyl motif on the nitrogen atom, alpha-hydroxy ynamides were easily isomerized to the corresponding ortho-(2-oxazolyl)phenyl ketones in a CuCl-catalyzed tandem decyclization-cyclization reaction under mild conditions. PMID- 27243752 TI - Self-Assembly of Hydrofluorinated Janus Graphene Monolayer: A Versatile Route for Designing Novel Janus Nanoscrolls. AB - With remarkably interesting surface activities, two-dimensional Janus materials arouse intensive interests recently in many fields. We demonstrate by molecular dynamic simulations that hydrofluorinated Janus graphene (J-GN) can self-assemble into Janus nanoscroll (J-NS) at room temperature. The van der Waals (vdW) interaction and the coupling of C-H/pi/C-F interaction and pi/pi interaction are proven to offer the continuous driving force of self-assembly of J-GN. The results show that J-GN can self-assemble into various J-NSs structures, including arcs, multi-wall J-NS and arm-chair-like J-NS by manipulating its original geometry (size and aspect ratio). Moreover, we also investigated self-assembly of hydrofluorinated J-GN and Fe nanowires (NWs), suggesting that Fe NW is a good alternative to activate J-GN to form J-NS. Differently, the strong vdW interaction between J-GN and Fe NW provides the main driving force of the self assembly. Finally, we studied the hydrogen sorption over the formed J-NS with a considerable interlayer spacing, which reaches the US DOE target, indicating that J-NS is a promising candidate for hydrogen storage by controlling the temperature of system. Our theoretical results firstly provide a versatile route for designing novel J-NS from 2D Janus nanomaterials, which has a great potential application in the realm of hydrogen storage/separation. PMID- 27243753 TI - The alpha7 nicotinic receptor dual allosteric agonist and positive allosteric modulator GAT107 reverses nociception in mouse models of inflammatory and neuropathic pain. AB - BACKGROUND AND PURPOSE: Orthosteric agonists and positive allosteric modulators (PAMs) of the alpha7 nicotinic ACh receptor (nAChR) represent novel therapeutic approaches for pain modulation. Moreover, compounds with dual function as allosteric agonists and PAMs, known as ago-PAMs, add further regulation of receptor function. EXPERIMENTAL APPROACH: Initial studies examined the alpha7 ago PAM, GAT107, in the formalin, complete Freund's adjuvant (CFA), LPS inflammatory pain models, the chronic constriction injury neuropathic pain model and the tail flick and hot plate acute thermal nociceptive assays. Additional studies examined the locus of action of GAT107 and immunohistochemical markers in the dorsal horn of the spinal cord in the CFA model. KEY RESULTS: Complementary pharmacological and genetic approaches confirmed that the dose-dependent antinociceptive effects of GAT107 were mediated through alpha7 nAChR. However, GAT107 was inactive in the tail flick and hot plate assays. In addition, GAT107 blocked conditioned place aversion elicited by acetic acid injection. Furthermore, intrathecal, but not intraplantar, injections of GAT107 reversed nociception in the CFA model, suggesting a spinal component of action. Immunohistochemical evaluation revealed an increase in the expression of astrocyte-specific glial fibrillary acidic protein and phosphorylated p38MAPK within the spinal cords of mice treated with CFA, which was attenuated by intrathecal GAT107 treatment. Importantly, GAT107 did not elicit motor impairment and continued to produce antinociceptive effects after subchronic administration in both phases of the formalin test. CONCLUSIONS AND IMPLICATIONS: Collectively, these results provide the first proof of principle that alpha7 ago-PAMs represent an effective pharmacological strategy for treating inflammatory and neuropathic pain. PMID- 27243761 TI - Anxiety in late adulthood: Associations with gender, education, and physical and cognitive functioning. AB - Anxiety is common in late adulthood and can complicate adjustment in several areas. This study used data from 2 measurement points of a representative European longitudinal study (Survey of Health, Ageing, and Retirement in Europe) with a large sample size (N = 28,326) and a broad age range (45-90) to examine age effects on cross-sectional mean levels of anxiety as well as longitudinal mean-level changes over 2 years with respect to gender, education, and changes in physical and cognitive functioning. Furthermore, we analyzed generalizability of the findings for different European countries. Latent change models and locally weighted smoothing curves revealed 3 main findings: (1) Mean levels of anxiety were relatively stable over the course of middle adulthood and increased during late adulthood, (2) women and individuals with less education were more anxious than men and individuals with more education, and (3) increases in anxiety in late adulthood were associated with age-associated losses in physical and cognitive functioning. (PsycINFO Database Record PMID- 27243754 TI - Global methylation, oxidative stress, and relative telomere length in biliary atresia patients. AB - Alu and LINE-1 elements are retrotransposons with a ubiquitous presence in the human genome that can cause genomic instability, specifically relating to telomere length. Genotoxic agents may induce methylation of retrotransposons, in addition to oxidative DNA damage in the form of 8-hydroxy-2'-deoxyguanosine (8 OHdG). Methylation of retrotransposons induced by these agents may contribute to biliary atresia (BA) etiology. Here, we investigated correlations between global methylation, 8-OHdG, and relative telomere length, as well as reporting on Alu and LINE-1 hypomethylation in BA patients. Alu and LINE-1 hypomethylation were found to be associated with elevated risk of BA (OR = 4.07; 95% CI: 2.27-7.32; P < 0.0001 and OR = 3.51; 95% CI: 1.87-6.59; P < 0.0001, respectively). Furthermore, LINE-1 methylation was associated with liver stiffness in BA patients (beta coefficient = -0.17; 95% CI: -0.24 to -0.10; P < 0.0001). Stratified analysis revealed negative correlations between Alu and LINE-1 methylation and 8-OHdG in BA patients (P < 0.0001). In contrast, positive relationships were identified between Alu and LINE-1 methylation and relative telomere length in BA patients (P < 0.0001). These findings suggest that retrotransposon hypomethylation is associated with plasma 8-OHdG and telomere length in BA patients. PMID- 27243762 TI - Plasticity of inhibitory processes and associated far-transfer effects in older adults. AB - Inhibition deficit plays a crucial part in cognitive aging; however, few studies have systematically investigated the plasticity of various inhibitory processes among older adults. We studied the plasticity of 3 inhibitory processes (access, deletion, and restraint) and the extent of far transfer of inhibition training to other general cognitive abilities. Thirty-six participants (aged 60 years and above, M = 70.06, SD = 5.53) were randomly assigned to an adaptive training group that received 12 sessions of training covering 3 inhibitory processes or an active control group that received 4 sessions of mental health lectures. Participants in both groups completed pre- and posttest assessments, in which behavioral and electrophysiological measures were used to evaluate potential transfer effects. Direct training gains were observed for trained tasks of all inhibitory processes, but near-transfer effects were only found within untrained tasks associated with deletion at a composite score level. Furthermore, far transfer effects were demonstrated for fluid intelligence (Gf) but not for working memory or other general cognitive abilities. Near transfer to deletion and far transfer to Gf persisted at a 3-month follow-up assessment session. We discussed differences in plasticity between the 3 inhibitory processes as well as their possible associations with far transfer to Gf. (PsycINFO Database Record PMID- 27243763 TI - Time perspective and social preference in older and younger adults: Effects of self-regulatory fatigue. AB - Socioemotional selectivity theory predicts that when perceived time in life is limited, people will prefer emotionally close social partners over less emotionally rewarding partners. Regulating social choices with regard to time perspective can make the best use of time with regard to well-being. However, doing so may depend on the self-regulatory capacity of the individual. Two studies, 1 with younger adults (N = 101) and 1 with younger (N = 42) and older (N = 39) adults, experimentally tested the effects of time perspective and self regulatory fatigue on preferences for emotionally close partners and knowledgeable partners. In both studies and across younger and older adults, when self-regulatory fatigue was low, the perception of limited time resulted in a greater preference for close social partners relative to knowledgeable social partners. However, this shift was eliminated by self-regulatory fatigue. In Study 2, when fatigued, younger adults preferred close social partners to knowledgeable partners across time perspectives; older adults preferred close and knowledgeable partners more equally across time perspectives. These findings have implications for social decision-making and satisfaction among people who experience chronic self-regulatory fatigue. They also contradict previous suggestions that only younger adults are susceptible to self-regulatory fatigue. (PsycINFO Database Record PMID- 27243764 TI - Future time perspective and awareness of age-related change: Examining their role in predicting psychological well-being. AB - This study examined how 2 distinct facets of perceived personal lifetime-future time perspective (FTP) and awareness of age-related change (AARC)-are associated with another, and how they may interact to predict psychological well-being. To better understand associations among subjective perceptions of lifetime, aging, and well-being, we tested a series of models to investigate questions of directionality, indirect effects, and conditional processes among FTP, AARC Gains, AARC-Losses, and psychological well-being. In all models, we tested for differences between middle-aged and older adults, and between adults from the United States and Germany. Analyses were conducted within a structural equation modeling framework on a cross-national, 2.5-year longitudinal sample of 537 community-residing adults (age 40-98 years). Awareness of age-related losses (AARC-Losses) at Time 1 predicted FTP at Time 2, but FTP did not predict AARC Gains or AARC-Losses. Furthermore, future time perspective mediated the association between AARC-Losses and well-being. Moderation analyses revealed a buffering effect of awareness of age-related gains (AARC-Gains) in which perceptions of more age-related gains diminished the negative effect of a limited future time perspective on well-being. Effects were robust across age groups and countries. Taken together, these findings suggest that perceived age-related loss experiences may sensitize individuals to perceive a more limited future lifetime which may then lead to lower psychological well-being. In contrast, perceived age related gains may function as a resource to preserve psychological well-being, in particular when time is perceived as running out. (PsycINFO Database Record PMID- 27243765 TI - Semantic prosody and judgment. AB - Some words tend to co-occur exclusively with a positive or negative context in natural language use, even though such valence patterns are not dictated by definitions or are part of the words' core meaning. These words contain semantic prosody, a subtle valenced meaning derived from co-occurrence in language. As language and thought are heavily intertwined, we hypothesized that semantic prosody can affect evaluative inferences about related ambiguous concepts. Participants inferred that an ambiguous medical outcome was more negative when it was caused, a verb with negative semantic prosody, than when it was produced, a synonymous verb with no semantic prosody (Studies 1a, 1b). Participants completed sentence fragments in a manner consistent with semantic prosody (Study 2), and semantic prosody affected various other judgments in line with evaluative inferences (estimates of an event's likelihood in Study 3). Finally, semantic prosody elicited both positive and negative evaluations of outcomes across a large set of semantically prosodic verbs (Study 4). Thus, semantic prosody can exert a strong influence on evaluative judgment. (PsycINFO Database Record PMID- 27243766 TI - Core-Shell Soy Protein-Soy Polysaccharide Complex (Nano)particles as Carriers for Improved Stability and Sustained Release of Curcumin. AB - Using soy protein isolate (SPI) and soy-soluble polysaccharides (SSPS) as polymer matrixes, this study reported a novel process to fabricate unique core-shell complex (nano)particles to perform as carriers for curcumin (a typical poorly soluble bioactive). In the process, curcumin-SPI nanocomplexes were first formed at pH 7.0 and then coated by SSPS. At this pH, the core-shell complex was formed in a way the SPI nanoparticles might be incorporated into the interior of SSPS molecules without distinctly affecting the size and morphology of particles. The core-shell structure was distinctly changed by adjusting pH from 7.0 to 4.0. At pH 4.0, SSPS was strongly bound to the surface of highly aggregated SPI nanoparticles, and as a consequence, much larger complexes were formed. The bioaccessibility of curcumin in the SPI-curcumin complexes was unaffected by the SSPS coating. However, the core-shell complex formation greatly improved the thermal stability and controlled release properties of encapsulated curcumin. The improvement was much better at pH 4.0 than that at pH 7.0. All of the freeze dried core-shell complex preparations exhibited good redispersion behavior. The findings provide a simple approach to fabricate food-grade delivery systems for improved water dispersion, heat stability, and even controlled release of poorly soluble bioactives. PMID- 27243767 TI - Physiotherapy and Occupational Therapy and Mild to Moderate Parkinson Disease. PMID- 27243768 TI - Diversity Enhances NPP, N Retention, and Soil Microbial Diversity in Experimental Urban Grassland Assemblages. AB - Urban grasslands, landscapes dominated by turfgrasses for aesthetic or recreational groundcovers, are rapidly expanding in the United States and globally. These managed ecosystems are often less diverse than the natural or agricultural lands they replace, leading to potential losses in ecosystem functioning. Research in non-urban systems has provided evidence for increases in multiple ecosystem functions associated with greater plant diversity. To test if biodiversity-ecosystem function findings are applicable to urban grasslands, we examined the effect of plant species and genotypic diversity on three ecosystem functions, using grassland assemblages of increasing diversity that were grown within a controlled environment facility. We found positive effects of plant diversity on reduced nitrate leaching and plant productivity. Soil microbial diversity (Mean Shannon Diversity, H') of bacteria and fungi were also enhanced in multi-species plantings, suggesting that moderate increments in plant diversity influence the composition of soil biota. The results from this study indicate that plant diversity impacts multiple functions that are important in urban ecosystems; therefore, further tests of urban grassland biodiversity should be examined in situ to determine the feasibility of manipulating plant diversity as an explicit landscape design and function trait. PMID- 27243770 TI - Systematic Review of Traumatic Brain Injury and the Impact of Antioxidant Therapy on Clinical Outcomes. AB - BACKGROUND: Traumatic brain injury (TBI) is an acquired brain injury that occurs when there is sudden trauma that leads to brain damage. This acute complex event can happen when the head is violently or suddenly struck or an object pierces the skull or brain. The current principal treatment of TBI includes various pharmaceutical agents, hyperbaric oxygen, and hypothermia. There is evidence that secondary injury from a TBI is specifically related to oxidative stress. However, the clinical management of TBI often does not include antioxidants to reduce oxidative stress and prevent secondary injury. AIMS: The purpose of this article is to examine current literature regarding the use of antioxidant therapies in treating TBI. This review evaluates the evidence of antioxidant therapy as an adjunctive treatment used to reduce the underlying mechanisms involved in secondary TBI injury. METHODS: A systematic review of the literature published between January 2005 and September 2015 was conducted. Five databases were searched including CINAHL, PubMed, the Cochrane Library, PsycINFO, and Web of Science. FINDINGS: Critical evaluation of the six studies that met inclusion criteria suggests that antioxidant therapies such as amino acids, vitamins C and E, progesterone, N-acetylcysteine, and enzogenol may be safe and effective adjunctive therapies in adult patients with TBI. Although certain limitations were found, the overall trend of using antioxidant therapies to improve the clinical outcomes of TBI was positive. LINKING EVIDENCE TO ACTION: By incorporating antioxidant therapies into practice, clinicians can help attenuate the oxidative posttraumatic brain damage and optimize patients' recovery. PMID- 27243769 TI - Stellettin B Induces G1 Arrest, Apoptosis and Autophagy in Human Non-small Cell Lung Cancer A549 Cells via Blocking PI3K/Akt/mTOR Pathway. AB - Until now, there is not yet antitumor drug with dramatically improved efficacy on non-small cell lung cancer (NSCLC). Marine organisms are rich source of novel compounds with various activities. We isolated stellettin B (Stel B) from marine sponge Jaspis stellifera, and demonstrated that it induced G1 arrest, apoptosis and autophagy at low concentrations in human NSCLC A549 cells. G1 arrest by Stel B might be attributed to the reduction of cyclin D1 and enhancement of p27 expression. The apoptosis induction might be related to the cleavage of PARP and increase of ROS generation. Moreover, we demonstrated that Stel B induced autophagy in A549 cells by use of various assays including monodansylcadaverine (MDC) staining, transmission electron microscopy (TEM), tandem mRFP-GFP-LC3 fluorescence microscopy, and western blot detection of the autophagy markers of LC3B, p62 and Atg5. Meanwhile, Stel B inhibited the expression of PI3K-p110, and the phosphorylation of PDK1, Akt, mTOR, p70S6K as well as GSK-3beta, suggesting the correlation of blocking PI3K/Akt/mTOR pathway with the above antitumor activities. Together, our findings indicate the antitumor potential of Stel B for NSCLC by targeting PI3K/Akt/mTOR pathway. PMID- 27243771 TI - Accuracy of urinary human papillomavirus testing for the presence of cervical human papillomaviruses and higher grades of cervical intraepithelial neoplasia. AB - BACKGROUND: Although urine-based testing for human papillomavirus (HPV) is being explored as a practical approach for cervical cancer screening, whether the results differ by age, race, or indicators of excess body weight or in populations exposed to HPV vaccines has not been documented by previous studies. The purpose of this study was to determine the accuracy of urinary HPV testing for the presence of cervical HPVs and high-grade cervical intraepithelial lesions (grade 2 and 3 cervical intraepithelial neoplasia [CIN]) by the aforementioned population characteristics. METHODS: The study population consisted of 502 women diagnosed with different grades of CIN. HPV testing was performed with paired urine and cervical cell DNA with the Roche Diagnostics Linear Array test. Agreement coefficient 1 and probabilities were calculated to determine the accuracy of urinary HPV testing for the presence of cervical HPVs and CIN lesions. RESULTS: Substantial to almost perfect agreement (0.66-0.83) was observed in the detection of any HPV genotype in urine specimens versus cervical specimens, regardless of the population characteristics. Although the positive predictive value for the detection of CIN lesions was relatively low, the negative predictive value for CIN-3 was high (>=90%) among women positive for any of the urinary or cervical high-risk human papillomavirus (HR-HPV) genotypes or HPV genotypes not included in currently available HPV vaccines. CONCLUSIONS: The results demonstrate that urinary HPV testing provides highly satisfactory results for excluding the possibility of any cervical HPV infections, including HPV types not included in vaccines and CIN lesions associated with any HR-HPV, regardless of a woman's age, race, or excess body weight. Cancer 2016. (c) 2016 American Cancer Society. Cancer 2016;122:2836-2844. (c) 2016 American Cancer Society. PMID- 27243772 TI - Seasonal Dynamics of Water Use Strategy of Two Salix Shrubs in Alpine Sandy Land, Tibetan Plateau. AB - Water is a limiting factor for plant growth and vegetation dynamics in alpine sandy land of the Tibetan Plateau, especially with the increasing frequency of extreme precipitation events and drought caused by climate change. Therefore, a relatively stable water source from either deeper soil profiles or ground water is necessary for plant growth. Understanding the water use strategy of dominant species in the alpine sandy land ecosystem is important for vegetative rehabilitation and ecological restoration. The stable isotope methodology of deltaD, delta18O, and delta13C was used to determine main water source and long term water use efficiency of Salix psammophila and S. cheilophila, two dominant shrubs on interdune of alpine sandy land in northeastern Tibetan Plateau. The root systems of two Salix shrubs were investigated to determine their distribution pattern. The results showed that S. psammophila and S. cheilophila absorbed soil water at different soil depths or ground water in different seasons, depending on water availability and water use strategy. Salix psammophila used ground water during the growing season and relied on shallow soil water recharged by rain in summer. Salix cheilophila used ground water in spring and summer, but relied on shallow soil water recharged by rain in spring and deep soil water recharged by ground water in fall. The two shrubs had dimorphic root systems, which is coincident with their water use strategy. Higher biomass of fine roots in S. psammophila and longer fine roots in S. cheilophila facilitated to absorb water in deeper soil layers. The long-term water use efficiency of two Salix shrubs increased during the dry season in spring. The long-term water use efficiency was higher in S. psammophila than in S. cheilophila, as the former species is better adapted to semiarid climate of alpine sandy land. PMID- 27243773 TI - Neutralizing antibody affords comparable protection against vaginal and rectal simian/human immunodeficiency virus challenge in macaques. AB - OBJECTIVE: Passive administration of broadly neutralizing antibodies has been shown to protect against both vaginal and rectal challenge in the simian/human immunodeficiency virus (SHIV)/macaque model of HIV transmission. However, the relative efficacy of antibody against the two modes of exposure is unknown and, given differences in the composition and immunology of the two tissue compartments, this is an important gap in knowledge. To investigate the significance of the challenge route for antibody-mediated protection, we performed a comparative protection study in macaques using the highly potent human monoclonal antibody, PGT126. DESIGN: Animals were administered PGT126 at three different doses before challenged either vaginally or rectally with a single dose of SHIVSF163P3. METHODS: Viral loads, PGT126 serum concentrations, and serum neutralizing titers were monitored. RESULTS: In vaginally challenged animals, sterilizing immunity was achieved in all animals administered 10 mg/kg, in two of five animals administered 2 mg/kg and in one of five animals administered 0.4 mg/kg PGT126. Comparable protection was observed for the corresponding groups challenged rectally as sterilizing immunity was achieved in three of four animals administered 10 mg/kg, in two of four animals administered 2 mg/kg and in none of four animals administered 0.4 mg/kg PGT126. Serological analysis showed similar serum concentrations of PGT126 and serum neutralization titers in animals administered the same antibody dose. CONCLUSION: Our data suggest that broadly neutralizing antibody-mediated protection is not strongly dependent on the mucosal route of challenge, which indicates that a vaccine aimed to induce a neutralizing antibody response would have broadly similar efficacy against both primary transmission routes for HIV. PMID- 27243775 TI - Postcoital penile washing and the risk of HIV acquisition in uncircumcised men. AB - BACKGROUND: Postcoital genital washing by uncircumcised men may affect the risk of male HIV acquisition. METHOD: We assessed the association between self reported washing after sex in 2976 initially HIV-negative, uncircumcised men enrolled in a prospective cohort study in Rakai, Uganda. RESULTS: Data from the 2976 participants who reported sexual intercourse in the past 12 months contributed 4290 visits, with 7316.6 person-years of observation during the 2 year follow-up. The overall HIV-incidence was 1.28/100 person-years 95%CI (1.04 1.57). About 91.0% of men reported washing their penis after sex, and their HIV incidence was 1.34/100 person-years (95%CI 1.08-1.66), compared with an incidence of 0.62/100 person-years (95%CI 0.17-1.60) in men who did not wash their penis after intercourse. Using Poisson multivariable regression, the adjusted incidence rate ratio of HIV acquisition associated with postcoital washing was 1.94 (95%CI 0.71-5.29). CONCLUSION: Postcoital penile washing, as practiced in this rural African population does not afford protection from HIV acquisition among uncircumcised men, and may increase risk. PMID- 27243776 TI - New insights on the phenotype of HIV reservoirs. PMID- 27243774 TI - Three months of weekly rifapentine and isoniazid for treatment of Mycobacterium tuberculosis infection in HIV-coinfected persons. AB - OBJECTIVE: Compare the effectiveness, tolerability, and safety of 3 months of weekly rifapentine and isoniazid under direct observation (3HP) versus 9 months of daily isoniazid (9H) in HIV-infected persons. DESIGN: Prospective, randomized, and open-label noninferiority trial. SETTING: The United States , Brazil, Spain, Peru, Canada, and Hong Kong. PARTICIPANTS: HIV-infected persons who were tuberculin skin test positive or close contacts of tuberculosis cases. INTERVENTION: 3HP versus 9H. MAIN OUTCOME MEASURES: The effectiveness endpoint was tuberculosis; the noninferiority margin was 0.75%. The tolerability endpoint was treatment completion; the safety endpoint was drug discontinuation because of adverse drug reaction. RESULTS: Median baseline CD4 cell counts were 495 (IQR 389 675) and 538 (IQR 418-729) cells/MUl in the 3HP and 9H arms, respectively (P = 0.09). In the modified intention-to-treat analysis, there were two tuberculosis cases among 206 persons [517 person-years (p-y) of follow-up] in the 3HP arm (0.39 per 100 p-y) and six tuberculosis cases among 193 persons (481 p-y of follow-up) in the 9H arm (1.25 per 100 p-y). Cumulative tuberculosis rates were 1.01 versus 3.50% in the 3HP and 9H arms, respectively (rate difference: -2.49%; upper bound of the 95% confidence interval of the difference: 0.60%). Treatment completion was higher with 3HP (89%) than 9H (64%) (P < 0.001), and drug discontinuation because of an adverse drug reaction was similar (3 vs. 4%; P = 0.79) in 3HP and 9H, respectively. CONCLUSION: Among HIV-infected persons with median CD4 cell count of approximately 500 cells/MUl, 3HP was as effective and safe for treatment of latent Mycobacterium tuberculosis infection as 9H, and better tolerated. PMID- 27243777 TI - Response to the calculation of population attributable fractions (PAFs) of risk factors for hepatitis C transmission. PMID- 27243778 TI - Response to the calculation of population attributable fractions of risk factors for hepatitis C transmission: authors' reply. PMID- 27243779 TI - Determinants of bone diseases in tenofovir-treated HIV patients. PMID- 27243780 TI - Transmitted drug resistance in drug-naive HIV-2 infected patients. PMID- 27243781 TI - Developmental validation of forensic DNA-STR kits: Expressmarker 16+10Y and expressmarker 16+18Y. AB - DNA-STR analysis is widely used in the forensic science field and obtaining results in shorter time is highly demanded. The developed forensic STR Kit, referred to as Expressmarker 16+10Y (EX16+10Y) and Expressmarker 16+18Y (EX16+18Y), could amplify the common autosomal and Y chromosome STR loci simultaneously. The kits are validated by a series of tests, including DNA mixtures, stutter ratios, PCR based studies, species specificities, inhibitors, sensitivity, sizing precision, reproducibility and parallel tests. The results demonstrated that EX16+10Y and EX16+18Y were useful tools for rapid criminal investigation. PMID- 27243782 TI - Genetic analysis of the Yavapai Native Americans from West-Central Arizona using the Illumina MiSeq FGxTM forensic genomics system. AB - Forensically-relevant genetic markers were typed for sixty-two Yavapai Native Americans using the ForenSeqTM DNA Signature Prep Kit.These data are invaluable to the human identity community due to the greater genetic differentiation among Native American tribes than among other subdivisions within major populations of the United States. Autosomal, X-chromosomal, and Y-chromosomal short tandem repeat (STR) and identity-informative (iSNPs), ancestry-informative (aSNPs), and phenotype-informative (pSNPs) single nucleotide polymorphism (SNP) allele frequencies are reported. Sequence-based allelic variants were observed in 13 autosomal, 3 X, and 3 Y STRs. These observations increased observed and expected heterozygosities for autosomal STRs by 0.081+/-0.068 and 0.073+/-0.063, respectively, and decreased single-locus random match probabilities by 0.051+/ 0.043 for 13 autosomal STRs. The autosomal random match probabilities (RMPs) were 2.37*10-26 and 2.81*10-29 for length-based and sequence-based alleles, respectively. There were 22 and 25 unique Y-STR haplotypes among 26 males, generating haplotype diversities of 0.95 and 0.96, for length-based and sequencebased alleles, respectively. Of the 26 haplotypes generated, 17 were assigned to haplogroup Q, three to haplogroup R1b, two each to haplogroups E1b1b and L, and one each to haplogroups R1a and I1. Male and female sequence-based X STR random match probabilities were 3.28*10-7 and 1.22*10-6, respectively. The average observed and expected heterozygosities for 94 iSNPs were 0.39+/-0.12 and 0.39+/-0.13, respectively, and the combined iSNP RMP was 1.08*10-32. The combined STR and iSNP RMPs were 2.55*10-58 and 3.02*10-61 for length-based and sequence based STR alleles, respectively. Ancestry and phenotypic SNP information, performed using the ForenSeqTM Universal Analysis Software, predicted black hair, brown eyes, and some probability of East Asian ancestry for all but one sample that clustered between European and Admixed American ancestry on a principal components analysis. These data serve as the first population assessment using the ForenSeqTM panel and highlight the value of employing sequence-based alleles for forensic DNA typing to increase heterozygosity, which is beneficial for identity testing in populations with reduced genetic diversity. PMID- 27243783 TI - SPONTANEOUS CLOSURE OF A FULL-THICKNESS MACULAR HOLE SECONDARY TO IRVINE-GASS SYNDROME. AB - PURPOSE: To report a case of spontaneous closure of a full-thickness macular hole after a posterior subtenon injection of triamcinolone in a patient with Irvine Gass syndrome. METHODS: Case report and literature review. RESULTS: A 70-year-old man presented to the retina clinic with visual disturbance in his right eye after an uneventful cataract surgery. Patient was found to have macular edema associated with a full-thickness macular hole, treated with a posterior subtenon injection of triamcinolone with subsequent spontaneous closure of the hole and excellent visual acuity. CONCLUSION: This case demonstrates possible resolution of a condition which traditionally requires surgical intervention, with a nonsurgical approach. PMID- 27243784 TI - ACUTE ZONAL OCCULT OUTER RETINOPATHY AFFECTING THE PERIPHERAL RETINA WITH CENTRIPETAL PROGRESSION. AB - PURPOSE: To describe a variant of acute zonal occult outer retinopathy (AZOOR) that has concentric involvement of the peripheral retina with centripetal progression toward the posterior pole. METHODS: Three patients with AZOOR were reported to show peripheral concentric zonal involvement with centripetal progression of their disease from the periphery to the posterior fundus. RESULTS: All three cases involved elderly hyperopic women with a history of autoimmune disease. All six eyes showed bilateral central peripapillary AZOOR lesions that progressed in a centrifugal manner to the periphery. Five of the six eyes showed the presence of concentric peripheral zonal abnormalities that progressed in a centripetal manner to the posterior pole. In one case, the peripheral and central zonal abnormalities became confluent, leaving only a small island of normal retina temporal to the fovea. CONCLUSION: A variant of AZOOR may involve the peripheral retina, causing concentric zonal atrophy with centripetal progression, with central peripapillary zonal abnormalities that have centrifugal progression. This may eventually lead to widespread atrophic degeneration with severe visual field loss. Wide-field imaging of the peripheral retina and monitoring of the visual fields are important to document this rare atypical presentation of AZOOR and any subsequent disease progression. PMID- 27243785 TI - Spectroscopic Properties of Anisole at the Air-Ice Interface: A Combined Experimental-Computational Approach. AB - A combined experimental and computational approach was used to investigate the spectroscopic properties of anisole in aqueous solutions and at the ice-air interface in the temperature range of 77-298 K. The absorption, diffuse reflectance, and emission spectra of ice samples containing anisole prepared by different techniques, such as slow freezing (frozen aqueous solutions), shock freezing (ice grains), or anisole vapor deposition on ice grains, were measured to evaluate changes in the contaminated ice matrix that occur at different temperatures. It was found that the position of the lowest absorption band of anisole and its tail shift bathochromically by ~4 nm in frozen samples compared to liquid aqueous solutions. On the other hand, the emission spectra of aqueous anisole solutions were found to fundamentally change upon freezing. While one emission band (~290 nm) was observed under all circumstances, the second band at ~350 nm, assigned to an anisole excimer, appeared only at certain temperatures (150-250 K). Its disappearance at lower temperatures is attributed to the formation of crystalline anisole on the ice surface. DFT and ADC(2) calculations were used to interpret the absorption and emission spectra of anisole monomer and dimer associates. Various stable arrangements of the anisole associates were found at the disordered water-air interface in the ground and excited states, but only those with a substantial overlap of the aromatic rings are manifested by the emission band at ~350 nm. PMID- 27243786 TI - Microwave-Assisted Synthesis of SnO2@polypyrrole Nanotubes and Their Pyrolyzed Composite as Anode for Lithium-Ion Batteries. AB - Tin dioxide (SnO2) as lithium-ion batteries (LIBs) anode has attracted numerous interests due to its huge Li(+) storage capacity. However, more than 300% volume variation of SnO2 during the charge/discharge process results in dramatic degradation of electrochemical performance and thus poor cyclic stability, which has hindered its application in LIBs. Here, a new strategy is proposed to suppress this volume change via anchoring mesoporous SnO2 on robust polypyrrole nanotubes (PPy NTs) to fabricate nanoarchitectured SnO2 composite. Benefiting from this nanoarchitecture design, the anode presents outstanding rate performance with a reversible specific capacity of about 770 mA h g(-1) at 2000 mA g(-1) and remarkable cyclability accompanied by a high specific capacity of about 790 mA h g(-1) at 200 mA g(-1) after 200 cycles. PMID- 27243787 TI - Novel fluoroimmunoassays for detecting ochratoxin A using CdTe quantum dots. AB - Novel direct and indirect competitive fluorescence-linked immunosorbent assays (cFLISA and icFLISA) for detection of ochratoxin A (OTA) were described using CdTe quantum dots (QDs) as fluorescent label. CdTe QDs were successfully synthesized, which had an emission wavelength of 615 nm. The high purity monoclonal antibody against OTA was prepared through cell thawing and the octylic acid-ammonium sulfate method. The OTA MAbs were successfully coupled with CdTe QDs, and which also retained the original biological activity. The 50% inhibition values (IC50 ) of the cFLISA and icFLISA were 0.630 ng/mL, 0.234 ng/mL, the limits of detection (LOD) were 7.06 * 10-3 and 4.15 * 10-3 ng/mL, and detection ranges were 7.06 * 10-3 - 18.34 ng/mL and 4.15 * 10-3 - 4.88 ng/mL, in-order. The recoveries were 96.0-104.7% along with coefficients of variation (CVs) below 10%. The FLISA provided novel method for determination of OTA and the potential of MAb CdTe QDs for the establishment of fluorescent immunochromatographic test strip. PMID- 27243789 TI - Corrigendum. PMID- 27243790 TI - The Musical Footprint of Cushing Syndrome. PMID- 27243788 TI - Transcriptome Signatures Reveal Rapid Induction of Immune-Responsive Genes in Human Memory CD8(+) T Cells. AB - Memory T cells (TM) play a prominent role in protection and auto-immunity due to their ability to mount a more effective response than naive T cells (TN). However, the molecular mechanisms underlying enhanced functionality of TM are not well defined, particularly in human TM. We examined the global gene expression profiles of human CD8(+) TN and TM before and after stimulation. There were 1,284, 1,373 and 1,629 differentially expressed genes between TN and TM at 0 hr, 4 hr and 24 hr after stimulation, respectively, with more genes expressed to higher levels in TM. Genes rapidly up-regulated in TN cells were largely involved in nitrogen, nucleoside and amino acid metabolisms. In contrast, those in CD8(+) TM were significantly enriched for immune-response-associated processes, including cytokine production, lymphocyte activation and chemotaxis. Multiple cytokines were rapidly up-regulated in TM cells, including effector cytokines known to be produced by CD8(+) T cells and important for their functions, as well as regulatory cytokines, both pro- and anti-inflammatory, that are not typically produced by CD8(+) T cells. These results provide new insights into molecular mechanisms that contribute to the enhanced functionality of human CD8(+) TM and their prominent role in protection and auto-immunity. PMID- 27243791 TI - A Paper-Based "Pop-up" Electrochemical Device for Analysis of Beta Hydroxybutyrate. AB - This paper describes the design and fabrication of a "pop-up" electrochemical paper-based analytical device (pop-up-EPAD) to measure beta-hydroxybutyrate (BHB) a biomarker for diabetic ketoacidosis-using a commercial combination BHB/glucometer. Pop-up-EPADs are inspired by pop-up greeting cards and children's books. They are made from a single sheet of paper folded into a three-dimensional (3D) device that changes shape, and fluidic and electrical connectivity, by simply folding and unfolding the structure. The reconfigurable 3D structure makes it possible to change the fluidic path and to control timing; it also provides mechanical support for the folded and unfolded structures that enables good registration and repeatability on folding. A pop-up-EPAD designed to detect BHB shows performance comparable to commercially available plastic test strips over the clinically relevant range of BHB in blood when used with a commercial glucometer that integrates the ability to measure glucose and BHB (combination BHB/glucometer). With simple modifications of the electrode and the design of the fluidic path, the pop-up-EPAD also detects BHB in buffer using a simple glucometer-a device that is more available than the combination BHB/glucometer. Strategies that use a "3D pop-up"-that is, large-scale changes in 3D structure and fluidic paths-by folding/unfolding add functionality to EPADs (e.g., controlled timing, fluidic handling and path programming, control over complex sequences of steps, and alterations in electrical connectivity) and should enable the development of new classes of paper-based diagnostic devices. PMID- 27243792 TI - Spatiotemporal variations in the abundance and composition of bulk and chromophoric dissolved organic matter in seasonally hypoxia-influenced Green Bay, Lake Michigan, USA. AB - Green Bay, Lake Michigan, USA, is the largest freshwater estuary in the Laurentian Great Lakes and receives disproportional terrestrial inputs as a result of a high watershed to bay surface area ratio. While seasonal hypoxia and the formation of "dead zones" in Green Bay have received increasing attention, there are no systematic studies on the dynamics of dissolved organic matter (DOM) and its linkage to the development of hypoxia. During summer 2014, bulk dissolved organic carbon (DOC) analysis, UV-vis spectroscopy, and fluorescence excitation emission matrices (EEMs) coupled with PARAFAC analysis were used to quantify the abundance, composition and source of DOM and their spatiotemporal variations in Green Bay, Lake Michigan. Concentrations of DOC ranged from 202 to 571MUM-C (average=361+/-73MUM-C) in June and from 279 to 610MUM-C (average=349+/-64MUM-C) in August. In both months, absorption coefficient at 254nm (a254) was strongly correlated to bulk DOC and was most abundant in the Fox River, attesting a dominant terrestrial input. Non-chromophoric DOC comprised, on average, ~32% of bulk DOC in June with higher terrestrial DOM and ~47% in August with higher aquagenic DOM, indicating that autochthonous and more degraded DOM is of lower optical activity. PARAFAC modeling on EEM data resulted in four major fluorescent DOM components, including two terrestrial humic-like, one aquagenic humic-like, and one protein-like component. Variations in the abundance of DOM components further supported changes in DOM sources. Mixing behavior of DOM components also indicated that while bulk DOM behaved quasi-conservatively, significant compositional changes occurred during transport from the Fox River to the open bay. PMID- 27243794 TI - Anatomic Tunnel Placement in Anterior Cruciate Ligament Reconstruction. AB - The anatomic anterior cruciate ligament (ACL) reconstruction concept has developed in part from renewed interest in the insertional anatomy of the ACL, using surgical techniques that can reproduce this anatomy reliably and accurately during surgical reconstruction. Several technical tools are available to help identify and place the tibial and femoral grafts anatomically, including arthroscopic anatomic landmarks, a malleable ruler device, and intraoperative fluoroscopy. The changes in technique for anatomic tunnel placement in ACL reconstruction follow recent biomechanical and kinematic data that demonstrate improved time zero characteristics. A better re-creation of native ACL kinematics and biomechanics is achieved with independent femoral drilling techniques that re create a central footprint single-bundle ACL reconstruction or double-bundle reconstruction. However, to date, limited short-term and long-term clinical outcome data have been reported that support using either of these techniques rather than a transtibial drilling technique. This lack of clear clinical advantage for femoral independent and/or double-bundle techniques may arise because of the potentially offsetting biologic incorporation challenges of these grafts when placed using these techniques or could result from modifications made in traditional endoscopic transtibial techniques that allow improved femoral and tibial footprint restoration. PMID- 27243793 TI - Synthesis of Iminodiacetate Functionalized Polypropylene Films and Their Efficacy as Antioxidant Active-Packaging Materials. AB - The introduction of metal-chelating ligands to the food-contact surface of packaging materials may enable the removal of synthetic chelators (e.g., ethylenediamine tetra-acetic acid (EDTA)) from food products. In this study, the metal-chelating ligand iminodiacetate (IDA) was covalently grafted onto polypropylene surfaces to produce metal-chelating active-packaging films. The resulting films were able to chelate 138.1 +/- 26 and 210.0 +/- 28 nmol/cm(2) Fe(3+) and Cu(2+) ions, respectively, under acidic conditions (pH 3.0). The films demonstrated potent antioxidant efficacy in two model food systems. In an emulsified-oil system, the chelating materials extended the lag phase of both lipid hydroperoxide and hexanal formation from 5 to 25 days and were as effective as EDTA. The degradation half-life of ascorbic acid in an aqueous solution was extended from 5 to 14 days. This work demonstrates the potential application of surface-grafted chelating IDA ligands as effective antioxidant active food packaging materials. PMID- 27243795 TI - Reverse Dynamization: A Novel Approach to Bone Healing. PMID- 27243796 TI - Comic art inspired patient information - Megan Llewellyn. PMID- 27243797 TI - Comment to letter to the editor Re: ISPRM Discussion Paper: Proposing Dimensions for an International Classification System for Service Organisation in Health related Rehabilitation (ICSO-R). AB - is missing. PMID- 27243798 TI - Segmental bioimpedance analysis in professional cyclists during a three week stage race. AB - Bioelectrical impedance analysis has been widely used in the clinical and sport areas because it is a safe, non-invasive, rapid and inexpensive technique that evaluates some electrical properties of the body, such as resistance (R), reactance (X c ) and phase angle (PhA). The aim of this study is to evaluate body composition changes in professional cyclists, participating at the Giro D'Italia 2012, a three week stage race, and in particular PhA modifications as an expression of fat free mass nutritional status. Data were collected at the beginning, in the middle and at the end of the competition. Body weight, circumferences, skinfold thickness and BIA variables (total and segmental body) were measured. Body composition, measured by skinfold thickness, changed during the competition: fat free mass increased, but not significantly, in the middle and at the end of the competition, whereas fat mass significantly decreased versus the baseline in the middle and at the end of the competition. The total PhA did not significantly change in the middle of the competition but was significantly reduced at the end. The arm PhA did not change significantly at both times of the competition, whereas a significant reduction was reported for leg PhA in the middle and at the end of the competition. These results suggest the use of bioimpedance analysis, in particular PhA measurement, to monitor athletes' fat free mass characteristics during medium- and long-term competitions. PMID- 27243799 TI - Silicon Diphosphide: A Si-Based Three-Dimensional Crystalline Framework as a High Performance Li-Ion Battery Anode. AB - The development of an electrode material for rechargeable Li-ion batteries (LIBs) and the understanding of its reaction mechanism play key roles in enhancing the electrochemical characteristics of LIBs for use in various portable electronics and electric vehicles. Here, we report a three-dimensional (3D) crystalline framework-structured silicon diphosphide (SiP2) and its interesting electrochemical behaviors for superior LIBs. During Li insertion in the SiP2, a three-step electrochemical reaction mechanism, sequentially comprised of a topotactic transition (0.55-2 V), an amorphization (0.25-2 V), and a conversion (0-2 V), was thoroughly analyzed. On the basis of the three-step electrochemical reaction mechanism, excellent electrochemical properties, such as high initial capacities, high initial Coulombic efficiencies, stable cycle behaviors, and fast rate capabilities, were attained from the preparation of a nanostructured SiP2/C composite. This 3D crystalline-framework-structured SiP2 compound will be a promising alternative anode material in the realization and mass production of excellent, rechargeable LIBs. PMID- 27243800 TI - Sequence-Dependent Photocurrent Generation through Long-Distance Excess-Electron Transfer in DNA. AB - Given its well-ordered continuous pi stacking of nucleobases, DNA has been considered as a biomaterial for charge transfer in biosensors. For cathodic photocurrent generation resulting from hole transfer in DNA, sensitivity to DNA structure and base-pair stacking has been confirmed. However, such information has not been provided for anodic photocurrent generation resulting from excess electron transfer in DNA. In the present study, we measured the anodic photocurrent of a DNA-modified Au electrode. Our results demonstrate long distance excess-electron transfer in DNA, which is dominated by a hopping mechanism, and the photocurrent generation is sequence dependent. PMID- 27243801 TI - Effects of pH and Salts on Physical and Mechanical Properties of Pea Starch Films. AB - To identify the significant contribution of intermolecular hydrogen bonds of starch molecules to the film structure formation, pH of film-forming solutions was adjusted and also various salts (NaCl, CaCl2 , CaSO4 , and K2 SO4 ) were mixed into the glycerol-plasticized pea starch film. The film made from pH 7 possessed the highest tensile strength-at-break (2 times) and elastic modulus (4 to 15 times) and the lowest elongation-at-break compared with those of the films made from acid and alkali environments. The pH 7 film also has the highest film density and the lowest total soluble matter. At the level of 0.01 to 0.1 M of CaSO4 and 0.1 M of K2 SO4 in a kilogram of starch, the water solubility of the film increased, while chloride salts slightly lowered the solubility. NaCl and CaSO4 reduced water vapor permeability (WVP), while CaCl2 slightly increased WVP at 0.01 and 0.06 M concentrations, and K2 SO4 significantly increased WVP at 0.03 and 0.15 M. Presence of salts increased tensile strength (5 to 14 times than the control films) and elastic modulus (35 to 180 times) of starch film at 0.01 to 0.03 M of CaSO4 and K2 SO4 . Elongation-at-break increased significantly as salt concentration increases to an optimal level. However, when the concentration exceeded above the optimal level, the E of starch films decreased and showed no significant difference from the control film. Overall, the addition of salts modified physical and mechanical properties of pea starch films more than pH adjustment without any salt addition. PMID- 27243802 TI - Structure-activity relationship studies on acremomannolipin A, the potent calcium signal modulator with a novel glycolipid structure 4: Role of acyl side chains on d-mannose. AB - As part of an ongoing study on the structure-activity relationship of acremomannolipin A (1)-the novel glycolipid isolated from Acremonium strictum possessing potent calcium signal-modulating activity-the role of acyl substituents on the d-mannose moiety was examined. Three partially deacylated homologs (2a-2c) and 20 homologs (2d-2w) bearing different acyloxy side chains were synthesized via the stereoselective beta-mannosylation of appropriately protected mannosyl sulfoxides (3) with d-mannitol derivatives (4), and their calcium signal-modulating activities were examined. The activities of 2a-2c were completely lost. Homologs bearing relatively short acyloxy groups at C-3, C-4, and C-6 positions (2t-2v) exhibited less activity than 1, whereas a heptanoyl homolog (2w: C7) maintained activity nearly equal to that of 1. When the acyl groups at these three positions were substituted by an octanoyl group (2i: C8), the activity was completely lost. On the other hand, of the 10 homologs in which the octanoyl at C-2 was substituted by other acyloxy moieties (2j-2s), three (2m: C7, 2n: C9, 2o: C10) maintained potent activity. These results suggested that peracylated mannose structure is critical for calcium signal-modulating activity, and this activity is precisely dependent on the length of four acyl side chains on d-mannose. PMID- 27243804 TI - Ilizarov bone transport versus fibular graft for reconstruction of tibial bone defects in children. AB - The aim of this study was to compare the results of treatment of segmental tibial defects in the pediatric age group using an Ilizarov external fixator versus a nonvascularized fibular bone graft. This study included 24 patients (age range from 5.5 to 15 years) with tibial bone defects: 13 patients were treated with bone transport (BT) and 11 patients were treated with a nonvascularized fibular graft (FG). The outcome parameters were bone results (union, deformity, infection, leg-length discrepancy) and functional results: external fixation index and external fixation time. In group A (BT), one patient developed refracture at the regenerate site, whereas, in group B (FG), after removal of the external fixator, one of the FGs developed a stress fracture. The external fixator time in group A was 10.7 months (range 8-14.5) versus 7.8 months (range 4 11.5 months) in group B (FG). In group A (BT), one patient had a limb-length discrepancy (LLD), whereas, in group B (FG), three patients had LLD. The functional and bone results of the Ilizarov BT technique were excellent in 23.1 and 30.8%, good in 38.5 and 46.2, fair in 30.8 and 15.4, and poor in 7.6 and 7.6%, respectively. The poor functional result was related to the poor bone result because of prolonged external fixator time resulting in significant pain, limited ankle motion, whereas the functional and bone results of fibular grafting were excellent in 9.1 and 18.2%, good in 63.6 and 45.5%, fair in 18.2 and 27.2%, and poor in 9.1 and 9.1%, respectively. Segmental tibial defects can be effectively treated with both methods. The FG method provides satisfactory results, with early removal of the external fixator. However, it had a limitation in patients with severe infection and those with LLD. Also, it requires a long duration of limb bracing until adequate hypertrophy of the graft. The Ilizarov method has the advantages of early weight bearing, treatment of postinfection bone defect in a one-stage surgery, and the possibility to treat the associated LLD. However, it has a long external fixation time. PMID- 27243803 TI - Safety and Efficacy of Nivolumab in Patients With Metastatic Renal Cell Carcinoma Treated Beyond Progression: A Subgroup Analysis of a Randomized Clinical Trial. AB - IMPORTANCE: Response patterns with immunotherapy may differ from those of other treatments. This warrants further investigation because some patients may benefit from continued immunotherapy beyond Response Evaluation Criteria in Solid Tumors (RECIST)-defined first progression. OBJECTIVE: To evaluate the safety and potential benefit of treatment with nivolumab, a programmed cell death 1 immune checkpoint inhibitor, beyond investigator-assessed first progression in patients with metastatic renal cell carcinoma (mRCC). DESIGN, SETTING, AND PARTICIPANTS: Subgroup analysis of a blinded, randomized, multicenter, phase 2 dose-ranging trial initiated May 31, 2011, including patients with clear-cell mRCC previously treated with antiangiogenic therapy. Data cutoffs for this subgroup analysis were May 15, 2013, for progression-free survival and objective response rate and March 5, 2014, for overall survival and duration of response. In this analysis, patients treated beyond first progression received their last dose of nivolumab more than 6 weeks after RECIST-defined progression, and patients not treated beyond first progression discontinued nivolumab before or at RECIST-defined progression. INTERVENTIONS: Nivolumab 0.3, 2, or 10 mg/kg intravenously every 3 weeks. MAIN OUTCOMES AND MEASURES: Safety and efficacy of nivolumab treatment. RESULTS: Of 168 patients (median [range] age, 61 [37-81] years; 72% male) randomized to nivolumab, 154 experienced progression (36 were treated beyond first progression, 26 were treated beyond first progression for <=6 weeks, and 92 were not treated beyond first progression), 13 were treated and did not experience progression, and 1 was not treated. Prior to first progression, the RECIST-defined objective response rate was 14% (5 patients) and 16% (15 patients), and median progression-free survival was 4.2 (95% CI, 2.8-5.5) and 2.6 (95% CI, 1.5-3.9) months in patients treated and not treated beyond progression, respectively. Following initial progression, 25 (69%) patients treated beyond progression experienced subsequent tumor reduction or stabilization in target lesion size. The incidence of treatment-related adverse events was higher in patients treated beyond progression (n = 29 [81%]) vs those not treated beyond progression (n = 61 [66%]); however, after adjusting for length of treatment exposure, incidence was lower in patients treated beyond progression (322.9 vs 518.7 incidence rate/100 patient-years for patients treated vs not treated beyond progression). CONCLUSIONS AND RELEVANCE: In this subgroup analysis, a proportion of patients who continued treatment beyond RECIST-defined first progression demonstrated sustained reductions in tumor burden or stabilization in the size of target lesions, with an acceptable safety profile. Further analysis will help define the clinical benefit for patients with mRCC treated with nivolumab beyond progression. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01354431. PMID- 27243805 TI - An unusual case of chondrolysis of the hip: a possible etiology for a rare condition - a case report. AB - Idiopathic chondrolysis of the hip (ICH) is a rare condition of unknown etiology, and is characterized by rapid, progressive destruction of the articular cartilage in the coxofemoral joint. This condition has an insidious onset, and is observed more commonly in female preadolescents. Patients report intense pain, motion restriction, and often present with an antalgic gait. Medical imaging techniques are required to make a differential diagnosis and biological markers for inflammation and infection should be evaluated. Avascular necrosis, septic arthritis, and juvenile idiopathic arthritis are the primary alternatives that should be precluded before making a diagnosis. Conservative treatment focuses on pain control and preservation of joint mobility. However, surgical treatment may be an option for these patients. We present a rare case of a 10-year-old boy where imaging tests and physical examination were consistent with conventional idiopathic hip chondrolysis. Following hip joint biopsy and culture, we observed the presence of bacteria originating from the mouth, which could have been responsible for the pathogenesis of ICH. This is the first report of ICH in which common bacteria of the mouth were found upon joint biopsy. In addition, with respect to the pathogenesis of hip chondrolysis, this case emphasizes that numerous factors are involved, many of which remain unknown. LEVEL OF EVIDENCE: V. PMID- 27243806 TI - Molecular Dynamics Simulations of Intrinsically Disordered Proteins: On the Accuracy of the TIP4P-D Water Model and the Representativeness of Protein Disorder Models. AB - Here, we first present a follow-up to a previous work by our group on the problematic of molecular dynamics simulations of intrinsically disordered proteins (IDPs) [ Henriques et al. J. Chem. Theory Comput. 2015 , 11 , 3420 - 3431 ], using the recently developed TIP4P-D water model. When used in conjunction with the standard AMBER ff99SB-ILDN force field and applied to the simulation of Histatin 5, our IDP model, we obtain results which are in excellent agreement with the best performing IDP-suitable force field from the earlier study and with experiment. We then assess the representativeness of the IDP models used in these and similar studies, finding that most are too short in comparison to the average IDP and contain a bias toward hydrophilic amino acid residues. Moreover, several key order- and disorder-promoting residues are also found to be misrepresented. It seems appropriate for future studies to address these issues. PMID- 27243807 TI - The organization of defensive behavior elicited by optogenetic excitation of rat lateral or ventrolateral periaqueductal gray. AB - Rodents display characteristic defense responses to predators that are influenced by predatory imminence. The midbrain periaqueductal gray (PAG) serves an important role controlling these responses. The most influential model states that variations in defensive topography are due to distinct PAG regions: ventrolateral PAG (VLPAG) controls postencounter defense, such as freezing and immobility, whereas lateral PAG (LPAG) controls circa-strike defense, such as escape and flight. Here we used channel rhodopsin (ChR2) stimulation to probe the structure of defensive behavior controlled by LPAG and VLPAG. Suprathreshold LPAG stimulation evoked circa-strike defense that was replaced by freezing at stimulation offset. Suprathreshold VLPAG stimulation evoked postencounter- freezing and immobility--but never circa-strike defense. More interestingly, the topography of defensive behavior evoked from LPAG scaled with variations in 465 nm light power. As light power increased, LPAG animals expressed the full defensive syntax of freezing then activity then flight characteristic of increasing predatory imminence. In contrast, the frequency, not topography, of defensive behavior evoked from VLPAG scaled with variations in light power. These findings suggest that LPAG and VLPAG can control variations in defense with increasing predatory imminence in 2 ways. First, consistent with past models, topographical variation can be assembled from different defensive responses controlled by the LPAG (circa-strike) and VLPAG (postencounter). Second, topographical variation can be assembled from variations in LPAG activity itself. (PsycINFO Database Record PMID- 27243808 TI - Aggressive and chronic periodontitis in a population of Moroccan school students. AB - AIM: This study assessed the prevalence, clinical characteristics, and demographics of chronic and aggressive periodontitis in a representative sample drawn from a subpopulation in Morocco. MATERIALS & METHODS: Eight hundred and thirty students representative of 12+ years old attending schools in the Province of Benslimane, Morocco were selected by a multi-phased, probability sampling. Their age was 12-25 years (mean: 16.1 years) and comprised of 50% males and 50% females. Chronic and aggressive periodontitis were determined clinically. RESULTS: A total of 31% and 10.1% of the subjects had >=4 mm and >=6 mm attachment loss, respectively; 4.9% had aggressive periodontitis, and 6.4% had chronic periodontitis. Subjects with chronic periodontitis typically had 4-5 mm attachment loss affecting a few molars or premolars. Subjects with aggressive periodontitis had >=5 mm attachment loss affecting multiple teeth, and 68% and 73% of these subjects had >=6 mm attachment loss affecting maxillary and mandibular molars respectively. Attachment loss and periodontitis were significantly more prevalent in the 19-25 years group, than the 12-18 years age group. There were no significant differences in disease prevalence by gender or ethnic groups (Arab versus Berber). CONCLUSION: This young Moroccan population is at high risk of destructive periodontal disease, and further studies are indicated to investigate the biological and environmental factors that may contribute to the increased risk of disease in this population. PMID- 27243809 TI - A Novel Phenanthridionone Based Scaffold As a Potential Inhibitor of the BRD2 Bromodomain: Crystal Structure of the Complex. AB - Bromodomain containing proteins recognize the level of histone acetylation and regulate epigenetically controlled processes like gene transcription and chromatin modification. The BET (bromodomain and extra-terminal) family proteins, which are transcriptional co-regulators, have been implicated in the pathogenesis of cancer, neurodegenerative disorders, and defects in embryonic stem cell differentiation. Inhibitors selectively targeting the BET bromodomains can pave the path for new drug discovery against several forms of major diseases. By a rational structure-based approach, we have identified a new inhibitor (NSC127133) of the second bromodomain (BD2) of the BET family protein BRD2 using the NCI Diversity Set III library. A high-resolution crystal structure of the BRD2-BD2 in complex with this compound and in apo- form is refined to 0.91 and 0.94 A, respectively. The compound, which is a phenanthridinone derivative, binds well to the acetyl-lysine binding pocket of BD2 and displays significant hydrophobic and hydrophilic interactions. Moreover, the atomic resolution data obtained in this study allowed us to visualize certain structural features of BD2 which remained unobserved so far. We propose that the discovered compound may be a potential molecule to develop a new library for inhibiting the BRD2-BD2 function. PMID- 27243810 TI - The Course of Pain Intensity in Patients Undergoing Herniated Disc Surgery: A 5 Year Longitudinal Observational Study. AB - OBJECTIVES: The aims of this study are to answer the following questions (1) How does the pain intensity of lumbar and cervical disc surgery patients change within a postoperative time frame of 5 years? (2) Which sociodemographic, medical, work-related, and psychological factors are associated with postoperative pain in lumbar and cervical disc surgery patients? METHODS: The baseline survey (T0; n = 534) was conducted 3.6 days (SD 2.48) post-surgery in the form of face-to-face interviews. The follow-up interviews were conducted 3 months (T1; n = 486 patients), 9 months (T2; n = 457), 15 months (T3; n = 438), and 5 years (T4; n = 404) post-surgery. Pain intensity was measured on a numeric rating-scale (NRS 0-100). Estimated changes to and influences on postoperative pain by random effects were accounted by regression models. RESULTS: Average pain decreased continuously over time in patients with lumbar herniated disc (Wald Chi2 = 25.97, p<0.001). In patients with cervical herniated disc a reduction of pain was observed, albeit not significant (Chi2 = 7.02, p = 0.135). Two predictors were associated with postoperative pain in lumbar and cervical disc surgery patients: the subjective prognosis of gainful employment (p<0.001) and depression (p<0.001). CONCLUSION: In the majority of disc surgery patients, a long-term reduction of pain was observed. Cervical surgery patients seemed to benefit less from surgery than the lumbar surgery patients. A negative subjective prognosis of gainful employment and stronger depressive symptoms were associated with postoperative pain. The findings may promote multimodal rehabilitation concepts including psychological and work-related support. PMID- 27243812 TI - Correction: Improved Methodical Approach for Quantitative BRET Analysis of G Protein Coupled Receptor Dimerization. AB - [This corrects the article DOI: 10.1371/journal.pone.0109503.]. PMID- 27243811 TI - Clinical and Parasitological Features of Patients with American Cutaneous Leishmaniasis that Did Not Respond to Treatment with Meglumine Antimoniate. AB - BACKGROUND: American cutaneous leishmaniasis (ACL) is a complicated disease producing about 67.000 new cases per year. The severity of the disease depends on the parasite species; however in the vast majority of cases species confirmation is not feasible. WHO suggestion for ACL produced by Leishmania braziliensis, as first line treatment, are pentavalent antimonial derivatives (Glucantime or Sodium Stibogluconate) under systemic administration. According to different authors, pentavalent antimonial derivatives as treatment for ACL show a healing rate of about 75% and reasons for treatment failure are not well known. METHODS: In order to characterise the clinical and parasitological features of patients with ACL that did not respond to Glucantime, a cross-sectional observational study was carried out in a cohort of 43 patients recruited in three of the Colombian Army National reference centers for complicated ACL. Clinical and paraclinical examination, and epidemiological and geographic information were recorded for each patient. Parasitological, histopathological and PCR infection confirmation were performed. Glucantime IC50 and in vitro infectivity for the isolated parasites were estimated. RESULTS: Predominant infecting Leishmania species corresponds to L. braziliensis (95.4%) and 35% of the parasites isolated showed a significant decrease in in vitro Glucanatime susceptibility associated with previous administration of the medicament. Lesion size and in vitro infectivity of the parasite are negatively correlated with decline in Glucantime susceptibility (Spearman: r = (-)0,548 and r = (-)0,726; respectively). CONCLUSION: A negative correlation between lesion size and parasite resistance is documented. L. braziliensis was found as the main parasite species associated to lesion of patients that underwent treatment failure or relapse. The indication of a second round of treatment in therapeutic failure of ACL, produced by L. braziliensis, with pentavalent antimonial derivatives is discussable. PMID- 27243813 TI - IL-17 Expression in the Time Course of Acute Anti-Thy1 Glomerulonephritis. AB - BACKGROUND: Interleukin-17 (IL-17) is a new pro-inflammatory cytokine involved in immune response and inflammatory disease. The main source of IL-17 is a subset of CD4+ T-helper cells, but is also secreted by non-immune cells. The present study analyzes expression of IL-17 in the time course of acute anti-thy1 glomerulonephritis and the role of IL-17 as a potential link between inflammation and fibrosis. METHODS: Anti-thy1 glomerulonephritis was induced into male Wistar rats by OX-7 antibody injection. After that, samples were taken on days 1, 5, 10 (matrix expansion phase), 15 and 20 (resolution phase). PBS-injected animals served as controls. Proteinuria and histological matrixes score served as the main markers for disease severity. In in vitro experiments, NRK-52E cells were used. For cytokine expressions, mRNA and protein levels were analyzed by utilizing RT-PCR, in situ hybridization and immunofluorescence. RESULTS: Highest IL-17 mRNA-expression (6.50-fold vs. con; p<0.05) was found on day 5 after induction of anti-thy1 glomerulonephritis along the maximum levels of proteinuria (113 +/- 13 mg/d; p<0.001), histological glomerular-matrix accumulation (82%; p<0.001) and TGF-beta1 (2.2-fold; p<0.05), IL-6 mRNA expression (36-fold; p<0.05). IL-17 protein expression co-localized with the endothelial cell marker PECAM in immunofluorescence. In NRK-52E cells, co-administration of TGF-beta1 and IL-6 synergistically up-regulated IL-17 mRNA 4986-fold (p<0.001). CONCLUSIONS: The pro-inflammatory cytokine IL-17 is up-regulated in endothelial cells during the time course of acute anti-thy1 glomerulonephritis. In vitro, NRK-52E cells secrete IL-17 under pro-fibrotic and pro-inflammatory conditions. PMID- 27243815 TI - Influence of the sFlt-1/PlGF Ratio on Clinical Decision-Making in Women with Suspected Preeclampsia. AB - OBJECTIVE: To evaluate the influence of the soluble fms-like tyrosine kinase 1/placental growth factor ratio in physicians' decision making in pregnant women with signs and symptoms of preeclampsia in routine clinical practice. METHODS: A multicenter, prospective, open, non-interventional study enrolled pregnant women presenting with preeclampsia signs and symptoms in several European perinatal care centers. Before the soluble fms-like tyrosine kinase 1/placental growth factor ratio result was known, physicians documented intended clinical procedures using an iPad(r) application (data locked/time stamped). After the result was available, clinical decisions were confirmed or revised and documented. An independent adjudication committee evaluated the appropriateness of decisions based on maternal/fetal outcomes. Clinician decision making with regard to hospitalization was the primary outcome. RESULTS: In 16.9% of mothers (20/118) the hospitalization decision was changed after knowledge of the ratio. In 13 women (11.0%), the initial decision to hospitalize was changed to no hospitalization. In seven women (5.9%) the revised decision was hospitalization. All revised decisions were considered appropriate by the panel of adjudicators (McNemar test; p < 0.0001). CONCLUSIONS: The use of the soluble fms-like tyrosine kinase 1/placental growth factor test influenced clinical decision making towards appropriate hospitalization in a considerable proportion of women with suspected preeclampsia. This is the first study to demonstrate the impact of angiogenic biomarkers on decision making in a routine clinical practice. PMID- 27243814 TI - Generation of Functional Beta-Like Cells from Human Exocrine Pancreas. AB - Transcription factor mediated lineage reprogramming of human pancreatic exocrine tissue could conceivably provide an unlimited supply of islets for transplantation in the treatment of diabetes. Exocrine tissue can be efficiently reprogrammed to islet-like cells using a cocktail of transcription factors: Pdx1, Ngn3, MafA and Pax4 in combination with growth factors. We show here that overexpression of exogenous Pax4 in combination with suppression of the endogenous transcription factor ARX considerably enhances the production of functional insulin-secreting beta-like cells with concomitant suppression of alpha-cells. The efficiency was further increased by culture on laminin-coated plates in media containing low glucose concentrations. Immunocytochemistry revealed that reprogrammed cultures were composed of ~45% islet-like clusters comprising >80% monohormonal insulin+ cells. The resultant beta-like cells expressed insulin protein levels at ~15-30% of that in adult human islets, efficiently processed proinsulin and packaged insulin into secretory granules, exhibited glucose responsive insulin secretion, and had an immediate and prolonged effect in normalising blood glucose levels upon transplantation into diabetic mice. We estimate that approximately 3 billion of these cells would have an immediate therapeutic effect following engraftment in type 1 diabetes patients and that one pancreas would provide sufficient tissue for numerous transplants. PMID- 27243817 TI - Accuracy, Precision, Ease-Of-Use, and Cost of Methods to Test Ebola-Relevant Chlorine Solutions. AB - To prevent transmission in Ebola Virus Disease (EVD) outbreaks, it is recommended to disinfect living things (hands and people) with 0.05% chlorine solution and non-living things (surfaces, personal protective equipment, dead bodies) with 0.5% chlorine solution. In the current West African EVD outbreak, these solutions (manufactured from calcium hypochlorite (HTH), sodium dichloroisocyanurate (NaDCC), and sodium hypochlorite (NaOCl)) have been widely used in both Ebola Treatment Unit and community settings. To ensure solution quality, testing is necessary, however test method appropriateness for these Ebola-relevant concentrations has not previously been evaluated. We identified fourteen commercially-available methods to test Ebola-relevant chlorine solution concentrations, including two titration methods, four DPD dilution methods, and six test strips. We assessed these methods by: 1) determining accuracy and precision by measuring in quintuplicate five different 0.05% and 0.5% chlorine solutions manufactured from NaDCC, HTH, and NaOCl; 2) conducting volunteer testing to assess ease-of-use; and, 3) determining costs. Accuracy was greatest in titration methods (reference-12.4% error compared to reference method), then DPD dilution methods (2.4-19% error), then test strips (5.2-48% error); precision followed this same trend. Two methods had an accuracy of <10% error across all five chlorine solutions with good precision: Hach digital titration for 0.05% and 0.5% solutions (recommended for contexts with trained personnel and financial resources), and Serim test strips for 0.05% solutions (recommended for contexts where rapid, inexpensive, and low-training burden testing is needed). Measurement error from test methods not including pH adjustment varied significantly across the five chlorine solutions, which had pH values 5-11. Volunteers found test strip easiest and titration hardest; costs per 100 tests were $14-37 for test strips and $33-609 for titration. Given the ease-of-use and cost benefits of test strips, we recommend further development of test strips robust to pH variation and appropriate for Ebola-relevant chlorine solution concentrations. PMID- 27243816 TI - Characterization of Channelrhodopsin and Archaerhodopsin in Cholinergic Neurons of Cre-Lox Transgenic Mice. AB - The study of cholinergic signaling in the mammalian CNS has been greatly facilitated by the advent of mouse lines that permit the expression of reporter proteins, such as opsins, in cholinergic neurons. However, the expression of opsins could potentially perturb the physiology of opsin-expressing cholinergic neurons or mouse behavior. Indeed, the published literature includes examples of cellular and behavioral perturbations in preparations designed to drive expression of opsins in cholinergic neurons. Here we investigate expression of opsins, cellular physiology of cholinergic neurons and behavior in two mouse lines, in which channelrhodopsin-2 (ChR2) and archaerhodopsin (Arch) are expressed in cholinergic neurons using the Cre-lox system. The two mouse lines were generated by crossing ChAT-Cre mice with Cre-dependent reporter lines Ai32(ChR2-YFP) and Ai35(Arch-GFP). In most mice from these crosses, we observed expression of ChR2 and Arch in only cholinergic neurons in the basal forebrain and in other putative cholinergic neurons in the forebrain. In small numbers of mice, off-target expression occurred, in which fluorescence did not appear limited to cholinergic neurons. Whole-cell recordings from fluorescently-labeled basal forebrain neurons revealed that both proteins were functional, driving depolarization (ChR2) or hyperpolarization (Arch) upon illumination, with little effect on passive membrane properties, spiking pattern or spike waveform. Finally, performance on a behavioral discrimination task was comparable to that of wild-type mice. Our results indicate that ChAT-Cre x reporter line crosses provide a simple, effective resource for driving indicator and opsin expression in cholinergic neurons with few adverse consequences and are therefore an valuable resource for studying the cholinergic system. PMID- 27243818 TI - High-Pressure Polymorph of NaBiO3. AB - A new high-pressure polymorph of NaBiO3 (hereafter beta-NaBiO3) was synthesized under the conditions of 6 GPa and 600 degrees C. The powder X-ray diffraction pattern of this new phase was indexed with a hexagonal cell of a = 9.968(1) A and c = 3.2933(4) A. Crystal structure refinement using synchrotron powder X-ray diffraction data led to RWP = 8.53% and RP = 5.55%, and the crystal structure was closely related with that of Ba2SrY6O12. No photocatalytic activity for phenol decomposition was observed under visible-light irradiation in spite of a good performance for its mother compound, NaBiO3. The optical band-gap energy of beta NaBiO3 was narrower than that of NaBiO3, which was confirmed with density of states curves simulated by first-principles density functional theory calculation. PMID- 27243819 TI - How can clinical ethics guide the management of comorbidities in the child with Rett syndrome? AB - Rett syndrome is a rare disorder caused by a mutation in the MECP2 gene. Those affected generally have severe functional impairments, and medical comorbidities such as scoliosis and poor growth are common. There is a paucity of information on the natural history of many rare disorders and an even greater deficit of evidence to guide best practice. The population-based and longitudinal Australian Rett Syndrome Database established in 1993 has supported investigations of the natural history of Rett syndrome and effectiveness of treatments. This paper reviews the disorder Rett syndrome and evidence for the management of scoliosis and poor growth within a clinical ethics framework. Compared with conservative management, we have shown that spinal fusion is associated with reduced mortality and better respiratory health. We have also shown that gastrostomy insertion is associated with subsequent weight gain. Family counselling for both procedures necessarily must include family perspectives and careful clinical attention to their needs and wishes. Vignettes describing family decision-making and experiences are presented to illustrate the principals of beneficence and autonomy in determining the best interests of the child and family. A blend of evidence-based practice with a strong clinical ethics framework has capacity to build existing strengths in families and reduce the negative impacts of disability and in so doing, optimise the health and wellbeing of those with Rett syndrome. PMID- 27243820 TI - Prenatal Antidepressant Use and Risk of Autism Spectrum Disorders in Children. PMID- 27243821 TI - Correction: PCR-Free Enrichment of Mitochondrial DNA from Human Blood and Cell Lines for High Quality Next-Generation DNA Sequencing. AB - [This corrects the article DOI: 10.1371/journal.pone.0139253.]. PMID- 27243822 TI - Optimization of Proton CT Detector System and Image Reconstruction Algorithm for On-Line Proton Therapy. AB - The purposes of this study were to optimize a proton computed tomography system (pCT) for proton range verification and to confirm the pCT image reconstruction algorithm based on projection images generated with optimized parameters. For this purpose, we developed a new pCT scanner using the Geometry and Tracking (GEANT) 4.9.6 simulation toolkit. GEANT4 simulations were performed to optimize the geometric parameters representing the detector thickness and the distance between the detectors for pCT. The system consisted of four silicon strip detectors for particle tracking and a calorimeter to measure the residual energies of the individual protons. The optimized pCT system design was then adjusted to ensure that the solution to a CS-based convex optimization problem would converge to yield the desired pCT images after a reasonable number of iterative corrections. In particular, we used a total variation-based formulation that has been useful in exploiting prior knowledge about the minimal variations of proton attenuation characteristics in the human body. Examinations performed using our CS algorithm showed that high-quality pCT images could be reconstructed using sets of 72 projections within 20 iterations and without any streaks or noise, which can be caused by under-sampling and proton starvation. Moreover, the images yielded by this CS algorithm were found to be of higher quality than those obtained using other reconstruction algorithms. The optimized pCT scanner system demonstrated the potential to perform high-quality pCT during on-line image guided proton therapy, without increasing the imaging dose, by applying our CS based proton CT reconstruction algorithm. Further, we make our optimized detector system and CS-based proton CT reconstruction algorithm potentially useful in on line proton therapy. PMID- 27243823 TI - Effect of Chronic Athletic Activity on Brown Fat in Young Women. AB - BACKGROUND: The effect of chronic exercise activity on brown adipose tissue (BAT) is not clear, with some studies showing positive and others showing negative associations. Chronic exercise is associated with increased resting energy expenditure (REE) secondary to increased lean mass and a probable increase in BAT. Many athletes are in a state of relative energy deficit suggested by lower fat mass and hypothalamic amenorrhea. States of severe energy deficit such as anorexia nervosa are associated with reduced BAT. There are no data regarding the impact of chronic exercise activity on BAT volume or activity in young women and it is unclear whether relative energy deficiency modifies the effects of exercise on BAT. PURPOSE: We assessed cold induced BAT volume and activity in young female athletes compared with non-athletes, and further evaluated associations of BAT with measures of REE, body composition and menstrual status. METHODS: The protocol was approved by our Institutional Review Board. Written informed consent was obtained from all participants prior to study initiation. This was a cross sectional study of 24 women (16 athletes and8 non-athletes) between 18-25 years of age. Athletes were either oligo-amenorrheic (n = 8) or eumenorrheic (n = 8).We used PET/CT scans to determine cold induced BAT activity, VMAX Encore 29 metabolic cart to obtain measures of REE, and DXA for body composition. RESULTS: Athletes and non-athletes did not differ for age or BMI. Compared with non athletes, athletes had lower percent body fat (p = 0.002), higher percent lean mass (p = 0.01) and trended higher in REE (p = 0.09). BAT volume and activity in athletes trended lower than in non-athletes (p = 0.06; p = 0.07, respectively). We found negative associations of BAT activity with duration of amenorrhea (r = 0.46, p = 0.02).BAT volume correlated inversely with lean mass (r = -0.46, p = 0.02), and positively with percent body fat, irisin and thyroid hormones. CONCLUSIONS: Our study shows a trend for lower BAT in young female athletes compared with non-athletes, and shows associations of brown fat with menstrual status and body composition. Brown fat may undergo adaptive reductions with increasing energy deficit. PMID- 27243825 TI - Genetic and protein biomarkers in blood for the improved detection of GH abuse. AB - Human Growth Hormone (hGH, somatotropin) is one of the relevant forbidden substances to be detected in sport drug testing. Since the appearance of recombinant hGH (rhGH) in the 80's, its expansion and availability through the black market have increased, so the detection of its abuse continues to be a challenge at present. New techniques or biomarkers that are robust, reliable, sensitive and allowing a large detection time window are welcome. rhGH produces an increase of insulin-like growth factor 1 (IGF-1). FN1 (fibronectin 1) and RAB31 (member of RAS oncogene family) genes have been suggested as two potential biomarkers for IGF-1 abuse. Following this line, in the present study some genetic and proteomic approaches have been performed with fourteen healthy male subjects treated with rhGH (which produces increase of IGF-1 concentrations) to study FN1 gene, FN1 protein, RAB31 gene and RAB31 protein as potential biomarkers for rhGH abuse. The results showed that both, RAB31 and FN1 genes and FN1 protein could be potential biomarkers for rhGH administration. Preliminary assessments of gender, age, acute sport activities and GHRP-2 (pralmorelin, a rhGH releasing peptide) influence suggest they are not relevant confounding factors. Thus, the selected markers present high sensitivity and a larger detection window for rhGH detection than IGF-1 itself. PMID- 27243824 TI - Computational Identification of Novel Stage-Specific Biomarkers in Colorectal Cancer Progression. AB - It is well-known that the conversion of normal colon epithelium to adenoma and then to carcinoma stems from acquired molecular changes in the genome. The genetic basis of colorectal cancer has been elucidated to a certain extent, and much remains to be known about the identity of specific cancer genes that are associated with the advancement of colorectal cancer from one stage to the next. Here in this study we attempted to identify novel cancer genes that could underlie the stage-specific progression and metastasis of colorectal cancer. We conducted a stage-based meta-analysis of the voluminous tumor genome-sequencing data and mined using multiple approaches for novel genes driving the progression to stage-II, stage-III and stage-IV colorectal cancer. The consensus of these driver genes seeded the construction of stage-specific networks, which were then analyzed for the centrality of genes, clustering of subnetworks, and enrichment of gene-ontology processes. Our study identified three novel driver genes as hubs for stage-II progression: DYNC1H1, GRIN2A, GRM1. Four novel driver genes were identified as hubs for stage-III progression: IGF1R, CPS1, SPTA1, DSP. Three novel driver genes were identified as hubs for stage-IV progression: GSK3B, GGT1, EIF2B5. We also identified several non-driver genes that appeared to underscore the progression of colorectal cancer. Our study yielded potential diagnostic biomarkers for colorectal cancer as well as novel stage-specific drug targets for rational intervention. Our methodology is extendable to the analysis of other types of cancer to fill the gaps in our knowledge. PMID- 27243826 TI - Rapid analysis of the skin irritant p-phenylenediamine (PPD) in henna products using atmospheric solids analysis probe mass spectrometry. AB - Henna (Lawsonia inermis) is applied to stain keratin, present in hair, skin and fingernails, a red-orange or rust colour. Producers of temporary tattoos mix the aromatic amine compound, para-phenylenediamine (PPD) into natural henna to create 'black henna' that rapidly stains the skin black. However, PPD may cause severe delayed hypersensitivity reactions following skin contact. This study proposes a rapid direct-analysis method to detect and identify PPD using an atmospheric solids analysis probe (ASAP) coupled to a Q-ToF mass spectrometer (MS). Since laborious, multistep methods of analysis to determine PPD are undesirable, due to the instability of the compound in solution, a screening method involving no sample preparation steps was developed. Experiments were carried out to optimise the corona current, sample cone voltage, source temperature, and desolvation gas temperature to determine ideal ASAP-Q-ToF-MS analysing conditions. Eleven of the 109 henna samples, originating from various countries, tested positive for PPD when henna products were screened using ASAP-MS, without any form of sample preparation other than grinding. Ultra-performance liquid chromatography electrospray ionisation-mass spectrometry (UPLC-Q-ToF-MS) was subsequently used to confirm the results from ASAP and to determine the concentrations of PPD in henna products. The allergen was detected in the same eleven samples, with concentrations ranging from 0.05-4.21% (w/w). It can be concluded that the sensitivity of the ASAP-MS technique is sufficient (limit of detection=0.025% w/w) to allow screening of henna samples for the presence of PPD. This relatively new technique can be applied to commercial products without extraction, sample treatment or chromatographic separation. PMID- 27243828 TI - Rehabilitation of balance disturbances due to chemotherapy-induced peripheral neuropathy: a pilot study. AB - BACKGROUND: Cancer patients with chemotherapy-induced peripheral neuropathy (CIPN) have sensory and motor deficits leading to inappropriate proprioceptive feedback, impaired postural control, and fall risk. Balance training with computerized force platforms has been successfully used in rehabilitation of balance disturbances, but programs specifically developed for CIPN patients are lacking. AIM: This pilot study evaluated a rehabilitation protocol exclusively based on visual computer-feedback balance training (VCFBT) to improve balance in patients with CIPN. DESIGN: Open-label, non-randomized pilot study, 4-week intervention with pre- vs. post-treatment evaluation. SETTING: Outpatients of the Rehabilitation Institute of the Salvatore Maugeri Foundation, in Genoa, Italy. POPULATION: Seven out-patients with clinical-instrumental diagnosis of CIPN. METHODS: At admission, patients were administered the Berg Balance Scale (BBS) and underwent static-dynamic posturography using a computerized force platform to objectively quantify their balance impairment. Their performance was compared to values of a normal age-matched population. Patients then underwent 4 weeks of VCFBT (three 60-minute sessions/week). At discharge, BBS and posturography were repeated and the results compared with those at admission. RESULTS: A significant pre- vs. post-treatment improvement was found in balance as measured by static dynamic posturography (P=0.004) and BBS (P<0.002). CONCLUSIONS: Despite caution needed for the low sample size, this pilot study has shown preliminary evidence that intensive rehabilitation, based on VCFBT can produce a significant improvement in balance outcomes. CLINICAL REHABILITATION IMPACT: To our knowledge, this is the first report in CIPN patients of a rehabilitation program based exclusively on VCFBT. PMID- 27243827 TI - Intrahepatic mRNA Expression of FAS, FASL, and FOXP3 Genes Is Associated with the Pathophysiology of Chronic HCV Infection. AB - This study aimed to evaluate the relative mRNA expression of Fas receptor (FAS), Fas ligand (FASL), and forkhead box protein 3 (FOXP3) in liver biopsy specimens obtained from patients with viral and non-viral chronic hepatitis and correlate their expression with the fibrosis stage. A total of 51 liver biopsy specimens obtained from HBV (n = 6), HCV (n = 28), and non-viral hepatic disease (NVHD) (n = 9) patients and from individuals with normal liver histology (n = 8) (control CT) were analyzed. Quantifications of the target genes were assessed using qPCR, and liver biopsies according to the METAVIR classification. The mRNA expression levels of FAS and FASL were lower in the CT group compared to the groups of patients. The increase in the mRNA expression of FAS and FASL was correlated with higher levels of inflammation and disease progression, followed by a decline in tissues with cirrhosis, and it was also associated with increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Higher mRNA expression of FOXP3 was observed in the HCV and NVHD groups, with the peak observed among patients with cirrhosis. The increased FOXP3 mRNA expression was positively correlated with increased FAS and FASL mRNA expression and the AST and ALT levels in all patients. CONCLUSIONS: These results suggest that regardless of the cause, the course of chronic liver disease may be modulated by the analyzed genes and correlated with an increase in regulatory T cells during the liver damage followed by hepatocyte destruction by Fas/FasL system and subsequent non specific lymphocytic infiltrate accumulation. PMID- 27243829 TI - Three new 1-(p-hydroxybenzyl)phenanthrenes from Bletilla striata. AB - Three new benzylphenanthrenes, named 1-(p-hydroxybenzyl)-4,7 dimethoxyphenanthrene-2-ol (1), 1-(p-hydroxybenzyl)-4,7-dimethoxyphenanthrene-2,8 diol (2), and 1-(p-hydroxybenzyl)-4,7-dimethoxyphenanthrene-2,6-diol (3), along with a known analog were isolated from tubers of Bletilla striata. The structures of these new compounds were established by means of HR-ESI-MS, 1D, and 2D NMR. PMID- 27243896 TI - Hematopoietic Stem Cells from Ts65Dn Mice Are Deficient in the Repair of DNA Double-Strand Breaks. AB - Down syndrome (DS) is a genetic disorder caused by the presence of an extra partial or whole copy of chromosome 21. In addition to musculoskeletal and neurodevelopmental abnormalities, children with DS exhibit various hematologic disorders and have an increased risk of developing acute lymphoblastic leukemia and acute megakaryocytic leukemia. Using the Ts65Dn mouse model, we investigated bone marrow defects caused by trisomy for 132 orthologs of the genes on human chromosome 21. The results showed that, although the total bone marrow cellularity as well as the frequency of hematopoietic progenitor cells (HPCs) was comparable between Ts65Dn mice and their age-matched euploid wild-type (WT) control littermates, human chromosome 21 trisomy led to a significant reduction in hematopoietic stem cell (HSC) numbers and clonogenic function in Ts65Dn mice. We also found that spontaneous DNA double-strand breaks (DSBs) were significantly increased in HSCs from the Ts65Dn mice, which was correlated with the significant reduction in HSC clonogenic activity compared to those from WT controls. Moreover, analysis of the repair kinetics of radiation-induced DSBs revealed that HSCs from Ts65Dn mice were less proficient in DSB repair than the cells from WT controls. This deficiency was associated with a higher sensitivity of Ts65Dn HSCs to radiation-induced suppression of HSC clonogenic activity than that of euploid HSCs. These findings suggest that an additional copy of genes on human chromosome 21 may selectively impair the ability of HSCs to repair DSBs, which may contribute to DS-associated hematological abnormalities and malignancies. PMID- 27243897 TI - The Enhancement of Radiation Sensitivity in Nasopharyngeal Carcinoma Cells via Activation of the Rac1/NADPH Signaling Pathway. AB - We reported in an earlier study that using mass spectrometry and bioinformatic analysis demonstrated Rac1 protein might be mostly mitochondrial target in the radiosensitization process of nasopharyngeal carcinoma CNE-1 cells. The goal of our current study was to reveal the relationship between Rac1/NADPH pathway and radiosensitization in CNE-1 cells using Rac1 activator, phorbol 12-myristate 13 acetate (PMA) and Rac1 inhibitor NSC23766. The Rac1-GTP expression was determined using a pulldown assay, the Rac1 location using a immunofluorescence with a laser scanning confocal microscope, the NADPH oxidase activity with NBT assay and the reactive oxygen species with DCFH-DA probe. The apoptosis rate was analyzed by flow cytometry, and the expressions of p67(phox) and NFkappaB-p105/p50 were analyzed by Western blot. After treatment with PMA and 2 Gy radiation (compared to the control), Rac1-GTP was activated and translocated to the cell membrane. NADPH oxidase activity, reactive oxygen species of intracellular concentration and the apoptosis rate increased significantly. The expression of p67(phox) and NFkappaB-p50 protein also increased. However, in the cells treated with NSC23766 alone or NSC23766 combined with 2 Gy irradiation, the results were just the opposite. Overall, these results indicate that the Rac1 protein may be the key target involved in the radiosensitization of nasopharyngeal carcinoma cells. The activated Rac1/NADPH pathway combined with radiation can increase the radiosensitivity of nasopharyngeal carcinoma cells, and the Rac1/NADPH pathway may be the signaling pathway involved in the radiosensitization process. PMID- 27243898 TI - Optimal design of the Wilcoxon-Mann-Whitney-test. AB - In scientific research, many hypotheses relate to the comparison of two independent groups. Usually, it is of interest to use a design (i.e., the allocation of sample sizes m and n for fixed N=m+n) that maximizes the power of the applied statistical test. It is known that the two-sample t-tests for homogeneous and heterogeneous variances may lose substantial power when variances are unequal but equally large samples are used. We demonstrate that this is not the case for the nonparametric Wilcoxon-Mann-Whitney-test, whose application in biometrical research fields is motivated by two examples from cancer research. We prove the optimality of the design m=n in case of symmetric and identically shaped distributions using normal approximations and show that this design generally offers power only negligibly lower than the optimal design for a wide range of distributions. PMID- 27243899 TI - Comparison of Posthospitalization Function and Community Mobility in Hospital Mobility Program and Usual Care Patients: A Randomized Clinical Trial. AB - IMPORTANCE: Low mobility is common during hospitalization and associated with loss or declines in ability to perform activities of daily living (ADL) and limitations in community mobility. OBJECTIVE: To examine the effect of an in hospital mobility program (MP) on posthospitalization function and community mobility. DESIGN, SETTING, AND PARTICIPANTS: This single-blind randomized clinical trial used masked assessors to compare a MP with usual care (UC). Patients admitted to the medical wards of the Birmingham Veterans Affairs Medical Center from January 12, 2010, through June 29, 2011, were followed up throughout hospitalization with 1-month posthospitalization telephone follow-up. One hundred hospitalized patients 65 years or older were randomly assigned to the MP or UC groups. Patients were cognitively intact and able to walk 2 weeks before hospitalization. Data analysis was performed from November 21, 2012, to March 14, 2016. INTERVENTIONS: Patients in the MP group were assisted with ambulation up to twice daily, and a behavioral strategy was used to encourage mobility. Patients in the UC group received twice-daily visits. MAIN OUTCOMES AND MEASURES: Changes in self-reported ADL and community mobility were assessed using the Katz ADL scale and the University of Alabama at Birmingham Study of Aging Life-Space Assessment (LSA), respectively. The LSA measures community mobility based on the distance through which a person reports moving during the preceding 4 weeks. RESULTS: Of 100 patients, 8 did not complete the study (6 in the MP group and 2 in the UC group). Patients (mean age, 73.9 years; 97 male [97.0%]; and 19 black [19.0%]) had a median length of stay of 3 days. No significant differences were found between groups at baseline. For all periods, groups were similar in ability to perform ADL; however, at 1-month after hospitalization, the LSA score was significantly higher in the MP (LSA score, 52.5) compared with the UC group (LSA score, 41.6) (P = .02). For the MP group, the 1-month posthospitalization LSA score was similar to the LSA score measured at admission. For the UC group, the LSA score decreased by approximately 10 points. CONCLUSIONS AND RELEVANCE: A simple MP intervention had no effect on ADL function. However, the MP intervention enabled patients to maintain their prehospitalization community mobility, whereas those in the UC group experienced clinically significant declines. Lower life-space mobility is associated with increased risk of death, nursing home admission, and functional decline, suggesting that declines such as those observed in the UC group would be of great clinical importance. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00715962. PMID- 27243901 TI - Assessment of Anti-HIV-1 Antibodies in Oral and Nasal Compartments of Volunteers From 3 Different Populations. AB - In this study, we assessed the feasibility of collecting standardized nasal and salivary samples at centers in Nairobi (Kenya), Kigali (Rwanda), and London (United Kingdom) using different collection devices and media (synthetic absorptive matrices versus flocked swabs, and Salimetrics oral swabs versus whole oral fluid collection). We detected anti-Gag (p24) and envelope (gp140) antibodies in both nasal fluid and salivary collections from all HIV-infected individuals, and cross-reactive anti-p24 antibodies were detected in 10% of HIV uninfected individuals enrolled at one site. Collections from the nasal turbinates were comparable with samples collected deeper in the nasopharyngeal tract, and the yield of anti-p24 IgA in the whole oral fluid samples was higher than in samples collected from the parotid gland. We noted a trend toward reduced levels of anti-HIV antibody in the volunteers receiving anti-retroviral therapy. Levels of antibodies were stable over multiple collection visits. Overall, this study shows that nasal and salivary samples can be collected in a standardized manner over repeated visits in both low- and high-resource settings. These methods may be used in support for future HIV vaccine clinical trials. PMID- 27243902 TI - Brief Report: HIV-1 Infection Results in Increased Frequency of Active and Inflammatory SlanDCs that Produce High Level of IL-1beta. AB - HIV infection is marked by phenotypic and functional alterations of immune cells. Different studies have shown both numerical and functional deterioration of dendritic cells in HIV-1-infected patients. In this study, we report an increase of inflammatory 6-sulfo LacNAc dendritic cells (slanDCs) that are more activated and produce higher amounts of interleukin (IL)-1beta during HIV-1 infection as compared with healthy controls. IL-1beta plays a regulatory role in chronic inflammatory disorders. Therefore, our findings might reveal a compensatory regulatory function of slanDCs during HIV-1 infection. PMID- 27243900 TI - Intimate Partner Violence and Adherence to HIV Pre-exposure Prophylaxis (PrEP) in African Women in HIV Serodiscordant Relationships: A Prospective Cohort Study. AB - BACKGROUND: Intimate partner violence (IPV) is associated with higher HIV incidence, reduced condom use, and poor adherence to antiretroviral therapy and other medications. IPV may also affect adherence to pre-exposure prophylaxis (PrEP). METHODS: We analyzed data from 1785 HIV-uninfected women enrolled in a clinical trial of PrEP among African HIV serodiscordant couples. Experience of verbal, physical, or economic IPV was assessed at monthly visits by face-to-face interviews. Low PrEP adherence was defined as clinic-based pill count coverage <80% or plasma tenofovir levels <40 ng/mL. The association between IPV and low adherence was analyzed using generalized estimating equations, adjusting for potential confounders. In-depth interview transcripts were examined to explain how IPV could impact adherence. RESULTS: Sixteen percent of women reported IPV during a median of 34.8 months of follow-up (interquartile range 27.0-35.0). Overall, 7% of visits had pill count coverage <80%, and 32% had plasma tenofovir <40 ng/mL. Women reporting IPV in the past 3 months had increased risk of low adherence by pill count (adjusted risk ratio 1.49, 95% confidence interval: 1.17 to 1.89) and by plasma tenofovir (adjusted risk ratio 1.51, 95% confidence interval: 1.06 to 2.15). Verbal, economic, and physical IPV were all associated with low adherence. However, the impact of IPV diminished and was not statistically significant 3 months after the reported exposure. In qualitative interviews, women identified several ways in which IPV affected adherence, including stress and forgetting, leaving home without pills, and partners throwing pills away. CONCLUSIONS: Women who reported recent IPV in the Partners PrEP Study were at increased risk of low PrEP adherence. Strategies to mitigate PrEP nonadherence in the context of IPV should be evaluated. PMID- 27243903 TI - Who Needs to Be Targeted for HIV Testing and Treatment in KwaZulu-Natal? Results From a Population-Based Survey. AB - INTRODUCTION: Identifying gaps in HIV testing and treatment is essential to design specific strategies targeting those not accessing HIV services. We assessed the prevalence and factors associated with being HIV untested, unaware, untreated, and virally unsuppressed in KwaZulu-Natal, South Africa. METHODS: Cross-sectional population-based survey. People aged 15-59 years were eligible. Interviews, HIV testing, and blood collection for antiretroviral drug presence test, CD4, and viral load were done at the participants' home. RESULTS: Of the 5649 individuals included, 81.4% (95% CI: 79.8 to 82.9) had previously been tested. HIV prevalence was 25.2%. HIV-positivity awareness rate was 75.2% (95% CI: 72.9 to 77.4). Of all unaware, 73.3% of people were aged <35 years and 68.7% were women. Antiretroviral therapy coverage was 75.0% (95% CI: 72.0 to 77.8) among those eligible for treatment (CD4 < 350, PMTCT-B) and 53.1% (95% CI: 50.4 to 55.7) among all HIV-positive individuals. Viral load was <1000 copies per milliliter in 57.1% of all HIV-positive individuals. Although 66.3% and 71.7% of people with viral load >=1000 copies per milliliter were people aged <35 years and women respectively, men had 4.4, 1.8, 1.6, and 1.7 times the odds of being untested, unaware, untreated, and virally unsuppressed. In addition, people with more than 1 sexual partner had 1.3, 2.2, and 1.9 times the odds of being untested, unaware, and untreated. CONCLUSIONS: The majority of HIV-positive people unaware of their status, untreated, and virally unsuppressed were individuals aged <35 years and women. However, men were disproportionately untested, unaware HIV positivity, untreated, and virally unsuppressed. In this context, HIV testing and treatment should be prioritized to target young people and women, whereas novel strategies are necessary to reach men. PMID- 27243904 TI - Heavy Alcohol Use Is Associated With Worse Retention in HIV Care. AB - BACKGROUND: Poor retention in HIV care is associated with worse clinical outcomes and increased HIV transmission. We examined the relationship between self reported alcohol use, a potentially modifiable behavior, and retention. METHODS: A total of 9694 people living with HIV from 7 participating US HIV clinical sites (the Centers for AIDS Research Network of Integrated Clinical Systems) contributed 23,225 observations from January 2011 to June 2014. The retention outcomes were (1) Institute of Medicine (IOM) retention: 2 visits within 1 year at least 90 days apart and (2) visit adherence [proportion of kept visits/(scheduled + kept visits)]. Alcohol use was measured with Alcohol Use Disorders Identification Test-C, generating drinking (never, moderate, and heavy) and binge frequency (never, monthly/less than monthly, weekly/daily) categories. Adjusted multivariable logistic models, accounting for repeat measures, were generated. RESULTS: Of our sample, 82% was men, 46% white, 35% black, and 14% Hispanic. At first assessment, 37% of participants reported never drinking, 38% moderate, and 25% heavy, and 89% of the patients were retained (IOM retention measure). Participants' mean (SD) visit adherence was 84% (25%). Heavy alcohol use was associated with inferior IOM-defined retention (adjusted odds ratio 0.78, 95% confidence interval: 0.69 to 0.88), and daily/weekly binge drinking was associated with lower visit adherence (adjusted odds ratio = 0.90, 95% confidence interval: 0.82 to 0.98). CONCLUSIONS: Both heavy drinking and frequent binge drinking were associated with worse retention in HIV care. Increased identification and treatment of heavy and binge drinking in HIV clinical care settings may improve retention in HIV care, with downstream effects of improved clinical outcomes and decreased HIV transmission. PMID- 27243906 TI - Toward the definition of specific protection goals for the environmental risk assessment of chemicals: A perspective on environmental regulation in Europe. AB - This critical review examines the definition and implementation of environmental protection goals for chemicals in current European Union (EU) legislation, guidelines, and international agreements to which EU countries are party. The European chemical industry is highly regulated, and prospective environmental risk assessments (ERAs) are tailored for different classes of chemical, according to their specific hazards, uses, and environmental exposure profiles. However, environmental protection goals are often highly generic, requiring the prevention of "unacceptable" or "adverse" impacts on "biodiversity" and "ecosystems" or the "environment as a whole." This review aims to highlight working examples, challenges, solutions, and best practices for defining specific protection goals (SPGs), which are seen to be essential for refining and improving ERA. Specific protection goals hinge on discerning acceptable versus unacceptable adverse effects on the key attributes of relevant, sensitive ecological entities (ranging from organisms to ecosystems). Some isolated examples of SPGs for terrestrial and aquatic biota can be found in prospective ERA guidance for plant protection products (PPPs). However, SPGs are generally limited to environmental or nature legislation that requires environmental monitoring and retrospective ERA. This limitation is due mainly to the availability of baselines, which define acceptable versus unacceptable environmental effects on the key attributes of sentinel species, populations and/or communities, such as reproductive status, abundance, or diversity. Nevertheless, very few regulatory case examples exist in which SPGs incorporate effect magnitude, spatial extent, and temporal duration. We conclude that more holistic approaches are needed for defining SPGs, particularly with respect to protecting population sustainability, ecosystem function, and integrity, which are implicit in generic protection goals and explicit in the International Programme for Chemical Safety (IPCS) definition of "adverse effect." A possible solution, which the chemical industry is currently assessing, is wider application of the ecosystem services approach proposed by the European Food Safety Authority (EFSA) for the risk assessment of PPPs. Integr Environ Assess Manag 2017;13:17-37. (c) 2016 SETAC. PMID- 27243905 TI - MitoNEET Protects HL-1 Cardiomyocytes from Oxidative Stress Mediated Apoptosis in an In Vitro Model of Hypoxia and Reoxygenation. AB - The iron-sulfur cluster containing protein mitoNEET is known to modulate the oxidative capacity of cardiac mitochondria but its function during myocardial reperfusion injury after transient ischemia is unknown. The purpose of this study was to analyze the impact of mitoNEET on oxidative stress induced cell death and its relation to the glutathione-redox system in cardiomyocytes in an in vitro model of hypoxia and reoxygenation (H/R). Our results show that siRNA knockdown (KD) of mitoNEET caused an 1.9-fold increase in H/R induced apoptosis compared to H/R control while overexpression of mitoNEET caused a 53% decrease in apoptosis. Necrosis was not affected. Apoptosis of both, mitoNEET-KD and control cells was diminished to comparable levels by using the antioxidants Tiron and glutathione compound glutathione reduced ethyl ester (GSH-MEE), indicating that mitoNEET dependent apoptosis is mediated by oxidative stress. The interplay between mitoNEET and glutathione redox system was assessed by treating cardiomyocytes with 2-acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylthio-carbonylamino) phenylthiocarbamoylsulfanyl] propionic acid (2-AAPA), known to effectively inhibit glutathione reductase (GSR) and to decrease the GSH/GSSG ratio. Surprisingly, inhibition of GSR-activity to 20% by 2-AAPA decreased apoptosis of control and mitoNEET-KD cells to 23% and 25% respectively, while at the same time mitoNEET-protein was increased 4-fold. This effect on mitoNEET-protein was not accessible by mitoNEET-KD but was reversed by GSH-MEE. In conclusion we show that mitoNEET protects cardiomyocytes from oxidative stress-induced apoptosis during H/R. Inhibition of GSH-recycling, GSR-activity by 2-AAPA increased mitoNEET protein, accompanied by reduced apoptosis. Addition of GSH reversed these effects suggesting that mitoNEET can in part compensate for imbalances in the antioxidative glutathione-system and therefore could serve as a potential therapeutic approach for the oxidatively stressed myocardium. PMID- 27243908 TI - [(Me3 Si)Si]3 EtGe9 Pd(PPh3 ), a Pentafunctionalized Deltahedral Zintl Cluster: Synthesis, Structure, and Solution Dynamics. AB - The title compound, which has a ten-atom deltahedral cluster core of Ge9 Pd, was synthesized through insertion of Pd(PPh3 ) into the tetrasubstituted nona germanium cluster [(Me3 Si)Si]3 EtGe9 through a reaction of the latter with Pd(PPh3 )4 . This first reaction of neutral tetrasubstituted nine-atom clusters shows that they retain reactivity despite their neutral charge. The Ge9 Pd core is the first that incorporates a 5-connected transition metal other than from Group VI, a noble metal in this case. Single-crystal X-ray diffraction shows that the ten-atom core is a closo-cluster with the expected shape of a bicapped square antiprism. (1) H and (13) C NMR spectroscopy show that, in contrast to the parent tetra-substituted [(Me3 Si)Si]3 EtGe9 , the new compound does not exhibit dynamics. Relativistic DFT calculations are used to explain the differences. PMID- 27243907 TI - Microinfarcts are common and strongly related to dementia in the oldest-old: The 90+ study. AB - INTRODUCTION: We estimated the prevalence of microinfarcts and their association with dementia in a cohort of oldest-old participants. METHODS: Participants were from The 90+ Study, a population-based study of people 90 years and older. Dementia diagnoses were assigned postmortem during a consensus conference. Microinfarcts were evaluated in six brain regions. RESULTS: At death, the 213 participants were on average 97 years old, 69% were women, and 52% had dementia. Of the participants, 51% had microinfarcts and 17% had 3+ microinfarcts. The odds ratio (OR) for dementia was similar for 3+ microinfarcts (OR = 4.75, P < .01) and tangle stage V-VI (OR = 4.70, P < .001). Only microinfarcts in cortical regions (other than occipital) were associated to dementia. DISCUSSION: In this oldest old cohort, microinfarcts are common and contribute independently and similarly in magnitude to dementia as tangles. As risk factors for microinfarcts and other dementing pathologies are likely to differ, identifying these factors is crucial to developing prevention strategies for dementia in the oldest-old. PMID- 27243909 TI - Rapid formation and evolution of an extreme haze episode in Northern China during winter 2015. AB - We investigate the rapid formation and evolutionary mechanisms of an extremely severe and persistent haze episode that occurred in northern China during winter 2015 using comprehensive ground and vertical measurements, along with receptor and dispersion model analysis. Our results indicate that the life cycle of a severe winter haze episode typically consists of four stages: (1) rapid formation initiated by sudden changes in meteorological parameters and synchronous increases in most aerosol species, (2) persistent evolution with relatively constant variations in secondary inorganic aerosols and secondary organic aerosols, (3) further evolution associated with fog processing and significantly enhanced sulfate levels, and (4) clearing due to dry, cold north-northwesterly winds. Aerosol composition showed substantial changes during the formation and evolution of the haze episode but was generally dominated by regional secondary aerosols (53-67%). Our results demonstrate the important role of regional transport, largely from the southwest but also from the east, and of coal combustion emissions for winter haze formation in Beijing. Also, we observed an important downward mixing pathway during the severe haze in 2015 that can lead to rapid increases in certain aerosol species. PMID- 27243911 TI - Effects of Two Warm-up Programs on Balance and Isokinetic Strength in Male High School Soccer Players. AB - Ghareeb, DM, McLaine, AJ, Wojcik, JR, and Boyd, JM. Effects of two warm-up programs on balance and isokinetic strength in male high school soccer players. J Strength Cond Res 31(2): 372-379, 2017-One of the most common warm-up programs used to prevent injury in soccer, FIFA11+, integrates aerobic, strength, and balance. The purpose of this study was to compare FIFA11+ to a new warm-up program (NWP) on balance and isokinetic strength of the quadriceps and hamstrings at 60, 180, and 300 degrees .s in male high school soccer players. Participants at one school (n = 17) performed the NWP before practice for 6 weeks during one soccer season, whereas participants at another school (n = 17) performed FIFA11+. There were no differences at baseline. At posttest, players in NWP significantly improved (p < 0.01) in Overall Stability Index Balance, Anterior/Posterior Index Balance, and Medial Lateral Index with large effect sizes (ES) > 1.3. No changes were seen in FIFA11+. Isokinetic strength peak torque increased at 60 degrees .s in the quadriceps and hamstrings in dominant and nondominant legs in NWP (p < 0.01, ES, 0.59-1.02) and in hamstrings in FIFA11+ (p <= 0.05, ES, 0.32-0.40). At 180 degrees .s, NWP improved peak torque (p < 0.01, ES, 0.74-0.90) except hamstrings in the nondominant leg, whereas FIFA11+ showed improvements across all muscle groups (p < 0.01), but with smaller ES, 0.25-0.84. Both programs improved isokinetic peak torque at 300 degrees .s except hamstrings in the nondominant leg in NWP, although ES were higher in NWP (ES, 0.60-1.03) than FIFA11+ (ES, 0.31 0.42). The NWP seems to be effective for soccer conditioning by improving balance and isokinetic strength. PMID- 27243910 TI - Low-level laser therapy stimulates the oxidative burst in human neutrophils and increases their fungicidal capacity. AB - Low-level laser therapy (LLLT) is known to enhance mitochondrial electron transfer and ATP production; thus, this study asked whether LLLT could stimulate the oxidative burst in human neutrophils (PMN) and improve their ability to kill microorganisms. Blood from healthy human subjects was collected and PMN were isolated from the samples. PMN were treated in vitro with 660 nm or 780 nm CW laser light at 40 mW power and increasing energies up to 19.2 J and were subsequently incubated with Candida albicans cells. Generation of hydroxyl radicals, hypochlorite anions and superoxide anions by PMN were checked using fluorescent probes and chemiluminescence assays; a microbicidal activity assay against C. albicans was also performed. LLLT excited PMN to a higher functional profile, which was translated as superior production of reactive oxygen species (ROS) and increased fungicidal capacity. The most efficacious energy was 19.2 J and, interestingly, the 660 nm light was even more efficacious than 780 nm at increasing the respiratory burst of PMN and the fungicidal capacity. Human neutrophils (PMN) were stimulated in vitro with 660 nm or 780 nm CW laser light at 40 mW of power and a total energy of 19.2 J. Low-level laser therapy (LLLT) excited PMN to a higher functional profile, which was translated as a superior production of reactive oxygen species (ROS) such as hydroxyl radicals (HO* ) and hypochlorite anions (ClO- ) (Figure) and increased fungicidal capacity against Candida albicans cells. PMID- 27243912 TI - Self-Reported Wellness Profiles of Professional Australian Football Players During the Competition Phase of the Season. AB - Gallo, TF, Cormack, SJ, Gabbett, TJ, and Lorenzen, CH. Self-reported wellness profiles of professional Australian football players during the competition phase of the season. J Strength Cond Res 31(2): 495-502, 2017-With the prevalence of customized self-report measures in high-performance sport, and the incomplete understanding of athletes' perceived wellness in response to matches and training load, the objective of this study was to explore weekly wellness profiles within the context of the competitive season of professional Australian football. Internal match load, measured through the session-rating of perceived exertion method, match-to-match microcycle, stage of the season, and training load were included in multivariate linear models to determine their effect on weekly wellness profile (n = 1,835). There was a lower weekly training load on a 6-day microcycle compared with a 7-day and 8-day microcycle. Match load had no significant impact on weekly wellness profile, while there was an interaction between microcycle and days postmatch. There was a likely moderately lower wellness Z-score 1 day postmatch for an 8-day microcycle (mean; 95% confidence interval: -1.79; -2.02 to -1.56) compared with a 6-day (-1.19; -1.30 to -1.08) and 7-day (-1.22; -1.34 to -1.09) cycle (d; 95% confidence interval: -0.82; -1.3 to -0.36, -0.78; -1.3 to -0.28, respectively). The second half of the season saw a possibly small reduction in overall wellness Z-score than the first half of the season (0.22; 0.12-0.32). Finally, training load had no effect on wellness Z score when controlled for days postmatch, microcycle, and stage of the season. These results provide information on the status of players in response to matches and fixed conditions. Knowing when wellness Z-score returns to baseline relative to the length of the microcycle may lead practitioners to prescribe the heaviest load of the week accordingly. Furthermore, wellness "red flags" should be made relative to the microcycles and stage of the season to determine an athlete's status relative to their typical weekly profile. PMID- 27243913 TI - Monitoring Training Loads in Professional Basketball Players Engaged in a Periodized Training Program. AB - Aoki, MS, Ronda, LT, Marcelino, PR, Drago, G, Carling, C, Bradley, PS, and Moreira, A. Monitoring training loads in professional basketball players engaged in a periodized training program. J Strength Cond Res 31(2): 348-358, 2017-The aim of this study was to investigate the dynamics of external training load (eTL) and internal training load (iTL) during seasonal periods, and examine the effect of a periodized training program on physical performance in professional basketball players. Repeated measures for 9 players (28 +/- 6 years; 199 +/- 8 cm; 101 +/- 12 kg) were collected from 45 training sessions, over a 6-week preseason phase and a 5-week in-season phase. Physical tests were conducted at baseline (T1), week 4 (T2), and week 9 (T3). Differences in means are presented as % +/- confident limits. A very likely difference was observed during in-season compared with preseason for the eTL variables (measured by multivariable monitoring device), mechanical load (13.5 +/- 8.8) and peak acceleration (11.0 +/ 11.2), respectively. Regarding iTL responses, a very large decrement in TRIMP (most likely difference, -20.6 +/- 3.8) and in session rating of perceived exertion training load (very likely difference, -14.2 +/- 9.0) was detected from preseason to in-season. Physical performance improved from T1 to T3 for Yo-Yo intermittent recovery test 1 (62.2 +/- 34.3, effect size [ES] > 1.2); countermovement jump (8.8 +/- 6.1, ES > 0.6); and squat jump (14.8 +/- 10.2, ES > 0.8). Heart rate (HR; %HRpeak) exercise responses during a submaximal running test decreased from T1 to T3 (3.2 +/- 4.3, ES < 0.6), as well as the HR recovery after the test (14.7 +/- 8.8, ES > 1.2). These results provide valuable information to coaches about training loads and physical performance across different seasonal periods. The data demonstrate that both eTL and iTL measures should be monitored in association with physical tests, to provide a comprehensive understanding of the training process. PMID- 27243914 TI - Simultaneous Knee Extensor Muscle Action Induces an Increase in Voluntary Force Generation of Plantar Flexor Muscles. AB - Suzuki, T, Shioda, K, Kinugasa, R, and Fukashiro, S. Simultaneous knee extensor muscle action induces an increase in voluntary force generation of plantar flexor muscles. J Strength Cond Res 31(2): 365-371, 2017-Maximum activation of the plantar flexor muscles is required for various sporting activities that involve simultaneous plantar flexion and knee extension. During a multi-joint movement, activation of the plantar flexor muscles is affected by the activity of the knee extensor muscles. We hypothesized that coactivation of the plantar flexor muscles and knee extensor muscles would result in a higher plantar flexion torque. To test this hypothesis, 8 male volunteers performed maximum voluntary isometric action of the plantar flexor muscles with and without isometric action of the knee extensor muscles. Surface electromyographic data were collected from 8 muscles of the right lower limb. Voluntary activation of the triceps surae muscles, evaluated using the interpolated twitch technique, significantly increased by 6.4 percentage points with intentional knee extensor action (p = 0.0491). This finding is in line with a significant increase in the average rectified value of the electromyographic activity of the vastus lateralis, fibularis longus, and soleus muscles (p = 0.013, 0.010, and 0.045, respectively). The resultant plantar flexion torque also significantly increased by 11.5% of the predetermined maximum (p = 0.031). These results suggest that higher plantar flexor activation coupled with knee extensor activation facilitates force generation during a multi-joint task. PMID- 27243916 TI - Muscle Damage and Muscle Activity Induced by Strength Training Super-Sets in Physically Active Men. AB - Brentano, MA, Umpierre, D, Santos, LP, Lopes, AL, Radaelli, R, Pinto, RS, and Kruel, LFM. Muscle damage and muscle activity induced by strength training super sets in physically active men. J Strength Cond Res 31(7): 1847-1858, 2017-In strength training, muscle activity is often analyzed by surface electromyography (EMG) and muscle damage through indirect markers, such as plasma concentrations of creatine kinase (CK) after exercise. However, there is little information about the influence of the strength exercises order on these parameters. The purpose of this study is to analyze the effect of strength exercises order (super sets) in muscle activity and indirect markers of muscle damage. Twenty men were randomly assigned to one of the strength training sessions (TS). Each TS (5 sets * 8-10 repetition maximum) consisted of 2 exercises for the knee extensor muscles and 2 exercises for the horizontal shoulder flexors performed in a different order: exercises for the same muscle group grouped (grouped exercises [GE]: n = 10; 26.6 +/- 3.4 years; 17.4 +/- 3.4 body fat) or separated (separated exercises [SE]: n = 10; 24.9 +/- 2.6 years; 15.4 +/- 5.9 body fat). Muscle activity was analyzed by surface EMG (vastus lateralis [VL], vastus medialis [VM], rectus femoris [RF], pectoralis major [PM], and anterior deltoid [AD]), and the main indirect marker of muscle damage was the CK, evaluated immediately before and after the first 5 days of each TS. There was a higher EMG activity of GE in the RF (GE: 88.4% * SE: 73.6%) and AD (GE: 176.4% * SE: 100.0%), in addition to greater concentration of CK (GE: 632.4% * SE: 330.5%) after exercise. Our findings suggest that, in physically active men, implementing super-sets with GE promotes greater muscle effort and muscle damage, wherein 5 days are not enough to recover the trained muscle groups. PMID- 27243917 TI - Intraday and Interday Reliability of Ultra-Short-Term Heart Rate Variability in Rugby Union Players. AB - Nakamura, FY, Pereira, LA, Esco, MR, Flatt, AA, Moraes, JE, Cal Abad, CC, and Loturco, I. Intraday and interday reliability of ultra-short-term heart rate variability in rugby union players. J Strength Cond Res 31(2): 548-551, 2017-The aim of this study was to examine the intraday and interday reliability of ultra short-term vagal-related heart rate variability (HRV) in elite rugby union players. Forty players from the Brazilian National Rugby Team volunteered to participate in this study. The natural log of the root mean square of successive RR interval differences (lnRMSSD) assessments were performed on 4 different days. The HRV was assessed twice (intraday reliability) on the first day and once per day on the following 3 days (interday reliability). The RR interval recordings were obtained from 2-minute recordings using a portable heart rate monitor. The relative reliability of intraday and interday lnRMSSD measures was analyzed using the intraclass correlation coefficient (ICC). The typical error of measurement (absolute reliability) of intraday and interday lnRMSSD assessments was analyzed using the coefficient of variation (CV). Both intraday (ICC = 0.96; CV = 3.99%) and interday (ICC = 0.90; CV = 7.65%) measures were highly reliable. The ultra short-term lnRMSSD is a consistent measure for evaluating elite rugby union players, in both intraday and interday settings. This study provides further validity to using this shortened method in practical field conditions with highly trained team sports athletes. PMID- 27243918 TI - RPE and Velocity Relationships for the Back Squat, Bench Press, and Deadlift in Powerlifters. AB - Helms, ER, Storey, A, Cross, MR, Browm, SR, Lenetsky, S, Ramsay, H, Dillen, C, and Zourdos, MC. RPE and velocity relationships for the back squat, bench press, and deadlift in powerlifters. J Strength Cond Res 31(2): 292-297, 2017-The purpose of this study was to compare average concentric velocity (ACV) and rating of perceived exertion (RPE) based on repetitions in reserve on the squat, bench press, and deadlift. Fifteen powerlifters (3 women and 12 men, mean age 28.4 +/- 8.5 years) worked up to a one repetition maximum (1RM) on each lift. Rating of perceived exertion was recorded on all sets, and the ACV was recorded for all sets performed at 80% of estimated 1RM and higher, up to 1RM. Rating of perceived exertion at 1RM on squat, bench press, and deadlift was 9.6 +/- 0.5, 9.7 +/- 0.4, and 9.6 +/- 0.5, respectively and was not significantly different (p > 0.05). The ACV at 1RM on squat, bench press and deadlift was 0.23 +/- 0.05, 0.10 +/- 0.04, and 0.14 +/- 0.05 m.second, respectively. Squat was faster than both bench press and deadlift (p > 0.001), and deadlift was faster than bench press (p = 0.05). Very strong relationships (r = 0.88-0.91) between percentage 1RM and RPE were observed on each lift. The ACV showed strong (r = -0.79 to -0.87) and very strong (r = -0.90 to 92) inverse relationships with RPE and percentage 1RM on each lift, respectively. We conclude that RPE may be a useful tool for prescribing intensity for squat, bench press, and deadlift in powerlifters, in addition to traditional methods such as percentage of 1RM. Despite high correlations between percentage 1RM and ACV, a "velocity load profile" should be developed to prescribe intensity on an individual basis with appropriate accuracy. PMID- 27243919 TI - What Is a Personality Disorder? AB - The goal of this article is to describe, characterize, and differentiate personality disorders by connecting their conceptual features to their foundations in the natural sciences. What is proposed is akin to Freud's abandoned Project for a Scientific Psychology and Wilson's (1975) highly controversial Sociobiology. Both were worthy endeavors to advance our understanding of the styles and traits of human nature; this was to be done by exploring interconnections among the diverse disciplines of nature that evolved ostensibly unrelated bodies of research and manifestly dissimilar languages. PMID- 27243920 TI - Examining the reliability and validity of an abbreviated Psychopathic Personality Inventory-Revised (PPI-R) in four samples. AB - A recently developed 40-item short-form of the Psychopathic Personality Inventory Revised (PPI-R; Lilienfeld & Widows, 2005) has shown considerable promise as an alternative to the long-form of the instrument (Eisenbarth, Lilienfeld, & Yarkoni, 2015). Beyond the initial construction of the short-form, however, Eisenbarth et al. only evaluated a small number of external correlates in a German college student sample. In this study, we evaluate the internal consistency of the short-form scales in 4 samples previously administered the full PPI-R (3 U.S. college student samples and 1 U.S. forensic psychiatric inpatient sample) and examine a wide range of external correlates to compare the nomological nets of the short- and long-forms. Across all 4 samples, correlations between each short-form scale and its corresponding long-form scale were uniformly high (all rs > .75). In terms of external correlates, the pattern of associations was exceedingly similar, for the short-form and long-form composites with a largely trivial reduction in effect size. Collectively, our findings offer considerable support for the utility of this new short-form as a substitute for the full PPI-R. (PsycINFO Database Record PMID- 27243921 TI - Phase Boundary Propagation in Li-Alloying Battery Electrodes Revealed by Liquid Cell Transmission Electron Microscopy. AB - Battery cycle life is directly influenced by the microstructural changes occurring in the electrodes during charge and discharge cycles. Here, we image in situ the nanoscale phase evolution in negative electrode materials for Li-ion batteries using a fully enclosed liquid cell in a transmission electron microscope (TEM) to reveal early degradation that is not evident in the charge discharge curves. To compare the electrochemical phase transformation behavior between three model materials, thin films of amorphous Si, crystalline Al, and crystalline Au were lithiated and delithiated at controlled rates while immersed in a commercial liquid electrolyte. This method allowed for the direct observation of lithiation mechanisms in nanoscale negative electrodes, revealing that a simplistic model of a surface-to-interior lithiation front is insufficient. For the crystalline films, a lithiation front spread laterally from a few initial nucleation points, with continued grain nucleation along the growing interface. The intermediate lithiated phases were identified using electron diffraction, and high-resolution postmortem imaging revealed the details of the final microstructure. Our results show that electrochemically induced solid-solid phase transformations can lead to highly concentrated stresses at the laterally propagating phase boundary which should be considered for future designs of nanostructured electrodes for Li-ion batteries. PMID- 27243922 TI - Dryofragin inhibits the migration and invasion of human osteosarcoma U2OS cells by suppressing MMP-2/9 and elevating TIMP-1/2 through PI3K/AKT and p38 MAPK signaling pathways. AB - Dryofragin, a phloroglucinol derivative extracted from Dryopteris fragrans (L.) Schott, was found to inhibit proliferation and induce apoptosis of tumor cells. However, the mechanism involved in the suppression of cancer cell metastasis by dryofragin remains unclear. Our study investigated the mechanisms for the antitumor properties of dryofragin on the migration and invasion of human osteosarcoma U2OS cells. Dryofragin suppressed the migration and invasive ability of U2OS cells, and it decreased the expression of MMP-2 and MMP-9 and elevated the expression of TIMP-1 and TIMP-2. Western blotting assays indicated that dryofragin was effective in suppressing the phosphorylation of phosphatidylinositide-3 kinase (PI3K), Akt, and p38 MAPK. These results suggest that dryofragin inhibited U2OS cell migration and invasion by reducing the expression of MMP-2 and MMP-9 and elevating the expression of TIMP-1 and TIMP-2 through the PI3K/AKT and p38 MAPK signaling pathways. Above all, we conclude that dryofragin represents an anti-invasive agent and may potentially be applicable in osteosarcoma therapy. PMID- 27243923 TI - Impact of extraction methods on bio-flocculants recovered from backwashed sludge of bio-filtration unit. AB - Effect of ten extraction methods on flocculation activity and chemical composition of bio-flocculants recovered from backwashed sludge of bio-filtration unit was studied. The results showed that the chemical method was better than physical method with respect to the extracted BFs weight and its flocculation activity. Cell lysis did not affect to the flocculation activity of BFs. Among ten extraction methods, EDTA (20 g/L) was the best one with extracted BFs dry weight of 6242 mg/L and flocculation activity of 83%. Optimization of EDTA concentration showed that 5 g EDTA/L (or 0.2 g EDTA/g SS) was suitable for recovery of BFs from backwashed sludge. The flocculation activity of BFs was 94% when using 2.4 mg of BFs/g of kaolin. The outcome of this study suggested that backwashed sludge of the bio-filtration unit was a potential source for exploiting bio-flocculants. PMID- 27243924 TI - Postoperative Radiotherapy After Breast-Conserving Surgery for Early-Stage Breast Cancer: A Review. AB - IMPORTANCE: Radiotherapy (RT) after breast-conserving surgery for early-stage disease has become an integral part of breast cancer treatment. This article reviews the rationale and indications for adjuvant radiotherapy to the breast and regional lymph nodes. OBSERVATIONS: Randomized trials have demonstrated a significant benefit in tumor control in the treated breast following whole-breast RT that, in aggregate, has resulted in an overall survival advantage compared with breast-conserving surgery alone. Recent studies have further assessed the impact of regional nodal irradiation in women with either high-risk node-negative or node-positive disease and suggest a significant benefit in regional control and breast cancer recurrence, but not in overall survival. Toxic effects, including lymphedema, were increased in the cohorts receiving comprehensive nodal RT. The benefits from regional RT should be weighed against potential radiation associated toxic effects. Randomized trials have also demonstrated equal efficacy and toxic effects between hypofractionated and conventionally fractionated RT in appropriately selected patients. In addition, current efforts incorporating clinical, pathologic, and molecular features are under way to identify patients for whom RT to the breast can be safely omitted. CONCLUSIONS AND RELEVANCE: Adjuvant RT in early-stage breast cancer significantly reduces in-breast tumor recurrence and improves overall survival. Although risk reductions observed in randomized trials have been relatively consistent across series, the absolute benefit of RT is not equal for all women. Efforts are under way to identify which patients benefit the most from local or locoregional RT vs those at very low risk for recurrence in whom RT can be omitted. For patients who will benefit from RT and are appropriate candidates, hypofractionated RT should be strongly considered. PMID- 27243925 TI - Creating a digital medical illustration. AB - This paper covers the steps required to complete a medical illustration in a digital format using Adobe Illustrator and Photoshop. The project example is the surgical procedure for the release of the glenohumeral joint for the condition known as 'frozen shoulder'. The purpose is to demonstrate one method which an artist can use within digital media to create a colour illustration such as the release of the glenohumeral joint. Included is a general overview as how to deal with the administration of a medical illustration commission through the experience of a professional freelance artist. PMID- 27243926 TI - Chemical Profiling Using Uplc Q-Tof/Ms and Antioxidant Activities of Fortunella Fruits. AB - The fruits of Fortunella Swingle are widely consumed as fresh fruits and traditional medicine in China. China is the origin center and has the largest cultivated area of the genus Fortunella. In this study, the chemical compositions of ethanol extracts of the major Fortunella cultivated types including Fortunella japonica Swingle, Fortunella margarita Swingle, Fortunella crassifolia Swingle 1 (Lanshang) and Fortunella crassifolia Swingle 2 (Liuyang) were determined using ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC Q-TOF/MS) method, and their antioxidant activities were evaluated. 12 compounds were identified and 5 compounds were tentatively characterized. The results showed that the chemical compositions of the ethanol extracts of 4 Fortunella cultivated types were largely the same. 3', 5'-di-C glucopyranosylphloretin was the predominant flavonoid in Fortunella fruits, and Fortunella margarita Swingle had higher contents of flavonoids than other species. In addition, the data demonstrated high antioxidant activities of Fortunella fruits. The developed method could be available to rapidly analyze the chemical compounds in Fortunella fruits and its products. This study will provide information for further quality assessment and utilization of Fortunella resources. PMID- 27243927 TI - EFFECTIVENESS OF DIFFERENT MONITORING MODALITIES IN THE DETECTION OF NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: The Home Study, Report Number 3. AB - PURPOSE: To determine the effectiveness of different monitoring modalities to detect incident neovascularization associated with age-related macular degeneration (AMD). METHODS: Secondary analyses compared the rates of detecting incident neovascular AMD in prescheduled office visits versus office visits triggered by monitoring device or by symptom realization in a randomized trial evaluating home telemonitoring device plus standard care (device arm) versus standard care alone. RESULTS: At prescheduled office visits, neovascular AMD was detected in 14/1927 visits (0.7%, 95% confidence interval [CI]: 0.4%-1.1%) and 14/1949 visits (0.7%, 95% CI: 0.3%-1.1%) in the device and standard care alone arms, respectively. Thirty-seven participants with neovascular AMD were detected in 318 office visits (11.6%, 95% CI: 8.1%-15.2%) triggered by device or symptom realization and 17 neovascular AMD in 65 office visits (26%, 95% CI: 15.5%-36.8%) triggered by symptom realization in the device and standard care alone arms, respectively. The home device strategy had a higher neovascular-AMD detection rate than prescheduled office visits (relative risk = 16.0 [95% CI: 8.8-29.3]). Neovascular AMD detected at triggered visits were associated with less vision loss from baseline in the device arm versus standard care alone arm (-3 letters vs. -11.5 letters, respectively, P = 0.03). CONCLUSION: Telemonitoring may alter the management of patients with AMD and improve vision outcomes. PMID- 27243928 TI - COMPREHENSIVE REVIEW OF GOLF-RELATED OCULAR INJURIES. AB - PURPOSE: The authors aimed to analyze the causes and outcomes of golf-related ocular injuries in this retrospective meta-analysis, literature review, and original case series. METHODS: Forty-one articles identified by PubMed search resulted in 11 included studies yielding 102 subjects. Included articles described all ocular golf injuries that presented to an institution during a determined period. Eight factors were analyzed: age, sex, location and mechanism of injury, protective eyewear use, resulting open-globe injury, resulting enucleation, and visual acuity changes. RESULTS: No subjects wore adequate protective eyewear. Significantly more subjects were injured by golf balls (72%) than golf clubs (27%) or foreign body (1%) (P < 0.0001). The ratio of golf ball to club injuries was significantly higher in adults (92%) than in children (23%) (P < 0.0001). Forty-seven of 93 (51%) injuries resulted in an open globe, whereas 27/82 (33%) injuries resulted in enucleation. The mean +/- SD logMAR visual acuity improved by -0.641 +/- 0.745 after treatment (>6 lines of improvement; P = 0.0001). CONCLUSION: Reported ocular golf injuries occur less frequently than other ocular sports injuries, but may result in devastating outcomes. Supervision of children using golf equipment should be encouraged. PMID- 27243929 TI - Correspondence. PMID- 27243930 TI - Reply. PMID- 27243931 TI - Acute embryo toxicity and teratogenicity of three potential biofuels also used as flavor or solvent. AB - The demand for biofuels increases due to concerns regarding greenhouse gas emissions and depletion of fossil oil reserves. Many substances identified as potential biofuels are solvents or already used as flavors or fragrances. Although humans and the environment may be readily exposed little is known regarding their (eco)toxicological effects. In this study, the three potential biofuels ethyl levulinate (EL), 2-methyltetrahydrofuran (2-MTHF) and 2 methylfuran (2-MF) were investigated for their acute embryo toxicity and teratogenicity using the fish embryo toxicity (FET) test to identify unknown hazard potentials and to allow focusing further research on substances with low toxic potentials. In addition, two fossil fuels (diesel and gasoline) and an established biofuel (rapeseed oil methyl ester) were investigated as references. The FET test is widely accepted and used in (eco)toxicology. It was performed using the zebrafish Danio rerio, a model organism useful for the prediction of human teratogenicity. Testing revealed a higher acute toxicity for EL (LC50: 83mg/L) compared to 2-MTHF (LC50: 2980mg/L), 2-MF (LC50: 405mg/L) and water accommodated fractions of the reference fuels including gasoline (LC50: 244mg DOC/L). In addition, EL caused a statistically significant effect on head development resulting in elevated head lengths in zebrafish embryos. Results for EL reduce its likelihood of use as a biofuel since other substances with a lower toxic potential are available. The FET test applied at an early stage of development might be a useful tool to avoid further time and money requiring steps regarding research on unfavorable biofuels. PMID- 27243932 TI - Biotransformation of pharmaceuticals by ammonia oxidizing bacteria in wastewater treatment processes. AB - Pharmaceutical residues could potentially pose detrimental effects on aquatic ecosystems and human health, with wastewater treatment being one of the major pathways for pharmaceuticals to enter into the environment. Enhanced removal of pharmaceuticals by ammonia oxidizing bacteria (AOB) has been widely observed in wastewater treatment processes. This article reviews the current knowledge on the biotransformation of pharmaceuticals by AOB. The relationship between the pharmaceuticals removal and nitrification process was revealed. The important role of AOB-induced cometabolism on the biotransformation of pharmaceuticals as well as their transformation products and pathways was elucidated. Kinetics and mathematical models describing the biotransformation of pharmaceuticals by AOB were also reviewed. The results highlighted the high degradation capabilities of AOB toward some refractory pharmaceuticals, with their degradations being clearly related to the nitrification rate and their transformation products being identified, which may exhibit similar or higher ecotoxicological impacts compared to the parent compound. PMID- 27243933 TI - Sewage sludge stabilisation and fertiliser value in a silvopastoral system developed with Eucalyptus nitens Maiden in Lugo (Spain). AB - Copper (Cu) is one of the heavy metals with highest proportion in sewage sludge. In Europe, sewage sludge should be stabilised before using it as a fertiliser in agriculture. Depending on the stabilisation process, sewage sludge has different Cu contents, and soil Cu incorporation rates. This study was undertaken to examine the effect of fertilisation with different types of sewage sludge (anaerobic, composted, and pelletised) on the concentration of total and available Cu in the soil, the tree growth, the pasture production, and the concentration of Cu in the pasture when compared with control treatments (i.e. no fertilisation and mineral fertilisation) in a silvopastoral system under Eucalyptus nitens Maiden. The results of this experiment show that an improvement of the soil pH increased the incorporation and the mineralisation of the sewage sludge and litter, and therefore, the release of Cu from the soil. Moreover, the concentration of Cu in the pasture and the levels of Cu extracted by the pasture improved when the soil organic matter decreased because the high levels of organic matter in the soil could have formed Cu complex. The composted sewage sludge (COM) increased a) the soil variables studied (pH, total Cu, and available Cu) and b) the Cu extracted by the pasture, both probably due to the higher inputs of cations made with it. In any case, the levels of Cu found in the soil never exceeded the maximums as set by Spanish regulations and did not cause harmful effects on the plants and animals. Therefore, the use of COM as an organic fertiliser should be promoted in silvopastoral systems established in edaphoclimatic conditions similar to this study because COM enhanced the productivity of the system from a viewpoint of the soil and the pasture, without causing any environmental damage. PMID- 27243934 TI - Indium-Mediated Intramolecular Reaction of N-(2 Iodobenzoyl)azabenzonorbornadienes: A General Access to Dihydrobenzo[c]phenanthridinones. AB - An efficient synthesis of dihydrobenzo[c]phenanthridinones was achieved by utilizing an indium(0)-mediated intramolecular cyclization reaction under ligand- and base-free conditions. A variety of functional groups were tolerated in the present protocol. PMID- 27243935 TI - Flour Quality and Related Molecular Characterization of High Molecular Weight Glutenin Subunit Genes from Wild Emmer Wheat Accession TD-256. AB - To clarify the effect of high molecular weight glutenin subunit (HMW-GS) from wild emmer wheat on flour quality, which has the same mobility as that from common wheat, the composition and molecular characterization of HMW-GS from wild emmer wheat accession TD-256, as well as its flour quality, were intensively analyzed. It is found that the mobilities of Glu-A1 and Glu-B1 subunits from TD 256 are consistent with those of bread wheat cv. 'XiaoYan 6'. Nevertheless, dough rheological properties of TD-256 reveal its poor flour quality. In the aspect of molecular structure from HMW-GS, only two conserved cysteine residues can be observed in the deduced protein sequence of 1Bx14* from TD-256, while most Glu 1Bx contain four conserved cysteine residues. In addition, as can be predicted from secondary structure, the quantity both of alpha-helixes and their amino acid residues of the subunits from TD-256 is fewer than those of common wheat. Though low molecular weight glutenin subunit (LMW-GS) and gliadin can also greatly influence flour quality, the protein structure of the HMW-GS revealed in this work can partly explain the poor flour quality of wild emmer accession TD-256. PMID- 27243936 TI - Photoactivation of Luminescent Centers in Single SiO2 Nanoparticles. AB - Photobleaching of fluorophores is one of the key problems in fluorescence microscopy. Overcoming the limitation of the maximum number of photons, which can be detected from a single emitter, would allow one to enhance the signal-to-noise ratio and thus the temporal and spatial resolution in fluorescence imaging. It would be a breakthrough for many applications of fluorescence spectroscopy, which are unachievable up to now. So far, the only approach for diminishing the effect of photobleaching has been to enhance the photostability of an emitter. Here, we present a fundamentally new solution for increasing the number of photons emitted by a fluorophore. We show that, by exposing a single SiO2 nanoparticle to UV illumination, one can create new luminescent centers within this particle. By analogy with nanodiamonds, SiO2 nanoparticles can possess luminescent defects in their regular SiO2 structure. However, due to the much weaker chemical bonds, it is possible to generate new defects in SiO2 nanostructures using UV light. This allows for the reactivation of the nanoparticle's fluorescence after its photobleaching. PMID- 27243937 TI - Costs and Benefits to Pregnant Male Pipefish Caring for Broods of Different Sizes. AB - Trade-offs between brood size and offspring size, offspring survival, parental condition or parental survival are classic assumptions in life history biology. A reduction in brood size may lessen these costs of care, but offspring mortality can also result in an energetic gain, if parents are able to utilize the nutrients from the demised young. Males of the broad-nosed pipefish (Syngnathus typhle) care for the offspring by brooding embryos in a brood pouch. Brooding males can absorb nutrients that emanate from embryos, and there is often a reduction in offspring number over the brooding period. In this study, using two experimentally determined brood sizes (partially and fully filled brood pouches), we found that full broods resulted in larger number of developing offspring, despite significantly higher absolute and relative embryo mortality, compared to partial broods. Male survival was also affected by brood size, with males caring for full broods having poorer survival, an effect that together with the reduced embryo survival was found to negate the benefit of large broods. We found that embryo mortality was lower when the brooding males were in good initial condition, that embryos in broods with low embryo mortality weighed more, and surprisingly, that males in higher initial condition had embryos of lower weight. Brood size, however, did not affect embryo weight. Male final condition, but not initial condition, correlated with higher male survival. Taken together, our results show costs and benefits of caring for large brood sizes, where the numerical benefits come with costs in terms of both embryo survival and survival of the brooding father, effects that are often mediated via male condition. PMID- 27243941 TI - Corrigendum: Matrix metalloproteinase 11 protects from diabesity and promotes metabolic switch. PMID- 27243940 TI - Current and future immunotherapeutic approaches in Hodgkin lymphoma. AB - Hodgkin lymphoma (HL) has become a highly curable malignancy even in advanced stages when treated adequately. However, relapsed or refractory disease and treatment-related toxicity constitute a significant clinical challenge. Innovative approaches are thus needed to improve treatment of these mainly young patients. In HL lesions, very few malignant Hodgkin and Reed-Sternberg (HRS) cells are embedded in an immunosuppressive microenvironment of reactive cells. Novel approaches such as bispecific antibodies, antibody-drug conjugates, immune checkpoint inhibitors or adoptive cellular therapies are currently being investigated with promising results in relapsed or refractory patients. Encouraging response rates and a favorable toxicity profile have recently been reported in early phase clinical trials with antibodies blocking the programed death receptor 1 (PD1). This review will summarize the current clinical knowledge on mechanism, safety and efficacy of the different agents and discuss potential future strategies, which are partly already investigated within clinical trials. PMID- 27243942 TI - Feasibility of noise reduction by a modification in ICU environment. AB - Noise is a proven cause of wakefulness and qualitative sleep disturbance in critically ill patients. A sound pressure level reduction can improve sleep quality, but there are no studies showing the feasibility of such a noise reduction in the intensive care unit (ICU) setting. Considering all available evidence, we redesigned two ICU rooms with the aim of investigating the physiological and clinical impact of a healing environment, including a noise reduction and day-night variations of sound level. Within an experimental design, we recorded 96 h of sound-pressure levels in standard ICU rooms and the modified ICU rooms. In addition, we performed a sound source observation by human observers. Our results show that we reduced A-weighted equivalent sound pressure levels and maximum sound pressure levels with our architectural interventions. During night-time, the modification led to a significant decrease in 50 dB threshold overruns from 65.5% to 39.9% (door side) and from 50% to 10.5% (window side). Sound peaks of more than 60 decibels were significantly reduced from 62.0% to 26.7% (door side) and 59.3% to 30.3% (window side). Time-series analysis of linear trends revealed a significantly more distinct day-night pattern in the modified rooms with lower sound levels during night-times. Observed sound sources during night revealed four times as many talking events in the standard room compared to the modified room. In summary, we show that it is feasible to reduce sound pressure levels using architectural modifications. PMID- 27243943 TI - Reply to another solution that enables ablative radiotherapy for large liver tumors: Percutaneous interstitial high-dose rate brachytherapy. PMID- 27243944 TI - Silicide Coating Fabricated by HAPC/SAPS Combination to Protect Niobium Alloy from Oxidation. AB - A combined silicide coating, including inner NbSi2 layer and outer MoSi2 layer, was fabricated through a two-step method. The NbSi2 was deposited on niobium alloy by halide activated pack cementation (HAPC) in the first step. Then, supersonic atmospheric plasma spray (SAPS) was applied to obtain the outer MoSi2 layer, forming a combined silicide coating. Results show that the combined coating possessed a compact structure. The phase constitution of the combined coating prepared by HAPC and SAPS was NbSi2 and MoSi2, respectively. The adhesion strength of the combined coating increased nearly two times than that for single sprayed coating, attributing to the rougher surface of the HAPC-bond layer whose roughness increased about three times than that of the grit-blast substrate. After exposure at 1200 degrees C in air, the mass increasing rate for single HAPC-silicide coating was 3.5 mg/cm(2) because of the pest oxidation of niobium alloy, whereas the combined coating displayed better oxidation resistance with a mass gain of only 1.2 mg/cm(2). Even more, the combined coating could significantly improve the antioxidation ability of niobium based alloy at 1500 degrees C. The good oxidation resistance of the combined silicide coating was attributed to the integrity of the combined coating and the continuous SiO2 protective scale provided by the oxidation of MoSi2. PMID- 27243946 TI - Physiotherapy and Occupational Therapy and Mild to Moderate Parkinson Disease Reply. PMID- 27243945 TI - Dietary, circulating beta-carotene and risk of all-cause mortality: a meta analysis from prospective studies. AB - Observational studies evaluating the relation between dietary or circulating level of beta-carotene and risk of total mortality yielded inconsistent results. We conducted a comprehensive search on publications of PubMed and EMBASE up to 31 March 2016. Random effect models were used to combine the results. Potential publication bias was assessed using Egger's and Begg's test. Seven studies that evaluated dietary beta-carotene intake in relation to overall mortality, indicated that a higher intake of beta-carotene was related to a significant lower risk of all-cause mortality (RR for highest vs. lowest group = 0.83, 95%CI: 0.78-0.88) with no evidence of heterogeneity between studies (I(2) = 1.0%, P = 0.416). A random-effect analysis comprising seven studies showed high beta carotene level in serum or plasma was associated with a significant lower risk of all-cause mortality (RR for highest vs. lowest group = 0.69, 95%CI: 0.59-0.80) with low heterogeneity (I(2) = 37.1%, P = 0.145). No evidence of publication bias was detected by Begg's and Egger's regression tests. In conclusion, dietary or circulating beta-carotene was inversely associated with risk of all-cause mortality. More studies should be conducted to clarify the dose-response relationship between beta-carotene and all-cause mortality. PMID- 27243948 TI - Interspecialty Differences in Physicians' Attitudes, Beliefs, and Reasons for Withdrawing or Withholding Hypercalcemia Treatment in Terminally Ill Patients. PMID- 27243947 TI - Development of a Surface Plasmon Resonance-Based Immunosensor for Detection of 10 Major O-Antigens on Shiga Toxin-Producing Escherichia coli, with a Gel Displacement Technique To Remove Bound Bacteria. AB - A surface plasmon resonance-based immunosensor (SPR-immunosensor) was developed for the detection of Shiga toxin-producing Escherichia coli (STEC) belonging to the O-antigen groups O26, O91, O103, O111, O115, O121, O128, O145, O157, and O159. The polyclonal antibodies (PoAbs) generated against each of the STEC O antigen types in rabbits were purified and were immobilized on the sensor chip at 0.5 mg/mL. The limit of detection for STEC O157 by the SPR-immunosensor was found to be 6.3 * 10(4) cells for 75 s. Each of the examined 10 O-antigens on the STECs was detected by the corresponding PoAb with almost no reaction to the other PoAbs. The detected STECs were sufficiently removed from the PoAbs using gelatin or agarose gel without deactivation of the PoAbs, enabling repeatable use of the sensor chip. The developed SPR-immunosensor can be applied for the detection of multiple STEC O-antigens. Furthermore, the new antigen removal technique using the gel displacement approach can be utilized with various immunosensors to improve the detection of pathogens in clinical and public health settings. PMID- 27243949 TI - Structure, Electronic Properties, and Electrochemical Behavior of a Boron-Doped Diamond/Quartz Optically Transparent Electrode. AB - The morphology, microstructure, chemistry, electronic properties, and electrochemical behavior of a boron-doped nanocrystalline diamond (BDD) thin film grown on quartz were evaluated. Diamond optically transparent electrodes (OTEs) are useful for transmission spectroelectrochemical measurements, offering excellent stability during anodic and cathodic polarization and exposure to a variety of chemical environments. We report on the characterization of a BDD OTE by atomic force microscopy, optical spectroscopy, Raman spectroscopic mapping, alternating-current Hall effect measurements, X-ray photoelectron spectroscopy, and electrochemical methods. The results reported herein provide the first comprehensive study of the relationship between the physical and chemical structure and electronic properties of a diamond OTE and the electrode's electrochemical activity. PMID- 27243960 TI - Electronic Coupling between Two Covalently Bonded Dimolybdenum Units Bridged by a Naphthalene Group. AB - Using 2,6-naphthalenedicarboxylate and its thiolated derivatives as bridging ligands, three Mo2 dimers of the type [Mo2(DAniF)3](E2CC10H6CE2)[Mo2(DAniF)3] (DAniF = N,N'-di-p-anisylformamidinate; E = O, S) have been synthesized and characterized by X-ray diffraction. These compounds can be generally formulated as [Mo2]-naph-[Mo2], where the complex unit [Mo2] ([Mo2(DAniF)3(MU-E2C)]) functions as an electron donor (acceptor) and the naphthalene (naph) group is the bridge. The mixed-valence (MV) complexes, generated by one-electron oxidation of the neutral precursors, display weak, very broad intervalence charge-transfer absorption bands in the near-to-mid-IR regions. The electronic coupling matrix elements for the MV complexes, Hab = 390-570 cm(-1), are calculated from the Mulliken-Hush equation, which fall between those for the phenyl (ph) and biphenyl (biph) analogues reported previously. The three series consisting of three complexes with the same [Mo2] units exhibit exponential decay of Hab as the bridge changes from ph to biph via naph, with decay factors of 0.21-0.17 A(-1). Therefore, it is evidenced that while the extent of the bridge conjugacy varies, the electronic coupling between the two [Mo2] units is dominated by the Mo2...Mo2 separation. The absorption band energies for metal-to-ligand charge transfer are in the middle of those for the ph and biph analogues, which is consistent with variation of the HOMO-LUMO energy gaps for the complex series. These results indicate that the interplay of the bridge length and conjugacy is to affect the enegy for charge transfer crossing the intervening moiety, in accordance with a superechange mechanism. PMID- 27243962 TI - Exchange-Correlation Effects for Noncovalent Interactions in Density Functional Theory. AB - In this article, we develop an understanding of how errors from exchange correlation functionals affect the modeling of noncovalent interactions in dispersion-corrected density-functional theory. Computed CCSD(T) reference binding energies for a collection of small-molecule clusters are decomposed via a molecular many-body expansion and are used to benchmark density-functional approximations, including the effect of semilocal approximation, exact-exchange admixture, and range separation. Three sources of error are identified. Repulsion error arises from the choice of semilocal functional approximation. This error affects intermolecular repulsions and is present in all n-body exchange-repulsion energies with a sign that alternates with the order n of the interaction. Delocalization error is independent of the choice of semilocal functional but does depend on the exact exchange fraction. Delocalization error misrepresents the induction energies, leading to overbinding in all induction n-body terms, and underestimates the electrostatic contribution to the 2-body energies. Deformation error affects only monomer relaxation (deformation) energies and behaves similarly to bond-dissociation energy errors. Delocalization and deformation errors affect systems with significant intermolecular orbital interactions (e.g., hydrogen- and halogen-bonded systems), whereas repulsion error is ubiquitous. Many-body errors from the underlying exchange-correlation functional greatly exceed in general the magnitude of the many-body dispersion energy term. A functional built to accurately model noncovalent interactions must contain a dispersion correction, semilocal exchange, and correlation components that minimize the repulsion error independently and must also incorporate exact exchange in such a way that delocalization error is absent. PMID- 27243961 TI - Insight into different environmental niches adaptation and allergenicity from the Cladosporium sphaerospermum genome, a common human allergy-eliciting Dothideomycetes. AB - Cladosporium sphaerospermum, a dematiaceous saprophytic fungus commonly found in diverse environments, has been reported to cause allergy and other occasional diseases in humans. However, its basic biology and genetic information are largely unexplored. A clinical isolate C. sphaerospermum genome, UM 843, was re sequenced and combined with previously generated sequences to form a model 26.89 Mb genome containing 9,652 predicted genes. Functional annotation on predicted genes suggests the ability of this fungus to degrade carbohydrate and protein complexes. Several putative peptidases responsible for lung tissue hydrolysis were identified. These genes shared high similarity with the Aspergillus peptidases. The UM 843 genome encodes a wide array of proteins involved in the biosynthesis of melanin, siderophores, cladosins and survival in high salinity environment. In addition, a total of 28 genes were predicted to be associated with allergy. Orthologous gene analysis together with 22 other Dothideomycetes showed genes uniquely present in UM 843 that encode four class 1 hydrophobins which may be allergens specific to Cladosporium. The mRNA of these hydrophobins were detected by RT-PCR. The genomic analysis of UM 843 contributes to the understanding of the biology and allergenicity of this widely-prevalent species. PMID- 27243963 TI - The Network Spinal Wave as a Central Pattern Generator. AB - OBJECTIVES: This article explains the research on a unique spinal wave visibly observed in association with network spinal analysis care. Since 1997, the network wave has been studied using surface electromyography (sEMG), characterized mathematically, and determined to be a unique and repeatable phenomenon. METHODS: The authors provide a narrative review of the research and a context for the network wave's development. RESULTS: The sEMG research demonstrates that the movement of the musculature of the spine during the wave phenomenon is electromagnetic and mechanical. The changes running along the spine were characterized mathematically at three distinct levels of care. Additionally, the wave has the mathematical properties of a central pattern generator (CPG). CONCLUSIONS: The network wave may be the first CPG discovered in the spine unrelated to locomotion. The mathematical characterization of the signal also demonstrates coherence at a distance between the sacral to cervical spine. According to mathematical engineers, based on studies conducted a decade apart, the wave itself is a robust phenomenon and the detection methods for this coherence may represent a new measure for central nervous system health. This phenomenon has implications for recovery from spinal cord injury and for reorganizational healing development. PMID- 27243964 TI - A Novel Destabilizing Domain Based on a Small-Molecule Dependent Fluorophore. AB - Tools that can directly regulate the activity of any protein-of-interest are valuable in the study of complex biological processes. Herein, we describe the development of a novel protein domain that exhibits small molecule-dependent stability and fluorescence based on the bilirubin-inducible fluorescent protein, UnaG. When genetically fused to any protein-of-interest, this fluorescent destabilizing domain (FDD) confers its instability to the entire fusion protein, facilitating the rapid degradation of the fusion. In the presence of its cognate ligand bilirubin (BR), the FDD fusion becomes stable and fluorescent. This new chemical genetic tool allows for rapid, reversible, and tunable control over the stability and fluorescence of a wide range of protein targets. PMID- 27243965 TI - What Difference Does a Visit Make? Changes in Animal Welfare Perceptions after Interested Citizens Tour a Dairy Farm. AB - Citizens' concerns about farm animal welfare are often dismissed on the assumption that they are not well informed about farming practices. We conducted exploratory surveys of interested citizens (n = 50) before and after a self guided tour of a 500-head dairy farm. 'Before' survey questions explored perceptions, concerns, and values about dairy cattle farming and welfare, in addition to a short knowledge-based quiz on dairy cattle husbandry. An 'after' survey explored the extent to which these constructs shifted after the tour. Before, most participants correctly answered quiz questions about general feeding and housing practices, but scores were low on questions about specific practices such as cow-calf separation. Participants considered several elements as necessary for a 'good' life for dairy cattle: fresh food and water, pasture access, gentle handling, space, shelter, hygiene, fresh air and sunshine, social companions, absence of stress, health, and safety from predators. These elements reflect a diverse conception of animal welfare that incorporates values for physical and mental well-being, natural living, and humane care. The visit had a mixed effect on perceptions of whether dairy cows had a 'good' life, improving perceptions for a quarter of participants, worsening perceptions in a third, with no shift in the remaining participants. The visit appeared to mitigate some concerns (e.g., provision of adequate food and water, gentle humane care) while reinforcing or eliciting others (e.g., lack of pasture access, early cow-calf separation). Moreover, animal welfare-relevant values held by participants (e.g., natural living, care) appeared to play an important role in influencing perceptions of farm practices. These results suggest that education and exposure to livestock farming may resolve certain concerns, but other concerns will likely persist, especially when practices conflict with deeply held values around animal care. PMID- 27243966 TI - Separation of intra- and intermolecular contributions to the PELDOR signal. AB - Pulsed Electron-electron Double Resonance (PELDOR) is commonly used to measure distances between native paramagnetic centers or spin labels attached to complex biological macromolecules. In PELDOR the energies of electron magnetic dipolar interactions are measured by analyzing the oscillation frequencies of the recorded time resolved signal. Since PELDOR is an ensemble method, the detected signal contains contributions from intramolecular, as well as intermolecular electron spin interactions. The intramolecular part of the signal contains the information about the structure of the studied molecules, thus it is very important to accurately separate intra- and intermolecular contributions to the total signal. This separation can become ambiguous, when the length of the PELDOR signal is not much longer than twice the oscillation period of the signal. In this work we suggest a modulation depth scaling method, which can use short PELDOR signals in order to extract the intermolecular contribution. Using synthetic data we demonstrate the advantages of the new approach and analyze its stability with regard to signal noise. The method was also successfully tested on experimental data of three systems measured at Q-Band frequencies, two model compounds in deuterated and protonated solvents and one biological sample, namely BetP. The application of the new method with an assigned value of the signal modulation depth enables us to determine the interspin distances in all cases. This is especially interesting for the model compound with an interspin distance of 5.2nm in the protonated solvent and the biological sample, since an accurate separation of the intra- and intermolecular PELDOR signal contributions would be difficult with the standard approach in those cases. PMID- 27243967 TI - Does changing social influence engender changes in alcohol intake? A meta analysis. AB - OBJECTIVE: Past research has suggested that social influences on drinking can be manipulated with subsequent reductions in alcohol intake. However, the experimental evidence for this and the best strategies to positively change these social influences have not been meta-analyzed. This research addressed these gaps. METHOD: Randomized controlled trials testing social influence-based interventions on adults' drinking were systematically reviewed and meta-analyzed. The behavior change techniques used in each study were coded and the effect sizes showing the impact of each intervention on (a) social influence and (b) alcohol intake were calculated. Metaregressions identified the association between these effect sizes, as well as the effect of specific behavior change techniques on social influences. RESULTS: Forty-one studies comprising 17,445 participants were included. Changes in social influences were significantly associated with changes in alcohol intake. However, even moderate-to-large changes in social influences corresponded with only a small change in drinking behavior and changing social influences did not reduce alcohol-related problems. Providing normative information about others' behavior and experiences was the most effective technique to change social influences. CONCLUSIONS: Social influences and normative beliefs can be changed in drinkers, particularly by providing normative information about how much others' drink. However, even generating large changes in these constructs are likely to engender only small changes in alcohol intake. (PsycINFO Database Record PMID- 27243968 TI - A case of intensive care unit-acquired weakness after emergency surgery for acute abdomen. AB - INTRODUCTION: Surgeons often perform surgery for patients who are critically ill. Intensive care unit (ICU)-acquired weakness (ICUAW) is a condition in which systemic and prolonged muscle weakness occurs and causes worse short-term and long-term outcomes. PRESENTATION OF CASE: A 60-year-old woman with sudden nausea and vomiting presented to our hospital and developed shock. Abdominal CT showed thickness of the descending colon and ascites. She was diagnosed with sepsis due to descending colon cancer. Colectomy of the descending colon was performed due to necrosis, and a stoma was created. After surgery, she received intensive care in the ICU. It was difficult to wean her from the ventilator, and she developed severe flaccid weakness of the limbs. Her Medical Research Council (MRC) sum score was 0. Since other organic disorders causing prolonged paralysis were excluded, she was finally diagnosed as having ICUAW. Active rehabilitation, nutritional support, and glycemic control were continued. Now, 6 months after surgery, her MRC score has improved to 30. DISCUSSION: The treatment for ICUAW has been reported to include recovery from the critical illness, early rehabilitation, and nutritional support, and it requires close cooperation among health care providers. CONCLUSION: All physicians and surgeons who care for critically ill patients should take active steps to diagnose ICUAW in order to avoid deterioration of patients' activities of daily living. PMID- 27243970 TI - Whole-exome sequencing of a family with local anesthetic resistance. AB - BACKGROUND: Local anesthetics (LA) work by blocking sodium conductance through voltage-gated sodium channels. Complete local anesthetic resistance is infrequent, and the cause is unknown. Genetic variation in sodium channels is a potential mechanism for local anesthetic resistance. A patient with a history of inadequate loss of sensation following LA administration underwent an ultrasound guided brachial plexus nerve block with a complete failure of the block. We hypothesized that LA resistance is due to a variant form of voltage-gated sodium channel. METHODS: Whole-Exome Sequencing. The patient and her immediate family provided consent for exome sequencing, and they were screened with a questionnaire to identify family members with a history of LA resistance. Exome sequencing results for four individuals were referenced to the 1000 Genomes Project and the NHLBI ESP to identify variants associated with local anesthetic resistance present in less than 1% of the general population and located in functional regions of the genome. RESULTS: Exome sequencing of the four family members identified one genetic variant in the voltage-gated sodium channel shared by the three individuals with LA resistance but not present in the unaffected family member. Specifically, we noted the A572D mutation in the SCN5A gene encoding for Nav1.5. CONCLUSIONS: We identified a genetic variant that is associated with LA resistance in the gene encoding for Nav1.5. We also demonstrate that Nav1.5 is present in human peripheral nerves to support the plausibility that an abnormal form of the Nav1.5 protein could be responsible for the observed local anesthetic resistance. PMID- 27243969 TI - Flavin Derivatives with Tailored Redox Properties: Synthesis, Characterization, and Electrochemical Behavior. AB - This study establishes structure-property relationships for four synthetic flavin molecules as bioinspired redox mediators in electro- and photocatalysis applications. The studied flavin compounds were disubstituted with polar substituents at the N1 and N3 positions (alloxazine) or at the N3 and N10 positions (isoalloxazines). The electrochemical behavior of one such synthetic flavin analogue was examined in detail in aqueous solutions of varying pH in the range from 1 to 10. Cyclic voltammetry, used in conjunction with hydrodynamic (rotating disk electrode) voltammetry, showed quasi-reversible behavior consistent with freely diffusing molecules and an overall global 2e(-) , 2H(+) proton-coupled electron transfer scheme. UV/Vis spectroelectrochemical data was also employed to study the pH-dependent electrochemical behavior of this derivative. Substituent effects on the redox behavior were compared and contrasted for all the four compounds, and visualized within a scatter plot framework to afford comparison with prior knowledge on mostly natural flavins in aqueous media. Finally, a preliminary assessment of one of the synthetic flavins was performed of its electrocatalytic activity toward dioxygen reduction as a prelude to further (quantitative) studies of both freely diffusing and tethered molecules on various electrode surfaces. PMID- 27243971 TI - Basics to perform and present statistical analyses in scientific biomedical reports Part 1. PMID- 27243972 TI - Videolaryngoscopes: can we finally get the view around the corner? PMID- 27243973 TI - Correction: Linking Genetic Variation in Adaptive Plant Traits to Climate in Tetraploid and Octoploid Basin Wildrye [Leymus cinereus (Scribn. & Merr.) A. Love] in the Western U.S. AB - [This corrects the article DOI: 10.1371/journal.pone.0148982.]. PMID- 27243974 TI - Targeted Next Generation Sequencing in Patients with Inborn Errors of Metabolism. AB - BACKGROUND: Next-generation sequencing (NGS) technology has allowed the promotion of genetic diagnosis and are becoming increasingly inexpensive and faster. To evaluate the utility of NGS in the clinical field, a targeted genetic panel approach was designed for the diagnosis of a set of inborn errors of metabolism (IEM). The final aim of the study was to compare the findings for the diagnostic yield of NGS in patients who presented with consistent clinical and biochemical suspicion of IEM with those obtained for patients who did not have specific biomarkers. METHODS: The subjects studied (n = 146) were classified into two categories: Group 1 (n = 81), which consisted of patients with clinical and biochemical suspicion of IEM, and Group 2 (n = 65), which consisted of IEM cases with clinical suspicion and unspecific biomarkers. A total of 171 genes were analyzed using a custom targeted panel of genes followed by Sanger validation. RESULTS: Genetic diagnosis was achieved in 50% of patients (73/146). In addition, the diagnostic yield obtained for Group 1 was 78% (63/81), and this rate decreased to 15.4% (10/65) in Group 2 (X2 = 76.171; p < 0.0001). CONCLUSIONS: A rapid and effective genetic diagnosis was achieved in our cohort, particularly the group that had both clinical and biochemical indications for the diagnosis. PMID- 27243975 TI - HMGB1 Induces Secretion of Matrix Vesicles by Macrophages to Enhance Ectopic Mineralization. AB - Numerous clinical conditions have been linked to ectopic mineralization (EM). This process of pathological biomineralization is complex and not fully elucidated, but thought to be started within matrix vesicles (MVs). We hypothesized that high mobility group box 1 (HMGB1), a cytokine associated with biomineralizing process under physiological and pathological conditions, induces EM via promoting MVs secretion from macrophages. In this study, we found that HMGB1 significantly promoted secretion of MVs from macrophages and subsequently led to mineral deposition in elevated Ca/Pi medium in vitro. Transmission electron microscopy of calcifying MVs showed formation of hydroxyapatite crystals in the vesicle interior. Subcutaneous injection into mice with MVs derived from HMGB1-treated cells showed a greater potential to initiate regional mineralization. Mechanistic experiments revealed that HMGB1 activated neutral sphingomyelinase2 (nSMase2) that involved the receptor for advanced glycation end products (RAGE) and p38 MAPK (upstream of nSMase2). Inhibition of nSMase2 with GW4869 or p38 MAPK with SB-239063 prevented MVs secretion and mineral deposition. Collectively, HMGB1 induces MVs secretion from macrophages at least in part, via the RAGE/p38 MAPK/nSMase2 signaling pathway. Our findings thus reveal a novel mechanism by which HMGB1 induces ectopic mineralization. PMID- 27243976 TI - Functional and Structural Analyses of CYP1B1 Variants Linked to Congenital and Adult-Onset Glaucoma to Investigate the Molecular Basis of These Diseases. AB - Glaucoma, the leading cause of irreversible blindness, appears in various forms. Mutations in CYP1B1 result in primary congenital glaucoma (PCG) by an autosomal recessive mode of inheritance while it acts as a modifier locus for primary open angle glaucoma (POAG). We investigated the molecular basis of the variable phenotypes resulting from the defects in CYP1B1 by using subclones of 23 CYP1B1 mutants reported in glaucoma patients, in a cell based system by measuring the dual activity of the enzyme to metabolize both retinol and 17beta-estradiol. Most variants linked to POAG showed low steroid metabolism while null or very high retinol metabolism was observed in variants identified in PCG. We examined the translational turnover rates of mutant proteins after the addition of cycloheximide and observed that the levels of enzyme activity mostly corroborated the translational turnover rate. We performed extensive normal mode analysis and molecular-dynamics-simulations-based structural analyses and observed significant variation of fluctuation in certain segmental parts of the mutant proteins, especially at the B-C and F-G loops, which were previously shown to affect the dynamic behavior and ligand entry/exit properties of the cytochrome P450 family of proteins. Our molecular study corroborates the structural analysis, and suggests that the pathologic state of the carrier of CYP1B1 mutations is determined by the allelic state of the gene. To our knowledge, this is the first attempt to dissect biological activities of CYP1B1 for correlation with congenital and adult onset glaucomas. PMID- 27243977 TI - Life-History Traits of Spodoptera frugiperda Populations Exposed to Low-Dose Bt Maize. AB - Exposure to Bacillus thuringiensis (Bt) toxins in low- and moderate-dose transgenic crops may induce sublethal effects and increase the rate of Bt resistance evolution, potentially compromising control efficacy against target pests. We tested this hypothesis using the fall armyworm Spodoptera frugiperda, a major polyphagous lepidopteran pest relatively tolerant to Bt notorious for evolving field-relevant resistance to single-gene Bt maize. Late-instar larvae were collected from Bt Cry1Ab and non-Bt maize fields in five locations in Brazil, and their offspring was compared for survival, development, and population growth in rearing environment without and with Cry1Ab throughout larval development. Larval survival on Cry1Ab maize leaves varied from 20 to 80% among the populations. Larvae reared on Cry1Ab maize had seven-day delay in development time in relation to control larvae, and such delay was shorter in offspring of armyworms from Cry1Ab maize. Population growth rates were 50-70% lower for insects continuously exposed to Cry1Ab maize relative to controls, showing the population-level effect of Cry1Ab, which varied among the populations and prior exposure to Cry1Ab maize in the field. In three out of five populations, armyworms derived from Bt maize reared on Cry1Ab maize showed higher larval weight, faster larval development and better reproductive performance than the armyworms derived from non-Bt maize, and one of these populations showed better performance on both Cry1Ab and control diets, indicating no fitness cost of the resistance trait. Altogether, these results indicate that offspring of armyworms that developed on field-grown, single-gene Bt Cry1Ab maize had reduced performance on Cry1Ab maize foliage in two populations studied, but in other three populations, these offspring had better overall performance on the Bt maize foliage than that of the armyworms from non-Bt maize fields, possibly because of Cry1Ab resistance alleles in these populations. Implications of these findings for resistance management of S. frugiperda in Bt crops are discussed. PMID- 27243978 TI - Are all safety behaviours created equal? A comparison of novel and routinely used safety behaviours in obsessive-compulsive disorder. AB - Contamination fear is one of the most common symptoms of obsessive-compulsive disorder (OCD). Exposure and response prevention (ERP) is effective for OCD, but a significant minority of treatment-seeking individuals refuse ERP entirely or drop out prematurely. Research suggests that safety behaviour (SB) may enhance the acceptability of ERP; however, questions remain about how to incorporate SB into existing treatments. Clinical participants with OCD and contamination fear (N = 57) were randomized to receive an exposure session with no SB (ERP), a routinely used SB (RU), or a never-used SB (NU). Significant reductions in contamination fear severity were observed in all conditions. Although omnibus comparisons were only marginally significant, pairwise comparisons revealed some condition differences. NU demonstrated significantly lower self-reported contamination fear severity at post-exposure, as well as marginally higher treatment acceptability ratings. Findings suggest that exposure with SB may be effective and acceptable, and are discussed in terms of cognitive-behavioural theory and treatment of anxiety and related disorders. PMID- 27244040 TI - Two new xyloketals from the endophytic fungus Endomelanconiopsis endophytica derived from medicinal plant Ficus hirta. AB - Chemical examination of the liquid culture of Endomelanconiopsis endophytica A326 isolated from the Chinese folk medicine Ficus hirta resulted in the isolation of two new xyloketals named xyloketals K and L (1-2) and three known analogs (3-5) including a new natural product (5). Their structures were determined on the basis of extensive spectroscopic analysis. All compounds were evaluated for their cytotoxic activities against the SF-268, MCF-7, NCI-H460, and HepG-2 tumor cell lines. Nonetheless, no significant activity was observed. PMID- 27244041 TI - Plant-Derived Urease Inhibitors as Alternative Chemotherapeutic Agents. AB - Inhibition of the metalloenzyme urease has important pharmacologic applications in the field of antiulcer and antigastric cancer agents. Urease is involved in many serious infections caused by Helicobacter pylori in the gastric tract as well as by Proteus and related species in the urinary tract. Although numerous studies have described several novel urease inhibitors (UIs) used for the treatment of gastric and urinary infections, all these compounds have exhibited severe side effects, toxicity, and instability. Therefore, to overcome such problems, it is necessary to search for new sources of UIs, such as natural products, that provide reduced side effects, low toxicity, greater stability, and bioavailability. As limited studies have been conducted on plant-derived UIs, this paper aims to highlight and summarize the most promising compounds isolated and identified from plants, such as terpenoids, phenolic compounds, alkaloids, and other substances with inhibitory activities against plant and bacterial ureases; these are in vitro and in vivo studies with an emphasis on structure activity relationship studies and types of inhibition that show high and promising levels of anti-urease activity. This will aid medicinal chemists in the design and synthesis of novel and pharmacologically potent UIs useful for the development of antiulcer drugs. PMID- 27244043 TI - DFT Studies of SN2 Dechlorination of Polychlorinated Biphenyls. AB - Nucleophilic dechlorination of all 209 PCBs congeners by ethylene glycol anion has been studied theoretically at the DFT level. The obtained Gibbs free energies of activation are in the range 7-22 kcal/mol. The reaction Gibbs free energies indicate that all reactions are virtually irreversible. Due to geometric constrains these reactions undergo rather untypical attack with attacking oxygen atom being nearly perpendicular to the attacked C-Cl bond. The most prone to substitution are chlorine atoms that occupy ortho- (2, 2', 6, 6') positions. These results provide extensive information on the PEG/KOH dependent PCBs degradation. They can also be used in further developments of reaction class transition state theory (RC-TST) for description of complex reactive systems encountered for example in combustion processes. PMID- 27244042 TI - Synthesis of (+)-7,20-Diisocyanoadociane and Liver-Stage Antiplasmodial Activity of the Isocyanoterpene Class. AB - 7,20-Diisocyanoadociane, a scarce marine metabolite with potent antimalarial activity, was synthesized as a single enantiomer in 13 steps from simple building blocks (17 linear steps). Chemical synthesis enabled identification of isocyanoterpene antiplasmodial activity against liver-stage parasites, which suggested that inhibition of heme detoxification does not exclusively underlie the mechanism of action of this class. PMID- 27244044 TI - Comparison of Low-Value Care in Medicaid vs Commercially Insured Populations. AB - IMPORTANCE: Reducing unnecessary tests and treatments is a potentially promising approach for improving the value of health care. However, relatively little is known about whether insurance type or local practice patterns are associated with delivery of low-value care. OBJECTIVES: To compare low-value care in the Medicaid and commercially insured populations, test whether provision of low-value care is associated with insurance type, and assess whether local practice patterns are associated with the provision of low-value care. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study of claims data from the Oregon Division of Medical Assistance Programs and the Oregon All-Payer All-Claims database included Medicaid and commercially insured adults aged 18 to 64 years. The study period was January 1, 2013, through December 31, 2013. MAIN OUTCOMES AND MEASURES: Low-value care was assessed using 16 claims-based measures. Logistic regression was used to test the association between Medicaid vs commercial insurance coverage and low-value care and the association between Medicaid and commercial low-value care rates within primary care service areas (PCSAs). RESULTS: This study included 286 769 Medicaid and 1 376 308 commercial enrollees in 2013. Medicaid enrollees were younger (167 847 [58.5%] of Medicaid enrollees were aged 18-34 years vs 505 628 [36.7%] of those with commercial insurance) but generally had worse health status compared with those with commercial insurance. Medicaid enrollees were also more likely to be female (180 363 [62.9%] vs 702 165 [51.0%]) and live in a rural area (120 232 [41.9%] vs 389 964 [28.3%]). A total of 10 304 of 69 338 qualifying Medicaid patients (14.9%; 95% CI, 14.6%-15.1%) received at least 1 low-value service during 2013; the corresponding rate for commercially insured patients was 35 739 of 314 023 (11.4%; 95% CI, 11.3%-11.5%). No consistent association was found between insurance type and low-value care. Compared with commercial patients, Medicaid patients were more likely to receive low-value care for 10 measures and less likely to receive low-value care for 5 others. For 7 of 11 low-value care measures, Medicaid patients were significantly more likely to receive low-value care if they resided in a PCSA with a higher rate of low-value care for commercial patients. CONCLUSIONS AND RELEVANCE: Oregon Medicaid and commercially insured patients received moderate amounts of low-value care in 2013. No consistent association was found between insurance type and low value care. However, Medicaid and commercial rates of low-value care were associated with one another within PCSAs. Low-value care may be more closely related to local practice patterns than to reimbursement generosity or insurance benefit structures. PMID- 27244045 TI - Neonatal Abstinence Syndrome: Presentation and Treatment Considerations. AB - This clinical case conference discusses the treatment of a pregnant woman with opioid use disorder in a comprehensive care program that includes buprenorphine pharmacotherapy. The presentation summarizes common experiences that pregnant women who receive buprenorphine pharmacotherapy face, and also what their prenatally opioid-exposed children confront in the immediate postpartum period. It describes the elements of a successful comprehensive care model and corollary neonatal abstinence syndrome treatment regimen. Expert commentary is included on issues that arise in the buprenorphine induction and maintenance throughout the prenatal and postpartum periods and in the treatment of co-occurring mental health problems during both the prenatal and postpartum periods, particularly the treatment of depression. There is also expert commentary on the care of opioid exposed neonates, with attention to the treatment for neonatal abstinence syndrome. PMID- 27244046 TI - iRGD peptide as effective transporter of CuInZnxS2+x quantum dots into human cancer cells. AB - In this paper, iRGD peptide-mediated quantum dots (QDs) delivery was studied. In the first step, dodecanethiol-capped CuInZnxS2+x (ZCIS) QDs were prepared and subsequently transferred into water using a standard and facile ligand exchange approach involving 3-mercaptopropionic acid (MPA). ZCIS@MPA nanocrystals possess a photoluminescence quantum yield (PL QY) of 25%, a PL emission centered at ca. 640nm and low distributions in size and shape. Next, the iRGD peptide was electrostatically associated to ZCIS@MPA QDs. After cytotoxicity evaluation, the tumor-targeting and penetrating activities of the iRGD/QD assembly were investigated by confocal microscopy. The experiments performed on various cancer cell lines revealed a high penetration ability of the assembly, while the bare QDs were not internalized. Additionally, imaging experiments were conducted on three-dimensional multicellular tumor spheroids in order to mimic the tumor microenvironment in vivo. iRGD/QD assemblies were found to be evenly distributed throughout the whole HeLa spheroid contrary to normal cells where they were not present. Therefore, iRGD/QD assemblies have a great potential to be used as targeted imaging agents and/or nanocarriers specific to cancer cells. PMID- 27244047 TI - Development of an inhalable, stimuli-responsive particulate system for delivery to deep lung tissue. AB - Lung cancer, the deadliest solid tumor among all types of cancer, remains difficult to treat. This is a result of unavoidable exposure to carcinogens, poor diagnosis, the lack of targeted drug delivery platforms and limitations associated with delivery of drug to deep lung tissues. Development of a non invasive, patient-convenient formula for the targeted delivery of chemotherapeutics to cancer in deep lung tissue is the aim of this study. The formulation consisted of inhalable polyvinylpyrrolidone (PVP)/maltodextrin (MD) based microparticles (MPs) encapsulating chitosan (CS) nanoparticles (NPs) loaded with either drug only or drug and magnetic nanoparticles (MNPs). Drug release from CS NPs was enhanced with the aid of MNPs by a factor of 1.7 in response to external magnetic field. Preferential toxicity by CS NPs was shown towards tumor cells (A549) in comparison to cultured fibroblasts (L929). The prepared spray freeze dried (SFD) powders for CS NPs and CS MNPs were of the same size at ~6MUm. They had a fine particle fraction (FPF<=5.2MUm) of 40-42% w/w and mass median aerodynamic diameter (MMAD) of 5-6MUm as determined by the Next Generation Impactor (NGI). SFD-MPs of CS MNPs possess higher MMAD due to the high density associated with encapsulated MNPs. The developed formulation demonstrates several capabilities including tissue targeting, controlled drug release, and the possible imaging and diagnostic values (due to its MNPs content) and therefore represents an improved therapeutic platform for drug delivery to cancer in deep lung tissue. PMID- 27244048 TI - In vivo pharmacokinetics, biodistribution and the anti-tumor effect of cyclic RGD modified doxorubicin-loaded polymers in tumor-bearing mice. AB - In our previous study, we successfully produced and characterized a multifunctional drug delivery system with doxorubicin (RC/GO/DOX), which was based on graphene oxide (GO) and cyclic RGD-modified chitosan (RC). Its characteristics include: pH-responsiveness, active targeting of hepatocarcinoma cells, and efficient loading with controlled drug release. Here, we report the pharmacokinetics, biodistribution, and anti-tumor efficacy of RC/GO/DOX polymers in tumor-bearing nude mice. The objective of this study is to assess its targeting potential for tumors. Pharmacokinetic and biodistribution profiles demonstrated that tumor accumulation of RC/GO/DOX polymers was almost three times higher than the others, highlighting the efficacy of the active targeting strategy. Furthermore, the tumor inhibition rate of RC/GO/DOX polymers was 56.64%, 2.09 and 2.93 times higher than that of CS/GO/DOX polymers (without modification) and the DOX solution, respectively. Anti-tumor efficacy results indicated that the tumor growth was better controlled by RC/GO/DOX polymers than the others. Hematoxylin and eosin (H&E) staining showed remarkable changes in tumor histology. Compared with the saline group, the tumor section from the RC/GO/DOX group revealed a marked increase in the quantity of apoptotic and necrotic cells, and a reduction in the quantity of the blood vessels. Together, these studies show that this new system could be regarded as a suitable form of DOX-based treatment of the hepatocellular carcinoma. PMID- 27244049 TI - Physical measurements of Chinese children in Hong Kong-A pilot study in preschools and kindergartens. AB - Normal growth is essential to a developing child. Most syndromes with dysmorphic features demonstrate recognizable patterns of disproportionate growth, thus physical measurements are an important aspect of patient evaluation. Delineating the abnormal growth pattern depends greatly on the accuracy of the normal range. However, the currently available reference data are restricted in terms of ethnicity and geographical location, hence may not be applicable to all children worldwide. In Hong Kong, reference data are limited only to the neonatal period. The aim of our pilot study is to obtain a set of region-specific physical measurement data for Chinese children in Hong Kong. Two to six year olds were recruited from preschools and kindergartens in different regions of Hong Kong. Twenty-six parameters found in previous publications were measured with minor modifications. Three medical personnel trained by a clinical geneticist obtained these parameters. Satisfactory inter-rater reliability was achieved in a training cohort prior to the study. Raw measurement data collected were normalized and fitted into growth curves modeled by LMS method. We recruited 448 children (55.6% male) between 2 and 6 years old from five preschools and kindergartens. Growth curves with essential percentile lines were drawn. Significant differences were identified in 11 parameters when compared with Caucasian children, including canthal distances and facial width/height. Our current pilot study presents the first local- and ethnicity-specific data on physical measurements of 2-6 year olds. Our findings highlighted the substantial ethnic variability in physical measurements and the need for an ethnic-specific reference for Chinese children. (c) 2016 Wiley Periodicals, Inc. PMID- 27244050 TI - Gene Expression Deconvolution for Uncovering Molecular Signatures in Response to Therapy in Juvenile Idiopathic Arthritis. AB - Gene expression-based signatures help identify pathways relevant to diseases and treatments, but are challenging to construct when there is a diversity of disease mechanisms and treatments in patients with complex diseases. To overcome this challenge, we present a new application of an in silico gene expression deconvolution method, ISOpure-S1, and apply it to identify a common gene expression signature corresponding to response to treatment in 33 juvenile idiopathic arthritis (JIA) patients. Using pre- and post-treatment gene expression profiles only, we found a gene expression signature that significantly correlated with a reduction in the number of joints with active arthritis, a measure of clinical outcome (Spearman rho = 0.44, p = 0.040, Bonferroni correction). This signature may be associated with a decrease in T-cells, monocytes, neutrophils and platelets. The products of most differentially expressed genes include known biomarkers for JIA such as major histocompatibility complexes and interleukins, as well as novel biomarkers including alpha defensins. This method is readily applicable to expression datasets of other complex diseases to uncover shared mechanistic patterns in heterogeneous samples. PMID- 27244052 TI - Light-Emitting Diode Irradiation (640 nm) Regulates Keratinocyte Migration and Cytoskeletal Reorganization Via Hypoxia-Inducible Factor-1alpha. AB - OBJECTIVE: The objective of this study was to determine the effect of light emitting diode (LED) irradiation on the migration and proliferation of keratinocytes. BACKGROUND DATA: Keratinocytes play a key role in re epithelialization during wound healing; it is speculated that low-level LED therapy might improve keratinocyte migration and proliferation. MATERIALS AND METHODS: Human keratinocyte cells (HKCs) were isolated from child or adult foreskins and irradiated with LED light with a wavelength of 640 nm and a dosage of 12 or 24 J/cm(2). Cell motility, migration, and proliferation were examined using live cell imaging, scratch assay, and a colorimetric cell counting assay, respectively. Hypoxia-inducible factor-1alpha (HIF-1alpha) protein levels were analyzed by using Western blotting. Filamentous actin (F-actin) was stained by phalloidin. YC-1 [3-(5-hydroxymethyl-2-furyl)-1-benzylindazole] was used as an HIF-1 inhibitor, and CoCl2 (cobalt chloride) and DMOG (dimethyloxaloyl glycine) are HIF-1alpha activators. RESULTS: LED irradiation significantly promoted cell motility and migration, but did not significantly influence cell proliferation in HKCs. Furthermore, LED irradiation resulted in a reorganization of cellular F actin and a dramatic upregulation of HIF-1alpha expression. Suppression of HIF 1alpha using the compound YC-1 prevented reorganization of the actin cytoskeleton following LED irradiation, suggesting that the effect of LED irradiation on the cytoskeleton is mediated through HIF-1alpha. Conversely, chemical activation of HIF-1alpha via DMOG or CoCl2 resulted in a reorganization of F-actin. CONCLUSIONS: LED irradiation may increase keratinocyte migration via HIF-1alpha dependent cytoskeletal reorganization. PMID- 27244053 TI - Fixed dilated pupils: Clues to an ACTA2 mutation allowing early stroke prevention. PMID- 27244051 TI - Elucidation of the Covalent and Tertiary Structures of Biologically Active Ts3 Toxin. AB - Ts3 is an alpha scorpion toxin from the venom of the Brazilian scorpion Tityus serrulatus. Ts3 binds to the domain IV voltage sensor of voltage-gated sodium channels (Nav ) and slows down their fast inactivation. The covalent structure of the Ts3 toxin is uncertain, and the structure of the folded protein molecule is unknown. Herein, we report the total chemical synthesis of four candidate Ts3 toxin protein molecules and the results of structure-activity studies that enabled us to establish the covalent structure of biologically active Ts3 toxin. We also report the synthesis of the mirror image form of the Ts3 protein molecule, and the use of racemic protein crystallography to determine the folded (tertiary) structure of biologically active Ts3 toxin by X-ray diffraction. PMID- 27244054 TI - Prenatal Antidepressant Use and Risk of Autism Spectrum Disorders in the Children. PMID- 27244056 TI - Vital Signs: Core Metrics for Health and Health Care Progress. PMID- 27244055 TI - HIV Testing among Patients with Presumptive Tuberculosis: How Do We Implement in a Routine Programmatic Setting? Results of a Large Operational Research from India. AB - BACKGROUND: In March 2012, World Health Organization recommended that HIV testing should be offered to all patients with presumptive TB (previously called TB suspects). How this is best implemented and monitored in routine health care settings in India was not known. An operational research was conducted in Karnataka State (South India, population 64 million, accounts for 10% of India's HIV burden), to test processes and learn results and challenges of screening presumptive TB patients for HIV within routine health care settings. METHODS: In this cross-sectional study conducted between January-March 2012, all presumptive TB patients attending public sector sputum microscopy centres state-wide were offered HIV testing by the laboratory technician, and referred to the nearest public sector HIV counselling and testing services, usually within the same facility. The HIV status of the patients was recorded in the routine TB laboratory form and TB laboratory register. The laboratory register was compiled to obtain the number of presumptive TB patients whose HIV status was ascertained, and the number found HIV positive. Aggregate data on reasons for non-testing were compiled at district level. RESULTS: Overall, 115,308 patients with presumptive TB were examined for sputum smear microscopy at 645 microscopy centres state wide. Of these, HIV status was ascertained for 62,847(55%) among whom 7,559(12%) were HIV-positive, and of these, 3,034(40%) were newly diagnosed. Reasons for non testing were reported for 37,700(72%) of the 52,461 patients without HIV testing; non-availability of testing services at site of sputum collection was cited by health staff in 54% of respondents. Only 4% of patients opted out of HIV testing. CONCLUSION: Offering HIV testing routinely to presumptive TB patients detected large numbers of previously-undetected instances of HIV infection. Several operational challenges were noted which provide useful lessons for improving uptake of HIV testing in this important group. PMID- 27244057 TI - U.S. National Strategies and DoD Global Health Engagement. PMID- 27244058 TI - 30-Year-Old Man With Painless Forehead Swelling, Proptosis, and Diplopia. PMID- 27244059 TI - RE: Free-Tissue Transfer for the Reconstruction of War-Related Extremity Injuries: A Systematic Review of Current Practice. PMID- 27244060 TI - Factors Influencing Running-Related Musculoskeletal Injury Risk Among U.S. Military Recruits. AB - Running-related musculoskeletal injuries among U.S. military recruits negatively impact military readiness. Low aerobic fitness, prior injury, and weekly running distance are known risk factors. Physical fitness screening and remedial physical training (or discharging the most poorly fit recruits) before entry-level military training have tended to reduce injury rates while decreasing attrition, training, and medical costs. Incorporating anaerobic running sessions into training programs can offset decreased weekly running distance and decrease injury risk. Varying lower extremity loading patterns, stride length or cadence manipulation, and hip stability/strengthening programming may further decrease injury risk. No footstrike pattern is ideal for all runners; transitioning to forefoot striking may reduce risk for hip, knee, or tibial injuries, but increase risk for calf, Achilles, foot or ankle injuries. Minimal evidence associates running surfaces with injury risk. Footwear interventions should focus on proper fit and comfort; the evidence does not support running shoe prescription per foot type to reduce injury risk among recruits. Primary injury mitigation efforts should focus on physical fitness screening, remedial physical training (or discharge for unfit recruits), and continued inclusion of anaerobic running sessions to offset decreased weekly running distance. PMID- 27244061 TI - Prevalence of Staphylococcus aureus Colonization and Risk Factors for Infection Among Military Personnel in a Shipboard Setting. AB - Staphylococcal skin and soft tissue infections (SSTIs), especially those due to methicillin-resistant Staphylococcus aureus (MRSA) are an important public health issue for the military. Limited data exist regarding the prevalence of S. aureus colonization in the shipboard setting. We conducted a cross-sectional, observational study to determine the point prevalence of S. aureus colonization among military personnel onboard a naval vessel. Asymptomatic active duty personnel completed a survey for risk factors associated with colonization and SSTIs. Culture specimens were obtained from the anterior nares, pharynx, groin, and perirectal regions. MRSA isolates underwent testing for antimicrobial resistance, virulence factors, and pulsed-field type. 400 individuals were enrolled, 198 (49.5%) of whom were colonized with S. aureus, with MRSA identified in 14 participants (3.5%). No significant risk factors were associated with MRSA colonization. USA800 was the most common colonizing MRSA strain in the cohort and was detected in 10 participants (71%). Two participants (14%) were colonized with USA300 MRSA. In this first report of S. aureus epidemiology in a shipboard setting, we observed high rates of S. aureus and MRSA colonization. Longitudinal studies are needed to document the incident rates of S. aureus colonization during shipboard deployment and its impact on SSTI risk. PMID- 27244062 TI - Isolation of Rapidly Growing Nontuberculous Mycobacteria in Wounds Following Combat-Related Injury. AB - OBJECTIVES: Rapidly growing nontuberculous mycobacteria (RGNTM) have yet to be described in combat-related injuries. This study investigates the epidemiology, clinical findings, treatment, and outcomes of RGNTM infections among combat casualties wounded in Afghanistan from 2010 to 2012. METHODS: Patients with RGNTM were identified from the Department of Defense Trauma Registry through the Trauma Infectious Disease Outcomes Study. Trauma history, surgical management, and clinical data were collected. Six isolates from patients requiring antimycobacterial therapy were sequenced. RESULTS: Seventeen cases were identified. Six cases, predominantly associated with Mycobacterium abscessus, required aggressive debridement and a median of 180 days of multidrug antimycobacterial therapy that included clofazimine. M. abscessus isolates expressed the erythromycin resistance methylase (erm(41)) gene for inducible macrolide resistance, yet there were no clinical treatment failures when macrolides were utilized in combination therapy. No clonal similarity between M. abscessus isolates was found. Eleven cases had positive wound cultures, but did not require antimycobacterial therapy. The median duration of time of injury to first detection of a RGNTM was 57 days. CONCLUSIONS: This represents the first report of RGNTM infections in war-wounded patients. RGNTM should be recognized as potential pathogens in grossly infected combat wounds. Surgical debridement and multidrug antimycobacterial therapy, when clinically indicated, was associated with satisfactory clinical outcomes. PMID- 27244063 TI - Mental Health and Comorbidities in U.S. Military Members. AB - OBJECTIVES: Using data from a prospective cohort study of U.S. service members who joined after September 11, 2001 to determine incidence rates and comorbidities of mental and behavioral disorders. METHODS: Calculated age and sex adjusted incidence rates of mental and behavioral conditions determined by validated instruments and electronic medical records. RESULTS: Of 10,671 service members, 3,379 (32%) deployed between baseline and follow-up, of whom 49% reported combat experience. Combat deployers had highest incidence rates of post traumatic stress disorder (PTSD) (25 cases/1,000 person-years [PY]), panic/anxiety (21/1,000 PY), and any mental disorder (34/1,000 PY). Nondeployers had substantial rates of mental conditions (11, 13, and 18 cases/1,000 PY). Among combat deployers, 12% screened positive for mental disorder, 59% binge drinking, 16% alcohol problem, 19% cigarette smoking, and 20% smokeless tobacco at follow up. Of those with recent PTSD, 73% concurrently developed >1 incident mental or behavioral conditions. Of those screening positive for PTSD, 11% had electronic medical record diagnosis. CONCLUSIONS: U.S. service members joining during recent conflicts experienced high rates of mental and behavioral disorders. Highest rates were among combat deployers. Most cases were not represented in medical codes, suggesting targeted interventions are needed to address the burden of mental disorders among service members and Veterans. PMID- 27244064 TI - Personality Traits and Family Styles of Combat Medics in Training. AB - This descriptive study examines the relationship between four family types and five personality traits. The four family types are balanced, moderately balanced, midrange, and extreme. The five personality traits are extraversion, openness to experiences, agreeableness, emotional stability, and conscientiousness. Data were collected through anonymous questionnaires distributed to combat-naive Soldiers at the beginning of their advanced individual training. This study utilized the Family Adaptability and Cohesion Evaluation Scale1 and the Ten-Item Personality Inventory2 as measures. Overall the analyses found that participants classified as a balanced family type scored significantly higher on the personality traits of extraversion, agreeableness, and openness to experience than those classified in the family types of extreme, midrange, and moderately balanced. It appears that family types are associated with personality traits. This study opens doors to future research including looking at how family and personality types relate to each other in military units and personnel. PMID- 27244066 TI - Use of Assistive Technology for Cognition Among People With Traumatic Brain Injury: A Survey Study. AB - A survey was designed and administered in this study to assess the use of assistive technology for cognition (ATC), especially portable electronic ATC, among veterans with traumatic brain injury (TBI). The aim of the survey was to obtain information on current ATC devices and applications use, users' experience with different features of ATC, and relevant training/support for their ATC. Twenty-nine veterans with TBI participated in this study. Results showed that portable electronic ATC, especially smartphones and a variety of apps, were widely used by the participants to compensate for cognitive limitations. Portable electronic devices such as smartphones and smart pads received higher usability ratings than paper-based tools. More than 75% of participants did not go through a service delivery process for these electronic ATC. The information collected in the study provided a more updated picture of ATC use, especially portable electronic ATC use, among people with TBI. It also potentially informs the future development of ATC and supports the need for training and an appropriate acquisition process of portable electronic ATC devices. PMID- 27244065 TI - Recent Advances in Forward Surgical Team Training at the U.S. Army Trauma Training Department. AB - U.S. Army Forward Surgical Teams (FSTs) are elite, multidisciplinary units that are highly mobile, and rapidly deployable. The mission of the FST is to provide resuscitative and damage control surgery for stabilization of life-threatening injuries in austere environments. The Army Trauma Training Center began in 2001 at the University of Miami Ryder Trauma Center under the direction of COL T. E. Knuth, MC USA (Ret.), as a multimodality combination of lectures, laboratory exercises, and clinical experiences that provided the only predeployment mass casualty and clinical trauma training center for all FSTs. Each of the subsequent five directors has restructured the training based on dynamic feedback from trainees, current military needs, and on the rapid advances in combat casualty care. We have highlighted these evolutionary changes at the Army Trauma Training Center in previous reviews. Under the current director, LTC J. M. Seery, MC USA, there are new team-building exercises, mobile learning modules and simulators, and other alternative methods in the mass casualty exercise. This report summarizes the latest updates to the state of the art training since the last review. PMID- 27244067 TI - A Surgical Business Composite Score for Army Medicine. AB - Measuring surgical business performance for Army military treatment facilities is currently done through 6 business metrics developed by the Army Medical Command (MEDCOM) Surgical Services Service Line (3SL). Development of a composite score for business performance has the potential to simplify and synthesize measurement, improving focus for strategic goal setting and implementation. However, several considerations, ranging from data availability to submetric selection, must be addressed to ensure the score is accurate and representative. This article presents the methodology used in the composite score's creation and presents a metric based on return on investment and a measure of cases recaptured from private networks. PMID- 27244068 TI - Return to Duty Rates in Active Duty Service Members After Elective Surgery of the Lumbar Spine. AB - OBJECTIVES: The aim of this study is to define the percentage of military service members returned to active duty following elective lumbar spine surgery. METHODS: We reviewed 331 elective lumbar spine procedures performed on active duty service members over a 5-year period. All patients underwent a decompressive lumbar procedure with or without fusion. Return to duty (RTD) was our primary outcome, defined as no referral to a Medical Evaluation Board by the 12-month postoperative follow-up visit. All subject's final disposition was recorded as a binomial distribution and stratified by demographic parameters. Subgroup analysis comparing the return rates for specific procedures was performed. RESULTS: 232 patients met our study inclusion criteria. 136 underwent isolated decompressive procedures and 96 patients underwent fusion procedures. The overall RTD rate following elective lumbar spine surgery was 64% (n = 149) (95% confidence interval, CI [58, 70]). The RTD rate for isolated decompressive procedures was 63% (n = 86) (95% CI [55, 71]), and 66% (n = 63) (95% CI [56, 75]) after decompression with lumbar fusion. CONCLUSIONS: The RTD rate following elective lumbar spine surgery is 64%. When stratified by procedure type, isolated decompression procedures (63% RTD rate) and fusion procedures (66% RTD rate) displayed similar results. PMID- 27244069 TI - Incidence and Characteristics of Traumatic Shoulder Instability in Japanese Military Cadets. AB - Little is known regarding the incidence of the shoulder instability in Japan. The aim of this study was to evaluate the incidence of traumatic shoulder instability among Japanese military cadets. A prospective cohort study was performed to capture all traumatic shoulder instability events between 2009 and 2012 among cadets in a military educational academy of the Japan Self Defense Forces. The total number of cadets in the cohort was 5,402 (average age 20.6 years). The incidence of instability events, including dislocation or subluxation, was calculated. Chronicity, demographics of participants, mechanism of injury, and athletic events were also evaluated. The incidence of traumatic dislocation was 4.1/1,000 person-years and that of subluxation was 6.1/1,000 person-years. The incidence of primary dislocation or subluxation was 5.4/1,000 person-years and that of recurrent dislocation or subluxation was 4.7/1,000 person-years. Of first dislocations or subluxations, 92% occurred during sports activities, including after-school sports activities, military training, and gym classes. In conclusion, the overall incidence of shoulder instability events among Japanese military cadets was 10.3/1,000 person-years, and was extremely high. Most shoulder instability events occurred during sports activities, and a program to prevent such injuries during sports activities is necessary for young participants. PMID- 27244070 TI - Using Lean Six Sigma Methodology to Improve a Mass Immunizations Process at the United States Naval Academy. AB - Lean Six Sigma (LSS) is a process improvement methodology developed in the manufacturing industry to increase process efficiency while maintaining product quality. The efficacy of LSS application to the health care setting has not been adequately studied. This article presents a quality improvement project at the U.S. Naval Academy that uses LSS to improve the mass immunizations process for Midshipmen during in-processing. The process was standardized to give all vaccinations at one station instead of giving a different vaccination at each station. After project implementation, the average immunizations lead time decreased by 79% and staffing decreased by 10%. The process was shown to be in control with a capability index of 1.18 and performance index of 1.10, resulting in a defect rate of 0.04%. This project demonstrates that the LSS methodology can be applied successfully to the health care setting to make sustainable process improvements if used correctly and completely. PMID- 27244071 TI - Normal Weight Status in Military Service Members Was Associated With Intuitive Eating Characteristic. AB - The purpose of this study was to determine the relationship between individual weight status and intuitive eating or motivation for eating characteristics. Participants were predominantly white (57%), Army (91%), enlisted (72%), males (71%), with a mean age of 30 +/- 9 years and mean body mass index (BMI) of 27.0 +/- 4.2 kg/m(2). The cross-sectional, descriptive study included active duty service members (n = 295) recruited from Texas and Washington. Validated Motivation for Eating Scale (MFES) and Intuitive Eating Scale were administered and BMI (m/kg(2)) was dichotomized at <25 or >=25 kg/m(2). Descriptive, correlation, t-test, and logistic regression analysis were conducted for BMI category with demographic, lifestyle, and MFES/Intuitive Eating Scale scores (alpha = 0.05; 80% power). Thirty-six percent were normal BMI (22.7 +/- 1.6 kg/m(2)) and 64% were overweight/obese BMI (29.3 +/- 3.3 kg/m(2)). Mean BMI was 27.8 +/- 4.2 kg/m(2) (males) and 24.8 +/- 3.4 kg/m(2) (females) (p < 0.001). Physical MFES type was predominant (77% normal BMI vs. 66% overweight; p = 0.001). Males ate for physical rather than emotional reasons (p = 0.014). Each 1 point increase in Reliance on Internal Hunger Satiety Score was associated with 34% lower odds of being overweight. Disparity existed between sex and intuitive eating characteristic. Increasing awareness of eating influences may improve weight-related dietary behaviors. PMID- 27244072 TI - Installation Tobacco Control Programs in the U.S. Military. AB - Tobacco use prevalence is unacceptably high in the U.S. military, and the Department of Defense and service branches have implemented tobacco control policies and cessation programs. To explore aspects of programs regarded as exemplary by their services, we visited four installations, nominated by their service's health promotion leaders, and conducted interviews, observations, and focus groups. Installations included Naval Hospital Guam, Tripler Army Medical Center, MacDill Air Force Base, and the Naval Hospital at Marine Corps Air Ground Combat Center Twentynine Palms. The tobacco control managers (TCMs) at the programs studied were all civilian employees, highly motivated and enthusiastic, and had remained in their positions for approximately a decade. Other commonalities included support from command, a "culture" of health, and location in warm climates. Programs varied in their involvement in establishing designated tobacco use areas, and length and requirement of attending cessation classes; however, no evaluation of cessation programs is currently underway. TCMs should be more engaged in policy discussions for the larger installations they serve. A strong policy framework and command support for TCMs will be necessary to achieve the goal of a tobacco-free military. PMID- 27244073 TI - Binocular Visual Acuity and Corrective Lens Use in the United States Army. AB - PURPOSE: To assess uncorrected and corrected distance and near binocular visual acuity (VA) and the use of corrective lenses in U.S. Army Active Duty, Guard, and Reserve Soldiers. METHODS: A descriptive statistical analysis of VA group data from the U.S. Army Vision Readiness Classification Screening system was performed. Data pulls from June 2012 to January 2015 were compared. RESULTS: In January 2015, 62.3% of Soldiers had an uncorrected binocular distance VA of 20/20, 21.2% of Soldiers were worse than 20/40, and 41.4% of Soldiers wore corrective eyewear for distance vision. With correction, 92.5% had a binocular distance VA of 20/20 and 1.4% were worse than 20/40. In January 2015, 32.6% of Soldiers age >45 had an uncorrected binocular near VA of 20/20, 28.4% of Soldiers age >45 were worse than 20/40, and 61.9% of Soldiers age >45 wore corrective eyewear for near vision. With correction, 74.6% had a binocular near VA of 20/20 and 3.0% were worse than 20/40. Data for both years were similar, although there were differences between individual service components. CONCLUSIONS: In comparison to the U.S. adult population, U.S. Army Soldiers have better uncorrected and corrected vision and are less likely to wear vision correction. PMID- 27244074 TI - Dr. Daniel S. Lamb (1843-1929) of the Army Medical Museum. PMID- 27244075 TI - Acute Eosinophilic Pneumonia After Resumption of Cigarette Smoking. AB - Acute eosinophilic pneumonia is a rare entity characterized by rapidly progressive infiltration of eosinophils into the lungs and is often associated with drug exposure or infection. We report a case of a previously healthy 19-year old woman who presented with acute progressive dyspnea. Chest radiograph revealed diffuse bilateral infiltrates. Based on the results of bronchoalveolar lavage fluid and her clinical course, she was diagnosed as having acute eosinophilic pneumonia. We suspect that the disease was related to smoking because she had started smoking 3 weeks before the onset of symptoms. Given the high prevalence of smoking and initiation of smoking in the military population, it is important for physicians taking care of this population to be aware of this disorder. PMID- 27244076 TI - Ablative Fractional Laser Resurfacing: A Promising Adjunct to Surgical Reconstruction. AB - Ablative fractional laser resurfacing (AFLR) is emerging as a safe and effective treatment option for the mitigation of cosmetic and functional deficits resulting from traumatic scars and scar contractures. Military centers of excellence engaged in the multidisciplinary rehabilitation of wounded warriors have been instrumental in the widening acceptance of the technique in both the military and civilian realms. Despite the end of large-scale combat operations, AFLR remains a promising complement to surgical reconstruction and a novel option in challenging clinical situations that defy resolution with traditional methods. Herein, we present the case of a man in his 50s who underwent extensive genital and perineal debridement related to Fournier's gangrene. Despite successful reconstruction including extensive skin grafting, the patient suffered from intractable discomfort related to developing scar contractures that responded rapidly to a course of AFLR. This case serves to highlight the potential benefits of AFLR for postoperative wound management, and the importance of a multidisciplinary approach for the care of complex injuries. PMID- 27244077 TI - Performance of Cervical Arthroplasty at a Pseudarthrosed Level of a MultiLevel Anterior Cervical Discectomy and Fusion: Case Report. AB - OBJECTIVE: To present a conversion from an anterior cervical discectomy and fusion (ACDF) to cervical arthroplasty in a 40-year-old, active duty member and perform a review of the literature. METHODS: A helicopter pilot in the U.S. Army underwent a three-level ACDF in 2010 at a nonmilitary institution for symptoms of bilateral upper-extremity radiculopathy. His symptoms resolved; however, per regulations, he was grounded. The patient recently presented at our clinic for evaluation of axial neck and intrascapular pain with radiographic evaluation revealing pseudarthrosis at C6-7 with segmental motion without facet joint degeneration. Surgery was performed to remove the existing allograft and replace it with an artificial disc, thus restoring a motion segment. RESULTS: Postoperative imaging reveals appropriate placement of the artificial disc and range of motion at C6-7 with the patient reporting improvement in neck pain. He has since been granted a waiver to return to active flight status. CONCLUSIONS: Revision of ACDF to arthroplasty is an exceedingly rare procedure with only two cases reported in the literature. Here, the authors demonstrate use of the procedure for a military career-specific application. When facet joint degeneration or ankylosis is absent, restoration of motion can successfully, and safely, be achieved. PMID- 27244078 TI - Mobilization of Metal From Retained Embedded Fragments in a Blast-Injured Iraq War Veteran. AB - A frequent comorbidity of traumatic injury due to a blast or explosion, commonly reported in Iraq and Afghanistan veterans, is that of retained embedded fragments typically of unknown content. Because of concerns over both local and systemic health effects related to both the physical presence of and mobilization of materials from embedded fragments, the Department of Veterans Affairs established a surveillance program for this group of veterans. We present here the case of a surveillance-enrolled veteran who submitted: (1) three surgically removed fragments for content analyses, (2) tissue adhered to the fragments for histology and metal concentration evaluation, and (3) pre- and postfragment removal urine samples to assess concentrations of various metals often found in fragments. Results indicate that removed fragments were aluminum-copper alloys. Surrounding tissue analyses revealed elevated concentrations of these metals and evidence of chronic inflammation, but no neoplastic changes. Urine aluminum concentrations, initially elevated compared to normal population values, decreased significantly after fragment removal, illustrating the utility of urine biomonitoring to provide insight into fragment composition. A medical surveillance program integrating fragment composition data, tissue analyses, and repeat urine biomonitoring can help inform the patient-specific medical management of both the local and systemic effects of retained metal fragments. PMID- 27244079 TI - Soybean Trade: Balancing Environmental and Socio-Economic Impacts of an Intercontinental Market. AB - The trade in soybean, an important animal feed product, exemplifies the environmental and socio-economic impact of global markets and global agricultural policy. This paper analyses the impact of increasing production of soybean in the exporting countries (deforestation and grassland conversion) as well as in importing regions (decrease in permanent grassland by substitution of grass as feed). Ecosystem services monetary values were used to calculate the environmental and socio-economic impact of observed land use changes. This is balanced against the economic value of the global soybean trade. The results prove that consumption choices in one region have real effects on the supply of ecosystem services at a large spatial scale. Conclusively, solutions to make this global market more sustainable are discussed. PMID- 27244081 TI - Isotopic Evidence of a Wide Spectrum of Feeding Strategies in Southern Hemisphere Humpback Whale Baleen Records. AB - Our current understanding of Southern hemisphere humpback whale (Megaptera novaeangliae) ecology assumes high-fidelity feeding on Antarctic krill in Antarctic waters during summer, followed by fasting during their annual migration to and from equatorial breeding grounds. An increase in the number of reported departures from this feeding/fasting model suggests that the current model may be oversimplified or, alternatively, undergoing contemporary change. Information about the feeding and fasting cycles of the two Australian breeding populations of humpback whales were obtained through stable isotope analysis of baleen plates from stranded adult individuals. Comparison of isotope profiles showed that individuals from the West Australian breeding population strongly adhered to the classical feeding model. By contrast, East Australian population individuals demonstrated greater heterogeneity in their feeding. On a spectrum from exclusive Antarctic feeding to exclusive feeding in temperate waters, three different strategies were assigned and discussed: classical feeders, supplemental feeders, and temperate zone feeders. Diversity in the inter-annual feeding strategies of humpback whales demonstrates the feeding plasticity of the species, but could also be indicative of changing dynamics within the Antarctic sea-ice ecosystem. This study presents the first investigation of trophodynamics in Southern hemisphere humpback whales derived from baleen plates, and further provides the first estimates of baleen plate elongation rates in the species. PMID- 27244082 TI - Raman spectroscopic analysis of Lactobacillus rhamnosus GG in response to dehydration reveals DNA conformation changes. AB - Dehydration of bacterial cells elicits cellular stress responses in bacteria. Microencapsulation has been used to protect cells against the environmental stress. In this study, Confocal Raman Spectroscopy was used to examine DNA changes in the chemical composition of non-encapsulated and microencapsulated Lactobacillus rhamnosus GG and the reversibility of these changes upon freeze drying and rehydration. The viability of cells upon freeze drying was also enumerated using culture methods and membrane integrity was measured using BacLight Live/Dead staining. Raman analyses show changes in the spectral features associated with various biochemical compounds, which are interpreted as the result of detrimental freeze drying effects on the bacterial cells. Specifically, analyses based on Principal Components Analysis (PCA) of Raman spectra, confirm that microencapsulation protects cells from environmental stress. The results also reveal a B- to A-like DNA conformation change in dormant cells that provided insights into the extent of reversibility of this transition upon rehydration. The extent of this reversibility is less in non-encapsulated than in microencapsulated cells. These findings indicate the potential application of Raman spectroscopy in rapid sensing of microbial dehydration stress responses. PMID- 27244080 TI - miR-139-5p Inhibits the Epithelial-Mesenchymal Transition and Enhances the Chemotherapeutic Sensitivity of Colorectal Cancer Cells by Downregulating BCL2. AB - MicroRNAs (miRNAs) are important regulators involved in various cancers, including colorectal cancer (CRC). The functions and mechanisms of the miRNAs involved in CRC progress and metastasis are largely unknown. In this study, miRNA microarray analysis was performed to screen crucial miRNAs involved in CRC progress, and miR-139-5p was chosen for further study. The functional roles of miR-139-5p in colon cancer were demonstrated by CCK-8 proliferation assay, cell invasion and migration, cell apoptosis and in a KO mouse study. miR-139-5p expression was significantly decreased in cancer tissues compared to normal tissues. The miR-139-5p expression level was associated with tumour stage (P < 0.01). Function studies revealed that miR-139-5p was significantly correlated with the metastasis potential and drug resistance of colon cancer cells by affecting the epithelial-mesenchymal transition (EMT). Then, we identified BCL2 as a direct target of miR-139-5p cells in vitro. The patient samples and KO mice model showed that BCL2 expression was inversely correlated with the expression of miR-139-5p. In conclusion, we found that miR-139-5p targeted the BCL2 pathway to reduce tumour metastasis and drug sensitivity in CRC. This axis provided insight into the mechanism underlying miRNA regulation of CRC metastasis and a novel therapeutic target for CRC therapy. PMID- 27244083 TI - Erratum: CAP2 in cardiac conduction, sudden cardiac death and eye development. PMID- 27244084 TI - Impact of Type of Health Insurance on Infection Rates among Young Trauma Patients. AB - BACKGROUND: Many studies have described the detrimental effect of lack of health insurance on trauma-related outcomes. It is unclear, though, whether these effects are related to pre-injury health status, access to trauma centers, or differences in quality of care after presentation. The aim of this study was to determine if patient and insurance type affect outcomes after trauma surgery. METHODS: We conducted a retrospective chart review of prospectively collected data at the American College of Surgeons level 1 trauma registry in Rhode Island. All blunt trauma patients aged 18-45 observed from 2004 to 2014 were included. Patients were divided into one of four groups on the basis of their type of insurance: Private/commercial, Medicare, Medicaid, and uninsured. Co-morbidities and infections were recorded. Analysis of variance or the Mann-Whitney U test, as appropriate, was used to analyze the data. RESULTS: A total of 8,018 patients were included. Uninsured patients were more likely to be male and younger, whereas the Medicare patient group had significantly fewer male patients. Rates of co-morbidities were highest in the Medicare group (28.1%) versus the private insurance (16.7%), Medicaid (19.9%), and uninsured (12.9%) groups (p < 0.05). However, among patients with any co-morbidity, there was no difference in the average number of co-morbidities between insurance groups. The rate of infection was highest in Medicaid patients (7.7%) versus private (5.6%), Medicare (6.3%), and uninsured (4.3%) patients (p < 0.05). Only Medicaid was associated with a significantly greater risk of developing a post-injury infection (odds ratio 1.6; 95% confidence interval 1.1-2.3). CONCLUSION: The presence of insurance, namely Medicaid, does not equate to diagnosis and management of conditions that affect trauma outcomes. Medicaid is associated with worse pre-trauma health maintenance and a greater risk of infection. PMID- 27244086 TI - Molecular docking, 3D QSAR and dynamics simulation studies of imidazo pyrrolopyridines as janus kinase 1 (JAK 1) inhibitors. AB - Janus kinase 1 (JAK 1) plays a critical role in initiating responses to cytokines by the JAK-signal transducer and activator of transcription (JAK-STAT). This controls survival, proliferation and differentiation of a variety of cells. Docking, 3D quantitative structure activity relationship (3D-QSAR) and molecular dynamics (MD) studies were performed on a series of Imidazo-pyrrolopyridine derivatives reported as JAK 1 inhibitors. QSAR model was generated using 30 molecules in the training set; developed model showed good statistical reliability, which is evident from r2ncv and r2loo values. The predictive ability of this model was determined using a test set of 13 molecules that gave acceptable predictive correlation (r2Pred) values. Finally, molecular dynamics simulation was performed to validate docking results and MM/GBSA calculations. This facilitated us to compare binding free energies of cocrystal ligand and newly designed molecule R1. The good concordance between the docking results and CoMFA/CoMSIA contour maps afforded obliging clues for the rational modification of molecules to design more potent JAK 1 inhibitors. PMID- 27244087 TI - Molecular dynamics and high throughput binding free energy calculation of anti actin anticancer drugs-New insights for better design. AB - Actin cytoskeleton plays an important role in cancerous cell progression. Till date many anticancer toxins are discovered that binds to different sites of actin. Mechanism of action of these toxins varies with respect to the site where they bind to actin. Latrunculin A (LAT) binds closely to nucleotide binding site and Reidispongiolide binds to the barbed end of actin. LAT is reported to reduce the displacement of domain 2 with respect to domain 1 and allosterically modulate nucleotide exchange. On the other hand Reidispongiolide binds with the higher affinity to actin and competes with the DNaseI binding loop once the inter monomer interaction has been formed. Evolving better actin binders being the aim of this study we conducted a comparative molecular dynamics of these two actin drug complexes and actin complexed with ATP alone, 50ns each. High throughput binding free energy calculations in conjugation with the high-throughput MD simulations was used to predict modifications in these two renowned anti-actin anticancer drugs for better design. Per residue energy profiling that contribute to free energy of binding shows that there is an unfavourable energy at the site where Asp157 interacts with 2-thiazolidinone moiety of LAT. Similarly, unfavourable energies are reported near macrocyclic region of Reidispongiolide specifically near carbons 7, 11 & 25 and tail region carbons 27 & 30. These predicted sites can be used for modifications and few of these are discussed in this work based on the interactions with the binding site residues. The study reveals specific interactions that are involved in the allosteric modulation of ATP by these two compounds. Glu207 closely interacting with LAT A initiates the allosteric effect on ATP binding site specifically affecting residues Asp184, Lys215 and Lys336. RGA bound actin shows high anti-correlated motions between sub domain 3 and 4. Unlike LAT A, Reidispongiolide induces a flat structure of actin which definitely should affect actin polymerisation and lead to disassembly of actin filaments. PMID- 27244088 TI - Exposure to Famine at a Young Age and Unhealthy Lifestyle Behavior Later in Life. AB - BACKGROUND: A healthy diet is important for normal growth and development. Exposure to undernutrition during important developmental periods such as childhood and adolescence can have effects later in life. Inhabitants of the west of the Netherlands were exposed to severe undernutrition during the famine in the last winter of the second World War (1944-1945). OBJECTIVE: We investigated if exposure of women to the Dutch famine during childhood and adolescence was associated with an unhealthy lifestyle later in life. DESIGN: We studied 7,525 women from the Prospect-EPIC cohort, recruited in 1993-97 and aged 0-18 years during the Dutch famine. An individual famine score was calculated based on self reported information about experience of hunger and weight loss. We investigated the association between famine exposure in early life and four lifestyle factors in adulthood: smoking, alcohol consumption, physical activity level and a Mediterranean-style diet. RESULTS: Of the 7,525 included women, 46% were unexposed, 38% moderately exposed and 16% severely exposed to the Dutch famine. Moderately and severely exposed women were more often former or current smokers compared to women that did not suffer from the famine: adjusted prevalence ratio 1.10 (95% CI: 1.05; 1.14) and 1.18 (1.12; 1.25), respectively. They also smoked more pack years than unexposed women. Severely exposed women were more often physically inactive than unexposed women, adjusted prevalence ratio 1.32 (1.06; 1.64). Results did not differ between exposure age categories (0-9 and 10-17 years). We found no associations of famine exposure with alcohol consumption and no dose-dependent relations with diet. CONCLUSIONS: Exposure to famine early in female life may be associated with higher prevalence of smoking and physical inactivity later in life, but not with unhealthy diet and alcohol consumption. PMID- 27244089 TI - Design and synthesis of new tetrandrine derivatives and their antitumor activities. AB - A series of tetrandrine derivatives were designed and synthesized using Suzuki coupling reaction. Eleven targeted compounds with over 50% inhibition against HL60 and A549 human cancer cell lines at 10 MUM were further evaluated for the in vitro antitumor activities by MTT or SRB assay. The biological results revealed that some compounds exhibited potent antitumor activities. Thiophene derivative 6 and acetylphenyl derivative 5 were the most active ones against HL60 and A549 cell lines, with IC50 values less than 5 MUM, which thus could be considered as useful candidate for further development of new antitumor agents. PMID- 27244090 TI - The need of a correct experimental model in microsurgery: An issue that may invalidate the resultsis. It time for an international scientific "Bank"? PMID- 27244091 TI - Atom Transfer Radical Polymerization of Methacrylic Acid: A Won Challenge. AB - Polymerization of acidic monomers is one of the biggest challenges for atom transfer radical polymerization (ATRP). An intramolecular cyclization reaction leading to the loss of the C-X chain-end functionality was found to be the main reason for the partial termination of the growing polymer chains. Three approaches were used to overcome this problem: using Cl as the chain-end halogen, lowering the pH (to 0.9), and increasing polymerization rate. Methacrylic acid (MAA) was polymerized by both electrochemically mediated ATRP and supplemental activator and reducing agent ATRP up to high conversion (>90%), in t <= 4 h at 25 degrees C, using inexpensive and nontoxic reagents (NaCl, diluted HCl, water). Control over molecular weight (MW) dispersity was satisfactory, and MWs were in agreement with theoretical values. The "livingness" of the process was confirmed by an electrochemical switch, used to repeatedly and periodically deactivate/reactivate growing chains. PMID- 27244092 TI - Encoding, training and retrieval in ferroelectric tunnel junctions. AB - Ferroelectric tunnel junctions (FTJs) are quantum nanostructures that have great potential in the hardware basis for future neuromorphic applications. Among recently proposed possibilities, the artificial cognition has high hopes, where encoding, training, memory solidification and retrieval constitute a whole chain that is inseparable. However, it is yet envisioned but experimentally unconfirmed. The poor retention or short-term store of tunneling electroresistance, in particular the intermediate states, is still a key challenge in FTJs. Here we report the encoding, training and retrieval in BaTiO3 FTJs, emulating the key features of information processing in terms of cognitive neuroscience. This is implemented and exemplified through processing characters. Using training inputs that are validated by the evolution of both barrier profile and domain configuration, accurate recalling of encoded characters in the retrieval stage is demonstrated. PMID- 27244093 TI - Outpatient Advance Care Planning Internal Medicine Resident Curriculum: Valuing Our Patients' Wishes. AB - BACKGROUND: Although many studies have illustrated the discomfort that resident physicians feel when discussing end-of-life (EOL) issues with their patients, fewer studies have addressed interventions to directly increase medical resident proficiency and comfort in conducting these discussions and for translating these beliefs into a formal advance care plan. OBJECTIVES: We report on an innovative curriculum conducted at The University of Chicago (NorthShore) internal medicine residency to improve residents' proficiency and comfort in leading outpatient advance care planning (ACP) discussions. METHODS: Four educational components were executed. First, residents completed an on-line module introducing ACP and guiding residents to complete their own ACP. Second, residents attended a didactic "How To" lecture given by physicians with expertise in ACP that emphasized ACP communication tools and a video demonstration. Third, residents completed a video-recorded simulation-based ACP discussion with a standardized patient. Finally, residents conducted an ACP outpatient encounter with one of their continuity clinic patients. Expert preceptors directly observed, evaluated, and provided feedback to residents during both patient encounters. Residents were surveyed before and immediately after the curriculum using a nine-variable questionnaire, which assessed the resident's training and comfort with ACP. RESULTS: Sixteen second year residents completed the curriculum and surveys. Precurriculum and post-curriculum mean change on a Likert scale of 1 (uncomfortable) to 5 (very comfortable) was compared using paired t-tests. Results demonstrated statistically significant improvements in the following comfort level variables: eliciting understanding of health and prognosis (pre 3.63 vs. post 4.38, p = 0.035), discussing EOL care based on patient values (pre 3.50 vs. post 4.38, p = 0.008), specifically discussing EOL care based on patient values in the outpatient setting (pre 2.75 vs. post 4.31, p = 0.001) and initiating an advance directive and medical power of attorney (pre 2.56 vs. post 4.19, p < 0.001). CONCLUSION: A multimodality curriculum including self-directed learning, lectures, and practice with simulated and actual outpatients with active reflection and feedback is effective in improving resident comfort level and formal training in ACP. Further research is needed to understand whether these interventions will translate into an increased frequency of discussions with patients about ACP after residency training. PMID- 27244094 TI - Ductal Carcinoma In Situ Stage 0 Breast Cancer: When Less May Be Better. PMID- 27244095 TI - Serial position encoding of signs. AB - Reduced short-term memory (STM) capacity has been reported for sign as compared to speech when items have to be recalled in a specific order. This difference has been attributed to a more precise and efficient serial position encoding in verbal STM (used for speech) than visuo-spatial STM (used for sign). We tested in the present investigation whether the reduced STM capacity with signs stems from a lack of positional encoding available in verbal STM. Error analyses reported in prior studies have revealed that positions are defined in verbal STM by distance from both the start and the end of the sequence (both-edges positional encoding scheme). Our analyses of the errors made by deaf participants with finger-spelled letters revealed that the both-edges positional encoding scheme underlies the STM representation of signs. These results indicate that the cause of the STM disadvantage is not the type of positional encoding but rather the difficulties in binding an item in visuo-spatial STM to its specific position in the sequence. Both-edges positional encoding scheme could be specific of sign, since it has not been found in visuo-spatial STM tasks conducted with hearing participants. PMID- 27244096 TI - Smart Superstructures with Ultrahigh pH-Sensitivity for Targeting Acidic Tumor Microenvironment: Instantaneous Size Switching and Improved Tumor Penetration. AB - The currently low delivery efficiency and limited tumor penetration of nanoparticles remain two major challenges of cancer nanomedicine. Here, we report a class of pH-responsive nanoparticle superstructures with ultrasensitive size switching in the acidic tumor microenvironment for improved tumor penetration and effective in vivo drug delivery. The superstructures were constructed from amphiphilic polymer directed assembly of platinum-prodrug conjugated polyamidoamine (PAMAM) dendrimers, in which the amphiphilic polymer contains ionizable tertiary amine groups for rapid pH-responsiveness. These superstructures had an initial size of ~80 nm at neutral pH (e.g., in blood circulation), but once deposited in the slightly acidic tumor microenvironment (pH ~6.5-7.0), they underwent a dramatic and sharp size transition within a very narrow range of acidity (less than 0.1-0.2 pH units) and dissociated instantaneously into the dendrimer building blocks (less than 10 nm in diameter). This rapid size-switching feature not only can facilitate nanoparticle extravasation and accumulation via the enhanced permeability and retention effect but also allows faster nanoparticle diffusion and more efficient tumor penetration. We have further carried out comparative studies of pH-sensitive and insensitive nanostructures with similar size, surface charge, and chemical composition in both multicellular spheroids and poorly permeable BxPC-3 pancreatic tumor models, whose results demonstrate that the pH-triggered size switching is a viable strategy for improving drug penetration and therapeutic efficacy. PMID- 27244097 TI - Absolute Intramolecular Distance Measurements with Angstrom-Resolution Using Anomalous Small-Angle X-ray Scattering. AB - Accurate determination of molecular distances is fundamental to understanding the structure, dynamics, and conformational ensembles of biological macromolecules. Here we present a method to determine the full distance distribution between small (~7 A radius) gold labels attached to macromolecules with very high precision (<=1 A) and on an absolute distance scale. Our method uses anomalous small-angle X-ray scattering close to a gold absorption edge to separate the gold gold interference pattern from other scattering contributions. Results for 10-30 bp DNA constructs achieve excellent signal-to-noise and are in good agreement with previous results obtained by single-energy SAXS measurements without requiring the preparation and measurement of single labeled and unlabeled samples. The use of small gold labels in combination with ASAXS read out provides an attractive approach to determining molecular distance distributions that will be applicable to a broad range of macromolecular systems. PMID- 27244098 TI - Large electrostrain and high optical temperature sensitivity in BaTiO3 (Na0.5Ho0.5)TiO3 multifunctional ferroelectric ceramics. AB - Ferroelectric (1 -x)BaTiO3-x(Na0.5Ho0.5)TiO3 ceramics with ferroelectric and up conversion luminescent multifunctions were designed and fabricated by a solid state reaction process. Their structure, ferroelectric, piezoelectric, up conversion photoluminescence and relative optical temperature sensing properties were investigated systematically. Crystal structure analysis and Rietveld refinements based on the powder X-ray diffraction data show that the ceramics crystallized in the tetragonal perovskite space group P4mm at room temperature. Enhanced electrical properties and strong green up-conversion luminescence with thermally coupled green emission bands centered at 523 and 553 nm were observed. For a typical sample x equals 0.05, a large electrostrain of 0.279% was obtained under a 70 kV cm(-1) electric field that is comparable to that of the PZT4. Meanwhile, the excellent optical temperature sensitivity (0.0063 K(-1) at 480 K) is higher than that of Er-doped BaTiO3 nanocrystal materials. The results suggest that the BaTiO3-(Na0.5Ho0.5)TiO3 material should be an attractive material for piezoelectric actuator and temperature sensing device applications. PMID- 27244099 TI - Frequency of telomerase reverse transcripter promoter mutations in desmoplastic melanoma subtypes: analyses of 76 cases. AB - Estimates of the frequency of telomerase reverse transcripter (TERT) mutations in desmoplastic melanoma (DM) are limited. DM is categorized into subtypes, pure and mixed, differing in prognosis, suggesting genetic heterogeneity. Given this, our aims were to determine the incidence of TERT promoter mutations in DM subtypes and to evaluate its relationship with established histopathologic prognosticators, BRAF and RETp status, and neurofibromin protein expression. Of the archival annotated samples retrieved, 76 cases of DM (48 pure and 28 mixed) fulfilled the criteria for inclusion. PCR amplification of the TERT promoter region was performed on DNA extracted from formalin-fixed paraffin-embedded tissue using primers5'-GCCGATTCGACCTCTCTCC-3' (forward) and 5'-CAGCGCTGCCTGAAACTC 3' (reverse). For each case, appropriate C>T mutations were identified on the electropherograms. Univariate analysis using chi-test was carried out to identify potential confounders; a nested case-control study of demographic, clinical, histopathological, and genetic determinants was carried out using multiple logistic regression. Significant differences in TERT promoter mutation frequencies were noted in the subtypes (mixed vs. pure; 15/28, 54% vs. 11/48, 23%, respectively, P=0.0066). After adjusting for potential confounding, multivariate analyses indicated a three-fold increase in the odds of the TERT mutation for those with the mixed subtype compared with the pure subtype (P=0.04, adjusted odds ratio =3.32). No other significant associations were noted (sex/junctional component/Breslow depth/ulceration/mitoses/host response/RETp, BRAF status, and neurofibromin protein expression). Our findings, the largest to date investigating TERT promoter mutations in DM, support the hypothesis that the subtypes have distinct genetic drivers and underscore the relevance of telomere integrity in the etiopathogenesis of the mixed variant. PMID- 27244100 TI - Bowel Ischemia and Portal Venous Gas: What to Do? AB - The etiology of pneumatosis and portal venous gas in ischemic colitis is debated, but one theorized cause is transmural ischemia and subsequent bacterial translocation. Traditionally though as a surgical emergency, today not all patients with pneumatosis and portal venous gas need an operation. We have reviewed recent published algorithms and applied them to our practice. PMID- 27244101 TI - Response of phytohormones and correlation of SAR signal pathway genes to the different resistance levels of grapevine against Plasmopara viticola infection. AB - Phytohormones play an important role in the process of disease resistance in plants. Here, we investigated which among salicylic acid, jasmonic acid, and abscisic acid performs a key role in plant defense after Plasmopara viticola infection in grapevine. We used grapevines possessing different resistance levels against P. viticola infection to study the relationship between the expression of key genes in the related resistance signaling pathways and the level of resistance. We performed high-performance liquid chromatography-mass spectrometry to estimate the phytohormone contents in grape leaves at different time points after the infection. Furthermore, we performed quantitative analyses of key genes such as EDS1, PAD4, ICS2, PAL, NPR1, TGA1, and PR1 in the systemic acquired resistance pathway by quantitative reverse transcription-polymerase chain reaction. The results showed an increased variation in the SA content, which was maintained at high levels, after P. viticola infection in plant species exhibiting stronger resistance to the pathogen; this finding highlights the importance of SA in plant defense mechanisms. Moreover, EDS1 and PAD4 expression did not show a positive correlation with disease resistance in grape; however, higher expression of other genes that were analyzed was observed in highly resistant grape varieties. Our results provide insights into the role of phytohormone regulation in the induction and maintenance of plant defense response to pathogens. PMID- 27244103 TI - Combining Linear-Scaling DFT with Subsystem DFT in Born-Oppenheimer and Ehrenfest Molecular Dynamics Simulations: From Molecules to a Virus in Solution. AB - In this work, methods for the efficient simulation of large systems embedded in a molecular environment are presented. These methods combine linear-scaling (LS) Kohn-Sham (KS) density functional theory (DFT) with subsystem (SS) DFT. LS DFT is efficient for large subsystems, while SS DFT is linear scaling with a smaller prefactor for large sets of small molecules. The combination of SS and LS, which is an embedding approach, can result in a 10-fold speedup over a pure LS simulation for large systems in aqueous solution. In addition to a ground-state Born-Oppenheimer SS+LS implementation, a time-dependent density functional theory based Ehrenfest molecular dynamics (EMD) using density matrix propagation is presented that allows for performing nonadiabatic dynamics. Density matrix-based EMD in the SS framework is naturally linear scaling and appears suitable to study the electronic dynamics of molecules in solution. In the LS framework, linear scaling results as long as the density matrix remains sparse during time propagation. However, we generally find a less than exponential decay of the density matrix after a sufficiently long EMD run, preventing LS EMD simulations with arbitrary accuracy. The methods are tested on various systems, including spectroscopy on dyes, the electronic structure of TiO2 nanoparticles, electronic transport in carbon nanotubes, and the satellite tobacco mosaic virus in explicit solution. PMID- 27244102 TI - The emerging threat of superwarfarins: history, detection, mechanisms, and countermeasures. AB - Superwarfarins were developed following the emergence of warfarin resistance in rodents. Compared to warfarin, superwarfarins have much longer half-lives and stronger affinity to vitamin K epoxide reductase and therefore can cause death in warfarin-resistant rodents. By the mid-1970s, the superwarfarins brodifacoum and difenacoum were the most widely used rodenticides throughout the world. Unfortunately, increased use was accompanied by a rise in accidental poisonings, reaching >16,000 per year in the United States. Risk of exposure has become a concern since large quantities, up to hundreds of kilograms of rodent bait, are applied by aerial dispersion over regions with rodent infestations. Reports of intentional use of superwarfarins in civilian and military scenarios raise the specter of larger incidents or mass casualties. Unlike warfarin overdose, for which 1-2 days of treatment with vitamin K is effective, treatment of superwarfarin poisoning with vitamin K is limited by extremely high cost and can require daily treatment for a year or longer. Furthermore, superwarfarins have actions that are independent of their anticoagulant effects, including both vitamin K-dependent and -independent effects, which are not mitigated by vitamin K therapy. In this review, we summarize superwarfarin development, biology and pathophysiology, their threat as weapons, and possible therapeutic approaches. PMID- 27244104 TI - Another solution that enables ablative radiotherapy for large liver tumors: Percutaneous interstitial high-dose rate brachytherapy. PMID- 27244105 TI - Combined factor IIa and Xa inhibitor therapy for thrombosis whilst on therapeutic anticoagulant. PMID- 27244106 TI - Multifunctional Environmental Smart Fertilizer Based on l-Aspartic Acid for Sustained Nutrient Release. AB - Fertilizer is one of the most important elements of modern agriculture. However, conventional fertilizer, when applied to crops, is vulnerable to losses through volatilization, leaching, nitrification, or other means. Such a loss limits crop yields and pollutes the environment. In an effort to enhance nutrient use efficiency and reduce environmental pollution, an environmental smart fertilizer was reported in the current study. Poly(aspartic acid) and a degradable macro cross-linker based on l-aspartic acid were synthesized and introduced into the fertilizer as a superabsorbent to improve the fertilizer degradability and soil moisture-retention capacity. Sustained release behavior of the fertilizer was achieved in soil. Cumulative release of nitrogen and phosphorus was 79.8% and 64.4% after 30 days, respectively. The water-holding and water-retention capacities of soil with the superabsorbent are obviously higher than those of the control soil without superabsorbent. For the sample of 200 g of soil with 1.5 g of superabsorbent, the water-holding capacity is 81.8%, and the water-retention capacity remains 22.6% after 23 days. All of the current results in this study indicated that the as-prepared fertilizer has a promising application in sustainable modern agriculture. PMID- 27244111 TI - The Institute of Medical Illustrators (IMI) Awards 2015. PMID- 27244113 TI - Reorganization in Secondary Somatosensory Cortex in Chronic Low Back Pain Patients. AB - STUDY DESIGN: A cross-sectional comparative study between chronic low back pain (CLBP) patients and healthy control subjects. OBJECTIVE: The aim of this study was to investigate reorganization in the sensory cortex by comparing cortical activity due to mechanosensory stimulation of the lumbar spine in CLBP patients versus a control group by using functional magnetic resonance imaging (fMRI). SUMMARY OF BACKGROUND DATA: LBP is now the number 1 condition across the world in terms of years living with a disability. There is growing evidence that maladaptive changes in the processing of sensory input by the central nervous system are central to understanding chronic (back) pain. METHODS: Nonpainful, posterior-anterior (PA) movement pressure was applied manually to lumbar vertebrae at L1, L3, and L5 in 13 healthy subjects and 13 CLBP patients. The manual pressure (30 N) was monitored and controlled using sensors. A randomized stimulation protocol was used consisting of 51 pressure stimuli of 5 seconds duration. fMRI data analysis was performed for the group activation within the primary and secondary sensory cortices (S1 and S2, respectively) and the representation of the individual vertebrae was extracted and statistically analyzed. RESULTS: Nonpainful PA pressure revealed no cortical reorganization in S1. In contrast, the extent of S2 activation in the CLBP group was significantly reduced in both hemispheres. In the control group, a somatotopy was identified for the lumbar vertebrae between L1 and L3, respectively, and L5 in S2 of the right hemisphere. Most importantly, a blurring of the somatotopic representation of the lumbar spine in S2 was observed in the patient group. CONCLUSION: Together, these maladaptive changes suggest a reorganization of higher-order processing for sensory information in CLBP patients that might have implications for a decreased sensory acuity, also related to body perception and subsequent altered functioning of the lumbar spine. LEVEL OF EVIDENCE: 2. PMID- 27244112 TI - Interest of Denosumab for the Treatment of Giant-cells Tumors and Aneurysmal Bone Cysts of the Spine. About Nine Cases. AB - STUDY DESIGN: A prospective cohort study. OBJECTIVE: The aim of this study was to evaluate the interest of denosumab in the treatment of spinal giant-cells tumors (GCTs) and aneurysmal bone cysts (ABCs). SUMMARY OF BACKGROUND DATA: To treat GCTs and ABCs, surgical resection remains the best treatment to limit local recurrence (LR) but constitutes an aggressive treatment with potential morbidity. Denosumab, a human antibody anti-RankL, inhibiting the differentiation of osteoclasts, could be an alternative treatment to avoid aggressive surgery. METHODS: Patients suffering from GCTs and ABCs of the spine were included. Patients received a monthly subcutaneous injection of denosumab (120 mg) during a minimum of 6 months either as a neoadjuvant or as an adjuvant therapy. In association with denosumab, an osteosynthesis was added in case of vertebral fracture and a laminectomy in case of spinal cord compression. Clinical and computed tomography (CT)-scan outcomes were analyzed. RESULTS: Eight GCTs and one ABC were included. The mean age was 35 years (range: 22-55 yr). Five patients had neurologic deficit. All patients were operated: six osteosynthesis, one "en bloc" resection, four curettages, and two of them associated with an osteosynthesis. Average duration of denosumab therapy was 12.9 months (range: 3.2-24 months). Among them, four patients began denosumab 6 months at least before the surgery. With a mean follow-up of 19.3 months (range: 3.2-52.4 months), back pain and neurologic deficit improved for all patients. Systematic CT-scan at 6 months showed decrease of tumor size and bone consolidation. Regarding patients treated by neoadjuvant denosumab treatment, intraoperative histologic analysis showed an absence of giant cells and a maximum of 10% of alive tumor cells. CONCLUSION: Denosumab allows bone formation and tumor regression with a maximum efficacy after 6 months of treatment without widely substituting surgery. Long-term results are mandatory to confirm the interest of denosumab and to evaluate LR when stopping denosumab. LEVEL OF EVIDENCE: 3. PMID- 27244114 TI - Cross-Cultural Adaptation and Validation of the Back Beliefs Questionnaire to the Arabic Language. AB - STUDY DESIGN: Translation, cross-cultural adaptation, and psychometric testing. OBJECTIVE: To translate the Back Beliefs Questionnaire (BBQ) into Arabic and investigate its psychometric properties in an Arabic-speaking sample of individuals with low back pain (LBP). SUMMARY OF BACKGROUND DATA: Back pain beliefs are associated with pain chronicity and disability in people with LBP. The BBQ is a recognized and frequently used tool for measuring these beliefs. To date the BBQ has not been translated into Arabic. METHODS: The English version of the BBQ was translated and culturally adapted into Arabic (BBQ-Ar) according to published guidelines. The BBQ-Ar was then tested in a sample of 115 Arabic speaking individuals with LBP. Reliability was evaluated through internal consistency (Cronbach alpha) and test-retest reliability (intraclass correlation coefficient), the latter in a subgroup of 25. Construct validity was assessed using exploratory factor analysis and by examining the correlation between the BBQ-Ar, the Oswestry Disability Index and a Numerical Pain Rating Scale. RESULTS: Internal consistency of the BBQ-Ar was good (Cronbach alpha = 0.77). Test-retest reliability was good (intraclass correlation coefficient [2,1] = 0.88). Exploratory factor analysis revealed a three-factor structure, explaining 46% of total variance, with the first factor alone explaining 24%. Eight of the nine scoring items were loaded on the first factor thus forming a unidimensional scale. A significant negative correlation was found between Oswestry Disability Index and BBQ-Ar scores (r = -0.307; P < 0.01), whereas no significant correlation was found between BBQ-Ar and Pain Rating Scale scores. No floor or celling effects were observed. CONCLUSION: The BBQ-Ar is a valid and reliable tool that can be used to assess back pain beliefs in Arabic-speaking individuals. LEVEL OF EVIDENCE: N/A. PMID- 27244116 TI - Enantioselective Synthesis of Quaternary alpha-Amino Acids via l-tert-Leucine Derived Squaramide-Catalyzed Conjugate Addition of alpha-Nitrocarboxylates to Enones. AB - Enantioselective Michael addition of tertiary alpha-nitroesters to beta unsubstituted vinyl ketones has been carried out in the presence of an l-tert leucine-derived squaramide as organocatalyst. The products, quaternary alpha nitroesters, were formed in excellent yield and moderate to good ee's in most cases. Scale-up of the reaction and synthetic applications of the products, including transformation to representative quaternary alpha-amino acids, have also been demonstrated. PMID- 27244117 TI - The Reliability, Validity and Responsiveness of Two Disease Scores (BPDAI and ABSIS) for Bullous Pemphigoid: Which One to Use? AB - A significant obstacle in guiding evidence-based management of bullous pemphigoid (BP) is the lack of a standardised, validated scoring system for the condition. The aim of this study is to evaluate the suitability of the Bullous Pemphigoid Disease Area Index (BPDAI) and the Autoimmune Bullous Skin disorder Intensity Score (ABSIS) as outcome measures for BP in clinical trials. Thirty-two BP patients were repeatedly assessed over four years using Physician Global Assessment (PGA), anti-BP180 ELISA titres, BPDAI, ABSIS, BPDAI-Pruritus, Autoimmune Bullous Disease Quality of Life (ABQOL) and Treatment of Autoimmune Bullous Disease Quality of Life (TABQOL) questionnaires. The reliability, validity, responsiveness, and minimal clinically important differences (MCIDs) were calculated. For inter-rater reliability, the intraclass correlation coefficients (95% CI) were: BPDAI 0.957 (0.901-0.982) and ABSIS 0.881 (0.736 0.949). Compared to ABSIS, BPDAI was better correlated with PGA(r = 0.875, p < 0.001), BPDAI-Pruritus (r=0.632, p = 0.004), ABQOL (r = 0.521, p = 0.011) and TABQOL (r=0.538, p = 0.008). MCIDs for BPDAI were 4-points for assessing clinical improvement and 3-points for deterioration. ABSIS demonstrated less responsiveness with MCIDs at 8.6-points for improvement and 4-points for deterioration. These results indicate that BPDAI demonstrated excellent reliability, validity and responsiveness, while ABSIS had moderate to good reliability, validity and responsiveness. PMID- 27244115 TI - ALG-2 interacting protein-X (Alix) is essential for clathrin-independent endocytosis and signaling. AB - The molecular mechanisms and the biological functions of clathrin independent endocytosis (CIE) remain largely elusive. Alix (ALG-2 interacting protein X), has been assigned roles in membrane deformation and fission both in endosomes and at the plasma membrane. Using Alix ko cells, we show for the first time that Alix regulates fluid phase endocytosis and internalization of cargoes entering cells via CIE, but has no apparent effect on clathrin mediated endocytosis or downstream endosomal trafficking. We show that Alix acts with endophilin-A to promote CIE of cholera toxin and to regulate cell migration. We also found that Alix is required for fast endocytosis and downstream signaling of the interleukin 2 receptor giving a first indication that CIE is necessary for activation of at least some surface receptors. In addition to characterizing a new function for Alix, our results highlight Alix ko cells as a unique tool to unravel the biological consequences of CIE. PMID- 27244118 TI - Corrigendum: Glucagon-like peptide-1 prevents methylglyoxal-induced apoptosis of beta cells through improving mitochondrial function and suppressing prolonged AMPK activation. PMID- 27244119 TI - Free-Standing, Nanopatterned Janus Membranes of Conducting Polymer-Virus Nanoparticle Arrays. AB - Nanostructured mesoscale materials find wide-ranging applications in medicine and energy. Top-down manufacturing schemes are limited by the smallest dimension accessible; therefore, we set out to study a bottom-up approach mimicking biological systems, which self-assemble into systems that orchestrate complex energy conversion functionalities. Inspired by nature, we turned toward protein based nanoparticle structures formed by plant viruses, specifically the cowpea mosaic virus (CPMV). We report the formation of hierarchical CPMV nanoparticle assemblies on colloidal-patterned, conducting polymer arrays using a protocol combining colloidal lithography, electrochemical polymerization, and electrostatic adsorption. In this approach, a hexagonally close-packed array of polystyrene microspheres was assembled on a conductive electrode to function as the sacrificial colloidal template. A thin layer of conducting polypyrrole material was electrodeposited within the interstices of the colloidal microspheres and monitored in situ using electrochemical quartz crystal microbalance with dissipation (EC-QCM-D). Etching the template revealed an inverse opaline conducting polymer pattern capable of forming strong electrostatic interactions with CPMV and therefore enabling immobilization of CPMV on the surface. The CPMV-polymer films were characterized by atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS). Furthermore, molecular probe diffusion experiments revealed selective ion transport properties as a function of the presence of the CPMV nanoparticles on the surface. Lastly, by utilizing its electromechanical behavior, the polymer/protein membrane was electrochemically released as a free-standing film, which can potentially be used for developing high surface area cargo delivery systems, stimuli-responsive plasmonic devices, and chemical and biological sensors. PMID- 27244120 TI - Mass Barcode Signal Amplification for Multiplex Allergy Diagnosis by MALDI-MS. AB - A highly sensitive method based on mass-barcoded gold nanoparticles (AuNPs) and immunomagnetic separation has been developed for multiplex allergy diagnosis by MALDI mass spectrometry in a component-resolved manner. Different analytical probes were prepared by coating AuNPs with individual allergenic proteins and mass barcode, represented by polyethylene glycol molecules of various chain lengths. Magnetic beads (MBs) functionalized with antihuman IgE antibodies (Abs) were used as immunomagnetic capture probes. IgE Abs were extracted from a patient's blood serum by the formation of a sandwich structure between the AuNPs and MBs. Multiple specific IgE Abs were simultaneously identified by mass spectrometry detection of the mass barcodes, providing an efficient component resolved allergy diagnosis. Because of the signal amplification provided by the mass barcodes, the developed diagnosis method is very sensitive, with a limit of detection down to picograms per milliliter level for specific IgE Abs. The method can be potentially useful when the sample amount is highly limited and a multiplex diagnostic procedure is required. PMID- 27244124 TI - Spectroscopic Characterization of the 3+ and 2+ Oxidation States of Europium in a Macrocyclic Tetraglycinate Complex. AB - The 3+ and 2+ oxidation states of europium have drastically different magnetic and spectroscopic properties. Electrochemical measurements are often used to probe EuIII/II oxidation state changes, but a full suite of spectroscopic characterization is necessary to demonstrate conversion between these two oxidation states in solution. Here, we report the facile conversion of an europium(III) tetraglycinate complex into its EuII analogue. We present electrochemical, luminescence, electron paramagnetic resonance, UV-visible, and NMR spectroscopic data demonstrating complete reversibility from the reduction and oxidation of the 3+ and 2+ oxidation states, respectively. The EuII containing analogue has kinetic stability within the range of clinically approved GdIII-containing complexes using an acid-catalyzed dissociation experiment. Additionally, we demonstrate that the 3+ and 2+ oxidation states provide redox responsive behavior through chemical-exchange saturation transfer or proton relaxation, respectively. These results will be applicable to a wide range of redox-responsive contrast agents and Eu-containing complexes. PMID- 27244125 TI - Analysis of Injury Incidences in Male Professional Adult and Elite Youth Soccer Players: A Systematic Review. AB - CONTEXT: The incidence of injury for elite youth and professional adult soccer players is an important concern, but the risk factors for these groups are different. OBJECTIVE: To summarize and compare the injury incidences and injury characteristics of male professional adult and elite youth soccer players. DATA SOURCES: We searched MEDLINE and Web of Science using the search terms elite, international, European, soccer, football, injury, injuries, epidemiology, incidence, prevalence, not female, not American football, and not rugby. We also used the search terms professional for studies on professional adult soccer players and high-level, soccer academy, youth, adolescent, and young for studies on elite youth soccer players. STUDY SELECTION: Eligible studies were published in English, had a prospective cohort design, and had a minimum study period of 6 months. To ensure that injury data were assessed in relationship to the athlete's individual exposure, we included only studies that reported on injuries and documented exposure volume. DATA EXTRACTION: Two independent reviewers applied the selection criteria and assessed the quality of the studies. DATA SYNTHESIS: A total of 676 studies were retrieved from the literature search. Eighteen articles met the inclusion criteria: 6 for elite youth and 12 for professional adult soccer players. CONCLUSIONS: Injury rates were higher for matches than for training for both youth and adult players. Youth players had a higher incidence of training injuries than professionals. Efforts must be made to reduce the overall injury rate in matches. Therefore, preventive interventions, such as adequately enforcing rules and focusing on fair play, must be analyzed and developed to reduce match-related injury incidences. Reducing training injuries should be a particular focus for youth soccer players. PMID- 27244126 TI - Early Operative Versus Delayed or Nonoperative Treatment of Anterior Cruciate Ligament Injuries in Pediatric Patients. AB - Reference: Ramski DE, Kanj WW, Franklin CC, Baldwin KD, Ganley TJ. Anterior cruciate ligament tears in children and adolescents: a meta-analysis of nonoperative versus operative treatment. Am J Sports Med. 2014;42(11):2769-2776. Clinical Questions: In pediatric patients, does early operative treatment of an anterior cruciate ligament (ACL) injury result in decreased knee instability compared with delayed or nonoperative treatment? DATA SOURCES: This review focused on the PubMed/MEDLINE and EMBASE databases. The following query searches were used: ACL or anterior cruciate ligament and young or child or children or pediatric or immature. Dates searched were not specified. A separate search was also conducted of abstracts published between 2009 and 2011 from the American Academy of Orthopaedic Surgeons; American Orthopaedic Society for Sports Medicine; International Society of Arthroscopy, Knee Surgery, and Orthopaedic Sports Medicine; European Society of Sports Traumatology, Knee Surgery, and Arthroscopy; American Orthopaedic Association; Arthroscopy Association of North America; Pediatric Orthopaedic Society of North America; and American Academy of Pediatrics conferences. STUDY SELECTION: Available studies were included only if they were written in English; were of level 1, 2, or 3 evidence (grading taxonomy not stated); were cohort designs that compared nonoperative and operative treatments; involved an early versus delayed ACL reconstruction that could be prospective or retrospective; and reported primary outcome interest measures. Animal studies, basic science studies, case series, reviews, commentaries, and editorials were excluded from the review. DATA EXTRACTION: A systematic assessment tool, Guide to Community Preventive Services: Systematic Reviews and Evidence-Based Recommendations, was used by 2 of the authors to independently grade the quality of each study that met the inclusion criteria. The tool focused on 6 areas: intervention and study description, sampling, measurement, analysis, interpretation of results, and other execution factors. This tool helped to ensure consistency, reduce bias, and improve the validity and reliability of preventive health care studies. Eleven studies met the inclusion criteria. Six studies compared nonoperative with operative treatment, and 5 studies compared early reconstruction (open physes) with delayed reconstruction (closed physes). Studies in this meta-analysis consisted of the following: four level-3 prospective studies, four level-3 retrospective studies, one level-2 retrospective study, one level-3 case-control study, and one level-3 study with both prospective and retrospective data collection. All of the studies included data related to patient demographics, treatment interventions, follow-up duration, presence of any meniscal symptoms, time to return to sport participation, patient-reported outcomes (International Knee Documentation Committee [IKDC], Lysholm, or Tegner scores), the need for a second surgical procedure, and any posttreatment problems. MAIN RESULTS: Of those who chose the nonoperative route, 75% reported instability, whereas only 13.6% of those who had surgery reported instability. These data also showed that nonoperative or delayed operative patients were 33.7 times more likely to report instability than the early operative group. Those who chose the nonoperative route had a 12 times greater risk (odds ratio = 12.2, 95% confidence interval = 1.55, 96.3) of developing a meniscal tear after the initial injury. Three studies included in the meta-analysis reported return to sport status, but only 2 studies provided adequate data for both operative and nonoperative patients. In 1 study, 92% of operative patients were able to return to sport, but only 43.75% of nonoperative patients were able to do so. The second study reported that all operative and nonoperative patients were able to return to the same level of sport after injury. Of those in the early operative group, 6% required a repeat surgical intervention for either an ACL rerupture or a meniscal tear, and 19% of those who initially chose nonoperative treatment eventually needed surgery to repair the ACL or meniscus. Findings favor the early operative group over the delayed operative and nonoperative groups based on IKDC scores. One study reported a significant difference in operative patients, with an IKDC mean score of 95 compared with 87 in the nonoperative group. Similarly, a different study reported a mean score of 94.6 in the early operative group compared with 82.4 in the delayed operative group and was stated to have met the minimal clinically important difference (MCID). The MCID was not met for the Lysholm and Tegner scores between operative and nonoperative patients. CONCLUSIONS: The results of this meta-analysis favor early operative treatment for pediatric patients with ACL tears over delayed or nonoperative treatment. Early operative treatment is initiated shortly after the injury, while the patient is still skeletally immature and the growth plates are open. Current evidence suggests that early ACL reconstruction will result in less knee instability and a more likely return to the preinjury activity level without affecting the growth plates or causing growth disturbances. PMID- 27244127 TI - Internal Mammary Node Radiation in Light of the EORTC 22922 and MA.20 Trials-What Have We Really Learned? PMID- 27244129 TI - Relationships between global physical activity and bone mineral density in a group of male and female students. AB - BACKGROUND: Peak of bone mass (PBM) is generally reached about the age of 18 both in boys and girls. Maximizing PBM during growth may contribute to fracture risk reduction in adulthood and in the elderly. The aim of our study was to evaluate the effects on bone mineral density (BMD) of global physical activity (PA), carried out in the past 15 years, in a population of 70 healthy, young male and female subjects aged 22 to 25. METHODS: BMD of the lumbar spine and total hip was measured using dual-energy X-ray absorptiometry (DEXA); global PA, resulting from sports-related, occupational and commuting PA, was evaluated using validated questionnaires. RESULTS: Women spent more time than men both in sports-related, occupational and commuting PA in the age range between 10-15 years. In the female group global PA positively correlated with BMD of the lumbar spine (r=0.38; P=0.02) and the total hip (r=0.36; P=0.04) and BMD of the lumbar spine was independently predicted by global PA and Body Mass Index. CONCLUSIONS: Our retrospective cross-sectional study indicates that global PA, not only sports related PA, performed during prepubertal age, is associated with a greater PBM in women. PMID- 27244130 TI - One repetition maximum test in octogenarian: evaluation of blood pressure. AB - BACKGROUND: The gold standard for resistance training prescription is the one repetition maximum strength test (1RM). However, there are fears that, by making maximum effort, octogenarian may elevate their blood pressure (BP). METHODS: Forty subjects (25 women) aged 83.3+/-3.2 years underwent two days of office BP measurements (V1 and V2). On the 1RM test day, measurements were performed before (BASAL) and after (POST) test. 1RM tests were performed in the Seated Chest Press (SCP), Leg Press (LP) and Seated Back Row (SBR), with BP measurements immediately after (1RM) and one minute after (1RM(1')) each exercise. RESULTS: Maximum systolic BP (SBP) in the SCP was 137 mmHg in 1RM, with no difference compared to V1 (P=0.29). In LP, maximum SBP was 143 mmHg in 1RM(1'), but BP came down quickly, with SBP in POST equal to V1 (P=0.95). There were differences over time in SBR (P<0.01), but SBP in 1RM and in 1RM(1') was similar to V1 (P=0.20). There was a small difference in diastolic BP over time. CONCLUSIONS: There was a moderate SBP increase in 1RMand 1RM(1'), with emphasis on the LP. In general, BP after 1RM did not differ from the first assessment day. PMID- 27244128 TI - Demographic, Reproductive, and Dietary Determinants of Perfluorooctane Sulfonic (PFOS) and Perfluorooctanoic Acid (PFOA) Concentrations in Human Colostrum. AB - To determine demographic, reproductive, and maternal dietary factors that predict perfluoroalkyl substance (PFAS) concentrations in breast milk, we measured perfluorooctane sulfonic (PFOS) and perfluorooctanoic acid (PFOA) concentrations, using liquid chromatography-mass spectrometry, in 184 colostrum samples collected from women participating in a cohort study in Eastern Slovakia between 2002 and 2004. During their hospital delivery stay, mothers completed a food frequency questionnaire, and demographic and reproductive data were also collected. PFOS and PFOA predictors were identified by optimizing multiple linear regression models using Akaike's information criterion (AIC). The geometric mean concentration in colostrum was 35.3 pg/mL for PFOS and 32.8 pg/mL for PFOA. In multivariable models, parous women had 40% lower PFOS (95% CI: -56 to -17%) and 40% lower PFOA (95% CI: -54 to -23%) concentrations compared with nulliparous women. Moreover, fresh/frozen fish consumption, longer birth intervals, and Slovak ethnicity were associated with higher PFOS and PFOA concentrations in colostrum. These results will help guide the design of future epidemiologic studies examining milk PFAS concentrations in relation to health end points in children. PMID- 27244131 TI - Effects of one-night sleep deprivation on selective attention and isometric force in adolescent karate athletes. AB - BACKGROUND: Most of the available literature related to aspects of sleep deprivation is primarily focused on memory and learning, and studies regarding its effects on selective attention and/or physical performance are scarce. Moreover, the available literature includes general population or people involved in team sports (e.g. volleyball). However, only few studies were performed on athletes involved in combat sports (e.g. karate). The aim of the present study was to determine the effects of a total one-night sleep deprivation (1NSD) on activation and inhibition processes of selective attention and on maximal isometric force in karate athletes. METHODS: Twelve young karate athletes (mean age 16.9+/-0.8 years) were enrolled. The protocol consists of two successive sessions: a normal night's sleep (NNS) and a total 1NSD. After each night, athletes performed selective attention and muscle strength tests during the same following three times (T) of the day: T1NNS or T11NSD: 8-9 a.m.; T2NNS or T21NSD: 12 a.m.-1 p.m.; T3NNS or T31NSD: 4-5 p.m. Activation (simple [SRT] and choice reaction times [CRT]) and inhibition (negative priming) processes were evaluated using Superlab v. 4.5 software (Cedrus Corporation, San Pedro, CA, USA). Maximal force and maximal force time (MFT) of brachial biceps isometric contraction were evaluated (Ergo System(r), Globus, Codogne, Italy). A non-parametric test was used to evaluate the sessions (NNS vs. SND for the same time period) and time (T1NNS vs. 1NSD) effects. RESULTS: All athletes completed all tests after a NNS. Twelve, eleven and four athletes completed all tests at T11NSD, T21NSD and T31NSD, respectively. As for sessions effects, no statistically significant difference was found. As for time effects, a significant increase in SRT at T21NSD vs. T1NNS (345+/-47 vs. 317+/-33 ms, respectively), a significant increase in MFT at T21NSD vs. T1NNS (2172+/-260 vs.1885+/-292 ms, respectively), and no significant changes in CRT and negative priming reaction time or MFT data were observed. CONCLUSIONS: 1NSD affects both activation processes of selective attention and maximal isometric strength, two key skills in combat sports. PMID- 27244132 TI - Effect of pre-task music on sports or exercise performance. AB - INTRODUCTION: Pre-task music is a very common strategy among sports competitors. However, as opposed to in-task music, the scientific evidence to support its ergogenic effects on either sports or exercise performance is limited. This brief review critically addresses the existing literature investigating the effects of pre-task music on sports and exercise performance, focusing on the methods and results of experimental studies, and offers basic and practical recommendations. EVIDENCE ACQUISITION: In July 2015, a comprehensive literature search was performed in Web of Science, PubMed, and Google Scholar using the following key words in combination: "pre-task music," "pre-test music," "pre-exercise music," "exercise performance," "sports performance." The literature search was further expanded by both hand searching review articles on the topic and by searching the reference lists from the articles retrieved for any relevant references. Overall, a total of 15 studies in 14 articles were included. EVIDENCE SYNTHESIS: Pre-task music research has been unsystematic, methodologically limited and infrequent. Using this review as a starting point to overcome previous methodological limitations when designing future experiments may contribute to the development of pre-task music research, which is still in its infancy. CONCLUSIONS: Currently, there is no sufficient evidence to support the overall ergogenic effects of pre-task music on sports or exercise performance. Nonetheless, pre task music has showed a likely ergogenic effect on shorter and predominantly anaerobic tasks such as grip strength, Wingate test, and short-duration sports or sports-like tasks, in contrast to longer and predominantly aerobic tasks. PMID- 27244133 TI - The Impact of Lactobacillus casei on the Composition of the Cecal Microbiota and Innate Immune System Is Strain Specific. AB - The probiotic function to impact human health is thought to be related to their ability to alter the composition of the gut microbiota and modulate the human innate immune system. The ability to function as a probiotic is believed to be strain specific. Strains of Lactobacillus casei are commonly utilized as probiotics that when consumed alter the composition of the gut microbiota and modulate the host immune response. L. casei strains are known to differ significantly in gene content. The objective of this study was to investigate seven different L. casei strains for their ability to alter the murine gut microbiota and modulate the murine immune system. C57BL/6 mice were fed L. casei strains at a dose of 108 CFU/day/mouse for seven days and sacrificed 3.5h after the last administration. The cecal content and the ileum tissue were collected for microbiota analysis and immune profiling, respectively. While 5 of the L. casei strains altered the gut microbiota in a strain specific manner, two of the strains did not alter the overall cecal microbiota composition. The observed changes cluster into three groups containing between 1 and 2 strains. Two strains that did not affect the gut microbiota composition cluster together with the control in their impact on pattern recognition receptors (PRRs) expression, suggesting that the ability to alter the cecal microbiota correlates with the ability to alter PRR expression. They also cluster together in their impact on the expression of intestinal antimicrobial peptides (AMPs). This result suggests that a relationship exists between the capability of a L. casei strains to alter the composition of the gut microbiota, PRR regulation, and AMP regulation. PMID- 27244188 TI - HIV Prevention Among Diverse Young MSM: Research Needs, Priorities, and Opportunities. AB - There remains a profound need for innovative and effective interventions designed for young men who have sex with men (YMSM) generally, and racial and ethnic minority YMSM, YMSM living in rural communities, and low-income YMSM, particularly, to prevent HIV and improve health outcomes in the United States. This introduction to this theme issue, "Behavioral HIV Prevention Interventions for Diverse YMSM," of AIDS Education and Prevention identifies some of the research needs, priorities, and opportunities that emerged during a seminal NIMHD sponsored workshop on HIV prevention behavioral interventions for diverse YMSM. It provides researchers, practitioners, and federal partners guidance in next steps to reduce the impact of the HIV epidemic among YMSM. The needs, priorities, and opportunities identified serve as a foundation to push both the science and the practice of HIV prevention forward. We recognize that considerably more research is needed, and this issue highlights intervention research-where we have been and where we should go. With the disparities faced by YMSM, we must act rapidly to do the work it will take to meet their prevention needs, reduce infections, and save lives. PMID- 27244189 TI - "Let Me Help You Help Me": Church-Based HIV Prevention for Young Black Men Who Have Sex With Men. AB - The goal of this study was to identify strategies that could yield more inclusive church-based HIV prevention efforts. In-depth interviews were conducted with 30 young Black men who have sex with men (YBMSM) living in Baltimore, Maryland. The sample had an equal number of regular and infrequent church attendees. Nearly one fourth of the sample was HIV-positive. Interviews were transcribed verbatim and analyzed inductively using a qualitative content analytic approach. Two main recommendations emerged for churches to offer more inclusive HIV prevention efforts: (1) reduce homosexuality stigma by increasing interpersonal and institutional acceptance, and (2) address the sexual health needs of all congregants by offering universal and targeted sexual health promotion. Thus, results support a tiered approached to providing more inclusive church-based HIV prevention efforts. We conclude that Black churches can be a critical access point for HIV prevention among YBMSM and represent an important setting to intervene. PMID- 27244191 TI - Implementation and Evaluation of the Keep It Up! Online HIV Prevention Intervention in a Community-Based Setting. AB - Once HIV prevention programs have proven efficacy in research settings, it is important that ongoing data are collected to demonstrate effects in public health applications, yet such evaluations are rare in the published literature. This project describes the adaptation, implementation, and outcome evaluation of the Keep It Up! (KIU!) online HIV prevention intervention as a prevention service delivered in a community-based organization. Compared to pilot research examining KIU! feasibility and efficacy, intervention outcomes were robust to service delivery and client characteristics. In a sample of ethnically and racially diverse young men who have sex with men (N = 343), the intervention produced significant decreases in condomless anal sex acts with casual male partners at the 3-month follow-up compared to baseline (p < .05). In both qualitative and quantitative measures, participants reported that the intervention was highly acceptable and valuable to their sexual health needs. PMID- 27244190 TI - weCARE: A Social Media-Based Intervention Designed to Increase HIV Care Linkage, Retention, and Health Outcomes for Racially and Ethnically Diverse Young MSM. AB - Estimates suggest that only about 30% of all individuals living with HIV in the U.S. have achieved viral suppression. Men who have sex with men (MSM), particularly racial/ethnic minority young MSM, are at increased risk for HIV infection and may have even lower viral suppression rates. HIV testing rates among MSM are low, and when tested, racial/ethnic minority young MSM have disproportionately lower rates of retention in care and viral suppression compared to other subgroups. This article describes the design and development of weCare, our social media-based intervention to improve care linkage and retention and health outcomes among racially and ethnically diverse MSM, ages 13-34, living with HIV that will be implemented and evaluated beginning in late 2016. The intervention harnesses established social media that MSM between these ages commonly use, including Facebook, text messaging, and established GPS-based mobile applications (apps). We are using community-based participatory research (CBPR) to enhance the quality and validity of weCare, equitably involving community members, organization representatives, healthcare providers, clinic staff, and academic researchers. PMID- 27244193 TI - Enhancing HIV Prevention Among Young Men Who Have Sex With Men: A Systematic Review of HIV Behavioral Interventions for Young Gay and Bisexual Men. AB - Men who have sex with men (MSM) represent 64.0% of people living with HIV (PLWH) over the age of 13 years. Young men who have sex with men (YMSM) are particularly affected by HIV/AIDS; the rate of HIV infection for YMSM between the ages of 13 and 24 represents 72.0% of new infections among youth. To understand the current state of the science meant to prevent HIV for YMSM, we reviewed studies of HIV behavioral prevention interventions for YMSM. Five literature databases were searched, from their inception through October 2015, using key words associated with HIV prevention intervention evaluation studies for YMSM. The review criteria included behavioral HIV/AIDS prevention interventions, articles published in English-language peer-reviewed journals, YMSM between 13 and 24 years of age, and longitudinal repeated measures design. A total of 15 YMSM behavioral HIV prevention intervention studies were identified that met inclusion criteria and reported statistically significant findings. Common outcomes included unprotected sexual intercourse, HIV/AIDS risk behavior, condom use, HIV testing, safer sex attitude, and HIV prevention communication. Participant age, representation of Black/African American YMSM, application of theoretical and model underpinnings, congruence of assessment measures used, follow-up assessment times, and application of process evaluation were inconsistent across studies. To advance HIV prevention intervention research for YMSM, future studies should be theory based, identify common constructs, utilize standard measures, include process evaluation, and evaluate sustained change over standard periods of time. HIV prevention interventions should incorporate the needs of the diverse, well educated, web-connected millennial generation and differentiate between adolescent YMSM (13 to 18 years of age) and young adulthood YMSM (19 to 24 years of age). Because Black/African American YMSM represent more than 50% of new HIV infections, future HIV prevention intervention studies should prioritize these young men. PMID- 27244192 TI - Does Age Matter Among Young Black Men Who Have Sex With Men? A Comparison of Risk Behaviors Stratified by Age Category. AB - The purpose of this study is to assess whether different sexual risk behavior exists among young Black men who have sex with men (YBMSM) as a function of age. A total of 382 YBMSM completed a computer-assisted self-interview at a sexual health clinic. The frequency/prevalence of fifteen sexual risk behaviors was compared between three groups (ages 16-19, 20-25, and 26-29, respectively) in the 90 days prior to enrollment in the study. Regression models were used to control for the confounding influence of Human Immunodeficiency Virus (HIV) status. One hundred seven participants were HIV-infected at study enrollment. Of the 15 measures assessed, none significantly differed among the groups. These null findings did not change in multivariate analyses. Our findings suggest that there is no differential sexual risk based on age among YBMSM and that this group should be considered a homogenous population with regards to intervention strategies that aim to reduce the sexual risk behaviors of YBMSM. PMID- 27244194 TI - Unheard Voices: The Need for HIV Research and Prevention Priorities for YMSM in the Global Context. AB - This commentary considers the AIDS Education and Prevention special issue (volume 28, number 3) entitled "Behavioral HIV Prevention Interventions for Diverse Young Men Who Have Sex with Men (MSM)." The research presented in this special issue highlights the importance of addressing sub-populations of young MSM in order to better understand the unique realities and risk-factors affecting HIV epidemics and intervention needs. Here, we focus on several broad topics raised in this special issue and comment on their implications for HIV research and practice targeting young MSM in low- and middle-income countries. We consider issues relevant to reaching hidden populations, tailoring interventions, and integrating new communications and bio-medical technologies in research and practice in low resource settings. PMID- 27244196 TI - Revisiting the frequency domain: the multiple and partial coherence of cerebral blood flow velocity in the assessment of dynamic cerebral autoregulation. AB - Despite advances in modelling dynamic autoregulation, only part of the variability of cerebral blood flow velocity (CBFV) in the low frequency range has been explained. We investigate whether a multivariate representation can be used for this purpose. Pseudorandom sequences were used to inflate thigh cuffs and to administer 5% CO2. Multiple and partial coherence were estimated, using arterial blood pressure (ABP), end-tidal CO2 (EtCO2) and resistance area product as input and CBFV as output variables. The inclusion of second and third input variables increased the amount of CBFV variability that can be accounted for (p < 10(-4) in both cases). Partial coherence estimates in the low frequency range (<0.07 Hz) were not influenced by the use of thigh cuffs, but CO2 administration had a statistically significant effect (p < 10(-4) in all cases). We conclude that the inclusion of additional inputs of a priori known physiological significance can help account for a greater amount of CBFV variability and may represent a viable alternative to more conventional non-linear modelling. The results of partial coherence analysis suggest that dynamic autoregulation and CO2 reactivity are likely to be the result of different physiological mechanisms. PMID- 27244195 TI - Mastering Dendrimer Self-Assembly for Efficient siRNA Delivery: From Conceptual Design to In Vivo Efficient Gene Silencing. AB - Self-assembly is a fundamental concept and a powerful approach in molecular science. However, creating functional materials with the desired properties through self-assembly remains challenging. In this work, through a combination of experimental and computational approaches, the self-assembly of small amphiphilic dendrons into nanosized supramolecular dendrimer micelles with a degree of structural definition similar to traditional covalent high-generation dendrimers is reported. It is demonstrated that, with the optimal balance of hydrophobicity and hydrophilicity, one of the self-assembled nanomicellar systems, totally devoid of toxic side effects, is able to deliver small interfering RNA and achieve effective gene silencing both in cells - including the highly refractory human hematopoietic CD34(+) stem cells - and in vivo, thus paving the way for future biomedical implementation. This work presents a case study of the concept of generating functional supramolecular dendrimers via self-assembly. The ability of carefully designed and gauged building blocks to assemble into supramolecular structures opens new perspectives on the design of self-assembling nanosystems for complex and functional applications. PMID- 27244198 TI - Experimental Design for Composite Face Transplantation. AB - Face allotransplantation represents a novel frontier in complex human facial defect reconstruction. To develop more refined surgical techniques and yield fine results, it is first imperative to make a suitable animal model. The development of a composite facial allograft model in swine is more appealing: the facial anatomy, including facial nerve and vascular anatomy, is similar to that of humans. Two operative teams performed simultaneously, one assigned to harvest the donor and the other to prepare the recipient in efforts to shorten operative time. The flap was harvested with the common carotid artery and external jugular vein, and it was transferred to the recipient. After insetting the maxilla, mandible, muscles, and skins, the anastomosis of the external jugular vein, external carotid artery, and facial nerve were performed. The total mean time of transplantation was 7 hours, and most allografts survived without vascular problems. The authors documented that this model is well qualified to be used as a standard transplantation training model and future research work, in every aspect. PMID- 27244197 TI - Identification and Validation of Reference Genes for RT-qPCR Studies of Hypoxia in Squamous Cervical Cancer Patients. AB - Hypoxia is an adverse factor in cervical cancer, and hypoxia-related gene expression could be a powerful biomarker for identifying the aggressive hypoxic tumors. Reverse transcription quantitative PCR (RT-qPCR) is a valuable method for gene expression studies, but suitable reference genes for data normalization that are independent of hypoxia status and clinical parameters of cervical tumors are lacking. In the present work, we aimed to identify reference genes for RT-qPCR studies of hypoxia in squamous cervical cancer. From 422 candidate reference genes selected from the literature, we used Illumina array-based expression profiles to identify 182 genes not affected by hypoxia in cervical cancer, i.e. genes regulated by hypoxia in eight cervical cancer cell lines or correlating with the hypoxia-associated dynamic contrast-enhanced magnetic resonance imaging parameter ABrix in 42 patients, were excluded. Among the 182 genes, nine candidates (CHCHD1, GNB2L1, IPO8, LASP1, RPL27A, RPS12, SOD1, SRSF9, TMBIM6) that were not associated with tumor volume, stage, lymph node involvement or disease progression in array data of 150 patients, were selected for further testing by RT-qPCR. geNorm and NormFinder analyses of RT-qPCR data of 74 patients identified CHCHD1, SRSF9 and TMBIM6 as the optimal set of reference genes, with stable expression both overall and across patient subgroups with different hypoxia status (ABrix) and clinical parameters. The suitability of the three reference genes were validated in studies of the hypoxia-induced genes DDIT3, ERO1A, and STC2. After normalization, the RT-qPCR data of these genes showed a significant correlation with Illumina expression (P<0.001, n = 74) and ABrix (P<0.05, n = 32), and the STC2 data were associated with clinical outcome, in accordance with the Illumina data. Thus, CHCHD1, SRSF9 and TMBIM6 seem to be suitable reference genes for studying hypoxia-related gene expression in squamous cervical cancer samples by RT-qPCR. Moreover, STC2 is a promising prognostic hypoxia biomarker in cervical cancer. PMID- 27244199 TI - Traumatic Epidermoid Inclusion Cyst on Cheek Area. AB - An epidermoid inclusion cyst is basically an epidermoid cyst resulting from the traumatic implantation of epidermal elements into the dermis with their subsequent cystic transformation. A case of an epidermal inclusion cyst of the cheek region is described in a 54-year-old man, whose feature was rather unusual, in that it presented as a fixed, indurated, inflamed, and sometimes, mimicking a parotid gland infection. The cyst was particularly persistent and recurred within a month of its medical treatment and had to be re-excised along with the adjacent parotid mass. PMID- 27244200 TI - Endoscopic Reconstruction of Isolated Orbital Floor Wall Fracture Considering Orbital Floor Slope. AB - PURPOSE: To present a surgical technique for the reconstruction of the orbital floor slope in patients of isolated orbital floor fracture and to evaluate the effectiveness of this technique. METHODS: The authors conducted a retrospective review of all patients who underwent reconstruction of isolated orbital floor wall fracture between June 2010 and July 2015. The authors reviewed patient demographics, degree of enophthalmos, ocular motility and diplopia test results, and surgical complications. RESULTS: This study included 33 eyes from 33 patients. The mean time interval from trauma to surgery was 24.9 days (range, 5 360 days). The average postoperative follow-up period was 7.4 months (range, 3-28 months). The degree of enophthalmos preoperatively and 1 week, 1 month, and 3 months postoperatively was -1.55 mm (range, -3 to -0.5 mm), 0.22 mm (range, -0.5 to +1.0 mm), -0.06 mm (range, -1.0 to +1.0 mm), and -0.13 mm (range, -0.5 to +0.5 mm), respectively. The mean improvement in enophthalmos at postoperative 3 months was 1.41 mm compared with that in the preoperative data (P value <0.001). There were no patients with residual enophthalmos greater than 1 mm after reconstruction. CONCLUSION: Endoscopic orbital floor slope reconstruction in isolated orbital floor wall fracture using a layered porous polyethylene barrier implant is a very useful surgical technique for safely identifying the posterior margin of a fracture and easily reconstructing the orbital floor slope. The demonstration of slight exophthalmos of the corrected side about 1 to 2 mm at the end of the operation was also necessary. PMID- 27244201 TI - Unsuccessful Treatment of Atrophic Mandible Fracture by Use of Improper Materials. AB - Fractures of atrophic mandibles are present on the day by day of buccomaxillofacial surgeons. Mandible atrophy occurs due to tooth loss, which over time induces bone resorption leading to a fragile and susceptible to fracture structure. This paper reports the case of a patient victim of face trauma resulting in atrophic mandible fracture with treatment failure through the use of shared load miniplate. Therefore, a new treatment was performed with miniplate of system 2.4 along with bone graft. After 6 months, the patient was rehabilitated with implant-supported prosthesis installation. It is concluded that for successful treatment of atrophic mandible fractures, the use of rigid plates is necessary, allowing an excellent rehabilitation of the stomatognathic system. PMID- 27244202 TI - Radiofrequency Ablation Is Low Invasive and Effective in Treat Pleomorphic Adenoma in Trachea Without Recurrence for At Least Five Years. AB - The authors reported 6 patients of pleomophic adenoma in trachea in patients (57 +/- 3.6 years old). Swellings in trachea (2 +/- 0.85 cm) were revealed by computed tomography and bronchoscopy. All swellings were removed successfully using radiofrequency ablation through flexible bronchoscopy. Histopathological examinations of tumor specimens confirmed their diagnosis of pleomorphic adenoma. No complication nor tumor recurrences were reported throughout the 5-year postoperative follow-up period in each patient which indicate good prognosis. The authors here report an effect but mini-invasive approach to treat rare trachea tumor and demonstrate a way of successful treatment using a mini-invasive way. Compared with other treating procedures, the authors consider radiofrequency ablation is of low invasion with the consequence of cure all treated patients of pleomorphic adenoma in trachea. PMID- 27244203 TI - Behavior of Osteoblast-Like Cells on a beta-Tricalcium Phosphate Synthetic Scaffold Coated With Calcium Phosphate and Magnesium. AB - OBJECTIVES: Tricalcium phosphate (TCP) is one of the most useful synthetic scaffolds for bone grafts and has several advantages. However, the rapid degradation of TCP makes it less osteoconductive than the other candidates, and represents a major shortcoming. To overcome this problem, the authors investigated magnesium (Mg) and/or hydroxyapatite (HA) coating on a beta-TCP substrate using a sputtering technique. METHODS: Biocompatibility tests were carried out on beta-TCP discs that were either uncoated (TCP), coated with HA by radio frequency magnetron sputtering (HA-TCP), coated with Mg by DC sputtering (Mg-TCP), or multicoated with Mg and HA by DC and radio frequency magnetron sputtering (MgHA-TCP). RESULTS: Cells showed similar morphology in all 4 groups, and were widely spread, had flattened elongated shapes, and were connected to adjacent cells by pseudopods. An MTT assay revealed higher cell proliferation on HA-TCP, Mg-TCP, and MgHA-TCP compared with TCP at 3 and 5 days. MgHA-TCP also showed significantly higher alkaline phosphatase activity levels compared with TCP, HA-TCP, and Mg-TCP (P < 0.05). CONCLUSIONS: Results suggest that Mg-coated beta-TCP could have great potential as a bone graft material for future applications in hard tissue regeneration. PMID- 27244204 TI - The Supine Position Technique Method Is Better Than the Conventional Method for Manual Reduction of Acute Nontraumatic Temporomandibular Joint Dislocation. AB - OBJECTIVE: To comparatively assess the effectiveness of the supine position technique versus the conventional method, for the manual reduction of acute nontraumatic temporomandibular joint (TMJ) dislocation. METHODS: This randomized single blind trial included a total of 40 patients, aged 18 to 80 years presenting with acute nontraumatic TMJ dislocation. Based on the randomization procedure, patients were treated with either conventional method or the supine position technique method. The visibility of dynamic occlusion during jaw manipulation, operation time, and visual analogue scale scores for pain perception were comparatively studied. RESULTS: All patients with dislocated mandible were successfully managed. Unlike the conventional technique, the ability to monitor the dynamic occlusion during jaw manipulation was possible only in the supine position method group. The operation time (P < 0.05) and visual analogue scale scores for pain perception (P < 0.01) during the treatment were significantly reduced in the supine position technique group. No accidental finger biting was reported in any groups. CONCLUSIONS: Reduced operation time and reduced pain perception indicated that the supine position technique method might be a more viable alternative to the conventional method of reduction of acute nontraumatic TMJ dislocation. PMID- 27244205 TI - The Complication of Middle Facelift Surgery Resulting in Migration of Temporal Augmentation Implant. AB - A 66-year-old woman admitted with induration, peri-wound marceration, swelling, and tenderness on temporal area. She had repeated painful tenderness on temporal area for 10 days. In the peri-wound, discharge volume increased when she ate spicy food or drank lemon juice. She had no trauma history and special medical history. But 3 weeks ago, she had midface lift surgery at another local clinic. Initially, the authors had aspiration to swelling spot, checked 50 cc serotic discharge. The authors checked contrast enhance facial computed tomography and found homogenous fluid collection and peripheral enhancing low attenuated lesion in the anterior portion of tragus and inferior aspect of left ear lobe. Also migration of ipsilateral temporal augmentation implant was shown as a result of seroma in temporal fossa. The authors decided to proceed with the surgical removal and diversion of fluid collection. Under local anesthesia, the authors had incision and drainage, inserted drainage tube and bag. After inserting a drainage device, daily discharge was reduced and the condition was treated conservatively with additional drainage and resolved completely in 3 weeks. There were no wound problems such as infection, disruption, and so on. PMID- 27244206 TI - Secondary Reconstruction of Residual Enophthalmos Using an Endoscope and Considering the Orbital Floor and Medial Wall Slope. AB - PURPOSE: To present a transconjunctival and transcaruncular endoscopy approach involving layered porous polyethylene barrier implants to manage residual posttraumatic enophthalmos and to evaluate the effectiveness of this technique. METHODS: The authors performed a retrospective review of all patients who underwent secondary reconstruction of orbital wall fractures because of residual enophthalmos between June 2008 and July 2015. Patients' demographics, degree of enophthalmos, ocular motility, diplopia test results, and surgical complications were reviewed. RESULTS: This study included 16 eyes (4 right eyes and 12 left eyes) of 16 patients (14 males and 2 females). The mean time interval from trauma to surgery was 7.1 months (range, 1-18 months). The average postoperative follow up period was 6.4 months (range, 3-18 months). The degree of enophthalmos preoperatively and at 1 week, 1 month, and 3 months postoperatively was -2.47 mm (range, -2 to -3 mm), 0.5 mm (range, -0.5 to +2.5 mm), -0.06 mm (range, -0.5 to +1.5 mm), and -0.44 mm (range, -1.5 to +1.0 mm), respectively. There were no definite surgical complications in any patients. CONCLUSION: Dissection to the posterior margin of the fracture and reconstruction of the orbital floor slope are the most important surgical factors to prevent residual enophthalmos and scarring with recurrent diplopia. Demonstration of slight exophthalmos of the corrected side of about 1 to 2 mm at the end of the operation is also necessary. The authors believe that surgery using an endoscope and layered porous polyethylene is very useful for secondary reconstruction. PMID- 27244207 TI - Spontaneous Healing of Mandibular Noncontinuous Defect Caused by Medication Related Osteonecrosis of the Jaw. AB - BACKGROUND: Bisphosphonates are used throughout supportive cancer therapies for the treatment of osteoporosis and metastatic bone diseases, but they invariably induce medication-related osteonecrosis of the jaw (MRONJ). This medicational modality may induce consequential losses that can lead to spontaneous or surgical therapy related bone fractures or defects. MRONJ stages and treatment alternatives are described in the current procedures. Accordingly, treatments for stages 0 and 1 are conservative whereas the treatment for stage 3 is surgical resection of the necrotic bone. Stage III MRONJ therapy is still controversial within the scope of conceivable bone fractures or defects. When the development of MRONJ is refractory to conventional treatment modalities, surgical management can be suggested. The aim of this study was to evaluate the results of the surgical treatment of MRONJ as part of a medical patient. METHODS: A 72-year-old man was referred to our department for extensive pain of the left mandibular region that occurred after tooth extraction. It was identified in his medical history that he had received a nitrogen-containing intravenous bisphosphonate (Zometa; Novartis, East Hanover, NJ) therapy for prostate cancer. He had been administered 4 mg. IV Zolenat 9 times during the first year of therapy, followed by 2 doses of the same amount of Zolenat in the second year. RESULTS: The treatment started with a therapy that combined antibiotics and antibacterial mouth rinse with chlorhexidine for maintaining oral hygiene. After the maturity of the sequestrum was identified through radiographic examination, the patient was treated by the segmental resection of the extensive necrotic bone, resulting in discontinuity of the mandibular corpus. Two years later, spontaneous bone healing occurred along the residual defect on the mandible. CONCLUSION: Treatment options for the defects resulting from MRONJ are still under debate, and no evidence-based guidelines are available. However, due to the results displayed in this patient; it may be a sound approach to closely follow up and observe MRONJ related bone to prevent additional complications. PMID- 27244208 TI - Cerebral Vasospasm Following Transsphenoidal Hypophysectomy in the Treatment of Lymphocytic Hypophysitis. AB - Cerebral vasospasm following transsphenoidal hypophysectomy is an exceedingly rare but serious complication with high morbidity and mortality. The initial signs and symptoms of cerebral vasospasm following transsphenoidal hypophysectomy are changes in mental status, motor deficits, and speech difficulties. Symptomatic vasospasm is difficult to reverse despite treatment and often only resolves with time. Furthermore, most transsphenoidal hypophysectomy patients have been discharged before the onset of vasospasm, so when they do present it is often in a fulminant form and recalcitrant to available treatments.All previously reported patients of cerebral vasospasm following transsphenoidal hypophysectomy were status postresection of a pituitary macroadenoma. The authors report the first patient of vasospasm following transsphenoidal hypophysectomy in the treatment of lymphocytic hypophysitis; a rare inflammatory disorder characterized by lymphocytic infiltration of the pituitary gland causing destruction glandular tissue. PMID- 27244209 TI - Transnasal Prelacrimal Recess Approach for Recurrent Antrachoanal Polyp. AB - PURPOSE: To assess the effectiveness and usefulness of transnasal prelacrimal recess approach (TPRA) in patients with recurrent antrochoanal polyps. METHODS: Twelve patients with antrochoanal polyp recurrence underwent surgery with a transnasal endoscopic prelacrimal recess approach. Success for visualization of the origin of the polyps, surgical complications, and recurrence was evaluated. RESULTS: Transnasal prelacrimal recess approach was successful in 83% of the patients (10/12); polyps that originated from a posterior location (2 patients) were excised using the middle meatal approach. Nasolacrimal duct injury occurred in 2 patients but neither had epiphora postoperatively. Three patients (3/12; 25%) had synechia formation between the lateral nasal wall and septum just superior to the inferior turbinate. One of the 3 patients (1/12; 8.3%) with synechia was symptomatic and required surgical treatment under local anesthesia. During a mean follow-up period of 14.2 months (range, 8-21 months) no recurrence had developed. CONCLUSION: In experienced hands, TPRA is a novel, reliable, and useful method for the treatment of recurrent antrochoanal polyps. It ensures good exploration of the maxillary antrum and easy access to the polyp origin on the maxillary wall without the need of additional approaches. PMID- 27244210 TI - Three-Dimensional Upper Lip and Nostril Sill Changes After Cleft Alveolus Reconstruction Using Autologous Bone Grafting Versus Recombinant Human Bone Morphogenetic Protein-2. AB - Cleft alveolus in patients with unilateral complete cleft lip and palate has been alternatively reconstructed with recombinant human bone morphogenetic protein (rhBMP)-2. However, its effects on upper lip and nostril sill anatomy are not known. Thus, the objective of this investigation was to assess and compare upper lip and nostril sill changes after cleft alveolus reconstruction with autologous bone from the iliac crest region and rhBMP-2. Patients were randomly allocated into 2 groups. In group 1, autologous bone from the iliac crest region was used to fill the cleft alveolus (n = 4), and in group 2, rhBMP-2 was used to fill the cleft alveolus (n = 8). Preoperatively and at one after the surgery, computerized tomography (CT) was performed. Reformatted CT imaging was used to perform cephalometric linear measurements of the upper lip and nostril sill regions. Inter- and intragroup data of the pre and postoperative reformatted CT measurements of the upper lip and nostril sill regions did not show differences (P >0.05) in cutaneous upper lip height and projection, nostril sill elevation, and subnasale projection. There were no significant upper lip and nostril sill anatomical changes after cleft alveolus reconstruction using autologous bone grafting and rhBMP-2. PMID- 27244211 TI - Life Priorities in Head and Neck Cancer Patients Between Ages of 45 to 65. AB - Diseases in head and neck cancer patients and applied therapies according to former affect life quality to a higher extent. In this paper, life priorities in 49 patients with head and neck cancer who referred to Gulhane Military Medical Academy for diagnostic and therapeutic purposes and the relationship between these priorities and sociodemographic properties have been studied. Following life priorities have been observed more important for the patients: to communicate with people in social places, to eat without any help by themselves, external appearance, taste and odor sense, continuing sexual life. Other priorities have been observed less important for the patients: attending social activities like cinema and theater, swimming pool and sea sports, money required for check-ups, necessities like time. Besides, these necessities do not show dissimilarities to any significant extent according to sociodemographic properties of the patients. PMID- 27244212 TI - Management of Laryngoceles by Transoral Robotic Approach. AB - OBJECTIVES: Laryngoceles are air-filled sacs which communicate with the laryngeal lumen. When filled with mucus or pus, they are called laryngomucoceles and laryngopyoceles, respectively. Transoral robotic surgery (TORS) is a new and remarkable technique that expands its usefullness in otorhinolaryngology. Conventional treatments for laryngoceles were previously performed using external approaches, with aesthetically unfavorable and less function-sparing results. Transoral laser microsurgical approaches for laryngoceles were seldom reported. It is aimed to present authors' clinical experience on laryngocele management with TORS which is a rather new technique. STUDY DESIGN: A retrospective patient serial. METHODS: Patients were evaluated for demographic data, type of lesion, reasons for hospital admittance, complaint duration, and previous surgery. Robotic surgery panel including anesthesia time, duration of surgery, need for tracheotomy, postoperative care, follow-up, and recurrence rates were also summarized. RESULTS: Six men (mean age 51.7 years; range 41-62) with laryngoceles underwent successful TORS. Dyspnea and hoarseness were the main complaints. Two patients had undergone previous laryngeal surgery due to laryngeal cancer, with no recurrence of malignancy at admittance for laryngocele. Three had simple laryngocele, 2 had laryngomucocele, and 1 had laryngopyocele. No laryngoceles recurred and no complication such as dysphonia or prolonged dysphagia occurred. CONCLUSION: Transoral robotic surgery was found superior in safety, technical feasibility and curative effectiveness, when compared with classical methods, especially due to absence of skin incisions. Surgical modalities for laryngocele excision should be directed toward a curative target including cosmetic and functional success, technical achievability, and surgically curative methods. Transoral robotic surgery provided all these features. PMID- 27244213 TI - Removal of a Solitary Synovial Chondromatosis of the Temporomandibular Joint Using Arthroscopy. AB - The diagnosis of synovial chrondromatosis of temporomandibular joint (TMJ) requires a combined assessment consisting of clinical, radiologic, and histopathologic examinations. The purpose of this study is to report in 1 patient the removal of a single large cartilaginous nodule floating in the upper joint compartment using arthroscopy. A 30-year-old woman was referred to our department complaining about pain in preauricular area and restricted mouth opening. Imaging of magnetic resonance reveals anterior disc displacement and right joint effusion. Arthroscopy of TMJ was performed for diagnosis and treatment. During the arthroscopy a large loose body was identified and removed with a biopsy forceps; lavage was conducted with ringer solution. Hyaluronic acid was injected in TMJ at surgery, 1 and 3 months after surgery. Postoperative magnetic resonance imaging showed articular disc on position and no effusion. The patient was followed up of 1 year without sign and symptoms. Arthroscopic procedure of TMJ was effective in diagnosis and removal of a solitary loose body of synovial chrondromatosis. Viscosupplementation appers to offer benefits in controlling pain and functional improvements. PMID- 27244214 TI - Secondary Alveolar Bone Grafting and Iliac Cancellous Bone Harvesting for Patients With Alveolar Cleft. AB - To assess the efficacy of present interventions optimizing the result of secondary alveolar bone grafting (SABG) and the interventions alleviating the donor site morbidity after iliac cancellous bone harvesting. Researches were identified by searching the electronic database of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Chinese BioMedical Literature Database, and the China National Knowledge Infrastructure. In addition, relevant journals and references of the included studies were searched manually. The Oxford 2011 Levels of Evidence were applied to assess the methodological quality of selected studies, and the best evidence synthesis system was applied afterward to measure the strength of evidence. As a result, 42 studies were considered eligible and included, among which 4 were of high quality while 38 were of low quality. Thirty lines of evidences were acquired after the synthesis, among which 13 were rated as moderate while 17 were rated as insufficient. As for the interventions optimizing the result of SABG, moderate evidence confirmed the efficacy of preoperative orthodontic treatment, the superiority of performing SABG before the eruption of canine, and the accuracy of cone beam computed tomography in preoperative estimation of the cleft volume. As for the interventions alleviating the morbidity of iliac cancellous bone harvesting, moderate evidence confirmed the treatment benefit of the interventions below: minimally invasive technique, including trephine and Shepard osteotomy; preemptive analgesia, including continuous bupivacaine infusion or transversus abdominis plane block. As for the rest interventions, only insufficient evidence was found. PMID- 27244215 TI - Polarization Energies at Organic-Organic Interfaces: Impact on the Charge Separation Barrier at Donor-Acceptor Interfaces in Organic Solar Cells. AB - We probe the energetic landscape at a model pentacene/fullerene (C60) interface to investigate the interactions between positive and negative charges, which are critical to the processes of charge separation and recombination in organic solar cells. Using a polarizable force field, we find that polarization energy, i.e., the stabilization a charge feels due to its environment, is larger at the interface than in the bulk for both a positive and a negative charge. The combination of the charge being more stabilized at the interface and the Coulomb attraction between the charges results in a barrier to charge separation at the pentacene/C60 interface that can be in excess of 0.7 eV for static configurations of the donor and acceptor locations. However, the impact of molecular motions, i.e., the dynamics, at the interface at room temperature results in a distribution of polarization energies and in charge separation barriers that can be significantly reduced. The dynamic nature of the interface is thus critical, with the polarization energy distributions indicating that sites along the interface shift in time between favorable and unfavorable configurations for charge separation. PMID- 27244216 TI - A Highly Efficient Sandwich-Like Symmetrical Dual-Phase Oxygen-Transporting Membrane Reactor for Hydrogen Production by Water Splitting. AB - Water splitting coupled with partial oxidation of methane (POM) using an oxygen transporting membrane (OTM) would be a potentially ideal way to produce high purity hydrogen as well as syngas. Over the past decades, substantial efforts have been devoted to the development of supported membranes with appropriate configurations to achieve considerable performance improvements. Herein, we describe the design of a novel symmetrical membrane reactor with a sandwich-like structure, whereby a largescale production (>10 mL min(-1) cm(-2) ) of hydrogen and syngas can be obtained simultaneously on opposite sides of the OTM. Furthermore, this special membrane reactor could regenerate the coke-deactivated catalyst in situ by water steam in a single unit. These results represent an important first step in the development of membrane separation technologies for the integration of multiple chemical processes. PMID- 27244219 TI - Risk, resilience, and depressive symptoms in low-income African American fathers. AB - OBJECTIVE: Parental depression influences family health but research on low income African American fathers is limited. The primary goal of the present study was to examine the role of paternal risk factors and resilience resources in predicting depressive symptoms in the year after birth of a child in a sample of African American fathers. We hypothesized that paternal risk factors (low socioeconomic status [SES], perceived stress, negative life events, racism, avoidant coping style) and resources (social support, self-esteem, collective efficacy, approach-oriented coping style) would predict depressive symptoms in fathers at 1 year postbirth controlling for depressive symptoms at 1 month postbirth. METHOD: African American fathers (n = 296) of predominantly low SES from 5 U.S. regions were interviewed at 1 and 12 months after birth of a child regarding potential risk factors, resilience resources, and depressive symptoms. RESULTS: Depressive symptoms were low on average. However, hierarchical linear regression analyses revealed that avoidant coping style and experiences of racism predicted more depressive symptoms in fathers nearly a year after the birth of a child controlling for symptoms at 1 month. CONCLUSIONS: How fathers cope with stress and common everyday experiences of racism contributed to depressive symptoms in the year following birth of a child. Interventions that target race related stressors and decrease avoidant coping may promote better outcomes in this important and understudied population. (PsycINFO Database Record PMID- 27244218 TI - Increased incidence of FBXW7 and POLE proofreading domain mutations in young adult colorectal cancers. AB - BACKGROUND: The incidence and outcomes of patients with colorectal cancer (CRC) varies by age. Younger patients tend to have sporadic cancers that are not detected by screening and worse survival. To understand whether genetic differences exist between age cohorts, the authors sought to characterize unique genetic alterations in patients with CRC. METHODS: In total, 283 patients who were diagnosed with sporadic CRC between 1998 and 2010 were identified and divided by age into 2 cohorts-ages <=45 years (the younger cohort) and >=65 years (the older cohort)-and targeted exome sequencing was performed. The Fisher exact test was used to detect differences in mutation frequencies between the 2 groups. Whole exome sequencing was performed on 21 additional younger patient samples for validation. Findings were confirmed in The Cancer Genome Atlas CRC data set. RESULTS: In total, 246 samples were included for final analysis (195 from the older cohort and 51 from the younger cohort). Mutations in the FBXW7 gene were more common in the younger cohort (27.5% vs 9.7%; P = .0022) as were mutations in the proofreading domain of polymerase epsilon catalytic subunit (POLE) (9.8% vs 1%; P = .0048). There were similar mutation rates between cohorts with regard to TP53 (64.7% vs 61.5%), KRAS (43.1% vs 46.2%), and APC (60.8% vs 73.8%). BRAF mutations were numerically more common in the older cohort, although the difference did not reach statistical significance (2% vs 9.7%; P = .082). CONCLUSIONS: In this retrospective study, a unique genetic profile was identified for younger patients who have CRC compared with patients who are diagnosed at an older age. These findings should be validated in a larger study and could have an impact on future screening and treatment modalities for younger patients with CRC. Cancer 2016. (c) 2016 American Cancer Society. Cancer 2016;122:2828-2835. (c) 2016 American Cancer Society. PMID- 27244217 TI - Association of a Locus in the CAMTA1 Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis. AB - IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disorder with a poor prognosis and a median survival of 3 years. However, a significant proportion of patients survive more than 10 years from symptom onset. OBJECTIVE: To identify gene variants influencing survival in ALS. DESIGN, SETTING, AND PARTICIPANTS: This genome-wide association study (GWAS) analyzed survival in data sets from several European countries and the United States that were collected by the Italian Consortium for the Genetics of ALS and the International Consortium on Amyotrophic Lateral Sclerosis Genetics. The study population included 4256 patients with ALS (3125 [73.4%] deceased) with genotype data extended to 7 174 392 variants by imputation analysis. Samples of DNA were collected from January 1, 1993, to December 31, 2009, and analyzed from March 1, 2014, to February 28, 2015. MAIN OUTCOMES AND MEASURES: Cox proportional hazards regression under an additive model with adjustment for age at onset, sex, and the first 4 principal components of ancestry, followed by meta-analysis, were used to analyze data. Survival distributions for the most associated genetic variants were assessed by Kaplan-Meier analysis. RESULTS: Among the 4256 patients included in the analysis (2589 male [60.8%] and 1667 female [39.2%]; mean [SD] age at onset, 59 [12] years), the following 2 novel loci were significantly associated with ALS survival: at 10q23 (rs139550538; P = 1.87 * 10-9) and in the CAMTA1 gene at 1p36 (rs2412208, P = 3.53 * 10-8). At locus 10q23, the adjusted hazard ratio for patients with the rs139550538 AA or AT genotype was 1.61 (95% CI, 1.38-1.89; P = 1.87 * 10-9), corresponding to an 8-month reduction in survival compared with TT carriers. For rs2412208 CAMTA1, the adjusted hazard ratio for patients with the GG or GT genotype was 1.17 (95% CI, 1.11-1.24; P = 3.53 * 10-8), corresponding to a 4-month reduction in survival compared with TT carriers. CONCLUSIONS AND RELEVANCE: This GWAS robustly identified 2 loci at genome-wide levels of significance that influence survival in patients with ALS. Because ALS is a rare disease and prevention is not feasible, treatment that modifies survival is the most realistic strategy. Therefore, identification of modifier genes that might influence ALS survival could improve the understanding of the biology of the disease and suggest biological targets for pharmaceutical intervention. In addition, genetic risk scores for survival could be used as an adjunct to clinical trials to account for the genetic contribution to survival. PMID- 27244220 TI - Mesenchymal Stem Cells Synergize with 635, 532, and 405 nm Laser Wavelengths in Renal Fibrosis: A Pilot Study. AB - OBJECTIVE: To address whether a single treatment of one of three visible light wavelengths, 635, 532, and 405 nm (constant wave, energy density 2.9 J/m2), could affect the hallmarks of established renal fibrosis and whether these wavelengths could facilitate mesenchymal stem cell (MSC) beneficence. BACKGROUND DATA: Chronic kidney disease is a global health problem with only 20% receiving care worldwide. Kidneys with compromised function have ongoing inflammation, including increased oxidative stress and apoptosis, peritubular capillary loss, tubular atrophy, and tubulointerstitial fibrosis. Promising studies have highlighted the significant potential of MSC-based strategies to mitigate fibrosis; however, reversal of established fibrosis has been problematic, suggesting that methods to potentiate MSC effects require further development. Laser treatments at visible wavelengths have been reported to enhance mitochondrial potential and available cellular ATP, facilitate proliferation, and inhibit apoptosis. We hypothesized that laser-delivered energy might provide wavelength-specific effects in the fibrotic kidney and enhance MSC responses. MATERIALS AND METHODS: Renal fibrosis, established in C57BL6 mice following 21 days of unilateral ureter obstruction (UUO), was treated with one of three wavelengths alone or with autologous MSC. Mitochondrial activity, cell proliferation, apoptosis, and cytokines were measured 24 h later. RESULTS: Wavelengths 405, 532, and 635 nm all significantly synergized with MSC to enhance mitochondrial activity and reduce apoptosis. Proliferative activity was observed in the renal cortices following combined treatment with the 532 nm laser and MSC; endothelial proliferation increased in response to the 635 nm laser alone and to the combined effects of MSC and the 405 nm wavelength. Reductions of transforming growth factor-beta were observed with 532 nm alone and when combined with MSC. CONCLUSIONS: Specific wavelengths of laser energy appear to induce different responses in renal fibrotic tissue. These findings support further study in the development of a customized laser therapy program of combined wavelengths to optimize MSC effects in the treatment of renal fibrosis. PMID- 27244221 TI - Recombinant Bile Salt-Stimulated Lipase in Preterm Infant Feeding: A Randomized Phase 3 Study. AB - INTRODUCTION: Feeding strategies are critical for healthy growth in preterm infants. Bile salt-stimulated lipase (BSSL), present in human milk, is important for fat digestion and absorption but is inactivated during pasteurization and absent in formula. This study evaluated if recombinant human BSSL (rhBSSL) improves growth in preterm infants when added to formula or pasteurized breast milk. PATIENTS AND METHODS: LAIF (Lipase Added to Infant Feeding) was a randomized, double-blind, placebo-controlled phase 3 study in infants born before 32 weeks of gestation. The primary efficacy variable was growth velocity (g/kg/day) during 4 weeks intervention. Follow-up visits were at 3 and 12 months. The study was performed at 54 centers in 10 European countries. RESULTS: In total 415 patients were randomized (rhBSSL n = 207, placebo n = 208), 410 patients were analyzed (rhBSSL n = 206, placebo n = 204) and 365 patients were followed until 12 months. Overall, there was no significantly improved growth velocity during rhBSSL treatment compared to placebo (16.77 vs. 16.56 g/kg/day, estimated difference 0.21 g/kg/day, 95% CI [-0.40; 0.83]), nor were secondary endpoints met. However, in a predefined subgroup, small for gestational age infants, there was a significant effect on growth in favor of rhBSSL during treatment. The incidence of adverse events was higher in the rhBSSL group during treatment. CONCLUSIONS: Although this study did not meet its primary endpoint, except in a subgroup of infants small for gestational age, and there was an imbalance in short-term safety, these data provide insights in nutrition, growth and development in preterm infants. TRIAL REGISTRATION: ClinicalTrials.gov NCT01413581. PMID- 27244222 TI - A longitudinal study assessing childcare services' adoption of obesity prevention policies and practices. AB - AIM: Despite ongoing investments to improve the obesogenic environments of childcare settings, little is known regarding how these services have changed their physical activity and nutrition-promoting practices. This study aims to describe changes in the proportion of Australian childcare services that have adopted best-practice healthy eating and physical activity practices between 2006 and 2013 and to assess whether adoption varied by socio-economic status and locality. METHODS: A randomly selected sample of nominated supervisors (n = 358) from childcare services located in New South Wales, Australia, participated in a telephone survey in 2006, 2009, 2010 and 2013. Supervisors reported on their service's adoption of six practices: (i) having written nutrition and physical activity policies; (ii) staff trained in physical activity and nutrition in the past year; (iii) scheduled time for fundamental movement skills and (iv) outdoor play; (v) weekly or less screen time opportunities; and (vi) serving only non sweetened beverages. RESULTS: A significant increase in the prevalence of services adopting all but one practice, between 2006 and 2013 was identified. Ninety one percent of services adopted four or more practices, a significant increase from 38% in 2006. There were no differences in the proportion of services adopting each practice by locality and socio-economic status. CONCLUSIONS: Government investment in obesity prevention programmes can equitably improve childcare service's adoption of healthy eating and physical activity promoting practices on a jurisdiction-wide basis. The establishment of a routine system to monitor adoption of a broader range of practices by childcare services is warranted. PMID- 27244223 TI - Helicenes as All-in-One Organic Materials for Application in OLEDs: Synthesis and Diverse Applications of Carbo- and Aza[5]helical Diamines. AB - A set of eight helical diamines were designed and synthesized to demonstrate their relevance as all-in-one materials for multifarious applications in organic light-emitting diodes (OLEDs), that is, as hole-transporting materials (HTMs), EMs, bifunctional hole transporting + emissive materials, and host materials. Azahelical diamines function very well as HTMs. Indeed, with high Tg values (127 214 degrees C), they are superior alternatives to popular N,N'-di(1-naphthyl) N,N'-diphenyl-(1,1'-biphenyl)-4,4'-diamine (NPB). All the helical diamines exhibit emissive properties when employed in nondoped as well as doped devices, the performance characteristics being superior in the latter. One of the carbohelical diamines (CHTPA) serves the dual function of hole transport as well as emission in simple double-layer devices; the efficiencies observed were better by quite some margin than those of other emissive helicenes reported. The twisting endows helical diamines with significantly high triplet energies such that they also function as host materials for red and green phosphors, that is, [Ir(btp)2 acac] (btp=2-(2'-benzothienyl)pyridine; acac=acetylacetonate) and [Ir(ppy)3 ] (ppy=2-phenylpyridine), respectively. The results of device fabrications demonstrate how helicity/ helical scaffold may be diligently exploited to create molecular systems for maneuvering diverse applications in OLEDs. PMID- 27244224 TI - Prenatal Antidepressant Use and Risk of Autism Spectrum Disorders in Children Reply. PMID- 27244226 TI - Transanal Total Mesorectal Excision: Can it Achieve the Standard of TME? PMID- 27244225 TI - Hypomethylation of let-7a-3 is associated with poor prognosis in myelodysplastic syndrome. AB - Abnormal methylation of let-7a-3 has been found in various cancers and may consequently affect their survival. In this study, real-time quantitative methylation specific PCR (RQ-MSP) was used to determine the unmethylation level of let-7a-3 in 95 patients with myelodysplastic syndrome (MDS). The hypomethylation of let-7a-3 promoter was detected in 22 of 95 (23.2%) patients with MDS compared to 4.2% (1/24) of controls (p= 0.0419). Moreover, the frequency of let-7a-3 hypomethylation was higher in older patients (>=70 years) than in younger patients (<70 years). No significant difference was observed in distribution of WHO, IPSS, and cytogenetic classification. However, hypomethylated patients had significantly shorter overall survival than those without hypomethylation (p= 0.007). Moreover both Kaplan-Meier and Multivariate Cox analyses confirmed that let-7a-3 hypomethylation was an independent prognostic risk factor in cohorts of MDS patients with lower-risk disease. Our study suggested that let-7a-3 hypomethylation may predict poor outcome in MDS. PMID- 27244228 TI - Role of Ultraviolet Radiation in Papillomavirus-Induced Disease. AB - Human papillomaviruses are causally associated with 5% of human cancers. The recent discovery of a papillomavirus (MmuPV1) that infects laboratory mice provides unique opportunities to study the life cycle and pathogenesis of papillomaviruses in the context of a genetically manipulatable host organism. To date, MmuPV1-induced disease has been found largely to be restricted to severely immunodeficient strains of mice. In this study, we report that ultraviolet radiation (UVR), specifically UVB spectra, causes wild-type strains of mice to become highly susceptible to MmuPV1-induced disease. MmuPV1-infected mice treated with UVB develop warts that progress to squamous cell carcinoma. Our studies further indicate that UVB induces systemic immunosuppression in mice that correlates with susceptibility to MmuPV1-associated disease. These findings provide new insight into how MmuPV1 can be used to study the life cycle of papillomaviruses and their role in carcinogenesis, the role of host immunity in controlling papillomavirus-associated pathogenesis, and a basis for understanding in part the role of UVR in promoting HPV infection in humans. PMID- 27244227 TI - Abdominal Pain, the Adolescent and Altered Brain Structure and Function. AB - Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder of unknown etiology. Although relatively common in children, how this condition affects brain structure and function in a pediatric population remains unclear. Here, we investigate brain changes in adolescents with IBS and healthy controls. Imaging was performed with a Siemens 3 Tesla Trio Tim MRI scanner equipped with a 32-channel head coil. A high-resolution T1-weighted anatomical scan was acquired followed by a T2-weighted functional scan. We used a surface-based morphometric approach along with a seed-based resting-state functional connectivity (RS-FC) analysis to determine if groups differed in cortical thickness and whether areas showing structural differences also showed abnormal RS-FC patterns. Patients completed the Abdominal Pain Index and the GI Module of the Pediatric Quality of Life Inventory to assess abdominal pain severity and impact of GI symptoms on health-related quality of life (HRQOL). Disease duration and pain intensity were also assessed. Pediatric IBS patients, relative to controls, showed cortical thickening in the posterior cingulate (PCC), whereas cortical thinning in posterior parietal and prefrontal areas were found, including the dorsolateral prefrontal cortex (DLPFC). In patients, abdominal pain severity was related to cortical thickening in the intra-abdominal area of the primary somatosensory cortex (SI), whereas HRQOL was associated with insular cortical thinning. Disease severity measures correlated with cortical thickness in bilateral DLPFC and orbitofrontal cortex. Patients also showed reduced anti-correlations between PCC and DLPFC compared to controls, a finding that may reflect aberrant connectivity between default mode and cognitive control networks. We are the first to demonstrate concomitant structural and functional brain changes associated with abdominal pain severity, HRQOL related to GI-specific symptoms, and disease specific measures in adolescents with IBS. It is possible such changes will be responsive to therapeutic intervention and may be useful as potential markers of disease progression or reversal. PMID- 27244229 TI - Peripheral Immune Cell Populations Associated with Cognitive Deficits and Negative Symptoms of Treatment-Resistant Schizophrenia. AB - BACKGROUND: Hypothetically, psychotic disorders could be caused or conditioned by immunological mechanisms. If so, one might expect there to be peripheral immune system phenotypes that are measurable in blood cells as biomarkers of psychotic states. METHODS: We used multi-parameter flow cytometry of venous blood to quantify and determine the activation state of 73 immune cell subsets for 18 patients with chronic schizophrenia (17 treated with clozapine), and 18 healthy volunteers matched for age, sex, BMI and smoking. We used multivariate methods (partial least squares) to reduce dimensionality and define populations of differentially co-expressed cell counts in the cases compared to controls. RESULTS: Schizophrenia cases had increased relative numbers of NK cells, naive B cells, CXCR5+ memory T cells and classical monocytes; and decreased numbers of dendritic cells (DC), HLA-DR+ regulatory T-cells (Tregs), and CD4+ memory T cells. Likewise, within the patient group, more severe negative and cognitive symptoms were associated with decreased relative numbers of dendritic cells, HLA DR+ Tregs, and CD4+ memory T cells. Motivated by the importance of central nervous system dopamine signalling for psychosis, we measured dopamine receptor gene expression in separated CD4+ cells. Expression of the dopamine D3 (DRD3) receptor was significantly increased in clozapine-treated schizophrenia and covaried significantly with differentiated T cell classes in the CD4+ lineage. CONCLUSIONS: Peripheral immune cell populations and dopaminergic signalling are disrupted in clozapine-treated schizophrenia. Immuno-phenotypes may provide peripherally accessible and mechanistically specific biomarkers of residual cognitive and negative symptoms in this treatment-resistant subgroup of patients. PMID- 27244230 TI - Detection and Genotyping of Coxiella burnetii and Coxiella-Like Bacteria in Horses in South Korea. AB - Coxiella burnetii and Coxiella-like bacteria (CLB) are genetically and ecologically distinct despite some genetic similarities. Furthermore, CLB are exceptionally diverse and widespread in ticks, but rarely detected in domestic animals. Since Coxiella bacteria can be transmitted from infected horses by inhalation or by coming in contact with ticks during activities such as horseback riding, it is necessary to study their prevalence. To the best of our knowledge, this is the first large-scale nationwide investigation of the prevalence of C. burnetii and CLB among horses reared in South Korea. Of 816 blood samples collected between 2007 and 2013, 11 (1.3%) were identified as C. burnetii by ELISA, and six (0.7%) as CLB by 16S rRNA sequencing. While a sequence from Jeju Island was similar (97.9-100%) to those within clade B, five sequences obtained from the northern region were categorized into a new clade, indicating the sequence diversity of the genus Coxiella. Studies until date had detected CLB only in ticks; here, we describe their detection in mammals. Given their zoonotic potential, strategic monitoring and appropriate control programs for Coxiella species need to be established. PMID- 27244231 TI - Prenatal immune programming of the sex-dependent risk for major depression. AB - Maternal immune functioning during pregnancy contributes to sex-dependent deficits in neurodevelopment and to behaviors associated with affective traits in preclinical studies, and has been indirectly associated with offspring depression in epidemiologic studies. We therefore investigated the association between immune activity during pregnancy and the risk of depression among male and female offspring. We conducted a case-control study of depression (n=484 cases and n=774 controls) using data from the New England Family Study, a pregnancy cohort enrolled between 1959 and 1966 that assessed psychiatric outcomes in adult offspring (mean age=39.7 years). We assayed concentrations of three pro inflammatory cytokines, interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha, and the anti-inflammatory cytokine, IL-10, in maternal serum collected at the end of the second and beginning of the third trimesters. High maternal TNF-alpha was associated with reduced odds of depression among both male and female offspring (odds ratio (OR)=0.68; confidence interval (CI)=0.48, 0.98). However, when considering the TNF-alpha to IL-10 ratio, a measure of the ratio of pro- to anti-inflammatory loading, maternal immune effects on offspring depression differed significantly by sex (chi(2)=13.9, degrees of freedom=4, P=0.008). Among females, higher maternal TNF-alpha:IL-10 was associated with reduced odds of depression (OR=0.51; CI=0.32, 0.81), whereas, among males, high maternal TNF-alpha:IL-10 was associated with elevated odds of depression (OR=1.86; CI=1.02, 3.39). Thus, the balance between TNF-alpha and IL-10 in maternal prenatal serum was associated with depression in a sex-dependent manner. These findings are consistent with the role of TNF-alpha in the maturation of the sexually dimorphic fetal brain circuitry that regulates stress and affective responses, and support a prenatal stress-immune model of depression pathogenesis. PMID- 27244232 TI - The effects of a probiotic formulation (Lactobacillus rhamnosus and L. helveticus) on developmental trajectories of emotional learning in stressed infant rats. AB - Recently, scientific interest in the brain-gut axis has grown dramatically, particularly with respect to the link between gastrointestinal and psychiatric dysfunction. However, the role of gut function in early emotional dysregulation is yet to be examined, despite the prevalence and treatment resistance of early onset psychiatric disorders. The present studies utilized a developmental rodent model of early-life stress (ELS) to explore this gap. Rats were exposed to maternal separation (MS) on postnatal days 2-14. Throughout MS, dams received either vehicle or a probiotic formulation (previously shown to reduce gastrointestinal dysfunction) in their drinking water. Replicating past research, untreated MS infants exhibited an adult-like profile of long-lasting fear memories and fear relapse following extinction. In contrast, probiotic-exposed MS infants exhibited age-appropriate infantile amnesia and resistance to relapse. These effects were not mediated by changes in pups' or dams' anxiety at the time of training, nor by maternal responsiveness. Overall, probiotics acted as an effective and non-invasive treatment to restore normal developmental trajectories of emotion-related behaviors in infant rats exposed to ELS. These results provide promising initial evidence for this novel approach to reduce the risk of mental health problems in vulnerable individuals. Future studies are needed to test this treatment in humans exposed to ELS and to elucidate mechanisms for the observed behavioral changes. PMID- 27244233 TI - A pilot study on commonality and specificity of copy number variants in schizophrenia and bipolar disorder. AB - Schizophrenia (SZ) and bipolar disorder (BD) are known to share genetic risks. In this work, we conducted whole-genome scanning to identify cross-disorder and disorder-specific copy number variants (CNVs) for these two disorders. The Database of Genotypes and Phenotypes (dbGaP) data were used for discovery, deriving from 2416 SZ patients, 592 BD patients and 2393 controls of European Ancestry, as well as 998 SZ patients, 121 BD patients and 822 controls of African Ancestry. PennCNV and Birdsuite detected high-confidence CNVs that were aggregated into CNV regions (CNVRs) and compared with the database of genomic variants for confirmation. Then, large (size?500 kb) and small common CNVRs (size <500 kb, frequency?1%) were examined for their associations with SZ and BD. Particularly for the European Ancestry samples, the dbGaP findings were further evaluated in the Wellcome Trust Case Control Consortium (WTCCC) data set for replication. Previously implicated variants (1q21.1, 15q13.3, 16p11.2 and 22q11.21) were replicated. Some cross-disorder variants were noted to differentially affect SZ and BD, including CNVRs in chromosomal regions encoding immunoglobulins and T-cell receptors that were associated more with SZ, and the 10q11.21 small CNVR (GPRIN2) associated more with BD. Disorder-specific CNVRs were also found. The 22q11.21 CNVR (COMT) and small CNVRs in 11p15.4 (TRIM5) and 15q13.2 (ARHGAP11B and FAN1) appeared to be SZ-specific. CNVRs in 17q21.2, 9p21.3 and 9q21.13 might be BD-specific. Overall, our primary findings in individual disorders largely echo previous reports. In addition, the comparison between SZ and BD reveals both specific and common risk CNVs. Particularly for the latter, differential involvement is noted, motivating further comparative studies and quantitative models. PMID- 27244234 TI - Cytokine production capacity in depression and anxiety. AB - Recent studies have suggested that immune function may be dysregulated in persons with depressive and anxiety disorders. Few studies examined the expression of cytokines in response to ex vivo stimulation of blood by lipopolysaccharide (LPS) to study the innate production capacity of cytokines in depression and anxiety. To investigate this, baseline data from the Netherlands Study of Depression and Anxiety (NESDA) were used, including persons (18-65 years; 66% women) with current (that is, past month; N=591) or remitted (N=354) DSM-IV depressive or anxiety disorders and healthy controls (N=297). Depressive and anxiety symptoms were measured by means of the Inventory of Depressive Symptomatology (IDS) and the Beck Anxiety Inventory (BAI). Using Multi-Analyte Profiling technology, plasma levels of 13 cytokines were assayed after whole blood stimulation by addition of LPS. Basal plasma levels of C-reactive protein, interleukin-6 and tumor necrosis factor-alpha were also available. A basal and a LPS summary index were created. Results show that LPS-stimulated inflammation was associated with increased odds of current depressive/anxiety disorders (odds ratio (OR)=1.28, P=0.009), as was the case for basal inflammation (OR=1.28, P=0.001). These associations were no longer significant after adjustment for lifestyle and health (OR=1.13, P=0.21; OR=1.07, P=0.45, respectively). After adjustment for lifestyle and health, interleukin-8 was associated with both remitted (OR=1.25, P=0.02) and current (OR=1.28, P=0.005) disorders. In addition, LPS-stimulated inflammation was associated with more severe depressive (beta=0.129, P<0.001) and anxiety (beta=0.165, P<0.001) symptoms, as was basal inflammation. Unlike basal inflammation, LPS-stimulated inflammation was still associated with (anxiety) symptom severity after adjustment for lifestyle and health (IDS: interleukin (IL) 8, MCP-1, MMP2; BAI: LPS index, IL-6, IL-8, IL-10, IL-18, MCP-1, MMP2, TNF-beta). To conclude, lifestyle and health factors may partly explain higher levels of basal, as well as LPS-stimulated inflammation in persons with depressive and anxiety disorders. However, production capacity of several cytokines was positively associated with severity of depressive and in particular anxiety symptoms, even while taking lifestyle and health factors into account. Elevated IL-8 production capacity in both previously and currently depressed and anxious persons might indicate a genetic vulnerability for these disorders. PMID- 27244235 TI - Ibogaine and addiction in the animal model, a systematic review and meta analysis. AB - Ibogaine is a naturally occurring substance which has been increasingly used in the lay-scene to reduce craving and relapse in patients with substance use disorders (SUDs). Although human clinical trials on the safety and efficacy of ibogaine are lacking, animal studies do support the efficacy of ibogaine. In this systematic review and meta-analysis (MA), we summarise these animal findings, addressing three questions: (1) does ibogaine reduce addictive behaviour in animal models of SUDs?; (2) what are the toxic effects of ibogaine on motor functioning, cerebellum and heart rhythm?; (3) what are neuropharmacological working mechanisms of ibogaine treatment in animal models of SUDs? MA of 27 studies showed that ibogaine reduced drug self-administration, particularly during the first 24 h after administration. Ibogaine had no effect on drug induced conditioned place preference. Ibogaine administration resulted in motor impairment in the first 24 h after supplementation, and cerebral cell loss even weeks after administration. Data on ibogaines effect on cardiac rhythm, as well as on its neuropharmacological working mechanisms are limited. Our results warrant further studies into the clinical efficacy of ibogaine in SUD patients in reducing craving and substance use, but close monitoring of the patients is recommended because of the possible toxic effects. In addition, more work is needed to unravel the neuropharmacological working mechanisms of ibogaine and to investigate its effects on heart rhythm. PMID- 27244236 TI - Decreased sensitivity to paroxetine-induced inhibition of peripheral blood mononuclear cell growth in depressed and antidepressant treatment-resistant patients. AB - Major depression disorder (MDD) is the most widespread mental disorder. Selective serotonin reuptake inhibitors (SSRIs) are used as first-line MDD treatment but are effective in <70% of patients. Thus, biomarkers for the early identification of treatment-resistant (TR) MDD patients are needed for prioritizing them for alternative therapeutics. SSRI-induced inhibition of the growth of peripheral blood mononuclear cells (PBMCs) is mediated via their target, the serotonin transporter (SERT). Here, we examined whether antidepressant drug-induced inhibition of the growth of PBMCs differed between MDD patients and healthy controls. PBMCs from well-characterized 33 treatment-sensitive (TS) and 33 TR MDD patients, and 24 healthy volunteers were studied. Dose-dependent inhibition of PBMCs growth was observed for both the non-SSRI antidepressant mirtazapine and the SSRI antidepressant paroxetine. Significantly lower sensitivities to 20 MUm paroxetine were observed in MDD compared with control PBMCs prior to treatment onset (13% and 46%, respectively; P<0.05). Following antidepressant drug treatment for 4 or 7 weeks, the ex vivo paroxetine sensitivity increased to control levels in PBMCs from TS but not from TR MDD patients. This suggests that the low ex vivo paroxetine sensitivity phenotype reflects a state marker of depression. A significantly lower expression of integrin beta-3 (ITGB3), a co factor of the SERT, was observed in the PBMCs of MDD patients prior to treatment onset compared with healthy controls, and may explain their lower paroxetine sensitivity. Further studies with larger cohorts are required for clarifying the potential of reduced PBMCs paroxetine sensitivity and lower ITGB3 expression as MDD biomarkers. PMID- 27244238 TI - Comparative Analysis of Clinicopathologic Features of, Treatment in, and Survival of Americans with Lung or Bronchial Cancer. AB - Ethnic disparities in lung and bronchial cancer diagnoses and disease-specific survival (DSS) rates in the United States are well known. However, few studies have specifically assessed these differences in Asian subgroups. The primary objectives of the retrospective analysis described herein were to identify any significant differences in clinicopathologic features, treatment, and survival rate between Asian lung cancer patients and lung cancer patients in other broad ethnic groups in the United States and to determine the reasons for these differences among subgroups of Asian patients with lung or bronchial cancer. We searched the Surveillance, Epidemiology, and End Results Program database to identify patients diagnosed with lung or bronchial cancer from 1990 to 2012. Differences in clinicopathologic features, treatment, and DSS rate in four broad ethnic groups and eight Asian subgroups were compared. The study population consisted of 849,088 patients, 5.2% of whom were of Asian descent. Female Asian patients had the lowest lung and bronchial cancer incidence rates, whereas male black patients had the highest rates. Asian patients had the best 5-year DSS rate. In our Asian subgroup analysis, Indian/Pakistani patients had the best 5 year DSS rate, whereas Hawaiian/Pacific Islander patients had the worst 5-year DSS rates. We found the differences in DSS rate among the four broad ethnic groups and eight Asian subgroups when we grouped patients by age and disease stage, as well. Asian patients had better DSS rates than those in the other three broad ethnic groups in almost every age and disease-stage group, especially in older patients and those with advanced-stage disease. In conclusion, we found that clinicopathologic features and treatment of lung and bronchial cancer differ by ethnicity in the United States, and the differences impact survival in each ethnic group. PMID- 27244237 TI - Association between striatal dopamine D2/D3 receptors and brain activation during visual attention: effects of sleep deprivation. AB - Sleep deprivation (SD) disrupts dopamine (DA) signaling and impairs attention. However, the interpretation of these concomitant effects requires a better understanding of dopamine's role in attention processing. Here we test the hypotheses that D2/D3 receptors (D2/D3R) in dorsal and ventral striatum would distinctly regulate the activation of attention regions and that, by decreasing D2/D3, SD would disrupt these associations. We measured striatal D2/D3R using positron emission tomography with [(11)C]raclopride and brain activation to a visual attention (VA) task using 4-Tesla functional magnetic resonance imaging. Fourteen healthy men were studied during rested wakefulness and also during SD. Increased D2/D3R in striatum (caudate, putamen and ventral striatum) were linearly associated with higher thalamic activation. Subjects with higher D2/D3R in caudate relative to ventral striatum had higher activation in superior parietal cortex and ventral precuneus, and those with higher D2/D3R in putamen relative to ventral striatum had higher activation in anterior cingulate. SD impaired the association between striatal D2/D3R and VA-induced thalamic activation, which is essential for alertness. Findings suggest a robust DAergic modulation of cortical activation during the VA task, such that D2/D3R in dorsal striatum counterbalanced the stimulatory influence of D2/D3R in ventral striatum, which was not significantly disrupted by SD. In contrast, SD disrupted thalamic activation, which did not show counterbalanced DAergic modulation but a positive association with D2/D3R in both dorsal and ventral striatum. The counterbalanced dorsal versus ventral striatal DAergic modulation of VA activation mirrors similar findings during sensorimotor processing (Tomasi et al., 2015) suggesting a bidirectional influence in signaling between the dorsal caudate and putamen and the ventral striatum. PMID- 27244239 TI - Salicylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity. AB - Salicylate and acetylsalicylic acid are potent and widely used anti-inflammatory drugs. They are thought to exert their therapeutic effects through multiple mechanisms, including the inhibition of cyclo-oxygenases, modulation of NF-kappaB activity, and direct activation of AMPK. However, the full spectrum of their activities is incompletely understood. Here we show that salicylate specifically inhibits CBP and p300 lysine acetyltransferase activity in vitro by direct competition with acetyl-Coenzyme A at the catalytic site. We used a chemical structure-similarity search to identify another anti-inflammatory drug, diflunisal, that inhibits p300 more potently than salicylate. At concentrations attainable in human plasma after oral administration, both salicylate and diflunisal blocked the acetylation of lysine residues on histone and non-histone proteins in cells. Finally, we found that diflunisal suppressed the growth of p300-dependent leukemia cell lines expressing AML1-ETO fusion protein in vitro and in vivo. These results highlight a novel epigenetic regulatory mechanism of action for salicylate and derivative drugs. PMID- 27244242 TI - Multi-stage hybrid subsurface flow constructed wetlands for treating piggery and dairy wastewater in cold climate. AB - This study followed three field-scale hybrid subsurface flow constructed wetland (CW) systems constructed in Hokkaido, northern Japan: piggery O (2009), dairy G (2011), and dairy S (2006). Treatment performance was monitored from the outset of operation for each CW. The ranges of overall purification efficiency for these systems were 70-86%, 40-85%, 71-90%, 91-96%, 94-98%, 84-97%, and 70-97% for total N (TN), NH4-N, total P, chemical oxygen demand (COD), biochemical oxygen demand, suspended solid, and total Coliform, respectively. The hybrid system's removal rates were highest when influent loads were high. COD removal rates were 46.4 +/- 49.2, 94.1 +/- 36.6, and 25.1 +/- 15.5 g COD m-2 d-1 in piggery O, dairy G, and dairy S, with average influent loads of 50.5 +/- 51.5, 98.9 +/- 37.1, and 26.9 +/ 16.0 g COD m-2 d-1, respectively. The systems had overall COD removal efficiencies of around 90%. TN removal efficiencies were 62 +/- 19%, 82 +/- 9%, and 82 +/- 15% in piggery O, dairy G, and dairy S, respectively. NH4-N removal efficiency was adversely affected by the COD/TN ratio. Results from this study prove that these treatment systems have sustained and positive pollutant removal efficiencies, which were achieved even under extremely cold climate conditions and many years after initial construction. PMID- 27244243 TI - Direct oxygen removal technique for recycling titanium using molten MgCl2 salt. AB - Deoxidation of Ti, or direct removal of O dissolved in metallic Ti, is known to be extremely difficult when Mg is used as the deoxidizing agent. This difficulty arises because the chemical potential of O2, pO2, under Mg/MgO equilibrium is high (approximately 10(-41) atm at 1200 K) and is equivalent to that of Ti containing ~2 mass% O at 1200 K. Therefore, when deoxidizing Ti to the commercial level of high-grade pure Ti (below 0.05 mass% O) using an Mg reductant at 1200 K, the activity of the reaction product MgO (aMgO) must be decreased to below ~0.025, which is difficult in practice. In this study, the removal of O in Ti in molten MgCl2 salt using an electrochemical technique was examined at ~1173 K with the objective of obtaining Ti containing less than 0.05 mass% O. Ti samples and graphite electrodes immersed in molten MgCl2 served as the cathode and anode, respectively. A constant voltage was applied between the electrodes using an external DC source. Molten MgCl2 was employed to produce the deoxidizing agent Mg and to facilitate deoxidation of Ti by decreasing the activity of the reaction product MgO. By applying a voltage of approximately 3.1 V between the electrodes, the chemical potential of Mg in the molten MgCl2 was increased at the surface of the Ti cathode, and the Ti samples were deoxidized. The resulting O species, mainly formed O(2-) dissolved in the molten MgCl2, was removed from the molten salt by reacting with the C anode to form CO (or CO2) gas. Ti wires containing 0.12 mass% O were deoxidized to less than 0.02 mass% O. In some cases, the O concentration in the Ti samples was reduced to the level of 0.01 mass%, which cannot be accomplished using the conventional Kroll process. The possible application of this deoxidation technique to practical industrial recycling processes is discussed. PMID- 27244240 TI - Single molecule analysis reveals reversible and irreversible steps during spliceosome activation. AB - The spliceosome is a complex machine composed of small nuclear ribonucleoproteins (snRNPs) and accessory proteins that excises introns from pre-mRNAs. After assembly the spliceosome is activated for catalysis by rearrangement of subunits to form an active site. How this rearrangement is coordinated is not well understood. During activation, U4 must be released to allow U6 conformational change, while Prp19 complex (NTC) recruitment is essential for stabilizing the active site. We used multi-wavelength colocalization single molecule spectroscopy to directly observe the key events in Saccharomyces cerevisiae spliceosome activation. Following binding of the U4/U6.U5 tri-snRNP, the spliceosome either reverses assembly by discarding tri-snRNP or proceeds to activation by irreversible U4 loss. The major pathway for NTC recruitment occurs after U4 release. ATP stimulates both the competing U4 release and tri-snRNP discard processes. The data reveal the activation mechanism and show that overall splicing efficiency may be maintained through repeated rounds of disassembly and tri-snRNP reassociation. PMID- 27244244 TI - A Hydrogel-Based Hybrid Theranostic Contact Lens for Fungal Keratitis. AB - Fungal keratitis, a severe ocular disease, is one of the leading causes of ocular morbidity and blindness, yet it is often neglected, especially in developing countries. Therapeutic efficacy of traditional treatment such as eye drops is very limited due to poor bioavailability, whereas intraocular injection might cause serious side effects. Herein, we designed and fabricated a hybrid hydrogel based contact lens which comprises quaternized chitosan (HTCC), silver nanoparticles, and graphene oxide (GO) with a combination of antibacterial and antifungal functions. The hydrogel is cross-linked through electrostatic interactions between GO and HTCC, resulting in strong mechanical properties. Voriconazole (Vor), an antifungal drug, can be loaded onto GO which retains the drug and promotes its sustained release from the hydrogel-based contact lenses. The contact lenses also exhibited good antimicrobial functions in view of glycidyltrimethylammonium chloride and silver nanoparticles. The results from in vitro and in vivo experiments demonstrate that contact lenses loaded with Vor have excellent efficacy in antifungal activity in vitro and could significantly enhance the therapeutic effects on a fungus-infected mouse model. The results indicate that this hydrogel contact lenses-based drug delivery system might be a promising therapeutic approach for a rapid and effective treatment of fungal keratitis. PMID- 27244245 TI - Corrigendum: Adiponectin-derived active peptide ADP355 exerts anti-inflammatory and anti-fibrotic activities in thioacetamide-induced liver injury. PMID- 27244241 TI - Cell type specificity of neurovascular coupling in cerebral cortex. AB - Identification of the cellular players and molecular messengers that communicate neuronal activity to the vasculature driving cerebral hemodynamics is important for (1) the basic understanding of cerebrovascular regulation and (2) interpretation of functional Magnetic Resonance Imaging (fMRI) signals. Using a combination of optogenetic stimulation and 2-photon imaging in mice, we demonstrate that selective activation of cortical excitation and inhibition elicits distinct vascular responses and identify the vasoconstrictive mechanism as Neuropeptide Y (NPY) acting on Y1 receptors. The latter implies that task related negative Blood Oxygenation Level Dependent (BOLD) fMRI signals in the cerebral cortex under normal physiological conditions may be mainly driven by the NPY-positive inhibitory neurons. Further, the NPY-Y1 pathway may offer a potential therapeutic target in cerebrovascular disease. PMID- 27244246 TI - Which Patients Need Palliative Care Most? Challenges of Rationing in Medicine's Newest Specialty. PMID- 27244247 TI - Novel back-reflector architecture with nanoparticle based buried light-scattering microstructures for improved solar cell performance. AB - A new back-reflector architecture for light-management in thin-film solar cells is proposed that includes a morphologically smooth top surface with light scattering microstructures buried within. The microstructures are pyramid shaped, fabricated on a planar reflector using TiO2 nanoparticles and subsequently covered with a layer of Si nanoparticles to obtain a flattened top surface, thus enabling growth of good quality thin-film solar cells. The optical properties of this back-reflector show high broadband haze parameter and wide angular distribution of diffuse light-scattering. The n-i-p amorphous silicon thin-film solar cells grown on such a back-reflector show enhanced light absorption resulting in improved external quantum efficiency. The benefit of the light trapping in those solar cells is evidenced by the gains in short-circuit current density and efficiency up to 15.6% and 19.3% respectively, compared to the reference flat solar cells. This improvement in the current generation in the solar cells grown on the flat-topped (buried pyramid) back-reflector is observed even when the irradiation takes place at large oblique angles of incidence. Finite-difference-time-domain simulation results of optical absorption and ideal short-circuit current density values agree well with the experimental findings. The proposed approach uses a low cost and simple fabrication technique and allows effective light manipulation by utilizing the optical properties of micro-scale structures and nanoscale constituent particles. PMID- 27244248 TI - Light as a key driver of freshwater biofouling surface roughness in an experimental hydrocanal pipe rig. AB - Biofouling in canals and pipelines used for hydroelectric power generation decreases the flow capacity of conduits. A pipeline rig was designed consisting of test sections of varying substrata (PVC, painted steel) and light levels (transparent, frosted, opaque). Stalk-forming diatoms were abundant in both the frosted and transparent PVC pipes but negligible in the painted steel and opaque PVC pipes. Fungi were slightly more abundant in the painted steel pipe but equally present in all the other pipes while bacterial diversity was similar in all pipes. Photosynthetically functional biofouling (mainly diatoms) was able to develop in near darkness. Different biological fouling compositions generated differing friction factors. The highest friction factor was observed in the transparent pipe (densest diatom fouling), the lowest peak friction for the opaque PVC pipe (lowest fouling biomass), and with the painted steel pipe (high fouling biomass, but composed of fungal and bacterial crusts) being intermediate between the opaque and frosted PVC pipes. PMID- 27244250 TI - Convergent and Biomimetic Enantioselective Total Synthesis of (-)-Communesin F. AB - The first biomimetic enantioselective total synthesis of (-)-communesin F based on a late-stage heterodimerization and aminal exchange is described. Our synthesis features the expedient diazene-directed assembly of two advanced fragments to secure the congested C3a-C3a' linkage in three steps, followed by a highly efficient biogenetically inspired aminal reorganization to access the heptacyclic communesin core in only two additional steps. Enantioselective syntheses of the two fragments were developed, with highlights including the catalytic asymmetric halocyclization and diastereoselective oxyamination reactions of tryptamine derivatives, a stereoselective sulfinimine allylation, and an efficient cyclotryptamine-C3a-sulfamate synthesis by either a new silver promoted nucleophilic amination or a rhodium-catalyzed C-H amination protocol. The versatile syntheses of the fragments, their stereocontrolled assembly, and the efficient aminal exchange as supported by in situ monitoring experiments, in addition to the final stage N1'-acylation of the communesin core, provide a highly convergent synthesis of (-)-communesin F. PMID- 27244249 TI - Scoping Review of the Zika Virus Literature. AB - The global primary literature on Zika virus (ZIKV) (n = 233 studies and reports, up to March 1, 2016) has been compiled using a scoping review methodology to systematically identify and characterise the literature underpinning this broad topic using methods that are documented, updateable and reproducible. Our results indicate that more than half the primary literature on ZIKV has been published since 2011. The articles mainly covered three topic categories: epidemiology of ZIKV (surveillance and outbreak investigations) 56.6% (132/233), pathogenesis of ZIKV (case symptoms/ outcomes and diagnosis) 38.2% (89/233) and ZIKV studies (molecular characterisation and in vitro evaluation of the virus) 18.5% (43/233). There has been little reported in the primary literature on ZIKV vectors (12/233), surveillance for ZIKV (13/233), diagnostic tests (12/233) and transmission (10/233). Three papers reported on ZIKV prevention/control strategies, one investigated knowledge and attitudes of health professionals and two vector mapping studies were reported. The majority of studies used observational study designs, 89.7% (209/233), of which 62/233 were case studies or case series, while fewer (24/233) used experimental study designs. Several knowledge gaps were identified by this review with respect to ZIKV epidemiology, the importance of potential non-human primates and other hosts in the transmission cycle, the burden of disease in humans, and complications related to human infection with ZIKV. Historically there has been little research on ZIKV; however, given its current spread through Australasia and the Americas, research resources are now being allocated to close many of the knowledge gaps identified in this scoping review. Future updates of this project will probably demonstrate enhanced evidence and understanding of ZIKV and its impact on public health. PMID- 27244253 TI - The Ethical and Practical Challenges of Value-Based Cancer Care at the Patient's Bedside. PMID- 27244251 TI - Vascular growth responses to chronic arterial occlusion are unaffected by myeloid specific focal adhesion kinase (FAK) deletion. AB - Arteriogenesis, or the lumenal expansion of pre-existing arterioles in the presence of an upstream occlusion, is a fundamental vascular growth response. Though alterations in shear stress stimulate arteriogenesis, the migration of monocytes into the perivascular space surrounding collateral arteries and their differentiation into macrophages is critical for this vascular growth response to occur. Focal adhesion kinase's (FAK) role in regulating cell migration has recently been expanded to primary macrophages. We therefore investigated the effect of the myeloid-specific conditional deletion of FAK on vascular remodeling in the mouse femoral arterial ligation (FAL) model. Using laser Doppler perfusion imaging, whole mount imaging of vascular casted gracilis muscles, and immunostaining for CD31 in gastrocnemius muscles cross-sections, we found that there were no statistical differences in perfusion recovery, arteriogenesis, or angiogenesis 28 days after FAL. We therefore sought to determine FAK expression in different myeloid cell populations. We found that FAK is expressed at equally low levels in Ly6C(hi) and Ly6C(lo) blood monocytes, however expression is increased over 2-fold in bone marrow derived macrophages. Ultimately, these results suggest that FAK is not required for monocyte migration to the perivascular space and that vascular remodeling following arterial occlusion occurs independently of myeloid specific FAK. PMID- 27244254 TI - The inclusion of an online journal in PubMed central - a difficult path. AB - The indexing of a journal in a prominent database (such as PubMed) is an important imprimatur. Journals accepted for inclusion in PubMed Central (PMC) are automatically indexed in PubMed but must provide the entire contents of their publications as XML-tagged (Extensible Markup Language) data files compliant with PubMed's document type definition (DTD). This paper describes the various attempts that the journal Images in Paediatric Cardiology made in its efforts to convert the journal contents (including all of the extant backlog) to PMC compliant XML for archiving and indexing in PubMed after the journal was accepted for inclusion by the database. PMID- 27244255 TI - The sensitivity of chronic myeloid leukemia CD34 cells to Bcr-Abl tyrosine kinase inhibitors is modulated by ceramide levels. AB - Despite BCR-ABL tyrosine kinase inhibitors (TKIs) improved outcome of patients with chronic myeloid leukemia (CML), resistance still develops when progresses to blast phase (BP). The mechanisms underlying resistance to TKIs are not well understood. In this study, we analyzed ceramide levels in CD34 cells derived from BP-CML patients and healthy donor bone marrow (BM) using liquid chromatography mass spectrometry. We found that ceramide level was significantly lower in BP-CML CD34 compared with normal BM counterparts. BP-CML CD34 ceramide(low) were more resistant to BCR-ABL TKIs compared to BP-CML CD34 ceramide(normal). Both mRNA and proteins levels of sphingomyelin synthase 1 and 2 are lower in BP-CML CD34 ceramide(low) compared to normal BM CD34 cells, suggesting that these two ceramide synthesis enzymes maybe the mechanism of how ceramide level is suppressed. Importantly, up-regulation of cellular ceramide level induces apoptosis of multiple CML cell lines and BP-CML CD34 progenitors. Combination of BCR-ABL TKIs with ceramide analog is synergistic in targeting BP-CML 34 progenitors. Collectively, our work provides evidence that down-regulation of ceramide level is involved in the resistance of BP-CML CD34 progenitors to TKIs treatment. Targeting ceramide metabolism together with BCR-ABL inhibition makes it an attractive addition to the armamentarium in BP-CML treatment. PMID- 27244256 TI - Single cell genotyping of exome sequencing-identified mutations to characterize the clonal composition and evolution of inv(16) AML in a CBL mutated clonal hematopoiesis. AB - We recently described the development of an inv(16) acute myeloid leukemia (AML) in a CBL mutated clonal hematopoiesis. Here, we further characterized the clonal composition and evolution of the AML based on the genetic information from the bulk specimen and analyses of individual bone marrow cells for mutations in CAND1, PTPRT, and DOCK6. To control for allele dropout, heterozygous polymorphisms located close to the respective mutation loci were assessed in parallel. The clonal composition concluded from exome sequencing suggested a proliferation advantage associated with the acquisition of mutations in CAND1, PTPRT, and DOCK6. Out of 102 single cell sequencing reactions on these mutations and the respective polymorphisms, analyses yielded conclusive results for at least 2 mutation sites in 12 cells. The single cell genotyping not only confirmed the co-occurrence of the PTPRT, CAND1 and DOCK6 mutations in the same AML clone but also revealed a clonal hierarchy, as the PTPRT mutation was likely acquired after the CAND1 and DOCK6 mutations. This insight had not been possible based solely on the exome sequencing data and suggests that the mutation in PTPRT, which encodes a STAT3-inhibiting protein tyrosine phosphatase, contributed to the AML development at a later stage by enhancing proliferation. PMID- 27244257 TI - Acute megakaryoblastic leukemia, unlike acute erythroid leukemia, predicts an unfavorable outcome after allogeneic HSCT. AB - Acute erythroid leukemia (FAB-M6) and acute megakaryoblastic leukemia (FAB-M7) exhibit closely related properties in cells regarding morphology and the gene expression profile. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered the mainstay of the treatment for both subtypes of leukemia due to their refractoriness to chemotherapy and high rates of relapse, it remains unclear whether allo-HSCT is curative in such cases due to their scarcity. We retrospectively examined the impact of allo-HSCT in 382 patients with M6 and 108 patients with M7 using nationwide HSCT data and found the overall survival (OS) and relapse rates of the M6 patients to be significantly better than those of the M7 patients after adjusting for confounding factors and statistically comparable with those of the patients with M0/M1/M2/M4/M5 disease. Consequently, the factors of age, gender, performance status, karyotype, disease status at HSCT and development of graft-vs.-host disease predicted the OS for the M6 patients, while the performance status and disease status at HSCT were predictive of the OS for the M7 patients. These findings substantiate the importance of distinguishing between M6 and M7 in the HSCT setting and suggest that unknown mechanisms influence the HSCT outcomes of these closely related subtypes of leukemia. PMID- 27244259 TI - Time-Based Billing: What Primary Care in the United States Can Learn From Switzerland. PMID- 27244258 TI - Stability of Reference Genes for Messenger RNA Quantification by Real-Time PCR in Mouse Dextran Sodium Sulfate Experimental Colitis. AB - BACKGROUND: Many animal models have been developed to characterize the complexity of colonic inflammation. In dextran sodium sulfate (DSS) experimental colitis in mice the choice of reference genes is critical for accurate quantification of target genes using quantitative real time PCR (RT-qPCR). No studies have addressed the performance of reference genes in mice DSS-experimental colitis. This study aimed to determine the stability of reference genes expression (RGE) in DSS-experimental murine colitis. METHODS: Colitis was induced in male C57BL/6 mice using DSS5% for 5 days, control group received water. RNA was extracted from inflamed and non-inflamed colon. Using RT-qPCR, comparative analysis of 13 RGE was performed according to predefined criteria and relative colonic TNF-alpha and IL-1beta gene expression was determined by calculating the difference in the threshold cycle. RESULTS: Colitis significantly altered the stability of mucosal RGE. Commonly used glyceraldehyde-3-phosphate dehydrogenase (Gapdh), beta-actin (Actb), or beta2-microglobulin (beta2m) showed the highest variability within the inflamed and control groups. Conversely, TATA-box-binding protein (Tbp) and eukaryotic translation elongation factor 2 (Eef2) were not affected by inflammation and were the most stable genes. Normalization of colonic TNF-alpha and IL-1beta mRNA levels was dependent on the reference gene used. Depending on the genes used to normalize the data, statistical significance varied from significant when TBP / Eef2 were used to non-significant when Gapdh, Actb or beta2m were used. CONCLUSIONS: This study highlights the appropriate choice of RGE to ensure adequate normalization of RT-qPCR data when using this model. Suboptimal RGE may explain controversial results from published studies. We recommend using Tbp and Eef2 instead of Gapdh, Actb or beta2m as reference genes. PMID- 27244260 TI - MRI Signal Intensity Classification in Cervical Ossification of the Posterior Longitudinal Ligament: Predictor of Surgical Outcomes. AB - STUDY DESIGN: Prospective cohort study. OBJECTIVE: To investigate whether classification of increased signal intensity (ISI) on magnetic resonance imaging (MRI) of spinal cord in patients with cervical ossification of the posterior longitudinal ligament (C-OPLL) reflects severity of myelopathy and surgical outcome. SUMMARY OF BACKGROUND DATA: The relationship between classification of ISI on C-OPLL and severity is unknown. METHODS: The 119 consecutive patients (91 men, 28 women) with C-OPLL who underwent surgery were enrolled. T2-weighted MRI was performed before surgery and ISI was classified into three groups as follows, Grade 0, none; Grade 1, light (obscure); and Grade 2, intense (bright). The severity of myelopathy and surgical outcome were evaluated by the Japanese Orthopedic Association score. To determine factors that influence ISI, the change of the spinal cord cross-sectional area (SCA) during flexion and extension was calculated by computed tomography after myelography. RESULTS: The preoperative MRI showed 55 patients in Grade 0, 46 patients in Grade 1, and 18 patients in Grade 2. The preoperative Japanese Orthopedic Association score (Grade 0, 11.2; Grade 1, 10.3; Grade 2, 9.6 points) and surgical outcome got worsened with increasing ISI grade. The patients in Grade 2 had a longer duration of disease, while those in Grade 1 and Grade 2 had a larger change of SCA during flexion and extension (Grade 0, 4.8 mm; Grade 1, 7.3 mm; Grade 2, 7.8 mm). However age, alignment of the cervical spine, range of motion, and occupying ratio of the ossification were not different in the three grades. CONCLUSION: Grade of ISI correlated with preoperative severity of myelopathy and surgical outcome in patients with C-OPLL. Increased signal intensity of the spinal cord on MRI was associated with a larger change in SCA and longer duration of disease. LEVEL OF EVIDENCE: 3. PMID- 27244261 TI - Surgical Management of Civilian Gunshot-Induced Spinal Cord Injury: Is It Overutilized? AB - STUDY DESIGN: Retrospective chart review. OBJECTIVE: Assess appropriate utilization of surgery for civilian gunshot-induced spinal cord injuries (CGSWSCI) according to literature standards in a large cohort. SUMMARY OF BACKGROUND DATA: CGSWSCI are mechanically stable injuries that rarely require surgery. Nonetheless, we continue to see high numbers of these patients undergo surgical treatment. This study compares indications for surgeries performed in a large cohort of CGSWSCI patients to established indications for surgical management of such injuries. The rate of over-utilization of surgical management was calculated. METHODS: Four hundred eighty-nine CGSWSCI patients transferred for rehabilitation to our institution between 2000 and 2014 were identified. Retrospective chart review was performed to identify patients who underwent initial surgical treatment, the specific surgeries performed, and indications given. We assessed appropriateness of surgery according to literature standards. Patients treated surgically were followed to assess for complications and the need for additional intervention and compared to nonsurgical patients. Secondarily, visual analog scale pain scores (0-10) and patient perceived improvement were compared between surgical and nonsurgical patients after telephone survey of both groups. RESULTS: Of 489 patients, 91 (18%) underwent initial surgery. Of 91 surgeries, 69 (75%) were not indicated by literature standards. Five of 91 (5.5%) of initially operated patients required a secondary surgery compared with two of 398 (0.5%) of the nonoperative group (P = 0.003). Over-utilization rate of the entire cohort was 14.1%. No difference was seen for pain scores or patient perceived improvement between operative and nonoperative patients. CONCLUSION: We report a high overutilization rate (14%) of surgery for CGSWSCI in our cohort. Surgical management was associated with higher infection and secondary surgery rates compared to nonsurgical management. Surgery done without a clear, demonstrable benefit poses unnecessary risk to patients and accumulates unwarranted healthcare costs. LEVEL OF EVIDENCE: 3. PMID- 27244262 TI - Electroencephalogram associations to cognitive performance in clinically active nurses. AB - Cognitive impairment is traditionally identified via cognitive screening tools that have limited ability in detecting early or transitional stages of impairment. The dynamic nature of physiological variables such as the electroencephalogram (EEG) may provide alternate means for detecting these transitions. However, previous research examining EEG and cognitive performance is largely confined to samples with diagnosed cognitive impairments, and research examining non-impaired, and occupation specific samples, is limited. The present study aimed to investigate the associations between frontal pole and central EEG and cognitive performance in a sample of male and female nurses, and to determine the significance of these associations. Fifty seven nurses participated in the study, in which two lead bipolar EEG was recorded at positions Fp1 (frontal polar), Fp2, C3 (central) and C4 during a baseline and an active phase involving the common neuropsychological Stroop test. Participants' cognitive performance was assessed using the mini-mental state exam (MMSE) and Cognistat screening tools. Significant correlations between EEG beta activity and the outcome of MMSE and Cognistat were revealed, where an increased beta activity was associated to an increased global cognitive performance. Additionally, domain specific cognitive performance was also significantly associated to various EEG variables. The study identified potential EEG biomarkers for global and domain specific cognitive performance, and provides initial groundwork for the development of future EEG based biomarkers for detection of cognitive pathologies. PMID- 27244264 TI - Semantic memory influences episodic retrieval by increased familiarity. AB - The role of familiarity in associative recognition has been investigated in a number of studies, which have indicated that familiarity can facilitate recognition under certain circumstances. The ability of a pre-experimentally existing common representation to boost the contribution of familiarity has rarely been investigated. In addition, although many studies have investigated the interactions between semantic memory and episodic retrieval, the conditions that influence the presence of specific patterns were unclear. This study aimed to address these two questions. We manipulated the degree of overlap between the two representations using synonym and nonsynonym pairs in an associative recognition task. Results indicated that an increased degree of overlap enhanced recognition performance. The analysis of event-related potentials effects in the test phase showed that synonym pairs elicited both types of old/rearranged effects, whereas nonsynonym pairs elicited a late old/rearranged effect. These results confirmed that a common representation, irrespective of source, was necessary for assuring the presence of familiarity, but a common representation could not distinguish associative recognition depending on familiarity alone. Moreover, our expected double dissociation between familiarity and recollection was absent, which indicated that mode selection may be influenced by the degree of distinctness between old and rearranged pairs rather than the degree of overlap between representations. PMID- 27244263 TI - Role of heme in bromine-induced lung injury. AB - Bromine (Br2 ) gas inhalation poses an environmental and occupational hazard resulting in high morbidity and mortality. In this review, we underline the acute lung pathology (within 24 h of exposure) and potential therapeutic interventions that may be utilized to mitigate Br2 -induced human toxicity. We discuss our latest published data, which suggest that an increase in heme-dependent tissue injury underlies the pathogenesis of Br2 toxicity. Our study was based on previous findings that demonstrated that Br2 upregulates the heme-degrading enzyme heme oxygenase-1 (HO-1), which converts toxic heme into bilverdin. Interestingly, following Br2 inhalation, heme levels were indeed elevated in bronchoalveolar lavage fluid, plasma, and whole lung tissue in C57BL/6 mice. High heme levels correlated with increased lung oxidative stress, lung inflammation, respiratory acidosis, lung edema, higher airway resistance, and mortality. However, therapeutic reduction of heme levels, by either scavenging with hemopexin or degradation by HO-1, improved lung function and survival. Therefore, heme attenuation may prove a useful adjuvant therapy to treat patients after Br2 exposure. PMID- 27244265 TI - Applications of Smartphone thermal camera imaging system in monitoring of the deep inferior epigastric perforator flap for breast reconstruction. PMID- 27244266 TI - Fate of Free and Conjugated Mycotoxins within the Production of Distiller's Dried Grains with Solubles (DDGS). AB - Contamination of feed with mycotoxins represents a serious worldwide problem concerning animal health and related economic losses. The present paper provides comprehensive knowledge about the fate of mycotoxins during the production of distiller's dried grains with solubles (DDGS). The study was carried out using naturally infected maize material in five repetitions. For mycotoxin analysis, a QuEChERS-like ("Quick, Easy, Cheap, Effective, Rugged, and Safe") isolation approach and ultrahigh-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) was used. A significant increase of deoxynivalenol (DON) and its glycosylated form, DON-3-glucoside (DON-3-Glc), was observed during the first part of fermentation, when hydrolytic enzymes were added. After yeast addition, the total DON content rapidly decreased. An opposite trend was observed for fumonisin B1 (FB1), in which yeast addition contributed to increase of its content. Further considerable change in mycotoxin content occurred during the drying step, in which approximately two-thirds of the original content was lost. PMID- 27244268 TI - Self-critical perfectionism, dependency, and symptomatic distress in patients with personality disorder during hospitalization-based psychodynamic treatment: A parallel process growth modeling approach. AB - There is growing evidence for the efficacy and effectiveness of psychotherapy in patients with personality disorder (PD), but very little is known about the factors underlying these effects. Two-polarities models of personality development provide an empirically supported approach to studying therapeutic change. Briefly, these models argue that personality pathology is characterized by an imbalance between development of the capacity for self-definition and for relatedness, with an exaggerated emphasis on issues regarding self-definition and relatedness being expressed in high levels of self-critical perfectionism (SCP) and dependency, respectively. This study used data from a study of 111 patients with PD who received long-term hospitalization-based psychodynamic treatment to investigate whether (a) treatment was related to changes in SCP, dependency, and symptomatic distress; (b) these changes could be explained by pretreatment levels of SCP, dependency, and/or symptomatic distress; and (c) changes in these personality dimensions over time were associated with symptomatic improvement. SCP, dependency, and symptomatic distress were assessed at admission (baseline), at 12 and 24 weeks into treatment, and at discharge. Parallel process multilevel growth modeling showed that (a) treatment was associated with a significant decrease in levels of SCP, dependency, and symptomatic distress, whereas (b) pretreatment levels of each of these three factors did not predict the decreases observed, and (c) changes in SCP, but not dependency, were associated with the rate of decrease in symptomatic distress over time. Implications of these findings for our understanding of therapeutic change in the treatment of PD are discussed. (PsycINFO Database Record PMID- 27244269 TI - Cloning and Expression of L1 Protein Human Papillomavirus Type 31 Isolated from Iranian Patients in Escherichia coli. AB - Human papillomavirus (HPV), a major pathogen of human cervical cancer, contains a full-length L1 gene encoding its surface capsid protein. One group of potential vaccine candidates against this virus in Iranian patients is based on surface protein components such as HPV31 L1 protein that can make virus-like particles (VLPs). The high immunity response stimulation of this effecter VLP was observed in host, suggesting that the individual characteristics of a particular effecter may require empirical testing for vaccination. In the present study, we decided to clone and express HPV31 L1 protein to investigate its use as a subunit vaccine and furthermore to insert the gene into an Escherichia coli background so as to analyze production of this recombinant protein. We report the presentation of HPV31 in 100 cervical lesion tissue samples based on polymerase chain reaction (PCR). Type of lesion, age, and other characteristics were reviewed and confirmed by a pathologist. The sequence from L1 genes of HPV was selected using special primers. The gene encoding the major capsid protein L1 was used for subcloning in pTG19-T and pET-32a plasmid. The recombinant protein expression was confirmed by RT-PCR using L1 primers and detected by absorption sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblot testing. The results presented here offer new insights into the in vivo response of HPV31 in Iranian patients and European models. On the other hand, the use of recombinant L1 protein for Iranian patient protection as well as vaccination studies will permit testing of this antigen protection rate and open the way to the discovery of protein biomarkers for monitoring clinical and subclinical cervical cancers. PMID- 27244270 TI - Silver(I) 1,3,5-Triaza-7-phosphaadamantane Coordination Polymers Driven by Substituted Glutarate and Malonate Building Blocks: Self-Assembly Synthesis, Structural Features, and Antimicrobial Properties. AB - Three new bioactive silver(I) coordination polymers formulated as [Ag2(MU2 PTA)(MU3-PTA)(MU2-pga)(H2O)]n.6H2O (1), [Ag2(MU2-PTA)(MU3-PTA)(Hpmal)2]n.2H2O (2), and [Ag(MU3-PTA) (Hdmga)]n (3) were self-assembled from Ag2O, 1,3,5-triaza-7 phosphaadamantane (PTA), and a substituted dicarboxylic acid (3-phenylglutaric acid (H2pga), phenylmalonic acid (H2pmal), or 3,3-dimethylglutaric acid (H2dmga)) as an ancillary ligand. Compounds 1-3 were fully characterized by IR and NMR spectroscopy, ESI-MS(+/-), elemental analysis, and single-crystal X-ray diffraction, revealing that their architectural and topological diversity is governed by structural modulation of a dicarboxylate building block. The structures vary from a 1D cyclic chain with the SP 1-periodic net (4,4)(0,2) topology in 2 to distinct 2D metal-organic layers with the cem-d and hcb topologies in 1 and 3, respectively. In addition, compounds 1-3 exhibit a notable antimicrobial efficiency against a panel of common Gram-negative (E. coli and P. aeruginosa) and Gram-positive (S. aureus) bacteria and yeast (C. albicans). The best normalized minimum inhibitory concentrations (normalized MIC) of 11-23 nmol mL(-1) (for bacterial strains) or 68 nmol mL(-1) (for a yeast strain) are shown by compound 2, and the eventual structure-bioactivity correlations are discussed. PMID- 27244271 TI - Crosstalk between microglia and T cells contributes to brain damage and recovery after ischemic stroke. AB - OBJECTIVES: To summarize available knowledge regarding the crosstalk, thereby providing a more detailed explanation for the mechanism of brain damage and recovery after ischemic stroke. METHODS: An extensive review of the literature on the crosstalk between microglia and T cells in ischemic stroke was performed. We review the relevant publications in PubMed database. RESULTS: After cerebral ischemia, microglia are activated and peripheral T cells infiltrated into the brain. The crosstalk between microglia and T cells has both pro-inflammatory and anti-inflammatory effects in the inflammation after stroke. The crosstalk between M1 and Th1/Th17 cells promotes immune response after stroke and contributes to brain damage, while the crosstalk between M2 and Th2/Treg cells plays an anti inflammatory role and contributes to brain recovery. Meanwhile, the crosstalk can be regulated by many factors, in both contact dependent and non-contact dependent way. CONCLUSION: Inflammation mediated by microglia crosstalking to T cells contributes to brain damage and recovery after ischemic stroke. Extensive evidence supports a critical role for the crosstalk of microglia and T cells in the prognosis of brain injury after ischemic stroke. The regulation of the crosstalk may provide a potential therapeutic target for improving the ischemic brain damage. PMID- 27244272 TI - Fabrication of Nonperiodic Metasurfaces by Microlens Projection Lithography. AB - This paper describes a strategy that uses template-directed self-assembly of micrometer-scale microspheres to fabricate arrays of microlenses for projection photolithography of periodic, quasiperiodic, and aperiodic infrared metasurfaces. This method of "template-encoded microlens projection lithography" (TEMPL) enables rapid prototyping of planar, multiscale patterns of similarly shaped structures with critical dimensions down to ~400 nm. Each of these structures is defined by local projection lithography with a single microsphere acting as a lens. This paper explores the use of TEMPL for the fabrication of a broad range of two-dimensional lattices with varying types of nonperiodic spatial distribution. The matching optical spectra of the fabricated and simulated metasurfaces confirm that TEMPL can produce structures that conform to expected optical behavior. PMID- 27244273 TI - Rapamycin: A promising agent to treat cancer pain? PMID- 27244274 TI - Reconstruction of Temporal Hollowing Defect With Anterior-Lateral Thigh Free Flap Following Resection of Recurrent Ameloblastoma of the Infratemporal Fossa and Right Mandible (a Case Report). AB - Recurrent invasive ameloblastoma of the infratemporal fossa is an uncommonly encountered phenomenon in the practice of oral and maxillofacial surgery and presents many surgical challenges for the practitioner. This case report describes a patient who underwent previous resection of a mandibular ameloblastoma with multiple recurrences. The patient was diagnosed with a recurrent ameloblastoma of the infratemporal fossa that was subsequently resected and reconstructed using an anterolateral thigh (ALT) free tissue transfer. There are few reported cases of recurrent ameloblastomas in the infratemporal fossa and none that describe surgical resection and reconstruction of such a lesion. Owing to the uniqueness of the surgical defect, an ALT flap was used to correct the temporal hollowing. There have been multiple reported cases of reconstruction of temporal hollowing defects using autogenous fat or allograft; however, none have described the use of a de-epithelialized ALT microvascular reconstruction of a temporal hollowing defect. This case report describes a unique clinical situation of surgical resection and reconstruction that resulted in a satisfactory outcome for the patient. PMID- 27244275 TI - Corrigendum: Operational stability enhancement in organic light-emitting diodes with ultrathin Liq interlayers. PMID- 27244276 TI - Improved Method for the Quantification of Methane Concentrations in Unconsolidated Lake Sediments. AB - There is conclusive evidence that the methods most commonly used to sample methane (CH4) dissolved in the pore water of lake sediments produce results that are likely to be affected by gas loss or gas exchange with the atmosphere. To determine the in situ amount of CH4 per unit mass of pore water in sediments, we developed and validated a new method that combines techniques developed for noble gas analysis in pore waters with a standard headspace technique to quantify the CH4 present in the pore space in dissolved and gaseous form. The method was tested at two sites: Lake Lungern, where CH4 concentrations were close to saturation; and Lake Rotsee, where CH4 concentrations are known to exceed saturation and where CH4 bubble formation and gas ebullition are commonly observed. We demonstrate that the new method, in contrast to the available methods, more reliably captures the total amount of CH4 per unit mass of pore water consisting of both dissolved and free CH4 (i.e., gas bubbles) in the pore space of the sediment. PMID- 27244277 TI - Differential compromise of prospective and retrospective metamemory monitoring and their dissociable structural brain correlates. AB - Metamemory refers to personal knowledge about one's own memory ability that invokes cognitive processes relevant to monitoring and controlling memory. An impaired monitoring system can potentially result in unawareness of symptoms as can occur in addiction denial. Monitoring processes can be assessed with prospective measures such as Feeling-Of-Knowing (FOK) judgments on prediction of future recognition performance, or retrospective confidence judgments (RCJ) made on previous memory performance. Alcoholic patients with amnesia showed poor FOK but intact RCJ. The neuropsychological continuum from mild to moderate deficits in nonamnesic to amnesic alcoholism raised the possibility that alcoholics uncomplicated by clinically-detectable amnesia may suffer anosognosia for their mild memory deficits. Herein 24 abstinent alcoholics and 26 age-matched controls completed an episodic memory paradigm including prospective FOK and retrospective RCJ monitoring measures and underwent 3T structural magnetic resonance imaging. Alcoholics were less accurate than controls in recognition and in assessing their future recognition performance, which was marked by overestimation, but were as accurate as controls on confidence ratings of actual recognition performance. Examination of brain structure-function relations revealed a double dissociation where FOK accuracy was selectively related to insular volume, and retrospective confidence accuracy was selectively related to frontolimbic structural volumes. Impaired FOK with intact RCJ was consistent with mild anosognosia and suggested evidence for neuropsychological and neural mechanisms of unawareness in addiction. PMID- 27244278 TI - Transdiagnostic Internet-delivered cognitive behaviour therapy in Canada: An open trial comparing results of a specialized online clinic and nonspecialized community clinics. AB - Effects of Internet-delivered cognitive behaviour therapy (ICBT) for anxiety and depression are not well understood when delivered in non-specialized as compared to specialized clinic settings. This open trial (n=458 patients) examined the benefits of transdiagnostic-ICBT when delivered in Canada by therapists (registered providers or graduate students) working in either a specialized online clinic or one of eight nonspecialized community clinics. Symptoms of depression and anxiety were assessed at pre-treatment, post-treatment and at 3 month follow-up. Completion rates and satisfaction were high. Significant and large reductions (effect sizes 1.17-1.31) were found on symptom measures. Completion rates, satisfaction levels and outcomes did not differ whether ICBT was delivered by therapists working in a specialized online clinic or nonspecialized community clinics. Differences were also not found between registered providers and graduate students, or therapists trained in psychology or another discipline. The findings support the public health potential of ICBT. PMID- 27244279 TI - [Not Available]. PMID- 27244280 TI - [Not Available]. AB - This article describes a long term infection control program (2002-2014) that has been conducted at Karolinska University Hospital Huddinge Intensive Care Unit. By using a combination of bundles for ventilator-associated pneumonia (VAP) and central-lines associated bloodstream infections (CLABSI) combined with on-line data from the Swedish Intensive Care Registry (SIR) concerning the infection rates for VAP and CLABSI, the ward has been able to keep a sustainable low frequency of these infections over the years. Key message is "to never stop improving" when it concerns quality improvement. PMID- 27244281 TI - [Not Available]. PMID- 27244282 TI - [Not Available]. PMID- 27244283 TI - [In Process Citation]. PMID- 27244284 TI - [In Process Citation]. PMID- 27244285 TI - [In Process Citation]. PMID- 27244286 TI - [In Process Citation]. PMID- 27244287 TI - [In Process Citation]. PMID- 27244288 TI - [In Process Citation]. PMID- 27244289 TI - [In Process Citation]. PMID- 27244290 TI - [In Process Citation]. PMID- 27244291 TI - Endothelium-Mediated Action of Analogues of the Endogenous Neuropeptide Kyotorphin (Tyrosil-Arginine): Mechanistic Insights from Permeation and Effects on Microcirculation. AB - Kyotorphin (KTP) is an endogenous peptide with analgesic properties when administered into the central nervous system (CNS). Its amidated form (l-Tyr-l Arg-NH2; KTP-NH2) has improved analgesic efficacy after systemic administration, suggesting blood-brain barrier (BBB) crossing. KTP-NH2 also has anti-inflammatory action impacting on microcirculation. In this work, selected derivatives of KTP NH2 were synthesized to improve lipophilicity and resistance to enzymatic degradation while introducing only minor changes in the chemical structure: N terminal methylation and/or use of d amino acid residues. Intravital microscopy data show that KTP-NH2 having a d-Tyr residue, KTP-NH2-DL, efficiently decreases the number of leukocyte rolling in a murine model of inflammation induced by bacterial lipopolysaccharide (LPS): down to 46% after 30 min with 96 MUM KTP-NH2 DL. The same molecule has lower ability to permeate membranes (relative permeability of 0.38) and no significant activity in a behavioral test which evaluates thermal nociception (hot-plate test). On the contrary, methylated isomers at 96 MUM increase leukocyte rolling up to nearly 5-fold after 30 min, suggesting a proinflammatory activity. They have maximal ability to permeate membranes (relative permeability of 0.8) and induce long-lasting antinociception. PMID- 27244293 TI - Valorization of lubricant-based wastewater for bacterial neutral lipids production: Growth-linked biosynthesis. AB - Lipids produced by microorganisms are currently of great interest as raw material for either biofuels or oleochemicals production. Significant biosynthesis of neutral lipids, such as triacylglycerol (TAG) and wax esters (WE) are thought to be limited to a few strains. Hydrocarbonoclastic bacteria (HCB), key players in bioremediation of hydrocarbon contaminated ecosystems, are among this group of strains. Hydrocarbon rich wastewaters have been overlooked concerning their potential as raw material for microbial lipids production. In this study, lubricant-based wastewater was fed, as sole carbon source, to two HCB representative wild strains: Alcanivorax borkumensis SK2, and Rhodococcus opacus PD630. Neutral lipid production was observed with both strains cultivated under uncontrolled conditions of pH and dissolved oxygen. A. borkumensis SK2 was further investigated in a pH- and OD-controlled fermenter. Different phases were assessed separately in terms of lipids production and alkanes removal. The maximum TAG production rate occurred during stationary phase (4 mg-TAG/L h). The maximum production rate of WE-like compounds was 15 mg/L h, and was observed during exponential growth phase. Hydrocarbons removal was 97% of the gas chromatography (GC) resolved straight-chain alkanes. The maximum removal rate was observed during exponential growth phase (6 mg-alkanes/L h). This investigation proposes a novel approach for the management of lubricant waste oil, aiming at its conversion into valuable lipids. The feasibility of the concept is demonstrated under low salt (0.3%) and saline (3.3%) conditions, and presents clues for its technological development, since growth associated oil production opens the possibility for establishing continuous fermentation processes. PMID- 27244292 TI - Exact results for Schrodinger cats in driven-dissipative systems and their feedback control. AB - In quantum optics, photonic Schrodinger cats are superpositions of two coherent states with opposite phases and with a significant number of photons. Recently, these states have been observed in the transient dynamics of driven-dissipative resonators subject to engineered two-photon processes. Here we present an exact analytical solution of the steady-state density matrix for this class of systems, including one-photon losses, which are considered detrimental for the achievement of cat states. We demonstrate that the unique steady state is a statistical mixture of two cat-like states with opposite parity, in spite of significant one photon losses. The transient dynamics to the steady state depends dramatically on the initial state and can pass through a metastable regime lasting orders of magnitudes longer than the photon lifetime. By considering individual quantum trajectories in photon-counting configuration, we find that the system intermittently jumps between two cats. Finally, we propose and study a feedback protocol based on this behaviour to generate a pure cat-like steady state. PMID- 27244294 TI - Manipulating nutrient limitation using modified local soils: A case study at Lake Taihu (China). AB - The effect of geo-engineering materials of chitosan modified local soil (MLS) on nutrient limitation was studied in comparable whole ponds in Lake Taihu in October 2013. After 20 kg MLS were sprayed in the whole water pond (400 m(2)), the chlorophyll-a (Chl-a) concentration was decreased from 42 to 18 MUg L(-1) within 2 h and remained below 20 MUg L(-1) in the following 15 months, while the average Chl-a was 36 MUg L(-1) in the control pond throughout the experiment. In situ nutrient addition bioassay experiments indicated that the nutrient limitation was shifted from nitrogen (N) and phosphorus (P) co-limitation to P limitation after MLS treatment from October 2013 to March 2014 compared to the control pond. In the cyanobacterial bloom season of June 2014, N and P co limitation remained and N was the primary limiting nutrient and P was a secondary one in the control pond where phytoplankton biomass showed significant increase by N addition and further increase by N + P additions, while both N and P became the limiting nutrient for phytoplankton growth where only combined N and P additions showed significant Chl-a stimulation in the treatment pond. In the next summer (June 2014), a cyanobacteria-dominated state still remained in the control pond but chlorophytes, bacillariophytes and cyanophytes distributed equally and submerged vegetation was largely restored in the treatment pond. Meanwhile, the upper limiting concentration of DIN was enhanced from 0.8 to 1.5 mg L(-1) and SRP from 0.1 to 0.3 mg L(-1) compared to the control pond. This study indicates that nutrient limitation can be manipulated by using MLS technology. PMID- 27244295 TI - Quantifying potential sources of surface water contamination with Campylobacter jejuni and Campylobacter coli. AB - Campylobacter is the most common causative agent of human bacterial gastroenteritis and is frequently found in surface water, where it indicates recent contamination with animal faeces, sewage effluent, and agricultural run off. The contribution of different animal reservoirs to surface water contamination with Campylobacter is largely unknown. In the Netherlands, the massive poultry culling to control the 2003 avian influenza epidemic coincided with a 44-50% reduction in human campylobacteriosis cases in the culling areas, suggesting substantial environment-mediated spread of poultry-borne Campylobacter. We inferred the origin of surface water Campylobacter jejuni and Campylobacter coli strains in Luxembourg and the Netherlands, as defined by multilocus sequence typing, by comparison to strains from poultry, pigs, ruminants, and wild birds, using the asymmetric island model for source attribution. Most Luxembourgish water strains were attributed to wild birds (61.0%), followed by poultry (18.8%), ruminants (15.9%), and pigs (4.3%); whereas the Dutch water strains were mainly attributed to poultry (51.7%), wild birds (37.3%), ruminants (9.8%), and pigs (1.2%). Attributions varied over seasons and surface water types, and geographical variation in the relative contribution of poultry correlated with the magnitude of poultry production at either the national or provincial level, suggesting that environmental dissemination of Campylobacter from poultry farms and slaughterhouses can be substantial in poultry-rich regions. PMID- 27244297 TI - Commentary on Sleep in Pediatric and Developmental Conditions: The Three-Journal Special Issue Collaboration Between the Journal of Developmental and Behavioral Pediatrics, Journal of Pediatric Psychology, and Clinical Practice in Pediatric Psychology. PMID- 27244296 TI - Association of HLA Genetic Risk Burden With Disease Phenotypes in Multiple Sclerosis. AB - IMPORTANCE: Although multiple HLA alleles associated with multiple sclerosis (MS) risk have been identified, genotype-phenotype studies in the HLA region remain scarce and inconclusive. OBJECTIVES: To investigate whether MS risk-associated HLA alleles also affect disease phenotypes. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional, case-control study comprising 652 patients with MS who had comprehensive phenotypic information and 455 individuals of European origin serving as controls was conducted at a single academic research site. Patients evaluated at the Multiple Sclerosis Center at University of California, San Francisco between July 2004 and September 2005 were invited to participate. Spinal cord imaging in the data set was acquired between July 2013 and March 2014; analysis was performed between December 2014 and December 2015. MAIN OUTCOMES AND MEASURES: Cumulative HLA genetic burden (HLAGB) calculated using the most updated MS-associated HLA alleles vs clinical and magnetic resonance imaging outcomes, including age at onset, disease severity, conversion time from clinically isolated syndrome to clinically definite MS, fractions of cortical and subcortical gray matter and cerebral white matter, brain lesion volume, spinal cord gray and white matter areas, upper cervical cord area, and the ratio of gray matter to the upper cervical cord area. Multivariate modeling was applied separately for each sex data set. RESULTS: Of the 652 patients with MS, 586 had no missing genetic data and were included in the HLAGB analysis. In these 586 patients (404 women [68.9%]; mean [SD] age at disease onset, 33.6 [9.4] years), HLAGB was higher than in controls (median [IQR], 0.7 [0-1.4] and 0 [-0.3 to 0.5], respectively; P = 1.8 * 10-27). A total of 619 (95.8%) had relapsing-onset MS and 27 (4.2%) had progressive-onset MS. No significant difference was observed between relapsing-onset MS and primary progressive MS. A higher HLAGB was associated with younger age at onset and the atrophy of subcortical gray matter fraction in women with relapsing-onset MS (standard beta = -1.20 * 10-1; P = 1.7 * 10-2 and standard beta = -1.67 * 10-1; P = 2.3 * 10-4, respectively), which were driven mainly by the HLA-DRB1*15:01 haplotype. In addition, we observed the distinct role of the HLA-A*24:02-B*07:02-DRB1*15:01 haplotype among the other common DRB1*15:01 haplotypes and a nominally protective effect of HLA-B*44:02 to the subcortical gray atrophy (standard beta = -1.28 * 10-1; P = 5.1 * 10-3 and standard beta = 9.52 * 10-2; P = 3.6 * 10-2, respectively). CONCLUSIONS AND RELEVANCE: We confirm and extend previous observations linking HLA MS susceptibility alleles with disease progression and specific clinical and magnetic resonance imaging phenotypic traits. PMID- 27244298 TI - The Pediatric Sleep Clinical Global Impressions Scale-A New Tool to Measure Pediatric Insomnia in Autism Spectrum Disorders. AB - OBJECTIVE: To pilot a clinician-based outcome measure that provides complementary information to objective measures and parent-based questionnaires for insomnia in children with autism spectrum disorders (ASD). METHOD: The authors developed a Pediatric Sleep Clinical Global Impressions Scale (CGI). Questions included (1) the child's ability to fall asleep and remain sleeping independently (i.e., apart from parents); (2) bedtime resistance; (3) sleep onset delay; (4) night awakening; (5) parental satisfaction with their child's current sleep patterns; (6) family functioning as affected by their child's current sleep patterns; and (7) clinician's overall concern with the child's sleep. After refining the instrument through the evaluation of vignettes by ASD and sleep experts, the authors piloted the Pediatric Sleep CGI in a 12-week randomized trial of iron supplementation in children with ASD. Clinicians completed Pediatric Sleep CGIs and structured sleep histories, parents completed the Children's Sleep Habits Questionnaire (CSHQ), and children wore actigraphy watches. RESULTS: In repeated measures models, the Pediatric Sleep CGI and CSHQ were correlated for sleep onset delay (r = .66, p < .001), night wakings (r = .40, p < .001), and total score (r = .29, p < .001). The CGI-S sleep onset delay and actigraphy sleep onset delay scores (r = .75, p = .0095) were also correlated. The overall CGI-S showed improvement with therapy (p = .047). CONCLUSION: The Pediatric Sleep CGI shows promise in measuring clinician-rated outcomes in pediatric insomnia in children with ASD. Larger samples will be necessary to examine reliability, validity, and measure to change, as well as applicability to other populations with pediatric insomnia. PMID- 27244300 TI - Role of Gas Type on Foam Transport in Porous Media. AB - We present the results of an experimental investigation of the effect of gas type and composition on foam transport in porous media. Steady-state foam strengths with respect to three cases of distinct gases and two cases containing binary mixtures of these gases were compared. The effects of gas solubility, the stability of lamellae, and the gas diffusion rate across the lamellae were examined. Our experimental results showed that the steady-state foam strength is inversely correlated with the gas permeability across a liquid lamella, a parameter that characterizes the rate of mass transport. The results are also in good agreement with existing observations that the foam strength for a mixture of gases is correlated with the less soluble component. Three hypotheses with different predictions of the underlying mechanism that explain the role of gas type and composition in foam strength are discussed in detail. PMID- 27244299 TI - A Pilot Study of the Association of Markers of Cholesterol Synthesis with Disturbed Sleep in Smith-Lemli-Opitz Syndrome. AB - OBJECTIVE: Smith-Lemli-Opitz syndrome (SLOS) is a rare genetic disorder characterized by cholesterol synthesis impairment. A host of physical, developmental, and behavioral presentations are associated with SLOS, many of which have been related with disorder severity. Sleep disturbance is commonly reported in SLOS. This study is the first to examine the association between sleep disturbance and biomarkers of cholesterol synthesis defect. METHOD: Twenty youth with SLOS participated. Biomarkers of cholesterol synthesis were obtained, including plasma sterols (i.e., 7-dehydrocholesterol, 8-dehydrocholesterol, and cholesterol), mevalonic acid, and 24-S hydroxycholsterol. A ratio of plasma cholesterol precursors to cholesterol levels was used as a measure of biochemical severity. Parents reported their children's sleep problems using the Children's Sleep Habits Questionnaire. RESULTS: Most markers of cholesterol synthesis disruption were associated with overall sleep disturbance. Biochemical severity of SLOS was also associated with specific sleep problems (e.g., decreased sleep duration and increased sleep onset delay) and was identified as a significant predictor of these factors. CONCLUSION: This study is the first to demonstrate associative relationships between cholesterol levels and sleep disturbance in youth with SLOS. These results add to the current understanding of how cholesterol levels may contribute to the behavioral phenotype of SLOS. These findings may inform future studies related to the role cholesterol synthesis defects play in the behavioral phenotype of SLOS and, subsequently, modalities of intervention for behavioral symptoms. PMID- 27244345 TI - Electroresponsive Supramolecular Graphene Oxide Hydrogels for Active Bacteria Adsorption and Removal. AB - Bacteria contamination in drinking water and medical products can cause severe health problems. However, currently available sterilization methods, mainly based on the size-exclusion mechanism, are typically slow and require the entire contaminated water to pass through the filter. Here, we present an electroresponsive hydrogel based approach for bacteria adsorption and removal. We successfully engineered a series of graphene oxide hydrogels using redox-active ruthenium complexes as noncovalent cross-linkers. The resulting hydrogels can reversibly switch their physical properties in response to the applied electric field along with the changes of oxidation states of the ruthenium ions. The hydrogels display strong bacteria adsorbing capability. A hydrogel of 1 cm(3) can adsorb a maximum of 1 * 10(8) E. coli. The adsorbed bacteria in the hydrogels can then be inactivated by a high voltage electric pulse and removed from the hydrogels subsequently. Owing to the high bacteria removal rate, reusability, and low production cost, these hydrogels represent promising candidates for the emergent sterilization of medical products or large-scale purification of drinking water. PMID- 27244346 TI - Untangling the Diverse Interior and Multiple Exterior Guest Interactions of a Supramolecular Host by the Simultaneous Analysis of Complementary Observables. AB - The entropic and enthalpic driving forces for encapsulation versus sequential exterior guest binding to the [Ga4L6](12-) supramolecular host in solution are very different, which significantly complicates the determination of these thermodynamic parameters. The simultaneous use of complementary techniques, such as NMR, UV-vis, and isothermal titration calorimetry, enables the disentanglement of such multiple host-guest interactions. Indeed, data collected by each technique measure different components of the host-guest equilibria and together provide a complete picture of the solution thermodynamics. Unfortunately, commercially available programs do not allow for global analysis of different physical observables. We thus resorted to a novel procedure for the simultaneous refinement of multiple parameters (DeltaG degrees , DeltaH degrees , and DeltaS degrees ) by treating different observables through a weighted nonlinear least squares analysis of a constrained model. The refinement procedure is discussed for the multiple binding of the Et4N(+) guest, but it is broadly applicable to the deconvolution of other intricate host-guest equilibria. PMID- 27244348 TI - Low-Level Laser Therapy May Have Cancer Fighting Role. PMID- 27244347 TI - Malignancy-associated hemophagocytic lymphohistiocytosis in adults: Relation to hemophagocytosis, characteristics, and outcomes. AB - BACKGROUND: Malignancy-associated hemophagocytic lymphohistiocytosis (HLH) in adults is a highly lethal disorder. Knowledge gaps have resulted in under diagnosis or delayed diagnosis. METHODS: The University of Texas MD Anderson Cancer Center pathology database (1991-2014) was retrospectively interrogated for the keywords "hemophagocytosis" and/or "lymphohistiocytosis." Seventy-seven adult patients were identified. All had an underlying malignancy. Sixteen patients who had insufficient documentation were excluded. RESULTS: The majority of patients who had pathologic evidence of hemophagocytosis/lymphohistiocytosis had an incomplete workup to confirm or refute HLH using the 2004 HLH criteria (HLH-2004; n = 8 variables), which is a common problem in adult HLH. Only 13 of 61 patients (21%) met the HLH-2004 diagnostic criteria based on available retrospective data. To identify potentially missed cases of HLH, the published literature was reviewed, and selected additional variables known to be associated with adult HLH were selected, resulting in extended diagnostic criteria of 18 variables. Thirty five patients met the extended criteria, and 33 had follow-up data available. The median overall survival of the 13 patients who met both the extended criteria and the HLH-2004 criteria was similar to that of the 20 patients who met the extended criteria but NOT the HLH-2004 criteria (1.43 vs 1.76 months, respectively; P = .34) indicating a similar underlying, aggressive, systemic process. Twenty-six patients did not meet either criteria, and 17 had follow-up data available. The median overall survival of the 17 patients who had pathologic hemophagocytosis or lymphohistiocytosis but met neither criteria was significantly superior to the survival of those who met both the extended criteria and the HLH-2004 criteria and those who met the extended criteria but not the HLH-2004 criteria (17.27 vs 1.43 vs 1.76, respectively; P = .002). CONCLUSIONS: The addition of diagnostic laboratory variables that are more easily and rapidly available in smaller institutions and primary care settings than the HLH-2004 variables may be a good surrogate to raise early suspicion of malignancy-associated HLH. Prospective validation is warranted. Cancer 2016. (c) 2016 American Cancer Society. Cancer 2016;122:2857-2866. (c) 2016 American Cancer Society. PMID- 27244349 TI - Rhodium-Catalyzed Enantioselective Intermolecular Hydroalkoxylation of Allenes and Alkynes with Alcohols: Synthesis of Branched Allylic Ethers. AB - Regio- and enantioselective additions of alcohols to either terminal allenes or internal alkynes provides access to allylic ethers by using a Rh(I) /diphenyl phosphate catalytic system. This method provides an atom-economic way to obtain chiral aliphatic and aryl allylic ethers in moderate to good yield with good to excellent enantioselectivities. PMID- 27244350 TI - The benefits of studying by production . . . And of studying production: Introduction to the special issue on the production effect in memory. AB - The production effect refers to enhanced memory for materials that were produced at study (e.g., those read aloud) relative to materials that were not produced (e.g., those read silently). The effect has generated a wave of interest since being named in 2010 (MacLeod, Gopie, Hourihan, Neary, and Ozubko, 2010)-likely because of the simplicity of production tasks and of the substantial memory improvements that they can yield. This special issue of the Canadian Journal of Experimental Psychology brings together 10 new studies on the production effect in memory. Our introduction provides an expanded definition of the effect along with some examples to help orient readers. The present studies contribute to our understanding of the production effect and to memory more broadly. Just as important, they also raise new questions and provide a honed set of methodological tools that will help to guide further research and theorizing about memory. (PsycINFO Database Record PMID- 27244351 TI - The production effect in recognition memory: Weakening strength can strengthen distinctiveness. AB - Producing items (e.g., by saying them aloud or typing them) can improve recognition memory. To evaluate whether production increases item distinctiveness and/or memory strength we compared this effect as a function of the percentage of items that participants typed at encoding (i.e., 0%, 20%, 50%, 80%, and 100%). Experiment 1 revealed a strength-based pattern: The production effect was similar across pure-list (i.e., 0% vs. 100%) and mixed-list (i.e., 20%, 50%, 80%) designs, and there was no observed influence of statistical distinctiveness (i.e., 20% vs. 80%). In Experiment 2, we increased the study time for unproduced items to minimise the strength difference between produced and unproduced items. The manipulation attenuated the pure-list effect without eliminating the mixed list effect, providing support for the inference that the mixed-list effect reflects distinctiveness. An influence of statistical distinctiveness also emerged: The mixed-list effect was larger when participants produced only 20%, rather than 80%, of the items. These findings suggest that both strength and distinctiveness contribute to the production effect in recognition. (PsycINFO Database Record PMID- 27244353 TI - Auditory presentation at test does not diminish the production effect in recognition. AB - Three experiments investigated whether auditory information at test would undermine the relational distinctiveness of vocal production at study, diminishing the production effect. In Experiment 1, with visual presentation during study, the production effect was equivalently large regardless of whether participants read each test word out loud prior to making their recognition decision. In Experiment 2, incorporating auditory presentation during study, the production effect was unaltered by whether recognition test words were presented visually or auditorily. In Experiment 3, the authors manipulated whether presentation was visual or auditory both at study and at test. Once again, presentation modality at test did not affect the size of the production effect, although the effect was significantly smaller when words were presented auditorily at study. These experiments demonstrate that production at the time of study stands out as distinct above and beyond auditory information. Moreover, this distinct aloud information need not "stand out" against a background of silent unstudied words on a recognition test. Consistent with the distinctiveness account, encoding via production enhances later recognition consistently, regardless of study or test modality. (PsycINFO Database Record PMID- 27244354 TI - Order information is used to guide recall of long lists: Further evidence for the item-order account. AB - Differences in memory for item order have been used to explain the absence of between-subjects (i.e., pure-list) effects in free recall for several encoding techniques, including the production effect, the finding that reading aloud benefits memory compared with reading silently. Notably, however, evidence in support of the item-order account (Nairne, Riegler, & Serra, 1991) has derived primarily from short-list paradigms. We provide novel evidence that the item order account also applies when recalling long lists. In Experiment 1, participants studied and then free recalled 3 different long lists of words: pure aloud, pure silent, and mixed (half aloud, half silent). A Bayesian analysis supported a null pure-list production effect, and subsequent order analyses were largely consistent with the item-order account. These findings indicate that order information is retained in long-term memory and is useful in guiding subsequent free recall. In Experiment 2, a distractor task was inserted between the study and test phases, ensuring that only long-term memory processes were involved in recall: The pattern of results remained consistent with the item order account. Order information can be retained in long-term memory for long lists, and is useful in guiding subsequent free recall, extending the domain of the item-order account. (PsycINFO Database Record PMID- 27244352 TI - Familiarity, but not recollection, supports the between-subject production effect in recognition memory. AB - Five experiments explored the basis of the between-subjects production effect in recognition memory as represented by differences in the recollection and familiarity of produced (read aloud) and nonproduced (read silently) words. Using remember-know judgments (Experiment 1b) and a dual-process signal-detection approach applied to confidence ratings (Experiments 2b and 3), we observed that production influences familiarity but not recollection when manipulated between subjects. This is in contrast to within-subject designs, which reveal a clear effect of production on both recollection and familiarity (Experiments 1a and 2a). Our findings resolve contention concerning apparent design effects: Whereas the within-subject production effect is subserved by separable recollective- and familiarity-based components, the between-subjects production effect is subserved by the familiarity-based component alone. Our findings support a role for the relative distinctiveness of production as a means of guiding recognition judgments (at least when manipulated within-subjects), but we also propose that production influences the strength of produced items, explaining the persistence of the effect in between-subjects designs. (PsycINFO Database Record PMID- 27244355 TI - A preliminary investigation into the neural basis of the production effect. AB - Items that are produced (e.g., read aloud) during encoding typically are better remembered than items that are not produced (e.g., read silently). This "production effect" has been explained by distinctiveness: Produced items have more distinct features than nonproduced items, leading to enhanced retrieval. The goal of the current study was to use electroencephalography (EEG) to examine the neural basis of the production effect. During study, participants were presented with words that they were required to read silently, read aloud, or sing while EEG data were recorded. Subsequent memory performance was tested using a yes/no recognition test. Analysis focused on the event-related brain potentials (ERPs) evoked by the encoding instruction cue for each instruction condition. Our data revealed enhanced memory performance for produced items and a greater P300 ERP amplitude for instructions to sing or read aloud compared with instructions to read silently. Our results demonstrate that the amplitude of the P300 is modulated by at least 1 aspect of production, vocalization (singing/reading aloud relative to reading silently), and are consistent with the distinctiveness account of the production effect. The ERP methodology is a viable tool for investigating the production effect. (PsycINFO Database Record PMID- 27244356 TI - Production does not improve memory for face-name associations. AB - Strategies for learning face-name associations are generally difficult and time consuming. However, research has shown that saying a word aloud improves our memory for that word relative to words from the same set that were read silently. Such production effects have been shown for words, pictures, text material, and even word pairs. Can production improve memory for face-name associations? In Experiment 1, participants studied face-name pairs by reading half of the names aloud and half of the names silently, and were tested with cued recall. In Experiment 2, names were repeated aloud (or silently) for the full trial duration. Neither experiment showed a production effect in cued recall. Bayesian analyses showed positive support for the null effect. One possibility is that participants spontaneously implemented more elaborate encoding strategies that overrode any influence of production. However, a more likely explanation for the null production effect is that only half of each stimulus pair was produced-the name, but not the face. Consistent with this explanation, in Experiment 3 a production effect was not observed in cued recall of word-word pairs in which only the target words were read aloud or silently. Averaged across all 3 experiments, aloud targets were more likely to be recalled than silent targets (though not associated with the correct cue). The production effect in associative memory appears to require both members of a pair to be produced. Surprisingly, production shows little promise as a strategy for improving memory for the names of people we have just met. (PsycINFO Database Record PMID- 27244357 TI - A computational account of the production effect: Still playing twenty questions with nature. AB - People remember words that they read aloud better than words that they read silently, a result known as the production effect. The standing explanation for the production effect is that producing a word renders it distinctive in memory and, thus, memorable at test. By 1 key account, distinctiveness is defined in terms of sensory feedback. We formalize the sensory-feedback account using MINERVA 2, a standard model of memory. The model accommodates the basic result in recognition as well as the fact that the mixed-list production effect is larger than its pure-list counterpart, that the production effect is robust to forgetting, and that the production and generation effects have additive influences on performance. A final simulation addresses the strength-based account and suggests that it will be more difficult to distinguish a strength based versus distinctiveness-based explanation than is typically thought. We conclude that the production effect is consistent with existing theory and discuss our analysis in relation to Alan Newell's (1973) classic criticism of psychology and call for an analysis of psychological principles instead of laboratory phenomena. (PsycINFO Database Record PMID- 27244358 TI - The production effect in long-list recall: In no particular order? AB - The production effect reflects a memory advantage for words read aloud versus silently. We investigated how production influences free recall of a single long list of words. In each of 4 experiments, a production effect occurred in a mixed list group but not across pure-list groups. When compared to the pure-list groups, the mixed-list effects typically reflected a cost to silent words rather than a benefit to aloud words. This cost persisted when participants had to perform a generation or imagery task for the silent items, ruling out a lazy reading explanation. This recall pattern challenges both distinctiveness and strength accounts, but is consistent with an item-order account. By this account, the aloud words in a mixed list disrupt the encoding of item-order information for the silent words, thus impairing silent word recall. However, item-order measures and a forced-choice order test did not provide much evidence that recall was guided by retrieval of item-order information. We discuss our pattern of results in light of another recent study of the effects of production on long list recall. (PsycINFO Database Record PMID- 27244359 TI - Influence of retrieval mode on effects of production: Evidence for costs in free recall. AB - Study modality (visual, auditory) of words as well as production mode (reading aloud, writing down) have been shown to influence the production effect (PE). When study words are presented visually, reading them aloud yields superior memory. However, when the same study words are presented aurally, writing them down leads to superior memory. Missing in PE studies is the variable of retrieval mode (written, aloud), which was addressed in the present study. In a pair of experiments, we manipulated the 3 variables-study modality, production mode, and retrieval mode-in a factorial fashion. With visual study, aloud production mode (vocalizing) was found to be superior to written production, in both retrieval modes (written and aloud). However, the difference between the productions was significantly smaller in the aloud retrieval mode relative to the written retrieval mode. With auditory study, written production mode was superior to aloud production mode, in the written as well as in the aloud retrieval modes. Here, the difference between the productions was significantly smaller in the written relative to the aloud retrieval mode. In other words, the difference between productions was smaller for the retrieval mode that matched the superior production. We interpret these findings using a retrieval-cost account. (PsycINFO Database Record PMID- 27244360 TI - Evaluating the basis of the between-group production effect in recognition. AB - Reading a list of words aloud can improve recognition over silently reading them. This between-groups production effect (PE) cannot be due to relative distinctiveness because each group studies only 1 type of item. We tested 2 other possibilities. By a strategy account, a pure-aloud group might benefit from use of a production-based distinctiveness strategy at test (e.g., "Did I say this word aloud?"). By a strength account, aloud items may simply be more strongly encoded than silent items. To evaluate these accounts, we tested whether a between-group PE occurs when participants experience a salient within-group manipulation of font size, generation, or imagery at study. The answer was yes, except when imagery was the within-group task. This pattern, and aspects of participants' strategy reports, fit well with a strategy account if it is assumed that the imagery task led participants to abandon a production-based strategy. However, many of our findings were also compatible with an evaluated strength account if it is assumed that the imagery task led participants to abandon evaluating memory strength. In conjunction with recent findings, we suggest that multiple processes may contribute to the PE, and the relevant subset in play will differ as a function of study design, study task, and memory test. (PsycINFO Database Record PMID- 27244361 TI - Brain Connectivity and Functional Recovery in Patients With Ischemic Stroke. AB - BACKGROUND: Brain mapping studies have demonstrated that functional poststroke brain reorganization is associated with recovery of motor function. Nonetheless, the specific mechanisms associated with functional reorganization leading to motor recovery are still partly unknown. In this study, we performed a cross sectional evaluation of poststroke subjects with the following goals: (1) To assess intra- and interhemispheric functional brain activation patterns associated with motor function in poststroke patients with variable degrees of recovery; (2) to investigate the involvement of other nonmotor functional networks in relationship with recovery. METHODS: We studied 59 individuals: 13 patients with function Rankin > 1 and Barthel < 100; 19 patients with preserved function with Rankin 0-1 and Barthel = 100; and 27 healthy controls. All subjects underwent structural and functional magnetic resonance imaging (3T Philips Achieva, Holland) using the same protocol (TR = 2 seconds, TE = 30 ms, FOV = 240 * 240 * 117, slice = 39). Resting state functional connectivity was used by in house software, based on SPM12. Among patients with and without preserved function, the functional connectivity between the primary motor region (M1) and the contralateral hemisphere was increased compared with controls. Nonetheless, only patients with decreased function exhibited decreased functional connectivity between executive control, sensorimotor and visuospatial networks. CONCLUSION: Functional recovery after stroke is associated with preserved functional connectivity of motor to nonmotor networks. PMID- 27244367 TI - Rational Design of an Ultrasensitive and Highly Selective Chemodosimeter by a Dual Quenching Mechanism for Cysteine Based on a Facile Michael-Transcyclization Cascade Reaction. AB - Differentiation of biologically important thiols, such as cysteine (Cys), homocysteine (Hcy), and glutathione (GSH) is still a challenging task. Herein, we present a novel fluorescent chemodosimeter capable of selectively detecting Cys over other biothiols including Hcy and GSH and other amino acids by a facile thiol-Michael addition/transcyclization rearrangement cascade click process. The unique transcyclization step is critical for the selectivity as a result of the kinetically favorable formation of a six-membered ring with the Cys Michael adduct. Moreover, the probe adopts a distinctive dual quenching mechanism photoinduced electron transfer (PET) and photoinduced intramolecular charge transfer (ICT) to deliver a drastic turn-on fluorescence response only at the Cys selective transcylization step. The judicious selection of strong electron withdrawing naphthalimide fluorophore with maleimide group enhances the electrophilicity and thus reactivity for the cascade process leading to fast detection and ultrasensitivity with a detection limit of 2.0 nm (S/N=3). The probe has demonstrated its practical utility potential in Cys imaging in live cells. PMID- 27244368 TI - Point of Health Care Entry for Youth With Concussion Within a Large Pediatric Care Network. AB - IMPORTANCE: Previous epidemiologic research on concussions has primarily been limited to patient populations presenting to sport concussion clinics or to emergency departments (EDs) and to those high school age or older. By examining concussion visits across an entire pediatric health care network, a better estimate of the scope of the problem can be obtained. OBJECTIVE: To comprehensively describe point of entry for children with concussion, overall and by relevant factors including age, sex, race/ethnicity, and payor, to quantify where children initially seek care for this injury. DESIGN, SETTING, AND PARTICIPANTS: In this descriptive epidemiologic study, data were collected from primary care, specialty care, ED, urgent care, and inpatient settings. The initial concussion-related visit was selected and variation in the initial health care location (primary care, specialty care, ED, or hospital) was examined in relation to relevant variables. All patients aged 0 to 17 years who received their primary care from The Children's Hospital of Philadelphia's (CHOP) network and had 1 or more in-person clinical visits for concussion in the CHOP unified electronic health record (EHR) system (July 1, 2010, to June 30, 2014) were selected. MAIN OUTCOMES AND MEASURES: Frequency of initial concussion visits at each type of health care location. Concussion visits in the EHR were defined based on International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes indicative of concussion. RESULTS: A total of 8083 patients were included (median age, 13 years; interquartile range, 10-15 years). Overall, 81.9% (95% CI, 81.1%-82.8%; n = 6624) had their first visit at CHOP within primary care, 5.2% (95% CI, 4.7%-5.7%; n = 418) within specialty care, and 11.7% (95% CI, 11.0%-12.4%; n = 947) within the ED. Health care entry varied by age: 52% (191/368) of children aged 0 to 4 years entered CHOP via the ED, whereas more than three-quarters of those aged 5 to 17 years entered via primary care (5 11 years: 1995/2492; 12-14 years: 2415/2820; and 15-17 years: 2056/2403). Insurance status also influenced the pattern of health care use, with more Medicaid patients using the ED for concussion care (478/1290 Medicaid patients [37%] used the ED vs 435/6652 private patients [7%] and 34/141 self-pay patients [24%]). CONCLUSIONS AND RELEVANCE: The findings suggest estimates of concussion incidence based solely on ED visits underestimate the burden of injury, highlight the importance of the primary care setting in concussion care management, and demonstrate the potential for EHR systems to advance research in this area. PMID- 27244369 TI - Alterations of the bone marrow stromal microenvironment in adult patients with acute myeloid and lymphoblastic leukemias before and after allogeneic hematopoietic stem cell transplantation. AB - Bone marrow (BM) derived adult multipotent mesenchymal stromal cells (MMSCs) and fibroblast colony-forming units (CFU-Fs) of 20 patients with acute myeloid leukemia (AML) and 15 patients with acute lymphoblastic leukemia (ALL) before and during 1 year after receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT) were studied. The growth characteristics of MMSCs of all patients before allo-HSCT were not altered; however, relative expression level (REL) of some genes in MMSCs, but not in CFU-Fs, from AML and ALL patients significantly changed. After allo-HSCT, CFU-F concentration and MMSC production were significantly decreased for 1 year; REL of several genes in MMSCs and CFU-F derived colonies were also significantly downregulated. Thus, chemotherapy that was used for induction of remission did not impair the function of stromal precursors, but gene expression levels were altered. Allo-HSCT conditioning regimens significantly damaged MMSCs and CFU-Fs, and the effect lasted for at least 1 year. PMID- 27244372 TI - Spectral compression of femtosecond pulses using chirped volume Bragg gratings. AB - In this Letter, we demonstrate a 360 fold spectral bandwidth reduction of femtosecond laser pulses using the method of sum frequency generation of pulses with opposite chirps. The reduction has been achieved in a compact setup in which a single chirped volume Bragg grating replaces conventional stretcher and compressor units. Starting with 180 fs pulses, we have obtained, with a 30% overall efficiency, pulses longer than 100 ps with the spectral bandwidth of 0.23 cm-1 (7 GHz). We also discuss our method on theoretical grounds. PMID- 27244371 TI - Clinical results of single and multiple bioresorbable drug-eluting scaffolds for treatment of de-novo coronary artery disease. AB - OBJECTIVES: Data on multiple bioresorbable vascular scaffolds (BVS) for the treatment of coronary lesions are limited. We compared clinical results after implantation of single or multiple BVS for the treatment of de-novo coronary artery disease. METHODS: We enrolled 236 patients with 311 lesions treated with Absorb BVS. Quantitative coronary angiography before and after scaffold implantation was performed. All lesions were predilated. Absorb was implanted with slow inflation and 81% were postdilated with a high-pressure balloon. Patients received dual antiplatelet therapy for 6 months for stable angina pectoris and for 12 months for acute coronary syndrome. Patients were clinically followed for 12 months. Acute gain was 1.39+/-0.47 mm. Multiple scaffolds per lesion were implanted in 23.8% (N=74/311 lesions). The mean scaffold length was 21 mm for single and 48 mm (range 28-112 mm) for multiple BVS. Periprocedural myocardial infarction (13.5 vs. 4.6%, P<0.013) and target lesion revascularization (6.8 vs. 0.8%; P=0.003) were significantly higher in the multiple-scaffold group compared with the single-scaffold group. There was no definite scaffold thrombosis. (http://www.clinicaltrials.gov, NCT02162056). CONCLUSION: Target lesion revascularization within 12 months and periprocedural myocardial infarction were higher for lesions treated with multiple scaffolds compared with lesions treated with single BVS. PMID- 27244370 TI - Altered Disrupted-in-Schizophrenia-1 Function Affects the Development of Cortical Parvalbumin Interneurons by an Indirect Mechanism. AB - Disrupted-in-Schizophrenia-1 (DISC1) gene has been linked to schizophrenia and related major mental illness. Mouse Disc1 has been implicated in brain development, mainly in the proliferation, differentiation, lamination, neurite outgrowth and synapse formation and maintenance of cortical excitatory neurons. Here, the effects of two loss-of-function point mutations in the mouse Disc1 sequence (Q31L and L100P) on cortical inhibitory interneurons were investigated. None of the mutations affected the overall number of interneurons. However, the 100P, but not the 31L, mutation resulted in a significant decrease in the numbers of interneurons expressing parvalbumin mRNA and protein across the sensory cortex. To investigate role of Disc1 in regulation of parvalbumin expression, mouse wild-type Disc-1 or the 100P mutant form were electroporated in utero into cortical excitatory neurons. Overexpression of wild-type Disc1 in these cells caused increased densities of parvalbumin-expressing interneurons in the electroporated area and in areas connected with it, whereas expression of Disc1 100P did not. We conclude that the 100P mutation prevents expression of parvalbumin by a normally sized cohort of interneurons and that altering Disc1 function in cortical excitatory neurons indirectly affects parvalbumin expression by cortical interneurons, perhaps as a result of altered functional input from the excitatory neurons. PMID- 27244373 TI - Highly efficient spectrally encoded imaging using a 45 degrees tilted fiber grating. AB - A novel highly efficient, fiber-compatible spectrally encoded imaging (SEI) system using a 45 degrees tilted fiber grating (TFG) is proposed and experimentally demonstrated for the first time, to the best of our knowledge. The TFG serves as an in-fiber lateral diffraction element, eliminating the need for bulky and lossy free-space diffraction gratings in conventional SEI systems. Under proper polarization control, due to the strong tilted reflection, the 45 degrees TFG offers a diffraction efficiency as high as 93.5%. Our new design significantly reduces the volume of the SEI system and improves energy efficiency and system stability. As a proof-of-principle experiment, spectrally encoded imaging of a customer-designed sample (9.6 mm*3.0 mm) using the TFG-based system is demonstrated. The lateral resolution of the SEI system is measured to be 42 MUm in our experiment. PMID- 27244374 TI - Origin and stability of dark pulse Kerr combs in normal dispersion resonators. AB - We analyze dark pulse Kerr frequency combs in optical resonators with normal group-velocity dispersion using the Lugiato-Lefever model. We show that in the time domain the combs correspond to interlocked switching waves between the upper and lower homogeneous states, and explain how this fact accounts for many of their experimentally observed properties. Modulational instability does not play any role in their existence. We provide a detailed map indicating for which parameters stable dark pulse Kerr combs can be found, and how they are destabilized for increasing values of frequency detuning. PMID- 27244375 TI - Atmospheric turbulence mitigation in an OAM-based MIMO free-space optical link using spatial diversity combined with MIMO equalization. AB - We explore the mitigation of atmospheric turbulence effects for orbital angular momentum (OAM)-based free-space optical (FSO) communications with multiple-input multiple-output (MIMO) architecture. Such a system employs multiple spatially separated aperture elements at the transmitter/receiver, and each transmitter aperture contains multiplexed data-carrying OAM beams. We propose to use spatial diversity combined with MIMO equalization to mitigate both weak and strong turbulence distortions. In a 2*2 FSO link with each transmitter aperture containing two multiplexed OAM modes of l=+1 and l=+3, we experimentally show that at least two OAM data channels could be recovered under both weak and strong turbulence distortions using selection diversity assisted with MIMO equalization. PMID- 27244376 TI - Quasi-phase matching via femtosecond laser-induced domain inversion in lithium niobate waveguides. AB - We demonstrate an all-optical fabrication method of quasi-phase matching structures in lithium niobate (LiNbO3) waveguides using a tightly focused femtosecond near-infrared laser beam (wavelength of 800 nm). In contrast to other all-optical schemes that utilize a periodic lowering of the nonlinear coefficient chi(2) by material modification, here the illumination of femtosecond pulses directly reverses the sign of chi(2) through the process of ferroelectric domain inversion. The resulting quasi-phase matching structures, therefore, lead to more efficient nonlinear interactions. As an experimental demonstration, we fabricate a structure with the period of 2.74 MUm to frequency double 815 nm light. A maximum conversion efficiency of 17.45% is obtained for a 10 mm long waveguide. PMID- 27244377 TI - Transport in Sawtooth photonic lattices. AB - We investigate, theoretically and experimentally, a photonic realization of a Sawtooth lattice. This special lattice exhibits two spectral bands, with one of them experiencing a complete collapse to a highly degenerate flat band for a special set of inter-site coupling constants. We report the observation of different transport regimes, including strong transport inhibition due to the appearance of the non-diffractive flat band. Moreover, we excite localized Shockley surface states residing in the gap between the two linear bands. PMID- 27244378 TI - Four-wave mixing and nonlinear losses in thick silicon waveguides. AB - We experimentally investigate four-wave mixing and nonlinear losses in low-loss 3 MUm thick silicon strip waveguides. Adiabatic bends allow for single-mode operation in an ultra-compact 35 cm long spiral. The waveguides exhibited reduced nonlinear losses due to the large mode area of 2.75 MUm2. The nonlinear coefficient gamma was measured as 5.5 m-1 W-1. These features, along with the low propagation loss of 0.17 dB/cm, enable large idler power generation at 1550 nm. PMID- 27244379 TI - Strong coupling optical spectra in dipole-dipole interacting optomechanical Tavis Cummings models. AB - We theoretically investigate the emission spectrum of an optomechanical Tavis Cummings model: two dipole-dipole interacting atoms coupled to an optomechanical cavity (OMC). In particular, we study the influence of dipole-dipole interaction (DDI) on the single-photon spectrum emitted by this hybrid system in the presence of a strong atom-cavity as well as strong optomechanical interaction (hereafter called the strong-strong coupling). We also show that our analysis is amenable to inclusion of the mechanical losses (under the weak mechanical damping limit) and single-photon loss through spontaneous emission from the two-level emitters under a nonlocal Lindblad model. PMID- 27244380 TI - Optical trapping and moving of microparticles by using asymmetrical Laguerre Gaussian beams. AB - We considered a generalization of the Laguerre-Gaussian (LG) laser beam family by using a complex shift of the beam complex amplitude in Cartesian coordinates. In this case, LG-beams lose their axial symmetry. The normalized orbital angular momentum is the sum of the beam topological charge and the term which is in square dependence on the asymmetry parameter. By optical trapping and moving the polystyrene microspheres in the focus of the asymmetric LG-beam, it is proven that the velocity of the microspheres increases with increasing the asymmetry parameter and constant topological charge. PMID- 27244381 TI - Dual-wavelength in-line phase-shifting interferometry based on two dc-term suppressed intensities with a special phase shift for quantitative phase extraction. AB - To efficiently promote the phase retrieval in quantitative phase imaging, a new approach of quantitative phase extraction is proposed based on two intensities with dual wavelength after filtering the corresponding dc terms for each wavelength, in which a special phase shift is used. In this approach, only the combination of the phase-shifting technique and subtraction procedures is needed, and no additional algorithms are required. The thickness of the phase object can be achieved from the phase image, which is related to the synthetic beat wavelength. The feasibility of this method is verified by the simulated experiments of the optically transparent objects. PMID- 27244382 TI - Miniature, sub-nanometer resolution Talbot spectrometer. AB - Miniaturization of optical spectrometers has a significant practical value as it can enable compact, affordable spectroscopic systems for chemical and biological sensing applications. For many applications, the spectrometer must gather light from sources that span a wide range of emission angles and wavelengths. Here, we report a lens-free spectrometer that is simultaneously compact (<0.6 cm3), of high resolution (<1 nm), and has a clear aperture (of 10*10 mm). The wavelength-scale pattern in the dispersive element strongly diffracts the input light to produce non-paraxial mid-field diffraction patterns that are then recorded using an optimally matched image sensor and processed to reconstruct the spectrum. PMID- 27244383 TI - Shape-induced optical activity of chiral nanocrystals. AB - We present a general approach to analyzing the optical activity of semiconductor nanocrystals of chiral shapes. By using a coordinate transformation that turns a chiral nanocrystal into a nanocuboid, we calculate the rotatory strengths, dissymmetry factors, and peak values of the circular dichroism (CD) signal upon intraband transitions inside the nanocrystal. It is shown that the atomic roughness of the nanocrystal surface can result in rotatory strengths as high as 10-36 erg*cm3 and in peak CD signals of about 0.1 cm 1 for typical nanocrystal densities of 1016 cm-3. The developed approach may prove useful for other nanocrystal shapes whereas the derived expressions apply directly for the modeling and interpretation of experimental CD spectra of quantum dots, nanorods, and nanoplatelets. PMID- 27244384 TI - Emulation of Fabry-Perot and Bragg resonators with temporal optical solitons. AB - The scattering of weak dispersive waves (DWs) on several equally spaced temporal solitons is studied. It is shown by systematic numerical simulations that the reflection of the DWs from the soliton trains strongly depends on the distance between the solitons. The dependence of the reflection and transmission coefficients on the inter-soliton distance and the frequency of the incident waves are studied in detail, revealing fascinating quasi-periodic behavior. The analogy between the observed nonlinear phenomena in the temporal domain and the usual Fabry-Perot and Bragg resonators is discussed. PMID- 27244385 TI - Highly efficient mid-infrared difference-frequency generation using synchronously pulsed fiber lasers. AB - We report the development of a high average power, picosecond-pulse, mid-infrared source based on difference-frequency generation (DFG) of two synchronous master oscillator power fiber amplifier systems. The generated idler can be tuned over the range 3.28-3.45 MUm delivering greater than 3.4 W of average power, with a maximum pump to total DFG power conversion efficiency of 78%. The benefits of a synchronously pumped scheme, compared to CW seeding of DFG sources, are discussed. PMID- 27244386 TI - Silicon band-rejection and band-pass filter based on asymmetric Bragg sidewall gratings in a multimode waveguide. AB - A silicon photonic wire filter based on an asymmetric sidewall Bragg grating in a multimode silicon-on-insulator strip waveguide is demonstrated. The operating principle is based on the contra-directional coupling between the transverse electric fundamental (TE0) and first-order (TE1) modes, which is enabled by the asymmetric spatially periodic refractive-index perturbations. An asymmetric Y junction is cascaded at the input port of the filter so as to drop the Bragg reflection. Compared with conventional Bragg grating-based filters, this device eliminates the back reflection at the input port and the 6 dB inherent insertion loss at the drop port; moreover, a narrow 3 dB bandwidth can be obtained with a large critical dimension as a result of the weak coupling strength between the TE0 and TE1 modes inside the multimode waveguide. Experimental results show that a bandwidth of ~2.8 nm is achieved by a large corrugation width of 150 nm. The insertion loss at the drop port is -2.1 dB, and the extinction ratio is -33 dB at the through port. PMID- 27244387 TI - Emission of dispersive waves from a train of dark solitons in optical fibers. AB - We report the experimental observation of multiple dispersive waves (DWs) emitted in the anomalous dispersion region of an optical fiber from a train of dark solitons. Each DW can be associated to one dark soliton of the train, using phase matching arguments involving higher-order dispersion and soliton velocity. For a large number of dark solitons (>10), we observe the formation of a continuum associated with the efficient emission of DWs. PMID- 27244388 TI - Harmonics generation of a terahertz wakefield free-electron laser from a dielectric loaded waveguide excited by a direct current electron beam. AB - We propose to generate high-power terahertz (THz) radiation from a cylindrical dielectric loaded waveguide (DLW) excited by a direct-current electron beam with the harmonics generation method. The DLW supports a discrete set of modes that can be excited by an electron beam passing through the structure. The interaction of these modes with the co-propagating electron beam results in micro-bunching and the coherent enhancement of the wakefield radiation, which is dominated by the fundamental mode. By properly choosing the parameters of DLW and beam energy, the high order modes can be the harmonics of the fundamental one; thus, high frequency radiation corresponding to the high order modes will benefit from the dominating bunching process at the fundamental eigenfrequency and can also be coherently excited. With the proposed method, high power THz radiation can be obtained with an easily achievable electron beam and a large DLW structure. PMID- 27244389 TI - Ultraviolet femtosecond Kerr-gated wide-field fluorescence microscopy. AB - A Kerr-gated microscope capable of imaging ultraviolet luminescence with femtosecond time resolution has been developed. The system allows the spatial, spectral, and temporal measurement of UV-emitting samples. The instrumentation was optimized for emission collection in the UV, resulting in sub 90 fs time resolution of gated signals. ZnO nanowires were used to demonstrate the performance of the instrument. The evolution of the emission from a single nanowire was tracked via ultrafast transient spectroscopy and through sequential imaging. Transient dynamics were extracted from a region of intense emission on a single ZnO nanowire. This technique is a powerful tool capable of contactless ultrafast measurements of charge carrier dynamics in single nanoparticles. PMID- 27244390 TI - Upconversion imaging using an all-fiber supercontinuum source. AB - In this Letter, the first demonstration, to the best of our knowledge, of pulsed upconversion imaging using supercontinuum light is presented. A mid-infrared (IR) imaging system was built by combining a mid-IR supercontinuum source emitting between 1.8 and 2.6 MUm with upconversion detection. The infrared signal is used to probe a sample and mixed with a synchronized 1550 nm laser pulse inside a lithium niobate (LiNbO3) crystal. The signal is thus upconverted to the 860-970 nm range and acquired on a standard silicon CCD array at a rate of 22 frames per second. In our implementation, spatial features in the sample plane as small as 55 MUm could be resolved. PMID- 27244391 TI - Thermally triggered fiber lasers based on secondary-type-In Bragg gratings. AB - The secondary-type-In grating formed in a small-core photosensitivity active fiber is discovered and investigated. Due to the different grating types, the transmission dip of a secondary grating structure chases and integrates with the type-In grating structure as the temperature increases, which strengthens the reflectivity of the grating. By use of these secondary-type-In gratings as Bragg reflectors, a thermally activated distributed Bragg reflector (DBR) fiber laser is proposed, which can be potentially used in high-temperature alarms and sensors. PMID- 27244392 TI - Optically tunable Fano resonance in a grating-based Fabry-Perot cavity-coupled microring resonator on a silicon chip. AB - A grating-based Fabry-Perot (FP) cavity-coupled microring resonator on a silicon chip is reported to demonstrate an all-optically tunable Fano resonance. In the device, an add-drop microring resonator (MRR) is employed, and one of the two bus waveguides is replaced by an FP cavity consisting of two sidewall Bragg gratings. By choosing the parameters of the gratings, the resonant mode of the FP cavity is coupled to one of the resonant modes of the MRR. Due to the coupling between the resonant modes, a Fano resonance with an asymmetric line shape resulted. Measurement results show a Fano resonance with an extinction ratio of 22.54 dB, and a slope rate of 250.4 dB/nm is achieved. A further study of the effect of the coupling on the Fano resonance is performed numerically and experimentally. Thanks to the strong light-confinement capacity of the MRR and the FP cavity, a strong two-photon absorption induced nonlinear thermal-optic effect resulted, which is used to tune the Fano resonance optically. PMID- 27244393 TI - Enhancing photonic spin Hall effect via long-range surface plasmon resonance. AB - We presented the significant enhancement of the photonic spin Hall effect by taking advantage of long-range surface plasmon resonance (LRSPR). The influence of the thicknesses of metal and dielectric layers in the insulator-metal insulator structure which supports LRSPR was investigated. Under the optimal parameter setup, the largest transverse separation with a 632.8 nm incident Gaussian beam reaches 7.85 MUm, which is much larger than previous reported values. PMID- 27244394 TI - Unpolarized resonance grating reflectors with 44% fractional bandwidth. AB - There is immense scientific interest in the properties of resonant thin films embroidered with periodic nanoscale features. This device class possesses considerable innovation potential. Accordingly, we report unpolarized broadband reflectors enabled by a serial arrangement of a pair of polarized subwavelength gratings. Optimized with numerical methods, our elemental gratings consist of a partially etched crystalline-silicon film on a quartz substrate. The resulting reflectors exhibit extremely wide spectral reflection bands in one polarization. By arranging two such reflectors sequentially with orthogonal periodicities, there results an unpolarized spectral band that exceeds those of the individual polarized bands. In the experiments reported herein, we achieve zero-order reflectance exceeding 97% under unpolarized light incidence over a 500 nm wide wavelength band. This wideband represents a ~44% fractional band in the near infrared. Moreover, the resonant unpolarized broadband accommodates an ultra-high reflection band spanning ~85 nm and exceeding 99.9% in efficiency. The elemental polarization-sensitive reflectors based on one-dimensional (1D) resonant gratings have a simple design and robust performance, and are straightforward to fabricate. Hence, this technology is a promising alternative to traditional multilayer thin-film reflectors, especially at longer wavelengths of light where multilayer deposition may be infeasible or impractical. PMID- 27244395 TI - Holographic display for see-through augmented reality using mirror-lens holographic optical element. AB - A holographic display system for realizing a three-dimensional optical see through augmented reality (AR) is proposed. A multi-functional holographic optical element (HOE), which simultaneously performs the optical functions of a mirror and a lens, is adopted in the system. In the proposed method, a mirror that is used to guide the light source into a reflection type spatial light modulator (SLM) and a lens that functions as Fourier transforming optics are recorded on a single holographic recording material by utilizing an angular multiplexing technique of volume hologram. The HOE is transparent and performs the optical functions just for Bragg matched condition. Therefore, the real-world scenes that are usually distorted by a Fourier lens or an SLM in the conventional holographic display can be observed without visual disturbance by using the proposed mirror-lens HOE (MLHOE). Furthermore, to achieve an optimized optical recording condition of the MLHOE, the optical characteristics of the holographic material are measured. The proposed holographic AR display system is verified experimentally. PMID- 27244396 TI - Statistical dispersion relation for spatially broadband fields. AB - The dispersion relation is fundamental to a physical phenomenon that develops in both space and time. This equation connects the spatial and temporal frequencies involved in the dynamic process through the material constants. Electromagnetic plane waves propagating in homogeneous media are bound by simple dispersion relation, which sets the magnitude of the spatial frequency, k, as being proportional to the temporal frequency, omega, with the proportionality constant dependent on the refractive index, n, and the speed of light in vacuum, c. Here we show that, for spatially broadband fields, an analog dispersion relation can be derived, except in this case the k-vector variance is connected with the temporal frequency through the statistics of the refractive index fluctuations in the medium. We discuss how this relationship can be used to retrieve information about refractive index distributions in biological tissues. This result is particularly significant in measurements of angular light scattering and quantitative phase imaging of biological structures. PMID- 27244397 TI - Mid-infrared surface plasmon polariton chemical sensing on fiber-coupled ITO coated glass. AB - A novel fiber-coupled indium tin oxide (ITO) coated glass slide sensor for performing surface plasmon polariton chemical monitoring in the ~3.5 MUm mid infrared (IR) range is reported. Efficient mid-IR fiber coupling is achieved with 3D laser written waveguides, and the coupling of glass waveguide modes to ITO surface plasmon polaritons (SPPs) is driven by the varying phase matching conditions of different aqueous analytes across the anomalous dispersion range determined by their molecular fingerprints. By means of using both a mid-IR fiber supercontinuum source and a diode laser, the excitation of SPPs is demonstrated. The sensor sensitivity is tested by discriminating CH from OH features of ethanol in water solutions, demonstrating an instrumental ethanol limit of detection of 0.02% in a wide concentration range of at least 0%-50%. The efficient optical monitoring of mid-IR SPPs in smart glass could have a broad range of applications in biological and chemical sensing. PMID- 27244398 TI - Three-dimensional single-pixel imaging with far fewer measurements than effective image pixels. AB - Typical single-pixel imaging techniques inherently consume a large number of measurements to reconstruct a high-quality and high-resolution image. Three dimensional (3-D) single-pixel imaging with both high sampling efficiency and high depth accuracy remains a challenge. We implement fringe projection virtually by exploiting Helmholtz reciprocity. Depth information is modulated into a deformed fringe pattern whose Fourier spectrum is sampled by using sinusoidal intensity pattern illumination and single-pixel detection. The fringe pattern has a highly focused first-order component in its Fourier spectrum, which allows us to efficiently acquire the depth information from measurements far fewer than illumination pattern pixels. The 3-D information is retrieved through Fourier analysis. We experimentally obtained a 3-D reconstruction of a complex object with 599*599 effective pixels, achieving a measurement-to-pixel ratio of 5.78%. The depth accuracy is evaluated at sub-millimetric level by using a test object. PMID- 27244399 TI - Design of electro-optic modulators based on graphene-on-silicon slot waveguides. AB - We present a graphene-on-silicon (GoS) suspended vertical slot waveguide. By changing the Fermi level of graphene, the variation in the effective refractive index (RI) of the waveguide is a factor of two larger than that in the traditional GoS rib waveguide. The improvement is due to the light-intensity enhancement and the poor confinement of the optical mode in the slot nanostructure. We design Mach-Zehnder interferometer (MZI) and microring modulators based on the GoS suspended vertical slot waveguide. Our calculations show that the modulators can be energy-efficient and footprint-compact due to the large phase shift of the propagating mode in the waveguide after applying a gate voltage on the graphene. Fabrication of our design is easy and CMOS-compatible. It paves the way for chip-integrated electronic-RI modulators. PMID- 27244400 TI - Time-of-flight detection of ultra-cold atoms using resonant frequency modulation imaging. AB - Resonant frequency modulation imaging is used to detect free falling ultra-cold atoms. A theoretical comparison of fluorescence imaging (FI) and frequency modulation imaging (FMI) is made, indicating that for low optical depth clouds, FMI accomplished a higher signal-to-noise ratio under conditions necessary for a 200 MUm spatially resolved atom interferometer. A 750 ms time-of-flight measurement reveals near atom shot-noise limited number measurements of 2*106 Bose-condensed Rb87 atoms. The detection system is applied to high precision spinor BEC based atom interferometer. PMID- 27244401 TI - Comparison of DSP-based nonlinear equalizers for intra-channel nonlinearity compensation in coherent optical OFDM. AB - A novel versatile digital signal processing (DSP)-based equalizer using support vector machine regression (SVR) is proposed for 16-quadrature amplitude modulated (16-QAM) coherent optical orthogonal frequency-division multiplexing (CO-OFDM) and experimentally compared to traditional DSP-based deterministic fiber-induced nonlinearity equalizers (NLEs), namely the full-field digital back-propagation (DBP) and the inverse Volterra series transfer function-based NLE (V-NLE). For a 40 Gb/s 16-QAM CO-OFDM at 2000 km, SVR-NLE extends the optimum launched optical power (LOP) by 4 dB compared to V-NLE by means of reduction of fiber nonlinearity. In comparison to full-field DBP at a LOP of 6 dBm, SVR-NLE outperforms by ~1 dB in Q-factor. In addition, SVR-NLE is the most computational efficient DSP-NLE. PMID- 27244402 TI - Polarization-insensitive, shallow Ti-diffused near-stoichiometric LiTaO3 strip waveguide for integrated optics. AB - We report on a Ti-diffused near-stoichiometric (NS) LiTaO3 strip waveguide fabricated by diffusion of an 8 MUm wide, 160 nm thick Ti-strip followed by Li-rich vapor transport equilibration. It is found that the waveguide surface caves in ~60 nm below the crystal surface. X-ray single-crystal diffraction shows that the indentation is due to Ti-induced lattice contraction. Optical studies show that the waveguide is in an NS composition environment, supports TE and TM single-mode propagation at 1.5 MUm wavelength, is polarization insensitive, and has a shallow mode field profile and a loss of 0.2/0.3 dB/cm for the TE/TM mode. Secondary ion mass spectrometry analysis shows that the Ti profile follows a sum of two error functions in the width direction and a Gaussian function in the depth direction of the waveguide. With the optimized fabrication condition, the waveguide is promising for developing an optical damage-resistant device that requires a shallow mode field profile. PMID- 27244403 TI - Thermal effects on the photoelastic coefficient of polymer optical fibers. AB - We measure the radial profile of the photoelastic coefficient C(r) in single-mode polymer optical fibers (POFs), and we determine the evolution of C(r) after annealing the fibers at temperatures from 40 degrees C to 80 degrees C. We demonstrate that C(r) in the fibers drawn from a preform without specific thermal pre-treatment changes and converges to values between 1.2 and 1.6*10 12 Pa-1 following annealing at 80 degrees C. The annealed fibers display a smoothened radial profile of C(r) and a lowered residual birefringence. In contrast, the mean value of C(r) of the fiber drawn from a preform that has been pre-annealed remains constant after our annealing process and is significantly higher, i.e., 4*10-12 Pa-1. The annealing process decreases the residual birefringence to a lower extent as well. These measurements indicate the impact of annealing on the thermal stability of the photoelastic coefficient of POFs, which is an essential characteristic in view of developing POF-based thermo-mechanical sensors. PMID- 27244404 TI - Evaluation of low viscosity variations in fluids using temporal and spatial analysis of the speckle pattern. AB - The noninvasive detection of a material's viscoelasticity is of great importance in the medical field. In fact, certain diseases cause changes in tissue structure and biological fluid viscosity; tracking those changes allows for detection of these diseases. Rheological measurements are also imperative in the industrial field, where it is necessary to characterize a material's viscoelasticity for manufacturing purposes. In this Letter, we present a noncontact, noninvasive, and low cost method for determining low viscosity values and variations in fluids. Laser speckle and viscometric measurements are performed on test samples having low scattering coefficients and low viscosities. The speckle spatial analysis proved to be as accurate as the speckle temporal correlation method reported in previous studies. Very low viscosities of the order of 1 mPa.s were retrieved for the first time using speckle images with either a frame rate of 1950 fps or a single acquired image. PMID- 27244405 TI - Spatially and temporally resolved temperature measurement in laser media. AB - A technique to measure the spatially resolved temperature distribution in a laser medium is presented. It is based on the temperature dependence of the absorption cross section close to the zero-phonon line of the active medium. Since other materials in the beam path exhibit a high (and constant) transmission at this wavelength, the method can easily be applied in realistic amplifier setups. The method was successfully tested on three different samples, which were pumped by a pulsed laser diode with up to 150 W average power: side-cooled Yb:YAG and Yb:fluoride-phosphate glass at room temperature and face-cooled Yb:CaF2 at 120 K. PMID- 27244406 TI - Multimode waveguide speckle patterns for compressive sensing. AB - Compressive sensing (CS) of sparse gigahertz-band RF signals using microwave photonics may achieve better performances with smaller size, weight, and power than electronic CS or conventional Nyquist rate sampling. The critical element in a CS system is the device that produces the CS measurement matrix (MM). We show that passive speckle patterns in multimode waveguides potentially provide excellent MMs for CS. We measure and calculate the MM for a multimode fiber and perform simulations using this MM in a CS system. We show that the speckle MM exhibits the sharp phase transition and coherence properties needed for CS and that these properties are similar to those of a sub-Gaussian MM with the same mean and standard deviation. We calculate the MM for a multimode planar waveguide and find dimensions of the planar guide that give a speckle MM with a performance similar to that of the multimode fiber. The CS simulations show that all measured and calculated speckle MMs exhibit a robust performance with equal amplitude signals that are sparse in time, in frequency, and in wavelets (Haar wavelet transform). The planar waveguide results indicate a path to a microwave photonic integrated circuit for measuring sparse gigahertz-band RF signals using CS. PMID- 27244407 TI - Few-photon scattering in dispersive waveguides with multiple qubits. AB - We extend the Krylov-subspace-based time-dependent numerical simulation technique for a qubit interacting with photons in a waveguide to the multiple qubit case. We analyze photon scattering from two qubits and derive expressions for the bound states in the continuum (BICs). We show how the BIC can be excited. We use the BIC in a recent Pauli-Z gate proposal involving decoherence free subspaces and obtain the gate fidelity as a function of the gate parameters. The techniques presented in this Letter are useful for investigating the time evolution of quantum gates and other many-body systems with multiple quenches in the Hamiltonian. PMID- 27244408 TI - Experimental demonstration of coherent perfect absorption in a silicon photonic racetrack resonator. AB - We present the first experimental demonstration of coherent perfect absorption (CPA) in an integrated device using a silicon racetrack resonator at telecommunication wavelengths. Absorption in the racetrack is achieved by Si+-ion-implantation, allowing for phase controllable amplitude modulation at the resonant wavelength. The device is measured to have an extinction of 24.5 dB and a quality-factor exceeding 3000. Our results will enable integrated CPA devices for data modulation and detection. PMID- 27244409 TI - Fourier transform and Vernier spectroscopy using an optical frequency comb at 3 5.4 MUm. AB - We present a versatile mid-infrared frequency comb spectroscopy system based on a doubly resonant optical parametric oscillator tunable in the 3-5.4 MUm range and two detection methods: a Fourier transform spectrometer (FTS) and a continuous filtering Vernier spectrometer (CF-VS). Using the FTS with a multipass cell, we measure high precision broadband absorption spectra of CH4 at 3.3 MUm and NO at 5.25 MUm, the latter for the first time with comb spectroscopy, and we detect atmospheric species (CH4, CO, CO2, and H2O) in air in the signal and idler ranges. Multiline fitting yields minimum detectable concentrations of 10-20 ppb Hz-1/2 for CH4, NO, and CO. For the first time in the mid-infrared, we perform CF VS using an enhancement cavity, a grating, and a single detector, and we measure the absorption spectrum of CH4 and H2O in ambient air at ~3.3 MUm, reaching a 40 ppb concentration detection limit for CH4 in 2 ms. PMID- 27244410 TI - High-peak-power single-oscillator actively Q-switched mode-locked Tm3+ doped fiber laser and its application for high-average output power mid-IR supercontinuum generation in a ZBLAN fiber. AB - A single-oscillator actively Q-switched mode-locked (QML) thulium-doped silica fiber laser is presented and used to pump a ZrF4-BaF2 LaF3-AlF3-NaF (ZBLAN) fiber for mid-infrared (mid-IR) supercontinuum (SC) generation. The fiber laser provided high-peak-power levels directly from the oscillator delivering single mode-locked pulse energies up to 48 MUJ, being 2-4 orders of magnitude higher than conventional continuous wave mode-locked lasers. By pumping a ZBLAN fiber specially designed for high-output power SC generation, 7.8 W have been achieved in all spectral bands with a spectrum extending to 4.2 MUm. PMID- 27244411 TI - Measurement of the rotational Doppler frequency shift of a spinning object using a radio frequency orbital angular momentum beam. AB - An indirect approach based on phase measurement is proposed to measure the rotational Doppler frequency shift, which takes full advantage of the phase structure of orbital angular momentum (OAM) beams in radio domain, using a vector network analyzer (VNA) as a phase discriminator. A proof-of-concept experiment is established by an optical-controlled system with the OAM state of 1. By analyzing the experiment's results, the rotational Doppler frequency shift is measured as 24.83 Hz (max error rate 0.67%) at 50pi rad/s rotational velocity, deducing the rotational velocity as 50.18pi (average error rate 0.36%). PMID- 27244412 TI - Visible supercontinuum generation in a graded index multimode fiber pumped at 1064 nm. AB - We observe efficient supercontinuum generation that extends into the visible spectral range by pumping a low differential mode group delay graded index multimode fiber in the normal dispersion regime. For a 28.5 m long fiber, the generated spectrum spans more than two octaves, starting from below 450 nm and extending beyond 2400 nm. The main nonlinear mechanisms contributing to the visible spectrum generation are attributed to multipath four-wave mixing processes and periodic spatio-temporal breathing dynamics. Moreover, by exploiting the highly multimodal nature of this system, we demonstrate versatile generation of visible spectral peaks in shorter fiber spans by altering the launching conditions. A nonlinearly induced mode cleanup was also observed at the pump wavelength. Our results could pave the way for high brightness, high power, and compact, multi-octave continuum sources. PMID- 27244413 TI - Photonic RF vector signal generation with enhanced spectral efficiency using precoded double single-sideband modulation. AB - In this study, a novel photonic vector signal at frequency (RF) bands generation scheme based on the beating of double single sidebands (SSBs) is proposed and experimentally demonstrated. The double SSBs carry separate constant- or multi amplitude quadrature-amplitude-modulation vector signals are generated from a single I/Q modulator. By adopting phase and amplitude precoding, different constellations can be generated, such as 3-ary phase-shift keying (PSK), 4-PSK, 7 PSK, 8-PSK, and so on. In this work, 10-Gbaud 7-PSK vector signal generation at 20 GHz enabled by two precoded 4-PSK SSB signals via a single I/Q modulator is theoretically and experimentally investigated. Compared to a single-drive Mach Zehnder modulator or conventional I/Q modulator-based photonic vector signal generation scheme, the spectrum efficiency can be doubled. Differential coding is also implemented at the transmitter side for accurate demodulation of 7-PSK into two 4-PSK signals. The bit-error ratio for 10-Gbaud 7-PSK vector signals can be under hard-decision forward-error-correction threshold of 3.8*10-3 after 10 km standard single-mode fiber transmission. PMID- 27244414 TI - Artificial neural network approaches for fluorescence lifetime imaging techniques. AB - A novel high-speed fluorescence lifetime imaging (FLIM) analysis method based on artificial neural networks (ANN) has been proposed. In terms of image generation, the proposed ANN-FLIM method does not require iterative searching procedures or initial conditions, and it can generate lifetime images at least 180-fold faster than conventional least squares curve-fitting software tools. The advantages of ANN-FLIM were demonstrated on both synthesized and experimental data, showing that it has great potential to fuel current revolutions in rapid FLIM technologies. PMID- 27244415 TI - Thermally controlled comb generation and soliton modelocking in microresonators. AB - We report, to the best of our knowledge, the first demonstration of thermally controlled soliton mode-locked frequency comb generation in microresonators. By controlling the electric current through heaters integrated with silicon nitride microresonators, we demonstrate a systematic and repeatable pathway to single- and multi-soliton mode-locked states without adjusting the pump laser wavelength. Such an approach could greatly simplify the generation of mode-locked frequency combs and facilitate applications such as chip-based dual-comb spectroscopy. PMID- 27244416 TI - Increasing applicability of slow light in molecular aggregate nanofilms with two exciton dynamics. AB - We study the slow-light performance in the presence of exciton-exciton interaction in films of linear molecular aggregates at the nanometer scale. In particular, we consider a four-level model to describe the creation/annihilation of two-exciton states that are relevant for high-intensity fields. Numerical simulations show delays comparable to those obtained for longer propagation distances in other media. Two-exciton dynamics could lead to larger fractional delays, even in presence of disorder, in comparison to the two-level approximation. We conclude that slow-light performance is a robust phenomenon in these systems under the increasing complexity of the two-exciton dynamics. PMID- 27244417 TI - Zinc selenide-based large aperture photo-controlled deformable mirror. AB - Realization of large aperture deformable mirrors with a large density of actuators is important in many applications, and photo-controlled deformable mirrors (PCDMs) represent an innovation. Herein we show that PCDMs are scalable realizing a 2-inch aperture device based on a polycrystalline zinc selenide (ZnSe) as the photoconductive substrate and a thin polymeric reflective membrane. ZnSe is electrically characterized and analyzed through a model that we previously introduced. The PCDM is then optically tested, demonstrating its capabilities in adaptive optics. PMID- 27244418 TI - Generation of optical frequency combs in a fiber-ring/microresonator laser system. AB - We propose and experimentally demonstrate a simple scheme for generating optical frequency combs (OFCs) in a fiber-ring/microresonator laser system. The ultrahigh Q whispering gallery mode microresonator is employed both as a mode reflection mirror to generate erbium lasing and as a Kerr-nonlinearity initiator that introduces optical parametric oscillation signals to form OFCs. By controlling the coupling position between the fiber taper and microresonator, optimizing the fiber polarization, as well as the pump power from a 974 nm laser diode (LD), versatile OFCs can be tuned out from single-wavelength states. The OFCs have single, multiple, or combined free spectral ranges. In addition, a Raman-gain assisted OFC is also observed with a bandwidth of ~230 nm. This LD-pumped and multifunctional laser system could find applications in precision spectroscopy, biochemical sensing, and optical fiber communication systems. PMID- 27244419 TI - High magneto-optical characteristics of Holmium-doped terbium gallium garnet crystal. AB - Magneto-optical characteristics of a new magneto-active material, (Tb(1 x)Hox)3Ga5O12 crystal, have been grown by the Czochralski (Cz) method. A high value of the Verdet constant was obtained at room temperature-namely, 214.9 and 77.8 rad.m-1 T-1 for 632.8 and 1064 nm, respectively. The Verdet constant of the Ho doped terbium gallium garnet crystal at 1064 nm is about 2 times higher than that of terbium gallium garnet crystal. High value of magneto-optical figure-of-merit makes it an attractive next-generation magneto-optics material for high-power Faraday isolators. PMID- 27244420 TI - Polarized random laser emission from an oriented disorder polymer optical fiber. AB - We demonstrate the realization of a polarized random polymer fiber laser (RPFL) in the different disordered gain media doped polymer optical fibers (POFs). Multiple scattering of disordered media in the orientated POF was experimentally verified to account for polarized lasing observed in our RPFL system. This Letter presents a new avenue for fabricating polarized RPFLs in a large scale. Meanwhile, the polarization-maintaining property of random lasing for different disorder POF are researched, which will open a window to designing a polarization maintaining random fiber laser. PMID- 27244421 TI - Few-mode erbium-doped fiber amplifier with photonic lantern for pump spatial mode control. AB - We demonstrate a few-mode erbium-doped fiber amplifier employing a mode-selective photonic lantern for controlling the modal content of the pump light. Amplification of six spatial modes in a 5 m long erbium-doped fiber to ~6.2 dBm average power is obtained while maintaining high modal fidelity. Through mode selective forward pumping of the two degenerate LP21 modes operating at 976 nm, differential modal gains of <1 dB between all modes and signal gains of ~16 dB at 1550 nm are achieved. In addition, low differential modal gain for near-full C-band operation is demonstrated. PMID- 27244422 TI - All-fiber Ho-doped mode-locked oscillator based on a graphene saturable absorber. AB - In this Letter, we demonstrate a graphene mode-locked, all-fiber Ho-doped fiber laser generating 1.3 nJ energy pulses directly from the oscillator. The graphene used as a saturable absorber was obtained via chemical vapor deposition on copper substrate and immersed in a poly(methyl methacrylate) support. The laser generated ultrashort soliton pulses at 2080 nm with bandwidth up to 6.1 nm. The influence of the output coupling ratio and the SA modulation depth on the mode locking performance was also investigated. PMID- 27244423 TI - High-pulse-energy mid-infrared fractional-image-rotation-enhancement ZnGeP2 optical parametric oscillator. AB - A high-energy mid-infrared ZnGeP2 (ZGP) optical parametric oscillator (OPO) based on the nonplanar fractional-image-rotation enhancement resonator pumped by a 2.05 MUm Ho3+:YLF laser is presented. Up to 120 mJ pulse energy in a rotationally symmetric beam is generated in the 3-5 MUm wavelength range at 1 Hz repetition rate. Slope efficiencies of up to 78% are achieved with respect to the pump pulse energy incident onto the ZGP crystal. The OPO pulses have a duration close to 15 ns, corresponding to a maximum peak power of 8 MW. A measurement of M2 dependence on pump beam diameter is presented. PMID- 27244424 TI - Wideband tuning of four-wave mixing in solid-core liquid-filled photonic crystal fibers. AB - We present an experimental study of parametric four-wave mixing generation in photonic crystal fibers that have been infiltrated with ethanol. A silica photonic crystal fiber was designed to have the proper dispersion properties after ethanol infiltration for the generation of widely spaced four-wave mixing (FWM) bands under 1064 nm pumping. We demonstrate that the FWM bands can be tuned in a wide wavelength range through the thermo-optic effect. Band shifts of 175 and over 500 nm for the signal and idler bands, respectively, are reported. The reported results can be of interest in many applications, such as CARS microscopy. PMID- 27244425 TI - Enhanced strain and temperature sensing by reduced graphene oxide coated etched fiber Bragg gratings. AB - This Letter reports on an etched fiber Bragg grating (eFBG) sensor coated with reduced graphene oxide (RGO) having enhanced sensitivity for physical parameters such as strain and temperature. The synergetic effect of the changes in grating pitch and refractive index of RGO with change in temperature or strain enhances the shift in Bragg wavelength (lambdaB). The RGO-coated eFBG sensors exhibit a strain sensitivity of 5.5 pm/MUepsilon (~5 times that of bare fiber Bragg gratings) and temperature sensitivity of 33 pm/ degrees C (~3 times that of bare fiber Bragg gratings). The resolutions of ~1 MUepsilon and ~0.3 degrees C have been obtained for strain and temperature respectively, using RGO-coated eFBG sensors. PMID- 27244426 TI - High-brightness semipolar (2021-) blue InGaN/GaN superluminescent diodes for droop-free solid-state lighting and visible-light communications. AB - A high-brightness, droop-free, and speckle-free InGaN/GaN quantum well blue superluminescent diode (SLD) was demonstrated on a semipolar (2021-) GaN substrate. The 447-nm emitting SLD has a broad spectral linewidth of 6.3 nm at an optical power of 123 mW. A peak optical power of 256 mW was achieved at 700 mA CW injection current. By combining YAG:Ce phosphor, SLD-generated white light shows a color-rendering index (CRI) of 68.9 and a correlated color temperature (CCT) of 4340 K. The measured frequency response of the SLD revealed a -3 dB bandwidth of 560 MHz, thus demonstrating the feasibility of the device for both solid-state lighting (SSL) and visible-light communication (VLC) applications. PMID- 27244427 TI - Spectrally-isolated violet to blue wavelength generation by cascaded degenerate four-wave mixing in a photonic crystal fiber. AB - Generation of spectrally-isolated wavelengths in the violet to blue region based on cascaded degenerate four-wave mixing (FWM) is experimentally demonstrated for the first time in a tailor-made photonic crystal fiber, which has two adjacent zero dispersion wavelengths (ZDWs) at 696 and 852 nm in the fundamental mode. The influences of the wavelength lambdap and the input average power Pav of the femtosecond pump pulses on the phase-matched frequency conversion process are studied. When femtosecond pump pulses at lambdap of 880, 870, and 860 nm and Pav of 500 mW are coupled into the normal dispersion region close to the second ZDW, the first anti Stokes waves generated near the first ZDW act as a secondary pump for the next FWM process. The conversion efficiency etaas2 of the second anti Stokes waves, which are generated at the violet to blue wavelengths of 430, 456, and 472 nm, are 4.8, 6.48, and 9.66%, for lambdap equalling 880, 870, and 860 nm, respectively. PMID- 27244428 TI - Scattering of light from a stationary nonuniformly correlated medium. AB - A mathematical model for describing a three-dimensional, nonuniformly correlated, weak scattering medium is introduced. It is assumed that the medium occupies a volume in which a relatively high degree of spatial refractive index correlation may exist in some small sub-region, whether on or off its center. Within the validity of the first-order Born approximation, the far-zone spectral density of a plane wave scattered from such a medium is determined. We find that the introduced scatterer has a remarkable capability for producing a focused peak on or off the scattering axis. It is shown that by altering the position of the high correlation center within the medium, it is possible to control the peak position and peak intensity of the scattered spectral density. For certain combinations of the average medium's correlation width and the location of the highly correlated region, the scattered spectral density (intensity) may also acquire one dimensional sidelobes. PMID- 27244429 TI - Sub-nanosecond Yb:KLu(WO4)2 microchip laser. AB - A diode-pumped Yb:KLu(WO4)2 microchip laser passively Q switched by a Cr4+:YAG saturable absorber generated a maximum average output power of 590 mW at 1031 nm with a slope efficiency of 55%. The pulse characteristics were 690 ps/47.6 MUJ at a pulse repetition frequency of 12.4 kHz. The output beam had an excellent circular profile with M2<1.05. Yb:KLu(WO4)2 is very promising for ultrathin sub-ns microchip lasers. PMID- 27244430 TI - Fabrication tolerances in As2S3 negative-curvature antiresonant fibers. AB - We computationally investigate fabrication tolerances in As2S3 negative-curvature antiresonant tube-lattice fibers. Since the dominant loss mechanisms for silica in the mid-infrared (mid-IR) is material absorption, As2S3, which offers a reduced loss over that wavelength range, is a natural candidate for mid-IR antiresonant fibers. However, any fiber fabrication technology, including for soft glasses, will have imperfections. Therefore, it is important to know how imperfect fabrication will affect the results of a fiber design. We study perturbations to the fiber, including a nonconstant tube-wall thickness, a single cladding tube with a different radius, a single cladding tube with a different tube-wall thickness, and "key" sections in the jacket. PMID- 27244431 TI - Dual-soliton Stokes-based background-free coherent anti-Stokes Raman scattering spectroscopy and microscopy. AB - We propose an all-fiber-generated, dual-soliton, Stokes-based scheme for background-free coherent anti-Stokes Raman scattering (CARS) under the spectral focusing mechanism. Owing to the strong birefringence and high nonlinearity of a polarization-maintaining PCF (PM-PCF), two soliton pulses can be simultaneously emitted along different eigenpolarization axes and both serve as Stokes pulses, while allowing feasible tunability of frequency distance and temporal interval between them. This proposed scheme, based on an all-fiber light source, exploits a unique combination of slight frequency-shift temporal walk-off of these two solitons to achieve efficient suppression of the nonresonant background and beat the inaccessibility and complexity of the excitation source. Capability is experimentally demonstrated by background-free CARS spectroscopy and unambiguous CARS microscopy in the fingerprint region. PMID- 27244432 TI - Monolithic thulium fiber laser with 567 W output power at 1970 nm. AB - We report on a monolithic thulium fiber laser with 567 W output power at 1970 nm which, to the best of our knowledge, is the highest power reported so far directly from a thulium oscillator. This is achieved by optimization of the splice parameters for the active fiber (minimizing signal light in the fiber cladding) and direct water cooling. Dual transverse mode operation is visible from the optical spectrum and can be deduced from the measured beam quality of M2=2.6. PMID- 27244433 TI - Rigorous theoretical analysis of a surface-plasmon nanolaser with monolayer MoS2 gain medium. AB - Lasers based on monolayer (ML) transition-metal dichalcogenide semiconductor crystals have the potential for low threshold operation and a small device footprint; however, nanophotonic engineering is required to maximize the interaction between the optical fields and the three-atom-thick gain medium. Here, we develop a theoretical model to design a direct bandgap optically pumped nanophotonic integrated laser. Our device utilizes a gap-surface-plasmon optical mode to achieve subwavelength optical confinement and consists of a high-index GaP nanowire atop an ML MoS2 film on an Ag substrate. The optical field and material medium are analyzed using a three dimensional finite difference time-domain method and a first-principles calculation based on the density functional theory, respectively. The nanolaser is designed to have a threshold of ~0.6 MUW under quasi-continuous wave operation on an excitonic transition at room temperature. PMID- 27244434 TI - Photonic downconversion with tunable wideband phase shift. AB - A microwave photonic frequency downconversion system with wideband and continuous phase-shift function is proposed and experimentally demonstrated. In the proposed system, a radio frequency (RF) and a local oscillator (LO) signal drive two arms of a dual-drive Mach-Zehnder modulator (DMZM). A fiber Bragg grating (FBG) is used for reflecting the first-order sidebands of both RF and LO signals. Due to phase independence between RF and LO optical sidebands, the phase-shifting operation for an output intermediate frequency (IF) signal can be implemented either by adjusting the bias voltage of DMZM or by controlling the optical wavelength of laser. Experimental results demonstrate a full 0 degrees to 360 degrees phase shift, while an RF signal between 12 GHz to 20 GHz is downconverted to IFs below 4 GHz. The phase deviation is measured less than 2 degrees , and the fluctuation of magnitude response is measured less than +/-1 dB over a wideband frequency range. PMID- 27244435 TI - Generation of 14 W at 589 nm by frequency doubling of high-power CW linearly polarized Raman fiber laser radiation in MgO:sPPLT crystal. AB - We introduce an efficient, single-mode, linearly polarized continuous wave (CW) Raman fiber laser (RFL), operating at 1178 nm, with 65 W maximum output power and a narrow linewidth of 0.1 nm. Single-pass second-harmonic generation was demonstrated using a 20 mm long MgO-doped stoichiometric periodically polled lithium tantalate (MgO:sPPLT) crystal pumped by RFL radiation. Output power of 14 W at 589 nm with 22% conversion efficiency was achieved. The possibility of further power scaling is considered, as no crystal degradation was observed at these power levels. PMID- 27244436 TI - Geometric phase shifting digital holography. AB - A new phase shifting digital holographic technique using a purely geometric phase in Michelson interferometric geometry is proposed. The geometric phase in the system does not depend upon either optical path length or wavelength, unlike dynamic phase. The amount of geometric phase generated is controllable through a rotating wave plate. The new approach has unique features and major advantages in holographic measurement of transparent and reflecting three-dimensional (3D) objects. Experimental results on surface shape measurement and imaging of 3D objects are presented using the proposed method. PMID- 27244437 TI - Switching of nanoparticles in large-scale hybrid electro-optofluidics integration. AB - We numerically demonstrate the scheme of independent optofluidic switching of nanoparticles on a silicon-based lab-on-a-chip system, using an electronic logic activated ring-assisted Mach-Zehnder interferometer (RAMZI). By using the carrier injection method with a tiny refractive index change of 8.00*10-4 to adjust the phase delay of a ring resonator sitting on one arm of the MZI, the light passing through could be switched to any output port of MZI followed by a directional coupler (DC). Meanwhile, the trapping force and scattering force of the guided lightwave could provide the actuation for sample delivery. Therefore, the switching logic of the guided mode is mapping to its loaded sample of nanomaterials. Our structure possesses high compactness, scalability, and time effectiveness and, thereby, it is very appropriate for on-chip optical manipulation. The introduction of the RAMZI and cascaded RAMZIs in an optofluidic chip can form a scalable switching module with an independent electronic logic trigger signal, and make the chip dynamically configurable and scalable, which is very critical and opens a new horizon for the large-scale hybrid electro optofluidics integration of a lab-on-a-chip system. PMID- 27244438 TI - Shock wave generation triggered by a weak background in optical fibers. AB - We experimentally report the observation of dispersive shock waves from a short pulse superimposed onto a small continuous wave background in optical fibers. We show that the background allows us to strongly enhance the extension and contrast of the oscillatory wave train inherent to the dispersive shock. More than seven periods of oscillations with high contrast are observed experimentally and confirmed with numerical simulations. The dynamics of the process are simply explained from spectro-temporal representations. PMID- 27244439 TI - Polarization-tunable terahertz radiation in the high-field regime. AB - Polarization control of terahertz (THz) pulses in the high-field regime is a challenging subject. Here we propose and numerically demonstrate an all-optical scheme to generate a polarization-tunable high-field THz source based on relativistic laser plasma interactions. By adjusting the polarization state of the driving laser, collective oscillation of the plasmas can be steered. Phase difference between the laser field components is inherited in the plasma dynamics, as well as in the resulting THz generation process. Single-cycle extremely intense THz pulses with field strength ~ GV/cm can be generated. The THz polarization state can be tuned from linear through elliptical to circular by changing the polarization state of the driving laser. PMID- 27244440 TI - Polarization switching and injection locking in vertical-cavity surface-emitting lasers subject to parallel optical injection. AB - Polarization switching in a long-wavelength vertical-cavity surface-emitting laser (VCSEL) under parallel optical injection is analyzed in a theoretical and experimental way. For the first time, to our knowledge, we report experimentally a state in which injection locking of the parallel polarization and excitation of the free-running orthogonal polarization of the VCSEL are simultaneously obtained. We obtain very simple analytical expressions that describe both linear polarizations. We show that the power of both linear polarizations depend linearly on the injected power in such a way that the total power emitted by the VCSEL is constant. We perform a linear stability analysis of this solution to characterize the region of parameters in which it can be observed. Our measurements qualitatively confirm the previous theoretical predictions. PMID- 27244441 TI - Transverse electric surface mode in atomically thin Boron-Nitride. AB - The spatial confinement and the propagation length of surface waves in a single layer two-dimensional atomic crystal are analyzed in terms of its surface susceptibility and its surface conductivity. Based on the values of these macroscopic parameters, extracted from experimental observations, it is confirmed that graphene supports a transverse magnetic nonradiating surface mode in the ultraviolet spectral region while a single-layer hexagonal Boron-Nitride is predicted to support a transverse electric nonradiating surface mode in the visible spectrum. This last mode, at a vacuum wavelength of 633 nm, has a spatial confinement of 15 MUm and an intensity-propagation distance greater than 2 cm. PMID- 27244443 TI - Driving a better driving experience: a questionnaire survey of older compared with younger drivers. AB - A questionnaire survey of drivers (n = 903) was conducted covering musculoskeletal symptoms, the vehicle seat, access to specific vehicle features, ingress/egress, driving performance and driving behaviours. Significantly, more discomfort was reported by older drivers (aged 65+) in the hips/thighs/buttocks and knees. Older drivers reported more difficulty parallel parking (p <= 0.01), driving on a foggy day (p <= 0.01), and turning their head and body to reverse (p <= 0.001). They also reported that their reactions were slower than they used to be (p <= 0.01). Dissatisfaction was found by all drivers with adjusting the headrest (height and distance), seat belt height and opening/closing the boot. There is a growing population of older people globally, and the number of older drivers is showing a parallel increase. Clearly, efforts are needed to ensure car design of the future is more inclusive of older drivers. Practitioner Summary: This paper describes a questionnaire survey of drivers on their driving experience - the vehicle seat, access to specific vehicle features, ingress/egress, driving performance and driving behaviours. Comparisons are made by age and gender. Issues with driving and vehicle design particularly for older drivers in the UK are identified. PMID- 27244442 TI - Viral hijacking of a replicative helicase loader and its implications for helicase loading control and phage replication. AB - Replisome assembly requires the loading of replicative hexameric helicases onto origins by AAA+ ATPases. How loader activity is appropriately controlled remains unclear. Here, we use structural and biochemical analyses to establish how an antimicrobial phage protein interferes with the function of the Staphylococcus aureus replicative helicase loader, DnaI. The viral protein binds to the loader's AAA+ ATPase domain, allowing binding of the host replicative helicase but impeding loader self-assembly and ATPase activity. Close inspection of the complex highlights an unexpected locus for the binding of an interdomain linker element in DnaI/DnaC-family proteins. We find that the inhibitor protein is genetically coupled to a phage-encoded homolog of the bacterial helicase loader, which we show binds to the host helicase but not to the inhibitor itself. These findings establish a new approach by which viruses can hijack host replication processes and explain how loader activity is internally regulated to prevent aberrant auto-association. PMID- 27244444 TI - Using Neutron Reflectometry to Discern the Structure of Fibrinogen Adsorption at the Stainless Steel/Aqueous Interface. AB - Neutron reflectometry has been successfully used to study adsorption on a stainless steel surface by means of depositing a thin steel film on silicon. The film was characterized using XPS (X-ray photoelectron spectroscopy), TOF-SIMS (time-of-flight secondary ion mass spectrometry), and GIXRD (grazing incidence X ray diffraction), demonstrating the retention both of the austenitic phase and of the required composition for 316L stainless steel. The adsorption of fibrinogen from a physiologically-relevant solution onto the steel surface was studied using neutron reflectometry and QCM (quartz crystal microbalance) and compared to that on a deposited chromium oxide surface. It was found that the protein forms an irreversibly bound layer at low concentrations, with maximum protein concentration a distance of around 20 A from the surface. Evidence for a further diffuse reversibly-bound layer forming at higher concentrations was also observed. Both the structure of the layer revealed by the neutron reflectometry data and the high water retention predicted by the QCM data suggest that there is a significant extent of protein unfolding upon adsorption. A lower extent of adsorption was seen on the chromium surfaces, although the adsorbed layer structures were similar, suggesting comparable adsorption mechanisms. PMID- 27244445 TI - Multiplex Real-Time PCR Assays that Measure the Abundance of Extremely Rare Mutations Associated with Cancer. AB - We describe the use of "SuperSelective" primers that enable the detection and quantitation of somatic mutations whose presence relates to cancer diagnosis, prognosis, and therapy, in real-time PCR assays that can potentially analyze rare DNA fragments present in blood samples (liquid biopsies). The design of these deoxyribonucleotide primers incorporates both a relatively long "5' anchor sequence" that hybridizes strongly to target DNA fragments, and a very short, physically and functionally separate, "3' foot sequence" that is perfectly complementary to the mutant target sequence, but mismatches the wild-type sequence. As few as ten mutant fragments can reliably be detected in the presence of 1,000,000 wild-type fragments, even when the difference between the mutant and the wild type is only a single nucleotide polymorphism. Multiplex PCR assays employing a set of SuperSelective primers, and a corresponding set of differently colored molecular beacon probes, can be used in situations where the different mutations, though occurring in different cells, are located in the same codon. These non-symmetric real-time multiplex PCR assays contain limited concentrations of each SuperSelective primer, thereby enabling the simultaneous determination of each mutation's abundance by comparing its threshold value to the threshold value of a reference gene present in the sample. PMID- 27244446 TI - The Telomeric Repeats of Human Herpesvirus 6A (HHV-6A) Are Required for Efficient Virus Integration. AB - Human herpesvirus 6A (HHV-6A) and 6B (HHV-6B) are ubiquitous betaherpesviruses that infects humans within the first years of life and establishes latency in various cell types. Both viruses can integrate their genomes into telomeres of host chromosomes in latently infected cells. The molecular mechanism of viral integration remains elusive. Intriguingly, HHV-6A, HHV-6B and several other herpesviruses harbor arrays of telomeric repeats (TMR) identical to human telomere sequences at the ends of their genomes. The HHV-6A and HHV-6B genomes harbor two TMR arrays, the perfect TMR (pTMR) and the imperfect TMR (impTMR). To determine if the TMR are involved in virus integration, we deleted both pTMR and impTMR in the HHV-6A genome. Upon reconstitution, the TMR mutant virus replicated comparable to wild type (wt) virus, indicating that the TMR are not essential for HHV-6A replication. To assess the integration properties of the recombinant viruses, we established an in vitro integration system that allows assessment of integration efficiency and genome maintenance in latently infected cells. Integration of HHV-6A was severely impaired in the absence of the TMR and the virus genome was lost rapidly, suggesting that integration is crucial for the maintenance of the virus genome. Individual deletion of the pTMR and impTMR revealed that the pTMR play the major role in HHV-6A integration, whereas the impTMR only make a minor contribution, allowing us to establish a model for HHV 6A integration. Taken together, our data shows that the HHV-6A TMR are dispensable for virus replication, but are crucial for integration and maintenance of the virus genome in latently infected cells. PMID- 27244449 TI - Observation of Space Charge Dynamics Inside an All Oxide Based Solar Cell. AB - The charge transfer dynamics at interfaces are fundamental to know the mechanism of photovoltaic processes. The internal potential in solar cell devices depends on the basic processes of photovoltaic effect such as charge carrier generation, separation, transport, recombination, etc. Here we report the direct observation of the surface potential depth profile over the cross-section of the ZnO nanorods/Cu2O based solar cell for two different layer thicknesses at different wavelengths of light using Kelvin probe force microscopy. The topography and phase images across the cross-section of the solar cell are also observed, where the interfaces are well-defined on the nanoscale. The potential profiling results demonstrate that under white light illumination, the photoinduced electrons in Cu2O inject into ZnO due to the interfacial electric field, which results in the large difference in surface potential between two active layers. However, under a single wavelength illumination, the charge carrier generation, separation, and transport processes between two active layers are limited, which affect the surface potential images and corresponding potential depth profile. Because of changes in the active layer thicknesses, small variations have been observed in the charge carrier transport mechanism inside the device. These results provide the clear idea about the charge carrier distribution inside the solar cell in different conditions and show the perfect illumination condition for large carrier transport in a high performance solar cell. PMID- 27244447 TI - Proteomics of Breast Muscle Tissue Associated with the Phenotypic Expression of Feed Efficiency within a Pedigree Male Broiler Line: I. Highlight on Mitochondria. AB - As feed represents 60 to 70% of the cost of raising an animal to market weight, feed efficiency (the amount of dry weight intake to amount of wet weight gain) remains an important genetic trait in animal agriculture. To gain greater understanding of cellular mechanisms of feed efficiency (FE), shotgun proteomics was conducted using in-gel trypsin digestion and tandem mass spectrometry on breast muscle samples obtained from pedigree male (PedM) broilers exhibiting high feed efficiency (FE) or low FE phenotypes (n = 4 per group). The high FE group had greater body weight gain (P = 0.004) but consumed the same amount of feed (P = 0.30) from 6 to 7 wk resulting in higher FE (P < 0.001). Over 1800 proteins were identified, of which 152 were different (P < 0.05) by at least 1.3 fold and <= 15 fold between the high and low FE phenotypes. Data were analyzed for a modified differential expression (DE) metric (Phenotypic Impact Factors or PIF) and interpretation of protein expression data facilitated using the Ingenuity Pathway Analysis (IPA) program. In the entire data set, 228 mitochondrial proteins were identified whose collective expression indicates a higher mitochondrial expression in the high FE phenotype (binomial probability P < 0.00001). Within the top up and down 5% PIF molecules in the dataset, there were 15 mitoproteome proteins up-regulated and only 5 down-regulated in the high FE phenotype. Pathway enrichment analysis also identified mitochondrial dysfunction and oxidative phosphorylation as the number 1 and 5 differentially expressed canonical pathways (up-regulated in high FE) in the proteomic dataset. Upstream analysis (based on DE of downstream molecules) predicted that insulin receptor, insulin like growth receptor 1, nuclear factor, erythroid 2-like 2, AMP activated protein kinase (alpha subunit), progesterone and triiodothyronine would be activated in the high FE phenotype whereas rapamycin independent companion of target of rapamycin, mitogen activated protein kinase 4, and serum response factor would be inhibited in the high FE phenotype. The results provide additional insight into the fundamental molecular landscape of feed efficiency in breast muscle of broilers as well as further support for a role of mitochondria in the phenotypic expression of FE. Funding provided by USDA-NIFA (#2013-01953), Arkansas Biosciences Institute (Little Rock, AR), McMaster Fellowship (AUS to WB) and the Agricultural Experiment Station (Univ. of Arkansas, Fayetteville). PMID- 27244448 TI - Chronic Iron Overload Results in Impaired Bacterial Killing of THP-1 Derived Macrophage through the Inhibition of Lysosomal Acidification. AB - Iron is essential for living organisms and the disturbance of iron homeostasis is associated with altered immune function. Additionally, bacterial infections can cause major complications in instances of chronic iron overload, such as patients with transfusion-dependent thalassemia. Monocytes and macrophages play important roles in maintaining systemic iron homoeostasis and in defense against invading pathogens. However, the effect of iron overload on the function of monocytes and macrophages is unclear. We elucidated the effects of chronic iron overload on human monocytic cell line (THP-1) and THP-1 derived macrophages (TDM) by continuously exposing them to high levels of iron (100 MUM) to create I-THP-1 and I-TDM, respectively. Our results show that iron overload did not affect morphology or granularity of I-THP-1, but increased the granularity of I-TDM. Bactericidal assays for non-pathogenic E. coli DH5alpha, JM109 and pathogenic P. aeruginosa all revealed decreased efficiency with increasing iron concentration in I-TDM. The impaired P. aeruginosa killing ability of human primary monocyte derived macrophages (hMDM) was also found when cells are cultured in iron contained medium. Further studies on the bactericidal activity of I-TDM revealed lysosomal dysfunction associated with the inhibition of lysosomal acidification resulting in increasing lysosomal pH, the impairment of post-translational processing of cathepsins (especially cathepsin D), and decreased autophagic flux. These findings may explain the impaired innate immunity of thalassemic patients with chronic iron overload, suggesting the manipulation of lysosomal function as a novel therapeutic approach. PMID- 27244450 TI - Investigating the Role of Loop C Hydrophilic Residue 'T244' in the Binding Site of rho1 GABAC Receptors via Site Mutation and Partial Agonism. AB - The loop C hydrophilic residue, threonine 244 lines the orthosteric binding site of rho1 GABAC receptors was studied by point mutation into serine, alanine and cysteine, and tested with GABA, some representative partial agonists and antagonists. Thr244 has a hydroxyl group essential for GABA activity that is constrained by the threonine methyl group, orienting it toward the binding site. Significant decreases in activation effects of the studied ligands at rho1 T244S mutant receptors, suggests a critical role for this residue. Results of aliphatic and heteroaromatic partial agonists demonstrate different pharmacological effects at rho1 T244S mutant receptors when co-applied with GABA EC50 responses. rho1 T244A and rho1 T244C mutant receptors have minimal sensitivity to GABA at high mM concentrations, whereas, the rho1 WT partial agonists, beta-alanine and MTSEA demonstrate more efficacy and potency, respectively, than GABA at these mutant receptors. This study explores the role of Thr244 in the binding of agonists as an initial step during channel gating by moving loop C towards the ligand. PMID- 27244451 TI - Corrigendum: Mapping the small-world properties of brain networks in deception with functional near-infrared spectroscopy. PMID- 27244452 TI - Evaluation of the Effectiveness of Workshops on the Availability and Rational Use of Opioids in Latin America. AB - BACKGROUND: Many patients around the globe do not have access to pain treatment. A series of workshops on the availability and rational use of opioids in Latin America (LA) were implemented. AIM: To evaluate the effectiveness of action plans (APs) resulting from workshops to eliminate barriers to the availability and accessibility of opioids in 13 Latin American countries (Bolivia, Chile, Colombia, Costa Rica, Ecuador, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Panama, Peru, and Venezuela). Effectiveness was measured qualitatively and quantitatively. METHODS: A cross-sectional study was conducted from September to October 2015. Outcome variables were qualitative: the country coordinators (CCs) perceived workshop benefit and effectiveness and ability to implement the resulting AP and quantitative: (1) 2013 opioid consumption; (2) opioid consumption change from 2010 to 2013; (3) formulations available. For analysis we used nonparametric tests [Wilcoxon, Mann-Whitney, Spearman correlation (Rs)] and content analysis. RESULTS: Qualitative: 10 CCs rated the workshop very useful or useful and the resulting AP helpful in eliminating barriers. Communication/collaboration with regulators improved in 11 countries. Content, organization, and methodology were rated positively. Quantitative: no significant difference was found between countries that had one, two, or no workshops and the outcome variables. A positive significant correlation was found between Human Development Index and consumption (Rs [Spearman's rank correlation coefficient] = 0.688; p = 0.009) and in consumption changes: (Rs = 0.445; p = 0.128), but not in number of formulations available. DISCUSSION: The APs were rated useful in eliminating barriers but only four countries were able to implement >75% of their APs, which may suggest that the barriers were overwhelming and beyond their means to eliminate. CONCLUSION: Limited access to pain treatment is multifactorial, including restrictive laws and regulations. Strategies to eliminate barriers need to be broad and include clinical and government representatives to be effective. It may take several years before results are observed. PMID- 27244453 TI - QTL mapping of early flowering and resistance to ascochyta blight in chickpea. AB - In western Canada, chickpea (Cicer arietinum L.) production is challenged by short growing seasons and infestations with ascochyta blight. Research was conducted to determine the genetic basis of the association between flowering time and reaction to ascochyta blight in chickpea. Ninety-two chickpea recombinant inbred lines (RILs) developed from a cross between ICCV 96029 and CDC Frontier were evaluated for flowering responses and ascochyta blight reactions in growth chambers and fields at multiple locations and during several years. A wide range of variation was exhibited by the RILs for days to flower, days to maturity, node of first flowering, plant height, and ascochyta blight resistance. Moderate to high broad sense heritability was estimated for ascochyta blight reaction (H(2) = 0.14-0.34) and for days to flowering (H(2) = 0.45-0.87) depending on the environments. Negative correlations were observed among the RILs for days to flowering and ascochyta blight resistance, ranging from r = -0.21 (P < 0.05) to -0.58 (P < 0.0001). A genetic linkage map consisting of eight linkage groups was developed using 349 SNP markers. Seven QTLs for days to flowering were identified that individually explained 9%-44% of the phenotypic variation. Eight QTLs were identified for ascochyta blight resistance that explained phenotypic variation ranging from 10% to 19%. Clusters of QTLs for days to flowering and ascochyta blight resistances were found on chromosome 3 at the interval of 8.6 23.11 cM and on chromosome 8 at the interval of 53.88-62.33 cM. PMID- 27244454 TI - Use of microsatellite markers for the assessment of bambara groundnut breeding system and varietal purity before genome sequencing. AB - Maximizing the research output from a limited investment is often the major challenge for minor and underutilized crops. However, such crops may be tolerant to biotic and abiotic stresses and are adapted to local, marginal, and low-input environments. Their development through breeding will provide an important resource for future agricultural system resilience and diversification in the context of changing climates and the need to achieve food security. The African Orphan Crops Consortium recognizes the values of genomic resources in facilitating the improvement of such crops. Prior to beginning genome sequencing there is a need for an assessment of line varietal purity and to estimate any residual heterozygosity. Here we present an example from bambara groundnut (Vigna subterranea (L.) Verdc.), an underutilized drought tolerant African legume. Two released varieties from Zimbabwe, identified as potential genotypes for whole genome sequencing (WGS), were genotyped with 20 species-specific SSR markers. The results indicate that the cultivars are actually a mix of related inbred genotypes, and the analysis allowed a strategy of single plant selection to be used to generate non-heterogeneous DNA for WGS. The markers also confirmed very low levels of heterozygosity within individual plants. The application of a pre screen using co-dominant microsatellite markers is expected to substantially improve the genome assembly, compared to a cultivar bulking approach that could have been adopted. PMID- 27244455 TI - Sequence-Specific Electrical Purification of Nucleic Acids with Nanoporous Gold Electrodes. AB - Nucleic-acid-based biosensors have enabled rapid and sensitive detection of pathogenic targets; however, these devices often require purified nucleic acids for analysis since the constituents of complex biological fluids adversely affect sensor performance. This purification step is typically performed outside the device, thereby increasing sample-to-answer time and introducing contaminants. We report a novel approach using a multifunctional matrix, nanoporous gold (np-Au), which enables both detection of specific target sequences in a complex biological sample and their subsequent purification. The np-Au electrodes modified with 26 mer DNA probes (via thiol-gold chemistry) enabled sensitive detection and capture of complementary DNA targets in the presence of complex media (fetal bovine serum) and other interfering DNA fragments in the range of 50-1500 base pairs. Upon capture, the noncomplementary DNA fragments and serum constituents of varying sizes were washed away. Finally, the surface-bound DNA-DNA hybrids were released by electrochemically cleaving the thiol-gold linkage, and the hybrids were iontophoretically eluted from the nanoporous matrix. The optical and electrophoretic characterization of the analytes before and after the detection purification process revealed that low target DNA concentrations (80 pg/MUL) can be successfully detected in complex biological fluids and subsequently released to yield pure hybrids free of polydisperse digested DNA fragments and serum biomolecules. Taken together, this multifunctional platform is expected to enable seamless integration of detection and purification of nucleic acid biomarkers of pathogens and diseases in miniaturized diagnostic devices. PMID- 27244458 TI - Exploring medical undergraduates' perceptions of the educational value of a novel ENT iBook: a qualitative study. AB - Undergraduate otolaryngology exposure is limited. It may be consolidated by the use of an iBook as a self-study tool. Following invitation to participate by email, five focus groups were formed, each consisting of six medical students (18 female, 12 male, median age 23 years). The focus group transcripts were imported to the qualitative data analysis software NVivo (QSR International, UK). The iBook was found to have a clear and consistent presentation, and a focused and user-friendly style, with reasonable interactivity and a good range of well integrated media elements. It was, overall, perceived to be a valuable educational resource by the medical students. PMID- 27244456 TI - Proteasome activity is required for the initiation of precancerous pancreatic lesions. AB - Proteasome activity is significantly increased in advanced cancers, but its role in cancer initiation is not clear, due to difficulties in monitoring this process in vivo. We established a line of transgenic mice that carried the ZsGreen degron(ODC) (Gdeg) proteasome reporter to monitor the proteasome activity. In combination with Pdx-1-Cre;LSL-Kras(G12D) model, proteasome activity was investigated in the initiation of precancerous pancreatic lesions (PanINs). Normal pancreatic acini in Gdeg mice had low proteasome activity. By contrast, proteasome activity was increased in the PanIN lesions that developed in Gdeg;Pdx 1-Cre;LSL-Kras(G12D) mice. Caerulein administration to Gdeg;Pdx-1-Cre;LSL Kras(G12D) mice induced constitutive elevation of proteasome activity in pancreatic tissues and accelerated PanIN formation. The proteasome inhibitor markedly reduced PanIN formation in Gdeg;Pdx-1-Cre;LSL-Kras(G12D) mice (P = 0.001), whereas it had no effect on PanIN lesions that had already formed. These observations indicated the significance of proteasome activity in the initiation of PanIN but not the maintenance per se. In addition, the expressions of pERK and its downstream factors including cyclin D1, NF-kappaB, and Cox2 were decreased after proteasome inhibition in PanINs. Our studies showed activation of proteasome is required specifically for the initiation of PanIN. The roles of proteasome in the early stages of pancreatic carcinogenesis warrant further investigation. PMID- 27244459 TI - Depression among Low-Income Female Muslim Uyghur and Kazakh Informal Caregivers of Disabled Elders in Far Western China: Influence on the Caregivers' Burden and the Disabled Elders' Quality of Life. AB - BACKGROUND: Paying attention to and improving the mental health of the informal caregivers of disabled elders has become a global public health priority. This study focused on low-income female Uyghur and Kazakh informal caregivers of disabled elders residing in China's far west. It investigated the prevalence of and the major related factors of depressive emotion. METHODS: A cross-sectional study was performed from September 2013 to January 2014 in Shawan Prefectures, Tuokexun Prefectures, Bole Prefecture and Urumchi city. Shawan Prefecture has the highest proportion of Kazakhs, whereas Tuokexun Prefectures, Bole Prefecture and Urumchi city have the highest proportion of Uyghurs in Muslim ethnic Uygur and Kazakh communities. Xinjiang Uyghur Autonomous Region is located in remote western China; this area is approximately 3,105 km (1,929 miles) away from Beijing. A total of 444 female Uyghur and Kazakh informal caregivers of disabled elders participated in this study. The self-rating depression scale, the Zarit burden interview, and the SF-36 questionnaire were used to evaluate the state of caregiver depression, caregiver burden, and quality of life (QOL), respectively. Statistical analyses were performed using multivariate logistic regression analyses, correlation with Spearman's rho and independent-sample t-tests; a P value of <0.05 was considered statistically significant. RESULTS: Up to 38.5% (n = 217) of informal caregivers reported having depression, whereas 61.5% (n = 273) of them reported a lack of depression. Age of disabled elders more than 60 years old, total hours spent on caring daily>=8h, duration of caring>=5 years, negative self-evaluation of health condition, having caregiver burden, elders' medium degree of disability and elders' heavy degree of disability had a higher risk of caregiver depression. By contrast, daughter/daughter-in-law of disabled elders; unemployed carers, family's per capita income >US$235.48(1500 yuan), high social support, and high QOL of disabled elders were each associated with a lower risk of depressive emotion. Moreover, informal caregivers with depression obtained high care burden scores; at the same time, disabled elders who were looked after by caregivers with depression obtained low QOL scores. CONCLUSIONS: Our findings suggest that the demographics characteristics of informal caregivers, and caregiver burden, and the disabled elders' degree of disability and QOL had the most significant correlation with depressive emotion among women informal caregivers. The results had a enlighten that these variables should be considered while planning interventions to improve depression of informal caregivers. PMID- 27244460 TI - Changes in cerebral hemodynamics during a sleep-deprived video electroencephalogram in healthy children. AB - This study investigates the cerebral hemodynamic changes during a routine sleep deprived video-electroencephalogram (SD-VEEG) in healthy children. Forty-two children with normal intelligence were examined. The children were 5-14 years of age, and their electroencephalograms (EEGs) were within the normal range. Each subject was deprived of a routine night's sleep and then examined during non-drug induced sleep in the daytime. The awake and sleep stages were evaluated using EEGs, according to the American Academy of Sleep Medicine. Stable transcranial Doppler ultrasound (TCD) tracings through real-time TCD-VEEG monitoring were recorded. The mean systolic cerebral blood flow velocity (CBFV), diastolic CBFV, pulsatility index and resistance index of each artery were analyzed for 30 s per stage. A multivariate analysis of variance was conducted to compare the hemodynamic parameters for the awake stage versus light sleep and deep sleep stages. Non-rapid eye movement sleep was associated with an increased CBFV in the middle (164.38 +/- 27.28) and anterior cerebral artery (131.81 +/- 21.55) during light sleep (stages N1 and N2) (P = 0.0001), a reduced systolic CBFV in all vascular arteries (LMCA, 138.73 +/- 20.64; LACA, 108.33 +/- 22.33; LPCA, 83.9 +/- 18.6) during deep sleep (stage N3) compared with light sleep (P = 0.0001), and a sustained increased PI (LMCA, 0.92 +/- 0.13; LACA, 0.964 +/- 0.18) during deep sleep (P < 0.05). These findings indicate distinct cerebral hemodynamic alterations during SD-VEEG in children. This study utilized real-time TCD-VEEG monitoring during SD-EEG to further investigate neurovascular coupling in interictal epileptic discharges and understand its potential influence on cognition in the developing brain. PMID- 27244461 TI - Meteorological variability and infectious disease in Central Africa: a review of meteorological data quality. AB - Central African countries may bear high climate change-related infectious disease burdens because of preexisting high rates of disease, poor healthcare infrastructure, land use changes, and high environmental change vulnerabilities. However, making connections between climate and infectious diseases in this region is hampered by the paucity of high-quality meteorological data. This review analyzes the sources and quality of meteorological data used to study the interactions between weather and infectious diseases in Central African countries. Results show that 23% of studies used meteorological data that mismatched with the disease spatial scale of interest. Use of inappropriate weather data was most frequently identified in analyses using meteorological station data or gridded data products. These findings have implications for the interpretation of existing analyses and provide guidance for the use of climate data in future analyses of the connections between meteorology and infectious diseases in Central Africa. PMID- 27244462 TI - Variability in Amyotrophic Lateral Sclerosis. PMID- 27244463 TI - Radical Wrist Denervation and Preliminary Results. AB - Denervation is a well recognized procedure to treat degenerative or posttraumatic joint conditions, especially in cases where pain is a significant impediment to function even in the presence of stable and supple joint. However, this procedure currently is not as widely used for wrist surgeries as it merits. Denervation procedure obeys all-or-none phenomenon and we believe that even a few residual intact sensory fibers are able to transmit severe pain sensation and therefore every attempt should be made to target all the sensory supply to the wrist joint. In the present article a modified and radical technique using a single dorsal incision is proposed to address the hypothetical pitfalls of leaving undivided sensitive branches. Preliminary results of 21 cases operated on by this method are presented. PMID- 27244464 TI - Association Patterns of Simultaneous Intraventricular and Intraparenchymal Intracranial Pressure Measurements. AB - BACKGROUND: The process of measuring intracranial pressure (ICP) can be accomplished using a variety of monitors placed primarily either in the ventricles or brain parenchyma. OBJECTIVE: There is inadequate data to support the conclusion that ICP measured simultaneously from 2 different sites using 2 different devices produces similar findings in the same subject. The purpose of this study was to identify the correlation between simultaneous measurements from both an external ventricular drain (EVD) and an intraparenchymal monitor (IPM). METHODS: In this retrospective observational study, manual chart abstraction was used to obtain time-indexed ICP values during a period of 2 years from patients diagnosed with severe traumatic brain injury who had received simultaneous EVD and IPM placement. RESULTS: When all time points were compared, the correlation between EVD and IPM was strong (r = 0.6955). However, when limiting the ICP values to be <20 or <25 in either the EVD or the IPM, the correlation was noted to be weaker (r = 0.3576 and r = 0.4232, respectively). CONCLUSION: There is inadequate evidence to support that intraparenchymal ICP values can be treated in a similar manner to ICP values obtained from an EVD. ABBREVIATIONS: CSF, cerebrospinal fluidEVD, external ventricular drainICP, intracranial pressureIPM, intraparenchymal monitorTBI, traumatic brain injury. PMID- 27244465 TI - Combined Anterior and Posterior Lumbar Rhizotomy for Treatment of Mixed Dystonia and Spasticity in Children With Cerebral Palsy. AB - BACKGROUND: Children with cerebral palsy (CP) can present with severe secondary dystonia with or without associated spasticity of their extremities. OBJECTIVE: To assess the outcomes of combined anterior and posterior lumbar rhizotomy for the treatment of mixed hypertonia in the lower extremities of children with CP. METHODS: Fifty children with CP were subjected to combined anterior and posterior lumbar rhizotomies in a prospective study. Clinical outcome measurements were recorded preoperatively and were evaluated at 2, 6, and 12 months postoperatively. The operative techniques were performed by laminotomy from L1 S1, and intraoperative monitoring was used in all cases. All patients underwent intensive postoperative physiotherapy programs. RESULTS: Changes in muscle tone, joint range of motion, and dystonia were significant (P = .000) at postoperative assessment visits. CONCLUSION: This study demonstrated the potential of combined anterior and posterior lumbar rhizotomies to improve activities of daily living in children with CP and with mixed spasticity and dystonia. ABBREVIATIONS: BAD, Barry-Albright Dystonia ScaleCAPR, combined anterior and posterior lumbar rhizotomyCP, cerebral palsyITB, intrathecal baclofenMAS, modified Ashworth ScaleROM, range of motionSDR, selective dorsal rhizotomy. PMID- 27244467 TI - Surgery for Nontumoral Insular Epilepsy Explored by Stereoelectroencephalography. AB - BACKGROUND: Hidden by the perisylvian operculi, insular cortex has long been underexplored in the context of epilepsy surgery. Recent studies advocated stereoelectroencephalography (SEEG) as a reliable tool to explore insular cortex and its involvement in intractable epilepsy and suggested that insular seizures could be an underestimated entity. However, the results of insular resection to treat pharmacoresistant epilepsy are rarely reported. OBJECTIVE: We report 6 consecutive cases of right insular resection performed based on anatomoelectroclinical correlations provided by SEEG. METHODS: Six right-handed patients (3 male, 3 female) with drug-resistant epilepsy underwent comprehensive presurgical evaluation. Based on video electroencephalographic recordings, they all underwent SEEG evaluation with bilateral (n = 4) or unilateral right (n = 2) insular depth electrode placement. All patients had both orthogonal and oblique (1 anterior, 1 posterior) insular electrodes (n = 4-6 electrodes). Preoperative magnetic resonance imaging findings were normal in 4 patients, 1 patient had right insular focal cortical dysplasia, and 1 patient had a right opercular postoperative scar (cavernous angioma). All patients underwent right partial insular corticectomy via the subpial transopercular approach. RESULTS: Intracerebral recordings demonstrated an epileptogenic zone confined to the right insula in all patients. After selective insular resection, 5 of 6 patients were seizure free (Engel class I) with a mean follow-up of 36.2 months (range, 18-68 months). Histological findings revealed focal cortical dysplasia in 5 patients and a gliosis scar in 1 patient. All patients had minor transient neurological deficit (eg, facial paresis, dysarthria). CONCLUSION: Insular resection based on SEEG findings can be performed safely with a significant chance of seizure freedom. ABBREVIATIONS: EEG, electroencephalographyEZ, epileptic zoneFCD, focal cortical dysplasiaILE, insular lobe epilepsySEEG, stereoelectroencephalography. PMID- 27244466 TI - Neuroprotective Effects of Valproic Acid on Blood-Brain Barrier Disruption and Apoptosis-Related Early Brain Injury in Rats Subjected to Subarachnoid Hemorrhage Are Modulated by Heat Shock Protein 70/Matrix Metalloproteinases and Heat Shock Protein 70/AKT Pathways. AB - BACKGROUND: Blood-brain barrier (BBB) disruption and neural apoptosis are thought to promote early brain injury (EBI) after subarachnoid hemorrhage (SAH). Previous studies have demonstrated that valproic acid (VPA) decreased brain injury in a prechiasmatic injection model of SAH in mice. It should be noted that the beneficial effects of VPA and the underlying mechanisms have not been fully elucidated. OBJECTIVE: To characterize the effects of VPA on BBB disruption and neural apoptosis and to determine mechanisms involved in EBI after SAH. METHODS: An endovascular perforation model was used to induce SAH in rats. VPA (300 mg/kg) was promptly administered after SAH induction, and the same dose was given 12 hours later. Quercetin (100 mg/kg), an inhibitor of heat shock protein 70 (HSP70), was injected into the peritoneum 2 hours before SAH induction. Mortality, SAH grades, neurological function, Evans Blue extravasation, brain edema, transmission electron microscopy, Western blot, double fluorescence labeling, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling staining also were used. RESULTS: VPA treatment decreased BBB disruption and brain edema, attenuated neural apoptosis, and improved neurobehavioral functions in EBI after SAH. Double fluorescence labeling indicated that matrix metallopeptidase 9 (MMP-9) was located predominately in neurons and endothelial cells. VPA upregulated the expression of HSP70, effectively decreased the expression and activity of MMP-9, and reduced claudin-5 and occludin degradation. Meanwhile, VPA also upregulated the expression of phosphorylated Akt and bcl-2. Both the anti-BBB disruption and antiapoptotic effects of VPA were abolished by quercetin. CONCLUSION: VPA prevented BBB disruption and alleviated neural apoptosis after SAH. The action of VPA appeared to be mediated though the HSP70/MMPs and HSP70/Akt pathways. ABBREVIATIONS: BBB, blood-brain barrierEBI, early brain injuryHSP, heat shock proteinMMP, matrix metalloproteinasePBS, phosphate-buffered salineSAH, subarachnoid hemorrhageTUNEL, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelingVPA, valproic acid. PMID- 27244468 TI - Endoventricular Deep Brain Stimulation of the Third Ventricle: Proof of Concept and Application to Cluster Headache. AB - BACKGROUND: The third ventricle (3rd V) is surrounded by centers related to satiety, homeostasis, hormones, sleep, memory, and pain. Stimulation of the wall of the 3rd V could be useful to treat disorders related to dysfunction of the hypothalamus. OBJECTIVE: To assess safety and efficacy of endoventricular electrical stimulation of the hypothalamus using a floating deep brain stimulation (DBS) lead laid on the floor of the 3rd V to treat refractory cluster headaches (CH). METHODS: Seven patients, aged 24 to 60 years, experiencing chronic CH (mean chronic duration 5.8 +/- 2.5 years) were enrolled in this pilot, prospective, open study assessing the safety and potential efficacy of chronic DBS of the 3rd V. Number of attacks was collected during baseline and was compared with those occurring at 3, 6, and 12 months postoperation. Any side effects that occurred during or after surgery were reported. Effect on mood was assessed using the Hospital Anxiety and Depression scale during baseline and at 6 and 12 months postoperation. RESULTS: Insertion of the lead into the posterior 3rd V and chronic stimulation was feasible and safe in all patients. The voltage ranged from 0.9 to 2.3 volts. The most common side effect was transient trembling vision during stimulation. At 12 months, 3 of 7 patients were pain free, 2 had 90% improvement, 1 of 7 had 75% improvement, and 1 of 7 was not significantly improved. CONCLUSION: This proof of concept demonstrates the feasibility, safety, and potential efficacy of 3rd V DBS using an endoventricular road that could be applied to treat various diseases involving hypothalamic areas. ABBREVIATIONS: CCH, chronic cluster headacheCH, cluster headacheDBS, deep brain stimulationHAD, hospital anxiety depressionONS, occipital nerve stimulationPAG, periaqueductal gray matterPH, posterior hypothalamusPVG, periventricular gray matter3rd V, third ventricle. PMID- 27244469 TI - The Effect of Lumbar Spinal Muscle on Spinal Sagittal Alignment: Evaluating Muscle Quantity and Quality. AB - BACKGROUND: The majority of earlier studies of the parameters of sagittal balance did not consider the influence of spinal muscles on spinal sagittal alignment. OBJECTIVE: To analyze the relationship between the paraspinal muscle (quantity and quality) and sagittal alignment in elderly patients. METHODS: We reviewed 50 full-spine lateral standing radiographs and lumbar magnetic resonance images of elderly patients at a single center. The radiographic parameters examined were thoracic kyphosis, lumbar lordosis (LL), sagittal vertical axis, pelvic tilt, sacral slope, and pelvic incidence (PI). The lumbar muscularity (LM; quantity) and fatty degeneration ratio (FD; quality) in the paraspinal muscle were measured at the L3 level on magnetic resonance images. The relationships between the parameters, LM, and FD were analyzed with the Pearson correlation coefficient and multiple linear regression. RESULTS: Pearson analysis demonstrated that the FD had significant correlations with age (r = 0.393), thoracic kyphosis (r = 0.559), pelvic tilt (r = 0.430), sagittal vertical axis (r = 0.488), and PI - LL (r = 0.479, P < .05), and a close negative correlation was found between the FD and LL (r = -0.505, P < .01). The LM had significant correlations with the LL (r = 0.342) and PI - LL (r = -0.283, P < .05). Regression models that controlled for confounding factors such as body mass index confirmed the correlations between the above parameters and FD (P < .05). CONCLUSION: The quality of the paraspinal muscle could be one of the various factors that influence sagittal balance. ABBREVIATIONS: BMI, body mass indexCSA, cross-sectional areaFD, fatty degeneration ratioLL, lumbar lordosisLM, lumbar muscularityPI, pelvic incidencePT, pelvic tiltSC, subcutaneous fatSS, sacral slopeSVA, sagittal vertical axisTK, thoracic kyphosisVB, vertebral body. PMID- 27244470 TI - Non-Temperature Induced Effects of Magnetized Iron Oxide Nanoparticles in Alternating Magnetic Field in Cancer Cells. AB - This paper reports the damaging effects of magnetic iron-oxide nanoparticles (MNP) on magnetically labeled cancer cells when subjected to oscillating gradients in a strong external magnetic field. Human breast cancer MDA-MB-231 cells were labeled with MNP, placed in the high magnetic field, and subjected to oscillating gradients generated by an imaging gradient system of a 9.4T preclinical MRI system. Changes in cell morphology and a decrease in cell viability were detected in cells treated with oscillating gradients. The cytotoxicity was determined qualitatively and quantitatively by microscopic imaging and cell viability assays. An approximately 26.6% reduction in cell viability was detected in magnetically labeled cells subjected to the combined effect of a static magnetic field and oscillating gradients. No reduction in cell viability was observed in unlabeled cells subjected to gradients, or in MNP labeled cells in the static magnetic field. As no increase in local temperature was observed, the cell damage was not a result of hyperthermia. Currently, we consider the coherent motion of internalized and aggregated nanoparticles that produce mechanical moments as a potential mechanism of cell destruction. The formation and dynamics of the intracellular aggregates of nanoparticles were visualized by optical and transmission electron microscopy (TEM). The images revealed a rapid formation of elongated MNP aggregates in the cells, which were aligned with the external magnetic field. This strategy provides a new way to eradicate a specific population of MNP-labeled cells, potentially with magnetic resonance imaging guidance using standard MRI equipment, with minimal side effects for the host. PMID- 27244472 TI - Pyrrolizidine Alkaloids from Echium vulgare in Honey Originate Primarily from Floral Nectar. AB - Pyrrolizidine alkaloids (PAs) in honey can be a potential human health risk. So far, it has remained unclear whether PAs in honey originate from pollen or floral nectar. We obtained honey, nectar, and plant pollen from two observation sites where Echium vulgare L. was naturally abundant. The PA concentration of honey was determined by targeted analysis using a high pressure liquid chromatography-mass spectrometry system (HPLC-MS/MS), allowing the quantification of six different PAs and PA-N-oxides present in E. vulgare. Echium-type PAs were detected up to 0.153 MUg/g in honey. Nectar and plant pollen were analyzed by nontargeted analysis using ultrahigh pressure liquid chromatography-high resolution-mass spectrometry (UHPLC-HR-MS), allowing the detection of 10 alkaloids in small size samples. Echium-type PAs were detected between 0.3-95.1 MUg/g in nectar and 500 35000 MUg/g in plant pollen. The PA composition in nectar and plant pollen was compared to the composition in honey. Echimidine (+N-oxide) was the main alkaloid detected in honey and nectar samples, while echivulgarine (+N-oxide) was the main PA found in plant pollen. These results suggest that nectar contributes more significantly to PA contamination in honey than plant pollen. PMID- 27244473 TI - X-ray and Electron Spectroscopy of Water. AB - Here we present an overview of recent developments of X-ray and electron spectroscopy to probe water at different temperatures. Photon-induced ionization followed by detection of electrons from either the O 1s level or the valence band is the basis of photoelectron spectroscopy. Excitation between the O 1s and the unoccupied states or occupied states is utilized in X-ray absorption and X-ray emission spectroscopies. These techniques probe the electronic structure of the liquid phase and show sensitivity to the local hydrogen-bonding structure. Both experimental aspects related to the measurements and theoretical simulations to assist in the interpretation are discussed in detail. Different model systems are presented such as the different bulk phases of ice and various adsorbed monolayer structures on metal surfaces. PMID- 27244471 TI - Computational, electrochemical, and spectroscopic studies of two mononuclear cobaloximes: the influence of an axial pyridine and solvent on the redox behaviour and evidence for pyridine coordination to cobalt(i) and cobalt(ii) metal centres. AB - [Co(dmgBF2)2(H2O)2] (where dmgBF2 = difluoroboryldimethylglyoximato) was used to synthesize [Co(dmgBF2)2(H2O)(py)].0.5(CH3)2CO (where py = pyridine) in acetone. The formulation of complex was confirmed by elemental analysis, high resolution MS, and various spectroscopic techniques. The complex [Co(dmgBF2)2(solv)(py)] (where solv = solvent) was readily formed in situ upon the addition of pyridine to complex . A spectrophotometric titration involving complex and pyridine proved the formation of such a species, with formation constants, log K = 5.5, 5.1, 5.0, 4.4, and 3.1 in 2-butanone, dichloromethane, acetone, 1,2-difluorobenzene/acetone (4 : 1, v/v), and acetonitrile, respectively, at 20 degrees C. In strongly coordinating solvents, such as acetonitrile, the lower magnitude of K along with cyclic voltammetry, NMR, and UV-visible spectroscopic measurements indicated extensive dissociation of the axial pyridine. In strongly coordinating solvents, [Co(dmgBF2)2(solv)(py)] can only be distinguished from [Co(dmgBF2)2(solv)2] upon addition of an excess of pyridine, however, in weakly coordinating solvents the distinctions were apparent without the need for excess pyridine. The coordination of pyridine to the cobalt(ii) centre diminished the peak current at the Epc value of the Co(I/0) redox couple, which was indicative of the relative position of the reaction equilibrium. Herein we report the first experimental and theoretical (59)Co NMR spectroscopic data for the formation of Co(i) species of reduced cobaloximes in the presence and absence of py (and its derivatives) in CD3CN. From spectroelectrochemical studies, it was found that pyridine coordination to a cobalt(i) metal centre is more favourable than coordination to a cobalt(ii) metal centre as evident by the larger formation constant, log K = 4.6 versus 3.1, respectively, in acetonitrile at 20 degrees C. The electrosynthesis of hydrogen by complexes and in various solvents demonstrated the dramatic effects of the axial ligand and the solvent on the turnover number of the respective catalyst. PMID- 27244474 TI - Contribution of Antibody Hydrodynamic Size to Vitreal Clearance Revealed through Rabbit Studies Using a Species-Matched Fab. AB - We have developed a tool Fab fragment of a rabbit monoclonal antibody that is useful for early evaluation in rabbit models of technologies for long acting delivery (LAD) of proteins to the eye. Using this Fab we show that vitreal clearance can be slowed through increased hydrodynamic size. Fab (G10rabFab) and Fab' (G10rabFab') fragments of a rabbit monoclonal antibody (G10rabIgG) were expressed in Chinese hamster ovary (CHO) cells and purified using antigen-based affinity chromatography. G10rabFab retains antigen-binding upon thermal stress (37 degrees C) for 8 weeks in phosphate-buffered saline (PBS) and can be detected in rabbit tissues using an antigen-based ELISA. Hydrodynamic radius, measured using quasi-elastic light scattering (QELS), was increased through site specific modification of the G10rabFab' free cysteine with linear methoxy polyethylene glycol(PEG)-maleimide of 20000 or 40000 molecular weight. Pharmacokinetic studies upon intravitreal dosing in New Zealand white rabbits were conducted on the G10rabFab and PEGylated G10rabFab'. Results of single and multidose pharmacokinetic experiments yield reproducible results and a vitreal half-life for G10rabFab of 3.2 days. Clearance from the eye is slowed through increased hydrodynamic size, with vitreal half-life showing a linear dependence on hydrodynamic radius (RH). A linear dependence of vitreal half-life on RH suggests that molecule diffusivity makes an important contribution to vitreal clearance. A method for prediction of vitreal half-life from RH measurements is proposed. PMID- 27244475 TI - "Presumed fair: Ironic effects of organizational diversity structures": Correction to Kaiser et al. (2013). AB - Reports an error in "Presumed fair: Ironic effects of organizational diversity structures" by Cheryl R. Kaiser, Brenda Major, Ines Jurcevic, Tessa L. Dover, Laura M. Brady and Jenessa R. Shapiro (Journal of Personality and Social Psychology, 2013[Mar], Vol 104[3], 504-519). In the article, a raw data merging error in one racial discrimination claim condition from Experiment 6 inadvertently resulted in data analyses on an inaccurate data set. When the error was discovered by the authors and corrected, all analyses reported in Experiment 6 for claim validity, seriousness of the claim, and support for the claimant were inaccurate and none were statistically significant. The conclusions should be altered to indicate that participants with management experience who reflected on their own workplace diversity policies did not show the predicted effects. The literature review, remaining five studies, and remaining conclusions in the article are unaffected by this error. Experiment 6 should also report that 26.4% (not 26.4.7%) of participants had a graduate degree and eight participants (not 8%) did not provide educational data. Experiment 5 should have referred to the claim validity measure as a six-item measure ( .92) rather than a five-item measure; analyses on claim validity are accurate in text. Table 2's note should have said standard errors, not standard deviations. (The following abstract of the original article appeared in record 2012-31077-001.) This research tests the hypothesis that the presence (vs. absence) of organizational diversity structures causes high-status group members (Whites, men) to perceive organizations with diversity structures as procedurally fairer environments for underrepresented groups (racial minorities, women), even when it is clear that underrepresented groups have been unfairly disadvantaged within these organizations. Furthermore, this illusory sense of fairness derived from the mere presence of diversity structures causes high-status group members to legitimize the status quo by becoming less sensitive to discrimination targeted at underrepresented groups and reacting more harshly toward underrepresented group members who claim discrimination. Six experiments support these hypotheses in designs using 4 types of diversity structures (diversity policies, diversity training, diversity awards, idiosyncratically generated diversity structures from participants' own organizations) among 2 high-status groups in tests involving several types of discrimination (discriminatory promotion practices, adverse impact in hiring, wage discrimination). Implications of these experiments for organizational diversity and employment discrimination law are discussed. (PsycINFO Database Record PMID- 27244476 TI - Light-Triggered Release of Biomolecules from Diamond Nanowire Electrodes. AB - The controlled release of biomolecules from a substrate surface is a challenging task. Photocleavable linkers appear as attractive candidates for light-triggered delivery. We show here the possibility of creating photoactivable diamond nanowire interfaces, from which molecules can be photochemically released upon irradiation at 365 nm for several minutes. The approach is based on the covalent modification of boron-doped diamond nanowires (BDD NWs) with o-nitrobenzyl containing ligands, to which different biomolecules can be attached via amide bond formation. The photodecomposition reaction and the subsequent release of small proteins such as lysozyme or enzymes such as horseradish peroxidase (HRP) are investigated using electrochemical impedance spectroscopy. Using a colorimetric assay, we demonstrate that, while complete cleavage of HRP was achieved upon irradiation for 10 min at 1 W cm(-2), this exposure time resulted in a partial loss of enzymatic activity. PMID- 27244478 TI - All-Dielectric Antenna Wavelength Router with Bidirectional Scattering of Visible Light. AB - An optical antenna forms the subwavelength bridge between free space optical radiation and localized electromagnetic energy. Its localized electromagnetic modes strongly depend on its geometry and material composition. Here, we present the design and experimental realization of a novel V-shaped all-dielectric antenna based on high-index amorphous silicon with a strong magnetic dipole resonance in the visible range. As a result, it exhibits extraordinary bidirectional scattering into diametrically opposite directions. The scattering direction is effectively controlled by the incident wavelength, rendering the antenna a passive bidirectional wavelength router. A detailed multipole decomposition analysis reveals that the excitation and abrupt phase change of an out-of-plane polarized magnetic dipole and an in-plane electric quadrupole are essential for the directivity switching. Previously, noble metals have been extensively exploited for plasmonic directional nanoantenna design. However, these inevitably suffer from high intrinsic ohmic losses and a relatively weak magnetic response to the incident light. Compared to a similar gold plasmonic nanoantenna design, we show that the silicon-based antennas demonstrate stronger magnetic scattering with minimal absorption losses. Our results indicate that all dielectric antennas will open exciting possibilities for efficient manipulation of light-matter interactions. PMID- 27244477 TI - Few Amino Acid Exchanges Expand the Substrate Spectrum of Monocarboxylate Transporter 10. AB - Monocarboxylate transporters (MCTs) belong to the SLC16 family within the major facilitator superfamily of transmembrane transporters. MCT8 is a thyroid hormone transporter mutated in the Allan-Herndon-Dudley syndrome, a severe psychomotor retardation syndrome. MCT10 is closely related to MCT8 and is known as T-type amino acid transporter. Both transporters mediate T3 transport, but although MCT8 also transports rT3 and T4, these compounds are not efficiently transported by MCT10, which, in contrast, transports aromatic amino acids. Based on the 58% amino acid identity within the transmembrane regions among MCT8 and MCT10, we reasoned that substrate specificity may be primarily determined by a small number of amino acid differences between MCT8 and MCT10 along the substrate translocation channel. Inspecting the homology model of MCT8 and a structure guided alignment between both proteins, we selected 8 amino acid positions and prepared chimeric MCT10 proteins with selected amino acids changed to the corresponding amino acids in MCT8. The MCT10 mutant harboring 8 amino acid substitutions was stably expressed in Madin-Darby canine kidney 1 cells and found to exhibit T4 transport activity. We then successively reduced the number of amino acid substitutions and eventually identified a minimal set of 2-3 amino acid exchanges which were sufficient to allow T4 transport. The resulting MCT10 chimeras exhibited KM values for T4 similar to MCT8 but transported T4 at a slower rate. The acquisition of T4 transport by MCT10 was associated with complete loss of the capacity to transport Phe, when Tyr184 was mutated to Phe. PMID- 27244479 TI - Brief report: Changes in parent-adolescent joint activities between 2002 and 2014 in the Czech Republic, Health Behaviour in School-aged Children (HBSC) study. AB - Joint family activities (JFA) are linked to healthy adolescent development. The aim of the present study is to report time trends in JFA between 2002 and 2014. The sample concerned 16 396 adolescents aged 11, 13, and 15 years (48.4% boys) from the 2002, 2006, 2010, and 2014 surveys of the Health Behaviour in School aged Children (HBSC) study in the Czech Republic. The overall changes in JFA were evaluated using logistic regression. Compared with 2002, there was a slight increase in four out of the six selected JFA in 2014. In particular, the likelihood of engaging in joint active activities (sports and walks) increased in the 2002-2014 period. Conversely, nowadays adolescents watch TV with their parents less frequently. Moreover, families today do not eat together as often as in 2002, which might have negative consequences for healthy adolescent development. Adolescents aged 11 get involved in JFA more than their older counterparts. PMID- 27244480 TI - Photorelease and Cellular Delivery of Mitocurcumin from Its Cytotoxic Cobalt(III) Complex in Visible Light. AB - Ternary cobalt(III) complexes of curcumin (Hcur) and mitocurcumin [Hmitocur, a dicationic bis(triphenylphosphonium) derivative of curcumin] having a tetradentate phenolate-based ligand (H2L), namely, [Co(cur)(L)] (1) and [Co(mitocur)(L)]Cl2 (2), were prepared and structurally characterized, and their photoinduced cytotoxicity was studied. The diamagnetic cobalt(III) complexes show an irreversible Co(III)-Co(II) redox response and a quasireversible curcuminoid based reduction near -1.45 and -1.74 V SCE, respectively, in DMF/0.1 M [(n)Bu4N](ClO4). The complexes exhibit a curcumin/mitocurcumin-based absorption band near 420 nm. Complex 1 was structurally characterized by X-ray crystallography. The structure contains the metal in a CoN2O4 distorted octahedral coordination arrangement with curcumin binding to the metal in its enolic form. Binding to cobalt(III) increases the hydrolytic stability of curcumin. Complex 2, having a dicationic curcuminoid, shows significant cellular uptake and photoinduced cytotoxicity compared to its curcumin analogue 1. The dicationic cobalt(III) complex 2 has significantly better cellular uptake and bioactivity than the neutral species 1. Complex 2 with mitochondrial localization releases the mitocurcumin dye upon exposure to visible light (400-700 nm) in human breast cancer MCF-7 cells through photoreduction of cobalt(III) to cobalt(II). Complex 2 displays a remarkable photodynamic therapy (PDT) effect, giving an IC50 value of ~3.9 MUM in visible light (400-700 nm) in MCF-7 cells while being much less toxic in the dark (>50 MUM). The released mitocurcumin acts as a phototoxin, generating intracellular reactive oxygen species (ROSs). The overall process leads to light-controlled delivery of a curcuminoid (mitocur) into the tumor cells while the dye alone suffers from hydrolytic instability and poor bioavailability. PMID- 27244481 TI - Toward Smarter Lumping and Smarter Splitting: Rethinking Strategies for Sepsis and Acute Respiratory Distress Syndrome Clinical Trial Design. AB - Both quality improvement and clinical research efforts over the past few decades have focused on consensus definition of sepsis and acute respiratory distress syndrome (ARDS). Although clinical definitions based on readily available clinical data have advanced recognition and timely use of broad supportive treatments, they likely hinder the identification of more targeted therapies that manipulate select biological mechanisms underlying critical illness. Sepsis and ARDS are by definition heterogeneous, and patients vary in both their underlying biology and their severity of illness. We have long been able to identify subtypes of sepsis and ARDS that confer different prognoses. The key is that we are now on the verge of identifying subtypes that may confer different response to therapy. In this perspective, inspired by a 2015 American Thoracic Society International Conference Symposium entitled "Lumpers and Splitters: Phenotyping in Critical Illness," we highlight promising approaches to uncovering patient subtypes that may predict treatment responsiveness and not just differences in prognosis. We then discuss how this information can be leveraged to improve the success and translatability of clinical trials by using predictive enrichment and other design strategies. Last, we discuss the challenges and limitations to identifying biomarkers and endotypes and incorporating them into routine clinical practice. PMID- 27244482 TI - Corrigendum: Integration of CdSe/CdSexTe1-x Type-II Heterojunction Nanorods into Hierarchically Porous TiO2 Electrode for Efficient Solar Energy Conversion. PMID- 27244483 TI - A Method for Continuous (239)Pu Determinations in Arctic and Antarctic Ice Cores. AB - Atmospheric nuclear weapons testing (NWT) resulted in the injection of plutonium (Pu) into the atmosphere and subsequent global deposition. We present a new method for continuous semiquantitative measurement of (239)Pu in ice cores, which was used to develop annual records of fallout from NWT in ten ice cores from Greenland and Antarctica. The (239)Pu was measured directly using an inductively coupled plasma-sector field mass spectrometer, thereby reducing analysis time and increasing depth-resolution with respect to previous methods. To validate this method, we compared our one year averaged results to published (239)Pu records and other records of NWT. The (239)Pu profiles from the Arctic ice cores reflected global trends in NWT and were in agreement with discrete Pu profiles from lower latitude ice cores. The (239)Pu measurements in the Antarctic ice cores tracked low latitude NWT, consistent with previously published discrete records from Antarctica. Advantages of the continuous (239)Pu measurement method are (1) reduced sample preparation and analysis time; (2) no requirement for additional ice samples for NWT fallout determinations; (3) measurements are exactly coregistered with all other chemical, elemental, isotopic, and gas measurements from the continuous analytical system; and (4) the long half-life means the (239)Pu record is stable through time. PMID- 27244484 TI - New Pb(Mg1/3Nb2/3)O3-Pb(In1/2Nb1/2)O3-PbZrO3-PbTiO3 Quaternary Ceramics: Morphotropic Phase Boundary Design and Electrical Properties. AB - Four series of Pb(Mg1/3Nb2/3)O3-Pb(In1/2Nb1/2)O3-PbZrO3-PbTiO3 (PMN-PIN-PZ-PT) quaternary ceramics with compositions located at the morphotropic phase boundary (MPB) regions were prepared. The MPBs of the multicomponent system were predicted using a linear combination rule and experimentally confirmed by X-ray powder diffraction and electrical measurement. The positions of MPBs in multicomponent systems were found in linear correlation with the tolerance factor and ionic radii of non-PT end-members. The phase structure, piezoelectric coefficient, electromechanical coupling coefficient, unipolar strains, and dielectric properties of as-prepared ceramics were systematically investigated. The largest d33s were obtained at S36.8, L37.4, M39.6, and N35.8, with the corresponding values of 580, 450, 420, and 530 pC/N, respectively, while the largest kps were found at S34.8, L37.4, M39.6, and N35.8, with the respective values of 0.54, 0.50, 0.47, and 0.53. The largest unipolar strain Smax and high-field piezoelectric strain coefficients d33* were also observed around the respective MPB regions. The rhombohedral-to-tetragonal phase transition temperature Trt increased with increasing PIN and PZ contents. Of particular importance is that high Trt of 140-197 degrees C was achieved in the M series with PZ and PIN contents being around 0.208 and 0.158, which will broaden the temperature usage range. PMID- 27244485 TI - Discovery of New Chemical Entities for Old Targets: Insights on the Lead Optimization of Chromone-Based Monoamine Oxidase B (MAO-B) Inhibitors. AB - The discovery of new chemical entities endowed with potent, selective, and reversible monoamine oxidase B inhibitory activity is a clinically relevant subject. Therefore, a small library of chromone derivatives was synthesized and screened toward human monoamine oxidase isoforms (hMAO-A and hMAO-B). The structure-activity relationships studies strengthen the importance of the amide spacer and the direct linkage of carbonyl group to the gamma-pyrone ring, along with the presence of meta and para substituents in the exocyclic ring. The most potent MAO-B inhibitors were N-(3'-chlorophenyl)-4-oxo-4H-chromene-3-carboxamide (20) (IC50 = 403 pM) and N-(3',4'-dimethylphenyl)-4-oxo-4H-chromene-3-carboxamide (27) (IC50 = 669 pM), acting as competitive and noncompetitive reversible inhibitors, respectively. Computational docking studies provided insights into enzyme-inhibitor interactions and a rationale for the observed selectivity and potency. Compound 27 stands out due to its favorable toxicological profile and physicochemical properties, which pointed toward blood-brain barrier permeability, thus being a valid candidate for subsequent animal studies. PMID- 27244486 TI - The molecular, temporal and region-specific requirements of the beta isoform of Calcium/Calmodulin-dependent protein kinase type 2 (CAMK2B) in mouse locomotion. AB - Genetic approaches using temporal and brain region-specific restricted gene deletions have provided a wealth of insight in the brain regions and temporal aspects underlying spatial and associative learning. However, for locomotion such extensive studies are still scarce. Previous studies demonstrated that Camk2b(-/ ) mice, which lack the beta isoform of Calcium/Calmodulin-dependent protein kinase 2 (CAMK2B), show very severe locomotion deficits. However, where these locomotion deficits originate is unknown. Here we made use of novel Camk2b mutants (Camk2b(f/f) and Camk2b(T287A)), to explore the molecular, temporal and brain region-specific requirements of CAMK2B for locomotion. At the molecular level we found that normal locomotion requires Calcium/Calmodulin mediated activation of CAMK2B, but CAMK2B autonomous activity is largely dispensable. At a systems level, we found that global deletion of Camk2b in the adult mouse causes only mild locomotion deficits, suggesting that the severe locomotion deficits of Camk2b(-/-) mice are largely of developmental origin. However, early onset deletion of Camk2b in cerebellum, striatum or forebrain did not recapitulate the locomotion deficits, suggesting that these deficits cannot be attributed to a single brain area. Taken together, these results provide the first insights into the molecular, temporal and region-specific role of CAMK2B in locomotion. PMID- 27244487 TI - International trends in liver cancer incidence, overall and by histologic subtype, 1978-2007. AB - Primary liver cancer, the most common histologic types of which are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), is the second leading cause of cancer death worldwide. While rising incidence of liver cancer in low-risk areas and decreasing incidence in some high-risk areas has been reported, trends have not been thoroughly explored by country or by histologic type. We examined liver cancer incidence overall and by histology by calendar time and birth cohort for selected countries between 1978 and 2007. For each successive 5-year period, age-standardized incidence rates were calculated from volumes V-IX of the Cancer Incidence in Five Continents electronic database (CI5plus) and the newly released CI5X (volume X) database. Wide global variations persist in liver cancer incidence. Rates of liver cancer remain highest in Asian countries, specifically Eastern and South-Eastern Asian countries. While rates in most of these high-risk countries have been decreasing in recent years, rates in India and several low-risk countries of Africa, Europe, the Americas, and Oceania have been on the rise. Liver cancer rates by histologic type tend to convey a similar temporal profile. However, in Thailand, France, and Italy, ICC rates have increased while HCC rates have declined. We expect rates in high-risk countries to continue to decrease, as the population seroprevalence of hepatitis B virus (HBV) continues to decline. In low-risk countries, targeted screening and treatment of the hepatitis C virus (HCV), treatment of diabetes and primary prevention of obesity, will be key in reducing future liver cancer incidence. PMID- 27244532 TI - Developmental Design of Synthetic Bacterial Architectures by Morphogenetic Engineering. AB - Synthetic biology is an emerging scientific field that promotes the standardized manufacturing of biological components without natural equivalents. Its goal is to create artificial living systems that can meet various needs in health care or energy domains. While most works are focused on the individual bacterium as a chemical reactor, our project, SynBioTIC, addresses a novel and more complex challenge: shape engineering; that is, the redesign of natural morphogenesis toward a new kind of developmental 3D printing. Potential applications include organ growth, natural computing in biocircuits, or future vegetal houses. To create in silico multicellular organisms that exhibit specific shapes, we construe their development as an iterative process combining fundamental collective phenomena such as homeostasis, patterning, segmentation, and limb growth. Our numerical experiments rely on the existing Escherichia coli simulator Gro, a physicochemical computation platform offering reaction-diffusion and collision dynamics solvers. The synthetic bioware of our model executes a set of rules, or genome, in each cell. Cells can differentiate into several predefined types associated with specific actions (divide, emit signal, detect signal, die). Transitions between types are triggered by conditions involving internal and external sensors that detect various protein levels inside and around the cell. Indirect communication between bacteria is relayed by morphogen diffusion and the mechanical constraints of 2D packing. Starting from a single bacterium, the overall architecture emerges in a purely endogenous fashion through a series of developmental stages, inlcuding proliferation, differentiation, morphogen diffusion, and synchronization. The genome can be parametrized to control the growth and features of appendages individually. As exemplified by the L and T shapes that we obtain, certain precursor cells can be inhibited while others can create limbs of varying size (divergence of the homology). Such morphogenetic phenotypes open the way to more complex shapes made of a recursive array of core bodies and limbs and, most importantly, to an evolutionary developmental exploration of unplanned functional forms. PMID- 27244533 TI - Local spatial distortion caused by simple geometrical figures. AB - Dynamic distortion of the visual field has been shown to affect perceptual judgment of visual dimensions such as size, length, and distance. Here, we report four experiments demonstrating that the different aspects of a triangle differently influence judgments of distance. Specifically, when the base of the triangle faces the centre of the display, participants consistently underestimate and overestimate the distance of a small dot from the unmarked centre of the display relative to conditions in which the vertex of the triangle faces the centre. When the dot is close to the figure, the distance of the dot to the centre is underestimated. Conversely, when the dot is close to the figure, the distance to the centre is overestimated. The effect is replicated when the internal distances are equalized and when ellipses are used instead of triangles. These results support a ripple model of spatial distortion in which local curvature acts to attract or repel objects. In conclusion, we suggest some implications of our findings for theories of perceptual organization. PMID- 27244531 TI - The Distribution of Human Stem Cell-like Memory T Cell in Lung Cancer. AB - Human stem cell-like memory T (Tscm) cells are long-lived, self-renewing memory lymphocytes that can differentiate into effector cells and mediate strong antitumour response in murine model. The distribution and function of Tscm cells in human lung cancer remain unknown. In this study, we investigated the properties of human Tscm cells in the blood and lymph node of non-small cell lung cancer (NSCLC) patients. There were more CD4 Tscm cells in blood from NSCLC patients than from healthy donors, fewer CD4 and CD8 TSCM cells in blood than in lymph node from NSCLC patients. To further analyze their properties, we stimulated peripheral blood mononuclear cells from NSCLC patients by mitogens to examine cytokine production. Our data suggest that both CD4 and CD8 Tscm cells in blood produced interferon-gamma significantly increased in NSCLC patients compare with healthy subjects. In addition, fewer Tscm cells produced interferon-gamma in lymph node than in blood from NSCLC patients. Our results strongly suggest that the distribution and function of CD4 Tscm cells in NSCLC patients is upregulated. Understanding of the properties of stem-like memory T cells will supply a good rationale for designing the new adoptive immunotherapy in cancer. PMID- 27244534 TI - Left atrial appendage closure for prevention of cardioembolic events. AB - Atrial fibrillation (AF) is the most common atrial arrhythmia, with a prevalence of 1-2% in the general population. It increases with age, affecting approximately 7% of individuals age >65 years and 15-20% of octogenarians. The human left atrium has a blind sac-like remnant, called left atrial appendage (LAA). It originates from a primordial pulmonary vein. Due to its complicated structure, blind end and inner surface trabeculated by pectinate muscles, thrombi in nonvalvular AF form almost exclusively in the LAA and not in the smooth-walled left atrium. For the last 50 years, oral anticoagulation (OAC) with vitamin K antagonists (VKAs) has been the only treatment option to prevent stroke and systemic embolism from thrombi in AF. More recently, non-vitamin K-dependant oral anticoagulants (NOACs) have been shown to be noninferior or even superior to VKA with respect to efficacy and safety. In light of the limitations of indefinite OAC, particularly among patients at increased risk for bleeding and because thrombi arise predominantly from the LAA among AF patients, exclusion of the LAA with closure devices (LAAC) provides a novel treatment strategy for prevention of stroke and bleeding. Recently, LAAC has been compared with VKA therapy in prospective randomised trials with promising results. Today, the decision to provide the most appropriate treatment for a patient with AF (OAC, NOAC or LAAC) is complex and needs to be individualised. This review provides an update on the current state of LAAC in the field of stroke prevention in patients suffering from nonvalvular AF. We describe the pathophysiology of the LAA with regard to stroke. Aside from the evidence and limitations of anticoagulation as the classical treatment paradigm for stroke prevention, devices and techniques for LAAC are outlined and the current clinical evidence with regard to efficacy and safety is reviewed. Finally, contemporary recommendations for patient selection are provided. PMID- 27244535 TI - Dynamics of intermolecular interactions in CCl4via the isotope effect by femtosecond time-resolved spectroscopy. AB - We report our study on the ultrafast dynamics of intermolecular interactions in liquid CCl4. A transient transmission time domain signal, obtained in the 40 ps delay range, exhibits beating at the difference frequency of the totally symmetric stretching vibrations of the tetrachloride isotopologues. We show that the spectra obtained as the windowed Fourier transform of different parts of the time domain signal in the range of this totally symmetric vibration, split due to the isotope effect, carry the information about the dynamics of the coherently excited, coupled molecules. We use a simple theoretical model in order to prove that the intermolecular interaction influences the relative amplitudes of the isotopologue peaks in the spectrum. Moreover, we demonstrate that the pump induced coherence in the system leads to additional strengthening of the interaction, which can be observed in the spectra obtained from the experimental time domain signal. PMID- 27244536 TI - Palladium(II)-Catalyzed Tandem Synthesis of Acenes Using Carboxylic Acids as Traceless Directing Groups. AB - A straightforward synthetic strategy for generating useful anthracene derivatives was developed involving palladium(II)-catalyzed tandem transformation with carboxylic acids as traceless directing groups. Carboxyl-directed C-H alkenylation, carboxyl-directed secondary C-H activation and rollover, intramolecular C-C bond formation, and decarboxylative aromatization are proposed as the key steps in the tandem reaction pathway. This novel synthetic route utilizes a broad range of substrates and provides a convenient synthetic tool that allows access to acenes. PMID- 27244537 TI - Survival results of a randomised two-by-two factorial phase II trial comparing neoadjuvant chemotherapy with two and four courses of S-1 plus cisplatin (SC) and paclitaxel plus cisplatin (PC) followed by D2 gastrectomy for resectable advanced gastric cancer. AB - BACKGROUND: The prognosis for stage III gastric cancer is unsatisfactory by D2 gastrectomy and S-1 adjuvant chemotherapy. Both S-1 plus cisplatin (SC) and paclitaxel plus cisplatin (PC) are promising regimens as neoadjuvant chemotherapy; however, the optimal duration remains unclear. PATIENTS AND METHODS: In this 2*2 randomised phase II trial, stage III gastric cancer patients, those with a prognosis corresponding to stage III, and macroscopically resectable stage IV cases were randomised to two or four courses of S-1 (80 mg/m(2) for 21 d with 1 week rest)/cisplatin (60 mg/m(2) at day 8) or PC (80 and 25 mg/m(2), respectively, on days 1, 8, and 15 with 1 week rest) as neoadjuvant chemotherapy. The primary end-point was the 3-year overall survival (OS). RESULTS: Between October 2009 and July 2011, 83 patients received 2 courses of SC (n=21), 4 courses of SC (n=20), 2 courses of PC (n=21) and 4 courses of PC (n=21). The 3-year OS was 60.9% for SC and 64.3% for PC and 64.3% for the two courses and 61.0% for the four courses. Subset analyses demonstrated no subgroup which showed any potential survival benefit by PC in comparison to SC or by four courses as in comparison to two courses. CONCLUSIONS: Two courses of SC as neoadjuvant chemotherapy are recommended as a test arm of a future phase III study for patients with locally advanced gastric cancer. CLINICAL TRIAL NUMBER: UMIN-000002595. PMID- 27244538 TI - Wolves (Canis lupus) and dogs (Canis familiaris) differ in following human gaze into distant space but respond similar to their packmates' gaze. AB - Gaze following into distant space is defined as visual co-orientation with another individual's head direction allowing the gaze follower to gain information on its environment. Human and nonhuman animals share this basic gaze following behavior, suggested to rely on a simple reflexive mechanism and believed to be an important prerequisite for complex forms of social cognition. Pet dogs differ from other species in that they follow only communicative human gaze clearly addressed to them. However, in an earlier experiment we showed that wolves follow human gaze into distant space. Here we set out to investigate whether domestication has affected gaze following in dogs by comparing pack living dogs and wolves raised and kept under the same conditions. In Study 1 we found that in contrast to the wolves, these dogs did not follow minimally communicative human gaze into distant space in the same test paradigm. In the observational Study 2 we found that pack-living dogs and wolves, similarly vigilant to environmental stimuli, follow the spontaneous gaze of their conspecifics similarly often. Our findings suggest that domestication did not affect the gaze following ability of dogs itself. The results raise hypotheses about which other dog skills might have been altered through domestication that may have influenced their performance in Study 1. Because following human gaze in dogs might be influenced by special evolutionary as well as developmental adaptations to interactions with humans, we suggest that comparing dogs to other animal species might be more informative when done in intraspecific social contexts. (PsycINFO Database Record PMID- 27244539 TI - Evaluation of Effectiveness of Mixed Rotavirus Vaccine Course for Rotavirus Gastroenteritis. PMID- 27244540 TI - Codon 13 KRAS mutation predicts patterns of recurrence in patients undergoing hepatectomy for colorectal liver metastases. AB - BACKGROUND: Investigations regarding the impact of tumor biology after surgical management of colorectal liver metastasis have focused largely on overall survival. We investigated the impact of codon-specific KRAS mutations on the rates and patterns of recurrence in patients after surgery for colorectal liver metastasis (CRLM). METHODS: All patients who underwent curative-intent surgery for CRLM between 2002 and 2015 at Johns Hopkins who had available data on KRAS mutation status were identified. Clinico-pathologic data, recurrence patterns, and recurrence-free survival (RFS) were assessed using univariable and multivariable analyses. RESULTS: A total of 512 patients underwent resection only (83.2%) or resection plus radiofrequency ablation (16.8%). Although 5-year overall survival was 64.6%, 284 (55.5%) patients recurred with a median RFS time of 18.1 months. The liver was the initial recurrence site for 181 patients, whereas extrahepatic recurrence was observed in 162 patients. Among patients with an extrahepatic recurrence, 102 (63%) had a lung recurrence. Although overall KRAS mutation was not associated with overall RFS (P = 0.186), it was independently associated with a worse extrahepatic (P = 0.004) and lung RFS (P = 0.007). Among patients with known KRAS codon-specific mutations, patients with codon 13 KRAS mutation had a worse 5-year extrahepatic RFS (P = 0.01), whereas codon 12 mutations were not associated with extrahepatic (P = 0.11) or lung specific recurrence rate (P = 0.24). On multivariable analysis, only codon 13 mutation independently predicted worse overall extrahepatic RFS (P = 0.004) and lung-specific RFS (P = 0.023). CONCLUSIONS: Among patients undergoing resection of CRLM, overall KRAS mutation was not associated with RFS. KRAS codon 13 mutations, but not codon 12 mutations, were associated with a higher risk for overall extrahepatic recurrence and lung-specific recurrence. Cancer 2016. (c) 2016 American Cancer Society. Cancer 2016;122:2698-2707. (c) 2016 American Cancer Society. PMID- 27244549 TI - Interphase Induced Dynamic Self-Stiffening in Graphene-Based Polydimethylsiloxane Nanocomposites. AB - The ability to rearrange microstructures and self-stiffen in response to dynamic external mechanical stimuli is critical for biological tissues to adapt to the environment. While for most synthetic materials, subjecting to repeated mechanical stress lower than their yield point would lead to structural failure. Here, it is reported that the graphene-based polydimethylsiloxane (PDMS) nanocomposite, a chemically and physically cross-linked system, exhibits an increase in the storage modulus under low-frequency, low-amplitude dynamic compressive loading. Cross-linking density statistics and molecular dynamics calculations show that the dynamic self-stiffening could be attributed to the increase in physical cross-linking density, resulted from the re-alignment and re orientation of polymer chains along the surface of nano-fillers that constitute an interphase. Consequently, the interfacial interaction between PDMS-nano fillers and the mobility of polymer chain, which depend on the degree of chemical cross-linking and temperature, are important factors defining the observed performance of self-stiffening. The understanding of the dynamic self-stiffening mechanism lays the ground for the future development of adaptive structural materials and bio-compatible, load-bearing materials for tissue engineering applications. PMID- 27244550 TI - Dependence of Mesomorphic Behaviour of Methylene-Linked Dimers and the Stability of the NTB /NX Phase upon Choice of Mesogenic Units and Terminal Chain Length. AB - Twelve symmetrical dimeric materials consisting of a nonamethylene (C9) spacer and either phenyl 4-(4'-alkylphenyl)benzoate, phenyl 4-(4' alkylcyclohexyl)benzoate or phenyl 4-(4'-alkylbicyclohexyl)carboxylate mesogenic units were prepared and their mesogenic behaviour characterised by POM, DSC and XRD. All of the materials exhibited nematic phases with clearing points in excess of 200 degrees C. Four compounds were found to exhibit the twist-bend nematic phase, with one material exhibiting a transition from the NTB phase into an anticlinic smectic 'X' phase. Across all three series of compounds the length of terminal chain is seen to dictate, to some degree, the type of mesophase formed: shorter terminal chains favour nematic and NTB mesophases, whereas longer terminal aliphatic chains were found to promote smectic phases. PMID- 27244551 TI - Surface Microstructural Changes and Release of Ions from Dental Metal Alloy Removable Prostheses in Patients Suffering from Acid Reflux. AB - PURPOSE: To investigate the surface microstructural changes and the release of ions from metal alloys used in removable dental prostheses and the potential effects of acidic reflux found in patients suffering from gastroesophageal reflux disease (GERD). MATERIALS AND METHODS: Thirty-seven (37) patients were recruited. Data were gathered through a questionnaire and clinical examination. Samples of metal alloy from the dentures and patient's saliva were collected. GERD was confirmed using the GerdQ questionnaire. Denture samples were characterized using scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS), while salivary samples were tested for trace metal ions using inductively coupled plasma (ICP). RESULTS: Characterization of denture samples revealed the presence of nickel, cobalt, and chromium. Nickel-chromium exhibited an etched surface appearance, while cobalt-chromium exhibited no noticeable surface microstructural changes. Higher mean salivary levels of chromium and cobalt in patients wearing any metal alloy-based denture and of chromium and nickel in patients wearing Ni Cr prostheses were found to be significant. No differences were found in salivary metal ion levels of patients suffering from GERD. CONCLUSIONS: Nickel-chromium alloy is prone to acid etching in the oral cavity, while cobalt-chromium alloy appears to be more resistant. Cobalt, chromium, and nickel are leached in saliva of patients using cast removable prostheses. The impact of gastric acid on metal ion release from dental metal alloys deserves further investigations. CLINICAL SIGNIFICANCE: This preliminary study suggests that metal-based removable prostheses leach trace metal ions in saliva. Nickel-chromium-based dentures exhibit an etched appearance unrelated to GERD. PMID- 27244553 TI - Corrigendum. PMID- 27244552 TI - Shelf-Life of Chlorine Solutions Recommended in Ebola Virus Disease Response. AB - In Ebola Virus Disease (EVD) outbreaks, it is widely recommended to wash living things (handwashing) with 0.05% (500 mg/L) chlorine solution and non-living things (surfaces, personal protective equipment, dead bodies) with 0.5% (5,000 mg/L) chlorine solution. Chlorine solutions used in EVD response are primarily made from powdered calcium hypochlorite (HTH), granular sodium dichloroisocyanurate (NaDCC), and liquid sodium hypochlorite (NaOCl), and have a pH range of 5-11. Chlorine solutions degrade following a reaction highly dependent on, and unusually sensitive to, pH, temperature, and concentration. We determined the shelf-life of 0.05% and 0.5% chlorine solutions used in EVD response, including HTH, NaDCC, stabilized NaOCl, generated NaOCl, and neutralized NaOCl solutions. Solutions were stored for 30 days at 25, 30, and 35 degrees C, and tested daily for chlorine concentration and pH. Maximum shelf-life was defined as days until initial concentration fell to <90% of initial concentration in ideal laboratory conditions. At 25-35 degrees C, neutralized NaOCl solutions (pH = 7) had a maximum shelf-life of a few hours, NaDCC solutions (pH = 6) 2 days, generated NaOCl solutions (pH = 9) 6 days, and HTH and stabilized NaOCl solutions (pH 9-11) >30 days. Models were developed for solutions with maximum shelf-lives between 1-30 days. Extrapolating to 40 degrees C, the maximum predicted shelf-life for 0.05% and 0.5% NaDCC solutions were 0.38 and 0.82 hours, respectively; predicted shelf-life for 0.05% and 0.5% generated NaOCl solutions were >30 and 5.4 days, respectively. Each chlorine solution type offers advantages and disadvantages to responders, as: NaDCC is an easy-to-import high-concentration effervescent powder; HTH is similar, but forms a precipitate that may clog pipes; and, NaOCl solutions can be made locally, but are difficult to transport. We recommend responders chose the most appropriate source chlorine compound for their use, and ensure solutions are stored at appropriate temperatures and used or replaced before expiring. PMID- 27244554 TI - Study Links Periodontal Disease Bacteria to Pancreatic Cancer Risk. PMID- 27244557 TI - Phylogenetic sleuthing reveals pair of paralogous genes. AB - The complex evolutionary history of the IFIT family of antiviral genes has been shaped by continuous interactions between mammalian hosts and their many viruses. PMID- 27244556 TI - Olfactory Ensheathing Cell Transplantation in Experimental Spinal Cord Injury: Effect size and Reporting Bias of 62 Experimental Treatments: A Systematic Review and Meta-Analysis. AB - Olfactory ensheathing cell (OEC) transplantation is a candidate cellular treatment approach for human spinal cord injury (SCI) due to their unique regenerative potential and autologous origin. The objective of this study was, through a meta-epidemiologic approach, (i) to assess the efficacy of OEC transplantation on locomotor recovery after traumatic experimental SCI and (ii) to estimate the likelihood of reporting bias and/or missing data. A study protocol was finalized before data collection. Embedded into a systematic review and meta-analysis, we conducted a literature research of databases including PubMed, EMBASE, and ISI Web of Science from 1949/01 to 2014/10 with no language restrictions, screened by two independent investigators. Studies were included if they assessed neurobehavioral improvement after traumatic experimental SCI, administrated no combined interventions, and reported the number of animals in the treatment and control group. Individual effect sizes were pooled using a random effects model. Details regarding the study design were extracted and impact of these on locomotor outcome was assessed by meta-regression. Missing data (reporting bias) was determined by Egger regression and Funnel-plotting. The primary study outcome assessed was improvement in locomotor function at the final time point of measurement. We included 49 studies (62 experiments, 1,164 animals) in the final analysis. The overall improvement in locomotor function after OEC transplantation, measured using the Basso, Beattie, and Bresnahan (BBB) score, was 20.3% (95% CI 17.8-29.5). One missing study was imputed by trim and fill analysis, suggesting only slight publication bias and reducing the overall effect to a 19.2% improvement of locomotor activity. Dose-response ratio supports neurobiological plausibility. Studies were assessed using a 9-point item quality score, resulting in a median score of 5 (interquartile range [IQR] 3-5). In conclusion, OEC transplantation exerts considerable beneficial effects on neurobehavioral recovery after traumatic experimental SCI. Publication bias was minimal and affirms the translational potential of efficacy, but safety cannot be adequately assessed. The data justify OECs as a cellular substrate to develop and optimize minimally invasive and safe cellular transplantation paradigms for the lesioned spinal cord embedded into state-of-the-art Phase I/II clinical trial design studies for human SCI. PMID- 27244555 TI - Genome-wide association study identifies 8p21.3 associated with persistent hepatitis B virus infection among Chinese. AB - Hepatitis B virus (HBV) infection is a common infectious disease. Here we perform a genome-wide association study (GWAS) among Chinese populations to identify novel genetic loci involved in persistent HBV infection. GWAS scan is performed in 1,251 persistently HBV infected subjects (PIs, cases) and 1,057 spontaneously recovered subjects (SRs, controls), followed by replications in four independent populations totally consisting of 3,905 PIs and 3,356 SRs. We identify a novel locus at 8p21.3 (index rs7000921, odds ratio=0.78, P=3.2 * 10(-12)). Furthermore, we identify significant expression quantitative trait locus associations for INTS10 gene at 8p21.3. We demonstrate that INST10 suppresses HBV replication via IRF3 in liver cells. In clinical plasma samples, we confirm that INST10 levels are significantly decreased in PIs compared with SRs, and negatively correlated with the HBV load. These findings highlight a novel antiviral gene INTS10 at 8p21.3 in the clearance of HBV infection. PMID- 27244558 TI - CD4 T Cell-Derived IFN-gamma Plays a Minimal Role in Control of Pulmonary Mycobacterium tuberculosis Infection and Must Be Actively Repressed by PD-1 to Prevent Lethal Disease. AB - IFN-gamma-producing CD4 T cells are required for protection against Mycobacterium tuberculosis (Mtb) infection, but the extent to which IFN-gamma contributes to overall CD4 T cell-mediated protection remains unclear. Furthermore, it is not known if increasing IFN-gamma production by CD4 T cells is desirable in Mtb infection. Here we show that IFN-gamma accounts for only ~30% of CD4 T cell dependent cumulative bacterial control in the lungs over the first six weeks of infection, but >80% of control in the spleen. Moreover, increasing the IFN-gamma producing capacity of CD4 T cells by ~2 fold exacerbates lung infection and leads to the early death of the host, despite enhancing control in the spleen. In addition, we show that the inhibitory receptor PD-1 facilitates host resistance to Mtb by preventing the detrimental over-production of IFN-gamma by CD4 T cells. Specifically, PD-1 suppressed the parenchymal accumulation of and pathogenic IFN gamma production by the CXCR3+KLRG1-CX3CR1- subset of lung-homing CD4 T cells that otherwise mediates control of Mtb infection. Therefore, the primary role for T cell-derived IFN-gamma in Mtb infection is at extra-pulmonary sites, and the host-protective subset of CD4 T cells requires negative regulation of IFN-gamma production by PD-1 to prevent lethal immune-mediated pathology. PMID- 27244559 TI - Modeling Effects of RNA on Capsid Assembly Pathways via Coarse-Grained Stochastic Simulation. AB - The environment of a living cell is vastly different from that of an in vitro reaction system, an issue that presents great challenges to the use of in vitro models, or computer simulations based on them, for understanding biochemistry in vivo. Virus capsids make an excellent model system for such questions because they typically have few distinct components, making them amenable to in vitro and modeling studies, yet their assembly can involve complex networks of possible reactions that cannot be resolved in detail by any current experimental technology. We previously fit kinetic simulation parameters to bulk in vitro assembly data to yield a close match between simulated and real data, and then used the simulations to study features of assembly that cannot be monitored experimentally. The present work seeks to project how assembly in these simulations fit to in vitro data would be altered by computationally adding features of the cellular environment to the system, specifically the presence of nucleic acid about which many capsids assemble. The major challenge of such work is computational: simulating fine-scale assembly pathways on the scale and in the parameter domains of real viruses is far too computationally costly to allow for explicit models of nucleic acid interaction. We bypass that limitation by applying analytical models of nucleic acid effects to adjust kinetic rate parameters learned from in vitro data to see how these adjustments, singly or in combination, might affect fine-scale assembly progress. The resulting simulations exhibit surprising behavioral complexity, with distinct effects often acting synergistically to drive efficient assembly and alter pathways relative to the in vitro model. The work demonstrates how computer simulations can help us understand how assembly might differ between the in vitro and in vivo environments and what features of the cellular environment account for these differences. PMID- 27244560 TI - Critical Illness in Patients with Multiple Sclerosis: A Matched Case-Control Study. AB - BACKGROUND: Over the course of multiple sclerosis (MS) several conditions may arise that require critical care. We aimed to study the reasons for admission and outcome in patients with MS admitted to a neuro-intensive care unit (NICU). METHODS: We retrospectively searched the electronic charts of a 9-bedded NICU in a tertiary hospital for patients with a diagnosis of multiple sclerosis (MS) from 1993-2015, and matched them to NICU controls without MS based on age and gender. Conditional logistic regression was used to compare admission causes, Charlson's Comorbidity Index, indicators of disease severity, and survival between MS and non-MS patients. RESULTS: We identified 61 MS patients and 181 non-MS controls. Respiratory dysfunction was the most frequent reason for NICU admission among MS patients (34.4%), having infectious context as a rule. In a matched analysis, after adjusting for co-morbidities and immunosuppressive medications, patients with MS were more likely to be admitted to the NICU because of respiratory dysfunction (OR = 7.86, 95% CI 3.02-20.42, p<0.001), non-respiratory infections (OR = 3.71, 95% CI 1.29-10.68, p = 0.02), had a higher rate of multiple NICU admissions (OR = 2.53, 95% CI 1.05-6.05, p = 0.04) than non-MS patients. Mortality after NICU admission at a median follow-up time of 1 year was higher in MS than control patients (adjusted OR = 4.21, 95% CI 1.49-11.85, p = 0.04). CONCLUSION: The most common reason for NICU admission in MS patients was respiratory dysfunction due to infection. Compared to non-MS patients, critically ill MS patients had a higher NICU re-admission rate, and a higher mortality. PMID- 27244561 TI - Novel Detection of Coxiella spp., Theileria luwenshuni, and T. ovis Endosymbionts in Deer Keds (Lipoptena fortisetosa). AB - We describe for the first time the detection of Coxiella-like bacteria (CLB), Theileria luwenshuni, and T. ovis endosymbionts in blood-sucking deer keds. Eight deer keds attached to a Korean water deer were identified as Lipoptena fortisetosa (Diptera: Hippoboscidae) by morphological and genetic analyses. Among the endosymbionts assessed, CLB, Theileria luwenshuni, and T. ovis were identified in L. fortisetosa by PCR and nucleotide sequencing. Based on phylogeny, CLB 16S rRNA sequences were classified into clade B, sharing 99.4% identity with CLB from Haemaphysalis longicornis in South Korea. Although the virulence of CLB to vertebrates is still controversial, several studies have reported clinical symptoms in birds due to CLB infections. The 18S rRNA sequences of T. luwenshuni and T. ovis in this study were 98.8-100% identical to those in GenBank, and all of the obtained sequences of T. ovis and T. luwenshuni in this study were 100% identical to each other, respectively. Although further studies are required to positively confirm L. fortisetosa as a biological vector of these pathogens, strong genetic relationships among sequences from this and previous studies suggest potential transmission among mammalian hosts by ticks and keds. PMID- 27244562 TI - Drying Mechanisms in Plasticized Latex Films: Role of Horizontal Drying Fronts. AB - This article presents studies on the drying kinetics of latexes with particles made progressively softer by adding increasing amounts of a plasticizer, in relation to speeds of horizontal drying fronts and particle deformation mechanisms. Global drying rates were measured by gravimetry, and speeds of the horizontal fronts were recorded using a video camera and image processing. Particle deformation mechanisms were inferred using the deformation map established by Routh and Russel (RR). This required precise measurements of the rheological properties of the polymers using a piezorheometer. The results show that latexes with softer particles dry slowly, but in our systems, this is not due to skin formation. A correlation between global drying rates and speeds of horizontal fronts could be established and interpreted in terms of the evolution of mass transfer coefficients of water in different areas of the drying system. The speeds of the horizontal drying fronts were compared with the RR model. A remarkable qualitative agreement of the curve shapes was observed; however, the fit could not be considered good. These results call for further research efforts in modeling and simulation. PMID- 27244564 TI - Connexin43 contributes to electrotonic conduction across scar tissue in the intact heart. AB - Studies have demonstrated non-myocytes, including fibroblasts, can electrically couple to myocytes in culture. However, evidence demonstrating current can passively spread across scar tissue in the intact heart remains elusive. We hypothesize electrotonic conduction occurs across non-myocyte gaps in the heart and is partly mediated by Connexin43 (Cx43). We investigated whether non-myocytes in ventricular scar tissue are electrically connected to surrounding myocardial tissue in wild type and fibroblast-specific protein-1 driven conditional Cx43 knock-out mice (Cx43fsp1KO). Electrical coupling between the scar and uninjured myocardium was demonstrated by injecting current into the myocardium and recording depolarization in the scar through optical mapping. Coupling was significantly reduced in Cx43fsp1KO hearts. Voltage signals were recorded using microelectrodes from control scars but no signals were obtained from Cx43fsp1KO hearts. Recordings showed significantly decreased amplitude, depolarized resting membrane potential, increased duration and reduced upstroke velocity compared to surrounding myocytes, suggesting that the non-excitable cells in the scar closely follow myocyte action potentials. These results were further validated by mathematical simulations. Optical mapping demonstrated that current delivered within the scar could induce activation of the surrounding myocardium. These data demonstrate non-myocytes in the scar are electrically coupled to myocytes, and coupling depends on Cx43 expression. PMID- 27244565 TI - Aggregation of germlings is a major contributing factor towards mycelial heterogeneity of Streptomyces. AB - Streptomycetes are filamentous bacteria that produce numerous valuable compounds, including the majority of clinically used antibiotics. At an industrial scale, most of these compounds are produced in bioreactors. Growth of streptomycetes under these conditions is characterized by the formation of complex mycelial particles, whose sizes follow a bimodal distribution. Given the correlation between specific productivity and morphology, this size heterogeneity poses a potential drawback in industry. Recent work indicates that mycelial morphology is controlled by a number of genes that encode proteins required for the synthesis of cell surface-associated glycans. Using a quantifiable system based on fluorescent markers, we here show that these glycans mediate aggregation between germlings and young mycelia, yielding mycelial particles that originate from many different individuals. We also demonstrate that at later time points aggregation between distinct particles is no longer detectable. Notably, the absence of the corresponding glycan synthases yields mycelia that are homogeneous in size, identifying mycelial aggregation as a driving factor towards size heterogeneity. Given that aggregation is widespread within streptomycetes and can also occur between different Streptomyces strains, our work paves the way to improve Streptomyces as a cell factory for the production of known metabolites, but possibly also to discover new ones. PMID- 27244566 TI - Patient Acceptance of Advance Care Planning Guidebook Distribution at Hospital Admission. PMID- 27244567 TI - A new sesquiterpene from the South China Sea gorgonian coral Subergorgia suberosa. AB - A new sesquiterpene, namely suberosoid (1), was isolated from the South China Sea gorgonian coral Subergorgia suberosa. The chemical structure of 1 was established as an unusual sesquiterpene containing 4-methylenecyclohex-2-enone system, by extensive analyses of NMR spectroscopy and high-resolution mass spectrometry. Suberosoid (1) exhibited cytotoxic effect against HeLa cell lines with IC50 value being 10.6 MUM. PMID- 27244568 TI - Speech Perception in Classroom Acoustics by Children With Cochlear Implants and With Typical Hearing. AB - PURPOSE: This study measured speech perception ability in children with cochlear implants and children with typical hearing when listening across ranges of reverberation times (RTs) and speech-to-noise ratios. METHOD: Participants listened in classroom RTs of 0.3, 0.6, and 0.9 s combined with a 21-dB range of speech-to-noise ratios. Subsets also listened in a low-reverberant audiological sound booth. Performance measures using the Bamford-Kowal-Bench Speech-in-Noise Test (Etymotic Research, Inc., 2005) were 50% correct word recognition across these acoustic conditions, with supplementary analyses of percent correct. RESULTS: Reduction in RT from 0.9 to 0.6 s benefited both groups of children. A further reduction in RT to 0.3 s provided additional benefit to the children with cochlear implants, with no further benefit or harm to those with typical hearing. Scores in the sound booth were significantly higher for the participants with implants than in the classroom. CONCLUSIONS: These results support the acoustic standards of 0.6 s RT for children with typical hearing and 0.3 s RT for children with auditory issues in learning spaces (<=283 m3) as specified in standards S12.60-2010/Part 1 of the American National Standards Institute /Acoustical Society of America (2010). In addition, speech perception testing in a low reverberant booth overestimated classroom listening ability in children with cochlear implants. PMID- 27244570 TI - Minor changes in the macrocyclic ligands but major consequences on the efficiency of gold nanoparticles designed for radiosensitization. AB - Many studies have been devoted to adapting the design of gold nanoparticles to efficiently exploit their promising capability to enhance the effects of radiotherapy. In particular, the addition of magnetic resonance imaging modality constitutes an attractive strategy for enhancing the selectivity of radiotherapy since it allows the determination of the most suited delay between the injection of nanoparticles and irradiation. This requires the functionalization of the gold core by an organic shell composed of thiolated gadolinium chelates. The risk of nephrogenic systemic fibrosis induced by the release of gadolinium ions should encourage the use of macrocyclic chelators which form highly stable and inert complexes with gadolinium ions. In this context, three types of gold nanoparticles (Au@DTDOTA, Au@TADOTA and Au@TADOTAGA) combining MRI, nuclear imaging and radiosensitization have been developed with different macrocyclic ligands anchored onto the gold cores. Despite similarities in size and organic shell composition, the distribution of gadolinium chelate-coated gold nanoparticles (Au@TADOTA-Gd and Au@TADOTAGA-Gd) in the tumor zone is clearly different. As a result, the intravenous injection of Au@TADOTAGA-Gd prior to the irradiation of 9L gliosarcoma bearing rats leads to the highest increase in lifespan whereas the radiophysical effects of Au@TADOTAGA-Gd and Au@TADOTA-Gd are very similar. PMID- 27244571 TI - A Role for the Anti-Viral Host Defense Mechanism in the Phylogenetic Divergence in Baculovirus Evolution. AB - Although phylogenic analysis often suggests co-evolutionary relationships between viruses and host organisms, few examples have been reported at the microevolutionary level. Here, we show a possible example in which a species specific anti-viral response may drive phylogenic divergence in insect virus evolution. Two baculoviruses, Autographa californica multiple nucleopolyhedrovirus (AcMNPV) and Bombyx mori nucleopolyhedrovirus (BmNPV), have a high degree of DNA sequence similarity, but exhibit non-overlapping host specificity. In our study of their host-range determination, we found that BmNPV replication in B. mori cells was prevented by AcMNPV-P143 (AcP143), but not BmNPV P143 (BmP143) or a hybrid P143 protein from a host-range expanded phenotype. This suggests that AcMNPV resistance in B. mori cells depends on AcP143 recognition and that BmNPV uses BmP143 to escapes this recognition. Based on these data, we propose an insect-baculovirus co-evolution scenario in which an ancestor of silkworms exploited an AcMNPV-resistant mechanism; AcMNPV counteracted this resistance via P143 mutations, resulting in the birth of BmNPV. PMID- 27244572 TI - Effect of injection velocity and particle concentration on transport of nanoscale zero-valent iron and hydraulic conductivity in saturated porous media. AB - Successful groundwater remediation by injecting nanoscale zero-valent iron (NZVI) particles requires efficient particle transportation and distribution in the subsurface. This study focused on the influence of injection velocity and particle concentration on the spatial NZVI particle distribution, the deposition processes and on quantifying the induced decrease in hydraulic conductivity (K) as a result of particle retention by lab tests and numerical simulations. Horizontal column tests of 2m length were performed with initial Darcy injection velocities (q0) of 0.5, 1.5, and 4.1m/h and elemental iron input concentrations (Fe(0)in) of 0.6, 10, and 17g/L. Concentrations of Fe(0) in the sand were determined by magnetic susceptibility scans, which provide detailed Fe(0) distribution profiles along the column. NZVI particles were transported farther at higher injection velocity and higher input concentrations. K decreased by one order of magnitude during injection in all experiments, with a stronger decrease after reaching Fe(0) concentrations of about 14-18g/kg(sand). To simulate the observed nanoparticle transport behavior the existing finite-element code OGS has been successfully extended and parameterized for the investigated experiments using blocking, ripening, and straining as governing deposition processes. Considering parameter relationships deduced from single simulations for each experiment (e.g. deposition rate constants as a function of flow velocity) one mean parameter set has been generated reproducing the observations in an adequate way for most cases of the investigated realistic injection conditions. An assessment of the deposition processes related to clogging effects showed that the percentage of retention due to straining and ripening increased during experimental run time resulting in an ongoing reduction of K. Clogging is mainly evoked by straining which dominates particle deposition at higher flow velocities, while blocking and ripening play a significant role for attachment, mainly at lower injection velocities. Since the injection of fluids at real sites leads to descending flow velocities with increasing radial distance from the injection point, the simulation of particle transport requires accounting for all deposition processes mentioned above. Thus, the derived mean parameter set can be used as a basis for quantitative and predictive simulations of particle distributions and clogging effects at both lab and field scale. Since decreases in K can change the flow system, which may have positive as well as negative implications for the in situ remediation technology at a contaminated site, a reliable simulation is thus of great importance for NZVI injection and prediction. PMID- 27244573 TI - [Not Available]. PMID- 27244574 TI - The effectiveness and safety of pharmacological prophylaxis against venous thromboembolism in patients with moderate to severe traumatic brain injury: A systematic review and meta-analysis. AB - BACKGROUND: Venous thromboembolism (VTE) is a common, potentially fatal complication after traumatic brain injury (TBI). The objective was to evaluate the effectiveness and safety of pharmacologic VTE prophylaxis in moderate to severe TBI patients, and its use in hospitals. DATA SOURCES: A systematic review of the literature was conducted using Medline, Embase, Central database, Google scholar, and the SciELO from 1966 to 2014. STUDY SELECTION & DATA EXTRACTION: All studies providing information on the following variables-use of VTE prophylaxis (both pharmacological and nonpharmacological), initiation of treatment, application of specific protocols, rates of VTE and hemorrhagic progression of the traumatic brain injury on computed tomographic scan-were included. The random effects model was used to calculate pooled effect estimates. Heterogeneity among studies was assessed using the Cochran Q homogeneity test. A forest plot was constructed, and aggregate odds ratio was computed. Potential publication bias was evaluated using funnel plots. METHODS & MAIN RESULTS: A total of 12 retrospective observational studies were identified, totaling 8,747 patients. Six studies (3,325 patients) were used to analyze the safety and five (2,105 patients) to analyze the effectiveness of pharmacological versus nonpharmacological prophylaxis, without considering the timing of treatment. Four studies (1,371 patients) were used to evaluate early versus late pharmacologic prophylaxis, with results favoring early administration (odds ratio, 0.46; 95% confidence interval, 0.24-0.88; p < 0.05; I, 46%) and showing no significant differences regarding safety. Three studies (4,133 patients), used to analyze VTE prophylaxis protocols, showed significant heterogeneity (p < 0.01). CONCLUSION: When we compared mechanical and pharmacological prophylaxis, the results were heterogeneous; and thus, their potential differences could not be assessed. In some studies, the introduction of prophylaxis protocols in neurocritical patient care improved their effectiveness. Early pharmacologic prophylaxis, in the first 72 hours after TBI, was more effective than late, when there was no hemorrhagic progression within 24 hours after injury; no significant differences were found regarding safety. LEVEL OF EVEDINCE: Systematic review/meta-analysis, level III. PMID- 27244576 TI - Smaller introducer sheaths for REBOA may be associated with fewer complications. AB - INTRODUCTION: Large arterial sheaths currently used for resuscitative endovascular balloon occlusion of the aorta (REBOA) may be associated with severe complications. Smaller diameter catheters compatible with 7Fr sheaths may improve the safety profile. METHODS: A retrospective review of patients receiving REBOA through a 7Fr sheath for refractory traumatic hemorrhagic shock was performed from January 2014 to June 2015 at five tertiary-care hospitals in Japan. Demographics were collected including method of arterial access; outcomes included mortality and REBOA-related access complications. RESULTS: Thirty-three patients underwent REBOA at Zone 1 (level of the diaphragm). Most patients were male (70%), with a mean age (+SD) 50 +/- 18 years, mean BMI 23 +/- 4, and a median [IQR] ISS of 38 [34, 52]. Ninety-four percent of patients presented after sustaining injuries from blunt mechanisms. Twenty-four percent underwent CPR before arrival, and an additional 15% received CPR after admission. Percutaneous arterial access without ultrasound or fluoroscopy was achieved in all patients. Systolic blood pressure increased significantly following balloon occlusion (mean 62 +/- 36 to 106 +/- 40 mm Hg, p < 0.001). Median total duration of complete initial occlusion was 26 [range 10-35] minutes. Sixteen patients (49%) survived beyond 24 hours, and 14 patients (42%) survived beyond 30 days. Twenty-four-hour and 30-day survival were 48% and 42%, respectively. Of the patients surviving 24 hours (n = 16), median duration of sheath placement was 28 [range 18-45] hours with all removed using manual pressure to achieve hemostasis. Of 33 REBOAs, 20 were performed by Emergency Medicine practitioners, 10 by Emergency Medicine practitioners with endovascular training, and 3 by Interventional Radiologists. No complication related to sheath insertion or removal was identified during the follow-up period, including dissection, pseudoaneurysm, retroperitoneal hematoma, leg ischemia, or distal embolism. CONCLUSIONS: 7Fr REBOA catheters can significantly elevate systolic blood pressure with no access-related complications. Our results suggest that a 7Fr introducer device for REBOA may be a safe and effective alternative to large-bore sheaths, and may remain in place during the post-procedure resuscitative phase without sequelae. LEVEL OF EVIDENCE: Therapeutic/care management, level V. PMID- 27244575 TI - If some is good, more is better: An enoxaparin dosing strategy to improve pharmacologic venous thromboembolism prophylaxis. AB - BACKGROUND: Empiric enoxaparin dosing is inadequate for most trauma patients, leading to below target initial anti-Xa levels and requiring dose adjustment for optimal venous thromboembolism prophylaxis. We hypothesize that patient factors affecting initial anti-Xa levels can be identified based on drug pharmacokinetics, allowing creation of a new dosing protocol that will provide a higher percentage of in-target (0.2-0.4 IU/mL) patients at initial anti-Xa level assessment. METHODS: Records of 318 trauma patients were evaluated, and NONMEM and PSN software were used to analyze 11 variables for their effects on anti-Xa levels. Computer modeling was used to select a new dosing protocol, which was implemented on the trauma service as a quality improvement project. The first 145 patients appropriately enrolled were assessed for response and complications. RESULTS: Only 29.5% of the pre-intervention group had initial anti-Xa levels in the appropriate prophylactic range (). Levels were most strongly influenced by patient weight, outweighing contributions from all other variables. A new regimen for initial dosing was therefore designed with three weight-defined categories for ease of administration. The post-intervention group showed an increase in in target initial anti-Xa levels to 74.5% (p < 0.001), with a corresponding decrease in subprophylactic patients from 68.0% to 20.7%. There was an increase in supraprophylactic levels to 4.8%, but no supraprophylactic patients had hemorrhagic complications.(Figure is included in full-text article.) CONCLUSIONS: Implementation of a new, categorized, weight-based enoxaparin dosing protocol was safe and significantly improved the percentage of trauma patients with in-target anti-Xa levels on initial assessment. Further studies are needed to determine whether such dosing decreases venous thromboembolism rates. LEVEL OF EVIDENCE: Therapeutic/care management study, level II. PMID- 27244578 TI - Partial resuscitative balloon occlusion of the aorta (P-REBOA): Clinical technique and rationale. PMID- 27244579 TI - Suicide in Illinois, 2005-2010: A reflection of patterns and risks by age groups and opportunities for targeted prevention. AB - BACKGROUND: Suicide accounts for two thirds of all deaths from intentional or violence-related injury and is a leading cause of death in the United States. Patterns of suicide have been well described among high-risk groups, but few studies have compared the circumstances related to suicides across all age groups. We sought to understand the epidemiology of suicide cases in Illinois and to characterize the risks and patterns for suicide among different age groups. METHODS: We used suicide data collected from the Illinois Violent Death Reporting System to assess demographics, method of suicide, circumstances, and mental health status among different age groups. RESULTS: Between 2005 and 2010, 3,016 suicides were reported; 692 (23%) were female, and the median age (n = 3,013) was 45 years (range, 10-98 years). The most common method/weapon types were hanging/strangulation (33%), firearm (32%) and poisoning (21%). Hanging was more common (74%) among young people aged 10 to 19 years, while firearm use was more common among elderly persons age 65 years and older (55%). The percentage of victims within an age group experiencing a crisis within two weeks before committing suicide was highest among 10- to 14-year-olds, while the risk factor of having a family member or friend die in the past 5 years was highest among older victims. CONCLUSION: The final analysis demonstrated age-related trends in suicide in Illinois, suggesting prevention programs should tailor services by age. LEVEL OF EVIDENCE: Epidemiologic study, level IV. PMID- 27244580 TI - Trauma health literacy: In need of remediation. AB - INTRODUCTION: Little is known regarding health literacy among trauma patients. Anecdotal experience at our institution has suggested that a profound lack of understanding of basic health care information exists at some level in our patients after hospital discharge. The purpose of this study was to report the results of a pilot quality improvement project to determine trauma patient injury comprehension and how this affects their overall satisfaction with care received. METHODS: Trauma patients were surveyed for knowledge of their injuries, operations, and satisfaction with their care at the first outpatient visit following hospital discharge from a Level 1 trauma center. RESULTS: One hundred seventy-five surveys were distributed and 35 were returned complete and eligible for analysis. Average time from discharge to survey completion was 16 days. Seventy-five percent of patients were male, and the mean age was 37. Fifty-six percent of the injuries were from a blunt mechanism. Seventy-one percent reported household income of less than $25,000 per annum, and 61% had an education level of high school diploma or less. Forty percent of patients were unable to correctly recall their injuries, and 54% were unable to correctly recall operations performed. Seventy-two percent were unable to recall the name of any physician that provided care during their hospital stay. Nonetheless, 90% of patients were at least somewhat satisfied with their injury understanding, and only 3% felt that their level of understanding had a negative impact on their overall satisfaction with care received. There was no correlation between education or income level and ability to correctly recall injuries or operations. In addition, there was no correlation between ability to recall injuries or operations and patients' satisfaction. CONCLUSION: The observed deficiency in postdischarge health literacy among our patients is alarming and demonstrates that current hospital discharge education is lacking. Although this deficit did not affect satisfaction with care, we feel a responsibility to improve the health literacy of our patients. The next step at our institution will be to implement a revised discharge education program followed by surveillance to evaluate for improvement. LEVEL OF EVIDENCE: Therapeutic/care management study, level IV. PMID- 27244581 TI - Low baseline (pre-injury) blood pressure predicts inpatient mortality in elderly trauma patients: A bi-institutional study. AB - OBJECTIVE: The relationship between baseline (i.e., pre-injury) blood pressure and trauma outcomes in elderly patients is unknown. We therefore aimed to identify the independent impact of baseline systolic blood pressure (SBP) on inpatient mortality among elderly trauma patients. METHODS: The 2004 to 2014 trauma registries of two Level I Trauma Centers were linked to electronic health records then reviewed to identify patients >=65 years old with available baseline vital signs. Baseline SBP was defined as mean outpatient SBP within 2 years before injury. Trauma SBP was defined as first SBP reading after presentation for trauma. Baseline and Trauma SBP were classified as Low (<110 mm Hg), Normal (110 139 mm Hg), or High (>=140 mm Hg). Logistic multivariable regression models were constructed to assess the independent impact of Baseline SBP on inpatient mortality, controlling for demographics, comorbidities, injury mechanism/severity, and Trauma SBP. RESULTS: Of 37,494 patient admissions, 4,233 met inclusion criteria. Median age was 81 years; 63.6% were female. Mortality was 5.39%. In unadjusted analyses, mortality rates were 11.01%, 5.28%, and 4.52% in the Low, Normal, and High Baseline SBP groups, respectively (p = 0.001). In multivariable analyses, patients with Low Baseline SBP had significantly increased mortality risk [OR 3.19 (95% CI 1.62-6.26), p = 0.001] compared to patients with Normal Baseline SBP, in particular when they presented with Low Trauma SBP (<110 mm Hg) [OR 6.14 (2.17-17.36), p = 0.001] or Normal Trauma SBP (110-139 mm Hg) [OR 3.87 (1.43-10.45), p = 0.008]. The mortality risk associated with Low Baseline SBP was particularly elevated among patients with a pre existing diagnosis of hypertension [OR 4.78 (1.97-11.62), p = 0.001]. CONCLUSION: Low baseline pre-injury SBP is independently associated with more than a threefold increase in inpatient mortality among elderly trauma patients and a fivefold increase in mortality risk among patients with pre-existing hypertension. Given that blood pressure control in the elderly offers a long-term survival advantage, the paradoxical finding of decreased survival after trauma warrants further investigation. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level III. PMID- 27244582 TI - Crown Group Lejeuneaceae and Pleurocarpous Mosses in Early Eocene (Ypresian) Indian Amber. AB - Cambay amber originates from the warmest period of the Eocene, which is also well known for the appearance of early angiosperm-dominated megathermal forests. The humid climate of these forests may have triggered the evolution of epiphytic lineages of bryophytes; however, early Eocene fossils of bryophytes are rare. Here, we present evidence for lejeuneoid liverworts and pleurocarpous mosses in Cambay amber. The preserved morphology of the moss fossil is inconclusive for a detailed taxonomic treatment. The liverwort fossil is, however, distinctive; its zig-zagged stems, suberect complicate-bilobed leaves, large leaf lobules, and small, deeply bifid underleaves suggest a member of Lejeuneaceae subtribe Lejeuneinae (Harpalejeunea, Lejeunea, Microlejeunea). We tested alternative classification possibilities by conducting divergence time estimates based on DNA sequence variation of Lejeuneinae using the age of the fossil for corresponding age constraints. Consideration of the fossil as a stem group member of Microlejeunea or Lejeunea resulted in an Eocene to Late Cretaceous age of the Lejeuneinae crown group. This reconstruction is in good accordance with published divergence time estimates generated without the newly presented fossil evidence. Balancing available evidence, we describe the liverwort fossil as the extinct species Microlejeunea nyiahae, representing the oldest crown group fossil of Lejeuneaceae. PMID- 27244583 TI - Linking Genotype to Clinical Phenotype in Multiple Sclerosis: In Search of the Holy Grail. PMID- 27244585 TI - A non-contact approach for PWV detection: application in a clinical setting. AB - A need for screening methods for arteriosclerosis led to the development of several approaches to measure pulse wave velocity (PWV) being indicative of arterial stiffness. Carotid-femoral PWV (cfPWV) can be measured between common carotid artery (CCA) and femoral artery (FA) displaying the physiologically important stiffness of the conduit arteries. However, this measurement approach has several disadvantages, and a local PWV-measurement of CCA-stiffness has been proposed as an alternative in the past. In the presented pilot study, laser Doppler vibrometry (LDV) is used to measure PWV locally in the CCA (PWVLDV) in 48 patients aged between 48 and 70, with known atherosclerotic arterial disease: stabilized coronary artery disease (CAD), cerebro-vascular disease (CVD) or peripheral artery disease (PAD). Additionally, cfPWV, CCA distensibility coefficient (DC), CCA intima-media thickness (IMT), blood pressure (BP) and age were evaluated. LDV is a valid method for local PWV-measurement. The method is potentially easy to use, and causes no discomfort to the patient. PWVLDV correlates with age (R = 0.432; p = 0.002) as reported in related studies using other techniques, and measured values lay between 2.5 and 5.8 m s(-1), which is well in line with literature measures of local PWV in the CCA. In conclusion, PWVLDV potentially is a marker for arterial health, but more research in a larger and more homogeneous patient population is mandatory. In future studies, blood velocity measurements should be incorporated, as well as a reference method such as pulse wave imaging (PWI) or magnetic resonance imaging (MRI). PMID- 27244584 TI - Correlation of pretreatment 18F-FDG uptake with clinicopathological factors and prognosis in patients with newly diagnosed diffuse large B-cell lymphoma. AB - OBJECTIVES: The aim of this study is to determine the correlation of pretreatment fluorine-18 fluorodeoxyglucose uptake with clinicopathological factors and its prognostic value in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: A cohort of 162 patients with newly diagnosed DLBCL who had undergone pretreatment PET/computed tomography was retrospectively reviewed. The relationship of pretreatment maximum standard uptake value (SUVmax) with clinical factors, molecular markers, and efficacy was evaluated. The value of SUVmax in predicting progression-free survival (PFS) and overall survival was analyzed. RESULTS: In all, 72.9% of the patients received R-CHOP treatment; the rest received CHOP chemotherapy. The median follow-up duration was 30 months (range, 4-124 months). The median SUVmax was 12.2 (range, 1.7-42.7). SUVmax between groups differed significantly with respect to each of International Prognostic Index (IPI) factors, except for age and performance status. High SUVmax was associated with high Ki-67 and Glut-3 protein expression, but not with Glut-1. Complete remission rate differed significantly between the low (SUVmax<=9.0) and the high SUVmax (SUVmax>9.0) groups (91.7 vs. 61.1%, P=0.000). Patients with low SUVmax showed favorable survival (3-year PFS: 92.2 vs. 63.6%, P=0.000; 3-year overall survival: 95.5 vs. 78.3%, P=0.003). On multivariate analyses, SUVmax predicted PFS independent of revised-IPI (SUVmax: P=0.011, hazard ratio 4.784; revised-IPI: P=0.004, hazard ratio 2.551). CONCLUSION: Pretreatment SUVmax was associated with clinicopathological factors, efficacy, and survival outcome. A novel prognostic model on the basis of IPI score/pretreatment SUVmax might be useful for risk stratification of patients with newly diagnosed DLBCL Video abstract: http://links.lww.com/NMC/A55. PMID- 27244587 TI - Chirality Detection Using Nematic Liquid Crystal Droplets on Anisotropic Surfaces. AB - Nematic liquid crystals (NLCs) form helical macroscopic structures through chiral induction when doped with chiral species. We describe a very simple, though highly sensitive method for determination of handedness and pitch of the induced twist in the case of very weak twisting powers of such chiral dopants. A tiny drop-typically less than 10 nL-of the chiral doped NLC is placed on a plate promoting a uniform planar surface anchoring of the liquid crystal director. At the curved NLC-air interface the anchoring is homeotropic and in the sessile droplets we get a locally twisted hybrid director structure with a disclination line extending across the droplet. The configuration of the disclination line (S like or backwards S-like) reveals the sign of twisting power and extremely large pitch values in the range of 10 mm can easily be measured. We demonstrate the method using the standard NLC 4-cyano-4'-pentylbiphenyl (5CB), weakly doped with the chiral material 2-hydroxy-2-phenylacetic acid (mandelic acid). PMID- 27244586 TI - The Association Between Complementary and Alternative Medicine and Health Status Following Acute Myocardial Infarction. AB - BACKGROUND: Complementary and alternative medicines (CAM) are commonly used in patients with cardiovascular disease. Although there is lack of evidence regarding the benefit of CAM on cardiovascular morbidity and mortality, health status benefits could justify CAM use. HYPOTHESIS: Adoption of mind-body CAM after acute myocardial infarction (AMI) is associated with improved health status, though other forms of CAM are not associated with health-status improvement. METHODS: Patients with AMI from 24 US sites were assessed for CAM use (categorized as mind-body, biological, and manipulative therapies) prior to and 1 year after AMI. Among patients who reported not using CAM prior to their AMI, association of initiating CAM on patients' health status at 1 year after AMI was assessed using Angina Frequency and Quality of Life domains from the Seattle Angina Questionnaire and the Short Form-12 Physical and Mental Component scales. Multivariable regression helped examine association between use of different CAM therapies and health status. RESULTS: Among 1884 patients not using CAM at the time of their AMI, 33% reported initiating >=1 forms of CAM therapy 1 year following AMI: 62% adopted mind-body therapies, 42% adopted biological therapies, and 15% began using manipulative therapies. In both unadjusted and adjusted analyses, we found no association between different types of CAM use and health status improvement after AMI. CONCLUSIONS: There was no association between CAM use and health-status recovery after AMI. Until randomized trials suggest otherwise, these findings underscore the importance of focusing on therapies with proven effectiveness after AMI. PMID- 27244588 TI - Erratum. PMID- 27244589 TI - Pirfenidone for Idiopathic Pulmonary Fibrosis. PMID- 27244590 TI - The Analysis of the Influence of Odorant's Complexity on Fractal Dynamics of Human Respiration. AB - One of the major challenges in olfaction research is to relate the structural features of the odorants to different features of olfactory system. However, no relationship has been yet discovered between the structure of the olfactory stimulus, and the structure of respiratory signal. This study reveals the plasticity of human respiratory signal in relation to 'complex' olfactory stimulus (odorant). We demonstrated that fractal temporal structure of respiration dynamics shifts towards the properties of the odorants used. The results show for the first time that more structurally complex a monomolecular odorant will result in less fractal respiratory signal. On the other hand, odorant with higher entropy will result the respiratory signal with lower entropy. The capability observed in this research can be further investigated and applied for treatment of patients with different respiratory diseases. PMID- 27244591 TI - Chromophore-Based Luminescent Metal-Organic Frameworks as Lighting Phosphors. AB - Energy-efficient solid-state-lighting (SSL) technologies are rapidly developing, but the lack of stable, high-performance rare-earth free phosphors may impede the growth of the SSL market. One possible alternative is organic phosphor materials, but these can suffer from lower quantum yields and thermal instability compared to rare-earth phosphors. However, if luminescent organic chromophores can be built into a rigid metal-organic framework, their quantum yields and thermal stability can be greatly improved. This Forum Article discusses the design of a group of such chromophore-based luminescent metal-organic frameworks with exceptionally high performance and rational control of the important parameters that influence their emission properties, including electronic structures of chromophore, coligands, metal ions, and guest molecules. PMID- 27244592 TI - Eco-friendly functionalized superhydrophobic recycled paper with enhanced flame retardancy. AB - Recycled paper with superhydrophobicity and flame-retardancy has been demonstrated here due to the synergistic action of dopamine-silica trimethylsilyl modified gel powder and stearic acid modified Mg(OH)2. This multifunctional recycled paper displays great self-cleaning and anti-fouling ability and can be used for oil-water separation. Surprisingly, the absorbed organic can be reused as fuel via simple combustion method for multiple cycles. This work will not only expand the usable range of paper but also ease the energy and environment crisis. PMID- 27244593 TI - Mixed phase lamellar titania-titanate anchored with Ag2O and polypyrrole for enhanced adsorption and photocatalytic activity. AB - Ag2O/TiO2/polypyrrole composite was synthesized by stepwise modification of the rutile TiO2 though hydrothermal alkaline treatment to obtain mixed phase sodium titanate/titania (Na-TiO2) followed ion-exchange replacement of Na(+) by Ag(+) to get Ag2O/TiO2 (through precipitation) and H2O2 oxidative polymerization of pyrrole onto Ag2O/TiO2 to get final composite Ag2O/TiO2/polypyrrole (Ag2O/TiO2/PPY). Composite materials were characterized by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), Field emission scanning electron microscopy (FE-SEM), Fourier transform infrared spectroscopy (FTIR), Diffuse reflectance ultraviolet-visible spectroscopy (UV-vis DRS) and Raman analysis. The synthesized materials showed increase in the optical property, adsorption and photocatalytic scavenging of the methylene blue (MB). The adsorption capacity of MB onto the prepared materials was observed in the following order: TiO210(4)), high-quantum-yield (>50%) spontaneous emission, even as the gap size vanishes (3-5 nm). The enhancement has almost spatially independent efficiency and does not suffer from quenching effects that commonly exist in previous structures. PMID- 27244597 TI - Impact of socio-economic position on cancer stage at presentation: Findings from a large hospital-based study in Germany. AB - We explored the relationship between socio-economic characteristics and cancer stage at presentation. Patients admitted to a university hospital for diagnosis and treatment of cancer provided data on their education, vocational training, income, employment, job, health insurance and postcode. Tumor stage was classified according to the Union International Contre le Cancer (UICC). To analyze disparities in the likelihood of late-stage (UICC III/IV vs. I/II) diagnoses, logistic regression models adjusting for age and gender were used. Out of 1,012 patients, 572 (59%) had late-stage cancer. Separately tested, increased odds of advanced disease were associated with post-compulsory education compared to college degrees, with apprenticeship and no vocational training, with unemployment, disability pension, jobs with a low hierarchy level, blue collar jobs and with low income. Health insurance and community size were not related with late-stage cancer. Jointly modelled, there was evidence for an independent effect of unemployment (odds ratio (OR) 1.7, CI 1.0-2.8), disability pension (OR 1.8, CI 1.0-3.2) and very low income (OR 2.6, CI 1.1-6.1) on the likelihood of advanced disease stage. It is of great concern that these socio-economic gradients occur even in systems with equal access to health care. PMID- 27244598 TI - Two for the Price of One: PAMAM-Dendrimers with Mixed Phosphoryl Choline and Oligomeric Poly(Caprolactone) Surfaces. AB - The application of dendrimers for biological and medical purposes is highly dependent on the type of surface group in relation to cytotoxicity. Since amine terminated PAMAM dendrimers have been shown to have toxic properties and thereby limited applications in the medical field, the discovery of a new nontoxic surface coating is of great interest. In the present work, amine terminated DAB PAMAM dendrimers from generation zero to four have been coated with statistical surface functionalization giving a dendrimer surface consisting of an approximately 1:1 mixture of zwitterionic phosphoryl choline hexanamide and 6-((6 hydroxyhexanoyl)oxy)hexanamide. The cytotoxic properties of generation two to four were tested on three different human cancer cell lines, SKBR3 human breast cancer cells, HeLa human cervical cancer cells, and Hep G2 human hepatocellular liver carcinoma cells and compared to the toxicity of amine terminated PAMAM dendrimers. In addition to lower cytotoxicity than observed for amine terminated dendrimers, the coated dendrimers showed minor cytotoxicity against all three human cell lines, negligible influence on ROS generation and mitochondrial membrane potential. These observations support the conclusion that the analyzed group of phosphorylcholine dendrimers may be suitable for medical applications. PMID- 27244600 TI - Current management of pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a vascular disease of unknown aetiology, characterised by an abnormal thickening of the arterial wall that is responsible for an increase in pulmonary vascular resistance. The haemodynamic consequence of PAH is an increased afterload for the right ventricle and, eventually, right heart failure. When untreated, PAH has a grim prognosis with a median survival of about 2 to 4 years from diagnosis. In the last 10 years new orally administered compounds have demonstrated clinical efficacy in controlled trials using various surrogate endpoints to survival. Although the disease remains without cure until now, the available phase III trials have allowed evidence-based recommendations for the medical management of these patients to be established. It appears, however, that none of the compounds from the three main therapeutic classes, endothelin receptor antagonists, agents acting on the nitric oxide-cyclic guanosine monophosphate pathway (including phosphodiesterase type 5 inhibitors and guanylate cyclase stimulator), and prostanoid receptor agonists are able alone to control disease progression in every patient. Therefore combination therapy with two or three drugs may be necessary in a significant number of patients in order to maintain patients in, or bring them to, a low risk profile. Several recent studies have now validated this approach for specific double or triple drug regimens. It remains, however, unclear whether an upfront combination is preferable to a sequential step-up approach based on clinical response. In addition, some specific combination therapies have failed to demonstrate superiority to single drug alone in randomised controlled trials. Besides PAH specific treatment, the place of nonspecific pharmaceutical and nonpharmaceutical treatment has been also recently clarified. PMID- 27244645 TI - Reversible Luminescence Modulation upon an Electric Field on a Full Solid-State Device Based on Lanthanide Dimers. AB - Switching luminescence of lanthanide-based molecules through an external electric field is considered as a promising approach toward novel functional molecule based devices. Classic routes use casted films and liquid electrolyte as media for redox reactions. Such protocol, even if efficient, is relatively hard to turn into an effective solid-state device. In this work, we explicitly synthesize lanthanide-based dimers whose luminescent behavior is affected by the presence of Cu(2+) ions. Excellent evaporability of the dimers and utilization of Cu(2+) based solid-state electrolyte makes it possible to reproduce solution behavior at the solid state. Reversible modulation of Cu(2+) ions transport can be achieved by an electric field in a solid-state device, where lanthanide-related luminescence is driven by an electric field. These findings provide a proof-of concept alternative approach for electrically driven modulation of solid-state luminescence and show promising potential for information storage media in the future. PMID- 27244599 TI - Aerobic Exercise and Pharmacological Treatments Counteract Cachexia by Modulating Autophagy in Colon Cancer. AB - Recent studies have correlated physical activity with a better prognosis in cachectic patients, although the underlying mechanisms are not yet understood. In order to identify the pathways involved in the physical activity-mediated rescue of skeletal muscle mass and function, we investigated the effects of voluntary exercise on cachexia in colon carcinoma (C26)-bearing mice. Voluntary exercise prevented loss of muscle mass and function, ultimately increasing survival of C26 bearing mice. We found that the autophagic flux is overloaded in skeletal muscle of both colon carcinoma murine models and patients, but not in running C26 bearing mice, thus suggesting that exercise may release the autophagic flux and ultimately rescue muscle homeostasis. Treatment of C26-bearing mice with either AICAR or rapamycin, two drugs that trigger the autophagic flux, also rescued muscle mass and prevented atrogene induction. Similar effects were reproduced on myotubes in vitro, which displayed atrophy following exposure to C26-conditioned medium, a phenomenon that was rescued by AICAR or rapamycin treatment and relies on autophagosome-lysosome fusion (inhibited by chloroquine). Since AICAR, rapamycin and exercise equally affect the autophagic system and counteract cachexia, we believe autophagy-triggering drugs may be exploited to treat cachexia in conditions in which exercise cannot be prescribed. PMID- 27244646 TI - Does translation involve structural priming? AB - When asked to translate utterances, people might merely make sure that their translations have the same meaning as the source, but they might also maintain aspects of sentence form across languages. We report two experiments in which English-German and German-English bilinguals (without specialist translator training) repeated German ditransitive sentences whose meaning was compatible with more than one grammatical form or translated them into English. Participants almost invariably repeated the sentences accurately, thereby retaining the grammatical structure. Importantly, Experiment 1 found that they tended to repeat grammatical form across languages. Experiment 2 included a condition with sentences that had no grammatical equivalent form in English; here participants tended to persist in the order of thematic roles. We argue that cross-linguistic structural priming plays a major role in the act of translation. PMID- 27244647 TI - Prenatal Antidepressant Use and Risk of Autism Spectrum Disorders in Children. PMID- 27244648 TI - Distribution pattern and allocation of defects in hydrogenated ZnO thin films. AB - A polycrystalline ZnO thin film prepared by atomic layer deposition was annealed in hydrogen at 10 bar and 350-450 degrees C. Hydrogenation induced simultaneous formation of oxygen and zinc vacancies whose concentrations were closely related to the temperature of treatment. Spatial distributions of these defects were analyzed by photoluminescence confocal mapping which revealed that their localized appearances are linked to each other. It was also demonstrated that nanomechanical mapping of elastic modulus distribution could be used to assess the allocation of accumulated defects on the topmost surface of ZnO with a depth resolution of only several atomic layers. The higher the temperature of hydrogenation, the higher the concentration, and more uniform the distribution of surface defects. In addition, the correlation between the surface morphology and the accumulated defects was established. PMID- 27244649 TI - Somatostatin Receptor-Mediated Tumor-Targeting Nanocarriers Based on Octreotide PEG Conjugated Nanographene Oxide for Combined Chemo and Photothermal Therapy. AB - Nano-sized in vivo active targeting drug delivery systems have been developed to a high anti-tumor efficacy strategy against certain cancer-cells-specific. Graphene based nanocarriers with unique physical and chemical properties have shown significant potentials in this aspect. Here, octreotide (OCT), an efficient biotarget molecule, is conjugated to PEGylated nanographene oxide (NGO) drug carriers for the first time. The obtained NGO-PEG-OCT complex shows low toxicity and excellent stability in vivo and is able to achieve somatostatin receptor mediated tumor-specific targeting delivery. Owing to the high loading efficiency and accurate targeting delivery of anti-cancer drug doxorubicin (DOX), our DOX loaded NGO-PEG-OCT complex offers a remarkably improved cancer-cell-specific cellular uptake, chemo-cytotoxicity, and decreased systemic toxicity compared to free DOX or NGO-PEG. More importantly, due to its strong near-infrared absorption, the NGO-PEG-OCT complex further enhances efficient photothermal ablation of tumors, delivering combined chemo and photothermal therapeutic effect against cancer cells. PMID- 27244651 TI - Can't take my eyes off of you: Tendency to maintain cognitive activation of significant other representations. AB - Attachment is related to behaviors, including contact maintenance/proximity seeking, and to the keeping of the attachment figure physically, visually, or mentally accessible. In a series of experiments, we observed an analogous behavior in a simple laboratory task in the absence of any stress-related manipulations. Participants performed an easy, choice reaction time (RT) task (often emotionally neutral) on pictures (or names) of significant others versus other persons, both familiar and unfamiliar to them. Results showed that participants took longer to press the key, which started the next trial, when the current trial involved the picture (or name) of their significant other. This effect was observed among parents who responded to their children's pictures, people who are in a romantic relationship, and young adults who responded to the name of a parent; it was only eliminated when participants adopted an analytic approach (i.e., judged the person's age). These results indicate that attachment related behavioral tendencies, associated with keeping the representation of the significant other active, may be easily invoked in a simple task, even without any apparent stress manipulation. (PsycINFO Database Record PMID- 27244650 TI - Mechanistic Studies on the Stereoselectivity of the Serotonin 5-HT1A Receptor. AB - G-protein-coupled receptors (GPCRs) are involved in a wide range of physiological processes, and they have attracted considerable attention as important targets for developing new medicines. A central and largely unresolved question in drug discovery, which is especially relevant to GPCRs, concerns ligand selectivity: Why do certain molecules act as activators (agonists) whereas others, with nearly identical structures, act as blockers (antagonists) of GPCRs? To address this question, we employed all-atom, long-timescale molecular dynamics simulations to investigate how two diastereomers (epimers) of dihydrofuroaporphine bind to the serotonin 5-HT1A receptor and exert opposite effects. By using molecular interaction fingerprints, we discovered that the agonist could mobilize nearby amino acid residues to act as molecular switches for the formation of a continuous water channel. In contrast, the antagonist epimer remained firmly stabilized in the binding pocket. PMID- 27244652 TI - Faunal Communities Are Invariant to Fragmentation in Experimental Seagrass Landscapes. AB - Human-driven habitat fragmentation is cited as one of the most pressing threats facing many coastal ecosystems today. Many experiments have explored the consequences of fragmentation on fauna in one foundational habitat, seagrass beds, but have either surveyed along a gradient of existing patchiness, used artificial materials to mimic a natural bed, or sampled over short timescales. Here, we describe faunal responses to constructed fragmented landscapes varying from 4-400 m2 in two transplant garden experiments incorporating live eelgrass (Zostera marina L.). In experiments replicated within two subestuaries of the Chesapeake Bay, USA across multiple seasons and non-consecutive years, we comprehensively censused mesopredators and epifaunal communities using complementary quantitative methods. We found that community properties, including abundance, species richness, Simpson and functional diversity, and composition were generally unaffected by the number of patches and the size of the landscape, or the intensity of sampling. Additionally, an index of competition based on species co-occurrences revealed no trends with increasing patch size, contrary to theoretical predictions. We extend conclusions concerning the invariance of animal communities to habitat fragmentation from small-scale observational surveys and artificial experiments to experiments conducted with actual living plants and at more realistic scales. Our findings are likely a consequence of the rapid life histories and high mobility of the organisms common to eelgrass beds, and have implications for both conservation and restoration, suggesting that even small patches can rapidly promote abundant and diverse faunal communities. PMID- 27244654 TI - Helping parents live with the hole in their heart: The role of health care providers and institutions in the bereaved parents' grief journeys. AB - BACKGROUND: Bereaved parents experience significant psychosocial and health sequelae, suggesting that this population may benefit from the ongoing extension of support and resources throughout the grief journey. The interaction of hospital staff with patients and families at the end of a child's life and after death profoundly affects parental grief, offering a unique opportunity for the medical community to positively impact the bereavement experience. The current study was conducted to explore the role of the health care team and medical institutions in the grief journeys of parents whose child died a cancer-related death. METHODS: Eleven bereaved parents participated in 2 focus groups. Responses to each of the 3 main prompts were coded and analyzed independently using semantic content analysis techniques. RESULTS: Four main concepts were identified within the parental narratives, including the importance of strong and ongoing relationships between providers and bereaved families, the importance of high quality communication, the effect of negative experiences between providers and families on parental grief, and the importance of the institution's role in the grief journeys of bereaved parents. CONCLUSIONS: Bereaved parents consistently identified the critical role played by medical staff and medical institutions throughout the grief journey. Key components of bereavement support identified by parents should serve to guide the actions of providers as well as provide a template for the development of a comprehensive bereavement program within an institution. Cancer 2016. (c) 2016 American Cancer Society. Cancer 2016;122:2757 2765. (c) 2016 American Cancer Society. PMID- 27244655 TI - Facile Synthesis of Graphene Sponge from Graphene Oxide for Efficient Dye Sensitized H2 Evolution. AB - Graphene is an advanced carbon energy material due to its excellent properties. Reduction of graphene oxide (GO) is the most promising mass production route of graphene/reduced graphene oxide (rGO). To maintain graphene's properties and avoid restacking of rGO sheets in bulk, the preparation of 3-dimensional porous graphene sponge via 2-dimensional rGO sheets is considered as a good strategy. This article presents a facile route to synthesize graphene sponge by thermal treating GO powder at low temperature of 250 degrees C under N2 atmosphere. The sponge possesses macroporous structure (5-200 nm in size) with BET specific surface area of 404 m(2) g(-1) and high conductivity. The photocatalytic H2 production activity of the rGO sponge with a sensitizer Eosin Y (EY) and cocatalyst Pt was investigated. The rGO sponge shows highly efficient dye sensitized photocatalytic H2 evolution compared to that obtained via a chemical reduction method. The maximum apparent quantum yield (AQY) reaches up to 75.0% at 420 nm. The possible mechanisms are discussed. The synthesis method can be expanded to prepare other graphene-based materials. PMID- 27244653 TI - Financial Relationships between Organizations That Produce Clinical Practice Guidelines and the Biomedical Industry: A Cross-Sectional Study. AB - BACKGROUND: Financial relationships between organizations that produce clinical practice guidelines and biomedical companies are vulnerable to conflicts of interest. We sought to determine whether organizations that produce clinical practice guidelines have financial relationships with biomedical companies and whether there are associations between organizations' conflict of interest policies and recommendations and disclosures provided in guidelines. METHODS AND FINDINGS: We conducted a cross-sectional survey and review of websites of 95 national/international medical organizations that produced 290 clinical practice guidelines published on the National Guideline Clearinghouse website from January 1 to December 31, 2012. Survey responses were available for 68% (65/95) of organizations (167/290 guidelines, 58%), and websites were reviewed for 100% (95/95) of organizations (290/290 guidelines, 100%). In all, 63% (60/95) of organizations producing clinical practice guidelines reported receiving funds from a biomedical company; 80% (76/95) of organizations reported having a policy for managing conflicts of interest. Disclosure statements (disclosing presence or absence of financial relationships with biomedical companies) were available in 65% (188/290) of clinical practice guidelines for direct funding sources to produce the guideline, 51% (147/290) for financial relationships of the guideline committee members, and 1% (4/290) for financial relationships of the organizations producing the guidelines. Among all guidelines, 6% (18/290) disclosed direct funding by biomedical companies, 40% (117/290) disclosed financial relationships between committee members and biomedical companies (38% of guideline committee members, 773/2,043), and 1% (4/290) disclosed financial relationships between the organizations producing the guidelines and biomedical companies. In the survey responses, 60 organizations reported the procedures that they included in their conflict of interest policies (158 guidelines): guidelines produced by organizations reporting more comprehensive conflict of interest policies (per additional procedure, range 5-17) included fewer positive (rate ratio [RR] 0.91, 95% CI 0.86-0.95) and more negative (RR 1.32, 95% CI 1.09-1.60) recommendations regarding patented biomedical products. The clinical practice guidelines produced by organizations reporting more comprehensive conflict of interest policies were also more likely to include disclosure statements for direct funding sources (odds ratio [OR] 1.31, 95% CI 1.10-1.56) and financial relationships of guideline committee members (OR 1.36, 95% CI 1.09-1.79), but not financial relationships of the organizations (0 disclosures). Limitations of the study include the use of the National Guideline Clearinghouse as the single source of clinical practice guidelines and the self-report of survey responses and organizations' website postings. CONCLUSIONS: Financial relationships between organizations that produce clinical practice guidelines and biomedical companies are common and infrequently disclosed in guidelines. Our study highlights the need for an effective policy to manage organizational conflicts of interest and disclosure of financial relationships. PMID- 27244664 TI - Psychometric Properties of the Chinese Version of the M.D. Anderson Dysphagia Inventory for Head and Neck Cancer Patients. AB - BACKGROUND: Dysphagia is a common side effect of anticancer treatments in patients with head and neck cancer (HNC) and can worsen patients' quality of life. A well-established measure is essential to evaluate dysphagia in HNC patients. OBJECTIVES: The aim of this study is to determine the psychometric properties of the Chinese version of the M.D. Anderson Dysphagia Inventory (MDADI C) for HNC patients. METHODS: A total of 220 subjects were included in the study. Reliability was examined by internal consistency (Cronbach's alpha) and test retest reliability (intraclass correlation coefficient). Validity was evaluated with Spearman correlations (r). RESULTS: The Cronbach's alpha and intraclass correlation coefficient of the MDADI-C were .923 and 0.942, respectively. The criterion validity of the MDADI-C was 0.777. The Spearman correlation coefficients of the MDADI-C with the European Organization for Research Into the Treatment of Cancer Quality of Life Questionnaire for Head and Neck Cancer (r = 0.851), Hospital Anxiety and Depression Scale (r = -0.424), radiotherapy dose (r = -0.553), and treatment regimens (r = -0.407) demonstrated good construct validity (all P < .01). CONCLUSIONS: The MDADI-C demonstrated good psychometric properties and would be a valuable tool for clinicians to screen dysphagia rapidly and evaluate its impact on the quality of life of HNC patients. IMPLICATIONS FOR PRACTICE: The MDADI-C could be used to document and monitor the dysphagia level of HNC patients for clinicians, nurses, and researchers. This validated questionnaire will help nurses and doctors to improve dysphagia management in HNC patients and will allow researchers to compare the study results across different countries. PMID- 27244665 TI - Validation of the Korean Version of the Breast Cancer Screening Beliefs Questionnaire. AB - BACKGROUND: Korean immigrant women have been consistently reported as having low participation in breast cancer screening practices. A valid and reliable instrument to explore factors that affect their cancer screening behaviors is essential. OBJECTIVE: The aim of this study was to report the psychometric properties of the Korean version of the Breast Cancer Screening Beliefs Questionnaire (BCSBQ). METHODS: A convenience sample of 249 Korean Australian women was recruited through a number of Korean community organizations in Sydney. RESULTS: Exploratory factor analysis supports a similar fit for the original 3 factor structure of our data set. A significant association was found between the attitudes of these women toward general health checkups and the frequency of their performance of the breast awareness practices and having mammograms. Furthermore, it was found that knowledge and perceptions about the breast cancer scales were significantly associated with education level and that barriers to mammographic screening were much less evident among women who engaged in the 3 screening practices. The results indicated that the Korean version of the BCSBQ had satisfactory validity and internal consistency. The Cronbach's alpha of the 3 subscales ranged between .80 and .88. CONCLUSION: The Korean version of the BCSBQ was confirmed to be a culturally appropriate, valid, and reliable instrument for assessing the beliefs, knowledge, and attitudes to breast cancer and breast cancer screening practices among women of Korean background living in Australia. IMPLICATION FOR PRACTICE: The Korean version of the BCBSQ can provide nurses with insights into the development of culturally sensitive breast health education programs. PMID- 27244666 TI - Development and Psychometric Evaluation of the Lung Cancer Screening Health Belief Scales. AB - BACKGROUND: Lung cancer screening is a recent recommendation for long-term smokers. Understanding individual health beliefs about screening is a critical component in future efforts to facilitate patient-provider conversations about screening participation. OBJECTIVE: The aim of this study was to describe the development and psychometric testing of 4 new scales to measure lung cancer screening health beliefs (perceived risk, perceived benefits, perceived barriers, self-efficacy). METHODS: In phase I, 4 scales were developed from extensive literature review, item modification from existing Breast and Colorectal Cancer Screening Health Belief Scales, focus groups with long-term smokers, and evaluation/feedback from a panel of 10 content experts. In phase II, we conducted a survey of 497 long-term smokers to assess the final scales' reliability and validity. RESULTS: Phase I: content validity was established with the content expert panel. Phase II: internal consistency reliability of the scales was supported with Cronbach's alpha's ranging from .88 to .92. Construct validity was established with confirmatory factor analysis and testing for differences between screeners and nonscreeners in theoretically proposed directions. CONCLUSIONS: Initial testing supports the scales are valid and reliable. These new scales can help investigators identify long-term smokers more likely to screen for lung cancer and are useful for the development and testing of behavioral interventions regarding lung cancer screening. IMPLICATIONS FOR PRACTICE: Development of effective interventions to enhance shared decision making about lung cancer screening between patients and providers must first identify factors influencing the individual's screening participation. Future efforts facilitating patient provider conversations are better informed by understanding the perspective of the individual making the decision. PMID- 27244667 TI - Bowel Dysfunction and Self-management for Bowel Symptoms After Sphincter Preserving Surgery: A Cross-sectional Survey of Chinese Rectal Cancer Patients. AB - BACKGROUND: After sphincter-preserving surgery (SPS), patients with rectal cancer present multiple bowel symptoms, which significantly affect their daily lives. However, to date, few studies have been conducted in China to identify bowel symptoms and self-management behaviors and to explore the relationship between these behaviors and bowel symptoms. OBJECTIVE: To describe bowel symptoms among Chinese patients with rectal cancer after SPS, the self-management behaviors used, and the relationship between the symptoms and behaviors. METHODS: A convenience sample of 175 rectal cancer patients who underwent SPS was recruited from 2 tertiary hospitals in Beijing, China, between July and December 2014. The participants completed a general information structural questionnaire, the Chinese version of the Memorial Sloan-Kettering Cancer Center Bowel Function Instrument, and the Bowel Symptoms Self-Management Behaviors Questionnaire. RESULTS: The frequencies of 18 bowel symptoms ranged between 16.0% and 96.0%. Diet self-management was the most common behavior and therapy self-management was the least frequent behavior. Although therapy self-management had best effects relatively, other effective behaviors included self-management of the perianal skin and self-management of social activities. The frequency of use of self management behaviors was significantly positively associated with bowel symptoms (r=-0.232 to -0.580, P < .01). CONCLUSIONS: Several bowel symptoms after SPS are highly prevalent. Patients with severe bowel symptoms are more likely to use self management behaviors regularly; however, there is no scientific evidence that these behaviors produce satisfactory results. IMPLICATIONS FOR PRACTICE: Healthcare providers should identify bowel symptoms after SPS and develop supportive interventions for the self-management of symptoms. PMID- 27244668 TI - Investigation of Acrylic Resin Disinfection Using Chemicals and Ultrasound. AB - PURPOSE: Dental prosthetic and orthodontic appliances are transported from the clinic to the laboratory for additions and repairs. These appliances, containing microbes from the oral flora, are a high risk for cross-contamination. The aim of this study was to evaluate the effect of chemical and ultrasound disinfection against two in vitro biofilms and an in vivo formed biofilm grown on unprepared and polished polymethyl methacrylate (PMMA) surfaces. MATERIALS AND METHODS: Rough and polished self-curing PMMA surfaces were infected with strains of both Candida albicans and Streptococcus oralis. After incubation, the samples were treated with different disinfection methods, including ultrasound treatment for both 15 and 30 seconds, and immersion in glutaraldehyde and alcohol-based chemical disinfectants (MD520 and Minuten, respectively). The disinfecting efficacy was assessed by colony forming units (CFU) analysis and by scanning electron microscopy (SEM). Furthermore the adequacy of bacterial elimination of application of 30-second ultrasound and MD520 was assessed on PMMA retrieved from ten volunteers by CFU analyses. ANOVA with p = 0.05 followed by the Tukey post hoc test and the Student t-test was used to analyze the data. RESULTS: The ultrasound treatment for 30 seconds, MD520, and Minuten were the most effective disinfectant methods as they reduced the microbial counts compared to the control (p < 0.05) as shown in the in vitro analyses. S. oralis adhered more to rough acrylic resin surfaces (p < 0.05). Ultrasound treatment was the most effective way to reduce microbial counts on PMMA exposed to oral flora (p = 0.043). CONCLUSION: Ultrasound treatment for 30 seconds was effective against C. albicans, S. oralis, and the oral flora as shown by testing microbial growth on agar plates and SEM. PMID- 27244669 TI - Iron(III)-Catalyzed Arylation of Spiro-Epoxyoxindoles with Phenols/Naphthols towards the Synthesis of Spirocyclic Oxindoles. AB - An efficient and highly regioselective iron(III)-catalyzed Friedel-Crafts-type arylation of spiro-epoxyoxindoles with phenols was developed for rapid access to 3-(3-indolyl)-oxindole-3-methanols, which could be further elaborated into benzofuranyl-spirooxindoles under Mitsunobu conditions. When spiro-epoxyoxindoles were reacted with naphthols in the presence of a catalytic amount of FeCl3 ?6 H2 O in dichloromethane, they underwent a tandem Friedel-Crafts-type arylation and O cyclization to yield novel naphthofuranyl-spirooxindoles in excellent yields. This method is applied to enable the efficient and highly regioselective synthesis of a small-molecule inhibitor of the sodium channel Nav 1.7 (+/-) XEN402, which is currently in a phase IIb clinical trial for the treatment of pain. PMID- 27244670 TI - Sense of coherence and periodontal health outcomes. AB - OBJECTIVE: Sense of Coherence (SOC) has been associated with perceived oral health measures, but the contribution of SOC to clinical measures is still unclear. The aim of the present cross-sectional study was to evaluate the potential association between periodontal health outcomes, such as periodontal clinical parameters and perceived periodontal health, and SOC. MATERIALS AND METHODS: The study sample comprised 276 individuals, aged 18-60 years, from Belo Horizonte, Brazil. Participants answered questionnaires covering sociodemographic variables, self-perceived periodontal health and SOC. Full-mouth periodontal examinations were performed. The sample was divided into three groups according to SOC score: (a) SOC1 = weak (24-46); (b) SOC2 = moderate (47-51); (c) SOC3 = strong (52-65). Multivariate analyses including appropriate logistic or linear regression models were performed to evaluate the association between periodontal health outcomes and biological, sociodemographic and behavioural variables. RESULTS: Perceived general oral health was associated with family income bracket (p = 0.010), smoking (p = 0.004), dental flossing (p = 0.017) and SOC (weak SOC: p = 0.005). Perceived gum disease and perceived periodontal disease were associated with SOC (weak SOC: p = 0.001 and p = 0.015, respectively). CONCLUSIONS: Overall, perceived periodontal health outcomes were associated with SOC. However, no association between clinical periodontal health outcomes and SOC were observed. PMID- 27244672 TI - An asteroidal origin for water in the Moon. AB - The Apollo-derived tenet of an anhydrous Moon has been contested following measurement of water in several lunar samples that require water to be present in the lunar interior. However, significant uncertainties exist regarding the flux, sources and timing of water delivery to the Moon. Here we address those fundamental issues by constraining the mass of water accreted to the Moon and modelling the relative proportions of asteroidal and cometary sources for water that are consistent with measured isotopic compositions of lunar samples. We determine that a combination of carbonaceous chondrite-type materials were responsible for the majority of water (and nitrogen) delivered to the Earth-Moon system. Crucially, we conclude that comets containing water enriched in deuterium contributed significantly <20% of the water in the Moon. Therefore, our work places important constraints on the types of objects impacting the Moon ~4.5-4.3 billion years ago and on the origin of water in the inner Solar System. PMID- 27244671 TI - The E3 ubiquitin ligase ZNRF2 is a substrate of mTORC1 and regulates its activation by amino acids. AB - The mechanistic Target of Rapamycin complex 1 (mTORC1) senses intracellular amino acid levels through an intricate machinery, which includes the Rag GTPases, Ragulator and vacuolar ATPase (V-ATPase). The membrane-associated E3 ubiquitin ligase ZNRF2 is released into the cytosol upon its phosphorylation by Akt. In this study, we show that ZNRF2 interacts with mTOR on membranes, promoting the amino acid-stimulated translocation of mTORC1 to lysosomes and its activation in human cells. ZNRF2 also interacts with the V-ATPase and preserves lysosomal acidity. Moreover, knockdown of ZNRF2 decreases cell size and cell proliferation. Upon growth factor and amino acid stimulation, mTORC1 phosphorylates ZNRF2 on Ser145, and this phosphosite is dephosphorylated by protein phosphatase 6. Ser145 phosphorylation stimulates vesicle-to-cytosol translocation of ZNRF2 and forms a novel negative feedback on mTORC1. Our findings uncover ZNRF2 as a component of the amino acid sensing machinery that acts upstream of Rag-GTPases and the V ATPase to activate mTORC1. PMID- 27244674 TI - Better Palliative Care for All: Improving the Lived Experience With Cancer. PMID- 27244673 TI - Preserved Nephrogenesis Following Partial Nephrectomy in Early Neonates. AB - Reconstitution of total nephron segments after resection in the adult kidney has not been achieved; however, whether the neonatal kidney can maintain the capacity for neo-nephrogenesis after resection is unknown. We performed partial resection of the kidney in neonatal rats on postnatal days 1 (P1x kidney) and 4 (P4x kidney) and examined morphological changes and relevant factors. The P1x kidney bulged into the newly formed cortex from the wound edge, while nephrogenesis failure was prominent in the P4x kidney. Twenty-eight days post-resection, the glomerular number, cortex area, and collecting duct were preserved in the P1x kidney, whereas these parameters were markedly decreased in the P4x kidney. During normal development, Six2 expression and Six2+ nephron progenitor cells in the cap mesenchyme both rapidly disappear after birth. However, time course analysis for the P1x kidney showed that Six2 expression and Six2+ cells were well preserved in the tissue surrounding the resected area even 2 days after resection. In conclusion, our results indicate that kidneys in early neonate rats retain the capability for neo-nephrogenesis after resection; however, this ability is lost soon after birth, which may be attributed to a declining amount of Six2+ cells. PMID- 27244675 TI - School Choice, School Quality and Postsecondary Attainment. AB - We study the impact of a public school choice lottery in Charlotte-Mecklenburg schools on college enrollment and degree completion. We find a significant overall increase in college attainment among lottery winners who attend their first choice school. Using rich administrative data on peers, teachers, course offerings and other inputs, we show that the impacts of choice are strongly predicted by gains on several measures of school quality. Gains in attainment are concentrated among girls. Girls respond to attending a better school with higher grades and increases in college-preparatory course-taking, while boys do not. PMID- 27244678 TI - Adverse Health Effects of Intermittent vs Continuous Androgen Deprivation Therapy for Metastatic Prostate Cancer: Relating 33 Years of Patient Clinical Care. PMID- 27244679 TI - Adverse Health Effects of Intermittent vs Continuous Androgen Deprivation Therapy for Metastatic Prostate Cancer-Reply. PMID- 27244680 TI - beta- and gamma-Human Papillomavirus Types and Smoking in Head and Neck Cancer. PMID- 27244681 TI - beta- and gamma-Human Papillomavirus Types and Smoking in Head and Neck Cancer Reply. PMID- 27244682 TI - BRCA1 and BRCA2 Testing Among Young Breast Cancer Survivors. PMID- 27244683 TI - Use of Very Small Embryonic-Like Stem Cells to Avoid Legal, Ethical, and Safety Issues Associated With Oncofertility. PMID- 27244684 TI - Use of Very Small Embryonic-Like Stem Cells to Avoid Legal, Ethical, and Safety Issues Associated With Oncofertility-Reply. PMID- 27244686 TI - Cartilage-inspired superelastic ultradurable graphene aerogels prepared by the selective gluing of intersheet joints. AB - In this study, we demonstrate a cartilage-inspired superelastic and ultradurable nanocomposite strategy for the selective inclusion of viscoelastic poly(dimethylsiloxane) (PDMS) into graphene sheet junctions to create effective stress-transfer pathways within three-dimensional (3D) graphene aerogels (GAs). Inspired by the joint architectures in the human body, where small amounts of soft cartilage connect stiff (or hard) but hollow (and thus lightweight) bones, the 3D internetworked GA@PDMS achieves synergistic toughening. The resulting GA@PDMS nanocomposites exhibit fully reversible structural deformations (99.8% recovery even at a 90% compressive strain) and high compressive mechanical strength (448.2 kPa at a compressive strain of 90%) at repeated compression cycles. Owing to the combination of excellent mechanical and electrical properties, the GA@PDMS nanocomposites are used as signal transducers for strain sensors, showing very short response and recovery times (in the millisecond range) with reliable sensitivity and extreme durability. Furthermore, the proposed system is applied to electronic scales with a large detectable weight of about 4600 times greater than its own weight. Such bio-inspired cartilage architecture opens the door to fabricate new 3D multifunctional and mechanically durable nanocomposites for emerging applications, which include sensors, actuators, and flexible devices. PMID- 27244687 TI - Vegetation community change in Atlantic oak woodlands along a nitrogen deposition gradient. AB - Atlantic old sessile oak woodlands are of high conservation importance in Europe, listed in the European Union (EU) Habitats Directive Annex I, and known for their rich bryophyte communities. Their conservation status ranges from unfavourable to bad across their known distribution, which is predominantly within the UK and Ireland, but also extends into Iberia and Brittany. The objectives of this study were to determine if nitrogen (N) deposition, a known driver of terrestrial biodiversity loss, was a significant predictor of community composition in old sessile oak woodlands (i.e., EU Habitats Directive Annex I class: 91A0), and to identify significant changes in individual plant species and community-level abundance (i.e., change points) along an N deposition gradient. Releve data from 260 Irish oak woodland plots were evaluated using Canonical Correspondence Analysis (CCA) and Threshold Indicator Taxa ANalysis (TITAN). Nitrogen deposition accounted for 14% of the explainable variation in the dataset (inertia = 0.069, p < 0.005). A community scale change point of 13.2 kg N ha(-1) yr(-1) was indicated by TITAN, which falls within the current recommended critical load (CL) range for acidophilous Quercus-dominated (oak) woodlands (10-15 kg N ha(-1) yr(-1)). The results suggest that the current CL is sufficient for maintaining a core group of indicator species in old sessile oak woodlands, but many nutrient sensitive species may disappear even at the CL range minimum. PMID- 27244688 TI - Impact of the increased adoption of prenatal cfDNA screening on non-profit patient advocacy organizations in the United States. AB - The 'Stakeholder Perspectives on Noninvasive Prenatal Genetic Screening' Symposium was held in conjunction with the 2015 annual meeting of the International Society for Prenatal Diagnosis. During the day-long meeting, a panel of patient advocacy group (PAG) representatives discussed concerns and challenges raised by prenatal cell-free DNA (cfDNA) screening, which has resulted in larger demands upon PAGs from concerned patients receiving prenatal cfDNA screening results. Prominent concerns included confusion about the accuracy of cfDNA screening and a lack of patient education resources about genetic conditions included in cfDNA screens. Some of the challenges faced by PAGs included funding limitations, lack of consistently implemented standards of care and oversight, diverse perspectives among PAGs and questions about neutrality, and lack of access to training and genetic counselors. PAG representatives also put forward suggestions for addressing these challenges, including improving educational and PAG funding and increasing collaboration between PAGs and the medical community. (c) 2016 John Wiley & Sons, Ltd. PMID- 27244685 TI - Pharmacological activation of lysophosphatidic acid receptors regulates erythropoiesis. AB - Lysophosphatidic acid (LPA), a growth factor-like phospholipid, regulates numerous physiological functions, including cell proliferation and differentiation. In a previous study, we have demonstrated that LPA activates erythropoiesis by activating the LPA 3 receptor subtype (LPA3) under erythropoietin (EPO) induction. In the present study, we applied a pharmacological approach to further elucidate the functions of LPA receptors during red blood cell (RBC) differentiation. In K562 human erythroleukemia cells, knockdown of LPA2 enhanced erythropoiesis, whereas knockdown of LPA3 inhibited RBC differentiation. In CD34(+) human hematopoietic stem cells (hHSC) and K526 cells, the LPA3 agonist 1-oleoyl-2-methyl-sn-glycero-3-phosphothionate (2S-OMPT) promoted erythropoiesis, whereas the LPA2 agonist dodecyl monophosphate (DMP) and the nonlipid specific agonist GRI977143 (GRI) suppressed this process. In zebrafish embryos, hemoglobin expression was significantly increased by 2S-OMPT treatment but was inhibited by GRI. Furthermore, GRI treatment decreased, whereas 2S-OMPT treatment increased RBC counts and amount of hemoglobin level in adult BALB/c mice. These results indicate that LPA2 and LPA3 play opposing roles during RBC differentiation. The pharmacological activation of LPA receptor subtypes represent a novel strategies for augmenting or inhibiting erythropoiesis. PMID- 27244689 TI - A Broadband THz-TDS System Based on DSTMS Emitter and LTG InGaAs/InAlAs Photoconductive Antenna Detector. AB - We demonstrate a 4-f terahertz time-domain spectroscopy (THz-TDS) system using an organic crystal DSTMS as the THz emitter and a low temperature grown (LTG) InGaAs/InAlAs photoconductive antenna as the receiver. The system covers a frequency range from 0.2 up to 8 THz. The influences of the pump laser power, the probe laser power and the azimuthal angle of the DSTMS crystal on the time-domain THz amplitude are experimentally analyzed. The frequency accuracy of the system is verified by measuring two metamaterial samples and a lactose film in this THz TDS system. The proposed combination of DSTMS emission and PC antenna detection realizes a compact and low-cost THz-TDS scheme with an ultra-broad bandwidth, which may promote the development and the applications of THz-TDS techniques. PMID- 27244690 TI - Synthetic high-density lipoprotein-like nanoparticles potently inhibit cell signaling and production of inflammatory mediators induced by lipopolysaccharide binding Toll-like receptor 4. AB - Toll-like receptor 4 (TLR4) plays a critical role in the innate immune system. Stimulation of TLR4 occurs upon binding lipopolysaccharide (LPS), a component of Gram-negative bacterial cell walls. Due to the potency of the induced inflammatory response, there is a growing interest in agents that can most proximally modulate this LPS/TLR4 interaction to prevent downstream cell signaling events and the production of inflammatory mediators. Building on the natural ability of human high-density lipoprotein (HDL) to bind LPS, we synthesized a suite of HDL-like nanoparticles (HDL-like NP). We identified one HDL-like NP that was particularly effective at decreasing TLR4 signaling caused by addition of purified LPS or Gram-negative bacteria to model human cell lines or primary human peripheral blood cells. The HDL-like NP functioned to inhibit TLR4-dependent inflammatory response to LPS derived from multiple bacterial species. Mechanistically, data show that the NP mainly functions by scavenging and neutralizing the LPS toxin. Taken together, HDL-like NPs constitute a powerful endotoxin scavenger with the potential to significantly reduce LPS mediated inflammation. PMID- 27244692 TI - Human amniotic fluid stem cells labeled with up-conversion nanoparticles for imaging-monitored repairing of acute lung injury. AB - Human amniotic fluid stem (hAFS) cells have generated a great deal of excitement in cell-based therapies and regenerative medicine. Here, we examined the effect of hAFS cells labeled with dual-polymer-coated UCNP-PEG-PEI nanoparticles in a murine model of acute lung injury (ALI). We observed hAFS cells migration to the lung using highly sensitive in vivo upconversion luminescence (UCL) imaging. We demonstrated that hAFS cells remained viable and retained their ability to differentiate even after UCNP-PEG-PEI labeling. More importantly, hAFS cells displayed remarkable positive effects on ALI-damaged lung tissue repair compared with mouse bone marrow mesenchymal stem cells (mBMSCs), which include recovery of the integrity of alveolar-capillary membrane, attenuation of transepithelial leukocyte and neutrophil migration, and down-regulation of proinflammatory cytokine and chemokine expression. Our work highlights a promising role for imaging-guided hAFS cell-based therapy in ALI. PMID- 27244691 TI - Near infrared light responsive hybrid nanoparticles for synergistic therapy. AB - A near infrared (NIR) light responsive chromophore 7-(diethylamino)-4 (hydroxymethyl)-2H-chromen-2-one (DEACM) was synthesized and incorporated to beta cyclodextrins with cRGD functionalized poly(ethylene glycol), the amphiphiles were coordinated with Au nanorods or nanoparticles to load anticancer drug doxorubicin (DOX) for fabricating hybrid nanoparticles. The pi-pi stacking interaction between DEACM and DOX was formed in the hybrid nanoparticles, which contributed to the high drug loading content. The Au nanorods or nanoparticles enhanced the photosolvolysis of DEACM under the irradiation of NIR with 808 nm wavelength and triggered the accelerated drug release from the nanoparticles. The drug loaded hybrid nanoparticles with NIR irradiation exhibited efficient inhibition effect on the proliferation of 4T1 breast cancer cells in vitro. The in vivo anticancer activity study on breast cancer bearing mice revealed that the hybrid nanoparticles containing Au nanorods exhibited excellent anticancer activity under the irradiation of 808 nm wavelength NIR with 800 mW. PMID- 27244693 TI - A systematic study of protein labeling by fluorogenic probes using cysteine targeting vinyl sulfone-cyclooctyne tags. AB - Fluorescent tagging of proteins via accessible cysteine residues is of paramount importance. In this study, model proteins of interest (mitogen-activated protein kinases) were labeled successfully in native state on their free thiols by direct fluorescence derivatization, or in a sequential manner where conjugation of the site specific linker and the fluorophore is carried out in two steps. To this end we designed and prepared two novel chemical reporters carrying vinyl sulfone as Cys targeting function and cyclooctyne motifs, suitable for subsequent conjugation with fluorogenic azides via copper free strain-promoted azide-alkyne click chemistry. Direct and sequential labeling reaction steps were analyzed by native PAGE, capillary zone electrophoresis and tandem mass spectrometry. The efficiency of tagging was correlated with solvent accessibility of the Cys residues. Our results indicated that conjugation of native proteins by vinyl sulfone linkers was fast and thiol-selective. Subsequent click reaction with fluorogenic dyes generates intensive fluorescence signals and fulfills all requirements of bioorthogonality. PMID- 27244694 TI - Authors' reply to Rapamycin: A promising agent to treat cancer pain? PMID- 27244696 TI - The spatial distribution of pollutants in pipe-scale of large-diameter pipelines in a drinking water distribution system. AB - In large-diameter drinking water pipelines, spatial differences in hydraulic and physiochemical conditions may also result in spatial variations in pipe corrosion, biofilm growth and pollutant accumulation. In this article, the spatial distributions of various metals and organic contaminants in two 19-year old grey cast iron pipes which had an internal diameter of 600mm (DN600), were investigated and analyzed by Atomic Absorption Spectrometry, Gas Chromatography Mass Spectrometry, Energy Dispersive Spectrometer, X-ray Diffraction, etc. The spatial distribution of heavy metals varied significantly across the pipe section, and iron, manganese, lead, copper, and chromium were highest in concentration in the upper portion pipe-scales. However, the highest aluminum and zinc content was detected in the lower portion pipe-scales. Apart from some common types of hydrocarbons formed by microbial metabolites, there were also some microalgae metabolites and exogenous contaminants accumulated in pipe-scale, which also exhibited high diversity between different spatial locations. The spatial distributions of the physical and chemical properties of pipe-scale and contaminants were quite different in large-diameter pipes. The finding put forward higher requirements on the research method about drinking water distribution system chemical safety. And the scientific community need understand trend and dynamics of drinking water pipe systems better. PMID- 27244695 TI - Identification of a reticulocyte-specific binding domain of Plasmodium vivax reticulocyte-binding protein 1 that is homologous to the PfRh4 erythrocyte binding domain. AB - The Plasmodium vivax reticulocyte-binding protein (RBP) family was identified based on the annotation of adhesive ligands in the P. vivax genome. Reticulocyte specific interactions with the PvRBPs (PvRBP1 and PvRBP2) were previously reported. Plasmodium falciparum reticulocyte-binding protein homologue 4 (PfRh4, a homologue of PvRBP1) was observed to possess erythrocyte-binding activity via complement receptor 1 on the erythrocyte surface. However, the reticulocyte binding mechanisms of P. vivax are unclear because of the large molecular mass of PvRBP1 (>326 kDa) and the difficulty associated with in vitro cultivation. In the present study, 34 kDa of PvRBP1a (PlasmoDB ID: PVX_098585) and 32 kDa of PvRBP1b (PVX_098582) were selected from a 30 kDa fragment of PfRh4 for reticulocyte specific binding activity analysis. Both PvRBP1a and PvRBP1b were found to be localized at the microneme in the mature schizont-stage parasites. Naturally acquired immune responses against PvRBP1a-34 and PvRBP1b-32 were observed lower than PvDBP-RII. The reticulocyte-specific binding activities of PvRBP1a-34 and PvRBP1b-32 were significantly higher than normocyte binding activity and were significantly reduced by chymotrypsin treatment. PvRBP1a and 1b, bind to reticulocytes and that this suggests that these ligands may have an important role in P. vivax merozoite invasion. PMID- 27244697 TI - Prenatal Antidepressant Use and Risk of Autism Spectrum Disorders in Children. PMID- 27244698 TI - Technical note for post-auricular route surgery in Mongolian gerbil. AB - The Mongolian gerbil (Meriones unguiculatus) is commonly used in hearing research because the hearing frequency spectrum of the gerbil is rather similar to that of the human being. However, a precise description of the surgical post-auricular route has not been reported. The aim of this technical note is to provide details on the procedure and the surgical anatomy of the post-auricular route in the Mongolian gerbil. Surgery was performed under general anesthesia on eight (2 males and 6 females) adult Mongolian gerbils. All steps of the post-auricular route were detailed. This surgery provided an access to the following structures: the semi-circular posterior and lateral canals, the external auditory meatus, the tympanic membrane, the round window, the stapes, the stapedial artery and the reliefs of the cochlea. No anatomic variation was noticed among the 8 animals. This post-auricular route in the Mongolian gerbil defines a brief and simple surgery, overall standardized as a consequence of the absence of common anatomic variation, with painless and uncomplicated post-operative stage. PMID- 27244699 TI - Emerging trends in surgical and adjuvant radiation therapies among women diagnosed with ductal carcinoma in situ. AB - BACKGROUND: The use of surgery and radiation therapy in treating ductal carcinoma in situ (DCIS) is directed by treatment guidelines and evidence from research. This study investigated recent patterns in DCIS treatment by demographic factors. METHODS: Data for women diagnosed with DCIS between 1998 and 2011 (n = 416,232) in the National Cancer Data Base were assessed for trends in treatment patterns by age group, calendar year, ancestral/ethnic group, and geographic region. The likelihood of receiving specific treatment modalities was analyzed with multivariable logistic regression. RESULTS: DCIS cases were most frequently treated with breast-conserving surgery (BCS) and adjuvant radiation (45.6%). After an initial rise, the use of adjuvant radiation after BCS plateaued at approximately 70% after 2007, with increasing utilization of mastectomy beyond 2005. In addition, there was an increasing trend in postmastectomy reconstruction over time, and women of African ancestry (odds ratio [OR], 0.69; 95% confidence interval [CI], 0.66-0.72) and Hispanic women (OR, 0.83; 95% CI, 0.78-0.89) were less likely to undergo reconstruction in comparison with women of European ancestry. A similar trend was observed in contralateral risk-reducing mastectomy utilization, with women of European ancestry having a more rapid rise in the utilization of contralateral risk-reducing mastectomy in comparison with all other ancestral/ethnic groups. CONCLUSIONS: Recent trends demonstrate a plateau in radiation therapy administration after BCS along with increasing utilization of mastectomy, reconstruction, and contralateral risk-reducing mastectomy. There are substantial differences in treatment utilization according to ancestry/ethnicity and geographical region. Further studies examining patient physician decision making surrounding DCIS treatment are warranted. Cancer 2016. (c) 2016 American Cancer Society. Cancer 2016;122:2810-2818. (c) 2016 American Cancer Society. PMID- 27244700 TI - HYADD 4 versus methylprednisolone acetate in symptomatic knee osteoarthritis: a single-centre single blind prospective randomised controlled clinical study with 1-year follow-up. AB - OBJECTIVES: The aim of the present study was to compare the clinical results and the quality of life in patients with symptomatic knee osteoarthritis randomised to either a new HA (HYADD 4) or corticosteroid (CS). A separate rationale was to evaluate the safety profile of HYADD 4. METHODS: All the patients presenting for unilateral symptomatic primary knee osteoarthritis were prospectively randomly assigned to receive 2 injections of either HYADD 4 or CS, and were evaluated before the injections and at 6, 12, 26 and 52 weeks. Primary end point was WOMAC score at 26 weeks; secondary end points were WOMAC score, VAS for pain, and SF-36 score at any time point. RESULTS: There were 53 females and 22 males in the HYADD 4 group (mean age 71.5+/-10.6 years), and 50 females and 25 males in the CS group (mean age 68.6+/-9.9 years). The observed sided effects were mild and their incidence was similar in the two groups. Patients in the HYADD 4 group reported significantly better WOMAC scores at 26 weeks. The patients improved in all considered outcomes after the injections, with a peak of therapeutic effect between 6 and 12 weeks. Patients in the HYADD 4 group obtained significantly better scores than the CS group up to 26 weeks. At the 1-year follow-up no statistically significant differences between treatments were detected. CONCLUSIONS: HYADD 4 did not have significantly higher side effects when compared to CS injections and provided better short-term (but not long-term) control of symptoms in patients with mild to moderate knee osteoarthritis. Patients with less pain and dysfunction at baseline may be the best candidates for HYADD 4 injections. PMID- 27244701 TI - Stereoselective Koenigs-Knorr Glycosylation Catalyzed by Urea. AB - A stereoselective Koenigs-Knorr glycosylation reaction under the catalysis of urea is described. This method is characterized by urea-mediated hydrogen-bond activation and subsequent glycosylation with glycosyl chlorides or bromides. Excellent yields and high anomeric selectivity can be achieved in most cases. Moreover, the low alpha-stereoselectivity of glycosylations observed when using perbenzylated glucosyl donors can be greatly improved by the addition of tri (2,4,6-trimethoxyphenyl)phosphine (TTMPP). PMID- 27244702 TI - A highly selective colorimetric and fluorescent turn-on chemosensor for Al(3+) based on naphthalimide derivative. AB - A new chemosensor L based on the naphthalimide moiety was synthesized and characterized. L exhibited the high selectivity and sensitivity for Al(3+) in CH3OH, along with colorimetric and fluorometric dual-signaling responses based on the joint contribution of the ICT and CHEF processes. A 1:1 stoichiometry for the L-Al(3+) complex was formed with an association constant of 7.6*10(4)M(-1), and the limit of detection for Al(3+) was determined as 6.9MUM. In addition, L was successfully applied to the determination of Al(3+) in real water samples. PMID- 27244703 TI - Hollow Gold Cages and Their Topological Relationship to Dual Fullerenes. AB - Golden fullerenes have recently been identified by photoelectron spectra by Bulusu et al. [S. Bulusu, X. Li, L.-S. Wang, X. C. Zeng, PNAS 2006, 103, 8326 8330]. These unique triangulations of a sphere are related to fullerene duals having exactly 12 vertices of degree five, and the icosahedral hollow gold cages previously postulated are related to the Goldberg-Coxeter transforms of C20 starting from a triangulated surface (hexagonal lattice, dual of a graphene sheet). This also relates topologically the (chiral) gold nanowires observed to the (chiral) carbon nanotubes. In fact, the Mackay icosahedra well known in gold cluster chemistry are related topologically to the dual halma transforms of the smallest possible fullerene C20 . The basic building block here is the (111) fcc sheet of bulk gold which is dual to graphene. Because of this interesting one-to one relationship through Euler's polyhedral formula, there are as many golden fullerene isomers as there are fullerene isomers, with the number of isomers Niso increasing polynomially as O(Niso9 ). For the recently observed Au16- , Au17- , and Au18- we present simulated photoelectron spectra including all isomers. We also predict the photoelectron spectrum of Au32- . The stability of the golden fullerenes is discussed in relation with the more compact structures for the neutral and negatively charged Au12 to Au20 and Au32 clusters. As for the compact gold clusters we observe a clear trend in stability of the hollow gold cages towards the (111) fcc sheet. The high stability of the (111) fcc sheet of gold compared to the bulk 3D structure explains the unusual stability of these hollow gold cages. PMID- 27244704 TI - Error in Funding Statement. PMID- 27244705 TI - Neurodevelopmental Outcomes Following Bevacizumab Injections for Retinopathy of Prematurity. AB - BACKGROUND AND OBJECTIVE: Bevacizumab intravitreal injection, a vascular endothelial growth factor inhibitor, is used to treat retinopathy of prematurity (ROP). However, concerns have been raised regarding its systemic absorption and effect on developing tissues including brain. This study compared neurodevelopment at 18 months' corrected age in preterm infants of <29 weeks' gestation treated with bevacizumab versus laser ablation. METHODS: Data from the Canadian Neonatal Network and the Canadian Neonatal Follow-Up Network databases were retrospectively reviewed. Infants born at <29 weeks' in 2010-2011 with treated ROP were studied. Neurodevelopmental outcome at 18 months was assessed by using neurologic examination and the Bayley Scales of Infant and Toddler Development Third Edition. Regression analyses were performed. RESULTS: Of 125 treated infants, 27 received bevacizumab and 98 laser. The bevacizumab group, compared with laser, obtained a median Bayley Scales of Infant and Toddler Development Third Edition motor composite score of 81 (interquartile range, 70 91) versus 88 (79-97), a language composite score of 79 (65-97) versus 89 (74 97), and a cognitive score of 90 (80-100) versus 90 (85-100). Difference was detected on the motor score only (P = .02). Odds of severe neurodevelopmental disabilities (Bayley scores <70, severe cerebral palsy, hearing aids, or bilateral blindness) was 3.1 times higher (95% confidence interval: 1.2-8.4) in infants treated with bevacizumab versus laser after adjusting for gestational age, gender, maternal education, Score for Neonatal Acute Physiology-II score, bronchopulmonary dysplasia, sepsis, and severe brain injury. CONCLUSIONS: Preterm infants treated with bevacizumab versus laser had higher odds of severe neurodevelopmental disabilities. Further investigation on the long-term safety of antivascular endothelial growth factor treatment of ROP is needed. PMID- 27244706 TI - Parent Mentors and Insuring Uninsured Children: A Randomized Controlled Trial. AB - BACKGROUND: Six million US children are uninsured, despite two-thirds being eligible for Medicaid/Children's Health Insurance Program (CHIP), and minority children are at especially high risk. The most effective way to insure uninsured children, however, is unclear. METHODS: We conducted a randomized trial of the effects of parent mentors (PMs) on insuring uninsured minority children. PMs were experienced parents with >=1 Medicaid/CHIP-covered child who received 2 days of training, then assisted families for 1 year with insurance applications, retaining coverage, medical homes, and social needs; controls received traditional Medicaid/CHIP outreach. The primary outcome was obtaining insurance 1 year post-enrollment. RESULTS: We enrolled 237 participants (114 controls; 123 in PM group). PMs were more effective (P< .05 for all comparisons) than traditional methods in insuring children (95% vs 68%), and achieving faster coverage (median = 62 vs 140 days), high parental satisfaction (84% vs 62%), and coverage renewal (85% vs 60%). PM children were less likely to have no primary care provider (15% vs 39%), problems getting specialty care (11% vs 46%), unmet preventive (4% vs 22%) or dental (18% vs 31%) care needs, dissatisfaction with doctors (6% vs 16%), and needed additional income for medical expenses (6% vs 13%). Two years post-PM cessation, more PM children were insured (100% vs 76%). PMs cost $53.05 per child per month, but saved $6045.22 per child insured per year. CONCLUSIONS: PMs are more effective than traditional Medicaid/CHIP methods in insuring uninsured minority children, improving health care access, and achieving parental satisfaction, but are inexpensive and highly cost-effective. PMID- 27244707 TI - Concerns for Development After Bevacizumab Treatment of ROP. PMID- 27244708 TI - An Enhanced Visualization Process Model for Incremental Visualization. AB - With today's technical possibilities, a stable visualization scenario can no longer be assumed as a matter of course, as underlying data and targeted display setup are much more in flux than in traditional scenarios. Incremental visualization approaches are a means to address this challenge, as they permit the user to interact with, steer, and change the visualization at intermediate time points and not just after it has been completed. In this paper, we put forward a model for incremental visualizations that is based on the established Data State Reference Model, but extends it in ways to also represent partitioned data and visualization operators to facilitate intermediate visualization updates. In combination, partitioned data and operators can be used independently and in combination to strike tailored compromises between output quality, shown data quantity, and responsiveness-i.e., frame rates. We showcase the new expressive power of this model by discussing the opportunities and challenges of incremental visualization in general and its usage in a real world scenario in particular. PMID- 27244709 TI - Interactive Urban Context-Aware Visualization via Multiple Disocclusion Operators. AB - In 3D urban environments, features of interest (FOIs) are often occluded by clusters of buildings, which prevent a clear overview of important spatial features. State-of-the-art disocclusion methods for urban environments fall short of preserving cityscape appearance or require time-consuming computation. These methods use only one or two operators for disocclusion and might not strike a good balance between disocclusion and distortion control. We present a novel, automatic method enabling interactive context-aware visualization of urban features of interest, which combines four effective disocclusion operators including viewpoint elevation, road shifting, building scaling, and building displacement to disocclude the features of interest. Our method provides an optimum compromise among the disocclusion operators via an efficient constrained optimization and the post-polishing phrases, which minimizes the distortions while enforcing the visibility of the FOIs. The 3D views generated at interactive frame rates ensure a resemblance in the cityscape appearance to its original ones and provide a good overview of the FOIs. The experiments with real data demonstrate that our method can greatly facilitate tasks such as navigation, wayfinding, and information overlay. PMID- 27244710 TI - Parallel On-Demand Hierarchy Construction on Contemporary GPUs. AB - We present the first parallel on-demand spatial hierarchy construction algorithm targeting ray tracing on many-core processors such as GPUs. The method performs simultaneous ray traversal and spatial hierarchy construction focused on the parts of the data structure being traversed. The method is based on a versatile framework built around a task pool and runs entirely on the GPU. We show that the on-demand construction can improve rendering times compared to full hierarchy construction. We evaluate our method on both object (BVH) and space (kd-tree) subdivision data structures and compare them mutually. The on-demand method is particularly beneficial for rendering large scenes with high occlusion. We also present SAH kd-tree builder that outperforms previous state-of-the-art builders running on the GPU. PMID- 27244712 TI - Detecting Interactions between the Renal Autoregulation Mechanisms in Time and Space. AB - OBJECTIVE: Our objective is to identify localized interactions between the renal autoregulation mechanisms over time. METHODS: A time-varying phase-randomized wavelet bicoherence detector for quadratic phase coupling between tubuloglomerular feedback and the myogenic response is presented. Through simulations we show its ability to interrogate quadratic phase coupling. The method is applied to kidney blood flow and laser speckle imaging sequences of cortical perfusion from anesthetized rats before and after nonselective inhibition of nitric-oxide synthase. RESULTS: Quadratic phase coupling in kidney blood flow data was present in four out of nine animals during the control period for 13.0 +/- 5.6% (mean +/- SD) of time and in five out of nine animals during inhibition of nitric-oxide synthase for 15.8 +/- 8.2% of time. Approximately 60% of time-series extracted from laser speckle imaging pixels of the renal cortex showed significant quadratic phase coupling. Pixels with significant coupling had a median coupling length of 10.8 +/- 2.2% and 12.1 +/- 3.1% of time with the 95th percentile of pixels being coupled for 25.5 +/- 4.4% and 30.9 +/- 6.4% of time during control and inhibition of nitric-oxide synthase, respectively. CONCLUSION: These results indicate quadratic phase coupling exists in short time intervals between tubuloglomerular feedback and the myogenic response and is detected more often in local renal perfusion signals than whole kidney blood flow in anesthetized rats. SIGNIFICANCE: Combining the detector and laser speckle imaging provides identification of coordination between renal autoregulation mechanisms that is localized in time and space. PMID- 27244714 TI - Oblong-Shaped-Focused Transducers for Intravascular Ultrasound Imaging. AB - In intravascular ultrasound (IVUS) imaging, a transducer is inserted into a blood vessel and rotated to obtain image data. For this purpose, the transducer aperture is typically less than 0.5 mm in diameter, which causes natural focusing to occur in the imaging depth ranging from 1 to 5 mm. Due to the small aperture, however, it is not viable to conduct geometric focusing in order to enhance the spatial resolution of IVUS images. Furthermore, this hampers narrowing the slice thickness of a cross-sectional scan plane in the imaging depth, which leads to lowering spatial and contrast resolutions of IVUS images. To solve this problem, we propose an oblong-shaped-focused transducer for IVUS imaging. Unlike the conventional IVUS transducers with either a circular or a square flat aperture, the proposed transducer has an oblong aperture of which long side is positioned along a blood vessel. This unique configuration makes it possible to conduct geometric focusing at a desired depth in the elevation direction. In this study, furthermore, it is demonstrated that a spherically shaped aperture in both lateral and elevation directions also improves lateral resolution, compared to the conventional flat aperture. To ascertain this, the conventional and the proposed IVUS transducers were designed and fabricated to evaluate and to compare their imaging performances through wire phantom and tissue-mimicking phantom experiments. For the proposed 50-MHz IVUS transducer, a PZT piece of 0.5 * 1.0 mm2 was spherically shaped for elevation focus at 3 mm by using the conventional press-focusing technique whereas the conventional one has a flat aperture of 0.5 * 0.5 mm2. The experimental results demonstrated that the proposed IVUS transducer is capable of improving spatial and contrast resolutions of IVUS images. PMID- 27244715 TI - Intratidal Overdistention and Derecruitment in the Injured Lung: A Simulation Study. AB - GOAL: Ventilated patients with the acute respiratory distress syndrome (ARDS) are predisposed to cyclic parenchymal overdistention and derecruitment, which may worsen existing injury. We hypothesized that intratidal variations in global mechanics, as assessed at the airway opening, would reflect such distributed processes. METHODS: We developed a computational lung model for determining local instantaneous pressure distributions and mechanical impedances continuously during a breath. Based on these distributions and previous literature, we simulated the within-breath variability of airway segment dimensions, parenchymal viscoelasticity, and acinar recruitment in an injured canine lung for tidal volumes( VT ) of 10, 15, and 20 mL.kg-1 and positive end-expiratory pressures (PEEP) of 5, 10, and 15 cm H2O. Acini were allowed to transition between recruited and derecruited states when exposed to stochastically determined critical opening and closing pressures, respectively. RESULTS: For conditions of low VT and low PEEP, we observed small intratidal variations in global resistance and elastance, with a small number of cyclically recruited acini. However, with higher VT and PEEP, larger variations in resistance and elastance were observed, and the majority of acini remained open throughout the breath. Changes in intratidal resistance, elastance, and impedance followed well-defined parabolic trajectories with tracheal pressure, achieving minima near 12 to 16 cm H2O. CONCLUSION: Intratidal variations in lung mechanics may allow for optimization of ventilator settings in patients with ARDS, by balancing lung recruitment against parenchymal overdistention. SIGNIFICANCE: Titration of airway pressures based on variations in intratidal mechanics may mitigate processes associated with injurious ventilation. PMID- 27244716 TI - Bicomponent Conformal Electrode for Radiofrequency Sequential Ablation and Circumferential Separation of Large Tumors in Solid Organs: Development and In Vitro Evaluation. AB - OBJECTIVE: Complete destruction of large tumors by radiofrequency ablation (RFA) with surrounding tumor-free margin is difficult because of incomplete or nonuniform heating due to both heat-sink effect of circulating blood and limitations of existing RF electrode design. A new RF electrode is described to overcome this limitation. METHODS: A bicomponent conformal (BCC) RFA probe providing sectorial sequential ablation followed by circumferential cutting is designed and evaluated. Three-dimensional finite-element analysis model was developed with temperature feedback-controlled simulation of RFA for electrode design and optimization. The prototype bipolar BCC probe with three embedded thermocouples was constructed and evaluated in tissue-mimicking phantoms. RESULTS: Maximum tissue temperature was kept <100 oC with power applied <15 W. A 10-min ablation time was used for each sequence and after four sequential RFA, a large ablation zone of 55 cm3 was achieved. Our experiment confirmed that lesions exceeding 3.7 cm could be ablated and separated from the surrounded tissue. CONCLUSION: The new BCC probe is, thus, capable of controlled ablation followed by circumferential separation of the lesions, when required. SIGNIFICANCE: The results of these experiments provide the proof of concept validation that the BCC probe has the potential to ablate by sequential heating tumors in solid organs >3.5 cm then separate them by electrosurgical cutting from the surrounding normal parenchyma. The combined RF ablation and physical separation could completely destroy the cancer cells at the ablation site, thus, avoid any local recurrence of cancer. It requires further in vivo validation studies in large animals. PMID- 27244717 TI - Fully Convolutional Networks for Semantic Segmentation. AB - Convolutional networks are powerful visual models that yield hierarchies of features. We show that convolutional networks by themselves, trained end-to-end, pixels-to-pixels, improve on the previous best result in semantic segmentation. Our key insight is to build "fully convolutional" networks that take input of arbitrary size and produce correspondingly-sized output with efficient inference and learning. We define and detail the space of fully convolutional networks, explain their application to spatially dense prediction tasks, and draw connections to prior models. We adapt contemporary classification networks (AlexNet, the VGG net, and GoogLeNet) into fully convolutional networks and transfer their learned representations by fine-tuning to the segmentation task. We then define a skip architecture that combines semantic information from a deep, coarse layer with appearance information from a shallow, fine layer to produce accurate and detailed segmentations. Our fully convolutional networks achieve improved segmentation of PASCAL VOC (30% relative improvement to 67.2% mean IU on 2012), NYUDv2, SIFT Flow, and PASCAL-Context, while inference takes one tenth of a second for a typical image. PMID- 27244718 TI - Multi-Language Online Handwriting Recognition. AB - We describe Google's online handwriting recognition system that currently supports 22 scripts and 97 languages. The system's focus is on fast, high accuracy text entry for mobile, touch-enabled devices. We use a combination of state-of-the-art components and combine them with novel additions in a flexible framework. This architecture allows us to easily transfer improvements between languages and scripts. This made it possible to build recognizers for languages that, to the best of our knowledge, are not handled by any other online handwriting recognition system. The approach also enabled us to use the same architecture both on very powerful machines for recognition in the cloud as well as on mobile devices with more limited computational power by changing some of the settings of the system. In this paper we give a general overview of the system architecture and the novel components, such as unified time- and position based input interpretation, trainable segmentation, minimum-error rate training for feature combination, and a cascade of pruning strategies. We present experimental results for different setups. The system is currently publicly available in several Google products, for example in Google Translate and as an input method for Android devices. PMID- 27244719 TI - Solid Mathematical Marbling. AB - Years of research have been devoted to computer-generated 2D marbling, whereas 3D marbling has yet to be explored. The proposed mathematical marbling of 3D solids supports a compact random-access vector representation, creating solid marbling textures by composing closed-form 3D pattern tool functions. The resulting representation is feature-preserving and resolution-independent, and it consumes very little memory. To facilitate the solid-marbling texture authoring process, the authors also developed an intuitive user interface and a genetic algorithm. PMID- 27244720 TI - Applying Computational Aesthetics to a Video Game Application Using Machine Learning. AB - The authors have developed a novel approach to evaluating the aesthetic quality of the camera direction in video game scenes rendered in real time while the game is being played. Their goal was to improve the visual aesthetic quality of computer-generated images using a computational aesthetics approach via a regression machine learning model. Considering the challenges and limitations involved, the proposed approach yielded promising prediction performance. The results show that near-real-time aesthetic analysis and visual improvement is possible using a virtual camera director. PMID- 27244721 TI - Beaming into the News: A System for and Case Study of Tele-Immersive Journalism. AB - We show how a combination of virtual reality and robotics can be used to beam a physical representation of a person to a distant location, and describe an application of this system in the context of journalism. Full body motion capture data of a person is streamed and mapped in real time, onto the limbs of a humanoid robot present at the remote location. A pair of cameras in the robot's 'eyes' stream stereoscopic video back to the HMD worn by the visitor, and a two way audio connection allows the visitor to talk to people in the remote destination. By fusing the multisensory data of the visitor with the robot, the visitor's 'consciousness' is transformed to the robot's body. This system was used by a journalist to interview a neuroscientist and a chef 900 miles distant, about food for the brain, resulting in an article published in the popular press. PMID- 27244722 TI - The Accuracy of Gauge-Figure Tasks in Monoscopic and Stereo Displays. AB - The gauge-figure task (GFT) is a widespread method used to study surface perception for evaluating rendering and visualization techniques. The authors investigate how accurately slant angles probed on well-defined objects align with the ground truth (GT) in monoscopic and stereoscopic displays. Their results show that the GFT probes taken with well-defined objects align well with the GT in the all-monoscopic and all-stereoscopic conditions. However, they found that a GF rendered in stereo over a monoscopic stimulus results in a strong slant underestimation and that an overestimation occurred in the inverse case (monoscopic GF andstereoscopic stimulus). They discuss how their findings affect the interpretation of absolute GFT measures, compared to the GT normal. PMID- 27244723 TI - Objective Quality Assessment and Perceptual Compression of Screen Content Images. AB - Screen content image (SCI) has recently emerged as an active topic due to the rapidly increasing demand in many graphically rich services such as wireless displays and virtual desktops. SCIs are often composed of pictorial regions and computer generated textual/graphical content, which exhibit different statistical properties that often lead to different viewer behaviors. Inspired by this, we propose an objective quality assessment approach for SCIs that incorporates both visual field adaptation and information content weighting into structural similarity based local quality assessment. Furthermore, we develop a perceptual screen content coding scheme based on the newly proposed quality assessment measure, targeting at further improving the SCI compression performance. Experimental results show that the proposed quality assessment method not only better predicts the perceptual quality of SCIs, but also demonstrates great potentials in the design of perceptually optimal SCI compression schemes. PMID- 27244724 TI - Measuring the Visual Salience of 3D Printed Objects. AB - To investigate human viewing behavior on physical realizations of 3D objects, the authors use an eye tracker with scene camera and fiducial markers on 3D objects to gather fixations on the presented stimuli. They use this data to validate assumptions regarding visual saliency that so far have experimentally only been analyzed for flat stimuli. They provide a way to compare fixation sequences from different subjects and developed a model for generating test sequences of fixations unrelated to the stimuli. Their results suggest that human observers agree in their fixations for the same object under similar viewing conditions. They also developed a simple procedure to validate computational models for visual saliency of 3D objects and found that popular models of mesh saliency based on center surround patterns fail to predict fixations. PMID- 27244725 TI - VisAdapt: A Visualization Tool to Support Climate Change Adaptation. AB - The web-based visualization VisAdapt tool was developed to help laypeople in the Nordic countries assess how anticipated climate change will impact their homes. The tool guides users through a three-step visual process that helps them explore risks and identify adaptive actions specifically modified to their location and house type. This article walks through the tool's multistep, user-centered design process. Although VisAdapt's target end users are Nordic homeowners, the insights gained from the development process and the lessons learned from the project are applicable to a wide range of domains. PMID- 27244726 TI - Crosswalk Localization from Low Resolution Satellite Images to Assist Visually Impaired People. AB - In this article, we propose a model for crosswalk detection and localization by using satellite images captured from Google Maps, for the purpose of assisting visually impaired people. The detection is performed by an SVM classifier, which is combined with Google Road Map to speed up computation time and to eliminate some possible false alarms. We assume that a visually impaired person holds a smartphone with an embedded GPS, which is used to initialize the extraction of images from Google Maps, as well as to assist its user by providing audio feedback of the nearest detected crosswalk. This issue brings forward significant interest and it is also very challenging, mainly due to illumination changes, occlusion, image noise and resolution, besides the quality of crosswalks that sometimes are badly painted in many developing countries. Experimental results indicate that the proposed model works well in low resolution images, effectively detecting and localizing crosswalks in simulated scenarios. PMID- 27244727 TI - Glyph Visualization: A Fail-Safe Design Scheme Based on Quasi-Hamming Distances. AB - In many spatial and temporal visualization applications, glyphs provide an effective means for encoding multivariate data. However, because glyphs are typically small, they are vulnerable to various perceptual errors. This article introduces the concept of a quasi-Hamming distance in the context of glyph design and examines the feasibility of estimating the quasi-Hamming distance between a pair of glyphs and the minimal Hamming distance for a glyph set. The authors demonstrate the design concept by developing a file-system event visualization that can depict the activities of multiple users. PMID- 27244728 TI - A Machine-Learning-Driven Sky Model. AB - Sky illumination is responsible for much of the lighting in a virtual environment. A machine-learning-based approach can compactly represent sky illumination from both existing analytic sky models and from captured environment maps. The proposed approach can approximate the captured lighting at a significantly reduced memory cost and enable smooth transitions of sky lighting to be created from a small set of environment maps captured at discrete times of day. The author's results demonstrate accuracy close to the ground truth for both analytical and capture-based methods. The approach has a low runtime overhead, so it can be used as a generic approach for both offline and real-time applications. PMID- 27244729 TI - 3D Human Model Reconstruction from Sparse Uncalibrated Views. AB - Using a two-stage algorithm, the proposed technique can tackle the challenges of reconstructing high-quality 3D models of humans wearing regular clothes from sparse uncalibrated cameras. The proposed algorithm based on nonrigid dense correspondences (NRDC) requires fewer images than previous methods because it does not require an initial sparse matching. The authors validated the proposed algorithm using images from an existing dataset and images captured by a cell phone camera. PMID- 27244730 TI - Renal Segmentation From 3D Ultrasound via Fuzzy Appearance Models and Patient Specific Alpha Shapes. AB - Ultrasound (US) imaging is the primary imaging modality for pediatric hydronephrosis, which manifests as the dilation of the renal collecting system (CS). In this paper, we present a new framework for the segmentation of renal structures, kidney and CS, from 3DUS scans. First, the kidney is segmented using an active shape model-based approach, tailored to deal with the challenges raised by US images. A weighted statistical shape model allows to compensate the image variation with the propagation direction of the US wavefront. The model is completed with a new fuzzy appearance model and a multi-scale omnidirectional Gabor-based appearance descriptor. Next, the CS is segmented using an active contour formulation, which combines contour- and intensity-based terms. The new positive alpha detector presented here allows to control the propagation process by means of a patient-specific stopping function created from the bands of adipose tissue within the kidney. The performance of the new segmentation approach was evaluated on a dataset of 39 cases, showing an average Dice's coefficient of 0.86+/-0.05 for the kidney, and 0.74 +/- 0.10 for the CS segmentation, respectively. These promising results demonstrate the potential utility of this framework for the US-based assessment of the severity of pediatric hydronephrosis. PMID- 27244731 TI - The Omega Counter, a Frequency Counter Based on the Linear Regression. AB - This paper introduces the Omega counter, a frequency counter-i.e., a frequency-to digital converter-based on the linear regression (LR) algorithm on time stamps. We discuss the noise of the electronics. We derive the statistical properties of the Omega counter on rigorous mathematical basis, including the weighted measure and the frequency response. We describe an implementation based on a system on chip, under test in our laboratory, and we compare the Omega counter to the traditional Pi and Lambda counters. The LR exhibits the optimum rejection of white phase noise, superior to that of the Pi and Lambda counters. White noise is the major practical problem of wideband digital electronics, both in the instrument internal circuits and in the fast processes, which we may want to measure. With a measurement time tau , the variance is proportional to 1/tau(2) for the Pi counter, and to 1/tau(3) for both the Lambda and Omega counters. However, the Omega counter has the smallest possible variance, 1.25 dB smaller than that of the Lambda counter. The Omega counter finds a natural application in the measurement of the parabolic variance, described in the companion article in this Journal [vol. 63 no. 4 pp. 611-623, April 2016 (Special Issue on the 50th Anniversary of the Allan Variance), DOI 10.1109/TUFFC.2015.2499325]. PMID- 27244732 TI - The Use of Binary Quantization for the Acquisition of Low SNR Ultrasonic Signals: A Study of the Input Dynamic Range. AB - Low-power excitation and/or low sensitivity transducers, such as electromagnetic acoustic transducers, piezoelectric paints, air-coupled transducers, and small elements of dense arrays, may produce signals below the noise threshold at the receiver. The information from those noisy signals can be recovered after averaging or pulse compression using binary (1-b) quantization only without experiencing significant losses. Hence, no analog-to-digital converter is required, which reduces the data throughput and makes the electronics faster, more compact, and energy efficient. All these are especially attractive for applications that require arrays with many channels and high sampling rates, where the sampling rate can be as high as the system clock. In this paper, the theory of binary quantization is reviewed, mainly from previous work on wireless sensor networks, and the signal-to-noise ratio (SNR) of the input signals under which binary quantization is of practical interest for ultrasound applications is investigated. The main findings are that in most practical cases binary quantization can be used with small errors when the input SNR is on the order of 8 dB or less. Moreover, the maximum SNR after binary quantization and averaging can be estimated as 10log10N-2 dB , where N is the number of averages. PMID- 27244733 TI - Efficiency of U.S. Tissue Perfusion Estimators. AB - We measure the detection and discrimination efficiencies of conventional power Doppler estimation of perfusion without contrast enhancement. The measurements are made in a phantom with known blood-mimicking fluid flow rates in the presence of clutter and noise. Efficiency is measured by comparing functions of the areas under the receiver operating characteristic curve for Doppler estimators with those of the ideal discriminator, for which we estimate the temporal covariance matrix from echo data. Principal-component analysis is examined as a technique for increasing the accuracy of covariance matrices estimated from echo data. We find that Doppler estimators are <50% efficient at directed perfusion detection between 0.1 and 2.0 mL/min per 2 cm(2) flow area. The efficiency was 20%-40% for the task of discriminating between two perfusion rates in the same range. We conclude that there are reasons to search for more efficient perfusion estimators, one that incorporates covariance matrix information that could significantly enhance the utility of Doppler ultrasound without contrast enhancement. PMID- 27244734 TI - Damping Constant (Linewidth) and the Relaxation Time of the Brillouin LA Mode for the Ferroelectric-Paraelectric Transition in PbZr1-xTixO3. AB - The damping constant (linewidth) of the longitudinal acoustic (LA) mode is calculated as a function of temperature using the observed Brillouin frequencies of this mode from the literature for the ferroelectric-paraelectric transition ( TC = 657 K) in PbZr1-xTixO3 ( x = 0.45 ). For this calculation of the damping constant, the pseudospin-phonon coupled model and the energy fluctuation model are used by fitting to the observed data for the Brillouin frequencies of the LA mode in the ferroelectric ( ) and paraelectric ( T > TC) phases of this compound ( x = 0.45 ). Values of the activation energy are deduced for both ferroelectric and paraelectric phases. The relaxation time is also obtained by means of fitting to the observed data from the literature for the inverse relaxation time at various temperatures in the paraelectric phase of PbZr1-xTixO3. The temperature dependences of the damping constant and of the relaxation time with the values of the activation energy that we have calculated indicate that the pseudospin-phonon coupled model and the energy fluctuation model are capable of describing the ferroelectric-paraelectric transition ( TC = 657 K) in PbZr1-xTixO3 ( x = 0.45 ) adequately. PMID- 27244735 TI - Shear-Mode-Based Cantilever Driving Low-Frequency Piezoelectric Energy Harvester Using 0.67Pb(Mg1/3Nb2/3)O3-0.33PbTiO3. AB - Energy harvesting from external mechanical excitation has become a hot interest area, and relaxor piezoelectric single crystal ( 1 - x )Pb(Mg1/3Nb2/3)O3- x PbTiO3 (PMN- x PT or PMN-PT) has attracted continuous attention due to the well known ultrahigh shear-mode electromechanical response. To exploit the low frequency application of excellent shear-mode performance of the PMN-PT single crystal, we proposed a Shear-mode-based CANtilever Driving Low-frequency Energy harvester. The device is composed of two symmetrically assembled sandwich structures and a cantilever, in which sandwich structures can be driven by the cantilever. An analytical method was used to illustrate the high output mechanism, and a finite-element method model of the device was also established to optimize the generated electric energy in this device. The electrical properties of the device under different excitation frequencies and load resistances were studied systematically. The maximum voltage and power density at resonance frequency (43.8 Hz) were measured to be 60.8 V and 10.8 mW/cm(3) under a proof mass of 13.5 g, respectively. Both theoretical and experimental results demonstrate the considerable potential of the resonance-excited shear-mode energy harvester applied to wireless sensors and low-power portable electronics. PMID- 27244736 TI - Evaluation of Acoustic Properties for Ca3Nb(Ga0.75Al0.25)3Si2O14 Single Crystal Using the Ultrasonic Microspectroscopy System. AB - Acoustically related physical constants were experimentally determined for Ca3Nb(Ga0.75Al0.25)3Si2O14 (CNGAS) single crystal for the first time. Several plate specimens of the X-, Y -, Z -, 40.24 degrees Y -, and 144.98 degrees Y cut were prepared from a CNGAS single crystal ingot grown by Czochralski technique. Elastic constants, piezoelectric constants, and their temperature coefficients for CNGAS were determined from longitudinal wave and shear wave velocities at around room temperature, measured by the ultrasonic microspectroscopy system. Dielectric constants, density, and coefficients of thermal expansion were also measured. It was demonstrated that the determined constants could provide calculation accuracy within +/-0.12% in leaky surface acoustic wave velocity. The piezoelectric constants for CNGAS were a 7.2% increase in e11 and a 1.7% decrease in e14 due to Al-substitution effect, compared with those of Ca3NbGa3Si2O14. The appropriate cut angle for thickness shear mode resonator with zero temperature coefficient of velocity was estimated to be around 150 degrees Y -cut from calculations using the determined constants of CNGAS exhibiting electromechanical coupling factor k2 of 3.19% and power flow angle of -1.70 degrees . PMID- 27244737 TI - Facial Sketch Synthesis Using 2D Direct Combined Model-Based Face-Specific Markov Network. AB - A facial sketch synthesis system is proposed, featuring a 2D direct combined model (2DDCM)-based face-specific Markov network. In contrast to the existing facial sketch synthesis systems, the proposed scheme aims to synthesize sketches, which reproduce the unique drawing style of a particular artist, where this drawing style is learned from a data set consisting of a large number of image/sketch pairwise training samples. The synthesis system comprises three modules, namely, a global module, a local module, and an enhancement module. The global module applies a 2DDCM approach to synthesize the global facial geometry and texture of the input image. The detailed texture is then added to the synthesized sketch in a local patch-based manner using a parametric 2DDCM model and a non-parametric Markov random field (MRF) network. Notably, the MRF approach gives the synthesized results an appearance more consistent with the drawing style of the training samples, while the 2DDCM approach enables the synthesis of outcomes with a more derivative style. As a result, the similarity between the synthesized sketches and the input images is greatly improved. Finally, a post processing operation is performed to enhance the shadowed regions of the synthesized image by adding strong lines or curves to emphasize the lighting conditions. The experimental results confirm that the synthesized facial images are in good qualitative and quantitative agreement with the input images as well as the ground-truth sketches provided by the same artist. The representing power of the proposed framework is demonstrated by synthesizing facial sketches from input images with a wide variety of facial poses, lighting conditions, and races even when such images are not included in the training data set. Moreover, the practical applicability of the proposed framework is demonstrated by means of automatic facial recognition tests. PMID- 27244738 TI - Inter-Layer Prediction of Color in High Dynamic Range Image Scalable Compression. AB - This paper presents a color inter-layer prediction (ILP) method for scalable coding of high dynamic range (HDR) video content with a low dynamic range (LDR) base layer. Relying on the assumption of hue preservation between the colors of an HDR image and its LDR tone mapped version, we derived equations for predicting the chromatic components of the HDR layer given the decoded LDR layer. Two color representations are studied. In a first encoding scheme, the HDR image is represented in the classical Y'CbCr format. In addition, a second scheme is proposed using a colorspace based on the CIE u'v' uniform chromaticity scale diagram. In each case, different prediction equations are derived based on a color model ensuring the hue preservation. Our experiments highlight several advantages of using a CIE u'v'-based colorspace for the compression of HDR content, especially in a scalable context. In addition, our ILP scheme using this color representation improves on the state-of-the-art ILP method, which directly predicts the HDR layer u'v' components by computing the LDR layers u'v' values of each pixel. PMID- 27244739 TI - Merge Frame Design for Video Stream Switching Using Piecewise Constant Functions. AB - The ability to efficiently switch from one pre-encoded video stream to another (e.g., for bitrate adaptation or view switching) is important for many interactive streaming applications. Recently, stream-switching mechanisms based on distributed source coding (DSC) have been proposed. In order to reduce the overall transmission rate, these approaches provide a merge mechanism, where information is sent to the decoder, such that the exact same frame can be reconstructed given that any one of a known set of side information (SI) frames is available at the decoder (e.g., each SI frame may correspond to a different stream from which we are switching). However, the use of bit-plane coding and channel coding in many DSC approaches leads to complex coding and decoding. In this paper, we propose an alternative approach for merging multiple SI frames, using a piecewise constant (PWC) function as the merge operator. In our approach, for each block to be reconstructed, a series of parameters of these PWC merge functions are transmitted in order to guarantee identical reconstruction given the known SI blocks. We consider two different scenarios. In the first case, a target frame is first given, and then merge parameters are chosen, so that this frame can be reconstructed exactly at the decoder. In contrast, in the second scenario, the reconstructed frame and the merge parameters are jointly optimized to meet a rate-distortion criteria. Experiments show that for both scenarios, our proposed merge techniques can outperform both a recent approach based on DSC and the SP-frame approach in H.264, in terms of compression efficiency and decoder complexity. PMID- 27244740 TI - A Unified Framework for Salient Structure Detection by Contour-Guided Visual Search. AB - We define the task of salient structure (SS) detection to unify the saliency related tasks, such as fixation prediction, salient object detection, and detection of other structures of interest in cluttered environments. To solve such SS detection tasks, a unified framework inspired by the two-pathway-based search strategy of biological vision is proposed in this paper. First, a contour based spatial prior (CBSP) is extracted based on the layout of edges in the given scene along a fast non-selective pathway, which provides a rough, task irrelevant, and robust estimation of the locations where the potential SSs are present. Second, another flow of local feature extraction is executed in parallel along the selective pathway. Finally, Bayesian inference is used to auto-weight and integrate the local cues guided by CBSP and to predict the exact locations of SSs. This model is invariant to the size and features of objects. The experimental results on six large datasets (three fixation prediction datasets and three salient object datasets) demonstrate that our system achieves competitive performance for SS detection (i.e., both the tasks of fixation prediction and salient object detection) compared with the state-of-the-art methods. In addition, our system also performs well for salient object construction from saliency maps and can be easily extended for salient edge detection. PMID- 27244741 TI - Learning Discriminatively Reconstructed Source Data for Object Recognition With Few Examples. AB - We aim at improving the object recognition with few training data in the target domain by leveraging abundant auxiliary data in the source domain. The major issue obstructing knowledge transfer from source to target is the limited correlation between the two domains. Transferring irrelevant information from the source domain usually leads to performance degradation in the target domain. To address this issue, we propose a transfer learning framework with the two key components, such as discriminative source data reconstruction and dual-domain boosting. The former correlates the two domains via reconstructing source data by target data in a discriminative manner. The latter discovers and delivers only knowledge shared by the target data and the reconstructed source data. Hence, it facilitates recognition in the target. The promising experimental results on three benchmarks of object recognition demonstrate the effectiveness of our approach. PMID- 27244742 TI - Frustum-Traced Irregular Z-Buffers: Fast, Sub-pixel Accurate Hard Shadows. AB - We further describe and analyze a real-time system for rendering antialiased hard shadows using irregular z-buffers (IZBs) that we first presented in Wyman et al. [1]. We focus on identifying bottlenecks, exploring these from an algorithmic complexity standpoint, and presenting techniques to improve performance. Our system remains interactive on a variety of game assets and CAD models while running at resolutions 1920 1080 and above and imposes no constraints on light, camera or geometry, allowing fully dynamic scenes without precomputation. We render sub-pixel accurate, 32 sample per pixel hard shadows at roughly twice the cost of a single sample per pixel. This allows us to smoothly animate even subpixel shadows from grass or wires without introducing spatial or temporal aliasing. Prior algorithms for irregular z-buffer shadows rely heavily on the GPU's compute pipeline. Instead we leverage the standard rasterization-based graphics pipeline, including hardware conservative raster and early-z culling. Our key observation is noting a duality between irregular z-buffer performance and shadow map quality; irregular z-buffering is most costly exactly where shadow maps exhibit the worst aliasing. This allows us to use common shadow map algorithms, which typically improve aliasing, to instead reduce our cost. Compared to state of the art ray tracers, we spawn similar numbers of triangle intersections per pixel yet completely rebuild our data structure in under 1 ms per frame. PMID- 27244744 TI - Multi-Indenter Device for in Vivo Biomechanical Tissue Measurement. AB - Biomechanical tissue properties have been hypothesized to play a critical role in the quantification of prosthetic socket production for individuals with limb amputation. In this investigation, a novel indenter platform is presented and its performance evaluated for the purposes of residual-limb tissue characterization. The indenter comprised 14 position- and force-controllable actuators that circumferentially surround a biological residuum to form an actuator ring. Each indenter actuator was individually controllable in position ( [Formula: see text] accuracy) and force (330 mN accuracy) at a PC controller feedback rate of 500 Hz, allowing for a range of measurement across a residual stump. Data were collected from 162 sensors over an EtherCAT fieldbus to characterize the mechanical hyperviscoelastic tissue response of two transtibial residual-limbs from a study participant with bilateral amputations. At five distinct anatomical locations across the residual-limb, force versus deflection data-including hyperviscoelastic tissue properties-are presented, demonstrating the accuracy and versatility of the multi-indenter platform for residual-limb tissue characterization. PMID- 27244743 TI - Auditory-Inspired Speech Envelope Extraction Methods for Improved EEG-Based Auditory Attention Detection in a Cocktail Party Scenario. AB - This paper considers the auditory attention detection (AAD) paradigm, where the goal is to determine which of two simultaneous speakers a person is attending to. The paradigm relies on recordings of the listener's brain activity, e.g., from electroencephalography (EEG). To perform AAD, decoded EEG signals are typically correlated with the temporal envelopes of the speech signals of the separate speakers. In this paper, we study how the inclusion of various degrees of auditory modelling in this speech envelope extraction process affects the AAD performance, where the best performance is found for an auditory-inspired linear filter bank followed by power law compression. These two modelling stages are computationally cheap, which is important for implementation in wearable devices, such as future neuro-steered auditory prostheses. We also introduce a more natural way to combine recordings (over trials and subjects) to train the decoder, which reduces the dependence of the algorithm on regularization parameters. Finally, we investigate the simultaneous design of the EEG decoder and the audio subband envelope recombination weights vector using either a norm constrained least squares or a canonical correlation analysis, but conclude that this increases computational complexity without improving AAD performance. PMID- 27244745 TI - A BCI System Based on Somatosensory Attentional Orientation. AB - We propose and test a novel brain-computer interface (BCI) based on imagined tactile sensation. During an imagined tactile sensation, referred to as somatosensory attentional orientation (SAO), the subject shifts and maintains somatosensory attention on a body part, e.g., left or right hand. The SAO can be detected from EEG recordings for establishing a communication channel. To test for the hypothesis that SAO on different body parts can be discriminated from EEG, 14 subjects were assigned to a group who received an actual sensory stimulation (STE-Group), and 18 subjects were assigned to the SAO only group (SAO Group). In single trials, the STE-Group received tactile stimulation first (both wrists simultaneously stimulated), and then maintained the attention on the selected body part (without stimulation). The same group also performed the SAO task first and then received the tactile stimulation. Conversely, the SAO-Group performed SAO without any stimulation, neither before nor after the SAO. In both the STE-Group and SAO-Group, it was possible to identify the SAO-related oscillatory activation that corresponded to a contralateral event-related desynchronization (ERD) stronger than the ipsilateral ERD. Discriminative information, represented as R2 , was found mainly on the somatosensory area of the cortex. In the STE-Group, the average classification accuracy of SAO was 83.6%, and it was comparable with tactile BCI based on selective sensation (paired-t test, P > 0.05 ). In the SAO-Group the average online performance was 75.7%. For this group, after frequency band selection the offline performance reached 82.5% on average, with >= 80% for 12 subjects and >= 95% for four subjects. Complementary to tactile sensation, the SAO does not require sensory stimulation, with the advantage of being completely independent from the stimulus. PMID- 27244746 TI - A Space Affine Matching Approach to fMRI Time Series Analysis. AB - For fMRI time series analysis, an important challenge is to overcome the potential delay between hemodynamic response signal and cognitive stimuli signal, namely the same frequency but different phase (SFDP) problem. In this paper, a novel space affine matching feature is presented by introducing the time domain and frequency domain features. The time domain feature is used to discern different stimuli, while the frequency domain feature to eliminate the delay. And then we propose a space affine matching (SAM) algorithm to match fMRI time series by our affine feature, in which a normal vector is estimated using gradient descent to explore the time series matching optimally. The experimental results illustrate that the SAM algorithm is insensitive to the delay between the hemodynamic response signal and the cognitive stimuli signal. Our approach significantly outperforms GLM method while there exists the delay. The approach can help us solve the SFDP problem in fMRI time series matching and thus of great promise to reveal brain dynamics. PMID- 27244748 TI - A High Input Impedance Low Noise Integrated Front-End Amplifier for Neural Monitoring. AB - Within neural monitoring systems, the front-end amplifier forms the critical element for signal detection and pre-processing, which determines not only the fidelity of the biosignal, but also impacts power consumption and detector size. In this paper, a novel combined feedback loop-controlled approach is proposed to compensate for input leakage currents generated by low noise amplifiers when in integrated circuit form alongside signal leakage into the input bias network. This loop topology ensures the Front-End Amplifier (FEA) maintains a high input impedance across all manufacturing and operational variations. Measured results from a prototype manufactured on the AMS 0.35 [Formula: see text] CMOS technology is provided. This FEA consumes 3.1 [Formula: see text] in 0.042 [Formula: see text], achieves input impedance of 42 [Formula: see text], and 18.2 [Formula: see text] input-referred noise. PMID- 27244749 TI - Mechanistic Modeling of a Rewritable Recombinase Addressable Data Module. AB - Many of the most important applications predicted to arise from Synthetic Biology will require engineered cellular memory with the capability to store data in a rewritable and reversible manner upon induction by transient stimuli. DNA recombination provides an ideal platform for cellular data storage and has allowed the development of a rewritable recombinase addressable data (RAD) module, capable of efficient data storage within a chromosome. Here, we develop the first detailed mechanistic model of DNA recombination, and validate it against a new set of in vitro data on recombination efficiencies across a range of different concentrations of integrase and gp3. Investigation of in vivo recombination dynamics using our model reveals the importance of fully accounting for all mechanistic features of DNA recombination in order to accurately predict the effect of different switching strategies on RAD module performance, and highlights its usefulness as a design tool for building future synthetic circuitry. PMID- 27244750 TI - Data-Driven Haptic Modeling and Rendering of Viscoelastic and Frictional Responses of Deformable Objects. AB - In this paper, we present an extended data-driven haptic rendering method capable of reproducing force responses during pushing and sliding interaction on a large surface area. The main part of the approach is a novel input variable set for the training of an interpolation model, which incorporates the position of a proxy - an imaginary contact point on the undeformed surface. This allows us to estimate friction in both sliding and sticking states in a unified framework. Estimating the proxy position is done in real-time based on simulation using a sliding yield surface - a surface defining a border between the sliding and sticking regions in the external force space. During modeling, the sliding yield surface is first identified via an automated palpation procedure. Then, through manual palpation on a target surface, input data and resultant force data are acquired. The data are used to build a radial basis interpolation model. During rendering, this input-output mapping interpolation model is used to estimate force responses in real-time in accordance with the interaction input. Physical performance evaluation demonstrates that our approach achieves reasonably high estimation accuracy. A user study also shows plausible perceptual realism under diverse and extensive exploration. PMID- 27244751 TI - Vibrotactile Force Perception - Absolute and Differential Thresholds and External Influences. AB - Three experiments were carried out to determine absolute and differential thresholds for vibrotactile forces and external influences in the frequency range of 5 to 1,000 Hz at the tip of the index finger. Differential thresholds were obtained for reference stimuli of 0.5, 0.25 N, and near the individual threshold. Frequency, temperature, age, fingertip size, and contact force were investigated as parameters in a full-factorial design. Experiments were conducted with at least 27 subjects and a 1up-2down staircase procedure with 3IFC paradigm. We find absolute thresholds ranging from 1.7 to 19 mN with the lowest threshold at 320 Hz. Weber fractions from 18 to 41 dB are found near the absolute threshold. For larger references, they range from 4.9 to 23 dB. ANOVA finds frequency as significant medium effect for both absolute and differential thresholds. Results imply impact of age on the absolute threshold, but no effect of motor skill, temperature, fingertip size, and contact force. Differential thresholds are affected by frequency only, which is attributed to saturation effects of the Pacinian channel. Fingertip size and motor skill are not able to explain effects on thresholds and the interpersonal variance. Results of this work are intended as requirement source for the design of task-specific haptic interfaces. PMID- 27244752 TI - Dynamical Analysis of the Hindmarsh-Rose Neuron With Time Delays. AB - This brief is mainly concerned with a series of dynamical analyses of the Hindmarsh-Rose (HR) neuron with state-dependent time delays. The dynamical analyses focus on stability, Hopf bifurcation, as well as chaos and chaos control. Through the stability and bifurcation analysis, we determine that increasing the external current causes the excitable HR neuron to exhibit periodic or chaotic bursting/spiking behaviors and emit subcritical Hopf bifurcation. Furthermore, by choosing a fixed external current and varying the time delay, the stability of the HR neuron is affected. We analyze the chaotic behaviors of the HR neuron under a fixed external current through time series, bifurcation diagram, Lyapunov exponents, and Lyapunov dimension. We also analyze the synchronization of the chaotic time-delayed HR neuron through nonlinear control. Based on an appropriate Lyapunov-Krasovskii functional with triple integral terms, a nonlinear feedback control scheme is designed to achieve synchronization between the uncontrolled and controlled models. The proposed synchronization criteria are derived in terms of linear matrix inequalities to achieve the global asymptotical stability of the considered error model under the designed control scheme. Finally, numerical simulations pertaining to stability, Hopf bifurcation, periodic, chaotic, and synchronized models are provided to demonstrate the effectiveness of the derived theoretical results. PMID- 27244754 TI - Multi-Step Ahead Predictions for Critical Levels in Physiological Time Series. AB - Standard modeling and evaluation methods have been classically used in analyzing engineering dynamical systems where the fundamental problem is to minimize the (mean) error between the real and predicted systems. Although these methods have been applied to multi-step ahead predictions of physiological signals, it is often more important to predict clinically relevant events than just to match these signals. Adverse clinical events, which occur after a physiological signal breaches a clinically defined critical threshold, are a popular class of such events. This paper presents a framework for multi-step ahead predictions of critical levels of abnormality in physiological signals. First, a performance metric is presented for evaluating multi-step ahead predictions. Then, this metric is used to identify personalized models optimized with respect to predictions of critical levels of abnormality. To address the paucity of adverse events, weighted support vector machines and cost-sensitive learning are used to optimize the proposed framework with respect to statistical metrics that can take into account the relative rarity of such events. PMID- 27244756 TI - Low-Rank Discriminant Embedding for Multiview Learning. AB - This paper focuses on the specific problem of multiview learning where samples have the same feature set but different probability distributions, e.g., different viewpoints or different modalities. Since samples lying in different distributions cannot be compared directly, this paper aims to learn a latent subspace shared by multiple views assuming that the input views are generated from this latent subspace. Previous approaches usually learn the common subspace by either maximizing the empirical likelihood, or preserving the geometric structure. However, considering the complementarity between the two objectives, this paper proposes a novel approach, named low-rank discriminant embedding (LRDE), for multiview learning by taking full advantage of both sides. By further considering the duality between data points and features of multiview scene, i.e., data points can be grouped based on their distribution on features, while features can be grouped based on their distribution on the data points, LRDE not only deploys low-rank constraints on both sample level and feature level to dig out the shared factors across different views, but also preserves geometric information in both the ambient sample space and the embedding feature space by designing a novel graph structure under the framework of graph embedding. Finally, LRDE jointly optimizes low-rank representation and graph embedding in a unified framework. Comprehensive experiments in both multiview manner and pairwise manner demonstrate that LRDE performs much better than previous approaches proposed in recent literatures. PMID- 27244757 TI - A One-Layer Recurrent Neural Network for Pseudoconvex Optimization Problems With Equality and Inequality Constraints. AB - Pseudoconvex optimization problem, as an important nonconvex optimization problem, plays an important role in scientific and engineering applications. In this paper, a recurrent one-layer neural network is proposed for solving the pseudoconvex optimization problem with equality and inequality constraints. It is proved that from any initial state, the state of the proposed neural network reaches the feasible region in finite time and stays there thereafter. It is also proved that the state of the proposed neural network is convergent to an optimal solution of the related problem. Compared with the related existing recurrent neural networks for the pseudoconvex optimization problems, the proposed neural network in this paper does not need the penalty parameters and has a better convergence. Meanwhile, the proposed neural network is used to solve three nonsmooth optimization problems, and we make some detailed comparisons with the known related conclusions. In the end, some numerical examples are provided to illustrate the effectiveness of the performance of the proposed neural network. PMID- 27244758 TI - Event-Driven Control for Networked Control Systems With Quantization and Markov Packet Losses. AB - In this paper, event-driven is used in a networked control system (NCS) which is subjected to the effect of quantization and packet losses. A discrete event detector is used to monitor specific events in the NCS. Both an arbitrary region quantizer and Markov jump packet losses are also considered for the NCS. Based on zoom strategy and Lyapunov theory, a complete proof is given to guarantee mean square stability of the closed-loop system. Stabilization of the NCS is ensured by designing a feedback controller. Lastly, an inverted pendulum model is given to show the advantages and effectiveness of the proposed results. PMID- 27244759 TI - Persistence of pulmonary arteriovenous malformations after successful embolotherapy with Amplatzer vascular plug: long-term results. AB - PURPOSE: We aimed to evaluate the frequency of persistence and complication rates of pulmonary arteriovenous malformations (PAVMs) treated with Amplatzer vascular plug (AVP) or Amplatzer vascular plug type 2 (AVP2). METHODS: We retrospectively reviewed a total of 22 patients with 54 PAVMs between June 2004 and June 2014. We included 12 patients with 35 PAVMs who received percutaneous embolization using AVP or AVP2 only without the use of any other embolic devices. The mean follow-up was 54+/-24.3 months (range, 31-97 months). The primary end-points of the study were the efficacy of embolotherapy, the increase in oxygen saturation, and the persistence of PAVM on follow-up. Secondary end point was the incidence of complications. RESULTS: The study included 10 female and two male patients with a mean age of 50.2+/-13.7 years (range, 21-66 years). All PAVMs had a simple angioarchitecture. The technical success of the procedure for PAVM occlusion was 100%. There was a significant increase in the oxygen saturation following embolotherapy (P < 0.0001). Follow-up computed tomography angiography revealed successful treatment in 34 PAVMs (97%) and failed treatment in one PAVM (3%). Twenty-three aneurysmal sacs (67%) showed complete disappearance. The failed treatment was due to persistence of PAVM caused by subsequent development of systemic reperfusion, which did not require further intervention. There were two minor complications but no major complications were encountered. CONCLUSION: Embolotherapy of PAVMs using AVP or AVP2 devices is safe and effective, with high technical success rate, low persistence and complication rates, and with excellent long-term results. PMID- 27244760 TI - Total motile sperm count: a better way to rate the severity of male factor infertility? PMID- 27244761 TI - Assisted reproductive techniques in Latin America: The Latin American Registry, 2013. AB - Multinational data on assisted reproduction techniques undertaken in 2013 were collected from 158 institutions in 15 Latin American countries. Individualized cycle-based data included 57,456 initiated cycles. Treatments included autologous IVF and intracytoplasmic sperm injection (ICSI), frozen embryo transfers, oocyte donations. In autologous reproduction, 29.22% of women were younger than 35 years, 40.1% were 35-39 years and 30.6% were 40 years or older. Overall delivery rate per oocyte retrieval was 20.6% for ICSI and 25.4% for IVF. Multiple births included 20.7% for twins and 1.1% for triplets and over. In oocyte donations, twins reached 30% and triplets 1.4%. In singletons, pre-term births were 7.5%: 36.58% in twins and 65.52% in triplets. The relative risk for prematurity was 4.9 (95% CI 4.5 to 5.3) in twins and 8.7 (95% CI 7.6 to 10.0) in triplets and above. Perinatal mortality was 29.4 per 1000 in singletons, 39.9 per 1000 in twins and 71.6 per 1000 in high order multiples. Elective single embryo transfer represented only 2% of cycles, with delivery rate of 39.1% in women aged 34 years or less. Given the effect of multiple births and prematurity, it is mandatory to reduce the number of embryos transferred in the region. PMID- 27244763 TI - Male cytogenetic evaluation prior to assisted reproduction procedures performed in Mar del Plata, Argentina. AB - OBJECTIVE: This paper aimed to estimate the frequency of occurrence and the types of chromosomal abnormalities found in 141 infertile men with abnormal semen parameters. METHODS: the frequency and type of chromosomal abnormalities were determined with male mitotic karyotype analysis from peripheral blood through chromosome banding techniques before assisted reproduction procedures. RESULTS: In this series of 141 infertile men, 19 (13%) had chromosomal anomalies and 35 (25%) had polymorphic variants. The main chromosome abnormalities were reciprocal translocations and marker chromosomes in mosaic. CONCLUSIONS: These results stress the relevance of cytogenetic studies for infertile males as a diagnostic tool and a valuable input in genetic counseling. PMID- 27244762 TI - Comparing stimulation requirements and final outcome between early follicular and mid luteal pituitary suppression in the long gonadotropin releasing hormone agonist protocol. AB - OBJECTIVE: To compare stimulation requirements and ICSI outcome when agonist treatment is started in the early follicular phase or in mid luteal phase of the cycle. METHODS: 181 infertile patients were randomly assigned to: group A (N=66) and group B (N=115). GnRH-a (Triptorelin) subcutaneous daily injections started on day 20-22 of the previous cycle till pituitary suppression is achieved where gonadotropins stimulation commenced. In group A, agonist treatment was started on the first or second days of the cycle, in group B it was started on day 20-22 of the cycle. The agonist treatment was continued till the day of (hCG) administration. RESULTS: The stimulation requirements were similar in the two groups. The days of t agonist treatment required to reach pituitary suppression were higher in group A: 12.5+/-6.4 than in group B, 11+/-4.5. Days of stimulation (10.4+/-1.7 and 10.3+/-1.6) and number of gonadotropin vials (40.1+/-8.7and 39.3+/-9.5) did not differ between both groups. The mean number of oocytes retrieved, mean number of embryos produced (11.7+/-7.4 and 13.3+/-9.3) (5.9+/ 4.2and 6+/-5.2) were similar in both groups. The rates of fertilization and cleavage were similar in the two groups. Pregnancy rates were similar in both groups. The clinical pregnancy rates per cycle was 31.8% and 33%, while pregnancy rates per embryo transfer was 36.2 % and 36.5% in groups A and B respectively. CONCLUSION: Starting pituitary suppression with GnRH agonist in the early follicular phase or mid luteal phase were comparable regarding stimulation requirements and final outcomes. PMID- 27244764 TI - Does basal luteinizing hormone help predict the fate of in vitro fertilization? AB - OBJECTIVE: Evaluate the role of baseline serum luteinizing hormone (LH) in predicting the success of in-vitro fertilization (IVF) in terms of clinical pregnancy and live birth rate. METHODS: Women who underwent IVF and/or intracytoplasmic sperm injection (ICSI), following either the agonist or the antagonist protocol, were retrospectively evaluated over a period of two years at the All India Institute of Medical Sciences, New Delhi. We investigated the correlation of serum LH levels in the follicular phase with pregnancy outcomes. A P-value lower than 0.05 was considered as statistically significant. RESULTS: The individuals (351) were divided into four groups based on LH and FSH baseline values, and the levels were correlated with clinical pregnancy and live births. The highest clinical pregnancy rate (25%) was achieved in women with low LH (< 2IU/l); whereas the miscarriage rate was almost similar in all the groups. The pregnancy rate was the lowest (16%) in women with high LH levels (> 8IU/L). Pregnancy rates were intermediate (20%) if LH was intermediate (2-8IU/L). However, none of the results had statistical significance. CONCLUSIONS: Early follicular serum LH levels before an IVF/ICSI treatment cycle did not have any clear relationship with clinical pregnancy or live birth rates. PMID- 27244765 TI - Hormonal responses and clinical outcome are the same with three doses of gonadotropin-releasing hormone agonist used in the short stimulation protocol. AB - OBJECTIVE: The aim of this study was to compare 3 different doses of GnRH-a in a short protocol on ICSI outcome. METHODS: 91 ovulatory patients were randomly assigned to three groups; group A (N=34), group B (N=34) and group C (N=23). All started treatment with urinary gonadotropins, 2 ampoules per day and GnRH-a (Triptorelin) on the first day of the menstrual period and continued till the day of (hCG) administration. The daily dose of Triptorelin was 0.1 mg, 50 ug, and 25 ug in groups A, B and C respectively. RESULTS: Stimulation requirements, days of stimulation and total ampoules of gonadotropins did not differ between the three groups. The mean number of follicles aspirated and the mean number of Metaphase 2 oocytes retrieved were similar in the three groups. Fertilization and cleavage rates were similar in the three groups. The mean number of embryos available for transfer was 6.4+/-0.5, 9.4+/-0.5 and 7+/-0.7 in groups A, B and C, with a significant difference only between groups A and B. Pregnancy rates per cycle were 35.3%, 35.3% and 34.8 % for groups A, B and C, respectively with no significant difference. CONCLUSION: Early and late hormonal changes, stimulation requirements and final outcome were similar with the different doses of the agonist. Other factors should be considered, most importantly: treatment cost and side effects. PMID- 27244766 TI - Use of recombinant luteinizing hormone for controlled ovarian hyperstimulation in infertile patients. AB - Controlled ovarian stimulation has become an integral part of a high complexity infertility treatment. Treatment options with recombinant gonadotrophins add more to knowledge on folliculogenesis and ovarian steroidogenesis. Therefore, a literature search was conducted in the following data bases: Medline, Scielo and PubMed. The descriptors/ key words used were ovarian stimulation, in vitro fertilization, recombinant luteinizing hormone, supplementation LH. The aim of this study was to review the available literature and to assess the benefits of using recombinant luteinizing hormone associated with recombinant follicle stimulating hormone in different populations who have undergone assisted reproduction procedures. PMID- 27244768 TI - Heterotopic cervical pregnancy management after a high-complexity assisted reproduction procedure. AB - Heterotopic cervical pregnancies with a viable intrauterine pregnancy are rare, the conservative and prudent management of these cases should be focused on the selective reduction of cervical pregnancies in order to maintain eutopic pregnancy. This paper reports the first case in Ecuador of a heterotopic cervical pregnancy after ICSI procedure and its proper management by ultrasound-guided curettage, allowing the normal development as an intrauterine pregnancy. PMID- 27244767 TI - Aromatase inhibitors in the treatment of oligozoospermic or azoospermic men: a systematic review of randomized controlled trials. AB - The aim of this study as to analyze published evidence regarding the effectiveness of aromatase inhibitor therapy on improving spermatogenesis in infertile men. We carried out a systematic review of randomized controlled trials. The date of the most recent search was October 4, 2015. Two authors independently selected relevant clinical trials, assessing their methodological quality and extracting data. Three studies were included in this review with a total of 100 participants; however, we were able to include data from only 54 participants in the analysis. In the representation of meta-analysis with a single study comparing testolactone versus placebo, related to the hormone concentrations, there was a statistically significance difference favoring the use of testolactone for Luteinizing Hormone (LH); Estrogen (E2); free Testosterone (free T); free Estrogen (free E2); 17-Hydroxyprogesterone (17OHP); prolactin (PRL). In another analysis from a single study comparing letrozole versus anastrozole, there was also a statistically significance difference favoring the use of letrozole for the increase in both the sperm count and LH. There is only low quality evidence regarding the effectiveness of aromatase inhibitor therapy in infertile men. Further trials are needed with standardized interventions and outcomes. PMID- 27244769 TI - Rates of Prevalent HIV Infection, Prevalent Diagnoses, and New Diagnoses Among Men Who Have Sex With Men in US States, Metropolitan Statistical Areas, and Counties, 2012-2013. AB - BACKGROUND: In the United States, men who have sex with men (MSM) increasingly represent the majority of people living with and acquiring human immunodeficiency virus (HIV) infection. Local and federal surveillance programs estimate the number of persons living with an HIV diagnosis, persons living with HIV infection, and new diagnoses. Given the absence of population-based estimates of the number of MSM for US states, metropolitan statistical areas (MSAs), or counties, it is not possible to accurately estimate rates using these indicators at these levels, inhibiting the ability to understand HIV burden and to direct prevention efforts. OBJECTIVE: To synthesize recently published estimates of MSM population size with publicly available HIV surveillance data, in order to estimate the prevalence of HIV diagnosis and infection and the rate of new diagnoses, at the national, state, MSA, and county levels. METHODS: The number of MSM living with HIV infection in 2012 (prevalence), living with an HIV diagnosis in 2012 (diagnosed prevalence), and newly diagnosed with HIV infection in 2013 (new diagnosis), at state, MSA, and county levels, were obtained from publicly available data from AIDSVu.org and the US Centers for Disease Control and Prevention. The estimated number of MSM living in every US county was calculated using recently published methodology that utilized data from the National Health and Nutrition Examination Survey and American Community Survey. Estimated county level MSM counts were aggregated to form MSA- and state-level totals. From this, we estimated HIV prevalence, diagnosed prevalence, and new diagnosis rates. RESULTS: The estimated HIV prevalence among MSM in the United States in 2012 was 15.0% (666,900/4,452,772), the diagnosed HIV prevalence in 2012 was 11.1% (493,453/4,452,772), and the new diagnosis rate for 2013 was 0.7 per 100 MSM. For diagnosed prevalence at the state level, 6 states had both <15,000 cases and diagnosed prevalence rates of >=15%, all in the South. Five highly populated states had >=15,000 cases and rates between 10% and 15%. Georgia was the only state with >=15,000 cases and >=15% diagnosed prevalence rate. Of the 25 MSAs with the highest diagnosed prevalence rates in the United States, 21 were in the South and 6 had diagnosed prevalence of >=25%. County-level data showed high diagnosed prevalence rates in both urban and rural counties of the South. CONCLUSIONS: HIV infection is hyperendemic among MSM in many areas of the United States, particularly in the South. Our data emphasize the priorities for HIV prevention and care set forth in the United States National HIV/AIDS Strategy (NHAS) and provide updatable local estimates of NHAS indicators. Jurisdictions can use these results to direct resources, programs, and policies to optimally benefit the health of MSM. PMID- 27244770 TI - The Annual American Men's Internet Survey of Behaviors of Men Who have Sex with Men in the United States: 2014 Key Indicators Report. AB - The American Men's Internet Survey (AMIS) is an annual Web-based behavioral survey of men who have sex with men (MSM) who live in the United States. The purpose of this Rapid Surveillance Report is to report on the second cycle of data collection (November 2014 through April 2015; AMIS-2014) on the same key indicators previously reported for AMIS (December 2013 through May 2014; AMIS 2013). The AMIS survey methodology has not substantively changed since AMIS-2013. MSM were recruited from a variety of websites using banner advertisements or email blasts. Adult men currently residing in the United States were eligible to participate if they had ever had sex with a man. We examined demographic and recruitment characteristics using multivariable regression modeling (P<.05) stratified by the participants' self-reported human immunodeficiency virus (HIV) status. The AMIS-2014 round of data collection resulted in 9248 completed surveys from MSM representing every US state. Participants were mainly white, 40 years or older, living in the US South, living in urban/suburban areas, and recruited from a general social networking website. Self-reported HIV prevalence was 11.34% (1049/9248). Compared with HIV-negative/unknown status participants, HIV-positive participants were more likely to have had anal sex without a condom with any male partner in the past 12 months (76.55% vs 67.17%; P<.001) and more likely to have had anal sex without a condom with their last male sex partner who was discordant/unknown HIV status (39.66% vs 18.77%; P<.001). Marijuana and other illicit substance use in the past 12 months was more likely to be reported by HIV positive participants than HIV-negative/unknown status participants (26.02% vs 21.27%, and 27.26% vs 17.60%, respectively; both P<.001). The vast majority (86.90%, 7127/8199) of HIV-negative/unknown status participants had been previously HIV tested, and 58.23% (4799/8199) had been tested in the past 12 months. Sexually transmitted infection (STI) testing and diagnosis was also more likely to be reported by HIV-positive participants than HIV-negative/unknown status participants (71.02% vs 37.34%, and 20.59% vs 7.54%, respectively; both P<.001). HIV-negative/unknown status participants <40 years of age were more likely than those 40 years or older to have had anal sex without a condom, were more likely to report substance use, were less likely to have been HIV tested, but were more likely to been tested for and diagnosed with an STI. Compared with those from general social networking, HIV-negative/unknown status participants from a geospatial social networking website were more likely to have reported all risk behaviors but were more likely to have been HIV tested, STI tested, and diagnosed with an STI. PMID- 27244771 TI - Construct Validity of the eHealth Literacy Scale (eHEALS) Among Two Adult Populations: A Rasch Analysis. AB - BACKGROUND: The Internet has become a ubiquitous venue for information seeking, especially for health information. Public health practitioners have noticed the promise and potential of the Internet, however, little is known about individuals' skills of their eHealth literacy. The eHealth Literacy Scale, eHEALS, was designed to measure perceptions of individuals' eHealth literacy skills. OBJECTIVE: The objective of the study was to examine the psychometric validity and reliability of the eHEALS with two adult populations using the Rasch Model. METHODS: A college-aged sample and an Internet-based sample (Amazon's MTurk) were recruited to complete the eHEALS, demographic questions, and a health literacy scale. Using WINSTEPS and SPSS, unidimensionality, item fit, rating scale, item hierarchy, person ability-item match, and reliability were analyzed, compared, and contrasted against each sample and to other samples found in the literature. RESULTS: An exploratory factor analysis supported unidimensionality in both samples. More than 90% of respondents from both samples fit the model. No items were outright misfitting. Both samples separated into three distinct groups. CONCLUSIONS: Based on the results, the eHEALS is a reliable and consistent measurement tool for a college sample and an Internet-based sample. As these individuals are most likely to use the Internet as a health resource, it is necessary to learn and know their skills versus perceiving that they can critically and successfully navigate the Internet. Further analyses are necessary to ensure that the eHEALS can serve as a standard eHealth literacy measure for public health. PMID- 27244772 TI - Shining a Light on America's HIV Epidemic among Men who Have Sex with Men. PMID- 27244773 TI - The Importance of Population Denominators for High-Impact Public Health for Marginalized Populations. PMID- 27244774 TI - Facebook Advertising Across an Engagement Spectrum: A Case Example for Public Health Communication. AB - BACKGROUND: The interpersonal, dialogic features of social networking sites have untapped potential for public health communication. We ran a Facebook advertising campaign to raise statewide awareness of Michigan's newborn screening and biobanking programs. OBJECTIVE: We ran a Facebook advertising campaign to stimulate public engagement on the complex and sensitive issue of Michigan's newborn screening and biobank programs. METHODS: We ran an 11-week, US $15,000 Facebook advertising campaign engaging Michigan Facebook users aged 18-64 years about the state's newborn screening and population biobank programs, and we used a novel "engagement spectrum" framework to contextualize and evaluate engagement outcomes ranging from observation to multi-way conversation. RESULTS: The campaign reached 1.88 million Facebook users, yielding a range of engagement outcomes across ad sets that varied by objective, content, budget, duration, and bid type. Ad sets yielded 9009 page likes (US $4125), 15,958 website clicks (US $5578), and 12,909 complete video views to 100% (US $3750). "Boosted posts" yielded 528 comments and 35,966 page post engagements (US $1500). Overall, the campaign led to 452 shares and 642 comments, including 176 discussing newborn screening and biobanking. CONCLUSIONS: Facebook advertising campaigns can efficiently reach large populations and achieve a range of engagement outcomes by diversifying ad types, bid types, and content. This campaign provided a population-based approach to communication that also increased transparency on a sensitive and complex topic by creating a forum for multi-way interaction. PMID- 27244775 TI - A Quality Assessment of a Collaborative Model of a Pediatric Antimicrobial Stewardship Program. AB - BACKGROUND: Infectious Diseases Society of America guidelines recommend that key antimicrobial stewardship program (ASP) personnel include an infectious disease (ID) physician leader and dedicated ID-trained clinical pharmacist. Limited resources prompted development of an alternative model by using ID physicians and service-based clinical pharmacists at a pediatric hospital. The aim of this study was to analyze the effectiveness and impact of this alternative ASP model. METHODS: The collaborative ASP model incorporated key strategies of education, antimicrobial restriction, day 3 audits, and practice guidelines. High-use and/or high-cost antimicrobial agents were chosen with audits targeting vancomycin, caspofungin, and meropenem. The electronic medical record was used to identify patients requiring day 3 audits and to communicate ASP recommendations. Segmented regression analyses were used to analyze quarterly antimicrobial agent prescription data for the institution and selected services over time. RESULTS: Initiation of ASP and day 3 auditing was associated with blunting of a preexisting increasing trend for caspofungin drug starts and use and a significant downward trend for vancomycin drug starts (relative change -12%) and use (-25%), with the largest reduction in critical care areas. Although meropenem use was already low due to preexisting requirements for preauthorization, a decline in drug use (-31%, P = .021) and a nonsignificant decline in drug starts (-21%, P = .067) were noted. A 3-month review of acceptance of ASP recommendations found rates of 90%, 93%, and 100% for vancomycin, caspofungin, and meropenem, respectively. CONCLUSIONS: This nontraditional ASP model significantly reduced targeted drug usage demonstrating acceptance of integration of service-based clinical pharmacists and ID consultants. PMID- 27244777 TI - Practice-Based Quality Improvement Collaborative to Increase Chlamydia Screening in Young Women. AB - BACKGROUND AND OBJECTIVE: Chlamydia trachomatis infections are common among sexually active young women. We developed a practice-based quality improvement (QI) collaborative to increase Chlamydia screening in at-risk young women. METHODS: Structured data fields were integrated into the electronic record for practices affiliated with Boston Children's Hospital. A learning community (LC) was developed. Content included the adolescent well visit, assessment of sexual/risk behaviors, epidemiology of sexually transmitted diseases, and screening methods. The QI initiative effectiveness was assessed by comparing preintervention and postintervention rates of Chlamydia screening by using statistical process control analyses and logistic regressions. RESULTS: LC participants demonstrated significant increases in recommended Chlamydia screening, as illustrated by using Healthcare Effectiveness Data and Information Set (HEDIS) screening rates (LC1: 52.8% preintervention vs 66.7% postintervention [P < .0001]; LC2: 57.8% preintervention vs 69.3% postintervention [P < .0001]). Participating practices reported total improvements larger than nonparticipating practices (13.9% LC1, 11.5% LC2, and 7.8% nonparticipants). QI and LC efforts also led to increased documentation of sexual activity status in the record (LC1: 61.2% preintervention to 91.2% postintervention [P < .0001]; LC2: 43.3% preintervention to 61.2% postintervention [P < .0001]). Nonparticipating practices were more likely to perform indiscriminate screening. CONCLUSIONS: Through our QI and LC efforts, statistically and clinically meaningful improvements in Chlamydia screening rates were attained. Differences in rates of improvement indicate that LC participation likely had effects beyond electronic medical record changes alone. During the project time frame, national HEDIS screening rates remained unchanged, suggesting that the observed improvements were related to the interventions and not to a national trend. As a result of QI tools provided through the LCs, HEDIS screening goals were achieved in a primary care setting. PMID- 27244778 TI - Quality Improvement Initiative to Reduce the Necrotizing Enterocolitis Rate in Premature Infants. AB - OBJECTIVE: To reduce the incidence of necrotizing enterocolitis (NEC) among very low birth weight (VLBW) infants admitted to 8 intensive care nurseries from a 2010 baseline of 8.0% to <4.0% by 2012 and sustain for 6 months using quality improvement (QI) methodology. METHODS: A multidisciplinary NEC QI team used the Vermont Oxford Network definition of NEC and the Institute for Healthcare Improvement model. The specific aims were evidenced based and included (1) standardized early human milk feedings, (2) conservative feeding guidelines during blood transfusions and indomethacin treatment, and (3) restriction of ranitidine use in VLBW infants. Inclusion criteria included VLBW infants admitted within the study period without NEC. Exclusion criteria included established NEC or spontaneous intestinal perforation unrelated to NEC. The incidence of NEC and NEC-related surgery were tracked using statistical process control methodology. RESULTS: The baseline NEC rate in 2010 was 8% (27 NEC cases in 335 VLBW infants). After initiation of early human-milk feeding and conservative feeds during blood transfusions guidelines in November 2011, only 3.1% (19 of 606 VLBW infants) had developed NEC through December 2013 (P = .001). Special cause variation was noted in June 2012 establishing a new centerline at 3.1%. NEC-related mortality decreased from a 2010 baseline mean of 2.7% to a new baseline mean of 0.9% from January 2011 to December 2013. CONCLUSIONS: Implementation of QI initiatives decreased the NEC rate from 8.0% to <4.0%. Early human milk feedings and conservative feeding during blood transfusion policies appear to have significant impact on NEC reduction. PMID- 27244776 TI - Pediatric Obesity-Related Asthma: The Role of Metabolic Dysregulation. AB - The burden of obesity-related asthma among children, particularly among ethnic minorities, necessitates an improved understanding of the underlying disease mechanisms. Although obesity is an independent risk factor for asthma, not all obese children develop asthma. Several recent studies have elucidated mechanisms, including the role of diet, sedentary lifestyle, mechanical fat load, and adiposity-mediated inflammation that may underlie the obese asthma pathophysiology. Here, we review these recent studies and emerging scientific evidence that suggest metabolic dysregulation may play a role in pediatric obesity-related asthma. We also review the genetic and epigenetic factors that may underlie susceptibility to metabolic dysregulation and associated pulmonary morbidity among children. Lastly, we identify knowledge gaps that need further exploration to better define pathways that will allow development of primary preventive strategies for obesity-related asthma in children. PMID- 27244779 TI - Management of Acute Severe Colitis in Children With Ulcerative Colitis in the Biologics Era. AB - BACKGROUND AND OBJECTIVE: Approximately one-third of children with ulcerative colitis will experience at least 1 attack of acute severe colitis (ASC) before 15 years of age. Severe disease can be defined in children when Pediatric Ulcerative Colitis Activity Index is >65 and/or >=6 bloody stools per day, and/or 1 of the following: tachycardia, fever, anemia, and elevated erythrocyte sedimentation rate with or without systemic toxicity. Our aim was to provide practical suggestions on the management of ASC in children. The goal of medical therapy is to avoid colectomy while preventing complications of disease, side effects of medications, and mortality. METHODS: A systematic search was carried out through Medline via PubMed to identify all articles published in English to date, based on the following keywords "ulcerative colitis," "pediatric ulcerative colitis," "biological therapy," and "acute severe colitis." Multidisciplinary clinical evaluation is recommended to identify early nonresponders to conventional treatment with intravenous corticosteroids, and to start, if indicated, second line therapy or "rescue therapy," such as calcineurin inhibitors (cyclosporine, tacrolimus) and anti-tumor necrosis factor molecules (infliximab). RESULTS: Pediatric Ulcerative Colitis Activity Index is a valid predictive tool that can guide clinicians in evaluating response to therapy. Surgery should be considered in the case of complications or rapid clinical deterioration during medical treatment. CONCLUSIONS: Several pitfalls may be present in the management of ASC, and a correct clinical and therapeutic approach is recommended to reduce surgical risk. PMID- 27244780 TI - Cow's Milk Allergy and Bone Mineral Density in Prepubertal Children. AB - BACKGROUND AND OBJECTIVES: Recent data suggest that cow's milk allergy (CMA) has become more persistent, prolonging treatment via strict elimination of cow's milk products into a period of skeletal growth. The objectives of this study were to compare bone mineral density (BMD), vitamin D status, and dietary intakes of calcium and vitamin D between prepubertal children with persistent CMA and those with non-cow's milk food allergies (NCMA) as control subjects and to assess the use of and compliance to calcium and vitamin D supplementation among children with persistent CMA. METHODS: Fifty-two children with persistent CMA and 29 with NCMA were recruited. BMD was measured by using dual energy radiograph absorptiometry, and vitamin D status was assessed by using plasma 25 hydroxyvitamin D concentrations. Calcium and vitamin D intakes, as well as compliance to calcium and vitamin D supplementation, were recorded. RESULTS: Lumbar spine BMD z scores were significantly lower in children with CMA. Low bone mass was detected in 6% of the CMA group compared with none in the NCMA group. Children with CMA displayed significantly lower calcium intakes than control subjects. Vitamin D status was not reduced in children with CMA compared with control subjects. Fewer than one-half of children with CMA reported the use of calcium and vitamin D supplements. However, adherence was high among supplement users, with a mean compliance rate of 5.5 days per week. CONCLUSIONS: These prepubertal children with persistent CMA had lower lumbar spine BMD z scores than children with NCMA, which likely resulted from lower calcium intake. PMID- 27244781 TI - Implementation of Electronic Clinical Decision Support for Pediatric Appendicitis. AB - BACKGROUND AND OBJECTIVE: Computed tomography (CT) and ultrasound (US) are commonly used in patients with acute abdominal pain. We sought to standardize care and reduce CT use while maintaining patient safety through implementation of a multicomponent electronic clinical decision support tool for pediatric patients with possible appendicitis. METHODS: We conducted a quasi-experimental study of children 3 to 18 years old who presented with possible appendicitis to the pediatric emergency department (ED) between January 2011 and December 2013. Outcomes were use of CT and US. Balancing measures included missed appendicitis, ED revisits within 30 days, appendiceal perforation, and ED length of stay. RESULTS: Of 2803 patients with acute abdominal pain over the 3-year study period, 794 (28%) had appendicitis and 207 (26.1% of those with appendicitis) had a perforation. CT use during the 10-month preimplementation period was 38.8% and declined to 17.7% by the end of the study (54% relative decrease). For CT, segmented regression analysis revealed that there was a significant change in trend from the preimplementation period to implementation (monthly decrease 3.5%; 95% confidence interval: -5.9% to -0.9%; P = .007). US use was 45.7% preimplementation and 59.7% during implementation. However, there was no significant change in US or total imaging trends. There were also no statistically significant differences in rates of missed appendicitis, ED revisits within 30 days, appendiceal perforation, or ED length of stay between time periods. CONCLUSIONS: Our electronic clinical decision support tool was associated with a decrease in CT use while maintaining safety and high quality care for patients with possible appendicitis. PMID- 27244782 TI - Cognitive Behavioral Therapy in Primary Care for Youth Declining Antidepressants: A Randomized Trial. AB - BACKGROUND AND OBJECTIVE: Health care providers have few alternatives for youth depression other than antidepressants. We examined whether brief cognitive behavioral therapy (CBT) is a viable alternative in primary care. METHODS: A total of 212 adolescents aged 12 to 18 with major depression who had recently declined or quickly discontinued new antidepressant treatment were randomized to self-selected treatment as usual (TAU) control condition or TAU plus brief individual CBT. Blinded evaluators followed youth for 2 years. The primary outcome was time to major depression diagnostic recovery. RESULTS: CBT was superior to the control condition on the primary outcome of time to diagnostic recovery from major depression, with number needed to treat from 4 to 10 across follow-up. A similar CBT advantage was found for time to depression diagnosis response, with number needed to treat of 5 to 50 across time points. We observed a significant advantage for CBT on many secondary outcomes over the first year of follow-up but not the second year. Cohen's d effect sizes for significant continuous measures ranged from 0.28 to 0.44, in the small to medium effect range. Most TAU health care services did not differ across conditions, except for psychiatric hospitalizations, which occurred at a significantly higher rate in the control condition through the first year of follow-up. CONCLUSIONS: Observed results were consistent with recent meta-analyses of CBT for youth depression. The initial year of CBT superiority imparted an important clinical benefit and may reduce the risk of future recurrent depression episodes. PMID- 27244783 TI - Myelin Oligodendrocyte Glycoprotein Antibody Persistency in a Steroid-Dependent ADEM Case. AB - Myelin oligodendrocyte glycoprotein (MOG) is a candidate target antigen in demyelinating central nervous system diseases, including acute disseminated encephalomyelitis (ADEM), neuromyelitis optica, and multiple sclerosis. It may give prognostic information regarding monophasic or recurrent course of the disease. MOG antibodies have been shown to be positive in high titers during the first episode of ADEM with rapidly decreasing to undetectable limits after recovery. However, persistent MOG antibodies are considered as a predicting factor for multiple sclerosis, optic neuritis relapses, and incomplete recovery of ADEM. Here we report a unique case with persistent MOG antibodies presented with multiphasic ADEM-like attacks. A 6-year-old girl was consulted with encephalopathy, gait disturbance, and oculomotor nerve palsy. Periventricular white matter lesions were seen on cranial magnetic resonance imaging studies. ADEM was diagnosed and treated with steroid. During follow-up, she experienced repeated episodes after steroid therapy termination. We were able to search MOG antibody at the ninth attack. The positivity of this antibody remained. It was thought to be associated with steroid-dependent course, and azathioprine and intravenous human immunoglobulin treatment were added. Patients with persistent MOG antibodies may benefit from addition of immunosuppressant agents, which may decrease the number of attacks. PMID- 27244784 TI - Association Between Age and Obesity Over Time. AB - BACKGROUND AND OBJECTIVES: A decline in the prevalence of obesity among 2- to 5 year-olds in the United States was recently reported. This decline may be due to changes in the population composition of children over time or may be a consequence of changes in how strongly individual- or family-level factors are linked to childhood obesity. We applied regression decomposition techniques to identify the sources of the decline. METHODS: We used data from the 2003-2004 and 2011-2012 NHANES restricted to 2- to 5-year-old children and Blinder-Oaxaca regression decomposition techniques to partition the decline in early childhood obesity into 2 components: changes resulting from (1) how demographic, economic, and health characteristics of children have changed over this period (ie, changes in population composition) and (2) changes in how these demographic, economic, and health factors are associated with obesity (ie, changes in associations). RESULTS: The obesity rate was lower in 2011-2012 than it was in 2003-2004 mainly because obesity was strongly and positively associated with age in 2003-2004 (ie, older children were more likely to be obese than younger children) but not in 2011-2012 (ie, older children were not more likely to be obese than younger children). CONCLUSIONS: If the weaker association between age and obesity we observed for this cohort of 2- to 5-year-old children in 2011-2012 persists for subsequent cohorts of young children, the obesity rate for young children will remain at or near the lower rate seen in 2011-2012. PMID- 27244785 TI - Ovarian Cystadenoma in a Trafficked Patient. AB - The topic of child sex trafficking is receiving increased attention both in the lay press and in research articles. Recently, a number of physician organizations have issued policy statements calling for the education and involvement of physicians in combating this form of "modern-day slavery." Primary care and emergency medicine physicians have led these efforts, but a number of these victims may present to surgeons. Surgeons are in a unique position to identify trafficked patients; during the process of undraping, intubation, and surgical preparation, signs of trafficking such as tattoos, scars, dental injuries, and bruising may be evident. In addition, these patients may have specific needs in terms of anesthesia and postoperative care due to substance abuse. Here, we report the case of an 18-year-old girl with a history of sexual exploitation who presents for cystadenoma excision. To our knowledge, this is the first report of a sex-trafficked pediatric patient presenting for surgery. PMID- 27244786 TI - Emotional and Behavioral Problems of Preterm and Full-Term Children at School Entry. AB - BACKGROUND AND OBJECTIVES: Preterm children, compared with term children, are at increased risk of emotional and behavioral problems (EB-problems). Prevalences of EB-problems seem to vary with degree of prematurity and age at assessment. We therefore assessed individual stability of EB-problems in preterm compared with term children first before school entry and again 1 year after school entry, and variation in stability within the preterm group. METHODS: We used data of 401 early preterm (25-31 weeks' gestational age), 653 moderately preterm (32-35 weeks' gestational age), and 389 term children from the Longitudinal Preterm Outcome Project cohort study. We classified EB-problems based on the Child Behavior Checklist at ages 4 and 5; this resulted in 4 categories: consistently normal (2 normal scores), emerging (normal score at age 4 and clinical/subclinical score at age 5), resolving, and persistent EB-problems. RESULTS: All preterm children had higher rates than term children of persistent (7.2% vs 3.6%), emerging (4.3% vs 2.3%), and resolving (7.5% vs 3.6%) EB problems. Early preterm children had the highest rates of persistent (8.2%) and emerging (5.2%) problems, and moderately preterm children had the highest rates of resolving problems (8.7%). In both preterm and term children, predictive values of normal scores at age 4 for normal scores at age 5 were ~96%, and of clinical/subclinical scores at age 4 for clinical/subclinical scores at age 5 were ~50%, except for early preterm children (60%). CONCLUSIONS: Compared with term children, all preterm children are at risk for persistent and changing EB problems at school entry; individual stability, however, is difficult to predict based solely on the factor of preterm-birth. PMID- 27244787 TI - Chronic Illness and Developmental Vulnerability at School Entry. AB - OBJECTIVE: This study examined the association between chronic illness and school readiness, by using linked administrative population data. METHODS: The sample included children born in 2003-2004 who were residing in Western Australia in 2009 and had a complete Australian Early Development Census record (N = 22 890). Health and demographic information was also analyzed for 19 227 mothers and 19 030 fathers. The impact of child chronic illness on 5 developmental domains (social, emotional, language, cognitive, and physical) at school entry was analyzed. Analyses examined the association between child developmental outcomes and chronic illness generally, single or multiple chronic illness diagnosis, and diagnosis type. Logistic regression models estimated odds ratios for each outcome, adjusted for child, parent, and community sociodemographic variables. RESULTS: In the adjusted models, children with a chronic illness had an increased risk of being classified as developmentally vulnerable on all domains, compared with children without a chronic illness (20%-35% increase in risk). There was no increased risk for children with multiple chronic illness diagnoses over those with a single diagnosis (all Ps > .05). There was no evidence of a disease specific effect driving this risk. CONCLUSIONS: Regardless of the number or type of conditions, chronic illness in young children is a risk factor for reduced school readiness. These effects were seen for health conditions not traditionally considered detrimental to school readiness, such as chronic otitis media. Thus, the implications of a broader range of chronic health conditions in early childhood on school readiness need to be considered. PMID- 27244788 TI - Two-Year BMI Outcomes From a School-Based Intervention for Nutrition and Exercise: A Randomized Trial. AB - OBJECTIVES: This study examined the long-term effects on BMI of a randomized controlled trial of Students for Nutrition and Exercise, a 5-week, middle school based obesity prevention intervention combining school-wide environmental changes, encouragement to eat healthy school cafeteria foods, and peer-led education and marketing. METHODS: We randomly selected schools from the Los Angeles Unified School District and assigned 5 to the intervention group and 5 to a wait-list control group. Of the 4022 seventh-graders across schools, a total of 1368 students had their height and weight assessed at baseline and 2 years' postintervention. RESULTS: A multivariable linear regression was used to predict BMI percentile at ninth grade by using BMI percentile at seventh grade, school indicators, and sociodemographic characteristics (child gender, age, Latino race/ethnicity, US-born status, and National School Lunch Program eligibility [as a proxy for low-income status]). Although the Students for Nutrition and Exercise intervention did not exhibit significant effects on BMI percentile overall, intervention students who were classified as obese at baseline (in seventh grade) showed significant reductions in BMI percentile in ninth grade (b = -2.33 percentiles; SE, 0.83; P = .005) compared with control students. This outcome translated into ~9 pounds (~4.1 kg) lower expected body weight after 2 years for an obese student in the intervention school at the mean height and age of the sample at baseline. CONCLUSIONS: Multilevel school-based interventions can have long-term effects on BMI among students who are obese. Future research should examine the mechanisms by which school-based obesity interventions can affect BMI over time. PMID- 27244789 TI - Pubertal Height Growth and Adult Height in Cystic Fibrosis After Newborn Screening. AB - BACKGROUND: To examine long-term growth benefit of newborn screening (NBS), adolescent peak height velocity (PHV), and adult height were compared between the screened (diagnosed early via NBS) and the control (identified generally by symptoms) in the Wisconsin Randomized Clinical Trial. METHODS: Data from 107 children born in 1985-1994 and followed through 2012 were analyzed. PHV was estimated by a semiparametric growth curve model and compared with Tanner reference. RESULTS: Meconium ileus (MI; n = 25) was associated with the worst pubertal growth and adult height, including 1 child who did not experience apparent PHV; children with pancreatic sufficiency (n = 18) achieved the best growth (normal PHV and adult height). In children with pancreatic insufficiency without meconium ileus (n = 64), the subgroup most likely to benefit from NBS, screened children had similar PHV but better adult height compared with controls. Specifically, in boys, the screened group (n = 22) achieved normal PHV (9.5 cm at 13.5 years); the control group (n = 19) had similar onset age (13.6 years) but 0.6-cm lower magnitude (P = .08). In girls, the screened group (n = 10) had somewhat later (12.5 years vs 11.7 years, P = .12) and lower PHV (7.3 cm vs 7.9 cm, P = .33) than the controls (n = 13), coinciding with later menarche (13.6 years vs 12.2 years, P = .10). Adult height was taller in the screened than the control (50th vs 29th percentile, P = .02), even after adjusted for genetic potential (32nd vs15th percentile, P = .006). Differences in adult height were primarily attributable to NBS and better prepubertal growth. CONCLUSIONS: Early linear growth benefits of NBS were sustained through puberty, leading to better adult height in cystic fibrosis. PMID- 27244790 TI - Human Metapneumovirus Circulation in the United States, 2008 to 2014. AB - BACKGROUND: Human metapneumovirus (HMPV) infection causes respiratory illness, including bronchiolitis and pneumonia. However, national HMPV seasonality, as it compares with respiratory syncytial virus (RSV) and influenza seasonality patterns, has not been well described. METHODS: Hospital and clinical laboratories reported weekly aggregates of specimens tested and positive detections for HMPV, RSV, and influenza to the National Respiratory and Enteric Virus Surveillance System from 2008 to 2014. A season was defined as consecutive weeks with >=3% positivity for HMPV and >=10% positivity for RSV and influenza during a surveillance year (June through July). For each virus, the season, onset, offset, duration, peak, and 6-season medians were calculated. RESULTS: Among consistently reporting laboratories, 33 583 (3.6%) specimens were positive for HMPV, 281 581 (15.3%) for RSV, and 401 342 (18.2%) for influenza. Annually, 6 distinct HMPV seasons occurred from 2008 to 2014, with onsets ranging from November to February and offsets from April to July. Based on the 6-season medians, RSV, influenza, and HMPV onsets occurred sequentially and season durations were similar at 21 to 22 weeks. HMPV demonstrated a unique biennial pattern of early and late seasonal onsets. RSV seasons (onset, offset, peak) were most consistent and occurred before HMPV seasons. There were no consistent patterns between HMPV and influenza circulations. CONCLUSIONS: HMPV circulation begins in winter and lasts until spring and demonstrates distinct seasons each year, with the onset beginning after that of RSV. HMPV, RSV, and influenza can circulate simultaneously during the respiratory season. PMID- 27244791 TI - Variations in Mental Health Diagnosis and Prescribing Across Pediatric Primary Care Practices. AB - BACKGROUND: Primary care pediatricians increasingly care for children's mental health problems, but little is known about practice-level variation in diagnosis and psychotropic medication prescribing practices. METHODS: This retrospective review of electronic heath records from 43 US primary care practices included children aged 4 to 18 years with >=1 office visit from January 1, 2009, to June 30, 2014. We examined variability in diagnosis and psychotropic prescribing across practices using logistic regression with practice fixed effects and evaluated associations of the availability of colocated or community-based mental health providers or the proportion of children in foster care with diagnosis and prescribing using generalized linear mixed models. RESULTS: Among 294 748 children, 40 932 (15%) received a mental health diagnosis and 39 695 (14%) were prescribed psychotropic medication. Attention deficit/hyperactivity disorder was most commonly diagnosed (1%-16% per practice). The proportion of children receiving any psychotropic medication (4%-26%) and the proportion receiving >=2 medication classes (1%-12%) varied across practices. Prescribing of specific medication classes also varied (stimulants, 3%-18%; antidepressants, 1%-12%; alpha-agonists, 0%-8%; second-generation antipsychotics, 0%-5%). Variability was partially explained by community availability of psychiatrists (significantly higher odds of a diagnosis or prescription when not available) but not by colocation of mental health professionals or percentage of children in foster care. CONCLUSIONS: The prevalence of mental health diagnosis and psychotropic medication prescribing varies substantially across practices and is only partially explained by psychiatrist availability. Research is needed to better define the causes of variable practice-level diagnosis and prescribing and implications for child mental health outcomes. PMID- 27244792 TI - Utility of Decision Rules for Transcutaneous Bilirubin Measurements. AB - BACKGROUND: Transcutaneous bilirubin (TcB) meters are widely used for screening newborns for jaundice, with a total serum bilirubin (TSB) measurement indicated when the TcB value is classified as "positive" by using a decision rule. The goal of our study was to assess the clinical utility of 3 recommended TcB screening decision rules. METHODS: Paired TcB/TSB measurements were collected at 34 newborn nursery sites. At 27 sites (sample 1), newborns were routinely screened with a TcB measurement. For sample 2, sites that typically screen with TSB levels also obtained a TcB measurement for the study. Three decision rules to define a positive TcB measurement were evaluated: >=75th percentile on the Bhutani nomogram, 70% of the phototherapy level, and within 3 mg/dL of the phototherapy threshold. The primary outcome was a TSB level at/above the phototherapy threshold. The rate of false-negative TcB screens and percentage of blood draws avoided were calculated for each decision rule. RESULTS: For sample 1, data were analyzed on 911 paired TcB-TSB measurements from a total of 8316 TcB measurements. False-negative rates were <10% with all decision rules; none identified all 31 newborns with a TSB level at/above the phototherapy threshold. The percentage of blood draws avoided ranged from 79.4% to 90.7%. In sample 2, each rule correctly identified all 8 newborns with TSB levels at/above the phototherapy threshold. CONCLUSIONS: Although all of the decision rules can be used effectively to screen newborns for jaundice, each will "miss" some infants with a TSB level at/above the phototherapy threshold. PMID- 27244793 TI - Motivational Interviewing to Prevent Childhood Obesity: A Cluster RCT. AB - OBJECTIVE: The objective was to evaluate a manualized theory-driven primary preventive intervention aimed at early childhood obesity. The intervention was embedded in Swedish child health services, starting when eligible children were 9 to 10 months of age and continuing until the children reached age 4. METHODS: Child health care centers in 8 Swedish counties were randomized into intervention and control units and included 1355 families with 1369 infants. Over ~39 months, families in the intervention group participated in 1 group session and 8 individual sessions with a nurse trained in motivational interviewing, focusing on healthy food habits and physical activity. Families in the control group received care as usual. Primary outcomes were children's BMI, overweight prevalence, and waist circumference at age 4. Secondary outcomes were children's and mothers' food and physical activity habits and mothers' anthropometrics. Effects were assessed in linear and log-binominal regression models using generalized estimating equations. RESULTS: There were no statistically significant differences in children's BMI (beta = -0.11, 95% confidence interval [CI]: -0.31 to 0.08), waist circumference (beta = -0.48, 95% CI: -0.99 to 0.04), and prevalence of overweight (relative risk = 0.95, 95% CI: 0.69 to 1.32). No significant intervention effects were observed in mothers' anthropometric data or regarding mothers' and children's physical activity habits. There was a small intervention effect in terms of healthier food habits among children and mothers. CONCLUSIONS: There were no significant group differences in children's and mothers' anthropometric data and physical activity habits. There was, however, some evidence suggesting healthier food habits, but this should be interpreted with caution. PMID- 27244794 TI - Characteristics of Rural Children Admitted to Pediatric Hospitals. AB - BACKGROUND AND OBJECTIVES: Delivering high-quality care to children living in rural areas can be challenging. Compared with nonrural children, rural children often experience worse health outcomes. We assessed characteristics and hospitalizations of rural children admitted to US children's hospitals in 2012. METHODS: Retrospective cohort analysis of 672190 admissions between January 1, 2012, and December 31, 2012, to 41 children's hospitals in the Pediatric Health Information System database. ZIP codes were used to assess the patients' rurality (by using Rural-Urban Community Areas classification), residence in a Health Professional Shortage Area, and family income. Multivariable regression was used to compare patient characteristics and hospital utilization between rural and nonrural children. RESULTS: Rural children accounted for 12% of all admissions (n = 81 360) to the children's hospitals. Compared with nonrural children, rural children lived farther from the hospital (median [interquartile range]: 68 [48 104] vs 12 [6-24] miles) and more often resided in low-income ZIP codes (53% vs 24%) and Health Professional Shortage Areas (20% vs 4%) (P < .001 for all). Rural children had a higher prevalence of complex chronic conditions (44% vs 37%; P < .001) and medical technology assistance (15% vs 12%; P < .001). In multivariable analysis, rural children experienced higher inpatient costs (mean: $8507 vs $7814; P < .001) and higher odds of 30-day readmission (odds ratio: 1.1; 95% confidence interval: 1.0-1.1; P < .001). CONCLUSIONS: Rural children hospitalized at children's hospitals have high rates of medical complexity and often reside in low-income and medically underserved areas. Compared with nonrural children, rural children experience more expensive hospitalizations and more frequent readmissions. PMID- 27244796 TI - A 17-Year-Old With Steroid-Resistant Nephrotic Syndrome. AB - A 17-year-old girl presented with facial swelling and shortness of breath to an outside emergency department. She was treated for an allergic reaction with steroids and antihistamines, and discharged from the hospital. Subsequently, she was referred as an outpatient to pediatric nephrology for recurrent edema and proteinuria. Initial laboratory workup by nephrology was significant for a normal complete blood count and reassuring electrolyte panel. Pertinent laboratories were a creatinine of 0.5 mg/dL (0.4-1.1 mg/dL) and an albumin 2.3 g/dL (3.5-5.0 g/dL). The urine protein-to-creatinine ratio was >7 (<0.2). A renal ultrasound showed symmetrically sized kidneys with normal echotexture. The patient's renal biopsy results were consistent with minimal change disease. Based on the biopsy results, prednisone was started. Due to a poor response to prednisone, an alternate immunomodulator therapy was selected. Her subsequent complete blood counts showed a downward trend of all cell lines and an elevated serum uric acid. Concurrently, she reported worsening fatigue, low back pain, nausea, vomiting, night sweats, and pruritus. More details of her case and the outcome are presented. PMID- 27244797 TI - Congenital Rubella Syndrome: A Case Report on Changes in Viral Load and Rubella Antibody Titers. AB - To our knowledge, this is the first report of the use of real-time reverse transcription-polymerase chain reaction to assess changes in viral load in a patient with congenital rubella syndrome (CRS). Rubella-specific antibody titers were also determined. The patient was a male neonate born to a primipara with rubella infection at 10 weeks of gestation. He had no symptoms at birth, but rubella virus was detected in his pharynx, blood, and urine. His mental and physical development was normal for 1 year; however, he was diagnosed with deafness at 13 months of age. Thus, the patient was diagnosed with CRS. Rubella infection in the pharynx was almost constant until 5 months of age; however, it increased dramatically at 6 months of age. No infection was detected at 13 months. Rubella-specific immunoglobulin M titer was consistently low until 9 months of age and then decreased gradually until it became negative at 20 months of age. Rubella-specific immunoglobulin G titer was high at birth. However, it decreased at 3 months and increased again at 4 months. This titer peaked at ~9 months and then decreased again at 13 months. This case shows that the period after the decline in maternal antibody titers, not the neonatal period, may be the most contagious period in patients with CRS. PMID- 27244795 TI - Risk of Suicidal Events With Atomoxetine Compared to Stimulant Treatment: A Cohort Study. AB - BACKGROUND: Antidepressant effects on increased suicidality in children have raised public concern in recent years. Approved in 2002 for attention deficit/hyperactivity disorder treatment, the selective noradrenalin-reuptake inhibitor atomoxetine was initially investigated for the treatment of depression. In post-hoc analyses of clinical trial data, atomoxetine has been associated with an increased risk of suicidal ideation in children and adolescents. We analyzed whether the observed increased risk of suicidal ideation in clinical trials translates into an increased risk of suicidal events in pediatric patients treated with atomoxetine compared with stimulants in 26 Medicaid programs. METHODS: Employing a retrospective cohort design, we used propensity score adjusted Cox proportional hazard models to evaluate the risk of suicide and suicide attempt in pediatric patients initiating treatment with atomoxetine compared with stimulants from 2002 to 2006. RESULTS: The first-line treatment cohort included 279 315 patients. During the first year of follow-up, the adjusted hazard ratio for current atomoxetine use compared with current stimulant use was 0.95 (95% CI 0.47-1.92, P = .88). The second-line treatment cohort included 220 215 patients. During the first year of follow-up, the adjusted hazard ratio for current atomoxetine use compared with current stimulant use was 0.71 (95% CI 0.30-1.67, P = .43). CONCLUSIONS: First- and second-line treatment of youths age 5 to 18 with atomoxetine compared with stimulants was not significantly associated with an increased risk of suicidal events. The low incidence of suicide and suicide attempt resulted in wide confidence intervals and did not allow stratified analysis of high-risk groups or assessment of suicidal risk associated with long-term use of atomoxetine. PMID- 27244798 TI - First-year Daycare and Incidence of Acute Gastroenteritis. AB - BACKGROUND: Daycare attendance has been associated with increased acute gastroenteritis (AGE) incidence in the first years of life. We investigated the effects of first-year daycare attendance on AGE incidence and primary care contact rate up to age 6 years. METHODS: Children enrolled in the Wheezing Illnesses Study Leidsche Rijn cohort were managed until age 6 years. Data on primary care diagnosed AGE episodes and number of associated contacts per episode were collected from health records. Children were categorized according to first year daycare attendance and age-month at entry when applicable. Generalized estimating equations were used to assess associations between first-year daycare and AGE incidence or primary care contact rate. RESULTS: A total of 1344 out of 2220 children (83%) attended daycare before age 1 year. Overall, the 6-year primary care AGE incidence rate (IR) among first-year daycare attendees and nonattendees was comparable (IR: 12.2/100 vs 13.3/100 child-years). First-year daycare attendees had a higher AGE incidence during the first year (IRR: 1.13; 95% confidence interval: 1.06-1.21) and lower during the third to sixth year of age compared with nonattendees (P < .001). The daycare-associated increase in AGE incidence was most pronounced during the first 12 months after enrollment into daycare and demonstrated clear seasonality. A similar pattern was observed for primary care contact rate per AGE episode. CONCLUSIONS: First-year daycare attendance advances the timing of AGE infections, resulting in increased AGE disease burden in the first year and relative protection thereafter. Protection against AGE infection persists at least up to age 6 years. Future studies should address whether this protective effect persists during later childhood. PMID- 27244799 TI - Childhood Sexual Violence Against Boys: A Study in 3 Countries. AB - BACKGROUND AND OBJECTIVE: Globally, little evidence exists on sexual violence against boys. We sought to produce the first internationally comparable estimates of the magnitude, characteristics, risk factors, and consequences of sexual violence against boys in 3 diverse countries. METHODS: We conducted nationally representative, multistage cluster Violence Against Children Surveys in Haiti, Kenya, and Cambodia among males aged 13 to 24 years. Differences between countries for boys experiencing sexual violence (including sexual touching, attempted sex, and forced/coerced sex) before age 18 years were examined by using chi(2) and logistic regression analyses. RESULTS: In Haiti, Kenya, and Cambodia, respectively, 1459, 1456, and 1255 males completed surveys. The prevalence of experiencing any form of sexual violence ranged from 23.1% (95% confidence Interval [CI]: 20.0-26.2) in Haiti to 14.8% (95% CI: 12.0-17.7) in Kenya, and 5.6% (95% CI: 4.0-7.2) in Cambodia. The largest share of perpetrators in Haiti, Kenya, and Cambodia, respectively, were friends/neighbors (64.7%), romantic partners (37.2%), and relatives (37.0%). Most episodes occurred inside perpetrators' or victims' homes in Haiti (60.4%), contrasted with outside the home in Kenya (65.3%) and Cambodia (52.1%). The most common time period for violence in Haiti, Kenya, and Cambodia was the afternoon (55.0%), evening (41.3%), and morning (38.2%), respectively. Adverse health effects associated with violence were common, including increased odds of transactional sex, alcohol abuse, sexually transmitted infections, anxiety/depression, suicidal ideation/attempts, and violent gender attitudes. CONCLUSIONS: Differences were noted between countries in the prevalence, characteristics, and risk factors of sexual violence, yet associations with adverse health effects were pervasive. Prevention strategies tailored to individual locales are needed. PMID- 27244800 TI - Primary Care-Based Interventions to Promote Positive Parenting Behaviors: A Meta analysis. AB - CONTEXT: Utilization of primary care settings offers a promising approach to enhance parenting practices that are critical for promoting early childhood development. Determining the impact of existing primary care interventions on key parenting behaviors will aid providers and policy makers as they seek strategies to improve early child outcomes. OBJECTIVE: To evaluate the efficacy of primary care-based interventions on parenting practices that promote early child development among children younger than 36 months. DATA SOURCES: PubMed, Excerpta Medica dataBASE, PsycINFO, and Cumulative Index to Nursing and Allied Health Literature databases were searched electronically. STUDY SELECTION: English language articles that were quasi-randomized or randomized controlled trials, included parents of children <36 months of age, and reported outcomes related to parenting behaviors that promote early child development. DATA EXTRACTION: Two reviewers independently extracted data regarding participants, interventions, and outcomes. Quantitative meta-analyses were conducted with random effects for study and fitted with restricted maximum likelihood methods. RESULTS: The review included 13 studies reporting parenting outcomes in 2 categories: participation in cognitively stimulating activities and positive parent-child interactions. We found a statistically significant positive effect of primary care-delivered interventions and parent-child interactions (summary standardized mean difference 0.29, 95% confidence interval [CI] 0.06-0.52, P < .0001) and participation in cognitively stimulating activities (summary standardized mean difference 0.34, 95% CI 0.03-0.54; summary odds ratio 0.13, 95% CI 0.01-0.25, P < .0001). LIMITATIONS: Limitations included heterogeneity in measures used, outcomes, and timing of assessments. CONCLUSIONS: Primary care-based interventions modestly affect positive parenting behaviors important for early childhood development. Randomized controlled trials with comparable outcome measures using standardized assessments are needed to assess further beneficial impacts. PMID- 27244801 TI - Case Report: The Specter of Untreated Congenital Hypothyroidism in Immigrant Families. AB - Newborn screening has dramatically reduced rates of untreated congenital hypothyroidism (CH). However, in low-income nations where newborn screening programs do not exist, untreated CH remains a significant health and societal challenge. The goal of this report is to alert health care providers about the potential of undiagnosed CH in unscreened immigrant children. We report 3 siblings of Somali descent with CH who started treatment with levothyroxine at age 0.5 years, 7.7 years, and 14.8 years and were followed for 8 years. This case series demonstrates a spectrum of severity, response to treatment, and neurocognitive and growth outcomes depending on the age at treatment initiation. Patient 1, now 22 years old, went undiagnosed for 14.8 years. On diagnosis, his height was -7.5 SDs with a very delayed bone age of -13.5 SDs. His longstanding CH was associated with empty sella syndrome, static encephalopathy, and severe musculoskeletal deformities. Even after treatment, his height (-5.2 SDs) and cognitive deficits remained the most severe of the 3 siblings. Patient 2, diagnosed at 7.7 years, had moderate CH manifestations and thus a relatively intermediate outcome after treatment. Patient 3, who had the earliest diagnosis at 0.5 years, displayed the best response, but continues to have residual global developmental delay. In conclusion, untreated CH remains an important diagnostic consideration among immigrant children. PMID- 27244802 TI - Birth Spacing and Risk of Autism and Other Neurodevelopmental Disabilities: A Systematic Review. AB - CONTEXT: Both short and long interpregnancy intervals (IPIs) have recently been associated with increased risk of autism spectrum disorder (ASD). However, this association has not been systematically evaluated. OBJECTIVE: To examine the relationship between birth spacing and the risk of ASD and other neurodevelopmental disabilities. DATA SOURCES: Electronic databases from their inception to December 2015, bibliographies, and conference proceedings. STUDY SELECTION: Observational studies with results adjusted for potential confounding factors that reported on the association between IPIs or birth intervals and neurodevelopmental disabilities. DATA EXTRACTION: Two reviewers independently extracted data on study characteristics, IPIs/birth intervals, and outcome measures. RESULTS: Seven studies (1 140 210 children) reported an association between short IPIs and increased risk of ASD, mainly the former subtype autistic disorder. Compared with children born to women with IPIs of >=36 months, children born to women with IPIs of <12 months had a significantly increased risk of any ASD (pooled adjusted odds ratio [OR] 1.90, 95% confidence interval [CI] 1.16 3.09). This association was stronger for autistic disorder (pooled adjusted OR 2.62, 95% CI 1.53-4.50). Three of these studies also reported a significant association between long IPIs and increased risk of ASD. Short intervals were associated with a significantly increased risk of developmental delay (3 studies; 174 940 children) and cerebral palsy (2 studies; 19 419 children). LIMITATIONS: Substantial heterogeneity, and few studies assessing neurodevelopmental disabilities other than ASD. CONCLUSIONS: Short IPIs are associated with a significantly increased risk of ASD. Long IPIs also appear to increase the risk of ASD. PMID- 27244803 TI - Infant BMI or Weight-for-Length and Obesity Risk in Early Childhood. AB - BACKGROUND: Weight-for-length (WFL) is currently used to assess adiposity under 2 years. We assessed WFL- versus BMI-based estimates of adiposity in healthy infants in determining risk for early obesity. METHODS: Anthropometrics were extracted from electronic medical records for well-child visits for 73 949 full term infants from a large pediatric network. World Health Organization WFL and BMI z scores (WFL-z and BMI-z, respectively) were calculated up to age 24 months. Correlation analyses assessed the agreement between WFL-z and BMI-z and within subject tracking over time. Logistic regression determined odds of obesity at 2 years on the basis of adiposity classification at 2 months. RESULTS: Agreement between WFL-z and BMI-z increased from birth to 6 months and remained high thereafter. BMI-z at 2 months was more consistent with measurements at older ages than WFL-z at 2 months. Infants with high BMI (>=85th percentile) and reference WFL (5th-85th percentiles) at 2 months had greater odds of obesity at 2 years than those with high WFL (>=85th percentile) and reference BMI (5th-85th percentiles; odds ratio, 5.49 vs 1.40; P < .001). At 2 months, BMI had a higher positive predictive value than WFL for obesity at 2 years using cut-points of either the 85th percentile (31% vs 23%) or 97.7th percentile (47% vs 29%). CONCLUSIONS: High BMI in early infancy is more strongly associated with early childhood obesity than high WFL. Forty-seven percent of infants with BMI >=97.7th percentile at 2 months (versus 29% of infants with WFL >=97.7th percentile at 2 months) were obese at 2 years. Epidemiologic studies focused on assessing childhood obesity risk should consider using BMI in early infancy. PMID- 27244804 TI - Revised WIC Food Package and Children's Diet Quality. AB - BACKGROUND AND OBJECTIVES: In October 2009, the Special Supplemental Nutrition Program for Women, Infant, and Children (WIC) food package was revised to include more fruits, vegetables, whole grains, and lower-fat milk. We examined the impact of the WIC food package revisions on the diet quality of children in households using WIC. METHODS: A total of 1197 children aged 2 to 4 years from low-income households were studied from before and after the policy implementation (using the 2003-2008 and 2011-2012 National Health and Nutrition Examination Survey). The Healthy Eating Index-2010 (HEI-2010) was calculated using two 24-hour diet recalls. Linear regression was used to examine the difference in HEI-2010 score attributable to the food package change, adjusting for baseline and secular trends among WIC participants and nonparticipants, as well as child and household characteristics. Component scores of the HEI-2010 index were analyzed with generalized linear models. RESULTS: Average HEI-2010 scores for participants and nonparticipants were 52.4 and 50.0 at baseline, and 58.3 and 52.4 after the policy change, respectively. The WIC food package revisions were associated with an adjusted average of 3.7 additional HEI-2010 points (95% confidence interval, 0.6-6.9) for WIC participants compared with nonparticipants. In particular, the revisions were associated with a 3.4-fold relative increase (95% confidence interval, 1.3-9.4) in the Greens and Beans component score for WIC participants compared with nonparticipants. CONCLUSIONS: Results from this national sample indicate that the WIC food package revisions were associated with higher diet quality for children participating in WIC. PMID- 27244805 TI - Hypoglossal Nerve Stimulator Implantation in an Adolescent With Down Syndrome and Sleep Apnea. AB - Obstructive sleep apnea (OSA) is more common in children with Down syndrome, affecting up to 60% of patients, and may persist in up to 50% of patients after adenotonsillectomy. These children with persistent moderate to severe OSA require continuous positive airway pressure, which is often poorly tolerated, or even tracheotomy for severe cases. The hypoglossal nerve stimulator is an implantable device that produces an electrical impulse to the anterior branches of the hypoglossal nerve, resulting in tongue protrusion in response to respiratory variation. It is an effective treatment of sleep apnea in select adult patients because it allows for alleviation of tongue base collapse, improving airway obstruction. Herein we describe the first pediatric hypoglossal nerve stimulator implantation, which was performed in an adolescent with Down syndrome and refractory severe OSA (apnea hypopnea index [AHI]: 48.5 events/hour). The patient would not tolerate continuous positive airway pressure and required a long standing tracheotomy. Hypoglossal nerve stimulator therapy was well tolerated and effective, resulting in significant improvement in the patient's OSA (overall AHI: 3.4 events/hour; AHI: 2.5-9.7 events/hour at optimal voltage settings depending on sleep stage and body position). Five months after implantation, the patient's tracheotomy was successfully removed and he continues to do well with nightly therapy. PMID- 27244806 TI - Socioeconomic Disparities in the Economic Impact of Childhood Food Allergy. AB - OBJECTIVES: We compared direct medical costs borne by the health care system and out-of-pocket costs borne by families for children with food allergy by socioeconomic characteristics. METHODS: We analyzed cross-sectional survey data collected between November 2011 and January 2012 from 1643 US caregivers with a food-allergic child. We used a 2-part regression model to estimate mean costs and identified differences by levels of household income and race or ethnicity. RESULTS: Children in the lowest income stratum incurred 2.5 times the amount of emergency department and hospitalization costs as a result of their food allergy than higher-income children ($1021, SE +/-$209, vs $416, SE +/-$94; P < .05). Costs incurred for specialist visits were lower in the lowest income group ($228, SE +/-$21) compared with the highest income group ($311, SE +/-$18; P < .01) as was spending on out-of-pocket medication costs ($117, SE +/- $26, lowest income; $366, SE +/-$44, highest income; P < .001). African American caregivers incurred the lowest amount of direct medical costs and spent the least on out-of-pocket costs, with average adjusted costs of $493 (SE +/-$109) and $395 (SE +/-$452), respectively. CONCLUSIONS: Disparities exist in the economic impact of food allergy based on socioeconomic status. Affordable access to specialty care, medications, and allergen-free foods are critical to keep all food-allergic children safe, regardless of income and race. PMID- 27244807 TI - The Challenges in Measuring Local Immunization Coverage: A Statewide Case Study. AB - There are many forms of existing immunization surveillance in the United States and Washington state, but all are limited in their ability to provide timely identification of clusters of unimmunized individuals and assess the risk of vaccine-preventable diseases. This article aims to: (1) describe challenges to measuring immunization coverage at a local level in the United States using Washington State as a case study; and (2) propose improvements to existing surveillance systems that address the challenges identified. PMID- 27244808 TI - Eating in the Absence of Hunger and Weight Gain in Low-income Toddlers. AB - OBJECTIVE: To identify predictors of eating in the absence of hunger (EAH) in low income toddlers, describe affect during EAH, test EAH as a predictor of body mass index (BMI), and examine the type of food eaten as a predictor of BMI. METHODS: EAH, indexed as kilocalories (sweet, salty, and total) of palatable foods consumed after a satiating meal, was measured (n = 209) at ages 21, 27, and 33 months. Child gender, age, race/ethnicity, and previous exposure to the foods; maternal education and depressive symptoms; and family chaos, food insecurity, and structure were obtained via questionnaire. Child and mother BMI were measured. Child affect was coded from videotape. Linear regression was used to examine predictors of EAH and the association of kilocalories consumed and affect with 33 month BMI z-score (BMIz). RESULTS: Predictors of greater total kilocalories included the child being a boy (P < .01), being older (P < .001), and greater maternal education (P < .01). Being in the the top quartile of sweet kilocalories consumed at 27 months and showing negative affect at food removal had higher BMIz (beta = 0.29 [95% confidence interval 0.10 to 0.48] and beta = 0.34 [95% confidence interval, 0.12 to 0.56], respectively).There was no association of salty kilocalories consumed or positive affect with BMIz. CONCLUSIONS: There was little evidence that maternal or family characteristics contribute to EAH. EAH for sweet food predicts higher BMIz in toddlerhood. Studies investigating the etiology of EAH and interventions to reduce EAH in early childhood are needed. PMID- 27244809 TI - Improving Care for Neonatal Abstinence Syndrome. AB - BACKGROUND AND OBJECTIVE: Care for neonatal abstinence syndrome (NAS), a postnatal drug withdrawal syndrome, remains variable. We designed and implemented a multicenter quality improvement collaborative for infants with NAS. Our objective was to determine if the collaborative was effective in standardizing hospital policies and improving patient outcomes. METHODS: From 2012 to 2014, data were collected through serial cross-sectional audits of participating centers. Hospitals assessed institutional policies and patient-level data for infants with NAS requiring pharmacotherapy, including length of pharmacologic treatment and length of hospital stay (LOS). Models were fit, clustered according to hospital, to evaluate changes in patient outcomes over time. RESULTS: Among 199 participating centers, the mean number of NAS-focused guidelines increased from 3.7 to 5.1 of a possible 6 (P < .001), with improvements noted in all measured domains. Among infants cared for at participating centers, decreases occurred in median (interquartile range) length of pharmacologic treatment, from 16 days (10 to 27 days) to 15 days (10 to 24 days; P = .02), and LOS from 21 days (14 to 33 days) to 19 days (15 to 28 days; P = .002). In addition, there was a statistically significant decrease in the proportion of infants discharged on medication for NAS, from 39.7% to 26.5% (P = .02). After adjusting for potential confounders, standardized NAS scoring process was associated with shorter LOS ( 3.3 days,95% confidence interval, -4.9 to -1.4). CONCLUSIONS: Involvement in a multicenter, multistate quality improvement collaborative focused on infants requiring pharmacologic treatment for NAS was associated with increases in standardizing hospital patient care policies and decreases in health care utilization. PMID- 27244810 TI - Iatrogenic Cushing's Syndrome Due to Intranasal Usage of Ophthalmic Dexamethasone: A Case Report. AB - Iatrogenic Cushing's syndrome (ICS) is caused by exogenous corticosteroid administration with suppression of the hypothalamic-pituitary-adrenal axis. It has been commonly described with oral and topical steroid use, but scarce reports have documented intranasal steroid usage as the etiology in infancy. In this article, we describe a case of a 4-month-old infant who developed ICS after 6 weeks of intranasal dexamethasone ophthalmic solution administration for nasal obstruction. To our knowledge, this is the youngest patient reported with ICS due to intranasal use of a prescribed dose of an ophthalmic steroid. His hypothalamic pituitary-adrenal axis recovered fully 4.5 months after steroid discontinuation. Because of the small body surface area and supine position during administration, infants are particularly susceptible to ICS. Given that intranasal steroids are commonly prescribed to infants and children for a variety of diagnoses, this case highlights the risks inherent in the use of intranasal steroid drops, particularly in young infants, for both adrenal suppression and linear growth deceleration, even with short-term use. Close monitoring of these patients' height and weight should occur while on steroid treatment, with every effort made to decrease or discontinue steroid use when possible. PMID- 27244811 TI - Parental Perception of Weight Status and Weight Gain Across Childhood. AB - BACKGROUND AND OBJECTIVE: Parents of children who are overweight often fail to accurately identify their child's weight status. Although these misperceptions are presumed to be a major public health concern, little research has examined whether parental perceptions of child weight status are protective against weight gain during childhood. Our objective was to examine whether parental perceptions of child weight status are associated with weight gain across childhood. METHODS: Data from the Longitudinal Study of Australian Children were used to assess parental perceptions of child weight status and to examine changes in researcher measured child BMI z scores across childhood, from 4 to 13 years old. Participants included 3557 Australian children and their parents. RESULTS: Children whose parents perceived their weight as being "overweight," as opposed to "about the right weight," gained more weight (increase in BMI z score) from baseline to follow-up in all analyses. This finding did not depend on the actual weight of the child; the association between perceiving one's child as being overweight and future weight gain was similar among children whose parents accurately and inaccurately believed their child was overweight. CONCLUSIONS: Contrary to popular belief, parental identification of child overweight is not protective against further weight gain. Rather, it is associated with more weight gain across childhood. Further research is needed to understand how parental perceptions of child weight may counterintuitively contribute to obesity. PMID- 27244812 TI - Alcohol-Branded Merchandise Ownership and Drinking. AB - CONTEXTS: Alcohol-branded merchandise (ABM) has a longer shelf-life than other forms of alcohol marketing and the potential to become integrated into children's self-identities. OBJECTIVE: This review sought to explore the current literature on children's exposure to, and the impact of, ABM. DATA SOURCES: PsycInfo, Proquest, Science Direct, and ABI-Inform databases were searched from the earliest available date to May 2015. Additional studies were identified by a manual review of the reference lists of retrieved articles and contacting the corresponding author of each included study. STUDY SELECTION: Articles that reported on child or adolescent ownership of ABM and/or the relationship between ABM ownership and drinking were included. DATA EXTRACTION: Data on key measures were tabulated; where data of interest were not reported, requests for further information were sent to the articles' authors. RESULTS: Nine cross-sectional and 4 longitudinal studies were identified. ABM ownership ranged from 11% to 59% and was higher among older children and males. Seven cross-sectional studies reported associations between ABM ownership and drinking-related behaviors. All 4 longitudinal studies reported a significant relationship between ownership at baseline and drinking initiation at follow-up. LIMITATIONS: The small number of available studies, with different measures of ABM ownership and of associations/effects. CONCLUSIONS: The few studies exploring ABM ownership are consistent in showing high rates of ownership and associations between ownership and current and future drinking. There is a need for further research into specific aspects of ABM ownership. However, there is also a need for policy interventions to reduce children's access to and ownership of ABM. PMID- 27244813 TI - Pertussis Vaccine Effectiveness in the Setting of Pertactin-Deficient Pertussis. AB - BACKGROUND: In the United States, the proportion of Bordetella pertussis isolates lacking pertactin, a component of acellular pertussis vaccines, increased from 14% in 2010 to 85% in 2012. The impact on vaccine effectiveness (VE) is unknown. METHODS: We conducted 2 matched case-control evaluations in Vermont to assess VE of the 5-dose diphtheria, tetanus, and acellular pertussis vaccine (DTaP) series among 4- to 10-year-olds, and tetanus, diphtheria, and acellular pertussis vaccine (Tdap) among 11- to 19-year-olds. Cases reported during 2011 to 2013 were included. Three controls were matched to each case by medical home, and additionally by birth year for the Tdap evaluation. Vaccination history was obtained from medical records and parent interviews. Odds ratios (OR) were calculated by using conditional logistic regression; VE was estimated as (1-OR) * 100%. Pertactin status was determined for cases with available isolates. RESULTS: Overall DTaP VE was 84% (95% confidence interval [CI] 58%-94%). VE within 12 months of dose 5 was 90% (95% CI 71%-97%), declining to 68% (95% CI 10%-88%) by 5 7 years post-vaccination. Overall Tdap VE was 70% (95% CI 54%-81%). Within 12 months of Tdap vaccination, VE was 76% (95% CI 60%-85%), declining to 56% (95% CI 16%-77%) by 2-4 years post-vaccination. Of cases with available isolates, >90% were pertactin-deficient. CONCLUSIONS: Our DTaP and Tdap VE estimates remain similar to those found in other settings, despite high prevalence of pertactin deficiency in Vermont, suggesting these vaccines continue to be protective against reported pertussis disease. PMID- 27244814 TI - Metformin or Oral Contraceptives for Adolescents With Polycystic Ovarian Syndrome: A Meta-analysis. AB - BACKGROUND: Polycystic ovarian syndrome (PCOS) is a common disease. There is limited evidence to support various treatment choices. This leads to variable treatment practices. OBJECTIVES: To conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the use of metformin versus oral contraceptive pills (OCPs) for the treatment of PCOS in adolescents aged 11 to 19 years. DATA SOURCES: We performed literature searches through Ovid Medline, Ovid Embase, Cochrane Central Register of Controlled Trials, and gray literature resources, up to January 29, 2015. STUDY SELECTION AND DATA EXTRACTION: Two reviewers screened titles and abstracts of identified citations, assessed full text eligibility, and extracted information from eligible trials. RESULTS: Four RCTs met the inclusion and exclusion criteria. The reviewed evidence came from 170 patients. Overall, OCP treatment resulted in modest improvement in menstrual cycle frequency (weighted mean difference [WMD] = 0.27, P < .01, 95% confidence interval [CI] -0.33 to -0.21) and mild reduction of acne scores (WMD = 0.3, P = .02, 95% CI 0.05 to 0.55). While metformin resulted in greater BMI reduction (WMD = -4.02, P < .01, 95% CI -5.23 to -2.81) it was associated with decreased dysglycemia prevalence (risk ratio: 0.41, P = .02, 95% CI 0.19 to 0.86) and improved total cholesterol and low-density lipoprotein levels. Metformin and OCPs were similar in terms of impact on hirsutism. CONCLUSIONS AND LIMITATIONS: Current evidence is derived from very low to low quality evidence. Therefore, treatment choice should be guided by patient values and preferences while balancing potential side effects. Future high quality RCTs are needed to address several questions for the treatment of adolescents with PCOS. PMID- 27244815 TI - Exposure to Advertisements and Electronic Cigarette Use Among US Middle and High School Students. AB - BACKGROUND: Electronic cigarette (e-cigarette) use among US students increased significantly during 2011 to 2014. We examined the association between e cigarette advertisement exposure and current e-cigarette use among US middle school and high school students. METHODS: Data came from the 2014 National Youth Tobacco Survey (n = 22 007), a survey of students in grades 6 through 12. The association between current e-cigarette use and exposure to e-cigarette advertisements via 4 sources (Internet, newspapers/magazines, retail stores, and TV/movies) was assessed. Three advertising exposure categories were assessed: never/rarely, sometimes, and most of the time/always. Separate logistic regression models were used to measure the association, adjusting for gender, race/ethnicity, grade, and other tobacco use. RESULTS: Compared with students who reported exposure to e-cigarette advertisements never/rarely, the odds of current e-cigarette use were significantly (P < .05) greater among those reporting exposure sometimes and most of the time/always, respectively, as follows: Internet (adjusted odds ratio: middle school, 1.44 and 2.91; high school, 1.49, and 2.02); newspapers/magazines (middle school, 0.93 [not significant] and 1.87; high school, 1.26 and 1.71); retail stores (middle school, 1.78 and 2.34; high school, 1.37, and 1.91); and TV/movies (middle school, 1.25 [not significant] and 1.80; high school, 1.24 and 1.54). CONCLUSIONS: E-cigarette advertisement exposure is associated with current e-cigarette use among students; greater exposure is associated with higher odds of use. Given that youth use of tobacco in any form is unsafe, comprehensive tobacco prevention and control strategies, including efforts to reduce youth exposure to advertising, are critical to prevent all forms of tobacco use among youth. PMID- 27244816 TI - Children and Solitary Confinement: A Call to Action. PMID- 27244817 TI - Clinical Decision Support Tool for Parental Tobacco Treatment in Primary Care. AB - OBJECTIVES: We created a clinical decision support (CDS) tool and evaluated its feasibility, acceptability, usability, and clinical impact within the electronic health record to help primary care pediatricians provide smoking cessation treatment to parents/caregivers who smoke. METHODS: This prospective study of pediatric clinicians and parents was conducted at 1 urban primary care site. Clinicians received training in smoking cessation counseling, nicotine replacement therapy (NRT) prescribing, referral to an adult treatment program, and use of the CDS tool. The tool prompted clinicians to ask about secondhand smoke exposure, provide an electronic NRT prescription, and refer. Feasibility was measured by using electronic health record utilization data, and acceptability and usability were assessed with the use of clinician surveys. Parents reported clinical impact, including NRT accepted and used. RESULTS: From June to August 2015, clinicians used the tool to screen for secondhand smoke exposure at 2286 (76%) of 3023 visits. Parent smokers were identified at 308 visits, and 165 parents (55% of smokers) were interested in and offered treatment. Twenty-four (80%) of 30 eligible pediatric clinicians used the tool. Ninety-four percent of clinicians surveyed (n = 17) were satisfied with the tool, and the average system usability scale score was 83 of 100 (good to excellent range). We reached 69 of 100 parents sampled who received treatment; 44 (64%) received NRT, and 17 (25%) were currently using NRT. CONCLUSIONS: A CDS tool to help urban primary care pediatric clinicians provide smoking cessation treatment was feasible, acceptable, usable, and influenced clinical care. A larger scale investigation in varied practice settings is warranted. PMID- 27244819 TI - Respiratory Decompensation and Immunization of Preterm Infants. AB - BACKGROUND: Concern for respiratory decompensation after immunization in premature infants, particularly those with bronchopulmonary dysplasia (BPD), may lead to delayed and altered immunization schedules. METHODS: A retrospective cohort of premature infants at <32 weeks' gestational age cared for in a tertiary level 4 NICU and immunized during their hospital stay were evaluated for respiratory decompensation within 72 hours of immunization. Respiratory measurements including change in respiratory support, mean fraction of inspired oxygen, and apnea, bradycardia, and desaturation events were compared between those infants with BPD and those without. The primary outcome was the difference in respiratory decompensation defined as a composite of increased respiratory support or increased fraction of inspired oxygen >=10% within 72 hours of immunization. RESULTS: Of 403 infants admitted to the NICU and immunized, 240 met the study criteria. Of those infants, 172 had a diagnosis of BPD. There was no difference in the primary outcome of respiratory decompensation after immunization between groups (P = .65). There was also no significant difference in apnea, bradycardia, and desaturation events between groups (P = .51). CONCLUSIONS: In this cohort, respiratory decompensation requiring clinical intervention after immunization of preterm infants both with and without BPD was uncommon and not significantly different between groups. Consideration for immunization of this vulnerable population should not be delayed out of concern for clinical deterioration. PMID- 27244818 TI - Prophylactic Dosing of Vitamin K to Prevent Bleeding. AB - BACKGROUND AND OBJECTIVES: Based on a high incidence of Vitamin K deficiency bleeding (VKDB) in breastfed infants with thus far unrecognized cholestasis, such as biliary atresia (BA), the Dutch regimen to prevent VKDB in breastfed infants was changed from a daily oral dosage of 25 ug to 150 ug vitamin K. Infants continued to receive 1 mg of vitamin K orally at birth. We compared the efficacy of the 150-ug regimen with the 25-ug regimen and with the Danish regimen of a single intramuscular (IM) dose of 2 mg vitamin K at birth. METHODS: Data were retrieved from the national BA registries: 25 ug group (Netherlands, January 1991 to February 2011); 150 ug group (Netherlands, March 2011 to January 2015); and IM 2 mg group (Denmark, July 2000 to November 2014). We compared the incidence of VKDB in the groups. RESULTS: VKDB occurred in 45 of 55 (82%) infants of the 25 ug group, in 9 of 11 (82%) of the 150 ug group, but in only 1 of 25 (4%) of the IM 2 mg group (P < .001). Forty percent of all infants of the 25 ug group had an intracranial hemorrhage as presenting symptom, compared with 27% of the infants of the 150 ug group (P = .43). Intracranial hemorrhage was not observed in the IM 2 mg group (0%; P < .001). CONCLUSIONS: A vitamin K prophylactic regimen of 1 mg of vitamin K orally at birth followed by a daily oral dosage of either 25 or 150 ug fails to prevent VKDB in breastfed infants with still unrecognized BA. The data support 2 mg vitamin K IM at birth as prophylaxis against VKDB. PMID- 27244820 TI - Diabetes in Pregnancy and Childhood Cognitive Development: A Systematic Review. AB - CONTEXT: The effect of diabetes during pregnancy on the cognitive development of offspring is unclear because of inconsistent findings from limited studies. OBJECTIVE: This review was aimed to provide the best available scientific evidence on the associations between maternal pregnancy diabetes and the cognitive development of offspring. DATA SOURCES: A search was conducted in the Embase, CINAHL, PubMed, PsycINFO, and Scopus databases. STUDY SELECTION: Studies addressing the cognitive development of offspring (aged <=12 years) as outcome and any diabetes in pregnancy as an exposure were included. DATA EXTRACTION: Data were extracted and evaluated for quality by 2 independent reviewers. RESULTS: Fourteen articles were eligible for the review. Ten studies investigated the associations between maternal pregestational diabetes or both pregestational and gestational diabetes and offspring's cognitive development; 6 studies found at least 1 negative association. Four studies exclusively examined the relationships between gestational diabetes and offspring's cognitive development; 2 studies found a negative association, 1 a positive association, and 1 a null association. The use of diverse cognitive and diabetes assessment tools/criteria, as well as statistical power, contributed to the inconsistent findings. LIMITATIONS: The English-language restriction and publication bias in the included studies are potential limitations. CONCLUSIONS: Although there are few data available regarding the associations between maternal pregnancy diabetes and offspring's cognitive development, this review found that maternal diabetes during pregnancy seems to be negatively associated with offspring's cognitive development. Large prospective studies that address potential confounders are needed to confirm the independent effect of maternal diabetes during pregnancy. PMID- 27244821 TI - Foreskin Morbidity in Uncircumcised Males. AB - OBJECTIVE: As a consequence of the discussion on whether the health benefits of newborn male circumcision outweigh the risks and the discrepancies in reported figures of complications, we evaluated the incidence and morbidity of foreskin surgery due to medical indications in boys from the Capital Region of Denmark in 2014. METHODS: Medical records from all boys operated on the foreskin due to medical reasons in the Capital Region in 2014 were reviewed. Patients with hypospadias, ritual circumcision, and redo-surgery because of complications to nontherapeutic circumcision were excluded. RESULTS: A total of 181 patients were included. The cumulative risk of undergoing foreskin operation before 18 years of age was 1.7%. Forty patients had histologic verified balanitis xerotica obliterans (BXO) corresponding to a total risk of 0.37% of developing BXO. Mean age at surgery was 10.1 years (range 1-17). Phimosis was the most frequently reported indication (95.0%). The remaining 5.0% underwent surgery because of frenulum breve causing problems during erection. Before surgery, 27.1% had foreskin-related voiding problems and 17.1% had at least 1 episode of balanitis. Circumcision was initially performed in 44 cases. The remaining 137 patients had a foreskin-preserving operation performed. Nine boys had secondary circumcision after initially having foreskin-preserving operation. Fifty patients initially had preputial histology performed. BXO was verified in 37 patients. Of the 9 patients with redo-surgery due to recurrent phimosis, a further 3 had histologically verified BXO. CONCLUSIONS: Childhood foreskin-related problems in a region with no tradition of newborn male circumcision should not be neglected. PMID- 27244822 TI - Changing Societal and Lifestyle Factors and Breastfeeding Patterns Over Time. AB - BACKGROUND: Breastfeeding is an important determinant of early infant immune function and potentially future health. Although numerous studies have reported rising breastfeeding initiation rates and duration, few longitudinally investigated the impact of shifting societal and lifestyle factors on breastfeeding patterns in developed nations. METHODS: The Ulm Birth Cohort Study (UBCS) and Ulm SPATZ Health Study (SPATZ) cohorts consist of newborns and their mothers recruited, respectively, from 2000 to 2001 and 2012 to 2013 at the University Medical Center Ulm, Germany. Cox proportional hazards models were used to estimate crude and mutually adjusted hazard ratios for study effect (time trend) and individual risk factors on noninitiation and duration of predominant and total breastfeeding. RESULTS: Compared with UBCS mothers, SPATZ mothers had lower cessation rates of both predominant breastfeeding by 4 months and total breastfeeding by 6 months: hazard ratio (95% confidence interval) 0.79 (0.67 0.93) and 0.71 (0.60-0.82), respectively. However, this crude time trend was limited to mothers with higher educational achievement. Similar time trend effects were observed among less educated mothers only after adjustment for early cessation risk factors. Mutually adjusted hazard ratios for individual risk factors were similar in both studies: low education, high BMI, smoking within 6 weeks of delivery, and cesarean delivery were associated with early breastfeeding cessation beginning at 6 weeks. In addition, actively abstaining from drinking alcohol was associated with lower rates of early cessation. CONCLUSIONS: Our results suggest widening socioeconomic disparity in breastfeeding and potentially subsequent child health, which may require new targeted interventions. PMID- 27244823 TI - Using Simulation for Global Health Preparation. PMID- 27244824 TI - What If the Prenatal Diagnosis of a Lethal Anomaly Turns Out to Be Wrong? AB - Advances in prenatal diagnosis create a unique set of clinical ethics dilemmas. Doctors routinely obtain genetic screening, radiologic images, and biophysical profiling. These allow more accurate diagnosis and prognosis than has ever before been possible. However, they also reveal a wider range of disease manifestations than were apparent when prenatal diagnosis was less sophisticated. Sometimes, the best estimates of prognosis turn out to be wrong. The infant's symptoms may be less severe or more severe than anticipated based on prenatal assessment. We present a case in which a prenatal diagnosis was made of severe osteogenesis imperfecta, leading to a decision to induce delivery at 31 weeks. On postnatal evaluation, the infant's disease did not appear to be as bad as had been anticipated. We discuss the ethical implications of such diagnostic and prognostic errors. PMID- 27244825 TI - Pediatric Exposures to Laundry and Dishwasher Detergents in the United States: 2013-2014. AB - OBJECTIVE: This study analyzes and compares pediatric exposures to packet and nonpacket forms of laundry and dishwasher detergents in the United States. METHODS: Data from the National Poison Data System involving exposures to laundry and dishwasher detergents among children younger than 6 years old from 2013 through 2014 were analyzed. RESULTS: There were 62 254 children younger than 6 years old exposed to laundry and dishwasher detergents from 2013 to 2014. The number of exposures to detergent increased over the study period, but the increase was greatest for laundry detergent packets (17.0%) and dishwasher detergent packets (14.0%). Eighty-five percent of children were exposed through ingestion. The odds of clinical effects (3.9-8.2), hospitalization (4.8-23.5), intubation (6.9-71.3), and serious medical outcomes (8.4-22.6) were significantly higher for laundry detergent packet exposures than for other types of detergent. There were 117 children who required intubation, and 104 of these were exposed to laundry detergent packets. There were 2 deaths, and both were associated with laundry detergent packets. CONCLUSIONS: This national study demonstrates that pediatric laundry detergent packet exposures are more severe than laundry detergent nonpacket and dishwasher detergent (packet and nonpacket) exposures. Pediatric exposures to laundry detergent packets increased by 17% during the study period nationally and should be closely monitored to assess the effectiveness of the newly adopted voluntary safety standard; this standard should be strengthened if the number of exposures does not demonstrate a substantial decrease. PMID- 27244827 TI - Role of Operative or Interventional Radiology-Guided Cultures for Osteomyelitis. AB - BACKGROUND AND OBJECTIVE: Acute hematogenous osteomyelitis (AHO) is a severe infection in children. Drainage of purulent collections in bones provides specimens for culture as well as therapeutic benefit. Interventional radiology (IR)-guided procedures may serve as a less invasive means of culture in select patients. We examined the impact of IR and surgically obtained cultures in the diagnosis and management of AHO. METHODS: A retrospective review of cases of AHO was performed from 2011 to 2014. Patients with chronic disease, orthopedic hardware, puncture wounds, or an infected contiguous focus were excluded. RESULTS: A total of 250 cases met inclusion criteria. Blood cultures were positive in 107 of 231 cases (46.3%), and 123 of 150 patients had positive cultures (82%) obtained by orthopedic surgery. Of these 123 patients, 62 (50.4%) had organisms identified only through operating room (OR) cultures. Of the 66 patients who had cultures obtained by IR, 34 (51.5%) had positive IR cultures. For those with positive IR cultures, 18 (52.9%) had negative blood cultures. Among the 80 patients with negative blood culture and positive OR/IR culture, the results changed antibiotic therapy in 68 (85%) patients. CONCLUSIONS: IR or OR culture was the only means of identifying a pathogen in 80 of 216 cases (37%), and in >80% changed medical management. IR can be used effectively to obtain bone cultures in children with AHO not requiring open surgical drainage. Further research is needed to better understand the optimal utilization of IR and OR culture in pediatric AHO. PMID- 27244826 TI - Lessons Learned From Newborn Screening for Critical Congenital Heart Defects. AB - Newborn screening for critical congenital heart defects (CCHD) was added to the US Recommended Uniform Screening Panel in 2011. Within 4 years, 46 states and the District of Columbia had adopted it into their newborn screening program, leading to CCHD screening being nearly universal in the United States. This rapid adoption occurred while there were still questions about the effectiveness of the recommended screening protocol and barriers to follow-up for infants with a positive screen. In response, the Centers for Disease Control and Prevention partnered with the American Academy of Pediatrics to convene an expert panel between January and September 2015 representing a broad array of primary care, neonatology, pediatric cardiology, nursing, midwifery, public health, and advocacy communities. The panel's goal was to review current practices in newborn screening for CCHD and to identify opportunities for improvement. In this article, we describe the experience of CCHD screening in the United States with regard to: (1) identifying the target lesions for CCHD screening; (2) optimizing the algorithm for screening; (3) determining state-level challenges to implementation and surveillance of CCHD; (4) educating all stakeholders; (5) performing screening using the proper equipment and in a cost-effective manner; and (6) implementing screening in special settings such as the NICU, out-of hospital settings, and areas of high altitude. PMID- 27244828 TI - Can Hospitalization Precipitate Toxic Stress? PMID- 27244829 TI - FDA Approval of Extended-Release Oxycodone for Children With Severe Pain. PMID- 27244830 TI - Rural-Urban Migration for Pediatric Inpatient Care. PMID- 27244831 TI - Is It Time to Embrace the Caffeine Level? PMID- 27244832 TI - Response From Committee on Fetus and Newborn. PMID- 27244833 TI - Seifert et al. Health Effects of Energy Drinks on Children, Adolescents, and Young Adults. Pediatrics. 2011;127(3):511-528. PMID- 27244834 TI - Standard Terminology for Fetal, Infant, and Perinatal Deaths. AB - Accurately defining and reporting perinatal deaths (ie, fetal and infant deaths) is a critical first step in understanding the magnitude and causes of these important events. In addition to obstetric health care providers, neonatologists and pediatricians should have easy access to current and updated resources that clearly provide US definitions and reporting requirements for live births, fetal deaths, and infant deaths. Correct identification of these vital events will improve local, state, and national data so that these deaths can be better addressed and prevented. PMID- 27244835 TI - Brief Resolved Unexplained Events (Formerly Apparent Life-Threatening Events) and Evaluation of Lower-Risk Infants. AB - This is the first clinical practice guideline from the American Academy of Pediatrics that specifically applies to patients who have experienced an apparent life-threatening event (ALTE). This clinical practice guideline has 3 objectives. First, it recommends the replacement of the term ALTE with a new term, brief resolved unexplained event (BRUE). Second, it provides an approach to patient evaluation that is based on the risk that the infant will have a repeat event or has a serious underlying disorder. Finally, it provides management recommendations, or key action statements, for lower-risk infants. The term BRUE is defined as an event occurring in an infant younger than 1 year when the observer reports a sudden, brief, and now resolved episode of >=1 of the following: (1) cyanosis or pallor; (2) absent, decreased, or irregular breathing; (3) marked change in tone (hyper- or hypotonia); and (4) altered level of responsiveness. A BRUE is diagnosed only when there is no explanation for a qualifying event after conducting an appropriate history and physical examination. By using this definition and framework, infants younger than 1 year who present with a BRUE are categorized either as (1) a lower-risk patient on the basis of history and physical examination for whom evidence-based recommendations for evaluation and management are offered or (2) a higher-risk patient whose history and physical examination suggest the need for further investigation and treatment but for whom recommendations are not offered. This clinical practice guideline is intended to foster a patient- and family-centered approach to care, reduce unnecessary and costly medical interventions, improve patient outcomes, support implementation, and provide direction for future research. Each key action statement indicates a level of evidence, the benefit-harm relationship, and the strength of recommendation. PMID- 27244838 TI - Confidentiality Protections for Adolescents and Young Adults in the Health Care Billing and Insurance Claims Process. PMID- 27244836 TI - Brief Resolved Unexplained Events (Formerly Apparent Life-Threatening Events) and Evaluation of Lower-Risk Infants: Executive Summary. PMID- 27244839 TI - The Circumcision Debate: Beyond Benefits and Risks. PMID- 27244840 TI - Lanou et al. Prenatal Nutrient Supplementation and Postnatal Growth in a Developing Nation: An RCT. Pediatrics. 2014;133(4): e1001-e1008. PMID- 27244841 TI - Improving Early Identification and Ongoing Care of Children With Autism Spectrum Disorder. AB - BACKGROUND AND OBJECTIVE: Poor adherence to recommended screening for autism spectrum disorder (ASD) and pediatricians' lack of confidence in providing care for children with ASD reflect quality gaps in primary care. This study aimed to increase the proportion of toddlers screened for ASD and improve physicians' self efficacy in providing care to children with ASD. METHODS: Twenty-six Utah primary care practices participated in a 3 to 6 month learning collaborative (LC) to improve identification and ongoing care of children with ASD. Monthly chart audits assessed whether an ASD screening tool was administered at 18- and 24 month visits. Physicians completed pre-LC and post-LC surveys to assess changes in self-efficacy in providing care and changes in perceived barriers to implementation of screening and caring for children with ASD. RESULTS: Before the LC, 15% of 18- and 24-month visits had documented ASD screening, compared with 91% during the last month of the LC (P < .001). This rate of ASD screening was sustained 4 years after the LC by most practices. Compared with survey responses before the LC, physicians reported significant improvement in their ability to care for children with ASD and decreases in their perceived barriers to screening and caring for children with ASD. CONCLUSIONS: The LC was effective in increasing and sustaining recommended ASD screening of toddlers and improving physicians' perceived self-efficacy in caring for children with ASD. Improving primary care screening, skills, and knowledge may improve the timing of diagnosis, initiation of treatment, quality of care, and outcomes for children with ASD. PMID- 27244842 TI - Presumed Pseudotumor Cerebri Syndrome After Withdrawal of Inhaled Glucocorticoids. AB - Pseudotumor cerebri syndrome (PTCS) is characterized by increased intracranial pressure with normal brain parenchyma and cerebrospinal fluid constituents. PTCS after withdrawal of systemic corticosteroids also has been described in children. In contrast, to our knowledge, PTCS after withdrawal of inhaled glucocorticoids has not previously been described. Here we report the case of an 8-year and 6 month-old girl who developed signs and symptoms consistent with PTCS after withdrawal of inhaled glucocorticoids. The patient had excellent adherence to inhaled glucocorticoid therapy for ~1 year before presentation, after which the therapy was stopped for concern related to poor growth. The withdrawal of inhaled glucocorticoids was associated with the development of severe headaches and diplopia, and further clinical examination led to the patient's diagnosis of likely PTCS. Although its occurrence is likely rare, clinicians caring for the many children receiving inhaled glucocorticoid therapy should be aware of the potential for PTCS after abrupt withdrawal of such treatment, and consider ophthalmology evaluation if patients report suggestive symptoms, such as headaches or vision changes in this context. PMID- 27244843 TI - Influenza in Infants Born to Women Vaccinated During Pregnancy. AB - BACKGROUND: Infants <6 months old with influenza are at risk for adverse outcomes. Our objective was to compare influenza outcomes in infants <6 months old born to women who did and did not report influenza vaccine during pregnancy. METHODS: The study included all women who delivered from 12/2005 to 3/2014 at Intermountain facilities and their infants. Influenza outcomes included infant influenza-like illness (ILI), laboratory-confirmed influenza, and influenza hospitalizations. RESULTS: The cohort included 245 386 women and 249 387 infants. Overall, 23 383 (10%) pregnant women reported influenza immunization. This number increased from 2.2% before the H1N1 pandemic to 21% postpandemic (P < .001). A total of 866 infants <6 months old had >=1 ILI encounter: 32 (1.34/1000) infants born to women reporting immunization and 834 (3.70/1000) born to women who did not report immunization (relative risk [RR] 0.36; 95% confidence interval [CI], 0.26-0.52; P < .001). A total of 658 infants had laboratory-confirmed influenza: 20 (0.84/1000) born to women reporting immunization and 638 (2.83/1000) born to unimmunized women (RR 0.30; 95% CI, 0.19-0.46; P < .001). A total of 151 infants with laboratory-confirmed influenza were hospitalized: 3 (0.13/1000) born to women reporting immunization and 148 (0.66/1000) born to unimmunized women (RR 0.19; 95% CI, 0.06-0.60; P = .005). CONCLUSIONS: Self-reported influenza immunization during pregnancy was low but increased after the H1N1 pandemic. Infants born to women reporting influenza immunization during pregnancy had risk reductions of 64% for ILI, 70% for laboratory-confirmed influenza, and 81% for influenza hospitalizations in their first 6 months. Maternal influenza immunization during pregnancy is a public health priority. PMID- 27244845 TI - Nonfatal Playground-Related Traumatic Brain Injuries Among Children, 2001-2013. AB - OBJECTIVE: To describe the circumstances, characteristics, and trends of emergency department (ED) visits for nonfatal, playground-related traumatic brain injury (TBI) among persons aged <=14 years. METHODS: The National Electronic Injury Surveillance System-All Injury Program from January 1, 2001, through December 31, 2013, was examined. US Census bridged-race population estimates were used as the denominator to compute rates per 100 000 population. SAS and Joinpoint linear weighted regression analyses were used to analyze the best fitting join-point and the annual modeled rate change. These models were used to indicate the magnitude and direction of rate trends for each segment or period. RESULTS: During the study period, an annual average of 21 101 persons aged <=14 years were treated in EDs for playground-related TBI. The ED visit rate for boys was 39.7 per 100 000 and 53.5 for persons aged 5-9 years. Overall, 95.6% were treated and released, 33.5% occurred at places of recreation or sports, and 32.5% occurred at school. Monkey bars or playground gyms (28.3%) and swings (28.1%) were the most frequently associated with TBI, but equipment involvement varied by age group. The annual rate of TBI ED visits increased significantly from 2005 to 2013 (P < .05). CONCLUSIONS: Playgrounds remain an important location of injury risk to children. Strategies to reduce the incidence and severity of playground related TBIs are needed. These may include improved adult supervision, methods to reduce child risk behavior, regular equipment maintenance, and improvements in playground surfaces and environments. PMID- 27244844 TI - Breaking the Intergenerational Cycle of Disadvantage: The Three Generation Approach. AB - Health disparities in the United States related to socioeconomic status are persistent and pervasive. This review highlights how social disadvantage, particularly low socioeconomic status and the health burden it brings, is passed from 1 generation to the next. First, we review current frameworks for understanding the intergenerational transmission of health disparities and provide 4 illustrative examples relevant to child health, development, and well being. Second, the leading strategy to break the cycle of poverty in young families in the United States, the 2-generation approach, is reviewed. Finally, we propose a new 3-generation approach that must combine with the 2-generation approach to interrupt the intergenerational cycle of disadvantage and eliminate health disparities. PMID- 27244846 TI - Unconditional Prenatal Income Supplement and Birth Outcomes. AB - BACKGROUND AND OBJECTIVES: Perinatal outcomes have improved in developed countries but remain poor for disadvantaged populations. We examined whether an unconditional income supplement to low-income pregnant women was associated with improved birth outcomes. METHODS: This study included all mother-newborn pairs (2003-2010) in Manitoba, Canada, where the mother received prenatal social assistance, the infant was born in the hospital, and the pair had a risk screen (N = 14 591). Low-income women who received the income supplement (Healthy Baby Prenatal Benefit [HBPB], n = 10 738) were compared with low-income women who did not receive HBPB (n = 3853) on the following factors: low birth weight, preterm, small and large for gestational age, Apgar score, breastfeeding initiation, neonatal readmission, and newborn hospital length of stay (LOS). Covariates from risk screens were used to develop propensity scores and to balance differences between groups in regression models; gamma sensitivity analyses were conducted to assess sensitivity to unmeasured confounding. Population-attributable and preventable fractions were calculated. RESULTS: HBPB was associated with reductions in low birth weight (aRR, 0.71 [95% CI, 0.63-0.81]), preterm births (aRR, 0.76 [95% CI, 0.69-0.84]) and small for gestational age births (aRR, 0.90 [95% CI, 0.81-0.99]) and increases in breastfeeding (aRR, 1.06 [95% CI, 1.03 1.09]) and large for gestational age births (aRR, 1.13 [95% CI, 1.05-1.23]). For vaginal births, HBPB was associated with shortened LOS (weighted mean, 2.86; P < .0001). Results for breastfeeding, low birth weight, preterm birth, and LOS were robust to unmeasured confounding. Reductions of 21% (95% CI, 13.6-28.3) for low birth weight births and 17.5% (95% CI, 11.2-23.8) for preterm births were associated with HBPB. CONCLUSIONS: Receipt of an unconditional prenatal income supplement was associated with positive outcomes. Placing conditions on income supplements may not be necessary to promote prenatal and perinatal health. PMID- 27244847 TI - Swaddling and the Risk of Sudden Infant Death Syndrome: A Meta-analysis. AB - CONTEXT: Swaddling is a traditional practice of wrapping infants to promote calming and sleep. Although the benefits and risks of swaddling in general have been studied, the practice in relation to sudden infant death syndrome remains unclear. OBJECTIVE: The goal of this study was to conduct an individual-level meta-analysis of sudden infant death syndrome risk for infants swaddled for sleep. DATA SOURCES: Additional data on sleeping position and age were provided by authors of included studies. STUDY SELECTION: Observational studies that measured swaddling for the last or reference sleep were included. DATA EXTRACTION: Of 283 articles screened, 4 studies met the inclusion criteria. RESULTS: There was significant heterogeneity among studies (I(2) = 65.5%; P = .03), and a random effects model was therefore used for analysis. The overall age adjusted pooled odds ratio (OR) for swaddling in all 4 studies was 1.58 (95% confidence interval [CI], 0.97-2.58). Removing the most recent study conducted in the United Kingdom reduced the heterogeneity (I(2) = 28.2%; P = .25) and provided a pooled OR (using a fixed effects model) of 1.38 (95% CI, 1.05-1.80). Swaddling risk varied according to position placed for sleep; the risk was highest for prone sleeping (OR, 12.99 [95% CI, 4.14-40.77]), followed by side sleeping (OR, 3.16 [95% CI, 2.08-4.81]) and supine sleeping (OR, 1.93 [95% CI, 1.27-2.93]). Limited evidence suggested swaddling risk increased with infant age and was associated with a twofold risk for infants aged >6 months. LIMITATIONS: Heterogeneity among the few studies available, imprecise definitions of swaddling, and difficulties controlling for further known risks make interpretation difficult. CONCLUSIONS: Current advice to avoid front or side positions for sleep especially applies to infants who are swaddled. Consideration should be given to an age after which swaddling should be discouraged. PMID- 27244848 TI - A QI Initiative to Reduce Hospitalization for Children With Isolated Skull Fractures. AB - BACKGROUND AND OBJECTIVE: Although children with isolated skull fractures rarely require acute interventions, most are hospitalized. Our aim was to safely decrease the hospitalization rate for children with isolated skull fractures. METHODS: We designed and executed this multifaceted quality improvement (QI) initiative between January 2008 and July 2015 to reduce hospitalization rates for children <=21 years old with isolated skull fractures at a single tertiary care pediatric institution. We defined an isolated skull fracture as a skull fracture without intracranial injury. The QI intervention consisted of 2 steps: (1) development and implementation of an evidence-based guideline, and (2) dissemination of a provider survey designed to reinforce guideline awareness and adherence. Our primary outcome was hospitalization rate and our balancing measure was hospital readmission within 72 hours. We used standard statistical process control methodology to assess change over time. To assess for secular trends, we examined admission rates for children with an isolated skull fracture in the Pediatric Health Information System administrative database. RESULTS: We identified 321 children with an isolated skull fracture with a median age of 11 months (interquartile range 5-16 months). The baseline admission rate was 71% (179/249, 95% confidence interval, 66%-77%) and decreased to 46% (34/72, 95% confidence interval, 35%-60%) after implementation of our QI initiative. No child was readmitted after discharge. The admission rate in our secular trend control group remained unchanged at 78%. CONCLUSIONS: We safely reduced the hospitalization rate for children with isolated skull fractures without an increase in the readmissions. PMID- 27244850 TI - Outpatient Rehabilitation for Medicaid-Insured Children Hospitalized With Traumatic Brain Injury. AB - OBJECTIVES: To describe the prevalence of postdischarge outpatient rehabilitation among Medicaid-insured children hospitalized with a traumatic brain injury (TBI) and to identify factors associated with receipt of services. METHODS: Retrospective cohort of children <21 years, hospitalized for a TBI between 2007 and 2012, from a national Medicaid claims database. Outcome measures were receipt of outpatient rehabilitation (physical, occupational, or speech therapies or physician visits to a rehabilitation provider) 1 and 3 years after discharge. Multivariable regression analyses determined the association of demographic variables, injury severity, and receipt of inpatient services with receipt of outpatient rehabilitation at 1 and 3 years. The mean number of services was compared between racial/ethnic groups. RESULTS: Among 9361 children, only 29% received any type of outpatient rehabilitation therapy during the first year after injury, although 62% sustained a moderate to severe TBI. The proportion of children receiving outpatient therapies declined to 12% in the second and third years. The most important predictor of receipt of outpatient rehabilitation was receipt of inpatient therapies or consultation with a rehabilitation physician during acute care. Compared with children of other racial/ethnic groups, Hispanic children had lower rates of receipt of outpatient speech therapy. CONCLUSIONS: Hospitalized children who received inpatient assessment of rehabilitation needs were more likely to continue outpatient rehabilitation care. Hispanic children with TBI were less likely than non-Hispanics to receive speech therapy. Interventions to increase inpatient rehabilitation during acute care might increase outpatient rehabilitation and improve outcomes for all children. PMID- 27244849 TI - Outcomes of Extremely Preterm Infants Born to Insulin-Dependent Diabetic Mothers. AB - BACKGROUND AND OBJECTIVE: Little is known about in-hospital morbidities and neurodevelopmental outcomes among extremely preterm infants born to women with insulin-dependent diabetes mellitus (IDDM). We examined risks of mortality, in hospital morbidities, and neurodevelopmental outcomes at 18 to 22 months' corrected age between extremely preterm infants of women with insulin use before pregnancy (IBP), with insulin use started during pregnancy (IDP), and without IDDM. METHODS: Infants 22 to 28 weeks' gestation born or cared for at a Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network center (2006-2011) were studied. Regression models compared the association between maternal IDDM and timing of insulin use and the outcomes of the 3 groups. RESULTS: Of 10 781 infants, 536 (5%) were born to women with IDDM; 58% had IBP, and 36% had IDP. Infants of mothers with IBP had higher risks of necrotizing enterocolitis (adjusted relative risk [RR] = 1.55 [95% confidence interval (CI) 1.17-2.05]) and late-onset sepsis (adjusted RR = 1.26 [95% CI 1.07 1.48]) than infants of mothers without IDDM. There was some indication of higher in-hospital mortality risk among infants of mothers with IBP compared with those with IDP (adjusted RR = 1.33 [95% CI 1.00-1.79]). Among survivors evaluated at 18 to 22 months' corrected age, average head circumference z score was lower for infants of mothers with IBP compared with those without IDDM, but there were no differences in risk of neurodevelopmental impairment. CONCLUSIONS: In this cohort of extremely preterm infants, infants of mothers with IBP had higher risks of necrotizing enterocolitis, sepsis, and small head circumference. PMID- 27244851 TI - Effect of Patient-Centered Medical Home on Preventive Services for Adolescents and Young Adults. AB - OBJECTIVE: To determine the association between enrollment in patient-centered medical homes (PCMHs) and the receipt of preventive services among adolescents and young adults. METHODS: Retrospective cohort study including patients of Hennepin County aged 10 to 24 who had face-to-face or telephone encounters with health care providers between 2010 and 2014 at clinics with PCMHs at the Hennepin County Medical Center, Minnesota. Exposure was enrollment in PCMHs. Outcomes were receipt of (1) preventive visits; (2) prescriptions for influenza, meningococcal, and human papillomavirus vaccinations; (3) screening for sexually transmitted infections; (4) prescription of any contraceptive and long-acting reversible contraceptives; and (5) cervical cancer screening. Generalized mixed effect models in a propensity-score-matched sample were used for data analysis. RESULTS: Overall, 21 704 patients were included. Most patients were female, US-born, Hispanic/Latino, with an average age of 20.8 years. Patients enrolled in PCMH (n = 729) were more likely to be Latino, students, and have health insurance (P < .001). Adjusted odds ratios (99% confidence intervals) comparing the receipt of preventive services of patients enrolled in PCMHs to youth who did not receive these services were as follows: (1) preventive visits 1.10 (0.93-1.29); (2) influenza 0.89 (0.74-1.07), meningococcal 1.53 (1.30-1.80), and human papillomavirus vaccinations 1.53 (1.28-1.84); (3) screening for sexually transmitted infections 1.69 (1.28-2.24); (4) prescription of any type of contraception 2.18 (1.56-3.03) and long-acting reversible contraceptives 2.66 (1.89-3.74); and (5) cervical cancer screening 1.14 (0.87-1.48). CONCLUSIONS: Overall, patients enrolled in PCMHs had higher odds of receiving multiple preventive services. PMID- 27244852 TI - Timing of Return to Work and Breastfeeding in Australia. AB - OBJECTIVE: To examine the effects of timing of return to work, number of hours worked, and their interaction, on the likelihood of breastfeeding at 6 months and predominant breastfeeding at 16 weeks. METHODS: A nationally representative sample of Australian mothers in paid employment in the 13 months before giving birth (n = 2300) were surveyed by telephone. Four multivariate logistic regression models were used to analyze the effects of timing of return to work and work hours, independently and in interaction, on any breastfeeding at 6 months and on predominant breastfeeding at 16 weeks, controlling for maternal sociodemographics, employment patterns, and health measures. RESULTS: Mothers who returned to work within 6 months and who worked for >=20 hours per week were significantly less likely than mothers who had not returned to work to be breastfeeding at 6 months. However, returning to work for <=19 hours per week had no significant impact on the likelihood of breastfeeding regardless of when mothers returned to work. Older maternal age, higher educational attainment, better physical or mental health, managerial or professional maternal occupation, and being self-employed all significantly contributed to the increased likelihood of any breastfeeding at 6 months. Similar patterns exist for predominant breastfeeding at 16 weeks. CONCLUSIONS: The effects of timing of return to work are secondary to the hours of employment. Working <=19 hours per week is associated with higher likelihood of maintaining breastfeeding, regardless of timing of return to work. PMID- 27244853 TI - Breastfeeding and Risk of Kawasaki Disease: A Nationwide Longitudinal Survey in Japan. AB - BACKGROUND AND OBJECTIVES: Kawasaki disease (KD) is the most common cause of childhood-acquired heart disease in developed countries. However, the etiology of KD is not known. Aberrant immune responses are considered to play key roles in disease initiation and breastfeeding can mature immune system in infants. We thus examined the association between breastfeeding and the development of KD. METHODS: We used a nationwide population-based longitudinal survey ongoing since 2010 and restricted participants to a total of 37 630 children who had data on their feeding during infancy. Infant feeding practice was queried at 6 to 7 months of age, and responses to questions about hospital admission for KD during the period from 6 to 30 months of age were used as outcome. We conducted logistic regression analyses controlling for child and maternal factors with formula feeding without colostrum as our reference group. RESULTS: A total of 232 hospital admissions were observed. Children who were breastfed exclusively or partially were less likely to be hospitalized for KD compared with those who were formula fed without colostrum; odds ratios for hospitalization were 0.26 (95% confidence interval: 0.12-0.55) for exclusive breastfeeding and 0.27 (95% confidence interval: 0.13-0.55) for partial breastfeeding. Although the risk reduction was not statistically significant, feeding colostrum only also provided a protective effect. CONCLUSIONS: We observed protective effects of breastfeeding on the development of KD during the period from 6 to 30 months of age in a nationwide, population-based, longitudinal survey in Japan, the country in which KD is most common. PMID- 27244854 TI - Iodine Deficiency and Hypothyroidism From Voluntary Diet Restrictions in the US: Case Reports. AB - Iodine deficiency is rare in the United States today, and this is largely due to the effectiveness of iodization in the general food supply. Recent trends among specific populations of children in the United States include adopting food restrictions, such casein-free and gluten-free diets. Although the effect of these types of diets on overall nutrition status and certain micronutrients has been studied in children with autism spectrum disorder, the effect of these limitations on iodine levels in children has not been assessed. We present here 2 cases of iodine deficiency resulting from severe food restriction and associated primary hypothyroidism. In 1 case a classic presentation with a goiter was seen. These children were able to discontinue thyroid hormone treatment once iodine levels were normalized. There were no adverse events or unanticipated outcomes. The occurrence of these cases of iodine deficiency in the United States points to the need for thyroid function testing in children with severe food restrictions, especially those who have limited exposure to dairy, baked goods, and table salt. PMID- 27244855 TI - Using Newborn Screening Bloodspots for Research: Public Preferences for Policy Options. AB - OBJECTIVES: Retaining residual newborn screening (NBS) bloodspots for medical research remains contentious. To inform this debate, we sought to understand public preferences for, and reasons for preferring, alternative policy options. METHODS: We assessed preferences among 4 policy options for research use of residual bloodspots through a bilingual national Internet survey of a representative sample of Canadians. Fifty percent of respondents were randomly assigned to select reasons supporting these preferences. Understanding of and attitudes toward screening and research concepts, and demographics were assessed. RESULTS: Of 1102 respondents (94% participation rate; 47% completion rate), the overall preference among policy options was ask permission (67%); this option was also the most acceptable choice (80%). Assume permission was acceptable to 46%, no permission required was acceptable to 29%, and no research allowed was acceptable to 26%. The acceptability of the ask permission option was reduced among participants assigned to the reasoning exercise (84% vs 76%; P = .004). Compared with assume/no permission required, ordered logistic regression showed a significant reduction in preference for the ask permission option with greater understanding of concepts (odds ratio, 0.87; P < .001), greater confidence in science (odds ratio, 0.16; P < .001), and a perceived responsibility to contribute to research (odds ratio, 0.39; P < .001). CONCLUSIONS: Surveyed Canadians prefer that explicit permission is sought for storage and research use of NBS bloodspots. This preference was diminished when reasons supporting and opposing routine storage, and other policy options, were presented. Findings warrant consideration as NBS communities strategize to respond to shifting legislative contexts. PMID- 27244856 TI - Immunization Data Exchange With Electronic Health Records. AB - OBJECTIVE: To assess the impact of exchange of immunization information between an immunization information system (IIS) and an electronic health record on up-to date rates, overimmunization, and immunization record completeness for low income, urban children and adolescents. METHODS: The New York City Department of Health maintains a population-based IIS, the Citywide Immunization Registry (CIR). Five community clinics in New York City implemented direct linkage of immunization data from the CIR to their local electronic health record. We compared immunization status and overimmunization in children and adolescents 19 to 35 month, 7 to 10 year, and 13 to 17 year-olds with provider visits in the 6 month period before data exchange implementation (2009; n = 6452) versus 6-months post-implementation (2010; n = 6124). We also assessed immunization record completeness with and without addition of CIR data for 8548 children and adolescents with visits in 2012-2013. RESULTS: Up-to-date status increased from before to after implementation from 75.0% to 81.6% (absolute difference, 6.6%; 95% confidence interval [CI], 5.2% to 8.1%) and was significant for all age groups. The percentage overimmunized decreased from 8.8% to 4.7% (absolute difference, -4.1%; 95% CI, -7.8% to -0.3%) and was significant for adolescents (16.4% vs 1.2%; absolute difference, -15.2%; 95% CI, -26.7 to -3.6). Up-to-date status for those seen in 2012 to 2013 was higher when IIS data were added (74.6% vs 59.5%). CONCLUSIONS: This study demonstrates that data exchange can improve child and adolescent immunization status. Development of the technology to support such exchange and continued focus on local, state, and federal policies to support such exchanges are needed. PMID- 27244857 TI - Industry Relationships With Pediatricians: Findings From the Open Payments Sunshine Act. AB - BACKGROUND AND OBJECTIVES: Ties between physicians and pharmaceutical/medical device manufactures have received considerable attention. The Open Payments program, part of the Affordable Care Act, requires public reporting of payments to physicians from industry. We sought to describe payments from industry to physicians caring for children by (1) comparing payments to pediatricians to other medical specialties, (2) determining variation in payments among pediatric subspecialties, and (3) identifying the types of payment and the products associated with payments to pediatricians. METHODS: We conducted a descriptive, cross-sectional analysis of Open Payments data from January 1 to December 31, 2014. The primary outcomes included percent of physicians receiving payments, median total pay per physician, the types of payments received, and the drugs and devices associated with payments. RESULTS: There were 9 638 825 payments to physicians, totaling $1 186 217 157. There were 244 915 payments to general pediatricians and pediatric subspecialists, totaling >$32 million. The median individual payment to general pediatricians was $14.63 (interquartile range 12 20), and median total pay per general pediatrician was $89 (interquartile range 32-186). General pediatricians accounted for 1.7% of total payments, and 0.9% of the sum of payments. Developmental pediatricians had the highest percentage of pediatric physicians receiving payment, and pediatric endocrinologists received the highest median payment. Top marketed medications were for attention deficient/hyperactivity disorder and vaccinations. CONCLUSIONS: More than 40% of pediatricians received payments from industry in 2014, a lower percentage than family physicians or internists. There was considerable variation in physician industry ties among the pediatric subspecialties. Most payments were associated with medications that treat attention-deficient/hyperactivity disorder and vaccinations. PMID- 27244858 TI - Provider and Patient Attitudes Regarding Sexual Health in Young Women With Cystic Fibrosis. AB - OBJECTIVE: To explore the attitudes, preferences, and experiences of patients with cystic fibrosis (CF) and CF providers toward sexual and reproductive health (SRH) care for young women with CF. METHODS: Young women with CF aged 18 to 30 years from a US CF care center and pediatric and adult CF program directors from a national sample participated in qualitative interviews investigating their experiences regarding SRH care and their attitudes and preferences toward SRH care provision in the CF setting. Interviews were audio-recorded, transcribed, and coded by using a thematic analysis approach. RESULTS: Twenty-two patient participants and 16 CF program directors were interviewed. Themes shared by both groups included the importance of SRH discussion in the CF care setting, patient and provider discomfort as a barrier to SRH care, and the need for SRH educational resources and provider training to improve SRH care. Providers highlighted the lack of standardization around SRH care in the current CF care model. Patients desired SRH educational resources coupled with early SRH discussions initiated by their CF provider. CONCLUSIONS: Both CF providers and patients agree that the CF provider has a fundamental role in providing CF specific SRH care. Educational resources coupled with individualized SRH discussions may facilitate improved SRH care for young women with CF. Investigation into the implementation of SRH education and services into pediatric-onset chronic disease care models is needed. PMID- 27244859 TI - Strategies for Improving Vaccine Delivery: A Cluster-Randomized Trial. AB - OBJECTIVE: New emphasis on and requirements for demonstrating health care quality have increased the need for evidence-based methods to disseminate practice guidelines. With regard to impact on pediatric immunization coverage, we aimed to compare a financial incentive program (pay-for-performance [P4P]) and a virtual quality improvement technical support (QITS) learning collaborative. METHODS: This single-blinded (to outcomes assessor), cluster-randomized trial was conducted among unaffiliated pediatric practices across the United States from June 2013 to June 2014. Practices received either the P4P or QITS intervention. All practices received a Vaccinator Toolkit. P4P practices participated in a tiered financial incentives program for immunization coverage improvement. QITS practices participated in a virtual learning collaborative. Primary outcome was percentage of all needed vaccines received (PANVR). We also assessed immunization up-to-date (UTD) status. RESULTS: Data were analyzed from 3,147 patient records from 32 practices. Practices in the study arms reported similar QI activities (~6 to 7 activities). We found no difference in PANVR between P4P and QITS (mean +/- SE, 90.7% +/- 1.1% vs 86.1% +/- 1.3%, P = 0.46). Likewise, there was no difference in odds of being UTD between study arms (adjusted odds ratio 1.02, 95% confidence interval 0.68 to 1.52, P = .93). In within-group analysis, patients in both arms experienced nonsignificant increases in PANVR. Similarly, the change in adjusted odds of UTD over time was modest and nonsignificant for P4P but reached significance in the QITS arm (adjusted odds ratio 1.28, 95% confidence interval 1.02 to 1.60, P = .03). CONCLUSIONS: Participation in either a financial incentives program or a virtual learning collaborative led to self-reported improvements in immunization practices but minimal change in objectively measured immunization coverage. PMID- 27244860 TI - Buying a Better Baby: Unconditional Income Transfers and Birth Outcomes. PMID- 27244861 TI - Pediatric Exposure to E-Cigarettes, Nicotine, and Tobacco Products in the United States. AB - OBJECTIVES: To investigate the epidemiologic characteristics and outcomes of exposures to electronic cigarettes (e-cigarettes), nicotine, and tobacco products among young children in the United States. METHODS: A retrospective analysis of exposures associated with nicotine and tobacco products among children younger than 6 years old was conducted by using National Poison Data System data. RESULTS: From January 2012 through April 2015, the National Poison Data System received 29 141 calls for nicotine and tobacco product exposures among children younger than 6 years, averaging 729 child exposures per month. Cigarettes accounted for 60.1% of exposures, followed by other tobacco products (16.4%) and e-cigarettes (14.2%). The monthly number of exposures associated with e cigarettes increased by 1492.9% during the study period. Children <2 years old accounted for 44.1% of e-cigarette exposures, 91.6% of cigarette exposures, and 75.4% of other tobacco exposures. Children exposed to e-cigarettes had 5.2 times higher odds of a health care facility admission and 2.6 times higher odds of having a severe outcome than children exposed to cigarettes. One death occurred in association with a nicotine liquid exposure. CONCLUSIONS: The frequency of exposures to e-cigarettes and nicotine liquid among young children is increasing rapidly and severe outcomes are being reported. Swift government action is needed to regulate these products to help prevent child poisoning. Prevention strategies include public education; appropriate product storage and use away from children; warning labels; and modifications of e-cigarette devices, e-liquid, and e-liquid containers and packaging to make them less appealing and less accessible to children. PMID- 27244862 TI - High-Dose Erythropoietin and Hypothermia for Hypoxic-Ischemic Encephalopathy: A Phase II Trial. AB - OBJECTIVE: To determine if multiple doses of erythropoietin (Epo) administered with hypothermia improve neuroradiographic and short-term outcomes of newborns with hypoxic-ischemic encephalopathy. METHODS: In a phase II double-blinded, placebo-controlled trial, we randomized newborns to receive Epo (1000 U/kg intravenously; n = 24) or placebo (n = 26) at 1, 2, 3, 5, and 7 days of age. All infants had moderate/severe encephalopathy; perinatal depression (10 minute Apgar <5, pH <7.00 or base deficit >=15, or resuscitation at 10 minutes); and received hypothermia. Primary outcome was neurodevelopment at 12 months assessed by the Alberta Infant Motor Scale and Warner Initial Developmental Evaluation. Two independent observers rated MRI brain injury severity by using an established scoring system. RESULTS: The mean age at first study drug was 16.5 hours (SD, 5.9). Neonatal deaths did not significantly differ between Epo and placebo groups (8% vs 19%, P = .42). Brain MRI at mean 5.1 days (SD, 2.3) showed a lower global brain injury score in Epo-treated infants (median, 2 vs 11, P = .01). Moderate/severe brain injury (4% vs 44%, P = .002), subcortical (30% vs 68%, P = .02), and cerebellar injury (0% vs 20%, P = .05) were less frequent in the Epo than placebo group. At mean age 12.7 months (SD, 0.9), motor performance in Epo treated (n = 21) versus placebo-treated (n = 20) infants were as follows: Alberta Infant Motor Scale (53.2 vs 42.8, P = .03); Warner Initial Developmental Evaluation (28.6 vs 23.8, P = .05). CONCLUSIONS: High doses of Epo given with hypothermia for hypoxic-ischemic encephalopathy may result in less MRI brain injury and improved 1-year motor function. PMID- 27244863 TI - Time to Invest in Sickle Cell Anemia as a Global Health Priority. PMID- 27244864 TI - Withholding Information to Protect a Loved One. AB - Parents respond to the death of a child in very different ways. Some parents may be violent or angry, some sad and tearful, some quiet and withdrawn, and some frankly delusional. We present a case in which a father's reaction to his daughter's death is a desire to protect his wife from the stressful information. The wife is in the second trimester of a high-risk pregnancy and so is particularly fragile. We asked pediatricians and bioethicists to discuss the ways in which they might respond to the father's understandable but troubling request. PMID- 27244865 TI - Immunization Delivery and Policy as an Ongoing Model for Systems Improvement. PMID- 27244866 TI - 21st century psychiatry: The need for a unitary framework. PMID- 27244867 TI - [Commentary for Guest Editorial: Mario Maj: 21st century psychiatry: The need for a unitary framework]. PMID- 27244868 TI - [The nosological evolution of bipolar affective disorder]. AB - The nosological improvement of the bipolar disorder (manic-depression) follow the written history of psychiatry. The symptoms of manic and depressive episodes and mixed states were described in the ancient times. In my summary I accompany the taxonomic improvement, the changing of diagnostic categories and the work of the most important researchers from the beginning to these days. PMID- 27244869 TI - [Prevalence of eating disorders among women with polycystic ovary syndrome]. AB - INTRODUCTION: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders among women of reproductive age. Symptomes and complications of PCOS have adverse effect on quality of life among concerned women. Most research findings suggest that PCOS is associated with eating disorders, but there are inconsistent results in connection with their relationship in the published literature. OBJECTIVE: The aim of this study was to determine the prevalence of eating disorders among women with PCOS. METHOD: Body mass index (BMI), Eating Attitudes Test (EAT) and Eating Behaviour Severity Scale (EBSS) were used to measure eating attitudes and behaviors. Furthermore PCOS symptomes were measured by Ferriman-Gallwey Score, Global Acne Grading Score, Savin Scale and other pcos symptoms were also accessed. A total of 318 women were included in this analysis. The sample consists of a PCOS group (N=95), a control group (N=100) and a hyperandrogen group (N=123). The Prevalence of clinical bulimia nervosa was 5.3%, subclinical anorexia nervosa 1.1% and subclinical bulimia nervosa was 10.5% among PCOS women. 1.6% subclinical bulimia nervosa was detected in the hyperandrogen group. CONCLUSIONS: The results of the study indicate that the prevalence of clinical and subclinical bulimia nervosa is increased among women with PCOS compared to healthy women. Eating disorders can have significant negative influence on the outcome of the treatment of PCOS. To sum up, these findings suggest that it should be necessary to pay attention to the screening of eating disorders, and the findings also reveals that psychological treatment of eating disorders among women with PCOS is relevant. PMID- 27244870 TI - [Being online without a purpose -- study of background variables of problematic internet use]. AB - BACKGROUND AND AIMS OF THE STUDY: These days, use of the Internet is unavoidable for the younger generations. The online world is the primary source of infomation and quick communication, and these activities can take many hours per day. The main goal of the present study was to examine the correlations among problematic internet use, social factors, stress and life satisfaction. METHOD: Data collection was going online during the first semester of the year 2014 (N= 386 girls). The anonymous questionnaire contained items on perceived social support and the amount of online activites beyond sociodemographics. After descriptive statistics, factor, correlation and multiple linear regression analyses were applied to detect interrelationships. RESULTS: According to our data, 78% of the participants spent daily at least 2 hours, 40% more than 4 hours online. Using factor analysis, four factors of online activities were identified: Social networking-surfing, News-information, Risky and Lonely game factors. Only the News-information factor was not related to the problematic internet use. Based on multiple regression analyses, we may conclude that shyness, stress, loneliness and two factors, the Social networking-surfing and the Risky factors acted as background variables for problematic internet use. CONCLUSIONS: As a summary we may conclude that the internet has an important role in the everyday life of the participants. In case of the direct aim of the online activities the problematic use did not appear. These activities were mostly searching for information and news. In introduction of prevention, education about the correct use of the internet may be reasonable as early as possible. PMID- 27244871 TI - [Antidepressant-resistant depression and the bipolar spectrum -- diagnostic and therapeutic considerations]. AB - According to the results of epidemiological studies mood disorders with unipolar (major and minor depressive disorder; dysthymia) or bipolar features are among the most prevalent psychiatric disorders. These disorders with their frequent comorbidities (alcohol and/or drug use disorders, smoking, suicide, cardiovascular disorders) pose great public health challenge and cause substantial individual and familar burdens as well. Since SSRIs and other new antidepressant agents entered the market the possibilities to treat depression improved substantially but 25-35 percent of major depressives do not respond even to the second antidepressant trial but the rate of patients who are resistant after the third and fourth adequate antidepressant trial are around only 15-25 and 10 percent, respectively. Pharmacotherapy-resistant depression is a multicausal phenomenon. Along with its well-known risk-factors investigations of the past decade have revealed that unrecognised or hidden (subsyndromal or subthreshold) bipolarity is one of the most frequent causes of treatment resistance. In the case of bipolar depression (either as a part of syndromal bipolar I or II disorder or a subsyndromal manifestation) antidepressant monotherapy should be avoided and, instead of it, the administration of a mood stabilizer (primarily lithium and lamotrigine) or some atypical antipsychotics (preferably quetiapine) are recommended. If antidepressant is inevitably necessary in bipolar depression, we should use it always in combination with mood stabilizers or atypical antipsychotics. PMID- 27244872 TI - [Gambling disorder and alcohol use disorder -- similarities and differences]. AB - Gambling disorder has been listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM) for more than three decades. During this time, its diagnostic set of criteria has gone through significant changes. In the DSM-5, gambling disorder has been moved from Disruptive, Impulse-Control and Conduct Disorders to Substance- Related and Addictive Disorders, which acknowledges and expresses that gambling disorder has similar features compared to substance related disorders. The aim of the present review is to reveal the reasons behind this category replacement, and to examine the similarities between gambling disorder and alcohol dependence from the perspectives of symptomatology, etiology and epidemiology. PMID- 27244873 TI - [Investigation of the association between arsenic levels in drinking water and suicide rate of Hungarian settlements between 2005 and 2011. A preliminary study]. AB - INTRODUCTION: Both suicidal behaviour and consumption of arsenic-contaminated drinking-water represent major public health problems. Previous epidemiological and animal studies showed that high arsenic intake may also be associated with the elevated risk for depression. Since untreated depression is the most powerful risk factor for suicidal behaviour, we postulated that the consumption of arsenic contaminated tap drinking-water may also be related to suicide. METHOD: Based on the level of arsenic in their drinking water Hungarian settlements with more then 500 inhabitants (n=1639) were divided into four groups. Then average age standardized suicide rates of the four groups were compared. RESULTS AND DISCUSSION: We found that the higher is the arsenic level in the drinking water the higher is the suicide rate of the settlements. In addition to the practical consequences of our preliminary results (e.g. in the suicide prevention) they also suggest that high level of arsenic in drinking water might contribute, at least in part, to the well-known and stable in time regional differences in suicide mortality of Hungary since the highest arsenic levels in drinking water have been found in counties with traditionally high suicide rates, such as Bacs Kiskun, Csongrad, Bekes and Hajdu- Bihar. PMID- 27244874 TI - [Psychiatric aspects of rare epileptic seizure phenomena]. PMID- 27244875 TI - [School shooters. Understanding and interventions]. PMID- 27244876 TI - [Summary of the work of the Professional Organizations of Clinical Psychology and Clinical Psychotherapy in Hungary, in the years 2011-2015]. PMID- 27244877 TI - Exposure to pesticides and prostate cancer: systematic review of the literature. AB - INTRODUCTION: Investigations about the association between prostate cancer and environmental and/or occupational pesticide exposure have evidenced a possible role of these chemical substances on tumor etiology, related to their action as endocrine disruptors. OBJECTIVE: To assess the association between pesticide exposure and prostate cancer by conducting a systematic review of the scientific literature. MATERIALS AND METHODS: Articles published until August 18, 2015 were searched in the databases MEDLINE/Pubmed, Scielo, and Lilacs using the keywords "pesticides" and "prostate cancer". Only the analytical observational studies whose methodological quality met the criteria established by the New Castle Ottawa scale were included in this review. RESULTS: The review included 49 studies published between 1993 and 2015. All studies were in English and analyzed exposure to pesticides and/or agricultural activities. Most studies (32 articles) found a positive association between prostate cancer and pesticides or agricultural occupations, with estimates ranging from 1.01 to 14.10. CONCLUSION: The evidence provided by the reviewed studies indicates a possible association between the development of prostate cancer and pesticide exposure and/or agricultural occupations. PMID- 27244878 TI - What constitutes environmental health? PMID- 27244879 TI - When obtaining a blood sample from the right arm was not the right thing to do: a case of elevated parathyroid hormone levels 27 years after thyroidectomy. PMID- 27244880 TI - Histopathological investigation of glioblastomas resected under bevacizumab treatment. AB - To date, no clinical observations have been reported for histopathological changes in human gliomas under antiangiogenic treatment.We collected six glioblastomas resected under bevacizumab treatment. Histopathological investigation was performed by hematoxilyn-eosin staining and immunohistochemistry for CD34, VEGF, VEGFR1/2, HIF-1alpha, CA9, and nestin as compared to eleven control glioblastomas to assess the differences in histological features, microvessel density, expression of VEGF and its receptors, tumor oxygenation, and status of glioma stem-like cells.In the six tumors resected under bevacizumab, microvascular proliferation was absent, and microvessel density had significantly decreased compared with that of the controls. The expressions of VEGF and its receptors were downregulated in two cases of partial response. HIF-1alpha or CA9 expression was decreased in five of the six tumors, whereas the decreased expression of these markers was noted in only one of the 11 control glioblastomas. The expression of nestin significantly decreased in the six tumors compared with that of the controls, with the remaining nestin-positive cells being relatively concentrated around vessels.We provide the first clinicopathological evidence that antiangiogenic therapy induces the apparent normalization of vascular structure, decrease of microvessel density, and improvement of tumor oxygenation in glioblastomas. These in situ observations will help to optimize therapy. PMID- 27244881 TI - Conjugation to the sigma-2 ligand SV119 overcomes uptake blockade and converts dm Erastin into a potent pancreatic cancer therapeutic. AB - Cancer-selective drug delivery is an important concept in improving treatment while minimizing off-site toxicities, and sigma-2 receptors, which are overexpressed in solid tumors, represent attractive pharmacologic targets. Select sigma-2 ligands have been shown to be rapidly internalized selectively into cancer cells while retaining the capacity to deliver small molecules as drug cargoes. We utilized the sigma-2-based drug delivery concept to convert Erastin, a clinically underperforming drug, into a potent pancreatic cancer therapeutic. The Erastin derivative des-methyl Erastin (dm-Erastin) was chemically linked to sigma-2 ligand SV119 to create SW V-49. Conjugation increased the killing capacity of dm-Erastin by nearly 35-fold in vitro and reduced the size of established tumors and doubled the median survival in syngeneic and patient derived xenograft models when compared to non-targeted dm-Erastin. Mechanistic analyses demonstrated that cell death was associated with robust reactive oxygen species production and could be efficiently antagonized with antioxidants. Mass spectrometry was employed to demonstrate selective uptake into pancreatic cancer cells. Thus, targeted delivery of dm-Erastin via conjugation to the sigma-2 ligand SV119 produced efficient tumor control and prolonged animal survival with minimal off-target toxicities, and SW V-49 represents a promising new therapeutic with the potential to advance the fight against pancreatic cancer. PMID- 27244882 TI - Phase II study of neoadjuvant therapy with nab-paclitaxel and cisplatin followed by surgery in patients with locally advanced esophageal squamous cell carcinoma. AB - BACKGROUND: We carried out a phase II study to evaluate the efficiency and safety of the combination of nanoparticle albumin bound-paclitaxel (nab-paclitaxel) and cisplatin as preoperative chemotherapy for locally advanced esophageal squamous cell carcinoma (ESCC)Results: From Oct 2011 to Dec 2012, 35 patients were enrolled and received neoadjuvant chemotherapy. Thirty patients underwent surgery and achieved a 100% R0 resection. Pathological complete response (pCR) rate was 13.3% and near pCR rate was 6.7%. Down-staging was achieved in 19 patients. With median follow-up of 37.8 months, 16 patients were still alive. One-, 2- and 3- year overall survival (OS) rate was 90.0%, 70.0% and 43.3%, respectively. This treatment resulted in a median disease-free survival (DFS) of 34.7 months and a median OS of 37.8 months. Median DFS and OS of down-staged patients were significantly longer than those of non-downstaged patients. The grade 4 toxicities during neoadjuvant chemotherapy were limited to neutropenia (2.9%) and vomiting (2.9%). METHODS: Patients with locally advanced ESCC (stage IIA to IIIC) and performance status 0-1 were enrolled and received two cycles of nab paclitaxel (100 mg/m2) on day 1, 8, 22 and 29, and cisplatin (75 mg/m2) on day 1 and 22, followed by resection. Two cycles of adjuvant chemotherapy with the same regimen were given. Postoperative radiotherapy was permitted and decided by radiation therapist. CONCLUSION: Weekly nab-paclitaxel with three-weekly cisplatin seems effective and safe as a neoadjuvant chemotherapy strategy for locally advanced ESCC. Down-staged patients have favorable outcome.ClinicalTrials.gov Identifier: NCT01258192. PMID- 27244883 TI - MS4A6A genotypes are associated with the atrophy rates of Alzheimer's disease related brain structures. AB - Membrane-spanning 4-domains, subfamily A, member 6A (MS4A6A) has been identified as susceptibility loci of Alzheimer's disease (AD) by several recent genome-wide association studies (GWAS), whereas little is known about the potential roles of these variants in the brain structure and function of AD. In this study, we included a total of 812 individuals from the Alzheimer's disease Neuroimaging Initiative (ADNI) database. Using multiple linear regression models, we found MS4A6A genotypes were strongly related to atrophy rate of left middle temporal (rs610932: Pc = 0.017, rs7232: Pc = 0.022), precuneus (rs610932: Pc = 0.015) and entorhinal (rs610932, Pc = 0.022) on MRI in the entire group. In the subgroup analysis, MS4A6A SNPs were significantly accelerated the percentage of volume loss of middle temporal, precuneus and entorhinal, especially in the MCI subgroup. These findings reveal that MS4A6A genotypes affect AD specific brain structures which supported the possible role of MS4A6A polymorphisms in influencing AD-related neuroimaging phenotypes. PMID- 27244884 TI - Thigh muscle size and vascular function after blood flow-restricted elastic band training in older women. AB - We examined the effect of elastic band training with blood flow restriction (BFR) on thigh muscle size and vascular function in older women. Older women were divided into three groups: low-intensity elastic band BFR training (BFR-Tr, n = 10), middle- to high-intensity elastic band training (MH-Tr, n = 10), and no training (Ctrl, n = 10) groups. BFR-Tr and MH-Tr groups performed squat and knee extension exercises using elastic band, 2 days/week for 12 weeks. During BFR-Tr exercise session, subjects wore pressure cuffs around the most proximal region of both thighs. The following measurements were taken before (pre) and 3-5 days after (post) the final training session: MRI-measured muscle cross-sectional area (CSA) at mid-thigh, maximum voluntary isometric contraction (MVIC) of knee extension, central systolic blood pressure (c-SBP), central-augmentation index (c AIx), cardio-ankle vascular index testing (CAVI), ankle-brachial pressure index (ABI). Quadriceps muscle CSA (6.9%) and knee extension MVIC (13.7%) were increased (p < 0.05) in the BFR-Tr group, but not in the MH-Tr and the Ctrl groups. Regarding c-SBP, c-AIx, CAVI and ABI, there were no changes between pre- and post- results among the three groups. Elastic band BFR training increases thigh muscle CSA as well as maximal muscle strength, but does not decrease vascular function in older women. PMID- 27244885 TI - Natural polymerase fusion as an initiation regulator? PMID- 27244886 TI - Indolin-2-one compounds targeting thioredoxin reductase as potential anticancer drug leads. AB - Several compounds bearing the indolinone chemical scaffold are known to possess anticancer properties. For example, the tyrosine kinase inhibitor sunitinib is an arylideneindolin-2-one compound. The chemical versatility associated with structural modifications of indolinone compounds underlies the potential to discover additional derivatives possessing anticancer properties. Previously synthesized 3-(2-oxoethylidene)indolin-2-one compounds, also known as supercinnamaldehyde (SCA) compounds in reference to the parent compound 1 [1 methyl-3(2-oxopropylidene)indolin-2-one], bear a nitrogen-linked alpha,beta unsaturated carbonyl (Michael acceptor) moiety. Here we found that analogs bearing N-substituents, in particular compound 4 and 5 carrying an N-butyl and N benzyl substituent, respectively, were strongly cytotoxic towards human HCT 116 colorectal and MCF-7 breast carcinoma cells. These compounds also displayed strong thioredoxin reductase (TrxR) inhibitory activity that was likely attributed to the electrophilicity of the Michael acceptor moiety. Their selectivity towards cellular TrxR inhibition over related antioxidant enzymes glutathione reductase (GR), thioredoxin (Trx) and glutathione peroxidase (GPx) was mediated through targeting of the selenocysteine (Sec) residue in the highly accessible C-terminal active site of TrxR. TrxR inhibition mediated by indolin-2 one compounds led to cellular Trx oxidation, increased oxidative stress and activation of apoptosis signal-regulating kinase 1 (ASK1). These events also led to activation of p38 and JNK mitogen-activated protein kinase (MAPK) signaling pathways, and cell death with apoptotic features of PARP cleavage and caspase 3 activation. In conclusion, these results suggest that indolin-2-one-based compounds specifically targeting TrxR may serve as novel drug leads for anticancer therapy. PMID- 27244888 TI - Isoliensinine induces dephosphorylation of NF-kB p65 subunit at Ser536 via a PP2A dependent mechanism in hepatocellular carcinoma cells: roles of impairing PP2A/I2PP2A interaction. AB - Our previous study discovered that isoliensinine (isolie) triggers hepatocellular carcinoma (HCC) cell apoptosis via inducing p65 dephosphorylation at Ser536 and inhibition of NF-kappaB. Here, we showed that isolie promoted p65/PP2A interaction in vitro and in vivo. Repression of PP2A activity or knockdown of the expression of PP2A-C (the catalytic subunit of PP2A) abrogated isolie-provoked p65 dephosphorylation. I2PP2A is an endogenous PP2A inhibitor. Isolie directly impaired PP2A/I2PP2A interaction. Knockdown of I2PP2A boosted p65/PP2A association and p65 dephosphorylation. Overexpression of I2PP2A restrained isolie induced p65 dephosphorylation. Untransformed hepatocytes were insensitive to isolie-induced NF-kappaB inhibition and cell apoptosis. In these cells, basal levels of I2PP2A and p65 phosphorylation at Ser536 were lower than in HCC cells. These findings collectively indicated that isolie suppresses NF-kappaB in HCC cells through impairing PP2A/I2PP2A interaction and stimulating PP2A-dependent p65 dephosphorylation at Ser536. PMID- 27244887 TI - Chemotherapeutics-induced Oct4 expression contributes to drug resistance and tumor recurrence in bladder cancer. AB - Cancer cells initially characterized as sensitive to chemotherapy may acquire resistance to chemotherapy and lead to tumor recurrence through the expansion of drug-resistant population. Acquisition of drug resistance to conventional chemotherapy is a major obstacle in the treatment of recurrent cancer. Here we investigated whether anticancer drugs induced Oct4 expression, thereby contributing to acquired drug resistance and tumor recurrence in bladder cancer. We identified a positive correlation of Oct4 expression with tumor recurrence in 122 clinical specimens of superficial high-grade (stages T1-2) bladder transitional cell carcinoma (TCC). Increased Oct4 levels in bladder tumors were associated with short recurrence-free intervals in the patients. Chemotherapy induced Oct4 expression in bladder cancer cells. Notably, treatment with cisplatin increased CD44-positive bladder cancer cells expressing Oct4, representing cancer stem-like cell subpopulation. Forced expression of Oct4 reduced, whereas knockdown of Oct4 enhanced, drug sensitivity in bladder cancer cells. Furthermore, tumor cells overexpressing Oct4 responded poorly to cisplatin in vivo. In regard to clinical relevance, inhibition of Oct4 by all-trans retinoic acid (ATRA) synergistically increased sensitivity to cisplatin in bladder cancer cells. Furthermore, the combination of cisplatin and ATRA was superior to cisplatin alone in suppressing tumor growth. Therefore, our results provide evidence that Oct4 increases drug resistance and implicate that inhibition of Oct4 may be a therapeutic strategy to circumvent drug resistance. PMID- 27244889 TI - Combined sequential use of HAP and ART scores to predict survival outcome and treatment failure following chemoembolization in hepatocellular carcinoma: a multi-center comparative study. AB - BACKGROUND: The prognosis of patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE) is variable, despite a myriad of prognostic markers. We compared and integrated the established prognostic models, HAP and ART scores, for their accuracy of overall survival (OS) prediction. RESULTS: In both training and validation sets, HAP and ART scores emerged as independent predictors of OS (p<0.01) with HAP achieving better prognostic accuracy (c-index: 0.68) over ART (0.57). We tested both scores in combination to evaluate their combined ability to predict OS. Subgroup analysis of BCLC-C patients revealed favorable HAP stage (p<0.001) and radiological response after initial TACE (p<0.001) as positive prognostic factors. PATIENTS AND METHODS: Prognostic scores were studied using multivariable Cox regression and c-index analysis in 83 subjects with Barcelona Clinic Liver Cancer (BCLC) A/B stage from UK and Italy (training set), and 660 from Korea and Japan (validation set), all treated with conventional TACE. Scores were further validated in an separate analysis of patients with BCLC-C stage disease (n=63) receiving initial TACE. CONCLUSION: ART and HAP scores are validated indices in patients with intermediate stage HCC undergoing TACE. The HAP score is best suited for screening patients prior to initial TACE, whilst sequential ART assessment improves early detection of chemoembolization failure. BCLC-C patients with low HAP stage may be a subgroup where TACE should be explored in clinical studies. PMID- 27244890 TI - EGR1 mediates miR-203a suppress the hepatocellular carcinoma cells progression by targeting HOXD3 through EGFR signaling pathway. AB - EGR1 plays a critical role in cancer progression. However, its precise role in hepatocellular carcinoma has not been elucidated. In this study, we found that the overexpression of EGR1 suppresses hepatocellular carcinoma cell proliferation and increases cell apoptosis by binding to the miR-203a promoter sequence. In addition, we investigated the function of miR-203a on progression of HCC cells. We verified that the effect of overexpression of miR-203a is consistent with that of EGR1 in regulation of cell progression. Through bioinformatic analysis and luciferase assays, we confirmed that miR-203a targets HOXD3. Silencing HOXD3 could block transition of the G2/M phase, increase cell apoptosis, decrease the expression of cell cycle and apoptosis-related proteins, EGFR, p-AKT, p-ERK, CCNB1, CDK1 and Bcl2 by targeting EGFR through EGFR/AKT and ERK cell signaling pathways. Likewise, restoration of HOXD3 counteracted the effects of miR-203a expression.In conclusion, our findings are the first to demonstrate that EGR1 is a key player in the transcriptional control of miR-203a, and that miR-203a acts as an anti-oncogene to suppress HCC tumorigenesis by targeting HOXD3 through EGFR related cell signaling pathways. PMID- 27244891 TI - Survival benefits from postoperative radiation therapy on lymph node positive patients with pancreatic adenocarcinoma. AB - The benefit of combining postoperative radiation therapy (PORT) with chemotherapy for resected patients with pancreatic adenocarcinoma is controversial. We sought to determine the effects of PORT on survival in patients with pancreatic adenocarcinoma who underwent primary site surgery. Patients with pancreatic adenocarcinoma receiving primary tumor surgery between 1988 and 2012 were identified from the Surveillance, Epidemiology and End Results (SEER) database. We estimated the association between PORT and other clinicopathologic factors and survival. In total, 5304 patients were identified who underwent pancreatic resection including 2093 patients who had PORT and 3211 patients who had no PORT. Median overall, cancer-specific, and other-cause survival were 19.0, 20.0, and 196.0 months, respectively, with PORT versus 14.0, 15.0, and 163.0 months, respectively, without PORT (all P < 0.001). Subset analysis revealed that the benefit of PORT was limited to patients with N1 disease. Median overall, cancer specific, and other-cause survival for patients with N1 disease were 18.0, 18.0, and NA months, respectively, with PORT versus 12.0, 13.0, and 154.0 months, respectively, without PORT (all P < 0.001). Regardless the number of positive lymph node count (PLN) and lymph node ratio (LNR), PORT was always associated with increased survival on multivariate analysis in patients with N1 disease (all P < 0.001). In summary, survival benefits might be obtained from PORT on lymph node positive patients with pancreatic adenocarcinoma. PMID- 27244892 TI - TREM-1low is a novel characteristic for tumor-associated macrophages in lung cancer. AB - OBJECTIVE: To explore the expression feature and biological functions of TREM-1 on tumor-associated macrophages (TAMs) in lung cancer. RESULTS: The levels of TREM-1 on tissue-infiltrating monocytes/macrophage from tumor nest were significantly lower than those from nonturmor tissue or peripheral blood samples. Clinical analysis indicated that the levels of TREM-1-related TAMs were significantly decreased during cancer stages progression. The tumor-bearing mouse model further confirmed that the expression of TREM-1 on TAMs was significantly decreased with tumor growth. In addition, we found the activation of TREM-1 could significantly enhance the secretion of IL-1beta by TAM in vitro. Furthermore, T bet but not Eomes was found to be the key transcription factor for the TREM-1 expression on monocytes/macrophage. METHODS: A total of 40 patients with non small cell lung cancer (NSCLC) were enrolled in this study. The expression characteristics of TREM-1 in blood and tissue-infiltrating monocytes/macrophage were examined by flow cytometry analysis. After the treatment of TREM-1 antibody, which is an agonist of TREM-1, cytokines secreted by TAM were then analyzed. In LLC-tumor bearing mouse model, we further investigated the dynamic expression feature of TREM-1 on macrophage with tumor growth. Moreover, we explored the transcription factor for regulating TREM-1 expression on monocyes/macrophage with wildtype, T-bet Ko or Eomes Ko mice. CONCLUSION: The levels of TREM-1 were remarkably decreased during tumor progression. The low expression level of TREM-1 might be a characteristic for TAMs in lung cancer. PMID- 27244893 TI - Expression and mutational analysis of c-CBL and its relationship to the MET receptor in head and neck squamous cell carcinoma. AB - MET is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and degraded by c-CBL E3-ubiquitin ligase. We investigated genetic variations of c-CBL in HNSCC and the relationship between c-CBL and MET expression. High MET, low c-CBL expression was detected in 10 cell lines and 73 tumor tissues. Two novel mutations (L254S, L281F), and the single nucleotide polymorphism (SNP) P782L were identified from archival tumor tissues. 27.3% of loss of heterozygosity was found at CBL locus. Ectopic expression of wild-type c-CBL in SCC-35 cells downregulated MET expression and decreased cell viability. These results suggest MET overexpression is related to altered c-CBL expression, which may influence tumorigenesis. PMID- 27244895 TI - Hypoxia potentiates the cytotoxic effect of piperlongumine in pheochromocytoma models. AB - Hypoxia is a common feature of solid tumors that activates a plethora of pathways, resulting in proliferation and resistance of cancer cells to radio- and chemotherapy. Pheochromocytomas/paragangliomas (PHEOs/PGLs) with mutations in the gene coding for the subunit B of succinate dehydrogenase (SDHB) are the most aggressive forms of the disease, which is partially due to their pseudohypoxic character, metabolic abnormalities, and elevated reactive oxygen species (ROS) levels. We investigated the effect of piperlongumine (PL), a natural product with cytotoxic properties restricted to cancer cells by significantly increasing intracellular ROS levels, on PHEO cells. Here we report for the first time that PL mediates PHEO cell death by activating both apoptosis and necroptosis in vitro and in vivo. This effect is magnified in hypoxic conditions, making PL a promising potential candidate for use as a therapeutic option for patients with PHEO/PGL, including those with SDHB mutations. PMID- 27244897 TI - Mesenchymal stem cell-like properties of CD133+ glioblastoma initiating cells. AB - Glioblastoma is composed of dividing tumor cells, stromal cells and tumor initiating CD133+ cells. Recent reports have discussed the origin of the glioblastoma CD133+ cells and their function in the tumor microenvironment. The present work sought to investigate the multipotent and mesenchymal properties of primary highly purified human CD133+ glioblastoma-initiating cells. To accomplish this aim, we used the following approaches: i) generation of tumor subspheres of CD133+ selected cells from primary cell cultures of glioblastoma; ii) analysis of the expression of pluripotency stem cell markers and mesenchymal stem cell (MSC) markers in the CD133+ glioblastoma-initiating cells; iii) side-by-side ultrastructural characterization of the CD133+ glioblastoma cells, MSC and CD133+ hematopoietic stem cells isolated from human umbilical cord blood (UCB); iv) assessment of adipogenic differentiation of CD133+ glioblastoma cells to test their MSC-like in vitro differentiation ability; and v) use of an orthotopic glioblastoma xenograft model in the absence of immune suppression. We found that the CD133+ glioblastoma cells expressed both the pluripotency stem cell markers (Nanog, Mush-1 and SSEA-3) and MSC markers. In addition, the CD133+ cells were able to differentiate into adipocyte-like cells. Transmission electron microscopy (TEM) demonstrated that the CD133+ glioblastoma-initiating cells had ultrastructural features similar to those of undifferentiated MSCs. In addition, when administered in vivo to non-immunocompromised animals, the CD133+ cells were also able to mimic the phenotype of the original patient's tumor. In summary, we showed that the CD133+ glioblastoma cells express molecular signatures of MSCs, neural stem cells and pluripotent stem cells, thus possibly enabling differentiation into both neural and mesodermal cell types. PMID- 27244896 TI - Role of FOXO1 in aldosterone-induced autophagy: a compensatory protective mechanism related to podocyte injury. AB - This study was undertaken to elucidate whether and how autophagy was regulated in aldosterone (Aldo)-induced podocyte injury and to examine its role in this model both in vitro and in vivo. In cultured podocytes, Aldo increased autophagy flux as indicated by the enhanced expression of LC3-II/LC3-I and the reduction of p62. Autophagy induction with rapamycin (RP) provided a cytoprotective effect, and inhibition of autophagy with Atg7-specific siRNA, chloroquine (CQ) or 3 methyladenine (3-MA) worsened Aldo-induced podocyte injury by attenuating endoplasmic reticulum (ER) stress. Aldo inhibited Akt phosphorylation but increased the mammalian target of rapamycin (mTOR) signaling pathway; however, Aldo up-regulated the expression of FOXO1 and its downstream effector Rab7. Either knockdown of FOXO1 or Rab7 inhibited Aldo-induced autophagy. Additionally, an elevated level of P300-regulated acetylation of FOXO1 and the interaction of acetylated FOXO1 and Atg7 were also confirmed to be involved in regulating autophagy in Aldo-induced podocytes. Similar results were further confirmed in vivo. We propose that autophagy enhancement through enhancing of the FOXO1/Rab7 axis and post-translational modification of FOXO1 may represent a potential therapeutic strategy against podocyte injury by promoting autophagy. PMID- 27244898 TI - Opposite prognostic roles of HIF1alpha and HIF2alpha expressions in bone metastatic clear cell renal cell cancer. AB - BACKGROUND: Prognostic markers of bone metastatic clear cell renal cell cancer (ccRCC) are poorly established. We tested prognostic value of HIF1alpha/HIF2alpha and their selected target genes in primary tumors and corresponding bone metastases. RESULTS: Expression of HIF2alpha was lower in mRCC both at mRNA and protein levels (p/mRNA/=0.011, p/protein/=0.001) while HIF1alpha was similar to nmRCC. At the protein level, CAIX, GAPDH and GLUT1 were increased in mRCC. In all primary RCCs, low HIF2alpha and high HIF1alpha as well as CAIX, GAPDH and GLUT1 expressions correlated with adverse prognosis, while VEGFR2 and EPOR gene expressions were associated with favorable prognosis. Multivariate analysis confirmed high HIF2alpha protein expression as an independent risk factor. Prognostic validation of HIFs, LDH, EPOR and VEGFR2 in RNA-Seq data confirmed higher HIF1alpha gene expression in primary RCC as an adverse (p=0.07), whereas higher HIF2alpha and VEGFR2 expressions as favorable prognostic factors. HIF1alpha/HIF2alpha-index (HIF-index) proved to be an independent prognostic factor in both the discovery and the TCGA cohort. PATIENTS AND METHODS: Expressions of HIF1alpha and HIF2alpha as well as their 7 target genes were analysed on the mRNA and protein level in 59 non-metastatic ccRCCs (nmRCC), 40 bone metastatic primary ccRCCs (mRCC) and 55 corresponding bone metastases. Results were validated in 399 ccRCCs from the TCGA project. CONCLUSIONS: We identified HIF2alpha protein as an independent marker of the metastatic potential of ccRCC, however, unlike HIF1alpha, increased HIF2alpha expression is a favorable prognostic factor. The HIF-index incorporated these two markers into a strong prognostic biomarker of ccRCC. PMID- 27244899 TI - FERMT2 rs17125944 polymorphism with Alzheimer's disease risk: a replication and meta-analysis. AB - A recent meta-analysis of genome-wide association studies (GWAS) in population of Caucasian identified a single nucleotide polymorphism (SNP) rs17125944 in the FERMT2 gene as a new susceptibility locus for late-onset Alzheimer's disease (LOAD). In order to validate the association of the rs17125944 polymorphism with LOAD risk in the northern Han Chinese, we recruited a case-control study of 2338 Han Chinese subjects (984 cases and 1354 age- and gender-matched controls). Our results demonstrated that there was no significant association between the rs17125944 polymorphism and LOAD (genotype: P = 0.953; allele: P = 0.975). Furthermore, no significant differences were observed in alleles and genotypes distribution after stratification by apolipoprotein E (APOE) epsilon4 and multivariate logistic regression analysis. We also performed a meta-analysis in 81908 individuals. The meta-analysis showed that the C allele is the risk factor for LOAD in Caucasian group (OR = 1.15, 95 % CI = 1.10-1.20) and combined population (OR = 1.13, 95 % CI = 1.08-1.19). While in Chinese population, the C allele is not associated with increased risk of LOAD (OR = 1.07, 95 % CI = 0.89 1.28). In conclusion, our study showed that the rs17125944 polymorphism in FERMT2 gene might not be association with LOAD in northern Han Chinese population. PMID- 27244902 TI - [Physicians in handcuffs: how dangerous is the new anti-corruption regulation?]. PMID- 27244901 TI - [Compulsory continuing education in the rehabilitation regulation will be eliminated]. PMID- 27244900 TI - Retinoic acid treated human dendritic cells induce T regulatory cells via the expression of CD141 and GARP which is impaired with age. AB - Aged subjects display increased susceptibility to mucosal diseases. Retinoic Acid (RA) plays a major role in inducing tolerance in the mucosa. RA acts on Dendritic cells (DCs) to induce mucosal tolerance. Here we compared the response of DCs from aged and young individuals to RA with a view to understand the role of DCs in age-associated increased susceptibility to mucosal diseases. Our investigations revealed that compared to young DCs, RA stimulated DCs from aged subjects are defective in inducing IL-10 and T regulatory cells. Examinations of the underlying mechanisms indicated that RA exposure led to the upregulation of CD141 and GARP on DCs which rendered the DCs tolerogenic. CD141(hi), GARP(+) DCs displayed enhanced capacity to induce T regulatory cells compared to CD141(lo) and GARP(-) DCs. Unlike RA stimulated DCs from young, DCs from aged subjects exhibited diminished upregulation of both CD141 and GARP. The percentage of DCs expressing CD141 and GARP on RA treatment was significantly reduced in DCs from aged individuals. Furthermore, the remaining CD141(hi), GARP(+) DCs from aged individuals were also deficient in inducing T regs. In summary, reduced response of aged DCs to RA enhances mucosal inflammation in the elderly, increasing their susceptibility to mucosal diseases. PMID- 27244903 TI - [Clinical Features of the Pediatric Acquired Cholesteatoma Based on the Staging Criteria for Cholesteatoma 2010 Japan]. AB - In this study, we retrospectively evaluated the clinical features of the pediatric acquired cholesteatoma based on the staging criteria for cholesteatoma 2010 Japan. Between 2001 and 2012, total of 36 pediatric patients underwent otologic surgery at our hospital, 29 patients (29 ears) with pars flaccida cholesteatoma and 7 patients (7 ears) with pars tensa cholesteatoma. The age range was 4 to 15 years, (median was 10.5 years). Stage 11 was the most common for both the pars flaccida and pars tensa. A staged operation was performed in 24 ears with pars flaccida cholesteatoma, and 4 ears with pars tensa cholesteatoma. The success rate of hearing improvement was 72% (21/29) in pars flaccida cholesteatoma and 57% (4/7) in pars tensa cholesteatoma. Hearing improvement decreased in advanced cases. In staged operations, residual cholesteatoma was found in 11 ears (46%) with pars flaccida cholesteatoma and 2 ears (50%) with pars tensa cholesteatoma. These results suggest that the residual rate of cholesteatoma in the pediatric population is high. In conclusion, a high rate of residual cholesteatoma in the pediatric population was observed in our study. Thus a staged operation would be the recommended treatment approach in pediatric acquired cholesteatoma. PMID- 27244904 TI - [Newborn Hearing Screening and Subsequent Diagnostic Evaluation: Analysis and Outcomes of 6,063 Infants Born in a Community Hospital]. AB - A retrospective study was conducted to examine the implementation status of newborn hearing screening (NHS) of 6,063 infants born in a single community hospital in Japan between 2005 and 2013. An automated auditory brainstem response device was used for NHS and an auditory brainstem response was mainly used for further diagnostic evaluation. Although the participation rate in the NHS was 88.8% in 2013, increasing year by year, it failed to reach 100% probably because NHS is a charged option under the current Japanese healthcare system. Among 40 (0.66%) infants who finally failed their NHS, 34 were referred for subsequent diagnostic evaluation and the remaining 6 were lost to follow-up. Thirty-one of these 34 were diagnosed as having hearing impairment and 3 (0.05%) were identified as having normal hearing, which is considered as a false positive. Both the final referral rate and the hearing impairment rate were significantly higher in the high-risk than in the low-risk group. Compared to the previous national report, the rate of bilateral hearing impairment (0.33%) was significantly higher in this study. Ten (38.5%) out of 26 in the high-risk group were most often diagnosed with otitis media with effusion (OME), while 4 (50%) out of 8 in the low-risk group were diagnosed as having sensorineural hearing loss. Seven (35%) out of 20 with bilateral hearing impairment attained a normal hearing level at a median age of 18 months. Although the primary aim of NHS is early detection of congenital permanent hearing loss, OME is observed commonly in NHS-failed infants. It is therefore important to examine the middle ear status carefully as part of the diagnostic evaluation. Thirty-four infants underwent further diagnostic evaluation at a median age of 46 days, and hearing aids were given in 10 of them at a median age of 5.6 months without delay. Because high risk patients often tend to be lost to follow-up, otolaryngologists have to give a detailed explanation to caregivers and to build a solid support system for children with hearing impairment. PMID- 27244906 TI - [A Case of Pneumocystis Pneumonia after Cetuximab-based Bioradiotherapy]. AB - Reports of drug-induced interstitial pneumonia caused by Cetuximab have been increasing. Pneumocystis pneumonia is important as a differential diagnosis of drug-induced interstitial pneumonia. We report herein on a 64-year-old man with pneumocystis pneumonia after cetuximab-based bioradiotherapy for laryngeal cancer. After radiotherapy, the patient developed multi-drug resistant pneumonia. Chest CT imaging revealed diffuse ground-glass opacities in the lung field. He was diagnosed as having pneumocystis pneumonia based on the bronchoalveolar lavage (BAL) findings, and then his symptoms improved after treatment with Trimethoprim/Sulfamethoxazole. It is important to assess the risk factor for pneumocystis pneumonia for early its detection and treatment. PMID- 27244905 TI - [Surgical Management for Benign Parotid Tumors: Review of a 16-year Experience with 633 Patients]. AB - OBJECTIVE: The objective of this study was to analyze the diagnosis and postoperative complications of benign parotid tumors for a series of 633 patients who underwent the same diagnostic methods and operation procedure in a single institute. MATERIALS & METHODS: A series of 633 patients who underwent parotidectomy for benign parotid tumors over a 16-year period was reviewed. RESULTS: There were 345 female and 288 male patients. The site of the tumors was divided among three groups, superficial, deep, and lower pole tumors. The numbers of each type of above tumors were 342, 122, and 169 cases, respectively. The most common pathology of the parotid tumor was a pleomorphic adenoma (372 cases) followed by a Warthin tumor (166 cases). Pleomorphic adenomas and Warthin tumors accounted for 85% of all benign tumors. The accuracy rate of fine needle aspiration cytology (FNAC) for all benign tumors was 71%, 84% for pleomorphic adenomas and 72% for Warthin tumors. Transient facial nerve dysfunction was observed in 130 patients (21%) in 612 cases of primary benign parotid tumors, and only one patient developed a permanent weakness. The incidence of transient facial nerve dysfunction was 18% in superficial tumors, 39% in deep tumors, and 15% in lower pole tumors. Significant risk factors for development of a transient facial palsy were the site of the tumors, the size of the tumors, operation time, and bleeding volume. Among these risk factors, for the site of the tumors, the deep lobe was the most important factor associated with transient facial nerve dysfunction. Transient facial nerve dysfunction recovered within 6 months in 90% of all cases. CONCLUSIONS: The accuracy rate of FNAC for benign parotid tumors was 72%. The incidence of transient facial nerve dysfunction in deep tumors was significantly higher compared to that in superficial and lower pole tumors. According to the rate of facial palsy, operation time, and bleeding volume, benign parotid tumor should be divided among three groups, namely superficial, deep, and lower pole tumors. PMID- 27244907 TI - [THE RISK FACTORS OF LETHAL COMPLICATIONS IN EARLY POSTOPERATIVE PERIOD IN PATIENTS, SUFFERING GASTROESOPHAGEAL ZONE MALIGNANCIES]. AB - Abstract The factors, determining possibility of early postoperative morbidity occurrence in patients, suffering gastro-esophageal zone cancer, were analyzed. After radical operation performance (gastrectomy, gastric and esophageal resection) 5.7% patients died. Insufficience of the anastomosis sutures with peritonitis occurrence, an acute hepato-renal insufficience, an acute coronary syndrome, pulmonary thromboembolism, pneumonia, the brain insult, pancreonecrosis and mesenterial thrombosis constituted the main morbidities. The complications occurrence depends upon the tumoral process course severity, morphological variant of cancer, presence of concomitant diaphragmatic hernia and the blood rheological properties. Initially high indices of the blood sera present a rheological properties of blood serum may serve as a prognostic criterion of the postoperative complications occurrence in the patients. PMID- 27244908 TI - [DYNAMICS OF INDICES OF A LOCAL IMMUNITY IN AN ACUTE APPENDICITIS]. AB - Abstract The results of investigation on dynamics of a local immunity indices in an acute appendicitis, depending on the pathological process stage as well as on bacteriological investigation of parietal microflora of processus vermicularis, were adduced. The sIgA and lisocymal dynamics have witnessed that while a destructive process progressing their concentration was enhanced, and in a gangrenous acute appendicitis they practically disappeared. Due to affection of a barrier function of the processus vermicularis wall a favorable conditions were created for the microorganisms intramural translocation as well as to abdominal cavity. PMID- 27244909 TI - [THE WAYS TO IMPROVE SURGICAL TREATMENT OF PILONIDAL DISEASE]. AB - Analysis of the surgical treatment results in 54 patients, suffering pilonidal disease in 2011 - 2013 yrs, was done. Introduction of procedure, proposed in the clinic, for the operative wound closure after pilonidal disease surgical treatment have promoted the postoperative morbidity rate reduction and the patients treatment results improvement. A summation of a two-layered horizontal suture on different levels of subcutaneous layer and of vertical knot cutaneous sutures have guaranteed the possibility of the wound healing by a primary tension fashion, without durable filling of the wound defect with granulations. PMID- 27244910 TI - [CORRECTION OF ENTERAL INSUFFICIENCY SYNDROME IN PATIENTS, SUFFERING DIFFUSE PERITONITIS]. AB - The results of treatment of 65 patients, suffering diffuse peritonitis, were analyzed. For the abdominal cavity sanation and intestinal decontamination the adopted selective bacteriophages (polyvalent pyobacteriophage, intesti bacteriophage, and the coliproteus one) were applied. The abdominal cavity state was estimated while doing a programmed relaparotomy. Bacteriologic investigation of exudate, excreted along nasointestinal probe, and of peritoneal exudate was conducted. The intestinal motor-evacuation function restoration was estimated in accordance to data of ultrasonographic investigation. Application of the procedure proposed have promoted earlier restoration of intestinal motor and the barrier functions, and elimination of enteral insufficiency syndrome. PMID- 27244912 TI - [MORPHOLOGICAL CHANGES OF THE LIVER IN OBTURATION JAUNDICE, CAUSED BY CHOLEDOCHOLITHIASIS, DEPENDING ON ITS DURATION]. AB - Abstract The results of surgical treatment of 184 patients for obturation jaundice, caused by choledocholithiasis, were analyzed. Morphological changes of the liver were studied in 20 patients. There were three groups of patients delineated, depending on the obturation jaundice duration: up to 7 days, from 8 to 14 days, more than 15 days, and also a group of patients after the bile outflow restoration. The obturation jaundice occurrence in choledocholithiasis is accompanied by significant morphological changes in the liver, severity of which is enhancing while the obturation jaundice persistence increasing. While persistence of obturation jaundice through 8 days and more the connective tissue volume is enhancing, a relative volume of hepatocytes is reducing and a stromal parenchymatous index is increasing. The bile outflow restoration secures significant reduction of intensity of alterative and inflammatory changes in hepatic parenchyma, as well as activation of reparative processes in the tissue. In cholangitis, caused by P. aeruginosa and E. coli, according to morphological investigations data, in the liver a diffuse purulent cholangitis on background of chronic changes in accordance to duration of the obturation jaundice persists. PMID- 27244911 TI - [PROGNOSTICATION OF AN ACUTE POSTRESECTIONAL HEPATIC INSUFFICIENCY]. AB - An acute postresection hepatic insufficiency (PHI) constitutes a necessary moment before the hepatic resection planning, permits in some situations to conduct prophylactic measures and to avoid this severe complication. Possibility of PHI occurrence was prognosticated for results of surgical treatment improvement in patients, suffering focal hepatic affection, using introduction of certain preoperative preparation and surgical tactics. The main task of the investigation was to determine the diagnostic and prognostic value of the investigation methods and elaboration of prognostic algorithm of an acute PHI occurrence. PMID- 27244913 TI - [IMPACT OF RONCOLEUKIN ON BALANCE OF CYTOKINS IN COMPLEX TREATMENT OF OBTURATION JAUNDICE OF NONTUMORAL GENESIS]. AB - The results of surgical treatment of 137 patients, suffering obturation jaundice of non-tumoral etiology, were analyzed. In all the patients the cause of obturation jaundice was choledocholithiasis. Roncoleukin was infused intravenously additionally in a complex of therapy. A degree of hepatic dysfunction was determined, taking into account the cholestasis markers. In 23 patients purulent cholangitis have occurred on background of obturation jaundice. Concentration of cytokins TNF-alpha, IFN-gamma, IL-1, IL-2, IL-4, IL-6, IL-10 in sera were determined, using immunoassay analysis. The cytokins dysbalance severity preoperatively and dynamics of its changes have depended upon the hepatic dysbalance degree and presence of purulent cholangitis; a dysbalance is deeper, when the hepatic dysfunction is higher. Application of pathogenetically substantiated purposeful cytokinotherapy, including roncoleukin, have promoted the cytokins dysbalance elimination and improvement of the patients treatment results. PMID- 27244914 TI - [DIAGNOSIS OF VASCULAR INVASION BY PANCREATIC TUMORS]. AB - Basing on analysis of own material (84 patients) and data of literature there was established, that vascular invasion by pancreatic tumors constitutes the main obstacle for conduction of the patients' radical treatment. Early diagnosis permits radical resectability of the patients, what constitutes the only one effective method of treatment. In vascular invasion by tumor a surgeon experience and professional preparation determines possibility of the extended operation performance with intervention on affected main vessel, enhancing the treatment radicalism. PMID- 27244915 TI - [EFFICACY AND SECURITY OF A CONVENTIONAL PROCEDURE OF PLASMAPHERESIS IN COMPLEX OF TREATMENT OF NONBILIARY ACUTE PANCREATITIS IN EARLY PHASE OF THE DISEASE]. AB - Abstract Efficacy and security of a plasmapheresis procedure in complex of treatment of nonbiliary acute pancreatitis in early phase of the disease were established, basing on the treatment results analysis in 48 patients. The plasmapheresis results were estimated in accordance to changes revealed in the intoxication leukocytic index (ILI), a general protein (GP) content, general calcium (GC) in the blood plasm and of the activated partial thrombin time (APTHT). Application of plasmapheresis in patients, suffering purulent pancreatitis in the enzymal phase, have guaranteed a staged reduction of ILI by (34.86 +/- 1.27)%, the APTHT enhancement from (35.15 +/- 0.37) to (52.01 +/- 0.62) sec, a trustworthy lowering of the GP by (4.35 +/- 0.02) g/L at average and of GC in a blood plasmby (10.45 +/- 0.38)%. PMID- 27244916 TI - [BILIARY HYPERTENSION IN CHRONIC PANCREATITIS AND PECULIARITIES OF ITS DIAGNOSIS]. AB - Possibilities of various diagnostic methods for biliary hypertension detection in chronic pancreatitis were analyzed. Biliary hypertension was revealed in 163 (31%) patients, suffering chronic pancreatitis. The laboratory investigations data, ultrasonographic investigation, computer tomography, endoscopic retrograde cholangiopancreatography, magnet-resonance cholangiopancreatography, intraoperative measurement of the biliary ducts width, intraoperative measurement of biliary pressure were applied for diagnosis. Endoscopic retrograde cholangiopancreatography, magnet-resonance cholangiopancreatography and intraoperative measurement of biliary pressure are considered the most sensitive methods for chronic pancreatitis diagnosis. PMID- 27244917 TI - [THE RESULTS OF ENDOVASCULAR CLOSURE OF A SECONDARY DEFECT OF INTERATRIAL SEPTUM]. AB - Efficacy and security of transcutaneous closure for secondary defect of interatrial septum (DIAS) in 299 patients, using occluders, were studied. Cardiac dysrythmia was the most frequent complication--in 10 (3.3%) patients, the apparatus shift was noted in 4 (1.3%), in 1 (0.3%)--the air embolism of right parts of the heart have occurred. In 289 (98.2%) patients normalization of right parts of heart was achieved. In 84.4% of patients the absence of a residual shunt immediately after the procedure was observed, before the check-out from the hospital--in 89.2%, and in 6 mo--in 97.7%. Transcutaneous closure of secondary DIAS constitutes a secure, effective and less traumatic method, than surgical treatment. Today endovascular method is considered a "gold standard" in treatment of this heart failure. Keywords: secondary defect of interatrial septum; transcutaneous closure; occluder. PMID- 27244918 TI - [EXTRAANATOMIC ARTERIAL RECONSTRUCTION IN PATIENTS WITH ATEROSCLEROTIC AFFECTION OF THE AORTAL ARCH BRANCHES]. AB - Own experience of extraanatomical reconstruction, made for atherosclerotic affection of the aortal arch branches, was analyzed. A subclavian artery (SA) transposition into common carotid artery (CCA) was conducted for symptomatic subtotal stenosis or occlusion of the SA I segment. While extension of atherosclerotic process beyond boundaries of the SA I segment or technical difficulties a carotid-subclavian shunting was preferred. Carotid-carotid shunting was applied in necessity of revascularization of extracranial arteries before endovascular implantation of a stent-graft down to aortal arch with closure of the left CCA branching. The authors consider extraanatomic reconstruction the method of choice in the patients surgical treatment for central atherosclerotic affection of the aortal arch branches, when possibilities of endovascular revascularization methods are exhausted, and this guarantees good and satisfactory results in 91.7% of them. PMID- 27244919 TI - [SURGICAL TREATMENT OF TRAUMATIC ARTERIAL ANEURYSM]. AB - The results of treatment of 47 patients, suffering traumatic arterial aneurysm, were analyzed. Restoration of functions of injured extremities, rehabilitation of patients, prophylaxis of complications were guaranteed due to conduction of reconstruction-restoration operations. A lateral suture of the vessel was applied in 5 patients and a circular suture--in 8. Vascular plasty, using high technology -the balloon vascular occlusion, and autovein or synthetic prosthesis--in 17 patients, while inability to formate a lateral or circular suture. The wound healing in a primary tension fashion was noted in 32 (72%) patients, and in a secondary one--in 3 (6.8%). PMID- 27244920 TI - [A MIDDLE-TERM RESULTS OF ENDOVENOUS LASER ABLATION FOR VARICOSE DISEASE OF THE LOWER EXTREMITIES]. AB - Abstract The results of endovascular laser ablation (EVLA) under ultrasonographic control in treatment of the lower extremities varicose disease (LEVD) in 189 patients (214 extremities) were analyzed. There was established, that for the trustworthy information obtaining the ultrasonographic duplex angioscanning conduction is necessary. The fibrous involution of a big subcutaneous vein trunk was achieved in (97.7 +/- 1.0)% observations, in (1.9 +/- 0.9)%--while the clinical signs absence--there were revealed the echo-signs of a reflux recurrence -the "ultrasonographic recurrence", and in one observation--a clinical recurrence of LEVD. In (5.1 +/- 1.5)% observations in fibrous involution of the segments treated the signs of venous insufficiency in earlier competent parts were revealed--the disease progress registered. The recurrence rate and the pain syndrome severity did not depend on the treated veins diameter. High security of EVLA was established while the complications analyzing. PMID- 27244921 TI - [VARICOSE DISEASE OF THE LOWER EXTREMITIES: CAUSES, COMPLICATIONS, CHOICE OF METHODS FOR TREATMENT AND PROPHYLAXIS]. AB - Abstract The results of 1142 patients treatment for varicose disease of the lower extremities in 2006-2014 yrs were adduced. The patients were divided on 3 groups, depending on the clinical signs severity and method of treatment. There were operated 59 patients, in 65--the proposed scheme of treatment was applied. PMID- 27244922 TI - [DIAGNOSTIC SIGNIFICANCE OF CYTOLOGICAL AND HISTOLOGICAL INVESTIGATION OF THE BIOPSY MATERIAL FOR DETERMINATION OF ETIOLOGY OF THE INTRATHORACIC LYMPHADENOPATHY SYNDROME]. AB - In Department of Thoracic Surgery and Invasive Methods of Diagnosis in 2008-2014 yrs 132 biopsy specimen of intrathoracic lymph nodes with further cytological and histological investigation, taken in patients, who were treated for the intrathoracic lymphadenopathy syndrome of unknown etiology, were analyzed. Sensitivity, specificity and general accuracy of cytological and histological diagnosis were determined, while applying various methods of the biopsy material selection. PMID- 27244923 TI - [RESPIRATORY DISORDERS AFTER PROSTHESIS FOR THE ANTERIOR ABDOMINAL WALL HERNIA AND THEIR PREDICTORS]. AB - Postoperative respiratory disorders after prosthesis for the anterior abdominal wall hernia and their predictors were analyzed in 37 patients. Hypoxemic respiratory disorders were revealed in 59% patients. Speciphic predictors for the respiratory disorders occurrence after prosthesis for the anterior abdominal wall hernia were determined: obesity, syndrome of obstructive sleep apnoe, intraabdominal pressure raising to more than 16 cm of a water column immediately after the prosthesis. The prosthesis duration have constituted more than 3 yrs. PMID- 27244924 TI - [ANALYSIS OF A LETHAL OUTCOME RISK AFTER TRAUMA IN HIV-INFECTED PATIENTS IN POLYSYSTEMIC INJURY]. AB - Abstract The data, concerning clinic--epidemiologic and clinic--nosological characteristic of a HIV-infected injured persons in polytrauma were adduced. There was established, that polysystemic injuries (PSI) in a HIV-infected persons occur in a younger injured patients, a trauma environment is quite a speciphic one (criminal trauma prevails), as well as mechanism of the injury occurrence (falling down is much more freqent), and the risk of a lethal outcome is determined by predominantly cranial, thoracic and abdominal components of injury. A lethal outcome occurrence risk in HIV-infected injured persons in PSI in accordance to the age signs and traumagenesis is lesser, than in a control body. It is necessary to prolong the investigations, concerning studying this phenomenon and other peculiarities of a traumatic disease in HIV-infected injured persons in polytrauma. PMID- 27244926 TI - [THE SPLEEN FIXING AS IMPORTANT ELEMENT OF PERFORMANCE OF LAPAROSCOPIC LEFT-SIDED ADRENALECTOMY]. AB - Abstract The necessity of performance of orthotopic fixing of spleen after main stage of a left-sided laparoscopic adrenalectomy was substantiated. The majority of patients, first of all ordinary or with a lean stature, are complaining on a temporary discomfort and pain in abdomen of various degree, what is connected with transition of a mobilized spleen in early postoperative period. A simple method of surgical fixation of spleen is putting of 2 or 3 sutures on dissected sheets of parietal peritoneum in region of mobilization of spleen and pancreatic tail, what is securely prevents such an unwanted signs and facilitate a postoperative period course. PMID- 27244925 TI - [IMPACT OF URANOSTAPHILOPLASTY ON QUALITY OF LIFE OF THE PATIENTS]. AB - Abstract Retrospective analysis was conducted in 78 patients of various age, who suffered the inborn lip and palate fissura, for estimation of the patients quality of life after uranostaphiloplasty. The operations were performed on clinical base of The Oral Cavity Surgery and The Jaw-Facial Surgery Cathedra in Department of The Jaw-Facial Surgery of Clinical Medical Center (Baku). There was established, that application of uranostaphiloplasty procedure, as well as timely initiated rehabilitation, influences a further establishment of the patient personality. A timely refer to a speech therapeutist and the treatment began also have great significance for further establishment of the patient personality. Disorders of speech, incorrect bite hampers obtaining of education, working, interferes with a family creation, hampers the employment and worsens a quality of life. PMID- 27244927 TI - [EXPERIENCE OF THE RATIONAL ANTIBACTERIAL THERAPY CONDUCTION IN TREATMENT OF CHILDREN FOR THE BURN TRAUMA]. AB - Abstract The principles of rational antibacterial therapy in children for the burn trauma were analyzed. The results of the completed treatment of 808 children for the burn trauma in a Combustiological Department of Municipal clinical hospital of City of Zaporozhye were studied. In 326 (40.3%) children antibacterial therapy was conducted, including one antibiotic--in 268 (82.2%), two and more--in 37 (11.3%). The preparations were prescribed empirically, taking into account bacteriological profile of the Department and the patients premorbidity background present. Prescription of modern anticlostridial probiotics, containing stamms of Lactobacillus rhamnosus R0011 and Lactobacillus acedofilus R0052, on background of continuing antibacterial therapy, have constituted the effective measure of prophylaxis for the antibiotic-associated diarrhea, as the most frequent complication of antibacterial therapy. PMID- 27244928 TI - [COMPARATIVE CHARACTERISTIC OF VARIOUS METHODS OF SIMULATION OF BILIARY PERITONITIS IN EXPERIMENT]. AB - In experiment on rabbits a comparative analysis of various methods of a biliary peritonitis simulation was conducted. In 6 animals a biliary peritonitis was simulated, using perforation of a gallbladder, local serous-fibrinous peritonitis have occurred in 50% of them. In 7 animals biliary peritonitis was simulated, applying intraabdominal injection of medical sterile bile in a 5-40 ml volume. Diffuse peritonitis with exudates and stratification of fibrin was absent. Most effective method have appeared that, when intraabdominal injection of bile was done together with E. coli culture in the rate of 0.33 microbal bodies McF (1.0 x 10(8) CFU/ml) on 1 kg of the animal body mass. Diffuse biliary peritonitis have occurred in all 23 animals, including serous-fibrinous one--in 17 (76%), and purulent-fibrinous--in 6 (24%). PMID- 27244929 TI - [SURGICAL TREATMENT OF OVARIAN CARCINOSARCOMA THAT DEVELOPED IN GIANT CYSTIC TERATOMA]. PMID- 27244930 TI - [Possibilities of bacteriophage therapy]. AB - Antibiotic resistance of bacterial pathogens has increased, and new therapies are urgently needed. Bacteriophages (phages), viruses infecting and killing bacteria, are the most abundant organisms on earth. In nature there are several specific phages for every bacterium, controlling bacterial numbers and maintaining ecological balance. Phage therapy, i.e., treating bacterial infections with phages, offers an alternative complementary to antibiotics as phages infect and kill also multi-resistant bacteria. Phages possess narrow host specificity, each phage infecting only a few bacterial species or strains. Thereby phages do not harm the normal microbiota as antibiotics do. We aim to begin clinical trials of phage therapy in Finland. PMID- 27244931 TI - [Immuno-oncology--silver bullets or mass destruction weapons?]. AB - Modes of treatment affecting the regulatory mechanisms of cell-mediated immunity are changing the treatment practices of various types of cancer. Antibodies inhibiting regulatory molecules of the immune response, i.e. checkpoint inhibitors, are of particular interest. The mechanism of action is enhancement of the body's intrinsic responses to cancer cells through inhibition of negative regulation of the immune defense. Cell-mediated immunity directed to cancerous tissue can be enhanced by removing the brake associated with T-cell activation (CTLA-4 inhibitors). A more physiological mode of action is to abolish the attenuation mechanism of already activated T cells (PD-1 inhibitors). The physiological purpose of both mechanisms is to prevent an excessively strong immune reaction and thus autoimmunity. PMID- 27244932 TI - [Heterotopic pregnancy during the second trimester is a severe complication of pregnancy]. AB - Heterotopic pregnancy is a rare form of ectopic pregnancy in which one gestational sac is found in the uterus and another one in an extrauterine location. The spontaneous heterotopic pregnancy of our patient continued until the second trimester. In the 19th week of pregnancy, undiagnosed ectopic pregnancy in the left fallopian tube ruptured into the abdominal cavity, leading to a massive intra-abdominal hemorrhage. Left-side uterine appendages were excised in open surgery, but intrauterine pregnancy continued in vital form. Histologic examination revealed the excised tumor to be an ectopic pregnancy. The hypotension experienced by the patient led, however, to severe brain damage of the intrauterine fetus and induced abortion. PMID- 27244933 TI - [Herpes zoster in the pharynx]. AB - A 74-year-old woman was suspected of having a peritonsillar abscess. She had a light-coloured coating on the pharynx and the larynx, bordering to the left of the median line, as well as laryngeal edema on the side of the lesion. On the basis of precisely unilateral findings we arrived at pharyngeal herpes zoster as the working diagnosis. The diagnosis was further supported by the detection of varicella-zoster virus DNA in the mucosa and the presence of positive IgM antibody levels. The patient was treated with an antiviral drug, an antimicrobial drug and a glucocorticoid. Mucosal lesions and edema returned to normal, and the patient was discharged. The precise unilaterality of the symptoms is essential to the diagnosis. PMID- 27244934 TI - [Update on current care guidelines. Pain]. AB - Management of patients suffering from chronic pain is based on long-term therapeutic relationship. The main objectives of the treatment are pain relief, restoration of function and improvement of quality of life. Interventions for treatment and rehabilitation need to be planned in agreement with the patient. Non-pharmaceutical interventions form the basics of the treatment. If medication is needed, it should be tailored to meet the individual needs of the patient according to the etiology and intensity of pain, comorbidities and psychosocial situation. PMID- 27244935 TI - [Ultrasound in the hands of emergency physicians]. AB - Emergency ultrasound (US) offers additive value in the diagnosis and treatment of emergency and/or critically ill patients. Emergency Medicine (EM) became a new specialty in Finland in the beginning of 2013. Since then, the training of emergency US has dramatically increased. We discuss the current situation of emergency US as a part of specialist training of EM in Finland and compare it with that in the United States and Canada. Practical indications, limitations and future prospects of emergency US are also presented. PMID- 27244936 TI - [Ultrasonography-guided procedures of the doctor on call]. AB - The use of ultrasonography in guiding minor procedures reduces the possibility of procedural complications. Fluid is easy to identify, enabling the utilization of ultrasonography even with a lesser experience. In skilled hands, drainage of ascitic fluid, pleurocentesis and insertion of a suprapubic catheter are safe procedures. Careful planning of the procedure in advance will contribute to safety. Before undertaking the procedure, one should confirm the patient's coagulation status and appropriate interruption of possible antithrombotic medication. The injection site is chosen on anatomical grounds, avoiding any blood vessels. The ultrasound view is adjusted optimally so that the route of injection can be seen as clearly as possible on the screen. PMID- 27244937 TI - [Gynecological ultrasound examination at the general health care emergency department]. AB - Vaginal ultrasound examination is a possible addition for the general health care emergency department. It gives additional information of gynecological illnesses and pregnancy. Ultrasound can guide treatment and make consulting the right specialty easier when treating women with acute abdominal pain. Correctly used ultrasound can also reduce the need for consultation and speed up treatment, especially in early pregnancy. The physician performing the ultrasound should know the diagnostic capabilities of ultrasound and compare findings to the clinical status and history. Ultrasound can't replace clinical history and status in any situation. A pregnancy test, hemoglobin or CRP are often required to achieve diagnosis. PMID- 27244939 TI - [FAST ultrasonography]. AB - FAST ultrasonography has established its status as part of the initial evaluation of a trauma patient. FAST allows for the rapid identification of the presence of free fluid (blood) in the pericardium or in the abdominal cavity. In practical work, examination of the pleurae is usually included in the approach and examination. In addition to free fluid, findings indicating pneumothorax can be searched from them. PMID- 27244938 TI - [FATE echocardiography at the emergency outpatient unit]. AB - FATE (Focus Assessed Transthoracic Echocardiography) echocardiography can be learned more quickly than extensive cardiologic examination. It is intended to be used in emergency situations as a qualitative examination to resolve the cardiogenic mechanism of circulatory insufficiency and possible hypovolemia. The procedure is worth utilizing as a dynamic method in the assessment of the response to fluid therapy and vasoactive medications. In many cases, however, a more profound ultrasound imaging will provide essential further information. PMID- 27244940 TI - HIM's Professional SHAKE-UP WAKE-UP. PMID- 27244941 TI - Expanding CDI to Physician Practices. FIVE DOCUMENTATION VULNERABILITIES TO ADDRESS IN 2016. PMID- 27244942 TI - LESSONS LEARNED from Training an International Workforce. PMID- 27244944 TI - Recognizing the Characteristics of Quality Documentation. PMID- 27244943 TI - Understanding Disclosures for Firearm Background Checks. PMID- 27244945 TI - New International Standard for Health Information Privacy Workforce Education. PMID- 27244946 TI - The Information Governance Roadmap: Mile Marker 1--Engaging IG Leadership and Celebrating Quick Wins. PMID- 27244947 TI - EHRs Serving as the Business and Legal Records of Healthcare Organizations (2016 Update). PMID- 27244948 TI - ICD-10-CM Coding for Injury Resulting from Terrorism. PMID- 27244949 TI - Continuing on the Intriguing ICD-10 Journey. PMID- 27244950 TI - Significant heat sensitivity increase detected in various types of diabetes mellitus patients by Akabane test for use of management of diabetic patients. AB - In order to assess patterns of heat sensitivity thresholds in patients with diabetes mellitus, the Akabane test was carried out on patients with insulin dependent diabetes mellitus (IDDM) (250 men and 309 women) and patients with noninsulin dependent diabetes mellitus (NIDDM) (158 men and 227 women). For comparison, a group of healthy subjects made up of 116 men and 277 women was also used. As soon as we revealed the influence of factors of pathology with a high significance level and gender and the interaction "gender*pathology", all the results are described separately for groups of men and women and for groups with IDDM and NIDDM. Simple effects of paired comparisons between healthy subjects, IDDM and NIDDM in groups of men and women, as well as comparisons between the profiles of men and women with IDDM and NIDDM showed significant differences between ACs in healthy subjects and those with each type of diabetes. The most significant differences are seen in the AC connected with the digestive system (SP pancreas channel), LR (liver channel), ST (stomach channel), GB (gall bladder channel). Thus, we revealed characteristic pattern of acupuncture channels (AC) lesions inherent to diabetes pathology, i.e. most vulnerable in diabetes ACs, being compromised in dependence from such factors, as type of diabetes, hyper or hypoglycemia, and from gender. The main value of the method lies in the fact that we observe the entire food chain from food ingestion to the utilization of carbohydrates with the opportunity to assess the activity of each organ and its regulatory contribution. On the basis of the body's response, an individual selection of medicines can be made, and by evaluating the individual biorhythms it is possible to determine the optimal time of administration. PMID- 27244951 TI - Acupuncture Stimulation Analyzed from Multiple Aspects of Western Medical Science. AB - Skin is the biggest and most important organ of us. It has a large surface area and it is easily accessible. While we touch skin, piezoelectric stimulation starts, fundamental property of biological tissues, pressure electrification. And after this stimulation, ferroelectric and pyroelectric effects occur. While we insert the acupuncture needle into skin, we have created a conscious trauma and damage. After this, inflammatory phase, proliferation and tissue formation phase and tissue remodeling phase start. With embryological perspective, at that moment, we give stimulus ectodermal and mesodermal layer of the skin also. We stimulate these embryologic layers and cells not only into skin but also whole body. Because, while we start stimulation with a cell, cell stimulates other cells and cells stimulate body. Also we stimulate neuropeptides, neurotransmitters, neuro-hormones and receptors. The skin is the largest immunologically active receptor organ in the body. And we see, peripheral local stress response (brain-skin) works same as hypothalamic-pituitary-adrenal axis. So, what we have done? We only insert the acupuncture needle into skin consciously. PMID- 27244952 TI - Optimal Dose of Vitamin D3 400 I.U. for Average Adults has A Significant Anti Cancer Effect, While Widely Used 2000 I.U. or Higher Promotes Cancer: Marked Reduction of Taurine & 1alpha, 25(OH)2D3 Was Found In Various Cancer Tissues and Oral Intake of Optimal Dose of Taurine 175mg for Average Adults, Rather Than 500mg, Was Found to Be A New Potentially Safe and More Effective Method of Cancer Treatment. AB - During the past 10 years, the author had found that the optimal dose of Vitamin D3 400 I.U. has safe & effective anticancer effects, while commonly used 2000 5000 I.U. of Vit. D3 often creates a 2-3 time increase in cancer markers. We examined the concentration of Taurine in normal internal organs and in cancer using Bi-Digital O-Ring Test. We found that Taurine levels in normal tissue are 4 6ng. But, the amount of Taurine of average normal value of 5.0-5.25ng was strikingly reduced to 0.0025-0.0028ng in this study of several examples in adenocarcinomas of the esophagus, stomach, pancreas, colon, prostate, and lung, as well as breast cancer. The lowest Taurine levels of 0.0002-0.0005ng were found in so called Zika virus infected babies from Brazil with microcephaly. While Vitamin D3 receptor stimulant 1alpha, 25 (OH)2D3 in normal tissues was 0.45 0.53ng, they were reduced to 0.025-0.006ng in cancers (1/100th-1/200th of normal value), particularly in various adenocarcinomas. All of these adenocarcinomas had about 1500ng HPV-16 viral infection. In 500 breast cancers, about 97% had HPV-16. The optimal dose of Taurine for average adult has been found to be about 175mg, rather than the widely used 500mg. In addition, since Taurine is markedly reduced to close to 1/1000th-1/2000th of its normal value in these cancer tissues, we examined the effect of the optimal dose of Taurine on cancer patients. Optimal dose of Taurine produced a very significant decrease in cancer-associated parameters, such as Oncogene C-fosAb2 & Integrin alpha5beta1 being reduced to less than 1/1,000th, and 8-OH-dG (which increases in the presence of DNA mutation) reduced to less than 1/10th. The optimal dose of Taurine 175mg for average adult various cancer patient 3 times a day alone provide beneficial effects with very significant anti-cancer effects with strikingly increased urinary excretion of bacteria, viruses, & funguses, asbestos, toxic metals & other toxic substances. However, optimal doses of Taurine combined with optimal individualized doses of psi3 fish oil [EPA 180mg & DHA 120mg] & special cilantro tablet 3 times/day without creating harmful drug interactions among them including other essential drugs, is often extremely safe, more effective, economical & non-invasive new treatment for various cancer patients. PMID- 27244953 TI - VIABILITY AND INFECTIVITY OF CRYOPRESERVED PLASMODIUM VIVAX SPOROZOITES. AB - Plasmodium vivax presents a great challenge to malaria control because of the ability of its dormant form in the liver, the hypnozoite, to cause relapse in otherwise fully recovered patient. Research efforts to better understand P. vivax hypnozoite biology have been hampered by the limited availability of its sporozoite form responsible for liver infection. Thus, the ability to cryopreserve and recover P. vivax sporozoites is an essential procedure. In this study, protective effects of hydroxyethyl starch (HES) alone and in combination with other cryoprotectants on P. vivax sporozoite recovery, viability and in vitro infectivity of a human liver HC-04 cell line were investigated. Sporozoites were harvested from P. vivax-infected female Anopheles mosquitoes and cryopreserved at a freezing rate of -1 degrees C/minute to a final temperature of -80 degrees C before being stored in a vapor phase liquid nitrogen tank. Cryopreserved sporozoites were thawed at 37 degrees C and recovery of intact sporozoites assessed using a hemocytometer. Sporozoite viability and in vitro infectivity was measured using a gliding and an indirect immunofluorescence assay, respectively. A combination of 10% HES + 50% fetal bovine serum was the best cryopreservant compared to HES solution alone or mixed with cryopreservants such as dimethyl sulfoxide (DMSO) and sucrose. A mixture of bovine serum albumin, DMSO and sucrose in RPMI 1640 medium constituted an alternative cryopreservant. Sporozoites recovered from all cryopreservation media exhibited motility and infectivity of < 0.1% and < 0.001%, respectively. Thus, there is an urgent need for a vast improvement in cryopreservation procedures of viable and infective P. vivax sporozoites necessary for advancing research on hypnozoite biology. PMID- 27244954 TI - DETECTION OF PUTATIVE ANTIMALARIAL-RESISTANT PLASMODIUM VIVAX IN ANOPHELES VECTORS AT THAILAND-CAMBODIA AND THAILAND-MYANMAR BORDERS. AB - Monitoring of multidrug-resistant (MDR)falciparum and vivax malaria has recently been included in the Global Plan for Artemisinin Resistance Containment (GPARC) of the Greater Mekong Sub-region, particularly at the Thailand-Cambodia and Thailand-Myanmar borders. In parallel to GPARC, monitoring MDR malaria parasites in anopheline vectors is an ideal augment to entomological surveillance. Employing Plasmodium- and species-specific nested PCR techniques, only P. vivax was detected in 3/109 salivary gland DNA extracts of anopheline vectors collected during a rainy season between 24-26 August 2009 and 22-24 September 2009 and a dry season between 29-31 December 2009 and 16-18 January 2010. Indoor and out- door resting mosquitoes were collected in Thong Pha Phum District, Kanchanaburi Province (border of Thailand-Myanmar) and Bo Rai District, Trat Province (border of Thailand-Cambodia): one sample from Anopheles dirus at the Thailand-Cambodia border and two samples from An. aconitus from Thailand-Myanmar border isolate. Nucleotide sequencing of dihydrofolate reductase gene revealed the presence in all three samples of four mutations known to cause high resistance to antifolate pyrimethamine, but no mutations were found in multidrug resistance transporter 1 gene that are associated with (falciparum) resistance to quinoline antimalarials. Such findings indicate the potential usefulness of this approach in monitoring the prevalence of drug-resistant malaria parasites in geographically regions prone to the development of drug resistance and where screening of human population at risk poses logistical and ethical problems. Keywords: Anopheles spp, Plasmodium vivax, antimalarial resistance, Greater Mekong Sub-region, nested PCR, vector surveillance PMID- 27244955 TI - SURVEY OF HOUSE RAT INTESTINAL PARASITES FROM SURABAYA DISTRICT, EAST JAVA, INDONESIA THAT CAN CAUSE OPPORTUNISTIC INFECTIONS IN HUMANS. AB - The purpose of this study was to investigate the prevalence of house rat zoonotic intestinal parasites from Surabaya District, East Java, Indonesia that have the potential to cause opportunistic infection in humans. House rat fecal samples were collected from an area of Surabaya District with a dense rat population during May 2015. Intestinal parasites were detected microscopically using direct smear of feces stained with Lugol's iodine and modified Ziehl-Neelsen stains. The fecal samples were also cultured for Strongyloides stercoralis. Ninety-eight house rat fecal samples were examined. The potential opportunistic infection parasite densities found in those samples were Strongyloides stercoralis in 53%, Hymenolepis nana in 42%, Cryptosporidium spp in 33%, and Blastocystis spp in 6%. This is the first report of this kind in Surabaya District. Measures need to be taken to control the house rat population in the study area to reduce the risk of the public health problem. Keywords: zoonotic intestinal parasites, opportunistic infection, house rat, densely populated area, Indonesia PMID- 27244956 TI - DISCRIMINATION 28S RIBOSOMAL GENE OF TREMATODE CERCARIAE IN SNAILS FROM CHIANG MAI PROVINCE, THAILAND. AB - Trematode cercariae are commonly found in many freshwater gastropods. These cercariae can serve to identify the occurrence of such trematodes as Centrocestus formosanus, Haplorchis taichui, Haplorchoides sp, and Stellantchasmus falcatus, which are important parasites in Chiang Mai Province, Thailand. As the species of these cercariae cannot be identified accurately based on morphology, this study employed sequencing of a fragment of 28S ribosomal DNA and phylogenetic analysis to identify the trematode cercariae found in freshwater gastropods in Chiang Mai Province. Eight types of trematode cercariae were identified, namely, distome cercaria (grouped with Philophthalmus spp clade), echinostome cercaria (grouped with Echinostoma spp clade), furcocercous cercaria (grouped with Posthodiplostomum sp/Alaria taxideae/Hysteromorpha triloba clade), monostome cercaria (grouped with Catatropis indicus clade), parapleurolophocercous cercaria (grouped with Haplorchoides sp clade), pleurolophocercous cercaria (grouped with Centrocestusformosanus clade), transversotrema cercaria (grouped with Transversotrema spp clade), and xiphidiocercaria (grouped with Prosthodendrium spp clade). These results provide important information that can be used for identifying these parasites in epidemiological surveys. PMID- 27244957 TI - PREVALENCE OF DEMODEX ECTOPARASITES AMONG HUMANS IN ORDU PROVINCE IN TURKEY. AB - Demodex folliculorum and Demodex brevis are common ectoparasites in humans. Demodex parasite infestations have not been determined in the province of Ordu. We determined the prevalence of Demodex species among humans in Ordu Provience, Turkey. Seven hundred ninety-nine subjects (438 males and 361 females) aged >= 18 years living in the central districts of Ordu Province, Turkey, were selected using the World Health Organization cluster sampling method. A superficial skin biopsy of the face was obtained from each subject. Six hundred sixty-nine subjects (83.7%) had a Demodex parasite. Factors significantly associated with the presence of Demodex infestation were: female gender, employment in the private sector, people who only occasionally wash their face and district of residence. Since Demodex ectoparasites were common in Ordu Province, it is suggested that the diagnosis and treatment of this ectoparasite should be carried out in the hospitals of this region. PMID- 27244958 TI - HIGH RATE OF HEPATITIS B VIRUS MOTHER-TO-CHILD TRANSMISSION IN LAO PEOPLE'S DEMOCRATIC REPUBLIC. AB - Hepatitis B virus infection is endemic in Lao People's Democratic Republic (PDR). Among 3,000 pregnant women attending an antenatal clinic at Mother and Child Hospital in Vientiane, Lao PDR, 5.8% were HBsAg positive by a rapid test. Among serum samples of 47 infants aged 9-12 months born to HBsAg-positive mothers, 38% were anti-HBs negative. Percent anti-HBs negative children is significantly higher in those born to HBeAg positive mothers than in those born to HBeAg negative mothers (60% vs 25%, p < 0.05). Out of 47 HBsAg-positive mothers, 10 had infants who were HBsAg positive. None of the infants born to HBsAg negative mothers became HBsAg positive but 10/19 (52.6%) of infants born to HBeAg positive mothers became HBsAg positive. This high rate of mother-to-child transmission of HBV in an endemic country is of concern and indicates that routine vaccination program for Lao infants needs strengthening. PMID- 27244960 TI - HEPATIC LYMPHOMA AND SPLENIC ASPERGILLOSIS MIMICKING HEPATOSPLENIC ABSCESSES FROM MELIOIDOSIS IN THAILAND. AB - We report here a case of hepatic lymphoma and splenic aspergillosis in an elderly patient with diabetes mellitus, exhibiting hepatosplenic abscesses mimicking melioidosis. Immunohistochemistry confirmed the diagnosis of a diffuse hepatic large B-cell lymphoma. Biopsy of the spleen revealed a clump of fungus with a slender shape and dichotomous branching, morphologically consistent with aspergillosis. Hepatosplenic abscesses are a common presentation in melioidosis, but this case reveals this assumption can lead to misdiagnosis. Histological and microbiological confirmation are required, especially in patients with hepatosplenic lesions. PMID- 27244959 TI - AN IMPORTED CASE OF ACUTE MELIOIDOSIS CAUSED BY ST881 BURKHOLDERIA PSEUDOMALLEI. AB - A previously healthy Chinese male working in Malaysia returned to China with high fever. A blood culture showed Burkholderia pseudomallei strain WCBP1. This isolate was sequenced, showing type, ST881, which appears to be present in Malaysia. WCP1 had unusual susceptibility to aminoglycosides and habored the Yersinia-like fimbrial gene cluster for virulence. The patient's condition deteriorated rapidly but he recovered after receiving meropenem and intensive care support. Melioidosis is a potential problem among Chinese imigrant workers with strains new to China being identified. PMID- 27244961 TI - FACTORS ASSOCIATED WITH EXTENDED SPECTRUM beta-LACTAMASE PRODUCING ESCHERICHIA COLI IN COMMUNITY-ACQUIRED URINARY TRACT INFECTION AT HOSPITAL EMERGENCY DEPARTMENT, BANGKOK, THAILAND. AB - Urinary tract infection or UTI is most commonly caused by Escherichia coli. This study investigated the prevalence of and risk factors for extended spectrum beta lactamase-producing (ESBL) E. coli in community-acquired UTI presenting at the Emergency Department, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. A retrospective review was conducted over a one year period (2014) of case histories of patients over 15 years of age diagnosed with (n = 159) and without culture-positive (n = 249) ESBL E. coli. Backward stepwise multivariate logistic regression analysis revealed four independent risk factors for UTI caused by ESBL E. coli, namely, urinary catheter use, previous UTI in which ESBL E. coli was present, and previous use of antibiotics cephalosporin and penicillin. This information should be useful in devising future public health prevention and control programs for ESBL E. coli-associated community-acquired UTI. PMID- 27244962 TI - METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS: 1-YEAR COLLECTION AND CHARACTERIZATION FROM PATIENTS IN TWO TERTIARY HOSPITALS, SOUTHERN THAILAND. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen causing nosocomial and other types of infections worldwide. In a one-year survey of patients in two tertiary hospitals, namely, Maharaj Nakhon Si Thammarat and VachiraPhuket Hospitals, southern Thailand, 64 MRSA strains (prevalence of 8.1%) were obtained mainly from the elderly (> 45 years of age). PCR-based assay revealed high prevalence of virulence genes, femB (30%) and spa (34%), and of SCCmec type II from VachiraPhuket (36%) and Maharaj Nakhon Si Thammarat (38%) Hospitals. The majority of MRSA strains were resistant to clindamycin (98%), erythromycin (95%), gentamicin (84%), and tetracycline (80%), while still sensitive to chloramphenicol, cotrimoxazole, fusidic acid, and vancomycin. These data are important for effective treatment of MRSA-infected patients and for implementing control strategies to prevent spread of MRSA within hospitals. PMID- 27244963 TI - FRANCISELLA-LIKE ENDOSYMBIONT IN A TICK COLLECTED FROM A CHICKEN IN SOUTHERN THAILAND. AB - Francisella is a genus of bacterial pathogens potentially lethal to humans. We report here for the first time a novel Francisella-like endosymbiont discovered in a hard-tick (Rhipicephalus sanguineus s.l.) obtained from a chicken (Gallus domesticus) in Thailand. The phylogenetic results indicate the 16S rDNA sequences of this Francisella bacterium form a unique clade with the Francisella-like endosymbiont of the tick species, Amblyomma varanense and Amblyomma helvolum, that have previously been found on snakes in Thailand. This species of Francisella is in a different group from the other Francisella-like endosymbionts previously reported from other countries. No Francisella was detected in Haemaphysalis wellingtoni ticks obtained from chickens in this study. PMID- 27244964 TI - OVERWEIGHT, OBESITY AND ASSOCIATED FACTORS AMONG 13-15 YEARS OLD STUDENTS IN THE ASSOCIATION OF SOUTHEAST ASIAN NATIONS MEMBER COUNTRIES, 2007-2014. AB - The aim of this study was to assess overweight or obesity and associated factors in school-going adolescents in the Association of Southeast Asian Nations (ASEAN) member countries. The analysis included 30,284 school children 13-15 years of age from seven ASEAN members participating in the Global School-based Student Health Survey (GSHS) between 2007 and 2013. The overall prevalence of overweight or obesity across seven ASEAN countries (excluding Brunei) was 9.9%, significantly higher in boys (11.5%) than in girls (8.3%). Among eight ASEAN countries, the highest prevalence of overweight or obesity was in Brunei Darus-salam (36.1%), followed by Malaysia (23.7%), and the lowest was in Myanmar (3.4%) and Cambodia (3.7%). Multivariate logistic regression analysis found that younger age, coming from an upper middle country, never been hungry, and not walking or biking to school were associated with overweight or obesity. In addition, among boys, having three or more servings of vegetables per day and having no close friends, and among girls, having fast foods two or more times per week, been victims of bullying and having peer support were additional factors associated with overweight or obesity. Increased strategies utilizing a number of the risk factors identified are needed to prevent and treat overweight or obesity in adolescents in ASEAN member countries. PMID- 27244965 TI - THE RELATIONSHIP BETWEEN METABOLIC SYNDROME AND ITS COMPONENTS WITH SOCIO ECONOMIC STATUS AMONG ADOLESCENTS IN SHIRAZ, SOUTHERN IRAN. AB - The objective of this study was to investigate the relationship between metabolic syndrome and its individual components with socio-economic factors among 14-18 year-old adolescents in Shiraz, Iran. Using a multistage random sampling, a total of 538 (289 males and 249 females) adolescents consented to the study. Socio economic status was obtained using a self-administered questionnaire while presence of metabolic syndrome and its individual components was ascertained using NCEP-ATP III criteria. The relationships between the participants' socio economic status and metabolic syndrome and its components were determined using bivariate and multivariate statistical analyses. Approximately 6% of the adolescents had metabolic syndrome, with significantly more males than females (9.3% vs 2.4%, p < 0.001). The most commonly found abnormality was low high density lipoprotein cholesterol (42.4%), followed by hypertensive (16.3%). The prevalence rates of elevated triglycerides, abdominal obesity and high fasting plasma glucose were 15.6%, 8.6% and 3.1%, respectively. Metabolic syndrome was significantly more prevalent in obese participants (44.4%) than those with normal body weight (2.0%) or overweight (9.3%). There were positive associations between the components of metabolic syndrome and parental education, school location and household monthly income. Having a family history of obesity was associated with metabolic syndrome after controlling for other variables (OR = 2.1; 95% CI: 0.9 5.2, p = 0.042). Overweight and obese subjects were approximately 8 times and 15 times more likely to develop metabolic syndrome, respectively (overweight: OR = 8.2; 95% CI: 3.6-17.2; obese: OR = 15.4; 95% CI: 4.8-43.7). In conclusion, a positive association exists between socio-economic status and metabolic syndrome and its individual components among the studied participants. An intervention program to prevent metabolic syndrome needs to be developed for this young generation, especially among those who are overweight or obese and those with a family history of obesity. Keywords: adolescents, metabolic syndrome, components of metabolic syndrome, socio-economic status, Iran PMID- 27244967 TI - RATE OF ADHERENCE TO AND FACTORS ASSOCIATED WITH METHADONE MAINTENANCE TREATMENT PROGRAM (MMTP) COMPLIANCE AMONG INJECTING DRUG USE PATIENTS IN NEPAL. AB - We conducted a survey to determine the rate of adherence to and factors associated with compliance with a methadone maintenance treatment program (MMTP) among injecting drug users in Nepal. We conducted face-to-face structured interviews with 165 methadone treatment patients aged 20-54 years during 5-20 April 2015. Data analysis included percentages, means, standard deviations, chi square tests and multiple logistic regression analysis. Seventy-two point one percent of respondents had good adherence to a MMTP. Multiple logistic regression with 81.8% prediction showed respondents without a previous history of relapse were 2.7 times more likely to adhere to the MMTP than those with a history of relapse [Adjusted OR = 2.772; 95% Confidence interval (CI): 1.163-6.605]. Respondents with a good knowledge of the MMTP 9.4 times more likely to be adherent to the MMTP than those with a poor to fair knowledge of the MMTP (Adjusted OR = 9.464; 95% CI: 3.873-23.126). The likelihood of MMTP adherence was 4.5 times more likely when methadone treatment services were available than those where the availability of methadone treatment services were low to moderate (Adjusted OR = 4.553; 95% CI: 1.883-11.008). Knowledge and availability of MMTP need to be improved in the study area in Nepal. PMID- 27244966 TI - FACTORS ASSOCIATED WITH VITAMIN D STATUS AMONG THAI CHILDREN AGED 3-13 YEARS. AB - The impact of vitamin D status on bone health and other health conditions is receiving increasingly attention. We aimed to determine the association between environmental factors and vitamin D intake by examining serum 25-hydroxy vitamin D [25(OH)D] levels in Thai children. We conducted a cross sectional study among 477 Thai children from 4 regions in Thailand. Vitamin D intake was assessed using a self-administered questionnaire completed by the older children or by the parents for younger children. Dietary vitamin D intake was assessed using a semi quantitative food frequency questionnaire. A serum 25(OH)D level was examined for each subject using a chemiluminescence immunoassay. We used structural equation modeling (SEM) to assess the association between studied factors and the serum 25(OH)D level. The final model showed a significant association between sunlight exposure and the serum 25(OH)D level (beta = 0.65, p < 0.01), but not between dietary vitamin D intake and the serum 25(OH)D level (p = 0.01, p = 0.77), suggesting sunlight exposure is more important for the vitamin D status than dietary vitamin D intake. PMID- 27244968 TI - A STUDY OF THE ASSOCIATION BETWEEN SELENIUM AND CARDIOVASCULAR DISEASE IN LAMPUNG, INDONESIA. AB - Selenium deficient areas have been associated with a higher prevalence of cardiovascular disease in some countries. In this study, we investigated the correlation between cardiovascular disease prevalence and selenium concentration in paddy soil and rice grains, the main staple food in Lampung, Indonesia. Paddy soil and rice samples (n(s) = 35) from eight regencies (n(d) = 8) in Lampung were analyzed for selenium content. The prevalences of heart disease, stroke, and hypertension in those regencies were obtained from the Ministry of Health of Indonesia. The Shapiro-Wilk's test was used to examine the data distribution. The Pearson's correlation was used to examine the correlation between cardiovascular disease prevalence and selenium concentration in the paddy soil and rice grains. Heart disease prevalence was negatively correlated with the selenium concentration in the paddy soil (r = -0.77, p = 0.02) and rice grain (r = -0.71, p = 0.05). A negative correlation was seen for stroke prevalence and selenium concentration in paddy soil (r = -0.76, p = 0.02). Hypertension prevalence was negatively correlated with the selenium concentration in the rice grains (r = 0.83, p = 0.01). These findings suggest that the selenium concentration in paddy soil and rice grains in the Lampung area may play a role in the fact the area has the lowest cardiovascular disease prevalence in Indonesia. Keywords: selenium, cardiovascular diseases, paddy soil, rice grain, Indonesia PMID- 27244969 TI - MODELING FOR DEMOGRAPHIC AND REGIONAL PREVALENCE AND TRENDS OF SMOKING IN THAI MALES. AB - This study aimed to describe using national survey data the demographic and regional prevalence and trends of smoking in Thai males during the past 25 years. Data from eight national surveys conducted by the National Statistics Office from 1986 to 2011 were used to examine the prevalence of smoking. Males aged 15 and older were included in this study. Logistic regression was used to model smoking patterns, according to year of survey, age group, urbanization, and Public Health Area (PHA). The prevalence of smoking among males aged 15 years and older in 2011 was 38.4%. Sharply increasing smoking prevalence was found in the 15-24 years-old age group in all surveys. Before survey year 1999, the prevalence of smoking started to level off near retirement age, and subsequently, it leveled off after 40 years of age. The prevalence of smoking in all age groups decreased after 1986 except in the 15-19 years-old age group. Higher prevalence of smoking was found in rural areas. Males from the Northeast and the lower South regions had the highest prevalence. More effective anti-smoking policies should focus on males aged below 25 years to reduce the increasing prevalence of smoking in this group. PMID- 27244970 TI - EPIDEMIOLOGICAL PATTERNS OF TRANSPORT ACCIDENT MORTALITY IN THAILAND. AB - This study aimed to explore patterns of transport accident mortality in Thailand between 2004 and 2009. Vital Registration (VR) data were obtained from the Thai Ministry of Public Health and corrected causes of death were derived from Verbal Autopsy (VA) data collected in 2005. A total of 136,164 deaths were analyzed. Poisson regression was used for identifying mortality patterns with respect to gender-age groups and province-year groups. Regression coefficients were used to classify mortality trends for the 76 provinces. The estimated number of transport accident deaths was 2.2 times higher than VR records. The mean estimated transport accident mortality rate was 34.5 per 100,000 population. The estimated transport accident mortality rates were highest among males aged 20-29 years and in the central region, lower northern region and Nakhon Ratchasima Province in the northeastern region. The patterns of transport accident mortality rates were separated into nine groups. Increasing trends were found in three provinces in the northern region, four provinces in the central and eastern regions and five provinces in the southern region. Nine models developed for these nine groups may be helpful for estimating future transport accident mortality rates in Thailand and developing appropriate responses. PMID- 27244972 TI - From HFMA's Leadership magazine. Going to School on Population Health Management: An interview with David Nash, MD, MBA. PMID- 27244971 TI - COMPARISON OF CHILDREN'S FOLLOW-ON INSTANT POWDERED COW'S MILK FORMULA, BUFFALO MILK FORMULA AND CHICKEN-BASED FORMULA ON ENAMEL MICROHARDNESS OF BOVINE TEETH IN VITRO. AB - Dental caries are a major public health problem worldwide. The aim of this study was to compare the effects of children's follow-on instant powdered cow's milk formula, buffalo milk formula and a chicken-based formula on microhardness of bovine enamel with artificial caries-like lesions. Forty bovine teeth were each placed in acrylic blocks and the enamel surfaces were polished to create flat 5 x 5 millimeter surfaces. The teeth surfaces were then demineralized using 0.1M lactic acid (pH 4.5) to achieve an enamel microhardness of 35-65 Vickers Hardness Numbers (VHN). All specimens were then randomly allocated into one of 4 groups (n=10/group). For remineralization, each group was soaked in a different kind of milk formula for 2 hours at 37 degrees C except group 1 which was a negative control (artificial saliva) group. Group 2 was soaked in MurrahTM buffalo milk formula (a positive control ), group 3 in S-26-Promil-GoldTM (cow's milk formula) and group 4 in a chicken-based formula (Siriraj Hospital, Mahidol University). The microhardness of the specimens was then measured again. Data were analyzed using a one-way ANOVA and paired t-test with a 95% confidence interval. After exposure to the formula, the mean VHN for each study group was significantly higher (paired t-test, p < 0.05) except for group 1 (p = 0.345). The mean VHN for the the MurrahTM buffalo milk formula, the chicken-based formula and the S-26 Promil-GoldTM formula group were not significantly different from each other (one way ANOVA, p > 0.05). In conclusion, S-26-Promil-GoldTM follow-on cow milk formula, MurrahTM buffalo milk formula and the chicken-based formula all increased bovine enamel microhardness after soaking for 2 hours. PMID- 27244973 TI - Margins under pressure. PMID- 27244974 TI - Improvement over disruption. AB - Although healthcare organizations typically shy away from undertaking multiple systemwide changes all at once, such reticence may limit potential improvements. When Stanford Children's Health undertook several major information system changes as part of a single, overarching initiative, three imperatives quickly emerged. Focus on automating processes through technology, and don't underestimate the impact of seemingly minor improvements. Zero in on manual processes, and seek technological solutions. Don't just automate-simplify. PMID- 27244975 TI - Proposed reporting model update creates dialogue between FASB and not-for profits. AB - Seeing a need to refresh the current guidelines, the Financial Accounting Standards Board (FASB) proposed an update to the financial accounting and reporting model for not-for-profit entities. In a response to solicited feedback, the board is now revisiting its proposed update and has set forth a plan to finalize its new guidelines. The FASB continues to solicit and respond to feedback as the process progresses. PMID- 27244976 TI - Managing risk in today's healthcare M&A transaction. AB - Beyond customary business diligence, mergers in the healthcare arena must clear an array of federal and state regulatory hurdles and compliance risks that have grown more pronounced in recent years. Primary challenge are posed by: Antitrust issues. Licensing and compliance practices. Data privacy and security. Payment and revenue stability. Cultural fit and post-merger integration. PMID- 27244977 TI - The great risk shift: a strategic road map for providers. AB - Healthcare providers that are assessing their readiness to assume financial risk for care delivery should understand the full range of risk options available to them. Available options fall into two broad categories: episode-based risk (e.g., the Medicare BPCI initiative and CJR model, commercial insurance models, and direct-to-employer models) and population-based risk (e.g., shared savings models and professional or institutional capitation models). Providers also require a deep understanding of both internal and market-based factors that are essential for success under any risk option being contemplated. PMID- 27244978 TI - Producing an ROI with a PCMH. AB - Although the expense of establishing a patient-centered medical home can be high, an organization can improve its ROI from adopting such a care delivery model by following four basic guidelines: Align care with payment. Develop a realistic timeline. Define expenses. Identify new revenue streams. PMID- 27244979 TI - The complexity and value of mid-level patterns of denials. AB - Finding patterns in denied claims makes the task of correcting and resubmitting them far more efficient. But ICD-10 exacerbates the problem. As use of ICD-10 grows, it will: Increase the number of codes substantially, increasing the granularity of data being captured about each claim, and combinatorial complexity will explode. Alter both payer and provider behavior, blowing away carefully cultivated pockets of tribal knowledge. Significantly challenge any method that uses the hierarchy or heuristics of existing code sets, rendering many software stopgaps useless. Spread codes far more broadly for a given procedure, making patterns far more difficult to detect using traditional analytics. PMID- 27244980 TI - Aligning incentive payments with outcomes: lessons from a Medicaid Section 1115 waiver program. AB - By obtaining a Medicaid waiver under Section 1115 of the Social Security Act, many states have taken advantage of an opportunity to innovate and transform their Medicaid programs. The Center for Medicare and Medicaid Innovation has granted Section 1115 waivers to several states to develop Delivery System Reform Incentive Payment (DSRIP) programs, which vary in their federal funding pools, structures, and goals, but share key characteristics, such as the withholding of payment until certain milestones and metrics are met. The DSRIP project in New York--as exemplified by Finger Lakes Performing Provider System--is being closely watched across the country as CMS and state Medicaid programs contemplate similar measures to transform Medicaid and bend its cost curve. PMID- 27244981 TI - When leaders see eye to eye. PMID- 27244982 TI - Healthcare reform and the presidential election campaign. PMID- 27244984 TI - Trends in insured versus uninsured patient debt. PMID- 27244985 TI - Oral Cancer Marches On. PMID- 27244983 TI - Implications of the Federal Reserve's actions for healthcare borrowers. PMID- 27244986 TI - Plea From an Oral Cancer Survivor. PMID- 27244987 TI - FOCUS ON: Treatment Planning for Success. PMID- 27244989 TI - The Demise of the Dreaded Dental Drill? PMID- 27244988 TI - Here, There, and Everywhere. PMID- 27244990 TI - DENTSPLY International and Sirona Dental Systems Complete Merger. PMID- 27244991 TI - The Importance of Increasing the Success Rate. A Look at Procedures, Factors, and Clinical Practices. PMID- 27244992 TI - Creating Well-Obturated Canals. The Use of Warm Vertical Condensation Techniques. PMID- 27244993 TI - The Implant Practice. PMID- 27244994 TI - The Implant Practice. PMID- 27244995 TI - A Simple and Cost-Effective Socket Preservation Technique. PMID- 27244996 TI - Composite Versus Porcelain, Part 2. The 360 degrees Composite Resin Veneer. PMID- 27244997 TI - Clinical Tips to Ensure Successful Whitening Outcomes. PMID- 27244998 TI - Selecting Ideal Materials for Full-Mouth Rehabilitation. PMID- 27244999 TI - Aesthetic Implications of Restorative Material Choice. Considering Soft-Tissue Factors. PMID- 27245000 TI - Seven Protective Reflexes Every Dentist Should Know. PMID- 27245001 TI - [Dose-Response Dependences for Frequency of RET/PTC Gene Rearrangements in Papillary Thyroid Carcinoma after Irradiation. Simple Pooling Analysis of Molecular Epidemiological Data]. AB - On the basis of all possible publications on the theme included in the previously formed base of sources on molecular epidemiology of RET/PTC rearrangements in thyroid papillary carcinoma a pooled analysis ("simple pooling data") on determination of the dose-effect dependences for RET/PTC frequency in radiogenic carcinomas of various irradiated groups was performed. (They are groups subjected to radiotherapeutic exposure, residents near the Chernobyl nuclear power plant (CNPP) and victims of nuclear bombing). The tendency to Pearson linear correlation (r = 0.746; p = 0.148) between the frequency of RET/PTC and the estimated dose on thyroid in the regions affected by the CNPP accident was revealed. But this tendency was recognized to be random owing to abnormally low values of the indicator for the most contaminated Gomel region. The method tentatively called "case-control" showed reliable differences in thyroid dose values for carcinomas with RET/PTC and without those. The versatility of changes was found: the lack of RET/PTC for radiotherapeutic impacts was associated with higher doses, whereas in case of the CNPP accident and for nuclear bombing victims it was the opposite. Probably, in the first case the "cellular cleaning" phenomenon after exposure to very high doses took place. Search of direct Pearson correlations between average/median thyroid doses on groups and RET/PTC frequency in carcinomas of these groups showed a high reliability for the dose-effect dependences- at the continuous dose scale (for RET/PTC in total and RET/PTC1 respectively: r = 0.830; p = 0.002 and r = 0.906; p = 0.0003); while there was no significant correlation received for RET/PTC3. When using the weighting least square regression analysis (proceeding from the number of carcinomas in samples), the specified regularities remained. Attempts to influence the strength of correlation by exception ofthe data of all the samples connected with the accident on the CNPP did not significantly reduce the strength of associations for RET/PTC in total. On the basis of ordinal scale doses (background, "low" (0.1 Gy), "middle" (0.1-1 Gy) and "large" (1-10 Gy) dose) also found was a significant correlation (Spearman) with the dose for the frequency RET/PTC in total (r = 0.736; p = 0.0098), but for certain types of rearrangements the results were reverse to the previous analysis (the effect was significant only for the RET/PTC3: r = 0.731; p = 0.024). The linear dose-response trends of the Cochrane Armitage-test for the frequency of RET/PTC in total, RET/PTC1 and RET/PTC3 depending on the dose to the thyroid in the ordinal scale were registered (p, respectively: < 0.0001 < 0.0001 and 0.007). Thus; after more than 20 years of the molecular and epidemiological research of RET/PTC in thyroid radiogenic carcinomas the comprehensive evidence of the dose-effect dependence existence indicating a real relationship between the studied parameters and a radiation factor was obtained for the first time. PMID- 27245002 TI - [Apoptosis of Peripheral Blood Lymphocytes in the Members of the Techa River Cohort Chronically Exposed to Radiation]. AB - The purpose of the present research was to estimate the intensity of the apoptotic death of lymphocytes during the period of carcinogenic effect realization in the residents of the Techa riverside villages. The investigation included analyses of the frequency of lymphocytes at the early and late stages of apoptosis and necrosis of peripheral blood lymphocytes using the method of FITC Annexin V, lymphocyte counts at the stage of DNA fragmentation using the TUNEL method, and the number of CD95(+)-lymphocytes. In the capacity of additional tests, loading tests involving in vitro irradiation at the dose of 1 Gy of a suspension of lymphocytes and incubations for 5 and 24 hours were used. Activation of the initial apoptotic and necrotic death of peripheral blood lymphocytes was revealed in the persons chronically exposed to low-intensity radiation within the range from 0.01 to 4.23 Gy. Exposed patients demonstrated a decrease in the number of CD95(+)-cells as compared to unexposed patients. The results of the cell death studies in the persons residing in the Techa riverside villages testify indirectly to the genomic instability of the peripheral blood lymphocytes. PMID- 27245003 TI - [Effects of Low and Sublethal Doses of gamma-Radiation on Mesenchymal and Neural Stem Cells from Mouse Brain]. AB - Mesenchymal stem cells (MSC) exist in the brain in addition to the neural stem cells (NSC). The aim of this work was to investigate the sensitivity of mouse brain MSC (MSC(BR)) to sublethal doses of gamma-radiation in comparison with the sensitivity of bone marrow MSC (MSC(BM)) and NSC and to study the effects of gamma-irradiation at low doses on these cells. Cells were exposed to gamma radiation (137Cs) at the doses of 10 to 200 mGy at a dose rate of 10 mGy/min; higher doses were achieved at the dose rates of 200 and 500 mGy/min (60Co). The survival of cells was assessed by counting living cells after staining with trypan blue in the Goryaev's chamber or using the MTT test for NSC growing as neurospheres. SP fraction was measured using flow cytometry after incubation with rhodamine-123. Exposure to the doses in the range of 10 to 500 mGy stimulated cell proliferation. The maximum decrease in the cells number was seen on the seventh day after irradiation and it was practically the same for the MSC(BR) and MSC(BM). NCS were more radiosensitive than MSC. Exposure to the doses of 100 to 500 mGy stimulated cells proliferation of all SCs except of MSC(BM). It was shown that the size of SP fraction of MSC(BR) was diminished after gamma-irradiation at low doses. Thus, the stimulation of cell proliferation after gamma-irradiation at low doses is accompanied by the redistribution of distinct cell subpopulations: the decrease in the SP fraction and the increase in the general population of cells were observed. PMID- 27245004 TI - [The Influence of the Ionizing Radiation on the Development of Atherosclerosis]. AB - The results of the epidemiological research of the last decade demonstrate the increased risk of circulatory system diseases in the cohorts of people exposed to professional, anthropogenic or medical irradiation, which causes the development of atherosclerosis of the vessels. It was shown that ionizing radiation is one of the promoters of the development of atherosclerosis. PMID- 27245005 TI - [Effect of External Irradiation and Immobilization Stress on the Reproductive System of Male Rats]. AB - We studied the state of the reproductive system of male rats after irradiation at a dose of 2.0 Gy, immobilization stress (6 hours/day for 7 days) and their combined effects. On the 30th day after the combined treatment (37 days after irradiation) a decrease in the testicular weight by almost 50% compared with the control and lesions connected with the process of spermatogenesis are observed. In the remote period--on the 60th day (67th after irradiation) the effect of irradiation and irradiation in combination with immobilization stress leads to a sharp drop in the number of epididymal sperm (up to 18% of the control), and a reduction of their viability. The reaction ofthe reproductive system to the immobilization stress is expressed in a certain increase in the mass of the testes and epididymis, moderate imbalances in the composition of spermatogenic cells in the testis tissue, and in the long term--in the increased number of epididymal sperm and the decrease in their viability. Changes of testosterone in the blood serum, especially significant for the combined effect, reflect impairments of the regulation of the reproductive system of males under these conditions. With regard to individual indicators of the reproductive system of male rats in some cases, the- combined effects of radiation and stress had a synergistic, or, on the contrary, antagonistic character. PMID- 27245006 TI - [Administration of Palonosetron and Phenotropil for Prophylaxis of the N-V-D Stage of Acute Radiation Syndrome]. AB - Experiments on small (rats) and large (dogs) animals have shown that a sequential administration of Palonosetron and Phenotropil decreases the intensity of the main manifestations of the N-V-D stage of acute radiation syndrome. These data show the appropriateness of a combined administration of Palonosetron and Phenotropil to prevent a reduced work capacity in the individuals participating in elimination of the consequences of accidents associated with overexposure to radiation. PMID- 27245007 TI - [The Influence of UV-Light on the Sub-Populational Composition and Expression of Membrane Markers of Lymphocytes of Donor Blood]. AB - The influence of UV-light (240-390 nm) at dozes of 151 and 755 J/m2 on the content of membrane markers of lymphocytes using the method of flow cytometry was investigated. It was demonstrated that during incubation of UV-irradiated lymphocytes the change of their populational and sub-populational composition occurs. Expression of complexes of CD3, CD 19,.CD8, CD 16, CD25 and CD95 increased. This increase was caused mainly by de novo synthesis. UV-light had immunostimulating effect on CD8+ T-lymphocyte population. Together with the increase of cytotoxic cells and NK-cells, activation of lymphocytes (increased amount of CD25+ and CD95+ cells) took place. Amount of cells undergone apoptosis or necrosis increased proportionally to the dosage. These changes were more expressed during incubation of lymphocytes in nutrition medium without autological blood serum, e.g. under deficiency of growth factors and antioxidants. PMID- 27245008 TI - [Role of Radionuclide Technologies in Medicine]. AB - The paper describes the role of radionuclide technologies among the nuclear physical methods used in medicine. The condition and prospects of the development of nuclear technology with use of radionuclides in medicine, and in particular, the method of brachytherapy are analyzed. The analysis of the current state of applying radionuclide facilities in medicine is provided. PMID- 27245009 TI - [Methodological Approaches to the Organization of Counter Measures Taking into Account Landscape Features of Radioactively Contaminated Territories]. AB - Methodological approaches to the organization of counter measures are considered taking into account the landscape features of the radioactively contaminated territories. The current status and new requirements to the organization of counter measures in the contaminated agricultural areas are analyzed. The basic principles, objectives and problems of the formation of counter measures with regard to the landscape characteristics of the territory are presented; also substantiated are the organization and optimization of the counter measures in radioactively contaminated agricultural landscapes. PMID- 27245010 TI - [Tritium in the Water System of the Techa River]. AB - The aim of the paper is to study modern tritium levels in various sources of the drinking water supply in the settlements situated in the riverside zone of the Techa. Almost everywhere the water entering water-conduit wells from deep slits (100-180 m) contains averagely 2-3 times higher tritium concentrations than the water from less deep personal wells, slits and springs. Tritium levels in the drinking water supply decrease with the distance from the dam; while in wells, springs and personal wells they are constant all along the river. The observed phenomenon can be explained by the fact that the river bed of the Techa is situated at a break zone of the earth crust, where the contaminated deep water penetrates from the reservoirs of the "Mayak" enterprise situated in the upper part of the regulated river bed. Less deep water sources (personal wells, slits and springs) receive predominantly flood, atmospheric and subsoil waters and are not connected with the reservoirs. PMID- 27245011 TI - [In Memory of Yuri Borisovich Kudryashov]. PMID- 27245012 TI - [To explore evidence evaluation for harm: establishing the body of evidence for harm for postmarketing traditional Chinese medicine]. AB - There has been much difference between effectiveness and harm in evidence evaluation. Many evidence ranking or grading systems have been developed'by researchers in the world. However, no evidence ranking or grading systems are based on safety research reality. Those existing evidence ranking or grading systems are prone to evaluating effectiveness evidence not proper for harm evidence. It is necessary to develop a new system for harm evidence. We put forward to establishing the body of evidence for harm for postmarketing traditional Chinese medicine as required by our daily research work. We do hope such an ideal could be helpful and indicative for evidence evaluation for harm. PMID- 27245013 TI - [Application analysis of adverse drug reaction terminology WHOART and MedDRA]. AB - Drug safety has always been a global focus. Discovery and accurate information acquisition of adverse drug reaction have been the most crucial concern. Terminology of adverse drug reaction makes adverse reaction medical report meaningful, standardized and accurate. This paper discussed the domestic use of the terminology WHOART and MedDRA in terms of content, structure, and application situation. It also analysed the differences between the two terminologies and discusses the future trend of application in our country PMID- 27245014 TI - [An introduction of RECORD and GRACE checklist for studies in real world]. AB - Statement of the REporting of studies conducted using routinely collected data (RECORD) and evaluating checklist of good research for comparative effectiveness (GRACE) were translated and introduced in this paper. The two evaluation tools would help researchers of Chinese medicine to conduct real world study in future. RECORD statement focus on unique aspects of studies conducted with routinely collected health data and the perceived need for better reporting of methodological issues. Researchers of comparative effectiveness research could refer to GRACE checklist. It was believed that researchers of Chinese medicines who were keen on real world studies would be benefited from the two tools. PMID- 27245015 TI - [Clinical safety studies based on 30 026 post-marketing cases of Shenqi Fuzheng injection by intensive hospital monitoring nested NCCS]. AB - This study adopted a large sample, multicenter, registered hospital centralized monitoring nested prospective case-control study design. From the real world clinical application of Shenqi Fuzheng injection, monitored 30 026 cases of patients with the use of Shenqi Fuzheng injection. A total of 51 adverse drug reaction (ADR) cases was monitored, including 1 case of severe adverse reactions. ADR incidence rate was 1.7 per 1,000. Blood samples were collected from patients with allergic reactions and their matched controls. Related biological indicators of allergic reactions were unified detected and analysed in order to explore the mechanism of allergic reaction and promote the clinical safety. PMID- 27245016 TI - [Analysis of influencing factors on adverse reaction of Shengfu injection based on prospective active safety monitoring]. AB - This study collected demographic data, past history, personal history, family history, dosage, solvent, combined medication information of adverse reaction cases from a prospective, multi center, large sample intensive hospital monitoring, and found the influencing factors with cross-tab analysis. The results showed that in the medication group of 19-45, patients with allergic histories had a higher proportion in ADR; in the medication group of 46-65, male patients with allergic histories had a higher proportion in ADR; indication and non-indication group, patients of 19-45 years old, with combined medications and allergy histories had a higher proportion in ADR; Non-indication medication group, patients with combined medication, higher concentration, out-instruction solvent and dosage, had a higher proportion in ADR. So, the ADRs of Shenfu injection were related to the history of drug allergy, and also related to the indication, dosage, solvent, concentration when it was used. PMID- 27245017 TI - [Post-marketing clinical safety assessment of Shenmai injection based on active monitoring and passive monitoring in large data background]. AB - This paper adopted a series of related analysis methods to comprehensively analyze post-marketing clinical safety data of Shenmai injection from 4,220 cases of SRS and 32,358 cases of multicenter, prospective, registered hospital centralized monitoring in large data background, calculated ADR incidence rate was 0.93 per 1,000, main symptoms of ADR includes chest pain, chills, skin itching, palpitations, fever, nausea, dizziness, vomiting, flushing, numbness, allergic reaction, cyanosis, rash, low back pain, and "breath", "anaphylactoid reaction" and "flush" were the safety warning signals of Shenmai injection. Primary disease for chronic pulmonary heart disease, thyroid disease, and combined with cerebral vascular disease, prior to the injection and continuous use of alprostadil, cyclic adenosine monophosphate, combined with quinolones, penicillins were suspicious influence factors of ADR of Shenmai injection, these promot the clinical safety. PMID- 27245018 TI - [A postmarketing surveillance study on 31,724 patients using Dengzhan Xixin injection in hospital]. AB - Aim to explore the adverse drug reactions (ADR) characteristic and calculate the ADR incidence of Dengzhan Xixin injection (DZXX). A multicenter, large sample, and prospective cohort study was conducted from August 2012 to December 2014. A total of 31 724 patients using DZXX were observed. A total of 31 724 patients with 15 ADR cases among 31 724 patients, accounting for 0.06% , were reported. There were 8 male patients ADRs and 7 female patients with ADRs. ADRs included skin rashes, itching, headache, red face, abdominal pain, etc. 1 case with rhubarb radix scutellariae allergies. These ADRs happened from 5 min to within 0.5 h after DZXX were used to treat patients. ADR patients discontinued treatment, of which 2 patients used promethazine for recovery and improvement. There were 2 cases with different DZXX concentration, out of the normal range. DZXX injection could cause some ADRs. Users must not ignore these and be careful of its related side effects. This study was a cohort with large sample, which should produce strong evidence for clinical practice. However, there was still weak evidence to conclude that it was a safe Chinese medicine injection in clinical practice. PMID- 27245019 TI - [Analysis of the allergic reaction types of Chinese medicine injection based on immunotoxicty]. AB - The purpose of the study is to find the allergic reaction types and characteristics of Chinese medicine injection ( CMI). The authors monitored patients who used Shuxuetong injection, Dengzhan Xixin injection, Shenqi Fuzheng injection, Shenmai injection, Ciwujia injection, Shuxuening injection, Tanreqing injection, Reduning injection, a total of 150,000 cases were monitored. They used a nested case-control design to group the patients and obtained the serum samples from 14 allergic patients and 55 matched patients. They used enzyme-linked immunosorbent assay (ELISA) to detect serum C3, C4, IgE, IgG, MCT-P, and judge the allergic reaction types: Shuxuetong injection hypersensitivity (1 case), can not determine (1 case); Dengzhan Xixin injection hypersensitivity (1 case), hypersensitivity & anaphylactoid reaction (1 case), can not determine (1 case); Shenqi Fuzheng injection hypersensitivity (3 cases), can not determine (1 case); Shenmai injection anaphylactoid reaction (1 case); Ciwujia injection can not determine (1 case), Shuxuening injection can not determine (1 case), Tanreqing injection can not determine (1 case), Reduning injection can not determine (1 case). The results showed that the main type of allergic reaction of CMI was hypersensitivity, the type of allergic reaction was closely related to the varieties of CMI, the hypersensitivity and anaphylactoid reaction might occur in one patient at the same time which used Dengzhan Xixin injection. PMID- 27245020 TI - [Construction and implementation of quality control index for clinical safety of Chinese medicine injection]. AB - In order to ensure the authenticity and accuracy of traditional Chinese medicine injection safety monitoring data, Chinese medicine injection safety monitoring quality control indicators, including the monitoring center, monitoring personnel, hardware conditions, monitoring progress and the number of patients into the group, original documents and archives management, electronic data, adverse events, quality management were constructed. Its application in the creation of major new drugs technology major projects, 10 kinds of traditional Chinese medicine injections clinical safety monitoring quality control work, found the missing case surveillance, not reported adverse events, only reported adverse reactions, electronic data reporting lag, lack of level of efforts to control the problem, and corrected, the traditional Chinese medicine injection safety monitoring of quality control and quality assurance, and subsequent Chinese medicine safety monitoring quality control to provide the reference. PMID- 27245021 TI - [Incidence rate of adverse reaction/event by Qingkailing injection: a Meta analysis of single rate]. AB - To systematically review the incidence rate of adverse drug reaction/event by Qingkailing injection. Such databases as the PubMed, EMbase, the Cochrane library, CNKI, VIP WanFang data and CBM were searched by computer from foundation to July 30, 2015. Two reviewers independently screened literature according to the inclusion and exclusion criteria, extracted data and cross check data. Then, Meta-analysis was performed by using the R 3.2.0 software, subgroup sensitivity analysis was performed based on age, mode of medicine, observation time and research quality. Sixty-three studies involving 9,793 patients with Qingkailing injection were included, 367 cases of adverse reactions/events were reported in total. The incidence rate of adverse reaction in skin and mucosa group was 2% [95% CI (0.02; 0.03)]; the digestive system adverse reaction was 6% [95% CI(0.05; 0.07); the injection site adverse reaction was 4% [95% CI (0.02; 0.07)]. In the digestive system as the main types of adverse reactions/events, incidence of children and adults were 4.6% [0.021 1; 0.097 7] and 6.9% [0.053 5; 0.089 8], respectively. Adverse reactions to skin and mucous membrane damage as the main performance/event type, the observation time > 7 days and <= 7 days incidence of 3% [0.012 9; 0.068 3] and 1.9% [0.007 8; 0.046 1], respectively. Subgroup analysis showed that different types of adverse reactions, combination in the incidence of adverse reactions/events were higher than that of single drug, the difference was statistically significant (P < 0.05). This study suggested the influence factors of adverse reactions occur, and clinical rational drug use, such as combination, age and other fators, and the influence factors vary in different populations. Therefore, clinical doctors for children and the elderly use special care was required for a clear and open spirit injection, the implementation of individualized medication. PMID- 27245022 TI - [Advantages of population pharmacokinetics and its application in the field of traditional Chinese medicine]. AB - The accurate medical treatment is based on the information of the genome, which is the best treatment for the patients. Population pharmacokinetic study can be formulated according to the individual differences of patients to the dose, in the accurate medical model which has a unique advantage. At present, there are many problems such as adverse drug reaction in Chinese traditional medicine, and it is necessary to introduce a group of medicine on the basis of precise medical treatment. However, due to the different characteristics of traditional Chinese medicine and chemical medicine, it is necessary to combine the population pharmacokinetics, genetics and statistical methods to establish a research method which is in line with the characteristics of Chinese medicine. The key scientific problem is to make clear the active components of Chinese medicine metabolism of the drug metabolic enzyme gene, and pay attention to the analysis of the polymorphism of the overall role of drug metabolism enzymes in the human body. Clear key scientific issues and break through the bottleneck, so as to achieve the precise medical treatment, to international. PMID- 27245023 TI - [Complex network analysis on dynamic change regularity of combining use of Chinese and western medicine in 27,678 cases with ischemic stroke in acute phase]. AB - The acute phase of ischemic stroke patients are often treated with both Chinese patent medicine:and western medicine therapies in clinical practice. This research included 27,678 cases of the acute phase of ischemic stroke came from 14 3A level hospitals. We collected data from patients with ischemic stroke who used both Chinese patent medicine and western medicine and were hopitalized within 14 days from hospital information system (HIS). Constructing complex network of Chinese patent medicine and western medicine were found to show scale-free network. Hierarchical structure of the core algorithm was used to analyze the characteristics of combined core Chinese patent medicine and western medicine in admission condition of "acute", "critically", and "general" of ischemic stroke acute phase patient within one day, 2-3 days, 4-7 days and 8-14 days. We found that the core Chinese patent medicine mainly used for activate blood and resolve stasis medicine, and phlegm eliminating brain refreshing medicine in all kinds of patients, but the phlegm eliminating brain refreshing medicine were used to reduce with time elapsing. The core western medicine mainly used for anti platelet medicine, improve circulation medicine, neuroprotective medicine, anticoagulants medicine and dehydration medicine. The dehydration medicine as the core western medicine for critically patients within 14 days, but the patients for general admission as core western medicine within 3 days. The neuroprotective medicine was used to decreases after 7 days in hospital. Combination of Chinese patent medicine and western medicine were mainly for neuroprotective medicine + activate blood and resolve stasis medicine, and anti-platelet medicine + activate blood and resolve stasis medicine, and improve circulation medicine + activate blood and resolve stasis medicine. The phlegm eliminating brain refreshing medicine was mainly combined with neuroprotective medicine by urgent and general admission condition patients, and it was more combined with dehydration medicine by critically admission condition patients. This research found that the dynamic characteristics for the combination of Chinese patent medicine and western medicine of acute phase of ischemic stroke patients by big data analytics and complex networks modeling, and provide basis for acute phase of ischemic stroke patients, it provide basis for ischemic stroke treatment strategy making. PMID- 27245024 TI - [Explore Xueshuan Xinmaining tablet effecting on treatment outcome of coronary heart disease based on propensity score]. AB - Xueshuan Xinmaining tablet is a Chinese patent medicine for treating chest pain caused by blood stasis. It is widely used in clinical prevention and treatment of coronary heart disease. In order to understand the treatment effect of Xueshuan Xinmaining tablet in patients with coronary heart disease, we extracted electronic medical record data from 18 large hospitals nationwide. We matched the coronary artery disease patients with or without Xueshuan Xinmaining tablet treatment on gender, age, condition at admission and whether combined with cardiac insufficiency on a one to one ratio. After matching, both groups, patients using Xueshuan Xinmaining tablet (group A) and patients not using Xueshuan Xinmaining tablet (group B), ended up with 1,122 people. In order to evaluate the effectiveness of treatment, the endpoint of effective group was defined as "cure" and "better" while the endpoint of invalid group was defined as "invalid" and "death". Chi-square test showed a statistical significant difference (P < 0.05) between the two groups of patients with coronary heart disease, with a higher efficiency in Xueshuan Xinmaining group. Classic logistic regression analysis showed no statistical significant difference between the two groups on treatment outcome efficiency. Generalized boosted models (GBM) and propensity score (PS) weighted Logistic regression were then applied to balance 45 variables between the two groups. The results showed a regression coefficient greater than 0 and a statistical significant difference (P < 0.05) between the two groups. Based on the existing results of the analysis, we considered that coronary heart disease patients using Xueshuan Xinmaining tablet had a higher efficiency in clinical efficiency than the patients not using Xueshuan Xinmaining tablet. Since this study did not certainly eliminate all the possible confounders and patients from the hospitals included in this study were not yet well represent the overall situation of the source population, the study conclusion only provided drug use reference for clinical doctors for coronary heart disease. Large randomized controlled trials needs to be done for more reliable results to guide clinical rational and effective medication. PMID- 27245025 TI - [Recent advances in natural product induced DNA damage response in cancer cells]. AB - The DNA structures could be altered or even damaged by exogeous or endogenous factors during cell proliferation. Failure of effective and timely repair will lead to cell cycle arrest or apoptosis. By taking the advantage of the quick proliferation of cancer cells, DNA damage induction, cell cycle arrest and apoptosis promotion have become important strategies for ant-cancer chemotherapy. Previous reports showed that an array of natural compounds inhibit cancer cell proliferation by inducing DNA damage, which have therapeutic potentials for anti cancer drug research and development. PMID- 27245026 TI - [Research progress on anti-tumor effect of Huaier]. AB - Huaier (Trametes robiniophila) has been widely used as an adjuvant drug for cancer treatment in China. The anti-cancer effect of Huaier extract has been confirmed in liver cancer, lung cancer, breast cancer, ovarian cancer, gastric cancer, and so on. The main mechanisms by which Huaier exerts an anti-neoplastic effect include inhibition of the growth and proliferation of cancer cells, induction of apoptosis of cancer cells, suppression of angiogenesis, inhibition of the invasion and migration of cancer cells, regulation of oncogenes and tumor suppressor genes expression, improving immunity, and reversal of drug resistance in cancer cells. In order to provide references for further study and clinical application on anti-tumor effect of Huaier, the latest research progress on anti tumor effect of Huaier in recent years is summarized in this paper. PMID- 27245027 TI - [Advances in study of anticancer properties of Allii Macrostemonis Bulbus]. AB - A commonly used Chinese crude drug Allii Macrostemonis Bulbus has been shown to possess good anticancer activities and related properties such as antioxidation, nitrite scavenging, nitrosamine synthesis blocking and immune enhancement, and has been widely used as an effective auxiliary drug in the treatment of some malignant tumors. This paper systematically reviews the advances in the study of anticancer-related activities of Allii Macrostemonis Bulbus's various components such as raw juice, extracts, saponins, volatile oil, polysaccharides, nitrogen compounds, etc. PMID- 27245028 TI - [De novo sequencing and analysis of root transcriptome to reveal regulation of gene expression by moderate drought stress in Glycyrrhiza uralensis]. AB - Moderate drought stress has been found to promote the accumulation of active ingredients in Glycyrrhiza uralensis root and hence improve the medicinal quality. In this study, the transcriptomes of 6-month-old moderate drought stressed and control G. uralensis root (the relative water content in soil was 40%-45% and 70%-75%, respectively) were sequenced using Illumina HiSeq 2000. A total of 80,490 490 and 82 588 278 clean reads, 94,828 and 305,100 unigenes with N50 sequence of 1,007 and 1,125 nt were obtained in drought treated and control transcriptome, respectively. Differentially expressed genes analysis revealed that the genes of some cell wall enzymes such as beta-xylosidase, legumain and GDP-L-fucose synthase were down-regulated indicating that moderate drought stress might inhibit the primary cell wall degradation and programmed cell death in root cells. The genes of some key enzymes involved in terpenoid and flavonoid biosynthesis were up-regulated by moderate drought stress might be the reason for the enhancement for the active ingredients accumulation in G. uralensis root. The promotion of the biosynthesis and signal transduction of auxin, ethylene and cytokinins by moderate drought stress might enhance the root formation and cell proliferation. The promotion of the biosynthesis and signal transduction of abscisic acid and jasmonic acid by moderate drought stress might enhance the drought stress tolerance in G. uralensis. The inhibition of the biosynthesis and signal transduction of gibberellin and brassinolide by moderate drought stress might retard the shoot growth in G. uralensis. PMID- 27245029 TI - [Cloning and tissue expression of 4-coumarate coenzyme A ligase gene in Angelica sinensis]. AB - 4-coumarate coenzyme A ligase is a key enzyme of phenylpropanoid metabolic pathway in higher plant and may regulate the biosynthesis of ferulic acid in Angelica sinensis. In this study, the homology-based cloning and rapid amplification of cDNA ends (RACE) technique were used to clone a full length cDNA encoding 4-coumarate coenzyme A ligase gene (4CL), and then qRT-PCR was taken for analyzing 4CL gene expression levels in the root, stem and root tissue at different growth stages of seedlings of A. sinensis. The results showed that a full-length 4CL cDNA (1,815 bp) was obtained (GenBank accession number: KT880508) which shares an open reading frame (ORF) of 1 632 bp, encodes 544 amino acid polypeptides. We found 4CL gene was expressed in all tissues including leaf, stem and root of seedlings of A. sinensis. The expressions in the leave and stem were increased significantly with the growth of seedlings of A. sinensis (P < 0.05), while it in the root showed little change. It indicates a time-space pattern of 4CL gene expression in seedlings of A. sinensis. These findings will be useful for establishing an experiment basis for studying the structure and function of 4CL gene and elucidating mechanism of ferulic acid biosynthesis and space-time regulation in A. sinensis. PMID- 27245030 TI - [Comparative study of biological characters and paeoniflorin content of wild and asexual cultivated Paeonia lactiflora growing at Duolun county, Inner Mongolia]. AB - This study aims to investigate whether the cultivation peony, can take the place of wild herbaceous peony by comparing the biological traits and paeoniflorin content between them. The result showed that the biomass of the stem, leaf, crown, fleshy root and fine root of wild plants were all smaller than that of bud asexual cultivated plants, while there was no significant differences in below ground and aboveground biomass ratio between these two plants. The stele diameter, the proportion of stele, and the ratio of stele diameter to cortex thickness of wild plants were significantly higher than that of bud asexual cultivated plants, while the cortex thickness and the proportion of cortex were significantly smaller than bud asexual cultivated plants. Although the biological traits of bud asexual cultivated plants have changed significantly, the paeoniflorin content in fleshy roots has no significant difference between wild and bud asexual cultivated plants. Therefore, it is feasible to use the bud asexual cultivation to the conservation and large-scale cultivation of Paeonia laciflora, which is an endangered species. PMID- 27245031 TI - [Distribution laws of 5 compounds in rhizome and root of Polygonum cuspidate]. AB - To understand the distribution and accumulation rules of polydatin, resveratrol, anthraglycoside B, emodin and physicion in different tissue structure of rhizome and root of Polygonum cospidatum, the content of 5 active compounds were analyzed simultaneously by HPLC, based on plant anatomy and histochemistry. The rhizome and root consist of different tissues, with an increased diameter, the proportions of the secondary xylem and phloem have increased. Resveratrol and polydatin mainly distributed in the pith, the secondary phloem and periderm of rhizome, and the secondary phloem and periderm of the root, while emodin and anthraglycoside B concentrated in the secondary structure and pith of rhizome mostly. In different thickness of the measured samples, the total contents of 5 compounds were correspondingly higher in thinner rhizome and root than those in the coarse ones. PMID- 27245032 TI - [Liquisolid technique for enhancement of dissolution prosperities of tanshinone II(A)]. AB - The technique of liquisolid compress is a new technique developed in 1990s, which was considered to be the most promising technique to improve the dissolution of water-insoluble drugs. In this article, tanshinone II(A) and the extracts of the ester-solubility fractions were chosen as the model drugs to evaluate the effects of the liquisolid technique for enhancement of dissolution properties of tanshinone II(A). Several liquisolid tablets (LS) formulations containing different dosage of drugs and various liquid vehicle were pre-pared and for all the formulations, microcrystalline cellulose and silica were chosen as the carrier and coating materials to evaluate their flow properties, such as angle of repose, Carr's compressibility index and Hausner's ratio. The interaction between drug and excipients in prepared LS compacts were studied by differential scanning calorimetry(DSC) and X-ray powder diffraction (XRPD). The dissolution curves of tanshinone II(A) from liquisolid compacts were investigated to determine the technique's effect in improving the dissolution of tanshinone II(A) and its impacting factors. According to the results, the dissolution increased with the rise in the dissolution of the liquid-phase solvent. The R-value and drug dosage can significantly affect the drug release, but with less impact on active fractions. This indicated that liquisolid technique is a promising alternative for improvement of dissolution property of water-soluble drugs, and can make a synergistic effect with other ester-soluble constituents and bettern improve the release of tanshinone II(A). Therefore, the technique of liquisolid compress will have a better development prospect in traditional Chinese medicines. PMID- 27245033 TI - [Preparation and release behaviour of mPEG-PLA alpha-asarone nanoparticles designed for nasal administration]. AB - Taking alpha-asarone as model drug, mono methoxy polyethylene glycol-polylactic acid copolymer (mPEG-PLA) as the drug carrier material to prepare drug-loading nanoparticles by premix membrane emulsification for nasal administration. The prepared nanoparticles were spherical with smooth surface and average particle size of 360 nm. Polydispersity index (PDI) was 0. 030, average drug loading of (11.5 +/- 0.045) % (n = 3), and the encapsulation efficiency of (86.34 +/- 0.11) % (n = 3). X-ray diffraction and differential scanning calorimetry results showed that, alpha-asarone existed in mPEG-PLA carrier in amorphous or molecular state, different from simple physical mixture. In the in vitro release test in simulated human nasal cavity, alpha-asarone apis can be released quickly at close to 94% at 102 h, in line with the first-order kinetics (R2 = 0.981 9). mPEG-PLA drug loading nanoparticles release only 54%, with slow release effect, in line with Riger-Peppas model (R2 = 0.967 9, n = 0.630 2), for non-fick diffusion, released by the spread of drugs and skeleton dissolution dual control. This provided the foundation for nasal drug delivery in vivo pharmacokinetic study. PMID- 27245034 TI - [Evaluation on intestinal absorption of alkaloids extracted by different methods from Rhizoma Coptidis-Rheum rhabarum herbal pair via everted gut sacs]. AB - The research aimed to evaluate the intestinal absorption of alkaloids extracted by decoction and alcohol extraction proces- ses from Rhizoma Coptidis-Rheum rhabarum herbal pair via everted gut sacs. Berberine, palmatine, coptisine and epiberberine were the main alkaloids in this herbal pair and taken as the standard indexes in the quantitative analysis with multi-components by single marker (QAMS) method, in order to calculate absorption rate constant (Ka) and evaluate intestinal absorption characteristics of these four alkaloids extracted by different extraction methods in different intestinal segments in rats. The results showed that the four alkaloids extracted by two different processes in high, medium and low doses had linear absorption properties in the small intestine segment, which conformed to zero-order absorption rate, intestinal segment than 0.99. The absorption rate constant (Ka) of decoction group was higher than that of alcohol extraction group. PMID- 27245035 TI - [Effect of drying methods on monoterpenes, phenolic acids and flavonoids in Mentha haplocalyx]. AB - To provide a scientific basis for the selection of the appropriate drying method for Mentha Haplocalyx Herba (MHH), determine 2 monoterpenes, 4 phenolic acids and 5 flavonoids in MHH by GC-MS and UPLC-TQ-MS methods, and investigate the effects of the drying methods on the changes in contents of these analytes. The qualities of products obtained with different drying methods were evaluated by the multivariate statistical method of Technique for Order Preference by Similarity to Ideal Solution (TOPSIS). Results showed that the drying methods had the greatest impact on menthol, caffeic acid, and rosemary acid, which were followed by chlorogenic acid and diosmetin-7-O-glucoside. The contents in these analytes processed with hot-air-drying method were higher than those with microwave-drying and infrared-drying methods at the same temperatures. The contents in these analytes processed under low temperature (40-45 degrees C) were higher than those under higher temperature (60-70 degrees C). Above all, the contents in phenolic acids processed with microwave fixation (exposed under microwave at 100 degrees C for several minutes) were obviously higher than those of not being processed, showing an inhibition of some enzymes in samples after fixation. The TOPSIS evaluation showed that the variable temperature drying method of 'Hot-Air 45-60 degrees C' was the most suitable approach for the primary drying processing of MHH. The results could provide the scientific basis for the selection of appropriate drying method for MHH, and helpful reference for the primary drying proces of herbs containing volatile chemical components. PMID- 27245036 TI - [A new flavonoid glycoside from leaves of Eucalyptus robusta]. AB - A new flavonoid glycoside, (-)-2S-8-methyl-5,7,4'-trihydroxyflavanone-7-O-beta-D glucopyranoside (1), along with five known ones, quercetin-3-O-(2"-galloyl)-alpha L-arabinoside (2), kaempferol-3-O-alpha-L-arabinoside (3), guaijaverin (4), trifolin (5) and hyperin (6), was isolated from the leaves of Eucalyptus robusta. Their structures with absolute configurations were elucidated by NMR, HR-ESI-MS, CD spectra data and physicochemical methods. In addition, 2-6 were isolated from E. robusta for the first time. PMID- 27245037 TI - [Determination of markers from characteristic HPLC chromatogram of phenols in three official origins of Ephedrae Herba and quantitative analysis of four phenols]. AB - This study is to establish the characteristic HPLC chromatogram of phenols in Ephedrae Herba, from which to pick out the marker peaks, followed by the analysis of the regularity of their distribution and content in the herbaceous stems of Ephedra sinica, E. intermedia and E. equisetina. The HPLC-DAD method for the characteristic chromatogram as well as quantitative analysis was established. The separation was carried out on a YMC-Pack ODS-A column (4.6 mm x 250 mm, 5 um), eluted with the mobile phases as 0.01% formic acid aqueous solution (A) and acetonitrile (B) in a linear gradient (0-10 min, 17% B; 10-25 min, 17%-19% B; 25- 33 min, 19%-48% B; 33-35 min, 48%-51% B; 35-44 min, 51% B). The flow rate was kept at 1.0 mL . min-1. The column tem- perature was 40 degrees C, and the detection wavelength was set at 350 nm (0-16 min) and 330 nm (16-44 min). Forty six batches of collected samples from three official origins of Ephedrae Herba were detected, whose liquid chromatograms proven to be helpful to the differentiation of different origins. With principal component analysis and the analysis of distribution of peak area, twelve key peaks from the chromatogram were discussed in details on their contributions to the characteristics and differences of three official origins of the herb: peak area of peak 10, 11, 12 were found out to be significantly higher in E. equisetina than in other two origins, whose sum (higher than 146 mAU in E. equisetina) was useful for the discrimination between E. equisetina and the other two origins; peak area of 1 and 4 were respectively higher in E. sinica and E. intermedia than in other official origins, indicating their important effect on the differen- tiation of corresponding origins; peak 8 and 9 were picked out as two characteristic common peaks in three official origins of the herb, whose peak area showed little difference among different origins; further, peak area of other key peaks in the chromatogram also showed some difference among three origins, which make contributions to the differentiation of origins as well. Then, four phenols as 2" O-alpha- L-rhamnosyl-isovitexin (1), vitexin (2), pollenitin B (5) and herbacetin 7-O-beta-D-glucoside (6) were quantitative analyzed with the above-mentioned method, with good linear relationship and accuracy (recoveries in a range of 97.8%-102.5%). The content of the four phenols were firstly reported in Ephedrae Herba from official origins, which were respectively trace-1.55 (1), trace-0.160 (2), trace-0.284 (5) and trace-0.620 (6) mg . g-1 in all of the tested samples. In addition, the content of these phenols showed differences in three official origins, especially 1, whose content in E. sinica [(0.670 +/- 0.88) mg +/- g-1] were significantly higher than in other two origins (lower than 0.16 mg +/- g-1 besides sample Ei-060630-2-2), and 6, whose average content in E. equisetina [(0.260 +/- 0.039 2) mg . g-1] were twice as high as in E. sinica [(0.120 +/- 0.270) mg . g-1] and E. intermedia [(0.136 +/- 0.485) mg g-1], indicating the important effects of the two constituents on the differentiation among three official origins of the herb. The method established for the characteristic HPLC chromatogram and quantitative analysis of phenols was simple and accurate, and the marker constituents selected may provide new guides for the discrimination of official origins as well as the improvement of quality criteria of EphedraeHerba. PMID- 27245038 TI - [Simultaneous determination of 3 phenolic acids in Usnea by HPLC-ESI-MS/MS]. AB - A quick HPLC-ESI-MS/MS method was established for simultaneous determination of three chemical compositions in Usnea, including usnic acid, diffractaic acid, and ramalic acid. The separation was performed on a chromatographic column of Agilent ZORBAX SB-C, (4.6 mm x 250 mm, 5 um), and the mobile phase was methanol (0.05% formic acid)-0.05% formic acid solution (4 mmol ammonium acetate), with an isocratic elution at a flow rate of 0.8 ml . min-1. Multiple reaction monitoring scanning mode (MRM) was performed combined with the ion switching technology in positive and negative ion switching mode to apply for the quantitative determination. The calibration curves for the above three compounds were linear in corresponding injection amount. Their average recoveries were 95.0%-105.1%, with RSDs of 1.1%-5.2%. The method was simple, rapid, accurate with high repeatability, which could provide a reference for overcalling evaluation the quality of Usnea. PMID- 27245039 TI - [Study of reason of "the older, the better" of Pericarpium Citri Reticulatae (PCR) which contributed increase of flavonoids]. AB - This study is to explore the reason of "the older, the better" of PCR and itsincrease of flavonoids. We identified the fun- gus isolated from the PCR using microscopic and molecular identification. HPLC method was used to determine the content of 4 fla- vonoids and to clarifythe regularity of them; UV spectrophotometry method was used to determine the total content of flavonoids; reverse thinking was applied to screen the fungus that have close relation to the change of flavonoids. Finally, we have isolated and identified 25 fungusfrom the PCR, which belong to 2 genus and 4 species, including pencillium commune, P. minioluteeum, P. citrinum, Aspergillus flavus and A. niger. The content of flavonoids was increased in the mildew PCR due to A. niger and other fungus. Therefore, "the ol- der, the better" of PCR had its scientific reason that the increase of flavonoids had a close relation of the metabolic activity of A. niger and other fungus. PMID- 27245040 TI - [Oleanolic acid induces G2/M phase arrest and apoptosis in human hepatocellular carcinoma Bel-7402 cells]. AB - This study was to examine the mechanism of oleanolic acid (OA) induces G2/M phase arrest and apoptosis in human hepatocellular carcinoma Bel-7402 cells. MTT and trypan blue exclusion test assay were adopted to detect the proliferate status of cells treated with OA. We assayed the cell cycle by flow cytometry using PI staining. Apoptosis was determined by Annexin V-FITC staining and PI labeling. The expressions of cycle related proteins and apoptotic related proteins were determined by Western blot analysis. OA strongly inhibited human hepatoma cells proliferation. When Bel-7402 cells were pretreated with OA for 24 h, OA induced apoptosis and G2/M phase cell cycle arrest in a concentration-dependent manner. Analysis of the cell cycle regulatory proteins demonstrated that OA decreased the protein levels of cyclin B1, but increased the protein levels of p-Cdk1 (Tyr15) and p-Cdc25C (Ser 216). Moreover, OA modulated the phosphorylation of protein kinases Chk1 and p2l. Western blotting assay also showed significant decrease of Bcl-2 protein expression and increase of Bax protein expression, the cytosol Cyt c level, cleaved-caspase-9 and cleaved-caspase-3 activity. These data suggest that OA produces anti-tumor effect via induction of G2/M cell cycle arrest and apoptosis. PMID- 27245041 TI - [Effect of paeonol on blood pressure and blood flow in artery of spontaneously hypertensive rats and its mechanisms related on vasomotion]. AB - Previous studies have shown that paeonol can antagonize acute myocardial ischemia and infarction in rat. This study further researched the effects of paeonol on blood pressure and blood flow in the artery of spontaneously hypertensive rats and its mechanisms related on vasomotion. Firstly, thirty spontaneously hypertensive rats were randomly divided into spontaneously hypertensive control group and paeonol-treating groups of high dose and low dose, and also, the other ten Wistar rats as healthy control group. Before and after the intraduodenal administration of the drug, arterial blood pressure was measured by carotid artery and blood flow through the renal artery and carotid artery in vivo were measured by animal flowmeter. The same volume of solvent was given to the spontaneously hypertensive control group and the healthy control group, and the other operations were same. In order to further study the effect of paeonol on vasomotor function, the superior mesenteric artery, renal artery and coronary artery of the spontaneously hypertensive rat were removed and separated, precontracted by a certain concentration of potassium chloride (KCl) and 5 serotonin (5-HT) respectively, and dilatory responses were assessed by cumulative addition of paeonol. Results showed that after duodenal one-time delivery of paeonol, the blood pressure significantly lowered, the renal arterial blood flow and the carotid arterial blood flow significantly increased in spontaneously hypertensive rat. And also, paeonol relaxed the mesenteric artery, renal artery and the coronary artery of spontaneously hypertensive rat in a concentration dependent manner. These results indicated that the effect of paeonol on decreasing arterial blood pressure and increasing the arterial blood flow was related to its vasodilative effect. PMID- 27245043 TI - [Analysis of varieties and standards of Leguminosae plants used in Tibetan medicine]. AB - In this paper, the domestic varieties and quality standard of Leguminosae medicinal plants used in Tibetan medicine were analyzed. The results showed that there were 36 genera and 142 species (including varieties), as well as 64 medicinal materials varieties of Leguminosae plants were recorded in relevant literatures. In relevant Tibetan standards and literatures, there are great differences in varieties, sources, used parts, and efficacy of medicinal plants. Among them, about 38.0% (including 54 species) of the endemic plants, about 25.4% (including 36 species) of the original plants have medicinal standard legal records, except 9 kinds of traditional Chinese medicine general quality standard more fairly completed, the most varieties have only description about characters, identification, etc. Therefore it is necessary to reinforce study for the herbal textual, resources and the use present situation, chemical components and biological activity, quality standard, medicinal terms specification, to promote establishment of quality standard system for variety-terminologies-sources of Tibetan medicinal plants. PMID- 27245042 TI - [Effect of Jingui Shenqi pill combined with nifedipine for the treatment of elderly hypertensive patients with spleen-kidney Yang deficiency syndrome]. AB - Totally 96 elderly patients with spleen-kidney Yang deficiency type hypertension were selected in this study. Patients were randomly divided into study and control group. It was treated with the Jingui Shenqi pill combined nifedipine sustained-release tablets in the study group and only nifedipine sustained release tablets for the control group. Meanwhile, the clinical features including reducing blood pressure, blood lipid and traditional Chinese medicine (TCM) syndromes of the two groups were observed pre and post treatment. Finally, the results showed that it could significantly reduce the hypertensive, hyperlipidemia and TCM syndromes in the study group compared with the control group (P < 0.05), which indicated that the combination of the Jingui Shenqi pill with nifedipine sustained-release tablets was effective for the patients with hypertension with spleen-kidney Yang deficiency type, especially for decreasing TCM syndromes and the blood lipid. PMID- 27245044 TI - [Identification of ancient Chinese medicinal specimens preserved at Natural History Museum in London]. AB - On-site field investigation was conducted to authenticate a batch of ancient Chinese medicinal decoction pieces that have been preserved in a rare collection at the Natural History Museum in London. These treasured artifacts comprise a portion of the Sloane Collection, and the nearly one hundred Chinese medicinal specimens examined within provide an objective record of the real situation regarding the Chinese medicinal materials in commercial circulation three hundred years ago. The precious data from this collection pro-vides an extremely valuable reference for the research into the history of medicinal exchange between China and the West during the Age of Exploration, shedding light on the evolution and historical changes in the species used in Chinese medicine, as well as the history of medicinal processing and decoction pieces. PMID- 27245045 TI - [Inheritance on and innovation of traditional Chinese medicine (TCM) flavor theory and TCM flavor standardization principle flavor theory in Compendium of Materia Medica]. AB - All previous literatures about Chinese herbal medicines show distinctive traditional Chinese medicine (TCM) flavors. Compendium of Materia Medica is an influential book in TCM history. The TCM flavor theory and flavor standardization principle in this book has important significance for modern TCM flavor standardization. Compendium of Materia Medica pays attention to the flavor theory, explain the relations between the flavor of medicine and its therapeutic effects by means of Neo-Confucianism of the Song and Ming Dynasties. However,the book has not reflected and further developed the systemic theory, which originated in the Jin and Yuan dynasty. In Compendium of Materia Medica , flavor are standardized just by tasting medicines, instead of deducing flavors. Therefore, medicine tasting should be adopted as the major method to standardize the flavor of medicine. PMID- 27245046 TI - Efficacy of cinnamon bark oil and cinnamaldehyde on anti-multidrug resistant Pseudomonas aeruginosa and the synergistic effects in combination with other antimicrobial agents. AB - BACKGROUND: The emergence of drug resistant pathogens becomes a crucial problem for infectious diseases worldwide. Among these bacteria, Pseudomonas aeruginosa is one of which highly resists to many currently used drugs and becomes a major concern in public health. Up till now, the search for potential antimicrobial agents has been still a challenge for researchers. METHODS: Broth microdilution assay was used to determine minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of the essential oils and antibiotics against P. aeruginosa. Inhibition activity of the essential oils under vapor condition was examined to obtain the minimum inhibitory dose (MID). Time-kill assay included in this study was performed according to CLSI guideline. Bioautographic assay was used to detect active components of the essential oil. Synergistic effect with currently used antibiotics was further examined by checkerboard assay. RESULTS AND DISCUSSION: In this study, a variety of essential oils were examined for anti-multidrug resistant P. aeruginosa (MDR-PA) activity, of which cinnamon bark oil showed the strongest antimicrobial activity against all clinical-isolated MDR-PA strains with MIC of 0.0562-0.225 % v/v and MBC of 0.1125 1.8 % v/v. Bioautographic results demonstrated that the active compounds of cinnamon bark oil were cinnamaldehyde and eugenol which showed strong inhibitory effect against P. aeruginosa. Interestingly, cinnamaldehyde, a major constituent of cinnamon bark oil, possessed stronger antimicrobial effect to P. aeruginosa than eugenol. Under gaseous condition, cinnamon bark oil and cinnamaldehyde showed antibacterial activity against MDR-PA strains with MID of 0.5-1 mg/L. Moreover, combination of cinnamon bark oil or cinnamaldehyde with currently used antibiotics was further studied by checkerboard assay to examine synergistic interactions on clinically isolated MDR-PA strains. Cinnamon bark oil and cinnamaldehyde combined with colistin demonstrated synergistic rates at 16.7 and 10 %, respectively. CONCLUSION: These results indicated that cinnamon bark oil and cinnamaldehyde might be active natural compounds which could be further examined as alternative treatment for multidrug-resistant P. aeruginosa infection. PMID- 27245047 TI - Fishers' knowledge on the coast of Brazil. AB - BACKGROUND: Although fishers' knowledge has been recently considered into management programmes, there is still the need to establish a better understanding of fishers' perceptions and cognition. Fishers can provide novel information on the biology and ecology of species, which can potentially be used in the management of fisheries. The knowledge fishers have and how they classify nature is empirically based. It is common, for example, to observe that fishers' taxonomy is often represented by the generic level, one of the hierarchical categories of folk classification that is somewhat analogous to the Linnean genus, as it groups organisms of a higher rank than the folk species.In this study we compiled the knowledge fishers have on local fish, such as their folk names, diet and habitat. METHODS: Five coastal communities widely distributed along the Brazilian coast were studied: two from the northeast (Porto Sauipe and Itacimirim, in Bahia State, n of interviewees = 34), two from the southeast (Itaipu at Niteroi and Copacabana at Rio de Janeiro, Rio de Janeiro State, n = 35) and one from the south coast (Pantano do Sul, in Santa Catarina State, n = 23). Fish pictures were randomly ordered and the same order was presented to all interviewees (n = 92), when they were then asked about the species name and classification and its habitat and diet preferences. RESULTS: Fishers make clusters of fish species, usually hierarchically; fishers of the coast of Brazil use mostly primary lexemes (generic names) to name fish; and fishers did not differentiate between scientific species, since the same folk generic name included two different scientific species. Fishers provide information on species to which there is scarce or no information on diet and habitat, such as Rhinobatos percellens (chola guitarfish, arraia viola or cacao viola), Sphoeroides dorsalis (marbled puffer, baiacu), Mycteroperca acutirostris (comb grouper, badejo) and Dasyatis guttata (longnose stingray, arraia, arraia manteiga). CONCLUSIONS: fishers' knowledge on fish diet and fish habitat can be strategic to management, since their knowledge concentrates on the fishery target species, which are the ones under higher fishing pressure. Besides, fishers showed to have knowledge on species still poorly known to science. PMID- 27245048 TI - A statistical shape modelling framework to extract 3D shape biomarkers from medical imaging data: assessing arch morphology of repaired coarctation of the aorta. AB - BACKGROUND: Medical image analysis in clinical practice is commonly carried out on 2D image data, without fully exploiting the detailed 3D anatomical information that is provided by modern non-invasive medical imaging techniques. In this paper, a statistical shape analysis method is presented, which enables the extraction of 3D anatomical shape features from cardiovascular magnetic resonance (CMR) image data, with no need for manual landmarking. The method was applied to repaired aortic coarctation arches that present complex shapes, with the aim of capturing shape features as biomarkers of potential functional relevance. The method is presented from the user-perspective and is evaluated by comparing results with traditional morphometric measurements. METHODS: Steps required to set up the statistical shape modelling analyses, from pre-processing of the CMR images to parameter setting and strategies to account for size differences and outliers, are described in detail. The anatomical mean shape of 20 aortic arches post-aortic coarctation repair (CoA) was computed based on surface models reconstructed from CMR data. By analysing transformations that deform the mean shape towards each of the individual patient's anatomy, shape patterns related to differences in body surface area (BSA) and ejection fraction (EF) were extracted. The resulting shape vectors, describing shape features in 3D, were compared with traditionally measured 2D and 3D morphometric parameters. RESULTS: The computed 3D mean shape was close to population mean values of geometric shape descriptors and visually integrated characteristic shape features associated with our population of CoA shapes. After removing size effects due to differences in body surface area (BSA) between patients, distinct 3D shape features of the aortic arch correlated significantly with EF (r = 0.521, p = .022) and were well in agreement with trends as shown by traditional shape descriptors. CONCLUSIONS: The suggested method has the potential to discover previously unknown 3D shape biomarkers from medical imaging data. Thus, it could contribute to improving diagnosis and risk stratification in complex cardiac disease. PMID- 27245050 TI - Assessment of learning curves in complex surgical interventions: a consecutive case-series study. AB - BACKGROUND: Surgical interventions are complex, which complicates their rigorous assessment through randomised clinical trials. An important component of complexity relates to surgeon experience and the rate at which the required level of skill is achieved, known as the learning curve. There is considerable evidence that operator performance for surgical innovations will change with increasing experience. Such learning effects complicate evaluations; the start of the trial might be delayed, resulting in loss of surgeon equipoise or, if an assessment is undertaken before performance has stabilised, the true impact of the intervention may be distorted. METHODS: Formal estimation of learning parameters is necessary to characterise the learning curve, model its evolution and adjust for its presence during assessment. Current methods are either descriptive or model the learning curve through three main features: the initial skill level, the learning rate and the final skill level achieved. We introduce a fourth characterising feature, the duration of the learning period, which provides an estimate of the point at which learning has stabilised. We propose a two-phase model to estimate formally all four learning curve features. RESULTS: We demonstrate that the two phase model can be used to estimate the end of the learning period by incorporating a parameter for estimating the duration of learning. This is achieved by breaking down the model into a phase describing the learning period and one describing cases after the final skill level is reached, with the break point representing the length of learning. We illustrate the method using cardiac surgery data. CONCLUSIONS: This modelling extension is useful as it provides a measure of the potential cost of learning an intervention and enables statisticians to accommodate cases undertaken during the learning phase and assess the intervention after the optimal skill level is reached. The limitations of the method and implications for the optimal timing of a definitive randomised controlled trial are also discussed. PMID- 27245049 TI - Association of IL-10 polymorphisms with hepatitis B virus infection and outcome in Han population. AB - BACKGROUND: This study evaluated the correlation of single nucleotide polymorphisms interleukin (IL)-10-592 and -1082 with hepatitis B virus (HBV) susceptibility and recovery. METHODS: Total 190 chronic hepatitis B (CHB) patients, 81 individuals with self-limited HBV infections and 81 normal controls from the first Hospital of Jilin University were recruited. The IL-10 polymorphisms were detected by polymerase chain reaction with restriction fragment length polymorphism (PCR-RFLP). The chi (2) test (p < 0.05) and Fisher's exact test were separately performed to analyze and compare the genotype frequencies of IL-10-592 and -1082 among different groups. Furthermore, logistic regression analysis (p < 0.05) was conducted to determine the correlation of genotypes with HBV infection and recovery. Genotype A/A, A/C and C/C of IL-10-592 had been detected in the three groups. RESULTS: The frequencies of -592A separately were 55.56, 64.67 and 55.33 % in the three groups. Genotypes of IL-10 592 only had significant difference among the patients and normal controls (p = 0.021). Genotypes A/A, A/G and G/G of IL-10-1082 were detected in CHB patients and individuals with self-limited HBV infection; however, genotype G/G had not been detected in normal controls. The frequencies of -1082G separately were 3.68, 6.17 and 11.11 % in the three groups. Genotypes of IL-10-1082 only had no significant difference among the patients and individuals with self-limited HBV infections (p = 0.130). We found that their risks of HBV infection existed significant difference. CONCLUSION: The IL-10-592 and -1082 polymorphisms might be associated with HBV infection, but not with the recovery after HBV infection. PMID- 27245051 TI - Human trophoblast cell during first trimester after IVF-ET differs from natural conceived pregnancy in development and function. AB - OBJECTIVE: To explore the differences of the trophoblast cell function in first trimester between natural pregnancy and pregnancy after IVF-ET therapy. METHODS: 102 cases with twin to singleton fetal reduction after IVF-ET treatment from July 2010 to August 2013 in Peking University Third Hospital were involved in analysis, and eight specimens were obtained from this group. 10 natural-pregnancy cases undergoing artificial abortion with unwanted pregnancy were recruited as control. Semi-quantitative immunohistochemical method was used to detect the expression of EGFR, Bcl-2, tubulin-alpha, metallothionein and AFP in villi in both groups. RESULTS: Of the 102 cases, 14 cases (13.73%) were aborted. Preterm birth occurred in seven cases (7.86%). Low birth weight occurred in three patients (3.37%), and extremely low birth weight occurred in four cases (4.49%). The expression of EGFR, tubulin-alpha, Bcl-2, and metallothionein in the IVF-ET group was significantly lower than that in the control group (P<0.05). However, AFP expression was significantly higher in IVF-ET group than in control group (P<0.05). In IVF-ET group, the miscarriage case had weaker EGFR, tubulin-alpha, and metallothionein expression than full-term pregnancy; the early preterm labor case had weaker Bcl-2, tubulin-alpha, and metallothionein expression; and velamentous cord insertion case had weaker tubulin-alpha expression. CONCLUSIONS: The trophoblast cell function of IVF-ET group in first trimester is different from control group in proliferation, invasion, apoptosis and vascular development, and optimal pregnancy outcome depends on the self-healing balance of trophoblast cells. PMID- 27245052 TI - Changes in Social Function as a Trigger to Screen for Cognitive Impairment. PMID- 27245053 TI - Effects of epidermal growth factor receptor kinase inhibition on radiation response in canine osteosarcoma cells. AB - BACKGROUND: Radiation therapy is a palliative treatment modality for canine osteosarcoma, with transient improvement in analgesia observed in many cases. However there is room for improvement in outcome for these patients. It is possible that the addition of sensitizing agents may increase tumor response to radiation therapy and prolong quality of life. Epidermal growth factor receptor (EGFR) expression has been documented in canine osteosarcoma and higher EGFR levels have been correlated to a worse prognosis. However, effects of EGFR inhibition on radiation responsiveness in canine osteosarcoma have not been previously characterized. This study examined the effects of the small molecule EGFR inhibitor erlotinib on canine osteosarcoma radiation responses, target and downstream protein expression in vitro. Additionally, to assess the potential impact of treatment on tumor angiogenesis, vascular endothelial growth factor (VEGF) levels in conditioned media were measured. RESULTS: Erlotinib as a single agent reduced clonogenic survival in two canine osteosarcoma cell lines and enhanced the impact of radiation in one out of three cell lines investigated. In cell viability assays, erlotinib enhanced radiation effects and demonstrated single agent effects. Erlotinib did not alter total levels of EGFR, nor inhibit downstream protein kinase B (PKB/Akt) activation. On the contrary, erlotinib treatment increased phosphorylated Akt in these osteosarcoma cell lines. VEGF levels in conditioned media increased after erlotinib treatment as a single agent and in combination with radiation in two out of three cell lines investigated. However, VEGF levels decreased with erlotinib treatment in the third cell line. CONCLUSIONS: Erlotinib treatment promoted modest enhancement of radiation effects in canine osteosarcoma cells, and possessed activity as a single agent in some cell lines, indicating a potential role for EGFR inhibition in the treatment of a subset of osteosarcoma patients. The relative radioresistance of osteosarcoma cells does not appear to be related to EGFR signalling exclusively. Angiogenic responses to radiation and kinase inhibitors are similarly likely to be multifactorial and require further investigation. PMID- 27245055 TI - Hepatocyte Nuclear Factor-4 Alfa Mutation Associated with Hyperinsulinaemic Hypoglycaemia and Atypical Renal Fanconi Syndrome: Expanding the Clinical Phenotype. AB - BACKGROUND: The p.R63W mutation in the hepatocyte nuclear factor-4 alpha (HNF4A) results in macrosomia and atypical Fanconi syndrome, in addition to hyperinsulinaemic hypoglycaemia (HI). We describe 2 infants carrying this mutation, presenting with additional features. Cases Series: Patient 1, a male born with a birth weight of 1.7 SDS, was diagnosed with HI on day 2 of life. He responded to 3-10 mg/kg/day of diazoxide. Raised serum creatinine led to the investigation of renal tubular function, showing leaking of electrolytes and protein. The patient also had conjugated hyperbilirubinaemia with liver steatosis. Patient 2 was a male born with a weight of 0.36 SDS. His mother had renal Fanconi syndrome. He received parenteral nutrition and presented with HI at 1 month of age, while establishing enteral feeds. Biochemistry workup showed renal tubular leaking of calcium, sodium, and phosphate. A hypoglycaemia screen documented HI, and the patient was commenced on 2 mg/kg/day of diazoxide. Continuous glucose monitoring was performed in his mother, revealing overnight hypoglycaemia. CONCLUSION: Renal Fanconi syndrome represents the only HNF4A feature showing complete penetrance. Our cases suggest that the p.R63W HNF4A mutation must be considered in subjects with a normal birth weight and postulate the possibility of liver involvement as a part of this condition. PMID- 27245054 TI - Can fiberoptic bronchoscopy be applied to critically ill patients treated with noninvasive ventilation for acute respiratory distress syndrome? Prospective observational study. AB - BACKGROUND: Noninvasive ventilation (NIV) is a cornerstone for the treatment of acute respiratory failure of various etiologies. Using NIV is discussed in mild to-moderate acute respiratory distress syndrome (ARDS) patients (PaO2/FiO2 > 150). These patients often have comorbidities that increase the risk for bronchoscopy related complications. The primary outcome of this prospective observational study was to evaluate the feasibility, safety and contribution in diagnosis and/or modification of the ongoing treatment of fiberoptic bronchoscopy (FOB) in patients with ARDS treated with NIV. METHODS: ARDS patients treated with NIV and who require FOB as the diagnostic or therapeutic procedure were included the study. Intensive care ventilators or other dedicated NIV ventilators were used. NIV was applied via simple oro-nasal mask or full-face mask. Pressure support or inspiratory positive airway pressure (IPAP), external positive end expiratory pressure (PEEP) or expiratory positive airway pressure (EPAP) levels were titrated to achieve an expiratory tidal volume of 8 to 10 ml/kg according to ideal body weight, SpO2 > 90 % and respiratory rate below 25/min. RESULTS: Twenty eight subjects (mean age 63.3 +/- 15.9 years, 15 men, 13 women, PaO2/FiO2 rate 145 +/- 50.1 at admission) were included the study. Overall the procedure was well tolerated with only 5 (17.9 %) patients showing minor complications. There was no impairment in arterial blood gas and cardiopulmonary parameters after FOB. PaO2/FiO2 rate increased from 132.2 +/- 49.8 to 172.9 +/- 63.2 (p = 0.001). No patient was intubated within 2 h after the bronchoscopy. 10.7, 32.1 and 39.3 % of the patients required invasive mechanical ventilation after 8 h, 24 h and 48 h, respectively. Bronchoscopy provided diagnosis in 27 (96.4 %) patients. Appropriate treatment was decided according to the results of the bronchoscopic sampling in 20 (71.4 %) patients. CONCLUSION: FOB under NIV could be considered as a feasible tool for diagnosis and guide for treatment of patients with ARDS treated via NIV in intensive care units. However, FOB-correlated life-treathening complications in severe hypoxemia should not be forgotten. Furthermore, further controlled studies involving a larger series of homogeneous ARDS patients undergoing FOB under NIV are needed to confirm these preliminary findings. PMID- 27245057 TI - Comment on: "Submaximal, Perceptually Regulated Exercise Testing Predicts Maximal Oxygen Uptake: A Meta-Analysis Study". PMID- 27245056 TI - Aggravation of spinal cord compromise following new osteoporotic vertebral compression fracture prevented by teriparatide in patients with surgical contraindications. AB - : Patients with spinal cord deficits following new unstable osteoporotic compression fracture and surgical contraindications were considered to receive conservative treatment. Teriparatide was better than alendronate at improving bone mineral density and bone turnover parameters, as well as preventing aggravation of spinal cord compromise. INTRODUCTION: This study compared the preventive effects of teriparatide and alendronate on aggravation of spinal cord compromise following new unstable osteoporotic vertebral compression fracture (OVCF) in patients with surgical contraindications. METHODS: This was a 12-month, randomized, open-label study of teriparatide versus alendronate in 49 patients with new unstable OVCF and surgical contraindications. Neurological function was evaluated using modified Japanese Orthopedic Association (mJOA) score (11-point scale, the maximum score of 11 implies normalcy). Visual analog scale (VAS) scores, kyphotic angles, anterior-border heights and diameters of the spinal canal of the fractured vertebrae, any incident of new OVCFs (onset of OVCF during follow-up), spine bone mineral density (BMD), and serum markers of bone resorption and bone formation were also examined at baseline and 1, 3, 6, and 12 months after initiation of the medication regimen. RESULTS: At 12 months, mean mJOA score had improved in the teriparatide group and decreased in the alendronate group. Mean concentrations of bone formation and bone resorption biomarkers, mean spine BMD, and mean anterior-border height and spinal canal diameter of the fractured vertebrae were significantly greater in the teriparatide group than in the alendronate group. Mean VAS score, mean kyphotic angle of the fractured vertebrae, and incidence of new OVCFs were significantly smaller in the teriparatide group than in the alendronate group. CONCLUSIONS: In patients with neurological deficits following new unstable OVCF and with surgical contraindications, teriparatide was better than alendronate at improving the BMD and the bone turnover parameters, as well as preventing aggravation of spinal cord compromise. PMID- 27245058 TI - Author's Reply to Will G. Hopkins: "Submaximal, Perceptually Regulated Exercise Testing Predicts Maximal Oxygen Uptake: A Meta-Analysis Study". PMID- 27245059 TI - Multi-Dimensional Interacting Constraints on Physical Activity Behaviours in the Finnish Population. AB - Finnish sports organisations, local and federal government, and healthcare organisations have widely adopted the World Health Organization and national recommendations for physical activity for different age groups. However, studies have indicated that only 46 % of 3-year-old preschool children, approximately 50 % of primary school students (7-12 years), 10-17 % of secondary school students (13-15 years) and 16 % of Finnish adults (20-54 years) attain those recommendations. In Finland there are 33,620 built sports facilities and over 9000 sport clubs, meaning there are many possibilities for physical activity, yet people are still rather inactive. In this paper we argue that availability of facilities, although an important element, is not enough to promote physical activity. It is possible that the current built physical environmental design does not fulfil people's needs regarding participation in physical activity. More emphasis should be placed on the design and operation of the facilities to develop new affordances for physical activity. PMID- 27245060 TI - Muscle Dysmorphia Symptomatology and Associated Psychological Features in Bodybuilders and Non-Bodybuilder Resistance Trainers: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Muscle dysmorphia (MD) is associated with a self-perceived lack of size and muscularity, and is characterized by a preoccupation with and pursuit of a hyper-mesomorphic body. MD symptoms may hypothetically be more prevalent in bodybuilders (BBs) than in non-bodybuilder resistance trainers (NBBRTs). OBJECTIVE: Our objective was to compare MD symptomatology in BBs versus NBBRTs and identify psychological and other characteristics associated with MD in these groups. METHODS: We searched relevant databases from earliest record to February 2015 for studies examining MD symptoms in BBs and/or NBBRTs. Included studies needed to assess MD using a psychometrically validated assessment tool. Study quality was evaluated using an adapted version of the validated Downs and Black tool. We calculated between-group standardized mean difference (effect sizes [ESs]) and 95 % confidence intervals (CIs) for each MD subscale, and performed meta-analysis when five or more studies used the same MD tool. We also extracted data describing psychological or other characteristics associated with MD. RESULTS: Of the 2135 studies initially identified, 31 analyzing data on 5880 participants (BBs: n = 1895, NBBRTs: n = 3523, controls: n = 462) were eligible for inclusion, though study quality was generally poor-moderate (range 7-19/22). Most participants were male (90 %). Eight different MD assessment tools were used. Meta-analysis for five studies all using the Muscle Dysmorphia Inventory (MDI) revealed there was a medium to large pooled ES for greater MD symptomatology in BBs than in NBBRTs on all MDI subscales (ES 0.53-1.12; p <= 0.01). Competitive BBs scored higher than non-competitive BBs (ES 1.21, 95 % CI 0.82-1.60; p < 0.001). MD symptoms were associated with anxiety (r 0.32-0.42; p <= 0.01), social physique anxiety (r 0.26-0.75; p < 0.01), depression (r 0.23 0.53; p <= 0.01), neuroticism (r 0.38; p < 0.001), and perfectionism (r 0.35; p < 0.05) and were inversely associated with self-concept (r -0.32 to -0.36; p < 0.01) and self-esteem (r -0.42 to -0.47; p < 0.01). CONCLUSIONS: MD symptomatology was greater in BBs than in NBBRTs. Anxiety and social physique anxiety, depression, neuroticism, and perfectionism were positively associated with MD, while self-concept and self-esteem were negatively associated. It remains unclear whether these characteristics are exacerbated by bodybuilding, or whether individuals with these characteristics are attracted to the bodybuilding context. PMID- 27245061 TI - Effectiveness of Exercise Interventions to Improve Postural Control in Older Adults: A Systematic Review and Meta-Analyses of Centre of Pressure Measurements. AB - BACKGROUND: Previous reviews have shown balance in older adults to be improved with exercise. However, it is currently unclear whether postural control, indicated by centre of pressure (COP) measurement, can be improved in older adults and thus whether postural control could be a mechanism to improve balance. OBJECTIVES: The purpose of this systematic review was to assess the effectiveness of force platform COP variables to identify changes in postural control following exercise interventions in older adults. In addition, a secondary purpose was to determine whether the exercise types (balance, resistance or multi-component exercise interventions) are equally effective to improve postural control. METHODS: Randomised controlled trials were identified using searches of databases and reference lists (PROSPERO registration number CRD42014010617). Trials performing exercise interventions, reporting force platform COP measurements, in participants with a mean age of >=60 years were included. Risk of bias assessments were performed following the Cochrane guidelines. Data were pooled in meta-analyses, and standardised mean differences (SMDs) with 95 % confidence intervals (CIs) were calculated. RESULTS: Twenty-three trials met the inclusion criteria for the systematic review. Twenty-two trials could be defined as either utilising a balance, resistance or multi-component exercise intervention. These 22 trials were used in the meta-analyses. All trials reported measurements of double leg stance; eight trials reported additional stance conditions. The meta analyses of double leg stance showed that balance exercise interventions significantly decreased total sway path length/velocity [SMD -1.13, 95 % CI -1.75 to -0.51 (eyes open); SMD -0.79, 95 % CI -1.33 to -0.26 (eyes closed)] and anterior-posterior sway path length/velocity [SMD -1.02, 95 % CI -2.01 to -0.02 (eyes open); SMD -0.82, 95 % CI -1.46 to -0.17 (eyes closed)] in both eyes open and eyes closed conditions. Balance exercise interventions also decreased sway area in eyes closed conditions (SMD -0.57, 95 % CI -1.01 to -0.13) and medio lateral sway path length/velocity in eyes open conditions (SMD -0.8, 95 % CI 1.48 to -0.12). In contrast, neither resistance nor multi-component exercise interventions affected any of the included COP measurements. CONCLUSIONS: Postural control is improved by balance exercise interventions. In contrast, strength or multi-component exercise interventions did not influence postural control measurements in older adults. In addition, a lack of standardisation in collection protocol and COP variables calculated across trials was identified. PMID- 27245062 TI - Influence of 1,2-alkanediols on the structure of their intercalates with strontium phenylphosphonate solved by molecular simulation and experimental methods. AB - Strontium phenylphosphonate intercalates with 1,2-diols (from 1,2-ethanediol to 1,2-hexanediol) were synthesized and characterized by X-ray diffraction, thermogravimetry, chemical analysis, and molecular simulation methods. Prepared samples exhibit a very good stability at ambient conditions. Structural arrangement calculated by simulation methods suggested formation of cavities surrounded by six benzene rings. Each cavity contained one molecule of diol and one molecule of water for the 1,2-ethanediol to 1,2-butanediol intercalates. In the case of 1,2-pentanediol two types of cavities alternated: one with diol molecules and another one with two water molecules. In the 1,2-hexanediol intercalate the benzene rings created two types of cavities containing one or two diol molecules, respectively, and this conformational variability led to a more disordered arrangement with respect to the models with shorter alkyl chains. Coordination of the oxygen atoms of the diols to the strontium atoms of the host follows the same pattern for all 1,2-diol intercalates except the 1,2-hexanediol intercalate, where these oxygen atoms can be mutually exchanged at their positions. The calculated basal spacings and structural models are in good agreement with experimental basal spacings obtained from X-ray powder diffraction and with other experimental results. PMID- 27245063 TI - Identifying significant microRNA-mRNA pairs associated with breast cancer subtypes. AB - MicroRNAs (miRNAs) are small non-coding RNAs that help in post-transcriptional gene silencing. These endogenous RNAs develop a post-transcriptional gene regulatory network by binding to complementary sequences of target mRNAs and essentially degrade them. Cancer is a class of diseases that is caused by the uncontrolled cell growth, thereby resulting into a gradual degradation of cell structure. Earlier researches have shown that miRNAs have significant biological involvement in cancer. Prolonged research in this genre has led to the identification of the functions of numerous miRNAs in cancer development. Studying the differential expression profiles of miRNAs and mRNAs together could help us in recognizing the significant miRNA-mRNA pairs from cancer samples. In this paper, we have analyzed the simultaneous over-expression of miRNAs and under expression of mRNAs and vice versa to establish their association with cancer. This study focuses on breast tumor samples and the miRNA-mRNA target pairs that have a visible signature in such breast tumor samples. We have been able to identify the differentially expressed miRNAs and mRNAs, and further established relations between them to extract the miRNA-mRNA pairs that might be significant in the breast cancer types. This gives us the clue about the potential biomarkers for the breast cancer subtypes that can further help in understanding the progression of each of the subtypes separately. This might be helpful for the joint miRNA-mRNA biomarker identification. PMID- 27245064 TI - Molecular authentication of Tetrastigma hemsleyanum from its adulterant species using ISSR, CAPS, and ITS2 barcode. AB - Tetrastigma hemsleyanum is a rare and endangered herb, which is commercialized as the resource of anti-cancer drugs. Wild T. hemsleyanum plants are on the verge of extinction recently, there are increasing numbers of counterfeits on the market. In the present study, inter-simple sequence repeat (ISSR), Cleaved amplified polymorphic sequence (CAPS), and the internal transcribed spacer region II (ITS2) barcode were used for the first time for the authentication of T. hemsleyanum from its commonly counterfeits. ISSR analysis suggested that it was a useful method for distinguishing T. hemsleyanum from its adulterants of different genus. However, it was insufficient to distinguish T. hemsleyanum from those adulterants of the same genus. ITS2 of T. hemsleyanum and the commonly counterfeits were amplified and sequenced. The Neighbor-Joining tree constructed from the ITS2 sequences showed that T. hemsleyanum was clearly differentiated from all counterfeits samples. A mutation site in the ITS2 region of T. hemsleyanum had been found which could be recognized by the restriction endonuclease NcoI. T. hemsleyanum could be readily distinguished from counterfeits as the PCR products from T. hemsleyanum could be digested sufficiently by NcoI, while the PCR products from counterfeits could not be digested. The results indicated that CAPS and ITS2 barcode methods provided effective and accurate identification of T. hemsleyanum from all its adulterants, while ISSR could only distinguish T. hemsleyanum from its adulterants of different genus. The CAPS method developed in the present study will serve as a reliable tool for safe and effective use of T. hemsleyanum in the clinic application. It will also play an important role for the identification, management and conservation of this endangered species. PMID- 27245065 TI - A Cross-sectional Investigation of Cancer-Screening Intentions, Sources of Information, and Understanding of Cancer in Japanese Adolescents. AB - The purpose of this study was to describe the cancer-screening intention, sources of cancer information, and cancer understanding among Japanese adolescents. A cross-sectional nationwide survey involving a self-administered questionnaire was conducted. Response rates of the target schools were 46.4 % (n = 103) for junior high schools and 55.8 % (n = 116) for high schools. From these, we analyzed the data of 2960 junior high school students (1520 males, 1440 females) and 3703 high school students (1546 males, 2157 females) to examine the association between cancer-screening intention and sources of cancer-related information and understanding. A significant association between cancer-screening intention and sources of cancer information and cancer understanding was observed. The screening intention group identified more sources of cancer information than the no-screening intention group did. Understanding about cancer was reported by a higher proportion of students in the screening intention group compared with the no-screening intention group. Recognition that healthy people must take part in cancer screening was significantly associated with screening intention in both junior high (odds ratio (OR), 1.859; 95 % confidence interval (CI), 1.582-2.185; P < 0.001) and high school (OR, 2.485; 95 % CI, 2.139-2.887; P < 0.001) students. Health education at school was indicated by a high proportion of students as a source of cancer-related information, although the association was not significant. The present survey indicated that those in of our sample who intended to undergo future cancer screening (67.8 %) had more sources of information and understanding regarding cancer. Thus, schools should enrich health education curricula with more information and understanding about cancer to promote cancer-screening intention among Japanese adolescents. PMID- 27245066 TI - Post-wildfire physiological ecology of an Australian microbat. AB - Historical patterns of wildfires are being altered as a result of changing climate and therefore are becoming an increasingly pressing global issue. How small mammals deal physiologically with changes in landscape and food availability due to fire remains largely unknown, although recent studies on small heterothermic terrestrial mammals have shown an increase in post-fire torpor use to reduce energy and foraging requirements. However, data on the behavioural and physiological responses of bats after fires are scarce, although potentially these volant species may differ from terrestrial mammals. Therefore, we investigated the post-fire thermal biology and activity of lesser long-eared bats (Nyctophilus geoffroyi) using temperature-telemetry in Warrumbungle National Park, NSW, which experienced a devastating wildfire in 2013. The study comprised two field seasons, one in 2013 within 4 months after the fire, and one in 2015 two years after the fire to identify potential changes in behaviour and physiology. Interestingly, soon after the fire, bats showed significantly shorter torpor bout duration (11.8 +/- 12.5 h) and longer normothermia duration (8.7 +/- 4.6 h) in comparison to those in 2015 (torpor bout duration: 24.1 +/- 23.5 h; normothermia duration: 2.5 +/- 1.5 h). Insect availability was significantly (20 fold) higher in 2013 than in 2015, which was likely an important factor resulting in the short average torpor bout duration by N. geoffroyi after the fire. Our data indicate that volant bats appear to show the opposite post-fire behavioural and physiological responses to small terrestrial mammals, showing longer normothermic and active periods and shorter torpor bouts to capitalise on an increase in available post-fire resources. PMID- 27245067 TI - Migration of rigid gas permeable contact lens into the upper eyelid after trauma: a case report. AB - BACKGROUND: Migration of a rigid gas permeable (RGP) contact lens after trauma is rare, and its clinical characteristics have not been fully discussed. CASE PRESENTATION: A 36-year-old female showed mild swelling in the right upper eyelid. She lost her RGP contact lens seven months prior to her first visit, from trauma by her child's kick to the right eye. At the first examination, we felt a firm lump inferior to the right brow. Eversion of the upper eyelid also revealed a firm subconjunctival mass superior to the upper tarsus. After incising the conjunctiva, the RGP contact lens was found without a fibrous capsule and granulation tissue in the subconjunctival space. Three years after removal of the lens, the patient did not show any complications, including ptosis. CONCLUSION: The RGP contact lens in the present case migrated into the subconjunctival space superior to the upper tarsus without a fibrous capsule and granulation tissue. These findings are similar to those in previously reported traumatic cases but are different from those in some spontaneous migration cases. This difference may be caused by differences in the migration mechanisms. PMID- 27245068 TI - Effect of a Low Fat Diet Intervention on Blood Pressure and Hypertension: Rather Switch to a Mediterranean Diet? PMID- 27245069 TI - Prediction of aptamer-protein interacting pairs using an ensemble classifier in combination with various protein sequence attributes. AB - BACKGROUND: Aptamer-protein interacting pairs play a variety of physiological functions and therapeutic potentials in organisms. Rapidly and effectively predicting aptamer-protein interacting pairs is significant to design aptamers binding to certain interested proteins, which will give insight into understanding mechanisms of aptamer-protein interacting pairs and developing aptamer-based therapies. RESULTS: In this study, an ensemble method is presented to predict aptamer-protein interacting pairs with hybrid features. The features for aptamers are extracted from Pseudo K-tuple Nucleotide Composition (PseKNC) while the features for proteins incorporate Discrete Cosine Transformation (DCT), disorder information, and bi-gram Position Specific Scoring Matrix (PSSM). We investigate predictive capabilities of various feature spaces. The proposed ensemble method obtains the best performance with Youden's Index of 0.380, using the hybrid feature space of PseKNC, DCT, bi-gram PSSM, and disorder information by 10-fold cross validation. The Relief-Incremental Feature Selection (IFS) method is adopted to obtain the optimal feature set. Based on the optimal feature set, the proposed method achieves a balanced performance with a sensitivity of 0.753 and a specificity of 0.725 on the training dataset, which indicates that this method can solve the imbalanced data problem effectively. To evaluate the prediction performance objectively, an independent testing dataset is used to evaluate the proposed method. Encouragingly, our proposed method performs better than previous study with a sensitivity of 0.738 and a Youden's Index of 0.451. CONCLUSIONS: These results suggest that the proposed method can be a potential candidate for aptamer-protein interacting pair prediction, which may contribute to finding novel aptamer-protein interacting pairs and understanding the relationship between aptamers and proteins. PMID- 27245070 TI - Use of Contraindicated Antiplatelet Medications in the Setting of Percutaneous Coronary Intervention: Insights From the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program. AB - BACKGROUND: Several antiplatelet medications used during and after percutaneous coronary intervention (PCI) are contraindicated for specific patient groups. A broad assessment of contraindicated medication use and associated clinical outcomes is not well described. METHODS AND RESULTS: Using national Veterans Affairs Clinical Assessment, Reporting, and Tracking Program data for all PCI between 2007 and 2013, we evaluated patients with contraindications to commonly used antiplatelet medications during and after PCI, defined in accordance with package inserts. Adjusted association between contraindicated medication use and outcomes of periprocedural bleeding and 30-day mortality were assessed using Cox proportional hazards with inverse probability weighting. Among 64 294 patients undergoing PCI, 11 315(17.6%) had a contraindication to a common antiplatelet medication and 737 (6.5%) of these patients received a contraindicated medication. In unadjusted analyses, any contraindicated medication use was associated with both increased bleeding and 30-day mortality. In adjusted models, contraindicated abciximab use in patients with thrombocytopenia (hazard ratio, 2.23; 95% confidence interval, 1.58-3.16) and in patients with a previous stroke (hazard ratio, 1.93; 95% confidence interval, 1.37-2.71) remained significantly associated with increased bleeding. Contraindicated abciximab use was not significantly associated with 30-day mortality in adjusted models. Use of eptifibatide in dialysis patients was not significantly associated with an increased risk of bleeding or mortality. CONCLUSIONS: In this national cohort, ~18% of patients undergoing PCI had contraindications to common antiplatelet medications. Approximately 6% of those patients received a contraindicated medication with attendant bleeding risk, although this did not translate into significantly higher risk of 30-day mortality. Continued efforts to reduce contraindicated medication use may help avoid periprocedural complications. PMID- 27245071 TI - Optical coherence tomography visualization of stent deformation with subsequent thrombus adhesion at very early phase after everolimus-eluting stent implantation: a case report. AB - BACKGROUND: Stent malapposition, stent fracture, and deformity, and inadequate anti-thrombotic therapy are known as the risk of stent thrombosis. We report a case of stent deformation with subsequent thrombus adhesion at the site of a partial stent fracture detected by intravascular ultrasound (IVUS) and optical coherence tomography (OCT). CASE PRESENTATION: A 61-year-old male patient was diagnosed as effort angina pectoris. Coronary angiography revealed obstructions in the proximal segment of the left anterior descending (LAD) and left circumflex artery (LCx). Elective percutaneous coronary intervention (PCI) was scheduled for these lesions in the prior hospital. First, an everolimus-eluting stent (EES) was implanted in the just proximal LAD slightly protruding into left main trunk. One week later, the treatment to residual obstruction at proximal LCx was attempted. During delivery of the stent to LCx, the proximal edge of the previously implanted LAD stent got stuck with the newly-deploying stent and deformed into the intravascular lumen when retracting the stent into the guide-catheter. He was immediately transferred to our hospital to repair these procedural problems. Two days later after the index procedure to LCx, intracoronary imaging with an IVUS and OCT were performed, and the IVUS/OCT imaging revealed thrombus adhesion around the deformed struts. The three-dimensional OCT guide also helped the detection of the deformed stent and the repair of deformed struts by additional stenting and kissing balloon technique. CONCLUSION: The current case suggested that thrombus adhesion can occur at the site of deformed and/or fractured stent at very early phase after stent implantation. PMID- 27245072 TI - A comprehensive survey of larval digenean trematodes and their snail hosts in central Alberta, Canada. AB - Digenean trematode distributions, compatibility profiles with their snail hosts, and complete life cycles remain mysteries in many parts of the world. Surveys of digenean biology and ecology provide further insight and perspective into just how incredibly diverse and important helminth parasites are in shaping local ecosystems. Past surveys have provided substantial characterizations of adult digeneans within their definitive hosts, and many now have contributed toward furthering our understanding of larval digeneans within their intermediate host communities. However, much information about the diversity of digeneans and their relationships with their snail intermediate hosts are lacking in many locations across the globe. This is certainly true in Canada, where few records related to digenean-snail relationships exist. Currently, there is a need for more information about the presence and distribution of digeneans across Canada, and how this compares to other parts of North America and beyond. To address this diversity gap in Western Canada, six lakes within central Alberta were surveyed for the presence of snails and larval digenean species and their associations. This investigation into the diversity of digeneans utilized a combined approach of morphological and molecular tools to identify 39 digenean species among five snail host species, from biweekly collections, taken over the course of 2 years (2013-2014). Here, digenean-snail combinations, presence, and distribution across sampling sites and lakes are reported. Overall, this survey contributes new information toward digenean-snail compatibility, life cycles, and distribution in Northern lake ecosystems within North America. PMID- 27245073 TI - Ecological study on antimicrobial-resistant zoonotic bacteria transmitted by flies in cattle farms. AB - Flies were qualitatively and quantitatively monitored on both livestock animals and the surrounding environment to investigate their role as a potential carrier for antimicrobial-resistant bacteria of zoonotic importance in cattle farms. This was done by the use of visual observations and animal photography; meanwhile, in the surrounding environment, flies were collected using sticky cards and then microscopically identified. Representative fly samples were cultured for bacterial isolation, biochemical identification, and then tested against common 12 antibiotics. The total average of dipterous flies in examined farms was 400.42 +/- 6.2. Culicoides biting midges were the most common existing species (70.01 %) followed by house flies, stable flies, and mosquitoes (18.31, 7.74, and 3.91 %, respectively) at X (2) = 9.0, P < 0.05. The most predominant bacterial isolates were Escherichia coli (22.6 %), Staphylococcus aureus and Enterobacter (17.3 % each), coagulase-negative Staphylococci (CNS) (14.7 %), Klebsiella sp. (8 %), Salmonella spp. (6.7 %), and Shigella spp. and Proteus spp. (6.7 % each). The tested bacterial isolates were resistant to variant antibiotics used. S. aureus exhibited 100 % resistance to colistine. However, E. coli revealed 92.9 and 78.6 % resistance against tetracycline and colistine, respectively. Both Salmonella spp. and Shigella spp. were 100 % resistant to penicillin, and Klebsiella sp. had 100 % resistance to tetracycline. In conclusion, Culicoides biting midges and house flies could be considered as a potential carrier for multi-drug-resistant bacteria of zoonotic importance. Furthermore, cows' environment has an essential role in propagation and wide spread of antimicrobial-resistant bacterial pathogens. PMID- 27245074 TI - Molecular detection and phylogenetic analysis of Hepatozoon spp. in questing Ixodes ricinus ticks and rodents from Slovakia and Czech Republic. AB - By amplification and sequencing of 18S rRNA gene fragments, Hepatozoon spp. DNA was detected in 0.08 % (4/5057) and 0.04 % (1/2473) of questing Ixodes ricinus ticks from Slovakia and Czech Republic, respectively. Hepatozoon spp. DNA was also detected in spleen and/or lungs of 4.45 % (27/606) of rodents from Slovakia. Prevalence of infection was significantly higher in Myodes glareolus (11.45 %) than in Apodemus spp. (0.28 %) (P < 0.001). Sequencing of 18S rRNA Hepatozoon spp. gene amplicons from I. ricinus showed 100 % identity with Hepatozoon canis isolates from red foxes or dogs in Europe. Phylogenetic analysis showed that at least two H. canis 18S rRNA genotypes exist in Slovakia of which one was identified also in the Czech Republic. The finding of H. canis in questing I. ricinus suggests the geographical spread of the parasite and a potential role of other ticks as its vectors in areas where Rhipicephalus sanguineus is not endemic. Sequencing of 18S rRNA gene amplicons from M. glareolus revealed the presence of two closely related genetic variants, Hepatozoon sp. SK1 and Hepatozoon sp. SK2, showing 99-100 % identity with isolates from M. glareolus from other European countries. Phylogenetic analysis demonstrates that 18S rRNA variants SK1 and SK2 correspond to previously described genotypes UR1 and UR2 of H. erhardovae, respectively. The isolate from Apodemus flavicollis (Hepatozoon sp. SK3b) was 99 % identical with isolates from reptiles in Africa and Asia. Further studies are necessary to identify the taxonomic status of Hepatozoon spp. parasitizing rodents in Europe and the host-parasite interactions in natural foci. PMID- 27245076 TI - Aggressive TAFRO syndrome with reversible cardiomyopathy successfully treated with combination chemotherapy. AB - TAFRO (thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly) syndrome is an atypical manifestation of Castleman's disease. However, the mechanism underlying this very rare syndrome remains unknown, and there is no established standard treatment. Here we report cases of two young females with TAFRO syndrome who showed similar clinical courses. Both cases showed severe anasarca, ascites, and thrombocytopenia. Although high-dose steroids were ineffective, combination chemotherapy showed remarkable effects. However, both patients developed severe but reversible heart failure after CHOP therapy owing to diffuse cardiomyopathy, which was presumably associated with TAFRO syndrome. Therefore, although combination chemotherapy may be very effective in the treatment of TAFRO syndrome, careful observation for cardiomyopathy development is needed, particularly when using adriamycin containing regimens. PMID- 27245077 TI - Relationship between spontaneous frequency of aneuploidy and cancer risk in 2145 healthy Hungarian subjects. AB - Numerical and structural chromosomal abnormalities are the hallmarks of cancer. Whereas the structural chromosome aberrations got more substantial attention for cancer risk assessment in a healthy population, the role of aneuploidy is much less understood in this respect. We analysed the frequency of numerical (and structural) aberrations in peripheral blood lymphocytes of 2145 healthy individuals between 1989 and 2010, taking into account different biological- and exposure-conditions. We also studied to what extent chromosome gains or losses may predict the probability of cancer. The average frequency of all aneuploid cells was 1.78+/-0.06% in the entire study population, which increased linearly with age. Gender and smoking did not influence the values, however, occupational exposures did. The highest frequency of aneuploidy was found in chemical industry workers (1.89+/-0.05%) compared with the lowest value of medical radiation workers (1.44+/-0.10%), respectively. No correlation was found between numerical and structural chromosomal aberrations. Cancer incidence followed for 1-23 years after the chromosome analysis showed a 1.26-fold relative risk (confidence interval: 1.02-1.58; P = 0.04) for those with higher frequency of aneuploid cells (1.82% vs. 1.44% in controls). Hypodiploidy had higher impact on the cancer risk than hyperdiploidy (1.72% vs. 0.10%). Our findings on the frequency of numerical aberrations in a healthy cohort represent the largest cytogenetic database from one laboratory with an unchanged mechanistic scoring method during a 30-year period, and provide basic information not only for genotoxicological studies but also confirm the association between numerical aberrations and cancer risk. PMID- 27245078 TI - The cardiovascular safety of methylphenidate. PMID- 27245075 TI - mTOR inhibitors effects on regulatory T cells and on dendritic cells. AB - The mammalian target of rapamycin (mTOR), a cytoplasmic serine/threonine kinase, represents a key biologic "switch" modulating cell metabolisms in response to environmental signals and is now recognized as a central regulator of the immune system. There is an increasing body of evidence supporting the hypothesis that mTOR inhibitors exhibit several biological properties in addition to immunosuppression, including anti-neoplastic effects, cardio-protective activities, and an array of immunomodulatory actions facilitating the development of an operational graft tolerance. The biological mechanisms explaining how mTOR inhibition can enable a tolerogenic state are still largely unclear. The induction of transplant tolerance might at the same time decrease rejection rate and minimize immunosuppression-related side effects, leading to an improvement in long-term graft outcome. In this scenario, T cell immunoregulation has been defined as the hallmark of peripheral tolerance. Two main immunologic cell populations have been reported to play a central role in this setting: regulatory T cells (Tregs) and dendritic cells (DCs). In this review we focus on mTOR inhibitors effects on Treg and DCs differentiation, activation, and function in the transplantation setting. PMID- 27245079 TI - Current and Evolving Methods to Visualize Biological Data in Cancer Research. AB - Although the measurements of clinical outcomes for cancer treatments have become diverse and complex, there remains a need for clear, easily interpreted representations of patients' experiences. With oncology trials increasingly reporting non-time-to-event outcomes, data visualization has evolved to incorporate parameters such as responses to therapy, duration and degree of response, and novel representations of underlying tumor biology. We review both commonly used and newly developed methods to display outcomes in oncology, with a focus on those that have evolved to represent complex datasets. PMID- 27245081 TI - A New Editor for Psychiatric Services in 2017. PMID- 27245080 TI - Correlates of Patient Activation and Acute Care Utilization Among Multimorbid Patients. AB - Patient activation and self-management have been associated with improved patient outcomes, including decreased re-hospitalization; however, little research has identified factors that predict patient activation in the multimorbid hospitalized patient. This descriptive correlational study included 200 patients with three or more chronic diseases discharged to home post-hospitalization. Standard multiple regression was used to identify correlates of patient activation. Multimorbid patients with lower activation scores had more acute care utilization (re-hospitalization and emergency department visits) 30 days post discharge than patients with higher activation scores. Predictors of patient activation were health literacy (p = .013), satisfaction with social role (p = .014), and involvement in chronic illness care (p = .001). Care transition programs focusing on health literacy, role satisfaction, and promoting patient centered care may improve patient outcomes for multimorbid patients. PMID- 27245083 TI - Brothers: Remembering Oliver Sacks. PMID- 27245084 TI - Smoke Free Program at Massachusetts Mental Health Center: A Peer-Supported Approach. PMID- 27245085 TI - A CBT Intervention Targeting Competitive Work Outcomes for Persons With Mental Illness. PMID- 27245086 TI - News & Notes. PMID- 27245087 TI - Routine Prophylactic Cardioprotective Therapy Should Not Be Given to All Recipients of Potentially Cardiotoxic Cancer Chemotherapy. AB - With growing recognition of the associations between cancer therapy and cardiotoxicity, attention has increasingly focused on the prevention of cancer therapy-related cardiovascular disease. Various strategies for cardioprotection have been proposed, including routine administration of therapies such as inhibitors of the renin-angiotensin-aldosterone system and beta-blockers. We argue this approach is unsupported by the evidence and will be associated with a high likelihood of adverse effects. We highlight alternate strategies for managing this emerging issue, which focus on a targeted approach to primary prevention driven by early identification of cardiotoxicity and selective prophylaxis of patients at increased risk for developing cardiotoxicity. PMID- 27245088 TI - "What Will Become of Me if They Take This Away?" Zimbabwean Women's Perceptions of "Free" ART. AB - The evolution of antiretroviral therapies (ART) has redefined HIV infection from a life-threatening disease to a chronic manageable condition. Despite ART, HIV infection remains a serious health burden in Zimbabwe, particularly among women of reproductive age. In this interpretive phenomenology study, we interviewed 17 women with advanced HIV infection to uncover and understand their experiences of living with HIV infection in the ART era. Two themes (knowing the restorative power of ART and the heavy burden of being infected with HIV) reflected the women's experiences. ART brought physical and mental relief, but did not change the sobering reality of poverty or the challenges posed by the infective nature of HIV. The heavily donor-funded Zimbabwean ART program has been a success story, but there is uncertainty over its long-term sustainability. In resource-limited countries, clinicians and other stakeholders should continue to focus on HIV prevention as the cornerstone of HIV programming. PMID- 27245089 TI - Does ex vivo CD34+ positive selection influence outcome after autologous hematopoietic stem cell transplantation in systemic sclerosis patients? PMID- 27245090 TI - Identification and validation of biomarkers associated with acute and chronic graft versus host disease. PMID- 27245091 TI - NODULES WITH ACTIVATED DEFENSE 1 is required for maintenance of rhizobial endosymbiosis in Medicago truncatula. AB - The symbiotic interaction between legume plants and rhizobia results in the formation of root nodules, in which symbiotic plant cells host and harbor thousands of nitrogen-fixing rhizobia. Here, a Medicago truncatula nodules with activated defense 1 (nad1) mutant was identified using reverse genetics methods. The mutant phenotype was characterized using cell and molecular biology approaches. An RNA-sequencing technique was used to analyze the transcriptomic reprogramming of nad1 mutant nodules. In the nad1 mutant plants, rhizobial infection and propagation in infection threads are normal, whereas rhizobia and their symbiotic plant cells become necrotic immediately after rhizobia are released from infection threads into symbiotic cells of nodules. Defense associated responses were detected in nad1 nodules. NAD1 is specifically present in root nodule symbiosis plants with the exception of Morus notabilis, and the transcript is highly induced in nodules. NAD1 encodes a small uncharacterized protein with two predicted transmembrane helices and is localized at the endoplasmic reticulum. Our data demonstrate a positive role for NAD1 in the maintenance of rhizobial endosymbiosis during nodulation. PMID- 27245092 TI - Evaluating the Role of Genetic Variants on first-line antiepileptic drug response in North India: Significance of SCN1A and GABRA1 Gene Variants in Phenytoin Monotherapy and its Serum Drug Levels. AB - AIM: The present study aimed to evaluate association of genetic variants on drug response and therapy optimization parameters in patients treated with first-line antiepileptic drugs (AEDs). Genetic variants from ion channels, their functionally related genes, and synaptic vesicle cycle (SVC) genes with a potential role in epilepsy pathophysiology were thus prioritized. METHODS: A total of 12 genes from ion channels and related gene set and seven genes from SVC comprising 155 SNPs were genotyped and evaluated with drug response, dose levels, and drug levels in 408 patients with epilepsy. RESULTS: Both GABRA1 and SCN1A variants showed haplotypic and diplotypic associations in response to phenytoin (PHT). Diplotype analysis of GABRA1 variants revealed association of rs12658835|rs7735530 (AG/AG) (P-valuecorrected = 0.034, OR = 3.75, 95% CI = 1.36 11.05) and rs12658835|rs7735530|rs7732641|rs2279020 (AGCA/AGCA) (P-valuecorrected = 0.035, OR = 2.48, 95% CI = 0.96-6.41) with recurrent seizures. SCN1A haplotype rs6432860|rs3812718 (AC: P-valuecorrected = 0.022, OR = 2.72, 95% CI = 1.39 5.35) and diplotype (AC/AC: P-valuecorrected = 0.034, OR = 6.42, 95% CI = 1.10 65.76) were further observed to be associated with recurrent seizures. With respect to therapy optimization parameters, we observed significantly lower dose adjusted drug levels at maximum dose of PHT in patients carrying AC/AC diplotype (P-value = 0.021). CONCLUSION: The results further substantiate the role of GABRA1 in PHT mode of action and contribution of SCN1A in response and therapy optimization with PHT monotherapy. PMID- 27245093 TI - Synthetic Antenna Functioning As Light Harvester in the Whole Visible Region for Enhanced Hybrid Photosynthetic Reaction Centers. AB - The photosynthetic reaction center (RC) from the Rhodobacter sphaeroides bacterium has been covalently bioconjugated with a NIR-emitting fluorophore (AE800) whose synthesis was specifically tailored to act as artificial antenna harvesting light in the entire visible region. AE800 has a broad absorption spectrum with peaks centered in the absorption gaps of the RC and its emission overlaps the most intense RC absorption bands, ensuring a consistent increase of the protein optical cross section. The covalent hybrid AE800-RC is stable and fully functional. The energy collected by the artificial antenna is transferred to the protein via FRET mechanism, and the hybrid system outperforms by a noteworthy 30% the overall photochemical activity of the native protein under the entire range of visible light. This improvement in the optical characteristic of the photoenzyme demonstrates the effectiveness of the bioconjugation approach as a suitable route to new biohybrid materials for energy conversion, photocatalysis, and biosensing. PMID- 27245095 TI - Panobinostat-A Potential Treatment for Metastasized Ewing Sarcoma? A Case Report. AB - Ewing sarcoma (ES) is a form of primary bone cancer, with few treatment options for patients who develop relapse with an overall 5-year survival of 13%. New treatment options are needed and histone deacetylase (HDAC) inhibitors show encouraging results in preclinical studies. Our patient developed inoperable progressive lung metastases and was treated with the HDAC inhibitor panobinostat. During 18 months of treatment, no new lesions appeared; the treatment was stopped due to progression. This clinical observation warrants further evaluation of HDAC inhibitors in ES. Combination with chemotherapy and biomarker studies could improve the therapeutic index of these classes of compounds. PMID- 27245094 TI - Global assessment of imprinted gene expression in the bovine conceptus by next generation sequencing. AB - Genomic imprinting is an epigenetic mechanism that leads to parental-allele specific gene expression. Approximately 150 imprinted genes have been identified in humans and mice but less than 30 have been described as imprinted in cattle. For the purpose of de novo identification of imprinted genes in bovine, we determined global monoallelic gene expression in brain, skeletal muscle, liver, kidney and placenta of day ~105 Bos taurus indicus * Bos taurus taurus F1 conceptuses using RNA sequencing. To accomplish this, we developed a bioinformatics pipeline to identify parent-specific single nucleotide polymorphism alleles after filtering adenosine to inosine (A-to-I) RNA editing sites. We identified 53 genes subject to monoallelic expression. Twenty three are genes known to be imprinted in the cow and an additional 7 have previously been characterized as imprinted in human and/or mouse that have not been reported as imprinted in cattle. Of the remaining 23 genes, we found that 10 are uncharacterized or unannotated transcripts located in known imprinted clusters, whereas the other 13 genes are distributed throughout the bovine genome and are not close to any known imprinted clusters. To exclude potential cis-eQTL effects on allele expression, we corroborated the parental specificity of monoallelic expression in day 86 Bos taurus taurus * Bos taurus taurus conceptuses and identified 8 novel bovine imprinted genes. Further, we identified 671 candidate A to-I RNA editing sites and describe random X-inactivation in day 15 bovine extraembryonic membranes. Our results expand the imprinted gene list in bovine and demonstrate that monoallelic gene expression can be the result of cis-eQTL effects. PMID- 27245097 TI - Genetic comparison of two color morphs of northern snakehead (Channa argus) and Chnannidae family. AB - Relationships of two species of Channa argus (northern snakeheads) named "Bicolor type" and "White type", as well as other six Channa species were investigated based on their partial sequence of mitochondrial DNA 16S rRNA genes in the present study. For the Channa family, the average genetic distance was 0.0863 with the inter-species genetic distance ranged from 0.0173 to 0.1384, and the average intra-species genetic distance in the genus channa was estimated as 0.00273 (range: 0.0019 to 0.0038). For the two C. argus species, the mean pair wise genetic distance between "Bicolor type" and "White type" northern snakehead was estimated as 0.00218, which was within the intra-species genetic distance interval for Channa species, indicating that they belonged to the same species at molecular level. Moreover, these snakeheads can be divided into two distinct groups via 16S rRNA, which might be more accurate for Channa classification than traditional method based on the absence or presence of the pelvic fins of the fish. PMID- 27245098 TI - A Greedy reassignment algorithm for the PBS minimum monitor unit constraint. AB - Proton pencil beam scanning (PBS) treatment plans are made of numerous unique spots of different weights. These weights are optimized by the treatment planning systems, and sometimes fall below the deliverable threshold set by the treatment delivery system. The purpose of this work is to investigate a Greedy reassignment algorithm to mitigate the effects of these low weight pencil beams. The algorithm is applied during post-processing to the optimized plan to generate deliverable plans for the treatment delivery system. The Greedy reassignment method developed in this work deletes the smallest weight spot in the entire field and reassigns its weight to its nearest neighbor(s) and repeats until all spots are above the minimum monitor unit (MU) constraint. Its performance was evaluated using plans collected from 190 patients (496 fields) treated at our facility. The Greedy reassignment method was compared against two other post-processing methods. The evaluation criteria was the gamma-index pass rate that compares the pre-processed and post-processed dose distributions. A planning metric was developed to predict the impact of post-processing on treatment plans for various treatment planning, machine, and dose tolerance parameters. For fields with a pass rate of 90 +/- 1% the planning metric has a standard deviation equal to 18% of the centroid value showing that the planning metric and gamma-index pass rate are correlated for the Greedy reassignment algorithm. Using a 3rd order polynomial fit to the data, the Greedy reassignment method has 1.8 times better planning metric at 90% pass rate compared to other post-processing methods. As the planning metric and pass rate are correlated, the planning metric could provide an aid for implementing parameters during treatment planning, or even during facility design, in order to yield acceptable pass rates. More facilities are starting to implement PBS and some have spot sizes (one standard deviation) smaller than 5 mm, hence would require small spot spacing. While this is not the only parameter that affects the optimized plan, the perturbation due to the minimum MU constraint increases with decreasing spot spacing. This work could help to design the minimum MU threshold with the goal to keep the gamma-index pass rate above an acceptable value. PMID- 27245096 TI - The Wheat GT Factor TaGT2L1D Negatively Regulates Drought Tolerance and Plant Development. AB - GT factors are trihelix transcription factors that specifically regulate plant development and stress responses. Recently, several GT factors have been characterized in different plant species; however, little is known about the role of GT factors in wheat. Here, we show that TaGT2L1A, TaGT2L1B, and TaGT2L1D are highly homologous in hexaploid wheat, and are localized to wheat chromosomes 2A, 2B, and 2D, respectively. These TaGT2L1 genes encode proteins containing two SANT domains and one central helix. All three homologs were ubiquitously expressed during wheat development and were responsive to osmotic stress. Functional analyses demonstrated that TaGT2L1D acts as a transcriptional repressor; it was able to suppress the expression of AtSDD1 in Arabidopsis by binding directly to the GT3 box in its promoter that negatively regulates drought tolerance. TaGT2L1D overexpression markedly increased the number of stomata and reduced drought tolerance in gtl1-3 plants. Notably, ectopic expression of TaGT2L1D also affected floral organ development and overall plant growth. These results demonstrate that TaGT2L1 is an ortholog of AtGTL1, and that it plays an evolutionarily conserved role in drought resistance by fine tuning stomatal density in wheat. Our data also highlight the role of TaGT2L1 in plant growth and development. PMID- 27245099 TI - Sustained Resistive Switching in a Single Cu:7,7,8,8-tetracyanoquinodimethane Nanowire: A Promising Material for Resistive Random Access Memory. AB - We report a new type of sustained and reversible unipolar resistive switching in a nanowire device made from a single strand of Cu:7,7,8,8 tetracyanoquinodimethane (Cu:TCNQ) nanowire (diameter <100 nm) that shows high ON/OFF ratio (~10(3)), low threshold voltage of switching (~3.5 V) and large cycling endurance (>10(3)). This indicates a promising material for high density resistive random access memory (ReRAM) device integration. Switching is observed in Cu:TCNQ single nanowire devices with two different electrode configuration: symmetric (C-Pt/Cu:TCNQ/C-Pt) and asymmetric (Cu/Cu:TCNQ/C-Pt), where contacts connecting the nanowire play an important role. This report also developed a method of separating out the electrode and material contributions in switching using metal-semiconductor-metal (MSM) device model along with a direct 4-probe resistivity measurement of the nanowire in the OFF as well as ON state. The device model was followed by a phenomenological model of current transport through the nanowire device which shows that lowering of potential barrier at the contacts likely occur due to formation of Cu filaments in the interface between nanowire and contact electrodes. We obtain quantitative agreement of numerically analyzed results with the experimental switching data. PMID- 27245100 TI - Describing Self-Care Self-Efficacy: Definition, Measurement, Outcomes, and Implications. AB - PURPOSE: The pragmatic utility method of concept analysis was used to explore the usefulness of the concept self-care self-efficacy. DATA SOURCES: Empirical studies across disciplines published between 1996 and 2015 were used as data. DATA SYNTHESIS: A data matrix was developed. Analytical questions and responses were derived from the data to understand patterns, develop new knowledge and achieve synthesis. CONCLUSION: Usefulness of the concept is contingent on how it is defined and measured. Self-care self-efficacy is associated with performance of self-care activities and positive health outcomes in diverse populations. IMPLICATIONS: Research can guide development of targeted interventions to increase patients' self-care self-efficacy, thus reducing costs, and assisting people to achieve optimal health. PMID- 27245101 TI - Itch promotes the neddylation of JunB and regulates JunB-dependent transcription. AB - Protein neddylation is essential for the viability of most organisms and is widely involved in the regulation of immunity, DNA damage and repair, cell signaling and cell cycle. Unlike RING-type neddylation ligases, HECT-type neddylation ligase remains less defined. Here, we show that Itch is a novel HECT type neddylation E3 ligase and we identify JunB as a substrate of Nedd8 modification by Itch. JunB neddylation attenuates its transcriptional activity. In addition, JunB neddylation mediated by Itch promotes its ubiquitination dependent degradation. Therefore, these findings define a new HECT-type neddylation ligase and its neddylation substrate. PMID- 27245102 TI - Description, measurement and evaluation of tertiary-education food environments. AB - Obesity in young adults is an increasing health problem in Australia and many other countries. Evidence-based information is needed to guide interventions that reduce the obesity-promoting elements in tertiary-education environments. In a food environmental audit survey, 252 outlets were audited across seven institutions: three universities and four technical and further education institutions campuses. A scoring instrument called the food environment-quality index was developed and used to assess all food outlets on these campuses. Information was collated on the availability, accessibility and promotion of foods and beverages and a composite score (maximum score=148; higher score indicates healthier outlets) was calculated. Each outlet and the overall campus were ranked into tertiles based on their 'healthiness'. Differences in median scores for each outcome measure were compared between institutions and outlet types using one-way ANOVA with post hoc Scheffe's testing, chi 2 tests, Kruskal Wallis H test and the Mann-Whitney U test. Binomial logistic regressions were used to compare the proportion of healthy v. unhealthy food categories across different types of outlets. Overall, the most frequently available items were sugar-sweetened beverages (20 % of all food/drink items) followed by chocolates (12 %), high-energy (>600 kJ/serve) foods (10 %), chips (10 %) and confectionery (10 %). Healthy food and beverages were observed to be less available, accessible and promoted than unhealthy options. The median score across all outlets was 72 (interquartile range=7). Tertiary-education food environments are dominated by high-energy, nutrient-poor foods and beverages. Interventions to decrease availability, accessibility and promotion of unhealthy foods are needed. PMID- 27245103 TI - A high-fat, high-glycaemic index, low-fibre dietary pattern is prospectively associated with type 2 diabetes in a British birth cohort. AB - The combined association of dietary fat, glycaemic index (GI) and fibre with type 2 diabetes has rarely been investigated. The objective was to examine the relationship between a high-fat, high-GI, low-fibre dietary pattern across adult life and type 2 diabetes risk using reduced rank regression. Data were from the MRC National Survey of Health and Development. Repeated measures of dietary intake estimated using 5-d diet diaries were available at the age of 36, 43 and 53 years for 1180 study members. Associations between dietary pattern scores at each age, as well as longitudinal changes in dietary pattern z-scores, and type 2 diabetes incidence (n 106) from 53 to 60-64 years were analysed. The high-fat, high-GI, low-fibre dietary pattern was characterised by low intakes of fruit, vegetables, low-fat dairy products and whole-grain cereals, and high intakes of white bread, fried potatoes, processed meat and animal fats. There was an increasing trend in OR for type 2 diabetes with increasing quintile of dietary pattern z-scores at the age of 43 years among women but not among men. Women in the highest z-score quintile at the age of 43 years had an OR for type 2 diabetes of 5.45 (95 % CI 2.01, 14.79). Long-term increases in this dietary pattern, independently of BMI and waist circumference, were also detrimental among women: for each 1 sd unit increase in dietary pattern z-score between 36 and 53 years, the OR for type 2 diabetes was 1.67 (95 % CI 1.20, 2.43) independently of changes in BMI and waist circumference in the same periods. A high-fat, high-GI, low fibre dietary pattern was associated with increased type 2 diabetes risk in middle-aged British women but not in men. PMID- 27245105 TI - Pragmatist Epistemology and Jane Addams: Fundamental Concepts for the Social Paradigm of Occupational Therapy. AB - The objective of this manuscript is to contribute to the education of future occupational therapists within the current paradigm of the profession. To this purpose, some of the conceptual foundations of pragmatist epistemology and philosophical contributions of the philosopher Jane Addams are presented. Some pragmatist fundamentals such as the holistic vision of the human being, the paradox of separating "knowing from doing", and giving the usefulness of the activity and knowledge primacy in the process of human development, inspired the profession of Occupational Therapy in the United States at the beginning of the twentieth century. Today, almost 100 years after the founding of the National Society for the Promotion of Occupational Therapy, pragmatism is still relevant to the profession. Specifically, its pertinence is related to the current scenario of the profession, and its powerful development in working scopes related to socio-community fields. This helps identify how we are on the verge of another paradigm, known as Social Paradigm of the Occupation. This new social understanding of the discipline allows us to understand the relevance of professional work in community or social contexts. Future research could address how the pragmatism contributes to the understanding of occupation as a social phenomenon within this new paradigm. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27245106 TI - Corrigendum to "Intracellular mechanisms coupled to NPY Y2 and Y5 receptor activation and lipid accumulation in murine adipocytes" [neuropeptides 46/6 (2012) 359-366]. PMID- 27245107 TI - Religion and Public Perceptions of Gays and Lesbians in South Korea. AB - Public support for gay and lesbian rights has increased in Western democracies, yet less is known regarding views in South Korea, or East Asia more broadly. Rather than broad cultural claims, this analysis asks to what extent religious identification explains perceptions of gays and lesbians. Public opinion survey data from South Korea finds that Protestants were consistently less supportive of homosexual issues compared to Catholics, Buddhists, and those without a religious identification. Furthermore, after controlling for religion, identification with the largest conservative party associated with less support. PMID- 27245109 TI - Feedbacks and tipping points in organismal response to oxidative stress. AB - Biological feedbacks play a crucial role in determining effects of toxicants, radiation, and other environmental stressors on organisms. Focusing on reactive oxygen species (ROS) that are increasingly recognized as a crucial mediator of many stressor effects, we investigate how feedback strength affects the ability of organisms to control negative effects of exposure. We do this by developing a general theoretical framework for describing effects of a wide range of stressors and species. The framework accounts for positive and negative feedbacks representing cellular processes: (i) production of ROS due to metabolism and the stressor, (ii) ROS reactions with cellular compounds that cause damage, and (iii) cellular control of both ROS and damage. We suggest functional forms that capture generic properties of cellular control mechanisms constituting the feedbacks, assess stability of equilibrium states in the resulting models, and investigate tipping points at which cellular control breaks down causing unregulated increase of ROS and damage. Depending on the chosen functional forms, the models can have zero, one, or two positive steady states; except in one singular case, the steady state with lowest values of ROS and damage is locally stable. We found two types of tipping points: those induced by changes in the parameters (including the stressor intensity), and those induced by the history of exposure, i.e. ROS and damage levels. The relatively simple models effectively describe several patterns of cellular responses to stress, such as the covariation of ROS and damage, the break-down of cellular control leading to explosion of ROS and/or damage, increase in damage even when ROS is (near)-constant, and the effects of exposure history on the ability of the cell to handle additional stress. The models quantify dynamics of cellular control, and could therefore be used to estimate the metabolic costs of stress and help integrate them into models that use energetic considerations to model organism's response to the environment. Although developed with unicellular organisms in mind, our models can be applied to all multicellular organisms that utilize similar feedbacks when dealing with stress. PMID- 27245104 TI - Vitamin D and colorectal cancer: molecular, epidemiological and clinical evidence. AB - In many cells throughout the body, vitamin D is converted into its active form calcitriol and binds to the vitamin D receptor (VDR), which functions as a transcription factor to regulate various biological processes including cellular differentiation and immune response. Vitamin D-metabolising enzymes (including CYP24A1 and CYP27B1) and VDR play major roles in exerting and regulating the effects of vitamin D. Preclinical and epidemiological studies have provided evidence for anti-cancer effects of vitamin D (particularly against colorectal cancer), although clinical trials have yet to prove its benefit. In addition, molecular pathological epidemiology research can provide insights into the interaction of vitamin D with tumour molecular and immunity status. Other future research directions include genome-wide research on VDR transcriptional targets, gene-environment interaction analyses and clinical trials on vitamin D efficacy in colorectal cancer patients. In this study, we review the literature on vitamin D and colorectal cancer from both mechanistic and population studies and discuss the links and controversies within and between the two parts of evidence. PMID- 27245110 TI - Adipokines and soluble cell adhesion molecules in insulin resistant and non insulin resistant women with polycystic ovary syndrome. AB - INTRODUCTION: Insulin resistance (IR) is closely associated with increased atherogenic risk. OBJECTIVE: To investigate leptin, adiponectin, soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1) levels and their relationship with each other and metabolic parameters in women with polycystic ovary syndrome (PCOS). METHODS: The study included 76 PCOS women divided into insulin resistant and non-insulin resistant. Anthropometric parameters, glucose and lipid parameters, leptin, adiponectin, sICAM-1 and sVCAM-1 were determined. Homeostasis model of IR index(HOMA-IR), atherogenic index of plasma(AIP) and leptin/adiponectin ratio were calculated. HOMA-IR > 2.5 and/or fasting plasma glucose/immunoreactive insulin ratio < 0.333 were used as markers for IR. RESULTS: Non-insulin resistant PCOS had significantly higher adiponectin and sVCAM-1 levels. AIP was significantly higher in insulin resistant PCOS. Adiponectin showed a positive correlation with sVCAM-1 and sICAM-1. CONCLUSION: Insulin resistant PCOS women were at higher atherogenic risk compared to non-insulin resistant group. sVCAM-1 data confirms the necessity of further investigations for clarifying its role in IR. PMID- 27245111 TI - Kinetic instability, symmetry breaking and role of geometric constraints on the upper bounds of disorder in two dimensional packings. AB - Although the energetics of grain boundaries are more or less understood, their mechanical description remains challenging primarily because of very fast dynamics in the atomic length scale. By contrast, granular dynamics are extraordinarily sluggish. In this study, two dimensional centripetal packings of macroscopic granular particles are employed to investigate the role of geometric aspects of grain boundary formation. Using a novel sampling scheme, the extensive configuration space is well represented by a few prominent structures. Our results suggest that cohesive effects "iron out" any disorder present and enforce a transition towards a "fixed point" basin associated with a universal high density jammed hexagonal structure. Two main conjectures are advanced: (i) the appearance of grain boundary like structures is the manifestation of the kinetic instabilities of the densification process and has its origin in the structural rearrangement and (ii) the departure from six-fold coordination in the final packing is bounded from above by a sixth of the angular dispersion present in the initial configuration. If similar predictive consequences are further developed for three dimensional cases, this may have far reaching consequences in many areas of science and technology. PMID- 27245113 TI - In search of morphological modules: a systematic review. AB - Morphological modularity arises in complex living beings due to a semi independent inheritance, development, and function of body parts. Modularity helps us to understand the evolvability and plasticity of organismal form, and how morphological variation is structured during evolution and development. For this reason, delimiting morphological modules and establishing the factors involved in their origins is a lively field of inquiry in biology today. Although it is thought that modularity is pervasive in all living beings, actually we do not know how often modularity is present in different morphological systems. We also do not know whether some methodological approaches tend to reveal modular patterns more easily than others, or whether some factors are more related to the formation of modules or the integration of the whole phenotype. This systematic review seeks to answer these type of questions through an examination of research investigating morphological modularity from 1958 to present. More than 200 original research articles were gathered in order to reach a quantitative appraisal on what is studied, how it is studied, and how the results are explained. The results reveal an heterogeneous picture, where some taxa, systems, and approaches are over-studied, while others receive minor attention. Thus, this review points out various trends and gaps in the study of morphological modularity, offering a broad picture of current knowledge and where we can direct future research efforts. PMID- 27245112 TI - Genetic Variation in the TAS2R38 Bitter Taste Receptor and Gastric Cancer Risk in Koreans. AB - The human TAS2R38 gene encodes a bitter taste receptor that regulates the bitterness perception and differentiation of ingested nutritional/poisonous compounds in the oral cavity and gastrointestinal tract. TAS2R38 gene variants are associated with alterations in individual sensitivity to bitter taste and food intake; hence, these genetic variants may modify the risk for diet-related diseases, including cancer. However, little is known about the association between TAS2R38 polymorphisms and gastric cancer susceptibility. The present case control study examined the influence of TAS2R38 polymorphisms on food intake and determined whether they predict gastric cancer risk in Koreans. A total of 1,580 subjects, including 449 gastric cancer cases, were genotyped for TAS2R38 A49P, V262A, I296V and diplotypes. Dietary data were analysed to determine the total consumption of energy, fibre, vegetables, fruits, sweets, fats, alcohol and cigarettes. TAS2R38 diplotype was not associated with food, alcohol or cigarette consumption, either independent or dependent of gastric cancer phenotype. However, the PAV/AVI diplotype significantly increased gastric cancer risk (adjusted odds ratio: 1.513; 95% confidence interval: 1.148-1.994) independent of dietary intake. Findings suggest that TAS2R38 may be associated with the risk for gastric cancer in Koreans, although the TAS2R38 diplotype did not influence dietary intake. PMID- 27245114 TI - Pirfenidone suppresses MAPK signalling pathway to reverse epithelial-mesenchymal transition and renal fibrosis. AB - AIM: Recent studies indicate that pirfenidone (PFD) may have anti-fibrotic effects in many tissues, but the potential molecular mechanism remains unknown. The purpose of this study is to investigate the potential effects of PFD on epithelial-to-mesenchymal transition (EMT) and renal fibrosis in a unilateral ureteral obstruction (UUO) rat model and the involved molecular mechanism related to cultured human renal proximal tubular epithelial cells (HK-2). METHODS: Sixty rats were randomly divided into three groups: sham-operated, vehicle-treated UUO, and PFD-treated UUO. Kidney specimens were collected at day 7 or 14 after UUO. PFD treatment was also performed for human HK-2. The tubulointerstitial injury, interstitial collagen deposition, and expression of type I and III collagen, alpha-SMA, S100A4, fibronection and E-cadherin were assessed. In addition, extracellular signal regulated kinase (ERK1/2), p38 MAPK (p38), and c-Jun N terminal kinase/stress-activated protein kinase (JNK) were also detected. RESULTS: In vitro, PFD significantly attenuated TGF-beta1-induced EMT and extracellular matrix (ECM) synthesis, as determined by reducing expression of alpha-SMA, type I and III collagen, S100A4, fibronection, and increased expression of E-cadherin. PFD treatment attenuated TGF-beta1-induced up regulation of phosphorylation of ERK1/2, p38 and JNK. In vivo, PFD reduced the degree of tubulointerstitial injury and renal fibrosis, which was associated with reduced expression of TGF-beta1, type III collagen, alpha-SMA, S100A4, fibronection, and increased expression of E-cadherin. CONCLUSION: These results suggest that pirfenidone is able to attenuate EMT and fibrosis in vivo and in vitro through antagonizing the MAPK pathway, providing a potential treatment to alleviate renal tubulointerstitial fibrosis. PMID- 27245116 TI - Biomarkers in Parkinson's disease: From pathophysiology to early diagnosis. PMID- 27245115 TI - Perceived Severity of and Susceptibility to Overdose Among Injection Drug Users: Relationships With Overdose History. AB - BACKGROUND: Overdose is relatively common among injection drug users (IDUs) yet little is known about how overdose-related health beliefs influence overdose experiences or risk reduction. OBJECTIVES: This study examines the association of perceived susceptibility to and perceived severity of nonfatal overdose with overdose history among IDUs attending needle exchange programs (NEPs) to inform prevention efforts. METHODS: In 2009-2010, IDUs (N = 91) attending NEPs completed self-report surveys. Negative binomial regression modeled the association between demographics, age of injection initiation, length of time attending the NEP, perceived severity of overdose, and perceived susceptibility to overdose with lifetime history of nonfatal overdose. RESULTS: Over half (55%) of participants reported lifetime overdose, with a mean of 2.9 overdoses. A multivariable negative binomial regression model revealed that younger current age, older age of first injection, non-Caucasian race, higher perceived severity of overdose, and lower perceived susceptibility to overdose were significantly correlated with fewer lifetime overdoses. CONCLUSIONS: Although our methodology precludes causal inferences, these findings are consistent with the hypothesis that perceived severity and perceived susceptibility are among several factors associated with IDUs' use of protective behaviors, which could influence the likelihood of overdose. Future prospective research to explore the impact of this and other health beliefs on risk behaviors and overdose could help improve the effectiveness of behavioral interventions. PMID- 27245117 TI - Fluorescence Dynamics in the Endoplasmic Reticulum of a Live Cell: Time-Resolved Confocal Microscopy. AB - Fluorescence dynamics in the endoplasmic reticulum (ER) of a live non-cancer lung cell (WI38) and a lung cancer cell (A549) are studied by using time-resolved confocal microscopy. To selectively study the organelle, ER, we have used an ER Tracker dye. From the emission maximum (lambdamaxem) of the ER-Tracker dye, polarity (i.e. dielectric constant, epsilon) in the ER region of the cells (~500 nm in WI38 and ~510 nm in A549) is estimated to be similar to that of chloroform (lambdamaxem =506 nm, epsilon~5). The red shift by 10 nm in lambdamaxem in the cancer cell (A549) suggests a slightly higher polarity compared to the non-cancer cell (WI38). The fluorescence intensity of the ER-Tracker dye exhibits prolonged intermittent oscillations on a timescale of 2-6 seconds for the cancer cell (A549). For the non-cancer cell (WI38), such fluorescence oscillations are much less prominent. The marked fluorescence intensity oscillations in the cancer cell are attributed to enhanced calcium oscillations. The average solvent relaxation time () of the ER region in the lung cancer cell (A549, 250+/-50 ps) is about four times faster than that in the non-cancer cell (WI38, 1000+/-50 ps). PMID- 27245119 TI - Nucleophilicity of Alkyl Zirconocene and Titanocene Precatalysts, and Kinetics of Activation by Carbenium Ions and by B(C6 F5 )3. AB - Kinetics of activation of methyl and benzyl metallocene precatalysts by benzhydrylium ions, tritylium ions, and triarylborane B(C6 F5 )3 were measured spectrophotometrically. The rate constants correlate linearly with the electrophilicity parameter E of the benzhydrylium and tritylium ions employed, allowing us to determine the sigma-nucleophilicities of the metal-carbon bond of several zirconocenes and titanocenes. Bridging, substitution, metal, and ligand effects on the rates of metal-alkyl bond cleavage (M=Zr, Ti) were studied and structure-reactivity correlations were used to predict the kinetics of generation of metallocenium ions pairs, which are active catalysts in polymerization reactions and are highly electrophilic Lewis acids in frustrated Lewis pair catalysis. PMID- 27245118 TI - Influences of yokukansankachimpihange on aggressive behavior of zinc-deficient mice and actions of the ingredients on excessive neural exocytosis in the hippocampus of zinc-deficient rats. AB - We examined the effect of Yokukansankachimpihange (YKSCH), a form of Yokukansan containing parts of two herbaceous plants, Citrus Unshiu Peel (Chimpi) and Pinellia Tuber (Hange), on aggressive behavior of mice housed individually. Mice were fed a zinc-deficient diet for 2 weeks. In a resident-intruder test, the cumulative duration of aggressive behavior was decreased in zinc-deficient mice administrated drinking water containing YKSCH (approximately 300 mg/kg body weight/day) for 2 weeks. We tested mice for geissoschizine methyl ether (GM), which is contained in Uncaria Hook, and 18beta-glycyrrhetinic acid (GA), a major metabolite of glycyrrhizin contained in Glycyrrhiza, which were contained in YKS and YKSCH. In hippocampal slices from zinc-deficient rats, excess exocytosis at mossy fiber boutons induced with 60 mM KCl was attenuated in the presence of GA (100-500 uM) or GM (100 uM). The intracellular Ca2+ level, which showed an increase induced by 60 mM KCl, was also attenuated in the presence of GA (100-500 uM) or GM (100 uM). These results suggest that GA and GM ameliorate excess glutamate release from mossy fiber boutons by suppressing the increase in intracellular Ca2+ signaling. These ameliorative actions may contribute to decreasing the aggressiveness of mice individually housed under zinc deficiency, potentially by suppressing excess glutamatergic neuron activity in the hippocampus. PMID- 27245120 TI - Postictal ammonia as a biomarker for electrographic convulsive seizures: A prospective study. AB - OBJECTIVE: Transient hyperammonemia (THA) was reported to follow generalized convulsions without sufficient evidence to confirm the epileptic nature of those events. We aimed to determine if postictal THA can differentiate between different types of events as confirmed electroencephalographically using video electroencephalography (vEEG) monitoring. METHODS: In our prospective cohort, we screened all consented adults (>18 years) admitted to the epilepsy monitoring unit. Ammonia was checked at baseline, within 60 min of the event (for all patients) and 24 h after event (whenever possible). Patients were grouped into generalized convulsive seizures (GCS), psychogenic nonepileptic seizures with convulsions (PNES-C), or focal seizures (FS) based on vEEG. Data were analyzed using descriptive statistics and parametric/nonparametric methods. RESULTS: Of 78 patients enrolled, 13 had GCS, 8 had FS, and 9 had PNES-C. The groups were different with regard to gender (p = 0.04) and baseline ammonia (p = 0.02), but not age. The change in ammonia postictally from baseline was significantly different among the three groups (p = 0.004). The area under the receiver operator characteristic (ROC) curve for postictal ammonia to distinguish GCS from other groups was 0.88 (95% confidence interval [CI] 0.69-0.96) suggesting ammonia to be a good test differentiating epileptic GCS from other events. An ammonia level of >=80 MUmol/L correctly classified 80% of our patients (sensitivity 53.9%, specificity 100%). SIGNIFICANCE: Our results provide objective evidence for the association between THA and GCS seizures utilizing vEEG monitoring, and a basis for future studies to determine the role of postictal ammonia as an inexpensive diagnostic test to diagnose GCS. PMID- 27245121 TI - A Randomized Trial of Complete Versus Culprit-Only Revascularization During Primary Percutaneous Coronary Intervention in Diabetic Patients With Acute ST Elevation Myocardial Infarction and Multi Vessel Disease. AB - BACKGROUND: Recent randomized trials and meta-analyses demonstrated that a complete revascularization of significant non culprit lesions in patients with ST elevation myocardial infarction (STEMI) is superior to a culprit only revascularization approach in reducing major adverse cardiac events (MACE), however the proportion of diabetic patients was low in these trials. OBJECTIVES: To investigate whether a complete revascularization approach is associated with better outcomes in diabetic patients with STEMI and multi-vessel disease. METHODS: One hundred diabetic patients with acute STEMI with at least one non culprit lesion were randomized to either complete revascularization (n = 50) or culprit-only treatment (n = 50). Complete revascularization was performed either at the time of primary percutaneous coronary intervention (PCI) or within 72 hours during hospitalization. The primary endpoint was the composite of all-cause mortality, recurrent MI, and ischemia-driven revascularization at 6 months. RESULTS: A complete revascularization approach was significantly associated with a reduction in the primary outcome (6% vs. 24%, P = 0.01), primarily due to reduction in ischemia driven revascularization in the complete revascularization group (2% vs. 12%; P = 0.047). There was no significant reduction in death or MI (2% vs. 8%; P = 0.17) and (2% vs. 4%; P = 0.56) respectively, or in the safety endpoints of major or minor bleeding, contrast-induced nephropathy, or stroke between the groups. CONCLUSIONS: In diabetic patients with multi-vessel coronary artery disease undergoing PPCI, complete revascularization is associated with significantly reduced risk of adverse cardiovascular events, as compared with culprit vessel only PCI. (J Interven Cardiol 2016;29:241-247). PMID- 27245122 TI - Comparison of 4.5-Year Outcomes of Bare-Metal and Zotarolimus-Eluting Stents in New York. AB - BACKGROUND: Both bare-metal stents (BMS; the first-generation coronary stent) and zotarolimus-eluting stents (ZES; a second-generation drug-eluting stent [DES]) have been widely utilized to treat coronary heart disease. However, the long-term comparative effectiveness of BMS and ZES remains unclear. The purpose of this study was to evaluate long-term comparative effectiveness of BMS versus ZES. METHODS: We created a longitudinal database by linking the New York State (NYS) cardiac registries, statewide hospital discharge data, the National Death Index (NDI), and the U.S. Census file (2010) for patients receiving either BMS or ZES during the 2008-2009 period. We examined the rates of all-cause mortality, acute myocardial infarction (AMI), target-lesion PCI (TLPCI), and target-vessel coronary artery bypass graft (TVCABG) surgery for a follow-up period of 4.5 years. A total of 10,443 propensity score matched pairs were compared using the Kaplan-Meier method and Cox proportional hazards regression adjusting for patient risk factors. RESULTS: We found that patients receiving ZES had a lower rate of 4.5-year mortality (adjusted hazard ratio AHR: 0.68, 95% confidence interval CI: 0.63-0.73), AMI (AHR: 0.89, 95% CI: 0.80-0.98), and TVCABG (AHR: 0.84, 95% CI: 0.71-0.99) but a similar rate of TLPCI (AHR: 1.02, 95% CI: 0.93-1.12). For "off label" and "high-risk" subgroups, ZES was associated with improved mortality and generally better or non-inferior AMI, TLPCI, and TVCABG outcomes relative to BMS. CONCLUSIONS: Compared with BMS, ZES was associated with lower long-term mortality, AMI and TVCABG. (J Interven Cardiol 2016;29:265-274). PMID- 27245123 TI - Edge-to-Edge Technique to Minimize Ovelapping of Multiple Bioresorbable Scaffolds Plus Drug Eluting Stents in Revascularization of Long Diffuse Left Anterior Descending Coronary Artery Disease. AB - BACKGROUND: Implantation of Drug Eluting Stents (DES) plus bioresorbable scaffolds (BVS) in very long diffuse left anterior descending coronary artery (LAD) disease may be problematic because of multiple devices overlapping. We sought to assess the short and mid-tern outcomes of combined implantation of DES and BVS using a novel "edge-to-edge" technique in patients with diffuse LAD disease. METHODS: Patients with long diffuse LAD disease were enrolled in a prospective registry from 1st August 2014 to 1st August 2015 and treated with IVUS-aided percutaneous coronary intervention using a DES plus a single or multiple BVS using a novel "edge-to-edge" technique. Clinical follow up and invasive follow up driven by clinical justification was performed. RESULTS: Twenty-three patients (5 females, mean age 59.1+/- 9.1 years) were enrolled. Mean length of LAD disease was 73.1 +/- 20.6 mm. Mean number of DES and BVS implanted was 1.2 +/- 0.4 and 1.7 +/- 1.3, respectively. At a mean follow-up of 11.3 +/- 3.8 months, no stent thrombosis or MACE were observed. Angiographic and IVUS follow-up at a mean of 6.6 +/- 0.7 months showed no significant angiographic restenosis and no appreciable stent gaps. CONCLUSIONS: In revascularization of long diffuse disease of the LAD, the edge-to-edge implantation technique appears to be feasible resulting in no restenosis or thrombosis on the short-term follow up. (J Interven Cardiol 2016;29:275-284). PMID- 27245124 TI - Second-Generation Drug-Eluting Balloon for Ostial Side Branch Lesions (001 Bifurcations): Mid-Term Clinical and Angiographic Results. AB - BACKGROUND: In the drug-eluting stent era, the best strategy to treat Medina 001 lesion remains unestablished. This is the first prospective registry assessing the efficacy and safety of the second-generation drug-coated balloon in patients with side-branch ostial lesion. METHODS: Forty-nine patients with de novo Medina 001 lesion and associated myocardial ischemia were treated with second-generation drug-coated balloon-Dior balloon catheter (Eurocor GmbH, Bonn Germany), and prospectively included in this study. After mandatory pre-dilatation, a paclitaxel-eluting balloon was inflated for a minimum of 45 seconds. Left main bifurcation, severely calcified lesions and cardiogenic shock, were the only exclusion criteria. RESULTS: The inclusion period was 2.7 years. Mean age was 62 +/- 12 years old, 41% diabetic, 65% presented with acute coronary syndrome. The most common vessel treated was the first diagonal (50%). Pre-dilatation with a cutting balloon was used in 59%. Angiographic success was 86% (in 14% a bare metal stent was implanted because of acute recoil [n = 5] or coronary dissection more than type B [n = 2]). At a mean of 12.2 +/- 2.2 months, major cardiac adverse events rate was 14.3% (1 myocardial infarction, 0 cardiac deaths, 7 target lesion revascularization). There was no thrombosis or occlusion. At a mean of 7.2 +/- 1.1 months, binary restenosis was 22.5% (n = 7) with a late loss of 0.32 +/- 0.73 mm. CONCLUSION: Medina 001 lesion is an infrequent type of coronary lesion. Drug-coated balloon-Dior is a safe and technically easy therapeutic option, associated with acceptable mid-term clinical outcomes. (J Interven Cardiol 2016;29:285-292). PMID- 27245125 TI - Same or Different Drug-Eluting Stent Re-Implantation for Drug-Eluting Stent Restenosis: An Assessment Including Second-Generation Drug-Eluting Stents. AB - OBJECTIVES: We examined the long-term outcomes of implanting a different type of drug-eluting stent (DES), including second-generation DES, for treatment of DES in stent restenosis (ISR). BACKGROUND: Treatment for DES-ISR has not been standardized. METHODS: The subjects were 80 patients with 89 lesions underwent DES implantation for DES-ISR. The patients were divided into the group of patients receiving the same DES for DES-ISR (Homo-stent: 24 patients, 25 lesions) and a different DES for DES-ISR (Hetero-stent: 56 patients, 64 lesions). The primary endpoint was survival free of major adverse cardiovascular events (MACE), including cardiac death, myocardial infarction, and target vessel revascularization (TVR). The secondary endpoint was late loss at 8-12 months follow-up. In the subgroup of patients who were treated with second-generation DES for DES-ISR, we also assessed the survival free of MACE. RESULTS: During a mean follow-up of 45.1 +/- 21.2 months, 26 patients experienced MACE. There was no significant difference in the survival free of MACE (Log rank P = 0.17). In the sub-analysis of second generation DES, MACE was significantly higher in the Homo-stent group compared to the Hetero-stent group (Log rank P = 0.04). Late loss was significantly higher in the Homo-stent group than in the Hetero-stent group (0.86 +/- 1.03 vs. 0.38 +/- 0.74 mm, P = 0.03). This trend was prominent in the first-generation DES group. CONCLUSIONS: Although there was no significant difference in MACE between the Hetero-stent and the Homo-stent groups including both first and second-generation DES, the sub-analysis demonstrated different DES implantation for DES-ISR significantly improved the MACE rate among patients treated with second-generation DES. (J Interven Cardiol 2016;29:311-318). PMID- 27245126 TI - Balloon-Expandable Transcatheter Aortic Valves Can Be Successfully and Safely Implanted Transfemorally Without Balloon Valvuloplasty. AB - OBJECTIVES: To assess the necessity for balloon aortic valvuloplasty (BAV) during transfemoral transcatheter aortic valve implantation (TAVI) when using balloon expandable valves. BACKGROUND: BAV is a usual part of TAVI procedures, prior to valve implantation. However, the benefits and necessity of this are unknown and recent evidence in self-expanding valves suggests it may not be necessary. METHODS: Retrospective single-center study of 154 patients undergoing first-time, transfemoral TAVI for native aortic valve stenosis, with (N = 76), and without (N = 78), BAV as part of the procedure. Data collected included demographic, procedural, and outcome data. RESULTS: BAV did not alter VARC-2 defined procedural success or early safety compared to not performing a BAV, including mortality, degree of aortic regurgitation, or need for post-TAVI balloon dilatation, although there was a strong trend to reduced stroke when not performing a BAV. There was a significantly reduced procedural time (P = 0.01) and fluoroscopic time (P < 0.001) without performing a BAV. There were no differences in cerebral embolization (solid, gaseous, or total emboli) noted between the 2 groups, as measured on transcranial doppler (TCD). CONCLUSIONS: TAVI can be effectively and safely performed without a BAV and this results in reduced procedural and fluoroscopic times, although embolization to the brain is not reduced. There is a trend toward reduced stroke risk. (J Interven Cardiol 2016;29:319-324). PMID- 27245127 TI - Comparison of Cutting Balloon Angioplasty and Percutaneous Balloon Angioplasty of Arteriovenous Fistula Stenosis: A Meta-Analysis and Systematic Review of Randomized Clinical Trials. PMID- 27245128 TI - Azlactone Reaction Developments. AB - Azlactones (also known as oxazolones) are heterocycles usually employed in the stereoselective synthesis of alpha,alpha-amino acids, heterocycles and natural products. The versatility of the azlactone scaffold arises from the numerous reactive sites, allowing its application in a diversity of transformations. This review aims to cover classical and recent applications of oxazolones, especially those involving stereoselective processes. After a short introduction on their structures and intrinsic reactivities, dynamic kinetic resolution (DKR) processes as well as reactions involving stereoselective formation of a new sigma C-C bond, such as alkylation/allylation/arylation, aldol, ene, Michael and Mannich reactions will be exposed. Additionally, cycloadditions, Steglich rearrangement and sulfenylation reactions will also be discussed. Recent developments of the well-known Erlenmeyer azlactones will be described. For the most examples, the proposed mechanism, activation modes and/or key reaction intermediates will be exposed to rationalize both the final product and the observed stereochemistry. Finally, this review gives an overview of the synthetic utility of oxazolones. PMID- 27245129 TI - Degradation of polynuclear aromatic hydrocarbons by two strains of Pseudomonas. AB - The goal of this investigation was to isolate competent polynuclear aromatic hydrocarbons degraders that can utilize polynuclear aromatic hydrocarbons of former industrial sites at McDoel Switchyard in Bloomington, Indiana. Using conventional enrichment method based on soil slurry, we isolated, screened and purified two bacterial species strains PB1 and PB2. Applying the ribotyping technique using the 16S rRNA gene analysis, the strains were assigned to the genus Pseudomonas (Pseudomonas plecoglossicida strain PB1 and Pseudomonas sp. PB2). Both isolates showed promising metabolic capacity on pyrene sprayed MS agar plates during the preliminary investigations. Using time course studies in the liquid cultures at calculated concentrations 123, 64, 97 and 94ppm for naphthalene, chrysene, fluroanthene and pyrene, P. plecoglossicida strain PB1 and Pseudomonas sp. PB2 showed partial utilization of the polynuclear aromatic hydrocarbons. Naphthalene was degraded between 26% and 40%, chrysene 14% and 16%, fluroanthene 5% and 7%; pyrene 8% and 13% by P. plecoglossicida strain PB1 and Pseudomonas sp. PB2 respectively. Based on their growth profile, we developed a model R(2)=1 to predict the degradation rate of slow polynuclear aromatic hydrocarbon-degraders where all the necessary parameters are constant. From this investigation, we confirm that the former industrial site soil microbial communities may be explored for the biorestoration of the industrial site. PMID- 27245130 TI - Evaluation and enhancement of heavy metals bioremediation in aqueous solutions by Nocardiopsis sp. MORSY1948, and Nocardia sp. MORSY2014. AB - An analysis of wastewater samples collected from different industrial regions of Egypt demonstrated dangerously high levels of nickel (0.27-31.50mgL(-1)), chromium (1.50-7.41mgL(-1)) and zinc (1.91-9.74mgL(-1)) in the effluents. Alarmingly, these heavy metals are among the most toxic knownones to humans and wildlife. Sixty-nine Actinomycete isolates derived from contaminated sites were evaluated under single, binary, and ternary systems for their biosorption capacity for Ni(2+), Cr(6+) and Zn(2+) from aqueous solutions. The results of the study identified isolates MORSY1948 and MORSY2014 as the most active biosorbents. Phenotypic and chemotypic characterization along with molecular phylogenetic evidence confirmed that the two strains are members of the Nocardiopsis and Nocardia genera, respectively. The results also proved that for both the strains, heavy metal reduction was more efficient with dead rather than live biomass. The affinity of the dead biomass of MORSY1948 strain for Ni(2+), Cr(6+) and Zn(2+) under the optimized pH conditions of 7, 8 and 7, respectively at 40 degrees C temperature with 0.3% biosorbent dosage was found to be as follows: Ni(2+) (87.90%)>Zn(2+) (84.15%)>Cr(6+) (63.75%). However, the dead biomass of MORSY2014 strain under conditions of pH 8 and 50 degrees C temperature with 0.3% biosorbent dose exhibited the highest affinity which was as follows: Cr(6+) (95.22%)>Ni(2+) (93.53%)>Zn(2+) (90.37%). All heavy metals under study were found to be removed from aqueous solutions in entirety when the sorbent dosage was increased to 0.4%. PMID- 27245131 TI - Speech processing and production in two-year-old children acquiring isiXhosa: A tale of two children. AB - We investigated the speech processing and production of 2-year-old children acquiring isiXhosa in South Africa. Two children (2 years, 5 months; 2 years, 8 months) are presented as single cases. Speech input processing, stored phonological knowledge and speech output are described, based on data from auditory discrimination, naming, and repetition tasks. Both children were approximating adult levels of accuracy in their speech output, although naming was constrained by vocabulary. Performance across tasks was variable: One child showed a relative strength with repetition, and experienced most difficulties with auditory discrimination. The other performed equally well in naming and repetition, and obtained 100% for her auditory task. There is limited data regarding typical development of isiXhosa, and the focus has mainly been on speech production. This exploratory study describes typical development of isiXhosa using a variety of tasks understood within a psycholinguistic framework. We describe some ways in which speech and language therapists can devise and carry out assessment with children in situations where few formal assessments exist, and also detail the challenges of such work. PMID- 27245132 TI - The comprehension and production of quantifiers in isiXhosa-speaking Grade 1 learners. AB - BACKGROUND: Quantifiers form part of the discourse-internal linguistic devices that children need to access and produce narratives and other classroom discourse. Little is known about the development - especially the prodiction - of quantifiers in child language, specifically in speakers of an African language. OBJECTIVES: The study aimed to ascertain how well Grade 1 isiXhosa first language (L1) learners perform at the beginning and at the end of Grade 1 on quantifier comprehension and production tasks. METHOD: Two low socioeconomic groups of L1 isiXhosa learners with either isiXhosa or English as language of learning and teaching (LOLT) were tested in February and November of their Grade 1 year with tasks targeting several quantifiers. RESULTS: The isiXhosa LOLT group comprehended no/none, any and all fully either in February or then in November of Grade 1, and they produced all assessed quantifiers in February of Grade 1. For the English LOLT group, neither the comprehension nor the production of quantifiers was mastered by the end of Grade 1, although there was a significant increase in both their comprehension and production scores. CONCLUSION: The English LOLT group made significant progress in comprehension and production of quantifiers, but still performed worse than peers who had their L1 as LOLT. Generally, children with no or very little prior knowledge of the LOLT need either, (1) more deliberate exposure to quantifier-rich language or, (2) longer exposure to general classroom language before quantifiers can be expected to be mastered sufficiently to allow access to quantifier-related curriculum content. PMID- 27245133 TI - Lexical and grammatical development in trilingual speakers of isiXhosa, English and Afrikaans. AB - BACKGROUND: There is a dearth of normative data on linguistic development among child speakers of Southern African languages, especially in the case of the multilingual children who constitute the largest part of this population. This inevitably impacts on the accuracy of developmental assessments of such speakers. Already negative lay opinion on the effect of early multilingualism on language development rates could be exacerbated by the lack of developmental data, ultimately affecting choices regarding home and school language policies. OBJECTIVES: To establish whether trilinguals necessarily exhibit developmental delay when compared to monolinguals and, if so, whether this delay (1) occurs in terms of both lexical and grammatical development; and (2) in all three the trilinguals' languages, regardless of input quantity. METHOD: Focusing on isiXhosa, South African English and Afrikaans, the study involved a comparison of 11 four-year-old developing trilinguals' acquisition of vocabulary and passive constructions with that of 10 age-matched monolingual speakers of each language. RESULTS: The trilinguals proved to be monolingual-like in their lexical development in the language to which, on average, they had been exposed most over time, that is, isiXhosa. No developmental delay was found in the trilinguals' acquisition of passive constructions, regardless of the language of testing. CONCLUSION: As previously found for bilingual development, necessarily reduced quantity of exposure does not hinder lexical development in the trilinguals' input dominant language. The overall lack of delay in their acquisition of the passive is interpreted as possible evidence of cross-linguistic bootstrapping and support for early multilingual exposure. PMID- 27245134 TI - Identifying phonological processing deficits in Northern Sotho-speaking children: The use of non-word repetition as a language assessment tool in the South African context. AB - Diagnostic testing of speech/language skills in the African languages spoken in South Africa is a challenging task, as standardised language tests in the official languages of South Africa barely exist. Commercially available language tests are in English, and have been standardised in other parts of the world. Such tests are often translated into African languages, a practice that speech language therapists deem linguistically and culturally inappropriate. In response to the need for developing clinical language assessment instruments that could be used in South Africa, this article reports on data collected with a Northern Sotho non-word repetition task (NRT). Non-word repetition measures various aspects of phonological processing, including phonological working memory (PWM), and is used widely by speech language therapists, linguists, and educational psychologists in the Western world. The design of a novel Northern Sotho NRT is described, and it is argued that the task could be used successfully in the South African context to discriminate between children with weak and strong Northern Sotho phonological processing ability, regardless of the language of learning and teaching. The NRT was piloted with 120 third graders, and showed moderate to strong correlations with other measures of PWM, such as digit span and English non-word repetition. Furthermore, the task was positively associated with both word and fluent reading in Northern Sotho, and it reliably predicted reading outcomes in the tested population. Suggestions are made for improving the current version of the Northern Sotho NRT, whereafter it should be suitable to test learners from various age groups. PMID- 27245135 TI - Imaging overview of metaplastic carcinomas of the breast: a large study of 71 cases. AB - OBJECTIVE: To review the clinical presentation, baseline imaging features, surgical management and final surgical pathology of metaplastic carcinoma of the breast. METHODS: A total of 71 cases were identified over a 10-year period from two major UK breast cancer institutions. Imaging at diagnosis including mammography, ultrasound, MRI and CT scans and histological diagnosis were reviewed. Follow-up data including local and systemic recurrence were retrieved. RESULTS: Of the 71 cases, 60 (84.5%) cases presented with a palpable lump. 60 (84.5%) cases showed a mass on mammography, of whom 47 (78.3%) cases were ill defined and 17.0% cases showed calcifications associated with a mass lesion. All 71 cases were seen as a mass on ultrasound. The imaging score was R3 or R4 in 26 cases and R5 in 47 cases. 16 patients underwent MRI with most (93.8%) showing a solid mass with central necrosis. No metastatic disease was seen in the 13 patients who underwent staging CT. Despite having a larger size, 50% of the cases successfully underwent breast conservative surgery. Positive axillary lymph nodes were seen in 11 (15.5%) cases. CONCLUSION: In this series, metaplastic cancers were palpable in 85% cases, tended to be large at the time of presentation and imaging showed characteristics of malignancy. Only 11 (15.5%) cases had nodal involvement. ADVANCES IN KNOWLEDGE: Metaplastic carcinomas are often palpable and of large size at the time of presentation. Metaplastic carcinomas raise the concern for malignancy on mammography and ultrasound, warranting further biopsy. Metaplastic carcinomas tend to be grade 3 and triple receptor negative. PMID- 27245136 TI - Prospective review of radiotherapy trials through implementation of standardized multicentre workflow and IT infrastructure. AB - OBJECTIVE: We sought to develop a process that would allow us to perform a prospective review of outlining in trials using expert reviewers based in multiple centres. METHODS: We implemented a specific information technology infrastructure and workflow that could serve all organizations involved in the radiotherapy quality assurance (RTQA) process. RESULTS: Data were processed and packaged in the computational environment for radiotherapy research (CERR) binary format and securely transmitted to the expert reviewer at the designated remote organization. It was opened and reviewed using the distributed CERR-compiled application, and a standardized report was sent to the respective centre. Centres were expected to correct any unacceptable deviations and resubmit outlining for approval prior to commencing treatment. 75% of reviews were completed and fed back to centres within 3 working days. There were no delays in treatment start date. CONCLUSION: Our distributed RTQA review approach provides a method of prospective outlining review at multiple centres, without compromising the quality, delaying the start of treatment or the need for significant additional infrastructure resources. Future progress in the area of prospective individual case review will need to be supported by additional resources for clinician time to undertake the reviews. ADVANCES IN KNOWLEDGE: Trial groups around the world have formulated different approaches to address the need for the prospective review of radiotherapy (RT) data with clinical trials, in line with available resources. We report a UK solution that has allowed the workload for outlining review to be distributed across a wider group of volunteer reviewers without the need for any additional infrastructure costs and has already been adopted within the UK RT trials community. PMID- 27245138 TI - Cone-beam computed tomography in lung stereotactic ablative radiation therapy: predictive parameters of early response. AB - OBJECTIVE: To analyze lung lesion volume variations by contouring on cone-beam CT (CBCT) images to evaluate the early predictive parameters of stereotactic ablative radiation therapy (SABR) treatment response. METHODS: The prescribed dose of SABR was varied according to the tumour site (central or peripheral) and maximum diameter of the lesions by using a strategy of risk-adapted dose prescription with a dose range between 48 and 70 Gy in 3-10 consecutive fractions. For the purpose of the analysis, the gross tumour volume (GTV) was recontoured for each patient at first and last CBCT using two lung levels/windows: (a) -600/1000 HU and (b) -1000/250 HU. Univariate analysis was performed to evaluate a correlation between lung lesion variations on CBCT using the two levels/windows and treatment response 6 months after SABR. Independent variables were the number of fractions, time between initial and final fraction, biologically effective dose and pre-SABR GTV. Cut points of lesion volume reduction were evaluated to determine the correlation with complete response 6 months after SABR. RESULTS: 41 lung lesions were evaluated. 82 lung lesions were recontoured for each CBCT level/window. A lung lesion shrinkage of at least 20% was revealed to be statistically related to complete response 6 months after SABR for both the CBCT levels/windows used. The probability of complete response ranged between six and eight times higher in respect to CBCT levels/windows 600/1000 HU and -1000/250 HU, respectively, compared with patients without a lesion shrinkage of 20% at the last session of SABR. CONCLUSION: According to current findings, a lung lesion shrinkage of at least 20% at the last session of SABR could be predictable of complete response 6 months thereafter. Further investigations about this topic are needed. ADVANCES IN KNOWLEDGE: Prediction of the early tumour response could be useful to personalize imaging restaging after the completion of SABR or to incorporate additional therapies in case of poor responders to improve clinical outcomes. PMID- 27245139 TI - Is ECG triggering for motion artefact reduction in dual-source CT angiography of the ascending aorta still required with high-pitch scanning? The role of ECG gating in high-pitch dual-source CT of the ascending aorta. AB - OBJECTIVE: To compare electrocardiographic (ECG)-triggered high-pitch (HP) dual source CT angiography (CTA) with non-ECG-triggered HP CTA of the aorta, particularly the ascending aorta, with regard to image quality, motion artefacts, contrast-to-noise ratio (CNR), signal-to-noise ratio (SNR) and radiation dose. METHODS: 59 consecutive patients who had been referred for CTA for known or suspected aortic disease, previous aortic intervention or planned transapical or transfemoral aortic valve implantation were prospectively included. Patients underwent CTAs with HP, using a dual-source CTA system, with [control group (Group A); n = 30] or without (Group B; n = 29) ECG triggering after randomization. For evaluation, image quality and a motion artefact score (MAS) were assessed in a blinded fashion at different predefined anatomic regions. CNR and SNR were measured at the same levels. Radiation dose estimates and contrast enhancement were compared between the two groups. RESULTS: There were no significant differences for image quality and MAS. The intra-arterial contrast resolution was significantly higher at the level of the aortic arch and descending aorta in the non-triggered group (CNR values, p = 0.002-0.018). No significant differences in the radiation dose were found. CONCLUSION: Non triggered HP dual-source CTA provided comparable results with regard to image quality, MAS, CNR, SNR and radiation doses compared with ECG-triggered HP CTA. Therefore, ECG triggering of the ascending aorta might be obviated when HP scanning is available. ADVANCES IN KNOWLEDGE: HP dual-source CTA might obviate ECG triggering in the ascending aorta. Non-triggered HP CTA of the ascending aorta provides an excellent image quality. PMID- 27245137 TI - Pulmonary imaging after stereotactic radiotherapy-does RECIST still apply? AB - The use of stereotactic ablative radiotherapy (SABR) for the treatment of primary lung cancer and metastatic disease is rapidly increasing. However, the presence of benign fibrotic changes on CT imaging makes response assessment following SABR a challenge, as these changes develop with an appearance similar to tumour recurrence. Misclassification of benign fibrosis as local recurrence has resulted in unnecessary interventions, including biopsy and surgical resection. Response evaluation criteria in solid tumours (RECIST) are widely used as a universal set of guidelines to assess tumour response following treatment. However, in the context of non-spherical and irregular post-SABR fibrotic changes, the RECIST criteria can have several limitations. Positron emission tomography can also play a role in response assessment following SABR; however, false-positive results in regions of inflammatory lung post-SABR can be a major clinical issue and optimal standardized uptake values to distinguish fibrosis and recurrence have not been determined. Although validated CT high-risk features show a high sensitivity and specificity for predicting recurrence, most recurrences are not detected until more than 1-year post-treatment. Advanced quantitative radiomic analysis on CT imaging has demonstrated promise in distinguishing benign fibrotic changes from local recurrence at earlier time points, and more accurately, than physician assessment. Overall, the use of RECIST alone may prove inferior to novel metrics of assessing response. PMID- 27245140 TI - Patient monitoring: the hidden costs of treatment with antipsychotics. PMID- 27245142 TI - Small Molecules Revealed in a Screen Targeting Epithelial Scattering Are Inhibitors of Microtubule Polymerization. AB - Stimulation of cultured epithelial cells with scatter factor/hepatocyte growth factor (HGF) results in the detachment of cell-cell junctions and initiation of cell migration. Instead of coordinating collective cell behavior within a tissue, cells become solitary and have few cell-cell interactions. Since epithelial scattering is recapitulated in cancer progression and since HGF signaling drives cancer metastasis in many cases, inhibitors of HGF signaling have been proposed to act as anticancer agents. We previously sought to better understand critical components required for HGF-induced epithelial scattering by performing a forward chemical genetics screen, which resulted in the identification of compounds with no previously reported biological activity that we report here. In efforts to determine the mechanism of these compounds, we find that many compounds have broad antiproliferative effects on cancer cell lines by arrest of cell division in G2/M with minimal induction of apoptosis. This effect is reminiscent of microtubule-targeting agents, and we find that several of these scaffolds directly inhibit microtubule polymerization. Compounds are assessed for their toxicity and pharmacokinetics in vivo. The identification of novel small-molecule inhibitors of microtubule polymerization highlights the role of the microtubule cytoskeleton in HGF-induced epithelial scattering. PMID- 27245143 TI - Screening and optimization of an efficient Bombyx mori nucleopolyhedrovirus inducible promoter. AB - Pathogen-inducible promoters have been studied extensively and widely used in resistance breeding and gene therapy. However, few reports have been published that explore the efficacy of Bombyx mori nucleopolyhedrovirus (BmNPV)-inducible promoters in antiviral research in the Bombyx mori (Lepidoptera). Here, we screened BmNPV promoters (VP1054, P33, Bm21, Bm122, 39K, P143, and P6.9) and found that the 39K promoter had the highest BmNPV-induced transcriptional activity by dual-luciferase reporter assays system. By 5' truncation analysis, two regions of 39K promoter were critical for optimal virus-inducible activity, indicated that they could serve as a candidate to produce synthetic pathogen induced promoters. Furthermore, we enhanced the virus-inducible activity of BmNPV 39K promoter using a hybrid enhancer comprising hr3 and polh-up (designated as HP39K). Finally, we showed that RNAi regulated by HP39K promoter could significantly inhibit the proliferation of BmNPV in silkworm cells. Taken together, our results have practical value in antiviral research of silkworm and baculovirus expression system. PMID- 27245141 TI - Transcriptional Inhibitors Identified in a 160,000-Compound Small-Molecule DUX4 Viability Screen. AB - Facioscapulohumeral muscular dystrophy is a genetically dominant, currently untreatable muscular dystrophy. It is caused by mutations that enable expression of the normally silent DUX4 gene, which encodes a pathogenic transcription factor. A screen based on Tet-on DUX4-induced mouse myoblast death previously uncovered compounds from a 44,000-compound library that protect against DUX4 toxicity. Many of those compounds acted downstream of DUX4 in an oxidative stress pathway. Here, we extend this screen to an additional 160,000 compounds and, using greater stringency, identify a new set of DUX4-protective compounds. From 640 hits, we performed secondary screens, repurchased 46 of the most desirable, confirmed activity, and tested each for activity against other cell death inducing insults. The majority of these compounds also protected against oxidative stress. Of the 100 repurchased compounds identified through both screens, only SHC40, 75, and 98 inhibited DUX4 target genes, but they also inhibited dox-mediated DUX4 expression. Using a target gene readout on the 640 compound hit set, we discovered three overlooked compounds, SHC351, 540, and 572, that inhibit DUX4 target gene upregulation without nonspecific effects on the Tet on system. These novel inhibitors of DUX4 transcriptional activity may thus act on pathways or cofactors needed by DUX4 for transcriptional activation in these cells. PMID- 27245144 TI - Complete genome sequence of a psychotrophic Pseudarthrobacter sulfonivorans strain Ar51 (CGMCC 4.7316), a novel crude oil and multi benzene compounds degradation strain. AB - Pseudarthrobacter sulfonivorans strain Ar51, a psychotrophic bacterium isolated from the Tibet permafrost of China, can degrade crude oil and multi benzene compounds efficiently in low temperature. Here we report the complete genome sequence of this bacterium. The complete genome sequence of Pseudarthrobacter sulfonivorans strain Ar51, consisting of a cycle chromosome with a size of 5.04Mbp and a cycle plasmid with a size of 12.39kbp. The availability of this genome sequence allows us to investigate the genetic basis of crude oil degradation and adaptation to growth in a nutrient-poor permafrost environment. PMID- 27245145 TI - Volumetric-modulated arc therapy (VMAT) versus 3D-conformal radiation therapy in supra-diaphragmatic Hodgkin's Lymphoma with mediastinal involvement: A dosimetric comparison. AB - PURPOSE: To compare volumetric-modulated arc therapy (VMAT) with 3D-conformal radiation therapy (3D-CRT) mediastinal irradiation for stage I-II supra diaphragmatic Hodgkin's Lymphoma (HL). PATIENTS AND METHODS: Eleven patients were planned for RT after 4-6 cycles of ABVD chemotherapy: conventional 3D-CRT (AP/PA) and VMAT plans were conformed to the same PTV. Objective was to choose the best PTV coverage plan with the least OAR dose. The 2 plans were compared for: PTV coverage, mean dose and V5,V20lung, mean dose and V30heart, V5, V10, V15breast (female patients), and the integral body dose. RESULTS: Both techniques achieved adequate PTV coverage. Mean lung and heart dose was consistently lower in VMAT plans. The lung V20 dose was acceptable for VMAT, but exceeded the tolerance threshold in 6 cases with 3DCRT plans. A mean difference of 15.9% for both lungs V20 favored VMAT plans; average MLD difference was 2.3Gy less for VMAT plans. Similarly, lower maximum and mean heart doses with a 3.3Gy dose reduction and a 9.4% difference in V30 favored VMAT plans. Mean V5lung/female breast and integral dose were invariably higher in VMAT plans because of the low-dose spread. CONCLUSIONS: VMAT is a valuable technique for treatment of large mediastinal HL. VMAT spares the lung and heart compared to 3DCRT using ISRT in select HL cases. VMAT allows dose escalation for post-chemotherapy residual disease with minimal dose to OARs. VMAT low radiation dose (V5) to the normal tissues, and the increased integral dose should be considered. PMID- 27245146 TI - Prevention of lymphatic injuries with lymphatic mapping: The combined technique. PMID- 27245149 TI - Necroptotic cell death - An unexpected driver of pancreatic oncogenesis. PMID- 27245148 TI - Population genetic structure and demographic history of the black fly vector, Simulium nodosum in Thailand. AB - An understanding of the genetic structure and diversity of vector species is crucial for effective control and management. In this study, mitochondrial DNA sequences were used to examine the genetic structure, diversity and demographic history of a black fly vector, Simulium nodosum Puri (Diptera: Simuliidae), in Thailand. A total of 145 sequences were obtained from 10 sampling locations collected across geographical ranges in the country. Low genetic diversity was found in populations of S. nodosum that could be explained by the recent population history of this species. Demographic history analysis revealed a signature of demographic expansion dating back to only 2600-5200 years ago. Recent population expansion in S. nodosum possibly followed an increase in agriculture that enabled its hosts', humans and domestic animals, densities to increase. Alternatively, the Thai populations could be a derivative of an older expansion event in the more northern populations. Mitochondrial DNA genealogy revealed no genetically divergent lineages, which agrees with the previous cytogenetic study. Genetic structure analyses found that only 27% of the pairwise comparisons were significantly different. The most likely explanation for the pattern of genetic structuring is the effect of genetic drift because of recent colonization. PMID- 27245147 TI - FGFR inhibitors: Effects on cancer cells, tumor microenvironment and whole-body homeostasis (Review). AB - Fibroblast growth factor (FGF)2, FGF4, FGF7 and FGF20 are representative paracrine FGFs binding to heparan-sulfate proteoglycan and fibroblast growth factor receptors (FGFRs), whereas FGF19, FGF21 and FGF23 are endocrine FGFs binding to Klotho and FGFRs. FGFR1 is relatively frequently amplified and overexpressed in breast and lung cancer, and FGFR2 in gastric cancer. BCR-FGFR1, CNTRL-FGFR1, CUX1-FGFR1, FGFR1OP-FGFR1, MYO18A-FGFR1 and ZMYM2-FGFR1 fusions in myeloproliferative neoplasms are non-receptor-type FGFR kinases, whereas FGFR1 TACC1, FGFR2-AFF3, FGFR2-BICC1, FGFR2-PPHLN1, FGFR3-BAIAP2L1 and FGFR3-TACC3 fusions in solid tumors are transmembrane-type FGFRs with C-terminal alterations. AZD4547, BGJ398 (infigratinib), Debio-1347 and dovitinib are FGFR1/2/3 inhibitors; BLU9931 is a selective FGFR4 inhibitor; FIIN-2, JNJ-42756493, LY2874455 and ponatinib are pan-FGFR inhibitors. AZD4547, dovitinib and ponatinib are multi-kinase inhibitors targeting FGFRs, colony stimulating factor 1 receptor (CSF1R), vascular endothelial growth factor (VEGF)R2, and others. The tumor microenvironment consists of cancer cells and stromal/immune cells, such as cancer-associated fibroblasts (CAFs), endothelial cells, M2-type tumor associating macrophages (M2-TAMs), myeloid-derived suppressor cells (MDSCs) and regulatory T cells. FGFR inhibitors elicit antitumor effects directly on cancer cells, as well as indirectly through the blockade of paracrine signaling. The dual inhibition of FGF and CSF1 or VEGF signaling is expected to enhance the antitumor effects through the targeting of immune evasion and angiogenesis in the tumor microenvironment. Combination therapy using tyrosine kinase inhibitors (FGFR or CSF1R inhibitors) and immune checkpoint blockers (anti-PD-1 or anti-CTLA 4 monoclonal antibodies) may be a promising choice for cancer patients. The inhibition of FGF19-FGFR4 signaling is associated with a risk of liver toxicity, whereas the activation of FGF23-FGFR4 signaling is associated with a risk of heart toxicity. Endocrine FGF signaling affects the pathophysiology of cancer patients who are prescribed FGFR inhibitors. Whole-genome sequencing is necessary for the detection of promoter/enhancer alterations of FGFR genes and rare alterations of other genes causing FGFR overexpression. To sustain the health care system in an aging society, a benefit-cost analysis should be performed with a focus on disease-free survival and the total medical cost before implementing genome-based precision medicine for cancer patients. PMID- 27245150 TI - Tuberculosis, genetic diversity and fitness in the red deer, Cervus elaphus. AB - Understanding how genetic diversity, infections and fitness interact in wild populations is a major challenge in ecology and management. These interactions were addressed through heterozygosity-fitness correlation analyses, by assessing the genetic diversity, tuberculosis (TB) and body size in adult red deer. Heterozygosity-fitness correlation models provided a better understanding of the link between genetic diversity and TB at individual and population levels. A single local effect was found for Ceh45 locus at individual level, enhancing the importance of its close functional genes in determining TB presence. At population level, the ability of the red deer to control TB progression correlated positively with population genetic diversity, indicating that inbred populations might represent more risk of deer TB severity. Statistical models also gained insights into the dynamics of multi-host interaction in natural environments. TB prevalence in neighbouring wild boar populations was positively associated with deer TB at both individual and population levels. Additionally, TB presence correlated positively with red deer body size, for which "general and local effect" hypotheses were found. Although body size might be correlated with age, an indirect genetic effect on TB presence could be implied. This study provides new insights towards understanding host-pathogen interactions in wild populations and their relation to fitness traits. PMID- 27245151 TI - Evidence of susceptibility to lamivudine-based HAART and genetic stability of hepatitis B virus (HBV) in HIV co-infected patients: A South African longitudinal HBV whole genome study. AB - BACKGROUND: Reports on the concomitant impact of HIV co-infection and long term highly active anti-retroviral therapy (HAART) on the genetic stability and molecular evolution of HBV are limited in sub-Saharan Africa. MATERIALS AND METHODS: This retrospective study investigated the molecular evolution of chronic HBV in HIV co-infected patients on lamivudine (3TC)-based HAART over a 5year period. Four HIV co-infected patients, consecutively recruited and followed-up, were screened for hepatitis B serological markers, and their viral loads determined. The HBV genome was amplified from longitudinal samples and characterized by Bayesian inference, mutational analysis, and identification of immune selection pressure. RESULTS: All patients exhibited persistent chronic HBV infection at baseline, as well as over the course of follow-up despite exposure to 3TC-based HAART. The polymerase gene in all isolates was relatively variable prior to HAART initiation at baseline and during the course of follow-up, although primary drug resistance mutations were not detected. All but one patient were infected with HBV subgenotype A1. The divergence rates between baseline and the last follow-up sequences ranged from 0 to 2.0*10(-3) substitutions per site per year (s/s/y). Positive selection pressure was evident within the surface and core genes. CONCLUSION: Despite persistent HBV infection in the HIV co-infected patients exposed to long term 3TC-based HAART, the molecular evolution of HBV over a 5year period was unremarkable. In addition, HBV exhibited minimal genetic variability overtime. PMID- 27245152 TI - Detailed phylogenetic analysis of primate T-lymphotropic virus type 1 (PTLV-1) sequences from orangutans (Pongo pygmaeus) reveals new insights into the evolutionary history of PTLV-1 in Asia. AB - While human T-lymphotropic virus type 1 (HTLV-1) originates from ancient cross species transmission of simian T-lymphotropic virus type 1 (STLV-1) from infected nonhuman primates, much debate exists on whether the first HTLV-1 occurred in Africa, or in Asia during early human evolution and migration. This topic is complicated by a lack of representative Asian STLV-1 to infer PTLV-1 evolutionary histories. In this study we obtained new STLV-1 LTR and tax sequences from a wild born Bornean orangutan (Pongo pygmaeus) and performed detailed phylogenetic analyses using both maximum likelihood and Bayesian inference of available Asian PTLV-1 and African STLV-1 sequences. Phylogenies, divergence dates and nucleotide substitution rates were co-inferred and compared using six different molecular clock calibrations in a Bayesian framework, including both archaeological and/or nucleotide substitution rate calibrations. We then combined our molecular results with paleobiogeographical and ecological data to infer the most likely evolutionary history of PTLV-1. Based on the preferred models our analyses robustly inferred an Asian source for PTLV-1 with cross-species transmission of STLV-1 likely from a macaque (Macaca sp.) to an orangutan about 37.9-48.9kya, and to humans between 20.3-25.5kya. An orangutan diversification of STLV-1 commenced approximately 6.4-7.3kya. Our analyses also inferred that HTLV-1 was first introduced into Australia ~3.1-3.7kya, corresponding to both genetic and archaeological changes occurring in Australia at that time. Finally, HTLV-1 appears in Melanesia at ~2.3-2.7kya corresponding to the migration of the Lapita peoples into the region. Our results also provide an important future reference for calibrating information essential for PTLV evolutionary timescale inference. Longer sequence data, or full genomes from a greater representation of Asian primates, including gibbons, leaf monkeys, and Sumatran orangutans are needed to fully elucidate these evolutionary dates and relationships using the model criteria suggested herein. PMID- 27245153 TI - New arrangements on several species subcomplexes of Triatoma genus based on the chromosomal position of ribosomal genes (Hemiptera - Triatominae). AB - The hemipteran subfamily Triatominae includes 150 blood-sucking species, vectors of Chagas disease. By far the most specious genus is Triatoma, assembled in groups, complexes and subcomplexes based on morphological similarities, geographic distribution and genetic data. However, many molecular studies questioned the species integration of several subcomplexes as monophyletic units. In triatomines, chromosomal position of major ribosomal DNA (rDNA) loci is extremely variable but seems to be species-specific and an evolutionary conserved genetic trait, so that closely related species tend to have ribosomal clusters in the same chromosomal location. Considering that the autosomal position as the ancestral character for all heteropteran species, including triatomines, we suggest that the movement of rDNA loci from autosomes to sex chromosomes rapidly established reproductive barriers between divergent lineages. We proposed that the rDNA translocation from the autosomes to the sex chromosomes restrict reproductive compatibility and eventually promote speciation processes. We analyzed the chromosomal position of 45S rDNA clusters in almost all species of the matogrossensis, rubrovaria, maculata and sordida subcomplexes. The fluorescent in situ hybridization results are discussed considering the available genetic data and we proposed new arrangements in the species that constitute each one of these subcomplexes. PMID- 27245155 TI - The role of therapeutic optimism in recruitment to a clinical trial in a peripartum setting: balancing hope and uncertainty. AB - BACKGROUND: Hope has therapeutic value because it enables people to cope with uncertainty about their future health. Indeed, hope, or therapeutic optimism (TO), is seen as an essential aspect of the provision and experience of medical care. The role of TO in clinical research has been briefly discussed, but the concept, and whether it can be transferred from care to research and from patients to clinicians, has not been fully investigated. The role played by TO in research emerged during interviews with staff involved in a peripartum trial. This paper unpacks the concept of TO in this setting and considers the role it may play in the wider delivery of clinical trials. METHODS: The Got-it trial is a UK-based, randomised placebo-controlled trial that investigates the use of sublingual glyceryl trinitrate (GTN) spray to treat retained placenta. Qualitative data were collected in open-ended interviews with obstetricians, research and clinical midwives (n =27) involved in trial recruitment. Data were analysed using the method of constant comparison. RESULTS: TO influenced staff engagement with Got-it at different points in the trial and in different ways. Prior knowledge of, and familiarity with, GTN meant that from the outset staff perceived the trial as low risk. TO facilitated staff involvement in the trial; staff who already understood GTN's effects were optimistic that it would work, and staff collaborated because they hoped that the trial would address what they identified as an important clinical need. TO could fluctuate over the course of the trial, and was sustained or undermined by unofficial observation of clinical outcomes and speculations about treatment allocation. Thus, TO appeared to be influenced by key situational factors: prior knowledge and experience, clinical need and observed participant outcomes. CONCLUSIONS: Situational TO plays a role in facilitating staff engagement with clinical research. TO may affect trial recruitment by enabling staff to sustain the levels of uncertainty, or individual equipoise, necessary to collaborate with research while also responding to patients' clinical needs. Staff may benefit from training to deal with fluctuations in TO. TRIAL REGISTRATION: ISCRTN88609453 . Registered on 26 March 2014. PMID- 27245156 TI - Productivity losses associated with tuberculosis deaths in the World Health Organization African region. AB - BACKGROUND: In 2014, almost half of the global tuberculosis deaths occurred in the World Health Organization (WHO) African Region. Approximately 21.5 % of the 6 060 742 TB cases (new and relapse) reported to the WHO in 2014 were in the African Region. The specific objective of this study was to estimate future gross domestic product (GDP) losses associated with TB deaths in the African Region for use in advocating for better strategies to prevent and control tuberculosis. METHODS: The cost-of-illness method was used to estimate non-health GDP losses associated with TB deaths. Future non-health GDP losses were discounted at 3 %. The analysis was conducted for three income groups of countries. One-way sensitivity analysis at 5 and 10 % discount rates was undertaken to assess the impact on the expected non-health GDP loss. RESULTS: The 0.753 million tuberculosis deaths that occurred in the African Region in 2014 would be expected to decrease the future non-health GDP by International Dollars (Int$) 50.4 billion. Nearly 40.8, 46.7 and 12.5 % of that loss would come from high and upper middle- countries or lower-middle- and low-income countries, respectively. The average total non-health GDP loss would be Int$66 872 per tuberculosis death. The average non-health GDP loss per TB death was Int$167 592 for Group 1, Int$69 808 for Group 2 and Int$21 513 for Group 3. CONCLUSION: Tuberculosis exerts a sizeable economic burden on the economies of the WHO AFR countries. This implies the need to strongly advocate for better strategies to prevent and control tuberculosis and to help countries end the epidemic of tuberculosis by 2030, as envisioned in the United Nations General Assembly resolution on Sustainable Development Goals (SDGs). PMID- 27245154 TI - Relationship between body composition and left ventricular geometry using three dimensional cardiovascular magnetic resonance. AB - BACKGROUND: Although obesity is associated with alterations in left ventricular (LV) mass and volume which are of prognostic significance, widely differing patterns of remodelling have been attributed to adiposity. Our aim was to define the relationship between body composition and LV geometry using three-dimensional cardiovascular magnetic resonance. METHODS: In an observational study 1530 volunteers (55 % female, mean age 41.3 years) without known cardiovascular disease underwent investigation including breath-hold high spatial resolution 3D cines. Atlas-based segmentation and co-registration was used to create a statistical model of wall thickness (WT) and relative wall thickness (RWT) throughout the LV. The relationship between bio-impedence body composition and LV geometry was assessed using 3D regression models adjusted for age, systolic blood pressure (BP), gender, race and height, with correction to control the false discovery rate. RESULTS: LV mass was positively associated with fat mass in women but not in men (LV mass: women beta = 0.11, p < 0.0001; men beta = -0.01, p = 0.82). The 3D models revealed that in males fat mass was strongly associated with a concentric increase in relative wall thickness (RWT) throughout most of the LV (beta = 0.37, significant area = 96 %) and a reduced mid-ventricular cavity (beta = -0.22, significant area = 91 %). In women the regional concentric hypertrophic association was weaker, and the basal lateral wall showed an inverse relationship between RWT and fat mass (beta = -0.11, significant area = 4.8 %). CONCLUSIONS: In an adult population without known cardiovascular disease increasing body fat is predominately associated with asymmetric concentric hypertrophy independent of systolic BP, with women demonstrating greater cavity dilatation than men. Conventional mass and volume measurements underestimate the impact of body composition on LV structure due to anatomic variation in remodelling. PMID- 27245157 TI - Are orphan genes protein-coding, prediction artifacts, or non-coding RNAs? AB - BACKGROUND: Current genome sequencing projects reveal substantial numbers of taxonomically restricted, so called orphan genes that lack homology with genes from other evolutionary lineages. However, it is not clear to what extent orphan genes are real, genomic artifacts, or represent non-coding RNAs. RESULTS: Here, we use a simple set of assumptions to test the nature of orphan genes. First, a sequence that is transcribed is considered a real biological entity. Second, every sequence that is supported by proteome data or shows a depletion of non synonymous substitutions is a protein-coding gene. Using genomic, transcriptomic and proteomic data for the nematode Pristionchus pacificus, we show that between 4129-7997 (42-81 %) of predicted orphan genes are expressed and 3818-7545 (39-76 %) of orphan genes are under negative selection. In three cases that exhibited strong evolutionary constraint but lacked expression evidence in 14 RNA-seq samples, we could experimentally validate the predicted gene structures. Comparing different data sets to infer selection on orphan gene clusters, we find that the presence of a closely related genome provides the most powerful resource to robustly identify evidence of negative selection. However, even in the absence of other genomic data, the availability of paralogous sequences was enough to show negative selection in 8-10 % of orphan genes. CONCLUSIONS: Our study shows that the great majority of previously identified orphan genes in P. pacificus are indeed protein-coding genes. Even though this work represents a case study on a single species, our approach can be transferred to genomic data of other non model organisms in order to ascertain the protein-coding nature of orphan genes. PMID- 27245159 TI - Short-term changes of intraocular pressure and ocular perfusion pressure after intravitreal injection of bevacizumab or ranibizumab. AB - BACKGROUND: The aim of this study was to investigate the effect of intravitreal anti-vascular endothothelial growth factor (VEGF) injection on intraocular pressure (IOP) and mean ocular perfusion pressure (MOPP). METHODS: MOPP results were obtained by measuring mean arterial pressure (MAP) and IOP just before the injection, immediately after the injection, at 30 min, 1 day, and 1 week after injection from 65 eyes of 42 patients. RESULTS: Pre-injection mean IOP was 16.66 +/- 3.50 mmHg, and mean IOP was 43.81 +/- 9.69 mmHg immediately after the injection, 17.57 +/- 4.44 mmHg at 30 min, 15.00 +/- 4.21 mmHg at 1 day, and 15.90 +/- 3.63 mmHg at 1 week after the injection. Pre-injection mean MOPP was 46.39 +/ 5.78 mmHg, and mean MOPP was 25.14 +/- 8.79 mmHg immediately after the injection, 45.87 +/- 6.31 mmHg at 30 min, 46.93 +/- 6.25 mmHg at 1 day, and 46.50 +/- 4.94 mmHg at 1 week after the injection. CONCLUSION: The instant increase in IOP by intravitreal anti-VEGF injection led to a transient decrease in MOPP. Based on this finding, the instant increase in IOP after intravitreal anti-VEGF injection does not significantly impair retinal blood flow. PMID- 27245160 TI - Development of a health literacy questionnaire for Taiwanese hemodialysis patients. AB - BACKGROUND: Dialysis has long been a critical issue in the field of nephrology, though the burden this lifesaving technology places on society can be immense. Effectively increasing the health literacy of hemodialysis patients can be beneficial for their health outcomes and self-care abilities. Thus, the aims of this study are to: (1) develop a health literacy assessment tool in Chinese for patients receiving hemodialysis treatment; (2) assess the health literacy level of the Taiwanese hemodialysis population using the tool developed. METHODS: The questionnaire was developed based on Nutbeam's three constructs of health literacy and seven sub-constructs identified for the purposes of this study. Experts were consulted for content validity assessment. The questionnaire then was used to conduct a census study at six hospitals and one dialysis clinic that provide hemodialysis treatment in the Taipei area (urban northern Taiwan). To be included, patients must have been at least 18 years old and receiving hemodialysis treatment at the time of the study. 468 eligible respondents were included in the analysis. RESULTS: The reliability of the tool was 0.81 and the confirmatory factor analysis indicated good construct validity. The mean literacy score for the sample was 19.7 (SD = 4.61) out of a maximum of 26 points, and the median was 21 (range from 6 to 26). Age, education level, primary language, primary caregiver identity, and willingness to receive a transplant were all factors that showed significant association to health literacy level in multiple categories. CONCLUSIONS: The health literacy assessment tool developed in this study is the first health literacy assessment instrument to be made available for a specific patient group in Taiwan. Hemodialysis patients' knowledge of day-to day care practices is satisfactory, while their critical literacy is weak. PMID- 27245158 TI - Can implementation support help community-based settings better deliver evidence based sexual health promotion programs? A randomized trial of Getting To Outcomes(r). AB - BACKGROUND: Research is needed to evaluate the impact of implementation support interventions over and above typical efforts by community settings to deploy evidence-based prevention programs. METHODS: Enhancing Quality Interventions Promoting Healthy Sexuality is a randomized controlled trial testing Getting To Outcomes (GTO), a 2-year implementation support intervention. It compares 16 Boys and Girls Club sites implementing Making Proud Choices (MPC, control group), a structured teen pregnancy prevention evidence-based program with 16 similar sites implementing MPC augmented with GTO (intervention group). All sites received training and manuals typical for MPC. GTO has its own manuals, training, and onsite technical assistance (TA) to help practitioners complete key programming practices specified by GTO. During the first year, TA providers helped the intervention group adopt, plan, and deliver MPC. This group then received training on the evaluation and quality improvement steps of GTO, including feedback reports summarizing their data, which were used in a TA-facilitated quality improvement process that yielded revised plans for the second MPC implementation. This paper presents results regarding GTO's impact on performance of the sites (i.e., how well key programming practices were carried out), fidelity of MPC implementation, and the relationship between amount of TA support, performance, and fidelity. Performance was measured using ratings made from a standardized, structured interview conducted with participating staff at all 32 Boys and Girls Clubs sites after the first and second years of MPC implementation. Multiple elements of fidelity (adherence, classroom delivery, dosage) were assessed at all sites by observer ratings and attendance logs. RESULTS: After 2 years, the intervention sites had higher ratings of performance, adherence, and classroom delivery (dosage remained similar). Higher performance predicted greater adherence in both years. CONCLUSIONS: These findings suggest that in typical community-based settings, manuals and training common to structured EBPs may be sufficient to yield low levels of performance and moderate levels of fidelity but that systematic implementation support is needed to achieve high levels of performance and fidelity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01818791. PMID- 27245161 TI - A rule-based model of insulin signalling pathway. AB - BACKGROUND: The insulin signalling pathway (ISP) is an important biochemical pathway, which regulates some fundamental biological functions such as glucose and lipid metabolism, protein synthesis, cell proliferation, cell differentiation and apoptosis. In the last years, different mathematical models based on ordinary differential equations have been proposed in the literature to describe specific features of the ISP, thus providing a description of the behaviour of the system and its emerging properties. However, protein-protein interactions potentially generate a multiplicity of distinct chemical species, an issue referred to as "combinatorial complexity", which results in defining a high number of state variables equal to the number of possible protein modifications. This often leads to complex, error prone and difficult to handle model definitions. RESULTS: In this work, we present a comprehensive model of the ISP, which integrates three models previously available in the literature by using the rule-based modelling (RBM) approach. RBM allows for a simple description of a number of signalling pathway characteristics, such as the phosphorylation of signalling proteins at multiple sites with different effects, the simultaneous interaction of many molecules of the signalling pathways with several binding partners, and the information about subcellular localization where reactions take place. Thanks to its modularity, it also allows an easy integration of different pathways. After RBM specification, we simulated the dynamic behaviour of the ISP model and validated it using experimental data. We the examined the predicted profiles of all the active species and clustered them in four clusters according to their dynamic behaviour. Finally, we used parametric sensitivity analysis to show the role of negative feedback loops in controlling the robustness of the system. CONCLUSIONS: The presented ISP model is a powerful tool for data simulation and can be used in combination with experimental approaches to guide the experimental design. The model is available at http://sysbiobig.dei.unipd.it/ was submitted to Biomodels Database ( https://www.ebi.ac.uk/biomodels-main/ # MODEL 1604100005). PMID- 27245162 TI - Antiproliferative and antimetabolic effects behind the anticancer property of fermented wheat germ extract. AB - BACKGROUND: Fermented wheat germ extract (FWGE) sold under the trade name Avemar exhibits anticancer activity in vitro and in vivo. Its mechanisms of action are divided into antiproliferative and antimetabolic effects. Its influcence on cancer cell metabolism needs further investigation. One objective of this study, therefore, was to further elucidate the antimetabolic action of FWGE. The anticancer compound 2,6-dimethoxy-1,4-benzoquinone (DMBQ) is the major bioactive compound in FWGE and is probably responsible for its anticancer activity. The second objective of this study was to compare the antiproliferative properties in vitro of FWGE and the DMBQ compound. METHODS: The IC50 values of FWGE were determined for nine human cancer cell lines after 24 h of culture. The DMBQ compound was used at a concentration of 24 MUmol/l, which is equal to the molar concentration of DMBQ in FWGE. Cell viability, cell cycle, cellular redox state, glucose consumption, lactic acid production, cellular ATP levels, and the NADH/NAD(+) ratio were measured. RESULTS: The mean IC50 value of FWGE for the nine human cancer cell lines tested was 10 mg/ml. Both FWGE (10 mg/ml) and the DMBQ compound (24 MUmol/l) induced massive cell damage within 24 h after starting treatment, with changes in the cellular redox state secondary to formation of intracellular reactive oxygen species. Unlike the DMBQ compound, which was only cytotoxic, FWGE exhibited cytostatic and growth delay effects in addition to cytotoxicity. Both cytostatic and growth delay effects were linked to impaired glucose utilization which influenced the cell cycle, cellular ATP levels, and the NADH/NAD(+) ratio. The growth delay effect in response to FWGE treatment led to induction of autophagy. CONCLUSIONS: FWGE and the DMBQ compound both induced oxidative stress-promoted cytotoxicity. In addition, FWGE exhibited cytostatic and growth delay effects associated with impaired glucose utilization which led to autophagy, a possible previously unknown mechanism behind the influence of FWGE on cancer cell metabolism. PMID- 27245163 TI - Potential use of telephone surveys for non-communicable disease surveillance in developing countries: evidence from a national household survey in Lebanon. AB - BACKGROUND: Given the worldwide proliferation of cellphones, this paper examines their potential use for the surveillance of non-communicable disease (NCD) risk factors in a Middle Eastern country. METHODS: Data were derived from a national household survey of 2,656 adults (aged 18 years or older) in Lebanon in 2009. Responses to questions on phone ownership yielded two subsamples, the 'cell phone sample' (n = 1,404) and the 'any phone sample' (n = 2,158). Prevalence estimates of various socio-demographics and 11 key NCD risk factors and comorbidities were compared between each subsample and the overall household sample. RESULTS: Adjusting for baseline age and sex distribution, no differences were observed for all NCD indicators when comparing either of subsamples to the overall household sample, except for binge drinking [(OR = 1.55, 95 % CI: 1.33-1.81) and (OR = 1.48, 95 % CI: 1.18-1.85) for 'cell phone subsample' and 'any phone subsample', respectively] and self-rated health (OR = 1.23, 95 % CI: 1.10-1.36) and (OR = 1.16, 95 % CI: 1.02-1.32), respectively). Differences in the odds of hyperlipidemia (OR = 1.27, 95 % CI: 1.06-1.51) was also found in the subsample of 'any phone' carriers. CONCLUSIONS: Multi-mode telephone surveillance techniques provide viable alternative to face-to-face surveys in developing countries. Cell phones may also be useful for personalized public health and medical care interventions in young populations. PMID- 27245164 TI - The effect of food withdrawal in children with rapid-transit constipation. AB - BACKGROUND: Rapid proximal colonic transit with anorectal holdup is a subtype of chronic constipation linked to food intolerance. We aimed to determine the effectiveness of dietary exclusion as a treatment for constipated children with rapid-transit constipation by scintigraphy. METHODS: Questionnaires on diet and symptoms were mailed out to 125 children with chronic constipation and rapid proximal colonic transit on nuclear transit study at our institute between 1998 and 2014 years. Patients were given instructions and encouraged to undertake a six-food elimination diet targeting common protein allergens (dairy, wheat, soy, eggs, nuts, seafood). Answers were completed by circling an option or on visual analogue scale. Results were evaluated statistically using GraphPad Prism 6 by a Wilcoxon matched-pairs rank test. P < 0.05 was considered significant. RESULTS: We received 44/125 responses, 26 patients [mean age 11 years (5-21)] had attempted elimination diet and 18 had not. Dairy and wheat were the most common foods eliminated and symptomatic improvement was greater for patients who had completely eliminated foods. Constipation, abdominal pain and pain on defecation were reduced (p < 0.01). Laxative usage decreased, although this was not statistically significant. Families encountered problems with dietary exclusion, particularly expense. Assistance from a dietician or nutritionist was sought by >50 % of families. CONCLUSION: Dietary exclusion is a promising strategy to treat constipation in children with rapid proximal colonic transit. However, it was hard for many families, demonstrating the need for identifying the cause more specifically and a better set of instructions for the family and/or dietitian to follow. PMID- 27245165 TI - Effect of resistance exercise training on expression of Hsp70 and inflammatory cytokines in skeletal muscle and adipose tissue of STZ-induced diabetic rats. AB - Impairment of adipose tissue and skeletal muscles accrued following type 1 diabetes is associated with protein misfolding and loss of adipose mass and skeletal muscle atrophy. Resistance training can maintain muscle mass by changing both inflammatory cytokines and stress factors in adipose tissue and skeletal muscle. The purpose of this study was to determine the effects of a 5-week ladder climbing resistance training program on the expression of Hsp70 and inflammatory cytokines in adipose tissue and fast-twitch flexor hallucis longus (FHL) and slow twitch soleus muscles in healthy and streptozotocin-induced diabetic rats. Induction of diabetes reduced body mass, while resistance training preserved FHL muscle weight in diabetic rats without any changes in body mass. Diabetes increased Hsp70 protein content in skeletal muscles, adipose tissue, and serum. Hsp70 protein levels were decreased in normal and diabetic rats by resistance training in the FHL, but not soleus muscle. Furthermore, resistance training decreased inflammatory cytokines in FHL skeletal muscle. On the other hand, Hsp70 and inflammatory cytokine protein levels were increased by training in adipose tissue. Also, significant positive correlations between inflammatory cytokines in adipose tissue and skeletal muscles with Hsp70 protein levels were observed. In conclusion, we found that in diabetic rats, resistance training decreased inflammatory cytokines and Hsp70 protein levels in fast skeletal muscle, increased adipose tissue inflammatory cytokines and Hsp70, and preserved FHL muscle mass. These results suggest that resistance training can maintain skeletal muscle mass in diabetes by changing inflammatory cytokines and stress factors such as Hsp70 in skeletal muscle and adipose tissue. PMID- 27245166 TI - MiR-130a regulates neurite outgrowth and dendritic spine density by targeting MeCP2. AB - MicroRNAs (miRNAs) are critical for both development and function of the central nervous system. Significant evidence suggests that abnormal expression of miRNAs is associated with neurodevelopmental disorders. MeCP2 protein is an epigenetic regulator repressing or activating gene transcription by binding to methylated DNA. Both loss-of-function and gain-of-function mutations in the MECP2 gene lead to neurodevelopmental disorders such as Rett syndrome, autism and MECP2 duplication syndrome. In this study, we demonstrate that miR-130a inhibits neurite outgrowth and reduces dendritic spine density as well as dendritic complexity. Bioinformatics analyses, cell cultures and biochemical experiments indicate that miR-130a targets MECP2 and down-regulates MeCP2 protein expression. Furthermore, expression of the wild-type MeCP2, but not a loss-of-function mutant, rescues the miR-130a-induced phenotype. Our study uncovers the MECP2 gene as a previous unknown target for miR-130a, supporting that miR-130a may play a role in neurodevelopment by regulating MeCP2. Together with data from other groups, our work suggests that a feedback regulatory mechanism involving both miR 130a and MeCP2 may serve to ensure their appropriate expression and function in neural development. PMID- 27245167 TI - Antifibrotic effect of meloxicam in rat liver: role of nuclear factor kappa B, proinflammatory cytokines, and oxidative stress. AB - This study was aimed at investigating the antifibrotic effect of meloxicam in CCl4-induced liver fibrosis and elucidating its underlying mechanism. Forty male rats were equally randomized for 8-week treatment with corn oil (negative control), CCl4 (to induce liver fibrosis), and/or meloxicam. Meloxicam effectively ameliorated the CCl4-induced alterations in liver histology, liver weight to body weight ratio, liver functions, and serum markers for liver fibrosis (hyaluronic acid, laminin, and PCIII). Meloxicam significantly abrogated CCl4-induced elevation of messenger RNA (mRNA) expressions for collagen I and alpha smooth muscle actin (alpha-SMA) and hepatic contents of hydroxyproline, transforming growth factor beta (TGF-beta), and tissue inhibitor of matrix metalloproteases (TIMP-1). Meloxicam mitigated CCl4-induced elevation in hepatic levels of nuclear factor kappa B (NF-kappaB), tumor necrosis factor alpha (TNF alpha), total nitric oxide (NO), interleukin-l beta (IL 1beta), and prostaglandin E2 (PGE2). Meloxicam modulated CCl4-induced disturbance of liver cytochrome P450 subfamily 2E1 (CYP2E1) and glutathione-S-transferase (GST). The attenuation of meloxicam to liver fibrosis was associated with suppression of oxidative stress via reduction of lipid peroxides along with induction of reduced glutathione content and enhancement of superoxide dismutase, glutathione peroxidase, and catalase activities. This study provides an evidence for antifibrotic effect of meloxicam against CCl4-induced liver fibrosis in rat. The antifibrotic mechanism of meloxicam could be through decreasing NF-kappaB level and subsequent proinflammatory cytokine production (TNF-alpha, NO, IL-1 beta, and PGE2) and, hence, collagen deposition through inhibition of TIMP-1 and TGF-beta. Abrogation of oxidative stress and modulation of liver-metabolizing enzymes (CYP2E1 and GST) were also involved. PMID- 27245168 TI - Identification of a homozygous nonsense mutation in KIAA0556 in a consanguineous family displaying Joubert syndrome. AB - Joubert Syndrome (JS) is an inherited ciliopathy associated with mutations in genes essential in primary cilium function. Whole exome sequencing in a multiplex consanguineous family from India revealed a KIAA0556 homozygous single base pair deletion mutation (c.4420del; p.Met1474Cysfs*11). Knockdown of the gene in zebrafish resulted in a ciliopathy phenotype, rescued by co-injection of wildtype cDNA. Affected siblings present a mild and classical form of Joubert syndrome allowing for further delineation of the JS associated genotypic spectrum. PMID- 27245169 TI - Lanthanide-Functionalized Hydrophilic Magnetic Hybrid Nanoparticles: Assembly, Magnetic Behaviour, and Photophysical Properties. AB - The lanthanide-functionalized multifunctional hybrid nanoparticles combining the superparamagnetic core and the luminescent europium complex were successfully designed and assembled via layer-by-layer strategy in this work. It is noted that the hybrid nanoparticles were modified by a hydrophilic polymer polyethyleneimine (PEI) through hydrogen bonding which bestowed excellent hydrophilicity and biocompatibility on this material. A bright-red luminescence was observed by fluorescence microscopy, revealing that these magnetic-luminescent nanoparticles were both colloidally and chemically stable in PBS solution. Therefore, the nanocomposite with magnetic resonance response and fluorescence probe property is considered to be of great potential in multi-modal bioimaging and diagnostic applications. PMID- 27245170 TI - Aspergillosis of the Heart and Lung and Review of Published Reports on Fungal Endocarditis. AB - Invasive aspergillosis (IA) is increasingly diagnosed in high-risk patients. The lesions are usually located in the lungs and/or sinuses, and the fungus may spread haematogenously to different organs; however, involvement of the heart during IA is very rare. We describe a unique case of invasive aspergillosis of the heart septum and the lungs in the allogeneic haematopoietic stem cell transplant recipient. PMID- 27245171 TI - TWIST1 Integrates Endothelial Responses to Flow in Vascular Dysfunction and Atherosclerosis. AB - RATIONALE: Blood flow-induced shear stress controls endothelial cell (EC) physiology during atherosclerosis via transcriptional mechanisms that are incompletely understood. The mechanosensitive transcription factor TWIST is expressed during embryogenesis, but its role in EC responses to shear stress and focal atherosclerosis is unknown. OBJECTIVE: To investigate whether TWIST regulates endothelial responses to shear stress during vascular dysfunction and atherosclerosis and compare TWIST function in vascular development and disease. METHODS AND RESULTS: The expression and function of TWIST1 was studied in EC in both developing vasculature and during the initiation of atherosclerosis. In zebrafish, twist was expressed in early embryonic vasculature where it promoted angiogenesis by inducing EC proliferation and migration. In adult porcine and murine arteries, TWIST1 was expressed preferentially at low shear stress regions as evidenced by quantitative polymerase chain reaction and en face staining. Moreover, studies of experimental murine carotid arteries and cultured EC revealed that TWIST1 was induced by low shear stress via a GATA4-dependent transcriptional mechanism. Gene silencing in cultured EC and EC-specific genetic deletion in mice demonstrated that TWIST1 promoted atherosclerosis by inducing inflammation and enhancing EC proliferation associated with vascular leakiness. CONCLUSIONS: TWIST expression promotes developmental angiogenesis by inducing EC proliferation and migration. In addition to its role in development, TWIST is expressed preferentially at low shear stress regions of adult arteries where it promotes atherosclerosis by inducing EC proliferation and inflammation. Thus, pleiotropic functions of TWIST control vascular disease and development. PMID- 27245172 TI - Traumatic Stress Disorders and Risk of Subsequent Schizophrenia Spectrum Disorder or Bipolar Disorder: A Nationwide Cohort Study. AB - OBJECTIVE: Traumatic stress disorders are prevalent in patients with schizophrenia and bipolar disorder. However, there is a lack of prospective longitudinal studies investigating the risk of severe mental illness for people diagnosed with traumatic stress disorders. We aimed to assess if patients with acute stress reaction (ASR) or post-traumatic stress disorder (PTSD) are at increased risk of schizophrenia spectrum disorders or bipolar disorder. METHODS: We performed a prospective cohort study covering the entire Danish population including information on inpatient and outpatient mental hospitals over 2 decades. Predictors were in- or outpatient diagnoses of ASR or PTSD. We calculated incidence rate ratios (IRR) with 95% CIs of schizophrenia, schizophrenia spectrum disorder, and bipolar disorder. RESULTS: Persons with a traumatic stress disorder had a significantly increased risk of schizophrenia (IRR 3.80, CI 2.33-5.80), schizophrenia spectrum disorder (IRR 2.34, CI 1.46 3.53), and bipolar disorder (IRR 4.22, CI 2.25-7.13). Risks were highest in the first year after diagnosis of the traumatic stress disorder and remained significantly elevated after more than 5 years. Mental illness in a parent could not explain the association. CONCLUSION: Our findings support an association between diagnosed traumatic stress disorders and subsequent schizophrenia spectrum disorder or bipolar disorder. If replicated, this may increase clinical focus on patients with traumatic stress disorders. PMID- 27245173 TI - Adjuvant Radiation Therapy and Chemotherapy in Merkel Cell Carcinoma: Survival Analyses of 6908 Cases From the National Cancer Data Base. AB - BACKGROUND: Merkel cell carcinoma (MCC) has a high risk of recurrence after initial surgical therapy. Adjuvant radiation therapy (RT) and chemotherapy may be used to reduce the risk of locoregional and systemic recurrence, respectively, but there are conflicting data regarding their impact on survival. We performed a retrospective analysis of MCC cases from the National Cancer Data Base (NCDB) to assess whether adjuvant therapy was associated with differences in survival. METHODS: Six thousand nine hundred and eight MCC patients with staging, treatment, and survival data were included. Multivariable analyses were conducted for overall survival (OS) with various treatment modalities while adjusting for prognostic variables including age, sex, comorbidities (Charlson/Deyo score), margin status, primary tumor site and size, and lymph node status. All statistical tests were two-sided. RESULTS: For localized MCC (stage I: n = 3369, stage II: n = 1474 ), surgery plus adjuvant RT was associated with statistically significantly better OS than with surgery alone in multivariable analyses (stage I: hazard ratio [HR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.80, P < .001; stage II: HR = 0.77, 95% CI = 0.66 to 0.89, P < .001). In patients with regional nodal metastases (stage III: n = 2065 ), neither adjuvant RT nor chemotherapy was associated with statistically significantly improved or worsened OS. CONCLUSIONS: In this study of the largest MCC cohort reported to date, adjuvant RT was associated with improved OS in stages I-II MCC. Neither adjuvant RT nor chemotherapy was associated with improved OS in stage III MCC. These results, with the limitations of retrospective analyses, are consistent with earlier studies suggesting benefit with adjuvant RT but do not support the routine use of adjuvant chemotherapy in MCC. PMID- 27245175 TI - Tooth avulsion. PMID- 27245174 TI - A new method for depth of interaction determination in PET detectors. AB - A new method for obtaining depth of interaction (DOI) information in PET detectors is presented in this study, based on sharing and redirection of scintillation light among multiple detectors, together with attenuation of light over the length of the crystals. The aim is to obtain continuous DOI encoding with single side readout, and at the same time without the need for one-to-one coupling between scintillators and detectors, allowing the development of a PET scanner with good spatial, energy and timing resolutions while keeping the complexity of the system low. A prototype module has been produced and characterized to test the proposed method, coupling a LYSO scintillator matrix to a commercial SiPMs array. Excellent crystal separation is obtained for all the scintillators in the array, light loss due to depolishing is found to be negligible, energy resolution is shown to be on average 12.7% FWHM. The mean DOI resolution achieved is 4.1 mm FWHM on a 15 mm long crystal and preliminary coincidence time resolution was estimated in 353 ps FWHM. PMID- 27245176 TI - Thermal treatment of electronic waste in a fluidised bed and chemical digestion of solid products. AB - The article presents the results of e-waste thermal treatment in a fluidised bed reactor and solid products digestion under acidic conditions. During the processes, measurements of carbon monoxide, carbon dioxide, volatile organic compounds, nitrogen oxides, sulphur dioxide, hydrogen chloride, hydrogen bromide, hydrogen cyanide, ammonia, phenol, aliphatic and aromatic hydrocarbons, hydrogen fluoride and phosgene were carried out. Several digestion tests of the solid residue in sulphuric acid (VI) at 25 degrees C-65 degrees C, for 55 min-24 h were conducted. In each case, the dilution method was used, i.e. preliminary digestion in concentrated sulphuric acid (VI) (95%) for 40 min, and then dilution to expected concentrations (30%-50%). Most preferred results were obtained using sulphuric acid (VI) with a target concentration of 40% at 65 degrees C, where the leaching degrees were 76.56% for copper, 71.67% for iron, 91.89% for zinc and 97.40% for tin. The time necessary to effectively carry out the digestion process was 220 min. PMID- 27245178 TI - Identification of Serum Metabolites Associated With Incident Hypertension in the European Prospective Investigation into Cancer and Nutrition-Potsdam Study. AB - Metabolomics is a promising tool to gain new insights into early metabolic alterations preceding the development of hypertension in humans. We therefore aimed to identify metabolites associated with incident hypertension using measured data of serum metabolites of the European Prospective Investigation Into Cancer and Nutrition (EPIC)-Potsdam study. Targeted metabolic profiling was conducted on serum blood samples of a randomly drawn EPIC-Potsdam subcohort consisting of 135 cases and 981 noncases of incident hypertension, all of them being free of hypertension and not on antihypertensive therapy at the time of blood sampling. Mean follow-up was 9.9 years. A validated set of 127 metabolites was statistically analyzed with a random survival forest backward selection algorithm to identify predictive metabolites of incident hypertension taking into account important epidemiological hypertension risk markers. Six metabolites were identified to be most predictive for the development of hypertension. Higher concentrations of serine, glycine, and acyl-alkyl-phosphatidylcholines C42:4 and C44:3 tended to be associated with higher and diacyl-phosphatidylcholines C38:4 and C38:3 with lower predicted 10-year hypertension-free survival, although visualization by partial plots revealed some nonlinearity in the above associations. The identified metabolites improved prediction of incident hypertension when used together with known risk markers of hypertension. In conclusion, these findings indicate that metabolic alterations occur early in the development of hypertension. However, these alterations are confined to a few members of the amino acid or phosphatidylcholine metabolism, respectively. PMID- 27245179 TI - Dietary Salt Intake Is a Determinant of Cardiac Changes After Treatment of Primary Aldosteronism: A Prospective Study. AB - Primary aldosteronism is associated with increased left ventricular (LV) mass independently of blood pressure. Previous studies suggest that elevated aldosterone causes cardiac damage only in the presence of an inappropriate salt status. We examined the relevance of dietary salt intake on cardiac changes in patients with primary aldosteronism before and after treatment. Sixty-five patients with tumoral or idiopathic primary aldosteronism were recruited at a University medical center and followed after either surgical (n=30) or medical (n=35) treatment. At baseline and 1 year after treatment, cardiac morphology and functional variables were measured by echocardiography together with duplicate 24 hour urinary sodium collections. At baseline, LV mass index was associated with urinary sodium excretion and plasma aldosterone levels. During follow-up, blood pressure (from 167/102-135/83 mm Hg; P<0.001) and LV mass index (from 50.5+/-13.0 44.4+/-8.9 g/m(2.7); P<0.001) decreased significantly with nonsignificant changes in LV geometry and functional properties. At the end of follow-up, percentage decrease in LV mass index was significantly greater in patients who had >10% reduction in urinary sodium excretion (15.0+/-12.5%) than in the remaining patients (5.5+/-9.3%; P<0.001). Changes in LV mass index induced by both surgical and medical treatment were directly and independently correlated with changes in blood pressure (beta=0.419; P=0.009) and urinary sodium excretion (beta=0.334; P=0.012) observed at follow-up. These findings strongly support the hypothesis that dietary salt intake has a crucial role in aldosterone-related LV changes and could contribute to cardiac damage in patients with primary aldosteronism. PMID- 27245180 TI - Heart Rate Dependency of Large Artery Stiffness. AB - Carotid-femoral pulse wave velocity (cfPWV) quantifies large artery stiffness, it is used in hemodynamic research and is considered a useful cardiovascular clinical marker. cfPWV is blood pressure (BP) dependent. Intrinsic heart rate (HR) dependency of cfPWV is unknown because increasing HR is commonly accompanied by increasing BP. This study aims to quantify cfPWV dependency on acute, sympathovagal-independent changes in HR, independent of BP. Individuals (n=52, age 40-93 years, 11 female) with in situ cardiac pacemakers or cardioverter defibrillators were paced at 60, 70, 80, 90, and 100 bpm. BP and cfPWV were measured at each HR. Both cfPWV (mean [95% CI], 0.31 [0.26-0.37] m/s per 10 bpm; P<0.001) and central aortic diastolic pressure (3.78 [3.40-4.17] mm Hg/10 bpm; P<0.001) increased with HR. The HR effect on cfPWV was isolated by correcting the BP effects by 3 different methods: (1) statistically, by a linear mixed model; (2) mathematically, using an exponential relationship between BP and cross sectional lumen area; and (3) using measured BP dependency of cfPWV derived from changes in BP induced by orthostatic changes (seated and supine) in a subset of subjects (n=17). The BP-independent effects of HR on cfPWV were quantified as 0.20 [0.11-0.28] m/s per 10 bpm (P<0.001, method 1), 0.16 [0.11-0.22] m/s per 10 bpm (P<0.001, method 2), and 0.16 [0.11-0.21] m/s per 10 bpm (P<0.001, method 3). With a mean HR dependency in the range of 0.16 to 0.20 m/s per 10 bpm, cfPWV may be considered to have minimal physiologically relevant changes for small changes in HR, but larger differences in HR must be considered as contributing to significant differences in cfPWV. PMID- 27245181 TI - Angiotensin 1-7 Is a Negative Modulator of Aldosterone Secretion In Vitro and In Vivo. AB - Angiotensin (1-7) [Ang 1-7] is a 7 amino acid peptide generated predominantly from Ang II by the action of Ang-converting enzyme 2. We previously showed that Ang 1-7 reduced plasma aldosterone and plasma renin activity in high fructose-fed rats, and that the reduction in circulating aldosterone seemed to accord a parallel reduction in plasma renin activity. Here, we tested the possibility that Ang 1-7 affects aldosterone secretion acting directly in glomerulosa cells. First, as detected by immunofluorescence, the receptor for Ang 1-7, Mas1 is localized predominantly at the rat adrenal subcapsular region. Second, in isolated rat glomerulosa cells incubates, Ang 1-7 attenuated the aldosterone response to Ang II, with the strongest effect seen on Ang II (10(-9) M) (control 22+/-2.5 pg/10(5) cells; Ang II [10(-9) M] 189+/-11 pg/10(5) cells; Ang II [10( 9) M]+Ang 1-7 [10(-6) M] 33+/-3.6 pg/10(5) cells; P<0.001) and the largest effect on adrenocorticotropic hormone (10(-8) M) (control 30+/-3.4 pg/10(5) cells; ACTH [10(-8) M] 409+/-32.5 pg/10(5) cells; ACTH [10(-8) M]+Ang 1-7 [10(-6) M] 280+/ 12.5 pg/10(5) cells; P<0.001). In contrast, Ang 1-7 did not affect the aldosterone response to potassium (K(+)). In rats subjected to a low-salt diet for 7 days, continuous infusion of Ang 1-7 (576 MUg/kg per day) resulted in a lesser rise in aldosterone (salt deplete+Ang 1-7, 16.4+/-4.8 ng/dL) compared with rats receiving vehicle (salt deplete+vehicle, 27.6+/-5.3 ng/dL; P<0.01) but did not modify plasma renin activity. Taken together, these results indicate that Ang 1-7 can act as a negative modulator of aldosterone secretion in vitro and in vivo. PMID- 27245177 TI - Research into the Physiology of Cerebrospinal Fluid Reaches a New Horizon: Intimate Exchange between Cerebrospinal Fluid and Interstitial Fluid May Contribute to Maintenance of Homeostasis in the Central Nervous System. AB - Cerebrospinal fluid (CSF) plays an essential role in maintaining the homeostasis of the central nervous system. The functions of CSF include: (1) buoyancy of the brain, spinal cord, and nerves; (2) volume adjustment in the cranial cavity; (3) nutrient transport; (4) protein or peptide transport; (5) brain volume regulation through osmoregulation; (6) buffering effect against external forces; (7) signal transduction; (8) drug transport; (9) immune system control; (10) elimination of metabolites and unnecessary substances; and finally (11) cooling of heat generated by neural activity. For CSF to fully mediate these functions, fluid like movement in the ventricles and subarachnoid space is necessary. Furthermore, the relationship between the behaviors of CSF and interstitial fluid in the brain and spinal cord is important. In this review, we will present classical studies on CSF circulation from its discovery over 2,000 years ago, and will subsequently introduce functions that were recently discovered such as CSF production and absorption, water molecule movement in the interstitial space, exchange between interstitial fluid and CSF, and drainage of CSF and interstitial fluid into both the venous and the lymphatic systems. Finally, we will summarize future challenges in research. This review includes articles published up to February 2016. PMID- 27245182 TI - Associations of Short-Term and Long-Term Exposure to Ambient Air Pollutants With Hypertension: A Systematic Review and Meta-Analysis. AB - Hypertension is a major disease of burden worldwide. Previous studies have indicated that air pollution might be a risk factor for hypertension, but the results were controversial. To fill this gap, we performed a meta-analysis of epidemiological studies to investigate the associations of short-term and long term exposure to ambient air pollutants with hypertension. We searched all of the studies published before September 1, 2015, on the associations of ozone (O3), carbon monoxide (CO), nitrogen oxide (NO2 and NOX), sulfur dioxide (SO2), and particulate matter (PM10 and PM2.5) with hypertension in the English electronic databases. A pooled odds ratio (OR) for hypertension in association with each 10 MUg/m(3) increase in air pollutant was calculated by a random-effects model (for studies with significant heterogeneity) or a fixed-effect model (for studies without significant heterogeneity). A total of 17 studies examining the effects of short-term (n=6) and long-term exposure (n=11) to air pollutants were identified. Short-term exposure to SO2 (OR=1.046, 95% confidence interval [CI]: 1.012-1.081), PM2.5 (OR=1.069, 95% CI: 1.003-1.141), and PM10 (OR=1.024, 95% CI: 1.016-1.032) were significantly associated with hypertension. Long-term exposure (a 10 MUg/m(3) increase) to NO2 (OR=1.034, 95% CI: 1.005-1.063) and PM10 (OR=1.054, 95% CI: 1.036-1.072) had significant associations with hypertension. Exposure to other ambient air pollutants (short-term exposure to NO2, O3, and CO and long-term exposure to NOx, PM2.5, and SO2) also had positive relationships with hypertension, but lacked statistical significance. Our results suggest that short-term or long-term exposure to some air pollutants may increase the risk of hypertension. PMID- 27245183 TI - Two Patients with Severe Short Stature due to a FBN1 Mutation (p.Ala1728Val) with a Mild Form of Acromicric Dysplasia. AB - BACKGROUND: Acromicric dysplasia (AD) and geleophysic dysplasia 2 (GD2) belong to the category of acromelic dysplasia syndromes, consisting of severe short stature, short hands and feet and skin thickening. Both can result from missense mutations in the transforming growth factor beta 5 domain of the fibrillin-1 gene (FBN1). METHODS: Two patients (P1 age 10, and P2 age 7) from unrelated families presented to their endocrinologist with severe short stature (approx. -4 SDS). They were otherwise asymptomatic and only had mild facial dysmorphisms. Extensive endocrine work-up did not reveal an underlying etiology. Exome sequencing was performed in each family. RESULTS: Exome sequencing identified the presence of the same heterozygous missense variant c.C5183T (p.Ala1728Val) in the FBN1 gene in both P1 and P2. This variant was previously reported in a patient with GD2 and associated cardiac valvulopathy and hepatomegaly. Detailed clinical re examination, cardiac and skeletal imaging did not reveal any abnormalities in P1 or P2 other than mild hip dysplasia. CONCLUSION: This report broadens the phenotypic spectrum of growth disorders associated with FBN1 mutations. Identical mutations give rise to a wide phenotypic spectrum, ranging from isolated short stature to a more classic picture of GD2 with cardiac involvement, distinct facial dysmorphisms and various skeletal anomalies. PMID- 27245184 TI - The Epidemiology of DSM-5 Cannabis Use Disorders Among U.S. Adults: Science to Inform Clinicians Working in a Shifting Social Landscape. PMID- 27245185 TI - Early Mortality Among People With Schizophrenia. PMID- 27245186 TI - Telomere Attrition: A Window Into Common Mental Disorders and Cellular Aging. PMID- 27245187 TI - First-Onset Postpartum Psychiatric Disorders Portend High 1-Year Unnatural-Cause Mortality Risk. PMID- 27245188 TI - The RDoC Controversy: Alternate Paradigm or Dominant Paradigm? PMID- 27245189 TI - Two-Generation Psychiatric Intervention in the Prevention of Early Childhood Maltreatment Recidivism. PMID- 27245190 TI - A Scientific Pioneer of Psychiatry. PMID- 27245191 TI - G-CSF Dosing to Prevent Recurrent Clozapine-Induced Agranulocytosis. PMID- 27245196 TI - Comparing the symptoms and mechanisms of "dissociation" in dissociative identity disorder and borderline personality disorder. AB - A total of 75 patients were diagnosed with the Structured Clinical Interview for DSM-IV Dissociative Disorders-Revised as having dissociative identity disorder (DID), and 100 patients were diagnosed with the Structured Interview for DSM-IV Personality as having borderline personality disorder (BPD). Both groups were administered the Multidimensional Inventory of Dissociation (MID). DID patients had significantly higher MID scores than BPD patients, different distributions of MID scores, and different MID subscale profiles in 3 ranges of MID scores (0-15, 15-30, 30-45). The core MID symptoms-exhibited at all ranges of MID scores-for DID patients (the presence of alters, identity confusion, and memory problems) and BPD patients (flashbacks, identity confusion, and memory problems) were ostensibly similar but were considered to be mostly produced by different underlying processes. Multiple regression analyses showed that the core MID symptoms of DID patients had different predictors than did the core MID symptoms of BPD patients. Alter identities seemed to generate most-but not all dissociative phenomena in DID patients, whereas only the 24% highest scoring BPD patients (MID >=45) seemed to manifest alter-driven dissociative experiences. Most BPD dissociative experiences appeared to be due to 5 other mechanisms: (a) BPD-specific, stress-driven, rapid shifts of self-state; (b and c) nondefensive disruptions of the framework of perceptual organization with or without an accompanying BPD-specific, dissociation-like disintegration of affective/neurocognitive functioning; (d) a defensive distancing or detachment from distress (i.e., simple depersonalization); and (e) Allen, Console, and Lewis's (1999) severe absorptive detachment. PMID- 27245197 TI - Erythrocyte senescence and membrane transporters in young and old rats. AB - Alterations at the level of plasma membrane are reported to play an important role in cellular senescence. The present study was undertaken to correlate cellular senescence, membrane transport processes and organismal aging. To achieve this objective activities of membrane linked Na+/K + ATPase (NKA), Na+/H+ exchanger (NHE) and correlation with membrane hydrxyperoxide level, sialic acid content and membrane protein oxidation was studied in density-gradient fractionated young and old erythrocytes from 4 and 24 month old Wistar rats. The results reveal that cellular aging within the tissue is associated with significant decrease in activities of NKA and NHE of senescent erythrocytes in comparison to younger cell population of same age group. The result shows that impaired ion homeostasis due to altered membrane transporters including functional and compositional changes may be one of the reasons responsible behind rat erythrocyte aging. PMID- 27245195 TI - DNA methylation and breast tumor clinicopathological features: The Western New York Exposures and Breast Cancer (WEB) study. AB - We evaluated the association between methylation of 9 genes, SCGB3A1, GSTP1, RARB, SYK, FHIT, CDKN2A, CCND2, BRCA1, and SFN in tumor samples from 720 breast cancer cases with clinicopathological features of the tumors and survival. Logistic regression was used to estimate odds ratios (OR) of methylation and Cox proportional hazards models to estimate hazard ratios (HR) between methylation and breast cancer related mortality. Estrogen receptor (ER) and progesterone receptor (PR) positivity were associated with increased SCGB3A1 methylation among pre- and post-menopausal cases. Among premenopausal women, compared with Stage 0 cases, cases of invasive cancer were more likely to have increased methylation of RARB (Stage I OR = 4.7, 95% CI: 1.1-19.0; Stage IIA/IIB OR = 9.7, 95% CI: 2.4 39.9; Stage III/IV OR = 5.6, 95% CI: 1.1-29.4) and lower methylation of FHIT (Stage I OR = 0.2, 95% CI: 0.1-0.9; Stage IIA/IIB OR = 0.2, 95% CI: 0.1-0.8; Stage III/IV OR = 0.6, 95% CI: 0.1-3.4). Among postmenopausal women, methylation of SYK was associated with increased tumor size (OR = 1.7, 95% CI: 1.0-2.7) and higher nuclear grade (OR = 2.0, 95% CI 1.2-3.6). Associations between methylation and breast cancer related mortality were observed among pre- but not post menopausal women. Methylation of SCGB3A1 was associated with reduced risk of death from breast cancer (HR = 0.41, 95% CI: 0.17-0.99) as was BRCA1 (HR = 0.41, 95% CI: 0.16-0.97). CCND2 methylation was associated with increased risk of breast cancer mortality (HR = 3.4, 95% CI: 1.1-10.5). We observed differences in methylation associated with tumor characteristics; methylation of these genes was also associated with breast cancer survival among premenopausal cases. Understanding of the associations of DNA methylation with other clinicopathological features may have implications for prevention and treatment. PMID- 27245198 TI - Outcome of a web-based mindfulness intervention for families living with mental illness - A feasibility study. AB - BACKGROUND: Families living with a person with mental illness can experience distress requiring therapeutic interventions. Web-based mindfulness interventions have shown beneficial health outcomes for both clinical and healthy populations, and may help families cope and overcome barriers that can otherwise hinder a help seeking process. AIMS: To develop and assess outcomes of a web-based mindfulness intervention for families living with a person with mental illness. METHODS: A pilot study investigating an 8-week web-based mindfulness intervention with a pre post design and follow-up after 3 months, with mindfulness as the primary outcome and perceived stress, caregiver burden and self-compassion as secondary outcomes. The study included a sample of 97 persons approached by advertisement in newspapers, newsletters, and online. RESULTS: The study showed significant improvements in levels of mindfulness post-intervention and at follow-up as well as significant improvements in levels of perceived stress, caregiver burden, and self-compassion both post-intervention and at follow-up. DISCUSSION: Acceptability and feasibility of the intervention were high, outcomes were relevant, and the intervention showed positive and significant results supporting the hypothesis that the intervention may help families cope with a stressful situation. CONCLUSION: Further randomized controlled studies of the intervention are needed to investigate the intervention's effectiveness, including dose-effect studies. PMID- 27245199 TI - The Isothiocyanate Isolated from Moringa oleifera Shows Potent Anti-Inflammatory Activity in the Treatment of Murine Subacute Parkinson's Disease. AB - The present study was aimed at estimating a possible neuroprotective effect of glucomoringin (GMG) [4-(alpha-L-rhamnopyranosyloxy)benzyl glucosinolate] bioactivated with the enzyme myrosinase to form the corresponding isothiocyanate [4-(alpha-L-rhamnopyranosyloxy)benzyl C; moringin] in the treatment or prevention of Parkinson's disease (PD). In this study, the beneficial effects of moringin were compared with those of pure GMG, not enzymatically activated, in an in vivo experimental mouse model of subacute PD. Subacute PD was induced in C57BL/6 mice by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Mice were pretreated daily for 1 week with moringin (10 mg/kg +5 MUL myrosinase/mouse) and with GMG (10 mg/kg). Behavioral evaluations were also performed to assess motor deficits and bradykinesia in MPTP mice. Besides, assuming that pretreatment with moringin could modulate the triggering of inflammatory cascade with a correlated response, we tested its in vitro anti-inflammatory activity by using a model of RAW 264.7 macrophages stimulated with lipopolysaccharide. Achieved results in vivo showed a higher efficacy of moringin compared with GMG not only to modulate the inflammatory pathway but also oxidative stress and apoptotic pathways. In addition, the greater effectiveness of moringin in countering mainly the inflammatory pathway has been corroborated by the results obtained in vitro. The relevance and innovation of the present study lie in the possible use of a safe formulation of a bioactive compound, resulting from exogenous myrosinase hydrolysis of the natural phytochemical GMG, which can be used in clinical practice as a useful drug for the treatment or prevention of PD. PMID- 27245200 TI - Patient, Program, and System Barriers and Facilitators to Detoxification Services in the U.S. Veterans Health Administration: A Qualitative Study of Provider Perspectives. AB - BACKGROUND: Because substance use disorder (SUD) treatment is expanding, and detoxification (detox) is often the entry point to SUD treatment, it is critical to provide ready access to detox services. OBJECTIVES: The purpose of the current study was to examine patient, program, and system barriers or facilitators to detox access within an integrated health care system with variable rates of detox utilization across facilities. METHODS: Inpatient and outpatient providers from 31 different U.S. Veterans Health Administration detox programs were interviewed. RESULTS: Qualitative analyses identified six facilitators and 11 barriers to detox access. Facilitators included program staff and program characteristics such as encouragement and immediate access, as well as systemic cooperation and patient circumstances. Barriers to detox included programmatic and systemic problems, including lack of available detox services, program rules or admission requirements, funding shortages, stigma related to a SUD diagnosis or receiving detox services, and a deficiency of education and training. Other major barriers pertained to patients' lack of motivation and competing responsibilities. CONCLUSIONS/IMPORTANCE: To improve detox access, health care settings should consider enhancing supportive relationships by emphasizing outreach, engagement, and rapport-building with patients, improving systemic communication and teamwork, educating patients on available detox services and the detox process, and addressing patient centered barriers such as resistance to detox or competing responsibilities. In addition, programs should consider open-door and immediate admission policies. These approaches may improve detox access, which is important for increasing the likelihood of transitioning patients to SUD treatment, thus improving outcomes and reducing utilization of high-cost services. PMID- 27245201 TI - Network analysis of genes involved in the enhancement of hyperthermia sensitivity by the knockdown of BAG3 in human oral squamous cell carcinoma cells. AB - BCL2-associated athanogene 3 (BAG3), a co-chaperone of the heat shock 70 kDa protein (HSPA) family of proteins, is a cytoprotective protein that acts against various stresses, including heat stress. The aim of the present study was to identify gene networks involved in the enhancement of hyperthermia (HT) sensitivity by the knockdown (KD) of BAG3 in human oral squamous cell carcinoma (OSCC) cells. Although a marked elevation in the protein expression of BAG3 was detected in human the OSCC HSC-3 cells exposed to HT at 44C for 90 min, its expression was almost completely suppressed in the cells transfected with small interfering RNA against BAG3 (siBAG) under normal and HT conditions. The silencing of BAG3 also enhanced the cell death that was increased in the HSC-3 cells by exposure to HT. Global gene expression analysis revealed many genes that were differentially expressed by >2-fold in the cells exposed to HT and transfected with siBAG. Moreover, Ingenuity(r) pathways analysis demonstrated two unique gene networks, designated as Pro-cell death and Anti-cell death, which were obtained from upregulated genes and were mainly associated with the biological functions of induction and the prevention of cell death, respectively. Of note, the expression levels of genes in the Pro-cell death and Anti-cell death gene networks were significantly elevated and reduced in the HT + BAG3-KD group compared to those in the HT control group, respectively. These results provide further insight into the molecular mechanisms involved in the enhancement of HT sensitivity by the silencing of BAG3 in human OSCC cells. PMID- 27245202 TI - HMGI-C suppressing induces P53/caspase9 axis to regulate apoptosis in breast adenocarcinoma cells. AB - PURPOSE: The HMGI-C (high mobility group protein isoform I-C) protein is a member of the high-mobility group AT-hook (HMGA) family of small non-histone chromosomal proteins that can modulate transcription of an ample number of genes. Genome-wide studies reveal upregulation of the HMGI-C gene in many human cancers, which suggests that HMGI-C might play a critical role in the progression of various tumors. However, the exact role of HMGI-C in breast adenocarcinoma has not been made clear. METHODS: HMGI-C mRNA expression in breast cancer samples and marginal normal tissues was characterized using qRT-PCR. The cytotoxic effects of HMGI-C siRNA on breast adenocarcinoma cells were determined using MTT assay. Relative HMGI-C mRNA and protein levels were measured by quantitative real-time PCR and western blotting, respectively. Apoptosis detection was done using TUNEL and Annexin-V/PI assays, P53, caspase 3, 9, 8 and Bcl2 proteins evaluated by protein gel blot and miR34a, Let-7a genes investigates by QRT-PCR assay. Cell cycle was analyzed by flow cytometry assay using propidium iodide DNA staining. RESULTS: An overexpression of HMGA2 was revealed with highly statistically significant differences between breast cancer samples and marginal normal tissues (P < 0.0001). HMGI-C siRNA significantly reduced both mRNA and protein expression levels in a 48-hour period after transfection and in a dose-dependent manner. We observed that the knockdown of HMGI-C led to the significant induction of apoptosis via mitochondrial pathway by inducing miR34a and cell cycle arrest in MDA-MB-468 cells in vitro. CONCLUSIONS: These results propose that HMGI-C might play a critical role in the progression of breast adenocarcinoma. Here we introduced HMGI-C as a potential therapeutic target for trigger apoptosis and cell cycle arrest in human breast adenocarcinoma. Therefore HMGI-C siRNA may be an effective adjuvant in human breast adenocarcinoma. PMID- 27245203 TI - Age dependence of pulmonary artery blood flow measured by 4D flow cardiovascular magnetic resonance: results of a population-based study. AB - BACKGROUND: It was our aim to systematically analyze pulmonary artery blood flow within different age-groups in the general population using 4D flow cardiovascular magnetic resonance (CMR) in order to provide a context for interpreting results of future studies (e.g., in pulmonary hypertension) using this technique. METHODS: An age-stratified sample (n = 126) of the population of the city of Freiburg, Germany, underwent ECG-triggered and navigator-gated 4D flow CMR at 3 T of the pulmonary arteries and the thoracic aorta. Analysis planes were placed in the main, left, and right pulmonary artery using dedicated software. Study participants were divided into three groups (1:20-39; 2:40-59; and 3:60-80 years of age). Subsequently, pulmonary blood flow was visualized, quantified and compared between groups. RESULTS: Time-to-peak of systolic antegrade flow was shorter, peak and average velocities and flow volumes were lower in older subjects. At the end of systole, retrograde flow in the main pulmonary artery was observed in all but one subject. Subsequently, a second antegrade flow peak occurred in diastole which was lower in older subjects. Age was an independent predictor of hemodynamic change after adjustment for cardiovascular risk factors and body-mass-index. During systole, abnormal vortices occurred in the main pulmonary artery in four male subjects. CONCLUSIONS: Comprehensive analysis of pulmonary blood flow was feasible in all subjects. We were able to detect an independent effect of ageing on pulmonary hemodynamics reflecting increased vessel stiffness and reduced pulmonary circulation. Findings of this study may be helpful for discriminating physiological from pathological flow in patients with pulmonary diseases in the future. PMID- 27245204 TI - Phase I Metabolic Stability and Electrophilic Reactivity of 2 Phenylaminophenylacetic Acid Derived Compounds. AB - Diclofenac and lumiracoxib are two highly analogous 2-phenylaminophenylacetic acid anti-inflammatory drugs exhibiting occasional dose-limiting hepatotoxicities. Prior data indicate that bioactivation and reactive metabolite formation play roles in the observed toxicity, but the exact chemical influence of the substituents remains elusive. In order to elucidate the role of chemical influence on metabolism related toxicity, metabolic stability and electrophilic reactivity were investigated for a series of structurally related analogues and their resulting metabolites. The resulting analogues embody progressive physiochemical changes through varying halogeno- and aliphatic substituents at two positions and were subjected to in vitro human liver microsomal metabolic stability and cell-based GSH depletion assays (to measure electrophilic reactivity). LC-MS/MS analysis of the GSH trapped reactive intermediates derived from the analogues was then used to identify the putative structures of reactive metabolites. We found that chemical modifications of the structural backbone led to noticeable perturbations of metabolic stability, electrophilic reactivity, and structures and composition of reactive metabolites. With the acquired data, the relationships between stability, reactivity, and toxicity were investigated in an attempt to correlate between Phase I metabolism and in vitro toxicity. A positive correlation was identified between reactivity and in vitro toxicity, indicating that electrophilic reactivity can be an indicator for in vitro toxicity. All in all, the effect of substituents on the structures and reactivity of the metabolites, however subtle the changes, should be taken into consideration during future drug design involving similar chemical features. PMID- 27245205 TI - Differences in DNA Repair Capacity, Cell Death and Transcriptional Response after Irradiation between a Radiosensitive and a Radioresistant Cell Line. AB - Normal tissue toxicity after radiotherapy shows variability between patients, indicating inter-individual differences in radiosensitivity. Genetic variation probably contributes to these differences. The aim of the present study was to determine if two cell lines, one radiosensitive (RS) and another radioresistant (RR), showed differences in DNA repair capacity, cell viability, cell cycle progression and, in turn, if this response could be characterised by a differential gene expression profile at different post-irradiation times. After irradiation, the RS cell line showed a slower rate of gamma-H2AX foci disappearance, a higher frequency of incomplete chromosomal aberrations, a reduced cell viability and a longer disturbance of the cell cycle when compared to the RR cell line. Moreover, a greater and prolonged transcriptional response after irradiation was induced in the RS cell line. Functional analysis showed that 24 h after irradiation genes involved in "DNA damage response", "direct p53 effectors" and apoptosis were still differentially up-regulated in the RS cell line but not in the RR cell line. The two cell lines showed different response to IR and can be distinguished with cell-based assays and differential gene expression analysis. The results emphasise the importance to identify biomarkers of radiosensitivity for tailoring individualized radiotherapy protocols. PMID- 27245206 TI - Efficacy of a galactogogue containing silymarin-phosphatidylserine and galega in mothers of preterm infants: a randomized controlled trial. AB - BACKGROUND/OBJECTIVES: Human milk (HM) is the best possible food for all infants, especially for preterm ones, but lactation and breastfeeding are very difficult for mothers of preterm babies and high rates of breastfeeding difficulties have been reported. Our aim was to investigate the efficacy of a galactogogue containing silymarin-phosphatidylserine and galega in increasing milk production during the first month after delivery in a population of mothers of preterm infants. SUBJECTS/METHODS: Mothers of infants with gestational age (GA) between 27+0 and 32+6 weeks were enrolled in this prospective, double-blind, randomized trial and were randomly allocated to receive either the galactogogue containing silymarin-phosphatidylserine and galega, 5 g/day (galactogogue group, GG), or a placebo, 5 g of lactose per day (placebo group, PG) from the 3rd to the 28th day after delivery. RESULTS: Fifty mothers were included in each group. General characteristics of mothers and pregnancies were similar. Milk production was significantly greater in the GG at the 7th day of life and at the 30th day of life. Daily milk production from the 7th to the 30th day of life was 200 (110 380) ml in the GG vs 115 (60-245) ml in the PG (P<0.0001). The total production of milk during the study period was significantly higher in the GG (6523+/-5298 ml vs 4136+/-4093 ml; P<0.02). At the end of the study, 45 mothers of the GG were able to reach the target of milk supply of 200 ml/day compared with 25 mothers of the PG (P<0.01). No adverse reactions were noticed in the study groups. CONCLUSIONS: Silymarin-phosphatidylserine and galega increased milk production in mothers of preterm infants without any significant side effects. PMID- 27245207 TI - A comparison of body composition estimates using dual-energy X-ray absorptiometry and air-displacement plethysmography in South African neonates. AB - BACKGROUND/OBJECTIVES: Neonatal body composition is an important predictor of future metabolic risk; however, the comparability of objective assessment techniques, particularly in African populations undergoing rapid health transition, is not known. This paper compares body composition estimates by air displacement plethysmography (ADP) and dual-energy X-ray absorptiometry (DXA) in South African neonates. SUBJECTS/METHODS: Fat mass, fat-free mass and body fat percentage (%fat) estimates by ADP and DXA were compared in 88 urban, black South African neonates. The level of agreement between the techniques was assessed using Bland-Altman analyses. RESULTS: Significant correlations were observed between ADP and DXA measurements of fat mass (r=0.766), fat-free mass (r=0.942) and %fat (r=0.630); however, ADP estimates of fat mass (408+/-172 g vs 337+/-165 g; P<0.001) and %fat (12.9+/-4.4% vs 9.9+/-4%; P<0.001) were significantly higher and fat-free mass (2681+/-348 g vs 2969+/-375 g; P<0.001) significantly lower than those by DXA. Fat-free mass estimates showed greater consistency in the level of agreement between the techniques compared with fat and %fat estimates where the differences between methods were less predictable. CONCLUSION: Although ADP and DXA body composition estimates are highly correlated in neonates, significant differences are observed between the techniques. This is particularly relevant for fat mass and %fat estimates, where differences are highly variable between methods. Further investigation is needed to minimise inter-method differences to ensure accurate and comparable assessment of body composition at birth and across longitudinal study follow-up. PMID- 27245208 TI - Resolution of non-psychogenic epileptic-like seizures utilizing a vasodilatory and anti-inflammatory dietary intervention. AB - A young female subject with ineffective pharmacological regulation of chronic vasoconstrictive-induced epilectic-like seizures was effectively treated with a dietary regimen targeted to promote vasodilatation and attenuate vascular inflammation. The intervention consisted of complete cessation of caffeinated beverages, supplementation with L-arginine to promote vasodilatation, consumption of foods rich in phytoestrogens, minimization of foods enriched with saturated fatty acids, supplementation with vitamin D concomitant with increased ingestion of dairy milk and supplementation with aged garlic extract. PMID- 27245209 TI - Prevalence of weakness and its relationship with limitations based on the Foundations for the National Institutes for Health project: data from the Health and Retirement Study. AB - BACKGROUND/OBJECTIVES: The objectives of this study were to determine the prevalence of muscle weakness using the two 2014 Foundation for the National Institutes of Health (FNIH) Sarcopenia Project criteria and its relationship with physical limitations, basic activities of daily living (ADL) and instrumental ADL. SUBJECTS/METHODS: We performed a cross-sectional analysis of community dwelling adults from the Health and Retirement Study 2006-2008 and identified a subsample of 5092 adults aged ?60 years with grip strength (GS) data. Self reported physical limitations, basic ADL and instrumental ADL were assessed. Criteria for GS (men<26 kg; women <16 kg) and GS adjusted for body mass index (GS/BMI; men <1.0; women <0.56) were applied to the sample. We determined the prevalence of muscle weakness in each sex. Multivariable logistic regression was used to calculate the association of physical limitations, basic ADL and instrument ADL with weakness definitions in each sex. RESULTS: Mean age was 72.1 years (54.9% female). Mean GS was 38.3 and 22.9 kg and mean BMI was 29 kg/m2, respectively, in men and women. Weakness prevalence using GS and GS:BMI definitions were 7.8 and 15.2 (P<0.001), respectively, in men and 11.4 and 13.3% (P=0.04) in women. Overall prevalence of physical limitations, basic ADL limitations and instrumental ADL limitations was 52.9, 28.1 and 35.9%, respectively. In those with weakness, prevalence of physical limitations, basic ADL and instrumental ADL was 78.5, 42.3 and 65.3%, respectively, using the GS definition, and 79.7, 40.7 and 58.8%, respectively, using the GS/BMI definition. GS and the GS/BMI definitions of weakness were strongly associated with physical limitations (odds ratio (OR) 2.19 (95% confidence interval (CI): (1.67-2.87)) and 2.52 (2.01-3.17)), basic ADL (OR 1.59 (1.22-2.07) and 1.66 (1.32-2.07)) and instrumental ADLs (OR 1.98 (1.28-2.54) and 1.78 (1.44-2.20)). CONCLUSIONS: The new FNIH guidelines for weakness are associated with higher prevalence of physical limitations, basic ADL impairments and instrumental ADL impairments as compared with individuals without weakness. PMID- 27245210 TI - Hypovitaminosis D and fat mass in healthy older people. AB - Prospective studies have suggested that hypovitaminosis D can predict the onset of obesity, but they relied mainly on body mass index, which could be scarcely reliable in older people. We investigated whether baseline hypovitaminosis D could predict higher fat mass (FM) levels using dual-energy X-ray absorptiometry in a sample of 116 fit and healthy older subjects. Although no significant differences in FM estimates emerged between subjects with and without hypovitaminosis D at the baseline, abdominal FM was found significantly higher in the former group (with hypovitaminosis D at the baseline) than in the latter after 3 years of follow-up. Adjusted logistic regression analysis confirmed these findings: hypovitaminosis D coincided with an approximately sixfold higher risk of subjects having higher abdominal FM levels at the follow-up. In conclusion, hypovitaminosis D predicts higher abdominal FM levels in the elderly. PMID- 27245211 TI - Reliability and validity of a revised version of the General Nutrition Knowledge Questionnaire. AB - BACKGROUND/OBJECTIVES: The General Nutrition Knowledge Questionnaire (GNKQ) was developed in the 1990s and has been widely used. Since then advances in understanding of associations between diet and disease have led to changes in dietary recommendations. This study reports the validity and reliability of an updated version of the GNKQ, bringing it into line with current nutritional advice. METHODS/SUBJECTS: Following a review of current recommendations, the revised version of the GNKQ (GNKQ-R) was created, consisting of 88 items and four sections. Reliability and validity of the GNKQ-R were determined in four validation studies: (1) reliability was examined using an online sample (n=266), (2) construct validity was assessed with 96 Dietetics students and 89 english students using the 'known-groups' method, (3) associations between nutrition knowledge and socio-demographic characteristics were examined using the previously described samples and (4) sensitivity to change was tested by measuring GNKQ-R scores pre- and post-exposure to online nutrition information in written (n=65) and video (n=41) formats. RESULTS: The reliability was >0.7 in all sections. Dietetics students scored significantly higher than english students. As predicted, GNKQ-R scores were significantly higher among females vs males, people with a degree vs without, and people with very good vs poor or good health status. They were lower in those older than 50 years vs younger adults. GNKQ-R scores were significantly greater after the nutrition interventions in both written and video formats. CONCLUSIONS: The GNKQ-R is a valid measure of nutrition knowledge that is consistent, reliable and sensitive to change. PMID- 27245212 TI - Identification of an Electrostatic Ruler Motif for Sequence-Specific Binding of Collagenase to Collagen. AB - Sequence-specific cleavage of collagen by mammalian collagenase plays a pivotal role in cell function. Collagenases are matrix metalloproteinases that cleave the peptide bond at a specific position on fibrillar collagen. The collagenase Hemopexin-like (HPX) domain has been proposed to be responsible for substrate recognition, but the mechanism by which collagenases identify the cleavage site on fibrillar collagen is not clearly understood. In this study, Brownian dynamics simulations coupled with atomic-detail and coarse-grained molecular dynamics simulations were performed to dock matrix metalloproteinase-1 (MMP-1) on a collagen IIIalpha1 triple helical peptide. We find that the HPX domain recognizes the collagen triple helix at a conserved R-X11-R motif C-terminal to the cleavage site to which the HPX domain of collagen is guided electrostatically. The binding of the HPX domain between the two arginine residues is energetically stabilized by hydrophobic contacts with collagen. From the simulations and analysis of the sequences and structural flexibility of collagen and collagenase, a mechanistic scheme by which MMP-1 can recognize and bind collagen for proteolysis is proposed. PMID- 27245213 TI - Expression analysis and biological characterization of Babesia sp. BQ1 (Lintan) (Babesia motasi-like) rhoptry-associated protein 1 and its potential use in serodiagnosis via ELISA. AB - BACKGROUND: In China, ovine babesiosis is one of the most important tick-borne haemoparasitic diseases of small ruminants. It has a significant economic impact, and several Babesia motasi-like isolates have been recently shown to be responsible for ovine babesiosis in this country. METHODS: Full-length and C terminal-truncated forms of the rap-1a61-1 gene of Babesia sp. BQ1 (Lintan) were cloned into the pET-30a plasmid and subsequently expressed as His-fusion proteins. The resulting recombinant RAP-1a proteins (rRAP-1a61-1 and rRAP-1a61 1/CT) were purified and evaluated as diagnostic antigens using Western blot analysis and ELISA. The native Babesia sp. BQ1 (Lintan) RAP-1 protein was recognized using Western blots and IFAT by antibodies that were raised in rabbits against rRAP-1a61-1/CT. The specificity, sensitivity and positive threshold values for rRAP-1a61-1/CT in ELISA were evaluated. RESULTS: Cross-reactivity was observed between rRAP-1a61-1/CT and positive sera for Babesia sp. BQ1 (Lintan), Babesia sp. BQ1 (Ningxian) and Babesia sp. Tianzhu isolates obtained from infected sheep. At one week post-inoculation, a significant increase was observed in the amount of antibodies produced against RAP-1a, and high levels of antibodies against RAP-1a were observed for 3 months (at 84 days p.i.). A total of 3198 serum samples were collected from small ruminants in 54 different regions in 23 provinces of China. These samples were tested using ELISA based on the rRAP 1a61-1/CT protein. The results indicated that the average positive rate was 36.02 %. CONCLUSIONS: The present study suggests that rRAP-1a61-1/CT might be a potential diagnostic antigen for detecting several isolates of B. motasi-like parasites infection. PMID- 27245214 TI - Nucleo-cytoplasmic shuttling of the endonuclease ankyrin repeats and LEM domain containing protein 1 (Ankle1) is mediated by canonical nuclear export- and nuclear import signals. AB - BACKGROUND: Ankyrin repeats and LEM domain containing protein 1 (Ankle1) belongs to the LEM protein family, whose members share a chromatin-interacting LEM motif. Unlike most other LEM proteins, Ankle1 is not an integral protein of the inner nuclear membrane but shuttles between the nucleus and the cytoplasm. It contains a GIY-YIG-type nuclease domain, but its function is unknown. The mammalian genome encodes only one other GIY-YIG domain protein, termed Slx1. Slx1 has been described as a resolvase that processes Holliday junctions during homologous recombination-mediated DNA double strand break repair. Resolvase activity is regulated in a spatial and temporal manner during the cell cycle. We hypothesized that Ankle1 may have a similar function and its nucleo-cytoplasmic shuttling may contribute to the regulation of Ankle1 activity. Hence, we aimed at identifying the domains mediating Ankle1 shuttling and investigating whether cellular localization is affected during DNA damage response. RESULTS: Sequence analysis predicts the presence of two canonical nuclear import and export signals in Ankle1. Immunofluorescence microscopy of cells expressing wild-type and various mutated Ankle1-fusion proteins revealed a C-terminally located classical monopartite nuclear localization signal and a centrally located CRM1-dependent nuclear export signal that mediate nucleo-cytoplasmic shuttling of Ankle1. These sequences are also functional in heterologous proteins. The predominant localization of Ankle1 in the cytoplasm, however, does not change upon induction of several DNA damage response pathways throughout the cell cycle. CONCLUSIONS: We identified the domains mediating nuclear import and export of Ankle1. Ankle1's cellular localization was not affected following DNA damage. PMID- 27245215 TI - Cholesterol Depletion from a Ceramide/Cholesterol Mixed Monolayer: A Brewster Angle Microscope Study. AB - Cholesterol is crucial to the mechanical properties of cell membranes that are important to cells' behavior. Its depletion from the cell membranes could be dramatic. Among cyclodextrins (CDs), methyl beta cyclodextrin (MbetaCD) is the most efficient to deplete cholesterol (Chol) from biomembranes. Here, we focus on the depletion of cholesterol from a C16 ceramide/cholesterol (C16-Cer/Chol) mixed monolayer using MbetaCD. While the removal of cholesterol by MbetaCD depends on the cholesterol concentration in most mixed lipid monolayers, it does not depend very much on the concentration of cholesterol in C16-Cer/Chol monolayers. The surface pressure decay during depletion were described by a stretched exponential that suggested that the cholesterol molecules are unable to diffuse laterally and behave like static traps for the MbetaCD molecules. Cholesterol depletion causes morphology changes of domains but these disrupted monolayers domains seem to reform even when cholesterol level was low. PMID- 27245216 TI - Impact of body fat changes in mediating the effects of antiretroviral therapy on blood pressure in HIV-infected persons in a sub-Saharan African setting. AB - BACKGROUND: Previous studies of HIV-infected patients have shown significant associations between highly active antiretroviral therapy (HAART) and increased blood pressure; however, the mechanisms involved are less clear. Therefore, we sought to investigate the potential impact of body fat changes in mediating the effects of HAART on blood pressure changes among people living with HIV. METHODS: Four hundred six consenting patients (>=18 years of age) attending a tertiary HIV clinic in semi-urban Nigeria were recruited between August and November 2014 as part of a cross-sectional study. We performed bias-corrected bootstrap tests of mediation using 95 % confidence intervals (CI) to determine the mediating effects of body mass index and waist circumference (mediators) on the total effects of HAART exposure (primary predictor) on blood pressure (outcome), while controlling for age, sex and other potential confounders. RESULTS: Waist circumference remained a significant partial mediator of the total effects of HAART exposure on increasing systolic blood pressure (coefficient: 1.01, 95 % CI: 0.33 to 2.52, 11 % mediated) and diastolic blood pressure (coefficient: 0.68, 95 % CI: 0.26 to 1.89, 9 % mediated) after adjusting for age, sex, smoking status, CD4 count and duration of HIV infection. No significant mediating effect was observed with body mass index alone or in combination with waist circumference after adjusting for all potential confounders. CONCLUSION: Waist circumference significantly mediates the effects of HAART on blood pressure in persons living with HIV, independent of the role of traditional risk factors. The use of waist circumference as a complementary body fat measure to body mass index may improve the clinical prediction of hypertension in HIV-infected patients on antiretroviral therapy. PMID- 27245217 TI - Proteomic analysis of Plasmodium falciparum parasites from patients with cerebral and uncomplicated malaria. AB - Plasmodium falciparum is responsible of severe malaria, including cerebral malaria (CM). During its intra-erythrocytic maturation, parasite-derived proteins are expressed, exported and presented at the infected erythrocyte membrane. To identify new CM-specific parasite membrane proteins, we conducted a mass spectrometry-based proteomic study and compared the protein expression profiles between 9 CM and 10 uncomplicated malaria (UM) samples. Among the 1097 Plasmodium proteins identified, we focused on the 499 membrane-associated and hypothetical proteins for comparative analysis. Filter-based feature selection methods combined with supervised data analysis identified a subset of 29 proteins distinguishing CM and UM samples with high classification accuracy. A hierarchical clustering analysis of these 29 proteins based on the similarity of their expression profiles revealed two clusters of 15 and 14 proteins, respectively under- and over-expressed in CM. Among the over-expressed proteins, the MESA protein is expressed at the erythrocyte membrane, involved in proteins trafficking and in the export of variant surface antigens (VSAs), but without antigenic function. Antigen 332 protein is exported at the erythrocyte, also involved in protein trafficking and in VSAs export, and exposed to the immune system. Our proteomics data demonstrate an association of selected proteins in the pathophysiology of CM. PMID- 27245218 TI - Investigation of MMP-1 genetic polymorphisms and protein expression and their effects on the risk of Kashin-Beck disease in the northwest Chinese Han population. AB - BACKGROUND: The etiology of Kashin-Beck disease (KBD), an endemic osteochondropathy, is largely unknown. Matrix metalloproteinase-1 (MMP-1) plays a central role in the initiation and progression of cartilage destruction; however, no study has reported on the relationship between KBD and MMP-1. This study was to investigate the role of MMP-1 in the pathogenesis and progression of KBD. METHODS: Single nucleotide polymorphism (SNP) genotyping was conducted for 274 KBD cases and 248 healthy controls using the Sequenom MassARRAY system. Additionally, the expression of MMP-1 in the knee articular cartilage of 22 KBD patients and 21 controls was analyzed by immunohistochemistry, and the concentration of MMP-1 in their joint fluid was also measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The results showed that two SNPs (rs470221 and rs1144396) had a weak association with increased KBD risk; however, the significance of these results did not survive Bonferroni's correction. Moreover, the percentages of cells expressing MMP-1 in each layer of cartilage were significantly higher in the KBD group than in the controls (F = 11.41-28.31, P = 0.002-0.000). The concentration of MMP-1 in KBD joint fluid was significantly higher than that in the controls (t = 9.83, P < 0.0001). CONCLUSIONS: The increased expression of MMP-1 has a potential effect on the risk of KBD in the northwest Chinese Han population. However, six selected SNPs in the MMP-1 gene might not be useful as significant markers for predicting KBD susceptibility in Chinese Han population. Therefore, future studies in the association of MMP-1 with KBD should focus on other candidate SNPs. PMID- 27245219 TI - A randomized, double-blind sham-controlled trial on the efficacy of arthroscopic tennis elbow release for the management of chronic lateral epicondylitis. AB - BACKGROUND: Tennis elbow is a common elbow pathology typically affecting middle aged individuals that can lead to significant disability. Most cases resolve within 2 years of symptom onset, but a subset of patients will develop persistent symptoms despite appropriate conservative management. There are several surgical approaches used to treat chronic tennis elbow, with arthroscopic surgery becoming an increasingly popular approach to address this pathology in North America. This procedure involves the arthroscopic release of the extensor carpi radialis brevis tendon (ECRB) origin at the elbow. The potential benefit of arthroscopic treatment of this condition is improved patient outcomes and shorter recovery time following surgery. The results of this technique have been reported only in the context of case series, which have shown positive results. However, in order to justify its widespread use and growing popularity, a high level of evidence study is required. The purpose of this prospective, randomized sham-controlled trial is to determine whether arthroscopic tennis elbow release is effective at treating chronic lateral epicondylitis. METHODS: We will conduct a prospective single center, double-blind, randomized sham-controlled parallel arm trial evaluating the efficacy of arthroscopic tennis elbow release in adult patients with symptoms for at least 6 months. Patients will undergo intraoperative randomization after diagnostic arthroscopy of the elbow to receive either ECRB release (through the creation of a lateral portal) or a sham lateral portal and no ECRB release. The primary outcome will be the Mayo Elbow Performance Score (MEPS) at 1 year follow-up. Secondary outcomes will be the abbreviated Disability of the Shoulder and Hand (DASH) score, American Shoulder and Elbow Surgeons elbow (ASES-e) score and grip strength at 3, 6, 12 and 24 months as well as return-to work time, ability to return to full duty and adverse outcomes. DISCUSSION: Results of this study will provide empirical high quality evidence to guide clinical decision-making in patients with chronic tennis elbow. TRIAL REGISTRATION: NCT02236689 (September 8, 2014). PMID- 27245220 TI - Phosphatidylinositol-3-phosphate is light-regulated and essential for survival in retinal rods. AB - Phosphoinositides play important roles in numerous intracellular membrane pathways. Little is known about the regulation or function of these lipids in rod photoreceptor cells, which have highly active membrane dynamics. Using new assays with femtomole sensitivity, we determined that whereas levels of phosphatidylinositol-3,4-bisphosphate and phosphatidylinositol-3,4,5 trisphosphate were below detection limits, phosphatidylinositol-3-phosphate (PI(3)P) levels in rod inner/outer segments increased more than 30-fold after light exposure. This increase was blocked in a rod-specific knockout of the PI-3 kinase Vps34, resulting in failure of endosomal and autophagy-related membranes to fuse with lysosomes, and accumulation of abnormal membrane structures. At early ages, rods displayed normal morphology, rhodopsin trafficking, and light responses, but underwent progressive neurodegeneration with eventual loss of both rods and cones by twelve weeks. The degeneration is considerably faster than in rod knockouts of autophagy genes, indicating defects in endosome recycling or other PI(3)P-dependent membrane trafficking pathways are also essential for rod survival. PMID- 27245221 TI - Multimodal evoked potentials for functional quantification and prognosis in multiple sclerosis. AB - BACKGROUND: Functional biomarkers able to identify multiple sclerosis (MS) patients at high risk of fast disability progression are lacking. The aim of this study was to evaluate the ability of multimodal (upper and lower limbs motor, visual, lower limbs somatosensory) evoked potentials (EP) to monitor disease course and identify patients exposed to unfavourable evolution. METHODS: One hundred MS patients were assessed with visual, somatosensory and motor EP and rated on the Expanded Disability Status Scale (EDSS) at baseline (T0) and about 6 years later (T1). The Spearman correlation (rS) was used to evaluate the relationship between conventional EP scores and clinical findings. Multiple (logistic) regression analysis estimated the predictive value of baseline electrophysiological data for three clinical outcomes: EDSS, annual EDSS progression, and the risk of EDSS worsening. RESULTS: In contrast to longitudinal correlations, cross-sectional correlations between the different EP scores and EDSS were all significant (0.33 <= rS < 0.67, p < 0.001). Baseline global EP score and EDSS were highly significant predictors (p < 0.0001) of EDSS progression 6 years later. The baseline global EP score was found to be an independent predictor of the EDSS annual progression rate (p < 0.001), and of the risk of disability progression over time (p < 0.005). Based on a ROC curve determination, we defined a Global EP Score cut off point (17/30) to identify patients at high risk of disability progression illustrated by a positive predictive value of 70%. CONCLUSION: This study provides a proof of the concept that electrophysiology could be added to MRI and used as another complementary prognostic tool in MS patients. PMID- 27245222 TI - ODMedit: uniform semantic annotation for data integration in medicine based on a public metadata repository. AB - BACKGROUND: The volume and complexity of patient data - especially in personalised medicine - is steadily increasing, both regarding clinical data and genomic profiles: Typically more than 1,000 items (e.g., laboratory values, vital signs, diagnostic tests etc.) are collected per patient in clinical trials. In oncology hundreds of mutations can potentially be detected for each patient by genomic profiling. Therefore data integration from multiple sources constitutes a key challenge for medical research and healthcare. METHODS: Semantic annotation of data elements can facilitate to identify matching data elements in different sources and thereby supports data integration. Millions of different annotations are required due to the semantic richness of patient data. These annotations should be uniform, i.e., two matching data elements shall contain the same annotations. However, large terminologies like SNOMED CT or UMLS don't provide uniform coding. It is proposed to develop semantic annotations of medical data elements based on a large-scale public metadata repository. To achieve uniform codes, semantic annotations shall be re-used if a matching data element is available in the metadata repository. RESULTS: A web-based tool called ODMedit ( https://odmeditor.uni-muenster.de/ ) was developed to create data models with uniform semantic annotations. It contains ~800,000 terms with semantic annotations which were derived from ~5,800 models from the portal of medical data models (MDM). The tool was successfully applied to manually annotate 22 forms with 292 data items from CDISC and to update 1,495 data models of the MDM portal. CONCLUSION: Uniform manual semantic annotation of data models is feasible in principle, but requires a large-scale collaborative effort due to the semantic richness of patient data. A web-based tool for these annotations is available, which is linked to a public metadata repository. PMID- 27245223 TI - Anterior chamber depth and angle-closure glaucoma after central retinal vein occlusion. AB - BACKGROUND: The purpose of this study was to report the anterior chamber (AC) depth and the attack of angle-closure glaucoma (ACG) in eyes with the recent onset of central retinal vein occlusion (CRVO). METHODS: This retrospective case series included 24 patients with recent onset of CRVO (within one month of attack) from July 2001 to December 2002. The mean follow-up period of the patients was 46 months (range: 3 to 92 months). AC depth was measured using an ultrasound biomicroscopy. Clinical data, including systemic disorders, intraocular pressure, and visual outcomes were recorded. The main outcome measures were AC depth in the diseased eye and the fellow eye of the same patient and the attack of ACG after CRVO. RESULTS: The mean AC depth in the diseased eyes was significantly shallower than in the unaffected fellow eyes (2.43 +/- 0.45 mm vs. 2.55 +/- 0.46 mm; p < 0.001). Four patients (17 %) developed ACG after the onset of CRVO within one month of the CRVO attack. In these four patients, the mean AC depth in the diseased eyes was 1.91 +/- 0.21 mm, which was much shallower than the eyes without ACG attack (2.53 +/- 0.40 mm). CONCLUSIONS: AC depth is significantly shallower following the onset of CRVO. ACG can occur in patients after the onset of CRVO. PMID- 27245224 TI - Inflammation, glucose, and vascular cell damage: the role of the pentose phosphate pathway. AB - BACKGROUND: Hyperglycemia is acknowledged as a pro-inflammatory condition and a major cause of vascular damage. Nevertheless, we have previously described that high glucose only promotes inflammation in human vascular cells previously primed with pro-inflammatory stimuli, such as the cytokine interleukin (IL)1beta. Here, we aimed to identify the cellular mechanisms by which high glucose exacerbates the vascular inflammation induced by IL1beta. METHODS: Cultured human aortic smooth muscle cells (HASMC) and isolated rat mesenteric microvessels were treated with IL1beta in medium containing 5.5-22 mmol/L glucose. Glucose uptake and consumption, lactate production, GLUT1 levels, NADPH oxidase activity and inflammatory signalling (nuclear factor-kappaB activation and inducible nitric oxide synthase expression) were measured in HASMC, while endothelium-dependent relaxations to acetylcholine were determined in rat microvessels. Pharmacological inhibition of IL1 receptors, NADPH oxidase and glucose-6-phosphate dehydrogenase (G6PD), as well as silencing of G6PD, were also performed. Moreover, the pentose phosphate pathway (PPP) activity and the levels of reduced glutathione were determined. RESULTS: We found that excess glucose uptake in HASMC cultured in 22 mM glucose only occurred following activation with IL1beta. However, the simple entry of glucose was not enough to be deleterious since over-expression of the glucose transporter GLUT1 or increased glucose uptake following inhibition of mitochondrial respiration by sodium azide was not sufficient to trigger inflammatory mechanisms. In fact, besides allowing glucose entry, IL1beta activated the PPP, thus permitting some of the excess glucose to be metabolized via this route. This in turn led to an over-activation NADPH oxidase, resulting in increased generation of free radicals and the subsequent downstream pro inflammatory signalling. Moreover, in rat mesenteric microvessels high glucose incubation enhanced the endothelial dysfunction induced by IL1beta by a mechanism which was abrogated by the inhibition of the PPP. CONCLUSIONS: A pro-inflammatory stimulus like IL1beta transforms excess glucose into a vascular deleterious agent by causing an increase in glucose uptake and its subsequent diversion into the PPP, promoting the pro-oxidant conditions required for the exacerbation of pro oxidant and pro-inflammatory pathways. We propose that over-activation of the PPP is a crucial mechanism for the vascular damage associated to hyperglycemia. PMID- 27245225 TI - Herbal formula GAPT prevents beta amyloid deposition induced Ca(2+)/Calmodulin dependent protein kinase II and Ca(2+)/Calmodulin-dependent protein phosphatase 2B imbalance in APPV717I mice. AB - BACKGROUND: Synaptic dysfunction is one of the pathological characteristics of Alzheimer's disease (AD), which is directly related to the progressive decline of cognitive function. CaMKII and CaN have been found to play important roles in memory processes and synaptic transmission. So present study aimed to elucidate relationships between CaMKII, CaN and cognitive decline in APPV717I mice, and to reveal whether the cognitive improving effects of GAPT is conducted through rebalance CaMKII and CaN. METHODS: Three-month-old-male APPV717I mice were randomly divided into ten groups (n = 12 per group) and received intragastrically administrated vehicle, donepezil or different doses of herbal formula GAPT for 8 or 4 months. Three-month-old male C57BL/6 J mice was set as vehicle control. RESULTS: Immunohistochemistry analysis showed that there were CaMKII expression decrease in the CA1 region of APPV717I transgenic mice, while the CaMKII expression of donepezil or GAPT treated transgenic mice were all increased. And there were CaN expression increase in the brain cortex of APPV717I transgenic mice, while there were decrease of CaN expression in donepezil or GAPT treated transgenic group. Western blot analysis showed the similar expression pattern without significant difference. CONCLUSION: GAPT extract have showed effectiveness in activating the expression of CaMKII and inhibiting the expression of CaN either before or after the formation of amyloid plaques in the brain of APPV717I transgenic mice, which may in certain way alleviated neuron synaptic dysfunction in AD. PMID- 27245226 TI - Modeling the Disease Progression from Healthy to Overt Diabetes in ZDSD Rats. AB - Studying the critical transitional phase between healthy to overtly diabetic in type 2 diabetes mellitus (T2DM) is of interest, but acquiring such clinical data is impractical due to ethical concerns and would require a long study duration. A population model using Zucker diabetic Sprague-Dawley (ZDSD) rats was developed to describe this transition through altering insulin sensitivity (IS, %) as a result of accumulating excess body weight and beta-cell function (BCF, %) to affect glucose-insulin homeostasis. Body weight, fasting plasma glucose (FPG), and fasting serum insulin (FSI) were collected biweekly over 24 weeks from ZDSD rats (n = 23) starting at age 7 weeks. A semi-mechanistic model previously developed with clinical data was adapted to rat data with BCF and IS estimated relative to humans. Non-linear mixed-effect model estimation was performed using NONMEM. Baseline IS and BCF were 41% compared to healthy humans. BCF was described with a non-linear rise which peaked at 14 weeks before gradually declining to a negligible level. A component for excess growth reflecting obesity was used to affect IS, and a glucose-dependent renal effect exerted a two- to sixfold increase on the elimination of glucose. A glucose-dependent weight loss effect towards the end of experiment was implemented. A semi-mechanistic model to describe the dynamics of glucose and insulin was successfully developed for a rat population, transitioning from healthy to advanced diabetes. It is also shown that weight loss can be modeled to mimic the glucotoxicity phenomenon seen in advanced hyperglycemia. PMID- 27245227 TI - [Should assistive robots have a "personality"? : Potential of simplified robot personalities]. AB - BACKGROUND: In the European Union (EU) research project "HOBBIT" prototypes of assistive robots were developed in order to support a more secure and independent life style and trials were run at the homes of elderly users. OBJECTIVE: The project "personAAL" aimed at investigating whether distinct behavioral forms of a robot ("personality"), despite an identical basic function (e.g. bringing a message) are perceived as different personalities by the test persons. MATERIAL AND METHODS: For this study a robot was equipped with two types of behavior, one more introverted (purely function-oriented, impersonal and factual) and the other more extroverted (lively and enriched). The two types of behavior were demonstrated to 13 test persons (mostly older persons and experts from the care domain). RESULTS: Nearly all of the test persons (12 out of 13) perceived a difference with respect to the behavior of the robot. Of the test persons 1 preferred the introverted robot, 9 the extroverted behavior of the robot and 3 had no preferences or stated that the preference depended on the context. The evaluation of answers to the Godspeed questionnaire resulted in significantly different perceptions of "anthropomorphism" and "animated" as well as in the total evaluation. It is also remarkable that no significant differences could be found for "likeability" and "perceived security". There was also no significant correlation between the preferred behavior of the robot and the self-assessment of the test person as being more introverted or extroverted. CONCLUSION: From these results it can be concluded that acceptance of a robot does not solely depend on the mere function, which of course is a precondition but that it is advisable to offer a choice between different types of behavior in order to optimize acceptance. PMID- 27245228 TI - Clinical factors influencing death rattle breathing in palliative care cancer patients : Non-interventional study. AB - BACKGROUND AND AIM: In the last days of life the clinical symptom of death rattle breathing is manifested in many awake or semiconscious patients in palliative care. Scientific studies on relevant influencing factors on the characteristics of the clinical symptom of death rattle breathing in patients in palliative care are rare. MATERIAL AND METHODS: The design of the study is based on a non interventional prospective study with questionnaire evaluation and was implemented at the palliative care unit at the Center for Interdisciplinary Pain Therapy, Oncology and Palliative Care at the Clinical Center Klagenfurt, Austria. The questionnaire was developed by the authors of this study. RESULTS: The study had a predefined duration of 10 months (from February to November 2012) and during this period a total of 273 patients were admitted to the palliative care unit of the Clinical Center in Klagenfurt. Of these 105 (38.5 %) died and could therefore be included in the evaluation but 3 patients in palliative care (2.9 %) did not fulfil the inclusion criteria of a malignant disease. In total 102 patients, 43 females (42.2 %) and 59 males (57.9 %) were evaluated. The average age was 69 years with a range of 41-92 years. The largest proportion of the random sample (62.8 %) was in the patient age group from 61 to 80 years old and death rattle breathing could be observed in 26 patients (25.3 %) of the total sample. In a specific subgroup analysis regarding the intensity of the symptom, many of the affected patients suffered noisy breathing or severe death rattle breathing. In these cases it was primarily women in the group of patients with death rattle breathing. Gender was found to be a statistically relevant influencing factor (p = 0.034) on the intensity of the symptom. CONCLUSION: The great majority of the variables studied showed no influence on the development of the symptom of death rattle breathing; however, more intensive forms were manifested in female patients. The small study population could be a limitation of the present study although the prospective design allows valid conclusions to be drawn. In the future studies should be implemented in order to improve treatment of patients suffering from death rattle breathing. PMID- 27245229 TI - Community Restructuring and Depressive Symptoms of Rural Mature and Elderly Adults: A Multilevel Analysis Based on a National Dataset in China. AB - Community restructuring is an important predictor for residents' mental health. However, few studies have investigated how it affects the depressive symptoms of rural ageing population. Using cross-sectional data from China Health and Retirement Longitudinal Study (CHARLS), this study examined how community restructuring was associated with depressive symptoms of Chinese rural mature and older adults and what community-level factors mediated the association. We found that people in restructuring communities reported .75 unit lower depression score (p < .01); community restructuring is associated with more infrastructure, recreational amenities, and grassroots organization (p < .001) in the community; and the availability of infrastructure (p < .01) and grassroots organization (p < .05) had significant indirect effect on the association between community restructuring and depressive symptoms. World countries' urbanization policy shall not only focus on community physical environment, but also on the development of grassroots organizations that involve and connect local people. PMID- 27245230 TI - Role of nucleus accumbens MU opioid receptors in the effects of morphine on ERK1/2 phosphorylation. AB - RATIONALE: Despite the critical role attributed to phosphorylated extracellular signal regulated kinase (pERK1/2) in the nucleus accumbens (Acb) in the actions of addictive drugs, the effects of morphine on ERK1/2 phosphorylation in this area are still controversial. OBJECTIVES: In order to investigate further this issue, we studied (1) the ability of morphine to affect ERK1/2 phosphorylation in the shell (AcbSh) and core (AcbC) of Sprague-Dawley and Wistar rats and of CD-1 and C57BL/6J mice and (2) the role of dopamine D1 and MU-opioid receptors in Sprague-Dawley rats and CD-1 mice. METHODS: The pERK1/2 expression was assessed by immunohistochemistry. RESULTS: In rats, morphine decreased AcbSh and AcbC pERK1/2 expression, whereas in mice, increased it preferentially in the AcbSh compared with the AcbC. Systemic SCH 39166 decreased pERK1/2 expression on its own in the AcbSh and AcbC of Sprague-Dawley rats and CD-1 mice; furthermore, in rats, SCH 39166 disclosed the ability of morphine to stimulate pERK1/2 expression. Systemic (rats and mice) and intra-Acb (rats) naltrexone prevented both decreases, in rats, and increases, in mice. CONCLUSIONS: These findings confirm the differential effects of morphine in rats and mice Acb and that D1 receptors exert a facilitatory role on ERK1/2 phosphorylation; furthermore, they indicate that, in rats, removal of the D1-dependent pERK1/2 expression discloses the stimulatory influence of morphine on ERK1/2 phosphorylation and that the morphine's ability to decrease pERK1/2 expression is mediated by Acb MU-opioid receptors. Future experiments may disentangle the psychopharmacological significance of the effects of morphine on pERK1/2 in the Acb. PMID- 27245231 TI - The MICOS complex of human mitochondria. AB - Mitochondria are organelles of endosymbiotic origin, surrounded by two membranes. The inner membrane forms invaginations called cristae that enhance its surface and are important for mitochondrial function. A recently described mitochondrial contact site and cristae organizing system (MICOS) in the inner mitochondrial membrane is crucial for the formation and maintenance of cristae structure. The MICOS complex in human mitochondria exhibits specificities and greater complexity in comparison to the yeast system. Many subunits of this complex have been previously described, but several others and their function remain to be explored. This review will summarize our present knowledge about the human MICOS complex and its constituents, while discussing the future research perspectives in this exciting and important field. PMID- 27245232 TI - Analytical model of coincidence resolving time in TOF-PET. AB - The coincidence resolving time (CRT) of scintillation detectors is the parameter determining noise reduction in time-of-flight PET. We derive an analytical CRT model based on the statistical distribution of photons for two different prototype scintillators. For the first one, characterized by single exponential decay, CRT is proportional to the decay time and inversely proportional to the number of photons, with a square root dependence on the trigger level. For the second scintillator prototype, characterized by exponential rise and decay, CRT is proportional to the square root of the product of rise time and decay time divided by the doubled number of photons, and it is nearly independent of the trigger level. This theory is verified by measurements of scintillation time constants, light yield and CRT on scintillator sticks. Trapping effects are taken into account by defining an effective decay time. We show that in terms of signal to-noise ratio, CRT is as important as patient dose, imaging time or PET system sensitivity. The noise reduction effect of better timing resolution is verified and visualized by Monte Carlo simulation of a NEMA image quality phantom. PMID- 27245233 TI - Predictive factors and oncological outcomes of persistently elevated prostate specific antigen in patients following robot-assisted radical prostatectomy. AB - Our aim was to evaluate factors associated with persistently elevated prostate specific antigen (PSA) and biochemical recurrence following robotic-assisted radical prostatectomy (RARP). The study population (N = 5300) consisted of consecutive patients who underwent RARP for localized prostate cancer by a single surgeon (VP) from January 2008 through July 2013. A query of our Institutional Review Board-approved registry identified 162 men with persistently elevated PSA (group A), defined as PSA level >=0.1 ng/ml at 6 weeks after surgery, who were compared with rest of the cohort group having undetectable PSA, group B (<0.1 ng/ml). A univariate and multivariate logistic regression analysis was used to evaluate the significant association between various variables and the following: (1) persistently elevated PSA, (2) BCR (PSA value >=0.2 ng/ml) on follow-up in the persistent PSA group. On multivariate analysis, only the following parameters were significantly associated with persistent PSA after RARP-preoperative [PSA >10 ng/ml (p = 0.01), Gleason Score >=8 (p = 0.001) and clinical stage(p = 0.001)]; postoperative [pathologic stage (p = 0.001), extraprostatic extension (EPE, p = 0.01), lymph node positivity (p = 0.001), positive surgical margin (PSM, p = 0.02), Gleason score (p = 0.01) and tumor volume percent (p < 0.001)]. The mean follow-up was 38.1 months. The BCR was significantly higher in group A as compared to group B(52.47 vs 7.9 %) respectively; p = 0.01). The mean time to BCR was significantly lesser in group A as compared to group B(8.9 vs 21.1 months respectively; p = 0.01). The BCR-free survival rates at 1 year and 3 years were significantly lower statistically in the persistent PSA group in comparison to other groups (69.7 vs 97.3 % and 48.5 vs 92.1 %, respectively; p = 0.01). On multivariate logistic regression analysis in patients with persistent PSA on follow-up, preoperative PSA >10 ng/ml, postoperative Gleason score >=8, postoperative stage >=pT3, positive pelvic lymph nodes, PSM >3 mm and post-RARP PSA doubling time (DT) <10 months (p < 0.001) were significantly associated with BCR. In patients after RARP, factors associated with aggressive disease (high preoperative PSA, Gleason score >=8, stage >=T3, PSM, high tumor volume percent and EPE) predict PSA persistence. Although these patients with persistent PSA after RARP are more likely to have BCR and that too earlier than those patients with undetectable PSA after RARP, a significant proportion of these patients (47.53 %) remain free of BCR. This subset of patients is associated with these favorable parameters (preoperative PSA <10 ng/ml, post-RARP PSA DT >=10 months, postoperative Gleason score <8, pathologic stage 200-fold) solubility/loading in Labrasol (the optimally determined lipid carrier). A SN38 loaded silica-lipid hybrid (SN38-SLH) particle delivery system was prepared by lyophilisation of mesoporous silica nanoparticle stabilised lipid emulsions. The subsequent free-flowing, SLH solid dosage form contained high loading levels of molecularly dispersed SN38 (5%w/w) and significantly enhanced in vitro dissolution in simulated gastrointestinal media. Furthermore, SN38 was chemically stable for at least 12months at 25 degrees C. Orally dosed pharmacokinetics in a rat model demonstrated a 176% increase in SN38 blood plasma exposure in comparison with a raw drug suspension and a significant increase in the period where therapeutic levels are established. SN38-SLH shows potential for enabling injection-to-oral transformation in cancer chemotherapy. PMID- 27245286 TI - Metalloporphyrin-Nitroxyl Interactions: The Low-Energy States of Reduced Manganese, Iron, and Cobalt Porphyrin Nitrosyls. AB - DFT calculations employing the OLYP and B3LYP functionals have been used to map out the low energy states of the metalloporphyrin-nitroxyl adducts "M(Por) + NO( )" and "M(Por) + HNO", where M = Fe, Co, and Mn and Por(2-) is the dianion of unsubstituted porphyrin. For [Fe(Por)(NO)](-), the calculations yield two low energy solutions, with MS = 0 and 1. The MS = 0 solution is thought to represent the experimentally observed diamagnetic ground states of {FeNO}(8) porphyrins, and both functionals yield FeNO geometrical parameters in excellent agreement with a recent crystal structure. For [Co(Por)(NO)](-), the lowest-energy solution for both OLYP and B3LYP is a true {CoNO}(9) state that appears to be best described as a high-spin Co(II) center with a dxy(2)dxz(1)dyz(1)dz2(2)dx2-y2(1) configuration antiferromagnetically coupled to a NO(-) diradical. Such an electronic configuration is expected to lead to diagnostic structural features, including long equatorial Co-N distances (~2.1 A), a strong displacement (~0.4 A) of the metal from the mean plane of the equatorial nitrogens, and a relatively short Co-N(O) distance (1.8 A), which should all be experimentally observable. The dx2-y2(1) electronic configuration should also lead to characteristic EPR hyperfine parameters. The calculations also indicate a number of other low-energy states for [Co(Por)(NO)](-), including multiple {CoNO}(8) porphyrin anion radical states. For [Mn(Por)(NO)](-), both functionals indicate a rather complex electronic state landscape, including multiple {MnNO}(6) porphyrin anion radical states as well as a high-spin S = 3/2 {MnNO}(7) state. Both functionals clearly indicate a low-spin Fe(II) state for [Fe(Por)(HNO)]. On the other hand, two comparably low-energy states are predicted for both [Co(Por)(HNO)] and [Mn(Por)(HNO)]. For [Co(Por)(HNO)], the two states are a low-spin Co(II) state with a dxy(2)dxz(2)dyz(2)dz2(1) configuration and a low-spin Co(III)(HNO)(*-) state. For [Mn(Por)(HNO)], the two states may be described as low- (S = 1/2) and intermediate-spin (S = 3/2) Mn(II). The latter state has a relatively long Mn N(O) distance of about 2.07 A, which may be indicative of facile HNO dissociation. PMID- 27245287 TI - Superior bit error rate and jitter due to improved switching field distribution in exchange spring magnetic recording media. AB - We report two effects that lead to a significant reduction of the switching field distribution in exchange spring media. The first effect relies on a subtle mechanism of the interplay between exchange coupling between soft and hard layers and anisotropy that allows significant reduction of the switching field distribution in exchange spring media. This effect reduces the switching field distribution by about 30% compared to single-phase media. A second effect is that due to the improved thermal stability of exchange spring media over single-phase media, the jitter due to thermal fluctuation is significantly smaller for exchange spring media than for single-phase media. The influence of this overall improved switching field distribution on the transition jitter in granular recording and the bit error rate in bit-patterned magnetic recording is discussed. The transition jitter in granular recording for a distribution of Khard values of 3% in the hard layer, taking into account thermal fluctuations during recording, is estimated to be a = 0.78 nm, which is similar to the best reported calculated jitter in optimized heat-assisted recording media. PMID- 27245282 TI - Translational and clinical implications of the genetic landscape of prostate cancer. AB - Over the past several years, analyses of data from high-throughput studies have elucidated many fundamental insights into prostate cancer biology. These insights include the identification of molecular alterations and subtypes that drive tumour progression, recurrent aberrations in signalling pathways, the existence of substantial intertumoural and intratumoural heterogeneity, Darwinian evolution in response to therapeutic pressures and the complicated multidirectional patterns of spread between primary tumours and metastatic sites. However, these concepts have not yet been fully translated into clinical tools to improve prognostication, prediction and personalization of treatment of patients with prostate cancer. The current and future clinical implications of 'omics' level knowledge is not only revolutionizing our understanding of prostate cancer biology, but is also shaping ongoing, and future clinical investigations and practice. In this Review, we summarize these advances, and the remaining challenges surrounding tumour heterogeneity and the ability to overcome treatment resistance are also described. PMID- 27245288 TI - Late First-Row Transition-Metal Complexes Containing a 2-Pyridylmethyl Pendant Armed 15-Membered Macrocyclic Ligand. Field-Induced Slow Magnetic Relaxation in a Seven-Coordinate Cobalt(II) Compound. AB - The 2-pyridylmethyl N-pendant-armed heptadentate macrocyclic ligand {3,12-bis(2 methylpyridine)-3,12,18-triaza-6,9-dioxabicyclo[12.3.1]octadeca-1,14,16-triene = L} and [M(L)](ClO4)2 complexes, where M = Mn(II) (1), Fe(II) (2), Co(II) (3), Ni(II) (4), and Cu(II) (5), were prepared and thoroughly characterized, including elucidation of X-ray structures of all the compounds studied. The complexes 1-5 crystallize in non-centrosymmetric Sohncke space groups as racemic compounds. The coordination numbers of 7, 6 + 1, and 5 were found in complexes 1-3, 4, and 5, respectively, with a distorted pentagonal bipyramidal (1-4) or square pyramidal (5) geometry. On the basis of the magnetic susceptibility experiments, a large axial zero-field splitting (ZFS) was found for 2, 3, and 4 (D(Fe) = -7.4(2) cm( 1), D(Co) = 34(1) cm(-1), and D(Ni) = -12.8(1) cm(-1), respectively) together with a rhombic ZFS (E/D = 0.136(3)) for 4. Despite the easy plane anisotropy (D > 0, E/D = 0) in 3, the slow relaxation of the magnetization below 8 K was observed and analyzed either with Orbach relaxation mechanism (the relaxation time tau0 = 9.90 * 10(-10) s and spin reversal barrier Ueff = 24.3 K (16.9 cm(-1))) or with Raman relaxation mechanism (C = 2.12 * 10(-5) and n = 2.84). Therefore, compound 3 enlarges the small family of field-induced single-molecule magnets with pentagonal-bipyramidal chromophore. The cyclic voltammetry in acetonitrile revealed reversible redox processes in 1-3 and 5, except for the Ni(II) complex 4, where a quasi-reversible process was dominantly observed. Presence of the two 2-pyridylmethyl pendant arms in L with a stronger sigma-donor/pi-acceptor ability had a great impact on the properties of all the complexes (1-5), concretely: (i) strong pyridine-metal bonds provided slight axial compression of the coordination sphere, (ii) substantial changes in magnetic anisotropy, and (iii) stabilization of lower oxidation states. PMID- 27245289 TI - Magnetic Resonance Imaging in Patients With Mechanical Low Back Pain Using a Novel Rapid-Acquisition Three-Dimensional SPACE Sequence at 1.5-T: A Pilot Study Comparing Lumbar Stenosis Assessment With Routine Two-Dimensional Magnetic Resonance Sequences. AB - PURPOSE: To minimize the burden of overutilisation of lumbar spine magnetic resonance imaging (MRI) on a resource-constrained public healthcare system, it may be helpful to image some patients with mechanical low-back pain (LBP) using a simplified rapid MRI screening protocol at 1.5-T. A rapid-acquisition 3 dimensional (3D) SPACE (Sampling Perfection with Application-optimized Contrasts using different flip angle Evolution) sequence can demonstrate common etiologies of LBP. We compared lumbar spinal canal stenosis (LSCS) and neural foraminal stenosis (LNFS) assessment on 3D SPACE against conventional 2-dimensional (2D) MRI. METHODS: We prospectively performed 3D SPACE and 2D spin-echo MRI sequences (axial or sagittal T1-weighted or T2-weighted) at 1.5-T in 20 patients. Two blinded readers assessed levels L3-4, L4-5 and L5-S1 using: 1) morphologic grading systems, 2) global impression on the presence or absence of clinically significant stenosis (n = 60 disc levels for LSCS, n = 120 foramina for LNFS). Reliability statistics were calculated. RESULTS: Acquisition time was ~5 minutes for SPACE and ~20 minutes for 2D MRI sequences. Interobserver agreement of LSCS was substantial to near perfect on both sequences (morphologic grading: kappa [k] = 0.71 SPACE, k = 0.69 T2-weighted; global impression: k = 0.85 SPACE, k = 0.78 T2-weighted). LNFS assessment had superior interobserver reliability using SPACE than T1-weighted (k = 0.54 vs 0.37). Intersequence agreement of findings between SPACE and 2D MRI was substantial to near perfect by global impression (LSCS: k = 0.78 Reader 1, k = 0.85 Reader 2; LNFS: k = 0.63 Reader 1, k = 0.66 Reader 2). CONCLUSIONS: 3D SPACE was acquired in one-quarter the time as the conventional 2D MRI protocol, had excellent agreement with 2D MRI for stenosis assessment, and had interobserver reliability superior to 2D MRI. These results justify future work to explore the role of 3D SPACE in a rapid MRI screening protocol at 1.5-T for mechanical LBP. PMID- 27245291 TI - Latent class regression models for simultaneously estimating test accuracy, true prevalence and risk factors for Brucella abortus. AB - In 2003/2004 a field trial was conducted in Northern Ireland to assess the diagnostic accuracy of six serological tests for bovine brucellosis caused by Brucella abortus. Whereas between-test comparisons have been used to calculate test performances so far, the present study used a latent class approach to estimate diagnostic test accuracy parameters in the absence of a gold standard for these six tests simultaneously and to estimate the true prevalence, while accounting for clustering in the study population and risk factors for true prevalence. Results obtained in this study with regard to prevalence, sensitivity and specificity were largely in accordance with previous findings. Screening tests (SAT and EDTA) appeared to be the most sensitive; however, at low prevalences the EDTA and CFT showed the highest positive predictive values of all investigated tests. The specificities and negative predictive values of all diagnostic tests were found to be very high. Differences of prevalence between three groups of the study population with different risk of exposure could be attributed to the mode of sampling indicating that a more risk-based sampling will result in a higher prevalence than a cross-sectional sampling mode. Age, dairy status and history of abortion were shown to influence the prediction of the latent true infection status. PMID- 27245290 TI - Molecular epidemiology of Bartonella species isolated from ground squirrels and other rodents in northern California. AB - Bartonella spp. are endemic in wild rodents in many parts of the world. A study conducted in two northern California counties (Sonoma and Yolo) sampling California ground squirrels (Otospermophilus beecheyi) and four other rodent species (Peromyscus maniculatus, P. boylii, P. truei and Neotoma fuscipes) led to the isolation of small Gram-negative bacilli which were identified as Bartonella spp. based on colony morphology, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and partial gene sequencing. Overall, Bartonella spp. were isolated from the blood of 71% (32/45) of the ground squirrels and one third (22/66) of the other rodents. PCR-RFLP analysis of the gltA and 16S rRNA genes yielded seven unique profiles, four for the ground squirrels and three for the other rodents. Isolates from each PCR-RFLP profiles were submitted for partial sequencing. Ground squirrel isolates were most closely related to B. washoensis, whereas the other rodent isolates were closest to B. vinsonii subsp. vinsonii and B. vinsonii subsp. arupensis. Two of these three species or subspecies are known zoonotic agents. PMID- 27245292 TI - The Pharmacological Costs for the Management of Skin Toxicity in Patients With Cancer Treated With Epidermal Growth Factor Receptor-Inhibitors. PMID- 27245293 TI - Reply. PMID- 27245294 TI - Subgroup models cannot tell the whole story when assessing relative age in attention deficit hyperactivity disorder. PMID- 27245296 TI - Differential Clubbing of the Lower Extremities. PMID- 27245295 TI - Maternal Antiretroviral Therapy Is Associated with Lower Risk of Diarrhea in Early Childhood. AB - OBJECTIVES: To identify risk factors, including maternal antiretroviral therapy (ART), for diarrhea in Tanzanian children exposed to HIV during the first 2 years of life. STUDY DESIGN: Using generalized estimating equations, we analyzed data from a cohort of 2387 Tanzanian children exposed to HIV from age 6 weeks to 2 years, as well as data from their mothers, to determine risk factors for diarrhea in children. Mothers recorded diarrhea in a diary and reported results at visits scheduled every four weeks. RESULTS: Body mass index was >=18.5 in 95.6% of mothers. World Health Organization HIV stage was 1/2 for 1255 (87.8%) mothers. ART was received by 24.3% of mothers, most initiating ART during pregnancy. At baseline (6 weeks of age) 264 (11.3%) children were infected with HIV. In children whose mothers received ART, the relative risk of diarrhea in children was 0.79 (95% CI 0.68-0.92), after we adjusted for multiple factors, including child HIV status and exclusive breastfeeding duration. Exclusive breastfeeding (relative risk 0.67, 95% CI 0.56-0.80) also was protective. CONCLUSION: Our results provide additional support to increase ART coverage for all pregnant mothers, to control clinical HIV progression, reduce perinatal HIV infection, but also to reduce the risk of a major cause of death and morbidity in young children worldwide. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00197730. PMID- 27245297 TI - Congenital Heart Defects and Measures of Fetal Growth in Newborns with Down Syndrome or 22q11.2 Deletion Syndrome. AB - OBJECTIVES: To estimate the association between congenital heart defects (CHD) and indices of fetal growth in Down and 22q11.2 deletion syndromes. STUDY DESIGN: We established 2 Danish nationwide cohorts of newborn singletons with either Down syndrome (n = 670) or 22q11.2 deletion syndrome (n = 155), born 1997-2011. In both cohorts, we analyzed the association between CHD, CHD severity, and indices of fetal growth by multivariable linear regression adjusted for potential confounders. We report mean differences in gestational age specific z-scores compared with newborns without CHD. RESULTS: Down syndrome and 22q11.2 deletion syndrome were both associated with lower mean birth weight and head circumference z-scores. We found no association between CHD or CHD severity and indices of fetal growth. In Down syndrome, the association between any CHD and the mean difference in head circumference z-score was 0.03 (95% CI -0.12, 0.18), and the estimate regarding birth weight z-score was 0.09 (95% CI -0.08, 0.25). The corresponding estimates in 22q11.2 deletion syndrome were 0.00 (95% CI -0.33, 0.32) and -0.09 (95% CI -0.45, 0.26). CONCLUSIONS: We found no association between CHD and fetal growth measures in newborns with Down syndrome or 22q11.2 deletion syndrome. Thus, in certain subtypes of CHD, the contribution of genetic factors to prenatal growth impairment may be more important than circulatory disturbances. PMID- 27245299 TI - Post-upgrade testing on a radiotherapy oncology information system with an embedded record and verify system following the IAEA Human Health Report No. 7 recommendations. AB - Record and verify (R&V) systems have proven that their application in radiotherapy clinics leads to a significant reduction in mis-treatments of patients. The purpose of this technical note is to share our experience of acceptance testing, commissioning and setting up a quality assurance programme for the MOSAIQ(r) oncology information system and R&V system after upgrading from software version 2.41 to 2.6 in a multi-vendor, multi-site environment. Testing was guided primarily by the IAEA Human Report No. 7 recommendations, but complemented by other departmental workflow specific tests. To the best of our knowledge, this is the first time successful implementation of the IAEA Human Health Report Series No. 7 recommendations have been reported in the literature. PMID- 27245298 TI - Identification of partial SLC20A2 deletions in primary brain calcification using whole-exome sequencing. AB - Primary brain calcification (PBC) is a dominantly inherited calcifying disorder of the brain. SLC20A2 loss-of-function variants account for the majority of families. Only one genomic deletion encompassing SLC20A2 and six other genes has been reported. We performed whole-exome sequencing (WES) in 24 unrelated French patients with PBC, negatively screened for sequence variant in the known genes SLC20A2, PDGFB, PDGFRB and XPR1. We used the CANOES tool to detect copy number variations (CNVs). We detected two deletions of exon 2 of SLC20A2 in two unrelated patients, which segregated with PBC in one family. We then reanalyzed the same series using a QMPSF assay including one amplicon in each exon of SLC20A2 and detected two supplemental partial deletions in two patients: one deletion of exon 4 and one deletion of exons 4 and 5. These deletions were missed by the first screening step of CANOES but could finally be detected after readjustment of bioinformatic parameters and use of a genotyping step of CANOES. This study reports the first partial deletions of SLC20A2 and strengthens its position as the major PBC-causative gene. It is possible to detect short CNVs from WES data, although the sensitivity of such tools should be evaluated in comparison with other methods. PMID- 27245300 TI - Treatment of hyperthyroidism with radioiodine targeted activity: A comparison between two dosimetric methods. AB - Radioiodine therapy is an effective and safe treatment of hyperthyroidism due to Graves' disease, toxic adenoma, toxic multinodular goiter. We compared the outcomes of a traditional calculation method based on an analytical fit of the uptake curve and subsequent dose calculation with the MIRD approach, and an alternative computation approach based on a formulation implemented in a public access website, searching for the best timing of radioiodine uptake measurements in pre-therapeutic dosimetry. We report about sixty-nine hyperthyroid patients that were treated after performing a pre-therapeutic dosimetry calculated by fitting a six-point uptake curve (3-168h). In order to evaluate the results of the radioiodine treatment, patients were followed up to sixty-four months after treatment (mean 47.4+/-16.9). Patient dosimetry was then retrospectively recalculated with the two above-mentioned methods. Several time schedules for uptake measurements were considered, with different timings and total number of points. Early time schedules, sampling uptake up to 48h, do not allow to set-up an accurate treatment plan, while schedules including the measurement at one week give significantly better results. The analytical fit procedure applied to the three-point time schedule 3(6)-24-168h gave results significantly more accurate than the website approach exploiting either the same schedule, or the single measurement at 168h. Consequently, the best strategy among the ones considered is to sample the uptake at 3(6)-24-168h, and carry out an analytical fit of the curve, while extra measurements at 48 and 72h lead only marginal improvements in the accuracy of therapeutic activity determination. PMID- 27245302 TI - Monitoring amino acid deficiencies in cancer. PMID- 27245301 TI - High resolution ion chamber array delivery quality assurance for robotic radiosurgery: Commissioning and validation. AB - PURPOSE: High precision radiosurgery demands comprehensive delivery-quality assurance techniques. The use of a liquid-filled ion-chamber-array for robotic radiosurgery delivery-quality-assurance was investigated and validated using several test scenarios and routine patient plans. METHODS AND MATERIAL: Preliminary evaluation consisted of beam profile validation and analysis of source-detector-distance and beam-incidence-angle response dependence. The delivery-quality-assurance analysis is performed in four steps: (1) Array-to-plan registration, (2) Evaluation with standard Gamma-Index criteria (local-dose difference?2%, distance-to-agreement?2mm, pass-rate?90%), (3) Dose profile alignment and dose distribution shift until maximum pass-rate is found, and (4) Final evaluation with 1mm distance-to-agreement criterion. Test scenarios consisted of intended phantom misalignments, dose miscalibrations, and undelivered Monitor Units. Preliminary method validation was performed on 55 clinical plans in five institutions. RESULTS: The 1000SRS profile measurements showed sufficient agreement compared with a microDiamond detector for all collimator sizes. The relative response changes can be up to 2.2% per 10cm source detector-distance change, but remains within 1% for the clinically relevant source-detector-distance range. Planned and measured dose under different beam incidence-angles showed deviations below 1% for angles between 0 degrees and 80 degrees . Small-intended errors were detected by 1mm distance-to-agreement criterion while 2mm criteria failed to reveal some of these deviations. All analyzed delivery-quality-assurance clinical patient plans were within our tight tolerance criteria. CONCLUSION: We demonstrated that a high-resolution liquid filled ion-chamber-array can be suitable for robotic radiosurgery delivery quality-assurance and that small errors can be detected with tight distance-to agreement criterion. Further improvement may come from beam specific correction for incidence angle and source-detector-distance response. PMID- 27245303 TI - Dynamics of intestinal metabolites and morphology in response to necrotic enteritis challenge in broiler chickens. AB - Despite the relatively small contribution to metabolizable energy that volatile fatty acids (VFAs) provide in chickens, these organic acids have been reported to play beneficial roles in the gastrointestinal tract (GIT) of birds, for example, inhibition of the growth of some pathogenic bacteria. However, information regarding the dynamics of these metabolites in the GIT of chickens is still scarce, especially under disease conditions such as necrotic enteritis (NE). Here, we investigated the dynamics of VFAs and lactic acid, and intestinal morphology in response to NE predisposing factors, that is, excessive dietary fishmeal and Eimeria inoculation, and causative agent Clostridium perfringens producing NetB toxin. The experiment was designed in a 2 * 2 * 2 factorial arrangement of treatments with or without: fishmeal feeding, Eimeria inoculation and C. perfringens challenge. The results showed that these factors significantly influenced composition and concentration of VFAs and lactic acids, pH and histomorphometry in one way or another. These changes may be important for the onset of NE or only the synergetic responses to micro environmental stress. Eimeria appeared to be more important than fishmeal in predisposing birds to NE, thus the application of Eimeria in NE challenge provides more consistent success in inducing the disease. The metabolic responses to various adverse factors such as excessive dietary fishmeal and Eimeria infection are complex. Thus, intensive efforts are required to better understand NE so as to achieve the control of the disease in the absence of antibiotics. PMID- 27245304 TI - Effect of encapsulated carvacrol on the incidence of necrotic enteritis in broiler chickens. AB - There is an urgent need to control necrotic enteritis (NE) caused by Clostridium perfringens in chickens when antibiotics are withdrawn from feed. Carvacrol has strong antimicrobial activity and its delivery to the animal intestine can be significantly enhanced after encapsulation. The present study has investigated the potential of encapsulated carvacrol in controlling NE. In general, micro encapsulation of carvacrol in an alginate-whey protein matrix showed no adverse effect on its antimicrobial activity towards C. perfringens in either Brain Heart Infusion (BHI) broth or a simulated gastrointestinal model. The minimum inhibitory concentrations of both encapsulated and un-encapsulated carvacrol were approximately 200 MUl/l against C. perfringens in BHI. In a broiler infection model with C. perfringens, the diets supplemented with encapsulated carvacrol at the dose of either 250 or 650 MUg/g significantly reduced NE in the chicken intestine, which was close to the degree of lesions observed in bacitracin/salinomycin treated birds. Supplementation with either bacitracin/salinomycin or encapsulated carvacrol showed no significant impact on intestinal burden of Lactobacillus. However, the treatment with bacitracin/salinomycin or the low dose of encapsulated carvacrol reduced the level of C. perfringens in the ileum of birds at 35 days of age. These results suggest that our encapsulated carvacrol can be used to combat NE disease in chickens. PMID- 27245307 TI - Continuity matters: Examining the 'information gap' in transfer from Residential Aged Care, ambulance to emergency triage in southern Tasmania. AB - BACKGROUND: Transfer of older people from Residential Aged Care Facilities to Emergency Departments requires multiple comprehensive handovers across different services. Significant information gaps exist in transferred information despite calls for standards. AIM: To investigate: (1) presence of minimum standard elements in the transfer text written by RACF nurses, paramedics and ED triage nurses, and (2) the transfer documentation used by services. METHODS: We analysed retrospective cross-sectional transfer narratives from the digital medical record system of an Australian tertiary referral hospital using the mnemonic SBAR (Situation, Background, Assessment Recommendation) as the measure of comprehensiveness. Transfer documents from 3 groups were also reviewed. FINDINGS: Inclusion of elements from SBAR was inconsistent across transfer. Rather, the written narratives focused on concerns relevant to the immediate priority, the type of information imposed by the document(s) in use, and clinical role of the author. CONCLUSION: Transfer documentation from Residential Aged Care nurses, paramedics and ED triage nurses do not contain comprehensive information of older persons complex conditions. Better communication between non-affiliated organisations is needed to improve timely appropriate care for RACF residents. PMID- 27245308 TI - Connecting Malfunctioning Glial Cells and Brain Degenerative Disorders. AB - The DNA damage response (DDR) is a complex biological system activated by different types of DNA damage. Mutations in certain components of the DDR machinery can lead to genomic instability disorders that culminate in tissue degeneration, premature aging, and various types of cancers. Intriguingly, malfunctioning DDR plays a role in the etiology of late onset brain degenerative disorders such as Parkinson's, Alzheimer's, and Huntington's diseases. For many years, brain degenerative disorders were thought to result from aberrant neural death. Here we discuss the evidence that supports our novel hypothesis that brain degenerative diseases involve dysfunction of glial cells (astrocytes, microglia, and oligodendrocytes). Impairment in the functionality of glial cells results in pathological neuro-glial interactions that, in turn, generate a "hostile" environment that impairs the functionality of neuronal cells. These events can lead to systematic neural demise on a scale that appears to be proportional to the severity of the neurological deficit. PMID- 27245309 TI - Self-crosslinkable and intracellularly decrosslinkable biodegradable micellar nanoparticles: A robust, simple and multifunctional nanoplatform for high efficiency targeted cancer chemotherapy. AB - Nanomedicines based on biodegradable micelles offer a most promising treatment for malignant tumors. Their clinical effectiveness, however, remains to be improved. Here, we report that self-crosslinkable and intracellularly decrosslinkable micellar nanoparticles (SCID-Ms) self-assembled from novel amphiphilic biodegradable poly(ethylene glycol)-b-poly(dithiolane trimethylene carbonate) block copolymer achieve high-efficiency targeted cancer chemotherapy in vivo. Interestingly, doxorubicin (DOX)-loaded SCID-Ms showed favorable features of superb stability, minimal drug leakage, long circulation time, triggered drug release inside the tumor cells, and an unprecedented maximum tolerated dose (MTD) of over 100mg DOX equiv./kg in mice, which was at least 10 times higher than free drug. The in vivo studies in malignant B16 melanoma bearing C57BL/6 mice revealed that DOX-SCID-Ms at a dosage of 30mg DOX equiv./kg could effectively suppress tumor growth and prolong mice survival time without causing obvious systemic toxicity. Moreover, DOX-SCID-Ms could be readily decorated with a targeting ligand like cRGD peptide. The biodistribution studies showed that cRGD20/DOX-SCID-Ms had a high tumor accumulation of 6.13% ID/g at 6h post injection, which was ca. 3-fold higher than that for clinically used pegylated liposomal doxorubicin (DOX-LPs). Accordingly, cRGD20/DOX-SCID-Ms exhibited significantly better therapeutic efficacy and lower side effects than DOX-LPs in B16 melanoma-bearing mice. These self-regulating biodegradable micellar nanoparticles offer a robust, multifunctional and viable nanoplatform for targeted cancer chemotherapy. PMID- 27245310 TI - Speech and language therapy for aphasia following stroke. AB - BACKGROUND: Aphasia is an acquired language impairment following brain damage that affects some or all language modalities: expression and understanding of speech, reading, and writing. Approximately one third of people who have a stroke experience aphasia. OBJECTIVES: To assess the effects of speech and language therapy (SLT) for aphasia following stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched 9 September 2015), CENTRAL (2015, Issue 5) and other Cochrane Library Databases (CDSR, DARE, HTA, to 22 September 2015), MEDLINE (1946 to September 2015), EMBASE (1980 to September 2015), CINAHL (1982 to September 2015), AMED (1985 to September 2015), LLBA (1973 to September 2015), and SpeechBITE (2008 to September 2015). We also searched major trials registers for ongoing trials including ClinicalTrials.gov (to 21 September 2015), the Stroke Trials Registry (to 21 September 2015), Current Controlled Trials (to 22 September 2015), and WHO ICTRP (to 22 September 2015). In an effort to identify further published, unpublished, and ongoing trials we also handsearched the International Journal of Language and Communication Disorders (1969 to 2005) and reference lists of relevant articles, and we contacted academic institutions and other researchers. There were no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing SLT (a formal intervention that aims to improve language and communication abilities, activity and participation) versus no SLT; social support or stimulation (an intervention that provides social support and communication stimulation but does not include targeted therapeutic interventions); or another SLT intervention (differing in duration, intensity, frequency, intervention methodology or theoretical approach). DATA COLLECTION AND ANALYSIS: We independently extracted the data and assessed the quality of included trials. We sought missing data from investigators. MAIN RESULTS: We included 57 RCTs (74 randomised comparisons) involving 3002 participants in this review (some appearing in more than one comparison). Twenty-seven randomised comparisons (1620 participants) assessed SLT versus no SLT; SLT resulted in clinically and statistically significant benefits to patients' functional communication (standardised mean difference (SMD) 0.28, 95% confidence interval (CI) 0.06 to 0.49, P = 0.01), reading, writing, and expressive language, but (based on smaller numbers) benefits were not evident at follow-up. Nine randomised comparisons (447 participants) assessed SLT with social support and stimulation; meta-analyses found no evidence of a difference in functional communication, but more participants withdrew from social support interventions than SLT. Thirty-eight randomised comparisons (1242 participants) assessed two approaches to SLT. Functional communication was significantly better in people with aphasia that received therapy at a high intensity, high dose, or over a long duration compared to those that received therapy at a lower intensity, lower dose, or over a shorter period of time. The benefits of a high intensity or a high dose of SLT were confounded by a significantly higher dropout rate in these intervention groups. Generally, trials randomised small numbers of participants across a range of characteristics (age, time since stroke, and severity profiles), interventions, and outcomes. AUTHORS' CONCLUSIONS: Our review provides evidence of the effectiveness of SLT for people with aphasia following stroke in terms of improved functional communication, reading, writing, and expressive language compared with no therapy. There is some indication that therapy at high intensity, high dose or over a longer period may be beneficial. HIgh-intensity and high dose interventions may not be acceptable to all. PMID- 27245311 TI - Autologous Stem Cell Mobilization in the Age of Plerixafor. AB - BACKGROUND: Autologous stem cell transplantation remains important in the treatment of myeloma and relapsed lymphoma. Plerixafor has been shown to significantly enhance stem cell mobilization but is very expensive. PATIENTS AND METHODS: We evaluated plerixafor use in the 3-year period after its approval in December 2008. RESULTS: A total of 277 patients with myeloma and lymphoma had stem cell mobilization; 97.5% were successfully mobilized, including 41.5% who received plerixafor. Plerixafor was generally used for rescue after suboptimal granulocyte-colony stimulating factor (G-CSF) mobilization ("just in time") or for remobilization after an unsuccessful attempt with chemotherapy plus G-CSF. In addition, 10% of patients received planned G-CSF plus plerixafor because of high risk factors for inadequate collection. Rescue plerixafor was more effective in patients with myeloma than lymphoma as after 1 dose of plerixafor; 85% versus 55% collected a minimum number of stem cells (2 * 10E6 CD34 cells/kg) for 1 transplant and 51% versus 15% collected > 5 * 10E6 CD34 cells/kg. After transplantation, there were no significant differences in engraftment as a consequence of plerixafor use. Among all patients, there were less platelet transfusions in patients provided >= 3.5 * 10E6 CD34(+) cells/kg. CONCLUSION: With the judicious use of plerixafor, nearly all patients can collect enough stem cells to proceed to transplantation. Further studies, including hematologic tolerance to posttransplantation therapy, are required to determine the cost effectiveness of using plerixafor to convert adequate to more optimal mobilizers. PMID- 27245312 TI - Evidence for Clinical Differentiation and Differentiation Syndrome in Patients With Acute Myeloid Leukemia and IDH1 Mutations Treated With the Targeted Mutant IDH1 Inhibitor, AG-120. AB - BACKGROUND: Cancer-associated isocitrate dehydrogenase (IDH) mutations block normal cellular differentiation via production of the oncometabolite, R-2 hydroxyglutarate. In patients with acute myeloid leukemia (AML) receiving targeted mutant IDH inhibitor therapy, neutrophil recovery within the setting of clinical differentiation syndrome (DS) has been anecdotally described. PATIENTS AND METHODS: We describe 3 patients who developed clinically apparent DS during monotherapy with the mutant IDH1 inhibitor, AG-120, for relapsed/refractory AML. RESULTS: AG-120-induced differentiation commenced within the first 60 days of treatment, notably in the same time frame as clinical response, strengthening the purported mechanism of targeted mutant IDH inhibitor therapy via successful myeloid maturation. Symptoms of DS were nonspecific and included culture-negative fever, edema, hypotension, malaise, and pleural and/or pericardial effusions, in addition to marked neutrophil-predominant leukocytosis. CONCLUSION: DS can occur during treatment with targeted mutant IDH1 inhibitor therapy. Patients might present with nonspecific clinical manifestations often in the setting of leukocytosis related to exuberant neutrophil recovery. Prompt identification and initiation of treatment interventions, including hydroxyurea, corticosteroids, and/or consideration of temporary treatment discontinuation, are important to facilitate prompt resolution. PMID- 27245313 TI - Comparison of Branded and Generic Imatinib Plasma Concentrations in Patients With Chronic Myelogenous Leukemia: Unicentric Study. AB - INTRODUCTION: For over a decade, imatinib has been the first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML). Doubts on the bioequivalence and bioavailability of emerging generic compounds have been expressed. Adequate imatinib plasma concentration ([IPC] >=1000 MUmol/L) is associated with a better chance of optimal treatment response in patients with CML. In this study, we compared the achieved IPCs between the branded compound and its 2 generic forms. PATIENTS AND METHODS: IPCs were compared in 24 consecutive patients with CML in the first chronic phase who changed from branded to generic imatinib. The median age was 49 years (range, 22-76 years). Fifteen of them were male. Six patients were switched to Neopax, 13 to Imakrebin, and 5 patients received both generics consecutively. All compounds were used in an equivalent dose of 400 mg orally once daily for at least 1 month before plasma concentrations were measured. High-performance liquid chromatography was used to determine imatinib plasma concentration from a specimen collected 21 to 24 hours after the last dose. RESULTS: The median IPC achieved with branded imatinib was 1454 MUmol/L (range, 485-2707 MUmol/L) with 18 patients (75%) having IPC >= 1000 MUmol/L. For Neopax and Imakrebin, median IPCs were 1717 MUmol/L (range, 1249 3630 MUmol/L) and 1458 MUmol/L (range, 707-880 MUmol/L), respectively, with 11 of 11 (100%) and 16 of 18 (89%) patients having IPC >= 1000 MUmol/L. No significant difference in measured IPCs between all 3 compounds was found (P > .257). CONCLUSION: When taken at equivalent doses, imatinib generics are bioequivalent and comparable in clinical efficacy and have the potential for substantial savings in the treatment cost for CML. PMID- 27245314 TI - Anti Myelin-Associated-Glycoprotein Antibody Peripheral Neuropathy Response to Combination Chemoimmunotherapy With Bendamustine/Rituximab in a Patient With Biclonal IgM kappa and IgM lambda: Case Report and Review of the Literature. PMID- 27245315 TI - A synthetic kisspeptin analog that triggers ovulation and advances puberty. AB - The neuropeptide kisspeptin and its receptor, KiSS1R, govern the reproductive timeline of mammals by triggering puberty onset and promoting ovulation by stimulating gonadotrophin-releasing hormone (GnRH) secretion. To overcome the drawback of kisspeptin short half-life we designed kisspeptin analogs combining original modifications, triazole peptidomimetic and albumin binding motif, to reduce proteolytic degradation and to slow down renal clearance, respectively. These analogs showed improved in vitro potency and dramatically enhanced pharmacodynamics. When injected intramuscularly into ewes (15 nmol/ewe) primed with a progestogen, the best analog (compound 6, C6) induced synchronized ovulations in both breeding and non-breeding seasons. Ovulations were fertile as demonstrated by the delivery of lambs at term. C6 was also fully active in both female and male mice but was completely inactive in KiSS1R KO mice. Electrophysiological recordings of GnRH neurons from brain slices of GnRH-GFP mice indicated that C6 exerted a direct excitatory action on GnRH neurons. Finally, in prepubertal female mice daily injections (0.3 nmol/mouse) for five days significantly advanced puberty. C6 ability to trigger ovulation and advance puberty demonstrates that kisspeptin analogs may find application in the management of livestock reproduction and opens new possibilities for the treatment of reproductive disorders in humans. PMID- 27245316 TI - Microbiological profiles of sputum and gastric juice aspirates in Cystic Fibrosis patients. AB - Gastro-Oesophageal Reflux (GOR) is a key problem in Cystic Fibrosis (CF), but the relationship between lung and gastric microbiomes is not well understood. We hypothesised that CF gastric and lung microbiomes are related. Gastric and sputum cultures were obtained from fifteen CF patients receiving percutaneous endoscopic gastrostomy feeding. Non-CF gastric juice data was obtained through endoscopy from 14 patients without lung disease. Bacterial and fungal isolates were identified by culture. Molecular bacterial profiling used next generation sequencing (NGS) of the 16S rRNA gene. Cultures grew bacteria and/or fungi in all CF gastric juice and sputa and in 9/14 non-CF gastric juices. Pseudomonas aeruginosa(Pa) was present in CF sputum in 11 patients, 4 had identical Pa strains in the stomach. NGS data from non-CF gastric juice samples were significantly more diverse compared to CF samples. NGS showed CF gastric juice had markedly lower abundance of normal gut bacteria; Bacteroides and Faecalibacterium, but increased Pseudomonas compared with non-CF. Multivariate partial least squares discriminant analysis demonstrated similar bacterial profiles of CF sputum and gastric juice samples, which were distinct from non-CF gastric juice. We provide novel evidence suggesting the existence of an aerodigestive microbiome in CF, which may have clinical relevance. PMID- 27245317 TI - Structural Brain Alterations Associated with Rapid Eye Movement Sleep Behavior Disorder in Parkinson's Disease. AB - Characterized by dream-enactment motor manifestations arising from rapid eye movement (REM) sleep, REM sleep behavior disorder (RBD) is frequently encountered in Parkinson's disease (PD). Yet the specific neurostructural changes associated with RBD in PD patients remain to be revealed by neuroimaging. Here we identified such neurostructural alterations by comparing large samples of magnetic resonance imaging (MRI) scans in 69 PD patients with probable RBD, 240 patients without RBD and 138 healthy controls, using deformation-based morphometry (p < 0.05 corrected for multiple comparisons). All data were extracted from the Parkinson's Progression Markers Initiative. PD patients with probable RBD showed smaller volumes than patients without RBD and than healthy controls in the pontomesencephalic tegmentum, medullary reticular formation, hypothalamus, thalamus, putamen, amygdala and anterior cingulate cortex. These results demonstrate that RBD is associated with a prominent loss of volume in the pontomesencephalic tegmentum, where cholinergic, GABAergic and glutamatergic neurons are located and implicated in the promotion of REM sleep and muscle atonia. It is additionally associated with more widespread atrophy in other subcortical and cortical regions whose loss also likely contributes to the altered regulation of sleep-wake states and motor activity underlying RBD in PD patients. PMID- 27245319 TI - Hollow porous carbon nitride immobilized on carbonized nanofibers for highly efficient visible light photocatalytic removal of NO. AB - With the deterioration of air quality, great efforts were devoted to designing various photocatalysts for effective removal of NOx in air. However, the present photocatalysts have a fatal problem of low photocatalytic efficiency. In this work, a hollow porous carbon nitride nanosphere coupled with reduced graphene oxide (HCNS/rGO) was exploited as a visible-light photocatalyst to remove nitrogen monoxide in air at a low concentration (600 ppb level) under irradiation of an energy saving lamp. HCNS/rGO showed a NO removal ratio of 64%, which was superior to that of most other visible-light photocatalysts. The excellent photocatalytic ability of HCNS/rGO originates from the hollow porous morphology of HCNS and the grafted rGO on the surface. HCNS/rGO was immobilized on porous carbonized polymer nanofibers to obtain a photocatalytic membrane without affecting photocatalytic efficiency. Furthermore, the membrane showed excellent photochemical stability and recyclability. PMID- 27245318 TI - Chronic spinal cord injury attenuates influenza virus-specific antiviral immunity. AB - BACKGROUND: Individuals suffering from spinal cord injury (SCI) are at higher risk for respiratory-related viral infections such as influenza. In a previous study (Zha et al., J Neuroinflammation 11:65, 2014), we demonstrated that chronic spinal cord injury caused impairment in CD8(+)T cell function with increased expression of the immunosuppressive protein, programmed cell death 1 (PD-1). The present study was undertaken to establish whether chronic SCI-induced immune deficits would affect antiviral immunity directed against primary and secondary infections. METHODS: Six to seven weeks following a SCI contusion at thoracic level T9, mice were infected intranasally with influenza virus. Virus-specific immunity was analyzed at various time points post-infection and compared to uninjured controls. RESULTS: We report that chronic thoracic SCI impairs the ability of the animals to mount an adequate antiviral immune response. While all uninjured control mice cleared the virus from their lungs by day 10 post infection, a significant number (approximately 70 %) of chronic SCI mice did not clear the virus and succumbed to infection-induced mortality. This was attributed to severe deficits in both virus-specific antibody production and CD8(+) T cell response in injured mice after primary infection. We also determined that previously acquired humoral immunity was maintained after spinal cord injury as vaccination against influenza A prior to injury-protected mice from a homologous viral challenge. In contrast, prior immunization did not protect mice from a heterotypic challenge with a different strain of influenza virus. CONCLUSIONS: Taken together, our data demonstrate that chronic SCI attenuates virus-specific humoral and cellular immunity during the establishment of primary response and impairs the development of memory CD8(+) T cells. In contrast, B cell memory acquired through vaccination prior to SCI is preserved after injury which demonstrates that antigen-specific memory cells are refractory following injury. Our study defines important parameters of the deficits of chronic SCI-induced immune depression during a viral respiratory infection. Our objective is to better understand the mechanisms of spinal cord injury-induced immune depression with the goal of developing more effective therapies and reduce mortality due to complications from influenza and other infections. PMID- 27245320 TI - Late stage definitive endodermal differentiation can be defined by Daf1 expression. AB - BACKGROUND: Definitive endoderm (DE) gives rise to the respiratory apparatus and digestive tract. Sox17 and Cxcr4 are useful markers of the DE. Previously, we identified a novel DE marker, Decay accelerating factor 1(Daf1/CD55), by identifying DE specific genes from the expression profile of DE derived from mouse embryonic stem cells (ESCs) by microarray analysis, and in situ hybridization of early embryos. Daf1 is expressed in a subpopulation of E cadherin + Cxcr4+ DE cells. The characteristics of the Daf1-expressing cells during DE differentiation has not been examined. RESULTS: In this report, we utilized the ESC differentiation system to examine the characteristics of Daf1 expressing DE cells. We found that Daf1 expression could discriminate late DE from early DE. Early DE cells are Daf1-negative (DE-) and late DE cells are Daf1 positive (DE+). We also found that Daf1+ late DE cells show low proliferative and low cell matrix adhesive characteristics. Furthermore, the purified SOX17(low) early DE cells gave rise to Daf1+ Sox17(high) late DE cells. CONCLUSION: Daf1 expressing late definitive endoderm proliferates slowly and show low adhesive capacity. PMID- 27245321 TI - Computed tomography angiography of aorta subjected to external wrapping. AB - BACKGROUND: External wrapping is a surgical technique used in patients with dilated ascending aorta. To date, there is no available data describing the radiographic features of the aorta subjected to external wrapping using a straight corrugated Dacron vascular prosthesis. The aim of this study was to find distinctive radiographic features of an externally constricted aorta. METHODS: Preoperative and early postoperative (7th postoperative day) CT angiography images of ten patients who underwent wrapping procedures were assessed and compared. The images were analyzed in order to find characteristic features of CT angiography images of the ascending aorta subjected to external wrapping. RESULTS: The CT-angiography images showed that the aortic wall deformed significantly (the wall plicated) after the wrapping procedure in one patient, whose aortic diameter was decreased by 47 %. The remaining nine patients did not have significant aortic wall deformations. All patients presented with a periaortic mass. This was a collection of blood clots and pericardial fluid that filled the empty space in the pericardium following a decrease in the diameter of the ascending aorta. A very thin (<1 mm) crescent-shaped uncontrasted layer was noticed between the aorta and the periaortic area in all patients. This, in turn, was an empty space between the aorta and the corrugated vascular prosthesis. CONCLUSIONS: The CT-angiography images of the aorta subjected to external wrapping may have unique features that are not observed after other operations on the ascending aorta. The knowledge about the details of this surgical procedure helps to correctly assess these images. PMID- 27245322 TI - Antifilarial activity of diterpenoids from Taxodium distichum. AB - BACKGROUND: Lymphatic filariasis caused by Wuchereria bancrofti, Brugia malayi and B. timori, is a debilitating disease with an adverse social and economic impact. The infection remains unabated in spite of treatment with existing antifilarial drugs diethylcarbamazine (DEC) and ivermectin which are chiefly microfilaricides. There is therefore, need for macrofilaricides, embryostatic agents and better microfilaricides. In the present study we explored the antifilarial potential of crude extract and its molecular fractions of the plant Taxodium distichum using in vitro assay systems and rodent models of B. malayi infection. METHODS: Ethanolic extract (A001) of aerial parts of T. distichum was solvent fractionated and sub-fractionated. Four molecules, 3-Acetoxylabda-8(20), 13-diene-15-oic acid (K001), Beta-sitosterol (K002), labda-8(20),13-diene-15-oic acid (K003) and Metasequoic acid A (K004) were isolated from the fractions and their structure determined by spectroscopic analysis. The extract, subfractions and molecules were evaluated for antifilarial activity against B. malayi by 3 (4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) reduction and motility assays in vitro and in two animal models, Meriones unguiculatus and Mastomys coucha, harbouring B. malayi infection. RESULTS: A001 was effective in killing microfilariae (mf) and adult worms in vitro. The diterpenoid K003 produced 100 % reduction in motility of both mf and adult worms and > 80 % inhibition in MTT reduction potential of adult female worms. In B. malayi-M. unguiculatus model, A001 killed all the adult worms in > 80 % of infected animals. K003 was embryostatic (> 95 %) in this model. In the B. malayi-M. coucha model, K003 killed ~54 % of adult worms (macrofilaricidal activity) and rendered > 36 % female worms sterile; it also stopped any further rise in microfilaraemia after day 42 post-initiation of treatment. CONCLUSION: Ethanolic extract of aerial parts of the plant T. distichum possesses potent antifilarial activity and the active principle was localised to K003 which showed significant macrofilaricidal activity and late suppression of peripheral microfilaraemia and some embryostatic activity. These findings indicate that labdane diterpenoid molecule(s) may provide valuable leads for design and development of new macrofilaricidal agent(s). To the best of our knowledge, this is the first report on antifilarial efficacy of products from the plant T. distichum. PMID- 27245323 TI - Coordinate and synergistic effects of extensive treadmill exercise and ovariectomy on articular cartilage degeneration. AB - BACKGROUND: Although osteoarthritis (OA) is a multifactorial disease, little has been reported regarding the cooperative interaction among these factors on cartilage metabolism. Here we examined the synergistic effect of ovariectomy (OVX) and excessive mechanical stress (forced running) on articular cartilage homeostasis in a mouse model resembling a human postmenopausal condition. METHODS: Mice were randomly divided into four groups, I: Sham, II: OVX, III: Sham and forced running (60 km in 6 weeks), and IV: OVX and forced running. Histological and immunohistochemical analyses were performed to evaluate the degeneration of articular cartilage and synovitis in the knee joint. Morphological changes of subchondral bone were analyzed by micro-CT. RESULTS: Micro-CT analyses showed significant loss of metaphyseal trabecular bone volume/tissue volume (BV/TV) after OVX as described previously. Forced running increased the trabecular BV/TV in all mice. In the epiphyseal region, no visible alteration in bone morphology or osteophyte formation was observed in any of the four groups. Histological analysis revealed that OVX or forced running respectively had subtle effects on cartilage degeneration. However, the combination of OVX and forced running synergistically enhanced synovitis and articular cartilage degeneration. Although morphological changes in chondrocytes were observed during OA initiation, no signs of bone marrow edema were observed in any of the four experimental groups. CONCLUSION: We report the coordinate and synergistic effects of extensive treadmill exercise and ovariectomy on articular cartilage degeneration. Since no surgical procedure was performed on the knee joint directly in this model, this model is useful in addressing the molecular pathogenesis of naturally occurring OA. PMID- 27245324 TI - Replication initiatives will not salvage the trustworthiness of psychology. AB - Replication initiatives in psychology continue to gather considerable attention from far outside the field, as well as controversy from within. Some accomplishments of these initiatives are noted, but this article focuses on why they do not provide a general solution for what ails psychology. There are inherent limitations to mass replications ever being conducted in many areas of psychology, both in terms of their practicality and their prospects for improving the science. Unnecessary compromises were built into the ground rules for design and publication of the Open Science Collaboration: Psychology that undermine its effectiveness. Some ground rules could actually be flipped into guidance for how not to conduct replications. Greater adherence to best publication practices, transparency in the design and publishing of research, strengthening of independent post-publication peer review and firmer enforcement of rules about data sharing and declarations of conflict of interest would make many replications unnecessary. Yet, it has been difficult to move beyond simple endorsement of these measures to consistent implementation. Given the strong institutional support for questionable publication practices, progress will depend on effective individual and collective use of social media to expose lapses and demand reform. Some recent incidents highlight the necessity of this. PMID- 27245325 TI - Intraocular pressure and ocular biometric parameters changes in migraine. AB - BACKGROUND: The aim of this study was to assess the intraocular pressure and ocular biometric parameters in migraine patients during acute migraine attacks and compare them with painless period and healthy controls using a new optical biometer AL-Scan. METHODS: In this prospective, case-control study, the axial length, corneal curvature radius, anterior chamber depth, central corneal thickness, and pupil size of 40 migraine patients during acute migraine attacks and painless period and 40 age- and sex-matched healthy subjects were measured using a AL-Scan optical biometer (Nidek Co., Gamagori, Japan). All patients underwent a complete ophthalmic examination before the measurements. IOP and biometer measurements were taken at the same time of day (10:00-12:00) in order to minimize the effects of diurnal variation. RESULTS: There was not a statistically significant difference in intraocular pressure between the migraine patients during acute migraine attacks (15.07 mmHg), painless period (14.10 mmHg), and the controls (15,73 +/- 0,81). Also, the ocular biometric parameters did not significantly vary during the acute migraine attacks. CONCLUSIONS: Further studies are needed to evaluate the etiopathologic relationship between intraocular pressure and ocular biometric parameters and acute migraine attack. PMID- 27245326 TI - Increasing the production of (R)-3-hydroxybutyrate in recombinant Escherichia coli by improved cofactor supply. AB - BACKGROUND: In a recently discovered microorganism, Halomonas boliviensis, polyhydroxybutyrate production was extensive and in contrast to other PHB producers, contained a set of alleles for the enzymes of this pathway. Also the monomer, (R)-3-hydroxybutyrate (3HB), possesses features that are interesting for commercial production, in particular the synthesis of fine chemicals with chiral specificity. Production with a halophilic organism is however not without serious drawbacks, wherefore it was desirable to introduce the 3HB pathway into Escherichia coli. RESULTS: The production of 3HB is a two-step process where the acetoacetyl-CoA reductase was shown to accept both NADH and NADPH, but where the V max for the latter was eight times higher. It was hypothesized that NADPH could be limiting production due to less abundance than NADH, and two strategies were employed to increase the availability; (1) glutamate was chosen as nitrogen source to minimize the NADPH consumption associated with ammonium salts and (2) glucose-6-phosphate dehydrogenase was overexpressed to improve NADPH production from the pentose phosphate pathway. Supplementation of glutamate during batch cultivation gave the highest specific productivity (q3HB = 0.12 g g(-1) h(-1)), while nitrogen depletion/zwf overexpression gave the highest yield (Y3HB/CDW = 0.53 g g(-1)) and a 3HB concentration of 1 g L(-1), which was 50% higher than the reference. A nitrogen-limited fedbatch process gave a concentration of 12.7 g L( 1) and a productivity of 0.42 g L(-1) h(-1), which is comparable to maximum values found in recombinant E. coli. CONCLUSIONS: Increased NADPH supply is a valuable tool to increase recombinant 3HB production in E. coli, and the inherent hydrolysis of CoA leads to a natural export of the product to the medium. Acetic acid production is still the dominating by-product and this needs attention in the future to increase the volumetric productivity further. PMID- 27245327 TI - Cerebrospinal fluid dissemination of anaplastic intraventricular meningioma: report of a case presenting with progressive brainstem dysfunction and multiple cranial nerve palsies. AB - BACKGROUND: It is extremely rare to see cerebrospinal fluid dissemination of intraventricular meningioma, particularly with the development of acute, progressive brainstem/cerebellar dysfunction with an absence of mass formation in the corresponding anatomical sites. CASE PRESENTATION: An 81-year-old man was admitted because of double vision, right facial nerve palsy and truncal ataxia. Brain magnetic resonance imaging showed normal findings except for a tumor mass in the left lateral ventricle, which had been noted over 6 months previously. The patient developed hiccups, hyperventilation, and drowsiness, which worsened progressively, and did not respond to corticosteroid or intraventricular immunoglobulin therapy. Cerebrospinal fluid study revealed a mild elevation of protein, and cytology was negative. The patient died and an autopsy was performed. Postmortem investigation disclosed a malignant transformation of benign fibroid meningioma with cerebrospinal fluid dissemination of the malignant cells, diversely involving the surface of brainstem, cerebellum, and spinal cords, secondarily resulting in extensive ischemia in the brain parenchyma by vessel occlusion. CONCLUSION: If a patient with an intraventricular tumor develops acute, progressive neurological symptoms, the possibility that it is be caused by cerebrospinal fluid dissemination of tumor cells, after malignant transformation, should be considered. PMID- 27245328 TI - Modeling the oxygen uptake kinetics during exercise testing of patients with chronic obstructive pulmonary diseases using nonlinear mixed models. AB - BACKGROUND: The six-minute walk test (6MWT) is commonly used to quantify exercise capacity in patients with several cardio-pulmonary diseases. Oxygen uptake ([Formula: see text]O2) kinetics during 6MWT typically follow 3 distinct phases (rest, exercise, recovery) that can be modeled by nonlinear regression. Simultaneous modeling of multiple kinetics requires nonlinear mixed models methodology. To the best of our knowledge, no such curve-fitting approach has been used to analyze multiple [Formula: see text]O2 kinetics in both research and clinical practice so far. METHODS: In the present study, we describe functionality of the R package medrc that extends the framework of the commonly used packages drc and nlme and allows fitting nonlinear mixed effects models for automated nonlinear regression modeling. The methodology was applied to a data set including 6MWT [Formula: see text]O2 kinetics from 61 patients with chronic obstructive pulmonary disease (disease severity stage II to IV). The mixed effects approach was compared to a traditional curve-by-curve approach. RESULTS: A six-parameter nonlinear regression model was jointly fitted to the set of [Formula: see text]O2 kinetics. Significant differences between disease stages were found regarding steady state [Formula: see text]O2 during exercise, [Formula: see text]O2 level after recovery and [Formula: see text]O2 inflection point in the recovery phase. Estimates obtained by the mixed effects approach showed standard errors that were consistently lower as compared to the curve-by curve approach. CONCLUSIONS: Hereby we demonstrate the novelty and usefulness of this methodology in the context of physiological exercise testing. PMID- 27245329 TI - Adherence to antithrombotic therapy guidelines improves mortality among elderly patients with atrial fibrillation: insights from the REPOSI study. AB - BACKGROUND: Atrial fibrillation (AF) is associated with a substantial risk of thromboembolism and mortality, significantly reduced by oral anticoagulation. Adherence to guidelines may lower the risks for both all cause and cardiovascular (CV) deaths. METHODS: Our objective was to evaluate if antithrombotic prophylaxis according to the 2012 European Society of Cardiology (ESC) guidelines is associated to a lower rate of adverse outcomes. Data were obtained from REPOSI; a prospective observational study enrolling inpatients aged >=65 years. Patients enrolled in 2012 and 2014 discharged with an AF diagnosis were analysed. RESULTS: Among 2535 patients, 558 (22.0 %) were discharged with a diagnosis of AF. Based on ESC guidelines, 40.9 % of patients were on guideline-adherent thromboprophylaxis, 6.8 % were overtreated, and 52.3 % were undertreated. Logistic analysis showed that increasing age (p = 0.01), heart failure (p = 0.04), coronary artery disease (p = 0.013), peripheral arterial disease (p = 0.03) and concomitant cancer (p = 0.003) were associated with non-adherence to guidelines. Specifically, undertreatment was significantly associated with increasing age (p = 0.001) and cancer (p < 0.001), and inversely associated with HF (p = 0.023). AF patients who were guideline adherent had a lower rate of both all-cause death (p = 0.007) and CV death (p = 0.024) compared to those non adherent. Kaplan-Meier analysis showed that guideline-adherent patients had a lower cumulative risk for both all-cause (p = 0.002) and CV deaths (p = 0.011). On Cox regression analysis, guideline adherence was independently associated with a lower risk of all-cause and CV deaths (p = 0.019 and p = 0.006). CONCLUSIONS: Non-adherence to guidelines is highly prevalent among elderly AF patients, despite guideline-adherent treatment being independently associated with lower risk of all-cause and CV deaths. Efforts to improve guideline adherence would lead to better outcomes for elderly AF patients. PMID- 27245330 TI - Development of a Prolonged-Release Pramipexole Transdermal Patch: In Vitro and In Vivo Evaluation. AB - The current study aimed to develop a prolonged-release pramipexole (PPX) transdermal patch for the treatment of Parkinson's disease. Permeation parameters of PPX were investigated using human cadaver skin. Pramipexole patches were prepared using DURO-TAK(r) pressure-sensitive-adhesive (PSA) and evaluated for drug stability, drug loading, in vitro drug release, and in vitro permeation through mouse skin. The results indicated that blends of DURO-TAK(r) 87-2852 and DURO-TAK(r) 87-2510 were suitable for creating a prolonged-release PPX patch due to their advantages in drug release, drug loading, and stability. The final formulation consisted of 87-2852/87-2510 (70:30), 10% PG, and 15% PPX and showed a cumulative permeation amount of 1497.19 +/- 102.90 MUg/cm2 with a continuous flux over 6.0 MUg/(cm2.h) across human cadaver skin for 7 days. In vivo studies in rats indicated that PPX patch produced a significantly longer (p < 0.001) half life (t 1/2, 75.16 +/- 17.37 h) and mean residence time (MRT, 135.89 +/- 24.12 h) relative to oral tablets (Sifrol(r)) and had a relative bioavailability of 51.64 +/- 21.32%. Therefore, this study demonstrated the feasibility of developing a prolonged-release PPX patch, which proposed the potential to serve as an alternate to conventional oral tablets and may therefore improve patient compliance. PMID- 27245331 TI - Feasibility of a wireless gamma probe in radioguided surgery. AB - Radioguided surgery through the use of a gamma probe is an established practice, and has been widely applied in the case of sentinel lymph node biopsies. A wide range of intraoperative gamma probes is commercially available. The primary characteristics of the gamma probes include their sensitivity, spatial resolution, and energy resolution. We present the results obtained from a prototype of a new wireless gamma probe. This prototype is composed of a 20 mm thick cerium-doped gadolinium aluminum gallium garnet (Ce:GAGG) inorganic scintillation crystal from Furukawa Denshi and a Hamamatsu S12572-100C multi pixel photon counter equipped with a designed electronics. The measured performance characteristics include the energy resolution, energy linearity, angular aperture, spatial resolution and sensitivity. Measurements were carried out using (57)Co, (133)Ba, (22)Na, and (137)Cs sources. The energy resolutions for 0.122 and 0.511 MeV were 17.2% and 6.9%, respectively. The designed prototype consumes an energy of approximately 4.4 W, weighs about 310 g (including battery) having a dimension of 20 mm (D) * 130 mm (L). PMID- 27245333 TI - Glucose uptake saturation explains glucose kinetics profiles measured by different tests. AB - It is known that for a given insulin level glucose clearance depends on glucose concentration. However, a quantitative representation of the concomitant effects of hyperinsulinemia and hyperglycemia on glucose clearance, necessary to describe heterogeneous tests such as euglycemic and hyperglycemic clamps and oral tests, is lacking. Data from five studies (123 subjects) using a glucose tracer and including all the above tests in normal and diabetic subjects were collected. A mathematical model was developed in which glucose utilization was represented as a Michaelis-Menten function of glucose with constant Km and insulin-controlled Vmax, consistently with the basic notions of glucose transport. Individual values for the model parameters were estimated using a population approach. Tracer data were accurately fitted in all tests. The estimated Km was 3.88 (2.83-5.32) mmol/l [median (interquartile range)]. Median model-derived glucose clearance at 600 pmol/l insulin was reduced from 246 to 158 ml.min(-1).m(-2) when glucose was raised from 5 to 10 mmol/l. The model reproduced the characteristic lack of increase in glucose clearance when moderate hyperinsulinemia was accompanied by hyperglycemia. In all tests, insulin sensitivity was inversely correlated with BMI, as expected (R(2) = 0.234, P = 0.0001). In conclusion, glucose clearance in euglycemic and hyperglycemic clamps and oral tests can be described with a unifying model, consistent with the notions of glucose transport and able to reproduce the suppression of glucose clearance due to hyperglycemia observed in previous studies. The model may be important for the design of reliable glucose homeostasis simulators. PMID- 27245332 TI - Subchronic oral administration of crude khat extract (Catha edulis forsk) induces schizophernic-like symptoms in mice. AB - BACKGROUND: Chewing fresh leaves of the khat plant (Catha edulis forsk) is a deep rooted and widespread habit in East Africa and the Middle East. Although a body of knowledge exists about the adverse effects of khat on health, data are sparse with regard to the consequences of long-term khat chewing in resulting schizophrenic like symptoms. METHODS: A crude extract of khat at different doses (100 mg/kg (K (khat)100), 200 mg/kg (K200) and 400 mg/kg (K400)) were administered for experimental group of mice whereas standard (ketamine (KT) 10 mg/kg- positive controls (KT10)) and vehicle (2 % v/v Tween-80 in distilled water - negative control groups (CON)) were administered for control groups of mice daily for two months to evaluate subchronic oral administration of crude khat extract to induce schizophrenic-like symptoms in mice. Mice were subjected to a battery of behavioural tests and parameters like locomotor activity, total time spent in social interaction and level of cognition among different groups of mice were measured and analyzed. RESULTS: Khat at all doses significantly increased (p < 0.001) the mean locomotor activity score of mice compared to CON. However, the mean locomotor activity score of mice treated with khat was significantly lower (p < 0.001) compared to the mean locomotor activity score of KT10 mice (p < 0.001). The mean total time score (in seconds) spent in social interaction, mean total time score (in seconds) spent in sniffing and following the partner was significantly higher (p < 0.001) in CON groups of mice compared to khat and ketamine treated groups. Moreover, in spatial memory task, the mean latency score (in seconds) to find the platform of khat and ketamine treated mice was significantly higher (p < 0.05) when compared to CON. CONCLUSIONS: Subchronic oral administration of khat showed an enhanced locomotor activity, reduced social interaction and impaired cognitive function, which demonstrated that long-term use of khat is associated with schizophernic-like symptoms. PMID- 27245334 TI - Hepcidin and 1,25(OH)2D3 effectively restore Ca2+ transport in beta-thalassemic mice: reciprocal phenomenon of Fe2+ and Ca2+ absorption. AB - Previously, beta-thalassemia, an inherited anemic disorder with iron overload caused by loss-of-function mutation of beta-globin gene, has been reported to induce osteopenia and impaired whole body calcium metabolism, but the pathogenesis of aberrant calcium homeostasis remains elusive. Herein, we investigated how beta-thalassemia impaired intestinal calcium absorption and whether it could be restored by administration of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] or hepcidin, the latter of which was the liver-derived antagonist of intestinal iron absorption. The results showed that, in hemizygous beta-globin knockout (BKO) mice, the duodenal calcium transport was lower than that in wild type littermates, and severity was especially pronounced in female mice. Both active and passive duodenal calcium fluxes in BKO mice were found to be less than those in normal mice. This impaired calcium transport could be restored by 7-day 1,25(OH)2D3 treatment. The 1,25(OH)2D3-induced calcium transport was diminished by inhibitors of calcium transporters, e.g., L-type calcium channel, NCX1, and PMCA1b, as well as vesicular transport inhibitors. Interestingly, the duodenal calcium transport exhibited an inverse correlation with transepithelial iron transport, which was markedly enhanced in thalassemic mice. Thus, 3-day subcutaneous hepcidin injection and acute direct hepcidin exposure in the Ussing chamber were capable of restoring the thalassemia-associated impairment of calcium transport; however, the positive effect of hepcidin on calcium transport was completely blocked by proteasome inhibitors MG132 and bortezomib. In conclusion, both 1,25(OH)2D3 and hepcidin could be used to alleviate the beta thalassemia-associated impairment of calcium absorption. Therefore, our study has shed light on the development of a treatment strategy to rescue calcium dysregulation in beta-thalassemia. PMID- 27245335 TI - The effects of paternal high-fat diet exposure on offspring metabolism with epigenetic changes in the mouse adiponectin and leptin gene promoters. AB - Recent studies have demonstrated that epigenetic changes resulting from malnutrition might play important roles in transgenerational links with metabolic diseases. Previously, we observed that exposure to a high-fat diet (HFD) in utero caused a metabolic syndrome-like phenomenon through epigenetic modifications of the adiponectin and leptin genes that persisted for multiple generations. Recent etiological studies indicated that paternal BMI had effects on offspring BMI that were independent of but additive to maternal BMI effects. Thus, we examined whether paternal HFD-induced obesity affected the metabolic status of offspring through epigenetic changes in the adiponectin and leptin genes. Additionally, we investigated whether a normal diet during subsequent generations abolished the epigenetic changes associated with paternal HFD exposure before conception. We observed the effects of paternal HFD exposure before conception over multiple generations on offspring metabolic traits, including weight and fat gain, glucose intolerance, hypertriglyceridemia, abnormal adipocytokine levels, hypertension, and adiponectin and leptin gene expression and epigenetic changes. Normal diet consumption by male offspring during the subsequent generation following paternal HFD exposure diminished whereas consumption for two generations completely abolished the effect of paternal HFD exposure on metabolic traits and adipocytokine promoter epigenetic changes in the offspring. The effects of paternal HFD exposure on offspring were relatively weaker than those following HFD exposure in utero. However, paternal HFD exposure had an additive metabolic effect for two generations, suggesting that both paternal and maternal nutrition might affect offspring metabolism through epigenetic modifications of adipocytokine genes for multiple generations. PMID- 27245336 TI - Dynamics of glucagon secretion in mice and rats revealed using a validated sandwich ELISA for small sample volumes. AB - Glucagon is a metabolically important hormone, but many aspects of its physiology remain obscure, because glucagon secretion is difficult to measure in mice and rats due to methodological inadequacies. Here, we introduce and validate a low volume, enzyme-linked immunosorbent glucagon assay according to current analytical guidelines, including tests of sensitivity, specificity, and accuracy, and compare it, using the Bland-Altman algorithm and size-exclusion chromatography, with three other widely cited assays. After demonstrating adequate performance of the assay, we measured glucagon secretion in response to intravenous glucose and arginine in anesthetized mice (isoflurane) and rats (Hypnorm/midazolam). Glucose caused a long-lasting suppression to very low values (1-2 pmol/l) within 2 min in both species. Arginine stimulated secretion 8- to 10 fold in both species, peaking at 1-2 min and returning to basal levels at 6 min (mice) and 12 min (rats). d-Mannitol (osmotic control) was without effect. Ketamine/xylazine anesthesia in mice strongly attenuated (P < 0.01) alpha-cell responses. Chromatography of pooled plasma samples confirmed the accuracy of the assay. In conclusion, dynamic analysis of glucagon secretion in rats and mice with the novel accurate sandwich enzyme-linked immunosorbent assay revealed extremely rapid and short-lived responses to arginine and rapid and profound suppression by glucose. PMID- 27245337 TI - Intake of branched-chain or essential amino acids attenuates the elevation in muscle levels of PGC-1alpha4 mRNA caused by resistance exercise. AB - The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha is recognized as the master regulator of mitochondrial biogenesis. However, recently a novel isoform, PGC-1alpha4, that specifically regulates muscle hypertrophy was discovered. Because stimulation of mechanistic target of rapamycin complex 1 (mTORC1) activity is tightly coupled to hypertrophy, we hypothesized that activation of this pathway would upregulate PGC 1alpha4. Eight male subjects performed heavy resistance exercise (10 * 8-12 repetitions at ~75% of 1 repetition maximum in leg press) on four different occasions, ingesting in random order a solution containing essential amino acids (EAA), branched-chain amino acids (BCAA), leucine, or flavored water (placebo) during and after the exercise. Biopsies were taken from the vastus lateralis muscle before and immediately after exercise, as well as following 90 and 180 min of recovery. Signaling through mTORC1, as reflected in p70S6 kinase phosphorylation, was stimulated to a greater extent by the EAA and BCAA than the leucine or placebo supplements. Unexpectedly, intake of EAA or BCAA attenuated the stimulatory effect of exercise on PGC-1alpha4 expression by ~50% (from a 10- to 5-fold increase with BCAA and EAA, P < 0.05) 3 h after exercise, whereas intake of leucine alone did not reduce this response. The 60% increase (P < 0.05) in the level of PGC-1alpha1 mRNA 90 min after exercise was uninfluenced by amino acid intake. Muscle glycogen levels were reduced and AMP-activated protein kinase alpha2 activity and phosphorylation of p38 mitogen-activated protein kinase enhanced to the same extent with all four supplements. In conclusion, induction of PGC-1alpha4 does not appear to regulate the nutritional (BCAA or EAA)-mediated activation of mTORC1 in human muscle. PMID- 27245338 TI - Differential regulation of lipid and protein metabolism in obese vs. lean subjects before and after a 72-h fast. AB - Increased availability of lipids may conserve muscle protein during catabolic stress. Our study was designed to define 1) intracellular mechanisms leading to increased lipolysis and 2) whether this scenario is associated with decreased amino acid and urea fluxes, and decreased muscle amino acid release in obese subjects under basal and fasting conditions. We therefore studied nine lean and nine obese subjects twice, after 12 and 72 h of fasting, using measurements of mRNA and protein expression and phosphorylation of lipolytic and protein metabolic signaling molecules in fat and muscle together with whole body and forearm tracer techniques. Obese subjects displayed increased whole body lipolysis, decreased urea production rates, and decreased forearm muscle protein breakdown per 100 ml of forearm tissue, differences that persisted after 72 h of fasting. Lipolysis per fat mass unit was reduced in obese subjects and, correspondingly, adipose tissue hormone-sensitive lipase (HSL) phosphorylation and mRNA and protein levels of the adipose triglyceride lipase (ATGL) coactivator CGI58 were decreased. Fasting resulted in higher HSL phosphorylations and lower protein levels of the ATGL inhibitor G0S2. Muscle protein expressions of mammalian target of rapamycin (mTOR) and 4EBP1 were lower in obese subjects, and MuRf1 mRNA was higher with fasting in lean but not obese subjects. Phosphorylation and signaling of mTOR decreased with fasting in both groups, whereas ULK1 protein and mRNA levels increased. In summary, obese subjects exhibit increased lipolysis due to a large fat mass with blunted prolipolytic signaling, together with decreased urea and amino acid fluxes both in the basal and 72-h fasted state; this is compatible with preservation of muscle and whole body protein. PMID- 27245339 TI - Formoterol decreases muscle wasting as well as inflammation in the rat model of rheumatoid arthritis. AB - Adjuvant-induced arthritis is an experimental model of rheumatoid arthritis that is associated with body weight loss and muscle wasting. beta2-adrenergic receptor agonists are powerful anabolic agents that trigger skeletal muscle hypertrophy and have been proposed as a promising treatment for muscle wasting in human patients. The aim of this work was to determine whether formoterol, a selective beta2-adrenoreceptor agonist, is able to ameliorate muscle wasting in arthritic rats. Arthritis was induced in male Wistar rats by intradermal injection of Freund's adjuvant. Control and arthritic rats were injected daily with 50 MUg/kg sc formoterol or saline for 12 days. Body weight change, food intake, and arthritis index were analyzed. After euthanasia, in the gastrocnemius mRNA was analyzed by PCR, and proteins were analyzed by Western blotting. Arthritis decreased gastrocnemius weight, cross-sectional area, and myofiber size, whereas formoterol increased those variables in both arthritic and control rats. Formoterol decreased the external signs of arthritis as well as NF-kappaB(p65) activation, TNFalpha, and COX-2 levels in the gastrocnemius of arthritic and control rats. Those effects of formoterol were associated with a decreased expression of myostatin, atrogin-1, and MuRF1 and in LC3b lipidation. Arthritis increased the expression of MyoD, myogenin, IGF-I, and IGFBP-3 and -5 in the gastrocnemius. In control and in arthritic rats, treatment with formoterol increased Akt phosphorylation and myogenin levels, whereas it decreased IGFBP-3 expression in the gastrocnemius. These data suggest that formoterol has an anti inflammatory effect and decreases muscle wasting in arthritic rats through increasing Akt activity and myogenin and decreasing myostatin, the p-NF kappaB(p65)/TNF pathway, and IGFBP-3. PMID- 27245340 TI - Assessment of Drug-Drug Interaction Potential Between Atorvastatin and LCZ696, A Novel Angiotensin Receptor Neprilysin Inhibitor, in Healthy Chinese Male Subjects. AB - BACKGROUND AND OBJECTIVE: LCZ696 (sacubitril/valsartan), a novel angiotensin receptor neprilysin inhibitor has been recently approved for the treatment of patients with heart failure (HF) and reduced ejection fraction. As several HF patients are likely to use statins as co-medications, the potential for a pharmacokinetic drug-drug interaction between atorvastatin and LCZ696 was evaluated. METHODS: This was an open-label, three-period, single-sequence study in 28 healthy Chinese male subjects wherein LCZ696 200 mg was administered twice daily for 5 days in period 1. Following a washout period, atorvastatin 80 mg was administered once daily for 4 days (period 2) and subsequently co-administered with LCZ696 200 mg for 5 days (period 3). Serial plasma samples were collected to determine pharmacokinetic parameters of LCZ696 analytes (sacubitril, LBQ657, and valsartan) and atorvastatin and its metabolites. RESULTS: Atorvastatin co administration had no effect on the pharmacokinetics of LBQ657, while the AUCtau,ss and C max,ss of sacubitril increased by 30 and 19 %, respectively, and the corresponding values for valsartan decreased by 19 and 9 %, respectively. Co administration with LCZ696 increased C max,ss of atorvastatin, o hydroxyatorvastatin, and p-hydroxyatorvastatin by 74, 68, and 108 %, respectively, and the AUCtau,ss of corresponding analytes increased by 34, 22, and 26 %, respectively. CONCLUSIONS: While atorvastatin had no significant impact on the pharmacokinetics of LCZ696 analytes upon co-administration, the C max of atorvastatin and its metabolites increased twofold, with a marginal increase in AUC (<1.3-fold). Multiple-dose administration of LCZ696 200 mg twice daily and atorvastatin 80 mg once daily either alone or in combination was generally safe and well tolerated in healthy subjects. PMID- 27245342 TI - The Return of Congenital Rickets, Are We Missing Occult Cases? AB - Congenital rickets is the term given to fetus born with clinical features of rickets, but those born with biochemical evidence of rickets without obvious clinical features still can be considered occult congenital rickets. Some of the affected babies with this disease have the intrauterine rachitic environment, but a calcium trans-placental pump prevents the fetus from having clinical features of rickets. They may present with hypocalcemia few days after birth or later with more florid features of rickets. Congenital rickets cases born with florid features reported over the last 40 years are few and can be divided into two groups. The first due to severe maternal osteomalacia in which their bones were so decalcified to have enough calcium to be pumped to their fetus. Another group in which newborn babies were hypocalcemic due to other maternal diseases as malabsorption, celiac disease, pre-eclampsia, and prematurity. All inherited rickets cases per se, or as part of other syndromes can be considered congenital rickets. Most cases seen in our region are due to maternal vitamin D deficiency with symptoms becoming obvious when the infants are breastfed, or may present with hypocalcemic convulsions or craniotabes. This is a review of congenital rickets with the aim of shedding light on this potentially acute disease that needs more attention and awareness in the neonatal period to avoid rare serious complications as cardiomyopathy or myelofibrosis and the complications of hypocalcemic convulsions. Congenital rickets cases seen simulate a tip of an ice burg and its prevention is an important issue, especially with the tremendous urbanization with tall buildings living in sun-deprived flats as the commonest type of residence leading to the increasing incidence of maternal osteomalacia and rickets. PMID- 27245341 TI - Co-lyophilized Aspirin with Trehalose Causes Less Injury to Human Gastric Cells and Gastric Mucosa of Rats. AB - BACKGROUND: Aspirin is one of the most popular NSAIDs worldwide because of its anti-inflammatory and anticoagulant effects, and however, gastrointestinal injury remains a major complication. We previously reported co-lyophilized aspirin/trehalose (Lyo A/T) decreased the aspirin-induced gastric lesions in dogs. AIM: This study investigated the mechanism of gastroprotective effects of trehalose in vitro and in vivo. METHODS: The apoptotic assays were performed in a human gastric carcinoma cell line, which was treated with aspirin, mixed aspirin/trehalose (Mix A/T) or Lyo A/T. Gastric ulcer severity was examined after oral administration of drugs in rats. In addition, the mucosal tissue apoptotic status in drug-treated rats was evaluated. Molecular dynamics simulations and laser Raman spectroscopy were performed in order to examine the molecular properties of Lyo A/T. RESULTS: DNA fragmentation was detected in AGS cells that were treated with aspirin and Mix A/T, but not in the Lyo A/T-treated cells. There were fewer apoptotic cells in the Lyo A/T-treated cells than in the other cells. Gastric injury was reduced in rats that received oral Lyo A/T compared with the others, while PGE2 synthesis was equally decreased in all groups. TUNEL assay and immunohistochemistry of cleaved caspase-3 in the mucosal tissues also revealed that Lyo A/T treatment induced less apoptosis than the others. The Lyo A/T spectrum showed clear differences in several Raman bands compared with that of Mix A/T. CONCLUSIONS: Our data showed that co-lyophilization of aspirin with trehalose reduced gastric injury, potentially through suppression of aspirin induced mucosal cell apoptosis while retaining its anti-inflammatory effects. PMID- 27245344 TI - Cross-habitat effects shape the ecosystem consequences of co-invasion by a pelagic and a benthic consumer. AB - Invasive species can have major impacts on ecosystems, yet little work has addressed the combined effects of multiple invaders that exploit different habitats. Two common invaders in aquatic systems are pelagic fishes and crayfishes. Pelagic-oriented fish effects are typically strong on the pelagic food web, whereas crayfish effects are strong on the benthic food web. Thus, co invasion may generate strong ecological responses in both habitats. We tested the effects of co-invasion on experimental pond ecosystems using two widespread invasive species, one pelagic (western mosquitofish) and one benthic (red swamp crayfish). As expected, mosquitofish had strong effects on the pelagic food web, reducing the abundance of Daphnia and causing a strong trophic cascade (increase in phytoplankton). Crayfish had strong effects on the benthic food web, reducing the abundance of benthic filamentous algae. Yet, we also found evidence for important cross-habitat effects. Mosquitofish treatments reduced the biomass of benthic filamentous algae, and crayfish treatments increased Daphnia and phytoplankton abundance. Combined effects of mosquitofish and crayfish were primarily positively or negatively additive, and completely offsetting for some responses, including gross primary production (GPP). Though co-invasion did not affect GPP, it strongly shifted primary production from the benthos into the water column. Effects on snail abundance revealed an interaction; snail abundance decreased only in the presence of both invaders. These results suggest that cross habitat effects of co-invaders may lead to a variety of ecological outcomes; some of which may be unpredictable based on an understanding of each invader alone. PMID- 27245343 TI - A dark cuticle allows higher investment in immunity, longevity and fecundity in a beetle upon a simulated parasite attack. AB - Cuticle melanism in insects is linked to a number of life history traits: a positive relationship is hypothesized between melanism, immune function, fecundity and lifespan. However, it is not clear how activation of the immune system affects trade-offs between life history traits in female mealworm beetles (Tenebrio molitor) differing in cuticle melanization. The females with tan, brown and black cuticles examined in the present study did not differ in the intensity of encapsulation response, fecundity and longevity when their immune system was not activated. However, we found that immune activation and cuticle melanization have a significant effect on life history traits. Offspring number and lifespan decreased in females with tan and brown cuticles, while the fecundity and lifespan of black females were not affected. Importantly, we inserted the implants again and found a significant decrease in the strength of encapsulation response in females with tan and brown cuticles. In contrast, black females increased melanotic reactions against the nylon implant, suggesting immunological priming. The results show that cuticle melanization plays an important adaptive role under the risk of being infected, while the lack of these benefits before the insertion of nylon monofilaments suggests that there are costs associated with an activated immunity system. PMID- 27245345 TI - Improved Butanol-Methanol (BUME) Method by Replacing Acetic Acid for Lipid Extraction of Biological Samples. AB - Extraction of lipids from biological samples is a critical step in lipidomics, especially for shotgun lipidomics where lipid extracts are directly infused into a mass spectrometer. The butanol-methanol (BUME) extraction method was originally developed to extract lipids from plasma samples with 1 % acetic acid. Considering some lipids are sensitive to acidic environments, we modified this protocol by replacing acetic acid with lithium chloride solution and extended the modified extraction to tissue samples. Although no significant reduction of plasmalogen levels in the acidic BUME extracts of rat heart samples was found, the modified method was established to extract various tissue samples, including rat liver, heart, and plasma. Essentially identical profiles of the majority of lipid classes were obtained from the extracts of the modified BUME and traditional Bligh-Dyer methods. However, it was found that neither the original, nor the modified BUME method was suitable for 4-hydroxyalkenal species measurement in biological samples. PMID- 27245346 TI - Response to Letter Regarding Article, "Antihypertensive Drug Use, Blood Pressure Variability, and Stroke Risk in Older Adults: Three-City Cohort Study". PMID- 27245347 TI - Letter by Nagai et al Regarding Article, "Antihypertensive Drug Use, Blood Pressure Variability, and Incident Stroke Risk in Older Adults: Three-City Cohort Study". PMID- 27245349 TI - TAK1 Regulates the Nrf2 Antioxidant System Through Modulating p62/SQSTM1. AB - AIMS: Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) is the master transcriptional regulator of antioxidant gene expression. On increased oxidative stress, an adaptor for Nrf2 degradation, Kelch-like ECH-associated protein 1 (Keap1), is directly modulated by oxidants in the cytoplasm, which results in stabilization and activation of Nrf2. Nrf2 is also constitutively active, to some extent, in the absence of exogenous oxidative stress. We have previously demonstrated that intestinal epithelium-specific TGF-beta-activated kinase 1 (TAK1) deletion downregulates the level of Nrf2 protein, resulting in an increase of reactive oxygen species (ROS) in a mouse model. We aim at determining the mechanism by which TAK1 modulates the level of Nrf2. RESULTS: We found that TAK1 upregulated serine 351 phosphorylation of an autophagic adaptor protein, p62/Sequestosome-1 (SQSTM1), which facilitates interaction between p62/SQSTM1 and Keap1 and subsequent Keap1 degradation. This, ultimately, causes increased Nrf2. Tak1 deficiency reduced the phosphorylation of p62/SQSTM1, resulting in decreased steady-state levels of Nrf2 along with increased Keap1. We also found that this regulation is independent of the canonical redox-mediated Nrf2 activation mechanism. In Tak1-deficient intestinal epithelium, a synthetic phenolic electrophile, butylated hydroxyanisole still effectively upregulated Nrf2 and reduced ROS. INNOVATION: Our results identify for the first time that TAK1 is a modulator of p62/SQSTM1-dependent Keap1 degradation and maintains the steady state-level of Nrf2. CONCLUSION: TAK1 regulates Nrf2 through modulation of Keap p62/SQSTM1 interaction. This regulation is important for homeostatic antioxidant protection in the intestinal epithelium. Antioxid. Redox Signal. 25, 953-964. PMID- 27245348 TI - Clinical Pregenetic Screening for Stroke Monogenic Diseases: Results From Lombardia GENS Registry. AB - BACKGROUND AND PURPOSE: Lombardia GENS is a multicentre prospective study aimed at diagnosing 5 single-gene disorders associated with stroke (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, Fabry disease, MELAS [mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes], hereditary cerebral amyloid angiopathy, and Marfan syndrome) by applying diagnostic algorithms specific for each clinically suspected disease METHODS: We enrolled a consecutive series of patients with ischemic or hemorrhagic stroke or transient ischemic attack admitted in stroke units in the Lombardia region participating in the project. Patients were defined as probable when presenting with stroke or transient ischemic attack of unknown etiopathogenic causes, or in the presence of <3 conventional vascular risk factors or young age at onset, or positive familial history or of specific clinical features. Patients fulfilling diagnostic algorithms specific for each monogenic disease (suspected) were referred for genetic analysis. RESULTS: In 209 patients (57.4+/-14.7 years), the application of the disease-specific algorithm identified 227 patients with possible monogenic disease. Genetic testing identified pathogenic mutations in 7% of these cases. Familial history of stroke was the only significant specific feature that distinguished mutated patients from nonmutated ones. The presence of cerebrovascular risk factors did not exclude a genetic disease. CONCLUSIONS: In patients prescreened using a clinical algorithm for monogenic disorders, we identified monogenic causes of events in 7% of patients in comparison to the 1% to 5% prevalence reported in previous series. PMID- 27245351 TI - Continuing violence against medical personnel in China: A flagrant violation of Chinese law. AB - Over the past few years, China has witnessed a surge in violence against medical personnel, including widely reported incidents of violent abuse, riots, attacks, and protests in hospitals, where doctors suffer from heavy workloads and little protection. China has engaged in serious efforts, such as investing large amounts into the healthcare system and implementing several decades of healthcare reform, to make medical care more accessible to and affordable for the public. However, incidents of violence against medical personnel have increased in intensity, reflecting deteriorating relations between medical staff and their patients in China over the past few decades. Hence, the effectiveness of healthcare legislation needs to be examined and medical reform and development of the healthcare system need to be reevaluated. Only by enhancing oversight, promoting healthcare reform, and improving the healthcare system can we repair the doctor patient relationship and decrease violence against doctors in China. PMID- 27245350 TI - Epimerization of Alanyl-Alanine Induced by gamma-Rays Irradiation in Aqueous Solutions. AB - Living organisms have homochiral L-amino acids in proteins and homochiral D mononucleotides in nucleic acids. The chemical evolutionary process to protein homochirality has been discussed for many years. Although many scenarios have been proposed for homochirality in the monomeric compounds, homochirality in amino acids and mononucleotides does not always guarantee homochirality in polypeptides and polynucleotides. Integrated scenarios containing the pathways from monomer to polymer should be proposed because in the pathways oligomers and polymers as well as monomers racemize (or epimerize), degrade, and condense. This research addresses epimerization and degradation of dipeptides under gamma-rays irradiation by a cobalt-60 (60Co) radiation source. The different rate constants of epimerization between diastereomeric dipeptides in the research suggest that the potential pathway toward homochirality could be much more complex. PMID- 27245353 TI - Erratum to: A novel oxidative stress marker in migraine patients: dynamic thiol disulphide homeostasis. PMID- 27245352 TI - Epigenetic dysregulation in the developing Down syndrome cortex. AB - Using Illumina 450K arrays, 1.85% of all analyzed CpG sites were significantly hypermethylated and 0.31% hypomethylated in fetal Down syndrome (DS) cortex throughout the genome. The methylation changes on chromosome 21 appeared to be balanced between hypo- and hyper-methylation, whereas, consistent with prior reports, all other chromosomes showed 3-11 times more hyper- than hypo-methylated sites. Reduced NRSF/REST expression due to upregulation of DYRK1A (on chromosome 21q22.13) and methylation of REST binding sites during early developmental stages may contribute to this genome-wide excess of hypermethylated sites. Upregulation of DNMT3L (on chromosome 21q22.4) could lead to de novo methylation in neuroprogenitors, which then persists in the fetal DS brain where DNMT3A and DNMT3B become downregulated. The vast majority of differentially methylated promoters and genes was hypermethylated in DS and located outside chromosome 21, including the protocadherin gamma (PCDHG) cluster on chromosome 5q31, which is crucial for neural circuit formation in the developing brain. Bisulfite pyrosequencing and targeted RNA sequencing showed that several genes of PCDHG subfamilies A and B are hypermethylated and transcriptionally downregulated in fetal DS cortex. Decreased PCDHG expression is expected to reduce dendrite arborization and growth in cortical neurons. Since constitutive hypermethylation of PCDHG and other genes affects multiple tissues, including blood, it may provide useful biomarkers for DS brain development and pharmacologic targets for therapeutic interventions. PMID- 27245354 TI - Cerebrospinal fluid levels of free fatty acid associated with ischemic stroke recurrence and functional outcome. AB - The aim of this study was to evaluate the association between cerebrospinal fluid (CSF) levels of free fatty acid (FFA) and functional outcome and stroke recurrence in patients with ischemic stroke. In a prospective study, CSF levels of FFA were measured using an enzyme cycling method on admission in 217 consecutive patients with first-ever ischemic stroke. Clinical information was collected. Functional outcome and stroke recurrence were evaluated at 1-year follow-up. Multivariate analyses were performed using logistic regression models. The CSF FFA level was obtained in all patients with a median value of 0.22 (IQR 0.12-0.33) mmol/l. At admission, 89 patients (41.0 %) had a minor stroke (NIHSS < 5). In these patients, the median FFA level was lower than that observed in patients with moderate-to-high clinical severity (0.16 vs 0.27 mmol/l, p < 0.001). Patients with unfavorable outcomes and stroke recurrence had significantly higher FFA CSF levels on admission (all p < 0.0001). Multivariate logistic regression analysis adjusted for common risk factors showed that CSF FFA >= 0.33 mmol/l (third quarters) was an independent predictor of functional outcome (OR = 2.825; 95 % CI 1.502-5.313, p = 0.001) and stroke recurrence (OR = 7.862; 95 % CI 3.248-19.031, p < 0.0001). Our results demonstrate that high FFA SCF levels were independently associated with both the poor functional prognosis and stroke recurrence in patients with ischemic stroke. PMID- 27245355 TI - Right ventricular function assessed by tissue Doppler echocardiography in older subjects without evidence for structural cardiac disease. AB - The aim of our study was to obtain right ventricular (RV) tissue Doppler imaging (TDI) data in older subjects (n = 95, mean age: 74.5 +/- 4.6 years) without evidence of hemodynamically significant structural heart disease recruited from a large population-based cohort (ActiFE-Ulm study). Our data indicate that aging may be accompanied by decreasing RV diastolic function and at most little alterations of RV systolic function. Mean values of all parameters were still within the guideline-suggested reference range with most of them closer to the abnormality thresholds. On an individual basis, respective thresholds were also exceeded in some subjects (almost all parameters <20 %) despite the absence of evidence for structural cardiac disease. RV-TDI is a feasible method for evaluation of RV systolic and diastolic function also in a geriatric population as sufficient TDI data was obtainable in the majority of our participants. Published reference values also seem to be mostly suitable although among older subjects, presumed pathological measures might still be compatible with physiological age-related alterations. Therefore, they always have to be interpreted across the clinical context and in relation to other parameters of morphology and function obtained by other ultrasound imaging techniques (M-mode, B-mode, etc.) in the context of echocardiographic evaluation of the right heart. PMID- 27245357 TI - NMR-based metabolomics to determine acute inhalation effects of nano- and fine sized ZnO particles in the rat lung. AB - Zinc oxide (ZnO) particles induce acute occupational inhalation illness in humans and rats. However, the possible molecular mechanisms of ZnO particles on the respiratory system remain unclear. In this study, metabolic responses of the respiratory system of rats inhaled ZnO particles were investigated by a nuclear magnetic resonance (NMR)-based metabolomic approach. Male Sprague-Dawley rats were treated with a series of doses of nano-sized (35 nm) or fine-sized (250 nm) ZnO particles. The corresponding control groups inhaled filtered air. After 24 h, bronchoalveolar lavage fluid (BALF) and lung tissues were collected, extracted and prepared for (1)H and J-resolved NMR analysis, followed by principal component analysis (PCA) and partial least squares discriminant analysis (PLS DA). PCA and PLSDA models from analysis of BALF and hydrophilic lung NMR spectra demonstrated that dose response trends were restricted to the 250 nm ZnO particle exposure group and were not observed in the 35 nm ZnO particle exposure group. Increased isoleucine and valine, as well as decreased acetate, trimethylamine n oxide, taurine, glycine, formate, ascorbate and glycerophosphocholine, were recorded in the BALF of rats treated with moderate and high dose 250 nm ZnO exposures. Decreases in taurine and glucose, as well as an increase of phosphorylcholine-containing lipids and fatty acyl chains, were detected in the lung tissues from 250 nm ZnO-treated rats. These metabolic changes may be associated with cell anti-oxidation, energy metabolism, DNA damage and membrane stability. We also concluded that a metabolic approach provides more complete measurements and suggests potential molecular mechanisms of adverse effects. PMID- 27245356 TI - Age-dependent divergent effects of OX40L treatment on the development of diabetes in NOD mice. AB - Earlier, we have shown that GM-CSF derived bone marrow (BM) dendritic cells (G BMDCs) can expand Foxp3(+) regulatory T-cells (Tregs) through a TCR-independent, but IL-2 dependent mechanism that required OX40L/OX40 interaction. While some reports have shown suppression of autoimmunity upon treatment with an OX40 agonist, others have shown exacerbation of autoimmune disease instead. To better understand the basis for these differing outcomes, we compared the effects of OX40L treatment in 6-week-old pre-diabetic and 12-week-old near diabetic NOD mice. Upon treatment with OX40L, 6-week-old NOD mice remained normoglycemic and showed a significant increase in Tregs in their spleen and lymph nodes, while 12 week-old NOD mice very rapidly developed hyperglycemia and failed to show Treg increase in spleen or LN. Interestingly, OX40L treatment increased Tregs in the thymus of both age groups. However, it induced Foxp3(+)CD103(+)CD38(-) stable phenotype Tregs in the thymus and reduced the frequency of autoreactive Teff cells in 6-week-old mice; while it induced Foxp3(+)CD103(-)CD38(+) labile phenotype Tregs in the thymus and increased autoreactive CD4(+) T cells in the periphery of 12-week-old mice. This increase in autoreactive CD4(+) T cells was likely due to either a poor suppressive function or conversion of labile Tregs into Teff cells. Using ex vivo cultures, we found that the reduction in Treg numbers in 12-week-old mice was likely due to IL-2 deficit, and their numbers could be increased upon addition of exogenous IL-2. The observed divergent effects of OX40L treatment were likely due to differences in the ability of 6- and 12-week-old NOD mice to produce IL-2. PMID- 27245358 TI - Desymmetrization of an Octahedral Coordination Complex Inside a Self-Assembled Exoskeleton. AB - The synthesis of a centrally functionalized, ribbon-shaped [6]polynorbornane ligand L that self-assembles with Pd(II) cations into a {Pd2 L4 } coordination cage is reported. The shape-persistent {Pd2 L4 } cage contains two axial cationic centers and an array of four equatorial H-bond donors pointing directly towards the center of the cavity. This precisely defined supramolecular environment is complementary to the geometry of classic octahedral complexes [M(XY)6 ] with six diatomic ligands. Very strong binding of [Pt(CN)6 ](2-) to the cage was observed, with the structure of the host-guest complex {[Pt(CN)6 ]@Pd2 L4 } supported by NMR spectroscopy, MS, and X-ray data. The self-assembled shell imprints its geometry on the encapsulated guest, and desymmetrization of the octahedral platinum species by the influence of the D4h -symmetric second coordination sphere was evidenced by IR spectroscopy. [Fe(CN)6 ](3-) and square-planar [Pt(CN)4 ](2-) were strongly bound. Smaller octahedral anions such as [SiF6 ](2-) , neutral carbonyl complexes ([M(CO)6 ]; M=Cr, Mo, W) and the linear [Ag(CN)2 ]( ) anion were only weakly bound, showing that both size and charge match are key factors for high-affinity binding. PMID- 27245360 TI - Melamine binding with arachidonic acid binding sites of albumin is a potential mechanism for melamine-induced inflammation. AB - Melamine adulteration of food is a public health concern. It has been seen that melamine causes disease in many organs. Melamine-induced kidney disease is a well recognized clinicopathological entity. Inflammation is thought to be important in melamine-induced pathology. Melamine is expected to bind with albumin because it has a positive charge. Albumin binds arachidonic acid. So if binding of melamine with albumin takes place, it has the potential to displace arachidonic acid from the albumin bound state. This phenomenon may be the source of mediators of inflammation in the melamine exposure state. This aspect is investigated in the present study by docking and molecular dynamics simulation. It is observed that melamine binds with some known arachidonic acid binding sites of albumin. This can lead to formation of more free arachidonic acid. It is also observed that melamine does not bind with extracellular signal regulated kinase 2 (ERK2). Therefore, the signal transduction mediated process involving ERK2 is not a likely mechanism of melamine-induced inflammation. Therefore, we think that an increased free arachidonic acid level may contribute more to inflammation in the melamine exposure state. PMID- 27245359 TI - Coupling between alternative polyadenylation and alternative splicing is limited to terminal introns. AB - Alternative polyadenylation has been implicated as an important regulator of gene expression. In some cases, alternative polyadenylation is known to couple with alternative splicing to influence last intron removal. However, it is unknown whether alternative polyadenylation events influence alternative splicing decisions at upstream exons. Knockdown of the polyadenylation factors CFIm25 or CstF64 in HeLa cells was used as an approach in identifying alternative polyadenylation and alternative splicing events on a genome-wide scale. Although hundreds of alternative splicing events were found to be differentially spliced in the knockdown of CstF64, genes associated with alternative polyadenylation did not exhibit an increased incidence of alternative splicing. These results demonstrate that the coupling between alternative polyadenylation and alternative splicing is usually limited to defining the last exon. The striking influence of CstF64 knockdown on alternative splicing can be explained through its effects on UTR selection of known splicing regulators such as hnRNP A2/B1, thereby indirectly influencing splice site selection. We conclude that changes in the expression of the polyadenylation factor CstF64 influences alternative splicing through indirect effects. PMID- 27245361 TI - Exploring the mitochondrial DNA variability of the Amazonian Yanomami. AB - OBJECTIVES: The aim of this study was to explore the mitochondrial variability in the Yanomami population to reconstruct its demographic history and explore its genetic composition in relation to its cultural and linguistic features. METHODS: A total of 174 human head hair shafts -collected in 1958- belonging to individuals from a Yanomami group living in Santa Isabel, Brazil, were analyzed. Automated extraction of the hairs was performed, and several methods were applied to optimize the analysis of the degraded DNA. The mtDNA hypervariable segments I II, along with the 9-bp COII-tRNALys deletion, were investigated. Using published data from the Yanomami and other Amazonian populations, several statistical analyses were carried out to explore the genetic variability within the study population. RESULTS: Ninety eight percent of the mitochondrial DNA (mtDNA) sequences analyzed belonged to Native American haplogroups, while 2% belonged to African haplogroups. Compared with the Yanomami groups previously studied, the Santa Isabel sample seemed more genetically similar to other Amazonian populations. CONCLUSIONS: Among the Yanomami samples studied to date, the Santa Isabel Yanomami show a higher genetic heterogeneity. This could be due to gene flow with non-Yanomami populations, as well as to the introduction of new mitochondrial haplotypes by gold miners. In both cases, the geographic location of Santa Isabel might have made this Yanomami village less isolated than the others, suggesting that the Rio Negro played a central role in increasing its genetic variability. On the whole, the Yanomami were quite genetically diversified, probably mirroring their great linguistic heterogeneity. Am. J. Hum. Biol. 28:846-856, 2016. (c) 2016Wiley Periodicals, Inc. PMID- 27245363 TI - Margaret McCartney: Asthma and the catwalk. PMID- 27245362 TI - How aligned are the perspectives of EU regulators and HTA bodies? A comparative analysis of regulatory-HTA parallel scientific advice. AB - BACKGROUND: In 2010, the European Medicines Agency (EMA) initiated a pilot project on parallel scientific advice with Health Technology Assessment bodies (HTABs) that allows manufacturers to receive simultaneous feedback from both the European Union (EU) regulators and HTABs on their development plans for medicines. AIMS: The present retrospective qualitative analysis aimed to explore how the parallel scientific advice system is working and levels of commonality between the EU regulators and HTABs, and among HTABs, when applicants obtain parallel scientific advice from both a regulatory and an HTA perspective. METHODS: We analysed the minutes of discussion meetings held at the EMA between 2010, when parallel advice was launched, and 1 May 2015, when the cutoff date for data extraction was set. The analysis was based on predefined criteria and conducted at two different levels of comparison: the answers of the HTABs vs. those of the regulators, and between the answers of the participating HTA agencies. RESULTS: The analysis was based on 31 procedures of parallel scientific advice. The level of full agreements was highest for questions on patient population (77%), while disagreements reached a peak for questions on the study comparator (30%). With regard to comparisons among HTABs, there was a high level of agreement for all domains. CONCLUSIONS: There is evident commonality, in terms of evidence requirements between the EU regulators and participating HTABs, as well as among HTABs, on most aspects of clinical development. Indeed, regardless of the question content, the analysis showed that a high level of overall agreement was reached through the process of parallel scientific advice. PMID- 27245364 TI - Concise Review: Stem Cell Interventions for People With Cerebral Palsy: Systematic Review With Meta-Analysis. AB - : Evidence for stem cells as a potential intervention for cerebral palsy is emerging. Our objective was to determine the efficacy and safety of stem cells for improving motor and cognitive function of people with cerebral palsy. Searches were conducted in October 2015 in CENTRAL, EMBASE, MEDLINE, and Cochrane Libraries. Randomized controlled trials and controlled clinical trials of stem cells for cerebral palsy were included. Two authors independently decided upon included trials, extracted data, quality, and risk of bias. The primary outcome was gross motor function. Secondary outcomes were cognitive function and adverse events (AEs). Effects were expressed as standardized mean differences (SMD) with 95% confidence intervals (CI), using a random-effects model. Five trials comprising 328 participants met inclusion criteria. Four cell types were studied: olfactory ensheathing, neural, neural progenitors, and allogeneic umbilical cord blood (UCBs). Transplantation procedures differed from central nervous system neurosurgical transplantation to intravenous/arterial infusion. Participants were followed short-term for only 6 months. Evidence of variable quality indicated a small statistically significant intervention effect from stem cells on gross motor skills (SMD 1.27; 95% CI 0.22, 2.33), with UCBs most effective. There were insufficient and heterogeneous data to compare cognitive effects. Serious AEs were rare (n = 4/135 [3%] stem cells; n = 3/139 [2%] controls). Stem cells appeared to induce short-term improvements in motor skills. Different types of stem cell interventions were compared, meaning the data were heterogeneous and are a study limitation. Further randomized controlled trials are warranted, using rigorous methodologies. SIGNIFICANCE: Stem cells are emerging as a scientifically plausible treatment and possible cure for cerebral palsy, but are not yet proven. The lack of valid animal models has significantly hampered the scope of clinical trials. Despite the state of current treatment evidence, parents remain optimistic about the potential improvements from stem cell intervention and feel compelled to exhaust all therapeutic options, including stem cell tourism. Receiving unproven therapies from unvalidated sources is potentially dangerous. Thus it is essential that researchers and clinicians stay up to date. A systematic review and meta-analysis summarizing and aggregating current research data may provide more conclusive evidence to inform treatment decision making and help direct future research. PMID- 27245365 TI - Identification and Characterization of Human Endometrial Mesenchymal Stem/Stromal Cells and Their Potential for Cellular Therapy. AB - SummaryHuman endometrium is a highly regenerative tissue, undergoing more than 400 cycles of proliferation, differentiation, and shedding during a woman's reproductive life. Adult stem cells, including mesenchymal stem/stromal cells (MSCs), are likely responsible for the immense cellular turnover in human endometrium. The unique properties of MSCs, including high proliferative ability, self-renewal, differentiation to mesodermal lineages, secretion of angiogenic factors, and many other growth-promoting factors make them useful candidates for cellular therapy and tissue engineering. In this review, we summarize the identification and characterization of newly discovered MSCs from the human endometrium: their properties, the surface markers used for their prospective isolation, their perivascular location in the endometrium, and their potential application in cellular therapies. SIGNIFICANCE: The endometrium, or the lining of uterus, has recently been identified as a new and accessible source of mesenchymal stem cells, which can be obtained without anesthesia. Endometrial mesenchymal stem cells have comparable properties to bone marrow and adipose tissue mesenchymal stem cells. Endometrial mesenchymal stem cells are purified with known and novel perivascular surface markers and are currently under investigation for their potential use in cellular therapy for several clinical conditions with significant burden of disease. PMID- 27245366 TI - Concise Review: Updated Advances and Current Challenges in Cell Therapy for Inborn Liver Metabolic Defects. AB - : The development of liver cell transplantation (LCT), considered a major biotechnological breakthrough, was intended to provide more accessible treatments for liver disease patients. By preserving the native recipient liver and decreasing hospitalization time, this innovative approach has progressively gained interest among clinicians. LCT initially targets inborn errors of liver metabolism, enabling the compensation of deficient metabolic functions for up to 18 months post-transplantation, supporting its use at least as a bridge to transplantation. The rigorous clinical development and widespread use of LCT depends strongly on controlled and consistent clinical trial data, which may help improve several critical factors, including the standardization of raw biological material and immunosuppression regimens. Substantial effort has also been made in defining and optimizing the most efficient cell population to be transplanted in the liver setting. Although isolated hepatocytes remain the best cell type, showing positive clinical results, their widespread use is hampered by their poor resistance to both cryopreservation and in vitro culture, as well as ever-more significant donor shortages. Hence, there is considerable interest in developing more standardized and widely accessible cell medicinal products to improve engraftment permanency and post-cell transplantation metabolic effects. SIGNIFICANCE: In this therapeutic approach to liver disease, new solutions are being designed and evaluated to bypass the documented limitations and move forward toward wide clinical use. Future developments also require a deep knowledge of regulatory framework to launch specific clinical trials that will allow clear assessment of cell therapy and help patients with significant unmet medical needs. PMID- 27245368 TI - Stretchable Silver Nanowire Microelectrodes for Combined Mechanical and Electrical Stimulation of Cells. AB - The use of stretchable electrodes interfaced with the human body has enabled a new frontier in biomedical engineering, and the miniaturization of such electrodes can allow for a more precise spatial control to monitor or stimulate tissues. The understanding of the response of cells or tissues to combined electromechanical stimulation, as made possible by stretchable electrodes, is essential to improve medical devices and therapies. Cheap to produce and easy to use platforms for in vitro cell studies are thus urgently needed. This study reports the successful implementation of silver nanowires (AgNWs) into an integrated miniaturized electromechanical stimulator, which is compatible with cell culture. The innovative steps include a lithography-based lift-off method to micropattern AgNWs onto an elastic silicone membrane. These stretchable microelectrodes are then integrated into a microfluidic device for cell culture, which enables the synchronous electromechanical stimulation of cells. In a proof of-concept study, it is furthermore shown that fibroblasts respond uniquely to mechanical stretching, electrical stimulation, and combined electromechanical stimulations in terms of cell alignment and morphology, as well as by producing the extracellular matrix protein collagen. This proof-of-concept study illustrates the functionality and usability of these stretchable AgNWs microelectrodes for either basic research or future biomedical applications. PMID- 27245367 TI - Early Intravenous Delivery of Human Brain Stromal Cells Modulates Systemic Inflammation and Leads to Vasoprotection in Traumatic Spinal Cord Injury. AB - : Spinal cord injury (SCI) is a life-threatening condition with multifaceted complications and limited treatment options. In SCI, the initial physical trauma is closely followed by a series of secondary events, including inflammation and blood spinal cord barrier (BSCB) disruption, which further exacerbate injury. This secondary pathology is partially mediated by the systemic immune response to trauma, in which cytokine production leads to the recruitment/activation of inflammatory cells. Because early intravenous delivery of mesenchymal stromal cells (MSCs) has been shown to mitigate inflammation in various models of neurologic disease, this study aimed to assess these effects in a rat model of SCI (C7-T1, 35-gram clip compression) using human brain-derived stromal cells. Quantitative polymerase chain reaction for a human-specific DNA sequence was used to assess cell biodistribution/clearance and confirmed that only a small proportion (approximately 0.001%-0.002%) of cells are delivered to the spinal cord, with the majority residing in the lung, liver, and spleen. Intriguingly, although cell populations drastically declined in all aforementioned organs, there remained a persistent population in the spleen at 7 days. Furthermore, the cell infusion significantly increased splenic and circulating levels of interleukin-10-a potent anti-inflammatory cytokine. Through this suppression of the systemic inflammatory response, the cells also reduced acute spinal cord BSCB permeability, hemorrhage, and lesion volume. These early effects further translated into enhanced functional recovery and tissue sparing 10 weeks after SCI. This work demonstrates an exciting therapeutic approach whereby a minimally invasive cell-transplantation procedure can effectively reduce secondary damage after SCI through systemic immunomodulation. SIGNIFICANCE: Central nervous system pericytes (perivascular stromal cells) have recently gained significant attention within the scientific community. In addition to being recognized as major players in neurotrauma, pericytes have been discovered to share a common origin and potentially function with traditionally defined mesenchymal stromal cells (MSCs). Although there have been several in vitro comparisons, the in vivo therapeutic application of human brain-derived stromal cells has not been previously evaluated. This study demonstrates that these cells not only display a MSC phenotype in vitro but also have similar in vivo immunomodulatory effects after spinal cord injury that are more potent than those of non-central nervous system tissue-derived cells. Therefore, these cells are of great interest for therapeutic use in spinal cord injury. PMID- 27245369 TI - Characterization of Arginine Kinase in the Barnacle Amphibalanus Amphitrite and Its Role in the Larval Settlement. AB - Energy metabolism is a key process in larval settlement of barnacles, but the underlying molecular mechanisms remain ambiguous. Arginine kinase (AK) mainly participates in energy metabolism in invertebrates. So far, its roles in barnacles have not been studied. In the present study, we raised an antibody against AK from Amphibalanus amphitrite Darwin to characterize the roles of AK in the larval settlement process. Among the developmental stages, AK was highly expressed during the cypris stage. Along with the aging process in cyprids, the level of AK decreased. The immunostaining results showed that AK was localized to muscular tissues in cyprids, including antennules, antennular muscles, and thoracic limbs. The larval settlement rate decreased and larval movement was inhibited in response to treatments with high concentrations of AK inhibitors (rutin and quercetin). These results demonstrated that AK was involved in the larval settlement of A. amphitrite through mediating energy supply in muscle tissues. Moreover, further analysis indicated that both the p38 MAPK and NO/cGMP pathways positively mediated the expression of AK in cyprids. PMID- 27245370 TI - Laparoscopic right hemicolectomy for a patient with idiopathic retroperitoneal fibrosis: A case report. AB - A 62-year-old man with abdominal pain and lumbago was admitted to our hospital. Blood examination revealed renal insufficiency, and CT revealed retroperitoneal fibrosis causing bilateral hydrocele and ureteral compression. A colonoscopy was performed to rule out secondary retroperitoneal fibrosis due to malignancies, and this imaging revealed an ascending colon cancer. Laparoscopic right hemicolectomy with lymphadenectomy and retroperitoneal biopsy were performed. The retroperitoneum was filled with hard, white fibrous tissue, which made it difficult to mobilize the right mesocolon from the retroperitoneum. Devascularization performed before mobilization allowed for a safe and oncologically feasible procedure. Histologically, there were no malignant cells in the retroperitoneal tissue. The patient has been without colon cancer reoccurrence for 4 years. When the surgical challenges that distinguish these patients from ordinary cases are recognized preoperatively, laparoscopic colectomy may be a feasible option for patients with colorectal cancer with idiopathic retroperitoneal fibrosis. PMID- 27245371 TI - Nanopattern Gradients for Cell Studies Fabricated Using Hole-Mask Colloidal Lithography. AB - Culturing cells on gradient nanopatterns provides a useful tool to explore cellular adhesion to mimics of the extracellular matrix or screen for cellular responses to nanopatterns. A method is presented to fabricate complex gradient protein patterns based on hole-mask colloidal lithography, which can generate nanopatterns in multiple materials and of multiple shapes. Gradients of gold structures were functionalized to form gradients of protein nanopatterns of different shapes (bars, dot pairs, and rings), where a key parameter was systematically varied in each gradient. Cells were grown on vitronectin nanopatterns, showing differential adhesion (spread area/focal adhesion size) along the gradients. PMID- 27245372 TI - Shape variation and ontogeny of the ruminant bony labyrinth, an example in Tragulidae. AB - Despite its growing use in anatomical and ecological studies, the morphological variability and ontogenetic development of the bony labyrinth have very rarely been investigated in ruminants. Here we study its morphology in 15 adult and 10 juvenile specimens in the three extant tragulid ruminant genera. Intraspecific and interspecific variability is quantified using morphometric and 3D geometric morphometrics analyses. The bony labyrinth of Tragulus, Hyemoschus, and Moschiola is strikingly different, clustering in clearly different morphospaces despite similar ecological adaptations. Although the bony labyrinths within two species of the same genus cannot be distinguished from each other based on the chosen semi-landmarks, discrete interspecific differences exist. We were able to show for the first time that an artiodactyl mammal in a late fetal stage possesses an almost fully formed bony labyrinth similar to that of adults. No significant change either occurs in size or morphology after ossification of the petrosal bone. Some intraspecific variation is observed on the shape of the lateral semi circular canal, the size and shape of the common crus, the coil of the cochlea or the stapedial ratio. Variable structures are expected to be highly informative characters for a large cladistic analysis. They can be used for phylogenetic studies in ruminants. Incorporating juvenile specimens in studies is not problematic, as they fall within the morphological range of adults. PMID- 27245373 TI - Information needs of patients with heart failure: Health professionals' perspectives. AB - This study aimed to understand information needs of patients with heart failure from the perspectives of health professionals. The exploratory qualitative study was conducted in 2011. Face-to-face interviews were performed to collect data from 24 health professionals. Data were evaluated through content analysis. Information identified by health professionals as essential for patients' learning included risk factors and symptom management, prognosis, medication and lifestyle adjustment. Factors related to both patients and health professionals were recognized as barriers to information acquisition. Moreover, health professionals provided several recommendations for improving the health condition of patients. Information needs identified by health professionals, as well as actual needs expressed by patients, can be incorporated in health education. The effectiveness of educating patients can be improved by addressing needs perceived by both patients and health professionals. PMID- 27245374 TI - The accuracy of cell-free fetal DNA-based non-invasive prenatal testing in singleton pregnancies: a systematic review and bivariate meta-analysis. AB - BACKGROUND: Cell-free fetal DNA (cffDNA) non-invasive prenatal testing (NIPT) is rapidly expanding, and is being introduced at varying rates depending on country and condition. OBJECTIVES: Determine accuracy of cffDNA-based NIPT for all conditions. Evaluate influence of other factors on test performance. SEARCH STRATEGY: Medline, Embase, CINAHL, Cochrane Library, from 1997 to April 2015. SELECTION CRITERIA: Cohort studies reporting cffDNA-based NIPT performance in singleton pregnancies. DATA COLLECTION AND ANALYSIS: Bivariate or univariate meta analysis and subgroup analysis performed to explore influence of test type and population risk. MAIN RESULTS: A total of 117 studies were included that analysed 18 conditions. Bivariate meta-analysis demonstrated sensitivities and specificities, respectively, for: fetal sex, 0.989 (95% CI 0.980-0.994) and 0.996 (95% CI 0.989-0.998), 11 179 tests; rhesus D, 0.993 (95% CI 0.982-0.997) and 0.984 (95% CI 0.964-0.993), 10 290 tests; trisomy 21, 0.994 (95% CI 0.983-0.998) and 0.999 (95% CI 0.999-1.000), 148 344 tests; trisomy 18, 0.977 (95% CI 0.952 0.989) and 0.999 (95% CI 0.998-1.000), 146 940 tests; monosomy X, 0.929 (95% CI 0.741-0.984) and 0.999 (95% CI 0.995-0.999), 6712 tests. Trisomy 13 was analysed by univariate meta-analysis, with a summary sensitivity of 0.906 (95% CI 0.823 0.958) and specificity of 1.00 (95% CI 0.999-0.100), from 134 691 tests. False and inconclusive results were poorly reported across all conditions. Although the test type affected both sensitivity and specificity, there was no evidence that population risk had any effect. CONCLUSION: Performance of cffDNA-based NIPT is affected by condition under investigation. For fetal sex and rhesus D status, NIPT can be considered diagnostic. For trisomy 21, 18, and 13, the lower sensitivity, specificity, and disease prevalence, combined with the biological influence of confined placental mosaicism, designates it a screening test. These factors must be considered when counselling patients and assessing the cost of introduction into routine care. TWEETABLE ABSTRACT: cffDNA NIPT accuracy high, can be diagnostic for fetal sex and rhesus D, but only screening test in aneuploidy. PMID- 27245376 TI - Simple benchmark for mesothelioma projection for Great Britain. AB - BACKGROUND: It is of considerable interest to forecast the future burden of mesothelioma mortality. Data on deaths are available, whereas no measure of asbestos exposure is available. METHODS: We compare two Poisson models: a response-only model with an age-cohort specification and a multinomial model with epidemiologically motivated frequencies. RESULTS: The response-only model has 5% higher peak mortality than the dose-response model. The former performs slightly better in out-of-sample comparison. CONCLUSIONS: Mortality is predicted to peak at about 2100 deaths around 2017 among males in cohorts until 1966 and below 90 years of age. The response-only model is a simple benchmark that forecasts just as well as more complicated models. PMID- 27245375 TI - Natural resource-based industries and prostate cancer risk in Northeastern Ontario: a case-control study. AB - OBJECTIVE: Prostate cancer continues to be the most commonly diagnosed cancer in men, and there is limited knowledge on its preventable risk factors. A number of occupational exposures in natural resource-based industries are suspected to be related to prostate cancer risk. This study investigates associations between employment in these industries and prostate cancer. METHODS: Data were from a population-based, case-control study previously conducted in Northeastern Ontario. Incident cases (N=760) aged 45-85 years and diagnosed with prostate cancer between 1995 and 1998 were identified from the Ontario Cancer Registry. Controls (N=1632) were recruited using telephone listings, and were frequency matched to cases by age. Lifetime occupational history was collected for all participants. Logistic regression was used to estimate ORs and their associated 95% CIs. RESULTS: Elevated risks were observed for employment in forestry and logging industries (OR=1.87, 95% CI 1.32 to 2.73) and occupations (OR=1.71, 95% CI 1.24 to 2.35), and these risks increased with duration of employment for >=10 years. Elevated risks were also found for employment in wood products industries (OR=1.45, 95% CI 1.07 to 1.97), and paper and allied products industries (OR=1.43, 95% CI 1.03 to 2.00), and when duration of employment was >=10 years. There were also elevated risks in agriculture and mining-related work; however, these findings were not consistent across industry and occupation categories. CONCLUSIONS: Prostate cancer risk may be associated with work in several natural resource industries, primarily in the forest industries. To further evaluate observed associations, studies should focus on natural resource-based exposures in larger populations with improved exposure assessment. PMID- 27245377 TI - Associations of ABO, D, and Lewis blood groups and HLA Class I and Class II alleles with West Nile virus Lineage 2 disease outcome in Greece, 2010 to 2013. AB - BACKGROUND: West Nile virus (WNV) infection, commonly asymptomatic, may cause mild West Nile fever (WNF) or potentially fatal neuroinvasive disease (WNND). An outbreak of 262 cases of the new Lineage 2 strain in Greece in 2010 continued with high mortality (17%) in WNND. The objective was to investigate ABO, D, and Lewis blood groups, as well as HLA Class I and Class II alleles, in relation to WNV Lineage 2 disease morbidity. STUDY DESIGN AND METHODS: A cohort of 132 Greek WNV cases in 2010 to 2013 (65% male; mean age 64 years; 41% WNF, 59% WNND) was compared to 51,339 healthy WNV-negative blood donors and 246 healthy subjects. RESULTS: Blood group A was more common in WNV cases (51%) than blood donors (39%) and group O less common (32% vs. 42%). D negativity within group A was higher in WNV than in blood donors (18% vs. 10%, p = 0.044). The frequency of secretors (Lewis(a-b+)) was 60% in WNV and 68% in donors (p = 0.16). HLA alleles C*08, DRB1*O4:O5, and DQB1*O2 occurred significantly less frequently in WNV than controls (p < 0.05 unadjusted for multiple testing) and DRB1*10:O1 more frequently (p = 0.039). CONCLUSION: This first study of symptomatic WNV Lineage 2 suggests A/D negativity as a new risk factor associated with WNV infection and level of morbidity. Further studies are required of the possibility that HLA C*08, DRB1*O4:O5, and DQB1*O2 are protective alleles and DRB1*10:O1 a "susceptible" allele to WNV infection and the role of secretor status in relation to WNV infection. PMID- 27245378 TI - Hermetically Coated and Well-Separated Co3 O4 Nanophase within Porous Graphitic Carbon Nanosheets: Synthesis, Confinement Effect, and Improved Lithium-Storage Capacity and Durability. AB - Considerable lithium-driven volume changes and loss of crystallinity on cycling have impeded the sustainable use of transition metal oxides (MOs) as attractive anode materials for advanced lithium-ion batteries that have almost six times the capacity of carbon per unit volume. Herein, Co3 O4 was used as a model MO in a facile process involving two pyrolysis steps for in situ encapsulation of nanosized MO in porous two-dimensional graphitic carbon nanosheets (2D-GCNs) with high surface areas and abundant active sites to overcome the above-mentioned problems. The proposed method is inexpensive, industrially scalable, and easy to operate with a high yield. TEM revealed that the encaged Co3 O4 is well separated and uniformly dispersed with surrounding onionlike graphitic layers. By taking advantage of the high electronic conductivity and confinement effect of the surrounding 2D-GCNs, a hierarchical GCNs-coated Co3 O4 (Co3 O4 @GCNs) anode with 43.5 wt % entrapped active nanoparticles delivered a remarkable initial specific capacity of 1816 mAh g(-1) at a current density of 100 mA g(-1) . After 50 cycles, the retained capacity is as high as 987 mAh g(-1) . When the current density was increased to 1000 mA g(-1) , the anode showed a capacity retention of 416 mAh g(-1) . Enhanced reversible rate capability and prolonged cycling stability were found for Co3 O4 @GCN compared to pure GCNs and Co3 O4 . The Co3 O4 @GCNs hybrid holds promise as an efficient candidate material for anodes due to its low cost, environmentally friendly nature, high capacity, and stability. PMID- 27245379 TI - Factors associated with the effect of open splenectomy for immune thrombocytopenic purpura. AB - OBJECTIVE: To assess the effect and complications of open splenectomy (OS) for immune thrombocytopenic purpura (ITP) and determine preoperative factors associated with surgical effect. METHODS: This was a retrospective analysis of ITP patients who failed medical therapy and were treated with OS between 1997 and 2014 at the Jinshan Hospital, China. Follow-up was 60 months. Surgical effect was determined from platelet counts and bleeding episodes. Complications were assessed including bleeding episodes. Preoperative factors were identified by logistic regression analysis. RESULTS: Fifty-six patients (48.2 +/- 16.2 yr old; 39 females) were included. Disease course was 31.2 +/- 48.2 months; 91.1% patients had preoperative platelet count <20 * 109 /L. OS effect at 1 wk, 1 month, 1 yr, and 5 yrs was in 91.1%, 92.9%, 91.1%, and 89.3% patients, respectively. Pneumonia or lower extremity thrombosis occurred in 7.1% patients. Postoperative mild, moderate, and severe bleeding occurred in 33.9%, 50.0%, and 16.1% patients, respectively. No patients required blood transfusion. Mortality was zero. Larger spleen size associated with surgical effect at 1 wk, 1 month, and 1 yr, and lower preoperative minimum platelet count associated with effect at 5 yrs (P < 0.05). CONCLUSIONS: Open splenectomy is an effective treatment with less complications for the management of ITP. Lower preoperative minimum platelet count associated with successful OS at 5 yrs. PMID- 27245380 TI - Nanoporous Gyroid-Structured Epoxy from Block Copolymer Templates for High Protein Adsorbability. AB - Nanoporous epoxy with gyroid texture is fabricated by using a nanoporous polymer with gyroid-forming nanochannels as a template for polymerization of epoxy. The nanoporous polymer template is obtained from the self-assembly of degradable block copolymer, polystyrene-b-poly(l-lactide) (PS-PLLA), followed by hydrolysis of PLLA blocks. Templated polymerization can be conducted under ambient conditions to create well-defined, bicontinuous epoxy networks in a PS matrix. By taking advantage of multistep curing of epoxy, well-ordered robust nanoporous epoxy can be obtained after removal of PS template, giving robust porous materials. The through-hole nanoporous epoxy in the film state can be used as a coated layer to enhance the adsorbability for both lysozyme and bovine serum albumin. PMID- 27245381 TI - Development and validation of an LC-MS/MS method for the determination of tigecycline in human plasma and cerebrospinal fluid and its application to a pharmacokinetic study. AB - Tigecycline (TGC) is an important antibiotic in treating various drug-resistant bacteria. The dosage regimen for cerebral intraventricular TGC is still unknown. The aim of the study was to develop and validate liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods for the determination of TGC in human plasma and cerebrospinal fluid (CSF) to obtain an applicable regimen. The ion transitions under ESI positive model were performed at m/z 586.3 > 513.2 and m/z 595.3 > 514.3 for TGC and d9-TGC internal standard (IS). For plasma and CSF samples, the calibration curve of TGC was linear within the ranges 25-2000 and 250-100,000 ng/mL; the IS normalized matrix effect was within the ranges 96.46 101.06% and 101.13-103.58%, respectively, for all. TGC was stable under all tested conditions. The patient received 1 mg intraventricular and 49 mg intravenous administration of TGC. The AUC0-12 in plasma and CSF calculated according to our noncompartment model were 4713 and 23,0238 h ng/mL, respectively. Given our findings cerebral intraventricular TGC may be a choice for clinicians to treat drug-resistant Gram-negative bacterial-induced meningitis and the safety and efficacy of this administration route warrants further study. PMID- 27245383 TI - Changes in habitat of fish populations: An inverse problem. AB - Mathematical modelling applies to a wide variety of application areas, and is an active area of research in many disciplines. It is often the case that accurate depiction of real-world phenomena require increasingly complex models. Unfortunately, this increased complexity in a model causes great difficulty when seeking solutions. What is more, developing a model with known parameters that produces results consistent with observed behaviors may prove to be a difficult or even impossible task. These difficulties have brought about an interest in inverse problems. In this paper we utilize a collage-based approach to solve an inverse problem for a model for the migration of three fish species through floodplain waters. A derivation of the mathematical model is presented and a generalized collage method is discussed and applied to this model to recover diffusion parameters. Theoretical and numerical particulars are discussed and results are presented. PMID- 27245385 TI - Reining in the supersized Phase I cancer trial. PMID- 27245382 TI - Synthetic combinations of missense polymorphic genetic changes underlying Down syndrome susceptibility. AB - Single nucleotide polymorphisms (SNPs) are important biomolecular markers in health and disease. Down syndrome, or Trisomy 21, is the most frequently occurring chromosomal abnormality in live-born children. Here, we highlight associations between SNPs in several important enzymes involved in the one-carbon folate metabolic pathway and the elevated maternal risk of having a child with Down syndrome. Our survey highlights that the combination of SNPs may be a more reliable predictor of the Down syndrome phenotype than single SNPs alone. We also describe recent links between SNPs in p53 and its related pathway proteins and Down syndrome, as well as highlight several proteins that help to associate apoptosis and p53 signaling with the Down syndrome phenotype. In addition to a comprehensive review of the literature, we also demonstrate that several SNPs reside within the same regions as these Down syndrome-linked SNPs, and propose that these closely located nucleotide changes may provide new candidates for future exploration. PMID- 27245384 TI - Associations among pain, depression, and functional limitation in low-income, home-dwelling older adults: An analysis of baseline data from CAPABLE. AB - A complex relationship exists between pain, depression, and functional limitation. These conditions, which substantially impact health care spending and quality of life, remain under-addressed in the current system of health care delivery, particularly among low-income and minority populations. This analysis uses baseline assessment data from CAPABLE, an ongoing randomized controlled trial (RCT), to examine associations between pain, depression, and functional limitation among a sample of low-income, community-dwelling elders with functional limitations. Linear regression revealed close associations between depression, pain, and activity of daily living (ADL) limitation. Mediation analyses indicated that depression fully mediated the relationship between pain intensity and functional limitation and partially mediated the relationship between pain interference and depression. Past research has shown that these conditions may be easily identified using validated assessment tools and effectively addressed through the introduction of interdisciplinary interventions. Several recommendations are presented for clinicians and health care organizations. PMID- 27245386 TI - Immuno-oncologists eye up macrophage targets. PMID- 27245387 TI - Tackling antimicrobial drug resistance. PMID- 27245388 TI - FDA approves first drug for Parkinson disease psychosis. PMID- 27245389 TI - NCATS launches 'periodic table' for medicinal product ingredients. PMID- 27245390 TI - Regulatory watch: The orphan drug pipeline in Europe. PMID- 27245391 TI - Anticancer drugs: RAS mimetic revealed. PMID- 27245392 TI - Cachexia: Inhibiting FAO rescues muscle-wasting. PMID- 27245393 TI - Cancer: Peptibodies rescue mice from lymphoma. PMID- 27245394 TI - GPCRs: Glucagon receptor antagonist binding site identified. PMID- 27245395 TI - Pain: Blocking pain in inherited erythromelalgia. PMID- 27245396 TI - Worldwide collaboration for orphan drug designation. PMID- 27245398 TI - Automated image analysis for quantification of reactive oxygen species in plant leaves. AB - The paper presents an image processing method for the quantitative assessment of ROS accumulation areas in leaves stained with DAB or NBT for H2O2 and O2- detection, respectively. Three types of images determined by the combination of staining method and background color are considered. The method is based on the principle of supervised machine learning with manually labeled image patterns used for training. The method's algorithm is developed as a JavaScript macro in the public domain Fiji (ImageJ) environment. It allows to select the stained regions of ROS-mediated histochemical reactions, subsequently fractionated according to the weak, medium and intense staining intensity and thus ROS accumulation. It also evaluates total leaf blade area. The precision of ROS accumulation area detection is validated by the Dice Similarity Coefficient in the case of manual patterns. The proposed framework reduces the computation complexity, once prepared, requires less image processing expertise than the competitive methods and represents a routine quantitative imaging assay for a general histochemical image classification. PMID- 27245397 TI - Gene- and genome-based analysis of significant codon patterns in yeast, rat and mice genomes with the CUT Codon UTilization tool. AB - The translation of mRNA in all forms of life uses a three-nucleotide codon and aminoacyl-tRNAs to synthesize a protein. There are 64 possible codons in the genetic code, with codons for the ~20 amino acids and 3 stop codons having 1- to 6-fold degeneracy. Recent studies have shown that families of stress response transcripts, termed modification tunable transcripts (MoTTs), use distinct codon biases that match specifically modified tRNAs to regulate their translation during a stress. Similarly, translational reprogramming of the UGA stop codon to generate selenoproteins or to perform programmed translational read-through (PTR) that results in a longer protein, requires distinct codon bias (i.e., more than one stop codon) and, in the case of selenoproteins, a specifically modified tRNA. In an effort to identify transcripts that have codon usage patterns that could be subject to translational control mechanisms, we have used existing genome and transcript data to develop the gene-specific Codon UTilization (CUT) tool and database, which details all 1-, 2-, 3-, 4- and 5-codon combinations for all genes or transcripts in yeast (Saccharomyces cerevisiae), mice (Mus musculus) and rats (Rattus norvegicus). Here, we describe the use of the CUT tool and database to characterize significant codon usage patterns in specific genes and groups of genes. In yeast, we demonstrate how the CUT database can be used to identify genes that have runs of specific codons (e.g., AGA, GAA, AAG) linked to translational regulation by tRNA methyltransferase 9 (Trm9). We further demonstrate how groups of genes can be analyzed to find significant dicodon patterns, with the 80 Gcn4-regulated transcripts significantly (P<0.00001) over represented with the AGA-GAA dicodon. We have also used the CUT database to identify mouse and rat transcripts with internal UGA codons, with the surprising finding of 45 and 120 such transcripts, respectively, which is much larger than expected. The UGA data suggest that there could be many more translationally reprogrammed transcripts than currently reported. CUT thus represents a multi species codon-counting database that can be used with mRNA-, translation- and proteomics-based results to better understand and model translational control mechanisms. PMID- 27245399 TI - Approaches to unravel pathways of reactive oxygen species in the photoinactivation of bacteria induced by a dicationic fulleropyrrolidinium derivative. AB - The photodynamic mechanism sensitized by N,N-dimethyl-2-[4-(3-N,N,N trimethylammoniopropoxy)phenyl]fulleropyrrolidinium (DPC602+) was investigated in Staphylococcus aureus cells. Different experimental conditions were used to detect reactive oxygen species (ROS) in S. aureus cell suspensions. First, a photoinactivation of 4 log decrease of S. aureus viability was chosen using 0.5MUM DPC602+ and 15min irradiation. An anoxic atmosphere indicated that oxygen was required for an effective photoinactivation. Also, photoprotection was found in the presence of sodium azide, whereas the photocytotoxicity induced by DPC602+ increased in D2O. The addition of diazabicyclo[2.2.2]octane or d-mannitol produced a reduction in the S. aureus photokilling. Moreover, singlet molecular oxygen, O2(1Deltag), was detected by the reaction with 9,10-dimethylanthracene into the S. aureus cells. A decrease in the photoinactivation of S. aureus was observed in the presence of beta-nicotinamide adenine dinucleotide reduced form, which was dependent on the NADH concentration. Therefore, under aerobic condition the photocytotoxicity activity induced by DPC602+ was mediated by mainly a contribution of type II process. Moreover, photoinactivation of S. aureus was possible with DPC602+ in the presence of azide anions under anoxic condition. However, these conditions were not effective to photoinactivate Escherichia coli. On the other hand, the addition of potassium iodide produced an increase in the photokilling of bacteria, depending on the KI concentration and irradiation times. The formation of reactive iodine species may be contributing to inactivate S. aureus cells photoinduced by DPC602+. PMID- 27245400 TI - Temperature-Dependent Hole Mobility and Its Limit in Crystal-Phase P3HT Calculated from First Principles. AB - We study temperature-dependent hole transport in ideal crystal-phase poly(3 hexylthiophene) (P3HT) with ab initio calculations, with the aim of estimating the maximum mobility in the limit of perfect order. To this end, the molecular transfer integrals, phonon frequencies, and electron-phonon coupling constants are obtained from density functional theory (DFT). This allows the determination of transport properties without fit parameters. The strong coupling between charge carriers and vibrations leads to strong scattering and polaronic effects that impact carrier transport. By providing an intrinsic mobility limit to ideal P3HT crystals, this work allows identification of the impact of disorder on the temperature-dependent transport in real samples. A detailed analysis of the transport-relevant phonon modes is provided that gives microscopic insight into the polaron effects and hints toward mobility optimization strategies. PMID- 27245401 TI - Neuronal activity in dorsomedial and dorsolateral striatum under the requirement for temporal credit assignment. AB - To investigate neural processes underlying temporal credit assignment in the striatum, we recorded neuronal activity in the dorsomedial and dorsolateral striatum (DMS and DLS, respectively) of rats performing a dynamic foraging task in which a choice has to be remembered until its outcome is revealed for correct credit assignment. Choice signals appeared sequentially, initially in the DMS and then in the DLS, and they were combined with action value and reward signals in the DLS when choice outcome was revealed. Unlike in conventional dynamic foraging tasks, neural signals for chosen value were elevated in neither brain structure. These results suggest that dynamics of striatal neural signals related to evaluating choice outcome might differ drastically depending on the requirement for temporal credit assignment. In a behavioral context requiring temporal credit assignment, the DLS, but not the DMS, might be in charge of updating the value of chosen action by integrating choice, action value, and reward signals together. PMID- 27245403 TI - Multinuclear Solid-State NMR Investigation of Hexaniobate and Hexatantalate Compounds. AB - This work determines the potential of solid-state NMR techniques to probe proton, alkali, and niobium environments in Lindqvist salts. Na7HNb6O19.15H2O (1), K8Nb6O19.16H2O (2), and Na8Ta6O19.24.5H2O (3) have been studied by solid-state static and magic angle spinning (MAS) NMR at high and ultrahigh magnetic field (16.4 and 19.9 T). (1)H MAS NMR was found to be a convenient and straightforward tool to discriminate between protonated and nonprotonated clusters AxH8 xM6O19.nH2O (A = alkali ion; M = Nb, Ta). (93)Nb MAS NMR studies at different fields and MAS rotation frequencies have been performed on 1. For the first time, the contributions of NbO5OMU2H sites were clearly distinguished from those assigned to NbO6 sites in the hexaniobate cluster. The strong broadening of the resonances obtained under MAS was interpreted by combining chemical shift anisotropy (CSA) with quadrupolar effects and by using extensive fitting of the line shapes. In order to obtain the highest accuracy for all NMR parameters (CSA and quadrupolar), (93)Nb WURST QCPMG spectra in the static mode were recorded at 16.4 T for sample 1. The (93)Nb NMR spectra were interpreted in connection with the XRD data available in the literature (i.e., fractional occupancies of the NbO5OMU2H sites). 1D (23)Na MAS and 2D (23)Na 3QMAS NMR studies of 1 revealed several distinct sodium sites. The multiplicity of the sites was again compared to structural details previously obtained by single-crystal X-ray diffraction (XRD) studies. The (23)Na MAS NMR study of 3 confirmed the presence of a much larger distribution of sodium sites in accordance with the 10 sodium sites predicted by XRD. Finally, the effect of Nb/Ta substitutions in 1 was also probed by multinuclear MAS NMR ((1)H, (23)Na, and (93)Nb). PMID- 27245402 TI - Comparative risk for cardiovascular diseases of dipeptidyl peptidase-4 inhibitors vs. sulfonylureas in combination with metformin: Results of a two-phase study. AB - AIMS: The aim was to assess whether the use of additional data from the Disease Management Program (DMP) diabetes mellitus type 2 to minimize the potential for residual confounding will alter the estimated risk of either myocardial infarction, ischemic stroke or heart failure in patients with type 2 diabetes using sulfonylureas compared to dipeptidyl peptidase-4 (DPP-4) inhibitors in addition to metformin based on routine health care data. METHODS: We conducted a nested two-phase case-control study using claims data of one German health insurance from 2004 to 2013 (phase 1) and data of the DMP from 2010 to 2013 (phase 2). Adjusted odds ratios (ORs) for the combined cardiovascular event myocardial infarction, ischemic stroke or heart failure were calculated using a two-phase logistic regression. RESULTS: Phase 1 comprised 3179 patients (289 cases; 2890 controls) and phase 2 comprised 1968 patients (168 cases; 1800 controls). We observed an adjusted OR of 0.83 for the combined cardiovascular event (95% CI: 0.61-1.13). CONCLUSIONS: We observed a non-significantly reduced risk for cardiovascular diseases in patients using DPP-4 inhibitors compared to sulfonylureas in addition to metformin. This finding was not altered by the inclusion of additional information of the DMP in the analysis. However, due to the low power of this study, further studies are needed to reproduce our findings. PMID- 27245405 TI - EDITORIAL RETRACTION. PMID- 27245404 TI - Psychometric Properties of the Portuguese Version of the Coping Health Inventory for Parents (CHIP) of Adolescents With Chronic Illness. AB - Parental coping allows the family of adolescents with chronic illness to manage their daily activities, provide the care that the adolescent needs to control the disease and influence illness adaptation and family wellbeing. This study analyzed the psychometric properties of the Portuguese version of the Coping Health Inventory for Parents (CHIP). METHODS: The sample consisted of 226 parents of adolescents (between 12 and 19years old) with type 1 diabetes, asthma or obesity, diagnosed more than a year ago, who accompanied the teenager during a routine visit. Participants answered the Coping Health Inventory for Parents (CHIP) and Illness Perception Questionnaire ((Brief-IPQ)). RESULTS: The Portuguese version consists of one less item than the original version (44 items) organized in the same three components - Maintaining Family Integration, Maintaining Social Support and Understanding the Medical Situation - with internal consistency of .80, .82 and .76, respectively. The components of parental coping were related to illness perceptions (personal control, treatment control and concerns) in adolescents with type 1 diabetes, revealing that parental coping was associated with a more threatening perception of the illness. No significant differences were observed on parental coping based on the adolescent's gender, parent's gender, age and education level, type of chronic illness, or single versus two parent families except for adolescence stage, showing that parents of younger teenagers presented higher parental coping than parents of older teenagers. CONCLUSION: The Portuguese version of the CHIP showed good psychometric properties to be used with parents of adolescents with chronic illness. PMID- 27245406 TI - [Bilateral renal infarction after discontinuation of anticoagulant therapy]. AB - Acute renal infarction is an uncommon and often under diagnosed condition mostly because of misleading symptoms. Accurate data regarding clinical presentation, laboratory tests, diagnostic and treatment are lacking. Detection is often delayed or missed because of non-specific clinical presentation. The mechanisms of acute renal infarction are various, mainly embolic or thrombotic. Abdominal CT scan remains the most valuable exam to confirm the diagnosis. Therapeutic guidelines for the treatment of renal embolism have not been well established. The standard treatment strategy includes anticoagulation with or without thrombolysis. Despite the uncertainty regarding management, the renal outcome remains favorable. Some patients do develop some degree of renal insufficiency during the acute episode. We report here the case of a 73-year-old woman with bilateral acute renal infarction after discontinuation of anticoagulant therapy. PMID- 27245407 TI - Slipping Rib Syndrome: An elusive diagnosis. AB - Slipping rib syndrome remains rarely recognized and frequently undiagnosed or misdiagnosed. Awareness of this condition may prevent extensive and unnecessary diagnostic evaluation and avoid chronic debilitating pain. Persistent lower chest and/or upper abdomen pain after analgesic treatment may suggest the possibility of this disorder. The diagnosis of this syndrome, is a clinical one, based on history and the hooking maneuver. A few cases have been published in the literature, giving no clear consensus about the treatment of this condition. In this overview article, clinical manifestations, diagnostic approach, and treatment modalities of this syndrome will be discussed. PMID- 27245408 TI - Helicobacter saguini, a Novel Helicobacter Isolated from Cotton-Top Tamarins with Ulcerative Colitis, Has Proinflammatory Properties and Induces Typhlocolitis and Dysplasia in Gnotobiotic IL-10-/- Mice. AB - A urease-negative, fusiform, novel bacterium named Helicobacter saguini was isolated from the intestines and feces of cotton-top tamarins (CTTs) with chronic colitis. Helicobacter sp. was detected in 69% of feces or intestinal samples from 116 CTTs. The draft genome sequence, obtained by Illumina MiSeq sequencing, for H. saguini isolate MIT 97-6194-5, consisting of ~2.9 Mb with a G+C content of 35% and 2,704 genes, was annotated using the NCBI Prokaryotic Genomes Automatic Annotation Pipeline. H. saguini contains homologous genes of known virulence factors found in other enterohepatic helicobacter species (EHS) and H. pylori These include flagellin, gamma-glutamyl transpeptidase (ggt), collagenase, the secreted serine protease htrA, and components of a type VI secretion system, but the genome does not harbor genes for cytolethal distending toxin (cdt). H. saguini MIT 97-6194-5 induced significant levels of interleukin-8 (IL-8) in HT-29 cell culture supernatants by 4 h, which increased through 24 h. mRNAs for the proinflammatory cytokines IL-1beta, tumor necrosis factor alpha (TNF-alpha), IL 10, and IL-6 and the chemokine CXCL1 were upregulated in cocultured HT-29 cells at 4 h compared to levels in control cells. At 3 months postinfection, all H. saguini-monoassociated gnotobiotic C57BL/129 IL-10(-/-) mice were colonized and had seroconverted to H. saguini antigen with a significant Th1-associated increase in IgG2c (P < 0.0001). H. saguini induced a significant typhlocolitis, associated epithelial defects, mucosa-associated lymphoid tissue (MALT) hyperplasia, and dysplasia. Inflammatory cytokines IL-22, IL-17a, IL-1beta, gamma interferon (IFN-gamma), and TNF-alpha, as well as inducible nitric oxide synthase (iNOS) were significantly upregulated in the cecal tissues of infected mice. The expression of the DNA damage response molecule gamma-H2AX was significantly higher in the ceca of H. saguini-infected gnotobiotic mice than in the controls. This model using a nonhuman primate Helicobacter sp. can be used to study the pathogenic potential of EHS isolated from primates with naturally occurring inflammatory bowel disease (IBD) and colon cancer. PMID- 27245409 TI - Interleukin-27 (IL-27) Mediates Susceptibility to Visceral Leishmaniasis by Suppressing the IL-17-Neutrophil Response. AB - The relationship established between Leishmania infantum and the vertebrate host can lead to a self-healing infection or to the manifestation of visceral leishmaniasis, a chronic systemic infection associated with high rates of mortality. We hypothesized that regulatory cytokines, such as interleukin-27 (IL 27), play a role in susceptibility to L. infantum infection. IL-27 is a heterodimeric cytokine composed of IL-27p28 and EBi3 subunits which, when combined, bind to IL-27R, leading to STAT-1 and -3 activation, playing a role in the regulation of the immune response. We observed in this work that IL-27 regulates the Th1/Th17 profiles in a mouse model of visceral leishmaniasis (VL) caused by L. infantum We showed here that the pathogen recognition by endosomal Toll-like receptors triggers a type I interferon (IFN) response, which acts through the type I IFN receptor and interferon regulatory factor 1 to induce IL 27 production by macrophages. Furthermore, IL-27 plays a major regulatory role in vivo, because Ebi3(-/-) mice can efficiently control parasite replication despite reduced levels of IFN-gamma compared to wild-type mice. On the other hand, the absence of Ebi3 leads to exacerbated IL-17A production in the infected organs as well as in a coculture system, suggesting a direct regulatory action of IL-27 during L. infantum infection. As a consequence of exacerbated IL-17A in Ebi3(-/-) mice, a greater neutrophil influx was observed in the target organs, playing a role in parasite control. Thus, this work unveiled the molecular steps of IL-27 production after L. infantum infection and demonstrated its regulatory role in the IL-17A-neutrophil axis. PMID- 27245410 TI - Chemically Attenuated Blood-Stage Plasmodium yoelii Parasites Induce Long-Lived and Strain-Transcending Protection. AB - The development of a vaccine is essential for the elimination of malaria. However, despite many years of effort, a successful vaccine has not been achieved. Most subunit vaccine candidates tested in clinical trials have provided limited efficacy, and thus attenuated whole-parasite vaccines are now receiving close scrutiny. Here, we test chemically attenuated Plasmodium yoelii 17X and demonstrate significant protection following homologous and heterologous blood stage challenge. Protection against blood-stage infection persisted for at least 9 months. Activation of both CD4(+) and CD8(+) T cells was shown after vaccination; however, in vivo studies demonstrated a pivotal role for both CD4(+) T cells and B cells since the absence of either cell type led to loss of vaccine induced protection. In spite of significant activation of circulating CD8(+) T cells, liver-stage immunity was not evident. Neither did vaccine-induced CD8(+) T cells contribute to blood-stage protection; rather, these cells contributed to pathogenesis, since all vaccinated mice depleted of both CD4(+) and CD8(+) T cells survived a challenge infection. This study provides critical insight into whole-parasite vaccine-induced immunity and strong support for testing whole parasite vaccines in humans. PMID- 27245411 TI - A Mutation in the 16S rRNA Decoding Region Attenuates the Virulence of Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis contains a single rRNA operon that encodes targets for antituberculosis agents, including kanamycin. To date, only four mutations in the kanamycin binding sites of 16S rRNA have been reported in kanamycin-resistant clinical isolates. We hypothesized that another mutation(s) in the region may dramatically decrease M. tuberculosis viability and virulence. Here, we describe an rRNA mutation, U1406A, which was generated in vitro and confers resistance to kanamycin while highly attenuating M. tuberculosis virulence. The mutant showed decreased expression of 20% (n = 361) of mycobacterial proteins, including central metabolic enzymes, mycolic acid biosynthesis enzymes, and virulence factors such as antigen 85 complexes and ESAT-6. The mutation also induced three proteins, including KsgA (Rv1010; 16S rRNA adenine dimethyltransferase), which closely bind to the U1406A mutation site on the ribosome; these proteins were associated with ribosome maturation and translation initiation processes. The mutant showed an increase in 17S rRNA (precursor 16S rRNA) and a decrease in the ratio of 30S subunits to the 70S ribosomes, suggesting that the U1406A mutation in 16S rRNA attenuated M. tuberculosis virulence by affecting these processes. PMID- 27245412 TI - Role of Metal-Dependent Regulation of ESX-3 Secretion in Intracellular Survival of Mycobacterium tuberculosis. AB - More people die every year from Mycobacterium tuberculosis infection than from infection by any other bacterial pathogen. Type VII secretion systems (T7SS) are used by both environmental and pathogenic mycobacteria to secrete proteins across their complex cell envelope. In the nonpathogen Mycobacterium smegmatis, the ESX 1 T7SS plays a role in conjugation, and the ESX-3 T7SS is involved in metal homeostasis. In M. tuberculosis, these secretion systems have taken on roles in virulence, and they also are targets of the host immune response. ESX-3 secretes a heterodimer composed of EsxG (TB9.8) and EsxH (TB10.4), which impairs phagosome maturation in macrophages and is essential for virulence in mice. Given the importance of EsxG and EsxH during infection, we examined their regulation. With M. tuberculosis, the secretion of EsxG and EsxH was regulated in response to iron and zinc, in accordance with the previously described transcriptional response of the esx-3 locus to these metals. While iron regulated the esx-3 expression in both M. tuberculosis and M. smegmatis, there is a significant difference in the dynamics of this regulation. In M. smegmatis, the esx-3 locus behaved like other iron-regulated genes such as mbtB In M. tuberculosis, both iron and zinc modestly repressed esx-3 expression. Diminished secretion of EsxG and EsxH in response to these metals altered the interaction of M. tuberculosis with macrophages, leading to impaired intracellular M. tuberculosis survival. Our findings detail the regulatory differences of esx-3 in M. tuberculosis and M. smegmatis and demonstrate the importance of metal-dependent regulation of ESX-3 for virulence in M. tuberculosis. PMID- 27245413 TI - Fecal Indole as a Biomarker of Susceptibility to Cryptosporidium Infection. AB - Cryptosporidium causes significant diarrhea worldwide, especially among children and immunocompromised individuals, and no effective drug treatment is currently available for those who need it most. In this report, previous volunteer infectivity studies have been extended to examine the association between fecal indole and indole-producing (IP) gut microbiota on the outcome of a Cryptosporidium infection. Fecal indole concentrations (FICs) of 50 subjects and 19 taxa of common gut microbiota, including six IP taxa (11 subjects) were determined in stool samples collected before and after a challenge with Cryptosporidium oocysts. At the baseline, the mean FIC (+/- the standard deviation) was 1.66 +/- 0.80 mM in those who became infected after a challenge versus 3.20 +/- 1.23 mM in those who remained uninfected (P = 0.0001). Only 11.1% of the subjects with a FIC of >2.5 mM became infected after a challenge versus 65.2% of the subjects with a FIC of <2.5 mM. In contrast, the FICs of infected subjects at the baseline or during diarrhea were not correlated with infection intensity or disease severity. The relative abundances (percent) of Escherichia coli, Bacillus spp., and Clostridium spp. were greater >=2.5-fold in volunteers with a baseline FIC of >2.5 mM, while those of Bacteroides pyogenes, B. fragilis, and Akkermansia muciniphila were greater in those with a baseline FIC of <2.5 mM. These data indicate that some IP bacteria, or perhaps indole alone, can influence the ability of Cryptosporidium to establish an infection. Thus, preexisting indole levels in the gut join the oocyst dose and immune status as important factors that determine the outcome of Cryptosporidium exposure. PMID- 27245414 TI - Routine venous thromboembolism screening after pneumonectomy: The more you look, the more you see. AB - OBJECTIVES: Symptomatic venous thromboembolism (VTE) after pneumonectomy is associated with poor prognosis. We describe a new care pathway for patients undergoing pneumonectomy in which asymptomatic lower-extremity VTE screening was performed to determine if it increases VTE detection and potentially decreases sequelae. METHODS: 112 patients underwent pneumonectomy from 2006 to 2013 at Cleveland Clinic and were enrolled in a care pathway that included VTE prophylaxis and routine, predischarge, lower-extremity VTE screening. These data were contrasted with a previously published cohort of 336 patients (1990-2001) who underwent pneumonectomy without routine VTE screening. RESULTS: 10 of 112 patients (8.9%) had VTE detected by screening before discharge. An additional 4 patients (3.6%) with a negative predischarge screen developed symptomatic VTE within 30 days. Six patients (5.4%) developed VTE after pneumonectomy beyond the first 30 days. Prevalence of in-hospital VTE in the screened cohort was significantly higher than that of the non-screened cohort (3.0%; P = .008). Similarly, VTE within 30 days in the screened cohort (13%) was significantly higher than in the nonscreened cohort (5.0%; P = .007). In both cohorts, a peak was observed approximately 6 days after pneumonectomy and plateaued after 30 days. The presence of a VTE portended worse long-term survival: 66% at 1 year versus 85% for those not developing a VTE. CONCLUSIONS: Prevalence of VTE after pneumonectomy is higher than previously thought. The risk of developing a VTE peaks at 6 days after pneumonectomy, and remains increased until 30 days, suggesting a need for additional screening or longer prophylaxis. PMID- 27245415 TI - Discussion. PMID- 27245416 TI - Impact of standardization of antimicrobial prophylaxis duration in pediatric cardiac surgery. AB - OBJECTIVES: The optimal duration of antimicrobial prophylaxis following pediatric cardiac surgery is still debated. Adult studies suggest that shorter durations are adequate, but there is a paucity of data on pediatric patients. METHODS: This quasi-experimental study reviewed the charts of patients 18 years and younger who underwent cardiac surgery from April 2011 to November 2014 at a single institution. Starting in April 2013, a protocol was implemented to limit antimicrobial prophylaxis to 48 hours following sternal closure. Two analyses were performed: (1) identification of risk factors for surgical site infections from the entire cohort, and (2) comparison of surgical site infection incidence in the pre- and postprotocol groups. RESULTS: In the entire cohort, delayed sternal closure (adjusted odds ratio [OR], 5.7; 95% confidence interval [CI], 1.8 17.9) and younger age (adjusted OR, 2.1; 95% CI, 1.1-3.8) were associated with incidence of surgical site infection. Following the protocol change, duration of antimicrobial prophylaxis decreased from 4.2 +/- 2.7 to 1.9 +/- 1.3 days (P < .0001). After adjusting for age and delayed sternal closure, the postprotocol group had an adjusted OR of 0.98 (95% CI, 0.32-3.00) for occurrence of surgical site infection. Other outcomes were not altered following the protocol change. CONCLUSIONS: Restricting antimicrobial prophylaxis to 48 hours following pediatric cardiac surgery did not increase the incidence of surgical site infection at our institution. Further study is needed to validate this finding and to identify practices that reduce surgical site infections in those with delayed sternal closure. PMID- 27245417 TI - Extended criteria donors: Closer to the truth. PMID- 27245418 TI - Outcomes of surgical repair of pediatric coronary artery fistulas. AB - OBJECTIVE: Isolated congenital coronary artery fistula is a rare condition, and the surgical experience for treating this condition is limited. METHODS: This was a retrospective review of 47 patients who underwent surgical repair of isolated congenital coronary artery fistula from January 2001 to March 2015. RESULTS: All but 1 patient presented with no symptoms. The median age at operation was 3.9 years (range, 0.4-15.2 years), and the median weight was 15.2 kg (range, 6.3-77.0 kg). Right coronary artery to right ventricle fistula was the most common pattern, which was present in 16 patients. Epicardial ligation without cardiopulmonary bypass was used to treat 4 patients, whereas cardiopulmonary bypass was used in the remaining 43 patients. Surgical techniques included transcoronary closure in 20 patients, transcameral or transpulmonary closure in 20 patients, a combination of both transcameral and transcoronary closure in 2 patients, and a conversion from transcameral closure to epicardial ligation in 1 patient. There were no deaths during our study period. Injury to the mitral valve occurred in 1 patient. Residual shunt was observed in 8 patients, 2 of which closed spontaneously during the follow-up. Extracardiac repair was associated with a higher risk of recanalization (P = .004). Freedom from recanalization was 89.4%, 85.1%, 83.0%, and 83.0% at discharge, 6 months, 1 year, and 5 years postsurgery, respectively. Two patients required transcatheter closure for residual shunts. CONCLUSIONS: Surgical repair of isolated congenital coronary artery fistula in pediatric patients can be performed with low mortality and morbidity. Careful evaluation after surgery is necessary to monitor the occurrence of residual shunt. PMID- 27245419 TI - Herpes zoster: Risk and prevention during immunomodulating therapy. AB - Herpes zoster can be serious or incapacitating, particularly in patients whose immune system is compromised by a disease or treatment. Immunomodulating drugs can increase the risk of infection. Well-established risk factors include advanced age and glucocorticoid therapy. The data are somewhat conflicting for medications such as methotrexate, tofacitinib, TNFalpha antagonists (infliximab, adalimumab, etanercept, certolizumab, and golimumab), abatacept, tocilizumab, and rituximab. Nevertheless, the risk of herpes zoster is increased in patients taking biological agents, because of the underlying diseases and/or effects of the drugs. A live attenuated herpes zoster vaccine has been proven effective and safe in immunocompetent individuals. At present, however, it is not recommended for patients with immunodeficiencies, including those taking biological drugs, as no studies have assessed its risk/benefit ratio in this population. This situation may change in the near future, as recent data support the effectiveness and safety of the herpes zoster vaccine in patients who take biotherapies or have other causes of immunodeficiency. Alternative approaches designed to protect these patients from herpes zoster and its complications are also under evaluation. There is a need to define the indications of the herpes zoster vaccine in terms of the target population, timing, modalities, and frequency, according to the underlying chronic systemic disease, age group, varicella-zoster virus status, and exposure to therapeutic agents. PMID- 27245420 TI - PKD3 deficiency causes alterations in microtubule dynamics during the cell cycle. AB - Protein kinase D 3 (PKD3) is a member of the PKD family that has been linked to many intracellular signaling pathways. However, defined statements regarding isoform specificity and in vivo functions are rare. Here, we use mouse embryonic fibroblast cells that are genetically depleted of PKD3 to identify isoform specific functions. We show that PKD3 is involved in the regulation of the cell cycle by modulating microtubule nucleation and dynamics. In addition we also show that PKD1 partially can compensate for PKD3 function. Taken together our data provide new insights of a specific PKD3 signaling pathway by identifying a new function, which has not been identified before. PMID- 27245421 TI - Stanniocalcin 2 induces oxaliplatin resistance in colorectal cancer cells by upregulating P-glycoprotein. AB - Multidrug resistance (MDR) limits the anticancer effects of chemotherapy in patients with metastatic colorectal cancer (CRC). Oxaliplatin is a common component of combinational therapeutic regimens administered to patients with metastatic CRC; however, it is also used as a constituent of adjuvant therapy for patients at a risk of recurrent disease. In the present study, we investigated the role of stanniocalcin 2 (STC2) in chemoresistance. STC2 knockdown sensitized chemoresistant CRC cells to oxaliplatin. Moreover, the expression of exogenous STC2 in chemonaive CRC cells induced oxaliplatin resistance. We confirmed that STC2 upregulated P-glycoprotein (P-gp) expression in CRC cells. Furthermore, shRNA against phosphoinositide 3-kinase (PI3K) or Akt inhibited the action of STC2 on P-gp upregulation and MDR in CRC. To our knowledge, this is the first report to demonstrate the induction of oxaliplatin resistance in CRC cells in response to STC2 stimulation of P-gp via the PI3K/Akt signaling pathway. PMID- 27245422 TI - A powerful test of independent assortment that determines genome-wide significance quickly and accurately. AB - In the analysis of DNA sequences on related individuals, most methods strive to incorporate as much information as possible, with little or no attention paid to the issue of statistical significance. For example, a modern workstation can easily handle the computations needed to perform a large-scale genome-wide inheritance-by-descent (IBD) scan, but accurate assessment of the significance of that scan is often hindered by inaccurate approximations and computationally intensive simulation. To address these issues, we developed gLOD-a test of co segregation that, for large samples, models chromosome-specific IBD statistics as a collection of stationary Gaussian processes. With this simple model, the parametric bootstrap yields an accurate and rapid assessment of significance-the genome-wide corrected P-value. Furthermore, we show that (i) under the null hypothesis, the limiting distribution of the gLOD is the standard Gumbel distribution; (ii) our parametric bootstrap simulator is approximately 40 000 times faster than gene-dropping methods, and it is more powerful than methods that approximate the adjusted P-value; and, (iii) the gLOD has the same statistical power as the widely used maximum Kong and Cox LOD. Thus, our approach gives researchers the ability to determine quickly and accurately the significance of most large-scale IBD scans, which may contain multiple traits, thousands of families and tens of thousands of DNA sequences. PMID- 27245423 TI - Introgression of chromosome segments from multiple alien species in wheat breeding lines with wheat streak mosaic virus resistance. AB - Pyramiding of alien-derived Wheat streak mosaic virus (WSMV) resistance and resistance enhancing genes in wheat is a cost-effective and environmentally safe strategy for disease control. PCR-based markers and cytogenetic analysis with genomic in situ hybridisation were applied to identify alien chromatin in four genetically diverse populations of wheat (Triticum aestivum) lines incorporating chromosome segments from Thinopyrum intermedium and Secale cereale (rye). Out of 20 experimental lines, 10 carried Th. intermedium chromatin as T4DL*4Ai#2S translocations, while, unexpectedly, 7 lines were positive for alien chromatin (Th. intermedium or rye) on chromosome 1B. The newly described rye 1RS chromatin, transmitted from early in the pedigree, was associated with enhanced WSMV resistance. Under field conditions, the 1RS chromatin alone showed some resistance, while together with the Th. intermedium 4Ai#2S offered superior resistance to that demonstrated by the known resistant cultivar Mace. Most alien wheat lines carry whole chromosome arms, and it is notable that these lines showed intra-arm recombination within the 1BS arm. The translocation breakpoints between 1BS and alien chromatin fell in three categories: (i) at or near to the centromere, (ii) intercalary between markers UL-Thin5 and Xgwm1130 and (iii) towards the telomere between Xgwm0911 and Xbarc194. Labelled genomic Th. intermedium DNA hybridised to the rye 1RS chromatin under high stringency conditions, indicating the presence of shared tandem repeats among the cereals. The novel small alien fragments may explain the difficulty in developing well adapted lines carrying Wsm1 despite improved tolerance to the virus. The results will facilitate directed chromosome engineering producing agronomically desirable WSMV-resistant germplasm. PMID- 27245424 TI - Immunoprecipitation. AB - Selective immunoprecipitation of proteins is a useful tool for characterizing proteins and protein-protein interactions. Clear step-by-step protocols are provided for preparing lysates of cells and yeast under a variety of conditions, for binding the antibody to a solid matrix, and for performing the actual immunoprecipitation. An additional method is provided for increasing the specificity of the technique by reprecipitating the antigen with the same or a different antibody. (c) 2016 by John Wiley & Sons, Inc. PMID- 27245425 TI - Preparation of Extracellular Matrices Produced by Cultured and Primary Fibroblasts. AB - Fibroblasts secrete and organize extracellular matrix (ECM), which provides structural support for their adhesion, migration, and tissue organization, besides regulating cellular functions such as growth and survival. Cell-to-matrix interactions are vital for vertebrate development. Disorders in these processes have been associated with fibrosis, developmental malformations, cancer, and other diseases. This unit describes a method for preparing a three-dimensional matrix derived from fibroblastic cells; the matrix is three-dimensional, cell and debris free, and attached to a two-dimensional culture surface. Cell adhesion and spreading are normal on these matrices. This matrix can also be compressed into a two-dimensional matrix and solubilized to study the matrix biochemically. (c) 2016 by John Wiley & Sons, Inc. PMID- 27245426 TI - Use of In Situ Proximity Ligation Assays for Systems Analysis of Signaling Pathways. AB - Understanding signaling pathway networks via protein-protein interactions (PPIs) at the cellular level is a significant task that has not yet been completed. Here, a systems approach that computationally infers interlinked pathways from numerous PPIs is described. The endogenous PPIs can be empirically detected using an in situ proximity ligation assay (PLA), which detects and visualizes endogenous PPIs and post-translational modifications of proteins with a high sensitivity and specificity. This unit includes two parts: (1) conversion of gene lists into PPIs for investigation and (2) large-scale detection and analysis of endogenous PPIs for elucidating pathway networks. (c) 2016 by John Wiley & Sons, Inc. PMID- 27245427 TI - Fluorescent Detection of Lipid Droplets and Associated Proteins. AB - Excess lipid is stored in intracellular organelles known as lipid droplets. This unit discusses techniques for the visualization of lipid droplets and associated proteins in cultured mammalian cells. Protocols for the detection of lipid droplets in fixed or live cells with BODIPY 493/503 are included. The best method for combining visualization of intracellular lipid droplets with indirect immunofluorescent detection of lipid droplet-associated proteins is described. Techniques for sample fixation and permeabilization must be chosen carefully to avoid alterations to lipid droplet morphology. Immunofluorescent detection of perilipin 2, a broadly expressed, lipid droplet-associated protein, widely used as a marker for lipid droplet accumulation, is presented as an example. Finally, a simple protocol for enhancing lipid droplet accumulation through supplementation with excess fatty acid is included. (c) 2016 by John Wiley & Sons, Inc. PMID- 27245428 TI - Release of bioactive peptides from polyurethane films in vitro and in vivo: Effect of polymer composition. AB - Thermoplastic polyurethanes (TPUs) are widely used in biomedical applications due to their excellent biocompatibility. Their role as matrices for the delivery of small molecule therapeutics has been widely reported. However, very little is known about the release of bioactive peptides from this class of polymers. Here, we report the release of linear and cyclic peptides from TPUs with different hard and soft segments. Solvent casting of the TPU at room temperature mixed with the different peptides resulted in reproducible efflux profiles with no evidence of drug degradation. Peptide release was dependent on the size as well as the composition of the TPU. Tecoflex 80A (T80A) showed more extensive release than ElastEon 5-325, which correlated with a degree of hydration. It was also shown that the composition of the medium influenced the rate and extent of peptide efflux. Blending the different TPUs allowed for better control of peptide efflux, especially the initial burst effect. Peptide-loaded TPU prolonged the plasma levels of the anti-inflammatory cyclic peptide PMX53, which normally has a plasma half-life of less than 30min. Using a blend of T80A and E5-325, therapeutic plasma levels of PMX53 were observed up to 9days following a single intraperitoneal implantation of the drug-loaded film. PMX53 released from the blended TPUs significantly inhibited B16-F10 melanoma tumor growth in mice demonstrating its bioactivity in vivo. This study provides important findings for TPU-based therapeutic peptide delivery that could improve the pharmacological utility of peptides as therapeutics. STATEMENT OF SIGNIFICANCE: Therapeutic peptides can be highly specific and potent pharmacological agents, but are poorly absorbed and rapidly degraded in the body. This can be overcome by using a matrix that protects the peptide in vivo and promotes its slow release so that a therapeutic effect can be achieved over days or weeks. Thermoplastic polyurethanes are a versatile family of polymers that are biocompatible and used for medical implants. Here, the release of several peptides from a range of polyurethanes was shown to depend on the type of polymer used in the polyurethane. This is the first study to examine polyurethane blends for peptide delivery and shows that the rate and extent of peptide release can be fine-tuned using different hard and soft segment mixtures in the polymer. PMID- 27245429 TI - Enhanced cell survival of pH-sensitive bioenergetic nucleotide nanoparticles in energy/oxygen-depleted cells and their intranasal delivery for reduced brain infarction. AB - Nucleotides (NTs) (e.g., adenosine triphosphate) are very important molecules in the body. They generate bioenergy through phosphate group release, are involved in various biological processes, and are used to treat various diseases that involve energy depletion. However, their highly anionic characteristics might limit delivery of exogenous NTs into the cell, which is required to realize their functions as bioenergy sources. In this study, ionic complexation between Ca(2+) and NT phosphates was used to form Ca(2+)/NT nanocomplexes (NCs), and branched polyethyleneimine (bPEI1.8kDa) was coated on the surface of Ca(2+)/NT NCs via a simple electrostatic coating. The resultant Ca(2+)/NT/bPEI1.8kDa NCs were approximately 10-25nm in size and had positive zeta-potentials, and their NT loading efficiency and content were approximately 60-75% and 10-20 wt%, respectively. Faster NT release from Ca(2+)/NT/bPEI1.8kDa NCs was induced by lower pH and by NTs with fewer phosphates. Reductions in cell viability in response to low temperature, serum deprivation, or hypoxia were recovered by NT delivery in Ca(2+)/NT/bPEI1.8kDa NCs. In a middle cerebral artery occlusion (MCAO)-induced post-ischemic rat model, the BBB (blood brain barrier)-detoured intranasal administration of Ca(2+)/ATP/bPEI1.8kDa NCs induced a better reduction in infarct volume and neurological deficits than did free ATP. In conclusion, intracellular NT delivery using Ca(2+)/NT/bPEI1.8kDa NCs might potentially enhance cell survival and reduce infarction in energy-/oxygen-depleted environments. STATEMENT OF SIGNIFICANCE: This study describes bioenergetic nucleotide delivery systems and their preparation, physicochemical characterization, and biological characterization both in vitro and in vivo. Nucleotides, such as adenosine triphosphate (ATP) and guanosine triphosphate (GTP), are very important signaling and energy molecules in the body. However, research on these nucleotides using nanosized carriers has been very limited. Liposomal ATP delivery has been reported in heart and renal ischemia studies. Notably, although this delivery system has potential in energy-depleted environments (e.g., low temperature, serum deprivation, and hypoxia) and in brain ischemia, studies are lacking regarding these systems. Thus, we designed polycation-shielded Ca(2+)/nucleotide nanocomplexes using simple mixing, which produced 10- to 25-nm-sized particles. The nanocomplexes released nucleotides in response to acidic pH, and they enhanced cell survival rates under conditions of low temperature, serum deprivation, or hypoxia. Importantly, the nanocomplexes reduced cerebral infarct volumes in a post-ischemic rat model. Thus, our study demonstrates that a novel nucleotide nanocomplex could have potential for preventing or treating diseases that involve energy depletion, such as cardiac, cerebral, and retinal ischemia, and liver failure. PMID- 27245430 TI - Hepatocyte vitamin D receptor regulates lipid metabolism and mediates experimental diet-induced steatosis. AB - BACKGROUND & AIMS: The pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD) is still incompletely understood. Several nuclear receptors play a role in liver lipid metabolism and can promote hepatosteatosis, but the possible role of vitamin D receptor (VDR) in NAFLD has not been investigated. METHODS: The expression of liver VDR was investigated in apolipoprotein E knockout (apoE(-/-)) mice on a high fat diet, in wild-type mice on methionine and choline deficient diet and in NAFLD patients with hepatosteatosis and non alcoholic steatohepatitis. The relevance of VDR was assessed in apoE(-/-) mice by deletion of VDR or paricalcitol treatment and in human HepG2 cells by VDR transfection or silencing. The role of VDR in fibrosis was also determined in VDR knockout mice (VDR(-/-)) treated with thioacetamide. RESULTS: Expression of liver VDR was markedly induced in two mouse models of NAFLD, as well as in patients with hepatosteatosis, but decreased in non-alcoholic steatohepatitis. VDR deletion in high fat diet-fed apoE(-/-) mice protected against fatty liver, dyslipidemia and insulin resistance, and caused a decrease in taurine-conjugated bile acids, but did not influence fibrosis by thioacetamide. apoE(-/-)VDR(-/-) mouse livers showed decreased gene expression of CD36, DGAT2, C/EBPalpha and FGF21, and increased expression of PNPLA2, LIPIN1 and PGC1alpha. Treatment of apoE(-/-) mice on high fat diet with paricalcitol had modest opposite effects on steatosis and gene expression. Finally, this set of genes showed concordant responses when VDR was overexpressed or silenced in HepG2 cells. CONCLUSIONS: Induced hepatocyte VDR in NAFLD regulates key hepatic lipid metabolism genes and promotes high fat diet-associated liver steatosis. Therapeutic inhibition of liver VDR may reverse steatosis in early NAFLD. LAY SUMMARY: The amount of vitamin D receptor is induced early in the livers of mice and humans when they develop non-alcoholic fatty liver disease. If the gene for the vitamin D receptor is deleted, hepatic lipid metabolism changes and mice do not accumulate fat in the liver. We conclude that the vitamin D receptor can contribute to the fatty liver disease promoted by a high fat diet. PMID- 27245431 TI - Serum hepatitis B virus RNA is encapsidated pregenome RNA that may be associated with persistence of viral infection and rebound. AB - BACKGROUND & AIMS: Hepatitis B virus (HBV) RNA in serum has recently been linked to efficacy and prognosis of chronic hepatitis B (CHB) treatment. This study explored the nature, origin, underlying mechanisms, and potential clinical significance of serum HBV RNA. METHODS: The levels of HBV DNA and RNA were determined in the supernatant of induced HepAD38, HBV-expressing HepG2.2.15 cells and primary human hepatocytes (PHH), and in the serum of transgenic mice and CHB patients. NP-40 and proteinase K treatment, sucrose density gradient centrifugation, electron microscopy, northern blot, multiple identification PCRs and 5' rapid-amplification of cDNA ends were performed to identify the nature of serum HBV RNA. RESULTS: Although significantly lower than HBV DNA levels, abundant HBV RNA was present in the serum of CHB patients. A series of experiments demonstrated that serum HBV RNA was pregenome RNA (pgRNA) and present in virus-like particles. HBV pgRNA virion levels increased after blocking the reverse transcription activity of HBV DNA polymerase, and decreased after blocking the encapsidation of pgRNA. Furthermore, the presence of HBV pgRNA virion was associated with risk of viral rebound after discontinuation of nucleot(s)ide analogues (NAs) therapy in CHB patients. CONCLUSIONS: Serum HBV RNA was confirmed to be pgRNA present in virus-like particles. HBV pgRNA virions were produced from encapsidated particles in which the pgRNA was non- or partially reverse transcribed. Clinically, HBV pgRNA virion might be a potential biomarker for monitoring safe discontinuation of NA-therapy. LAY SUMMARY: HBV may have another virion form in which the nucleic acid is composed of RNA, not DNA. The level of HBV RNA virion in serum may be associated with risk of HBV viral rebound after withdrawal of treatment, and therefore, a potential predictive biomarker to monitor the safe discontinuation of nucleot(s)ide analogues-therapy. PMID- 27245432 TI - Senescence in chronic liver disease: Is the future in aging? AB - Cellular senescence is a fundamental, complex mechanism with an important protective role present from embryogenesis to late life across all species. It limits the proliferative potential of damaged cells thus protecting against malignant change, but at the expense of substantial alterations to the microenvironment and tissue homeostasis, driving inflammation, fibrosis and paradoxically, malignant disease if the process is sustained. Cellular senescence has attracted considerable recent interest with recognition of pathways linking aging, malignancy and insulin resistance and the current focus on therapeutic interventions to extend health-span. There are major implications for hepatology in the field of fibrosis and cancer, where cellular senescence of hepatocytes, cholangiocytes, stellate cells and immune cells has been implicated in chronic liver disease progression. This review focuses on cellular senescence in chronic liver disease and explores therapeutic opportunities. PMID- 27245434 TI - Corrigendum: Direct Synthesis of Novel and Reactive Sulfide-modified Nano Iron through Nanoparticle Seeding for Improved Cadmium-Contaminated Water Treatment. PMID- 27245433 TI - CXCL10/CXCR3 signaling mobilized-regulatory T cells promote liver tumor recurrence after transplantation. AB - BACKGROUND & AIMS: Liver graft injury and tumor recurrence are the major challenges of liver transplantation for the patients with hepatocellular carcinoma (HCC). Here, we aimed to explore the role and mechanism of liver graft injury mobilizing regulatory T cells (Tregs), which lead to late phase tumor recurrence after liver transplantation. METHODS: The correlation among tumor recurrence, liver graft injury and Tregs mobilization were studied in 257 liver transplant recipients with HCC and orthotopic rat liver transplantation models. The direct roles of CXCL10/CXCR3 signaling on Tregs mobilization and tumor recurrence were investigated in CXCL10-/- and CXCR3-/- mice models with hepatic IR injury. RESULTS: Clinically, patients received the graft with graft weight ratio (GWR) <60% had higher HCC recurrence after liver transplantation than the recipients with GWR ?60% graft. More circulating Tregs and higher intragraft TLR4/CXCL10/CXCR3 levels were detected in recipients with GWR <60% graft. These results were further validated in rat transplantation model. Foxp3+ cells and expressions of TLR4, CXCL10, TGFbeta, CTLA-4 and CD274 were increased in rat liver tumor tissues from small-for-size graft group. In mouse model, the mobilization and recruitment of Tregs were decreased in TLR4-/-, CXCL10-/- and CXCR3-/- mice compared to wild-type mice. Moreover, less CXCR3+ Tregs were recruited into liver in CXCL10-/- mice after hepatic IR injury. The knockout of CXCL10 and depletion of Tregs inhibited tumor recurrence after hepatic IR injury. CONCLUSION: CXCL10/CXCR3 signaling upregulated at liver graft injury directly induced the mobilization and intragraft recruitment of Tregs, which further promoted HCC recurrence after transplantation. LAY SUMMARY: There were positive correlation among tumor recurrence, circulating Tregs and liver graft injury after human transplantation for HCC patients. The knockout of CXCL10 decreased hepatic recruitment of CXCR3+ Tregs and late phase tumor recurrence after hepatic IR injury. PMID- 27245435 TI - Bound States in the Continuum in double layer structures. AB - We have theoretically investigated the reflectivity spectrums of single- and double-layer photonic crystal slabs and the dielectric multilayer stack. It is shown that light can be perfectly confined in a single-layer photonic crystal slab at a given incident angle by changing the thickness, permittivity or hole radius of the structure. With a tunable double-layer photonic crystal slab, we demonstrate that the occurrence of tunable bound states in the continuum is dependent on the spacing between two slabs. Moreover, by analytically investigating the Drude lossless multilayer stack model, the spacing dependence of bound states in the continuum is characterized as the phase matching condition that illuminates these states can occur at any nonzero incident angles by adjusting the spacing. PMID- 27245436 TI - Whole-exome identifies RXRG and TH germline variants in familial isolated prolactinoma. AB - Familial isolated pituitary adenoma (FIPA) is a rare genetic disorder. In a subset of FIPA families AIP germline mutations have been reported, but in most FIPA cases the exact genetic defect remains unknown. The present study aimed to determine the genetic basis of FIPA in a Brazilian family. Three siblings presented with isolated prolactin genes. Further mutation screening was performed using whole-exome sequencing and all likely causative mutations were validated by Sanger sequencing. In silico analysis and secreting pituitary adenoma diagnosed through clinical, biochemical and imaging testing. Sanger sequencing was used to genotype candidate prolactinoma-mutated additional predictive algorithms were applied to prioritize likely pathogenic variants. No mutations in the coding and flanking intronic regions in the MEN1, AIP and PRLR genes were detected. Whole exome sequencing of three affected siblings revealed novel, predicted damaging, heterozygous variants in three different genes: RXRG, REXO4 and TH. In conclusion, the RXRG and TH possibly pathogenic variants may be associated with isolated prolactinoma in the studied family. The possible contribution of these genes to additional FIPA families should be explored. PMID- 27245438 TI - Synthesis of annulated pyridines as inhibitors of aldosterone synthase (CYP11B2). AB - A series of cyclopenta[c]pyridine aldosterone synthase (AS) inhibitors were conveniently accessed using batch or continuous flow Kondrat'eva reactions. Preparation of the analogous cyclohexa[c]pyridines led to the identification of a potent and more selective AS inhibitor. The structure-activity-relationship (SAR) in this new series was rationalized using binding mode models in the crystal structure of AS. PMID- 27245437 TI - Stemness and chemoresistance in epithelial ovarian carcinoma cells under shear stress. AB - One of greatest challenges to the successful treatment of cancer is drug resistance. An exciting approach is the eradication of cancer stem cells (CSCs). However, little is known about key signals regulating the formation and expansion of CSCs. Moreover, lack of a reliable predictive preclinical model has been a major obstacle to discover new cancer drugs and predict their clinical activity. Here, in ovarian cancer, a highly chemoresistant tumor that is rapidly fatal, we provide the first evidence demonstrating the causal involvement of mechanical stimulus in the CSC phenotype using a customizable microfluidic platform and three-dimensional spheroids, which most closely mimic tumor behavior. We found that ovarian cancer cells significantly acquired the expression of epithelial-to mesenchymal transition and CSC markers and a remarkable chemoresistance to clinically relevant doses of frontline chemotherapeutic drugs cisplatin and paclitaxel when grown under fluid shear stress, which corroborates with the physiological attainable levels in the malignant ascites, but not under static condition. Furthermore, we uncovered a new link of microRNA-199a-3p, phosphatidylinositol 3-kinase/Akt, and multidrug transporter activation in shear stress-induced CSC enrichment. Our findings shed new light on the significance of hydrodynamics in cancer progression, emphasizing the need of a flow-informed framework in the development of therapeutics. PMID- 27245439 TI - Reduced levels of alpha-1-antitrypsin in cerebrospinal fluid of amyotrophic lateral sclerosis patients: a novel approach for a potential treatment. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative motor neuron disease that involves activation of the immune system and inflammatory response in the nervous system. Reduced level of the immuno modulatory and anti-inflammatory protein alpha-1-antitrypsin (AAT) is associated with inflammation-related pathologies. The objective of the present is to determine AAT levels and IL-23 in the cerebrospinal fluid (CSF) of ALS patients and control group. FINDINGS: CSF samples from newly diagnosed ALS patients and age-matched controls were analyzed for AAT and IL-23 by ELISA and magnetic luminex screening, respectively. A statistically significant reduction of 45 % in mean AAT levels was observed in the CSF of ALS patients (21.4 MUg/ml) as compared to the control group (mean 38.8 MUg/ml, p = 0.013). A statistically significant increase of 30.8 % in CSF mean levels of the pro-inflammatory cytokine IL-23 was observed in ALS patients (1647 pg/ml) in comparison to the controls (1259 pg/ml, p = 0.012). A negative correlation coefficient (r = -0.543) was obtained by linear regression analysis of the two measured parameters (p = 0.036). CONCLUSIONS: Reduced AAT and elevated IL-23 CSF levels support the notion of neuroinflammatory process occurring in ALS patients. Increasing AAT levels in the patients' nervous system should be further investigated as a new therapeutic approach and a novel potential tool for ALS treatment. PMID- 27245440 TI - Truncating CHRNG mutations associated with interfamilial variability of the severity of the Escobar variant of multiple pterygium syndrome. AB - BACKGROUND: In humans, muscle-specific nicotinergic acetylcholine receptor (AChR) is a transmembrane protein with five different subunits, coded by CHRNA1, CHRNB, CHRND and CHRNG/CHRNE. The gamma subunit of AChR encoded by CHRNG is expressed during early foetal development, whereas in the adult, the gamma subunit is replaced by a epsilon subunit. Mutations in the CHRNG encoding the embryonal acetylcholine receptor may cause the non-lethal Escobar variant (EVMPS) and lethal form (LMPS) of multiple pterygium syndrome. The MPS is a condition characterised by prenatal growth failure with pterygium and akinesia leading to muscle weakness and severe congenital contractures, as well as scoliosis. RESULTS: Our whole exome sequencing studies have identified one novel and two previously reported homozygous mutations in CHRNG in three families affected by non-lethal EVMPS. The mutations consist of deletion of two nucleotides, cause a frameshift predicted to result in premature termination of the foetally expressed gamma subunit of the AChR. CONCLUSIONS: Our data suggest that severity of the phenotype varies significantly both within and between families with MPS and that there is no apparent correlation between mutation position and clinical phenotype. Although individuals with CHRNG mutations can survive, there is an increased frequency of abortions and stillbirth in their families. Furthermore, genetic background and environmental modifiers might be of significance for decisiveness of the lethal spectrum, rather than the state of the mutation per se. Detailed clinical examination of our patients further indicates the changing phenotype from infancy to childhood. PMID- 27245441 TI - Dysuria due to discospondylitis and intervertebral disc herniation in a male alpaca (Vicugna pacos). AB - BACKGROUND: Dysuria in camelids is usually associated with the presence of lower urinary tract disease such as urolithiasis. As another differential diagnosis, urine retention may be caused by neurological disturbances resulting from infections of the spinal cord, discospondylitis or trauma. CASE PRESENTATION: A 2.5-year-old male Huacaya alpaca (Vicugna pacos) presented with dysuria due to damage of the lumbosacral intumescence of the spinal cord. On presentation the alpaca was recumbent. Clinical examination revealed abdominal pain, oliguria, leucopenia with neutrophilia, and slightly elevated creatinine kinase. Ultrasonography of the abdomen showed an irregularly shaped, dilated urinary bladder with hyperechoic serosa. Magnetic resonance imaging revealed discospondylitis of the fourth and fifth lumbar vertebrae and herniation of the intervertebral disc between these vertebrae and the spinal cord. Postmortem examination confirmed severe chronic purulent discospondylitis with ventral spondylosis and narrowing of the spinal canal. Urolithiasis could not be verified. CONCLUSION: Although rare, diseases of the spinal cord should be considered as a differential diagnosis for impaired micturition in camelids. PMID- 27245442 TI - Update on the distribution of Mansonella perstans in the southern part of Cameroon: influence of ecological factors and mass drug administration with ivermectin. AB - BACKGROUND: Mansonellosis remains one of the most neglected of tropical diseases and its current distribution in the entire forest block of southern Cameroon is unknown. In order to address this issue, we have surveyed the distribution of Mansonella perstans in different bioecological zones and in addition, elucidated the influence of multiple rounds of ivermectin (IVM) based mass drug administration (MDA). METHODS: A mixed design was used. Between 2000 and 2014, both cross-sectional and longitudinal surveys were carried out in 137 communities selected from 12 health districts belonging to five main bioecological zones of the southern part of Cameroon. The zones comprised of grassland savanna (GS), mosaic forest savanna (MFS), forested savanna (FS), deciduous equatorial rainforest (DERF) and the dense humid equatorial rainforest (DHERF). The survey was carried out in some areas with no treatment history as well as those currently under IVM MDA. Individuals within the participatory communities were screened for the presence of M. perstans microfilariae (mf) in peripheral blood by the calibrated thick film method to determine both prevalence and geometric mean intensities at the community level. RESULTS: Apart from sporadic cases in savanna areas, distribution of M. perstans was strongly linked to the equatorial rainforest zones. Before CDTI, the highest mean prevalence (70.0 %) and intensity (17,382.2 mf/ml) were obtained in communities in Mamfes' DHERF areas followed by communities in the DHERF zone of Lolodorf (53.8 % and 7,814.8 mf/ml, respectively). A longitudinal survey in Mamfe further showed that M. perstans infections had reduced by 34.5 % in DERF (P < 0.001) but not DHERF zones after ten years of IVM MDA. Further data from the cross-sectional study revealed that there was a decrease in prevalence in DHERF zones only after ten years of MDA. In DERF zones however, the infection was relatively lower after four years of MDA. CONCLUSIONS: The distribution of M. perstans in the southern part of Cameroon varies with bioecological zones and IVM MDA history. The zones with high prevalence and intensities lie in forested areas while those with low endemicity are in the savanna areas. MDA with ivermectin induced significant reduction in the endemicity of mansonellosis in the decidious equatorial rainforest. In contrast, the prevalence and intensity remained relatively high and stable in the dense humid equatorial rainforest zones even after a decade of mass drug administration with ivermectin. Since it is known that M. perstans down-regulates host's immune system, the findings from this work would be useful in designing studies to understand the impact of M. perstans on host immune response to vaccination and co-infection with other pathogens such as Mycobacterium spp. and Plasmodium spp. in areas of contrasting endemicities. PMID- 27245443 TI - A questionnaire to identify patellofemoral pain in the community: an exploration of measurement properties. AB - BACKGROUND: Community-based studies of patellofemoral pain (PFP) need a questionnaire tool that discriminates between those with and those without the condition. To overcome these issues, we have designed a self-report questionnaire which aims to identify people with PFP in the community. METHODS: STUDY DESIGNS: comparative study and cross-sectional study. STUDY POPULATION: comparative study: PFP patients, soft-tissue injury patients and adults without knee problems. Cross sectional study: adults attending a science festival. INTERVENTION: comparative study participants completed the questionnaire at baseline and two weeks later. Cross-sectional study participants completed the questionnaire once. The optimal scoring system and threshold was explored using receiver operating characteristic curves, test-retest reliability using Cohen's kappa and measurement error using Bland-Altman plots and standard error of measurement. Known-group validity was explored by comparing PFP prevalence between genders and age groups. RESULTS: Eighty-four participants were recruited to the comparative study. The receiver operating characteristic curves suggested limiting the questionnaire to the clinical features and knee pain map sections (AUC 0.97 95 % CI 0.94 to 1.00). This combination had high sensitivity and specificity (over 90 %). Measurement error was less than the mean difference between the groups. Test-retest reliability estimates suggest good agreement (N = 51, k = 0.74, 95 % CI 0.52 0.91). The cross-sectional study (N = 110) showed expected differences between genders and age groups but these were not statistically significant. CONCLUSION: A shortened version of the questionnaire, based on clinical features and a knee pain map, has good measurement properties. Further work is needed to validate the questionnaire in community samples. PMID- 27245444 TI - The mental-attention Tai Chi effect with older adults. AB - BACKGROUND: Tai Chi practice has some fitness, wellness, and general cognitive effects in older adults. However, benefits of Tai Chi on specific mental attentional executive processes have not been investigated previously. We studied older Canadian adults of Chinese and non-Chinese origin and from low socioeconomic areas. METHODS: Sixty-four adults (51-87 years old) took part in a 16-week Tai Chi program. There were two groups: Chinese-background (n = 35) and Non-Chinese-background (n = 29). They received four mental-attention executive tasks before and after the 16-week period. These tasks measured visuospatial reasoning, mental-attentional activation (working memory), attentional inhibition, and balance between these attention factors (field-dependence independence). RESULTS: Chinese participants showed significant gain on Figural Intersections Task (mental-attentional capacity), Antisaccade (attentional inhibition), and Matrix Reasoning (fluid intelligence measure). Both groups evidenced gain on the Water Level Task (attentional balance). CONCLUSIONS: These gains suggest that Tai Chi can improve mental-attentional vigilance and executive control, when practitioners are sufficiently motivated to pursue this practice, and apply themselves (as our Chinese participants seem to have done). We found that Tai Chi enhanced mental attentional executives in the Chinese sample. The largely negative results with Non-Chinese participants might be explained by less strong motivation and by the relatively short Tai Chi practice period, which contrasts with the prior familiarity with Tai Chi of the Chinese participants. PMID- 27245445 TI - Exploring the presence of narcolepsy in patients with schizophrenia. AB - BACKGROUND: There are several case reports of patients with narcolepsy and schizophrenia, but a systematic examination of the association of both disorders has not been done. The aim of this work is to assess the frequency of narcolepsy with cataplexy in a large consecutive series of adult patients with schizophrenia and schizoaffective disorder. METHODS: We screened 366 consecutive patients with schizophrenia or schizoaffective disorder with a sleep questionnaire and the Epworth Sleepines scale (ESS) exploring narcoleptiform symptoms. Those who screened positive were assessed by a sleep specialist, and offered an HLA determination. CSF hypocretin-1 determination was proposed to those who were HLA DQB1*06:02 positive. RESULTS: On the screening questionnaire, 17 patients had an ESS score >=11 without cataplexy, 15 had cataplexy-like symptoms with an ESS score < 11, and four had an ESS score >=11 plus cataplexy-like symptoms. Of those, 24 patients were evaluated by a sleep specialist. Five of these 24 were HLA DQB1*06:02 positive, and three of these five subjects underwent lumbar puncture showing normal hypocretin-1 levels. CONCLUSIONS: Our results suggest that narcolepsy with cataplexy is not an unrecognized disease in adult patients with schizophrenia or schizoaffective disorder. PMID- 27245447 TI - A retrospective population-based study of induction of labour trends and associated factors among aboriginal and non-aboriginal mothers in the northern territory between 2001 and 2012. AB - BACKGROUND: Induction of labour (IOL) has become more common among many populations, but the trends and drivers of IOL in the Northern Territory (NT) of Australia are not known. This study investigated trends in IOL and associated factors among NT Aboriginal and non-Aboriginal mothers between 2001 and 2012. METHODS: A retrospective analysis of all NT resident women who birthed in the NT between 2001 and 2012 at >=32 weeks gestation. Demographic, medical and obstetric data were obtained from the NT Midwives' Collection. The prevalence of IOL was calculated by Aboriginal status and parity of the mother and year of birth. The prevalence of each main indication for induction among women was compared for 2001-2003 and 2010-2012. Linear and logistic regression was used to test for association between predictive factors and IOL in bivariate and multivariate analysis, separately for Aboriginal and non-Aboriginal mothers. RESULTS: A total of 42,765 eligible births between 2001 and 2012 were included. IOL was less common for Aboriginal than non-Aboriginal mothers in 2001 (18.0 % and 25.1 %, respectively), but increased to be similar to non-Aboriginal mothers in 2012 (22.6 % and 24.8 %, respectively). Aboriginal primiparous mothers demonstrated the greatest increase in IOL. The most common indication for IOL for both groups was post-dates, which changed little over time. Medical and obstetric complications were more common for Aboriginal mothers except late-term pregnancy. Prevalence of diabetes in pregnancy increased considerably among both Aboriginal and non-Aboriginal mothers, but was responsible for only a small proportion of IOLs. Increasing prevalence of risk factors did not explain the increased IOL prevalence for Aboriginal mothers. CONCLUSIONS: IOL is now as common for Aboriginal as non-Aboriginal mothers, though their demographic, medical and obstetric profiles are markedly different. Medical indications did not explain the recent increase in IOL among Aboriginal mothers; changes in maternal or clinical decision-making may have been involved. PMID- 27245446 TI - The biological function of antibodies induced by the RTS,S/AS01 malaria vaccine candidate is determined by their fine specificity. AB - BACKGROUND: Recent vaccine studies have shown that the magnitude of an antibody response is often insufficient to explain efficacy, suggesting that characteristics regarding the quality of the antibody response, such as its fine specificity and functional activity, may play a major role in protection. Previous studies of the lead malaria vaccine candidate, RTS,S, have shown that circumsporozoite protein (CSP)-specific antibodies and CD4(+) T cell responses are associated with protection, however the role of fine specificity and biological function of CSP-specific antibodies remains to be elucidated. Here, the relationship between fine specificity, opsonization-dependent phagocytic activity and protection in RTS,S-induced antibodies is explored. METHODS: A new method for measuring the phagocytic activity mediated by CSP-specific antibodies in THP-1 cells is presented and applied to samples from a recently completed phase 2 RTS,S/AS01 clinical trial. The fine specificity of the antibody response was assessed using ELISA against three antigen constructs of CSP: the central repeat region, the C-terminal domain and the full-length protein. A multi parameter analysis of phagocytic activity and fine-specificity data was carried out to identify potential correlates of protection in RTS,S. RESULTS: Results from the newly developed assay revealed that serum samples from RTS,S recipients displayed a wide range of robust and repeatable phagocytic activity. Phagocytic activity was correlated with full-length CSP and C-terminal specific antibody titres, but not to repeat region antibody titres, suggesting that phagocytic activity is primarily driven by C-terminal antibodies. Although no significant difference in overall phagocytic activity was observed with respect to protection, phagocytic activity expressed as 'opsonization index', a relative measure that normalizes phagocytic activity with CS antibody titres, was found to be significantly lower in protected subjects than non-protected subjects. CONCLUSIONS: Opsonization index was identified as a surrogate marker of protection induced by the RTS,S/AS01 vaccine and determined how antibody fine specificity is linked to opsonization activity. These findings suggest that the role of opsonization in protection in the RTS,S vaccine may be more complex than previously thought, and demonstrate how integrating multiple immune measures can provide insight into underlying mechanisms of immunity and protection. PMID- 27245448 TI - Non-oncology physician visits after diagnosis of cancer in children. AB - BACKGROUND: Children diagnosed with cancer often require extensive care for medical, psychosocial and educational problems during and after therapy. Part of this care is provided by family physicians and non-cancer specialists, but their involvement in the first years after diagnosis has barely been studied. Studying non-oncology physician visits may provide insight into the roles of different health care providers. METHODS: We included 757 children diagnosed with cancer under age 15 between 1991 and 2001 from a Canadian provincial registry, and matched each to 10 controls of the same birth year and sex. We determined the number of family physician and non-cancer specialist visits in the 5 years after diagnosis (for patients) or inclusion (for controls) using data from the provincial health insurance plan. RESULTS: In the first year after diagnosis, almost all patients visited both a family physician and non-cancer specialist. Although after 5 years percentages decreased to 85 and 76 %, respectively, these were still significantly higher than in controls. In the first year after diagnosis, both family physicians and non-cancer specialists were often consulted for neoplasms (62 and 90 %, respectively) and to discuss results of lab tests. In addition, family physicians were often consulted for general symptoms and non cancer specialists for nervous system problems and complications of medical care. CONCLUSIONS: Family physicians and non-cancer specialists are highly involved in the care for children with cancer in the first years after diagnosis, including for health problems related to cancer or its treatment. This necessitates good communication among all physicians. PMID- 27245449 TI - Detection of infectious dengue virus by selective real-time quantitative polymerase chain reaction. PMID- 27245450 TI - Structural and mutational analysis of the interaction between the Middle-East respiratory syndrome coronavirus (MERS-CoV) papain-like protease and human ubiquitin. AB - The papain-like protease (PL(pro)) of Middle-East respiratory syndrome coronavirus (MERS-CoV) has proteolytic, deubiquitinating, and deISGylating activities. The latter two are involved in the suppression of the antiviral innate immune response of the host cell. To contribute to an understanding of this process, we present here the X-ray crystal structure of a complex between MERS-CoV PL(pro) and human ubiquitin (Ub) that is devoid of any covalent linkage between the two proteins. Five regions of the PL(pro) bind to two areas of the Ub. The C-terminal five residues of Ub, RLRGG, are similar to the P5-P1 residues of the polyprotein substrates of the PL(pro) and are responsible for the major part of the interaction between the two macromolecules. Through sitedirected mutagenesis, we demonstrate that conserved Asp165 and non-conserved Asp164 are important for the catalytic activities of MERS-CoV PL(pro). The enzyme appears not to be optimized for catalytic efficiency; thus, replacement of Phe269 by Tyr leads to increased peptidolytic and deubiquitinating activities. Ubiquitin binding by MERS-CoV PL(pro) involves remarkable differences compared to the corresponding complex with SARS-CoV PL(pro). The structure and the mutational study help understand common and unique features of the deubiquitinating activity of MERS-CoV PL(pro). PMID- 27245451 TI - Functional anatomy of the lateral collateral ligament of the elbow. AB - INTRODUCTION: The aim of this study was to analyze the functional anatomy of the lateral collateral ligament complex (LCLC) and the surrounding forearm extensors. MATERIALS AND METHODS: Using 81 human cadaveric upper extremities, the anatomy of the forearm extensors-especially the anconeus, supinator and extensor carpi ulnaris (ECU)-was analyzed. After removal of aforementioned extensors the functional anatomy of the LCLC was analyzed. The origin of the LCLC was evaluated for isometry. The insertion types of the lateral ulnar collateral ligament (LUCL) were analyzed and classified. RESULTS: The ECU runs parallel to the RCL to dynamically preserve varus stability. The supinator and anconeus muscle fibers coalesce with the LCLC and lengthen during pronation. The anconeus fibers run parallel to the LUCL in full flexion. The LCLC consists of the annular ligament (AL) and the isometric radial collateral ligament (RCL). During elbow flexion, its posterior branches (LUCL) tighten while the anterior branches loosen. When performing a pivot shift test, the loosened LUCL fibers do not fully tighten in full extension. The LUCL inserts along with the AL at the supinator crest. Three different insertion types could be observed. CONCLUSIONS: The LUCL represents the posterior branch of the RCL rather than a distinct ligament. It is non-isometric and lengthens during elbow flexion. The RCL was found to be of vital importance for neutralization of posterolateral rotatory forces. Pronation of the forearm actively stabilizes the elbow joint as the supinator, anconeus and biceps muscle work in unison to increase posterolateral rotatory stability. PMID- 27245452 TI - Provisional pin fixation can maintain reduction in A3 intertrochanteric fractures. AB - A3 intertrochanteric fracture has a higher incidence of intraoperative re displacement than A1 and 2. The authors have also experienced difficulty with maintenance of reduction in A3 intertrochanteric fractures, as the technique depends on manual effort and can fail easily during the procedure. It induced us to develop this surgical technique to ease the surgical procedure and improve clinical outcomes. This paper introduces a modified provisional guide pin fixation technique applicable to even AO/OTA A3 intertrochanteric fractures, and presents preliminary results of 11 patients who were treated by provisional pin fixation-assisted nailing in A3 intertrochanteric fractures. Using this technique, we have reduced the chances of intraoperative reduction loss and achieved favorable clinical outcomes. PMID- 27245453 TI - Medicinal attributes of major phenylpropanoids present in cinnamon. AB - BACKGROUND: Excessive production of free radicals has been implicated in many diseases including cancer. They are highly reactive and bring about oxidation of biomolecules i.e., proteins, lipids and nucleic acids which are associated with many degenerative diseases. Natural products acting as antioxidants have ability to neutralize free radicals and their actions and hence they mitigate their harmful effects. The present study was designed to investigate pharmacological properties viz., antioxidant, antibacterial and antiproliferative activities of cinnamaldehyde and eugenol, the two naturally occurring phenylpropanoids present in Cinnamomum spp. and other plants. METHODS: The antioxidant potential of test compounds was evaluated by measuring DPPH free radical scavenging, reducing power and metal ion chelating activities. Protection against membrane damage was assayed by inhibition of lipid peroxidation in rat liver homogenate. Antibacterial activity was measured by Kirby-Bauer disc diffusion method while antiproliferative activity of test compounds was measured by sulforhodamine-B (SRB) assay. RESULTS: Eugenol exhibited noticeable antioxidant potential in DPPH radical scavenging (81 %) and reducing power (1.12) assays at 1.0 MUM/ml and 0.1 MUM/ml concentrations, respectively. IC50 value of eugenol for radical scavenging activity was found to be 0.495 MUM/ml. Cinnamaldehyde demonstrated considerable metal ion chelating ability (75 %) at 50 MUM/ml and moderate lipo-protective activity in lipid peroxidation assay at 3 MUM/ml. In addition cinnamaldehyde also showed appreciable antibacterial activity (zone of inhibition 32-42 mm) against Bacillus cereus (MTCC 6840), Streptococcus mutans (MTCC 497), Proteus vulgaris (MTCC 7299), Salmonella typhi (MTCC 3917) and Bordetella bronchiseptica (MTCC 6838) while eugenol produced moderate activity at 80 MUM/disc. Cinnamaldehyde exhibited comparatively better antiproliferative potential against breast (T47D) and lung (NCI-H322) cancer cell lines than eugenol in SRB assay at 50 MUM concentration. CONCLUSION: Cinnamaldehyde possessed metal ion chelating, lipo protective, antibacterial and antiproliferative activities while eugenol showed potent H-atom donating potential indicating radical quenching and reducing power abilities. Medicinal attributes shown by both the compounds indicated their usefulness in food and pharmaceutical sector. PMID- 27245454 TI - Unilateral negative electroretinogram presenting as photophobia. AB - PURPOSE: We aimed to describe four cases with an acquired unilateral negative electroretinogram (ERG) and severe unilateral photophobia and assess the underlying pathology. METHODS: We performed a retrospective chart view of the four cases by visiting two independent hospitals. RESULTS: Over the last 10 years, a 65-year-old man, 71-year-old woman, 68-year-old man, and 73-year-old woman presented to the hospitals with unilateral photophobia. Symptom onset was relatively obvious in all the patients. Comprehensive examinations, including visual acuity and visual field assessment, optical coherence tomography, and fluorescein angiography, showed minimal change in the eye with photophobia. However, only in the affected eye, the mixed rod-cone response in full-field ERG showed a markedly electronegative pattern, namely the amplitude of a-wave was preserved and larger than that of b-wave, and the rod and cone responses were very low. In fact, the cone responses were almost absent in all four patients. ERG findings indicate dysfunction of both rod and cone visual pathways, and the preserved a-wave in the mixed rod-cone ERG suggests that the disturbance of the rod visual pathway exists in post-photoreceptors. Moreover, although multifocal ERG showed a very low amplitude in the entire area, the preservation of the responses was detected to some extent only in the center. These symptoms and examination findings remained unchanged for more than 4 years. CONCLUSIONS: Four patients with acquired unilateral negative ERG associated with severe photophobia showed similar clinical findings. To our knowledge, no known disorders can explain these conditions. PMID- 27245455 TI - Gas Flow Dynamics in Inlet Capillaries: Evidence for non Laminar Conditions. AB - In this work, the characteristics of gas flow in inlet capillaries are examined. Such inlet capillaries are widely used as a first flow restriction stage in commercial atmospheric pressure ionization mass spectrometers. Contrary to the common assumption, we consider the gas flow in typical glass inlet capillaries with 0.5 to 0.6 mm inner diameters and lengths about 20 cm as transitional or turbulent. The measured volume flow of the choked turbulent gas stream in such capillaries is 0.8 L.min(-1) to 1.6 L.min(-1) under typical operation conditions, which is in good agreement to theoretically calculated values. Likewise, the change of the volume flow in dependence of the pressure difference along the capillary agrees well with a theoretical model for turbulent conditions as well as with exemplary measurements of the static pressure inside the capillary channel. However, the results for the volume flow of heated glass and metal inlet capillaries are neither in agreement with turbulent nor with laminar models. The velocity profile of the neutral gas in a quartz capillary with an inner diameter similar to commercial inlet capillaries was experimentally determined with spatially resolved ion transfer time measurements. The determined gas velocity profiles do not contradict the turbulent character of the flow. Finally, inducing disturbances of the gas flow by placing obstacles in the capillary channel is found to not change the flow characteristics significantly. In combination the findings suggest that laminar conditions inside inlet capillaries are not a valid primary explanation for the observed high ion transparency of inlet capillaries under common operation conditions. Graphical Abstract ?. PMID- 27245456 TI - SSPaQ: A Subtractive Segmentation Approach for the Exhaustive Parallel Quantification of the Extent of Protein Modification at Every Possible Site. AB - Protein modifications, whether chemically induced or post-translational (PTMs), play an essential role for the biological activity of proteins. Understanding biological processes and alterations thereof will rely on the quantification of these modifications on individual residues. Here we present SSPaQ, a subtractive method for the parallel quantification of the extent of modification at each possible site of a protein. The method combines uniform isotopic labeling and proteolysis with MS, followed by a segmentation approach, a powerful tool to refine the quantification of the degree of modification of a peptide to a segment containing a single modifiable amino acid. The strength of this strategy resides in: (1) quantification of all modifiable sites in a protein without prior knowledge of the type(s) of modified residues; (2) insensitivity to changes in the solubility and ionization efficiency of peptides upon modification; and (3) detection of missed cleavages caused by the modification for mitigation. The SSPaQ method was applied to quantify modifications resulting from the interaction of human phosphatidyl ethanolamine binding protein 1 (hPEBP1), a metastasis suppressor gene product, with locostatin, a covalent ligand and antimigratory compound with demonstrated activity towards hPEBP1. Locostatin is shown to react with several residues of the protein. SSPaQ can more generally be applied to induced modification in the context of drugs that covalently bind their target protein. With an alternate front-end protocol, it could also be applied to the quantification of protein PTMs, provided a removal tool is available for that PTM. Graphical Abstract ?. PMID- 27245457 TI - Total arch replacement in a patient with a tracheostoma through a reverse L shaped partial sternotomy. AB - A conventional median sternotomy in a patient with a tracheostoma is susceptible to postoperative mediastinitis or graft infection after total arch replacement (TAR). An optimal surgical procedure has still not been established to circumvent these complications in such patients. We report a successful case of a 74-year old man with a tracheostoma who received TAR through a reverse L-shaped partial sternotomy. This incision was simple and enabled us to secure an adequate operative field similar to that of a conventional median sternotomy. The patient was discharged without any evidence of infection or any other complications. PMID- 27245458 TI - Hair analysis for detection of triptans occasionally used or overused by migraine patients-a pilot study. AB - PURPOSE: The aim of this study is to evaluate the detection rate of almotriptan, eletriptan, frovatriptan, sumatriptan, rizatriptan, and zolmitriptan in the hair of migraineurs taking these drugs; the degree of agreement between type of self reported triptan and triptan found in hair; if the concentrations in hair were related to the reported cumulative doses of triptans; and whether hair analysis was able to distinguish occasional use from the overuse of these drugs. METHODS: Out of 300 headache patients consecutively enrolled, we included 147 migraine patients who reported to have taken at least one dose of one triptan in the previous 3 months; 51 % of the patients overused triptans. A detailed pharmacological history and a sample of hair were collected for each patient. Hair samples were analyzed by liquid chromatography-electrospray tandem mass spectrometry (LC-MS/MS) by a method that we developed. RESULTS: All the triptans could be detected in the hair of the patients. The agreement between type of self reported triptan and type of triptan found in hair was from fair to good for frovatriptan and zolmitriptan and excellent for almotriptan, eletriptan, sumatriptan, and rizatriptan (P < 0.01, Cohen's kappa). The correlation between the reported quantities of triptan and hair concentrations was statistically significant for almotriptan, eletriptan, rizatriptan, and sumatriptan (P < 0.01, Spearman's rank correlation coefficient). The accuracy of hair analysis in distinguishing occasionally users from overusers was high for almotriptan (ROC AUC = 0.9092), eletriptan (ROC AUC = 0.8721), rizatriptan (ROC AUC = 0.9724), and sumatriptan (ROC AUC = 0.9583). CONCLUSIONS: Hair analysis can be a valuable system to discriminate occasional use from triptan overuse. PMID- 27245459 TI - The Intracellular Effect of Relaxin on Female Anterior Cruciate Ligament Cells. AB - BACKGROUND: Female collegiate athletes with serum relaxin concentrations above 6.0 pg/mL have been shown to have more than 4 times increased risk for anterior cruciate ligament (ACL) tears. However, the intracellular effect of relaxin on ACL cells has not been elucidated. HYPOTHESES: The hypotheses were that relaxin binding to receptors on female ACL cells will result in (1) an increase in matrix metalloproteinase (MMP) and decrease in tissue inhibitor of metalloproteinase (TIMP) gene expression, (2) a decrease in collagen and alpha smooth muscle actin (alphaSMA) expression, (3) inhibition of transforming growth factor beta1 (TGFbeta1)-induced fibrosis, and (4) an increase in cyclic adenosine 3',5' monophosphate (cAMP) production and that these changes will not be observed in male ACL cells. STUDY DESIGN: Controlled laboratory study. METHODS: Ligament cells from ACL tissue were isolated from 7 male and 7 female human donors and expanded in vitro. The cells were incubated with escalating concentrations of relaxin-2, as well as with TGFbeta1 or 17beta-estradiol in certain groups. Cells were then lysed and analyzed for MMP1 (collagenase-1), MMP3 (stromelysin-1), MMP13 (collagenase-3), TIMP1, type I collagen, type III collagen, and/or alphaSMA mRNA expression using quantitative real-time polymerase chain reaction. Intracellular cAMP levels were assessed via an enzyme-linked immunoassay. RESULTS: ACL cells primed with estrogen and treated with 10 ng/mL and 100 ng/mL relaxin illustrated increased MMP1 expression (P = .012 and .006, respectively) and MMP3 expression (P = .005 and .001, respectively). Treatment with 100 ng/mL relaxin decreased alphaSMA expression (P = .001). When ACL tissue isolated from female donors with a history of oral contraceptive use was excluded from the analysis, 100 ng/mL of relaxin decreased type I collagen (P = .005) and type III collagen (P = .028) expression in cells primed with estrogen. Relaxin exhibited no significant effect on male-derived ACL cells. CONCLUSION: Relaxin-2 significantly upregulated intracellular processes in human female ACL cells, but no effect was observed in male cells. Relaxin increased MMP (MMP1 and MMP3) and decreased alphaSMA and type I and III collagen expression, which may act to alter the structural integrity of the ACL tissue over time. CLINICAL RELEVANCE: Female athletes with higher circulating relaxin levels may be more susceptible to ACL injury. PMID- 27245460 TI - Understanding motivators and barriers of hospital-based obstetric and pediatric health care worker influenza vaccination programs in Australia. AB - Understanding motivators and barriers of health care worker (HCW) vaccination programs is important for determining strategies to improve uptake. The aim of this study was to explore key drivers and HCW decision making related to recommended vaccines and seasonal influenza vaccination programs. We used a qualitative approach with semi-structured one-to-one interviews with 22 HCWs working at a tertiary pediatric and obstetric hospital in South Australia. A thematic analysis and coding were used to examine data. Key motivators that emerged included: sense of responsibility, convenience and ease of access, rotating trolleys, the influenza vaccine being free, basic knowledge about influenza and influenza vaccination, peer pressure, personal values and family culture, as well as the culture of support for the program. Personal decisions were the major barrier to HCWs receiving the influenza vaccine which were predominantly self-protection related or due to previous experience or fear of adverse reactions. Other barriers that emerged were misconceptions about the influenza vaccine, needle phobia and privacy concerns. This study identified both attitudinal and structural barriers that could be addressed to improve uptake of the seasonal influenza vaccine. PMID- 27245462 TI - Spatial adiabatic passage: a review of recent progress. AB - Adiabatic techniques are known to allow for engineering quantum states with high fidelity. This requirement is currently of large interest, as applications in quantum information require the preparation and manipulation of quantum states with minimal errors. Here we review recent progress on developing techniques for the preparation of spatial states through adiabatic passage, particularly focusing on three state systems. These techniques can be applied to matter waves in external potentials, such as cold atoms or electrons, and to classical waves in waveguides, such as light or sound. PMID- 27245461 TI - Vascular Smooth Muscle-Specific EP4 Receptor Deletion in Mice Exacerbates Angiotensin II-Induced Renal Injury. AB - AIMS: Cyclooxygenase inhibition by non-steroidal anti-inflammatory drugs is contraindicated in hypertension, as it may reduce glomerular filtration rate (GFR) and renal blood flow. However, the identity of the specific eicosanoid and receptor underlying these effects is not known. We hypothesized that vascular smooth muscle prostaglandin E2 (PGE2) E-prostanoid 4 (EP4) receptor deletion predisposes to renal injury via unchecked vasoconstrictive actions of angiotensin II (AngII) in a hypertension model. Mice with inducible vascular smooth muscle cell (VSMC)-specific EP4 receptor deletion were generated and subjected to AngII induced hypertension. RESULTS: EP4 deletion was verified by PCR of aorta and renal vessels, as well as functionally by loss of PGE2-mediated mesenteric artery relaxation. Both AngII-treated groups became similarly hypertensive, whereas albuminuria, foot process effacement, and renal hypertrophy were exacerbated in AngII-treated EP4VSMC-/- but not in EP4VSMC+/+ mice and were associated with glomerular scarring, tubulointerstitial injury, and reduced GFR. AngII-treated EP4VSMC-/- mice exhibited capillary damage and reduced renal perfusion as measured by fluorescent bead microangiography and magnetic resonance imaging, respectively. NADPH oxidase 2 (Nox2) expression was significantly elevated in AngII-treated EP4-/- mice. EP4-receptor silencing in primary VSMCs abolished PGE2 inhibition of AngII-induced Nox2 mRNA and superoxide production. INNOVATION: These data suggest that vascular EP4 receptors buffer the actions of AngII on renal hemodynamics and oxidative injury. CONCLUSION: EP4 agonists may, therefore, protect against hypertension-associated kidney damage. Antioxid. Redox Signal. 25, 642-656. PMID- 27245463 TI - Review of Cytology Practice at Thomas Jefferson University Hospital before and after High-Risk Human Papillomavirus Testing. AB - OBJECTIVE: We performed a retrospective review of Papanicolaou (Pap) testing to assess whether the cytology practice in our institution was affected by the introduction of high-risk (HR) human papillomavirus (HPV) assays over time. STUDY DESIGN: Cytology, HPV and histopathology records were retrieved from our laboratory information system from 2003 to 2015. Records for Digene Hybrid Capture 2(r), Hologic Cervista(r) and Roche Cobas(r) HPV assays were obtained. A 3-month follow-up for HPV detected cases was performed, and results were correlated with cytology and biopsies. A 1-year follow-up of HPV 16/18 and other HR HPV detected cases was also performed. RESULTS: From 2008 to 2015, a noticeable decrease in Pap testing volume occurred, from 11,792 to 4,664, while the percentage of HPV testing increased from 19 to 59%. Similar HPV detection rates and follow-up results for both reflex and cotesting were observed in the 3 HPV assays. CONCLUSIONS: The decrease in Pap testing was due to the lengthening of the test interval when cotesting results were negative. Practitioners adhering to guidelines accounts for increased molecular testing volume. A trend towards higher-grade cervical intraepithelial neoplasia in the follow-up of detected HPV 16/18 was noted. So far there has been no demand for HPV as a stand-alone test. PMID- 27245464 TI - A Mixed Micelle Formulation for Oral Delivery of Vitamin K. AB - PURPOSE: To develop a stable micellar formulation of vitamin K for oral delivery, because the commercial and clinically used formulation of vitamin K (Konakion(r) MM) destabilizes at gastric pH resulting in low bioavailability of this vitamin in neonates with cholestasis. METHODS: Mixed micelles composed of EPC, DSPE-PEG 2000 and glycocholic acid, with and without vitamin K, were prepared by a film hydration method. The influence of pH on the stability of the micelles was analyzed by dynamic light scattering (DLS). The critical micelle concentration (CMC) was determined by fluorescence spectroscopy using pyrene and the morphology was evaluated by transmission electron microscopy . Caco-2 cells were used to study the cytocompatibilty. RESULTS: Mixed micelles with mean diameters from 7.1 to 11.0 nm and a narrow size distribution (PDI < 0.2) were obtained after 3 membrane extrusion cycles. Konakion(r) MM formed aggregated particles at gastric pH, which was avoided through steric stabilization by introducing PEG. TEM showed that mixed micelles had a spherical size (diameter of around 10 nm) with a narrow size distribution in agreement with the DLS results. The loading capacities for vitamin K of mixed micelles with varying molar fractions of DSPE-PEG and EPC (from 0/100 to 50/50 (mol/mol)) were 10.8-5.0 w%, respectively. The mixed micelles showed good cytocompatibility at concentrations of glycocholic acid between 0.12 and 1.20 mM. CONCLUSIONS: Mixed micelles with superior stability to Konakion(r) MM at low pH were obtained by introducing DSPE-PEG 2000. These are therefore attractive oral formulations for vitamin K. PMID- 27245465 TI - Imiquimod Induces Apoptosis in Human Endometrial Cancer Cells In vitro and Prevents Tumor Progression In vivo. AB - PURPOSE: The increasing incidence of endometrial cancer (EC), in younger age at diagnosis, calls for new tissue-sparing treatment options. This work aims to evaluate the potential of imiquimod (IQ) in the treatment of low-grade EC. METHODS: Effects of IQ on the viabilities of Ishikawa and HEC-1A cells were evaluated using MTT assay. The ability of IQ to induce apoptosis was evaluated by testing changes in caspase 3/7 levels and expression of cleaved caspase-3, using luminescence assay and western blot. Apoptosis was confirmed by flow cytometry and the expression of cleaved PARP. Western blot was used to evaluate the effect of IQ on expression levels of Bcl-2, Bcl-xL, and BAX. Finally, the in vivo efficacy of IQ was tested in an EC mouse model. RESULTS: There was a decrease in EC cell viability following IQ treatment as well as increased caspase 3/7 activities, cleaved caspase-3 expression, and Annexin-V/ 7AAD positive cell population. Western blot results showed the ability of IQ in cleaving PARP, decreasing Bcl-2 and Bcl-xL expressions, but not affecting BAX expression. In vivo study demonstrated IQ's ability to inhibit EC tumor growth and progression without significant toxicity. CONCLUSIONS: IQ induces apoptosis in low-grade EC cells in vitro, probably through its direct effect on Bcl-2 family protein expression. In, vivo, IQ attenuates EC tumor growth and progression, without an obvious toxicity. Our study provides the first building block for the potential role of IQ in the non-surgical management of low-grades EC and encouraging further investigations. PMID- 27245466 TI - Solid Dispersion of Curcumin as Polymeric Films for Bioenhancement and Improved Therapy of Rheumatoid Arthritis. AB - PURPOSE: The aim of our study was development of advanced third generation Curcumin self microemulsifying composition solid dispersion (Cur SMEC-SD) with high drug loading, improved stability, rapid in-vitro dissolution and enhanced bioavailability for improved therapy of rheumatoid arthritis. METHOD: The Cur SMEC-SD comprising polymers (KollidonVA64[KVA], Eudragits, HPMC and Soluplus) and self microemulsifying composition of surfactant:co-surfactant:oil were coated onto rapidly disintegrating inert tablet core. SDs evaluated for stability, in vitro release and bioenhancement. RESULTS: Cur SMEC-SDs exhibited high Cur loading of 45% w/w and microemulsion formation with globule size (~100 nm) irrespective of polymers. Among the polymers, SD with KVA revealed exceptionally low contact angle (7 degrees C) and rapid in-vitro release (t50%-6.45 min). No crystallization was evident as confirmed by SEM, DSC and XRD and is attributed to SMEC aided solubilization/amorphisation, and interaction of KVA with Cur seen in the FTIR spectra. Stability was confirmed as per ICH guidelines. Remarkable bioenhancement with Cur SMEC-SD was confirmed by the > four fold and a two fold compared to Cur and Cur-SD without SMEC respectively. High efficacy ~ 80% compared to Indomethacin, seen with rheumatoid arthritis (RA) induced rats coupled with no adverse toxicity. CONCLUSION: The advanced third generation Cur SMEC-SD presents a practical technological advancement and suggests Cur SMEC-SD as promising alternative for RA therapy. PMID- 27245469 TI - DNA Methyltransferase Inhibitor Induced Fungal Biosynthetic Products: Diethylene Glycol Phthalate Ester Oligomers from the Marine-Derived Fungus Cochliobolus lunatus. AB - Chemical epigenetic manipulation was applied to the marine-derived fungus Cochliobolus lunatus (TA26-46) with a DNA methyltransferase inhibitor resulting in the significant changes of the secondary metabolites. Cultivation of C. lunatus (TA26-46) with 5-azacytidine led to the isolation of seven new diethylene glycol phthalate esters, cochphthesters A-G (1-6, 10), along with four known analogues (7-9, 11). Their structures were determined by extensive NMR spectroscopic spectra as well as MS data. Compounds 2-6 and 8-11, characterized by the cross-polymerization of phthalate across diethylene glycol via ester bonds, represent the first example of naturally occurring phthalate ester oligomers. Graphical Abstract Chemical epigenetic manipulation was applied to a marine-derived fungus resulting in significant changes of secondary metabolites. PMID- 27245470 TI - The "shirt collar sign" of cervical dystonia. AB - The diagnosis of cervical dystonia (CD) is clinical. We describe a physical examination observation that has been noted in CD patients. There is a tendency for their shirt collars to be shifted to one side. We validated this apparently consistent finding by having blinded evaluators rating the symmetry of the shirt collars in CD and non-cervical dystonia control subjects. A high correlation was found between the physical finding which we call "shirt collar sign" and the diagnosis. "Shirt collar sign" may be a helpful sign in diagnosing CD. PMID- 27245467 TI - Spray Dried Chitosan Microparticles for Intravesical Delivery of Celecoxib: Preparation and Characterization. AB - PURPOSE: Chitosan microparticles containing celecoxib (CB), were developed as chemoprevention of bladder cancer. Furthermore two inclusion complexes of CB with methyl-beta-cyclodextrin (C1 and C2) were prepared to improve the solubility of the drug. METHODS: C1 and C2 were obtained by freeze-drying and characterized in the solid state and in solution. Microparticles loaded with CB or C1 or C2 were prepared by spray drying and fully characterized. RESULTS: The yield and encapsulation efficiencies of microparticles depended by both the viscosity and the presence of the inclusion complex in the feed medium nebulised. Generally, the microparticles exhibited a spherical shape with mean diameter of approximately 2 MUm which was compatible with local intravesical administration using a catheter. The CB release studies from the microparticles allowed us to identify both immediate release systems (microparticles including the complexes) and prolonged release systems (microparticles including CB alone). The latter exhibited good adhesion to the bladder mucosa, as highlighted by a mucoadhesion study. Histological studies revealed a desquamation of the superficial cells when the bladder mucosa was treated with microparticles loaded with CB, while the morphology of the urothelium did not change when it was treated with microparticles loaded with the inclusion complex. CONCLUSION: A new CB intravesical formulation than can easily be administered with a catheter and is able to release the drug at the target site for several hours was realized. This new delivery system could be a good alternative to classic oral CB administration. PMID- 27245471 TI - Association of the polymorphisms of chemokine genes (IL8, RANTES, MIG, IP10, MCP1 and IL16) with the pathogenesis of autoimmune thyroid diseases. AB - Chemokines induce leukocyte chemotaxis and contribute to chronic inflammation. To clarify the association between functional polymorphisms in genes encoding some chemokines and the pathogenesis of Autoimmune thyroid disease (AITD), we genotyped IL8 -251T/A, Regulated upon Activation, Normal T cell Expressed and presumably Secreted (RANTES) - 403G/A, -28C/G, MIG rs2276886G/A, IP10 -1596C/T, Monocyte Chemoattractant Protein1 (MCP1) - 2518G/A and IL16 -295T/C polymorphisms. We genotyped these polymorphisms using the PCR-RFLP method in 149 Graves' disease (GD) patients, including 59 patients with intractable GD and 53 patients with GD in remission, as well as 131 Hashimoto's disease (HD) patients, including 54 patients with severe HD, 46 patients with mild HD and 99 healthy controls. The IL8 -251TT genotype and MIG rs2276886 A allele were more frequent in patients with AITD (p = 0.0139 and p = 0.0005, respectively). The RANTES - 403AA and -28GG genotypes were less frequent in patients with AITD (p = 0.0164 and p = 0.0221, respectively). The MCP1 -2518GG genotype was more frequent in HD patients (p = 0.0323). The MIG rs2276886 AG genotype was less frequent in patients with intractable GD (p = 0.0051). Interestingly, the age of onset in GD patients with the RANTES - 28CC genotype was younger than in those with -28CG and GG genotypes (p = 0.0028). In this study, we first reported that the polymorphisms in IL8, RANTES and MIG genes are associated with the development of AITD, and that the MIG rs2276886 AG genotype is associated with the intractability of GD. The RANTES - 28CC genotype is associated with young onset of GD. PMID- 27245472 TI - Designing Upconversion Nanocrystals Capable of 745 nm Sensitization and 803 nm Emission for Deep-Tissue Imaging. AB - A crystal design strategy is described that generates hexagonal-phased NaYF4 :Nd/Yb@NaYF4 :Yb/Tm luminescent nanocrystals with the ability to emit light at 803 nm when illuminated at 745 nm. This is accomplished by taking advantage of the large absorption cross-section of Nd(3+) between 720 and 760 nm plus efficient spatial energy transfer and migration through Nd(3+) ->Yb(3+) ->Yb(3+) >Tm(3+) . Mechanistic investigations suggest that a cascaded two-photon energy transfer upconversion process underlies the emission mechanism. This protocol enables deep-tissue imaging to be achieved while mitigating the attenuation effect associated with the visible emission and the overheating constraint imposed by conventional 980 nm excitation. PMID- 27245474 TI - High-Density Mapping of Counterclockwise to Clockwise Typical Atrial Flutter: Visualization of the Conduction Gap. PMID- 27245475 TI - Immunohistochemical expression profiles of solute carrier transporters in alpha fetoprotein-producing gastric cancer. AB - AIMS: Alpha-fetoprotein (AFP)-producing gastric cancer (GC) is an aggressive tumour with high rates of liver metastasis and poor prognosis, and for which a validated chemotherapy regimen has not been established. Drug uptake by solute carrier (SLC) transporters is proposed as one of the mechanisms involved in sensitivity to chemotherapy. In this study, we aimed to develop important insights into effective chemotherapeutic regimens for AFP-producing GC. METHODS AND RESULTS: We evaluated immunohistochemically the expression levels of a panel of SLC transporters in 20 AFP-producing GCs and 130 conventional GCs. SLC transporters examined were human equilibrative nucleoside transporter 1 (hENT1), organic anion transporter 2 (OAT2), organic cation transporter (OCT) 2, OCT6 and organic anion-transporting polypeptide 1B3 (OATP1B3). The rates of high expression levels of hENT1 (hENT1high ) and OAT2 (OAT2high ) were statistically higher in AFP-producing GC, compared with conventional GC. When analysing hENT1 and OAT2 in combination, hENT1high /OAT2high was the most particular expression profile for AFP-producing GC, with a greater significance than hENT1 or OAT2 alone. However, no significant differences in OCT2, OCT6 or OATP1B3 levels were detected between AFP-producing and conventional GCs. However, immunoreactivity for hENT1, OAT2 and OCT6 tended to be increased in GC tissues compared with non neoplastic epithelia. CONCLUSIONS: Because hENT1 and OAT2 are crucial for the uptake of gemcitabine and 5-fluorouracil, respectively, our results suggest that patients with AFP-producing GC could potentially benefit from gemcitabine/fluoropyrimidine combination chemotherapy. Increased expression of hENT1, OAT2 and OCT6 may also be associated with the progression of GC. PMID- 27245473 TI - Reduced stability and intracellular transport of dsRNA contribute to poor RNAi response in lepidopteran insects. AB - RNA interference (RNAi) has become a widely used reverse genetic tool to study gene function in eukaryotic organisms and is being developed as a technology for insect pest management. The efficiency of RNAi varies among organisms. Insects from different orders also display differential efficiency of RNAi, ranging from highly efficient (coleopterans) to very low efficient (lepidopterans). We investigated the reasons for varying RNAi efficiency between lepidopteran and coleopteran cell lines and also between the Colorado potato beetle, Leptinotarsa decemlineata and tobacco budworm, Heliothis virescens. The dsRNA either injected or fed was degraded faster in H. virescens than in L. decemlineata. Both lepidopteran and coleopteran cell lines and tissues efficiently took up the dsRNA. Interestingly, the dsRNA administered to coleopteran cell lines and tissues was taken up and processed to siRNA whereas the dsRNA was taken up by lepidopteran cell lines and tissues but no siRNA was detected in the total RNA isolated from these cell lines and tissues. The data included in this paper showed that the degradation and intracellular transport of dsRNA are the major factors responsible for reduced RNAi efficiency in lepidopteran insects. PMID- 27245476 TI - Effect of oligochitosan and oligo-beta-glucan supplementation on growth, innate immunity, and disease resistance of striped catfish (Pangasianodon hypophthalmus). AB - Oligochitosan (COS) and oligo-beta-glucan (betaOG) were prepared by gamma Co-60 irradiation of chitosan/H2 O2 and beta-glucan/H2 O2 solutions. The striped catfish (Pangasianodon hypophthalmus) was fed diets containing 0-200 mg COS, betaOG, and a mixture of COS/betaOG per kg feed for 45 days, and then challenged with Edwardsiella ictaluri bacterium. The effects of supplemented COS, betaOG, and a mixture of COS/betaOG on immune stimulation and growth performance in striped catfish were investigated. The results indicated that when striped catfish fed with 100-200 mg COS or betaOG/kg feed the growth performance was significantly improved and the mortality was considerably decreased. Furthermore, striped catfish fed with supplementation of 50 mg COS + 50 mg betaOG/kg feed was the best for increasing weight gain (~26%) and for decreasing mortality (~38%) compared with the control group. Moreover, phagocytic activity and lysozyme activity of fish were enhanced by feeding diet-supplemented COS and/or betaOG. Thus, COS and/or betaOG can be potentially utilized as the immunostimulants and growth promoters for aquaculture. PMID- 27245477 TI - Escherichia colimazEF Toxin-Antitoxin System as a Tool to Target Cell Ablation in Plants. AB - BACKGROUND/AIMS: The Escherichia coli MazF is an endoribonuclease that cleaves mRNA at ACA sequences, thereby triggering inhibition of protein synthesis. The aim of this study is to evaluate the efficiency of the mazEF toxin-antitoxin system in plants to develop biotechnological tools for targeted cell ablation. METHODS: A double transformation strategy, combining expression of the mazE antitoxin gene under the control of the CaMV 35S promoter, reported to drive expression in all plant cells except within the tapetum, together with the expression of the mazF gene under the control of the TA29 tapetum-specific promoter in transgenic tobacco, was applied. RESULTS: No transgenic TA29-mazF line could be regenerated, suggesting that the TA29 promoter is not strictly tapetum specific and that MazF is toxic for plant cells. The regenerated 35S mazE/TA29-mazF double-transformed lines gave a unique phenotype where the tapetal cell layer was necrosed resulting in the absence of pollen. CONCLUSION: These results show that the E. colimazEF system can be used to induce death of specific plant cell types and can provide a new tool to plant cell ablation. PMID- 27245478 TI - Enhanced Biological Functions of Human Mesenchymal Stem-Cell Aggregates Incorporating E-Cadherin-Modified PLGA Microparticles. AB - Mesenchymal stem cells (MSCs) have emerged as a promising source of multipotent cells for various cell-based therapies due to their unique properties, and formation of 3D MSC aggregates has been explored as a potential strategy to enhance therapeutic efficacy. In this study, poly(lactic-co-glycolic acid) (PLGA) microparticles modified with human E-cadherin fusion protein (hE-cad-PLGA microparticles) have been fabricated and integrated with human MSCs to form 3D cell aggregates. The results show that, compared with the plain PLGA, the hE-cad PLGA microparticles distribute within the aggregates more evenly and further result in a more significant improvement of cellular proliferation and secretion of a series of bioactive factors due to the synergistic effects from the bioactive E-cadherin fragments and the PLGA microparticles. Meanwhile, the hE-cad PLGA microparticles incorporated in the aggregates upregulate the phosphorylation of epidermal growth factor receptors and activate the AKT and ERK1/2 signaling pathways in the MSCs. Additionally, the E-cadherin/beta-catenin cellular membrane complex in the MSCs is markedly stimulated by the hE-cad-PLGA microparticles. Therefore, engineering 3D cell aggregates with hE-cad-PLGA microparticles can be a promising method for ex vivo multipotent stem-cell expansion with enhanced biological functions and may offer a novel route to expand multipotent stem-cell based clinical applications. PMID- 27245479 TI - Links between Evolution, Development, Human Anatomy, Pathology, and Medicine, with A Proposition of A Re-defined Anatomical Position and Notes on Constraints and Morphological "Imperfections". AB - Surprisingly the oldest formal discipline in medicine (anatomy) has not yet felt the full impact of evolutionary developmental biology. In medical anatomy courses and textbooks, the human body is still too often described as though it is a "perfect machine." In fact, the study of human anatomy predates evolutionary theory; therefore, many of its conventions continue to be outdated, making it difficult to study, understand, and treat the human body, and to compare it with that of other, nonbipedal animals, including other primates. Moreover, such an erroneous view of our anatomy as "perfect" can be used to fuel nonevolutionary ideologies such as intelligent design. In the section An Evolutionary and Developmental Approach to Human Anatomical Position of this paper, we propose the redefinition of the "human standard anatomical position" used in textbooks to be consistent with human evolutionary and developmental history. This redefined position also simplifies, for students and practitioners of the health professions, the study and learning of embryonic muscle groups (each group including muscles derived from the same/ontogenetically closely related primordium/primordia) and joint movements and highlights the topological correspondence between the upper and lower limbs. Section Evolutionary and Developmental Constraints, "Imperfections" and Sports Pathologies continues the theme by describing examples of apparently "illogical" characteristics of the human body that only make sense when one understands the developmental and evolutionary constraints that have accumulated over millions of years. We focus, in particular, on musculoskeletal functional problems and sports pathologies to emphasize the links with pathology and medicine. These examples demonstrate how incorporating evolutionary theory into anatomy education can be helpful for medical students, teachers, researchers, and physicians, as well as for anatomists, functional morphologists, and evolutionary and developmental biologists. PMID- 27245481 TI - Mechanistic Study of the Conversion of Superoxide to Oxygen and Hydrogen Peroxide in Carbon Nanoparticles. AB - Hydrophilic carbon clusters (HCCs) are oxidized carbon nanoparticles with a high affinity for electrons. The electron accepting strength of HCCs, employing the efficient conversion of superoxide (O2(*-)) to molecular oxygen (O2) via single electron oxidation, was monitored using cyclic voltammetry and electron paramagnetic resonance spectroscopy. We found that HCCs possess O2 reduction reaction (ORR) capabilities through a two-electron process with the formation of H2O2. By comparing results from aprotic solvents to those obtained from ORR activity in aqueous media, we propose a mechanism for the origin of the antioxidant and superoxide dismutase mimetic properties of poly(ethylene glycolated) hydrophilic carbon clusters (PEG-HCCs). PMID- 27245480 TI - A Potent Inhibitor of Protein Sequestration by Expanded Triplet (CUG) Repeats that Shows Phenotypic Improvements in a Drosophila Model of Myotonic Dystrophy. AB - Myotonic dystrophy is the most common form of adult-onset muscular dystrophy, originating in a CTG repeat expansion in the DMPK gene. The expanded CUG transcript sequesters MBNL1, a key regulator of alternative splicing, leading to the misregulation of numerous pre-mRNAs. We report an RNA-targeted agent as a possible lead compound for the treatment of myotonic dystrophy type 1 (DM1) that reveals both the promise and challenges for this type of small-molecule approach. The agent is a potent inhibitor of the MBNL1-rCUG complex with an inhibition constant (Ki ) of 25+/-8 nm, and is also relatively nontoxic to HeLa cells, able to dissolve nuclear foci, and correct the insulin receptor splicing defect in DM1 model cells. Moreover, treatment with this compound improves two separate disease phenotypes in a Drosophila model of DM1: adult external eye degeneration and larval crawling defect. However, the compound has a relatively low maximum tolerated dose in mice, and its cell uptake may be limited, providing insight into directions for future development. PMID- 27245483 TI - Health-related quality of life in adolescent survivors of bronchopulmonary dysplasia. AB - BACKGROUND AND OBJECTIVE: Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of infancy in the developed countries. Outcomes for BPD patients have traditionally been assessed using physiological parameters such as lung function, and no data are available on the health-related quality of life (HRQOL) for adolescents with BPD. The aim of this study was to assess HRQOL in adolescents with BPD, in comparison with age-matched and sex-matched control groups of healthy volunteers and asthmatic subjects. METHODS: We enrolled 27 BPD patients (age range 11-19 years), 27 asthmatic patients and 27 healthy controls. HRQOL was assessed by the Short Form 36 (SF-36) questionnaire. Lung function was assessed by spirometry. RESULTS: The BPD group did not differ significantly from the healthy controls in any scale or dimension of the SF-36 (the BPD group's summary scores were as follows: physical component summary mean 55.6 + 4.98 and mental component summary 51.8 + 7.75 vs 55.8 + 6.25 and 49.2 + 9.45 for the healthy control group, P > 0.5 and P = 0.26, respectively). Asthmatic adolescents scored lower than those of both healthy controls and patients with BPD in several SF-36 dimensions despite adolescents with BPD having lower lung function. No correlation emerged between lung function and HRQOL in BPD subjects. CONCLUSION: Despite their impaired lung function, BPD patients have an HRQOL comparable with healthy peers and better than asthmatic patients. We did not find any association between HRQOL and lung function parameters. PMID- 27245482 TI - Sluggish cognitive tempo is associated with suicide risk in psychiatrically hospitalized children. AB - BACKGROUND: Although identified as a significant public health concern, few studies have examined correlates of suicide risk in school-aged children. Recent studies show a relation between sluggish cognitive tempo (SCT) symptoms and a range of adverse outcomes linked to suicidal ideation, including depression, emotion dysregulation, lowered self-esteem, and peer problems/social withdrawal, yet no study to date has examined SCT in relation to suicide risk. METHODS: We tested the hypothesis that SCT would be associated with suicide risk in a sample of 95 psychiatrically hospitalized children (74% male; 62% black) between the ages of 8 and 12 (M = 10.01, SD = 1.50). Parents completed measures of their child's psychiatric symptoms, including SCT and depression, as well as a measure of their own psychopathology. Children completed measures assessing loneliness and depression. Both parents and children completed measures of suicide risk. RESULTS: White children reported greater suicide risk than nonwhite children. After controlling for demographic characteristics, loneliness, parental psychopathology, and correlated psychiatric symptoms, including both parent- and child self-reported depressive symptoms, SCT remained uniquely associated with children's suicide risk. Results were consistent across both parent and child measures of suicide risk. CONCLUSIONS: This multi-informant study provides strong preliminary support for an association between SCT symptoms and suicide risk in psychiatrically hospitalized children, above and beyond loneliness, depression, and demographic characteristics. Findings are discussed in the context of the interpersonal theory of suicide. Additional studies are needed to replicate and extend these findings, with a particular need for studies that examine the cognitive processes and daydreaming content of individuals displaying elevated SCT symptomatology. PMID- 27245484 TI - Physiologically Distributed Loading Patterns Drive the Formation of Zonally Organized Collagen Structures in Tissue-Engineered Meniscus. AB - The meniscus is a dense fibrocartilage tissue that withstands the complex loads of the knee via a unique organization of collagen fibers. Attempts to condition engineered menisci with compression or tensile loading alone have failed to reproduce complex structure on the microscale or anatomic scale. Here we show that axial loading of anatomically shaped tissue-engineered meniscus constructs produced spatial distributions of local strain similar to those seen in the meniscus when the knee is loaded at full extension. Such loading drove formation of tissue with large organized collagen fibers, levels of mechanical anisotropy, and compressive moduli that match native tissue. Loading accelerated the development of native-sized and aligned circumferential and radial collagen fibers. These loading patterns contained both tensile and compressive components that enhanced the major biochemical and functional properties of the meniscus, with loading significantly improved glycosaminoglycan (GAG) accumulation 200 250%, collagen accumulation 40-55%, equilibrium modulus 1000-1800%, and tensile moduli 500-1200% (radial and circumferential). Furthermore, this study demonstrates local changes in mechanical environment drive heterogeneous tissue development and organization within individual constructs, highlighting the importance of recapitulating native loading environments. Loaded menisci developed cartilage-like tissue with rounded cells, a dense collagen matrix, and increased GAG accumulation in the more compressively loaded horns, and fibrous collagen-rich tissue in the more tensile loaded outer 2/3, similar to native menisci. Loaded constructs reached a level of organization not seen in any previous engineered menisci and demonstrate great promise as meniscal replacements. PMID- 27245486 TI - The TIDieR Checklist Will Benefit the Physical Therapy Profession. AB - The TIDieR (template for intervention description and replication) checklist and guide were developed to improve the reporting of interventions in any evaluative study, including randomized trials. The checklist contains 12 items and was developed as an extension to the CONSORT 2010 and SPIRIT 2013 statements to provide further guidance for authors on the key information to include in trial reports. Incomplete reporting of interventions in physical therapy studies is an important problem, and we endorse the use of the TIDieR checklist as a potential solution. J Orthop Sports Phys Ther 2016;46(6):402-404. doi:10.2519/jospt.2016.0108. PMID- 27245487 TI - Idols of the Cave. AB - In this month's Viewpoint editorial, Drs Reiman, Thorborg, and Holmich provide a timely critique of the escalating diagnosis and surgical management of femoroacetabular impingement. They deconstruct an enthusiasm fueled by the imperfect evidence of passive observation. While almost always well meaning and not invaluable, it is too often enchanted with data skewed by invisible distortions, and interpreted by the human mind blind to its own credulities. J Orthop Sports Phys Ther 2016;46(6):405. doi:10.2519/jospt.2016.0109. PMID- 27245485 TI - One versus two years of elastic compression stockings for prevention of post thrombotic syndrome (OCTAVIA study): randomised controlled trial. AB - OBJECTIVE: To study whether stopping elastic compression stockings (ECS) after 12 months is non-inferior to continuing them for 24 months after proximal deep venous thrombosis. DESIGN: Multicentre single blind non-inferiority randomised controlled trial. SETTING: Outpatient clinics in eight teaching hospitals in the Netherlands, including one university medical centre. PARTICIPANTS: Patients compliant with compression therapy for 12 months after symptomatic, ultrasound proven proximal deep venous thrombosis of the leg. INTERVENTIONS: Continuation or cessation of ECS 12 months after deep venous thrombosis. MAIN OUTCOME MEASURES: The primary outcome was the incidence of post-thrombotic syndrome 24 months after diagnosis of deep venous thrombosis, as assessed by the standardised Villalta scale in an intention to treat analysis. The predefined non-inferiority margin was 10%. The main secondary outcome was quality of life (VEINES-QOL/Sym). RESULTS: 518 patients compliant with ECS and free of post-thrombotic syndrome were randomised one year after diagnosis of deep venous thrombosis to stop or continue ECS therapy for another year. In the stop-ECS group, 51 of 256 patients developed post-thrombotic syndrome, with an incidence of 19.9% (95% confidence interval 16% to 24%). In the continue-ECS group, 34 of 262 patients developed post-thrombotic syndrome (incidence 13.0%, 9.9% to 17%), of whom 85% used ECS six or seven days a week during the study period, for an absolute difference of 6.9% (95% confidence interval upper limit 12.3%). Because the upper limit of the 95% confidence interval exceeds the predefined margin of 10%, non-inferiority was not reached. The number needed to treat to prevent one case of post-thrombotic syndrome by continuing ECS was 14 (95% confidence interval lower limit 8). Quality of life did not differ between the two groups. CONCLUSION: Stopping ECS after one year in compliant patients with proximal deep venous thrombosis seemed not to be non-inferior to continuing ECS therapy for two years in this non inferiority trial. TRIAL REGISTRATION: Netherlands Trial Register NTR1442. PMID- 27245488 TI - Femoroacetabular Impingement Surgery Is on the Rise-But What Is the Next Step? AB - Surgery for femoroacetabular impingement (FAI) has been advocated for correction of cam and pincer hip joint morphology. Surgery for FAI was first pioneered by Myers et al, who surgically treated FAI by open dislocation. Arthroscopy was then introduced in 2005 by Sampson. Arthroscopy has continued to develop since then, with the intent of providing pain relief and improving function in patients with FAI. This Viewpoint discusses the escalating popularity of FAI surgery, the widespread acceptance of this relatively new surgical procedure, and next steps for determination of who benefits from this treatment. J Orthop Sports Phys Ther 2016;46(6):406-408. doi:10.2519/jospt.2016.0605. PMID- 27245489 TI - Acupuncture for Limb Conditions: Pinpointing the Evidence. AB - Acupuncture therapies include a range of interventions and are commonly used for managing musculoskeletal disorders of the extremities; however, their use is still controversial. A study published in the June 2016 issue of JOSPT conducted a systematic review of randomized clinical trials on the effectiveness of various acupuncture therapies for any musculoskeletal condition affecting the limbs. Importantly, the review critically appraised the quality of the evidence to reveal risks of bias. In this Perspectives for Practice, the authors explain the impact of their findings for clinicians treating patients with such musculoskeletal conditions. J Orthop Sports Phys Ther 2016;46(6):430. doi:10.2519/jospt.2016.0502. PMID- 27245490 TI - Tarsometatarsal (Lisfranc) Joint Injury in an Athlete With Persistent Foot Pain. AB - The patient was a 20-year-old female ultimate frisbee player who felt a "pop" in her left foot with resultant pain and bruising along the plantar aspect of her midfoot. She was seen by an orthopaedic physician, who ordered standard radiographs that were found to be unremarkable. Although initial non-weight bearing films were normal, these findings do not rule out tarsometatarsal joint injury. Following presentation to physical therapy 4 months after the initial injury, the patient was referred to a sports medicine physician. Weight-bearing radiographs and magnetic resonance imaging were ordered and confirmed a high grade Lisfranc ligament tear. J Orthop Sports Phys Ther 2016;46(6):494. doi:10.2519/jospt.2016.0408. PMID- 27245492 TI - June 2016 New Products. AB - A selection of products and developments of interest to JOSPT readers. J Orthop Sports Phys Ther 2016;46(6):496-498. doi:10.2519/jospt.2016.46.6.496. PMID- 27245491 TI - Acute Medial Plantar Fascia Tear. AB - A 32-year-old man who participated in competitive soccer came to physical therapy via direct access for a chief complaint of plantar foot pain. The clinical examination findings and mechanism of injury raised a concern for a plantar fascia tear, so the patient was referred to the physician and magnetic resonance imaging was obtained. The magnetic resonance image confirmed a high-grade, partial-thickness, proximal plantar fascia tear with localized edema at the location of the medial band. J Orthop Sports Phys Ther 2016;46(6):495. doi:10.2519/jospt.2016.0409. PMID- 27245493 TI - Mindfulness-of-breathing exercise modulates EEG alpha activity during cognitive performance. AB - The present study investigated whether engaging in a mindful breathing exercise would affect EEG oscillatory activity associated with self-monitoring processes, based on the notion that mindfulness enhances attentional awareness. Participants were assigned to either an audio exercise in mindful breathing or an audio control condition, and then completed a Stroop task while EEG was recorded. The primary EEG measure of interest was error-related alpha suppression (ERAS), an index of self-monitoring in which alpha power is reduced, suggesting mental engagement, following errors compared to correct responses. Participants in the mindful-breathing condition showed increased alpha power during the listening exercise and enhanced ERAS during the subsequent Stroop task. These results indicate enhanced error-monitoring among those in the mindful-breathing group. PMID- 27245494 TI - Using cell-free fetal DNA as a diagnostic and screening test: current understanding and uncertainties. PMID- 27245495 TI - Enzyme-Degradable Hybrid Polymer/Silica Microbubbles as Ultrasound Contrast Agents. AB - The fabrication of an enzyme-degradable polymer/silica hybrid microbubble is reported that produces an ultrasound contrast image. The polymer, a triethoxysilane end-capped polycaprolactone (SiPCL), is used to incorporate enzyme-degradable components into a silica microbubble synthesis, and to impart increased elasticity for enhanced acoustic responsiveness. Formulations of 75, 85, and 95 wt % SiPCL in the polymer feed produced quite similar ratios of SiPCL and silica in the final bubble but different surface properties. The data suggest that different regions of the microbubbles were SiPCL-rich: the inner layer next to the polystyrene template core and the outer surface layer, thereby creating a sandwiched silica-rich layer of the bubble shell. Overall, the thickness of the microbubble shell was dependent on the starting TEOS concentration and the reaction time. Despite the layered structure, the microbubble could be efficiently degraded by lipase enzyme, but was stable without enzyme. The ultrasound contrast showed a general trend of increase in image intensity with SiPCL feed ratio, although the 95 wt % SiPCL bubbles did not produce a contrast image, probably due to bubble collapse. At higher normalized peak negative acoustic pressure (mechanical index, MI), a nonlinear frequency response also emerges, characterized by the third harmonic at around 3f0, and increases with MI. The threshold MI transition from linear to nonlinear response increased with decrease in SiPCL. PMID- 27245496 TI - Lactobacillus crispatus strain SJ-3C-US induces human dendritic cells (DCs) maturation and confers an anti-inflammatory phenotype to DCs. AB - Lactobacillus crispatus is one of the most predominant species in the healthy vagina microbiota. Nevertheless, the interactions between this commensal bacterium and the immune system are largely unknown. Given the importance of the dendritic cells (DCs) in the regulation of the immunity, this study was performed to elucidate the influence of vaginal isolated L. crispatus SJ-3C-US from healthy Iranian women on DCs, either directly by exposure of DCs to ultraviolet inactivated (UVI) and heat-killed (HK) L. crispatus SJ-3C-US or indirectly to its cell-free supernatant (CFS), and the outcomes of immune response. In this work we showed that L. crispatus SJ-3C-US induced strong dose-dependent activation of dendritic cells and production of high levels of IL-10, whereas IL-12p70 production was induced at low level in an inverse dose-dependent manner. This stimulation skewed T cells polarization toward CD4(+) CD25(+) FOXP3(+) Treg cells and production of IL-10 in a dose-dependent manner in mixed leukocyte reaction (MLR) test. The mode of bacterial inactivation did not affect the DCs activation pattern, upon encounter with L. crispatus SJ-3C-US. Moreover, while DCs stimulated with CFS showed moderate phenotypic maturation and IL-10 production, it failed to skew T cells polarization toward CD4(+) CD25(+) FOXP3(+) regulatory T cells (Treg) and production of IL-10. This study showed that L. crispatus SJ-3C US confers an anti-inflammatory phenotype to DCs through up-regulation of anti inflammatory/regulatory IL-10 cytokine production and induction of CD4(+) CD25(+) FOXP3(+) T cells at optimal dosage. Our findings suggest that L. crispatus SJ-3C US could be a potent candidate as protective probiotic against human immune mediated pathologies, such as chronic inflammation, vaginitis or pelvic inflammatory disease (PID). PMID- 27245497 TI - Periodic Mesoporous Organosilica Nanoparticles with Controlled Morphologies and High Drug/Dye Loadings for Multicargo Delivery in Cancer Cells. AB - Despite the worldwide interest generated by periodic mesoporous organosilica (PMO) bulk materials, the design of PMO nanomaterials with controlled morphology remains largely unexplored and their properties unknown. In this work, we describe the first study of PMO nanoparticles (NPs) based on meta-phenylene bridges, and we conducted a comparative structure-property relationship investigation with para-phenylene-bridged PMO NPs. Our findings indicate that the change of the isomer drastically affects the structure, morphology, size, porosity and thermal stability of PMO materials. We observed a much higher porosity and thermal stability of the para-based PMO which was likely due to a higher molecular periodicity. Additionally, the para isomer could generate multipodal NPs at very low stirring speed and upon this discovery we designed a phenylene-ethylene bridged PMO with a controlled Janus morphology. Unprecedentedly high payloads could be obtained from 40 to 110 wt % regardless of the organic bridge of PMOs. Finally, we demonstrate for the first time the co delivery of two cargos by PMO NPs. Importantly, the cargo stability in PMOs did not require the capping of the pores, unlike pure silica, and the delivery could be autonomously triggered in cancer cells by acidic pH with nearly 70 % cell killing. PMID- 27245498 TI - Will peripherally restricted kappa-opioid receptor agonists (pKORAs) relieve pain with less opioid adverse effects and abuse potential? AB - WHAT IS KNOWN AND OBJECTIVE: Optimal utilization of opioid analgesics is significantly limited by the central nervous system adverse effects and misuse/abuse potential of currently available drugs. It has been postulated that opioid-associated adverse effects and abuse potential would be greatly reduced if opioids could be excluded from reaching the brain. We review the basic science and clinical evidence of one such approach - peripherally restricted kappa-opioid receptor (KOR) agonists (pKORAs). METHODS: Published and unpublished literature, websites and other sources were searched for basic science and clinical information related to the potential benefits and development of peripherally restricted kappa-opioid receptor agonists. Each source was summarized, reviewed and assessed. RESULTS: The historical development of pKORAs can be traced from the design of increasingly KOR-selective agonists, elucidation of the pharmacologic attributes of such compounds and strategies to restrict passage across the blood-brain barrier. Novel compounds are under development and have progressed to clinical trials. WHAT IS NEW AND CONCLUSIONS: The results from recent clinical trials suggest that peripherally restricted opioids can be successfully designed and that they can retain analgesic efficacy with a more favourable adverse effect profile. PMID- 27245499 TI - The kynurenine pathway in schizophrenia and bipolar disorder. AB - The kynurenine pathway of tryptophan degradation generates several neuroactive compounds. Of those, kynurenic acid is an N-methyl-d-aspartate (NMDA) and alpha7 nicotinic receptor antagonist. The kynurenic acid hypothesis of schizophrenia is built upon the fact that kynurenic acid blocks glutamate receptors and is elevated in schizophrenia. Kynurenic acid tightly controls glutamatergic and dopaminergic neurotransmission and elevated brain levels appear related to psychotic symptoms and cognitive impairments. Contributing to enhanced production of kynurenic acid, the expression and enzyme activity of kynurenine 3 monooxygenase (KMO) are reduced in schizophrenia and in bipolar patients with a history of psychosis. The kynurenine pathway is also critically regulated by cytokines, and, indeed, the pro-inflammatory cytokines interleukin (IL)-1beta and IL-6 are elevated in schizophrenia and bipolar disorder and stimulate the production of kynurenic acid. One physiological mechanism controlling the activity of the kynurenine pathway originates from the protein sorting nexin 7 (SNX7). This glial signaling pathway initiates a caspase-8-driven activation of IL-1beta that induces tryptophan-2,3-dioxygenase 2 (TDO2), an enzyme in the kynurenine pathway. A recent study shows that a genetic variation resulting in decreased expression of SNX7 is linked to increased central levels of kynurenic acid and ultimately to psychosis and cognitive dysfunction in bipolar disorder. Experimental studies highlight the detrimental effects of increased synthesis of kynurenic acid during sensitive periods of early brain development. Furthermore, experimental studies strongly support inhibition of kynurenine aminotransferase (KAT) II as a novel target and a valuable pharmacological strategy in the treatment of psychosis and for improving cognitive performance relevant for schizophrenia. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'. PMID- 27245500 TI - Mechanism of direct Cav2.2 channel block by the kappa-opioid receptor agonist U50488H. AB - U50488H is a benzeneacetamide kappa-opioid receptor (kappa-OR) agonist analgesic, widely used for investigating the pharmacology of G protein-coupled kappa-ORs. However, U50488H is also known to directly block various voltage-gated ion channels in a G protein-independent manner. We investigated the direct actions of U50488H on various high voltage-activated (HVA) and low voltage-activated (LVA) neuronal Ca(2+) channels heterologously expressed in human embryonic kidney (HEK293) cells. U50488H inhibited HVA rat Cav1.3 (rCav1.3), human Cav2.1 (hCav2.1), hCav2.2, hCav2.3, and LVA hCav3.1 and hCav3.2 channels in a concentration-dependent manner, with similar potencies characterised with half maximal inhibitory concentration (IC50) values of ~30 MUM. U50488H concentrations causing direct Cav inhibition are typically >100 times higher than those producing kappa-OR activation. Investigation of the mechanism of U50488H block of the Cav2.2 channel revealed that U50488H interacted with all major kinetic states of the channel - resting, open, and inactivated. U50488H did not affect the voltage dependence of activation but shifted the steady-state inactivation curve by ~11 mV to more hyperpolarized potentials. U50488H also increased the rate of Ba(2+) current inactivation during a step depolarization and significantly delayed recovery from slow inactivation, compared with control. Cav2.2 current inhibition was frequency dependent during repetitive step depolarization at 1 Hz and 3 Hz, consistent with use-dependent block. In summary, our results suggest that preferential interaction of U50488H with inactivated Cav2.2 channels significantly contributes to reduced Cav2.2 channel availability and slow recovery form inactivation. We conclude that U50488H non-selectively blocks heterologously expressed neuronal HVA and LVA Cav channels in the absence of kappa-ORs. This cross-reactivity also suggests potentially common U50488H binding motifs across Cav channel targets. PMID- 27245501 TI - Prostate cancer: Interfering with abiraterone metabolism to optimize therapy. PMID- 27245502 TI - Kidney cancer: Response to nivolumab in RCC: RECISTing progression. PMID- 27245503 TI - Prostate cancer: Combining endocrine treatment and radiotherapy: a bright future. PMID- 27245504 TI - The role of the prostate in male fertility, health and disease. AB - Ejaculation is a synchronized cascade of events that has the ultimate goal of activating sperm and enabling them to reach an egg for fertilization. The seminal plasma contains a complex mixture of fluids that is secreted from the testes, epididymis and male accessory glands. The prostate gland has a pivotal role in this process, as prostatic fluid enriched in Zn(2+), citrate and kallikreins is crucial for the molecular synchronization of the functional cascade triggered by ejaculatory stimuli. The prostate is the target of a number of common diseases that can affect male fertility at different ages. In both young and aged men, prostatic diseases or an unhealthy prostate can affect spermatozoa functioning and, therefore, male fertility. Consideration of prostate physiology emphasizes a number of points: the central role of Zn(2+) and citrate in the regulation of prostate epithelium homeostasis and in ejaculation; the influence of bacteria related prostatic inflammation on male fertility; and the potential role of prostatic inflammation in promoting the development of prostatic hyperplastic growth and carcinogenesis. PMID- 27245506 TI - Prostate cancer: SRRM4 drives NEPC progression. PMID- 27245507 TI - Production of recombinant human apoptosis signal-regulating kinase 1 (ASK1) in Escherichia coli. AB - Apoptosis signal-regulating kinase 1 (ASK1) is a mediator of the MAPK signaling cascade, which regulates different cellular processes including apoptosis, cell survival, and differentiation. The increased activity of ASK1 is associated with a number of human diseases and this protein kinase is considered as promising therapeutic target. In the present study, the kinase domain of human ASK1 was expressed in Escherichia coli (E. coli) in soluble form. The expression level of ASK1 was around 0.3-0.47 g per 1 L after using auto-induction protocol or IPTG induction. A one-step on column method for the efficient purification of recombinant ASK1 was performed. Our approach yields sufficient amount of recombinant ASK1, which can be used for inhibitor screening assays and different crystallographic studies. PMID- 27245505 TI - Does central sensitization help explain idiopathic overactive bladder? AB - The pathophysiological mechanisms underlying overactive bladder syndrome (OAB) can include dysfunction of sensory pathways of the peripheral and central nervous systems, resulting in bladder hypersensitivity. Central sensitization describes an induced state of spinal hypersensitivity that is associated with a variety of chronic pain disorders that share many attributes with OAB, albeit without the presence of pain. As such, the concept of central sensitization might be relevant to understanding the mechanisms and clinical manifestations of OAB syndrome. An understanding of the pathophysiology and clinical manifestations of central sensitization, and the evidence that supports a role of central sensitization in OAB, including the potential implications of mechanisms of central sensitization for the treatment of patients with OAB could provide a novel approach to the treatment of patients with this disease. Such an approach would be especially relevant to those patients with central sensitization-related comorbidities, and has the potential to improve the outcomes of these patients in particular. PMID- 27245510 TI - Anti-Inflammatory Effects of Modified Adenoviral Vectors for Gene Therapy: A View through Animal Models Tested. AB - The central dogma of gene therapy relies on the application of novel therapeutic genes to treat or prevent diseases. The main types of vectors used for gene transfer are adenovirus, retrovirus, lentivirus, liposome, and adeno-associated virus vectors. Gene therapy has emerged as a promising alternative for the treatment of inflammatory diseases. The main targets are cytokines, co stimulatory molecules, and different types of cells from hematological and mesenchymal sources. In this review, we focus on molecules with anti-inflammatory effects used for in vivo gene therapy mediated by adenoviral gene transfer in the treatment of immune-mediated inflammatory diseases, with particular emphasis on autoinflammatory and autoimmune diseases. PMID- 27245508 TI - Non integrative strategy decreases chromosome instability and improves endogenous pluripotency genes reactivation in porcine induced pluripotent-like stem cells. AB - The pig is an emerging animal model, complementary to rodents for basic research and for biomedical and agronomical purposes. However despite the progress made on mouse and rat models to produce genuine pluripotent cells, it remains impossible to produce porcine pluripotent cell lines with germline transmission. Reprogramming of pig somatic cells using conventional integrative strategies remains also unsatisfactory. In the present study, we compared the outcome of both integrative and non-integrative reprogramming strategies on pluripotency and chromosome stability during pig somatic cell reprogramming. The porcine cell lines produced with integrative strategies express several pluripotency genes but they do not silence the integrated exogenes and present a high genomic instability upon passaging. In contrast, pig induced pluripotent-like stem cells produced with non-integrative reprogramming system (NI-iPSLCs) exhibit a normal karyotype after more than 12 months in culture and reactivate endogenous pluripotency markers. Despite the persistent expression of exogenous OCT4 and MYC, these cells can differentiate into derivatives expressing markers of the three embryonic germ layers and we propose that these NI-iPSLCs can be used as a model to bring new insights into the molecular factors controlling and maintaining pluripotency in the pig and other non-rodent mammalians. PMID- 27245516 TI - From Africa and India to Blackpool: Military history and ambulance services. PMID- 27245511 TI - Effect of dietary energy and polymorphisms in BRAP and GHRL on obesity and metabolic traits. AB - OBJECTIVE: Obesity, a risk factor for all-cause and cardiovascular mortality, is a major health concerns among middle-aged men. The aim of this study was to investigate a possible association of dietary habits and obesity related single nucleotide polymorphisms (SNPs) with obesity and metabolic abnormalities. METHODS: We conducted a retrospective cohort study using annual health examination data of 5112 male workers, obtained between 2007 and 2011. Average dietary energy was estimated using electronically collected meal purchase data from cafeteria. We examined 8 SNPs related to obesity: GHRL rs696217, PPARG rs1175544, ADIPOQ rs2241766, ADIPOQ rs1501299, PPARD rs2016520, APOA5 rs662799, BRAP rs3782886, and ITGB2 rs235326. We also examined whether SNPs that were shown to associate with obesity affect other metabolic abnormalities such as blood pressure (BP), glucose, and lipid profile. RESULTS: Average dietary energy significantly associated with increased abdominal circumference (AC) and body mass index (BMI). The odds ratios (ORs) of overweight and obesity also increased. The major allele of rs696217 significantly increased BMI and an increased OR with obesity, while the minor allele of rs3782886 was associated with significantly decreased AC and the decreased ORs with overweight and obesity. The minor allele of rs3782886 was also associated with significantly decreased systolic BP (SBP), triglyceride (TG), high-density lipoprotein (HDL), and fasting blood sugar (FBS), while rs696217 was not associated with other metabolic abnormalities. CONCLUSIONS: Average dietary energy in lunch, rs3782886, and rs696217 were associated with obesity, and rs3782886 was associated with other metabolic abnormalities. PMID- 27245517 TI - Peter Beighton on Rapa Nui (Easter Island), 1964 - 1965. PMID- 27245518 TI - People and wildlife in the Tristan da Cunha islands. PMID- 27245519 TI - Tributes. PMID- 27245520 TI - Cytogenetics at the University of Cape Town: A 45-year journey. AB - This article is a brief record of the cytogenetics laboratory from its birth in 1971, under the auspices of the University of Cape Town, throughout its development within the Department of Human Genetics, under the leadership of Professor Peter Beighton, to its present position at Groote Schuur Hospital, as a multidisciplinary unit run by the National Health Laboratory Service. PMID- 27245521 TI - Inherited retinal disorders in South Africa and the clinical impact of evolving technologies. AB - Retinal degenerative disorders (RDDs) encompass a group of inherited diseases characterised by vision loss. The genetic and clinical complexity poses a challenge in unravelling the molecular genetic aetiology of this group of disorders. Furthermore, the population diversity in South Africa (SA) presents researchers with a particularly complicated task. Rapid advances in the development of cutting-edge technological platforms over the past two decades, however, have assisted in overcoming some of the challenges. The RDD research team has utilised these escalating technologies, which has facilitated a corresponding increase in molecular diagnoses. A biorepository has been established and comprises ~3 200 patient DNA samples archived with many forms of RDD (including retinitis pigmentosa, macular dystrophies, Stargardt disease, Leber congenital amaurosis, Usher syndrome and Bardet Biedl syndrome). A comprehensive review is presented of the SA journey spanning 25 years, into elucidating the molecular genetic basis of various forms of RDD in SA. PMID- 27245522 TI - The hereditary ataxias: Where are we now? Four decades of local research. AB - The hereditary ataxias have been studied at the University of Cape Town for more than 40 years, following from initial clinical investigations by Beighton and colleagues in the early 1970s. This group of inherited disorders is characterised by progressive neurodegeneration and associated symptoms, including the inability to coordinate movement. Following initial local and international linkage studies, and the discovery of the genes responsible for the key dominant and recessive inherited ataxias in the 1990s, a local molecular testing service was established at Groote Schuur Hospital. More than 1 600 individuals have been referred through this testing service (now offered by the National Health Laboratory Service), leading to the molecular diagnosis of 253 families with spinocerebellar ataxia types 1, 2, 3, 6 or 7, and 30 families with Friedreich's ataxia. This is likely to be an under-representation of the number of South Africans affected with hereditary ataxia, and future research efforts will focus on increasing the awareness of this group of disorders, both locally and throughout the rest of Africa. Next-generation technologies will be beneficial in identifying additional genes underlying inherited ataxia in indigenous patients to enable more appropriate management and treatment of individuals with molecularly undiagnosed forms of the disease. PMID- 27245523 TI - Joint laxity in the performing arts. AB - Traditional scoring systems for the assessment of joint flexibility are reviewed and reasons for variation in joint laxity are defined. The value of controlled joint laxity in the hands and arms of musicians is then discussed as well as the desirability of adjusting laxity at the various joints used in the different styles of dance, some of them ethnic, that depend on the specific articular characteristics of each different dancer. PMID- 27245524 TI - Ehlers-Danlos syndrome. AB - The Ehlers-Danlos syndromes (EDSs) were originally described by Ehlers in Denmark and Danlos in Paris in 1898 and 1908, respectively. They had both published individual case studies in which the common factor was laxity of ligaments leading to joint hypermobility and hyperextensibility of the skin. The choice of the name of this eponymous disease had been made by Dr Parkes Weber, an eminent London physician in the 1930s, who had a penchant for eponymous diseases, having had no less than seven attributed to himself, at least in part. Unfortunately, this was before the age of a computerised literature search, and Parkes Weber had inadvertently overlooked the very first description of EDS which had been made by Tchernabogov, a Russian dermatologist, whose description was published in 1891 and remains one of the best descriptions of EDS in the literature. PMID- 27245525 TI - Pamidronate treatment for osteogenesis imperfecta in black South Africans. AB - BACKGROUND: Osteogenesis imperfecta is a heritable disorder of bone connective tissue. Type III has a high incidence in the black pop-ulation of South Africa. Affected people experience numerous fractures, bone pain and progressive disability. Until the introduction of bisphosphonates to reduce fracture incidence, treatment revolved around orthopaedic and supportive care. Objective. To assess the subjective attitude of patients towards pamidronate treatment. METHODS: Thirty black patients with osteogenesis imperfecta type III treated at Universitas Hospital were approached and 26 were included in this study. Patients or their parents were interviewed using a standardised researcher-administered questionnaire, either in person or by telephone. RESULTS: Most patients reported a reduction in symptoms, a feeling of increased wellbeing, increased strength and rated the pamidronate treatment highly. The intravenous route of administration and the side-effects experienced were bearable. Overall all patients would recommend this treatment to other affected persons. CONCLUSION: This is first study to look at bisphosphonate treatment for osteogenesis imperfecta type III in black South Africans. The treatment is well tolerated and highly rated by the patients. Reported improvements and side-effects are similar to those reported in other populations. Using this form of treatment in this population is supported by these findings. PMID- 27245526 TI - Thanatophoric dysplasia: A review. AB - Thanatophoric dysplasia is a well-known cause of potentially lethal short-limbed dwarfism in the newborn. The diagnosis is usually made by the recognition of characteristic radiological changes and confirmed at autopsy by demonstration of specific morphological and histological changes in the brain. This review is based upon the author's personal experience and archived data of 19 cases and concerns the clinical and radiographic manifestations, autopsy findings, molecular pathogenesis and the approach to antenatal diagnosis. PMID- 27245527 TI - Spondyloepimetaphyseal dysplasia with joint laxity (Beighton type): A unique South African disorder. AB - Spondyloepimetaphyseal dysplasia with joint laxity (SEMD-JL) is an autosomal recessive skeletal dysplasia in which stunted stature, articular hypermobility and spinal malalignment are the major manifestations. Structural cardiac abnormalities are sometimes present. Approximately 30 affected children have been recognised previously in the Afrikaans-speaking community in South Africa, and in several, mutations in the B3GALT6 gene have been incriminated. In this article, case details of three additional affected children in two families are documented, and four additional families are mentioned. The Pierre-Robin sequence and unilateral renal agenesis are previously unreported concomitants. The mutational status where known is recorded. PMID- 27245528 TI - The rise of developmental genetics - a historical account of the fusion of embryology and cell biology with human genetics and the emergence of the Stem Cell Initiative. AB - Genetics and cell biology are very prominent areas of biological research with rapid advances being driven by a flood of theoretical, technological and informational knowledge. Big biology and small biology continue to feed off each other. In this paper, we provide a brief overview of the productive interactions that have taken place between human geneticists and cell biologists at UCT, and credit is given to the enabling environment created led by Prof. Peter Beighton. The growth of new disciplines and disciplinary mergers that have swept away division of the past to make new exciting syntheses are discussed. We show how our joint research has benefitted from worldwide advances in developmental genetics, cloning and stem cell technologies, genomics, bioinformatics and imaging. We conclude by describing the role of the UCT Stem Cell Initiative and show how we are using induced pluripotent cells to carry out disease-in-the- dish studies on retinal degeneration and fibrosis. PMID- 27245529 TI - Tributes. PMID- 27245530 TI - A possible heterozygous advantage in muscular dystrophy. AB - In certain autosomal recessive disorders there is suggestive evidence that heterozygous carriers may have some selective advantage over normal homozygotes. These include, for example, cystic fibrosis, Tay-Sachs disease and phenylketonuria. The best example so far, however, is that of significant heterozygous advantage in sickle-cell anaemia with increased resistance to falciparum malaria. PMID- 27245531 TI - Duchenne muscular dystrophy in the Western Cape, South Africa: Where do we come from and where are we going? AB - Duchenne muscular dystrophy (DMD) is one of the most common and severe of the inherited dystrophies, with an incidence of 1 in 3 500 live, male births worldwide. Becker muscular dystrophy (BMD) has a lower incidence of 1:14 000 - 18 000 boys and a milder progression and longer life expectancy. Over the last two decades, better understanding of the underlying disease aetiology as well as major advances in medical technology have brought about significantly improved genetic diagnosis and clinical care for B/DMD patients. Exciting developments in the field of gene-based therapies have once again put B/DMD in the limelight, with renewed focus on the importance of comprehensive genetic testing protocols. We present a historical overview of the medical and molecular service for B/DMD offered over the last three decades in South Africa, specifically in the Western Cape, from a clinical as well as a laboratory perspective. PMID- 27245532 TI - Bardet Biedl syndrome in South Africa: A single founder mutation. AB - BACKGROUND: Bardet Biedl syndrome (BBS) is a multisystem disorder characterised by obesity, polydactyly, intellectual disability and loss of vision due to a progressive retinopathy. Although typically a highly heterogeneous autosomal recessive disease, homozygosity for single mutation in BBS 10 has been identified in a significant number of affected individuals tested in South Africa (SA). Objectives. To delineate the ethnic distribution and clinical phenotype in a cohort of SA BBS patients with the K243IfsX15 mutation in BBS 10 and discuss the implications for genetic testing of and counselling for this disorder in SA. METHOD: This was a descriptive cross-sectional study collating clinical and laboratory data retrospectively in a genetically homogenous subgroup of BBS patients from SA. RESULTS: A total of 76 patients from 74 families were tested. Homozygosity for the K243IfsX15 BBS 10 mutation was found in 50 families (67%) and heterozygosity for the same mutation in an additional two affected individuals. With the exception of one patient of mixed ancestry, all were black South Africans from different language groups. This is in keeping with the observation that BBS is more common in this ethnic group compared with white and coloured patients in SA, first made by Prof. Beighton nearly 3 decades ago. A subset of 15 patients available for detailed phenotyping confirmed consistency with well-described features of the disorder, with some overlap with other ciliopathies. The onset of visual impairment was early in our cohort, before the age of 8 years, cognitive impairment was significant, and renal and cardiac abnormalities were infrequently encountered. Conclusion. The high frequency of homozygosity for a single mutation in an ethnic subset of the SA population is strongly suggestive of a founder effect. This has allowed establishment of a diagnostic test with a high yield in our local population. Better understanding of the phenotype will improve earlier recognition of the disorder to allow for appropriate intervention. Testing can confirm but not negate a clinical diagnosis, and can permit carrier and prenatal testing in informative families. PMID- 27245533 TI - Cone opsins, colour blindness and cone dystrophy: Genotype-phenotype correlations. AB - X-linked cone photoreceptor disorders caused by mutations in the OPN1LW (L) and OPN1MW (M) cone opsin genes on chromosome Xq28 include a range of conditions from mild stable red-green colour vision deficiencies to severe cone dystrophies causing progressive loss of vision and blindness. Advances in molecular genotyping and functional analyses of causative variants, combined with deep retinal phenotyping, are unravelling genetic mechanisms underlying the variability of cone opsin disorders. PMID- 27245534 TI - Interruption of enzyme replacement therapy in Gaucher disease. AB - In Australia, 58 patients with Gaucher disease were managed by a Gaucher Disease Advisory Committee (GDAC) through a centrally adminis-tered national programme, the Life Savings Drug Program (LSDP). In June 2009, Genzyme Corporation, which manufactures imiglucerase (Cerezyme), the only enzyme replacement therapy (ERT) registered for the treatment of Gaucher disease in Australia at that time, announced that due to a viral contamination problem there would be no further shipments of Cerezyme to Australia prior to the end of 2009. The GDAC allocated available drug supplies in order to maintain treatment to those most in need on a hierarchal clinical severity basis. A cohort of 24 patients with Type 1 Gaucher disease was withdrawn from therapy, 22 of whom had no discernible clinically significant adverse effects when reviewed off therapy for up to 6 months. In this paper, we review the course of 20 of the patients who have been on imiglucerase for periods of at least 24 months after the end of their 'drug holiday'. No patient experienced a bone crisis nor clinical nor magnetic resonance imaging evidence of new avascular necrosis events during this period. Two years after recommencing ERT after a 6-month drug holiday, no patient had developed an overt irreversible complication of their Gaucher disease, with the majority returning to their previous clinical status. PMID- 27245535 TI - Predicted v. real prevalence of the 22q11.2 deletion syndrome in children with congenital heart disease presenting to Red Cross War Memorial Children's Hospital, South Africa: A prospective study. AB - BACKGROUND: The 22q11.2 deletion syndrome (22qDS) has more than 180 associated phenotypic features, yet genotype-phenotype correlation remains obscure. Since many of the clinical characteristics are serious, yet treatable (including congenital heart disease), clinicians must maintain a high index of clinical suspicion to recognise a suite of co-occurring phenotypic features that suggest a diagnosis of 22qDS. Oskarsdottir's scoring schedule (the 'O score') is generally used to suggest the need for confirmatory fluorescent in situ hybridisation (FISH) testing, using the TUPLE 1 probe. An O score of two or more indicates the need for FISH testing. Objectives. A previous audit of FISH-positive results of patients with congenital heart disease at Red Cross War Memorial Children's Hospital (RCWMCH) revealed a clinical recognition rate of 1.7%. However, we were concerned that the syndrome may be under-recognised in our setting. Our aims were therefore to assess the predictive value of 'O scoring' and to accurately determine the prevalence of 22qDS in our patient population. Methods. A prospective trial of FISH testing every new patient with congenital heart disease presenting to RCWMCH was undertaken to accurately determine the prevalence of 22qDS. The results were then compared with the ability of the O score to indicate the need for FISH testing. RESULTS: Testing of 125 patients detected deletions in six (4.8%, 2.8 times the previously determined clinical detection rate), thereby vindicating our concern that 22qDS is under-diagnosed. Of these 125 patients, 37 had an O score of 2 or 3, yet only 6 were FISH-positive, giving the O score a positive predictive value of only 14%. Conclusion. Until a more robust alternative recognition tool is available, South African clinicians should use all clinical recognition criteria liberally to suggest the need for formal testing for 22qDS. PMID- 27245536 TI - Interpreting genetic risks. AB - Prof. Peter Beighton has given a professional lifetime to helping patients and their families who have been afflicted by inherited disease. His clinical skills have brought certainty, confidence and support to those confronted with some of the most difficult decisions in life's progress. Prof. Beighton's research has led to the discovery of new syndromes and the elucidation of accurate genetic risks in many diseases. This in turn has empowered patients and their families to make informed decisions and has provided doctors with the scientific knowledge to help patients. On the occasion of this festschrift, I join with so many members of Peter's international professional family to pay tribute to his leadership and service - not only in medical genetics - but also in the broadest domains of healthcare. PMID- 27245537 TI - Osteogenesis imperfecta type III in South Africa: Psychosocial challenges. AB - Individuals with osteogenesis imperfecta type III (OI III) are severely physically disabled due to frequent fracturing. Their disability poses numerous barriers that challenge their social development. Despite these limitations, several affected persons are able to rise above these problems and achieve success in their personal and professional life. This outcome is directly relevant to their psychosocial development.The achievements of five individuals with OI III living in Cape Town are highlighted in this article, as well as the challenges that they have experienced and continue to experience in their daily lives. The authors intend to promulgate understanding of the psychosocial circumstances of affected persons, thereby facilitating the deployment of appropriate efforts and resources to address these challenges. PMID- 27245538 TI - Dental needs of intellectualy disabled children attending six special educational facilities in Cape Town. AB - OBJECTIVE: To assess the dental needs of a group of children with intellectual disability (ID) attending six special educational facilities in Cape Town, South Africa. Methods. This was a cross-sectional study based on a convenience sampling method. One hundred and fifty-seven children with ID attending six special educational facilities in Cape Town were included in the survey. Five schools were exclusively funded by the State and one school received additional private financial support. The oral examinations complied with guidelines drafted by Special Olympics Special Smiles programme and the Centers for Disease Control, USA. RESULTS: The most common dental disorders requiring management were gingival disease (69%) and untreated dental caries (68%). Almost 50% of the children had missing teeth. Twenty-nine percent needed orthodontic correction of malocclusion and 7% had structural abnormalities of their teeth that required either aesthetic or functional intervention. Fillings were evident in only 8% of the children. Females required more dental treatment than males. The dental needs of children with ID increased with age. There were no significant differences in the dental needs of children attending State-funded schools and those attending the single school that received additional financial assistance. CONCLUSION: The frequency of unmet dental needs of children with ID attending special educational facilities in Cape Town was high and the dental care available to them was minimal. The study highlights the need for improved dental services to ensure that optimal oral health is accessible to children with ID attending special educational facilities in Cape Town. PMID- 27245539 TI - Hyperostosis in siblings. AB - Infantile cortical hyperostosis - Caffey-Silverman disease - is a familial disorder manifesting in the late fetal period or infancy with excessive periosteal bone formation. Signs and symptoms regress spontaneously within months and result in expanded, deformed bones. The paucity of clinical symptoms may lead to delayed investigation and confusion of the remaining bone changes with those in other conditions. This problem is exemplified by two siblings misdiagnosed as osteogenesis imperfecta. The diagnosis of Caffey-Silverman disease was confirmed by molecular analysis showing the specific COL1A1 mutation in the patients and their clinically unaffected mother. Reduced penetrance rather than autosomal recessive inheritance explains multiple affected siblings born to healthy parents. PMID- 27245540 TI - Osteoporosis-pseudoglioma syndrome in South Africa. AB - The osteoporosis-pseudoglioma syndrome (MIM 259770) is a rare autosomal recessive disorder in which bone fragility and frequent fractures are associated with serious ocular changes. The skeletal manifestations resemble those of osteogenesis imperfecta while hyperplasia of the vitreous, eye and corneal opacities often mimics the appearance of intraocular glioma. This disorder was previously reported in a South African family of Indian stock as 'the ocular form of osteogenesis imperfecta'. Terminological discussion followed and it was suggested that these individuals had osteoporosis-pseudoglioma syndrome. This article describes and depicts the manifestations of the disorder and discusses the nosology. PMID- 27245541 TI - Fetal alcohol spectrum disorders: Prevalence rates in South Africa. AB - BACKGROUND: Fetal alcohol spectrum disorder (FASD) is an under-diagnosed condition in South Africa (SA). Fetal alcohol syndrome and FASD community prevalence studies were undertaken in 17 towns in three of the nine provinces in SA. OBJECTIVE: The objective for all the studies was to determine the FASD prevalence rates by assessing the grade 1 learners in all the studies, using international FASD diagnostic criteria. METHODS: The same methodology was used for all the studies in Gauteng, Western and Northern Cape provinces. Consenting grade 1 learners received anthropometric screening, clinical examinations and neurodevelopmental assessments. Structured interviews were used to assess maternal alcohol consumption during pregnancy. RESULTS: Reported prevalence rates ranged from 29 to 290 per 1 000 live births. CONCLUSION: FASD rates from studies conducted in SA are among the highest worldwide. FASD affects all communities in SA and is therefore a major public health concern in SA. Multidisciplinary and intersectoral interventions are urgently required to raise awareness about the dangers of prenatal alcohol exposure and the devastating effect of FASD on the lives of children, families and communities. PMID- 27245542 TI - Spinocerebellar ataxia type 7 in South Africa: Epidemiology, pathogenesis and therapy. AB - Disorders of the nervous system represent a significant proportion of the global burden of non-communicable diseases, due to the trend towards ageing populations. The Department (now Division) of Human Genetics at the University of Cape Town (UCT) has been involved in pioneering research into these diseases since the appointment of Prof. Peter Beighton as Head of Department in 1972. Beighton's emphasis on understanding the genetic basis of disease laid the groundwork for investigations into several monogenic neurodegenerative conditions, including Huntington's disease and the polyglutamine spinocerebellar ataxias (SCAs). In particular, SCA7, which occurs at an unusually high frequency in the South African (SA) population, was identified as a target for further research and therapeutic development. Beginning with early epidemiological surveys, the SCA7 project progressed to molecular genetics-based investigations, leading to the identification of a founder effect in the SA SCA7 patient population in the mid 2000s. Capitalising on the founder haplotype shared by many SCA7 patients, UCT researchers went on to develop the first population-specific gene-silencing approach for the disease. More recently, efforts have shifted to the development of a more accurate model to decipher the precise mechanisms of neurodegeneration, using induced pluripotent stem cells derived from SA SCA7 patients. In many ways, the SA SCA7 journey reflects the legacy and vision of Prof. Peter Beighton, and his efforts to establish world-class, collaborative research into diseases affecting the African continent. PMID- 27245543 TI - Pyle metaphyseal dysplasia in an African child: Case report and review of the literature. AB - Pyle disease (OMIM 265900), also known as metaphyseal dysplasia, is a rare autosomal recessive disorder with no known gene mutation. We report a case of Pyle disease in a 7-year-old African boy of mixed ancestry who presented with finger and wrist fractures following minor trauma. The radiological findings revealed abnormally broad metaphyses of the tubular bones, known as Erlenmeyer flask bone deformity, and mild cranial sclerosis, both hallmarks of the condition. We report the first case in a patient with African ancestry, which could help in the gene discovery of this rare autosomal recessive skeletal dysplasia with unknown mutations. PMID- 27245544 TI - Application of advanced molecular technology in the diagnosis and management of genetic disorders in South Africa. AB - BACKGROUND: Genetic testing has evolved from a niche speciality for diagnosis of rare disorders and carrier screening to subtyping of complex medical conditions for targeted treatment. Genes causing monogenic disorders are well characterised, but risk management of multifactorial and polygenic disorders guided from the genetic background remains a challenge. Objective. This study describes the use of a pathology-supported genetic testing (PSGT) strategy designed to facilitate the move from single- to multi-gene testing and next-generation sequencing (NGS). Methods. In contrast to direct-to-consumer genetic testing, PSGT requires preselection of patients and data integration to determine current and future risk implications. To enable this process, a genomics database resource generated at the interface between the laboratory and clinic is available for clinical interpretation. Results. The PSGT approach led to the development of testing algorithms for improved clinical management of patients with cancer and other complex disorders with a genetic component. Local evidence is presented to demonstrate the application of PSGT for assessment of clinical relevance in patients with rare germline variants and functional polymorphisms underlying shared disease pathways. CONCLUSION: PSGT is ideally suited to serve as a screening step for microarray analysis and whole genome/exome sequencing as the next frontier in personalised medicine. Use of these advanced molecular technologies to match genotype with phenotype provides a resource for diagnosis and discovery over a lifetime. PMID- 27245545 TI - Evaluating the contribution of APOBEC3G haplotypes, on influencing HIV infection in a Zimbabwean paediatric population. AB - BACKGROUND: Apolipoprotein B mRNA-editing catalytic polypeptide like-3G (APOBEC3G) is an antiviral enzyme that reduces viral fitness by introducing uracil to thymidine hypermutations in viral genomes. Thus, polymorphisms in the APOBEC3G gene have been implicated in differential outcomes of HIV infection and disease progression. However, there is insufficient evidence on the role of APOBEC3G gene variants on HIV infection, especially in African populations. This study therefore describes polymorphisms in the APOBEC3G gene in a Zimbabwean paediatric population and evaluates their effects on susceptibility to HIV infection among children born to HIV-infected mothers. Methods. A total of 104 children aged between 7 and 9 years, comprising 68 perinatally exposed to HIV (32 born infected (EI) and 36 born uninfected (EU)) and 36 unexposed and uninfected (UEUI) controls were recruited. Allelic variants (n=5) in the APOBEC3G gene were characterised. Results. Frequencies for minor APOBEC3G alleles in the HIV uninfected groups (EU and UEUI) were c.557G (40%), g.-90C (32%), g.-571C (12%), c.467-85C (42%), and c.582-162G (6%). APOBEC3G c.467-85C frequency was statistically significantly different when compared to the Masai of Kinyawa, Kenya population (42% v. 18%). None of the single nucleotide polymorphisms individually or as part of haplotypes were significantly associated with HIV infection when comparing the EI and EU groups. Conclusions. Our findings suggest that APOBEC3G polymorphisms alone may not have significant predictive power for inferring genetic susceptibility to vertical transmission of HIV in children perinatally exposed to HIV. PMID- 27245546 TI - Tributes. PMID- 27245547 TI - A true mentor and pioneer in medical genetics. PMID- 27245548 TI - Using the skills of academic elders. PMID- 27245549 TI - A pillar of academic and research excellence: The enduring influence of mentorship in science. PMID- 27245550 TI - Osteogenesis imperfecta in southern Africa: Peter Beighton's legacy. PMID- 27245552 TI - The novel bisphosphonate disodium dihydrogen-4-[(methylthio) phenylthio] methanebisphosphonate increases bone mass in post-ovariectomy rats. AB - The novel bisphosphonate (BP) disodium dihydrogen-4-[(methylthio) phenylthio] methanebisphosphonate (MPMBP) is a non-nitrogen-containing BP with an antioxidant side chain that possesses anti-inflammatory properties. We investigated the systemic effects of this compound on bone loss induced by ovariectomy (OVX) in adult rats. Micro-computed tomography revealed that MPMBP increased bone mass and density in both the metaphysis and diaphysis, and improved the structural properties important for mechanical strength of osteoporotic bone. Sequential bone labeling with tetracycline and calcein indicated that MPMBP decreased longitudinal growth of the primary spongiosa (PS), but stimulated cortical bone formation in the diaphysis. MPMBP increased type I collagen accumulation in the PS, and decreased the number and size of adipocytes in the bone marrow, suggesting inhibition of increased bone marrow adipogenesis induced by OVX. Furthermore, MPMBP reduced the number of bone resorbing cathepsin K-positive osteoclasts induced by OVX. These results suggest that MPMBP could improve bone loss induced by estrogen deficiency. Both stimulation of bone formation and inhibition of bone resorption might play a role in the increase in bone mass and bone density after MPMBP treatment. PMID- 27245553 TI - The effects of rabeprazole on metformin pharmacokinetics and pharmacodynamics in Chinese healthy volunteers. AB - The aim was to investigate the role of rabeprazole on the pharmacokinetics (PK) and pharmacodynamics (PD) of metformin. The in vitro inhibition assays on metformin transport were carried out and showed that the half maximal inhibitory concentration (IC50) of rabeprazole on OCT2-mediated metformin transport was 26.0 MUM, whereas the IC50 on MATE1-mediated metformin transport inhibition was 4.6 MUM. Fifteen healthy Chinese male volunteers were enrolled and given two different doses of metformin plus the co-administration of placebo or rabeprazole. Plasma concentrations of metformin were measured up to 12 h after the second dose. The glucose-lowering effects and the variation of insulin concentrations were evaluated during the oral glucose tolerance test (OGTT). The AUC0-12 of metformin plus rabeprazole were 28,276 +/- 5187 ng/ml.h, which was significantly higher than AUC0-12 of metformin plus placebo (24,691 +/- 3129 ng/ml.h). Thus, rabeprazole can modestly influence the PK of metformin, suggesting the precaution of using the two drugs together. In OGTTs, rabeprazole decreased the values of AUCinsulin and the maximum insulin concentration. Although rabeprazole showed inhibition effect on OCT2-mediated metformin transport, the glucose-lowering effect of metformin remained the same regardless of its PK changes. Further studies are needed to warrant the effect of rabeprazole on metformin. PMID- 27245554 TI - Preliminary assessment of post-Haiyan mangrove damage and short-term recovery in Eastern Samar, central Philippines. AB - Strong winds and storm surges from Typhoon Haiyan caused damage of US$12 15billion and >10,000 human casualties in central Philippines in November 2013. To validate a proposed government US$22million mangrove replanting program, mangrove damage and short-term recovery were surveyed in seven natural and planted mangrove sites in Eastern Samar province at 2.5month and 4.5month post Haiyan. The preliminary assessment showed that natural mangroves (except for those directly hit by the storm) were recovering by means of tree sprouts and surviving seedlings and saplings compared to the devastated plantation. Likewise, tree mortality was higher in the plantation and natural forests hit by the storm surge, compared to more undamaged and partially damaged trees in natural mangroves. Hence the main recommendations to government are (1) to protect recovering mangroves by not releasing rehabilitation funds (that will inadvertently pay for clearing of live trees and for removal of seedlings), (2) to only plant in totally damaged sites (e.g., plantations), and (3) to only plant naturally dominant species, e.g., Sonneratia alba and Avicennia marina (instead of the popular Rhizophora apiculata, R. mucronata and R. stylosa). PMID- 27245555 TI - Levels, distributions and sources of veterinary antibiotics in the sediments of the Bohai Sea in China and surrounding estuaries. AB - Veterinary antibiotics are emerging contaminants of concern. A total of 139 samples comprising 104 marine sediments and 35 estuarine sediments were collected from the Bohai Sea area and analyzed for seventeen antibiotics. The results reveal that the presence and concentration of antibiotics were generally higher in the estuaries than in the sea. The highest antibiotic concentration, 4695MUgkg(-1) of oxytetracycline, occurred in the estuarine sediment from Ziya New River. Bohai Bay and Laizhou Bay and the surrounding estuaries had higher concentrations of antibiotics. However, low levels of antibiotics detected were detected in Liaodong Bay in contrast to the high concentrations present in the surrounding estuaries. Spatial heterogeneity and principal component analysis suggest a large impact of terrestrial sources of the antibiotics contaminating the Bohai Sea. Risk quotients indicate that current levels of norfloxacin and oxytetracycline might be potentially hazardous to sensitive biota both in the Bohai Sea and in its surrounding estuaries. PMID- 27245556 TI - Pinocembrin attenuates gentamicin-induced nephrotoxicity in rats. AB - Oxidative stress mediated apoptosis of renal tubular cells is a major pathology of gentamicin-induced nephrotoxicity, which is one of the prevailing causes of acute renal failure. Pinocembrin is a major flavonoid found in rhizomes of fingerroot (Boesenbergia pandurata). It has pharmacological and biological activities including antimicrobial, anti-inflammatory, and antioxidant effects. Preclinical studies have suggested that pinocembrin protects rat brain and heart against oxidation and apoptosis induced by ischemia-reperfusion. The aim of the current study was to investigate the mechanisms of renoprotection elicited by pinocembrin in gentamicin-induced nephrotoxicity. Nephrotoxicity was induced in rats by intraperitoneal injection (i.p.) of gentamicin, and pinocembrin was administered via i.p. 30 min before gentamicin treatment for 10 days. Gentamicin induced nephrotoxicity was indicated by the reduced renal function and renal Oat3 function and expression. Gentamicin treatment also stimulated Nrf2, HO-1, and NQO1, as well as the pro-apoptotic proteins Bax and caspase-3, concomitant with the attenuation of Bcl-XL expression in the renal cortical tissues. Pinocembrin pretreatment improved renal function and renal Oat3 function and reduced oxidative stress and apoptotic conditions. These findings indicate that pinocembrin has a protective effect against gentamicin-induced nephrotoxicity, which may be due in part to its antioxidant and anti-apoptotic effects, subsequently leading to improved renal function. PMID- 27245557 TI - Eighth Korea-Japan Chemical Biology symposium: chemical biology notes from a small island. PMID- 27245558 TI - Insights into polyketide biosynthesis gained from repurposing antibiotic producing polyketide synthases to produce fuels and chemicals. AB - Complex polyketides comprise a large number of natural products that have broad application in medicine and agriculture. They are produced in bacteria and fungi from enzyme complexes named type I polyketide synthases (PKSs) that are composed of multifunctional polypeptides containing discrete enzymatic domains organized into modules. The modular nature of PKSs has enabled a multitude of efforts to engineer the PKS genes to produce novel polyketides with enhanced or new properties. We have repurposed PKSs, employing up to three modules to produce a number of short-chain molecules that could have applications as fuels or industrial chemicals. Examining the enzymatic functions in vitro of these repurposed PKSs, we have uncovered a number of expanded substrate specificities and requirements of various PKS domains not previously reported and determined an unexpected difference in the order of enzymatic reactions within a module. In addition, we were able to efficiently change the stereochemistry of side chains in selected PKS products. PMID- 27245559 TI - Prognostic Significance of Preoperative Serum Carbohydrate Antigen 19-9 in Patients With Stage IV Colorectal Cancer. AB - INTRODUCTION: Carbohydrate antigen (CA) 19-9 is a widely used tumor marker in colorectal cancer (CRC). However, its prognostic impact in patients with stage IV CRC who have undergone curative resection is not clear. We evaluated the prognostic power of preoperative serum CA 19-9 in these patients. PATIENTS AND METHODS: We performed a retrospective review of 173 patients with stage IV CRC who had undergone curative resection at our institution. Patients were categorized into normal and high CA 19-9 groups, and relapse-free survival and overall survival were compared using Kaplan-Meier curves. Multivariate analyses were performed using a Cox proportional hazard model. RESULTS: The preoperative serum CA 19-9 level was elevated in 80 patients (46%). The 3-year relapse-free survival of the high CA 19-9 group was significantly worse than that of the normal CA 19-9 group (18% vs. 28%, respectively; P = .026). The 3-year overall survival of the high CA 19-9 group was significantly lower than that of the normal CA 19-9 group (75% vs. 82%; P = .047). Multivariate analyses indicated that elevated preoperative serum CA 19-9 level was an independent prognostic factor for poor relapse-free survival and overall survival, with a hazard ratio of 1.46 (95% confidence interval, 1.03-2.06; P = .035) and 1.90 (95% confidence interval, 1.10-3.29; P = .023), respectively. CONCLUSION: The preoperative serum CA 19-9 level is a good predictive marker of tumor recurrence and prognosis in patients with stage IV CRC who have undergone curative resection. PMID- 27245561 TI - Folie a deux and delusional disorder by proxy: an atypical presentation. AB - Delusion of parasitosis is a rare condition characterised by an individual harbouring the delusion of being infested with insects or parasites. We report a rare and interesting case of delusion of parasitosis presenting as folie a deux, that is, the delusion is shared by both the parents of an 18-month-old child, with proxy projection of parental delusion on the child. The case highlights the rare concomitant occurrence of two psychocutaneous disorders and emphasizes the importance of early recognition and appropriate intervention to safeguard the well-being of the child. PMID- 27245560 TI - Glutamate metabolism in HIV-1 infected macrophages: Role of HIV-1 Vpr. AB - HIV-1 infected macrophages play a significant role in the neuropathogenesis of AIDS. HIV-1 viral protein R (Vpr) not only facilitates HIV-1 infection but also contribute to long-lived persistence in macrophages. Our previous studies using SILAC-based proteomic analysis showed that the expression of critical metabolic enzymes in the glycolytic pathway and tricarboxylic acid (TCA) cycle were altered in response to Vpr expression in macrophages. We hypothesized that Vpr-induced modulation of glycolysis and TCA cycle regulates glutamate metabolism and release in HIV-1 infected macrophages. We assessed the amount of specific metabolites induced by Vpr and HIV-1 in macrophages at the intracellular and extracellular level in a time-dependent manner utilizing multiple reaction monitoring (MRM) targeted metabolomics. In addition, stable isotope-labeled glucose and an MRM targeted metabolomics assay were used to evaluate the de novo synthesis and release of glutamate in Vpr overexpressing macrophages and HIV-1 infected macrophages, throughout the metabolic flux of glycolytic pathway and TCA cycle activation. The metabolic flux studies demonstrated an increase in glucose uptake, glutamate release and accumulation of alpha-ketoglutarate (alpha-KG) and glutamine in the extracellular milieu in Vpr expressing and HIV-1 infected macrophages. Interestingly, glutamate pools and other intracellular intermediates (glucose-6-phosphate (G6P), fructose-6-phosphate (F6P), citrate, malate, alpha KG, and glutamine) showed a decreased trend except for fumarate, in contrast to the glutamine accumulation observed in the extracellular space in Vpr overexpressing macrophages. Our studies demonstrate that dysregulation of mitochondrial glutamate metabolism induced by Vpr in HIV-1 infected macrophages commonly seen, may contribute to neurodegeneration via excitotoxic mechanisms in the context of NeuroAIDS. PMID- 27245562 TI - Reversible Cerebral Metabolism Changes Using Proton Magnetic Resonance Spectroscopy in a Patient with Intracranial Dural Arteriovenous Fistula: A Case Report. AB - BACKGROUND: Cerebral metabolism can be disrupted by venous congestion in patients with intracranial dural arteriovenous fistula (DAVF), which may lead to adverse neurological outcomes. However, there are no clear indicators to guide cerebral evaluation and treatment selection in cases of DAVF. We describe a patient with a DAVF whose proton magnetic resonance spectroscopy ((1)H-MRS) findings were associated with improvements in clinical status. CASE DESCRIPTION: An elderly woman with a history of myocardial infarction presented with progressive dementia, aphasia, and a severe headache. We detected a transverse-sigmoid sinus DAVF, as well as abnormal levels of lactate and N-acetylaspartic acid (NAA) in the (1)H-MRS, and successfully treated the patient using surgical sinus skeletonization. However, follow-up (1)H-MRS revealed inconsistent reversals in the levels of lactate and NAA. In addition, we calculated the NAA/creatinine ratios from before and after surgery, which revealed postoperative increases in the ratios for the left temporal, right parietal, and left parietal regions. These increases occurred concurrently with improvements in the patient's cognitive function. CONCLUSIONS: (1)H-MRS may be useful for pretreatment detection of increased lactate levels, decreased NAA levels, and/or decreased NAA/creatinine ratios. These findings may indicate poorer cerebral metabolism, and show a need for more aggressive treatment. Furthermore, (1)H-MRS may be useful for evaluating the effect of conservative treatment and for indicating conversion to a more aggressive treatment. PMID- 27245563 TI - Marked Variation in Cervical Deformity Surgery: Apple Juice or Lemonade? PMID- 27245564 TI - Mild Traumatic Brain Injury in Patients on Long-Term Anticoagulation Therapy: Do They Really Need Repeated Head CT Scan? AB - BACKGROUND: Mild traumatic brain injury (mTBI), defined as blunt trauma to the head resulting in witnessed loss of consciousness, definite amnesia, or witnessed disorientation with a Glasgow Coma Scale (GCS) score of 14 or 15 is a common occurrence in the emergency department. In mTBI, oral anticoagulation is known to be an important risk factor for hemorrhage. Clinical guidelines recommend baseline computed tomographic (CT) scan and observation for 24 hours plus a CT scan before discharge. METHODS: We compared the non-anticoagulated and anticoagulated patients presenting at our emergency department with mTBI and no neurologic signs (GCS = 15). Every non-anticoagulated patient underwent only a baseline CT scan, whereas the anticoagulated group underwent a second CT scan after a 24-hour observation period. RESULTS: Between April 2012 and April 2013, we observed 908 adult patients with mTBI and a GCS score of 15; 74 patients (8.1%) were taking oral anticoagulant drugs as long-term therapy, whereas the remaining 834 patients (91.9%) were not. In the non-anticoagulation group, 38 patients (4.6%) were positive for hemorrhage. Two patients underwent neurosurgical intervention. In the anticoagulation group, 5 patients (6.8%) were positive for hemorrhage. No patient underwent neurosurgical intervention. None of them died. The differences between the two groups were not statistically significant. CONCLUSIONS: Patients with a GCS score of 15 who are taking long term anticoagulation therapy and who present with mTBI have a risk of cranial hemorrhage that is likely to be similar to that of non-anticoagulated patients. It may be reasonable to envision a protocol including only one CT scan and an appropriate observation period. PMID- 27245565 TI - Type II Odontoid Fracture with Atlantoaxial Dislocation Presenting as Symptomatic Seizures: A Case Report. AB - OBJECTIVE AND BACKGROUND: To report symptomatic seizures of a patient with an old type II odontoid fracture with atlantoaxial dislocation. The type II odontoid fracture is a dangerous disease and presents as neurological deficits. Because of the compression of upper cervical cord, without timely diagnosis and treatment, a type II odontoid fracture may result in sudden death. Although it has been shown that epileptic seizures may lead to type II odontoid fracture, there is no report of symptomatic seizures in patients with odontoid fracture. METHODS: A 16-year old adolescent boy with neurological deficits, especially grand mal seizures for duration of 5 years, was diagnosed as an old type II odontoid fracture with atlantoaxial dislocation and treated in our hospital. A 1-year follow-up was performed. RESULTS: Systematic analyses of the clinical history, manifestations, physical examination, and radiologic results of the patient revealed an old type II odontoid fracture. Magnetic resonance imaging showed spinal cord compression and degeneration. The patient received posterior atlantoaxial fixation and fusion procedure following successful closed reduction. The frequency of seizures was reduced to once a month and there was a thorough recovery in other neurological functions 1 year after the operation. CONCLUSIONS: Old type II odontoid fracture might present as symptomatic seizures in addition to other neurological deficits. Posterior atlantoaxial screw-plate fixation and fusion is an effective treatment for old type II odontoid fracture. PMID- 27245566 TI - Long-Term Prognosis of Spontaneous Intracerebral Hemorrhage on the Tibetan Plateau: A Prospective Cohort Study at 2 Hospitals. AB - BACKGROUND: Patterns of intracerebral hemorrhage (ICH) and outcomes in Tibetans are poorly understood. We aimed to investigate the long-term outcomes of Tibetan ICH patients. METHODS: This prospective study involved a consecutive series of ICH patients admitted within 1 month of onset to West China Hospital (WCH) on the Chengdu Plain or People's Hospital of Garze (PHG) on the Tibetan Plateau between January 2013 and December 2013. Basic characteristics and functional outcomes were compared between PHG and WCH groups. RESULTS: Of the 843 cases included, 105 (12.5%) were from PHG and 738 (87.5%) were from WCH. Compared with patients from WCH, patients from PHG were older and had higher blood pressure on admission, and a greater proportion had hypertension (all P < 0.001). Among patients from PHG, the 1-year death rate was 30.5%, similar to that in WCH (P = 0.987), and the adjusted 3-month disability risk was 2.0-fold higher than for WCH patients, while the adjusted 1-year disability risk was 2.5-fold higher than for WCH patients (both P <= 0.05). The adjusted 3-month risk of disability/death was 2.1-fold higher in PHG patients than in WCH patients, while the adjusted 1-year risk was 2.4-fold higher (both P <= 0.05). CONCLUSIONS: Most cases of ICH on the Tibetan Plateau involve concomitant hypertension. Tibetan patients are at higher risk of disability or disability/death on follow-up than are patients from Chengdu Plain. PMID- 27245567 TI - Treatment Summaries and Follow-Up Care Instructions for Cancer Survivors: Improving Survivor Self-Efficacy and Health Care Utilization. AB - BACKGROUND: Treatment summaries and follow-up care plan information should be provided to cancer survivors. This study examines the association of receiving summaries and care plans with cancer survivor self-efficacy for chronic illness management, and whether self-efficacy was associated with health care utilization. METHODS: Four hundred forty-one cancer survivors (>=2 years from diagnosis and had completed treatment) >=65 years old from 12 cancer centers across 5 states completed telephone surveys. Survivors responded to three questions about receiving a written treatment summary, written follow-up plan, and an explanation of follow-up care plans. Respondents completed the Stanford Chronic Illness Management Self-Efficacy Scale and reported emergency room visits and hospitalizations in the past year. Three multiple linear regression models estimated the association of written treatment summary, written follow-up care plan, and verbal explanation of follow-up plan with total self-efficacy score. Log-binomial models estimated the association of self-efficacy scores with emergency room visits and hospitalizations (yes/no). RESULTS: Among survivors, 40% and 35% received a written treatment summary and follow-up care plan, respectively. Seventy-nine percent received an explanation of follow-up care plans. Receiving a verbal explanation of follow-up care instructions was significantly associated with higher self-efficacy scores (beta = 0.72, p = .009). Higher self-efficacy scores were significantly associated with lower prevalence ratios of emergency room visits (prevalence ratio, 0.92; 95% confidence interval, 0.88-0.97) and hospitalizations (prevalence ratio, 0.94; 95% confidence interval, 0.89-0.99). CONCLUSION: Explanation of the follow-up care plan, beyond the written component, enhances survivor self-efficacy for managing cancer as a chronic condition-an important mediator for improving health care utilization outcomes. IMPLICATIONS FOR PRACTICE: Older cancer survivors (>65 years) are especially vulnerable to poor outcomes in survivorship because of the complexity of follow-up care and other chronic conditions. Delivering written treatment summaries, written follow-up care plans, and verbal explanations of follow-up care plans all independently increased the self-efficacy for chronic illness management among older survivors. In particular, delivering this information in the verbal format was significantly associated with higher self efficacy and, subsequently, a lower likelihood of emergency room visits. Understanding the mechanism through which summaries and follow-up care plans may positively influence survivor health is critical to increasing the delivery of the information. PMID- 27245568 TI - New Frameworks to Assess Value of Cancer Care: Strengths and Limitations. PMID- 27245570 TI - Screening for ALK Rearrangements in Lung Cancer: Time for a New Generation of Diagnostics? PMID- 27245569 TI - Comprehensive Genomic Profiling Identifies a Subset of Crizotinib-Responsive ALK Rearranged Non-Small Cell Lung Cancer Not Detected by Fluorescence In Situ Hybridization. AB - INTRODUCTION: For patients with non-small cell lung cancer (NSCLC) to benefit from ALK inhibitors, sensitive and specific detection of ALK genomic rearrangements is needed. ALK break-apart fluorescence in situ hybridization (FISH) is the U.S. Food and Drug Administration approved and standard-of-care diagnostic assay, but identification of ALK rearrangements by other methods reported in NSCLC cases that tested negative for ALK rearrangements by FISH suggests a significant false-negative rate. We report here a large series of NSCLC cases assayed by hybrid-capture-based comprehensive genomic profiling (CGP) in the course of clinical care. MATERIALS AND METHODS: Hybrid-capture-based CGP using next-generation sequencing was performed in the course of clinical care of 1,070 patients with advanced lung cancer. Each tumor sample was evaluated for all classes of genomic alterations, including base-pair substitutions, insertions/deletions, copy number alterations and rearrangements, as well as fusions/rearrangements. RESULTS: A total of 47 patients (4.4%) were found to harbor ALK rearrangements, of whom 41 had an EML4-ALK fusion, and 6 had other fusion partners, including 3 previously unreported rearrangement events: EIF2AK ALK, PPM1B-ALK, and PRKAR1A-ALK. Of 41 patients harboring ALK rearrangements, 31 had prior FISH testing results available. Of these, 20 were ALK FISH positive, and 11 (35%) were ALK FISH negative. Of the latter 11 patients, 9 received crizotinib based on the CGP results, and 7 achieved a response with median duration of 17 months. CONCLUSION: Comprehensive genomic profiling detected canonical ALK rearrangements and ALK rearrangements with noncanonical fusion partners in a subset of patients with NSCLC with previously negative ALK FISH results. In this series, such patients had durable responses to ALK inhibitors, comparable to historical response rates for ALK FISH-positive cases. IMPLICATIONS FOR PRACTICE: Comprehensive genomic profiling (CGP) that includes hybrid capture and specific baiting of intron 19 of ALK is a highly sensitive, alternative method for identification of drug-sensitive ALK fusions in patients with non small cell lung cancer (NSCLC) who had previously tested negative using standard ALK fluorescence in situ hybridization (FISH) diagnostic assays. Given the proven benefit of treatment with crizotinib and second-generation ALK inhibitors in patients with ALK fusions, CGP should be considered in patients with NSCLC, including those who have tested negative for other alterations, including negative results using ALK FISH testing. PMID- 27245571 TI - Newspaper debates on milk fats and vegetable oils in Finland, 1978-2013: An analysis of conflicts over risks, expertise, evidence and pleasure. AB - The study analysed public debates on the association of milk fats, vegetable oils and cardiovascular diseases (CVDs) between 1978 and 2013 in Finland, a country with a decades-long history of public health initiatives targeting fat consumption. The main agendas, conflicts and participants were analysed. The data were collected from the newspaper Helsingin Sanomat and consisted of 52 threads and 250 texts. We identified four themes around which there were repeated, often overlapping conflicts: the health risks of saturated fats, expertise of the risks of fat consumption, the adequate evidence of the risks of fat consumption, and framing the fat question. During the research period, the main arguments of the effects of consumption of fats have remained the same. References to epidemiological and intervention studies and framing of the fat question as a public health issue, have been ongoing, as has the definition of what constitutes genuine expertise. Yet, we also found discontinuities. In the early 2000s new emphases began to emerge: personal experiences were increasingly presented as evidence of the effects of dietary choices on human health, and the question of fat consumption was framed either as one of enjoyment or of a consumers' right to choose rather than only being a public health question. Moreover, new professional groups such as chefs and creative professionals now joined the discussion. PMID- 27245572 TI - Consumer segmentation as a means to investigate emotional associations to meals. AB - Consumers naturally associate emotions to meal occasions and understanding these can advance knowledge of food-related behaviours and attitudes. The present study used an online survey to investigate the emotional associations that people have with recalled meals: 'memorable' (MM) and 'routine' evening (RM). Heterogeneity in the studied consumer population (UK adults, n = 576 and 571, respectively) was accounted for using a data-driven approach to establish emotion-based segments. Two groups of people were identified with very different emotional response patterns to recalled meals. For 'memorable' and 'routine' meals the majority of people (Cluster 1) held strong positive and weak negative emotional associations. In Cluster 2, positive emotions remained more strongly associated than negative emotions, but much less so. In accordance with findings based on other response variables (e.g., preference, attitudes), psychographic variables accounted better for the heterogeneity found in the emotion associations than socio-demographic variables. Participants' level of meal engagement and difficulty in describing feelings (DDF scale) were the two most important predictors of cluster membership. PMID- 27245573 TI - Quantum uncertainty switches on or off the error-disturbance tradeoff. AB - The indeterminacy of quantum mechanics was originally presented by Heisenberg through the tradeoff between the measuring error of the observable A and the consequential disturbance to the value of another observable B. This tradeoff now has become a popular interpretation of the uncertainty principle. However, the historic idea has never been exactly formulated previously and is recently called into question. A theory built upon operational and state-relevant definitions of error and disturbance is called for to rigorously reexamine the relationship. Here by putting forward such natural definitions, we demonstrate both theoretically and experimentally that there is no tradeoff if the outcome of measuring B is more uncertain than that of A. Otherwise, the tradeoff will be switched on and well characterized by the Jensen-Shannon divergence. Our results reveal the hidden effect of the uncertain nature possessed by the measured state, and conclude that the state-relevant relation between error and disturbance is not almosteverywhere a tradeoff as people usually believe. PMID- 27245574 TI - Orientation selectivity in a multi-gated organic electrochemical transistor. AB - Neuromorphic devices offer promising computational paradigms that transcend the limitations of conventional technologies. A prominent example, inspired by the workings of the brain, is spatiotemporal information processing. Here we demonstrate orientation selectivity, a spatiotemporal processing function of the visual cortex, using a poly(3,4ethylenedioxythiophene):poly(styrene sulfonate) ( PEDOT: PSS) organic electrochemical transistor with multiple gates. Spatially distributed inputs on a gate electrode array are found to correlate with the output of the transistor, leading to the ability to discriminate between different stimuli orientations. The demonstration of spatiotemporal processing in an organic electronic device paves the way for neuromorphic devices with new form factors and a facile interface with biology. PMID- 27245575 TI - Multi-model attribution of upper-ocean temperature changes using an isothermal approach. AB - Both air-sea heat exchanges and changes in ocean advection have contributed to observed upper-ocean warming most evident in the late-twentieth century. However, it is predominantly via changes in air-sea heat fluxes that human-induced climate forcings, such as increasing greenhouse gases, and other natural factors such as volcanic aerosols, have influenced global ocean heat content. The present study builds on previous work using two different indicators of upper-ocean temperature changes for the detection of both anthropogenic and natural external climate forcings. Using simulations from phase 5 of the Coupled Model Intercomparison Project, we compare mean temperatures above a fixed isotherm with the more widely adopted approach of using a fixed depth. We present the first multi-model ensemble detection and attribution analysis using the fixed isotherm approach to robustly detect both anthropogenic and natural external influences on upper-ocean temperatures. Although contributions from multidecadal natural variability cannot be fully removed, both the large multi-model ensemble size and properties of the isotherm analysis reduce internal variability of the ocean, resulting in better observation-model comparison of temperature changes since the 1950s. We further show that the high temporal resolution afforded by the isotherm analysis is required to detect natural external influences such as volcanic cooling events in the upper-ocean because the radiative effect of volcanic forcings is short-lived. PMID- 27245576 TI - Endogenous analgesia mediated by CD4(+) T lymphocytes is dependent on enkephalins in mice. AB - BACKGROUND: T cell-derived opioids play a key role in the control of inflammatory pain. However, the nature of opioids produced by T cells is still matter of debate in mice. Whereas beta-endorphin has been found in T lymphocytes by using antibody-based methods, messenger RNA (mRNA) quantification shows mainly mRNA encoding for enkephalins. The objective of the study is to elucidate the nature of T cell-derived opioids responsible for analgesia and clarify discrepancy of the results at the protein and genetic levels. METHODS: CD4(+) T lymphocytes were isolated from wild-type and enkephalin-deficient mice. mRNA encoding for beta endorphin and enkephalin was quantified by RT-qPCR. The binding of commercially available polyclonal anti-endorphin antibodies to lymphocytes from wild-type or enkephalin knockout mice was assessed by cytofluorometry. Opioid-mediated analgesic properties of T lymphocytes from wild-type and enkephalin-deficient mice were compared in a model of inflammation-induced somatic pain by measuring sensitivity to mechanical stimuli using calibrated von Frey filaments. RESULTS: CD4(+) T lymphocytes expressed high level of mRNA encoding for enkephalins but not for beta-endorphin in mice. Anti-beta-endorphin polyclonal IgG antibodies are specific for beta-endorphin but cross-react with enkephalins. Anti-beta-endorphin polyclonal antibodies bound to wild-type but not enkephalin-deficient CD4(+) T lymphocytes. Endogenous regulation of inflammatory pain by wild-type T lymphocytes was completely abolished when T lymphocytes were deficient in enkephalins. Pain behavior of immune-deficient (i.e., without B and T lymphocytes) mice was superimposable to that of mice transferred with enkephalin deficient lymphocytes. CONCLUSIONS: Rabbit polyclonal anti-beta-endorphin serum IgG bind to CD4(+) T lymphocytes because of their cross-reactivity towards enkephalins. Thus, staining of T lymphocytes by anti-beta-endorphin polyclonal IgG reported in most of studies in mice is because of their binding to enkephalins. In mice, CD4(+) T lymphocytes completely lose their analgesic opioid mediated activity when lacking enkephalins. PMID- 27245577 TI - Genome-wide CNV analysis reveals variants associated with growth traits in Bos indicus. AB - BACKGROUND: Apart from single nucleotide polymorphism (SNP), copy number variation (CNV) is another important type of genetic variation, which may affect growth traits and play key roles for the production of beef cattle. To date, no genome-wide association study (GWAS) for CNV and body traits in beef cattle has been reported, so the present study aimed to investigate this type of association in one of the most important cattle subspecies: Bos indicus (Nellore breed). RESULTS: We have used intensity data from over 700,000 SNP probes across the bovine genome to detect common CNVs in a sample of 2230 Nellore cattle, and performed GWAS between the detected CNVs and nine growth traits. After filtering for frequency and length, a total of 231 CNVs ranging from 894 bp to 4,855,088 bp were kept and tested as predictors for each growth trait using linear regression analysis with principal components correction. There were 49 significant associations identified among 17 CNVs and seven body traits after false discovery rate correction (P < 0.05). Among the 17 CNVs, three were significant or marginally significant for all the traits. We have compared the locations of associated CNVs with quantitative trait locus and the RefGene database, and found two sets of 9 CNVs overlapping with either known QTLs or genes, respectively. The gene overlapping with CNV100, KCNJ12, is a functional candidate for muscle development and plays critical roles in muscling traits. CONCLUSION: This study presents the first CNV-based GWAS of growth traits using high density SNP microarray data in cattle. We detected 17 CNVs significantly associated with seven growth traits and one of them (CNV100) may be involved in growth traits through KCNJ12. PMID- 27245578 TI - Risk assessment of sheep welfare at small-scale slaughter in Nordic countries, comparing with large-scale slaughter. AB - BACKGROUND: During the pre-slaughter period, animals experience novel environment and procedures which may cause reduced welfare and suffering. Over the last decades, the slaughter industry has restructured into fewer and larger abattoirs, implying potential risks of transport stress, injuries, and impaired animal welfare. Since recently, however, there is growing interest in small-scale slaughter to supply locally or regionally produced meat. Risk managers at all levels thus need to assess animal welfare risks also at small-scale operations. This study aimed to assess risks of poor animal welfare at small-scale lamb slaughter (<=5000 sheep/year and <=70 sheep/day) in Norway, Iceland, Sweden and Finland, and to compare these risks to large-scale industrial slaughter. Assessment was done applying an individual expert opinion approach during a 2-day workshop. Nine experts in lamb slaughter procedures, behaviour, physiology, health, scoring schemes and/or risk assessment provided estimates of exposure, likelihood of negative consequences following exposure, and intensity and duration of negative consequences for 71 hazards. The methods applied mainly adhered to the risk assessment guidelines of the European Food Safety Authority. The list of hazards was modified from an earlier study and distributed to the experts before the assessment. No other literature was reviewed specifically for the purpose of the assessment. RESULTS: The highest risks to animal welfare identified in both small- and large-scale slaughter were related to inadequate conditions during overnight lairage at the slaughter plant. For most hazards, risk estimates were lower in small-scale slaughter. The reverse was true for splitting of groups and separation of one sheep from the group. CONCLUSIONS: Small-scale slaughter has a potential for improved sheep welfare in comparison with large-scale industrial slaughter. Keeping the animals overnight at the slaughterhouse and prolonged fasting before slaughter should be avoided. Solutions include continuing education and training of stockpersons and, especially in large-scale slaughter, application of existing techniques for efficient transport logistics that minimise stress. PMID- 27245579 TI - Plant resting site preferences and parity rates among the vectors of Rift Valley Fever in northeastern Kenya. AB - BACKGROUND: Mosquito lifespan can influence the circulation of disease causing pathogens because it affects the time available for infection and transmission. The life-cycle of mosquitoes is determined by intrinsic and environmental factors, which can include the availability of hosts and suitable resting environments that shelter mosquitoes from extreme temperature and desiccating conditions. This study determined the parity rates (an indirect measure of survival) and plant resting preference of vectors of Rift Valley fever (RVF) in northeastern Kenya. METHODS: Resting mosquitoes were trapped during the rainy and the dry season using a Prokopack aspirator from vegetation, whereas general adult populations were trapped using CDC light traps. At each site, sampling was conducted within a 1 km(2) area, subdivided into 500 * 500 m quadrants and four 250 * 250 m sub-quadrants from which two were randomly selected as sampling units. In each sampling unit, plants were randomly selected for aspiration of mosquitoes. Only Aedes mcintoshi and Ae. ochraceus were dissected to determine parity rates while all mosquito species were used to assess plant resting preference. RESULTS: Overall, 1124 (79 %, 95 % CI = 76.8-81.1 %) mosquitoes were parous. There was no significant difference in the number of parous Ae. mcintoshi and Ae. ochraceus. Parity was higher in the rainy season than in the dry season. Daily survival rate was estimated to be 0.93 and 0.92 among Ae. ochraceus and Ae. mcintoshi, respectively. Duosperma kilimandscharicum was the most preferred plant species with the highest average capture of primary (3.64) and secondary (5.83) vectors per plant, while Gisekia africana was least preferred. CONCLUSION: Survival rate of each of the two primary vectors of RVF reported in this study may provide an indication that these mosquitoes can potentially play important roles in the circulation of diseases in northern Kenya. Resting preference of the mosquitoes in vegetation may influence their physiology and enhance longevity. Thus, areas with such vegetation may be associated with an increased risk of transmission of arboviruses to livestock and humans. PMID- 27245580 TI - The use of a modified abbe island flap to reconstruct primary lip defects of over 80. AB - BACKGROUND: Lip reconstruction for defects greater than 80 % present a challenge in maintaining acceptable oral function and good aesthetic results. Abbe flaps offer an excellent reconstructive option but are limited to defects under 65 %. METHODS: We describe a two-stage "modified Abbe island flap" technique whereby a full-thickness myocutaneous flap is combined with a modified Karapandzic flap, allowing for reconstruction of total and near total lip defects. RESULTS: Six patients underwent successful two-stage lower and upper lip reconstruction with this technique. Oral competence and satisfactory aesthetic outcomes were achieved in all six cases. There were no complications. Although microstomia was noted to a certain extent, we argue this impact to be less than the morbidity of a free flap that lacks sphincteric function. CONCLUSION: The "Modified Abbe Island Flap" can be used to reconstruct near-total lip defects using locally innervated, well vascularized tissues that recreate the oral sphincter and restore oral competence. The combination of the conventional Abbe flap with a modified Karapandzic flap provides reliable results and significantly reduces operating time. PMID- 27245581 TI - A case of right-sided Bochdalek hernia incidentally diagnosed in a gastric cancer patient. AB - BACKGROUND: Bochdalek hernia (BH) is generally congenital, presenting with respiratory distress. However, this pathology is rarely detected in adults. Some adult cases of BH present with symptoms attributed to the hernia, but incidental detection of BH is increasing among asymptomatic adults due to advances in imaging modalities. This report presents the management of incidental BH patients detected in the preoperative period of gastric cancer. CASE PRESENTATION: An asymptomatic 76-year-old woman was diagnosed with advanced gastric cancer during follow-up after radiotherapy for uterine cervical cancer. Computed tomography (CT) was performed to exclude metastatic gastric cancer, incidentally detecting right-sided BH. We planned distal gastrectomy with lymph node dissection for gastric cancer and simultaneous repair of BH using a laparoscopic approach. We performed laparoscopic gastrectomy for gastric cancer and investigated the right sided BH to assess whether repair during surgery was warranted. Herniation of the liver into the right hemithorax was observed, but was followed-up without surgical repair because the right hepatic lobe was adherent to the remnant right anterior hemidiaphragm and covered the huge defect in the right hemidiaphragm. No intra- or postoperative pneumothorax was observed during pneumoperitoneum. CONCLUSION: Regardless of symptoms, repair of adult BH is generally recommended to prevent visceral incarceration. However, BH in asymptomatic adults appears to be more common than previously reported in the literature. Surgeons need to consider the management of incidental BH encountered during thoracic or abdominal surgery. PMID- 27245582 TI - Impact of IPDE-SQ personality disorders on the healthcare and societal costs of fibromyalgia patients: a cross-sectional study. AB - BACKGROUND: Data is lacking on comorbid personality disorders (PD) and fibromyalgia syndrome (FMS) in terms of prevalence, and associated healthcare and societal costs. The main aim of this study was to assess the prevalence of PD in FMS patients and to analyse whether the presence of comorbid PD is related to worse functional impairment and greater healthcare (medical visits, drug consumption, and medical tests) and societal costs. METHODS: A cross-sectional study was performed using the baseline data of 216 FMS patients participating in a randomized, controlled trial carried out in three primary health care centres situated in the region of Barcelona, Spain. Measurement instruments included the International Personality Disorder Examination - Screening Questionnaire (IPDE SQ), the Fibromyalgia Impact Questionnaire (FIQ), the Client Service Receipt Inventory (CSRI), and a socio-demographic questionnaire. RESULTS: Most patients (65 %) had a potential PD according to the IPDE-SQ. The most prevalent PD were the avoidant (41.4 %), obsessive-compulsive (33.1 %), and borderline (27 %). We found statistically significant differences in functional impairment (FIQ scores) between FMS patients with potential PD vs non-PD (59.2 vs 51.1; p < 0.001). Multivariate regression analyses revealed that higher FIQ total scores and the presence of potential PD were related to more healthcare costs (primary and specialised care visits). CONCLUSIONS: As expected, PD are frequent comorbid conditions in patients with FMS. Our results suggest that the screening of comorbid PD in patients with FMS might be recommendable in order to detect potential frequent attenders to primary and specialised care. PMID- 27245583 TI - Human cervix: an alternative substrate for detecting circulating pemphigus antibodies. AB - Monkey esophagus (ME) is a well-accepted substrate for diagnosing pemphigus vulgaris (PV) by indirect immunofluorescence (IIF). However, its availability is sometimes limited due to ethical concerns. This study aimed to investigate the usefulness of human cervix (HC) as a substrate in the diagnosis of PV by IIF. Initially, serum from 1 PV patient was incubated with tissues from 48 HCs. Median IIF titers on HCs that had different demographic and clinical characteristics were compared. Sera from 5 PV patients were then incubated with ME and 21 HCs. For each serum, the titer of IIF on HC that was not different from ME by more than two-fold dilutions was acceptable. Last, sera from 42 PV, 14 pemphigus foliaceous, and 62 non-pemphigus patients were used to evaluate sensitivity and specificity. The results demonstrate that differences in demographic data among HCs did not affect IIF titers. Titers obtained from ME and HC were comparable (81 100 % acceptable values). Sensitivity of HC for diagnosis of PV was better than for diagnosis of pemphigus foliaceus (90.5 and 71.4 %, respectively). Specificity for PV and PF was 96.2 %. We proposed that HC substrate can be used as an alternative substrate for diagnosis of PV by IIF. PMID- 27245584 TI - Advances in the microrheology of complex fluids. AB - New developments in the microrheology of complex fluids are considered. Firstly the requirements for a simple modern particle tracking microrheology experiment are introduced, the error analysis methods associated with it and the mathematical techniques required to calculate the linear viscoelasticity. Progress in microrheology instrumentation is then described with respect to detectors, light sources, colloidal probes, magnetic tweezers, optical tweezers, diffusing wave spectroscopy, optical coherence tomography, fluorescence correlation spectroscopy, elastic- and quasi-elastic scattering techniques, 3D tracking, single molecule methods, modern microscopy methods and microfluidics. New theoretical techniques are also reviewed such as Bayesian analysis, oversampling, inversion techniques, alternative statistical tools for tracks (angular correlations, first passage probabilities, the kurtosis, motor protein step segmentation etc), issues in micro/macro rheological agreement and two particle methodologies. Applications where microrheology has begun to make some impact are also considered including semi-flexible polymers, gels, microorganism biofilms, intracellular methods, high frequency viscoelasticity, comb polymers, active motile fluids, blood clots, colloids, granular materials, polymers, liquid crystals and foods. Two large emergent areas of microrheology, non-linear microrheology and surface microrheology are also discussed. PMID- 27245585 TI - Trajectories and the influencing factors of behavior problems in preschool children: a longitudinal study in Guangzhou, China. AB - BACKGROUND: Since child mental health problem was a global health issue, many researchers in western countries has focused on the trajectory of it to provide evidence for prevention programs. We designed this study to determine the trajectories of children's behavior problems, and to explore the effect of parent predictors on children's behavior problems in Guangzhou, China. METHODS: Children (N = 1480) for this longitudinal, population-based survey, were recruited from eight regular kindergartens (October, 2010) across four districts in Guangzhou. Repeated measurement design analysis was used to compare the variation in behavioral problems by gender, only child status, and temperament. Logistic regression was applied to analyze the effect of parents' risks (maternal depression, parenting style) on the change in child problem behaviors. RESULTS: The scores of behavior problems (externalizing, emotional, social communication problems) were stable during the entire preschool period by gender and child number. Children with difficult temperament exhibited more problem behaviors than children with easy temperament in the early years, and the misbehaviors declined significantly over time. Moreover, maternal depression and the increase in excessive interference/over protective or punishing parenting strategies resulted in an increase in child behavior problems. CONCLUSION: There was no difference between the only-child status and child with siblings in the trajectory of problem behaviors. Parent factors were significant predictions of trajectory of child behavior problem during preschool age. PMID- 27245586 TI - Factors associated with postnatal care utilisation in Rwanda: A secondary analysis of 2010 Demographic and Health Survey data. AB - BACKGROUND: Postnatal care (PNC) in the first seven days is important for preventing morbidity and mortality in mothers and new-borns. Sub-Saharan African countries, which account for 62 % of maternal deaths globally, have made major efforts to increase PNC utilisation, but utilisation rates remains low even in countries like Rwanda where PNC services are universally available for free. This study identifies key socio-economic and demographic factors associated with PNC utilisation in Rwanda to inform improved PNC policies and programs. METHODS: This is a secondary analysis of the 2010 Demographic and Health Survey, a national multi-stage, cross-sectional survey. In bivariate analysis, we used chi-square tests to identify demographic and socio-economic factors associated with PNC utilisation at alpha = 0.1. Pearson's R statistic (r > 0.5) was used to identify collinear covariates, and to choose which covariate was more strongly associated with PNC utilisation. Manual backward stepwise logistic regression was performed on the remaining covariates to identify key factors associated with PNC utilisation at alpha = 0.05. All analyses were performed in Stata 13 adjusting for sampling weights, clustering, and stratification. RESULTS: Of the 2,748 women with a live birth in the last two years who answered question about PNC utilisation, 353 (12.8 %) returned for PNC services within seven days after birth. Three factors were positively associated with PNC use: delivering at a health facility (OR: 2.97; 95 % CI: 2.28-3.87), being married but not involved with one's own health care decision-making (OR: 1.69; 95 % CI: 1.17, 2.44) compared to being married and involved; and being in the second (OR: 1.46; 95 % CI: 1.01-2.09) or richest wealth quintile (OR: 2.04; 95 % CI: 1.27-3.29) compared to the poorest. Mother's older age at delivery was negatively associated with PNC use (20-29 - OR: 0.51, 95 % CI: 0.29-0.87; 30-39 - OR: 0.47, 95 % CI: 0.27-0.83; 40-49 - OR: 0.32, 95 % CI: 0.16-0.64). CONCLUSIONS: Low PNC utilisation in Rwanda appears to be a universal problem though older age and poverty are further barriers to PNC utilisation. A recent change in the provision of BCG vaccination to new-borns might promote widespread PNC utilisation. We further recommend targeted campaigns to older mothers and poorest mothers, focusing on perceptions of health system quality, cultural beliefs, and pregnancy risks. PMID- 27245587 TI - Promotion of flu vaccination among healthcare workers in an Italian academic hospital: An experience with tailored web tools. AB - BACKGROUND: Influenza causes significant mortality particularly among the elderly and high-risk groups. Healthcare workers (HCWs) are at risk of occupational exposure due to contact with patients. Aims of this study was to promote flu shot among HCWs through a multimedia campaign in a large North-Eastern Italian Hospital. METHODS: The 2013/2014 flu vaccination multimedia campaign addressed to HCWs was developed by maintaining pre-existing tools (letters in pay slip and poster displayed in wards) and creating 4 on-line spots (30") delivered trough the hospital intranet. Campaign effectiveness was assessed in terms of changes in knowledge, attitude and practice comparing data of pre (10 items) and post test (20 items) survey on a randomized sample of HCWs. RESULTS: Response rates were 92.6% (464/501) in pre-test and 83.2% (417/501) in post-test. 93.8% (391/417) of HCWs reported to awareness of the campaign to promote vaccination. Spots were seen by 59.6% (233/391) of HCWs. Some reasons for vaccine denial, "not believing in vaccine efficacy" (34.7% to 14.9%), "not considering flu as a serious problem" (from 24% to 12.6%), "thinking not to get sick" (28.7% to 18.2%) or "being against the vaccine" (32.7% to 21%), showed a statistically significant reduction after the exposure to the campaign. The "intention to get vaccinated in the next year" instead, raised effectively (13.1% to 36.6%). Vaccinated HCWs rate in 2013 2014 season was 7.6% (221/2910), and 5.6% (164/2910) in 2012-2013 (p<0.005). CONCLUSIONS: The multimedia campaign succeeded with regard to KAP outcomes, but the vaccination rate is still far from the goal of 90%. Due to their impact, especially on younger age groups, web tools deserve to be better studied as effective approach to convey health information among HCWs. PMID- 27245588 TI - Health inequalities after austerity in Greece. AB - Since the beginning of economic crisis, Greece has been experiencing unprecedented levels of unemployment and profound cuts to public budgets. Health and welfare sectors were subject to severe austerity measures, which have endangered provision of as well as access to services, potentially widening health inequality gap. European Union Statistics on Income and Living Conditions data show that the proportion of individuals on low incomes reporting unmet medical need due to cost doubled from 7 % in 2008 to 13.9 % in 2013, while the relative gap in access to care between the richest and poorest population groups increased almost ten-fold. In addition, austerity cuts have affected other vulnerable groups, such as undocumented migrants and injecting drug users. Steps have been taken in attempt to mitigate the impact of the austerity, however addressing the growing health inequality gap will require persistent effort of the country's leadership for years to come. PMID- 27245590 TI - HLA-B27 Anterior Uveitis: Immunology and Immunopathology. AB - Acute anterior uveitis (AAU) is the commonest type of uveitis and HLA-B27 AAU is the most frequently recognized type of acute anterior uveitis and anterior uveitis overall. Recent evidence indicates that acute anterior uveitis is a heterogenous disease, is polygenic and is frequently associated with the spondyloarthropathies (SpA). Studies of patients with AAU and animal models of disease indicate a role for innate immunity, the IL-23 cytokine pathway and exogenous factors, in the pathogenesis of both SpA and acute anterior uveitis. Recently described genetic associations cluster around immunologic pathways, including the IL-17 and IL-23 pathways, antigen processing and presentation, and lymphocyte development and activation. Patients with ankylosing spondylitis (AS) and AAU share other genetic markers, such as ERAP-1, which show strong evidence of gene-gene interaction and point to new mechanisms of disease pathogenesis. These observations have major implications for understanding the pathogenesis of HLA-B27 diseases, such as AAU, and may lead to the development of more specific therapy for AAU. Received 6 January 2016; revised 6 February 2016; accepted 18 February 2016; published online 31 May 2016. PMID- 27245589 TI - A Peculiar Formula of Essential Amino Acids Prevents Rosuvastatin Myopathy in Mice. AB - AIMS: Myopathy, characterized by mitochondrial oxidative stress, occurs in ~10% of statin-treated patients, and a major risk exists with potent statins such as rosuvastatin (Rvs). We sought to determine whether a peculiar branched-chain amino acid-enriched mixture (BCAAem), found to improve mitochondrial function and reduce oxidative stress in muscle of middle-aged mice, was able to prevent Rvs myopathy. RESULTS: Dietary supplementation of BCAAem was able to prevent the structural and functional alterations of muscle induced by Rvs in young mice. Rvs increased plasma 3-methylhistidine (a marker of muscular protein degradation) was prevented by BCAAem. This was obtained without changes of Rvs ability to reduce cholesterol and triglyceride levels in blood. Rather, BCAAem promotes de novo protein synthesis and reduces proteolysis in cultured myotubes. Morphological alterations of C2C12 cells induced by statin were counteracted by amino acids, as were the Rvs-increased atrogin-1 mRNA and protein levels. Moreover, BCAAem maintained mitochondrial mass and density and citrate synthase activity in skeletal muscle of Rvs-treated mice beside oxygen consumption and ATP levels in C2C12 cells exposed to statin. Notably, BCAAem assisted Rvs to reduce oxidative stress and to increase the anti-reactive oxygen species (ROS) defense system in skeletal muscle. Innovation and Conclusions: The complex interplay between proteostasis and antioxidant properties may underlie the mechanism by which a specific amino acid formula preserves mitochondrial efficiency and muscle health in Rvs-treated mice. Strategies aimed at promoting protein balance and controlling mitochondrial ROS level may be used as therapeutics for the treatment of muscular diseases involving mitochondrial dysfunction, such as statin myopathy. Antioxid. Redox Signal. 25, 595-608. PMID- 27245591 TI - Acute myelitis as presenting symptom of HIV-HTLV-1 co-infection. AB - A 21-year-old woman presented with acute-onset spastic paraparesis. The MRI spinal scan revealed a contrast-enhanced T2 hyperintensity between C5-T2. The most common neurotropic pathogens were excluded by first level tests. Under suspicion of an acute immune-mediated myelitis, a corticosteroid therapy was administered. However, a seropositivity for both human immunodeficiency virus (HIV) type 1 and human T-lymphotropic virus (HTLV) subsequently emerged. An antiretroviral therapy was started while steroids discontinued. Patient's clinical conditions remained unchanged. HIV-HTLV-1 co-infection should be included in the differential diagnosis of any acute myelitis, even in patients with a preserved immune status and no risk factors. PMID- 27245592 TI - Utility of a brief computerized battery to assess HIV-associated neurocognitive impairment in a resource-limited setting. AB - Despite the persistently high prevalence of neurocognitive impairment in HIV positive patients, routine HIV care in many resource-limited settings does not include neuropsychological assessment. The objective of this study was to examine the utility of a brief computerized battery for identifying neurocognitive impairment in a busy HIV clinic in Uganda. Specifically, we compared performance on a gold standard neuropsychological exam to that on the CogState Brief Battery. In this cross-sectional study, 181 HIV-positive patients completed both assessment batteries in a randomized order. The primary outcome measures were neurocognitive impairment on the standard exam defined by the global deficit score and cumulative performance on the CogState Brief Battery. Sixty-nine participants (38 %) were classified as impaired on the standard neuropsychological exam, and participants who were classified as impaired performed significantly worse on CogState compared to those who were unimpaired (p < 0.001). CogState had adequate specificity but low sensitivity, suggesting that it may not be a clinically useful screening tool to identify patients who likely have neurocognitive impairment in Uganda. This study supports the feasibility of using a computerized battery for assessing neurocognitive impairment in HIV-positive patients in resource-limited settings, but additional research is needed to identify screening tools with higher sensitivity for use in HIV clinics. PMID- 27245594 TI - Preliminary study of a novel cognitive assessment device for the evaluation of HIV-associated neurocognitive impairment. AB - Given the high prevalence of HIV-associated neurocognitive disorders (HAND), we examined the performance of a novel computerized cognitive assessment device (NCAD) for the evaluation of neurocognitive impairment in the setting of HIV. In addition to a standard 8-test neuropsychological battery, each participant underwent testing with the NCAD, which requires approximately 20 min and has been shown to accurately measure neurocognition in elderly individuals. The NCAD yields seven subtest scores in addition to an overall predictive score that is calculated based on subtest results. Thirty-nine HIV-infected participants were included in this study; the majority of which (71.8 %) had undetectable plasma HIV RNA levels and a history of significant immunocompromise (median nadir CD4+ count 34 cells/MUl). The mean composite neuropsychological score (NPT-8) was 46.07, and mean global deficit score (GDS) was 0.59. NCAD total subtest accuracy correlated significantly with NPT-8 (Pearson correlation r = 0.59, p < 0.0001) as well as GDS (Spearman's rho = -0.36, p = 0.02). NCAD predictive score also correlated significantly with NPT-8 (Spearman's rho = -0.5601, p = 0.0016) and GDS (Spearman's rho = 0.45, p = 0.0144). When using the most recent nosology of HAND criteria for neurocognitive impairment, the area under the curve (AUC) for NCAD total subtest accuracy was 0.7562 (p = 0.012), while the AUC for the HIV dementia scale was 0.508 (p = 0.930). While not as comprehensive as a full neuropsychological battery, the NCAD shows promise as a rapid screening tool for HIV-infected individuals, and additional research of this device is indicated. PMID- 27245593 TI - Varicella zoster virus infection of human fetal lung cells alters mitochondrial morphology. AB - Varicella zoster virus (VZV) is a ubiquitous alphaherpesvirus that establishes latency in ganglionic neurons throughout the neuraxis after primary infection. Here, we show that VZV infection induces a time-dependent significant change in mitochondrial morphology, an important indicator of cellular health, since mitochondria are involved in essential cellular functions. VZV immediate-early protein 63 (IE63) was detected in mitochondria-rich cellular fractions extracted from infected human fetal lung fibroblasts (HFL) by Western blotting. IE63 interacted with cytochrome c oxidase in bacterial 2-hybrid analyses. Confocal microscopy of VZV-infected HFL cells at multiple times after infection revealed the presence of IE63 in the nucleus, mitochondria, and cytoplasm. Our data provide the first evidence that VZV infection induces alterations in mitochondrial morphology, including fragmentation, which may be involved in cellular damage and/or death during virus infection. PMID- 27245597 TI - Microbial Ecology of the Human Skin. AB - This review article on the skin microbiota was written in response to recent advances that transitioned from culture methods to PCR amplification and sequencing of bacterial and fungal genes as a result of the Human Microbiome Project. This transition enables the investigation of the full diversity of microorganisms inhabiting human skin. The skin provides a range of habitats with different microbiota associated with the three major regions of the skin, namely the moist axilla, perineum, and toe webs; oily or sebaceous head, neck, and trunk; and dry forearms and legs. These new culture-independent tools are revealing the diversity of the human skin microbiota in the different locations of the body and with skin depth. These tools should lead to a better understanding of the state of homeostasis between the microbiota and the host and the overall functionality of that microbiota. PMID- 27245598 TI - The Root-Associated Microbial Community of the World's Highest Growing Vascular Plants. AB - Upward migration of plants to barren subnival areas is occurring worldwide due to raising ambient temperatures and glacial recession. In summer 2012, the presence of six vascular plants, growing in a single patch, was recorded at an unprecedented elevation of 6150 m.a.s.l. close to the summit of Mount Shukule II in the Western Himalayas (Ladakh, India). Whilst showing multiple signs of stress, all plants have managed to establish stable growth and persist for several years. To learn about the role of microbes in the process of plant upward migration, we analysed the root-associated microbial community of the plants (three individuals from each) using microscopy and tagged amplicon sequencing. No mycorrhizae were found on the roots, implying they are of little importance to the establishment and early growth of the plants. However, all roots were associated with a complex bacterial community, with richness and diversity estimates similar or even higher than the surrounding bare soil. Both soil and root-associated communities were dominated by members of the orders Sphingomonadales and Sphingobacteriales, which are typical for hot desert soils, but were different from communities of temperate subnival soils and typical rhizosphere communities. Despite taxonomic similarity on the order level, the plants harboured a unique set of highly dominant operational taxonomic units which were not found in the bare soil. These bacteria have been likely transported with the dispersing seeds and became part of the root-associated community following germination. The results indicate that developing soils act not only as a source of inoculation to plant roots but also possibly as a sink for plant-associated bacteria. PMID- 27245599 TI - Buyang Huanwu Decoction attenuates H2O2-induced apoptosis by inhibiting reactive oxygen species-mediated mitochondrial dysfunction pathway in human umbilical vein endothelial cells. AB - BACKGROUND: Apoptosis of endothelial cells caused by reactive oxygen species plays an important role in ischemia/reperfusion injury after cerebral infarction. Buyang Huanwu Decoction (BYHWD) has been used to treat stroke and stroke-induced disability, however, the mechanism for this treatment remains unknown. In this study, we investigated whether BYHWD can protect human umbilical vein endothelial cells (HUVECs) from H2O2-induced apoptosis and explored the underlying mechanisms. METHODS: To investigate the effect of BYHWD on the apoptosis of HUVECs, we established a H2O2-induced oxidative stress model and detected apoptosis by Hoechst 33342 and propidium iodide staining. JC-1 and DCFH-DA assays,western blotting and electron microscopy were used to examine the mechanism of BYHWD on apoptosis. RESULTS: Pretreatment with BYHWD significantly inhibited H2O2-induced apoptosis and protein caspase-3 expression in a concentration-dependent manner. In addition, BYHWD reduced reactive oxygen species production and promoted endogenous antioxidant defenses. Furthermore, loss of mitochondrial membrane potential and structural disruption of mitochondria were both rescued by BYHWD. CONCLUSIONS: BYHWD protects HUVECs from H2O2-induced apoptosis by inhibiting oxidative stress damage and mitochondrial dysfunction. These findings indicate that BYHWD is a promising treatment for cerebral ischemia diseases. PMID- 27245601 TI - Exploring Methods to Measure the Prevalence of Meniere's Disease in the US ClinformaticsTM Database, 2010-2012. AB - Recent studies on the epidemiology of the inner-ear disorder Meniere's disease (MD) use disparate methods for sample selection, case identification and length of observation. Prevalence estimates vary geographically from 17 to 513 cases per 100,000 people. We explored the impact of case detection strategies and observation periods in estimating the prevalence of MD in the USA, using data from a large insurance claims database. Using case detection strategies of >=1, >=2 and >=3 ICD-9 claim codes for MD within a 1-year period, the 2012 prevalence estimates were 66, 27 and 14 cases per 100,000 people, respectively. For >=1, >=2 and >=3 insurance claims within a 3-year observation period, the prevalence estimates were 200, 104 and 66 cases per 100,000 people, respectively. Estimates based on a single claim are likely to overestimate prevalence; this conclusion is aligned with the American Academy of Otolaryngology-Head and Neck Foundation criteria requiring >=2 definitive episodes for a definite diagnosis, and it has implications for future epidemiologic research. We believe estimates for >=2 claims may be a more conservative estimate of the prevalence of MD, and multiyear estimates may be needed to allow for adequate follow-up time. PMID- 27245600 TI - Renal transplantation in Bardet-Biedl Syndrome. AB - BACKGROUND: Renal anomalies are common in patients with Bardet-Biedl syndrome (BBS), a renal cystic ciliopathy with multi-systemic features. Renal transplantation is indicated in cases of end-stage renal disease (ESRD), but transplant centers may be hesitant to perform the necessary transplant in light of the multitude of metabolic comorbidities these patients often face with the potential to complicate outcomes. METHODS: Data from the Clinical Registry Investigating BBS (CRIBBS) were used to investigate renal transplant outcomes in the largest BBS cohort described to date. RESULTS: Of the 206 patients enrolled in the CRIBBS, 21 children (10.2 %; 16 girls, 5 boys; median age 8.4 years) had been diagnosed with ESRD. Renal transplantation was performed in 18 of these individuals between 1982 and 2015, including repeat transplantation in some cases, for a total of 22 kidneys. Overall graft survival was 81.6 % at 1 year post-transplantation, 75.7 % at 5 years, 59 % at 10 years, and 49.2 % at 25 years. Patient survival was 94.4 % at 1 year post-transplantation, 87.2 % at 8 years, and 79.3 % at 25 years. CONCLUSIONS: At a median follow-up time of 97 months, relatively few complications of renal transplantation were reported in the patients of this study. However, body mass index was significantly elevated in transplanted individuals compared to non-transplanted individuals participating in CRIBBS at the most recent follow-up. Although the frequency of obesity and other manifestations of the metabolic syndrome warrant meticulous management in this high-risk population, favorable long-term outcomes suggest that renal transplantation is a viable option for patients with BBS and ESRD. PMID- 27245602 TI - Repetition-lag memory training is feasible in patients with chronic stroke, including those with memory problems. AB - PRIMARY OBJECTIVE: Repetition-lag memory training was developed to increase individuals' use of recollection as opposed to familiarity in recognition memory. The goals of this study were to examine the feasibility of repetition-lag training in patients with chronic stroke and to explore whether the training might show suggestions of transfer to non-trained tasks. RESEARCH DESIGN: Quasi experimental. METHODS AND PROCEDURES: Patients (n = 17) took part in six repetition-lag training sessions and their gains on the training and non-trained tasks were compared to those of age-matched healthy controls (n = 30). MAIN OUTCOMES AND RESULTS: All but two patients completed the training, indicating that the method is feasible with a wide range of stroke survivors. The amount patients gained on the training task was similar to that of healthy controls (that is, the Group * Time interactions were by-and-large not significant), suggesting that stroke survivors might benefit to the same degree as healthy adults from this training. Both groups showed some indication of transfer to the non-trained backward digit span task and visuospatial memory. CONCLUSIONS: These findings show that repetition-lag memory training is a possible approach with stroke survivors to enhance recollection. Further research on the method's efficacy and effectiveness is warranted. PMID- 27245603 TI - Daily weather generator with drought properties by copulas and standardized precipitation indices. AB - The weather generator is an essential process in water resource assessment. Most weather generators focus on extreme rainfall events and rainfall amounts in a relatively short time scale. However, drought events often last more than several months, which conventional weather generators hardly generate. Conventional weather generators assume that monthly rainfalls are independent, skewing drought event generation. The purpose of this study is to construct a weather generator with improved drought property generation, combining with monthly rainfall data from conventional weather generators and characteristics of standardized precipitation indices. The proposed weather generators employs four drought parameters, namely starting month, duration, average, and minimum standardized precipitation indices, generated using a copula method. Analytical results show that the four parameters generated by the copula method are consistent with historical records. The proposed weather generator overcomes the limitation of conventional weather generators and can generate both rainfall and drought properties. The results also indicate that the assumption of monthly independence in drought generation can cause underestimated occurrence and duration of drought events. The proposed generator is also demonstrated for climate change assessment. The analytical results show that the uncertainties from the selection of weather generators are even higher than those from the selections of global circulation models while applying to water shortage assessment. We therefore suggest that weather generators should consider drought characteristics which can be measured using the standardized precipitation index to reduce the uncertainty. PMID- 27245604 TI - Recurrence of hyperprolactinemia following dopamine agonist withdrawal and possible predictive factors of recurrence in prolactinomas. AB - BACKGROUND: The optimal duration of cabergoline (CAB) treatment of prolactinomas that minimizes recurrences is not well established. 2011 Endocrine Society Guidelines suggested that withdrawal may be safely undertaken after 2 years in patients achieving normoprolactinemia and tumor reduction. MATERIALS: We analyzed 74 patients (mean age = 46.9 +/- 14.4, M/F = 19/55, macro/micro = 18/56) bearing a prolactinoma divided in 3 groups: group A (23) treated for 3 years, group B (23) for a period between 3 and 5 years, and group C (28) for a period >5 years. CAB therapy was interrupted according to Endocrine Society Guidelines. Prolactin (PRL) levels were measured 3, 6, 12 and 24 months after withdrawal. Recurrence was defined with PRL levels >=30 ng/ml. RESULTS: Groups did not differ in pretreatment PRL levels (123.2 +/- 112.1, 120.9 +/- 123.8, 176.6 +/- 154.0), pituitary deficit (4, 17, 17 %), mean CAB weekly dose (0.7 +/- 0.4, 0.6 +/- 0.3, 0.7 +/- 0.4) and PRL levels before withdrawal (17.1 +/- 19.6, 11.4 +/- 8.8, 13.8 +/- 13.5). Recurrence occurred within 12 months in 34 patients (45.9 %), without significant differences among groups. Neuroradiological evaluation showed a significantly higher presence of macroadenoma in group C (13, 17 and 39 %, respectively). Recurrence rate of hyperprolactinemia did not depend on sex, tumor size or CAB dose but it was significantly correlated with PRL levels at diagnosis and before withdrawal (p = 0.03). Finally, patients with pituitary deficit at diagnosis showed a significantly higher recurrence rate (p = 0.03). CONCLUSIONS: The study provides additional evidence that prolonging therapy for more than 3 years does not reduce recurrence rate. In particular, recurrence risk was similar in micro- and macroadenomas, and higher in patients with pituitary deficits at diagnosis. PMID- 27245607 TI - A diagnostic head and neck fine needle aspiration service can be provided using liquid-based cytology only. AB - OBJECTIVE: Liquid-based cytology (LBC) has been used for non-gynaecological specimens since its introduction into routine use in cervical cytology in the mid 1990s. There are still relatively few large studies comparing performance in reporting the head and neck fine-needle aspirations (H&N FNA) processed by LBC only to conventional direct smears (CDS). METHODS: This study compared 686 H&N FNAs processed by LBC only with 3719 CDS. All were taken under ultrasound (US) guidance by a small cohort of three consultant radiologists and reported by the author. RESULTS: The (smaller) LBC sample was statistically representative of the larger CDS population at an alpha level of 0.05. There was no difference between CDS and LBC at a 95% confidence interval (CI) when comparing specificity and sensitivity (specificity: 94.8-96.5% versus 90.2-95.4%; sensitivity: 91.4-94.1% versus 86.8-93.4%). The inadequate rate between the two techniques was similar, 0.5-1.0% for CDS versus 0.7-2.5% for LBC. The significance difference was in the suspicious rate which was greater at 2.8-5.8% for LBC versus 1.7-2.6% for CDS. Consequently, there was a slight but non-significant difference between the two populations with respect to the overall accuracy: 93.5-95.1% for CDS versus 89.4 93.7% for LBC. CONCLUSIONS: While there are morphological differences between LBC and CDS in H&N FNAs, once a degree of familiarity is achieved, the two techniques have equivalent sensitivity, specificity and inadequate rates. PMID- 27245606 TI - Surgical safety of cervical pedicle screw placement with computer navigation system. AB - Cervical pedicle screw (CPS) may be the biomechanically best system for posterior cervical segmental fixation, but may carry a surgery-related risk. The purpose of this study was to evaluate the safety of CPS placement using computer navigation system for posterior cervical instrumented fixation and discuss its complication avoidance and management. Posterior cervical instrumented fixation using CPS was performed in a total of 128 patients during the period between 2007 and 2015. Intraoperative image guidance was achieved using a preoperative 3D CT-based or an intraoperative 3D CT-based navigation system. A total of 762 CPSs were placed in the spine level of C2 to Th3. The radiological accuracy of CPS placement was evaluated using postoperative CT. Accuracy of CPS placement using a preoperative 3D CT-based navigation system was 93.6 % (423 of 452 screws) in grade 0; the screw was completely contained in the pedicle, and accuracy of CPS placement using an intraoperative 3D CT-based navigation system was a little bit improved to 97.1 % (301 of 310 screws) in grade 0. CPS misplacement (more than half of screw) was 3.3 % (15 of 452 screws) using a preoperative 3D CT-based navigation system, and CPS misplacement (more than half of screw) was 0.6 % (2 of 310 screws) using an intraoperative 3D CT-based navigation system. In total, 38 screws (5.0 %) were found to perforate the cortex of pedicle, although any neural or vascular complications closely associated with CPS placement were not encountered. Twenty nine of 38 screws (76.3 %) were found to perforate laterally, and seven screws (18.4 %) were found to perforate medially. Image-guided CPS placement has been an important advancement to secure the safe surgery, although the use of CPS placement needs to be carefully determined based on the individual pathology. PMID- 27245605 TI - Lipid Abnormalities and Inflammation in HIV Inflection. AB - Infection with the human immunodeficiency virus (HIV), and subsequent treatment with antiretroviral therapy (ART), is often associated with perturbations in lipid profiles. Furthermore, persistent inflammation, in spite of suppression of viral replication by ART, likely contributes to modifications in lipid composition and function, exacerbating risk for development of cardiovascular disease (CVD). Increased levels of several pro-inflammatory lipid species, including oxidized low-density lipoprotein (LDL) and high-density lipoprotein (HDL), have been measured in HIV-infected persons and are associated with markers of immune activation. The mechanisms linked to this bidirectional relationship in which inflammation increases lipid levels and promotes their modification, and these modified lipid species perpetuate inflammatory processes, require further investigation. Treatment with statins and other lifestyle modifications, including improvement in dietary intake and exercise, are critical to reducing CVD risk. Well-designed clinical trials that take into account the complex relationships among lipids and inflammation within persons infected with HIV need to be considered. PMID- 27245609 TI - Differential Association of Exercise Intensity With Risk of Atrial Fibrillation in Men and Women: Evidence from a Meta-Analysis. AB - BACKGROUND: Despite widespread interest and extensive research, the association between different levels of physical activity (PA) and risk of atrial fibrillation (AF) is still not clearly defined. Therefore, we systematically evaluated and summarized the evidences regarding association of different intensity of PA with the risk of AF in this meta-analysis. METHODS AND RESULTS: An extensive literature search was performed on databases for studies showing association of exercise with AF risk. Twenty-two studies were identified that included 656,750 subjects. Meta-analytic estimates were derived using random effects models and pooled odds ratio estimates were obtained. Potential sources of heterogeneity were examined in sensitivity analyses, and publication biases were estimated. Pooled analysis of 7 studies with 93,995 participants reported high risk of incident AF with sedentary lifestyle (pooled OR 2.47 [95% CI 1.25 3.7], P = 0.005). In 3 trials, 149,048 women involved in moderate PA were 8.6% less likely to develop AF compared to women with sedentary life (OR 0.91 [95% CI 0.78-0.97], P = 0.002). Women performing intense exercise were found to have 28% lower risk of AF (OR 0.72 [95% CI 0.57-0.88], P < 0.001). The overall pooled estimate indicated a protective impact of moderate PA in men (pooled OR 0.8133 [95% CI 0.26-1.004], P = 0.06) whereas vigorous PA was associated with a significantly increased AF risk (pooled OR 3.30 [1.97-4.63], P = 0.0002). CONCLUSION: Sedentary lifestyle significantly increases and moderate amount of physical activity reduces the risk of AF in both men and women. However, intense exercise has a gender-specific association with AF risk. PMID- 27245608 TI - Targeting oncogenic protein kinase Ciota for treatment of mutant KRAS LADC. AB - Lung cancer is the leading cause of cancer death in the US with ~124,000 new cases annually, and a 5 y survival rate of ~16%. Mutant KRAS-driven lung adenocarcinoma (KRAS LADC) is a particularly prevalent and deadly form of lung cancer. Protein kinase Ciota (PKCiota) is an oncogenic effector of KRAS that activates multiple signaling pathways that stimulate transformed growth and invasion, and maintain a KRAS LADC tumor-initiating cell (TIC) phenotype. PKCiota inhibitors used alone and in strategic combination show promise as new therapeutic approaches to treatment of KRAS LADC. These novel drug combinations may improve clinical management of KRAS LADC. PMID- 27245610 TI - 4E-BP2 hardwires lymphocytes for rapamycin sensitivity. AB - The mTORC1 [mammalian (or mechanistic) target of rapamycin complex 1] inhibitor rapamycin is a potent inhibitor of T and B lymphocyte growth and proliferation. In this issue of Science Signaling, So et al found that the isoform of 4E-BP (4E BP2) in lymphocytes that regulates messenger RNA translation is more sensitive to the effects of rapamycin than is the 4E-BP isoform found in nonlymphoid cells. Furthermore, inhibition of 4E-BP2 blocks both the growth and proliferation of lymphocytes. PMID- 27245611 TI - Hydroxylation-independent HIF-1alpha stabilization through PKA: A new paradigm for hypoxia signaling. AB - In this issue of Science Signaling, Bullen et al demonstrate that protein kinase A (PKA) phosphorylates and stimulates the transcriptional activity of hypoxia inducible transcription factor-1alpha (HIF-1alpha). This finding may have implications in diseases processes that occur at the interface of hypoxia and inflammation, where HIF-1alpha stabilization can function to dampen hypoxia driven inflammation. PMID- 27245612 TI - Identification of a small-molecule ligand that activates the neuropeptide receptor GPR171 and increases food intake. AB - Several neuropeptide systems in the hypothalamus, including neuropeptide Y and agouti-related protein (AgRP), control food intake. Peptides derived from proSAAS, a precursor implicated in the regulation of body weight, also control food intake. GPR171 is a heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) for BigLEN (b-LEN), a peptide derived from proSAAS. To facilitate studies exploring the physiological role of GPR171, we sought to identify small-molecule ligands for this receptor by performing a virtual screen of a compound library for interaction with a homology model of GPR171. We identified MS0015203 as an agonist of GPR171 and demonstrated the selectivity of MS0015203 for GPR171 by testing the binding of this compound to 80 other membrane proteins, including family A GPCRs. Reducing the expression of GPR171 by shRNA (short hairpin RNA)-mediated knockdown blunted the cellular and tissue response to MS0015203. Peripheral injection of MS0015203 into mice increased food intake and body weight, and these responses were significantly attenuated in mice with decreased expression of GPR171 in the hypothalamus. Together, these results suggest that MS0015203 is a useful tool to probe the pharmacological and functional properties of GPR171 and that ligands targeting GPR171 may eventually lead to therapeutics for food-related disorders. PMID- 27245613 TI - Protein kinase A-dependent phosphorylation stimulates the transcriptional activity of hypoxia-inducible factor 1. AB - Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes encoding proteins that enable cells to adapt to reduced O2 availability. Proteins encoded by HIF-1 target genes play a central role in mediating physiological processes that are dysregulated in cancer and heart disease. These diseases are also characterized by increased production of cyclic adenosine monophosphate (cAMP), the allosteric activator of cAMP-dependent protein kinase A (PKA). Using glutathione S-transferase pull-down, coimmunoprecipitation, and mass spectrometry analyses, we demonstrated that PKA interacts with HIF-1alpha in HeLa cervical carcinoma cells and rat cardiomyocytes. PKA phosphorylated Thr(63) and Ser(692) on HIF-1alpha in vitro and enhanced HIF transcriptional activity and target gene expression in HeLa cells and rat cardiomyocytes. PKA inhibited the proteasomal degradation of HIF-1alpha in an O2-independent manner that required the phosphorylation of Thr(63) and Ser(692) and was not affected by prolyl hydroxylation. PKA also stimulated the binding of the coactivator p300 to HIF 1alpha to enhance its transcriptional activity and counteracted the inhibitory effect of asparaginyl hydroxylation on the association of p300 with HIF-1alpha. Furthermore, increased cAMP concentrations enhanced the expression of HIF target genes encoding CD39 and CD73, which are enzymes that convert extracellular adenosine 5'-triphosphate to adenosine, a molecule that enhances tumor immunosuppression and reduces heart rate and contractility. These data link stimuli that promote cAMP signaling, HIF-1alpha-dependent changes in gene expression, and increased adenosine, all of which contribute to the pathophysiology of cancer and heart disease. PMID- 27245615 TI - Effects of xylitol dehydrogenase (XYL2) on xylose fermentation by engineered Candida glycerinogenes. AB - Efficient bioconversion of d-xylose into various biochemicals is critical for lignocelluloses application. Candida glycerinogenes, expressing the xylitol dehydrogenase (XYL2) gene, has the ability to produce glycerol from xylose entered into pentose phosphate pathway. In this study, we demonstrate that low expression levels of the XYL2 gene derived from Scheffersomyces stipitis in C. glycerinogenes is a major bottleneck in efficient xylose fermentation. Through a metabolic engineering approach using an integrative expression, XYL2 was identified as an overexpression target for improving xylose metabolism. Two recombinant strains with XYL2 overexpression were constructed to ferment a mixture of glucose and xylose simultaneously in batch fermentation. Compared with C. glycerinogenes (wild type), glycerol production from xylose by C. glycerinogenes (PURGAPX2) and C. glycerinogenes (PURGPDX2) was increased by 94.5% and 103.3%, respectively. It was also found that additional overexpression of XYL2 under the control of strong promoters in a xylose-fermenting strain not only reduced xylitol accumulation but also increased glycerol yields. As the expression levels of XYL2 increased, the glycerol yields gradually improved from 30.6 to 63.3 g/L, whereas the xylitol yields significantly decreased from 38.7 to 19.9 g/L. These results suggest that strong expression of XYL2 is a necessary condition for developing efficient xylose-fermenting strains. PMID- 27245614 TI - The 4E-BP-eIF4E axis promotes rapamycin-sensitive growth and proliferation in lymphocytes. AB - Rapamycin has been used as a clinical immunosuppressant for many years; however, the molecular basis for its selective effects on lymphocytes remains unclear. We investigated the role of two canonical effectors of the mammalian target of rapamycin (mTOR): ribosomal S6 kinases (S6Ks) and eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BPs). S6Ks are thought to regulate cell growth (increase in cell size), and 4E-BPs are thought to control proliferation (increase in cell number), with mTORC1 signaling serving to integrate these processes. However, we found that the 4E-BP-eIF4E signaling axis controlled both the growth and proliferation of lymphocytes, processes for which the S6Ks were dispensable. Furthermore, rapamycin disrupted eIF4E function selectively in lymphocytes, which was due to the increased abundance of 4E-BP2 relative to that of 4E-BP1 in these cells and the greater sensitivity of 4E-BP2 to rapamycin. Together, our findings suggest that the 4E-BP-eIF4E axis is uniquely rapamycin sensitive in lymphocytes and that this axis promotes clonal expansion of these cells by coordinating growth and proliferation. PMID- 27245616 TI - Phospholipid End-Capped Acid-Degradable Polyurethane Micelles for Intracellular Delivery of Cancer Therapeutics. AB - Nanoscale drug carriers fabricated by phospholipid end-capped polyurethane bearing acetal backbones that degrade in acidic conditions are fabricated. These micelles effectively allow drugs to enter the blood circulation, and then disintegrate in acidic endosomes and lysosomes for intelligent delivery of payloads. PMID- 27245617 TI - The Effect of Hypoxia and Hyperoxia on Growth and Expression of Hypoxia-Related Genes and Proteins in Spotted Gar Lepisosteus oculatus Larvae and Juveniles. AB - We studied the molecular responses to different water oxygen levels in gills and swim bladder of spotted gar (Lepisosteus oculatus), a bimodal breather. Fish at swim-up stage were exposed for 71 days to normoxic, hypoxic, and hyperoxic water conditions. Then, all aquaria were switched to normoxic conditions for recovery until the end of the experiment (120 days). Fish were sampled at the beginning of the experiment, and then at 71 days of exposure and at 8 days of recovery. We first cloned three hypoxia-related genes, hypoxia-inducible factor 2alpha (HIF 2alpha), Na(+) /H(+) exchanger 1 (NHE-1), and NHE-3, and uploaded their cDNA sequences in the GeneBank database. We then used One Step Taqman(r) real-time PCR to quantify the mRNA copies of target genes in gills and swim bladder of fish exposed to different water O2 levels. We also determined the protein expression of HIF-2alpha and neuronal nitric oxide synthase (nNOS) in the swim bladder by using confocal immunofluorescence. Hypoxic stress for 71 days significantly increased the mRNA copies of HIF-2alpha and NHE-1 in gills and swim bladder, whereas normoxic recovery for 8 days decreased the HIF-2alpha mRNA copies to control values in both tissues. We did not found significant changes in mRNA copies of the NHE-3 gene in either gills or swim bladder in response to hypoxia and hyperoxia. Unlike in normoxic swim bladder, double immunohistochemical staining in hypoxic and hyperoxic swim bladder using nNOS/HIF-2alpha showed extensive bundles of HIF-2alpha-positive nerve fibers in the trabecular musculature associated with a few varicose nNOS immunoreactive nerve terminals. PMID- 27245618 TI - Improved cognitive flexibility after aortic valve replacement surgery. AB - OBJECTIVES: Aortic valve replacement (AVR) surgery is associated with potential risk to cerebral injury. On the other hand, improved cardiovascular functioning after the surgery may have positive impact on brain health. The aim of this preliminary study was to investigate the impact of AVR surgery on cognition, specifically on higher cognitive control functions, i.e. executive functions, that are typically implicated in cognitive decline due to vascular origin. METHODS: Patients (n = 16) undergoing elective AVR surgery due to aortic stenosis were recruited and their cognitive performance was assessed using a computer based Executive Reaction Time (RT) test. Testing was performed 1 day prior to AVR surgery and ~3 months after the surgery. In addition, the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) was used to assess everyday challenges in executive functions and self-regulation. Patient's postoperative test results were compared with each patient's preoperative results to determine changes in executive functions. RESULTS: Subjects' overall cognitive performance improved after AVR surgery. After surgery, patients responded in the Executive RT test more accurately with the same response speed (change from 297 to 298 ms). Their overall probability to commit an error (total errors) was reduced by 47%, reflecting improved executive functions in general (OR = 0.53, 95% CI = 0.46-0.59, error rate change from 44.8 to 28.0%). Furthermore, one key component of executive functions, inhibitory control, was improved after AVR surgery. This was seen in reduced probability of failing to withhold a response, i.e. making a commission error, by 89% (OR = 0.11, CI = 0.08-0.16, error rate change from 11.8 to 2.6%). The probability of missing a response was reduced by 48%, reflecting improved attention (OR = 0.52, 0.44-0.64, error rate change from 18.1 to 11.0%). No statistically significant differences in BRIEF-A scores were found. CONCLUSIONS: There was a marked improvement in cognitive performance following AVR surgery, specifically in executive control functions indicating improved cognitive flexibility. Cognitive improvement, as opposed to the typical trajectory of cognitive decline in an elderly population with vascular disease, emphasizes the importance of these results and points to AVR surgery as having potential benefits on brain health in general. CLINICAL TRIALS IDENTIFIER: NCT01953068. https://www.clinicaltrials.gov/ct2/show/NCT01953068?term=NCT01953068&rank=1. PMID- 27245619 TI - A prospective comparison of mid-term outcomes in patients treated with heart transplantation with advanced age donors versus left ventricular assist device implantation. AB - OBJECTIVES: In Europe, the age of heart donors is constantly increasing. Ageing of heart donors limits the probability of success of heart transplantation (HTx). The aim of this study is to compare the outcome of patients with advanced heart failure (HF) treated with a continuous-flow left ventricular assist device (CF LVAD) with indication as bridge to transplantation (BTT) or bridge to candidacy (BTC) versus recipients of HTx with the donor's age above 55 years (HTx with donors >55 years). METHODS: we prospectively evaluated 301 consecutive patients with advanced HF treated with a CF-LVAD (n = 83) or HTx without prior bridging (n = 218) in our hospital from January 2006 to January 2015. We compared the outcome of CF-LVAD-BTT (n = 37) versus HTx with donors >55 years (n = 45) and the outcome of CF-LVAD-BTT plus BTC (n = 62) versus HTx with donors >55 years at the 1- and 2 year follow-up. Survival was evaluated according to the first operation. RESULTS: The perioperative (30-day) mortality rate was 0% in the LVAD-BTT group vs 20% (n = 9) in the HTx group with donors >55 years (P = 0.003). Perioperative mortality occurred in 5% of the LVAD-BTT/BTC patients (n = 3) and in 20% of the HTx with donors >55 year group (P = 0.026). Kaplan-Meier curves estimated a 2-year survival rate of 94.6% in CF-LVAD-BTT vs 68.9% in HTx with donors >55 years [age- and sex-adjusted hazard ratio (HR) 0.25; 95% confidence interval (CI) 0.08-0.81; P = 0.02 in favour of CF-LVAD]. Considering the post-HTx outcome, a trend in favour of CF-LVAD-BTT was also observed (age- and sex-adjusted HR 0.45; 95% CI 0.17-1.16; P = 0.09 in favour of CF-LVAD), whereas CF-LVAD-BTT/BTC showed a similar survival at 2 years compared with HTx with donors >55 years, both censoring the follow-up at the time of HTx and considering the post-HTx outcome. CONCLUSIONS: Early and mid-term outcomes of patients treated with a CF-LVAD with BTT indication seem better than HTx with old donors. It must be emphasized that up to 19% of patients in the CF-LVAD/BTT group underwent transplantation in an urgent condition due to complications related to the LVAD. At the 2-year follow up, CF-LVAD with BTT and BTC indications have similar outcome than HTx using old heart donors. These results must be confirmed in a larger and multicentre population and extending the follow-up. PMID- 27245620 TI - Reduction of aberrant aortic haemodynamics following aortic root replacement with a mechanical valved conduit. AB - OBJECTIVES: Previous work suggests that aortic root and valve prostheses alter blood flow patterns in the ascending aorta, creating aberrant haemodynamics compared with those of healthy volunteers. Various valve designs have been proposed to better restore physiological haemodynamics. In this study, magnetic resonance imaging (MRI) was used to non-invasively assess three-dimensional (3D) ascending aortic haemodynamics after aortic root replacement (ARR) with a mechanical valved conduit postulated to create less turbulent blood flow. METHODS: Ten patients (40 +/- 9 years) underwent transthoracic echocardiography and contrast-enhanced multidimensional four-dimensional (4D) flow MRI at 1.5 T after ARR with an On-X mechanical valved conduit. Preoperative 4D flow MRI was available in 7 patients. Ten age- and gender-matched healthy volunteers (42 +/- 13 years) were also analysed to characterize physiological flow. The presence of vortex/helix formation was graded by two blinded observers. Peak transvalvular pressure gradients were computed using the simplified Bernoulli equation. Patients' postoperative pressure gradients and helicity/vorticity grades were compared with preoperative gradients and those from healthy volunteers. RESULTS: Intra- and interobserver ratings showed good agreement (kappa = 0.93, P < 0.01 and kappa = 0.84, P < 0.01, respectively). Highly helical and/or vortical flow was observed in all patients preoperatively, which was significantly reduced postoperatively (P < 0.01 and <0.01, respectively), restoring similar flow patterns similar to those seen in volunteers (P = 0.56 and 0.56). Peak transvalvular pressure gradients (DeltaP) were also significantly reduced [43 +/- 21 vs 12 +/- 7 mmHg, P < 0.05 (Echo); 48 +/- 22 vs 16 +/- 9 mmHg, P < 0.05 (MRI)], but remained significantly higher than those of volunteers (6 +/- 1 mmHg, P < 0.01). CONCLUSIONS: Preliminary evidence suggests that ARR with an On-X mechanical valve significantly reduces aberrant aortic haemodynamics, producing flow patterns that resemble those in healthy volunteers. PMID- 27245621 TI - Synthesis and Antimicrobial Activity of Albicidin Derivatives with Variations of the Central Cyanoalanine Building Block. AB - To investigate the pharmacophore regions of the antibiotic albicidin, derivatives with variations on the central amino acid were synthesized. Charged as well as uncharged residues were chosen to explore the influence of charge, chirality, and steric bulk. The bioactivity of the newly synthesized derivatives was determined by a microdilution technique to obtain minimum inhibitory concentrations (MIC) values. The compounds were also tested in a cell-free system to obtain information about their ability to inhibit their primary target, DNA gyrase. It was then shown that derivatives with uncharged side chains retain antibacterial activity, whereas incorporation of charged amino acid residues decreases the antibacterial activity dramatically, possibly due to restricted cell penetration of these derivatives. From the newly synthesized derivatives, the threonine derivative shows the most promising results in both tests. The information will help to develop the features of albicidin toward more drug-like structures. PMID- 27245622 TI - Corrugated Organic Light Emitting Diodes Using Low Tg Electron Transporting Materials. AB - A corrugated organic light emitting diode (OLED) with enhanced light extraction is realized by incorporating a corrugated composite electron transport layer (ETL) consisting of two ETLs with different glass transition temperatures. The morphology of the corrugated structure is characterized with atomic force microscopy. The results show that the corrugation can be controlled by the layer thicknesses and annealing temperature. Compared with the control planar device, the corrugated OLED shows a more than 35% enhancement in current efficiency from 31 cd/A to 43 cd/A and a 20% enhancement in external quantum efficiency from 10% to 12% at 100 cd/m(2). In addition, the corrugated OLED also has a greatly improved operational stability. The LT90 lifetime of a device operated at 1000 cd/m(2) is improved greater than 100-fold in the corrugated OLED. PMID- 27245623 TI - Gastric Cancer Patients with High PLK1 Expression and DNA Aneuploidy Correlate with Poor Prognosis. AB - Gastric cancer is the fourth most common cancer worldwide. Although it is important to identify patients at high risk for a poor outcome, factors correlating with prognosis in gastric cancer are largely unknown. Here, we focus on the correlations among expression of Polo-like kinase 1 (PLK1), DNA ploidy, and clinical outcome in gastric cancer patients. Gastric cancer specimens were analyzed from 207 consecutive patients. Patients were classified into two groups according to tumor PLK1 expression and DNA content, and an analysis of their clinical outcomes was carried out. Prognoses of patients with PLK1-high tumors were worse than those of patients with PLK1-low tumors, but the differences were not statistically significant. In cell lines, overexpression of PLK1 induced centrosome amplification and multipolar spindles, potentially leading to DNA aneuploidy. Indeed, high expression of PLK1 was also associated with DNA aneuploidy in clinical gastric cancer specimens. Patients with both high PLK1 expression and DNA aneuploidy had poor recurrence-free survival, whereas PLK1 expression and DNA ploidy status alone were not significantly associated with outcome. Here, we provide clinical evidence that high expression of PLK1 could have detrimental effects in tumors with DNA aneuploidy, which may increase the risk of recurrence in gastric cancer patients. PMID- 27245624 TI - Three decades of longlining in Bimini, Bahamas, reveals long-term trends in lemon shark Negaprion brevirostris (Carcharhinidae) catch per unit effort. AB - In Bimini, Bahamas, the consistent employment of longlines, beginning in 1982, provided a rare opportunity to explore population trends for large resident sharks. This study assessed three shallow water longline survey periods at this location; 1982-1989, 1992-2002 and 2003-2014, with the aim of determining trends in annual catch per unit effort (CPUE) for an IUCN listed near-threatened species, the lemon shark Negaprion brevirostris. A general additive model (GAM) was used to analyse the non-linear annual CPUE values over the entire 32-year research period. The GAM displayed high variability of annual CPUE, with a peak value of 0.026 N. brevirostris per hook day (hooks day(-1) ) in 2000. The temporal pattern of CPUE indicated an abundance trend with a complete cycle, from trough to trough, occurring over a period of approximately 18 years. The 1982 1989 survey period saw the highest proportion of mature individuals (19.8%) and the smallest average pre-caudal length (LPC ; 124.8 cm). The 1992-2002 survey period had the highest average annual CPUE (0.018 hooks day(-1) ), while the 2003 2014 research period saw largest average LPC size (134.8 cm) and the lowest average CPUE values (0.009 hooks day(-1) ) of the entire research period. The long-term trend identified in this study provides a baseline for future assessment. PMID- 27245625 TI - Biological data from a data-deficient shark: the Arabian smoothhound Mustelus mosis (Carcharhiniformes: Triakidae). AB - The present study provides information on length distribution, reproductive biology and diet of Mustelus mosis based on individuals caught in waters off the eastern Arabian Peninsula. Although ageing of vertebral centra was attempted, band pairs were of low clarity and counts could not be confidently assigned. PMID- 27245626 TI - Corrigendum. PMID- 27245631 TI - A Multicenter Evaluation of Emergency Department Pain Care Across Different Types of Fractures. AB - Objectives: To identify differences in emergency department (ED) pain-care based on the type of fracture sustained and to examine whether fracture type may influence the more aggressive analgesic use previously demonstrated in older patients. Design: Secondary analysis of retrospective cohort study. Setting: Five EDs (four academic, one community) in the United States. Participants: Patients (1,664) who presented in January, March, July, and October 2009 with a final diagnosis of fracture (774 long bone [LBF], 890 shorter bone [SBF]). Measurements: Primary-predictor was type of fracture (LBF vs. SBF). Pain-care process outcomes included likelihood of analgesic administration, opioid-dose, and time to first analgesic. General estimating equations were used to control for age, gender, race, baseline pain score, triage acuity, comorbidities and ED crowding. Subgroup analyses were conducted to analyze age-based differences in pain care by fracture type. Results: A larger proportion of patients with LBF (30%) were older (>65 years old) compared to SBF (13%). Compared with SBF, patients with LBF were associated with greater likelihood of analgesic administration (OR = 2.03; 95 CI = 1.58 to 2.62; P < 0.001) and higher opioid doses (parameter estimate = 0.268; 95 CI = 0.239 to 0.297; P < 0.001). When LBF were examined separately, older-patients had a trend to longer analgesic wait times (99 [55-163] vs. 76 [35-149] minutes, P = 0.057), but no other differences in process outcomes were found. Conclusion: Long bone fractures were associated with more aggressive pain care than SBF. When fracture types were examined separately, older patients did not appear to receive more aggressive pain care. This difference should be accounted for in further research. PMID- 27245632 TI - Metformin use and asthma outcomes among patients with concurrent asthma and diabetes. AB - BACKGROUND AND OBJECTIVE: Metformin is a first-line treatment for patients with diabetes. Recent animal studies indicated that metformin can reduce airway inflammation. However, it remains unclear whether the use of metformin can help patients maintain asthma control. The purpose of this study was to evaluate the association between the use of metformin and asthma-related outcomes, which include asthma-related hospitalization, asthma-related emergency room visits and asthma exacerbation, among patients with concurrent asthma and diabetes. METHODS: We conducted an 11-year (2001-2011) retrospective cohort study using the Taiwan National Health Insurance Research Database. Patients with concurrent asthma and diabetes were included. The date of the first observed prescription of metformin was defined as the index date. For each metformin user, two matched metformin non users of the same age and gender were randomly selected. Patients were followed for 3 years to measure the occurrence of asthma-related outcomes. Multivariable logistic regression models were used to assess the association between metformin use and asthma-related outcomes. RESULTS: Of 1332 patients with concurrent asthma and diabetes, 444 (33.3%) were metformin users. Compared with non-users, metformin users had a lower risk of asthma-related hospitalization (OR = 0.21, 95% CI: 0.07-0.63) and asthma exacerbation (OR = 0.39, 95% CI: 0.19-0.79). CONCLUSION: The risk of asthma-related outcomes was lower for metformin users than non-users. Health-care providers should consider metformin as a treatment strategy for patients with concurrent asthma and diabetes. PMID- 27245633 TI - Regenerative Medicine Strategies for Hypoplastic Left Heart Syndrome. AB - Hypoplastic left heart syndrome (HLHS), the most severe and common form of single ventricle congenital heart lesions, is characterized by hypoplasia of the mitral valve, left ventricle (LV), and all LV outflow structures. While advances in surgical technique and medical management have allowed survival into adulthood, HLHS patients have severe morbidities, decreased quality of life, and a shortened lifespan. The single right ventricle (RV) is especially prone to early failure because of its vulnerability to chronic pressure overload, a mode of failure distinct from ischemic cardiomyopathy encountered in acquired heart disease. As these patients enter early adulthood, an emerging epidemic of RV failure has become evident. Regenerative medicine strategies may help preserve or boost RV function in children and adults with HLHS by promoting angiogenesis and mitigating oxidative stress. Rescuing a RV in decompensated failure may also require the creation of new, functional myocardium. Although considerable hurdles remain before their clinical translation, stem cell therapy and cardiac tissue engineering possess revolutionary potential in the treatment of pediatric and adult patients with HLHS who currently have very limited long-term treatment options. PMID- 27245634 TI - Phylogenetic relationships, diversification and expansion of chili peppers (Capsicum, Solanaceae). AB - BACKGROUND AND AIMS: Capsicum (Solanaceae), native to the tropical and temperate Americas, comprises the well-known sweet and hot chili peppers and several wild species. So far, only partial taxonomic and phylogenetic analyses have been done for the genus. Here, the phylogenetic relationships between nearly all taxa of Capsicum were explored to test the monophyly of the genus and to obtain a better knowledge of species relationships, diversification and expansion. METHODS: Thirty-four of approximately 35 Capsicum species were sampled. Maximum parsimony and Bayesian inference analyses were performed using two plastid markers (matK and psbA-trnH) and one single-copy nuclear gene (waxy). The evolutionary changes of nine key features were reconstructed following the parsimony ancestral states method. Ancestral areas were reconstructed through a Bayesian Markov chain Monte Carlo analysis. KEY RESULTS: Capsicum forms a monophyletic clade, with Lycianthes as a sister group, following both phylogenetic approaches. Eleven well-supported clades (four of them monotypic) can be recognized within Capsicum, although some interspecific relationships need further analysis. A few features are useful to characterize different clades (e.g. fruit anatomy, chromosome base number), whereas some others are highly homoplastic (e.g. seed colour). The origin of Capsicum is postulated in an area along the Andes of western to north-western South America. The expansion of the genus has followed a clockwise direction around the Amazon basin, towards central and south-eastern Brazil, then back to western South America, and finally northwards to Central America. CONCLUSIONS: New insights are provided regarding interspecific relationships, character evolution, and geographical origin and expansion of Capsicum A clearly distinct early-diverging clade can be distinguished, centred in western-north-western South America. Subsequent rapid speciation has led to the origin of the remaining clades. The diversification of Capsicum has culminated in the origin of the main cultivated species in several regions of South to Central America. PMID- 27245635 TI - Neighbourhood structure and light availability influence the variations in plant design of shrubs in two cloud forests of different successional status. AB - BACKGROUND AND AIMS: Plant design refers to the construction of the plant body or its constituent parts in terms of form and function. Although neighbourhood structure is recognized as a factor that limits plant survival and species coexistence, its relative importance in plant design is not well understood. We conducted field research to analyse how the surrounding environment of neighbourhood structure and related effects on light availability are associated with changes in plant design in two understorey plants (Palicourea padifolia and Psychotria elata) within two successional stages of a cloud forest in Costa Rica. METHODS: Features of plant neighbourhood physical structure and light availability, estimated using hemispherical photographs, were used as variables that reflect the surrounding environment. Measures of plant biomechanics, allometry, branching and plant slenderness were used as functional plant attributes that reflect plant design. We propose a framework using a partial least squares path model and used it to test this association. KEY RESULTS: The multidimensional response of plant design of these species suggests that decreases in the height-based factor of safety and increases in mechanical load and developmental stability are influenced by increases in maximum height of neighbours and a distance-dependence interference index more than neighbourhood plant density or neighbour aggregation. Changes in plant branching and slenderness are associated positively with light availability and negatively with canopy cover. CONCLUSIONS: Although it has been proposed that plant design varies according to plant density and light availability, we found that neighbour size and distance-dependence interference are associated with changes in biomechanics, allometry and branching, and they must be considered as key factors that contribute to the adaptation and coexistence of these plants in this highly diverse forest community. PMID- 27245636 TI - The most prevalent genetic cause of ALS-FTD, C9orf72 synergizes the toxicity of ATXN2 intermediate polyglutamine repeats through the autophagy pathway. AB - The most common genetic cause for amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD) is repeat expansion of a hexanucleotide sequence (GGGGCC) within the C9orf72 genomic sequence. To elucidate the functional role of C9orf72 in disease pathogenesis, we identified certain molecular interactors of this factor. We determined that C9orf72 exists in a complex with SMCR8 and WDR41 and that this complex acts as a GDP/GTP exchange factor for RAB8 and RAB39, 2 RAB GTPases involved in macroautophagy/autophagy. Consequently, C9orf72 depletion in neuronal cultures leads to accumulation of unresolved aggregates of SQSTM1/p62 and phosphorylated TARDBP/TDP-43. However, C9orf72 reduction does not lead to major neuronal toxicity, suggesting that a second stress may be required to induce neuronal cell death. An intermediate size of polyglutamine repeats within ATXN2 is an important genetic modifier of ALS FTD. We found that coexpression of intermediate polyglutamine repeats (30Q) of ATXN2 combined with C9orf72 depletion increases the aggregation of ATXN2 and neuronal toxicity. These results were confirmed in zebrafish embryos where partial C9orf72 knockdown along with intermediate (but not normal) repeat expansions in ATXN2 causes locomotion deficits and abnormal axonal projections from spinal motor neurons. These results demonstrate that C9orf72 plays an important role in the autophagy pathway while genetically interacting with another major genetic risk factor, ATXN2, to contribute to ALS-FTD pathogenesis. PMID- 27245638 TI - Bifocal primary pancreatic Burkitt's lymphoma in a 4-year-old child. AB - Pancreatic tumors are uncommon in children and rarely result in biliary obstruction. Primary pancreatic Burkitt's lymphoma is an exceptionally rare entity with only a few cases described in the literature. We present a case of a bifocal primary pancreatic Burkitt's lymphoma in a 4-year-old child presenting with jaundice. (c) 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:171-174, 2017. PMID- 27245637 TI - Trends in the use of emergency contraception in Britain: evidence from the second and third National Surveys of Sexual Attitudes and Lifestyles. AB - OBJECTIVE: To examine the changes in the prevalence of, and the factors associated with, the use of emergency contraception (EC) in Britain between 2000 and 2010, spanning the period of deregulation and increase in pharmacy supply. DESIGN: Cross-sectional probability sample surveys. SETTING AND POPULATION: British general population. METHODS: Data were analysed from the second and third British National Surveys of Sexual Attitudes and Lifestyles (Natsal), undertaken in 1999-2001 and 2010-12. Univariate and logistic regression analyses were used to measure change in EC use amongst sexually active women aged 16-44 years not intending pregnancy. MAIN OUTCOME MEASURES: Prevalence of EC use and factors associated with use. RESULTS: Of the 5430 women surveyed in 1999-2001 and the 4825 women surveyed in 2010-12, 2.3 and 3.6%, respectively, reported using EC in the year prior to interview (P = 0.0019 for change over time). The prevalence of EC use increased amongst single women and those with higher educational attainment (adjusted odds ratio, aOR 1.51; 95% confidence interval, 95% CI 1.04 2.20; P = 0.0308). Increases in EC use were generally greater among women without behavioural risk factors, such as those with no history of abortion within 5 years (aOR 1.57; 95% CI 1.17-2.12; P = 0.0029), or those whose first heterosexual intercourse occurred after the age of 16 years (aOR 1.68; 95% CI 1.21-2.35; P = 0.0021). The increase in EC use was also more marked among women usually accessing contraception from retail sources than among those doing so from healthcare sources, which may reflect a use of condoms amongst EC users. CONCLUSION: The increase in EC use among women in Britain in the first decade of the 21st century was associated with some, but not all, risk factors for unplanned pregnancy. Advice and provision may need to be targeted at those at highest risk of unplanned pregnancy. TWEETABLE ABSTRACT: Despite pharmacy access, only a small rise in emergency contraception use has been seen in Britain over 10 years. PMID- 27245639 TI - Structure and Rheology of Poloxamine T1107 and Its Nanocomposite Hydrogels with Cyclodextrin-Modified Barium Titanate Nanoparticles. AB - We report the preparation of a nanocomposite hydrogel based on a poloxamine gel matrix (Tetronic T1107) and cyclodextrin (CD)-modified barium titanate (BT) nanoparticles. The micellization and sol-gel behavior of pH-responsive block copolymer T1107 were fully characterized by small-angle neutron scattering (SANS), dynamic light scattering (DLS), and Fourier transform infrared attenuated total reflectance (FTIR-ATR) spectroscopy as a function of concentration, pH and temperature. SANS results reveal that spherical micelles in the low concentration regime present a dehydrated core and highly hydrated shell, with a small aggregation number and size, highly dependent on the degree of protonation of the central amine spacer. At high concentration, T1107 undergoes a sol-gel transition, which is inhibited at acidic pH. Nanocomposites were prepared by incorporating CD-modified BT of two different sizes (50 and 200 nm) in concentrated polymer solutions. Rheological measurements show a broadening of the gel region, as well as an improvement of the mechanical properties, as assessed by the shear elastic modulus, G' (up to 200% increase). Initial cytocompatibility studies of the nanocomposites show that the materials are nontoxic with viabilities over 70% for NIH3T3 fibroblast cell lines. Overall, the combination of Tetronics and modified BaTiO3 provides easily customizable systems with promising applications as soft piezoelectric materials. PMID- 27245640 TI - Antioxidant enzymes in oral verrucous carcinoma. AB - BACKGROUND: Verrucous carcinoma is a non-metastasizing variant of welldifferentiated squamous cell carcinoma, which has been associated with reactive oxygen species generated by betel quid chewing. Salivary antioxidant systems have been suggested to play a protective role in reducing the oxidative damage. Herein, we investigated the difference of the enzymatic antioxidant system expressions in oral verrucous carcinoma and oral squamous cell carcinoma. METHODS: The enzymatic antioxidant system expressions, including manganese superoxide dismutase, glutathione peroxidase, and catalase were evaluated by immunohistochemistry in a series of 202 surgically resected oral squamous cell carcinoma and 20 oral verrucous carcinoma specimens, using tissue microarray slides. RESULTS: The immuno-staining intensities of superoxide dismutase and glutathione peroxidase were strongest in the oral squamous cell carcinoma group than in verrucous carcinoma. The catalase expression showed no difference between different pathological groups. CONCLUSIONS: The different degrees of superoxide dismutase and glutathione expressions in verrucous carcinoma and squamous cell carcinoma may be helpful for pathologists to differentiate these two entities, especially between oral verrucous carcinoma and well differentiated oral squamous cell carcinoma. PMID- 27245641 TI - Shiftwork and decline in endothelial function among police officers. AB - BACKGROUND: Our objective was to assess the influence of shiftwork on change in endothelial function. METHODS: This longitudinal study was conducted in 188 police officers (78.2% men). Shiftwork status (day, afternoon, night) was assessed objectively using daily Buffalo, NY payroll work history records. Brachial artery flow-mediated dilation (FMD) was assessed using ultrasound. Mean change in FMD% between 2004-2009 and 2010-2015 was compared across shiftwork using analysis of variance/covariance. RESULTS: Overall, mean FMD% decreased from 5.74 +/- 2.83 to 3.88 +/- 2.11 over an average of 7 years among all officers; P < 0.0001. Effect modification by gender was significant. Among men (but not women), those who worked day shifts had a smaller mean (+/-SE) decrease in FMD% (-0.89 +/ 0.35) compared with those who worked the afternoon (-2.69 +/- 0.39; P = 0.001) or night shifts (-2.31 +/- 0.45; P = 0.020) after risk factor adjustment. CONCLUSIONS: Larger declines in endothelial function were observed among men who worked afternoon or night shifts. Further investigation is warranted. Am. J. Ind. Med. 59:1001-1008, 2016. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. PMID- 27245642 TI - X-Ray Diffraction and Mossbauer Spectroscopy Studies of Pressure-Induced Phase Transitions in a Mixed-Valence Trinuclear Iron Complex. AB - The mixed-valence complex Fe3 O(cyanoacetate)6 (H2 O)3 (1) has been studied by single-crystal X-ray diffraction analysis at pressures up to 5.3(1) GPa and by (synchrotron) Mossbauer spectroscopy at pressures up to 8(1) GPa. Crystal structure refinements were possible up to 4.0(1) GPa. In this pressure range, 1 undergoes two pressure-induced phase transitions. The first phase transition at around 3 GPa is isosymmetric and involves a 60 degrees rotation of 50 % of the cyanoacetate ligands. The second phase transition at around 4 GPa reduces the symmetry from rhombohedral to triclinic. Mossbauer spectra show that the complex becomes partially valence-trapped after the second phase transition. This sluggish pressure-induced valence-trapping is in contrast to the very abrupt valence-trapping observed when compound 1 is cooled from 130 to 120 K at ambient pressure. PMID- 27245643 TI - Antioxidant trace elements serum levels in long-term parenteral nutrition (PN): Prevalence and infectious risk associated with deficiencies, a retrospective study from a tertiary home-PN center. AB - INTRODUCTION: Antioxidants essential trace elements (TEs), selenium (Se), zinc (Zn) and copper (Cu) are key dietary components and their supplementation in parenteral nutrition (PN) is recommended. However, the frequency of marginal deficiencies and related clinical outcomes remain poorly known in patients receiving long-term PN. METHODS AND OBJECTIVES: We conducted a retrospective observational study whose aim was to determine in a cohort of patients (n = 73) with chronic intestinal failure (CIF) enrolled in a tertiary home PN center and receiving long-term PN with systematic multi-TE supplementation, the prevalence of low serum TEs levels. The goal was also to assess mid-term incidence of serious infection and its associated factors. RESULTS: Among the 73 studied patients, 21.9%, 13.9% and 21.1% had low serum Se (<0.9 MUmol/l), Cu (<12.7 MUmol/l) and Zn (<12.5 MUmol/l) levels, respectively. There was no difference between short bowel syndrome (SBS) and non-SBS patients. 30 patients had at least one of the three serum TEs levels under the cut-off values of deficiency. No specific disease and/or underlying intestinal anatomy were associated with low serum TEs concentration. Cumulative incidence rates of serious infection were 11.1% 95CI[5.7-21.0] and 19.5% 95CI[12.0-30.7] at 6 months and 1 year, respectively. Central venous catheter-related bloodstream infection was the most common infection. Low serum Se was independently associated with a higher risk to develop serious infection (HR 2.65 95CI[1.01-6.97]). CONCLUSION: Low serum TEs concentration is a frequent condition in patients with CIF even with systematic multi-TE supplementations. Se deficiency exposes to a greater risk of serious infection. This suggests that frequent TEs dosage in this population as well as individually tailored supplementation may be beneficial. PMID- 27245644 TI - WHO to set up emergencies programme. PMID- 27245647 TI - Integration of Quantitative Positron Emission Tomography Absolute Myocardial Blood Flow Measurements in the Clinical Management of Coronary Artery Disease. AB - In the >40 years since planar myocardial imaging with(43)K-potassium was introduced into clinical research and management of patients with coronary artery disease (CAD), diagnosis and treatment have undergone profound scientific and technological changes. One such innovation is the current state-of-the-art hardware and software for positron emission tomography myocardial perfusion imaging, which has advanced it from a strictly research-oriented modality to a clinically valuable tool. This review traces the evolving role of quantitative positron emission tomography measurements of myocardial blood flow in the evaluation and management of patients with CAD. It presents methodology, currently or soon to be available, that offers a paradigm shift in CAD management. Heretofore, radionuclide myocardial perfusion imaging has been primarily qualitative or at best semiquantitative in nature, assessing regional perfusion in relative terms. Thus, unlike so many facets of modern cardiovascular practice and CAD management, which depend, for example, on absolute values of key parameters such as arterial and left ventricular pressures, serum lipoprotein, and other biomarker levels, the absolute levels of rest and maximal myocardial blood flow have yet to be incorporated into routine clinical practice even in most positron emission tomography centers where the potential to do so exists. Accordingly, this review focuses on potential value added for improving clinical CAD practice by measuring the absolute level of rest and maximal myocardial blood flow. Physiological principles and imaging fundamentals necessary to understand how positron emission tomography makes robust, quantitative measurements of myocardial blood flow possible are highlighted. PMID- 27245645 TI - Characterizing cognitive performance in a large longitudinal study of aging with computerized semantic indices of verbal fluency. AB - A computational approach for estimating several indices of performance on the animal category verbal fluency task was validated, and examined in a large longitudinal study of aging. The performance indices included the traditional verbal fluency score, size of semantic clusters, density of repeated words, as well as measures of semantic and lexical diversity. Change over time in these measures was modeled using mixed effects regression in several groups of participants, including those that remained cognitively normal throughout the study (CN) and those that were diagnosed with mild cognitive impairment (MCI) or Alzheimer's disease (AD) dementia at some point subsequent to the baseline visit. The results of the study show that, with the exception of mean cluster size, the indices showed significantly greater declines in the MCI and AD dementia groups as compared to CN participants. Examination of associations between the indices and cognitive domains of memory, attention and visuospatial functioning showed that the traditional verbal fluency scores were associated with declines in all three domains, whereas semantic and lexical diversity measures were associated with declines only in the visuospatial domain. Baseline repetition density was associated with declines in memory and visuospatial domains. Examination of lexical and semantic diversity measures in subgroups with high vs. low attention scores (but normal functioning in other domains) showed that the performance of individuals with low attention was influenced more by word frequency rather than strength of semantic relatedness between words. These findings suggest that various automatically semantic indices may be used to examine various aspects of cognitive performance affected by dementia. PMID- 27245646 TI - Quasi 2D electronic states with high spin-polarization in centrosymmetric MoS2 bulk crystals. AB - Time reversal dictates that nonmagnetic, centrosymmetric crystals cannot be spin polarized as a whole. However, it has been recently shown that the electronic structure in these crystals can in fact show regions of high spin-polarization, as long as it is probed locally in real and in reciprocal space. In this article we present the first observation of this type of compensated polarization in MoS2 bulk crystals. Using spin- and angle-resolved photoemission spectroscopy (ARPES), we directly observed a spin-polarization of more than 65% for distinct valleys in the electronic band structure. By additionally evaluating the probing depth of our method, we find that these valence band states at the point in the Brillouin zone are close to fully polarized for the individual atomic trilayers of MoS2, which is confirmed by our density functional theory calculations. Furthermore, we show that this spin-layer locking leads to the observation of highly spin polarized bands in ARPES since these states are almost completely confined within two dimensions. Our findings prove that these highly desired properties of MoS2 can be accessed without thinning it down to the monolayer limit. PMID- 27245648 TI - Current State of Value-Based Purchasing Programs. AB - The US healthcare system is rapidly moving toward rewarding value. Recent legislation, such as the Affordable Care Act and the Medicare Access and CHIP Reauthorization Act, solidified the role of value-based payment in Medicare. Many private insurers are following Medicare's lead. Much of the policy attention has been on programs such as accountable care organizations and bundled payments; yet, value-based purchasing (VBP) or pay-for-performance, defined as providers being paid fee-for-service with payment adjustments up or down based on value metrics, remains a core element of value payment in Medicare Access and CHIP Reauthorization Act and will likely remain so for the foreseeable future. This review article summarizes the current state of VBP programs and provides analysis of the strengths, weaknesses, and opportunities for the future. Multiple inpatient and outpatient VBP programs have been implemented and evaluated; the impact of those programs has been marginal. Opportunities to enhance the performance of VBP programs include improving the quality measurement science, strengthening both the size and design of incentives, reducing health disparities, establishing broad outcome measurement, choosing appropriate comparison targets, and determining the optimal role of VBP relative to alternative payment models. VBP programs will play a significant role in healthcare delivery for years to come, and they serve as an opportunity for providers to build the infrastructure needed for value-oriented care. PMID- 27245649 TI - Double Trouble: A Case of Valvular Disease in Pregnancy. PMID- 27245650 TI - The Changing Landscape of Academic Publishing: Two Librarians' Perspectives. PMID- 27245652 TI - Letter by Hoang et al Regarding Article, "Novel Biomarker of Oxidative Stress Is Associated With Risk of Death in Patients With Coronary Artery Disease". PMID- 27245653 TI - Response to Letter Regarding Article "Novel Biomarker of Oxidative Stress Is Associated With Risk of Death in Patients With Coronary Artery Disease". PMID- 27245654 TI - Letter by Boulon and Constans Regarding Article, "Relation of Nailfold Capillaries and Autoantibodies to Mortality in Patients With Raynaud Phenomenon". PMID- 27245655 TI - Response to Letter Regarding Article, "Relation of Nailfold Capillaries and Autoantibodies to Mortality in Patients With Raynaud Phenomenon". PMID- 27245656 TI - Correction. PMID- 27245657 TI - Correction. PMID- 27245658 TI - Correction. PMID- 27245659 TI - Trochanteric fragility fractures : Treatment using the cement-augmented proximal femoral nail antirotation. AB - OBJECTIVE: Use of standardized cement augmentation of the proximal femur nail antirotation (PFNA) for the treatment of trochanteric fragility fractures, which are associated with high morbidity and mortality, to achieve safer conditions for immediate full weight-bearing and mobilization, thus, improving preservation of function and independency of orthogeriatric patients. INDICATIONS: Trochanteric fragility fractures (type 31-A1-3). CONTRAINDICATIONS: Ipsilateral arthritis of the hip, leakage of contrast agent into the hip joint, femoral neck fractures. SURGICAL TECHNIQUE: Reduction of the fracture on a fracture table if possible, or minimally invasive open reduction of the proximal femur, i. e., using collinear forceps if necessary. Positioning of guidewires for adjustment of the PFNA and the spiral blade, respectively. Exclusion of leakage of contrast agent and subsequent injection of TRAUMACEMTM V(+) into the femoral head-neck fragment via a trauma needle kit introduced into the spiral blade. Dynamic or static locking of the PFNA at the diaphyseal level. POSTOPERATIVE MANAGEMENT: Immediate mobilization of the patients with full weight-bearing and secondary prevention, such as osteoporosis management is necessary to avoid further fractures in the treatment of these patients. RESULTS: A total of 110 patients older than 65 years underwent the procedure. Of the 72 patients available for follow-up (average age 85.3 years), all fractures healed after an average of 15.3 months. No complications related with cement augmentation were observed. Approximately 60 % of patients achieved the mobility level prior to trauma. PMID- 27245660 TI - Hospice Use for Infants With Life-Threatening Health Conditions, 2007 to 2010. AB - BACKGROUND: Infant deaths account for a majority of all pediatric deaths. However, little is known about the factors that influence parents to use hospice care for their infant with a life-threatening health condition. METHODS: Data were used from 2007 to 2010 California Medicaid claims files (N = 207). Analyses included logistic and negative binomial multivariate regression models. RESULTS: More than 15% of infants enrolled in hospice care for an average of 5 days. Infant girls and infants with congenital anomalies were more likely to enroll in hospice care and to have longer stays. However, cardiovascular and respiratory conditions were negatively related to hospice enrollment and hospice length of stay. CONCLUSIONS: This study provides insights for nurses and other clinicians who care for infants and their families at end of life and suggests that nurses can assist families in identifying infant hospice providers who may help families understand their options for end-of-life care. PMID- 27245661 TI - Activated brain mast cells contribute to postoperative cognitive dysfunction by evoking microglia activation and neuronal apoptosis. AB - BACKGROUND: Neuroinflammation plays a key role in the occurrence and development of postoperative cognitive dysfunction (POCD). Microglia, the resident immune cells in the brain, has been increasingly recognized to contribute to neuroinflammation. Although brain mast cells (MCs) are the "first responder" in the brain injury rather than microglia, little is known about the functional aspects of MCs-microglia interactions. METHODS: Male Sprague-Dawley (SD) rats were injected intracerebroventricular with MC stabilizer Cromolyn (100 MUg/MUl), MC stimulator C48/80 (1 MUg/MUl), or sterile saline 30 min before open tibial fracture surgery, and the levels of neuroinflammation and memory dysfunction were tested 1 and 3 days after surgery. In addition, the effect of activated MCs on microglia and neurons was determined in vitro. RESULTS: Tibial fracture surgery induced MCs degranulation, microglia activation, and inflammatory factors production, which initiated the acute brain inflammatory response and neuronal death and exhibited cognitive deficit. Site-directed preinjection of the "MCs stabilizer" disodium cromoglycate (Cromolyn) inhibited this effect, including decrease of inflammatory cytokines, reduced MCs degranulation, microglia activation, neuronal death, and improved cognitive function 24 h after the surgery. In vitro study, we found that the conditioned medium from lipopolysaccharide (LPS)-stimulated mast cells line (P815) could induce primary microglia activation through mitogen-activated protein kinase (MAPK) pathway signaling and subsequent production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). In addition, the activated P815 could directly induce neuronal apoptosis and synapse injury with microglia independently. Cromolyn could inhibit P815 activation following improved microglia activation and neuronal loss. CONCLUSIONS: These results implicate that activated MCs could trigger microglia activation and neuronal damage, resulting in central nervous system (CNS) inflammation, and communications of MCs with microglia and neuron could constitute a new and unique therapeutic target for CNS immune inflammation related diseases. PMID- 27245662 TI - Combined physiological, transcriptome, and cis-regulatory element analyses indicate that key aspects of ripening, metabolism, and transcriptional program in grapes (Vitis vinifera L.) are differentially modulated accordingly to fruit size. AB - BACKGROUND: In wine grape production, management practices have been adopted to optimize grape and wine quality attributes by producing, or screening for, berries of smaller size. Fruit size and composition are influenced by numerous factors that include both internal (e.g. berry hormone metabolism) and external (e.g. environment and cultural practices) factors. Combined physiological, biochemical, and transcriptome analyses were performed to improve our current understanding of metabolic and transcriptional pathways related to berry ripening and composition in berries of different sizes. RESULTS: The comparison of berry physiology between small and large berries throughout development (from 31 to 121 days after anthesis, DAA) revealed significant differences in firmness, the rate of softening, and sugar accumulation at specific developmental stages. Small berries had significantly higher skin to berry weight ratio, lower number of seeds per berry, and higher anthocyanin concentration compared to large berries. RNA-sequencing analyses of berry skins at 47, 74, 103, and 121 DAA revealed a total of 3482 differentially expressed genes between small and large berries. Abscisic acid, auxin, and ethylene hormone pathway genes were differentially modulated between berry sizes. Fatty acid degradation and stilbenoid pathway genes were upregulated at 47 DAA while cell wall degrading and modification genes were downregulated at 74 DAA in small compared to large berries. In the late ripening stage, concerted upregulation of the general phenylpropanoid and stilbenoid pathway genes and downregulation of flavonoid pathway genes were observed in skins of small compared to large berries. Cis-regulatory element analysis of differentially expressed hormone, fruit texture, flavor, and aroma genes revealed an enrichment of specific regulatory motifs related to bZIP, bHLH, AP2/ERF, NAC, MYB, and MADS-box transcription factors. CONCLUSIONS: The study demonstrates that physiological and compositional differences between berries of different sizes parallel transcriptome changes that involve fruit texture, flavor, and aroma pathways. These results suggest that, in addition to direct effects brought about by differences in size, key aspects involved in the regulation of ripening likely contribute to different quality profiles between small and large berries. PMID- 27245664 TI - Quantitative assessment of visual estimation of the infrared indocyanine green imaging of lymph nodes retrieved at sentinel node navigation surgery for gastric cancer. AB - BACKGROUND: Although the infrared indocyanine green (ICG) imaging is an effective method to identify sentinel lymph nodes (SLNs) of gastric cancer, its objectivity has not been verified. METHODS: We studied 563 lymph nodes under infrared light observation from the ICG-positive lymphatic basins of 36 patients who underwent SLN-navigated gastrectomy for clinically node-negative gastric cancer. First, the rate of SLN detection, the number of SLNs and sensitivities were compared between ordinary light observation and infrared light observation. Second, 563 lymph nodes were grouped into ICG-positive and -negative under infrared light observation. The intensities of the region of interest for each lymph node defined as the lymph node on which digital imaging was performed using an imaging software, and the region of reference defined as its surrounding background, were compared and quantified. RESULTS: In the comparison of ordinary light observation with infrared light observation, the SLN identification rates were 28/36 (78 %) vs. 36/36 (100 %), the mean +/- SD (minimum to maximum) number of SLNs was 3.4 +/ 3.7 (0-16) vs. 9.2 +/- 5.9 (2-25), and the sensitivities were 1/5 (20 %) vs. 5/5 (100 %). The ICG-positive group contained 358 lymph nodes with an intensity of 0.323 +/- 1.56 (mean +/- SD), and the ICG-negative group contained 205 lymph nodes with an intensity of 0.639 +/- 1.93 (mean +/- SD), demonstrating a significant difference between these two groups (P < 0.0001). CONCLUSIONS: The significant difference in the intensity as measured by an imaging-software between ICG-positive and ICG-negative lymph nodes would erase the concern about the objectivity of the infrared ICG method for SLN-navigated surgery for early gastric cancer. PMID- 27245663 TI - Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico pathological and genetic study. AB - Non-syndromic pituitary gigantism can result from AIP mutations or the recently identified Xq26.3 microduplication causing X-linked acrogigantism (XLAG). Within Xq26.3, GPR101 is believed to be the causative gene, and the c.924G > C (p.E308D) variant in this orphan G protein-coupled receptor has been suggested to play a role in the pathogenesis of acromegaly.We studied 153 patients (58 females and 95 males) with pituitary gigantism. AIP mutation-negative cases were screened for GPR101 duplication through copy number variation droplet digital PCR and high density aCGH. The genetic, clinical and histopathological features of XLAG patients were studied in detail. 395 peripheral blood and 193 pituitary tumor DNA samples from acromegaly patients were tested for GPR101 variants.We identified 12 patients (10 females and 2 males; 7.8 %) with XLAG. In one subject, the duplicated region only contained GPR101, but not the other three genes in found to be duplicated in the previously reported patients, defining a new smallest region of overlap of duplications. While females presented with germline mutations, the two male patients harbored the mutation in a mosaic state. Nine patients had pituitary adenomas, while three had hyperplasia. The comparison of the features of XLAG, AIP-positive and GPR101&AIP-negative patients revealed significant differences in sex distribution, age at onset, height, prolactin co secretion and histological features. The pathological features of XLAG-related adenomas were remarkably similar. These tumors had a sinusoidal and lobular architecture. Sparsely and densely granulated somatotrophs were admixed with lactotrophs; follicle-like structures and calcifications were commonly observed. Patients with sporadic of familial acromegaly did not have an increased prevalence of the c.924G > C (p.E308D) GPR101 variant compared to public databases.In conclusion, XLAG can result from germline or somatic duplication of GPR101. Duplication of GPR101 alone is sufficient for the development of XLAG, implicating it as the causative gene within the Xq26.3 region. The pathological features of XLAG-associated pituitary adenomas are typical and, together with the clinical phenotype, should prompt genetic testing. PMID- 27245666 TI - Peritoneal closure during laparoscopic supracervical hysterectomy. AB - OBJECTIVE: Our goal was to compare postoperative pain and analgesic requirements regarding closure and non-closure of the peritoneum in women undergoing laparoscopic supracervical hysterectomy (LSH). STUDY DESIGN: A prospective cohort study was designed to investigate the impact of peritoneal closure for LSH. Postoperative pain was measured by a visual analogue scale (VAS) and analgesic requirements were assessed. Intra- and postoperative complications and operative time were recorded. RESULTS: A total of 104 patients were enrolled. Fifty-two (50 %) women underwent a LSH with peritoneal closure and 52 (50 %) underwent LSH without closure. The baseline characteristics were well balanced between the groups except for age; women undergoing LSH without peritoneal closure were significantly younger (p < 0.008, t test). The median operative time was 53 (26 105) minutes for LSH with peritoneal closure and 44 (24-83) minutes for LSH without peritoneal closure, a median reduction of 9 minutes (p = 0.007). No differences were found in uterine weight, intra- and post-operative complications, median haemoglobin drop or time in hospital when contrasting both groups. Both groups had similar VAS-pain scores and needed similar analgesic therapies. CONCLUSIONS: The peritoneal closure at LSH provides no short-term postoperative advantages over a non-closure approach, and it prolongs the operative time and anaesthetic exposure. Our data suggest that peritoneal closure is not necessary in LSH. PMID- 27245665 TI - Multi-psychotropic drug prescription and the association to neuropsychiatric symptoms in three Norwegian nursing home cohorts between 2004 and 2011. AB - BACKGROUND: Neuropsychiatric symptoms, such as affective symptoms, psychosis, agitation, and apathy are common among nursing home patients with and without dementia. Treatment with one or more psychotropic drug is often without explicit clinical indication, despite low treatment efficacy, and potential side effects. We aim to investigate the multi-psychotropic drug use to identify factors and patient characteristics associated with multi-use. METHODS: We analysed three cohorts from 129 Norwegian nursing homes, collected between 2004 and 2011. Patients (N = 4739) were assessed with the Neuropsychiatric Inventory - Nursing Home version (NPI-NH), Clinical Dementia Rating scale, and Physical Self Maintenance Scale. We used ordinal logistic regression to analyse associations between psychotropics (antidepressants, antipsychotics, anxiolytics, hypnotics, and anti-dementia drugs), patient characteristics, and neuropsychiatric symptoms. RESULTS: Patients used on average 6.6 drugs; 27 % used no psychotropics, 32 % one, and 41 % multiple psychotropic drugs (24 % two, 17 % >=3). Thirty-nine percent were prescribed antidepressants, 30 % sedatives, 24 % anxiolytics, and 20 % antipsychotics. The total NPI-NH score was associated with multi-use (OR 1.02, 95 % CI 1.02-1.03), and increased from a mean of 13.5 (SD 16.3) for patients using none, to 25.5 (21.8) for patients using >=3 psychotropics. Affective symptoms (depression and anxiety) were most strongly associated with multi psychotropic drug use (OR 1.10, 95 % CI: 1.09-1.12). Female gender, independency in daily living, younger age, dementia, and many regular drugs were also associated with multi-use. CONCLUSION: Forty-one percent were exposed to multi psychotropic drug prescriptions. Contrary to current evidence and guidelines, there is an extensive use of multiple psychotropic drugs in patients with severe NPS and dementia. PMID- 27245667 TI - Color Doppler examination for the diagnosis of subacute puerperal uterine inversion. AB - PURPOSE: Obstetric uterine inversion is a rare and life-threatening complication. Diagnosis is often difficult to establish, particularly in recurrent or chronic cases. METHOD: We performed color Doppler examination in addition to B-mode sonography in a case of subacute recurrent uterine inversion. RESULTS: Identification of the vessels providing uterine blood supply helped to clarify the distorted anatomy; furthermore, information about tissue viability was gained. CONCLUSION: We propose to perform color Doppler examination in all cases with suspected uterine inversion or vaginal masses of unknown origin. PMID- 27245668 TI - Multifunction of Chrysin in Parkinson's Model: Anti-Neuronal Apoptosis, Neuroprotection via Activation of MEF2D, and Inhibition of Monoamine Oxidase-B. AB - Chrysin, a flavonoid compound existing in several plants, is applied as a dietary supplement because of its beneficial effects on general human health and alleviation of neurological disorders. However, mechanisms underlying neuroprotection of chrysin has not been fully elucidated, and the effects of chrysin on the Parkinson's disease (PD) model in vivo have not been investigated. It is here shown that chrysin protects primary granular neurons against 1-methyl 4-phenylpyridinium ion insult via antiapoptosis by reversing the dysregulated expression of Bcl-2, Bax, and caspase 3. The mechanisms also involved activating transcriptional factor myocyte enhancer factor 2D (MEF2D) via regulation of AKT GSK3beta signaling. In this in vivo model of PD, chrysin rescued the dopaminergic neurons loss and alleviated the decrease in dopamine level induced by 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine in mice. Moreover, chrysin markedly inhibited monoamine oxidase-B activity in vitro and in vivo. In conclusion, chrysin exerts beneficial effects to PD, possibly through multitarget mechanisms including antineuronal apoptosis, activation of the AKT-GSK3beta/MEF2D pathway, and inhibition of the MAO-B activity. PMID- 27245669 TI - The relationship between psychiatric morbidity and quality of life: interview study of Norwegian tsunami survivors 2 and 6 years post-disaster. AB - BACKGROUND: The study investigated the impact of psychiatric disorders on Quality of Life (QOL) cross-sectionally and longitudinally in a group of Norwegian tourists severely exposed to the 2004 tsunami. METHODS: Sixty-two adult Norwegian tsunami survivors were interviewed face to face 2 years post-tsunami (T1) and 58 were interviewed again by telephone 6 years post-tsunami (T2). The majority (81 %) reported direct exposure to the waves, and 14 participants (23 %) lost a close family member in the tsunami. Psychiatric morbidity was measured by structured clinical interviews and QOL was assessed with WHO's Quality of Life-Bref scale. Multiple linear regression analyses were performed to assess the independent effects of psychiatric disorders on QOL 2 and 6 years after the tsunami. RESULTS: Psychiatric disorders, especially depression, but also PTSD and other anxiety disorders, were associated with reduced QOL. Psychiatric disorders were more strongly related to QOL at 6 years after the tsunami than at 2 years. CONCLUSIONS: Psychiatric disorders, and especially depression, is related to reduced QOL in a disaster exposed population. Post-disaster psychiatric disorders, such as PTSD and especially depression, should be addressed properly in the aftermath of disasters. PMID- 27245671 TI - Health Information Exchange: What do patients want? AB - To determine whether emergency department patients want to share their medical records across health systems through Health Information Exchange and if so, whether they prefer to sign consent or share their records automatically, 982 adult patients presenting to an emergency department participated in a questionnaire-based interview. The majority (N = 906; 92.3%) were willing to share their data in a Health Information Exchange. Half (N = 490; 49.9%) reported routinely getting healthcare outside the system and 78.6 percent reported having records in other systems. Of those who were willing to share their data in a Health Information Exchange, 54.3 percent wanted to sign consent but 90 percent of those would waive consent in the case of an emergency. Privacy and security were primary concerns of patients not willing to participate in Health Information Exchange and preferring to sign consent. Improved privacy and security protections could increase participation, and findings support consideration of "break-the-glass" provider access to Health Information Exchange records in an emergent situation. PMID- 27245670 TI - Perinatal maternal depression and cortisol function in pregnancy and the postpartum period: a systematic literature review. AB - BACKGROUND: Perinatal depression has a significant impact on both mother and child. However, the influence of hormonal changes during pregnancy and the postpartum period remains unclear. This article provides a systematic review of studies examining the effects of maternal cortisol function on perinatal depression. METHOD: A systematic search was conducted of six electronic databases for published research on the relationship between cortisol and perinatal depression. The databases included; MEDLINE complete, PsychINFO, SCOPUS, Psychology and Behavioural Sciences, Science Direct and EBSCO, for the years 1960 to May 2015. Risk of bias was assessed and data extraction verified by two investigators. RESULTS: In total, 47 studies met criteria and studies showed considerable variation in terms of methodology including sample size, cortisol assays, cortisol substrates, sampling processes and outcome measures. Those studies identified as higher quality found that the cortisol awakening response is positively associated with momentary mood states but is blunted in cases of major maternal depression. Furthermore, results indicate that hypercortisolemia is linked to transient depressive states while hypocortisolemia is related to chronic postpartum depression. DISCUSSION AND CONCLUSION: Future research should aim to improve the accuracy of cortisol measurement over time, obtain multiple cortisol samples in a day and utilise diagnostic measures of depression. Future studies should also consider both antenatal and postnatal depression and the differential impact of atypical versus melancholic depression on cortisol levels, as this can help to further clarify the relationship between perinatal depression and maternal cortisol function across pregnancy and the postpartum period. PMID- 27245672 TI - A novel approach to population-based risk stratification, comprising individualized lifestyle intervention in Danish general practice to prevent chronic diseases: Results from a feasibility study. AB - Early detection of patients at risk seems to be effective for reducing the prevalence of lifestyle-related chronic diseases. We aim to test the feasibility of a novel intervention for early detection of lifestyle-related chronic diseases based on a population-based stratification using a combination of questionnaire and electronic patient record data. The intervention comprises four elements: (1) collection of information on lifestyle risk factors using a short 15-item questionnaire, (2) electronic transfer of questionnaire data to the general practitioners' electronic patient records, (3) identification of patients already diagnosed with a lifestyle-related chronic disease, and (4) risk estimation and stratification of apparently healthy patients using questionnaire and electronic patient record data on validated risk estimation models. We show that it is feasible to implement a novel intervention that identifies and stratifies patients for further examinations in general practice or behaviour change interventions at the municipal level without any additional workload for the general practitioner. PMID- 27245673 TI - Persuasive technology for health and wellness: State-of-the-art and emerging trends. AB - The evolving field of persuasive and behavior change technology is increasingly targeted at influencing behavior in the area of health and wellness. This paper provides an empirical review of 16 years (85 papers) of literature on persuasive technology for health and wellness to: (1.) answer important questions regarding the effectiveness of persuasive technology for health and wellness, (2.) summarize and highlight trends in the technology design, research methods, motivational strategies, theories, and health behaviors targeted by research to date, (3.) uncover pitfalls of existing persuasive technological interventions for health and wellness, and (4.) suggest directions for future research. PMID- 27245674 TI - Phenotypic and genetic changes in the life cycle of small colony variants of Salmonella enterica serotype Typhimurium induced by streptomycin. AB - BACKGROUND: Small colony variants (SCVs), constituting a slow-growing subpopulation of bacteria that facilitates persistence in lethal environmental conditions, are able to revert to the phenotype of rapid growth for further proliferation and transmission. Salmonella enterica serotype Typhimurium is one of the most important foodborne pathogens. This study investigated the genetic mechanisms how SCVs induced by streptomycin reverted to the fast-growing phenotype and the phenotypic changes of SCVs among their complete life cycle in S. Typhimurium. METHODS: Salmonella Typhimurium SCVs were obtained by streptomycin treatment and their revertants were collected in the absence of antibiotics. The fitness, antimicrobial susceptibility, biofilm formation, and the biofilm-related genes expression were analyzed in comparison to their wild type strain, and the whole genome sequencing was performed to identify the genetic changes in the life cycle of S. Typhimurium SCVs. RESULTS: Small colony variants were characterized by an increased antimicrobial resistance to streptomycin (64-fold), imipenem (twofold), and gentamicin (fourfold). A significant increase in biofilm production with higher expression of csgB was observed in SCVs (P < 0.01). The genetic alterations of all SCVs occurred in ubiE gene (coenzyme Q8 and menaquinone synthesis) with frameshift mutations. However, all fast-growing revertants again lost the trait of increased biofilm production (P > 0.05), in which two modes of the genetic changes for reversing to the rapidly growing form were observed: four revertants harbored a secondary mutation in ubiE, which reinstated most of the amino acid sequence of the ubiE, and other four revertants harbored a mutation in prfB. CONCLUSIONS: Salmonella Typhimurium could switch to the phenotype of SCVs under the treatment of streptomycin by a mutation in ubiE, partially combined with increased production of biofilm, and these SCVs could escape from growth restriction by a compensatory mutation in prfB or a new mutation in ubiE. These findings may contribute to establishing phenotype-directed treatments against SCVs of S. Typhimurium. PMID- 27245676 TI - Antibody-based magneto-elastic biosensors: potential devices for detection of pathogens and associated toxins. AB - This work describes the design and development process of an immunosensor. The creation of such devices goes through various steps, which complement each other, and choosing an efficient immobilization method that binds to a specific target is essential to achieve satisfactory diagnostic results. In this perspective, the emphasis here is on developing biosensors based on binding antigens/antibodies on particular surfaces of magneto-elastic sensors. Different aspects leading to the improvement of these sensors, such as the antibody structure, the chemical functionalization of the surface, and cross-linking antibody reticulation were summarized and discussed. This paper deals with the progress of magneto-elastic immunosensors to detect bacterial pathogens and associated toxins. Biologically modified surface characterization methods are further considered. Thus, research opportunities and trends of future development in these areas are finally discussed. PMID- 27245675 TI - Differentiation of entC1 from entC2/entC3 with a single primer pair using simple and rapid SYBR Green-based RT-PCR melt curve analysis. AB - In spite of their involvement in foodborne illness, the epidemiological relevance of staphylococcal enterotoxin C (SEC) subtypes is poorly documented may be due to high sequence similarity. Among subtypes, SEC1, SEC2, and SEC3 exhibit more than 97 % homology because of which specific detection tools are seldom available to identify and differentiate them. In this study, a SYBR Green-based RT-PCR followed by melt curve analysis was developed for differentiation of entC1 from entC2/entC3 using a single primer pair. Nucleotide sequences of all three subtypes were analyzed using Clustal Omega program and the region with significant sequence variation/heterogeneity (where utmost SNPs were closely located and accessible for RT-PCR) was selected for amplification by designing a single primer pair that could amplify all three subtypes. In spite of same amplicon size, entC1 showed distinct melt peak at 76 degrees C. However, due to high similarity between entC2 and entC3, the developed format was deficient to discriminate between them and both showed melt peak at 82 degrees C. Reliability of developed RT-PCR was evaluated using various naturally contaminated samples and 91 food and clinical Staphylococcus aureus isolates where satisfactory results were obtained in comparison with commercial immunoassay kit and conventional PCRs using validated primers. To the best of our knowledge, this is the first method being reported to differentiate entC1 from entC2/entC3 using single primer pair which is unachievable by conventional PCR due to same amplicon size. As benefits, the method is sensitive, rapid, and inexpensive with no requirement of fluorescent probes, multiple primers, and post-PCR procedures. Thus, the assay might find its utility as a detection tool in epidemiological survey of foodborne outbreaks for simultaneous identification and differentiation of entC1 from entC2/entC3. PMID- 27245677 TI - The functional properties of a xyloglucanase (GH12) of Aspergillus terreus expressed in Aspergillus nidulans may increase performance of biomass degradation. AB - Filamentous fungi are attractive hosts for heterologous protein expression due to their capacity to secrete large amounts of enzymes into the extracellular medium. Xyloglucanases, which specifically hydrolyze xyloglucan, have been recently applied in lignocellulosic biomass degradation and conversion in many other industrial processes. In this context, this work aimed to clone, express, and determine the functional properties of a recombinant xyloglucanase (AtXEG12) from Aspergillus terreus, and also its solid-state (SSF) and submerged (SmF) fermentation in bioreactors. The purified AtXEG12 showed optimum pH and temperature of 5.5 and 65 degrees C, respectively, demonstrating to be 90 % stable after 24 h of incubation at 50 degrees C. AtXEG12 activity increased in the presence of 2-mercaptoethanol (65 %) and Zn+2 (45 %), while Cu+2 and Ag+ ions drastically decreased its activity. A substrate assay showed, for the first time for this enzyme's family, xylanase activity. The enzyme exhibited high specificity for tamarind xyloglucan (K M 1.2 mg mL-1) and V max of 17.4 MUmol min 1 mg-1 of protein. The capillary zone electrophoresis analysis revealed that AtXEG12 is an endo-xyloglucanase. The heterologous xyloglucanase secretion was greater than the production by wild-type A. terreus cultivated in SmF. On the other hand, AtXEG12 activity reached by SSF was sevenfold higher than values achieved by SmF, showing that the expression of recombinant enzymes can be significantly improved by cultivation under SSF. PMID- 27245678 TI - Snake venom toxins: toxicity and medicinal applications. AB - Snake venoms are complex mixtures of small molecules and peptides/proteins, and most of them display certain kinds of bioactivities. They include neurotoxic, cytotoxic, cardiotoxic, myotoxic, and many different enzymatic activities. Snake envenomation is a significant health issue as millions of snakebites are reported annually. A large number of people are injured and die due to snake venom poisoning. However, several fatal snake venom toxins have found potential uses as diagnostic tools, therapeutic agent, or drug leads. In this review, different non enzymatically active snake venom toxins which have potential therapeutic properties such as antitumor, antimicrobial, anticoagulating, and analgesic activities will be discussed. PMID- 27245679 TI - Paediatric Cochlear Implantation in Patients with Waardenburg Syndrome. AB - OBJECTIVE: To analyse the benefit of cochlear implantation in young deaf children with Waardenburg syndrome (WS) compared to a reference group of young deaf children without additional disabilities. METHOD: A retrospective study was conducted on children with WS who underwent cochlear implantation at the age of 2 years or younger. The post-operative results for speech perception (phonetically balanced standard Dutch consonant-vocal-consonant word lists) and language comprehension (the Reynell Developmental Language Scales, RDLS), expressed as a language quotient (LQ), were compared between the WS group and the reference group by using multiple linear regression analysis. RESULTS: A total of 14 children were diagnosed with WS, and 6 of them had additional disabilities. The WS children were implanted at a mean age of 1.6 years and the 48 children of the reference group at a mean age of 1.3 years. The WS children had a mean phoneme score of 80% and a mean LQ of 0.74 at 3 years post-implantation, and these results were comparable to those of the reference group. Only the factor additional disabilities had a significant negative influence on auditory perception and language comprehension. CONCLUSIONS: Children with WS performed similarly to the reference group in the present study, and these outcomes are in line with the previous literature. Although good counselling about additional disabilities concomitant to the syndrome is relevant, cochlear implantation is a good rehabilitation method for children with WS. PMID- 27245680 TI - Serum insulin-like growth factor-1 levels in patients with pseudoexfoliation syndrome and glaucoma. AB - Insulin-like growth factor-1 (IGF-1) is altered in several neurodegenerative diseases, the association between serum IGF-1 levels and glaucoma has not been evaluated. This study was designed to evaluate whether serum IGF-1 levels are different in patients with Pseudoexfoliation (PEX) with or without glaucoma. The study was conducted with 110 participants aged 65 years or older who were divided into three groups: group 1, patients with PEX syndrome; group 2, patients with PEX glaucoma; and group 3, participants without PEX or glaucoma. All participants underwent full ophthalmological examination and a detailed medical history was recorded. Patients with known neurodegenerative diseases other than PEX glaucoma were excluded. Serum IGF-1 levels were measured by automated chemiluminescent assay. Groups 1, 2, and 3 included 35, 34, and 41 patients, respectively; there were no differences regarding age, gender, or systemic disease status. There were also no statistically significant differences between the groups in terms of IGF 1 levels, which were 91.7 +/- 39.1, 101.1 +/- 40.2, and 107.2 +/- 43.8 ng/ml for groups 1, 2, and 3, respectively (p = 0.276). Serum IGF-1 levels were similar by gender, the presence of systemic disease, status of diabetes mellitus, and laterality of the PEX material. There was no correlation between the cup-to-disk ratios and IGF-1 levels (r = -0.214, p = 0.223). IGF-1 levels in the circulation did not differ in the presence of PEX syndrome with or without glaucoma. This may indicate that the neurodegenerative process is local rather than systemic. PMID- 27245681 TI - Renal Denervation: a Field in Flux. AB - SYMPLICITY HTN-3 was a pivotal moment for renal denervation as a treatment option for resistant hypertension. Prior unblinded studies were called into question given the negative results of the first sham-controlled trial of renal denervation. Reevaluation of the renal denervation procedure demonstrated that a more precise approach was needed to adequately denervate the kidney. This new approach has been implemented in two ongoing clinical trials, one on and one off medications to assess the new procedure's efficacy and safety. These and other ongoing trials will be discussed in the context of older studies in this field. We focus on novel findings published following the release of SYMPLICITY HTN-3 data in early 2014 and look to the future of renal denervation in the treatment of primary hypertension. PMID- 27245682 TI - Cortical functional correlates of responsiveness to short-lasting preventive intervention with ketogenic diet in migraine: a multimodal evoked potentials study. AB - BACKGROUND: Here, we aim to identify cortical electrofunctional correlates of responsiveness to short-lasting preventiveintervention with ketogenic diet (KD) in migraine. METHODS: Eighteen interictal migraineurs underwent visual (VEPs) and median nerve somatosensory (SSEPs) evokedpotentials before and after 1 month of KD during ketogenesis. We measured VEPs N1-P1 and SSEPs N20-P25 amplitudes respectively in six and in two sequential blocks of 100 sweeps as well as habituation as theslope of the linear regression between block 1 to 6 for VEPs or between 1 to 2 for SSEPs. RESULTS: After 1-month of KD, a significant reduction in the mean attack frequency and duration was observed (all P< 0.001). The KD did not change the 1st SSEP and VEP block of responses, but significantly inducednormalization of the interictally reduced VEPs and SSEPs (all p < 0.01) habituation during the subsequentblocks. CONCLUSIONS: KD could restore normal EPs habituation curves during stimulus repetition without significantly changing theearly amplitude responses. Thus, we hypothesize that KD acts on habituation regulating the balancebetween excitation and inhibition at the cortical level. PMID- 27245684 TI - Isolation of Functional Components beta-Glucan and gamma-Amino Butyric Acid from Raw and Germinated Barnyard Millet (Echinochloa frumentaceae) and their Characterization. AB - The study was carried out to analyze the characteristics of two functional constituents' viz. gamma-amino butyric acid (GABA) and beta-glucan extracted from raw and germination barnyard millet (var. PRJ-1). A significant (P <= 0.05) effect of germination (sprouting) was observed in yield, chemical composition, functional, rheological and antioxidant properties of beta-glucan and GABA. The yield of GABA extract was 12.34 % and the content increased from 6.37 mg/100 g in raw to 35.70 mg/100 g in germinated sample. The DPPH, total antioxidant and hydrogen peroxide scavenging activities of GABA extract increased after germination from 45.34 to 65.34 %, 15.3 to 33.3 millimole/g and 38.4 to 64.7 millimole/g, respectively. The yield of beta-glucan extract of raw and germinated flour was 6.05 and 5.01 % whereas the beta-glucan contents were 83.30 and 79.64 %, respectively. The functional properties of beta-glucan i.e., swelling power, water binding capacity and DPPH scavenging activity increased from 1.45 to 1.76 g/g, 2.13 to 2.32 g/g and 44.39 to 57.42 %, respectively, after germination. Similarly there was an increase in the storage modulus after germination process which attributes a better viscoelastic capacity of beta-glucan at low frequencies. The results exploit that the beta-glucan and GABA might promise a polymeric incipient to be implemented as food additives with variable functional and structural characteristics. PMID- 27245683 TI - Headache, depression and anxiety: associations in the Eurolight project. AB - BACKGROUND: Headache disorders and psychiatric disorders are both common, while evidence, mostly pertaining to migraine, suggests they are comorbid more often than might be expected by chance. There are good reasons for establishing whether they are: symptoms of comorbid illnesses may summate synergistically; comorbidities hinder management, negatively influencing outcomes; high-level comorbidity indicates that, where one disease occurs, the other should be looked for. The Eurolight project gathered population-based data on these disorders from 6624 participants. METHODS: Eurolight was a cross-sectional survey sampling from the adult populations (18-65 years) of 10 EU countries. We used data from six. The questionnaire included headache-diagnostic questions based on ICHD-II, the Headache-Attributed Lost Time (HALT) questionnaire, and HADS for depression and anxiety. We estimated odds ratios (ORs) to show associations between migraine, tension-type headache (TTH) or probable medication-overuse headache (pMOH) and depression or anxiety. RESULTS: pMOH was most strongly associated with both psychiatric disorders: for depression, ORs (vs no headache) were 5.5 [2.2-13.5] (p < 0.0001) in males, 5.5 [2.9-10.5] (p < 0.0001) in females; for anxiety, ORs were 10.4 [4.9-21.8] (p < 0.0001) and 7.1 [4.5-11.2] (p < 0.0001). Migraine was also associated with both: for depression, ORs were 2.1 [1.3-3.4] (p = 0.002) and 1.8 [1.1-3.1] (p = 0.030); for anxiety 4.2 [2.8-6.3] (p < 0.0001) and 2.4 [1.7 3.4] (p < 0.0001). TTH showed associations only with anxiety: ORs 2.5 [1.7-3.7] (p < 0.0001) for males, 1.5 [1.1-2.1] (p = 0.021) for females. Participants with migraine carried 19.1 % probability of comorbid anxiety, 6.9 % of depression and 5.1 % of both, higher than the representative general-population sample (14.3, 5.6 and 3.8 %). Probabilities in those with MOH were 38.8, 16.9 and 14.4 %; in TTH, they did not exceed those of the whole sample. Comorbid psychiatric disorder did not add to headache-attributed productive time losses, but weak associations existed (R (2) = 0.020-0.082) for all headache types between lost productive time and probabilities of depression and, less so, anxiety. CONCLUSION: In this large study we confirmed that depression and especially anxiety are comorbid more than by chance with migraine, and showed the same is true, but more strongly, with MOH. Arguably, migraine patients and, more certainly, MOH patients should be screened with HADS in pursuit of best outcomes. PMID- 27245686 TI - Global Epidemiology of Head and Neck Cancers: A Continuing Challenge. AB - BACKGROUND: Head and neck cancers (HNCs) continue to remain a significant public health burden worldwide, causing significant mortality and morbidity despite significant clinical advances enabling their early diagnosis and treatment. METHODS: We used data from the GLOBOCAN 2012, Cancer Incidence in Five Continents, World Health Organization Mortality Database and Surveillance, Epidemiology, and End Results programmes to describe the current epidemiology of HNCs. RESULTS: Estimated age-standardised incidence/mortality rates for cancers of the lip and oral cavity among males and females (7.0/2.3 and 2.6/0.6 per 100,000 per annum) in more developed regions are higher compared to those in less developed regions (5.0/2.8 and 2.5/1.4 per 100,000 per annum). Similarly, the estimated rates for cancers of the tonsils and pharynx among males (7.5/2.5 per 100,000 per annum) and females (2.7/0.5 per 100,000 per annum) are reported to be the highest in Western Europe, whereas these rates for cancer of the larynx among males (7.9/4.0 per 100,000 per annum) and females (0.9/0.5 per 100,000 per annum) are reported to be the highest in the Caribbean. Cancer of the nasopharynx represents a significant HNC burden in the Asia-Pacific region and Northern Africa. CONCLUSION: The current and future estimated burden of HNCs is shifting to less developed regions which may be ill equipped to deal with this increasing burden. This needs urgent attention of policy makers through effective cancer control policy implementation with population-based interventions. PMID- 27245687 TI - Novel strip-cast Mg/Al clad sheets with excellent tensile and interfacial bonding properties. AB - In order to broaden industrial applications of Mg alloys, as lightest-weight metal alloys in practical uses, many efforts have been dedicated to manufacture various clad sheets which can complement inherent shortcomings of Mg alloys. Here, we present a new fabrication method of Mg/Al clad sheets by bonding thin Al alloy sheet on to Mg alloy melt during strip casting. In the as-strip-cast Mg/Al clad sheet, homogeneously distributed equi-axed dendrites existed in the Mg alloy side, and two types of thin reaction layers, i.e., gamma (Mg17Al12) and beta (Mg2Al3) phases, were formed along the Mg/Al interface. After post-treatments (homogenization, warm rolling, and annealing), the interfacial layers were deformed in a sawtooth shape by forming deformation bands in the Mg alloy and interfacial layers, which favorably led to dramatic improvement in tensile and interfacial bonding properties. This work presents new applications to multi functional lightweight alloy sheets requiring excellent formability, surface quality, and corrosion resistance as well as tensile and interfacial bonding properties. PMID- 27245685 TI - Development and clinical application of an integrative genomic approach to personalized cancer therapy. AB - BACKGROUND: Personalized therapy provides the best outcome of cancer care and its implementation in the clinic has been greatly facilitated by recent convergence of enormous progress in basic cancer research, rapid advancement of new tumor profiling technologies, and an expanding compendium of targeted cancer therapeutics. METHODS: We developed a personalized cancer therapy (PCT) program in a clinical setting, using an integrative genomics approach to fully characterize the complexity of each tumor. We carried out whole exome sequencing (WES) and single-nucleotide polymorphism (SNP) microarray genotyping on DNA from tumor and patient-matched normal specimens, as well as RNA sequencing (RNA-Seq) on available frozen specimens, to identify somatic (tumor-specific) mutations, copy number alterations (CNAs), gene expression changes, gene fusions, and also germline variants. To provide high sensitivity in known cancer mutation hotspots, Ion AmpliSeq Cancer Hotspot Panel v2 (CHPv2) was also employed. We integrated the resulting data with cancer knowledge bases and developed a specific workflow for each cancer type to improve interpretation of genomic data. RESULTS: We returned genomics findings to 46 patients and their physicians describing somatic alterations and predicting drug response, toxicity, and prognosis. Mean 17.3 cancer-relevant somatic mutations per patient were identified, 13.3-fold, 6.9 fold, and 4.7-fold more than could have been detected using CHPv2, Oncomine Cancer Panel (OCP), and FoundationOne, respectively. Our approach delineated the underlying genetic drivers at the pathway level and provided meaningful predictions of therapeutic efficacy and toxicity. Actionable alterations were found in 91 % of patients (mean 4.9 per patient, including somatic mutations, copy number alterations, gene expression alterations, and germline variants), a 7.5-fold, 2.0-fold, and 1.9-fold increase over what could have been uncovered by CHPv2, OCP, and FoundationOne, respectively. The findings altered the course of treatment in four cases. CONCLUSIONS: These results show that a comprehensive, integrative genomic approach as outlined above significantly enhanced genomics based PCT strategies. PMID- 27245688 TI - Treatment of nodular vasculitis with colchicine. AB - Nodular vasculitis (NV) refers to a chronic relapsing lobular panniculitis that is thought to be a hypersensitivity reaction to antigenic triggers. While it is commonly associated with tuberculosis, in many cases no underlying cause is found and the condition is difficult to manage. Here, we report three patients with refractory idiopathic NV effectively treated with colchicine, leading to a significant improvement or complete resolution of their symptoms. Colchicine was successfully used as a steroid-sparing agent, and in one patient its cessation was associated with a flare of disease. PMID- 27245690 TI - Electrocatalytic oxidation of Epinephrine and Norepinephrine at metal oxide doped phthalocyanine/MWCNT composite sensor. AB - Glassy carbon electrode (GCE) was modified with metal oxides (MO = Fe3O4, ZnO) nanoparticles doped phthalocyanine (Pc) and functionalized MWCNTs, and the electrocatalytic properties were studied. Successful synthesis of the metal oxide nanoparticles and the MO/Pc/MWCNT composite were confirmed using FTIR, Raman and SEM techniques. The electrodes were characterized using cyclic voltammetry (CV) technique. The electrocatalytic behaviour of the electrode towards epinephrine (EP) and norepinephrine (NE) oxidation was investigated using CV and DPV. Result showed that GCE-MWCNT/Fe3O4/2,3-Nc, GCE-MWCNT/Fe3O429H,31H-Pc, GCE-MWCNT/ZnO/2,3 Nc and GCE-MWCNT/ZnO/29H,31H-Pc electrodes gave enhanced EP and NE current response. Stability study indicated that the four GCE-MWCNT/MO/Pc modified electrodes were stable against electrode fouling effect with the percentage NE current drop of 5.56-5.88% after 20 scans. GCE-MWCNT/Fe3O4/29H,31H-Pc gave the lowest limit of detection (4.6 MUM) towards EP while MWCNT/ZnO/29H,31H-Pc gave the lowest limit of detection (1.7 MUM) towards NE. The limit of detection and sensitivity of the electrodes compared well with literature. Electrocatalytic oxidation of EP and NE on GCE-MWCNT/MO/Pc electrodes was diffusion controlled with some adsorption of electro-oxidation reaction intermediates products. The electrodes were found to be electrochemically stable, reusable and can be used for the analysis of EP and NE in real life samples. PMID- 27245689 TI - Monitoring alloimmune response in kidney transplantation. AB - Currently, immunosuppressive therapy in kidney transplant recipients is generally performed by protocols and adjusted according to functional or histological evaluation of the allograft and/or signs of drug toxicity or infection. As a result, a large fraction of patients are likely to receive too much or too little immunosuppression, exposing them to higher rates of infection, malignancy and drug toxicity, or increased risk of acute and chronic graft injury from rejection, respectively. Developing reliable biomarkers is crucial for individualizing therapy aimed at extending allograft survival. Emerging data indicate that many assays, likely used in panels rather than single assays, have potential to be diagnostic and predictive of short and also long-term outcome. While numerous cross-sectional studies have found associations between the results of these assays and the presence of clinically relevant post transplantation outcomes, data from prospective studies are still scanty, thereby preventing widespread implementation in the clinic. Of note, some prospective, randomized, multicenter biomarker-driven studies are currently on-going aiming at confirming such preliminary data. These works as well as other future studies are highly warranted to test the hypothesis that tailoring immunosuppression on the basis of results offered by these biomarkers leads to better outcomes than current standard clinical practice. PMID- 27245691 TI - pH-Switch Nanoprecipitation of Polymeric Nanoparticles for Multimodal Cancer Targeting and Intracellular Triggered Delivery of Doxorubicin. AB - Theranostic nanoparticles are emerging as potent tools for noninvasive diagnosis, treatment, and monitoring of solid tumors. Herein, an advanced targeted and multistimuli responsive theranostic platform is presented for the intracellular triggered delivery of doxorubicin. The system consists of a polymeric-drug conjugate solid nanoparticle containing encapsulated superparamagnetic iron oxide nanoparticles (IO@PNP) and decorated with a tumor homing peptide, iRGD. The production of this nanosystem is based on a pH-switch nanoprecipitation method in organic-free solvents, making it ideal for biomedical applications. The nanosystem shows sufficient magnetization saturation for magnetically guided therapy along with reduced cytotoxicity and hemolytic effects. IO@PNP are largely internalized by endothelial and metastatic cancer cells and iRGD decorated IO@PNP moderately enhance their internalization into endothelial cells, while no enhancement is found for the metastatic cancer cells. Poly(ethylene glycol)-block poly(histidine) with pH-responsive and proton-sponge properties promotes prompt lysosomal escape once the nanoparticles are endocyted. In addition, the polymer doxorubicin conjugate solid nanoparticles show both intracellular lysosomal escape and efficient translocation of doxorubicin to the nuclei of the cells via cleavage of the amide bond. Overall, IO@PNP-doxorubicin and the iRGD decorated counterpart demonstrate to enhance the toxicity of doxorubicin in cancer cells by improving the intracellular delivery of the drug carried in the IO@PNP. PMID- 27245692 TI - Study of the causes of facial fractures in a reference center in Rio de Janeiro, Brazil from 2003-2012. AB - OBJECTIVE: This study describes the facial fractures of patients at a reference center in oral and maxillofacial surgery of a Public University Hospital in the city of Rio de Janeiro, from January 2003 to December 2012. METHODS: The data were collected from medical records and included the fractured bones, etiology, gender, and age of the patients. A total of 202 cases were identified, and 159 were included in the study (129 men and 30 women). RESULTS: The mandible was the most commonly injured bone (90 cases, 73 men and 17 women) with a mean age of 33.7 years old (+/-15.2), and traffic accidents (75 cases) were shown to be the major cause. CONCLUSION: In the city of Rio de Janeiro, young men in their fourth decade of life are prone to trauma to their facial bones, especially the mandible, and they are most commonly caused by traffic accidents. PMID- 27245694 TI - Seven wood-inhabiting new species of the genus Trichoderma (Fungi, Ascomycota) in Viride clade. AB - More than 200 recent collections of Trichoderma from China were examined and 16 species belonging to the Viride clade were identified based on integrated studies of phenotypic and molecular data. Among them, seven wood-inhabiting new species, T. albofulvopsis, T. densum, T. laevisporum, T. sinokoningii, T. sparsum, T. sphaerosporum and T. subviride, are found. They form trichoderma- to verticillium like conidiophores, lageniform to subulate phialides and globose to ellipsoidal conidia, but vary greatly in colony features, growth rates, and sizes of phialides and conidia. To explore their taxonomic positions, the phylogenetic tree including all the known species of the Viride clade is constructed based on sequence analyses of the combined RNA polymerase II subunit b and translation elongation factor 1 alpha exon genes. Our results indicated that the seven new species were well-located in the Koningii, Rogersonii and Neorufum subclades as well as a few independent terminal branches. They are clearly distinguishable from any existing species. Morphological distinctions and sequence divergences between the new species and their close relatives were discussed. PMID- 27245693 TI - Acceptability of Interventions Delivered Online and Through Mobile Phones for People Who Experience Severe Mental Health Problems: A Systematic Review. AB - BACKGROUND: Psychological interventions are recommended for people with severe mental health problems (SMI). However, barriers exist in the provision of these services and access is limited. Therefore, researchers are beginning to develop and deliver interventions online and via mobile phones. Previous research has indicated that interventions delivered in this format are acceptable for people with SMI. However, a comprehensive systematic review is needed to investigate the acceptability of online and mobile phone-delivered interventions for SMI in depth. OBJECTIVE: This systematic review aimed to 1) identify the hypothetical acceptability (acceptability prior to or without the delivery of an intervention) and actual acceptability (acceptability where an intervention was delivered) of online and mobile phone-delivered interventions for SMI, 2) investigate the impact of factors such as demographic and clinical characteristics on acceptability, and 3) identify common participant views in qualitative studies that pinpoint factors influencing acceptability. METHODS: We conducted a systematic search of the databases PubMed, Embase, PsycINFO, CINAHL, and Web of Science in April 2015, which yielded a total of 8017 search results, with 49 studies meeting the full inclusion criteria. Studies were included if they measured acceptability through participant views, module completion rates, or intervention use. Studies delivering interventions were included if the delivery method was online or via mobile phones. RESULTS: The hypothetical acceptability of online and mobile phone-delivered interventions for SMI was relatively low, while actual acceptability tended to be high. Hypothetical acceptability was higher for interventions delivered via text messages than by emails. The majority of studies that assessed the impact of demographic characteristics on acceptability reported no significant relationships between the two. Additionally, actual acceptability was higher when participants were provided remote online support. Common qualitative factors relating to acceptability were safety and privacy concerns, the importance of an engaging and appealing delivery format, the inclusion of peer support, computer and mobile phone literacy, technical issues, and concerns about the impact of psychological state on intervention use. CONCLUSIONS: This systematic review provides an in-depth focus on the acceptability of online and mobile phone-delivered interventions for SMI and identified the need for further research in this area. Based on the results from this review, we recommend that researchers measure both hypothetical and actual acceptability to identify whether initial perceptions of online and mobile phone-delivered interventions change after access. In addition, more focus is needed on the potential impact of demographic and clinical characteristics on acceptability. The review also identified issues with module completion rates and intervention use as measures of acceptability. We therefore advise researchers to obtain qualitative reports of acceptability throughout each phase of intervention development and testing. Further implications and opportunities for future research are discussed. PMID- 27245695 TI - Effects of telmisartan and pioglitazone on high fructose induced metabolic syndrome in rats. AB - Metabolic syndrome (MS) is a cluster of hypertension, insulin resistance, dyslipidaemia, and hyperuricemia. This study was designed to assess the effect of telmisartan and pioglitazone on high fructose induced MS. Thirty-five male albino rats were classified into 5 groups: A, normal diet; B, high-fructose diet (HFD) subdivided into B1 (HFD only), B2 (telmisartan, 5 mg/kg), B3 (pioglitazone, 10 mg/kg), and B4 (telmisartan + pioglitazone). Administration of the drugs was started after the rats had been on HFD for 4 weeks and continued for 4 weeks. Body mass (BM), blood pressure (BP), uric acid (UA), total cholesterol, triglycerides (TG), high-density lipoprotein (HDL-c), low-density lipoprotein (LDL-c), blood urea nitrogen (BUN), creatinine, and nitric oxide (NO) were measured and the levels of fasting glucose and fasting insulin were estimated. Compared with group B1, telmisartan treatment significantly decreased BP, BM, serum glucose, insulin, UA, urea, cholesterol, TGA, and LDL and significantly increased HDL, whereas pioglitazone treatment significantly decreased BP, serum glucose, insulin, UA, urea, creatinine, cholesterol, TGA, and LDL and significantly increased HDL. Co-administration of pioglitazone + telmisartan significantly decreased insulin, urea, and creatinine compared with telmisartan alone. Combined telmisartan + pioglitazone allowed better control of BP, hyperglycaemia, insulin resistance, and the amelioration of BM increase that may be associated with pioglitazone treatment. PMID- 27245697 TI - The comparison of clinical and biological characteristics between IDH1 and IDH2 mutations in gliomas. AB - BACKGROUND: Mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) are frequent in low-grade gliomas and secondary glioblastomas (sGBM). Because they yield the same oncometabolite, D-2 hydroxyglutarate, they are often treated as equivalent and pooled. The objective of this study was to provide insight into the differences between IDH1 and IDH2 mutant gliomas. METHODS: To investigate the different clinical and molecular characterization between IDH1 mutant and IDH2 mutant gliomas, we studied 811 patients with IDH1 mutations, IDH2 mutations and IDH1/2 wild-type. In addition, whole-transcriptome sequencing and DNA methylation data were used to assess the distribution of genetic changes in IDH1 and IDH2 mutant gliomas in a Chinese population-based cohort. RESULTS: Among 811 gliomas in our cohort, 448 cases (55.2%) harbored an IDH1 mutation, 18 cases (2.2%) harbored an IDH2 mutation and 345 cases (42.6%) harbored an IDH1/2 wild-type. We found that IDH1 and IDH2 are mutually exclusive in gliomas, and IDH2 mutations are mutually exclusive with PTEN, P53 and ATRX mutations. Patients with IDH2 mutations had a higher frequency of 1p/19q co-deletion (p < 0.05) than IDH1 mutant patients. In addition, a Gene Set Enrichment Analysis (GSEA) showed that IDH2 mutant gliomas were associated with the oxidative phosphorylation gene set, and the four most representative biological processes for genes commonly altered by hypermethylation in IDH2 mutant gliomas were the regulation of cell proliferation, cell motion, cell migration and response to hypoxia. Patients with IDH2 mutant gliomas exhibited longer Overall survival (OS) (p < 0.05) and longer Progression-free survival (PFS) (p < 0.05) than patients with IDH1/2 wild-type gliomas. However, their OS and PFS did not differ from that of IDH1 mutant patients. CONCLUSIONS: Our study revealed an intrinsic distinction between IDH1 and IDH2 mutant gliomas, and these mutations should be considered separately because their differences could have implications for the diagnosis and treatment of IDH1/2 mutant gliomas. PMID- 27245696 TI - Ribosome quality control is a central protection mechanism for yeast exposed to deoxynivalenol and trichothecin. AB - BACKGROUND: The trichothecene mycotoxins deoxynivalenol (DON) and trichothecin (TTC) are inhibitors of eukaryotic protein synthesis. Their effect on cellular homeostasis is poorly understood. We report a systematic functional investigation of the effect of DON and TTC on the yeast Saccharomyces cerevisiae using genetic array, network and microarray analysis. To focus the genetic analysis on intracellular consequences of toxin action we eliminated the PDR5 gene coding for a potent pleiotropic drug efflux protein potentially confounding results. We therefore used a knockout library with a pdr5Delta strain background. RESULTS: DON or TTC treatment creates a fitness bottleneck connected to ribosome efficiency. Genes isolated by systematic genetic array analysis as contributing to toxin resistance function in ribosome quality control, translation fidelity, and in transcription. Mutants in the E3 ligase Hel2, involved in ribosome quality control, and several members of the Rpd3 histone deacetylase complex were highly sensitive to DON. DON and TTC have similar genetic profiles despite their different toxic potency. Network analysis shows a coherent and tight network of genetic interactions among the DON and TTC resistance conferring gene products. The networks exhibited topological properties commonly associated with efficient processing of information. Many sensitive mutants have a "slow growth" gene expression signature. DON-exposed yeast cells increase transcripts of ribosomal protein and histone genes indicating an internal signal for growth enhancement. CONCLUSIONS: The combination of gene expression profiling and analysis of mutants reveals cellular pathways which become bottlenecks under DON and TTC stress. These are generally directly or indirectly connected to ribosome biosynthesis such as the general secretory pathway, cytoskeleton, cell cycle delay, ribosome synthesis and translation quality control. Gene expression profiling points to an increased demand of ribosomal components and does not reveal activation of stress pathways. Our analysis highlights ribosome quality control and a contribution of a histone deacetylase complex as main sources of resistance against DON and TTC. PMID- 27245698 TI - Mechanism of gene-specificity of oncogenic regulators. PMID- 27245699 TI - Cardiovascular safety of methylphenidate among children and young people with attention-deficit/hyperactivity disorder (ADHD): nationwide self controlled case series study. AB - OBJECTIVE: To determine whether treatment with methylphenidate in children and young people with attention-deficit/hyperactivity disorder (ADHD) was associated with cardiovascular events. DESIGN: Self controlled case series analysis. SETTING: Nationwide health insurance database, 1 January 2008 to 31 December 2011, in South Korea. PARTICIPANTS: 1224 patients aged <=17 who had experienced an incident cardiovascular event and had had at least one incident prescription for methylphenidate. MAIN OUTCOME MEASURES: A recorded diagnosis (either a primary or secondary cause) of any of the following cardiovascular adverse events: arrhythmias (ICD-10 (international classification of diseases, 10th revision) codes I44, I45, I47, I48, I49), hypertension (codes I10-I15), myocardial infarction (code I21), ischemic stroke (code I63), or heart failure (code I50). Incidence rate ratios were calculated with conditional Poisson regression and adjusted for time varying comorbidity and comedication. RESULTS: Increased risk of arrhythmia was observed in all exposed time periods-that is, periods of treatment with methylphenidate-(incidence rate ratio 1.61, 95% confidence interval 1.48 to 1.74), and the risk was highest in the children who had congenital heart disease. No significant risk of myocardial infarction was observed for all exposed time periods (1.33, 0.90 to 1.98), though risk was higher in the early risk periods between eight and 56 days after the start of treatment with methylphenidate. No significant increased risk was observed for hypertension, ischemic stroke, or heart failure. CONCLUSION: The relative risk of myocardial infarction and arrhythmias is increased in the early period after the start of methylphenidate treatment for ADHD in children and young people. Though the absolute risk is likely to be low, the risk-benefit balance of methylphenidate should be carefully considered, particularly in children with mild ADHD. PMID- 27245700 TI - Emergency transcatheter aortic valve implantation in patients with severe aortic regurgitation and a left ventricle assist device: A case report and systematic review. AB - BACKGROUND: Cardiogenic shock due to severe aortic regurgitation in patients with left ventricle assist devices is a life threatening condition. Here, we consider transcatheter aortic valve implantation as a treatment option. METHODS AND RESULTS: A patient with a left ventricle assist device was presented to us with cardiogenic shock due to severe aortic regurgitation. We successfully implanted a transcatheter aortic valve in emergency setting. The patient recovered and underwent cardiac transplantation three months afterwards. We performed a systematic literature review and identified 10 cases of patients with a left ventricle assist device undergoing transcatheter aortic valve implantation. In these cases, there was no procedural related mortality reported. In four (40%) patients, transcatheter aortic valve implantation resulted in significant paravalvular aortic regurgitation. In two of these cases it was due to migration of the valve towards the left ventricle. CONCLUSIONS: Our case report and review of literature suggests that transcatheter aortic valve implantation is a feasible and lifesaving treatment option for left ventricle assist device patients presenting with severe aortic regurgitation. PMID- 27245701 TI - Overexpression of collagen XIII in extraocular fat affected by active thyroid associated ophthalmopathy: A crucial piece of the puzzle? AB - Thyroid-associated ophthalmopathy (TAO) causes irreversible increase in extraocular fat volume that contributes to the risk of exophthalmos and compressive optic neuropathy. Collagen XIII is implicated in uncontrolled cell growth in some tumours, but we are not aware of any studies of collagen XIII in TAO-affected solid tissue to date. We conducted immunohistochemical staining for collagen XIII alpha 1 (COL13A1), present in both the transmembrane and cleaved forms of collagen XIII, in consecutive prospectively collected human extraocular tissue specimens from patients with TAO and controls. We identified overexpression of collagen XIII in active TAO-affected fat. We discuss how species and cell-type specific responses of collagen XIII to stressors may help explain the different phenotypes of TAO. PMID- 27245702 TI - Efficient Phosphorus Cycling in Food Production: Predicting the Phosphorus Fertilization Effect of Sludge from Chemical Wastewater Treatment. AB - This study examined the P fertilization effects of 11 sewage sludges obtained from sewage treated with Al and/or Fe salts to remove P by a pot experiment with ryegrass (Lolium multiflorum) and a nutrient-deficient sand-peat mixture. Also it investigated whether fertilization effects could be predicted by chemical sludge characteristics and/or by P extraction. The mineral fertilizer equivalent (MFE) value varied significantly but was low for all sludges. MFE was best predicted by a negative correlation with ox-Al and ox-Fe in sludge, or by a positive correlation with P extracted with 2% citric acid. Ox-Al had a greater negative impact on MFE than ox-Fe, indicating that Fe salts are preferable as a coagulant when aiming to increase the plant availability of P in sludge. The results also indicate that sludge liming after chemical wastewater treatment with Al and/or Fe salts increases the P fertilization effect. PMID- 27245703 TI - Funny money: the attentional role of monetary feedback detached from expected value. AB - Stimuli associated with monetary reward can become powerful cues that effectively capture visual attention. We examined whether such value-driven attentional capture can be induced with monetary feedback in the absence of an expected cash payout. To this end, we implemented images of U.S. dollar bills as reward feedback. Participants knew in advance that they would not receive any money based on their performance. Our reward stimuli-$5 and $20 bill images-were thus dissociated from any practical utility. Strikingly, we observed a reliable attentional capture effect for the mere images of bills. Moreover, this finding generalized to Monopoly money. In two control experiments, we found no evidence in favor of nominal or symbolic monetary value. Hence, we claim that bill images are special monetary representations, such that there are strong associations between the defining visual features of bills and reward, probably due to a lifelong learning history. Together, we show that the motivation to earn cash plays a minor role when it comes to monetary rewards, while bill-defining visual features seem to be sufficient. These findings have the potential to influence human factor applications, such as gamification, and can be extended to novel value systems, such as the electronic cash Bitcoin being developed for use in mobile banking. Finally, our procedure represents a proof of concept on how images of money can be used to conserve expenditures in the experimental context. PMID- 27245704 TI - G534E Variant in HABP2 and Nonmedullary Thyroid Cancer. PMID- 27245706 TI - Round Table - new concept of the Arbeitsgemeinschaft Dermatologische Forschung to foster regional exchange between young clinician scientists in dermatology. PMID- 27245705 TI - Novel identification and characterisation of Transient receptor potential melastatin 3 ion channels on Natural Killer cells and B lymphocytes: effects on cell signalling in Chronic fatigue syndrome/Myalgic encephalomyelitis patients. AB - BACKGROUND: Transient receptor potential melastatin 3 (TRPM3) cation channels are ubiquitously expressed by multiple cells and have an important regulatory role in calcium-dependent cell signalling to help maintain cellular homeostasis. TRPM3 protein expression has yet to be determined on Natural Killer (NK) cells and B lymphocytes. Multiple single nucleotide polymorphisms have been reported in TRPM3 genes from isolated peripheral blood mononuclear cells, NK and B cells in Chronic fatigue syndrome/Myalgic encephalomyelitis (CFS/ME) patients and have been proposed to correlate with illness presentation. The object of the study was to assess TRPM3 surface expression on NK and B lymphocytes from healthy controls, followed by a comparative investigation examining TRPM3 surface expression, and cytoplasmic and mitochondrial calcium influx in CD19(+) B cells, CD56(bright) and CD56(dim) cell populations from CFS/ME patients. RESULTS: TRPM3 cell surface expression was identified for NK and B lymphocytes in healthy controls (CD56(bright) TRPM3 35.72 % +/- 7.37; CD56(dim) 5.74 % +/- 2.00; B lymphocytes 2.05 % +/- 0.19, respectively). There was a significant reduction of TRPM3 surface expression on CD19(+) B cells (1.56 +/- 0.191) and CD56(bright) NK cells (17.37 % +/- 5.34) in CFS/ME compared with healthy controls. Anti-CD21 and anti IgM conjugated biotin was cross-linked with streptavidin,and subsequently treatment with thapsigargin. This showed a significant reduction in cytoplasmic calcium ion concentration in CD19(+) B lymphocytes. CD56(bright) NK cells also had a significant decrease in cytoplasmic calcium in the presence of 2-APB and thapsigargin in CFS/ME patients. CONCLUSIONS: The results from this preliminary investigation identify, for the first time, TRPM3 surface expression on both NK and B lymphocytes in healthy controls. We also report for the first time, significant reduction in TRPM3 cell surface expression in NK and B lymphocytes, as well as decreased intracellular calcium within specific conditions in CFS/ME patients. This warrants further examination of these pathways to elucidate whether TRPM3 and impaired calcium mobilisation has a role in CFS/ME. PMID- 27245707 TI - Overall accuracy of cervical cytology and clinicopathological significance of LSIL cells in ASC-H cytology. AB - OBJECTIVE: The aims of this study were (i) to investigate the diagnostic accuracy of Papanicolaou (Pap) smears and (ii) to evaluate the clinicopathological significance of the presence of low-grade squamous intraepithelial lesion (LSIL) cells in atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion (HSIL) (ASC-H) cytology. METHODS: We retrospectively reviewed paired cytological and histological findings from 3141 patients. ASC-H cytology was classified as either ASC-H or LSIL with some features suggestive of the presence of a concurrent HSIL (LSIL-H). Clinicopathological characteristics were evaluated through a retrospective study and meta-analysis. RESULTS: The accuracy of the cytological diagnosis was 93.7% (2942 of 3141 cases). The positive predictive value (PPV) of ASC-H for cervical intraepithelial neoplasia grade 2 or worse (CIN 2+ ) was 51.4%. In cases of LSIL-H, CIN 2+ histology was more prevalent in the pre-menopausal period (19-44 years) than in peri- and postmenopausal periods (older than 45 years) (P = 0.024). There was no difference in the ability of LSIL-H and ASC-H to predict CIN 2+. CONCLUSION: The Pap smear is a good cervical cancer screening method. Although there was no difference in the predictive value for CIN 2+ between LSIL-H and ASC-H, the presence of definite LSIL cells was more predictive of CIN 2+ in younger patients than in older patients. PMID- 27245708 TI - The CROWN initiative: Journal editors invite researchers to develop core outcomes in women's health. PMID- 27245709 TI - Decreasing but still significant facilitation effect of cold-season macrophytes on wetlands purification function during cold winter. AB - To identify the facilitation effect of a cool-season aquatic macrophyte (FEam) for use in effluent purification via constructed floating wetlands (CFWs) and to determine the possible pathways used during a winter period with an average temperature of less than 5 degrees C, pilot-scale CFWs were planted with the cold-season macrophyte Oenanthe clecumbens and were operated as batch systems. Although some leaves withered, the roots retained relatively high levels of activity during the winter, which had average air and water temperatures of 3.63 and 5.04 degrees C, respectively. The N and P removal efficiencies in CFWs decreased significantly in winter relative to those in late autumn. The presence of cool-season plants resulted in significant improvements in N and P removal, with a FEam of 15.23-25.86% in winter. Microbial N removal accounted for 71.57% of the total N removed in winter, and the decrease in plant uptake was the dominant factor in the wintertime decrease in N removal relative to that in late autumn. These results demonstrate the importance of cold-season plants in CFWs for the treatment of secondary effluent during cold winters. PMID- 27245710 TI - Rich semantic networks applied to schizophrenia: A new framework. PMID- 27245711 TI - Reliability and Validity of the List of Mental Health Items (LISMEN). AB - BACKGROUND: The detection of risk factors is a key element in the prevention of mental health disorders. It is widely known that in the formation of personality and its disorders, relational experiences (vital events) in childhood condition both neurological and emotional development. The accumulation of these circumstances brings about altered life trajectories, which make people more vulnerable to mental health disorders. METHOD: A structured interview called LISMEN was designed based on the scientific literature to detect the risk of developing mental health disorders. A descriptive, reliability, and validity statistical study was carried out on four samples, one of which was the control group. There were 372 subjects in total. RESULTS: The technique was highly reliable (kappa coefficient 0.7 [p<0.05]) and internally consistent (Cronbach's alpha between 0.80 and 0.98). Sensitivity and specificity were high (AUC [Area Under Curve] OR =1.18 [1]), with the cut-off point between 9 and 10. CONCLUSIONS: LISMEN is a useful tool for detecting the risk of developing mental health disorders. A score of 10 or higher indicates that the subject belongs to the most sensitive or vulnerable population group at risk. PMID- 27245712 TI - Intrinsic aggregation propensity of the CsgB nucleator protein is crucial for curli fiber formation. AB - Several organisms exploit the extraordinary physical properties of amyloid fibrils forming natural protective amyloids, in an effort to support complex biological functions. Curli amyloid fibers are a major component of mature biofilms, which are produced by many Enterobacteriaceae species and are responsible, among other functions, for the initial adhesion of bacteria to surfaces or cells. The main axis of curli fibers is formed by a major structural subunit, known as CsgA. CsgA self-assembly is promoted by oligomeric nuclei formed by a minor curli subunit, known as the CsgB nucleator protein. Here, by implementing AMYLPRED2, a consensus prediction method for the identification of 'aggregation-prone' regions in protein sequences, developed in our laboratory, we have successfully identified potent amyloidogenic regions of the CsgB subunit. Peptide-analogues corresponding to the predicted 'aggregation-prone' segments of CsgB were chemically synthesized and studied, utilizing several biophysical techniques. Our experimental data indicate that these peptides self-assemble in solution, forming fibrils with characteristic amyloidogenic properties. Using comparative modeling techniques, we have developed three-dimensional models of both CsgA and CsgB subunits. Structural analysis revealed that the identified 'aggregation-prone' segments may promote gradual polymerization of CsgB. Briefly, our results indicate that the intrinsic self-aggregation propensity of the CsgB subunit, most probably has a pivotal role in initiating the formation of curli amyloid fibers by promoting the self-assembly process of the CsgB nucleator protein. PMID- 27245713 TI - Health financing lessons from Thailand for South Africa on the path towards universal health coverage. AB - Five years after the release of its Green Paper on National Health Insurance (NHI),years after the institution of NHI pilot sites and following the recent release of the White Pa 4 per on NHI, South Africa (SA) needs to move beyond the phase 1 plans of policy making and healthening activities to phase 2 - putting into place the legal and institutional frameth system strengworks and systems for implementation of its universal health coverage (UHC) system. In doing so, SA can draw on considerable practical lessons from other countries' reforms in managing UHC with favourable equity outcomes over the past decade. We outline some potentially significant lessons from the Thai health financing system for SA. PMID- 27245714 TI - Comment on the Central Drug Authority's position statement on cannabis. AB - The Central Drug Authority's 'Position statement on cannabis' in this issue of SAMJ is a welcome, if somewhat belated, article that gives an indication of the South African government's response to the shifting sands of local and international public opinion and global drug policies. This editorial comments on the statement. PMID- 27245715 TI - The role of appropriate diagnostic testing in acute respiratory tract infections: An antibiotic stewardship strategy to minimise diagnostic uncertainty in primary care. AB - Antibiotic resistance has increased worldwide to the extent that it is now regarded as a global public health crisis. Interventions to reduce excessive antibiotic prescribing to patients can reduce resistance and improve microbiological and clinical outcomes. Therefore, although improving outpatient antibiotic use is crucial, few data are provided on the key interventional components and the effectiveness of antibiotic stewardship in the primary care setting, in South Africa. The reasons driving the excessive prescription of antibiotics in the community are multifactorial but, perhaps most importantly, the overlapping clinical features of viral and bacterial infections dramatically reduce the ability of GPs to distinguish which patients would benefit from an antibiotic or not. As a consequence, the need for tools to reduce diagnostic uncertainty is critical. In this regard, besides clinical algorithms, a consensus of collaborators in European and UK consortia recently provided guidance for the use of C-reactive protein point-of-care testing in outpatients presenting with acute respiratory tract infections (ARTIs) and/or acute cough, if it is not clear after proper clinical assessment whether antibiotics should be prescribed or not. A targeted application of stewardship principles, including diagnostic stewardship as described in this review, to the ambulatory setting has the potential to affect the most common indications for systemic antibiotic use, in that the majority (80%) of antibiotic use occurs in the community, with ARTIs the most common indication. PMID- 27245716 TI - Emergence of vancomycin-resistant Enterococcus at a tertiary paediatric hospital in South Africa. AB - BACKGROUND: During 2013, the haematology/oncology unit at a tertiary level paediatric hospital in South Africa experienced the emergence of infection with vancomycin-resistant Enterococcus (VRE). OBJECTIVE: To describe the clinical and molecular aspects of the cases identified. METHODS: VRE isolates identified from blood culture specimens processed at the National Health Laboratory Service were screened for the presence of the vancomycin resistance genes vanA, B and C1, 2 and 3. Further characterisation of these isolates was carried out using pulsed field gel electrophoresis (PGFE) and multilocus sequence typing (MLST). Clinical records of infected patients were reviewed to identify possible risk factors, while surveillance with rectal swabs was performed to identify VRE-colonised patients. RESULTS: Four patients with haematological malignancies were identified with VRE bloodstream infections. Patients were immunocompromised at the time of the bloodstream infection (BSI), with receipt of vancomycin prior to VRE-BSI, and infections were treated with linezolid. Colonisation with VRE was found in 8 of 55 patients screened. Infected and colonised patients were isolated in the unit during their admission and strict contact precaution infection control practices were instituted. The vanA gene was identified in all of the isolates but one. PFGE and MLST results showed a degree of genetic relatedness between certain isolates obtained from rectal swab and blood culture samples, suggesting possible patient-to-patient transmission or persistence of the isolates in the unit. CONCLUSION: Strict infection control practices are necessary to prevent infection and transmission of resistant organisms among vulnerable patients. PMID- 27245717 TI - Heavy alcohol use in patients on highly active antiretroviral therapy: What responses are needed? AB - BACKGROUND: Alcohol has a negative effect on antiretroviral therapy (ART) adherence and HIV treatment outcomes. METHOD: As part of formative work for a project to test the efficacy of an alcohol-focused intervention to reduce alcohol consumption and improve HIV treatment outcomes, we investigated the extent of problem drinking among patients at ART clinics in Tshwane, South Africa (SA), using the Alcohol Use Disorders Identification Test (AUDIT). RESULTS: The finding that a third of drinkers reported hazardous drinking, roughly 10% reported harmful drinking, and a further 10% were possibly alcohol dependent replicates the findings of similar research in the Western Cape and Gauteng provinces of SA. It also points to the need for more routine screening of ART patients for problematic alcohol use. CONCLUSION: The 10-item AUDIT may be too time consuming for health workers in busy ART clinics to administer and score, necessitating even briefer screening instruments for assessing hazardous and harmful drinking. PMID- 27245718 TI - Position statement on cannabis. AB - There is an ongoing national debate around cannabis policy. This brief position statement by the Executive Committee of the Central Drug Authorityoutlines some of the factors that have contributed to this debate, delineates reduction strategies, summarises the harms and benefits ofmarijuana, and provides recommendations. These recommendations emphasise an integrated and evidence-based approach, the need forresources to implement harm reduction strategies against continued and chronic use of alcohol and cannabis, and the potential value of afocus on decriminalisation rather than the legalisation of cannabis. PMID- 27245719 TI - Complex adaptive HIV/AIDS risk reduction: Plausible implications from findings in Limpopo Province, South Africa. AB - This article emphasises that when working with complex adaptive systems it is possible to stimulate new social practices and/or cognitive perspectives that contribute to risk reduction, associated with reducing aggregate community viral loads. The process of achieving this is highly participatory and is methodologically possible because evidence of 'attractors' that influence the social practices can be identified using qualitative research techniques. Using findings from Limpopo Province, South Africa, we argue that working with 'wellness attractors' and increasing their presence within the HIV/AIDS landscape could influence aggregate community viral loads. While the analysis that is presented is unconventional, it is plausible that this perspective may hold potential to develop a biosocial response - which the Joint United Nations Programme on HIV and AIDS (UNAIDS) has called for - that reinforces the biomedical opportunities that are now available to achieve the ambition of ending AIDS by 2030. PMID- 27245720 TI - When are doctors legally obliged to stop and render assistance to injured persons at road accidents? AB - Unlike the USA, South Africa (SA) does not have 'Good Samaritan' laws that oblige doctors to stop at road accidents. In SA, the conduct of doctors in such situations is governed by the common law. Doctors coming across injured people at a road accident should stop and render assistance, unless they are likely to be exposed to personal danger or injury, they are mentally or physically incapable of assisting, or other medical or paramedical practitioners are at the scene. Where there is the threat of personal danger to the doctor, they must immediately report the accident to the police, advise the police to send protection and call for urgent ambulance assistance. Doctors should remain in a safe place near the scene until the police and ambulance arrive and check that paramedics are available to stabilise the injured before departing. Where there is the threat of danger, if doctors are mentally or physically unable to assist or if other medical or paramedical practitioners are at the scene, doctors may or may not be required to stop. PMID- 27245721 TI - Managing the remains of fetuses and abandoned infants: A call to urgently review South African law and medicolegal practice. AB - This article reviews South African (SA) law and its impact on the medicolegal management of fetal remains emanating from elective and therapeutic termination of pregnancies, stillbirths and miscarriages and the remains of abandoned or exposed infants. It was found that remains are treated differently, some constituting medical waste while others have sufficient status in law to allow for burial. This approach results in some women or couples being denied a choice with regard to disposal via culturally relevant practices, and is insensitive to the fact that all remains ultimately constitute human remains. The article argues that SA law is in urgent need of reform, and turns to foreign law and forensic practice to shed light on possible alternative approaches that could assist with developing the SA position and thereby improve the practical management of fetal and infant remains in SA. PMID- 27245722 TI - A case of biventricular endomyocardial fibrosis complicated by right ventricular outflow tract aneurysms. AB - Endomyocardial fibrosis remains a major public health problem worldwide. It is a restrictive cardiomyopathy, of uncertain aetiology, which may lead to right, left or biventricular heart failure. Progress continues to be made in understanding the prevalence and natural history of this disease. Specific treatment, apart from surgery, remains suboptimal. We report a case of advanced, biventricular EMF complicated by right ventricular outflow tract aneurysms. PMID- 27245723 TI - Thrombotic thrombocytopenic purpura in the presence of connective tissue disease and HIV infection: A diagnostic and therapeutic challenge in a resource- constrained setting. AB - Thrombotic thrombocytopenic purpura is a catastrophic disease and may occur in the presence of other confounding diseases. We present a case of TTP in a patient with connective tissue disease and HIV infection, in whom the diagnosis and management of TTP was challenging. It is important to understand the various underlying mechanisms that drive TTP in the presence of these comorbid diseases, so that an appropriate treatment strategy can be initiated. Our patient failed an initial trial of plasma infusion alone, but responded well to plasma exchange. PMID- 27245724 TI - Where have all the gun deaths gone? AB - BACKGROUND: The low number of firearm assaults and overall assault-related deaths in Statistics South Africa's death notification reports is incongruous with other recently released data, including police crime statistics. METHODS: We conducted a review of all gunshot injuries recorded in death notifications from 1997 to 2013, including all cases in which the underlying cause of death was ascribed to cause-specific codes in the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) that referred to a gunshot injury. RESULTS: We identified 105 694 gunshot-related injury deaths over the 17-year period, an average of 6 217 per annum. The total annual number of gunshot injuries increased from 1997 to 2000, at which point firearm-related deaths peaked at 9 540 recorded cases. Thereafter there was a steadily decreasing trend (interrupted only in 2006 and 2008) until 2011, when 3 793 deaths were attributed to gunshot-related injuries as the underlying cause - a decrease of >60% from the peak in 2000. CONCLUSION: The cause-specific profile for gunshot injury deaths in this study indicated extensive misclassification, which explained the near-absence of these injuries among assault cases. However, the trend in gunshot-related injury deaths irrespective of intent provides further support for the hypothesis that stricter gun control, coinciding with the implementation of the Firearms Control Act of 2000, accounts for this decrease. PMID- 27245725 TI - A meta-analysis of the efficacy of preoperative surgical safety checklists to improve perioperative outcomes. AB - BACKGROUND: Meta-analyses of the implementation of a surgical safety checklist (SSC) in observational studies have shown a significant decrease in mortality and surgical complications. OBJECTIVE: To determine the efficacy of the SSC using data from randomised controlled trials (RCTs). METHODS: This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was registered with PROSPERO (CRD42015017546). A comprehensive search of six databases was conducted using the OvidSP search engine. RESULTS: Four hundred and sixty-four citations revealed three eligible trials conducted in tertiary hospitals and a community hospital, with a total of 6 060 patients. All trials had allocation concealment bias and a lack of blinding of participants and personnel. A single trial that contributed 5 295 of the 6 060 patients to the meta-analysis had no detection, attrition or reporting biases. The SSC was associated with significantly decreased mortality (risk ratio (RR) 0.59, 95% confidence interval (CI) 0.42 - 0.85; p=0.0004; I2=0%) and surgical complications (RR 0.64, 95% CI 0.57 - 0.71; p<0.00001; I2=0%). The efficacy of the SSC on specific surgical complications was as follows: respiratory complications RR 0.59, 95% CI 0.21 - 1.70; p=0.33, cardiac complications RR 0.74, 95% CI 0.28 - 1.95; p=0.54, infectious complications RR 0.61, 95% CI 0.29 - 1.27; p=0.18, and perioperative bleeding RR 0.36, 95% CI 0.23 - 0.56; p<0.00001. CONCLUSIONS: There is sufficient RCT evidence to suggest that SSCs decrease hospital mortality and surgical outcomes in tertiary and community hospitals. However, randomised evidence of the efficacy of the SSC at rural hospital level is absent. PMID- 27245726 TI - Screening for retinopathy of prematurity in a provincial hospital in Port Elizabeth, South Africa. AB - Background. Retinopathy of prematurity (ROP) is an emerging public health problem in many middle-income countries where improved neonatal survival rates coupled with inadequate health resources have created a new epidemic. There are limited available data on the magnitude of the problem, and screening in South African (SA) hospitals has not been uniformly practised. OBJECTIVE: To describe the results of various interventions implemented over a 6-year period while developing a new ROP screening service in a provincial hospital in Port Elizabeth, SA. METHOD: A retrospective case folder review of ROP screening at Dora Nginza Hospital, Port Elizabeth, SA, over the 6-year period 2009 - 2014 was conducted. RESULTS: A total of 919 new cases were seen. Fifteen patients received treatment for type 1 ROP (T1ROP), 223 had type 2 (T2) or earlier ROP, 1 had stage 4 ROP and 6 had stage 5 ROP. The combination of healthcare worker education, improved equipment and human resources and the introduction of dual responsibility for case referrals resulted in an increase in the number of new infants screened from 33 in year 1 to 292 in year 6. The number of infants who were screened late decreased from 33/33 (100%) in year 1, prior to the interventions, to 23/292 in the final year (7.9%). Improved oxygen delivery and adequate oxygen saturation monitoring contributed to a decrease in the incidence of T1ROP from 1.5% to 1% over 1 year and in the incidence of T2 or earlier ROP from 30.3% to 24%. CONCLUSIONS: Better management of ROP can be achieved through adequate provision of healthcare professionals and material resources coupled with education and a well-supported referral system. A close working relationship between paediatricians and ophthalmologists results in a more efficient screening programme. PMID- 27245727 TI - Retinopathy of prematurity screening criteria and workload implications at Tygerberg Children's Hospital, South Africa: A cross-sectional study. AB - BACKGROUND: Screening guidelines for retinopathy of prematurity (ROP) used in high-income countries are not appropriate for middle- income countries, and screening requirements may vary even between units within one city. OBJECTIVE: To determine optimal ROP screening criteria, and its workload implications, for Tygerberg Children's Hospital (TCH), Cape Town, South Africa. METHODS: This cross sectional study included premature infants screened for ROP at TCH from 1 January 2009 to 31 December 2014. Logistic regression analysis for prediction and classification was performed. Predictors were birth weight (BW) and gestational age (GA). Endpoints were clinically significant ROP (CSROP) and type 1 ROP (T1ROP). RESULTS: Of 1 104 eligible infants, 33.4% had ROP (CSROP 9.1%, T1ROP 2.5%). All T1ROP infants received laser therapy. The number of screening examinations was inversely correlated with GA and BW. The number needed to screen to identify one infant requiring treatment was 41 (entailing 83 examinations, 4 screening hours, one technician and three doctors). Screening infants with a GA of <=28 weeks or a BW of <1 000 g would have detected all infants with T1ROP but missed two outliers with CSROP. These outliers would only have been detected with a GA of <=32 weeks or a BW <1 500 g. CONCLUSIONS: Detection of infants with T1ROP is resource intensive. Larger infants require screening to include a few outliers, but they require fewer examinations than smaller infants. Making local screening criteria narrower on the basis of a limited evidence base may be dangerous. Risk factors for CSROP in larger infants need to be researched. PMID- 27245728 TI - An overview of cancer research in South African academic and research institutions, 2013 - 2014. AB - BACKGROUND AND OBJECTIVES: Cancer is emerging as a critical public health problem in South Africa (SA). Recognising the importance of research in addressing the cancer burden, the Ministerial Advisory Committee on the Prevention and Control of Cancer (MACC) research working group undertook a review of the current cancer research landscape in SA and related this to the cancer burden. METHODS: Academic and research institutions in SA were contacted to provide information on the titles of all current and recently completed (2013/2014) cancer research projects. Three MACC research working group members used the project titles to independently classify the projects by type of research (basic, clinical and public health - projects could be classified in more than one category) and disease site. A more detailed classification of projects addressing the five most common cancers diagnosed in males and females in SA was conducted using an adapted Common Scientific Outline (CSO) categorisation. RESULTS: Information was available on 556 cancer research projects. Overall, 301 projects were classified as clinical, 254 as basic science and 71 as public health research. The most common cancers being researched were cancers of the breast (n=95 projects) and cervix (n=43), leukaemia (n=36), non-Hodgkin's lymphoma (n=35) and lung cancer (n=23). Classification of the five most common cancers in males and females in SA, using the adapted CSO categories, showed that the majority of projects related to treatment, with relatively few projects on prevention, survivorship and patient perspectives. CONCLUSION: Our findings established that there is a dearth of public health cancer research in SA. PMID- 27245729 TI - HAART in hand: The change in Kaposi's sarcoma presentation in KwaZulu-Natal, South Africa. AB - BACKGROUND: HIV/AIDS-related Kaposi's sarcoma (HIV-KS) is a public health problem in South Africa (SA). It is AIDS defining. There have been no studies evaluating its prevalence since the national roll-out of highly active antiretroviral therapy (HAART). OBJECTIVE: To evaluate the effect of HAART on the disease profile of HIV-KS in KwaZulu-Natal Province (KZN), SA. METHODS: Charts of patients with histologically confirmed HIV-KS were reviewed at an oncology clinic in KZN. The significance of associations of HAART with age, gender, CD4 count, urban/rural residence, fungating lesions, ulceration and lymphoedema, and treatment delay, was determined by t-tests for normally distributed continuous variables and chi2 tests for categorical variables. Logistic regression models were used to analyse the association of HAART with CD4 count. RESULTS: Of 198 patients, 194 were documented as HIV-positive; 168 (86.6%) were on HAART at the time of their KS diagnosis. The mean CD4 count of 266 cells/MUL was higher than that in previous studies at this site. The mean age at presentation was 36.6 (standard deviation 10.1) years. Females presented at a younger mean age than males (p<0.001). The mean age of females on HAART was 34.7 years and that of males 39.0 years (p=0.003). HAART-naive patients were three times more likely than those receiving HAART (15.4% v. 4.8%) to have visceral involvement (p=0.03). CONCLUSIONS: HAART use has resulted in outcome improvement. Mean age at presentation has increased in the group as a whole and for females in particular. The trend in mean CD4 counts has shown positive growth. Females no longer shoulder a disproportionate burden of disease. PMID- 27245730 TI - Oncogenic and incidental HPV types associated with histologically confirmed cervical intraepithelial neoplasia in HIV-positive and HIV-negative South African women. AB - BACKGROUND: In Africa, data on the relationship between oncogenic human papillomavirus (HPV) types, immune status and cervical preinvasive lesions are lacking. METHODS: We investigated low-risk (lrHPV) and high-risk (hrHPV) HPV types in a cohort of women with cervical intraepithelial neoplasia (CIN) II/III confirmed on histological examination, in an urban setting with a high prevalence of HIV infection. RESULTS: Of 270 women with confirmed CIN II/III, 45 were HIV negative and 225 HIV-positive. HIV-infected women had significantly more HPV type infections, including all HPV (p<0.001) and hrHPV (p=0.014) types. The prevalences of one or more hrHPV type/s were 93.3% and 92.9% in HIV-negative and positive patients, respectively. The most prevalent hrHPV type among HIV-negative women was HPV 16, followed by HPV 52, 31, 35 and 58. Among HIV-positive women, HPV 16 was followed by HPV 58, 35, 51 and 52. Not yet qualifying qualify for highly active antiretroviral therapy (HAART) (CD4 count >350 cells/MUL) or having received HAART for >=12 months were negatively associated with HPV 18, 33, 45, 51, 52, 59 and 82. CONCLUSIONS: In South Africa, burdened by the HIV pandemic, high numbers of high- and low-risk HPV type infections are present in women with cervical preneoplasia. HPV type distribution differs among varying levels of HIV induced immune depletion. PMID- 27245731 TI - Clinical findings and genetic screening for copy number variation mutations in a cohort of South African patients with Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD), with a prevalence of up to 4% in Western countries, appears to be less common in Africa, possibly in part because of genetic factors. African studies investigating the genetic causation of PD are limited. OBJECTIVE: To describe the clinical and genetic findings in a group of black South African patients with PD. METHODS: All black African patients with PD from a tertiary hospital neurology clinic were examined. Symptoms were scored according to the Unified Parkinson's Disease Rating Scale (UPDRS), and patients were classified according to motor features. Genomic DNA was extracted and multiplex ligation-dependent probe amplification was used for detection of copy number variation (CNV) mutations in the known PD-causing genes. RESULTS: Sixteen patients were identified (ages 56 - 82 years). Three had a family history of PD. Classification into motor subtypes showed 44% mixed, 31% akinetic-rigid, and 25% tremor-dominant subtypes. UPDRS scores ranged from 7 to 88, with dementia in 20%. No patient had G2019S LRRK2 and A30P SNCA mutations, and all except one had no CNV mutations in the known PD-causing genes. A female patient (age of onset 50 years, no family history) had a parkin gene heterozygous deletion of exon 4. She had hyperreflexia, bilateral Hoffmann's reflexes, normal plantar responses and no dystonia. CONCLUSION: This group of black African patients showed similar characteristics to patients in Western studies, possibly with a higher proportion having tremor-dominant disease. Genetic analysis showed one parkin gene mutation. The limited knowledge on PD-causing genes and mutations in black populations warrants further studies involving next-generation sequencing approaches. PMID- 27245732 TI - Delay and poor diagnosis of Down syndrome in KwaZulu-Natal, South Africa: A retrospective review of postnatal cytogenetic testing. AB - BACKGROUND: Down syndrome (DS) is the most common chromosomal disorder in newborns. Until 20 years ago DS was considered rare in black African children in South Africa (SA). Lack of awareness of DS on the part of medical staff in SA, and difficulty in diagnosing it, appear to persist. OBJECTIVES: To establish an epidemiological profile of DS and investigate the ability of clinicians in KwaZulu-Natal Province (KZN), SA, to make accurate clinical diagnoses of DS. METHODS: Records at the South African National Blood Service cytogenetic laboratory in Pinetown, KZN, were examined for all tests for clinically suspected DS undertaken during January 2009 - December 2013 and all cytogenetically proven DS test results. Age at diagnosis, the hospital from where the test was sent and type of chromosomal pattern for each confirmed DS test result were recorded. RESULTS: Of a total of 1 578 tests requested, 875 confirmed DS, indicating that clinicians correctly clinically diagnosed DS 55.4% of the time. The average age of cytogenetic diagnosis of DS was 1 year and 20 days. The minimum population prevalence of DS was 0.8/1 000. CONCLUSIONS: The diagnosis of DS is a challenge in KZN, potentiating missed opportunities for early intervention. The relatively low population prevalence of DS may be attributable to a lack of confirmatory cytogenetic tests or missed clinical diagnoses. It may also be attributable to a high mortality rate for children with DS in the province. PMID- 27245733 TI - Psoriatic arthritis: An assessment of clinical, biochemical and radiological features in a single-centre South African cohort. AB - BACKGROUND: Although psoriatic arthritis (PsA) is a well-documented clinical entity, epidemiological, clinical and radiological studies of South African (SA) patients are scarce. OBJECTIVES: To assess clinical, biochemical and radiological features in a single-centre SA cohort. METHODS: We conducted a prospective assessment of the clinical, biochemical and radiological features of 384 consecutive patients with PsA seen at the rheumatology clinic at Prince Mshiyeni Memorial Hospital, Durban, SA, between January 2007 and December 2013. Patients were assessed at enrolment and 6 months after enrolment. They were classified into five groups as described by Moll and Wright, being entered into the group that best described the clinical manifestations. Clinicopathological characteristics recorded at enrolment were age at the time of examination, racial background, personal and family medical history, age and symptoms at the onset of PsA, pattern of joint involvement, joint pain, and the relationship between joint pain and the onset of PsA. RESULTS: Of the patients, 59.1% had a polyarticular presentation indistinguishable from rheumatoid arthritis, 19.0% had distal interphalangeal involvement, 9.1% had spondyloarthropathy, 11.9% had oligoarthritis and 0.9% had arthritis mutilans. The epidemiological trends (male/female ratio 1.45:1, mean age at onset of arthritis 50.2 (standard deviation 11.8) years, female preponderance in the polyarticular group and male preponderance in the spondyloarthropathy and oligoarticular groups) were similar to trends published elsewhere. A notable characteristic of our cohort was the complete absence of black South Africans with PsA. CONCLUSIONS: The complete absence of black South Africans with PsA is interesting. We anticipate that our findings will prompt genetic studies to isolate both protective and susceptibility genes for further elucidating PsA. PMID- 27245734 TI - Hepatitis B infection in HIV-1-infected patients receiving highly active antiretroviral therapy in Lome, Togo: Prevalence and molecular consequences. AB - BACKGROUND: No data are available on HIV/hepatitis B virus (HBV) or hepatitis C virus coinfection in Togo, and patients are not routinely tested for HBV infection. OBJECTIVE: To determine the prevalence of HBV and the risk of HBV drug resistance during antiretroviral treatment in HIV-coinfected patients in Togo. METHOD: This cross-sectional study was carried out in Lome, Togo, from January 2010 to December 2011 among HIV-infected patients who had been on antiretroviral therapy (ART) for at least 6 months. RESULTS: In total, 1 212 patients (74.9% female) living with HIV/AIDS and treated with ART were included in the study. The seroprevalence of hepatitis B surface antigen (HBsAg) was 9.7% (117/1 212; 95% confidence interval (CI) 8.04 - 11.45). Of these 117 HBsAg-positive patients, 16 (13.7%) were hepatitis B e-antigen (HBeAg)-positive, and 115 (98.3%) were on lamivudine. The HBV DNA load was >10 IU/mL in 33/117 patients overall (38%), and in 87.5% of 16 HBeAg-positive patients (p<0.0001). In multivariate analysis, factors associated with HBV DNA load >10 IU/mLwere HBeAg positivity (adjusted odds ratio (aOR) 6.4; p=0.001) and a higher level of education (aOR 6.5; p=0.026). The prevalence of HBV resistance to lamivudine was 13.0% (15/115; 95% CI 7.0 - 19.0). The detected resistance mutations were rtL180M (14/15 patients) and rtM204V/I (15/15). CONCLUSION: The seroprevalence of HBV among ART-treated HIV-infected patients in Togo was 9.7%. The prevalence of HBV lamivudine resistance mutations after 2 years of ART was 13.0%. These results suggest that HBV screening before ART initiation can be based on HBsAg testing. PMID- 27245735 TI - Gun control saves lives. AB - Reducing firearm mortality by means of stricter gun control is one of the most important short- to medium-term measures to address the burden of violence in South Africa, while longer-term interventions and policy measures take effect. PMID- 27245736 TI - First-generation antipsychotics and QTc: any role for mediating variables? AB - OBJECTIVE: Corrected QT (QTc) interval prolongation is often associated with use of first-generation antipsychotics (FGAs). However, other factors require appropriate consideration, including age and gender, the role of other known medications associated with QTc prolongation, and severe comorbid conditions, such as co-occurring alcohol abuse/dependence. We aimed to study potential mediating roles of different, related, candidate variables on QTc. METHODS: We capitalized on data from a large (N = 2366), cross-sectional, national survey, the STAR Network QTc study, using a representative sample of people taking FGAs, and recruited from mental health services across Italy. RESULTS: About one-third of the sample was treated with FGAs, and almost one-tenth of the subjects took a different, additional, drug known to cause QTc prolongation. Our findings confirmed that there is an impact from FGAs, age, gender, alcohol misuse, and concurrent risky drugs on QTc. However, comorbid alcohol abuse/dependence and concurrent risky drugs did not mediate the effect of FGAs on QTc. CONCLUSIONS: Our findings showed that FGAs, concurrent risky drugs, and alcohol use disorders prolonged QTc. FGAs had a direct effect on QTc, confirming the need for clinicians to monitor a risk that could lead to sudden unexplained death. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27245737 TI - Evaluation of Eight Methods for Aligning Orientation of Two Coordinate Systems. AB - The aim of this study was to evaluate eight methods for aligning the orientation of two different local coordinate systems. Alignment is very important when combining two different systems of motion analysis. Two of the methods were developed specifically for biomechanical studies, and because there have been at least three decades of algorithm development in robotics, it was decided to include six methods from this field. To compare these methods, an Xsens sensor and two Optotrak clusters were attached to a Plexiglas plate. The first optical marker cluster was fixed on the sensor and 20 trials were recorded. The error of alignment was calculated for each trial, and the mean, the standard deviation, and the maximum values of this error over all trials were reported. One-way repeated measures analysis of variance revealed that the alignment error differed significantly across the eight methods. Post-hoc tests showed that the alignment error from the methods based on angular velocities was significantly lower than for the other methods. The method using angular velocities performed the best, with an average error of 0.17 +/- 0.08 deg. We therefore recommend this method, which is easy to perform and provides accurate alignment. PMID- 27245738 TI - Diversity of ABC transporter genes across the plant kingdom and their potential utility in biotechnology. AB - BACKGROUND: The ATP-binding cassette (ABC) transporter gene superfamily is ubiquitous among extant organisms and prominently represented in plants. ABC transporters act to transport compounds across cellular membranes and are involved in a diverse range of biological processes. Thus, the applicability to biotechnology is vast, including cancer resistance in humans, drug resistance among vertebrates, and herbicide and other xenobiotic resistance in plants. In addition, plants appear to harbor the highest diversity of ABC transporter genes compared with any other group of organisms. This study applied transcriptome analysis to survey the kingdom-wide ABC transporter diversity in plants and suggest biotechnology applications of this diversity. RESULTS: We utilized sequence similarity-based informatics techniques to infer the identity of ABC transporter gene candidates from 1295 phylogenetically-diverse plant transcriptomes. A total of 97,149 putative (approximately 25 % were full-length) ABC transporter gene members were identified; each RNA-Seq library (plant sample) had 88 +/- 30 gene members. As expected, simpler organisms, such as algae, had fewer unique members than vascular land plants. Differences were also noted in the richness of certain ABC transporter subfamilies. Land plants had more unique ABCB, ABCC, and ABCG transporter gene members on average (p < 0.005), and green algae, red algae, and bryophytes had significantly more ABCF transporter gene members (p < 0.005). Ferns had significantly fewer ABCA transporter gene members than all other plant groups (p < 0.005). CONCLUSIONS: We present a transcriptomic overview of ABC transporter gene members across all major plant groups. An increase in the number of gene family members present in the ABCB, ABCC, and ABCD transporter subfamilies may indicate an expansion of the ABC transporter superfamily among green land plants, which include all crop species. The striking difference between the number of ABCA subfamily transporter gene members between ferns and other plant taxa is surprising and merits further investigation. Discussed is the potential exploitation of ABC transporters in plant biotechnology, with an emphasis on crops. PMID- 27245739 TI - Autophagy promotes ferroptosis by degradation of ferritin. AB - Macroautophagy/autophagy is an evolutionarily conserved degradation pathway that maintains homeostasis. Ferroptosis, a novel form of regulated cell death, is characterized by a production of reactive oxygen species from accumulated iron and lipid peroxidation. However, the relationship between autophagy and ferroptosis at the genetic level remains unclear. Here, we demonstrated that autophagy contributes to ferroptosis by degradation of ferritin in fibroblasts and cancer cells. Knockout or knockdown of Atg5 (autophagy-related 5) and Atg7 limited erastin-induced ferroptosis with decreased intracellular ferrous iron levels, and lipid peroxidation. Remarkably, NCOA4 (nuclear receptor coactivator 4) was a selective cargo receptor for the selective autophagic turnover of ferritin (namely ferritinophagy) in ferroptosis. Consistently, genetic inhibition of NCOA4 inhibited ferritin degradation and suppressed ferroptosis. In contrast, overexpression of NCOA4 increased ferritin degradation and promoted ferroptosis. These findings provide novel insight into the interplay between autophagy and regulated cell death. PMID- 27245741 TI - Prolonged latency of preterm prelabour rupture of membranes and neurodevelopmental outcomes: a secondary analysis. AB - OBJECTIVE: To determine whether prolonged latency after preterm prelabour rupture of membranes (PPROM) is associated with an increased risk for adverse neurodevelopmental outcomes. DESIGN: This is a secondary analysis of the randomised controlled trial of magnesium sulphate for the prevention of cerebral palsy. SETTING: Multicentre trial. POPULATION: A total of 1305 women with PPROM were analysed, 1056 of whom had an interval of <3 weeks between diagnosis and delivery and 249 of whom had an interval of >=3 weeks between diagnosis and delivery. METHODS: We evaluated whether the time interval between diagnosis of PPROM and delivery was associated with an increased risk for adverse neurodevelopmental outcomes. Latency was analysed as a continuous variable and categorised by weeks of latency. MAIN OUTCOME MEASURES: The primary outcome was motor and mental Bayley scores of <70 at 2 years of age. Secondary outcomes included motor and mental Bayley scores <85 and mean Bayley scores. Logistic regression was used to control for confounding factors. RESULTS: In the univariate analysis, motor and mental Bayley scores of <70 were similar in the <3 weeks (16.8 and 14.4%) and >=3 weeks (15.3 and 14.1%) groups. In the regression analysis adjusting for confounding factors, PPROM for >=3 weeks was an independent risk factor for motor (adjusted odds ratio (aOR) 2.12; 95% confidence interval, 95% CI 1.29-3.49) and mental (aOR 1.83, 95% CI 1.13-3.00) Bayley scores of <70. Neonatal sepsis, gestational age at delivery, maternal education, and race were significantly associated with neurodevelopmental outcomes. CONCLUSIONS: Whereas delivery at later gestational age is associated with improved prognosis for many outcomes, prolonged exposure to an intrauterine environment of PPROM is an independent risk factor for adverse neurodevelopmental outcomes. TWEETABLE ABSTRACT: Prolonged PPROM was associated with motor and mental Bayley scores of <70. PMID- 27245742 TI - Quick assessment of the influence of the Hepatitis B vaccine event on children's vaccination. AB - OBJECTIVE: From December 2013 to January 2014, a large number of medias in China reported negative information about Hepatitis B vaccine (HepB) safety issues using eye-catching titles, such as "3 infants in Hunan inoculated with HepB occurred adverse event, and 2 died," and that caused crisis of confidence in vaccination, which we called "HepB event." The progress of "HepB event" could be divided into 3 stages which were initiation, peak and ending stages. In order to evaluate the influence of "HepB event" on the attitudes of participants toward Hepatitis B vaccine safety and their intention of vaccinating their children in different stages, and provide evidence for authority departments as soon as possible to take measures to prevent decrease of HepB coverage rate, a quick field investigation was carried out. METHODS: Using convenience sampling methods during the initiation, peak and ending stages of the "HepB event." RESULTS: In the 3 stages of the "HepB event," the awareness rate of the event among participants was rapidly rising, showing that the participants paid great attention to the event, and the information was spread very quickly. The proportion of participants who knew the event but thought that the Hepatitis B vaccine was unsafe were 31%, 37% and 26% respectively in 3 stages. In addition, the acceptance of vaccination by the participants was influenced, the proportion of participants who would like to delay or reject vaccinating their children was up to 43% in the peak stage of the event. CONCLUSIONS: The "HepB event" had impacted on the participants' confidence in the safety of Hepatitis B vaccine. For such event, relevant authority departments need effectively communicate with the media and the public, and promptly issue positive information and the investigation result, thereby reducing the negative impact of the event, and improve the vaccine confidence among the public. PMID- 27245743 TI - Building a Better Quaternary Ammonium Compound (QAC): Branched Tetracationic Antiseptic Amphiphiles. AB - Bacteria contaminate surfaces in a wide variety of environments, causing severe problems across a number of industries. In a continuation of our campaign to develop novel antibacterial quaternary ammonium compounds (QACs) as useful antiseptics, we have identified a starting material bearing four tertiary amines, enabling the rapid synthesis of several tris- and tetracationic QACs. Herein we report the synthesis and biological activity of a series of 24 multiQACs deemed the "superT" family, and an investigation of the role of cationic charge in antimicrobial and anti-biofilm activity, as well as toxicity. This class represents the most potent series of QACs reported to date against methicillin resistant Staphylococcus aureus (MRSA), with minimum inhibitory concentrations (MICs) and minimum biofilm eradication concentrations (MBECs) as low as 0.25 and 25 MUm, respectively. Based on the significant cell-surface-charge differences between bacterial and eukaryotic cells, in certain cases we observed excellent efficacy-to-toxicity profiles, exceeding a 100-fold differential. This work further elucidates the chemical underpinnings of disinfectant efficacy versus toxicity based on cationic charge. PMID- 27245744 TI - Photoresponsive Liquid Crystalline Epoxy Networks with Shape Memory Behavior and Dynamic Ester Bonds. AB - Functional polymers are intelligent materials that can respond to a variety of external stimuli. However, these materials have not yet found widespread real world applications because of the difficulties in fabrication and the limited number of functional building blocks that can be incorporated into a material. Here, we demonstrate a simple route to incorporate three functional building blocks (azobenzene chromophores, liquid crystals, and dynamic covalent bonds) into an epoxy-based liquid crystalline network (LCN), in which an azobenzene based epoxy monomer is polymerized with an aliphatic dicarboxylic acid to create exchangeable ester bonds that can be thermally activated. All three functional building blocks exhibited good compatibility, and the resulting materials exhibits various photomechanical, shape memory, and self-healing properties because of the azobenzene molecules, liquid crystals, and dynamic ester bonds, respectively. PMID- 27245745 TI - Erratum to: A new co-ultramicronized composite including palmitoylethanolamide and luteolin to prevent neuroinflammation in spinal cord injury. PMID- 27245746 TI - Regular use of pain medication due to musculoskeletal disorders in the general working population: Cross-sectional study among 10,000 workers. AB - BACKGROUND: We aimed to determine the association between work, health, and lifestyle with regular use of pain medication due to musculoskeletal disorders in the general working population. METHODS: Currently employed wage earners (N = 10,024) replied to questions about health, work, and lifestyle. The odds for regularly using medication for musculoskeletal disorders were modeled using logistic regression controlled for various confounders. RESULTS: Pain intensity increased the odds for using pain medication in a dose-response fashion. With seated work as reference, the odds for using pain medication were 1.26 (95%CI: 1.09-1.47) for workers engaged in standing or walking work that is not strenuous and 1.59 (95%CI: 1.39-1.82) for workers engaged in standing or walking work with lifting tasks or heavy and fast strenuous work. CONCLUSIONS: Workers with higher levels of physical activity at work are more likely to use pain medication on a regular basis for musculoskeletal disorders, even when adjusting for pain intensity, lifestyle, and influence at work. Am. J. Ind. Med. 59:934-941, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27245747 TI - Modeling Statistical Insensitivity: Sources of Suboptimal Behavior. AB - Children acquiring languages with noun classes (grammatical gender) have ample statistical information available that characterizes the distribution of nouns into these classes, but their use of this information to classify novel nouns differs from the predictions made by an optimal Bayesian classifier. We use rational analysis to investigate the hypothesis that children are classifying nouns optimally with respect to a distribution that does not match the surface distribution of statistical features in their input. We propose three ways in which children's apparent statistical insensitivity might arise, and find that all three provide ways to account for the difference between children's behavior and the optimal classifier. A fourth model combines two of these proposals and finds that children's insensitivity is best modeled as a bias to ignore certain features during classification, rather than an inability to encode those features during learning. These results provide insight into children's developing knowledge of noun classes and highlight the complex ways in which statistical information from the input interacts with children's learning processes. PMID- 27245748 TI - Evaluation of a subject-specific musculoskeletal modelling framework for load prediction in total knee arthroplasty. AB - Musculoskeletal (MSK) multibody dynamics (MBD) models have been used to predict in vivo biomechanics in total knee arthroplasty (TKA). However, a full lower limb MSK MBD modelling approach for TKA that combines subject-specific skeletal and prosthetic knee geometry has not yet been applied and evaluated over a range of patients. This study evaluated a subject-specific MSK MBD modelling framework for TKA using force-dependent kinematics (FDK) and applied it to predict knee contact forces during gait trials for three patients implanted with instrumented prosthetic knees. The prediction accuracy was quantified in terms of the mean absolute deviation (MAD), root mean square error (RMSE), Pearson correlation coefficient (rho), and Sprague and Geers metrics of magnitude (M), phase (P) and combined error (C). Generally good agreements were found between the predictions and the experimental measurements from all patients for the medial contact forces (150 N < MAD <178 N, 174 N < RMSE < 224 N, 0.87 < rho < 0.95, -0.04 < M < 0.20, 0.06 < P < 0.09, 0.08 < C < 0.22) and the lateral contact force (113 N < MAD <195 N, 131 N < RMSE < 240 N, 0.41 < rho < 0.82, -0.25 < M < 0.34, 0.08 < P < 0.22, 0.13 < C < 0.36). The results suggest that the subject-specific MSK MBD modelling framework for TKA using FDK has potential as a powerful tool for investigating the functional outcomes of knee implants. PMID- 27245749 TI - Monitoring contractile dermal lymphatic activity following uniaxial mechanical loading. AB - It is proposed that direct mechanical loading can impair dermal lymphatic function, contributing to the causal pathway of pressure ulcers. The present study aims to investigate the effects of loading on human dermal lymphatic vessels. Ten participants were recruited with ages ranging from 24 to 61 years. Participants had intradermal Indocyanine Green injections administrated between left finger digits. Fluorescence was imaged for 5min sequences with an infra-red camera prior to lymph vessel loading, immediately after axial loading (60mmHg) and following a recovery period. Image processing was employed to defined transient lymph packets and compare lymph function between each test phase. The results revealed that between 1-8 transient events (median=4) occurred at baseline, with a median velocity of 8.1mm/sec (range 4.1-20.1mm/sec). Immediately post-loading, there was a significant (p<0.05) reduction in velocity (median=6.4, range 2.2-13.5mm/sec), although the number of transient lymph packages varied between participants. During the recovery period the number (range 1-7) and velocity (recovery median=9.6mm/sec) of transient packets were largely restored to basal values. The present study revealed that some individuals present with impaired dermal lymphatic function immediately after uniaxial mechanical loading. More research is needed to investigate the effects of pressure and shear on lymphatic vessel patency. PMID- 27245750 TI - Attention attraction in an ophthalmic diagnostic device using sound-modulated fixation targets. AB - This study relates to eye fixation systems with combined optical and audio systems. Many devices for eye diagnostics and some devices for eye therapeutics require the patient to fixate on a small target for a certain period of time, during which the eyes do not move and data from substructures of one or both eyes are acquired and analyzed. With young pediatric patients, a monotonously blinking target is not sufficient to retain attention steadily. We developed a method for modulating the intensity of a point fixation target using sounds appropriate to the child's age and preference. The method was realized as a subsystem of a Pediatric Vision Screener which employs retinal birefringence scanning for detection of central fixation. Twenty-one children, age 2-18, were studied. Modulation of the fixation target using sounds ensured the eye fixated on the target, and with appropriate choice of sounds, performed significantly better than a monotonously blinking target accompanied by a plain beep. The method was particularly effective with children of ages up to 10, after which its benefit disappeared. Typical applications of target modulation would be as supplemental subsystems in pediatric ophthalmic diagnostic devices, such as scanning laser ophthalmoscopes, optical coherence tomography units, retinal birefringence scanners, fundus cameras, and perimeters. PMID- 27245752 TI - Skin flap complications after cochlear implantations. AB - The objective of the study was to analyse and present the surgical management strategy for major skin flap complications (MSFC) after cochlear implantations. Patients fitted with a titanium-silicone-coated implant of the same kind, operated on between 1994 and 2013 with a standardised procedure (1076 medical charts) were analysed. Analysis aimed to identify and study individuals with skin problems related to the cochlear implant treatment, i.e. requiring surgical treatment in hospital defined as MSFC and focused on incidence, risk factors and treatment of MSFC. MSFC were diagnosed in 1.76 % of patients: 2.06 % of children and 1.35 % of adults, 2.43 % after implantation with a long "C"-shaped incision and 1.28 % after short retroauricular incision. Registered risk factors included head trauma, acute otitis media, poor hygiene in children, and general comorbidities in adults. The primary intervention was dependent on skin complication severity and included revision surgery with wound closure over an implant (52.6 %) and revision surgery with explantation (47.4 %). Revision surgery without explantation was successful in 40 % and the most effective approach was debridement with a two-layer rotational flap. Explantation led to ultimate wound healing in all cases. Major skin flap complications after cochlear implantation are rare, but their treatment is complex and difficult. Revision surgery with resection of infected tissue, formation of a rotational two-layer flap preceded and supplemented by intensive targeted antibiotic therapy can be effective and should be the first treatment option. Spontaneous implant explantation, abscess formation or unsuccessful primary treatment necessitate implant removal as the ultimate solution. PMID- 27245751 TI - Platinum-induced ototoxicity: a review of prevailing ototoxicity criteria. AB - The antineoplastic agent's cisplatin and carboplatin are widely used as they are highly effective. Unfortunately, ototoxicity is a frequently encountered side effect of platinum-based chemotherapy. Clinically, patients generally develop a progressive, bilateral, and irreversible sensorineural hearing loss. With rising cancer survival rates, a greater proportion of patients are living with the side effects of their chemotherapy treatments. Consequently, the quality of life of cancer survivors has now become a major concern for clinicians. Various classification systems are currently available to grade side effects and provide a guideline for subsequent treatments. An extensive review of the literature revealed that a variety of criteria are used worldwide for grading platinum induced hearing loss in children and adults, including the National Cancer Institute criteria, Brock's grading system, the American Speech-Hearing-Language Association criteria, the World Health Organization criteria, the Pediatric Oncology Group criteria, and the Muenster classification. Less commonly used criteria include the Chang classification, the Functional Hearing Loss scale, the HIT system (German Hirntumor study grading system), and most recently, the International Society of Pediatric Oncology Boston ototoxicity grading scale. The objective of this review is to evaluate the commonly used ototoxicity criteria and discuss their benefits and limitations. PMID- 27245753 TI - How do older people describe their sensory experiences of the natural world? A systematic review of the qualitative evidence. AB - BACKGROUND: Despite the increased scholarly interest in the senses and sensory experiences, the topic of older people's sensory engagement with nature is currently under researched. This paper reviews and synthesises qualitative research evidence about how older people, including those living with dementia, describe their sensory engagement with the natural world. METHODS: Ten databases were searched from 1990 to September 2014: MEDLINE (Ovid), MEDLINE-in-Process (Ovid), PsycINFO (Ovid), CINAHL (EBSCO), GreenFILE (EBSCO), ProQuest Sociology, ASSIA (ProQuest), International Bibliography of the Social Sciences (ProQuest); HMIC (Ovid); Social Policy and Practice (Ovid). Forward and backward citation chasing of included articles was conducted; 20 organizations were contacted to identify unpublished reports. Screening was undertaken independently by two reviewers. RESULTS: Twenty seven studies were included. Thematic analysis revealed that descriptions of sensory experiences are encompassed within six themes: descriptions from 'the window'; sensory descriptions that emphasise vision; descriptions of 'being in nature'; descriptions of 'doing in nature'; barriers to sensory engagement; and meanings of being and doing in nature. CONCLUSIONS: Older people derive considerable pleasure and enjoyment from viewing nature, being and doing in nature which, in turn has a positive impact on their wellbeing and quality of life. Future research could usefully explore how sensory engagement with nature could be used to stimulate reminiscences of places and people, and evoke past sensory experiences to enrich everyday life and maintain a sense of self. The protocol was registered with PROSPERO ( CRD42015020736 ). PMID- 27245754 TI - Personality disorders and Axis I comorbidity in adolescent outpatients with ADHD. AB - BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a lifelong condition which carries great cost to society and has an extensive comorbidity. It has been assumed that ADHD is 2 to 5 times more frequent in boys than in girls. Several studies have suggested developmental trajectories that link ADHD and certain personality disorders. The present study investigated the prevalence of ADHD, common Axis I disorders, and their gender differences in a sample of adolescent outpatients. We also wanted to investigate the relationship between ADHD and personality disorders (PDs), as well as how this relationship was influenced by adjustment for Axis I disorders, age and gender. METHODS: We used a sample consisting of 153 adolescents, aged 14 to 17 years, who were referred to a non-specialized mental health outpatient clinic with a defined catchment area. ADHD, conduct disorder (CD) and other Axis I conditions were assessed using the Mini International Neuropsychiatric Interview (MINI). PDs were assessed using the Structured Interview for DSM-IV Personality (SIDP-IV). RESULTS: 13.7 % of the adolescents met diagnostic criteria for ADHD, with no significant gender difference. 21.6 % had at least one PD, 17.6 % had CD, and 4.6 % had both ADHD and a PD. There was a significantly elevated number of PD symptoms in adolescents with an ADHD diagnosis (p = 0.001), and this relationship was not significantly weakened when adjusted for age, gender and other Axis I disorders (p = 0.026). Antisocial (chi (2) = 21.18, p = 0.002) and borderline (chi (2) = 6.15, p = 0.042) PDs were significantly more frequent in girls than in boys with ADHD. CONCLUSIONS: We found no significant gender difference in the prevalence of ADHD in a sample of adolescents referred to a general mental health outpatient clinic. Adolescent girls with ADHD had more PDs than boys, with antisocial and borderline PDs significantly different. The present study suggests that ADHD in girls in a general outpatient population may be more prevalent than previously assumed. It especially highlights the importance of assessing antisocial and borderline personality pathology in adolescent girls presenting with ADHD symptoms. PMID- 27245755 TI - Reproductive trends in females with inflammatory joint disease. AB - BACKGROUND: The study assessed birth trends per decade in offspring of females with inflammatory joint diseases (IJD) compared with women without IJD. METHODS: This retrospective cohort study is based on data from the Medical Birth Registry of Norway from 1967 to 2009. We investigated singleton births in females with IJD (n = 7502) and compared with births from the general population (n = 2 437 110). Four periods were examined: 1967-79, 1980-89, 1990-99 and 2000-09. In the logistic regression analysis adjustments were made for maternal age at delivery and birth order. Odds ratios were obtained for the associations between IJD and birth outcome for each period. RESULTS: Females with IJD had in average 65 deliveries / year (0.08 % of all births) in the 1970ies and 274 deliveries / year (0.5 % of all births) from 2000 to 2009. Adjusted Odds ratios (aOR) for newborns small for gestational age were 1.5 (95 % CI 1.2, 1.9) in the earliest and 1.1 (95 % CI 0.9, 1.2) in the last period. Correspondingly, for birth weight < 2500 grams aOR decreased from 1.4 (95 % CI 1.0, 1.9) to 1.1 (95 % CI 0.9, 1.4). For preterm birth aOR was 1.1 (95 % CI 0.8, 1.5) in the first and 1.3 (95 % CI (1.1, 1.5) in the last period. CONCLUSION: An increasing number of births among females with IJD were observed in the study period. Birth weights of newborns of IJD women approached to birth weights in the general population, but preterm birth remained a problem. PMID- 27245756 TI - Identification and antifungal susceptibility of Candida species isolated from bloodstream infections in Konya, Turkey. AB - BACKGROUND: In this study, our aim was to identify Candida species isolated from bloodstream infections and to determine their susceptibilities to various antifungal agents to demonstrate the local resistance profiles and to guide empirical treatment for clinicians. METHODS: Two hundred Candida isolates (95 Candida albicans, 105 non-albicans Candida strains) were included in the study. Candida species were identified by conventional, biochemical and molecular methods. Antifungal susceptibility tests for amphotericin B, fluconazole, voriconazole, posaconazole, caspofungin and anidulafungin were performed with broth microdilution method according to the Clinical and Laboratory Standards Institute M27-A3 document. RESULTS: Of the 200 Candida strains, the most prevalent species were C. albicans (47.5 %), Candida glabrata (18.0 %) and Candida parapsilosis complex (14.0 %). All Candida species except for three (1.5 %) Candida kefyr strains were susceptible to amphotericin B. Only one (2.8 %) C. glabrata was resistant to fluconazole (MIC >= 64 MUg/ml), and the others (97.2 %) exhibited dose-dependent susceptibility. All species, but C. glabrata strains, were susceptible to fluconazole. Resistance to voriconazole, posaconazole, caspofungin and anidulafungin was not detected in any strain. CONCLUSION: Candida albicans were susceptible to all antifungal drugs. Three C. kefyr strains were resistant to amphotericin B. Only one C. glabrata was resistant to fluconazole. All the strains were susceptible to voriconazole, posaconazole, caspofungin and anidulafungin. In vitro antifungal susceptibility tests should be performed to select of appropriate and effective antifungal therapy, and monitor the development of resistance. PMID- 27245757 TI - Promoter methylation and mRNA expression of HLA-G in relation to HLA-G protein expression in colorectal cancer. AB - Expression of human leukocyte antigen-G (HLA-G) is a suggested mechanism used by tumor cells to escape from host immune recognition and destruction. Advances in the field have made it evident that HLA-G is expressed in different types of malignancies including colorectal cancer (CRC). We analyzed HLA-G expression in 21 low passage CRC cell lines. The level of DNA methylation of the HLA-G gene and the presence of mRNA encoding HLA-G was measured. Moreover, HLA-G protein expression was determined by flow cytometry and immunohistochemistry (IHC). IHC was performed with three different monoclonal antibodies (mAbs) (4H84, MEM-G/1 and MEM-G/2). In addition, HLA-G protein expression was measured in matching primary tumor tissues. RNA analysis using RT-PCR followed by sequencing in 6 samples indicated strong homology of the PCR product with HLA-G3 in 5 samples. In accordance, in none of the cell lines, HLA-G1 expression was detected by flow cytometry. Furthermore, no association between HLA-G DNA methylation patterns and HLA-G mRNA expression was observed. In addition, different immunohistochemical staining profiles among various anti-HLA-G mAbs were observed. In conclusion, the results of this study show that the HLA-G3 isoform was expressed in some of the CRC cell lines irrespective of the level of DNA methylation of HLA-G. PMID- 27245758 TI - Is (18)FDG uptake useful to decide on chemotherapy in ER+/HER2- breast cancer? PMID- 27245759 TI - The relationship between physical aggression, foreign policy and moral choices: Phenotypic and genetic findings. AB - Previous work has demonstrated that both leaders and other individuals vary in dispositional levels of physical aggression, which are genetically influenced. Yet the importance of individual differences in aggression for attitudes toward foreign policy or context-laden moral choices, such as sacrificing the lives of some for the greater good of many, has yet to be fully explored. Given the global importance of such decisions, we undertook this exploration in a sample of 586 Australians, including 250 complete twin pairs. We found that individuals who scored higher on Buss-Perry's physical aggression scale were more likely to support aggressive foreign policy interventions and displayed a more utilitarian moral calculus than those who scored lower on this scale. Furthermore, we found that the majority of variance in physical aggression lay in genetic factors for men, whereas the majority of the variance was in environmental factors for women. The source of covariation between aggression and political choices also differed between the sexes. A combination of genetic and environmental factors accounted for most of the cross-trait correlations among males, whereas common and unique environmental factors accounted for most of the cross-trait correlations among females. We consider the implications of our results for understanding how trait measures of aggression are associated with foreign policy and moral choices, providing evidence for why and how individuals differ in responding to complex social dilemmas. Aggr. Behav. 43:37-46, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27245761 TI - Integrative Nutrition and Health Models Targeting Low-Income Populations: A Pilot Intervention in Three Food Banks. PMID- 27245760 TI - Predictors of Supratentorial Deep Intracerebral Hemorrhage Volume and Their Effect on Short-Term Mortality in Asians. AB - BACKGROUND: The volume of intracerebral hemorrhage (ICH) measured at hospital admission is the strongest predictor of clinical outcomes in patients with ICH. Despite the high incidence rate of ICH in Asians, there is lack of data regarding predictors of ICH volume in this ethnic group. The purpose of this study was to determine predictors of deep ICH volume and examine their effect on short-term mortality in Asians. METHODS: Hematoma volume was measured using the ABC/2 method. ICH volume was transformed to the natural log scale to normalize distributions for all analyses. We estimated the coefficients of ICH volume based on relevant predictors using multivariable linear regression. We also determined the association between body mass index (BMI) and ICH volume using a regression line and a line determined by a locally weighted scatter plot smoothing. RESULTS: A total of 1,039 patients from 2 twin hospitals in Korea who were admitted with primary spontaneous supratentorial deep ICH over a 12-year period were enrolled in this study. The median ICH volume was 19.7 ml. The average patient age was 59.2, and 62.4% of patients were men. The mean ICH volume showed a gradual, approximately 2% decrease per 1 BMI increase in the current study, after adjusting for all relevant variables (beta = -0.024; SE 0.004; p < 0.001). In addition, patients with frequent alcohol consumption showed a 10% increase in mean ICH volume (beta = 0.098; SE 0.041; p = 0.016), and patients undergoing warfarin treatment showed a 30% increase in mean ICH volume after full adjustment of all relevant variables (beta = 0.296; SE 0.050; p < 0.001). Relative to overweight patients, there was a 47, 11, and 18% increase in admission mean ICH volume in underweight, normal weight and obese patients, respectively. Patients in the first quartile and underweight BMI groups had 1.45-fold (hazard ratio (HR) 1.45; 95% CI 1.03-2.03; p = 0.035) and 1.77-fold (HR 1.77; 95% CI 1.10-2.84; p = 0.019) higher increased risk of death during the first 3 months after ICH, retrospectively. In addition, patients in groups with frequent alcohol consumption and warfarin use both showed a significant association with mortality 90 days after ICH. CONCLUSIONS: We demonstrated the association between various predictors and admission ICH volume with short-term mortality in Asians. Further studies are needed to account for these observations and determine their underlying mechanisms. PMID- 27245762 TI - Evaluation of a Modified Italian European Prospective Investigation into Cancer and Nutrition Food Frequency Questionnaire for Individuals with Celiac Disease. AB - BACKGROUND: To date, it is unclear whether individuals with celiac disease following a gluten-free (GF) diet for several years have adequate intake of all recommended nutrients. Lack of a food frequency questionnaire (FFQ) for individuals with celiac disease could be partly responsible for this still debated issue. OBJECTIVE: The aim of the study is to evaluate the performance of a modified European Prospective Investigation into Cancer and Nutrition (EPIC) FFQ in estimating nutrient and food intake in a celiac population. DESIGN: In a cross-sectional study, the dietary habits of individuals with celiac disease were reported using a modified Italian EPIC FFQ and were compared to a 7-day weighed food record as a reference method. PARTICIPANTS/SETTING: A total of 200 individuals with histologically confirmed celiac disease were enrolled in the study between October 2012 and August 2014 at the Center for Prevention and Diagnosis of Celiac Disease (Milan, Italy). MAIN OUTCOME MEASURES: Nutrient and food category intake were calculated by 7-day weighed food record using an Italian food database integrated with the nutrient composition of 60 GF foods and the modified EPIC FFQ, in which 24 foods were substituted with GF foods comparable for energy and carbohydrate content. STATISTICAL ANALYSES PERFORMED: An evaluation of the modified FFQ compared to 7-day weighed food record in assessing the reported intake of nutrient and food groups was conducted using Spearman's correlation coefficients and weighted kappa. RESULTS: One hundred individuals completed the study. The Spearman's correlation coefficients of FFQ and 7-day weighed food record ranged from .13 to .73 for nutrients and from .23 to .75 for food groups. A moderate agreement, which was defined as a weighted kappa value of .40 to .60, was obtained for 30% of the analyzed nutrients, and 40% of the nutrients showed values between .30 and .40. The weighted kappa exceeded .40 for 60% of the 15 analyzed food groups. CONCLUSIONS: The modified EPIC FFQ demonstrated moderate congruence with a weighed food record in ranking individuals by dietary intakes, particularly food groups. PMID- 27245763 TI - A name for the 'blueberry tetra', an aquarium trade popular species of Hyphessobrycon Durbin (Characiformes, Characidae), with comments on fish species descriptions lacking accurate type locality. AB - A new species of Hyphessobrycon is described from a tributary of the upper Rio Tapajos, Amazon basin, Mato Grosso, Brazil. Its exuberant colour in life, with blue to purple body and red fins, is appreciated in the aquarium trade. Characters to diagnose the new species from all congeners are the presence of a single humeral blotch, absence of a distinct caudal-peduncle blotch, absence of a well-defined dark mid-lateral stripe on body, the presence of 16-18 branched anal fin rays, nine branched dorsal-fin rays and six branched pelvic-fin rays. A brief comment on fish species descriptions solely based on aquarium material and its consequence for conservation policies is provided. PMID- 27245764 TI - Reproducibility of placental maturity grade classification using a dynamic ultrasonography. AB - OBJECTIVE: To evaluate the agreement between ultrasonographers in classifying placental maturity grade using examination videos. METHODS: A prospective, cross sectional study was conducted using 25 videos of ultrasonographic examinations of single, healthy pregnancies >= 34 + 0 weeks. The Grannum (grades 0, I, II and III) and Julio (grades 0, 1, 2A, 2B and 3) classifications were used for placental maturity grade. The videos were evaluated on two occasions by 10 experienced ultrasonographers. Intra- and inter-observer agreements were evaluated using the Kappa (k) coefficient of agreement. RESULTS: According to the Grannum classification, the inter-observer agreement coefficients were good for grades III and 0 (k = 0.69 and 0.738, respectively) and moderate for grades I and II (k = 0.401 and 0.593, respectively) placentas. According to the Julio classification, the inter-observer agreement coefficients were good for grades 0 and 3 (k = 0.738 and 0.651, respectively), moderate for grades 1 and 2A (0.401 and 0.413, respectively) and poor for grade 2B (k = 0.161). Intra-observer coefficients for the Grannum and Julio classifications ranged from 0.567 to 0.890 and from 0.446 to 0.790, respectively. CONCLUSION: Placental maturity grading using the Grannum and Julio classifications demonstrated moderate/good intra- and inter-observer agreements on examination videos evaluation. PMID- 27245766 TI - Facile Fabrication of Well-Dispersed Pt Nanoparticles in Mesoporous Silica with Large Open Spaces and Their Catalytic Applications. AB - In this paper, a facile strategy is reported for the preparation of well dispersed Pt nanoparticles in ordered mesoporous silica (Pt@OMS) by using a hybrid mesoporous phenolic resin-silica nanocomposite as the parent material. The phenolic resin polymer is proposed herein to be the key in preventing the aggregation of Pt nanoparticles during their formation process and making contributions both to enhance the surface area and enlarge the pore size of the support. The Pt@OMS proves to be a highly active and stable catalyst for both gas phase oxidation of CO and liquid-phase hydrogenation of 4-nitrophenol. This work might open new avenues for the preparation of noble metal nanoparticles in mesoporous silica with unique structures for catalytic applications. PMID- 27245765 TI - Behavioral Profiles Associated with Objective Sleep Duration in Young Children with Insomnia Symptoms. AB - Based on previous studies reporting on the association of objective sleep duration and physiologic changes (i.e., increased cortisol) in children, we examined the role of objective sleep duration on differentiating behavioral profiles in children with insomnia symptoms. Seven hundred children (ages 5-12, 47.8% male) from the Penn State Child Cohort underwent a nine-hour polysomnography and parent completed Pediatric Behavior Scale. Insomnia symptoms were defined as parent report of difficulty falling and/or staying asleep, sleep disordered breathing as an AHI of >=1, and objective short sleep duration as a total sleep time < 7.7 h. Children with insomnia symptoms demonstrated more overall behavioral problems than controls. Significant interactions between insomnia symptoms and objective sleep duration on scores of externalizing behaviors, mood variability and school problems were found. Profile analyses showed that children with insomnia symptoms and normal sleep duration were associated with clinically elevated externalizing behaviors, inattention, mood variability, and school problems, while children with insomnia and short sleep duration were associated with an overall elevated profile in which internalizing behaviors were more prominent. Childhood insomnia symptoms are associated with a wide array of behavioral problems, for which objective sleep duration is useful in differentiating behavioral profiles. Children with insomnia symptoms and normal sleep duration had a behavioral profile consistent with limit-setting and rule-breaking behaviors, while children with insomnia symptoms and short sleep duration had a behavioral profile more consistent with internalizing behaviors resembling that of psychophysiological disorders. PMID- 27245767 TI - Stability of an ERP-based measure of brain network activation (BNA) in athletes: A new electrophysiological assessment tool for concussion. AB - PRIMARY OBJECTIVE: To determine test-re-test reliabilities of novel Evoked Response Potential (ERP)-based Brain Network Activation (BNA) scores in healthy athletes. RESEARCH DESIGN: Observational, repeated-measures study. METHODS AND DESIGN: Forty-two healthy male and female high school and collegiate athletes completed auditory oddball and go/no-go ERP assessments at baseline, 1 week, 6 weeks and 1 year. The BNA algorithm was applied to the ERP data, considering electrode location, frequency band, peak latency and normalized amplitude to generate seven unique BNA scores for each testing session. MAIN OUTCOMES AND RESULTS: Mean BNA scores, intra-class correlation coefficient (ICC) values and reliable change (RC) values were calculated for each of the seven BNA networks. BNA scores ranged from 46.3 +/- 34.9 to 69.9 +/- 22.8, ICC values ranged from 0.46-0.65 and 95% RC values ranged from 38.3-68.1 across the seven networks. CONCLUSIONS: The wide range of BNA scores observed in this population of healthy athletes suggests that a single BNA score or set of BNA scores from a single after-injury test session may be difficult to interpret in isolation without knowledge of the athlete's own baseline BNA score(s) and/or the results of serial tests performed at additional time points. The stability of each BNA network should be considered when interpreting test-re-test BNA score changes. PMID- 27245768 TI - Several synthetic progestins disrupt the glial cell specific-brain aromatase expression in developing zebra fish. AB - The effects of some progestins on fish reproduction have been recently reported revealing the hazard of this class of steroidal pharmaceuticals. However, their effects at the central nervous system level have been poorly studied until now. Notwithstanding, progesterone, although still widely considered primarily a sex hormone, is an important agent affecting many central nervous system functions. Herein, we investigated the effects of a large set of synthetic ligands of the nuclear progesterone receptor on the glial-specific expression of the zebrafish brain aromatase (cyp19a1b) using zebrafish mechanism-based assays. Progesterone and 24 progestins were first screened on transgenic cyp19a1b-GFP zebrafish embryos. We showed that progesterone, dydrogesterone, drospirenone and all the progesterone-derived progestins had no effect on GFP expression. Conversely, all progestins derived from 19-nortesterone induced GFP in a concentration-dependent manner with EC50 ranging from the low nM range to hundreds nM. The 19 nortestosterone derived progestins levonorgestrel (LNG) and norethindrone (NET) were further tested in a radial glial cell context using U251-MG cells co transfected with zebrafish ER subtypes (zfERalpha, zfERbeta1 or zfERbeta2) and cyp19a1b promoter linked to luciferase. Progesterone had no effect on luciferase activity while NET and LNG induced luciferase activity that was blocked by ICI 182,780. Zebrafish-ERs competition assays showed that NET and LNG were unable to bind to ERs, suggesting that the effects of these compounds on cyp19a1b require metabolic activation prior to elicit estrogenic activity. Overall, we demonstrate that 19-nortestosterone derived progestins elicit estrogenic activity by inducing cyp19a1b expression in radial glial cells. Given the crucial role of radial glial cells and neuro-estrogens in early development of brain, the consequences of exposure of fish to these compounds require further investigation. PMID- 27245769 TI - CORR Insights((r)): The NLRP3/Caspase-1/Interleukin-1beta Axis Is Active in Human Lumbar Cartilaginous Endplate Degeneration. PMID- 27245770 TI - CORR Insights((r)): Tendon Collagen Crosslinking Offers Potential to Improve Suture Pullout in Rotator Cuff Repair: An Ex Vivo Sheep Study. PMID- 27245771 TI - The Perry Initiative's Medical Student Outreach Program Recruits Women Into Orthopaedic Residency. AB - BACKGROUND: Orthopaedic surgery lags behind other surgical specialties in terms of gender diversity. The percentage of women entering orthopaedic residency persistently remains at 14% despite near equal ratios of women to men in medical school classes. This trend has been attributed to negative perceptions among women medical students of workplace culture and lifestyle in orthopaedics as well as lack of exposure, particularly during medical school when most women decide to enter the field. Since 2012, The Perry Initiative, a nonprofit organization that is focused on recruiting and retaining women in orthopaedics, had conducted extracurricular outreach programs for first- and second-year female medical students to provide exposure and mentoring opportunities specific to orthopaedics. This program, called the Medical Student Outreach Program (MSOP), is ongoing at medical centers nationwide and has reached over 300 medical students in its first 3 program years (2012-2014). QUESTIONS/PURPOSES: (1) What percentage of MSOP participants eventually match into orthopaedic surgery residency? (2) Does MSOP impact participants' perceptions of the orthopaedics profession as well as intellectual interest in the field? METHODS: The percentage of program alumnae who matched into orthopaedics was determined by annual followup for our first two cohorts who graduated from medical school. All program participants completed a survey immediately before and after the program that assessed the impact of MSOP on the student's intention to pursue orthopaedics as well as perceptions of the field and intellectual interest in the discipline. RESULTS: The orthopaedic surgery match rate for program participants was 31% in our first graduating class (five of 16 participants in 2015) and 28% in our second class (20 of 72 participants in 2016). Pre/post program comparisons showed that the MSOP influenced students' perceptions of the orthopaedics profession as well as overall intellectual interest in the field. CONCLUSIONS: The results of our study suggest that The Perry Initiative's MSOP positively influences women to choose orthopaedic surgery as a profession. The match rate for program alumnae is twice the percentage of females in current orthopaedic residency classes. Given these positive results, MSOP can serve as a model, both in its curricular content and logistic framework, for other diversity initiatives in the field. PMID- 27245772 TI - CORR Insights((r)): Are Females at Greater Risk for Revision Surgery After Hip Resurfacing Arthroplasty With the Articular Surface Replacement Prosthesis? PMID- 27245773 TI - Feedback on Measured Dust Concentrations Reduces Exposure Levels Among Farmers. AB - BACKGROUND: The high burden of exposure to organic dust among livestock farmers warrants the establishment of effective preventive and exposure control strategies for these workers. The number of intervention studies exploring the effectiveness of exposure reduction strategies through the use of objective measurements has been limited. OBJECTIVE: To examine whether dust exposure can be reduced by providing feedback to the farmers concerning measurements of the exposure to dust in their farm. METHODS: The personal dust levels of farmers in 54 pig and 26 dairy cattle farms were evaluated in two measurement series performed approximately 6 months apart. Detailed information on work tasks and farm characteristics during the measurements were registered. Participating farms were randomized a priori to a control (n = 40) and an intervention group (n = 40). Shortly after the first visit, owners of intervention farms only received a letter with information on the measured dust concentrations in the farm together with some general advises on exposure reduction strategies (e.g. use of respirators during certain tasks). Relationships between measured dust concentrations and intervention status were quantified by means of linear mixed effect analysis with farm and worker id as random effects. Season, type of farming, and work tasks were treated as fixed effects. Changes in exposure over time were explored primarily at a farm level in models combined, as well as separate for pig and cattle farmers. RESULTS: After adjustment for fixed effects, an overall reduction of 23% in personal dust exposures was estimated as a result of the intervention (P = 0.02). Exposure reductions attributable to the intervention were similar across pig and cattle farmers, but statistically significant only for pig farmers. Intervention effects among pig farmers did not depend on the individuals' information status; but among cattle farmers a significant 48% reduction in exposure was found only among individuals that reported to have been informed. No systematic differences in changes over time considering the use of respiratory protection between the intervention and control groups were observed. CONCLUSION: The results of the present study suggest reductions between 20 and 30% in personal exposure to inhalable dust to be feasible through simple information provided to the farm owners regarding actual levels of exposure together with instructions on basic measures of prevention. The exact reasons for these effects are unclear, but likely they involve changes in behavior and working practices among intervention farmers. PMID- 27245774 TI - A Foundation for Enterprise Imaging: HIMSS-SIIM Collaborative White Paper. AB - Care providers today routinely obtain valuable clinical multimedia with mobile devices, scope cameras, ultrasound, and many other modalities at the point of care. Image capture and storage workflows may be heterogeneous across an enterprise, and as a result, they often are not well incorporated in the electronic health record. Enterprise Imaging refers to a set of strategies, initiatives, and workflows implemented across a healthcare enterprise to consistently and optimally capture, index, manage, store, distribute, view, exchange, and analyze all clinical imaging and multimedia content to enhance the electronic health record. This paper is intended to introduce Enterprise Imaging as an important initiative to clinical and informatics leadership, and outline its key elements of governance, strategy, infrastructure, common multimedia content, acquisition workflows, enterprise image viewers, and image exchange services. PMID- 27245775 TI - Efficient scheme for hybrid teleportation via entangled coherent states in circuit quantum electrodynamics. AB - We propose a deterministic scheme for teleporting an unknown qubit state through continuous-variable entangled states in superconducting circuits. The qubit is a superconducting two-level system and the bipartite quantum channel is a microwave photonic entangled coherent state between two cavities. A Bell-type measurement performed on the hybrid state of solid and photonic states transfers a discrete variable unknown electronic state to a continuous-variable photonic cat state in a cavity mode. In order to facilitate the implementation of such complex protocols we propose a design for reducing the self-Kerr nonlinearity in the cavity. The teleporation scheme enables quantum information processing operations with circuit-QED based on entangled coherent states. These include state verification and single-qubit operations with entangled coherent states. These are shown to be experimentally feasible with the state of the art superconducting circuits. PMID- 27245776 TI - Coping, uncertainty and health-related quality of life as determinants of anxiety and depression on a sample of hospitalized cardiac patients in Southern Italy. AB - OBJECTIVES: Being hospitalized often causes psychological distress and compromises patients' psychological well-being, thereby augmenting the burden of illness. The aim of this paper is to investigate two possible determinants of anxiety and depression among hospitalized cardiac patients, namely uncertainty in illness, and coping strategies, controlling for the perceived health-related quality of life, and distinguishing between borderline and pathological levels of anxiety and depression. METHODS: Data on anxiety, depression, coping style, uncertainty in illness and self-assessed quality of life concerning 200 cardiac inpatients from a university hospital were collected through validated questionnaires. A biprobit analysis, whose dependent variables are hospital anxiety and depression, was carried out. RESULTS: Uncertainty in illness has a significant impact on the possibility of crossing the borderline level of both anxiety and depression. The coping strategy of Positive Reappraisal and Growth is inversely and significantly correlated to anxiety and depression, be it borderline or pathological; the Restraint Coping strategy is positively and significantly related to borderline anxiety. CONCLUSIONS: The reduction of uncertainty in illness and the development of adequate coping strategies should be promoted in order to decrease the patients' risk of crossing the borderline threshold of anxiety and depression. PMID- 27245777 TI - Phenylketonuria patients' and their parents' acceptance of the disease: multi centre study. AB - PURPOSE: Phenylketonuria (PKU) still poses a therapeutic challenge for patients and medical professionals. The aim of the study was to assess both patients' and their parents' acceptance of the disease. METHODS: The study included 218 PKU patients and 178 parents of PKU children who were enrolled in the study on the basis of questionnaire data. RESULTS: Regarding attitude towards the disease, our study demonstrated that 63 (28.9 %) PKU patients did not accept the disease. Patients who found accepting the disease difficult, more frequently perceived themselves as inferior/different in comparison with their peers. In total, 36 % of patients did not want their friends to be aware of their condition, while only 18 % of parents believed that their children's peers should not know about their disease. In total, 42 % of parents wanted to talk to other parents of PKU children and only 13 % to a doctor. Only 20 % of patients saw the need to discuss their condition with a doctor. In total, 8 % of children, regardless of age, and 14 % of parents preferred to talk to a psychologist. CONCLUSION: Our data demonstrated that disease acceptance played an essential role in patients' social integration. The study also indicated the need to overcome communication barriers between patients and their healthy peers and for patients to find the courage to be open about the disease. The importance of support groups for PKU families and the significance of strict cooperation between patients and their families with PKU treatment teams were also revealed. PMID- 27245779 TI - A diagnostic model for chronic hypersensitivity pneumonitis. AB - The objective of this study was to develop a diagnostic model that allows for a highly specific diagnosis of chronic hypersensitivity pneumonitis using clinical and radiological variables alone. Chronic hypersensitivity pneumonitis and other interstitial lung disease cases were retrospectively identified from a longitudinal database. High-resolution CT scans were blindly scored for radiographic features (eg, ground-glass opacity, mosaic perfusion) as well as the radiologist's diagnostic impression. Candidate models were developed then evaluated using clinical and radiographic variables and assessed by the cross validated C-statistic. Forty-four chronic hypersensitivity pneumonitis and eighty other interstitial lung disease cases were identified. Two models were selected based on their statistical performance, clinical applicability and face validity. Key model variables included age, down feather and/or bird exposure, radiographic presence of ground-glass opacity and mosaic perfusion and moderate or high confidence in the radiographic impression of chronic hypersensitivity pneumonitis. Models were internally validated with good performance, and cut-off values were established that resulted in high specificity for a diagnosis of chronic hypersensitivity pneumonitis. PMID- 27245778 TI - The IL-4/STAT6 signaling axis establishes a conserved microRNA signature in human and mouse macrophages regulating cell survival via miR-342-3p. AB - BACKGROUND: IL-4-driven alternative macrophage activation and proliferation are characteristic features of both antihelminthic immune responses and wound healing in contrast to classical macrophage activation, which primarily occurs during inflammatory responses. The signaling pathways defining the genome-wide microRNA expression profile as well as the cellular functions controlled by microRNAs during alternative macrophage activation are largely unknown. Hence, in the current work we examined the regulation and function of IL-4-regulated microRNAs in human and mouse alternative macrophage activation. METHODS: We utilized microarray-based microRNA profiling to detect the dynamic expression changes during human monocyte-macrophage differentiation and IL-4-mediated alternative macrophage activation. The expression changes and upstream regulatory pathways of selected microRNAs were further investigated in human and mouse in vitro and in vivo models of alternative macrophage activation by integrating small RNA-seq, ChIP-seq, ChIP-quantitative PCR, and gene expression data. MicroRNA-controlled gene networks and corresponding functions were identified using a combination of transcriptomic, bioinformatic, and functional approaches. RESULTS: The IL-4 controlled microRNA expression pattern was identified in models of human and mouse alternative macrophage activation. IL-4-dependent induction of miR-342-3p and repression of miR-99b along with miR-125a-5p occurred in both human and murine macrophages in vitro. In addition, a similar expression pattern was observed in peritoneal macrophages of Brugia malayi nematode-implanted mice in vivo. By using IL4Ralpha- and STAT6-deficient macrophages, we were able to show that IL-4-dependent regulation of miR-342-3p, miR-99b, and miR-125a-5p is mediated by the IL-4Ralpha-STAT6 signaling pathway. The combination of gene expression studies and chromatin immunoprecipitation experiments demonstrated that both miR-342-3p and its host gene, EVL, are coregulated directly by STAT6. Finally, we found that miR-342-3p is capable of controlling macrophage survival through targeting an anti-apoptotic gene network including Bcl2l1. CONCLUSIONS: Our findings identify a conserved IL-4/STAT6-regulated microRNA signature in alternatively activated human and mouse macrophages. Moreover, our study indicates that miR-342-3p likely plays a pro-apoptotic role in such cells, thereby providing a negative feedback arm to IL-4-dependent macrophage proliferation. PMID- 27245780 TI - Hypoxia and tissue destruction in pulmonary TB. AB - BACKGROUND: It is unknown whether lesions in human TB are hypoxic or whether this influences disease pathology. Human TB is characterised by extensive lung destruction driven by host matrix metalloproteinases (MMPs), particularly collagenases such as matrix metalloproteinase-1 (MMP-1). METHODS: We investigated tissue hypoxia in five patients with PET imaging using the tracer [18F] fluoromisonidazole ([18F]FMISO) and by immunohistochemistry. We studied the regulation of MMP secretion in primary human cell culture model systems in normoxia, hypoxia, chemical hypoxia and by small interfering RNA (siRNA) inhibition. RESULTS: [18F]FMISO accumulated in regions of TB consolidation and around pulmonary cavities, demonstrating for the first time severe tissue hypoxia in man. Patlak analysis of dynamic PET data showed heterogeneous levels of hypoxia within and between patients. In Mycobacterium tuberculosis (M.tb) infected human macrophages, hypoxia (1% pO2) upregulated MMP-1 gene expression 170-fold, driving secretion and caseinolytic activity. Dimethyloxalyl glycine (DMOG), a small molecule inhibitor which stabilises the transcription factor hypoxia-inducible factor (HIF)-1alpha, similarly upregulated MMP-1. Hypoxia did not affect mycobacterial replication. Hypoxia increased MMP-1 expression in primary respiratory epithelial cells via intercellular networks regulated by TB. HIF-1alpha and NF-kappaB regulated increased MMP-1 activity in hypoxia. Furthermore, M.tb infection drove HIF-1alpha accumulation even in normoxia. In human TB lung biopsies, epithelioid macrophages and multinucleate giant cells express HIF-1alpha. HIF-1alpha blockade, including by targeted siRNA, inhibited TB-driven MMP-1 gene expression and secretion. CONCLUSIONS: Human TB lesions are severely hypoxic and M.tb drives HIF-1alpha accumulation, synergistically increasing collagenase activity which will lead to lung destruction and cavitation. PMID- 27245781 TI - Sex-specific effects of relaxin-3 on food intake and body weight gain. AB - : Relaxin-3 (RLN3) is a neuropeptide that is strongly expressed in the pontine nucleus incertus (NI) and binds with high affinity to its cognate receptor RXFP3. Central administration of RLN3 in rats increases food intake and adiposity. In humans, RLN3 polymorphism has been associated with obesity and hypercholesterolaemia. Emerging evidence suggests that the effects of RLN3 may have sex-specific aspects. Thus, the RLN3 knockout female but not male mice are hypoactive. RLN3 produced stronger orexigenic and obesogenic effects in female rats compared with male rats. In addition, female rats demonstrated higher sensitivity to lower doses of RLN3. Repeated cycles of food restriction and stress were accompanied by an increase in RLN3 expression and hyperphagia in female but not in male rats. Furthermore, stress-induced binge eating in female rats was blocked by an RXFP3 receptor antagonist. RLN3 increased the expression of corticotropin releasing factor in the paraventricular hypothalamic nucleus in male but not in female rats. Conversely, in female rats, RLN3 increased the expression of orexin in the lateral hypothalamus. There is evidence that orexin directly activates the RLN3 neurons in the NI. The positive reinforcement of the RLN3 effects by orexin may intensify behavioural activation and feeding in females. Sex-specific effects of RLN3 may also depend on differential expression of RXFP3 receptors in the brain. Given the higher sensitivity of females to the orexigenic effects of RLN3 and the stress-induced activation of RLN3, the overall data suggest a possible role for RLN3 in eating disorders that show a higher propensity in women. LINKED ARTICLES: This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc. PMID- 27245782 TI - A neuron-in-capillary platform for facile collection and mass spectrometric characterization of a secreted neuropeptide. AB - The integration of microfluidic devices-which efficiently handle small liquid volumes-with separations/mass spectrometry (MS) is an effective approach for profiling the neurochemistry occurring in selected neurons. Interfacing the microfluidic cell culture to the mass spectrometer is challenging because of geometric and scaling issues. Here we demonstrate the hyphenation of a neuron-in capillary platform to a solid phase extraction device and off-line MS. A primary neuronal culture of Aplysia californica neurons was established directly inside a cylindrical polyimide capillary. The approach also uses a particle-embedded monolith to condition neuropeptide releasates collected from several Aplysia neurons cultured in the capillary, with the subsequent characterization of released peptides via MS. This system presents a number of advances compared to more traditional microfluidic devices fabricated with polydimethylsiloxane. These include low cost, easy access to cell culture, rigidity, ease of transport, and minimal fluid handling. The cylindrical geometry of the platform allows convenient interface with a wide range of analytical tools that utilize capillary columns. PMID- 27245783 TI - Tinnitus: Evaluation of Intratympanic Injection of Combined Lidocaine and Corticosteroids. AB - BACKGROUND: Tinnitus is an annoying problem and until now there is no consensus on its treatment. AIMS: In this prospective study, we evaluated the effectiveness of intratympanic lidocaine and dexamethasone (ITLD) injections for the management of subjective idiopathic tinnitus (SIT). METHODS: Forty patients with SIT attended the Department of Otorhinolaryngology, Tanta University Hospital, Egypt, between May 2013 and May 2014. The patients were categorized into two groups: group A included 20 patients treated with ITLD injection, and group B included 20 patients treated with intratympanic saline injection as a control. Intratympanic injections were performed four times within 4 weeks in a double-blind manner. At the end of the treatment program, we analyzed the improvement and worsening rates of tinnitus using the following parameters: tinnitus questionnaires, Tinnitus Handicap Index (THI), and loudness matching test. RESULTS: The effectiveness rates of the ITLD group reported in the tinnitus questionnaires, the THI and the loudness matching test were 74.3% in all tests, compared to 26.7, 40.0 and 26.7%, respectively, in the saline group. There was a statistically significant difference between the groups within 2 months after injection. To analyze the therapeutic effect of ITLD on tinnitus of 6 months duration, the improvement rates reported in the tinnitus questionnaires, the THI and the loudness matching test were 78.5% in all tests in the ITLD group, compared to 40.0, 40.0 and 30.0%, respectively, in the saline group. CONCLUSION: There were statistically significant differences between both groups. ITLD seems to be effective for idiopathic tinnitus. PMID- 27245784 TI - A mixed-methods approach to assessing barriers to physical activity among women with class I, class II, and class III obesity. PMID- 27245785 TI - Old Myths, New Concerns: the Long-Term Effects of Ascending Aorta Replacement with Dacron Grafts. Not All That Glitters Is Gold. AB - Synthetic grafts are widely used in cardiac and vascular surgery since the mid 1970s. Despite their general good performance, inability of mimicking the elastomechanical characteristics of the native arterial tissue, and the consequent lack of adequate compliance, leads to a cascade of hemodynamic and biological alterations deeply affecting cardiovascular homeostasis. Those concerns have been reconsidered in more contemporaneous surgical and experimental reports which also triggered some research efforts in the tissue engineering field towards the realization of biomimetic arterial surrogates. The present review focuses on the significance of the "compliance mismatch" phenomenon occurring after aortic root or ascending aorta replacement with prosthetic grafts and discusses the clinical reflexes of this state of tissue incompatibility, as the loss of the native elastomechanical properties of the aorta can translate into detrimental effects on the normal efficiency of the aortic root complex with impact in the long-term results of patients undergoing aortic replacement. PMID- 27245786 TI - Periodontal therapy and glycaemic control among individuals with type 2 diabetes: reflections from the PerioCardio study. AB - OBJECTIVES: Diabetes mellitus and periodontal disease are highly prevalent among Indigenous Australian adults. Untreated periodontitis impacts glycaemic control in people with diabetes. The aim of this study was to report on the effect of periodontal therapy on glycaemic control among people with obesity. METHODS: This subgroup analysis is limited to 62 participants with diabetes from the original 273 Aboriginal Australian adults enrolled into the PerioCardio study. Intervention participants received full-mouth non-surgical periodontal scaling during a single, untimed session while controls were untreated. Endpoints of interest included change in glycated haemoglobin (HbA1c), C-reactive protein (CRP) and periodontal status at 3 months post-intervention. RESULTS: There were more females randomized to the treatment group (n = 17) than control (n = 10) while the control group had a higher overall body mass index (BMI) [mean (SD)] 33.1 (9.7 kg m-2 ) versus 29.9 (6.0 kg m-2 ). A greater proportion of males were followed up at 3 months compared to females, P = 0.05. Periodontal therapy did not significantly reduce HbA1c: ancova difference in means 0.22 mmol mol-1 (95% CI -6.25 to 6.69), CRP: ancova difference in means 0.64 (95% CI -1.08, 2.37) or periodontal status at 3 months. CONCLUSIONS: Non-surgical periodontal therapy did not significantly reduce glycated haemoglobin in participants with type 2 diabetes. Reasons are likely to be multifactorial and may be influenced by persistent periodontal inflammation at the follow-up appointments. Alternatively, the BMI of study participants may impact glycaemic control via alternative mechanisms involving the interplay between inflammation and adiposity meaning HbA1c may not be amenable to periodontal therapy in these individuals. PMID- 27245787 TI - The Effect of Gradations in Mineral Content, Matrix Alignment, and Applied Strain on Human Mesenchymal Stem Cell Morphology within Collagen Biomaterials. AB - The tendon-bone junction is a unique, mechanically dynamic, structurally graded anatomical zone, which transmits tensile loads between tendon and bone. Current surgical repair techniques rely on mechanical fixation and can result in high re failure rates. A new class of collagen biomaterial that contains discrete mineralized and structurally aligned regions linked by a continuous interface to mimic the graded osteotendinous insertion has been recently described. Here the combined influence of graded biomaterial environment and increasing levels of applied strain (0%-20%) on mesenchymal stem cell (MSC) orientation and alignment have been reported. In osteotendinous scaffolds, which contain opposing gradients of mineral content and structural alignment characteristic of the native osteotendinous interface, MSC nuclear, and actin alignment is initially dictated by the local pore architecture, while applied tensile strain enhances cell alignment in the direction of strain. Comparatively, in layered scaffolds that do not contain any structural alignment cues, MSCs are randomly oriented in the unstrained condition, then become oriented in a direction perpendicular to applied strain. These findings provide an initial understanding of how scaffold architecture can provide significant, potentially competitive, feedback influencing MSC orientation under applied strain, and form the basis for future tissue engineering efforts to regenerate the osteotendinous enthesis. PMID- 27245788 TI - Cross-species validation of cell cycle arrest markers for acute kidney injury in the rat during sepsis. AB - BACKGROUND: The recent discovery of cell cycle arrest biomarkers, tissue inhibitor of metalloproteinases (TIMP)-2 and insulin-like growth factor binding protein 7 (IGFBP7), has led to a newly available clinical test for acute kidney injury. The performance of these markers in preclinical studies has not been established. Therefore, we sought to evaluate the performance of TIMP-2 and IGFBP7 in rats undergoing cecal ligation and puncture. METHODS: In this secondary analysis, we analyzed banked urine samples from 60 Sprague-Dawley rats undergoing cecal ligation and puncture (CLP). Samples were obtained from baseline, 18 h after CLP, at the end of fluid resuscitation (22 h after CLP), and again 24 h later. We measured TIMP-2 and IGFBP7 and compared the results to acute kidney injury by RIFLE criteria for creatinine using area under the receiver operating characteristic curve (AUC). The primary endpoint was moderate-to-severe acute kidney injury (AKI) (I or F criteria), and the primary time point was immediately after fluid resuscitation. Secondary outcomes included mortality and comparisons with other biomarkers: cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) in both urine and plasma. RESULTS: After fluid resuscitation, urine [TIMP 2] and [IGFBP7] were significantly higher in animals developing moderate-to severe AKI (p = 0.002 and p = 0.01). AUC of [TIMP-2].[IGFBP7] for AKI was 0.89 (95 % CI 0.80-0.98). By contrast, the next best AUC was seen with plasma cystatin C (0.78; 95 % CI 0.65-0.90). [TIMP-2].[IGFBP7] also predicted mortality (AUC 0.69; 95 % CI 0.53-0.85). CONCLUSIONS: In this experimental model of sepsis in the rat, cell cycle arrest biomarkers TIMP-2 and IGFBP7 are valid predictors of acute kidney injury. PMID- 27245789 TI - The Effectiveness of a Web-Based Computer-Tailored Intervention on Workplace Sitting: A Randomized Controlled Trial. AB - BACKGROUND: Effective interventions to influence workplace sitting are needed, as office-based workers demonstrate high levels of continued sitting, and sitting too much is associated with adverse health effects. Therefore, we developed a theory-driven, Web-based, interactive, computer-tailored intervention aimed at reducing and interrupting sitting at work. OBJECTIVE: The objective of our study was to investigate the effects of this intervention on objectively measured sitting time, standing time, and breaks from sitting, as well as self-reported context-specific sitting among Flemish employees in a field-based approach. METHODS: Employees (n=213) participated in a 3-group randomized controlled trial that assessed outcomes at baseline, 1-month follow-up, and 3-month follow-up through self-reports. A subsample (n=122) were willing to wear an activity monitor (activPAL) from Monday to Friday. The tailored group received an automated Web-based, computer-tailored intervention including personalized feedback and tips on how to reduce or interrupt workplace sitting. The generic group received an automated Web-based generic advice with tips. The control group was a wait-list control condition, initially receiving no intervention. Intervention effects were tested with repeated-measures multivariate analysis of variance. RESULTS: The tailored intervention was successful in decreasing self reported total workday sitting (time * group: P<.001), sitting at work (time * group: P<.001), and leisure time sitting (time * group: P=.03), and in increasing objectively measured breaks at work (time * group: P=.07); this was not the case in the other conditions. The changes in self-reported total nonworkday sitting, sitting during transport, television viewing, and personal computer use, objectively measured total sitting time, and sitting and standing time at work did not differ between conditions. CONCLUSIONS: Our results point out the significance of computer tailoring for sedentary behavior and its potential use in public health promotion, as the effects of the tailored condition were superior to the generic and control conditions. TRIAL REGISTRATION: Clinicaltrials.gov NCT02672215; http://clinicaltrials.gov/ct2/show/NCT02672215 (Archived by WebCite at http://www.webcitation.org/6glPFBLWv). PMID- 27245790 TI - Heterogeneity in a communal cattle-farming system in a zone endemic for foot and mouth disease in South Africa. AB - In South Africa, communal livestock farming is predominant in the foot and mouth disease control zone adjacent to the Greater Kruger National Park (KNP), where infected African buffaloes are common. During routine veterinary inspections of cattle in this area, a large amount of production and demographic parameters were being recorded. These data were collated for a five-year period (2003-2007) in three study sites to better understand the temporal dynamics and spatial heterogeneity in this system. A decreasing gradient from South to North with respect to both human and cattle population densities was observed. Rainfall and human population density alone could explain 71% of the variation in cattle density. Northern and central sites showed an overall decrease in total cattle numbers (15.1 and 2.9%, respectively), whereas a 28.6% increase was recorded in the South. The number of cattle owners in relation to cattle numbers remained stable during the study period. Only 4.0% of households in the South own cattle, compared to 13.7 and 12.7% in the North and Centre. The overall annual calving rate was 23.8%. Annual mortality rates ranged from 2.4 to 3.2%. Low calf mortality (2.1%) was recorded in the North compared to the South (11.6%). Annual off-take in the form of slaughter averaged 0.2, 11.7, and 11.0% in the North, Central and South sites, respectively. These figures provide valuable baseline data and demonstrate considerable spatial heterogeneity in cattle demography and production at this wildlife-livestock interface, which should be taken into consideration when performing disease risk assessments or designing disease control systems. PMID- 27245791 TI - The spatial distribution of injuries in need of surgical intervention in Nepal. AB - Geographic information system modelling can accurately represent the geospatial distribution of disease burdens to inform health service delivery. Given the dramatic topography of Nepal and a high prevalence of unmet surgical needs, we explored the consequences of topography on the prevalence of surgical conditions. The Nepalese Surgeons OverSeas Assessment of Surgical Need (SOSAS) is a validated, countrywide, cluster randomised survey that assesses surgical need in lowand middle-income countries; it was performed in Nepal in 2014. Data on conditions potentially affected by topography (e.g. fractures, hernias, injuries, burns) were extracted from the database. A national digital elevation model was used to determine altitude, aspect, slope steepness and curvature of the SOSAS survey sites. Forward stepwise linear regression was performed with prevalence of each surgical condition as the response variable and topographic data as explanatory variables. The highest correlation coefficient was for models predicting hernias and fractures, both explaining 21% of the variance. The model fitted to death due to fall would become significant when an outlier was excluded (P<0.001; R2=0.27). Excluding the outlier yielded a better-fitted model to burn injury (stepwise regression) without any explanatory variables. Other models trended towards a correlation, but did not have sufficient power to detect a difference. This study identified slight correlation between elevation and the prevalence of hernias and fall injuries. Further investigation on the effects of topography and geography on surgical conditions is needed to help determine if the data would be useful for directing allocation of surgical resources. PMID- 27245792 TI - Dynamic risk model for Rift Valley fever outbreaks in Kenya based on climate and disease outbreak data. AB - Rift Valley fever (RVF) is a mosquito-borne viral zoonotic disease that occurs throughout sub-Saharan Africa, Egypt and the Arabian Peninsula, with heavy impact in affected countries. Outbreaks are episodic and related to climate variability, especially rainfall and flooding. Despite great strides towards better prediction of RVF epidemics, there is still no observed climate data-based warning system with sufficient lead time for appropriate response and mitigation. We present a dynamic risk model based on historical RVF outbreaks and observed meteorological data. The model uses 30-year data on rainfall, temperature, relative humidity, normalised difference vegetation index and sea surface temperature data as predictors. Our research on RVF focused on Garissa, Murang'a and Kwale counties in Kenya using a research design based on a correlational, experimental, and evaluational approach. The weather data were obtained from the Kenya Meteorological Department while the RVF data were acquired from International Livestock Research Institute, and the Department of Veterinary Services. Performance of the model was evaluated by using the first 70% of the data for calibration and the remaining 30% for validation. The assessed components of the model accurately predicted already observed RVF events. The Brier score for each of the models (ranging from 0.007 to 0.022) indicated high skill. The coefficient of determination (R2) was higher in Garissa (0.66) than in Murang'a (0.21) and Kwale (0.16). The discrepancy was attributed to data distribution differences and varying ecosystems. The model outputs should complement existing early warning systems to detect risk factors that predispose for RVF outbreaks. PMID- 27245793 TI - Trends in obesity at the national and local level among South Korean adolescents. AB - Obesity is a global phenomenon affecting all socioeconomic groups, irrespective of age, gender or ethnicity. In many countries, obesity trends are causing serious public health concerns threatening the viability of basic health care delivery. In this article, we examine the trends of adolescent obesity at the national level in South Korea introducing a new approach for visualising data at the local level based on linked micromap plots. Our analysis shows that the obesity rates for 2013 have only increased slightly since 2006 for South Korean adolescents of both genders in various age groups. However, considerable increases could be observed for the subgroup of adolescent males and adolescent females living in rural areas. Trends at the local level show a slight increase of the prevalence of obesity in most regions of the country, with the highest obesity prevalence found in the Northeast. PMID- 27245794 TI - How much incident lung cancer was missed globally in 2012? An ecological country level study. AB - Lung cancer incidence is increasing in many low-to-middle-income countries and is significantly under-reported in Africa, which could potentially mislead policy makers when prioritising disease burden. We employed an ecological correlation study design using countrylevel lung cancer incidence data and associated determinant data. Lagged prevalence of smoking and other exposure data were used to account for exposure-disease latency. A multivariable Poisson model was employed to estimate missed lung cancer in countries lacking incidence data. Projections were further refined to remove potential deaths from infectious/external competing causes. Global lung cancer incidence was much lower among females vs males (13.6 vs 34.2 per 100,000). Distinct spatial heterogeneity was observed for incident lung cancer and appeared concentrated in contiguous regions. Our model predicted a revised global lung cancer incidence in 2012 of 23.6 compared to the Globocan 2012 estimate of 23.1, amounting to ~38,101 missed cases (95% confidence interval: 28,489-47,713). The largest relative under estimation was predicted for Africa, Central America and the Indian Ocean regions (Comoros, Madagascar, Mauritius, Mayotte, Reunion, Seychelles). Our results suggest substantial underreporting of lung cancer incidence, specifically in developing countries (e.g. Africa). The missed cost of treating these cases could amount to >US$ 130 million based on recent developing setting costs for treating earlier stage lung cancer. The full cost is not only under-estimated, but also requires substantial additional social/family inputs as evidenced in more developed settings like the European Union. This represents a major public health problem in developing settings (e.g. Africa) with limited healthcare resources. PMID- 27245795 TI - Perceived spatial stigma, body mass index and blood pressure: a global positioning system study among low-income housing residents in New York City. AB - Previous research has highlighted the salience of spatial stigma on the lives of low-income residents, but has been theoretical in nature and/or has predominantly utilised qualitative methods with limited generalisability and ability to draw associations between spatial stigma and measured cardiovascular health outcomes. The primary objective of this study was to evaluate relationships between perceived spatial stigma, body mass index (BMI), and blood pressure among a sample of low-income housing residents in New York City (NYC). Data come from the community-based NYC Low-income Housing, Neighborhoods and Health Study. We completed a crosssectional analysis with survey data, which included the four items on spatial stigma, as well objectively measured BMI and blood pressure data (analytic n=116; 96.7% of the total sample). Global positioning systems (GPS) tracking of the sample was conducted for a week. In multivariable models (controlling for individual-level age, gender, race/ethnicity, education level, employment status, total household income, neighborhood percent non-Hispanic Black and neighborhood median household income) we found that participants who reported living in an area with a bad neighborhood reputation had higher BMI (B=4.2, 95%CI: -0.01, 8.3, P=0.051), as well as higher systolic blood pressure (B=13.2, 95%CI: 3.2, 23.1, P=0.01) and diastolic blood pressure (B=8.5, 95%CI: 2.8, 14.3, P=0.004). In addition, participants who reported living in an area with a bad neighborhood reputation had increased risk of obesity/overweight [relative risk (RR)=1.32, 95%CI: 1.1, 1.4, P=0.02) and hypertension/pre hypertension (RR=1.66, 95%CI: 1.2, 2.4, P=0.007). However, we found no differences in spatial mobility (based GPS data) among participants who reported living in neighborhoods with and without spatial stigma (P>0.05). Further research is needed to investigate how placebased stigma may be associated with impaired cardiovascular health among individuals in stigmatised neighborhoods to inform effective cardiovascular risk reduction interventions. PMID- 27245796 TI - Is missing geographic positioning system data in accelerometry studies a problem, and is imputation the solution? AB - The main purpose of the present study was to assess the impact of global positioning system (GPS) signal lapse on physical activity analyses, discover any existing associations between missing GPS data and environmental and demographics attributes, and to determine whether imputation is an accurate and viable method for correcting GPS data loss. Accelerometer and GPS data of 782 participants from 8 studies were pooled to represent a range of lifestyles and interactions with the built environment. Periods of GPS signal lapse were identified and extracted. Generalised linear mixed models were run with the number of lapses and the length of lapses as outcomes. The signal lapses were imputed using a simple ruleset, and imputation was validated against person-worn camera imagery. A final generalised linear mixed model was used to identify the difference between the amount of GPS minutes pre- and post-imputation for the activity categories of sedentary, light, and moderate-to-vigorous physical activity. Over 17% of the dataset was comprised of GPS data lapses. No strong associations were found between increasing lapse length and number of lapses and the demographic and built environment variables. A significant difference was found between the pre- and postimputation minutes for each activity category. No demographic or environmental bias was found for length or number of lapses, but imputation of GPS data may make a significant difference for inclusion of physical activity data that occurred during a lapse. Imputing GPS data lapses is a viable technique for returning spatial context to accelerometer data and improving the completeness of the dataset. PMID- 27245797 TI - Comparison of single- and multi-scale models for the prediction of the Culicoides biting midge distribution in Germany. AB - This study analysed Culicoides presence-absence data from 46 sampling sites in Germany, where monitoring was carried out from April 2007 until May 2008. Culicoides presence-absence data were analysed in relation to land cover data, in order to study whether the prevalence of biting midges is correlated to land cover data with respect to the trapping sites. We differentiated eight scales, i.e. buffer zones with radii of 0.5, 1, 2, 3, 4, 5, 7.5 and 10 km, around each site, and chose several land cover variables. For each species, we built eight single-scale models (i.e. predictor variables from one of the eight scales for each model) based on averaged, generalised linear models and two multiscale models (i.e. predictor variables from all of the eight scales) based on averaged, generalised linear models and generalised linear models with random forest variable selection. There were no significant differences between performance indicators of models built with land cover data from different buffer zones around the trapping sites. However, the overall performance of multi-scale models was higher than the alternatives. Furthermore, these models mostly achieved the best performance for the different species using the index area under the receiver operating characteristic curve. However, as also presented in this study, the relevance of the different variables could significantly differ between various scales, including the number of species affected and the positive or negative direction. This is an even more severe problem if multi-scale models are concerned, in which one model can have the same variable at different scales but with different directions, i.e. negative and positive direction of the same variable at different scales. However, multi-scale modelling is a promising approach to model the distribution of Culicoides species, accounting much more for the ecology of biting midges, which uses different resources (breeding sites, hosts, etc.) at different scales. PMID- 27245799 TI - The spatial distribution pattern of human immunodeficiency virus/acquired immune deficiency syndrome in China. AB - Human immunodeficiency virus (HIV) infection and the acquired immune deficiency syndrome (AIDS) exhibit variable patterns among the provinces of China. Knowledge of the geographical distribution of the HIV/AIDS epidemic is needed for the prevention and control of AIDS. Thus, the cumulative number of reported cases of HIV/AIDS from the period 1985-2013, and the incidence rate of AIDS in 2013 were determined. Spatial autocorrelation analysis and hotspot analysis were conducted using ArcGIS10.2 to explore the spatial distribution of the HIV/AIDS epidemic. Both the thematic map and the global spatial autocorrelation Moran's I statistics revealed a clustered distribution of the spatial pattern. A local spatial autocorrelation analysis indicated hotspots of AIDS incidence rate that were confined to the provinces of Guangxi, Yunnan and Sichuan. The hotspots encompassed Guangxi and Yunnan, while Henan Province displayed a negative autocorrelation with more variable numbers that included neighbouring regions. The Getis-Ord Gi* statistics identified 6 hotspots and 8 coldspots for the incidence of AIDS, and 7 hotspots and 1 coldspot for the cumulative number of reported cases of HIV/AIDS. The spatial distribution pattern of the HIV/AIDS epidemic in China is clustered, demonstrating hotspots located in the Southwest. Specific interventions targeting provinces with severe HIV/AIDS epidemic are urgently needed. PMID- 27245798 TI - Spatial and temporal changes in household structure locations using high resolution satellite imagery for population assessment: an analysis in southern Zambia, 2006-2011. AB - Satellite imagery is increasingly available at high spatial resolution and can be used for various purposes in public health research and programme implementation. Comparing a census generated from two satellite images of the same region in rural southern Zambia obtained four and a half years apart identified patterns of household locations and change over time. The length of time that a satellite image-based census is accurate determines its utility. Households were enumerated manually from satellite images obtained in 2006 and 2011 of the same area. Spatial statistics were used to describe clustering, cluster detection, and spatial variation in the location of households. A total of 3821 household locations were enumerated in 2006 and 4256 in 2011, a net change of 435 houses (11.4% increase). Comparison of the images indicated that 971 (25.4%) structures were added and 536 (14.0%) removed. Further analysis suggested similar household clustering in the two images and no substantial difference in concentration of households across the study area. Cluster detection analysis identified a small area where significantly more household structures were removed than expected; however, the amount of change was of limited practical significance. These findings suggest that random sampling of households for study participation would not induce geographic bias if based on a 4.5-year-old image in this region. Application of spatial statistical methods provides insights into the population distribution changes between two time periods and can be helpful in assessing the accuracy of satellite imagery. PMID- 27245800 TI - Validation of an interactive map assessing the potential spread of Galba truncatula as intermediate host of Fasciola hepatica in Switzerland. AB - Bovine fasciolosis, caused by Fasciola hepatica, is widespread in Switzerland. The risk regions were modelled in 2008 by an interactive map, showing the monthly potential risk of transmission of F. hepatica in Switzerland. As this map is based on a mathematical model, the aim of the present study was to evaluate the interactive map by means of a field survey taking different data sources into account. It was found that the interactive map has a sensitivity of 40.7-88.9%, a specificity of 11.4-18.8%, a positive predictive value of 26.7-51.4%, and a negative predictive value of 13.1-83.6%, depending on the source of the data. In conclusion, the grid of the interactive map (100 x 100 m) does not reflect enough detail and the underlying model of the interactive map is lacking transmission data. PMID- 27245801 TI - Spatial analysis of the regional variation of hypertensive disease mortality and its socio-economic correlates in South Korea. AB - This paper presents a cross-sectional study based on the cause of death statistics in 2011 extracted from all 229 local governments in South Korea. The standardised hypertensive disease mortality rate (SHDMR) was defined by age- and sex-adjusted mortality by hypertensive diseases distinguished by International Classification of Disease- 10 (ICD-10). Variables taken into account were the number of doctors per 100,000 persons, the proportion with higher education (including university students and high school graduates), the number of recipients of basic livelihood support per 100,000 persons, the annual national health insurance premium per capita and the proportion of persons classified as high-risk drinkers. Ordinary least square (OLS) regression and geographically weighted regression (GWR) were applied to identify the potential associations. The statistical analysis was conducted with SAS ver. 9.3, while ArcGIS ver. 10.0 was utilised for the spatial analysis. The OLS results showed that the number of basic livelihood recipients per 100,000 persons had a significant positive association with the SHDMR, and the proportion with higher education had a significant negative one. GWR coefficients varied depending on region investigated and some regional variables had various directions. GWR showed higher adjusted R2 than that of OLS. It was found that the SHDMR was affected by socio-economic status, but as the effects observed were not consistent in all regions of the country, the development of health policies will need to consider the potential for regional variation. PMID- 27245802 TI - Climate change and species distribution: possible scenarios for thermophilic ticks in Romania. AB - Several zoonotic tick-borne diseases are emerging in Europe due to various factors, including changes of the cultural landscape, increasing human populations, variation of social habits and climate change. We have modelled the potential range changes for two thermophilic tick species (Hyalomma marginatum and Rhipicephalus annulatus) by use of MaxEnt(r) and 15 climatic predictors, taking into account the aptitude for future climatic change in Romania. Current models predict increased temperatures, both in the short term (up to 2050) and in the long term (up to 2070), together with possible changes also of the other climatic factors (e.g. precipitation), and may lead to higher zoonotic risks associated with an expansion of the range of the target species. Three different models were constructed (the present, 2050 and 2070) for four representative concentration pathways (RCPs) of greenhouse gas scenarios: RCP2.6, RCP4.5, RCP6, and RCP8.5. The most dramatic scenario (RCP8.5) produced the highest increase in the probable distribution range for both species. In concordance with similar continental-wide studies, both tick species displayed a shift of distribution towards previously cooler areas of Romania. In most scenarios, this would lead to wider ranges; from 9.7 to 43.1% for H. marginatum, and from 53.4 to 205.2% for R annulatus. Although the developed models demonstrate a good predictive power, the issue of species ecology should also be considered. PMID- 27245803 TI - Making the most of spatial information in health: a tutorial in Bayesian disease mapping for areal data. AB - Disease maps are effective tools for explaining and predicting patterns of disease outcomes across geographical space, identifying areas of potentially elevated risk, and formulating and validating aetiological hypotheses for a disease. Bayesian models have become a standard approach to disease mapping in recent decades. This article aims to provide a basic understanding of the key concepts involved in Bayesian disease mapping methods for areal data. It is anticipated that this will help in interpretation of published maps, and provide a useful starting point for anyone interested in running disease mapping methods for areal data. The article provides detailed motivation and descriptions on disease mapping methods by explaining the concepts, defining the technical terms, and illustrating the utility of disease mapping for epidemiological research by demonstrating various ways of visualising model outputs using a case study. The target audience includes spatial scientists in health and other fields, policy or decision makers, health geographers, spatial analysts, public health professionals, and epidemiologists. PMID- 27245804 TI - Zoning the territory of the Republic of Kazakhstan as to the risk of rabies among various categories of animals. AB - This paper presents the zoning of the territory of the Republic of Kazakhstan with respect to the risk of rabies outbreaks in domestic and wild animals considering environmental and climatic conditions. The national database of rabies outbreaks in Kazakhstan in the period 2003-2014 has been accessed in order to find which zones are consistently most exposed to the risk of rabies in animals. The database contains information on the cases in demes of farm livestock, domestic animals and wild animals. To identify the areas with the highest risk of outbreaks, we applied the maximum entropy modelling method. Designated outbreaks were used as input presence data, while the bioclim set of ecological and climatic variables, together with some geographic factors, were used as explanatory variables. The model demonstrated a high predictive ability. The area under the curve for farm livestock was 0.782, for domestic animals 0.859 and for wild animals - 0.809. Based on the model, the map of integral risk was designed by following four categories: negligible risk (disease-free or favourable zone), low risk (surveillance zone), medium risk (vaccination zone), and high risk (unfavourable zone). The map was produced to allow developing a set of preventive measures and is expected to contribute to a better distribution of supervisory efforts from the veterinary service of the country. PMID- 27245805 TI - Mapping, cluster detection and evaluation of risk factors of ovine toxoplasmosis in Southern Italy. AB - Toxoplasmosis, an important cause of reproductive failure in sheep, is responsible for significant economic losses to the ovine industry worldwide. Moreover, ovine meat contaminated by the parasite Toxoplasma gondii is considered as a common source of infection for humans. The aim of this study was to develop point and risk profiling maps of T. gondii seroprevalence in sheep bred in Campania Region (Southern Italy) and analyse risk factors associated at the flock level. We used serological data from a previous survey of 117 sheep flocks, while environmental and farm management information were obtained from an analysis based on geographical information systems and a questionnaire purveyance, respectively. An univariate Poisson regression model revealed that the type of farm production (milk and meat vs only meat) was the only independent variable associated with T. gondii positivity (P<0.02); the higher within-flock seroprevalence in milking herds suggests that milking practices might influence the spread of the infection on the farm. Neither environmental nor other management variables were significant. Since a majority of flocks were seasonally or permanently on pasture, the animals have a high exposure to infectious T. gondii oocysts, so the high within-flock seroprevalence might derive from this management factor. However, further studies are needed to better assess the actual epidemiological situation of toxoplasmosis in sheep and to clarify the factors that influence its presence and distribution. PMID- 27245806 TI - Topographic distribution of gastritis in heavy pigs investigated by a geographic information system approach. AB - The aim of this paper was to determine the topographic distribution of gastritis lesions in pigs through an open source geographic information system (GIS) software analysis. The stomachs of 146 Italian heavy pigs were collected at slaughter and subjected to macroscopic pathological examination of the internal mucosa. A total of 623 lesions were either classified as hyperplastic or follicular (97%) with the remaining minority of lesions categorised as atrophic and simple. The hyperplastic gastritis lesions had an average surface of 77.8 cm2 and were mainly located in an oval shaped area of the fundus region of the stomach near the Curvatura ventriculi major. The follicular gastritis lesions had generally a smaller surface (40.3 cm2) and were concentrated in two distinct small areas of the pyloric region. The GIS analysis provided the opportunity to produce useful maps showing the distribution and characteristics of gastritis in pigs. PMID- 27245807 TI - Air quality classification and its temporal trend in Tehran, Iran, 2002-2012. AB - Airborne particulate matter with a diameter of 2.5 microns or less (PM2.5), as well as slightly bigger particles (PM10), arrive from the westerly direction and collect in the city centre of Tehran, the capital of Iran. The statistical characteristics and daily trend of the air quality index (AQI) in Theran were studied over an 11-year period (2002- 2012). Various statistical analyses were applied including descriptive statistics, correlation analysis, trend analysis and the sequential nonparametric Mann-Kendall test. The significance of the series was investigated by regression analysis and Kriging interpolation. It was found that Tehran's daily AQI increased by 11.8% over the study period, with the frequency distribution of days with good and average air quality showing a strongly declining trend. The AQI of Tehran was shown to contain a large part of PM10 and PM2.5, the latter having the largest contribution (coefficient=0.853). PMID- 27245808 TI - Revealing spatio-temporal patterns of rabies spread among various categories of animals in the Republic of Kazakhstan, 2010-2013. AB - This study estimated the basic reproductive ratio of rabies at the population level in wild animals (foxes), farm animals (cattle, camels, horses, sheep) and what we classified as domestic animals (cats, dogs) in the Republic of Kazakhstan (RK). It also aimed at forecasting the possible number of new outbreaks in case of emergence of the disease in new territories. We considered cases of rabies in animals in RK from 2010 to 2013, recorded by regional veterinary services. Statistically significant space-time clusters of outbreaks in three subpopulations were detected by means of Kulldorff Scan statistics. Theoretical curves were then fitted to epidemiological data within each cluster assuming exponential initial growth, which was followed up by calculation of the basic reproductive ratio R0. For farm animals, the value of R0 was 1.62 (1.11-2.26) and for wild animals 1.84 (1.08- 3.13), while it was close to 1 for domestic animals. Using the values obtained, an initial phase of possible epidemic was simulated in order to predict the expected number of secondary cases if the disease were introduced into a new area. The possible number of new cases for 20 weeks was estimated at 5 (1-16) for farm animals, 17 (1-113) for wild animals and about 1 in the category of domestic animals. These results have been used to produce set of recommendations for organising of preventive and contra-epizootic measures against rabies expected to be applied by state veterinarian services. PMID- 27245809 TI - Characteristics of Youth With Combined Histories of Violent Behavior, Suicidal Ideation or Behavior, and Gun-Carrying. AB - BACKGROUND: Youth reporting combined histories of nonfatal violence, suicidal ideation/behavior, and gun-carrying (VSG) are at risk for perpetrating fatal interpersonal violence and self-harm. AIMS: We characterized these youth to inform prevention efforts. METHOD: We analyzed 2004 data from 3,931 seventh-, ninth-, and 11-12th-grade youth and compared VSG youth (n = 66) with non-gun carrying youth who either had no histories of violence or suicidal thoughts/behavior (n = 1,839), histories of violence (n = 884), histories of suicidal thoughts/behaviors (n = 552), or both (n = 590). We compared groups based on demographic factors, risk factors (i.e., friends who engage in delinquency, peer-violence victimization, depressive symptoms, illicit substance use), and protective factors (i.e., school connectedness, parental care and supervision). Regression models identified factors associated with VSG youth. RESULTS: Illicit substance use and having friends who engage in delinquency were more common among VSG youth in all comparisons; almost all VSG youth had high levels of these factors. Depressive symptoms were positively associated with VSG youth versus youth without either violent or suicide-related histories and youth with violent histories alone. School connectedness and parental supervision were negatively associated with VSG youth in most comparisons. CONCLUSION: Family focused and school-based interventions that increase connectedness while reducing delinquency and substance use might prevent these violent tendencies. PMID- 27245810 TI - Benefits of a Secondary Prevention Program in Suicide. AB - BACKGROUND: The effectiveness of suicide intervention programs has not been assessed with experimental designs. AIM: To determine the risk of suicide reattempts in patients engaged in a secondary prevention program. METHOD: We included 154 patients with suicidal behavior in a quasi-experimental study with a nontreatment concurrent control group. In all, 77 patients with suicidal behavior underwent the Suicide Behavior Prevention Program (SBPP), which includes specialized early assistance during a period of 3-6 months. A matched sample of patients with suicidal behavior (n = 77) was selected without undergoing any specific suicide prevention program. Data on sociodemographics, clinical characteristics, and suicidal behavior were collected at baseline (before SBPP) and at 12 months. RESULTS: After 12 months, SBPP patients showed a 67% lower relative risk of reattempt (chi2 = 11.75, p = .001, RR = 0.33 95% CI = 0.17 0.66). Cox proportional hazards models revealed that patients under SBPP made a new suicidal attempt significantly much later than control patients did (Cox regression = 0.293, 95% CI = 0.138-0.624, p = .001). The effect was even stronger among first attempters. LIMITATIONS: Sampling was naturalistic and patients were not randomized. CONCLUSION: The SBPP was effective in delaying and preventing suicide reattempts at least within the first year after the suicide behavior. In light of our results, implementation of suicide prevention programs is strongly advisable. PMID- 27245811 TI - Gender Differences in Youth Suicide and Healthcare Service Use. AB - BACKGROUND: Healthcare service use among suicide decedents must be well characterized and understood since a key strategy for preventing suicide is to improve healthcare providers' ability to effectively detect and treat those in need. AIMS: To determine gender differences in healthcare service use 12 months prior to suicide. METHOD: Data for 1,231 young Quebec residents (<= 25 years) who died by suicide between 2000 and 2007 were collected from public health insurance agency databases and coroner registers. Healthcare visits were categorized according to the setting (emergency department [ED], outpatient, and hospital) and their nature (mental health vs. non-mental health). RESULTS: Girls were more likely than boys (82.5% vs. 74.9%, p = .011) to have used healthcare services in the year prior to death. A higher proportion of girls had used outpatient services (79.0% vs. 69.5%, p = .003), had been hospitalized (25.7% vs. 15.6%, p < .001) and had received a mental health-related diagnosis (46.7% vs. 33.1%, p < .001). However, no gender differences were observed in ED visits (59.5% vs. 54.5%, p = .150). CONCLUSION: There is an important proportion of suicide decedents who did not receive a mental health diagnosis and healthcare services in the year prior to death. Future studies should focus on examining gender specific individual and health system barriers among suicide decedents as well as the quality of care offered regarding detection and treatment. PMID- 27245812 TI - Serious Suicide Attempts. AB - BACKGROUND: Suicidal behavior comprises a diverse set of behaviors with significant differences among several behavioral categories. One noteworthy category includes individuals who have made serious suicide attempts, epidemiologically very similar to those completing suicide. This behavioral category is important, since interviewing survivors of a potentially lethal incident of self-harm enables a detailed investigation of the psychological process leading to the suicidal act. AIM: To achieve a consensus definition and operational criteria of serious suicide attempts. METHOD: We reviewed studies that included the term serious suicide attempt or related terms (e.g., highly lethal), with a focus on the variety of operational criteria employed across studies. RESULTS: More than 60 papers addressing various types of serious suicide attempt were explored. We found a large variety of operational definitions, reflecting the lack of consensus regarding terminology and criteria related to the term. CONCLUSION: We undertook the challenge of developing an integrative and comprehensive set of criteria of serious suicide attempt and suggest a definition comprising three key dimensions: medical lethality, potential lethality of the method used, and severity of the objective circumstances of the suicide intent. Clinicians and researchers are strongly encouraged to consider using the term serious suicide attempt with its attendant components. PMID- 27245813 TI - Risk Factors for Suicidal Ideation Among Telephone Crisis Hotline Callers in Japan. AB - BACKGROUND: Telephone hotlines are a widely used type of suicide prevention program. AIMS: The aim of this study was to clarify the risk factors for suicidal ideation by investigating its association with a number of characteristics among telephone hotline callers. METHOD: Data were collected over a 10-year period from a total of 246,595 calls to Inochi No Denwa, a telephone crisis hotline in Ibaraki, Japan, and subsequently analyzed. Odds ratios for suicidal compared with nonsuicidal ideation were also calculated. RESULTS: About 6% of the calls to the hotline were suicide related, and about 2% of the callers had attempted suicide in the past. Odds ratios for suicidal ideation increased during winter, but no daily tendencies were evident. Those whose problems were related to their way of life were at the highest risk of suicidal ideation, followed by those with health related concerns. CONCLUSION: We were able to identify risk factors for suicidal ideation based on an analysis of enormous amounts of data from a telephone crisis hotline in Japan. Knowledge of these risk factors is expected to lead to improvements in suicide prevention programs. PMID- 27245815 TI - Development and Validation of the Gatekeeper Behavior Scale. AB - BACKGROUND: Community-based gatekeeper trainings are effective tools in increasing gatekeeper skills but few validated measures assess impact. AIMS: This study aimed at determining the validity of an 11-item Gatekeeper Behavior Scale (GBS) to assess gatekeeper skills that predict behavior. METHOD: To validate the scale, 8,931 users were administered GBS surveys at pretraining, posttraining, and follow-up periods. The training was one of five from the suite of online At Risk mental health learning simulations for university faculty/staff or students or high/middle school educators. RESULTS: A confirmatory factor analysis revealed the three-factor model based on the subscales of preparedness, likelihood, and self-efficacy fit the data best. Factor loadings showed all items correlated highly with theoretical constructs (r >= .84, p < .001). The GBS had high internal consistency (alpha = 0.93). Criterion-related validity for likelihood to discuss concerns at posttraining was significantly related to approaching students believed to be in psychological distress (r = .219, p < .001). Likelihood to refer significantly correlated with the number of students referred (r = .235, p < .001). Convergent validity was established via a correlation between self-efficacy in motivating someone to seek help and general self efficacy (r = .519, p < .001). CONCLUSION: The GBS appears to be a valid tool in measuring the impact of online gatekeeper training simulations and holds promise for assessing other delivery methods. PMID- 27245814 TI - Suicide Attempts and Deaths in Sofala, Mozambique, From 2011 to 2014. AB - BACKGROUND: Mozambique was recently estimated to have the highest suicide rate in Africa. AIMS: To fill a knowledge gap on suicide attempts and deaths in Mozambique. METHOD: We reviewed a census of 898 emergency psychiatric consultations from March 2013 to July 2014 and 1,173 violent death autopsy records from June 2011 to August 2014 at Beira Central Hospital in Sofala, Mozambique. RESULTS: In all, 18.0% of emergency psychiatric consultations were suicide attempts. Females were disproportionately represented (68.3%, p < .001), and the mean age was 26.8 years. Rat poison was used in 66% of attempts, followed by unspecified methods (19.8%), and unspecified poisoning (6.8%). Of the violent death autopsies, 10% were suicides. Suicide deaths were more likely to be male (67.3%, p < .001), and the mean age was 30.8 years. Common methods were hanging (43.2%), unspecified substance (28.0%), or rat poison (26.3%). Common places of death were the hospital or hospital transit (46.4%) and the household (35.7%). Female suicide deaths more often involved toxic substances and males more often employed hanging. CONCLUSION: Females more often present with suicide attempts, but deaths due to suicide are more frequent among males. Females more often use toxic substances, whereas males more often use lethal methods, such as hanging. Policies to reduce the availability or toxicity of rat poison should be considered. PMID- 27245816 TI - Prevalence and evaluation strategies for viral contamination in food products: Risk to human health-a review. AB - Nowadays, viruses of foodborne origin such as norovirus and hepatitis A are considered major causes of foodborne gastrointestinal illness with widespread distribution worldwide. A number of foodborne outbreaks associated with food products of animal and non-animal origins, which often involve multiple cases of variety of food streams, have been reported. Although several viruses, including rotavirus, adenovirus, astrovirus, parvovirus, and other enteroviruses, significantly contribute to incidence of gastrointestinal diseases, systematic information on the role of food in transmitting such viruses is limited. Most of the outbreak cases caused by infected food handlers were the source of 53% of total outbreaks. Therefore, prevention and hygiene measures to reduce the frequency of foodborne virus outbreaks should focus on food workers and production site of food products. Pivotal strategies, such as proper investigation, surveillance, and reports on foodborne viral illnesses, are needed in order to develop more accurate measures to detect the presence and pathogenesis of viral infection with detailed descriptions. Moreover, molecular epidemiology and surveillance of food samples may help analysis of public health hazards associated with exposure to foodborne viruses. In this present review, we discuss different aspects of foodborne viral contamination and its impact on human health. This review also aims to improve understanding of foodborne viral infections as major causes of human illness as well as provide descriptions of their control and prevention strategies and rapid detection by advanced molecular techniques. Further, a brief description of methods available for the detection of viruses in food and related matrices is provided. PMID- 27245817 TI - [Survival Benefit with Consolidative Radiotherapy in Early-Stage Diffuse Large B Cell Lymphoma patients]. PMID- 27245819 TI - [Consolidation radiotherapy in primary gastric diffuse large B-cell lymphoma with post-chemotherapy complete remission]. PMID- 27245818 TI - High dose-rate endoluminal brachytherapy for primary and recurrent esophageal cancer : Experience from a large single-center cohort. AB - PURPOSE: The aim of this work was to evaluate outcomes and toxicities of high dose-rate (HDR) endoluminal brachytherapy in a cohort of esophageal cancer patients. PATIENTS AND METHODS: We analyzed the records of 36 patients treated with HDR brachytherapy for histologically confirmed esophageal cancer. Brachytherapy was either applied as a boost treatment for definitive treatment regimens or as salvage therapy for recurrent tumors with single doses between 4 and 6 Gy. Survival and toxicities were retrospectively analyzed. RESULTS: Brachytherapy was performed as initially planned in all but one patient; 18 patients had a complete endoscopic response at the first follow-up examination. Locoregional recurrence was observed in 24 patients after a median time of 3 months; 1- and 2-year recurrence-free survival rates were 51 and 51 % for the patients treated for primary tumors and 11 and 6 % for patients treated for tumor recurrence, respectively. Median overall survival was 18 months; estimated overall survival rates at 1, 2, and 3 years were 63, 50, and 30 % after primary brachytherapy, and 60, 25, and 6 % after recurrence therapy. Adenocarcinoma histology, non-complete remission after treatment, and treatment for recurrent cancers were associated with significantly reduced prognoses. Mild dysphagia was the most common side effect in 17 patients; 8 patients suffered from locoregional grade 3 toxicities, and no grade 4 or 5 toxicities were observed. CONCLUSIONS: Endoluminal brachytherapy during the course of esophageal cancer treatment can be safely applied and results in good functional outcomes regarding dysphagia with low rates of severe toxicities. PMID- 27245820 TI - Clinically significant CMV (re)activation during or after radiotherapy/chemotherapy of the brain : Correlation with neurological deterioration and improvement upon antiviral treatment. AB - INTRODUCTION: For both patients with high-grade gliomas and multiple cerebral metastases, radio(chemo)therapy is the standard therapy. Neurological decline during treatment is rarely attributed to infections of the brain but to tumor progression or side effects of radiotherapy. CASE REPORTS: We present 4 cases of cytomegalovirus (CMV) viremia associated with neurological deterioration, which occurred during or shortly after radiotherapy and/or chemotherapy of the brain (brain metastases 2, high-grade glioma 1, carcinoma infiltrating brain 1). In all cases, neurological decline was sudden and unexpected, and causes such as increased intracranial pressure or tumor progression could be excluded radiologically. Treatment with dexamethasone and mannitol had no or only very short-term effects. General infections were either excluded or receding before the neurological symptoms occurred. All patients presented with decreasing levels of thrombocytes. In all cases, CMV (re)activation could be proven using blood test for CMV-DNA. The anti-CMV-IgG status suggested reactivation rather than a primary infection. One patient died within 72 h of onset of the symptoms (results of CMV tests were received postmortem). Diagnosis of 3 patients allowed successful administration of antiviral treatment, which greatly improved the general and neurological conditions of the patients within 48 h. DISCUSSION: Neurological deterioration during RT is hardly ever attributed to viral infections. These cases suggest that CMV reactivation and subsequent infection might actually be causative and has to be considered and treated. CONCLUSION: Further prospective studies verifying and investigating this observation in terms of frequency and clinical relevance seem indicated. PMID- 27245822 TI - Osteocutaneous radial forearm free flap with bone perfused through anomalous flexor carpi radialis brevis muscle. PMID- 27245821 TI - Genomic Clustering of differential DNA methylated regions (epimutations) associated with the epigenetic transgenerational inheritance of disease and phenotypic variation. AB - BACKGROUND: A variety of environmental factors have been shown to promote the epigenetic transgenerational inheritance of disease and phenotypic variation in numerous species. Exposure to environmental factors such as toxicants can promote epigenetic changes (epimutations) involving alterations in DNA methylation to produce specific differential DNA methylation regions (DMRs). The germline (e.g. sperm) transmission of epimutations is associated with epigenetic transgenerational inheritance phenomena. The current study was designed to determine the genomic locations of environmentally induced transgenerational DMRs and assess their potential clustering. RESULTS: The exposure specific DMRs (epimutations) from a number of different studies were used. The clustering approach identified areas of the genome that have statistically significant over represented numbers of epimutations. The location of DMR clusters was compared to the gene clusters of differentially expressed genes found in tissues and cells associated with the transgenerational inheritance of disease. Such gene clusters, termed epigenetic control regions (ECRs), have been previously suggested to regulate gene expression in regions spanning up to 2-5 million bases. DMR clusters were often found to associate with inherent gene clusters within the genome. CONCLUSION: The current study used a number of epigenetic datasets from previous studies to identify novel DMR clusters across the genome. Observations suggest these clustered DMR within an ECR may be susceptible to epigenetic reprogramming and dramatically influence genome activity. PMID- 27245823 TI - An anatomical study of the dorsal branches of the digital nerves. PMID- 27245824 TI - Paediatric trapeziometacarpal dislocation: a case report. PMID- 27245825 TI - HPV-mediated inactivation of tumor suppressor p53. PMID- 27245826 TI - The female advantage: sex as a possible protective factor against emotion recognition impairment following traumatic brain injury. AB - Although moderate to severe traumatic brain injury (TBI) leads to facial affect recognition impairments in up to 39% of individuals, protective and risk factors for these deficits are unknown. The aim of the current study was to examine the effect of sex on emotion recognition abilities following TBI. We administered two separate emotion recognition tests (one static and one dynamic) to 53 individuals with moderate to severe TBI (females = 28) and 49 demographically matched comparisons (females = 22). We then investigated the presence of a sex-by-group interaction in emotion recognition accuracy. In the comparison group, there were no sex differences. In the TBI group, however, females significantly outperformed males in the dynamic (but not the static) task. Moreover, males (but not females) with TBI performed significantly worse than comparison participants in the dynamic task. Further analysis revealed that sex differences in emotion recognition abilities within the TBI group could not be explained by lesion location, TBI severity, or other neuropsychological variables. These findings suggest that sex may serve as a protective factor for social impairment following TBI and inform clinicians working with TBI as well as research on the neurophysiological correlates of sex differences in social functioning. PMID- 27245828 TI - Stockings to prevent post-thrombotic syndrome. PMID- 27245827 TI - Women's participation in household decision-making and higher dietary diversity: findings from nationally representative data from Ghana. AB - BACKGROUND: Low-quality monotonous diet is a major problem confronting resource constrained settings across the world. Starchy staple foods dominate the diets in these settings. This places the population, especially women of reproductive age, at a risk of micronutrients deficiencies. This study seeks to examine the association between women's decision-making autonomy and women's achievement of higher dietary diversity (DD) and determine the socio-demographic factors that can independently predict women's attainment of higher DD. METHODS: The study used data from the 2008 Ghana Demographic and Health Survey. The participants comprised of 2262 women aged 15-49 years and who have complete dietary data. The DD score was derived from a 24-h recall of intake of foods from nine groups. The score was dichotomized into lower DD (DD <=4) and higher (DD >=5). Logistic regression was used to assess the association between women decision-making autonomy (final say on how to spend money, making household purchases, own health care, opinions on wife-beating, and sexual intercourse with husband) and the achievement of higher DD. The logistic regression models were adjusted for covariates at the individual and household levels. RESULTS: The analysis showed that women participation in decision-making regarding household purchases was significantly associated with higher DD, after adjusting for individual and household level covariates. The odds of achieving higher DD were higher among women who had a say in deciding household purchases, compared to women who did not have a say (OR = 1.74, 95 % CI = 1.24, 2.42). Women who had more than primary education were 1.6 times more likely to achieve higher DD, compared to those with no education (95 % CI = 1.12, 2.20). Compared to women who lived in polygamous households, those who lived in monogamous households had higher odds of achieving higher DD (OR = 1.42, 95 % CI = 1.04, 1.93). CONCLUSIONS: Net other covariates, women who have a say in making household purchases are more likely to achieve higher DD compare to those who do not have a say. This may indicate autonomy to buy nutritious foods, suggesting that improving women decision-making autonomy could have a positive impact on women dietary intake. PMID- 27245830 TI - Screening for Iron Deficiency. PMID- 27245829 TI - Alterations in Pericyte Subpopulations Are Associated with Elevated Blood-Tumor Barrier Permeability in Experimental Brain Metastasis of Breast Cancer. AB - PURPOSE: The blood-brain barrier (BBB) is modified to a blood-tumor barrier (BTB) as a brain metastasis develops from breast or other cancers. We (i) quantified the permeability of experimental brain metastases, (ii) determined the composition of the BTB, and (iii) identified which elements of the BTB distinguished metastases of lower permeability from those with higher permeability. EXPERIMENTAL DESIGN: A SUM190-BR3 experimental inflammatory breast cancer brain metastasis subline was established. Experimental brain metastases from this model system and two previously reported models (triple-negative MDA 231-BR6, HER2+ JIMT-1-BR3) were serially sectioned; low- and high-permeability lesions were identified with systemic 3-kDa Texas Red dextran dye. Adjoining sections were used for quantitative immunofluorescence to known BBB and neuroinflammatory components. One-sample comparisons against a hypothesized value of one were performed with the Wilcoxon signed-rank test. RESULTS: When uninvolved brain was compared with any brain metastasis, alterations in endothelial, pericytic, astrocytic, and microglial components were observed. When metastases with relatively low and high permeability were compared, increased expression of a desmin+ subpopulation of pericytes was associated with higher permeability (231-BR6 P = 0.0002; JIMT-1-BR3 P = 0.004; SUM190-BR3 P = 0.008); desmin+ pericytes were also identified in human craniotomy specimens. Trends of reduced CD13+ pericytes (231-BR6 P = 0.014; JIMT-1-BR3 P = 0.002, SUM190-BR3, NS) and laminin alpha2 (231-BR6 P = 0.001; JIMT-1-BR3 P = 0.049; SUM190-BR3 P = 0.023) were also observed with increased permeability. CONCLUSIONS: We provide the first account of the composition of the BTB in experimental brain metastasis. Desmin+ pericytes and laminin alpha2 are potential targets for the development of novel approaches to increase chemotherapeutic efficacy. Clin Cancer Res; 22(21); 5287-99. (c)2016 AACR. PMID- 27245831 TI - Interstitial Lung Disease in Children Younger Than 2 Years. AB - Childhood interstitial lung disease (chILD) represents a highly heterogeneous group of rare disorders associated with substantial morbidity and mortality. Although our understanding of chILD remains limited, important advances have recently been made, the most important being probably the appreciation that disorders that present in early life are distinct from those occurring in older children and adults, albeit with some overlap. chILD manifests with diffuse pulmonary infiltrates and nonspecific respiratory signs and symptoms, making exclusion of common conditions presenting in a similar fashion an essential preliminary step. Subsequently, a systematic approach to diagnosis includes a careful history and physical examination, computed tomography of the chest, and some or all of bronchoscopy with bronchoalveolar lavage, genetic testing, and if diagnostic uncertainty persists, lung biopsy. This review focuses on chILD presenting in infants younger than 2 years of age and discusses recent advances in the classification, diagnostic approach, and management of chILD in this age range. We describe novel genetic entities, along with initiatives that aim at collecting clinical data and biologic samples from carefully characterized patients in a prospective and standardized fashion. Early referral to expert centers and timely diagnosis may have important implications for patient management and prognosis, but effective therapies are often lacking. Following massive efforts, international collaborations among the key stakeholders are finally starting to be in place. These have allowed the setting up and conducting of the first randomized controlled trial of therapeutic interventions in patients with chILD. PMID- 27245832 TI - Kantorowska et al, Impact of Donor Milk Availability on Breast Milk Use and Necrotizing Enterocolitis Rates. Pediatrics. 2016;137(3):e20153123. PMID- 27245833 TI - Neurocognitive Development After Pediatric Heart Surgery. AB - OBJECTIVES: Children with congenital heart disease (CHD) often have neurocognitive deficits, sometimes with a detrimental impact on daily and school functioning. These deficits may increase through childhood. In this study, we investigated whether children with CHD, who underwent heart surgery as infants, show more neurocognitive deficits, especially in the executive functions, as they get older, compared with healthy controls. METHODS: In this longitudinal follow up study, 107 children with CHD and 77 healthy control children underwent extensive neurocognitive testing at 4 years of age. Ninety-three percent of the children (100 patients with CHDs and 72 controls) underwent a second neurocognitive testing 3 years later. Intelligence, visual-motor integration (VMI), alertness, motor coordination, executive functions, and psychosocial functioning were assessed. RESULTS: IQ scores were consistently lower in the CHD group (P < .001); however, the difference of 11.7 IQ points between both groups at follow-up 1 decreased to 7 IQ points at follow-up 2 (P = .003). Inhibition reaction time had improved in both study groups at follow-up 2 (P < .001) and did not differ between both groups from follow-up 1 to follow-up 2 (P = .849). Deficits in VMI, alertness, motor coordination, and psychosocial functioning also did not worsen for patients with CHDs at follow-up 2, compared with healthy controls. CONCLUSIONS: Children with CHD, who underwent heart surgery as infants, do not show an increase of neurocognitive deficits between the ages of 4 and 7 years, compared with healthy controls. Patients with CHDs keep deficits in intelligence, VMI, and psychosocial functioning, but seem to partially grow out of their deficits. PMID- 27245834 TI - Toxic Epidermal Necrolysis-Like Cutaneous Lupus in Pediatric Patients: A Case Series and Review. AB - Bullous eruptions in patients with underlying systemic lupus erythematosus (LE) can mimic toxic-epidermal necrolysis (TEN), a rapidly progressive mucocutaneous reaction usually associated with medication use. Differentiating between classic drug-induced TEN and TEN-like cutaneous LE is important but difficult. We report a series of 3 patients with pediatric systemic LE who were admitted with severe worsening of skin disease resembling TEN. However, the initial photo-distribution of the eruption, subacute progression, limited mucosal involvement, mild systemic symptoms, supportive biopsy and laboratory results, and lack of culprit drugs was more suggestive of a TEN-like cutaneous LE. These patients recovered with various systemic immunosuppressive medications including methylprednisolone, intravenous immunoglobulin, and plasmapheresis. Our cases are rare and demonstrate key clinical and histologic features of TEN-like cutaneous LE in young patients and the importance of differentiating this entity from drug-induced TEN. PMID- 27245835 TI - Author's Response: USPSTF Response to Pettei et al. PMID- 27245836 TI - Critical Issues and Controversies in Carotid Artery Stenosis: False Knowledge Is More Dangerous Than Ignorance. PMID- 27245837 TI - Vascular Educational Needs in the "Real World" and Teaching of Vascular Surgery in Medical Schools. PMID- 27245838 TI - Ethanol production from a biomass mixture of furfural residues with green liquor peroxide saccarified cassava liquid. AB - BACKGROUND: As the most abundant renewable resources, lignocellulosic materials are ideal candidates as alternative feedstock for bioethanol production. Cassava residues (CR) are byproducts of the cassava starch industry which can be mixed with lignocellulosic materials for ethanol production. The presence of lignin in lignocellulosic substrates can inhibit saccharification by reducing the cellulase activity. Simultaneous saccharification and fermentation (SSF) of furfural residues (FR) pretreated with green liquor and hydrogen peroxide (GL-H2O2) with CR saccharification liquid was investigated. The final ethanol concentration, yield, initial rate, number of live yeast cells, and the dead yeast ratio were compared to evaluate the effectiveness of combining delignificated lignocellulosic substrates and starchy substrates for ethanol production. RESULTS: Our results indicate that 42.0 % of FR lignin removal was achieved on FR using of 0.06 g H2O2/g-substrate and 9 mL GL/g-substrate at 80 degrees C. The highest overall ethanol yield was 93.6 % of the theoretical. When the ratio of 0.06 g/g-H2O2-GL-pretreated FR to CR was 5:1, the ethanol concentration was the same with that ratio of untreated FR to CR of 1:1. Using 0.06 g/g-H2O2-GL pretreated FR with CR at a ratio of 2:1 resulted in 51.9 g/L ethanol concentration. Moreover, FR pretreated with GL-H2O2 decreased the concentration of byproducts in SSF compared with that obtained in the previous study. CONCLUSIONS: The lignin in FR would inhibit enzyme activity and GL-H2O2 is an advantageous pretreatment method to treat FR and high intensity of FR pretreatment increased the final ethanol concentration. The efficiency of ethanol fermentation of was improved when delignification increased. GL-H2O2 is an advantageous pretreatment method to treat FR. As the pretreatment dosage of GL H2O2 on FR increased, the proportion of lignocellulosic substrates was enhanced in the SSF of the substrate mixture of CR and FR as compared with untreated FR. Moreover, the final ethanol concentration was increased with a high ethanol yield and lower byproduct concentrations. PMID- 27245841 TI - Corrigendum. PMID- 27245839 TI - KCa1.1, a calcium-activated potassium channel subunit alpha 1, is targeted by miR 17-5p and modulates cell migration in malignant pleural mesothelioma. AB - BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive, locally invasive, cancer elicited by asbestos exposure and almost invariably a fatal diagnosis. To date, we are one of the leading laboratory that compared microRNA expression profiles in MPM and normal mesothelium samples in order to identify dysregulated microRNAs with functional roles in mesothelioma. We interrogated a significant collection of MPM tumors and normal pleural samples in our biobank in search for novel therapeutic targets. METHODS: Utilizing mRNA-microRNA correlations based on differential gene expression using Gene Set Enrichment Analysis (GSEA), we systematically combined publicly available gene expression datasets with our own MPM data in order to identify candidate targets for MPM therapy. RESULTS: We identified enrichment of target binding sites for the miR-17 and miR-30 families in both MPM tumors and cell lines. RT-qPCR revealed that members of both families were significantly downregulated in MPM tumors and cell lines. Interestingly, lower expression of miR-17-5p (P = 0.022) and miR-20a-5p (P = 0.026) was clearly associated with epithelioid histology. We interrogated the predicted targets of these differentially expressed microRNA families in MPM cell lines, and identified KCa1.1, a calcium-activated potassium channel subunit alpha 1 encoded by the KCNMA1 gene, as a target of miR-17-5p. KCa1.1 was overexpressed in MPM cells compared to the (normal) mesothelial line MeT-5A, and was also upregulated in patient tumor samples compared to normal mesothelium. Transfection of MPM cells with a miR-17-5p mimic or KCNMA1-specific siRNAs reduced mRNA expression of KCa1.1 and inhibited MPM cell migration. Similarly, treatment with paxilline, a small molecule inhibitor of KCa1.1, resulted in suppression of MPM cell migration. CONCLUSION: These functional data implicating KCa1.1 in MPM cell migration support our integrative approach using MPM gene expression datasets to identify novel and potentially druggable targets. PMID- 27245840 TI - Cyclosporine A, a Potential Therapy of Ischemic Reperfusion Injury. A Common History for Heart and Brain. AB - BACKGROUND: Ischemic stroke (IS) and acute myocardial infarction require emergency reperfusion tissue in order to improve functional outcome. Intra arterial thrombectomy recently showed very encouraging improvement in IS patients' outcome. However, endovascular methods enhancing reperfusion may expose patients to increase in ischemic reperfusion injury. Experimental evidence indicates that brain ischemic reperfusion injury may be attenuated by ischemic pre- and postconditioning. The opening of mitochondrial permeability transition pore plays a critical role in the onset of reperfusion damage. This mechanism can be inhibited by immunosuppressive drugs like cyclosporine A (CsA). SUMMARY: In this review, we present existing experimental and clinical data suggesting that conditioning interventions may prevent brain ischemic reperfusion injury and future challenge for neuroprotection by CsA in acute IS. Key Messages: The concept of conditioning has been recently investigated clinically but to a lesser extent in the realm of IS. Recent experimental and phase II clinical research has suggested potential neuroprotective properties of cyclosporine; however, further larger clinical trials are needed to demonstrate that CsA improves clinical outcome in acute IS patients. PMID- 27245842 TI - STIMs and Orai1 regulate cytokine production in spinal astrocytes. AB - BACKGROUND: Our previous study demonstrated that a store-operated calcium channel (SOCC) inhibitor (YM-58483) has central analgesic effects. However, the cellular and molecular mechanisms of such effects remain to be determined. It is well known that glial cells play important roles in central sensitization. SOC entry (SOCE) has been implicated in many cell types including cortical astrocytes. However, the role of the SOCC family in the function of astrocytes has not been determined. Here, we thoroughly investigated the expression and the functional significance of SOCCs in spinal astrocytes. METHODS: Primary cultured astrocytes were prepared from neonatal (P2-P3) CD1 mice. Expressions of mRNAs and proteins were respectively assessed by real-time PCR and Western blot analysis. SOCE was measured using a calcium imaging system. Live-cell STIM1 translocation was detected using a confocal microscope. Cytokine levels were measured by the enzyme linked immunosorbent assay. RESULTS: We found that the SOCC family is expressed in spinal astrocytes and that depletion of calcium stores from the endoplasmic reticulum by cyclopiazonic acid (CPA) resulted in a large sustained calcium entry, which was blocked by SOCC inhibitors. Using the siRNA knockdown approach, we identified STIM1 and Orai1 as primary components of SOCCs in spinal astrocytes. We also observed thapsigargin (TG)- or CPA-induced puncta formation of STIM1 and Orai1. In addition, activation of SOCCs remarkably promoted TNF alpha and IL-6 production in spinal astrocytes, which were greatly attenuated by knockdown of STIM1 or Orai1. Importantly, knockdown of STIM2 and Orai1 dramatically decreased lipopolysaccharide-induced TNF-alpha and IL-6 production without changing cell viability. CONCLUSIONS: This study presents the first evidence that STIM1, STIM2, and Orai1 mediate SOCE and are involved in cytokine production in spinal astrocytes. Our findings provide the basis for future assessment of SOCCs in pain and other central nervous system disorders associated with abnormal astrocyte activities. PMID- 27245843 TI - Systems to identify potentially inappropriate prescribing in people with advanced dementia: a systematic review. AB - BACKGROUND: Systems for identifying potentially inappropriate medications in older adults are not immediately transferrable to advanced dementia, where the management goal is palliation. The aim of the systematic review was to identify and synthesise published systems and make recommendations for identifying potentially inappropriate prescribing in advanced dementia. METHODS: Studies were included if published in a peer-reviewed English language journal and concerned with identifying the appropriateness or otherwise of medications in advanced dementia or dementia and palliative care. The quality of each study was rated using the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) checklist. Synthesis was narrative due to heterogeneity among designs and measures. Medline (OVID), CINAHL, the Cochrane Database of Systematic Reviews (2005 - August 2014) and AMED were searched in October 2014. Reference lists of relevant reviews and included articles were searched manually. RESULTS: Eight studies were included, all of which were scored a high quality using the STROBE checklist. Five studies used the same system developed by the Palliative Excellence in Alzheimer Care Efforts (PEACE) Program. One study used number of medications as an index, and two studies surveyed health professionals' opinions on appropriateness of specific medications in different clinical scenarios. CONCLUSIONS: Future research is needed to develop and validate systems with clinical utility for improving safety and quality of prescribing in advanced dementia. Systems should account for individual clinical context and distinguish between deprescribing and initiation of medications. PMID- 27245844 TI - Validation of the German version of the insomnia severity index in adolescents, young adults and adult workers: results from three cross-sectional studies. AB - BACKGROUND: A variety of objective and subjective methods exist to assess insomnia. The Insomnia Severity Index (ISI) was developed to provide a brief self report instrument useful to assess people's perception of sleep complaints. The ISI was developed in English, and has been translated into several languages including German. Surprisingly, the psychometric properties of the German version have not been evaluated, although the ISI is often used with German-speaking populations. METHODS: The psychometric properties of the ISI are tested in three independent samples: 1475 adolescents, 862 university students, and 533 police and emergency response service officers. In all three studies, participants provide information about insomnia (ISI), sleep quality (Pittsburgh Sleep Quality Index), and psychological functioning (diverse instruments). Descriptive statistics, gender differences, homogeneity and internal consistency, convergent validity, and factorial validity (including measurement invariance across genders) are examined in each sample. RESULTS: The findings show that the German version of the ISI has generally acceptable psychometric properties and sufficient concurrent validity. Confirmatory factor analyses show that a 1-factor solution achieves good model fit. Furthermore, measurement invariance across gender is supported in all three samples. CONCLUSIONS: While the ISI has been widely used in German-speaking countries, this study is the first to provide empirical evidence that the German version of this instrument has good psychometric properties and satisfactory convergent and factorial validity across various age groups and both men and women. Thus, the German version of the ISI can be recommended as a brief screening measure in German-speaking populations. PMID- 27245845 TI - Case mix adjustment of health outcomes, resource use and process indicators in childbirth care: a register-based study. AB - BACKGROUND: Unwarranted variation in care practice and outcomes has gained attention and inter-hospital comparisons are increasingly being used to highlight and understand differences between hospitals. Adjustment for case mix is a prerequisite for meaningful comparisons between hospitals with different patient populations. The objective of this study was to identify and quantify maternal characteristics that impact a set of important indicators of health outcomes, resource use and care process and which could be used for case mix adjustment of comparisons between hospitals. METHODS: In this register-based study, 139 756 deliveries in 2011 and 2012 were identified in regional administrative systems from seven Swedish regions, which together cover 67 % of all deliveries in Sweden. Data were linked to the Medical birth register and Statistics Sweden's population data. A number of important indicators in childbirth care were studied: Caesarean section (CS), induction of labour, length of stay, perineal tears, haemorrhage > 1000 ml and post-partum infections. Sociodemographic and clinical characteristics deemed relevant for case mix adjustment of outcomes and resource use were identified based on previous literature and based on clinical expertise. Adjustment using logistic and ordinary least squares regression analysis was performed to quantify the impact of these characteristics on the studied indicators. RESULTS: Almost all case mix factors analysed had an impact on CS rate, induction rate and length of stay and the effect was highly statistically significant for most factors. Maternal age, parity, fetal presentation and multiple birth were strong predictors of all these indicators but a number of additional factors such as born outside the EU, body mass index (BMI) and several complications during pregnancy were also important risk factors. A number of maternal characteristics had a noticeable impact on risk of perineal tears, while the impact of case mix factors was less pronounced for risk of haemorrhage > 1000 ml and post-partum infections. CONCLUSIONS: Maternal characteristics have a large impact on care process, resource use and outcomes in childbirth care. For meaningful comparisons between hospitals and benchmarking, a broad spectrum of sociodemographic and clinical maternal characteristics should be accounted for. PMID- 27245846 TI - Classics in abdominal imaging: the bamboo spine. PMID- 27245847 TI - Threatened by mining, polymetallic nodules are required to preserve abyssal epifauna. AB - Polymetallic nodule mining at abyssal depths in the Clarion Clipperton Fracture Zone (Eastern Central Pacific) will impact one of the most remote and least known environments on Earth. Since vast areas are being targeted by concession holders for future mining, large-scale effects of these activities are expected. Hence, insight into the fauna associated with nodules is crucial to support effective environmental management. In this study video surveys were used to compare the epifauna from sites with contrasting nodule coverage in four license areas. Results showed that epifaunal densities are more than two times higher at dense nodule coverage (>25 versus <=10 individuals per 100 m(2)), and that taxa such as alcyonacean and antipatharian corals are virtually absent from nodule-free areas. Furthermore, surveys conducted along tracks from trawling or experimental mining simulations up to 37 years old, suggest that the removal of epifauna is almost complete and that its full recovery is slow. By highlighting the importance of nodules for the epifaunal biodiversity of this abyssal area, we urge for cautious consideration of the criteria for determining future preservation zones. PMID- 27245848 TI - The effect on pregnancy and multiples of transferring 1-3 embryos in women at least 40 years old. AB - PURPOSE "CAPSULE" IS MANDATORY. PLEASE PROVIDE.SINGLE EMRBYO TRANSFER (SET) IN WOMEN >=40 YEARS OLD APPEARS TO LOWER THE CHANCE OF A PREGNANCY. HOWEVER, IT MINIMIZES THE RISK OF MULTIPLE PREGNANCIES EVEN IN WOMEN OF ADVANCED MATERNAL AGE. THEREFORE, WOMEN 40 YEARS OF AGE OR OLDER SHOULD BE OFFERED (SET).: This study was performed to investigate the multiple pregnancies and live birth rates when 1-3 embryos are transferred at this age in women at least 40 years of age. METHOD: A retrospective analysis of data which included 631 women aged 40 to 46 years, who underwent 901 cycles of IVF, from August 2010 to June 2012 was undertaken. These women underwent embryo transfer of 1-3 non-donor fresh embryo(s). RESULTS: Results suggested that the average pregnancy rate when up to three embryos were transferred was 25 % for women 40 years old, 20 % for women 41 years old, 16 % for women 42 years old, 17 % for women 43 years old, 8 % for women 44 years old, 6 % for women 45 years old, and 0 % for women 46 years old. No live births occurred in women treated after their 44th birthday, and only patients younger than 42 years of age receiving double embryo transfer had a live birth of twins. Live birth rates increased as more embryos were transferred for 40- and 42-year-old subjects (p = 0.01 and 0.05, respectively). CONCLUSIONS: From these results, it was concluded that SET in women >=40 years old appears to lower the chance of a pregnancy. However, it minimizes the risk of multiple pregnancies even in women of advanced maternal age. Women 40 years of age or older should be offered single-embryo transfer. Further studies are needed to determine risk of multiple pregnancies in women 42 years of age or older when few embryos are transferred. Decisions on the number of embryos to transfer should be on a case by case basis, in discussion with the patient. PMID- 27245849 TI - A Characterization of Movement Skills in Obese Children With and Without Prader Willi Syndrome. AB - PURPOSE: The aim of this study was twofold: (a) to measure and compare motor proficiency in obese children with Prader-Willi syndrome (OB-PWS) to that in obese children without PWS (OB), and (b) to compare motor proficiency in OB-PWS and OB to normative data. METHOD: Motor proficiency was measured using the Bruininks-Oseretsky Test of Motor Proficiency-Second Edition-Complete Form, a norm-referenced assessment of motor function. Participants were 18 OB-PWS and 44 OB (8 to 11 years of age). The scores on the 8 subtests and the total motor composite were used to compare OB-PWS and OB. Furthermore, the scores on the 4 motor-area composites were used to compare OB-PWS and OB against normative data. RESULTS: OB-PWS scored significantly lower than OB across all 8 subtests. OB-PWS also had significantly lower motor proficiency scores on all motor-area composites when compared with the normative sample. OB-PWS most frequently (67% 83%) scored well below average on the gross motor subtests. Although not as high as on the gross motor subtests, this finding also held true for the fine motor subtests with 39% to 45% of OB-PWS scoring well below average. CONCLUSION: Motor proficiency is very poor in OB-PWS, in particular for gross motor skills. Physical, neurological, and developmental characteristics inherent to the syndrome may explain this low performance. PMID- 27245850 TI - Sub-clinical orthostatic hypotension is associated with greater subjective memory impairment in older adults. AB - INTRODUCTION: Orthostatic blood pressure (BP) is a measure of cardiovascular autonomic function. Orthostatic BP dysregulation may lie on the causal pathway to dementia. Subjective memory impairment (SMI) is commonly reported by older people some of whom may progress to dementia. We hypothesised that sub-clinical orthostatic hypotension would be associated with SMI and explored these associations according to sex. METHODS: Cross-sectional analysis of data from 4340 participants aged 50 and over collected during the first wave (2009-2011) of the cohort study, The Irish Longitudinal Study on Ageing. Subjective memory was rated according to a 5-point scale ranging from 'poor' to 'excellent'. BP was measured during orthostatic stress using continuous non-invasive beat-to-beat recording over 2 min. RESULTS: 2% reported 'poor' subjective memory, 12.3% 'fair' , 38% 'good', 33% 'very good' and 14.6% 'excellent'. After controlling for several potential confounding factors including cardiovascular risk, objective cognition, and depressive symptoms mean systolic orthostatic BP was lowest in those with poor subjective memory: 92.2 mmHg (CI95% = 87.1, 97.3) versus excellent 99.3 mmHg (CI95% = 97.4, 101.2); p = 0.011. Further adjustment for supine systolic BP suggested that men with poor subjective memory reached the lowest average systolic orthostatic BP and had the greatest impairment in systolic orthostatic BP stabilisation to baseline levels at 10 s post-stand ( 6.64 mmHg; CI95% = -11.49, -1.79; p = 0.007). CONCLUSIONS: Sub-clinical orthostatic hypotension is associated with SMI, and there are sex-specific relationships evident in this population-based cohort. Subtle cardiovascular autonomic dysfunction may represent a modifiable risk marker at an early stage of cognitive decline in older adults. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27245851 TI - New light on proteases regulating pigmentation. PMID- 27245852 TI - Restoration of Thickness, Density, and Volume for Highly Blurred Thin Cortical Bones in Clinical CT Images. AB - In clinical CT images containing thin osseous structures, accurate definition of the geometry and density is limited by the scanner's resolution and radiation dose. This study presents and validates a practical methodology for restoring information about thin bone structure by volumetric deblurring of images. The methodology involves 2 steps: a phantom-free, post-reconstruction estimation of the 3D point spread function (PSF) from CT data sets, followed by iterative deconvolution using the PSF estimate. Performance of 5 iterative deconvolution algorithms, blind, Richardson-Lucy (standard, plus Total Variation versions), modified residual norm steepest descent (MRNSD), and Conjugate Gradient Least Squares were evaluated using CT scans of synthetic cortical bone phantoms. The MRNSD algorithm resulted in the highest relative deblurring performance as assessed by a cortical bone thickness error (0.18 mm) and intensity error (150 HU), and was subsequently applied on a CT image of a cadaveric skull. Performance was compared against micro-CT images of the excised thin cortical bone samples from the skull (average thickness 1.08 +/- 0.77 mm). Error in quantitative measurements made from the deblurred images was reduced 82% (p < 0.01) for cortical thickness and 55% (p < 0.01) for bone mineral mass. These results demonstrate a significant restoration of geometrical and radiological density information derived for thin osseous features. PMID- 27245853 TI - Autophagy regulation depends on ER homeostasis controlled by lipid droplets. AB - Macroautophagy (hereafter autophagy) is a highly conserved homeostasis and quality control process critically linked to neurodegeneration, metabolic diseases, cancer, and aging. A key feature of autophagy is the de novo formation of autophagosomes, double-membrane vesicular structures encapsulating cytoplasmic cargo for vacuolar turnover and recycling. The membrane rearrangements underlying nucleation, expansion, closure, and vacuolar fusion of autophagosomes are driven by multicomponent core autophagy machinery in cooperation with numerous factors involved in a variety of cellular processes. Our current understanding of the origin and contribution of diverse membrane sources to autophagosome biogenesis and of cellular functions enabling stress-appropriate autophagy responses critical for cell health and survival remains limited. Here, we summarize and discuss our recent findings analyzing the role of lipid droplets (LDs), conserved intracellular storage compartments for neutral lipids, for autophagy regulation. Our data indicate that LDs are dispensable as membrane sources, but fulfill critical functions for maintaining endoplasmic reticulum (ER) homeostasis, including buffering of newly synthesized fatty acids and maintenance of phospholipid composition, required for intact autophagy regulation and cell survival during nutrient stress. PMID- 27245854 TI - Survey of community pharmacy residents' perceptions of transgender health management. AB - OBJECTIVES: 1) To measure the general perceptions and attitudes of community pharmacy residents toward transgender patients and health; 2) to identify gaps in didactic education regarding transgender health care among residents; and 3) to evaluate residents' level of support for pharmacists receiving education in transgender health care. METHODS: This study was a cross-sectional survey delivered online. Community residency directors were e-mailed a cover letter and a 34-question online survey. The directors were asked to forward the survey to their residents for completion within 4 weeks. Responses were anonymous with no identifiers collected on the survey. Survey responses used a combination of open response, multiple-choice, and Likert-scale questions aimed at gathering respondents' demographic information, perceptions of managing transgender patients and the need for receiving additional education in transgender health care. RESULTS: Overall, the results of the survey indicated that community pharmacy residents support integrating transgender health management into pharmacy education and recognize that the overwhelming barriers to care for these patients include discrimination and lack of provider knowledge. Significant findings include: 82.7% of community residents think that community pharmacists play an important role in providing care for transgender patients; 98.2% think that they have a responsibility to treat transgender patients; and 71.4% were not educated about transgender patient issues in pharmacy school. Only 36.2% of community residents felt confident in their ability to treat transgender patients. CONCLUSION: Community pharmacy residents list discrimination and lack of provider knowledge as the major barriers to care for transgender patients. Residents do not feel confident in their ability to treat and manage transgender patients. The majority of residents were not educated about transgender patient issues while in pharmacy school and think that community pharmacists need more education in this area. Residents support integrating transgender health education into continuing education programs and pharmacy school curricula. PMID- 27245855 TI - Pediatric asthma medication therapy management through community pharmacy and primary care collaboration. AB - OBJECTIVES: To design and implement a collaborative medication therapy management (MTM) program targeting pediatric patients with high-risk asthma in a community pharmacy. SETTING: Underserved inner city of Cincinnati, OH. PRACTICE DESCRIPTION: A large national grocery store chain pharmacy and an academic hospital developed a partnership aimed at improving asthma care for shared patients. An interdisciplinary project team was formed, including 2 clinical pharmacists, 1 pharmacy district clinical coordinator, 1 pharmacy division clinical coordinator, 1 associate professor at a college of pharmacy, 1 pharmacy resident, and 3 pediatric physicians. This pilot project involved 2 Kroger Pharmacy sites and Cincinnati Children's Hospital Medical Center's (CCHMC) 3 pediatric primary care centers. PRACTICE INNOVATION: Kroger and CCHMC staff identified shared high-risk asthma patients (those cared for at the included primary care centers who used Kroger for their medication fills) with the use of information from validated symptom assessments (Asthma Control Test), refill history, and recent health care utilization. Community pharmacists recruited jointly identified patients and provided a targeted MTM intervention. Education focused on asthma diagnosis, types of asthma medications, appropriate medication administration, and environmental triggers. Pharmacists suggested medication changes to prescribers via facsimile. Pharmacists followed up with patients in 30 days to assess asthma control, provide additional education, and propose further recommendations. EVALUATION: Outcomes evaluated included the average number of recommendations made to patients and prescribers and acceptance rates for each of those measures. RESULTS: Six patients completed the project. Pharmacists provided an average of 3.7 recommendations to each patient and 1.5 to prescribers for each patient; 77.3% and 100% recommendations were accepted, respectively. CONCLUSION: This pilot project describes the design and implementation of a pharmacist physician collaborative program for high-risk pediatric asthma patients. The greatest outcome of this project was the formation of a collaborative team between pharmacists and physicians that continues to work together on additional family-centered initiatives. PMID- 27245856 TI - Pseudophakic rhegmatogenous retinal detachment: combined pars plana vitrectomy and scleral buckle versus pars plana vitrectomy alone. AB - PURPOSE: To compare the outcomes of combined vitrectomy + scleral buckle (SB) and vitrectomy alone for pseudophakic rhegmatogenous retinal detachment (RRD). METHODS: Cases included 65 eyes of 63 patients with primary non-complex pseudophakic RRD. The first group underwent combined vitrectomy + SB between January 2010 and August 2012, and the second group was treated with vitrectomy alone between September 2012 and October 2013. The medical records of the patients were reviewed for preoperative examinations, follow-up examinations (including final visual acuity [VA]), appearance of redetachment and complications. The main outcomes were recurrent retinal detachment, complications, and VA improvement. RESULTS: The rate of single-surgery anatomic success was non-significantly lower in the combined vitrectomy + SB group compared with the vitrectomy alone group - 75.8 % versus 84.4 % respectively (P = 0.683). Complications were significantly more frequent in the former compared to the latter (P = 0.014). The final VAs were 0.580 (logMAR) and 0.486, respectively (P = 0.258). VA improvement of >=3 lines was achieved in 48.5 % and in 50 % of the eyes respectively (P = 0.769). CONCLUSIONS: There were no significant differences in single-surgery anatomic success rates and VA improvement between combined vitrectomy + SB and vitrectomy alone for pseudophakic RRD. Significantly more complications occurred in the combination group. PMID- 27245857 TI - Risk and prognostic factors of transplantation-associated thrombotic microangiopathy in allogeneic haematopoietic stem cell transplantation: a nested case control study. AB - Transplantation-associated thrombotic microangiopathy (TA-TMA) is a significant complication of haematopoietic stem cell transplantation. However, it remains controversial which clinical or laboratory markers are of evident risk and prognostic value. From 2006 to 2013, a nested case control study was carried out in our centre to study the risk and prognostic factors of TA-TMA. A total of 654 consecutive patients who underwent allogeneic haematopoietic stem cell transplantation were studied. Twenty-six (4.0%) patients matched the established diagnostic criteria. Subjects with TA-TMA had significantly higher 3-year none relapse mortality compared with those without (65.4% vs 15.4%, P < 0.0001). Grades 2 to 4 aGVHD and cytomegalovirus viremia were independent risk factors, and serum LDH level >500U/L as well as hypertension were early signs of TA-TMA occurrence. Liver dysfunction and significant gastric bleeding were independent risk factors for TA-TMA related mortality. Subjects with either liver dysfunction or significant gastric bleeding had significantly higher 3 year TA-TMA related mortality cumulative incidence than subjects without. These observations lead to the conclusion that allo-HSCT recipients with grades 2 to 4 aGVHD or cytomegalovirus viremia should be monitored for TA-TMA. Liver dysfunction and significant gastric bleeding are prognostic factors for TA-TMA. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27245859 TI - In response to Alqahtani et al. (2015 Jul; 24(7):709-15): suggesting an international regulatory harmonization for priority review drugs need further investigations. PMID- 27245860 TI - Response to letter to the editor regarding Alqahtani et al. Article on priority review drugs approved by the FDA and the EMA: time for international regulatory harmonization of pharmaceuticals? PMID- 27245858 TI - Recent advances in the modification of taste and food preferences following bariatric surgery. AB - There is a large body of evidence indicating that bariatric surgery provides durable weight loss and health benefits to patients who are obese and have comorbidities such as type 2 diabetes (T2D). However, there are still many questions related to mechanisms of metabolic improvement, predictors of success/failure, and long term consequences, which need to be answered. More recently, there has been a particular interest in the modulation of taste and food preferences that occurs after bariatric surgery and how this affects weight loss in different individuals. Animal models as well as human studies have shed some light on the role of taste in changing food preferences and how these changes may affect weight loss after surgery. The goal of this review is to discuss the physiological and behavioral consequences of bariatric surgery as a treatment for obesity and T2D, with particular emphasis on recent studies describing bariatric surgery-induced modifications in taste perception and food preferences. PMID- 27245861 TI - Enterovirus infections in Singaporean children: an assessment of neurological manifestations and clinical outcomes. AB - INTRODUCTION: Enterovirus infections in childhood can be associated with significant neurological morbidity. This study aimed to describe the prevalence and range of neurological manifestations, determine the clinical characteristics and assess differences in clinical outcomes for Singaporean children diagnosed with enterovirus infections. METHODS: In this single-centre, case-control study, clinical data was collected retrospectively from patients admitted to National University Hospital, Singapore, from August 2007 to October 2011 and diagnosed with enterovirus infection, based on the enterovirus polymerase chain reaction test, or cultures from throat and rectal swabs or cerebrospinal fluid samples. The occurrence of neurological manifestations was reviewed and clinical outcomes were assessed. RESULTS: A total of 48 patients (age range: six days-17.8 years) were included in the study. Neurological manifestations were seen in 75.0% of patients, 63.9% of whom presented with aseptic meningitis. Other neurological manifestations included encephalitis, acute cerebellitis, transverse myelitis and autonomic dysfunction. The incidence of neurological manifestations was significantly higher in patients aged > 1 year as compared to younger patients (p = 0.043). In patients without neurological manifestations, a significantly higher proportion presented with hand, foot and mouth disease and poor feeding. Long term neurological sequelae were seen in 16.7% of patients with neurological manifestations. CONCLUSION: A wide spectrum of neurological manifestations resulting in a relatively low incidence of long-term neurological sequelae was observed in our study of Singaporean children with enterovirus infections. As some of these neurological morbidities were severe, careful evaluation of children with neurological involvement is therefore necessary. PMID- 27245862 TI - Decision-to-delivery intervals and total duration of surgery for Caesarean sections in a tertiary general hospital. AB - INTRODUCTION: This study aimed to determine the decision-to-delivery intervals (DDIs), total duration of surgery and factors influencing these for Caesarean sections (CSs). METHODS: A retrospective study was conducted of all CSs performed from August 2013 to June 2014 at a single tertiary general hospital. Data collected included maternal demographics, indications for CS, category of urgency, DDI, total duration of surgery, grade of first surgeon and number of previous CSs. RESULTS: In total, 488 CSs (Category 1: n = 28; Category 2: n = 137; Category 3: n = 184; Category 4: n = 139) were studied. Overall mean duration of surgery was 41.7 minutes. Mean DDI was 23.9 minutes and 64.5 minutes for Category 1 and Category 2 CSs, respectively. For Category 1 CSs, deliveries during office hours had a significantly shorter DDI than deliveries out of office hours (p < 0.05). For Category 2 CSs, deliveries during office hours had a significantly longer DDI (p < 0.05). Total duration of surgery for senior surgeons was significantly shorter than for trainee surgeons (p < 0.05). Women with no previous CSs had a significantly shorter duration of surgery than those who had one or more (p < 0.05). CONCLUSION: The majority of the deliveries were within the recommended DDI corresponding to the degree of urgency of CS. The influence of time of day on DDI might be due to challenges of time taken to transfer patients to operating theatres. Total duration of surgery was influenced by surgical experience, history of previous CS and individual surgical styles and preferences. PMID- 27245863 TI - Patterns and predictors of treatment outcome for antenatal major depression. AB - INTRODUCTION: Antenatal major depression is a relatively common and potentially debilitating illness, but knowledge of its treatment outcomes and strategies is still lacking. This study aimed to explore the clinical profiles and treatment outcomes of patients with antenatal major depression, to look for patterns and associations that could guide subsequent research and clinical applications. METHODS: From May 2006 to November 2010, 118 consecutive patients with antenatal major depression were naturalistically assessed over eight months of individualised therapy, and their characteristics were assessed as potential predictors of treatment outcome. RESULTS: All participants accepted supportive counselling and case management, although only 51 (43.2%) participants accepted low-dose antidepressant therapy. Overall, 95 (80.5%) of them were successfully discharged, while 12 (10.2%) required extended treatment into the postnatal period. An equation for prognosticating the need for extended treatment was obtained using multiple logistic regression analysis, which incorporated three predictors: previous depression (odds ratio [OR] 12.4, 95% confidence interval [CI] 1.40-110; p = 0.024); maternal age < 26 years or > 35 years (OR 6.88, 95% CI 1.67-28.4; p = 0.008); and no use of antidepressant (OR 6.94, 95% CI 0.79-60.9; p = 0.080). Among participants with previous depression and at either extreme of maternal age, the number needed to treat with antidepressants to avert extended treatment was three. CONCLUSION: The majority of women with antenatal major depression recovered after receiving short-term treatment. Those with previous depression and who were of relative extreme maternal age were most likely to benefit from antidepressant treatment to expedite recovery. PMID- 27245864 TI - High frequency of antidrug antibodies and association of random drug levels with efficacy in certolizumab pegol-treated patients with rheumatoid arthritis: results from the BRAGGSS cohort. AB - OBJECTIVES: To evaluate (i) the association between random certolizumab drug levels, antidrug antibodies (ADAbs) and treatment response in patients with rheumatoid arthritis (RA); (ii) longitudinal factors associated with ADAbs and certolizumab drug levels. METHODS: This prospective cohort included 115 patients with RA treated with certolizumab. Serum samples were collected at 3, 6 and 12 months following treatment initiation. Drug levels and ADAbs were measured using ELISA and radioimmunoassay, respectively, at 3, 6 and 12 months. Disease Activity Score in 28 joints (DAS28) were measured at each visit and 12 months European League Against Rheumatism (EULAR) response was calculated. Patient self-reported adherence was collected longitudinally. Ordinal logistic regression and generalised estimating equation were used to test the association: (i) between drug levels, from serum sampled and treatment response; (ii) between ADAbs and drug levels; (iii) patient-centred factors and drug levels. RESULTS: ADAbs were detected in 37% (42/112 patients by 12 months). The presence of ADAbs were significantly associated with lower drug levels over 12 months (beta=-0.037, 95% CI -0.055 to 0.018, p<0.0001) but not independently with 12 months EULAR response (beta=0.0013 (95% CI -0.0032 to 0.00061), p=0.18). Drug level was associated with 12 months EULAR response (beta=0.032 (95% CI 0.0011 to 0.063), p=0.042). In the multivariate model, ADAb level and adherence were significantly associated with drug concentrations. CONCLUSIONS: This is the first study to demonstrate that higher certolizumab drug levels are associated with better 12 months EULAR response. ADAbs in certolizumab-treated patients with RA were detected at higher levels than previous studies and help determine the aetiology of a low drug level. PMID- 27245865 TI - Dupuytren's disease susceptibility gene, EPDR1, is involved in myofibroblast contractility. AB - BACKGROUND: Dupuytren's Disease is a common disorder of the connective tissue characterized by progressive and irreversible fibroblastic proliferation affecting the palmar fascia. Progressive flexion deformity appears over several months or years and although usually painless, it can result in a serious handicap causing loss of manual dexterity. There is no cure for the disease and the etiology is largely unknown. A genome-wide association study of Dupuytren's Disease identified nine susceptibility loci with the strongest genetic signal located in an intron of EPDR1, the gene encoding the Ependymin Related 1 protein. OBJECTIVE: Here, we investigate the role of EPDR1 in Dupuytren's Disease. METHODS: We research the role of EPDR1 by assessing gene expression in patient tissue and by gene silencing in fibroblast-populated collagen lattice (FPCL) assay, which is used as an in vitro model of Dupuytren's contractures. RESULTS: The three alternative transcripts produced by the EPDR1 gene are all detected in affected Dupuytren's tissue and control unaffected palmar fascia tissue. Dupuytren's tissue also contracts more in the FPCL paradigm. Dicer-substrate RNA mediated knockdown of EPDR1 results in moderate late stage attenuation of contraction rate in FPCL, implying a role in matrix contraction. CONCLUSION: Our results suggest functional involvement of EPDR1 in the etiology of Dupuytren's Disease. PMID- 27245866 TI - Molecular cloning and characterization of four caspases members in Apostichopus japonicus. AB - The caspase family representing aspartate-specific cysteine proteases have been demonstrated to possess key roles in apoptosis and immune response. We previously demonstrated that LPS challenged Apostichopus japonicus coelomocyte could significantly induced apoptosis in vitro. However, apoptosis related molecules were scarcely investigated in this economic species. In the present work, we cloned and characterized four members caspase family from A. japonicus (designated as Ajcaspase-2, Ajcaspase-3, Ajcaspase-6, and Ajcaspase-8, respectively) by RACE. Multiple sequence alignment and structural analysis revealed that all Ajcaspases contained the conservative CASC domain at C terminal, in which some unique features for each Ajcaspase made them different from each other. These specific domains together with phylogenetic analysis supported that all these four identified proteins belonged to novel members of apoptotic signaling pathway in sea cucumber. Tissue distribution analysis revealed that four Ajcaspase genes were constitutively expressed in all examined tissues. The expression of Ajcaspase-2 was tightly correlated with that of Ajcaspase-8 in each detected tissues. Ajcaspase-3 and Ajcaspase-6 transcripts were both highly expressed in immune tissue of coelomocytes. Furthermore, the Vibrio splendidus challenged sea cucumber coelomocytes could significantly up regulate the mRNA expressions of four genes. The expression levels of Ajcaspase-2 and Ajcaspase-8 were relative earlier than those of Ajcaspase-6 and Ajcaspase-3, respectively, which could be inferred that Ajcapase-2 might directly modulate Ajcaspase-6, and Ajcaspase-8 initiate the expression of Ajcaspase-3. The induce expressions differed among each Ajcaspase depending upon their roles such as initiator or effector caspase. All our results demonstrated that four Ajcaspases present diversified functions in apoptotic cascade signaling pathway of sea cucumber under immune response. PMID- 27245867 TI - Hemato - Immunological and biochemical parameters, skin antibacterial activity, and survival in rainbow trout (Oncorhynchus mykiss) following the diet supplemented with Mentha piperita against Yersinia ruckeri. AB - This study was aimed to assess the potential effects of Mentha piperita on the hemato - immunological and biochemical parameters, skin antibacterial activity and protection against Yersinia ruckeri infection in rainbow trout Oncorhynchus mykiss. Fish were divided into 4 groups before being fed diets supplemented with 0, 1, 2 and 3% of Mentha piperita (MP) plant extract for 8 weeks. Dose-dependent increases immune (both in skin mucus and blood serum) and hematological parameters (number of red and white cells, hematocrit and hemoglobin contents), as well as in respiratory burst activity, total protein, albumin, and neutrophil levels in fish fed supplemented diets compared to the control fish. Furthermore, dietary MP plant extract supplements have no significant effect on blood biochemical parameters and enzymatic activities of liver determined in serum of rainbow trout. After 8 weeks the cessation of feeding with MP plant extract, survival rates of 54.4%, 63.6% and 75.2% were recorded in groups which received 1, 2 and 3% of MP plant extract of feed, respectively, compared to 34.6% survivals in the control. This study underlying several positive effects of dietary administration of MP plant extract to farmed fish. PMID- 27245868 TI - Individual monitoring of immune responses in rainbow trout after cohabitation and intraperitoneal injection challenge with Yersinia ruckeri. AB - Yersinia ruckeri, the causative agent of enteric red mouth disease (ERM), is a widely studied pathogen in disease models using rainbow trout. This infection model, mostly based on intraperitoneally injection or bath immersion challenges, has an impact on both components (innate and adaptive) of the fish immune system. Although there has been much attention in studying its host-pathogen interactions, there is still a lack of knowledge regarding the impact of a cohabitation challenge. To tackle this we used a newly established non-lethal sampling method (by withdrawing a small amount of blood) in rainbow trout which allowed the individual immune monitoring before (non-infected) and after infection with Yersinia ruckeri either by intraperitoneal (i.p.) injection or by cohabitation (cohab). A range of key immune genes were monitored during the infection by real-time PCR, and results were compared between the two infection routes. Results indicated that inflammatory (IL-1beta1 and IL-8) cytokines and certain antimicrobial peptides (cathelicidins) revealed a different pattern of expression between the two infected groups (i.p. vs cohab), in comparison to adaptive immune cytokines (IL-22, IFN-gamma and IL-4/13A) and beta-defensins. This suggests a different involvement of distinct immune markers according to the infection model, and the importance of using a cohabitation challenge as a more natural disease model that likely simulates what would occur in the environment. PMID- 27245869 TI - Effects of cysteamine supplementation on the intestinal expression of amino acid and peptide transporters and intestinal health in finishing pigs. AB - This study aimed to evaluate the effects of cysteamine supplementation on the expression of jejunal amino acid and peptide transporters and intestinal health in finishing pigs. Sixty barrows were allocated into two experimental diets consisting of a basal control diet supplemented with 0 or 142 mg/kg cysteamine. After 41 days, 10 pigs per treatment were slaughtered. The results showed that cysteamine supplementation increased the apparent digestibility of crude protein (CP) (P < 0.05) and the trypsin activity in jejunal digesta (P < 0.01). Cysteamine supplementation also increased the messenger RNA abundance of SLC7A7, SLC7A9 and SLC15A1, occludin, claudin-1 and zonula occludens protein-1 (P < 0.001) in the jejunum mucosa. Increased glutathione content (P < 0.01) and glutathione peroxidase activity (P < 0.05) and decreased malondialdehyde content (P < 0.01) were observed in pigs receiving cysteamine. Additionally, cysteamine supplementation increased the concentrations of secretory immunoglobulin A (IgA) (P < 0.05), IgM (P < 0.001) and IgG (P < 0.001) in the jejunal mucosa. It is concluded that cysteamine supplementation could influence protein digestion and absorption via increasing trypsin activity, enhancing the digestibility of CP, and promoting the expression of jejunal amino acid and peptide transporters. Moreover, cysteamine improved intestinal integrity, antioxidant capacity and immune function in the jejunum, which were beneficial for intestinal health. PMID- 27245870 TI - Rod-cone based color vision in seals under photopic conditions. AB - Marine mammals have lost the ability to express S-cone opsin, and possess only one type of M/L-cone in addition to numerous rods. As they are cone monochromats they should be color blind. However, early behavioral experiments with fur seals and sea lions indicated discrimination ability between many shades of grey and blue or green. On the other hand, most recent training experiments with harbor seals under "mesopic" conditions demonstrated rod based color blindness (Scholtyssek et al., 2015). In our experiments we trained two harbor seals (Phoca vitulina) and two South African fur seals (Arctocephalus pusillus) with surface colors under photopic conditions. The seals had to detect a triangle on grey background shown on one of three test fields while the other two test fields were homogeneously grey. In a first series of experiments we determined brightness detection. We found a luminance contrast of >3% sufficient for correctly choosing the triangle. In the tests for color vision the triangle was blue, green or yellow in grey surround. The results show that the animals could see the colored triangle despite minimal or zero brightness contrast. Thus, seals have color vision based on the contribution of cones and rods even in bright daylight. PMID- 27245871 TI - Synthesis and Investigation of the V-shaped Troger's Base Derivatives as Hole transporting Materials. AB - V-shaped Troger's base core has been investigated as a central linking unit in the synthesis of new charge-transporting materials for optoelectronic applications. The studied molecules have been synthesized in two steps from relatively inexpensive starting materials, and demonstrate high glass transition temperatures, good stability of the amorphous state, and comparatively high hole drift mobility (up to 0.011 cm(2) V(-1) s(-1) ). PMID- 27245872 TI - Levels of serum vitamin D and calcium in pregnancies complicated with fetal congenital diaphragmatic hernia and normal pregnancies. AB - OBJECTIVE: Vitamin D (VD) deficiency is a common public health problem worldwide in all age groups. Receptors and enzymes related to VD metabolism have been shown in many cells and tissues of the body. VD plays a crucial role in cellular growth and differentiation during embryogenesis. It has been suggested that VD deficiency may be associated with various diseases, and that lower maternal serum levels may be associated with adverse perinatal outcomes. In this study, we aimed to compare serum VD levels of pregnant women whose pregnancies complicated by congenital diaphragmatic hernia (CDH) with healthy pregnant women. We also evaluated perinatal outcomes of these pregnancies. METHODS: Total of 77 patients was included in this prospective and cross-sectional case-controlled study. 24 pregnant women having a fetus with CDH diagnosed prenatally formed the study group, and 53 healthy pregnants were eligible for the control group. Demographics and clinical characteristics of the cases with some laboratory parameters were recorded. Perinatal outcomes were also investigated. RESULTS: No significant differences were observed between two groups in terms of demographics and clinical features. Mean maternal serum VD levels were significantly lower in the study group than in the controls (p: 0.019). Ionized calcium and corrected calcium levels were also found to be lower in pregnant women with CDH (p < 0.001). Moreover, the calcium-rich dietary habits were also more common in the control group. Four (16.7%) patients chose termination and one (4.2%) experienced a stillbirth. Fourteen (58.3%) infants died in the early neonatal period; although some had undergone surgical interventions, only 5 (20.8%) were still alive after surgery. CONCLUSIONS: Maternal serum VD and calcium levels were significantly lower in pregnancies complicated by CDH than healthy pregnant women. Hipovitaminosis D may play a vital role in the pathogenesis of CDH. PMID- 27245874 TI - Induced production of 6,9-dibromoflavasperone, a new radical scavenging naphthopyranone in the marine-mudflat-derived fungus Aspergillus niger. AB - The addition of metal bromides (NaBr and CaBr2) during fermentation of the marine mudflat-derived fungus Aspergillus niger induced production of a new radical scavenging brominated naphthopyranone, 6,9-dibromoflavasperone (1); and three known naphtho-gamma-pyranone monomers, flavasperone (2), TMC-256A1 (3), and fonsecin (4); and one naphtho-gamma-pyranone dimer, aurasperone B (5). The structure of 6,9-dibromoflavasperone (1) was assigned through the combination of spectroscopic data analyses and comparison with the spectral data of flavasperone (2). Compounds 1-5 displayed potent radical scavenging activity against 2,2 diphenyl-1-picrylhydrazyl, with IC50 values of 21, 25, 0.3, 0.02, and 0.01 MUM, respectively, and 3-5 were more potent than the positive control, ascorbic acid (IC50, 20.0 MUM). PMID- 27245873 TI - Hyperlipidemia-associated gene variations and expression patterns revealed by whole-genome and transcriptome sequencing of rabbit models. AB - The rabbit (Oryctolagus cuniculus) is an important experimental animal for studying human diseases, such as hypercholesterolemia and atherosclerosis. Despite this, genetic information and RNA expression profiling of laboratory rabbits are lacking. Here, we characterized the whole-genome variants of three breeds of the most popular experimental rabbits, New Zealand White (NZW), Japanese White (JW) and Watanabe heritable hyperlipidemic (WHHL) rabbits. Although the genetic diversity of WHHL rabbits was relatively low, they accumulated a large proportion of high-frequency deleterious mutations due to the small population size. Some of the deleterious mutations were associated with the pathophysiology of WHHL rabbits in addition to the LDLR deficiency. Furthermore, we conducted transcriptome sequencing of different organs of both WHHL and cholesterol-rich diet (Chol)-fed NZW rabbits. We found that gene expression profiles of the two rabbit models were essentially similar in the aorta, even though they exhibited different types of hypercholesterolemia. In contrast, Chol fed rabbits, but not WHHL rabbits, exhibited pronounced inflammatory responses and abnormal lipid metabolism in the liver. These results provide valuable insights into identifying therapeutic targets of hypercholesterolemia and atherosclerosis with rabbit models. PMID- 27245875 TI - The Rate of Magnetic Resonance Imaging in Patients with Deep Brain Stimulation. AB - BACKGROUND: For Parkinson's disease (PD), essential tremor (ET), and dystonia patients with deep brain stimulation (DBS) implants, magnetic resonance imaging (MRI) requires additional safety considerations due to potentially hazardous interactions. OBJECTIVE: A propensity-matched cohort of DBS-implanted patients was analyzed to determine the likelihood of needing MRI. METHODS: Patients with new DBS full-system implants (n = 576) were identified in the Truven Health MarketScan(r) Commercial Claims and Medicare Supplemental Databases (2009-2012). Patients diagnosed with PD, ET, or dystonia and no DBS implant were identified (DBS-indicated patients: n = 11,216). The DBS-indicated patients were continuously enrolled for 4 years and matched for age, gender, and propensity score based on comorbid conditions to DBS-implanted patients (n = 4,878 and 543, respectively). A Kaplan-Meier survival curve of time to first MRI was extrapolated to 10 years. RESULTS: An estimated 56-57% of DBS-indicated patients need an MRI within 5 years and 66-75% within 10 years after implantation. While 92% of DBS-implanted patients' MRI after implantation was of the head, for DBS indicated patients, 62% of MRIs were of the body, potentially unrelated to the primary diagnosis. CONCLUSIONS: This analysis highlights the projected utilization of MRI in the DBS population for head and full-body images. PMID- 27245876 TI - Rapid and sensitive detection of early esophageal squamous cell carcinoma with fluorescence probe targeting dipeptidylpeptidase IV. AB - Early detection of esophageal squamous cell carcinoma (ESCC) is an important prognosticator, but is difficult to achieve by conventional endoscopy. Conventional lugol chromoendoscopy and equipment-based image-enhanced endoscopy, such as narrow-band imaging (NBI), have various practical limitations. Since fluorescence-based visualization is considered a promising approach, we aimed to develop an activatable fluorescence probe to visualize ESCCs. First, based on the fact that various aminopeptidase activities are elevated in cancer, we screened freshly resected specimens from patients with a series of aminopeptidase activatable fluorescence probes. The results indicated that dipeptidylpeptidase IV (DPP-IV) is specifically activated in ESCCs, and would be a suitable molecular target for detection of esophageal cancer. Therefore, we designed, synthesized and characterized a series of DPP-IV-activatable fluorescence probes. When the selected probe was topically sprayed onto endoscopic submucosal dissection (ESD) or surgical specimens, tumors were visualized within 5 min, and when the probe was sprayed on biopsy samples, the sensitivity, specificity and accuracy reached 96.9%, 85.7% and 90.5%. We believe that DPP-IV-targeted activatable fluorescence probes are practically translatable as convenient tools for clinical application to enable rapid and accurate diagnosis of early esophageal cancer during endoscopic or surgical procedures. PMID- 27245877 TI - The Sp1-mediaded allelic regulation of MMP13 expression by an ESCC susceptibility SNP rs2252070. AB - Metallopeptidase 13 (MMP13), a well-known and highly regulated zinc-dependent MMP collagenase, plays a crucial part in development and progression of esophageal squamous cell carcinoma (ESCC). Therefore, we examined associations between ESCC susceptibility and four haplotype-tagging single nucleotide polymorphisms (htSNPs) using a two stage case-control strategy. Odds ratios (OR) and 95% confidence intervals (95% CI) were computed by logistic regression model. After analyzing 1588 ESCC patients and frequency-matched 1600 unaffected controls, we found that MMP13 rs2252070 G > A genetic polymorphism is significantly associated with ESCC risk in Chinese Han populations (GA: OR = 0.63, 95% CI = 0.54-0.74, P = 1.7 * 10(-6), AA: OR = 0.73, 95% CI = 0.66-0.81, P = 1.8 * 10(-6)). Interestingly, the rs2252070 G-to-A change was shown to diminish a Sp1-binding site in ESCC cells. Reporter gene assays indicated that the rs2252070 A allele locating in a potential MMP13 promoter has low promoter activities. After measuring MMP13 gene expression in sixty-six pairs of esophageal cancer and normal tissues, we observed that the rs2252070 A protective allele carriers showed decreased oncogene MMP13 expression. Results of these analyses underline the support of the notion that MMP13 might function as a key oncogene in esophageal carcinogenesis. PMID- 27245878 TI - Lack of Influence of Apolipoprotein E Status on Cognition or Brain Structure in Professional Fighters. AB - The role of the apolipoprotein e4 allele in moderating cognitive and neuroanatomical degeneration following repeated traumatic brain injury is controversial. Here we sought to establish the presence or absence of such a moderating relationship in a prospective study of active and retired boxers and mixed martial arts fighters. Fighters (n = 193) underwent cognitive evaluations, interviews regarding fight history, MRI of the brain, and genetic testing. We used a series of moderator analyses to test for any relationship of apolipoprotein genotype on structural volumes of brain regions previously established to be smaller in those with the most fight exposure, and on cognitive abilities also established to be sensitive to fight exposure. No moderating relationship was detected in any of the analyses. The results of this study suggest that there is no impact of apolipoprotein genotype on the apparent negative association between exposure to professional fighting and brain structure volume or aspects of cognition. PMID- 27245879 TI - Guidance on the selection of cohorts for the extended one-generation reproduction toxicity study (OECD test guideline 443). AB - The extended one-generation reproduction toxicity study (EOGRTS; OECD test guideline 433) is a new and technically complex design to evaluate the putative effects of chemicals on fertility and development, including effects upon the developing nervous and immune systems. In addition to offering a more comprehensive assessment of developmental toxicity, the EOGRTS offers important improvements in animal welfare through reduction and refinement in a modular study design. The challenge to the practitioner is to know how the modular aspects of the study should be triggered on the basis of prior knowledge of a particular chemical, or on earlier findings in the EOGRTS itself, requirements of specific regulatory frameworks notwithstanding. The purpose of this document is to offer guidance on science-based triggers for these extended evaluations. PMID- 27245881 TI - High hopes versus harsh realities: the population impact of emergency contraceptive pills. PMID- 27245880 TI - Bilateral transcervical submandibular gland excision for drooling: A study of the mature scar and long-term effects. AB - AIM: Several surgical techniques are available to treat drooling in neurologically disabled children and adolescents, with bilateral submandibular gland excision being the only transcervical procedure. External scars can be a reason to decline for this surgical approach. We investigated which factors influenced caregiver satisfaction by evaluating the long-term scar in relation to treatment outcome. METHODS: We identified a historical cohort, in which all neurologically disabled patients who underwent bilateral submandibular gland excision for drooling between January 2009 and December 2013 were identified (n = 41). The Patient and Observer Scar Assessment Scale (POSAS) was used to evaluate observer and clinician satisfaction. All included patients were contacted by telephone and completed a digital questionnaire that included digital images of the scars. RESULTS: Of the caregivers that responded the questionnaire 76% (19/25) were satisfied with the overall outcome. Twenty-four (96%) caregivers considered the scars acceptable. Caregiver satisfaction was not correlated to the appearance of scars, but was significantly correlated with the decrease in drooling severity on a visual analogue scale (p = 0.035) and decrease in lower respiratory tract infections (p = 0.042). INTERPRETATION: The appearance of scars does not influence satisfaction after bilateral submandibular gland excision for drooling. As expected, satisfaction is correlated to the treatment outcome. PMID- 27245882 TI - Effects of PTEN inhibition on the regulation of Tau phosphorylation in rat cortical neuronal injury after oxygen and glucose deprivation. AB - OBJECTIVE: This report investigated the involvement of the PTEN pathway in the regulation of Tau phosphorylation using an oxygen and glucose deprivation (OGD) model with rat cortical neurons. METHODS: Primary cortical neurons were used to establish the oxygen and glucose deprivation (OGD) model in vitro. These were randomly divided into control, OGD, bpV+OGD, As+OGD, Se+OGD and Mock treatment groups. The neuron viability was assessed by MTT, the cell apoptosis was detected using TUNEL staining. The expression of Phospho-PTEN/PTEN, Phospho-Tau/Tau, Phospho-Akt/Akt and Phospho-GSK-3beta/GSK-3beta were detected by Western blotting. RESULTS: OGD induced Tau phosphorylation through PTEN and glycogen synthase kinase-3beta (GSK-3beta) activation, together with a decrease in AKT activity. Pre-treatment with bpv, a potent PTEN inhibitor, and PTEN antisense nucleotides decreased PTEN and GSK-3beta activity and caused alterations in Tau phosphorylation. Neuronal apoptosis was also reduced. CONCLUSIONS: The PTEN/Akt/GSK-3beta/Tau pathway is involved in the regulation of neuronal injury, providing a novel route for protecting neurons following neonatal HI. PMID- 27245883 TI - Risk of malignancy according to sub-classification of the atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) category in the Bethesda system for reporting thyroid cytopathology. AB - OBJECTIVE: According to the Bethesda System for Reporting Thyroid Cytopathology, atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) is a heterogeneous category that includes cases with architectural and/or nuclear atypia insufficient to warrant classification as malignant neoplasms. The ambiguous and descriptive characteristics of the AUS/FLUS category mean that the impact of the present guidelines on repeat fine needle aspiration (FNA) is unclear. The present study reclassified AUS/FLUS cases into four sub-categories and then correlated them with histological or cytological follow-up data to clarify the risk of malignancy. METHODS: Ninety four cases of AUS/FLUS with available follow-up data were reviewed and assigned to one of four sub-categories: (i) AUS-N (nuclear atypia); (ii) AUS-A (architectural atypia); (iii) AUS-O (predominant oncocytic changes); and (iv) AUS N/A (both nuclear and architectural atypia). The four sub-categories were correlated with subsequent histological or cytological follow-up data, including core needle biopsy, resection, or repeat FNA. RESULTS: Malignancy was identified in 34 of 94 cases (36.2%). The upper limit estimate for malignancy was 43.6%, and the lower limit estimate was speculated as 9.8%. The malignancy rate was highest in cases within the AUS-N sub-category (65.8%, range 16.6%-78.1%). CONCLUSIONS: The present study suggests that cases in the AUS/FLUS category have a higher risk of malignancy than previously thought. Because of the heterogeneous nature of the AUS/FLUS category, further sub-classification might be more effective in achieving appropriate risk stratification and better clinical management. PMID- 27245885 TI - Understanding scoping reviews: Definition, purpose, and process. AB - BACKGROUND/PURPOSE: Scoping review design represents a methodology that allows assessment of emerging evidence, as well as a first step in research development. Despite its increasing use, to date no article reflecting use of scoping review methodology has been submitted for review at JAANP. The purpose of this article is to provide detailed information on scoping reviews, including definition, related processes, and uses, and discuss the relationship to nurse practitioner (NP) practice, policy, education, and research. The longer-term goal is that NPs will understand the related techniques, consider the methodology as a viable one for NP scholarship, and bring related reports to the forefront of NP publications. METHODS: This manuscript represents a brief report. Processes to develop the brief include detailed search and review of scoping review literature in CINAHL and PubMed. Both methodologic reports and reviews were included. Definitions and uses of scoping reviews were reviewed. CONCLUSION: The definition and process of scoping review are evolving. Although there is controversy regarding the methodology, there is increasing visibility of scoping review methodology in the published literature since the year 2000, with over 500 published reviews currently available. IMPLICATIONS FOR PRACTICE: A well-executed scoping review has potential to inform NP practice, policy, education, and research. PMID- 27245884 TI - Nitric oxide-fixation by non-symbiotic haemoglobin proteins in Arabidopsis thaliana under N-limited conditions. AB - Nitric oxide (NO) is an important signalling molecule that is involved in many different physiological processes in plants. Here, we report about a NO-fixing mechanism in Arabidopsis, which allows the fixation of atmospheric NO into nitrogen metabolism. We fumigated Arabidopsis plants cultivated in soil or as hydroponic cultures during the whole growing period with up to 3 ppmv of NO gas. Transcriptomic, proteomic and metabolomic analyses were used to identify non symbiotic haemoglobin proteins as key components of the NO-fixing process. Overexpressing non-symbiotic haemoglobin 1 or 2 genes resulted in fourfold higher nitrate levels in these plants compared with NO-treated wild-type. Correspondingly, rosettes size and weight, vegetative shoot thickness and seed yield were 25, 40, 30, and 50% higher, respectively, than in wild-type plants. Fumigation with 250 ppbv 15 NO confirmed the importance of non-symbiotic haemoglobin 1 and 2 for the NO-fixation pathway, and we calculated a daily uptake for non-symbiotic haemoglobin 2 overexpressing plants of 250 mg N/kg dry weight. This mechanism is probably important under conditions with limited N supply via the soil. Moreover, the plant-based NO uptake lowers the concentration of insanitary atmospheric NOx, and in this context, NO-fixation can be beneficial to air quality. PMID- 27245886 TI - Need for Methods to Investigate Endocannabinoid Signaling. AB - Endocannabinoids (eCBs) are endogenous lipids able to activate cannabinoid receptors, the primary molecular targets of the cannabis (Cannabis sativa) active principle Delta(9)-tetrahydrocannabinol. During the last 20 years, several N acylethanolamines and acylesters have been shown to act as eCBs, and a complex array of receptors, metabolic enzymes, and transporters (that altogether form the so-called eCB system) has been shown to finely tune their manifold biological activities. It appears now urgent to develop methods and protocols that allow to assay in a specific and quantitative manner the distinct components of the eCB system, and that can properly localize them within the cell. A brief overview of eCBs and of the proteins that bind, transport, and metabolize these lipids is presented here, in order to put in a better perspective the relevance of methodologies that help to disclose molecular details of eCB signaling in health and disease. Proper methodological approaches form also the basis for a more rationale and effective drug design and therapeutic strategy to combat human disorders. PMID- 27245887 TI - Extraction and Simultaneous Quantification of Endocannabinoids and Endocannabinoid-Like Lipids in Biological Tissues. AB - Extraction and quantification of endocannabinoids (eCBs) from biological tissues are essential to unravel their changes in physiological and pathophysiological conditions. We describe here an analytical protocol for extraction of endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), endocannabinoid-like lipids such as palmitoyl ethanolamide (PEA) and oleoyl ethanolamide (OEA), as well as arachidonic acid (AA) from biological tissues using liquid-liquid extraction method and simultaneous quantification by liquid chromatography multiple reaction monitoring (LC/MRM). PMID- 27245888 TI - Determination of 2-Arachidonoylglycerol by MUSPE-LC-MS/MS. AB - LC-MS/MS is a powerful analytical technique that provides unequivocal identification and reliable quantification of the analytes, using Selected Reaction Monitoring or Multi Reaction Monitoring acquisition mode.2 Arachidonoylglycerol (2-AG) is the most abundant endocannabinoid, which plays a major role in a wide variety of physiological and pathological processes. Analysis of 2-AG by means of LC-MS/MS allows the detection of very low concentrations in biological samples. Here, we describe how to determine 2-AG levels in tiny samples of tissues and plasma through LC-MS/MS, by using very quick and easy to perform extraction procedures, with reduced solvent consumption. PMID- 27245889 TI - Analysis of Omega-3 Fatty Acid Derived N-Acylethanolamines in Biological Matrices. AB - The adequate quantification of endocannabinoids can be complex due to their low endogenous levels and structural diversity. Therefore, advanced analytical approaches, such as LC-MS, are used to measure endocannabinoids in plasma, tissues, and other matrices. Recent work has shown that endocannabinoids that are synthesized from n-3 fatty acids, such as docosahexaenoylethanolamide (DHEA) and eicosapentaenoylethanolamide (EPEA), have anti-inflammatory and anti-tumorigenic properties and stimulate synapse formation in neurites. Here, an LC-MS based method for the quantification of n-3 endocannabinoids DHEA and EPEA which is also suited to measure a wider spectrum of endocannabinoids is described. The chapter contains a step-by-step protocol for the analysis of n-3 endocannabinoids in plasma, including sample collection and solid phase extraction, LC-MS analysis, and data processing. Modifications to the protocol that allow quantifying n-3 endocannabinoids in tissues and cell culture media will also be discussed. Finally, conditions that alter endocannabinoid concentrations are briefly discussed. PMID- 27245890 TI - Assay of CB1 Receptor Binding. AB - Type-1 cannabinoid receptor (CB1), one of the main targets of endocannabinoids, plays a key role in several pathophysiological conditions that affect both central nervous system and peripheral tissues. Today, its biochemical identification and pharmacological characterization, as well as the screening of thousands of novel ligands that might be useful for developing CB1-based therapies, are the subject of intense research. Among available techniques that allow the analysis of CB1 binding activity, radioligand-based assays represent one of the best, fast, and reliable methods.Here, we describe radioligand binding methods standardized in our laboratory to assess CB1 binding in both tissues and cultured cells. We also report a high-throughput radioligand binding assay that allows to evaluate efficacy and potency of different compounds, which might represent the basis for the development of new drugs that target CB1 receptor dependent human diseases. PMID- 27245891 TI - The Displacement Binding Assay Using Human Cannabinoid CB2 Receptor-Transfected Cells. AB - Displacement binding assays are nonfunctional assays mostly used with the aim of determining whether a certain compound (plant-derived or synthetic) is able to bind to a specific receptor with high affinity. Here, we describe the displacement binding assay that is carried out with a radioligand and CHO (Chinese Hamster Ovarian) cells stably transfected with the human cannabinoid CB2 receptor. PMID- 27245892 TI - Assay of TRPV1 Receptor Signaling. AB - The transient receptor potential vanilloid-1 ion channel (TRPV1) is a non selective ligand-gated cation channel. It is an integrator of a wide variety of exogenous and endogenous physical and chemical stimuli, including capsaicin, noxious heat (>42 degrees C), and protons (pH < 5.2). TRPV1 is expressed predominantly in primary sensory neurons involved in pain sensation, but also in other neuronal cell types, in the plasma membrane of different non-neuronal cells such as immune cells, keratinocytes, smooth muscle cells, and in the urothelium. Some of these cell types are involved in inflammation. When activated, TRPV1 leads to the gating of cations, including Ca(2+), thus generating changes in intracellular Ca(2+) concentration. Calcium ions play fundamental roles in many cellular processes, virtually in all cells. The use of Ca(2+) fluorescent indicators is a tool for monitoring intracellular Ca(2+) concentration.In this chapter, we describe a method for recording and monitoring Ca(2+) signals through the single wavelength fluorescent indicator Fluo-4 acetoxymethyl (AM), and the ratiometric fluorescent indicator Fura-2 AM in HEK-293 cells transfected with TRPV1 and other TRP channels. TRPV1 pharmacological modulation may potentially represent a strategy for the control of pain and inflammatory conditions in a variety of diseases and injury states. PMID- 27245893 TI - A Functional Assay for GPR55: Envision Protocol. AB - AlphaScreen((r)) SureFire((r)) assay is a novel technology that combines luminescent oxygen channeling technology, nano-beads, and monocloncal antibodies to detect the level of a selected protein in a volume lower than 5 MUl. This method is more sensitive compared with the traditional enzyme-linked immunosorbent assays (ELISA), and can detect an increasing number of new targets. Here, we described a method for AlphaScreen((r)) SureFire((r)) assay that targets ERK1/2 phosphorylation, a primary downstream signaling pathway that conveys activation of GPR55 by L-alpha-lysophosphatidylinositol (LPI) and certain cannabinoids. PMID- 27245894 TI - The Cyclic AMP Assay Using Human Cannabinoid CB2 Receptor-Transfected Cells. AB - The cyclic AMP assay is a functional assay that is commonly used to determine the pharmacological behavior (agonists, antagonists, inverse agonists) of G-protein coupled receptor (GPCR) ligands. Here, we describe the cyclic AMP assay that is carried out with commercially available non-radioligand ready-to-use kits and Chinese hamster ovarian (CHO) cells stably transfected with the human cannabinoid CB2 receptor. PMID- 27245895 TI - Assay of GTPgammaS Binding in Autoradiography. AB - Autoradiography of radiolabeled GTPgammaS ([(35)S]GTPgammaS) binding is a relevant method to study the function of G protein-coupled receptors (GPCRs), in tissue sections. Here, we describe the protocol for such a binding autoradiography, suitable to investigate the functionality of CB1 receptor in tissue slices from rodent brain. PMID- 27245896 TI - Protocol to Study beta-Arrestin Recruitment by CB1 and CB2 Cannabinoid Receptors. AB - Cannabinoid CB1 and CB2 receptors are G-protein-coupled receptors (GPCRs) that recruit beta-arrestins upon activation by (partial) agonists. beta-Arrestin recruitment is induced by phosphorylation of their C-terminal tails, and is associated with the termination of GPCR signaling; yet, it may also activate cellular signaling pathways independent of G-proteins. Here, we describe a detailed protocol to characterize the potency and efficacy of ligands to induce or inhibit beta-arrestin recruitment to the human CB1 and CB2 receptors, by using the PathHunter((r)) assay. The latter is a cellular assay that can be performed in plates with 384-wells. The PathHunter((r)) assay makes use of beta galactosidase complementation, and has a chemiluminescent readout. We used this assay to characterize a set of reference ligands (both agonists and antagonists) on human CB1 and CB2 receptors. PMID- 27245897 TI - Assay of NAT Activity. AB - In animal tissues, N-acyltransferase (NAT) catalyzes the first reaction in the biosynthetic pathway of bioactive N-acylethanolamines, in which an acyl chain is transferred from the sn-1 position of the donor phospholipid, such as phosphatidylcholine, to the amino group of phosphatidylethanolamine, resulting in the formation of N-acylphosphatidylethanolamine. NAT has long been known to be stimulated by Ca(2+), and hence it has been referred to as Ca(2+)-dependent NAT. On the other hand, members of the phospholipase A/acyltransferase (PLA/AT) family (also known as HRAS-like suppressor family) show Ca(2+)-independent NAT activity. In this chapter, we describe (1) partial purification of Ca(2+)-dependent NAT from rat brain, (2) purification of recombinant PLA/AT-2, and (3) NAT assay using radiolabeled substrate. PMID- 27245898 TI - Assay of NAPE-PLD Activity. AB - N-acyl-phosphatidylethanolamine (NAPE)-hydrolyzing phospholipase D (NAPE-PLD) is a prominent enzyme involved in the biosynthesis of fatty acid amides (FAAs), a family of bioactive lipids including anandamide (AEA) as the prototypical member. Here, we describe a NAPE-PLD assay based on radioactive substrates and product separation by thin-layer chromatography (TLC). PMID- 27245899 TI - Assay of FAAH Activity. AB - Fatty acid amide hydrolase (FAAH) is an intracellular enzyme responsible for the hydrolysis of endogenous anandamide (AEA), a reaction that terminates the biological effects of this lipid mediator. The final products of this reaction are arachidonic acid and ethanolamine. In the method described herein, FAAH activity is measured through the use of a radioactive substrate by quantification of reaction products, that is, [(14)C]-ethanolamine from [(14)C-ethanolamine] AEA. PMID- 27245900 TI - Assay of NAAA Activity. AB - N-acylethanolamine-hydrolyzing acid amidase (NAAA) is a lysosomal hydrolase degrading various N-acylethanolamines at acidic pH. Since NAAA prefers anti inflammatory and analgesic palmitoylethanolamide to other N-acylethanolamines as a substrate, its specific inhibitors are expected as a new class of anti inflammatory and analgesic agents. Here, we introduce an NAAA assay system, using [(14)C]palmitoylethanolamide and thin-layer chromatography. The preparation of NAAA enzyme from native and recombinant sources as well as the chemical synthesis of N-[1'-(14)C]palmitoyl-ethanolamine is also described. PMID- 27245901 TI - Assay of DAGLalpha/beta Activity. AB - The endocannabinoid 2-arachidonoylglycerol (2-AG) exerts its physiological action by binding to and functionally activating type-1 (CB1) and type-2 (CB2) cannabinoid receptors. It is thought to be produced through the action of sn-1 selective diacylglycerol lipase (DAGL) that catalyzes 2-AG biosynthesis from sn-2 arachidonate-containing diacylglycerols. Since 2-AG biosynthetic enzymes have been identified only recently, little information on methodological approaches for measuring DAGL activity is as yet available. Here, a highly sensitive radiometric assay to measure DAGL activity by using 1-oleoyl[1-(14)C]-2 arachidonoylglycerol as the substrate is reported. All the steps needed to perform lipid extraction, fractionation by thin-layer chromatography (TLC), and quantification of radiolabeled [(14)C]-oleic acid via scintillation counting are described in detail. PMID- 27245902 TI - Assay of Monoacylglycerol Lipase Activity. AB - Monoacylglycerol lipase (MGL) is a serine hydrolase involved in the biological deactivation of the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG). 2-AG is one of the main endogenous lipid agonists for cannabinoid receptors in the brain and elsewhere in the body. In the central nervous system (CNS), MGL is localized to presynaptic nerve terminals of both excitatory and inhibitory synapses, where it helps control the regulatory actions of 2-AG on synaptic transmission and plasticity. In this chapter, we describe an in vitro method to assess MGL activity by liquid chromatography/mass spectrometry (LC/MS)-based quantitation of the reaction product. This method may be used to determine the basal or altered MGL activity in various cells or animal tissues after pharmacological, genetic, or biological manipulations. In addition, this assay can be used for MGL inhibitor screening using purified recombinant enzyme or MGL-overexpressing cells. PMID- 27245903 TI - A Sensitive and Versatile Fluorescent Activity Assay for ABHD6. AB - The alpha/beta-hydrolase domain-containing 6 (ABHD6) enzyme is a newly found serine hydrolase whose substrate profile resembles that of monoacylglycerol lipase (MAGL), the major 2-arachidonoyl glycerol (2-AG) hydrolase in the brain. Here, we describe a sensitive fluorescent assay of ABHD6 activity in a 96-well plate format that allows parallel testing of inhibitor activities of up to 40 compounds in a single assay. The method utilizes lysates of HEK293 cells transiently overexpressing human ABHD6 as the enzymatic source, and kinetically monitors glycerol liberated in the hydrolysis of 1(3)-AG, the preferred arachidonoyl glycerol isomer. Glycerol output is coupled to an enzymatic cascade generating the fluorescent end-product resorufin. The approach has major benefits compared to laborious traditional mass spectrometric methods and liquid scintillation-based assays, or approaches using unnatural substrates. PMID- 27245904 TI - A Sensitive and Versatile Fluorescent Activity Assay for ABHD12. AB - Despite great progress in identifying and deorphanizing members of the human metabolic serine hydrolase (mSH) family, the fundamental role of numerous enzymes in this large protein class has remained unclear. One recently found mSH is alpha/beta-hydrolase domain containing 12 (ABHD12) enzyme, whose natural substrate in vivo appears to be the lysophospholipid lysophosphatidylserine (LPS). In vitro, ABHD12 together with monoacylglycerol lipase (MAGL) and ABHD6 hydrolyzes also monoacylglycerols (MAGs) such as the primary endocannabinoid 2 arachidonoyl glycerol (2-AG). Traditional approaches for determining 2-AG hydrolase activity are rather laborious, and often utilize unnatural substrates. Here, we describe a sensitive fluorescent assay of ABHD12 activity in a 96-well plate format that allows simultaneous testing of inhibitor activities of up to 40 compounds in a single assay. The method utilizes lysates of HEK293 cells transiently overexpressing human ABHD12 as the enzymatic source, and kinetically monitors glycerol liberated in the hydrolysis of 1(3)-AG, the preferred MAG substrate of this enzyme. Glycerol output is coupled to an enzymatic cascade generating the fluorescent end-product resorufin. This methodology has helped to identify the first class of inhibitors showing selectivity for ABHD12 over the other mSHs. PMID- 27245905 TI - Assay of Endocannabinoid Uptake. AB - Endocannabinoids at physiological concentrations are crossing cellular membranes by facilitated diffusion, a process that can be studied by measuring transport kinetics. Here, we describe a radiosubstrate-based assay using arachidonoyl[1 (3)H]ethanolamine or arachidonoyl[1,2,3-(3)H]glycerol to measure the cellular endocannabinoid uptake in a three-phase assay with human U937 cells. PMID- 27245906 TI - Assay of Endocannabinoid Oxidation by Cyclooxygenase-2. AB - The endocannabinoids, 2-arachidonoylglycerol (2-AG) and arachidonylethanolamide (AEA), are endogenous ligands for the cannabinoid receptors (CB1 and CB2) and are implicated in a wide array of physiological processes. These neutral arachidonic acid (AA) derivatives have been identified as efficient substrates for the second isoform of the cyclooxygenase enzyme (COX-2). A diverse family of prostaglandin glycerol esters (PG-Gs) and prostaglandin ethanolamides (PG-EAs) is generated by the action of COX-2 (and downstream prostaglandin synthases) on 2-AG and AEA. As the biological importance of the endocannabinoid system becomes more apparent, there is a tremendous need for robust, sensitive, and efficient analytical methodology for the endocannabinoids and their metabolites. In this chapter, we describe methodology suitable for carrying out oxygenation of endocannabinoids by COX-2, and analysis of products of endocannabinoid oxygenation by COX-2 and of endocannabinoids themselves from in vitro and cell assays. PMID- 27245907 TI - Oxygenation of Anandamide by Lipoxygenases. AB - The endocannabinoids anandamide and 2-arachidonoylglycerol are not only metabolized by serine hydrolases, such as fatty acid amide hydrolase, monoacylglycerol lipase, and alpha,beta-hydrolases 6 and 12, but they also serve as substrates for cyclooxygenases and lipoxygenases. These enzymes oxygenate the 1Z,4Z-pentadiene system of the arachidonic acid backbone of endocannabinoids, thereby giving rise to an entirely new array of bioactive lipids. Hereby, a protocol is provided for the enzymatic synthesis, purification, and characterization of various oxygenated metabolites of anandamide generated by lipoxygenases, which enables the biological study and detection of these metabolites. PMID- 27245908 TI - Assay of Endocannabinoid Oxidation by Cytochrome P450. AB - Cytochrome P450 enzymes are a large family of heme-containing proteins that have important functions in the biotransformation of xenobiotics, including pharmacologic and environmental agents, as well as of endogenously produced chemicals with broad structural and functional diversity. Anandamide and 2 arachidonoylglycerol (2-AG) are substrates for P450s expressed in multiple tissues, leading to the production of a diverse set of mono- and di-oxygenated metabolites. This chapter describes tools and methods that have been used to identify major endocannabinoid-metabolizing P450s and their corresponding products, by using subcellular tissue fractions, cultured cells, and purified recombinant enzymes in a reconstituted system. PMID- 27245909 TI - Assessing Gene Expression of the Endocannabinoid System. AB - Real-time quantitative reverse transcription polymerase chain reaction (real-time qRT-PCR), a major development of PCR technology, is a powerful and sensitive gene analysis technique that revolutionized the field of measuring gene expression. Here, we describe in detail RNA extraction, reverse transcription (RT), and relative quantification of genes belonging to the endocannabinoid system in mouse, rat, or human samples. PMID- 27245910 TI - Western Blotting of the Endocannabinoid System. AB - Measuring expression levels of G protein-coupled receptors (GPCRs) is an important step for understanding the distribution, function, and regulation of these receptors. A common approach for detecting proteins from complex biological systems is Western blotting. In this chapter, we describe a general approach to Western blotting protein components of the endocannabinoid system using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and nitrocellulose membranes, with a focus on detecting type 1 cannabinoid (CB1) receptors. When this technique is carefully used, specifically with validation of the primary antibodies, it can provide quantitative information on protein expression levels. Additional information can also be inferred from Western blotting such as potential posttranslational modifications that can be further evaluated by specific analytical techniques. PMID- 27245911 TI - Quantitation of Plasma Membrane (G Protein-Coupled) Receptor Trafficking in Cultured Cells. AB - Measuring the functional behavior of G protein-coupled receptors (GPCRs) has been a major focus of academic and pharmaceutical research for many decades. These efforts have led to the development of many assays to measure the downstream effects of ligand binding on receptor activity. In this chapter, we describe an internalization/recycling assay that can be used to track changes in receptor number at the plasma membrane. Used in concert with other assays, this antibody based technique can provide important information on GPCR activation by receptor specific ligands. PMID- 27245912 TI - Measuring ECS Interaction with Biomembranes. AB - Understanding the correct interaction among the different components of the endocannabinoid system (ECS) is fundamental for a proper assessment of the function of endocannabinoids (eCBs) as signaling molecules. The knowledge of how membrane environment is able to modulate intracellular trafficking of eCBs and their interacting proteins holds a huge potential in unraveling new mechanisms of ECS modulation.Here, fluorescence resonance energy transfer (FRET) technique is applied to measure the binding affinity of ECS proteins to model membranes (i.e., large unilamellar vesicles, LUVs). In particular, we describe in details the paradigmatic example of the interaction of recombinant rat FAAH-DeltaTM with LUVs constituted by 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). PMID- 27245913 TI - Visualization of Endocannabinoids in the Cell. AB - A still unsolved, although critical, issue in endocannabinoid research is the mechanism by which the lipophilic compound anandamide (AEA) moves from its site of synthesis, crosses the aqueous milieu, and reaches the different intracellular compartments, where its metabolic and signaling pathways take place. The difficulty of studying intracellular AEA transport and distribution results from the lack of specific probes and techniques to track and visualize this bioactive lipid within the cell. Here, we describe the use of a biotinylated, non hydrolyzable derivative of AEA (biotin-AEA, b-AEA) for visualizing the subcellular distribution of this endocannabinoid by means of confocal fluorescence microscopy. PMID- 27245914 TI - Effect of non-invasive oxygenation strategies in immunocompromised patients with severe acute respiratory failure: a post-hoc analysis of a randomised trial. AB - BACKGROUND: The use of non-invasive ventilation is controversial in immunocompromised patients with acute respiratory failure, whereas the use of high-flow nasal cannula oxygen therapy is growing as an alternative to standard oxygen. We aimed to compare outcomes of immunocompromised patients with acute respiratory failure treated with standard oxygen with those treated with high flow nasal cannula oxygen alone or high-flow nasal cannula oxygen associated with non-invasive ventilation. METHODS: We did a post-hoc subgroup analysis in a subset of immunocompromised patients with non-hypercapnic acute respiratory failure from a multicentre, randomised, controlled trial. In the trial, patients from 23 intensive care units in France and Belgium were randomly assigned (1:1:1) to receive either standard oxygen, high-flow nasal cannula alone, or non-invasive ventilation interspaced with high-flow nasal cannula between non-invasive ventilation sessions (non-invasive ventilation group). Patients with profound neutropenia, acute-on-chronic respiratory failure, cardiogenic pulmonary oedema, shock, or altered consciousness were excluded. The primary outcome was the proportion of patients who required endotracheal intubation within 28 days after randomisation. FINDINGS: Of the 82 immunocompromised patients, 30 were treated with standard oxygen, 26 with high-flow nasal cannula alone, and 26 with non invasive ventilation plus interspaced high-flow nasal cannula. 8 (31%) of 26 patients treated with high-flow nasal cannula alone, 13 (43%) of 30 patients treated with standard oxygen, and 17 (65%) of 26 patients treated with non invasive ventilation required intubation at 28 days (p=0.04). Odds ratios (ORs) for intubation were higher in patients treated with non-invasive ventilation than in those treated with high-flow nasal cannula: OR 4.25 (95% CI 1.33-13.56). ORs were not significantly different between patients treated with high-flow nasal cannula alone and standard oxygen: OR 1.72 (0.57-5.18). After multivariable logistic regression, the two factors independently associated with endotracheal intubation and mortality were age and use of non-invasive ventilation as first line therapy. INTERPRETATION: Non-invasive ventilation might be associated with an increased risk of intubation and mortality and should be used cautiously in immunocompromised patients with acute hypoxaemic respiratory failure. FUNDING: French Ministry of Health, the French societies of intensive care (Societe de Reanimation de Langue Francaise, SRLF) and pneumology (Societe de Pneumologie de Langue Francaise, SPLF), La Mutuelle de Poitiers, AADAIRC (Association pour l'Assistance a Domicile Aux Insuffisants Respiratoires Chroniques), and Fisher&Paykel Healthcare. PMID- 27245915 TI - Mild obstructive sleep apnoea: clinical relevance and approaches to management. AB - Obstructive sleep apnoea is highly prevalent in the general population worldwide, especially in its mild form. Clinical manifestations correlate poorly with disease severity measured by the apnoea-hypopnoea index (AHI), which complicates diagnosis. Full polysomnography might be more appropriate to assess suspected mild cases because limited ambulatory diagnostic systems are least accurate in mild disease. Treatment options in mild obstructive sleep apnoea include continuous positive airway pressure (CPAP) and oral appliance therapy, in addition to positional therapy and weight reduction when appropriate. The superior efficacy of CPAP in reducing AHI is offset by greater tolerance of oral appliances, especially in mild disease. Although severe obstructive sleep apnoea is associated with adverse health consequences, including cardiometabolic comorbidities, the association with mild disease is unclear, and reports differ regarding the clinical relevance of mild obstructive sleep apnoea. Improved diagnostic techniques and evidence-based approaches to management in mild obstructive sleep apnoea require further research. PMID- 27245916 TI - Non-invasive oxygenation strategies in hypoxaemic respiratory failure. PMID- 27245917 TI - External validity of trials should be taken into account before asthma drug candidates reach market authorisation. PMID- 27245918 TI - Freezing of gait in Parkinson's disease: Evidence of sensory rather than attentional mechanisms through muscle vibration. AB - INTRODUCTION: The role of proprioceptive integration impairments as the potential mechanism underlying Freezing of gait (FOG) in Parkinson's disease (PD) is still an open debate. The effects of muscle vibration (a well-known manipulation of proprioception) could provide the answer to the debate. The aim of this study was to determine whether proprioceptive manipulation, through muscle vibration, could reduce FOG severity. METHODS: Sixteen PD patients who experience FOG were required to walk with small step lengths (15 cm). Cylindrical vibration devices were positioned on triceps surae tendon. Three vibration conditions were tested: No vibration (OFF), vibration on the less affected limb (LA), or on the more affected limb (MA). Additionally, we assessed the effects of applying vibration before and after FOG onset. The FOG duration and the foot used to take the next step were assessed. RESULTS: FOG significantly decreased only with vibration of LA in comparison to OFF, and when vibration was applied after FOG onset. CONCLUSION: Our results show that muscle vibration is a promising technique to alleviate the severity of FOG. Improvements to FOG behavior were restricted to the less affected limb, suggesting that only the less damaged side of the basal ganglia may have preserved capacity to process sensory feedback. These results also suggest the likelihood of sensory deficits in FOG that cannot be explained by cognitive mechanisms, since vibration effects were only observed unilaterally. PMID- 27245919 TI - Low BDNF is associated with cognitive impairments in patients with Parkinson's disease. AB - OBJECTIVE: Increasing evidence show that brain-derived neurotrophic factor (BDNF) plays a critical role in neuroplasticity in the hippocampus that is related to learning and memory. Parkinson disease (PD) is associated with impairment of cognitive function that may evolve from decreased BDNF. The aim of the present study was to examine the association of BDNF with cognitive impairment in PD. METHODS: We compared 97 PD patients to 102 healthy controls on serum BDNF and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Hoehn Yahr staging test was used to assess motor abilities. RESULTS: Serum BDNF levels were significantly lower in PD patients than in healthy controls (p < 0.01). Cognitive performance shown on the RBANS total and all of its five index scores were significantly lower in PD patients than normal controls (all p < 0.05). For the patients only, BDNF was positively associated with all five index and total scores of RBANS. CONCLUSIONS: Our findings suggest extensive cognitive impairments and decreased BDNF in PD patients. Moreover, decreased BDNF is associated with cognitive deficits of Parkinson's disease. PMID- 27245921 TI - Liver function during mechanical circulatory support: from witness to prognostic determinant. AB - In recent years, the treatment options for patients with severe cardiorespiratory failure have been extended by the implementation of mechanical circulatory support (MCS). Identification of patients that benefit most from this cost intensive treatment modality is of central importance, but is also challenging. Previous studies unravelled certain patient characteristics that should be taken into account, such as age, weight, and underlying pathology, and also the delay until MCS implementation as well as tissue hypoxia as prognostic factors. Relevant comorbidities included neurologic, renal, and hepatic disorders. Of note, baseline liver function tests predicted outcome in patients on extracorporeal life support (ECLS), including short-term and long-term mortality. Most strikingly, increased levels of alkaline phosphatase and total bilirubin indicated unfavourable short-term and long-term survival even after adjustment for age, gender, left ventricular function, and relevant known comorbidities such as impaired renal function and diabetes. Therefore, the assessment of liver function tests may be regarded as another piece in the complex puzzle of our efforts perceiving the ideal ECLS candidate with positive long-term outcome. PMID- 27245920 TI - Eosinophils may play regionally disparate roles in influencing IgA(+) plasma cell numbers during large and small intestinal inflammation. AB - BACKGROUND: Eosinophils are innate immune cells present in the intestine during steady state conditions. An intestinal eosinophilia is a hallmark of many infections and an accumulation of eosinophils is also observed in the intestine during inflammatory disorders. Classically the function of eosinophils has been associated with tissue destruction, due to the release of cytotoxic granule contents. However, recent evidence has demonstrated that the eosinophil plays a more diverse role in the immune system than previously acknowledged, including shaping adaptive immune responses and providing plasma cell survival factors during the steady state. Importantly, it is known that there are regional differences in the underlying immunology of the small and large intestine, but whether there are differences in context of the intestinal eosinophil in the steady state or inflammation is not known. RESULTS: Our data demonstrates that there are fewer IgA(+) plasma cells in the small intestine of eosinophil deficient DeltadblGATA-1 mice compared to eosinophil-sufficient wild-type mice, with the difference becoming significant post-infection with Toxoplasma gondii. Remarkably, and in complete contrast, the absence of eosinophils in the inflamed large intestine does not impact on IgA(+) cell numbers during steady state, and is associated with a significant increase in IgA(+) cells post-infection with Trichuris muris compared to wild-type mice. Thus, the intestinal eosinophil appears to be less important in sustaining the IgA(+) cell pool in the large intestine compared to the small intestine, and in fact, our data suggests eosinophils play an inhibitory role. The dichotomy in the influence of the eosinophil over small and large intestinal IgA(+) cells did not depend on differences in plasma cell growth factors, recruitment potential or proliferation within the different regions of the gastrointestinal tract (GIT). CONCLUSIONS: We demonstrate for the first time that there are regional differences in the requirement of eosinophils for maintaining IgA+ cells between the large and small intestine, which are more pronounced during inflammation. This is an important step towards further delineation of the enigmatic functions of gut-resident eosinophils. PMID- 27245922 TI - [Perioperative management of transthoracic oesophagectomies : Fundamentals of interdisciplinary care and new approaches to accelerated recovery after surgery]. AB - Locally advanced carcinomas of the oesophagus require multimodal treatment. The core element of curative therapy is transthoracic en bloc oesophagectomy, which is the standard procedure carried out in most specialized centres. Reconstruction of intestinal continuity is usually achieved with a gastric sleeve, which is anastomosed either intrathoracically or cervically to the remaining oesophagus. This thoraco-abdominal operation is associated with significant postoperative morbidity, not least because of a vast array of pre-existing illnesses in the surgical patient. For an optimal outcome, the careful interdisciplinary selection of patients, preoperative risk evaluation and conditioning are essential. The caseload of the centres correlates inversely with the complication rate. The leading surgical complication is anastomotic leakage, which is diagnosed endoscopically and usually treated with the aid of endoscopic procedures. Pulmonary infections are the most frequent non-surgical complication. Thoracic epidural anaesthesia and perfusion-orientated fluid management can reduce the rate of pulmonary complications. Patients are ventilated protecting the lungs and are extubated as early as possible. Oesophagectomies should only be performed in high-volume centres with the close cooperation of surgeons and anaesthesia/intensive care specialists. Programmes of enhanced recovery after surgery (ERAS) hold further potential for the patient's quicker postoperative recovery. In this review article the fundamental aspects of the interdisciplinary perioperative management of transthoracic oesophagectomy are described. PMID- 27245923 TI - [Monitoring tidal volumes when using the Ventrain(r) emergency ventilator]. AB - BACKGROUND: The Ventrain(r) emergency ventilation device allows active inspiration and expiration through transtracheal catheters or the lumen of an airway exchange catheter. This single-use handheld device is manually operated and driven by an external pressurized oxygen source. The Ventrain(r) may be used to ventilate patients with a complete or pending upper airway obstruction reducing the risk of barotrauma due to the possibility of active expiration. However tidal volumes (V T) applied and withdrawn with the Ventrain(r) can only be controlled by visual inspection of chest movements; V T monitoring is not provided. Excessive inspiratory volumes or air trapping due to insufficient expiration may remain clinically undetected until pulmonary trauma and/or cardio respiratory deterioration occur. Active expiration itself carries the risk of overwhelming lung deflation with the formation of atelectasis. Thus, an inspiratory and expiratory tidal volume monitor is urgently required. The aim of this study was to evaluate efficacy and precision of the Florian respiratory function monitor (RFM) to monitor in- and expiratory V T administered by the Ventrain(r) emergency ventilation device through a small cannula to the ASL 5000 test lung (ASL). METHODS: In an in-vitro setting the RFM was used with its neonatal flow sensor to monitor inspiratory and expiratory V T applied by the Ventrain(r) emergency ventilation device through a 2 mm internal diameter (ID) transtracheal catheter to the ASL. Driving flows of 6, 9, 12 and 15 l min(-1) were chosen to vary tidal volumes at a constant respiratory rate of 15 min(-1) and an I:E ratio of 1:1. Experiments were repeated five times with two flow sensors. An initial set-up calibration run was performed to calculate a bias correction factor for inspiratory and expiratory V T measured by the RFM. This bias correction factor was used to simulate a correction of the in the RFM programmed linearization table. In a second, identical setting the experiments were repeated five times with two flow sensors. V T measured by the adjusted RFM were compared with those obtained from the ASL 5000 in this second run and the percentage differences were calculated. Bland Altman analysis was used to investigate the agreement of inspiratory or expiratory VT measured by both methods (ASL and RFM). Calculation of the mean of differences between both methods is given as bias and the 95 % agreement interval as precision. RESULTS: Tidal volumes measured by the ASL ranged from 140 to 675 ml. The percentage correction factor was 16.27 % (2.60 %) during inspiration for V T ranged from 0 to 700 ml and 11.51 % (2.56 %) during expiration for V T of 0 to 225 ml, 7.41 % (2.94 %) for VT 226 to 325 ml and 5.35 % (3.57 %) for TV e > 325 ml. Inspiratory and expiratory tidal volumes measured by the adjusted RFM demonstrated a percentage deviation (mean [SD]) of 2.59 % (1.86 %) during inspiration and 1.66 % (1.14 %) during expiration when compared with the ASL 5000. Bias (precision) of the Bland Altman plot for the adjusted RFM is 2.05 ml (23.20) during inspiration and 4.62 ml (10.40) for expiration. CONCLUSION: The tested respiratory function monitor using hot-wire anemometer technology has the potential to monitor tidal volumes applied by the Ventrain(r). With the software thus adapted, the RFM measures precise inspiratory and expiratory tidal volumes within common technical tolerance. This could help perform adequate patient ventilation with Ventrain(r) and reduce the potential risk of patient trauma. PMID- 27245924 TI - [Not either/or: both!]. PMID- 27245925 TI - [A Germany-wide survey on anaesthesia in thoracic surgery]. AB - BACKGROUND/OBJECTIVE: This study's objective was to evaluate current thoracic anaesthesia practice in Germany and to quantify potential differences depending on the hospital's level of care. MATERIALS AND METHODS: A four-part online survey containing 28 questions was mailed to all anaesthesiology department chairs (n = 777) registered with the German Society of Anaesthesiology and Intensive Care Medicine. RESULTS: The general response rate was 31.5 % (n = 245). High monthly volumes (>50 operations/month) of intrathoracic procedures, performed by specialized thoracic surgeons are mostly limited to hospitals of maximum care, university hospitals, and specialized thoracic clinics. In hospitals with a lower level of care, intrathoracic operations occur less frequently (1-5/month) and are commonly performed by general (69.3 %) rather than thoracic surgeons (15.4 %). Video-assisted thoracic surgeries are the most invasive intrathoracic procedures for most hospitals with a low level of care (61.5 %). Extended resections and pneumonectomies occur mainly in hospitals of maximum care and university hospitals. Thoracic anaesthesia is primarily performed by consultants or senior physicians (59.9 %). The double lumen tube (91.4 %) is the preferred method to enable one-lung ventilation (bronchial blockers: 2.7 %; missing answer: 5.9 %). A bronchoscopic confirmation of the correct placement of a double lumen tube is considered mandatory by 87.7 % of the respondents. Bronchial blockers are available in 64.7 % of all thoracic anaesthesia departments. While CPAP-valves for the deflated lung are commonly used (74.9 %), jet-ventilators are rarely accessible, especially in hospitals with a lower level of care (15.4 %). Although general algorithms for a difficult airway are widely available (87.7 %), specific recommendations for a difficult airway in thoracic anaesthesia are uncommon (4.8 %). Laryngeal mask airways (90.9 %) and videolaryngoscopy (88.8 %) are the primary adjuncts in store for a difficult airway. While hospitals with a lower level of care admitted patients routinely (92.3 %) to an intensive care unit after thoracic surgery, larger clinics used the postanaesthesia recovery room (12.5 %) and intermediate care units (14.6 %) more frequently for further surveillance. Thoracic epidural catheters (85.6 %) are predominantly chosen for peri- and postoperative analgesia, in contrast to paravertebral blockade (single shot: 8.6 %; catheter: 8.0 %) (multiple answers possible). Ultrasound is generally accessible (84.5 %) and mostly employed for the placement of central venous (81.3 %) and arterial (43.9 %) lines as well as a diagnostic tool for pulmonary pathology (62.0 %). CONCLUSION: The study reveals considerable differences in the anaesthetic practice in thoracic surgery. These focus mostly on the postoperative surveillance, the availability of bronchial blockers, and the use of regional anaesthetic techniques. Furthermore, it is evident that specific algorithms are needed for the difficult airway in thoracic anaesthesia. A recommendation for the high-tech work environment of thoracic anaesthesia could enhance the structural quality and optimize patient outcomes. Independent of a hospital's level of care, uniform requirements could help establish national quality standards in thoracic anaesthesia. PMID- 27245926 TI - The influence of feedback on predictions of future memory performance. AB - Kornell and Rhodes (Journal of Experimental Psychology: Applied, 19, 1-13, 2013) reported that correct answer feedback impairs the accuracy of prospective memory judgments. The current experiments explored the boundaries of this effect. In Experiment 1, participants studied Lithuanian-English word pairs, took an initial test, and were either given correct answer feedback or no feedback at all. They then made a judgment of learning (JOL) regarding the likelihood of correctly recalling the English translation on a later test. Presenting the correct answer as feedback increased average JOLs but impaired relative accuracy on a final test. Therefore, Experiments 2-4 aimed to specifically ameliorate impairments in relative accuracy following feedback. Participants in Experiment 2 were exposed to right/wrong feedback, no feedback, and correct answer feedback while making JOLs. Using such a within-subjects design did not improve relative accuracy following correct answer feedback. Experiment 3 showed that previous exposure to a test-feedback-test cycle did not improve relative accuracy. In Experiment 4, feedback was scaffolded such that the correct answer was progressively revealed. Participants corrected more errors if they could generate the correct response with fewer letter cues. However, relative accuracy did not improve in comparison to the previous experiments. Accordingly, the current experiments suggest that participants may understand that feedback is beneficial, but receiving feedback diminishes prediction accuracy for specific items and participants do not appreciate the magnitude of the benefits of feedback. PMID- 27245927 TI - Synthetically Tuning the 2-Position of Halogenated Quinolines: Optimizing Antibacterial and Biofilm Eradication Activities via Alkylation and Reductive Amination Pathways. AB - Agents capable of eradicating bacterial biofilms are of great importance to human health as biofilm-associated infections are tolerant to our current antibiotic therapies. We have recently discovered that halogenated quinoline (HQ) small molecules are: 1) capable of eradicating methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE) and vancomycin-resistant Enterococcus faecium (VRE) biofilms, and 2) synthetic tuning of the 2-position of the HQ scaffold has a significant impact on antibacterial and antibiofilm activities. Here, we report the chemical synthesis and biological evaluation of 39 HQ analogues that have a high degree of structural diversity at the 2-position. We identified diverse analogues that are alkylated and aminated at the 2-position of the HQ scaffold and demonstrate potent antibacterial (MIC<=0.39 MUm) and biofilm eradication (MBEC 1.0-93.8 MUm) activities against drug-resistant Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecium strains while demonstrating <5 % haemolysis activity against human red blood cells (RBCs) at 200 MUm. In addition, these HQs demonstrated low cytotoxicity against HeLa cells. Halogenated quinolines are a promising class of antibiofilm agents against Gram-positive pathogens that could lead to useful treatments against persistent bacterial infections. PMID- 27245928 TI - Water aerobics is followed by short-time and immediate systolic blood pressure reduction in overweight and obese hypertensive women. AB - One exercise training session such as walking, running, and resistance can lead to a decrease in blood pressure in normotensive and hypertensive individuals, but few studies have investigated the effects of exercise training in an aquatic environment for overweight and obese hypertensive individuals. We aimed to assess the acute effects of a water aerobics session on blood pressure changes in pharmacologically treated overweight and obese hypertensive women. A randomized crossover study was carried out with 18 hypertensive women, 10 of them were overweight (54.4 +/- 7.9 years; body mass index: 27.8 +/- 1.7 kg/m(2)) and eight obese (56.4 +/- 6.6 years; body mass index: 33.0 +/- 2.0 kg/m(2)). The water aerobics exercise session consisted of a 45-minute training at the intensity of 70%-75% of maximum heart rate adjusted for the aquatic environment. The control group did not enter the pool and did not perform any exercise. We measured systolic blood pressure (SBP) and diastolic blood pressure (DBP) before, immediately after, and every 10 minutes up to 30 minutes after the aerobic exercise or control session. Overall (n = 18), DBP did not change after the water aerobic exercise and control session, and SBP decreased at 10 and 20 minutes postexercise compared to the control session. Among overweight women, SBP decreased at 10 and 20 minutes postexercise. In contrast, among obese women, SBP decreased only at 10 minutes postexercise. SBP variation was -2.68 mm Hg in overweight and -1.24 mm Hg in obese women. In conclusion, the water aerobics session leads to a reduction in SBP, but not in DBP, during 10 and 20 minutes postexercise recovery. Thus, it may be safely prescribed to overweight and obese women. PMID- 27245931 TI - Does Making Something Move Matter? Representations of Goals and Sources in Motion Events With Causal Sources. AB - Previous studies have shown a robust bias to express the goal path over the source path when describing events ("the bird flew into the pitcher," rather than "... out of the bucket into the pitcher"). Motivated by linguistic theory, this study manipulated the causal structure of events (specifically, making the source cause the motion of the figure) and measured the extent to which adults and 3.5- to 4-year-old English-speaking children included the goal and source in their descriptions. We found that both children's and adults' encoding of the source increased for events in which the source caused the motion of the figure compared to nearly identical events in which the source played no such causal role. However, a goal bias persisted overall for both causal and noncausal motion events. These findings suggest that although the goal bias in language is highly robust, properties of the source (such as causal agency) influence its likelihood of being encoded in language, thus shedding light on how properties of an event can influence the mapping of event components into language. PMID- 27245933 TI - Effect of cold ischaemia time on outcome after living donor renal transplantation. AB - BACKGROUND: The aim of the present study was to determine the effects of cold ischaemia time (CIT) on living donor kidney transplant recipients in a large national data set. METHODS: Data from the National Health Service Blood and Transplant and UK Renal Registry databases for all patients receiving a living donor kidney transplant in the UK between January 2001 and December 2014 were analysed. Patients were divided into three groups depending on CIT (less than 2 h, 2-4 h, 4-8 h). Risk-adjusted outcomes were assessed by multivariable analysis adjusting for discordance in both donor and recipient characteristics. RESULTS: Outcomes of 9156 transplants were analysed (CIT less than 2 h in 2662, 2-4 h in 4652, and 4-8 h in 1842). After adjusting for confounders, there was no significant difference in patient survival between CIT groups. Recipients of kidneys with a CIT of 4-8 h had excellent graft outcomes, although these were slightly inferior to outcomes in those with a CIT of less than 2 h, with risk adjusted rates of delayed graft function of 8.6 versus 4.3 per cent, and 1-year graft survival rates of 96.2 versus 97.1 per cent, respectively. CONCLUSION: The detrimental effect of prolonging CIT for up to 8 h in living donation kidney transplantation is marginal. PMID- 27245932 TI - Linking up at the BAR: Oligomerization and F-BAR protein function. AB - As cells grow, move, and divide, they must reorganize and rearrange their membranes and cytoskeleton. The F-BAR protein family links cellular membranes with actin cytoskeletal rearrangements in processes including endocytosis, cytokinesis, and cell motility. Here we review emerging information on mechanisms of F-BAR domain oligomerization and membrane binding, and how these activities are coordinated with additional domains to accomplish scaffolding and signaling functions. PMID- 27245934 TI - Acute rhinosinusitis and intraorbital abscess caused by Citrobacter koseri infection. PMID- 27245935 TI - Assessment of Clarias gariepinus as a biological control agent against mosquito larvae. AB - BACKGROUND: The emergence and spread of insecticide resistant mosquitoes renewed interest in investigating the use of larvivorous fish as a biological control agent. The potential of Clarias gariepinus fish in controlling Anopheles arabiensis and culicine larvae was assessed under laboratory and semi-field conditions. RESULTS: Small size (15-20 cm) C. gariepinus fish consumed greater number of mosquito larvae than the large size fish (25-40 cm) in the multivariate regression model (beta = 13.36, 95 % CI = 4.57, 22.15). The Anopheles larvae consumed was greater in number than the culicines larvae consumed by the fish (beta = 12.10, 95 % CI = 3.31, 20.89). The number of larvae consumed was greater during the night hours than during the light hours (beta = 30.06, 95 % CI = 21.27, 38.85). Amount of supplementary fish food did not cause significant differences in the number of mosquito larvae consumed by the fish among different groups. C. gariepinus was observed to feed on mosquito larvae under laboratory and semi-field conditions. CONCLUSION: C. gariepinus fed on the larvae of An. arabiensis and culicines readily. Hence, it can be used as an alternative mosquito control agent in Ethiopia where the breeding habitats are small and localized. PMID- 27245936 TI - The prevalence, age distribution and comorbidity of personality disorders in Australian women. AB - OBJECTIVE: We aimed to describe the prevalence and age distribution of personality disorders and their comorbidity with other psychiatric disorders in an age-stratified sample of Australian women aged ?25 years. METHODS: Individual personality disorders (paranoid, schizoid, schizotypal, histrionic, narcissistic, borderline, antisocial, avoidant, dependent, obsessive-compulsive), lifetime mood, anxiety, eating and substance misuse disorders were diagnosed utilising validated semi-structured clinical interviews (Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Non-patient Edition and Structured Clinical Interview for DSM-IV Axis II Personality Disorders). The prevalence of personality disorders and Clusters were determined from the study population ( n = 768), and standardised to the Australian population using the 2011 Australian Bureau of Statistics census data. Prevalence by age and the association with mood, anxiety, eating and substance misuse disorders was also examined. RESULTS: The overall prevalence of personality disorders in women was 21.8% (95% confidence interval [CI]: 18.7, 24.9). Cluster C personality disorders (17.5%, 95% CI: 16.0, 18.9) were more common than Cluster A (5.3%, 95% CI: 3.5, 7.0) and Cluster B personality disorders (3.2%, 95% CI: 1.8, 4.6). Of the individual personality disorders, obsessive-compulsive (10.3%, 95% CI: 8.0, 12.6), avoidant (9.3%, 95% CI: 7.1, 11.5), paranoid (3.9%, 95% CI: 3.1, 4.7) and borderline (2.7%, 95% CI: 1.4, 4.0) were among the most prevalent. The prevalence of other personality disorders was low (?1.7%). Being younger (25-34 years) was predictive of having any personality disorder (odds ratio: 2.36, 95% CI: 1.18, 4.74), as was being middle-aged (odds ratio: 2.41, 95% CI: 1.23, 4.72). Among the strongest predictors of having any personality disorder was having a lifetime history of psychiatric disorders (odds ratio: 4.29, 95% CI: 2.90, 6.33). Mood and anxiety disorders were the most common comorbid lifetime psychiatric disorders. CONCLUSIONS: Approximately one in five women was identified with a personality disorder, emphasising that personality disorders are relatively common in the population. A more thorough understanding of the distribution of personality disorders and psychiatric comorbidity in the general population is crucial to assist allocation of health care resources to individuals living with these disorders. PMID- 27245937 TI - Epicardial fat tissue in patients with psoriasis:a systematic review and meta analysis. AB - BACKGROUND: Several studies have been performed to investigate the relationship between psoriasis and epicardial fat tissue (EFT). However, the number of patients of every single study is relatively small. OBJECTIVES: We carried out a meta-analysis to evaluate whether EFT is associated with psoriasis. METHODS: A search of PubMed, Ovid Embase, Ovid Medline, the Cochrane Library and Chinese BioMedical Literature Database (CBM) for controlled trials was done from inception to January 20th, 2016. Published trials that included a psoriasis group and a control group without psoriasis with data for at least epicardial fat tissue (EFT) were included. All statistical analyses were conducted using the Stata 12.0 (Stata Corporation, College Station, TX, USA). RESULTS: There were 5 trials involving 731 patients. Patients with psoriasis showed significantly higher EFT than control group (SMD: 0.86, 95 % CI: 0.27-1.46, P = 0.004). CONCLUSIONS: Patients with psoriasis have higher EFT compared to control subjects without psoriasis. PMID- 27245938 TI - Making pituitary hormone-producing cells in a dish [Review]. AB - The hypothalamic-pituitary system is essential for maintaining life and controlling systemic homeostasis. The functional disorder makes patients suffer from various symptoms all their lives. Pluripotent stem cells, such as embryonic stem (ES) cells and induced pluripotent stem (iPS) cells, differentiate into neuroectodermal progenitors when cultured as floating aggregates under serum-free conditions. Recent results have shown that strict removal of exogenous patterning factors during the early differentiation period induces rostral hypothalamic-like progenitors from mouse ES cells. The use of growth factor-free, chemically defined medium was critical for this induction. The ES cell-derived hypothalamic like progenitors generated rostral-dorsal hypothalamic neurons, in particular magnocellular vasopressinergic neurons. We subsequently reported self-formation of adenohypophysis in three-dimensional floating cultures of mouse ES cells. The ES cell aggregates were stimulated to differentiate into both non-neural head ectoderm and hypothalamic neuroectoderm in adjacent layers. Self-organization of Rathke's pouch-like structures occurred at the interface of the two epithelia in vitro. Various pituitary endocrine cells including corticotrophs and somatotrophs were subsequently produced from the Rathke's pouch-like structures. The induced corticotrophs efficiently secreted ACTH in response to CRH. Furthermore, when engrafted in vivo, these cells rescued systemic glucocorticoid levels in hypopituitary mice. Our latest study aimed to prepare hypothalamic and pituitary tissues from human pluripotent stem cells. We succeeded in establishing the differentiation method using human ES/iPS cells. The culture method is characterized by replication of stepwise embryonic differentiation. Therefore, these methods could potentially be used as developmental and disease models, as well as for future regenerative medicine. PMID- 27245939 TI - Tuning the Structural Color of a 2D Photonic Crystal Using a Bowl-like Nanostructure. AB - Structural colors of the ordered photonic nanostructures are widely used as an effective platform for manipulating the propagation of light. Although several approaches have been explored in attempts to mimic the structural colors, improving the reproducibility, mechanical stability, and the economic feasibility of sophisticated photonic crystals prepared by complicated processes continues to pose a challenge. In this study, we report on an alternative, simple method for fabricating a tunable photonic crystal at room temperature. A bowl-like nanostructure of TiO2 was periodically arranged on a thin Ti sheet through a two step anodization process where its diameters were systemically controlled by changing the applied voltage. Consequently, they displayed a broad color distribution, ranging from red to indigo, and the principal reason for color generation followed the Bragg diffraction theory. This noncolorant method was capable of reproducing a Mondrian painting on a centimeter scale without the need to employ complex architectures, where the generated structural colors were highly stable under mechanical or chemical influence. Such a color printing technique represents a potentially promising platform for practical applications for anticounterfeit trademarks, wearable sensors, and displays. PMID- 27245944 TI - Imagery in Dance: A Literature Review. AB - Dance imagery is a consciously created mental representation of an experience, either real or imaginary, that may affect the dancer and her or his movement. In this study, imagery research in dance was reviewed in order to: 1. describe the themes and ideas that the current literature has attempted to illuminate and 2. discover the extent to which this literature fits the Revised Applied Model of Deliberate Imagery Use. A systematic search was performed, and 43 articles from 24 journals were found to fit the inclusion criteria. The articles were reviewed, analyzed, and categorized. The findings from the articles were then reported using the Revised Applied Model as a framework. Detailed descriptions of Who, What, When and Where, Why, How, and Imagery Ability were provided, along with comparisons to the field of sports imagery. Limitations within the field, such as the use of non-dance-specific and study-specific measurements, make comparisons and clear conclusions difficult to formulate. Future research can address these problems through the creation of dance-specific measurements, higher participant rates, and consistent methodologies between studies. PMID- 27245943 TI - Dendritic cell vaccines: A review of recent developments and their potential pediatric application. AB - For many cancers the use of conventional chemotherapy has been maximized, and further intensification of chemotherapy generally results in excess toxicity with little long-term benefit for cure. Many tumors become resistant to chemotherapy, making the investigation of novel approaches such as immunotherapy of interest. Because the tumor microenvironment is known to promote immune tolerance and down regulate the body's natural defense mechanisms, modulating the immune system with the use of dendritic cell (DC) therapy is an attractive approach. Thousands of patients with diverse tumor types have been treated with DC vaccines. While antigen specific immune responses have been reported, the duration and magnitude of these responses are typically weak, and objective clinical responses have been limited. DC vaccine generation and administration is a multi-step process with opportunities for improvement in source of DC for vaccine, selection of target antigen, and boosting effector cell response via administration of vaccine adjuvant or concomitant pharmacologic immunomodulation. In this review we will discuss recent developments in each of these areas and highlight elements that could be moved into pediatric clinical trials. PMID- 27245945 TI - Resistance Training for Pediatric Female Dancers. AB - Resistance training often is not an inherent component of current dance training for pediatric female dancers. Reasons for this include concerns surrounding injury to the immature skeleton and diminishing dancer aesthetic appearance, as well as questions related to the effectiveness of such training for increasing dancer strength and muscle endurance. Many forms of dance demand sufficient muscle strength and endurance for prolonged periods of high intensity dance, power generation during leaps and jumps, as well as stabilization of the lower extremity to prevent injury. The benefits of resistance training for the pediatric female dancer are multiple, including improved muscle strength and bone health and decreased risk for stress related injuries to the actively growing skeleton. Understanding the biomechanical changes that occur during growth that may predispose the female dancer to injury is important, as well as initiating individualized resistance training protocols early in training that may serve to improve performance and prevent future injury. PMID- 27245946 TI - Comparison of Balance Performance Between Thai Classical Dancers and Non-Dancers. AB - Thai classical dance is a traditional dramatic art, the technique of which has many features in common with South East Asian performing art. The choreographic patterns consist of various forms of balance control together with limb movements in slow rhythm. The grace and beauty of the dancer are dependent on how well the limb movements curve and angle. The relationship of whole body proportion and balance control in various patterns of support base is also important. The purpose of this study was to compare balance abilities between Thai classical dancers and non-dancers in different balance conditions. Twenty-five Thai classical dancers and 25 non-dancers performed the modified Sensory Organization Test (mSOT) and were further challenged by adding dynamic head tilts (DHTs) in four different directions during mSOT. Mixed model ANOVA was applied to determine the equilibrium score in each balance condition and also the interaction between dancer and non-dancer groups. It was found that Thai classical dancers achieved better equilibrium scores in all mSOT conditions except the least challenging one. Moreover, additional multitask conditions (mSOT+DHT) were revealed to profoundly affect differences between dancers and controls. In conclusion, Thai classical dancers demonstrated a better ability to maintain postural stability during different challenging postural tests. This information suggests various ways of putting the practice of Thai classical dance to use in the future. PMID- 27245947 TI - Concussion Knowledge and Behaviors in a Sample of the Dance Community. AB - Despite recent improvements in their concussion knowledge, athletes still demonstrate risky concussion behaviors (e.g., playing while concussed or not reporting a concussion). Little has been published about dancers' concussion knowledge and behaviors, but research in dance contending with questions about injury in general has found that dancers often avoid physician consults and ignore the signs of injury. In the present study, an IRB approved anonymous online survey, it was hypothesized that dancers would demonstrate concussion knowledge deficits, fail to report concussions, and have difficulty adhering to management guidelines. In addition, it was hypothesized that dancers in companies or schools with an onsite health care practitioner present would demonstrate improved concussion knowledge and safer concussion behaviors compared with those that do not have onsite health care. Concussion knowledge and behavior questions were modified for a dance sample based on validated sports-specific tools developed by other investigators. One hundred fifty-three subjects were recruited to complete the survey from an urban orthopaedic clinic specializing in dance medicine and via Facebook, email, and newsletter announcements. Dancers in this sample had good foundational knowledge of concussion; however, this knowledge did not correlate with safe, self-reported concussion care behaviors. Future research should focus on determination of dance-specific barriers to practicing safe behaviors and seeking care for concussive injury, as well as further identifying dance concussion epidemiology and outcomes. PMID- 27245948 TI - Mobile Phone and Web-based Cognitive Behavior Therapy for Depressive Symptoms and Mental Health Comorbidities in People Living With Diabetes: Results of a Feasibility Study. AB - BACKGROUND: Depression is often comorbid with diabetes; however, undertreatment of depressive symptoms in people affected is common. OBJECTIVE: We studied preliminary acceptability and effectiveness of a fully automated, mobile phone, and web-based public health intervention, myCompass, for reducing depressive symptoms and improving mental health comorbidities in people with diabetes. METHODS: In this single-group feasibility study, 89 volunteers with type 1 (n=34) or type 2 (n=55) diabetes and at least mild depressive symptoms used myCompass for 7 weeks. Web-based measures of depressive and anxious symptoms, functional impairment, diabetes-specific variables, and user satisfaction were completed at baseline, postintervention, and 3-month follow-up. RESULTS: Retention rates were 54% (n=48) at postintervention and 36% (n=32) at follow-up. Depressive symptoms were significantly improved at postintervention (P<.001; within-group effect size d=1.05), with gains persisting at follow-up. Mental health comorbidities, including anxiety (P<.001), functioning (P<.001), and diabetes-specific distress (P<.001), also showed significant and sustained improvement. Satisfaction with myCompass was high, with convenience and ease of program use, and relevance of program content rated positively by participants. CONCLUSIONS: The myCompass program shows promise as an acceptable and effective treatment for depression and comorbid mental health problems in people with diabetes. The program is broadly available, free to use, and may benefit patients with diabetes who do not access services and/or wish to manage their mental health themselves. Replication of these findings in a controlled study is warranted. PMID- 27245949 TI - SCF/c-kit transactivates CXCR4-serine 339 phosphorylation through G protein coupled receptor kinase 6 and regulates cardiac stem cell migration. AB - C-kit positive cardiac stem cells (CSCs) have been shown to contribute to myocardial regeneration after infarction. Previously, we have shown that the c kit ligand stem cell factor (SCF) can induce CSC migration into the infarcted area during myocardial infarction (MI). However, the precise mechanism involved is not fully understood. In this study, we found that CSCs also express C-X-C chemokine receptor type 4 (CXCR4), which is a typical member of the seven transmembrane-spanning G protein-coupled receptor (GPCR). In vitro, activation of c-kit signalling by SCF promotes migration of CSCs with increased phosphorylation of CXCR4-serine 339, p38 mitogen-activated protein kinase (p38 MAPK) and extracellular regulated protein kinases 1/2 (ERK1/2). Knockdown of CXCR4 expression by siRNA reduces SCF/c-kit-induced migration and downstream signalling. As previously reported, CXCR4-serine 339 phosphorylation is mainly regulated by GPCR kinase 6 (GRK6); thus, silencing of GRK6 expression by siRNA impairs CXCR4-serine 339 phosphorylation and migration of CSCs caused by SCF. In vivo, knockdown of GRK6 impairs the ability of CSCs to migrate into peri infarcted areas. These results demonstrate that SCF-induced CSC migration is regulated by the transactivation of CXCR4-serine 339 phosphorylation, which is mediated by GRK6. PMID- 27245950 TI - The effect of chloride ions on the corroded surface layer of 00Cr22Ni5Mo3N duplex stainless steel under cavitation. AB - The effects of Cl(-) on the corroded surface layer of 00Cr22Ni5Mo3N duplex stainless steel under cavitation in chloride solutions were investigated using nanoindentation in conjunction with XRD and XPS. The results demonstrate that Cl( ) had a strong effect on the nano-mechanical properties of the corroded surface layer under cavitation, and there was a threshold Cl(-) concentration. Furthermore, a close relationship between the nano-mechanical properties and the cavitation corrosion resistance of 00Cr22Ni5Mo3N duplex stainless steel was observed. The degradation of the nano-mechanical properties of the corroded surface layer was accelerated by the synergistic effect between cavitation erosion and corrosion. A key factor was the adsorption of Cl(-), which caused a preferential dissolution of the ferrous oxides in the passive film layer on the corroded surface layer. Cavitation further promoted the preferential dissolution of the ferrous oxides in the passive film layer. Simultaneously, cavitation accelerated the erosion of the ferrite in the corroded surface layer, resulting in the degradation of the nano-mechanical properties of the corroded surface layer on 00Cr22Ni5Mo3N duplex stainless steel under cavitation. PMID- 27245951 TI - Enhancing the adhesion strength of micro electroforming layer by ultrasonic agitation method and the application. AB - Micro electroforming is widely used for fabricating micro metal devices in Micro Electro Mechanism System (MEMS). However, there is the problem of poor adhesion strength between micro electroforming layer and substrate. This dramatically influences the dimensional accuracy of the device. To solve this problem, ultrasonic agitation method is applied during the micro electroforming process. To explore the effect of the ultrasonic agitation on the adhesion strength, micro electroforming experiments were carried out under different ultrasonic power (0W, 100W, 150W, 200W, 250W) and different ultrasonic frequencies (0kHz, 40kHz, 80kHz, 120kHz, 200kHz). The effects of the ultrasonic power and the ultrasonic frequency on the micro electroforming process were investigated by polarization method and alternating current (a.c.) impedance method. The adhesion strength between the electroforming layer and the substrate was measured by scratch test. The compressive stress of the electroforming layer was measured by X-ray Diffraction (XRD) method. The crystallite size of the electroforming layer was measured by Transmission Electron Microscopy (TEM) method. The internal contact surface area of the electroforming layer was measured by cyclic voltammetry (CV) method. The experimental results indicate that the ultrasonic agitation can decrease the polarization overpotential and increase the charge transfer process. Generally, the internal contact surface area is increased and the compressive stress is reduced. And then the adhesion strength is enhanced. Due to the different depolarization effects of the ultrasonic power and the ultrasonic frequency, the effects on strengthening the adhesion strength are different. When the ultrasonic agitation is 200W and 40kHz, the effect on strengthening the adhesion strength is the best. In order to prove the effect which the ultrasonic agitation can improve the adhesion strength of the micro devices, micro pillar arrays were fabricated under ultrasonic agitation (200W, 40kHz). The experimental results show that the residual rate of the micro pillar arrays is increased about 17% by ultrasonic agitation method. This work contributes to fabricating the electroforming layer with large adhesion strength. PMID- 27245952 TI - Cleaning efficiency enhancement by ultrasounds for membranes used in dairy industries. AB - Membrane cleaning is a key point for the implementation of membrane technologies in the dairy industry for proteins concentration. In this study, four ultrafiltration (UF) membranes with different molecular weight cut-offs (MWCOs) (5, 15, 30 and 50kDa) and materials (polyethersulfone and ceramics) were fouled with three different whey model solutions: bovine serum albumin (BSA), BSA plus CaCl2 and whey protein concentrate solution (Renylat 45). The purpose of the study was to evaluate the effect of ultrasounds (US) on the membrane cleaning efficiency. The influence of ultrasonic frequency and the US application modes (submerging the membrane module inside the US bath or applying US to the cleaning solution) were also evaluated. The experiments were performed in a laboratory plant which included the US equipment and the possibility of using two membrane modules (flat sheet and tubular). The fouling solution that caused the highest fouling degree for all the membranes was Renylat 45. Results demonstrated that membrane cleaning with US was effective and this effectiveness increased at lower frequencies. Although no significant differences were observed between the two different US applications modes tested, slightly higher cleaning efficiencies values placing the membrane module at the bottom of the tank were achieved. PMID- 27245953 TI - Activation of microbubbles by low-intensity pulsed ultrasound enhances the cytotoxicity of curcumin involving apoptosis induction and cell motility inhibition in human breast cancer MDA-MB-231 cells. AB - Ultrasound and microbubbles-mediated drug delivery has become a promising strategy to promote drug delivery and its therapeutic efficacy. The aim of this research was to assess the effects of microbubbles (MBs)-combined low-intensity pulsed ultrasound (LPUS) on the delivery and cytotoxicity of curcumin (Cur) to human breast cancer MDA-MB-231 cells. Under the experimental condition, MBs raised the level of acoustic cavitation and enhanced plasma membrane permeability; and cellular uptake of Cur was notably improved by LPUS-MBs treatment, aggravating Cur-induced MDA-MB-231 cells death. The combined treatment markedly caused more obvious changes of cell morphology, F-actin cytoskeleton damage and cell migration inhibition. Our results demonstrated that combination of MBs and LPUS may be an efficient strategy for improving anti-tumor effect of Cur, suggesting a potential effective method for antineoplastic therapy. PMID- 27245954 TI - Preparation of zeolite nanorods by corona discharge plasma for degradation of phenazopyridine by heterogeneous sono-Fenton-like process. AB - The plasma-modified clinoptilolite (PMC) nanorods were prepared from natural clinoptilolite (NC) utilizing environmentally-friendly corona discharge plasma. The PMC and NC were characterized by XRD, FT-IR, SEM, EDX, XPS and BET, which confirmed the nanocatalyst formation. The catalytic performance of the PMC in the heterogeneous sono-Fenton-like process was greater than the NC for treatment of phenazopyridine (PhP). The desired amounts were obtained for experimental parameters including initial pH (5), PMC dosage (2g/L), K2S2O8 concentration (2mmol/L), ultrasonic power (300W) and PhP concentration (10mg/L). Reactive oxygen species scavengers decreased the removal efficiency of the PhP. The treatment process followed pseudo-first order kinetic and seven degradation intermediates were identified by the GC-MS technique. PMID- 27245955 TI - Effects of power ultrasound on oxidation and structure of beef proteins during curing processing. AB - The aim of this study was to evaluate the effects of power ultrasound intensity (PUS, 2.39, 6.23, 11.32 and 20.96Wcm(-2)) and treatment time (30, 60, 90 and 120min) on the oxidation and structure of beef proteins during the brining procedure with 6% NaCl concentration. The investigation was conducted with an ultrasonic generator with the frequency of 20kHz and fresh beef at 48h after slaughter. Analysis of TBARS (Thiobarbituric acid reactive substances) contents showed that PUS treatment significantly increased the extent of lipid oxidation compared to static brining (P<0.05). As indicators of protein oxidation, the carbonyl contents were significantly affected by PUS (P<0.05). SDS-PAGE analysis showed that PUS treatment increased protein aggregation through disulfide cross linking, indicated by the decreasing content of total sulfhydryl groups which would contribute to protein oxidation. In addition, changes in protein structure after PUS treatment are suggested by the increases in free sulfhydryl residues and protein surface hydrophobicity. Fourier transformed infrared spectroscopy (FTIR) provided further information about the changes in protein secondary structures with increases in beta-sheet and decreases in alpha-helix contents after PUS processing. These results indicate that PUS leads to changes in structures and oxidation of beef proteins caused by mechanical effects of cavitation and the resultant generation of free radicals. PMID- 27245956 TI - High adsorption capacity of two Zn-based metal-organic frameworks by ultrasound assisted synthesis. AB - Micro- and nano-rods and plates of two 3D, porous Zn(II)-based metal-organic frameworks [Zn(oba)(4-bpdh)0.5]n.(DMF)1.5 (TMU-5) and [Zn(oba)(4-bpmb)0.5]n (DMF)1.5 (TMU-6) were prepared by sonochemical process and characterized by scanning electron microscopy, X-ray powder diffraction and IR spectroscopy. These MOFs were synthesized using a non-linear dicarboxylate (H2oba=4,4-oxybisbenzoic acid) and two linear N-donor (4-bpdh=2,5-bis(4-pyridyl)-3,4-diaza-2,4-hexadiene and 4-bpmb=N(1),N(4)-bis((pyridin-4-yl)methylene)benzene-1,4-diamine) ligands by ultrasonic irradiation. Sonication time and concentration of initial reagents influencing size and morphology of nano-structured MOFs, were also studied. Calcination of TMU-5 and TMU-6 at 550 degrees C under air atmosphere yields ZnO nanoparticles. TMU-5 and TMU-6 exhibited maximum percent adsorption of 96.2% and 92.8% of 100ppm rhodamine B dye, respectively, which obeys first order reaction kinetics. PMID- 27245957 TI - Leaching of polycyclic aromatic hydrocarbons (PAHs) from industrial wastewater sludge by ultrasonic treatment. AB - Ultrasonic treatment for sludge reduction in wastewater treatment plants (WWTPs) can substantially affect the fate of trace pollutants. However, their fates in the different phases of sludge and mass balances have rarely been reported. In this study, wastewater sludge samples were ultrasonicated at 600W for 0-30min. Then, the leaching of the 16 priority polycyclic aromatic hydrocarbons (PAHs) from the sludge solids (sediment) to the liquid phase (supernatant) was investigated. The total concentration of PAHs (?16 PAHs) in the sludge sediment (2.10MUg/g) was comparable with those of previous worldwide studies. Among the 16 PAHs, naphthalene and acenaphthylene were dominant. The total concentrations of PAHs in the supernatant generally increased with sonication time, indicating that PAHs associated with sludge materials, such as microorganisms, were released into the supernatant. Lighter and more water soluble PAHs were released preferentially into the supernatant in dissolved form, whereas heavier and more hydrophobic PAHs were strongly bound to particles. According to mass balance calculations, 21% of the PAHs in the sludge sediment moved to the supernatant without discernible sonodegradation. An additional experiment for degradation of PAHs supported this interpretation, and several reasons for the no significant sonodegradation were discussed. This result suggests that leaching trace pollutants may significantly contaminate the sludge filtrate after ultrasonic treatment, and therefore their fates should be investigated. PMID- 27245958 TI - Synthesis and application of molecularly imprinted nanoparticles combined ultrasonic assisted for highly selective solid phase extraction trace amount of celecoxib from human plasma samples using design expert (DXB) software. AB - In this work molecular imprinted nanoparticles (MINPs) was synthesized and applied for ultrasonic assisted solid phase extraction of celecoxib (CEL) from human plasma sample following its combination by HPLC-UV. The MINPs were prepared in a non-covalent approach using methacrylic acid as monomer, CEL as template, ethylene glycol dimethacrylate as cross-linker, and 2,2-azobisisobutyronitrile (AIBN) as the initiator of polymerization. pH, volume of rinsing and eluent solvent and amount of sorbent influence on response were investigated using factorial experimental design, while optimum point was achieved and set as 250mg sorbent, pH 7.0, 1.5mL washing solvent and 2mL eluent by analysis of results according to design expert (DX) software. At above specified conditions, CEL in human plasma with complicated matrices with acceptable high recoveries (96%) and RSD% lower than 10% was quantified and estimated. The proposed MISPE-HPLC-UV method has linear responses among peak area and concentrations of CEL in the range of 0.2-2000MUgL(-1), with regression coefficient of 0.98. The limit of detection (LOD) and quantification (LOQ) based on three and ten times of the noise of HPLC peaks correspond to blank solution were 0.08 and 0.18MUgL(-1), respectively. PMID- 27245959 TI - Experimental design and modeling of ultrasound assisted simultaneous adsorption of cationic dyes onto ZnS: Mn-NPs-AC from binary mixture. AB - The manganese impregnated zinc sulfide nanoparticles deposited on activated carbon (ZnS: Mn-NPs-AC) which fully was synthesized and characterized successfully applied for simultaneous removal of malachite green and methylene blue in binary situation. The effects of variables such as pH (2.0-10.0), sonication time (1-5min), adsorbent mass (0.005-0.025g) and MB and MG concentration (4-20mgL(-1)) on their removal efficiency was studied dy central composite design (CCD) to correlate dyes removal percentage to above mention variables that guides amongst the maximum influence was seen by changing the sonication time and adsorbent mass. Sonication time, adsorbent mass and pH in despite of dyes concentrations has positive relation with removal percentage. Multiple regression analysis of the experimental results is associated with 3-D response surface and contour plots that guide setting condition at pH of 7.0, 3min sonication time, 0.025g Mn: ZnS-NPs-AC and 15mgL(-1) of MB and MG lead to achievement of removal efficiencies of 99.87% and 98.56% for MG and MB, respectively. The pseudo-second-order model as best choice efficiency describe the dyes adsorption behavior, while MG and MB maximum adsorption capacity according to Langmuir was 202.43 and 191.57mgg(-1). PMID- 27245960 TI - Sonochemical degradation of methyl orange in the presence of Bi2WO6: Effect of operating parameters and the generated reactive oxygen species. AB - The Bi2WO6 was prepared by the hydrothermal method and its sonocatalytic activity was studied in the degradation of methyl orange (MO) solutions. The effects of catalytic activity of Bi2WO6 on dye were inspected by the change in absorbance of dye with UV-vis spectrometer. The influences of operational parameters such as the addition amount of Bi2WO6, pH, the initial concentration of dyes, ultrasonic power and irradiation time on the degradation ratio were investigated. In addition, the obtained results indicated that the kinetics of sonochemical reactions of MO were consistent with the pseudo first-order kinetics and Bi2WO6 had excellent reusability and stability during the sonochemical degradation processes. The generation and kinds of reactive oxygen species (ROS) and their influence on the sonochemical degradation of MO were determined by the methods of oxidation-extraction spectrophotometry and ROS scavengers. The results indicate that the degradation of MO in the presence of Bi2WO6 under ultrasonic irradiation is related to the generation of ROS, in which both singlet molecular oxygen ((1)O2) and hydroxyl radical (OH) play important roles in the sonochemical degradation of MO. These experimental results provide a sound foundation for the further development of Bi2WO6 as a sonocatalyst in wastewater treatment. PMID- 27245961 TI - A facile one-pot ultrasound assisted for an efficient synthesis of benzo[g]chromenes using Fe3O4/polyethylene glycol (PEG) core/shell nanoparticles. AB - In this research, a general synthetic method for the synthesis of benzo[g]chromenes has been developed using Fe3O4/polyethylene glycol (PEG) core/shell nanoparticle under ultrasonic irradiations. Compared to the conventional methods, ultrasound procedure showed several advantages including mild reaction conditions, high yield products, short reaction times, reusability of the catalyst and little catalyst loading. PMID- 27245962 TI - High quantum yield ZnO quantum dots synthesizing via an ultrasonication microreactor method. AB - Green emission ZnO quantum dots were synthesized by an ultrasonic microreactor. Ultrasonic radiation brought bubbles through ultrasonic cavitation. These bubbles built microreactor inside the microreactor. The photoluminescence properties of ZnO quantum dots synthesized with different flow rate, ultrasonic power and temperature were discussed. Flow rate, ultrasonic power and temperature would influence the type and quantity of defects in ZnO quantum dots. The sizes of ZnO quantum dots would be controlled by those conditions as well. Flow rate affected the reaction time. With the increasing of flow rate, the sizes of ZnO quantum dots decreased and the quantum yields first increased then decreased. Ultrasonic power changed the ultrasonic cavitation intensity, which affected the reaction energy and the separation of the solution. With the increasing of ultrasonic power, sizes of ZnO quantum dots first decreased then increased, while the quantum yields kept increasing. The effect of ultrasonic temperature on the photoluminescence properties of ZnO quantum dots was influenced by the flow rate. Different flow rate related to opposite changing trend. Moreover, the quantum yields of ZnO QDs synthesized by ultrasonic microreactor could reach 64.7%, which is higher than those synthesized only under ultrasonic radiation or only by microreactor. PMID- 27245963 TI - Highly efficient ultrasonic-assisted removal of Hg(II) ions on graphene oxide modified with 2-pyridinecarboxaldehyde thiosemicarbazone: Adsorption isotherms and kinetics studies. AB - A novel adsorbent, based on modifying graphene oxide (GO) chemically with 2 pyridinecarboxaldehyde thiosemicarbazone (2-PTSC) as ligand, was designed by facile process for removal of Hg(II) from aqueous solution. Characterization of the adsorbent was performed using various techniques, such as FT-IR, XRD, XPS, SEM and AFM analysis. The adsorption capacity was affected by variables such as adsorbent dosage, pH solution, Hg(2+) initial concentration and sonicating time. These variables were optimized by rotatable central composite design (CCD) under response surface methodology (RSM). The predictive model for Hg(II) adsorption was constructed and applied to find the best conditions at which the responses were maximized. In this conditions, the adsorption capacity of this adsorbent for Hg(2+) ions was calculated to be 309mgg(-1) that was higher than that of GO. Appling the ultrasound power combined with adsorption method was very efficient in shortening the removal time of Hg(2+) ions by enhancing the dispersion of adsorbent and metal ions in solution and effective interactions among them. The adsorption process was well described by second-order kinetic and Langmuir isotherm model in which the maximum adsorption capacity (Qm) was found to be 555mgg(-1) for adsorption of Hg(2+) ions over the obtained adsorbent. The performance of adsorbent was examined on the real wastewaters and confirmed the applicability of adsorbent for practical applications. PMID- 27245964 TI - Trace determination of safranin O dye using ultrasound assisted dispersive solid phase micro extraction: Artificial neural network-genetic algorithm and response surface methodology. AB - In this study, ultrasound assisted dispersive solid-phase micro extraction combined with spectrophotometry (USA-DSPME-UV) method based on activated carbon modified with Fe2O3 nanoparticles (Fe2O3-NPs-AC) was developed for pre concentration and determination of safranin O (SO). It is known that the efficiency of USA-DSPME-UV method may be affected by pH, amount of adsorbent, ultrasound time and eluent volume and the extent and magnitude of their contribution on response (in term of main and interaction part) was studied by using central composite design (CCD) and artificial neural network-genetic algorithms (ANN-GA). Accordingly by adjustment of experimental conditions suggested by ANN-GA at pH 6.5, 1.1mg of adsorbent, 10min ultrasound and 150MUL of eluent volume led to achievement of best operation performance like low LOD (6.3ngmL(-1)) and LOQ (17.5ngmL(-1)) in the range of 25-3500ngmL(-1). In following stage, the SO content in real water and wastewater samples with recoveries between 93.27-99.41% with RSD lower than 3% was successfully determined. PMID- 27245965 TI - Enhancing the formation of tetragonal phase in perovskite nanocrystals using an ultrasound assisted wet chemical method. AB - Synthesis of highly-pure tetragonal perovskite nanocrystals is the key challenge facing the development of new electronic devices. Our results have indicated that ultrasonication is able in enhancing the formation of tetragonal phase in perovskite nanocrystals. In the current research, multicationic oxide perovskite (ATiO3; A: Ba, Sr, Ba0.6Sr0.4) nanopowders are synthesized successfully by a general methodology without a calcination step. The method is able to synthesize high-purity nanoscale ATiO3 (BaTiO3, SrTiO3, Ba0.6Sr0.4TiO3) with tetragonal symmetry at a lower temperature and in a shorter time span in contrast to the literature. To reach an in-depth understanding of the scientific basis of the proposed methodology, in-detail analysis was carried out via XRD, FTIR, FT-Raman, FE-SEM and HR-TEM. The effects of the sonication time and sonication (bath) temperature on the tetragonality of nanoscale products were examined. Furthermore, Raman spectroscopy provides clear evidence for local tetragonal symmetries, in particular when a band is observed at 310cm(-1). PMID- 27245966 TI - CO2-enhanced dehydrogenation of ethane over sonochemically synthesized Cr/clinoptilolite-ZrO2 nanocatalyst: Effects of ultrasound irradiation and ZrO2 loading on catalytic activity and stability. AB - CO2-enhanced oxidative dehydrogenation of ethane was investigated over sonochemically synthesized Cr/clinoptilolite-ZrO2 nanocatalyst with the aim of assessing the effect of composite support and ultrasonic irradiation on the nanocatalyst reactivity and stability. To this aim, ZrO2 promoted clinoptilolite supports varying in zirconia content (0, 25, 50wt%) were synthesized by hydrothermally precipitation method and impregnated with chromium nitrate under ultrasound irradiation. The samples were characterized by XRD, FESEM, EDX, TEM, ICP, BET, FTIR, TPR-H2 and TPD-NH3 techniques. The characterization results indicated that ultrasound irradiation could not only reduce the formation of Cr2O3 and decrease submicron particle size of chromium oxide to nanometer scale, but also promote the distribution of metallic particles and strengthen the chromium-support interaction. As a result, utilizing ultrasound irradiation in the synthesis of Cr/Clinoptilolite helped to maintain a high and stable catalytic activity. These features were more prominent in the presence of zirconia. It was found that the metal oxide nanoparticles with about 4-8nm are dispersed uniformly on the surface of composite support containing 25wt% ZrO2 (CLT-Z25). Moreover, the addition of ZrO2 resulted in the formation of new strong acid sites and a significant modification in the reducibility of chromium species, which alongside homogenous and small Cr nanoparticles account for the superior catalytic performance of ZrO2 containing samples. However, excessive loading of ZrO2 (50wt%) severely covered the surface of clinoptilolite, afforded the aggregations of metallic particles and thereupon, weakened the contact between clinoptilolite and ZrO2, which together with more acid strength seriously resulted in the deactivation of catalyst. In spite of superior initial activity of ZrO2-rich sample among the catalysts tested, ultrasonic synthesized Cr/CLT-Z25 nanocatalyst showed the best catalytic performance after 5h-catalytic reaction. PMID- 27245967 TI - Sono-Fenton process for metronidazole degradation in aqueous solution: Effect of acoustic cavitation and peroxydisulfate anion. AB - The present work investigates the application of an improved treatment approach based on the ultrasound irradiation as clean technology driven Fenton in the presence of peroxydisulfate anion (S2O8(2-)) for the removal of metronidazole (MTZ) from aqueous solution. The sono-generation of sulfate radicals (SO4(-)) as a stronger oxidizing agent from S2O8(2-) (redox potential of 2.6V) has improved the degradation of MTZ. However, no studies have focused on the removal of MTZ using peroxydisulfate anion under sono-Fenton process. The MTZ concentration measurement during the processing allowed the evaluation of the kinetics of organic matter decay. The results have shown that the degradation of MTZ dependent on Fe(2+)/H2O2 molar ratio, temperature and S2O8(2-) concentration. The MTZ concentration decay follows pseudo first-order kinetics, within the range studied. Sono-Fenton process using low iron and hydrogen peroxide doses was proved to be an efficient method for the elimination of MTZ with high degradation rates. At optimum conditions, 96% of MTZ removal was achieved at 60 degrees C in the presence of 1mM of S2O8(2-). PMID- 27245969 TI - Combined effect of blanching and sonication on quality parameters of bottle gourd (Lagenaria siceraria) juice. AB - This study evaluated the combined effect of blanching and sonication treatment on selected quality parameters of bottle gourd juice (BGJ). Bottle gourd cubes were blanched and juice was extracted. Effect of frequency (20-50kHz), amplitude (50 90%) and time (10-30min) was also studied on quality parameters like titratable acidity (TA), pH, total soluble solids (TSS), physical stability (PS), ascorbic acid (AA), total phenolics (TP), total carotenoids (TC), browning index (BI), total plate count (TPC) and yeast & mold count (Y&M) of BGJ to derive the level of these parameters. Combined effect of blanching followed by sonication (BFS) showed significant (P?0.05) change in all quality parameters except TA. Highest percentage of TSS (5.9 degrees B), PS (2%), AA (18.99mg/100g), TP (1010mg/100g) and TC (5.8mg/100g) was observed at 70% amplitude, 50kHz frequency and 20min. Results suggested 70% amplitude, 50kHz frequency and 20min as best treatment conditions for processing of BGJ. Microstructure examination, transmission electron microscopy (TEM) and laser diffraction analysis of BGJ showed significant change in particle size and distribution. Moreover, TEM of blanched and sonicated samples of BGJ also showed significant (P?0.05) change in microbial profile. PMID- 27245968 TI - Vortex dynamics of collapsing bubbles: Impact on the boundary layer measured by chronoamperometry. AB - Cavitation bubbles collapsing in the vicinity to a solid substrate induce intense micro-convection at the solid. Here we study the transient near-wall flows generated by single collapsing bubbles by chronoamperometric measurements synchronously coupled with high-speed imaging. The individual bubbles are created at confined positions by a focused laser pulse. They reach a maximum expansion radius of approximately 425MUm. Several stand-off distances to the flat solid boundary are investigated and all distances are chosen sufficiently large that no gas phase of the expanding and collapsing bubble touches the solid directly. With a microelectrode embedded into the substrate, the time-resolved perturbations in the liquid shear layer are probed by means of a chronoamperometric technique. The measurements of electric current are synchronized with high-speed imaging of the bubble dynamics. The perturbations of the near-wall layer are found to result mainly from ring vortices created by the jetting bubble. Other bubble induced flows, such as the jet and flows following the radial bubble oscillations are perceptible with this technique, but show a minor influence at the stand-off distances investigated. PMID- 27245970 TI - High frequency ultrasonic-assisted CO2 absorption in a high pressure water batch system. AB - Physical absorption process is always nullified by the presence of cavitation under low frequency ultrasonic irradiation. In the present study, high frequency ultrasonic of 1.7MHz was used for the physical absorption of CO2 in a water batch system under elevated pressure. The parameters including ultrasonic power and initial feed pressure for the system have been varied from 0 to 18W and 6 to 41bar, respectively. The mass transfer coefficient has been determined via the dynamic pressure-step method. Besides, the actual ultrasonic power that transmitted to the liquid was measured based on calorimetric method prior to the absorption study. Subsequently, desorption study was conducted as a comparison with the absorption process. The mechanism for the ultrasonic assisted absorption has also been discussed. Based on the results, the mass transfer coefficient has increased with the increasing of ultrasonic power. It means that, the presence of streaming effect and the formation of liquid fountain is more favorable under high frequency ultrasonic irradiation for the absorption process. Therefore, high frequency ultrasonic irradiation is suggested to be one of the potential alternatives for the gas separation process with its promising absorption enhancement and compact design. PMID- 27245971 TI - Application of ZnO nanorods loaded on activated carbon for ultrasonic assisted dyes removal: Experimental design and derivative spectrophotometry method. AB - A method based on application of ZnO nanorods loaded on activated carbon (ZnO-NRs AC) for adsorption of Bromocresol Green (BCG) and Eosin Y (EY) accelerated by ultrasound was described. The present material was synthesized under ultrasound assisted wet-chemical method and subsequently was characterized by FE-SEM, TEM, BET and XRD analysis. The extent of contribution of conventional variables like pH (2.0-10.0), BCG concentration (4-20mgL(-1)), EY concentration (3-23mgL(-1)), adsorbent dosage (0.01-0.03g), sonication time (1-5min) and centrifuge time (2 6min) as main and interaction part were investigated by central composite design under response surface methodology. Analysis of variance (ANOVA) was adapted to experimental data and guide the best operational conditions mass by set at 6.0, 9mgL(-1), 10mgL(-1), 0.02g, 4 and 4min for pH, BCG concentration, EY concentration, adsorbent dosage, sonication and centrifuge time, respectively. At these specified conditions dye adsorption efficiency was higher than 99.5%. The suitability and well prediction of optimum point was tested by conducting five experiments and respective results revel that RSD% was lower than 3% and high quality of fitting was confirmed by t-test. The experimental data were best fitted in Langmuir isotherm equation and the removal followed pseudo second order kinetics. The experimentally obtained maximum adsorption capacities were estimated as 57.80 and 61.73mgg(-1) of ZnO-NRs-AC for BCG and EY respectively from binary dye solutions. The mechanism of removal was explained by boundary layer diffusion via intraparticle diffusion. PMID- 27245972 TI - Effect of ultrasound on the synthesis of low-modulus zeolites from a metakaolin. AB - It was studied the effect of ultrasonic processing (22kHz) of the aqueous suspension of metakaolin, sodium hydroxide and alumina with a molar ratio 2Al2Si2O7:12NaOH:2Al2O3 on the low-modulus zeolite synthesis processes. To investigate the XRD, SEM, IR, EDS had been used. It was shown that after ultrasonic processing, sodium aluminates are formed, what leads to a change in process of further synthesis. It was found that without ultrasonic processing on the stage of thermal treatment at 650 degrees C, SOD zeolite (|Na6|[Al6Si6O24]) and sodium aluminosilicate (Na6Al4Si4O17) are synthesized. In the sample after ultrasound during thermal treatment, only sodium aluminosilicates of cubic syngony (Na6Al4Si4O17 and Na8Al4Si4O18) are formed. It was demonstrated that sodium aluminosilicates are precursors for the formation of LTA zeolite (|Na12|[Al12Si12O48]). As a result zeolitization of sodium aluminosilicates after the hydrothermal crystallization in alkaline solution, the sonicated sample contained 97wt% LTA. Without ultrasonic processing, the product of synthesis contained 50wt% SOD and 40wt% LTA. PMID- 27245973 TI - Biodiesel production process intensification using a rotor-stator type generator of hydrodynamic cavitation. AB - Triglyceride transesterification for biodiesel production is a model reaction which is used to compare the conversion efficiency, yield, reaction time, energy consumption, scalability and cost estimation of different reactor technology and energy source. This work describes an efficient, fast and cost-effective procedure for biodiesel preparation using a rotating generator of hydrodynamic cavitation (HC). The base-catalyzed transesterification (methanol/sodium hydroxide) has been carried out using refined and bleached palm oil and waste vegetable cooking oil. The novel HC unit is a continuous rotor-stator type reactor in which reagents are directly fed into the controlled cavitation chamber. The high-speed rotation of the reactor creates micron-sized droplets of the immiscible reacting mixture leading to outstanding mass and heat transfer and enhancing the kinetics of the transesterification reaction which completes much more quickly than traditional methods. All the biodiesel samples obtained respect the ASTM standard and present fatty acid methyl ester contents of >99% m/m in both feedstocks. The electrical energy consumption of the HC reactor is 0.030kWh per L of produced crude biodiesel, making this innovative technology really quite competitive. The reactor can be easily scaled-up, from producing a few hundred to thousands of liters of biodiesel per hour while avoiding the risk of orifices clogging with oil impurities, which may occur in conventional HC reactors. Furthermore it requires minimal installation space due to its compact design, which enhances overall security. PMID- 27245974 TI - Novel EGCG assisted ultrasound synthesis of self-assembled Ca2SiO4:Eu(3+) hierarchical superstructures: Photometric characteristics and LED applications. AB - This paper reports for the first time ultrasound, EGCG assisted synthesis of pure and Eu(3+) (1-5mol%) activated Ca2SiO4 nanophosphors having self-assembled superstructures with high purity. The shape, size and morphology of the product were tuned by controlling influential parameters. It was found that morphology was highly dependent on EGCG concentration, sonication time, pH and sonication power. The probable formation mechanism for various hierarchical superstructures was proposed. The PL studies of Ca2SiO4:Eu(3+) phosphors can be effectively excited by the near ultraviolet (UV) (396nm) light and exhibited strong red emission around 613nm, which was attributed to the Eu(3+) ((5)D0->(7)F2) transition. The concentration quenching phenomenon was explained based on energy transfer between defect and Eu(3+) ions, electron-phonon coupling and Eu(3+) Eu(3+) interaction. The Judd-Ofelt intensity parameters and radiative properties were estimated by using PL emission spectra. The photometric studies indicate that the obtained phosphors could be a promising red component for possible applications in the field of white light emitting diodes. PMID- 27245975 TI - Ultrasonic-assisted magnetic solid phase extraction of morphine in urine samples by new imprinted polymer-supported on MWCNT-Fe3O4-NPs: Central composite design optimization. AB - Multiwalled carbon nanotubes (MWCNTs) were magnetized with Fe3O4 nanoparticles (MWCNTs-Fe3O4-NPs) and subsequently coated by vinyl end groups (Vinyltrimethoxysilane). MWCNT-Fe3O4-NPs were used as support for a new morphine (MO) molecularly imprinted polymer (MWCNT-Fe3O4-NPs@MO-MIP) by surface imprinting polymerization method. The MWCNT-Fe3O4-NPs@MO-MIP was characterized by FTIR, VSM and SEM techniques and successfully used for determination of MO. Ultrasonic assisted magnetic solid phase extraction followed by UV-vis spectrophotometer (UAMSPE-UV-vis) was investigated for MWCNT-Fe3O4-NPs@MO-MIP and compared with non imprinted polymer (NIP) using batch method. Central composite design under response surface methodology was used for the evaluation of the effect of variables, individually, as well as their possible interaction effects on the adsorption process. The variables such as sonication time, MWCNT-Fe3O4-NPs@MO-MIP mass, initial concentration of MO and pH were investigated in this study. At optimum experimental conditions, UAMSPE-UV-vis method was exhibited a linear range of 0.8-8.7mgL(-1) of the MO concentration with a detection limit of 0.18mgL(-1). The relative standard deviation for the analyte was found to be lower than 2.32%. The MWCNT-Fe3O4-NPs@MO-MIP adsorption capacity was found to be 37.01mgg(-1). The enrichment and preconcentration factors were found to be 107.01 and 98.21, respectively. The developed method was finally applied successfully to the determination of MO in urine and wastewater samples with the recoveries ranged from 96.40 to 105.6%. PMID- 27245976 TI - Foreign-born aged care workers in Australia: A growing trend. AB - AIM: To address Australian aged care workforce challenges, a deeper understanding of the current care workforce is needed especially given estimated increases in demand. We provide a national picture of the aged care workforce in Australia focusing on country of birth. METHODS: Data from the 2006 and 2011 Australian censuses. RESULTS: The majority of care workers are Australia-born followed by those born in the United Kingdom, South-East Asia and South Asia. While the number of carers from all regions has grown, the increase from 2006 to 2011 has been highest for carers from South Asia (333% increase) and sub-Saharan Africa (145%). The state with the largest decrease in the proportion of Australian-born care workers is Western Australia where Australian-born workers dropped from 62% in 2006 to 49% in 2011. CONCLUSIONS: Understanding the migration patterns of the aged care workforce in Australia is critical to health workforce planning given increasing demand. PMID- 27245977 TI - Application of differential scanning calorimetry to estimate quality and nutritional properties of food products. AB - Over the past years, both food researchers and food industry have shown an increased interest in finding techniques that can estimate modifications in quality, nutritional, and thermophysical properties of food products during processing and/or storage. For instance, differential scanning calorimetry (DSC) has attracted the interest of scientific community because only a small amount of sample is needed for analysis. Moreover, it does not require any specific sample preparation, and is a repeatable and reliable method. In addition, DSC methodology needs a short time for experiments compared with other techniques used for the same purpose. At this stage of investigation, there is a need to evaluate the commonly accepted and new emerging DSC applications to establish the optimum conditions of emerging processing. This paper reviews the current and new insights of DSC technique for the estimation of quality, nutritional, and thermophysical properties of food products during conventional and emerging processing and/or subsequent storage. The estimation of different properties in several food matrices after processing and/or storage is also discussed. PMID- 27245978 TI - Safety and Appropriateness of Tourniquets in 105 Civilians. AB - BACKGROUND: The United States military considers tourniquets to be effective for controlling bleeding from major limb trauma. The purpose of this study was to assess whether tourniquets are safely applied to the appropriate civilian patient with major limb trauma of any etiology. METHODS: Following IRB approval, patients arriving to a level-1 trauma center between October 2008 and May 2013 with a prehospital (PH) or emergency department (ED) tourniquet were reviewed. Cases were assigned the following designations: absolute indication (operation within 2 hours for limb injury, vascular injury requiring repair/ligation, or traumatic amputation); relative indication (major musculoskeletal/soft-tissue injury requiring operation 2-8 hours after arrival, documented large blood loss); and non-indicated. Patients with absolute or relative indications for tourniquet placement were defined as indicated, while the remaining were designated as non indicated. Complications potentially associated with tourniquets, including amputation, acute renal failure, compartment syndrome, nerve palsies, and venous thromboembolic events, were adjudicated by orthopedic, hand or trauma surgical staff. Univariate analysis was performed to compare patients with indicated versus non-indicated tourniquet placement. RESULTS: A total of 105 patients received a tourniquet for injuries sustained via sharp objects, i.e., glass or knives (32%), motor vehicle collisions (30%), or other mechanisms (38%). A total of 94 patients (90%) had indicated tourniquet placement; 41 (44%) of which had a vascular injury. Demographics, mechanism, transport, and vitals were similar between patients that had indicated or non-indicated tourniquet placement. 48% of the indicated tourniquets placed PH were removed in the ED, compared to 100% of the non-indicated tourniquets (p < 0.01). The amputation rate was 32% among patients with indicated tourniquet placement (vs. 0%; p = 0.03). Acute renal failure (3.2 vs. 0%, p = 0.72), compartment syndrome (2.1 vs. 0%, p = 0.80), nerve palsies (5.3 vs. 0%; p = 0.57), and venous thromboembolic events (9.1 vs. 8.5%; p = 0.65) and were similar in patients that had indicated compared to non indicated tourniquet placement. After adjudication, no complication was a result of tourniquet use. CONCLUSION: The current study suggests that PH and ED tourniquets are used safely and appropriately in civilians with major limb trauma that occur via blunt and penetrating mechanisms. PMID- 27245979 TI - Acute hospital dementia care: results from a national audit. AB - BACKGROUND: Admission to an acute hospital can be distressing and disorientating for a person with dementia, and is associated with decline in cognitive and functional ability. The objective of this audit was to assess the quality of dementia care in acute hospitals in the Republic of Ireland. METHODS: Across all 35 acute public hospitals, data was collected on care from admission through discharge using a retrospective chart review (n = 660), hospital organisation interview with senior management (n = 35), and ward level organisation interview with ward managers (n = 76). Inclusion criteria included a diagnosis of dementia, and a length of stay greater than 5 days. RESULTS: Most patients received physical assessments, including mobility (89 %), continence (84 %) and pressure sore risk (87 %); however assessment of pain (75 %), and particularly functioning (36 %) was poor. Assessment for cognition (43 %) and delirium (30 %) was inadequate. Most wards have access at least 5 days per week to Liaison Psychiatry (93 %), Geriatric Medicine (84 %), Occupational Therapy (79 %), Speech & Language (81 %), Physiotherapy (99 %), and Palliative Care (89 %) Access to Psychology (9 %), Social Work (53 %), and Continence services (34 %) is limited. Dementia awareness training is provided on induction in only 2 hospitals, and almost half of hospitals did not offer dementia training to doctors (45 %) or nurses (48 %) in the previous 12 months. Staff cover could not be provided on 62 % of wards for attending dementia training. Most wards (84 %) had no dementia champion to guide best practice in care. Discharge planning was not initiated within 24 h of admission in 72 % of cases, less than 40 % had a single plan for discharge recorded, and 33 % of carers received no needs assessment prior to discharge. Length of stay was significantly greater for new discharges to residential care (p < .001). CONCLUSION: Dementia care relating to assessment, access to certain specialist services, staffing levels, training and support, and discharge planning is sub-optimal, which may increase the risk of adverse patient outcomes and the cost of acute care. Areas of good practice are also highlighted. PMID- 27245980 TI - Erratum to: Micronized/ultramicronized palmitoylethanolamide displays superior oral efficacy compared to nonmicronized palmitoylethanolamide in a rat model of inflammatory pain. PMID- 27245983 TI - Growth of the dolphinfish Coryphaena hippurus from north-eastern Brazil with an appraisal of the efficacy of scales and otoliths for ageing. AB - Age and growth of the dolphinfish Coryphaena hippurus caught off north-eastern Brazil were studied by counting growth increments on scales and otoliths. A sample (n = 2338) measuring 7.7-195 cm fork length (LF ) was collected from September 2001 to February 2003. The scales (n = 69) removed from six different regions of the body were examined and those from the caudal region exhibited greater morphological regularity, symmetry and a smaller rate of regeneration. The regression between caudal scale radius (RS ) and LF displayed was linear (LF = 28.334 RS + 9.186; r(2) = 0.754). Otolith micro-increments were counted assuming daily periodicity. Ages estimated from otoliths ranged from 64 to 659 days. The von Bertalanffy growth model was fitted based on the otolith readings generating Linfinity = 194.1 cm LF , k = 0.912 year(-1) and t0 = 0.081 years. Species longevity was estimated to be c. 4 years. Ninety-eight per cent of the overall sample was adult specimens well above the age of first maturity in the study area. The large variability between scale length and LF and the failure to ascertain increment deposition periodicity suggest that scales are not appropriate for ageing C. hippurus and analysis of otolith micro-increments is deemed the best structure for ageing this species in the study area. PMID- 27245981 TI - Long-term health-related quality of life improvements among patients treated with lurasidone: results from the open-label extension of a switch trial in schizophrenia. AB - BACKGROUND: Long-term improvement of health-related quality of life (HRQoL) in schizophrenia may improve adherence and reduce relapse and rehospitalization. This analysis examines long-term changes in HRQoL among patients with schizophrenia switched to lurasidone from other antipsychotics. METHODS: Patients who completed an open-label 6-week switch study continued on lurasidone for an additional 24-weeks. HRQoL was measured using the self-reported Personal Evaluation of Transitions in Treatment (PETiT) scale and Short-Form 12 (SF-12) questionnaire. The PETiT assessed HRQoL via total and domain scores (adherence related attitude and psychosocial functioning). The SF-12 assessed patients' mental and physical component summary scores (MCS and PCS). Mean changes from the initial baseline were calculated at extension baseline and extension endpoint using analysis of covariance models. Analyses were further stratified by prior antipsychotic medication and responder status; responders were defined as having a >=20 % improvement in Positive and Negative Syndrome Scale during the first 6 weeks of treatment. RESULTS: The analysis included 144 patients with PETIT or SF 12 data who received >=1 dose of lurasidone. Mean (standard deviation) PETiT total score improved significantly from 34.9 (9.3) at baseline to 39.5 (8.9) at extension baseline and 39.1 (9.0) at extension endpoint, representing improvements of 4.5 (7.9) and 5.1 (7.2) points, respectively (both p < 0.001). Significant improvements in adherence-related attitude and psychosocial functioning were observed at extension baseline and extension endpoint (all p < 0.001). Improvement in SF-12 MCS score was observed at extension baseline and endpoint, and PCS score at extension endpoint (all p < 0.01). Patients who switched from quetiapine and aripiprazole showed significant improvement of PETiT total score and adherence-related attitude at extension baseline and extension endpoint. In addition, patients who switched from quetiapine, risperidone, aripiprazole, or ziprasidone showed significant improvement in MCS scores from baseline to extension endpoint. Responders to lurasidone demonstrated greater improvement in PETiT total, psychosocial functioning, and MCS scores at extension baseline than nonresponders. CONCLUSIONS: After switching to lurasidone, patients with schizophrenia experienced HRQoL improvements that were sustained for an additional 24 weeks of treatment. Further study is warranted to understand the implications of these improvements in terms of employment, adherence, relapse, and rehospitalization. TRIAL REGISTRATION: Clinical trials.gov identifier NCT01143090 (June 10th, 2010). PMID- 27245982 TI - Selection of internal control genes for analysis of gene expression in normal and diseased human dermal fibroblasts using quantitative real-time PCR. PMID- 27245984 TI - Prevalence and associates of psychological distress in haematological cancer survivors. AB - PURPOSE: To explore outcomes of psychological distress, including anxiety, depression and stress, amongst adult haematological cancer survivors, with a specific focus on potential differences between rural and urban survivors. METHODS: One thousand four hundred fourteen urban and rural survivors were recruited from five Australian population-based cancer registries and completed a self-report pen-and-paper survey on their well-being, including the Depression Anxiety and Stress Scale 21-item version. RESULTS: A quarter of survivors were identified as reporting above normal levels of anxiety and depression, respectively, and almost one fifth (17 %) reported above normal levels of stress. There were no statistically significant differences in the percentage of rural and urban survivors reporting above normal levels of anxiety, depression, or stress. Survivors who had experienced financial burden due to their cancer or were of middle age had higher odds of reporting multiple domains of psychological distress, compared to their counterparts. CONCLUSIONS: Haematological cancer survivors diagnosed during middle age or who experience increased financial burden as a result of their diagnosis may require additional support and care with regards to psychological distress. PMID- 27245985 TI - Karyotype Evolution in Harvestmen of the Suborder Cyphophthalmi (Opiliones). AB - The morphologically uniform suborder Cyphophthalmi represents a basal group of harvestmen (Opiliones). As such, it plays an important role in the reconstruction of the karyotype evolution within this arachnid order. The cytogenetic analysis of 6 representatives of the suborder Cyphophthalmi, namely Miopsalis sp. (2n = 30; Stylocellidae), Austropurcellia arcticosa (Cantrell, 1980) (2n = 30; Pettalidae), Parapurcellia amatola de Bivort & Giribet, 2010 (2n = 32; Pettalidae), Paramiopsalis aff. ramulosus Juberthie, 1962 (2n = 28; Sironidae), Cyphophthalmus duricorius Joseph, 1868 (2n = 24; Sironidae), and Siro carpaticus Rafalski, 1956 (2n = 52; Sironidae) was performed. Fluorescence in situ hybridization with 18S rDNA probe was used to analyze the distribution of major ribosomal RNA genes in harvestmen. We confront the obtained cytogenetic data with current hypotheses on cyphophthalmid phylogeny to reconstruct their karyotype evolution. We conclude that the ancestral karyotype of harvestmen consisted of 2n = 30 elements with 1 chromosome pair bearing terminal rDNA clusters. The rDNA locus was multiplicated in the evolution of Cyphophthalmi. However, decreases as well as increases in the number of chromosomes have been detected in the karyotype evolution of Cyphophthalmi. Our data thus reveal unexpected diversity in cyphophthalmid karyotypes. PMID- 27245986 TI - Effectiveness of respite care in supporting informal caregivers of persons with dementia: a systematic review. AB - OBJECTIVE: Supporting informal caregivers of persons with dementia is considered to be an effective strategy for improving the well-being of caregivers and care recipients and for delaying nursing home placement. Although considerable research has been conducted to investigate the effectiveness of psychoeducational interventions, cognitive behavioral therapy, and occupational therapy, research into the effectiveness of respite care is rare. This systematic review aims to investigate the effectiveness of different types of respite care in supporting informal caregivers of persons with dementia. METHODS: A systematic literature search was conducted using Web of Science and PubMed, and the Quality Assessment Tool for Quantitative Studies was used to assess the methodological quality. Randomized controlled trials, quasi-experimental studies, pretest-posttest studies without a control group, and cohort studies were included. RESULTS: Seventeen papers met the inclusion criteria. Day care services are effective in decreasing caregiver burden and behavioral problems in persons with dementia, but they also accelerate time to nursing home admission. The results of temporary residential admission are rather mixed and show unexpected adverse effects on both caregivers and care recipients. High-quality comparable evidence on community-based respite care is still lacking, although earlier qualitative evidence indicated promising results. CONCLUSION: Unlike in previous reviews, we were able to draw some conclusions about the effectiveness of some types of respite care. There is nonetheless still a need for new intervention studies measuring the impact of respite care, especially in-home respite care programs, on the caregiver, the care recipient, and health care resource utilization. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27245987 TI - Correction to Libraries of Extremely Localized Molecular Orbitals. 2. Comparison with the Pseudoatoms Transferability. PMID- 27245988 TI - Late Life Immigration and Quality of Life among Asian Indian Older Adults. AB - Late-life immigration among seniors for purposes of family reunification is a growing phenomenon in developed countries. Using the World Health Organization's Quality of Life instrument short form (WHOQOL-BREF) and other psychosocial measures related to the political/legal context of immigration, and personal and environmental autonomy (mastery, immigration status, access to transportation, and language barrier), this study examined quality of life (QoL) in Asian Indian seniors (N = 109), who immigrated to the United States to reunite with their adult children. The sample scores on Overall QoL and QoL domains (physical and psychological health, social relationships, and environment) were similar to established norms. Although all QoL domains correlated significantly with Overall QoL at the bivariate level, multivariate analysis showed that only environmental domain contributed significantly to Overall QoL. Linear regressions indicated: Mastery contributed significantly to Overall QoL and all QoL domains; access to transport contributed to Overall QoL, physical health, and environmental QoL; immigration status (a proxy for political/legal context) contributed to environmental QoL whereas language barrier contributed to none. Implications for improving perceptions of QoL, mastery, access to transport and other services are discussed. PMID- 27245990 TI - Fetal movement in late pregnancy - a content analysis of women's experiences of how their unborn baby moved less or differently. AB - BACKGROUND: Pregnant women sometimes worry about their unborn baby's health, often due to decreased fetal movements. The aim of this study was to examine how women, who consulted health care due to decreased fetal movements, describe how the baby had moved less or differently. METHODS: Women were recruited from all seven delivery wards in Stockholm, Sweden, during 1/1 - 31/12 2014. The women completed a questionnaire after it was verified that the pregnancy was viable. A modified content analysis was used to analyse 876 questionnaires with the women's responses to, "Try to describe how your baby has moved less or had changes in movement". RESULTS: Four categories and six subcategories were identified: "Frequency" (decreased frequency, absence of kicks and movement), "Intensity" (weaker fetal movements, indistinct fetal movements), "Character" (changed pattern of movements, slower movements) and "Duration". In addition to the responses categorised in accordance with the question, the women also mentioned how they had tried to stimulate the fetus to move and that they had difficulty in distinguishing fetal movements from contractions. Further, they described worry due to incidents related to changed pattern of fetal movements. CONCLUSION: Women reported changes in fetal movement concerning frequency, intensity, character and duration. The challenge from a clinical perspective is to inform pregnant women about fetal movements with the goal of minimizing unnecessary consultations whilst at the same time diminishing the length of pre-hospital delay if the fetus is at risk of fetal compromise. TRIAL REGISTRATION: Not applicable. PMID- 27245989 TI - Mechanistic study of TRPM2-Ca(2+)-CAMK2-BECN1 signaling in oxidative stress induced autophagy inhibition. AB - Reactive oxygen species (ROS) have been commonly accepted as inducers of autophagy, and autophagy in turn is activated to relieve oxidative stress. Yet, whether and how oxidative stress, generated in various human pathologies, regulates autophagy remains unknown. Here, we mechanistically studied the role of TRPM2 (transient receptor potential cation channel subfamily M member 2)-mediated Ca(2+) influx in oxidative stress-mediated autophagy regulation. On the one hand, we demonstrated that oxidative stress triggered TRPM2-dependent Ca(2+) influx to inhibit the induction of early autophagy, which renders cells more susceptible to death. On the other hand, oxidative stress induced autophagy (and not cell death) in the absence of the TRPM2-mediated Ca(2+) influx. Moreover, in response to oxidative stress, TRPM2-mediated Ca(2+) influx activated CAMK2 (calcium/calmodulin dependent protein kinase II) at levels of both phosphorylation and oxidation, and the activated CAMK2 subsequently phosphorylated BECN1/Beclin 1 on Ser295. Ser295 phosphorylation of BECN1 in turn decreased the association between BECN1 and PIK3C3/VPS34, but induced binding between BECN1 and BCL2. Clinically, acetaminophen (APAP) overdose is the most common cause of acute liver failure worldwide. We demonstrated that APAP overdose also activated ROS-TRPM2-CAMK2-BECN1 signaling to suppress autophagy, thereby causing primary hepatocytes to be more vulnerable to death. Inhibiting the TRPM2 Ca(2+)-CAMK2 cascade significantly mitigated APAP-induced liver injury. In summary, our data clearly demonstrate that oxidative stress activates the TRPM2 Ca(2+)-CAMK2 cascade to phosphorylate BECN1 resulting in autophagy inhibition. PMID- 27245991 TI - Association of endothelial proliferation with the magnitude of weight loss during calorie restriction. AB - OBJECTIVES: Substantial weight loss through intense dietary regimens is thought to ameliorate endothelial dysfunction in obesity. It is less clear whether similar improvements can be achieved with modest dietary interventions. This study aimed to identify the parameters of endothelial cell status in obesity that are affected by mild calorie restriction. METHODS: Human umbilical vein endothelial cells (EA.hy926 line) in culture were exposed pairwise to serum from 57 individuals with simple obesity (BMI > 30 kg/m(2)) collected before and after 8-week dietary intervention with energy deficit of 300-500 kcal/day. RESULTS: Analysis of endothelial transcriptome suggested that the intervention could impact on endothelial cell growth. Cell proliferation was measured with the MTT test and verified by [(3)H]-thymidine incorporation. The participants were categorized according to a change in proliferation over time. Significant decrease in endothelial cell proliferation correlated with the extent of weight loss in men, but not in women. This effect corresponded with changes in serum levels of leptin and adiponectin, but was not related to serum concentrations of several known angiogenic mediators (VEGF, MCP-1, TSP-1, MMP-9, angiopoietin-2). CONCLUSION: Direction and magnitude of changes in serum-induced endothelial cell proliferation identifies patients with the greatest weight loss in response to modest calorie restriction. PMID- 27245992 TI - CT Scans and Cancer Risks-A Practical Middle Path. PMID- 27245993 TI - Pediatric Radiology Education in a Metropolitan Radiology Residency in West Africa: The Accra Experience. PMID- 27245994 TI - "From Gaming Machines to Thinking Machines . . . ". PMID- 27245995 TI - Support to Radiology Residency Programs in Developing Countries: Our Experience in Uganda With the Mbarara University of Science and Technology. PMID- 27245996 TI - The Effect of an Electronic Peer-Review Auditing System on Faculty-Dictated Radiology Report Error Rates. PMID- 27245997 TI - The Dilemma of Incentives. PMID- 27245999 TI - Correction: Role of sTREM-1 in predicting mortality of infection: a systematic review and meta-analysis. PMID- 27245998 TI - Epigenetic regulation of reelin expression in multiple myeloma. AB - Reelin (RELN) is a secreted extracellular matrix glycoprotein associated with the positioning and migration of neuronal cells and a few types of non-neuronal cells. We have previously reported RELN expression in multiple myeloma cells. High RELN expression was associated with poor prognosis and enhanced myeloma cell adhesion and survival. To examine the epigenetic regulation of RELN expression, its promoter methylation status in myeloma-derived cell lines and primary tumour cells from myeloma patients were analysed. RELN expression was moderate in CD19+ B cells and was upregulated in CD138+ plasma cells. A further upregulated RELN transcription was found in multiple myeloma cells. High expressions of RELN in myeloma cell lines as well as in patients were associated with hypomethylation in RELN promoter region. Demethylation increased RELN transcription in vitro. Together, we established that the methylation status of the promoter proximal cytosine-phospho-guanine dinucleotides determines the expression of RELN in myeloma cells. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27246000 TI - How is the sustainability of chronic disease health programmes empirically measured in hospital and related healthcare services?-a scoping review. AB - OBJECTIVES: Programmes to address chronic disease are a focus of governments worldwide. Despite growth in 'implementation science', there is a paucity of knowledge regarding the best means to measure sustainability. The aim of this review was to summarise current practice for measuring sustainability outcomes of chronic disease health programmes, providing guidance for programme planners and future directions for the academic field. SETTINGS: A scoping review of the literature spanning 1985-2015 was conducted using MEDLINE, CINAHL, PsychINFO and The Cochrane Library limited to English language and adults. Main search terms included chronic disease, acute care, sustainability, institutionalisation and health planning. A descriptive synthesis was required. Settings included primary care, hospitals, mental health centres and community health. PARTICIPANTS: Programmes included preventing or managing chronic conditions including diabetes, heart disease, depression, respiratory disease, cancer, obesity, dental hygiene and multiple chronic diseases. PRIMARY AND SECONDARY OUTCOME MEASURES: Outcome measures included clarifying a sustainability definition, types of methodologies used, timelines for assessment, criteria levels to determine outcomes and how methodology varies between intervention types. RESULTS: Among 153 abstracts retrieved, 87 were retained for full article review and 42 included in the qualitative synthesis. Five definitions for sustainability outcome were identified with 'maintenance of programme activities' most frequent. Achieving sustainability was dependent on inter-relationships between various organisational and social contexts supporting a broad scale approach to evaluation. An increasing trend in use of mixed methods designs over multiple time points to determine sustainability outcomes was found. CONCLUSIONS: Despite the importance and investment in chronic disease programmes, few studies are undertaken to measure sustainability. Methods to evaluate sustainability are diverse with some emerging patterns in measurement found. Use of mixed methods approaches over multiple time points may serve to better guide measurement of sustainability. Consensus on aspects of standardised measurement would promote the future possibility of meta-analytic syntheses. PMID- 27246001 TI - Weekday of oesophageal cancer surgery in relation to early postoperative outcomes in a nationwide Swedish cohort study. AB - OBJECTIVES: Later weekday of surgery for oesophageal cancer seems to increase 5 year mortality, but the mechanisms are unclear. We hypothesised that early postoperative reoperations and mortality might explain this association, since reoperation after oesophagectomy decreases long-term prognosis, and later weekday of elective surgery increases 30-day mortality. DESIGN: This was a population based cohort study during the study period 1987-2014. SETTING: All Swedish hospitals conducting elective surgery for oesophageal cancer in Sweden. PARTICIPANTS: Included were 1748 patients, representing almost all (98%) patients who underwent elective surgery for oesophageal cancer in Sweden during 1987-2010, with follow-up until 2014. PRIMARY AND SECONDARY OUTCOME MEASURES: The risk of reoperation or mortality within 30 days of oesophageal cancer surgery was assessed in relation to weekday of surgery by calculating ORs with 95% CIs using multivariable logistic regression. ORs were adjusted for age, comorbidity, tumour stage, histology, neoadjuvant therapy and surgeon volume. RESULTS: Surgery Wednesday to Friday did not increase the risk of reoperation or mortality compared with surgery Monday to Tuesday (OR=0.99, 95% CI 0.75 to 1.31). A decreased point estimate of reoperation (OR=0.88, 95% CI 0.64 to 1.21) was counteracted by an increased point estimate of mortality (OR=1.28, 95% CI 0.83 to 1.99). ORs did not increase from Monday to Friday when each weekday was analysed separately. There was no association between weekday of surgery and reoperation specifically for anastomotic leak, laparotomy or wound infection. Stratification for surgeon volume did not reveal any clear associations between weekday of surgery and risk of 30-day reoperation or mortality. CONCLUSIONS: Weekday of oesophageal cancer surgery does not seem to influence the risk of reoperation or mortality within 30 days of surgery, and thus cannot explain the association between weekday of surgery and long-term prognosis. PMID- 27246002 TI - An Acid-Adapted Endo-alpha-1,5-L-arabinanase for Pectin Releasing. AB - An arabinanase gene was cloned by overlap-PCR from Penicillium sp. Y702 and expressed in Pichia pastoris. The recombinant enzyme was named AbnC702 with 20 U/mg of endo-arabinanase activity toward linear alpha-1,5-L-arabinan. The optimal pH and temperature of AbnC702 were 5.0 and 50 degrees C, respectively. The recombinant AbnC702 was highly stable at pH 5.0-7.0 and 50 degrees C. It could retain about 72.3 % of maximum specific activity at pH 5.0 after incubation for 2.5 h, which indicated AbnC702 was an acid-adapted enzyme. The K m and V max values were 24.8 +/- 4.7 mg/ml and 88.5 +/- 5.6 U/mg, respectively. A three dimensional structure of AbnC702 was made by homology modeling, and the counting of acidic/basic amino residues within the region of 10 A around the active site, as well the hydrogen bonds within the area of 5 A around the active site, might theoretically interpret the acid adaptability of AbnC702. Analysis of hydrolysis products by thin layer chromatography (TLC) combined with high-performance liquid chromatography (HPLC) verified that the recombinant AbnC702 was an endo-1,5-alpha L-arabinanase, which yielded arabinobiose and arabinotriose as major products. AbnC702 was applied in pectin extraction from apple pomace with synergistic action of alpha-L-arabinofuranosidase. PMID- 27246003 TI - Dense small molecule labeling enables activator-dependent STORM by proximity mapping. AB - Stochastic optical reconstruction microscopy (STORM) enables high-resolution imaging, but multi-channel 3D imaging is problematic because of chromatic aberrations and alignment errors. The use of activator-dependent STORM in which spectrally distinct activators can be coupled with a single reporter can circumvent such issues. However, the standard approach of linking activators and reporters to a single antibody molecule is hampered by low labeling density and the large size of the antibody. We proposed that small molecule labels might enable activator-dependent STORM if the reporter or activator were linked to separate small molecules that bound within 3.5 nm of each other. This would greatly increase the labeling density and therefore improve resolution. We tested various mixtures of phalloidin- or mCling-conjugated fluorophore to demonstrate this feasibility. The specific activation was dependent on the choice of activator, its density, a matching activating laser and its power. In addition to providing an effective means of multi-channel 3D STORM imaging, this method also provides information about the local proximity between labels, potentially enabling super-resolved mapping of the conformation of the labeled structures. PMID- 27246005 TI - Erratum to: Novel hyaluronic acid-methotrexate conjugate suppresses joint inflammation in the rat knee: efficacy and safety evaluation in two rat arthritis models. PMID- 27246004 TI - Guanylin and uroguanylin are produced by mouse intestinal epithelial cells of columnar and secretory lineage. AB - Guanylin (GN) and uroguanylin (UGN), through activation of guanylyl cyclase C (GCC), serve to control intestinal fluid homeostasis. Both peptides are produced in the intestinal epithelium, but their cellular origin has not been fully charted. Using quantitative PCR and an improved in situ hybridization technique (RNAscope), we have assessed the expression of GN (Guca2a), UGN (Guca2b), and GCC (Gucy2c) in mouse intestine. In the crypts of Lieberkuhn, expression of Guca2a and Guca2b was restricted to cells of secretory lineage, at the crypt's base, and to a region above, previously identified as a common origin of cellular differentiation. In this compartment, comparatively uniform levels of Guca2a and Guca2b expression were observed throughout the length of the gut. In contrast, Guca2a and Guca2b expression in the villus-surface region was more variable, and reflected the distinct, but overlapping expression pattern observed previously. Accordingly, in jejunum and ileum, Guca2a and Guca2b were abundantly expressed by enterocytes, whereas in colon only Guca2a transcript was found in the surface region. In duodenum, only low levels of Guca2b transcript were observed in columnar cells, and Guca2a expression was restricted entirely to cells of the secretory lineage. Gucy2c was shown to be expressed relatively uniformly along the rostrocaudal and crypt-villus axes and was also found in the duodenal glands. Our study reveals novel aspects of the cellular localization of the GCC signaling axis that, apart from its role in the regulation of fluid balance, link it to pH regulation, cell cycle control, and host defense. PMID- 27246006 TI - Partner interfering behaviors affecting cancer quality of life. AB - OBJECTIVE: Because partners are an important and unpaid resource in cancer care, understanding how destructive, controlling or interfering partner behaviors influence women's cancer care may be particularly relevant for health care providers seeking to provide cancer care and enhance recovery. Using a new measure of partner interfering behaviors in cancer care (PIB-C), we investigated whether women with a recent cancer diagnosis who additionally endorsed any PIB-C would report (a) more symptoms of depression and stress, and (b) lower Functional Assessment of Cancer Therapy (FACT-G) and lower Functional Assessment of Chronic Illness Therapy-Spiritual Well-being (FACIT-SP) scale scores indicating poorer quality of life (QOL). METHODS: Women aged 18-79 included in cancer registries as having an incident, primary, biopsy-confirmed cancer in the past 12 months were eligible for this study. Consenting women completed a phone interview 9-12 months following cancer diagnosis between 2009 and 2015. Interviews provided data to measure outcomes (perceived stress and depressive symptoms, FACIT-SP and FACT-G scores), partner supportive and interfering behaviors, and other potentially confounding factors. RESULTS: Of the 2376 women in a relationship at cancer diagnosis, 14.7% endorsed one or more of 14 PIB-C items. Women endorsing any PIB C item reported more symptoms of depression and stress and lower FACT-G and FACIT SP scores than partnered women reporting no PIB-C even when controlling for partner supportive behaviors and lifetime intimate partner violence. Increasing PIB-C scores were also correlated, in a dose-response pattern, with these same outcomes. CONCLUSIONS: Partner interfering behaviors during cancer care impact patients' QOL across multiple domains. (c) 2016 The Authors. Psycho-Oncology Published by John Wiley & Sons Ltd. PMID- 27246008 TI - Association of miR-34a, miR-130a, miR-150 and miR-155 polymorphisms with the risk of ischemic stroke. AB - MicroRNAs (miRNAs or miRs) are small (19-23 nt) non-coding RNA molecules that are endogenous regulators of gene expression. Previous studies have found that some miRNAs are related to the progression of ischemia in the cerebral artery. Furthermore, a recent study found a significant association between miRNA single nucleotide polymorphisms (SNPs) and the risk of ischemic stroke. Therefore, it may be valuable to investigate associations between megakaryocyte formation related miRNA polymorphisms and the prevalence of ischemic stroke. We thus conducted a case-control study of 1,000 individuals who were screened for 4 miRNA polymorphisms (miR-34a rs6577555C>A, miR-130a rs731384C>T, miR-150 rs73056059G>A and miR-155 rs767649T>A) by PCR-RFLP analysis. The study population comprised 596 patients with ischemic stroke and 404 control subjects without any history of neurological disorders. We observed associations between miRNA polymorphisms and individual stroke subtypes. The miR-150 polymorphisms were significantly associated with ischemic stroke subgroups, such as left anterior descending artery (LAD) disease [GG vs. AA: adjusted odds ratio (AOR), 1.922; 95% confidence interval (CI), 1.003-3.681] and cardioembolism (GG vs. AA: AOR, 2.996; 95% CI, 1.293-6.939). Additionally, Cox proportional analysis indicated that the miR 150GA genotype was associated with survival in patients with ischemic stroke [adjusted hazard ratio (HR), 2.063; 95% CI, 1.142-3.727; P=0.017] and with the LAD subgroup [adjusted HR, 3.021; 95% CI, 1.345-6.785; P=0.008]. Our findings suggest that miR-150 polymorphisms may contribute to the development of ischemic stroke and may potentially act as biomarkers to predict the risk of ischemic stroke. To the best of our knowledge, this is the first study to evaluate the association between miRNA polymorphisms (miR-34aC>A, miR-130aC>T, miR-150G>A and miR-155T>A) and ischemic stroke. PMID- 27246009 TI - Tuning into Qualitative Research-A Channel for the Patient Voice. PMID- 27246007 TI - Strategies to enable the adoption of animal biotechnology to sustainably improve global food safety and security. AB - The ability to generate transgenic animals has existed for over 30 years, and from those early days many predicted that the technology would have beneficial applications in agriculture. Numerous transgenic agricultural animals now exist, however to date only one product from a transgenic animal has been approved for the food chain, due in part to cumbersome regulations. Recently, new techniques such as precision breeding have emerged, which enables the introduction of desired traits without the use of transgenes. The rapidly growing human population, environmental degradation, and concerns related to zoonotic and pandemic diseases have increased pressure on the animal agriculture sector to provide a safe, secure and sustainable food supply. There is a clear need to adopt transgenic technologies as well as new methods such as gene editing and precision breeding to meet these challenges and the rising demand for animal products. To achieve this goal, cooperation, education, and communication between multiple stakeholders-including scientists, industry, farmers, governments, trade organizations, NGOs and the public-is necessary. This report is the culmination of concepts first discussed at an OECD sponsored conference and aims to identify the main barriers to the adoption of animal biotechnology, tactics for navigating those barriers, strategies to improve public perception and trust, as well as industry engagement, and actions for governments and trade organizations including the OECD to harmonize regulations and trade agreements. Specifically, the report focuses on animal biotechnologies that are intended to improve breeding and genetics and currently are not routinely used in commercial animal agriculture. We put forward recommendations on how scientists, regulators, and trade organizations can work together to ensure that the potential benefits of animal biotechnology can be realized to meet the future needs of agriculture to feed the world. PMID- 27246011 TI - Health-Related Quality of Life in CKD-Advancing Patient-Centered Research to Transform Patient Care. PMID- 27246010 TI - A Thematic Synthesis of the Experiences of Adults Living with Hemodialysis. AB - BACKGROUND AND OBJECTIVES: Patients on in-center dialysis spend significant amounts of time in the dialysis unit; additionally, managing ESRD affects many aspects of life outside the dialysis unit. To improve the care provided to patients requiring hemodialysis, their experiences and beliefs regarding treatment must be understood. This systematic review aimed to synthesize the experiences of patients receiving in-center hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We searched Embase, MEDLINE, CINAHL, PsychINFO, Google Scholar, and reference lists for primary qualitative studies published from 1995 to 2015 that explored the experiences of adult patients receiving treatment with in-center hemodialysis. A thematic synthesis was conducted. RESULTS: Seventeen studies involving 576 patients were included in the synthesis. Four analytic themes were developed. The first theme (a new dialysis-dependent self) describes the changes in identity and perceptions of self that could result from dialysis dependence. The second theme (a restricted life) describes the physical and emotional constraints that patients described as a consequence of their dependence. Some patients reported strategies that allowed them to regain a sense of optimism and influence over the future, and these contributed to the third theme (regaining control). The first three themes describe a potential for change through acceptance, adaption, and regaining a sense of control. The final theme (relationships with health professionals) describes the importance of these relationships for in-center patients and their influence on perceptions of power and support. These relationships are seen to influence the other three themes through information sharing, continuity, and personalized support. CONCLUSIONS: Our synthesis has resulted in a framework that can be used to consider interventions to improve patients' experiences of in-center hemodialysis care. Focusing on interventions that are incorporated into the established relationships that patients have with their health care professionals may enable patients to progress toward a sense of control and improve satisfaction with care. PMID- 27246012 TI - Predictors and Outcomes of Health-Related Quality of Life in Adults with CKD. AB - BACKGROUND AND OBJECTIVES: Low health-related quality of life is associated with increased mortality in patients with ESRD. However, little is known about demographic and clinical factors associated with health-related quality of life or its effect on outcomes in adults with CKD. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: Data from 3837 adult participants with mild to severe CKD enrolled in the prospective observational Chronic Renal Insufficiency Cohort and Hispanic Chronic Renal Insufficiency Cohort Studies were analyzed. Health-related quality of life was assessed at baseline with the Kidney Disease Quality of Life-36 and its five subscales: mental component summary, physical component summary, burden of kidney disease (burden), effects of kidney disease (effects), and symptoms and problems of kidney disease (symptoms). Low health-related quality of life was defined as baseline score >1 SD below the mean. Using Cox proportional hazards analysis, the relationships between low health-related quality of life and the following outcomes were examined: (1) CKD progression (50% eGFR loss or incident ESRD), (2) incident cardiovascular events, and (3) all-cause death. RESULTS: Younger age, women, low education, diabetes, vascular disease, congestive heart failure, obesity, and lower eGFR were associated with low baseline health-related quality of life (P<0.05). During a median follow-up of 6.2 years, there were 1055 CKD progression events, 841 cardiovascular events, and 694 deaths. Significantly higher crude rates of CKD progression, incident cardiovascular events, and all cause death were observed among participants with low health-related quality of life in all subscales (P<0.05). In fully adjusted models, low physical component summary, effects, and symptoms subscales were independently associated with a higher risk of incident cardiovascular events and death, whereas low mental component summary was independently associated with a higher risk of death (P<0.05). Low health-related quality of life was not associated with CKD progression. CONCLUSIONS: Low health-related quality of life across several subscales was independently associated with a higher risk of incident cardiovascular events and death but not associated with CKD progression. PMID- 27246014 TI - Marker assisted pyramiding of two brown planthopper resistance genes, Bph3 and Bph27 (t), into elite rice Cultivars. AB - BACKGROUND: Brown planthopper (BPH) is the most destructive insect in rice production. Breeding of resistant cultivars is the most cost-effective and environment-friendly strategy for BPH management; however, resistant cultivars are currently hampered by the rapid breakdown of BPH resistance. Thus, there is an urgent need to use more effective BPH resistance genes or pyramiding different resistance genes to develop more durable resistant rice cultivars. RESULTS: Here a dominant BPH resistance gene Bph27(t) were introgressed into a susceptible commercial japonica variety Ningjing3 (NJ3) and indica variety 93-11 using marker assisted selection (MAS), respectively. Further, Bph27(t) and a durable BPH resistance gene Bph3 was pyramided by intercrossing single-gene introgressed lines through MAS. The introgression of BPH resistance genes significantly improved the BPH resistance and reduced the yield loss caused by BPH. CONCLUSION: The development of single and two genes pyramided lines in this study provides innovative resources for molecular breeding of durable BPH-resistant rice cultivars and BPH management through resistant cultivars. PMID- 27246013 TI - Proteomic and Glycomic Characterization of Rice Chalky Grains Produced Under Moderate and High-temperature Conditions in Field System. AB - BACKGROUND: Global climate models predict an increase in global mean temperature and a higher frequency of intense heat spikes during this century. Cereals such as rice (Oryza sativa L.) are more susceptible to heat stress, mainly during the gametogenesis and flowering stages. During periods of high temperatures, grain filling often causes serious damage to the grain quality of rice and, therefore, yield losses. While the genes encoding enzymes involved in carbohydrate metabolism of chalky grains have been established, a significant knowledge gap exists in the proteomic and glycomic responses to warm temperatures in situ. Here, we studied the translucent and opaque characters of high temperature stressed chalky grains of 2009 and 2010 (ripening temperatures: 24.4 and 28.0 degrees C, respectively). RESULTS: Appearance of chalky grains of both years showed some resemblance, and the high-temperature stress of 2010 remarkably extended the chalking of grain. Scanning electron microscopic observation showed that round-shaped starch granules with numerous small pits were loosely packed in the opaque part of the chalky grains. Proteomic analyzes of rice chalky grains revealed deregulations in the expression of multiple proteins implicated in diverse metabolic and physiological functions, such as protein synthesis, redox homeostasis, lipid metabolism, and starch biosynthesis and degradation. The glycomic profiling has shown slight differences in chain-length distributions of starches in the grains of 2009-to-2010. However, no significant changes were observed in the chain-length distributions between the translucent and opaque parts of perfect and chalky grains in both years. The glucose and soluble starch contents in opaque parts were increased by the high-temperature stress of 2010, though those in perfect grains were not different regardless of the environmental changes of 2009-to-2010. CONCLUSION: Together with previous findings on the increased expression of alpha-amylases in the endosperm, these results suggested that unusual starch degradation rather than starch synthesis is involved in occurring of chalky grains of rice under the high-temperature stress during grain filling period. PMID- 27246015 TI - [Spontaneously occurring, livid node of the umbilicus]. PMID- 27246017 TI - CRISPR/Cas9-Mediated Genome Editing of Mouse Small Intestinal Organoids. AB - The CRISPR/Cas9 system is an RNA-guided genome-editing tool that has been recently developed based on the bacterial CRISPR-Cas immune defense system. Due to its versatility and simplicity, it rapidly became the method of choice for genome editing in various biological systems, including mammalian cells. Here we describe a protocol for CRISPR/Cas9-mediated genome editing in murine small intestinal organoids, a culture system in which somatic stem cells are maintained by self-renewal, while giving rise to all major cell types of the intestinal epithelium. This protocol allows the study of gene function in intestinal epithelial homeostasis and pathophysiology and can be extended to epithelial organoids derived from other internal mouse and human organs. PMID- 27246018 TI - Lentivirus-Based Stable Gene Delivery into Intestinal Organoids. AB - Lentivirus-based gene delivery works efficiently for the majority of mammalian cells cultured under standard two-dimensional conditions. By contrast, intestinal epithelial organoids embedded into three-dimensional extracellular matrix appear to be resistant to lentiviral transduction. We observed that Matrigel, a matrix that reconstitutes a basement membrane and is indispensable for cell survival and proliferation, prevents lentiviruses from binding to intestinal cells. In this chapter, we describe a simple method of a highly efficient gene transduction into intestinal organoids. This method involves organoid dispersion into single intestinal epithelial cells, mixing these individual cells with lentiviral particles, plating on Matrigel, and subsequent re-embedding into Matrigel. Under these conditions, the majority of the cells are exposed to the virus in the absence of the matrix barrier while remaining attached to the matrix. Using a GFP labeled lentivirus, we demonstrate that this method allows for highly efficient infection of intestinal organoids after overnight incubation of Matrigel-attached cells with lentiviral particles. PMID- 27246016 TI - [Pathogenesis of psoriasis]. AB - Psoriasis is an inflammatory T cell-mediated autoimmune disease of skin and joints that affects 2-4 % of the adult population and 0.1-1 % of children. Genetic susceptibility, environmental triggering factors, and innate immune processes initiate psoriasis pathogenesis that results in an adaptive autoreactive response. The T cell response is orchestrated by CD 8(+) T cells in the epidermis and by CD 4(+) T cells in the dermis that predominantly produce interleukin-17 (IL-17). Research of the past 15 years unraveled cellular and molecular mechanisms as well as cytokines like TNF-alpha or IL-23 that contribute to psoriatic inflammation. This knowledge has been translated into clinical practice and a number of antipsoriatic small molecules and immunobiologics are now available. Here, we discuss the current principles of psoriasis pathogenesis in the context of modern therapies. PMID- 27246019 TI - Co-culture of Gastric Organoids and Immortalized Stomach Mesenchymal Cells. AB - Three-dimensional primary epithelial-derived gastric organoids have recently been established as an important tool to study gastric development, physiology, and disease. Specifically, mouse-derived fundic gastric organoids (mFGOs) co-cultured with Immortalized Stomach Mesenchymal Cells (ISMCs) reflect expression patterns of mature fundic cell types seen in vivo, thus allowing for long-term in vitro studies of gastric epithelial cell physiology, regeneration, and bacterial-host interactions. Here, we describe the development and culture of mFGOs, co-cultured with ISMCs. PMID- 27246020 TI - An Air-Liquid Interface Culture System for 3D Organoid Culture of Diverse Primary Gastrointestinal Tissues. AB - Conventional in vitro analysis of gastrointestinal epithelium usually relies on two-dimensional (2D) culture of epithelial cell lines as monolayer on impermeable surfaces. However, the lack of context of differentiation and tissue architecture in 2D culture can hinder the faithful recapitulation of the phenotypic and morphological characteristics of native epithelium. Here, we describe a robust long-term three-dimensional (3D) culture methodology for gastrointestinal culture, which incorporates both epithelial and mesenchymal/stromal components into a collagen-based air-liquid interface 3D culture system. This system allows vigorously expansion of primary gastrointestinal epithelium for over 60 days as organoids with both proliferation and multilineage differentiation, indicating successful long-term intestinal culture within a microenvironment accurately recapitulating the stem cell niche. PMID- 27246021 TI - Organotypical Tissue Cultures from Fetal and Neonatal Murine Colon. AB - The complex functions of the gastrointestinal tract rely on the coordinated interplay of several cell and tissue types involving epithelium, connective tissue, smooth muscles as well as cells of the immune and nervous system. It is therefore obvious, that these functions can hardly be investigated sufficiently using cell lines or two-dimensional cell cultures.Here, we describe an easy to produce three-dimensional organotypical explants culture from fetal and neonatal murine colon. This model is suitable for in vitro testing of intestinal function or the evaluation of developmental or pathological processes. PMID- 27246022 TI - Ussing Chamber Technique to Measure Intestinal Epithelial Permeability. AB - Epithelial cells are polarized and have tight junctions that contribute to barrier function. Assessment of barrier function typically involves measurement of electrophysiological parameters or movement of nonionic particles across an epithelium. Here, we describe measurement of transepithelial electrical conductance or resistance, determination of dilution potential, and assessment of flux of nonionic particles such as dextran or mannitol, with particular emphasis on Ussing chamber techniques. PMID- 27246023 TI - HPLC-Based Metabolomic Analysis of Normal and Inflamed Gut. AB - The idiopathic inflammatory bowel diseases, which include Crohn's disease and ulcerative colitis, are multifactorial chronic conditions that result in numerous perturbations of metabolism in the gastrointestinal mucosa. Thus, methodologies for the qualitative and quantitative analysis of small molecule metabolites in mucosal tissues are important for further elucidation of mechanisms driving inflammation and the metabolic consequences of inflammation. High-performance liquid chromatography (HPLC) is a ubiquitous analytical technique that can be adapted for both targeted and non-targeted metabolomic analysis. Here, protocols for reversed-phase (RP) HPLC-based methods using two different detection modalities are presented. Ultraviolet detection is used for the analysis of adenine nucleotide metabolites, whereas electrochemical detection is used for the analysis of multiple amino acid metabolites. These methodologies provide platforms for further characterization of the metabolic changes that occur during gastrointestinal inflammation. PMID- 27246024 TI - NMR-Based Metabolomic Analysis of Normal and Inflamed Gut. AB - Crohn's disease and ulcerative colitis, the two major forms of idiopathic inflammatory bowel disease (IBD), are thought to occur through a loss of intestinal barrier leading to an inappropriate immune response toward intestinal microbiota. While genome-wide association studies (GWAS) have provided much information about susceptibility loci associated with these diseases, the etiology of IBD is still unknown. Metabolomic analysis allows for the comprehensive measurement of multiple small molecule metabolites in biological samples. During the past decade, metabolomic techniques have yielded novel and potentially important findings, revealing insight into metabolic perturbations associated with these diseases. This chapter provides metabolomic methodologies describing a nuclear magnetic resonance (NMR)-based non-targeted approach that has been utilized to make important contributions toward a better understanding of IBD. PMID- 27246025 TI - Analysis of microRNA Levels in Intestinal Epithelial Cells. AB - The field of microRNA (miRNA) research is expanding rapidly with the crucial role of miRNAs in almost every biological process and their implication in many diseases. The role of miRNAs in modulating inflammatory responses in the gut has attracted many research groups including us. Here, we first briefly summarize our current understanding of the role of miRNAs in maintaining and regulating gut physiopathology and in inflammatory bowel diseases. We then describe in detail our techniques to analyze miRNA levels with notes that we have collected and summarized during our experiments. PMID- 27246026 TI - Detecting Reactive Oxygen Species Generation and Stem Cell Proliferation in the Drosophila Intestine. AB - The conservation of intestinal stem cell crypt dynamics between Drosophila melanogaster and mammals allows for the genetically tractable fly model to be used for analyses of intestinal development, homeostasis, and renewal in relation to microbiota. The invertebrate fly model is advantageous for genetic research due to its anatomical and genetic simplicity and short lifespan. Accordingly, experimental resources such as large numbers of mutant and genetically modified flies have been developed. We have developed techniques to generate germ-free Drosophila, monoassociate them with candidate bacteria, and assess ensuing physiological responses within the gut tissue that include the generation of reactive oxygen species and cell proliferation. PMID- 27246027 TI - Imaging Inflammatory Hypoxia in the Murine Gut. AB - The inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, result in chronic inflammation to the gastrointestinal tract. In ulcerative colitis, inflammation tends to be more superficial and restricted to the colon; contrastingly, Crohn's disease presents as patchy, more penetrative inflammation that can occur throughout the gastrointestinal tract. Other differences between these diseases include the nature of their respective immune responses-Crohn's disease presents as a Th1 and ulcerative colitis as a Th2-type inflammation. During any inflammatory episode, metabolic demand on the tissue increases accompanying the influx of inflammatory cells, increasing the demand for ATP and oxygen. When availability of oxygen is limiting, tissues become hypoxic, which results in adaptive pathways to enable survival of hypoxic episodes. The primary pathway activated is the HIF (hypoxia inducible factor) transcription factor, which regulates adaptive pathways including genes controlling glycolytic metabolism and angiogenesis. In adequately oxygenated tissues (i.e. normoxia), the HIF protein is constantly produced, but oxygen dependent enzymes called prolyl-hydroxylases utilize available oxygen to hydroxylate HIF on proline residues, targeting it for ubiquitination and subsequent degradation. Here we describe methods for inducing, visualizing, and quantifying in vivo "inflammatory hypoxia," using the murine gut as a model system. PMID- 27246028 TI - Label-Free Imaging of Eosinophilic Esophagitis Mouse Models Using Optical Coherence Tomography. AB - Eosinophilic esophagitis (EoE) is an immune-mediated disorder characterized by esophageal inflammation and related structural changes causing symptoms such as feeding difficulties and food impaction. The pathophysiological mechanisms underlying EoE remain poorly understood. Preclinical studies using mouse models have been critical in comprehending human disease mechanisms and associated pathways. In this chapter, we describe an experimental method using a noninvasive label-free optical imaging technique, optical coherence tomography, to characterize the pathophysiological changes in the esophagus of mice with EoE like disease ex vivo. PMID- 27246029 TI - Near-Infrared Fluorescence Endoscopy to Detect Dysplastic Lesions in the Mouse Colon. AB - Near-infrared fluorescence (NIRF) endoscopy has a great potential for efficient early detection of dysplastic lesions in the colon. For preclinical studies, we developed a small animal NIRF endoscope and successfully used this device to identify dysplastic lesions in a murine model of chronic colitis. In this chapter, we present a step-by-step protocol for using NIRF endoscopy to examine the location, the size, and the borders of the dysplastic lesions developed in murine colitis. Our studies suggest that NIRF endoscopy is a specific and sensitive technique that provides a unique opportunity to analyze early stages of tumorigenesis in animal models of colon cancer and to perform surveillance colonoscopy in patients with colitis-associated colon cancer. PMID- 27246030 TI - Visualization of Signaling Molecules During Neutrophil Recruitment in Transgenic Mice Expressing FRET Biosensors. AB - A number of chemical mediators regulate neutrophil recruitment to inflammatory sites either positively or negatively. Although the actions of each chemical mediator on the intracellular signaling networks controlling cell migration have been studied with neutrophils cultured in vitro, how such chemical mediators act cooperatively or counteractively in vivo remains largely unknown. To understand the mechanisms regulating neutrophil recruitment to the inflamed intestine in vivo, we recently generated transgenic mice expressing biosensors based on FRET (Forster resonance energy transfer) and set up two-photon excitation microscopy to observe the gastrointestinal tract in living mice. By measuring FRET in neutrophils, we showed activity changes of protein kinases in the neutrophils recruited to inflamed intestines. In this chapter, we describe the protocol used to visualize the protein kinase activities in neutrophils of the inflamed intestine of transgenic mice expressing the FRET biosensors. PMID- 27246031 TI - In Vivo Myeloperoxidase Imaging and Flow Cytometry Analysis of Intestinal Myeloid Cells. AB - Myeloperoxidase (MPO) imaging is a non-invasive method to detect cells that produce the enzyme MPO that is most abundant in neutrophils, macrophages, and inflammatory monocytes. While lacking specificity for any of these three cell types, MPO imaging can provide guidance for further flow cytometry-based analysis of tissues where these cell types reside. Isolation of leukocytes from the intestinal tract is an error-prone procedure. Here, we describe a protocol for intestinal leukocyte isolation that works reliable in our hands and allows for flow cytometry-based analysis, in particular of neutrophils. PMID- 27246032 TI - Macrophage Isolation from the Mouse Small and Large Intestine. AB - Macrophages play important roles in maintaining intestinal homeostasis via their ability to orchestrate responses to the normal microbiota as well as pathogens. One of the most important steps in beginning to understand the functions of these cells is the ability to effectively isolate them from the complex intestinal environment. Here, we detail methodology for the isolation and phenotypic characterization of macrophages from the mouse small and large intestine. PMID- 27246033 TI - Isolation and Functional Analysis of Lamina Propria Dendritic Cells from the Mouse Small Intestine. AB - Dendritic cells (DCs) are the most professional antigen-presenting cells that are indispensable for the initiation of adaptive immune responses. DCs are heterogeneous in terms of their origin, anatomical location, cell-surface markers, and functions. Previous studies have demonstrated that there exist several groups of DCs in the lamina propria (LPDC) of gastrointestinal tract, which collectively contribute to the maintenance of gut homeostasis through the regulation of the balance between active immunity and tolerance. However, although intestinal LPDCs are attractive research target for understanding the immunological mechanisms in the gut, isolation of the LPDCs is complicated and technically difficult for unskilled people. Therefore, establishment of the method to isolate intestinal LPDCs is a major obstacle in this research. Here, we describe the methods that we have established for the isolation of primary DCs from the LP of mouse small intestine. Our isolation method provides high yield of viable LP leukocytes (LPLs) including DCs. Combination with FACS sorting allows for the selective isolation of CD103(+)CD8alpha(+) DCs and CD103(+)CD8alpha(-) DCs from the LPLs. Furthermore, isolated LPDCs can be subjected to immunological assays, such as measurement of cytokine productions following stimulation of Toll like receptors. Thus, our methods would be useful for studying the functions of LPDCs of mouse small intestine. PMID- 27246034 TI - Purification and Adoptive Transfer of Group 3 Gut Innate Lymphoid Cells. AB - Recent studies have identified several related but distinct innate lymphoid cells (ILCs) populations that are relatively enriched in the intestinal mucosal and protect the host from various infections. Among ILCs, group 3 ILCs (ILC3s) produce lymphotoxin and IL-22, and play important roles in the development of the immune system and host-bacteria interactions. Here, we describe methods for the isolation and purification of ILC3s from the mouse intestine, and the adoptive transfer of purified ILC3s into recipient mice. PMID- 27246035 TI - Immunotherapy with iTreg and nTreg Cells in a Murine Model of Inflammatory Bowel Disease. AB - Regulatory T (Treg) cells that express the transcription factor Foxp3 are essential for maintaining tolerance at mucosal interfaces, where they act by controlling inflammation and promoting epithelial cell homeostasis. There are two major regulatory T-cell subsets, "natural" CD4(+) Treg (nTreg) cells that develop in the thymus and "induced" Treg (iTreg) cells that develop from conventional CD4(+) T (Tconv) cells in the periphery. Dysregulated Treg cell responses are associated with autoimmune diseases, including inflammatory bowel disease (IBD) and arthritis. Adoptive transfer of Treg cells can modulate innate and adaptive immune responses and cure disease in animal models, which has generated considerable interest in using Treg cells to treat human autoimmune disease, prevent rejection of transplanted organs, and to control graft-versus-host disease following hematopoietic stem cell transplantation. Herein, we describe our modifications of a treatment model of T-cell transfer colitis designed to allow mechanistic investigation of the two major Treg cell subsets and to compare their specific roles in mucosal tolerance. PMID- 27246036 TI - Isolation of Eosinophils from the Lamina Propria of the Murine Small Intestine. AB - Only recently has it become apparent that eosinophils play a crucial role in mucosal immune homeostasis. Although eosinophils are the main cellular component of the lamina propria of the gastrointestinal tract, they have often been overlooked because they express numerous markers, which are normally used to characterize macrophages and/or dendritic cells. To study their function in mucosal immunity, it is important to isolate them with high purity and viability. Here, we describe a protocol to purify eosinophils from the lamina propria of the murine small intestine. The method involves preparation of the small intestine, removal of epithelial cells and digestion of the lamina propria to release eosinophils. A protocol to sort eosinophils is included. PMID- 27246037 TI - Investigation of Host and Pathogen Contributions to Infectious Colitis Using the Citrobacter rodentium Mouse Model of Infection. AB - Citrobacter rodentium is used as a model organism to study enteric bacterial infections in mice. Infection occurs via the oral-fecal route and results in the pathogen forming attaching and effacing lesions on infected epithelial cells. Moreover, infection leads to a subsequent host-mediated form of colitis. C. rodentium infection is thus an excellent model to study infectious colitis in vivo, while the ability to genetically manipulate C. rodentium virulence genes provides the opportunity to develop clear insights into the pathogenesis of this and related infectious microbes. This chapter outlines the basic techniques involved in setting up a C. rodentium infection in mice and several different methodologies to assess the severity of the infection. PMID- 27246038 TI - Murine Trinitrobenzoic Acid-Induced Colitis as a Model of Crohn's Disease. AB - Inflammatory Bowel Diseases, Crohn's disease and ulcerative colitis, result from the uncontrolled inflammation that occurs in genetically susceptible individuals and the dysregulation of the innate and adaptive immune systems. The response of these immune systems to luminal gut microbiota and their products results in altered intestinal permeability, loss of barrier function, and mucosal inflammation and ulceration. Animal models of experiment intestinal inflammation have been developed that leverage the development of spontaneous inflammation in certain mouse strains, e.g. Samp1/Yit mice, or induction of inflammation using gene-targeting e.g. IL-10 null mice, administration of exogenous agents e.g. DSS, or adoptive transfer of T-cells into immunodeficient mice, e.g. CD4(+) CD45Rb(Hi) T-cell transfer. Colitis induced by rectal instillation of the haptenizing agent, 2,4,6 trinitrobenzene sulfonic acid, is one of the most commonly used and well characterized models of Crohn's disease in humans. PMID- 27246039 TI - Oxazolone-Induced Colitis as a Model of Th2 Immune Responses in the Intestinal Mucosa. AB - Murine models of intestinal inflammation have been widely used in biomedical research. Similarities in anatomy and physiology between such murine models and patients with inflammatory bowel diseases may allow a better understanding of the pathogenesis of Crohn's disease and ulcerative colitis. Additionally, models of intestinal inflammation may be used for the analysis of potentially new therapeutic agents. One key class of models consists of chemically induced inflammation models. Within this group, colitis induced by the haptenizing agent oxazolone is an important model that results in induction of acute or chronic inflammation of the large bowel. Here, we describe the induction and the analysis of this experimental colitis model. PMID- 27246041 TI - A Rapid Screenable Assay for Compounds That Protect Against Intestinal Injury in Zebrafish Larva. AB - This chapter describes a method to assay compounds modulating NSAID-induced intestinal injury in zebrafish larvae. The assay employs the NSAID glafenine, which causes intestinal epithelial cell damage and death by inducing organelle stress responses (endoplasmic reticulum and mitochondrial) and blocking the unfolded protein response pathway. This epithelial damage includes sloughing of intestinal cells into the lumen and out the cloaca of the zebrafish larvae. Exposing larvae to acridine orange highlights this injury when visualized under fluorescence microscope; injured fish develop intensely red-staining intestines, as well as a "tube" or cord of red color extending through the intestine and out the cloaca. Using this rapid visually screenable method, various candidate compounds were successfully tested for their ability to prevent glafenine-induced intestinal injury. Because this assay involves examination of larval zebrafish intestinal pathology, we have also included our protocol for preparation and analysis of zebrafish histology. The protocol includes numerous steps to generate high-quality zebrafish histology slides, as well as protocols to establish accurate anatomic localization of any given tissue cross-section-processes that are made technically difficult by the small size of zebrafish larvae. PMID- 27246040 TI - The Mongolian Gerbil: A Robust Model of Helicobacter pylori-Induced Gastric Inflammation and Cancer. AB - The Mongolian gerbil is an efficient, robust, and cost-effective rodent model that recapitulates many features of H. pylori-induced gastric inflammation and carcinogenesis in humans, allowing for targeted investigation of the bacterial determinants and environmental factors and, to a lesser degree, host constituents that govern H. pylori-mediated disease. This chapter discusses means through which the Mongolian gerbil model has been used to define mechanisms of H. pylori inflammation and cancer as well as the current materials and methods for utilizing this model of microbially induced disease. PMID- 27246042 TI - AOM/DSS Model of Colitis-Associated Cancer. AB - Our understanding of colitis-associated carcinoma (CAC) has benefited substantially from mouse models that faithfully recapitulate human CAC. Chemical models, in particular, have enabled fast and efficient analysis of genetic and environmental modulators of CAC without the added requirement of time-intensive genetic crossings. Here we describe the Azoxymethane (AOM)/Dextran Sodium Sulfate (DSS) mouse model of inflammatory colorectal cancer. PMID- 27246043 TI - Characterization of Colorectal Cancer Development in Apc (min/+) Mice. AB - The Apc (min/+) mouse provides an excellent experimental model for studying genetic, environmental, and therapeutic aspects of intestinal neoplasia in humans. In this chapter, we will describe techniques for studying colon cancer development in Apc (min/+) mice on C57BL/6J (B6) background, focusing on the roles of environmental modifiers, including Dextran Sulfate Sodium (DSS), high fat diet, and bile acid supplementation in the context of experimental colorectal cancer. This chapter also includes protocols describing extraction and purification of DSS-contaminated RNA, as well as sampling, harvesting, and tissue processing. The common pathologic lesions encountered in these animals are described in detail. PMID- 27246044 TI - Modeling Murine Gastric Metaplasia Through Tamoxifen-Induced Acute Parietal Cell Loss. AB - Parietal cell loss represents the initial step in the sequential progression toward gastric adenocarcinoma. In the setting of chronic inflammation, the expansion of the mucosal response to parietal cell loss characterizes a crucial transition en route to gastric dysplasia. Here, we detail methods for using the selective estrogen receptor modulator tamoxifen as a novel tool to rapidly and reversibly induce parietal cell loss in mice in order to study the mechanisms that underlie these pre-neoplastic events. PMID- 27246045 TI - The Hamster Buccal Pouch Model of Oral Carcinogenesis. AB - The hamster buccal pouch (HBP) carcinogenesis model is one of the most well characterized animal tumor models used as a prelude to investigate multistage oral carcinogenesis and to assess the efficacy of chemointervention. Hamster buccal pouch carcinomas induced by 7,12-dimethylbenz[a]anthracene (DMBA) show extensive similarities to human oral squamous cell carcinomas. The HBP model offers a number of advantages including a simple and predictable tumor induction procedure, easy accessibility for examination and follow-up of lesions, and reproducibility. This model can be used to test both chemopreventive and chemotherapeutic agents. PMID- 27246046 TI - A study of the effects of therapeutic doses of ionizing radiation in vitro on Lactobacillus isolates originating from the vagina - a pilot study. AB - BACKGROUND: Ionizing radiation is used as a therapeutic option in the treatment of certain neoplastic lesions located, among others, in the pelvic region. The therapeutic doses of radiation employed often result in adverse effects manifesting themselves primarily in the form of genital tract infections in patients or diarrhea. The data available in the literature indicate disorders in the microbial ecosystem caused by ionizing radiation, which leads to the problems mentioned above. In the present study, we examined the influence of ionizing radiation on 52 selected strains of bacteria: Lactobacillus crispatus, L. fermentum, L. plantarum, L. reuteri, L. acidophilus L. amylovorus, L. casei, L. helveticus, L. paracasei, L. rhamnosus, L. salivarius and L. gasseri. This collection of Lactobacillus bacteria isolates of various species, obtained from the genital tract and gastrointestinal tract of healthy women, was tested for resistance to therapeutic doses of ionizing radiation. RESULTS: The species studied, were isolated from the genital tract (n = 30) and from the anus (n = 22) of healthy pregnant women. Three doses of 3 Gy (fractionated dose) and 50 Gy (total dose of the whole radiotherapy cycle) were applied. The greatest differences in survival of the tested strains in comparison to the control group (not subjected to radiation) were observed at the dose of 50 Gy. However, the results were not statistically significant. Survival decrease to zero was not demonstrated for any of the tested strains. CONCLUSIONS: Therapeutic doses of radiation do not affect the Lactobacillus bacteria significantly. PMID- 27246048 TI - Identification of the transporter responsible for sucrose accumulation in sugar beet taproots. AB - Sugar beet provides around one third of the sugar consumed worldwide and serves as a significant source of bioenergy in the form of ethanol. Sucrose accounts for up to 18% of plant fresh weight in sugar beet. Most of the sucrose is concentrated in the taproot, where it accumulates in the vacuoles. Despite 30 years of intensive research, the transporter that facilitates taproot sucrose accumulation has escaped identification. Here, we combine proteomic analyses of the taproot vacuolar membrane, the tonoplast, with electrophysiological analyses to show that the transporter BvTST2.1 is responsible for vacuolar sucrose uptake in sugar beet taproots. We show that BvTST2.1 is a sucrose-specific transporter, and present evidence to suggest that it operates as a proton antiporter, coupling the import of sucrose into the vacuole to the export of protons. BvTST2.1 exhibits a high amino acid sequence similarity to members of the tonoplast monosaccharide transporter family in Arabidopsis, prompting us to rename this group of proteins 'tonoplast sugar transporters'. The identification of BvTST2.1 could help to increase sugar yields from sugar beet and other sugar-storing plants in future breeding programs. PMID- 27246047 TI - Metformin and lactic acidosis during shock: just the tip of the iceberg? PMID- 27246049 TI - Degradation of potent Rubisco inhibitor by selective sugar phosphatase. AB - Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) catalyses the conversion of atmospheric carbon dioxide into organic compounds in photosynthetic organisms. Alongside carboxylating the five-carbon sugar ribulose-1,5 bisphosphate (RuBP)(1-3), Rubisco produces a small amount of xylulose-1,5 bisphosphate (XuBP), a potent inhibitor of Rubisco(4). The AAA+ protein Rubisco activase removes XuBP from the active site of Rubisco in an ATP-dependent process(5,6). However, free XuBP rapidly rebinds to Rubisco, perpetuating its inhibitory effect. Here, we combine biochemical and structural analyses to show that the CbbY protein of the photosynthetic bacterium Rhodobacter sphaeroides and Arabidopsis thaliana is a highly selective XuBP phosphatase. We also show that CbbY converts XuBP to the non-inhibitory compound xylulose-5-phosphate, which is recycled back to RuBP. We solve the crystal structures of CbbY from R. sphaeroides and A. thaliana, and through mutational analysis show that the cap domain of the protein confers the selectivity for XuBP over RuBP. Finally, in vitro experiments with CbbY from R. sphaeroides reveal that CbbY cooperates with Rubisco activase to prevent a detrimental build-up of XuBP at the Rubisco active site. We suggest that CbbY, which is conserved in algae and plants, is an important component of the cellular machinery that has evolved to deal with the shortcomings of the ancient enzyme Rubisco. PMID- 27246051 TI - Conservation of ethylene as a plant hormone over 450 million years of evolution. AB - Land plants evolved more than 450 million years ago from a lineage of freshwater charophyte green algae(1). The extent to which plant signalling systems existed before the evolutionary transition to land is unknown. Although charophytes occupy a key phylogenetic position for elucidating the origins of such signalling systems(2-4), there is a paucity of sequence data for these organisms(5,6). Here we carry out de novo transcriptomics of five representative charophyte species, and find putative homologues for the biosynthesis, transport, perception and signalling of major plant hormones. Focusing on the plant hormone ethylene, we provide evidence that the filamentous charophyte Spirogyra pratensis possesses an ethylene hormone system homologous to that in plants. Spirogyra produces ethylene and exhibits a cell elongation response to ethylene. Spirogyra ethylene signalling homologues partially rescue mutants of the angiosperm Arabidopsis thaliana and respond post-translationally to ethylene when expressed in plant cells, indicative of unambiguously homologous ethylene-signalling pathways in Spirogyra and Arabidopsis. These findings imply that the common aquatic ancestor possessed this pathway prior to the colonization of land and that cell elongation was possibly an ancestral ethylene response. This highlights the importance of charophytes for investigating the origins of fundamental plant processes. PMID- 27246052 TI - Gene duplication and genetic exchange drive the evolution of S-RNase-based self incompatibility in Petunia. AB - Self-incompatibility (SI) systems in flowering plants distinguish self- and non self pollen to prevent inbreeding. While other SI systems rely on the self recognition between specific male- and female-determinants, the Solanaceae family has a non-self recognition system resulting in the detoxification of female determinants of S-ribonucleases (S-RNases), expressed in pistils, by multiple male-determinants of S-locus F-box proteins (SLFs), expressed in pollen. It is not known how many SLF components of this non-self recognition system there are in Solanaceae species, or how they evolved. We identified 16-20 SLFs in each S haplotype in SI Petunia, from a total of 168 SLF sequences using large-scale next generation sequencing and genomic polymerase chain reaction (PCR) techniques. We predicted the target S-RNases of SLFs by assuming that a particular S-allele must not have a conserved SLF that recognizes its own S-RNase, and validated these predictions by transformation experiments. A simple mathematical model confirmed that 16-20 SLF sequences would be adequate to recognize the vast majority of target S-RNases. We found evidence of gene conversion events, which we suggest are essential to the constitution of a non-self recognition system and also contribute to self-compatible mutations. PMID- 27246050 TI - The origin and evolution of maize in the Southwestern United States. AB - The origin of maize (Zea mays mays) in the US Southwest remains contentious, with conflicting archaeological data supporting either coastal(1-4) or highland(5,6) routes of diffusion of maize into the United States. Furthermore, the genetics of adaptation to the new environmental and cultural context of the Southwest is largely uncharacterized(7). To address these issues, we compared nuclear DNA from 32 archaeological maize samples spanning 6,000 years of evolution to modern landraces. We found that the initial diffusion of maize into the Southwest about 4,000 years ago is likely to have occurred along a highland route, followed by gene flow from a lowland coastal maize beginning at least 2,000 years ago. Our population genetic analysis also enabled us to differentiate selection during domestication for adaptation to the climatic and cultural environment of the Southwest, identifying adaptation loci relevant to drought tolerance and sugar content. PMID- 27246054 TI - Floral pigmentation patterns provide an example of Gloger's rule in plants. AB - Ecogeographic rules explain spatial trends in biodiversity, species interactions and phenotypes(1). Gloger's rule and its corollaries state that pigmentation of endothermic animals will increase from more polar to equatorial regions due to changing selective pressures including heat, humidity, predation and UV irradiance(2-4). In plants, floral pigmentation varies within and among taxa, yet causes of wide-scale geographic variation are lacking. We show that Gloger's rule explains patterns of variation in UV-absorbing floral pigmentation in a widespread plant, Argentina anserina (Rosaceae). Specifically, the floral pigmentation pattern unique to the UV spectrum (UV 'bullseye') increases with proximity to the Equator in both hemispheres, and larger bullseyes are associated with higher UVB incidence. Experiments confirm UV as an agent of selection and bullseye size as a target. Results extend the generality of an ecogeographic rule formulated for animals-to plants, implicating UV as a selective agent on a floral trait generally assumed to enhance plant-pollinator interactions. Global change is expected to alter UV irradiance in terrestrial systems(5), potentially intensifying the importance of UV-mediated selection to floral evolution. Because floral UV reflectance and pattern enhance pollinator attraction(6,7), altered selective regimes could disrupt coevolved plant-pollinator interactions, weakening an important ecosystem service(8). PMID- 27246055 TI - Crop domestication: Corn in the USA. PMID- 27246056 TI - Photosynthesis: Rubisco rescue. PMID- 27246057 TI - Regulatory uncertainty over genome editing. PMID- 27246059 TI - Flower colour: Gloger's rule isn't just for the birds. PMID- 27246058 TI - Redox homeostasis: Opening up ascorbate transport. PMID- 27246060 TI - En route to plentiful food production in Africa. PMID- 27246061 TI - From the marshes to your menu. PMID- 27246062 TI - Tropical tree growth: No signs of stimulation. PMID- 27246063 TI - Innate immunity: Defence by transcription. PMID- 27246064 TI - Genetics: Cucumber's bitter pill. PMID- 27246066 TI - Europe compromises on GM crops. PMID- 27246065 TI - Plant-microbe interactions: Microbiome remote control. PMID- 27246067 TI - Update on carbohydrates and health: the relevance of the Scientific Advisory Committee on Nutrition report for children. PMID- 27246068 TI - Chronic conditions in children and young people: learning from administrative data. PMID- 27246069 TI - Indications for gastrointestinal endoscopy in childhood. AB - Endoscopic examination of the gastrointestinal tract (GIT) for diagnostics and therapy in children has evolved markedly over the last 20 or so years and is now usually undertaken by paediatric endoscopists. Updated diagnostic and management guidelines for common disorders including coeliac disease, gastro-oesophageal reflux disease, eosinophilic oesophagitis and inflammatory bowel disease highlight the central role of endoscopy. Therapeutic endoscopic approaches are also now widely available and further broaden the referral spectrum to include treatment of GIT bleeding, gastrostomy insertion, dilation of strictures and polypectomy. Lastly, the advent of newer technologies allows the examination of hitherto inaccessible areas of the GIT such as the mid-small bowel by wireless capsule video-endoscopy and enteroscopy. We summarise recent current practice and clinical guidelines, focussing on the key indications for referrals that are likely to require endoscopic assessment. PMID- 27246070 TI - Vitamin D in corticosteroid-naive and corticosteroid-treated Duchenne muscular dystrophy: what dose achieves optimal 25(OH) vitamin D levels? AB - AIM: Assessment of the efficacy of vitamin D replenishment and maintenance doses required to attain optimal levels in boys with Duchenne muscular dystrophy (DMD). METHOD: 25(OH)-vitamin D levels and concurrent vitamin D dosage were collected from retrospective case-note review of boys with DMD at the Dubowitz Neuromuscular Centre. Vitamin D levels were stratified as deficient at <25 nmol/L, insufficient at 25-49 nmol/L, adequate at 50-75 nmol/L and optimal at >75 nmol/L. RESULT: 617 vitamin D samples were available from 197 boys (range 2-18 years)-69% from individuals on corticosteroids. Vitamin D-naive boys (154 samples) showed deficiency in 28%, insufficiency in 42%, adequate levels in 24% and optimal levels in 6%. The vitamin D-supplemented group (463 samples) was tested while on different maintenance/replenishment doses. Three-month replenishment of daily 3000 IU (23 samples) or 6000 IU (37 samples) achieved optimal levels in 52% and 84%, respectively. 182 samples taken on 400 IU revealed deficiency in 19 (10%), insufficiency in 84 (47%), adequate levels in 67 (37%) and optimal levels in 11 (6%). 97 samples taken on 800 IU showed deficiency in 2 (2%), insufficiency in 17 (17%), adequate levels in 56 (58%) and optimal levels in 22 (23%). 81 samples were on 1000 IU and 14 samples on 1500 IU, with optimal levels in 35 (43%) and 9 (64%), respectively. No toxic level was seen (highest level 230 nmol/L). CONCLUSIONS: The prevalence of vitamin D deficiency and insufficiency in DMD is high. A 2-month replenishment regimen of 6000 IU and maintenance regimen of 1000-1500 IU/day was associated with optimal vitamin D levels. These data have important implications for optimising vitamin D dosing in DMD. PMID- 27246071 TI - Bronchiectasthma and asthmectasis! PMID- 27246072 TI - Adding biological markers to COPD categorisation schemes: a way towards more personalised care? PMID- 27246073 TI - COPD treatment: about collateral channels and collapsing airways. PMID- 27246074 TI - When insulin has to work hard to keep the sugar at bay the upper airway collapses away. PMID- 27246075 TI - Sildenafil for pulmonary hypertension complicating idiopathic pulmonary fibrosis: a rationale grounded in basic science. PMID- 27246076 TI - How to follow-up patients with hereditary haemorrhagic telangiectasia and suspected pulmonary arteriovenous malformations. PMID- 27246077 TI - Interstitial pneumonitis with autoimmune features (IPAF): a work in progress. PMID- 27246078 TI - Beryllium disease and sarcoidosis: still besties after all these years? PMID- 27246079 TI - Genetic studies yield clues to the pathogenesis of Langerhans cell histiocytosis. PMID- 27246080 TI - A wider pathological network underlying breathlessness and respiratory failure in amyotrophic lateral sclerosis. PMID- 27246081 TI - Risk of COPD in smokers with low transfer factor. PMID- 27246082 TI - The birth of a new lung syndrome? PMID- 27246083 TI - Progression to COPD in smokers with normal spirometry/low DLCO using different methods to determine normal levels. PMID- 27246084 TI - Sensitivity to chemotherapy/tyrosine kinase inhibitors of mucinous lepidic adenocarcinoma should be tested in a phase III trial? PMID- 27246085 TI - "Blood basophil activation is a reliable biomarker of allergic bronchopulmonary aspergillosis in cystic fibrosis." Yael Gernez, Jeffrey Waters, Bojana Mirkovic, Gillian M. Lavelle, Colleen E. Dunn, Zoe A. Davies, Cassie Everson, Rabindra Tirouvanziam, Elana Silver, Sylvan Wallenstein, Sanjay H. Chotirmall, Noel G. McElvaney, Leonore A. Herzenberg and Richard B. Moss. Eur Respir J 2016; 47: 177 185. PMID- 27246087 TI - ERJ June Podcast: unfavourable effects of oral anticoagulants on survival in idiopathic pulmonary fibrosis. PMID- 27246086 TI - "Asthma inhaler adherence determinants in adults: systematic review of observational data." Alexandra L. Dima, Gimena Hernandez, Oriol Cunillera, Montserrat Ferrer, Marijn de Bruin and the ASTRO-LAB group. Eur Respir J 2015; 45: 994-1018. PMID- 27246088 TI - Synchronizing to auditory and tactile metronomes: a test of the auditory-motor enhancement hypothesis. AB - Humans show a striking advantage for synchronizing movements with discretely timed auditory metronomes (e.g., clicking sounds) over temporally matched visual metronomes (e.g., flashing lights), suggesting enhanced auditory-motor coupling for rhythmic processing. Does the auditory advantage persist for other modalities (not just vision)? Here, nonmusicians finger tapped to the beat of auditory, tactile, and bimodal metronomes. Stimulus magnitude and rhythmic complexity were also manipulated. In conditions involving a large area of stimulation and simple rhythmic sequences, tactile synchronization closely matched auditory. Although this finding shows a limitation to the hypothesis of enhanced auditory-motor coupling for rhythmic processing, other findings clearly support it. First, there was a robust advantage with auditory information for synchronization with complex rhythm sequences; moreover, in complex sequences a measure of error correction was found only when auditory information was present. Second, higher order grouping was evident only when auditory information was present. PMID- 27246089 TI - To not settle for small losses: evidence for an ecological aspiration level of zero in dynamic decision-making. AB - This work aimed to investigate how one's aspiration level is set in decision making involving losses and how people respond when all alternatives appear to be below the aspiration level. We hypothesized that the zero point would serve as an ecological aspiration level where losses cause participants to focus on improvements in payoffs. In two experiments, we investigated these issues by combining behavioral studies and computational modeling. Participants chose from two alternatives on each trial. A decreasing option consistently gave a larger immediate payoff, although it caused future payoffs for both options to decrease. Selecting an increasing option caused payoffs for both options to increase on future trials. We manipulated the incentive structure such that in the losses condition the smallest payoff for the decreasing option was a loss, whereas in the gains condition the smallest payoff for the decreasing option was a gain, while the differences in outcomes for the two options were kept equivalent across conditions. Participants selected the increasing option more often in the losses condition than in the gains condition, regardless of whether the increasing option was objectively optimal (Experiment 1) or suboptimal (Experiment 2). Further, computational modeling results revealed that participants in the losses condition exhibited heightened weight to the frequency of positive versus negative prediction errors, suggesting that they were more attentive to improvements and reductions in outcomes than to expected values. This supports our assertion that losses induce aspiration for larger payoffs. We discuss our results in the context of recent theories of how losses shape behavior. PMID- 27246090 TI - Garner interference is not solely driven by stimulus uncertainty. AB - The speeded classification tasks popularized by Garner (1974), with their accompanying labels of separable and integral dimensions, have become the dominant paradigm for characterizing perceptual interactions between stimulus dimensions. Separable dimensions like color and shape can be selectively attended to at will, but integral dimensions like hue and brightness cannot. When classifying stimuli with respect to a single dimension, integral stimuli lead to faster performance in the baseline block, where only that single dimension varies, than in the filtering block, in which a second dimension is allowed to vary irrelevantly. No such difference is predicted for separable dimensions lead to no difference. The comparison between baseline and filtering confounds a change in the number of stimuli with a change in the number of variant dimensions. A new experimental condition is proposed utilizing three stimulus dimensions to hold the number of stimuli constant while introducing variance along a second irrelevant dimension. Data indicate that interference increases, suggesting that changes in the number of potential stimuli within a block are not necessary for Garner interference, in contrast to the accounts provided by extant quantitative models. PMID- 27246091 TI - A generative joint model for spike trains and saccades during perceptual decision making. AB - Theory development in both psychology and neuroscience can benefit by consideration of both behavioral and neural data sets. However, the development of appropriate methods for linking these data sets is a difficult statistical and conceptual problem. Over the past decades, different linking approaches have been employed in the study of perceptual decision-making, beginning with rudimentary linking of the data sets at a qualitative, structural level, culminating in sophisticated statistical approaches with quantitative links. We outline a new approach, in which a single model is developed that jointly addresses neural and behavioral data. This approach allows for specification and testing of quantitative links between neural and behavioral aspects of the model. Estimating the model in a Bayesian framework allows both data sets to equally inform the estimation of all model parameters. The use of a hierarchical model architecture allows for a model, which accounts for and measures the variability between neurons. We demonstrate the approach by re-analysis of a classic data set containing behavioral recordings of decision-making with accompanying single-cell neural recordings. The joint model is able to capture most aspects of both data sets, and also supports the analysis of interesting questions about prediction, including predicting the times at which responses are made, and the corresponding neural firing rates. PMID- 27246092 TI - Conjugated linoleic acid influences the metabolism of tocopherol in lactating rats but has little effect on tissue tocopherol concentrations in pups. AB - BACKGROUND: Conjugated linoleic acid (CLA) is known to affect the lipid metabolism in growing and lactating animals. However, potential effects on the metabolism of fat-soluble vitamins in lactating animals and co-occurring effects on their offspring are unknown. We aimed to investigate the effects of dietary CLA on concentrations of tocopherol in various tissues of lactating rats and their offspring and expression of genes involved in tocopherol metabolism. METHODS: Twenty-eight Wistar Han rats were allocated to 2 groups and fed either a control diet (control group) or a diet containing 0.9 % of cis-9, trans-11 and trans-10, cis-12 (1:1) CLA (CLA group) during pregnancy and lactation. Feed intake of dams and body weight of dams and their pups were recorded weekly. Tocopherol concentrations in various body tissues were determined at day 14 of lactation in dams and 1, 7 and 14 days after birth in pups. Expression of selected genes involved in metabolism of tocopherol was determined in dams and pups. The data were statistically analysed by analysis of variance. RESULTS: Feed intake and body weight development of nursing rats and their pups was similar in both groups. In livers of CLA-fed dams, tocopherol concentrations decreased by 24 % but expression of TTPA and CYP3A1, involved in tocopherol transport and metabolism, were not influenced. In the dams' adipose tissue, gene expression of receptors involved in tissue tocopherol uptake, LDLR and SCARB1, but not of LPL, increased by 30 to 50 % and tocopherol concentrations increased by 47 % in CLA fed compared to control dams. Expression of LPL, LDLR and SCARB1 in mammary gland was not influenced by CLA-feeding. Tocopherol concentrations in the pup's livers and lungs were similar in both groups, but at 14 days of age, adipose tissue tocopherol concentrations, and LDLR and SCARB1 expression, were higher in the CLA exposed pups. CONCLUSIONS: We show that dietary CLA affects tissue concentrations of tocopherol in lactating rats and tocopherol metabolism in rats and pups, but hardly influences tissue tocopherol concentrations in their offspring. This indicates that supplementation of CLA in pregnant and lactating animals is uncritical considering the tocopherol status of new-borns. PMID- 27246093 TI - Not knowing what I feel: Emotional empathy in autism spectrum disorders. AB - While there is a general consensus in the literature that individuals with autism spectrum disorder have difficulty with cognitive empathy, much less is known about emotional empathy processing in these individuals. Most research has employed subjective self-report measures, which can often be misinterpreted or under-reported/over-reported. More objective measures such as psychophysiological recordings of arousal offer a more objective response. Furthermore, combining physiological responses with self-report ratings allows us to explore the relationship between these two responses to emotionally charged stimuli. A total of 25 individuals with autism spectrum disorder were compared with 25 matched controls on their physiological (arousal) and psychological (self-report) responses to emotionally distressing video scenes. These responses were also then compared with self-report cognitive and emotional trait empathy. Results indicate that while individuals with autism spectrum disorder appear to respond similarly to controls physiologically, their interpretation of this response is dampened emotionally. Furthermore, this dampening of self-report emotional response is associated with a general reduction in trait empathy. PMID- 27246094 TI - Ethylene Regulates the Physiology of the Cyanobacterium Synechocystis sp. PCC 6803 via an Ethylene Receptor. AB - Ethylene is a plant hormone that plays a crucial role in the growth and development of plants. The ethylene receptors in plants are well studied, and it is generally assumed that they are found only in plants. In a search of sequenced genomes, we found that many bacterial species contain putative ethylene receptors. Plants acquired many proteins from cyanobacteria as a result of the endosymbiotic event that led to chloroplasts. We provide data that the cyanobacterium Synechocystis (Synechocystis sp. PCC 6803) has a functional receptor for ethylene, Synechocystis Ethylene Response1 (SynEtr1). We first show that SynEtr1 directly binds ethylene. Second, we demonstrate that application of ethylene to Synechocystis cells or disruption of the SynEtr1 gene affects several processes, including phototaxis, type IV pilus biosynthesis, photosystem II levels, biofilm formation, and spontaneous cell sedimentation. Our data suggest a model where SynEtr1 inhibits downstream signaling and ethylene inhibits SynEtr1. This is similar to the inverse-agonist model of ethylene receptor signaling proposed for plants and suggests a conservation of structure and function that possibly originated over 1 billion years ago. Prior research showed that SynEtr1 also contains a light-responsive phytochrome-like domain. Thus, SynEtr1 is a bifunctional receptor that mediates responses to both light and ethylene. To our knowledge, this is the first demonstration of a functional ethylene receptor in a nonplant species and suggests that that the perception of ethylene is more widespread than previously thought. PMID- 27246095 TI - The ROS Wheel: Refining ROS Transcriptional Footprints. AB - In the last decade, microarray studies have delivered extensive inventories of transcriptome-wide changes in messenger RNA levels provoked by various types of oxidative stress in Arabidopsis (Arabidopsis thaliana). Previous cross-study comparisons indicated how different types of reactive oxygen species (ROS) and their subcellular accumulation sites are able to reshape the transcriptome in specific manners. However, these analyses often employed simplistic statistical frameworks that are not compatible with large-scale analyses. Here, we reanalyzed a total of 79 Affymetrix ATH1 microarray studies of redox homeostasis perturbation experiments. To create hierarchy in such a high number of transcriptomic data sets, all transcriptional profiles were clustered on the overlap extent of their differentially expressed transcripts. Subsequently, meta analysis determined a single magnitude of differential expression across studies and identified common transcriptional footprints per cluster. The resulting transcriptional footprints revealed the regulation of various metabolic pathways and gene families. The RESPIRATORY BURST OXIDASE HOMOLOG F-mediated respiratory burst had a major impact and was a converging point among several studies. Conversely, the timing of the oxidative stress response was a determining factor in shaping different transcriptome footprints. Our study emphasizes the need to interpret transcriptomic data sets in a systematic context, where initial, specific stress triggers can converge to common, aspecific transcriptional changes. We believe that these refined transcriptional footprints provide a valuable resource for assessing the involvement of ROS in biological processes in plants. PMID- 27246097 TI - Promises and Challenges of Eco-Physiological Genomics in the Field: Tests of Drought Responses in Switchgrass. AB - Identifying the physiological and genetic basis of stress tolerance in plants has proven to be critical to understanding adaptation in both agricultural and natural systems. However, many discoveries were initially made in the controlled conditions of greenhouses or laboratories, not in the field. To test the comparability of drought responses across field and greenhouse environments, we undertook three independent experiments using the switchgrass reference genotype Alamo AP13. We analyzed physiological and gene expression variation across four locations, two sampling times, and three years. Relatively similar physiological responses and expression coefficients of variation across experiments masked highly dissimilar gene expression responses to drought. Critically, a drought experiment utilizing small pots in the greenhouse elicited nearly identical physiological changes as an experiment conducted in the field, but an order of magnitude more differentially expressed genes. However, we were able to define a suite of several hundred genes that were differentially expressed across all experiments. This list was strongly enriched in photosynthesis, water status, and reactive oxygen species responsive genes. The strong across-experiment correlations between physiological plasticity-but not differential gene expression-highlight the complex and diverse genetic mechanisms that can produce phenotypically similar responses to various soil water deficits. PMID- 27246099 TI - Effects of elevated CO2 on photosynthetic traits of native and invasive C3 and C4 grasses. AB - BACKGROUND: Rising CO2 is expected to result in changes in plant traits that will increase plant productivity for some functional groups. Differential plant responses to elevated CO2 are likely to drive changes in competitive outcomes, with consequences for community structure and plant diversity. Many of the traits that are enhanced under elevated CO2 also confer competitive success to invasive species, and it is widely believed that invasive species will be more successful in high CO2. However, this is likely to depend on plant functional group, and evidence suggests that C3 plants tend to respond more strongly to CO2. RESULTS: We tested the hypothesis that invasive species would be more productive than noninvasive species under elevated CO2 and that stronger responses would be seen in C3 than C4 plants. We examined responses of 15 grass species (eight C3, seven C4), classified as noninvasive or invasive, to three levels of CO2 (390, 700 and 1000 ppm) in a closed chamber experiment. Elevated CO2 decreased conductance and %N and increased shoot biomass and C/N ratio across all species. Differences between invasive and noninvasive species depended on photosynthetic mechanism, with more differences for traits of C3 than C4 plants. Differences in trait means between invasive and noninvasive species tended to be similar across CO2 levels for many of the measured responses. However, noninvasive C3 grasses were more responsive than invasive C3 grasses in increasing tiller number and root biomass with elevated CO2, whereas noninvasive C4 grasses were more responsive than invasive C4 grasses in increasing shoot and root biomass with elevated CO2. For C3 grasses, these differences could be disadvantageous for noninvasive species under light competition, whereas for C4 grasses, noninvasive species may become better competitors with invasive species under increasing CO2. CONCLUSIONS: The ecophysiological mechanisms underlying invasion success of C3 and C4 grasses may differ. However, given that the direction of trait differences between invasive and noninvasive grasses remained consistent under ambient and elevated CO2, our results provide evidence that increases in CO2 are unlikely to change dramatically the competitive hierarchy of grasses in these functional groups. PMID- 27246098 TI - The Mediator Complex MED15 Subunit Mediates Activation of Downstream Lipid Related Genes by the WRINKLED1 Transcription Factor. AB - The Mediator complex is known to be a master coordinator of transcription by RNA polymerase II, and this complex is recruited by transcription factors (TFs) to target promoters for gene activation or repression. The plant-specific TF WRINKLED1 (WRI1) activates glycolysis-related and fatty acid biosynthetic genes during embryogenesis. However, no Mediator subunit has yet been identified that mediates WRI1 transcriptional activity. Promoter-beta-glucuronidase fusion experiments showed that MEDIATOR15 (MED15) is expressed in the same cells in the embryo as WRI1. We found that the Arabidopsis (Arabidopsis thaliana) MED15 subunit of the Mediator complex interacts directly with WRI1 in the nucleus. Overexpression of MED15 or WRI1 increased transcript levels of WRI1 target genes involved in glycolysis and fatty acid biosynthesis; these genes were down regulated in wild-type or WRI1-overexpressing plants by silencing of MED15 However, overexpression of MED15 in the wri1 mutant also increased transcript levels of WRI1 target genes, suggesting that MED15 also may act with other TFs to activate downstream lipid-related genes. Chromatin immunoprecipitation assays confirmed the association of MED15 with six WRI1 target gene promoters. Additionally, silencing of MED15 resulted in reduced fatty acid content in seedlings and mature seeds, whereas MED15 overexpression increased fatty acid content in both developmental stages. Similar results were found in wri1 mutant and WRI1 overexpression lines. Together, our results indicate that the WRI1/MED15 complex transcriptionally regulates glycolysis-related and fatty acid biosynthetic genes during embryogenesis. PMID- 27246096 TI - Defective Pollen Wall 2 (DPW2) Encodes an Acyl Transferase Required for Rice Pollen Development. AB - Aliphatic and aromatic lipids are both essential structural components of the plant cuticle, an important interface between the plant and environment. Although cross links between aromatic and aliphatic or other moieties are known to be associated with the formation of leaf cutin and root and seed suberin, the contribution of aromatic lipids to the biosynthesis of anther cuticles and pollen walls remains elusive. In this study, we characterized the rice (Oryza sativa) male sterile mutant, defective pollen wall 2 (dpw2), which showed an abnormal anther cuticle, a defective pollen wall, and complete male sterility. Compared with the wild type, dpw2 anthers have increased amounts of cutin and waxes and decreased levels of lipidic and phenolic compounds. DPW2 encodes a cytoplasmically localized BAHD acyltransferase. In vitro assays demonstrated that recombinant DPW2 specifically transfers hydroxycinnamic acid moieties, using omega-hydroxy fatty acids as acyl acceptors and hydroxycinnamoyl-CoAs as acyl donors. Thus, The cytoplasmic hydroxycinnamoyl-CoA:omega-hydroxy fatty acid transferase DPW2 plays a fundamental role in male reproduction via the biosynthesis of key components of the anther cuticle and pollen wall. PMID- 27246100 TI - Parthenogenesis through the ice ages: A biogeographic analysis of Caucasian rock lizards (genus Darevskia). AB - Darevskia rock lizards include both sexual and parthenogenetic species, mostly distributed in the heterogeneous and ecologically diverse Caucasus. The parthenogenetic species originated via directional hybridogenesis, with only some of the sexual species known to serve as parentals. However, it remains unclear when and where these events happened and how many parental lineages were involved. A multilocus phylogeographic analysis was performed on the parthenogens D. unisexualis, D. bendimahiensis and D. uzzeli, and their putative maternal species D. raddei. Results show the parthenogenetic species all have relatively recent origins, approximately 200-70kyr ago, and at least three hybridization events were involved in their formation. Ecological niche models identify the region where hybridization events leading to the formation of D. unisexualis took place, namely in the northeast of the current distribution. Models also suggest that the sexual D. raddei might have undergone a habitat shift between the Last Interglacial and the Last Glacial Maximum. PMID- 27246101 TI - Resolving the higher-order phylogenetic relationships of the circumtropical Mabuya group (Squamata: Scincidae): An out-of-Asia diversification. AB - Despite an abundance of phylogenetic studies focused on intrageneric relationships of members of the Mabuya group, the intergeneric relationships have remained difficult to resolve. The most-persistent unresolved regions of the phylogeny of the group include: (1) the placement of the Middle-Eastern Trachylepis with respect to the Afro-Malagasy Trachylepis and its taxonomic status; (2) the phylogenetic position of the Cape Verdean Chioninia within the larger Mabuya group; (3) support for the placement of Dasia with respect to the entire group; and (4) the phylogenetic placement of Eutropis novemcarinata with respect to other Eutropis and Dasia. In this study, we include representatives of all these taxa as well as African Eumecia and Neotropical Mabuya. We seek to address these phylogenetic and systematic issues by generating a well-resolved and supported phylogeny for the Mabuya group as a whole that can be used to develop a stable taxonomy and reconstruct the geographic patterns of diversification within the group. To meet these goals, we built a large multi locus dataset of 11 markers (nine nuclear and two mitochondrial), and performed concatenated and species tree analyses to generate a well-supported phylogeny for the group. Statistical topology tests reject the monophyly of Middle-Eastern Trachylepis with Afro-Malagasy Trachylepis, and to reflect monophyly we place the Middle-Eastern species into a previously described genus, Heremites. Cape-Verdean Chioninia are resolved as the strongly supported sister-group to Afro-Malagasy Trachylepis. Monophyly of the Southeast-Asian genera, Eutropis and Dasia, is not supported, with a clade composed of Dasia+Eutropis novemcarinata more closely related to the rest of the Mabuya group than to the remaining Eutropis. The phylogenetic position of E. novemcarinata renders Eutropis polyphyletic, and we therefore describe and place E. novemcarinata into a new monotypic genus, Toenayar, to preserve monophyly among the genera. In light of these novel findings, we review and discuss the historical biogeography of the entire Mabuya group. PMID- 27246102 TI - The Rusty-tailed Flycatcher (Muscicapa ruficauda; Aves: Muscicapidae) is a member of the genus Ficedula. AB - The phylogenetic relationships of the avian family Muscicapidae (Old World chats and flycatchers) have historically been enigmatic and remain an active area of study. Widespread instances of non-monophyly resulting from misleading morphological and behavioral similarities have merited numerous taxonomic revisions to the group. Here we report one such instance with regard to the Rusty tailed Flycatcher Muscicapa ruficauda, which has recently been placed in the newly proposed monotypic genus Ripleyia, due to inferred sister relationship to the genus Muscicapa and related genera (Voelker et al., 2016a). This name was later replaced by Ripleyornis, as it was realized that Ripleyia is a junior homonym of a genus of Mollusca (Voelker et al., 2016b). Using a Bayesian phylogenetic assessment of the Muscicapidae with near-complete taxon sampling of the genus Ficedula for five loci, along with an acoustic comparison of M. ruficauda to a subset of other flycatcher species, we show that this species should be reassigned to the genus Ficedula and accordingly that the names Ripleyia and Ripleyornis are both junior synonyms of Ficedula. PMID- 27246104 TI - Perceived and objective neighborhood support for outside of school physical activity in South African children. AB - BACKGROUND: The neighborhood environment has the potential to influence children's participation in physical activity. However, children's outdoor play is controlled by parents to a great extent. This study aimed to investigate whether parents' perceptions of the neighborhood environment and the objectively measured neighborhood environment were associated with children's moderate-to vigorous intensity physical activity (MVPA) outside of school hours; and to determine if these perceptions and objective measures of the neighborhood environment differ between high and low socio-economic status (SES) groups. METHODS: In total, 258 parents of 9-11 year-old children, recruited from the South African sample of the International Study of Childhood Obesity, Lifestyle and the Environment (ISCOLE), completed a questionnaire concerning the family and neighborhood environment. Objective measures of the environment were also obtained using Geographic Information Systems (GIS). Children wore an Actigraph (GT3X+) accelerometer for 7 days to measure levels of MVPA. Multilevel regression models were used to determine the association between the neighborhood environment and MVPA out of school hours. RESULTS: Parents' perceptions of the neighborhood physical activity facilities were positively associated with children's MVPA before school (beta = 1.50 +/- 0.51, p = 0.003). Objective measures of neighborhood safety and traffic risk were associated with children's after-school MVPA (beta = -2.72 +/- 1.35, p = 0.044 and beta = -2.63 +/- 1.26, p = 0.038, respectively). These associations were significant in the low SES group (beta = -3.38 +/- 1.65, p = 0.040 and beta = -3.76 +/- 1.61, p = 0.020, respectively), but unrelated to MVPA in the high SES group. CONCLUSIONS: This study found that several of the objective measures of the neighborhood environment were significantly associated with children's outside-of-school MVPA, while most of the parents' perceptions of the neighborhood environment were unrelated. PMID- 27246105 TI - Association of Vac A- and Cag A-specific Helicobacter pylori strain infection with spontaneous preterm birth. AB - PURPOSE: To better understand the correlation between Helicobacter pylori (H. pylori) seropositivity and spontaneous preterm birth. MATERIALS AND METHODS: A total of 320 pregnant women were classified into two groups: normal control singleton pregnant group (n = 264) and singleton spontaneous preterm birth group (n = 56). Blood samples were collected at the time of delivery, and the H. pylori IgG, various virulence factors and systemic inflammation status were compared between the two groups. RESULTS: Between the two groups, the serum H. pylori IgG, Cytotoxin-associated agntigen A (Cag A), Vacuolating cytotoxin A (Vac A) significantly increased in spontaneous preterm birth group than in the control group. Also, in preterm group, highly sensitive C-reactive protein (hsCRP) as a systemic inflammatory marker is statistically elevated at inflammatory status range. Whereas in the term pregnant group, hsCRP was normal range even though high incidence of H. pylori IgG seropositivity. Also, in the seropositive group, hsCRP is statistically correlated with H. pylori IgG, Cag A and Vac A. CONCLUSIONS: There is an association between the presence of antibodies against H. pylori in maternal serum and the development of preterm birth. Furthermore, serology type of H. pylori with Vac A, Cag A relates to preterm birth even though high H. pylori prevalence rate. PMID- 27246103 TI - The Sur1-Trpm4 channel regulates NOS2 transcription in TLR4-activated microglia. AB - BACKGROUND: Harmful effects of activated microglia are due, in part, to the formation of peroxynitrite radicals, which is attributable to the upregulation of inducible nitric oxide (NO) synthase (NOS2). Because NOS2 expression is determined by Ca(2+)-sensitive calcineurin (CN) dephosphorylating nuclear factor of activated T cells (NFAT), and because Sur1-Trpm4 channels are crucial for regulating Ca(2+) influx, we hypothesized that, in activated microglia, Sur1 Trpm4 channels play a central role in regulating CN/NFAT and downstream target genes such as Nos2. METHODS: We studied microglia in vivo and in primary culture from adult rats, and from wild type, Abcc8-/- and Trpm4-/- mice, and immortalized N9 microglia, following activation of Toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS), using in situ hybridization, immunohistochemistry, co immunoprecipitation, immunoblot, qPCR, patch clamp electrophysiology, calcium imaging, the Griess assay, and chromatin immunoprecipitation. RESULTS: In microglia in vivo and in vitro, LPS activation of TLR4 led to de novo upregulation of Sur1-Trpm4 channels and CN/NFAT-dependent upregulation of Nos2 mRNA, NOS2 protein, and NO. Pharmacological inhibition of Sur1 (glibenclamide), Trpm4 (9-phenanthrol), or gene silencing of Abcc8 or Trpm4 reduced Nos2 upregulation. Inhibiting Sur1-Trpm4 increased the intracellular calcium concentration ([Ca(2+)]i), as expected, but also decreased NFAT nuclear translocation. The increase in [Ca(2+)]i induced by inhibiting or silencing Sur1 Trpm4 resulted in phosphorylation of Ca(2+)/calmodulin protein kinase II and of CN, consistent with reduced nuclear translocation of NFAT. The regulation of NFAT by Sur1-Trpm4 was confirmed using chromatin immunoprecipitation. CONCLUSIONS: Sur1-Trpm4 constitutes a novel mechanism by which TLR4-activated microglia regulate pro-inflammatory, Ca(2+)-sensitive gene expression, including Nos2. PMID- 27246106 TI - A newly designed observation and response chart's effect upon adverse inpatient outcomes and rapid response team activity. AB - BACKGROUND: Adverse inpatient events may diminish with earlier response to clinical deterioration. Observation and response charts with a tiered escalation response are recommended for use. AIMS: To examine the impact of an observation and response chart and altered calling criteria on rapid response team (RRT) calls, cardiac arrests and intensive care unit (ICU) admissions from the ward and hospital deaths. METHODS: Linked administrative and clinical data from an Australian, adult tertiary hospital for August 2007 to June 2013 (pre-chart) and July 2013 to December 2014 (post-chart) and analysed using interrupted time series analysis. RESULTS: Pre-chart RRT calls were increasing by 1.7 calls per 10 000 hospital admissions per month, whilst ICU admissions from the ward, deaths and cardiac arrests were decreasing by 0.3, 0.25 and 0.079 per 10 000 admissions per month respectively. Immediately upon chart introduction, the RRT call rate increased by 82% (66-98% CI; P < 0.01), the ward admissions to ICU rate increased by 41% (14-67% CI; P < 0.01) and the rates of deaths and cardiac arrests did not change. In the post chart period, both the pre-chart increasing trend in the rate of RRT and decreasing trend in the rate of ICU admissions changed significantly to become constant. The pre chart trends in the cardiac arrest rate and hospital mortality did not change. CONCLUSION: Observation and response charts increased RRT and ICU workload without improving cardiac arrest rate or mortality. Future chart evaluation should identify features beneficial to patient outcomes and refine those that consume critical care resources that are not associated with improved patient outcomes. PMID- 27246108 TI - 21st International Chromosome Conference (ICC). July 10-13, Foz do Iguacu, Brazil. PMID- 27246109 TI - VLCAD deficiency: Follow-up and outcome of patients diagnosed through newborn screening in Victoria. AB - Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is an inherited metabolic disorder of fatty acid oxidation. Treatment practices of the disorder have changed over the past 10-15years since this disorder was included in newborn screening programs and patients were diagnosed pre-symptomatically. A genotype phenotype correlation has been suggested but the discovery of novel mutations make this knowledge limited. Herein, we describe our experience in treating patients (n=22) diagnosed through newborn screening and mutational confirmation and followed up over a median period of 104months. We report five novel mutations. In 2013 we formalised our treatment protocol, which essentially follows a European consensus paper from 2009 and our own experience. The prescribed low natural fat diet is relaxed for patients who are asymptomatic when reaching age 5years but medium-chain triglyceride oil is recommended before and after physical activity regardless of age. Metabolic stability, growth, development and cardiac function are satisfactory in all patients. There were no episodes of encephalopathy or hypoglycaemia but three patients had episodes of muscle pain with our without rhabdomyolysis. Body composition studies showed a negative association between dietary protein intake and percent body fat. Larger patient cohort and longer follow up time are required for further elucidation of genotype-phenotype correlations and for establishing the role of dietary protein in metabolic stability and long-term healthier body composition in patients with VLCAD deficiency. PMID- 27246110 TI - Molecular diagnosis of 65 families with mucopolysaccharidosis type II (Hunter syndrome) characterized by 16 novel mutations in the IDS gene: Genetic, pathological, and structural studies on iduronate-2-sulfatase. AB - Mucopolysaccharidosis type II (MPS II: also called as Hunter syndrome) is an X linked recessive lysosomal storage disorder characterized by the accumulation of extracellular glycosaminoglycans due to the deficiency of the enzyme iduronate-2 sulfatase (IDS). Previous observations suggested that MPS II can be classified into two distinct disease subtypes: (1) severe type of MPS II involves a decline in the cognitive ability of a patient and (2) attenuated type of MPS II exhibits no such intellectual phenotype. To determine whether such disease subtypes of MPS II could be explained by genetic diagnosis, we analyzed mutations in the IDS gene of 65 patients suffering from MPS II among the Japanese population who were diagnosed with both the accumulation of urinary glycosaminoglycans and a decrease in their IDS enzyme activity between 2004 and 2014. Among the specimens examined, we identified the following mutations: 33 missense, 8 nonsense, 7 frameshift, 4 intronic changes affecting splicing, 8 recombinations involving IDS-IDS2, and 7 other mutations including 4 large deletions. Consistent with the previous data, the results of our study showed that most of the attenuated phenotype was derived from the missense mutations of the IDS gene, whereas mutations associated with a large structural alteration including recombination, splicing, frameshift, and nonsense mutations were linked to the severe phenotype of MPS II. Furthermore, we conducted a homology modeling study of IDS P120R and N534I mutant as representatives of the causative mutation of the severe and attenuated type of MPS II, respectively. We found that the substitution of P120R of the IDS enzyme was predicted to deform the alpha-helix generated by I119-F123, leading to the major structural alteration of the wild-type IDS enzyme. In sharp contrast, the effect of the structural alteration of N534I was marginal; thus, this mutation was pathogenically predicted to be associated with the attenuated type of MPS II. These results suggest that a combination of the genomic diagnosis of the IDS gene and the structural prediction of the IDS enzyme could enable the prediction of a phenotype more effectively. PMID- 27246111 TI - Ventilator-Associated Pneumonia in Low Birth Weight Neonates at a Neonatal Intensive Care Unit: A Retrospective Observational Study. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) is one of the most common healthcare-associated infections among ventilated patients. The aim of this study was to determine the clinical characteristics and risk factors for the development of VAP in intubated low birth weight (LBW) neonates in a neonatal intensive care unit. METHODS: LBW infants (<2.5 kg) admitted to the neonatal intensive care unit of Kaohsiung Medical University Hospital from January 2005 to December 2009 were enrolled. We retrospectively analyzed perinatal and neonatal data of the enrolled intubated LBW infants by chart review. RESULTS: Six hundred and five LBW infants were analyzed. One hundred and fourteen of the infants were intubated for >48 hours, 15 (13.2%) of whom had VAP. Of these 15 patients, the average age at onset of VAP was 24.0 +/- 11.2 days, the average postmenstrual age was 30.6 +/- 1.8 weeks, and the mean gestational age was 27.1 +/- 2.3 weeks, which was significantly lower than the mean gestational age in the group without VAP (30.2 +/- 3.5 weeks). The mean birth body weight was 944.4 +/- 268.4 g in the VAP group and 1340.1 +/- 455.4 g in the group without VAP (p < 0.001). Longer duration of intubation (odds ratio: 1.35, 95% confidence interval: 1.12-1.62) and parenteral nutrition (odds ratio: 1.32, 95% confidence interval: 1.14-1.51) were found in the VAP group after adjusting for gestational age and birth weight. CONCLUSION: VAP was a problem for the LBW infants with intubation for >48 hours in our neonatal intensive care unit. VAP most frequently occurred at a postmenstrual age of 30-32 weeks in this study. Longer duration of tube placement and parenteral nutrition were found in the VAP group. Early removal of the endotracheal tube and adequate enteral nutrition may decrease the occurrence of VAP in LBW infants. PMID- 27246107 TI - Evidence-based clinical practice guidelines for liver cirrhosis 2015. AB - The Japanese Society of Gastroenterology revised the evidence-based clinical practice guidelines for liver cirrhosis in 2015. Eighty-three clinical questions were selected, and a literature search was performed for the clinical questions with use of the MEDLINE, Cochrane, and Igaku Chuo Zasshi databases for the period between 1983 and June 2012. Manual searching of the latest important literature was added until August 2015. The guidelines were developed with use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. This digest version in English introduces selected clinical questions and statements related to the management of liver cirrhosis and its complications. Branched-chain amino acids relieve hypoalbuminemia and hepatic encephalopathy and improve quality of life. Nucleoside analogues and peginterferon plus ribavirin combination therapy improve the prognosis of patients with hepatitis B virus related liver cirrhosis and hepatitis C related compensated liver cirrhosis, respectively, although the latter therapy may be replaced by direct-acting antivirals. For liver cirrhosis caused by primary biliary cirrhosis and active autoimmune hepatitis, urosodeoxycholic acid and steroid are recommended, respectively. The most adequate modalities for the management of variceal bleeding are the endoscopic injection sclerotherapy for esophageal varices and the balloon-occluded retrograde transvenous obliteration following endoscopic obturation with cyanoacrylate for gastric varices. Beta-blockers are useful for primary prophylaxis of esophageal variceal bleeding. The V2 receptor antagonist tolvaptan is a useful add-on therapy in careful diuretic therapy for ascites. Albumin infusion is useful for the prevention of paracentesis-induced circulatory disturbance and renal failure. In addition to disaccharides, the nonabsorbable antibiotic rifaximin is useful for the management of encephalopathy. Anticoagulation therapy is proposed for patients with acute-onset or progressive portal vein thrombosis. PMID- 27246113 TI - Parathyroid lesions: Difficult diagnosis on cytology. AB - Cytology of parathyroid lesion (PL) is often confused with that of thyroid lesions. Differentiation between thyroid and PL is very difficult on cytomorphology because of their similar features and close anatomical proximity. Three cases of PLs reported on cytology in last one year were retrieved from archives of cytology department. Their cytomorphological details were studied and were correlated with the available biochemical parameters. Histopathology was available in two cases. Radiological assistance and parathyroid hormone (PTH) assessment in our cases formed the basis of diagnosing PLs on cytology. We discuss the differential diagnosis and pitfalls in cytological diagnosis of PLs. However, histopathology remains the gold standard for diagnosis. Interpretation of PLs on cytology remains problematic due to its rarity and limited available literature. The cytomorphology combined with clinical and biochemical data supported by histopathology are necessary to improve the diagnostic sensitivity of PLs. Diagn. Cytopathol. 2016;44:704-709. (c) 2016 Wiley Periodicals, Inc. PMID- 27246114 TI - Adjuvant therapies for malignant melanoma. PMID- 27246112 TI - BCAT1, a key prognostic predictor of hepatocellular carcinoma, promotes cell proliferation and induces chemoresistance to cisplatin. AB - BACKGROUND & AIMS: BCAT1 initiates the catabolism of branched-chain amino acids. Here, we investigated the function of BCAT1 and its transcriptional regulatory mechanism in hepatocellular carcinoma (HCC). METHODS: RNASeq was used to evaluate BCAT1 mRNA levels in HCC and normal matched specimens. After the exogenous expression of BCAT1 in BEL-7404 cells and the suppression of endogenous BCAT1 expression with shRNA in HepG2 cells, the cell proliferation, clone-forming ability and cell-cycle changes were measured with MTT assay, colony-forming assay and flow cytometry respectively. A xenograft model was used to investigate the effect of BCAT1 on cancer growth in vivo. Chromatin immunoprecipitation and luciferase reporter technologies were used to confirm the transcriptional regulation of the BCAT1 gene by MYC. The expression of the BCAT1 and MYC proteins in 122 HCC tissues was determined with an immunohistochemical analysis. RESULTS: BCAT1 mRNA was clearly increased in HCC tissues and hepatomas. The ectopic expression of BCAT1 in BEL-7404 cells enhanced their proliferation, clone formation, tumourigenic properties, S-G2 /M phase transition and chemoresistance to cisplatin. The suppression of BCAT1 expression in HepG2 cells significantly inhibited their proliferation, clone formation, and S-G2 /M phase transition and caused their chemosensitization to cisplatin. MYC affected the transcriptional regulation of BCAT1. Clinical data showed that BCAT1 expression correlated with a significantly poorer prognosis. CONCLUSION: BCAT1 plays a pathogenic role in HCC by causing cell proliferation and chemoresistance. The MYC transcription factor is involved in regulating the transcriptional activity of BCAT1. BCAT1 expression has prognostic significance for the survival of patients with HCC. PMID- 27246115 TI - The associations between chronotype, a healthy diet and obesity. AB - Unhealthy diet has been associated with obesity. Evening type has been associated with unhealthier food and nutrient intake that could predict a higher risk of obesity among them as compared to morning type. However, thus far no study has examined the interrelationships between chronotype, a healthy diet and obesity. We examined whether a healthy diet mediates the association between chronotype and obesity and whether chronotype modifies the association between a healthy and obesity. The National FINRISK 2007 Study included 4421 subjects aged 25-74 years. Diet was assessed using a validated food frequency questionnaire. Baltic Sea diet score (BSDS), including nine dietary components, was used as a measure of adherence to a healthy Nordic diet. Weight, height, body fat percentage and waist circumference were measured, and body mass index values were calculated. Chronotype was assessed using a shortened version of Horne and Ostberg's morningness-eveningness questionnaire (MEQ). The sum score calculated from MEQ was either used as a continuous variable or divided into tertiles of which the lowest tertile demonstrated evening preference and the highest tertile demonstrated morning preference. A series of regression analyses were conducted to determine whether the BSDS mediates the association between chronotype and obesity. Likelihood ratio test was used to determine whether chronotype modifies the association between the BSDS and the obesity measures. After testing the interaction, chronotype-stratified analysis for the association between the BSDS and obesity measures was determined by linear regression. Generally, the evening types had lower adherence to the BSDS and were more often smokers (men), physically inactive and had lower perceived health than the other chronotypes (p < 0.05). The poorer health behavior of this group, however, was not manifested in their obesity measures, and no evidence that the BSDS would mediate the association between chronotype and obesity was found (p > 0.05). No evidence that chronotype would modify the association between the BSDS and obesity was found either (p > 0.05). PMID- 27246116 TI - Effects of Disfluency in Online Interpretation of Deception. AB - A speaker's manner of delivery of an utterance can affect a listener's pragmatic interpretation of the message. Disfluencies (such as filled pauses) influence a listener's off-line assessment of whether the speaker is truthful or deceptive. Do listeners also form this assessment during the moment-by-moment processing of the linguistic message? Here we present two experiments that examined listeners' judgments of whether a speaker was indicating the true location of the prize in a game during fluent and disfluent utterances. Participants' eye and mouse movements were biased toward the location named by the speaker during fluent utterances, whereas the opposite bias was observed during disfluent utterances. This difference emerged rapidly after the onset of the critical noun. Participants were similarly sensitive to disfluencies at the start of the utterance (Experiment 1) and in the middle (Experiment 2). Our findings support recent research showing that listeners integrate pragmatic information alongside semantic content during the earliest moments of language processing. Unlike prior work which has focused on pragmatic effects in the interpretation of the literal message, here we highlight disfluency's role in guiding a listener to an alternative non-literal message. PMID- 27246117 TI - Redox-Triggered Release of Moxifloxacin from Mesoporous Silica Nanoparticles Functionalized with Disulfide Snap-Tops Enhances Efficacy Against Pneumonic Tularemia in Mice. AB - Effective and rapid treatment of tularemia is needed to reduce morbidity and mortality of this potentially fatal infectious disease. The etiologic agent, Francisella tularensis, is a facultative intracellular bacterial pathogen which infects and multiplies to high numbers in macrophages. Nanotherapeutics are particularly promising for treatment of infectious diseases caused by intracellular pathogens, whose primary host cells are macrophages, because nanoparticles preferentially target and are avidly internalized by macrophages. A mesoporous silica nanoparticle (MSN) has been developed functionalized with disulfide snap-tops that has high drug loading and selectively releases drug intracellularly in response to the redox potential. These nanoparticles, when loaded with Hoechst fluorescent dye, release their cargo exclusively intracellularly and stain the nuclei of macrophages. The MSNs loaded with moxifloxacin kill F. tularensis in macrophages in a dose-dependent fashion. In a mouse model of lethal pneumonic tularemia, MSNs loaded with moxifloxacin prevent weight loss, illness, and death, markedly reduce the burden of F. tularensis in the lung, liver, and spleen, and are significantly more efficacious than an equivalent amount of free drug. An important proof-of-principle for the potential therapeutic use of a novel nanoparticle drug delivery platform for the treatment of infectious diseases is provided. PMID- 27246118 TI - Delirium in older adults: a chronic cognitive disorder? AB - Delirium is defined as a neurocognitive disorder characterized by sudden onset, fluctuating course, and disturbances in level of consciousness, attention, orientation, memory, thought, perception, and behavior (American Psychiatric Association, 2013). It occurs in hyperactive, hypoactive, or mixed forms in up to 50% of older hospital patients (Inouye et al., 2014) and 70% of older long-term care residents (McCusker et al., 2011), many with pre-existing dementia (Fick et al., 2002). PMID- 27246119 TI - Estimated incidence of pertussis in people aged <50 years in the United States. AB - The introduction of pertussis vaccination in the United States (US) in the 1940s has greatly reduced its burden. However, the incidence of pertussis is difficult to quantify, as many cases are not laboratory-confirmed or reported, particularly in adults. This study estimated pertussis incidence in a commercially insured US population aged <50 years. Data were extracted from IMS' PharMetrics Plus claims database for patients with a diagnosis of pertussis or cough illness using International Classification of Diseases (ICD-9) codes, a commercial outpatient laboratory database for patients with a pertussis laboratory test, and the Centers for Disease Control influenza surveillance database. US national pertussis incidence was projected using 3 methods: (1) diagnosed pertussis, defined as a claim for pertussis (ICD-9 033.0, 033.9, 484.3) during 2008-2013; (2) based on proxy pertussis predictive logistic regression models; (3) using the fraction of cough illness (ICD-9 033.0, 033.9, 484.3, 786.2, 466.0, 466.1, 487.1) attributed to laboratory-confirmed pertussis, estimated by time series linear regression models. Method 1 gave a projected annual incidence of diagnosed pertussis of 9/100,000, which was highest in those aged <1 year. Method 2 gave an average annual projected incidence of 21/100,000. Method 3 gave an overall regression-estimated weighted annual incidence of pertussis of 649/100,000, approximately 58-93 times higher than method 1 depending on the year. These estimations, which are consistent with considerable underreporting of pertussis in people aged <50 years and provide further evidence that the majority of cases go undetected, especially with increasing age, may aid in the development of public health programs to reduce pertussis burden. PMID- 27246121 TI - The Human and Physical Determinants of Wildfires and Burnt Areas in Israel. AB - Wildfires are expected to increase in Mediterranean landscapes as a result of climate change and changes in land-use practices. In order to advance our understanding of human and physical factors shaping spatial patterns of wildfires in the region, we compared two independently generated datasets of wildfires for Israel that cover approximately the same study period. We generated a site-based dataset containing the location of 10,879 wildfires (1991-2011), and compared it to a dataset of burnt areas derived from MODIS imagery (2000-2011). We hypothesized that the physical and human factors explaining the spatial distribution of burnt areas derived from remote sensing (mostly large fires, >100 ha) will differ from those explaining site-based wildfires recorded by national agencies (mostly small fires, <10 ha). Small wildfires recorded by forestry agencies were concentrated within planted forests and near built-up areas, whereas the largest wildfires were located in more remote regions, often associated with military training areas and herbaceous vegetation. We conclude that to better understand wildfire dynamics, consolidation of wildfire databases should be achieved, combining field reports and remote sensing. As nearly all wildfires in Mediterranean landscapes are caused by human activities, improving the management of forest areas and raising public awareness to fire risk are key considerations in reducing fire danger. PMID- 27246120 TI - Assessment of laparoscopic stomach preserving surgery with sentinel basin dissection versus standard gastrectomy with lymphadenectomy in early gastric cancer-A multicenter randomized phase III clinical trial (SENORITA trial) protocol. AB - BACKGROUND: Along with the marked increase in early gastric cancer (EGC) in the Eastern countries, there has been an effort to adopt the sentinel node concept in EGC to preserve gastric function and reduce the occurrence of postoperative complications. Based on promising results from a previous quality control study, this prospective multicenter randomized controlled phase III clinical trial aims to elucidate the oncologic safety of laparoscopic stomach-preserving surgery with sentinel basin dissection (SBD) compared to a standard laparoscopic gastrectomy. METHODS/DESIGN: This trial is an investigator-initiated, open-label, multicenter randomized controlled phase III trial with a non-inferiority design. Patients diagnosed with a single lesion of clinical stage T1N0M0 gastric adenocarcinoma, with a diameter of 3 cm or less are eligible for the present study. A total of 580 patients (290 per group) will be randomized to either laparoscopic stomach preserving surgery with SBD or standard surgery. The primary end-point is 3-year disease-free survival (DFS) and the secondary endpoints include postoperative morbidity and mortality, quality of life, 5-year DFS, and overall survival. Qualified investigators who completed the prior quality control study are exclusively allowed to participate in this phase III clinical trial. DISCUSSION: The proposed trial is expected to verify whether laparoscopic stomach-preserving surgery with SBD achieves similar oncologic outcomes and improved quality of life compared to a standard gastrectomy in EGC patients. TRIAL REGISTRATION: This study was registered at the NIH ClinicalTrial.gov database ( NCT01804998 ) on March 4th, 2013. PMID- 27246122 TI - [Treatment Strategy for Acute Type B Aortic Dissection with End-organ Malperfusion]. AB - Therapeutic strategies for treating Stanford type B dissection with endo-organ malperfusion remain controversial, and whether surgery or conservative treatment should be performed is a matter of ongoing debate. In this study, we examined the treatment strategies used in cases of malperfusion in which treatment was initiated conservatively at the onset of symptoms without superior mesenteric artery (SMA) or limb artery obstruction. A total of 16 patients had organ ischemia in this series. The obstructed branches were the SMA in 5 patients, the artery of Adamkiewicz in 2, the bilateral renal arteries in 3, the celiac artery in 3 and limb arteries in 3. The surgical procedure included bypass grafting in 2 patients with SMA obstruction and extra-anatomical bypass in 2 patients with limb artery obstruction. A total of 11 patients were treated without surgery. Three patients died, including 2 patients with SMA obstruction. The remaining patient who died had limb artery obstruction and did not undergo surgery. The results suggest that patients with acute type B aortic dissection with endo-organ malperfusion who develop SMA or limb artery obstruction require early surgery. PMID- 27246123 TI - [Effectiveness of Portable Thoracic Drainage Kit for Outpatient Treatment of Spontaneous Pneumothorax]. AB - The demand for outpatient management of spontaneous pneumothorax (SP) has been increased, therefore we evaluated the effectiveness of Thoracic Egg(TE), a portable thoracic drainage kit for SP. We studied 43 SP patients who had received TE treatment between May 2008 and October 2010. Ages were ranged 12~73 years (mean:29.1), with 39 males, 4 females, 25 had primary, 18 had recurrent, pneumothorax. Of the 43 patients, 23 were treated outpatient therapy with TE only, 20 were required hospitalization for persistent air leakage, poor expansion or intent to surgery. Surgical intervention was undergone in 18 patients for persistent air leaks or recurrent pneumothorax. The average length of treatment was 8.4 days for outpatient therapy only cases. Of 25 patients who had primary SP, 18( 72%) were not required hospitalization. Outpatient therapy using TE was considered very useful for SP, especially for primary cases. PMID- 27246124 TI - [Extended Right Pneumonectomy with Partial Resection of the Left Atrium without Cardiopulmonary Bypass]. AB - A 62-year-woman suffered a palpitation for 1 years and was admitted to our hospital with complaints of hemosputum. Chest computed tomography(CT) revealed right hilum tumor diffusely invaded to left atrium. The patient was resected without cardiopulmonary bypass, the interatrial groove (Waterston's or Sondergaard's groove) was carefully dissected and right pneumonectomy with systematic lymph nodes dissection and partial left atrium resection were performed. The posteoperative left atrial volume decreased to half of preoperative volume (from 73 ml to 36 ml) judging from 3D-CT scan. Her postoperative course was uneventful and palpitation, disappeared postoperatively. The histlogical examinarion revealed pleomorphic carcinoma with mediastinal single lymph nodes matastasis (#7), the pathological stage was pT4N2M0. She did not receive adjuvant chemotherapy, but has had no sign of recurrence for 3 years after surgery. PMID- 27246125 TI - [The Use of Octreotide Acetate in the Management of Refractory Chylothorax Following Surgical Treatment for Lung Cancer]. AB - A 78-year-old man underwent right upper lobectomy with systemic lymph node dissection for lung cancer. On the 1st operative day, chylothorax was suspected by a large amount of yellowish-white fluid through the chest tubes. In spite of stopping the oral intake as a conservative therapy, a lot of chylous drainage was continued, and we chose surgical treatment at day 7 after operation, however, chylous discharge did not decrease significantly. Finally we decided to try octreotide administration subcutaneously. After continuous subcutaneous infusion of octreotide, the amount of chylous discharge was reduced dramatically. Then we have done 2 times of pleurodesis with OK-432. The chest tubes were removed at day 17 after the 2nd operation, and the chylothorax was improved. It was suggested that octreotide administration was a highly effective therapy against postoperative refractory chylothorax. PMID- 27246126 TI - [Combined Anterior and Posterior Surgical Approaches for Resection of a 2nd-rib Chondrosarcoma Occupying the Superior Sulcus]. AB - A 77-year-old man with right chest wall chondrosarcoma invading vertebral bodies underwent resection. Computed tomography (CT) showed that the tumor occupied the right superior sulcus, and was close to mediastinal organs including the trachea and esophagus. We adopted a combined anterior and posterior approaches that made safe and curative resection possible. In the anterior approach, we dissected and mobilized the neurovascular structures and neighboring organs from the tumor. A-4 cm gutter on the ventral side of the 1st, 2nd, and 3rd thoracic vertebral bodies was created for safe resection. By the subsequent posterior approach, successful resection was achieved without violating tumor margins. PMID- 27246127 TI - [Ruptured Sinus of Valsalva due to Infective Endocarditis Associated with Ventricular Septal Defect]. AB - Rupture of sinus of Valsalva is a rare entity that occurs as a result of penetrating cardiac trauma or as a complication of infective endocarditis, aneurysm of the sinus of Valsalva, or aortic dissection. A 41-year-old man was admitted to our hospital with continual fever and general fatigue. Streptococcus mutans was detected from his blood cultures. Echocardiography showed perimembranous type ventricular septal defect and right Valsalva- right ventricle fistula. We performed surgery after 4 weeks'administration of antibiotics. After radical debridement, we closed ventricular septal defect and Valsalva-right ventricular fistula with double bovine pericardial patches. Postoperative echocardiography showed no aortic regurgitation or shunt flow. There has been no infection relapse for 2 years since surgery. PMID- 27246129 TI - [Tracheal Resection and Primary Anastomosis for Adenoid Cystic Carcinoma Using an Extracorporeal Membrane Oxygenation]. AB - We report a case of tracheal resection and primary anastomosis for adenoid cystic carcinoma using an extracorporeal membrane oxygenation (ECMO). A 45-year-old female was referred to our hospital because of a tracheal tumor that occupied most of the tracheal lumen. In case of airway obstruction by the tracheal tumor during anesthesia and operation, we decided to use ECMO before induction of general anesthesia. Under secure respiratory control using ECMO, tracheal resection and primary anastomosis was performed. Since histopathological examination revealed microscopically positive results at the surgical margin, postoperative adjuvant radiation therapy( 60 Gy/30 Fr) was conducted. Although a tracheal tumor is a relatively rare neoplasm, careful planning and a treatment strategy are necessary with special emphasis on the location and size of tumor. In this case, ECMO made a substantial contribution to secure respiratory control during surgery. PMID- 27246128 TI - [Emergency Thoracic Endovascular Aortic Repair of Ruptured Kommerell's Diverticulum with an Acute Aortic Dissection]. AB - This case report describes emergency thoracic endovascular aortic repair (TEVAR) of a ruptured Kommerell's diverticulum associated with a type B acute aortic dissection in a patient with a right aortic arch. A 64-year-old male was admitted with symptoms of sudden paraplegia and shock. The computed tomography imaging showed right aortic arch anomaly, with mirror image branching of the major arteries. The aorta was dissected from the origin of the right subclavian artery to the terminal aorta, with a thrombosed false lumen. Rupture was found in a 6.3 cm aneurysm located in the distal arch, which was diagnosed as Kommerell's diverticulum. We performed emergency TEVAR, and the aneurysm was successfully excluded using deployment of a Gore Tag stent-graft. At 3 months' follow-up, the patient was doing well and showed shrinkage of the aneurysm was confirmed. TEVAR is considered to be a suitable procedure for an emergency aortic catastrophe even in patients with aortic anomaly. PMID- 27246130 TI - [Intrapulmonary Sewing Needle]. AB - Intrapulmonary aberrant needles are rarely encountered in clinical practice. A 82 year-old woman, though she was asymptomatic, was referred to our department due to an abnormal shadow on a chest X-ray. Chest X-ray and chest computed tomography showed a foreign body suspected to be a sewing needle in the left upper lobe. The needle was successfully removed by video-assisted thoracoscopic surgery. PMID- 27246131 TI - [Pneumomediastinum Due to the Fracture of the Maxillary Antrum]. AB - A 47-year-old man was admitted to the emergency room, half a day after having fallen down on his right cheek drunkenly onto a concrete block. Physical examination revealed that the contusion was limited to the right side of his face, only around the cheek, without trauma to the neck, chest or abdomen. But wide ranging tactile crepitus with severe swelling was present on his face and neck due to widely spread emphysema. Computed tomography (CT) scan revealed some fractures of maxillary antrum, facial and cervical emphysema spreading to the lower part of mediastinum. After a conservative treatment, he recovered without any severe systematic complication. It was found that the facial and cervical emphysema and pneumomediastimum completely disappeared on the follow-up CT scan, 18 days after the event. PMID- 27246132 TI - [Unicuspid Aortic Valve Stenosis Combined with Aortic Coarctation;Report of a Case]. AB - Unicuspid aortic valve in an adult is extremely rare. In addition, 90% of the patients with aortic coarctation are reported to die before the age 50. A 60-year old woman was admitted to our hospital for further examination of exertional dyspnea which had begun one year before. She had been under medical treatment for hypertension since early thirties, and had been also diagnosed with moderate aortic stenosis at 50 years of age. She was at 1st diagnosed with aortic coarctation combined with bicuspid aortic valve stenosis. The aortic valve was then found unicuspid and was replaced under cardiopulmonary bypass with perfusion to both the ascending aorta and the femoral artery. Repair of aortic coarctation was performed 3 months later through left thoracotomy without extracorporeal circulation due to the rich collateral circulation. She had no postoperative complications, and hypertension as well as ankle-brachial index improved to the normal levels. PMID- 27246133 TI - [Quadricuspid Aortic Valve with Aortic Regurgitation;Report of a Case]. AB - A 65-year-old woman was admitted due to electrocardiographic abnormality and exertional dyspnea. Transthoracic echocardiography revealed quadricuspid aortic valve malformation with severe aortic regurgitation. All 4 cusps were of equal size, and the quadricuspid valve was classified as type a by Hurwitz classification. We replaced it with an 18 mm mechanical valve and her postoperative course was uneventful. PMID- 27246134 TI - [Total Endoscopic Left Atrial Appendectomy for Valvular Atrial Fibrillation;Report of a Case]. AB - Total endoscopic left atrial appendectomy for non-valvular atrial fibrillation(Af) has been reported to be a safe and effective procedure to prevent cardiogenic thromboembolism and also discontinue oral anticoagulant therapy. On the other hand, open-heart surgery is generally indicated for valvular Af. We report the case of a 67-year-old male patient with valvular Af and recurrent episodes of cardiogenic thromboembolism who underwent total endoscopic left atrial appendectomy. He was diagnosed as having mitral valve stenosis and scheduled for surgery, but presented with cerebellar hemorrhage after warfarin was replaced with heparin in the preoperative phase. Consequently, the operation was cancelled. The case was considered as a good relative indication for total endoscopic left atrial appendectomy, which does not need a cardiopulmonary bypass, to prevent future cardiogenic thromboembolism. The operation was performed and the postoperative course was uneventful. PMID- 27246135 TI - [Incomplete Surgical Resection of a Right Ventricular Hemangioma with Asymptomatic Gradual Enlargement for more than a Decade;Report of a Case]. AB - We encountered a case of a cardiac hemangioma protruding into the inner cavity of the right ventricle from the right ventricular free wall. The tumor gradually enlarged over 11 years (from 35 mm to 78mm) without presenting any symptoms. However, when it extended to the right ventricular outflow tract, non-sustained ventricular tachycardia occurred, and emergency surgery was required. The tumor was diagnosed as a cavernous benign hemangioma. Complete resection was not possible, and the part involving the right ventricle remained. This residual tumor caused postoperative ventricular arrhythmia, and an implantable cardioverter defibrillator was required. We concluded that non-surgically treated cardiac hemangiomas carry the risk of non-resectability, regardless of malignancy. PMID- 27246136 TI - [Total Aortic Arch Replacement by Minimally Invasive Approach in a Patient with Permanent Tracheostomy;Report of a Case]. AB - Standard full median sternotomy for total aortic arch replacement in patients with tracheostomy has higher risks for mediastinitis and graft infection. To avoid surgical site infection, it is necessary to keep a sufficient distance between the tracheostomy and the site of surgical skin incision. We herein report a case of a 74-year-old man with permanent tracheostomy after total laryngectomy, who underwent total aortic arch replacement for an aneurysm. Antero-lateral thoracotomy in the 2nd intercostal space with lower partial sternotomy( ALPS approach) provided an enough distance between the tracheostomy and the surgical field. It also provided a good view for surgical procedure and enabled the standard setup of cardiopulmonary bypass with ascending aortic cannulation, venous drainage from the right atrium and the left ventricular venting through the upper right pulmonary vein. The operation was completed in 345 minutes and the patient was discharged on the 11th postoperative day without any complications. PMID- 27246137 TI - [Primary Synovial Sarcoma in the Anterior Mediastinum;Report of a Case]. AB - We report a rare case of synovial sarcoma in the anterior mediastinum. A 43-year old man consulted our hospital with a complaint of dyspnea and chest discomfort. Chest computed tomography revealed an anterior mediastinal mass. Small open biopsy was performed, and the pathological examination revealed spindle-shaped cells with severe atypia. Tumor resection was performed. On pathology, fascicular and storiform patterns of spindle-shaped cells with severe atypia were noted. The tumor cells were positive for cytokeratin 7, vimentin, Bcl -2 and CD99, and the amplification of SYT-SSX fusion gene was also found. Therefore it was diagnosed as a synovial sarcoma. PMID- 27246138 TI - Changes in enjoyment, self-efficacy, and motivation during a randomized trial to promote habitual physical activity adoption in bariatric surgery patients. AB - BACKGROUND: The Bari-Active trial found that a physical activity (PA) intervention (PAI), versus standard presurgical care control (SC), produced significant increases in daily bout-related moderate-to-vigorous PA (MVPA, in>=10 min bouts) preoperatively. The present study examined whether PAI also produces superior improvements in psychological and/or motivational processes that may be important for PA adoption. OBJECTIVES: Compare PAI and SC on baseline to postintervention changes in PA-related enjoyment, self-efficacy, and motivations, and examine whether greater bout-related MVPA changes are associated with greater improvements in these variables. SETTING: University hospital, United States. METHODS: Participants (87% female; body mass index = 45.0+/-6.5 kg/m(2)) were randomly assigned to 6 weeks of PAI (n = 40) or SC (n = 35). PAI received weekly counseling sessions to increase daily walking exercise. At baseline and postintervention, both groups completed 7-day objective PA monitoring and questionnaires to evaluate changes in bout-related MVPA and PA enjoyment, self efficacy, and motivation. RESULTS: Retention was 84% at postintervention. Intent to-treat analyses showed that PAI on average reported more favorable changes than SC in PA enjoyment, self-efficacy, amotivation (i.e., lack of PA motivation), and identified and intrinsic regulations (i.e., more autonomous PA motivations; P<.01). In PAI completers (n = 33), changes in bout-related MVPA and psychological/motivational variables were unrelated. CONCLUSION: PAI produced greater improvements in PA-related enjoyment, self-efficacy, and motivations than SC. The lack of association between objectively measured PA changes and psychological/motivational processes highlights the need for future research to identify which processes are most important for PA adoption and maintenance in bariatric surgery patients, and to determine whether the method used to measure PA affects the pattern of association. PMID- 27246139 TI - Heart failure epidemiology 2000-2013: insights from the German Federal Health Monitoring System. AB - AIMS: Considerable differences in the long-term trends of heart failure (HF) exist between different countries. To extend the existing knowledge on HF epidemiology in Germany, we analysed trends of HF-related hospitalizations, hospital days and in-hospital deaths during a 14-year period (2000-2013). METHODS AND RESULTS: Data were derived from the official German Federal Health Monitoring System, which includes an annual and complete enumeration of inpatients at the time of discharge from the hospital. HF cases were identified by the primary diagnosis code for HF (I50). From 2000 to 2013, the absolute number of HF-related hospitalizations increased by 65.4% (239 694-396 380 cases) and by 28.4% after age-standardization (261-335 per 100 000 population). Accordingly, the absolute number of HF-related hospital days increased by 22.1% (3.4-4.2 million hospital days), despite a marked decrease by 25.9% in average length of stay (14.3-10.6 days). With approximately 35 000 in-hospital deaths (~45 per 100 000 population), the annual number of HF-related in-hospital deaths remained consistently high, and in-hospital mortality rate in HF patients constituted 9.3% in 2013. Patients aged >65 years were disproportionately affected. In 2013, HF was the leading cause of disease-related hospitalizations and in-hospital deaths, representing 2.1% and 8.8% of all cases, respectively. CONCLUSION: In Germany, the burden of HF is growing further, and the risk of death in HF remains high. These trends can only be partly attributed to demographic developments suggesting an exigent need for increased awareness and enhanced efforts in the prevention and management of HF. PMID- 27246141 TI - Circulating microRNAs as biomarkers in progressive multiple sclerosis. AB - BACKGROUND: In multiple sclerosis (MS), microRNA (miRNA) dysregulation is mostly reported in different immune cells, but less information is available on circulating miRNAs that exert strong biomarker potential due to their exceptional stability in body fluids. OBJECTIVE: The aim of this study was to profile expression of circulating miRNAs in primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS) and assess their association with neurological worsening. METHODS: The expressions of 84 different miRNAs were profiled in serum of 83 subjects (62 MS and 21 controls) using miScript miRNA techniques. First, they were screened on 18 PPMS and 10 controls; thereafter, 10 most aberrantly expressed miRNAs were validated on a larger cohort. RESULTS: In comparison with controls, upregulation of miR-191-5p was found in both progressive MS subtypes, while miR-376c-3p was overexpressed only in PPMS. Additionally, upregulation of miR-128-3p and miR-24-3p was detected in PPMS when compared to controls and SPMS. Progression index correlated with miR-128-3p in PPMS and miR-375 in SPMS. CONCLUSION: We detected overexpression of four miRNAs that have not been previously associated with progressive forms of MS. The increased expression of circulating miR-191-5p seems to be associated with progressive forms of MS, while miR-128-3p seems to be associated mostly with PPMS. PMID- 27246140 TI - Volume-Outcome Relationships in Pediatric Acute Lymphoblastic Leukemia: Association Between Hospital Pediatric and Pediatric Oncology Volume With Mortality and Intensive Care Resources During Initial Therapy. AB - BACKGROUND: There are few contemporary studies of volume-outcome relationships in pediatric oncology. Children with acute lymphoblastic leukemia (ALL) are treated at a wide variety of hospitals. We investigated if inpatient hospital volume influences outcomes. The objective of this study was to evaluate the relationship between inpatient pediatric and pediatric oncology volume and mortality and intensive care resources (ICU care). We hypothesized an inverse relationship between volume and these outcomes. PATIENTS AND METHODS: This was a retrospective cohort study. Patients 0 to 18 years of age in the Pediatric Health Information System or Perspective Premier Database from 2009 to 2011 with ALL were included. Exposures were considered as the average inpatient pediatric and pediatric oncology volume. The primary outcome was inpatient mortality; secondary outcome was need for ICU care. RESULTS: The included population comprised 3350 patients from 75 hospitals. The inpatient mortality rate was 0.86% (95% confidence interval, 0.58%-1.2%). In the unadjusted analysis, mortality increased as pediatric oncology volume increased from low (0%) to high volume (1.3%) (P = .009). The small number of deaths precluded multivariable analysis of this outcome. Pediatric and pediatric oncology volume was not associated with ICU care when we controlled for potential confounders. CONCLUSION: Induction mortality was low. We did not observe an inverse relationship between volume and mortality or ICU care. This suggests that in a modern treatment era, treatment at a low-volume center might not be associated with increased mortality or ICU care in the first portion of therapy. This relationship should be evaluated in other oncology populations with higher mortality rates and with longer-term outcomes. PMID- 27246142 TI - Brain atrophy after bone marrow transplantation for treatment of multiple sclerosis. AB - BACKGROUND: A cohort of patients with poor-prognosis multiple sclerosis (MS) underwent chemotherapy-based immune ablation followed by immune reconstitution with an autologous hematopoietic stem cell transplant (IA/aHSCT). This eliminated new focal inflammatory activity, but resulted in early acceleration of brain atrophy. OBJECTIVE: We modeled the time course of whole-brain volume in 19 patients to identify the baseline predictors of atrophy and to estimate the average rate of atrophy after IA/aHSCT. METHODS: Percentage whole-brain volume changes were calculated between the baseline and follow-up magnetic resonance imaging (MRI; mean duration: 5 years). A mixed-effects model was applied using two predictors: total busulfan dose and baseline volume of T1-weighted white matter lesions. RESULTS: Treatment was followed by accelerated whole-brain volume loss averaging 3.3%. Both the busulfan dose and the baseline lesion volume were significant predictors. The atrophy slowed progressively over approximately 2.5 years. There was no evidence that resolution of edema contributed to volume loss. The mean rate of long-term atrophy was -0.23% per year, consistent with the rate expected from normal aging. CONCLUSION: Following IA/aHSCT, MS patients showed accelerated whole-brain atrophy that was likely associated with treatment-related toxicity and degeneration of "committed" tissues. Atrophy eventually slowed to that expected from normal aging, suggesting that stopping inflammatory activity in MS can reduce secondary degeneration and atrophy. PMID- 27246143 TI - Increased structural white and grey matter network connectivity compensates for functional decline in early multiple sclerosis. AB - BACKGROUND: The pathology of multiple sclerosis (MS) consists of demyelination and neuronal injury, which occur early in the disease; yet, remission phases indicate repair. Whether and how the central nervous system (CNS) maintains homeostasis to counteract clinical impairment is not known. OBJECTIVE: We analyse the structural connectivity of white matter (WM) and grey matter (GM) networks to understand the absence of clinical decline as the disease progresses. METHODS: A total of 138 relapsing-remitting MS patients (classified into six groups by disease duration) and 32 healthy controls were investigated using 3-Tesla magnetic resonance imaging (MRI). Networks were analysed using graph theoretical approaches based on connectivity patterns derived from diffusion-tensor imaging with probabilistic tractography for WM and voxel-based morphometry and regional volume-correlation matrix for GM. RESULTS: In the first year after disease onset, WM networks evolved to a structure of increased modularity, strengthened local connectivity and increased local clustering while no clinical decline occurred. GM networks showed a similar dynamic of increasing modularity. This modified connectivity pattern mainly involved the cerebellum, cingulum and temporo parietal regions. Clinical impairment was associated at later disease stages with a divergence of the network patterns. CONCLUSION: Our findings suggest that network functionality in MS is maintained through structural adaptation towards increased local and modular connectivity, patterns linked to adaptability and homeostasis. PMID- 27246144 TI - Enhancing Tumor Cell Response to Chemotherapy through the Targeted Delivery of Platinum Drugs Mediated by Highly Stable, Multifunctional Carboxymethylcellulose Coated Magnetic Nanoparticles. AB - The fabrication of nanoparticles using different formulations, and which can be used for the delivery of chemotherapeutics, has recently attracted considerable attention. We describe herein an innovative approach that may ultimately allow for the selective delivery of anticancer drugs to tumor cells by using an external magnet. A conventional antitumor drug, cisplatin, has been incorporated into new carboxymethylcellulose-stabilized magnetite nanoparticles conjugated with the fluorescent marker Alexa Fluor 488 or folic acid as targeting agent. The magnetic nanocarriers possess exceptionally high biocompatibility and colloidal stability. These cisplatin-loaded nanoparticles overcome the resistance mechanisms typical of free cisplatin. Moreover, experiments aimed at the localization of the nanoparticles driven by an external magnet in a medium that mimics physiological conditions confirmed that this localization can inhibit tumor cell growth site-specifically. PMID- 27246145 TI - Probing local and electronic structure in Warm Dense Matter: single pulse synchrotron x-ray absorption spectroscopy on shocked Fe. AB - Understanding Warm Dense Matter (WDM), the state of planetary interiors, is a new frontier in scientific research. There exists very little experimental data probing WDM states at the atomic level to test current models and those performed up to now are limited in quality. Here, we report a proof-of-principle experiment that makes microscopic investigations of materials under dynamic compression easily accessible to users and with data quality close to that achievable at ambient. Using a single 100 ps synchrotron x-ray pulse, we have measured, by K edge absorption spectroscopy, ns-lived equilibrium states of WDM Fe. Structural and electronic changes in Fe are clearly observed for the first time at such extreme conditions. The amplitude of the EXAFS oscillations persists up to 500 GPa and 17000 K, suggesting an enduring local order. Moreover, a discrepancy exists with respect to theoretical calculations in the value of the energy shift of the absorption onset and so this comparison should help to refine the approximations used in models. PMID- 27246146 TI - Patients embodied and as-a-body within bedside teaching encounters: a video ethnographic study. AB - Bedside teaching encounters (BTEs) involve doctor-patient-student interactions, providing opportunities for students to learn with, from and about patients. How the differing concerns of patient care and student education are balanced in situ remains largely unknown and undefined. This video ethnographic study explores patient involvement during a largely student-centric activity: 'feedback sequences' where students learn clinical and practical skills. Drawing on a data subset from a multi-site study, we used Conversation Analysis to investigate verbal and non-verbal interactional practices to examine patients' inclusion and exclusion from teaching activities across 25 BTEs in General Practice and General Surgery and Medicine with 50 participants. Through analysis, we identified two representations of the patient: the patient embodied (where patients are actively involved) and the patient as-a-body (when they are used primarily as a prop for learning). Overall, patients were excluded more during physical examination than talk-based activities. Exclusion occurred through physical positioning of doctor patient-student, and through doctors and students talking about, rather than to, patients using medical jargon and online commentaries. Patients' exclusion was visibly noticeable through eye gaze: patients' middle-distance gaze coincided with medical terminology or complex wording. Inclusory activities maintained the patient embodied during teaching activities through doctors' skilful embedding of teaching within their care: including vocalising clinical reasoning processes through students, providing patients with a 'warrant to listen', allocating turns at-talk for them and eye-contact. This study uniquely demonstrates the visible nature patient exclusion, providing firm evidence of how this affects patient empowerment and engagement within educational activities for tomorrow's doctors. PMID- 27246148 TI - Contributions of Physical Therapists to Primary Preventive Health Care. AB - The limitations of what physical therapists can differ from country to country. In Japan, physical therapists are national licensed health care professionals who can help patients improve or restore their mobility. Most Japanese physical therapists provide care for people in health care facilities, medical-welfare transitional facilities, and welfare facilities for the elderly. Currently, physical therapists are unable to sufficiently contribute to primary preventive health care in Japan. However, there are many health problems that physical therapists could help alleviate. For example, low back pain (LBP) more likely than any other condition prevents people from working; thus, making the establishment of effective measures to prevent and reduce LBP vital. An estimated 20,500,000 Japanese individuals have diabetes mellitus (DM) or are at a high risk of developing the disease. DM commonly accompanies stroke and/or heart disease, and is characterized by complications that result from chronic hyperglycemia. Evidence-based physical therapy is effective for the prevention and treatment of LBP and DM. The Japanese Physical Therapy Association established the Japanese Society of Physical Therapy (JSPT) in June 2013. The JSPT has 12 departmental societies and 10 sections. We believe that the JSPT will advance the study of the potential role of physical therapists in primary preventive health care. In the future, it is expected that Japanese physical therapists will contribute to primary preventive health care. PMID- 27246147 TI - Development and Evaluation of a Rapid and Sensitive EBOV-RPA Test for Rapid Diagnosis of Ebola Virus Disease. AB - Confirming Ebola virus disease (EVD), a deadly infectious disease, requires real time RT-PCR, which takes up to a few hours to yield results. Therefore, a rapid diagnostic assay is imperative for EVD diagnosis. A rapid nucleic acid test based on recombinase polymerase amplification (EBOV-RPA) was developed to specifically detect the 2014 outbreak strains. The EBOV-RPA assay was evaluated by testing samples from suspected EVD patients in parallel with RT-PCR. An EBOV-RPA, which could be completed in 20 min, was successfully developed. Of 271 patients who tested positive for Ebola virus by RT-PCR, 264 (sensitivity: 97%, 95% CI: 95.5 99.3%) were positive by EBOV-RPA; 101 of 104 patients (specificity: 97%, 95% CI: 93.9-100%) who tested negative by RT-PCR were also negative by EBOV-RPA. The sensitivity values for samples with a Ct value of <34, which accounted for 95.59% of the samples, was 100%. Discordant samples positive by RT-PCR but negative by EBOV-RPA had significantly high Ct values. Results of external quality assessment samples with EBOV-RPA were 100%, consistent with those of RT-PCR. The EBOV-RPA assay showed 97% sensitivity and 97% specificity for all EVD samples tested, making it a rapid and sensitive test for EVD diagnosis. PMID- 27246149 TI - Physical Therapy for Musculoskeletal Disorders of Workers: Role of Physical Therapists in Occupational Health. AB - Musculoskeletal disorders in workers decrease the productivity of companies and result in socioeconomic losses. Low back pain accounted for approximately 60% of occupational diseases in the past and this is still true at present, making it a major occupational health problem in Japan. Herein, the findings about low back pain are explained as follows: the correlation between imaging examination findings and low back pain is low; psychosocial factors are involved in the onset of low back pain and how it becomes chronic; and improvement of activity is more useful than rest. Furthermore, the advantages of employing physical therapists for improving occupational health are as follows: they can 1) evaluate and intervene ergonomically; 2) provide instructions using a behavioral modification technique based on psychosocial factors; and 3) provide instructions regarding exercise programs considering obstacles to the development of a good exercise habit (painful diseases including osteoarthritis and other diseases such as hypertension and diabetes). In addition, falling, whose incidence has recently been increasing and is an important issue in occupational health, is examined from the aspect of musculoskeletal disorders. The following activities of physical therapists are introduced: the items to be checked during a tour of inspection of a workplace and detailed descriptions of work management and working environment management measures. Physical therapists are rarely involved in studies of low back pain and falling, but their knowledge and skills have been demonstrated to contribute to improving occupational health. PMID- 27246150 TI - Physical Therapy for Metabolic Syndrome Prevention in Workers: Novel Role of Physical Therapist. AB - In Japan, physical therapists have usually been involved in physical therapy for patients with functional disorders associated with cerebrovascular or orthopedic diseases in hospitals. With the aging of Japanese society, the number of diseased people will progressively increase; thus, it is important to pay much more attention to disease prevention. In this regard, physical therapists are expected to play a new role in the field of preventive medicine. Metabolic syndrome or central obesity with multiple cardiometabolic risks is associated with a high risk of type 2 diabetes or cardiovascular diseases and is now a central target for early detection and intervention for disease prevention. The incidence of metabolic syndrome increases with age, and men showed a higher incidence of metabolic syndrome than women in all generations. We have been involved in the guidance of workers with metabolic syndrome for a long time, and we conducted a multicenter study to establish effective guidance for these worker. In this paper, we will use our evidence to discuss the role of physical therapists in providing guidance for preventing metabolic syndrome. We are now conducting worksite supporting exercise intervention for workers who were resistant to conventional lifestyle guidance. In addition, the unique role of physical therapists in this new trial will be introduced. PMID- 27246151 TI - Role of Physical Therapists in Health Care of the Elderly. AB - Japan is one of the leading countries worldwide in terms of longevity. However, with the increase in the elderly population, the number of individuals requiring some type of daily living assistance has currently exceeded 6 million. Cerebrovascular disease is the main reason for the requirement of care among the elderly. However, individuals in the late old age (>=75 years)-the number of which is rapidly increasing-also experience problems related to the functional decline of their musculoskeletal system, owing to age-related frailty and falls/fractures. Increasing the amount of physical activity not only helps prevent the onset of lifestyle-related diseases, but can also prevent the age related decline in motor function. Hence, elderly individuals should perform exercises for health promotion and preventative care. However, as the physical functions and chronic diseases differ among individuals, it appears that the exercise programs offered as part of primary and secondary prevention programs may not be effective. Hence, physical therapists should play a large role in establishing appropriate and individualized exercise programs, as they have considerable experience in providing exercise therapy in the context of medical care for elderly people with varying conditions and risks. PMID- 27246152 TI - Survey on the Awareness of Genetic Testing in Japanese Workers: The Effect of Participant Characteristics on Awareness. AB - OBJECTIVES: The objectives of this study were to assess the possibility of utilization of genetic testing and to determine the effect of participant characteristics on genetic testing awareness in Japanese workers. METHODS: The subjects of this study consisted of 998 workers from two companies located in Kyusyu, Japan, from June to July, 2014. We examined the participant characteristics and genetic testing awareness using paper questionnaires. Ultimately, the data from 737 subjects (73.8%) was included in our analysis. RESULTS: Regarding participant characteristics, the percentage of respondents who replied "I have heard of genetic testing" (including knowledge about genetic testing) and "I would like to have genetic testing" were 82.5% and 58.2%, respectively. A significant age difference in genetic testing awareness was also observed in our study. Logistic regression analysis revealed both significant adjust odds ratios (ORs) of 3.02 (95% CI 1.67-5.46) and 3.82 (95% CI 1.71-8.53) in the 40-49-year-old group and the over 50 year old group, respectively, compared with the 20-29-year-old group. In addition, females and the participants who graduated from graduate schools showed greater interest in genetic testing. CONCLUSIONS: This survey showed that about 80% of Japanese workers know about genetic testing and about 60% would like to have a test. The results of our survey also suggest that the awareness of genetic testing is influenced by participant characteristics, namely age, sex, and education. PMID- 27246153 TI - Genetic and Environmental Risk Factors, Sleeping Environment, for Allergic Diseases in Infant: Analysis of a Data Subset from the South Kyushu and Okinawa Study Area of Japan Environment and Children's Study. AB - OBJECTIVES: The incidence of infant allergic diseases have increased recently, and it may be caused by multiple influences of both genetic and environmental factors from the fetal stage through infancy. In this study, we analyzed a data subset from the South Kyushu and Okinawa (SKO) Study Area of Japan Environment and Children's Study (JECS) to determine the relationship of allergic diseases in infants with mothers' characteristics and/or infants' life habits, especially sleeping. METHODS: A total of 3873 mother-infant pairs from the SKO Regional Center of JECS were included. The mothers responded to questionnaires in the first trimester of their pregnancy and the self-reported questionnaire when their infants were 1 year old. Student's t-test, chi-square test, trend test, and logistic regression analysis were carried out to analyze the associations between the infants' allergic diseases and the mothers' genetic characteristics and/or sleeping habits of infants. RESULTS: Maternal allergic diseases were significantly associated with increased infant allergy risk (OR: 1.93, 95% CI: 1.63-2.27). The number of allergic diseases of mothers was also significantly associated with infant allergy, and the trend test showed an increasing risk of infant allergy (p<0.001). Regarding infants' life habits, the infants who sleep in the prone position had a higher allergic disease risk than those who sleep in other positions (OR: 1.46, 95% CI: 1.17-1.83). These significant associations were observed regardless of the presence of allergy in mothers. CONCLUSIONS: This study suggests that the development of allergic diseases in infants may be caused by the multiple participation of both genetic and environmental factors. PMID- 27246154 TI - Type Classification Based on Inpatient Ratio According to Major Diagnosis Category of Group III in the Diagnosis Procedure Combination System. AB - OBJECTIVES: The target was 1,283 hospitals in group III of medical institutions. Using the Diagnosis Procedure Combination (DPC) data and the inpatient ratio according to the major diagnosis category (MDC), group III hospitals were clarified on the basis of the Mahalanobis distance (D(2)) calculated using the Mahalanobis.Taguchi (MT) method. METHODS: About 50 hospitals with the top inpatient ratio in each MDC and 1,233 other hospitals. The following were examined. 1) Significant difference between DPC data and inpatient ratio. 2) Distribution of D(2). 3) Classification based on the distribution of D(2). RESULTS: The top hospital was small scale, and there were few cases of emergency hospitalization, operation, general anesthesia induction, and chemotherapy. The number of cases involving the respiratory system, circulatory system, digestive and hepatobiliary systems, metabolic system, muscloskeletal system, kidney and urinary tracts was high with an inpatient ratio of more than 90%. On the bases of the distribution of D(2), the hospitals were classified into four types. Group one consisted of 213 special hospitals that showed high inpatient ratios of cases involving the nervous system, respiratory system, digestive and hepatobiliary systems, muscloskeletal system, injuries and burns. Group two consisted of 195 associate special hospitals that showed high inpatient ratios of cases involving the circulatory organ, metabolic system, kidney and urinary tracts, pediatric diseases, and mental diseases. Group three consisted of 223 hospitals for the seven remaining diseases. Group four consisted of 652 hospitals showing other distributions of D(2). CONCLUSION: Classification of hospitals to four types was possible by the MT method depending on the medical treatment results. PMID- 27246155 TI - Quality of Life and Its Related Factors in Female Postoperative Breast Cancer Patients Younger than 50 Years. AB - OBJECTIVES: Few reports on breast cancer patients have focused on the younger ages at which breast cancer morbidity increases. The purpose of this study was to clarify the quality of life (QOL) and its related factors in female postoperative breast cancer patients younger than 50 years. METHODS: A total of 166 (valid rate 57.8%) female postoperative patients were administered a questionnaire anonymously answered at their outpatient clinics specializing in breast cancer. QOL was evaluated using the QOL Questionnaire for Cancer Patients Treated with Anticancer Drugs (QOL-ACD). Multiple regression analysis of 13 items that showed a significant difference in the total points of QOL-ACD was performed with categories as independent variables and the total points of QOL-ACD as a dependent variable. RESULTS: The mean age of the subjects was 43.6 years. The median total points of QOL-ACD was 88. The multiple regression analysis showed the following seven factors were related to the total points of QOL-ACD: ability to fulfill roles in the family, no symptoms, no financial difficuies, requiring no support at hospital visit, the use of many kinds of stress-coping methods, taking no medication for diseases other than cancer, and not unsatisfied with the scars and shape of breasts. CONCLUSION: The QOL of young, postoperative breast cancer patients was lower than that of the patient groups that included older subjects. To improve their QOL, it is important to provide social support for their family roles and economic situations, in addition to physical and psychological support based on the characteristics of the disease. PMID- 27246156 TI - Role of the Occupational Physician in Corporate Management of Health Risks: An Important Aspect of Corporate Social Responsibility (CSR). AB - INTRODUCTION: There are various risks involved in corporate activities conducted both within and outside the corporation. Among these, health risks are very important and should be managed effectively as an integral part of corporate social responsibility (CSR). A corporation is responsible for health impairments caused by its activities and suffers great moral and economic loss when they occur. It is essential that corporate management takes proper preventive measures against such risks. Occupational physicians possess substantial knowledge of health risks in corporations. In this study, we examine the role of occupational physicians in the management of corporate health risks. METHOD: Information was obtained from articles in print and on the Internet. RESULTS AND DISCUSSION: Health risks due to corporate activities involve not only the employees of the corporation but also individuals outside the corporation. Each corporation should effectively use available resources to manage health risks. Occupational physicians are one such valuable resource. However, many corporations do not actively involve occupational physicians in health risk management. According to a current Japanese law, health risks for employees in corporations are managed by occupational physicians, but in general, health risks outside corporations are not. The 1984 Bhopal Disaster in India is an example in which physicians of the corporation were only minimally, if at all, involved in assessing and treating impaired health outside the corporation. The role of occupational physicians should be expanded to include management of health risks outside the corporation. This places a greater burden on the physicians and they must make the effort to train in many academic fields in order to better understand the entire context of health risks due to corporate activities. Some occupational physicians may be hesitant to take on such added responsibilities. Some corporations may not recognize the overall health risks due to its activities and do not understand the merit of occupational physicians working with the management to decrease health risks. However, an occupational physician is an important member of the corporation, so he/she must be involved in the management of health risks not only within the corporation itself, but also outside the corporation from the viewpoint of CSR. Effective management of health risks due to corporate activities should be widely discussed among occupational physicians, business entrepreneurs and managers of the division in charge of corporate health risk management as well as stakeholders. The authors propose expanding the role of occupational physicians to actively manage health risks not only inside but also outside the corporations. PMID- 27246157 TI - To the memory of the late Dr. Ichiro Hara. PMID- 27246158 TI - Editor's Note. PMID- 27246159 TI - Assessment of penetrant and vehicle mixture properties on transdermal permeability using a mixed effect pharmacokinetic model of ex vivo porcine skin. AB - The accurate prediction of the rate and extent of transdermal absorption from topical exposure to chemical mixtures would be beneficial in risk assessment and drug delivery applications. The isolated perfused porcine skin flap (IPPSF) has been used as an ex vivo model for assessing transdermal absorption from topical exposures. A mixed effect, pharmacokinetic tissue model was used to model finite dose, transdermal, absorption data from IPPSF experiments for 12 penetrants dosed in up to 10 different vehicles. The model was able to identify permeability constant, while accounting for between and within unit variability, across the entire data set. This approach provides a platform for exploring the relationship between covariates (chemical descriptors and functions thereof) and the model parameters. Successive models were employed that reduced the overall variability in the parameter estimate by modeling the parameters as functions of the covariates. Log kp was initially modeled as a function of LogP and MW of the pure penetrant (adjusted r2 = 0.48). The addition of mixture factors to account for the different dosing vehicles further improved the relationship: to r2 = 0.56 with Connolly molecular area (CMA) and r2 = 0.78 with the further addition of total polar surface area difference (TPSAd). The pharmacokinetic model and quantitative structure property relationship (QSPR) developed for the IPPSF may be relevant to clinical transdermal formulation development. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27246160 TI - High-Efficiency Nonfullerene Polymer Solar Cell Enabling by Integration of Film Morphology Optimization, Donor Selection, and Interfacial Engineering. AB - Carrier mobility is a vital factor determining the electrical performance of organic solar cells. In this paper we report that a high-efficiency nonfullerene organic solar cell (NF-OSC) with a power conversion efficiency of 6.94 +/- 0.27% was obtained by optimizing the hole and electron transportations via following judicious selection of polymer donor and engineering of film-morphology and cathode interlayers: (1) a combination of solvent annealing and solvent vapor annealing optimizes the film morphology and hence both hole and electron mobilities, leading to a trade-off of fill factor and short-circuit current density (Jsc); (2) the judicious selection of polymer donor affords a higher hole and electron mobility, giving a higher Jsc; and (3) engineering the cathode interlayer affords a higher electron mobility, which leads to a significant increase in electrical current generation and ultimately the power conversion efficiency (PCE). PMID- 27246161 TI - Estimation of illicit drug use in the main cities of Colombia by means of urban wastewater analysis. AB - Wastewater-based epidemiology (WBE) relies on the principle that traces of compounds, which a population is exposed to or consume, are excreted unchanged or as metabolites in urine and/or feces, and ultimately end up in the sewer network. Measuring target metabolic residues i.e. biomarkers in raw urban wastewater allows identifying the exposure or use of substances of interest in a community. Up to date, the most popular application of WBE is the estimation of illicit drug use and studies have been made mainly across Europe, which has allowed estimating and comparing drug use in many European cities. However, until now a comprehensive study applying WBE on the most frequently consumed illicit drugs has not been performed in South American countries. In this work, we applied this approach to samples from Colombia, selecting two of the most populated cities: Bogota and Medellin. Several biomarkers were selected to estimate drug use of cocaine, cannabis, amphetamine, methamphetamine, MDMA (ecstasy), heroin and ketamine. Composite samples (24-h) were collected at the corresponding municipal wastewater treatment plants. Sample treatment was performed at location by applying solid-phase extraction (SPE). Before SPE, the samples were spiked with appropriate isotope labeled internal standards. In parallel, samples (spiked with the analytes under study at two concentration levels) were also processed for quality control. Analysis of influent wastewater was made by liquid chromatography-tandem mass spectrometry, with triple quadrupole analyzer. Data shown in this paper reveal a high use of cocaine by the population of the selected Colombian cities, particularly from Medellin, while the use of other illicit drugs were low. The relevance of using quality control samples, particularly in collaborative studies, as those presented in this work, where research groups from different countries participate and where the samples had to be shipped overseas, is highlighted in this paper. PMID- 27246162 TI - Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel. AB - Familial hypercholesterolaemia is common in individuals who had a myocardial infarction at a young age. As many as one in 200 people could have heterozygous familial hypercholesterolaemia, and up to one in 300 000 individuals could be homozygous. The phenotypes of heterozygous and homozygous familial hypercholesterolaemia overlap considerably; the response to treatment is also heterogeneous. In this Review, we aim to define a phenotype for severe familial hypercholesterolaemia and identify people at highest risk for cardiovascular disease, based on the concentration of LDL cholesterol in blood and individuals' responsiveness to conventional lipid-lowering treatment. We assess the importance of molecular characterisation and define the role of other cardiovascular risk factors and advanced subclinical coronary atherosclerosis in risk stratification. Individuals with severe familial hypercholesterolaemia might benefit in particular from early and more aggressive cholesterol-lowering treatment (eg, with PCSK9 inhibitors). In addition to better tailored therapy, more precise characterisation of individuals with severe familial hypercholesterolaemia could improve resource use. PMID- 27246163 TI - FRET Sensor for Erythrosine Dye Based on Organic Nanoparticles: Application to Analysis of Food Stuff. AB - An aqueous suspension of fluorescent nanoparticles (PHNNPs) of naphthol based fluorescent organic compound 1-[(Z)-(2-phenylhydrazinylidene) methyl] naphthalene -2-ol (PHN) were prepared using reprecipitation method shows bathochromically shifted aggregation induced enhanced emission (AIEE) in the spectral region where erythrosine (ETS) food dye absorbs strongly. The average size of 72.6 nm of aqueous suspension of PHNNPs obtained by Dynamic light scattering results shows a narrow particle size distribution. The negative zeta potential of nano probe ( 22.6 mV) responsible to adsorb oppositely charged analyte on its surface and further permit to bind nano probe and analyte within the close distance proximity required for efficient fluorescence resonance energy transfer (FRET) to take place from donor (PHNNPs) to acceptor (ETS). Systematic FRET experiments performed by measuring fluorescence quenching of PHNNPs with successive addition of ETS solution exploited the use of the PHNNPs as a novel nano probe for the detection of ETS in aqueous solution with extremely lower limit of detection equal to 3.6 nM (3.1 ng/mL). The estimation of photo kinetic and thermodynamic parameters such as quenching rate constant, enthalpy change (?H), Gibbs free energy change (?G) and entropy change (?S) was obtained by the quenching results obtained at different constant temperatures which were found to fit the well known Stern-Volmer relation. The mechanism of binding and fluorescence quenching of PHNNPs by ETS food dye is proposed on the basis of results obtained in photophysical studies, thermodynamic parameter, energy transfer efficiency, critical energy transfer distance (R0) and distance of approach between donor acceptor molecules (r). The proposed FRET method based on fluorescence quenching of PHNNPs was successfully applied to develop an analytical method for estimation of ETS from food stuffs without interference of other complex ingredients. Graphical Abstract A fluorescent organic nanoprobe developed for the detection of erythrosine (ETS) food dye in aqueous medium based on fluorescence resonance energy transfer (FRET). The FRET process between donor (nanoparticles) and acceptor (ETS dye) arises due to oppositely charge attraction through hydrophobic interactions. The proposed method was successfully applied to quantitative determination of ETS dye in food stuff sample collected from local market. PMID- 27246164 TI - How vertical patterns in leaf traits shift seasonally and the implications for modeling canopy photosynthesis in a temperate deciduous forest. AB - Leaf functional traits are used in modeling forest canopy photosynthesis (Ac) due to strong correlations between photosynthetic capacity, leaf mass per area (LMA) and leaf nitrogen per area (Narea). Vertical distributions of these traits may change over time in temperate deciduous forests as a result of acclimation to light, which may result in seasonal changes in Ac To assess both spatial and temporal variations in key traits, we measured vertical profiles of Narea and LMA from leaf expansion through leaf senescence in a sugar maple (Acer saccharum Marshall) forest. To investigate mechanisms behind coordinated changes in leaf morphology and function, we also measured vertical variation in leaf carbon isotope composition (delta(13)C), predawn turgor pressure, leaf water potential and osmotic potential. Finally, we assessed potential biases in Ac estimations by parameterizing models with and without vertical and seasonal Narea variations following leaf expansion. Our data are consistent with the hypothesis that hydrostatic constraints on leaf morphology drive the vertical increase in LMA with height early in the growing season; however, LMA in the upper canopy continued to increase over time during light acclimation, indicating that light is primarily driving gradients in LMA later in the growing season. Models with no seasonal variation in Narea overestimated Ac by up to 11% early in the growing season, while models with no vertical variation in Narea overestimated Ac by up to 60% throughout the season. According to the multilayer model, the upper 25% of leaf area contributed to over 50% of Ac, but when gradients of intercellular CO2, as estimated from delta(13)C, were accounted for, the upper 25% of leaf area contributed to 26% of total Ac Our results suggest that ignoring vertical variation of key traits can lead to considerable overestimation of Ac. PMID- 27246165 TI - Schip1, a new upstream regulator of Hippo signaling. PMID- 27246166 TI - Characteristics of the case mix, organisation and delivery in cancer palliative care: a challenge for good-quality research. AB - OBJECTIVES: Palliative care (PC) services and patients differ across countries. Data on PC delivery paired with medical and self-reported data are seldom reported. Aims were to describe (1) PC organisation and services in participating centres and (2) characteristics of patients in PC programmes. METHODS: This was an international prospective multicentre study with a single web-based survey on PC organisation, services and academics and patients' self-reported symptoms collected at baseline and monthly thereafter, with concurrent registrations of medical data by healthcare providers. Participants were patients >=18 enrolled in a PC programme. RESULTS: 30 centres in 12 countries participated; 24 hospitals, 4 hospices, 1 nursing home, 1 home-care service. 22 centres (73%) had PC in-house teams and inpatient and outpatient services. 20 centres (67%) had integral chemotherapy/radiotherapy services, and most (28/30) had access to general medical or oncology inpatient units. Physicians or nurses were present 24 hours/7 days in 50% and 60% of centres, respectively. 50 centres (50%) had professorships, and 12 centres (40%) had full-time/part-time research staff. Data were available on 1698 patients: 50% females; median age 66 (range 21-97); median Karnofsky score 70 (10-100); 1409 patients (83%) had metastatic/disseminated disease; tiredness and pain in the past 24 hours were most prominent. During follow-up, 1060 patients (62%) died; 450 (44%) <3 months from inclusion and 701 (68%) within 6 months. ANOVA and chi2 tests showed that hospice/nursing home patients were significantly older, had poorer performance status and had shorter survival compared with hospital-patients (p<.0.001). CONCLUSIONS: There is a wide variation in PC services and patients across Europe. Detailed characterisation is the first step in improving PC services and research. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT01362816. PMID- 27246168 TI - Dramatic regression of macular and peripheral retinoschisis with dorzolamide 2 % in X-linked retinoschisis: a case report. AB - BACKGROUND: X-linked retinoschisis is one of the more frequently encountered inherited macular retinal disorders affecting young males, causing loss of vision. Patients exhibit macular schisis and peripheral schisis, which can mimic retinal detachment, a very different entity that requires surgical intervention. CASE PRESENTATION: An 8-month-old African-American boy was presented to our hospital with severe X-linked retinoschisis involving symmetrical bullous peripheral retinoschisis in both eyes, mimicking retinal detachment. One eye received multiple surgeries for retinal detachment repair that were complicated by proliferative vitreoretinopathy. Later, portable optical coherence tomography was used to confirm absence of retinal detachment despite a corrugated fundus appearance in the fellow eye. Following treatment with topical dorzolamide 2 % for 18 months, there was dramatic regression of both macular and peripheral schisis cavities in the nonoperative eye. CONCLUSIONS: Severe bullous peripheral schisis in infants with severe X-linked retinoschisis may produce posterior corrugations that mimic rhegmatogenous retinal detachment. Clinical suspicion for retinal detachment in infants with X-linked retinoschisis should be confirmed by portable optical coherence tomography before surgical intervention. Bullous peripheral schisis can remain clinically stable over time, but topical dorzolamide 2 % may facilitate collapse. PMID- 27246169 TI - Effect of LA on the Growth and Development of the Main Organs in Female Mice. AB - Effects of lead acetate (LA) on the growth and development of major organs in female mice were studied. Female mice were divided randomly into four treatment groups and one control group. In treatment groups, mice were injected with different concentrations of LA solution every 2 days; whereas control-group mice received equal volumes of sterile normal saline. Body weight (BW) and symptoms were recorded every 2 days. After LA exposure, mice were executed by cervical dislocation and main organs (heart, liver, spleen, lung, kidney) collected for evaluation of morphologic and histologic changes. LA could greatly affect increases in BW, and BW decreased with increasing dose and time of exposure to LA. Compared with the control group, organ coefficients in treatment groups were of the order kidney and spleen > liver and lung > heart and demonstrated obvious dose-time effects. LA exposure could damage the heart, liver, spleen, lung, and kidney. Damage to the kidney and spleen was the most severe, followed by that to the liver, heart, and lung. Damage was aggravated with increasing doses and exposure time to LA in an obvious dose-time relationship; when LA dose was >=20 mg/kg, the growth and development of mice were obviously inhibited. These results suggest that long-term exposure to low-dose LA can result in universal pathologic damage to mouse organs and that severity is dependent on the dose and duration of LA exposure. PMID- 27246167 TI - A critical look at the function of the P2Y11 receptor. AB - The P2Y11 receptor is a member of the purinergic receptor family. It has been overlooked, somewhat due to the lack of a P2ry11 gene orthologue in the murine genome, which prevents the generation of knockout mice, which have been so helpful for defining the roles of other P2Y receptors. Furthermore, some of the studies reported to date have methodological shortcomings, making it difficult to determine the function of P2Y11 with certainty. In this review, we discuss the lack of a murine "P2Y11-like receptor" and highlight the limitations of the currently available methods used to investigate the P2Y11 receptor. These methods include protein recognition with antibodies that show very little specificity, gene expression studies that completely overlook the existence of a fusion transcript between the adjacent PPAN gene and P2RY11, and agonists/antagonists reported to be specific for the P2Y11 receptor but which have not been tested for activity on numerous other adenosine 5'-triphosphate (ATP)-binding receptors. We suggest a set of criteria for evaluating whether a dataset describes effects mediated by the P2Y11 receptor. Following these criteria, we conclude that the current evidence suggests a role for P2Y11 in immune activation with cell type specific effects. PMID- 27246170 TI - The Gamma renewal process as an output of the diffusion leaky integrate-and-fire neuronal model. AB - Statistical properties of spike trains as well as other neurophysiological data suggest a number of mathematical models of neurons. These models range from entirely descriptive ones to those deduced from the properties of the real neurons. One of them, the diffusion leaky integrate-and-fire neuronal model, which is based on the Ornstein-Uhlenbeck (OU) stochastic process that is restricted by an absorbing barrier, can describe a wide range of neuronal activity in terms of its parameters. These parameters are readily associated with known physiological mechanisms. The other model is descriptive, Gamma renewal process, and its parameters only reflect the observed experimental data or assumed theoretical properties. Both of these commonly used models are related here. We show under which conditions the Gamma model is an output from the diffusion OU model. In some cases, we can see that the Gamma distribution is unrealistic to be achieved for the employed parameters of the OU process. PMID- 27246171 TI - Pharmacotherapy for Obesity and Changes in Eating Behavior: a Patient and Physician's Perspective. AB - This article, co-authored by a patient with obesity, diabetes, and hypertension, and an obesity medicine specialist, discusses the patient's experience with the onset of diabetes complicating obesity and with her frustration living with these diagnoses until finding an obesity medicine specialist physician who helped her lose weight and reverse her diabetes. The patient continues to maintain a significant weight loss and is diabetes free for 5.5 years after treatment initiation. The physician discusses the application of combination treatment that can be effective in diabetes reversal in such cases. He also discusses salient clinical lessons exemplified by this case. PMID- 27246172 TI - An Update on Triptorelin: Current Thinking on Androgen Deprivation Therapy for Prostate Cancer. AB - Androgen deprivation therapy (ADT) is the mainstay palliative treatment for men with locally advanced and metastatic prostate cancer, and aims to reduce testosterone to levels obtained by surgical castration. Use of gonadotropin releasing hormone (GnRH) agonists predominates among the ADT options. The GnRH agonist, triptorelin is a first-line hormonal therapy that has demonstrated efficacy and safety in clinical trials of patients with locally advanced non metastatic or metastatic disease. Sustained-release 1-, 3- and 6-month formulations of triptorelin, administered intramuscularly or subcutaneously, have been developed to provide improved flexibility and convenience for the patient. Head-to-head studies of GnRH agonists are lacking in the field of prostate cancer. Despite the inevitable progression to castration-resistant prostate cancer (CRPC) in most patients receiving ADT, monitoring of testosterone levels needs to improve in routine practice and physicians should not overlook the benefits of continued ADT in their patients when introducing one of the various new treatment options for CRPC. For improved survival outcomes, there remains a need to tailor ADT treatment regimens, novel hormonal agents and chemotherapy according to the individual patient with advanced prostate cancer. PMID- 27246173 TI - APPL1-mediated activation of STAT3 contributes to inhibitory effect of adiponectin on hepatic gluconeogenesis. AB - Adiponectin has been shown to suppress hepatic gluconeogenesis. However, the signaling pathways underlying its action remain ill-defined. The purpose of this study was to examine the potential role of APPL1 in mediating anti-gluconeogenic ability of adiponectin. Primary hepatocytes were isolated from male C57BL/6 mice. Western blot and RT-PCR were performed to detect protein expression and mRNA level, respectively. The protein-protein association was determined by immunoprecipitation and GST pull-down assay. We found that APPL1 protein levels were negatively associated with expressions of proteins and mRNAs of gluconeogenesis enzymes under stimulation with adiponectin. In addition, adiponectin-stimulated STAT3 phosphorylation and acetylation were positively regulated by APPL1 and negative regulated by SirT1. Pharmacological and genetic inhibition of STAT3 mitigated impact of adiponectin on hepatic gluconeogenesis. Furthermore, adiponectin administration facilitated the binding of APPL1 to SirT1 and suppressed the association of SirT1 with STAT3. Taken together, our study showed that APPL1-SirT1-STAT3 pathway mediated adiponectin signaling in primary hepatocytes. This new finding provides a novel mechanism by which adiponectin suppresses hepatic gluconeogenesis. PMID- 27246174 TI - Molecular analysis of mucinous nonneoplastic cyst of the pancreas. AB - Although a mucinous nonneoplastic cyst (MNNC) of the pancreas is defined as a benign nonneoplastic lesion with no malignant potential, its histogenesis and etiology are still uncertain. To explore the origin and development of MNNC, we searched for neoplasia-associated mutational change in oncogene and tumor suppressor genes. Specifically, we analyzed KRAS oncogene mutations by polymerase chain reaction/dideoxy DNA (Sanger) sequencing and tumor suppression gene deletion by loss of heterozygosity (LOH) using polymerase chain reaction/capillary gel electrophoresis for a panel of 16 polymorphic microsatellite repeat markers targeting common tumor suppression gene loci at 1p, 3p, 5q, 9p, 10q, 17p, 17q, 18q, 21q, and 22q on DNA isolated from the cystic lining epithelium microdissected from 15 surgically diagnosed MNNCs by microdissection of unstained histologic sections of fixed resection specimens. DNA mutations were demonstrated in 4 of 15 cases: 1 with KRAS mutation at codon 12 glycine (G) substitution by aspartic acid (D) (G12D), 1 with KRAS mutation at 12 glycine (G) substitution by arginine (R) (G12R), 1 with LOH at 10q (PTEN), and 1 with LOH at 17q (RNF43). Therefore, although the genomic mutation rate detected in MNNC is relatively low, our results indicate that MNNCs may acquire genetic alteration similar to low-grade pancreatic intraepithelial neoplasia, furthering debate of the true nature of these lesions. PMID- 27246175 TI - Crypt apoptotic body counts in normal ileal biopsies overlap with graft-versus host disease and acute cellular rejection of small bowel allografts. AB - Crypt apoptosis in intestinal epithelium is an important diagnostic feature of graft-versus-host disease (GVHD) and acute cellular rejection (ACR) of intestinal transplants (ITx). In ITx pathology, 2 or fewer apoptotic bodies in 10 consecutive crypts are considered normal, whereas 6 or more is consistent with mild ACR. The presence of 3 to 5 apoptotic bodies is problematic and is often classified as indeterminate for ACR. The minimum diagnostic threshold for GVHD is controversial but also depends on the apoptotic body count (ABC). We investigated how many crypt apoptotic bodies could be identified in histologically normal ileal biopsies from healthy subjects (native intestines, no bone marrow transplant) who underwent screening colonoscopy and had ileal biopsy to confirm complete colonoscopy. We recorded the number of biopsy pieces per specimen and the maximum ABC in 10 consecutive crypts. Twenty-six of 40 patients (65%) had an ABC of 3 or more in 10 crypts, thus only 35% were "normal." Four (10%) had an ABC of >=6 (positive for ACR). Twenty-two (55%) had 3-5 (indefinite for ACR). Depending on the criteria, up to 60% of the cases could be diagnosed as positive for GVHD. PMID- 27246176 TI - Ewing sarcoma: a chronicle of molecular pathogenesis. AB - Sarcomas have traditionally been classified according to their chromosomal alterations regardless of whether they accompany simple or complex genetic changes. Ewing sarcoma, a classic small round cell bone tumor, is a well-known mesenchymal malignancy that results from simple sarcoma-specific genetic alterations. The genetic alterations are translocations between genes of the TET/FET family (TLS/FUS, EWSR1, and TAF15) and genes of the E26 transformation specific (ETS) family. In this review, we intend to summarize a chronicle of molecular findings of Ewing sarcoma including recent advances and explain resultant molecular pathogenesis. PMID- 27246177 TI - p53 alteration in morphologically normal/benign breast tissue in patients with triple-negative high-grade breast carcinomas: breast p53 signature? AB - p53 alterations have been identified in approximately 23% of breast carcinomas, particularly in hormone receptor-negative high-grade carcinomas. It is considered to be an early event in breast carcinogenesis. Nevertheless, the putative precursor lesion of high-grade breast carcinoma remains elusive. Breast excision specimens from 93 triple-negative high-grade invasive ductal carcinomas, 48 estrogen receptor (ER)-positive/progesterone receptor-positive/Her2-negative non high-grade invasive ductal carcinomas, and 50 mammoplasty breasts were selected. At least 2 tissue blocks with tumor and adjacent benign tissue were sectioned and subjected to immunohistochemistry staining for p53. TP53 gene sequencing was performed on select tumors. Further immunohistochemistry staining for ER and Ki 67 was performed on consecutive sections of tissue with p53-positive normal/benign cells. Of the 93 high-grade carcinomas, 51 (55%) were positive for p53 alteration, whereas only 3 (6.25%) of the 48 non-high-grade carcinomas were p53 altered. Focal p53 positivity in adjacent normal/benign breast tissue was identified in 19 cases, and 18 of them also had p53 alteration in their carcinomas. Only 1 case had focal p53 staining in normal/benign tissue, but the tumor was negative for p53 alteration. No p53 staining positivity was identified in the mammoplasty specimens. The p53-stained normal/benign cells were ER negative and did not show an increase in the Ki-67 labeling index. These findings indicate that the p53 staining positivity in normal/benign breast tissue is not a random event. It could be considered as the "p53 signature" in breast and serve as an indicator for future potential risk of p53-positive high-grade breast carcinoma. PMID- 27246179 TI - Conformational Preferences and the Phase Stability of Fullerene Hexa-adducts. AB - Molecular conformation and the assembly structure determine the spatial arrangements of the constituent units and the functions of a molecule. Although, fullerene hexa-adducts (FHAs) have been known as functional materials with great versatility, their conformational preferences and phase stability remain a complicate issue. By choosing bithiophene (T2 ) and dodecyl bithiophene (C12 T2 ) as the peripheral units of FHA, and using microscopic, scattering and diffraction characterizations, our study reveals how the intramolecular interaction and environmental stimulus affects the conformational preferences and phase stability of FHAs. PMID- 27246178 TI - Distribution and components of interstitial inflammation and fibrosis in IgG4 related kidney disease: analysis of autopsy specimens. AB - IgG4-related kidney disease (IgG4-RKD) occasionally progresses to chronic renal failure and is pathologically characterized by IgG4-positive lymphoplasmacyte rich tubulointerstitial nephritis with storiform fibrosis (bird's-eye pattern fibrosis). Although radiology reveals a heterogeneous distribution of affected areas in this disease, their true distribution within the whole kidney is still unknown because of difficulty in estimating this from needle biopsy samples. Using 5 autopsy specimens, the present study histologically characterized the distribution and components of interstitial inflammation and fibrosis in IgG4 RKD. Interstitial lymphoplasmacytic infiltration or fibrosis was observed in a variety of anatomical locations such as intracapsular, subcapsular, cortical, perivascular, and perineural regions heterogeneously in a patchy distribution. They tended to be more markedly accumulated around medium- and small-sized vessels. Storiform fibrosis was limited to the cortex. Immunostaining revealed nonfibrillar collagens (collagen IV and VI) and fibronectin predominance in the cortical lesion, including storiform fibrosis. In contrast, fibril-forming collagens (collagen I and III), collagen VI, and fibronectin were the main components in the perivascular lesion. In addition, alpha-smooth muscle actin positive myofibroblasts were prominently accumulated in the early lesion and decreased with progression, suggesting that myofibroblasts produce extracellular matrices forming a peculiar fibrosis. In conclusion, perivascular inflammation or fibrosis of medium- and small-sized vessels is a newly identified pathologic feature of IgG4-RKD. Because storiform fibrosis contains mainly nonfibrillar collagens, "interstitial fibrosclerosis" would be a suitable term to reflect this. The relation between the location and components of fibrosis determined in whole kidney samples provides new clues to the pathophysiology underlying IgG4 RKD. PMID- 27246180 TI - Polymorphisms in the XPC gene affect urinary bladder cancer risk: a case-control study, meta-analyses and trial sequential analyses. AB - Compromised activity of the DNA repair enzymes may raise the risk of a number of cancers. We analyzed polymorphisms in the Xeroderma Pigmentosum, Complementation Group C (XPC) gene for their correlation with urinary bladder cancer. Ala499Val and Lys939Gln polymorphisms were genotyped in 234 urinary bladder cancer cases and 258 control samples. A significant association between Ala499Val polymorphism and bladder cancer was observed (OR = 1.78, CI = 1.19-2.66, p = 0.005); however, Lys939Gln was unrelated (OR = 0.97, CI = 0.65-1.45, P = 0.89). Further analysis revealed that Ala499Val was a significant risk factor only in the presence of smoking (OR = 2.23, CI = 1.28-3.87, p < 0.004) or tobacco chewing (OR = 2.40, CI = 1.43-4.04, p = 0.0008). To further appraise the association, we undertook meta analyses on seven studies (2893 cases and 3056 controls) on Ala499Val polymorphism and eleven studies (5064 cases and 5208 controls) on Lys939Gln polymorphism. Meta-analyses corroborated the above results, showing strong association of Ala499Val (OR = 1.54, CI = 1.21-1.97, p = 0.001) but not that of Lys939Gln (OR = 1.13, CI = 0.95-1.34, p = 0.171) with urinary bladder cancer risk. In conclusion, XPC Ala499Val substitution increases urinary bladder cancer risk, but Lys939Gln appears to be neutral. PMID- 27246181 TI - The discrepancy between social isolation and loneliness as a clinically meaningful metric: findings from the Irish and English longitudinal studies of ageing (TILDA and ELSA). AB - OBJECTIVE: Scant evidence is available on the discordance between loneliness and social isolation among older adults. We aimed to investigate this discordance and any health implications that it may have. METHOD: Using nationally representative datasets from ageing cohorts in Ireland (TILDA) and England (ELSA), we created a metric of discordance between loneliness and social isolation, to which we refer as Social Asymmetry. This metric was the categorised difference between standardised scores on a scale of loneliness and a scale of social isolation, giving categories of: Concordantly Lonely and Isolated, Discordant: Robust to Loneliness, or Discordant: Susceptible to Loneliness. We used regression and multilevel modelling to identify potential relationships between Social Asymmetry and cognitive outcomes. RESULTS: Social Asymmetry predicted cognitive outcomes cross-sectionally and at a two-year follow-up, such that Discordant: Robust to Loneliness individuals were superior performers, but we failed to find evidence for Social Asymmetry as a predictor of cognitive trajectory over time. CONCLUSIONS: We present a new metric and preliminary evidence of a relationship with clinical outcomes. Further research validating this metric in different populations, and evaluating its relationship with other outcomes, is warranted. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27246182 TI - A comparison of risks of treating anterior communicating aneurysms via surgical clipping or endovascular coiling. PMID- 27246183 TI - Multimodal interaction in the insect brain. AB - BACKGROUND: The magnitude of multimodal enhancement in the brain is believed to depend on the stimulus intensity and timing. Such an effect has been found in many species, but has not been previously investigated in insects. RESULTS: We investigated the responses to multimodal stimuli consisting of an odour and a colour in the antennal lobe and mushroom body of the moth Manduca sexta. The mushroom body shows enhanced responses for multimodal stimuli consisting of a general flower odour and a blue colour. No such effect was seen for a bergamot odour. The enhancement shows an inverse effectiveness where the responses to weaker multimodal stimuli are amplified more than those to stronger stimuli. Furthermore, the enhancement depends on the precise timing of the two stimulus components. CONCLUSIONS: Insect multimodal processing show both the principle of inverse effectiveness and the existence of an optimal temporal window. PMID- 27246184 TI - Cerebral Perfusion Pressure Targets Individualized to Pressure-Reactivity Index in Moderate to Severe Traumatic Brain Injury: A Systematic Review. AB - Traumatic brain injury (TBI) frequently triggers a disruption of cerebral autoregulation. The cerebral perfusion pressure (CPP) at which autoregulation is optimal ("CPPopt") varies between individuals, and can be calculated based on fluctuations between arterial blood pressure and intracranial pressure. This review assesses the effect of individualizing CPP targets to pressure reactivity index (a measure of autoregulation) in patients with TBI. Cochrane Central Register of Controlled Trials, MEDLINE(r), Embase, and Cumulative Index of Nursing and Allied Health Literature were searched in March 2015 for studies assessing the effect of targeting CPPopt in TBI. We included all studies that assessed the impact of targeting CPPopt on outcomes including mortality, neurological outcome, and physiological changes. Risk of bias was assessed using the RTI Item Bank and evidence quality was considered using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. Eight cohort studies (based on six distinct data sets) assessing the association between CPPopt and mortality, Glasgow Outcome Scale and physiological measures in TBI were included. The quality of evidence was deemed very low based on the GRADE criteria. Although the data suggest an association between variation from CPPopt and poor clinical outcome at 6 months, the quality of evidence prevents firm conclusions, particularly regarding causality, from being drawn. Available data suggest that targeting CPPopt might represent a technique to improve outcomes following TBI, but currently there is insufficient high-quality data to support a recommendation for use in clinical practice. Further prospective, randomized controlled studies should be undertaken to clarify its role in the acute management of TBI. PMID- 27246185 TI - Angiotensin II in the carotid body - a friend or foe? PMID- 27246186 TI - Renal glucose transporters 'sweeten' the pot. PMID- 27246187 TI - Engineering a solution to explore the cardiorespiratory limits to exercise performance: take a load off! PMID- 27246188 TI - Considerations for the use of transient tests of the peripheral chemoreflex in humans: the utility is in the question and the context. PMID- 27246189 TI - Shockwave Lithotripsy Practice Pattern Variations Among and Between American and Canadian Urologists: In Support of Guidelines. AB - PURPOSE: Shockwave lithotripsy (SWL) is a widely utilized form of treatment for urolithiasis. There are new evidence-based recommendations regarding pre-SWL patient work-up and the performance of SWL. The purpose of this study is to determine practice patterns for SWL and to determine if regional variation exists between Canada and the United States. MATERIALS AND METHODS: A 19-question survey was prepared. Canadian urologists were surveyed through e-mail correspondence. In the United States, members of the Endourologic Society and members of two large stone management groups were surveyed. Canadian and American results were compared using the chi-square and Fisher's exact tests. RESULTS: Ninety-four Canadian urologists and 187 U.S. urologists completed the survey. Practice patterns differed between countries. Intravenous sedation was more commonly used in Canada (Canada 94.7% vs United States 17.9%, p < 0.001); routine antibiotics were more commonly given in United States (Canada 2.1% vs United States 78.1%, p < 0.001); a shock rate of 2 Hz was more common in Canada (Canada 76.6% vs United States 16.2%, p < 0.00001); rate of discontinuing ASA for renal and ureteral stone treatment was higher in the United States (renal Canada 88.3% vs United States 95.7%, p < 0.02; ureteral Canada 62.4% vs 90.3%, p < 0.0001); and ureteral stents were more commonly used if treating a large stone or patients with solitary kidneys in the United States (large stones Canada 58.2% vs United States 88.8%, p = 0.0001; solitary kidney Canada 50.6% vs 66.3%, p = 0.02). CONCLUSIONS: This study highlights the absence of standardization of SWL. Significant regional differences exist in practice patterns and performance of SWL between Canadian and American urologists. PMID- 27246190 TI - Exopolysaccharides produced by Lactobacillus sp.: Biosynthesis and applications. AB - Lactobacillus sp. synthesize exopolysaccharides (EPS), including both homo- and heteropolysaccharides, which play an important role in the production of fermented foods, and especially in the dairy industry, improving the gustatory and rheological properties of the finished products. These polymers are generated by starter cultures in situ in fermented foods, and so they are treated as natural thickening agents. As some Lactobacillus strains are generally recognized as safe and have been shown to exhibit probiotic activity, EPS from those bacteria can be used as functional food ingredients, conferring both health and economic benefits to the consumers. However, their industrial applications are hindered by the low yield of EPS from Lactobacillus and high costs of their purification. This review focuses on the latest reports concerning the biosynthesis and properties of Lactobacillus EPS. PMID- 27246192 TI - Patients with oesophageal cancer report elevated distress and problems yet do not have an explicit wish for referral prior to receiving their medical treatment plan. AB - OBJECTIVE: This study aims to identify patients with oesophageal cancer's level of distress, type of problems, and wish for referral prior to treatment. To identify the clinical relevance of patients with oesophageal cancer's level of distress and type of problems, we build models to predict elevated distress, wish for referral, and overall survival. METHODS: We implemented the Distress Thermometer and Problem List in daily clinical practice. A score of >=5 on the Distress Thermometer reflected elevated distress. We first created an initial model including predictors based on the literature. We then added predictors to the initial model to create an extended model based on the sample data. We used the 'least absolute shrinkage and selection operator' to define our final model. RESULTS: We obtained data from 187 patients (47.9%, of 390 eligible patients with oesophageal cancer) which were similar to non-respondents in their demographic and clinical characteristics. One-hundred thirteen (60%) patients reported elevated distress. The five most frequently reported problems were as follows: eating, tension, weight change, fatigue, and pain. Most patients did not have a wish for referral. Predictors for elevated distress were as follows: being female, total number of practical, emotional, and physical problems, pain, and fatigue. For referral, we identified age, the total number of emotional problems, the level of distress, and fear. The level of distress added prognostic information in a model to predict overall survival. CONCLUSIONS: Patients with oesophageal cancer report elevated distress and a myriad of problems yet do not have an explicit wish for referral prior to receiving their medical treatment plan. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27246191 TI - Cholesterol biosynthesis pathway as a novel mechanism of resistance to estrogen deprivation in estrogen receptor-positive breast cancer. AB - BACKGROUND: Therapies targeting estrogenic stimulation in estrogen receptor positive (ER+) breast cancer (BC) reduce mortality, but resistance remains a major clinical problem. Molecular studies have shown few high-frequency mutations to be associated with endocrine resistance. In contrast, expression profiling of primary ER+ BC samples has identified several promising signatures/networks for targeting. METHODS: To identify common adaptive mechanisms associated with resistance to aromatase inhibitors (AIs), we assessed changes in global gene expression during adaptation to long-term estrogen deprivation (LTED) in a panel of ER+ BC cell lines cultured in 2D on plastic (MCF7, T47D, HCC1428, SUM44 and ZR75.1) or in 3D on collagen (MCF7) to model the stromal compartment. Furthermore, dimethyl labelling followed by LC-MS/MS was used to assess global changes in protein abundance. The role of target genes/proteins on proliferation, ER-mediated transcription and recruitment of ER to target gene promoters was analysed. RESULTS: The cholesterol biosynthesis pathway was the common upregulated pathway in the ER+ LTED but not the ER- LTED cell lines, suggesting a potential mechanism dependent on continued ER expression. Targeting the individual genes of the cholesterol biosynthesis pathway with siRNAs caused a 30 50 % drop in proliferation. Further analysis showed increased expression of 25 hydroxycholesterol (HC) in the MCF7 LTED cells. Exogenous 25-HC or 27-HC increased ER-mediated transcription and expression of the endogenous estrogen regulated gene TFF1 in ER+ LTED cells but not in the ER- LTED cells. Additionally, recruitment of the ER and CREB-binding protein (CBP) to the TFF1 and GREB1 promoters was increased upon treatment with 25-HC and 27-HC. In-silico analysis of two independent studies of primary ER+ BC patients treated with neoadjuvant AIs showed that increased expression of MSMO1, EBP, LBR and SQLE enzymes, required for cholesterol synthesis and increased in our in-vitro models, was significantly associated with poor response to endocrine therapy. CONCLUSION: Taken together, these data provide support for the role of cholesterol biosynthesis enzymes and the cholesterol metabolites, 25-HC and 27-HC, in a novel mechanism of resistance to endocrine therapy in ER+ BC that has potential as a therapeutic target. PMID- 27246196 TI - Altered expression of miR-92a correlates with Th17 cell frequency in patients with primary biliary cirrhosis. AB - MicroRNAs (miRNAs or miRs) are small, non-coding RNA molecules that play significant roles in numerous diseases. However, there is limited information regarding the plasma expression of miRNAs in patients with primary biliary cirrhosis (PBC) as well as the potential role of miRNAs in the development of PBC. miRNA microarray analysis was performed using plasma obtaind from three patients with PBC and three healthy controls. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to confirm the differential expression of miRNAs in the plasma and peripheral blood mononuclear cells (PBMCs) isolated from 20 patients with PBC, 20 patients with chronic hepatitis B (CHB) and 20 healthy controls. These miRNAs in PBMCs and plasma were validated by linear regression analyses. The T cell subset frequency was analyzed by flow cytometry. Correlations between altered miRNA expression and the frequency of the T cell subsets were determined by linear regression analyses. The co-expression of miRNAs and IL-17A was examined using fluorescence in situ hybridization (FISH) and immunohistochemistry. The microarray analysis identified sixteen miRNAs that were differentially expressed. Four miRNAs were validated by RT-qPCR. The expression pattern of miR-572 and miR-92a in the PBMCs correlated with the expression pattern in plasma. We also found that miR-92a expression closely correlated with the frequency of a subset of IL-17-producing T helper cells (Th17), and that miR-92a was co-expressed with IL-17A in patients with PBC. Taken together, these findings revealed that plasma from patients with PBC has a unique miRNA expression profile. Moreover, miR-92a may play an important role in the pathogenesis of PBC by regulating Th17 cell differentiation. PMID- 27246197 TI - Use of iPhones by Nurses in an Acute Care Setting to Improve Communication and Decision-Making Processes: Qualitative Analysis of Nurses' Perspectives on iPhone Use. AB - BACKGROUND: Smartphones and other mobile devices are having and will continue to have an impact on health care delivery in acute settings in Australia and overseas. Nurses, unlike physicians, have been slow to adopt these technologies and the reasons for this may relate to the status of both these professions within the hospital setting. OBJECTIVE: To explore nurses' perspectives on iPhone use within an acute care unit. We examined their experiences and views on how this device may improve communication and decision-making processes at the point of care. METHODS: Two focus group discussions, using a semistructured interview, were conducted over the trial period. The discussions focused on the nurses' experiences regarding ease of use, features, and capabilities of the device. The focus groups were recorded, transcribed, and analyzed using semistructured interview questions as a guide. RESULTS: The positive findings indicated that the iPhones were accessible and portable at point of care with patients, enhanced communication in the workplace, particularly among the nurses, and that this technology would evolve and be embraced by all nurses in the future. The negatives were the small screen size when undertaking bedside education for the patient and the invasive nature of the device. Another issue was the perception of being viewed as unprofessional when using the device in real time with the patients and their family. CONCLUSIONS: The use of iPhones by nurses in acute care settings has the potential to enhance patient care, especially through more effective communication among nurses, and other health care professionals. To ensure that the benefits of this technology is woven into the everyday practice of the nurse, it is important that leaders in these organizations develop the agenda or policy to ensure that this occurs. PMID- 27246198 TI - Implementation of coordinated global serotype 2 oral poliovirus vaccine cessation: risks of inadvertent trivalent oral poliovirus vaccine use. AB - BACKGROUND: The endgame for polio eradication includes coordinated global cessation of oral poliovirus vaccine (OPV), starting with the cessation of vaccine containing OPV serotype 2 (OPV2) by switching all trivalent OPV (tOPV) to bivalent OPV (bOPV). The logistics associated with this global switch represent a significant undertaking, with some possibility of inadvertent tOPV use after the switch. METHODS: We used a previously developed poliovirus transmission and OPV evolution model to explore the relationships between the extent of inadvertent tOPV use, the time after the switch of the inadvertent tOPV use and corresponding population immunity to serotype 2 poliovirus transmission, and the ability of the inadvertently introduced viruses to cause a serotype 2 circulating vaccine derived poliovirus (cVDPV2) outbreak in a hypothetical population. We then estimated the minimum time until inadvertent tOPV use in a supplemental immunization activity (SIA) or in routine immunization (RI) can lead to a cVDPV2 outbreak in realistic populations with properties like those of northern India, northern Pakistan and Afghanistan, northern Nigeria, and Ukraine. RESULTS: At low levels of inadvertent tOPV use, the minimum time after the switch for the inadvertent use to cause a cVDPV2 outbreak decreases sharply with increasing proportions of children inadvertently receiving tOPV. The minimum times until inadvertent tOPV use in an SIA or in RI can lead to a cVDPV2 outbreak varies widely among populations, with higher basic reproduction numbers, lower tOPV induced population immunity to serotype 2 poliovirus transmission prior to the switch, and a lower proportion of transmission occurring via the oropharyngeal route all resulting in shorter times. In populations with the lowest expected immunity to serotype 2 poliovirus transmission after the switch, inadvertent tOPV use in an SIA leads to a cVDPV2 outbreak if it occurs as soon as 9 months after the switch with 0.5 % of children aged 0-4 years inadvertently receiving tOPV, and as short as 6 months after the switch with 10-20 % of children aged 0-1 years inadvertently receiving tOPV. In the same populations, inadvertent tOPV use in RI leads to a cVDPV2 outbreak if 0.5 % of OPV RI doses given use tOPV instead of bOPV for at least 20 months after the switch, with the minimum length of use dropping to at least 9 months if inadvertent tOPV use occurs in 50 % of OPV RI doses. CONCLUSIONS: Efforts to ensure timely and complete tOPV withdrawal at all levels, particularly from locations storing large amounts of tOPV, will help minimize risks associated with the tOPV-bOPV switch. Under-vaccinated populations with poor hygiene become at risk of a cVDPV2 outbreak in the event of inadvertent tOPV use the soonest after the tOPV-bOPV switch and therefore should represent priority areas to ensure tOPV withdrawal from all OPV stocks. PMID- 27246199 TI - Participation in daily life of people with schizophrenia in comparison to the general population. AB - BACKGROUND: Participation in occupations is a basic human right. Although people with schizophrenia commonly experience restrictions in participation, there is a paucity of research in this area. PURPOSE: This study aimed to compare the participation patterns of people with schizophrenia to people without mental illness (control group). METHOD: A total of 140 people of similar age and sex completed the Adults Subjective Assessment of Participation and provided demographic and health-related data. FINDINGS: People with schizophrenia tend to participate in fewer activities and to participate alone. However, they participate with similar intensity as those in the control group. IMPLICATIONS: The participation patterns of people with schizophrenia are both unique and similar to those of the general population. The differences in participation raise concerns due to signs of restriction and social exclusion. However, it appears that people with schizophrenia benefit from occupation and community based services that promote and support participation with others in diverse activities. PMID- 27246200 TI - Structural determinant for inducing RORgamma specific inverse agonism triggered by a synthetic benzoxazinone ligand. AB - BACKGROUND: The nuclear hormone receptor RORgamma regulates transcriptional genes involved in the production of the pro-inflammatory interleukin IL-17 which has been linked to autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. This transcriptional activity of RORgamma is modulated through a protein-protein interaction involving the activation function 2 (AF2) helix on the ligand binding domain of RORgamma and a conserved LXXLL helix motif on coactivator proteins. Our goal was to develop a RORgamma specific inverse agonist that would help down regulate pro-inflammatory gene transcription by disrupting the protein protein interaction with coactivator proteins as a therapeutic agent. RESULTS: We identified a novel series of synthetic benzoxazinone ligands having an agonist (BIO592) and inverse agonist (BIO399) mode of action in a FRET based assay. We show that the AF2 helix of RORgamma is proteolytically sensitive when inverse agonist BIO399 binds. Using x ray crystallography we show how small modifications on the benzoxazinone agonist BIO592 trigger inverse agonism of RORgamma. Using an in vivo reporter assay, we show that the inverse agonist BIO399 displayed specificity for RORgamma over ROR sub-family members alpha and beta. CONCLUSION: The synthetic benzoxazinone ligands identified in our FRET assay have an agonist (BIO592) or inverse agonist (BIO399) effect by stabilizing or destabilizing the agonist conformation of RORgamma. The proteolytic sensitivity of the AF2 helix of RORgamma demonstrates that it destabilizes upon BIO399 inverse agonist binding perturbing the coactivator protein binding site. Our structural investigation of the BIO592 agonist and BIO399 inverse agonist structures identified residue Met358 on RORgamma as the trigger for RORgamma specific inverse agonism. PMID- 27246201 TI - Molecular clock of HIV-1 envelope genes under early immune selection. AB - BACKGROUND: The molecular clock hypothesis that genes or proteins evolve at a constant rate is a key tool to reveal phylogenetic relationships among species. Using the molecular clock, we can trace an infection back to transmission using HIV-1 sequences from a single time point. Whether or not a strict molecular clock applies to HIV-1's early evolution in the presence of immune selection has not yet been fully examined. RESULTS: We identified molecular clock signatures from 1587 previously published HIV-1 full envelope gene sequences obtained since acute infection in 15 subjects. Each subject's sequence diversity linearly increased during the first 150 days post infection, with rates ranging from [Formula: see text] to [Formula: see text] with a mean of [Formula: see text] per base per day. The rate of diversification for 12 out of the 15 subjects was comparable to the neutral evolution rate. While temporal diversification was consistent with evolution patterns in the absence of selection, mutations from the founder virus were highly clustered on statistically identified selection sites, which diversified more than 65 times faster than non-selection sites. By mathematically quantifying deviations from the molecular clock under various selection scenarios, we demonstrate that the deviation from a constant clock becomes negligible as multiple escape lineages emerge. The most recent common ancestor of a virus pair from distinct escape lineages is most likely the transmitted founder virus, indicating that HIV-1 molecular dating is feasible even after the founder viruses are no longer detectable. CONCLUSIONS: The ability of HIV-1 to escape from immune surveillance in many different directions is the driving force of molecular clock persistence. This finding advances our understanding of the robustness of HIV-1's molecular clock under immune selection, implying the potential for molecular dating. PMID- 27246203 TI - Strong but diverging clonality - climate relationships of different plant clades explain weak overall pattern across China. AB - The clonal strategy should be relatively important in stressful environments (i.e. of low resource availability or harsh climate), e.g. in cold habitats. However, our understanding of the distribution pattern of clonality along environmental gradients is still far from universal. The weakness and inconsistency of overall clonality-climate relationships across taxa, as reported in previous studies, may be due to different phylogenetic lineages having fundamental differences in functional traits other than clonality determining their climate response. Thus, in this study we compared the clonality-climate relationships along a latitudinal gradient within and between different lineages at several taxonomic levels, including four major angiosperm lineages (Magnoliidae, Monocotyledoneae, Superrosidae and Superasteridae), orders and families. To this aim we used a species clonality dataset for 4015 vascular plant species in 545 terrestrial communities across China. Our results revealed clear predictive patterns of clonality proportion in relation to environmental gradients for the predominant representatives of each of the taxonomic levels above, but the relationships differed in shape and strength between the 4 major angiosperm lineages, between the 12 orders and between the 12 families. These different relationships canceled out one another when all lineages at a certain taxonomic level were pooled. Our findings highlight the importance of explicitly accounting for the functional or taxonomic scale for studying variation in plant ecological strategy across environmental gradients. PMID- 27246202 TI - Maternal tea consumption and the risk of preterm delivery in urban China: a birth cohort study. AB - BACKGROUND: Studies investigating the relationship between maternal tea drinking and risk of preterm birth have reached inconsistent results. METHODS: The present study analyzed data from a birth cohort study including 10,179 women who delivered a singleton live birth were conducted in Lanzhou, China between 2010 and 2012. RESULTS: Drinking tea (OR = 1.36, 95 % CI: 1.09-1.69), and specifically green (OR = 1.42, 95 % CI: 1.08-1.85) or scented tea (OR = 1.61, 95 % CI: 1.04 2.50), was associated with an increased risk of preterm birth. Drinking tea was associated with both moderate preterm (OR = 1.41, 95 % CI: 1.12-1.79) and spontaneous preterm birth (OR = 1.41, 95 % CI: 1.09-1.83). Risk of preterm birth increased with decreasing age of starting tea drinking (<20 years, OR = 1.60, 95 % CI: 1.17-2.20) and increasing duration (p for trend < 0.01). The relationship between tea drinking and preterm birth is modified by both maternal age (p < 0.05) and gestational weight gain (p < 0.05). CONCLUSIONS: Despite conflicting findings in the previous literature, we saw a significant association with maternal tea drinking and risk of preterm birth in our cohort. More studies are needed both to confirm this finding and to elucidate the mechanism behind this association. PMID- 27246204 TI - A Sensitive and Flexible Assay for Determining Histone Deacetylase 1 (HDAC1) Activity. AB - Histones acetylation and deacetylation constitute part of the so-called "histone code" and work in concert with other posttranslational modifications to determine the activity of genes. Deacetylation of histone is carried out by a class of enzymes, known as histone deacetylases (HDACs). The action of HDAC is countered by histone acetyltransferases. Although histone is the best characterized substrate of HDACs, increasing evidence also indicates that non-histone proteins are equally important subtract of HDACs. Since HDACs play an important role in normal physiological and pathophysiological conditions, a sensitive and flexible deacetylation assay that can reliably detect HDAC activity and identify potential novel targets of HDACs is critical. PMID- 27246205 TI - Detection of Sumo Modification of Endogenous Histone Deacetylase 2 (HDAC2) in Mammalian Cells. AB - Small ubiquitin-related modifier (SUMO) is an ubiquitin-like protein that is covalently attached to a variety of target proteins and has a significant role in their regulation. HDAC2 is an important epigenetic regulator, promoting the deacetylation of histones and non-histone proteins. HDAC2 has been shown to be modified by SUMO1 at lysine 462. Here we describe how to detect SUMO modification of endogenous HDAC2 in mammalian cells by immunoblotting. Although in this chapter we use this method to detect HDAC2 modification in mammalian cells, this protocol can be used for any cell type or for any protein of interest. PMID- 27246206 TI - Analysis of Epigenetic Regulation of Hypoxia-Induced Epithelial-Mesenchymal Transition in Cancer Cells by Quantitative Chromatin Immunoprecipitation of Histone Deacetylase 3 (HDAC3). AB - Epigenetics plays a key role in gene expression control. Histone modifications including acetylation/deacetylation or methylation/demethylation are major epigenetic mechanisms known to regulate epithelial-mesenchymal transition (EMT) associated gene expression during hypoxia-induced cancer metastasis. Chromatin immunoprecipitation (ChIP) assay is a powerful tool for investigation of histone modification patterns of genes of interest. In this chapter, we describe a protocol that uses chromatin immunoprecipitation (ChIP) to analyze the epigenetic regulation of EMT marker genes by deacetylation of acetylated Histone 3 Lys 4 (H3K4Ac) under hypoxia in a head and neck cancer cell line FaDu cells. Not only a method of ChIP coupled by real-time quantitative PCR but also the detailed conditions are provided based on our previously published studies. PMID- 27246207 TI - Molecular and Functional Characterization of Histone Deacetylase 4 (HDAC4). AB - Histone deacetylases (HDACs) regulate various nuclear and cytoplasmic processes. In mammals, these enzymes are divided into four classes, with class II further divided into two subclasses: IIa (HDAC4, HDAC5, HDAC7, HDAC9) and IIb (HDAC6 and HDAC10). While HDAC6 is mainly cytoplasmic and HDAC10 is pancellular, class IIa HDACs are dynamically shuttled between the nucleus and cytoplasm in a signal dependent manner, indicating that they are unique signal transducers able to transduce signals from the cytoplasm to chromatin in the nucleus. Once inside the nucleus, class IIa HDACs interact with MEF2 and other transcription factors, mainly acting as transcriptional corepressors. Although class IIa HDACs share many molecular properties in vitro, they play quite distinct roles in vivo. This chapter lists methods that we have used for molecular and biochemical characterization of HDAC4, including development of regular and phospho-specific antibodies, deacetylase activity determination, reporter gene assays, analysis of subcellular localization, and determination of interaction with 14-3-3 and MEF2. Although described specifically for HDAC4, the protocols should be adaptable for analysis to the other three class IIa members, HDAC5, HDAC7, and HDAC9, as well as for other proteins with related properties. PMID- 27246209 TI - Analysis of Expression and Functions of Histone Deacetylase 6 (HDAC6). AB - Histone deacetylase 6 (HDAC6) is a member of class IIb HDAC family. HDAC6 exists predominantly in the cytoplasm and deacetylates mainly non-histone proteins in the cytoplasm. Via its deacetylase and ubiquitin binding domains, HDAC6 regulates microtubules, cytoskeleton, intracellular trafficking, and cellular responses to stress. HDAC6 plays a central role in physiology and pathobiology in various organs and tissues. Herein we describe the methods for analysis of expression and function of HDAC6 in diverse physiological and pathological contexts. PMID- 27246208 TI - Approaches for Studying the Subcellular Localization, Interactions, and Regulation of Histone Deacetylase 5 (HDAC5). AB - As a member of the class IIa family of histone deacetylases, the histone deacetylase 5 (HDAC5) is known to undergo nuclear-cytoplasmic shuttling and to be a critical transcriptional regulator. Its misregulation has been linked to prominent human diseases, including cardiac diseases and tumorigenesis. In this chapter, we describe several experimental methods that have proven effective for studying the functions and regulatory features of HDAC5. We present methods for assessing the subcellular localization, protein interactions, posttranslational modifications (PTMs), and activity of HDAC5 from the standpoint of investigating either the endogenous protein or tagged protein forms in human cells. Specifically, given that at the heart of HDAC5 regulation lie its dynamic localization, interactions, and PTMs, we present methods for assessing HDAC5 localization in fixed and live cells, for isolating HDAC5-containing protein complexes to identify its interactions and modifications, and for determining how these PTMs map to predicted HDAC5 structural motifs. Lastly, we provide examples of approaches for studying HDAC5 functions with a focus on its regulation during cell-cycle progression. These methods can readily be adapted for the study of other HDACs or non-HDAC-proteins of interest. Individually, these techniques capture temporal and spatial snapshots of HDAC5 functions; yet together, these approaches provide powerful tools for investigating both the regulation and regulatory roles of HDAC5 in different cell contexts relevant to health and disease. PMID- 27246210 TI - Analysis of Histone Deacetylase 7 (HDAC7) Alternative Splicing and Its Role in Embryonic Stem Cell Differentiation Toward Smooth Muscle Lineage. AB - Histone deacetylases (HDACs) have a central role in the regulation of gene expression, which undergoes alternative splicing during embryonic stem cell (ES) cell differentiation. Alternative splicing gives rise to vast diversity over gene information, arousing public concerns in the last decade. In this chapter, we describe a strategy to detect HDAC7 alternative splicing and analyze its function on ES cell differentiation. PMID- 27246211 TI - Large-Scale Overproduction and Purification of Recombinant Histone Deacetylase 8 (HDAC8) from the Human-Pathogenic Flatworm Schistosoma mansoni. AB - Epigenetic mechanisms underlie the morphological transformations and shifts in virulence of eukaryotic pathogens. The targeting of epigenetics-driven cellular programs thus represents an Achilles' heel of human parasites. Today, zinc dependent histone deacetylases (HDACs) belong to the most explored epigenetic drug targets in eukaryotic parasites. Here, we describe an optimized protocol for the large-scale overproduction and purification of recombinant smHDAC8, an emerging epigenetic drug target in the multicellular human-pathogenic flatworm Schistosoma mansoni. The strategy employs the robustness of recombinant expression in Escherichia coli together with initial purification through a poly histidine affinity tag that can be removed by the thrombin protease. This protocol is divided into two steps: (1) large-scale production of smHDAC8 in E. coli, and (2) purification of the target smHDAC8 protein through multiple purification steps. PMID- 27246212 TI - Visualization of HDAC9 Spatiotemporal Subcellular Localization in Primary Neuron Cultures. AB - Histone deacetylase (HDAC) 9 is one of class IIa HDACs which are expressed in developing cortical neurons. The translocation of HDAC9 from the nucleus to the cytoplasm is induced by neuronal activity during postnatal development, and is involved in regulation of various gene expressions. Visualization of HDAC9 subcellular localization is a powerful tool for studying activity-dependent gene expression. Here, we describe a time-lapse imaging method using fluorescent protein-tagged HDAC9 in dissociated cortical neurons. This method reveals dynamic HDAC9-mediated gene expression in response to various signals. PMID- 27246213 TI - Expression and Function of Histone Deacetylase 10 (HDAC10) in B Cell Malignancies. AB - Histone deacetylase 10 (HDAC10) belongs to the class IIb HDAC family and its biological role remains mostly unidentified. A decreased HDAC10 expression has been reported in patients with aggressive solid tumors (Osada et al. Int J Cancer 112: 26-32, 2004; Jin et al. Int J Clin Exp Pathol 7: 5872-5879, 2014), suggesting that loss of HDAC10 expression might confer a survival advantage to malignant cells. Consequently, results from our lab suggests that overexpression of HDAC10 in aggressive mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) Z138c and MEC1 cells, respectively, resulted in a rapid induction of cell death in vitro with only 5 % of cells being alive at 48 h, cell cycle arrest, and up-regulation of co-stimulatory molecules. Here we present several standard methods to study the function of HDAC10 in B cell malignancies. PMID- 27246214 TI - Functional Analysis of Histone Deacetylase 11 (HDAC11). AB - The physiological role of histone deacetylase 11 (HDAC11), the newest member of the HDAC family, remained largely unknown until the discovery of its regulatory function in immune cells. Among them, the regulation of cytokine production by antigen-presenting cells and the modulation of the suppressive ability of myeloid derived suppressor cells (MDSCs) (Sahakian et al. Mol Immunol 63: 579-585, 2015; Wang et al. J Immunol 186: 3986-3996, 2011; Villagra et al. Nat Immunol 10: 92 100, 2009). Our earlier data has demonstrated that HDAC11, by interacting at the chromatin level with the IL-10 promoter, downregulates il-10 transcription in both murine and human APCs in vitro and ex vivo models (Villagra et al. Nat Immunol 10: 92-100, 2009). However the role of HDAC11 in other cell types still remains unknown. Here we present several methods that can potentially be used to identify the functional role of HDAC11, assigning special attention to the evaluation of immunological parameters. PMID- 27246215 TI - Sirtuin1 (SIRT1) in the Acetylation of Downstream Target Proteins. AB - Acetylation has been shown to be an important posttranslational modification (PTM) of both histone and nonhistone proteins with particular implications in cell signaling and transcriptional regulation of gene expression. Many studies have already demonstrated that SIRT1 is able to deacetylate histones and lead to gene silencing. It can also regulate the function of tumor suppressors including FOXO proteins and p53 by deacetylation. Here, we describe three experimental approaches for studying the modulation of the acetylation status of some of the known downstream targets of SIRT1. PMID- 27246216 TI - Protocols for Cloning, Expression, and Functional Analysis of Sirtuin2 (SIRT2). AB - SIRT2 is a NAD(+)-dependent deacetylase that belongs to the sirtuin family, which is comprised of seven members (SIRT1-SIRT7) in humans. Furthermore, recent study shows that the Sirt2 gene has three transcript variants in mice. Several diverse proteins have been identified as SIRT2 substrates. SIRT2 activity involves multiple cell processes including growth, differentiation, and energy metabolism. However, little is known of SIRT2's role in oligodendrocytes or in the myelin sheath, where it is an important component. Here we describe procedures that detail Sirt2 gene cloning, identification, expression, and biological analysis in cultured cells. PMID- 27246217 TI - Cloning and Characterization of Sirtuin3 (SIRT3). AB - Mitochondria play a pivotal role in maintaining cellular homeostasis and regulating longevity. SIRT3 is a mitochondrial sirtuin mediating the deacetylation of various metabolic and antioxidant enzymes, in turn controlling energy metabolism, stress resistance, and the pace of ageing. To study the function of SIRT3, a proteomics-based approach is employed for identifying the protein-binding partners of this enzyme in mitochondria. PMID- 27246218 TI - Identification of Sirtuin4 (SIRT4) Protein Interactions: Uncovering Candidate Acyl-Modified Mitochondrial Substrates and Enzymatic Regulators. AB - Recent studies have highlighted the three mitochondrial human sirtuins (SIRT3, SIRT4, and SIRT5) as critical regulators of a wide range of cellular metabolic pathways. A key factor to understanding their impact on metabolism has been the discovery that, in addition to their ability to deacetylate substrates, mitochondrial sirtuins can have other prominent enzymatic activities. SIRT4, one of the least characterized mitochondrial sirtuins, was shown to be the first known cellular lipoamidase, removing lipoyl modifications from lysine residues of substrates. Specifically, SIRT4 was found to delipoylate and modulate the activity of the pyruvate dehydrogenase complex (PDH), a protein complex critical for the production of acetyl-CoA. Furthermore, SIRT4 is well known to have ADP ribosyltransferase activity and to regulate the activity of the glutamate dehydrogenase complex (GDH). Adding to its impressive range of enzymatic activities are its ability to deacetylate malonyl-CoA decarboxylase (MCD) to regulate lipid catabolism, and its newly recognized ability to remove biotinyl groups from substrates that remain to be defined. Given the wide range of enzymatic activities and the still limited knowledge of its substrates, further studies are needed to characterize its protein interactions and its impact on metabolic pathways. Here, we present several proven protocols for identifying SIRT4 protein interaction networks within the mitochondria. Specifically, we describe methods for generating human cell lines expressing SIRT4, purifying mitochondria from crude organelles, and effectively capturing SIRT4 with its interactions and substrates. PMID- 27246219 TI - Generation and Purification of Catalytically Active Recombinant Sirtuin5 (SIRT5) Protein. AB - Sirtuin-family deacylases promote health and longevity in mammals. The sirtuin SIRT5 localizes predominantly to the mitochondrial matrix. SIRT5 preferentially removes negatively charged modifications from its target lysines: succinylation, malonylation, and glutarylation. It regulates protein substrates involved in glucose oxidation, ketone body formation, ammonia detoxification, fatty acid oxidation, and ROS management. Like other sirtuins, SIRT5 has recently been linked with neoplasia. Therefore, targeting SIRT5 pharmacologically could conceivably provide new avenues for treatment of metabolic disease and cancer, necessitating development of SIRT5-selective modulators. Here we describe the generation of SIRT5 bacterial expression plasmids, and their use to express and purify catalytically active and inactive forms of SIRT5 protein from E. coli. Additionally, we describe an approach to assay the catalytic activity of purified SIRT5, potentially useful for identification and validation of SIRT5-specific modulators. PMID- 27246220 TI - Sirtuin 6 (SIRT6) Activity Assays. AB - SIRT6 has been shown to possess weak deacetylation, mono-ADP-ribosyltransferase activity, and deacylation activity in vitro. SIRT6 selectively deacetylates H3K9Ac and H3K56Ac. Several SIRT6 assays have been developed including HPLC assays, fluorogenic assays, FRET, magnetic beads, in silico, and bioaffinity chromatography assays. Herein, we describe detailed protocols for the HPLC based activity/inhibition assays, magnetic beads deacetylation assays, bioaffinity chromatographic assays as well as fluorogenic and in silico assays. PMID- 27246221 TI - Molecular, Cellular, and Physiological Characterization of Sirtuin 7 (SIRT7). AB - Sirtuin 7 (SIRT7), a histone 3 lysine 18 (H3K18) deacetylase, functions at chromatin to suppress endoplasmic reticulum (ER) stress and mitochondrial protein folding stress (PFS(mt)), and prevent the development of fatty liver disease and hematopoietic stem cell aging. In this chapter, we provide a methodology to characterize the molecular, cellular, and physiological functions of SIRT7. PMID- 27246222 TI - HDAC Inhibitors. AB - Lysine acetylation in proteins is one of the most abundant posttranslational modifications in eukaryotic cells. The dynamic homeostasis of lysine acetylation and deacetylation is dictated by the action of histone acetyltransferases (HAT) and histone deacetylases (HDAC). Important substrates for HATs and HDACs are histones, where lysine acetylation generally leads to an open and transcriptionally active chromatin conformation. Histone deacetylation forces the compaction of the chromatin with subsequent inhibition of transcription and reduced gene expression. Unbalanced HAT and HDAC activity, and therefore aberrant histone acetylation, has been shown to be involved in tumorigenesis and progression of malignancy in different types of cancer. Therefore, the development of HDAC inhibitors (HDIs) as therapeutic agents against cancer is of great interest. However, treatment with HDIs can also affect the acetylation status of many other non-histone proteins which play a role in different pathways including angiogenesis, cell cycle progression, autophagy and apoptosis. These effects have led HDIs to become anticancer agents, which can initiate apoptosis in tumor cells. Hematological malignancies in particular are responsive to HDIs, and four HDIs have already been approved as anticancer agents. There is a strong interest in finding adequate biomarkers to predict the response to HDI treatment. This chapter provides information on how to assess HDAC activity in vitro and determine the potency of HDIs on different HDACs. It also gives information on how to analyze cellular markers following HDI treatment and to analyze tissue biopsies from HDI-treated patients. Finally, a protocol is provided on how to detect HDI sensitivity determinants in human cells, based on a pRetroSuper shRNA screen upon HDI treatment. PMID- 27246223 TI - Assessment of the Antiproliferative Activity of a BET Bromodomain Inhibitor as Single Agent and in Combination in Non-Hodgkin Lymphoma Cell Lines. AB - To evaluate the antiproliferative activity of a novel BET Bromodomain inhibitor as single agent and in combination with the BTK inhibitor ibrutinib in non Hodgkin lymphoma cell lines, we performed the MTT proliferation assay. This assay is based on the direct correlation between absorbance (measured colorimetrically at a wavelength of 570 nm) and cell proliferation. Thiazolyl Blue Tetrazolium Blue (MTT) is a yellowish solution that distinguishes between proliferating and dead cells since it is converted to water-insoluble MTT-formazan of dark blue color by mitochondrial dehydrogenases of living cells only. PMID- 27246224 TI - Screening the Impact of Sirtuin Inhibitors on Inflammatory and Innate Immune Responses of Macrophages and in a Mouse Model of Endotoxic Shock. AB - The development and screening of pharmacological modulators of histone deacetylases (HDACs), and particularly sirtuins, is a promising field for the identification of new drugs susceptible to be used for treatment strategies in a large array of welfare-associated, autoimmune and oncologic diseases. Here we describe a comprehensive protocol to evaluate the impact of sirtuin-targeting drugs on inflammatory and innate immune responses in vitro and in a preclinical mouse model of endotoxemia. We first provide an overview on strategies to design in vitro experiments, then focus on the analysis of cytokine production by primary macrophages and RAW 267.7 macrophages at the mRNA and protein levels, and finally describe the setup and follow-up of a mouse model of inflammation-driven endotoxic shock. PMID- 27246225 TI - AM fungal communities inhabiting the roots of submerged aquatic plant Lobelia dortmanna are diverse and include a high proportion of novel taxa. AB - While the arbuscular mycorrhizal (AM) symbiosis is known to be widespread in terrestrial ecosystems, there is growing evidence that aquatic plants also form the symbiosis. It has been suggested that symbiosis with AM fungi may represent an important adaptation for isoetid plants growing on nutrient-poor sediments in oligotrophic lakes. In this study, we address AM fungal root colonization intensity, richness and community composition (based on small subunit (SSU) ribosomal RNA (rRNA) gene sequencing) in five populations of the isoetid plant species Lobelia dortmanna inhabiting oligotrophic lakes in Southern Sweden. We found that the roots of L. dortmanna hosted rich AM fungal communities and about 15 % of the detected molecular taxa were previously unrecorded. AM fungal root colonization intensity and taxon richness varied along an environmental gradient, being higher in oligotrophic and lower in mesotrophic lakes. The overall phylogenetic structure of this aquatic fungal community differed from that described in terrestrial systems: The roots of L. dortmanna hosted more Archaeosporaceae and fewer Glomeraceae taxa than would be expected based on global data from terrestrial AM fungal communities. PMID- 27246227 TI - Commentary on: The Effect of Lipoaspirates on Human Keratinocytes. PMID- 27246226 TI - The large (134.9 kb) mitochondrial genome of the glomeromycete Funneliformis mosseae. AB - Funneliformis mosseae is among the most ecologically and economically important glomeromycete species and occurs both in natural and disturbed areas in a wide range of habitats and climates. In this study, we report the sequencing of the complete mitochondrial (mt) genome of F. mosseae isolate FL299 using 454 pyrosequencing and Illumina HiSeq technologies. This mt genome is a full-length circular chromosome of 134,925 bp, placing it among the largest mitochondrial DNAs (mtDNAs) in the fungal kingdom. A comparative analysis with publically available arbuscular mycorrhizal fungal mtDNAs revealed that the mtDNA of F. mosseae FL299 contained a very large number of insertions contributing to its expansion. The gene synteny was completely reshuffled compared to previously published glomeromycotan mtDNAs and several genes were oriented in an anti-sense direction. Furthermore, the presence of different types of introns and insertions in rnl (14 introns) made this gene very distinctive in Glomeromycota. The presence of alternative genetic codes in both initiation (GUG) and termination (UGA) codons was another new feature in this mtDNA compared to previously published glomeromycotan mt genomes. The phylogenetic analysis inferred from the analysis of 14 protein mt genes confirmed the position of the Glomeromycota clade as a sister group of Mortierellomycotina. This mt genome is the largest observed so far in Glomeromycota and the first mt genome within the Funneliformis clade, providing new opportunities to better understand their evolution and to develop molecular markers. PMID- 27246228 TI - The Effect of Lipoaspirates on Human Keratinocytes. AB - BACKGROUND: One increasingly important trend in plastic, reconstructive, and aesthetic surgery is the use of fat grafts to improve cutaneous wound healing. In clinical practice, lipoaspirates (adipose tissue harvested by liposuction) are re injected in a procedure called lipofilling. Previous studies, however, mainly evaluated the regenerative effect of isolated adipocytes, adipose-derived stem cells, and excised en bloc adipose tissue on keratinocytes, whereas no study to date has examined the effect of lipoaspirates. OBJECTIVES: The authors aimed to investigate differences in the regenerative property of en bloc adipose tissue and lipoaspirates on keratinocytes. METHODS: Human keratinocytes, lipoaspirates, and en bloc adipose tissue from 36 healthy donors were isolated. In vitro proliferation, differentiation, migration, stratification, and wound healing of keratinocyte monolayers were measured. Furthermore, secreted levels of VEGF, bFGF, IGF-1, MMP-9, and MIF were detected by ELISA. RESULTS: Migration, proliferation, and wound healing of keratinocytes were increased by lipoaspirates. Interestingly, the effect of lipoaspirates on keratinocyte proliferation was significantly higher than by en bloc adipose tissue after 5 days. The differentiation of keratinocytes was equally attenuated by lipoaspirates and en bloc adipose tissue. Stratification of keratinocyte layers was enhanced by lipoaspirates and en bloc fat when compared to controls. Lipoaspirates secrete higher levels of bFGF, whereas higher levels of VEGF and IGF-1 are released by en bloc adipose tissue. CONCLUSION: We show that lipoaspirates and en bloc adipose tissue have a regenerative effect on keratinocytes. One reason for the higher effect of lipoaspirates on keratinocyte proliferation may be the secretion of different cytokines. PMID- 27246229 TI - In vitro Efficacy of Experimental Chitosan-Containing Solutions as Anti-Erosive Agents in Enamel. AB - The present study evaluated the effect of chitosans with different viscosities, dissolved in an AmF/SnCl2 solution, against erosion or erosion/abrasion. A total of 192 specimens were assigned to 2 * 6 groups (n = 16 specimens each): negative control, 4 chitosan solutions (groups Ch50, Ch500, Ch1000, and Ch2000, with viscosity of 50, 500, 1,000, or 2,000 mPas, respectively, 0.5% chitosan, 500 ppm F-, 800 ppm Sn2+, pH 4.4), and positive control (500 ppm F-, 800 ppm Sn2+, pH 4.3). One half of the groups was demineralized (experiment 1, E1; 10 days, 6 * 2 min/day, 0.5% citric acid, pH 2.8) and exposed to solutions (2 * 2 min/day); the other half was additionally brushed (15 s, 200 g) with non-fluoridated toothpaste before solution immersion (experiment 2, E2). Treatment effects were investigated by profilometry, energy-dispersive X-ray spectroscopy and scanning electron microscopy (SEM). In E1, all the chitosan-containing solutions reduced enamel loss by 77-80%, to the same extent as the positive control, except for Ch2000 (p <= 0.05), which completely inhibited tissue loss by the formation of precipitates. In E2, Ch50 and Ch500 showed best performance, with approximately 60% reduction of tissue loss compared to the negative control group (p <= 0.05 compared to other groups). SEM analysis showed differences between negative control and the other groups but only minor differences amongst the groups treated with active agents. In both E1 and E2, treatment with active agents resulted in surface enrichment of carbon and tin compared to negative control (p <= 0.001); brushing removed parts of carbon and tin (p <= 0.001). Chitosan shows different properties under erosive and erosive/abrasive conditions. Under erosive conditions high viscosity might be helpful, whereas lower viscosity seems to be more effective in cases of chemo-mechanical challenges. PMID- 27246230 TI - Impact of the PROVAUR stewardship programme on linezolid resistance in a tertiary university hospital: a before-and-after interventional study. AB - BACKGROUND: There is little evidence of the impact of antimicrobial stewardship programmes on antimicrobial resistance. OBJECTIVES: To study the efficacy and safety of a package of educational and interventional measures to optimize linezolid use and its impact on bacterial resistance. METHODS: A quasi experimental study was designed and carried out before and after implementation of a stewardship programme in hospitalized patients with Gram-positive infections treated with linezolid. RESULTS: The intervention reduced linezolid consumption by 76%. The risk of linezolid-resistant CoNS isolates (OR = 0.37; 95% CI = 0.27 0.49; P < 0.001) and Enterococcus faecalis (OR = 0.44; 95% CI = 0.21-0.90; P = 0.03) during the intervention period was lower than in the pre-intervention period. CONCLUSIONS: A programme to optimize linezolid use can contribute to reducing the resistance rate of CoNS and E. faecalis to this antibiotic. PMID- 27246231 TI - Emergence and evolution of an international cluster of MDR Bacteroides fragilis isolates. AB - OBJECTIVES: The aim of this study was to examine the antibiotic resistance profiles, antibiotic resistance mechanisms and possible 'clonal' nature of some MDR Bacteroides fragilis strains that simultaneously harboured cfiA, nimB, IS1186 and IS4351. METHODS: Antibiotic susceptibilities were determined by Etests and antibiotic resistance genes and different genetic elements were detected by applying PCR methods. The environments of the cfiA and nimB genes were also determined by sequencing. The transferability of the cfiA, nimB and tet(Q) genes was tested by conjugation. The genetic relatedness of the test strains was tested by ERIC-PCR or PFGE. The complete genome sequences of two strains (B. fragilis BF8 and O:21) were determined by next-generation sequencing. RESULTS: Most of the seven B. fragilis strains tested displayed multidrug resistance phenotypes; five strains were resistant to at least five types of antibiotics. Besides the common genetic constitution, ERIC-PCR implied high genetic relatedness. Similarities in some of the antibiotic resistance mechanisms [carbapenems (cfiA) and metronidazole (nimB)] also confirmed their common origin, but some other resistance mechanisms {MLSB [erm(F)] and tetracycline [tet(Q)]} and PFGE typing revealed differences. In B. fragilis BF8 and O:21, erm(F) and tet(X) genes were found with IS4351 borders, thus constituting Tn4351. All the strains were tet(Q) positive and transferred this gene in conjugation experiments, but not the cfiA and nimB genes. CONCLUSIONS: An international cluster of MDR B. fragilis strains has been identified and characterized. This 'clone' may have emerged early in the evolution of division II B. fragilis strains, which was suggested by the low complexity ERIC profiles and differences in the PFGE patterns. PMID- 27246232 TI - Microbiological efficacy and tolerability of a single-dose regimen of 1 g of ceftriaxone in men with gonococcal urethritis. AB - OBJECTIVES: We treated men with gonococcal urethritis with a single-dose regimen of 1 g of ceftriaxone, which is recommended as the first-line treatment for gonorrhoea in Japan, to determine its microbiological outcomes and tolerability. METHODS: We enrolled 255 men with gonococcal urethritis and treated them with a single-dose regimen of 1 g of ceftriaxone. We evaluated its microbiological outcomes and tolerability. We also determined ceftriaxone MICs for pretreatment isolates of Neisseria gonorrhoeae collected from the patients. RESULTS: The microbiological efficacy of the ceftriaxone regimen, which was determined between 5 and 9 days after treatment in 111 men based on the Japanese guideline for clinical research on antimicrobial agents in urogenital infections, was 100%. In the 194 men who returned to the clinic between 2 and 41 days after treatment, 191 (98.5%; 95% CI 96.8%-100%) were negative for N. gonorrhoeae after treatment. Ceftriaxone MICs determined for 136 pretreatment isolates obtained from these 194 men ranged from 0.001 to 0.25 mg/L. One isolate persisting after treatment exhibited a ceftriaxone MIC of 0.008 mg/L. For two isolates persisting after treatment, ceftriaxone MICs were not determined. Seven adverse events were observed in 7 (3.2%) of the 220 men treated with the ceftriaxone regimen. Four men had diarrhoea classified as grade 1. Three had urticaria during ceftriaxone administration, with one event classified as grade 1 and two events classified as grade 3. CONCLUSIONS: A single-dose regimen of 1 g of ceftriaxone was microbiologically effective against gonococcal urethritis and was safe and tolerable. PMID- 27246233 TI - Location of colistin resistance gene mcr-1 in Enterobacteriaceae from livestock and meat. PMID- 27246234 TI - Treatment of MDR urinary tract infections with oral fosfomycin: a retrospective analysis. AB - OBJECTIVES: Limited options for treating MDR organisms have led clinicians to turn to older antimicrobial agents that may display activity against such infections. One such agent is fosfomycin, an oral drug with activity against a variety of Gram-positive and -negative bacteria, but only approved for use in the USA for urinary tract infection (UTI) due to Escherichia coli and Enterococcus faecalis. The purpose of this study was to assess the efficacy of fosfomycin treatment of MDR UTI and identify predictors of outcome. PATIENTS AND METHODS: A retrospective review was performed of patients treated for MDR UTI at a large quaternary medical centre between 1 January 2010 and 30 September 2014. Sixty patients received 69 courses of fosfomycin in the inpatient or outpatient setting for UTIs due to Enterobacteriaceae, Pseudomonas aeruginosa or VRE. RESULTS: In the 58 patients for whom follow-up data were available, the treatment success rate (no persistent or recurrent infection) was 55%. Chronic kidney disease was associated with persistent infection (OR = 3.56, 95% CI = 1.02-12.40, P = 0.04). No other factors, including comorbidities, infecting organism, fosfomycin MIC or number of doses of fosfomycin received, were associated with recurrent infection or treatment failure. CONCLUSIONS: This study supports the use of fosfomycin as an oral option for treating MDR UTIs. Additional studies are required to assess the optimal dosing and utility of combination therapy to decrease the incidence of treatment failure. PMID- 27246235 TI - Inducible colistin resistance via a disrupted plasmid-borne mcr-1 gene in a 2008 Vietnamese Shigella sonnei isolate. AB - OBJECTIVES: The objective of this study was to assess the presence of mcr-1 in Shigella sonnei isolated in Vietnam. METHODS: WGS data were analysed for the presence of the mcr-1 gene sequence. The association of mcr-1 with a plasmid was assessed by PCR and by conjugation. RESULTS: Through genome sequencing we identified a plasmid-associated inactive form of mcr-1 in a 2008 Vietnamese isolate of Shigella sonnei. The plasmid was conjugated into Escherichia coli and mcr-1 was activated upon exposure to colistin, resulting in highly colistin resistant transconjugants. CONCLUSIONS: This is the first description of the mcr 1 gene in Shigella, which is atypical given that colistin is not ordinarily used to treat diarrhoea. Our data suggest the mcr-1 gene has been circulating in human restricted pathogens for some time but likely carries a selective fitness cost. PMID- 27246236 TI - A model-based analysis of the predictive performance of different renal function markers for cefepime clearance in the ICU. AB - OBJECTIVES: Several population pharmacokinetic models for cefepime in critically ill patients have been described, which all indicate that variability in renal clearance is the main determinant of the observed variability in exposure. The main objective of this study was to determine which renal marker best predicts cefepime clearance. METHODS: A pharmacokinetic model was developed using NONMEM based on 208 plasma and 51 urine samples from 20 ICU patients during a median follow-up of 3 days. Four serum-based kidney markers (creatinine, cystatin C, urea and uromodulin) and two urinary markers [measured creatinine clearance (CLCR) and kidney injury molecule-1] were evaluated as covariates in the model. RESULTS: A two-compartment model incorporating a renal and non-renal clearance component along with an additional term describing haemodialysis clearance provided an adequate description of the data. The Cockcroft-Gault formula was the best predictor for renal cefepime clearance. Compared with the base model without covariates, the objective function value decreased from 1971.7 to 1948.1, the median absolute prediction error from 42.4% to 29.9% and the between-subject variability in renal cefepime clearance from 135% to 50%. Other creatinine- and cystatin C-based formulae and measured CLCR performed similarly. Monte Carlo simulations using the Sanford guide dose recommendations indicated an insufficient dose reduction in patients with a decreased kidney function, leading to potentially toxic levels. CONCLUSIONS: The Cockcroft-Gault formula was the best predictor for cefepime clearance in critically ill patients, although other creatinine- and cystatin C-based formulae and measured CLCR performed similarly. PMID- 27246237 TI - Carriage of antimicrobial-resistant commensal bacteria in Dutch long-term-care facilities. AB - OBJECTIVES: The objective of this study was to assess carriage of antimicrobial resistant commensal microorganisms, i.e. Escherichia coli and Staphylococcus aureus, and its predictors in long-term-care facilities (LTCFs). METHODS: Nasal swabs and/or urine or incontinence samples were collected from participating residents in 111 LTCFs and tested for the presence of S. aureus and/or E. coli, respectively. Antimicrobial resistance to eight antimicrobials was linked to antimicrobial usage in the year preceding sampling and to LTCF characteristics. Using multilevel logistic regression, predictors of carriage of ESBL-producing E. coli in LTCFs were identified. RESULTS: S. aureus was identified in 1269/4763 (26.6%) nasal swabs, including 13/4763 (0.3%) MRSA carriers in 9/107 (8%) LTCFs. Of the 5359 urine/incontinence samples, 2934 (55%) yielded E. coli, including 123 (4.2%) producing ESBL, which were found in 53/107 locations (range 1%-33%). For all but one antimicrobial (i.e. nitrofurantoin) >20% of isolated E. coli were resistant. Multilevel multivariable logistic regression identified two predictors of carriage of ESBL-producing E. coli: (i) antimicrobial usage (OR 1.8, 95% CI 1.1-3.0 for each extra 50 DDD/1000 residents/day); and (ii) presence of MRSA carriers in the LTCFs (OR 2.4, 95% CI 1.0-5.6). CONCLUSIONS: The low proportion of 4.2% ESBL-producing E. coli and the low prevalence of 0.3% MRSA carriage found in LTCF residents suggest that Dutch LTCFs are not yet an important reservoir of MDR potential pathogens. Nevertheless, the large variation between LTCFs warrants close monitoring of antimicrobial resistance in LTCFs. Integrated surveillance, i.e. linking data sources on antimicrobial usage, microbiological testing, clinical background data and epidemiological data, is needed. PMID- 27246238 TI - Loss and gain of aminoglycoside resistance in global clone 2 Acinetobacter baumannii in Australia via modification of genomic resistance islands and acquisition of plasmids. AB - OBJECTIVES: The objective of this study was to examine the evolution of carbapenem-resistant global clone 2 (GC2) Acinetobacter baumannii in Australia focusing on the complement of aminoglycoside resistance genes and their location in resistance islands and plasmids. METHODS: Sixty-two carbapenem-resistant GC2 A. baumannii isolates with various aminoglycoside resistance profiles and resistance gene content that were recovered over the period 1999-2010 from hospitals on the east coast of Australia were examined. PCR was used to link relevant contigs retrieved from whole genomes sequenced using Illumina HiSeq and assembled de novo using Velvet. Resistance phenotypes were extended to include additional antibiotics using a disc diffusion assay. RESULTS: Sixty-one isolates were ST208 (formerly ST92; Oxford scheme) and one was ST425. All isolates included the oxa23 carbapenem resistance gene in Tn2006 located in the same position in AbGRI1-2, along with the ISAba1-sul2-CR2Delta-tetA(B)-tetA(R)-CR2 strB-strA configuration. All isolates harboured either AbGRI2-1 carrying the aacC1 (gentamicin resistance) cassette or a variant derived from it via loss of some of the island content. When aacC1 was lost, aminoglycoside resistance was sometimes regained via acquisition of aadB (gentamicin, kanamycin and tobramycin resistance) in pRAY*-v1 or TnaphA6 (amikacin, kanamycin and neomycin resistance) in a repAci6 plasmid. A small cryptic plasmid or a deletion variant of this plasmid was always present and a large cryptic plasmid was also variably present. CONCLUSIONS: The extensively antibiotic-resistant GC2 isolates from Sydney, Brisbane and Canberra appear to have arisen from a single import that was introduced into Australia in, or prior to, 1999 that then evolved and spread. PMID- 27246239 TI - Hepatic cyst penetration of cefazolin in patients receiving aspiration sclerotherapy. AB - BACKGROUND: Hepatic cyst infection is a potentially severe complication in cystic disease. Treatment demands effective antibiotic concentrations within the infected cyst. OBJECTIVES: The aim of this study was to use elective hepatic cyst drainage as a unique pharmacokinetic model to investigate whether cefazolin, a first-generation cephalosporin, is able to penetrate hepatic cysts. PATIENTS AND METHODS: Patients scheduled to undergo percutaneous aspiration sclerotherapy of a symptomatic non-infected, non-neoplastic hepatic cyst were eligible for this study. All participants received a single perioperative prophylactic dose of cefazolin (1000 mg, intravenously). We collected blood and cyst fluid samples to determine total and unbound cefazolin concentrations using HPLC. The primary outcome was hepatic cyst penetration, expressed as the ratio (%) of unbound concentration of cefazolin in cyst fluid to plasma (both in mg/L). RESULTS: We included eight patients [male = 25%, median age = 60 years (IQR 54-75), median estimated glomerular filtration rate = 97 mL/min/1.73 m(2) (IQR 67-102) and median serum albumin = 40 g/L (IQR 37-40)]. We detected low concentrations of unbound cefazolin in cyst fluid (<=1.0 mg/L). The median plasma unbound cefazolin peak level (immediately after cefazolin administration) was 36.6 mg/L (IQR 23.7 54.1) and the level at the time of cyst fluid aspiration was 16.1 mg/L (IQR 13.0 20.1). In total, the hepatic cyst penetration of free cefazolin was only 2.2% (IQR 0.7-5.2). CONCLUSIONS: We developed a study model to investigate the penetration of antibiotics into hepatic cysts. Cefazolin did not reach adequate intracystic concentrations. Future studies should explore alternatives. PMID- 27246240 TI - Echocardiographic markers of inducible myocardial ischemia at baseline evaluation preparatory to exercise stress echocardiography. AB - BACKGROUND: Tissue Doppler Imaging (TDI) is a sensible and feasible method to detect longitudinal left ventricular (LV) systolic dysfunction (LVSD) in patients with diabetes mellitus, hypertension or ischemic heart disease. In this study, we hypothesized that longitudinal LVSD assessed by TDI predicted inducible myocardial ischemia independently of other echocardiographic variables (assessed as coexisting potential markers) in patients at increased cardiovascular (CV) risk. METHODS: Two hundred one patients at high CV risk defined according to the ESC Guidelines 2012 underwent exercise stress echocardiography (ExSEcho) for primary prevention. Echocardiographic parameters were measured at rest and peak exercise. RESULTS: ExSEcho classified 168 (83.6 %) patients as non-ischemic and 33 (16,4 %) as ischemic. Baseline clinical characteristics were similar between the groups, but ischemic had higher blood pressure, received more frequently beta blockers and antiplatelet agents than non-ischemic patients. The former had greater LV size, lower relative wall thickness and higher left atrial systolic force (LASF) than the latter. LV systolic longitudinal function (measure as peak S') was significantly lower in ischemic than non-ischemic patients (8.7 +/- 2.1 vs 9.7 +/- 2.7 cm/sec, p = 0.001). The factors independently related to myocardial ischemia at multivariate logistic analysis were: lower peak S', higher LV circumferential end-systolic stress and LASF. CONCLUSIONS: In asymptomatic patients at increased risk for adverse CV events baseline longitudinal LVSD together with higher LV circumferential end-systolic stress and LASF were the factors associated with myocardial ischemia induced by ExSEcho. The assessment of these factors at standard echocardiography might help the physicians for improving the risk stratification among these patients for ExSEcho. PMID- 27246241 TI - Complete mitochondrial genome of the stoat (Mustela erminea) and New Zealand fur seal (Arctocephalus forsteri) and their significance for mammalian phylogeny. AB - The complete mitochondrial genome of three mustelid species, stoats (Mustela erminea), weasels (Mustela nivalis) and ferrets (Mustela furo), and the New Zealand fur seal (Arctocephalus forsteri) were sequenced using direct mitochondrial DNA extraction and overlapping long PCRs. The usual 37 mammalian mitochondrial genes (13 protein coding genes, 22 t-RNA and 2 r-RNA) were identified in all four mitogenomes. The divergence of stoats from other members of the sub-family Mustelinae was dated 4.5 million years ago. The mitogenomic data were consistent with a bear-like origin of seals. PMID- 27246242 TI - Cep78 is a new centriolar protein involved in Plk4-induced centriole overduplication. AB - Centrioles are core components of centrosomes, the major microtubule-organizing centers of animal cells, and act as basal bodies for cilia formation. Control of centriole number is therefore crucial for genome stability and embryogenesis. Centriole duplication requires the serine/threonine protein kinase Plk4. Here, we identify Cep78 as a human centrosomal protein and a new interaction partner of Plk4. Cep78 is mainly a centriolar protein that localizes to the centriolar wall. Furthermore, we find that Plk4 binds to Cep78 through its N-terminal domain but that Cep78 is not an in vitro Plk4 substrate. Cep78 colocalizes with Plk4 at centrioles and is required for Plk4-induced centriole overduplication. Interestingly, upon depletion of Cep78, newly synthesized Plk4 is not localized to centrosomes. Our results suggest that the interaction between Cep78 and the N terminal catalytic domain of Plk4 is a new and important element in the centrosome overduplication process. PMID- 27246244 TI - Tumor heterogeneity, clonality and single cells. PMID- 27246243 TI - The N-terminus of survivin is a mitochondrial-targeting sequence and Src regulator. AB - Survivin (also known as BIRC5) is a cancer-associated protein that exists in several locations in the cell. Its cytoplasmic residence in interphase cells is governed by CRM1 (also known as XPO1)-mediated nuclear exportation, and its localisation during mitosis to the centromeres and midzone microtubules is that of a canonical chromosomal passenger protein. In addition to these well established locations, survivin is also a mitochondrial protein, but how it gets there and its function therein is presently unclear. Here, we show that the first ten amino acids at the N-terminus of survivin are sufficient to target GFP to the mitochondria in vivo, and ectopic expression of this decapeptide decreases cell adhesion and accelerates proliferation. The data support a signalling mechanism in which this decapeptide regulates the tyrosine kinase Src, leading to reduced focal adhesion plaques and disruption of F-actin organisation. This strongly suggests that the N-terminus of survivin is a mitochondrial-targeting sequence that regulates Src, and that survivin acts in concert with Src to promote tumorigenesis. PMID- 27246245 TI - Cross-talk between the Tissue Factor/coagulation factor VIIa complex and the tyrosine kinase receptor EphA2 in cancer. AB - BACKGROUND: Tissue Factor (TF) forms a proteolytically active complex together with coagulation factor VIIa (FVIIa) and functions as the trigger of blood coagulation or alternatively activates cell signaling. We recently described that EphA2 of the Eph tyrosine kinase receptor family is cleaved directly by the TF/FVIIa complex. The aim of the present study was to further characterize the cross-talk between TF/FVIIa and EphA2 using in vitro model systems and human cancer specimens. METHODS: Cleavage and phosphorylation of EphA2 was studied by Western blot. Subcellular localization of TF and EphA2 was investigated by a proximity ligation assay and confocal microscopy. Phalloidin staining of the actin cytoskeleton was used to study cell rounding and retraction fiber formation. Expression of TF and EphA2 in human colorectal cancer specimens was examined by immunohistochemistry. RESULTS: TF and EphA2 co-localized constitutively in MDA-MB-231 cells, and addition of FVIIa resulted in cleavage of EphA2 by a PAR2-independent mechanism. Overexpression of TF in U251 glioblastoma cells lead to co-localization with EphA2 at the leading edge and FVIIa-dependent cleavage of EphA2. FVIIa potentiated ephrin-A1-induced cell rounding and retraction fiber formation in MDA-MB-231 cells through a RhoA/ROCK-dependent pathway that did not require PAR2-activation. TF and EphA2 were expressed in colorectal cancer specimens, and were significantly correlated. CONCLUSIONS: These results suggest that TF/FVIIa-EphA2 cross-talk might potentiate ligand dependent EphA2 signaling in human cancers, and provide initial evidence that it is possible for this interaction to occur in vivo. PMID- 27246246 TI - A prospective comparison of times to presentation and treatment of regional and remote head and neck patients in North Queensland, Australia. AB - BACKGROUND/AIM: This study aims to examine differences between outer regional (OR) and remote/very remote (RVR) patients in northern Queensland, Australia in the times taken to receive various aspects of head and neck cancer management. METHODS: Our study prospectively recruited head and neck cancer patients presenting to three North Queensland regional hospitals from January 2009 to January 2011. Data on demographic and cancer-specific details, comorbidities and timing of presentation to various services, were collected using a self administered questionnaire that included two questions in relation to possible reason for delays to health services. Multivariate linear regression analyses were conducted to assess the effects of various demographic characteristics on time delays. Survival and disease recurrence data were analysed in 2014. RESULTS: One hundred and fifty-eight patients participated. RVR patients had significantly longer median times between diagnosis and first treatment compared with OR patients (P = 0.015). Indigenous patients had significant delays from diagnosis to first treatment (P = 0.013) and visit to first specialist and treatment (P = 0.031) compared to non-Indigenous patients. Longer median times between symptoms and first treatment was associated with low income (P = 0.03) and lower education level (P = 0.04). Disease recurrence was higher for RVR patients compared with OR patients (P = 0.04), without significant differences in overall survival. Possible reasons for delays included patient and professional factors. CONCLUSION: Significant delays in various aspects of head and neck cancer management were associated with remoteness, Indigenous and socioeconomic status. While patient and professional factors could be addressed at local levels, sustainable improvement in outcomes requires a state and national level approach. PMID- 27246247 TI - Structural basis of FYCO1 and MAP1LC3A interaction reveals a novel binding mode for Atg8-family proteins. AB - FYCO1 (FYVE and coiled-coil domain containing 1) functions as an autophagy adaptor in directly linking autophagosomes with the microtubule-based kinesin motor, and plays an essential role in the microtubule plus end-directed transport of autophagic vesicles. The specific association of FYCO1 with autophagosomes is mediated by its interaction with Atg8-family proteins decorated on the outer surface of autophagosome. However, the mechanistic basis governing the interaction between FYCO1 and Atg8-family proteins is largely unknown. Here, using biochemical and structural analyses, we demonstrated that FYCO1 contains a unique LC3-interacting region (LIR), which discriminately binds to mammalian Atg8 orthologs and preferentially binds to the MAP1LC3A and MAP1LC3B. In addition to uncovering the detailed molecular mechanism underlying the FYCO1 LIR and MAP1LC3A interaction, the determined FYCO1-LIR-MAP1LC3A complex structure also reveals a unique LIR binding mode for Atg8-family proteins, and demonstrates, first, the functional relevance of adjacent sequences C-terminal to the LIR core motif for binding to Atg8-family proteins. Taken together, our findings not only provide new mechanistic insight into FYCO1-mediated transport of autophagosomes, but also expand our understanding of the interaction modes between LIR motifs and Atg8 family proteins in general. PMID- 27246248 TI - Managing the initiation and early implementation of health promotion interventions: a study of a parental support programme in primary care. AB - BACKGROUND: Mental health problems are increasing among children and adolescents worldwide, and parental support programmes have been suggested as one preventive intervention. However, the actual impact and low rates of adoption and sustainability of prevention programmes have proven to be a concern, and thus, further studies on their implementation are needed. AIM: This study focused on the initial implementation of the International Child Development Programme (ICDP) in primary care. The aim was to investigate the involved actors' views on factors likely to affect implementation and the strategies used to manage them. DESIGN: A case study design with a mixed-methods approach combining quantitative and qualitative data from questionnaires and interviews was used. METHODS: Eighty two professionals at different positions in the involved organisations participated. Directed content analysis was used for analyses, focusing on perceived levels of importance and the manifestation of implementation factors. FINDINGS: Interviews and questionnaires provided descriptions of factors influencing the initial ICDP implementation. Uncertainty on how to manage important factors and vague change strategies was reported. Discrepancies in the perceived levels of importance versus manifestation were found regarding several factors, including hands-on support, time and resources, communication and information, a comprehensive plan of action, follow-ups, and external and internal collaborations. Manifested factors were a need for change, motivation and the ICDP's compatibility with existing norms, values and practices. CONCLUSIONS: Implementing a parental support programme in a complex setting will benefit from being preceded by a thorough examination of the intervention and the target context and the development of clear implementation strategies based on the results of that examination. This study provides insights into how and by whom knowledge on implementation is applied during the launch of a health promotion programme, and these insights might help increase the rate of adoption and the use of such programmes and thereby increase their effectiveness. PMID- 27246250 TI - Mapping number to space in the two hemispheres of the avian brain. AB - Pre-verbal infants and non-human animals associate small numbers with the left space and large numbers with the right space. Birds and primates, trained to identify a given position in a sagittal series of identical positions, whenever required to respond on a left/right oriented series, referred the given position starting from the left end. Here, we extended this evidence by selectively investigating the role of either cerebral hemisphere, using the temporary monocular occlusion technique. In birds, lacking the corpus callosum, visual input is fed mainly to the contralateral hemisphere. We trained 4-day-old chicks to identify the 4th element in a sagittal series of 10 identical elements. At test, the series was identical but left/right oriented. Test was conducted in right monocular, left monocular or binocular condition of vision. Right monocular chicks pecked at the 4th right element; left monocular and binocular chicks pecked at the 4th left element. Data on monocular chicks demonstrate that both hemispheres deal with an ordinal (sequential) task. Data on binocular chicks indicate that the left bias is linked to a right hemisphere dominance, that allocates the attention toward the left hemispace. This constitutes a first step towards understanding the neural basis of number space mapping. PMID- 27246249 TI - Blocking glucocorticoid receptors at adolescent age prevents enhanced freezing between repeated cue-exposures after conditioned fear in adult mice raised under chronic early life stress. AB - Early life adversity can have long-lasting impact on learning and memory processes and increase the risk to develop stress-related psychopathologies later in life. In this study we investigated (i) how chronic early life stress (ELS) - elicited by limited nesting and bedding material from postnatal day 2 to 9 - affects conditioned fear in adult mice and (ii) whether these effects can be prevented by blocking glucocorticoid receptors (GRs) at adolescent age. In adult male and female mice, ELS did not affect freezing behavior to the first tone 24h after training in an auditory fear-conditioning paradigm. Exposure to repeated tones 24h after training also resulted in comparable freezing behavior in ELS and control mice, both in males and females. However, male (but not female) ELS compared to control mice showed significantly more freezing behavior between the tone-exposures, i.e. during the cue-off periods. Intraperitoneal administration of the GR antagonist RU38486 during adolescence (on postnatal days 28-30) fully prevented enhanced freezing behavior during the cue-off period in adult ELS males. Western blot analysis revealed no effects of ELS on hippocampal expression of glucocorticoid receptors, neither at postnatal day 28 nor at adult age, when mice were behaviorally tested. We conclude that ELS enhances freezing behavior in adult mice in a potentially safe context after cue-exposure, which can be normalized by brief blockade of glucocorticoid receptors during the critical developmental window of adolescence. PMID- 27246251 TI - Global hypoxia induced impairment in learning and spatial memory is associated with precocious hippocampal aging. AB - Both chronological aging and chronic hypoxia stress have been reported to cause degeneration of hippocampal CA3 neurons and spatial memory impairment through independent pathways. However, the possible occurrence of precocious biological aging on exposure to single episode of global hypoxia resulting in impairment of learning and memory remains to be established. The present study thus aimed at bridging this gap in existing literature on hypoxia induced biological aging. Male Sprague Dawley rats were exposed to simulated hypobaric hypoxia (25,000ft) for different durations and were compared with aged rats. Behavioral studies in Morris Water Maze showed decline in learning abilities of both chronologically aged as well as hypoxic rats as evident from increased latency and pathlength to reach target platform. These behavioral changes in rats exposed to global hypoxia were associated with deposition of lipofuscin and ultrastructural changes in the mitochondria of hippocampal neurons that serve as hallmarks of aging. A single episode of chronic hypobaric hypoxia exposure also resulted in the up-regulation of pro-aging protein, S100A9 and down regulation of Tau, SNAP25, APOE and Sod2 in the hippocampus similar to that in aged rats indicating hypoxia induced accelerated aging. The present study therefore provides evidence for role of biological aging of hippocampal neurons in hypoxia induced impairment of learning and memory. PMID- 27246252 TI - How Should We Manage Iatrogenic Perforation Caused by Colonoscopy? PMID- 27246253 TI - Advances in the Management of Upper Gastrointestinal Subepithelial Tumor: Pathologic Diagnosis Using Endoscopy without Endoscopic Ultrasound-Guided Biopsy. AB - Until now, biopsy methods for subepithelial tumors (SETs) have focused on endoscopic ultrasound (EUS)-guided biopsy; however, these methods have several limitations. We devised a simple method for pathologic diagnosis of SETs. SETs are occasionally diagnosed during endoscopy, and lesions are generally small and asymptomatic. It can be challenging to decide on a management plan for large asymptomatic SETs. EUS imaging provides information regarding the size, layer, and echo pattern of the lesions. Patient management plans have traditionally been determined based on EUS images, whereby the endoscopist chooses to either monitor or remove the tumor. However, EUS alone cannot diagnose and evaluate upper gastrointestinal SETs with high accuracy. As sufficient tissue samples are required for the accurate diagnosis of SETs, EUS-guided biopsy techniques such as EUS fine-needle aspiration and trucut biopsy are currently used. However, these methods have a relatively low diagnostic accuracy and do not always provide information upon immunohistochemical staining. Endoscopists can easily detect a submucosal mass after creating an iatrogenic mucosal ulcer, after which tissue sampling is performed by using endoscopic biopsy. Furthermore, pathologic results can differentiate between benign and premalignant lesions. Here, we introduce a simple method for the pathologic diagnosis of SETs. PMID- 27246254 TI - Bradycardia, Hypotension, and Midventricular Takotsubo Syndrome during Esophagogastroduodenoscopy. PMID- 27246255 TI - Rho-associated protein kinase 1 (ROCK1) is increased in Alzheimer's disease and ROCK1 depletion reduces amyloid-beta levels in brain. AB - Alzheimer's disease (AD) is the leading cause of dementia and mitigating amyloid beta (Abeta) levels may serve as a rational therapeutic avenue to slow AD progression. Pharmacologic inhibition of the Rho-associated protein kinases (ROCK1 and ROCK2) is proposed to curb Abeta levels, and mechanisms that underlie ROCK2's effects on Abeta production are defined. How ROCK1 affects Abeta generation remains a critical barrier. Here, we report that ROCK1 protein levels were elevated in mild cognitive impairment due to AD (MCI) and AD brains compared to controls. Abeta42 oligomers marginally increased ROCK1 and ROCK2 protein levels in neurons but strongly induced phosphorylation of Lim kinase 1 (LIMK1), suggesting that Abeta42 activates ROCKs. RNAi depletion of ROCK1 or ROCK2 suppressed endogenous Abeta40 production in neurons, and Abeta40 levels were reduced in brains of ROCK1 heterozygous knock-out mice compared to wild-type littermate controls. ROCK1 knockdown decreased amyloid precursor protein (APP), and treatment with bafilomycin accumulated APP levels in neurons depleted of ROCK1. These observations suggest that reduction of ROCK1 diminishes Abeta levels by enhancing APP protein degradation. Collectively, these findings support the hypothesis that both ROCK1 and ROCK2 are therapeutic targets to combat Abeta production in AD. Mitigating amyloid-beta (Abeta) levels is a rational strategy for Alzheimer's disease (AD) treatment, however, therapeutic targets with clinically available drugs are lacking. We hypothesize that Abeta accumulation in mild cognitive impairment because of AD (MCI) and AD activates the RhoA/ROCK pathway which in turn fuels production of Abeta. Escalation of this cycle over the course of many years may contribute to the buildup of amyloid pathology in MCI and/or AD. PMID- 27246256 TI - Prevalence, Correlates, and Impact of Uncorrected Presbyopia in a Multiethnic Asian Population. AB - PURPOSE: To examine the prevalence, correlates, and impact of uncorrected presbyopia on vision-specific functioning (VF) in a multiethnic Asian population. DESIGN: Population-based cross-sectional study. METHODS: We included 7890 presbyopic subjects (3909 female; age range, 40-86 years) of Malay, Indian, and Chinese ethnicities from the Singapore Epidemiology of Eye Disease study. Presbyopia was classified as corrected and uncorrected based on self-reported near correction use. VF was assessed with the VF-11 questionnaire validated using Rasch analysis. Multivariable logistic and linear regression models were used to investigate the associations of sociodemographic and clinical parameters with uncorrected presbyopia, and its impact on VF, respectively. As myopia may mitigate the impact of noncorrection, we performed a subgroup analysis on myopic subjects only (n = 2742). RESULTS: In total, 2678 of 7890 subjects (33.9%) had uncorrected presbyopia. In multivariable models, younger age, male sex, Malay and Indian ethnicities, presenting distance visual impairment (any eye), and lower education and income levels were associated with higher odds of uncorrected presbyopia (all P < .05). Compared with corrected presbyopia, noncorrection was associated with worse overall VF and reduced ability to perform individual near and distance vision-specific tasks even after adjusting for distance VA and other confounders (all P < .05). Results were very similar for myopic individuals. CONCLUSION: One-third of presbyopic Singaporean adults did not have near correction. Given its detrimental impact on both near and distance VF, public health strategies to increase uptake of presbyopic correction in younger individuals, male individuals, and those of Malay and Indian ethnicities are needed. PMID- 27246257 TI - The Influence of Social Interaction on Intuitions of Objectivity and Subjectivity. AB - We present experimental evidence that people's modes of social interaction influence their construal of truth. Participants who engaged in cooperative interactions were less inclined to agree that there was an objective truth about that topic than were those who engaged in a competitive interaction. Follow-up experiments ruled out alternative explanations and indicated that the changes in objectivity are explained by argumentative mindsets: When people are in cooperative arguments, they see the truth as more subjective. These findings can help inform research on moral objectivism and, more broadly, on the distinctive cognitive consequences of different types of social interaction. PMID- 27246258 TI - Perceptions of dental students in Japanese national universities about studying abroad. AB - PURPOSE: Dental faculties in Japan have organised many short-term international exchange programs to enable their undergraduates to study abroad. However, not many students apply for those programs. In this present study, we attempted to clarify the factors that discourage undergraduate dental students from studying abroad. METHODS: We administered a questionnaire survey to 512 undergraduate dental students in three national universities located in different areas in Japan. RESULTS: Although 61.7% of the participants expressed interest in studying abroad, only 19.1% of them had prior experiences of study abroad or plans to do so. Their main worries were about lack of sufficient language ability in academic fields. Comparing those who were interested in studying abroad with those who were not revealed significant differences regarding their concern about lack of language ability and lack of specialised knowledge in dentistry. Participants who did not want to study abroad indicated that they did not perceive a purpose in doing so and cited not having foreign friends as a problem. Household income was significantly correlated with concerns about overall expenses. CONCLUSION: Overall, language ability and academic knowledge appeared to be the two strongest factors affecting dental students' consideration of studying abroad. Dental schools in Japan can use the findings of this study to improve their undergraduate exchange programs in such a way as to stimulate greater interest amongst their students. PMID- 27246259 TI - Neuraminidase inhibitors for influenza: a systematic review and meta-analysis of regulatory and mortality data. AB - BACKGROUND: Neuraminidase inhibitors (NIs) are stockpiled and recommended by public health agencies for treating and preventing seasonal and pandemic influenza. They are used clinically worldwide. OBJECTIVES: To (1) describe the potential benefits and harms of NIs for influenza in all age groups by reviewing all clinical study reports (CSRs) of published and unpublished randomised, placebo-controlled trials and regulatory comments; and (2) determine the effect of oseltamivir (Tamiflu((r)), Roche) treatment on mortality in patients with 2009A/H1N1 influenza. METHODS: We searched trial registries, electronic databases and corresponded with regulators and sponsors to identify randomised trials of NIs. We requested full CSRs and accessed regulators' comments. We included only those trials for which we had CSRs. To examine the effects of oseltamivir on 2009A/H1N1 influenza mortality, we requested individual patient data (IPD) from corresponding authors of all included observational studies. RESULTS: Effect of oseltamivir and zanamivir (Relenza(r), GlaxoSmithKline) in the prevention and treatment of influenza: Oseltamivir reduced the time to first alleviation of symptoms in adults by 16.8 hours [95% confidence interval (CI) 8.4 to 25.1 hours]. Zanamivir reduced the time to first alleviation of symptoms in adults by 0.60 days (95% CI 0.39 to 0.81 days). Oseltamivir reduced unverified pneumonia in adult treatment [risk difference (RD) 1.00%, 95% CI 0.22% to 1.49%]; similar findings were observed with zanamivir prophylaxis in adults (RD 0.32%, 95% CI 0.09% to 0.41%). Oseltamivir treatment of adults increased the risk of nausea (RD 3.66%, 95% CI 0.90% to 7.39%) and vomiting (RD 4.56%, 95% CI 2.39% to 7.58%). In the treatment of children, oseltamivir induced vomiting (RD 5.34%, 95% CI 1.75% to 10.29%). Both oseltamivir and zanamivir prophylaxis reduced the risk of symptomatic influenza in individuals (oseltamivir RD 3.05%, 95% CI 1.83% to 3.88%; zanamivir RD 1.98%, 95% CI 0.98% to 2.54%) and in households (oseltamivir RD 13.6%, 95% CI 9.52% to 15.47%; zanamivir RD 14.84%, 95% CI 12.18% to 16.55%). Oseltamivir increased psychiatric adverse events in the combined on- and off treatment periods (RD 1.06%, 95% CI 0.07% to 2.76%) and the risk of headaches while on treatment (RD 3.15%, 95% CI 0.88% to 5.78%). Effect of oseltamivir on mortality in patients with 2009A/H1N1 influenza: Analysis of summary data of 30 studies as well as IPD of four studies showed evidence of time-dependent bias. After adjusting for time-dependent bias and potential confounding variables, competing risks analysis of the IPD showed insufficient evidence that oseltamivir reduced the risk of mortality (hazard ratio 1.03, 95% CI 0.64 to 1.65). CONCLUSIONS: Oseltamivir and zanamivir cause small reductions in the time to first alleviation of influenza symptoms in adults. The use of oseltamivir increases the risk of nausea, vomiting, psychiatric events in adults and vomiting in children. Oseltamivir has no protective effect on mortality among patients with 2009A/H1N1 influenza. Prophylaxis with either NI may reduce symptomatic influenza in individuals and in households. The balance between benefits and harms should be considered when making decisions about use of NIs for either prophylaxis or treatment of influenza. STUDY REGISTRATION: This study is registered as PROSPERO CRD42012002245. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 27246261 TI - Sharing (all) clinical data. PMID- 27246260 TI - The Cortical Development of Specialized Face Processing in Infancy. AB - The aim of this study was to examine specialized face processing in forty-eight 4.5- to 7.5-month-old infants by recording event-related potentials (ERPs) in response to faces and toys, and to determine the cortical sources of these signals using realistic, age-appropriate head models. All ERP components (i.e., N290, P400, Nc) showed greater amplitude during periods of attention than inattention. Amplitude was greater to faces than toys during attention at the N290, and greater to toys at the P400. Cortical source analysis revealed activity in occipital-temporal brain areas as the source of the N290, particularly the middle fusiform gyrus. The Nc and P400 were the result of activation in midline frontal and parietal, anterior temporal, and posterior temporal and occipital brain areas. PMID- 27246262 TI - Management of a dissection of matrix P right ventricular-to-pulmonary artery conduit by implanting two pre-stents and a melody valve. AB - Reconstructing the right ventricular outflow tract and pulmonary valve via a bovine-derived valve conduit such as Matrix-P-Xenograft is a common surgical repair technique for pulmonary atresia and ventricular septal defect. After conduit degeneration due to calcification or aneurysmal dilatation, percutaneous transvenous stenting of the right ventricular outflow tract followed by pulmonary valve implantation has become the standard interventional treatment. Applied to stenotic conduits, the method is considered safe and effective. An important but seldom-reported problem is graft failure related to the formation of a Matrix membrane due to inflammation and fibrosis inside the xenograft, which can cause serious problems when dissection and rupture occur during transcatheter intervention. The torn pseudomembrane may cause the complete obstruction of both pulmonary arteries, resulting in a life-threatening situation requiring rapid intervention, as in this case presentation. (c) 2016 Wiley Periodicals, Inc. PMID- 27246263 TI - Role and expression of cry1 in the adductor muscle of the oyster Crassostrea gigas during daily and tidal valve activity rhythms. AB - Cryptochromes are flavin- and pterin-containing photoreceptors of the cryptochrome/photolyase family. They play critical roles in organisms, among are which light-dependent and light-independent roles in biological rhythms. The present work aimed at describing a cryptochrome gene in the oyster Crassostrea gigas by (i) a characterization and phylogenetic analysis and (ii) by studying its expression in the relationship to rhythmic valve behavior in different entrainment regimes. Cryptochrome expression was focused on the adductor muscle of the oyster, the effector of the valve behavior. The results suggest involvement of Cgcry1 in oyster rhythmicity as a sensor of environmental zeitgebers, associated with circadian rhythms and potentially to tidal activity. The characterized gene belongs to type 1 cryptochrome/insect-type cry. Additionally, Cgcry1 presented a daily oscillation under L:D entrainment, which disappeared in constant darkness. Transcript expression of Cgcry1 also oscillated at tidal frequency under tidal entrainment and in constant darkness. Finally, exposure of tidally entrained oysters to saxitoxin (STX)-producing alga Alexandrium minutum induced a dose effect response in oysters by first altering Cgcry1 expression and then the behavior of oysters with increasing concentrations of toxins. This study initiates the characterization of the molecular clock in the oyster C. gigas and its interactions with environmental zeitgebers. PMID- 27246264 TI - Evidence of Splitting 1,2,3-Triazole into an Alkyne and Azide by Low Mechanical Force in the Presence of Other Covalent Bonds. AB - The cycloaddition reaction of an alkyne and azide to form a 1,2,3-triazole is widely used in many areas. However, the stability of the triazole moiety under mechanical stress is unclear. To see if a triazole could be selectively split into an alkyne and azide in the presence of other typical covalent bonds, a mica surface functionalized with a molecule containing a triazole moiety in the middle and an activated ester at the end was prepared. An atomic force microscope (AFM) tip with amino groups on its surface was ramped over the mica surface at predefined locations, which could temporarily link the tip to the surface through amide bond formation. During retraction, the triazole or another bond in the linkage broke, and a force was recorded. The forces varied widely at different ramps from close to 0 pN to 860 pN due to nonspecific adhesions and to the inherent inconsistency of single bond rupture. If some of the forces were from triazole cycloreversion, there would be alkynes at the predefined ramping locations. The surface was reacted with an azide carboxylic acid followed by labeling with amino Au nanoparticles (AuNPs). AFM imaging revealed AuNPs at the predicted locations, which provided evidence that under certain conditions triazole could be split selectively in the presence of other bonds at forces below 860 pN. PMID- 27246265 TI - Development of chylous ascites in an infant with ventricular septal defect: a case report. AB - This case report describes chylous ascites associated with a CHD in a 4-month-old infant. Although atraumatic chylous ascites are a rare clinical finding, the recognition and treatment of chylous ascites influence the timing of cardiac surgery. PMID- 27246268 TI - A coregionalization model can assist specification of Geographically Weighted Poisson Regression: Application to an ecological study. AB - The geographical distribution of health outcomes is influenced by socio-economic and environmental factors operating on different spatial scales. Geographical variations in relationships can be revealed with semi-parametric Geographically Weighted Poisson Regression (sGWPR), a model that can combine both geographically varying and geographically constant parameters. To decide whether a parameter should vary geographically, two models are compared: one in which all parameters are allowed to vary geographically and one in which all except the parameter being evaluated are allowed to vary geographically. The model with the lower corrected Akaike Information Criterion (AICc) is selected. Delivering model selection exclusively according to the AICc might hide important details in spatial variations of associations. We propose assisting the decision by using a Linear Model of Coregionalization (LMC). Here we show how LMC can refine sGWPR on ecological associations between socio-economic and environmental variables and low birth weight outcomes in the west-north-central region of Portugal. PMID- 27246266 TI - Dopamine Receptor Antagonists Enhance Proliferation and Neurogenesis of Midbrain Lmx1a-expressing Progenitors. AB - Degeneration of dopamine neurons in the midbrain causes symptoms of the movement disorder, Parkinson disease. Dopamine neurons are generated from proliferating progenitor cells localized in the embryonic ventral midbrain. However, it remains unclear for how long cells with dopamine progenitor character are retained and if there is any potential for reactivation of such cells after cessation of normal dopamine neurogenesis. We show here that cells expressing Lmx1a and other progenitor markers remain in the midbrain aqueductal zone beyond the major dopamine neurogenic period. These cells express dopamine receptors, are located in regions heavily innervated by midbrain dopamine fibres and their proliferation can be stimulated by antagonizing dopamine receptors, ultimately leading to increased neurogenesis in vivo. Furthermore, treatment with dopamine receptor antagonists enhances neurogenesis in vitro, both from embryonic midbrain progenitors as well as from embryonic stem cells. Altogether our results indicate a potential for reactivation of resident midbrain cells with dopamine progenitor potential beyond the normal period of dopamine neurogenesis. PMID- 27246269 TI - Model-based testing for space-time interaction using point processes: An application to psychiatric hospital admissions in an urban area. AB - Spatio-temporal interaction is inherent to cases of infectious diseases and occurrences of earthquakes, whereas the spread of other events, such as cancer or crime, is less evident. Statistical significance tests of space-time clustering usually assess the correlation between the spatial and temporal (transformed) distances of the events. Although appealing through simplicity, these classical tests do not adjust for the underlying population nor can they account for a distance decay of interaction. We propose to use the framework of an endemic epidemic point process model to jointly estimate a background event rate explained by seasonal and areal characteristics, as well as a superposed epidemic component representing the hypothesis of interest. We illustrate this new model based test for space-time interaction by analysing psychiatric inpatient admissions in Zurich, Switzerland (2007-2012). Several socio-economic factors were found to be associated with the admission rate, but there was no evidence of general clustering of the cases. PMID- 27246267 TI - SERS detection of Biomolecules at Physiological pH via aggregation of Gold Nanorods mediated by Optical Forces and Plasmonic Heating. AB - Strategies for in-liquid molecular detection via Surface Enhanced Raman Scattering (SERS) are currently based on chemically-driven aggregation or optical trapping of metal nanoparticles in presence of the target molecules. Such strategies allow the formation of SERS-active clusters that efficiently embed the molecule at the "hot spots" of the nanoparticles and enhance its Raman scattering by orders of magnitude. Here we report on a novel scheme that exploits the radiation pressure to locally push gold nanorods and induce their aggregation in buffered solutions of biomolecules, achieving biomolecular SERS detection at almost neutral pH. The sensor is applied to detect non-resonant amino acids and proteins, namely Phenylalanine (Phe), Bovine Serum Albumin (BSA) and Lysozyme (Lys), reaching detection limits in the MUg/mL range. Being a chemical free and contactless technique, our methodology is easy to implement, fast to operate, needs small sample volumes and has potential for integration in microfluidic circuits for biomarkers detection. PMID- 27246270 TI - Hantavirus seropositivity in rodents in relation to habitat heterogeneity in human-shaped landscapes of Southeast Asia. AB - To establish how the conversion of natural habitats for agricultural purposes may impact the distribution of hantaviruses in Southeast Asia, we tested how habitat structure affects hantavirus infection prevalence of common murine rodents that inhabit human-dominated landscapes in this region. For this, we used geo referenced data of rodents analysed for hantavirus infection and land cover maps produced for the seven study sites in Thailand, Cambodia and Lao PDR where they were collected. Rodents were tested by serological methods that detect several hantaviruses, including pathogenic ones. Rodents with a seropositive status were more likely to be found near to agriculture on steep land, and also in environments with a high proportion of agriculture on steep land. These results suggest that in Southeast Asia, hantaviruses, which are often associated with generalist rodent species with a preference for agricultural land, may benefit from land conversion to agriculture. PMID- 27246271 TI - Air pollution is associated with primary health care visits for asthma in Sweden: A case-crossover design with a distributed lag non-linear model. AB - BACKGROUND: Air pollution can increase the symptoms of asthma and has an acute effect on the number of emergency room visits and hospital admissions because of asthma, but little is known about the effect of air pollution on the number of primary health care (PHC) visits for asthma. OBJECTIVE: To investigate the association between air pollution and the number of PHC visits for asthma in Scania, southern Sweden. METHODS: Data on daily PHC visits for asthma were obtained from a regional healthcare database in Scania, which covers approximately half a million people. Air pollution data from 2005 to 2010 were obtained from six urban background stations. We used a case-crossover study design and a distributed lag non-linear model in the analysis. RESULTS: The air pollution levels were generally within the EU air quality guidelines. The mean number of daily PHC visits for asthma was 34. The number of PHC visits increased by 5% (95% confidence interval (CI): 3.91-6.25%) with every 10ug m(-3) increase in daily mean NO2 lag (0-15), suggesting that daily air pollution levels are associated with PHC visits for asthma. CONCLUSION: Even though the air quality in Scania between 2005 and 2010 was within EU's guidelines, the number of PHC visits for asthma increased with increasing levels of air pollution. This suggests that as well as increasing hospital and emergency room visits, air pollution increases the burden on PHC due to milder symptoms of asthma. PMID- 27246272 TI - Identifying spatial data availability and spatial data needs for Chagas disease mitigation in South America. AB - The objective of this paper on Chagas disease is to determine the availability and spatial resolution of existing data that can be used to address Chagas disease transmission risk in South America. A literature review was conducted to determine prominent variables that models utilize to assist with efforts to mitigate Chagas disease. Next, a Web search was performed to collect publicly available spatial data pertaining to these variables for the countries in South America. The data were classified based on type and spatial extent, which were then used to create maps of data availability of variables related to Chagas disease transmission. Governments can use this information to better direct their resources to collect data and control the spread of triatomines and Chagas more effectively, and potentially identify more cost-effective strategies for eliminating triatomine vectors. PMID- 27246273 TI - Stepwise and stagewise approaches for spatial cluster detection. AB - Spatial cluster detection is an important tool in many areas such as sociology, botany and public health. Previous work has mostly taken either a hypothesis testing framework or a Bayesian framework. In this paper, we propose a few approaches under a frequentist variable selection framework for spatial cluster detection. The forward stepwise methods search for multiple clusters by iteratively adding currently most likely cluster while adjusting for the effects of previously identified clusters. The stagewise methods also consist of a series of steps, but with a tiny step size in each iteration. We study the features and performances of our proposed methods using simulations on idealized grids or real geographic areas. From the simulations, we compare the performance of the proposed methods in terms of estimation accuracy and power. These methods are applied to the the well-known New York leukemia data as well as Indiana poverty data. PMID- 27246274 TI - Geographically weighted discriminant analysis of environmental conditions associated with Rift Valley fever outbreaks in South Africa. AB - Rift Valley fever (RVF) is a zoonotic arboviral infection that has occurred across Africa and parts of the Middle East. Geographically weighted discriminant analysis (GWDA) is a spatially-adaptive extension of traditional discriminant analysis (DA) which has rarely been applied to infectious disease epidemiology research. This study compares the classification performance of GWDA and traditional DA when used to distinguish between locations where livestock are at risk or are not at risk for acquiring RVF virus (RVFV) using 699 case reports of RVF (affecting 18,894 animals) from two outbreaks in South Africa in 2008-2009 and 2010-2011. GWDA produced better results than traditional DA for all bandwidth and kernel combinations. The best GWDA model correctly classified 96.6% of the original data versus 84.5% obtained with traditional DA. With GWDA, false positives decreased from 10.9% to 3.7%, and false negatives decreased from 19.9% to 3.2%. PMID- 27246275 TI - Exploring spatial patterns in the associations between local AIDS incidence and socioeconomic and demographic variables in the state of Rio de Janeiro, Brazil. AB - Access to antiretroviral therapy (ART), universally provided in Brazil since 1996, resulted in a reduction in overall morbidity and mortality due to AIDS or AIDS-related complications, but in some municipalities of Rio de Janeiro, AIDS incidence remains high. Public health surveillance remains an invaluable tool for understanding current AIDS epidemiologic patterns and local socioeconomic and demographic factors associated with increased incidence. Geographically Weighted Poisson Regression (GWPR) explores spatial varying impacts of these factors across the study area focusing attention on local variations in ecological associations. The set of sociodemographic variables under consideration revealed significant associations with local AIDS incidence and these associations varied geographically across the study area. We find the effects of predictors on AIDS incidence are not constant across the state, contrary to assumptions in the global models. We observe and quantify different local factors driving AIDS incidence in different parts of the state. PMID- 27246276 TI - Spatial data aggregation for spatio-temporal individual-level models of infectious disease transmission. AB - A class of complex statistical models, known as individual-level models, have been effectively used to model the spread of infectious diseases. These models are often fitted within a Bayesian Markov chain Monte Carlo framework, which can have a sig nificant computational expense due to the complex nature of the likelihood function associated with this class of models. Increases in population size or duration of the modeled epidemic can contribute to this computational burden. Here, we explore the effect of reducing this computational expense by aggregating the data into spatial clusters, and therefore reducing the overall population size. Individual-level models, reparameterized to account for this aggregation effect, may then be fitted to the spatially aggregated data. The ability of two reparameterized individual-level models, when fitted to this reduced data set, to identify a covariate effect is investigated through a simulation study. PMID- 27246277 TI - Joint modeling of Anaemia and Malaria in children under five in Nigeria. AB - Malaria and anaemia which jointly account for high proportion of morbidity and mortality among young children in developing countries have been individually studied using binary regression model. We adopt geoadditive latent variable model for binary/ordinal indicators to analyze the influence of variables of different types on the morbidity among young children in Nigeria. Latent variable models allow for the analysis of multidimensional response variables that reveal the indicator's underlying relationship that are caused by the latent variables. We extend the structural model to a semi-parametric geoadditive model in order to quantify the joint spatial structure of morbidity from malaria and anaemia. Findings revealed substantial geographical variations and the generated maps can guide policy makers and donors on how to prudently utilize the scarce resources for designing more cost-effective interventions. PMID- 27246278 TI - Uncertainty in maternal exposures to ambient PM2.5 and benzene during pregnancy: Sensitivity to exposure estimation decisions. AB - We investigate uncertainty in estimates of pregnant women's exposure to ambient PM2.5 and benzene derived from central-site monitoring data. Through a study of live births in Florida during 2000-2009, we discuss the selection of spatial and temporal scales of analysis, limiting distances, and aggregation method. We estimate exposure concentrations and classify exposure for a range of alternatives, and compare impacts. Estimated exposure concentrations were most sensitive to the temporal scale of analysis for PM2.5, with similar sensitivity to spatial scale for benzene. Using 1-12 versus 3-8 weeks of gestational age as the exposure window resulted in reclassification of exposure by at least one quartile for up to 37% of mothers for PM2.5 and 27% for benzene. The largest mean absolute differences in concentration resulting from any decision were 0.78 ug/m(3) and 0.44 ppbC, respectively. No bias toward systematically higher or lower estimates was found between choices for any decision. PMID- 27246279 TI - Erratum to: Sharing of Investigational Drug Among Participants in the Voice Trial. PMID- 27246280 TI - Switchable Charge Injection Barrier in an Organic Supramolecular Semiconductor. AB - We disclose a supramolecular material that combines semiconducting and dipolar functionalities. The material consists of a discotic semiconducting carbonyl bridged triarylamine core, which is surrounded by three dipolar amide groups. In thin films, the material self-organizes in a hexagonal columnar fashion through pi-stacking of the molecular core and hydrogen bonding between the amide groups. Alignment by an electrical field in a simple metal/semiconductor/metal geometry induces a polar order in the interface layers near the metal contacts that can be reversibly switched, while the bulk material remains nonpolarized. On suitably chosen electrodes, the presence of an interfacial polarization field leads to a modulation of the barrier for charge injection into the semiconductor. Consequently, a reversible switching is possible between a high-resistance, injection-limited off-state and a low-resistance, space-charge-limited on-state. The resulting memory diode shows switchable rectification with on/off ratios of up to two orders of magnitude. This demonstrated multifunctionality of a single material is a promising concept toward possible application in low-cost, large area, nonvolatile organic memories. PMID- 27246281 TI - Antimicrobial activity of tea catechin against canine oral bacteria and the functional mechanisms. AB - Epigallocatechin gallate (EGCG) is the major polyphenolic compound of green tea. Polyphenolic compounds were extracted from the leaf of Camellia sinensis (Japanese green tea), and the minimum inhibitory concentration against canine oral bacteria was measured. Subsequently, we investigated the inhibitory effects of polyphenolic compounds and EGCG on the growth of canine oral bacteria. EGCG showed antimicrobial activity against a model bacterium, Streptococcus mutans. Our results indicate that EGCG can inhibit the growth and biofilm formation of S. mutans and that EGCG does not interact with streptococcal lipoteichoic acid (LTA). Furthermore, our findings suggest that EGCG interacts with other component(s) of the bacterial membrane aside from streptococcal LTA to inhibit biofilm formation and damage biofilms. PMID- 27246282 TI - Kisspeptin Regulation of Neuronal Activity throughout the Central Nervous System. AB - Kisspeptin signaling at the gonadotropin-releasing hormone (GnRH) neuron is now relatively well characterized and established as being critical for the neural control of fertility. However, kisspeptin fibers and the kisspeptin receptor (KISS1R) are detected throughout the brain suggesting that kisspeptin is involved in regulating the activity of multiple neuronal circuits. We provide here a review of kisspeptin actions on neuronal populations throughout the brain including the magnocellular oxytocin and vasopressin neurons, and cells within the arcuate nucleus, hippocampus, and amygdala. The actions of kisspeptin in these brain regions are compared to its effects upon GnRH neurons. Two major themes arise from this analysis. First, it is apparent that kisspeptin signaling through KISS1R at the GnRH neuron is a unique, extremely potent form or neurotransmission whereas kisspeptin actions through KISS1R in other brain regions exhibit neuromodulatory actions typical of other neuropeptides. Second, it is becoming increasingly likely that kisspeptin acts as a neuromodulator not only through KISS1R but also through other RFamide receptors such as the neuropeptide FF receptors (NPFFRs). We suggest likely locations of kisspeptin signaling through NPFFRs but note that only limited tools are presently available for examining kisspeptin cross-signaling within the RFamide family of neuropeptides. PMID- 27246283 TI - Recent Advances in Diagnostic Strategies for Diabetic Peripheral Neuropathy. AB - Diabetes is an increasing epidemic in Korea, and associated diabetic peripheral neuropathy (DPN) is its most common and disabling complication. DPN has an insidious onset and heterogeneous clinical manifestations, making it difficult to detect high-risk patients of DPN. Early diagnosis is recommended and is the key factor for a better prognosis and preventing diabetic foot ulcers, amputation, or disability. However, diagnostic tests for DPN are not clearly established because of the various pathophysiology developing from the nerve injury to clinical manifestations, differences in mechanisms according to the type of diabetes, comorbidities, and the unclear natural history of DPN. Therefore, DPN remains a challenge for physicians to screen, diagnose, follow up, and evaluate for treatment response. In this review, diagnosing DPN using various methods to assess clinical symptoms and/or signs, sensorineural impairment, and nerve conduction studies will be discussed. Clinicians should rely on established modalities and utilize current available testing as complementary to specific clinical situations. PMID- 27246284 TI - Current Challenges in Diabetic Nephropathy: Early Diagnosis and Ways to Improve Outcomes. AB - Diabetes is often associated with chronic kidney disease (CKD) and is the primary cause of kidney failure in half of patients who receive dialysis therapy. Given the increasing prevalence of diabetes and its high morbidity and mortality, diabetic nephropathy is a serious drawback in individual patients and a tremendous socioeconomic burden on society. Despite growing concern for the management of diabetic nephropathy, the prevalence of CKD with diabetes is the same today as it was 20 years ago. The current strategy to manage diabetic nephropathy, including the control of hyperglycemia, dyslipidemia, and blood pressure and the wide-spread use of renin-angiotensin-aldosterone system inhibitors, is well established to be beneficial in the early stages of diabetic nephropathy. However, the effects are uncertain in patients with relatively progressed CKD. Therefore, early diagnosis or risk verification is extremely important in order to reduce the individual and socioeconomic burdens associated with diabetic nephropathy by providing appropriate management to prevent the development and progression of this condition. This review focuses on recent research and guidelines regarding risk assessment, advances in medical treatment, and challenges of and future treatments for diabetic nephropathy. PMID- 27246285 TI - 1,5-Anhydro-D-Glucitol Could Reflect Hypoglycemia Risk in Patients with Type 2 Diabetes Receiving Insulin Therapy. AB - BACKGROUND: The identification of a marker for hypoglycemia could help patients achieve strict glucose control with a lower risk of hypoglycemia. 1,5-Anhydro-D glucitol (1,5-AG) reflects postprandial hyperglycemia in patients with well controlled diabetes, which contributes to glycemic variability. Because glycemic variability is related to hypoglycemia, we aimed to evaluate the value of 1,5-AG as a marker of hypoglycemia. METHODS: We enrolled 18 adults with type 2 diabetes mellitus (T2DM) receiving insulin therapy and assessed the occurrence of hypoglycemia within a 3-month period. We measured 1,5-AG level, performed a survey to score the severity of hypoglycemia, and applied a continuous glucose monitoring system (CGMS). RESULTS: 1,5-AG was significantly lower in the high hypoglycemia-score group compared to the low-score group. Additionally, the duration of insulin treatment was significantly longer in the high-score group. Subsequent analyses were adjusted by the duration of insulin treatment and mean blood glucose, which was closely associated with both 1,5-AG level and hypoglycemia risk. In adjusted correlation analyses, 1,5-AG was negatively correlated with hypoglycemia score, area under the curve at 80 mg/dL, and low blood glucose index during CGMS (P=0.068, P=0.033, and P=0.060, respectively). CONCLUSION: 1,5-AG level was negatively associated with hypoglycemia score determined by recall and with documented hypoglycemia after adjusting for mean glucose and duration of insulin treatment. As a result, this level could be a marker of the risk of hypoglycemia in patients with well-controlled T2DM receiving insulin therapy. PMID- 27246286 TI - Ki67, PCNA, and MCM proteins: Markers of proliferation in the diagnosis of breast cancer. AB - The proliferative activity of tumour cells represents an important prognostic marker in the diagnosis of cancer. One of the methods for assessing the proliferative activity of cells is the immunohistochemical detection of cell cycle-specific antigens. For example, Ki67, proliferating cell nuclear antigen (PCNA), and minichromosome maintenance (MCM) proteins are standard markers of proliferation that are commonly used to assess the growth fraction of a cell population. The function of Ki67, the widely used marker of proliferation, still remains unclear. In contrast, PCNA and MCM proteins have been identified as important participants of DNA replication. All three proteins only manifest their expression during the cell division of normal and neoplastic cells. Since the expression of these proliferative markers was confirmed in several malignant tumours, their prognostic and predictive values have been evaluated to determine their significance in the diagnosis of cancer. This review offers insight into the discovery of the abovementioned proteins, as well as their current molecular and biological importance. In addition, the functions and properties of all three proteins and their use as markers of proliferation in the diagnosis of breast cancer are described. This work also reveals new findings about the role of Ki67 during the mitotic phase of the cell cycle. Finally, information is provided about the advantages and disadvantages of using all three antigens in the diagnosis of cancer. PMID- 27246287 TI - Model Minority Stereotype: Influence on Perceived Mental Health Needs of Asian Americans. AB - This study examined the influence of the model minority stereotype on the perceived mental health functioning of Asian Americans. It was hypothesized that college students would perceive Asian Americans as having fewer mental health problems and clinical symptoms than Whites due to the model minority stereotype. Four hundred and twenty-five undergraduate students from a predominately White college campus in the American northeast were randomly exposed to one of four conditions: (1) a clinical vignette describing a White college student suffering from adjustment disorder; (2) the same vignette describing an Asian American college student; (3) a newspaper article describing a success story of Whites and the White clinical vignette; (4) the same newspaper article and clinical vignette describing an Asian American. Following exposure to one of the conditions, participants completed a memory recall task and measures of colorblindness, attitudes towards Asian Americans, attitudes towards out-group members, and perceived mental health functioning. Participants exposed to the vignettes primed with the positive/model minority stereotype perceived the target regardless of race/ethnicity as having better mental health functioning and less clinical symptoms than the condition without the stereotype. Additionally, the stereotype primer was found to be a modest predictor for the perception of mental health functioning in Asian American vignettes. Results shed light on the impact of the model minority stereotype on the misperception of Asian Americans' mental health status, contributing to the invisibility or neglect of this minority group's mental health needs. PMID- 27246288 TI - Significant Enhancement of Water Splitting Activity of N-Carbon Electrocatalyst by Trace Level Co Doping. AB - Replacement of precious metal electrocatalysts with highly active and cost efficient alternatives for complete water splitting at low voltage has attracted a growing attention in recent years. Here, this study reports a carbon-based composite co-doped with nitrogen and trace amount of metallic cobalt (1 at%) as a bifunctional electrocatalyst for water splitting at low overpotential and high current density. An excellent electrochemical activity of the newly developed electrocatalyst originates from its graphitic nanostructure and highly active Co Nx sites. In the case of carefully optimized sample of this electrocatalyst, 10 mA cm(-2) current density can be achieved for two half reactions in alkaline solutions-hydrogen evolution reaction and oxygen evolution reaction-at low overpotentials of 220 and 350 mV, respectively, which are smaller than those previously reported for nonprecious metal and metal-free counterparts. Based on the spectroscopic and electrochemical investigations, the newly identified Co-Nx sites in the carbon framework are responsible for high electrocatalytic activity of the Co,N-doped carbon. This study indicates that a trace level of the introduced Co into N-doped carbon can significantly enhance its electrocatalytic activity toward water splitting. PMID- 27246289 TI - Recognition of Stroke by EMS is Associated with Improvement in Emergency Department Quality Measures. AB - OBJECTIVE: Hospital arrival via Emergency Medical Services (EMS) and EMS prenotification are associated with faster evaluation and treatment of stroke. We sought to determine the impact of diagnostic accuracy by prehospital providers on emergency department quality measures. METHODS: A retrospective study was performed of patients presenting via EMS between September 2009 and December 2012 with a discharge diagnosis of transient ischemic attack (TIA), ischemic stroke (IS), or intracerebral hemorrhage (ICH). Hospital and EMS databases were used to determine EMS impression, prehospital and in-hospital time intervals, EMS prenotification, NIH stroke scale (NIHSS), symptom duration, and thrombolysis rate. RESULTS: 399 cases were identified: 14.5% TIA, 67.2% IS, and 18.3% ICH. EMS providers correctly recognized 57.6% of cases. Compared to cases missed by EMS, correctly recognized cases had longer median on-scene time (17 vs. 15 min, p = 0.01) but shorter transport times (12 vs. 15 min, p = 0.001). Cases correctly recognized by EMS were associated with shorter door-to-physician time (4 vs. 11 min, p < 0.001) and shorter door-to-CT time (23 vs. 48 min, p < 0.001). These findings were independent of age, NIHSS, symptom duration, and EMS prenotification. Patients with ischemic stroke correctly recognized by EMS were more likely to receive thrombolytic therapy, independent of age, NIHSS, symptom duration both with and without prenotification. CONCLUSION: Recognition of stroke by EMS providers was independently associated with faster door-to-physician time, faster door-to-CT time, and greater odds of receiving thrombolysis. Quality initiatives to improve EMS recognition of stroke have the potential to improve hospital-based quality of stroke care. PMID- 27246290 TI - Axillary web syndrome following sentinel node biopsy for breast cancer. AB - A 49 year-old woman diagnosed with infiltrating lobular breast carcinoma, underwent a right mastectomy and sentinel node biopsy (SLNB). The resected sentinel lymph nodes were negative for malignancy, with an axillary lymphadenectomy not being performed. In the early post-operative period, the patient reported an axillary skin tension sensation, associated with a painful palpable cord. These are typical manifestations of axillary web syndrome (AWS), a poorly known axillary surgery complication, from both invasive and conservative interventions. By presenting this case we want to focus the attention on a pathological condition, for which its incidence may be underestimated by not including it in SLNB studies. It is important for nuclear medicine physicians to be aware of AWS as a more common complication than infection, seroma, or lymphoedema, and to discuss this possible event with the patient who is consenting to the procedure. PMID- 27246291 TI - Symptomatic hypophosphataemic osteomalacia secondary to the treatment with iron carboxymaltose detected in bone scintigraphy. AB - The development of hypophosphataemic osteomalacia has been linked with several treatments, mainly antiretroviral and intravenous iron administration. The frequency of the hypophosphataemia requires monitoring the phosphate after the administration of iron carboxymaltose. We describe a case of a woman with no calcium-phosphorous metabolism disorder, to whom this treatment was prescribed for anaemia due to menorrhagia and intolerance to oral iron. She started with oligoarticular pain, which was spreading with a significant functional loss. The relationship with the administration of intravenous iron was discovered when scintigraphic findings together with laboratory results led to a diagnosis of hypophosphataemic osteomalacia. The patient responded satisfactorily to treatment with phosphate both clinically and in the follow-up bone scintigraphy. PMID- 27246292 TI - Selective sentinel node biopsy after intratumour administration of radiotracer in breast cancer patients treated with neoadjuvant chemotherapy in relation to the level of tumour response. AB - PURPOSE: Our objective was to analyse the accuracy of the sentinel node biopsy, taking into consideration the scintigraphy detection rate after the intratumoural administration of the radiopharmaceutical in patients with breast cancer who received neoadjuvant chemotherapy. MATERIALS AND METHODS: The study included 60 patients with a diagnosis of invasive breast carcinoma, stage T1-T3, who received treatment with neoadjuvant chemotherapy, and were subsequently subjected to breast surgery and sentinel node biopsy after intra-tumour administration of the radiopharmaceutical. RESULTS: Scintigraphic detection of some sentinel node was achieved in 55/60 patients (91.6%). When those cases that received a second injection of the radiopharmaceutical, performed peri-areolarly due to a lack of tracer migration, were excluded, the detection rate dropped to 70% (42/60). When the detection of sentinel node, or its absence, was compared in those 42 patients, no differences were found with age, laterality-location of the lesion, size pre- and post-neoadjuvant chemotherapy, histological grade, or immunohistochemical profile. There were significant differences when comparing the groups according to the degree of pathological tumour response, both with the Miller-Payne system (non-detection 44.4%-detection 16.7%, p = 0.003) as well as the residual cancer burden (72.2%-28.6%, p<0.01). CONCLUSIONS: The scintigraphic detection of the sentinel node after intratumoural administration of the radiopharmaceutical in patients with breast cancer who received neoadjuvant chemotherapy was below the optimal value, and sometimes a further, peri-areolar, injection was necessary, probably in relation to an alteration in the lymphatic drainage pathways. There was a significant inverse relationship between the detection of the sentinel node and level of pathological tumour response. PMID- 27246293 TI - Best sensitivity of 18F-FDOPA PET/CT to detect metastasis in one case of neuroendocrine tumour of the ileum. AB - Neuroendocrine tumours (NET) are heterogeneous and frequently spread over the body, making their imaging difficult. With this aim, nuclear medicine imaging, using PET or SPECT with different tracers, has been proposed for decades, but there is currently no consensus on the most appropriate technique, even when only considering gastrointestinal NET. The case is presented of a 67year old woman with a well differentiated NET of the ileum with suspected recurrence, which was not detected by any imaging technique except 18F-FDOPA PET/CT. Subsequent follow up showed disease progression, which confirmed the true positivity of 18F-FDOPA. Using this case, we discuss and compare different radiotracers for the diagnosis of gastrointestinal NET, focusing on those embryologically originating from the mid-gut. PMID- 27246294 TI - Dual-time-point 18F-FDG-PET/CT imaging of a paravalvular pseudoaneurysm after infective endocarditis. PMID- 27246295 TI - It's the time of the nuclear medicine. PMID- 27246296 TI - Effect of antipyretic analgesics on immune responses to vaccination. AB - While antipyretic analgesics are widely used to ameliorate vaccine adverse reactions, their use has been associated with blunted vaccine immune responses. Our objective was to review literature evaluating the effect of antipyretic analgesics on vaccine immune responses and to highlight potential underlying mechanisms. Observational studies reporting on antipyretic use around the time of immunization concluded that their use did not affect antibody responses. Only few randomized clinical trials demonstrated blunted antibody response of unknown clinical significance. This effect has only been noted following primary vaccination with novel antigens and disappears following booster immunization. The mechanism by which antipyretic analgesics reduce antibody response remains unclear and not fully explained by COX enzyme inhibition. Recent work has focused on the involvement of nuclear and subcellular signaling pathways. More detailed immunological investigations and a systems biology approach are needed to precisely define the impact and mechanism of antipyretic effects on vaccine immune responses. PMID- 27246297 TI - Genetic insights into Map3k-dependent proliferative expansion of T cells. AB - Mapks are important regulators of T cell proliferative expansion and cell cycle progression. Detailed genetic analysis of unconventional iNKT cells in both Map3k1(DeltaKD) and Lck(Cre/+)Map3k1(f/f) mice demonstrated that Mekk1 (encoded by Map3k1) signaling activates Mapks to regulate Cdkn1b (encoding p27(Kip1)) expression and p27(Kip1)-dependent proliferative expansion in response to antigen. Mekk1 signaling and activation of E3 ubiquitin ligase Itch, by a phosphorylation-dependent conformational change, is also an important regulatory mechanism for the control of T helper cell cytokine production. Cdkn1b expression is regulated by Mekk1-dependent signaling in differentiated Th17 cells. Mekk1 is one of the 19 Ste11-like Map3ks, and Mekk1 signaling regulates iNKT cell proliferative expansion in response to glycolipid antigens and T cell homeostasis in the liver. Tak1 (encoded by Map3k7), a related Map3k to Mekk1, similarly regulates the proliferative expansion and homeostasis of T cells in the liver, and this illustrates the importance of multiple Map3ks for mammalian Mapk signaling. PMID- 27246298 TI - Erratum. PMID- 27246299 TI - Mechanism for Broadband White-Light Emission from Two-Dimensional (110) Hybrid Perovskites. AB - The recently discovered phenomenon of broadband white-light emission at room temperature in the (110) two-dimensional organic-inorganic perovskite (N MEDA)[PbBr4] (N-MEDA = N(1)-methylethane-1,2-diammonium) is promising for applications in solid-state lighting. However, the spectral broadening mechanism and, in particular, the processes and dynamics associated with the emissive species are still unclear. Herein, we apply a suite of ultrafast spectroscopic probes to measure the primary events directly following photoexcitation, which allows us to resolve the evolution of light-induced emissive states associated with white-light emission at femtosecond resolution. Terahertz spectra show fast free carrier trapping and transient absorption spectra show the formation of self trapped excitons on femtosecond time-scales. Emission-wavelength-dependent dynamics of the self-trapped exciton luminescence are observed, indicative of an energy distribution of photogenerated emissive states in the perovskite. Our results are consistent with photogenerated carriers self-trapped in a deformable lattice due to strong electron-phonon coupling, where permanent lattice defects and correlated self-trapped states lend further inhomogeneity to the excited state potential energy surface. PMID- 27246300 TI - Opposite effects of mu and delta opioid receptor agonists on excitatory propagation induced in rat somatosensory and insular cortices by dental pulp stimulation. AB - The insular cortex (IC) contributes to nociceptive information processing. IC neurons express opioid receptors, including the mu (MOR), kappa (KOR), and delta (DOR) subtypes. Opioidergic agonists suppress excitatory synaptic transmission in the cerebral cortex. In addition, morphine injection into the IC reduces responses to noxious thermal stimuli. However, the mechanisms of the opioid dependent modulation of cortical excitation at the macroscopic level, which bridge the cellular and behavioral findings, have remained unknown. The present in vivo optical imaging study aimed to examine the effects of the agonists of each subtype on cortical excitatory propagation in the IC and the neighboring cortices, the primary (S1) and secondary somatosensory (S2) areas. To assess the opioidergic effects on the cortical circuits, we applied electrical stimulation to the maxillary 1st molar pulp, which induced excitation in the ventral part of S1 and the S2/insular oral region (IOR). The initial excitatory response was observed 10-14ms after stimulation, and then excitation propagated concentrically. DAMGO (10-100MUM), an MOR agonist, suppressed the amplitude of cortical excitation and shrank the maximum excitation areas in S1 and S2/IOR. In contrast, 10-100MUM DPDPE, a DOR agonist, increased the amplitude of excitation and expanded the area of maximum excitation. U50488 (10-100MUM), a KOR agonist, had little effect on cortical excitation. These results suggest that MOR-induced suppression of excitatory propagation in the IC is an underlying mechanism of the powerful analgesic effects of MOR agonists. In contrast, DOR may play a minor role in suppressing acute pain. PMID- 27246302 TI - Robotic surgical training: Where are we? AB - BACKGROUND AND OBJECTIVE: Over the past 10years, robotic surgery has revolutionized the advancement of MIS in gynecologic oncology. As the use of robotic surgery has increased, so has the interest in the surgical training of gynecologic oncology fellows. The purpose of this review is to summarize the state of robotic surgical education in Gynecologic Oncology. METHODS: Several electronic databases were searched to identify studies that discussed robotic surgical education in gynecologic oncology. Particular attention was given to articles that discussed educational curriculum. The various curriculums were compared and summarized. RESULTS: The first reports of robotic surgery curriculums in gynecologic oncology emerged in 2008. Prior to that the early adapters had to rely on less structured curriculums that essentially used live animal models and cadaveric dissections on the robot to simulate live surgery. More recent surgical curriculums are more structured and include the same basic components: didactics and a graduated hands-on experience. There is also an accredited robotic educational curriculum, the Fundamentals of Robotic Surgery (FRS), which combine an on-line curriculum with dry lab and operating room components that can be scored using a validated assessment tool. CONCLUSIONS: Robotic surgical education has come a long way in the decade that the robotic platform has been available in the U.S. Although there is still no standardized curriculum, most fellowship training programs in gynecologic oncology have fairly consistent training. Simulation training is another tool that can help a surgeon achieve proficiency quicker. PMID- 27246301 TI - Increased Cx32 expression in spinal cord TrkB oligodendrocytes following peripheral axon injury. AB - Following injury to motor axons in the periphery, retrograde influences from the injury site lead to glial cell plasticity in the vicinity of the injured neurons. Following the transection of peripherally located preganglionic axons of the cervical sympathetic trunk (CST), a population of oligodendrocyte (OL) lineage cells expressing full length TrkB, the cognate receptor for brain derived neurotrophic factor (BDNF), is significantly increased in number in the spinal cord. Such robust plasticity in OL lineage cells in the spinal cord following peripheral axon transection led to the hypothesis that the gap junction communication protein connexin 32 (Cx32), which is specific to OL lineage cells, was influenced by the injury. Following CST transection, Cx32 expression in the spinal cord intermediolateral cell column (IML), the location of the parent cell bodies, was significantly increased. The increased Cx32 expression was localized specifically to TrkB OLs in the IML, rather than other cell types in the OL cell lineage, with the population of Cx32/TrkB cells increased by 59%. Cx32 expression in association with OPCs was significantly decreased at one week following the injury. The results of this study provide evidence that peripheral axon injury can differentially affect the gap junction protein expression in OL lineage cells in the adult rat spinal cord. We conclude that the retrograde influences originating from the peripheral injury site elicit dramatic changes in the CNS expression of Cx32, which in turn may mediate the plasticity of OL lineage cells observed in the spinal cord following peripheral axon injury. PMID- 27246303 TI - Feasibility of a physical activity intervention for obese, socioculturally diverse endometrial cancer survivors. AB - PURPOSE: Determine the feasibility of a 12-week physical activity intervention for obese, socioculturally diverse endometrial cancer survivors and to evaluate whether the intervention improves physical activity behavior, physical function, waist circumference, and quality of life. METHODS: Obese endometrial cancer survivors from Bronx, NY were assigned to either a 12-week physical activity intervention of behavioral counseling, physical activity and home-based walking (n=25), or wait-list control group (n=15). Mixed-design ANOVA (2 groups*2 time points) were analyzed to determine differences between the intervention and the control for the Yale Physical Activity Survey, six-minute walk test, 30-second chair stand test, waist circumference, and Functional Assessment of Cancer Therapy-Endometrial questionnaire. Data are presented as mean+/-standard deviation. RESULTS: The sample was diverse (38% non-Hispanic black, 38% Hispanic, 19% non-Hispanic white). Mean Body Mass Index was 37.3+/-6.5kg.m(-2). Although recruitment rate was low (20% of 140 contacted), 15 of 25 participants in the intervention group attended 75-100% of scheduled sessions. Participants reported walking 118+/-79min/week at home. There were large effect sizes for the improvements in the six-minute walk test (22+/-17m vs. 1+/-22m, d=1.10), waist circumference (-5.3+/-5.3cm vs. 2.6+/-6.7cm, d=-1.32), quality of life (10+/-12 vs. -1+/-11, d=0.86) and walking self-efficacy (24+/-30% vs. 1+/-55%, d=0.87) compared to the control group. CONCLUSIONS: The intervention appeared feasible in this population. The results show promising effects on several outcomes that should be confirmed in a larger randomized control trial, with more robust recruitment strategies. PMID- 27246304 TI - Role of cervical cytology in surveillance after radical trachelectomy for cervical cancer. AB - OBJECTIVE: There are currently no standard guidelines on the use of Papanicolaou (Pap) tests for surveillance after radical trachelectomy for cervical cancer. The goal of this study was to determine the usefulness of Pap tests in routine surveillance after radical trachelectomy for cervical cancer. METHODS: Cervical cancer patients who underwent radical trachelectomy from January 2004 through October 2015 and subsequently had at least one Pap test were retrospectively identified. Demographic and clinical characteristics were described and compared between patients with and without at least one abnormal Pap test. The Kaplan Meier method was used to estimate time to first abnormal Pap test. RESULTS: Forty one patients met inclusion criteria. Of these, 30 (73%) had at least one year in which more than one Pap test per year was obtained. Twenty-four (59%) had at least one abnormal Pap test. Of 238 total Pap tests collected, 44 (18%) were abnormal. The most common abnormality was ASCUS (52%, n=23). Other findings included LSIL (20%, n=9), HSIL (2%, n=1), and AGUS (25%, n=11). Median time from radical trachelectomy to first abnormal Pap test was 17.2months (range, 11.8 86.3). No patient had disease recurrence. Surgery type (laparoscopic, open, or robotic), trachelectomy specimen size, histology, device for stenosis prevention (pediatric Foley catheter or Smit Sleeve), and cerclage placement were not significant predictors of an abnormal Pap test. CONCLUSIONS: The rate of abnormal Pap tests after radical trachelectomy is high; however, the clinical significance of such abnormalities appears limited. The routine use of cervical cytology as surveillance after radical trachelectomy does not appear to substantially impact management decisions. PMID- 27246305 TI - Results of a multicenter phase I dose-finding trial of hyperthermic intraperitoneal cisplatin after neoadjuvant chemotherapy and complete cytoreductive surgery and followed by maintenance bevacizumab in initially unresectable ovarian cancer. AB - PURPOSE: Hyperthermic intraperitoneal chemotherapy (HIPEC) may improve the outcome of patients with initially unresectable ovarian cancer who are eligible for complete cytoreductive surgery (CCRS) after neoadjuvant chemotherapy. The main objective of this multicenter phase-I study was to identify the recommended dose of cisplatin for HIPEC at CCRS after neoadjuvant carboplatin and paclitaxel (CP). METHODS: Patients were treated with 6cycles of CP followed by CCRS and HIPEC using cisplatin heated for one hour at 42 degrees C+/-1 degrees C. Four cisplatin dose-levels were evaluated: 50, 60, 70, 80mg/m(2). Dose-limiting toxicities (DLTs) were defined as a grade>=IIIb adverse event (Dindo classification). The Continual Reassessment Method was used for this dose-finding study, with a target percentage of DLT set at 20%. Twenty-two cycles (15mg/kg/cycle) of maintenance bevacizumab therapy were planned after surgery. RESULTS: Between June-2011 and September-2012, 30 patients were recruited. No DLT occurred at the first three dose-levels (4, 4 and 5 patients at 50, 60 and 70mg/m(2) respectively). At dose-level 4 (80mg/m(2), 17 patients), four DLTs occurred: renal failure (n=2), peritonitis (n=1) and hemorrhage (n=1). Eight weeks after surgery, creatinine clearance was reduced to <30mL/min in 3 patients, all treated at 80mg/m(2), and between 30 and 60mL/min in 6 patients (2, 1, 1 and 2 at the four dose-levels respectively). Twenty patients started maintenance bevacizumab, and 7 received the 22 courses initially planned. CONCLUSIONS: Based on the observed DLTs and prolonged impairment of renal function, we recommend a dose of 70mg/m(2) of cisplatin for HIPEC. PMID- 27246306 TI - Molecular genotyping of placental site and epithelioid trophoblastic tumours; female predominance. AB - OBJECTIVE: To investigate a large series of placental site trophoblastic tumours (PSTT) and epithelioid trophoblastic tumours (ETT) and determine the relationship between their development and the type and sex of both the immediately antecedent and causative pregnancies. METHODS: The antecedent pregnancy was determined from patient records in 92 cases with a confirmed diagnosis of PSTT, ETT or mixed PSTT/ETT. In a subset of 57 cases, type and sex of the causative pregnancy was established by molecular genotyping of tumour tissue microdissected from formalin fixed, paraffin-embedded blocks. RESULTS: The antecedent pregnancy was a normal live birth in 59 (64%) cases, a hydatidiform mole in 19 (21%) and other pregnancy loss in 14 (15%). Where the sex was recorded, 36 (78%) of 46 antecedent normal pregnancies were female, a significantly greater proportion than expected (p<0.0001). Genotyping of 57 cases found 15 (26%) to derive from hydatidiform moles while 42 (74%) arose in non-molar pregnancies. Where the causative pregnancy was non-molar, 38 (91%) tumours arose in female conceptions, significantly greater than expected (p<0.0001). Analysis of short tandem repeats on the X chromosome in three tumours with an XY chromosomal constitution confirmed that the X chromosome was maternal in origin. CONCLUSIONS: PSTT and ETT predominantly arise in female pregnancies but can develop in male pregnancies. A male derived X chromosome is not required for the development of these tumours. While these tumours are predominantly female it is not because most originate in complete hydatidiform moles. PMID- 27246307 TI - Fish Consumption and Health: The Yin and Yang. PMID- 27246308 TI - When Is It Appropriate to Use Glutamine in Critical Illness? AB - Glutamine is a nonessential amino acid, which under trauma or critical illness can become essential. A number of historic small single-center randomized controlled trials (RCTs) have demonstrated positive treatment effects on clinical outcomes with glutamine supplementation. Meta-analyses based on these trials demonstrated a significant reduction in hospital mortality, intensive care unit (ICU) length of stay (LOS), and hospital LOS with intravenous (IV) glutamine. Similar results were not noted in 2 large multicenter RCTs (REDOXS and MetaPlus) assessing the efficacy of glutamine supplementation in ventilated ICU patients. The REDOXS trial of 40 ICUs randomized 1223 ventilated ICU patients to glutamine (IV and enteral), antioxidants, both glutamine and antioxidants, or placebo. The main conclusions were a trend toward increased 28-day mortality and significant increased hospital and 6-month mortality in those who received glutamine. The MetaPlus trial of 14 ICUs, which randomized 301 ventilated ICU patients to glutamine-enriched enteral vs an isocaloric diet, noted increased 6-month mortality in the glutamine-supplemented group. Newer RCTs have focused on specific populations and have demonstrated benefits in burn and elective surgery patients with glutamine supplementation. Whether larger studies will confirm these findings is yet to be determined. Recent American Society for Parenteral and Enteral Nutrition guidelines recommend that IV and enteral glutamine should not be used in the critical care setting based on the moderate quality of evidence available. We agree with these recommendations and would encourage larger multicenter studies to evaluate the risks and benefits of glutamine in burn and elective surgery patients. PMID- 27246309 TI - Expression and oxidative modifications of plasma proteins in autism spectrum disorders: Interplay between inflammatory response and lipid peroxidation. AB - PURPOSE: A role for inflammation and oxidative stress is reported in autism spectrum disorders (ASDs). Here, we tested possible changes in expression and/or oxidative status for plasma proteins in subjects with ASDs. EXPERIMENTAL DESIGN: To evaluate protein expression and protein adducts of lipid peroxidation-derived aldehyde, analysis of plasma proteins was performed in 30 subjects with ASDs and compared with 30 healthy controls with typical development, using a proteomic approach. RESULTS: Significant changes were evidenced for a total of 12 proteins. Of these, ten were identified as proteins involved in the acute inflammatory response including alpha-2-macroglobulin, alpha-1-antitrypsin, haptoglobin, fibrinogen, serum transferrin, prealbumin, apolipoprotein A-I apolipoprotein A IV, apolipoprotein J, and serum albumin. In addition, significant changes occurred for two immunoglobulins alpha and gamma chains. CONCLUSIONS AND CLINICAL RELEVANCE: Our present data indicate that an inflammatory response, coupled with increased lipid peroxidation, is present in subjects with ASDs. This information can provide new insight into the identification of potential plasma protein biomarkers in autism. PMID- 27246311 TI - A 4-year-old child presenting morning onset of spontaneous tracheal rupture due to bronchial mucous plug occlusion during the nighttime sleep: a case report. AB - BACKGROUND: Coughing is the most efficient mechanism for clearing mucus and fluid secretions from the airways and its reflex can be suppressed by sleep. Spontaneous tracheal ruptures are believed to result from raised intratracheal pressure against a closed glottis, such as for severe coughing. This is the first reported case of tracheal rupture presented on morning awakening after bronchial mucous plug formation during the nighttime sleep because of an ineffective cough reflex. CASE PRESENTATION: An otherwise healthy white 4-year-old child presented morning onset of dyspnea, chest pain and diffuse swelling of the neck. His history was significant only for nonsevere coughing episodes before his nighttime rest; the child's parents denied any recent fever, weight loss, pains, trauma, bronchial asthma, and sick contacts. A chest X-ray and computed tomography scan revealed pneumomediastinum, obstructive atelectasis of the lower lobe of his left lung, and a small tracheal laceration confirmed by an emergency bronchoscopy. After endoscopic removal of a mucous plug and secretions, the child's pulmonary gas exchange and respiratory rate improved, so our patient was managed conservatively. CONCLUSIONS: This report illustrates an unusual presentation of lung obstructive atelectasis due to a mucous plug manifested by tracheal rupture. This report also highlights the importance of the coughing reflex as one of several defensive mechanisms protecting the airways from the potentially damaging effects of aspirate and accumulated secretions. PMID- 27246310 TI - Impact of HCV core gene quasispecies on hepatocellular carcinoma risk among HALT C trial patients. AB - Mutations at positions 70 and/or 91 in the core protein of genotype-1b, hepatitis C virus (HCV) are associated with hepatocellular carcinoma (HCC) risk in Asian patients. To evaluate this in a US population, the relationship between the percentage of 70 and/or 91 mutant HCV quasispecies in baseline serum samples of chronic HCV patients from the HALT-C trial and the incidence of HCC was determined by deep sequencing. Quasispecies percentage cut-points, >=42% of non arginine at 70 (non-R(70)) or >=98.5% of non-leucine at 91 (non-L(91)) had optimal sensitivity at discerning higher or lower HCC risk. In baseline samples, 88.5% of chronic HCV patients who later developed HCC and 68.8% of matched HCC free control patients had >=42% non-R(70) quasispecies (P = 0.06). Furthermore, 30.8% of patients who developed HCC and 54.7% of matched HCC-free patients had quasispecies with >=98.5% non-L(91) (P = 0.06). By Kaplan-Meier analysis, HCC incidence was higher, but not statistically significant, among patients with quasispecies >=42% non-R(70) (P = 0.08), while HCC incidence was significantly reduced among patients with quasispecies >=98.5% non-L(91) (P = 0.01). In a Cox regression model, non-R(70) >=42% was associated with increased HCC risk. This study of US patients indicates the potential utility of HCV quasispecies analysis as a non-invasive biomarker of HCC risk. PMID- 27246312 TI - Imaging of Sleeping Beauty-Modified CD19-Specific T Cells Expressing HSV1 Thymidine Kinase by Positron Emission Tomography. AB - PURPOSE: We have incorporated a positron emission tomography (PET) functionality in T cells expressing a CD19-specific chimeric antigen receptor (CAR) to non invasively monitor the adoptively transferred cells. PROCEDURES: We engineered T cells to express CD19-specific CAR, firefly luciferase (ffLuc), and herpes simplex virus type-1 thymidine kinase (TK) using the non-viral-based Sleeping Beauty (SB) transposon/transposase system adapted for human application. Electroporated primary T cells were propagated on CD19+ artificial antigen presenting cells. RESULTS: After 4 weeks, 90 % of cultured cells exhibited specific killing of CD19+ targets in vitro, could be ablated by ganciclovir, and were detected in vivo by bioluminescent imaging and PET following injection of 2' deoxy-2'-[18F]fluoro-5-ethyl-1-beta-D-arabinofuranosyl-uracil ([18F]FEAU). CONCLUSION: This is the first report demonstrating the use of SB transposition to generate T cells which may be detected using PET laying the foundation for imaging the distribution and trafficking of T cells in patients treated for B cell malignancies. PMID- 27246314 TI - Cognitive performance in unipolar old-age depression: a longitudinal study. AB - OBJECTIVE: Previous studies on cognitive deficits in acute and remitted states of old-age depression have shown mixed findings. The episodic nature of depression makes repeated assessment of cognitive performance important in order to address reversibility and stability of cognitive deficits. METHODS: Dementia-free older participants (>=60 years) from the population-based Swedish National Study on Aging and Care in Kungsholmen who completed neuropsychological testing at baseline (T1) and follow-up (T2) formed the basis of the study sample. Participants were grouped according to depression status at T1 and T2: depressed remitted (n = 32), remitted-depressed (n = 45), and nondepressed-depressed (n = 29). These groups were compared with a group of randomly selected and matched (age, gender, education, and follow-up time) healthy controls (n = 106) over a period of maximum 6 years. RESULTS: Mixed ANCOVAs, controlling for age and gender, revealed depression-related deficits for processing speed, attention, executive function, and category fluency. In remitted states, only processing speed and attention were affected. However, these deficits were attenuated after exclusion of persons using benzodiazepine medications. A general pattern of cognitive decline was observed across all groups for processing speed, executive function, category fluency, and episodic and semantic memory; persons transitioning from a nondepressed to depressed state tended to show exacerbated cognitive decline. CONCLUSIONS: The results support the notion that cognitive deficits in depression may be more transient than stable. Consequently, cognitive deficits in depression might be regarded as potential treatment targets rather than stable vulnerabilities. As such, repeated assessment of cognitive functioning may provide an additional marker of treatment response. PMID- 27246313 TI - Promoter Variation and Expression Levels of Inflammatory Genes IL1A, IL1B, IL6 and TNF in Blood of Spinocerebellar Ataxia Type 3 (SCA3) Patients. AB - Age at onset in spinocerebellar ataxia type 3 (SCA3/MJD) is incompletely explained by the size of the CAG tract at the ATXN3 gene, implying the existence of genetic modifiers. A role of inflammation in SCA3 has been postulated, involving altered cytokines levels; promoter variants leading to alterations in cytokines expression could influence onset. Using blood from 86 SCA3 patients and 106 controls, this work aimed to analyse promoter variation of four cytokines (IL1A, IL1B, IL6 and TNF) and to investigate the association between variants detected and their transcript levels, evaluated by quantitative PCR. Moreover, the effect of APOE isoforms, known to modulate cytokines, was investigated. Correlations between cytokine variants and onset were tested; the cumulative modifier effects of cytokines and APOE were analysed. Patients carrying the IL6*C allele had a significant earlier onset (4 years in average) than patients carrying the G allele, in agreement with lower mRNA levels produced by IL6*C carriers. The presence of APOE*E2 allele seems to anticipate onset in average 10 years in patients carrying the IL6*C allele; a larger number of patients will be needed to confirm this result. These results highlight the pertinence of conducting further research on the role of cytokines as SCA3 modulators, pointing to the presence of shared mechanisms involving IL6 and APOE. PMID- 27246315 TI - An intercalary translocation from Agropyron cristatum 6P chromosome into common wheat confers enhanced kernel number per spike. AB - MAIN CONCLUSION: This study explored 6P chromosomal translocations in wheat, and determined the effects of 6P intercalary chromosome segments on kernel number per wheat spike. Exploiting and utilising gene(s) from wild relative species has become an essential strategy for wheat crop improvement. In the translocation line Pubing2978, the intercalary 6P chromosome segment from Agropyron cristatum (L.) Gaertn. (2n = 4x = 28, PPPP) carried valuable multi-kernel gene(s) and was selected from the offspring of the common wheat plant Fukuho and the irradiated wheat-A. cristatum 6P disomic substitution line 4844-8. Genomic in situ hybridisation (GISH), dual-colour fluorescence in situ hybridisation (FISH), and molecular markers were used to detect the small segmental 6P chromosome in the wheat background and its translocation breakpoint. Cytological studies demonstrated that Pubing2978 was a T1AS-6PL-1AS.1AL intercalary translocation with 42 chromosomes. The breakpoint was located near the centromeric region on the wheat chromosome 1AS and was flanked by the markers SSR12 and SSR283 based on an F2 linkage map. The genotypic data, combined with the phenotypic information, implied that A. cristatum 6P chromosomal segment plays an important role in regulating the kernel number per spike (KPS). By comparison, the mean value of KPS in plants with translocations was approximately 10 higher than that in plants without translocations in three segregated populations. Moreover, the improvement in KPS was likely achieved by increasing both the spikelet number per spike (SNS) and the kernel number per spikelet. These excellent agronomic traits laid the foundation for further investigation of valuable genes and make the Pubing2978 line a promising germplasm for wheat breeding. PMID- 27246316 TI - Spatial agreement between Goldmann visual field defects and fundus autofluorescence in patients with birdshot chorioretinopathy. AB - BACKGROUND: The purpose of this paper is to study the spatial agreement between visual field defects and ultra-wide field (UWF) fundus autofluorescence (FAF) in patients with birdshot chorioretinopathy (BSCR). The study is a retrospective, cross-sectional analysis of a university uveitis practice. Eight (8) eyes of five (5) patients with BSCR were included. Inclusion criteria were ability to fixate reliably. Goldmann visual fields (GVF) and UWF FAF were obtained, digitalized, and standardized. Analysis was performed by measuring areas of overlap of hypo autofluorescent FAF lesions and GVF scotomas within the central 60 degrees . Overlap was calculated as a percentage of the total area of FAF and GVF, respectively. Average areas were also calculated. RESULTS: The mean age of the subjects was 51 +/- 12.28 years (range 38-69 years). 14 +/- 23 % of the total lesion area identified as hypo-autofluorescent on FAF overlapped with scotoma. 28 +/- 41 % of the GVF scotomas overlapped with hypo-autofluorescent FAF lesions. Average area of FAF hypo-autofluorescence was much larger (15.19 disc areas) than GVF (3.45 disc areas). CONCLUSIONS: There appear to be larger total areas of hypo autofluorescence on FAF than scotoma evidenced by GVF and only a small amount of overlap. The finding suggests that GVF is relatively insensitive to anatomic loss, which can be detected using FAF. Further studies are required to assess whether this finding holds true for automated white-on-white perimetry. In addition, more selective psychophysical stimuli may have higher sensitivity in detecting early functional loss that accompanies anatomic damage. PMID- 27246317 TI - Brain Structure and Function Associated with a History of Sport Concussion: A Multi-Modal Magnetic Resonance Imaging Study. AB - There is growing concern about the potential long-term consequences of sport concussion for young, currently active athletes. However, there remains limited information about brain abnormalities associated with a history of concussion and how they relate to clinical factors. In this study, advanced MRI was used to comprehensively describe abnormalities in brain structure and function associated with a history of sport concussion. Forty-three athletes (21 male, 22 female) were recruited from interuniversity teams at the beginning of the season, including 21 with a history of concussion and 22 without prior concussion; both groups also contained a balanced sample of contact and noncontact sports. Multi modal MRI was used to evaluate abnormalities in brain structure and function. Athletes with a history of concussion showed frontal decreases in brain volume and blood flow. However, they also demonstrated increased posterior cortical volume and elevated markers of white matter microstructure. A greater number of prior concussions was associated with more extensive decreases in cerebral blood flow and insular volume, whereas recovery time from most recent concussion was correlated with reduced frontotemporal volume. White matter showed limited correlations with clinical factors, predominantly in the anterior corona radiata. This study provides the first evidence of the long-term effects of concussion on gray matter volume, blood flow, and white matter microstructure within a single athlete cohort. This was examined for a mixture of male and female athletes in both contact and noncontact sports, demonstrating the relevance of these findings for the overall sporting community. PMID- 27246318 TI - Australia, a consumptive society. AB - Until the mid-20th century, consumption, as tuberculosis was then known, was a major cause of illness and death in Australia. Unfortunately, since then, other so-called consumptive diseases have emerged to supplant tuberculosis, namely, those related to the use of alcohol and tobacco, and overweight and obesity. Over the last 30 years, much progress has been made in reducing and eliminating the use of and exposure to tobacco. Per capita consumption of alcohol is at a 50-year low, having reached peak levels in the 1970s. Since the 1960s, Australians have become increasingly overweight and obese. The major objective of the liquor, food and associated industries is to optimise profits, that is, to sell as much food and alcohol as possible. The problem for Australians is that any growth in per capita consumption of alcohol and a continuation of current levels of food consumption carries ever-increasing health risks and burdens. The protection and promotion of the health of Australian citizens are major responsibilities of Commonwealth, State and Territory Governments. They have a responsibility to intervene to maintain a balance between actions that support commercial growth and development and the health and welfare of its citizens. In this context, they have largely failed. Solutions to this impasse are only possible if APSAD and other relevant organisations and individuals are active professionally and politically as leaders and advocates for evidence-based actions by both governments and commercial groups. [James G. Rankin. Australia, a consumptive society. Drug Alcohol Rev 2017;36:270-277]. PMID- 27246319 TI - Impact of Obesity on Wound Complications Following Radical Prostatectomy Is Mitigated by Robotic Technique. AB - OBJECTIVES: To evaluate the impact of obesity on patients developing wound complications within 30 days of open and robotic radical prostatectomy using the National Surgical Quality Improvement Program (NSQIP). METHODS: Patients undergoing radical prostatectomy in 2011 to 2012 were identified from NSQIP, which is a multi-institutional database of comprehensive 30-day postoperative outcomes. Wound complication included superficial surgical site infections (SSIs), deep SSI, organ space infections, and dehiscence. Descriptive statistics and multiple logistic regression examined the relationship between obesity and wound complications in open and robotic radical prostatectomy. RESULTS: Of the 12,454 radical prostatectomy cases reported in the study period, 9248 were robotic (74%), 2244 (18%) patients were normal weight (body mass index [BMI] <25), 5836 (47%) were overweight (BMI 25-30), and 4374 (35%) were obese (BMI >30). Wound complications occurred in 134 (4%) of open and 114 (1%) of robotic radical prostatectomies. After adjusting for age, history of smoking, history of diabetes, history of chronic steroid use, and operative time, it was determined that obese patients were at 71% increased odds of developing a wound complication after open prostatectomy (p = 0.034), while there was no difference in the odds of a wound complication after robotic radical prostatectomy (odds ratio 1.14, p = 0.665). CONCLUSIONS: Obese patients are at increased risk of developing wound complications when undergoing open vs robotic radical prostatectomy. Obese patients likely benefit from robotic radical prostatectomy whenever feasible. PMID- 27246320 TI - An overview of the effect of probiotics and exercise on mood and associated health conditions. AB - The present paper provides a review of the current knowledge relating to the health benefits of probiotics, specially focused on the effects they may have together with physical exercise on mood disorders and related chronic medical conditions.With both these conditions being a substantial contributor to the global disease burden, any alternative therapy must be considered. Probiotics influence the gut microbiota through a complex network of events which can influence mechanisms leading to development of mood disorders such as depression and anxiety. Similarly, through a complex interaction between psychological and neurobiological mechanisms, exercise has been found to play a key role in mood enhancement. PMID- 27246321 TI - [Rational use of antibiotics]. AB - International and national campaigns draw attention worldwide to the rational use of the available antibiotics. This has been stimulated by the high prevalence rates of drug-resistant pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), a threatening spread of development of resistance in Gram-negative rod-shaped bacteria and the selection of Clostridium difficile with a simultaneous clear reduction in the development of new antibiotics. The implementation of antibiotic stewardship programs aims to maintain their effectiveness by a rational use of the available antibiotics. The essential target of therapy with antibiotics is successful treatment of individual patients with bacterial infections. The optimal clinical treatment results can only be achieved when the toxicity, selection of pathogens and development of resistance are minimized. This article presents the principles of a rational antibiotic therapy. PMID- 27246322 TI - Is heat pain detection threshold associated with the area of secondary hyperalgesia following brief thermal sensitization? A study of healthy volunteers - design and detailed plan of analysis. AB - BACKGROUND: Several factors are believed to influence the development and experience of pain. Human clinical pain models are central tools, in the investigation of basic physiologic pain responses, and can be applied in patients as well as in healthy volunteers. Each clinical pain model investigates different aspects of the human pain response. Brief thermal sensitization induces a mild burn injury, resulting in development of primary hyperalgesia at the site of stimulation, and secondary hyperalgesia surrounding the site of stimulation. Central sensitization is believed to play an important role in the development of secondary hyperalgesia; however, a possible association of secondary hyperalgesia following brief thermal sensitization and other heat pain models remains unknown. Our aim with this study is to investigate how close the heat pain detection threshold is associated with the size of the area of secondary hyperalgesia induced by the clinical heat pain model: Brief thermal sensitization. METHODS AND DESIGN: We aim to include 120 healthy participants. The participants will be tested on two separate study days with the following procedures: i) Brief thermal sensitization, ii) heat pain detection threshold and iii) pain during thermal stimulation. Additionally, the participants will be tested with the Pain Catastrophizing Scale and Hospital Anxiety and Depression Scale questionnaires. We conducted statistical simulations based on data from our previous study, to estimate an empirical power of 99.9 % with alpha of 0.05. We define that an R(2) < 0.25 and predictive intervals larger than +/-150 cm(2) are indications of a weak association. DISCUSSION: The area of secondary hyperalgesia may serve as a quantitative measure of the central sensitization induced by cutaneous heat stimulation, and thus may be a biomarker of an individual's pain sensitivity. The number of studies investigating secondary hyperalgesia is growing; however basic knowledge of the physiologic aspects of secondary hyperalgesia in humans is still incomplete. We therefore find it interesting to investigate if HPDT, a known quantitative sensory test, is associated with areas of secondary hyperalgesia following brief thermal sensitization TRIAL REGISTRATION: Clinicaltrials.gov (Identifier: NCT02527395 ). Danish Research Ethics Committee (Identifier: H-8 2014-012). Danish Data Protection Agency (Identifier: 30-1436). PMID- 27246323 TI - SEARCHBreast: a new online resource to make surplus material from in vivo models of breast cancer visible and accessible to researchers. PMID- 27246324 TI - IL-10-dependent Tr1 cells attenuate astrocyte activation and ameliorate chronic central nervous system inflammation. AB - SEE WINGER AND ZAMVIL DOI101093/BRAIN/AWW121 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: The innate immune system plays a central role in the chronic central nervous system inflammation that drives neurological disability in progressive forms of multiple sclerosis, for which there are no effective treatments. The mucosal immune system is a unique tolerogenic organ that provides a physiological approach for the induction of regulatory T cells. Here we report that nasal administration of CD3-specific antibody ameliorates disease in a progressive animal model of multiple sclerosis. This effect is IL-10-dependent and is mediated by the induction of regulatory T cells that share a similar transcriptional profile to Tr1 regulatory cells and that suppress the astrocyte inflammatory transcriptional program. Treatment results in an attenuated inflammatory milieu in the central nervous system, decreased microglia activation, reduced recruitment of peripheral monocytes, stabilization of the blood-brain barrier and less neurodegeneration. These findings suggest a new therapeutic approach for the treatment of progressive forms of multiple sclerosis and potentially other types of chronic central nervous system inflammation. PMID- 27246326 TI - Correlation of clinical outcomes with bremsstrahlung and Y-90 PET/CT imaging findings following Y-90 radiosynoviorthesis: a prospective study. AB - BACKGROUND: It is unclear how to predict which patients will respond to Y-90 radiosynoviorthesis. The aim of this study is to correlate clinical outcomes following Y-90 radiosynoviorthesis with bremsstrahlung and Y-90 PET/CT imaging findings. METHODS: Fifty-one joints underwent bremsstrahlung planar and Y-90 PET/CT imaging following Y-90 radiosynoviorthesis. The Y-90 distribution pattern on bremsstrahlung planar imaging was classified as diffuse or non-diffuse and compared with the intra or extra-articular location of activity on Y-90 PET/CT. Treatment response was assessed by patients and clinicians at 6 months. In patients who underwent bremsstrahlung SPECT, side-by-side comparison with PET was performed with image quality/resolution scored using a five-point-scale. FINDINGS: Bremsstrahlung planar images were classified as diffuse in 33/51 (65 %) and non-diffuse in 18/51 (35 %) scans. There was no association between treatment response and the bremsstrahlung planar imaging pattern. PET/CT confirmed an intra articular location in all 33/33 (100 %) diffuse scans and an extra-articular location in 3/18 (17 %) non-diffuse scans. Of the three joints with extra articular activity, none had any treatment response. Excluding these three joints, there remained no association between the bremsstrahlung planar imaging pattern and treatment response. Of the 42 joints imaged with SPECT, PET image quality/resolution was classified as superior in 40 (95 %). In one patient with extra-articular activity on PET/CT, SPECT/CT was unable to definitively localise the activity to the intra or extra-articular space. CONCLUSIONS: The distribution pattern on bremsstrahlung planar imaging did not correlate with clinical outcome following Y-90 radiosynoviorthesis in our study population. However, in patients with non-diffuse planar imaging patterns, Y-90 PET/CT should be considered to exclude extra-articular activity with PET providing superior image quality compared to SPECT. PMID- 27246325 TI - Transcranial magnetic stimulation and potential cortical and trigeminothalamic mechanisms in migraine. AB - A single pulse of transcranial magnetic stimulation has been shown to be effective for the acute treatment of migraine with and without aura. Here we aimed to investigate the potential mechanisms of action of transcranial magnetic stimulation, using a transcortical approach, in preclinical migraine models. We tested the susceptibility of cortical spreading depression, the experimental correlate of migraine aura, and further evaluated the response of spontaneous and evoked trigeminovascular activity of second order trigemontothalamic and third order thalamocortical neurons in rats. Single pulse transcranial magnetic stimulation significantly inhibited both mechanical and chemically-induced cortical spreading depression when administered immediately post-induction in rats, but not when administered preinduction, and when controlled by a sham stimulation. Additionally transcranial magnetic stimulation significantly inhibited the spontaneous and evoked firing rate of third order thalamocortical projection neurons, but not second order neurons in the trigeminocervical complex, suggesting a potential modulatory effect that may underlie its utility in migraine. In gyrencephalic cat cortices, when administered post-cortical spreading depression, transcranial magnetic stimulation blocked the propagation of cortical spreading depression in two of eight animals. These results are the first to demonstrate that cortical spreading depression can be blocked in vivo using single pulse transcranial magnetic stimulation and further highlight a novel thalamocortical modulatory capacity that may explain the efficacy of magnetic stimulation in the treatment of migraine with and without aura. PMID- 27246327 TI - (18)F-fluoride-PET for dynamic in vivo monitoring of bone formation in multiple myeloma. AB - BACKGROUND: Bone disease in multiple myeloma is characterized by reduced bone formation. The gold standard of bone formation is the mineral apposition rate (MAR), an invasive technique reflecting bone formation at a single site. We compared (18)F-fluoride-PET with the MAR in myeloma patients. METHODS: Bone formation was measured before and after bortezomib treatment by determination of the MAR in iliac bone marrow biopsies and the measurement of (18)F-uptake. RESULTS: The inter- and intra-individual variations in (18)F-uptake (SUVA50%) were pronounced as 33.50 (range 4.42 to 37.92) and 27.18 (range 4.00 to 31.18), respectively. A significant correlation between the MAR and (18)F-uptake was found (r = 0.80, p = 0.017). There was a heterogeneous response after treatment varying from -2.20 to 4.53. CONCLUSIONS: Iliac (18)F-uptake was associated with the local MAR in myeloma patients. Furthermore, (18)F-fluoride-PET demonstrated the heterogeneity of in vivo bone formation, enabling monitoring during treatment. PMID- 27246328 TI - Early mortality from external causes in Aboriginal mothers: a retrospective cohort study. AB - BACKGROUND: Maternal loss can have a deep-rooted impact on families. Whilst a disproportionate number of Aboriginal women die from potentially preventable causes, no research has investigated mortality in Aboriginal mothers. We aimed to examine the elevated mortality risk in Aboriginal mothers with a focus on external causes. METHODS: We linked data from four state administrative datasets to identify all women who had a child from 1983 to 2010 in Western Australia and ascertained their Aboriginality, socio-demographic details, and their dates and causes of death prior to 2011. Comparing Aboriginal mothers with other mothers, we estimated the hazard ratios (HRs) for death by any external cause and each of the sub-categories of accident, suicide, and homicide, and the corresponding age of their youngest child. RESULTS: Compared to non-Aboriginal mothers and after adjustment for parity, socio-economic status and remoteness, Aboriginal mothers were more likely to die from accidents [HR = 6.43 (95 % CI: 4.9, 8.4)], suicide [HR = 3.46 (95 % CI: 2.2, 5.4)], homicide [HR = 17.46 (95 % CI: 10.4, 29.2)] or any external cause [HR = 6.61 (95 % CI: 5.4, 8.1)]. For mothers experiencing death, the median age of their youngest child was 4.8 years. CONCLUSION: During the study period, Aboriginal mothers were much more likely to die than other mothers and they usually left more and younger children. These increased rates were only partly explained by socio-demographic circumstances. Further research is required to examine the risk factors associated with these potentially preventable deaths and to enable the development of informed health promotion to increase the life chances of Aboriginal mothers and their children. PMID- 27246329 TI - Modern contraceptive use among migrant and non-migrant women in Kenya. AB - BACKGROUND: Manifest socio-economic differences are a trigger for internal migration in many sub-Saharan settings including Kenya. An interplay of the social, political and economic factors often lead to internal migration. Internal migration potentially has significant consequences on an individual's economic growth and on access to health services, however, there has been little research on these dynamics. In Kenya, where regional differentials in population growth and poverty reduction continue to be priorities in the post MDG development agenda, understanding the relationships between contraceptive use and internal migration is highly relevant. METHODS: Using data from the 2008-09 Kenya Demographic and Health Survey (DHS), we analyze data from 5,905 women aged 15-49 years who reported being sexually active in the last 12 months prior to the survey. Bivariate and multivariate logistic regressions are fitted to predict correlates of contraceptive use in the presence of migration streams among other explanatory variables. RESULTS: Modern contraceptive use was significantly higher among women in all migration streams (non-migrant urban (OR = 2.8, p < 0.001), urban-urban (OR = 2.0, p < 0.001), urban-rural (OR = 2.0, p < 0.001), rural-urban (OR = 2.6, p < 0.001), rural-rural (OR = 1.7, p < 0.001), than non-migrant rural women. CONCLUSION: Women who internally migrate within Kenya, whether from rural to urban or between urban centres, were more likely to use modern contraception than non-migrant rural women. This phenomenon appears to be due to selection, adaption and disruption effects which are likely to promote use of modern contraceptives. Programmatically, the differentials in modern contraceptive use by the different migration streams should be considered when designing family planning programmes among migrant and non-migrant women. PMID- 27246330 TI - The Nuclear Receptor Superfamily at Thirty. AB - The human genome codes for 48 members of the nuclear receptor superfamily, half of which have known ligands. Natural ligands for nuclear receptors are generally lipophilic in nature and include steroid hormones, bile acids, fatty acids, thyroid hormones, certain vitamins, and prostaglandins. Nuclear receptors regulate gene expression programs controlling development, differentiation, metabolic homeostasis and reproduction, in both a temporal and a tissue-selective manner. Since the original cloning of the cDNAs for the estrogen and glucocorticoid receptors, large strides have been made in our understanding of the structure and function of this family of transcription factors and their role in pathophysiology. PMID- 27246331 TI - Lipid Homeostasis and Ligands for Liver X Receptors: Identification and Characterization. AB - Screening of bona fide ligands for nuclear receptors is a real tour de force as the identified molecules are supposed to be able to activate the targeted proteins in cell culture as well as in vivo. Indeed orphan nuclear receptors are putative pharmacologically targets for various diseases. It is thus necessary to have quick and reproductive systems that help in identifying new ligands, agonist or antagonist, before using them in vivo in animal models to check for secondary effects. Here, we describe the transient transfections (homologous and heterologous) used for the screening of ligands for liver X receptor alpha (LXRalpha, NR1H3) in HeLa cells. PMID- 27246332 TI - Use of Differential Scanning Fluorimetry to Identify Nuclear Receptor Ligands. AB - Identification of small molecules that interact specifically with the ligand binding domains (LBDs) of nuclear receptors (NRs) can be accomplished using a variety of methodologies. Here, we describe the use of differential scanning fluorimetry to identify these ligands, a technique that requires no modification or derivatization of either the protein or the ligand, and uses an instrument that is becoming increasingly affordable and common in modern molecular biology laboratories, the quantitative, or real-time, PCR machine. Upon being introduced to specific ligands, nuclear receptors undergo structural and dynamic changes that tend to increase molecular stability, which can be measured by the resistance of the protein to heat denaturation. Differential scanning fluorimetry (DSF) uses a dielectric sensitive fluorescent dye to measure the thermal denaturation, or "melting" point (Tm) of a protein under different conditions, in this case in the absence and presence of a candidate ligand. Using DSF, multiple candidates can be screened at once, in numbers corresponding to plate size of the instrument used (e.g., 96- or 384-well), allowing significant throughput if a modest library of compounds needs to be tested. PMID- 27246333 TI - Drug-Discovery Pipeline for Novel Inhibitors of the Androgen Receptor. AB - The androgen receptor (AR) is an important regulator of genes responsible for the development and recurrence of prostate cancer. Current therapies for this disease rely on small-molecule inhibitors that block the transcriptional activity of the AR. Recently, major advances in the development of novel AR inhibitors resulted from X-ray crystallographic information on the receptor and utilization of in silico drug design synergized with rigorous experimental testing.Herein, we describe a drug-discovery pipeline for in silico screening for small molecules that target an allosteric region on the AR termed the binding-function 3 (BF3) site. Following the identification of potential candidates, the compounds are tested in cell culture and biochemical assays for their ability to interact with and inhibit the AR. The described pipeline is readily accessible and could be applied in drug design efforts toward any surface-exposed region on the AR or other related steroid nuclear receptor. PMID- 27246334 TI - Use of BRET to Study Protein-Protein Interactions In Vitro and In Vivo. AB - Application of bioluminescence resonance energy transfer (BRET) assay has been of special value in measuring dynamic events such as protein-protein interactions (PPIs) in vitro or in vivo. It was only in the late 1990s the BRET assay using RLuc-YFP was introduced for biological research showing its use in determining interaction of two proteins involved in circadian rhythm. Several inherent attributes such as rapid and fairly sensitive ratiometric measurements, assessment of PPI irrespective of protein location in cellular compartment, and cost-effectiveness consenting to high-throughput assay development make BRET a popular genetic reporter-based assay for PPI studies. In BRET-based screening, within a defined proximity range of 10-100 A, excited state energy of the luminescence molecule can excite the acceptor fluorophore in the form of resonance energy transfer, causing it to emit at its characteristic emission wavelength. Based on this principle, several such donor-acceptor pairs, using the Renilla luciferase or its mutants as donor and either GFP2, YFP, mOrange, TagRFP, or TurboFP as acceptor, have been reported for use.In recent years, BRET-related research has become significantly versatile in the assay format and its applicability by adopting the assay on multiple detection devices such as small animal optical imaging platform or bioluminescence microscope. Beyond the scope of quantitative measurement of PPIs and protein dimerization, molecular optical imaging applications based on BRET assays have broadened its scope for screening of pharmacological compounds by unifying in vitro, live cell, and in vivo animal/plant measurement all on one platform. Taking examples from the literature, this chapter contributes to in-depth methodological details on how to perform in vitro and in vivo BRET experiments, and illustrates its advantages as a single-format assay. PMID- 27246335 TI - Studying Nuclear Receptor Complexes in the Cellular Environment. AB - The ligand-regulated structure and biochemistry of nuclear receptor complexes are commonly determined by in vitro studies of isolated receptors, cofactors, and their fragments. However, in the living cell, the complexes that form are governed not just by the relative affinities of isolated cofactors for the receptor but also by the cell-specific sequestration or concentration of subsets of competing or cooperating cofactors, receptors, and other effectors into distinct subcellular domains and/or their temporary diversion into other cellular activities. Most methods developed to understand nuclear receptor function in the cellular environment involve the direct tagging of the nuclear receptor or its cofactors with fluorescent proteins (FPs) and the tracking of those FP-tagged factors by fluorescence microscopy. One of those approaches, Forster resonance energy transfer (FRET) microscopy, quantifies the transfer of energy from a higher energy "donor" FP to a lower energy "acceptor" FP attached to a single protein or to interacting proteins. The amount of FRET is influenced by the ligand-induced changes in the proximities and orientations of the FPs within the tagged nuclear receptor complexes, which is an indicator of the structure of the complexes, and by the kinetics of the interaction between FP-tagged factors. Here, we provide a guide for parsing information about the structure and biochemistry of nuclear receptor complexes from FRET measurements in living cells. PMID- 27246336 TI - Posttranslational Modifications of Steroid Receptors: Phosphorylation. AB - The detection of phosphorylation status of proteins has become a critical component of the analysis of activity, localization, and turnover studies of most proteins, particularly for those involved in signaling. The androgen receptor is no exception to this rule with its localization, transcriptional activity, and interactions determined by a series of key phosphorylations on serine residues. Here we have presented a series of techniques for the investigation of the phosphorylation status and intracellular localization of the androgen receptor after hormone and growth factor stimulation of cells in culture (in vitro) and in prostate cancer tissue (in vivo). Modified methods for immunohistochemistry, immunoblotting and immunofluorescence detection with high efficacy for the measurement and monitoring of androgen receptor are presented here alongside examples of their use. PMID- 27246337 TI - Mapping Protein-DNA Interactions Using ChIP-exo and Illumina-Based Sequencing. AB - Chromatin immunoprecipitation (ChIP) provides a means of enriching DNA associated with transcription factors, histone modifications, and indeed any other proteins for which suitably characterized antibodies are available. Over the years, sequence detection has progressed from quantitative real-time PCR and Southern blotting to microarrays (ChIP-chip) and now high-throughput sequencing (ChIP seq). This progression has vastly increased the sequence coverage and data volumes generated. This in turn has enabled informaticians to predict the identity of multi-protein complexes on DNA based on the overrepresentation of sequence motifs in DNA enriched by ChIP with a single antibody against a single protein. In the course of the development of high-throughput sequencing, little has changed in the ChIP methodology until recently. In the last three years, a number of modifications have been made to the ChIP protocol with the goal of enhancing the sensitivity of the method and further reducing the levels of nonspecific background sequences in ChIPped samples. In this chapter, we provide a brief commentary on these methodological changes and describe a detailed ChIP exo method able to generate narrower peaks and greater peak coverage from ChIPped material. PMID- 27246338 TI - Methods to Identify Chromatin-Bound Protein Complexes: From Genome-Wide to Locus Specific Approaches. AB - High-throughput sequencing approaches coupled with functional genomics experiments have facilitated a rapid growth in our understanding of chromatin biology, from genome-wide maps of transcription factor binding and histone modifications to insights into higher order chromatin organization under specific cellular conditions. However in most cases these methods require a prior knowledge of the system of interest (e.g., targets for immunoprecipitation or modulation) and therefore are limited in their utility to identify novel components of pathways or for the study of uncharacterized pathways. Several orthologous proteomics approaches have been developed recently that bridge this gap, allowing the identification of protein complexes globally or at specific genomic loci. In this chapter the relative advantages of each approach will be explored and a detailed protocol given for DNA pull-down of a specific androgen receptor (AR) genomic target. PMID- 27246339 TI - Measuring the Expression of microRNAs Regulated by Androgens. AB - The discovery of microRNAs (miRNAs) provided yet another mechanism of gene expression regulation. miRNAs have recently been also implicated in many diseases, including prostate cancer (PC). As PC is a highly androgen-dependent disease, extensive effort has been invested to identify the miRNAs that are androgen regulated. However, relatively few of them have been shown to be directly androgen regulated in PC. In this chapter we introduce the commonly used techniques to study the androgen regulation of miRNAs. The most cost-effective tool to profile global miRNA expression is microarray-based hybridization, whereas real-time quantitative reverse transcription PCR (qRT-PCR) is commonly used for the study of individual miRNAs. PMID- 27246340 TI - Methods for Identifying and Quantifying mRNA Expression of Androgen Receptor Splicing Variants in Prostate Cancer. AB - Constitutively active androgen receptor (AR) variants (AR-Vs) lacking the AR ligand-binding domain have been identified as drivers of prostate cancer resistance to AR-targeted therapies. A definitive understanding of the role and origin of AR-Vs in the natural history of prostate cancer progression requires cataloging the entire spectrum of AR-Vs expressed in prostate cancer, as well as accurate determination of their expression levels relative to full-length AR in clinical tissues and models of progression. Exon constituency differences at the 3' terminus of mRNAs encoding AR-Vs compared with mRNAs encoding full-length AR can be exploited for discovery and quantification-based experiments. Here, we provide methodological details for 3' rapid amplification of cDNA ends (3' RACE) and absolute quantitative RT-PCR, which are cost-effective approaches for identifying new AR-Vs and quantifying their absolute expression levels in conjunction with full-length AR in RNA samples derived from various sources. PMID- 27246341 TI - Harvesting Human Prostate Tissue Material and Culturing Primary Prostate Epithelial Cells. AB - In order to fully explore the biology of a complex solid tumor such as prostate cancer, it is desirable to work with patient tissue. Only by working with cells from a tissue can we take into account patient variability and tumor heterogeneity. Cell lines have long been regarded as the workhorse of cancer research and it could be argued that they are of most use when considered within a panel of cell lines, thus taking into account specified mutations and variations in phenotype between different cell lines. However, often very different results are obtained when comparing cell lines to primary cells cultured from tissue. It stands to reason that cells cultured from patient tissue represents a close-to-patient model that should and does produce clinically relevant data. This chapter aims to illustrate the methods of processing, storing and culturing cells from prostate tissue, with a description of potential uses. PMID- 27246342 TI - In Vivo Imaging of Nuclear Receptor Transcriptional Activity. AB - Nuclear receptors drive key processes during development, reproduction, metabolism, and disease. In order to understand and analyze, as well as manipulate, their actions it is imperative that we are able to study them in whole animals and in a spatiotemporal manner. The increasing repertoire of transgenic animals, expressing reporter genes driven by a specific nuclear receptor, enables us to do this. Use of luciferase reporter genes is the method of choice of many researchers as it is well tolerated, relatively easy to use, and robust. Further, luciferase lends itself to the process as it can penetrate tissue and can be manipulated to degrade rapidly thus allowing a dynamic response. However, limited resolution, lack of quantitation, and the largely two dimensional images acquired make it desirable to support results using ex vivo imaging and enzymatic and/or immunohistochemical analysis of dissected tissue. As well as enabling the visualization of nuclear receptor signaling in wild-type animals, crossing these mouse models with models of disease will provide invaluable information on how such signaling is dysregulated during disease progression, and how we may manipulate nuclear receptor signaling in therapy. The use of in vivo imaging therefore provides the power to determine where and when in development, aging, and disease nuclear receptors are active and how ligands or receptor modulators affect this. PMID- 27246343 TI - Development and Characterization of Cell-Specific Androgen Receptor Knockout Mice. AB - Conditional gene targeting has revolutionized molecular genetic analysis of nuclear receptor proteins, however development and analysis of such conditional knockouts is far from simple, with many caveats and pitfalls waiting to snare the novice or unprepared. In this chapter, we describe our experience of generating and analyzing mouse models with conditional ablation of the androgen receptor (AR) from tissues of the reproductive system and other organs. The guidance, suggestions, and protocols outlined in the chapter provide the key starting point for analyses of conditional-ARKO mice, completing them as described provides an excellent framework for further focussed project-specific analyses, and applies equally well to analysis of reproductive tissues from any mouse model generated through conditional gene targeting. PMID- 27246344 TI - Isolation and Characterization of Rat Mesenchymal Stem Cells Derived from Granulocyte Colony-Stimulating Factor-Mobilized Peripheral Blood. AB - Mesenchymal stem cells (MSCs) have been isolated from many tissues and organs. However, there is much dispute as to whether MSCs exist in peripheral blood. This may be due to the limited identification methods of MSCs, especially the lack of detection markers for phenotypic characteristics. In this study, as many as 10 surface markers of MSCs derived from rat peripheral blood (rPBMSCs) were analyzed after granulocyte colony-stimulating factor mobilization. Our results suggest that mobilized rPBMSCs overexpress mesenchymal markers, including CD90, CD44, CD29, CD73 and CD105, but do not express CD45, CD11b, CD79a, CD34 or HLA-DR. This is in conformity with the standard definition of MSCs by the International Society for Cellular Therapy. In addition, the colony-forming efficiency of the mobilized rat peripheral blood was 15.83 +/- 1.61/106, significantly outnumbering that of the nonmobilized group, which was 0.28 +/- 0.1/106 (p < 0.01). Combining the growth characteristics with the differential capacities of mobilized rPBMSCs towards forming osteocytes, chondrocytes and adipocytes, we further confirmed the existence of rPBMSCs. Additionally, this treatment could improve locomotive function after spinal cord injury (SCI) in rats. Due to their convenient collection, fewer complications, cost effectiveness and suitability for autograft, PBMSCs might be a substitute for MSCs derived from bone marrow and provide promising prospects for the cell-based therapy of SCI. PMID- 27246345 TI - Beyond equipment distribution in Needle and Syringe Programmes: an exploratory analysis of blood-borne virus risk and other measures of client need. AB - BACKGROUND: Despite high levels of equipment distribution through Needle and Syringe Programmes (NSPs) in Australia, the levels of reuse of equipment among people who inject drugs remain concerning. This paper used an exploratory analysis to examine the needs of NSP client that could be addressed by NSPs to enhance service impact and blood-borne virus risk practices. METHODS: People who inject drugs were recruited from six NSP sites in Sydney, Australia, to undertake a self-completed survey. RESULTS: Using the responses of 236 NSP client participants, three factors were identified in an exploratory factor analysis: recent risky injection (Eigenvalue 3.63, 20.2 % of variance); disadvantage and disability (Eigenvalue 2.26, 12.5 % of variance); and drug use milieu (Eigenvalue 1.50, 8.4 % of variance). To understand the distribution of these factors, the standardised factor scores were dichotomised to explore those participants with 'above average' vulnerability on each factor. A small group of NSP clients reported a cluster of vulnerability measures. Most participants (55.5 %) reported vulnerability on none or only one factor, indicating that 45.5 % could be considered as having double (35.6 %) or triple (8.9 %) vulnerability. CONCLUSIONS: These results challenge NSPs to understand the heterogeneity among their client group and develop programmes that respond to their clients' range of needs beyond those immediately associated with blood-borne virus (BBV) risk. This paper contributes to the growing evidence base regarding the need for BBV prevention efforts to examine strategies beyond equipment distribution. PMID- 27246346 TI - Morbimortality in adult patients with septic arthritis: a three-year hospital based study. AB - BACKGROUND: The objective of this ambispective study was to determine outcomes and associated factors for adult patients with confirmed septic arthritis (SA). METHODS: All adult patients admitted to Amiens University Hospital between November 2010 and December 2013 with confirmed SA were included in the study. Patients with prosthetic joint infections were excluded. A statistical analysis was performed in order to identify risk factors associated with a poor outcome (including mortality directly attributable to SA). RESULTS: A total of 109 patients (mean +/- SD age: 60.1 +/- 20.1; 74 male/35 females) were diagnosed with SA during the study period. The most commonly involved sites were the small joints (n = 34, 31.2 %) and the knee (n = 25, 22.9 %). The most frequent concomitant conditions were cardiovascular disease (n = 45, 41.3 %) and rheumatic disease (n = 39, 35.8 %). One hundred patients (91.7 %) had a positive microbiological culture test, with Staphylococcus aureus as the most commonly detected pathogen (n = 59, 54.1 %). Mortality directly attributable to SA was relatively infrequent (n = 6, 5.6 %) and occurred soon after the onset of SA (median [range]: 24 days [1-42]). Major risk factors associated with death directly attributable to SA were older age (p = 0.023), high C-reactive protein levels (p = 0.002), diabetes mellitus (p = 0.028), rheumatoid arthritis and other inflammatory rheumatic diseases (p = 0.021), confusion on admission (p = 0.012), bacteraemia (p = 0.015), a low creatinine clearance rate (p = 0.009) and the presence of leg ulcers/eschars (p = 0.003). The median duration of follow-up (in patients who survived for more than 6 months) was 17 months [6-43]. The proportion of poor functional outcomes was high (31.8 %). Major risk factors associated with a poor functional outcome were older age (0.049), hip joint involvement (p = 0.003), the presence of leg ulcers/eschars (p = 0.012), longer time to presentation (0.034) and a low creatinine clearance rate (p = 0.013). CONCLUSIONS: In a university hospital setting, SA is still associated with high morbidity and mortality rates. PMID- 27246347 TI - Glucose levels as a prognostic marker in patients with ST-segment elevation myocardial infarction: a case-control study. AB - BACKGROUND: Patients with myocardial infarction (MI) have a high mortality. Therefore, new risk markers and predictors of an adverse outcome for MI are required. The role of hyperglycemia in the development of cardiovascular complications in MI patients is still unclear. METHODS: A total of 529 consecutive patients with the diagnosis of ST-segment elevation acute coronary syndrome within 24 h of the onset of symptoms were included in the study. All of the patients underwent blood glucose measurement at admission to hospital. The glycemic profile, including measurement of blood glucose levels early in the night and in the morning (3 a.m. and 5 a.m.), was assessed in 77 patients with diabetes on days 6-10 of the course of MI to monitor the efficiency of blood glucose-lowering therapy and to detect hypoglycemic episodes. RESULTS: In hospital mortality showed relationship between the level of blood glucose on admission and in-hospital mortality in patients with MI with ST-segment elevation in combination with diabetes mellitus. There was a direct linear relationship between blood glucose levels and in-hospital mortality in patients without diabetes. CONCLUSION: Episodes of hypoglycemia recorded in MI patients with diabetes in the hospital stage of treatment do not determine the prognosis, but enable identification of patients with an unfavorable course in the postinfarction period. PMID- 27246348 TI - Fear of cancer recurrence: a theoretical review and its relevance for clinical presentation and management. AB - BACKGROUND: There is increasing recognition of the unique physical and psychosocial concerns of the growing population of cancer survivors. An emerging literature demonstrates that fear of cancer recurrence (FCR) is a problematic long-term and late effect for cancer survivors. In fact, FCR is a top concern, and this article provides a necessary synthesis of the extant research evidence and theory. METHODS: Literature searches were conducted using databases including MEDLINE and PsychINFO using specified search terms including 'fear of recurrence' and 'worry about recurrence'. A comprehensive narrative review summarizes early empirical findings on FCR including current definitions, assessment tools, clinical presentations, quality of life impact, prevalence, trajectory and risk factors. This paper also critically reviews the relevant theoretical frameworks to best understand these findings and considers multiple psychosocial treatment models that may have relevance for addressing FCR in the clinical setting. RESULTS: There is evidence of substantial prevalence and quality of life impact of FCR. Several theories (e.g. self-regulation model of illness, a family-based model, uncertainty in illness theory, social-cognitive processing theory, terror management theory) directly or indirectly help conceptualize FCR and inform potential treatment options for those with clinically significant distress or impairment resulting from FCR. CONCLUSIONS: Further investigation into FCR is warranted to promote evidence-based care for this significant cancer survivorship concern. PMID- 27246349 TI - Electrophysiological and histological changes of paraspinal muscles in adolescent idiopathic scoliosis. AB - PURPOSE: The pathogenesis of adolescent idiopathic scoliosis (AIS) remains poorly understood. To date, potentially involved local changes in the deep paraspinal muscles still remain unknown. METHODS: Needle electromyography (EMG) and muscle biopsy of paraspinal muscles at convexity and concavity of the AIS main thoracic curve were performed in 25 subjects. In this group, EMG was performed in 16 AIS subjects (12 females, 12-27 years), muscle biopsy in 18 AIS subjects (15 females, 11-31 years) compared to 10 non-scoliotic controls (6 females, 12-55 years). Samples of muscle tissue were removed during corrective surgery and were examined histologically, enzyme histochemically and immunohistochemically. Both methods of EMG and muscle biopsy were performed in 9 subjects (7 women, 12-27 years). RESULTS: Right curve convexity was found in 24 AIS subjects. Amplitudes of motor unit action potentials (MUPs) were significantly increased on the AIS curve convexity versus concavity. Turns, duration and phases of MUPs were without any significant changes. In all 18 subjects, the histological examination revealed muscle fiber redistribution with numerical predominance of type I on the curve convexity which strongly correlated with the progression of the Cobb angle. CONCLUSION: Our findings demonstrate significant changes of muscle fiber redistribution in the paraspinal muscles of AIS with increased proportion of type I on the convexity corresponding to a significantly higher amplitude of MUPs on the same side. A possible explanation of this alteration is a secondary adaptation due to chronic high load demand. PMID- 27246350 TI - Can standard anterior Smith-Robinson supramanubrial approach be utilized for approach down to T2 or T3? AB - PURPOSE: The aim of this study was to determine a plain radiographic criterion for determining the feasibility of using the standard anterior Smith-Robinson supramanubrial approach for anterior surgery down to T2 or T3. METHODS: The surgical database (2002-2014) was searched to identify patients with anterior cervical surgery to T2 or T3. A method to determine whether a standard anterior Smith-Robinson approach can be used to operate on the upper thoracic levels was evaluated. The surgeon chose the surgical approach preoperatively using a lateral radiograph by determining if a line from the intended skin incision to the lower instrumented level (LIV) passed above the top of the manubrium. If so, a standard Smith-Robinson approach was selected. Another spine surgeon then analyzed all patients who had anterior thoracic fusion to T2 or below. The lateral radiographs were retrospectively reviewed. RESULTS: A total of 44 patients who underwent anterior surgery down to T2 or T3 vertebrae were identified. T2 was the LIV in 39 patients. T3 was the LIV in five patients. No surgery was abandoned or converted to a difference approach after making the standard Smith-Robinson approach. To increase visualization, T1 corpectomy was necessary in 4 of 39 patients when T2 was the LIV. T2 corpectomy was necessary in 2 of 5 patients when T3 was the LIV. CONCLUSION: If a line from the intended skin incision to the LIV passes over the top of the manubrium, a standard Smith-Robinson approach without sternotomy can be successfully used. PMID- 27246351 TI - The feasibility of inserting a C1 pedicle screw in patients with ponticulus posticus: a retrospective analysis of eleven patients. AB - BACKGROUND: Ponticulus posticus is a common anatomic variation that can be mistaken for a broad posterior arch during C1 pedicle screw placement. When the atlas lateral mass screws are placed via the posterior arch, injury to the vertebral artery may result. To our knowledge, there are few clinical studies that have analyzed the feasibility of C1 pedicle screw fixation in patients with ponticulus posticus, in clinical practice. PURPOSE: To evaluate the feasibility of inserting a C1 pedicle screw in patients with ponticulus posticus. METHODS: Between January 2008 and January 2012, 11 consecutive patients with atlantoaxial instability, and with a ponticulus posticus at C1, underwent posterior fusion surgery in our institution. According to preoperative computed tomography (CT) reconstruction, a complete ponticulus posticus was found unilaterally in nine patients and bilaterally in two. Postoperative CT reconstructive imaging was performed to assess whether C1 pedicle screw placement was successful. Patients were followed up at regular intervals and evaluated for symptoms of ponticulus posticus syndrome. RESULTS: Thirteen C1 pedicles (atlas vertebral artery groove), each with a complete ponticulus posticus, were successfully inserted with thirteen 3.5- or 4.0-mm diameter pedicle screws, without resection of the bony anomaly. No intraoperative complications (venous plexus, vertebral artery, or spinal cord injury) occurred. The mean follow-up period was 21 (range 14-30) months. Postoperative CT reconstructive images showed that all 13 pedicle screws were inserted in the C1 pedicles without destruction of the atlas pedicle cortical bone. In the follow-up period, none of the patients demonstrated clinical symptoms of ponticulus posticus syndrome or developed bone fusion. CONCLUSION: Three-dimensional CT imaging should be considered prior to C1 pedicle screw fixation in patients with ponticulus posticus, to avoid mistaking the ponticulus posticus for a widened dorsal arch of the atlas. If there is no ponticulus posticus syndrome preoperatively, C1 pedicle screw fixation can be successfully performed without removing the bony anomaly. PMID- 27246352 TI - A novel technique for unstable Hangman's fracture: lag screw-rod (LSR) technique. AB - PURPOSE: The goal of the study was to describe the lag screw-rod (LSR) technique for the treatment of unstable Hangman's fracture as an attempt to pull C2 vertebral body back to posterior elements easily and immobilize C2 relative to C3 simultaneously. METHODS: Twenty-one patients with unstable Hangman's fracture were treated with the LSR technique from January 2008 to October 2014. The clinical and radiological records were reviewed retrospectively. The angulation and displacement of C2 on C3 were evaluated. Complications, neck pain, neurological improvement, and fusion rate were assessed. RESULTS: The LSR technique was used for C2-C3 pedicle fixation and fusion in all the patients. The C2 vertebral body was pulled back to posterior elements successfully. The angulation and displacement of C2 on C3 were rectified obviously. No intra operative or post-operative spinal cord or vertebral injury was observed. Visual analogue scale (VAS) scores for neck pain decreased gradually after operation. The patients with spinal cord injury were recovered at final following up. All patients achieved bony fusion without internal fixation failures. CONCLUSIONS: The LSR technique is an effective and reliable treatment for unstable Hangman's fractures. The technique has the advantages of pulling back the C2 vertebral body back to posterior elements easily and immobilizing C2 relative to C3 simultaneously. PMID- 27246353 TI - Mycophenolate mofetil as an alternative treatment for autoimmune hepatitis. AB - Autoimmune hepatitis (AIH) is an immune-mediated chronic liver disease characterized by hepatocellular inflammation, necrosis, and fibrosis, which can progress to cirrhosis and fulminant hepatic failure. The standard treatment for AIH includes corticosteroids alone or in combination with azathioprine. Although most patients achieve remission using the standard regimen, some patients do not respond due to either drug intolerance or refractory disease; in such cases alternative immunosuppressive agents should be explored. The second-line therapies are cyclophilin inhibitors such as cyclosporine A or tacrolimus, and nowadays mycophenolate mofetil (MMF) is widely used if azathioprine-based therapies are not tolerated. Although these are recommended as an alternative to the first-line regimen, there is insufficient evidence for the efficacy of second line therapies, with the evidence based mainly on expert opinion. Therefore, we report an AIH patient receiving the standard regimen in whom remission did not occur due to side effects to azathioprine, but was successfully treated with MMF in combination with corticosteroids as an alternative to the standard regimen. PMID- 27246355 TI - Endovascular Aneurysm Repair and Sealing (EVARS): A Useful Adjunct in Treating Challenging Morphology: Response to Comments. PMID- 27246354 TI - L-Arginine supplementation inhibits the growth of breast cancer by enhancing innate and adaptive immune responses mediated by suppression of MDSCs in vivo. AB - BACKGROUND: L-Arg is involved in many biological activities, including the activation of T cells. In breast cancer patients, L-Arg is depleted by nitric oxide synthase 2 (NOS2) and arginase 1 (ARG-1) produced by myeloid-derived suppressor cells (MDSCs). Our aim was to test whether L-Arg supplementation could enhance antitumor immune response and improve survivorship in a rodent model of mammary tumor. METHODS: Tumor volumes in control and L-Arg treated 4 T1 tumor bearing (TB) BALB/c mice were measured and survival rates were recorded. The percentages of MDSCs, dendritic cells (DCs), regulatory T cells (Tregs), macrophages, CD4(+) T cells, and CD8(+) T cells were examined by flow cytometry. Additionally, levels of IL-10, TNF-alpha, and IFN-gamma were measured by enzyme linked immunosorbent assay (ELISA) and nitric oxide (NO) levels were measured by the Griess reaction. IFN-gamma, T-bet, Granzyme B, ARG-1 and iNOS mRNA levels were examined by real-time RT-PCR. RESULTS: L-Arg treatment inhibited tumor growth and prolonged the survival time of 4 T1 TB mice. The frequency of MDSCs was significantly suppressed in L-Arg treated TB mice. In contrast, the numbers and function of macrophages, CD4(+) T cells, and CD8(+) T cells were significantly enhanced. The IFN-gamma, TNF-alpha, NO levels in splenocytes supernatant, as well as iNOS, IFN-gamma, Granzyme B mRNA levels in splenocytes and tumor blocks were significantly increased. The ARG-1 mRNA level in tumor blocks, the frequency of Tregs, and IL-10 level were not affected. CONCLUSION: L Arg supplementation significantly inhibited tumor growth and prolonged the survival time of 4 T1 TB mice, which was associated with the reduction of MDSCs, and enhanced innate and adaptive immune responses. PMID- 27246356 TI - Hypothesis: New PCSK9 Inhibitors May Impact Calcific Aortic Valve Disease. AB - Calcific aortic valve disease (CAVD) is a common cardiovascular disease in the elderly individuals associated with major morbidity and mortality. The process is characterized by multiple steps: lipid infiltration, inflammation, fibrosis, and calcification. Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) represent a new therapeutic category of drugs for the treatment of dyslipidemia and atherosclerotic cardiovascular disease. Monoclonal antibodies of PCSK9 can result in substantial reductions in atherogenic lipoprotein cholesterol carrying particles, especially lipoprotein(a), and thereby hold the potential for further reducing events associated with atherosclerotic cardiovascular disease. In this article, we reviewed the clinical and experimental studies in order to find the evidence of the involvement of PCSK9 in CAVD and the potential benefits of PCSK9 monoclonal antibodies in clinical therapeutics. PMID- 27246357 TI - Running Exercise and Angiotensin II Type I Receptor Blocker Telmisartan Are Equally Effective in Preventing Angiotensin II-Mediated Vulnerable Atherosclerotic Lesions. AB - INTRODUCTION: The present study was conducted to directly compare the efficacy of running exercise and telmisartan treatment on angiotensin (Ang) II-mediated atherosclerosis and plaque vulnerability. MATERIALS AND METHODS: Apolipoprotein E deficient (ApoE-/-) mice with Ang II-mediated atherosclerosis (2-kidney, 1-clip [2K1C] renovascular hypertension model) were randomized into 3 groups: treadmill running exercise (RUN), telmisartan treatment (TEL), and sedentary untreated controls (SED) for 5 weeks. Atherosclerosis was assessed using histological and immunohistochemical analyses. Gene expression was determined by real-time reverse transcription polymerase chain reaction. RESULTS: TEL but not RUN mice significantly decreased (50%) atherosclerotic lesion size compared to SED. RUN and TEL promoted plaque stabilization to a similar degree in ApoE-/- 2K1C mice. However, plaque composition and vascular inflammatory markers were differently affected: RUN decreased plaque macrophage infiltration (35%), whereas TEL reduced lipid core size (88%); RUN significantly increased aortic peroxisome proliferator activated receptor (PPAR)-alpha, -delta, and -gamma expression, whereas TEL significantly modulated T-helper 1/T-helper 2 (Th1/Th2) aortic response toward an anti-inflammatory state (decreased aortic interleukin [IL] 2 to IL-10 and IL-2 to IL-13 expression ratios). Plaque smooth muscle cell content was similarly increased (128% and 141%, respectively). Aortic AT1 and AT2 receptor expression as well as aortic CD11c/CD206 and IL-1beta/IL-1ra expression ratios were not significantly modulated by either RUN or TEL. CONCLUSION: Running exercise and telmisartan treatment are equally effective in preventing Ang II-mediated plaque vulnerability but through distinct cellular and molecular mechanisms. Our findings further support the use of exercise training and selective AT1 receptor blocker therapies for atherosclerotic cardiovascular disease prevention. PMID- 27246358 TI - Age is a significant predictor of early and late improvement in semen parameters after microsurgical varicocele repair. AB - Accumulating evidence indicates that varicocele repair improves sperm quality. However, longitudinal changes in sperm parameters and predictors of improved semen characteristics after surgery have not been fully investigated. We retrospectively reviewed data from 100 men who underwent microsurgical subinguinal varicocele repair at a single centre. Follow-up semen examinations were carried out at 3, 6 and 12 months post-operatively. Logistic regression was used to identify predictors of early (3 months) and late (>=6 months) improvement in semen parameters after varicocele repair. At 3 months post-operatively, 76.1% of the patients had improved total motile sperm counts, which continued to improve significantly up to 12 months post-operatively (p = .016). When comparing changes in semen parameters between younger (<37 years) and older (>=37 years) men, post-operative improvements in sperm concentration and motility were greater among younger men. Multivariate analysis showed that younger age was associated with early (p = .043) and late (p = .010) post-operative improvement in total motile sperm count. Our findings indicate that early varicocele repair improved semen parameters after surgery. PMID- 27246359 TI - Quality assurance of carbon ion and proton beams: A feasibility study for using the 2D MatriXX detector. AB - PURPOSE: The quality assurance (QA) procedures in particle therapy centers with active beam scanning make extensive use of films, which do not provide immediate results. The purpose of this work is to verify whether the 2D MatriXX detector by IBA Dosimetry has enough sensitivity to replace films in some of the measurements. METHODS: MatriXX is a commercial detector composed of 32*32 parallel plate ionization chambers designed for pre-treatment dose verification in conventional radiation therapy. The detector and GAFCHROMIC(r) films were exposed simultaneously to a 131.44MeV proton and a 221.45MeV/u carbon-ion therapeutic beam at the CNAO therapy center of Pavia - Italy, and the results were analyzed and compared. RESULTS: The sensitivity MatriXX on the beam position, beam width and field flatness was investigated. For the first two quantities, a method for correcting systematic uncertainties, dependent on the beam size, was developed allowing to achieve a position resolution equal to 230MUm for carbon ions and less than 100MUm for protons. The beam size and the field flatness measured using MatriXX were compared with the same quantities measured with the irradiated film, showing a good agreement. CONCLUSIONS: The results indicate that a 2D detector such as MatriXX can be used to measure several parameters of a scanned ion beam quickly and precisely and suggest that the QA would benefit from a new protocol where the MatriXX detector is added to the existing systems. PMID- 27246361 TI - Glycobiology to the rescue ! PMID- 27246360 TI - Castration-Resistant Prostate Cancer Tissue Acquisition From Bone Metastases for Molecular Analyses. AB - BACKGROUND: The urgent need for castration-resistant prostate cancer molecular characterization to guide treatment has been constrained by the disease's predilection to metastasize primarily to bone. We hypothesized that the use of clinical and imaging criteria could maximize tissue acquisition from bone marrow biopsies (BMBs). We aimed to develop a score for the selection of patients undergoing BMB. MATERIALS AND METHODS: A total of 115 BMBs were performed in 101 patients: 57 were included in a derivation set and 58 were used as the validation set. The clinical and laboratory data and prebiopsy computed tomography parameters (Hounsfield units [HUs]) were determined. A score for the prediction of biopsy positivity was developed from logistic regression analysis of the derivation set and tested in the validation set. RESULTS: Of the 115 biopsy specimens, 75 (62.5%) were positive; 35 (61.4%) in the test set and 40 (69%) in the validation set. On univariable analysis, hemoglobin (P = .019), lactate dehydrogenase (P = .003), prostate-specific antigen (P = .005), and mean HUs (P = .004) were selected. A score based on the LDH level (>= 225 IU/L) and mean HUs (>= 125) was developed in multivariate analysis and was associated with BMB positivity in the validation set (odds ratio, 5.1; 95% confidence interval, 1.9% 13.4%; P = .001). The area under the curve of the score was 0.79 in the test set and 0.77 in the validation set. CONCLUSION: BMB of the iliac crest is a feasible technique for obtaining tumor tissue for genomic analysis in patients with castration-resistant prostate cancer metastatic to the bone. A signature based on the mean HUs and LDH level can predict a positive yield with acceptable internal validity. Prospective studies of independent cohorts are needed to establish the external validity of the score. PMID- 27246362 TI - Bifunctional Chiral Dehydroalanines for Peptide Coupling and Stereoselective S Michael Addition. AB - A second generation of chiral bicyclic dehydroalanines easily accessible from serine has been developed. These scaffolds behaved as excellent S-Michael acceptors when tri-O-acetyl-2-acetamido-2-deoxy-1-thio-alpha-d-galactopyranose (abbreviated as GalNAc-alpha-SH) was used as a nucleophile. This addition proceeds with total chemo- and stereoselectivity, complete atom economy, quickly, and at room temperature, making it a true click reaction. The Michael adducts were easily transformed into S-(2-acetamido-2-deoxy-alpha-d-galactopyranosyl)-l- and -d-cysteines, which can be regarded as mimics of the Tn antigen derived from l-Ser (alpha-d-GalNAc-l-Ser) and d-Ser (alpha-d-GalNAc-d-Ser), respectively. PMID- 27246363 TI - Psychiatric Patients Tracking Through a Private Social Network for Relatives: Development and Pilot Study. AB - The treatment of psychiatric patients requires different health care from that of patients from other medical specialties. In particular, in the case of Department of Psychiatry from the Zamora Hospital (Spain), the period of time which patients require institutionalized care is a tiny part of their treatment. A large part of health care provided to the patient is aimed at his/her rehabilitation and social integration through day-care centres, supervised flats or activities. Conversely, several reports reveal that approximately 50 % of Internet users use the network as a source of health information, which has led to the emergence of virtual communities where patients, relatives or health professionals share their knowledge concerning an illness, health problem or specific health condition. In this context, we have identified that the relatives have a lack of information regarding the daily activities of patients under psychiatric treatment. The social networks or the virtual communities regarding health problems do not provide a private space where relatives can follow the patient's progress, despite being in different places. The goal of the study was to use technologies to develop a private social network for being used by severe mental patients (mainly schizophrenic patients). SocialNet is a pioneer social network in the health sector because it provides a social interaction context restricted to persons authorized by the patient or his/her legal guardian in such a way that they can track his/her daily activity. Each patient has a private area only accessible to authorized persons and their caregivers, where they can share pictures, videos or texts regarding his/her progress. A preliminary study of usability of the system has been made for increasing the usefulness and usability of SocialNet. SocialNet is the first system for promoting personal interactions among formal caregivers, family, close friends and patient, promoting the recovery of schizophrenic patients. Future studies should study the network's potential usefulness for improving the prognosis and recovery of schizophrenia. PMID- 27246364 TI - An eco-friendly direct spectrofluorimetric method for the determination of irreversible tyrosine kinase inhibitors, neratinib and pelitinib: application to stability studies. AB - A new rapid and simple stability-indicating spectrofluorimetric method has been developed for the determination of two irreversible tyrosine kinase inhibitors (TKIs), neratinib (NER) and pelitinib (PEL). The method is based upon measurement of the native fluorescence intensity of both drugs at lambdaex 270 nm in aqueous borate buffer solutions (pH 10.5). The fluorescence intensity recorded at 545 nm (NER) and 465 nm (PEL) were rectilinear over the concentration range of 0.1-10 MUg/mL for both drugs with a high correlation coefficient (r > 0.999). The proposed method provided low limits of detection and of quantitation of 0.07, 0.11 MUg/mL (NER) and 0.02, 0.05 MUg/mL (PEL), respectively. The method was successfully applied for the determination of NER and PEL in bulk powder. The proposed methods were fully validated as per the International Conference on Harmonisation (ICH) guidelines. The application of the method was extended to stability studies of both NER and PEL under different forced-degradation conditions (acidic-induced, base-induced, oxidative, wet heat, and photolytic degradation). Moreover, the kinetics of the base-induced and oxidative degradation of both drugs was investigated and the pseudo-first-order rate constants and half-lives were estimated at different temperatures. Also, an Arrhenius plot was applied to predict the stability behaviour of the two drugs at room temperature. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27246365 TI - Enhanced immunoregulation of mesenchymal stem cells by IL-10-producing type 1 regulatory T cells in collagen-induced arthritis. AB - Mesenchymal stem cells (MSCs) possess immunomodulatory properties and have potential, however, there have been conflicting reports regarding their effects in rheumatoid arthritis (RA), which causes inflammation and destruction of the joints. Through a comparative analysis of regulatory T (Treg) and IL-10-producing type 1 regulatory T (Tr1) cells, we hypothesized that Tr1 cells enhance the immunoregulatory functions of MSCs, and that a combinatorial approach to cell therapy may exert synergistic immunomodulatory effects in an experimental animal model of rheumatoid arthritis (RA). A combination of MSCs and Tr1 cells prevented the development of destructive arthritis compared to single cell therapy. These therapeutic effects were associated with an increase in type II collagen (CII) specific CD4+CD25+Foxp3+ Treg cells and inhibition of CII-specific CD4+IL-17+ T cells. We observed that Tr1 cells produce high levels of IL-10-dependent interferon (IFN)-beta, which induces toll-like receptor (TLR) 3 expression in MSCs. Moreover, induction of indoleamine 2,3-dioxygenase (IDO) by TLR3 involved an autocrine IFN-beta that was dependent on STAT1 signaling. Furthermore, we observed that production of IFN-beta and IL-10 in Tr1 cells synergistically induces IDO in MSCs through the STAT1 pathway. These findings suggest co administration of MSCs and Tr1 cells to be a novel therapeutic modality for clinical autoimmune diseases. PMID- 27246369 TI - Late Mortality and Causes of Death among Long-Term Survivors after Allogeneic Stem Cell Transplantation. AB - We sought to assess the late mortality risks and causes of death among long-term survivors of allogeneic hematopoietic stem cell transplantation (HCT). The cases of 11,047 relapse-free survivors of a first HCT at least 2 years after HCT were analyzed. Standardized mortality ratios (SMR) were calculated and specific causes of death were compared with those of the Japanese population. Among relapse-free survivors at 2 years, overall survival percentages at 10 and 15 years were 87% and 83%, respectively. The overall risk of mortality was significantly higher compared with that of the general population. The risk of mortality was significantly higher from infection (SMR = 57.0), new hematologic malignancies (SMR = 2.2), other new malignancies (SMR = 3.0), respiratory causes (SMR = 109.3), gastrointestinal causes (SMR = 3.8), liver dysfunction (SMR = 6.1), genitourinary dysfunction (SMR = 17.6), and external or accidental causes (SMR = 2.3). The overall annual mortality rate showed a steep decrease from 2 to 5 years after HCT; however, the decrease rate slowed after 10 years but was still higher than that of the general population at 20 years after HCT. SMRs in the earlier period of 2 to 4 years after HCT and 5 years or longer after HCT were 16.1 and 7.4, respectively. Long-term survivors after allogeneic HCT are at higher risk of mortality from various causes other than the underlying disease that led to HCT. Screening and preventive measures should be given a central role in reducing the morbidity and mortality of HCT recipients on long-term follow-up. PMID- 27246370 TI - Influence of Previous Inflammatory Bowel Disease on the Outcome of Allogeneic Hematopoietic Stem Cell Transplantation: A Matched-Pair Analysis. AB - The idiopathic inflammatory bowel diseases (IBDs) Crohn's disease and ulcerative colitis are associated with increased risk of hematologic malignancies. Allogeneic hematopoietic stem cell transplantation (HSCT) could be a curative strategy in this setting, but has been thought to be associated with increased nonrelapse mortality (NRM). We conducted a national French retrospective analysis of patients with IBD who underwent allogeneic HSCT for hematologic malignancies and were matched with 3 controls according to recipient, donor, and transplant characteristics. Between 2004 and 2015, 18 patients with IBD underwent allogeneic HSCT. With a median follow-up of 33 months for the patients with IBD and 57 months for controls, the cumulative incidence of grade II-IV acute graft-versus host disease (GVHD) was 39% for the patients with IBD and 40% for controls (hazard ratio [HR], 1.10; P = .82). The cumulative incidence of chronic GVHD at 48 months was 52% for the patients with IBD and 43% for controls (HR, 0.92; P = .89). Nonrelapse mortality at 48 months was 19% for the patients with IBD and 11% for controls (HR, 4.93; P = .067). Overall survival at 48 months was 59% for the patients with IBD and 60% for matched controls (HR, 1.35; P = .56). In conclusion, IBD should not be considered a contraindication for transplantation, and its impact on comorbidity indexes should be reduced. PMID- 27246371 TI - Addition of High-Dose Cytarabine to Fludarabine-Based Conditioning for Hematopoietic Stem Cell Transplantation for Treating Fanconi Anemia Patients with Advanced Myeloid Malignancy: A Single-Center Experience and Literature Review. AB - The complication of Fanconi anemia (FA) with acute leukemia is rare and challenging to treat because of high relapse rates, despite the improved outcome of hematopoietic stem cell transplantation with fludarabine-based conditioning for treating FA patients with hematological abnormalities. We added high-dose cytarabine to fludarabine-based conditioning to promote an enhanced antitumor effect and successfully subjected 4 patients with FA, including 3 with acute leukemia, to hematopoietic stem cell transplantation. All patients remain alive without treatment-related mortality or evidence of disease. Adding high-dose cytarabine to fludarabine-based conditioning may be tolerable and effective for treating FA patients with acute leukemia. PMID- 27246372 TI - Impact of Donor and Recipient Cytomegalovirus Serostatus on Outcomes of Antithymocyte Globulin-Conditioned Hematopoietic Cell Transplantation. AB - Although previous studies involving allogeneic hematopoietic cell transplantation (HCT) without in vivo T cell depletion by rabbit antithymocyte globulin (ATG) have reported a substantial survival difference between D-R- and D+R- patients, but little to no survival difference between D-R+ and D+R+ patients (D, donor; R, recipient; +, cytomegalovirus [CMV] seropositive; -, CMV seronegative), whether this applies to HCT using ATG is unknown. We studied 928 patients who underwent myeloablative HCT for hematologic malignancies in Alberta between 1999 and 2014 who received graft-versus-host disease (GVHD) prophylaxis using ATG (Thymoglobulin, 4.5 mg/kg) in addition to methotrexate and cyclosporine. D-R- and D+R- patients had similar survival (no significant difference). D-R+ patients had a substantially lower survival than D+R+ patients (41% versus 59% at 5 years; P = .001). This difference was attributed to higher nonrelapse mortality, apparently due to higher GVHD-associated mortality. Survival rates were also lower for D-R+ HLA-matched sibling transplant recipients compared with D+R+ HLA-matched unrelated donor transplant recipients (44% versus 66% at 5 years; P = .009). In conclusion, when using ATG, choosing a seronegative donor for a seronegative patient is relatively unimportant, whereas choosing a seropositive donor for a seropositive patient is important, even if this requires the use of a seropositive matched unrelated donor graft. PMID- 27246373 TI - A Novel Diagnostic and Prognostic Biomarker Panel for Endothelial Cell Damage Related Complications in Allogeneic Transplantation. AB - Noninfectious transplantation-related complications (TRCs), such as graft-versus host disease or TRC with endothelial cell damage (TRC-EC), remain as the major obstacle for successful allogeneic hematopoietic cell transplantation (allo-HCT). However, the diagnosis and prognosis for the emergence of these complications are difficult to define during the early post allo-HCT period. Here, we tried to generate a novel diagnostic system for TRC-EC by analyzing 188 adult patients who received allo-HCT. Our study found that the peripheral blood levels of angiopoietin 2 (ANG2), C-reactive protein (CRP), D-dimer, and thrombomodulin (TM) at the onset of TRCs were significantly associated with the development of TRC EC. We next developed a composite biomarker panel incorporating the risk values of ANG2, CRP, D-dimer, and TM at the onset of TRCs, which classified these patients into 3 risk groups: low, intermediate, and high risk. As a result, the panel was useful not only for the diagnosis of TRC-EC with high specificity and sensitivity, but also for the prediction of the patients' long-term outcome. The 5-year overall survival (OS) rates of patients in the low-, intermediate-, and high-risk groups since the occurrence from TRCs were 76.2%, 54.9%, and 26.9%, respectively, and the high-risk score was significantly associated with both poor OS (hazard ratio [HR], 5.60; 95% confidence interval [CI], 2.81 to 11.20; P < .01) and frequent nonrelapse mortality (HR, 19.75; 95% CI, 5.59 to 69.77; P < .01). Thus, the composite panel proposed in this study provides a powerful tool for the diagnosis of TRC-EC and for the prediction of survival for patients with TRC-EC after allo-HCT. PMID- 27246374 TI - Tartrate/tripolyphosphate as co-crosslinker for water soluble chitosan used in protein antigens encapsulation. AB - In drug delivery research, several toxic chemical crosslinkers and non-toxic ionic crosslinkers have been exploited for the synthesis of microparticles from acetic acid soluble chitosan. This paper hypothesized the implementation of sodium potassium tartrate (SPT) as an alternative crosslinker for sodium tripolyphosphate (TPP) and SPT/TPP co-crosslinkers for synthesis of the microparticles using water soluble chitosan (WSC) for encapsulation of Bovine serum albumin (BSA) as a model protein, and Tetanus toxoid (TT) as a model vaccine. The crosslinking was confirmed by FT-IR, SEM with EDS. The XRD entailed molecular dispersion of proteins and thermal analysis confirmed the higher stability of STP/TPP co-crosslinked formulations. The resultant microparticles were exhibiting crosslinking degree (52-67%), entrapment efficiency (72-80%), particle size (0.3-1.7MUm), zeta potential (+24 to 46mV) and mucoadhesion (41 68%). The superiority of SPT over TPP was confirmed by higher crosslinking degree and entrapment efficiency. However, co-crosslinking were advantageous in higher regression values for Langmuir adsorption isotherm, slower swelling tendency and extended 30days controlled in-vitro release study. TT release obeyed the Quasi Fickian diffusion mechanism for single and cocrosslinked formulations. Overall, in crosslinking of chitosan as biological macromolecules, STP/TPP may be alternative for single ionic crosslinked formulations for protein antigen delivery. PMID- 27246375 TI - Effect of cooling-heating rate on sol-gel transformation of fish gelatin-gum arabic complex coacervate phase. AB - The objective of this study was to characterize influence of different cooling and heating rates on gelation of fish gelatin (FG)-gum arabic (GA) complex coacervate phase using rheological measurements. For the coacervate phase prepared at 10 degrees C, the gelling temperature, melting temperature, gel strength, and stress relaxation decreased with increasing cooling or heating rate, however, no gelation was observed at the highest cooling rate of 0.05 degrees C/min. Similar trends were obtained for the coacervates phase prepared at 30 degrees C, but the gelation did not occur at a cooling rate of 0.033 or 0.05 degrees C/min. The results indicated that rheological properties of FG-GA coacervate gels were highly dependent to the cooling process, where more thermos stable and stronger gels formed at slower cooling. This was probably because of higher degree of molecular rearrangements, more hydrogen bindings, and formation of greater junction zones into the gel network at slower cooling rates. However, all of the FG-GA coacervate gels obtained at different cooling rates were classified as a weak physical gel. PMID- 27246376 TI - Extraction, purification and anti-proliferative activities of polysaccharides from Lentinus edodes. AB - In this study, the enzyme-assisted extraction of polysaccharides from Lentinus edodes (LEPs) was optimized by response surface methodology, and a preliminary characterization of the extracted LEPs and their anti-proliferative activities were investigated. An orthogonal assay was constructed to determine the optimal amounts of cellulase, papain and pectinase, which were 15, 20 and 15g/kg, respectively. Then effects of extraction conditions were evaluated and optimized using a Box-Behnken design. The results showed that the highest polysaccharides yield of 15.65% was achieved with an extraction temperature of 54 degrees C, pH 5.0, enzymatic treatment time of 93min and a liquid/material ratio of 29:1mL/g, which correlated well with the predicted yield of 15.58%. Subsequently, the crude LEPs were further purified by DEAE-cellulose and Sephadex-100 chromatography to obtain two fractions, which were designated as LEP-1 and LEP-2 and their monosaccharide compositions were characterized by GC. Fourier-transform infrared spectra demonstrated that LEP-1 and LEP-2 were distinct from each other regarding their chemical structures. In addition, the LEPs exhibited inhibition of cell proliferation on HCT-116 and HeLa cells in vitro. In summary, this study provides an efficient enzyme-assisted extraction for LEPs, which can be used as natural antitumor agents in the pharmaceutical and functional food industries. PMID- 27246377 TI - Site-directed mutagenesis of a conserved Asn450 residue of Bacillus licheniformis gamma-glutamyltranspeptidase. AB - Bacillus licheniformis gamma-glutamyltranspeptidase (BlGGT) belongs to N-terminal nucleophile hydrolase superfamily in which all inclusive members are synthetized as single-chain precursors, and then self-processed to form mature enzymes. Here we investigated the role of a conserved Asn450 residue in BlGGT through site directed mutagenesis and molecular characterization of four relevant variants. Substitution of Asn450 by arginine resulted in a significant reduction in the catalytic activity of BlGGT. Conversely, N450A and N450D displayed an enhanced activity. The catalytic efficiency of BlGGT was calculated to be 16.04mM(-1)s( 1), but this value was either decreased to 8.93mM(-1)s(-1) in N450K or increased to more than 123.65mM(-1)s(-1) in N450A and N450D. In addition, the ratio of transpeptidation to hydrolysis was increased from 3.5 to more than 7.6 by the mutations. Structural analyses showed that fluorescence, circular dichroism spectra and thermal denaturation profiles of mutant proteins were essentially consistent with those of BlGGT. However, guanidine hydrochloride (GdnHCl)-induced transition was significantly reduced in comparison with the wild-type enzyme. Molecular modeling suggests that residue Asn450 of BlGGT is important to create suitable environments for both autoprocessing and catalytic reactions. PMID- 27246378 TI - Anti-tyrosinase kinetics and antibacterial process of caffeic acid N-nonyl ester in Chinese Olive (Canarium album) postharvest. AB - Enzymatic browning and bacterial putrefaction are mainly responsible for quality losses of Chinese Olive (Canarium album) postharvest and lead to very short shelf life on average. Screening anti-browning and anti-bacterial agents is important for preservation of Chinese Olive. Caffeic acid N-nonyl ester (C-9) and caffeic acid N- Heptyl ester (C-7) was synthesized as inhibitors of tyrosinase, which is a key enzyme in browning process. The compound of C-9 could inhibit the activity of tyrosinase strongly and its IC50 value was determined to be 37.5MUM, while the compound of C-7 had no inhibitory ability. Kinetic analyses showed that compound of C-9 has been a reversible inhibitory mechanism below 50MUM and been irreversible mechanisms above 50MUM. For the reversible inhibitory mechanism, the values of inhibitory constants (KI and KIS) were determined to be 24.6 and 37.4MUM, respectively. The results of Chinese Olive fruit postharvest showed that the compound of C-9 could effectively anti-browning and anti-bacterial putrefaction. In addition, this compound had strong antibacterial activities against Staphylococcus aureus, Escherichia coli, Bacillus subtilis and Salmonella. Therefore, C-9 could be a potential anti-browning and anti-bacterial reagent. PMID- 27246379 TI - Removal of toxic indigo blue with integrated biomaterials of sodium carboxymethyl cellulose and chitosan. AB - Sodium carboxymethyl cellulose (NaCMC) and chitosan (CS) are successfully combined via amidation, and the obtained product, CMC-CS-A, is used for the adsorption of toxic indigo blue (IB) for the first time. The results of control experiments indicate that the adsorption performance of CMC-CS-A is superior to that of NaCMC, CS, and the composites of NaCMC and CS integrated via electrostatic attractions (CMC-CS-E), which can be attributed to the unique interconnected porous network structure of the as-prepared CMC-CS-A. The mass fraction of CS in the CMC-CS-A is also investigated to achieve the best adsorption of IB, and it reveals that satisfactory removal of IB can be achieved at the CMC-CS-A (50wt%). Important parameters such as contact time, temperature and initial concentration are discussed in detail in this work. Finally, adsorption isotherms and adsorption kinetics are investigated and compared by using classic models, and the results indicate that the adsorption fits well with the Langmuir isotherm model and the pseudo-second-order kinetic model. It opens a new avenue for the effective and convenient treatment of textile wastewater with integrated natural biopolymers. PMID- 27246391 TI - Green Diesel from Kraft Lignin in Three Steps. AB - Precipitated kraft lignin from black liquor was converted into green diesel in three steps. A mild Ni-catalyzed transfer hydrogenation/hydrogenolysis using 2 propanol generated a lignin residue in which the ethers, carbonyls, and olefins were reduced. An organocatalyzed esterification of the lignin residue with an in situ prepared tall oil fatty acid anhydride gave an esterified lignin residue that was soluble in light gas oil. The esterified lignin residue was coprocessed with light gas oil in a continous hydrotreater to produce a green diesel. This approach will enable the development of new techniques to process commercial lignin in existing oil refinery infrastructures to standardized transportation fuels in the future. PMID- 27246392 TI - Within- and Between-Sector Quality Differences in Early Childhood Education and Care. AB - This study leverages nationally representative data (N ~ 6,000) to examine the magnitude of quality differences between (a) formal and informal early childhood education and care providers; (b) Head Start, prekindergarten, and other center based care; and (c) programs serving toddlers and those serving preschoolers. It then documents differences in children's reading and math skills at age 5 between those who had enrolled in formal and informal settings. Cross-sector differences are substantially reduced when accounting for a set of quality measures, though these measures do less to explain more modest differences in outcomes within the formal sector. Results inform current efforts aimed at improving the quality of early childhood settings by highlighting the large quality differences across sectors and their relationship with child development. PMID- 27246394 TI - Prevalence of Depression in Medical Students at the Lebanese University and Exploring its Correlation With Facebook Relevance: A Questionnaire Study. AB - BACKGROUND: The prevalence of major depression is particularly high in medical students, affecting around one-third of this population. Moreover, online social media, in particular Facebook, is becoming an intrinsic part in the life of a growing proportion of individuals worldwide. OBJECTIVE: Our primary objective is to identify the prevalence of depression in medical students at the Lebanese University Faculty of Medicine, a unique state university in Lebanon, its correlation with the utilization of the interactive features of Facebook, and the way students may resort to these features. METHODS: Students of the Lebanese University Faculty of Medicine were assessed for (1) depression and (2) Facebook activity. To screen for major depression, we used the Patient Health Questionnaire-9 (PHQ-9) scale. To test for Facebook activity, we developed the Facebook Resorting Questionnaire (FbRQ), which measures the degree to which students resort to Facebook. RESULTS: A total of 365 out of 480 students (76.0%) participated in the survey. A total of 25 students were excluded, hence 340 students were included in the final analysis. Current depression was reported in 117 students out of 340 (34.4%) and t tests showed female predominance. Moreover, PHQ-9 score multiple regression analysis showed that feeling depressed is explained 63.5% of the time by specific independent variables studied from the PHQ-9 and the FbRQ. Depression varied significantly among the different academic years (P<.001) and it peaked in the third-year students. One-way analysis of variance (ANOVA) showed that depression and resorting to Facebook had a positive and significant relationship (P=.003) and the different FbRQ categories had significant differences in resorting-to-Facebook power. The like, add friend, and check-in features students used when resorting to Facebook were significantly associated with depression. CONCLUSIONS: This study showed that depression was highly prevalent among students of the Faculty of Medicine at the Lebanese University. Moreover, Facebook may be a promising, helpful, psychological tool for optimizing the management of depression. Our study brought to bear further questions that now prompt further observation and scrutiny to know more about the high rates of depression in this student population, more so in the part of the world studied, and to the growing role of social media. PMID- 27246393 TI - Endogenous sulfur dioxide is a novel adipocyte-derived inflammatory inhibitor. AB - The present study was designed to determine whether sulfur dioxide (SO2) could be endogenously produced in adipocyte and served as a novel adipocyte-derived inflammatory inhibitor. SO2 was detected in adipose tissue using high-performance liquid chromatography with fluorescence detection. SO2 synthase aspartate aminotransferase (AAT1 and AAT2) mRNA and protein expressions in adipose tissues were measured. For in vitro study, 3T3-L1 adipocytes were cultured, infected with adenovirus carrying AAT1 gene or lentivirus carrying shRNA to AAT1, and then treated with tumor necrosis factor-alpha (TNF-alpha). We found that endogenous SO2/AAT pathway existed in adipose tissues including perivascular, perirenal, epididymal, subcutaneous and brown adipose tissue. AAT1 overexpression significantly increased SO2 production and inhibited TNF-alpha-induced inflammatory factors, monocyte chemoattractant protein-1 (MCP-1) and interleukin 8 (IL-8) secretion from 3T3-L1 adipocytes. By contrast, AAT1 knockdown decreased SO2 production and exacerbated TNF-alpha-stimulated MCP-1 and IL-8 secretion. Mechanistically, AAT1 overexpression attenuated TNF-alpha-induced IkappaBalpha phosphorylation and degradation, and nuclear factor-kappaB (NF-kappaB) p65 phosphorylation, while AAT1 knockdown aggravated TNF-alpha-activated NF-kappaB pathway, which was blocked by SO2. NF-kappaB inhibitors, PDTC or Bay 11-7082, abolished excessive p65 phosphorylation and adipocyte inflammation induced by AAT1 knockdown. This is the first report to suggest that endogenous SO2 is a novel adipocyte-derived inflammatory inhibitor. PMID- 27246395 TI - Multiple host switching events shape the evolution of symbiotic palaemonid shrimps (Crustacea: Decapoda). AB - The majority of the almost 1,000 species of Palaemonidae, the most speciose family of caridean shrimp, largely live in symbioses with marine invertebrates of different phyla. These associations range from weak epibiosis to obligatory endosymbiosis and from restricted commensalism to semi-parasitism, with the specialisation to particular hosts likely playing a role in the diversification of this shrimp group. Our study elucidates the evolutionary history of symbiotic palaemonids based on a phylogenetic analysis of 87 species belonging to 43 genera from the Indo-West Pacific and the Atlantic using two nuclear and two mitochondrial markers. A complementary three-marker analysis including taxa from GenBank raises this number to 107 species from 48 genera. Seven larger clades were recovered in the molecular phylogeny; the basal-most one includes mostly free-living shrimp, albeit with a few symbiotic species. Ancestral state reconstruction revealed that free-living forms likely colonised cnidarian hosts initially, and switching between different host phyla occurred multiple times in palaemonid evolutionary history. In some cases this was likely facilitated by the availability of analogous microhabitats in unrelated but morphologically similar host groups. Host switching and adaptations to newly colonised host groups must have played an important role in the evolution of this diverse shrimp group. PMID- 27246396 TI - Sequence of Stages in the Microstructure Evolution in Copper under Mild Reciprocating Tribological Loading. AB - Tailoring the surface properties of a material for low friction and little wear has long been a goal of tribological research. Since the microstructure of the material under the contact strongly influences tribological performance, the ability to control this microstructure is thereby of key importance. However, there is a significant lack of knowledge about the elementary mechanisms of microstructure evolution under tribological load. To cover different stages of this microstructure evolution, high-purity copper was investigated after increasing numbers of sliding cycles of a sapphire sphere in reciprocating motion. Scanning electron and focused ion beam (FIB) microscopy were applied to monitor the microstructure changes. A thin tribologically deformed layer which grew from tens of nanometers to several micrometers with increasing number of cycles was observed in cross-sections. By analyzing dislocation structures and local orientation changes in the cross-sectional areas, dislocation activity, the occurrence of a distinct dislocation trace line, and the emergence of new subgrain boundaries could be observed at different depths. These results strongly suggest that dislocation self-organization is a key elementary mechanism for the microstructure evolution under a tribological load. The distinct elementary processes at different stages of sliding identified here will be essential for the future modeling of the microstructure evolution in tribological contacts. PMID- 27246397 TI - Apoptosis inhibitor of macrophage (AIM) reduces cell number in canine histiocytic sarcoma cell lines. AB - Apoptosis inhibitor of macrophage (AIM) is initially reported to protect macrophages from apoptosis. In this study, we determined the effect of AIM on the macrophage-derived tumor, histiocytic sarcoma cell lines (HS) of dogs. Five HS and five other tumor cell lines were used. When recombinant canine AIM was applied to non-serum culture media, cell numbers of all the HS and two of other tumor cell lines decreased dose-dependently. The DNA fragmentation, TUNEL staining and flow cytometry tests revealed that AIM induced both of apoptosis and cell cycle arrest in the HS. Although AIM is known as an apoptosis inhibitor, these results suggest that a high dose of AIM could have an opposite function in HS and some tumor cell lines. PMID- 27246398 TI - Functional validation of tensin2 SH2-PTB domain by CRISPR/Cas9-mediated genome editing. AB - Podocytes are terminally differentiated and highly specialized cells in the glomerulus, and they form a crucial component of the glomerular filtration barrier. The ICGN mouse is a model of glomerular dysfunction that shows gross morphological changes in the podocyte foot process, accompanied by proteinuria. Previously, we demonstrated that proteinuria in ICR-derived glomerulonephritis mouse ICGN mice might be caused by a deletion mutation in the tensin2 (Tns2) gene (designated Tns2nph). To test whether this mutation causes the mutant phenotype, we created knockout (KO) mice carrying a Tns2 protein deletion in the C-terminal Src homology and phosphotyrosine binding (SH2-PTB) domains (designated Tns2DeltaC) via CRISPR/Cas9-mediated genome editing. Tns2nph/Tns2DeltaC compound heterozygotes and Tns2DeltaC/Tns2DeltaC homozygous KO mice displayed podocyte abnormalities and massive proteinuria similar to ICGN mice, indicating that these two mutations are allelic. Further, this result suggests that the SH2-PTB domain of Tns2 is required for podocyte integrity. Tns2 knockdown in a mouse podocyte cell line significantly enhanced actin stress fiber formation and cell migration. Thus, this study provides evidence that alteration of actin remodeling resulting from Tns2 deficiency causes morphological changes in podocytes and subsequent proteinuria. PMID- 27246400 TI - Period1 gates the circadian modulation of memory-relevant signaling in mouse hippocampus by regulating the nuclear shuttling of the CREB kinase pP90RSK. AB - Memory performance varies over a 24-h day/night cycle. While the detailed underlying mechanisms are yet unknown, recent evidence suggests that in the mouse hippocampus, rhythmic phosphorylation of mitogen-activated protein kinase (MAPK) and cyclic adenosine monophosphate response element-binding protein (CREB) are central to the circadian (~ 24 h) regulation of learning and memory. We recently identified the clock protein PERIOD1 (PER1) as a vehicle that translates information encoding time of day to hippocampal plasticity. We here elaborate how PER1 may gate the sensitivity of memory-relevant hippocampal signaling pathways. We found that in wild-type mice (WT), spatial learning triggers CREB phosphorylation only during the daytime, and that this effect depends on the presence of PER1. The time-of-day-dependent induction of CREB phosphorylation can be reproduced pharmacologically in acute hippocampal slices prepared from WT mice, but is absent in preparations made from Per1-knockout (Per1(-/-) ) mice. We showed that the PER1-dependent CREB phosphorylation is regulated downstream of MAPK. Stimulation of WT hippocampal neurons triggered the co-translocation of PER1 and the CREB kinase pP90RSK (pMAPK-activated ribosomal S6 kinase) into the nucleus. In hippocampal neurons from Per1(-/-) mice, however, pP90RSK remained perinuclear. A co-immunoprecipitation assay confirmed a high-affinity interaction between PER1 and pP90RSK. Knocking down endogenous PER1 in hippocampal cells inhibited adenylyl cyclase-dependent CREB activation. Taken together, the PER1 dependent modulation of cytoplasmic-to-nuclear signaling in the murine hippocampus provides a molecular explanation for how the circadian system potentially shapes a temporal framework for daytime-dependent memory performance, and adds a novel facet to the versatility of the clock gene protein PER1. We provide evidence that the circadian clock gene Period1 (Per1) regulates CREB phosphorylation in the mouse hippocampus, sculpturing time-of-day-dependent memory formation. This molecular mechanism constitutes the functional link between circadian rhythms and learning efficiency. In hippocampal neurons of wild type mice, pP90RSK translocates into the nucleus upon stimulation with forskolin (left), whereas in Period1-knockout (Per1(-/-) ) mice (right) the kinase is trapped at the nuclear periphery, unable to efficiently phosphorylate nuclear CREB. Consequently, the presence of PER1 in hippocampal neurons is a prerequisite for the time-of-day-dependent phosphorylation of CREB, as it regulates the shuttling of pP90RSK into the nucleus. Representative immunofluorescence images show a temporal difference in phosphorylated cAMP response element-binding protein (pCREB; green color) levels in all regions of the dorsal hippocampus between a wild-type C3H mouse (WT; left) and a Period1-knockout (Per1(-/-) ; right) mouse. Images were taken 2 h after lights on, thus, when fluctuating levels of pCREB peak in WT mouse hippocampus. Insets show a representative hippocampal neuron, in response to activating cAMP signaling, stained for the neuronal marker NeuN (red), the nuclear marker DAPI (blue) and the activated CREB kinase pP90RSK (green). The image was taken 2 h after light onset (at the peak of the endogenous CREB phosphorylation that fluctuates with time of day). Magnification: 100X, inset 400X. Read the Editorial Highlight for this article on page 650. Cover image for this issue: doi: 10.1111/jnc.13332. PMID- 27246399 TI - Pharmacological inhibition of MyD88 homodimerization counteracts renal ischemia reperfusion-induced progressive renal injury in vivo and in vitro. AB - The activation of innate immunity via myeloid differentiation factor 88 (MyD88) contributes to ischemia reperfusion (I/R) induced acute kidney injury (AKI) and chronic kidney injury. However, since there have not yet been any effective therapy, the exact pharmacological role of MyD88 in the prevention and treatment of renal ischemia reperfusion injury (IRI) is not known. We designed a small molecular compound, TJ-M2010-2, which inhibited MyD88 homodimerization. We used an established unilateral I/R mouse model. All mice undergoing 80 min ischemia through uninephrectomy died within five days without intervention. However, treatment with TJ-M2010-2 alone significantly improved the survival rate to 58.3%. Co-treatment of TJ-M2010-2 with the CD154 antagonist increased survival rates up to 100%. Twenty-eight days post-I/R of 60 min ischemia without nephrectomy, TJ-M2010-2 markedly attenuated renal interstitial and inhibited TGF beta1-induced epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells. Furthermore, TJ-M2010-2 remarkably inhibited TLR/MyD88 signaling in vivo and in vitro. In conclusion, our findings highlight the promising clinical potential of MyD88 inhibitor in preventing and treating acute or chronic renal I/R injuries, and the therapeutic functionality of dual-system inhibition strategy in IRI-induced AKI. Moreover, MyD88 inhibition ameliorates renal I/R injury-induced tubular interstitial fibrosis by suppressing EMT. PMID- 27246401 TI - Genetic Background, Adipocytokines, and Metabolic Disorders in Postmenopausal Overweight and Obese Women. AB - The relationship between the genetic background, adipocytokines, and metabolic state in postmenopausal women has not yet been fully described. The aim of this study was to determine the relationship between PPAR gamma-2 (Pro12Ala, C1431T) and ADRB3 (Trp64Arg) polymorphisms and serum adipocytokines (adiponectin, visfatin, and resistin) and metabolic disorders in 176 postmenopausal women with increased body mass (BMI >= 25 kg m(-2)). The distributions of selected alleles and genotype frequencies were determined with the PCR-RFLP method. The bioimpedance method was used to determine nutritional status, and enzyme-linked immunosorbent assays were applied to determine serum concentrations of adipocytokines. Viscerally obese postmenopausal women had higher body mass, body fat content, serum glucose, insulin, total cholesterol, LDL, triglycerides, uric acid, and HOMA-IR and a higher prevalence of the Ala12 allele. In models based on cytokine concentration, higher body mass and glucose concentration (visfatin model, p = 0.008) and higher insulin and triglyceride levels (resistin model, p = 0.002) were observed in visceral fat deposition and this was potentiated by the presence of the T1431 allele. In resistin models, co-existence of Ala12/X polymorphisms with the T1431 allele was associated with higher resistin and triglyceride concentrations (p = 0.045). In postmenopausal women, metabolic parameters are mainly determined by the distribution of body fat, but Ala12/X polymorphism may increase the metabolic disorders and this effect can be enhanced by the T1431 allele. PMID- 27246402 TI - Molecular Evaluation of Genetic Diversity in Wild-Type Mastic Tree (Pistacia lentiscus L.). AB - In this study, the patterns of genetic variation and phylogenetic relationships of mastic tree (Pistacia lentiscus L.) genotypes including 12 males and 12 females were evaluated using SSR, RAPD, ISSR, and ITS markers yielding 40, 703, 929 alleles, and 260-292 base pairs for ITS1 region, respectively. The average number of alleles produced from SSR, RAPD, and ISSR primers were 5.7, 14, and 18, respectively. The grouping pattern obtained from Bayesian clustering method based on each marker dataset was produced. Principal component analyses (PCA) of molecular data was investigated and neighbor joining dendrograms were subsequently created. Overall, the results indicated that ISSR and RAPD markers were the most powerful to differentiate the genotypes in comparison with other types of molecular markers used in this study. The ISSR results indicated that male and female genotypes were distinctly separated from each other. In this frame, M9 (Alacati) and M10 (Mesta Sakiz Adasi-Chios) were the closest genotypes and while F11 (Seferihisar) and F12 (Bornova/Gokdere) genotypes fall into same cluster and showing closer genetic relation. The RAPD pattern indicated that M8 (Urla) and M10 (Mesta Sakiz Adasi-Chios), and F10 (Mesta Sakiz Adasi-Chios) and F11 (Seferihisar) genotypes were the closest male and female genotypes, respectively. PMID- 27246404 TI - Extremely elevated alpha-fetoprotein due to acute exacerbation of chronic hepatitis B without malignancy: a case report. AB - BACKGROUND: Alpha-fetoprotein is produced by a variety of tumors such as hepatocellular carcinoma, hepatoblastoma, and germ cell tumors of the ovary and testes. However, we present a case of significantly elevated serum alpha fetoprotein without evidence of malignant disease in a patient who is a carrier of chronic hepatitis B. CASE PRESENTATION: A 60-year-old Korean man presented with markedly increased alpha-fetoprotein (2350 ng/mL; normal <5 ng/mL). Various diagnostic evaluations, including computed tomography of the abdomen and thorax and ultrasonography of the abdomen and testes, showed liver cirrhosis and mild splenomegaly; however, no mass was detected in the liver, testes, or other organs scanned. The laboratory findings showed elevated liver function, positivity for hepatitis B e antigen, and a marked increase in hepatitis B virus deoxyribonucleic acid copy number (>7 * 105 IU/mL). Our patient was diagnosed with acute exacerbation of chronic hepatitis B, and we presumed that this condition might be related to extremely elevated alpha-fetoprotein. When our patient was treated with entecavir, the serum alpha-fetoprotein level immediately decreased, in parallel with the hepatitis B virus deoxyribonucleic acid copy number. CONCLUSIONS: We report a rare case of extremely elevated alpha fetoprotein due to acute exacerbation of chronic hepatitis B without any malignancy, and a decrease in this tumor marker simultaneous with a decrease in hepatitis B virus deoxyribonucleic acid copy number on entecavir treatment. This case report is important due to the rarity of the case; furthermore, it provides details of a diagnostic process for a variety of benign diseases and malignant tumors that should be considered in patients with elevated alpha-fetoprotein. Thus, we present a case report, along with a review, that will be helpful for diagnosis and treatment of patients with elevated alpha-fetoprotein. PMID- 27246403 TI - A systematic review of ethical issues in vaccine studies involving pregnant women. AB - BACKGROUND: Immunization during pregnancy can provide protection for mother and child. However, there have been only a limited number of studies documenting the efficacy and safety of this strategy. AIMS: To determine the extent and nature of subject matter related to ethics in maternal immunization by systematically documenting the spectrum of ethical issues in vaccine studies involving pregnant women. METHOD: We conducted a systematic literature review of published works pertaining to vaccine and therapeutic studies involving pregnant women through searches of PubMed, EMBASE, Web of Science, the Cochrane Database, and ClinicalTrials.gov. We selected literature meeting the inclusion criteria published between 1988 and June 2014. We systematically abstracted subject matter pertaining to ethical issues in immunization studies during pregnancy. Immunization-specific ethical issues were matched and grouped into major categories and subcategories. RESULTS: Seventy-seven published articles met the inclusion criteria. Published articles reported findings on data that had been collected in 26 countries, the majority of which were classified as high-income or upper-middle-income nations according to World Bank criteria. Review of these publications produced 60 immunization-specific ethical issues, grouped into six major categories. Notably, many studies demonstrated limited acknowledgment of key ethical issues including the rights and welfare of participants. Additionally, there was no discussion pertaining to the ethics of program implementation, including integration of maternal immunization programs into existing routine immunization programs. CONCLUSION: This review of ethical issues in immunization studies of pregnant women can be used to help inform future vaccine trials in this important population. Consistent documentation of these ethical issues by investigators will facilitate a broader and more nuanced discussion of ethics in immunization of pregnant women - offering new and valuable insights for programs developed to prevent disease in newborn children in low- and middle-income countries. PMID- 27246405 TI - Goal Management Training and Mindfulness Meditation improve executive functions and transfer to ecological tasks of daily life in polysubstance users enrolled in therapeutic community treatment. AB - BACKGROUND: We have previously shown that Goal Management Training+Mindfulness Meditation (GMT+MM) improves executive functions in polysubstance users enrolled in outpatient treatment. The aim of this study was to establish if GMT+MM has similar positive effects on executive functions in polysubstance users in residential treatment, and if executive functions' gains transfer to more ecologically valid goal-oriented tasks. METHODS: Thirty-two polysbustance users were randomly allocated to eight weeks of GMT+MM (n=16) or control, i.e., no intervention (n=16); both groups received treatment as usual. Outcome measures included performance in laboratory tasks of basic and complex executive functions (i.e., basic: working memory and inhibition; complex: planning and self regulation) and in an ecological task of goal-directed behavior (the Multiple Errands Test - contextualized version, MET-CV) measured post-interventions. RESULTS: Results showed that GMT+MM was superior to control in improving basic measures of working memory (Letter-number sequencing; F=4.516, p=0.049) and reflection impulsivity (Information Sampling Test; F=6.217, p=0.018), along with initial thinking times during planning (Zoo Map Test; F=8.143, p=0.008). In addition, GMT+MM was superior to control in improving performance in the MET-CV (task failures; F=8.485, p=0.007). CONCLUSION: Our findings demonstrate that GMT+MM increases reflective processes and the achievement of goals in daily activities, furthermore ecological test can detects changes easily than laboratory tasks. PMID- 27246408 TI - 'Get a grip', MPs tell the organisations managing NHS workforce issues. PMID- 27246406 TI - A more inclusive nursing strategy. PMID- 27246409 TI - Ombudsman asks why problems persist with hospital discharges. PMID- 27246411 TI - NHS England launches new framework to guide staff. PMID- 27246413 TI - New course boosts care and district nurses' morale. PMID- 27246414 TI - Compassion in Practice model lacked junior nurse buy-in. PMID- 27246415 TI - Mental health laws must change. PMID- 27246416 TI - When help is at hand. PMID- 27246422 TI - Vantage point--New response in crisis. PMID- 27246431 TI - How to make the most of the reflective discussion. AB - The Nursing and Midwifery Council's new process for re-registering nurses and midwives--revalidation--went live on April 1. Nurse managers will be expected to play a pivotal role in ensuring their staff are able to revalidate by acting as their reflective discussion partners and/or their confirmers. This article sets out the steps involved in reflective discussions and confirmation, along with the responsibilities of nurse managers involved. There is also a case study that offers tips from a nurse manager who has acted as confirmer on several occasions. PMID- 27246432 TI - Supporting practice learning time for non-medical prescribing students: managers' views. AB - Managers in healthcare services have ever-increasing demands to consider in relation to front line care, including the continuing professional education needs of qualified practitioners who are advancing their roles. One advancement is non-medical prescribing, and this article reports part of the findings from a survey undertaken in Scotland which explored managers' views of the clinical support of staff enrolled on a non-medical prescribing programme. The article discusses how managers have an important role to play in supporting these learners in practice, and suggests all stakeholders should be aware of the pressure this adds to managers, and seek creative solutions to support the process of learning. PMID- 27246434 TI - Keep it in the family. PMID- 27246433 TI - Performing dual roles in education and practice. AB - AIM: To examine the benefits and challenges of dual posts, defined here as lecturers who work in clinical practice and have separate contracts with different organisations. METHODS: A case study approach was used to collate different perspectives. Equal numbers of participants were selected from lecturers (n=3) and dual post holders (n= 3), and one manager was included (n=1). Semi-structured interviews were recorded and transcribed verbatim to collect data. Key words were identified then highlighted throughout the transcripts and text retrievers searched the large amounts of data gathered. Key words were grouped into multiple sub-themes, which were then further grouped into four themes. FINDINGS: Four main themes emerged from the data: duality, theory/practice, credibility and student experience. Some benefits and challenges of dual posts were identified. Benefits included helping students contextualise theory into practice and maintaining currency in practice. Challenges were maintaining a multifaceted role and managing expectations in both roles. CONCLUSION: Dual post holders are regarded as an important part of the team by all stakeholders involved in this study. However, more clarification about the expectations of each role is required and post holders should have more support from their organisations. PMID- 27246435 TI - Molecular identification and phylogenetic analysis of Siluriformes from the Paraguay River basin, Brazil. AB - The objective of this study was to identify, through the DNA barcode, fishable Siluriformes which were collected from the Paraguay River basin in Pantanal. It was analyzed for genetic distance calculation using the Kimura-two-model parameters and the dendrogram was builtusing the Neighbour-Joining algorithm. The average genetic distance within species, genus and families were 0.2%, 1.6% and 4.2%, respectively. These values were lower than those reported in studies from other continents, probably due to the recent radiation process undergone by Neotropical fish. The dendrogram revealed two possible cases of hybridization, one individual Pseudoplatystoma corruscans, it was not possible to identify whether it was a natural event or commercial production exhaust and other of Pimelodus cf. argenteus leading to the assumption that the aspects of reproductive isolation cannot be clearly defined. Besides, the populations of the species Hemisorubim platyrhynchos and e Platydora armatulus may be undergoing a substructuring process, with genetic differences 3% and 4%, respectively. PMID- 27246436 TI - A Note on the Linearly and Quadratically Weighted Kappa Coefficients. AB - The linearly and quadratically weighted kappa coefficients are popular statistics in measuring inter-rater agreement on an ordinal scale. It has been recently demonstrated that the linearly weighted kappa is a weighted average of the kappa coefficients of the embedded 2 by 2 agreement matrices, while the quadratically weighted kappa is insensitive to the agreement matrices that are row or column reflection symmetric. A rank-one matrix decomposition approach to the weighting schemes is presented in this note such that these phenomena can be demonstrated in a concise manner. PMID- 27246437 TI - Office-Based Ultrasound-Guided FNA with Molecular Testing for Thyroid Nodules. AB - OBJECTIVE: Ultrasound-guided fine-needle aspiration (FNA) biopsy is the primary method of evaluating thyroid nodules. Up to one-third of FNA results are reported to be of "indeterminate" cytology, which carries a 25% malignancy risk. Most of these patients are referred for diagnostic surgery, which results in many unnecessary interventions. We implemented an FNA protocol combining expert thyroid cytopathology and molecular testing of indeterminate lesion in our community practice. This study is a report of the outcomes from this protocol as compared with historical data in the same setting over a similar period. STUDY DESIGN: Case series with planned data collections and retrospective chart reviews. SETTING: A large community-based practice with multiple satellite offices. SUBJECTS AND METHODS: A total of 264 thyroid nodules (196 patients) were evaluated under the new protocol from January to December 2014, and data were collected in a prospective manner. Historical data for a similar period (2012), obtained by chart review, included 164 nodules (134 patients) biopsied in a hospital setting by a number of radiologists, with cytologic interpretations completed by community-based pathologists. Statistical analyses included chi(2) and Fischer's exact tests. RESULTS: Based on the new protocol, the rate of indeterminate lesion diagnosis was reduced from 24% to 10% (P = .006) and the rate of diagnostic surgery from 24% to 6% (P < .001). Of the patients who underwent diagnostic surgery, 58% had evidence of malignancy, as compared with 12% in our previous experience (P = .04). CONCLUSION: Expert cytopathologic analysis combined with molecular testing of indeterminate FNA samples significantly reduced unnecessary operations. PMID- 27246440 TI - Mechanisms of influence: Alcohol industry submissions to the inquiry into fetal alcohol spectrum disorders. AB - INTRODUCTION AND AIMS: Industry groups with vested interests in policy regularly work to protect their profits via the endorsement of ineffective voluntary regulation and interventions, extensive lobbying activity and minimising the health impact of consumption behaviours. This study aims to examine all alcohol industry submissions to the Australian House of Representatives Standing Committee on Social Policy and Legal Affairs into Fetal Alcohol Spectrum Disorders (FASD), to assist in understanding how those with vested interests contribute to policy development. The analysis aims to document the strategies and arguments used by alcohol industry bodies in their submissions and to compare these with known strategies of vested-interest groups. DESIGN AND METHODS: All 92 submissions to the Inquiry were screened to include only those submitted by alcohol industry bodies (five submissions). Content domains were derived based on the major themes emerging from the industry submissions and on common vested interest behaviours identified in previous literature. RESULTS: The following content categories were identified: Concerns about FASD; Current industry activities and FASD prevention; Value of mandatory warning labels; and Credibility of independent public health researchers and organisations. DISCUSSION AND CONCLUSIONS: Alcohol industry submissions sought to undermine community concern, debate the evidence, promote ineffective measure which are no threat to the profit margins and attack independent health professionals and researchers. In doing so, their behaviour is entirely consistent with their responses to other issues, such as violence and chronic health, and copies the tactics employed by the tobacco industry. [Avery MR, Droste N, Giorgi C, Ferguson A, Martino F, Coomber K, Miller P. Mechanisms of influence: Alcohol industry submissions to the inquiry into fetal alcohol spectrum disorders. Drug Alcohol Rev 2016;35:665-672]. PMID- 27246439 TI - Development of a Low-Cost Stem-Loop Real-Time Quantification PCR Technique for EBV miRNA Expression Analysis. AB - MicroRNAs (miRNAs) are short, single stranded, non-coding RNA molecules. They are produced by many different species and are key regulators of several physiological processes. miRNAs are also encoded by the genomes of multiple virus families, such as herpesvirus family. In particular, miRNAs from Epstein Barr virus were found at high concentrations in different associated pathologies, such as Burkitt's lymphoma, Hodgkin disease, and nasopharyngeal carcinoma. Thanks to their stability, these molecules could possibly serve as biomarkers for EBV associated diseases. In this study, a stem-loop real-time PCR for miR-BART2-5p, miR-BART15, and miR-BART22 EBV miRNAs detection and quantification has been developed. Evaluation of these miRNAs in 31 serum samples (12 from patients affected by primary immunodeficiency, 9 from X-linked agammaglobulinemia and 10 from healthy subjects) has been carried out. The amplification performance showed a wide dynamic range (10(8)-10(2) copies/reaction) and sensibility equal to 10(2) copies/reaction for all the target tested. Serum samples analysis, on the other hand, showed a statistical significant higher level of miR-BART22 in primary immunodeficiency patients (P = 0.0001) compared to other groups and targets. The results confirmed the potential use of this assay as a tool for monitoring EBV associated disease and for miRNAs expression profile analysis. PMID- 27246441 TI - Persistent GABAA/C responses to gabazine, taurine and beta-alanine in rat hypoglossal motoneurons. AB - In hypoglossal motoneurons, a sustained anionic current, sensitive to a blocker of rho-containing GABA receptors, (1,2,5,6-tetrahydropyridin-4 yl)methylphosphinic acid (TPMPA) and insensitive to bicuculline, was previously shown to be activated by gabazine. In order to better characterize the receptors involved, the sensitivity of this atypical response to pentobarbital (30MUM), allopregnanolone (0.3MUM) and midazolam (0.5MUM) was first investigated. Pentobarbital potentiated the response, whereas the steroid and the benzodiazepine were ineffective. The results indicate the involvement of hybrid heteromeric receptors, including at least a GABA receptor rho subunit and a gamma subunit, accounting for the pentobarbital-sensitivity. The effects of the endogenous beta amino acids, taurine and beta-alanine, which are released under various pathological conditions and show neuroprotective properties, were then studied. In the presence of the glycine receptor blocker strychnine (1MUM), both taurine (0.3-1mM) and beta-alanine (0.3mM) activated sustained anionic currents, which were partly blocked by TPMPA (100MUM). Thus, both beta amino acids activated rho-containing GABA receptors in hypoglossal motoneurons. Bicuculline (20MUM) reduced responses to taurine and beta-alanine, but small sustained responses persisted in the presence of both strychnine and bicuculline. Responses to beta-alanine were slightly increased by allopregnanolone, indicating a contribution of the bicuculline- and neurosteroid-sensitive GABAA receptors underlying tonic inhibition in these motoneurons. Since sustained activation of anionic channels inhibits most mature principal neurons, the rho-containing GABA receptors permanently activated by taurine and beta-alanine might contribute to some of their neuroprotective properties under damaging overexcitatory situations. PMID- 27246442 TI - Differential amygdala activation during simulated personal space intrusion by men and women. AB - Responses to personal space (PS) violations are variable and depend (besides many other factors) on the sex of the person who enters this space. The neuronal basis of this effect is still largely unknown. A previous neuroimaging investigation had shown that male participants responded with increased amygdala activation to PS violation, but only when the intruder was male. Gender-specific responses by females have not been studied yet. In the present study we recorded affective as well as hemodynamic responses of 30 women (mean age: M=27.3years; SD=8.1). The participants were exposed to images of neutral facial expressions from men and women. All stimuli were once shown as photos (static), and once were zoomed in (picture enlargement by the factor 2.75) in order to simulate PS intrusion. In both conditions ('static' and 'approaching' faces) the eyes and mouth region of the depicted persons were always completely visible. Approaching faces generally provoked activation of a parietal network (e.g., intraparietal sulcus, superior/inferior parietal cortex). When the approaching person was male additional amygdala activation was detected. Because the amygdala is a central structure for the initiation of defense responses, the heightened activation might reflect that male intrusion was decoded as potential threat. Hence, we observed a similar gender bias to simulated space intrusion in women as previously in men. PMID- 27246443 TI - An alternative allergen risk management approach. AB - Protein components in food can trigger immune-mediated response in susceptible individuals. International law requires risk assessment to be undertaken by competent individuals to minimize food safety risk to consumers. Historically, allergen control legislation has been food-focused and on the requirement for on pack labeling, and the need for formal food recalls in the event of misleading or inappropriate labeling. In order to develop a mechanism for decision makers when assessing allergenic risk from plant-derived materials, the aim of this research was to consider a more holistic risk assessment method whereby rather than just using the food-based approach, an additive element in terms of considering the families of proteins is included. This approach reflects the need for food professionals to fully understand the role of proteins in triggering an allergic response to plant material and the health risk to individuals who show cross reactivity to such proteins. PMID- 27246445 TI - Third Cranial Nerve Palsy in the Setting of Chikungunya Virus Infection. AB - We report the case of a 62-year-old patient who developed an acute painless isolated left third cranial nerve palsy sparing the pupil in the setting of an acute chikungunya infection. The patient had no significant medical history. Specifically, he had no vascular risk factors. Ocular involvement in chikungunya fever is uncommon. The potential virus- and infection-related mechanisms of this third cranial nerve palsy are discussed. PMID- 27246444 TI - Enteroviruses and Rhinoviruses: Molecular Epidemiology of the Most Influenza-Like Illness Associated Viruses in Senegal. AB - Different viruses have been identified as etiologic agents of respiratory tract infections, including severe cases. Among these, human rhinoviruses (HRVs) and human enteroviruses (HEVs) are recognized as leading causes. The present study describes the molecular epidemiology of HRVs and HEVs in Senegal over a 3-year surveillance period. From January 2012 to December 2014, nasopharyngeal and oropharyngeal swabs specimen were collected from patients with influenza-like illness (ILI). A real-time reverse transcription polymerase chain reaction was performed for HRV and HEV detection using the RV16 kit. Two regions were targeted for the molecular characterization of RVs: 5' untranslated region (5'UTR) and viral protein 4/viral protein 2 (VP4/VP2) transition region. For enteroviruses (EVs) phylogeny, VP1 gene was targeted. A total of 4,194 samples were collected. Children up to 5 years accounted for 52.9%. Among them, 1,415 (33.7%) were positive for HRV, 857 (20.4%) for HEV, and 437 cases of dual infections HRV/HEV. HRVs and HEVs were identified significantly in children aged 5 years or less. Only cough and vomiting signs were observed with significant association with viral infection. Both viruses co-circulated all year long with a marked increase of activity during rainy and cold period. All HRV types circulate in Senegal. HRV A and C groups were the most common. HEV serotyping identified coxsackie B viruses (CBV) only. VP1 region revealed different CBV (CBV1, CBV2, CBV3, CBV4, and CBV5), echoviruses, coxsackieviruses A4-like strains and a poliovirus 2. The results suggest strong year-round respiratory picornavirus activity in children up to 5 years of age. Molecular studies identified a wide variety of RVs along with diverse EVs in samples from patients with ILI. PMID- 27246446 TI - Hepatitis E Virus Genotype 3 in Sewage and Genotype 1 in Acute Hepatitis Cases, Israel. AB - Hepatitis E virus (HEV) is an emerging infectious agent in developed countries. HEV genotypes 1 (G1) and 3 (G3) have been identified in environmental and clinical samples in Europe. In Israel, the overall prevalence of anti-HEV IgG antibodies was found to be 10.6%; however, reports of HEV infection are scarce. In this study, the presence of HEV in Israel was investigated using 169 sewage samples from 32 treatment facilities and 49 samples from acute hepatitis patients, all collected between 2013 and 2015. Fourteen sewage samples, from Haifa (11/18 samples), Tel Aviv (2/29 samples), and Beer Sheva (1/17 samples), regions with good sanitary conditions and middle-high socioeconomic populations, were HEV positive. Among the patient samples, 6.1% (3/49) were HEV positive, all returning travelers from India. Genotype analysis revealed G1 HEV in patients and G3 HEV sequences in sewage. Evidence that HEV could be establishing itself in our region may justify more active surveillance to monitor its spread. PMID- 27246447 TI - Promising Efficacy of Benznidazole Nanoparticles in Acute Trypanosoma cruzi Murine Model: In-Vitro and In-Vivo Studies. AB - The aim of this study was to evaluate the effectiveness of benznidazole nanoparticles (BNZ-nps) on trypomastigote forms and on intracellular infection in mammalian cells and primary cardiac myocyte cells. Its effectiveness was also evaluated on acute Trypanosoma cruzi Nicaragua mice infection. Trypomastigotes from culture were treated with different concentrations of BNZ-nps to determine the drug concentration that lyses 50% of trypomastigotes (LC50). Infected mammalian cells were incubated with different concentrations of BNZ-nps to determine the percentage of amastigote inhibition. C3H/HeN mice with lethal acute infection were treated with 10, 25, and 50 mg/kg/day of BNZ-nps for 30 and 15 days to control the survival rate of animals. BNZ-nps having a mean particle size of 63.3 nm, a size distribution of 3.35, and a zeta potential of -18.30 were successfully prepared using poloxamer 188 as a stabilizer. BNZ-nps 25 and 50 MUg/mL showed no significant differences in the percentage of inhibition of infected mammalian cells. Infected mice treated with BNZ-nps (50, 25, and 10 mg/kg/day) for 30 days and with BNZ-nps (50 and 25 mg/kg/day) for 15 days presented a 100% survival, whereas the animals treated with 10 mg/kg/day for 15 days of BNZ-nps showed a 70% survival rate. The results obtained demonstrate, for the first time, that benznidazole nanoparticles are a useful and attractive approach to treat Chagas disease in infected mice. PMID- 27246449 TI - Integrating Neglected Tropical Disease and Immunization Programs: The Experiences of the Tanzanian Ministry of Health. AB - Global health practitioners are increasingly advocating for the integration of community-based health-care platforms as a strategy for increasing the coverage of programs, encouraging program efficiency, and promoting universal health-care goals. To leverage the strengths of compatible programs and avoid geographic and temporal duplications in efforts, the Tanzanian Ministry of Health and Social Welfare coordinated immunization and neglected tropical disease programs for the first time in 2014. Specifically, a measles and rubella supplementary vaccine campaign, mass drug administration (MDA) of ivermectin and albendazole, and Vitamin A were provisionally integrated into a shared community-based delivery platform. Over 21 million people were targeted by the integrated campaign, with the immunization program and MDA program reaching 97% and 93% of targeted individuals, respectively. The purpose of this short report is to share the Tanzanian experience of launching and managing this integrated campaign with key stakeholders. PMID- 27246448 TI - Species-Specific Associations Between Soil-Transmitted Helminths and Micronutrients in Vietnamese Schoolchildren. AB - Soil-transmitted helminth (STH) infections and micronutrient deficiencies are closely related and often coexist among low-income populations. We studied the association between infections with specific STH species and micronutrient status in rural Vietnamese schoolchildren. Children (N = 510) aged 6-9 years were recruited from two primary schools. STH infections were determined in stool samples. Hemoglobin, ferritin, retinol, and zinc were measured in blood samples, as well as C-reactive protein to control for inflammation. Iodine excretion was measured in urine. Associations of single and multiple infections with Ascaris lumbricoides, Trichuris trichiura, and hookworm with micronutrient status (hemoglobin, plasma ferritin, retinol, zinc, and urinary iodine) were estimated by multiple regression analysis. Ascaris infections showed a specific and intensity-dependent negative association with vitamin A. Trichuris and hookworm infections were associated with lower hemoglobin concentration, but not with plasma ferritin. Trichuris-infected children had zinc deficiency less often than uninfected children. In conclusion, our study shows species-specific associations between STH infections and micronutrient status in children. The different life cycles of STH species might have specific effects on the absorption or loss of specific micronutrients. Tailor-made combinations of deworming and nutritional interventions may be needed to improve child health and nutrition. PMID- 27246450 TI - Apixaban versus enoxaparin in the prevention of venous thromboembolism following total knee arthroplasty: a single-centre, single-surgeon, retrospective analysis. AB - BACKGROUND: There is a high risk of developing venous thromboembolism (VTE) following total knee arthroplasty (TKA). Conventional thromboprophylactic agents have limitations, such as route of administration, the need for monitoring, narrow therapeutic windows and interactions. Apixaban is a new oral anticoagulant with the potential to overcome these limitations. AIMS: To report the efficacy and safety of apixaban and low-molecular-weight heparin, enoxaparin, in VTE prophylaxis following TKA. METHODS: This single-centre, single-surgeon, retrospective analysis included 506 consecutive patients who underwent TKA between 2009 and 2015 and received enoxaparin or apixaban as thromboprophylaxis. Baseline characteristics of patients, in-hospital rates of VTE, total DVT, proximal or distal DVT, pulmonary embolism, bleeding outcomes and mortality were compared between the two groups. RESULTS: In-hospital VTE occurred in 22 (8.9%) patients in the enoxaparin group and 11 (4.5%) patients in the apixaban group (P = 0.049). Nine (3.6%) patients in the enoxaparin group and one (0.4%) in the apixaban group experienced a postoperative drop in haemoglobin >=20 g/L that either necessitated transfusion of >=2 units blood, caused haemodynamic instability or both (P = 0.020). Thirty-five patients experienced other bleeding events, with 25 (9.9%) in the enoxaparin group and 10 (4.0%) in the apixaban group (P = 0.009). There were no statistically significant differences in rates of total DVT, proximal or distal DVT, pulmonary embolism or mortality between the groups. CONCLUSIONS: Compared with enoxaparin, thromboprophylaxis with apixaban resulted in a lower VTE incidence and fewer haemorrhagic complications. PMID- 27246451 TI - Discovery, Synthesis, and Functional Characterization of a Novel Neuroprotective Natural Product from the Fruit of Alpinia oxyphylla for use in Parkinson's Disease Through LC/MS-Based Multivariate Data Analysis-Guided Fractionation. AB - Herein we report the discovery of a novel lead compound, oxyphylla A [(R)-4-(2 hydroxy-5-methylphenyl)-5-methylhexanoic acid] (from the fruit of Alpinia oxyphylla), which functions as a neuroprotective agent against Parkinson's disease. To identify a shortlist of candidates from the extract of A. oxyphylla, we employed an integrated strategy combining liquid chromatography/mass spectrometry, bioactivity-guided fractionation, and chemometric analysis. The neuroprotective effects of the shortlisted candidates were validated prior to scaling up the finalized list of potential neuroprotective constituents for more detailed chemical and biological characterization. Oxyphylla A has promising neuroprotective effects: (i) it ameliorates in vitro chemical-induced primary neuronal cell damage and (ii) alleviates chemical-induced dopaminergic neuron loss and behavioral impairment in both zebrafish and mice in vivo. Quantitative proteomics analyses of oxyphylla A-treated primary cerebellar granule neurons that had been intoxicated with 1-methyl-4-phenylpyridinium revealed that oxyphylla A activates nuclear factor-erythroid 2-related factor 2 (NRF2)-a master redox switch-and triggers a cascade of antioxidative responses. These observations were verified independently through western blot analyses. Our integrated metabolomics, chemometrics, and pharmacological strategy led to the efficient discovery of novel bioactive ingredients from A. oxyphylla while avoiding the nontargeting, labor-intensive steps usually required for identification of bioactive compounds. Our successful development of a synthetic route toward oxyphylla A should lead to its availability on a large scale for further functional development and pathological studies. PMID- 27246453 TI - [Not Available]. PMID- 27246452 TI - [Not Available]. PMID- 27246454 TI - Concern About Hunger May Increase Receptivity to GMOs. AB - Due to a phenomenon known as the 'backfire effect', intuition-based opinions can be inadvertently strengthened by evidence-based counterarguments. Students' views on genetically modified organisms (GMOs) may be subject to this effect. We explored the impact of an empathetically accessible topic, world hunger, on receptivity to GMO technology as an alternative to direct evidence-based approaches. PMID- 27246455 TI - 26S Proteasome: Hunter and Prey in Auxin Signaling. AB - Auxin binds to TRANSPORT INHIBITOR RESPONSE 1 and AUXIN SIGNALLING F-BOX proteins (TIR1/AFBs) and promotes the degradation of Aux/IAA transcriptional repressors. The proteasome regulator PROTEASOME REGULATOR1 (PTRE1) has now been shown to be required for auxin-mediated repression of 26S proteasome activity, thus providing new insights into the fine-tuning of the homoeostasis of Aux/IAA proteins and auxin signaling. PMID- 27246456 TI - Enhanced long-term organics and nitrogen removal and associated microbial community in intermittently aerated subsurface flow constructed wetlands. AB - The long-term enhanced removal efficiency of organics and nitrogen in subsurface flow constructed wetlands (SSF CWs) with and without intermittent aeration for decentralized domestic wastewater was evaluated, and the function of intermittent aeration on microbial community was also investigated in this study. The high and long-term 95.6% COD, 96.1% NH4(+)-N and 85.8% TN removal efficiencies were achieved in experimental intermittently aerated SSF CW compared with non-aerated SSF CW. Aerated SSF CWs also exhibited the excellent removal performance when comparatively comparing with other strategies and techniques applied in CWs. In addition, fluorescence in situ hybridization (FISH) analysis revealed that associated microbial abundance significantly increased owing to intermittent aeration. These results indicated intermittent aeration CWs might be an effective and sustainable strategy for wastewater treatment in rural areas, but require further full-scale investigation in future. PMID- 27246457 TI - Dynamics of chromosomal aberrations, induction of apoptosis, BRCA2 degradation and sensitization to radiation by hyperthermia. AB - Hyperthermia can transiently degrade BRCA2 and thereby inhibit the homologous recombination pathway. Induced DNA-double strand breaks (DSB) then have to be repaired via the error prone non-homologous end-joining pathway. In the present study, to investigate the role of hyperthermia in genotoxicity and radiosensitization, the induction of chromosomal aberrations was examined by premature chromosome condensation and fluorescence in situ hybridisation (PCC FISH), and cell survival was determined by clonogenic assay shortly (0-1 h) and 24 h following exposure to hyperthermia in combination with ionizing radiation. Prior to exposure to 4 Gy gamma-irradiation, confluent cultures of SW-1573 (human lung carcinoma) and RKO (human colorectal carcinoma) cells were exposed to mild hyperthermia (1 h, 41C). At 1 h, the frequency of chromosomal translocations was higher following combined exposure than following exposure to irradiation alone. At 24 h, the number of translocations following combined exposure was lower than following exposure to irradiation only, and was also lower than at 1 h following combined exposure. These dynamics in translocation frequency can be explained by the hyperthermia-induced transient reduction of BRCA2 observed in both cell lines. In both cell lines exposed to radiation only, potentially lethal damage repair (PLDR) correlated with a decreased number of chromosomal fragments at 24 h compared to 1 h. With combined exposure, PLDR did not correlate with a decrease in fragments, as in the RKO cells at 24 h following combined exposure, the frequency of fragments remained at the level found after 1 h of exposure and was also significantly higher than that found following exposure to radiation alone. This was not observed in the SW-1573 cells. Cell survival experiments demonstrated that exposure to hyperthermia radiosensitized the RKO cells, but not the SW-1573 cells. This radiosensitization was at least partly due to the induction of apoptosis, which was only observed in the RKO cells and which may have been induced by BRCA2 degradation or different types of chromosomal aberrations. An important observation of this study is that the genotoxic effect of hyperthermia shortly after combined epxosure (to hyperthermia and radiation) is not observed at 24 h after treatment. PMID- 27246458 TI - Lower spatial QRS-T angle rules out sustained ventricular arrhythmias in children with hypertrophic cardiomyopathy. AB - : Introduction The spatial peaks QRS-T angle accurately distinguishes children with hypertrophic cardiomyopathy from their healthy counterparts. The spatial peaks QRS-T angle is also useful in risk stratification for ventricular arrhythmias. We hypothesised that the spatial peaks QRS-T angle would be useful for the prediction of ventricular arrhythmias in hypertrophic cardiomyopathy patients under 23 years of age. METHODS: Corrected QT interval and spatial peaks QRS-T angles were retrospectively assessed in 133 paediatric hypertrophic cardiomyopathy patients (12.4+/-6.6 years) with versus without ventricular arrhythmias of 30 seconds or longer. Significance, positive/negative predictive values, and odds ratios were calculated based on receiver operating characteristic curve cut-off values. RESULTS: In total, 10 patients with ventricular arrhythmias were identified. Although the corrected QT interval did not differentiate those with versus without ventricular arrhythmias, the spatial peaks QRS-T angle did (151.4+/-19.0 versus 116.8+/-42.6 degrees, respectively, p<0.001). At an optimal cut-off value (124.1 degrees), the positive and negative predictive values of the spatial peaks QRS-T angle were 15.4 and 100.0%, respectively, with an odds ratio of 25.9 (95% CI 1.5-452.2). CONCLUSION: In children with hypertrophic cardiomyopathy, the spatial peaks QRS-T angle is associated with ventricular arrhythmia burden with high negative predictive value and odds ratio. PMID- 27246459 TI - Crystal Structure Analysis of the Repair of Iron Centers Protein YtfE and Its Interaction with NO. AB - Molecular mechanisms underlying the repair of nitrosylated [Fe-S] clusters by the microbial protein YtfE remain poorly understood. The X-ray crystal structure of YtfE, in combination with EPR, magnetic circular dichroism (MCD), UV, and (17) O labeling electron spin echo envelope modulation measurements, show that each iron of the oxo-bridged Fe(II) -Fe(III) diiron core is coordinatively unsaturated with each iron bound to two bridging carboxylates and two terminal histidines in addition to an oxo-bridge. Structural analysis reveals that there are two solvent accessible tunnels, both of which converge to the diiron center and are critical for capturing substrates. The reactivity of the reduced-form Fe(II) -Fe(II) YtfE toward nitric oxide demonstrates that the prerequisite for N2 O production requires the two iron sites to be nitrosylated simultaneously. Specifically, the nitrosylation of the two iron sites prior to their reductive coupling to produce N2 O is cooperative. This result suggests that, in addition to any repair of iron centers (RIC) activity, YtfE acts as an NO-trapping scavenger to promote the NO to N2 O transformation under low NO flux, which precedes nitrosative stress. PMID- 27246460 TI - Single-cell sequencing reveals karyotype heterogeneity in murine and human malignancies. AB - BACKGROUND: Chromosome instability leads to aneuploidy, a state in which cells have abnormal numbers of chromosomes, and is found in two out of three cancers. In a chromosomal instable p53 deficient mouse model with accelerated lymphomagenesis, we previously observed whole chromosome copy number changes affecting all lymphoma cells. This suggests that chromosome instability is somehow suppressed in the aneuploid lymphomas or that selection for frequently lost/gained chromosomes out-competes the CIN-imposed mis-segregation. RESULTS: To distinguish between these explanations and to examine karyotype dynamics in chromosome instable lymphoma, we use a newly developed single-cell whole genome sequencing (scWGS) platform that provides a complete and unbiased overview of copy number variations (CNV) in individual cells. To analyse these scWGS data, we develop AneuFinder, which allows annotation of copy number changes in a fully automated fashion and quantification of CNV heterogeneity between cells. Single cell sequencing and AneuFinder analysis reveals high levels of copy number heterogeneity in chromosome instability-driven murine T-cell lymphoma samples, indicating ongoing chromosome instability. Application of this technology to human B cell leukaemias reveals different levels of karyotype heterogeneity in these cancers. CONCLUSION: Our data show that even though aneuploid tumours select for particular and recurring chromosome combinations, single-cell analysis using AneuFinder reveals copy number heterogeneity. This suggests ongoing chromosome instability that other platforms fail to detect. As chromosome instability might drive tumour evolution, karyotype analysis using single-cell sequencing technology could become an essential tool for cancer treatment stratification. PMID- 27246462 TI - Saving wild ungulate diversity through enhanced management and sperm cryopreservation. AB - Wild ungulates throughout the world face the impending risk of extinction. Small founding population size, lack of interest in exhibiting wild ungulates and declining space in zoos are not sustaining ex situ populations. Animals managed in ex situ collections continue to experience >20% neonate loss globally. To ensure population sustainability there is a critical need to: (1) manage ungulates in large herds, increasing mate choice and reproductive efficiency; (2) improve husbandry and genetic management; and (3) develop consistent assisted reproductive technologies, including sperm cryopreservation and AI. Recently, new models in the management of ungulates have begun to emerge. Animal managers and researchers are also beginning to exploit advances in genomics to improve genetic management of their collections. Furthermore, the past decade has witnessed significant advances particularly in semen collection and cryopreservation in numerous species. Advances in gonadal tissue cryopreservation now offer additional opportunities to preserve male genomes. The new knowledge generated is enabling the creation of genetic (sperm) banks to rescue and enhance reproductive management of wild ungulates. The present paper reviews the threats to ungulate populations, the status and relevance of animal management and biomaterial banking efforts to ensure long-term survival of these charismatic species. PMID- 27246461 TI - Neuroticism, depression and anxiety in takotsubo cardiomyopathy. AB - BACKGROUND: Takotsubo cardiomypathy (TTC) causes acute reversible heart failure. Prior studies have indicated that the syndrome is associated with traits such as social inhibition, chronic psychological stress, and anxio-depressive disorders. The objective of this study was to further characterize key psychological/psychopathological traits of patients with TTC. METHODS: A survey of three groups was conducted: I) Female post-recovery TTC patients admitted between October 1(st) 2009 and December 10(th) 2014, II) Age, gender and geographically matched ST-elevation myocardial infarction (STEMI) patients, and III) Age, gender and geographically matched individuals from the background population. The following questionnaires were used in the survey: the WHO-5 Well Being Index, Eysenck's Neuroticism Scale, the Major Depression Inventory, and the anxiety subscale of Symptoms Checklist (SCL-90). RESULTS: In total, 173 of 230 invitees (75 %) participated in the study. In comparison to the background controls, TTC patients reported significantly less well-being, more neuroticism, more depression, and more anxiety. The levels of well-being, depression and neuroticism were comparable between TTC and STEMI patients, but the level of anxiety was higher in the TTC patients. There was a negative correlation between the time since TTC admission and the total scores on the psychopathology rating scales. CONCLUSIONS: Patients with TTC reported significantly higher anxiety levels compared to both STEMI patients and background controls. However, unlike the STEMI patients, the TTC patients appeared to improve psychologically during the post-recovery phase. This may be a consolation for TTC patients in acute psychological distress. PMID- 27246463 TI - Practice of hemodynamic monitoring and management in German, Austrian, and Swiss intensive care units: the multicenter cross-sectional ICU-CardioMan Study. AB - BACKGROUND: Hemodynamic instability is frequent and outcome-relevant in critical illness. The understanding of complex hemodynamic disturbances and their monitoring and management plays an important role in treatment of intensive care patients. An increasing number of treatment recommendations and guidelines in intensive care medicine emphasize hemodynamic goals, which go beyond the measurement of blood pressures. Yet, it is not known to which extent the infrastructural prerequisites for extended hemodynamic monitoring are given in intensive care units (ICUs) and how hemodynamic management is performed in clinical practice. Further, it is still unclear which factors trigger the use of extended hemodynamic monitoring. METHODS: In this multicenter, 1-day (November 7, 2013, and the preceding 24 h) cross-sectional study, we retrieved data on patient monitoring from ICUs in Germany, Austria, and Switzerland by means of a web-based case report form. One hundred and sixty-one intensive care units contributed detailed information on availability of hemodynamic monitoring. In addition, detailed information on hemodynamic monitoring of 1789 patients that were treated on due date was collected, and independent factors triggering the use of extended hemodynamic monitoring were identified by multivariate analysis. RESULTS: Besides basic monitoring with electrocardiography (ECG), pulse oximetry, and blood pressure monitoring, the majority of patients received invasive arterial (77.9 %) and central venous catheterization (55.2 %). All over, additional extended hemodynamic monitoring for assessment of cardiac output was only performed in 12.3 % of patients, while echocardiographic examination was used in only 1.9 %. The strongest independent predictors for the use of extended hemodynamic monitoring of any kind were mechanical ventilation, the need for catecholamine therapy, and treatment backed by protocols. In 71.6 % of patients in whom extended hemodynamic monitoring was added during the study period, this extension led to changes in treatment. CONCLUSIONS: Extended hemodynamic monitoring, which goes beyond the measurement of blood pressures, to date plays a minor role in the surveillance of critically ill patients in German, Austrian, and Swiss ICUs. This includes also consensus-based recommended diagnostic and monitoring applications, such as echocardiography and cardiac output monitoring. Mechanical ventilation, the use of catecholamines, and treatment backed by protocol could be identified as factors independently associated with higher use of extended hemodynamic monitoring. PMID- 27246464 TI - Direct comparisons of commercial weight-loss programs on weight, waist circumference, and blood pressure: a systematic review. AB - BACKGROUND: Obesity is common in the U.S. and many individuals turn to commercial programs to lose weight. Our objective was to directly compare weight loss, waist circumference, and systolic and diastolic blood pressure (SBP, DBP) outcomes between commercially available weight-loss programs. METHODS: We conducted a systematic review by searching MEDLINE and the Cochrane Database of Systematic Reviews from inception to November 2014 and by using references identified by commercial programs. We included randomized, controlled trials (RCTs) of at least 12 weeks duration that reported comparisons with other commercial weight-loss programs. Two reviewers extracted information on mean change in weight, waist circumference, SBP and DBP and assessed risk of bias. RESULTS: We included seven articles representing three RCTs. Curves participants lost 1.8 kg (95%CI: 0.1, 3.5 kg) more than Weight Watchers in one comparison. There was no statistically significant difference in waist circumference change among the included programs. The mean reduction in SBP for SlimFast participants was 4.5 mmHg (95%CI: 0.4, 8.6 mmHg) more than that of Atkins participants in one comparison. There was no significant difference in mean DBP changes among programs. CONCLUSIONS: There is limited evidence that any one of the commercial weight-loss programs has superior results for mean weight change, mean waist circumference change, or mean blood pressure change. PMID- 27246465 TI - Enhancing transcranial direct current stimulation via motor imagery and kinesthetic illusion: crossing internal and external tools. AB - BACKGROUND: Transcranial direct current stimulation is a safe technique which is now part of the therapeutic armamentarium for the neuromodulation of motor functions and cognitive operations. It is currently considered that tDCS is an intervention that might promote functional recovery after a lesion in the central nervous system, thus reducing long-term disability and associated socio-economic burden. DISCUSSION: A recent study shows that kinesthetic illusion and motor imagery prolong the effects of tDCS on corticospinal excitability, overcoming one of the limitations of this intervention. CONCLUSION: Because changes in excitability anticipate changes in structural plasticity in the CNS, this interesting multi-modal approach might very soon find applications in neurorehabilitation. PMID- 27246467 TI - Helicobacter pylori Treatment Failure: The Rationale for Alternative Antibiotics. PMID- 27246466 TI - Four Years of Diagnostic Challenges with Tetrahydrobiopterin Deficiencies in Iranian Patients. AB - Hyperphenylalaninemia (HPA) is a condition caused by tetrahydrobiopterin (BH4) and phenylalanine hydroxylase (PAH) deficiencies. It is essential that differential diagnosis be conducted to distinguish these two causes of HPA, because BH4 deficiency is a more severe disease involving progressive neurologic deterioration. Based on the biological findings, HPA is defined as a plasma phenylalanine level of >2.0 mg/dl (>120 MUmol/l). The National Biochemistry Reference Laboratory at the Pasteur Institute of Iran initiated BH4 deficiency screening tests for the first time during the implementation of a nationwide phenylketonuria (PKU) screening program. Measurement of blood phenylalanine and urinary neopterin and biopterin was conducted by high-performance liquid chromatography in 617 patients with HPA. Dihydropteridine reductase (DHPR) activity was measured in all patients by kinetic spectrophotometry. Differential diagnosis was conducted for PKU, transient HPA, and BH4 deficiencies.Our results indicated that out of 76 cases involving BH4 deficiencies, 37 had 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency, 35 had DHPR deficiency, 1 case had pterin-4a-carbinolamine dehydratase (PCD) deficiency, and 3 cases had GTP cyclohydrolase I (GTPCH) deficiency. In this study, 1 novel deletion mutation and 18 novel missense mutations were reported in addition to mutations that had previously been identified and registered in BIOMDB. At present, the screening program for PKU in Iran includes tests that detect different forms of BH4 deficiency presenting with HPA. Newborns that are BH4-deficient benefit from the availability of the tests because they can receive necessary care before being clinically affected. PMID- 27246469 TI - [Bundnis JUNGE ARZTE: position paper : Compatibility of family and career - where is the change in minds?]. PMID- 27246468 TI - Clinical illness and outcomes in Nigerian children with late-appearing anaemia after artemisinin-based combination treatments of uncomplicated falciparum malaria. AB - BACKGROUND: Late-appearing anaemia (LAA) following treatment with artemisinins for severe malaria has been reported and well described, but there are limited clinical and parasitological data on LAA in African children with uncomplicated falciparum malaria following oral artemisinin-based combination therapies (ACTs). METHODS: This was an open label study with the main objectives of evaluating the clinical features, the risk factors for, the temporal changes in haematocrit and the outcomes of a LAA in malarious children treated with artesunate-amodiaquine (AA), artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DHP). The diagnosis of LAA was made using the criteria: clearance of parasitaemia, fever and other symptoms within 1 week of commencing treatment; adequate clinical and parasitological response at 4-6 weeks after treatment began; haematocrit >=30 % 1 and/or 2 weeks after treatment began; and haematocrit <30 %, parasite negativity by microscopy and polymerase chain reaction and absence of concomitant illness 3 6 weeks after treatment began. RESULTS: LAA occurred in 84 of 609 children, was mild, moderate or severe in 77, 6 or 1 child, respectively and was relatively asymptomatic. Mean time elapsing from commencement of treatment to LAA was 27.1 days (95 % CI 25.3-28.9). In a multivariate analysis, an age <3 years (adjusted odd ratio [AOR] = 2.6, 95 % CI 1.3-5.2, P = 0.005), fever 1 day after treatment began (AOR = 3.8, 95 % CI 1.8-8.2, P < 0.0001), haematocrit <25 % at presentation (AOR = 2.2, 95 % CI 1.3-3.7, P = 0.003), haematocrit <30 % 1 day after treatment began (AOR = 2.1, 95 % CI 1.0-4.3, P = 0.04), parasite reduction ratio >10(4) 2 days after treatment began (AOR = 2.1, 95 % CI 1.1-3.9, P = 0.03) and spleen enlargement at presentation (AOR = 2.0, 95 % CI 1.1-3.9, P < 0.0001) were independent predictors of LAA. During 6 weeks of follow-up, uneventful recovery from anaemia occurred in 56 children [mean recovery time of 11.8 days (95 % CI 10.3-13.3)]. The only independent predictor of failure of recovery was LAA occurring 4 weeks after starting treatment (AOR = 7.5, 95 % CI 2.5-22.9, P < 0.0001). CONCLUSION: A relatively asymptomatic LAA with uneventful recovery can occur in young malarious children following ACTs. Its occurrence may have implications for case and community management of anaemia and for anaemia control efforts in sub-Saharan Africa where ACTs have become first-line antimalarials. TRIALS REGISTRATION: Pan African Clinical Trial Registry PACTR201508001188143, 3 July 2015; PACTR201510001189370, 3 July 2015; PACTR201508001191898, 7 July 2015 and PACTR201508001193368, 8 July 2015 http://www.pactr.org . PMID- 27246471 TI - [Not Available]. PMID- 27246470 TI - [GeSRU Academics research group "BPS & functional urology"]. PMID- 27246472 TI - [Not Available]. PMID- 27246473 TI - [Rehabilitation of prostate cancer patients : A multidisciplinary consensus]. AB - BACKGROUND: Even though several specialist groups, including the German Pension Insurance (Deutsche Rentenversicherung) and health insurance funds, participate in the rehabilitation of patients with prostate carcinoma, there is no standardized rehabilitation program available for these patients. Consequently, there is no transparency regarding the services provided within the scope of rehabilitation for the referring physicians to uro-oncological rehabilitation, in particular, neither for physicians at urological acute-care clinics, nor for the patients concerned. Rehabilitation clinics are rather left to their own devices as to which services they provide in the treatment of the respective disease and in social situations, but also with regard to the consulting services offered. PROBLEM: Development of a standard for the rehabilitation of patients with prostate carcinoma, taking into account both specialist circles and self-help groups relevant to this matter. METHODS: Specialist groups, including self-help groups participating in the rehabilitation of patients with prostate cancer, have formed an expert group and developed the present standard. To this end, a thematic unsystematic literature review was carried out in advance to provide an evidence-based foundation. RESULTS: Views were given with regard to rehabilitation diagnostics, the therapy of urinary incontinence and erectile dysfunction, sport and physical exercise therapy, psycho-oncology, and social- and disease-related consulting. In this context, the focus was set on classification as well as on the consensus strength of the respective recommendations. CONCLUSION: All parties involved in the rehabilitation of prostate cancer patients, as well as the patients and the responsible cost bearers, can now use the standard as an orientation guide. PMID- 27246474 TI - [Alpha-blockers as medical expulsive therapy for ureteral stones]. PMID- 27246475 TI - [Can circulating tumor cells be a predicative biomarker?]. PMID- 27246476 TI - [Karyometry of BBN-induced precancerosis of the urothelium : An experimental analysis]. AB - BACKGROUND: The morphology of experimental precancerous lesions of the urinary bladder has been interpreted quite differently by various authors. OBJECTIVES: The aim of this investigation was to quantify these lesions by karyometry and, thus, to gain a more reliable understanding of the process. MATERIALS AND METHODS: A total of 60 Wistar rats were fed with N-butyl-N-(4 hydroxybutyl)nitrosamine (BBN) at a concentration of 0.05 % in their drinking water to induce preneoplastic changes of the urothelium. After the second week of BBN exposition, 6 animals were killed every 2 weeks up to week 20. Smears of the scraped off urothelium of 3 urinary bladders of each group were analyzed cytologically and karyometrically. RESULTS: BBN exposition led to statistically significant changes of the karyometric values using the chi2 test to differentiate the control animals from the ones that had ingested BBN and the 2 week groups from each other. These changes consisted mainly in significant deviations of the size of the nuclear area within the different groups. CONCLUSION: Morphological and karyometrical analysis showed that biologically relevant stages in the development of chemically induced urothelial precancerous lesions could be realized much earlier than had been assumed in recent publications. Karyometric analysis offered a valid basis to describe the early morphologic alterations of carcinogenesis. PMID- 27246477 TI - The death enzyme CP14 is a unique papain-like cysteine proteinase with a pronounced S2 subsite selectivity. AB - The cysteine protease CP14 has been identified as a central component of a molecular module regulating programmed cell death in plant embryos. CP14 belongs to a distinct subfamily of papain-like cysteine proteinases of which no representative has been characterized thoroughly to date. However, it has been proposed that CP14 is a cathepsin H-like protease. We have now produced recombinant Nicotiana benthamiana CP14 (NbCP14) lacking the C-terminal granulin domain. As typical for papain-like cysteine proteinases, NbCP14 undergoes rapid autocatalytic activation when incubated at low pH. The mature protease is capable of hydrolysing several synthetic endopeptidase substrates, but cathepsin H-like aminopeptidase activity could not be detected. NbCP14 displays a strong preference for aliphatic over aromatic amino acids in the specificity-determining P2 position. This subsite selectivity was also observed upon digestion of proteome-derived peptide libraries. Notably, the specificity profile of NbCP14 differs from that of aleurain-like protease, the N. benthamiana orthologue of cathepsin H. We conclude that CP14 is a papain-like cysteine proteinase with unusual enzymatic properties which may prove of central importance for the execution of programmed cell death during plant development. PMID- 27246478 TI - Dexamethasone rapidly inhibits glucose uptake via non-genomic mechanisms in contracting myotubes. AB - Glucocorticoids (GCs) are a class of steroid hormones that regulate multiple aspects of glucose homeostasis. In skeletal muscle, it is well established that prolonged GC excess inhibits glucose uptake and utilization through glucocorticoid receptor (GR)-mediated transcriptional changes. However, it remains obscure that whether the rapid non-genomic effects of GC on glucose uptake are involved in acute exercise stress. Therefore, we used electric pulse stimulation (EPS)-evoked contracting myotubes to determine whether the non genomic actions of GC were involved and its underlying mechanism(s). Pretreatment with dexamethasone (Dex, 10 MUM) significantly prevented contraction-stimulated glucose uptake and glucose transporter 4 (Glut4) translocation within 20 min in C2C12 myotubes. Neither GC nuclear receptor antagonist (RU486) nor protein synthesis inhibitor (cycloheximide, Chx) affected the rapid inhibition effects of Dex. AMPK and CaMKII-dependent signaling pathways were associated with the non genomic effects of Dex. These results provide evidence that GC rapidly suppresses glucose uptake in contracting myotubes via GR-independent non-genomic mechanisms. AMPK and CaMKII-mediated Glut4 translocation may play a critical role in GC induced rapid inhibition of glucose uptake. PMID- 27246479 TI - Introduction: Degenerative cervical myelopathy: diagnostic, assessment, and management strategies, surgical complications, and outcome prediction. PMID- 27246480 TI - Complications following central corpectomy in 468 consecutive patients with degenerative cervical spine disease. AB - OBJECTIVE This study was performed to describe the incidence and predictors of perioperative complications following central corpectomy (CC) in 468 consecutive patients with cervical spondylotic myelopathy (CSM) or ossification of the posterior longitudinal ligament (OPLL). METHODS The authors performed a retrospective review of a cohort of patients who had undergone surgery for CSM (n = 338) or OPLL (n = 130) performed by a single surgeon over a 15-year period. All patients underwent uninstrumented CC with autologous iliac crest or fibular strut grafting. Preoperative clinical and imaging details were collected, and the type and incidence of complications were studied. Univariate and multivariate analyses were performed to establish risk factors for the development of perioperative complications. RESULTS Overall, 12.4% of patients suffered at least 1 complication following CC. The incidence of major complications was as follows: C 5 radiculopathy, 1.3%; recurrent laryngeal nerve injury, 0.4%; dysphagia, 0.8%; surgical-site infection, 3.4%; and dural tear, 4.3%. There was 1 postoperative death (0.2%). On multivariate analysis, patients in whom the corpectomy involved the C-4 vertebral body (alone or as part of multilevel CC) were significantly more likely to suffer complications (p = 0.004). OPLL and skip corpectomy were risk factors for dural tear (p = 0.015 and p = 0.001, respectively). No factors were found to be significantly associated with postoperative C-5 palsy, dysphagia, or acute graft extrusion on univariate or multivariate analysis. Patients who underwent multilevel CC were predisposed to surgical-site infections, with a slight trend toward statistical significance (p = 0.094). The occurrence of a complication after surgery significantly increased the mean duration of postoperative hospital stay from 5.0 +/- 2.3 days to 8.9 +/- 6 days (p < 0.001). CONCLUSIONS Complications following CC for CSM or OPLL are infrequent, but they significantly prolong hospital stay. The most frequent complication following CC is dural tear, for which a diagnosis of OPLL and a skip corpectomy are significant risk factors. PMID- 27246481 TI - Surgical outcomes of cervical spondylotic myelopathy: an analysis of a national, administrative, longitudinal database. AB - OBJECTIVE The authors performed a population-based analysis of national trends, costs, and outcomes associated with cervical spondylotic myelopathy (CSM) in the United States. They assessed postoperative complications, resource utilization, and predictors of costs, in this surgically treated CSM population. METHODS MarketScan data (2006-2010) were used to retrospectively analyze the complications and costs of different spine surgeries for CSM. The authors determined outcomes following anterior cervical discectomy and fusion (ACDF), posterior fusion, combined anterior/posterior fusion, and laminoplasty procedures. RESULTS The authors identified 35,962 CSM patients, comprising 5154 elderly (age >= 65 years) patients (mean 72.2 years, 54.9% male) and 30,808 nonelderly patients (mean 51.1 years, 49.3% male). They found an overall complication rate of 15.6% after ACDF, 29.2% after posterior fusion, 41.1% after combined anterior and posterior fusion, and 22.4% after laminoplasty. Following ACDF and posterior fusion, a significantly higher risk of complication was seen in the elderly compared with the nonelderly (reference group). The fusion level and comorbidity-adjusted ORs with 95% CIs for these groups were 1.54 (1.40-1.68) and 1.25 (1.06-1.46), respectively. In contrast, the elderly population had lower 30-day readmission rates in all 4 surgical cohorts (ACDF, 2.6%; posterior fusion, 5.3%; anterior/posterior fusion, 3.4%; and laminoplasty, 3.6%). The fusion level and comorbidity-adjusted odds ratios for 30-day readmissions for ACDF, posterior fusion, combined anterior and posterior fusion, and laminoplasty were 0.54 (0.44 0.68), 0.32 (0.24-0.44), 0.17 (0.08-0.38), and 0.39 (0.18-0.85), respectively. CONCLUSIONS The authors' analysis of the MarketScan database suggests a higher complication rate in the surgical treatment of CSM than previous national estimates. They found that elderly age (>= 65 years) significantly increased complication risk following ACDF and posterior fusion. Elderly patients were less likely to experience a readmission within 30 days of surgery. Postoperative complication occurrence, and 30-day readmission were significant drivers of total cost within 90 days of the index surgical procedure. PMID- 27246482 TI - Clinical adjacent-segment pathology after central corpectomy for cervical spondylotic myelopathy: incidence and risk factors. AB - OBJECTIVE The goal of this study was to investigate the prevalence and risk factors of clinical adjacent-segment pathology (CASP) following central corpectomy for cervical spondylotic myelopathy (CSM) or ossification of the posterior longitudinal ligament (OPLL). METHODS The authors reviewed 353 cases involving patients operated on by a single surgeon with a minimum 12-month follow up after central corpectomy for CSM or OPLL between 1995 and 2007. Patients with symptoms consistent with CASP at follow-up were selected for the study. The authors analyzed the prevalence and risk factors for CASP after central corpectomy for CSM/OPLL. RESULTS Fourteen patients (13 male, 1 female; mean age 46.9 +/- 7.7 years) were diagnosed with symptoms of CASP (3.9% of 353 patients) at follow-up. The mean interval between the initial surgery and presentation with symptoms of CASP was 95.6 +/- 54.1 months (range 40-213 months). Preoperative Nurick grades ranged from 2 to 5 (mean 3.5 +/- 1.2), and the Nurick grades at follow-up ranged from 1 to 5 (mean 3.0 +/- 1.3, p = 0.27). Twelve patients had myelopathic symptoms and 2 had radiculopathy at follow-up. Patients with poorer preoperative Nurick grades had a higher risk for development of CASP (HR 2.6 [95% CI 1.2-5.3], p = 0.01). CONCLUSIONS In the present study, CASP was seen in 3.9% of patients following central corpectomy for CSM/OPLL. The risk of CASP after central corpectomy for CSM/OPLL was higher in patients with poorer preoperative Nurick grades. PMID- 27246483 TI - Surgical outcomes of elderly patients with cervical spondylotic myelopathy: a meta-analysis of studies reporting on 2868 patients. AB - OBJECTIVE Cervical spondylotic myelopathy usually presents in the 5th decade of life or later but can also present earlier in patients with congenital spinal stenosis. As life expectancy continues to increase in the United States, the preconceived reluctance toward operating on the elderly population based on older publications must be rethought. It is a known fact that outcomes in the elderly cannot be as robust as those in the younger population. There are no publications with detailed meta-analyses to determine an acceptable level of outcome in this population. In this review, the authors compare elderly patients older than 75 years to a nonelderly population, and they discuss some of the relevant strategies to minimize complications. METHODS In accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, the authors performed a PubMed database search to identify English-language literature published between 1995 and 2015. Combinations of the following phrases that describe the age group ("elderly," "non-elderly," "old," "age") and the disease of interest as well as management ("surgical outcome," "surgery," "cervical spondylotic myelopathy," "cervical degenerative myelopathy") were constructed when searching for relevant articles. Two reviewers independently assessed the outcomes, and any disagreement was discussed with the first author until it was resolved. A random-effects model was applied to assess pooled data due to high heterogeneity between studies. The mean difference (MD) and odds ratio were calculated for continuous and dichromatic parameters, respectively. RESULTS Eighteen studies comprising elderly (n = 1169) and nonelderly (n = 1699) patients who received surgical treatment for cervical spondylotic myelopathy were included in this meta-analysis. Of these studies, 5 were prospective and 13 were retrospective. Intraoperatively, both groups required a similar amount of operation time (p = 0.35). The elderly group had lower Japanese Orthopaedic Association (JOA) scores (MD -1.36, 95% CI -1.62 to -1.09; p < 0.00001) to begin with compared with the nonelderly group. The nonelderly group also had a higher postoperative JOA score (MD -1.11, 95% CI -1.44 to -0.79; p < 0.00001), therefore demonstrating a higher recovery rate from surgeries (MD -11.98, 95% CI -16.16 to 7.79; p < 0.00001). The length of stay (MD 4.14, 95% CI 3.54-4.73; p < 0.00001) was slightly longer in the elderly group. In terms of radiological outcomes, the elderly group had a smaller postoperative Cobb angle but a greater increase in spinal canal diameter compared with the nonelderly group. The complication rates were not significant. CONCLUSIONS Cervical myelopathy is a disease of the elderly, and age is an independent factor for recovery from surgery. Postoperative and long-term outcomes have been remarkable in terms of improvement in mobility and independence requiring reduced nursing care. There is definitely a higher potential risk while operating on the elderly population, but no significant difference in the incidence of postoperative complications was noted. Withholding surgery from the elderly population can lead to increased morbidity due to rapid progression of symptoms in addition to deconditioning from lack of mobility and independence. Reduction in operative time under anesthesia, lower blood loss, and perioperative fluid management have been shown to minimize the complication rate. The authors request that neurosurgeons weigh the potential benefit against the risks for every patient before withholding surgery from elderly patients. PMID- 27246484 TI - Predicting the minimum clinically important difference in patients undergoing surgery for the treatment of degenerative cervical myelopathy. AB - OBJECTIVE The minimum clinically important difference (MCID) is defined as the minimum change in a measurement that a patient would identify as beneficial. Before undergoing surgery, patients are likely to inquire about the ultimate goals of the operation and of their chances of experiencing meaningful improvements. The objective of this study was to define significant predictors of achieving an MCID on the modified Japanese Orthopaedic Association (mJOA) scale at 2 years following surgery for the treatment of degenerative cervical myelopathy (DCM). METHODS Seven hundred fifty-seven patients were prospectively enrolled in either the AOSpine North America or International study at 26 global sites. Fourteen patients had a perfect preoperative mJOA score of 18 and were excluded from this analysis (n = 743). Data were collected for each participating subject, including demographic information, symptomatology, medical history, causative pathology, and functional impairment. Univariate log-binominal regression analyses were conducted to evaluate the association between preoperative clinical factors and achieving an MCID on the mJOA scale. Modified Poisson regression using robust error variances was used to create the final multivariate model and compute the relative risk for each predictor. RESULTS The sample consisted of 463 men (62.31%) and 280 women (37.69%), with an average age of 56.48 +/- 11.85 years. At 2 years following surgery, patients exhibited a mean change in functional status of 2.71 +/- 2.89 points on the mJOA scale. Of the 687 patients with available follow-up data, 481 (70.01%) exhibited meaningful gains on the mJOA scale, whereas 206 (29.98%) failed to achieve an MCID. Based on univariate analysis, significant predictors of achieving the MCID on the mJOA scale were younger age; female sex; shorter duration of symptoms; nonsmoking status; a lower comorbidity score and absence of cardiovascular disease; and absence of upgoing plantar responses, lower-limb spasticity, and broad-based unstable gait. The final model included age (relative risk [RR] 0.924, p < 0.0001), smoking status (RR 0.837, p = 0.0043), broad-based unstable gait (RR 0.869, p = 0.0036), and duration of symptoms (RR 0.943, p = 0.0003). CONCLUSIONS In this large multinational prospective cohort, 70% of patients treated surgically for DCM exhibited a meaningful functional gain on the mJOA scale. The key predictors of achieving an MCID on the mJOA scale were younger age, shorter duration of symptoms, nonsmoking status, and lack of significant gait impairment. PMID- 27246485 TI - Functional cortical reorganization in cases of cervical spondylotic myelopathy and changes associated with surgery. AB - OBJECTIVE The physiological mechanisms underlying the recovery of motor function after cervical spondylotic myelopathy (CSM) surgery are poorly understood. Neuronal plasticity allows neurons to compensate for injury and disease and to adjust their activities in response to new situations or changes in their environment. Cortical reorganization as well as improvement in corticospinal conduction happens during motor recovery after stroke and spinal cord injury. In this study the authors aimed to understand the cortical changes that occur due to CSM and following CSM surgery and to correlate these changes with functional recovery by using blood oxygen level-dependent (BOLD) functional MRI (fMRI). METHODS Twenty-two patients having symptoms related to cervical cord compression due to spondylotic changes along with 12 age- and sex-matched healthy controls were included in this study. Patients underwent cervical spine MRI and BOLD fMRI at 1 month before surgery (baseline) and 6 months after surgery. RESULTS Five patients were excluded from analysis because of technical problems; thus, 17 patients made up the study cohort. The mean overall modified Japanese Orthopaedic Association score improved in patients following surgery. Mean upper-extremity, lower-extremity, and sensory scores improved significantly. In the preoperative patient group the volume of activation (VOA) was significantly higher than that in controls. The VOA after surgery was reduced as compared with that before surgery, although it remained higher than that in the control group. In the preoperative patient group, activations were noted only in the left precentral gyrus (PrCG). In the postoperative group, activations were seen in the left postcentral gyrus (PoCG), as well as the PrCG and premotor and supplementary motor cortices. In postoperative group, the VOA was higher in both the PrCG and PoCG as compared with those in the control group. CONCLUSIONS There is over recruitment of sensorimotor cortices during nondexterous relative to dexterous movements before surgery. After surgery, there was recruitment of other cortical areas such as the PoCG and premotor and supplementary motor cortices, which correlated with improvement in dexterity, but activation in these areas was greater than that found in controls. The results show that improvement in dexterity and finer movements of the upper limbs is associated with recruitment areas other than the premotor cortex to compensate for the damage in the cervical spinal cord. PMID- 27246486 TI - Subclinical respiratory dysfunction in chronic cervical cord compression: a pulmonary function test correlation. AB - OBJECTIVE Respiratory abnormalities are well documented in acute spinal cord injury; however, the literature available for respiratory dysfunction in chronic compressive myelopathy (CCM) is limited. Respiratory dysfunction in CCM is often subtle and subclinical. The authors studied the pattern of respiratory dysfunction in patients with chronic cord compression by using spirometry, and the clinical and surgical implications of this dysfunction. In this study they also attempted to address the postoperative respiratory function in these patients. METHODS A prospective study was done in 30 patients in whom cervical CCM due to either cervical spondylosis or ossification of the posterior longitudinal ligament (OPLL) was diagnosed. Thirty age-matched healthy volunteers were recruited as controls. None of the patients included in the study had any symptoms or signs of respiratory dysfunction. After clinical and radiological diagnosis, all patients underwent pulmonary function tests (PFTs) performed using a standardized Spirometry Kit Micro before and after surgery. The data were analyzed using Statistical Software SPSS version 13.0. Comparison between the 2 groups was done using the Student t-test. The Pearson correlation coefficient was used for PFT results and Nurick classification scores. A p value < 0.05 was considered significant. RESULTS Cervical spondylotic myelopathy (prolapsed intervertebral disc) was the predominant cause of compression (n = 21, 70%) followed by OPLL (n = 9, 30%). The average patient age was 45.06 years. Degenerative cervical spine disease has a relatively younger onset in the Indian population. The majority of the patients (n = 28, 93.3%) had compression at or above the C-5 level. Ten patients (33.3%) underwent an anterior approach and discectomy, 11 patients (36.7%) underwent decompressive laminectomy, and the remaining 9 underwent either corpectomy with fusion or laminoplasty. The mean preoperative forced vital capacity (FVC) (65%) of the patients was significantly lower than that of the controls (88%) (p < 0.001). The mean postoperative FVC (73.7%) in the patients showed significant improvement compared with the preoperative values (p = 0.003). The mean postoperative FVC was still significantly lower than the control value (p = 0.002). The mean preoperative forced expiratory volume in 1 second (FEV1) (72%) of the patients was significantly lower than that of the controls (96%) (p < 0.001). The mean postoperative FEV1 (75.3%) in the cases showed no significant improvement compared with the preoperative values (p = 0.212). The mean postoperative FEV1 was still significantly lower than the control value (p < 0.001). The mean postoperative FEV1/FVC was not significantly different from the control value (p = 0.204). The mean postoperative peak expiratory flow rate was significantly lower than the control value (p = 0.01). The mean postoperative maximal voluntary ventilation was still significantly lower than the control value (p < 0.001). On correlating the FVC and Nurick scores using the Pearson correlation coefficient, a negative correlation was found. CONCLUSIONS There is subclinical respiratory dysfunction and significant impairment of various lung capacities in patients with CCM. The FVC showed significant improvement postoperatively. Respiratory function needs to be evaluated and monitored to avoid potential respiratory complications. PMID- 27246487 TI - Risk of spinal cord injury in patients with cervical spondylotic myelopathy and ossification of posterior longitudinal ligament: a national cohort study. AB - OBJECTIVE This study aimed to estimate the risk of spinal cord injury (SCI) in patients with cervical spondylotic myelopathy (CSM) with and without ossification of posterior longitudinal ligament (OPLL). Also, the study compared the incidence rates of SCI in patients who were managed surgically and conservatively. METHODS This retrospective cohort study covering 15 years analyzed the incidence of SCI in patients with CSM. All patients, identified from the National Health Insurance Research Database, were hospitalized with the diagnosis of CSM and followed up during the study period. These patients with CSM were categorized into 4 groups according to whether they had OPLL or not and whether they received surgery or not: 1) surgically managed CSM without OPLL; 2) conservatively managed CSM without OPLL; 3) surgically managed CSM with OPLL; and 4) conservatively managed CSM with OPLL. The incidence rates of subsequent SCI in each group during follow up were then compared. Kaplan-Meier and Cox regression analyses were performed to compare the risk of SCI between the groups. RESULTS Between January 1, 1999, and December 31, 2013, there were 17,258 patients with CSM who were followed up for 89,003.78 person-years. The overall incidence of SCI in these patients with CSM was 2.022 per 1000 person-years. Patients who had CSM with OPLL and were conservatively managed had the highest incidence of SCI, at 4.11 per 1000 person years. Patients who had CSM with OPLL and were surgically managed had a lower incidence of SCI, at 3.69 per 1000 person-years. Patients who had CSM without OPLL and were conservatively managed had an even lower incidence of SCI, at 2.41 per 1000 person-years. Patients who had CSM without OPLL and were surgically managed had the lowest incidence of SCI, at 1.31 per 1000 person-years. The Cox regression model demonstrated that SCIs are significantly more likely to happen in male patients and in those with OPLL (HR 2.00 and 2.24, p < 0.001 and p = 0.007, respectively). Surgery could significantly lower the risk for approximately 50% of patients (HR 0.52, p < 0.001). CONCLUSIONS Patients with CSM had an overall incidence rate of SCI at approximately 0.2% per year. Male sex, the coexistence of OPLL, and conservative management are twice as likely to be associated with subsequent SCI. Surgery is therefore suggested for male patients with CSM who also have OPLL. PMID- 27246488 TI - Magnetic resonance imaging assessment of degenerative cervical myelopathy: a review of structural changes and measurement techniques. AB - Degenerative cervical myelopathy encompasses a spectrum of age-related structural changes of the cervical spine that result in static and dynamic injury to the spinal cord and collectively represent the most common cause of myelopathy in adults. Although cervical myelopathy is determined clinically, the diagnosis requires confirmation via imaging, and MRI is the preferred modality. Because of the heterogeneity of the condition and evolution of MRI technology, multiple techniques have been developed over the years in an attempt to quantify the degree of baseline severity and potential for neurological recovery. In this review, these techniques are categorized anatomically into those that focus on bone, ligaments, discs, and the spinal cord. In addition, measurements for the cervical spine canal size and sagittal alignment are also described briefly. These tools have resulted collectively in the identification of numerous useful parameters. However, the development of multiple techniques for assessing the same feature, such as cord compression, has also resulted in a number of challenges, including introducing ambiguity in terms of which methods to use and hindering effective comparisons of analysis in the literature. In addition, newer techniques that use advanced MRI are emerging and providing exciting new tools for assessing the spinal cord in patients with degenerative cervical myelopathy. PMID- 27246489 TI - Psychometric analysis and critical appraisal of the original, revised, and modified versions of the Japanese Orthopaedic Association score in the assessment of patients with cervical spondylotic myelopathy. AB - OBJECTIVE Cervical spondylotic myelopathy (CSM) is the most common cause of nontraumatic spinal cord impairment and disability in the world. Given that the Japanese Orthopaedic Association (JOA) score is the most frequently used outcome measure in clinical research and practice for treating patients with CSM, this review was undertaken to comprehensively and critically evaluate the psychometric properties of the JOA score. METHODS The authors identified studies (published in the period of January 1975 to November 2015) on the psychometric properties of the original, revised, and modified versions of the JOA score in Medline, PsycINFO, Excerpta Medica dataBASE (EMBASE), American College of Physicians Journal Club, and Cochrane Database of Systematic Reviews. Additional publications were captured in a secondary search of the bibliographies in both original research articles and literature reviews identified in the original search. The JOA scores were evaluated for item generation and reduction, internal consistency, reliability, validity, and responsiveness. This review included all those versions of the JOA score whose psychometric properties had been reported in at least 2 published studies. RESULTS The primary search strategy identified 59 studies, of which 9 fulfilled the inclusion and exclusion criteria. An additional 18 publications were captured in the secondary search and included in the analysis. The key findings from the 27 studies analyzed indicated the following: 1) the original JOA score (1975) was the source for the revised JOA score (1994) and 3 modified versions (1991, 1993, and 1999 JOA scores) reported or used in at least 2 published studies; 2) the revised and modified versions of the JOA score are markedly different from each other; 3) only the revised JOA score (1994) was validated with the original JOA score; and 4) the 1975 JOA score is the most appropriate instrument for assessing patients in Asian populations (especially from Japan) because of its psychometric attributes, and the 1991 JOA score is the most appropriate version for use in Western populations. CONCLUSIONS The authors' results indicate that the original (1975), revised (1994), and modified (1991, 1993, and 1999) versions of the JOA score are substantially different from each other in terms of their content and have been incompletely examined for their psychometric properties and cultural sensitivity. Whereas the 1975 JOA score is the most appropriate version for assessing individuals from Asian populations (particularly those eating with chopsticks), the 1991 JOA score is most suitable for evaluating patients in Western populations. Nonetheless, further investigation of the psychometric properties of the 1975 and 1991 JOA scores is recommended because of a paucity of studies reporting on the responsiveness of these 2 scoring instruments. PMID- 27246490 TI - A comparison of minimally invasive posterior cervical decompression and open anterior cervical decompression and instrumented fusion in the surgical management of degenerative cervical myelopathy. AB - OBJECTIVE Minimally invasive posterior cervical decompression (miPCD) has been described in several case series with promising preliminary results. The object of the current study was to compare the clinical outcomes between patients undergoing miPCD with anterior cervical discectomy and instrumented fusion (ACDFi). METHODS A retrospective study of 74 patients undergoing surgery (45 using miPCD and 29 using ACDFi) for myelopathy was performed. Outcomes were categorized into short-term, intermediate, and long-term follow-up, corresponding to averages of 1.7, 7.7, and 30.9 months, respectively. Mean scores for the Neck Disability Index (NDI), neck visual analog scale (VAS) score, SF-12 Physical Component Summary (PCS), and SF-12 Mental Component Summary (MCS) were compared for each follow-up period. The percentage of patients meeting substantial clinical benefit (SCB) was also compared for each outcome measure. RESULTS Baseline patient characteristics were well-matched, with the exception that patients undergoing miPCD were older (mean age 57.6 +/- 10.0 years [miPCD] vs 51.1 +/- 9.2 years [ACDFi]; p = 0.006) and underwent surgery at more levels (mean 2.8 +/- 0.9 levels [miPCD] vs 1.5 +/- 0.7 levels [ACDFi]; p < 0.0001) while the ACDFi patients reported higher preoperative neck VAS scores (mean 3.8 +/- 3.0 [miPCD] vs 5.4 +/- 2.6 [ACDFi]; p = 0.047). The mean PCS, NDI, neck VAS, and MCS scores were not significantly different with the exception of the MCS score at the short-term follow-up period (mean 46.8 +/- 10.6 [miPCD] vs 41.3 +/- 10.7 [ACDFi]; p = 0.033). The percentage of patients reporting SCB based on thresholds derived for PCS, NDI, neck VAS, and MCS scores were not significantly different, with the exception of the PCS score at the intermediate follow-up period (52% [miPCD] vs 80% [ACDFi]; p = 0.011). CONCLUSIONS The current report suggests that the optimal surgical strategy in patients requiring dorsal surgery may be enhanced by the adoption of a minimally invasive surgical approach that appears to result in similar clinical outcomes when compared with a well-accepted strategy of ventral decompression and instrumented fusion. The current results suggest that future comparative effectiveness studies are warranted as the miPCD technique avoids instrumented fusion. PMID- 27246491 TI - Comparison of anterior corpectomy and fusion versus laminoplasty for the treatment of cervical ossification of posterior longitudinal ligament: a meta analysis. AB - OBJECTIVE The purpose of this study was to compare the effectiveness and safety of anterior corpectomy and fusion (ACF) with laminoplasty for the treatment of patients diagnosed with cervical ossification of the posterior longitudinal ligament (OPLL). METHODS The authors searched electronic databases for relevant studies that compared the use of ACF with laminoplasty for the treatment of patients with OPLL. Data extraction and quality assessment were conducted, and statistical software was used for data analysis. The random effects model was used if there was heterogeneity between studies; otherwise, the fixed effects model was used. RESULTS A total of 10 nonrandomized controlled studies involving 819 patients were included. Postoperative Japanese Orthopaedic Association (JOA) score (p = 0.02, 95% CI 0.30-2.81) was better in the ACF group than in the laminoplasty group. The recovery rate was superior in the ACF group for patients with an occupying ratio of OPLL of >= 60% (p < 0.00001, 95% CI 21.27-34.44) and for patients with kyphotic alignment (p < 0.00001, 95% CI 16.49-27.17). Data analysis also showed that the ACF group was associated with a higher incidence of complications (p = 0.02, 95% CI 1.08-2.59) and reoperations (p = 0.002, 95% CI 1.83-14.79), longer operation time (p = 0.01, 95% CI 17.72 -160.75), and more blood loss (p = 0.0004, 95% CI 42.22-148.45). CONCLUSIONS For patients with an occupying ratio >= 60% or with kyphotic cervical alignment, ACF appears to be the preferable treatment method. Nevertheless, laminoplasty seems to be effective and safe enough for patients with an occupying ratio < 60% or with adequate cervical lordosis. However, it must be emphasized that a surgical strategy should be made based on the individual patient. Further randomized controlled trials comparing the use of ACF with laminoplasty for the treatment of OPLL should be performed to make a more convincing conclusion. PMID- 27246492 TI - Comparison of clinical outcomes in decompression and fusion versus decompression only in patients with ossification of the posterior longitudinal ligament: a meta analysis. AB - OBJECTIVE Ossification of the posterior longitudinal ligament (OPLL) is a pathological calcification or ossification of the PLL, predominantly occurring in the cervical spine. Although surgery is often necessary for patients with symptomatic neurological deterioration, there remains controversy with regard to the optimal surgical treatment. In this systematic review and meta-analysis, the authors identified differences in complications and outcomes after anterior or posterior decompression and fusion versus after decompression alone for the treatment of cervical myelopathy due to OPLL. METHODS A MEDLINE, SCOPUS, and Web of Science search was performed for studies reporting complications and outcomes after decompression and fusion or after decompression alone for patients with OPLL. A meta-analysis was performed to calculate effect summary mean values, 95% CIs, Q statistics, and I(2) values. Forest plots were constructed for each analysis group. RESULTS Of the 2630 retrieved articles, 32 met the inclusion criteria. There was no statistically significant difference in the incidence of excellent and good outcomes and of fair and poor outcomes between the decompression and fusion and the decompression-only cohorts. However, the decompression and fusion cohort had a statistically significantly higher recovery rate (63.2% vs 53.9%; p < 0.0001), a higher final Japanese Orthopaedic Association score (14.0 vs 13.5; p < 0.0001), and a lower incidence of OPLL progression (< 1% vs 6.3%; p < 0.0001) compared with the decompression-only cohort. There was no statistically significant difference in the incidence of complications between the 2 cohorts. CONCLUSIONS This study represents the only comprehensive review of outcomes and complications after decompression and fusion or after decompression alone for OPLL across a heterogeneous group of surgeons and patients. Based on these results, decompression and fusion is a superior surgical technique compared with posterior decompression alone in patients with OPLL. These results indicate that surgical decompression and fusion lead to a faster recovery, improved postoperative neurological functioning, and a lower incidence of OPLL progression compared with posterior decompression only. Furthermore, decompression and fusion did not lead to a greater incidence of complications compared with posterior decompression only. PMID- 27246493 TI - Presidential address: launching the Korea Health Personnel Licensing Examination Institute, a government-supported special foundation from December 23, 2015. PMID- 27246494 TI - Evaluation of a continuing professional development training program for physicians and physician assistants in hospitals in Laos based on the Kirkpatrick model. AB - PURPOSE: Medical professionals from Korea and Laos have been working together to develop a continuing professional development training program covering the major clinical fields of primary care. This study aimed to evaluate the effectiveness of the program from 2013 to 2014 using the Kirkpatrick model. METHODS: A questionnaire was used to evaluate the reaction of the trainees, and the trainers assessed the level of trainees' performance at the beginning and the end of each clinical section. The transfer (behavioral change) of the trainees was evaluated through the review of medical records written by the trainees before and after the training program. RESULTS: The trainees were satisfied with the training program, for which the average score was 4.48 out of 5.0. The average score of the trainees' performance at the beginning was 2.39 out of 5.0, and rose to 3.88 at the end of each section. The average score of the medical records written before the training was 2.92 out of 5.0, and it rose to 3.34 after the training. The number of patient visits to the district hospitals increased. CONCLUSION: The continuing professional development training program, which was planned and implemented with the full engagement and responsibility of Lao health professionals, proved to be effective. PMID- 27246495 TI - Construct validity test of evaluation tool for professional behaviors of entry level occupational therapy students in the United States. AB - PURPOSE: This study aimed to test the construct validity of an instrument to measure student professional behaviors in entry-level occupational therapy (OT) students in the academic setting. METHODS: A total of 718 students from 37 OT programs across the United States answered a self-assessment survey of professional behavior that we developed. The survey consisted of ranking 28 attributes, each on a 5-point Likert scale. A split-sample approach was used for exploratory and then confirmatory factor analysis. RESULTS: A three-factor solution with nine items was extracted using exploratory factor analysis [EFA] (n=430, 60%). The factors were 'Commitment to Learning' (2 items), 'Skills for Learning' (4 items), and 'Cultural Competence' (3 items). Confirmatory factor analysis (CFA) on the validation split (n=288, 40%) indicated fair fit for this three-factor model (fit indices: CFI=0.96, RMSEA=0.06, and SRMR=0.05). Internal consistency reliability estimates of each factor and the instrument ranged from 0.63 to 0.79. CONCLUSION: Results of the CFA in a separate validation dataset provided robust measures of goodness-of-fit for the three-factor solution developed in the EFA, and indicated that the three-factor model fitted the data well enough. Therefore, we can conclude that this student professional behavior evaluation instrument is a structurally validated tool to measure professional behaviors reported by entry-level OT students. The internal consistency reliability of each individual factor and the whole instrument was considered to be adequate to good. PMID- 27246496 TI - Potential efficacy of therapies targeting intrahepatic lesions after sorafenib treatment of patients with hepatocellular carcinoma. AB - BACKGROUND: We investigated the contribution of subsequent therapy for advanced hepatocellular carcinoma refractory or intolerant to sorafenib. Further, we investigated the impact of sorafenib on overall survival using individual data. METHODS: We reviewed the medical records of patients with advanced hepatocellular carcinoma treated with sorafenib. Survival after sorafenib treatment and overall survival were defined as the time when we discovered that patients were either refractory or intolerant to sorafenib and the period from the start of sorafenib treatment, respectively, until death during the study. We compared patients' prognoses according to their subsequent treatment as follows: group A, therapies targeting intrahepatic lesions; group B, systemic therapies alone; group C, no subsequent therapy. We used linear regression analysis to determine whether there was an association with survival after sorafenib treatment and with overall survival. RESULTS: Of 79 patients, 63 (79.7 %) received one or more subsequent therapies (44 and 19 patients in groups A and B, respectively). The five patients who survived more than two years after sorafenib treatment was discontinued responded to therapies targeting intrahepatic lesions. The median survival times of groups A, B, and C were 11.9 months, 5.8 months, and 3.6 months, respectively. Multivariate analysis revealed that group A, Child-Pugh score, serum alpha fetoprotein level, and cause of failure of sorafenib treatment were independent prognostic factors for survival after sorafenib treatment. Individual survival after sorafenib treatment correlated highly with overall survival. CONCLUSIONS: Targeting intrahepatic lesions may be useful for treating patients with advanced hepatocellular carcinoma patients after sorafenib treatment is discontinued. PMID- 27246497 TI - Inhibition of Adhesion of Enteropathogenic Escherichia coli to HEp-2 Cells by Binding of a Novel Peptide to EspB Protein. AB - Enteropathogenic Escherichia coli (EPEC) is a major cause of infantile diarrhea in developing countries. The translocator EspB is a key virulence factor in the process of the attaching and effacing effect of EPEC and plays a critical role in the pathogenesis of the bacteria. In this study, we aimed to select the peptides binding to EspB protein by phage display library and further investigate whether these peptides can decrease the extent of invasion and virulence of EPEC on host cells by targeting to EspB protein. The expression and purification of EspB protein from E. coli was demonstrated by Western blotting. The Ph.D. 12-mer peptide phage display library was used to screen the candidate peptides binding specifically to EspB protein. Furthermore, the affinity of these candidate peptides bound to EspB was identified by enzyme-linked immunosorbent assay (ELISA). Moreover, we investigated whether these screened peptides could decrease the adherence ratio of EPEC to HEp-2 cells with increasing concentration. Successful purification of EspB protein from pET21b-EspB-transformed E. coli was identified by Western blotting. Then, the candidate peptides including phages 6, 7, 8, and 12 were screened by the Ph.D. 12-mer peptide phage display library and ELISA test demonstrated that their affinity binding to EspB protein was high compared with the control. Functional analysis indicated that synthetic peptide-6 (YFPYSHTSPRQP) significantly decreased the adherence ratio of EPEC to HEp-2 cells with increasing concentration (P < 0.01). Peptide-6 (100 ug/mL) could lead to a 40 % decrease in the adherence ratio of EPEC to HEp-2 cells compared with control (P < 0.01). However, the other three peptides at different concentrations showed only a slight ability to block the adherence of EPEC to host cells. Our data provided a potential strategy to inhibit the adhesion of EPEC to epithelial cells by a candidate peptide targeted toward EspB protein. PMID- 27246499 TI - Potential of Pseudomonas putida PCI2 for the Protection of Tomato Plants Against Fungal Pathogens. AB - Tomato is one of the most economically attractive vegetable crops due to its high yields. Diseases cause significant losses in tomato production worldwide. We carried out Polymerase Chain Reaction studies to detect the presence of genes encoding antifungal compounds in the DNA of Pseudomonas putida strain PCI2. We also used liquid chromatography-electrospray tandem mass spectrometry to detect and quantify the production of compounds that increase the resistance of plants to diseases from culture supernatants of PCI2. In addition, we investigated the presence of 1-aminocyclopropane-1-carboxylic acid (ACC) deaminase in PCI2. Finally, PCI2 was used for inoculation of tomato seeds to study its potential biocontrol activity against Fusarium oxysporum MR193. The obtained results showed that no fragments for the encoding genes of hydrogen cyanide, pyoluteorin, 2,4 diacetylphloroglucinol, pyrrolnitrin, or phenazine-1-carboxylic acid were amplified from the DNA of PCI2. On the other hand, PCI2 produced salicylic acid and jasmonic acid in Luria-Bertani medium and grew in a culture medium containing ACC as the sole nitrogen source. We observed a reduction in disease incidence from 53.33 % in the pathogen control to 30 % in tomato plants pre-inoculated with PCI2 as well as increases in shoot and root dry weights in inoculated plants, as compared to the pathogenicity control. This study suggests that inoculation of tomato seeds with P. putida PCI2 increases the resistance of plants to root rot caused by F. oxysporum and that PCI2 produces compounds that may be involved at different levels in increasing such resistance. Thus, PCI2 could represent a non contaminating management strategy potentially applicable in vegetable crops such as tomato. PMID- 27246498 TI - Nitropelagi marinus gen. nov., sp. nov., Isolated From Seawater, Je-bu island, South Korea. AB - A Gram-stain-negative, non-spore forming, non-motile and aerobic strain, designated JB22(T), was isolated from seawater, Je-bu Island, South Korea. Strain JB22(T) was catalase and oxidase positive. Optimal growth of JB22(T) was observed at 30 degrees C and pH 7.0. NaCl tolerance range was 1-9 % (w/v) with an optimum of 2.0 % concentration. The phylogenetic analysis based on 16S rRNA gene sequence of strain JB22(T) showed the highest sequence similarity to those of Pelagicola litorisediminis D1-W8(T) (95.8 %), Roseovarius litoreus GSW-M15(T) (95.2 %), Roseovarius aestuarii SMK-122(T) (95.0 %), Donghicola eburmeus SW-277(T) (95.0 %), and Roseovarius halotolerans HJ50(T) (94.9 %). It contained ubiquine-10 as the major respiratory quinone and C18:1 omega7c (69.3 %), :0 (9.9 %), C18:1 omega7c 11-methyl (9.6 %) as the major fatty acid. The polar lipid profile included phosphatidylcholine, phosphatidylglycerol, and unidentified aminolipid. The DNA G+C content of the strain JB22(T) was 47 mol %. Based on physiological and chemotaxonomic characteristics, strain JB22(T) should be regarded as a new genus of the family Rhodobacteraceae, for which the Nitropelagi marinus gen. nov., sp. nov. is proposed. The type strain is JB22(T) (= KEMB 3001-101(T) = JCM 30822(T)). PMID- 27246500 TI - NCW2, a Gene Involved in the Tolerance to Polyhexamethylene Biguanide (PHMB), May Help in the Organisation of beta-1,3-Glucan Structure of Saccharomyces cerevisiae Cell Wall. AB - In the present work, we provide biological evidences supporting the participation of NCW2 gene in the mechanism responsible for cell tolerance to polyhexamethylene biguanide (PHMB), an antifungal agent. The growth rate of yeast cells exposed to this agent was significantly reduced in ?ncw2 strain and the mRNA levels of NCW2 gene in the presence of PHMB showed a 7-fold up-regulation. Moreover, lack of NCW2 gene turns yeast cell more resistant to zymolyase treatment, indicating that alterations in the beta-glucan network do occur when Ncw2p is absent. Computational analysis of the translated protein indicated neither catalytic nor transmembrane sites and reinforced the hypothesis of secretion and anchoring to cell surface. Altogether, these results indicated that NCW2 gene codes for a protein which participates in the cell wall biogenesis in yeasts and that Ncw2p might play a role in the organisation of the beta-glucan assembly. PMID- 27246501 TI - Competence, competency-based education, and undergraduate dental education: a discussion paper. AB - INTRODUCTION: The aim of undergraduate dental education is to provide competent dentists to serve societal needs and improve population oral healthcare. Competency-based education has influenced the development of dental education for decades but this term is problematic. This article explores components of competency-based undergraduate health professional education in order to help the dental profession have a better understanding of the context and purposes of undergraduate dental education. METHODS: This is a discussion paper based on a wide reading of the literature on the education of health professionals with a specific focus on competency-based undergraduate education. RESULTS AND DISCUSSION: Competence comprises an integration of knowledge, skills and attitudes indicating a capability to perform professional tasks safely and ethically. The process of becoming a competent practitioner is complex. Four characteristics of competency-based education are: curriculum components and content shaped by societal needs; focused on student-centred learning; learning achievement; and limited attention to time-based training and numerical targets. Alongside a competency-based approach, undergraduate dental education can be influenced by institutional features and external factors but these receive little consideration in the literature. CONCLUSION: Understanding competence, competency-based education, and institutional and external factors will help to improve educational quality, define roles and professional development for the dental educator, and inform further research. PMID- 27246502 TI - Two approaches to the clinical dilemma of treating TTP with therapeutic plasma exchange in patients with a history of anaphylactic reactions to plasma. AB - BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a rare but serious disease caused by autoantibody-mediated deficiency in von Willebrand factor (VWF) cleaving protease, ADAMTS-13. The primary acute treatment is therapeutic plasma exchange (TPE). However, some patients can develop allergic/anaphylactic reactions to the replacement (i.e., donor) plasma over time. Two potential treatment strategies for patients with TTP who demonstrate severe allergic reactions to plasma used for exchange were examined. METHODS: Two patients with TTP exacerbations who developed severe allergic reactions to donor plasma were identified. One patient's TPE was re-initiated with Octaplas, a lot-batched solvent and detergent treated, type-specific, pooled donor plasma product. The other patient was exchanged with primarily albumin, followed by slow incremental exposures to donor plasma to mitigate exposures and allergic risks. Both patients were assessed for anaphylaxis. RESULTS: Both treatment strategies were successful in preventing any further clinically significant allergic/anaphylactic reactions and facilitated both patients' TTP remissions. CONCLUSIONS: Based on our experience with two similar patients with TTP exacerbations and history of anaphylactic reactions to plasma during TPE, we have identified two possible treatment protocols to achieve remission in this clinical dilemma. Substituting Octaplas for standard plasma or, alternatively, using albumin with slowly increasing amounts of standard plasma may help to mitigate the risk of further anaphylactic adverse events. J. Clin. Apheresis 32:158-162, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27246504 TI - Human papillomavirus not detected in esophageal adenocarcinoma tumor specimens Reply. PMID- 27246503 TI - Malaria research and its influence on anti-malarial drug policy in Malawi: a case study. AB - BACKGROUND: In 1993, Malawi changed its first-line anti-malarial treatment for uncomplicated malaria from chloroquine to sulfadoxine-pyrimethamine (SP), and in 2007, it changed from SP to lumefantrine-artemether. The change in 1993 raised concerns about whether it had occurred timely and whether it had potentially led to early development of Plasmodium falciparum resistance to SP. This case study examined evidence from Malawi in order to assess if the policy changes were justifiable and supported by evidence. METHODS: A systematic review of documents and published evidence between 1984 and 1993, when chloroquine was the first-line drug, and 1994 and 2007, when SP was the first-line drug, was conducted herein. The review was accompanied with key informant interviews. RESULTS: A total of 1287 publications related to malaria drug policy changes in sub-Saharan Africa were identified. Using the inclusion criteria, four articles from 1984 to 1993 and eight articles from 1994 to 2007 were reviewed. Between 1984 and 1993, three studies reported on chloroquine poor efficacy prompting policy change according to WHO's recommendation. From 1994 to 2007, four studies conducted in the early years of policy change reported a high SP efficacy of above 80%, retaining it as a first-line drug. Unpublished sentinel site studies between 2005 and 2007 showed a reduced efficacy of SP, influencing policy change to lumefantrine-artemether. The views of key informants indicate that the switch from chloroquine to SP was justified based on local evidence despite unavailability of WHO's policy recommendations, while the switch to lumefantrine-artemether was uncomplicated as the country was following the recommendations from WHO. CONCLUSION: Ample evidence from Malawi influenced and justified the policy changes. Therefore, locally generated evidence is vital for decision making during policy change. PMID- 27246505 TI - Glycaemic control in type 1 diabetes mellitus among children and adolescents in a resource limited setting in Dar es Salaam - Tanzania. AB - BACKGROUND: Type 1 Diabetes Mellitus is a rapidly growing problem in Tanzania. Children and adolescents with type 1 diabetes have previously been found to have poor glycaemic control and high prevalence of complications. Strict glycaemic control reduces the incidence and progression of chronic complications. The aim of this study was to identify the factors associated with glycaemic control among children and adolescents. METHODS: A cross sectional study was done at the diabetes clinic for children and adolescents. Data on socioeconomic, demographic and diabetes specific variables including adherence, diabetes knowledge, caregivers knowledge and their involvement in the care of the child was obtained. Glycaemic control was assessed by measuring glycosylated hemoglobin. (HbA1C). Linear regression analysis was done to determine factors associated with glycaemic control RESULTS: Seventy-five participants were recruited into the study (51 % males). The mean HbA1c was 11.1 +/- 2.1 %. Children aged <10 years were found to have a significantly better glycaemic control (9.8 %) as compared to 10-14 year olds (11.5 %) and >14 year olds (11.4 %) (P value = 0.022). Sixty eight percent of patients had good adherence to insulin while adherence to blood glucose monitoring regimen was 48 % and to diet control was 28 %. Younger age, having the mother as the primary caregiver, better caregiver knowledge of diabetes, better adherence to blood glucose monitoring regimen and diabetes duration of less than 1 year were associated with better glycaemic control. In multivariate analysis, age, adherence to blood glucose monitoring regimen and the mother as the primary caregiver were found to independently predict glycaemic control (R(2) = 0.332, p value = 0.00). CONCLUSIONS: Children and adolescents with type 1 diabetes in Dar es Salaam have poor glycaemic control. In order to improve metabolic control, adherence to blood glucose monitoring should be encouraged and caregivers encouraged to participate in care of their children especially the adolescents. PMID- 27246506 TI - Co-administration of ginseng and ciprofloxacin ameliorates epididymo-orchitis induced alterations in sperm quality and spermatogenic cells apoptosis following infection in rats. AB - Korean red ginseng (KRG) may be a beneficial adjuvant along with ciprofloxacin to ameliorate devastating effects of epididymo-orchitis (EO) on male fertility. This study intends to assay the effects of KRG and ciprofloxacin on sperm quality and spermatogenic cells apoptosis in EO rats. We divided 54 adult rats into nine groups (n = 6 rats per group): control (CO), sham-operated (SH), EO (E); ciprofloxacin (C), EO-ciprofloxacin (EC), KRG (G), EO-KRG (EG), ciprofloxacin-KRG (CG) and EO-ciprofloxacin-KRG (ECG). We administered ciprofloxacin and KRG 48 hr after the Escherichia coli (E. coli) injection for 10 days. Bilateral orchiectomy was performed after one sperm cycle (14 days) following the last treatment with ciprofloxacin and KRG. Total and progressive motility of E, C and EC groups decreased. However, motility is improved in CG and ECG in comparison with these groups. The E group induced negative changes in the architecture of testes tissue and dramatic increase in apoptosis indices. Interestingly, co-administration of ciprofloxacin and KRG has dramatically improved Miller's and Johnsen's scores and decreased the apoptosis indices of animals in the ECG group. Combined treatment of ciprofloxacin and KRG may improve the quality of spermatozoa and attenuated apoptosis indices in the ECG group. PMID- 27246507 TI - People with dementia: what is known about their experience of cancer treatment and cancer treatment outcomes? A systematic review. AB - OBJECTIVE: The objective of the study is to report a systematic review of what is currently known about the experience of cancer treatment and cancer treatment in adults with dementia. METHODS: The analytic plan and inclusion/exclusion criteria were specified in advance of the search process in a protocol. Searches were conducted in MEDLINE, CINAHL, PsycINFO and the Cochrane Library for publications about people with cancer and a pre-existing dementia. Limits were English language; 2000 to 12/2015; adults; >18 years old. The search identified 5214 titles and abstracts that were assessed against eligibility criteria and 101 were selected for full-text examination by two researchers who agreed inclusion of nine papers, extracted data independently then conducted a content analysis and narrative synthesis. RESULTS: Nine studies conducted in four resource rich countries were included in the review. These studies evidence that when compared with other cancer patients, those with dementia are diagnosed at a later stage, receive less treatment, are more likely to experience complications from treatment and have poorer survival. The experience of supportive care and preferences of people with dementia receiving cancer services and cancer treatment have not been investigated. Research into how the cancer team manage the particular needs of people with dementia and their family members has been limited to one study that reported how a cancer team managed the particular needs of seven people with dementia. CONCLUSION: Further work is needed to establish practice guidelines for the management of cancer in people with dementia. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27246509 TI - Changing faces: can a new identity stop balding? PMID- 27246508 TI - Minimally invasive surgery for diaphragmatic diseases in neonates and infants. AB - Owing to recent advances in minimally invasive surgery (MIS), laparoscopic and thoracoscopic surgery have been gradually introduced for use in neonates and infants. This review focuses on two popular MIS procedures for diaphragmatic diseases in neonates and infants: congenital diaphragmatic hernia (CHD) repair and plication for diaphragmatic eventration. While several advantages of MIS are proposed for CDH repair in neonates, there are also some concerns, namely intraoperative hypercapnia and acidosis and a higher recurrence rate than open techniques. Thus, neonates with severe CDH, along with an unstable circulatory and respiratory status, may be unsuitable for MIS repair, and the use of selection criteria is, therefore, important in these patients. It is generally believed that a learning curve is associated with the higher recurrence rate. Contrary to CDH repair, no major disadvantages associated with the use of MIS for diaphragmatic eventration have been reported in the literature, other than technical difficulty. Thus, if technically feasible, all pediatric patients with diaphragmatic eventration requiring surgical treatment are potential candidates for MIS. Due to a shortage of studies on this procedure, the potential advantages of MIS compared to open techniques for diaphragmatic eventration, such as early recovery and more rapid extubation, need to be confirmed by further studies. PMID- 27246510 TI - Age-related effects of dexmedetomidine on myocardial contraction and coronary circulation in isolated guinea pig hearts. AB - Dexmedetomidine is a selective alpha2 adrenergic agonist. Although dexmedetomidine is widely used for sedation and analgesia, it frequently produces hypotension and bradycardia. The present study aimed to evaluate the effects of dexmedetomidine on cardiac function and coronary circulation using Langendorff perfused guinea pig hearts. Coronary perfusion pressure (CPP) and left ventricular pressure (LVP) were continuously monitored, and electric field stimulation (EFS) was applied to stimulate sympathetic nerve terminals. Dexmedetomidine almost completely inhibited the EFS-induced increase in LVP at all ages. The effect of dexmedetomidine on coronary artery resistance varied according to postnatal age, i.e., dexmedetomidine had little effect on CPP in young hearts (<4 weeks) but increased CPP by 10 mmHg at 4-8 weeks and by 15 mmHg at >8 weeks. The increase in CPP in adult hearts was inhibited by imiloxan, an alpha2B antagonist, and prazosin, an alpha1 antagonist. The results suggest that dexmedetomidine acts on alpha2 adrenergic receptors at sympathetic nerve terminals to suppress the release of norepinephrine. In addition, the findings suggest that dexmedetomidine directly affects alpha1 adrenoceptors and/or alpha2B adrenoceptors on coronary smooth muscles to increase CPP. The age-related changes in alpha adrenoceptor subtypes may be linked to the cardiodepressant effects of dexmedetomidine. PMID- 27246513 TI - Anti-Inflammatory Effects and Prediction of Blood Pressure Response by Baseline Inflammatory State in Catheter-Based Renal Denervation. AB - This retrospective analysis aimed to examine off-target effects on inflammatory and renal function parameters in n=78 subsequent patients treated with renal denervation (RDN) for resistant hypertension. Ambulatory and office blood pressure (ABP/OBP), serum creatinine, glomerular filtration rate (GFR), cystatin C, C-reactive protein (CRP), interleukin-6 (IL-6), and white blood cell count (WBC) were assessed before, 6 and 12 months after RDN. ABP was significantly reduced by -8.2/-3.8 mm Hg (P=.002/.021) at 1 year after RDN, while an initial OBP reduction was not sustained during follow-up. IL-6 levels significantly decreased by -0.5 pg/mL (P=.042) and by -1.7 pg/mL (P<.001) at 6 and 12 months, baseline IL-6 levels possibly predicting ABP response to RDN (r=-0.295; P=.020). Concurrently, leukocyte count was reduced by -0.5 * 103 /MUL (P=.017) and -0.8 * 103 /MUL (P<.001), respectively. Serum creatinine and GFR remained unchanged, but we observed a significant increase in cystatin C by 0.04 mg/L (P=.026) and 0.14 mg/L (P<.001) at 6 and 12 months after the intervention. PMID- 27246511 TI - Exploring ecological modelling to investigate factors governing the colonization success in nosocomial environment of Candida albicans and other pathogenic yeasts. AB - Two hundred seventy seven strains from eleven opportunistic species of the genus Candida, isolated from two Italian hospitals, were identified and analyzed for their ability to form biofilm in laboratory conditions. The majority of Candida albicans strains formed biofilm while among the NCAC species there were different level of biofilm forming ability, in accordance with the current literature. The relation between the variables considered, i.e. the departments and the hospitals or the species and their ability to form biofilm, was tested with the assessment of the probability associated to each combination. Species and biofilm forming ability appeared to be distributed almost randomly, although some combinations suggest a potential preference of some species or of biofilm forming strains for specific wards. On the contrary, the relation between biofilm formation and species isolation frequency was highly significant (R(2) around 0.98). Interestingly, the regression analyses carried out on the data of the two hospitals separately were rather different and the analysis on the data merged together gave a much lower correlation. These findings suggest that, harsh environments shape the composition of microbial species significantly and that each environment should be considered per se to avoid less significant statistical treatments. PMID- 27246512 TI - Genome stability versus transcript diversity. AB - Our genome is protected from the introduction of mutations by high fidelity replication and an extensive network of DNA damage response and repair mechanisms. However, the expression of our genome, via RNA and protein synthesis, allows for more diversity in translating genetic information. In addition, the splicing process has become less stringent over evolutionary time allowing for a substantial increase in the diversity of transcripts generated. The result is a diverse transcriptome and proteome that harbor selective advantages over a more tightly regulated system. Here, we describe mechanisms in place that both safeguard the genome and promote translational diversity, with emphasis on post transcriptional RNA processing. PMID- 27246516 TI - Group-based multimodal exercises integrated with cognitive-behavioural therapy improve disability, pain and quality of life of subjects with chronic neck pain: a randomized controlled trial with one-year follow-up. AB - OBJECTIVE: To evaluate the effect of a group-based multidisciplinary rehabilitation programme on disability, pain and quality of life in subjects with chronic neck pain. DESIGN: Randomized controlled trial. SETTING: Specialized rehabilitation centre. SUBJECTS: A total of 170 patients (mean age of 53 years (13); 121 females). INTERVENTIONS: The multidisciplinary group underwent a multidisciplinary rehabilitation programme combining multimodal exercises with psychologist-lead cognitive-behavioural therapy sessions. The general exercise group underwent general physiotherapy. Both groups followed group-based programmes once a week for ten weeks. Additionally, the multidisciplinary group met with the psychologist once a week for a 60-minute session. MAIN MEASURES: The Neck Disability Index (primary outcome), the Tampa Scale for Kinesiophobia, the Pain Catastrophizing Scale, a pain numerical rating scale and the Short-Form Health Survey. The participants were evaluated before, after training and after 12 months. RESULTS: A linear mixed model for repeated measures was used for each outcome measure. Significant effects ( p-value <0.001) were found over time and between groups for all outcome measures. After training, significant improvements were found for both groups for all outcome measures except kinesiophobia and catastrophizing, which did not change in the control group; however, the improvements were significantly greater for the multidisciplinary group. At 12 month follow-up a clinically meaningful between-group difference of 12.4 Neck Disability Index points was found for disability. CONCLUSIONS: A group-based multidisciplinary rehabilitation programme including cognitive-behavioural therapy was superior to group-based general physiotherapy in improving disability, pain and quality of life of subjects with chronic neck pain. The effects lasted for at least one year. PMID- 27246517 TI - Fibronectin adsorption on surface-modified polyetherurethanes and their differentiated effect on specific blood elements related to inflammatory and clotting processes. AB - After the introduction of a medical device into the body, adhesive proteins such as fibronectin (Fn) will adsorb to the surface of the biomaterial. Monocytes (MCs) will interact with these adsorbed proteins, and adopt either a proinflammatory and/or prowound healing phenotype, thereby influencing many blood interaction events including thrombogenesis. In this work, Fn adsorption as well as subsequent MC response and thrombus formation were investigated on two surfaces-modified polyetherurethanes (PEUs) using different surface modifiers: an anionic/dihydroxyl oligomeric (ADO) additive, known to enable cell adhesion, and a fluorinated polypropylene oxide oligomer (PPO), known to reduce platelet adhesion. Results indicated that at 24 h of MC culture, PEU-ADO and PEU-PPO promoted an anti-inflammatory character relative to the base PEU. Longer clotting times, based on a free hemoglobin assay, were also found on the two surface modified PEUs relative to the native one, suggesting their potential for the reduction of thrombus formation. In presence of a Fn monolayer, the surface modified PEUs conserved a lower thrombogenic character than the base PEU, and was however significantly decreased when compared to prior protein adsorption. Furthermore, Fn coatings increased the MC production levels of tumor necrosis factor-alpha and interleukin-10 at 24 h, while not affecting the anti inflammatory effect of the modifications relative to the base PEU. This finding was most prominent on PEU-PPO, suggesting that the interaction of the adsorbed Fn with blood cells was different for the two additives. Hence, the results highlighted differentiating effects of Fn adsorption on specific blood activating processes related to inflammatory and thrombotic responses. PMID- 27246518 TI - The gray phenotype and tristable phenotypic transitions in the human fungal pathogen Candida tropicalis. AB - Phenotypic plasticity, the ability to switch between different morphological types, plays critical roles in environmental adaptation, leading to infections, and allowing for sexual reproduction in pathogenic Candida species. Candida tropicalis, which is both an emerging human fungal pathogen and an environmental fungus, can switch between two heritable cell types termed white and opaque. In this study, we report the discovery of a novel phenotype in C. tropicalis, named the gray phenotype. Similar to Candida albicans and Candida dubliniensis, white, gray, and opaque cell types of C. tropicalis also form a tristable switching system, where gray cells are relatively small and elongated. In C. tropicalis, gray cells exhibit intermediate levels of mating competency and virulence in a mouse systemic infection model compared to the white and opaque cell types, express a set of cell type-enriched genes, and exhibit both common and species specific biological features. The key regulators of white-opaque transitions, Wor1 and Efg1, are not required for the gray phenotype. A comparative study of the gray phenotypes in C. tropicalis, C. albicans, and C. dubliniensis provides clues to explain the virulence properties and niche preferences of C. tropicalis. PMID- 27246519 TI - Reward deficiency and anti-reward in pain chronification. AB - Converging lines of evidence suggest that the pathophysiology of pain is mediated to a substantial degree via allostatic neuroadaptations in reward- and stress related brain circuits. Thus, reward deficiency (RD) represents a within-system neuroadaptation to pain-induced protracted activation of the reward circuits that leads to depletion-like hypodopaminergia, clinically manifested anhedonia, and diminished motivation for natural reinforcers. Anti-reward (AR) conversely pertains to a between-systems neuroadaptation involving over-recruitment of key limbic structures (e.g., the central and basolateral amygdala nuclei, the bed nucleus of the stria terminalis, the lateral tegmental noradrenergic nuclei of the brain stem, the hippocampus and the habenula) responsible for massive outpouring of stressogenic neurochemicals (e.g., norepinephrine, corticotropin releasing factor, vasopressin, hypocretin, and substance P) giving rise to such negative affective states as anxiety, fear and depression. We propose here the Combined Reward deficiency and Anti-reward Model (CReAM), in which biopsychosocial variables modulating brain reward, motivation and stress functions can interact in a 'downward spiral' fashion to exacerbate the intensity, chronicity and comorbidities of chronic pain syndromes (i.e., pain chronification). PMID- 27246520 TI - An Investigation into the Processing of Lexicalized English Blend Words: Evidence from Lexical Decisions and Eye Movements During Reading. AB - New words enter the language through several word formation processes [see Simonini (Engl J 55:752-757, 1966)]. One such process, blending, occurs when two source words are combined to represent a new concept (e.g., SMOG, BRUNCH, BLOG, and INFOMERCIAL). While there have been examinations of the structure of blends [see Gries (Linguistics 42:639-667, 2004) and Lehrer (Am Speech 73:3-28, 1998)], relatively little attention has been given to how lexicalized blends are recognized and if this process differs from other types of words. In the present study, blend words were matched to non-blend control words on length, familiarity, and frequency. Two tasks were used to examine blend processing: lexical decision and sentence reading. The results demonstrated that blend words were processed differently than non-blend control words. However, the nature of the effect varied as a function of task demands. Blends were recognized slower than control words in the lexical decision task but received shorter fixation durations when embedded in sentences. PMID- 27246521 TI - Development of Bengali Audio-Visual Test Battery for Assessment of Pragmatic Skills: Preliminary Normative Data Based on Educational Level. AB - Pragmatic competence may be disrupted due to psychological and neurological causes. For appropriate remedy and rehabilitation, a precise assessment of pragmatic skills is important. However, there is no test battery in the Bengali language, and consequently, there is no published data on pragmatic ability of Bengali speakers. Due to the vast diversity of the population, it becomes increasingly difficult to assess pragmatic ability of an individual without a proper knowledge of the normal variations. To address this problem we have developed a test battery in Bengali, and to begin with, we have administered it to one hundred and five (105) normal healthy persons having different levels of education. The four groups having 17 years and above, 15 to < 17 years, 12 to < 15 years and 10 to < 12 years of education yielded a normative score of 193, 189, 171 and 150, respectively. These normative scores will allow clinicians to make a proper assessment of patients suffering from pragmatic deficits and help avoid interpreting social differences as neurological deficits. PMID- 27246522 TI - Fish oil supplementation during pregnancy and allergic respiratory disease in the adult offspring. AB - BACKGROUND: Maternal supplementation with long-chain n-3 polyunsaturated fatty acids can have immunologic effects on the developing fetus through several anti inflammatory pathways. However, there is limited knowledge of the long-term programming effects. OBJECTIVE: In a randomized controlled trial from 1990 with 24 years of follow-up, our aim was to determine whether supplementation with 2.7 g of long-chain n-3 polyunsaturated fatty acids in pregnancy can reduce the risk of asthma in offspring and allergic respiratory disease. METHODS: The randomized controlled trial included 533 women who were randomly assigned to receive fish oil during the third trimester of pregnancy, olive oil, or no oil in the ratio 2:1:1. The offspring were followed in a mandatory national prescription register, with complete follow-up for prescriptions related to the treatment of asthma and allergic rhinitis as primary outcomes. Furthermore, the offspring were invited to complete a questionnaire (74% participated) and attend a clinical examination (47% participated) at age 18 to 19 years. RESULTS: In intention-to-treat analyses the probability of having had asthma medication prescribed was significantly reduced in the fish oil group compared with the olive oil group (hazard ratio, 0.54, 95% CI, 0.32-0.90; P = .02). The probability of having had allergic rhinitis medication prescribed was also reduced in the fish oil group compared with the olive oil group (hazard ratio, 0.70, 95% CI, 0.47-1.05; P = .09), but the difference was not statistically significant. Self-reported information collected at age 18 to 19 years supported these findings. No associations were detected with respect to lung function outcomes or allergic sensitization at 18 to 19 years of age. CONCLUSION: Maternal supplementation with fish oil might have prophylactic potential for long-term prevention of asthma in offspring. PMID- 27246524 TI - Specific T cells for the treatment of cytomegalovirus and/or adenovirus in the context of hematopoietic stem cell transplantation. PMID- 27246523 TI - IgG subclasses determine pathways of anaphylaxis in mice. AB - BACKGROUND: Animal models have demonstrated that allergen-specific IgG confers sensitivity to systemic anaphylaxis that relies on IgG Fc receptors (FcgammaRs). Mouse IgG2a and IgG2b bind activating FcgammaRI, FcgammaRIII, and FcgammaRIV and inhibitory FcgammaRIIB; mouse IgG1 binds only FcgammaRIII and FcgammaRIIB. Although these interactions are of strikingly different affinities, these 3 IgG subclasses have been shown to enable induction of systemic anaphylaxis. OBJECTIVE: We sought to determine which pathways control the induction of IgG1-, IgG2a-, and IgG2b-dependent passive systemic anaphylaxis. METHODS: Mice were sensitized with IgG1, IgG2a, or IgG2b anti-trinitrophenyl mAbs and challenged with trinitrophenyl-BSA intravenously to induce systemic anaphylaxis that was monitored by using rectal temperature. Anaphylaxis was evaluated in mice deficient for FcgammaRs injected with mediator antagonists or in which basophils, monocytes/macrophages, or neutrophils had been depleted. FcgammaR expression was evaluated on these cells before and after anaphylaxis. RESULTS: Activating FcgammaRIII is the receptor primarily responsible for all 3 models of anaphylaxis, and subsequent downregulation of this receptor was observed. These models differentially relied on histamine release and the contribution of mast cells, basophils, macrophages, and neutrophils. Strikingly, basophil contribution and histamine predominance in mice with IgG1- and IgG2b-induced anaphylaxis correlated with the ability of inhibitory FcgammaRIIB to negatively regulate these models of anaphylaxis. CONCLUSION: We propose that the differential expression of inhibitory FcgammaRIIB on myeloid cells and its differential binding of IgG subclasses controls the contributions of mast cells, basophils, neutrophils, and macrophages to IgG subclass-dependent anaphylaxis. Collectively, our results unravel novel complexities in the involvement and regulation of cell populations in IgG-dependent reactions in vivo. PMID- 27246525 TI - Daily global stress is associated with nocturnal asthma awakenings in school-age children. PMID- 27246526 TI - Angioedema attacks in patients with hereditary angioedema: Local manifestations of a systemic activation process. AB - Hereditary angioedema (HAE) caused by a deficiency of functional C1-inhibitor (C1INH) becomes clinically manifest as attacks of angioedema. C1INH is the main inhibitor of the contact system. Poor control of a local activation process of this system at the site of the attack is believed to lead to the formation of bradykinin (BK), which increases local vasopermeability and mediates angioedema on interaction with BK receptor 2 on the endothelium. However, several observations in patients with HAE are difficult to explain from a pathogenic model claiming a local activation process at the site of the angioedema attack. Therefore we postulate an alternative model for angioedema attacks in patients with HAE, which assumes a systemic, fluid-phase activation of the contact system to generate BK and its breakdown products. Interaction of these peptides with endothelial receptors that are locally expressed in the affected tissues rather than with receptors constitutively expressed by the endothelium throughout the whole body explains that such a systemic activation process results in local manifestations of an attack. In particular, BK receptor 1, which is induced on the endothelium by inflammatory stimuli, such as kinins and cytokines, meets the specifications of the involved receptor. The pathogenic model discussed here also provides an explanation for why angioedema can occur at multiple sites during an attack and why HAE attacks respond well to modest increases of circulating C1INH activity levels because inhibition of fluid-phase Factor XIIa and kallikrein requires lower C1INH levels than inhibition of activator-bound factors. PMID- 27246528 TI - Biochemical analysis of Centaurea depressa phenylalanine ammonia lyase (PAL) for biotechnological applications in phenylketonuria (PKU). AB - CONTEXT: Phenylketonuria (PKU) is the most common hereditary defect of phenylalanine hydroxylase (PAH) enzyme achieving the hydroxylation of phenylalanine (Phe). Phenylalanine ammonia lyase (PAL) converts Phe to a harmless metabolite, trans-cinnamic acid (TCA) in plants and PAL enzyme activity is fairly high in plants rich in flavonoids. OBJECTIVE: The study aimed the biochemical analysis of PAL form Centaurea depressa BIEB. (Asteraceae) a flavonoid rich plant. This study may form the main frame of future research efforts for the development of a plant preparation aimed for oral intake in PKU patients in an attempt to enrich their diet by allowing them to ingest some food stuff containing Phe without being exposed to complications. MATERIALS AND METHODS: PAL was partially purified from the leaves of C. depressa. Enzyme activity was determined in comparison with that of other herbs that reportedly have a high PAL activity. Enzyme optimization was achieved and the PAL protein was detected by western blotting. RESULTS: C. depressa PAL demonstrated high activity (34.9 +/- 0.6 U/mg protein). The enzyme was purified by 1.92-fold, which resulted in an activity of 53.30 +/- 0.2 U/mg protein. The high-performance liquid chromatography analyzes of the PAL activity both before and after purification were in agreement. Western blot of PAL exhibited a 70 kDa protein band. The optimum pH and temperature are pH 8.8 and 37 degrees C. The optimum activities under gastric and intestinal digestion conditions were observed at pH 4.0 and pH 8.0, respectively. DISCUSSION AND CONCLUSION: PAL activity of C. depressa is high, and does not disappear under different environmental conditions. This enzyme could be used for the development of dietary foods and biotechnological products for patients with PKU. PMID- 27246529 TI - Graphene from Alginate Pyrolysis as a Metal-Free Catalyst for Hydrogenation of Nitro Compounds. AB - Graphene obtained by pyrolysis of alginate at 900 degrees C under inert atmosphere and exfoliation is used as a metal-free catalyst for reduction of nitro to amino groups with hydrogen as a reagent. The process is general for aromatic and aliphatic, conjugated and isolated nitro groups, and occurs with low selectivity over hydrogenation of carbon-carbon double bonds. PMID- 27246530 TI - An Age-Related Mechanism of Emotion Regulation: Regulating Sadness Promotes Children's Learning by Broadening Information Processing. AB - Emotion regulation predicts positive academic outcomes like learning, but little is known about why. Effective emotion regulation likely promotes learning by broadening the scope of what may be attended to after an emotional event. One hundred twenty-six 6- to 13-year-olds' (54% boys) regulation of sadness was examined for changes in emotional experience, information processing, and memory for subsequent neutral information. Instructions to use specific strategies (distancing, positive reappraisal, rumination, or no strategy) predicted changes in sadness and happiness but did not predict information processing or memory. Effective regulation of sadness (regardless of instructions) predicted better memory through the indirect effect of broadened information processing but only for older children. Implications for emotion regulation processes in childhood are discussed. PMID- 27246527 TI - Sex-specific risk factors for childhood wheeze and longitudinal phenotypes of wheeze. AB - BACKGROUND: Although sexual dimorphism in wheeze and asthma prevalence are well documented, sex-specific risk factors for wheeze and longitudinal wheeze phenotypes have not been well elucidated. OBJECTIVE: By using a large prebirth cohort, this study aimed to identify sex-specific risk factors for wheeze from birth through midchildhood and identify distinct longitudinal wheeze phenotypes and the sex-specific risk factors associated with these phenotypes. METHODS: Mothers reported child wheeze symptoms over the past year approximately yearly on 9 occasions starting at age 1 year. We identified sex-specific predictors of wheeze, wheeze phenotypes, and sex-specific predictors of these phenotypes by using generalized estimating equations, latent class mixed models, and multinomial logistic analysis, respectively. RESULTS: A total of 1623 children had information on wheeze at 1 or more time points. Paternal asthma was a stronger predictor of ever wheezing in boys (odds ratio [OR], 2.15; 95% CI, 1.74 2.66) than in girls (OR, 1.53; 95% CI, 1.19-1.96; P for sex by paternal asthma interaction = .03), whereas being black or Hispanic, birth weight for gestational age z score, and breast-feeding duration had stronger associations among girls. We identified 3 longitudinal wheeze phenotypes: never/infrequent wheeze (74.1%), early transient wheeze (12.7%), and persistent wheeze (13.1%). Compared with never/infrequent wheeze, maternal asthma, infant bronchiolitis, and atopic dermatitis were associated with persistent wheeze in both sexes, but paternal asthma was associated with persistent wheeze in boys only (OR, 4.27; 95% CI, 2.33 7.83; P for sex by paternal asthma interaction = .02), whereas being black or Hispanic was a predictor for girls only. CONCLUSION: We identified sex-specific predictors of wheeze and longitudinal wheeze patterns, which might have important prognostic value and allow for a more personalized approach to wheeze and asthma treatment. PMID- 27246531 TI - A light-controlled switch after dual targeting of proliferating tumor cells via the membrane receptor EGFR and the nuclear protein Ki-67. AB - Using nanotechnology for optical manipulation of molecular processes in cells with high spatial and temporal precision promises new therapeutic options. Especially tumor therapy may profit as it requires a combination of both selectivity and an effective cell killing mechanism. Here we show a dual targeting approach for selective and efficient light-controlled killing of cells which are positive for epidermal growth factor receptor (EGFR) and Ki-67. Liposomes with the covalently linked EGFR antibody Erbitux enabled selective uptake of FITC-labeled Ki-67 antibody TuBB-9 in EGFR-positive cells pre-loaded with the photoactive dye BPD. After irradiation at 690 nm, BPD disrupted the endosomal membranes and delivered the antibodies to the nucleoli of the cells. The second irradiation at 490 nm activated the FITC-labeled TuBB-9, which caused inactivation of the Ki-67 protein and subsequent cell death via apoptosis. Efficient cell killing was possible at nanomolar concentrations of TuBB-9 due to the effective transport by immune liposomes and the high efficacy of the Ki-67 light-inactivation. Delivery of the liposomal constructs and cell destruction correlated well with the EGFR expression pattern of different cell lines (HeLa, OVCAR-5, MCF-7, and human fibroblasts), demonstrating an excellent selectivity. PMID- 27246532 TI - Engineering bacteriophage for a pragmatic low-resource setting bacterial diagnostic platform. AB - Bacteriophages represent multifaceted building blocks that can be incorporated as substitutes for, or in unison with other detection methods, to create powerful new diagnostics for the detection of bacteria. The ease of phage manipulation, production, and detection speed clearly highlights that there remains unrealized opportunities to leverage these phage-based components in diagnostics amenable to resource-limited settings. The passage of regulations like the Food Safety Modernization act, and the ever increasing extent of global trade and travel, will create further demand for these types of diagnostics. While phage-based diagnostics have begun to entering the market place, further research is needed to ensure the potential benefits of phage-based technologies for public health are fully realized. We are just beginning to explore the possibilities that phage based detection can offer us in the future. The combination of engineered phages as well as engineered enzymes could result in ultrasensitive detection systems for low-resource settings. Because the reporter enzyme is synthesized in vivo, we need to consider the options outside of normal enzyme reporters. In this case, common enzyme issues such as purification and long-term stability are less important. Phage-based diagnostics were conceptualized from out-of-the box thinking and the evolution of these systems should be as well. PMID- 27246534 TI - Direct Laser Writing of Porous-Carbon/Silver Nanocomposite for Flexible Electronics. AB - In this Research Article, we demonstrate a facile method for the fabrication of porous-carbon/silver nanocomposites using direct laser writing on polymeric substrates. Our technique uses a combination of CO2 laser-induced carbonization and selective silver deposition on a polyimide sheet to create flexible highly conductive traces. The localized laser irradiation selectively converts the polyimide to a highly porous and conductive carbonized film with superhydrophilic wettability. The resulting pattern allows for selective trapping of aqueous silver ionic ink solutions into the carbonized regions, which are converted to silver nanoparticle fillers upon an annealing step. Elemental and surface morphology analysis via XRD and SEM reveals a uniform coating of Ag nanoparticles on the porous carbon. The Ag/C composite lowers the sheet resistance of the original laser carbonized polyimide from 50 to 0.02 Omega/?. The resulting patterns are flexible and electromechanically robust with less than 0.6 Omega variation in resistance after >15000 bending flexion cycles at a radius of curvature of 5 mm. Furthermore, using this technique, we demonstrate the fabrication of a wireless resonant pressure sensor capable of detecting pressures ranging from 0 to 97 kPa with an average sensitivity of -26 kHz/kPa. PMID- 27246533 TI - The study of the relation of DNA repair pathway genes SNPs and the sensitivity to radiotherapy and chemotherapy of NSCLC. AB - To analyze the relation between SNPs in DNA repair pathway-related genes and sensitivity of tumor radio-chemotherapy, 26 SNPs in 20 DNA repair genes were genotyped on 176 patients of NSCLC undertaking radio-chemotherapy treatment. In squamous cell carcinoma (SCC), as the rs2228000, rs2228001 (XPC), rs2273953 (TP73), rs2279744 (MDM2), rs2299939 (PTEN) and rs8178085, rs12334811 (DNA-PKcs) affected the sensitivity to chemotherapy, so did the rs8178085, rs12334811 to radiotherapy. Moreover rs344781, rs2273953 and rs12334811 were related with the survival time of SCC. In general, the "good" genotype GG (rs12334811) showed greater efficacy of radio-chemotherapy and MSF (24 months) on SCC. In adenocarcinoma, as the rs2699887 (PIK3), rs12334811 (DNA-PKcs) influenced the sensitivity to chemotherapy, so did the rs2299939, rs2735343 (PTEN) to radiotherapy. And rs402710, rs80270, rs2279744 and rs2909430 impacted the survival time of the adenocarcinoma patients. Both GG (rs2279744) and AG (rs2909430) showed a shorter survival time (MFS = 6). Additionally, some SNPs such as rs2228000, rs2228001 and rs344781 were found to regulate the expression of DNA repair pathway genes through eQTLs dataset analysis. These results indicate that SNPs in DNA repair pathway genes might regulate the expression and affect the DNA damage repair, and thereby impact the efficacy of radio chemotherapy and the survival time of NSCLC. PMID- 27246535 TI - Enhanced chitinase production by Chitinolyticbacter meiyuanensis SYBC-H1 using staged pH control. AB - The pH of a microbiological culture is important for both cell growth and chitinase accumulation, but the optimal pH is not normally the same for both. The objective of this study was to investigate the effect of pH on chitinase production by Chitinolyticbacter meiyuanensis strain SYBC-H1 (ATCC BAA-2140) in a mineral medium. The results of batch culture at different pH values showed that the optimum pH for cell growth and chitinase production varied with time, although KOH produced the best results for cell growth and chitinase production, NaOH was chosen because of cost considerations. We designed a three-stage pH control strategy using NaOH as the neutralizing agent. Maximum cell growth (1.07 g dry cell weight/l) and maximum chitinase activity (13.6 U/ml) were observed after culture at 26 degrees C for 72 h in a mineral medium. These values were greater by 129% and 162%, respectively, and the length of time to attain maximum chitinase activity was decreased by 12 h, compared with results from an earlier study (Hao et al., 2011b). PMID- 27246536 TI - Vacuolar amino acid transporters upregulated by exogenous proline and involved in cellular localization of proline in Saccharomyces cerevisiae. AB - In the budding yeast Saccharomyces cerevisiae, the AVT genes (AVT1-7), which encode vacuolar amino acid transporters belonging to the amino acid vacuolar transport (AVT)-family, were significantly upregulated in response to exogenous proline. To reveal a novel role of the Avt proteins in proline homeostasis, we analyzed the effects of deletion or overexpression of the AVT genes on the subcellular distribution of amino acids after the addition of proline to the cells grown in minimal medium. Among seven AVT gene disruptants, avt1Delta and avt7Delta showed the lowest ratios of vacuolar proline. Consistently, overexpression of the AVT1 gene specifically enhanced the vacuolar localization of proline. Since double disruption of the AVT1 and AVT7 genes did not completely abrogate vacuolar accumulation of proline, it is presumed that Avt1 has a dominant role, and Avt7 and other Avt proteins have redundant functions, in the localization of proline into the vacuolar lumen. In contrast, deletion of the AVT3 gene increased vacuolar proline, although the highly expressed AVT3 gene interfered with the accumulation of proline in the vacuole. Based on these results, it appears that Avt3 is the major protein involved in the export of proline from the vacuole. We also observed vacuolar membrane localization of GFP fused Avt1, Avt3, and Avt7 proteins. Taken together, our data suggest that the AVT genes induced by exogenous proline are involved in the bidirectional transport of proline across the vacuolar membrane. PMID- 27246537 TI - Reconstruction of a chromatic response system in Escherichia coli. AB - Two-component signal transduction systems (TCS) are involved in widespread cellular responses to diverse signals from bacteria to plants. Cyanobacteria have evolved photoperception systems for efficient photosynthesis, and some histidine kinases are known to function as photosensors. In this study, we attempt to reconstruct the photoperception system in Escherichia coli to make an easily controllable ON/OFF switch for gene expressions. For this purpose, a CcaS-CcaR two-component system from Nostoc punctiforme was expressed with phycocyanobilin (PCB) producing enzymes in E. coli which carries a G-box-controlled reporter gene. We succeeded to endow E. coli with a gene activation switch that is regulated in a light-color dependent manner. The possibility of such a switch for the development of synthetic biology is pointed out. PMID- 27246538 TI - Piecing Together the Adrenal Cancer Puzzle. AB - Through an international collaboration, researchers have produced an extensive characterization of adrenocortical carcinoma, a rare endocrine cancer with limited treatment options. They found that the disease has three DNA methylation driven subtypes with distinct clinical outcomes, and is prone to genomic instability. PMID- 27246540 TI - 4-Trifluoromethyl-p-quinols as dielectrophiles: three-component, double nucleophilic addition/aromatization reactions. AB - In recent years, numerous methods have emerged for the synthesis of trifluoromethylated arenes based on the late-stage introduction of a trifluoromethyl group onto an aryl ring. In sharp comparison, the synthesis of trifluoromethylated arenes based on the pre-introduction of a trifluoromethyl group onto an "aromatic to be" carbon has rarely been addressed. It has been found that 4-trifluoromethyl-p-quinol silyl ethers, the readily available and relatively stable compounds, can act as dielectrophiles to be applied to multi component reactions for the synthesis of various trifluoromethylated arenes. Catalyzed by In(OTf)3, 4-trifluoromethyl-p-quinol silyl ethers react with C-, N-, and S-nucleophiles, respectively, in a regiospecific 1,2-addition manner to generate the corresponding highly reactive electrophilic intermediates. Further reaction of the in-situ generated electrophiles with a C-nucleophile followed by spontaneous aromatization enables the construction of functionalized trifluoromethyl arenes. This three-component, double nucleophilic addition/aromatization reaction based on the pre-introduction of a trifluoromethyl group onto an "aromatic to be" carbon provides a divergent strategy for the synthesis of trifluoromethylated arenes under mild reaction conditions in a single operation. PMID- 27246541 TI - Strict glucose control and artificial regulation of the NO-ADMA-DDAH system in order to prevent endothelial dysfunction. PMID- 27246539 TI - Obesity-Induced Inflammation and Desmoplasia Promote Pancreatic Cancer Progression and Resistance to Chemotherapy. AB - It remains unclear how obesity worsens treatment outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). In normal pancreas, obesity promotes inflammation and fibrosis. We found in mouse models of PDAC that obesity also promotes desmoplasia associated with accelerated tumor growth and impaired delivery/efficacy of chemotherapeutics through reduced perfusion. Genetic and pharmacologic inhibition of angiotensin-II type-1 receptor reverses obesity augmented desmoplasia and tumor growth and improves response to chemotherapy. Augmented activation of pancreatic stellate cells (PSC) in obesity is induced by tumor-associated neutrophils (TAN) recruited by adipocyte-secreted IL1beta. PSCs further secrete IL1beta, and inactivation of PSCs reduces IL1beta expression and TAN recruitment. Furthermore, depletion of TANs, IL1beta inhibition, or inactivation of PSCs prevents obesity-accelerated tumor growth. In patients with pancreatic cancer, we confirmed that obesity is associated with increased desmoplasia and reduced response to chemotherapy. We conclude that cross-talk between adipocytes, TANs, and PSCs exacerbates desmoplasia and promotes tumor progression in obesity. SIGNIFICANCE: Considering the current obesity pandemic, unraveling the mechanisms underlying obesity-induced cancer progression is an urgent need. We found that the aggravation of desmoplasia is a key mechanism of obesity-promoted PDAC progression. Importantly, we discovered that clinically available antifibrotic/inflammatory agents can improve the treatment response of PDAC in obese hosts. Cancer Discov; 6(8); 852-69. (c)2016 AACR.See related commentary by Bronte and Tortora, p. 821This article is highlighted in the In This Issue feature, p. 803. PMID- 27246543 TI - Balancing SR Ca(2+) uptake and release in the cycle of heart rhythm. PMID- 27246542 TI - Understanding complexity of physiology by combined molecular simulations and experiments: anion channels as a proof of concept. PMID- 27246544 TI - Exercise-induced cardiac fatigue: the need for speed. PMID- 27246545 TI - The plateau phase is a slippery slope: raising blood pressure may lower brain perfusion. PMID- 27246546 TI - TMEM16F: function from (iso)form. PMID- 27246547 TI - Advances in intracellular Ca(2+) signalling. PMID- 27246548 TI - Extracellular vesicles in cardiovascular disease: focus on vascular calcification. PMID- 27246549 TI - Investigating the effect of exercise duration on functional and biochemical perturbations in the human heart: total work or 'isoeffort' matching? PMID- 27246550 TI - Reply from Glenn M. Stewart, Justin J. Kavanagh, Luke J. Haseler and Surendran Sabapathy. PMID- 27246551 TI - Inactivation of the intrinsic muscle clock does not cause sarcopenia. PMID- 27246552 TI - Reply from Elizabeth Schroder, Brian Hodge, Lance Riley, Xiping Zhang and Karyn Esser. PMID- 27246554 TI - Three Rare Anomalies of the Large Vessels in an Infant with Tetralogy of Fallot. AB - Isolated left subclavian artery (LSA) from the pulmonary artery (PA) is a very rare vascular anomaly. We report a case of abnormal origin of the LSA from the PA via a very large ductus arteriosus (DA) in association with a rare communication between the left common carotid artery (LCCA) and the LSA in a patient with tetralogy of Fallot. doi: 10.1111/jocs.12770 (J Card Surg 2016;31:461-463). PMID- 27246553 TI - Quantitative proteome profiling of dystrophic dog skeletal muscle reveals a stabilized muscular architecture and protection against oxidative stress after systemic delivery of MuStem cells. AB - Proteomic profiling plays a decisive role in the elucidation of molecular signatures representative of a specific clinical context. MuStem cell based therapy represents a promising approach for clinical applications to cure Duchenne muscular dystrophy (DMD). To expand our previous studies collected in the clinically relevant DMD animal model, we decided to investigate the skeletal muscle proteome 4 months after systemic delivery of allogenic MuStem cells. Quantitative proteomics with isotope-coded protein labeling was used to compile quantitative changes in the protein expression profiles of muscle in transplanted Golden Retriever muscular dystrophy (GRMD) dogs as compared to Golden Retriever muscular dystrophy dogs. A total of 492 proteins were quantified, including 25 that were overrepresented and 46 that were underrepresented after MuStem cell transplantation. Interestingly, this study demonstrates that somatic stem cell therapy impacts on the structural integrity of the muscle fascicle by acting on fibers and its connections with the extracellular matrix. We also show that cell infusion promotes protective mechanisms against oxidative stress and favors the initial phase of muscle repair. This study allows us to identify putative candidates for tissue markers that might be of great value in objectively exploring the clinical benefits resulting from our cell-based therapy for DMD. All MS data have been deposited in the ProteomeXchange with identifier PXD001768 (http://proteomecentral.proteomexchange.org/dataset/PXD001768). PMID- 27246555 TI - Activity of phosphino palladium(II) and platinum(II) complexes against HIV-1 and Mycobacterium tuberculosis. AB - Treatment of human immunodeficiency virus (HIV) is currently complicated by increased prevalence of co-infection with Mycobacterium tuberculosis. The development of drug candidates that offer the simultaneous management of HIV and tuberculosis (TB) would be of great benefit in the holistic treatment of HIV/AIDS, especially in sub-Saharan Africa which has the highest global prevalence of HIV-TB coinfection. Bis(diphenylphosphino)-2-pyridylpalladium(II) chloride (1), bis(diphenylphosphino)-2-pyridylplatinum(II) chloride (2), bis(diphenylphosphino)-2-ethylpyridylpalladium(II) chloride (3) and bis(diphenylphosphino)-2-ethylpyridylplatinum(II) (4) were investigated for the inhibition of HIV-1 through interactions with the viral protease. The complexes were subsequently assessed for biological potency against Mycobacterium tuberculosis H37Rv by determining the minimal inhibitory concentration (MIC) using broth microdilution. Complex (3) showed the most significant and competitive inhibition of HIV-1 protease (p = 0.014 at 100 uM). Further studies on its in vitro effects on whole virus showed reduced viral infectivity by over 80 % at 63 uM (p < 0.05). In addition, the complex inhibited the growth of Mycobacterium tuberculosis at an MIC of 5 uM and was non-toxic to host cells at all active concentrations (assessed by tetrazolium dye and real time cell electronic sensing). In vitro evidence is provided here for the possibility of utilizing a single metal-based compound for the treatment of HIV/AIDS and TB. PMID- 27246557 TI - Sternoclavicular joint infection caused by Coxiella burnetii: a case report. AB - BACKGROUND: Few cases of Q fever osteoarticular infection have been reported, with chronic osteomyelitis as the most common manifestation of Q fever osteoarticular infection. Here we present the case of a sternoclavicular joint infection caused by Coxiella burnetii and localized by positron emission tomography scanning. CASE PRESENTATION: A 67-year-old French man from south France was hospitalized for fever and confusion. An examination revealed subclavicular and axillary lymph node enlargement. Computed tomography scanning and transesophageal echocardiogram were normal, and magnetic resonance imaging scanning did not reveal signs of infection. An immunofluorescence assay of an acute serum sample was positive for C. burnetii and he was treated with 200 mg doxycycline for 21 days. An immunofluorescence assay of convalescent serum sampled after 2 months revealed very high C. burnetii antibody titers. To localize the site of the infection, we performed positron emission tomography scanning, which revealed intense fluorodeoxyglucose uptake in his right sternoclavicular joint; treatment with 200 mg oral doxycycline daily and 200 mg oral hydroxychloroquine three times daily for 18 months was initiated. CONCLUSIONS: Q fever articular infections may be undiagnosed, and we strongly urge the use of positron emission tomography scanning in patients with high C. burnetii antibody titers to localize the site of C. burnetii infection. PMID- 27246556 TI - Fluzone(r) intra-dermal (Intanza(r)/Istivac(r) Intra-dermal): An updated overview. AB - Influenza is a highly contagious respiratory acute viral disease which imposes a very heavy burden both in terms of epidemiology and costs, in the developed countries as well as in the developing ones. It represents a serious public health concern and vaccination constitutes an important tool to reduce or at least mitigate its burden. Despite the existence of a broad armamentarium against influenza and despite all the efforts and recommendations of international organisms to broaden immunization, influenza vaccination coverage is still far from being optimal. This, taken together with logistic and technical difficulties that can result into vaccine shortage, makes intra-dermal (ID) vaccines, such as Fluzone(r) ID and Intanza(r), particularly attractive. ID vaccines are comparable and, in some cases, superior to intra-muscular/sub-cutaneous vaccines in terms of immunogenicity, safety, reactogenicity, tolerability and cross-protection profiles, as well as in terms of patient preference, acceptance and vaccine selection. Further advances, such as Fluzone(r) ID with alternative B strains and Quadrivalent Fluzone(r) ID or the possibility of self-administering the vaccines, make influenza ID vaccines even more valuable. PMID- 27246558 TI - First molecular phylogeny of scorpions of the family Buthidae from India. AB - Scorpions of the family Buthidae are widespread species in India. While studies are available on diversity and distribution of Indian buthid scorpions, no information is available on the phylogenetic relationships among the members of the family, within India and Asia in general. In the current study, we provide the first molecular phylogeny of buthid scorpions from central western India based on the mitochondrial cytochrome oxidase subunit I (COI) gene. Our analysis confirms the current placement of the species, previously assigned to Mesobuthus in the genus Hottentotta. However, the analysis also suggests that the member of this genus from India form a monophyletic group distinct from the members of Hottentotta from Africa. Species of Lychas formed a monophyletic group. Although Orthochirus was nested within the larger clade of buthidae comprising genera such as Androctonus, Buthacus, Buthus and Odontobuthus, the exact phylogenetic placement will require more taxonomic sampling of the known genera of Buthidae. We also show that there is a substantial genetic variation among the populations of medically important scorpion species Hottentotta tamulus, and the genetic distance is linearly correlated with the geographical distance between the populations. PMID- 27246559 TI - Neuronal commitment of human circulating multipotent cells by carbon nanotube polymer scaffolds and biomimetic peptides. AB - AIM: We aimed to set up a self-standing, biomimetic scaffold system able to induce and support per se neuronal differentiation of autologous multipotent cells. MATERIALS & METHODS: We isolated a population of human circulating multipotent cells (hCMCs), and used carbon nanotube/polymer nanocomposite scaffolds to mimic electrical/nanotopographical features of the neural environment, and biomimetic peptides reproducing axon guidance cues from neural proteins. RESULTS: hCMCs showed high degree of stemness and multidifferentiative potential; stimuli from the scaffolds and biomimetic peptides could induce and boost hCMC differentiation toward neuronal lineage despite the absence of exogenously added, specific growth factors. CONCLUSION: This work suggests the scaffold-peptides system combined with autologous hCMCs as a functional biomimetic, self-standing prototype for neural regenerative medicine applications. PMID- 27246560 TI - Bio-inspired sustainable and green synthesis of plasmonic Ag/AgCl nanoparticles for enhanced degradation of organic compound from aqueous phase. AB - In the current study, we report the utilization of the biogenic potential of Benincasa hispida (ash gourd) peel extract for the synthesis of Ag embedded AgCl nanoparticles nanoparticles (Ag/AgCl NPs) without the use of any external organic solvents. The appearance of dark brown color from the pale yellow color confirmed the formation of Ag/AgCl nanoparticles which was further validated by absorbance peak using UV-visible spectroscopy. The phytochemicals (flavones) present in the B. hispida peel extract acts as a reducing/stabilizing agents. The morphology and size of the synthesized NPs were characterized by transmission electron microscope (TEM), selected area electron microscope (SAED) and high resolution transmission electron microscope (HR-TEM). FT-IR spectra of the B. hispida peel extract and after the development of nanoparticles are determined to identify the functional groups responsible for the conversion of metal ions to metal nanoparticles. The synthesized nanoparticles showed an excellent photocatalytic property in the degradation of toxic dye like malachite green oxalate under sunlight irradiation. For the first time, malachite green oxalate dye was degraded by Ag/AgCl nanoparticles under sunlight irradiation. PMID- 27246561 TI - Enhanced phytoremediation of cadmium polluted water through two aquatic plants Veronica anagallis-aquatica and Epilobium laxum. AB - Toxic metal-contaminated water is a major threat to sustainable agriculture and environment. Plants have the natural ability to absorb and concentrate essential elements in its tissues from water solution, and this ability of plants can be exploited to remove heavy/toxic metals from the contaminated water. For this purpose, two plants Veronica anagallis-aquatica and Epilobium laxum were hydroponically studied. The effect of different fertilizers (NPK) and plant growth regulators (GA3 and IAA) were evaluated on growth, biomass, free proline, phenolics, and chlorophyll contents, and their role in Cd phytoaccumulation was investigated. Results showed that in both plants, fertilizer addition to media (treatment T4) produced the highest significant increase in growth, biomass (fresh and dry), cadmium concentration, proline, phenolics, and chlorophyll concentrations. The significant effect of GA3 in combination with NPK foliar spray (treatment T12) was observed on most of the growth parameters, Cd concentration, and proline and phenolic contents of the plants. The free proline and total phenolics showed positive correlation with cadmium concentration within plant tissues. Proline showed significantly positive correlation with phenolic contents of root and shoot. Veronica plant demonstrated the hyperaccumulator potential for cadmium as bioconcentration factor (BCF >1) which was much higher than 1, while Epilobium plant showed non-hyperaccumulator potential. It is recommended for further study to investigate the role of Veronica plant for other metals and to study the role of phenolics and proline contents in heavy metal phytoextraction by various plant species. PMID- 27246562 TI - Pilot scale thin film plate reactors for the photocatalytic treatment of sugar refinery wastewater. AB - Pilot scale thin film plate reactors (TFPR) were fabricated to study the solar photocatalytic treatment of wastewater obtained from the secondary treatment plant of a sugar refinery. Silver-impregnated titanium dioxide (TiO2) was prepared by a facile chemical reduction method, characterized, and immobilized onto the surface of ceramic tiles used in the pilot scale reactors. On 8 h of solar irradiation, percentage reduction of chemical oxygen demand (COD) of the wastewater by Ag/TiO2, pure TiO2, and control (without catalyst) TFPR was about 95, 86, and 22 % respectively. The effects of operational parameters such as, flow rate, pH, and addition of hydrogen peroxide (H2O2) were optimized as they influence the rate of COD reduction. Under 3 h of solar irradiation, 99 % COD reduction was observed at an optimum flow rate of 15 L h(-1), initial pH of 2, and addition of 5 mM of H2O2. The results show that Ag/TiO2 TFPR could be effectively used for the tertiary treatment of sugar refinery effluent using sunlight as the energy source. The treated water could be reused for industrial purposes, thus reducing the water footprint of the industry. Graphical Abstract Sugar refinery effluent treatment by solar photocatalytic TFPR. PMID- 27246563 TI - Fenced cultivation of water hyacinth for cyanobacterial bloom control. AB - To achieve the goals of harmful cyanobacterial bloom control and nutrient removal, an eco-engineering project with water hyacinth planted in large-scale enclosures was conducted based on meteorological and hydrographical conditions in Lake Dianchi. Water quality, cyanobacteria distribution, and nutrient (TN, TP) bioaccumulation were investigated. Elevated concentrations of N and P and low Secchi depth (SD) were relevant to large amount of cyanobacteria trapped in regions with water hyacinth, where biomass of the dominant cyanobacteria Microcystis (4.95 * 10(10) cells L(-1)) was more than 30-fold compared with values of the control. A dramatic increase of TN and TP contents in the plants was found throughout the sampling period. Results from the present study confirmed the great potential to use water hyacinth for cyanobacterial bloom control and nutrient removal in algal lakes such as Lake Dianchi. PMID- 27246564 TI - Soil quality is key for planning and managing urban allotments intended for the sustainable production of home-consumption vegetables. AB - The growing importance of urban allotments in planning and managing urban areas is due to the combined positive effects on ecosystem services, the economy and human well-being, especially of groups of the urban population that can be vulnerable (e.g. the elderly, immigrants, low-income families). Some studies have highlighted the potential risk of contamination by metals of vegetables grown in urban areas and the lack of appropriate site-specific risk assessments. However, surveys are still lacking on the possibilities of using urban soil as a good substrate to produce vegetables for home consumption. We assessed the soil quality in two areas in Pisa (Italy), one intended for urban horticulture and the other already cultivated for that purpose. We analysed the soils for the main chemical and physical characteristics (texture, bulk density, water stability index, pH, cation exchange capacity, organic carbon, total nitrogen, phosphorous) and elements (Pb, Cu, Ni, Cr, Zn, Cd, As, K, Al and Mn). Our results showed that both areas had physical and chemical heterogeneity due to the effects of urbanization and to the different cultivation techniques employed. The metal content was lower than the guidelines limits, and the soil conditions (pH = 8) greatly reduced the metal mobility. Copper concentration in some of the cultivated area samples was higher than the limits, representing a possible stress factor for the microbial biodiversity and fauna. Our findings demonstrate that site-specific surveys are necessary before planning urban cultivation areas, and educating urban gardeners regarding sustainable cultivation techniques is a priority for a safe environment. PMID- 27246565 TI - Hypothesizing Music Intervention Enhances Brain Functional Connectivity Involving Dopaminergic Recruitment: Common Neuro-correlates to Abusable Drugs. AB - The goal of this review is to explore the clinical significance of music listening on neuroplasticity and dopaminergic activation by understanding the role of music therapy in addictive behavior treatment. fMRI data has shown that music listening intensely modifies mesolimbic structural changes responsible for reward processing (e.g., nucleus accumbens [NAc]) and may control the emotional stimuli's effect on autonomic and physiological responses (e.g., hypothalamus). Music listening has been proven to induce the endorphinergic response blocked by naloxone, a common opioid antagonist. NAc opioid transmission is linked to the ventral tegmental area (VTA) dopamine release. There are remarkable commonalities between listening to music and the effect of drugs on mesolimbic dopaminergic activation. It has been found that musical training before the age of 7 results in changes in white-matter connectivity, protecting carriers with low dopaminergic function (DRD2A1 allele, etc.) from poor decision-making, reward dependence, and impulsivity. In this article, we briefly review a few studies on the neurochemical effects of music and propose that these findings are relevant to the positive clinical findings observed in the literature. We hypothesize that music intervention enhances brain white matter plasticity through dopaminergic recruitment and that more research is needed to explore the efficacy of these therapies. PMID- 27246566 TI - Omega-3 Fatty Acids and Mood Stabilizers Alter Behavioural and Energy Metabolism Parameters in Animals Subjected to an Animal Model of Mania Induced by Fenproporex. AB - Studies have shown that changes in energy metabolism are involved in the pathophysiology of bipolar disorder (BD). It was suggested that omega-3 (omega3) fatty acids have beneficial properties in the central nervous system and that this fatty acid plays an important role in energy metabolism. Therefore, the study aimed to evaluate the effect of omega3 fatty acids alone and in combination with lithium (Li) or valproate (VPA) on behaviour and parameters of energy metabolism in an animal model of mania induced by fenproporex. Our results showed that co-administration of omega3 fatty acids and Li was able to prevent and reverse the increase in locomotor and exploratory activity induced by fenproporex. The combination of omega3 fatty acids with VPA was only able to prevent the fenproporex-induced hyperactivity. For the energy metabolism parameters, our results showed that the administration of Fen for the reversal or prevention protocol inhibited the activities of succinate dehydrogenase, complex II and complex IV in the hippocampus. However, hippocampal creatine kinase (CK) activity was decreased only for the reversal protocol. The omega3 fatty acids, alone and in combination with VPA or Li, prevented and reversed the decrease in complex II, IV and succinate dehydrogenase activity, whereas the decrease in CK activity was only reversed after the co-administration of omega3 fatty acids and VPA. In conclusion, our results showed that the omega3 fatty acids combined with VPA or Li were able to prevent and reverse manic-like hyperactivity and the inhibition of energy metabolism in the hippocampus, suggesting that omega3 fatty acids may play an important role in the modulation of behavioural parameters and energy metabolism. PMID- 27246567 TI - Effect of Varenicline Combined with High-Dose Alcohol on Craving, Subjective Intoxication, Perceptual Motor Response, and Executive Cognitive Function in Adults with Alcohol Use Disorders: Preliminary Findings. AB - BACKGROUND: Varenicline has been found to decrease alcohol-motivated behaviors. Recent warnings regarding aversive events associated with varenicline used in conjunction with alcohol warrant further investigation into the safety of the drug when combined with alcohol. The purpose of this preliminary investigation was to examine the effect of combining varenicline with a high, fixed dose of alcohol on subjective reactivity and cognitive function in adults with alcohol use disorders (AUDs). METHODS: This double-blind, placebo-controlled preliminary investigation examined the effects of varenicline (0, 1, 2 mg/d) on subjective reactivity, cognition, perceptual motor function, and physiologic reactivity to a fixed dose of alcohol (vs. nonalcohol control beverage) using an established laboratory paradigm in smokers and nonsmokers meeting criteria for AUDs (n = 44). All participants had completed a parent varenicline study evaluating alcohol self administration. Each subject completed 2 fixed-dose laboratory sessions assessing reactivity to a high-dose alcohol (0.08 g/dl) or a nonalcoholic control beverage, order counterbalanced. RESULTS: Varenicline attenuated alcohol-related increases in subjective intoxication and alcohol-related decreases in executive cognitive function. At baseline, varenicline reduced alcohol craving and diastolic blood pressure, and increased associative learning, working memory, and perceptual motor function. Varenicline produced nonspecific effects on diastolic blood pressure and heart rate. Overall, there were few differences in effects between 1 and 2 mg/d varenicline versus placebo. CONCLUSIONS: These preliminary results continue to support the safety and use of varenicline in combination with alcohol in individuals meeting criteria for AUDs. PMID- 27246568 TI - Interrogating Genes That Mediate Chlamydia trachomatis Survival in Cell Culture Using Conditional Mutants and Recombination. AB - Intracellular bacterial pathogens in the family Chlamydiaceae are causes of human blindness, sexually transmitted disease, and pneumonia. Genetic dissection of the mechanisms of chlamydial pathogenicity has been hindered by multiple limitations, including the inability to inactivate genes that would prevent the production of elementary bodies. Many genes are also Chlamydia-specific genes, and chlamydial genomes have undergone extensive reductive evolution, so functions often cannot be inferred from homologs in other organisms. Conditional mutants have been used to study essential genes of many microorganisms, so we screened a library of 4,184 ethyl methanesulfonate-mutagenized Chlamydia trachomatis isolates for temperature-sensitive (TS) mutants that developed normally at physiological temperature (37 degrees C) but not at nonphysiological temperatures. Heat sensitive TS mutants were identified at a high frequency, while cold-sensitive mutants were less common. Twelve TS mutants were mapped using a novel markerless recombination approach, PCR, and genome sequencing. TS alleles of genes that play essential roles in other bacteria and chlamydia-specific open reading frames (ORFs) of unknown function were identified. Temperature-shift assays determined that phenotypes of the mutants manifested at distinct points in the developmental cycle. Genome sequencing of a larger population of TS mutants also revealed that the screen had not reached saturation. In summary, we describe the first approach for studying essential chlamydial genes and broadly applicable strategies for genetic mapping in Chlamydia spp. and mutants that both define checkpoints and provide insights into the biology of the chlamydial developmental cycle. IMPORTANCE: Study of the pathogenesis of Chlamydia spp. has historically been hampered by a lack of genetic tools. Although there has been recent progress in chlamydial genetics, the existing approaches have limitations for the study of the genes that mediate growth of these organisms in cell culture. We used a genetic screen to identify conditional Chlamydia mutants and then mapped these alleles using a broadly applicable recombination strategy. Phenotypes of the mutants provide fundamental insights into unexplored areas of chlamydial pathogenesis and intracellular biology. Finally, the reagents and approaches we describe are powerful resources for the investigation of these organisms. PMID- 27246569 TI - The Bacterial iprA Gene Is Conserved across Enterobacteriaceae, Is Involved in Oxidative Stress Resistance, and Influences Gene Expression in Salmonella enterica Serovar Typhimurium. AB - The iprA gene (formerly known as yaiV or STM0374) is located in a two-gene operon in the Salmonella enterica serovar Typhimurium genome and is associated with altered expression during spaceflight and rotating-wall-vessel culture conditions that increase virulence. However, iprA is uncharacterized in the literature. In this report, we present the first targeted characterization of this gene, which revealed that iprA is highly conserved across Enterobacteriaceae We found that S Typhimurium, Escherichia coli, and Enterobacter cloacae DeltaiprA mutant strains display a multi-log-fold increase in oxidative stress resistance that is complemented using a plasmid-borne wild-type (WT) copy of the S Typhimurium iprA gene. This observation was also associated with increased catalase activity, increased S Typhimurium survival in macrophages, and partial dependence on the katE gene and full dependence on the rpoS gene. Our results indicate that IprA protein activity is sensitive to deletion of the N- and C-terminal 10 amino acids, while a region that includes amino acids 56 to 80 is dispensable for activity. RNA sequencing (RNA-Seq) analysis revealed several genes altered in expression in the S Typhimurium DeltaiprA mutant strain compared to the WT, including those involved in fimbria formation, spvABCD-mediated virulence, ethanolamine utilization, the phosphotransferase system (PTS) transport, and flagellin phase switching from FlgB to FliC (likely a stochastic event) and several genes of hypothetical or putative function. IMPORTANCE: Overall, this work reveals that the conserved iprA gene measurably influences bacterial biology and highlights the pool of currently uncharacterized genes that are conserved across bacterial genomes. These genes represent potentially useful targets for bacterial engineering, vaccine design, and other possible applications. PMID- 27246572 TI - Rotation of Vibrio fischeri Flagella Produces Outer Membrane Vesicles That Induce Host Development. AB - Using the squid-vibrio association, we aimed to characterize the mechanism through which Vibrio fischeri cells signal morphogenesis of the symbiotic light emitting organ. The symbiont releases two cell envelope molecules, peptidoglycan (PG) and lipopolysaccharide (LPS) that, within 12 h of light organ colonization, act in synergy to trigger normal tissue development. Recent work has shown that outer membrane vesicles (OMVs) produced by V. fischeri are sufficient to induce PG-dependent morphogenesis; however, the mechanism(s) of OMV release by these bacteria has not been described. Like several genera of both beneficial and pathogenic bacteria, V. fischeri cells elaborate polar flagella that are enclosed by an extension of the outer membrane, whose function remains unclear. Here, we present evidence that along with the well-recognized phenomenon of blebbing from the cell's surface, rotation of this sheathed flagellum also results in the release of OMVs. In addition, we demonstrate that most of the development inducing LPS is associated with these OMVs and that the presence of the outer membrane protein OmpU but not the LPS O antigen on these OMVs is important in triggering normal host development. These results also present insights into a possible new mechanism of LPS release by pathogens with sheathed flagella. IMPORTANCE: Determining the function(s) of sheathed flagella in bacteria has been challenging, because no known mutation results only in the loss of this outer membrane-derived casing. Nevertheless, the presence of a sheathed flagellum in such host-associated genera as Vibrio, Helicobacter, and Brucella has led to several proposed functions, including physical protection of the flagella and masking of their immunogenic flagellins. Using the squid-vibrio light organ symbiosis, we demonstrate another role, that of V. fischeri cells require rotating flagella to induce apoptotic cell death within surface epithelium, which is a normal step in the organ's development. Further, we present evidence that this rotation releases apoptosis-triggering lipopolysaccharide in the form of outer membrane vesicles. Such release may also occur by pathogens but with different outcomes for the host. PMID- 27246571 TI - Distinct Residues Contribute to Motility Repression and Autoregulation in the Proteus mirabilis Fimbria-Associated Transcriptional Regulator AtfJ. AB - Proteus mirabilis contributes to a significant number of catheter-associated urinary tract infections, where coordinated regulation of adherence and motility is critical for ascending disease progression. Previously, the mannose-resistant Proteus-like (MR/P) fimbria-associated transcriptional regulator MrpJ has been shown to both repress motility and directly induce the transcription of its own operon; in addition, it affects the expression of a wide range of cellular processes. Interestingly, 14 additional mrpJ paralogs are included in the P. mirabilis genome. Looking at a selection of MrpJ paralogs, we discovered that these proteins, which consistently repress motility, also have nonidentical functions that include cross-regulation of fimbrial operons. A subset of paralogs, including AtfJ (encoded by the ambient temperature fimbrial operon), Fim8J, and MrpJ, are capable of autoinduction. We identified an element of the atf promoter extending from 487 to 655 nucleotides upstream of the transcriptional start site that is responsive to AtfJ, and we found that AtfJ directly binds this fragment. Mutational analysis of AtfJ revealed that its two identified functions, autoregulation and motility repression, are not invariably linked. Residues within the DNA-binding helix-turn-helix domain are required for motility repression but not necessarily autoregulation. Likewise, the C-terminal domain is dispensable for motility repression but is essential for autoregulation. Supported by a three-dimensional (3D) structural model, we hypothesize that the C-terminal domain confers unique regulatory capacities on the AtfJ family of regulators. IMPORTANCE: Balancing adherence with motility is essential for uropathogens to successfully establish a foothold in their host. Proteus mirabilis uses a fimbria-associated transcriptional regulator to switch between these antagonistic processes by increasing fimbrial adherence while simultaneously downregulating flagella. The discovery of multiple related proteins, many of which also function as motility repressors, encoded in the P. mirabilis genome has raised considerable interest as to their functionality and potential redundancy in this organism. This study provides an important advance in this field by elucidating the nonidentical effects of these paralogs on a molecular level. Our mechanistic studies of one member of this group, AtfJ, shed light on how these differing functions may be conferred despite the limited sequence variety exhibited by the paralogous proteins. PMID- 27246570 TI - Multifaceted Interfaces of Bacterial Competition. AB - Microbial communities span many orders of magnitude, ranging in scale from hundreds of cells on a single particle of soil to billions of cells within the lumen of the gastrointestinal tract. Bacterial cells in all habitats are members of densely populated local environments that facilitate competition between neighboring cells. Accordingly, bacteria require dynamic systems to respond to the competitive challenges and the fluctuations in environmental circumstances that tax their fitness. The assemblage of bacteria into communities provides an environment where competitive mechanisms are developed into new strategies for survival. In this minireview, we highlight a number of mechanisms used by bacteria to compete between species. We focus on recent discoveries that illustrate the dynamic and multifaceted functions used in bacterial competition and discuss how specific mechanisms provide a foundation for understanding bacterial community development and function. PMID- 27246573 TI - CodY-Dependent Regulation of Sporulation in Clostridium difficile. AB - Clostridium difficile must form a spore to survive outside the gastrointestinal tract. The factors that trigger sporulation in C. difficile remain poorly understood. Previous studies have suggested that a link exists between nutritional status and sporulation initiation in C. difficile In this study, we investigated the impact of the global nutritional regulator CodY on sporulation in C. difficile strains from the historical 012 ribotype and the current epidemic 027 ribotype. Sporulation frequencies were increased in both backgrounds, demonstrating that CodY represses sporulation in C. difficile The 027 codY mutant exhibited a greater increase in spore formation than the 012 codY mutant. To determine the role of CodY in the observed sporulation phenotypes, we examined several factors that are known to influence sporulation in C. difficile Using transcriptional reporter fusions and quantitative reverse transcription-PCR (qRT PCR) analysis, we found that two loci associated with the initiation of sporulation, opp and sinR, are regulated by CodY. The data demonstrate that CodY is a repressor of sporulation in C. difficile and that the impact of CodY on sporulation and expression of specific genes is significantly influenced by the strain background. These results suggest that the variability of CodY-dependent regulation is an important contributor to virulence and sporulation in current epidemic isolates. This report provides further evidence that nutritional state, virulence, and sporulation are linked in C. difficile IMPORTANCE: This study sought to examine the relationship between nutrition and sporulation in C. difficile by examining the global nutritional regulator CodY. CodY is a known virulence and nutritional regulator of C. difficile, but its role in sporulation was unknown. Here, we demonstrate that CodY is a negative regulator of sporulation in two different ribotypes of C. difficile We also demonstrate that CodY regulates known effectors of sporulation, Opp and SinR. These results support the idea that nutrient limitation is a trigger for sporulation in C. difficile and that the response to nutrient limitation is coordinated by CodY. Additionally, we demonstrate that CodY has an altered role in sporulation regulation for some strains. PMID- 27246574 TI - Characterization of the Neisseria gonorrhoeae Iron and Fur Regulatory Network. AB - The Neisseria gonorrhoeae ferric uptake regulator (Fur) protein controls expression of iron homeostasis genes in response to intracellular iron levels. In this study, using transcriptome sequencing (RNA-seq) analysis of an N. gonorrhoeae fur strain, we defined the gonococcal Fur and iron regulons and characterized Fur-controlled expression of an ArsR-like DNA binding protein. We observed that 158 genes (8% of the genome) showed differential expression in response to iron in an N. gonorrhoeae wild-type or fur strain, while 54 genes exhibited differential expression in response to Fur. The Fur regulon was extended to additional regulators, including NrrF and 13 other small RNAs (sRNAs), and two transcriptional factors. One transcriptional factor, coding for an ArsR-like regulator (ArsR), exhibited increased expression under iron-replete conditions in the wild-type strain but showed decreased expression across iron conditions in the fur strain, an effect that was reversed in a fur-complemented strain. Fur was shown to bind to the promoter region of the arsR gene downstream of a predicted sigma(70) promoter region. Electrophoretic mobility shift assay (EMSA) analysis confirmed binding of the ArsR protein to the norB promoter region, and sequence analysis identified two additional putative targets, NGO1411 and NGO1646. A gonococcal arsR strain demonstrated decreased survival in human endocervical epithelial cells compared to that of the wild-type and arsR complemented strains, suggesting that the ArsR regulon includes genes required for survival in host cells. Collectively, these results demonstrate that the N. gonorrhoeae Fur functions as a global regulatory protein to repress or activate expression of a large repertoire of genes, including additional transcriptional regulatory proteins. IMPORTANCE: Gene regulation in bacteria in response to environmental stimuli, including iron, is of paramount importance to both bacterial replication and, in the case of pathogenic bacteria, successful infection. Bacterial DNA binding proteins are a common mechanism utilized by pathogens to control gene expression under various environmental conditions. Here, we show that the DNA binding protein Fur, expressed by the human pathogen Neisseria gonorrhoeae, controls the expression of a large repertoire of genes and extends this regulon by controlling expression of additional DNA binding proteins. One of these proteins, an ArsR-like regulator, was required for N. gonorrhoeae survival within host cells. These results show that the Fur regulon extends to additional regulatory proteins, which together contribute to gonococcal mechanisms of pathogenesis. PMID- 27246577 TI - Toward predictive food process models: A protocol for parameter estimation. AB - Mathematical models, in particular, physics-based models, are essential tools to food product and process design, optimization and control. The success of mathematical models relies on their predictive capabilities. However, describing physical, chemical and biological changes in food processing requires the values of some, typically unknown, parameters. Therefore, parameter estimation from experimental data is critical to achieving desired model predictive properties. This work takes a new look into the parameter estimation (or identification) problem in food process modeling. First, we examine common pitfalls such as lack of identifiability and multimodality. Second, we present the theoretical background of a parameter identification protocol intended to deal with those challenges. And, to finish, we illustrate the performance of the proposed protocol with an example related to the thermal processing of packaged foods. PMID- 27246575 TI - Functional Interaction between the Cytoplasmic ABC Protein LptB and the Inner Membrane LptC Protein, Components of the Lipopolysaccharide Transport Machinery in Escherichia coli. AB - The assembly of lipopolysaccharide (LPS) in the outer leaflet of the outer membrane (OM) requires the transenvelope Lpt (lipopolysaccharide transport) complex, made in Escherichia coli of seven essential proteins located in the inner membrane (IM) (LptBCFG), periplasm (LptA), and OM (LptDE). At the IM, LptBFG constitute an unusual ATP binding cassette (ABC) transporter, composed by the transmembrane LptFG proteins and the cytoplasmic LptB ATPase, which is thought to extract LPS from the IM and to provide the energy for its export across the periplasm to the cell surface. LptC is a small IM bitopic protein that binds to LptBFG and recruits LptA via its N- and C-terminal regions, and its role in LPS export is not completely understood. Here, we show that the expression level of lptB is a critical factor for suppressing lethality of deletions in the C-terminal region of LptC and the functioning of a hybrid Lpt machinery that carries Pa-LptC, the highly divergent LptC orthologue from Pseudomonas aeruginosa We found that LptB overexpression stabilizes C-terminally truncated LptC mutant proteins, thereby allowing the formation of a sufficient amount of stable IM complexes to support growth. Moreover, the LptB level seems also critical for the assembly of IM complexes carrying Pa-LptC which is otherwise defective in interactions with the E. coli LptFG components. Overall, our data suggest that LptB and LptC functionally interact and support a model whereby LptB plays a key role in the assembly of the Lpt machinery. IMPORTANCE: The asymmetric outer membrane (OM) of Gram-negative bacteria contains in its outer leaflet an unusual glycolipid, the lipopolysaccharide (LPS). LPS largely contributes to the peculiar permeability barrier properties of the OM that prevent the entry of many antibiotics, thus making Gram-negative pathogens difficult to treat. In Escherichia coli the LPS transporter (the Lpt machine) is made of seven essential proteins (LptABCDEFG) that form a transenvelope complex. Here, we show that increased expression of the membrane-associated ABC protein LptB can suppress defects of LptC, which participates in the formation of the periplasmic bridge. This reveals functional interactions between these two components and supports a role of LptB in the assembly of the Lpt machine. PMID- 27246576 TI - A preliminary study of the effects of individual response to challenge tests and stress induced by humans on learning performance of weaned piglets (Sus scrofa). AB - This study investigated whether individual behavioural characteristics of piglets and stress induced by experience with humans can influence learning performance. After weaning, piglets received a chronic experience with humans to modulate their emotional state: rough (ROU), gentle (GEN), or minimal (MIN) experience. Simultaneously, they were trained on a discrimination task. Afterward, their behaviour during challenge tests was assessed. The first learning step of the task involved associating a positive sound cue with a response (approach a trough) and success of piglets depended mostly on motivation to seek for reward. Although the experience with humans did not have direct effect, the degree of fear of handler, measured based on their reactivity to a human approach test, was related to motivation to seek rewards and learning speed of this first step in stressed ROU piglets, but not in MIN and GEN piglets. In contrast, the second learning step was more cognitively challenging, since it involved discrimination learning, including negative cues during which piglets had to learn to avoid the trough. Locomotion activity, measured during an open-field test, was associated with performance of the discrimination learning. To conclude, fearfulness towards humans and locomotion activity are linked with learning performance in relation to task complexity, highlighting the necessity to take into account these factors in animal research and management. PMID- 27246578 TI - Money well-spent: Further evidence of improved outcomes for methamphetamine users following treatment. PMID- 27246579 TI - Efficacy of intermittently administered dasatinib with a reduced dose in an elderly patient with chronic myeloid leukemia. PMID- 27246580 TI - Association between polypharmacy and multiple uses of medical facilities in nursing home residents. PMID- 27246581 TI - Metabolomics Reveals Altered Lipid Metabolism in a Mouse Model of Endometriosis. AB - Endometriosis is a common chronic estrogen-dependent gynecological disease affecting 10% of women in their reproductive age. It is characterized by proliferation of functional endometrial glands and stroma outside the uterine cavity. In the present study, we used mass spectrometry-based lipidomics to investigate the alterations in serum lipid profiles of mice induced with endometriosis. We identified several dysregulated lipids such as phosphatidylcholines, sphingomyelins, phosphatidylethanolamines, and triglycerides and show that triglycerides may be due to a general inflammatory condition in the peritoneum. We also show that in addition to phosphatidylcholine alteration, there is also an effect in the ratio of phosphatidylcholine/phosphatidylethanolamine in serum of mice induced with the disease and that this change may be due to increased expression of the phosphatidylethanolamine N-methyltransferase gene. The study provides new insight into the etiology of endometriosis. PMID- 27246582 TI - Sentence plausibility influences the link between action words and the perception of biological human movements. AB - The present study aimed to assess the role of sentence plausibility in the functional link between action words and visual judgments of point-light human actions. Following the oral presentation of action verbs included in a plausible or implausible sentence, participants were asked to detect the presence of congruent or incongruent biological movements. Sentence plausibility was manipulated by inverting the positions of the subject and the complement (e.g., the neighbor is running in the garden vs the garden is running in the neighbor). The results showed that for both plausible and implausible sentences, the detection of human movements is greater following presentation of congruent action verbs. These results suggest that the presentation of action verbs affects the subsequent perception of point-light human movements, regardless of the associated semantic context. However, the link between action verbs and judgment of biological movements is strengthened when plausible sentences are presented, as illustrated by the increase in visual detection capacity in plausible congruent conditions. Concerning the analysis of the detection speed, the performance is only affected in plausible sentences with slower response times associated with the presentation of an incongruent action verb. These findings are discussed in light of an embodied mechanism and the domain of biological movement perception. PMID- 27246584 TI - Why we should care about ultra-rare disease. PMID- 27246583 TI - Initiation of and long-term adherence to secondary preventive drugs after acute myocardial infarction. AB - BACKGROUND: Secondary preventive drug therapy following acute myocardial infarction (AMI) is recommended to reduce the risk of new cardiovascular events. The aim of this nationwide cohort study was to examine the initiation and long term use of secondary preventive drugs after AMI. METHODS: The prescription of drugs in 42,707 patients < 85 years discharged alive from hospital after AMI in 2009-2013 was retrieved by linkage of the Norwegian Patient Register, the Norwegian Prescription Database, and the Norwegian Cause of Death Registry. Patients were followed for up to 24 months. RESULTS: The majority of patients were discharged on single or dual antiplatelet therapy (91 %), statins (90 %), beta-blockers (82 %), and angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor II blockers (ARB) (60 %). Patients not undergoing percutaneous coronary intervention (PCI) (42 %) were less likely to be prescribed secondary preventive drugs compared with patients undergoing PCI. This was particular the case for dual antiplatelet therapy (43 % vs. 87 %). The adherence to prescribed drugs was high: 12 months after index AMI, 84 % of patients were still on aspirin, 84 % on statins, 77 % on beta-blockers and 57 % on ACEI/ARB. Few drug and dose adjustments were made during follow-up. CONCLUSION: Guideline recommended secondary preventive drugs were prescribed to most patients discharged from hospital after AMI, but the percentage receiving such therapy was significantly lower in non-PCI patients. The long-time adherence was high, but few drug adjustments were performed during follow-up. More attention is needed to secondary preventive drug therapy in AMI patients not undergoing PCI. PMID- 27246585 TI - ERS Lung Science Conference 2016 report. PMID- 27246586 TI - Advances in pleural disease. PMID- 27246587 TI - Pulmonary manifestations of Sjogren's syndrome. AB - In 9-20% of cases, Sjogren's syndrome is associated with various respiratory symptoms. The most typical manifestations are chronic interstitial lung disease (ILD) and tracheobronchial disease. The most common manifestation of ILD is nonspecific interstitial pneumonia in its fibrosing variant. Other types of ILD, such as organising pneumonia, usual interstitial pneumonia and lymphocytic interstitial pneumonitis, are rare. Their radiological presentation is less distinctive, and definitive diagnosis may require the use of transbronchial or surgical lung biopsy. Corticosteroid therapy is the mainstay of ILD treatment in Sjogren's syndrome, but the use of other immunosuppressive drugs needs to be determined. ILD is a significant cause of death in Sjogren's syndrome. Tracheobronchial disease is common in Sjogren's syndrome, characterised by diffuse lymphocytic infiltration of the airway. It is sometimes responsible for a crippling chronic cough. It can also present in the form of bronchial hyperresponsiveness, bronchiectasis, bronchiolitis or recurrent respiratory infections. The management of these manifestations may require treatment for dryness and/or inflammation of the airways. Airway disease has little effect on respiratory function and is rarely the cause of death in Sjogren's syndrome patients. Rare respiratory complications such as amyloidosis, lymphoma or pulmonary hypertension should not be disregarded in Sjogren's syndrome patients. PMID- 27246588 TI - The exposome concept: a challenge and a potential driver for environmental health research. AB - The exposome concept was defined in 2005 as encompassing all environmental exposures from conception onwards, as a new strategy to evidence environmental disease risk factors. Although very appealing, the exposome concept is challenging in many respects. In terms of assessment, several hundreds of time varying exposures need to be considered, but increasing the number of exposures assessed should not be done at the cost of increased exposure misclassification. Accurately assessing the exposome currently requires numerous measurements, which rely on different technologies; resulting in an expensive set of protocols. In the future, high-throughput 'omics technologies may be a promising technique to integrate a wide range of exposures from a small numbers of biological matrices. Assessing the association between many exposures and health raises statistical challenges. Due to the correlation structure of the exposome, existing statistical methods cannot fully and efficiently untangle the exposures truly affecting the health outcome from correlated exposures. Other statistical challenges relate to accounting for exposure misclassification or identifying synergistic effects between exposures. On-going exposome projects are trying to overcome technical and statistical challenges. From a public health perspective, a better understanding of the environmental risk factors should open the way to improved prevention strategies. PMID- 27246589 TI - Natural experiments and large databases in respiratory and cardiovascular disease. AB - A number of scientific questions cannot be tested in a laboratory, clinic or clinical trial setting. In many cases, observational data can be used to test such hypotheses.This article illustrates how epidemiology can contribute and shows the different ways of using observational data through three approaches: 1) prospective cohort study design; 2) time series analysis; and 3) a nested case control design in pharmacoepidemiology.In a prospective cohort study design, three cohorts were merged to study lung function decline, testing the importance of different trajectories of lung function decline for developing chronic obstructive pulmonary disease (COPD). Using these three well-described cohorts it was documented that maximally attained lung function in early adulthood is as important as excess decline in forced expiratory volume in 1 s for the development of COPD. Time series analysis is used to examine exposures and disease over time. In a recent review of cardiovascular disease some interesting associations, and not least lack of associations, were presented. Assessing effects of drugs in database studies is challenging. In a nested case-control design in a large cohort study, statins were found to reduce the risk of COPD exacerbations. These findings will be discussed.Observational data from large databases, as well as carefully collected data in cohort studies, can be used to test hypotheses that may not be addressed in a traditional experimental setting. PMID- 27246590 TI - Epigenetic mechanisms in pulmonary arterial hypertension: the need for global perspectives. AB - Pulmonary arterial hypertension (PAH) is a severe and progressive disease, characterised by high pulmonary artery pressure that usually culminates in right heart failure. Recent findings of alterations in the DNA methylation state of superoxide dismutase 2 and granulysin gene loci; histone H1 levels; aberrant expression levels of histone deacetylases and bromodomain-containing protein 4; and dysregulated microRNA networks together suggest the involvement of epigenetics in PAH pathogenesis. Thus, PAH pathogenesis evidently involves the interplay of a predisposed genetic background, epigenetic state and injurious events. Profiling the genome-wide alterations in the epigenetic mechanisms, such as DNA methylation or histone modification pattern in PAH vascular cells, may explain the great variability in susceptibility and disease severity that is frequently associated with pronounced remodelling and worse clinical outcome. Moreover, the influence of genetic predisposition and the acquisition of epigenetic alterations in response to environmental cues in PAH progression and establishment has largely been unexplored on a genome-wide scale. In order to gain insights into the molecular mechanisms leading to the development of PAH and to design novel therapeutic strategies, high-throughput approaches have to be adopted to facilitate systematic identification of the disease-specific networks using next-generation sequencing technologies, the application of these technologies in PAH has been relatively trivial to date. PMID- 27246591 TI - Management of sarcoidosis in clinical practice. AB - Sarcoidosis is a systemic disease of unknown cause with very diverse presentation, outcome, severity and need for treatments. While some presentations may be very typical, for many patients, the presentation is nonspecific, with shared associations with other diseases at times being by far more frequent or misleading, which can be a cause of significant delay and often several consultations before a diagnosis of sarcoidosis can be confirmed. This is particularly the case when pulmonary manifestations are in the forefront. The diagnosis relies on three well-known criteria. In clinical practice, these criteria are not easily implemented, particularly by physicians without expertise in sarcoidosis, which can lead to a risk of either under- or over-diagnosis. Qualifying the presentation according to sarcoidosis diagnosis is essential. However, it is often not easy to classify the presentation as typical versus compatible or compatible versus inconsistent. Further investigations are needed before any other hypothesis is to be considered. It is important to detect events and to determine whether or not they are indicative of a flare of sarcoidosis. Eventually, treatment needs to be related to the correct indications. The evaluation of the efficacy and safety of treatments is crucial. To address such issues, we present five emblematic cases that illustrate this. PMID- 27246592 TI - Tobacco control in Europe: a policy review. AB - Tobacco is responsible for the death of 6 million people every year globally, of whom 700 000 are in Europe. Effective policies for tobacco control exist; however, the status of their implementation varies across the World Health Organization (WHO) European Region. In order to tackle the tobacco epidemic, action has been taken though the implementation of both legally binding and non legally binding measures. This article aims to present the achievements and challenges of tobacco control in Europe, focussing on the available legally binding instruments such as the WHO Framework Convention on Tobacco Control and the revision of the Tobacco Products Directive at the European Union level. Tobacco still faces heavy lobbying of the tobacco industry, which has systematically contrasted policies to achieve public health objectives. The legal instruments for tobacco control in Europe presented here are not always adequately enforced in all the countries and there is certainly room for improving their implementation. Finally, the need for a strong political commitment towards the end-game of the tobacco epidemic is emphasised. PMID- 27246593 TI - Bronchial epithelium in children: a key player in asthma. AB - Bronchial epithelium is a key element of the respiratory airways. It constitutes the interface between the environment and the host. It is a physical barrier with many chemical and immunological properties. The bronchial epithelium is abnormal in asthma, even in children. It represents a key component promoting airway inflammation and remodelling that can lead to chronic symptoms. In this review, we present an overview of bronchial epithelium and how to study it, with a specific focus on children. We report physical, chemical and immunological properties from ex vivo and in vitro studies. The responses to various deleterious agents, such as viruses or allergens, may lead to persistent abnormalities orchestrated by bronchial epithelial cells. As epithelium dysfunctions occur early in asthma, reprogramming the epithelium may represent an ambitious goal to induce asthma remission in children. PMID- 27246594 TI - Thoracic involvement in generalised lymphatic anomaly (or lymphangiomatosis). AB - Generalised lymphatic anomaly (GLA), also known as lymphangiomatosis, is a rare disease caused by congenital abnormalities of lymphatic development. It usually presents in childhood but can also be diagnosed in adults. GLA encompasses a wide spectrum of clinical manifestations ranging from single-organ involvement to generalised disease. Given the rarity of the disease, most of the information regarding it comes from case reports. To date, no clinical trials concerning treatment are available. This review focuses on thoracic GLA and summarises possible diagnostic and therapeutic approaches. PMID- 27246595 TI - Viral infection in community-acquired pneumonia: a systematic review and meta analysis. AB - The advent of PCR has improved the identification of viruses in patients with community-acquired pneumonia (CAP). Several studies have used PCR to establish the importance of viruses in the aetiology of CAP.We performed a systematic review and meta-analysis of the studies that reported the proportion of viral infection detected via PCR in patients with CAP. We excluded studies with paediatric populations. The primary outcome was the proportion of patients with viral infection. The secondary outcome was short-term mortality.Our review included 31 studies. Most obtained PCR via nasopharyngeal or oropharyngeal swab. The pooled proportion of patients with viral infection was 24.5% (95% CI 21.5 27.5%). In studies that obtained lower respiratory samples in >50% of patients, the proportion was 44.2% (95% CI 35.1-53.3%). The odds of death were higher in patients with dual bacterial and viral infection (OR 2.1, 95% CI 1.32-3.31).Viral infection is present in a high proportion of patients with CAP. The true proportion of viral infection is probably underestimated because of negative test results from nasopharyngeal or oropharyngeal swab PCR. There is increased mortality in patients with dual bacterial and viral infection. PMID- 27246596 TI - Malignant pleural effusion: from bench to bedside. AB - Malignant pleural effusion (MPE) is a common but serious condition that is related with poor quality of life, morbidity and mortality. Its incidence and associated healthcare costs are rising and its management remains palliative, with median survival ranging from 3 to 12 months. During the last decade there has been significant progress in unravelling the pathophysiology of MPE, as well as its diagnostics, imaging, and management. Nowadays, formerly bed-ridden patients are genotyped, phenotyped, and treated on an ambulatory basis. This article attempts to provide a comprehensive overview of current advances in MPE from bench to bedside. In addition, it highlights unanswered questions in current clinical practice and suggests future directions for basic and clinical research in the field. PMID- 27246597 TI - Advanced medical interventions in pleural disease. AB - The burden of a number of pleural diseases continues to increase internationally. Although many pleural procedures have historically been the domain of interventional radiologists or thoracic surgeons, in recent years, there has been a marked expansion in the techniques available to the pulmonologist. This has been due in part to both technological advancements and a greater recognition that pleural disease is an important subspecialty of respiratory medicine. This article summarises the important literature relating to a number of advanced pleural interventions, including medical thoracoscopy, the insertion and use of indwelling pleural catheters, pleural manometry, point-of-care thoracic ultrasound, and image-guided closed pleural biopsy. We also aim to inform the reader regarding the latest updates to more established procedures such as chemical pleurodesis, thoracentesis and the management of chest drains, drawing on contemporary data from recent randomised trials. Finally, we shall look to explore the challenges faced by those practicing pleural medicine, especially relating to training, as well as possible future directions for the use and expansion of advanced medical interventions in pleural disease. PMID- 27246598 TI - Can asthmatic subjects dive? AB - Recreational diving with self-contained underwater breathing apparatus (scuba) has grown in popularity. Asthma is a common disease with a similar prevalence in divers as in the general population. Due to theoretical concern about an increased risk for pulmonary barotrauma and decompression sickness in asthmatic divers, in the past the approach to asthmatic diver candidates was very conservative, with scuba disallowed. However, experience in the field and data in the current literature do not support this dogmatic approach. In this review the theoretical risk factors of diving with asthma, the epidemiological data and the recommended approach to the asthmatic diver candidate will be described. PMID- 27246599 TI - Single-cell whole genome sequencing reveals no evidence for common aneuploidy in normal and Alzheimer's disease neurons. AB - BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease of the brain and the most common form of dementia in the elderly. Aneuploidy, a state in which cells have an abnormal number of chromosomes, has been proposed to play a role in neurodegeneration in AD patients. Several studies using fluorescence in situ hybridization have shown that the brains of AD patients contain an increased number of aneuploid cells. However, because the reported rate of aneuploidy in neurons ranges widely, a more sensitive method is needed to establish a possible role of aneuploidy in AD pathology. RESULTS: In the current study, we used a novel single-cell whole genome sequencing (scWGS) approach to assess aneuploidy in isolated neurons from the frontal cortex of normal control individuals (n = 6) and patients with AD (n = 10). The sensitivity and specificity of our method was shown by the presence of three copies of chromosome 21 in all analyzed neuronal nuclei of a Down's syndrome sample (n = 36). Very low levels of aneuploidy were found in the brains from control individuals (n = 589) and AD patients (n = 893). In contrast to other studies, we observe no selective gain of chromosomes 17 or 21 in neurons of AD patients. CONCLUSION: scWGS showed no evidence for common aneuploidy in normal and AD neurons. Therefore, our results do not support an important role for aneuploidy in neuronal cells in the pathogenesis of AD. This will need to be confirmed by future studies in larger cohorts. PMID- 27246600 TI - The correlates and course of multiple health risk behaviour in adolescence. AB - BACKGROUND: Health risk behaviours often co-occur in adolescence. This may be partially explained by a set of common risk and protective factors. The current study examines the association between risk behaviours throughout adolescence and identifies common risk factors for multiple risk behaviour in late adolescence. METHODS: We use data from the Longitudinal Study of Young People in England. We examined the association between risk behaviours at age 14 (n = 15,588), age 16 (n = 12,416) and age 19 (n = 9,548). The associations between age 19 risk behaviour and earlier risk behaviours and risk and protective factors were assessed longitudinally. Health risk behaviours included smoking, alcohol use, illicit drug use, delinquency and unsafe sexual behaviour. RESULTS: All risk behaviours were found to be associated with other risk behaviours with associations weakening through adolescence. A number of sociodemographic, interpersonal, school and family factors at age 14 predicted risk behaviour and multiple risk behaviour at 19, though predictors for heavy alcohol use often differed from other health risk behaviours. Past risk behaviour was a strong predictor of age 19 risk behaviour though many involved in only one form of risk behaviour in mid-adolescence do not progress to multiple risk behaviour. CONCLUSIONS: Our findings reaffirm the links between health risk behaviours, but these diminish throughout adolescence with multiple risk behaviour usually initiated in mid-adolescence. Multiple risk behaviour is initiated in early or mid adolescence with a number of common risk factors explaining the co-occurrence of risk behaviours. PMID- 27246601 TI - The Cybathlon promotes the development of assistive technology for people with physical disabilities. AB - BACKGROUND: The Cybathlon is a new kind of championship, where people with physical disabilities compete against each other at tasks of daily life, with the aid of advanced assistive devices including robotic technologies. The first championship will take place at the Swiss Arena Kloten, Zurich, on 8 October 2016. THE IDEA: Six disciplines are part of the competition comprising races with powered leg prostheses, powered arm prostheses, functional electrical stimulation driven bikes, powered wheelchairs, powered exoskeletons and brain-computer interfaces. This commentary describes the six disciplines and explains the current technological deficiencies that have to be addressed by the competing teams. These deficiencies at present often lead to disappointment or even rejection of some of the related technologies in daily applications. CONCLUSION: The Cybathlon aims to promote the development of useful technologies that facilitate the lives of people with disabilities. In the long run, the developed devices should become affordable and functional for all relevant activities in daily life. PMID- 27246602 TI - Chronic Urticaria in Returning Travellers: The Role of Anthelmintic Treatment. AB - BACKGROUND: Chronic urticaria often poses a therapeutic challenge. The human immune response to helminths has a high degree of similarity to an allergic response in terms of skin manifestations, eosinophilia, and IgE elevation. Unfortunately, it is often complicated to diagnose such infections. OBJECTIVE: We sought to assess the effect of empirical anthelmintic treatment among returning travellers diagnosed with chronic urticaria, without clear proof of helminthic infection. METHODS: This is a retrospective case series of 19 returning travellers with chronic urticaria. All patients were treated with anthelmintic treatment given based on clinical suspicion only. A randomly selected control group of 20 patients with chronic urticaria, with no history of travel, was also enrolled. RESULTS: A positive clinical response was reported in 68.4% (13 patients) of the travellers' group within 3 months after treatment with anthelmintic therapy compared with 10% (2 patients) of chronic urticaria patients in the control group. No adverse effects from treatment were recorded. CONCLUSION: In patients with chronic urticaria, travel history to developing countries must be obtained. Empiric anthelmintic therapy might be beneficial, even in the absence of findings suggestive of helminthic infection. PMID- 27246603 TI - Unusual acute ischemic stroke of the ipsilateral middle and posterior cerebral artery territory. PMID- 27246604 TI - HIV infection is associated with higher levels of monocyte chemoattractant protein-1 and eotaxin among people with recent hepatitis C virus infection. AB - BACKGROUND: Human immunodeficiency virus (HIV) infection leads to more rapid progression of hepatitis C virus (HCV)-related liver fibrosis, which could be linked to differences in the severity of liver inflammation among HIV/HCV co infected individuals compared to HCV mono-infected individuals. This study assessed the association of HIV co-infection with pro-inflammatory and pro fibrogenic cytokines and chemokines during recent HCV infection. METHODS: Participants from the ATAHC study, a prospective cohort of recent HCV infection, with detectable HCV RNA at the time of acute HCV detection were included. Concentrations of 27 plasma cytokines and chemokines were measured by multiplex immunoassays and compared between those with, and without, HIV co-infection. RESULTS: Out of 117 individuals with recent HCV infection included in analysis, 73 had HCV mono-infection and 44 had HIV/HCV co-infection. Individuals with HIV/HCV co-infection had significantly higher mean levels of eotaxin (1.79 vs. 1.62 log pg/mL; P < 0.001), monocyte chemotactic protein 1 (MCP-1; 2.10 vs. 1.98 log pg/mL; P < 0.001), and interferon-gamma inducible protein-10 (IP-10; 3.11 vs. 2.98 log pg/mL; P = 0.013). Linear regression analyses adjusting for age, alanine transaminase (ALT), HCV RNA levels, and assay run, higher eotaxin levels were independently associated with HIV/HCV co-infection (adjusted beta: 0.12; 95%CI: 0.01, 0.24; P = 0.039). Higher MCP-1 levels were also independently associated with HIV/HCV co-infection in adjusted analysis (adjusted beta: 0.11; 95%CI: 0.03, 0.18; P = 0.009). CONCLUSIONS: During recent HCV, those with HIV/HCV co-infection had a stronger pro-fibrogenic mediator profile compared to those with HCV mono infection. These findings may provide a potential explanation for accelerated liver fibrosis in HIV/HCV co-infection. TRIAL REGISTRATION: Australian Trial in Acute Hepatitis C (ATAHC) study was registered with ClinicalTrials.gov registry on September 11, 2005. NCT00192569 . PMID- 27246605 TI - Posttranslational control of the scaffold for Fe-S cluster biogenesis as a compensatory regulatory mechanism. AB - Though toxic in excess, iron is vital for life. Thus, its use in all cells is tightly regulated. Analysis of Saccharomyces cerevisiae, which has been used extensively as a model system, has revealed layers of regulation of cellular iron trafficking and utilization. This regulation is based on the availability of both elemental iron and functionality of the Fe-S cluster biogenesis system. Here, we discuss a possible "first responder" regulatory mechanism centered on the stability of the scaffold protein on which Fe-S clusters are built. PMID- 27246606 TI - A Facile Process for the Preparation of Three-Dimensional Hollow Zn(OH)2 Nanoflowers at Room Temperature. AB - A facile strategy has been developed to synthesize double-shelled Zn(OH)2 nanoflowers (DNFs) at room temperature. The nanoflowers were generated via conversion of Cu2 O nanoparticles (NPs) using ZnCl2 and Na2 S2 O3 by a simple process. Outward diffusion of the Cu(2+) , produced by an oxidation process on the surface of NPs, and the inward diffusion of Zn(2+) by coordination and migration, eventually lead to a hollow cavity in the inner NPs with a double shelled 3D hollow flower shapes. The thickness of the inner and outer shells is estimated to be about 20 nm, and the thickness of nanopetals is about 7 nm. The nanoflowers have large surface areas and excellent adsorption properties. As a proof of potential applications, the DNFs exhibited an excellent ability to remove organic molecules from aqueous solutions. PMID- 27246608 TI - Safety in numbers for cyclists-conclusions from a multidisciplinary study of seasonal change in interplay and conflicts. AB - In many European countries, it is a political goal that future growth in local travel should be absorbed by sustainable transport modes. Concerns that increased walking and cycling produce more accidents have been countered by the "safety in numbers" (SiN) argument. According to SiN, the more walkers/cyclists there are in a population, the lower their risk. SiN has been demonstrated in cross sectional and longitudinal studies, but the mechanisms behind the effect have yet to be proven. Previous studies have mostly relied on register data. The current study, carried out in 2013 and 2014 tests the existence of this effect in a more controlled manner. This is achieved through the use of three data sets: (1) roadside survey data with cyclists, pedestrians and car drivers from Oslo carried out at three time points in the cycling season (2) a panel study covering the same time period, and (3) video observations at four different locations in Oslo. By exploiting the natural seasonal variation in cycling frequency, and by using a repeated measures design we can further control for other factors suggested to lie behind the SiN mechanism, such as differences in infrastructure and traffic culture. The results suggest that bicyclists experience a short term Safety in Numbers effect through the season. Each individual cyclist experiences fewer occasions of being overlooked by cars and fewer safety critical situations (near misses). Video observation data confirm this pattern. However, the SiN effect seems to be countered by another mechanism taking place at the same time: the influx of inexperienced and risk-taking cyclists through the season. Thus car drivers and pedestrians also report to find themselves being surprised by cyclists in traffic late in the season. PMID- 27246607 TI - Psychiatric disorders among adolescents from Lebanon: prevalence, correlates, and treatment gap. AB - PURPOSE: Adolescence is a critical age for the development of psychiatric disorders. Although Lebanon, a low-to-middle income country, has suffered from decades of war and political instability, the burden of psychiatric disorders among adolescents in Lebanon remains unclear. This study aims to estimate the prevalence of psychiatric disorders among adolescents in the Lebanese capital, Beirut, and to study the correlates and treatment seeking behavior associated with these disorders. METHODS: Through a multistage cluster sampling design, 510 adolescents, aged 11-17 years were recruited from a household sample in Beirut in 2012. Parents and adolescents completed a battery of self-reported questionnaires and interviews including the Development and Well-being Assessment (DAWBA), the Peer-Relations Questionnaire (PRQ), and a demographic/clinical information questionnaire. Logistic regression models were used to study the correlates of psychiatric disorders. RESULTS: The 30-day prevalence of psychiatric disorders was 26.1 %, with anxiety disorders (13.1 %) and ADHD (10.2 %) being the most prevalent disorders. Only 6 % of those with disorders reported seeking professional help. Parental marital status, not attending school, having a chronic medical condition, having a family history of psychiatric disorders, as well as propensity to bullying and to being victimized by peers emerged as correlates of having psychiatric disorders. CONCLUSIONS: A clear treatment gap is evident with a high 30-day prevalence of psychiatric disorders among adolescents in Beirut coupled with a very low percentage seeking treatment. Scaling up mental health services and addressing potential barriers to seeking care would be important to close this gap. PMID- 27246609 TI - Upregulation of microRNA-450 inhibits the progression of lung cancer in vitro and in vivo by targeting interferon regulatory factor 2. AB - MicroRNAs (miRNAs) are a class of non-coding RNAs that play pivotal roles in human lung cancer development. The majority of studies have focused on either non small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). In the present study, we investigated a plausible mechanism of action of miR-450 in these types of lung cancer. We found that the level of miR-450 was decreased in lung cancer cell lines, as well as in solid tumors. As exemplified in the H510A (SCLC) and H2291 (NSCLC) cells, transfection with lentivirus carrying miR-450 upregulated miR-450 expression and significantly attenuated lung cancer cell proliferation and invasion, as well as the growth of implantated tumors. Interferon regulatory factor 2 (IRF2) was also verified to be a direct target of miR-450 in lung cancer cells. The overexpression of IRF2 in the H510A and H2291 cells abrogated the inhibitory effects of miR-450 on lung cancer cell proliferation and invasion. Taken together, in this study, we identified a novel role of miR-450 in lung cancer. miR-450 targets IRF2 and thus supresses lung cancer cell proliferation and invasion. PMID- 27246610 TI - Absence of an association of human polyomavirus and papillomavirus infection with lung cancer in China: a nested case-control study. AB - BACKGROUND: Studies of human polyomavirus (HPyV) infection and lung cancer are limited and those regarding the association of human papillomavirus (HPV) infection and lung cancer have produced inconsistent results. METHODS: We conducted a nested case-control study to assess the association between incident lung cancer of various histologies and evidence of prior infection with HPyVs and HPVs. We selected serum from 183 cases and 217 frequency matched controls from the Yunnan Tin Miner's Cohort study, which was designed to identify biomarkers for early detection of lung cancer. Using multiplex liquid bead microarray (LBMA) antibody assays, we tested for antibodies to the VP1 structural protein and small T antigen (ST-Ag) of Merkel cell, KI, and WU HPyVs. We also tested for antibodies against HPV L1 structural proteins (high-risk types 16, 18, 31, 33, 52, and 58 and low-risk types 6 and 11) and E6 and E7 oncoproteins (high risk types 16 and 18). Measures of antibody reactivity were log transformed and analyzed using logistic regression. RESULTS: We found no association between KIV, WUV, and MCV antibody levels and incident lung cancer (P-corrected for multiple comparisons >0.10 for all trend tests). We also found no association with HPV-16, 18, 31, 33, 52, and 58 seropositivity (P-corrected for multiple comparisons >0.05 for all). CONCLUSIONS: Future studies of infectious etiologies of lung cancer should look beyond HPyVs and HPVs as candidate infectious agents. PMID- 27246612 TI - Translating Perceptual Learning from the Laboratory to Applications. AB - Human training studies in the laboratory have demonstrated plasticity in brain systems and, in some cases, large improvements in perceptual performance, inspiring a quest to develop training apps and systems. We consider the next steps in the translation from the laboratory to the clinic and commerce. PMID- 27246611 TI - Genetic variants of DNA repair genes predict the survival of patients with esophageal squamous cell cancer receiving platinum-based adjuvant chemotherapy. AB - BACKGROUND: Adjuvant chemotherapy in patients with resected esophageal squamous cell cancer (ESCC) remains controversial for its uncertain role in improving overall survival (OS). Nucleotide excision repair (NER) removes DNA-adducts in tumor cells induced by the platinum-based chemotherapy and thus may modulate efficacy of the treatment. The present study evaluated if single nucleotide polymorphisms (SNPs) of NER genes were prognostic biomarkers in ESCC patients treated with platinum-based adjuvant chemotherapy (PAC). METHODS: The analysis included 572 patients, for whom six SNPs of NER genes [i.e., XPC (rs1870134 and rs2228001), ERCC2/XPD rs238406 and ERCC5/XPG (rs2094258, rs2296147 and rs873601)] were detected with the TaqMan assay. Kaplan-Meier analyses and Cox proportional hazards models were used to evaluate their associations with disease free survival (DFS) and OS of these ESCC patients receiving PAC. Receiving operating characteristic curve analysis was used to evaluate the role of the risk genotypes in the DFS and OS. RESULTS: We found that ERCC5/XPG rs2094258 and rs873601 and ERCC2/XPD rs238406 SNPs were independently associated with poorer DFS and OS of ESCC patients [ERCC5/XPG rs2094258: CT+TT vs. CC: adjusted hazards ratio (adjHR) = 1.68 and P = 0.012 for DFS; adjHR = 1.99 and P = 0.0001 for OS; ERCC5/XPG rs873601: GA+GG vs. AA: adjHR = 1.59 and P = 0.024 for DFS; adjHR = 1.91 and P = 0.0005 for OS; ERCC2/XPD rs238406: TT vs. GG+GT: adjHR = 1.43 and P = 0.020 for DFS; adjHR = 1.52 and P = 0.008 for OS]. These HRs increased as the number of risk genotypes increased in the combined analysis. The model combining the risk genotypes with clinical characteristics or the TNM stage system was better in predicting outcomes in ESCC patients with PAC. CONCLUSION: SNPs of ERCC2/XPD and ERCC5/XPG may independently and jointly predict survival of ESCC patients treated with PAC in this study population. Further validation in other study populations is warranted. PMID- 27246613 TI - Validation of an instrument to measure registered dietitians'/nutritionists' knowledge, attitudes and practices of an intuitive eating approach. AB - OBJECTIVE: The purpose of the present study was to develop and assess the construct validity of a tool to measure knowledge, attitudes and practices of registered dietitians/nutritionists (RD/N) regarding an intuitive eating lifestyle. DESIGN: Cross-sectional study design that utilized a survey administered to a random sample and remaining full population of RD/N. SETTING: A national survey conducted via online survey software. SUBJECTS: A random sample of 10 % of all RD/N in the USA (n 8834) was invited to participate. Survey completion rate was 22.2 % (n 1897). After initial validation, the survey was distributed to the remaining 90 % of RD/N to confirm validation. RESULTS: After removing items with insufficient factor loadings, results were consistent with a four-factor solution: (i) knowledge of intuitive eating; (ii) attitudes towards intuitive eating; (iii) traditional and restrictive practices; and (iv) non restrictive and intuitive eating practices. Confirmatory factor analysis provided further evidence of the validity of the four factors and the factors had strong reliability. CONCLUSIONS: Unlike the hypothesized three-factor solution (knowledge, attitudes and practices), validation analysis revealed that the survey measures knowledge of intuitive eating, attitudes towards intuitive eating, use of traditional and restrictive weight-management practices, and use of non-restrictive and intuitive eating practices. With the landscape of weight management and health promotion undergoing a shift towards a health centred, size acceptance approach, this instrument will provide valuable information regarding the current knowledge, attitudes and practices of RD/N and other health promotion professionals. PMID- 27246614 TI - Testosterone and trenbolone enanthate increase mature myostatin protein expression despite increasing skeletal muscle hypertrophy and satellite cell number in rodent muscle. AB - The androgen-induced alterations in adult rodent skeletal muscle fibre cross sectional area (fCSA), satellite cell content and myostatin (Mstn) were examined in 10-month-old Fisher 344 rats (n = 41) assigned to Sham surgery, orchiectomy (ORX), ORX + testosterone (TEST; 7.0 mg week-1 ) or ORX + trenbolone (TREN; 1.0 mg week-1 ). After 29 days, animals were euthanised and the levator ani/bulbocavernosus (LABC) muscle complex was harvested for analyses. LABC muscle fCSA was 102% and 94% higher in ORX + TEST and ORX + TREN compared to ORX (p < .001). ORX + TEST and ORX + TREN increased satellite cell numbers by 181% and 178% compared to ORX, respectively (p < .01), with no differences between conditions for myonuclear number per muscle fibre (p = .948). Mstn protein was increased 159% and 169% in the ORX + TEST and ORX + TREN compared to ORX (p < .01). pan-SMAD2/3 protein was ~30-50% greater in ORX compared to SHAM (p = .006), ORX + TEST (p = .037) and ORX + TREN (p = .043), although there were no between treatment effects regarding phosphorylated SMAD2/3. Mstn, ActrIIb and Mighty mRNAs were lower in ORX, ORX + TEST and ORX + TREN compared to SHAM (p < .05). Testosterone and trenbolone administration increased muscle fCSA and satellite cell number without increasing myonuclei number, and increased Mstn protein levels. Several genes and signalling proteins related to myostatin signalling were differentially regulated by ORX or androgen therapy. PMID- 27246615 TI - Jatrophane and ingenane-type diterpenoids from Euphorbia kansui inhibit the LPS induced NO production in RAW 264.7 cells. AB - Bioactivity-guided fractionation of the MeOH extract from the roots of Euphorbia kansui resulted in the isolation of two new jatrophane-type diterpenoids, kanesulones A (1) and B (2), together with six known jatrophane-type diterpenoids (3-8) and ten known ingenane-type diterpenoids (9-18). Their chemical structures were elucidated on the basis of spectroscopic data interpretation, especially 1D and 2D NMR such as HMQC, HMBC, COSY and NOESY, and HRESIMS data as well as CD analysis. Compounds 1-8 and 11-18 exhibited the inhibitory effects on LPS-induced nitric oxide production with IC50 values ranging from 0.7 to 46.5MUM in RAW 264.7 macrophages. PMID- 27246616 TI - A one-pot synthesis of alpha-l-threofuranosyl nucleoside triphosphates (tNTPs). AB - TNA (alpha-l-threofuranosyl nucleoside) triphosphates of adenosine (tATP), guanosine (tGTP), cytidine (tCTP), and thymidine (tTTP) were synthesized from their corresponding 3'-O-phosphoramidite derivatives using a novel one-pot reaction that is less moisture sensitive than traditional methods. The chemically synthesized tNTPs, despite containing an unnatural 3'-triphosphate moiety, are similar in thermal stability to natural nucleotide triphosphates. PMID- 27246617 TI - Three new 16-membered macrolide compounds from a genetically engineered strain S. avermitilis MHJ1011. AB - Three new 16-membered macrolide compounds, 13alpha-O-alpha-l-oleandrosyl milbemycin beta3 (1), 13alpha-O-alpha-l-oleandrosyl-25-ethyl milbemycin beta3 (2), 13alpha-O-alpha-l-oleandrosyl-25-isopropyl milbemycin beta3 (3), were isolated from the genetically engineered strains Streptomyces avermitilis MHJ1011. Their structures were determined on the basis of spectroscopic analysis, including 1D and 2D NMR techniques as well as ESI-MS and comparison with data from the literature. Both compounds 1-3 displayed impressive acaricidal activity against larval mites with the IC50 values of 0.0327, 0.0276 and 0.0235mg/L, respectively, which are higher than those of 13alpha-hydroxy milbemycin beta3 and 13alpha-hydroxy-25-ethyl milbemycin beta3. PMID- 27246618 TI - GSK114: A selective inhibitor for elucidating the biological role of TNNI3K. AB - A series of selective TNNI3K inhibitors were developed by modifying the hinge binding heterocycle of a previously reported dual TNNI3K/B-Raf inhibitor. The resulting quinazoline-containing compounds exhibit a large preference (up to 250 fold) for binding to TNNI3K versus B-Raf, are useful probes for elucidating the biological pathways associated with TNNI3K, and are leads for discovering novel cardiac medicines. GSK114 emerged as a leading inhibitor, displaying significant bias (40-fold) for TNNI3K over B-Raf, exceptional broad spectrum kinase selectivity, and adequate oral exposure to enable its use in cellular and in vivo studies. PMID- 27246619 TI - Clinical characteristics and outcomes of the oldest old people with type 2 diabetes - perspective from a tertiary diabetes center in Thailand. AB - BACKGROUND: Advance in medicine has led to an increase in life expectancy of elderly diabetic patients especially on the growing population called the "oldest old", those in their mid-80s upwards. The aim of this study is to describe clinical characteristics and outcomes of "oldest old" patients in a specialized diabetes center. METHODS: A retrospective review was conducted on medical records of type 2 diabetes who were older than 85 years at Theptarin hospital from September 2014 to August 2015. RESULTS: During the study period, there were 143 oldest old diabetic patients who visited our hospital regularly. Of the 133 active follow-up patients (median time of follow-up 15 years, range 1-30 years), 70.7 % was female, the mean age of onset was 68.3 +/- 11.5 years and duration of diabetes was 20.1 +/- 11.1 years. According to the Charlson co-morbidity index (CCI), 35.3 % of patients were classified as having severe co-morbidities. The mean A1C, blood pressure, LDL were 6.7 +/- 1.1 %, 132/65 mmHg and 80 +/- 29 mg/dl respectively. 66.9 % of patients had tight glycemic control (A1C <7 %) while 12.0 % had poor control (A1C >8 %). Oral hypoglycemic agent (OHA) dual therapy was the most common treatment (26.3 %) followed by OHA monotherapy (22.6 %), insulin alone (19.5 %), diet therapy alone (12.7 %), and insulin plus OHA (8.3 %). Hypoglycemia was found in 10.5 % of patients in previous 12 months. Diabetic retinopathy, chronic kidney disease, cardiovascular disease, and stroke were presented in 23.4, 54.9, 15.8, 18.0 % of patients, respectively. Among patients whose received diabetic medications and resulted in very low level of A1C (A1C less than 6.0 %), only 20.0 % underwent deintensification. CONCLUSIONS: Our results revealed that real-world clinical outcomes of extreme elderly diabetic patients were diverse and being too "aggressive" diabetes treatment with older patients did occur frequently. Decision making in older people with diabetes is complex as chronic co-morbidities are very common. PMID- 27246620 TI - Medical Treatment for Acromegaly does not Increase the Risk of Central Adrenal Insufficiency: A Long-Term Follow-Up Study. AB - Central adrenal insufficiency (CAI) in acromegaly may be related to pituitary adenoma or induced by various medical treatments, transsphenoidal neurosurgery (TNS) or radiotherapy (RT), alone or combined. We assessed the role of all available treatments for acromegaly in inducing CAI. We retrospectively studied 97 patients. CAI was diagnosed if morning serum cortisol was <138 nmol/l, or if its response was inadequate in the low-dose short synacthen test. Seventy-four subjects underwent TNS (and 17 of whom also underwent RT), and 23 were on primary medical therapy: overall we diagnosed 21 cases of CAI. Duration of acromegaly, invasion of cavernous sinus, disease control, and type of medical treatment were much the same for patients with and without CAI, which was identified in 18% of patients (10/57) after one TNS, and in 53% (9/17) after RT (p=0.01); repeat surgery increased the risk of CAI (p=0.02). The risk of CAI onset during the follow-up was lower among patients treated with TNS or medical therapy than after RT (p=0.035). Medical treatment did not raise the risk of CAI, whereas a 5- and 4 fold higher risk of CAI was associated with repeat TNS and RT, respectively. Basal or stimulated cortisol levels were similar among acromegalic patients without CAI and matched controls with nonsecreting pituitary lesions. A significant proportion of patients with acromegaly developed CAI over time. While primary or secondary medical treatment did not contribute to the risk of CAI, repeat TNS and RT correlated with pituitary-adrenal axis impairment. PMID- 27246621 TI - Effects of Type 1 Insulin-Like Growth Factor Receptor Silencing in a Human Adrenocortical Cell Line. AB - Type 1 insulin-like growth factor receptor (IGF-1R) is overexpressed in a variety of human cancers, including adrenocortical tumors. The aim of the work was to investigate the effects of IGF-1R downregulation in a human adrenocortical cell line by small interfering RNA (siRNA). The human adrenocortical tumor cell line NCI H295R was transfected with 2 specific IGF1R siRNAs (# 1 and # 2) and compared with untreated cells and a negative control siRNA. IGF1R expression was determined by quantitative reverse-transcription PCR (qRTPCR) and Western blot. The effects of IGF-1R downregulation on cell proliferation and apoptosis were assessed. IGF-1R levels were significantly decreased in cells treated with IGF-1R siRNA # 1 or # 2. Relative expression of IGF1R mRNA decreased approximately 50% and Western blot analysis revealed a 30% of reduction in IGF-1R protein. Downregulation of this gene resulted in 40% reduction in cell growth in vitro and 45% increase in apoptosis using siRNA # 2. These findings demonstrate that decreasing IGF-1R mRNA and protein expression in NCI H295R cells can partially inhibit adrenal tumor cell growth in vitro. Targeting IGF1R is a promising therapy for pediatric malignant adrenocortical tumor and can still be an option for adult adrenocortical cancer based on personalized genomic tumor profiling. PMID- 27246622 TI - Cryopreservation and other assisted reproductive technologies for the conservation of threatened amphibians and reptiles: bringing the ARTs up to speed. AB - Amphibians and reptiles are experiencing serious declines, with the number of threatened species and extinctions growing rapidly as the modern biodiversity crisis unfolds. For amphibians, the panzootic of chytridiomycosis is a major driver. For reptiles, habitat loss and harvesting from the wild are key threats. Cryopreservation and other assisted reproductive technologies (ARTs) could play a role in slowing the loss of amphibian and reptile biodiversity and managing threatened populations through genome storage and the production of live animals from stored material. These vertebrate classes are at different stages of development in cryopreservation and other ARTs, and each class faces different technical challenges arising from the separate evolutionary end-points of their reproductive biology. For amphibians, the generation of live offspring from cryopreserved spermatozoa has been achieved, but the cryopreservation of oocytes and embryos remains elusive. With reptiles, spermatozoa have been cryopreserved in a few species, but no offspring from cryopreserved spermatozoa have been reported, and the generation of live young from AI has only occurred in a small number of species. Cryopreservation and ARTs are more developed and advanced for amphibians than reptiles. Future work on both groups needs to concentrate on achieving proof of concept examples that demonstrate the use of genome storage and ARTs in successfully recovering threatened species to increase awareness and support for this approach to conservation. PMID- 27246623 TI - Variations in Inpatient Rehabilitation Functional Outcomes Across Centers in the Traumatic Brain Injury Model Systems Study and the Influence of Demographics and Injury Severity on Patient Outcomes. AB - OBJECTIVE: To compare patient functional outcomes across Traumatic Brain Injury Model Systems (TBIMS) rehabilitation centers using an enhanced statistical model and to determine factors that influence those outcomes. DESIGN: Multicenter observational cohort study. SETTING: TBIMS centers. PARTICIPANTS: Patients with traumatic brain injury (TBI) admitted to 19 TBIMS rehabilitation centers from 2003-2012 (N=5505). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Functional outcomes of patients with TBI. RESULTS: Individuals with lower functional status at the time of admission, longer duration of posttraumatic amnesia, and higher burden of medical comorbidities continued to have worse functional outcomes at discharge from inpatient rehabilitation and at the 1-year follow-up, whereas those who were employed at the time of injury had better outcomes at both time periods. Risk-adjusted patient functional outcomes for patients in most TBIMS centers were consistent with previous research. However, there were wide performance differences for a few centers even after using more recently collected data, improving on the regression models by adding predictors known to influence functional outcomes, and using bootstrapping to eliminate confounds. CONCLUSIONS: Specific patient, injury, and clinical factors are associated with differences in functional outcomes within and across TBIMS rehabilitation centers. However, these factors did not explain all the variance in patient outcomes, suggesting a role of some other predictors that remain unknown. PMID- 27246624 TI - FGF13 modulates the gating properties of the cardiac sodium channel Nav1.5 in an isoform-specific manner. AB - FGF13 (FHF2), the major fibroblast growth factor homologous factor (FHF) in rodent heart, directly binds to the C-terminus of the main cardiac sodium channel, NaV1.5. Knockdown of FGF13 in cardiomyocytes induces slowed ventricular conduction by altering NaV1.5 function. FGF13 has five splice variants, each of which possess the same core region and C terminus but differing in their respective N termini. Whether and how these alternatively spliced N termini impart isoform-specific regulation of NaV1.5, however, has not been reported. Here, we exploited a heterologous expression to explore the specific modulatory effects of FGF13 splice variants FGF13S, FGF13U and FGF13YV on NaV1.5 function. We found these three splice variants differentially modulated NaV1.5 current density. Although steady-state activation was unaltered by any of the FGF13 isoforms (compared to control cells expressing Nav1.5 but not expressing FGF13), open-state fast inactivation and closed-state fast inactivation were markedly slowed, steady-state availability was significantly shifted toward the depolarizing direction, and the window current was increased by each of FGF13 isoforms. Most strikingly, FGF13S hastened the rate of NaV1.5 entry into the slow inactivation state and induced a dramatic slowing of recovery from inactivation, which caused a large decrease in current after either low or high frequency stimulation. Overall, these data showed the diversity of the roles of the FGF13 N termini in NaV1.5 channel modulation and suggested the importance of isoform specific regulation. PMID- 27246625 TI - Association between markers of endothelial dysfunction and early signs of renal dysfunction in pediatric obesity and type 1 diabetes. AB - BACKGROUND: To evaluate whether circulating markers of endothelial dysfunction, such as intercellular adhesion molecule-1 (ICAM-1) and myeloperoxidase (MPO), are increased in youth with obesity and in those with type 1 diabetes (T1D) at similar levels, and whether their levels are associated with markers of renal function. METHODS: A total of 60 obese youth [M/F: 30/30, age: 12.5 +/- 2.8 yr; body mass index (BMI) z-score: 2.26 +/- 0.46], 30 with T1D (M/F: 15/15; age: 12.9 +/- 2.4 yr; BMI z-score: 0.45 +/- 0.77), and 30 healthy controls (M/F: 15/15, age: 12.4 +/- 3.3 yr, BMI z-score: -0.25 +/- 0.56) were recruited. Anthropometric measurements were assessed and a blood sample was collected to measure ICAM-1, MPO, creatinine, cystatin C and lipid levels. A 24-h urine collection was obtained for assessing albumin excretion rate (AER). RESULTS: Levels of ICAM-1 and MPO were significantly higher in obese [ICAM-1: 0.606 (0.460-1.033) ug/mL; MPO: 136.6 (69.7-220.8) ng/mL] and T1D children [ICAM-1: 0.729 (0.507-0.990) ug/mL; MPO: 139.5 (51.0-321.3) ng/mL] compared with control children [ICAM-1: 0.395 (0.272-0.596) ug/mL MPO: 41.3 (39.7-106.9) ng/mL], whereas no significant difference was found between T1D and obese children. BMI z-score was significantly associated with ICAM-1 (beta = 0.21, p = 0.02) and MPO (beta = 0.41, p < 0.001). A statistically significant association was also found between ICAM-1 and markers of renal function (AER: beta = 0.21, p = 0.03; e-GFR: beta = 0.19, p = 0.04), after adjusting for BMI. CONCLUSIONS: Obese children have increased markers of endothelial dysfunction and early signs of renal damage, similarly to children with T1D, confirming obesity to be a cardiovascular risk factor as T1D. The association between ICAM-1 with e-GFR and AER confirm the known the association between general endothelial and renal dysfunction. PMID- 27246626 TI - Hepatitis B Reactivation After Ifosfamide Therapy for Retroperitoneal Sarcoma. AB - BACKGROUND: Patients receiving cancer treatment are at risk for hepatitis B virus (HBV) reactivation. Ifosfamide is an alkylating agent and is considered to be one of the important drugs for the treatment of metastatic sarcoma. No association of ifosfamide and HBV reactivation has been reported so far. CASE REPORT: We report a case of a 61-year-old Asian man with metastatic retroperitoneal liposarcoma who was HBcAb positive and was treated with ifosfamide and dacarbazine, developed HBV reactivation secondary to ifosfamide requiring treatment with tenofovir. To the best of our knowledge, this is the first report describing HBV reactivation in a patient with positive HBcAb who was treated with ifosfamide. CONCLUSIONS: We recommend close surveillance of possible HBV reactivation while employing ifosfamide chemotherapy. PMID- 27246628 TI - Pancreatic cancer: yesterday, today and tomorrow. AB - Pancreatic cancer is one of our most lethal malignancies. Despite substantial improvements in the survival rates for other major cancer forms, pancreatic cancer survival rates have remained relatively unchanged since the 1960s. Pancreatic cancer is usually detected at an advanced stage and most treatment regimens are ineffective, contributing to the poor overall prognosis. Herein, we review the current understanding of pancreatic cancer, focusing on central aspects of disease management from radiology, surgery and pathology to oncology. PMID- 27246627 TI - Catabolic effects of endothelial cell-derived microparticles on disc cells: Implications in intervertebral disc neovascularization and degeneration. AB - Neovascularization of intervertebral discs, a phenomenon considered pathological since normal discs are primarily avascular structures, occurs most frequently in annulus fibrosus (AF) of degenerated discs. Endothelial cells (ECs) are involved in this process, but the mechanism of the interaction between AF and endothelial cells is unclear. In this study, we evaluated the effects on matrix catabolic activity of AF cells by the extracellular endothelial microparticles (EMPs) and soluble protein factors (SUP fraction) produced from ECs. Passage 1 human AF cells grown in monolayer cultures were treated for 72 h with 250 ug of EMPs or SUP fraction isolated from culture of the microvascular endothelial cell line, HEMC-I. Live-cell imaging revealed uptake of EMPs by AF cells. RT-PCR analysis demonstrated increased mRNA expression of MMP-1 (50.3-fold), MMP-3 (4.5-fold) and MMP-13 (5.5-fold) in AF cell cultures treated with EMPs compared to untreated control. Western analysis also demonstrated increased MMP protein expression in EMP-treated AF cells. AF cells treated with the SUP fraction also exhibited a dramatic increase in MMP mRNA and protein expression. Increased MMP expression is primarily due to EMP or SUP stimulation of AF cells since EMPs or SUP fraction alone contained negligible amount of MMPs. Interestingly, MMP activity was elevated in AF cell cultures treated with EMPs but not with SUP. This study revealed enhanced matrix catabolism as a molecular consequence of action of ECs on AF cells via EMPs, which might be expected during neo-angiogenesis of degenerating disc. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1466-1474, 2016. PMID- 27246629 TI - Intellectual development of childhood ALL patients: a multicenter longitudinal study. AB - BACKGROUND: In childhood acute lymphoblastic leukemia (ALL), radiotherapy for CNS prophylaxis is not used in frontline therapy anymore. Standard treatment for ALL nowadays consists of polychemotherapy. Therefore, assessment of potential chemotherapy-induced cognitive side effects becomes important. Although neurotoxicity was demonstrated in cross-sectional studies, longitudinal studies remain scarce. PROCEDURE: We evaluated intellectual development of 94 pediatric ALL patients between 1990 and 1997, diagnosed before the age of 12 years, treated according to the European Organisation for Research and Treatment of Cancer Children's Leukemia Group 58881 protocol. Three assessments of the Wechsler Intelligence Scale for Children Revised were performed since diagnosis, according to age. Using repeated measures regression analysis, we investigated the effect of gender (low versus increased) risk group, parents' education, age at diagnosis, intelligence quotient (IQ) subscale (verbal (VIQ) versus performance (PIQ) intelligence), and test session. RESULTS: PIQ scores were lower than VIQ at baseline (-5.3 points on average, p = 0.0032), yet PIQ increased more strongly (PIQ: +3.9 points per test session; VIQ: +0.8, p = 0.0079), so this baseline difference disappeared (p = 0.0079). There were no clear effects of gender (girls: +0.6 points; p = 0.78) or risk group (low risk: +1.5 points; p = 0.49), but IQ scores were higher when one parent had followed higher education (+9.5 points, p < 0.0001). Finally, diagnosis at younger age predicted lower IQ scores (-1.3 points per year, p = 0.0009). CONCLUSION: Given that IQ scores did not decline, our findings demonstrate a stable pattern. However, the lower PIQ scores at baseline may indicate that performance functioning is vulnerable to acute neurotoxicity. Also, lower scores for younger patients highlight the stronger impact of the disease and/or treatment at younger age.Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27246630 TI - Combining a chimeric antigen receptor and a conventional T-cell receptor to generate T cells expressing two additional receptors (TETARs) for a multi-hit immunotherapy of melanoma. AB - The adoptive transfer of engineered T cells represents an important approach in immunotherapy of melanoma. However, relapse of the tumor can occur due to immune escape mechanisms developed by the tumor cells, for example antigen loss, downregulation of the major histocompatibility complex presentation machinery and defects in antigen processing. To counteract these mechanisms, we combined a T cell receptor and a chimeric antigen receptor, specific for different common melanoma antigens, gp100 (PMEL) and MCSP (HMW-MAA), to generate functional CD8+ T cells expressing two additional receptors (TETARs) by electroporation of receptor encoding mRNA. These TETARs produced cytokines and were lytic upon recognition of each of their cognate antigens, while no reciprocal inhibition of the receptors occurred. When stimulated with target cells, which express both antigens, an enhanced effect was suggested. The confirmation that chimeric antigen receptors and T-cell receptors can be functionally combined opens up new avenues in cancer immunotherapy, and the generation of TETARs helps by-passing major mechanisms by which tumor cells escape immune recognition. PMID- 27246631 TI - Second order anisotropy contribution in perpendicular magnetic tunnel junctions. AB - Hard-axis magnetoresistance loops were measured on perpendicular magnetic tunnel junction pillars of diameter ranging from 50 to 150 nm. By fitting these loops to an analytical model, the effective anisotropy fields in both free and reference layers were derived and their variations in temperature range between 340 K and 5 K were determined. It is found that a second-order anisotropy term of the form K2cos(4)theta must be added to the conventional uniaxial -K1cos(2)theta term to explain the experimental data. This higher order contribution exists both in the free and reference layers. At T = 300 K, the estimated -K2/K1 ratios are 0.1 and 0.24 for the free and reference layers, respectively. The ratio is more than doubled at low temperatures changing the ground state of the reference layer from "easy-axis" to "easy-cone" regime. The easy-cone regime has clear signatures in the shape of the hard-axis magnetoresistance loops. The existence of this higher order anisotropy was also confirmed by ferromagnetic resonance experiments on FeCoB/MgO sheet films. It is of interfacial nature and is believed to be due to spatial fluctuations at the nanoscale of the first order anisotropy parameter at the FeCoB/MgO interface. PMID- 27246632 TI - Surgical implications of frontoethmoidal pneumosinus dilatans-associated proptosis caused by meningioma. AB - Pneumosinus dilatans (PSD) involves paranasal sinus enlargement without radiologic evidence of localized bone destruction, hyperostosis, or mucous membrane thickening. We discuss the surgical implications of PSD-associated proptosis in patients with anterior skull-base meningioma. A 20-year-old man with proptosis, hypoglobus, and lateral globe displacement had WHO grade I anterior skull-base and orbital meningiomas. Aggressive resection using anterior/medial orbitotomy and an anterior interhemispheric skull-base approach achieved Simpson grade I resection. Postoperatively, his symptoms improved, with no recurrence at 2-year follow-up. Although PSD-associated proptosis is relatively uncommon, it carries important clinical implications in surgical management of skull-base and orbital meningiomas. PMID- 27246633 TI - Study of the pathogenesis and treatment of diabetes mellitus through animal models. AB - Most research in diabetes mellitus (DM) has been conducted in animals, and their replacement is currently a chimera. As compared to when they started to be used by modern science in the 17th century, a very high number of animal models of diabetes is now available, and they provide new insights into almost every aspect of diabetes. Approaches combining human, in vitro, and animal studies are probably the best strategy to improve our understanding of the underlying mechanisms of diabetes, and the choice of the best model to achieve such objective is crucial. Traditionally classified based on pathogenesis as spontaneous or induced models, each has its own advantages and disadvantages. The most common animal models of diabetes are described, and in addition to non-obese diabetic mice, biobreeding diabetes-prone (BB-DP) rats, streptozotocin-induced models, or high-fat diet-induced diabetic C57Bl/6J mice, new valuable models, such as dogs and cats with spontaneous diabetes, are described. PMID- 27246634 TI - Medullary thyroid carcinoma as manifestation of the loss of heterozygosity in a patient with MEN1. PMID- 27246635 TI - Nonadherence to Recommended Guidelines for Blood Pressure Measurement. AB - Accuracy of blood pressure readings, both in the physician's office and at home, is crucial in properly managing hypertension. Few studies have investigated adherence to measurement guidelines. This study focused on two important aspects of blood pressure measurement: waiting time before measurement and number of readings taken. A total of 103 patients completed self-report questionnaires about office and home blood pressure measurements, with 77% reporting that physician measurements were obtained without waiting, and 56% reporting that only one reading was obtained. The proportions were even higher when measured by a nurse/technician, 96% and 81%, respectively. Home readings were taken without waiting by 60%, and 40% reported taking only a single reading. Most patients received no measurement instructions. Nonadherence to measurement guidelines is common, and may be affecting the validity of readings obtained both in physicians' offices and at home, with significant and potentially harmful effects on treatment decisions. PMID- 27246638 TI - Enhanced nitric oxide-mediated autophagy contributes to the hepatoprotective effects of ischemic preconditioning during ischemia and reperfusion. AB - Ischemic preconditioning (IPC) protects against liver ischemia/reperfusion (I/R) injury. Autophagy is an essential cytoprotective system that is rapidly activated by multiple stressors. Nitric oxide (NO) acts as an inducer of IPC. We examined the impact of autophagy in liver IPC and its regulation by NO. Male C57BL/6 mice were subjected to 60 min of hepatic ischemia followed by 6 h of reperfusion. IPC was achieved for 10 min of ischemia followed by 10 min of reperfusion prior to sustained ischemia. N(omega)-Nitro-l-arginine methyl ester (L-NAME, 15 mg/kg, i.v., all NOS inhibitor) and aminoguanidine (AG, 10 mg/kg, i.v., iNOS inhibitor) were injected 10 min before IPC. SB203580 (10 mg/kg, i.p., p38 inhibitor) was injected 30 min before IPC. I/R increased serum alanine aminotransferase activity. IPC attenuated this increase, which was abolished by L-NAME, but not AG. Microtubule-associated protein-1 light chain 3-II levels increased and p62 protein levels decreased after I/R; these changes were augmented by IPC and abolished by L-NAME. I/R increased liver protein expression of autophagy-related protein (Atg)12-Atg5 complex and lysosome-associated membrane protein-2. IPC augmented the expression of these proteins, which were abolished by L-NAME, but not AG. IPC also augmented the level of phosphorylated p38 MAPK induced by I/R and this phosphorylation was abolished by L-NAME. Our findings suggest that IPC mediated NO protects against I/R-induced liver injury by enhancing autophagic flux. PMID- 27246639 TI - [Hepatitidis E virus]. AB - The number of detected cases of hepatitis E (HE) shows an increasing trend in the Czech Republic, probably due the introduction of new diagnostic methods and greater awareness of HE. In most cases, the source of infection has remained unconfirmed or entirely unclear. The causative agent, the hepatitis E virus (HEV), belongs to the Hepeviridae family. Recently, many isolates from mammals, birds, and fish have been identified. HEV is widespread among farm pigs and wild boar populations all over the word. Both species serve as HEV reservoirs. Consumption of undercooked meat or offal from the reservoir animals is considered to be unsafe due to zoonotic transmission of HEV. The aim of the present article is to summarize recent findings regarding HEV. KEY WORDS: hepatitis E - zoonosis food-borne infection. PMID- 27246640 TI - [Antibiotic treatment of clostridial colitis]. AB - The advantages and disadvantages of various antibiotics used in the treatment of Clostridium difficile infection (CDI) are compared with respect to their pharmacokinetic and pharmacodynamic properties. Recommendations are made for their optimal use in clinical practice. Metronidazole is suitable for the treatment of mild forms of CDI which are essentially self-limiting. Vancomycin kills clostridia reliably but the treatment is encumbered with considerable risk of recurrence. This can be decreased by shortening the treatment to seven days and then switching to a (pulse, taper, chaser) regimen to prevent recurrence or by active restoration of the intestinal ecosystem (fecal transplant). Fidaxomicin works faster than vancomycin and is associated with a lower risk of recurrence. Thus, it can be profitably used in patients with impending ileus and also in those whose medical condition does not allow prolonged treatment. The duration of fidaxomicin treatment could be reduced to as few as five days. Rifaximin does not have a clear place in the treatment of CDI because no compelling data are available on its efficacy in this disease. The risk of resistance is also important. Tigecycline is a promising antibiotic for parenteral use. According to the available data, it should be more effective than intravenous metronidazole which has been considered the drug of choice.Clostridial colitis is associated with intestinal dysmicrobia which is the major cause of recurrence. Severe dysmicrobia cannot be treated by antibiotics but only by gut flora restoration; stool transplant from a healthy donor is the only proven therapy for this condition. PMID- 27246641 TI - Prevalence of infectious complications in burn patients requiring intensive care: data from a pan-European study. AB - The objective of this study was to determine the prevalence of infectious complications in burn patients requiring intensive care in a one-day multicenter study encompassing burn centers in various European countries. MATERIAL AND METHODS: The European Burns Association database identified 87 centers in Western and Eastern Europe, 27 of which agreed to cooperate. American Burn Association recommendations were used for diagnosis of various infectious complications in patients with thermal trauma. RESULTS: From those centers, we randomly assigned 134 patients (44 women) to the analysis. Mean age of the group was 40.39 +/- 22.17(SD) years. Mean abbreviated burn severity index was 7.5+/-2.54, mean size of burned area was 30.49 +/- 20.14% of total body surface area. Mean length of hospitalization to date was 24.32 +/- 30.64 days. Infectious complications were observed in 92 patients (68.7%), 76 (56.7%) of whom met the criteria for infection of the burned area, 26 patients (19.4%) for bloodstream infection, 21 (15.7%) for pneumonia, and 13 (9.7%) for urinary system infection. Multifocal infections were found in 29 patients (21.6%). Gram-positive bacterial strains as potentially pathogenic microorganisms were identified in 67 patients (50.0%), Gram-negative bacterial strains in 73 (54.5%), and yeasts in 18 (13.4%) patients. Filamentous fungi were not isolated from any patient in the group. CONCLUSION: Cornerstone future standards in individual burn centers should be to monitor the occurrence of infectious complications in burn patients, prevent the spread of these complications, and report resistant pathogens. This work constitutes an important project in this area. PMID- 27246642 TI - [The prevalence of Candida pelliculosa, Candida utilis, and Candida fabianii in the Olomouc University Hospital: epidemiological study]. AB - BACKGROUND: The aims of this study were to determine the prevalence of C. pelliculosa, C. utilis, and C. fabianii in clinical samples collected from patients hospitalized in the Olomouc University Hospital and compare their minimum inhibitory concentrations (MICs ) to nine systemic antifungals with respect to yeast species, patient age, gender, and site of infection. MATERIAL AND METHODS: Identification was performed biochemically and using mass spectrometry (MALDI-TOF MS). MICs were determined by the broth dilution method. RESULTS: Of a total of 163 clinical isolates, 119 were biochemically identified as C. pelliculosa and 44 as C. utilis. Using MALDI-TOF MS, 152 isolates were identified as C. fabianii, six as C. pelliculosa, three as C. utilis, and one as Ogataea polymorpha. The highest mean MICs were found in C. fabianii and in yeasts isolated from blood cultures and central venous catheters. CONCLUSIONS: The MALDI TOF MS found C. fabianii to be most prevalent in clinical samples as compared with the other studied species. The probable cause of discordant results between the two methods was the absence of C. fabianii in the database of the biochemical test kit which led to misidentification of this species. Higher MIC values in C. fabianii demonstrate the importance of the precise identification of this species. PMID- 27246643 TI - [The benefit from mumps virus IgG antibody avidity testing in the population with high vaccine coverage in the context of other serological methods for laboratory diagnosis of mumps and the current epidemiological]. AB - AIM: Regular vaccination against mumps resulted in a significant reduction in epidemic mumps in the Czech Republic. However, mumps cases have recently shown an upward trend, even in the vaccinated population where a considerable proportion of cases have occurred. The aim of this study was to find out, by mumps virus IgG antibody avidity testing, whether the high incidence of mumps in the vaccinated population is a result of primary or secondary vaccine failure and whether the vaccinated differ from the naturally immunised in anamnestic antibody avidity. Given the problematic laboratory diagnosis of mumps in the population with high vaccination coverage, the informative value of the detected IgM, IgA, and IgG antibodies was also considered as well as the potential of antibody avidity testing for improving laboratory diagnosis from a single sample of blood, the most commonly analysed clinical material, in patients with suspected mumps. MATERIAL AND METHODS: Sixty-four patients laboratory confirmed with mumps, whose vaccination status was known, were included in the study (groups 1 and 2). Other study groups were 30 healthy naturally immunised subjects (group 3) and 22 vaccinated children 2-4-years of age with no etiological link to the mumps virus (group 4). The avidity index (AI) was determined using the Siemens Enzygnost Anti Mumps/IgG kit and 6M urea, able to induce the dissociation of antigen-antibody bonds proportionally to the antibody avidity. IgM, IgG, and IgA antibodies were tested using the Siemens Enzygnost Anti-Mumps/IgM and /IgG, and Mast Diagnostica Mastazyme Mumps IgA kits. The EPIDAT system served as the data source. RESULTS: The results showed that the mumps virus induces antibodies with a low AI after both vaccination, even recent, and natural immunisation. Antibodies with a high AI were only detected in convalescent sera of the vaccinated patients or in re infected, naturally immunised persons, as a result of recent contact with the mumps virus. The comparison of the results of acute sera testing revealed that in the vaccinated patients, 56% of cases were laboratory confirmed based on IgA positivity, i.e. 20% more cases in comparison with routine detection of IgM antibodies, while of unvaccinated cases, 87% were IgA positive and 74% IgM positive. CONCLUSION: The results of mumps virus IgG antibody avidity testing suggest that the high proportion of cases in the vaccinated patients result from secondary vaccine failure, also known as waning immunity. Diagnostic benefit from antibody avidity testing has been observed in convalescent sera and/or acute sera from both vaccinated and naturally immunised patients collected from day 6 after the onset of the disease when significant increase in AI occurs.The comparison of the serological methods for the detection of IgM, IgG, and IgA antibodies in acute sera revealed that the highest percentage of mumps infection was detected by IgA antibody testing. The addition of this serological method to mumps laboratory diagnosis made the latter considerably more effective, particularly in the vaccinated patients. PMID- 27246644 TI - Influenza in the pediatric population in Istanbul: a one center experience 2009 2014. AB - INTRODUCTION: The aim of the study was to evaluate the clinical characteristics of pediatric patients with influenza infection. MATERIAL AND METHODS: The patients hospitalized with confirmed influenza between October 2009 and May 2014 were enrolled in this study. RESULTS: The mean age of the patients was 66 +/- 53 months (1-204 months). Fifty-four percent of patients had a chronic underlying disease. Twenty-four patients needed mechanical ventilation support and a two month-old patient with liver disease died. Except for the 2009-2010 season, all patients who received mechanical ventilation had underlying disease. The hospital admission months were December-February in 2010-2011 and January-March in 2011 2012 as well as in 2012-2013. Convulsion was observed frequently in influenza A cases, and influenza B tended to be detected in older patients (p = 0.024). The most common symptoms in pediatric patients were fever and cough. CONCLUSION: It is obvious that to protect against circulating influenza viruses, the risk-based strategy of annual influenza immunization should target school-aged children and children with underlying conditions, especially neurological and pulmonary diseases. PMID- 27246645 TI - [Assessment of invalidity as a result of infectious diseases]. AB - AIM: The article features the new medical assessment paradigm for invalidity as a result of infectious disease which is applied as of 1 January 2010. MATERIAL AND METHODS: The invalidity assessment criteria are regulated specifically by Regulation No. 359/2009. Chapter I of the Annexe to the invalidity assessment regulation addresses the area of infectious diseases with respect to functional impairment and its impact on the quality of life. Since 2010, the invalidity has also been newly categorized into three groups. The new assessment approach makes it possible to evaluate a persons functional capacity, type of disability, and eligibility for compensation for reduced capacity for work. RESULTS: In 2010, a total of 170 375 invalidity cases were assessed, and in 2014, 147 121 invalidity assessments were made. Invalidity as a result of infectious disease was assessed in 177 persons in 2010, and 128 invalidity assessments were made in 2014. The most common causes of invalidity as a result of infectious disease are chronic viral hepatitis, other spirochetal infections, tuberculosis of the respiratory tract, tick-borne viral encephalitis, and HIV/AIDS. CONCLUSION: The number of assessments of invalidity as a result of infectious disease showed a declining trend between 2010 and 2014, similarly to the total of invalidity assessments. In spite of this fact, the cases of invalidity as a result of infectious disease account for approximately half percent of all invalidity assessments made in the above-mentioned period of time. PMID- 27246646 TI - [Infectious and other somatic comorbidity in problem drug users - results of a cross-sectional study with medical examination]. AB - BACKGROUND: Problem drug use is associated with excess risk of infectious and other somatic diseases resulting mainly from injecting drug use. MATERIAL AND METHODS: At the end of 2013, a complete medical history and physical examination was done in 40 problem drug users (30 males and 10 females), mean age 35.5 years (37.0 and 30.9, respectively), recruited in 4 low-threshold facilities in Prague. Of them, 37 were ex- or active injecting drug users, predominantly of methamphetamine (pervitin) and less often of buprenorphine. RESULTS: The study physician rated the health status as -good or satisfactory in 35 participants and as unsatisfactory in five participants (12.5%). The most common pathologies were dental problems (36 participants, i.e. 90.0%) and skin conditions (15.0%). The most prevalent dental pathology was caries while dermatological disorders were mostly trophic skin lesions on the lower legs, including crural ulcers, and injection site infections. Gynaecological pathology was found in 2 of 10 females. The study subjects were most commonly diagnosed with chronic hepatitis C, status post hepatitis A and B, chronic caries, missing teeth, post-thrombotic swelling and trophic skin lesions on the lower legs, purulent skin lesions, and gastroduo denal ulcer. A vast majority of the study participants were smokers. All were referred to various specialists for further examination or treatment, mostly to stomatology, hepatology, gastroenterology, and internal/general medicine departments. However, in reality the treatment participation rate is low among problem drug users due to the drug use-specific factors and needs that limit access to treatment. CONCLUSION: The incidence of diverse somatic comorbidities requiring standard general medical care is significant among problem drug users. Infectious, dermatological, and dental pathologies are predominant. In areas with high prevalence of problem drug use, implementation of a special program should be considered to provide comprehensive medical care taking account of the special needs of this target group. PMID- 27246647 TI - Rapid selection for resistance to diamide insecticides in Plutella xylostella via specific amino acid polymorphisms in the ryanodine receptor. AB - Diamide insecticides, such as flubendiamide and chlorantraniliprole, are a new class of insecticide with a novel mode of action, selectively activating the insect ryanodine receptor (RyR). They are particularly active against lepidopteran pests of cruciferous vegetable crops, including the diamondback moth, Plutella xylostella. However, within a relatively short period following their commercialisation, a comparatively large number of control failures have been reported in the field. In this review we summarise the current body of knowledge regarding the molecular mechanisms of diamide resistance in P. xylostella. Resistant phenotypes collected from different countries can often be linked to specific target-site mutation(s) in the ryanodine receptors' transmembrane domain. Metabolic mechanisms of resistance have also been proposed. Rapid resistance development is probably a consequence of over-reliance on this one class of chemistry for diamondback moth control. PMID- 27246649 TI - Neurobehavioral effects of exposure to propionic acid revisited-Does psychosocial stress interfere with distractive effects in volunteers? AB - Local irritants stimulate the nervous system via chemosensory pathways that trigger cognitive distraction, subjective complaints about impaired health, and physiological defense reflexes (e.g. eye-blinks). At workplaces and in the environment chemical exposures often co-occur with psychosocial stress. This study investigated if stress modulates adverse effects of exposure to the local irritant and malodorant propionic acid (PA). Forty-eight participants were randomly assigned to an experimental (false negative feedback+salient surveillance) or control group. In a cross-over design, both groups were exposed for 4h to PA in concentrations of 0.3 and 0-20ppm (time-weighted average=10ppm). In the experimental group, the stress protocol induced moderate psychosocial stress as indicated by salivary cortisol and subjective responses. Despite concentration-dependent increases in chemosensory perceptions and symptoms, the level of exposure to PA had no impact upon the results of four out of six neurobehavioral tests. In the sustained attention test, there was a significant increase in error rates that corresponded to the exposure levels. However, a concentration-dependent impairment of spatial working memory and an adverse increase in eye-blink frequency were restricted to the control group. Stressed participants had shorter simple reaction times and high eye-blink frequency irrespective of exposure suggesting enhanced alertness. Psychosocial stress increased complaints, ocular irritation and unspecific symptoms at the end of the 0.3ppm exposure to a level that was comparable with that in the control group during exposure to 0-20ppm. Results indicate that the adverse effects of a local irritant and psychosocial stress are non-additive. PMID- 27246648 TI - Lower sulfurtransferase detoxification rates of cyanide in konzo-A tropical spastic paralysis linked to cassava cyanogenic poisoning. AB - Using a matched case-control design, we sought to determine whether the odds of konzo, a distinct spastic paraparesis associated with food (cassava) cyanogenic exposure in the tropics, were associated with lower cyanide detoxification rates (CDR) and malnutrition. Children with konzo (N=122, 5-17 years of age) were age- and sex-matched with presumably healthy controls (N=87) and assessed for motor and cognition performances, cyanogenic exposure, nutritional status, and cyanide detoxification rates (CDR). Cyanogenic exposure was ascertained by thiocyanate (SCN) concentrations in plasma (P-SCN) and urine (U-SCN). Children with a height for-age z-score (HAZNCHS)<-2 were classified as nutritionally stunted. CDR was measured as time required to convert cyanide to SCN, and expressed as ms/MUmol SCN/mg protein or as mmolSCN/ml plasma/min. Mean (SD) U-SCN in children with konzo was 521.9 (353.6) MUmol/l and was, significantly higher than 384.6 (223.7) MUmol/l in those without konzo. Conditional regression analysis of data for age- and sex- matched case-control pairs showed that konzo was associated with stunting (OR: 5.8; 95% CI: 2.7-12.8; p<0.01; N=83 paired groups) and higher U-SCN (OR: 1.1; 95% CI: 1.02-1.20 per 50-MUmol increase in U-SCN; p=0.02; N=47 paired groups). After adjusting for stunting and U-SCN, the odds of developing konzo was reduced by 63% (95% CI: 11-85%, p=0.03; N=41 paired groups) for each 5mmol SCN/(ml plasma/min)-increase in CDR. Linear regression analysis indicated a significant association between BOT-2 or KABC-II scores and both the HAZNCHS z score and the U-SCN concentration, but not the CDR. Our findings provide evidence in support of interventions to remove cyanogenic compounds from cassava prior to human consumption or, peharps, enhance the detoxification of cyanide in those relying on the cassava as the main source of food. PMID- 27246651 TI - Characterization of the natural products in cocoyam (Colocasia esculenta) using GC-MS. AB - CONTEXT: There is paucity of information in literature on the natural products in cocoyam [Colocasia esculenta Linn (Araceae)] that confer it with biological properties. OBJECTIVES: This study investigated the antioxidant properties of C. esculenta and also reported for the first time the natural products in C. esculenta that justify its biological properties. MATERIALS AND METHODS: The antioxidant activity of the methanol extract (50-250 MUg/mL) of C. esculenta was determined using the 2,2-diphenyl-1-picryl hydrazyl (DPPH) radical and reducing power assays. Characterization of the natural products in C. esculenta was done using the gas chromatographic-mass spectrometric (GC-MS) technique. The experiment lasted for 3 months. RESULTS: GC-MS analysis of methanol/chloroform extract of the flour of C. esculenta indicated the presence of eight compounds, namely hexadecanoic acid methyl ester (0.43%), octadecanoic acid (20.91%), 9,12 octadecadienoyl chloride (0.77%), 11-octadecenoic acid methyl ester (2.12%), 9 octadecenoic acid (64.37%), 3-hexadecyloxycarbonyl-5-(2-hydroxylethyl)-4 methylimidazolium(1.36%), hexanedioic acid, bis(2-ethylhexyl)ester (1.36%) and 3,5-di-t-butyl phenol (3.27%). The total phenolic content of C. esculenta was 15.15 +/- 0.35 mg Gallic Acid Equivalence/g and it was significantly higher (p < 0.05) than the total flavonoid (8.50 +/- 0.42 mg Quercetin Equivalence/g) and condensed tannin (4.40 +/- 0.14 mg Catechin Equivalence/g) contents, respectively. C. esculenta possessed strong antioxidant capacity though it was lower than that of standard quercetin. DISCUSSION AND CONCLUSION: Results showed that C. esculenta possesses strong antioxidant activity and also contains some important bioactive compounds that justify its medicinal properties as used in ethno-medicine. PMID- 27246650 TI - Phosphatidylinositol 3-Kinase and Protein Kinase C Signaling Pathways Are Involved in Stromal Cell-derived Factor-1alpha-mediated Transmigration of Stem Cells from Apical Papilla. AB - INTRODUCTION: Previously, we have shown that stem cells from apical papilla (SCAPs) can be chemoattracted by stromal cell-derived factor-1alpha (SDF-1alpha). The purpose of this study was to investigate the intracellular signaling pathways involved in SDF-1alpha-mediated migration of SCAPs. METHODS: Chemotaxis assays were performed to assess the effect of phosphatidylinositol 3-kinase (PI3K) and protein kinase C (PKC) signaling pathways in the SDF-1alpha-mediated migration of SCAPs using inhibitors of PI3K (LY294002) or PKC (GF109203X). The Cell Counting Kit-8 assay (Dojindo Laboratories, Kumamoto, Japan) was used to evaluate the effect of the inhibitors on the proliferation of SCAPs. The expression of focal adhesion-related proteins was examined by immunofluorescence staining and Western blot analysis. Phosphorylation of PI3K subunit p85 and PKC after SDF-1alpha induction was evaluated by Western blot. RESULTS: The inhibition of PI3K or PKC signaling pathways significantly reduced SDF-1alpha-mediated migration of SCAPs. The inhibitors had no effect on the proliferation of SCAPs. Immunofluorescence analysis revealed that SDF-1alpha stimulated focal adhesion formation and stress fiber assembly in SCAPs, in addition to up-regulation of the expression of focal adhesion molecules, including p-focal adhesion kinase, p-paxillin, and vinculin. Pretreatment with PI3K or PKC inhibitors before SDF-1alpha induction significantly inhibited focal adhesion molecule expression. Moreover, increased phosphorylation of p85 and PKC were observed after SDF-1alpha stimulation, whereas these phosphorylations were down-regulated by the inhibition of PI3K or PKC signaling pathways. CONCLUSIONS: PI3K and PKC signaling pathways appear to be required for SDF-1alpha-mediated transmigration of SCAPs. These findings provide insights into the signaling mechanisms that underlie SDF-1alpha-mediated migration of SCAPs. PMID- 27246652 TI - Atomic Layer Deposition of Bismuth Vanadates for Solar Energy Materials. AB - The fabrication of porous nanocomposites is key to the advancement of energy conversion and storage devices that interface with electrolytes. Bismuth vanadate, BiVO4 , is a promising oxide for solar water splitting where the controlled fabrication of BiVO4 layers within porous, conducting scaffolds has remained a challenge. Here, the atomic layer deposition of bismuth vanadates is reported from BiPh3 , vanadium(V) oxytriisopropoxide, and water. The resulting films have tunable stoichiometry and may be crystallized to form the photoactive scheelite structure of BiVO4 . A selective etching process was used with vanadium rich depositions to enable the synthesis of phase-pure BiVO4 after spinodal decomposition. BiVO4 thin films were measured for photoelectrochemical performance under AM 1.5 illumination. The average photocurrents were 1.17 mA cm( 2) at 1.23 V versus the reversible hydrogen electrode using a hole-scavenging sulfite electrolyte. The capability to deposit conformal bismuth vanadates will enable a new generation of nanocomposite architectures for solar water splitting. PMID- 27246654 TI - A Dual Identity Approach for Conceptualizing and Measuring Children's Gender Identity. AB - The goal was to test a new dual identity perspective on gender identity by asking children (n = 467) in three grades (Mage = 5.7, 7.6, 9.5) to consider the relation of the self to both boys and girls. This change shifted the conceptualization of gender identity from one to two dimensions, provided insights into the meaning and measurement of gender identity, and allowed for revisiting ideas about the roles of gender identity in adjustment. Using a graphical measure to allow assessment of identity in young children and cluster analyses to determine types of identity, it was found that individual and developmental differences in how similar children feel to both genders, and these variations matter for many important personal and social outcomes. PMID- 27246653 TI - Evaluation of Yoga for Preventing Adolescent Substance Use Risk Factors in a Middle School Setting: A Preliminary Group-Randomized Controlled Trial. AB - Adolescence is a key developmental period for preventing substance use initiation, however prevention programs solely providing educational information about the dangers of substance use rarely change adolescent substance use behaviors. Recent research suggests that mind-body practices such as yoga may have beneficial effects on several substance use risk factors, and that these practices may serve as promising interventions for preventing adolescent substance use. The primary aim of the present study was to test the efficacy of yoga for reducing substance use risk factors during early adolescence. Seventh grade students in a public school were randomly assigned by classroom to receive either a 32-session yoga intervention (n = 117) in place of their regular physical education classes or to continue with physical-education-as-usual (n = 94). Participants (63.2 % female; 53.6 % White) completed pre- and post intervention questionnaires assessing emotional self-regulation, perceived stress, mood impairment, impulsivity, substance use willingness, and actual substance use. Participants also completed questionnaires at 6-months and 1-year post-intervention. Results revealed that participants in the control condition were significantly more willing to try smoking cigarettes immediately post intervention than participants in the yoga condition. Immediate pre- to post intervention differences did not emerge for the remaining outcomes. However, long term follow-up analyses revealed a pattern of delayed effects in which females in the yoga condition, and males in the control condition, demonstrated improvements in emotional self-control. The findings suggest that school-based yoga may have beneficial effects with regard to preventing males' and females' willingness to smoke cigarettes, as well as improving emotional self-control in females. However additional research is required, particularly with regard to the potential long term effects of mind-body interventions in school settings. The present study contributes to the literature on adolescence by examining school-based yoga as a novel prevention program for substance use risk factors. PMID- 27246655 TI - Association of Non-alcoholic Fatty Liver Disease with Metabolic Syndrome Independently of Central Obesity and Insulin Resistance. AB - Non-alcoholic fatty liver disease (NAFLD) is an emerging chronic liver disease that may lead to liver cirrhosis and hepatocellular carcinoma. We aimed to determine the association between the prevalence of metabolic syndrome (MetS) and NAFLD severity using semi-quantitative ultrasonography (US). A total of 614 participants were recruited from the community. NAFLD was evaluated according to the ultrasonographic Fatty Liver Indicator (US-FLI), which is a semi-quantitative liver ultrasound score. Insulin resistance was estimated with the homeostasis model assessment index for insulin resistance (HOMA-IR). NAFLD and MetS were found in 53.7 and 17.3% of the participants, respectively. Linear relationships were found between the severity of NAFLD and waist circumference, fasting glucose, HOMA-IR, triglycerides, HDL-C and blood pressure. After adjusting for confounding factors, i.e., body mass index and HOMA-IR, the odds ratios for MetS were 3.64 (95% confidence interval (CI): 1.5-8.83) for those with mild NAFLD and 9.4 (95% CI: 3.54-24.98) for those with moderate-to-severe NAFLD compared to those without NAFLD. The combination of the HOMA-IR and US-FLI scores better differentiated MetS than the HOMA-IR alone. In addition to obesity, the severity of NAFLD and the HOMA-IR both play important roles in MetS. Whether NAFLD is a component of MetS warrants further research. PMID- 27246657 TI - Establishment and application of a real-time loop-mediated isothermal amplification system for the detection of CYP2C19 polymorphisms. AB - Single-nucleotide polymorphisms (SNPs) represent the most widespread type of genetic variation (approximately 90%) in the human genome, and the demand to overcome such variation has received more attention now than ever before. The capacity to rapidly assess SNPs that correlate with disease predisposition, drug efficacy and drug toxicity is a key step for the development of personalized medicine. In this work, a rapid one-step SNP detection method, real-time loop mediated isothermal amplification (RT-LAMP), was first applied for CYP2C19 polymorphisms testing. The optimized method was established with specifically designed primers for target amplification by real-time detection in approximately 30 min under isothermal conditions. RT-LAMP amplified few copies of template to produce significant amounts of product and quantitatively detected human DNA with compatible specificity and sensitivity. The success in the establishment of this RT-LAMP protocol for CYP2C19 polymorphism testing is significant for the extension of this technique for the detection of other SNPs, which will further facilitate the development of personalized medicine. PMID- 27246658 TI - Cycloaddition Chemistry of Tetrafluorothiophene S,S-Dioxide. AB - Tetrafluorothiophene S,S-dioxide has been found to be a powerful and versatile cycloaddend that undergoes a wide range of reactions as a Diels-Alder diene, dienophile, and [2 + 2] addend. Because it dimerizes only slowly at high temperatures, a broad range of conditions are available for these transformations. Reactions with terminal alkynes yield products of both Diels Alder and [2 + 2] cycloaddition. Remarkably, the orbital topology-forbidden [2 + 2] process sometimes dominates over the allowed Diels-Alder reaction. PMID- 27246656 TI - Recent advances in the production of recombinant subunit vaccines in Pichia pastoris. AB - Recombinant protein subunit vaccines are formulated using defined protein antigens that can be produced in heterologous expression systems. The methylotrophic yeast Pichia pastoris has become an important host system for the production of recombinant subunit vaccines. Although many basic elements of P. pastoris expression system are now well developed, there is still room for further optimization of protein production. Codon bias, gene dosage, endoplasmic reticulum protein folding and culture condition are important considerations for improved production of recombinant vaccine antigens. Here we comment on current advances in the application of P. pastoris for the synthesis of recombinant subunit vaccines. PMID- 27246659 TI - Stereochemistry-Guided DNA Probe for Single Nucleotide Polymorphisms Analysis. AB - Single nucleotide polymorphisms (SNPs) are the most abundant genetic polymorphisms and are responsible for many genetic diseases and cancers. In general, SNPs detection is performed by a single probe system (SPS), in which a single probe specifically hybridizes to one target. However, with the use of this method it is hard to improve the hybridization specificity and single mismatched discrimination factors (DF). In addition, the multiprobe system (MPS) requires complex probe designs and introduces at least one auxiliary probe except for the probe complementary to the target, resulting in a complicated detection system. Faced with these difficulties, we perform the SNP detection using a d/l tryptophan (Trp) guided DNA probe and regulate the DF of electrochemical DNA (E DNA) sensors by molecular chirality. We show that the DF of the d-Trp incubated E DNA sensor (d-sensor) is larger than that of the l-sensor. More importantly, we achieve the high specificity by coupling d-Trp and l-Trp incubated E-DNA sensors, and the median DF is 7.21. Furthermore, the specificity of SNP detection can be further improved by supersandwich assay, and the median DF is enlarged to 37.23, which is comparable to that obtained with a multiprobe detection system. PMID- 27246660 TI - Correlating the Sonographic Finding of Echogenic Debris in the Bladder Lumen With Urinalysis. AB - OBJECTIVES: The purpose of this study was to determine the significance of urinary bladder debris detected by sonography. METHODS: We conducted a retrospective analysis of urinalysis results in age-matched patients with and without bladder debris detected by transabdominal sonography. Patients were recruited from a radiology database search for bladder sonograms either with words suggesting echogenic debris or by a clinical history suggesting an infectious course. The sonograms were randomized and read by a single radiologist, who was blinded to case versus control. The urinalysis and sonographic results were analyzed by the Fisher exact test. RESULTS: There was no statistically significant correlation between the finding of debris on sonography and the frequency of abnormal urinalysis results, regardless of the quality of debris (layering versus floating). The only variable that was significantly associated with abnormal urinalysis results was a clinical history suggesting infection. CONCLUSIONS: A urinalysis should not be routinely recommended to work up the finding of urinary bladder debris on sonography. PMID- 27246661 TI - The Rapid Assessment of Competency in Echocardiography Scale: Validation of a Tool for Point-of-Care Ultrasound. AB - OBJECTIVES: Increased use of point-of-care ultrasound (US) requires the development of assessment tools that measure the competency of learners. In this study, we developed and tested a tool to assess the quality of point-of-care cardiac US studies performed by novices. METHODS: In phase 1, the Rapid Assessment of Competency in Echocardiography (RACE) scale was developed on the basis of structured interviews with subject matter experts; the tool was then piloted on a small series of US studies in phase 2. In phase 3, the tool was applied to a sample of 154 point-of-care US studies performed by 12 learners; each study was independently rated by 2 experts, with quantitative analysis subsequently performed. RESULTS: Evidence of the content validity of the RACE scale was supported by a consensus exercise, wherein experts agreed on the assessment dimensions and specific items that made up the RACE scale. The tool showed good inter-rater reliability. An analysis of inter-item correlations provided support for the internal structure of the scale, and the tool was able to discriminate between learners early in their point-of-care US learning and those who were more advanced in their training. CONCLUSIONS: The RACE scale provides a straightforward means to assess learner performance with minimal requirements for evaluator training. Our results support the conclusion that the tool is an effective means of making valid judgments regarding competency in point-of-care cardiac US. PMID- 27246662 TI - A Randomized Double-Blinded Trial on the Effects of Ultrasound Transducer Orientation on Teaching and Learning Ultrasound-Guided Regional Anesthesia. AB - OBJECTIVES: Learning ultrasound-guided regional anesthesia skills, especially needle/ beam alignment, can be especially difficulty for trainees, who can often become frustrated. We hypothesized that teaching novices to orient the transducer and needle perpendicular to their shoulders will improve performance on a standardized task, compared to holding the transducer and needle parallel to the shoulders. METHODS: This study compared the effects of transducer orientation on trainees' ability to complete a standardized ultrasound-guided nerve block simulation. The time to task completion and percentage of the attempt time without adequate needle visualization were measured. Participants were right handed healthy adults with no previous ultrasound experience and were randomly assigned to training in either transducer and needle alignment in a coronal plane, parallel to the shoulders (parallel group) or transducer and needle alignment in a sagittal plane, perpendicular to the shoulders (perpendicular group). Participants used ultrasound to direct a needle to 3 targets in a standardized gelatin phantom and repeated this task 3 times. Their efforts were timed and evaluated by an assessor, who was blinded to group assignment. RESULTS: Data were analyzed on 28 participants. The perpendicular group was able to complete the task more quickly (P < .001) and with a smaller proportion of time lost to inadequate needle visualization (P < .001). CONCLUSIONS: Ultrasound guided regional anesthesia trainees complete a standardized task more quickly and efficiently when instructed to hold the transducer and needle in an orientation perpendicular to their shoulders. PMID- 27246663 TI - Role of Arrival Time Difference Between Lesions and Lung Tissue on Contrast Enhanced Sonography in the Differential Diagnosis of Subpleural Pulmonary Lesions. AB - OBJECTIVES: The purpose of this study was to explore the diagnostic value of the arrival time difference between lesions and surrounding lung tissue on contrast enhanced sonography of subpleural pulmonary lesions. METHODS: A total of 110 patients with subpleural pulmonary lesions who underwent both conventional and contrast-enhanced sonography and had a definite diagnosis were enrolled. After contrast agent injection, the arrival times in the lesion, lung, and chest wall were recorded. The arrival time differences between various tissues were also calculated. RESULTS: Statistical analysis showed a significant difference in the lesion arrival time, the arrival time difference between the lesion and lung, and the arrival time difference between the chest wall and lesion (all P < .001) for benign and malignant lesions. Receiver operating characteristic curve analysis revealed that the optimal diagnostic criterion was the arrival time difference between the lesion and lung, and that the best cutoff point was 2.5 seconds (later arrival signified malignancy). This new diagnostic criterion showed superior diagnostic accuracy (97.1%) compared to conventional diagnostic criteria. CONCLUSIONS: The individualized diagnostic method based on an arrival time comparison using contrast-enhanced sonography had high diagnostic accuracy (97.1%) with good feasibility and could provide useful diagnostic information for subpleural pulmonary lesions. PMID- 27246664 TI - HDlive Silhouette Mode With Spatiotemporal Image Correlation for Assessment of the Fetal Heart. AB - OBJECTIVES: The purpose of this article is to present our experience with normal and abnormal fetal cardiac structures reconstructed in the HDlive silhouette mode (GE Healthcare Japan, Tokyo, Japan) with spatiotemporal image correlation (STIC). METHODS: Twenty-two fetuses with normal hearts and 1 fetus with a congenital heart anomaly (Ebstein anomaly) at 20 to 36 weeks' gestation were studied in the HDlive silhouette mode with STIC. RESULTS: In normal fetal hearts, 4 cardiac chambers and crisscross arrangements of the pulmonary artery and aorta were clearly identified. This modality facilitated visualization of the relationships and course of the outflow and inflow tracts, thus helping the operators more effectively understand the spatial relationships among the cardiac chambers and vessels. The opening and closing of mitral, tricuspid, pulmonary, and aortic valves were ascertained in the en face view of both atrioventricular valves and great vessels. In the fetus with Ebstein anomaly, a low attachment of the tricuspid valve and an enlarged right atrium were evident. CONCLUSIONS: The HDlive silhouette mode with STIC provides new visual experiences for physicians, owing to the anatomically clear depiction of fetal cardiac structures, and it may be an easier way to depict the spatial relationships among fetal cardiac chambers, great arteries, and veins. PMID- 27246665 TI - Airborne Fine Particulate Matter Induces Oxidative Stress and Inflammation in Human Nasal Epithelial Cells. AB - Airborne fine particulate matter with an aerodynamic diameter equal to or smaller than 2.5 MUm is abbreviated as PM2.5, which is one of the main components in air pollution. Exposure to PM2.5 is associated with increased risk of many human diseases, including chronic and allergic rhinitis, but the underlying molecular mechanism for its toxicity has not been fully elucidated. We have hypothesized that PM2.5 may cause oxidative stress and enhance inflammatory responses in nasal epithelial cells. Accordingly, we used human RPMI 2650 cells, derived from squamous cell carcinoma of the nasal septum, as a model of nasal epithelial cells, and exposed them to PM2.5 that was collected at Fudan University (31.3 degrees N, 121.5 degrees E) in Shanghai, China. PM2.5 exposure decreased the viability of RPMI 2650 cells, suggesting that PM2.5 may impair the barrier function of nasal epithelial cells. Moreover, PM2.5 increased the levels of intracellular reactive oxygen species (ROS) and the nuclear translocation of NF E2-related factor-2 (Nrf2). Importantly, PM2.5 also decreased the activities of superoxide dismutase, catalase and glutathione peroxidase. Pretreatment with N Acetyl-L-cysteine (an anti-oxidant) reduced the degree of the PM2.5-induced oxidative stress in RPMI 2650 cells. In addition, PM2.5 increased the production of granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, interleukin-13 and eotaxin (C-C motif chemokine ligand 11), each of which initiates and/or augments local inflammation. These results suggest that PM2.5 may induce oxidative stress and inflammatory responses in human nasal epithelial cells, thereby leading to nasal inflammatory diseases. The present study provides insights into cellular injury induced by PM2.5. PMID- 27246666 TI - Using an inertial navigation algorithm and accelerometer to monitor chest compression depth during cardiopulmonary resuscitation. AB - We present an original method using a low cost accelerometer and a Kalman-filter based algorithm to monitor cardiopulmonary resuscitation chest compressions (CC) depth. A three-axis accelerometer connected to a computer was used during CC. A Kalman filter was used to retrieve speed and position from acceleration data. We first tested the algorithm for its accuracy and stability on surrogate data. The device was implemented for CC performed on a manikin. Different accelerometer locations were tested. We used a classical inertial navigation algorithm to reconstruct CPR depth and frequency. The device was found accurate enough to monitor CPR depth and its stability was checked for half an hour without any drift. Average error on displacement was +/-0.5mm. We showed that depth measurement was dependent on the device location on the patient or the rescuer. The accuracy and stability of this small low-cost accelerometer coupled to a Kalman-filter based algorithm to reconstruct CC depth and frequency, was found well adapted and could be easily implemented. PMID- 27246667 TI - Measuring temperature rise during orthopaedic surgical procedures. AB - A reliable means for measuring temperatures generated during surgical procedures is needed to recommend best practices for inserting fixation devices and minimizing the risk of osteonecrosis. Twenty four screw tests for three surgical procedures were conducted using the four thermocouples in the bone and one thermocouple in the screw. The maximum temperature rise recorded from the thermocouple in the screw (92.7+/-8.9 degrees C, 158.7+/-20.9 degrees C, 204.4+/ 35.2 degrees C) was consistently higher than the average temperature rise recorded in the bone (31.8+/-9.3 degrees C, 44.9+/-12.4 degrees C, 77.3+/-12.7 degrees C). The same overall trend between the temperatures that resulted from three screw insertion procedures was recorded with significant statistical analyses using either the thermocouple in the screw or the average of several in bone thermocouples. Placing a single thermocouple in the bone was determined to have limitations in accurately comparing temperatures from different external fixation screw insertion procedures. Using the preferred measurement techniques, a standard screw with a predrilled hole was found to have the lowest maximum temperatures for the shortest duration compared to the other two insertion procedures. Future studies evaluating bone temperature increase need to use reliable temperature measurements for recommending best practices to surgeons. PMID- 27246668 TI - Single-shot and single-sensor high/super-resolution microwave imaging based on metasurface. AB - Real-time high-resolution (including super-resolution) imaging with low-cost hardware is a long sought-after goal in various imaging applications. Here, we propose broadband single-shot and single-sensor high-/super-resolution imaging by using a spatio-temporal dispersive metasurface and an imaging reconstruction algorithm. The metasurface with spatio-temporal dispersive property ensures the feasibility of the single-shot and single-sensor imager for super- and high resolution imaging, since it can convert efficiently the detailed spatial information of the probed object into one-dimensional time- or frequency dependent signal acquired by a single sensor fixed in the far-field region. The imaging quality can be improved by applying a feature-enhanced reconstruction algorithm in post-processing, and the desired imaging resolution is related to the distance between the object and metasurface. When the object is placed in the vicinity of the metasurface, the super-resolution imaging can be realized. The proposed imaging methodology provides a unique means to perform real-time data acquisition, high-/super-resolution images without employing expensive hardware (e.g. mechanical scanner, antenna array, etc.). We expect that this methodology could make potential breakthroughs in the areas of microwave, terahertz, optical, and even ultrasound imaging. PMID- 27246669 TI - Monitoring Location-Specific Physical Activity via Integration of Accelerometry and Geotechnology Within Patients With or At Risk of Diabetic Foot Ulcers: A Technological Report. AB - OBJECTIVE: Physical activity variability is a risk factor for diabetic foot ulcers (DFU). Geographic context may influence variability. This study developed initial methods for monitoring location-specific physical activity in this population. Secondarily, preliminary comparisons in location-specific physical activity were made between patients at risk versus patients with active DFU. METHODS: Five at-risk and 5 actively ulcerated patients were monitored continuously for 72 hours with physical activity and GPS monitors. A custom algorithm time synchronized the 2 devices' data. RESULTS: On average for all 10 subjects, 1.5 +/- 2.1% of activity lacked a corresponding GPS location. 80 +/- 11% of self-reported activity events per subject had a GPS identified location. The GPS identified locations were in agreement with the self-reported locations 98 +/- 6% of the time. DFU participants' weight-bearing activity was 188% higher at home than away from home. At-risk participants showed similar weight-bearing activity at home as active DFU participants, however, at-risk participants had 132% more weight-bearing activity away-from-home. CONCLUSIONS: Objectively monitoring location-specific physical activity proved feasible. Future studies using such methodology may enhance understanding of pathomechanics and treatment of DFU. PMID- 27246670 TI - Impact of Disease Management Programs on HbA1c Values in Type 2 Diabetes Patients in Germany. AB - BACKGROUND: The aim was to analyze the impact of disease management programs on HbA1c values in type 2 diabetes mellitus (T2DM) patients in Germany. METHODS: This study included 9017 patients followed in disease management programs (DMPs) who started an antihyperglycemic treatment upon inclusion in a DMP. Standard care (SC) patients were included after individual matching (1:1) to DMP cases based on age, gender, physician (diabetologist versus nondiabetologist care), HbA1c values at baseline, and index year. The main outcome was the share of patients with HbA1c <7.5% or 6.5% after at least 6 months and less than 12 months of therapy in DMP and SC groups. Multivariate logistic regression models were fitted with HbA1c level as a dependent variable and the potential predictor (DMP versus SC). RESULTS: The mean age was 64.3 years and 54.7% of the patients were men. The mean HbA1c level at baseline was equal to 8.7%. In diabetologist practices, 64.7% of DMP patients and 55.1% of SC patients had HbA1c levels <7.5%, while 23.4% of DMP patients and 16.9% of SC patients had HbA1c levels <6.5% ( P values < .001). By comparison, in general practices, 72.4% of DMP patients and 65.7% of SC patients had HbA1c levels <7.5%, while 29.0% of DMP patients and 25.4% of SC patients had HbA1c levels <6.5% ( P values < .001). DMPs increased the likelihood of HbA1c levels lower than 7.5% or 6.5% after 6 months of therapy in both diabetologist and general care practices. CONCLUSION: The present study indicates that the enrollment of T2DM patients in DMPs has a positive impact on HbA1c values in Germany. PMID- 27246671 TI - Off-Pump CABG in a Patient with Laryngectomy and Permanent Tracheostomy Utilizing Low Midline Skin Incision with Transverse Skin Flaps and Manubrium Sparing Sternotomy. AB - Patients that have undergone previous laryngectomy with permanent stoma placement are at increased risk of wound infection, mediastinitis, and tracheal injury when undergoing coronary artery bypass grafting (CABG) via standard skin incision and sternotomy. We present a case of off-pump CABG via a low midline skin incision with transverse skin flaps and a manubrium sparing sternotomy. doi: 10.1111/jocs.12771 (J Card Surg 2016;31:439-440). PMID- 27246672 TI - Significance of the School Physical Environment - A Commentary. PMID- 27246673 TI - Availability of Reproductive Health Care Services at Schools and Subsequent Birth Outcomes Among Adolescent Mothers. AB - BACKGROUND: Adverse birth outcomes are more common among adolescent versus adult mothers, but little is known about school-based services that may improve birth outcomes in this group. METHODS: Data from Waves I and IV of the National Longitudinal Study of Adolescent Health were analyzed. Girls and women who gave birth to singleton live infants after Wave I and before age 20, were still in secondary school while pregnant, and had complete data (N = 402) were included. Mothers reported infants' birthweight and gestational age. School administrators reported whether family planning counseling, diagnostic screening (including sexually transmitted diseases [STDs]), STD treatment, and prenatal/postpartum health care were provided on-site at school at Wave I. Multilevel models adjusted for individual and school characteristics were conducted. RESULTS: Few schools offered reproductive health care services on-site. In multilevel analyses, availability of family planning counseling (Est. beta = 0.21, 95% confidence interval [CI] 0.04-0.38 p < 0.05) and prenatal/postpartum health care (Est. beta = 0.21, 95% CI 0.02-0.40 p < 0.05) were significantly associated with increased infant birthweight. No services examined were significantly associated with increased gestational age. CONCLUSIONS: Some school-based reproductive health services may improve subsequent birth outcomes among adolescent mothers. Future analyses should examine the mechanisms by which services impact birth outcomes. PMID- 27246675 TI - Policy Actions to Address Weight-Based Bullying and Eating Disorders in Schools: Views of Teachers and School Administrators. AB - BACKGROUND: Weight-related bullying is prevalent among youth and associated with adverse health consequences, including increased risk for body dissatisfaction and disordered eating behaviors, which are risk factors for eating disorders. Although concerns about these problems have stimulated calls for broader intervention efforts in schools, actions thus far have been limited. This study examined educators' perspectives about potential policy actions to address these issues in schools. METHODS: Educators (N = 240) completed an online questionnaire assessing their support for 11 potential school-based policy actions to address weight-related bullying and eating disorders. Participants also rated policies according to their feasibility and potential for positive impact. RESULTS: Forty eight percent of participants observed weight-related bullying in their school and 99% expressed the importance of intervening in such incidents. A large majority (75%-94%) supported 8 of the 11 policies, especially actions requiring school-based health curriculum to include content on eating disorder prevention (94%), and addressing weight-bullying through antibullying policies (92%), staff training (89%), and school curriculum (89%). Strongly supported policies were viewed by participants as being the most impactful and feasible to implement. CONCLUSIONS: Educators recognize weight-related bullying and eating disorders as problems in their schools that warrant improved prevention and intervention efforts at the policy level. PMID- 27246674 TI - Exploring Categorical Body Mass Index Trajectories in Elementary School Children. AB - BACKGROUND: Studies of body mass index (BMI) change have focused on understanding growth trajectories from childhood to adolescence and adolescence to adulthood, but few have explored BMI trajectories solely in elementary (grades K-5) school children. This report complements these studies by exploring changes in obesity status using analytic methods developed to investigate categorical changes in life-course events. METHODS: Sequences of a 4-state BMI variable (underweight, normal, overweight, and obese) were calculated using height and weight data collected annually (2008-2013) from 414 kindergarten and first-grade students participating in the Community and Schools Together (CAST) project. These sequences were explored using the TraMineR software package to investigate the distribution of sequences and states, calculate transition rates among states, and examine clustering of sequences. RESULTS: Aggregated cluster solutions were identified consisting of either 4 clusters (normal, stepped, mixed, and obese) or 3 clusters (aggregation of obese cluster cases into stepped cluster) with membership in the former predicted by ethnicity and socioeconomic status (SES) and the latter by SES alone. Transition rate patterns among states varied markedly by cluster and state. CONCLUSION: The finding of early emergence of stable obesity states, especially in Hispanic children confirms the need for early childhood interventions to influence BMI. PMID- 27246676 TI - Promoting Fitness and Safety in Elementary Students: A Randomized Control Study of the Michigan Model for Health. AB - BACKGROUND: In elementary grades, comprehensive health education curricula have demonstrated effectiveness in addressing singular health issues. The Michigan Model for Health (MMH) was implemented and evaluated to determine its impact on nutrition, physical fitness, and safety knowledge and skills. METHODS: Schools (N = 52) were randomly assigned to intervention and control conditions. Participants received MMH with 24 lessons in grade 4 and 28 more lessons in grade 5 including material focusing on nutrition, physical fitness, and safety attitudes and skills. The 40-minute lessons were taught by the classroom teacher who received curriculum training and provided feedback on implementation fidelity. Self-report survey data were collected from the fourth-grade students (N = 1983) prior to the intervention, immediately after the intervention, and 6 weeks after the intervention, with the same data collection schedule repeated in fifth grade. Analysis of the scales was conducted using a mixed-model approach. RESULTS: Students who received the curriculum had better nutrition, physical activity, and safety skills than the control-group students. Intervention students also reported higher consumption of fruits; however, no difference was reported for other types of food consumption. CONCLUSION: The effectiveness of the MMH in promoting fitness and safety supports the call for integrated strategies that begin in elementary grades, target multiple risk behaviors, and result in practical and financial benefits to schools. PMID- 27246677 TI - Feasibility and Effects of Short Activity Breaks for Increasing Preschool-Age Children's Physical Activity Levels. AB - BACKGROUND: We examined the effects of short bouts of structured physical activity (SBS-PA) implemented within the classroom setting as part of designated gross-motor playtime on preschoolers PA. METHODS: Preschools were randomized to SBS-PA (centers, N = 5; participants, N = 141) or unstructured free playtime (UPA) (centers, N = 5; participants, N = 150). SBS-PA consisted of structured PA implemented in the classroom during the first 10 minutes of gross-motor playtime followed by 20 minutes of free playtime. UPA consisted of 30 minutes of unstructured free playtime. Teachers implemented both conditions for 5 days/week for 6 months. PA was assessed with accelerometers (preschool-day) and direct observation (30-minute sessions). Generalized linear mixed models were used to examine the impact of the intervention. RESULTS: Regarding the 30-minute sessions, significant group main effects were observed for intervals spent at light (p < .001) and moderate-to-vigorous PA (MVPA, p < .001). Regarding the preschool-day PA, significant group by visit interaction was observed for percent time spent in total preschool-day MVPA (F (2, 254) = 3.54, p = .03). Percent of time spent in MVPA significantly decreased in both groups at 3 months and at 6 months. CONCLUSION: SBS-PA can be implemented in classroom settings; however, further research is needed to examine its impact on preschoolers PA levels. PMID- 27246678 TI - Adoption of Preventive Measures and Attitudes Toward the H1N1 Influenza Pandemic in Schools. AB - BACKGROUND: This study describes the perceived impact of H1N1 influenza and the adoption of the recommended measures to address the pandemic in schools. METHODS: A cross-sectional self-reported survey was conducted in 433 schools in Barcelona addressed to the school principal or the H1N1 influenza designated person. A descriptive analysis was performed, stratifying by educational level and type of school. A logistic regression analysis also was conducted. RESULTS: Around 70% of the respondents reported that there had been H1N1 influenza cases among students, being this percentage significantly higher among those schools offering primary education (74.4%) (p < .05). The main measures (single-use paper towels, availability of sanitizer solutions and 15 minutes ventilation per day of enclosed spaces) were implemented in most of the centers. However, the correct adoption of the main measures took place in around 30% of the schools, being the percentage lower in those offering only secondary education (Odds ratio [OR]: 0.518; 95% confidence interval [CI]:0.272-0.986) and those located in medium (OR: 0.438, 95% CI: 0.234-0.811) or low socioeconomic status (SES) districts (OR: 0.321, 95% CI: 0.159-0.649). CONCLUSIONS: Despite the climate of social alarm, the perceived impact of H1N1 influenza in most schools was moderate. In future potential threats, the educational level and the SES of the school should be considered, especially when measures requiring purchasing any product are recommended but not provided. PMID- 27246679 TI - Project ReFresh: Testing the Efficacy of a School-Based Classroom and Cafeteria Intervention in Elementary School Children. AB - BACKGROUND: The purpose of this study was to assess the effect of a school-based nutrition program using a cafeteria environment intervention and classroom nutrition education on self-reported fruit and vegetable (FV) consumption, self efficacy to select FV, and preference for healthy foods. METHODS: Using quasi experimental pre-post design with 3 study conditions, a total of 665 fourth- and fifth-grade students participated in the study. The comprehensive intervention included a behavioral economics cafeteria intervention and weekly classroom nutrition education for 1 academic year. The intervention was designed and delivered by the extension system. RESULTS: The comprehensive group showed significant improvement in some indicators including eating vegetables for lunch (p = .007), number of days eating vegetables (p < .001) and fruits (p < .001) in the last week, and self-efficacy in preparing FV at home (p = .034) compared to the control and cafeteria groups. Food preference of some food items, including oatmeal (p = .036 for cafeteria group, p < .001 for comprehensive group), whole grain noodles (p = .011 for comprehensive group), and vegetables (p = .003 for comprehensive group), significantly improved in the cafeteria and/or comprehensive group. CONCLUSIONS: Classroom nutrition education combined with cafeteria improvement has the potential to improve diet-related behavior of elementary school children. Also, collaborative partnership between schools and extension can enhance program sustainability. PMID- 27246680 TI - Setting Adolescents Up for Success: Promoting a Policy to Delay High School Start Times. AB - BACKGROUND: A unique biological shift in sleep cycles occurs during adolescence causing later sleep and wake times. This shift is not matched by a concurrent modification in school start times, resulting in sleep curtailment for a large majority of adolescents. Chronic inadequate sleep is associated with poor academic performance including executive function impairments, mood, and behavioral issues, as well as adverse health outcomes such as an increased risk of obesity, hypertension, and cardiovascular disease. In order to address sleep deficits and the potential negative outcomes associated with chronic sleep deprivation, the American Academy of Pediatrics (AAP) and US Centers for Disease Control and Prevention (CDC) support delaying school start times for middle and high school students. METHODS: We summarize current evidence, explicate the need for policy change, and urge school districts to put adolescent students' health as top priority and implement school start times consistent with their developmental needs. RESULTS: Whereas substantial evidence illustrating adverse consequences of inadequate sleep on psychological and physical health, and recommendations exist to adapt daytime school schedules to match sleep needs have been released, actual implementation of these recommendations have been limited. CONCLUSIONS: This is a call to action for the implementation of AAP/CDC recommendations across the state and nation. PMID- 27246682 TI - Vaxine. PMID- 27246681 TI - Untargeted, spectral library-free analysis of data-independent acquisition proteomics data generated using Orbitrap mass spectrometers. AB - We describe an improved version of the data-independent acquisition (DIA) computational analysis tool DIA-Umpire, and show that it enables highly sensitive, untargeted, and direct (spectral library-free) analysis of DIA data obtained using the Orbitrap family of mass spectrometers. DIA-Umpire v2 implements an improved feature detection algorithm with two additional filters based on the isotope pattern and fractional peptide mass analysis. The targeted re-extraction step of DIA-Umpire is updated with an improved scoring function and a more robust, semiparametric mixture modeling of the resulting scores for computing posterior probabilities of correct peptide identification in a targeted setting. Using two publicly available Q Exactive DIA datasets generated using HEK 293 cells and human liver microtissues, we demonstrate that DIA-Umpire can identify similar number of peptide ions, but with better identification reproducibility between replicates and samples, as with conventional data dependent acquisition. We further demonstrate the utility of DIA-Umpire using a series of Orbitrap Fusion DIA experiments with HeLa cell lysates profiled using conventional data-dependent acquisition and using DIA with different isolation window widths. PMID- 27246683 TI - Analytical characterization of cyclodextrins: History, official methods and recommended new techniques. AB - The main goal of this review is to provide a comprehensive overview on the methods used for analysis of cyclodextrins (CDs) and CD-derivatives. The paper intends to act as a guide for the readers in looking around the classical and modern instrumental analytical methods suitable for identification, characterization and determination of CDs themselves, CDs in finished products or even in biological samples. At present, in the European and United States Pharmacopoeias, the three parent CDs and two synthetic derivatives, namely the (2 hydroxypropyl)-beta-CD and sulfobutylether-beta-CD Na salt are official. Besides these modified CDs, two other derivatives are approved as excipients in human pharmaceutical products: the (2-hydroxypropyl)-gamma-CD and the randomly methylated-beta-CD. Although most of the official analysis methods in the pharmacopoeias have been well used for decades, new aspects of the functional excipient CD characterization suggest a need to revisit compendial methods. Comparison of strengths and weaknesses of current official methods with new improved techniques intends to help analysts to decide on changing traditional analytical methods with improved new ones. This review also deals with the analytical aspects of the first single isomer CD derivative approved as a drug active (Sugammadex/Bridion(r)) as well as analytical considerations of using CDs themselves as active pharmaceutical ingredients. Stability-indicating instrumental methods suitable to adequately follow chemical- and enzymatic degradation of CDs will also be discussed. Challenges in the determination of CDs in different biological matrices will be illustrated on real pharmaco- and toxicokinetic studies of CD-enabled drug formulations. PMID- 27246684 TI - Plasma 25-Hydroxyvitamin D, Vitamin D Binding Protein, and Risk of Colorectal Cancer in the Nurses' Health Study. AB - Total circulating 25-hydroxyvitamin D [25(OH)D)] has been associated with lower risk of colorectal cancer. The physiologic mechanism, however, may be more directly related to the free or bioavailable fraction of 25(OH)D, which is influenced by levels of vitamin D binding protein (VDBP). We assessed the association of prediagnosis total, free, and bioavailable 25(OH)D and VDBP with colorectal cancer risk among predominantly white women in the Nurses' Health Study (NHS) who provided a blood specimen in 1989-1990. We documented 378 cases of colorectal cancer through 2011 and matched them to 689 controls according to age and time of blood draw. We genotyped two common polymorphisms in the gene coding VDBP and calculated free and bioavailable 25(OH)D levels based on total 25(OH)D, VDBP, albumin, and their estimated genotype-specific binding affinities. Total 25(OH)D was associated with lower colorectal cancer risk (P for trend = 0.01). Compared with women in the lowest quintile of total 25(OH)D, those in the highest quintile had a multivariable-adjusted odds ratio (OR) for colorectal cancer of 0.54 [95% confidence interval (CI), 0.33-0.87]. Comparing extreme quintiles, we did not find any significant association with risk of colorectal cancer for VDBP (OR, 0.98; 95% CI, 0.65-1.47), free 25(OH)D (OR, 0.71; 95% CI, 0.46-1.10), or bioavailable 25(OH)D (OR, 0.92; 95% CI, 0.60-1.42). In conclusion, prediagnosis levels of total, but not free or bioavailable 25(OH)D, were associated with lower colorectal cancer risk. Although our findings support an inverse association of vitamin D with colorectal cancer, this association does not appear to be due to the unbound or bioavailable fraction of circulating vitamin D. Cancer Prev Res; 9(8); 664-72. (c)2016 AACR. PMID- 27246685 TI - Morphological description of genetically identified Cortez bonefish (Albula gilberti, Pfeiler and van der Heiden 2011) leptocephali from the southern Gulf of California. AB - Bonefish leptocephali of the genus Albula are difficult to identify to the species level due to morphological similarities between two different species present in the Northeastern Pacific Ocean, A. esuncula and A. gilberti. In this study, 22 bonefish leptocephali (premetamorphic and early metamorphic), collected from two locations in the southern Gulf of California were identified as Albula gilberti by comparing 459 bp of their mitochondrial cytochrome b gene sequences to those of four other species of bonefish. The characteristics of these A. gilberti leptocephali were compared to those of previously described bonefish leptocephali in the region. No distinctive morphological characteristics (meristic and pigmentation) were found that differentiate premetamorphic leptocephali of A. gilberti from those of other Albula species, making species identification by molecular-genetics a necessity. In early metamorphic leptocephali some differences in horizontal eye diameter-head length ratio, number of rays of pelvic and anal fins and myomere of pelvic-fin origin may help to differentiate A. gilberti from A. esuncula. PMID- 27246687 TI - Unexpected Success of Watch and Wait Strategy in a Ponatinib-Intolerant Patient With Chronic Myeloid Leukemia. PMID- 27246686 TI - Light-triggered RNA release and induction of hMSC osteogenesis via photodegradable, dual-crosslinked hydrogels. AB - AIM: To engineer a photodegradable hydrogel system for actively controlled release of bioactive unmodified RNA at designated time points to induce hMSC osteogenesis. MATERIALS & METHODS: RNA/polyethylenimine complexes were loaded into dual-crosslinked photodegradable hydrogels to examine the capacity of UV light application to trigger their release. The ability of released RNA to drive hMSC osteogenic differentiation was also investigated. RESULTS & CONCLUSION: RNA release from photodegradable hydrogels was accelerated upon UV application, which was not observed in non-photodegradable hydrogels. Regardless of the presence of UV light, released siGFP exhibited high bioactivity by silencing GFP expression in HeLa cells. Importantly, siNoggin or miRNA-20a released from the hydrogels induced hMSC osteogenesis. This system provides a potentially valuable physician/patient-controlled 'on-demand' RNA delivery platform for biomedical applications. PMID- 27246688 TI - Clinical Benefits Associated With Medicaid Coverage Before Diagnosis of Gynecologic Cancers. AB - PURPOSE: Many low-income patients enroll in Medicaid at the time of cancer diagnosis, which improves survival outcomes. Medicaid enrollment before cancer diagnosis may confer additional benefits. Our objective was to compare stage at diagnosis and overall mortality between women with and without Medicaid enrollment before gynecologic cancer diagnosis. METHODS AND MATERIALS: Women younger than 65 years with a gynecologic cancer (2003 to 2008) were identified through the North Carolina Central Cancer Registry and linked to state Medicaid enrollment files. Those with and without Medicaid enrollment within 6 months before diagnosis were identified. Propensity matching was used to balance the exposure groups. Stage at diagnosis was evaluated by using logistic regression, and all-cause mortality was assessed with Cox proportional hazard models. RESULTS: Of 564 women, one half (n = 282) had prediagnosis Medicaid enrollment. Disease sites included the cervix (44%), uterus (25%), ovary (26%), and vulva/vagina (5%). More than one half (51%) of cancers were advanced stage. Women without prediagnosis Medicaid had an increased odds of advanced-stage disease (hazard ratio, 1.46; 95% CI, 1.03 to 2.05). Crude survival outcomes differed significantly between the groups; however, when adjusted for stage at diagnosis, lack of prediagnosis Medicaid coverage had a hazard ratio of 1.19 (95% CI, 0.92 to 1.53). CONCLUSION: Medicaid enrollment before gynecologic cancer diagnosis is associated with an earlier stage at presentation. Given the existence of a cervical cancer screening program in North Carolina and lack of Medicaid expansion, these data suggest that screening programs alone are not sufficient to counteract the delay in diagnosis that is common for uninsured individuals. PMID- 27246689 TI - Is FDA-Approved Bevacizumab Cost-Effective When Included in the Treatment of Platinum-Resistant Recurrent Ovarian Cancer? AB - PURPOSE: Although the Food and Drug Administration has approved incorporation of bevacizumab (BEV) into the treatment of platinum-resistant ovarian cancer (PROC), cost-value measures are an essential consideration, as evidenced by the recent ASCO Value Framework initiative. We assessed the cost-effectiveness and reviewed the net health benefit (NHB) of this expensive treatment. METHODS: A cost effectiveness decision model was constructed using results from a phase III trial comparing BEV plus cytotoxic chemotherapy with chemotherapy alone in patients with PROC. The Avastin Use in Platinum-Resistant Epithelial Ovarian Cancer (AURELIA) trial demonstrated improvement in progression-free survival and quality of life in patients receiving BEV. Costs, paracentesis rates, and adverse events were incorporated, including subgroup analysis of different partner chemotherapy agents. RESULTS: Inclusion of BEV in the treatment of platinum-resistant recurrent ovarian cancer meets the common willingness-to-pay incremental cost effectiveness ratio (ICER) threshold of $100,000 per progression-free life-year saved (LYS) for 15-mg/kg dosing and approaches this threshold for 10-mg/kg dosing, with an ICER of $160,000. In sensitivity analysis, reducing the cost of BEV by 13% (from $9,338 to $8,100 per cycle) allows 10-mg/kg dosing to reach a $100,000 ICER. Exploratory analysis of different BEV chemotherapy partners showed an ICER of $76,000 per progression-free LYS (6.5-month progression-free survival improvement) and $54,000 per LYS (9.1-month overall survival improvement) for the addition of BEV to paclitaxel once per week. Using the ASCO framework for value assessment, the NHB score for BEV plus paclitaxel once per week is 48. CONCLUSION: Using a willingness-to-pay threshold of $100,000 ICER, the addition of BEV to chemotherapy either demonstrates or approaches cost-effectiveness and NHB when added to the treatment of patients with PROC. PMID- 27246690 TI - Effect of gold nanoparticles on thermal gradient generation and thermotaxis of E. coli cells in microfluidic device. AB - Bacteria responds to changing chemical and thermal environment by moving towards or away from a particular location. In this report, we looked into thermal gradient generation and response of E. coli DH5alpha cells to thermal gradient in the presence and in the absence of spherical gold nanoparticles (size: 15 to 22 nm) in a static microfluidic environment using a polydimethylsiloxane (PDMS) made microfluidic device. A PDMS-agarose based microfluidic device for generating thermal gradient has been developed and the thermal gradient generation in the device has been validated with the numerical simulation. Our studies revealed that the presence of gold nanoparticles, AuNPs (0.649 MUg/mL) has no effect on the thermal gradient generation. The E. coli DH5alpha cells have been treated with AuNPs of two different concentrations (0.649 MUg/mL and 0.008 MUg/mL). The thermotaxis behavior of cells in the presence of AuNPs has been studied and compared to the thermotaxis of E.coli DH5alpha cells in the absence of AuNPs. In case of thermotaxis, in the absence of the AuNPs, the E. coli DH5alpha cells showed better thermotaxis towards lower temperature range, whereas in the presence of AuNPs (0.649 MUg/mL and 0.008 MUg/mL) thermotaxis of the E. coli DH5alpha cells has been inhibited. The results show that the spherical AuNPs intervenes in the themotaxis of E. coli DH5alpha cells and inhibits the cell migration. The reason for the failure in thermotaxis response mechanism may be due to decreased F-type ATP synthase activity and collapse of membrane potential by AuNPs, which, in turn, leads to decreased ATP levels. This has been hypothesized since both thermotaxis and chemotaxis follows the same response mechanism for migration in which ATP plays critical role. PMID- 27246692 TI - Erratum to: Optimization of adipose tissue-derived mesenchymal stem cells by rapamycin in a murine model of acute graft-versus-host disease. PMID- 27246691 TI - Episodic Future Thinking: Expansion of the Temporal Window in Individuals with Alcohol Dependence. AB - BACKGROUND: Episodic future thinking (EFT) requires an individual to vividly pre experience a realistic future event. Inspired by previous reports of reducing delay discounting following EFT in other populations, we examined the effects of engaging alcohol-dependent individuals in EFT or episodic recent thinking (ERT; control) to examine its effects on delay discounting and alcohol purchasing. METHODS: Participants (n = 50) with alcohol dependence were allocated into EFT or ERT groups and asked to generate positive future or recent past events for each of 5 time points. Participants then completed a delay-discounting task, during which event cues were displayed, and a hypothetical alcohol purchase task. RESULTS: EFT significantly increased valuation of future monetary rewards, while decreasing initial consumption (Q0 ) of alcoholic drinks indicative of lower demand intensity. Two additional findings suggest potential moderators of this effect. EFT more readily influenced individuals with lower Alcohol Use Disorders Identification Test scores, and self-reported cue valence differed between groups. CONCLUSIONS: Together, these results suggest a widening of alcohol dependent individuals' temporal window following engagement of EFT. While our data suggest that EFT may be moderated by certain susceptibility criteria, exercises such as EFT could be easily adaptable as a potential therapeutic tool for use in rehabilitation programs. PMID- 27246693 TI - Cristacarpin promotes ER stress-mediated ROS generation leading to premature senescence by activation of p21(waf-1). AB - Stress-induced premature senescence (SIPS) is quite similar to replicative senescence that is committed by cells exposed to various stress conditions viz. ultraviolet radiation (DNA damage), hydrogen peroxide (oxidative stress), chemotherapeutic agents (cytotoxic threat), etc. Here, we report that cristacarpin, a natural product obtained from the stem bark of Erythrina suberosa, promotes endoplasmic reticulum (ER) stress, leading to sub-lethal reactive oxygen species (ROS) generation and which eventually terminates by triggering senescence in pancreatic and breast cancer cells through blocking the cell cycle in the G1 phase. The majority of cristacarpin-treated cells responded to conventional SA-beta-gal stains; showed characteristic p21(waf1) upregulation along with enlarged and flattened morphology; and increased volume, granularity, and formation of heterochromatin foci-all of these features are the hallmarks of senescence. Inhibition of ROS generation by N-acetyl-L-cysteine (NAC) significantly reduced the expression of p21(waf1), confirming that the modulation in p21(waf1) by anti-proliferative cristacarpin was ROS dependent. Further, the elevation in p21(waf1) expression in PANC-1 and MCF-7 cells was consistent with the decrease in the expression of Cdk-2 and cyclinD1. Here, we provide evidence that cristacarpin promotes senescence in a p53-independent manner. Moreover, cristacarpin treatment induced p38MAPK, indicating the ROS-dependent activation of the MAP kinase pathway, and thus abrogates the tumor growth in mouse allograft tumor model. PMID- 27246694 TI - Factors producing over-selectivity in older individuals. AB - Stimulus over-selectivity describes a phenomenon where only a subset of the relevant stimuli present in the environment, control an individual's behavior. The current experiment explored the degree to which over-selectivity increases in old age. The level of over-selectivity in a visual discrimination task in 60 individuals aged 60-89 years was assessed, as well as the degree to which this reflected attentional control. In addition, the intellectual functioning and cognitive flexibility of the participants were assessed. Results showed that, as age increased, three effects were revealed: levels of stimulus over-selectivity increased, IQ scores decreased, and cognitive flexibility decreased. However, over-selectivity was not related to IQ or cognitive flexibility, and appeared related most to attentional impairments. Thus, ageing is related to significant declines in effective stimulus control. These effects can have a serious impact on the physical and psychological health of old adults, as well as their quality of life, and, therefore, this area of research warrants further exploration. The results are discussed in relation to the attention-deficit and comparator theory of over-selectivity. PMID- 27246695 TI - Toll-like receptor 4 knockout alleviates paraquat-induced cardiomyocyte contractile dysfunction through an autophagy-dependent mechanism. AB - Paraquat, a quarternary nitrogen herbicide, is a toxic prooxidant leading to multi-organ failure including the heart although the underlying mechanism remains poorly understood. This study was designed to examine the role of the innate proinflammatory mediator toll-like receptor 4 (TLR4) in paraquat-induced cardiac contractile anomalies and the underlying mechanisms involved with a focus on autophagy, a conservative machinery governing protein and organelle degradation and recycling for cardiac homeostasis. Wild-type (WT) and TLR4 knockout (TLR4(-/ )) mice were challenged with paraquat (45mg/kg, i.p.) for 48h. Paraquat challenge did not affect mRNA levels of TLR2, TLR4 and TLR9 in WT mice nor did paraquat treatment alter TREM-1 levels. Paraquat challenge elicited cardiac mechanical defects including compromised cardiomyocyte contractile function, intracellular Ca(2+) handling, and overt autophagy as manifested by increased LC3BII-to-LC3BI ratio, Atg5, Atg7 and p62 levels. Interestingly, TLR4 knockout significantly attenuated paraquat-induced cardiac contractile and intracellular Ca(2+) derangement as well as alterations of autophagy markers. Paraquat-elicited changes in cardiac autophagy markers (LC3BII, LC3BII-to-LC3BI ratio and p62) were augmented by lysosomal inhibition using bafilomycin A1 in WT mice. TLR4 knockout significantly attenuated or negated paraquat-elicited increase in LC3BII, LC3BII to-LC3BI ratio and p62 levels in the presence of lysosomal inhibition. In addition, paraquat challenge promoted phosphorylation of AMPK while suppressing the phosphorylation of mTOR and ULK1 (the autophagy inhibitory Ser(757)), the effects of which were significantly attenuated by TLR4 ablation. In vitro study revealed that AMPK activation using AICAR or mTOR inhibition using rapamycin effectively negated the beneficial cardiomyocyte mechanical effects of TLR4 inhibition (CLI-095) against paraquat toxicity, supporting a permissive role for AMPK-mTOR in TLR4 inhibition-offered cardioprotection against paraquat. Our results suggested that TLR4 knockout alleviated paraquat-induced cardiac dysfunction possibly through regulation of AMPK-mediated cardiac autophagy. PMID- 27246696 TI - HBsAg loss in chronic hepatitis B: pointers to the benefits of curative therapy. PMID- 27246697 TI - Targeting the renin-angiotensin system in liver fibrosis. PMID- 27246698 TI - Current trends of tropical fruit waste utilization. AB - Recent rapid growth of the world's population has increased food demands. This phenomenon poses a great challenge for food manufacturers in maximizing the existing food or plant resources. Nowadays, the recovery of health benefit bioactive compounds from fruit wastes is a research trend not only to help minimize the waste burden, but also to meet the intensive demand from the public for phenolic compounds which are believed to have protective effects against chronic diseases. This review is focused on polyphenolic compounds recovery from tropical fruit wastes and its current trend of utilization. The tropical fruit wastes include in discussion are durian (Durio zibethinus), mangosteen (Garcinia mangostana L.), rambutan (Nephelium lappaceum), mango (Mangifera indica L.), jackfruit (Artocarpus heterophyllus), papaya (Carica papaya), passion fruit (Passiflora edulis), dragon fruit (Hylocereus spp), and pineapple (Ananas comosus). Highlights of bioactive compounds in different parts of a tropical fruit are targeted primarily for food industries as pragmatic references to create novel innovative health enhancement food products. This information is intended to inspire further research ideas in areas that are still under-explored and for food processing manufacturers who would like to minimize wastes as the norm of present day industry (design) objective. PMID- 27246699 TI - From both sides: Participant and facilitator perceptions of SMART Recovery groups. AB - INTRODUCTION AND AIMS: The Self-Management and Recovery Training (SMART Recovery) program provides facilitated mutual aid for people with addictions. To date, little research has examined SMART Recovery. This paper examined participant and facilitator perceptions of the helpfulness of cognitive behaviour therapy tools in SMART Recovery groups. SMART Recovery's strengths and areas for improvement were also explored, as well as overall participant satisfaction with SMART Recovery. DESIGN AND METHODS: This exploratory study was conducted as part of the first national survey of SMART Recovery in Australia. Paper surveys were posted to all registered SMART Recovery groups for participants. SMART Recovery facilitators were emailed a link to an online survey. RESULTS: Overall, satisfaction with SMART Recovery was moderate to strong. Participants and facilitators perceived the cognitive behaviour therapy tools incorporated within SMART Recovery to be helpful. Participants and facilitators nominated the group experience and the SMART Recovery tools and strategies as helpful aspects of SMART Recovery. Participants and facilitators were concerned with improving public knowledge about SMART Recovery groups, updating the structure and content of SMART Recovery groups, and increasing training for facilitators. DISCUSSION AND CONCLUSIONS: SMART Recovery displays strengths as communicated by those who utilise its services. However, there are opportunities to continue to improve SMART Recovery. Updating the training for facilitators and increasing communication between SMART Recovery Australia's head office and its facilitators may serve to improve service delivery. Future research should focus on examining the efficacy of SMART Recovery groups on participant outcomes.[Kelly PJ, Raftery D, Deane FP, Baker AL, Hunt D, Shakeshaft A. From both sides: Participant and facilitator perceptions of SMART Recovery groups. Drug Alcohol Rev 2017;36:325 332]. PMID- 27246700 TI - Identification of Novel N-Glycosylation Sites at Noncanonical Protein Consensus Motifs. AB - N-glycosylation of proteins is well known to occur at asparagine residues that fall within the canonical consensus sequence N-X-S/T but has also been identified at a small number of asparagine residues within N-X-C motifs, including the N491 residue of human serotransferrin. Here we report novel glycosylation sites within noncanonical consensus motifs, in the conformation N-X-C, based on mass spectrometry analysis of partially deglycosylated glycopeptide targets. Alpha-1 acid glycoprotein (A1AG) and serotransferrin (Tf) were observed for the first time to be N-glycosylated on asparagine residues within a total of six unique noncanonical motifs. N-glycosylation was initially predicted in silico based on the evolutionary conservation of the N-X-C motif among related mammalian species and demonstrated experimentally in A1AG from porcine, canine, and feline sources and in human serotransferrin. High-resolution liquid chromatography-tandem mass spectrometry was employed to collect fragmentation data of predicted GlcNAcylated peptides and to assign modification sites within N-X-C motifs. A combination of targeted analytical techniques that includes complementary mass spectrometry platforms, enzymatic digestions, and partial-deglycosylation procedures was developed to confirm the novel observations. Additionally, we found that A1AG in porcine and canine sources is highly N-glycosylated at a noncanonical motif (N-Q C) based on semiquantitative multiple reaction monitoring analysis-the first report of an N-X-C motif exhibiting substantial N-glycosylation. Although reports of N-X-C motif N-glycosylation are relatively uncommon in the literature, this work adds to a growing list of glycoproteins reported with glycosylation at various forms of noncanonical motifs. PMID- 27246701 TI - Application of qualitative response models in a relevance study of older adults' health depreciation and medical care demand. AB - AIM: The effect of health depreciation in older people on medical care demand is not well understood. We tried to assess the medical care demand with length of hospitalization and their impact on profits as a result of health depreciation. METHODS: All participants who underwent comprehensive geriatric assessment were from a prospective cohort study at a tertiary hospital. A total of 1191 cases between September 2008 to October 2012 were investigated. Three sets of qualitative response models were constructed to estimate the impact of older adults' health depreciation on multidisciplinary geriatric care services. Furthermore, we analyzed the factors affecting the composite end-point of rehospitalization within 14 days, re-admission to the emergency department within 3 days and patient death. RESULTS: Greater health depreciation in elderly patients was positively correlated with greater medical care demand. Three major components were defined as health depreciation: elderly adaptation function, geriatric syndromes and multiple chronic diseases. On admission, the better the basic living functions, the shorter the length of hospitalization (coefficient = 0.35, P < 0.001 in Poisson regression; coefficient = -0.33, P < 0.001 in order choice profit model; coefficient = -0.29, P < 0.001 in binary choice profit model). The major determinants for poor outcome were male sex, middle old age and length of hospitalization. However, factors that correlated with relatively good outcome were functional improvement after medical care services and level of disease education. CONCLUSIONS: An optimal allocation system for selection of cases into multidisciplinary geriatric care is required because of limited resources. Outcomes will improve with health promotion and preventive care services. Geriatr Gerontol Int 2017; 17: 645-652. PMID- 27246704 TI - Erratum to: Host lifestyle affects human microbiota on daily timescales. PMID- 27246703 TI - Galectin 3: association to neurohumoral activity, echocardiographic parameters and renal function in outpatients with heart failure. AB - BACKGROUND: Galectin 3 (Gal-3) reflects cardiac fibrosis in heart failure HF, but has also been associated to renal fibrosis and impaired renal function. Previous research has suggested that Gal-3 could be a cardio-renal biomarker, but it has never been tested simultaneous in a single study whether Gal-3 reflects echocardiographic measures, neurohumoral activity and renal function. The aim of this study was to evaluate the relationship between plasma concentrations of Gal 3 and neurohumoral activity, myocardial and renal function in patients with HF, including advanced echocardiographic measures and 24-h urinary albumin excretion (albuminuria). METHODS: We prospectively enrolled 132 patients with reduced left ventricular ejection fraction (LVEF) referred to an outpatient HF clinic. The patients had a median age of 70 years (interquartile rage: 64-75), 26.5 % were female, median LVEF was 33 % (27-39 %) and 30 % were in NYHA class III-IV. RESULTS: Patients with plasma concentrations of Gal-3 above the median had significantly lower estimated glomerular filtration rate (eGFR) and this association remained significant in multivariate regression analysis (beta: 0.010; 95 % CI -0.012--0.008; P < 0.001), adjusted for age, gender, medical treatment. Plasma concentrations of Gal-3 were not associated with albuminuria (Beta: 0.008; 95 % CI:-0.028-0.045; P = 0.652). There were no association between plasma concentrations of Gal-3 and myocardial function or structure estimated by LVEF, LVmassIndex, LVIDd, E/e or LV global longitudinal strain (P > 0.05 for all). In multivariate analyses plasma concentrations of Gal-3 were significantly associated with the cardiac biomarkers: NT-proBNP (beta: 0.047; 95 % CI: 0.008 0.086; P = 0.020), proANP (beta: 0.137; 95 % CI: 0.067-0.207; P < 0.001), chromogranin A (beta: 0.123; 95 % CI: 0.052-0.194; P < 0.001) and Copeptin (beta: 0.080; 95 % CI: 0.000-0.160; P = 0.049). Multivariate analysis was adjusted for eGFR, age, gender and medical treatment. CONCLUSIONS: Increased plasma concentrations of Gal-3 are associated with reduced eGFR and increased plasma concentrations of NT-proBNP, proANP, chromogranin A and Copeptin, but not with echocardiographic parameters reflecting myocardial function. These results suggest that Gal-3 reflects both increased neurohumoral activity and reduced eGFR, but not myocardial function in patients with systolic HF. PMID- 27246705 TI - The effectiveness bundling of zinc with Oral Rehydration Salts (ORS) for improving adherence to acute watery diarrhea treatment in Ethiopia: cluster randomised controlled trial. AB - BACKGROUND: Presumably bundling/co-packaging of zinc with ORS encourages the combined use of the products for diarrhea treatment; however, empirical evidences are scarce. The purpose of this work is to evaluate whether co-packing using a plastic pouch can enhance the joint adherence to the treatment or not. The study also compares the cost effectiveness (CE) of two co-packaging options: 'central' and 'health center (HC)' level bundling. METHODS: This cluster-randomised controlled trial was conducted in 2015 in eight districts of Ethiopia. Thirty two HCs were randomly assigned to one of the following four intervention arms: (i) 'Central bundling' (zinc and ORS bundled using a pouch that had instructional message, distributed to HCs); (ii) 'HC level bundling' (zinc, ORS and a similar pouch distributed to the HCs and bundled by health workers); (iii) 'Bundling without message' (zinc, ORS and plain pouch distributed and bundled by the health workers); and, (iv) 'Status quo' (zinc and ORS co-administered without bundling). In each of the four arms, 176 children 6-59 months of age, presented with acute diarrhea were enrolled. Twelve days after enrollment, level of adherence was assessed. A composite scale of adherence was developed and modeled using mixed effects linear regression analysis. The unit costs associated with the arms were estimated using secondary data sources. Incremental CE analysis was made by taking the cost and level of adherence in fourth arm as a base value. RESULTS: The follow-up rate was 95.6 %. As compared with the 'status quo' arm, the joint adherences in the 'central' and 'HC level' bundling arms raised substantially by 14.8 and 15.7 percentage points (PP), respectively (P < 0.05). No significant difference was observed between 'bundling without message' and the 'status quo' arms. The unit cost incurred by the 'central bundling' is relatively higher (USD 0.658/episode) as compared with the 'HC level bundling' approach (USD 0.608/episode). The incremental CE ratio in the 'central bundling' modality was two times higher than in the 'HC based bundling' approach. CONCLUSION: Bundling zinc with ORS using a pouch with instructional messages increases adherence to the treatment. 'HC level bundling' is more CE than the 'central bundling' approach. PMID- 27246707 TI - Transition from a Metal-Localized Mixed-Valence Compound to a Fully Delocalized and Bridge-Biased Electrophore in a Ruthenium-Amine-Ruthenium Tricenter System. AB - A series of cyclometalated diruthenium complexes with a redox-active amine bridge were synthesized. Depending on the terminal ligands of the ruthenium components and the substituent on the amine unit, the one-electron-oxidized state can be either in the form of a weakly or strongly coupled mixed-valence diruthenium complex, a fully charge-delocalized three-center system, or a bridge-biased electrophore. This transition among different electronic forms was supported by electrochemistry, near-infrared absorption, electron paramagnetic resonance, and density functional theory analysis. PMID- 27246706 TI - MicroRNA-155 contributes to shear-resistant leukocyte adhesion to human brain endothelium in vitro. AB - BACKGROUND: Increased leukocyte adhesion to brain endothelial cells forming the blood-brain barrier (BBB) precedes extravasation into the central nervous system (CNS) in neuroinflammatory diseases such as multiple sclerosis (MS). Previously, we reported that microRNA-155 (miR-155) is up-regulated in MS and by inflammatory cytokines in human brain endothelium, with consequent modulation of endothelial paracellular permeability. Here, we investigated the role of endothelial miR-155 in leukocyte adhesion to the human cerebral microvascular endothelial cell line, hCMEC/D3, under shear forces mimicking blood flow in vivo. RESULTS: Using a gain- and loss-of-function approach, we show that miR-155 up-regulation increases leukocyte firm adhesion of both monocyte and T cells to hCMEC/D3 cells. Inhibition of endogenous endothelial miR-155 reduced monocytic and T cell firm adhesion to naive and cytokines-induced human brain endothelium. Furthermore, this effect is partially associated with modulation of the endothelial cell adhesion molecules VCAM1 and ICAM1 by miR-155. CONCLUSIONS: Our results suggest that endothelial miR-155 contribute to the regulation of leukocyte adhesion at the inflamed BBB. Taken together with previous observations, brain endothelial miR-155 may constitute a potential molecular target for treatment of neuroinflammation diseases. PMID- 27246708 TI - Randomized Controlled Trial of Prophylactic Negative-Pressure Wound Therapy at Ostomy Closure for the Prevention of Delayed Wound Healing and Surgical Site Infection in Patients with Ulcerative Colitis. AB - BACKGROUND/AIMS: Although negative-pressure wound therapy (NPWT) is likely advantageous for wound healing, the efficacy and safety of its prophylactic use remain unclear for digestive surgery. We performed a prospective randomized controlled study to evaluate the efficacy and safety of this procedure during ileostomy closure. METHODS: We conducted a prospective, randomized study between November 2014 and September 2015. Patients with ulcerative colitis scheduled to undergo ileostomy closure with purse-string suture (PSS) were randomly divided into groups with or without NPWT. The primary endpoint was complete wound healing. The secondary endpoints were incidences of wound complications. RESULTS: A total of 31 patients with PSS alone and 28 patients with PSS + NPWT were enrolled. Wound infection was observed in 1 patient in the PSS-alone condition and 3 patients in the PSS + NPWT condition (p = 0.76). The mean duration of complete wound healing was 37.6 +/- 11.7 days in the PSS-alone condition and 33.5 +/- 10.0 days in the PSS + NPWT condition (p = 0.18). CONCLUSION: Although no adverse effects were observed in this series, the efficacy of PSS + NPWT was not confirmed. Further clarification of the indication of prophylactic NPWT and its efficacy must be obtained, and the efficacy and safety of NPWT in different dirty/infected surgeries should be evaluated. PMID- 27246709 TI - Cell fate control by pioneer transcription factors. AB - Distinct combinations of transcription factors are necessary to elicit cell fate changes in embryonic development. Yet within each group of fate-changing transcription factors, a subset called 'pioneer factors' are dominant in their ability to engage silent, unmarked chromatin and initiate the recruitment of other factors, thereby imparting new function to regulatory DNA sequences. Recent studies have shown that pioneer factors are also crucial for cellular reprogramming and that they are implicated in the marked changes in gene regulatory networks that occur in various cancers. Here, we provide an overview of the contexts in which pioneer factors function, how they can target silent genes, and their limitations at regions of heterochromatin. Understanding how pioneer factors regulate gene expression greatly enhances our understanding of how specific developmental lineages are established as well as how cell fates can be manipulated. PMID- 27246711 TI - The regulation and plasticity of root hair patterning and morphogenesis. AB - Root hairs are highly specialized cells found in the epidermis of plant roots that play a key role in providing the plant with water and mineral nutrients. Root hairs have been used as a model system for understanding both cell fate determination and the morphogenetic plasticity of cell differentiation. Indeed, many studies have shown that the fate of root epidermal cells, which differentiate into either root hair or non-hair cells, is determined by a complex interplay of intrinsic and extrinsic cues that results in a predictable but highly plastic pattern of epidermal cells that can vary in shape, size and function. Here, we review these studies and discuss recent evidence suggesting that environmental information can be integrated at multiple points in the root hair morphogenetic pathway and affects multifaceted processes at the chromatin, transcriptional and post-transcriptional levels. PMID- 27246710 TI - Circular RNAs: analysis, expression and potential functions. AB - Just a few years ago, it had been assumed that the dominant RNA isoforms produced from eukaryotic genes were variants of messenger RNA, functioning as intermediates in gene expression. In early 2012, however, a surprising discovery was made: circular RNA (circRNA) was shown to be a transcriptional product in thousands of human and mouse genes and in hundreds of cases constituted the dominant RNA isoform. Subsequent studies revealed that the expression of circRNAs is developmentally regulated, tissue and cell-type specific, and shared across the eukaryotic tree of life. These features suggest important functions for these molecules. Here, we describe major advances in the field of circRNA biology, focusing on the regulation of and functional roles played by these molecules. PMID- 27246712 TI - Development-on-chip: in vitro neural tube patterning with a microfluidic device. AB - Embryogenesis is a highly regulated process in which the precise spatial and temporal release of soluble cues directs differentiation of multipotent stem cells into discrete populations of specialized adult cell types. In the spinal cord, neural progenitor cells are directed to differentiate into adult neurons through the action of mediators released from nearby organizing centers, such as the floor plate and paraxial mesoderm. These signals combine to create spatiotemporal diffusional landscapes that precisely regulate the development of the central nervous system (CNS). Currently, in vivo and ex vivo studies of these signaling factors present some inherent ambiguity. In vitro methods are preferred for their enhanced experimental clarity but often lack the technical sophistication required for biological realism. In this article, we present a versatile microfluidic platform capable of mimicking the spatial and temporal chemical environments found in vivo during neural tube development. Simultaneous opposing and/or orthogonal gradients of developmental morphogens can be maintained, resulting in neural tube patterning analogous to that observed in vivo. PMID- 27246714 TI - beta-catenin-mediated adhesion is required for successful preimplantation mouse embryo development. AB - beta-catenin (CTNNB1) is integral to cell adhesion and to the canonical Wnt signaling pathway. The effects of maternal and zygotic CTNNB1 on embryogenesis have each been separately assessed, whereas the effect of its total absence has not. As the 'traditional' conditional Ctnnb1 knockout alleles give rise to truncated CTNNB1 fragments, we designed a new knockout allele incapable of CTNNB1 production. Mouse embryos lacking intact maternal/zygotic CTNNB1 from two knockout strains were examined in detail. Preimplantation embryos are formed, yet abnormalities in their size and shape were found throughout pre- and early postimplantation development. In the absence of the zona pellucida, embryos lacking CTNNB1 undergo fission and these separated blastomeres can become small trophoblastic vesicles, which in turn induce decidual reactions. Comparing the severity of this defective adhesion phenotype in embryos bearing the null allele with those carrying the 'traditional' knockout allele suggests a hypomorphic effect of the truncated CTNNB1 protein fragment, an important observation with possible impact on previous and future studies. PMID- 27246717 TI - Selective separation of oil and water with mesh membranes by capillarity. AB - The separation of oil and water from wastewater generated in the oil-production industries, as well as in frequent oil spillage events, is important in mitigating severe environmental and ecological damage. Additionally, a wide arrange of industrial processes require oils or fats to be removed from aqueous systems. The immiscibility of oil and water allows for the wettability of solid surfaces to be engineered to achieve the separation of oil and water through capillarity. Mesh membranes with extreme, selective wettability can efficiently remove oil or water from oil/water mixtures through a simple filtration process using gravity. A wide range of different types of mesh membranes have been successfully rendered with extreme wettability and applied to oil/water separation in the laboratory. These mesh materials have typically shown good durability, stability as well as reusability, which makes them promising candidates for an ever widening range of practical applications. PMID- 27246718 TI - Solution-phase synthesis of transition metal oxide nanocrystals: Morphologies, formulae, and mechanisms. AB - In this review, we provide a broad overview of solution-phase synthesis of transition metal oxide nanocrystals (NCs), including a substantial catalog of published methods, and a unifying classification and discussion. Prevalent subcategories of solution-phase synthesis are delineated and general features are summarized. The diverse morphologies achievable by solution-phase synthesis are defined and exemplified. This is followed by sequential consideration of the solution-phase synthesis of first-row transition metal oxides. The common oxides of Ti, V, Mn, Fe, Co, Ni, Cu, and Zn are introduced; major crystal lattices are presented and illustrated; representative examples are explained; and numerous synthesis formulae are tabulated. Following this presentation of experimental studies, we present an introduction to theories of NC nucleation and growth. Various models of NC nucleation and growth are addressed, and important concepts determining the growth and structure of colloidal NCs are explained. Overall, this review provides an entry into systematic understanding of solution-phase synthesis of nanocrystals, with a reasonably comprehensive survey of results for the important category of transition metal oxide NCs. PMID- 27246713 TI - Chromatin remodeling enzyme Snf2h regulates embryonic lens differentiation and denucleation. AB - Ocular lens morphogenesis is a model for investigating mechanisms of cellular differentiation, spatial and temporal gene expression control, and chromatin regulation. Brg1 (Smarca4) and Snf2h (Smarca5) are catalytic subunits of distinct ATP-dependent chromatin remodeling complexes implicated in transcriptional regulation. Previous studies have shown that Brg1 regulates both lens fiber cell differentiation and organized degradation of their nuclei (denucleation). Here, we employed a conditional Snf2h(flox) mouse model to probe the cellular and molecular mechanisms of lens formation. Depletion of Snf2h induces premature and expanded differentiation of lens precursor cells forming the lens vesicle, implicating Snf2h as a key regulator of lens vesicle polarity through spatial control of Prox1, Jag1, p27(Kip1) (Cdkn1b) and p57(Kip2) (Cdkn1c) gene expression. The abnormal Snf2h(-/-) fiber cells also retain their nuclei. RNA profiling of Snf2h(-/) (-) and Brg1(-/-) eyes revealed differences in multiple transcripts, including prominent downregulation of those encoding Hsf4 and DNase IIbeta, which are implicated in the denucleation process. In summary, our data suggest that Snf2h is essential for the establishment of lens vesicle polarity, partitioning of prospective lens epithelial and fiber cell compartments, lens fiber cell differentiation, and lens fiber cell nuclear degradation. PMID- 27246719 TI - False-positive cerebrospinal fluid cryptococcus antigen in Libman-Sacks endocarditis. AB - BACKGROUND: Cryptococcus meningoencephalitis is a serious opportunistic infection associated with high morbidity and mortality in immunocompromised hosts, particularly patients with advanced AIDS disease. The diagnosis is established through cerebrospinal fluid (CSF) cryptococcus antigen detection and cultures. Cryptococcus antigen testing is usually the initial test of choice due its high sensitivity and specificity along with the quick availability of the results. CASE REPORT: We hereby report a case of a false-positive CSF cryptococcus antigen assay in a patient with systemic lupus erythematosus presenting with acute confusion. While initial CSF evaluation revealed a positive cryptococcus antigen assay, the patient's symptoms were inconsistent with cryptococcus meningoencephalitis. A repeat CSF evaluation, done 3 days later, revealed a negative CSF cryptococcus antigen assay. CONCLUSION: Given the patient's active lupus disease and the elevated antinuclear antibody titers, we believe that the initial positive result was a false positive caused by interference from autoantibodies. PMID- 27246720 TI - Pancreatic MRI for the surveillance of cystic neoplasms: comparison of a short with a comprehensive imaging protocol. AB - OBJECTIVES: The study aims were to evaluate: (1) whether a short-protocol (SP) MRI for the surveillance of pancreatic cystic neoplasms (PCN) provides equivalent clinical information as a comprehensive-protocol (CP), and (2) the cost reduction from substituting CP with SP for patient surveillance. METHODS: This retrospective study included 154 consecutive patients (median age: 66, 52 % men) with working-diagnosis of PCN and available contrast-enhanced MRI/MRCP. Three radiologists evaluated independently two imaging sets (SP/CP) per patient. The CP included: T2-weighted (HASTE/MRCP), DWI and T1-weighted (chemical-shift/pre-/post contrast) images [acquisition time (AT) ~ 35 min], whereas the SP included: T2 weighted HASTE and T1-weighted pre-contrast images (AT ~ 8 min). Mean values of largest cyst/main pancreatic duct diameter (DC/DMPD) were compared. Agreement regarding presence/absence of cystic/MPD mural nodules (MNC/MNMPD), inter observer agreement and cost differences between SP/CP were calculated. RESULTS: For DC and DMPD, mean values with SP/CP were 21.4/21.7 mm and 3.52/3.58 mm, while mean differences SP-CP were 0.3 mm (p = 0.02) and 0.06 mm (p = 0.12), respectively. For presence/absence of MNC and MNMPD, SP/CP coincided in 93 % and 98 % of cases, respectively. Inter-observer agreement was strong for SP/CP. SP cost was 25 % of CP-cost. CONCLUSIONS: For the surveillance of PCN, short protocol MRI provides information equivalent to the more time-consuming and costly comprehensive-protocol. KEY POINTS: * Pancreatic cystic neoplasms (PCN) are increasingly diagnosed in the general population. * Multiple imaging controls are recommended for the surveillance of patients with PCN. * Short and comprehensive MRI-protocols are equivalent for decision-making in PCN under surveillance. * Evaluation of imaging risk factors in PCNs is comparable with both MRI-protocols. * Use of the short MRI-protocol may rationalise healthcare resources. PMID- 27246721 TI - Tomosynthesis of the thoracic spine: added value in diagnosing vertebral fractures in the elderly. AB - OBJECTIVES: Thoracic spine radiography becomes more difficult with age. Tomosynthesis is a low-dose tomographic extension of radiography which may facilitate thoracic spine evaluation. This study assessed the added value of tomosynthesis in imaging of the thoracic spine in the elderly. METHODS: Four observers compared the image quality of 50 consecutive thoracic spine radiography and tomosynthesis data sets from 48 patients (median age 67 years, range 55-92 years) on a number of image quality criteria. Observer variation was determined by free-marginal multirater kappa. The conversion factor and effective dose were determined from the dose-area product values. RESULTS: For all observers significantly more vertebrae were seen with tomosynthesis than with radiography (mean 12.4/9.3, P < 0.001) as well as significantly more fractures (mean 0.9/0.7, P = 0.017). The image quality score for tomosynthesis was significantly higher than for radiography, for all evaluated structures. Tomosynthesis took longer to evaluate than radiography. Despite this, all observers scored a clear preference for tomosynthesis. Observer agreement was substantial (mean kappa = 0.73, range 0.51-0.94). The calibration or conversion factor was 0.11 mSv/(Gy cm2) for the combined examination. The resulting effective dose was 0.87 mSv. CONCLUSION: Tomosynthesis can increase the detection rate of thoracic vertebral fractures in the elderly, at low added radiation dose. KEY POINTS: * Tomosynthesis helps evaluate the thoracic spine in the elderly. * Observer agreement for thoracic spine tomosynthesis was substantial (mean kappa = 0.73). * Significantly more vertebrae and significantly more fractures were seen with tomosynthesis. * Tomosynthesis took longer to evaluate than radiography. * There was a clear preference among all observers for tomosynthesis over radiography. PMID- 27246722 TI - High-resolution T2-weighted cervical cancer imaging: a feasibility study on ultra high-field 7.0-T MRI with an endorectal monopole antenna. AB - OBJECTIVES: We studied the feasibility of high-resolution T2-weighted cervical cancer imaging on an ultra-high-field 7.0-T magnetic resonance imaging (MRI) system using an endorectal antenna of 4.7-mm thickness. METHODS: A feasibility study on 20 stage IB1-IIB cervical cancer patients was conducted. All underwent pre-treatment 1.5-T MRI. At 7.0-T MRI, an external transmit/receive array with seven dipole antennae and a single endorectal monopole receive antenna were used. Discomfort levels were assessed. Following individualised phase-based B1+ shimming, T2-weighted turbo spin echo sequences were completed. RESULTS: Patients had stage IB1 (n = 9), IB2 (n = 4), IIA1 (n = 1) or IIB (n = 6) cervical cancer. Discomfort (ten-point scale) was minimal at placement and removal of the endorectal antenna with a median score of 1 (range, 0-5) and 0 (range, 0-2) respectively. Its use did not result in adverse events or pre-term session discontinuation. To demonstrate feasibility, T2-weighted acquisitions from 7.0-T MRI are presented in comparison to 1.5-T MRI. Artefacts on 7.0-T MRI were due to motion, locally destructive B1 interference, excessive B1 under the external antennae and SENSE reconstruction. CONCLUSIONS: High-resolution T2-weighted 7.0-T MRI of stage IB1-IIB cervical cancer is feasible. The addition of an endorectal antenna is well tolerated by patients. KEY POINTS: * High resolution T 2 weighted 7.0-T MRI of the inner female pelvis is challenging * We demonstrate a feasible approach for T 2 -weighted 7.0-T MRI of cervical cancer * An endorectal monopole receive antenna is well tolerated by participants * The endorectal antenna did not lead to adverse events or session discontinuation. PMID- 27246723 TI - Enrichment of bacterial DNA for the diagnosis of blood stream infections. AB - BACKGROUND: Blood cultures are commonly employed to identify bacterial pathogens causing sepsis. PCR assays to diagnose septicemia require extraction of bacterial DNA from blood samples and thus, delay the initiation of appropriate antimicrobial treatment. The presence of abundant human DNA may hamper the sensitivity of PCR in the detection of bacteria. METHODS: We used serial dilutions of E. Coli spiked pseudo-blood-sepsis samples to develop a simple method that combines the use of a polar detergent solvent and adjustment of the basic pH to remove human DNA. A 16S rRNA gene-based screening algorithm was established to differentiate Gram-positive and Gram-negative groups of bacteria and the family of Enterobacteriaceae. A stringent validation with appropriate controls was implemented. The method of human DNA removal was then applied on 194 sepsis blood samples and 44 cerebrospinal fluid (CSF) samples by real-time PCR. RESULTS: This uncomplicated and straightforward approach allows to remove up to 98 % of human DNA from peripheral blood of septic patients. The inhibitory effect of human DNA is efficiently prevented and the detection limit of real-time PCR is increased to 10 E. Coli CFUs/ml. This sensitivity is 10 times higher compared to conventional real-time PCR assays. The classical blood culture detected 58/194 (30 %) of sepsis and 9/44 (21 %) of CSF samples. Out of the 194 blood samples tested, the conventional real-time PCR targeting 13 common sepsis causing pathogens correctly detected the bacterial DNA in 16/194 (8 %) only and 14/44 (32 %) in cerebrospinal fluid samples. Our newly established approach was able to provide correct diagnoses in 78 (40 %) of the 194 blood samples and in 14 (32 %) of the CSF samples. The combination of both blood cultures and our technique raised the rate of sepsis diagnoses to 112/194 (58 %). Of the total group tested positive, 46 (24 %) cases showed overlap with the classical methodology. CONCLUSION: We report a simple optimized in-house protocol for removal of human DNA from blood sepsis samples as a pre-analytical tool to prepare DNA for subsequent PCR assays. With the detection increase of our in-house DNA removal approach, subsequent PCR assays can reach detection limits of 10 E. coli CFUs/ml and significantly improve the diagnostic rate in blood sepsis cases. PMID- 27246724 TI - Copper Levels in Tissues of Dolphins Tursiops truncatus, Stenella coeruleoalba and Grampus griseus from the Croatian Adriatic Coast. AB - Copper concentrations were determined in muscle, liver, kidney, spleen and lung tissues of three dolphin species. Dolphins of Tursiops truncatus (young and adult), Stenella coeruleoalba and Grampus griseus were stranded along the Croatian coast. Concentrations in tissues of all three dolphin species were highest in the liver (4.92-16.5 MUg/g) followed by kidney (2.85-5.29 MUg/g). Similar levels were measured in muscle, spleen and lung in range 1.13-3.67 MUg/g. Statistics analysis showed significant differences of Cu concentrations for muscle (p = 0.008), kidney (p = 0.04) and liver (p = 0.02) between the three dolphin species. Also, for all three species significant differences between tissue types of the same species were determined (p < 0.001, all). However, there were no significant differences in Cu levels of the same tissues between males and females within same species. Also, significant differences of body length and weight between three dolphin were found (p < 0.001, both). PMID- 27246725 TI - MicroRNA-205-5b inhibits HMGB1 expression in LPS-induced sepsis. AB - Inflammatory cytokines belonging to high mobility group box (HMGB)1 play a key role in sepsis through yet unknown mechanisms. The inflammatory response is modulated by microRNAs (miRNAs or miRs) at multiple levels and is poorly understood. In this study, the regulation of HMGB1 by miRNAs was evaluated using 3-(2,4-dimethoxybenzylidene)anabaseine (GTS-21) to activate the cholinergic anti inflammatory pathway (CAP) and decrease HMGB1 expression in RAW264.7 cells. Microarray-based miRNA expression profiling of RAW264.7 cells was used to screen target miRNAs through genetic screening, GO analysis and hierarchical clustering. The expression of miRNA targets in the serum, colon, spleen, livers and lungs of BALB/c mice was quantified by RT-qPCR. Serum protein levels were quantified by ELISA. Western blot analysis and RT-qPCR were used for verification in vitro. Using miRNA array analysis, we screened 3 miRNAs (miR-205-5b, miR-196a and miR 193b). Animal experiments with miR-205-5b indicated its high degree of expression in the serum, colon, spleen, liver and lungs following the downregulation of HMGB1 in the tissues. RAW264.7 cells transfected with miR-205-5b mimics downregulated HMGB1 protein expression, suggesting translational regulation. HMGB1 expression negatively correlated with miR-205-5b expression in LPS-induced sepsis. By contrast, HMGB1 expression in LPS-stimulated RAW264.7 cells was increased following transfection with miR-205-5b inhibitor. miR-205-5b is a critical mediator of cholinergic anti-inflammatory activity in late sepsis. The upregulation of miR-205-5b as a potential therapeutic target for the treatment of inflammatory diseases is a possible novel therapeutic strategy against late sepsis. The mechanisms involved include the by post-transcriptional suppression of HMGB1 in cells and tissues. PMID- 27246727 TI - Role of Ca2+ in the IVM of spermatozoa from the sterlet Acipenser ruthenus. AB - The role of Ca2+ in sturgeon sperm maturation and motility was investigated. Sperm from mature male sterlets (Acipenser ruthenus) were collected from the Wolffian duct and testis 24h after hormone induction. Testicular spermatozoa (TS) were incubated in Wolffian duct seminal fluid (WDSF) for 5min at 20 degrees C and were designated 'TS after IVM' (TSM). Sperm motility was activated in media with different ion compositions, with motility parameters analysed from standard video microscopy records. To investigate the role of calcium transport in the IVM process, IVM was performed (5min at 20 degrees C) in the presence of 2mM EGTA, 100uM Verapamil or 100uM Tetracaine. No motility was observed in the case of TS (10mM Tris, 25mM NaCl, 50mM Sucr with or without the addition of 2mM EGTA). Both incubation of TS in WDSF and supplementation of the activation medium with Ca2+ led to sperm motility. The minimal Ca2+ concentration required for motility activation of Wolffian duct spermatozoa, TS and TSM was determined (1-2nM for Wolffian duct spermatozoa and TSM; approximately 0.6mM for TS). Motility was obtained after the addition of verapamil to the incubation medium during IVM, whereas the addition of EGTA completely suppressed motility, implying Ca2+ involvement in sturgeon sperm maturation. Further studies into the roles of Ca2+ transport in sturgeon sperm maturation and motility are required. PMID- 27246728 TI - How accurate and reproducible are the identification of cruciate and collateral ligament insertions using MRI? AB - BACKGROUND: At present, increasing the accuracy of identification of knee ligament insertions is fundamental in developing accurate patient-specific three dimensional (3D) models for preoperative planning surgeries, designing patient specific instrumentation or implants, and conducting biomechanical analyses. The accuracy and reproducibility of magnetic resonance imaging (MRI) scans in identifying cruciate and collateral ligament insertions have not been investigated thus far, despite their wide use. This study aimed to define and validate a method for this purpose. METHODS: First, the femur and tibia bones were oriented. Then, the sites of cruciate and collateral ligament insertions were identified. The inter- and intra-class correlation coefficients (ICCs) were calculated after multiple operators were applied to the images of different patients. The effect of the quality of the available MRI scans on the accuracy of identifying ligament insertions was also investigated. Moreover, non-expert operators were also found to be capable of performing the procedure after a video tutorial, and its efficacy was tested. RESULTS: The mean intra-observer variability was always <1.5mm for all landmarks, whereas the mean inter-observer variability was always <2.5mm except for the medial collateral ligament localized on the tibia (6.7mm). The ICCs showed good results, up to 0.99. A lower image quality had no noticeable effect on the procedure for identifying cruciate ligaments. Video tutorials were found to improve the ICCs up to 45%. CONCLUSIONS: This procedure is suitable for the univocal and accurate identification of cruciate and lateral collateral ligaments on MRI scans. CLINICAL RELEVANCE: This study demonstrates that MRI scans are highly suited to identifying cruciate ligament insertions. PMID- 27246726 TI - ICECREAM: randomised phase II study of cetuximab alone or in combination with irinotecan in patients with metastatic colorectal cancer with either KRAS, NRAS, BRAF and PI3KCA wild type, or G13D mutated tumours. AB - BACKGROUND: Patients with metastatic colorectal cancer whose disease has progressed on oxaliplatin- and irinotecan-containing regimens may benefit from EGFR-inhibiting monoclonal antibodies if they do not contain mutations in the KRAS gene (are "wild type"). It is unknown whether these antibodies, such as cetuximab, are more efficacious in refractory metastatic colorectal cancer as monotherapy, or in combination with irinotecan. Lack of mutation in KRAS, BRAF and PIK3CA predicts response to EFGR-inhibitors. The ICECREAM trial examines the question of monotherapy versus combination with chemotherapy in two groups of patients: those with a "quadruple wild type" tumour genotype (no mutations in KRAS, NRAS, PI3KCA or BRAF genes) and those with the specific KRAS mutation in codon G13D, for whom possibly EGFR-inhibitor efficacy may be equivalent. METHODS AND DESIGN: ICECREAM is a randomised, phase II, open-label, controlled trial comparing the efficacy of cetuximab alone or with irinotecan in patients with "quadruple wild type" or G13D-mutated metastatic colorectal cancer, whose disease has progressed on, or who are intolerant of oxaliplatin- and fluoropyrimidine based chemotherapy. The primary endpoint is the 6-month progression-free survival benefit of the treatment regimen. Secondary endpoints are response rate, overall survival, and quality of life. The tertiary endpoint is prediction of outcome with further biological markers. International collaboration has facilitated recruitment in this prospective trial of treatment in these infrequently found molecular subsets of colorectal cancer. DISCUSSION: This unique trial will yield prospective information on the efficacy of cetuximab and whether this is further enhanced with chemotherapy in two distinct populations of patients with metastatic colorectal cancer: the "quadruple wild type", which may 'superselect' for tumours sensitive to EGFR-inhibition, and the rare KRAS G13D mutated tumours, which are also postulated to be sensitive to the drug. The focus on establishing both positive and negative predictive factors for the response to targeted therapy is an attempt to improve outcomes, reduce toxicity and contain treatment costs. Tissue and blood will yield a resource for molecular studies. Recruitment, particularly of patients with the rare G13D mutation, will demonstrate the ability for international collaboration to run prospective trials in small colorectal cancer molecular subgroups. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry: ACTRN12612000901808 , registered 16 August 2012. PMID- 27246729 TI - The potential of Nigerian bioactive plants for controlling gastrointestinal nematode infection in livestock. AB - Bioactive compounds from marine and terrestrial organisms have been used extensively in the treatment of many diseases in both their natural form and as templates for synthetic modifications. This review summarizes present knowledge about anthelmintic effects of the extracts of bioactive plants in Nigeria against helminth parasites of ruminants. Plants traditionally used in livestock production are discussed. The main focus is hinged on in vitro and in vivo activities of secondary plant metabolites against nematodes of livestock. This review provides insight into preliminary studies of medicinal plants, which can be investigated further to discover promising molecules in the search for novel anthelmintic drugs and nutraceuticals. PMID- 27246730 TI - How to Treat INI1 Negative Non-Rhabdoid Tumours in Adolescents: Following Genotype or Histological Phenotype? PMID- 27246731 TI - Cathepsin A inhibition attenuates myocardial infarction-induced heart failure on the functional and proteomic levels. AB - BACKGROUND: Myocardial infarction (MI) is a major cause of heart failure. The carboxypeptidase cathepsin A is a novel target in the treatment of cardiac failure. We aim to show that recently developed inhibitors of the protease cathepsin A attenuate post-MI heart failure. METHODS: Mice were subjected to permanent left anterior descending artery (LAD) ligation or sham operation. 24 h post-surgery, LAD-ligated animals were treated with daily doses of the cathepsin A inhibitor SAR1 or placebo. After 4 weeks, the three groups (sham, MI-placebo, MI-SAR1) were evaluated. RESULTS: Compared to sham-operated animals, placebo treated mice showed significantly impaired cardiac function and increased plasma BNP levels. Cathepsin A inhibition prevented the increase of plasma BNP levels and displayed a trend towards improved cardiac functionality. Proteomic profiling was performed for the three groups (sham, MI-placebo, MI-SAR1). More than 100 proteins were significantly altered in placebo-treated LAD ligation compared to the sham operation, including known markers of cardiac failure as well as extracellular/matricellular proteins. This ensemble constitutes a proteome fingerprint of myocardial infarction induced by LAD ligation in mice. Cathepsin A inhibitor treatment normalized the marked increase of the muscle stress marker CA3 as well as of Iggamma 2b and fatty acid synthase. For numerous further proteins, cathepsin A inhibition partially dampened the LAD ligation-induced proteome alterations. CONCLUSIONS: Our proteomic and functional data suggest that cathepsin A inhibition has cardioprotective properties and support a beneficial effect of cathepsin A inhibition in the treatment of heart failure after myocardial infarction. PMID- 27246732 TI - mTORC1 is a critical mediator of oncogenic Semaphorin3A signaling. AB - Aberration of signaling pathways by genetic mutations or alterations in the surrounding tissue environments can result in tumor development or metastasis. However, signaling molecules responsible for these processes have not been completely elucidated. Here, we used mouse Lewis lung carcinoma cells (LLC) to explore the mechanism by which the oncogenic activity of Semaphorin3A (Sema3A) signaling is regulated. Sema3A knockdown by shRNA did not affect apoptosis, but decreased cell proliferation in LLCs; both the mammalian target of rapamycin complex 1 (mTORC1) level and glycolytic activity were also decreased. In addition, Sema3A knockdown sensitized cells to inhibition of oxidative phosphorylation by oligomycin, but conferred resistance to decreased cell viability induced by glucose starvation. Furthermore, recombinant SEMA3A rescued the attenuation of cell proliferation and glycolytic activity in LLCs after Sema3A knockdown, whereas mTORC1 inhibition by rapamycin completely counteracted this effect. These results demonstrate that Sema3A signaling exerts its oncogenic effect by promoting an mTORC1-mediated metabolic shift from oxidative phosphorylation to aerobic glycolysis. PMID- 27246733 TI - Expanding the substrate scope and reactivity of cytochrome P450 OleT. AB - The efficient hydrogen peroxide-dependent hydroxylation and epoxidation of hydrocarbons is catalysed by a P450 fatty acid decarboxylase (OleT) active-site variant. The introduction of an acidic functionality in the protein framework circumvents the necessity for a carboxylate that is typically provided by the substrate for efficient H2O2 heterolysis. Spectroscopic and turnover studies show that the mutation eliminates the binding and metabolism of prototypical fatty acid substrates, but permits the oxidation of a broad range of inert hydrocarbon substrates. PMID- 27246734 TI - Metformin preconditioning provide neuroprotection through enhancement of autophagy and suppression of inflammation and apoptosis after spinal cord injury. AB - Spinal cord injury (SCI) is one of the most serious nervous system disorders characterised by high morbidity and disability. Inflammatory and autophagy responses play an important role in the development of SCI. Metformin, a first line drug for type-2 diabetes, features autophagy promotion as well as anti inflammatory and anti-apoptotic properties in the nervous system. In this study, we investigated the neuroprotection effects of metformin preconditioning on rats after SCI. Results of Basso, Beattie and Bresnahan scores, HE staining and Nissl staining showed that the function and quantity of motor neurons were protected by metformin after SCI. Western blot revealed that the expression of Beclin-1 and LC3B-II was enhanced, and the phosphorylation levels of the mammalian target of rapamycin (mTOR) protein and p70S6K were reduced by metformin after SCI. Metformin significantly reduced the expression of NF-kappaB. Moreover, Western blot and immunofluorescence results indicated that caspase 3 activation was reduced, whereas bcl-2 level was significantly increased by metformin. Hence, metformin attenuated SCI by inhibiting apoptosis and inflammation and enhancing the autophagy via the mTOR/p70S6K signalling pathway. PMID- 27246735 TI - tRNA modification profiles of the fast-proliferating cancer cells. AB - Despite the recent progress in RNA modification study, a comprehensive modification profile is still lacking for mammalian cells. Using a quantitative HPLC/MS/MS assay, we present here a study where RNA modifications are examined in term of the major RNA species. With paired slow- and fast-proliferating cell lines, distinct RNA modification profiles are first revealed for diverse RNA species. Compared to mRNAs, increased ribose and nucleobase modifications are shown for the highly-structured tRNAs and rRNAs, lending support to their contribution to the formation of high-order structures. This study also reveals a dynamic tRNA modification profile in the fast-proliferating cells. In addition to cultured cells, this unique tRNA profile has been further confirmed with endometrial cancers and their adjacent normal tissues. Taken together, the results indicate that tRNA is a actively regulated RNA species in the fast proliferating cancer cells, and suggest that they may play a more active role in biological process than expected. PMID- 27246736 TI - Tetrandrine has anti-adipogenic effect on 3T3-L1 preadipocytes through the reduced expression and/or phosphorylation levels of C/EBP-alpha, PPAR-gamma, FAS, perilipin A, and STAT-3. AB - Tetrandrine is a bisbenzylisoquinoline alkaloid isolated from the roots of Stephania tetrandra S. Moore and has been shown to possess anti-inflammatory and anti-cancerous activities. In this study, the effect of tetrandrine on adipogenesis in 3T3-L1 preadipocytes was investigated. Tetrandrine at 10 MUM concentration strongly inhibited lipid accumulation and triglyceride (TG) synthesis during the differentiation of 3T3-L1 preadipocytes into adipocytes. On mechanistic levels, tetrandrine reduced not only the expressions of CCAAT/enhancer-binding protein-alpha (C/EBP-alpha), peroxisome proliferator activated receptor-gamma (PPAR-gamma), fatty acid synthase (FAS), and perilipin A but also the phosphorylation levels of signal transducer and activator of transcription-3 (STAT-3) during 3T3-L1 adipocyte differentiation. Tetrandrine also reduced the mRNA expression of leptin, but not adiponectin, during 3T3-L1 adipocyte differentiation. Collectively, these findings show that tetrandrine has strong anti-adipogenic effect on 3T3-L1 preadipocytes and the effect is largely attributable to the reduced expression and/or phosphorylation levels of C/EBP alpha, PPAR-gamma, FAS, perilipin A, and STAT-3. PMID- 27246737 TI - Supplementing dietary sugar promotes endoplasmic reticulum stress-independent insulin resistance and fatty liver in goose. AB - It is known that endoplasmic reticulum stress (ERS) contributes to insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD) in mammals. However, we recently demonstrated that overfeeding with a traditional diet (mainly consisting of cooked maize) does not induce ERS in goose. As cellular studies show that high glucose and palmitate can trigger ERS in mammalian cells, we hypothesized that supplementing sugar to the traditional diet could induce ERS, thus promoting insulin resistance and fatty liver. To test the hypothesis, we first treated goose primary hepatocytes with high glucose (25 mM and 50 mM) and palmitate (0.5 mM) supplemented with or without 0.25 mM oleate. Data indicated that, as in mammalian cells, high glucose and palmitate indeed induced ERS in goose primary hepatocytes, and palmitate-induced ERS was suppressed by supplemental 0.25 mM oleate. We then tested the hypothesis with an in vivo study, in which Landes geese overfed with traditional or novel diets (i.e., the traditional diet supplemented with sugar) were compared with control geese (normally fed with cooked maize) for ERS, IR and fatty liver. The differences in glucose tolerance, insulin tolerance and postprandial blood glucose between the geese overfed with traditional and novel diets suggested that supplementing dietary sugar promoted IR. This promotion was accompanied with an increasing trend of liver weight and abdominal fat weight relative to body weight. Surprisingly, compared to overfeeding with the traditional diet, overfeeding with the novel diet did not induce ERS, even further suppressed ERS in goose fatty liver. Together, our findings suggest that supplementing dietary sugar promotes ERS-independent IR and fatty liver in goose. It is intriguing to discover the factor(s) protecting goose liver from ERS as well as the non-ERS mechanism underlying IR. PMID- 27246738 TI - Adipocyte insulin receptor activity maintains adipose tissue mass and lifespan. AB - Type 2 diabetes follows a well-defined progressive pathogenesis, beginning with insulin resistance in metabolic tissues such as the adipose. Intracellular signaling downstream of insulin receptor activation regulates critical metabolic functions of adipose tissue, including glucose uptake, lipogenesis, lipolysis and adipokine secretion. Previous studies have used the aP2 promoter to drive Cre recombinase expression in adipose tissue. Insulin receptor (IR) knockout mice created using this aP2-Cre strategy (FIRKO mice) were protected from obesity and glucose intolerance. Later studies demonstrated the promiscuity of the aP2 promoter, casting doubts upon the tissue specificity of aP2-Cre models. It is our goal to use the increased precision of the Adipoq promoter to investigate adipocyte-specific IR function. Towards this end we generated an adipocyte specific IR knockout (AIRKO) mouse using an Adipoq-driven Cre recombinase. Here we report AIRKO mice are less insulin sensitive throughout life, and less glucose tolerant than wild-type (WT) littermates at the age of 16 weeks. In contrast to WT littermates, the insulin sensitivity of AIRKO mice is unaffected by age or dietary regimen. At any age, AIRKO mice are comparably insulin resistant to old or obese WT mice and have a significantly reduced lifespan. Similar results were obtained when these phenotypes were re-examined in FIRKO mice. We also found that the AIRKO mouse is protected from high-fat diet-induced weight gain, corresponding with a 90% reduction in tissue weight of major adipose depots compared to WT littermates. Adipose tissue mass reduction is accompanied by hepatomegaly and increased hepatic steatosis. These data indicate that adipocyte IR function is crucial to systemic energy metabolism and has profound effects on adiposity, hepatic homeostasis and lifespan. PMID- 27246739 TI - The SHIP2 interactor Myo1c is required for cell migration in 1321 N1 glioblastoma cells. AB - The phosphoinositide 5-phosphatases consist of several enzymes that have been shown to modulate cell migration and invasion. SHIP2, one family member, is known to interact with growth factor receptors and cytoskeletal proteins. In a human model of glioblastoma 1321 N1 cells, we recently identified Myo1c as a new interactor of SHIP2. This was shown in a complex of proteins also containing filamin A. We show here that SHIP2 localization at lamellipodia and ruffles is impaired in Myo1c depleted cells. In the absence of Myo1c, N1 cells tend to associate to form clusters. Cell migration is very much reduced in Myo1c depleted cells, concomitantly with a decrease in FAK Tyr397 phosphorylation, focal adhesion length and PI(4,5)P2 immunostaining. In N1 cells, Myo1c is thus important for lamellipodia formation to assemble a protein complex containing SHIP2 to facilitate cell migration. PMID- 27246740 TI - Nutrient patterns and asthenozoospermia: a case-control study. AB - The association of dietary nutrient patterns and sperm motility is not yet well elucidated, and previous studies have just focused on the isolated nutrients. This case-control study examined the association of nutrient patterns with asthenozoospermia among Iranian men. In total, 107 incident asthenozoospermic men and 235 age-matched controls were interviewed through the infertility clinics in Tehran, Iran, from January 2012 to November 2013. Semen quality data were analysed according to the fifth edition of WHO guideline. Nutrient patterns were identified using principal component analysis based on semiquantitative 168-item food frequency questionnaires. All nutrient intakes were energy-adjusted by the residual method. In principal component analysis, three dietary patterns emerged. The first pattern, which was high in vitamin E, vitamin D, vitamin C, zinc, folate, total fibre, selenium and polyunsaturated fatty acids, was significantly associated with lower risk of asthenozoospermia. After adjustment for potential confounders, participants in the highest tertile of the first pattern scores had 51% lower risk of asthenozoospermia compared with those in the lowest (p-trend: .004). Our findings suggest that adherence to the pattern comprising mainly of antioxidant nutrients may be inversely associated with asthenozoospermia. PMID- 27246741 TI - Receptive speech in early implanted children later diagnosed with autism. AB - INTRODUCTION: Incidence of children with autism spectrum disorder (ASD) is rising through the years with estimated 1 in 68 in the US in 2014. This incidence is also rising in the population of congenitally deaf children. Favorable outcome after early cochlear implantation is expected due to plasticity and reorganization capacity of brain in infants and toddlers, but outcomes could be significantly modified in children with diagnosed ASD. Current methods of screening for autism have difficulties in establishing diagnosis in children who have both autism and other developmental delays, especially at such an early age. The aim of the study was to assess the development of auditory perception and speech intelligibility in implanted children with profound congenital hearing loss who were diagnosed with ASD comparing to those who were typically developing. MATERIAL AND METHODS: Fourteen children underwent cochlear implantation; four were later diagnosed with ASD and ten were typically developing. All children underwent intensive postoperative speech and hearing therapy. The development of auditory perception and speech intelligibility was assessed using the Categories of Auditory Performance (CAP) and the Speech Intelligibility Rating (SIR) during the 5-years follow-up. RESULTS: In children later diagnosed with ASD, auditory processing developed slowly. Depending on the individual capabilities, by the age of six they could identify environmental sounds or discriminate speech sounds. Speech Intelligibility in children with ASD was at best rated as category 2, with very little or no progress up to the age of six, despite extensive speech and language therapy. Communication skills were strongly affected by a degree of autistic features expression. CONCLUSION: Preoperative psychological assessment in congenitally deaf infants should be expanded by the use of validated instruments for early detection of autism. The possibility of developing ASD should be kept in mind by all professionals involved in programs for cochlear implantation. PMID- 27246742 TI - Cochlear implants in Belgium: Prevalence in paediatric and adult cochlear implantation. AB - OBJECTIVES: Belgium, and especially the northern region called Flanders, has been a centre of expertise in cochlear implants and early hearing screening for many years. Cochlear implants are reimbursed by the Belgian National Institute for Health and Disability (BNIHD) Insurance in adults and in children since October 1994. More than 20 years later, we would like to measure the prevalence of cochlear implants in adults and in children till now. MATERIALS AND METHODS: Based on scientific research data on the prevalence of severe to profound hearing loss in adults and in children and on the number of implantations from the data of the BNIHD, we could measure the percentages of paediatric and adult CI users in comparing to the number of CI candidates. RESULTS: The degree of utilisation of cochlear implantation varies considerably between the paediatric and the adult population. On average, 78% of deaf children are receiving cochlear implants, but in adults only 6.6% of CI candidates are receiving one. CONCLUSION: There are big differences in Belgium in utilisation of cochlear implants between adults and children. Because of the underutilisation of cochlear implants, especially in adults, we have to work on raising the general awareness of the benefits of cochlear implants, and its improvement in quality of life, based on cost effectiveness data and on guidelines for good clinical practice. PMID- 27246743 TI - Optimal electrode length to match patient specific cochlear anatomy. AB - Cochlear implantation (CI) has reached over years of practicing high standards of surgical outcomes. Even patients with significant residual hearing are nowadays benefiting from a cochlear implant. However, the speech perception still depends to great extent on the adequate pitch match between the frequency components delivered by an electrode array and individual cochlear tonotopic map. Compression, deletion or shift of frequency components can be tolerated by patients only to some extent. Furthermore, low frequency information delivered to the cochlear apex is particularly important for spatial hearing. It is therefore important to use the electrode array of an appropriate length for each individual cochlea. The large variability in the anatomy makes this task difficult as a single design does not fit all cochlear shapes. Fortunately, preoperative CT imaging, routinely taken in most of ENT clinics, can be exploited also for the prediction of the cochlear duct length (CDL). It turns out that a single radiological measurement, the diameter of the basal turn, is highly correlated with CDL and its measurement can be used for the informed selection of the most suitable electrode array length from the available array portfolio for each CI patient. PMID- 27246744 TI - Music-based training for pediatric CI recipients: A systematic analysis of published studies. AB - In recent years, there has been growing interest in the use of music-based training to enhance speech and language development in children with normal hearing and some forms of communication disorders, including pediatric CI users. The use of music training for CI users may initially seem incongruous given that signal processing for CIs presents a degraded version of pitch and timbre, both key elements in music. Furthermore, empirical data of systematic studies of music training, particularly in relation to transfer to speech skills are limited. This study describes the rationale for music training of CI users, describes key features of published studies of music training with CI users, and highlights some developmental and logistical issues that should be taken into account when interpreting or planning studies of music training and speech outcomes with pediatric CI recipients. PMID- 27246745 TI - Perception in noise with the Digisonic SP cochlear implant: Clinical trial of Saphyr processor's upgraded signal processing. AB - OBJECTIVES: In 2012, Bergeron et al. presented the outcomes of a study where speech recognition abilities were compared between the four major cochlear implant manufacturers from comparable samples assessed with the same protocols. At this moment, results showed no significant difference in speech perception between devices in quiet and in different noise conditions. But, while most devices appeared only slightly disturbed by the presence of a low to moderate noise level, the Oticon Medical device appeared significantly more sensitive to a degraded environment. In 2013, the signal processing strategy of this device has been upgraded. This study proposes to assess the benefits derived from this upgrade. MATERIALS AND METHODS: The study involves eighteen adults; most were also part of the 2012 study. All were tested before the implementation of the new signal processing strategy, immediately following the implementation of the strategy and after a one-month experience with the strategy. The same speech recognition test and conditions used in the 2012 study were applied, that is the HINT in quiet and in noise at +10, +5 and 0dB signal to noise ratio. Subjective impressions on the upgraded strategy were also gathered. RESULTS: The study evidences similar performance for speech perception in quiet, but significant improvements for speech perception in noise with the new processing strategy compared to the original. Subjective reports confirm this improvement in more challenging conditions. CONCLUSION: The high sensitivity to a degraded environment observed with the original Oticon Medical device has been significantly reduced by the introduction of more efficient noise reduction processing strategies. PMID- 27246746 TI - Optimal electrode diameter in relation to volume of the cochlea. AB - The volume of the cochlea is a key parameter for electrode-array design. Indeed, it constrains the diameter of the electrode-array for low-traumatic positioning in the scala timpani. The present report shows a model of scala timpani volume extraction from temporal bones images in order to estimate a maximum diameter of an electrode-array. Nine temporal bones were used, and passed to high-resolution computed tomography scan. Using image-processing techniques, scala timpani were extracted from images, and cross-section areas were estimated along cochlear turns. Cochlear implant electrode-array was fitted in these cross-sections. Results show that the electrode-array diameter is small enough to fit in the scala timpani, however the diameter is restricted at the apical part. PMID- 27246747 TI - The rational for a mid-scala electrode array. AB - Today increasing numbers of cochlear implant candidates have residual hearing that can be aided and hence is worth trying to preserve. This means that surgical technique and electrode array design must be adapted to minimize trauma. Wide opening of the round window is often preferred to reduce drill related trauma and to avoid pressure spikes during electrode array insertion. A recent meta-analysis suggested that there is no significant correlation between hearing preservation and either insertion depth or scala position. However, a slow insertion speed of at least 30seconds was associated with better hearing preservation. An electrode design is proposed that targets the middle of the scala tympani. This minimizes frictional forces from either lateral or medial wall during insertion and imposes less static pressure on cochlear structures following insertion. The flexibility to insert via the round window requires a 0.7-mm maximum dimension at the proximal end of the array. Micro-anatomical analysis by micro-CT indicated that a 420-degree insertion depth was optimal between cochlear coverage and available space within the scala tympani. Physical measurements showed that mean insertion forces remained below 10mN during insertion. A series of 20 human temporal bone insertions found a mean insertion depth of 400 degrees with no scala dislocations. Six clinical series, in total 94 cases, found postoperative hearing in 81% of cases with a mean loss of 12dB compared to preoperative levels. Speech understanding out to one year post-fitting trended better for a mid-scala design group than for a straight electrode array group; although the differences were not statistically significant. A mid-scala array design appears able to be inserted with minimal trauma, to return a predictable insertion depth across various sizes of cochleae and to support reasonable levels of speech understanding without relying on residual hearing. PMID- 27246749 TI - Corrigendum: Enzyme- and Ruthenium-Catalyzed Enantioselective Transformation of alpha-Allenic Alcohols into 2,3-Dihydrofurans. PMID- 27246748 TI - Amomum cardamomum L. ethyl acetate fraction protects against carbon tetrachloride induced liver injury via an antioxidant mechanism in rats. AB - BACKGROUND: Medicinal herb-derived drug development has become important in the relief of liver pathology. Amomun cardamomum is traditionally used therapeutically in Korea to treat various human ailments including dyspepsia, hiccupping, and vomiting. We investigated to assess the protective effect of A. cardamomum on carbon tetrachloride (CCl4)-induced liver damage through antioxidant activity in hepatic tissues of Sprague-Dawley rats. METHODS: Antioxidant properties of different fractions from A. cardamomum from ethanol extracts were evaluated by an in vitro free radical scavenging systems. The protective effect of the ethyl acetate fraction from A. cardamomum (EAAC) against CCl4-induced cytotoxicity was determined by a cell viability assay using HepG2 hepatocarcinoma cells. In vivo study, the influence of EAAC concentrations of 100 and 200 mg/kg following CCl4-induced hepatic injury was assessed. Serum levels of glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), and alkaline phosphatase (ALP) were determined, as was lipid peroxidation (malondialdehyde, MDA). Effect of EAAC on liver detoxification enzymes including superoxide dismutase (SOD), total glutathione (GSH), and glutathione S transferase (GST) activity was measured in rat liver homogenates. Liver cytochrome P450 (CYP2E1) expression level was determined by quantification of mRNA. RESULTS: Phytochemical analysis of A. cardamomum indicated that EAAC was enriched in total polyphenol and total flavonoid. Most of the tannins were confined to the hexane fraction. Hepatoprotective properties of EAAC were evident, with significantly reduced serum levels of GOT, GPT, and ALP compared with the control group. Improved hepatic antioxidant status was evident by increased SOD, GSH, and GST enzymes in rat liver tissue. Liver lipid peroxidation induced by CCl4 was apparent by increased intracellular MDA level. EAAC suppressed lipid peroxidation as evidenced by the significant decrease in MDA production. Expression of CYP2E1 was also significantly decreased at the higher concentration of EAAC, indicating the hepatoprotective efficacy of EAAC on acute liver damage. CONCLUSION: These results indicated that EAAC has a significant hepatoprotective activity on CCl4-induced acute hepatic injury in rats, which might be derived from its antioxidant properties and CYP2E1 downregulation. PMID- 27246751 TI - Adverse Events in Young and Preterm Infants Receiving Topical Timolol for Infantile Hemangioma. AB - BACKGROUND: The success of oral propranolol for treatment of infantile hemangiomas (IHs) has led practitioners to use topical beta-blockers. In preterm infants, clinicians frequently turn to topical timolol, with the presumption that topical application will result in less systemic absorption. We used Holter monitoring to assess for drug-induced bradycardia in high-risk infants. METHODS: We retrospectively reviewed the charts of 22 at-risk infants who received a Holter monitor to assess for association between timolol administration and development of significant bradycardia. RESULTS: Four infants had episodic bradycardia detected by Holter monitoring. Two of these infants were full term; weighed more than 3,000 g; and had rare, brief, asymptomatic episodes unrelated to the timing of the timolol application. The other two infants had symptomatic bradycardia while on timolol and were the only two babies that weighed less than 2,500 g at initiation of therapy. Both were young (postmenstrual age [PMA] 34 and 37 wks) at initiation and had a timolol dose above the average exposure for the cohort. CONCLUSION: In this cohort of at-risk infants, topical timolol appeared to provide safe treatment for IHs in full-term infants receiving a dose of less than 0.2 mg/kg/day, but infants with a PMA of less than 44 weeks and weight at treatment initiation of less than 2,500 g may be at risk of adverse events, including bradycardia, hypotension, apnea, and hypothermia. We recommend close monitoring of temperature, blood pressure, and heart rate in premature and low birthweight infants with IHs at initiation of and during therapy with topical timolol. PMID- 27246752 TI - Decoy Receptor 3 (DcR3) as a Biomarker of Tumor Deterioration in Female Reproductive Cancers: A Meta-Analysis. AB - BACKGROUND DcR3 (decoy receptor 3) has been proposed be involved in development and prognosis of female reproductive cancers, including cervical cancer, ovarian cancer, and breast cancer. The purpose of this meta-analysis was to explore the evidence for the correlation between DcR3 and the clinicopathological characteristics, as well as the overall survival time, in female reproductive cancers. MATERIAL AND METHODS Relevant studies were searched for in PubMed, Wiley Online Library, Web of Science, Science Direct, Cochrane Central Register of Controlled Trials, Google Scholar, EMBASE, Ovid, LILACS, Chinese CNKI, Chong Qing VIP, Wan Fang, and China Biology Medicine disc up to 30 September 2015. Data on the relationship between DcR3 expression and TNM stage, differentiation, lymph node metastasis, age, and overall survival time were extracted. Pooled odds ratios (ORs) and 95% CIs (confidence intervals) were estimated by forest plot. RESULTS Twelve studies with 1127 patients met the inclusion criteria for this meta-analysis. Overexpression of DcR3 was significantly related to the risk of female reproductive cancers (OR=10.69, 95% CI: 6.33-18.05), TNM stage (OR=5.51, 95% CI: 2.83-10.71), differentiation (OR=4.16, 95% CI: 2.28-7.60), lymph node metastasis (OR=5.89, 95% CI: 3.16-10.9), age (OR=0.85, 95% CI: 0.51-1.44), and overall survival time (OR=1.84, 95% CI: 0.58-5.83). Subgroup analyses showed that overexpression of DcR3 in cervical, ovarian, and breast cancer all had similar relationships with these clinicopathological parameters. CONCLUSIONS Our meta analysis suggests that overexpression of DcR3 may play vital roles in the tumorigenesis and deterioration of female reproductive cancers. However, the relationship between DcR3 expression and prognosis needs further investigation. PMID- 27246753 TI - Estimation of snow and glacier melt contribution to Liddar stream in a mountainous catchment, western Himalaya: an isotopic approach. AB - Snow- and glacier-dominated catchments in the Himalayas are important sources of fresh water to more than one billion people. However, the contribution of snowmelt and glacier melt to stream flow remains largely unquantified in most parts of the Himalayas. We used environmental isotopes and geochemical tracers to determine the source water and flow paths of stream flow draining the snow- and glacier-dominated mountainous catchment of the western Himalaya. The study suggested that the stream flow in the spring season is dominated by the snowmelt released from low altitudes and becomes isotopically depleted as the melt season progressed. The tracer-based mixing models suggested that snowmelt contributed a significant proportion (5-66 %) to stream flow throughout the year with the maximum contribution in spring and summer seasons (from March to July). In 2013 a large and persistent snowpack contributed significantly (~51 %) to stream flow in autumn (September and October) as well. The average annual contribution of glacier melt to stream flow is little (5 %). However, the monthly contribution of glacier melt to stream flow reaches up to 19 % in September during years of less persistent snow pack. PMID- 27246754 TI - A comparison of lower canine retraction and loss of anchorage between conventional and self-ligating brackets: a single-center randomized split-mouth controlled trial. AB - OBJECTIVE: To evaluate the rate of lower canine retraction, anchorage loss, and changes on lower canines and first molars axial inclination using self-ligating and conventional brackets. MATERIALS AND METHODS: Twenty-five adult patients with a treatment plan involving extractions of four first premolars were selected for this split-mouth trial and had either conventional or self-ligating brackets bonded to lower canines in a block randomization. Retraction was accomplished using 100-g nickel titanium closed-coil springs, which were reactivated each 4 weeks. Oblique radiographs were taken before and after total canine retraction and the cephalograms were superimposed on stable structures of the mandible. Cephalometric points were digitized twice by a single-blinded operator for error control and the average of the points were used to determine the following variables: canine cusp horizontal changes, molar cusp horizontal changes, and angulation changes in canines and molars. Paired t tests were used to analyze the blinded data for group differences. RESULTS: All patients reached final phase without bracket debonds. No differences were found between the two groups for all variables tested. No serious harm was observed. CONCLUSION: Both brackets showed the same rate of canine retraction and loss of anteroposterior anchorage of the molars. No changes were found between brackets regarding the inclination of canines and first molars. CLINICAL RELEVANCE: Using self-ligating brackets to retract lower canines will not increase the velocity of tooth movement, does not increase anchorage, and does not decrease tipping. PMID- 27246756 TI - Light-harvesting complex Lhcb9 confers a green alga-type photosystem I supercomplex to the moss Physcomitrella patens. AB - Light-harvesting complex (LHC) proteins in chloroplast thylakoid membranes not only transfer absorbed light energy to the two photosystems but also regulate the rate of energy transfer to avoid photodamage. Here we demonstrate that Lhcb9, a recently discovered LHC protein in the moss Physcomitrella patens, functions to connect LHC proteins with photosystem I (PSI), resulting in the formation of two different types of PSI supercomplexes in thylakoid membranes. We observed that the Lhcb9-containing PSI supercomplex is disassembled in response to excess light conditions. On the basis of our phylogenetic analysis, it appears that P. patens acquired Lhcb9 by horizontal gene transfer from the earlier green algal lineage, leading to the presence of both green alga-type and vascular plant-type PSI supercomplexes, which would have been crucial for conquering the dynamic environmental interface between aquatic and terrestrial conditions it faced during evolution. PMID- 27246755 TI - Polymorphisms of interleukin-1beta and MUC7 genes in burning mouth syndrome. AB - OBJECTIVE: The objectives of the present study are to compare polymorphisms of the IL-1beta and MUC7 genes between patients with burning mouth syndrome (BMS) and controls and to investigate relationships between these polymorphisms and clinical characteristics in BMS patients. MATERIALS AND METHODS: Forty female BMS patients and 40 gender- and age-matched controls were included. Genomic DNA was extracted from saliva samples. Single-nucleotide polymorphisms of IL-1beta -511 and +3954 and variation in number of tandem repeat (VNTR) polymorphism of MUC7 were analyzed. Relationships between genotypic polymorphism data and clinical characteristics in BMS patients were also analyzed. RESULTS: There were no significant differences in the genotypes of IL-1beta -511 and +3954 and of MUC7 between the groups. There were no significant differences in symptom duration and intensity of BMS patients according to their IL-1beta and MUC7 genotypes. The T allele of IL-1beta -511 showed associations with psychometry results in BMS patients: paranoid ideation (P = 0.014), Global Severity Index (P = 0.025), and Positive Symptom Total (P = 0.008). CONCLUSIONS: The genotypic polymorphisms of IL-1beta -511 and +3954, and of MUC7 VNTR, had no direct associations with the development of BMS. However, the T allele of IL-1beta -511 may increase the risk of BMS by increasing psychological asthenia. CLINICAL RELEVANCE: The genotypic polymorphisms of IL-1beta -511 may increase the risk for the development of BMS by increasing psychological asthenia. PMID- 27246757 TI - Ppd-1 is a key regulator of inflorescence architecture and paired spikelet development in wheat. AB - The domestication of cereal crops such as wheat, maize, rice and barley has included the modification of inflorescence architecture to improve grain yield and ease harvesting(1). Yield increases have often been achieved through modifying the number and arrangement of spikelets, which are specialized reproductive branches that form part of the inflorescence. Multiple genes that control spikelet development have been identified in maize, rice and barley(2-5). However, little is known about the genetic underpinnings of this process in wheat. Here, we describe a modified spikelet arrangement in wheat, termed paired spikelets. Combining comprehensive QTL and mutant analyses, we show that Photoperiod-1 (Ppd-1), a pseudo-response regulator gene that controls photoperiod dependent floral induction, has a major inhibitory effect on paired spikelet formation by regulating the expression of FLOWERING LOCUS T (FT)(6,7). These findings show that modulated expression of the two important flowering genes, Ppd 1 and FT, can be used to form a wheat inflorescence with a more elaborate arrangement and increased number of grain producing spikelets. PMID- 27246758 TI - A reservoir of ethnobotanical knowledge informs resilient food security and health strategies in the Balkans. AB - While all peoples are nested in their environments, their decisions and actions are mediated by culturally constructed values, beliefs and priorities. Ethnobotanical methods can show how different ethnic groups living within the same geographic landscape interact with environmental resources. Here, we explore the impact of culture on ethnobotanical knowledge, and practice on local food security and human health. Gora, a mountainous territory of northeastern Albania, is home to two culturally and linguistically distinct peoples: Gorani and Albanians. We investigated the divergences and convergences of ethnobotanical strategies among the groups with respect to the use of 104 plant species. Local knowledge modulated by cultural history has moulded these peoples' use of their natural environment, fostering resilience during periods of food insecurity. PMID- 27246760 TI - The SCAR/WAVE complex polarizes PAN receptors and promotes division asymmetry in maize. AB - Pre-mitotic establishment of polarity is a key event in the preparation of mother cells for asymmetric cell divisions that produce daughters of distinct fates, and ensures correct cellular patterning of tissues and eventual organ function. Previous work has shown that two receptor-like kinases, PANGLOSS2 (PAN2) and PAN1, and the small GTPase RHO GTPASE OF PLANTS (ROP) promote mother cell polarity and subsequent division asymmetry in developing maize stomata. PAN proteins become polarized prior to asymmetric cell division, however, the mechanism of this polarization is unknown. Here we show that the SCAR/WAVE regulatory complex, which activates the actin-nucleating ARP2/3 complex, is the first known marker of polarity in this asymmetric division model and is required for PAN polarization. These findings implicate actin, and specifically branched actin networks, in PAN polarization and asymmetric cell division. PMID- 27246759 TI - Genome expansion of Arabis alpina linked with retrotransposition and reduced symmetric DNA methylation. AB - Despite evolutionary conserved mechanisms to silence transposable element activity, there are drastic differences in the abundance of transposable elements even among closely related plant species. We conducted a de novo assembly for the 375 Mb genome of the perennial model plant, Arabis alpina. Analysing this genome revealed long-lasting and recent transposable element activity predominately driven by Gypsy long terminal repeat retrotransposons, which extended the low recombining pericentromeres and transformed large formerly euchromatic regions into repeat-rich pericentromeric regions. This reduced capacity for long terminal repeat retrotransposon silencing and removal in A. alpina co-occurs with unexpectedly low levels of DNA methylation. Most remarkably, the striking reduction of symmetrical CG and CHG methylation suggests weakened DNA methylation maintenance in A. alpina compared with Arabidopsis thaliana. Phylogenetic analyses indicate a highly dynamic evolution of some components of methylation maintenance machinery that might be related to the unique methylation in A. alpina. PMID- 27246761 TI - Climate-induced reduction in US-wide soybean yields underpinned by region- and in season-specific responses. AB - The United States is one of the largest soybean exporters in the world. Production is concentrated in the upper Midwest(1). Much of this region is not irrigated, rendering soybean production systems in the area highly sensitive to in-season variations in weather. Although the influence of in-season weather trends on the yields of crops such as soybean, wheat and maize has been explored in several countries(2-6), the potentially confounding influence of genetic improvements on yields has been overlooked. Here we assess the effect of in season weather trends on soybean yields in the United States between 1994 and 2013, using field trial data, meteorological data and information on crop management practices, including the adoption of new cultivars. We show that in season temperature trends had a greater impact on soybean yields than in-season precipitation trends over the measurement period. Averaging across the United States, we show that soybean yields fell by around 2.4% for every 1 degrees C rise in growing season temperature. However, the response varied significantly among individual states, ranging from -22% to +9%, and also with the month of the year in which the warming occurred. We estimate that year-to-year changes in precipitation and temperature combined suppressed the US average yield gain by around 30% over the measurement period, leading to a loss of US$11 billion. Our data highlight the importance of developing location-specific adaptation strategies for climate change based on early-, mid- and late-growing season climate trends. PMID- 27246763 TI - Wheat yields: Doubling-up on grain numbers. PMID- 27246762 TI - Plant hormones: On-the-spot reporting. PMID- 27246764 TI - Newton and the ascent of water in plants. PMID- 27246765 TI - Development: Early events in asymmetric division. PMID- 27246766 TI - Ecophysiology: Root-cluster control. PMID- 27246767 TI - Guard cells: Finding a MATE. PMID- 27246768 TI - Rice yield: Swelling the grain. PMID- 27246770 TI - Plant science's human factor. PMID- 27246769 TI - Cell wall formation: Xylem differentiation. PMID- 27246771 TI - Comparison between resting state fMRI networks and responsive cortical stimulations in glioma patients. AB - OBJECTIVES: To validate the functional relevance of resting state networks (RSNs) by means of a comparison of resting state connectivity (RSC) between language regions elicited by direct cortical stimulation versus RSC between random regions; and to evaluate the accuracy of resting state fMRI in surgical planning by assessing the overlap between RSNs and intraoperative functional mapping results. METHODS: Sensorimotor and language eloquent sites were identified by direct electrical cortical stimulation in 98 patients with a diffuse low-grade glioma. A seed to voxel analysis with inter-language stimulation point connectivity versus inter-random ROIs connectivity was performed (19 patients). An independant component analysis (ICA) was also applied to rsfMRI data. Language and sensorimotor components were selected over 20 independent components and compared to the corresponding stimulation points and resected cortex masks (31 and 90 patients, respectively). RESULTS: Mean connectivity value between language seeds was significantly higher than the one between random seeds (0.68 +/- 0.39 and 0.12 +/- 0.21 respectively, P < 10-10 ). 96 +/- 11% of sensorimotor stimulation points were located within 10 mm from sensorimotor ICA maps versus 92 +/- 21% for language. 3.1 and 15% of resected cortex overlapped sensorimotor and language networks, respectively. Mean sensorimotor stimulation points and resected cortex z-scores were 2.0 +/- 1.2 and -0.050 +/- 0.60, respectively (P < 10-10 ). Mean language stimulation points and resected cortex z-scores were 1.6 +/- 1.9 and 0.68 +/- 0.91, respectively, P < 0.005. CONCLUSION: The significantly higher RSC between language seeds than between random seeds validated the functional relevance of RSC. ICA partly succeeded to distinguish eloquent versus surgically removable areas and may be possibly used as a complementary tool to intraoperative mapping. Hum Brain Mapp 37:3721-3732, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27246772 TI - Minoxidil for Treatment of Resistant Hypertension in Chronic Kidney Disease--A Retrospective Cohort Analysis. AB - Resistant hypertension is still a challenge and reserve antihypertensive agents are often necessary to achieve blood pressure control. One reserve antihypertensive is minoxidil, a direct vasodilator that is known for its strong blood pressure-lowering effect, but contemporary studies are sparse. The authors retrospectively analyzed 54 inpatients with uncontrolled hypertension despite the combined use of current antihypertensive agents. To investigate the effect of minoxidil when added to other antihypertensive agents, blood pressure was evaluated at the time minoxidil treatment was initiated and at discharge. Minoxidil treatment was associated with a significant reduction in blood pressure from 162.4+/-15.1/83.2+/-12.7 mm Hg to 135.8+/-12.2/72.8+/-6.9 mm Hg (P<.0001). This effect was sustained across all analyzed subgroups. Although the well-known adverse events of minoxidil limit its widespread use, these data show that minoxidil as a reserve antihypertensive agent still has a niche indication in the particular subgroup of patients with treatment-resistant or uncontrolled hypertension. PMID- 27246773 TI - Antimicrobial Susceptibility and Clonality of Clinical Ureaplasma Isolates in the United States. AB - Ureaplasma urealyticum and Ureaplasma parvum are pathogens involved in urogenital tract and intrauterine infections and also in systemic diseases in newborns and immunosuppressed patients. There is limited information on the antimicrobial susceptibility and clonality of these species. In this study, we report the susceptibility of 250 contemporary isolates of Ureaplasma (202 U. parvum and 48 U. urealyticum isolates) recovered at Mayo Clinic, Rochester, MN. MICs of doxycycline, azithromycin, ciprofloxacin, tetracycline, erythromycin, and levofloxacin were determined by broth microdilution, with MICS of the last three interpreted according to CLSI guidelines. Levofloxacin resistance was found in 6.4% and 5.2% of U. parvum and U. urealyticum isolates, respectively, while 27.2% and 68.8% of isolates, respectively, showed ciprofloxacin MICs of >=4 MUg/ml. The resistance mechanism of levofloxacin-resistant isolates was due to mutations in parC, with the Ser83Leu substitution being most frequent, followed by Glu87Lys. No macrolide resistance was found among the 250 isolates studied; a single U. parvum isolate was tetracycline resistant. tet(M) was found in 10 U. parvum isolates, including the single tetracycline-resistant isolate, as well as in 9 isolates which had low tetracycline and doxycycline MICs. Multilocus sequence typing (MLST) performed on a selection of 46 isolates showed high diversity within the clinical Ureaplasma isolates studied, regardless of antimicrobial susceptibility. The present work extends previous knowledge regarding susceptibility to antimicrobial agents, resistance mechanisms, and clonality of Ureaplasma species in the United States. PMID- 27246774 TI - Discovery and Analysis of Natural-Product Compounds Inhibiting Protein Synthesis in Pseudomonas aeruginosa. AB - Bacterial protein synthesis is the target for numerous natural and synthetic antibacterial agents. We have developed a poly(U) mRNA-directed aminoacylation/translation (A/T) protein synthesis system composed of phenylalanyl-tRNA synthetases (PheRS), ribosomes, and ribosomal factors from Pseudomonas aeruginosa This system has been used for high-throughput screening of a natural-compound library. Assays were developed for each component of the system to ascertain the specific target of inhibitory compounds. In high throughput screens, 13 compounds were identified that inhibit protein synthesis with 50% inhibitory concentrations ranging from 0.3 to >80 MUM. MICs were determined for the compounds against the growth of a panel of pathogenic organisms, including Enterococcus faecalis, Escherichia coli, Haemophilus influenzae, Moraxella catarrhalis, P. aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae Three of the compounds were observed to have broad spectrum activity and inhibited a hypersensitive strain of P. aeruginosa with MICs of 8 to 16 MUg/ml. The molecular target of each of the three compounds was determined to be PheRS. One compound was found to be bacteriostatic, and one compound was bactericidal against both Gram-positive and Gram-negative pathogens. The third compound was observed to be bacteriostatic against Gram-positive and bactericidal against Gram-negative bacteria. All three compounds were competitive with the substrate ATP; however, one compound was competitive, one was uncompetitive, and one noncompetitive with the amino acid substrate. Macromolecular synthesis assays confirm the compounds inhibit protein synthesis. The compounds were shown to be more than 25,000-fold less active than the control staurosporine in cytotoxicity MTT testing in human cell lines. PMID- 27246775 TI - Optimization of a Class of Tryptophan Dendrimers That Inhibit HIV Replication Leads to a Selective, Specific, and Low-Nanomolar Inhibitor of Clinical Isolates of Enterovirus A71. AB - Tryptophan dendrimers that inhibit HIV replication by binding to the HIV envelope glycoproteins gp120 and gp41 have unexpectedly also proven to be potent, specific, and selective inhibitors of the replication of the unrelated enterovirus A71. Dendrimer 12, a consensus compound that was synthesized on the basis of the structure-activity relationship analysis of this series, is 3-fold more potent against the BrCr lab strain and, surprisingly, inhibits a large panel of clinical isolates in the low-nanomolar/high-picomolar range. PMID- 27246776 TI - Dimethyl Sulfoxide Protects Escherichia coli from Rapid Antimicrobial-Mediated Killing. AB - The contribution of reactive oxygen species (ROS) to antimicrobial lethality was examined by treating Escherichia coli with dimethyl sulfoxide (DMSO), an antioxidant solvent frequently used in antimicrobial studies. DMSO inhibited killing by ampicillin, kanamycin, and two quinolones and had little effect on MICs. DMSO-mediated protection correlated with decreased ROS accumulation and provided evidence for ROS-mediated programmed cell death. These data support the contribution of ROS to antimicrobial lethality and suggest caution when using DMSO-dissolved antimicrobials for short-time killing assays. PMID- 27246777 TI - First Report of blaIMP-14 on a Plasmid Harboring Multiple Drug Resistance Genes in Escherichia coli Sequence Type 131. AB - The blaIMP-14 carbapenem resistance gene has largely previously been observed in Pseudomonas aeruginosa and Acinetobacter spp. As part of global surveillance and sequencing of carbapenem-resistant Escherichia coli, we identified a sequence type 131 strain harboring blaIMP-14 within a class 1 integron, itself nested within an ~54-kb multidrug resistance region on an epidemic IncA/C2 plasmid. The emergence of blaIMP-14 in this context in the ST131 lineage is of potential clinical concern. PMID- 27246779 TI - Determination of MIC Breakpoints for Second-Line Drugs Associated with Clinical Outcomes in Multidrug-Resistant Tuberculosis Treatment in China. AB - Our study aims to identify the clinical breakpoints (CBPs) of second-line drugs (SLDs) above which standard therapy fails in order to improve multidrug-resistant tuberculosis (MDR-TB) treatment. MICs of SLDs were determined for M. tuberculosis isolates cultured from 207 MDR-TB patients in a prospective cohort study in China between January 2010 and December 2012. Classification and regression tree (CART) analysis was used to identify the CBPs predictive of treatment outcome. Of the 207 MDR-TB isolates included in the present study, the proportion of isolates above the critical concentration recommended by WHO ranged from 5.3% in pyrazinamide to 62.8% in amikacin. By selecting pyrazinamide as the primary node (CBP, 18.75 mg/liter), 72.1% of sputum culture conversions at month four could be predicted. As for treatment outcome, pyrazinamide (CBP, 37.5 mg/liter) was selected as the primary node to predict 89% of the treatment success, followed by ofloxacin (CBP, 3 mg/liter), improving the predictive capacity of the primary node by 10.6%. Adjusted by identified confounders, the CART-derived pyrazinamide CBP remained the strongest predictor in the model of treatment outcome. Our findings indicate that the critical breakpoints of some second-line drugs and PZA need to be reconsidered in order to better indicate MDR-TB treatment outcome. PMID- 27246778 TI - Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans. AB - Ivermectin and moxidectin are the most widely administered anthelmintic macrocyclic lactones (MLs) to treat human and animal nematode infections. Their widespread and frequent use has led to a high level of resistance to these drugs. Although they have the same mode of action, differences in terms of selection for drug resistance have been reported. Our objective was to study and compare changes occurring upon ivermectin or moxidectin selection in the model nematode Caenorhabditis elegans C. elegans worms were submitted to stepwise exposure to increasing doses of moxidectin. The sensitivity of moxidectin-selected worms to MLs was determined in a larval development assay and compared with those of wild type and ivermectin-selected strains. Selection with either ivermectin or moxidectin led to acquired tolerance to ivermectin, moxidectin, and eprinomectin. Importantly, moxidectin was the most potent ML in both ivermectin- and moxidectin selected strains. Interestingly, this order of potency was also observed in a resistant Haemonchus contortus isolate. In addition, ivermectin- and moxidectin selected strains displayed constitutive overexpression of several genes involved in xenobiotic metabolism and transport. Moreover, verapamil potentiated sensitivity to ivermectin and moxidectin, demonstrating that ABC transporters play a role in ML sensitivity in ML-selected C. elegans strains. Finally, both ivermectin- and moxidectin-selected strains displayed a dye-filling-defective phenotype. Overall, this work demonstrated that selection with ivermectin or moxidectin led to cross-resistance to several MLs in nematodes and that the induction of detoxification systems and defects in the integrity of amphidial neurons are two mechanisms that appear to affect the responsiveness of worms to both ivermectin and moxidectin. PMID- 27246780 TI - Extensive Shared Chemosensitivity between Malaria and Babesiosis Blood-Stage Parasites. AB - The apicomplexan parasites that cause malaria and babesiosis invade and proliferate within erythrocytes. To assess the potential for common antiparasitic treatments, we measured the sensitivities of multiple species of Plasmodium and Babesia parasites to the chemically diverse collection of antimalarial compounds in the Malaria Box library. We observed that these parasites share sensitivities to a large fraction of the same inhibitors and we identified compounds with strong babesiacidal activity. PMID- 27246781 TI - rRNA Binding Sites and the Molecular Mechanism of Action of the Tetracyclines. AB - The tetracycline antibiotics are known to be effective in the treatment of both infectious and noninfectious disease conditions. The 16S rRNA binding mechanism currently held for the antibacterial action of the tetracyclines does not explain their activity against viruses, protozoa that lack mitochondria, and noninfectious conditions. Also, the mechanism by which the tetracyclines selectively inhibit microbial protein synthesis against host eukaryotic protein synthesis despite conservation of ribosome structure and functions is still questionable. Many studies have investigated the binding of the tetracyclines to the 16S rRNA using the small ribosomal subunit of different bacterial species, but there seems to be no agreement between various reports on the exact binding site on the 16S rRNA. The wide range of activity of the tetracyclines against a broad spectrum of bacterial pathogens, viruses, protozoa, and helminths, as well as noninfectious conditions, indicates a more generalized effect on RNA. In the light of recent evidence that the tetracyclines bind to various synthetic double stranded RNAs (dsRNAs) of random base sequences, suggesting that the double stranded structures may play a more important role in the binding of the tetracyclines to RNA than the specific base pairs, as earlier speculated, it is imperative to consider possible alternative binding modes or sites that could help explain the mechanisms of action of the tetracyclines against various pathogens and disease conditions. PMID- 27246782 TI - Repurposing of Aspirin and Ibuprofen as Candidate Anti-Cryptococcus Drugs. AB - The usage of fluconazole and amphotericin B in clinical settings is often limited by, among other things, drug resistance development and undesired side effects. Thus, there is a constant need to find new drugs to better manage fungal infections. Toward this end, the study described in this paper considered the repurposing of aspirin (acetylsalicylic acid) and ibuprofen as alternative drugs to control the growth of cryptococcal cells. In vitro susceptibility tests, including a checkerboard assay, were performed to assess the response of Cryptococcus neoformans and Cryptococcus gattii to the above-mentioned anti inflammatory drugs. Next, the capacity of these two drugs to induce stress as well as their mode of action in the killing of cryptococcal cells was determined. The studied fungal strains revealed a response to both aspirin and ibuprofen that was dose dependent, with ibuprofen exerting greater antimicrobial action. More importantly, the MICs of these drugs did not negatively (i) affect growth or (ii) impair the functioning of macrophages; rather, they enhanced the ability of these immune cells to phagocytose cryptococcal cells. Ibuprofen was also shown to act in synergy with fluconazole and amphotericin B. The treatment of cryptococcal cells with aspirin or ibuprofen led to stress induction via activation of the high-osmolarity glycerol (HOG) pathway, and cell death was eventually achieved through reactive oxygen species (ROS)-mediated membrane damage. The presented data highlight the potential clinical application of aspirin and ibuprofen as candidate anti-Cryptococcus drugs. PMID- 27246783 TI - Systematic Review and Meta-analysis of Clinical and Economic Outcomes from the Implementation of Hospital-Based Antimicrobial Stewardship Programs. AB - The implementation of antimicrobial stewardship programs (ASPs) is a promising strategy to help address the problem of antimicrobial resistance. We sought to determine the efficacy of ASPs and their effect on clinical and economic parameters. We searched PubMed, EMBASE, and Google Scholar looking for studies on the efficacy of ASPs in hospitals. Based on 26 studies (extracted from 24,917 citations) with pre- and postimplementation periods from 6 months to 3 years, the pooled percentage change of total antimicrobial consumption after the implementation of ASPs was -19.1% (95% confidence interval [CI] = -30.1 to -7.5), and the use of restricted antimicrobial agents decreased by -26.6% (95% CI = 52.3 to -0.8). Interestingly, in intensive care units, the decrease in antimicrobial consumption was -39.5% (95% CI = -72.5 to -6.4). The use of broad spectrum antibiotics (-18.5% [95% CI = -32 to -5.0] for carbapenems and -14.7% [95% CI = -27.7 to -1.7] for glycopeptides), the overall antimicrobial cost ( 33.9% [95% CI = -42.0 to -25.9]), and the hospital length of stay (-8.9% [95% CI = -12.8 to -5]) decreased. Among hospital pathogens, the implementation of ASPs was associated with a decrease in infections due to methicillin-resistant Staphylococcus aureus (risk difference [RD] = -0.017 [95% CI = -0.029 to 0.005]), imipenem-resistant Pseudomonas aeruginosa (RD = -0.079 [95% CI = -0.114 to -0.040]), and extended-spectrum beta-lactamase Klebsiella spp. (RD = -0.104 [95% CI = -0.153 to -0.055]). Notably, these improvements were not associated with adverse outcomes, since the all-cause, infection-related 30-day mortality and infection rates were not significantly different after implementation of an ASP (RD = -0.001 [95% CI = -0.009 to 0.006], RD = -0.005 [95% CI = -0.016 to 0.007], and RD = -0.045% [95% CI = -0.241 to 0.150], respectively). Hospital ASPs result in significant decreases in antimicrobial consumption and cost, and the benefit is higher in the critical care setting. Infections due to specific antimicrobial-resistant pathogens and the overall hospital length of stay are improved as well. Future studies should focus on the sustainability of these outcomes and evaluate potential beneficial long-term effects of ASPs in mortality and infection rates. PMID- 27246784 TI - In Vitro and In Vivo Characterization of the Novel Oxabicyclooctane-Linked Bacterial Topoisomerase Inhibitor AM-8722, a Selective, Potent Inhibitor of Bacterial DNA Gyrase. AB - Oxabicyclooctane-linked novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of recently described antibacterial agents with broad spectrum activity. NBTIs dually inhibit the clinically validated bacterial targets DNA gyrase and topoisomerase IV and have been shown to bind distinctly from known classes of antibacterial agents directed against these targets. Herein we report the molecular, cellular, and in vivo characterization of AM-8722 as a representative N-alkylated-1,5-naphthyridone left-hand-side-substituted NBTI. Consistent with its mode of action, macromolecular labeling studies revealed a specific effect of AM-8722 to dose dependently inhibit bacterial DNA synthesis. AM-8722 displayed greater intrinsic enzymatic potency than levofloxacin versus both DNA gyrase and topoisomerase IV from Staphylococcus aureus and Escherichia coli and displayed selectivity against human topoisomerase II. AM-8722 was rapidly bactericidal and exhibited whole-cell activity versus a range of Gram negative and Gram-positive organisms, with no whole-cell potency shift due to the presence of DNA or human serum. Frequency-of-resistance studies demonstrated an acceptable rate of resistance emergence in vitro at concentrations 16- to 32-fold the MIC. AM-8722 displayed acceptable pharmacokinetic properties and was shown to be efficacious in mouse models of bacterial septicemia. Overall, AM-8722 is a selective and potent NBTI that displays broad-spectrum antimicrobial activity in vitro and in vivo. PMID- 27246785 TI - Azithromycin differentially affects the IL-13-induced expression profile in human bronchial epithelial cells. AB - The T helper 2 (Th2) cytokine interleukin(IL)-13 is a central regulator in goblet cell metaplasia and induces the recently described Th2 gene signature consisting of periostin (POSTN), chloride channel regulator 1 (CLCA1) and serpin B2 (SERPINB2) in airway epithelial cells. This Th2 gene signature has been proposed as a biomarker to classify asthma into Th2-high and Th2-low phenotypes. Clinical studies have shown that the macrolide antibiotic azithromycin reduced clinical symptoms in neutrophilic asthma, but not in the classical Th2-mediated asthma despite the ability of azithromycin to reduce IL-13-induced mucus production. We therefore hypothesize that azithromycin differentially affects the IL-13-induced expression profile. To investigate this, we focus on IL-13-induced mucin and Th2 signature expression in human bronchial epithelial cells and how this combined expression profile is affected by azithromycin treatment. Primary bronchial epithelial cells were differentiated at air liquid interface in presence of IL-13 with or without azithromycin. Azithromycin inhibited IL-13-induced MUC5AC, which was accompanied by inhibition of IL-13-induced CLCA1 and SERPINB2 expression. In contrast, IL-13-induced expression of POSTN was further increased in cells treated with azithromycin. This indicates that azithromycin has a differential effect on the IL-13-induced Th2 gene signature. Furthermore, the ability of azithromycin to decrease IL-13-induced MUC5AC expression may be mediated by a reduction in CLCA1. PMID- 27246787 TI - Inhibition of methicillin-resistant Staphylococcus aureus (MRSA) by antimicrobial peptides (AMPs) and plant essential oils. AB - CONTEXT: Drug-resistant bacterial infections cause considerable patient mortality and morbidity. The annual frequency of deaths from methicillin-resistant Staphylococcus aureus (MRSA) has surpassed those caused by human immunodeficiency virus/acquired immune deficiency syndrome. The antimicrobial peptides (AMPs), plant essential oils (EOs) and their combinations have proven to be quite effective in killing a wide selection of bacterial pathogens including MRSA. OBJECTIVES: This review summarizes the studies in the use of AMPs, plant EOs and their combinations for coping with MRSA bacteria, and to formulate new prospects for future studies on this topic. METHODS: The sources of scientific literature such as PubMed, library search, Google Scholar, Science Direct and electronic databases such as 'The Antimicrobial Peptide Database', 'Collection of Anti Microbial Peptides' and 'YADAMP'. Physicochemical data of anti-MRSA peptides were determined by Scientific DataBase Maker software. RESULTS: Of the 118 peptides, 88 exhibited an activity against MRSA with the highest activity of minimum inhibitory concentration values. Various plant EOs have been effective against MRSA. Remarkably, lemongrass EOs completely inhibited all MRSA growth on the plate. Lemon myrtle, Mountain savory, Cinnamon bark and Melissa EOs showed a significant inhibition. CONCLUSION: Several of these AMPs, EOs and their combinations were effective against MRSA. Their activities have implications for the development of new drugs for medical use. PMID- 27246786 TI - Prediction of miRNA-disease associations with a vector space model. AB - MicroRNAs play critical roles in many physiological processes. Their dysregulations are also closely related to the development and progression of various human diseases, including cancer. Therefore, identifying new microRNAs that are associated with diseases contributes to a better understanding of pathogenicity mechanisms. MicroRNAs also represent a tremendous opportunity in biotechnology for early diagnosis. To date, several in silico methods have been developed to address the issue of microRNA-disease association prediction. However, these methods have various limitations. In this study, we investigate the hypothesis that information attached to miRNAs and diseases can be revealed by distributional semantics. Our basic approach is to represent distributional information on miRNAs and diseases in a high-dimensional vector space and to define associations between miRNAs and diseases in terms of their vector similarity. Cross validations performed on a dataset of known miRNA-disease associations demonstrate the excellent performance of our method. Moreover, the case study focused on breast cancer confirms the ability of our method to discover new disease-miRNA associations and to identify putative false associations reported in databases. PMID- 27246788 TI - Palladium(II)-Catalyzed Enantioselective Synthesis of alpha (Trifluoromethyl)arylmethylamines. AB - We describe a method for the synthesis of alpha-(trifluoromethyl)arylmethylamines that consists of the palladium(II)-catalyzed addition of arylboroxines to imines derived from trifluoroacetaldehyde. Palladium acetate is used as a catalyst with electron-neutral or electron-rich arylboroxines, and it was found that addition of an ammonium or silver salt was crucial to promote the reaction of electron poor boroxines. With (S)-t-Bu-PyOX as the chiral ligand, this method delivers a variety of alpha-trifluoromethylated amines in 57-91% yield and with greater than 92% ee in most cases. PMID- 27246789 TI - Knowledge and uptake of occupational post-exposure prophylaxis amongst nurses caring for people living with HIV. AB - BACKGROUND: Nurses caring for people living with HIV (PLWH) are at higher risk of exposure to the human immunodeficiency virus (HIV) by needle sticks, cuts, getting body fluids in their eyes or mouth and skin when bruised or affected by dermatitis. OBJECTIVES: To determine knowledge, insight and uptake of occupational post-exposure prophylaxis (OPEP) amongst nurses caring for PLWH. METHOD: A cross-sectional descriptive design was used in this study. Stratified random sampling was used to sample 240 nurses. The study was conducted in a regional hospital in Limpopo province. Both parametric and non-parametric statistics were employed to analyse data. RESULTS: A total of 233 nurses participated in the study. Sixty per cent (n = 138) of all nurses had a situation at work when they thought that they were infected by HIV and 100 (43%) nurses had experienced the situation once or more in the past 12 month. Approximately 40% did not know what PEP (post-exposure prophylaxis) is, and 22% did not know or were not sure if it was available in the hospital. Only few participants (n = 68, 29%) had sought PEP and most (n = 37, 54%) of them did not receive PEP when they needed it. There was a significant association between the knowledge and availability of PEP (r = 0.622). CONCLUSION: The study recommend an urgent need for policy makers in the health sector to put in place policies, guidelines and programmes that will rapidly scale up PEP services in health care settings, so that preventable occupationally acquired HIV infection can be minimised amongst nurses. PMID- 27246790 TI - Students' views on the block evaluation process: A descriptive analysis. AB - BACKGROUND: Higher education institutions have executed policies and practices intended to determine and promote good teaching. Students' evaluation of the teaching and learning process is seen as one measure of evaluating quality and effectiveness of instruction and courses. Policies and procedures guiding this process are discernible in universities, but it isoften not the case for nursing colleges. OBJECTIVE: To analyse and describe the views of nursing students on block evaluation, and how feedback obtained from this process was managed. METHOD: A quantitative descriptive study was conducted amongst nursing students (n = 177) in their second to fourth year of training from one nursing college in KwaZulu-Natal. A questionnaire was administered by the researcher and data were analysed using the Statistical Package of Social Sciences Version 19.0. RESULTS: The response rate was 145 (81.9%). The participants perceived the aim of block evaluation as improving the quality of teaching and enhancing their experiences as students.They questioned the significance of their input as stakeholders given that they had never been consulted about the development or review of the evaluation tool, or the administration process; and they often did not receive feedback from the evaluation they participated in. CONCLUSION: The college management should develop a clear organisational structure with supporting policies and operational guidelines for administering the evaluation process. The administration, implementation procedures, reporting of results and follow-up mechanisms should be made transparent and communicated to all concerned. Reports and actions related to these evaluations should provide feedback into relevant courses or programmes. PMID- 27246791 TI - A systematic review: Are herbal and homeopathic remedies used during pregnancy safe? AB - BACKGROUND: Herbal and homeopathic remedies have been used to assist with child bearing and pregnancy for centuries. Allopathic ('Western') medicine is traditionally avoided during pregnancy because of limited drug trials and the suspected teratogenic effects of these medications. This has led to an increase in the use of herbal and homeopathic remedies, asthey are viewed to have no teratogenic effect on the developing foetus. Health providers are faced with questions from their clients regarding the safety of these remedies, but much of the evidence about these herbal and homeopathic remedies is anecdotal and few remedies havebeen tested scientifically. OBJECTIVES: By conducting a systematic review, the primary objective was to evaluate maternal and neonatal outcomes of ingested herbal and homeopathic remedies during pregnancy. METHOD: A systematic review was conducted to synthesise all the evidence with the purpose of evaluating the safety of herbal and homeopathic remedies based on adverse maternal and neonatal outcomes. Only randomised and quasi-randomised controlled trials that met allinclusion criteria were included in the review. RESULTS: The ingestion of ginger for nausea and vomiting during pregnancy was shown to have no harmful maternal or neonatal effects. Ingestion of castor oil for induction of labour showed a tendency towards an increase in the incidence of caesarean section and meconiumstained liquor, warranting further research into its safety issues. CONCLUSION: Larger randomised controlled trials need to be conducted, especially in South Africa, to establish the safety and efficacy of commonly-used remedies. PMID- 27246792 TI - An assessment of the outcomes of prevention of mother-to-child transmission of HIV services in Addis Ababa, Ethiopia. AB - BACKGROUND: This article assessed maternal and neonatal outcomes amongst users of prevention of mother-to-child transmission (PMTCT) of HIV services in Addis Ababa, Ethiopia. OBJECTIVES: The study aimed to assess the health outcomes (antiretroviral prophylaxis versus antiretroviral treatment, CD4 counts, World Health Organization (WHO) stages of illness, other illnesses) of women who had used these services, as well as the HIV status of their babies and the infant feeding method adopted. METHODS: A quantitative, cross sectional, retrospective cohort design was used. Document reviews were conducted with a sample of 384 mother-infant pairs (out of a population of 796) who had used PMTCT services. RESULTS: All respondents were using prophylactic antiretrovirals or antiretroviral therapy, but some were on the wrong treatment based on their CD4 counts. The CD4 counts increased four times more for women on antiretroviral treatment than for those on prophylactic antiretrovirals. The WHO's stages of HIV illness did not improve but deteriorated in some cases, and 52 other illnesses were recorded. Out of the 384 infants, 6.0% (n = 23) were HIV-positive. Most respondents opted for exclusive breast feeding but some used mixed feeding during the first six months of their infants' lives, despite having received health education related to infant feeding options. CONCLUSION: The respondents' improved CD4 counts were inadequate to improve their World Health Organization stages of HIV illness. Some babies received mixed feeding during the first six months of their lives and 6% of the babies were HIV-positive despite their mothers' utilisation of PMTCT services. PMID- 27246793 TI - Effects of increased nurses' workload on quality documentation of patient information at selected Primary Health Care facilities in Vhembe District, Limpopo Province. AB - BACKGROUND: Recording of information on multiple documents increases professional nurses' responsibilities and workload during working hours. There are multiple registers and books at Primary Health Care (PHC) facilities in which a patient's information is to be recorded for different services during a visit to a health professional. Antenatal patients coming for the first visit must be recorded in the following documents: tick register; Prevention of Mother-ToChild Transmission (PMTCT) register; consent form for HIV and AIDS testing; HIV Counselling and Testing (HCT) register (if tested positive for HIV and AIDS then this must be recorded in the Antiretroviral Therapy (ART) wellness register); ART file with an accompanying single file, completion of which is time-consuming; tuberculosis (TB) suspects register; blood specimen register; maternity case record book and Basic Antenatal Care (BANC) checklist. Nurses forget to record information in some documents which leads to the omission of important data. Omitting information might lead to mismanagement of patients. Some of the documents have incomplete and inaccurate information. As PHC facilities in Vhembe District render twenty four hour services through a call system, the same nurses are expected to resume duty at 07:00 the following morning. They are expected to work effectively and when tired a nurse may record illegible information which may cause problems when the document is retrieved by the next person for continuity of care. OBJECTIVES: The objective of this study was to investigate and describe the effects of increased nurses' workload on quality documentation of patient information at PHC facilities in Vhembe District, Limpopo Province. METHODS: The study was conducted in Vhembe District, Limpopo Province, where the effects of increased nurses' workload on quality documentation of information is currently experienced. The research design was explorative, descriptive and contextual in nature. The population consisted of all nurses who work at PHC facilities in Vhembe District. Purposive sampling was used to select nurses and three professional nurses were sampled from each PHC facility. An in-depth face-to-face interview was used to collect data using an interview guide. RESULTS: PHC facilities encountered several effects due to increased nurses' workload where incomplete patient information is documented. Unavailability of patient information was observed, whilst some documented information was found to be illegible, inaccurate and incomplete. CONCLUSION: Documentation of information at PHC facilities is an evidence of effective communication amongst professional nurses. There should always be active follow-up and mentoring of the nurses' documentation to ensure that information is accurately and fully documented in their respective facilities. Nurses find it difficult to cope with the increased workload associated with documenting patient information on the multiple records that are utilized at PHC facilities, leading to incomplete information. The number of nurses at facilities should be increased to reduce the increased workload. PMID- 27246794 TI - Accumulation of phosphorylated p62 is associated with NF-E2-related factor 2 activation in hepatocellular carcinoma. AB - BACKGROUND: Frequent alterations are observed in glucose metabolism in hepatocellular carcinoma (HCC). Activation of various enzymes, including ones involved in the pentose phosphate pathway, by NF-E2-related factor 2 (NRF2), controls redox homeostasis in HCC. However, the mechanisms mediating NRF2 activation remain unclear. Here, we aimed to investigate the correlation between NRF2, Kelch-like ECH-associated protein 1 (KEAP1) syntheses and p62 phosphorylation in HCC. METHODS: Biospecimens were collected from 30 patients with HCC. Protein samples were prepared through subcellular localization. Protein synthesis and phosphorylation were measured by sodium dodecyl sulfate polyacrylamide gel electrophoresis and immunoblotting. Statistical correlations among immunoblotting data and clinical features were analyzed using SPSS. RESULTS: Compared to non-tumor counterpart, phosphorylated p62 was accumulated in HCC (12/30; 40% of patients). Nuclear localization of NRF2 was frequently augmented in HCC (19/30; 63.3%). Statistically, p62 phosphorylation was associated with augmented activation of NRF2 (P = 0.001). Accumulation of p62 per se was moderately associated with NRF2 activation (P = 0.132). Loss of KEAP1 protein, on the other hand, poorly correlated with NRF2 activation (P = 1.000). CONCLUSION: In Japanese HCC, NRF2 activation is associated with phosphorylation of p62, but not with KEAP1 status. PMID- 27246795 TI - Nomogram for hepatic steatosis: A simple and economical diagnostic tool for massive screening. AB - AIM: To establish a simple economical diagnostic tool for prediction of hepatic steatosis in patients with hepatitis B virus (HBV) infection. METHODS: From January 2006 to January 2015,a total of 1325 consecutive subjects who underwent liver biopsy were enrolled. According to the results of multivariate logistic regression analysis, a new nomogram was conducted. Then discrimination and calibration were conducted to assess the clinical diagnostic value of nomogram. RESULTS: The nomogram consisted of age, triglyceride (TG), low-density lipoprotein (LDL), uric acid (UA), haemoglobin (HGB). For prediction of hepatic steatosis, the AUROC of nomogram was 0.792 (95%CI: 0.758-0.826). With cut off value of 0.11, 699 (52.8%) of 1325 patients could be free from liver biopsy with a correct rate of 95.3% for diagnosis of hepatic steatosis. CONCLUSION: The nomogram for hepatic steatosis has a better clinical diagnostic value for prediction of hepatic steatosis in patients with HBV infection. From the perspective of cost-effectiveness and clinical practice, it is worth considering the use of the nomogram as a mass screening tool before further liver biopsy or imaging examinations. PMID- 27246796 TI - A preliminary feasibility study: Narrow-band imaging targeted versus standard white light endoscopy non-targeted biopsies in a surveillance Barrett's population. AB - BACKGROUND: Narrow band imaging (NBI) is used in the detection of intestinal metaplasia (IM) and dysplasia in patients with Barrett's oesophagus (BE). AIMS: The study compared the usefulness of NBI with white-light standard endoscopy (WLSE) for the detection of dysplasia and IM in BE and determined the prediction of the histological diagnosis according to the mucosal and vascular patterns obtained by NBI. PATIENTS AND METHODS: A total of 84 patients were prospectively enrolled in the study. Every patient underwent a WLSE with random biopsies and after 4-6 weeks, a NBI examination was performed. RESULTS: NBI detected significant more IM positive biopsies than WLSE (74.5% vs. 35.9%; p<0.0001) and significant more patients with low grade dysplasia (LGD) (7.1% vs. 0%; p=0.03). Taking biopsy samples from the villous pattern determined the diagnosis of IM (80%) and biopsies from the area covered by the irregular pattern lead to the identification of LGD in 45.4% of the cases and indefinite dysplasia (ID) in 18.2% of the cases. CONCLUSION: A thorough analysis of NBI patterns may lead to real-time IM diagnosis in the absence of the histological examination and may require targeted biopsies from the areas with an irregular pattern for diagnosing dysplasia. PMID- 27246797 TI - Increased small intestinal permeability and RNA expression profiles of mucosa from terminal ileum in patients with diarrhoea-predominant irritable bowel syndrome. AB - BACKGROUND: Altered intestinal permeability in diarrhoea-predominant irritable bowel syndrome (IBS-D) has been reported in some studies. AIMS: The study aimed to investigate the altered intestinal permeability and its associated clinical characteristics and RNA expression profiles in IBS-D. METHODS: We stratified IBS D patients into two groups according to the P95 value of the permeability in controls. The clinical characteristics of the two groups were evaluated, and two biopsy cases from each of the two groups were selected for the RNA-seq analysis. RESULTS: IBS-D patients had a significant increase in the small intestinal permeability compared with controls [0.0245 (0.0229) median (interquartile range)] versus 0.0156 (0.0098), P=0.010), but no significant difference was found in the colonic permeability [23.286 (10.470) versus 21.650 (6.650), P=0.574]. The IBS-D patients with increased small intestinal permeability had worse psychological effects (P=0.027) and quality of life (P=0.044). Analysis of RNA seq data revealed 185 genes differentially expressed, many of which were related to mucosal inflammation and immunity. CONCLUSIONS: Small intestinal permeability, but not colonic permeability, is increased in IBS-D patients. IBS-D patients with increased small intestinal permeability tend to be more severely impaired in terms of psychological effects and quality of life, and analysis of RNA-seq data reveals that increased small intestinal permeability is related to mucosal inflammation and immunity. PMID- 27246798 TI - Targeted genomic enrichment and massively parallel sequencing identifies novel nonsyndromic hearing impairment pathogenic variants in Cameroonian families. AB - In sub-Saharan Africa GJB2-related nonsyndromic hearing impairment (NSHI) is rare. Ten Cameroonian families was studied using a platform (OtoSCOPE(r)) with 116 genes. In seven of 10 families (70%), 12 pathogenic variants were identified in six genes. Five of the 12 (41.6%) variants are novel. These results confirm the efficiency of comprehensive genetic testing in defining the causes of NSHI in sub-Saharan Africa. PMID- 27246799 TI - Overcoming inter-subspecific hybrid sterility in rice by developing indica compatible japonica lines. AB - Rice (Oryza sativa L.) is an important staple crop. The exploitation of the great heterosis that exists in the inter-subspecific crosses between the indica and japonica rice has long been considered as a promising way to increase the yield potential. However, the male and female sterility frequently occurred in the inter-subspecific hybrids hampered the utilization of the heterosis. Here we report that the inter-subspecific hybrid sterility in rice is mainly affected by the genes at Sb, Sc, Sd and Se loci for F1 male sterility and the gene at S5 locus for F1 female sterility. The indica-compatible japonica lines (ICJLs) developed by pyramiding the indica allele (S-i) at Sb, Sc, Sd and Se loci and the neutral allele (S-n) at S5 locus in japonica genetic background through marker assisted selection are compatible with indica rice in pollen fertility and in spikelet fertility. These results showed a great promise of overcoming the inter subspecific hybrid sterility and exploiting the heterosis by developing ICJLs. PMID- 27246800 TI - mGluR6 regulates keratinocyte phagocytosis by modulating CaM KII/ERK/MLC signalling pathway. PMID- 27246802 TI - Erratum to: Fragmentation of Care in Ectopic Pregnancy. PMID- 27246801 TI - High morbidity and mortality of Clostridium difficile infection and its associations with ribotype 002 in Hong Kong. AB - OBJECTIVES: We aim to study the disease burden, risk factors and severity of Clostridium difficile infection (CDI) in Hong Kong. METHODS: We conducted a prospective, case-control study in three acute-care hospitals in Hong Kong. Adult inpatients who developed CDI diarrhoea confirmed by PCR (n = 139) were compared with the non-CDI controls (n = 114). Ribotyping of isolates and antimicrobial susceptibility testing were performed. RESULTS: The estimated crude annual incidence of CDI was 23-33/100,000 population, and 133-207/100,000 population among those aged >=65 years. The mean age of CDI patients was 71.5. Nursing home care, recent hospitalization, antibiotics exposure (adjusted OR 3.0, 95% CI 1.3 7.1) and proton-pump inhibitors use (adjusted OR 2.2, 95% CI 1.2-3.9) were risk factors. Severe CDI occurred in 41.7%. Overall mortality was 16.5% (among severe CDI, 26.5%). The commonest ribotypes were 002 (22.8%), 014 (14.1%), 012 and 046; ribotype 027 was absent. Ribotype 002 was associated with fluoroquinolone resistance and higher mortality (47.6% vs. 12.7%; adjusted HR 2.8, 95% CI 1.1 7.0). CONCLUSIONS: Our findings show high morbidity and mortality of CDI in the older adults, and identify ribotype 002 as a possible virulent strain causing serious infections in this cohort. PMID- 27246803 TI - Shear-induced enhancements of crystallization kinetics and morphological transformation for long chain branched polylactides with different branching degrees. AB - The effects of long chain branching (LCB) degree on the shear-induced isothermal crystallization kinetics of a series of LCB polylactides (LCB PLAs) have been investigated by using rotational rheometer, polarized optical microscopy (POM) and scanning electron microscopy (SEM). Dynamic viscoelastic properties obtained by small-amplitude oscillatory shear (SAOS) tests indicate that LCB PLAs show more broadened relaxation time spectra with increasing LCB degree. Upon a pre shear at the shear rate of 1 s(-1) LCB PLAs show much faster crystallization kinetics than linear PLA and the crystallization kinetics is enhanced with increasing LCB degree. By modeling the system as a suspension the quantitative evaluation of nucleation density can be derived from rheological experiments. The nucleation density is greatly enhanced with increasing LCB degree and a saturation in shear time is observed. Crystalline morphologies for LCB PLAs observed by POM and SEM demonstrate the enhancement of nucleation density with increasing LCB degree and a transformation from spherulitic to orientated crystalline morphologies. The observation can be ascribed to longer relaxation time of the longest macromolecular chains and broadened, complex relaxation behaviors due to the introduction of LCB into PLA, which is essential in stabilizing the orientated crystal nuclei after pre-shear. PMID- 27246804 TI - Critical data-based re-evaluation of minocycline as a putative specific microglia inhibitor. AB - Minocycline, a second generation broad-spectrum antibiotic, has been frequently postulated to be a "microglia inhibitor." A considerable number of publications have used minocycline as a tool and concluded, after achieving a pharmacological effect, that the effect must be due to "inhibition" of microglia. It is, however, unclear how this "inhibition" is achieved at the molecular and cellular levels. Here, we weigh the evidence whether minocycline is indeed a bona fide microglia inhibitor and discuss how data generated with minocycline should be interpreted. GLIA 2016;64:1788-1794. PMID- 27246805 TI - Cultural, Transcriptomic, and Proteomic Analyses of Water-Stressed Cells of Actinobacterial Strains Isolated from Compost: Ecological Implications in the Fed Batch Composting Process. AB - This study was undertaken to examine the effects of water activity (aw) on the viability of actinobacterial isolates from a fed-batch composting (FBC) process by comparing culturability and stainability with 5-cyano-2,3-ditoryl tetrazolium chloride (CTC). The FBC reactor as the source of these bacteria was operated with the daily loading of household biowaste for 70 d. During this period of composting, aw in the reactor decreased linearly with time and reached approximately 0.95 at the end of operation. The plate counts of aerobic chemoorganotrophic bacteria were 3.2-fold higher than CTC-positive (CTC+) counts on average at the fully acclimated stage (after 7 weeks of operation), in which Actinobacteria predominated, as shown by lipoquinone profiling and cultivation methods. When the actinobacterial isolates from the FBC process were grown under aw stress, no significant differences were observed in culturability among the cultures, whereas CTC stainability decreased with reductions in aw levels. A cDNA microarray-based transcriptomic analysis of a representative isolate showed that many of the genes involved in cellular metabolism and genetic information processing were down-regulated by aw stress. This result was fully supported by a proteomic analysis. The results of the present study suggest that, in low aw mature compost, the metabolic activity of the community with Actinobacteria predominating is temporarily reduced to a level that hardly reacts with CTC; however, these bacteria are easily recoverable by exposure to a high aw culture medium. This may be a plausible reason why acclimated FBC reactors in which Actinobacteria predominate yields higher plate counts than CTC+ counts. PMID- 27246806 TI - Differentiating feline inflammatory bowel disease from alimentary lymphoma in duodenal endoscopic biopsies. AB - OBJECTIVES: This study aimed to evaluate the agreement between microscopic and molecular testing for differentiating feline intestinal bowel disease and small cell alimentary lymphoma in duodenal endoscopic biopsies. METHODS: Four different diagnostic methods (cytology, histology, immunohistochemistry and clonality) were sequentially applied to 77 cases of feline chronic enteropathies. The agreement between the different diagnostic methods was calculated and survival data were obtained to assess the most reliable method for predicting outcome. RESULTS: Seventy-seven cases were included in the study. On multivariate survival analysis, only the clonality-based diagnosis of lymphoma was significantly associated with poor survival, with a risk of enteropathy-related death 2.8 times higher. By comparing the other tests with clonality, specificity was high (87 to 97%), whereas sensitivity was 36.8% for cytology, 39.5% for histology, 63.2% for immunohistochemistry, resulting in an overall accuracy of 62.3, 68.8 and 80.5%, respectively. CLINICAL SIGNIFICANCE: Clonality analysis can consistently increase the possibility of correctly and early diagnosing small cell lymphoma on endoscopic biopsies. Histological suspicion of alimentary lymphoma, even if not confirmed by clonality, should never be ignored, as it may represent a debutant form of lymphoma or it may later progress to lymphoma. PMID- 27246807 TI - Effects of shear stress on endothelial cells: go with the flow. AB - Haemodynamic forces influence the functional properties of vascular endothelium. Endothelial cells (ECs) have a variety of receptors, which sense flow and transmit mechanical signals through mechanosensitive signalling pathways to recipient molecules that lead to phenotypic and functional changes. Arterial architecture varies greatly exhibiting bifurcations, branch points and curved regions, which are exposed to various flow patterns. Clinical studies showed that atherosclerotic plaques develop preferentially at arterial branches and curvatures, that is in the regions exposed to disturbed flow and shear stress. In the atheroprone regions, the endothelium has a proinflammatory phenotype associated with low nitric oxide production, reduced barrier function and increased proadhesive, procoagulant and proproliferative properties. Atheroresistant regions are exposed to laminar flow and high shear stress that induce prosurvival antioxidant signals and maintain the quiescent phenotype in ECs. Indeed, various flow patterns contribute to phenotypic and functional heterogeneity of arterial endothelium whose response to proatherogenic stimuli is differentiated. This may explain the preferential development of endothelial dysfunction in arterial sites with disturbed flow. PMID- 27246808 TI - Cytotoxicity and genotoxicity of bacterial magnetosomes against human retinal pigment epithelium cells. AB - A variety of nanomaterials have been developed for ocular diseases. The ability of these nanomaterials to pass through the blood-ocular barrier and their biocompatibility are essential characteristics that must be considered. Bacterial magnetosomes (BMs) are a type of biogenic magnetic nanomaterials synthesized by magnetotactic bacteria. Due to their unique biomolecular membrane shell and narrow size distribution of approximately 30 nm, BMs can pass through the blood brain barrier. The similarity of the blood-ocular barrier to the blood-brain barrier suggests that BMs have great potential as treatments for ocular diseases. In this work, BMs were isolated from magnetotactic bacteria and evaluated in various cytotoxicity and genotoxicity studies in human retinal pigment epithelium (ARPE-19) cells. The BMs entered ARPE-19 cells by endocytosis after a 6-h incubation and displayed much lower cytotoxicity than chemically synthesized magnetic nanoparticles (MNPs). MNPs exhibited significantly higher genotoxicity than BMs and promoted the expression of Bax (the programmed cell death acceleration protein) and the induction of greater cell necrosis. In BM-treated cells, apoptosis tended to be suppressed via increased expression of the Bcl-2 protein. In conclusion, BMs display excellent biocompatibility and potential for use in the treatment of ocular diseases. PMID- 27246809 TI - Ginsenoside Rg3 prevents INS-1 cell death from intermittent high glucose stress. AB - BACKGROUND: Ginsenoside Rg3 has been proposed to mediate anti-diabetic effects, but their direct effect on pancreatic beta cell viability and mechanisms are not clearly understood. Recent studies suggest that intermittent high glucose (IHG) could be more harmful to pancreatic beta cells than sustained high glucose. There are few reports about the effect of the ginsenosideRg3 to beta cell apoptosis and proliferation against IHG. METHODS: INS-1 cells were treated with alternative glucose concentration with or without ginsenoside Rg3. Cell apoptosis and viability were detected by Annexin V staining and MTT assay. The activation of mitogen-activated protein kinases (MAPKs) was analyzed by Western blotting using specific antibodies. Quantification of secreted insulin protein was measured using rat/mouse Insulin ELISA kits. Bromodeoxyuridine (BrdU) staining and florescence in situ hybridization (FISH) analysis was performed to compare cell proliferation. RESULT: INS-1 cell viability was decreased under IHG and increased with Rg3 treatment.Rg3 significantly reduced the apoptotic INS-1 cells against IHG. The quantification of secreted insulin concentration was increased with Rg3. Rg3 increased INS-1 cell proliferation. ERK and p38 MAPK pathways reduced by IHG were activated by the ginsenoside Rg3. CONCLUSION: Ginsenoside Rg3 protected INS 1 cell death from IHG with reducing apoptosis and increasing proliferation. PMID- 27246811 TI - Investigation on maternal lineage of a Neolithic group from northern Shaanxi based on ancient DNA. AB - A magnetic bead purification method was successfully used to extract ancient DNA from the skeletal remains of 10 specimens excavated from Wuzhuangguoliang (Wzhgl) site, which was located in northern Shaanxi. The multidimensional scaling (MDS) and analysis of molecular variance approach (AMOVA) revealed that ancient Wzhgl people bored a very high similarity to southern Han Chinese. By constructing the MJ-network of various modern people including Han Chinese and Japanese, the phylogenetic analysis indicated that the Wzhgl population had close maternal distance with ancient Shandong and Xinjiang people. These findings indicated that Wzhgl contributed to the gene pool of Han Chinese and modern Japanese. In addition, population migration and interflow between Wzhgl people and ancient Shandong or Xinjiang probably occurred in Neolithic period. PMID- 27246810 TI - Insights into islet development and biology through characterization of a human iPSC-derived endocrine pancreas model. AB - Directed differentiation of stem cells offers a scalable solution to the need for human cell models recapitulating islet biology and T2D pathogenesis. We profiled mRNA expression at 6 stages of an induced pluripotent stem cell (iPSC) model of endocrine pancreas development from 2 donors, and characterized the distinct transcriptomic profiles associated with each stage. Established regulators of endodermal lineage commitment, such as SOX17 (log2 fold change [FC] compared to iPSCs = 14.2, p-value = 4.9 * 10(-5)) and the pancreatic agenesis gene GATA6 (log2 FC = 12.1, p-value = 8.6 * 10(-5)), showed transcriptional variation consistent with their known developmental roles. However, these analyses highlighted many other genes with stage-specific expression patterns, some of which may be novel drivers or markers of islet development. For example, the leptin receptor gene, LEPR, was most highly expressed in published data from in vivo-matured cells compared to our endocrine pancreas-like cells (log2 FC = 5.5, p-value = 2.0 * 10(-12)), suggesting a role for the leptin pathway in the maturation process. Endocrine pancreas-like cells showed significant stage selective expression of adult islet genes, including INS, ABCC8, and GLP1R, and enrichment of relevant GO-terms (e.g. "insulin secretion"; odds ratio = 4.2, p value = 1.9 * 10(-3)): however, principal component analysis indicated that in vitro-differentiated cells were more immature than adult islets. Integration of the stage-specific expression information with genetic data from T2D genome-wide association studies revealed that 46 of 82 T2D-associated loci harbor genes present in at least one developmental stage, facilitating refinement of potential effector transcripts. Together, these data show that expression profiling in an iPSC islet development model can further understanding of islet biology and T2D pathogenesis. PMID- 27246812 TI - Nanofiber technology: its transformative role in nanomedicine. PMID- 27246813 TI - Emoting infertility online: A qualitative analysis of men's forum posts. AB - Relatively little research on infertility focuses exclusively or significantly on men's experiences, particularly in relation to emotional aspects. Evidence that does exist around male infertility suggests that it is a distressing experience for men, due to stigma, threats to masculinity and the perceived need to suppress emotions, and that men and women experience infertility differently. Using thematic analysis, this article examines the online emoting of men in relation to infertility via forum posts from a men-only infertility discussion board. It was noted that men 'talked' to each other about the emotional burdens of infertility, personal coping strategies and relationships with others. Three major themes were identified following in-depth analysis: 'the emotional rollercoaster', 'the tyranny of infertility' and 'infertility paranoia'. This article then offers insights into how men experience infertility emotionally, negotiate the emotional challenges involved (especially pertaining to diagnosis, treatment outcomes and their intimate relationships) and how they share (and find value in doing so) with other men the lived experience of infertility. PMID- 27246814 TI - Survival and disease-free benefits with mastectomy versus breast conservation therapy for early breast cancer: a meta-analysis. AB - The objective of the present meta-analysis was to estimate the magnitude of survival and disease-free benefits from mastectomy compared with breast conservation therapy (BCT) in patients with early breast cancer. We searched PubMed, Embase, the Cochrane Library, Web of Science, and Chinese biomedical literature database from their inception to May 2015. All the data were independently extracted from the publications by two reviewers. Results regarding the overall survival (OS) and disease-free survival (DFS) in the meta-analysis were expressed as hazard ratios (HRs) with 95 % confidence intervals (CIs). Nine randomized control trials were eligible for final meta-analysis. Meta-analysis showed that mastectomy provided significant benefit in OS compared with BCT (HR 1.09, 95 % CI 1.01-1.19; P = 0.03). Sensitivity analysis gives similar OS estimates (HR 1.12, 95 % CI 1.01-1.25). In the subgroup analysis of patients according to tumor size, the pooled HRs for OS indicated that there is a borderline statistical difference between two arms in the subgroup with tumor size ranging between >=2 cm and <5 cm (HR 1.09, 95 % CI 1.00-1.19), but subgroup analysis of tumor size <2 cm showed no statistically significant difference in OS (HR 1.08, 95 % CI 0.88-1.33) when comparing the BCT arm with the mastectomy arm. There was no significant difference in DFS between BCT and mastectomy groups (HR 1.08, 95 % CI 0.99-1.18; P = 0.08). Sensitivity analysis also gives similar DFS estimates (HR 1.11, 95 % CI 0.96-1.27). Subgroup analysis indicated that the pooled HRs for DFS did not favor mastectomy arm or BCT arm either in the subgroup with tumor size <2 cm (HR 1.09, 95 % CI 0.78-1.52) or in the subgroup with tumor size ranging between >=2 cm and <5 cm (HR 1.08, 95 % CI 0.99-1.18) according to tumor size. Five-year OS decreased from 70 to 68 % with BCT. The present meta analysis indicated that mastectomy might provide slight OS benefit compared with BCT in early breast cancer patients with larger tumor size, but the absolute survival gain is small. PMID- 27246815 TI - Sustained-release microsphere formulation containing an agrochemical by polyurethane polymerization during an agitation granulation process. AB - In this report, a new solventless microencapsulation method by synthesizing polyurethane (PU) from polyol and isocyanate during an agglomeration process in a high-speed mixing apparatus was developed. Clothianidin (CTD), which is a neonicotinoid insecticide and highly effective against a wide variety of insect pests, was used as the model compound. The microencapsulated samples covered with PU (CTD microspheres) had a median diameter of <75MUm and sustained-release properties. The CTD microspheres were analyzed by synchrotron X-ray computed tomography measurements. Multiple cores of CTD and other solid excipient were dispersed in PU. Although voids appeared in the CTD microspheres after CTD release, the spherical shape of the microspheres remained stable and no change in its framework was observed. The experimental release data were highly consistent with the Baker-Lonsdale model derived from drug release of spherical monolithic dispersions and consistent with the computed tomography measurements. PMID- 27246816 TI - Thiolated graphene oxide as promising mucoadhesive carrier for hydrophobic drugs. AB - The aim of this study was to improve the mucoadhesive properties of graphene by conjugating thiol ligands, in order to formulate an oral delivery system for hydrophobic drugs showing long mucus residence time. Graphene oxide was obtained by oxidation of graphite and then was thiolated following two synthetic paths. On the one hand, the hydroxyl groups were conjugated with thiourea passing through the formation of a brominated intermediate. On the other hand, the carboxylic acid groups were conjugated with cysteamine via carbodiimide chemistry. The mucoadhesive properties of thiolated graphene were evaluated by rheological measurements and by residence time assay. Then, valsartan was loaded on thiolated graphene and the release profile was evaluated in simulated intestinal fluid. Following both synthetic paths it was possible to obtain thiolated graphene bearing 215-302MUmol SH/g product. Both products induced after 1h incubation an increase of mucus viscosity of about 22-33-fold compared to unmodified graphite. The residence time assay confirmed that 60% of thiolated graphene could be retained on intestinal mucosa after 4h incubation, whereas just 20% of unmodified graphite could be retained. Valsartan could be loaded with a drug loading of about 31+/-0.3% and a sustained release profile was observed for both formulations. According to the presented data, the thiolation of graphene could improve its mucoadhesive properties. Therefore, thiolated graphene represents a promising platform for oral delivery of hydrophobic drugs, possessing a long residence time on intestinal mucosa which allows the release of the loaded drug close to the adsorptive epithelium. PMID- 27246817 TI - Pharmacokinetic study of benzylpenicillin potassium after intramuscular administration in rabbits. PMID- 27246818 TI - Why don't boys apply to vet school? A pilot study. PMID- 27246819 TI - The BioHub Knowledge Base: Ontology and Repository for Sustainable Biosourcing. AB - BACKGROUND: The motivation for the BioHub project is to create an Integrated Knowledge Management System (IKMS) that will enable chemists to source ingredients from bio-renewables, rather than from non-sustainable sources such as fossil oil and its derivatives. METHOD: The BioHubKB is the data repository of the IKMS; it employs Semantic Web technologies, especially OWL, to host data about chemical transformations, bio-renewable feedstocks, co-product streams and their chemical components. Access to this knowledge base is provided to other modules within the IKMS through a set of RESTful web services, driven by SPARQL queries to a Sesame back-end. The BioHubKB re-uses several bio-ontologies and bespoke extensions, primarily for chemical feedstocks and products, to form its knowledge organisation schema. RESULTS: Parts of plants form feedstocks, while various processes generate co-product streams that contain certain chemicals. Both chemicals and transformations are associated with certain qualities, which the BioHubKB also attempts to capture. Of immediate commercial and industrial importance is to estimate the cost of particular sets of chemical transformations (leading to candidate surfactants) performed in sequence, and these costs too are captured. Data are sourced from companies' internal knowledge and document stores, and from the publicly available literature. Both text analytics and manual curation play their part in populating the ontology. We describe the prototype IKMS, the BioHubKB and the services that it supports for the IKMS. AVAILABILITY: The BioHubKB can be found via http://biohub.cs.manchester.ac.uk/ontology/biohub-kb.owl . PMID- 27246820 TI - Fermented and malted millet products in Africa: Expedition from traditional/ethnic foods to industrial value-added products. AB - With the prevalent food insecurity in Africa, there is a growing need to utilize the available crops to develop nutritious, affordable and palatable food for the populace. Millet is critical in this role, relative to its abundance in the continent and good nutritional composition. For ages, fermentation and malting have been traditionally used to transform millet into variety of produce. A paradigm shift has however occurred over the years, giving birth to new commercially available products. This review thus appraises and gives an overview of traditional and modern fermented and malted products. Although, millet has been diversified to several products, its major food uses are still restrained to traditional consumers and largely remains underutilized. Considering the potential embedded in this grain, it is important to explore this crop through the application of appropriate modern fermentation and malting technologies. This will ensure the availability of ready to eat (RTE) and ready to use (RTU) food products and to a large extent address the incessant food security challenges plaguing Africa. PMID- 27246821 TI - Mental disorders and harmful substance use in children of substance abusing parents: A longitudinal register-based study on a complete birth cohort born in 1991. AB - INTRODUCTION AND AIMS: Adverse childhood experiences and their accumulation over childhood have negative outcomes to children, yet earlier findings on the independent effect of parental substance abuse seem inconsistent. Our aims were to examine: (i) whether parental substance abuse is associated with children's mental disorders in mid-childhood (7-12 years) and mental disorders and own substance use in adolescence (13-17 years); and (ii) whether children are affected differently by a mother or father's substance abuse. DESIGN AND METHODS: A register-based longitudinal data on a complete birth cohort of children born in Finland in 1991 (n = 65 117) and their biological parents. The children were followed until their 18th birthday. Data were derived from the Finnish administrative registries. Bivariate and multivariate logistic regression models were used in the analysis. RESULTS: Maternal, paternal and both parents' substance abuse were significant predictors of mental disorders and harmful substance use in children aged 13-17 years, even after controlling for other adverse childhood experiences, parental education and child's gender. Parental substance abuse predicted mental disorders in children aged 7-12 years in bivariate model but in multivariate model the association disappeared. Maternal substance abuse had stronger effect on harmful substance use in adolescent children than paternal. There were no significant interactions between substance abusing parents' gender and the child's gender. DISCUSSION AND CONCLUSIONS: Early identification, prevention and treatment of substance abuse in families with children in primary health care, child welfare and other services are crucial in preventing intergenerational transmission of the problems associated with parental substance abuse. [Jaaskelainen M, Holmila M, Notkola I-L, Raitasalo K. Mental disorders and harmful substance use in children of substance abusing parents: A longitudinal register-based study on a complete birth cohort born in 1991. Drug Alcohol Rev 2016;35:728-740]. PMID- 27246823 TI - Pseudomonas aeruginosa Cell Membrane Protein Expression from Phenotypically Diverse Cystic Fibrosis Isolates Demonstrates Host-Specific Adaptations. AB - Pseudomonas aeruginosa is a Gram-negative, nosocomial, highly adaptable opportunistic pathogen especially prevalent in immuno-compromised cystic fibrosis (CF) patients. The bacterial cell surface proteins are important contributors to virulence, yet the membrane subproteomes of phenotypically diverse P. aeruginosa strains are poorly characterized. We carried out mass spectrometry (MS)-based proteome analysis of the membrane proteins of three novel P. aeruginosa strains isolated from the sputum of CF patients and compared protein expression to the widely used laboratory strain, PAO1. Microbes were grown in planktonic growth condition using minimal M9 media, and a defined synthetic lung nutrient mimicking medium (SCFM) limited passaging. Two-dimensional LC-MS/MS using iTRAQ labeling enabled quantitative comparisons among 3171 and 2442 proteins from the minimal M9 medium and in the SCFM, respectively. The CF isolates showed marked differences in membrane protein expression in comparison with PAO1 including up-regulation of drug resistance proteins (MexY, MexB, MexC) and down-regulation of chemotaxis and aerotaxis proteins (PA1561, PctA, PctB) and motility and adhesion proteins (FliK, FlgE, FliD, PilJ). Phenotypic analysis using adhesion, motility, and drug susceptibility assays confirmed the proteomics findings. These results provide evidence of host-specific microevolution of P. aeruginosa in the CF lung and shed light on the adaptation strategies used by CF pathogens. PMID- 27246822 TI - Dabrafenib plus Trametinib: a Review in Advanced Melanoma with a BRAF (V600) Mutation. AB - The BRAF inhibitor dabrafenib (Tafinlar((r))) and the MEK inhibitor trametinib (Mekinist((r))) are indicated, as monotherapy or in combination with each other, for the treatment of patients with unresectable or metastatic melanoma with a BRAF (V600) mutation. This article reviews the therapeutic efficacy and tolerability of combination treatment with dabrafenib and trametinib in this indication and summarizes relevant pharmacological data. Dabrafenib plus trametinib significantly prolonged progression-free survival (PFS) and overall survival (OS), improved objective response rates (ORRs) and preserved health related quality of life (HR-QOL) to a greater extent than dabrafenib (in the double-blind COMBI-d study) and vemurafenib (in the open-label COMBI-v study) in two large, randomized, phase III studies in treatment-naive patients with unresectable or metastatic melanoma with BRAF (V600E/K) mutation. Limited treatment benefit with the combination was also seen in patients who had progressed on prior BRAF inhibitor therapy, as indicated by ORRs of <= 15 % and stable disease in <= 50 % of patients in small phase I and II studies. Combination therapy did not increase overall toxicity relative to dabrafenib or vemurafenib monotherapy, with most adverse events (AEs) mild or moderate in severity and generally manageable. Fewer skin-related AEs (e.g. cutaneous malignancies, hyperkeratinosis and hand-foot syndrome) were reported with combination therapy than with dabrafenib or vemurafenib, probably because of reduced paradoxical activation of the MAPK pathway. Thus, dabrafenib plus trametinib provides an important treatment option for patients with BRAF (V600) mutation-positive unresectable or metastatic melanoma. PMID- 27246824 TI - Factors associated with the severity of obstructive sleep apnea in older adults. AB - AIM: Epidemiological studies have shown that severe obstructive sleep apnea (OSA) is associated with higher mortality when compared with mild to moderate OSA. Because aging is a well-known risk factor for OSA, we aimed to elucidate the underlying factors associated with the severity of OSA in elderly patients. METHODS: Patients who underwent polysomnography were divided into the non-elderly group (aged <65 years; n = 44) and the elderly group (aged >=65 years; n = 46). The severity of OSA was determined by the apnea hypopnea index (AHI), and each group was subdivided into two groups: mild to moderate OSA (5 < AHI < 30) and severe OSA (AHI >=30) . In the elderly group, geriatric assessments to evaluate physical and neuropsychiatric function were carried out. RESULTS: All patients had OSA as diagnosed by an AHI >5. Whereas body mass index was positively correlated with AHI in both groups, age was correlated with AHI only in the elderly group. Body mass index and age were higher in severe OSA than mild to moderate OSA in the elderly group. Unexpectedly, no significant difference was observed in physical strength, cognitive function, apathy scale, depression scale or activities of daily living between mild to moderate OSA and severe OSA in the elderly group. Binary logistic regression analysis showed that male sex, body mass index and aging were independent risk factors of severe OSA in the elderly group. CONCLUSIONS: Our findings suggest that aging increases the severity of OSA in elderly patients, even if they are physically active and neuropsychiatrically unimpaired. Geriatr Gerontol Int 2017; 17: 614-621. PMID- 27246825 TI - Managing Developmental Dysplasia of the Hip. AB - Developmental dysplasia of the hip (DDH) involves a spectrum of hip disorders that affect hip anatomy and development and can range from mild anatomical deformity with a reduced but subluxatable hip to a frankly dislocated hip. It was previously known as congenital dislocation of the hip (CDH) but this name is no longer used due to the fact that the hip may be anatomically abnormal whilst not being dislocated. The key aim of clinical management of DDH is early diagnosis and referral as this can often mean less invasive treatment is possible, and outcomes are significantly improved if treatment is initiated at an early stage and certainly before 6 wk of age. PMID- 27246827 TI - Access and Acceptability of Digital Technology Amongst Caregivers/Parents in Government Sector. PMID- 27246826 TI - Human Bocavirus Infection Associated Transient Benign Hyperphosphatasemia in an Infant. PMID- 27246828 TI - Direct Cost of Critical Illness Associated Healthcare Expenditures among Children Admitted in Pediatric Intensive Care Unit in Rural India. AB - OBJECTIVE: To assess the direct costs involved in treatment of children receiving intensive care in a university-affiliated teaching hospital and its associated implications on the children's families, in rural India. METHODS: It was a prospective observational study for cost-analysis using questionnaire based interviews and billing records data collection for admissions to the PICU over 27 consecutive months (January 2010 through March 2012). RESULTS: A total of 784 children were admitted to the unit during the assessment period. Full details of 633 children were included for analysis. The average length of stay was 6.16 d, average hospital expenditure was US$185.67, average hospital expenses per day was US$44.00, average pharmacy expenditure was US$109.67 and average pharmacy expenditure per day was US$20.62 per patient. Children who were ventilated had approximately 61 % more expense per day as compared to non-ventilated ones. Boys and those with health insurance reported higher length of stay. Linear hierarchical regression with backward LR model showed that mechanical ventilation, multiple organ dysfunction, length of stay and insurance cover were the variables significantly affecting the final expenses. CONCLUSIONS: There is a high direct expenditure incurred by families of children receiving intensive care when seen in perspective of high rates of extreme poverty in rural India. These high expenditures make critical care unaffordable to majority of the population lacking insurance cover in resource limited regions with limited universal health coverage, which ultimately leads to suboptimal care and high childhood mortality. It is highly imperative for the governments and global health organizations to be sensitive towards this issue and to plan strategies for the same across different nations. PMID- 27246829 TI - Follicular B Lymphomas Generate Regulatory T Cells via the ICOS/ICOSL Pathway and Are Susceptible to Treatment by Anti-ICOS/ICOSL Therapy. AB - The prognosis of follicular lymphoma (FL) patients is suspected to be influenced by tumor-infiltrating regulatory T cells (Treg). The mechanism of Treg enrichment in FL and their impact on malignant FL B cells remains to be elucidated. We analyzed 46 fresh lymph node biopsy samples, including FL (n = 20), diffuse large B-cell lymphoma (n = 10), classical Hodgkin lymphoma (n = 9), and reactive lymphadenitis (n = 7). Using multicolor flow cytometry and cell sorting, we observed an accumulation of CD25(high)CD127(low/neg) Tregs in FL tissues. These Tregs comprised activated ICOS(+) Tregs that were able to suppress not only conventional T cells, but also FL B cells. These FL B cells were able to express ICOSL in vitro and to generate CD25(high)FoxP3(high) Tregs expressing ICOS. Treg generation was associated with ICOS/ICOSL engagement and was abrogated by antagonist anti-ICOS and anti-ICOSL antibodies. Interactions between Tregs and FL B cells resulted in ICOSL downregulation on FL B cells. Our results highlight a key role for Tregs in FL pathogenesis and suggest that targeting the ICOS/ICOSL pathway may be a promising immunotherapy for FL treatment. Cancer Res; 76(16); 4648-60. (c)2016 AACR. PMID- 27246830 TI - miR-182-5p Induced by STAT3 Activation Promotes Glioma Tumorigenesis. AB - Malignant glioma is an often fatal type of cancer. Aberrant activation of STAT3 leads to glioma tumorigenesis. STAT3-induced transcription of protein-coding genes has been extensively studied; however, little is known about STAT3 regulated miRNA gene transcription in glioma tumorigenesis. In this study, we found that abnormal activation or decreased expression of STAT3 promotes or inhibits the expression of miR-182-5p, respectively. Bioinformatics analyses determined that tumor suppressor protocadherin-8 (PCDH8) is a candidate target gene of miR-182-5p. miR-182-5p negatively regulated PCDH8 expression by directly targeting its 3'-untranslated region. PCDH8 knockdown induced the proliferative and invasive capacities of glioma cells. Silencing of PCDH8 or miR-182-5p mimics could reverse the inhibitory effect of WP1066, a STAT3 inhibitor, or STAT3 knockdown in vitro and in vivo on glioma progression. Clinically, expression levels of PCDH8 were inversely correlated with those of p-STAT3 or miR-182-5p in glioblastoma tissues. These findings reveal that the STAT3/miR-182-5p/PCDH8 axis has a critical role in glioma tumorigenesis and that targeting the axis may provide a new therapeutic approach for human glioma. Cancer Res; 76(14); 4293 304. (c)2016 AACR. PMID- 27246831 TI - Occurrence of subdural hematomas in Dutch glutaric aciduria type 1 patients. AB - Patients with glutaric aciduria type 1 (GA1), a rare inherited metabolic disorder, have an increased risk for subdural hematomas (SDHs). GA1 is therefore generally included in the differential diagnosis of children presenting with SDHs. This retrospective cohort study reviews all 25 registered, in the Dutch Diagnosis Registration for Metabolic Disorders, GA1 patients in the Netherlands. This was done between May 2014 and November 2014 to determine the lifetime incidence of SDHs in this population. Seventeen patients were diagnosed either due to clinical symptoms or because of family members with GA1. One out of these 17 had a SDH. This patient showed widened Sylvian fissures on MRI, characteristic for GA1. Eight patients were diagnosed by newborn screening. Three of them had neuroimaging results, and none of them had SDHs. This study shows an overall lower incidence (4.0 %) of SDHs in patients with GA1 than reported in the literature (20-30 %). CONCLUSION: This finding, in combination with the fact that SDHs in GA1 appear to occur only in the presence of characteristic brain abnormalities on imaging, we recommend that GA1 should not routinely be a part of the differential diagnosis of children with unexplained SDHs in the absence of imaging characteristics suggestive of GA1. WHAT IS KNOWN: * Glutaric aciduria type 1 is a rare metabolic disorder predisposing children to subdural hematoma development due to brain abnormalities. * Because of these subdural hematomas, glutaric aciduria type 1 testing is part of abusive head trauma work-up. What is new: * The overall subdural hematoma incidence in glutaric aciduria type 1 patients is much lower than previously reported and only occurs in case of predisposing brain abnormalities. PMID- 27246832 TI - Kinetics and Mechanism of the Reaction of a Ruthenium(VI) Nitrido Complex with HSO3 (-) and SO3 (2-) in Aqueous Solution. AB - The kinetics and mechanism of the reaction of S(IV) (SO3 (2-) +HSO3 (-) ) with a ruthenium(VI) nitrido complex, [(L)Ru(VI) (N)(OH2 )](+) (Ru(VI) N, L=N,N' bis(salicylidene)-o-cyclohexyldiamine dianion), in aqueous acidic solutions are reported. The kinetic results are consistent with parallel pathways involving oxidation of HSO3 (-) and SO3 (2-) by Ru(VI) N. A deuterium isotope effect of 4.7 is observed in the HSO3 (-) pathway. Based on experimental results and DFT calculations the proposed mechanism involves concerted N-S bond formation (partial N-atom transfer) between Ru(VI) N and HSO3 (-) and H(+) transfer from HSO3 (-) to a H2 O molecule. PMID- 27246833 TI - Bone health and vitamin D status in alcoholic liver disease. AB - Alcohol consumption is harmful to many organs and tissues, including bones, and it leads to osteoporosis. Hepatic osteodystrophy is abnormal bone metabolism that has been defined in patients with chronic liver disease (CLD), including osteopenia, osteoporosis, and osteomalacia. Decreased bone density in patients with CLD results from decreased bone formation or increased bone resorption. The prevalence of osteopenia in alcoholic liver disease (ALD) patients is between 34 % and 48 %, and the prevalence of osteoporosis is between 11 % and 36 %. Cirrhosis is also a risk factor for osteoporosis. The liver has an important role in vitamin D metabolism. Ninety percent of patients with alcoholic liver cirrhosis have vitamin D inadequacy (<80 nmol/L). The lowest serum vitamin D levels were observed in patients with Child-Pugh class C. Bone densitometry is used for the definitive diagnosis of osteoporosis in ALD. There are no specific controlled clinical studies on the treatment of osteoporosis in patients with ALD. Alcohol cessation and abstinence are principal for the prevention and treatment of osteoporosis in ALD patients, and the progression of osteopenia can be stopped in this way. Calcium and vitamin D supplementation is recommended, and associated nutritional deficiencies should also be corrected. The treatment recommendations of osteoporosis in CLD tend to be extended to ALD. Bisphosphonates have been proven to be effective in increasing bone mineral density (BMD) in chronic cholestatic disease and post-transplant patients, and they can be used in ALD patients. Randomized studies assessing the management of CLD-associated osteoporosis and the development of new drugs for osteoporosis may change the future. Here, we will discuss bone quality, vitamin D status, mechanism of bone effects, and diagnosis and treatment of osteoporosis in ALD. PMID- 27246834 TI - Cardioprotection provided by Echinatin against ischemia/reperfusion in isolated rat hearts. AB - BACKGROUND: This study evaluated the protective effect of Echinatin against myocardial ischemia/reperfusion (I/R) injury in rats. METHODS: The effect of Echinatin on cardiac function in rats subjected to I/R was demonstrated through improved Langendorff retrograde perfusion technology. Adult Sprague-Dawley rats were randomly divided into five groups, and myocardial infarct size was macroscopically estimated through 2,3,5-triphenyltetrazolium chloride staining. The coronary effluent was analyzed for the release of lactate dehydrogenase (LDH) and creatine kinase (CK) to assess the degree of cardiac injury. The concentrations of malondialdehyde (MDA), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) were determined along with superoxide dismutase (SOD) activity using ELISA. Finally, cardiomyocyte apoptosis analysis was conducted with POD, an in situ cell death detection kit. RESULTS: Echinatin (0.5 and 2.5 MUg/mL) pretreatment enhanced the maximum up/down rate of the left ventricular pressure (+/-dp/dtmax), improved the heart rate, increased the left ventricular developed pressure (LVDP), enhanced the coronary flow, and reduced the CK and LDH levels in the coronary flow of the treated group compared with the I/R group. Echinatin limited the contents of CK and LDH, improved the LVDP, reduced the contents of MDA, IL-6, and TNF-alpha, and increased the SOD activity. The infarct size and cell apoptosis in the hearts of the rats in the Echinatin-treated group were smaller and lower, respectively, than those in the hearts of the rats in the I/R control group. CONCLUSION: Echinatin exerts a protective effect against I/R induced myocardial injury on hearts. This effect may be attributed to the antioxidant and anti-inflammatory activities of this compound. PMID- 27246835 TI - Computational recognition and analysis of hitherto uncharacterized nucleotide cyclase-like proteins in bacteria. AB - Evolutionary relationship between class III nucleotide cyclases and an uncharacterized set of bacterial proteins from Actinobacteria, Bacteroidetes and Proteobacteria has been recognized and analyzed. Detailed analyses of sequence and structural features resulted in the recognition of potential cyclase function conferring residues and presence of signature topological motif (betaalphaalphabetabetaalphabeta) in the uncharacterized set of bacterial proteins. Lack of transmembrane domains and signal peptide cleavage sites is suggestive of their cytosolic subcellular localization. Furthermore, analysis on evolutionarily conserved gene clusters of the predicted nucleotide cyclase-like proteins and their evolutionary relationship with nucleotide cyclases suggest their participation in cellular signalling events. Our analyses suggest expansion of class III nucleotide cyclases. REVIEWERS: This article was reviewed by Eugene Koonin and Michael Gromiha. PMID- 27246836 TI - Rationale, design and methods for the RIGHT Track Health Study: pathways from childhood self-regulation to cardiovascular risk in adolescence. AB - BACKGROUND: Cardiovascular risk factors during adolescence-including obesity, elevated lipids, altered glucose metabolism, hypertension, and elevated low-grade inflammation-is cause for serious concern and potentially impacts subsequent morbidity and mortality. Despite the importance of these cardiovascular risk factors, very little is known about their developmental origins in childhood. In addition, since adolescence is a time when individuals are navigating major life changes and gaining increasing autonomy from their parents or parental figures, it is a period when control over their own health behaviors (e.g. drug use, sleep, nutrition) also increases. The primary aim of this paper is to describe the rationale, design and methods for the RIGHT Track Health Study. This study examines self-regulation as a key factor in the development of cardiovascular risk, and further explores health behaviors as an explanatory mechanism of this association. We also examine potential moderators (e.g. psychosocial adversities such as harsh parenting) of this association. METHOD/DESIGN: RIGHT Track is a longitudinal study that investigates social and emotional development. The RIGHT Track Health Study prospectively follows participants from age 2 through young adulthood in an effort to understand how self-regulatory behavior throughout childhood alters the trajectories of various cardiovascular risk factors during late adolescence via health behaviors. Individuals from RIGHT Track were re contacted and invited to participate in adolescent data collection (~16.5, 17.5 and 18(+) years old). Individuals completed assessments of body composition, anthropometric indicators, fitness testing (via peak oxygen consumption), heart rate variability during orthostatic challenge, 7-day accelerometry for physical activity and sleep, 24-h dietary recalls, and blood analysis for biomarkers related to metabolic syndrome, inflammatory status and various hormones and cytokines. Individuals also completed extensive self-report measures on diet and eating regulation, physical activity and sedentary behaviors, sleep, substance use, medical history, medication use and a laboratory-day checklist, which chronicled previous day activities and menstrual information for female participants. DISCUSSION: Insights emerging from this analysis can help researchers and public health policy administrators target intervention efforts in early childhood, when preventing chronic disease is most cost-effective and behavior is more malleable. PMID- 27246837 TI - Diffusion tensor imaging with direct cytopathological validation: characterisation of decorin treatment in experimental juvenile communicating hydrocephalus. AB - BACKGROUND: In an effort to develop novel treatments for communicating hydrocephalus, we have shown previously that the transforming growth factor-beta antagonist, decorin, inhibits subarachnoid fibrosis mediated ventriculomegaly; however decorin's ability to prevent cerebral cytopathology in communicating hydrocephalus has not been fully examined. Furthermore, the capacity for diffusion tensor imaging to act as a proxy measure of cerebral pathology in multiple sclerosis and spinal cord injury has recently been demonstrated. However, the use of diffusion tensor imaging to investigate cytopathological changes in communicating hydrocephalus is yet to occur. Hence, this study aimed to determine whether decorin treatment influences alterations in diffusion tensor imaging parameters and cytopathology in experimental communicating hydrocephalus. Moreover, the study also explored whether diffusion tensor imaging parameters correlate with cellular pathology in communicating hydrocephalus. METHODS: Accordingly, communicating hydrocephalus was induced by injecting kaolin into the basal cisterns in 3-week old rats followed immediately by 14 days of continuous intraventricular delivery of either human recombinant decorin (n = 5) or vehicle (n = 6). Four rats remained as intact controls and a further four rats served as kaolin only controls. At 14-days post-kaolin, just prior to sacrifice, routine magnetic resonance imaging and magnetic resonance diffusion tensor imaging was conducted and the mean diffusivity, fractional anisotropy, radial and axial diffusivity of seven cerebral regions were assessed by voxel-based analysis in the corpus callosum, periventricular white matter, caudal internal capsule, CA1 hippocampus, and outer and inner parietal cortex. Myelin integrity, gliosis and aquaporin-4 levels were evaluated by post-mortem immunohistochemistry in the CA3 hippocampus and in the caudal brain of the same cerebral structures analysed by diffusion tensor imaging. RESULTS: Decorin significantly decreased myelin damage in the caudal internal capsule and prevented caudal periventricular white matter oedema and astrogliosis. Furthermore, decorin treatment prevented the increase in caudal periventricular white matter mean diffusivity (p = 0.032) as well as caudal corpus callosum axial diffusivity (p = 0.004) and radial diffusivity (p = 0.034). Furthermore, diffusion tensor imaging parameters correlated primarily with periventricular white matter astrocyte and aquaporin-4 levels. CONCLUSIONS: Overall, these findings suggest that decorin has the therapeutic potential to reduce white matter cytopathology in hydrocephalus. Moreover, diffusion tensor imaging is a useful tool to provide surrogate measures of periventricular white matter pathology in communicating hydrocephalus. PMID- 27246839 TI - Methadone-Related Overdose Deaths in a Liberal Opioid Maintenance Treatment Programme. AB - BACKGROUND/AIMS: Increasing rates of overdose deaths involving opioid maintenance treatment (OMT) medications and particularly methadone have been observed concurrently with the implementation of liberal OMT strategies (i.e. minimum of control and high doses prescribed). This study examined methadone-related overdose deaths in a liberal OMT programme. METHODS: Drug-overdose deaths (n = 130) with detection of methadone in Copenhagen, Aarhus, and Odense Municipality, Denmark, during the period 2008-2011 were identified from a registry. Cases with and without prescribed methadone as OMT were compared. Treatment delivery strategy among OMT-prescribed methadone cases was investigated. RESULTS: Methadone was detected in 130 overdose deaths (71.4% of all overdose deaths). Among these, 63.1% were receiving methadone maintenance treatment. Of these, 79.3% had co-detection of benzodiazepines. Concomitant detection of heroin, non prescribed benzodiazepines, and younger age were associated with having non prescribed methadone in the toxicological findings (adjusted OR 3.1, 4.0 and 9.5, respectively). Of the decedents, 43.8% were prescribed a higher methadone dose than recommended (>120 mg daily), of which 80.0% did not have supervised intake of methadone. CONCLUSIONS: Liberal OMT access does not necessarily prevent overdose deaths overall. Prescription of higher doses of methadone combined with benzodiazepines may result in an increased risk of overdose for individuals in as well as outside OMT. PMID- 27246838 TI - Jumonji AT-rich interactive domain 1B overexpression is associated with the development and progression of glioma. AB - Previous studies have suggested that jumonji AT-rich interactive domain 1B (JARID1B) plays an important role in the genesis of some types of cancer, and it is therefore considered to be an important drug target protein. Although the expression of JARID1B has been researched in some types of cancer, little is known about JARID1B expression in glioma and its function in the tumorigenesis of gliomas. In the present study, we examined the expression of JARID1B in glioma. In addition, RT-PCR, western blot analysis and immunohistochemical analysis were performed using glioma tissue samples and the results revealed that JARID1B expression increased according to the histological grade of glioma. However, in the normal brain tissue samples JARID1B expression was barely detected. Kaplan Meier analysis revealed that higher JARID1B expression in patients with glioma was associated with a poorer prognosis. The overexpression of JARID1B stimulated the proliferation and migration of glioma cells as well as sphere formation, whereas suppressing the expression of JARID1B produced opposite effects. The overexpression of JARID1B increased the tumorigenicity of glioma cells in vivo in a nude mouse xenograft model of glioma. Moreover, the activation of phosphorylated (p-)Smad2 contributes to JARID1B-induced oncogenic activities. These findings suggest that JARID1B is involved in the pathogenesis of glioma, and that the downregulation of JARID1B in glioma cells may be a therapeutic target for the treatment of patients with glioma. PMID- 27246840 TI - National Registry of Cardiac Rehabilitation Programs in Mexico II (RENAPREC II). AB - OBJECTIVE: The aim of this paper is to compare the state of Cardiac Rehabilitation Programs (CRP) in 2009 with 2015. Focus is directed on health care, training of health-providers, research, and the barriers to their implementation. METHODS: All authors of RENAPREC-2009, and other cardiac rehabilitation leaders in Mexico were requested to participate. These centres were distributed into two groups: RENAPREC-2009 centres that participated in 2015, and the new CRP units. RESULTS: In 2009 there were 14 centres, two of which disappeared and another two did not respond. CRP-units increased by 71% (n=24), and their geographic distribution shows a centripetal pattern. The coverage of CRP-units was 0.02 centres per 100,000 inhabitants. Only 4.4% of eligible patients were referred to CRP, with a rate of 10.4 patients/100,000 inhabitants in 2015. The ratio of Clinical Cardiologists to Cardiac Rehabilitation Specialists was 94:1, and the ratio of Intervention Specialists to cardiac rehabilitation experts was 16:1. Cardiac rehabilitation activities and costs varied widely. Patient dropout rate in phase II was 12%. Several barriers were identified: financial crisis (83%), lack of skilled personnel (67%), deficient equipment (46%), inadequate areas (42%), and a reduced number of operating centres (38%). CONCLUSIONS: CRPs in Mexico are still in the process of maturing. Mexican CRP-centres have several strengths, like the quality of the education of the professionals and the multidisciplinary programs. However, the lack of referral of patients and the heterogeneity of procedures are still their main weaknesses. PMID- 27246841 TI - [Prevalence of atrial fibrillation and predictors of its occurrence in patients with dual-chamber pacemakers]. AB - OBJECTIVES: To assess the prevalence of atrial fibrillation (AF) in patients with dual-chamber pacemakers (DP), determine the variables associated with development of AF and evaluate the changes in AF's management by physicians. METHODS: Five hundred patients with DP were prospectively included and interrogated. When AF was detected physicians in charge of the patient were warned. Changes in AF's management were evaluated. RESULTS: Mean age of the study population was 77 years, with 51% of men. AF was detected in 13.2% of patients. These findings led treatment changes in 64.7%. The variables analyzed by logistic regression model which were associated with the occurrence of AF were: arterial hypertension (OR=2.62; CI 95% 1.01-6.8; P<.048), history of AF (OR=4.30; CI 95% 2.26-8.32; P<.001), sick sinus syndrome as cause of device implantation (OR=2.09; CI 95% 1.09-3.97; P<.025) and burden of supraventricular extrasystoles series(OR= 1.000033 per serie; CI 95% 0.000011-0.000055; P<.003.). CONCLUSION: We have detected a high prevalence of AF in patients with DP. The diagnose of AF led to change in treatment. Four clinical variables increase the likelihood of developing this arrhythmia. PMID- 27246847 TI - Antimicrobial prophylaxis for transrectal ultrasound-guided prostate biopsy: fosfomycin trometamol, an attractive alternative. AB - OBJECTIVE: To compare fosfomycin trometamol (FT) and ciprofloxacin (CIP) for antibiotic prophylaxis in transrectal prostate biopsy (TR-PB). PATIENTS AND METHODS: Data for 1109 patients (mean age 66.7 +/- 8.45) who underwent TR-PB between March to September 2015 in seven Italian urological institutions were retrospectively reviewed, of which 632 received FT (Group 1) and 477 received CIP (Group 2) for prophylaxis. We reviewed all urine culture results obtained after the procedure, all adverse drug reactions (ADRs) related to the drug and all febrile and/or symptomatic urinary tract infections (UTIs) occurring within 1 month after TR-PB. The rate of symptomatic UTIs and the rate of ADRs were considered the main outcome measures. RESULTS: In the total study population, 72/1109 (6.5 %) patients experienced symptomatic UTIs and among these 11 (0.9 % of total) had urosepsis. Out of 72, 53 (73.6 %) symptomatic UTIs were caused by fluoroquinolone-resistant strains. Out of 632, 10 (1.6 %) patients in Group 1 and 62/477 (12.9 %) patients in Group 2 had symptomatic UTIs (p < 0.001); in particular, 2/632 (0.3 %) patients in Group 1 and 9/477 (1.8 %) patients in Group 2 had urosepsis (p < 0.001). No differences were reported in terms of adverse events (0.6 vs 0.4 %; p = 0.70). A Charlson comorbidity index <=1 and type of antimicrobial prophylaxis (FT) were found to be associated with a lower probability of symptomatic UTIs in the multivariate model. CONCLUSIONS: Antibiotic prophylaxis with FT for TR-PB had a lower rate of adverse events and a lower rate of symptomatic UTIs as compared with CIP. Fosfomycin trometamol appears as an attractive alternative prophylactic regimen in prostate biopsies. PMID- 27246848 TI - Clinical characterisation and phylogeny of respiratory syncytial virus infection in hospitalised children at Red Cross War Memorial Children's Hospital, Cape Town. AB - BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in young children in both the community and hospital setting. METHODS: The clinical presentation, patient and phylogenetic characteristicsof laboratory-confirmed cases of RSV, as well as risk factors for nosocomial infectionat Red Cross War Memorial Children's Hospital in Cape Town were analysed. A multiplex PCR assay that detects 7 respiratory viruses was used to identify RSV nucleic acid on respiratory specimens. RESULTS: A total of 226 children were studied, ages ranging between 1 week and 92.5 months (median: 2.8 months, IQR: 1.3-6.3 months) and 51.8 % were males. The median duration of symptoms prior to diagnosis was 2 days (IQR: 1-4 days). Nosocomial infections wereidentified in 22 (9.7 %) children. There were pre-existing medical conditions in 113 (50.0 %) excluding HIV, most commonly prematurity (n = 58, 50.0 %) and congenital heart disease (n = 34, 29.3 %). The commonest presenting symptoms were cough (196, 86.7 %), difficulty in breathing (115, 50.9 %) and fever (91, 41.6 %).A case fatality rate of 0.9 % was recorded. RSV group A predominated (n = 181, 80.1 %) while group B accounted for only 45 (19.9 %) of the infections. The prevalent genotypes were NA1 (n = 127,70.1 %), ON1 (n = 45,24.9 %) and NA2 (n = 9,5.0 %) for group A while the only circulating RSV B genotype was BA4. There was no significant difference in the genotype distribution between the nosocomial and community-acquired RSV infections. Age >= 6 months was independently associated with nosocomial infection. CONCLUSIONS: A large percentage of children with RSV infection had pre-existing conditions. Approximately one tenth of the infections were nosocomial with age 6 months or older being a risk factor. Though both RSV groups co-circulated during the season, group A was predominant and included the novel ON1 genotype. Continued surveillance is necessary to identify prevalent and newly emerging genotypes ahead of vaccine development and efficacy studies. PMID- 27246849 TI - MYB Promotes Desmoplasia in Pancreatic Cancer through Direct Transcriptional Up regulation and Cooperative Action of Sonic Hedgehog and Adrenomedullin. AB - Extensive desmoplasia is a prominent pathological characteristic of pancreatic cancer (PC) that not only impacts tumor development, but therapeutic outcome as well. Recently, we demonstrated a novel role of MYB, an oncogenic transcription factor, in PC growth and metastasis. Here we studied its effect on pancreatic tumor histopathology and associated molecular and biological mechanisms. Tumor xenografts derived from orthotopic-inoculation of MYB-overexpressing PC cells exhibited far-greater desmoplasia in histological analyses compared with those derived from MYB-silenced PC cells. These findings were further confirmed by immunostaining of tumor-xenograft sections with collagen-I, fibronectin (major extracellular-matrix proteins), and alpha-SMA (well-characterized marker of myofibroblasts or activated pancreatic stellate cells (PSCs)). Likewise, MYB overexpressing PC cells provided significantly greater growth benefit to PSCs in a co-culture system as compared with the MYB-silenced cells. Interrogation of deep-sequencing data from MYB-overexpressing versus -silenced PC cells identified Sonic-hedgehog (SHH) and Adrenomedullin (ADM) as two differentially-expressed genes among others, which encode for secretory ligands involved in tumor-stromal cross-talk. In-silico analyses predicted putative MYB-binding sites in SHH and ADM promoters, which was later confirmed by chromatin-immunoprecipitation. A cooperative role of SHH and ADM in growth promotion of PSCs was confirmed in co culture by using their specific-inhibitors and exogenous recombinant-proteins. Importantly, while SHH acted exclusively in a paracrine fashion on PSCs and influenced the growth of PC cells only indirectly, ADM could directly impact the growth of both PC cells and PSCs. In summary, we identified MYB as novel regulator of pancreatic tumor desmoplasia, which is suggestive of its diverse roles in PC pathobiology. PMID- 27246850 TI - The Clustered, Regularly Interspaced, Short Palindromic Repeats-associated Endonuclease 9 (CRISPR/Cas9)-created MDM2 T309G Mutation Enhances Vitreous induced Expression of MDM2 and Proliferation and Survival of Cells. AB - The G309 allele of SNPs in the mouse double minute (MDM2) promoter locus is associated with a higher risk of cancer and proliferative vitreoretinopathy (PVR), but whether SNP G309 contributes to the pathogenesis of PVR is to date unknown. The clustered regularly interspaced short palindromic repeats (CRISPR) associated endonuclease (Cas) 9 from Streptococcus pyogenes (SpCas9) can be harnessed to manipulate a single or multiple nucleotides in mammalian cells. Here we delivered SpCas9 and guide RNAs using dual adeno-associated virus-derived vectors to target the MDM2 genomic locus together with a homologous repair template for creating the mutation of MDM2 T309G in human primary retinal pigment epithelial (hPRPE) cells whose genotype is MDM2 T309T. The next-generation sequencing results indicated that there was 42.51% MDM2 G309 in the edited hPRPE cells using adeno-associated viral CRISPR/Cas9. Our data showed that vitreous induced an increase in MDM2 and subsequent attenuation of p53 expression in MDM2 T309G hPRPE cells. Furthermore, our experimental results demonstrated that MDM2 T309G in hPRPE cells enhanced vitreous-induced cell proliferation and survival, suggesting that this SNP contributes to the pathogenesis of PVR. PMID- 27246851 TI - Characterization of Eicosanoids Produced by Adipocyte Lipolysis: IMPLICATION OF CYCLOOXYGENASE-2 IN ADIPOSE INFLAMMATION. AB - Excessive adipocyte lipolysis generates lipid mediators and triggers inflammation in adipose tissue. However, the specific roles of lipolysis-generated mediators in adipose inflammation remain to be elucidated. In the present study, cultured 3T3-L1 adipocytes were treated with isoproterenol to activate lipolysis and the fatty acyl lipidome of released lipids was determined by using LC-MS/MS. We observed that beta-adrenergic activation elevated levels of approximately fifty lipid species, including metabolites of cyclooxygenases, lipoxygenases, epoxygenases, and other sources. Moreover, we found that beta-adrenergic activation induced cyclooxygenase 2 (COX-2), not COX-1, expression in a manner that depended on activation of hormone-sensitive lipase (HSL) in cultured adipocytes and in the epididymal white adipose tissue (EWAT) of C57BL/6 mice. We found that lipolysis activates the JNK/NFkappaB signaling pathway and inhibition of the JNK/NFkappaB axis abrogated the lipolysis-stimulated COX-2 expression. In addition, pharmacological inhibition of COX-2 activity diminished levels of COX-2 metabolites during lipolytic activation. Inhibition of COX-2 abrogated the induction of CCL2/MCP-1 expression by beta-adrenergic activation and prevented recruitment of macrophage/monocyte to adipose tissue. Collectively, our data indicate that excessive adipocyte lipolysis activates the JNK/NFkappaB pathway leading to the up-regulation of COX-2 expression and recruitment of inflammatory macrophages. PMID- 27246852 TI - Molecular Mechanism of Z alpha1-Antitrypsin Deficiency. AB - The Z mutation (E342K) of alpha1-antitrypsin (alpha1-AT), carried by 4% of Northern Europeans, predisposes to early onset of emphysema due to decreased functional alpha1-AT in the lung and to liver cirrhosis due to accumulation of polymers in hepatocytes. However, it remains unclear why the Z mutation causes intracellular polymerization of nascent Z alpha1-AT and why 15% of the expressed Z alpha1-AT is secreted into circulation as functional, but polymerogenic, monomers. Here, we solve the crystal structure of the Z-monomer and have engineered replacements to assess the conformational role of residue Glu-342 in alpha1-AT. The results reveal that Z alpha1-AT has a labile strand 5 of the central beta-sheet A (s5A) with a consequent equilibrium between a native inhibitory conformation, as in its crystal structure here, and an aberrant conformation with s5A only partially incorporated into the central beta-sheet. This aberrant conformation, induced by the loss of interactions from the Glu-342 side chain, explains why Z alpha1-AT is prone to polymerization and readily binds to a 6-mer peptide, and it supports that annealing of s5A into the central beta sheet is a crucial step in the serpins' metastable conformational formation. The demonstration that the aberrant conformation can be rectified through stabilization of the labile s5A by binding of a small molecule opens a potential therapeutic approach for Z alpha1-AT deficiency. PMID- 27246853 TI - Protein-Protein Interactions, Not Substrate Recognition, Dominate the Turnover of Chimeric Assembly Line Polyketide Synthases. AB - The potential for recombining intact polyketide synthase (PKS) modules has been extensively explored. Both enzyme-substrate and protein-protein interactions influence chimeric PKS activity, but their relative contributions are unclear. We now address this issue by studying a library of 11 bimodular and 8 trimodular chimeric PKSs harboring modules from the erythromycin, rifamycin, and rapamycin synthases. Although many chimeras yielded detectable products, nearly all had specific activities below 10% of the reference natural PKSs. Analysis of selected bimodular chimeras, each with the same upstream module, revealed that turnover correlated with the efficiency of intermodular chain translocation. Mutation of the acyl carrier protein (ACP) domain of the upstream module in one chimera at a residue predicted to influence ketosynthase-ACP recognition led to improved turnover. In contrast, replacement of the ketoreductase domain of the upstream module by a paralog that produced the enantiomeric ACP-bound diketide caused no changes in processing rates for each of six heterologous downstream modules compared with those of the native diketide. Taken together, these results demonstrate that protein-protein interactions play a larger role than enzyme substrate recognition in the evolution or design of catalytically efficient chimeric PKSs. PMID- 27246854 TI - Molecular Basis of the Interaction of the Human Protein Tyrosine Phosphatase Non receptor Type 4 (PTPN4) with the Mitogen-activated Protein Kinase p38gamma. AB - The human protein tyrosine phosphatase non-receptor type 4 (PTPN4) prevents cell death induction in neuroblastoma and glioblastoma cell lines in a PDZ.PDZ binding motifs-dependent manner, but the cellular partners of PTPN4 involved in cell protection are unknown. Here, we described the mitogen-activated protein kinase p38gamma as a cellular partner of PTPN4. The main contribution to the p38gamma.PTPN4 complex formation is the tight interaction between the C terminus of p38gamma and the PDZ domain of PTPN4. We solved the crystal structure of the PDZ domain of PTPN4 bound to the p38gamma C terminus. We identified the molecular basis of recognition of the C-terminal sequence of p38gamma that displays the highest affinity among all endogenous partners of PTPN4. We showed that the p38gamma C terminus is also an efficient inducer of cell death after its intracellular delivery. In addition to recruiting the kinase, the binding of the C-terminal sequence of p38gamma to PTPN4 abolishes the catalytic autoinhibition of PTPN4 and thus activates the phosphatase, which can efficiently dephosphorylate the activation loop of p38gamma. We presume that the p38gamma.PTPN4 interaction promotes cellular signaling, preventing cell death induction. PMID- 27246855 TI - The CaMKII/GluN2B Protein Interaction Maintains Synaptic Strength. AB - Learning, memory, and cognition are thought to require normal long-term potentiation (LTP) of synaptic strength, which in turn requires binding of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) to the NMDA-type glutamate receptor (NMDAR) subunit GluN2B. For LTP induction, many additional required players are known. Here we tested the hypothesis that CaMKII/GluN2B binding also mediates the more elusive maintenance of synaptic strength. Intriguingly, the CaMKII inhibitor tatCN21 reduces synaptic strength only at high concentrations necessary for CaMKII/NMDAR disruption (20 MUm) but not at lower concentrations sufficient for kinase inhibition (5 MUm). However, increased concentration also causes unrelated effects. Thus, to distinguish between correlation and causality, we used a pharmacogenetic approach. In a mouse with a mutant NMDAR GluN2B subunit that is CaMKII binding-incompetent, any tatCN21 effects that are specific to the CaMKII/GluN2B interaction should be abolished, and any remaining tatCN21 effects have to be nonspecific (i.e. mediated by other targets). The results showed that the persistent reduction of synaptic strength by transient application of 20 MUm tatCN21 had a nonspecific presynaptic component (on fiber volley amplitude) that was unrelated to the CaMKII/GluN2B interaction or CaMKII activity. However, the remaining component of the persistent tatCN21 effect was almost completely abolished in the GluN2B mutant mouse. These results highlight the requirement for stringent pharmacogenetic approaches to separate specific on-target effects from nonspecific off-target effects. Importantly, they also demonstrate that the CaMKII/GluN2B interaction is required not only for normal LTP induction but also for the maintenance of synaptic strength. PMID- 27246856 TI - Tetrodecamycin: An unusual and interesting tetronate antibiotic. AB - The tetrodecamycins are a group of secondary metabolites that are characterized by the presence of a tetronate ring in their structure. Originally discovered for their antibiotic activity against Photobacterium damselae ssp. piscicida, the causative agent of pseudotuberculosis in fish, this family of molecules has also been shown to have potent antibiotic activity against methicillin-resistant Staphylococcus aureus. Due to their small size and highly cyclized nature, they represent an unusual member of the much larger group of bioactive molecules called the tetronates. Herein, we review what is known about the mechanism of action of these molecules and also present a hypothesis for their biosynthesis. A deeper understanding of the tetrodecamycins will provide a more holistic view of the tetronate-family, provide new chemical probes of bacterial biology, and may provide therapeutic lead molecules. PMID- 27246857 TI - Identification, characterization, kinetics, and molecular docking of flavonoid constituents from Archidendron clypearia (Jack.) Nielsen leaves and twigs. AB - In our search for natural soluble epoxide hydrolase (sEH) inhibitors from plants, we found that the methanolic extract of the leaves and twigs of Archidendron clypearia (Jack.) Nielsen (Fabaceae) significantly inhibits sEH in vitro. In a phytochemical investigation of the water layer of A. clypearia, we isolated two new chalcones, clypesides A-B (1-2), 13 flavonoid derivatives (3-15) and established their structures based on an extensive 1D and 2D NMR, CD data, and MS analysis. All of the flavonoid derivatives inhibited sEH enzymatic activity in a dose-dependent manner, with IC50 values ranging from 10.0+/-0.4 to 30.1+/-2.1MUM. A kinetic analysis of compounds 4, 8-10, 12, 13, and 15 revealed that the compounds 8-10 were non-competitive, 4, 13, and 15 were mixed-type, and 12 was competitive inhibitors. Additionally, molecular docking increased our understanding of their receptor-ligand binding. These results demonstrated that flavonoid derivatives from A. clypearia are potential sEH inhibitors. PMID- 27246858 TI - Extended rhodamine photosensitizers for photodynamic therapy of cancer cells. AB - Extended thio- and selenorhodamines with a linear or angular fused benzo group were prepared. The absorption maxima for these compounds fell between 640 and 700nm. The extended rhodamines were evaluated for their potential as photosensitizers for photodynamic therapy in Colo-26 cells. These compounds were examined for their photophysical properties (absorption, fluorescence, and ability to generate singlet oxygen), for their dark and phototoxicity toward Colo 26 cells, and for their co-localization with mitochondrial-specific agents in Colo-26 and HUT-78 cells. The angular extended rhodamines were effective photosensitizers toward Colo-26 cells with 1.0Jcm(-2) laser light delivered at lambdamax+/-2nm with values of EC50 of (2.8+/-0.4)*10(-7)M for sulfur-containing analogue 6-S and (6.4+/-0.4)*10(-8)M for selenium-containing analogue 6-Se. The linear extended rhodamines were effective photosensitizers toward Colo-26 cells with 5 and 10Jcm(-2) of broad-band light (EC50's?2.4*10(-7)M). PMID- 27246859 TI - Structure-activity relationship of lipid core peptide-based Group A Streptococcus vaccine candidates. AB - Infection with Group A Streptococcus (GAS) can result in a range of different illnesses, some of which are fatal. Currently, our efforts to develop a vaccine against GAS focuses on the lipid core peptide (LCP) system, a subunit vaccine containing a lipoamino acid (LAA) moiety which allows the stimulation of systemic antibody activity. In the present study, a peptide (J14) representing the B-cell epitope from the GAS M protein was incorporated alongside a universal T-helper epitope (P25) in four LCP constructs of different spatial orientation or LAA lengths. Through structure-activity studies, it was discovered that while the alteration of the LCP orientation had a weaker effect on immunostimulation, increasing the LAA side chain length within the construct increased antibody responses in murine models. Furthermore, the mice immunised with the lead LCP construct were also able to maintain antibody activity throughout the course of five months. These findings highlight the importance of LAA moieties in the development of intranasal peptide vaccines and confirmed that its side chain length has an effect on the immunogenicity of the structure. PMID- 27246860 TI - The Impact of Obsessive Compulsive Personality Disorder on Cognitive Behaviour Therapy for Obsessive Compulsive Disorder. AB - BACKGROUND: It is often suggested that, in general, co-morbid personality disorders are likely to interfere with CBT based treatment of Axis I disorders, given that personality disorders are regarded as dispositional and are therefore considered less amenable to change than axis I psychiatric disorders. AIMS: The present study aimed to investigate the impact of co-occurring obsessive compulsive disorder (OCD) and obsessive-compulsive personality disorder (OCPD) on cognitive-behavioural treatment for OCD. METHOD: 92 individuals with a diagnosis of OCD participated in this study. Data were drawn from measures taken at initial assessment and following cognitive-behavioural treatment at a specialist treatment centre for anxiety disorders. RESULTS: At assessment, participants with OCD and OCPD had greater overall OCD symptom severity, as well as doubting, ordering and hoarding symptoms relative to those without OCPD; however, participants with co-morbid OCD and OCPD demonstrated greater treatment gains in terms of OCD severity, checking and ordering than those without OCPD. Individuals with OCD and OCPD had higher levels of checking, ordering and overall OCD severity at initial assessment; however, at post-treatment they had similar scores to those without OCPD. CONCLUSION: The implications of these findings are discussed in the light of research on axis I and II co-morbidity and the impact of axis II disorders on treatment for axis I disorders. PMID- 27246861 TI - [Reconstruction of the Bile Duct with the Umbilical Vein after Laparoscopic Cholecystectomy]. AB - Background: Roux-Y hepaticojejunostomy is currently the standard surgical procedure for the reconstruction of the bile duct after iatrogenic transection in laparoscopic cholecystectomy. However, about 30 % of all hepaticojejunostomies develop a stenosis after some time and in 7 % a cholangiocellular carcinoma occurs. Therefore, alternative procedures have been investigated. Patients: Between September 2009 and October 2013 an iatrogenic bile duct lesion was treated in 6 consecutive patients by using the pedicled umbilical vein. The median follow-up period was 16 months. Methods: In 3 cases, the bile duct lesion was detected during cholecystectomy and reconstructed in the same session. In the other 3 cases, the reconstruction was performed between the fourth and the seventh day after cholecystectomy. The pedicled umbilical vein was used as a patch in 4 cases and as an interposition graft in the other 2 cases. Results: Two out of 6 patients suffered from cholangitis after bile duct reconstruction, which was brought to complete remission by temporary endoscopic dilatation treatment. Conclusion: The use of the pedicled umbilical vein is a new surgical option for the treatment of iatrogenic bile duct lesions and seems to provide advantages over hepaticojejunostomy regarding the development and treatment of anastomotic stenosis and the risk of cholangiocellular carcinoma. PMID- 27246862 TI - [Should we use hip-ankle radiographs to assess the coronal alignment after total knee arthroplasty?]. AB - BACKGROUND: There is no consensus on whether hip-ankle radiographs or rather standardized a-p knee-radiographs should be used to assess implant position and coronal alignment after total knee arthroplasty (TKA). This study investigates whether implant position and alignment after TKA can reproducibly be assessed using a-p knee-radiographs rather than hip-ankle radiographs. MATERIALS AND METHODS: This study was performed on 100 weight-bearing hip-ankle radiographs after conventional primary TKA. The true mechanical and anatomical femorotibial angle as well as coronal implant position was assessed on hip-ankle radiographs. The radiographs were then cropped to 80, 60 and 40 % of the leg-length and tibial coronal implant position, and the anatomical axis and a surrogate mechanical axis were obtained. The difference in the alignment parameters between the hip-ankle radiographs were statistically compared with the cropped radiographs and the inter-observer correlation coefficient (ICC) was calculated. RESULTS: The ICC for measurement of the mechanical femorotibial angle was higher in hip-ankle radiographs (0.95) when compared with a radiograph cropped to 40 % (0.61). There was a significant difference in the mechanical femorotibial angle between hip ankle radiographs and any cropped radiograph. However, there were no significant differences in coronal implant position and the anatomical femorotibial angle between hip-ankle radiographs and any cropped radiograph. CONCLUSIONS: We conclude that standard a-p knee-radiographs are insufficient to assess the mechanical alignment following TKA. However, standard a-p knee-radiographs are appropriate to assess the implant position when referenced against the anatomical axes. Weight-bearing hip-ankle radiographs should be questioned as a routine after TKA. PMID- 27246863 TI - [Intertrochanteric femoral osteotomy : Indications, surgical technique, results]. AB - BACKGROUND: Intertrochanteric osteotomies are part of joint-preserving hip surgery. Indications involve not only the mature but also the growing skeleton. After identification of the causative pathologies multidimensional corrections with the aim of a better joint situation and prevention of early osteoarthritis are possible. METHODS: The surgical technique of intertrochanteric osteotomies is presented. Potential indications are discussed on the basis of results in the literature. RESULTS: In the surgical treatment of developmental dysplasia of the hip intertrochanteric osteotomies are used as additional surgery. In Perthes disease the containment is improved while the onset of osteoarthritis in epiphysis capitis femoris can be decelerated. Treatment of torsion pathologies is reliable. Avascular necrosis of the femoral head and beginning osteoarthritis are critical indications. CONCLUSION: For appropriate indications intertrochanteric osteotomies are a valuable element in joint-preserving surgery with very good long-term results. PMID- 27246864 TI - The high osteotomy cut of Dega procedure for developmental dysplasia of the hip in children under 6 years of age. AB - BACKGROUND: Dega osteotomy has gained popularity for the acetabular reconstruction of developmental dysplasia of the hip (DDH). A high-level Dega osteotomy combining the typical Dega procedure with an age limit of under 6 years and the higher pelvic cut height of the Salter osteotomy for walking DDH patients aged 6 or younger was advocated in our department. The purpose of this retrospective study is to introduce this modified Dega procedure and report the preliminary clinical and radiological results in DDH patients under 6. MATERIALS AND METHODS: From September 2000 to September 2010, a total of 162 patients with 191 dysplastic hips between 1.5 and 6 years old were managed with this high-level Dega osteotomy. From each patient's record, clinical status was retrospectively assessed using modified McKay criteria; radiological evaluations were assessed according to the modified Severin classification, the mean acetabular index (AI), Sharp angle and center-edge (CE) angle. Any occurrence of complications was recorded postoperatively. RESULTS: The average age at surgery was 3.6 years (range 1.5 to 6.0), mean duration of follow-up 11.3 years (range 5.0 to 16.9). The latest follow-up fineness (favorable and good) rate in clinical and radiological evaluations was 92.7 % and 91.1 % respectively. There was a marked trend toward normalization of radiographic indices during the follow-up period: the mean AI changed from 38.0 degrees to 20.8 degrees , the mean Sharp's angle decreased from 59.9 degrees to 39.2 degrees , and the mean CE angle increased from -10.7 degrees to 29.4 degrees , preoperatively and at the latest follow-up respectively. No major complications were recorded during follow-up. CONCLUSION: The high osteotomy cut Dega procedure for patients between 1.5 and 6 years of age was found to be sufficient for improving clinical and radiographic outcomes and inducing little morbidity and few complications for late-detected pediatric walking DDH patients. PMID- 27246865 TI - Building Motivation in African American Caregivers of Adolescents With Obesity: Application of Sequential Analysis. AB - Objective: We sought to examine communication between counselors and caregivers of adolescents with obesity to determine what types of counselor behaviors increased caregivers' motivational statements regarding supporting their child's weight loss. Methods: We coded 20-min Motivational Interviewing sessions with 37 caregivers of African American 12-16-year-olds using the Minority Youth Sequential Coding for Observing Process Exchanges. We used sequential analysis to determine which counselor communication codes predicted caregiver motivational statements. Results: Counselors' questions to elicit motivational statements and emphasis on autonomy increased the likelihood of both caregiver change talk and commitment language statements. Counselors' reflections of change talk predicted further change talk, and reflections of commitment language predicted more commitment language. Conclusions: When working to increase motivation among caregivers of adolescents with overweight or obesity, providers should strive to reflect motivational statements, ask questions to elicit motivational statements, and emphasize caregivers' autonomy. PMID- 27246867 TI - Neighborhood, Family and Peer-Level Predictors of Obesity-Related Health Behaviors Among Young Adolescents. AB - Objective: This longitudinal study examines peer social functioning (PSF), familism, and neighborhood socioeconomic status (NSES) on adolescents' obesity risk. Methods: Participants ( N = 2,144) were originally sampled from 16 middle schools in Southern California (45% male; 45% Hispanic) as part of an alcohol and other drug use prevention program (CHOICE). Multilevel regression modeling tested main effects and interaction terms of PSF, familism, and NSES assessed at Wave 5 ( M age = 14.15) on body mass index and risk of obesity-related behaviors at Wave 6. Results: Higher PSF predicted healthier eating habits, less screen time, and more physical activity. Higher familism also predicted more physical activity. The positive effect of PSF on healthy eating was stronger among youth who reported higher familism. PSF also moderated the associations of NSES with healthy eating and physical activity. Conclusion: Findings emphasize the importance of targeting both peer and family factors, which may be more amenable to change than NSES. PMID- 27246868 TI - A qualitative appraisal of stakeholder reactions to a tool for burden of disease based health system budgeting in Ghana. AB - BACKGROUND: In 2010, the Ghana Health Service launched a program of cooperation with the Tanzania Ministry of Health and Social Welfare that was designed to adapt Tanzania's PLANREP budgeting and reporting tool to Ghana's primary health care program. The product of this collaboration is a system of budgeting, data visualization, and reporting that is known as the District Health Planning and Reporting Tool (DiHPART). OBJECTIVE: This study was conducted to evaluate the design and implementation processes (technical, procedures, feedback, maintenance, and monitoring) of the DiHPART tool in northern Ghana. DESIGN: This paper reports on a qualitative appraisal of user reactions to the DiHPART system and implications of pilot experience for national scale-up. A total of 20 health officials responsible for financial planning operations were drawn from the national, regional, and district levels of the health system and interviewed in open-ended discussions about their reactions to DiHPART and suggestions for systems development. RESULTS: The findings show that technical shortcomings merit correction before scale-up can proceed. The review makes note of features of the software system that could be developed, based on experience gained from the pilot. Changes in the national system of financial reporting and budgeting complicate DiHPART utilization. This attests to the importance of pursuing a software application framework that anticipates the need for automated software generation. CONCLUSIONS: Despite challenges encountered in the pilot, the results lend support to the notion that evidence-based budgeting merits development and implementation in Ghana. PMID- 27246869 TI - Accuracy of PlusOptix A09 distance refraction in pediatric myopia and hyperopia. AB - BACKGROUND: The PlusOptix photoscreeners (PlusOptix GmbH, Nuremberg, Germany) is used in many vision screening programs. The purpose of the present study was to further explore the accuracy of the PlusOptix A09 photoscreener in children with ametropia (myopia or hyperopia). METHODS: A total of 70 eyes (35 children) were prospectively included. Before administration with the cycloplegia treatment 1 % cyclopentolate hydrochloride, children underwent refraction measurement with the PlusOptix A09. A refraction was then performed after cycloplegia with either Retinomax hand-held or Nidek autorefractor before and after 3 years old, respectively. RESULTS: The median (interquartile range) age was 58 (18 to 86) months. The mean (SD) spherical equivalent differed between PlusOptix A09 and cycloplegic autorefraction (+0.54 [1.82] D vs +1.06 [2.04] D, p = 0.04). PlusOptix A09 refraction was positively correlated with cycloplegic autorefraction (r = 0.81, p < 0.001) with higher coefficient in myopic than in hyperopic children (r = 0.91, p = 0.0002 and r = 0.52, p = 0.01, respectively). The mean (SD) difference between PlusOptix A09 and cycloplegic autorefraction was higher with hyperopia than myopia (0.73 [1.34] vs 0.05 [0.66], p = 0.01). The proportion of children with < 1-D difference between cycloplegic and PlusOptix A09 refraction was 68.8 %, higher with myopia than hyperopia (90 % vs 54.5 %, p = 0.01). CONCLUSION: The spherical equivalent value with non-cycloplegic PlusOptix A09 refraction is closer to that with cycloplegic autorefraction than non cycloplegic autorefraction. The PlusOptix A09 photoscreener underestimated the hyperopia of 0.73 D and slightly overestimated myopia of 0.05 D. The PlusOptix A09 could be used for screening with higher accuracy in myopic than hyperopic children. PMID- 27246870 TI - Assessment of seminal mast cells in infertile men with varicocele after surgical repair. AB - This study aimed to assess seminal mast cells in infertile men associated with varicocele (Vx) pre- and post-surgical repair. Forty-five infertile men associated with Vx were subjected to history taking and clinical examination. In addition, semen parameters and seminal mast cells stained with 1% toluidine blue were estimated pre-varicocelectomy and three months post-varicocelectomy. Vx surgical repair revealed a significant improvement in the mean sperm concentration, progressive sperm motility, total sperm motility and sperm abnormal morphology and a significant decrement in seminal mast cells (mean +/- SD, 3.56 +/- 2.23 cells per high-power field (HPF) vs. 2.22 +/- 1.06 cells per HPF, p = .01). The pre-operative mean mast cell count demonstrated significant increases in cases with Vx grade III compared with other Vx grades and in cases with bilateral Vx compared with unilateral Vx cases. Seminal mast cells demonstrated a significant correlation with sperm concentration, progressive sperm motility and total sperm motility and a nonsignificant correlation with age and sperm abnormal morphology. It is concluded that seminal mast cells decrease significantly in infertile men with Vx after surgical repair showing a significant negative correlation with sperm concentration, progressive sperm motility and total sperm motility. PMID- 27246871 TI - Association between serum bile acid profiles and gestational diabetes mellitus: A targeted metabolomics study. AB - BACKGROUND: Given the potential influence of aberrant bile acid metabolism on glucose homeostasis, we hypothesized that serum bile acid metabolism is altered in gestational diabetes mellitus (GDM). We characterized the metabolic profiling changes of serum bile acids in GDM and to find the potential biomarkers for the diagnosis and differential diagnosis of GDM. METHODS: Based on ultrahigh performance liquid chromatography/hybrid quadrupole time-of-flight mass spectrometry, a targeted metabolomics study that involved targeted and untargeted screening techniques was performed to explore the changes in serum bile acid metabolism of GDM cases, intrahepatic cholestasis of pregnancy (ICP) cases and healthy controls. RESULTS: There were 3 significantly different profiling of serum bile acids for GDM, ICP and controls. Compared to the controls, GDM individuals demonstrated significant increases in 8 bile acid species, including 2 dihydroxy conjugated, 1 trihydroxy unconjugated and 5 sulfated bile acids. beta muricholic acid (beta-MCA) and di-2 were well-suited to use as the metabolic markers for the diagnosis and differential diagnosis of GDM, respectively. CONCLUSIONS: These preliminary findings revealed the protective effect of body against cytotoxicity via elimination of increased sulfated bile acids and aberrant enzyme activity participated in the cycle beta-MCA->hyodeoxycholic acid (HDCA) of the bile acid metabolism pathway for the women with GDM, which gave us further insights into the etiology and pathophysiology of GDM. PMID- 27246872 TI - Novel anionic polymer as a carrier for CNS delivery of anti-Alzheimer drug. AB - Natural and plant-based polymers could be used for control release of drugs and also helps in targeting drug to the site of action. The main objective of present work was to check the feasibility of plant-based, namely, mango gum polymeric nanoparticles (NPs) as a carrier for central nervous system (CNS) delivery using model drug donepezil (DZP). The NPs were prepared by modified ionic gelation method and emulsion cross-linking method. Zeta sizer results showed that the diameter of NPs was about 90-130 nm. The polymeric DZP-loaded NPs were almost spherical in shape, as revealed by transmission electron microscopy (TEM). On increasing concentration of NPs suspension from 50 MUg/ml to 5000 MUg/ml there was no significant increase in % hemolysis. In vivo studies showed that brain targeting was achieved. So on the basis of above results, the extracted water soluble fraction of mango gum is a suitable candidate for brain delivery in the form of nanoformulations. PMID- 27246874 TI - An Air-Stable Na3 SbS4 Superionic Conductor Prepared by a Rapid and Economic Synthetic Procedure. AB - All-solid-state sodium batteries, using solid electrolyte and abundant sodium resources, show great promise for safe, low-cost, and large-scale energy storage applications. The exploration of novel solid electrolytes is critical for the room temperature operation of all-solid-state Na batteries. An ideal solid electrolyte must have high ionic conductivity, hold outstanding chemical and electrochemical stability, and employ low-cost synthetic methods. Achieving the combination of these properties is a grand challenge for the synthesis of sulfide based solid electrolytes. Design of the solid electrolyte Na3 SbS4 is described, realizing excellent air stability and an economic synthesis based on hard and soft acid and base (HSAB) theory. This new solid electrolyte also exhibits a remarkably high ionic conductivity of 1 mS cm(-1) at 25 degrees C and ideal compatibility with a metallic sodium anode. PMID- 27246873 TI - Melittin-MIL-2 fusion protein as a candidate for cancer immunotherapy. AB - BACKGROUND: Cytokine fusion protein that modulates the immune response holds great potential for cancer immunotherapy. IL-2 is an effective treatment against advanced cancers. However, the therapeutic efficacy of IL-2 is limited by severe systemic toxicity. Several mutants recombinant IL-2 can increase antitumor activity and minimize systemic toxicity. Melittin is an attractive anticancer candidate because of its wide-spectrum lytic properties. We previously generated a bifunctional fusion protein melittin-MIL-2, composed of melittin and a mutant IL-2. The melittin-MIL-2 inhibited the growth of human ovarian cancer SKOV3 cells in vitro and in vivo tumor growth. However, whether this antitumor effect could also be used in cancer immunotherapy was unknown. To assess its cancer immunotherapy potential, we further investigated its more effective antitumor immune response and antitumor effect against cancers of different tissue origins in vitro and in vivo. METHODS: The specific IL-2 activity of the melittin-MIL-2 fusion protein was tested on the cytokine growth dependent cell line CTLL-2. The cytolytic activity was detected by standard 4-h (51)Cr-release assays. PBMC stimulation in response to the melittin-MIL-2 was determined by IFN-gamma release assay. We observed the cancer cell proliferation of different tissue origins by MTT assay. The ability of melittin-MIL-2 to inhibit tumor growth in vivo was evaluated by using human liver (SMMC-7721 cancer cells), lung (A549 cancer cells) and ovarian (SKOV3 cancer cells) cancer xenograft models. To assess the immunity within the tumor microenvironment, the level of some cytokines including IFN gamma, TNF-alpha, IL-12 and IL-4 was analyzed by ELISA. We injected the MDA-MB 231 cells and the melittin-MIL-2 into mice, and the anti-metastatic effect was examined by counting nodules in the lung. RESULTS: The melittin-MIL-2 was more effective in inducing T cell and NK-cell cytotoxicity. The fusion protein significantly increased IFN-gamma production in PBMCs. In vitro, the melittin-MIL 2 mediated immune cells killing or directly killed the cancer cell lines of different tissue origins. In vivo, the fusion protein exhibited stronger inhibition on the growth of transplanted human tumors compared to rIL-2. The melittin-MIL-2 treatment promoted the IFN-gamma secretion in tumor tissues and decreased the immunosuppressive cells in vivo. Furthermore, the fusion protein reduced lung metastasis of breast cancer. CONCLUSIONS: This study provides the evidence that the melittin-MIL-2 can produce stronger immune stimulation and antitumor effects, and the fusion protein is a potent candidate for cancer immunotherapy. PMID- 27246875 TI - The vertical posteromedial thigh (vPMT) flap for autologous breast reconstruction: A novel flap design. AB - BACKGROUND: The vertical posteromedial thigh (vPMT) perforator flap is a new reliable flap with versatility. The purpose of this article was to report our experience with the use of free vPMT flap for reconstruction of the breast. PATIENTS AND METHODS: From May 2015 to December 2015, seven patients received immediate unilateral breast reconstruction with seven free vPMT flaps. The flaps were raised based on the first medial perforator of the profunda femoris artery (PFA). The internal mammary artery and vein were dissected as recipient vessels. RESULTS: The flap sizes varied from 25 * 9 cm to 30 * 10 cm. The average weight of the flap and mastectomy specimen was 431 g (range: 390 to 470 g) and 410 g (range: 360 to 450 g) respectively. The average pedicle length was 10.4 cm (range, 8.5 to 12.5 cm) and the average arterial diameter was 2.1 mm (range, 1.8 to 2.6 mm). All of the flaps survived completely after surgery. The donor sites were all primarily closed with minimal morbidities. Follow-up observations were conducted from 3 to 9 months. All of patients were satisfactory with the reconstruction. CONCLUSION: The vertical vPMT is suitable for breast reconstruction in women with small to moderate breast size; the vertical pattern of the PMT avoids some of the problems related to other flaps with transverse patterns and represents an alternative design that can be successfully used for breast reconstruction. (c) 2016 Wiley Periodicals, Inc. Microsurgery 37:371-376, 2017. PMID- 27246876 TI - Primary ovarian carcinoid tumors: effective management of a rare and challenging condition. PMID- 27246877 TI - Assessment of antioxidant, anticancer and antimicrobial activity of two vegetable species of Amaranthus in Bangladesh. AB - BACKGROUND: Amaranthus (Amaranthaceae) has previously been reported to possess different bioactive phytochemicals including phenols, tannins and flavonoids. The current study was designed to evaluate the antioxidant, anti-proliferative and antimicrobial activity of stem and seed extracts of Amaranthus lividus (AL) and Amaranthus hybridus (AH), respectively. METHODS: Antioxidant activity of methanol extract was assessed by DPPH radical scavenging assay. Determination of lectin activity of Amaranthus extract was carried out using hemagglutination assay on mouse blood. A total of thirty six Swiss albino mice containing Ehrlich's ascites carcinoma (EAC) cells were treated with AL and AH extract at 25, 50 and 100 MUg/ml/day/mouse for six days. Growth inhibitory activity was determined by haemocytometer counting of EAC cells using trypan blue dye and DAPI (4?,6 diamidino-2-phenylindole) staining was used to assess apoptotic cells. Gene amplification study was conducted to observe the expression pattern of p53, Bax, Bcl-2 and caspase-3 mRNA using PCR (polymer chain reaction) technique. In vitro susceptibility of five pathogenic bacteria including Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Salmonella typhi and Staphylococcus aureus was detected using disk diffusion assay. RESULTS: The radical scavenging assay indicated that AH and AL possesses potent antioxidant potential, exhibiting IC50 value of 28 +/- 1.5 and 93 +/- 3.23 MUg/ml, respectively. Hemagglutination assay revealed that AH and AL agglutinated mice blood at 1.565 and 3.125 MUg/wall, respectively. Administration of AH and AL extract led to 45 and 43 % growth inhibition of EAC cells, respectively at 100 MUg/ml with marked features of apoptosis including cell shrinkage, condensation of cytoplasm and aggregation of apoptotic bodies etc. Up-regulation of p53, Bax and caspase-3 and down regulation of Bcl-2 mRNA in Amaranthus treated mice indicated mitochondria mediated apoptosis of EAC cells in comparison with control. None of the bacterial species showed susceptibility to the extract of both the Amaranthus species. CONCLUSION: Our current findings suggest that both of the Amaranthus species have strong antioxidant, lectin and anti-proliferative activity on EAC cells. The current anticancer potential was observed due mainly to the mitochondria mediated apoptosis of EAC cells. PMID- 27246878 TI - Competing Priorities: Partner-Specific Relationship Characteristics and Motives for Condom Use Among At-Risk Young Adults. AB - Condoms protect against human immunodeficiency virus (HIV)/sexually transmitted infections (STIs) and unintended pregnancy and are essential to sexual health efforts targeting young adults, who are disproportionately affected by both outcomes. Understanding condom use motives is critical to increasing condom use. Research in this area is limited, particularly regarding the roles of partners and relationship factors. Using a longitudinal sample of 441 young adults and 684 reported partnerships we examined associations between relationship factors and condom use motives (pregnancy prevention, disease prevention, or dual protection). Simultaneous multilevel models identified variables associated with motives; level-specific models identified the levels (individual, partnership, time) variables impacted motives. Participants reported choosing condoms for pregnancy prevention, disease prevention, and dual protection in 51%, 17%, and 33% of partnerships, respectively. Partner-specific factors varied, to a differing degree, across the three levels. Seven variables (duration, condom self efficacy, commitment, sexual decision-making, power, and vulnerability to harm [HIV/STIs] and pregnancy) distinguished condom use motives. The level of this association varied but was most pronounced at the partner and individual levels. Researchers and practitioners should consider the impact of both individual- and partner-level factors on condom use motives, in both research and sexual health programs. PMID- 27246879 TI - Touch-induced changes in Arabidopsis morphology dependent on gibberellin breakdown. AB - Touch can lead to a reduction in plant growth and a delay in flowering time. Touch-induced changes in plant morphology, termed thigmomorphogenesis, have been shown to depend on the phytohormone jasmonate(1). However, touch-induced phenotypes are also reminiscent of plants deficient in the phytohormone gibberellin(2). Here we assess the effect of touch on wild-type Arabidopsis plants and mutants deficient in gibberellin signalling. We show that touch leads to stunted growth and delayed flowering in wild-type plants, as expected. These touch-induced changes in morphology are accompanied by a reduction in gibberellin levels, and can be reversed through the application of a bioactive form of gibberellin. We further show that touch induces the expression of AtGA2ox7, which encodes an enzyme involved in gibberellin catabolism. Arabidopsis ga2ox7 loss-of function mutants do not respond to touch, suggesting that this gene is a key regulator of thigmomorphogenesis. We conclude that touch-induced changes in Arabidopsis morphology depend on gibberellin catabolism. Given that AtGA2ox7 helps to confer resistance to salt stress, and that touch can increase plant resistance to pathogens, we suggest that gibberellin catabolism could be targeted to improve plant resistance to abiotic and biotic stress. PMID- 27246880 TI - Gene regulation by translational inhibition is determined by Dicer partnering proteins. AB - MicroRNAs (miRNAs) are small regulatory RNAs produced by Dicer proteins that regulate gene expression in development and adaptive responses to the environment(1-4). In animals, the degree of base pairing between a miRNA and its target messenger RNA seems to determine whether the regulation occurs through cleavage or translation inhibition(1). In contrast, the selection of regulatory mechanisms is independent of the degree of mismatch between a plant miRNA and its target transcript(5). However, the components and mechanism(s) that determine whether a plant miRNA ultimately regulates its targets by guiding cleavage or translational inhibition are unknown(6). Here we show that the form of regulatory action directed by a plant miRNA is determined by DRB2, a DICER-LIKE1 (DCL1) partnering protein. The dependence of DCL1 on DRB1 for miRNA biogenesis is well characterized(7-9), but we show that it is only required for miRNA-guided transcript cleavage. We found that DRB2 determines miRNA-guided translational inhibition and represses DRB1 expression, thereby allowing the active selection of miRNA regulatory action. Furthermore, our results reveal that the core silencing proteins ARGONAUTE1 (AGO1) and SERRATE (SE) are highly regulated by miRNA-guided translational inhibition. DRB2 has been remarkably conserved throughout plant evolution, raising the possibility that translational repression is the ancient form of miRNA-directed gene regulation in plants, and that Dicer partnering proteins, such as human TRBP, might play a similar role in other eukaryotic systems. PMID- 27246881 TI - Patterning mechanisms of cytoskeletal and cell wall systems during leaf trichome morphogenesis. AB - The plant actin cytoskeleton is an unstable network of filaments that influences polarized growth through poorly understood mechanisms. Here, we used a combination of live cell imaging and finite element computational modelling of Arabidopsis trichome morphogenesis to determine how the actin and microtubule cytoskeletons cooperate to pattern the cell wall and growth. The actin-related protein (ARP)2/3 complex generates an actin meshwork that operates within a tip localized, microtubule-depleted zone to modulate cell wall anisotropy locally. The actin meshwork also positions an actin bundle network that organizes organelle flow patterns. This activity is required to maintain cell wall thickness gradients that enable tip-biased diffuse growth. These newly discovered couplings between cytoskeletal patterns and wall textures provide important insights into the cellular mechanism of growth control in plants. PMID- 27246882 TI - Multiple mechanisms of nitrate sensing by Arabidopsis nitrate transceptor NRT1.1. AB - In Arabidopsis the plasma membrane nitrate transceptor (transporter/receptor) NRT1.1 governs many physiological and developmental responses to nitrate. Alongside facilitating nitrate uptake, NRT1.1 regulates the expression levels of many nitrate assimilation pathway genes, modulates root system architecture, relieves seed dormancy and protects plants from ammonium toxicity. Here, we assess the functional and phenotypic consequences of point mutations in two key residues of NRT1.1 (P492 and T101). We show that the point mutations differentially affect several of the NRT1.1-dependent responses to nitrate, namely the repression of lateral root development at low nitrate concentrations, and the short-term upregulation of the nitrate-uptake gene NRT2.1, and its longer term downregulation, at high nitrate concentrations. We also show that these mutations have differential effects on genome-wide gene expression. Our findings indicate that NRT1.1 activates four separate signalling mechanisms, which have independent structural bases in the protein. In particular, we present evidence to suggest that the phosphorylated and non-phosphorylated forms of NRT1.1 at T101 have distinct signalling functions, and that the nitrate-dependent regulation of root development depends on the phosphorylated form. Our findings add to the evidence that NRT1.1 is able to trigger independent signalling pathways in Arabidopsis in response to different environmental conditions. PMID- 27246883 TI - Insect herbivory alters impact of atmospheric change on northern temperate forests. AB - Stimulation of forest productivity by elevated concentrations of CO2 is expected to partially offset continued increases in anthropogenic CO2 emissions. However, multiple factors can impair the capacity of forests to act as carbon sinks; prominent among these are tropospheric O3 and nutrient limitations(1,2). Herbivorous insects also influence carbon and nutrient dynamics in forest ecosystems, yet are often ignored in ecosystem models of forest productivity. Here we assess the effects of elevated levels of CO2 and O3 on insect-mediated canopy damage and organic matter deposition in aspen and birch stands at the Aspen FACE facility in northern Wisconsin, United States. Canopy damage was markedly higher in the elevated CO2 stands, as was the deposition of organic substrates and nitrogen. The opposite trends were apparent in the elevated O3 stands. Using a light-use efficiency model, we show that the negative impacts of herbivorous insects on net primary production more than doubled under elevated concentrations of CO2, but decreased under elevated concentrations of O3. We conclude that herbivorous insects may limit the capacity of forests to function as sinks for anthropogenic carbon emissions in a high CO2 world. PMID- 27246884 TI - Protein turnover in plant biology. AB - The protein content of plant cells is constantly being updated. This process is driven by the opposing actions of protein degradation, which defines the half life of each polypeptide, and protein synthesis. Our understanding of the processes that regulate protein synthesis and degradation in plants has advanced significantly over the past decade. Post-transcriptional modifications that influence features of the mRNA populations, such as poly(A) tail length and secondary structure, contribute to the regulation of protein synthesis. Post translational modifications such as phosphorylation, ubiquitination and non enzymatic processes such as nitrosylation and carbonylation, govern the rate of degradation. Regulators such as the plant TOR kinase, and effectors such as the E3 ligases, allow plants to balance protein synthesis and degradation under developmental and environmental change. Establishing an integrated understanding of the processes that underpin changes in protein abundance under various physiological and developmental scenarios will accelerate our ability to model and rationally engineer plants. PMID- 27246885 TI - Strategic pre-breeding for wheat improvement. PMID- 27246886 TI - Gene silencing: Mode of miRNA biogenesis matters. PMID- 27246887 TI - Heterosis: The genetic basis of hybrid vigour. PMID- 27246888 TI - Nitrate signalling: Functions of a nitrate transceptor. PMID- 27246889 TI - Gates Foundation backs high-risk science for big wins. PMID- 27246890 TI - Auxin: Harnessing a loose cannon. PMID- 27246891 TI - Plant defence: Rubber bullets. PMID- 27246892 TI - Crop engineering: Hijacking hormone receptors. PMID- 27246893 TI - Auxin signalling: ABP1 springs a surprise. PMID- 27246894 TI - Crop phenology: Winter wheat escapes heat. PMID- 27246895 TI - Orchid systematics: Illustrating change. PMID- 27246896 TI - Making the greatest impact. PMID- 27246898 TI - The importance of collecting structured clinical information on multiple sclerosis. AB - BACKGROUND: Randomized controlled trials (RCTs) are the 'gold standard' in the generation of drug efficacy and safety evidence. However, enrolment criteria, timelines and atypical comparators of RCTs limit their relevance to standard clinical practice. DISCUSSION: Real-world data (RWD) provide longitudinal information on the comparative effectiveness and tolerability of drugs, as well as their impact on resource use, medical costs, and pharmacoeconomic and patient reported outcomes. This is particularly important in multiple sclerosis (MS), where economic treatment benefits of long-term disability reduction are a cornerstone of payer drug approvals - these are typically not examined in the RCT itself but modelled using real-world datasets. Importantly, surrogate markers used in RCTs to predict the prevention of long-term disability progression can only truly be assessed through RWD methodologies. We discuss the differences between RCTs and RWD studies, describe how RWD complements the evidence base from RCTs in MS, summarize the different methods of RWD collection, and explain the importance of structuring data analysis to avoid bias. Guidance on performing and identifying high-quality real-world evidence studies is also provided. PMID- 27246897 TI - Brain activity and connectivity in response to negative affective stimuli: Impact of dysphoric mood and sex across diagnoses. AB - Negative affective stimuli elicit behavioral and neural responses which vary on a continuum from adaptive to maladaptive, yet are typically investigated in a dichotomous manner (healthy controls vs. psychiatric diagnoses). This practice may limit our ability to fully capture variance from acute responses to negative affective stimuli to psychopathology at the extreme end. To address this, we conducted a functional magnetic resonance imaging study to examine the neural responses to negative valence/high arousal and neutral valence/low arousal images as a function of dysphoric mood and sex across individuals (n = 99) who represented traditional categories of healthy controls, major depressive disorder, bipolar psychosis, and schizophrenia. Observation of negative (vs. neutral) stimuli elicited blood oxygen-level dependent responses in the following circuitry: periaqueductal gray, hypothalamus (HYPO), amygdala (AMYG), hippocampus (HIPP), orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and greater connectivity between AMYG and mPFC. Across all subjects, severity of dysphoric mood was associated with hyperactivity of HYPO, and, among females, right (R) AMYG. Females also demonstrated inverse relationships between severity of dysphoric mood and connectivity between HYPO - R OFC, R AMYG - R OFC, and R AMYG R HIPP. Overall, our findings demonstrated sex-dependent deficits in response to negative affective stimuli increasing as a function of dysphoric mood state. Females demonstrated greater inability to regulate arousal as mood became more dysphoric. These findings contribute to elucidating biosignatures associated with response to negative stimuli across disorders and suggest the importance of a sex dependent lens in determining these biosignatures. Hum Brain Mapp 37:3733-3744, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27246899 TI - Acute Sildenafil Use Reduces 24-Hour Blood Pressure Levels in Patients With Resistant Hypertension: A Placebo-Controlled, Crossover Trial. AB - The authors previously demonstrated that acute administration of sildenafil-a phosphodiesterase 5 (PDE5) inhibitor-improves hemodynamic parameters in patients with resistant hypertensive (RH), but its effect on ambulatory blood pressure monitoring (ABPM) is unknown. This interventional, nonrandomized, single-blinded, placebo-controlled, crossover trial included 26 patients with RH. A dose of sildenafil (187.5mg) was given, and after a washout period of 14 days the patients received a single oral dose of placebo and the protocol was repeated. The patients underwent 24-hour ABPM recordings the day before and immediately after the protocols. The reduction of systolic (-8.8+/-1.4 vs 1.3+/-1.2 mm Hg, P=.02), diastolic (-5.3+/-3.3 vs 1.8+/-1.1 mm Hg, P=.03), and mean (-7.9+/-3.6 vs 0.8+/-0.9 mm Hg, P=.01) 24-hour BP were found after the use of sildenafil compared with placebo. Improvement in daytime BP levels was also observed (systolic -6.0+/-4.7 vs 4.4+/-1.5 mm Hg [P=.02] and mean -4.8+/-3.9 vs 3.5+/-1.4 mm Hg [P=.02] for sildenafil vs placebo, respectively). Considering its antihypertensive effect, sildenafil may represent a therapeutic option for RH treatment. PMID- 27246900 TI - Gestational age and chronic 'body-mind' health problems in childhood: dose response association and risk factors. AB - Understanding the developmental course of all health issues associated with preterm birth is important from an individual, clinical and public health point of-view. Both the number of preterm births and proportion of survivors have increased steadily in recent years. The UK Millennium Cohort Study (n = 18,818) was used to examine the association of gestational age with maternal ratings of general health and behavior problems at ages 5 and 11 years using binary and multinomial logistic regression analyses. The association between mothers' ratings of general health and behavior problems was relatively weak at each time point. Children rated as being in poor general health remained constant over time (4.0 % at age 5, 3.8 % at age 11), but children rated as having behavioral problems increased by almost 100 % (5.6 % at 5; 10.5 % at 11). A gradient of increasing risk with decreasing gestational age was observed for a composite health measure (general health problems and/or behavior problems) at age 5, amplified at age 11 and was strongest for those with chronic problems (poor health at both age 5 and age 11). This association was found to be compounded by child sex, maternal characteristics at birth (education, employment, marital status) and duration of breast feeding. Integrated support to at-risk families initiated during, or soon after pregnancy, may prevent chronic problems and might potentially reduce long term health costs for both the individual and health services. PMID- 27246901 TI - The expression of prostaglandin-E2 and its receptor in the oviduct of Chinese brown frog (Rana dybowskii). AB - The Chinese brown frog (Rana dybowskii) has one special physiological phenomenon, which is that its oviduct expands prior to hibernation rather than in the breeding period. In this study, we investigated the immunolocalization and expression levels of prostaglandin-E2 (PGE2), cyclooxygenase (COX)-1 and COX-2, as well as one of its receptor subtypes 4 (EP4) in the oviduct of Rana dybowskii during the pre-hibernation and breeding period. PGE2, COX-1, COX-2 and EP4 have been observed in glandular and epithelial cells in the breeding period, whereas only in the epithelial cells during the pre-hibernation. Consistently, the protein levels of COX-2 and EP4 were higher in the pre-hibernation as compared to the breeding period, but the diversity of COX-1 was not obvious. In addition, oviductal PGE2 concentration was also significantly higher in the pre hibernation. These results suggested that prostaglandin-E2 may play an important autocrine or paracrine role in oviductal cell proliferation and differentiation of Rana dybowskii during pre-hibernation. PMID- 27246902 TI - Lower bound for the spatial extent of localized modes in photonic-crystal waveguides with small random imperfections. AB - Light localization due to random imperfections in periodic media is paramount in photonics research. The group index is known to be a key parameter for localization near photonic band edges, since small group velocities reinforce light interaction with imperfections. Here, we show that the size of the smallest localized mode that is formed at the band edge of a one-dimensional periodic medium is driven instead by the effective photon mass, i.e. the flatness of the dispersion curve. Our theoretical prediction is supported by numerical simulations, which reveal that photonic-crystal waveguides can exhibit surprisingly small localized modes, much smaller than those observed in Bragg stacks thanks to their larger effective photon mass. This possibility is demonstrated experimentally with a photonic-crystal waveguide fabricated without any intentional disorder, for which near-field measurements allow us to distinctly observe a wavelength-scale localized mode despite the smallness (~1/1000 of a wavelength) of the fabrication imperfections. PMID- 27246903 TI - Recurrence and mortality prognostic factors in childhood adrenocortical tumors: Analysis from the Brazilian National Institute of Cancer experience. AB - Prognostic markers that can help identifying precocious risk of unfavorable outcomes in patients with childhood adrenocortical tumors (ACTs) are still unclear. This observational and retrospective study aimed to identify clinical and pathology prognostic factors of recurrence and death in a tertiary cancer center population. Clinical, pathology, demographic, staging, and therapy data from patients with childhood ACT (median age: 3.6 years) treated at the Brazilian National Institute of Cancer between 1997 and 2015 were assessed. Univariate and bivariate analyses were used to study the association of clinical and pathology characteristics with recurrence and mortality. Recurrence and disease-related mortality were the main outcomes. Twenty-seven patients were included. Complete tumor resection was performed in 21 cases. The median tumor size was 8.2 cm. Mitotane was the most common adjuvant/palliative therapy (n = 13). Recurrence occurred in 6 patients, after a median time of 7.2 months, and was more common among those with larger tumors (P =.008), higher Weiss score (P =.001), and microscopic tumoral necrosis (P =.002). Ten patients died from the disease. Older age (P =.04), larger tumor size (P =.002), metastatic disease (P =.003), previous recurrence (P =.003), incomplete resection (P =.002), intraoperative tumor spillage (P =.005), higher Weiss score (P =.03), microscopic necrosis (P =.005), and capsular invasion (P =.02) were all associated with increased death risk. Even though complete tumor resection was performed in most cases, a considerable number of cases of childhood ACT resulted in recurrence and death. Early identification of unfavorable outcomes is essential to determine ideal therapy and appropriate surveillance. PMID- 27246904 TI - Animal-adapted members of the Mycobacterium tuberculosis complex endemic to the southern African subregion. AB - Members of the Mycobacterium tuberculosis complex (MTC) cause tuberculosis (TB) in both animals and humans. In this article, three animal-adapted MTC strains that are endemic to the southern African subregion - that is, Mycobacterium suricattae, Mycobacterium mungi, and the dassie bacillus - are reviewed with a focus on clinical and pathological presentations, geographic distribution, genotyping methods, diagnostic tools and evolution. Moreover, factors influencing the transmission and establishment of TB pathogens in novel host populations, including ecological, immunological and genetic factors of both the host and pathogen, are discussed. The risks associated with these infections are currently unknown and further studies will be required for greater understanding of this disease in the context of the southern African ecosystem. PMID- 27246905 TI - Pancreatic volume is one of the independent prognostic factors for resectable pancreatic ductal adenocarcinomas. AB - BACKGROUND: It is well known that pancreatic ductal adenocarcinoma (PDAC) is accompanied with pancreatic atrophy and fibrosis. We previously reported the correlation between pancreatic volume and body surface area (BSA) and significant reduction of BSA-adjusted pancreatic volume in pancreatic cancer patients. We evaluated potential correlation between BSA-adjusted pancreatic volume and PDAC prognosis. METHODS: The study subjects were 48 pancreatic cancer patients received pancreatectomy at our department from June 2006 to September 2012. Pancreatic volumetry was retrospectively performed using the images obtained from multidetector computed tomography before the surgery. BSA-adjusted pancreatic volumes were calculated and analyzed for potential correlation with the prognosis. RESULTS: Average BSA-adjusted pancreatic volume among 48 cases was 35.4 +/- 11.9 ml/m(2) . Types of surgery included 24 cases with pancreaticoduodenectomy and 24 cases with distal pancreatectomy. The cases with BSA-adjusted pancreatic volume less than 40 ml/m(2) had significantly poorer prognosis compared to the cases of 40 ml/m(2) and greater (3-year survival rate: 32.4% vs. 64.3%). Statistical analysis identified four prognosis factors, i.e. BSA-adjusted pancreatic volume less than 40 ml/m(2) , postoperative adjuvant chemotherapy, lymph node metastasis and lymphatic invasion. CONCLUSIONS: This study demonstrated BSA-adjusted pancreatic volume as a prognosis factor for PDAC and the volume of 40 ml/m(2) is considered to be the cutoff value. PMID- 27246906 TI - Dual inhibition of Mcl-1 by the combination of carfilzomib and TG02 in multiple myeloma. AB - Carfilzomib (Kyprolis(r)), a second generation proteasome inhibitor, is FDA approved for single-agent use among relapsed/refractory multiple myeloma (MM). To enhance the therapeutic efficacy of carfilzomib, we sought to combine carfilzomib with other novel agents. TG02, a multi-kinase inhibitor, targets JAK2 and CDK9. The rationale for co-treatment with carfilzomib and TG02 is that both independently target Mcl-1 and most myeloma cells are dependent on this anti apoptotic protein for survival. We observed at least additive effects using the combination treatment in MM cell lines and patient samples. To determine how the bone marrow environment affects the efficacy of the combination we conducted co culture experiments with Hs-5 stromal cells. We also examined the mechanism of increased apoptosis by determining the affect on expression of the Bcl-2 family of proteins. We found that carfilzomib increases NOXA mRNA expression, as expected, and TG02 treatment caused a decrease in Mcl-1 protein but not mRNA levels. Consistent with this possibility, we find silencing CDK9 does not change carfilzomib sensitivity in the same manner as addition of TG02. Since changes in Mcl-1 protein occur in the presence of a proteasome inhibitor we hypothesize that regulation of Mcl-1 translation is the most likely mechanism. Taken together our data suggest that dual inhibition of Mcl-1 via decreased expression and the induction of its antagonist NOXA by the combination of carfilzomib and TG02 is active in myeloma and warrants further testing preclinically and in clinical trials. Moreover, regulation of Mcl-1 by TG02 is more complex than initially appreciated. PMID- 27246907 TI - Characterization of SPATA5-related encephalopathy in early childhood. AB - Mutations in SPATA5 have recently been shown to result in a phenotype of microcephaly, intellectual disability, seizures, and hearing loss in childhood. Our aim in this report is to delineate the SPATA5 syndrome as a clinical entity, including the facial appearance, neurophysiological, and neuroimaging findings. Using whole-exome sequencing and Sanger sequencing, we identified three children with SPATA5 mutations from two families. Two siblings carried compound heterozygous mutations, c.989_991del (p.Thr330del) and c.2130_2133del (p.Glu711Profs*21), and the third child had c.967T>A (p.Phe323Ile) and c.2146G>C (p.Ala716Pro) mutations. The three patients manifested microcephaly, psychomotor retardation, hypotonus or hypertonus, and bilateral hearing loss from early infancy. Common facies were a depressed nasal bridge/ridge, broad eyebrows, and retrognathia. Epileptic spasms or tonic seizures emerged at 6-12 months of age. Interictal electroencephalography showed multifocal spikes and bursts of asynchronous diffuse spike-wave complexes. Augmented amplitudes of visually evoked potentials were detected in two patients. Magnetic resonance imaging revealed hypomyelination, thin corpus callosum, and progressive cerebral atrophy. Blood copper levels were also elevated or close to the upper normal levels in these children. Clinical delineation of the SPATA5-related encephalopathy should improve diagnosis, facilitating further clinical and molecular investigation. PMID- 27246908 TI - SYBR((r)) Green-based real-time quantitative reverse-transcription PCR for detection and discrimination of grapevine viruses. AB - A SYBR((r)) Green-based real-time quantitative reverse transcription PCR (qRT PCR) assay in combination with melt-curve analysis (MCA) was optimized for the detection of nine grapevine viruses. The detection limits for simplex qRT-PCR for all nine grapevine viruses were estimated to be in the range of 214-1112 copies of the virus genome. Amplicons with melting temperatures (Tm) separated by at least 2 degrees C in the MCA could differentiate two viruses in the same reaction. Therefore, eight of the nine viruses could be co-diagnosed in five different combinations of duplex assays. Of 305 grape leaf samples from the field or greenhouse, 162 were positive for at least one of the nine grapevine viruses using the duplex qRT-PCR assays. In contrast, only 127 samples were positive using endpoint RT-PCR and PCR assays, indicating the enhanced sensitivity of duplex real-time PCR. In addition, the duplex qRT-PCR assays were be used to detect Grapevine leafroll associated virus 3 (GLRaV-3) in its vector, the grape mealybug (Pseudococcus maritimus Ehrhorn), and Grapevine red blotch-associated virus (GRBaV) in Virginia creeper leafhopper (Erythroneura ziczac Walsh). The simplex and duplex real-time PCR assays developed in this study can be used to examine transmission of co-occruing viruses by insect vectors as well as for rapid and sensitive detection of viruses in infected grapevines. PMID- 27246910 TI - beta-Lapachone Prevents Diet-Induced Obesity by Increasing Energy Expenditure and Stimulating the Browning of White Adipose Tissue via Downregulation of miR-382 Expression. AB - There has been great interest in the browning of fat for the treatment of obesity. Although beta-lapachone (BLC) has potential therapeutic effects on obesity, the fat-browning effect and thermogenic capacity of BLC on obesity have never been demonstrated. Here, we showed that BLC stimulated the browning of white adipose tissue (WAT), increased the expression of brown adipocyte-specific genes (e.g., uncoupling protein 1 [UCP1]), decreased body weight gain, and ameliorated metabolic parameters in mice fed a high-fat diet. Consistently, BLC treated mice showed significantly higher energy expenditure compared with control mice. In vitro, BLC increased the expression of brown adipocyte-specific genes in stromal vascular fraction-differentiated adipocytes. BLC also controlled the expression of miR-382, which led to the upregulation of its direct target, Dio2. Upregulation of miR-382 markedly inhibited the differentiation of adipocytes into beige adipocytes, whereas BLC recovered beige adipocyte differentiation and increased the expression of Dio2 and UCP1. Our findings suggest that the BLC mediated increase in the browning of WAT and the thermogenic capacity of BAT significantly results in increases in energy expenditure. Browning of WAT by BLC was partially controlled via the regulation of miR-382 targeting Dio2 and may lead to the prevention of diet-induced obesity. PMID- 27246909 TI - Microsomal membrane proteome of low grade diffuse astrocytomas: Differentially expressed proteins and candidate surveillance biomarkers. AB - Diffuse astrocytoma (DA; WHO grade II) is a low-grade, primary brain neoplasm with high potential of recurrence as higher grade malignant form. We have analyzed differentially expressed membrane proteins from these tumors, using high resolution mass spectrometry. A total of 2803 proteins were identified, 340 of them differentially expressed with minimum of 2 fold change and based on >=2 unique peptides. Bioinformatics analysis of this dataset also revealed important molecular networks and pathways relevant to tumorigenesis, mTOR signaling pathway being a major pathway identified. Comparison of 340 differentially expressed proteins with the transcript data from Grade II diffuse astrocytomas reported earlier, revealed about 190 of the proteins correlate in their trends in expression. Considering progressive and recurrent nature of these tumors, we have mapped the differentially expressed proteins for their secretory potential, integrated the resulting list with similar list of proteins from anaplastic astrocytoma (WHO Grade III) tumors and provide a panel of proteins along with their proteotypic peptides, as a resource that would be useful for investigation as circulatory plasma markers for post-treatment surveillance of DA patients. PMID- 27246911 TI - Renal Denervation for Resistant Hypertension Fails to Improve Insulin Resistance as Assessed by Hyperinsulinemic-Euglycemic Step Clamp. AB - We assessed whether insulin sensitivity improved after renal denervation (RDN) for resistant hypertension. Twenty-three patients underwent a two-step hyperinsulinemic-euglycemic clamp (HEC) with glucose tracer and labeled glucose infusion and oral glucose tolerance test (OGTT) before and 6 months after RDN. Eighteen patients had metabolic syndrome at baseline. Blood pressure declined significantly after RDN, whereas mean (SD) fasting plasma glucose concentration (5.9 +/- 0.7 mmol/L), median (minimum-maximum) insulin concentration (254 pmol/L [88-797 pmol/L]), and median C-peptide concentration (2.4 nmol/L [0.9-5.7 nmol/L]) remained unchanged. Endogenous glucose release during HEC was less suppressed after RDN, suggesting a slight decrease in hepatic insulin sensitivity. During high-dose insulin infusion, whole-body glucose disposal was low and remained unchanged after RDN, indicating persistent peripheral insulin resistance (IR). Area under the curve for 0-120 min for glucose and insulin during OGTT, Quantitative Insulin Sensitivity Check Index, Simple Index Assessing Insulin Sensitivity Oral Glucose Tolerance, and HOMA-IR were high, and did not improve after RDN. Despite a significant decrease in blood pressure, neither peripheral nor hepatic insulin sensitivity improved 6 months after RDN treatment in this group of insulin-resistant patients without diabetes and with resistant hypertension, as measured with gold standard methods. PMID- 27246912 TI - Protein Phosphatase 1-alpha Regulates AS160 Ser588 and Thr642 Dephosphorylation in Skeletal Muscle. AB - Akt substrate of 160 kDa (AS160) phosphorylation on Thr(642) and Ser(588) by Akt is essential for insulin's full effect on glucose transport. However, protein phosphorylation is determined by the balance of actions by kinases and phosphatases, and the specific phosphatase(s) controlling AS160 dephosphorylation is (are) unknown. Accordingly, we assessed roles of highly expressed skeletal muscle serine/threonine phosphatases (PP1, PP2A, PP2B, and PP2C) on AS160 dephosphorylation. Preliminary screening of candidate phosphatases used an AS160 dephosphorylation assay. Lysates from insulin-stimulated skeletal muscle were treated with pharmacological phosphatase inhibitors and assessed for AS160 Ser(588) and Thr(642) dephosphorylation. AS160 dephosphorylation on both phosphorylation sites was unaltered by PP2B or PP2C inhibitors. Okadaic acid (low dose inhibits PP2A; high dose inhibits PP1) delayed AS160 Ser(588) (both doses) and Thr(642) (high dose only) dephosphorylation concomitant with greater Akt phosphorylation (both doses). AS160 was coimmunoprecipitated with PP1-alpha but not with PP1-beta, PP1-gamma1, or PP2A. Recombinant inhibitor-2 protein (a selective PP1 inhibitor) delayed AS160 dephosphorylation on both phosphorylation sites without altering Akt phosphorylation. Furthermore, knockdown of PP1-alpha but not PP1-beta or PP1-gamma1 by small interfering RNA caused greater AS160 Ser(588) and Thr(642) phosphorylation concomitant with unaltered Akt phosphorylation. Together, these results identified PP1-alpha as a regulator of AS160 Thr(642) and Ser(588) dephosphorylation in skeletal muscle. PMID- 27246913 TI - Nitric Oxide Produced by Macrophages Inhibits Adipocyte Differentiation and Promotes Profibrogenic Responses in Preadipocytes to Induce Adipose Tissue Fibrosis. AB - Fibrosis of adipose tissue induces ectopic fat accumulation and insulin resistance by inhibiting adipose tissue expandability. Mechanisms responsible for the induction of adipose tissue fibrosis may provide therapeutic targets but are poorly understood. In this study, high-fat diet (HFD)-fed wild-type (WT) and iNOS(-/-) mice were used to examine the relationship between nitric oxide (NO) produced by macrophages and adipose tissue fibrosis. In contrast to WT mice, iNOS(-/-) mice fed an HFD were protected from infiltration of proinflammatory macrophages and adipose tissue fibrosis. Hypoxia-inducible factor 1alpha (HIF 1alpha) protein level was increased in adipose tissue of HFD-fed WT mice, but not iNOS(-/-) mice. In contrast, the expression of mitochondrial biogenesis factors was decreased in HFD-fed WT mice, but not iNOS(-/-) mice. In studies with cultured cells, macrophage-derived NO decreased the expression of mitochondrial biogenesis factors, and increased HIF-1alpha protein level, DNA damage, and phosphorylated p53 in preadipocytes. By activating p53 signaling, NO suppressed peroxisome proliferator-activated receptor gamma coactivator 1alpha expression, which induced mitochondrial dysfunction and inhibited preadipocyte differentiation in adipocytes. The effects of NO were blocked by rosiglitazone. The findings suggest that NO produced by macrophages induces mitochondrial dysfunction in preadipocytes by activating p53 signaling, which in turn increases HIF-1alpha protein level and promotes a profibrogenic response in preadipocytes that results in adipose tissue fibrosis. PMID- 27246914 TI - Hyaluronidase 1 Deficiency Preserves Endothelial Function and Glycocalyx Integrity in Early Streptozotocin-Induced Diabetes. AB - Hyaluronic acid (HA) is a major component of the glycocalyx involved in the vascular wall and endothelial glomerular permeability barrier. Endocytosed hyaluronidase HYAL1 is known to degrade HA into small fragments in different cell types, including endothelial cells. In diabetes, the size and permeability of the glycocalyx are altered. In addition, patients with type 1 diabetes present increased plasma levels of both HA and HYAL1. To investigate the potential implication of HYAL1 in the development of diabetes-induced endothelium dysfunction, we measured endothelial markers, endothelium-dependent vasodilation, arteriolar glycocalyx size, and glomerular barrier properties in wild-type and HYAL1 knockout (KO) mice with or without streptozotocin (STZ)-induced diabetes. We observed that 4 weeks after STZ injections, the lack of HYAL1 1) prevents diabetes-induced increases in soluble P-selectin concentrations and limits the impact of the disease on endothelium-dependent hyperpolarization (EDH)-mediated vasorelaxation; 2) increases glycocalyx thickness and maintains glycocalyx structure and HA content during diabetes; and 3) prevents diabetes-induced glomerular barrier dysfunction assessed using the urinary albumin-to-creatinine ratio and urinary ratio of 70- to 40-kDa dextran. Our findings suggest that HYAL1 contributes to endothelial and glycocalyx dysfunction induced by diabetes. HYAL1 inhibitors could be explored as a new therapeutic approach to prevent vascular complications in diabetes. PMID- 27246915 TI - Paraquat-Melanin Redox-Cycling: Evidence from Electrochemical Reverse Engineering. AB - Parkinson's disease is a neurodegenerative disorder associated with oxidative stress and the death of melanin-containing neurons of the substantia nigra. Epidemiological evidence links exposure to the pesticide paraquat (PQ) to Parkinson's disease, and this link has been explained by a redox cycling mechanism that induces oxidative stress. Here, we used a novel electrochemistry based reverse engineering methodology to test the hypothesis that PQ can undergo reductive redox cycling with melanin. In this method, (i) an insoluble natural melanin (from Sepia melanin) and a synthetic model melanin (having a cysteinyldopamine-melanin core and dopamine-melanin shell) were entrapped in a nonconducting hydrogel film adjacent to an electrode, (ii) the film-coated electrode was immersed in solutions containing PQ (putative redox cycling reductant) and a redox cycling oxidant (ferrocene dimethanol), (iii) sequences of input potentials (i.e., voltages) were imposed to the underlying electrode to systematically engage reductive and oxidative redox cycling, and (iv) output response currents were analyzed for signatures of redox cycling. The response characteristics of the PQ-melanin systems to various input potential sequences support the hypothesis that PQ can directly donate electrons to melanin. This observation of PQ-melanin redox interactions demonstrates an association between two components that have been individually linked to oxidative stress and Parkinson's disease. Potentially, melanin's redox activity could be an important component in understanding the etiology of neurological disorders such as Parkinson's disease. PMID- 27246916 TI - An insight into elasticity analysis of common carotid artery using ultrasonography. AB - Elastance is a distinguished marker in diagnosing various arterial diseases as studies have reported carotid artery-related diseases linked with stiffness index (beta) values greater than 5. This study was to estimate elasticity of common carotid artery by measuring the diameter during systolic and diastolic phases using pixel tracing of successive frames and blood pressure. The B-mode ultrasonography video containing arterial wall motion was captured and fragmented into image frames. Each pixel on the greyscale image was converted into RGB intensity values. The diameter of the artery as well as the thickness of the wall was measured by tracing the pixel displacements from successive frames during arterial pulsation. The study was conducted on 19 subjects aged 25-40 years. The systolic and diastolic carotid artery lumen diameters and carotid intima-media thickness were calculated as 7.1 +/- 0.7, 6.3 +/- 0.6 and 0.5 +/- 0.05 mm (mean +/- standard deviation), respectively. The mean stiffness index (beta), Peterson's modulus and Young's modulus of elasticity were 5.2 +/- 1.1, 69 +/- 15 kPa and 453 +/- 99 kPa, respectively. The pixel displacements in tunica intima, tunica media and tunica adventitia were not homogeneous, due to varied macro constituents such as endothelial tissues, smooth muscle cells, elastin lamina, fibrous tissue and micro-constituents such as collagen, fibroblast and elastin. We found that women have smaller arteries, and the stiffness increased during the systolic phase. PMID- 27246917 TI - Exploring physicians' extended use of electronic health records (EHRs): A social influence perspective. AB - BACKGROUND: Once electronic health records (EHRs) have been fully implemented and integrated into the daily work of a healthcare organisation/hospital, there is considerable pressure on management to demonstrate the benefits that these systems can deliver to the organisation. One practical way to maximise the value and highlight the benefits of EHRs is to encourage physicians to increase and extend their use of EHR functions. OBJECTIVE: This study used a social influence theory context to examine the impact of mechanisms of social influence on the intentions of physicians to extend their use of EHRs. METHOD: A survey of physicians (n = 205) in a first-class comprehensive hospital in southern China was conducted approximately 2 years after the hospital's introduction of EHRs. A 16-item questionnaire was developed to measure the impact of four social influence factors (reward, punishment, social image and group norm) on physicians' intentions to extend their use of EHRs. The research model included two additional control variables (perceived usefulness and perceived ease of use) to account for potential covariance among social influence measures. RESULTS: The study's research model showed significant relationships between physicians' responses on two of the social influence measures (rewards and group norm) and their intentions to extend their use of EHRs. Punishment and social image measures did not influence physicians' intentions to increase their use of EHRs. CONCLUSION: These findings have suggested that for healthcare organisations to maximise the benefits of EHRs, the efforts of hospital management should be directed towards rewarding those physicians who increase their use of EHRs; and to promoting and reinforcing the increased usage of EHRs among physicians as a group norm. PMID- 27246918 TI - Nanowires: Quantitative Probing of Cu(2+) Ions Naturally Present in Single Living Cells (Adv. Mater. 21/2016). AB - Quantitative probing of the Cu(2+) ions naturally present in single living cells is accomplished by a probe made from a quantum-dot-embedded-nanowire waveguide. After inserting the active nanowire-based waveguide probe into single living cells, J. H. Je and co-workers directly observe photoluminescence (PL) quenching of the embedded quantum dots by the Cu(2+) ions diffused into the probe as described on page 4071. This results in quantitative measurement of intracellular Cu(2+) ions. PMID- 27246920 TI - Sensors: A Highly Sensitive Diketopyrrolopyrrole-Based Ambipolar Transistor for Selective Detection and Discrimination of Xylene Isomers (Adv. Mater. 21/2016). AB - An ambipolar organic field-effect transistor (OFET) based on poly(diketopyrrolopyrrole-terthiophene) (PDPPHD-T3) is shown by P. Sonar, H. Haick, and co-workers on page 4012 to sensitively detect xylene isomers at low to 40 ppm level in multiple sensing features. Combined with pattern-recognition algorithms, a sole ambipolar FET sensor, rather than arrays of sensors, is able to discriminate highly similar xylene structural isomers from each other. PMID- 27246921 TI - Phosphorene: Enhanced Photoresponse from Phosphorene-Phosphorene-Suboxide Junction Fashioned by Focused Laser Micromachining (Adv. Mater. 21/2016). AB - On page 4090, B. Ozyilmaz, C. H. Sow, and co-workers use a focused laser beam to modify the surface of a phosphorene device. With a simple focused laser beam, a part of the phosphorene can be scanned and converted into phosphorene-suboxide species, leaving behind a functional and active phosphorene-phosphorene suboxide junction in the device. Once the junction is formed, the photoresponsivity and photocurrent distribution of the device can be significantly altered with a qualitative difference in behavior. Photovoltaic-like behavior is observed, which is not found in the pristine sample. PMID- 27246923 TI - methylFlow: cell-specific methylation pattern reconstruction from high-throughput bisulfite-converted DNA sequencing. AB - MOTIVATION: DNA methylation aberrations are now known to, almost universally, accompany the initiation and progression of cancers. In particular, the colon cancer epigenome contains specific genomic regions that, along with differences in methylation levels with respect to normal colon tissue, also show increased epigenetic and gene expression heterogeneity at the population level, i.e. across tumor samples, in comparison with other regions in the genome. Tumors are highly heterogeneous at the clonal level as well, and the relationship between clonal and population heterogeneity is poorly understood. RESULTS: We present an approach that uses sequencing reads from high-throughput sequencing of bisulfite converted DNA to reconstruct heterogeneous cell populations by assembling cell specific methylation patterns. Our methodology is based on the solution of a specific class of minimum cost network flow problems. We use our methods to analyze the relationship between clonal heterogeneity and population heterogeneity in high-coverage data from multiple samples of colon tumor and matched normal tissues. AVAILABILITY AND IMPLEMENTATION: http://github.com/hcorrada/methylFlow CONTACT: hcorrada@umiacs.umd.edu SUPPLEMENTARY INFORMATION: SUPPLEMENTARY INFORMATION is available at Bioinformatics online. PMID- 27246924 TI - Message from the ISCB: 2016 ISCB Accomplishment by a Senior Scientist Award Given to Soren Brunak. PMID- 27246925 TI - Message from the ISCB: 2016 Outstanding Contributions to ISCB Award: Burkhard Rost. PMID- 27246926 TI - Serum-derived exosomes from non-viremic animals previously exposed to the porcine respiratory and reproductive virus contain antigenic viral proteins. AB - PRRSV is the etiological agent of one of the most important swine diseases with a significant economic burden worldwide and limitations in vaccinology. Exosomes are 30-100 nm vesicles of endocytic origin. Remarkably, immunizations with exosomes containing antigens from tumors or pathogens are capable of eliciting protective immune responses, albeit variably, in cancer and infectious diseases. Here we describe the isolation, molecular composition and immunogenicity of serum derived exosomes from naive animals, from PRRSV viremic animals and from animals previously PRRSV infected but already free of viruses (non viremic). Exosomes were isolated through size exclusion chromatography and characterized by different methodologies. Exosome-enriched fractions from naive and natural infected animals contained classical tetraspanin exosomal markers (CD63 and CD81) and high concentrations of particles in the size-range of exosomes as detected by nanoparticle tracking analysis and cryo-TEM. NanoLC-MS/MS was used to identify viral antigens associated to exosomes. PRRSV-proteins were detected in serum samples from only viremic animals and from animals previously infected already free of viruses (non-viremic), but not in controls. Moreover, immune sera from pigs previously exposed to PRRSV specifically reacted against exosomes purified from non-viremic pig sera in a dose-dependent manner, a reactivity not detected when naive sera was used in the assay. To facilitate future studies, a scaling-up process was implemented. To the best of our knowledge, this is the first molecular characterization of serum-derived exosomes from naive pigs and pigs actively or previously infected with PRRSV. The presence of antigenic viral proteins in serum-derived exosomes free of virus, suggest their use as a novel vaccine approach against PRRSV. PMID- 27246927 TI - Adiposity assessed by anthropometric measures has a similar or greater predictive ability than dual-energy X-ray absorptiometry measures for abdominal aortic calcification in community-dwelling older adults. AB - To determine whether adiposity assessed by dual-energy X-ray absorptiometry (DXA) compared to simple anthropometric assessments, are more predictive of abdominal aortic calcification (AAC), a risk factor for atherosclerosis. A cross-sectional study of 312 participants (60.3 % female) aged 70.6 +/- 5.6 years was conducted in 2010-2011. AAC was assessed by radiography. Adiposity was estimated for whole body, trunk, android, gynoid and visceral regions using DXA in addition to body mass index (BMI), waist circumference (WC) and waist to hip ratio (WHR). WHR [tertile 1 as reference, OR (95 % CI) for tertile 3: 3.62 (1.35-9.72)] and android to gynoid fat ratio [tertile 3: 2.87 (1.03-8.01)] were independent predictors of AAC severity among men. Positive associations with AAC severity were observed for WC [tertile 1 as reference, OR for tertile 3: 2.46 (1.12 5.41)], % trunk fat mass [tertile 2: 3.26 (1.52-7.03)], % android fat mass [tertile 2: 2.42 (1.13-5.18), tertile 3: 2.20 (1.02-4.73)] and visceral fat area [tertile 2: 2.28 (1.06-4.87), tertile 3: 2.32 (1.01-5.34)] among women. Indices of total body composition, BMI and % body fat mass were not associated with AAC severity in either men or women. Simple anthropometric measures, WHR and WC were the best predictors of AAC severity in men and women respectively, although higher android to gynoid fat ratio and central fat, assessed by DXA, were also predictive of higher risks of AAC severity in men and women respectively. Our findings add to existing evidence that relatively inexpensive and easily obtained anthropometric measures can be clinically useful indicators of atherosclerosis risk. PMID- 27246928 TI - Evaluation of the structural, physicochemical, and biological characteristics of SB4, a biosimilar of etanercept. AB - A biosimilar is a biological medicinal product that is comparable to a reference medicinal product in terms of quality, safety, and efficacy. SB4 was developed as a biosimilar to Enbrel(r) (etanercept) and was approved as Benepali(r), the first biosimilar of etanercept licensed in the European Union (EU). The quality assessment of SB4 was performed in accordance with the ICH comparability guideline and the biosimilar guidelines of the European Medicines Agency and Food and Drug Administration. Extensive structural, physicochemical, and biological testing was performed with state-of-the-art technologies during a side-by-side comparison of the products. Similarity of critical quality attributes (CQAs) was evaluated on the basis of tolerance intervals established from quality data obtained from more than 60 lots of EU-sourced and US-sourced etanercept. Additional quality assessment was focused on a detailed investigation of immunogenicity-related quality attributes, including hydrophobic variants, high molecular-weight (HMW) species, N-glycolylneuraminic acid (NGNA), and alpha-1,3 galactose. This comprehensive characterization study demonstrated that SB4 is highly similar to the reference product, Enbrel(r), in structural, physicochemical, and biological quality attributes. In addition, the levels of potential immunogenicity-related quality attributes of SB4 such as hydrophobic variants, HMW aggregates, and alpha-1,3-galactose were less than those of the reference product. PMID- 27246930 TI - Microglia are less pro-inflammatory than myeloid infiltrates in the hippocampus of mice exposed to status epilepticus. AB - Activated microglia, astrogliosis, expression of pro-inflammatory cytokines, blood brain barrier (BBB) leakage and peripheral immune cell infiltration are features of mesial temporal lobe epilepsy. Numerous studies correlated the expression of pro-inflammatory cytokines with the activated morphology of microglia, attributing them a pro-epileptogenic role. However, microglia and myeloid cells such as macrophages have always been difficult to distinguish due to an overlap in expressed cell surface molecules. Thus, the detrimental role in epilepsy that is attributed to microglia might be shared with myeloid infiltrates. Here, we used a FACS-based approach to discriminate between microglia and myeloid infiltrates isolated from the hippocampus 24 h and 96 h after status epilepticus (SE) in pilocarpine-treated CD1 mice. We observed that microglia do not express MHCII whereas myeloid infiltrates express high levels of MHCII and CD40 96 h after SE. This antigen-presenting cell phenotype correlated with the presence of CD4(pos) T cells. Moreover, microglia only expressed TNFalpha 24 h after SE while myeloid infiltrates expressed high levels of IL 1beta and TNFalpha. Immunofluorescence showed that astrocytes but not microglia expressed IL-1beta. Myeloid infiltrates also expressed matrix metalloproteinase (MMP)-9 and 12 while microglia only expressed MMP-12, suggesting the involvement of both cell types in the BBB leakage that follows SE. Finally, both cell types expressed the phagocytosis receptor Axl, pointing to phagocytosis of apoptotic cells as one of the main functions of microglia. Our data suggests that, during early epileptogenesis, microglia from the hippocampus remain rather immune supressed whereas myeloid infiltrates display a strong inflammatory profile. GLIA 2016 GLIA 2016;64:1350-1362. PMID- 27246929 TI - Large area molybdenum disulphide- epitaxial graphene vertical Van der Waals heterostructures. AB - Two-dimensional layered transition metal dichalcogenides (TMDCs) show great potential for optoelectronic devices due to their electronic and optical properties. A metal-semiconductor interface, as epitaxial graphene - molybdenum disulfide (MoS2), is of great interest from the standpoint of fundamental science, as it constitutes an outstanding platform to investigate the interlayer interaction in van der Waals heterostructures. Here, we study large area MoS2 graphene-heterostructures formed by direct transfer of chemical-vapor deposited MoS2 layer onto epitaxial graphene/SiC. We show that via a direct transfer, which minimizes interface contamination, we can obtain high quality and homogeneous van der Waals heterostructures. Angle-resolved photoemission spectroscopy (ARPES) measurements combined with Density Functional Theory (DFT) calculations show that the transition from indirect to direct bandgap in monolayer MoS2 is maintained in these heterostructures due to the weak van der Waals interaction with epitaxial graphene. A downshift of the Raman 2D band of the graphene, an up shift of the A1g peak of MoS2 and a significant photoluminescence quenching are observed for both monolayer and bilayer MoS2 as a result of charge transfer from MoS2 to epitaxial graphene under illumination. Our work provides a possible route to modify the thin film TDMCs photoluminescence properties via substrate engineering for future device design. PMID- 27246931 TI - Multiple Types of Guanine Nucleotide Exchange Factors (GEFs) for Rab Small GTPases. AB - Rab small GTPases are highly conserved master regulators of membrane traffic in all eukaryotes. The same as the activation and inactivation of other small GTPases, the activation and inactivation of Rabs are tightly controlled by specific GEFs (guanine nucleotide exchange factors) and GAPs (GTPase-activating proteins), respectively. Although almost all Rab-GAPs reported thus far have a TBC (Tre-2/Bub2/Cdc16)/Rab-GAP domain in common, recent accumulating evidence has indicated the existence of a number of structurally unrelated types of Rab-GEFs, including DENN proteins, VPS9 proteins, Sec2 proteins, TRAPP complexes, heterodimer GEFs (Mon1-Ccz1, HPS1-HPS4 (BLOC-3 complex), Ric1-Rgp1 and Rab3GAP1/2), and other GEFs (e.g., REI-1 and RPGR). In this review article we provide an up-to-date overview of the structures and functions of all putative Rab-GEFs in mammals, with a special focus on their substrate Rabs, interacting proteins, associations with genetic diseases, and intracellular localizations. PMID- 27246932 TI - Autocalibrating pulse contour analysis based on radial artery applanation tonometry for continuous non-invasive cardiac output monitoring in intensive care unit patients after major gastrointestinal surgery--a prospective method comparison study. AB - The T-Line((r)) system (Tensys((r)) Medical Inc., San Diego, CA, USA) non invasively estimates cardiac output (CO) using autocalibrating pulse contour analysis of the radial artery applanation tonometry-derived arterial waveform. We compared T-Line CO measurements (TL-CO) with invasively obtained CO measurements using transpulmonary thermodilution (TDCO) and calibrated pulse contour analysis (PC-CO) in patients after major gastrointestinal surgery. We compared 1) TL-CO versus TD-CO and 2) TL-CO versus PC-CO in 27 patients treated in the intensive care unit (ICU) after major gastrointestinal surgery. For the assessment of TD-CO and PC-CO we used the PiCCO((r)) system (Pulsion Medical Systems SE, Feldkirchen, Germany). Per patient, we compared two sets of TD-CO and 30 minutes of PC-CO measurements with the simultaneously recorded TL-CO values using Bland-Altman analysis. The mean of differences (+/- standard deviation; 95% limits of agreement) between TL-CO and TD-CO was -0.8 (+/-1.6; -4.0 to +2.3) l/minute with a percentage error of 45%. For TL-CO versus PC-CO, we observed a mean of differences of -0.4 (+/-1.5; -3.4 to +2.5) l/minute with a percentage error of 43%. In ICU patients after major gastrointestinal surgery, continuous non invasive CO measurement based on autocalibrating pulse contour analysis of the radial artery applanation tonometry-derived arterial waveform (TL-CO) is feasible in a clinical study setting. However, the agreement of TL-CO with TD-CO and PC-CO observed in our study indicates that further improvements are needed before the technology can be recommended for clinical use in these patients. PMID- 27246933 TI - Perioperative management of patients treated with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers: a quality improvement audit. AB - Previous studies have shown that patients continuing angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers on the day of surgery are more likely to have significant intraoperative hypotension, higher rates of postoperative acute kidney injury, and lower incidences of postoperative atrial fibrillation. However, many of these studies were prone to bias and confounding, and questions remain over the validity of these outcomes. This observational, before-and-after quality improvement audit aimed to assess the effect of withholding these medications on the morning of surgery. We recruited 323 participants, with 83 (26%) having their preoperative angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) withheld on the day of surgery. There were only very small Spearman rank-order correlations between time since last dose of these medications (rho -0.12, P=0.057) and intraoperative and recovery room intravenous fluid administration (rho -0.11, P=0.042). There was no statistically significant difference between the continued or withheld groups in vasopressor (metaraminol use 3.5 [1.5-8.3] mg versus 3.5 [1.5-8.5] mg, P=0.67) or intravenous fluid administration (1000 ml [800-1500] ml versus 1000 [800-1500] ml, P=0.096), nor rates of postoperative acute kidney injury (13% vs 18%, P=0.25) or atrial fibrillation (15% versus 18%, P=0.71). This audit found no significant differences in measured outcomes between the continued or withheld ACEi/ARB groups. This finding should be interpreted with caution due to the possibility of confounding and an insufficient sample size. However, as the finding is in contrast to many previous studies, future prospective randomised clinical trials are required to answer this important question. PMID- 27246934 TI - Automated external defibrillator use for in-hospital emergency management. AB - The in-hospital spread of automated external defibrillators (AEDs) is aimed to allow for a shock-delivery within three minutes. However, it has to be questioned if the implementation of AED alone really contributes to a 'heart-safe hospital'. We performed a cohort study of 1008 in-hospital emergency calls in a university tertiary care hospital, analysing cardiopulmonary resuscitation (CPR) cases with and without AED use. In total, 484 patients (48%) had cardiac arrest and received CPR. Response time of the emergency team was 4.3 +/- 4.0 minutes. Only 8% percent of the CPR cases had a shockable rhythm. In three of 43 placements a shock was delivered by the AED. There were no differences in survival between patients with CPR only and CPR with AED use. Our data do not support the use of an AED for in hospital CPR if a professional response team is rapidly available. PMID- 27246935 TI - Effect of interscalene anaesthesia on cerebral oxygen saturation. AB - Interscalene blockade (ISB) is commonly associated with Horner's syndrome, indicating spread of injectate to the cervical sympathetic chain. Cervical sympathetic nerve activity (SNA) is believed to influence cerebral autoregulation, and a decrease in sympathetic tone may alter cerebral blood flow (CBF). This study investigated whether ISB influenced CBF in patients undergoing shoulder surgery. Patients (n=30) scheduled for elective shoulder arthroscopy were recruited. Cerebral oxygen saturation (ScO(2)) of the left and right frontal cortices was continuously measured during ISB administration, sedation and anaesthetic induction. Baseline ScO(2) was similar in blocked and unblocked sides (74 +/- 5% and 73 +/- 5% respectively, P=0.70). ScO(2) decreased with sedation ( 3 +/- 3% and -4 +/- 3%, P=0.93), and increased with pre-oxygenation and general anaesthesia (P <0.01). Following ISB there was no change in ScO(2) between blocked and unblocked sides (P=0.18), or any difference between right- or left sided ISB. ISB is not associated with an increase in CBF as indicated by ScO(2), despite the presence of Horner's syndrome. PMID- 27246936 TI - Night shift fatigue among anaesthesia trainees at a major metropolitan teaching hospital. AB - Night shifts expose anaesthesia trainees to the risk of fatigue and, potentially, fatigue-related performance impairment. This study examined the workload, fatigue and coping strategies of anaesthesia trainees during night shifts. A blinded survey-based study was undertaken at a major single centre metropolitan teaching hospital in Australia. All ten anaesthesia trainees who worked night shifts participated. The survey collected data on duration of night shifts, workload, and sleep patterns. Fatigue was assessed using the Karolinska Sleepiness Scale (KSS). There were 93 night shifts generating data out of a potential 165. Trainees tended to sleep an increasing amount before their shift as the nights progressed from 1 to 5. Night 1 was identified as an 'at risk' night due to the amount of time spent awake before arriving at work (32% awake for U+003E8 hours); on all other nights trainees were most likely to have slept 6-8 hours. The KSS demonstrated an increase in sleepiness of 3 to 4 points on the scale from commencement to conclusion of a night shift. The Night 1 conclusion sleepiness was markedly worse than any other night with 42% falling into an 'at-risk' category. The findings demonstrate fatigue and inadequate sleep in anaesthesia trainees during night shifts in a major metropolitan teaching hospital. The data obtained may help administrators prepare safer rosters, and junior staff develop improved strategies to reduce the likelihood of fatigue. PMID- 27246937 TI - Percutaneous dilatational tracheostomy using a tracheoscopic ventilation tube in an experimental ex vivo animal model. AB - The ETView((r)) tube is a standard endotracheal tube with an embedded miniature video camera that permits real-time video imaging of the tracheal lumen. We evaluated its use when performing percutaneous dilatational tracheostomy (PDT) in an ex vivo animal model. The model consisted of a pig larynyx and trachea. The ETView tube was used as an alternative to bronchoscopy, to see all manoeuvres of PDT in real time. At the end of the PDT, operative time and any complications such as trauma to the cricoid cartilage, tracheal wall or tube cuff were assessed. Nine PDT procedures were performed by two experienced operators. The mean operative time was 7.1 +/- 0.9 minutes. No complications were observed. Our study supports the use of the ETView tube as a suitable alternative to bronchoscopy when performing PDT, although clinical studies are required to confirm our experimental results. . PMID- 27246938 TI - Potential rapid solutions to maintain ventilation in the event of anaesthesia machine failure with no access to the patient's airway. AB - Anaesthesia machine failure requires rapid solutions to maintain ventilation and anaesthesia. During procedures with poor access to the patient's airway, it may not be possible to use a self-inflating mechanical ventilation device (SIMVD) for emergency ventilation, and alternative solutions are needed. We evaluated five methods for rescue ventilation using a patient simulator. In Method 1, we used the inspiratory and expiratory tubes and the alternative common gas outlet (ACGO) on the anaesthesia machine to produce a Mapleson E system. In Method 2, we used the tubes, ACGO and an open-ended reservoir bag to produce a Mapleson F system, controlling the bag to achieve ventilation. In Method 3, we attached a SIMVD to the inspiratory tube, and controlled occlusion of the expiratory tube. In Method 4, we used the tubes and ACGO in a Mapleson F configuration, replacing the open ended bag with a SIMVD to facilitate manual ventilation. In Method 5, we attached a SIMVD to the expiratory tube and left the inspiratory tube attached to its mounting. We were able to achieve ventilation, maintain inhalational anaesthesia, and prevent expired gas rebreathing in Methods 1 and 2. In Method 3 ventilation was achieved with minimal rebreathing of expiratory gas, but with no inhalational agent. Methods 4 and 5 led to rebreathing. Our findings indicate that Methods 1 or 2 are the preferred rapid solutions to maintain ventilation and inhalational anaesthesia in the event of anaesthesia machine failure where there is poor airway access. PMID- 27246939 TI - Minimally invasive cardiac output monitoring: agreement of oesophageal Doppler, LiDCOrapidTM and Vigileo FloTracTM monitors in non-cardiac surgery. AB - There is lack of data about the agreement of minimally invasive cardiac output monitors, which make it impossible to determine if they are interchangeable or differ objectively in tracking physiological trends. We studied three commonly used devices: the oesophageal Doppler and two arterial pressure-based devices, the Vigileo FloTracTM and LiDCOrapidTM. The aim of this study was to compare the agreement of these three monitors in adult patients undergoing elective non cardiac surgery. Measurements were taken at baseline and after predefined clinical interventions of fluid, metaraminol or ephedrine bolus. From 24 patients, 131 events, averaging 5.2 events per patient, were analysed. The cardiac index of LiDCOrapid versus FloTrac had a mean bias of -6.0% (limits of agreement from -51% to 39%) and concordance of over 80% to the three clinical interventions. The cardiac index of Doppler versus LiDCOrapid and Doppler versus FloTrac, had an increasing negative bias at higher mean cardiac outputs and there was significantly poorer concordance to all interventions. Of the preload responsive parameters, Doppler stroke volume index, Doppler systolic flow time and FloTrac stroke volume variation were fair at predicting fluid responsiveness while other parameters were poor. While there is reasonable agreement between the two arterial pressure-derived cardiac output devices (LiDCOrapid and Vigileo FloTrac), these two devices differ significantly to the oesophageal Doppler technology in response to common clinical intraoperative interventions, representing a limitation to how interchangeable these technologies are in measuring cardiac output. PMID- 27246940 TI - Rapid Response Team activation in New Zealand hospitals-a multicentre prospective observational study. AB - We aimed to describe the epidemiology of Rapid Response Team (RRT) activation in New Zealand public hospitals. We undertook a prospective multicentre observational study of RRT activations in 11 hospitals for consecutive 14-day periods during October-December 2014. A standardised case report form was used to collect data on patient demographics, RRT activation criteria and timing, vital signs on RRT arrival, team composition and intervention, treatment limitation and patient outcome at day 30. Three hundred and thirteen patients received 351 RRT calls during the study period. Patients were admitted under a medical specialty in 177 (56.5%) instances. Median duration from hospital admission to first RRT call was two days. Eighty-six percent of RRT calls were to inpatient wards. A total of 43.4% of RRT calls occurred between 0800 and 1700 hours (38% of the day) and 75.5% of RRT calls were activated by ward nurses. A median of three staff attended each call. Common triggers for RRT activation were increased Early Warning Score (56.2%) and staff concern (25.7%). During the RRT call, 2.8% of patients died; 19.8% died by day 30. New 'Not For Resuscitation' orders were written in 22.5% of RRT calls. By day 30, 56.2% of patients had been discharged home alive. In conclusion, RRTs in New Zealand are multidisciplinary, mostly nurse-activated and predominantly respond to deteriorating medical (rather than surgical) patients. Most patients remain on the ward. The RRT frequently implements treatment limitations. Given almost one in five patients die within 30 days, over half of whom die within 72 hours of RRT review, surviving the RRT call may provide false reassurance that the patient will subsequently do well. PMID- 27246941 TI - A prospective observational study of the association between cabin and outside air temperature, and patient temperature gradient during helicopter transport in New South Wales. AB - The prevalence of hypothermia in patients following helicopter transport varies widely. Low outside air temperature has been identified as a risk factor. Modern helicopters are insulated and have heating; therefore outside temperature may be unimportant if cabin heat is maintained. We sought to describe the association between outside air, cabin and patient temperature, and having the cabin temperature in the thermoneutral zone (18-36 degrees C) in our helicopter transported patients. We conducted a prospective observational study over one year. Patient temperature was measured on loading and engines off. Cabin and outside air temperature were recorded for the same time periods for each patient, as well as in-flight. Previously identified risk factors were recorded. Complete data was obtained for 133 patients. Patients' temperature increased by a median of 0.15 degrees C (P=0.013). There was no association between outside air temperature or cabin temperature and patient temperature gradient. The best predictor of patient temperature on landing was patient temperature on loading (R2=0.86) and was not improved significantly when other risk factors were added (P=0.63). Thirty-five percent of patients were hypothermic on loading, including those transferred from district hospitals. No patient loaded normothermic became hypothermic when the cabin temperature was in the thermoneutral zone (P=0.04). A large proportion of patients in our sample were hypothermic at the referring hospital. The best predictor of patient temperature on landing is patient temperature on loading. This has implications for studies that fail to account for pre-flight temperature. PMID- 27246942 TI - The effect of augmenting early nutritional energy delivery on quality of life and employment status one year after ICU admission. AB - Augmenting energy delivery during the acute phase of critical illness may reduce mortality and improve functional outcomes. The objective of this sub-study was to evaluate the effect of early augmented enteral nutrition (EN) during critical illness, on outcomes one year later. We performed prospective longitudinal evaluation of study participants, initially enrolled in The Augmented versus Routine approach to Giving Energy Trial (TARGET), a feasibility study that randomised critically ill patients to 1.5 kcal/ml (augmented) or 1.0 kcal/ml (routine) EN administered at the same rate for up to ten days, who were alive at one year. One year after randomisation Short Form-36 version 2 (SF-36v2) and EuroQol-5D-5L quality of life surveys, and employment status were assessed via telephone survey. At one year there were 71 survivors (1.5 kcal/ml 38 versus 1.0 kcal/ml 33; P=0.55). Thirty-nine (55%) patients consented to this follow-up study and completed the surveys (n = 23 and 16, respectively). The SF-36v2 physical and mental component summary scores were below normal population means but were similar in 1.5 kcal/ml and 1.0 kcal/ml groups (P=0.90 and P=0.71). EuroQol-5D-5L data were also comparable between groups (P=0.70). However, at one-year follow up, more patients who received 1.5 kcal/ml were employed (7 versus 2; P=0.022). The delivery of 1.5 kcal/ml for a maximum of ten days did not affect self-rated quality of life one year later. PMID- 27246943 TI - A feasibility study of functional status and follow-up clinic preferences of patients at high risk of post intensive care syndrome. AB - After prolonged mechanical ventilation patients may experience the 'post intensive care syndrome' (PICS) and may be candidates for post-discharge follow up clinics. We aimed to ascertain the incidence and severity of PICS symptoms in patients surviving prolonged mechanical ventilation and to describe their views regarding follow-up clinics. In a teaching hospital, we conducted a cohort study of all adult patients discharged alive after ventilation in ICU for >=7 days during 2013. We administered the EuroQol-5D (EQ-5D) and Hospital Anxiety and Depression Scale (HADS) via telephone interview and asked patients their views about the possible utility of a follow-up clinic. We studied 48 patients. At follow-up (average 19.5 months), seven (15%) patients had died and 14 (29%) did not participate (eight declined; two were non-English speakers; four were non contactable). Among the 27 responders, 16 (59%) reported at least moderate problems in >=1 EQ-5D dimension; 10 (37%) in >=2 dimensions, and 8 (30%) in >=3 dimensions. Moreover, 10 (37%) patients reported marked psychological symptoms; six (22%) scored borderline or abnormal on the HADS for both anxiety and depression; and four (15%) scored borderline or abnormal for one component. Finally, 21/26 (81%) patients stated that an ICU follow-up clinic would have been beneficial. At long-term follow-up, the majority of survivors of prolonged mechanical ventilation reported impaired quality of life and significant psychological symptoms. Most believed that a follow-up clinic would have been beneficial. PMID- 27246944 TI - Global safe anaesthesia and surgery initiatives: implications for anaesthesia in the Pacific region. AB - In 2015 three major events occurred for global anaesthesia and surgery. In January, the World Bank published Disease Control Priorities 3rd edition (DCP 3rd edition). This volume, Essential Surgery, highlighted the cost effective role of anaesthesia and surgery in global health. In April, the Lancet Commission on Global Surgery released its report "Global Surgery 2030: Evidence and solutions for achieving health, welfare, and economic development". The report focuses on five key areas to promote change including: access to timely surgery, surgical workforce and procedural capability, surgical volume, data collection such as perioperative mortality rate, and financial protection. In May, the 68th World Health Assembly (WHA) voted in favour of Resolution A68/31: Strengthening emergency and essential surgical and anaesthesia care as a component of universal health coverage. The resolution was passed unanimously and it is the first time that surgery and anaesthesia have received such prominence at WHA level. These three events all have profound implications for the provision and access of safe anaesthesia and surgery in the Pacific region in the next 15 years. This article considers some of the regional factors that affect these five key areas, especially with regard to anaesthetic specialist workforce density in different parts of the region. There are many challenges to improve anaesthesia access, safety, and workforce density in the Pacific region. Future efforts, initiatives and support will help address these problems. PMID- 27246945 TI - Early skin and challenge testing after rocuronium anaphylaxis. AB - We present a case of early skin and challenge testing in a patient following severe anaphylaxis to rocuronium. The patient presented for semi-elective laparoscopic cholecystectomy and developed anaphylaxis with severe cardiovascular collapse after induction of anaesthesia. Surgery was cancelled but was considered necessary before the recommended four to six weeks for formal allergy testing. Limited skin and challenge testing was performed to rocuronium and cisatracurium while the patient was in the intensive care unit to identify a safe neuromuscular blocking drug for subsequent early surgery. The subsequent surgery, 48 hours after the initial reaction, was uneventful. The case highlights the difficulties when anaesthetising patients with recent anaphylaxis who have not yet had formal allergy testing and presents a potential management strategy involving early skin testing. PMID- 27246946 TI - Tracheal injury using a gum elastic bougie within a RAE endotracheal tube. PMID- 27246947 TI - How to avoid the Aintree Intubation Catheter getting stuck inside the LMA. PMID- 27246948 TI - Corrigendum. PMID- 27246949 TI - Identifying perioperative predictors of acute kidney injury after liver transplantation. PMID- 27246950 TI - Robotic-assisted real-time MRI-guided TAVR: from system deployment to in vivo experiment in swine model. AB - PURPOSE: Real-time magnetic resonance imaging (rtMRI) guidance provides significant advantages during transcatheter aortic valve replacement (TAVR) as it provides superior real-time visualization and accurate device delivery tracking. However, performing a TAVR within an MRI scanner remains difficult due to a constrained procedural environment. To address these concerns, a magnetic resonance (MR)-compatible robotic system to assist in TAVR deployments was developed. This study evaluates the technical design and interface considerations of an MR-compatible robotic-assisted TAVR system with the purpose of demonstrating that such a system can be developed and executed safely and precisely in a preclinical model. METHODS: An MR-compatible robotic surgical assistant system was built for TAVR deployment. This system integrates a 5 degrees of freedom (DoF) robotic arm with a 3-DoF robotic valve delivery module. A user interface system was designed for procedural planning and real-time intraoperative manipulation of the robot. The robotic device was constructed of plastic materials, pneumatic actuators, and fiber-optical encoders. RESULTS: The mechanical profile and MR compatibility of the robotic system were evaluated. The system-level error based on a phantom model was 1.14 +/- 0.33 mm. A self expanding prosthesis was successfully deployed in eight Yorkshire swine under rtMRI guidance. Post-deployment imaging and necropsy confirmed placement of the stent within 3 mm of the aortic valve annulus. CONCLUSIONS: These phantom and in vivo studies demonstrate the feasibility and advantages of robotic-assisted TAVR under rtMRI guidance. This robotic system increases the precision of valve deployments, diminishes environmental constraints, and improves the overall success of TAVR. PMID- 27246951 TI - Cerebral blood flow and metabolism associated with cerebral microbleeds in small vessel disease. AB - OBJECTIVE: Cerebral microbleeds (CMBs), probably reflecting microangiopathy, have not yet sufficiently been examined in association with cerebral blood flow (CBF) and metabolism. We investigated the relationships between CMBs, and CBF and metabolism in symptomatic small vessel disease. METHODS: We enrolled 22 patients with symptomatic small vessel disease without severe stenosis (>50 %) in major cerebral arteries. Volumes of white matter lesions (WMLs) and number of CMBs were assessed on images of fluid-attenuated inversion recovery and gradient-echo T2* weighted magnetic resonance imaging, respectively. Patients were divided into two groups according to the median number of CMBs (group I <5, n = 10; group II >=5, n = 12). Parametric images of CBF, cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction and cerebral blood volume were estimated using positron emission tomography and (15)O-labeled gases. The functional values in the cortex-subcortex, basal ganglia, and centrum semiovale were compared between the two groups. RESULTS: Volumes of WMLs of group II were larger than those of group I (median: 38.4; range: 25.1-91.5 mL vs. median: 11.3; range: 4.2-73.4 mL, p = 0.01). In the centrum semiovale, the mean CBF of group II was significantly lower than that of group I (12.6 +/- 2.6 vs. 15.6 +/- 3.3 mL/100 g/min, p = 0.04). In the other regions, there were no significant differences in either CBF or CMRO2 between the two groups. CONCLUSIONS: Our study indicated that increases in the number of CMBs with larger volumes of WMLs were associated with cerebral ischemia in the deep white matter in patients with symptomatic small vessel disease. PMID- 27246952 TI - Interim FDG-PET/CT in Hodgkin lymphoma: the prognostic role of the ratio between target lesion and liver SUVmax (rPET). AB - OBJECTIVE: To evaluate the prognostic role of the ratio between target lesion and liver SUVmax (rPET) in patients with Hodgkin lymphoma (HL) undergoing interim FDG PET/CT and to compare rPET with the 5-point Deauville Score (5p-DS). METHODS: Sixty-eight patients with HL undergoing interim FDG-PET/CT after first courses of chemotherapy were evaluated. The receiver operating characteristic (ROC) approach was applied to identify the optimal cutpoint of rPET with respect to progression free survival (PFS). The prognostic significance of rPET was compared with 5p-DS (scores 4 and 5 considered as positive). Positive predictive value (PPV) and negative predictive value (NPV) were calculated using the presence of an adverse event as the gold standard. RESULTS: The ROC analysis for rPET as a predictor of progression showed an optimal rPET cutpoint of 1.14. Both 5p-DS and rPET were strong outcome predictors (p < 0.001). Patients with negative 5p-DS and patients with rPET <1.14 had a similar two-year PFS (86 and 87 %, respectively). Patients with a positive 5p-DS had a 2-year PFS of 27 %, while patients with rPET >1.14 had a 2-year PFS of 15 %. 5p-DS and rPET cutoff of 1.14 showed a PPV of 58 versus 70 %, and a NPV of 85 versus 86 %, respectively. CONCLUSIONS: rPET could be considered an accurate prognostic factor in patients with HL undergoing interim FDG-PET/CT. Larger prospective studies are needed to confirm these data. PMID- 27246953 TI - Roles of long noncoding RNAs in gastric cancer and their clinical applications. AB - PURPOSE: Gastric cancer ranks as the most common cancer in the world. However, the progresses of its diagnosis and treatment are still not satisfactory. The purpose of this study is to summarize the roles of lncRNAs associated with gastric cancer. METHODS: We searched lncRNAs associated with gastric cancer in PubMed. RESULTS: Long noncoding RNAs (lncRNAs), transcripts larger than 200 nucleotides, regulate gene expression at various levels. They are playing important roles in the occurrence and development of gastric cancer. They are involved in signaling pathways, crosstalk with microRNAs, and affecting metastasis by regulating epithelial-to-mesenchymal transition. By acting as oncogenes or tumor suppressors, lncRNAs contribute to gastric cancer occurrence and development. Several lncRNAs including HOTAIR, HULC, LINC00152, MALAT2, H19, GHET1, and GACAT3 have been demonstrated having oncogene activities, while other lncRNAs including LEIGC, GAS5, and FER1L4 have been thought as tumor suppressors. CONCLUSIONS: Several lncRNAs from tissue, blood, and gastric juice have shown potential values in gastric cancer diagnosis or prognosis evaluation. PMID- 27246954 TI - A pilot study evaluating the effects of a youth advocacy program on youth readiness to advocate for environment and policy changes for obesity prevention. AB - Youth advocacy for obesity prevention is a promising but under-evaluated intervention. The aims of this study are to evaluate a youth advocacy program's outcomes related to youth perceptions and behaviors, develop an index of youth advocacy readiness, and assess potential predictors of advocacy readiness. Youth ages 9-22 in an advocacy training program (n = 92 matched pairs) completed surveys before and after training. Youth outcomes and potential predictors of advocacy readiness were assessed with evaluated scales. All 20 groups who completed the evaluation study presented their advocacy projects to a decision maker. Two of six perception subscales increased following participation in the advocacy program: self-efficacy for advocacy behaviors (p < .001) and participation in advocacy (p < .01). Four of five knowledge and skills subscales increased: assertiveness (p < .01), health advocacy history (p < .001), knowledge of resources (p < .01), and social support for health behaviors (p < .001). Youth increased days of meeting physical activity recommendations (p < .05). In a mixed regression model, four subscales were associated with the advocacy readiness index: optimism for change (B = 1.46, 95 % CI = .49-2.44), sports and physical activity enjoyment (B = .55, 95 % CI = .05-1.05), roles and participation (B = 1.81, 95 % CI = .60-3.02), and advocacy activities (B = 1.49, 95 % CI = .64 2.32). The youth advocacy readiness index is a novel way to determine the effects of multiple correlates of advocacy readiness. Childhood obesity-related advocacy training appeared to improve youths' readiness for advocacy and physical activity. PMID- 27246955 TI - Impaired or Not Impaired, That Is the Question: Navigating the Challenges Associated with Using Canadian Normative Data in a Comprehensive Test Battery That Contains American Tests. AB - It has been well documented that IQ scores calculated using Canadian norms are generally 2-5 points lower than those calculated using American norms on the Wechsler IQ scales. However, recent findings have demonstrated that the difference may be significantly larger for individuals with certain demographic characteristics, and this has prompted discussion about the appropriateness of using the Canadian normative system with a clinical population in Canada. This study compared the interpretive effects of applying the American and Canadian normative systems in a clinical sample. We used a multivariate analysis of variance (ANOVA) to calculate differences between IQ and Index scores in a clinical sample, and mixed model ANOVAs to assess the pattern of differences across age and ability level. As expected, Full Scale IQ scores calculated using Canadian norms were systematically lower than those calculated using American norms, but differences were significantly larger for individuals classified as having extremely low or borderline intellectual functioning when compared with those who scored in the average range. Implications of clinically different conclusions for up to 52.8% of patients based on these discrepancies highlight a unique dilemma facing Canadian clinicians, and underscore the need for caution when choosing a normative system with which to interpret WAIS-IV results in the context of a neuropsychological test battery in Canada. Based on these findings, we offer guidelines for best practice for Canadian clinicians when interpreting data from neuropsychological test batteries that include different normative systems, and suggestions to assist with future test development. PMID- 27246956 TI - Case Report of Vestibularly evoked Visual Hallucinations in a Patient with Cortical Blindness. AB - Previous work has shown that caloric vestibular stimulation may evoke elementary visual hallucinations in healthy humans, such as different colored lines or dots. Surprisingly, the present case report reveals that the same stimulation can evoke visual hallucinations in a patient with cortical blindness, but with fundamentally different characteristics. The visual hallucinations evoked were complex and came from daily life experiences. Moreover, they did not include other senses beyond vision. This case report suggests that in conditions of cerebral pathology, vestibular-visual interaction may stimulate hallucinogenic subcortical, or undamaged cortical structures, and arouse mechanisms that can generate visual images exclusively. PMID- 27246957 TI - Remote Neuropsychological Assessment in Rural American Indians with and without Cognitive Impairment. AB - OBJECTIVE: To determine the feasibility and reliability of a brief battery of standard neuropsychological tests administered via video teleconference (VTC) to a sample of rural American Indians compared with traditional face-to-face administration. METHODS: The sample consisted of 84 participants from the Choctaw Nation in Oklahoma, including 53 females and 31 males [M age = 64.89 (SD = 9.73), M education = 12.58 (SD = 2.35)]. Of these, 29 had a diagnosis of mild cognitive impairment or dementia, and 55 were cognitively normal. Tests included the MMSE, Clock Drawing, Digit Span Forward and Backward, Oral Trails, Hopkins Verbal Learning Test-Revised, Letter and Category Fluency, and a short form Boston Naming Test. Alternative forms of tests were administered in counterbalanced fashion in both face-to-face and VTC conditions. Intraclass correlation coefficients (ICCs) were used to compare test scores between test conditions across the entire sample. RESULTS: All ICCs were significant (p< .0001) and ranged from 0.65 (Clock Drawing) to 0.93 (Boston Naming Test), with a mean ICC of 0.82. CONCLUSION: Results add to the expanding literature supporting the feasibility and reliability of remote videoconference-based neuropsychological test administration and extend findings to American Indians. PMID- 27246958 TI - The Hayling Test: Development and Normalization of the Spanish Version. AB - OBJECTIVE: The Hayling Sentence Completion Test evaluates the ability to inhibit an automatic response. It has also been suggested for the assessment of orbitofrontal cortex function. The aim of the study was to develop a Spanish version of the Hayling test and to obtain normative data. METHOD: Responses to 60 sentences from 50 healthy controls were used to develop the task. Additionally, 185 healthy controls aged between 18 and 99 years were examined with the test in order to obtain normative data. The overlapping interval strategy was used to maximize the sample size. Age- and education-adjusted scores were obtained using linear regression analysis. RESULTS: Age and educational level had a significant effect on the different scores. Good internal reliability and inter-rater variability were observed. CONCLUSIONS: We provide normative data adjusted for age and education. Our results enable the use of this test for clinical and research purposes in the field of neuropsychological assessment. PMID- 27246959 TI - The Victoria Stroop Test: Normative Data in Quebec-French Adults and Elderly. AB - OBJECTIVE: Despite the widespread use of the Victoria Stroop Test (VST; Regard, 1981) in clinical and research settings, information regarding the impact of sociodemographic variables on test performance in Quebec-French adults and elderly people is still nonexistent. Thus, this study aimed to establish normative data for error scores and completion time on all test trials (Dot, Word, and Interference) taking into account the impact of age, education, and sex on test performance. METHOD: The sample consisted of 646 community-dwelling and healthy Quebec-French individuals aged between 47 and 87 years. RESULTS: Regression analyses indicated that age was associated with completion time and error scores on all trials. The association was also positive for low and high interference conditions. Education was associated with completion time on Word and Interference trials, and with both interference scores. Finally, sex was associated with completion time on all trials, with women being consistently faster than men. Equations to calculate Z scores and percentiles are presented. CONCLUSIONS: Norms for the VST will ease interpretation of executive functioning in Quebec-French adults and elderly and favor accurate discrimination between normal and pathological cognitive states. PMID- 27246960 TI - Current technologies and new insights for the recovery of high valuable compounds from fruits by-products. AB - The recovery of high valuable compounds from food waste is becoming a tighten issue in food processing. The large amount of non-edible residues produced by food industries causes pollution, difficulties in the management, and economic loss. The waste produced during the transformation of fruits includes a huge amount of materials such as peels, seeds, and bagasse, whose disposal usually represents a problem. Research over the past 20 years revealed that many food wastes could serve as a source of potentially valuable bioactive compounds, such as antioxidants and vitamins with increasing scientific interest thanks to their beneficial effects on human health. The challenge for the recovery of these compounds is to find the most appropriate and environment friendly extraction technique able to achieve the maximum extraction yield without compromising the stability of the extracted products. Based on this scenario, the aim of the current review is twofold. The first is to give a brief overview of the most important bioactive compounds occurring in fruit wastes. The second is to describe the pro and cons of the most up-to-dated innovative and environment friendly extraction technologies that can be an alternative to the classical solvent extraction procedures for the recovery of valuable compounds from fruit processing. Furthermore, a final section will take into account published findings on the combination of some of these technologies to increase the extracts yields of bioactives. PMID- 27246961 TI - Pitfalls in mitochondrial epigenetics. AB - 5-Methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are fingerprints of epigenetic modifications. These bases have been found in the mitochondrial DNA (mtDNA) and together with the discovery of mitochondrial localization of DNA methyltransferases, this implies that mtDNA is under epigenetic regulation. However, the indirect methods hitherto used to assess mitochondrial 5mC and 5hmC require attention as they readily generate artificial signals that may lead to erroneous conclusions. Here, we demonstrate how three independent, frequently used methods to identify epigenetic modification of DNA readily generate false mtDNA epigenetic signals. The three methods were selective 5mC/5hmC-mediated inhibition of restriction enzymes, bisulfite conversion and 5hmC glucosylation dependent immunocapture. Adequate controls for all methods are suggested. PMID- 27246962 TI - Role of magnetic resonance imaging in the management of intestinal obstruction during the first trimester of pregnancy. PMID- 27246963 TI - Wallenberg's lateral medullary syndrome in an adolescent. PMID- 27246964 TI - Learning to manage complexity through simulation: students' challenges and possible strategies. AB - Many have called for medical students to learn how to manage complexity in healthcare. This study examines the nuances of students' challenges in coping with a complex simulation learning activity, using concepts from complexity theory, and suggests strategies to help them better understand and manage complexity.Wearing video glasses, participants took part in a simulation ward based exercise that incorporated characteristics of complexity. Video footage was used to elicit interviews, which were transcribed. Using complexity theory as a theoretical lens, an iterative approach was taken to identify the challenges that participants faced and possible coping strategies using both interview transcripts and video footage.Students' challenges in coping with clinical complexity included being: a) unprepared for 'diving in', b) caught in an escalating system, c) captured by the patient, and d) unable to assert boundaries of acceptable practice.Many characteristics of complexity can be recreated in a ward-based simulation learning activity, affording learners an embodied and immersive experience of these complexity challenges. Possible strategies for managing complexity themes include: a) taking time to size up the system, b) attuning to what emerges, c) reducing complexity, d) boundary practices, and e) working with uncertainty. This study signals pedagogical opportunities for recognizing and dealing with complexity. PMID- 27246965 TI - Exploring cognitive integration of basic science and its effect on diagnostic reasoning in novices. AB - Integration of basic and clinical science knowledge is increasingly being recognized as important for practice in the health professions. The concept of 'cognitive integration' places emphasis on the value of basic science in providing critical connections to clinical signs and symptoms while accounting for the fact that clinicians may not spontaneously articulate their use of basic science knowledge in clinical reasoning. In this study we used a diagnostic justification test to explore the impact of integrated basic science instruction on novices' diagnostic reasoning process. Participants were allocated to an integrated basic science or clinical science training group. The integrated basic science group was taught the clinical features along with the underlying causal mechanisms of four musculoskeletal pathologies while the clinical science group was taught only the clinical features. Participants completed a diagnostic accuracy test immediately after initial learning, and one week later a diagnostic accuracy and justification test. The results showed that novices who learned the integrated causal mechanisms had superior diagnostic accuracy and better understanding of the relative importance of key clinical features. These findings further our understanding of cognitive integration by providing evidence of the specific changes in clinical reasoning when basic and clinical sciences are integrated during learning. PMID- 27246966 TI - Reducing length of stay and satisfying learner needs. AB - A complicated relationship exists between emergency department (ED) learner needs and patient flow with solutions to one issue often negatively affecting the other. Teaching shifts that allow clinical teachers and learners to interact without the pressure of patient care may offer a mutually beneficial solution. This study investigated the relationship between teaching shifts on ED length of stay, student self-efficacy and knowledge application.In 2012-2013, a prospective, cohort study was undertaken in a large Canadian acute-care teaching centre. All 132 clinical clerks completing their mandatory two-week emergency medicine rotation participated in three teaching shifts supervised by one faculty member without patient care responsibilities. The curriculum emphasized advanced clinical skills and included low fidelity simulation exercises, a suturing lab, image interpretation modules and discussion about psychosocial issues in emergency medicine. The clerks then completed seven clinical shifts in the traditional manner caring for patients under the supervision of an ED attending physician. Length of stay was compared during and one week following teaching shifts. A self-efficacy questionnaire was validated through exploratory factor analysis. Pre/post knowledge application was assessed using a paper-based clinical case activity.Across 40.998 patient visits, median length of stay was shortened overall by 5 minutes (95 % CI:1.2, 8.8) when clerks were involved in their teaching shifts. In the first academic block, median length of stay was reduced by 20 minutes per patient (95 % CI:12.7, 27.3). Self-efficacy showed significant improvement post teaching shifts (p < 0.001) with large effect sizes (d > 1.25) on dimensions of knowledge base, suturing, trauma and team efficacy. Students' knowledge application scores improved from pre to post (p < 0.01), with notable gains in the generation of differential diagnoses.Teaching shifts are an effective educational intervention that has a positive relation to ED patient flow while successfully attending to learner needs. Teaching shifts for the most naive clerks in the first academic block appear to maximally benefit length of stay. Students demonstrated improved self-efficacy and knowledge application after their teaching shifts. PMID- 27246967 TI - Intimate partner violence among men and women who use methamphetamine: A mixed methods study in South Africa. AB - INTRODUCTION: The prevalence of methamphetamine use has risen dramatically in parts of South Africa. Globally, methamphetamine has been linked to intimate partner violence (IPV) and other forms of aggression. The aim of this mixed methods study was to examine the experiences of physical IPV and its contextual factors among methamphetamine users in an urban community in Cape Town, South Africa. METHODS: Active methamphetamine users were recruited using respondent driven sampling. All participants (n = 360) completed structured surveys, and a subset (n = 30) completed in-depth interviews with discussions of personal IPV experiences. Quantitative data were examined separately by gender, and regression models were used to identify factors that were associated with physical IPV victimisation and perpetration. Qualitative data were analysed to provide contextual understanding. RESULTS: In the past 3 months, 47% of women and 31% of men reported being a victim of IPV, and 30% of women and 28% men reported being a perpetrator of IPV. Victimisation and perpetration were highly correlated, and both were significantly associated with histories of other traumas. Although the survey data suggests gender equivalence in IPV, the qualitative data provides a more nuanced context, with female victimisation by male partners being particularly frequent and intense. In narratives, IPV was a product of male aggression while using methamphetamine, norms around sex trading and gender-based attitudes endorsing violence against women. CONCLUSION: Addiction to methamphetamine creates heightened risks of IPV, especially among those with previous traumas. The findings emphasise the importance of identifying and addressing IPV among methamphetamine users in South Africa. [Watt MH, Guidera KE, Hobkirk AL, Skinner D, Meade CS. Intimate partner violence among men and women who use methamphetamine: A mixed-methods study in South Africa. Drug Alcohol Rev 2017;36:97-106]. PMID- 27246968 TI - The dynamics of cardiac autonomic control in sleeping preterm neonates exposed in utero to smoking. AB - OBJECTIVE: We aimed to determine whether in utero exposure to smoking may influence the activity and dynamics of cardiac autonomic control in preterm infants. We hypothesized that cardiac autonomic control is altered in preterm infants exposed prenatally to smoking and that these effects may vary as a function of the sleep state. METHODS: We studied healthy, preterm neonates born to mothers who had smoked throughout pregnancy but not since birth (n=16). In utero-exposed neonates were matched with control preterm neonates born to non smoking mothers (n=18). Cardiac autonomic control was monitored as a function of the sleep state by assessing heart rate variability with both linear and non linear methods. RESULTS: Preterm neonates with in utero exposure to smoking displayed alterations (relative to control neonates) in short-term cardiac autonomic control in all sleep states. These alterations included low vagal activity, elevated sympathetic activity, and low complexity and adaptability in heart rate control dynamics. CONCLUSIONS: Our results constitute direct evidence that cardiac autonomic activity and control are altered in sleeping preterm infants exposed to smoking in utero. SIGNIFICANCE: These alterations may place the affected infants at a higher risk of neurological and cardiovascular complications, which could conceivably persist throughout childhood and adulthood. PMID- 27246969 TI - Microwave flow and conventional heating effects on the physicochemical properties, bioactive compounds and enzymatic activity of tomato puree. AB - BACKGROUND: Thermal processing causes a number of undesirable changes in physicochemical and bioactive properties of tomato products. Microwave (MW) technology is an emergent thermal industrial process that offers a rapid and uniform heating, high energy efficiency and high overall quality of the final product. The main quality changes of tomato puree after pasteurization at 96 +/- 2 degrees C for 35 s, provided by a semi-industrial continuous microwave oven (MWP) under different doses (low power/long time to high power/short time) or by conventional method (CP) were studied. RESULTS: All heat treatments reduced colour quality, total antioxidant capacity and vitamin C, with a greater reduction in CP than in MWP. On the other hand, use of an MWP, in particular high power/short time (1900 W/180 s, 2700 W/160 s and 3150 W/150 s) enhanced the viscosity and lycopene extraction and decreased the enzyme residual activity better than with CP samples. For tomato puree, polygalacturonase was the more thermo-resistant enzyme, and could be used as an indicator of pasteurization efficiency. CONCLUSION: MWP was an excellent pasteurization technique that provided tomato puree with improved nutritional quality, reducing process times compared to the standard pasteurization process. (c) 2016 Society of Chemical Industry. PMID- 27246970 TI - In-Depth Proteomics Identifies a Role for Autophagy in Controlling Reactive Oxygen Species Mediated Endothelial Permeability. AB - Endothelial cells (ECs) form the inner layer of blood vessels and physically separate the blood from the surrounding tissue. To support tissues with nutrients and oxygen, the endothelial monolayer is semipermeable. When EC permeability is altered, blood vessels are not functional, and this is associated with disease. A comprehensive knowledge of the mechanisms regulating EC permeability is key in developing strategies to target this mechanism in pathologies. Here we have used an in vitro model of human umbilical vein endothelial cells mimicking the formation of a physiologically permeable vessel and performed time-resolved in depth molecular profiling using stable isotope labeling by amino acids in cell culture mass spectrometry (MS)-proteomics. Autophagy is induced when ECs are assembled into a physiologically permeable monolayer. By using siRNA and drug treatment to block autophagy in combination with functional assays and MS proteomics, we show that ECs require autophagy flux to maintain intracellular reactive oxygen species levels, and this is required to maintain the physiological permeability of the cells. PMID- 27246971 TI - Scintigraphic Tracking of Allogeneic Mesenchymal Stem Cells in the Distal Limb After Intra-Arterial Injection in Standing Horses. AB - OBJECTIVE: To assess the feasibility of intra-arterial administration of allogeneic mesenchymal stem cells (MSC) in the median artery of standing horses and evaluate the distribution and retention of radiolabeled cells. STUDY DESIGN: In vivo experimental study. ANIMALS: Six research horses. METHODS: Technetium(99m) -HexaMethyl-Propylene-Amine Oxime-labeled MSC were injected under ultrasound guidance in the median artery of 6 front limbs of 3 horses, standing under sedation. Scintigraphic images were obtained at the time of injection, and at 1, 6, and 24 hours postinjection. Six additional limbs from 3 horses were similarly injected with unlabeled MSC. Ultrasound was performed the following day for assessment of vascular changes. RESULTS: Intra-arterial injection was performed successfully in 11 of 12 limbs. In 1 limb, partial periarterial injection compromised the success of the procedure. Homogeneous distribution of radiolabeled MSC was observed through the entire distal limb, including within the hoof. Partial venous thrombosis was found in both groups of horses, but was subjectively less severe in horses injected with unlabeled MSC. No lameness was observed. Transient swelling of the distal limb occurred in only 1 limb. CONCLUSION: Intra-arterial injection of MSC can be performed in standing horses under sedation and successfully distribute MSC to the distal limb. A risk of periarterial injection was identified but can be reduced with proper sedation, local anesthesia, and increased experience. Partial venous thrombosis was observed as a complication, but did not cause changes of clinical importance, other than rare transient swelling. PMID- 27246972 TI - Paf15 expression correlates with rectal cancer prognosis, cell proliferation and radiation response. AB - Paf15, which participates in DNA repair, is overexpressed in numerous solid tumors. Blocking of Paf15 inhibits the growth of many types of cancer cells; while simultaneously enhancing cellular sensitivity to UV radiation. However, its expression and function in rectal cancer (RC) remain unknown. The current study was undertaken to assess the association of Paf15 expression with RC prognosis, as well as to explore the participation of Paf15 in the response of RC cells to irradiation. Increased Paf15 expression was observed in RC tissues and associated with pTNM stage and poor survival. In vitro, Paf15 induced increased RC cell proliferation while accelerating cell cycle progression, inhibiting cell death, and protecting against gamma radiation-induced DNA damage in RC cells. In conclusion, increased Paf15 expression is associated with increased RC proliferation, decreased patient survival, and a worse radiotherapeutic response. PMID- 27246973 TI - Rare SNPs in receptor tyrosine kinases are negative outcome predictors in multiple myeloma. AB - Multiple myeloma (MM) is a plasma cell disorder that is characterized by a great genetic heterogeneity. Recent next generation sequencing studies revealed an accumulation of tumor-associated mutations in receptor tyrosine kinases (RTKs) which may also contribute to the activation of survival pathways in MM. To investigate the clinical role of RTK-mutations in MM, we deep-sequenced the coding DNA-sequence of EGFR, EPHA2, ERBB3, IGF1R, NTRK1 and NTRK2 which were previously found to be mutated in MM, in 75 uniformly treated MM patients of the "Deutsche Studiengruppe Multiples Myelom". Subsequently, we correlated the detected mutations with common cytogenetic alterations and clinical parameters. We identified 11 novel non-synonymous SNVs or rare patient-specific SNPs, not listed in the SNP databases 1000 genomes and dbSNP, in 10 primary MM cases. The mutations predominantly affected the tyrosine-kinase and ligand-binding domains and no correlation with cytogenetic parameters was found. Interestingly, however, patients with RTK-mutations, specifically those with rare patient-specific SNPs, showed a significantly lower overall, event-free and progression-free survival. This indicates that RTK SNVs and rare patient-specific RTK SNPs are of prognostic relevance and suggests that MM patients with RTK-mutations could potentially profit from treatment with RTK-inhibitors. PMID- 27246974 TI - Association of HOTAIR polymorphisms rs4759314 and rs920778 with cancer susceptibility on the basis of ethnicity and cancer type. AB - Polymorphisms in the HOX transcript antisense intergenic RNA (HOTAIR) have been recently associated with susceptibility to different cancers. Here, a meta analysis was performed to derive a more precise estimation of the involvement of HOTAIR polymorphisms in cancer development. Data from cases (n = 7,772) and controls (n = 9,075) were extracted from eligible studies (n = 10) identified in a comprehensive literature search conducted in PubMed, Embase, and the Web of Science databases through January 20, 2016. Overall, association between polymorphism rs920778 and increased cancer risk was significant in allele contrast (odds ratio (OR) = 1.239, 95% confidence interval (CI) = 1.032 - 1.487) and recessive models (OR = 1.614, 95% CI = 1.082 - 2.406). In subgroup analysis based on ethnicity, a significant association between polymorphism rs920778 and cancer susceptibility was observed in Asians under all models, but was most compelling under recessive (OR = 2.128, 95% CI = 1.417 - 3.197) and homozygous models (OR = 2.764, 95% CI = 2.221 - 3.440). Subgroup analysis by cancer type revealed a significant association between polymorphism rs4759314 and susceptibility to gastric cancer in allele contrast (OR = 1.262, 95% CI = 1.073 - 1.486), dominant (OR = 1.280, 95% CI = 1.060 - 1.547), and heterozygous models (OR = 1.288, 95% CI = 1.057 - 1.570). In conclusion, the results indicated that HOTAIR polymorphism rs920778 was more generally associated with cancer risk, particularly in Asians, while rs4759314 was a risk factor for gastric cancer. PMID- 27246975 TI - Nuclear p16INK4a expression predicts enhanced radiation response in head and neck cancers. AB - Immunohistochemistry analysis of p16INK4a in head and neck squamous cell carcinomas (HNSCC) tumor samples revealed that 28% of tumors showed nuclear/cytoplasmic p16INK4a localization, while 37% of tumors had cytoplasmic p16INK4a. Our previous study showed that p16INK4a inhibits the DNA repair response independently of its function in the cell cycle, suggesting that p16INK4a subcellular localization should be considered during stratification of HNSCC patients.Using p16INK4a mutants with different localization signals, we found that expression of nuclear p16INK4a, but not cytoplasmic p16INK4a impaired RAD51 foci formation, indicating that nuclear localization of p16INK4a is crucial for its function in DNA repair. We next investigated the role of p16INK4a subcellular localization in radiation response in a retrospective cohort of 261 HNSCC patients treated with chemoradiation. We found that only HNSCC patients expressing nuclear p16INK4a expression showed better outcome, locoregional control and disease free survival, after chemoradiation. In concordance with the patient data, only expression of nuclear p16INK4a increased radiosensitivity of HNSCC cells. These results implicate nuclear p16INK4a expression as a potent marker to predict radiation response of HNSCC patients and should be taken into account in intensification or de-escalation studies. PMID- 27246976 TI - Long noncoding RNA ZFAS1 promotes gastric cancer cells proliferation by epigenetically repressing KLF2 and NKD2 expression. AB - Recently, long noncoding RNAs have been emerged as critical regulators of human disease and prognostic markers in several cancers, including gastric cancer. In this study, we globally assessed the transcriptomic differences of lncRNAs in gastric cancer using publicly available microarray data from Gene Expression Omnibus (GEO) and identified an oncogenetic lncRNA ZFAS1, which may promote gastric tumorigenesis. ZFAS1 has been found to be upregulated and function as oncogene in colorectal cancer and hepatocellular carcinoma, but its expression pattern, biological function and underlying mechanism in gastric cancer is still undetermined. Here, we reported that ZFAS1 expression is also overexpressed in gastric cancer, and its increased level is associated with poor prognosis and shorter survival. Knockdown of ZFAS1 impaired gastric cancer cells proliferation and induced apoptosis in vitro, and inhibited tumorigenicity of gastric cancer cells in vivo. Mechanistically, RNA immunoprecipitation and RNA pull-down experiment showed that ZFAS1 could simultaneously interact with EZH2 and LSD1/CoREST to repress underlying targets KLF2 and NKD2 transcription. In addition, rescue experiments determined that ZFAS1 oncogenic function is partly dependent on repressing KLF2 and NKD2. Taken together, our findings illuminate how ZFAS1 over-expression confers an oncogenic function in gastric cancer. PMID- 27246977 TI - Technetium-99m-labeled rituximab for use as a specific tracer of sentinel lymph node biopsy: a translational research study. AB - PURPOSE: We aimed to develop and translate a CD20-antigen-targeted radiopharmaceutical, Technetium-99 m-labeled (99mTc) rituximab, for sentinel lymph node (SLN) detection. METHODS: 99mTc-rituximab was synthesized and tested for stability in human serum. The binding affinity to CD20 was evaluated in Raji cells by flow cytometric analysis. Biodistribution and sentinel node mapping were carried out in bal b/c mice. Eighty-five patients with breast cancer participated in this study. Dynamic sentinel lymphoscintigraphy was first assessed in 12 patients before planar lymphoscintigraphy was assessed in a larger cohort. All patients underwent sentinel lymph node biopsy (SLNB), followed by axillary lymph node dissection. RESULTS: The cell-binding study showed that 99mTc-rituximab possessed compatible affinity to human CD20. In the mechanism study, 99mTc labeled anti-mouse CD20 monoclonal antibodies could bind to mouse CD20 and accumulate in the SLN with 2.62+/-1.25 % of the percentage of injected activity, which could be blocked by excessive unlabeled antibody. Low uptake of non sentinel nodes and fast clearance from the injection site were observed in the mice. Sentinel nodes were identified in 82 of 85 breast cancer patients (96.5%) by lymphoscintigraphy and SLNB. The sensitivity, specificity, and accuracy were 96.8% (30/31), 100% (51/51), and 98.8% (81/82), respectively. CONCLUSION: 99mTc rituximab, specifically binding to CD20, met most of the requirements of an ideal sentinel mapping agent for use in clinical settings. PMID- 27246978 TI - Downregulation of HSP60 disrupts mitochondrial proteostasis to promote tumorigenesis and progression in clear cell renal cell carcinoma. AB - In the present study, we demonstrate that HSP60 is unequivocally downregulated in clear cell renal cell carcinoma (ccRCC) tissues compared to pericarcinous tissues. Overexpression of HSP60 in ccRCC cancer cells suppresses cell growth. HSP60 knockdown increases cell growth and proliferation in both cell culture and nude mice xenografts, and drives cells to undergo epithelial to mesenchymal transition (EMT). Our results propose that HSP60 silencing disrupts the integrity of the respiratory complex I and triggers the excessive ROS production, which promotes tumor progression in the following aspects: (1) ROS activates the AMPK pathway that promotes acquisition of the Warburg phenotype in HSP60-KN cells; (2) ROS generated by HSP60 knockdown or by rotenone inhibition drives cells to undergo EMT; and (3) the high level of ROS may also fragment the Fe-S clusters that up regulates ADHFe1 expression and the 2-hydroxygluterate (2-HG) production leading to changes in DNA methylation. These results suggest that the high level of ROS is needed for tumorigenesis and progression in tumors with the low HSP60 expression and HSP60 is a potential diagnostic biomarker as well as a therapeutic target in ccRCC. PMID- 27246979 TI - Cdc6 contributes to cisplatin-resistance by activation of ATR-Chk1 pathway in bladder cancer cells. AB - High activation of DNA damage response is implicated in cisplatin (CDDP) resistance which presents as a serious obstacle for bladder cancer treatment. Cdc6 plays an important role in the malignant progression of tumor. Here, we reported that Cdc6 expression is up-regulated in bladder cancer tissues and is positively correlated to high tumor grade. Cdc6 depletion can attenuate the malignant properties of bladder cancer cells, including DNA replication, migration and invasion. Furthermore, higher levels of chromatin-binding Cdc6 and ATR were detected in CDDP-resistant bladder cancer cells than in the parent bladder cancer cells. Intriguingly, down-regulation of Cdc6 can enhance sensitivity to CDDP both in bladder cancer cells and CDDP-resistant bladder cancer cells. Cdc6 depletion abrogates S phase arrest caused by CDDP, leading to aberrant mitosis by inactivating ATR-Chk1-Cdc25C pathway. Our results indicate that Cdc6 may be a promising target for overcoming CDDP resistance in bladder cancer. PMID- 27246980 TI - Radioimmunotherapy of pancreatic cancer xenografts in nude mice using 90Y-labeled anti-alpha6beta4 integrin antibody. AB - The contribution of integrin alpha6beta4 (alpha6beta4) overexpression to the pancreatic cancer invasion and metastasis has been previously shown. We have reported immunotargeting of alpha6beta4 for radionuclide-based and near-infrared fluorescence imaging in a pancreatic cancer model. In this study, we prepared yttrium-90 labeled anti-alpha6beta4 antibody (90Y-ITGA6B4) and evaluated its radioimmunotherapeutic efficacy against pancreatic cancer xenografts in nude mice. Mice bearing xenograft tumors were randomly divided into 5 groups: (1) single administration of 90Y-ITGA6B4 (3.7MBq), (2) double administrations of 90Y ITGA6B4 with once-weekly schedule (3.7MBq x 2), (3) single administration of unlabeled ITGA6B4, (4) double administrations of unlabeled ITGA6B4 with once weekly schedule and (5) the untreated control. Biweekly tumor volume measurements and immunohistochemical analyses of tumors at 2 days post-administration were performed to monitor the response to treatments. To assess the toxicity, body weight was measured biweekly. Additionally, at 27 days post-administration, blood samples were collected through cardiac puncture, and hematological parameters, hepatic and renal functions were analyzed. Both 90Y-ITGA6B4 treatment groups showed reduction in tumor volumes (P < 0.04), decreased cell proliferation marker Ki-67-positive cells and increased DNA damage marker p-H2AX-positive cells, compared with the other groups. Mice treated with double administrations of 90Y ITGA6B4, exhibited myelosuppression. There were no significant differences in hepatic and renal functions between the 2 treatment groups and the other groups. Our results suggest that 90Y-ITGA6B4 is a promising radioimmunotherapeutic agent against alpha6beta4 overexpressing tumors. In the future studies, dose adjustment for fractionated RIT should be considered carefully in order to get the optimal effect while avoiding myelotoxicity. PMID- 27246981 TI - Differences in somatic mutation landscape of hepatocellular carcinoma in Asian American and European American populations. AB - The incidence rate of hepatocellular carcinoma (HCC) is higher in populations of Asian ancestry than European ancestry (EA). We sought to investigate HCC mutational differences between the two populations, which may reflect differences in the prevalence of etiological factors. We compared HCC somatic mutations in patients of self-reported Asian American and EA from The Cancer Genome Atlas (TCGA), and assessed associations of tumor mutations with established HCC risk factors. Although the average mutation burden was similar, TP53 and RB1 were mutated at a much higher frequency in Asian Americans than in EAs (TP53: 43% vs. 21%; RB1: 19% vs. 2%). Three putative oncogenic genes, including TRPM3, SAGE1, and ADAMTS7, were mutated exclusively in Asians. In addition, VEGF binding pathway, a druggable target by tyrosine kinase inhibitors such as sorafenib, was mutated at a higher frequency among Asians (13% vs. 2%); while the negative regulation of IL17 production, involved in inflammation and autoimmunity, was mutated only in EAs (12% vs. 0). Accounting for HCC risk factors had little impact on any of the mutational differences. In conclusion, we demonstrated here mutational differences in important cancer genes and pathways between Asian and European ancestries. These differences may have implications for the prevention and treatment of HCC. PMID- 27246983 TI - Clinical factors that influence the outcome of selective devascularization in the treatment of portal hypertension. AB - There is a high incidence of death due to variceal hemorrhage in patients with portal hypertension. Factors to consider when choosing selective devascularization in the treatment of variceal hemorrhage remain a controversy. This study aims to generate the prevalent clinical risk factors that affect the outcomes of selective devascularization procedures. Elucidating these features may guide future treatment of esophageal varices in patients with portal hypertension. We retrospectively analyzed medical records of 455 patients who underwent selective devascularization procedures in our center. Patients were subject to splenectomy, selective devascularization with or without esophageal transection. The mode of surgery recurred in comparable rates in both the group with major complications postoperatively (high-risk group which consisted of 63 patients) or the group without major postoperative complications (low-risk group, 392). Risk factors that negatively influenced outcomes of surgery include severe symptoms (89% in high risk group and 71% in low risk group), large volume of blood loss in the hemorrhage before surgery (81% in high risk group and 16% in low risk group), sever liver cirrhosis (83% in high risk group and 67% in low risk group), previous endotherapy, prolonged prothrombin time, and poor liver function. Selective devascularization is a feasible option to treat variceal hemorrhage in patients with portal hypertension. PMID- 27246984 TI - Isolation frequency of Candida present on the surfaces of mobile phones and handsx. AB - BACKGROUND: It is known that mobile phones may play a role in microorganism transmission. The aim of this study was to analyze the relationship between the number of Candida genera/species isolated from samples collected from the surfaces of mobile phones and the hands of the staff as well as the preferred health-related behavior. METHODS: The mycological evaluation included 175 mobile telephones and the hands of staff members at the University Hospital in Bialystok, Poland. We used the Count-Tact(TM) applicator, with CandiSelect (Bio Rad). Self-administered questionnaire was used to gather data on mobile phones disinfection practices. Assessment of the preferred health-related behavior was based on The Multidemensional Health Locus of Control Scale (MHLC). RESULTS: Out of 175 mobile phones, 131 (74.9 %) were colonized. Candida glabrata, C. albicans and C.krusei were isolated more frequently from the hand as well as phone surface. The mean number of Candida colonies was higher in samples collected from hand surfaces than mobile phone surfaces. No significant correlation was found between the preferred health-related behavior and the frequency of washing hands, the way of using a mobile phone, the number of colonies or the isolation frequency for the fungi collected from the surface of the phones and hands of their owners. Only 19.4 % of the participants cleaned the surface of their phones. CONCLUSION: The prevalence of mobile phone contamination by Candida is high in the University Hospital in Bialystok, Poland. Candida albicans, C. glabrata, and C. krusei were the dominant species in the samples collected from mobile phones and hands. These results pose the need to develop guidelines for mobile phone disinfection. PMID- 27246982 TI - Proliferation and ovarian hormone signaling are impaired in normal breast tissues from women with BRCA1 mutations: benefit of a progesterone receptor modulator treatment as a breast cancer preventive strategy in women with inherited BRCA1 mutations. AB - Women with inherited BRCA1 mutations have an elevated risk (40-80%) for developing breast and ovarian cancers. Reproductive history has been reported to alter this risk, suggesting a relationship between ovarian hormone signaling and BRCA1-related tumor development. BRCA1 interactions with estrogen receptor (ER) and progesterone receptor (PR) signaling were previously described in human breast cancer cell lines and mouse models. However, few studies have examined the effect of ovarian hormone regulation in normal human breast tissues bearing a heterozygous BRCA1 mutation. This study compares the proliferation level (Ki67) and the expression of ER, PR, and of the PR target gene, fatty acid synthase (FASN), in histologically normal breast tissues from women with BRCA1 mutations (BRCA1+/mut, n=23) or without BRCA1 mutations (BRCA1+/+, n=28). BRCA1+/mut tissues showed an increased proliferation and impaired hormone receptor expression with a marked loss of the PR isoform, PR-B. Responses to estradiol and progesterone treatments in BRCA1+/mut and BRCA1+/+ breast tissues were studied in a mouse xenograft model, and showed that PR and FASN expression were deregulated in BRCA1+/mut breast tissues. Progesterone added to estradiol treatment increased the proliferation in a subset of BRCA1+/mut breast tissues. The PR inhibitor, ulipristal acetate (UPA), was able to reverse this aberrant progesterone-induced proliferation. This study suggests that a subset of women with BRCA1 mutations could be candidates for a UPA treatment as a preventive breast cancer strategy. PMID- 27246985 TI - A systematic review of the reporting of tinnitus prevalence and severity. AB - INTRODUCTION: There is no standard diagnostic criterion for tinnitus, although some clinical assessment instruments do exist for identifying patient complaints. Within epidemiological studies the presence of tinnitus is determined primarily by self-report, typically in response to a single question. Using these methods prevalence figures vary widely. Given the variety of published estimates worldwide, we assessed and collated published prevalence estimates of tinnitus and tinnitus severity, creating a narrative synthesis of the data. The variability between prevalence estimates was investigated in order to determine any barriers to data synthesis and to identify reasons for heterogeneity. METHODS: and analysis: A systematic review included all adult population studies reporting the prevalence of tinnitus from January 1980 to July 2015. We searched five databases (Embase, Medline, PsychInfo, CINAHL and Web Of Science), using a combination of medical subject headings (MeSH) and relevant text words. Observational studies including cross-sectional studies were included, but studies estimating the incidence of tinnitus (e.g. cohort studies) were outside the scope of this systematic review. RESULTS: The databases identified 875 papers and a further 16 were identified through manual searching. After duplicates were removed, 515 remained. On the basis of the title, abstract and full-text screening, 400, 48 and 27 papers respectively were removed. This left 40 papers, reporting 39 different studies, for data extraction. Sixteen countries were represented, with the majority of the studies from the European region (38.5%). Publications since 2010 represented half of all included studies (48.7%). Overall prevalence figures for each study ranged from 5.1% to 42.7%. For the 12 studies that used the same definition of tinnitus, prevalence ranged from 11.9% to 30.3%. Twenty-six studies (66.7%) reported tinnitus prevalence by different age groups, and generally showed an increase in prevalence as age increases. Half the studies reported tinnitus prevalence by gender. The pattern generally showed higher tinnitus prevalence among males than females. There were 8 different types of definitions of tinnitus, the most common being "tinnitus lasting for more than five minutes at a time" (34.3%). Only seven studies gave any justification for the question that was used, or acknowledged the lack of standard questions for tinnitus. There is widespread inconsistency in defining and reporting tinnitus, leading to variability in prevalence estimates among studies. Nearly half of the included studies had a high risk of bias and this limits the generalisability of prevalence estimates. In addition, the available prevalence data is heterogeneous thereby preventing the ability to pool the data and perform meta-analyses. Sources of heterogeneity include different diagnostic criteria, different age groups, different study focus and differences in reporting and analysis of the results. Heterogeneity thus made comparison across studies impracticable. CONCLUSION: Deriving global estimates of the prevalence of tinnitus involves combining results from studies which are consistent in their definition and measurement of tinnitus, survey methodology and in the reporting and analysis of the results. Ultimately comparison among studies is unachievable without such consistency. The strength of this systematic review is in providing a record of all the available, recent epidemiological data in each global region and in making recommendations for promoting standardisation. PMID- 27246986 TI - Is plasminogen activator inhibitor-1 a physiological bottleneck bridging major depressive disorder and cardiovascular disease? AB - Major depressive disorder (MDD) is estimated to affect one in twenty people worldwide. MDD is highly comorbid with cardiovascular disease (CVD), itself one of the single largest causes of mortality worldwide. A number of pathological changes observed in MDD are believed to contribute to the development of cardiovascular disease, although no single mechanism has been identified. There are also no biological markers capable of predicting the future risk of developing heart disease in depressed individuals. Plasminogen activator inhibitor-1 (PAI-1) is a prothrombotic plasma protein secreted by endothelial tissue and has long been implicated in CVD. An expanding body of literature has recently implicated it in the pathogenesis of major depressive disorder as well. In this study, we review candidate pathways implicating MDD in CVD and consider how PAI-1 might act as a mediator by which MDD induces CVD development: chiefly through sleep disruption, adiposity, brain-derived neurotrophic factor (BDNF) metabolism, systemic inflammation and hypothalamic-pituitary-adrenal (HPA)-axis dysregulation. As both MDD and CVD are more prevalent in women than in men, and incidence of either condition is dramatically increased during reproductive milestones, we also explore hormonal and sex-specific associations between MDD, PAI-1 and CVD. Of special interest is the role PAI-1 plays in perinatal depression and in cardiovascular complications of pregnancy. Finally, we propose a theoretical model whereby PAI-1 might serve as a useful biomarker for CVD risk in those with depression, and as a potential target for future treatments. PMID- 27246987 TI - Heterogenized Water Oxidation Catalysts Prepared by Immobilizing Klaui-Type Organometallic Precursors. AB - An efficient heterogenized water oxidation catalyst (2_TiO2 ) has been synthesized by immobilizing the Klaui-type organometallic precursor [Cp*Ir{P(O)(OH)2 }3 ]Na (2, Cp*=1,2,3,4,5-pentamethylcyclopentadienyl ligand) onto rutile TiO2 . Iridium is homogeneously distributed at the molecular and atomic/small cluster level in 2_TiO2 and 2'_TiO2 (solid catalyst recovered after the first catalytic run), respectively, as indicated by STEM-HAADF (scanning transmission electron microscopy - high angle annular dark field) studies. 2'_TiO2 exhibits TOF values up to 23.7 min(-1) in the oxidation of water to O2 driven by NaIO4 at nearly neutral pH, and a TON only limited by the amount of NaIO4 used, as indicated by multiple run experiments. Furthermore, while roughly 40 % leaching is observed during the first catalytic run, 2'_TiO2 does not undergo any further leaching even when in contact with strongly basic solutions and completely maintains its activity for thousands of cycles. NMR studies, in combination with ICP-OES (inductively coupled plasma optical emission spectrometry), indicate that the activation of 2_TiO2 occurs through the initial oxidative dissociation of PO4 (3-) , ultimately leading to active centers in which a 1:1 P/Ir ratio is present (derived from the removal of two PO4 (3-) units) likely missing the Cp* ligand. PMID- 27246988 TI - Targeted next-generation sequencing reveals multiple deleterious variants in OPLL associated genes. AB - Ossification of the posterior longitudinal ligament of the spine (OPLL), which is characterized by ectopic bone formation in the spinal ligaments, can cause spinal cord compression. To date, at least 11 susceptibility genes have been genetically linked to OPLL. In order to identify potential deleterious alleles in these OPLL associated genes, we designed a capture array encompassing all coding regions of the target genes for next-generation sequencing (NGS) in a cohort of 55 unrelated patients with OPLL. By bioinformatics analyses, we successfully identified three novel and five extremely rare variants (MAF < 0.005). These variants were predicted to be deleterious by commonly used various algorithms, thereby resulting in missense mutations in four OPLL-associated genes (i.e., COL6A1, COL11A2, FGFR1, and BMP2). Furthermore, potential effects of the patient with p.Q89E of BMP2 were confirmed by a markedly increased BMP2 level in peripheral blood samples. Notably, seven of the variants were found to be associated with the patients with continuous subtype changes by cervical spinal radiological analyses. Taken together, our findings revealed for the first time that deleterious coding variants of the four OPLL-associated genes are potentially pathogenic in the patients with OPLL. PMID- 27246989 TI - Epigallocatechin gallate exerts protective effects against myocardial ischemia/reperfusion injury through the PI3K/Akt pathway-mediated inhibition of apoptosis and the restoration of the autophagic flux. AB - Epigallocatechin gallate (EGCG), a polyphenol derived from green tea, exhibits a wide range of biological activities, including antioxidant, atherosclerosis and antitumor activities. In this study, the cardioprotective effects of EGCG on myocardial ischemia/reperfusion (I/R) injury in rats and the underlying mechanisms were investigated. A rat model of I/R injury was established by ligating the left anterior descending coronary artery for 30 min, followed by reperfusion for 2 h. The levels of I/R-induced creatine kinase-MB (CK-MB) and the release of lactate dehydrogenase (LDH), as well as the infarct size, cardiomyocyte apoptosis and cardiac functional impairment were examined and compared. Western blot analysis was carried out to elucidate the potential molecular mechanisms of action of EGCG. The results revealed that EGCG post conditioning significantly decreased the levels of CK-MB and the release of LDH, reduced the myocardial infarct size, decreased the apoptotic rate and partially preserved heart function. Furthermore, EGCG decreased the expression of cleaved caspase-3 concomitantly with the upregulation of PI3K, and the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS). It also inhibited I/R-induced overautophagy and promoted the clearance of autophagosomes, as evidenced by a decrease in the ratio of microtubule-associated protein 1 light chain 3 (LC3) II/LC3-I, the downregulation of Beclin1, Atg5 and p62, and the upregulation of active cathepsin D. Additionally, we observed an increase in the phosphorylation levels of the mammalian target of rapamycin (mTOR) following treatment with EGCG. Taken together, the findings of this study demonstrate that, EGCG post conditioning alleviates myocardial I/R injury by inhibiting apoptosis and restoring the autophagic flux, which is associated with several targets of the PI3K/Akt signaling pathway. PMID- 27246990 TI - The impact of perioperative warm-up jackets on surgical site infection: cost without benefit? AB - BACKGROUND: On July 1st, 2012, the University of Minnesota Medical Centers adopted a policy requiring all personnel to wear cover jackets in perioperative areas. This policy is based on the Association of Perioperative Registered Nurses recommended practice for cover jacket usage. We hypothesized that the cover jacket policy had no effect on the surgical site infection rate. METHODS: We compared surgical site infection data from 1 year before the policy and 1 year after the policy. Twenty six thousand three hundred procedures were included: 13,302 before the policy and 12,998 after the policy. Rates between periods were compared using the z-test for proportions. RESULTS: The SSI rate precover and postcover jacket policy was 2.42% and 2.76% respectively. The P value was .1998. Our hypothesis was rejected because the change in rate was not statistically significant. CONCLUSIONS: This study demonstrates that there was not a decrease in SSI rates with this cover jacket policy; in fact, the data show a trend toward an increase in SSI rate thus making the argument for the abandonment of the cover up jackets. PMID- 27246991 TI - Pediatric Patient with Incidental Os Odontoideum Safely Treated with Posterior Fixation Using Rod-Hook System and Preoperative Planning Using 3D Printer: A Case Report. AB - Os odontoideum is often found incidentally. Surgical treatment is recommended for patients with atlantoaxial instability or neurologic deficits. Although various techniques have been used for C1-C2 fusion in adults, the use of these procedures in children is not widely accepted. We present a 12-year-old boy with incidental os odontoideum and obvious C1-C2 instability, in which bony union was achieved safely and successfully by posterior fixation using a rod-hook system and perioperative planning using a three-dimensional printer. At the 2-year follow up, bone formation around the gap of the dens, which has been generally considered as pseudoarthrosis, was obtained after union of the posterior element of C1-C2. PMID- 27246992 TI - Improved CT Imaging for Mastoid Emissary Vein Visualization Prior to Posterior Fossa Approaches. AB - Background The clinical relevance of emissary veins (EVs) is often neglected. However, for posterior fossa approaches, especially in semisitting positions, these transosseous connections become potentially life threatening. Therefore, knowledge of the presence and configuration of EVs is essential in preoperative planning. We report on the use of preoperative computed tomography (CT) imaging techniques to visualize EVs reliably. Methods A total of 100 consecutive patients were evaluated by helical CT in bone window mode reconstructed using the standard technique (4.5-mm slices) and the high-resolution technique (1 mm) for the posterior fossa. The presence and size of the EVs, their entry point in the sigmoid sinus, their predilection site, and their visibility using either CT technique were evaluated. Statistical analyses included a comparison of the data from both sides of the head. Results We noted impressive anatomical variations (high standard deviations) in the number, size, and intraosseous length of the EVs among the study population and between the sides (right and left) of an individual patient; however, no statistical significance was observed for any of these parameters. The detection rate of EVs in thin-slice CT scans versus standard CT scans is significantly different (p = 0.0001 on both sides). Conclusions Thin-slice CT is essential in the preoperative planning of posterior fossa approaches to identify the presence and the course of EVs, reducing preventable approach-related morbidity during surgery. PMID- 27246993 TI - Assessment of the midflexion rotational laxity in posterior-stabilized total knee arthroplasty. AB - PURPOSE: To evaluate changes in midflexion rotational laxity before and after posterior-stabilized (PS)-total knee arthroplasty (TKA). METHODS: Twenty-nine knees that underwent PS-TKA were evaluated. Manual mild passive rotational stress was applied to the knees, and the internal-external rotational angle was measured automatically by a navigation system at 30 degrees , 45 degrees , 60 degrees , and 90 degrees of knee flexion. RESULTS: The post-operative internal rotational laxity was statistically significantly increased compared to the preoperative level at 30 degrees , 45 degrees , 60 degrees , and 90 degrees of flexion. The post-operative external rotational laxity was statistically significantly decreased compared to the preoperative level at 45 degrees and 60 degrees of flexion. The post-operative internal-external rotational laxity was statistically significantly increased compared to the preoperative level only at 30 degrees of flexion. The preoperative and post-operative rotational laxity showed a significant correlation at 30 degrees , 45 degrees , 60 degrees , and 90 degrees of flexion. CONCLUSION: Internal-external rotational laxity increases at the initial flexion range due to resection of both the anterior or posterior cruciate ligaments and retention of the collateral ligaments in PS-TKA. Preoperative and post-operative rotational laxity indicated a significant correlation at the midflexion range. This study showed that a large preoperative rotational laxity increased the risk of a large post-operative laxity, especially at the initial flexion range in PS-TKA. LEVEL OF EVIDENCE: III. PMID- 27246994 TI - Effect of zinc oxide (ZnO) nanoparticles on physiology and steviol glycosides production in micropropagated shoots of Stevia rebaudiana Bertoni. AB - This study aims to address the effects of different concentrations (0, 0.1, 1.0, 10, 100 or 1000 mg L-1) of engineered zinc oxide (ZnO) nanoparticles (34 nm in size) on growth parameters, steviol glycosides (rebaudioside A and stevioside) production and antioxidant activities in the tissue culture grown shoots of Stevia rebaudiana Bertoni. The highest percentage of shoot formation (89.6%) at 1 mg L-1 of ZnO nanoparticles concentration suggests a positive influence of ZnO nanoparticles on S. rebaudiana growth as compared to other treatments with or without ZnO nanoparticles. Additionally, HPLC results illustrate a significant enhancement of steviol glycosides (almost doubled as compared to the control) in micropropagated shoots grown under an oxidative stress of 1 mg L-1 of ZnO nanoparticles. This finding is further affirmed by an increased 2,2-diphenyl-1 picryl hydrazyl (DPPH) scavenging activity, total anti-oxidant capacity, total reducing power, total flavonoid content and total phenolic content, with an ascending oxidative pressure and generation of reactive oxygen species (ROS). However, the antioxidant activities, formation of secondary metabolites and the physiological parameters showed a sudden decline after crossing a threshold of 1 mg L-1 concentration of ZnO nanoparticles and falls to a minimum at 1000 mg L-1, elucidating maximum phytotoxic effect of ZnO nanoparticles at this concentration. This is the first study evaluating both the favorable and adverse effects of ZnO nanoparticles employed to a highly valuable medicinal plant, S. rebaudiana. PMID- 27246995 TI - Intratumoral multinucleated giant cells are not a prognostic pathologic feature in cutaneous melanoma. AB - BACKGROUND: Histopathologic diagnostic features such as tumor thickness, ulceration, mitoses, microsatellitosis and nodal metastases are principal pathologic staging components of cutaneous melanomas. We chose to focus on evaluating the presence of multinucleated giant cells in microscopic sections as a putative novel prognosticating diagnostic feature of melanoma. METHODS: We assembled a retrospective cohort comprised of 562 cases of melanoma. We annotated each case for a multitude of known clinicopathologic variables to allow robust statistical evaluation of our cohort. RESULTS: Only 37 cases (6.6%) exhibited the multinucleated giant cells phenotype. Virtually all multinucleated giant cells were localized in the reticular dermis. Of interest, melanomas with multinucleated giant cells were roughly twice more likely to occur on head and neck sites (p = 0.04). Melanomas with multinucleated giant cells phenotype had both comparable melanoma recurrence (p = 0.12) and similar melanoma-specific mortality when compared with melanomas without multinucleated giant cells phenotype (p = 0.26). CONCLUSION: Despite prior anecdotal reports possibly linking multinucleated giant cells phenotype to more aggressive clinical course, we find that melanomas with multinucleated giant cells phenotype is not associated with shorter survival. PMID- 27246998 TI - Developmental plasticity in the neural control of breathing. AB - The respiratory control system undergoes a diversity of morphological and physiological transformational stages during intrauterine development as it prepares to transition into an air-breathing lifestyle. Following birth, the respiratory system continues to develop and may pass through critical periods of heightened vulnerability to acute environmental stressors. Over a similar time course, however, the developing respiratory control system exhibits substantial capacity to undergo plasticity in response to chronic or repeated environmental stimuli. A hallmark of developmental plasticity is that it requires an interaction between a stimulus (e.g., hypoxia, hyperoxia, or psychosocial stress) and a unique window of development; the same stimulus experienced beyond the boundaries of this critical window of plasticity (e.g., at maturity), therefore, will have little if any appreciable effect on the phenotype. However, there are major gaps in our understanding of the mechanistic basis of developmental plasticity. Filling these gaps in our knowledge may be crucial to advancing our understanding of the developmental origin of adult health and disease. In this review, we: i) begin by clarifying some ambiguities in the definitions of plasticity and related terms that have arisen in recent years; ii) describe various levels of the respiratory control system where plasticity can (or has been identified to) occur; iii) emphasize the importance of understanding the mechanistic basis of developmental plasticity; iv) consider factors that influence whether developmental plasticity is permanent or whether function can be restored; v) discuss genetic and sex-based variation in the expression of developmental plasticity; and vi) provide a translational perspective to developmental plasticity. PMID- 27246997 TI - Dynamic changes of depolarizing GABA in a computational model of epileptogenic brain: Insight for Dravet syndrome. AB - Abnormal reemergence of depolarizing GABAA current during postnatal brain maturation may play a major role in paediatric epilepsies, Dravet syndrome (DS) being among the most severe. To study the impact of depolarizing GABA onto distinct patterns of EEG activity, we extended a neural mass model as follows: one sub-population of pyramidal cells was added as well as two sub-populations of interacting interneurons, perisomatic-projecting interneurons (basket-like) with fast synaptic kinetics GABAA (fast, I1) and dendritic-projecting interneurons with slow synaptic kinetics GABAA (slow, I2). Basket-like cells were interconnected to reproduce mutual inhibition mechanisms (I1?I1). The firing rate of interneurons was adapted to mimic the genetic alteration of voltage gated sodium channels found in DS patients, SCN1A(+/-). We implemented the "dynamic depolarizing GABAA" mediated post-synaptic potential in the model, as some studies reported that the chloride reversal potential can switch from negative to more positive value depending on interneuron activity. The "shunting inhibition" promoted by GABAA receptor activation was also implemented. We found that increasing the proportion of depolarizing GABAA mediated IPSP (I1?I1 and I1?P) only (i.e., other parameters left unchanged) was sufficient to sequentially switch the EEG activity from background to (1) interictal isolated polymorphic epileptic spikes, (2) fast onset activity, (3) seizure like activity and (4) seizure termination. The interictal and ictal EEG patterns observed in 4 DS patients were reproduced by the model via tuning the amount of depolarizing GABAA postsynaptic potential. Finally, we implemented the modes of action of benzodiazepines and stiripentol, two drugs recommended in DS. Both drugs blocked seizure-like activity, partially and dose-dependently when applied separately, completely and with a synergic effect when combined, as has been observed in DS patients. This computational modeling study constitutes an innovative approach to better define the role of depolarizing GABA in infantile onset epilepsy and opens the way for new therapeutic hypotheses, especially in Dravet syndrome. PMID- 27246996 TI - Posttraumatic stress disorder: A metabolic disorder in disguise? AB - Posttraumatic stress disorder (PTSD) is a heterogeneous psychiatric disorder that affects individuals exposed to trauma and is highly co-morbid with other adverse health outcomes, including cardiovascular disease and obesity. The unique pathophysiological feature of PTSD is the inability to inhibit fear responses, such that individuals suffering from PTSD re-experience traumatic memories and are unable to control psychophysiological responses to trauma-associated stimuli. However, underlying alterations in sympathetic nervous system activity, neuroendocrine systems, and metabolism associated with PTSD are similar to those present in traditional metabolic disorders, such as obesity and diabetes. The current review highlights existing clinical, translational, and preclinical data that support the notion that underneath the primary indication of impaired fear inhibition, PTSD is itself also a metabolic disorder and proposes altered function of inflammatory responses as a common underlying mechanism. The therapeutic implications of treating PTSD as a whole-body condition are significant, as targeting any underlying biological system whose activity is altered in both PTSD and metabolic disorders, (i.e. HPA axis, sympathetic nervous systems, inflammation) may elicit symptomatic relief in individuals suffering from these whole-body adverse outcomes. PMID- 27246999 TI - Primary blast injury causes cognitive impairments and hippocampal circuit alterations. AB - Blast-induced traumatic brain injury (bTBI) and its long term consequences are a major health concern among veterans. Despite recent work enhancing our knowledge about bTBI, very little is known about the contribution of the blast wave alone to the observed sequelae. Herein, we isolated its contribution in a mouse model by constraining the animals' heads during exposure to a shockwave (primary blast). Our results show that exposure to primary blast alone results in changes in hippocampus-dependent behaviors that correspond with electrophysiological changes in area CA1 and are accompanied by reactive gliosis. Specifically, five days after exposure, behavior in an open field and performance in a spatial object recognition (SOR) task were significantly different from sham. Network electrophysiology, also performed five days after injury, demonstrated a significant decrease in excitability and increase in inhibitory tone. Immunohistochemistry for GFAP and Iba1 performed ten days after injury showed a significant increase in staining. Interestingly, a threefold increase in the impulse of the primary blast wave did not exacerbate these measures. However, we observed a significant reduction in the contribution of the NMDA receptors to the field EPSP at the highest blast exposure level. Our results emphasize the need to account for the effects of primary blast loading when studying the sequelae of bTBI. PMID- 27247000 TI - The Cardenolide Glycoside Acovenoside A Affords Protective Activity in Doxorubicin-Induced Cardiotoxicity in Mice. AB - The current study aimed to investigate the protective effect of the cardenolide glycoside acovenoside A (AcoA) against doxorubicin-induced cardiotoxicity in mice. AcoA was isolated from the pericarps of Acokanthera oppositifolia to chemical homogeneity and characterized by means of one- and two-dimensional nuclear magnetic resonance spectroscopy. AcoA exhibited relatively low toxicity in mice (LD50 = 223.3 mg/kg bw). Repeated administration of doxorubicin induced cardiotoxicity manifested by reduced activity of myocardial membrane-bound ion pumps and elevated serum biomarkers of myocardial dysfunction, oxidative stress, and inflammation. Pretreatment of doxorubicin-exposed mice with AcoA (11.16 or 22.33 mg/kg bw, i.p.) for 2 weeks after 2 weeks of combined administration of AcoA and doxorubicin protected the animals dose dependently against doxorubicin induced cardiotoxicity as indicated by normalization of the levels of different myocardial markers of oxidative stress (malondialdehyde, nitric oxide, total antioxidant capacity, and cardiac glutathione), serum myocardial diagnostic marker enzymes (serum cardiac troponin T, creatine kinase isoenzyme MB, aspartate aminotransferase, and lactate dehydrogenase), and inflammatory markers (c reactive protein, tumor necrosis factor-alpha, and interleukin-6), as well as myocardial Na(+)/K(+)-ATPase activity. These effects were attributed to the negative impact of AcoA on transcription factors nuclear factor kappaB and interferon regulatory factor 3/7. Thus acovenoside A might act as a cardioprotective agent to prevent doxorubicin-induced cardiotoxicity. PMID- 27247001 TI - Zika Virus Infects Human Placental Macrophages. AB - The recent Zika virus (ZIKV) outbreak in Brazil has been directly linked to increased cases of microcephaly in newborns. Current evidence indicates that ZIKV is transmitted vertically from mother to fetus. However, the mechanism of intrauterine transmission and the cell types involved remain unknown. We demonstrate that the contemporary ZIKV strain PRVABC59 (PR 2015) infects and replicates in primary human placental macrophages, called Hofbauer cells, and to a lesser extent in cytotrophoblasts, isolated from villous tissue of full-term placentae. Viral replication coincides with induction of type I interferon (IFN), pro-inflammatory cytokines, and antiviral gene expression, but with minimal cell death. Our results suggest a mechanism for intrauterine transmission in which ZIKV gains access to the fetal compartment by directly infecting placental cells and disrupting the placental barrier. PMID- 27247002 TI - Ablation index, a novel marker of ablation lesion quality: prediction of pulmonary vein reconnection at repeat electrophysiology study and regional differences in target values. AB - Aims: Force-Time Integral (FTI) is commonly used as a marker of ablation lesion quality during pulmonary vein isolation (PVI), but does not incorporate power. Ablation Index (AI) is a novel lesion quality marker that utilizes contact force, time, and power in a weighted formula. Furthermore, only a single FTI target value has been suggested despite regional variation in left atrial wall thickness. We aimed to study AI's and FTI's relationships with PV reconnection at repeat electrophysiology study, and regional threshold values that predicted no reconnection. Methods and results: Forty paroxysmal atrial fibrillation patients underwent contact force-guided PVI, and the minimum and mean AI and FTI values for each segment were identified according to a 12-segment model. All patients underwent repeat electrophysiology study at 2 months, regardless of symptoms, to identify sites of PV reconnection. Late PV reconnection was seen in 53 (11%) segments in 25 (62%) patients. Reconnected segments had significantly lower minimum AI [308 (252-336) vs. 373 (323-423), P < 0.0001] and FTI [137 (92-182) vs. 228 (157-334), P < 0.0001] compared with non-reconnected segments. Minimum AI and FTI were both independently predictive, but AI had a smaller P value. Higher minimum AI and FTI values were required to avoid reconnection in anterior/roof segments than for posterior/inferior segments (P < 0.0001). No reconnection was seen where the minimum AI value was >=370 for posterior/inferior segments and >=480 for anterior/roof segments. Conclusion: The minimum AI value in a PVI segment is independently predictive of reconnection of that segment at repeat electrophysiology study. Higher AI and FTI values are required for anterior/roof segments than for posterior/inferior segments to prevent reconnection. PMID- 27247003 TI - Safety and efficacy of the nMARQ catheter for paroxysmal and persistent atrial fibrillation. AB - AIMS: Circular irrigated radiofrequency ablation using the nMARQ catheter has recently been introduced for the treatment of atrial fibrillation (AF). The aim of this study is to report the safety and efficacy of catheter ablation using this technology in patients with paroxysmal and persistent AF. METHODS AND RESULTS: The data of a prospective registry describing the experience of a single operator using this technology on 327 consecutive patients were analysed. The mean procedure time was 69 +/- 22 min for paroxysmal AF (n = 228) and 75 +/- 23 min for persistent AF (n = 97). Follow-up was available for 206 (63%) patients for 6 +/- 5 months (range 1-23, median 3.3). Single procedure success off antiarrhythmic drugs was 75% in paroxysmal AF and 52% in persistent AF. Including the 5% redo cases and those on antiarrhythmic medication, freedom from AF was documented in 90 and 83% of paroxysmal and persistent AF patients, respectively. There were no serious complications in the first 325 patients, but the last two consecutive patients (0.6%) developed atrio-oesophageal fistulas and had a fatal outcome. The catheter has been recalled from market. CONCLUSION: The nMARQ catheter is a highly effective tool for treatment of paroxysmal and persistent AF. Nevertheless, the occurrence of life-threatening oesophageal fistulas is of major concern and requires further investigation. PMID- 27247004 TI - Atrial fibrillation and gastroesophageal reflux disease: the cardiogastric interaction. AB - Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with significant morbidity and mortality. Multiple conditions like hypertension, heart failure, diabetes, sleep apnoea, and obesity play a role for the initiation and perpetuation of AF. Recently, a potential association between gastroesophageal reflux disease (GERD) and AF development has been proposed due to the close anatomic vicinity of the oesophagus and the left atrium. As an understanding of the association between acid reflux disease and AF may be important in the global multimodal treatment strategy to further improve outcomes in a subset of patients with AF, we discuss potential atrial arrhythmogenic mechanisms in patients with GERD, such as gastric and subsequent systemic inflammation, impaired autonomic stimulation, mechanical irritation due to anatomical proximity of the left atrium and the oesophagus, as well as common comorbidities like obesity and sleep-disordered breathing. Data on GERD and oesophageal lesions after AF-ablation procedures will be reviewed. Treatment of GERD to avoid AF or to reduce AF burden might represent a future treatment perspective but needs to be scrutinized in prospective trials. PMID- 27247006 TI - Sudden cardiac death in adult congenital heart disease: can the unpredictable be foreseen? AB - Aims: Sudden cardiac death (SCD) is a major cause of mortality in adults with congenital heart disease (CHD). Several risk factors for SCD including conduction disturbances and ventricular dysfunction have been described previously. However, electrocardiogram (ECG) and echocardiographic parameters may change over time, and the predictive value of such temporal changes, rather than their point estimates, for SCD remains unknown. Methods and results: This was a retrospective case-control study in adults with CHD and proven or presumed SCD and matched controls. Data were obtained from three databases including 25 000 adults with CHD. Sequential measurements were performed on electrocardiograms and echocardiograms. Ventricular function was assessed by echocardiography and graded on a four-point ordinal scale: 1, normal [ejection fraction (EF) >=50%]; 2, mildly impaired (EF 40-49%); 3, moderately impaired (EF 30-39%); and 4, severely impaired (EF < 30%). Overall, 131 SCDs (mean age 36 +/- 14 years, 67% male) and 260 controls (mean age 37 +/- 13 years, 63% male) were included. At baseline, median QRS duration was 108 ms (range 58-168 ms) in SCDs and 97 ms (range 50-168 ms) in controls and increased over time at a rate of 1.6 +/- 0.5 vs. 0.5 +/- 0.2 ms/year in SCDs and controls, respectively (P = 0.011). QT dispersion at baseline was 61 ms (range 31-168 ms) in SCDs and 50 ms (range 21-129 ms) in controls. QT dispersion increased at a rate of 1.1 +/- 0.4 ms/year in SCD victims and decreased at a rate of 0.2 +/- 0.2 ms/year in controls (P = 0.004). Increase of QRS duration >=5 ms/year was associated with an increased risk of SCD [OR 1.9, 95% confidence interval (CI) 1.1-3.3, P = 0.013]. Change from any baseline systemic ventricular function (normal, mild, or moderately impaired) to severe ventricular dysfunction over time was associated with the highest risk of SCD (OR 16.9, 95% CI 1.8-120.1, P = 0.008). Conclusion: In adults with CHD, QRS duration and ventricular dysfunction progress over time. Progression of QRS duration and the rate of impairment of ventricular function served to identify those at increased risk of SCD. PMID- 27247008 TI - Heart failure due to right ventricular apical pacing: the importance of flow patterns. AB - In patients receiving permanent cardiac electrical stimulation, a high burden of apical right ventricular pacing is associated with an increased incidence of heart failure. Despite the large body of electrocardiographic, echocardiographic, and pathological data, mechanisms underlying this serious complication are not fully understood. Moreover, the empirical use of alternative right ventricular pacing sites, both in the experimental and in the clinical setting, has not provided better results in terms of clinical outcome. Recent data derived by echocardiographic particle image velocimetry of intracardiac flows have shown abnormal flow patterns in patients with dyssynchrony of left ventricular wall contraction, and the reversion to normal flow dynamics after successful electrical cardiac resynchronization therapy. This suggests that a normal intraventricular flow pattern is strongly dependent on the highly coordinated contraction of the ventricular wall segments and that an abnormal sequence of wall contraction may trigger the development of overt heart failure. This review summarizes the state of the art on this topic, highlighting postulated underlying basic mechanisms linking abnormal flow with the development of pacing-induced heart failure. This research line suggests the importance of studying intraventricular fluid dynamics as a new powerful tool for a more complete understanding of mechanisms involved, and ultimately to prevent pacing-related heart failure. PMID- 27247007 TI - The role of myocardial wall thickness in atrial arrhythmogenesis. AB - Changes in the structure and electrical behaviour of the left atrium are known to occur with conditions that predispose to atrial fibrillation (AF) and in response to prolonged periods of AF. We review the evidence that changes in myocardial thickness in the left atrium are an important part of this pathological remodelling process. Autopsy studies have demonstrated changes in the thickness of the atrial wall between patients with different clinical histories. Comparison of the reported tissue dimensions from pathological studies provides an indication of normal ranges for atrial wall thickness. Imaging studies, most commonly done using cardiac computed tomography, have demonstrated that these changes may be identified non-invasively. Experimental evidence using isolated tissue preparations, animal models of AF, and computer simulations proves that the three-dimensional tissue structure will be an important determinant of the electrical behaviour of atrial tissue. Accurately identifying the thickness of the atrial may have an important role in the non-invasive assessment of atrial structure. In combination with atrial tissue characterization, a comprehensive assessment of the atrial dimensions may allow prediction of atrial electrophysiological behaviour and in the future, guide radiofrequency delivery in regions based on their tissue thickness. PMID- 27247009 TI - Geometry of Koch's triangle. AB - Aims: The first aim of this study was to determine the size of the Koch's triangle. The second one was to investigate relation between its dimensions and other individual-specific and heart-specific parameters as well as to create universal formula to estimate triangle dimensions based on these parameters. Methods and results: This study is a prospective one, presenting 120 randomly selected autopsied hearts dissected from adult humans (Caucasian) of both sexes (31.7% females), with mean age of 49.3 +/- 17.4 years. The length of triangle sides and angles were measured and the triangle area was calculated as well. Sixteen additional heart parameters were measured in order to analyse potential relationship between the dimensions of Koch's triangle and other dimensions of the heart, using linear regression analysis. The mean (+/-SD) length of the anterior edge was approximated to 18.0 +/- 3.8 mm, the posterior edge to 20.3 +/- 4.3 mm, and the basal edge to 18.5 +/- 4.0 mm. The average values of the apex angle, the Eustachian angle, and the septal leaflet angle were 58.0 +/- 14.4 degrees , 53.8 +/- 10.6 degrees , and 67.6 +/- 14.4 degrees , respectively. The mean value of the Koch's triangle area was 151.5 +/- 55.8 mm2. The 95th percentile of triangle's height (the distance from the apex to the coronary sinus) was 21.8 mm. Conclusion: Mean values and proportions of triangle's sides and angles were presented. Koch's triangle showed considerable individual variations in size. The dimensions of the triangle were strongly independent from individual-specific and heart-specific morphometric parameters; however, the maximum triangle's height can be estimated as 22 mm. PMID- 27247011 TI - Midterm clinical outcomes of concomitant thoracoscopic epicardial and transcatheter endocardial ablation for persistent and long-standing persistent atrial fibrillation: a single-centre experience. AB - AIMS: The purpose of this study was to analyse the efficacy and complication rates of the simultaneous hybrid procedure in a series of patients with persistent and long-standing persistent atrial fibrillation (AF) in a midterm follow-up. METHODS AND RESULTS: Sixty-four consecutive patients (56 males, 59.7 +/- 8.7 years) having undergone isolation of pulmonary veins (PVs) and posterior wall of left atrium (LA) by means of hybrid thoracoscopic ablation for symptomatic persistent (n = 21, 33%) and long-standing persistent AF (n = 43, 67%) were analysed. At a mean follow-up of 23.1 +/- 14.1 months (median 21; range 6-57), the success rate without antiarrhythmic therapy was achieved in 67.2% of patients. Procedure-related complications were observed in 13 patients (20.3%) including 2 LA perforations (3.1%) requiring, respectively, conversion to sternotomy and small left-sided thoracotomy. The success rate did not significantly differ between persistent and long-standing persistent AF (respectively, 71.4 and 65.1%; P = 0.4). Patients with AF relapse during the blanking period were 4.60 times more likely to have AF recurrence after 3 months from the ablation procedure. CONCLUSION: The hybrid procedure yields promising results in the setting of both persistent and long-standing persistent AF after midterm follow-up, at the expense of a non-negligible rate of adverse events. Our findings need to be confirmed by further larger and prospective studies. PMID- 27247012 TI - Premature termination of radiofrequency delivery during pulmonary vein isolation due to oesophageal temperature alerts: impact on acute and chronic pulmonary vein reconnection. AB - Aims: Oesophageal temperature monitoring is currently used during atrial fibrillation (AF) ablation to prevent atrio-oesophageal fistula. The aim of our study was to investigate if oesophageal temperature alerts, leading to early termination of radiofrequency (RF) energy and/or reduction in power during pulmonary vein isolation, can promote pulmonary vein reconnection (PVR). Methods and results: Patients undergone two consecutive AF ablation procedures with a three-dimensional electro-anatomical mapping system and oesophageal temperature monitoring were studied. Any lesions causing oesophageal temperature rises >39 degrees C during the index procedure, leading to premature cessation of RF and/or reduction in power, were labelled on the left atrial geometry in a different colour from standard uninterrupted RF lesions. Acute (at the time of the index procedure) and chronic (at the time of there-do procedure) PVR and the site of subsequent re-isolation were compared with the lesion markers for temperature alerts from the index procedure. Fifty-four patients were included (36 male, mean age 68 +/- 8, 59% persistent AF). Forty-six PVs (21% of the total) in 30 patients (56%) had been subject to at least one temperature alert during the index procedure. In 12 patients, 23 PVs had acute PVR requiring further ablation. At the re-do procedure, 103 PVs were found to be reconnected in 44 patients. No correlation was found between the occurrence of temperature alerts at the index procedure and acute or chronic PVR in the associated PV. Conclusion: Just over half of patients undergoing PV isolation will have an oesophageal temperature alert, however, precautionary oesophageal temperature monitoring does not compromise ablation efficacy. PMID- 27247013 TI - Is modification of the VVI backup mode in implantable cardioverter-defibrillators from St Jude medical required due to increased risk of inappropriate shocks? AB - Inappropriate implantable cardioverter-defibrillator (ICD) shock therapy is painful, stressful, and typically occurs unexpected in conscious patients and may be related to a less favourable prognosis. In our institution, we have observed four cases of multiple inappropriate ICD shocks during reset to VVI backup mode. All four patients were implanted with a St Jude Medical ICD since 2010. The reset to VVI backup mode happens as a 'safety' response when the ICD encounters errors in the software or hardware often due to electromagnetic interference. The ICD then operates in a simple mode, with only a ventricular fibrillation (VF) zone starting at 146 b.p.m., with shock therapy only and changes in sensitivity settings making the ICD more sensitive. In all cases, the reason for the multiple inappropriate shocks was that the VF zone was reached due to exercise-induced sinus tachycardia or due to oversensing during sinus rhythm. The VVI backup mode has to balance between protection from failure of ICD therapy during life threatening ventricular arrhythmias and from inappropriate shocks. It seems the non-programmable parameters in VVI backup mode of St Jude Medical ICDs carry an unacceptable high risk of inappropriate shocks during normal rhythm as illustrated by our four cases. A higher VF zone comparable with the zones chosen by the other manufacturer would give a better balance, since it is very unlikely that a patient will need shock therapy urgently for slow ventricular tachycardia. PMID- 27247017 TI - Propofol sedation administered by cardiologists for patients undergoing catheter ablation for ventricular tachycardia. AB - AIMS: Propofol sedation has been shown to be safe for atrial fibrillation ablation and internal cardioverter-defibrillator implantation but its use for catheter ablation (CA) of ventricular tachycardia (VT) has yet to be evaluated. Here, we tested the hypothesis that VT ablation can be performed using propofol sedation administered by trained nurses under a cardiologist's supervision. METHODS AND RESULTS: Data of 205 procedures (157 patients, 1.3 procedures/patient) undergoing CA for sustained VT under propofol sedation were analysed. The primary endpoint was change of sedation and/or discontinuation of propofol sedation due to side effects and/or haemodynamic instability. Propofol cessation was necessary in 24 of 205 procedures. These procedures (Group A; n = 24, 11.7%) were compared with those with continued propofol sedation (Group B; n = 181, 88.3%). Propofol sedation was discontinued due to hypotension (n = 22; 10.7%), insufficient oxygenation (n = 1, 0.5%), or hypersalivation (n = 1, 0.5%). Procedures in Group A were significantly longer (210 [180-260] vs. 180 [125-220] min, P = 0.005), had a lower per hour propofol rate (3.0 +/- 1.2 vs. 3.8 +/- 1.2 mg/kg of body weight/h, P = 0.004), and higher cumulative dose of fentanyl administered (0.15 [0.13-0.25] vs. 0.1 [0.05-0.13] mg, P < 0.001), compared with patients in Group B. Five (2.4%) adverse events occurred. CONCLUSION: Sedation using propofol can be safely performed for VT ablation under the supervision of cardiologists. Close haemodynamic monitoring is required, especially in elderly patients and during lengthy procedures, which carrying a higher risk for systolic blood pressure decline. PMID- 27247018 TI - Development of a biocompatible creatinine-based niosomal delivery system for enhanced oral bioavailability of clarithromycin. AB - CONTEXT: Nonionic surfactant vesicles have gained increasing scientific attention for hydrophobic drugs delivery due to their biocompatibility, stability and low cost. OBJECTIVE: The aim of the present study was to synthesize and evaluate a novel creatinine-based nonionic surfactant in terms of its ability to generate biocompatible niosomal system for the delivery of Clarithromycin. MATERIALS AND METHODS: The surfactant was synthesized by reacting creatinine with lauroyl chloride followed by characterization using 1HNMR and MS. The drug-loaded niosomal vesicles of the surfactant were characterized for drug encapsulation efficiency (EE) using LC-MS, vesicle size using dynamic light scattering (DLS) and vesicle shape using atomic force microscopy (AFM). The surfactant was also investigated for blood hemolysis, in vitro cytotoxicity against different cell lines and in vivo acute toxicity in mice. Furthermore, the in vivo bioavailability of Clarithromycin encapsulated in the novel niosomal formulation was investigated using rabbits and quantified through validated LC-MS/MS method. RESULTS AND DISCUSSION: Findings showed that vesicles were able to entrap up to 67.82 +/- 1.27% of the drug, and were rounded in shape with a size around 202.73 +/- 5.30 nm and low polydispersity. The surfactant caused negligible blood hemolysis, very low cytotoxicity and was found to be safe up to 2500 mg/kg body weight using mice. The niosomal formulation showed twofold enhanced oral bioavailability of Clarithromycin as compared to commercial formulations of the drug. CONCLUSION: The study has shown that the creatinine-based niosomes developed in our laboratory were biocompatible, safe and increased the oral bioavailability of the model hydrophobic Clarithromycin using experimental animals. PMID- 27247019 TI - Is there a future for other glutamate receptor modulators in the pharmacotherapy of mood disorders? PMID- 27247020 TI - The hydrogen sulfide metabolite trimethylsulfonium is found in human urine. AB - Hydrogen sulfide is the third and most recently discovered gaseous signaling molecule following nitric oxide and carbon monoxide, playing important roles both in normal physiological conditions and disease progression. The trimethylsulfonium ion (TMS) can result from successive methylation reactions of hydrogen sulfide. No report exists so far about the presence or quantities of TMS in human urine. We developed a method for determining TMS in urine using liquid chromatography-electrospray ionization-triple quadrupole mass spectrometry (LC ESI-QQQ), and applied the method to establish the urinary levels of TMS in a group of human volunteers. The measured urinary levels of TMS were in the nanomolar range, which is commensurate with the steady-state tissue concentrations of hydrogen sulfide previously reported in the literature. The developed method can be used in future studies for the quantification of urinary TMS as a potential biomarker for hydrogen sulfide body pools. PMID- 27247021 TI - Hyperuricemia and the Prognosis of Hypertensive Patients: A Systematic Review and Meta-Analysis. AB - The aim of this study was to assess the prognostic value of hyperuricemia in patients with established hypertension by systematic review and meta-analysis of cohort studies. MEDLINE, Embase, and the Chinese Biomedical Literature Database were searched through January 2015. Seventeen cohort studies were included and their methodological quality was moderate to high, with Newcastle-Ottawa Scale scores ranging from 6 to 9. Random-effects model meta-analyses showed that in terms of adjusted categorical data, hyperuricemia significantly correlated with cardiovascular diseases in hypertensive patients (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.13-2.03), all-cause mortality (HR, 1.12; 95%CI, 1.02 1.23), and diabetes (HR, 1.84; 95% CI, 1.02-3.30) but not with stroke (HR, 0.85; 95%CI, 0.57-1.27); while, in terms of adjusted continuous data, the corresponding pooled HRs were 1.17 (95% CI, 1.07-1.27), 1.05 (95% CI, 0.98-1.13), 1.28 (95% CI, 1.18-1.38), and 1.06 (95% CI, 0.98-1.16), respectively. The findings of our meta analysis suggest that hyperuricemia could slightly increase the risk of cardiovascular diseases and diabetes in patients with hypertension. PMID- 27247022 TI - Long noncoding RNA H19 is up-regulated in esophageal squamous cell carcinoma and promotes cell proliferation and metastasis. AB - Long noncoding RNAs (lncRNAs) have been shown to play various roles in tumorigenesis, among which lncRNA H19 has been revealed as an ambivalent factor that acts as both an oncogene and a tumor suppressor in carcinogenesis. However, the exact biological role of H19 in esophageal squamous cell carcinoma (ESCC) remains to be determined. The aim of this study was to examine the expression pattern of H19 in ESCC and evaluate its biological role and clinical significance in the progression of ESCC. Expression of H19 was analyzed in 64 ESCC tissues and four ESCC cell lines by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Proliferation, cell cycle, migration, and invasion assays were performed in ESCC cell lines following knockdown of H19 to determine the biological function of H19 in the progression of ESCC both in vitro and in vivo. Western blot analysis was also performed to identify the potential mechanisms involved. H19 was highly expressed both in ESCC samples and cell lines compared with corresponding normal counterparts. The up-regulation of of H19 was significantly correlated with ESCC clinical stage and lymph node metastasis. Knockdown of H19 not only exerted inhibitory effect on tumor proliferation in vitro and in vivo, but also repressed the migratory and invasive capacity. G0/G1 phase arrest was also found in H19 knockdown cell lines. In addition, silencing of H19 up-regulated epithelial marker E-cadherin while down-regulating mesenchymal marker vimentin and metastasis-associated protein such as MMP-9. These findings indicate that H19 acts as an oncogene and promotes ESCC cell proliferation and metastasis, which may infer H19 as a marker of poor prognosis and, thus, a potential therapeutic target for treating ESCC patients. PMID- 27247023 TI - Stereoselectivity in (Acyloxy)borane-Catalyzed Mukaiyama Aldol Reactions. AB - The origin of diastereo- and enantioselectivity in a Lewis acid-catalyzed Mukaiyama aldol reaction is investigated using a combination of dispersion corrected DFT calculations and transition state force fields (TSFF) developed using the quantum guided molecular mechanics (Q2MM) method. The reaction proceeds via a closed transition structure involving a nontraditional hydrogen bond that is 3.3 kJ/mol lower in energy than the corresponding open transition structure. The correct prediction of the diastereoselectivity of a Mukaiyama aldol reaction catalyzed by the conformationally flexible Yamamoto chiral (acyloxy) borane (CAB) requires extensive conformational sampling at the transition structure, which is achieved using a Q2MM-derived TSFF, followed by DFT calculations of the low energy conformational clusters. Finally, a conceptual model for the rationalization of the observed diastereo- and enantioselectivity of the reaction using a closed transition state model is proposed. PMID- 27247024 TI - A Method for Detecting Circulating Tumor Cells Based on the Measurement of Single Cell Metabolism in Droplet-Based Microfluidics. AB - The number of circulating tumor cells (CTCs) in blood is strongly correlated with the progress of metastatic cancer. Current methods to detect CTCs are based on immunostaining or discrimination of physical properties. Herein, a label-free method is presented exploiting the abnormal metabolic behavior of cancer cells. A single-cell analysis technique is used to measure the secretion of acid from individual living tumor cells compartmentalized in microfluidically prepared, monodisperse, picoliter (pL) droplets. As few as 10 tumor cells can be detected in a background of 200 000 white blood cells and proof-of-concept data is shown on the detection of CTCs in the blood of metastatic patients. PMID- 27247025 TI - Inhibition of autophagy promotes apoptosis and enhances anticancer efficacy of adriamycin via augmented ROS generation in prostate cancer cells. AB - The interplay between autophagy and apoptosis response to chemotherapy is still a subject of intense debate in recent years. More efforts have focused on the regulation effects of apoptosis on autophagy, whereas how autophagy affects apoptosis remains poorly understood. In this study performed on prostate cancer cells, we investigated the role of autophagy in adriamycin-induced apoptosis, as well as the mechanisms mediating the effects of autophagy on apoptosis response to adriamycin (ADM). The results show that ADM not only inhibited cell viability and enhanced apoptosis, but also promoted autophagy via PI3K/Akt(T308)/mTOR signal pathway. Inhibition of autophagy by either pharmacological inhibitor chloroquine (CQ) or RNA interference of Atg5 increased ADM-induced apoptosis and enhanced the chemosensitivity of prostate cancer cells. Moreover, blockade of autophagy augmented reactive oxygen species (ROS) generation induced by ADM. Scavenging of ROS by antioxidant N-acetyl-cysteine (NAC) reversed the strengthened effects of CQ on ADM-induced apoptosis and rescued the cells from apoptosis. The results identified ROS as a potential mediator directing the modulation effects of the protective autophagy on apoptosis response to ADM. Suppression of the protective autophagy might provide a promising strategy to increase the anticancer efficacy of agents in the treatment of prostate cancer. PMID- 27247026 TI - Relational Anxiety and Sexting. AB - Individuals in pursuit of, or currently in, a romantic relationship typically communicate via technology, extending to sexting with one another. Sexting is commonly understood as the sending and receiving of sexually suggestive or sexually explicit photos, video, or text via cell phone or other technologies. The characteristics that fuel whether one engages in sexting are not well understood. In this study, 459 unmarried, heterosexual undergraduate students (female = 328; male = 131), aged 18 to 25 years, from three universities completed an online questionnaire about their behaviors with technology and romantic relationships. In general, low attachment avoidance and high fear of negative evaluation from the dating partner predicted sending a sexually suggestive photo or video, sending a photo or video in one's underwear or lingerie, and sending a sexually suggestive text. High fear of negative evaluation predicted sending a nude photo or video as well as sending a text message propositioning sex. Low attachment avoidance, greater fear of negative evaluation, and greater social distress when dating were associated with sexting behaviors. PMID- 27247027 TI - Analyzing Association Mapping in Pedigree-Based GWAS Using a Penalized Multitrait Mixed Model. AB - Genome-wide association studies (GWAS) have led to the identification of many genetic variants associated with complex diseases in the past 10 years. Penalization methods, with significant numerical and statistical advantages, have been extensively adopted in analyzing GWAS. This study has been partly motivated by the analysis of Genetic Analysis Workshop (GAW) 18 data, which have two notable characteristics. First, the subjects are from a small number of pedigrees and hence related. Second, for each subject, multiple correlated traits have been measured. Most of the existing penalization methods assume independence between subjects and traits and can be suboptimal. There are a few methods in the literature based on mixed modeling that can accommodate correlations. However, they cannot fully accommodate the two types of correlations while conducting effective marker selection. In this study, we develop a penalized multitrait mixed modeling approach. It accommodates the two different types of correlations and includes several existing methods as special cases. Effective penalization is adopted for marker selection. Simulation demonstrates its satisfactory performance. The GAW 18 data are analyzed using the proposed method. PMID- 27247029 TI - The Fifth International Meeting of ISEV, ISEV2016, Rotterdam, The Netherlands, 4 7 May, 2016. PMID- 27247028 TI - Photosynthetic efficiency, temperature induction response, carbon isotope discrimination correlate with expression profiling in Indian wheat cultivars. AB - In the backdrop of global warming and increase in temperatures, wheat productivity worldwide would be limited. This study was therefore undertaken to analyze the heat stress response in 12 different cultivars of Indian wheat. Three developmental stages were used i.e. germination stage, seedling stage and anthesis stage, to characterize thermotolerant and thermosusceptible cultivars on the basis of different physiological and molecular parameters. Lethal temperature stress on germinating seeds showed a clear reduction in percentage germination. At the seedling stage, higher decrease in Fv/Fm, total chlorophyll content, membrane injury and carbon isotope discrimination was observed in thermosusceptible cultivars. Results similar to seedling stage were obtained at anthesis stage. PSII efficiency of late-sown cultivars and timely-sown cultivars also indicated that thermosusceptible cultivars are more prone to terminal heat stress than thermotolerant cultivars. Heat Susceptibility Index (HSI) was calculated on the basis of physiological parameters. Based on HSI, thermotolerant and thermosusceptible cultivars were identified. HSI revealed comparatively low heat susceptibility in K7903, CBW12 and C306 and high heat susceptibility in PBW343, HD2329 and HD2428. On the basis of HSI, expression analysis of stress induced genes was performed between 2 tolerant cultivars C306 and K7903 along with 2 susceptible cultivars, HD2329 and PBW343. Higher expression of stress induced genes was observed in the 2 thermotolerant cultivars C306 and K7903 as compared to the 2 thermosusceptible cultivars HD2329 and PBW343. Thus further reconfirms that stress inducible genes can be employed for categorizing cultivars into susceptible and tolerant groups. PMID- 27247030 TI - The Decoy Effect Within Alcohol Purchasing Decisions. AB - BACKGROUND: The decoy effect is the phenomenon where the introduction of a third choice to a decision dyad changes the distribution of preferences between options. OBJECTIVES: Examine whether this effect exists in alcohol purchasing decisions and whether testing context impacts this. METHOD: Fifty-two participants tested in either a bar or library context and were asked to choose one of a series of beer and water deals presented for timed intervals. In some cases, two options were presented (with similar attractiveness) and in other cases a third, less preferable, decoy option was added. RESULTS: A basic decoy effect in both alcohol and water purchasing decisions. Specifically, there were reductions in the selection of both the original options when the decoy was added into choice dyads. A significant interaction demonstrated in the bar context there was a significant difference such that there was a slight increase in participants selecting the most cost effective option when the decoy was added, and a simultaneous decrease in those choosing the moderately cost effective option. There were no such differences observed in the library condition. CONCLUSION: The same product may be perceived differently across contexts and, as such, consumers in a pub environment may be particularly vulnerable to the decoy effect. PMID- 27247031 TI - Endogenous Arabidopsis messenger RNAs transported to distant tissues. AB - The concept that proteins and small RNAs can move to and function in distant body parts is well established. However, non-cell-autonomy of small RNA molecules raises the question: To what extent are protein-coding messenger RNAs (mRNAs) exchanged between tissues in plants? Here we report the comprehensive identification of 2,006 genes producing mobile RNAs in Arabidopsis thaliana. The analysis of variant ecotype transcripts that were present in heterografted plants allowed the identification of mRNAs moving between various organs under normal or nutrient-limiting conditions. Most of these mobile transcripts seem to follow the phloem-dependent allocation pathway transporting sugars from photosynthetic tissues to roots via the vasculature. Notably, a high number of transcripts also move in the opposite, root-to-shoot direction and are transported to specific tissues including flowers. Proteomic data on grafted plants indicate the presence of proteins from mobile RNAs, allowing the possibility that they may be translated at their destination site. The mobility of a high number of mRNAs suggests that a postulated tissue-specific gene expression profile might not be predictive for the actual plant body part in which a transcript exerts its function. PMID- 27247032 TI - Regulation of organ straightening and plant posture by an actin-myosin XI cytoskeleton. AB - Plants are able to bend nearly every organ in response to environmental stimuli such as gravity and light(1,2). After this first phase, the responses to stimuli are restrained by an independent mechanism, or even reversed, so that the organ will stop bending and attain its desired posture. This phenomenon of organ straightening has been called autotropism(3) and autostraightening(4) and modelled as proprioception(5). However, the machinery that drives organ straightening and where it occurs are mostly unknown. Here, we show that the straightening of inflorescence stems is regulated by an actin-myosin XI cytoskeleton in specialized immature fibre cells that are parallel to the stem and encircle it in a thin band. Arabidopsis mutants defective in myosin XI (specifically XIf and XIk) or ACTIN8 exhibit hyperbending of stems in response to gravity, an effect independent of the physical properties of the shoots. The actin-myosin XI cytoskeleton enables organs to attain their new position more rapidly than would an oscillating series of diminishing overshoots in environmental stimuli. We propose that the long actin filaments in elongating fibre cells act as a bending tensile sensor to perceive the organ's posture and trigger the straightening system. PMID- 27247033 TI - Complementary effects of species and genetic diversity on productivity and stability of sown grasslands. AB - Plant species diversity regulates the productivity(1-3) and stability(2,4) of natural ecosystems, along with their resilience to disturbance(5,6). The influence of species diversity on the productivity of agronomic systems is less clear(7-10). Plant genetic diversity is also suspected to influence ecosystem function(3,11-14), although empirical evidence is scarce. Given the large range of genotypes that can be generated per species through artificial selection, genetic diversity is a potentially important leverage of productivity in cultivated systems. Here we assess the effect of species and genetic diversity on the production and sustainable supply of livestock fodder in sown grasslands, comprising single and multispecies assemblages characterized by different levels of genetic diversity, exposed to drought and non-drought conditions. Multispecies assemblages proved more productive than monocultures when subject to drought, regardless of the number of genotypes per species present. Conversely, the temporal stability of production increased only with the number of genotypes present under both drought and non-drought conditions, and was unaffected by the number of species. We conclude that taxonomic and genetic diversity can play complementary roles when it comes to optimizing livestock fodder production in managed grasslands, and suggest that both levels of diversity should be considered in plant breeding programmes designed to boost the productivity and resilience of managed grasslands in the face of increasing environmental hazards. PMID- 27247034 TI - Elicitin recognition confers enhanced resistance to Phytophthora infestans in potato. AB - Potato late blight, caused by the destructive Irish famine pathogen Phytophthora infestans, is a major threat to global food security(1,2). All late blight resistance genes identified to date belong to the coiled-coil, nucleotide binding, leucine-rich repeat class of intracellular immune receptors(3). However, virulent races of the pathogen quickly evolved to evade recognition by these cytoplasmic immune receptors(4). Here we demonstrate that the receptor-like protein ELR (elicitin response) from the wild potato Solanum microdontum mediates extracellular recognition of the elicitin domain, a molecular pattern that is conserved in Phytophthora species. ELR associates with the immune co-receptor BAK1/SERK3 and mediates broad-spectrum recognition of elicitin proteins from several Phytophthora species, including four diverse elicitins from P. infestans. Transfer of ELR into cultivated potato resulted in enhanced resistance to P. infestans. Pyramiding cell surface pattern recognition receptors with intracellular immune receptors could maximize the potential of generating a broader and potentially more durable resistance to this devastating plant pathogen. PMID- 27247035 TI - Physical interaction between peroxisomes and chloroplasts elucidated by in situ laser analysis. AB - Life on earth relies upon photosynthesis, which consumes carbon dioxide and generates oxygen and carbohydrates. Photosynthesis is sustained by a dynamic environment within the plant cell involving numerous organelles with cytoplasmic streaming. Physiological studies of chloroplasts, mitochondria and peroxisomes show that these organelles actively communicate during photorespiration, a process by which by-products produced by photosynthesis are salvaged. Nevertheless, the mechanisms enabling efficient exchange of metabolites have not been clearly defined. We found that peroxisomes along chloroplasts changed shape from spherical to elliptical and their interaction area increased during photorespiration. We applied a recent femtosecond laser technology to analyse adhesion between the organelles inside palisade mesophyll cells of Arabidopsis leaves and succeeded in estimating their physical interactions under different environmental conditions. This is the first application of this estimation method within living cells. Our findings suggest that photosynthetic-dependent interactions play a critical role in ensuring efficient metabolite flow during photorespiration. PMID- 27247036 TI - microRNA regulation of fruit growth. AB - Growth is a major factor in plant organ morphogenesis and is influenced by exogenous and endogenous signals including hormones. Although recent studies have identified regulatory pathways for the control of growth during vegetative development, there is little mechanistic understanding of how growth is controlled during the reproductive phase. Using Arabidopsis fruit morphogenesis as a platform for our studies, we show that the microRNA miR172 is critical for fruit growth, as the growth of fruit is blocked when miR172 activity is compromised. Furthermore, our data are consistent with the FRUITFULL (FUL) MADS domain protein and Auxin Response Factors (ARFs) directly activating the expression of a miR172-encoding gene to promote fruit valve growth. We have also revealed that MADS-domain (such as FUL) and ARF proteins directly associate in planta. This study defines a novel and conserved microRNA-dependent regulatory module integrating developmental and hormone signalling pathways in the control of plant growth. PMID- 27247037 TI - Fruit development: miRNA pumps up the volume. PMID- 27247038 TI - RNA transport: Delivering the message. PMID- 27247039 TI - Peroxisomes: Dynamic shape-shifters. PMID- 27247040 TI - Adventures in loveable science. PMID- 27247041 TI - Agroecology: Agroecosystem diversification. PMID- 27247042 TI - Arctic ecosystems: Tundra carbon gain. PMID- 27247044 TI - Innate immunity: Septic shock. PMID- 27247043 TI - Insect resistance: Triple whammy. PMID- 27247045 TI - Measuring chlorophyll: Looking-glass logic. PMID- 27247046 TI - Synthesizing tomorrow. PMID- 27247047 TI - Cystine/glutamate antiporter blockage induces myelin degeneration. AB - The cystine/glutamate antiporter is a membrane transport system responsible for the uptake of extracellular cystine and release of intracellular glutamate. It is the major source of cystine in most cells, and a key regulator of extrasynaptic glutamate in the CNS. Because cystine is the limiting factor in the biosynthesis of glutathione, and glutamate is the most abundant neurotransmitter, the cystine/glutamate antiporter is a central player both in antioxidant defense and glutamatergic signaling, two events critical to brain function. However, distribution of cystine/glutamate antiporter in CNS has not been well characterized. Here, we analyzed expression of the catalytic subunit of the cystine/glutamate antiporter, xCT, by immunohistochemistry in histological sections of the forebrain and spinal cord. We detected labeling in neurons, oligodendrocytes, microglia, and oligodendrocyte precursor cells, but not in GFAP(+) astrocytes. In addition, we examined xCT expression and function by qPCR and cystine uptake in primary rat cultures of CNS, detecting higher levels of antiporter expression in neurons and oligodendrocytes. Chronic inhibition of cystine/glutamate antiporter caused high toxicity to cultured oligodendrocytes. In accordance, chronic blockage of cystine/glutamate antiporter as well as glutathione depletion caused myelin disruption in organotypic cerebellar slices. Finally, mice chronically treated with sulfasalazine, a cystine/glutamate antiporter inhibitor, showed a reduction in the levels of myelin and an increase in the myelinated fiber g-ratio. Together, these results reveal that cystine/glutamate antiporter is expressed in oligodendrocytes, where it is a key factor to the maintenance of cell homeostasis. GLIA 2016. GLIA 2016;64:1381-1395. PMID- 27247048 TI - Efficient and Selective Chemical Labeling of Electrochemically Generated Peptides Based on Spirolactone Chemistry. AB - Specific digestion of proteins is an essential step for mass spectrometry-based proteomics, and the chemical labeling of the resulting peptides is often used for peptide enrichment or the introduction of desirable tags. Cleavage of the peptide bond following electrochemical oxidation of Tyr or Trp results in a spirolactone moiety at the newly formed C-terminus offering a handle for chemical labeling. In this work, we developed a highly efficient and selective chemical labeling approach based on spirolactone chemistry. Electrochemically generated peptide spirolactones readily undergo an intramolecular rearrangement yielding isomeric diketopiperazines precluding further chemical labeling. A strategy was established to prevent intramolecular arrangement by acetylating the N-terminal amino group prior to electrochemical oxidation and cleavage allowing the complete and selective chemical labeling of the tripeptide LWL and the decapeptide ACTH 1 10 with amine-containing reagents. As examples, we show the successful introduction of a fluorescent label and biotin for detection or affinity enrichment. Electrochemical digestion of peptides and proteins followed by efficient chemical labeling constitutes a new, powerful tool in protein chemistry and protein analysis. PMID- 27247049 TI - Expanding the clinical picture of the MECP2 Duplication syndrome. AB - Individuals with two or more copies of the MECP2 gene, located at Xq28, share clinical features and a distinct facial phenotype known as MECP2 Duplication syndrome. We have examined perinatal characteristics, early childhood development and medical co-morbidities in this disorder. The International Rett Syndrome Phenotype Database (InterRett), which collects information from caregivers and clinicians on individuals with Rett syndrome and MECP2 associated disorders, was used as the data source. Data were available on 56 cases (49 males and 7 females) with MECP2 Duplication syndrome. Median age at ascertainment was 7.9 years (range: 1.2-37.6 years) and at diagnosis 3.0 years (range: 3 weeks-37 years). Less than a third (29%) learned to walk. Speech deterioration was reported in 34% and only 20% used word approximations or better at ascertainment. Over half (55%) had been hospitalised for respiratory infections in the first 2 years of life. Just under half (44%) had seizures, occurring daily in nearly half of this group. The majority (89%) had gastrointestinal problems and a third had a gastrostomy. Following the recent demonstration of phenotype reversal in a mouse model of MECP2 Duplication, a clear understanding of the natural history is crucial to the design and implementation of future therapeutic strategies. PMID- 27247051 TI - EXD2 - a new player joins the DSB resection team. PMID- 27247050 TI - Clinical application of the biomarkers for the selection of adjuvant chemotherapy in pancreatic ductal adenocarcinoma. AB - BACKGROUND: For the establishment of personalized therapy, we investigated biomarkers that can contribute to the selection of adjuvant therapy for pancreatic ductal adenocarcinoma (PDAC). METHODS: Between 2005 and 2014, of 141 consecutive patients with PDAC who underwent R0 or R1 resection, 61 patients given gemcitabine and 31 patients given S-1 as adjuvant therapy were enrolled. We evaluated the correlation between treatment outcomes and the expressions of intratumoral human antigen R (HuR), human equilibrative nucleoside transporter 1 (hENT1), thymidylate synthetase (TS) and dihydropyrimidine dehydrogenase (DPD). RESULTS: There were no significant differences in clinicopathological features between the gemcitabine and S-1 groups. Among those with high HuR expression and high hENT1 expression, the disease-free survival (DFS) was significantly higher with gemcitabine than with S-1 (MST: 26.2 vs. 11.8 months, P = 0.024; 20.2 vs. 10.2 months, P = 0.029, respectively). Moreover, high HuR/hENT1 (high HuR or high hENT1) was significantly associated with better outcome for gemcitabine (HR for DFS: 0.43, P = 0.027) and low HuR/hENT1 was significantly associated with worse outcome for gemcitabine (HR for DFS: 2.24, P = 0.021). TS and DPD expression levels were not informative in this examination. CONCLUSIONS: HuR and hENT1 were good candidates as selective biomarkers and this study's concept could contribute to personalized therapy for PDAC patients. PMID- 27247052 TI - Gelatin-Graphene Nanocomposites with Ultralow Electrical Percolation Threshold. AB - Gelatin-graphene conductive biopolymer nanocomposites (CPCs) with ultralow percolation threshold are designed by reducing in situ graphene oxide nanosheets with ascorbic acid and suppressing the aggregation of the graphene nanosheets. The resulting conductive nanocomposites show a record-low electrical percolation threshold of 3.3 * 10(-2) vol%, which arises from the homogeneous dispersion of the graphene nanosheets within the gelatin matrix. PMID- 27247054 TI - The Nobel Prize runner-up Leopold Freund and the origin of radiotherapy. PMID- 27247053 TI - Tumour control and Quality of Life in children with rhabdomyosarcoma treated with pencil beam scanning proton therapy. AB - PURPOSE: To assess clinical outcomes in children with rhabdomyosarcoma (RMS) treated with pencil beam scanning (PBS) proton therapy (PT). METHODS AND MATERIALS: Eighty-three RMS (embryonal, n=74; 89%) patients treated between January 2000 and December 2014 were included. The median age was 4.5years (range, 0.8-15.5). All patients received systemic chemotherapy according to prospective protocols. Patients had low-, intermediate-, and high-risk disease in 24%, 63%, and 13% of cases, respectively. The median total dose delivered was 54Gy(RBE) (range, 41.4-64.8). RESULTS: After a median follow-up time of 55.5 months (range, 0.9-126.3), local failure occurred in 16 patients. The 5-year local-control survival rate was 78.5% [95% confidence interval (CI), 69.5-88.5%]. Significant predictors for local failure were group/stage, tumour location, and size. Fourteen patients (16%) died, all from tumour progression. The 5-year overall survival was 80.6% (95%CI, 71.8-90.0%). The 5-year incidence of grade 3 non ocular late toxicity was 3.6% (95%CI, 1-12%). No grade 4-5 late toxicities were observed. One radiation-induced malignancy was observed (1.2%). The Quality of Life (QoL) scores increased significantly after PT compared to baseline values. CONCLUSIONS: PBS PT led to excellent outcome in children with RMS. Late non ocular toxicity was minimal and QoL good. PMID- 27247055 TI - Factors associated with patient-reported cosmetic outcome in the Young Boost Breast Trial. AB - PURPOSE: To investigate which factors are related to patient reported cosmetic outcome (PRCO) after breast conserving therapy. METHODS: From 2004 to 2011, 2421 cT1-2N0-2a breast cancer patients were randomised in the Young Boost Trial between a 16 and a 26Gy boost to the tumour bed. Cosmesis was scored subjectively by the patient and physician, and objectively using BCCT.core, at baseline, one and four years after treatment. Presence of fibrosis, QoL and rib pain at four years were also scored. Data were complete for 864 patients. The relation between the separate components was investigated using a proportional odds model. RESULTS: Of the 7 BCCT.core parameters, the distance from nipple to inframammary fold and the length of the breast contour were significantly related to the overall PRCO at four years. Patients with more fibrosis and poorer QoL scored their cosmesis worse, while rib pain was not related. The agreement between the different scores was low (kappa 0.26-0.42). CONCLUSION: The distance from nipple to inframammary fold, the length of the breast contour and the severity of fibrosis were the main factors related to patient-reported cosmetic outcome. Patients with better QoL scored their cosmesis better. PMID- 27247056 TI - The radiosensitizing effects of Nelfinavir on pancreatic cancer with and without pancreatic stellate cells. AB - AIMS: We have previously shown in a phase I trial that nelfinavir (NFV) is safe with chemoradiation in PDAC with good signs for efficacy. Reverse translationally, we aimed to test the influence of PSCs on nelfinavir mediated radiosensitization to PDAC preclinically, because PDAC is very rich in desmoplasia and PSCs are known to mediate radioresistance. METHODS: In a direct co-culture model of several PDAC cell lines with PSC we performed clonogenic assays +/- nelfinavir. This was repeated exposing cells to hypoxic conditions. In xenograft PDAC tumors we tested radiation +/- nelfinavir +/- PSC. RESULTS: NFV sensitized both, PDAC only and PDAC cocultured with PSC (PDAC: Panc-1, MiaPaCa-2, PSN-1). In Panc-1 and PSN-1 this effect was larger +PSC compared to -PSC. Human pancreatic stellate cells (hPSC) were also sensitized by NFV which reduced p-FAK levels in hPSC, an effect that we previously found to sensitize specifically PDAC/PSC coculture. Contrarily, LY294002 reduced p-Akt in PSC (hPSC and LTC-14) but had no impact on PSC radiation survival. In vitro, nelfinavir sensitized Panc 1 and PSN-1 under normoxic and hypoxic conditions. In PSN-1 xenografts, +PSC led to faster tumor regrowth after radiation vs -PSC. The regrowth delay effect of nelfinavir after radiation was dramatically larger +PSC vs -PSC (time to reach 250mm(3) 183% vs 22%). CONCLUSION: NFV mediated radiosensitization in PDAC with stroma is partly mediated by p-FAK inhibition (Chen et al., 2013). In vitro, NFV sensitizes both normoxic and hypoxic PDAC +/- PSC to a roughly similar extent. The dramatic increased effect of xenograft regrowth inhibition by nelfinavir in tumors with PSC is attributed to vascular normalization (Brunner et al., 2014) rather than direct modification of hypoxia as shown by the tumor regrowth after gemcitabine with NFV. PMID- 27247057 TI - Long term outcomes of patients with skull-base low-grade chondrosarcoma and chordoma patients treated with pencil beam scanning proton therapy. AB - PURPOSE: To evaluate the long term tumor control and toxicity of skull base tumors treated with pencil beam scanning proton therapy (PT). MATERIALS AND METHODS: PT was delivered to 151 (68%) and 71 (32%) chordoma and chondrosarcoma (ChSa) patients, respectively. Mean age of patients was 40.8+/-18.4years and the male to female ratio was 0.53. The postoperative tumor was abutting the brainstem or optic apparatus in 71 (32.0%) patients. The postoperative mean gross tumor volume (GTV) was 35.7+/-29.1cm(3). The delivered mean PT dose was 72.5+/ 2.2GyRBE. RESULTS: After a mean follow-up of 50 (range, 4-176) months, 35 local (15.8%) failures were observed between 10.9 and 85.4months. The estimated 7-year LC rate for chordoma (70.9%; CI95% 61.5-81.8) was significantly lower compared to the LC rate for ChSa patients (93.6%; 95%CI 87.8-99.9; P=0.014). The estimated 7 year distant metastasis-free- and overall survival rate was 91.6% (95%CI 91.6 98.6) and 81.7% (95%CI 74.7-89.5), respectively. On multivariate analysis, optic apparatus and/or brainstem compression, histology and GTV were independent prognostic factors for LC and OS. The 7-year high grade toxicity-free survival was 87.2 (95%CI 82.4-92.3). CONCLUSIONS: PBS PT is an effective treatment for skull base tumors with acceptable late toxicity. Optic apparatus and/or brainstem compression, histology and GTV allow independent prediction of the risk of local failure and death in skull base tumor patients. PMID- 27247058 TI - Quantification of vaginal motion associated with daily endorectal balloon placement during whole pelvis radiotherapy for gynecologic cancers. AB - BACKGROUND AND PURPOSE: To quantify intra-treatment vaginal motion in women treated with daily endorectal balloon (ERB) placement and external beam radiotherapy for gynecologic cancers. MATERIALS AND METHODS: Eighteen post hysterectomy women with gynecologic cancers underwent computed tomography (CT) simulation scans and daily treatment with ERB. Fiducial markers were placed at the vaginal apex prior to simulation and patients were counseled on a pre treatment bladder filling protocol. Weekly to biweekly verification CT scans were used to calculate the intra-treatment change in bladder volumes, rectal volumes, and fiducial coordinates along all axes. The planning target volume (PTV) margins required to encompass 95% of intra-treatment fiducial movement were calculated using the van Herk margin recipe. RESULTS: The median bladder volume was 223 (range, 29-879)cc for verification CT scans. Mean intra-treatment fiducial displacements were 1.7 (range, 0-9.1)mm, 2.9 (range, 0-15.5)mm, and 2.5 (range, 0 11.8)mm along the left-right (L/R), superior-inferior (S/I), and anterior posterior (A/P) axes, respectively. The van Herk PTV margins were 3mm (L/R), 10mm (S/I) and 7mm (A/P). CONCLUSION: When compared to existing studies, the use of daily ERB with post-hysterectomy radiotherapy reduces vaginal motion along the A/P axis. The impact of variable bladder filling on vaginal motion is most evident along the S/I axis. PMID- 27247059 TI - Small groups and long memories promote cooperation. AB - Complex social behaviors lie at the heart of many of the challenges facing evolutionary biology, sociology, economics, and beyond. For evolutionary biologists the question is often how group behaviors such as collective action, or decision making that accounts for memories of past experience, can emerge and persist in an evolving system. Evolutionary game theory provides a framework for formalizing these questions and admitting them to rigorous study. Here we develop such a framework to study the evolution of sustained collective action in multi player public-goods games, in which players have arbitrarily long memories of prior rounds of play and can react to their experience in an arbitrary way. We construct a coordinate system for memory-m strategies in iterated n-player games that permits us to characterize all cooperative strategies that resist invasion by any mutant strategy, and stabilize cooperative behavior. We show that, especially when groups are small, longer-memory strategies make cooperation easier to evolve, by increasing the number of ways to stabilize cooperation. We also explore the co-evolution of behavior and memory. We find that even when memory has a cost, longer-memory strategies often evolve, which in turn drives the evolution of cooperation, even when the benefits for cooperation are low. PMID- 27247060 TI - A critical role of T follicular helper cells in human mucosal anti-influenza response that can be enhanced by immunological adjuvant CpG-DNA. AB - T Follicular helper cells (TFH) are considered critical for B cell antibody response, and recent efforts have focused on promoting TFH in order to enhance vaccine efficacy. We studied the frequency and function of TFH in nasopharynx associated lymphoid tissues (NALT) from children and adults, and its role in anti influenza antibody response following stimulation by a live-attenuated influenza vaccine (LAIV) or an inactivated seasonal virus antigen (sH1N1). We further studied whether CpG-DNA promotes TFH and by which enhances anti-influenza response. We showed NALT from children aged 1.5-10 years contained abundant TFH, suggesting efficient priming of TFH during early childhood. Stimulation by LAIV induced a marked increase in TFH that correlated with a strong production of anti hemagglutinin (HA) IgA/IgG/IgM antibodies in tonsillar cells. Stimulation by the inactivated sH1N1 antigen induced a small increase in TFH which was markedly enhanced by CpG-DNA, accompanied by enhanced anti-HA antibody responses. In B cell co-culture experiment, anti-HA responses were only seen in the presence of TFH, and addition of plasmacytoid dendritic cell to TFH-B cell co-culture enhanced the TFH-mediated antibody production following CpG-DNA and sH1N1 antigen stimulation. Induction of TFH differentiation from naive T cells was also shown following the stimulation. Our results support a critical role of TFH in human mucosal anti-influenza antibody response. Use of an adjuvant such as CpG-DNA that has the capacity to promote TFH by which to enhance antigen-induced antibody responses in NALT tissue may have important implications for future vaccination strategies against respiratory pathogens. PMID- 27247061 TI - Medicinal plants used to control internal and external parasites in goats. AB - The use of medicinal plants plays a major role in the primary health care of animals in South Africa. A survey was conducted to document medicinal plants used to control parasites in goats in Kwezi and Ntambethemba villages in the Eastern Cape Province, South Africa. Information from 50 farmers and 3 herbalists was obtained through the use of a structured questionnaire, and a snowball sampling technique was used to identify key informants. The obtained data were analysed using PROC FREQ of SAS (2003), and fidelity level values were determined to estimate the healing potential of the mentioned plants. The survey revealed nine plant species belonging to eight families that were used to control parasites in goats. Asphodelaceae (22.22%) was the most frequently used plant family. Leaves were the most used plant parts, constituting 60.38%. They were prepared either as infusions or decoctions of single plants or in mixtures. Aloe ferox, Acokanthera oppositifolia and Elephantorrhiza elephantina were the plants having the highest fidelity level for their use to control parasites, each scoring 100%, followed by Albuca setosa (83.33%). The study revealed low knowledge about ethnoveterinary medicine in the study area. It also revealed that information on ethno-veterinary medicine in this area is mostly confined to older people and there is danger that this knowledge can be lost before being passed on to other generations. Therefore, there is an urgent need to document information on these plant species so that the future generation can benefit. Further investigation should be carried out to validate the efficacy and safety of the above-mentioned plants so as to provide cheap alternative ways of controlling parasites. PMID- 27247062 TI - Diagnosis and genotyping of African swine fever viruses from 2015 outbreaks in Zambia. AB - In early 2015, a highly fatal haemorrhagic disease of domestic pigs resembling African swine fever (ASF) occurred in North Western, Copperbelt, and Lusaka provinces of Zambia. Molecular diagnosis by polymerase chain reaction targeting specific amplification of p72 (B646L) gene of ASF virus (ASFV) was conducted. Fourteen out of 16 domestic pigs from the affected provinces were found to be positive for ASFV. Phylogenetic analyses based on part of the p72 and the complete p54 (E183L) genes revealed that all the ASFVs detected belonged to genotypes I and Id, respectively. Additionally, epidemiological data suggest that the same ASFV spread from Lusaka to other provinces possibly through uncontrolled and/or illegal pig movements. Although the origin of the ASFV that caused outbreaks in domestic pigs in Zambia could not be ascertained, it appears likely that the virus may have emerged from within the country or region, probably from a sylvatic cycle. It is recommended that surveillance of ASF, strict biosecurity, and quarantine measures be imposed in order to prevent further spread and emergence of new ASF outbreaks in Zambia. PMID- 27247063 TI - A description of village chicken production systems and prevalence of gastrointestinal parasites: Case studies in Limpopo and KwaZulu-Natal provinces of South Africa. AB - The majority of rural households in developing countries own village chickens that are reared under traditional scavenging systems with few inputs and exposure to various parasitic infestations. Understanding of the village chicken farming system and its influence on helminth infestation is a prerequisite for optimal prevention and control strategies. This study investigated the village chicken production system and associated gastrointestinal parasites in 87 households from Limpopo (n = 39) and KwaZulu-Natal (n = 48) provinces of South Africa. A total of 191 village chicken faecal samples and 145 intestines were collected to determine the prevalence of gastrointestinal parasites in villages of Limpopo and KwaZulu Natal provinces, respectively. The faecal floatation analysis of samples from Limpopo and KwaZulu-Natal provinces indicated infestations by Ascaridia galli (18.77%), Heterakis gallinarum (15.56%) and Capillaria spp. (4.00%); tapeworms Choanotaenia infundibulum (2.10%) and Raillietina cesticillus (6.00%) and Eimeria spp. (29.46%). Mixed infestations were observed in five (4.90%) samples from Limpopo province and in only four (4.49%) from KwaZulu-Natal province, of which 1.12% were a mixture of C. infundibulum and Eimeria spp. and 3.37% a combination of H. gallinarum and Eimeria spp. In Limpopo, 2.94% of the chickens were positive for H. gallinarum and Eimeria spp., whilst 0.98% had A. galli and Capillaria spp. infestations. Further investigation is needed to understand the impact of gastrointestinal parasites on village chicken health and production and develop appropriate intervention and control strategies feasible for smallholder farmers. PMID- 27247064 TI - Is a 10-sow unit economically sustainable? A profitability assessment of productivity amongst small-holder pig farmers, Mpumalanga, South Africa. AB - The majority of small-holder pig farmers in Mpumalanga had between 1- and 10-sow herds. The main aim of this study is to evaluate the current government agricultural intervention (supply of 10 sows and a boar) in terms of technical and economic feasibilities and ascertain whether the small-scale pig value chain system alleviates poverty. Data were obtained from 220 randomly selected small holder pig farmers using a semi-structured questionnaire. The results showed that 58% farrowed <= 10 piglets/born/sow/litter, 44.2% practiced no weaning method and many fed swill and leftovers alone (41.6%). Pair-wise association revealed that the feeding of commercial feeds had a relationship with pigs in relatively good to very good body condition. Pigs in poor body condition were positively correlated with the feeding of swill alone. The economic models for the 10-sow unit proved that pig farming is unprofitable if the current management and feeding systems that operate in the commercial industry are utilised. However, only through a combination of cooperative systems, benefits of economies of scale, reduction of preweaning mortalities and structured government inputs can pig production be profitable at this scale of production. PMID- 27247065 TI - Sero-epidemiological survey and risk factors associated with bovine brucellosis among slaughtered cattle in Nigeria. AB - Bovine brucellosis is endemic in Nigeria; however, limited data exist on nationwide studies and risk factors associated with the disease. Using a cross sectional sero-epidemiological survey, we determined the prevalence of and risk factors for brucellosis in slaughtered cattle in three geographical regions of Nigeria. Serum samples from randomly selected unvaccinated cattle slaughtered over a period of 3 years (between December 2010 and September 2013) from northern, southern and south-western Nigeria were tested for antibodies to Brucella abortus using the Rose Bengal test. Data associated with risk factors of brucellosis were analysed by Stata Version 12. In all, 8105 cattle were screened. An overall seroprevalence of 3.9% (315/8105) was recorded by the Rose Bengal test, with 3.8%, 3.4% and 4.0% from the northern, southern and south-western regions, respectively. Bivariate analysis showed that cattle screened in northern Nigeria were less likely to be seropositive for antibodies to Brucella spp. than those from south-western Nigeria (odds ratio = 0.94; 95% confidence interval: 0.73-1.22). However, logistic regression analysis revealed that breed ( p = 0.04) and sex ( p L 0.0001) of cattle were statistically significant for seropositivity to Brucella spp. The study found that brucellosis was endemic at a low prevalence among slaughtered cattle in Nigeria, with sex and breed of cattle being significant risk factors. Considering the public health implications of brucellosis, we advocate coordinated surveillance for the disease among diverse cattle populations in Nigeria, as is carried out in most developed countries. PMID- 27247066 TI - Contagious bovine pleuropneumonia: Seroprevalence and risk factors in Western Oromia, Ethiopia. AB - Contagious bovine pleuropneumonia (CBPP) is one of the most important threats to cattle health and production in Ethiopia. At the livestock farm of the Bako Agricultural Research Center, an outbreak of respiratory disease of cattle occurred in May 2011, and many animals were affected and died before the disease was diagnosed. Therefore, this study was designed to determine the seroprevalence of CBPP antibodies in selected districts of Western Oromia Region and to assess the potential risk factors for the occurrence of the disease. A crosssectional study was conducted from November 2013 to March 2014 in three selected districts of Western Oromia Region. A total of 386 sera were examined for the presence of specific antibodies against Mycoplasma mycoidesmycoides small colony (MmmSC), using a competitive enzyme-linked immunosorbent assay. The risk factors that were evaluated in this study were geographical location, age, sex, breed and body condition. The overall seroprevalence in this study was 28.5%. The seroprevalence of Mycoplasma mycoidesmycoides small colony antibodies at the district level was 40.3%, 19.0% and 5.7% in Gobbu Sayyo, BakoTibbe and Horro districts, respectively. There was a statistically significant variation ( p < 0.05) in the prevalence of antibodies amongst the districts. However, animal-related risk factors, such as age, sex, breed and body condition, were not significantly associated ( p > 0.05) with the serological status of the animal. This study showed that the overall prevalence of CBPP in Western Oromia Zones was high. This warrants the implementation of appropriate preventive and control measures to minimise the economic losses associated with the disease. PMID- 27247067 TI - Cryptosporidium genotypes in children and calves living at the wildlife or livestock interface of the Kruger National Park, South Africa. AB - Cryptosporidium infection is one of the most common causes of parasitic diarrhoea worldwide in cattle and humans. In developing countries, human cryptosporidiosis is most prevalent during early childhood and links between zoonotic infection and animal related activities have been demonstrated. This study investigated the prevalence and species/genotype distribution of Cryptosporidium among children (< 5 years) and calves (< 6 months) living in a rural farming area adjacent to the Kruger National Park in South Africa, where interactions between humans and wild and domestic animals are known to occur. Cryptosporidium oocysts were detected in 8/143 stool samples of children recruited within the hospital system (5.6%; 95% CI 2.4%, 10.7%) and in 2/352 faecal samples of calves (0.6%; 95% CI 0.1%, 2.0%) using the modified Ziehl-Neelsen (MZN) staining technique. Microscopy positive samples from children were further analysed by PCR targeting the 18S rRNA gene and identified as Cryptosporidium hominis (3/4) and Cryptosporidium meleagridis (1/4). Regardless of the microscopy outcome, randomly selected samples (n = 36) from calves 0-4 months of age were amplified and sequenced at the 18S rRNA gene using nested PCR. Two calves tested positive (5.6%; 95% CI 1.7%, 18.7%), and revealed the presence of Cryptosporidium parvum and Cryptosporidium bovis. The detection of only two zoonotic species (C. parvum in one calf and C. meleagridis in one child) suggests that zoonotic cryptosporidiosis is not currently widespread in our study area; however, the potential exists for amplification of transmission in an immunocompromised population. PMID- 27247068 TI - The African swine fever control zone in South Africa and its current relevance. AB - African swine fever (ASF) has been reported in South Africa since the early 20th century. The disease has been controlled and confined to northern South Africa over the past 80 years by means of a well-defined boundary line, with strict control measures and movement restrictions north of this line. In 2012, the first outbreak of ASF outside the ASF control zone since 1996 occurred. The objective of this study was to evaluate the current relevance of the ASF control line as a demarcation line between endemic ASF (north) areas and ASF-free (south) area and to determine whether there was a need to realign its trajectory, given the recent outbreaks of ASF, global climate changes and urban development since the line's inception. A study of ASF determinants was conducted in an area 20 km north and 20 km south of the ASF control line, in Limpopo, Mpumalanga, North West and Gauteng provinces between May 2008 and September 2012. The study confirmed that warthogs, warthog burrows and the soft tick reservoir, Ornithodoros moubata, are present south of the ASF control line, but no virus or viral DNA was detected in these ticks. There appears to be an increasing trend in the diurnal maximum temperature and a decrease in humidity along the line, but the impact of these changes is uncertain. No discernible changes in minimum temperatures and average rainfall along the disease control line were observed between 1992 and 2014. Even though the reservoirs were found south of the ASF boundary line, the study concluded that there was no need to realign the trajectory of the ASF disease control line, with the exception of Limpopo Province. However, the provincial surveillance programmes for the reservoir, vector and ASF virus south of this line needs to be maintained and intensified as changing farming practices may favour the spread of ASF virus beyond the control line. PMID- 27247069 TI - Taeniasis in non-descript dogs in Ngorongoro, Tanzania: Prevalence and predisposing factors. AB - The prevalence of taeniasis was determined during the period January to April 2013 in a cross-sectional study of non-descript domestic dogs from the livestock wildlife ecosystem of Ngorongoro, Tanzania. Taeniid eggs were determined by screening faecal samples using the formalin-ether sedimentation technique. Predisposing factors for dog infection were assessed in relation to demographic, husbandry and management data. Of the 205 faecal samples screened, 150 (73.2%) were positive for taeniid eggs. The prevalence of dogs harbouring taeniid eggs was 80%, 30.2% and 75.3% in the less than 1 year, 1-3 years and greater than 3 years of age groups, respectively. Age group and sex prevalence in dogs did not differ significantly (P > 0.05), although the females showed a marginally higher prevalence (73.8%) in comparison to the males (72.7%). Taeniid eggs were significantly more likely to be found in the faeces of dogs located in Waso (80.6%) and Endulen (75%) than in Malambo (63.2%, P < 0.05). The study revealed that dogs owned and raised by agro-pastoralists were at a lower risk of acquiring Taenia spp. infection (P = 0.001) than those that were raised by pastoralists. The majority of dog owners were not aware of the predisposing factors and the mode of transmission of taeniids. Dogs were frequently fed on viscera, trimmings and the heads of slaughtered animals, and they were not treated for parasitic infections. The findings of this study indicate that taeniasis is prevalent among non-descript dogs in Ngorongoro, underscoring the need for further research and active surveillance to better understand the transmission cycle of Taenia spp. in a wider geographical area in Tanzania. PMID- 27247070 TI - Prevalence of Theileria and Babesia species in Tunisian sheep. AB - In this study, the prevalence of Theileria and Babesia species in sheep was assessed with Giemsastained blood smear examination and polymerase chain reaction to identify the different piroplasms in 270 sheep from three Tunisian bioclimatic zones (north, centre, and south). The overall infection prevalence by Babesia spp. and Theileria spp. in Giemsa-stained blood smears was 2.9% (8/270) and 4.8% (13/270) respectively. The molecular results showed that sheep were more often infected by Theileria ovis than Babesia ovis with an overall prevalence of 16.3% (44/270) and 7.8% (21/270) respectively (p = 0.01). The molecular prevalence by Babesia ovis was significantly higher in females than in males (p < 0.05). According to localities B. ovis was found exclusively in sheep from the centre of Tunisia (Kairouan) whereas Theileria ovis was found in all regions. Infections with T. ovis and B. ovis were confirmed by sequencing. The sequence of T. ovis in this study (accession numbers KM924442) falls into the same clade as T. ovis deposited in GenBank. The T. ovis amplicons (KM924442) showed 99%-100% identities with GenBank sequences. Moreover, comparison of the partial sequences of 18S rRNA gene of B. ovis described in this study (KP670199) revealed 99.4% similarity with B. ovis recently reported in northern Tunisia from sheep and goats. Three nucleotides were different at positions 73 (A/T), 417 (A/T), and 420 (G/T). It also had 99% identity with B. ovis from Spain, Turkey and Iraq. The results suggest a high T. ovis prevalence in Tunisia with a decreasing north-south gradient. This could be correlated to the vector tick distribution. PMID- 27247071 TI - An acetone extract of Clausena anisata may be a potential control agent for flies encountered in cutaneous myiasis. AB - Clausena anisata is a medicinal plant used traditionally to treat myiasis and as an insect repellent by various communities. We have previously demonstrated the effects of C. anisata extracts on blowfly feeding and development in our laboratory. The impact of C. anisata leaf extracts on populations of different fly species on farms in Mpumalanga, South Africa was investigated in this study under field conditions. Flies were exposed to liver baits treated with acetone leaf extracts of C. anisata (150 mg/mL). Fly numbers and composition on two farms, with and without C. anisata treated liver, were compared during a period of 12 weeks when fly populations were expected to be high. Observations were made on fly behaviour and development, adult sizes and numbers. The flies exposed to liver treated with the leaf extract of C. anisata had a decreased rate of development, prolonged larval period, smaller body sizes and more sluggish behaviour compared to those subjected to the control treatment. No significant differences were, however, found between the numbers and sizes of flies on the treated and on the control farm, which was most likely due to the limited nature of the baiting programme we followed. The effects of C. anisata extracts on blowfly behaviour and development observed in previous laboratory studies were confirmed in this field evaluation. Although the extracts did not have a significant effect on the overall population size in this experiment, we believe that the C. anisata leaf extract could be useful in integrated pest management based on its effect on larval development. In addition, species such as Lucilia cuprina and Chrysomya marginalis seemed to have been repelled by the C. anisata treated liver; as a result, further work should explore this aspect and how it can be used for the protection of animals. PMID- 27247072 TI - Prevalence of virulence and antimicrobial resistance genes in Salmonella spp. isolated from commercial chickens and human clinical isolates from South Africa and Brazil. AB - Salmonellosis is a significant public health concern around the world. The injudicious use of antimicrobial agents in poultry production for treatment, growth promotion and prophylaxis has resulted in the emergence of drug resistant strains of Salmonella. The current study was conducted to investigate the prevalence of virulence and antimicrobial resistance genes from Salmonella isolated from South African and Brazilian broiler chickens as well as human clinical isolates. Out of a total of 200 chicken samples that were collected from South Africa 102 (51%) tested positive for Salmonella using the InvA gene. Of the overall 146 Salmonella positive samples that were screened for the iroB gene most of them were confirmed to be Salmonella enterica with the following prevalence rates: 85% of human clinical samples, 68.6% of South African chicken isolates and 70.8% of Brazilian chicken samples. All Salmonella isolates obtained were subjected to antimicrobial susceptibility testing with 10 antibiotics. Salmonella isolates from South African chickens exhibited resistance to almost all antimicrobial agents used, such as tetracycline (93%), trimethoprim sulfamthoxazole (84%), trimethoprim (78.4%), kanamycin (74%), gentamicin (48%), ampicillin (47%), amoxicillin (31%), chloramphenicol (31%), erythromycin (18%) and streptomycin (12%). All samples were further subjected to PCR in order to screen some common antimicrobial and virulence genes of interest namely spiC, pipD, misL, orfL, pse-1, tet A, tet B, ant (3")-la, sul 1 and sul. All Salmonella positive isolates exhibited resistance to at least one antimicrobial agent; however, antimicrobial resistance patterns demonstrated that multiple drug resistance was prevalent. The findings provide evidence that broiler chickens are colonised by pathogenic Salmonella harbouring antimicrobial resistance genes. Therefore, it is evident that there is a need for prudent use of antimicrobial agents in poultry production systems in order to mitigate the proliferation of multiple drug resistance across species. PMID- 27247073 TI - Prevalence, distribution and pattern of gastric lesions in slaughtered pigs in south-western Nigeria. AB - Gastric lesions, especially ulceration, cause significant economic losses in the swine industry worldwide. The study was designed to assess its prevalence, distribution and pattern in pigs in south-western Nigeria. Slaughter house surveys were conducted on three government-established abattoirs in Lagos, Ogun and Oyo states. Stomachs from 480 pigs were assessed for gross lesions, which were graded using a modification of a standard technique. Tissues from different regions of the stomach were routinely stained to assess histopathologic changes. Data were presented as frequency counts and analysed using analysis of variance and chi-square technique. Significance was determined at p <= 0.05. Gastric lesions were encountered across the four regions of the stomach with a point prevalence of 57.29%. The prevalence of lesions in the non-glandular region was 32.9%, with severe hyperkeratosis (13.13%) being most frequently observed (p < 0.05). Erosions were significantly higher in the cardia (8.54%) (p < 0.05), followed by fundus (8.33%). Gastric ulcers were significantly higher in the fundus (19.58%) (p < 0.05). Scars of healed ulcers and lacerations were also observed in the fundus (5.42%) (p < 0.05). The gastric lesion distribution across the four regions of the stomach and the occurrence of ulceration in the fundus showed an unusual pattern, which is rarely reported in other parts of the world. The reason for these findings in pigs in Nigeria is not fully understood; therefore, further studies are required to identify and manage these factors for increased productivity, improved animal welfare and enhanced food security. PMID- 27247074 TI - Salmonella contamination, serovars and antimicrobial resistance profiles of cattle slaughtered in South Africa. AB - Antimicrobial resistant Salmonella are among the leading causes of foodborne infections. Our aim was to determine Salmonella contamination during cattle slaughter in South African rural abattoirs (n = 23) and environmental samples. Furthermore, antimicrobial resistance patterns of the Salmonella isolates were determined. Samples of cattle faeces (n = 400), carcass sponges (n = 100), intestinal contents (n = 62), hides (n = 67), and water from the abattoirs (n = 75) were investigated for Salmonella species using microbiological techniques and species-specific polymerase chain reaction targeting the invA gene. In total 92 Salmonella species isolates were recovered. The Salmonella mean frequency of occurrence on hides, carcasses, and intestinal contents was 35.37% (n = 81). Eleven faecal samples (2.75%) tested positive for Salmonella. The predominant serovar was Salmonella Enteritidis. Diverse serovars that were identified on carcasses were not necessarily found on the hides and intestinal contents. The inconsistent occurrence of the diverse Salmonella serovars on hides, carcasses, and intestinal contents implies that in addition to carriage on hides and in intestinal contents, other external factors also play an important role regarding carcass contamination. The 92 Salmonella were serotyped and tested for susceptibility towards the following antimicrobials: ampicillin, cefotaxime, enrofloxacin, kanamycin, and oxytetracycline using the disk diffusion method. Most Salmonella (n = 66; 71.7%) isolates were resistant to at least one antimicrobial with highest resistance observed towards oxytetracycline (51.90%), which highlights the need for strict hygiene during slaughter and prudent antimicrobial use during animal production. In conclusion, cattle slaughtered in South African rural abattoirs harbour diverse Salmonella serovars that are resistant to antimicrobials, which could be a public health risk. The findings should assist policymakers with improving implementation of hygienic slaughter of cattle in rural abattoirs, which is paramount from socioeconomic, public health, and epidemiological standpoints. PMID- 27247075 TI - Prevalence of brucellosis in the human, livestock and wildlife interface areas of Serengeti National Park, Tanzania. AB - Between 2005 and 2006, a cross-sectional survey was carried out in domestic ruminants in agropastoral communities of Serengeti district, Tanzania to determine the seroprevalence of brucellosis in domestic-wildlife interface villages. Both the Rose Bengal Plate Test (RBPT) and Competitive Enzyme Linked immunosorbent Assay (c-ELISA) were used to analyse 82 human and 413 livestock sera from four randomly selected villages located along game reserve areas of Serengeti National Park. Although both cattle (288) and small ruminants (125) were screened, seropositivity was detected only in cattle. The overall seroprevalence based on c-ELISA as a confirmatory test was 5.6%. In cattle both age and sex were not statistically associated with brucellosis seropositivity (P = 0.63; 95% CI = 0.03, 0.8 and 0.33; 95% CI = 0.6, 3.7, respectively). Overall herd level seropositivity was 46.7% (n = 7), ranging from 25% to 66.7% (n = 4 10). Each village had at least one brucellosis seropositive herd. None of the 82 humans tested with both RBPT and c-ELISA were seropositive. Detecting Brucella infection in cattle in such areas warrants further investigation to establish the circulating strains for eventual appropriate control interventions in domestic animals. PMID- 27247076 TI - PCR-fingerprint profiles of mitochondrial and genomic DNA extracted from Fetus cervi using different extraction methods. AB - The use of Fetus cervi, which is derived from the embryo and placenta of Cervus Nippon Temminck or Cervs elaphus Linnaeus, has been documented for a long time in China. There are abundant species of deer worldwide. Those recorded by China Pharmacopeia (2010 edition) from all the species were either authentic or adulterants/counterfeits. Identification of their origins or authenticity became a key in the preparation of the authentic products. The traditional SDS alkaline lysis and salt-outing methods were modified to extract mt DNA and genomic DNA from fresh and dry Fetus cervi in addition to Fetus from false animals, respectively. A set of primers were designed by bioinformatics to target the intra-and inter-variation. The mt DNA and genomic DNA extracted from Fetus cervi using the two methods meet the requirement for authenticity. Extraction of mt DNA by SDS alkaline lysis is more practical and accurate than extraction of genomic DNA by salt-outing method. There were differences in length and number of segments amplified by PCR between mt DNA from authentic Fetus cervi and false animals Fetus. The distinctive PCR-fingerprint patterns can distinguish the Fetus cervi from adulterants and counterfeit animal Fetus. PMID- 27247077 TI - Multiplexed Fluorescence Imaging of ERK and Akt Activities and Cell-cycle Progression. AB - The Ras-ERK pathway controls cell proliferation and differentiation, whereas the PI3K-Akt pathway plays a role in the process of cell-cycle progression and cell survival. Both pathways are activated by many stimuli such as epidermal growth factor (EGF), and coordinately regulate each other through cross-talk. However, it remains unclear how cells accommodate the dynamics and interplay between the Ras-ERK and PI3K-Akt pathways to regulate cell-fate decisions, mainly because of the lack of good tools to visualize ERK and Akt activities simultaneously in live cells. Here, we developed a multiplexed fluorescence system for imaging ERK and Akt signaling and the cell-cycle status at the single cell level. Based on the principle of the kinase translocation reporter (KTR), we created Akt-FoxO3a-KTR, which shuttled between nucleus and cytoplasm in a manner regulated by Akt phosphorylation. To simultaneously measure ERK, Akt and the cell-cycle status, we generated a polycistronic vector expressing ERK-KTR, Akt-FoxO3a-KTR, a cell-cycle reporter and a nuclear reporter, and applied linear unmixing to these four images to remove spectral overlap among fluorescent proteins. The specificity and sensitivity of ERK-KTR and Akt-FoxO3a-KTR were characterized quantitatively. We examined the cellular heterogeneity of relationship between ERK and Akt activities under a basal or EGF-stimulated condition, and found that ERK and Akt were regulated in a highly cooperative and cell-cycle-dependent manner. Our study provides a useful tool for quantifying the dynamics among ERK and Akt activities and the cell cycle in a live cell, and for addressing the mechanisms underlying intrinsic resistance to molecularly targeted drugs. PMID- 27247078 TI - Privacy Preserving Quantum Anonymous Transmission via Entanglement Relay. AB - Anonymous transmission is an interesting and crucial issue in computer communication area, which plays a supplementary role to data privacy. In this paper, we put forward a privacy preserving quantum anonymous transmission protocol based on entanglement relay, which constructs anonymous entanglement from EPR pairs instead of multi-particle entangled state, e.g. GHZ state. Our protocol achieves both sender anonymity and receiver anonymity against an active adversary and tolerates any number of corrupt participants. Meanwhile, our protocol obtains an improvement in efficiency compared to quantum schemes in previous literature. PMID- 27247079 TI - Perspectives on mycobacterial vacuole-to-cytosol translocation: the importance of cytosolic access. AB - Mycobacterium tuberculosis, the infectious agent of human tuberculosis is a master player in circumventing the defense mechanisms of the host immune system. The host-pathogen interaction in the case of an infection with M. tuberculosis is highly complex, involving dedicated mycobacterial virulence factors as well as the action of the innate and adapted immune systems, which determine the outcome of infection. Macrophages play a key role in this process through internalizing the bacterium in a phagosomal vacuole. While this action has normally the function of eliminating invading bacteria, M. tuberculosis employs efficient strategies to prevent its extermination. The question on how-and-where the bacterium succeeds in doing so has interested generations of scientists and still remains a fascinating and important research subject focused on mycobacterial lipids, secretion systems and other contributing factors. This topic is also central to the longstanding and partially controversial discussion on mycobacterial phagosomal rupture and vacuole-to-cytosol translocation, to be reviewed here in more detail. PMID- 27247080 TI - A review of the associations between single nucleotide polymorphisms in taste receptors, eating behaviors, and health. AB - Food preferences and dietary habits are heavily influenced by taste perception. There is growing interest in characterizing taste preferences based on genetic variation. Genetic differences in the ability to perceive key tastes may impact eating behavior and nutritional intake. Therefore, increased understanding of taste biology and genetics may lead to new personalized strategies, which may prevent or influence the trajectory of chronic disease risk. Recent advances show that single nucleotide polymorphisms (SNPs) in the CD36 fat taste receptor are linked to differences in fat perception, fat preference, and chronic-disease biomarkers. Genetic variation in the sweet taste receptor T1R2 has been shown to alter sweet taste preferences, eating behaviors, and risk of dental caries. Polymorphisms in the bitter taste receptor T2R38 have been shown to influence taste for brassica vegetables. Individuals that intensely taste the bitterness of brassica vegetables ("supertasters") may avoid vegetable consumption and compensate by increasing their consumption of sweet and fatty foods, which may increase risk for chronic disease. Emerging evidence also suggests that the role of genetics in taste perception may be more impactful in children due to the lack of cultural influence compared to adults. This review examines the current knowledge of SNPs in taste receptors associated with fat, sweet, bitter, umami, and salt taste modalities and their contributions to food preferences, and chronic disease. Overall, these SNPs demonstrate the potential to influence food preferences and consequently health. PMID- 27247081 TI - Wide distribution of airborne ice-nucleation active Pseudomonas syringae in agricultural environments. AB - Pseudomonas syringae, a phytopathogen with a wide host range, inhabits various environments. Among these habitats, air is an important transport environment for microbes, allowing them to disperse over long distances; however, information on the distribution and composition of airborne P. syringae is limited. Here, we report the isolation of several groups of airborne P. syringae in Japan. Since 2013, we have trapped 43 strains of airborne P. syringae species complex, most of which were ice-nucleation active (INA), suggesting an important role for INA in atmospheric environments. Airborne P. syringae were isolated mainly between March and May, when the temperature is optimal for the epiphytic growth of P. syringae strains, indicates that plants are the main sources for airborne INA P. syringae. Multilocus sequence typing analyses categorized these strains into six clades. The most abundant clade, KID0033, clustered with strain UMAF0158, a pathogen of mango isolated in Spain, and Cit7, isolated in the USA. The second most abundant clade, KID0001, did not clustered with any pathovar or environmental strain reported previously. In addition, we isolated 14 P. syringae strains belonging to these two clades from asymptomatic and symptomatic leaves of kiwifruit, okra, and tea from different sites over the past decade. These strains are less virulent on originally isolated plants and other plant species under our inoculum conditions. These data indicate that certain groups of INA P. syringae, which were not previously recognized as pathogens, exist both in the air and on plants, and may be quite common throughout the world. PMID- 27247082 TI - Identification and Differentiation of Monilinia Species Causing Brown Rot of Pome and Stone Fruit using High-Resolution Melting (HRM) Analysis. AB - Brown rot is a devastating disease of stone fruit caused by Monilinia spp. Among these species, Monilinia fructicola is a quarantine pathogen in Europe but has recently been detected in several European countries. Identification of brown rot agents relies on morphological differences or use of molecular methods requiring fungal isolation. The current study was initiated to develop and validate a high resolution melting (HRM) method for the identification of the Monilinia spp. and for the detection of M. fructicola among other brown rot pathogens. Based on the sequence of the cytb intron from M. laxa, M. fructicola, M. fructigena, M. mumecola, M. linhartiana, and M. yunnanensis isolates originating from several countries, a pair of universal primers for species identification and a pair of primers specific to M. fructicola were designed. The specificity of the primers was verified to ensure against cross-reaction with other fungal species. The melting curve analysis using the universal primers generated six different HRM curve profiles, each one specific for each species. Tauhe HRM analysis primers specific to M. fructicola amplified a 120-bp region with a distinct melt profile corresponding to the presence of M. fructicola, regardless of the presence of other species. HRM analysis can be a useful tool for rapid identification and differentiation of the six Monilinia spp. using a single primer pair. This novel assay has the potential for simultaneous identification and differentiation of the closely related Monilinia spp. as well as for the differentiation of M. fructicola from other common pathogens or saprophytes that may occur on the diseased fruit. PMID- 27247083 TI - Psychiatric Emergencies for Clinicians: Emergency Department Management of Neuroleptic Malignant Syndrome. PMID- 27247084 TI - Alcohol consumption among rural African American and White adolescents: The role of religion, parents, and peers. AB - Although studies have examined ethnic differences in psychosocial factors and adolescent alcohol use, most have not examined these relationships for rural adolescents. The Community Drug and Alcohol Survey (CDAS) was completed by 23,163 rural adolescents attending African American secondary schools. Multilevel analysis tested the hypothesis of stronger relationships of peer use and religiosity with alcohol use and a weaker relationship for parental permissiveness and alcohol use for White compared to African American adolescents. Results suggested that peer use, religiosity, and parental permissiveness were more strongly associated with changes in alcohol use for White adolescents. Findings provide insight for alcohol prevention among rural adolescents. PMID- 27247085 TI - Validation of the Alcohol, Smoking and Substance Involvement Screening Test in a low- and middle-income country cross-sectional emergency centre study. AB - INTRODUCTION AND AIM: Given the high prevalence and detrimental consequences of alcohol or other drug (AOD) use in low- and middle-income countries, a screening tool for early detection in health care, including emergency care, is critical. We set out to validate the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) for the South African context. DESIGN AND METHODS: We interviewed emergency centre patients (n = 200) in Cape Town for this cross-sectional study conducted from January to March 2013 utilising a questionnaire battery, including the ASSIST and Mini International Neuropsychiatric Interview. Internal consistency (Cronbach's alpha) and screening properties of the ASSIST (receiver operating characteristic analysis) were examined utilising the Mini International Neuropsychiatric Interview AOD use modules as the gold standard. RESULTS: Cronbach's alpha for alcohol and illicit drugs ranged from 0.81 to 0.95 indicating good internal consistency. ASSIST cut-off scores show a good sensitivity and specificity for discrimination particularly when distinguishing between substance use and abuse, rather than dependence. For alcohol, the area under the curve was 0.94 for distinguishing between use and abuse, and this dropped to 0.68 for distinguishing between abuse and dependence, while the statistic remained high for both use/abuse and abuse/dependence for illicit drugs: 0.95 and 0.96. DISCUSSION AND CONCLUSION: AOD abuse was associated with cut-off scores below the World Health Organization recommended levels, in keeping with various international studies suggesting that individuals with lower scores be offered interventions. The ASSIST was found to be useful for South African health care and holds promise for cost-effective task-shifting approaches in lower resourced settings. [van der Westhuizen C, Wyatt G, Williams JK, Stein DJ, Sorsdahl K. Validation of the Alcohol, Smoking and Substance Involvement Screening Test in a low- and middle-income country cross-sectional emergency centre study. Drug Alcohol Rev 2016;35:702-709]. PMID- 27247086 TI - To explore the relationship between the use of midazolam and cessation of oral intake in the terminal phase of hospice inpatients: A retrospective case note review: Does midazolam affect oral intake in the dying? AB - BACKGROUND: Sedative drugs are used to improve comfort in dying patients but have been accused of shortening survival by reducing patients' ability to maintain nutrition and hydration. However, as part of the dying process, patients in the last days of life often have impaired conscious levels and an inability to maintain oral intake. AIM: To establish whether the decline in oral intake is related to the use of midazolam in the last week of life. DESIGN: This is a retrospective case note review. SETTING/PARTICIPANTS: The data were obtained from nursing records and medication charts of 125 consecutive hospice inpatients who died at a hospice in South London. RESULTS: A total of 72 patients received midazolam on one or more days within the last 7 days of life (midazolam group) and 49 patients received no midazolam (control group). CONCLUSION: Mean oral intake was reduced 7 days prior to death and declined sequentially over subsequent days in both patient groups. More patients required midazolam as death approached and most patients received midazolam for less than 3 days. Mean doses of midazolam used were low. Patients in the midazolam group had lower oral intake than those in the control group, but this association does not indicate causation. PMID- 27247087 TI - Health-related quality-of-life outcome measures in paediatric palliative care: A systematic review of psychometric properties and feasibility of use. AB - BACKGROUND: The number of children worldwide requiring palliative care services is increasing due to advances in medical care and technology. The use of outcome measures is important to improve the quality and effectiveness of care. AIM: To systematically identify health-related quality-of-life outcome measures that could be used in paediatric palliative care and examine their feasibility of use and psychometric properties. DESIGN: A systematic literature review and analysis of psychometric properties. DATA SOURCES: PsychInfo, Medline and EMBASE were searched from 1 January 1990 to 10 December 2014. Hand searches of the reference list of included studies and relevant reviews were also performed. RESULTS: From 3460 articles, 125 papers were selected for full-text assessment. A total of 41 articles met the eligibility criteria and examined the psychometric properties of 22 health-related quality-of-life measures. Evidence was limited as at least half of the information on psychometric properties per instrument was missing. Measurement error was not analysed in any of the included articles and responsiveness was only analysed in one study. The methodological quality of included studies varied greatly. CONCLUSION: There is currently no 'ideal' outcome assessment measure for use in paediatric palliative care. The domains of generic health-related quality-of-life measures are not relevant to all children receiving palliative care and some domains within disease-specific measures are only relevant for that specific population. Potential solutions include adapting an existing measure or developing more individualized patient-centred outcome and experience measures. Either way, it is important to continue work on outcome measurement in this field. PMID- 27247088 TI - Identifying High-Risk Stage II Colon Cancer Patients: A Three-MicroRNA-Based Score as a Prognostic Biomarker. AB - BACKGROUND: The potential benefit of adjuvant chemotherapy in surgically resected patients with stage II colorectal cancer is controversial. The current guidelines, which are based solely on clinical factors, have limited usefulness, and a clear need exists for biomarkers to supplement the clinical information. MicroRNAs (miRNAs) have previously been shown to be useful cancer biomarkers. In the present study, we assessed the usefulness of a miRNA score to help identify the subset of high-risk patients likely to benefit from adjuvant chemotherapy. PATIENTS AND METHODS: Six miRNAs previously identified as prognostic markers in Asian patients (miR-21-5p, miR-20a-5p, miR-103a-3p, miR-106b-5p, miR-143-5p, and miR-215) were studied in tumor samples from 71 white patients with stage II colon cancer. RESULTS: Three miRNAs (miR-103a-3p, miR-143-5p, and miR-215) emerged as independent prognostic markers on multivariate analysis and were used to construct a miRNA-based score that classified patients into high- and low-risk groups. The patients in the high-risk group had significantly shorter disease free survival compared with their low-risk counterparts (P = .003). The time dependent receiver operating characteristic curve analysis showed that our 3 miRNA score improved the prediction of outcome when added to the clinical features (P = .023). CONCLUSION: Our 3-miRNA score added valuable prognostic information to the clinical features in stage II colon cancer. Further research in this field could provide useful tools to determine whether adjuvant chemotherapy would benefit patients with stage II colon cancer after surgery. PMID- 27247089 TI - Evaluation of Bevacizumab in Advanced Small Bowel Adenocarcinoma. AB - BACKGROUND: Small bowel adenocarcinomas (SBAs) are rarely seen tumors. Data regarding the use of chemotherapy together with bevacizumab in patients with advanced SBA are lacking. The aim of this study was the evaluation of treatment with bevacizumab in advanced SBA. MATERIALS AND METHODS: Twenty-eight patients from 5 centers with a diagnosis of advanced SBA who received first-line treatments with modified FOLFOX6 (mFOLFOX6; oxaliplatin, leucovorin, and 5 fluorouracil) and FOLFIRI (leucovorin, 5-fluorouracil, and irinotecan) chemotherapy regimens were involved in the study. All patients were divided into 2 groups; those who received bevacizumab together with these chemotherapy regimens (Chemo+Bev group) and those who did not receive bevacizumab (Chemo group). RESULTS: The median progression-free survival (PFS) and overall survival (OS) times of all population were 8.7 months and 16.9 months, respectively. The overall response rate was 43.7% in the Chemo group and 58.3% in the Chemo+Bev group. The median PFSs in the Chemo and Chemo+Bev groups were found to be 7.7 months and 9.6 months, respectively, and the median OSs were 14.8 months and 18.5 months, respectively. There was not a significant difference between the groups in terms of overall response rate, PFS, and OS. CONCLUSION: Although there was no significant difference in any of the outcomes, use of bevacizumab together with chemotherapy is a more effective treatment approach compared with chemotherapy alone, and it does not cause an excess of significant toxicity. PMID- 27247091 TI - Do no harm: Balancing the costs and benefits of patient outcomes in health psychology research and practice. AB - This article analyses research exploring medication adherence, help-seeking behaviour, screening and behaviour change to argue that all interventions have the potential for both benefit and harm. Accordingly, health psychology may have inadvertently contributed to psychological harms (e.g. lead times, anxiety, risk compensation and rebound effects); medical harms (e.g. medication side effects, unnecessary procedures) and social harms (e.g. financial costs, increased consultations rates). Such harms may result from medicalisation or pharmaceuticalisation. Or, they may reflect the ways in which we manage probabilities and an optimistic bias that emphasises benefit over cost. PMID- 27247090 TI - Unraveling the target genes of RIN transcription factor during tomato fruit ripening and softening. AB - BACKGROUND: The RIN transcription factor is one of the MADS box family members and predominantly controls fruit ripening. In this study, effort was made to demonstrate the regulation network of RIN transcription factor during tomato fruit ripening and softening. Novel RIN target genes were identified by proteomics, electrophoresis mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) analysis. RESULTS: Over 700 protein spots were achieved by two-dimensional gel electrophoresis, and 42 proteins were successfully identified. Among them, 1-aminocyclopropane-1-carboxylate oxidase (LeACO4, ethylene synthesis, spot 3) and alpha-galactosidase-like isoform 2 (alpha-Gal, cell wall metabolism, spot 26) exhibited varied expression levels in different tomato fruits. Particularly high expression levels of LeACO4 and alpha Gal were observed in wild type but not in the rin mutant. Additionally, CArG box, a RIN-binding site, was discovered in the promoter regions of both LeACO4 and alpha-Gal genes, suggesting that RIN possibly directly regulates their transcriptions, and this assumption was further confirmed by EMSA and ChIP assay. CONCLUSION: Functional annotations of RIN target genes demonstrated the specific role of RIN in the process of fruit ripening and softening, especially in cell wall degradation and ethylene biosynthesis. This study will further illuminate the mechanism of tomato ripening and softening. (c) 2016 Society of Chemical Industry. PMID- 27247092 TI - Feasibility of the Prototype Willingness Model as the basis for school-delivered alcohol misuse prevention: A qualitative think-aloud study to explore acceptability of 'The Alcohol Smart Quiz' with adolescents and teachers. AB - This study sought feedback from teachers and adolescents on a novel intervention to reduce alcohol misuse based on the Prototype Willingness Model. A qualitative, think-aloud interview study was conducted with 17 adolescents aged 11-14 years and nine teachers. Transcripts were analysed using thematic analysis. Adolescents found the content of the intervention appealing and credible. Teachers welcomed the content and format as a means of generating discussion. 'Moderate' drinking appeared to be an acceptable message, although difficult to define. Enacting 'if then' plans in real social situations might be challenging and representations of drinking on social media should be considered. PMID- 27247093 TI - Factors associated with fetal shunt dislodgement in lower urinary tract obstruction. AB - OBJECTIVE: To identify factors associated with fetal shunt dislodgement in lower urinary tract obstruction (LUTO). METHODS: We conducted a retrospective study of 42 consecutive fetuses with a diagnosis of LUTO in a tertiary fetal center between April 2013 and November 2015. Possible factors associated with prenatal shunt dislodgment were evaluated in fetuses who underwent shunt placement, including gestational age at diagnosis, gestational age at procedure, presence of 'keyhole sign', initial fetal bladder volume and wall thickness, prenatal ultrasonographic renal characteristics, amniotic fluid volume, presence of ascites prior to shunting, and type of fetal shunt. RESULTS: Nineteen (46.3%) fetuses underwent shunt placement at a median gestational age of 19 (range: 16.3 31.1) weeks. Shunt dislodgement occurred in 10 (52.6%) patients. A total of 35 procedures were performed; among which 16 (45.7%) were repeat procedures. The only prenatal factor associated with shunt dislodgement was the type of the shunt; Kaplan-Meier analysis indicated that the Rocket was associated with increased likelihood of remaining orthotopic (p = 0.04). CONCLUSION: Fetal shunt dislodgement occurs in approximately half of the patients and appears to be associated with the type of the shunt. Future research is necessary to develop better shunt systems and to investigate different fetal therapeutic approaches. (c) 2016 John Wiley & Sons, Ltd. PMID- 27247094 TI - Multi-locus variable number tandem repeat analysis of Vibrio cholerae isolates from 2012 to 2013 cholera outbreaks in Iran. AB - Cholera remains to be an international threat, with high rates of illness and death. In 2012 and 2013, two cholera outbreak happened in Iran, affecting lots of people. Vibrio cholerae O1 was confirmed as the etiological agent. Source identification and controlling the spread of the cholera disease are two critical approaches in cholera outbreaks. In this study, thirty V. cholerae O1 isolates were selected and has been evaluated for antimicrobial resistant as well as molecular typing by multilocus variable-number tandem-repeat analysis (MLVA) method. Twenty-nine (97%) isolates were sero-grouped as El Tor (one isolate was classical) and 100% were related to Inaba serotype. All of the isolates were susceptible to ciprofloxacin, chloramphenicol, ampicillin and gentamicin. On the other hand, 60% of the isolates were MDR (resistant to 3 or more classes). There were three resistance patterns. The most prevalent pattern was resistance to streptomycin, erythromycin, trimethoprim-sulfamethoxazole, and tetracycline (ST SXT-E-T) which was seen in 50% of isolates. Using MLVA method 14 MLVA types were identified. MLVA type 2 (5-7-7-16-15) accounted for 43% of isolates. Isolates with the same genotype often did not have the same antibiogram. Overall, the data indicate that the Iranian V. cholerae were MDR and clonaly related. Furthermore, the results of this study shows that MLVA can be used as useful method for V. cholerae genotyping in epidemiological investigations. PMID- 27247095 TI - Molecular characterization of antibiotic resistant Vibrio harveyi isolated from shrimp aquaculture environment in the south east coast of India. AB - Vibrio harveyi is a strategic human pathogen that occurs naturally in marine and estuarine environments. The pathogen is believed to cause acute septicemia, gastroenteritis, severe necrotizing soft-tissue infection, and high rate of lethality through ingestion of V. harveyi contaminated seafood. In this study, we isolated and characterized V. harveyi from water suspended sediment samples of black tiger shrimp ponds and from the sea coasts, in the east coast of the Bay of Bengal, India. Initial isolations of putative V. harveyi isolates were grown on thiosulfate-citrate-bill salts-sucrose agar (TCBS) plates for 36 h. Gram-negative and oxidase-positive colonies alone were selected and subsequently identified by 12 different conventional biochemical tests. The species specificity was confirmed by 16S rRNA, hemolysin and toxRvh genes were used through PCR targeted primers. Furthermore, genomic fingerprinting was carried out using randomly amplified polymorphic DNA fingerprinting, which showed that all the five V. harveyi were genetically distinct. From a total of 256 samples, a total of five strains of V. harveyi were isolated, of which three were from various shrimp ponds and two were from the coastal area. These five isolates were subjected to profiling against 15 antibiotics and the perusal results emphasized the V. harveyi resistance to ciprofloxacin, penicillin, rifampicin, and vancomycin compared to other tested antibiotics. The present findings were helpful in understanding the multiple antibiotics resistance of V. harveyi, which indicates the urgent need for targeted alternative biocontrol strategies to enhance the prospects of commercially viable shrimp cultivation. PMID- 27247096 TI - Molecular epidemiology of vancomycin resistant enterococci in a tertiary care hospital in Saudi Arabia. AB - AIM: Vancomycin-resistant enterococci (VRE) are a major cause of nosocomial infections with high mortality and morbidity. There is limited data on the molecular characterization of VRE in Saudi Arabia. This study was carried out to investigate the premise that a shift in VRE epidemiology is occurring in our setting. METHODS: Enterococcus species identification and susceptibility testing plus VRE phenotypic confirmation by vancomycin and teicoplanin E-test were carried out. Vancomycin resistance genes were detected by PCR. Strain typing was conducted using PFGE. RESULTS: Among the strains of Enterococcus spp. investigated in this study, 17 (4.5%) were VRE. With the exception of one isolate from rectal swab, all others were clinical specimens with blood being the commonest source (n = 11; 64.7%), followed by urine (n = 3; 17.6%). The 17 VRE isolates were Enterococcus faecium (n/N = 13/17) and Enterococcus gallinarum (n/N = 4/17). Among E. faecium isolates, vanA(+)/vanB(+) (n/N = 8/13; 62%) exhibiting VanB phenotype were predominant. One of the five vanA(+)E. faecium isolates exhibited a VanB phenotype indicative of vanA genotype-VanB phenotype incongruence. E. gallinarum isolates exhibited a Van C phenotype although two were vanA(+)/vanC1(+). PFGE revealed a polyclonal distribution with eight pulsotypes. CONCLUSION: These findings indicate an evolving VRE epidemiology with vanA(+)/vanB(+) isolates and vanA genotype-VanB phenotype incongruence isolates, which were previously described as colonizers, are now causing clinical infection. PMID- 27247097 TI - Uraemia: an unrecognized driver of central neurohumoral dysfunction in chronic kidney disease? AB - Chronic kidney disease (CKD) carries a large cardiovascular burden in part due to hypertension and neurohumoral dysfunction - manifesting as sympathetic overactivity, baroreflex dysfunction and chronically elevated circulating vasopressin. Alterations within the central nervous system (CNS) are necessary for the expression of neurohumoral dysfunction in CKD; however, the underlying mechanisms are poorly defined. Uraemic toxins are a diverse group of compounds that accumulate as a direct result of renal disease and drive dysfunction in multiple organs, including the brain. Intensive haemodialysis improves both sympathetic overactivity and cardiac baroreflex sensitivity in renal failure patients, indicating that uraemic toxins participate in the maintenance of autonomic dysfunction in CKD. In rodents exposed to uraemia, immediate early gene expression analysis suggests upregulated activity of not only pre-sympathetic but also vasopressin-secretory nuclei. We outline several potential mechanisms by which uraemia might drive neurohumoral dysfunction in CKD. These include superoxide-dependent effects on neural activity, depletion of nitric oxide and induction of low-grade systemic inflammation. Recent evidence has highlighted superoxide production as an intermediate for the depolarizing effect of some uraemic toxins on neuronal cells. We provide preliminary data indicating augmented superoxide production within the hypothalamic paraventricular nucleus in the Lewis polycystic kidney rat, which might be important for mediating the neurohumoral dysfunction exhibited in this CKD model. We speculate that the uraemic state might serve to sensitize the central actions of other sympathoexcitatory factors, including renal afferent nerve inputs to the CNS and angiotensin II, by way of recruiting convergent superoxide-dependent and pro inflammatory pathways. PMID- 27247099 TI - Interassociation consensus statement on cardiovascular care of college student athletes. AB - Cardiovascular evaluation and care of college student-athletes is gaining increasing attention from both the public and medical communities. Emerging strategies include screening of the general athlete population, recommendations of permissible levels of participation by athletes with identified cardiovascular conditions and preparation for responding to unanticipated cardiac events in athletic venues. The primary focus has been sudden cardiac death and the usefulness of screening with or without advanced cardiac screening. The National Collegiate Athletic Association convened a multidisciplinary task force to address cardiovascular concerns in collegiate student-athletes, and to develop consensus for an interassociation statement. This document summarises the task force deliberations and follow-up discussions, and includes available evidence on cardiovascular risk, preparticipation evaluation and the recognition of and response to cardiac arrest. Future recommendations for cardiac research initiatives, education and collaboration are also provided. PMID- 27247098 TI - 2016 Patellofemoral pain consensus statement from the 4th International Patellofemoral Pain Research Retreat, Manchester. Part 2: recommended physical interventions (exercise, taping, bracing, foot orthoses and combined interventions). PMID- 27247100 TI - Why are back pain guidelines left on the sidelines? Three myths appear to be guiding management of back pain in sport. PMID- 27247101 TI - SigmaB regulates ccrAB expression and SCCmec excision in methicillin-resistant Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a worldwide pathogen that is resistant to practically the entire class of beta-lactam antibiotics due to the presence of the mecA gene. The mecA gene is located on a large mobile genetic element referred to as staphylococcal cassette chromosome mec (SCCmec), and the excision and integration of SCCmec are mediated by the Ccr recombinase encoded by ccrAB or ccrC, which are also located on SCCmec. Previous studies have shown that the ccrAB genes are only expressed in a minority of cells and that their expression levels can be affected by certain environmental stimuli, but the molecular mechanisms controlling these phenotypes remain elusive. Here, we found that overexpression of SigB can dramatically enhance ccrA transcription and SCCmec excision in MRSA strain N315, revealing an important role for this alternative sigma factor in the lateral transfer of SCCmec. Further primer extension-blot analysis and 5'RACE (Rapid Amplification of cDNA Ends) indicated that an unrecognized SigB-dependent promoter region, which exists in certain SCCmec type II and IV strains, is responsible for the enhancement, and the ccrAB genes are in fact transcribed in a two-promoter pattern with a low activity of the SigB-dependent promoter under normal growth conditions. PMID- 27247102 TI - Subtle genotypic changes can be observed soon after diagnosis in Mycobacterium tuberculosis infection. AB - Clonal variants of Mycobacterium tuberculosis (MTB) coexist in specific patients, although the dynamics of their emergence is unknown. We used MIRU-VNTR to detect microevolution leading to variants of MTB in 3 out of 19 patients (15%) soon after diagnosis (61-85days). Most harbored SNPs and for some of them a potential functional role was suggested. Microevolution in tuberculosis seems to occur sooner and more often than expected and could affect tracking of transmission. PMID- 27247103 TI - Liquid-containing Refluxes and Acid Refluxes May Be Less Frequent in the Japanese Population Than in Other Populations: Normal Values of 24- hour Esophageal Impedance and pH Monitoring. AB - Background/Aims: Twenty-four-hour esophageal impedance and pH monitoring allows detection of all types of reflux episodes and is considered the best technique for identifying gastroesophageal refluxes. However, normative data for the Japanese population are lacking. This multicenter study aimed to establish the normal range of 24-hour esophageal impedance and pH data both in the distal and the proximal esophagus in Japanese subjects. Methods: Forty-two healthy volunteers (25 men and 17 women) with a mean +/- standard deviation age of 33.3 +/- 12.4 years (range: 22-72 years) underwent a combined 24-hour esophageal impedance and pH monitoring. According to the physical and pH properties, distal or proximal esophageal reflux events were categorized. Results: Median 45 reflux events occurred in 24 hours, and the 95th percentile was 85 events. Unlike previous reports, liquid-containing reflux events are median 25/24 hours with the 95th percentile of 62/24 hours. Acidic reflux events were median 11/24 hours with the 95th percentile of 39/24 hours. Non-acidic gas reflux events were median 15/24 hours with the 95th percentile of 39/24 hours. Proximal reflux events accounted for 80% of the total reflux events and were mainly non-acidic gas refluxes. About 19% of liquid and mixed refluxes reached the proximal esophagus. Conclusions: Unlike previous studies, liquid-containing and acidic reflux events may be less frequent in the Japanese population. Non-acidic gas reflux events may be frequent and a cause of frequent proximal reflux events. This study provides important normative data for 24-hour impedance and pH monitoring in both the distal and the proximal esophagus in the Japanese population. PMID- 27247104 TI - Deep-Ultraviolet Nonlinear Optics in a Borate Framework with 21-Ring Channels. AB - A new borate LiBa3 (OH)[B9 O16 ][B(OH)4 ], which combines the uniform porosity of open-frameworks with the extraordinary NLO properties of borates, has been obtained under hydrothermal conditions by using mixed lithium and barium ions as templates. The framework displays an acs-type net with large 21-ring channels. The second harmonic generation (SHG) measurement shows that it is a type I phase matchable material with a strong SHG signal intensity about 3.1 times that of KDP (KH2 PO4 ). UV/Vis-NIR diffuse reflectance analysis indicates that the compound has a wide transparency range with the short-wavelength absorption edge below 200 nm. These characteristics reveal that the compound is a promising deep-UV nonlinear optical material. PMID- 27247105 TI - Polyamine transporter in Streptococcus pneumoniae is essential for evading early innate immune responses in pneumococcal pneumonia. AB - Streptococcus pneumoniae is the most common bacterial etiology of pneumococcal pneumonia in adults worldwide. Genomic plasticity, antibiotic resistance and extreme capsular antigenic variation complicates the design of effective therapeutic strategies. Polyamines are ubiquitous small cationic molecules necessary for full expression of pneumococcal virulence. Polyamine transport system is an attractive therapeutic target as it is highly conserved across pneumococcal serotypes. In this study, we compared an isogenic deletion strain of S. pneumoniae TIGR4 in polyamine transport operon (DeltapotABCD) with the wild type in a mouse model of pneumococcal pneumonia. Our results show that the wild type persists in mouse lung 24 h post infection while the mutant strain is cleared by host defense mechanisms. We show that intact potABCD is required for survival in the host by providing resistance to neutrophil killing. Comparative proteomics analysis of murine lungs infected with wild type and DeltapotABCD pneumococci identified expression of proteins that could confer protection to wild type strain and help establish infection. We identified ERM complex, PGLYRP1, PTPRC/CD45 and POSTN as new players in the pathogenesis of pneumococcal pneumonia. Additionally, we found that deficiency of polyamine transport leads to up regulation of the polyamine synthesis genes speE and cad in vitro. PMID- 27247106 TI - Forests of opportunities and mischief: disentangling the interactions between forests, parasites and immune responses. AB - Habitat characteristics determine the presence of individuals through resource availability, but at the same time, such features also influence the occurrence of parasites. We analyzed how birds respond to changes in interior forest structures, to forest management regimes, and to the risk of haemosporidian infections. We captured and took blood samples from blackcaps (Sylvia atricapilla) and chaffinches (Fringilla coelebs) in three different forest types (beech, mixed deciduous, spruce). We measured birds' body asymmetries, detected avian haemosporidians, and counted white blood cells as an immune measure of each individual per forest type. We used, to our knowledge for the first time, continuous forest structural parameters to quantify habitat structure, and found significant effects of habitat structure on parasite prevalence that previously have been undetected. We found three times higher prevalence for blackcaps compared with chaffinches. Parasite intensity varied significantly within host species depending on forest type, being lowest in beech forests for both host species. Structurally complex habitats with a high degree of entropy had a positive effect on the likelihood of acquiring an infection, but the effect on prevalence was negative for forest sections with a south facing aspect. For blackcaps, forest gaps also had a positive effect on prevalence, but canopy height had a negative one. Our results suggest that forest types and variations in forest structure influence the likelihood of acquiring an infection, which subsequently has an influence on host health status and body condition; however, responses to some environmental factors are host-specific. PMID- 27247107 TI - Brazilin exerts protective effects against renal ischemia-reperfusion injury by inhibiting the NF-kappaB signaling pathway. AB - Renal ischemia-reperfusion (I/R) injury is associated with high morbidity and mortality as there is currently no available effective therapeutic strategy with which to treat this injury. Thus, the aim of this study was to investigate the potential protective effects of brazilin, a major active component of the Chinese medicine Caesalpinia sappan L., against renal I/R injury in vitro and in vivo. Rats were subjected to removal of the right kidney and I/R injury to the left kidney (ischemia for 45 min followed by reperfusion for 24 h). Treatment with brazilin (30 mg/kg, administered intravenously at 30 min prior to ischemia) led to the reversal of I/R-induced changes in serum creatinine (Scr) and blood urea nitrogen (BUN) levels, and also attenuated the histopathological damage induced by I/R. Furthermore, TUNEL assay revealed that brazilin reduced cell necrosis, and significantly decreased the expression of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta in renal tissue. Moreover, HK-2 cells were used in order to elucidate the mechanisms responsible for the protective effects of brazilin. The levels of phosphorylated IkappaBalpha and the nuclear translocation of nuclear factor-kappaB (NF-kappaB) were all evidently decreased by brazilin. These findings suggested that pre-treatment with brazilin protects against I/R induced renal damage and suppresses the inflammatory response by inhibiting the activation of the NF-kappaB signaling pathway. PMID- 27247108 TI - Association between uric acid and renal function in hypertensive patients: which role for systemic vascular involvement? AB - The role of systemic vascular involvement in mediating the association between serum uric acid (SUA) and renal function in hypertension has not been explored. Main purpose of our study was to investigate whether morphofunctional vascular changes, assessed as carotid intima-media thickness (cIMT) and aortic pulse wave velocity (aPWV), might mediate the association between SUA and renal damage. We enrolled 523 hypertensive subjects with or without chronic kidney disease and divided population into tertiles of SUA based on sex-specific cutoff values. cIMT and aPWV were higher in uppermost SUA-tertile patients when compared to those in the lowest ones (all P < .001). Uricemia strongly correlated with cIMT and aPWV at univariate analysis (P < .001) and with cIMT after adjustment for confounders (P < .001). Adjustment for cIMT attenuated the relationship between SUA and estimated glomerular filtration rate (P = .019). Systemic vascular changes seem partially to mediate the association between SUA and renal function in hypertensive patients, regardless of kidney function. PMID- 27247109 TI - Achieving consensus for the histopathologic diagnosis of melanocytic lesions: use of the modified Delphi method. AB - OBJECTIVE: To understand the sophisticated nature of coming to consensus when diagnosing complex melanocytic lesions among a panel of experienced dermatopathologists. METHODS: A total of 240 melanocytic lesions were assessed independently by three experienced dermatopathologists with their diagnoses mapped into one of five Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-DX) categories: (I) nevus/mild atypia, (II) moderate atypia, (III) severe atypia/melanoma in situ, (IV) T1a invasive melanoma and (V) >= T1b invasive melanoma. The dermatopathologists then discussed the cases, using a modified Delphi method to facilitated consensus building for cases with discordant diagnoses. RESULTS: For most cases, a majority of interpretations (two or three of three) agreed with the consensus diagnosis in 95% of Category I, 64% of Category II, 84% of Category III, 88% for Category IV and 100% of Category V cases. Disagreements were typically due to diagnostic threshold differences (64.5%), differing contents on slides even though the slides were sequential cuts (18.5%), and missed findings (15.3%). Disagreements were resolved via discussion of histopathologic features and their significance while reviewing the slides using a multi-headed microscope, considering treatment recommendations, citing existing literature, reviewing additional slides for a case, and choosing a provisional/borderline diagnosis to capture diverse opinions. All experienced pathologists participating in this study reported that the process of coming to consensus was challenging for borderline cases and may have represented compromise rather than consensus. They also reported the process changed their approaches to diagnosing complex melanocytic lesions. CONCLUSIONS: The most frequent reason for disagreement of experienced dermatopathologists was differences in diagnostic thresholds related to observer viewpoints. A range of approaches was needed to come to consensus, and this may guide pathology groups who do not currently hold consensus conferences. PMID- 27247110 TI - Re: Undergraduate radiology teaching in a UK medical school: a systematic evaluation of current practice. PMID- 27247111 TI - The neutrophil-lymphocyte ratio and atherosclerosis. PMID- 27247113 TI - Hydroxyapatite and calcium pyrophosphate crystals mimicking gout in systemic sclerosis. PMID- 27247112 TI - Identification of lesion subtypes in biopsies of ductal carcinoma in situ of the breast using biomarker ratio imaging microscopy. AB - Although epidemiological studies propose aggressive and non-aggressive forms of ductal carcinoma in situ (DCIS), they cannot be identified with conventional histopathology. We now report a retrospective study of human biopsy samples using biomarker ratio imaging microscopy (BRIM). Using BRIM, micrographs of biomarkers whose expression correlates with breast cancer aggressiveness are divided by micrographs of biomarkers whose expression negatively correlates with aggressiveness to create computed micrographs reflecting aggressiveness. The biomarker pairs CD44/CD24, N-cadherin/E-cadherin, and CD74/CD59 stratified DCIS samples. BRIM identified subpopulations of DCIS lesions with ratiometric properties resembling either benign fibroadenoma or invasive carcinoma samples. Our work confirms the existence of distinct subpopulations of DCIS lesions, which will likely have utility in breast cancer research and clinical practice. PMID- 27247114 TI - Savouring and Self-compassion as Protective Factors for Depression. AB - Within positive psychology, researchers and clinicians vocalize the need to expand upon how the treatment for major depressive disorder is conceptualized and implemented. The impetus of the current study was to examine preliminary criteria for identifying savouring and self-compassion as protective factors for depression. Undergraduate students (N = 133) completed a series of surveys at two points in time, 5 weeks apart. Results revealed that savouring and self compassion were inversely related to depression scores cross-sectionally and prospectively. However, savouring was the only positive psychological variable to predict changes in depression scores across time. Cross-sectionally, savouring was also found to moderate the relation between negative life events and depression, such that the strength of the relation between negative life events and depression decreased when higher savouring was present. However, this same effect was not significant prospectively. There was no evidence, cross sectionally or prospectively, that self-compassion moderated the relation between negative life events and depression. Taken together, results provide preliminary support for savouring as a protective factor for depressive symptoms. Mental health professionals should consider teaching savouring strategies to help at risk clients stimulate and sustain positive affect as a means of preventing and reducing depressive symptoms. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27247115 TI - Epidemiology of poisonings, fractures and burns among 0-24 year olds in England using linked health and mortality data. AB - BACKGROUND: Understanding patterns of injury in England is challenging due to a lack of national injury surveillance data. Through recent linkage of a large primary care research database to hospitalization and mortality data, we describe the epidemiology of poisonings, fractures and burns over a 14-year period. METHODS: We used linked English primary care, hospitalisation and mortality data from the Clinical Practice Research Datalink, Hospital Episode Statistics and Office for National Statistics between 1998 and 2011 to establish a cohort of 2,106,420 0-24 year olds. Incidence rates, per 10 000 person-years (PY) were estimated by age, sex, calendar year and socioeconomic status. Using Poisson regression we estimated incidence rate ratios, adjusting for age and sex. RESULTS: Age patterns of injury incidence varied by injury type, with peaks at age 2 (74.3/10 000 PY) and 18 (74.7/10 000 PY) for poisonings, age 13 for fractures (305.1/10 000 PY) and age 1 for burns (116.8/10 000 PY). Over time, fracture incidence increased, whereas poisoning incidence increased only among 15 24 year olds and burns incidence reduced. Poisoning and burns incidence increased with deprivation, with the steepest socioeconomic gradient for poisonings among 20-24 year olds (IRR 2.63, 95% confidence interval 2.24-3.09). CONCLUSION: Differing patterns according to age and injury type reflect differences in underlying injury mechanisms, highlighting the importance of developing tailored preventative interventions across the life course. Inequalities in injury occurrences support the targeting of preventative interventions to children and young people living in the most deprived areas. PMID- 27247116 TI - Persistence of dysphagia and odynophagia after mediastinal radiation and chemotherapy in patients with lung cancer or lymphoma. AB - Esophageal symptoms are common during radiation and chemotherapy. It is unclear how often these symptoms persist after therapy. We retrospectively reviewed medical records of 320 adults treated for nonmetastatic breast cancer (84), lung cancer (109), or Hodgkin and non-Hodgkin lymphoma (127) who were disease-free at 10-14 months after therapy. Treatment included chemotherapy with or without nonmediastinal radiation therapy (150 patients), chemotherapy plus sequential mediastinal radiation therapy (MRT) (48 patients), chemotherapy plus concurrent MRT (61 patients), or non-MRT only (61 patients). Proton pump inhibitor use was documented. All treatment groups had similar prevalence of the esophageal symptom of heartburn before therapy. Rates were higher during treatment in those who received MRT with or without chemotherapy, but declined by 10-14 months after treatment. However, low baseline rates of dysphagia (4%) and odynophagia (2%) increased significantly after combined chemotherapy and MRT to 72% for dysphagia and 62% for odynophagia (P < 0.01) during treatment and stayed significantly elevated over baseline with 27% of the patients having dysphagia and 11% having odynophagia at 10-14 months after treatment. The use of proton pump inhibitors by patients who had MRT with chemotherapy was significantly increased during and after treatment (P = 0.002). Dysphagia, odynophagia and the use of proton pump inhibitors were significantly more common both during and after treatment than before treatment in patients who received both chemotherapy and mediastinal radiation. Our data highlight the important challenge for clinicians of managing patients with lung cancer and lymphoma who have persistent esophageal problems, particularly dysphagia and odynophagia, at approximately 1 year after treatment. PMID- 27247117 TI - Cutaneous paraneoplastic disorders in stomach cancer: Collaboration between oncologically active dermatologists and clinical oncologists. AB - To our knowledge this is the first systemic review that provides an overview of the cutaneous paraneoplastic syndromes (CPS) (i.e., clinical manifestations, pathomechanisms, and treatment modalities) occurring in stomach cancer. CPS are caused by substances produced by stomach cancer and may precede, coincide with, or follow the diagnosis of this malignancy. More than 20 possible CPS in association with stomach cancer have been identified. CPS mostly compromises the patient's quality of life by skin impairment plus discomfort and are often associated with a dismal prognosis on survival. Studies of these CPS not only in stomach cancer have partially contributed to the understanding of pathomechanism and since CPS may be the presenting sign of an occult cancer, cognizance of their features and clinical implications are of considerable importance. Patients with these syndromes should have an appropriate work-up for a possibly occult malignancy with consecutive successful early treatment. PMID- 27247118 TI - Past approaches and future directions for targeting tumor hypoxia in squamous cell carcinomas of the head and neck. AB - Recurrent squamous cell carcinoma of the head and neck (SCCHN) carries a poor prognosis. Tumor hypoxia (TH) has been implicated as one of many factors contributing to SCCHN recurrence. TH leads to radiation resistance by reversing radiation-induced DNA damage. Effective strategies to overcome TH may improve outcomes in patients with SCCHN. We searched the English literature on PubMed and reviewed the reference sections of key articles related to TH (publications spanning from the early 1900s to the present). We summarized the underlying theory of TH in SCCHN, methods for quantifying it, and the numerous therapies developed to modulate it. We included articles that set the foundation of TH as a theory and the most relevant articles published within the last 15 years related to TH quantification and therapeutic targeting. Despite extensive research, targeting TH in SCCHN has not become a part of routine clinical practice in North America, and we analyze the pitfalls in hypoxia research that have led to this failure. We propose that future studies should test a combined approach of targeting the immune system in addition to cellular pathways rendered aberrant in TH and should include development of novel surrogate markers of TH and/or TH imaging. PMID- 27247119 TI - Harnessing the immune system in acute myeloid leukaemia. AB - Acute myeloid leukaemia (AML) is an aggressive blood cancer caused by the proliferation of immature myeloid cells. The genetic abnormalities underlying AML affect signal transduction pathways, transcription factors and epigenetic modifiers. In solid tumours, it is emerging that the genetic landscape of the tumour has a direct effect on the anti-tumour immune responses and response to immunotherapeutic treatment. However, there remains little information as to whether genetic abnormalities affect anti-leukemic immune responses. This review discusses current knowledge of AML antigens and immune responses to AML with a particular focus on the role of T cells and natural killer cells. Understanding immune responses to AML has implications for the development and use of immunotherapies to treat AML patients with distinct genetic abnormalities. PMID- 27247120 TI - Tecto-GIRz: Engineered Group I Ribozyme the Catalytic Ability of Which Can Be Controlled by Self-Dimerization. AB - RNA is a promising biomaterial for self-assembly of nano-sized structures with a wide range of applications in nanotechnology and synthetic biology. Several RNA based nanostructures have been reported, but most are unrelated to intracellular RNA, which possesses modular structures that are sufficiently large and complex to serve as catalysts to promote sophisticated chemical reactions. In this study, we designed dimeric RNA structures based on the Tetrahymena group I ribozyme. The resulting dimeric RNAs (tecto group I ribozyme; tecto-GIRz) exhibit catalytic ability that depended on controlled dimerization, by which a pair of ribozymes can be activated to perform cleavage and splicing reactions of two distinct substrates. Modular redesign of complex RNA structures affords large ribozymes for use as modules in RNA nanotechnology and RNA synthetic biology. PMID- 27247121 TI - An audit of tuberculosis health services in prisons and immigration removal centres. AB - Background: Tuberculosis (TB) is the second leading cause of death worldwide due to a single infectious agent. Rates of active TB in places of prescribed detention (PPD), which include Prisons, Young Offender Institutions and Immigration Removal Centres, are high compared with the general population. PPD therefore present an opportunity to develop targeted health programmes for TB control. This audit aims to assess current service provisions and identify barriers to achieving best practice standards in PPD across London. Methods: Twelve healthcare teams within PPD commissioned by NHS England (London Region) were included in the audit. Services were evaluated against the National Institute for Health and Care Excellence standards for TB best practice. Results: None of the health providers with a digital X-ray machine were conducting active case finding in new prisoners and no health providers routinely conduct Latent TB infection testing and preventative treatment. Barriers to implementing standards include the lack of staff skills and staff skills mix, structural and technical barriers, and demands of custodial and health services. Conclusions: This audit restates the importance of national public health TB strategies to consider healthcare provisions across PPD. PMID- 27247122 TI - Barriers and facilitators to the use of an immunization application: a qualitative study supplemented with Google Analytics data. AB - Background: Barriers and facilitators of mobile app adoption are not known. This study examined usage of a new Pan-Canadian immunization app to identify factors that contributed to usage. Methods: Women in their third trimester of pregnancy or had given birth in the previous 3 months were recruited from a hospital obstetrical unit. Fifty-five participants were instructed to download the ImmunizeCA app. After at least 6 months, 10 interviews were conducted, transcribed and coded. Themes identified were compared with aggregate ImmunizeCA usage data (n = 74 212 users). Results: Facilitators included features that address logistical challenges, improved convenience and information access. Barriers included absence of system integration. Concerns regarding the privacy and security of personal health information were not an inhibitor as long as best practices are followed. Google Analytics data on usage supported qualitative findings. Conclusion: Future studies should evaluate the quantitative impact of factors we identified on app uptake and usage. Subsequent mobile app studies may benefit from the use of analytic data as they were found to be effective in helping to validate qualitative data derived from interviews with study participants. PMID- 27247124 TI - Current status of Blastocystis: A personal view. AB - Despite Blastocystis being one of the most widespread and prevalent intestinal eukaryotes, its role in health and disease remains elusive. DNA-based detection methods have led to a recognition that the organism is much more common than previously thought, at least in some geographic regions and some groups of individuals. Molecular methods have also enabled us to start categorizing the vast genetic heterogeneity that exists among Blastocystis isolates, wherein the key to potential differences in the clinical outcome of Blastocystis carriage may lie. In this review we summarize some of the recent developments and advances in Blastocystis research, including updates on diagnostic methods, molecular epidemiology, genetic diversity, host specificity, clinical significance, taxonomy, and genomics. As we are now in the microbiome era, we also review some of the steps taken towards understanding the place of Blastocystis in the intestinal microbiota. PMID- 27247125 TI - The Power of the Like in Adolescence: Effects of Peer Influence on Neural and Behavioral Responses to Social Media. AB - We investigated a unique way in which adolescent peer influence occurs on social media. We developed a novel functional MRI (fMRI) paradigm to simulate Instagram, a popular social photo-sharing tool, and measured adolescents' behavioral and neural responses to likes, a quantifiable form of social endorsement and potential source of peer influence. Adolescents underwent fMRI while viewing photos ostensibly submitted to Instagram. They were more likely to like photos depicted with many likes than photos with few likes; this finding showed the influence of virtual peer endorsement and held for both neutral photos and photos of risky behaviors (e.g., drinking, smoking). Viewing photos with many (compared with few) likes was associated with greater activity in neural regions implicated in reward processing, social cognition, imitation, and attention. Furthermore, when adolescents viewed risky photos (as opposed to neutral photos), activation in the cognitive-control network decreased. These findings highlight possible mechanisms underlying peer influence during adolescence. PMID- 27247126 TI - Life Course Pathways to Racial Disparities in Cognitive Impairment among Older Americans. AB - Blacks are especially hard hit by cognitive impairment at older ages compared to whites. Here, we take advantage of the Health and Retirement Study (1998-2010) to assess how this racial divide in cognitive impairment is associated with the racial stratification of life course exposures and resources over a 12-year period among 8,946 non-Hispanic whites and blacks ages 65 and older in 1998. We find that blacks suffer from a higher risk of moderate/severe cognitive impairment at baseline and during the follow-up. Blacks are also more likely to report childhood adversity and to have grown up in the segregated South, and these early-life adversities put blacks at a significantly higher risk of cognitive impairment. Adulthood socioeconomic status is strongly associated with the risk of cognitive impairment, net of childhood conditions. However, racial disparities in cognitive impairment, though substantially reduced, are not eliminated when controlling for these life course factors. PMID- 27247128 TI - Abnormal Methylation of Imprinted Genes and Cigarette Smoking: Assessment of Their Association With the Risk of Male Infertility. AB - Male infertility is a complicated disease with causes generally split into 2 broad categories: genetic factors and environmental factors. The present study was designed to investigate the association between the methylation patterns of H19 and SNRPN imprinting control region (ICR) and male infertility and to assess the gene-environment interactions between environmental factors and methylation patterns. A total of 205 DNA samples from 48 oligozoospermia (OZ), 52 asthenozoospermia (AZ), 55 teratozoospermia (TZ) patients, and 50 normozoospermia (NZ) men were analyzed. The mean methylation level of H19-ICR in OZ (80.40% +/- 12.74%) and AZ patients (81.17% +/- 13.18%) was significantly lower than methylation in men with NZ (88.51% +/- 10.54%, P<.001, P<.001, respectively). The mean methylation level of SNRPN-ICR in AZ patients (7.74% +/- 5.71%) and TZ patients (9.33% +/- 5.48%) was significantly higher than in NZ men (6.32% +/- 3.54%, P<.001, P<.001, respectively). Among environmental factors, smoking was correlated with OZ (odds ratio [OR] = 5.12, 95% CI: 2.05-12.83), AZ (OR = 5.65, 95% CI: 2.13-14.99), and TZ (OR = 5.54, 95% CI: 2.21-13.89). Gene-environment interaction analysis revealed that hypomethylation of H19-ICR in OZ patients and hypermethylation of SNRPN-ICR in AZ and TZ patients were significantly associated with an increased the risk of infertility in men who were smokers (OR = 15.30, 95% CI: 1.13-207.97; OR = 13.20, 95% CI: 1.21-143.57; OR = 10.59, 95% CI: 1.04 107.39, respectively). This study demonstrated that hypomethylation of H19-ICR and hypermethylation of SNRPN-ICR are associated with male infertility, and the risk is potentiated by smoking. PMID- 27247127 TI - Tetraspanin-2 promotes glucotoxic apoptosis by regulating the JNK/beta-catenin signaling pathway in human pancreatic beta cells. AB - Diabetes mellitus is a complex and heterogeneous disease, which has beta-cell dysfunction at its core. Glucotoxicity affects pancreatic islets, causing beta cell apoptosis. However, the role of JNK/beta-catenin signaling in glucotoxic beta-cell apoptosis is not well understood. Recently, we identified tetraspanin-2 (TSPAN2) protein as a proapoptotic beta-cell factor induced by glucose, suggesting that TSPAN2 might contribute to pancreatic beta-cell glucotoxicity. To investigate the effects of glucose concentration on TSPAN2 expression and apoptosis, we used reverted immortalized RNAKT-15 human pancreatic beta cells. High TSPAN2 levels up-regulated phosphorylated (p) JNK and induced apoptosis. p JNK enhanced the phosphorylation of beta-catenin and Dickkopf-1 (Dkk1). Dkk1 knockdown by small interfering (si)RNA up-regulated nuclear beta-catenin, suggesting that it is a JNK/beta-catenin-dependent pathway. siRNA-mediated TSPAN2 depletion in RNAKT-15 cells increased nuclear beta-catenin. This decreased BCL2 associated X protein (Bax) activation, leading to marked protection against high glucose-induced apoptosis. Bax subfamily proteins induced apoptosis through caspase-3. Thus, TSPAN2 might have induced Bax translocation and caspase-3 activation in pancreatic beta cells, thereby promoting the apoptosis of RNAKT-15 cells by regulating the JNK/beta-catenin pathway in response to high glucose concentrations. Targeting TSPAN2 could be a potential therapeutic strategy to treat glucose toxicity-induced beta-cell failure.-Hwang, I.-H., Park, J., Kim, J. M., Kim, S. I., Choi, J.-S., Lee, K.-B., Yun, S. H., Lee, M.-G., Park, S. J., Jang, I.-S. Tetraspanin-2 promotes glucotoxic apoptosis by regulating the JNK/beta-catenin signaling pathway in human pancreatic beta cells. PMID- 27247129 TI - Automated prostate tissue referencing for cancer detection and diagnosis. AB - BACKGROUND: The current practice of histopathology review is limited in speed and accuracy. The current diagnostic paradigm does not fully describe the complex and complicated patterns of cancer. To address these needs, we develop an automated and objective system that facilitates a comprehensive and easy information management and decision-making. We also develop a tissue similarity measure scheme to broaden our understanding of tissue characteristics. RESULTS: The system includes a database of previously evaluated prostate tissue images, clinical information and a tissue retrieval process. In the system, a tissue is characterized by its morphology. The retrieval process seeks to find the closest matching cases with the tissue of interest. Moreover, we define 9 morphologic criteria by which a pathologist arrives at a histomorphologic diagnosis. Based on the 9 criteria, true tissue similarity is determined and serves as the gold standard of tissue retrieval. Here, we found a minimum of 4 and 3 matching cases, out of 5, for ~80 % and ~60 % of the queries when a match was defined as the tissue similarity score >=5 and >=6, respectively. We were also able to examine the relationship between tissues beyond the Gleason grading system due to the tissue similarity scoring system. CONCLUSIONS: Providing the closest matching cases and their clinical information with pathologists will help to conduct consistent and reliable diagnoses. Thus, we expect the system to facilitate quality maintenance and quality improvement of cancer pathology. PMID- 27247130 TI - Adaptation to warmer climates by parallel functional evolution of CBF genes in Arabidopsis thaliana. AB - The evolutionary processes and genetics underlying local adaptation at a specieswide level are largely unknown. Recent work has indicated that a frameshift mutation in a member of a family of transcription factors, C-repeat binding factors or CBFs, underlies local adaptation and freezing tolerance divergence between two European populations of Arabidopsis thaliana. To ask whether the specieswide evolution of CBF genes in Arabidopsis is consistent with local adaptation, we surveyed CBF variation from 477 wild accessions collected across the species' range. We found that CBF sequence variation is strongly associated with winter temperature variables. Looking specifically at the minimum temperature experienced during the coldest month, we found that Arabidopsis from warmer climates exhibit a significant excess of nonsynonymous polymorphisms in CBF genes and revealed a CBF haplotype network whose structure points to multiple independent transitions to warmer climates. We also identified a number of newly described mutations of significant functional effect in CBF genes, similar to the frameshift mutation previously indicated to be locally adaptive in Italy, and find that they are significantly associated with warm winters. Lastly, we uncover relationships between climate and the position of significant functional effect mutations between and within CBF paralogs, suggesting variation in adaptive function of different mutations. Cumulatively, these findings support the hypothesis that disruption of CBF gene function is adaptive in warmer climates, and illustrate how parallel evolution in a transcription factor can underlie adaptation to climate. PMID- 27247131 TI - In vitro hemocompatibility and cytocompatibility of a three-layered vascular scaffold fabricated by sequential electrospinning of PCL, collagen, and PLLA nanofibers. AB - Aiming to mimic a blood vessel structurally, morphologically, and mechanically, a sequential electrospinning technique using a small diameter mandrel collector was performed and a three-layered tubular scaffold composed of nanofibers of polycaprolactone, collagen, and poly(l-lactic acid) as inner, intermediate, and outer layers, respectively, was developed. Biological performances of the scaffold in terms of compatibility with blood and endothelial cells were assessed to get some insights into its potential use as a tissue engineered small-diameter vascular replacement compared to an expanded polytetrafluoroethylene vascular graft. Due to direct contact of the blood and endothelial cells with inner surface of the scaffold, polycaprolactone fibers were characterized using SEM, water contact angle measurement, and ATR-FTIR. Despite similar surface wettability of the electrospun scaffold and the expanded polytetrafluoroethylene graft, the three-layered scaffold significantly reduced platelet adhesion and hemolysis ratio compared to expanded polytetrafluoroethylene graft while comparable blood clotting profiles were observed for both electrospun scaffold and expanded polytetrafluoroethylene graft. However, inflammatory response to nanofibrous surface of the scaffold was reduced compared to expanded polytetrafluoroethylene graft. The electrospun scaffold also presented a significantly more supportive substrate for endothelialization than the expanded polytetrafluoroethylene graft. The results described herein suggested that the three-layered scaffold has superior biological properties compared to an expanded polytetrafluoroethylene graft for vascular tissue engineering. PMID- 27247132 TI - Asian American and White College Students' Heavy Episodic Drinking Behaviors and Alcohol-Related Problems. AB - BACKGROUND: Heavy episodic drinking (HED) and alcohol-related problems appears to be a growing problem among young adult Asian Americans. One promising factor that helps explain within-group differences among Asian American includes nativity. Nativity refers to whether an individual was born in (i.e., second generation or higher) or outside (i.e., first generation) of the United States. Despite this theoretically promising variable, there has been a paucity of literature examining comparing drinking patterns between first and second generation Asians Americans and White college men. OBJECTIVES: The current study examined the relationship between HED and alcohol-related problems among first- and second generation Asian American, and White college male students. Interaction between race and the variables in HED and alcohol-related problems models were also investigated. METHOD: A total of 630 men were recruited of which 489 were Asian American men (407 second generation and 82 first generation) and 148 White students attending a public university in southern California (USA) were recruited. RESULTS: Results revealed no differences in HED rates between second generation Asian American and White male college students; however, White students reported higher rates of HED compared to first-generation Asian Americans. No differences in alcohol-related problems were found between all three groups. There were no significant interactions between racial groups, drinking to cope, Greek/fraternity status, and descriptive norms on the alcohol outcomes. Conclusion/importance: Second-generation Asian American young adult men reported similar HED and rates of alcohol-related problems as White men. The present findings suggest that alcohol-related problems among Asian American men are a larger public health concern than previously believed. PMID- 27247133 TI - Thermal ablative therapies for treatment of localised renal cell carcinoma: a systematic review of the literature. AB - BACKGROUND AND AIMS: Small renal masses are commonly diagnosed incidentally. The majority are malignant and require intervention. The gold standard treatment is partial nephrectomy unless the patient has significant co-morbidities when surveillance or ablative therapies are utilised. The latter are relatively novel and their long-term efficacy and safety remain generally poorly understood. We performed a literature review to establish the current evidence on the oncological outcome of thermal ablative techniques in small renal masses treatment. METHODS AND RESULTS: A systematic literature search was performed using PubMed, supplemented with additional references. Articles were reviewed for data on indications, tumour characteristics, ablative techniques, oncological outcome, impact on renal function and complications. The vast majority of articles identified were observational studies. There has not been any direct comparison against partial nephrectomy. Radiofrequency ablation and cryoablation are the techniques that are more commonly used. They have favourable oncological results on intermediate follow-up and indications that successful outcome is sustained long term. The morbidity and impact on renal function appear to be minimal. CONCLUSION: Thermal ablative therapies are valid alternatives to partial nephrectomy for the treatment of small renal masses in patients unfit for surgery. Prospective long-term data will be needed before the indications for their use expand further. PMID- 27247134 TI - Therapists' continuations following I don't know-responses of adolescents in psychotherapy. AB - OBJECTIVE: In psychotherapy clients' I don't know-responses (IDK-responses) to therapists' questions are typically considered to be non-cooperating behaviors. How therapists actually handle these behaviors remains unclear. This study therefore aims to assess client-therapist interactions following IDK-responses. METHODS: Data were collected in a Dutch child and adolescent mental healthcare service by observing Dialectical Behavior Therapy aimed at adolescents with severe emotional distress. Eighteen individual psychotherapy sessions involving two therapists with six clients were video-recorded and transcribed. Stand-alone IDK-responses were selected (n=77) and analyzed using conversation analysis. RESULTS: Adolescents' IDK-responses led to varying actions of therapists. We identified five categories of continuations after IDK-responses: no IDK-related continuation; redoing of the question; proposing a candidate answer; employing therapy-specific techniques; and meta-talk on the problematic nature of the IDK response. CONCLUSIONS: Therapists treat IDK-responses not just as non-cooperative behavior on the part of the client; IDK-responses are also used as a starting point to collaboratively enhance clients' insights in their own thoughts, emotions, and behaviors. PRACTICE IMPLICATIONS: After IDK-responses therapists can use a variety of continuation strategies with varying therapeutic functions. These strategies can be embedded in training of therapists to deal with potentially non-cooperative behavior. PMID- 27247135 TI - The risk of atrial fibrillation with ibrutinib use: a systematic review and meta analysis. PMID- 27247138 TI - Abuse of Older Persons With Dementia: A Review of the Literature. AB - In view of the rapidly aging population, increasing attention has been paid to studying persons with dementia. Factors associated with its onset, prognosis, and treatment as well as ways to support caregivers in the community have been extensively studied. Despite the fact that older persons with dementia are at higher risk of abuse compared to their cognitively unimpaired counterparts in institutions and the community, however, relatively little attention has been paid to understanding such abuse. This review summarizes the available literature on abuse of older persons with dementia. It compares methodologies used across studies and highlights the implications of using different informants, sampling strategies, and abuse subtypes in studying abuse of persons with dementia and discussed the relevant cultural considerations for research. The results of this review provide important information for researchers, policy makers, and practitioners. PMID- 27247136 TI - Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity. AB - Idelalisib is a small-molecule inhibitor of PI3Kdelta with demonstrated efficacy for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL). To evaluate idelalisib as front-line therapy, we enrolled 24 subjects in a phase 2 study consisting of 2 months of idelalisib monotherapy followed by 6 months of combination therapy with idelalisib and the anti-CD20 antibody ofatumumab. After a median follow-up period of 14.7 months, hepatotoxicity was found to be a frequent and often severe adverse event. A total of 19 subjects (79%) experienced either grade >=1 ALT or AST elevation during the study, and 13 subjects (54%) experienced grade >=3 transaminitis. The median time to development of transaminitis was 28 days, occurring before ofatumumab introduction. Younger age and mutated immunoglobulin heavy chain status were significant risk factors for the development of hepatotoxicity. Multiple lines of evidence suggest that this hepatotoxicity was immune mediated. A lymphocytic infiltrate was seen on liver biopsy specimens taken from 2 subjects with transaminitis, and levels of the proinflammatory cytokines CCL-3 and CCL-4 were higher in subjects experiencing hepatotoxicity. All cases of transaminitis resolved either by holding the drug, initiating immunosuppressants, or both, and rates of recurrent toxicity were lower in patients taking steroids when idelalisib was reinitiated. A decrease in peripheral blood regulatory T cells was seen in patients experiencing toxicity on therapy, which is consistent with an immune-mediated mechanism. These results suggest that caution should be taken as drugs within this class are developed for CLL, particularly in younger patients who have not received prior disease specific therapy. This study was registered at www.clinicaltrials.gov as #NCT02135133. PMID- 27247139 TI - Comparing two treatments by decision theory. AB - Decision theory is applied to the general problem of comparing two treatments in an experiment with subjects assigned to the treatments at random. The inferential agenda covers collection of evidence about superiority, non-inferiority and average bioequivalence of the treatments. The proposed approach requires defining the terms 'small' and 'large' to qualify the magnitude of the treatment effect and specifying the losses (or loss functions) that quantify the consequences of the incorrect conclusions. We argue that any analysis that ignores these two inputs is deficient, and so is any ad hoc way of taking them into account. Sample size calculation for studies intended to be analysed by this approach is also discussed. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27247140 TI - Informed consent in implantable BCI research: identification of research risks and recommendations for development of best practices. AB - OBJECTIVE: Implantable brain-computer interface (BCI) research promises improvements in human health and enhancements in quality of life. Informed consent of subjects is a central tenet of this research. Rapid advances in neuroscience, and the intimate connection between functioning of the brain and conceptions of the self, make informed consent particularly challenging in BCI research. Identification of safety and research-related risks associated with BCI devices is an important step in ensuring meaningful informed consent. APPROACH: This paper highlights a number of BCI research risks, including safety concerns, cognitive and communicative impairments, inappropriate subject expectations, group vulnerabilities, privacy and security, and disruptions of identity. MAIN RESULTS: Based on identified BCI research risks, best practices are needed for understanding and incorporating BCI-related risks into informed consent protocols. SIGNIFICANCE: Development of best practices should be guided by processes that are: multidisciplinary, systematic and transparent, iterative, relational and exploratory. PMID- 27247137 TI - Specific combinations of donor and recipient KIR-HLA genotypes predict for large differences in outcome after cord blood transplantation. AB - The ability of cord blood transplantation (CBT) to prevent relapse depends partly on donor natural killer (NK) cell alloreactivity. NK effector function depends on specific killer-cell immunoglobulin-like receptors (KIR) and HLA interactions. Thus, it is important to identify optimal combinations of KIR-HLA genotypes in donors and recipients that could improve CBT outcome. We studied clinical data, KIR and HLA genotypes, and NK-cell reconstitution in CBT patients (n = 110). Results were validated in an independent cohort (n = 94). HLA-KIR genotyping of recipient germline and transplanted cord blood (CB) grafts predicted for large differences in outcome. Patients homozygous for HLA-C2 group alleles had higher 1 year relapse rate and worse survival after CBT than did HLA-C1/C1 or HLA-C1/C2 (HLA-C1/x) patients: 67.8% vs 26.0% and 15.0% vs 52.9%, respectively. This inferior outcome was associated with delayed posttransplant recovery of NK cells expressing the HLA-C2-specific KIR2DL1/S1 receptors. HLA-C1/x patients receiving a CB graft with the combined HLA-C1-KIR2DL2/L3/S2 genotype had lower 1-year relapse rate (6.7% vs 40.1%) and superior survival (74.2% vs 41.3%) compared with recipients of grafts lacking KIR2DS2 or HLA-C1 HLA-C2/C2 patients had lower relapse rate (44.7% vs 93.4%) and better survival (30.1% vs 0%) if they received a graft with the combined HLA-C2-KIR2DL1/S1 genotype. Relapsed/refractory disease at CBT, recipient HLA-C2/C2 genotype, and donor HLA-KIR genotype were independent predictors of outcome. Thus, we propose the inclusion of KIR genotyping in graft selection criteria for CBT. HLA-C1/x patients should receive an HLA-C1 KIR2DL2/L3/S2 CB graft, while HLA-C2/C2 patients may benefit from an HLA-C2 KIR2DL1/S1 graft. PMID- 27247141 TI - Increased susceptibility to pentylenetetrazol following survival of cerebral malaria in mice. AB - Malaria is considered a neglected disease and public health problem, affecting >200 million people worldwide. In the present study we used the Plasmodium berghei ANKA (PbA) model of experimental cerebral malaria (CM) in C57BL/6 mice. After rescue from CM and parasite clearance, animals were submitted to a seizure susceptibility test (45 days after infection) using a low dose of pentylenetetrazol (PTZ, 30 mg/kg) and monitored with use of behavioral and electroencephalography (EEG) methods. Mice rescued from CM presented a reduced latency to myoclonic and tonic-clonic seizures and an increased duration of tonic clonic seizures. In addition, quantitative analysis of EEG revealed a decrease in relative power at beta frequency band in PbA-infected animals after PTZ injection. Our results suggest that CM may lead to increased susceptibility to seizures in mice. PMID- 27247142 TI - Oxytocin reversed MK-801-induced social interaction and aggression deficits in zebrafish. AB - Changes in social behavior occur in several neuropsychiatric disorders such as schizophrenia and autism. The interaction between individuals is an essential aspect and an adaptive response of several species, among them the zebrafish. Oxytocin is a neuroendocrine hormone associated with social behavior. The aim of the present study was to investigate the effects of MK-801, a non-competitive antagonist of glutamate NMDA receptors, on social interaction and aggression in zebrafish. We also examined the modulation of those effects by oxytocin, the oxytocin receptor agonist carbetocin and the oxytocin receptor antagonist L 368,899. Our results showed that MK-801 induced a decrease in the time spent in the segment closest to the conspecific school and in the time spent in the segment nearest to the mirror image, suggesting an effect on social behavior. The treatment with oxytocin after the exposure to MK-801 was able to reestablish the time spent in the segment closest to the conspecific school, as well as the time spent in the segment nearest to the mirror image. In addition, in support of the role of the oxytocin pathway in modulating those responses, we showed that the oxytocin receptor agonist carbetocin reestablished the social and aggressive behavioral deficits induced by MK-801. However, the oxytocin receptor antagonist L-368,899 was not able to reverse the behavioral changes induced by MK-801. This study supports the critical role for NMDA receptors and the oxytocinergic system in the regulation of social behavior and aggression which may be relevant for the mechanisms associated to autism and schizophrenia. PMID- 27247143 TI - Estrogen and voluntary exercise interact to attenuate stress-induced corticosterone release but not anxiety-like behaviors in female rats. AB - The beneficial effects of physical exercise to reduce anxiety and depression and to alleviate stress are increasingly supported in research studies. The role of ovarian hormones in interactions between exercise and anxiety/stress has important implications for women's health, given that women are at increased risk of developing anxiety-related disorders, particularly during and after the menopausal transition. In these experiments, we tested the hypothesis that estrogen enhances the positive impact of exercise on stress responses by investigating the combined effects of exercise and estrogen on anxiety-like behaviors and stress hormone levels in female rats after an acute stressor. Ovariectomized female rats with or without estrogen were given access to running wheels for one or three days of voluntary running immediately after or two days prior to being subjected to restraint stress. We found that voluntary running was not effective at reducing anxiety-like behaviors, whether or not rats were subjected to restraint stress. In contrast, stress-induced elevations of stress hormone levels were attenuated by exercise experience in estrogen-treated rats, but were increased in rats without estrogen. These results suggest that voluntary exercise may be more effective at reducing stress hormone levels if estrogen is present. Additionally, exercise experience, or the distance run, may be important in reducing stress. PMID- 27247144 TI - Quantitative proteomics analysis of the liver reveals immune regulation and lipid metabolism dysregulation in a mouse model of depression. AB - Major depressive disorder (MDD) is a highly prevalent and debilitating mental illness with substantial impairments in quality of life and functioning. However, the pathophysiology of major depression remains poorly understood. Combining the brain and body should provide a comprehensive understanding of the etiology of MDD. As the largest internal organ of the human body, the liver has an important function, yet no proteomic study has assessed liver protein expression in a preclinical model of depression. Using the chronic unpredictable mild stress (CUMS) mouse model of depression, differential protein expression between CUMS and control (CON) mice was examined in the liver proteome using isobaric tag for relative and absolute quantitation (iTRAQ) coupled with tandem mass spectrometry. More than 4000 proteins were identified and 66 most significantly differentiated proteins were used for further bioinformatic analysis. According to the ingenuity pathway analysis (IPA), we found that proteins related to the inflammation response, immune regulation, lipid metabolism and NFkappaB signaling network were altered by CUMS. Moreover, four proteins closely associated with these processes, hemopexin, haptoglobin, cytochrome P450 2A4 (CYP2A4) and bile salt sulfotransferase 1 (SULT2A1), were validated by western blotting. In conclusion, we report, for the first time, the liver protein expression profile in the CUMS mouse model of depression. Our findings provide novel insight (liver-brain axis) into the multifaceted mechanisms of major depressive disorder. PMID- 27247145 TI - Sublethal effects of zinc oxide nanoparticles on male reproductive cells. AB - Environmental exposure to nanomaterials is inevitable as nanomaterials become part of our daily life, and as a result, nanotoxicity research is gaining attention. Most investigators focused on the effects of zinc oxide nanoparticles (ZnO NPs) on human health, while limited information was available on the male reproductive system. Herein, mouse Sertoli cell line (TM-4) and spermatocyte cell line (GC2-spd) were used as in vitro models to explore the reproductive effects of ZnO NPs at sublethal dose and its underlying mechanisms. Cells were treated with different concentrations of ZnO NPs. By cell viability assay, a dose of 8MUg/mL was found as a sublethal dose and increased the ROS levels in both cells. The decreased glutathione level and increased MDA level were also found in ZnO NPs treated group. In TM4 cells, the expressions of BTB proteins (ZO-1, occludin, claudin-5, and connexin-43) were lower in the ZnO NPs group. The increased cell permeability and increased TNF-alpha secretion were also observed in ZnO NPs group. In GC2-spd cells, S phase arrest and DNA damage occurred in ZnO NPs group, which could be partially rescued by NAC. Our findings demonstrated that exposure to ZnO NPs induced ROS generation, caused DNA damage of germ cells, and down regulated the expression of BTB proteins in Sertoli cells which could compromise the integrity of the blood-testis barrier. All these contributed to the male reproductive cytotoxic effects of ZnO NPs that could be partially rescued by anti oxidants. PMID- 27247146 TI - Calmidazolium chloride inhibits growth of murine embryonal carcinoma cells, a model of cancer stem-like cells. AB - Calmidazolium chloride (CMZ) is widely used as a calmodulin (CaM) antagonist, but is also known to induce apoptosis in certain cancer cell lines. However, in spite of the importance of cancer stem cells (CSCs) in cancer therapy, the effects of CMZ on CSCs are not yet well understood. We investigated the effects of CMZ on the F9 embryonal carcinoma cell (ECC) line as a surrogate model of CSCs. To avoid bias due to culture conditions, F9 ECCs and E14 embryonic stem cells (ESCs) were grown in the same culture medium. Results obtained using a cell-counting kit showed that CMZ significantly inhibited growth in F9 ECCs compared with growth in E14 ESCs. CMZ also induced apoptosis of F9 ECCs, but not of E14 ESCs, which was associated with caspase-3 activation and an increased fraction of the sub-G1 cell population. In addition, our data revealed that the expression of stemness related genes including c-Myc was selectively down regulated in CMZ-treated F9 ECCs. Our results suggest that CMZ can inhibit the growth of ECCs by inducing apoptosis and down regulating stemness-related genes, without causing any harm to normal stem cells. These findings indicate a potential application of CMZ in the development of anti-CSC therapeutics. PMID- 27247147 TI - Functional analysis of HBO1 in tumor development and inhibitor screening. AB - The aim of the present study was to explore the functions of histone acetyltransferase binding to origin recog-nition complex (ORC) 1 (HBO1) during tumor development and to screen for HBO1 inhibitors. The chromatin immuno precipitation sequencing (ChIP-seq) data of HBO1 in the RKO human colon cancer cell line (GSE33007) were downloaded from the Gene Expression Omnibus (GEO) database. The reads were then mapped back to a reference genome hg19. The PCR duplicate reads were removed by using SAMtools software and the shift was calculated using SPP and MaSC software. The peak calling was carried out using MACS 1.4.0 software. Furthermore, the inhibitors of HBO1 were screened out from the Specs database using Dock 6.6 software. The binding sites of HBO1 were mainly distributed in the intergenic, intronic and 3'-end regions. Further analysis revealed that a total of 9,467 target genes was identified around HBO1 binding sites in the RKO cell lines and those genes mainly participated in the cell cycle, biosynthetic process, as well as other processes. Finally, 5 inhibitors with best binding affinity in the positively charged cavity of HBO1 were screened out: i) 5-[(2-hydroxybenzylidene)amino] -2-(2-{4-[(2-hydroxy-benzylidene)amino]-2 sulfonatophenyl}vinyl)benzenesulfonate, ii) 3-[4-(3-bromo-4-{2-[4 (ethoxycarbonyl)anilino]-2-oxo-ethoxy}-5-methoxybenzylidene)-3-methyl-5-oxo -4,5 dihydro-1H-pyrazol-1-yl]benzoic acid, iii) 4-(4-{3-iodo-5- methoxy-4-[2-(2 methoxyanilino)-2-oxoethoxy]benzylidene}-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1 yl)benzoic acid, iv) 5-chloro-1,3-bis{[3,5,6-trihydroxy-4-(octyloxy)tetrahydro-2H pyran-2-yl]methyl}-1,3-dihydro-2H-benzimidazol-2-one and v) 4-{[4 (tetradecylamino)-1-naphthyl]diazenyl}benzoic acid. As a whole, in this study, we identified the possible binding sites and biological functions of HBO1. The potential inhibitors of HBO1 were also screened, which prove to be helpful for the inhibition of HBO1 during tumor development. PMID- 27247149 TI - The ins and outs of the Mycobacterium tuberculosis-containing vacuole. AB - The past few years have seen publication of reports from several groups documenting the escape of Mycobacterium tuberculosis (Mtb) from its intracellular vacuole to access the cytosol. The major questions addressed in these publications are the mechanism(s) underlying this process, the frequency of its occurrence and, most importantly, the biological significance of this phenomenon to bacterial survival, growth and virulence. I believe that the first two questions are moving towards resolution, but questions relating to biological context have yet to be answered fully. In this viewpoint article, I will try to convince the readers why escape from the vacuole in no way diminishes the significance of Mtb's intravacuolar survival mechanisms and why, as a lab, we continue to focus the majority of our efforts on the 'bug in the bag'. PMID- 27247148 TI - Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain. AB - TRPV4 ion channels represent osmo-mechano-TRP channels with pleiotropic function and wide-spread expression. One of the critical functions of TRPV4 in this spectrum is its involvement in pain and inflammation. However, few small-molecule inhibitors of TRPV4 are available. Here we developed TRPV4-inhibitory molecules based on modifications of a known TRPV4-selective tool-compound, GSK205. We not only increased TRPV4-inhibitory potency, but surprisingly also generated two compounds that potently co-inhibit TRPA1, known to function as chemical sensor of noxious and irritant signaling. We demonstrate TRPV4 inhibition by these compounds in primary cells with known TRPV4 expression - articular chondrocytes and astrocytes. Importantly, our novel compounds attenuate pain behavior in a trigeminal irritant pain model that is known to rely on TRPV4 and TRPA1. Furthermore, our novel dual-channel blocker inhibited inflammation and pain associated behavior in a model of acute pancreatitis - known to also rely on TRPV4 and TRPA1. Our results illustrate proof of a novel concept inherent in our prototype compounds of a drug that targets two functionally-related TRP channels, and thus can be used to combat isoforms of pain and inflammation in-vivo that involve more than one TRP channel. This approach could provide a novel paradigm for treating other relevant health conditions. PMID- 27247150 TI - Averting the legacy of kidney disease - focus on childhood. AB - World Kidney Day 2016 focuses on kidney disease in childhood and the antecedents of adult kidney disease that can begin in earliest childhood. Chronic kidney disease (CKD) in childhood differs from that in adults, as the largest diagnostic group amongst children includes congenital anomalies and inherited disorders, with glomerulopathies and kidney disease in the setting of diabetes being relatively uncommon. In addition, many children with acute kidney injury will ultimately develop sequelae that may lead to hypertensionand CKD in later childhood or in adult life. Children born early or who are small-for-date newborns have relatively increased risk for the development of CKD later in life. Persons with a high-risk birth and early childhood history should be watched closely to help to detect early signs of kidney disease in time to provide effective prevention or treatment. Successful therapy is feasible for advanced CKD in childhood; there is evidence that children fare better than adults, if they receive kidney replacement therapy including dialysis and transplantation, whilst only a minority of children may require this ultimate intervention. Because there are disparities in access to care, effort is needed so that children with kidney disease, wherever they live, may be treated effectively, irrespective of their geographic oreconomic circumstances. Our hope is that World Kidney Day will inform the general public, policymakers and caregivers about the needs and possibilities surrounding kidney disease in childhood. PMID- 27247151 TI - Access to health in city slum dwellers: The case of Sodom and Gomorrah in Accra, Ghana. AB - BACKGROUND: Rapid rural-urban migration of people to cities is a reality around the globe that has increased city slum dwellers. Sodom and Gomorrah is a city slum located in the heart of Accra, Ghana. Like other slums, it lacks basic amenities necessary for dwellers' quality of life. This study describes residents' access to health and factors associated with the use of healthcarefacilities. METHODS: Questionnaires were administered in systematically selected shacks across the entire slum. Data on demographic characteristics, existent health facilities and number of users, health-insured residents and knowledge of common diseases were collected. RESULTS: Majority of the residents were from the northern parts of Ghana, relative to the south and a few of them come from other parts of West Africa. Seventy-one percent of residents had never visited a health facility in the last 5 years. When necessary, they access health care from drug stores (61.1%) or hospitals (33.1%). Residents' age, educational status, income, health knowledge and membership of National Health Insurance Scheme were significantly (p < 0.05) associated with the use of healthcare facilities. Younger residents and those without National Health Insurance Scheme membership, formal education, no knowledge of common illnesses and regular income were significantly less likely to use a healthcare facility. For most residents, neither distance (73.2%) nor transportation to health facilities was a problem (74.1%). CONCLUSION: Conditions of profound environmental hazards, overcrowding, poor-quality housing and lack of health care in Sodom and Gomorrah pose grave threats to the health of the inhabitants. Multisectoral interventions and resource mobilisation championed by the Ministry of Local Government and Rural Development are needed to alter the trend. PMID- 27247152 TI - Perceptions of doctors and nurses at a Ugandan hospital regarding the introduction and use of the South African Triage Scale. AB - BACKGROUND: International Hospital Kampala (IHK) experienced a challenge with how to standardise the triaging and sorting of patients. There was no triage tool to help to prioritise which patients to attend to first, with very sick patient often being missed. AIM AND SETTING: To explore whether the introduction of the South African Triage Scale (SATS) was seen as valuable and sustainable by the IHK's outpatient department and emergency unit (OPD and EU) staff. METHODS: The study used qualitative methods to introduce SATS in the OPD and EU at IHK and to obtain the perceptions of doctors and nurses who had used it for 3-6 months on its applicability and sustainability. Specific questions about challenges faced prior to its introduction, strengths and weaknesses of the triage tool, the impact it had on staff practices, and their recommendations on the continued use of the tool were asked. In-depth interviews were conducted with 4 doctors and 12 nurses. RESULTS: SATS was found to be necessary, applicable and recommended for use in the IHK setting. It improved the sorting of patients, as well as nurse patient and nurse-doctor communication.The IHK OPD & EU staff attained new skills, with nurses becoming more involved in-patient care. It is possibly also useful in telephone triaging and planning of hospital staffing. CONCLUSION: Adequate nurse staffing, a computer application for automated coding of patients, and regular training would encourage consistent use and sustainability of SATS. Setting up a hospital committee to review signs and symptoms would increase acceptability and sustainability. SATS is valuable in the IHK setting because it improved overall efficiency of triaging and care, with significantly more strengths than weaknesses. PMID- 27247153 TI - Chart review of acute myocardial infarction at a district hospital in KwaZulu Natal, South Africa. AB - BACKGROUND: Incidence and prevalence of non-communicable diseases, including ischaemic heart disease (IHD) and associated acute myocardial infarction (AMI), are increasing in South Africa. Local studies are needed as contextual factors, such as healthcare systems, gender and ethnicity, may affect presentation and management. In AMI, reviews on time between onset of chest pain and initiation of urgent treatment are useful, as delays in initiation of thrombolytic treatment significantly increase morbidity and mortality. AIM: The aim of the study was to determine the profile and management of patients admitted with ischaemic chest pain. SETTING: The study was carried out in a busy urban-based district hospital in KwaZulu-Natal, South Africa. The population served is poor, and patients are mainly Indian with associated high risk of IHD. METHODS: A chart review of all patients seen at the hospital with acute ischaemic chest pain between 01 March and 31 August 2014 was undertaken. RESULTS: More male than female patients were admitted, with a wide variation in age. Most eligible patients received required thrombolytic intervention within an acceptable time period after arrival at hospital. CONCLUSION: Chest pain and AMI were a relatively common presentation at the study site, and urgent diagnosis and initiation of fibrinolytic therapy are essential. The encouraging door-toneedle time may have been influenced by the availability of specialist family physicians, trained as 'expert generalists' to provide appropriate care in a variety of settings and consultant support to junior staff. The role of the family physician and primary healthcare doctor in primary prevention are re-emphasised through the study findings. PMID- 27247154 TI - Assessment of oral health promotion services offered as part of maternal and child health services in the Tshwane Health District, Pretoria, South Africa. AB - OBJECTIVES: The study aimed to assess the oral health promotion services provided as part of the maternal and child health (MCH) services in the Tshwane Health District, Pretoria, South Africa. METHODS: The research design was a descriptive cross-sectional study using a modified standard questionnaire. The population was drawn from the parents/caregivers (PCGs) and the MCH nurses at seven clinics during June 2012 and June 2013 in Pretoria. RESULTS: The nurses' response rate was 83%; average age of 37 years. The majority of the nurses (65%) were females; 60% were professional nurses. Most (63%) of the nurses reported that they provided oral health education (OHE) services. A shortage of dental education materials (43%), staff time (48%), and staff training (52%) were large constraints to nurses providing OHE. The majority of PCGs (n = 382; mean age 31.5 years) had a low education level (76%). About 55% of PCGs received information on children's oral health from the television and 35% at the MCH clinics. PCGs beliefs were worrying as about 38% believed primary dentition is not important and need not be saved. CONCLUSION: There is evidence of minimal integration of OHE at MCH sites. Parents' beliefs are still worrying as a significant number do not regard the primary dentition as important. The MCH site remains an important easily accessible area for integration of oral health services with general health in complementing efforts in prevention of early childhood caries. PMID- 27247155 TI - Knowledge of midwives about hypertensive disorders during pregnancy in primary healthcare. AB - BACKGROUND: Many factors or medical conditions may influence the outcome of pregnancy,which in turn, may increase infant and maternal morbidity and mortality. One such condition is an increase in blood pressure (BP). SETTING: The study was conducted in maternity obstetrical units (MOUs) in primary healthcare clinics (PHCs) in the Eastern Cape, South Africa. OBJECTIVES: To determine the knowledge about hypertensive disorders during pregnancy (HDPs) of registered midwives working in MOUs in PHCs. METHODS: A quantitative descriptive correlation research design was applied. A simple random sample of 43 (44%) rural and urban clinics was selected, and all registered midwives (n = 101) working in these clinics completed a self-administered questionnaire. Data were collected over a period of 1 month. The reliability and validity of the methodology were supported by experts and a pilot study. Descriptive statistics including various statistical tests to determine any associations between variables using a 95% confidence interval were applied. RESULTS: A gap in the knowledge of midwives about HDPs was identified. Only 56.4% of the participants correctly answered the questions on the clinical manifestations of severe pre-eclampsia and 68.3% on the factors affecting BP, whereas 27.7% had no understanding about pre-eclampsia. Significant statistical differences were identified in the knowledge of staff in clinics where doctors visit regularly versus those in clinics where there are no visits (p = 0.04), and between experience of midwives and management of HDPs (p = 0.02). CONCLUSION: The knowledge of midwives is deficient regarding HDPs. Continuous professional development is critical in midwifery both in theory and in clinical practice. PMID- 27247156 TI - Modifiable antenatal risk factors for stillbirth amongst pregnant women in the Omusati region, Namibia. AB - BACKGROUND: Reduction of stillbirth rates is important because of the social and economic implications. Access to quality antenatal care is important in preventing the risk factors associated with stillbirth. AIM: To determine the prevalence of modifiable antenatal risk factors associated with stillbirth so as to determine possible gaps in their prevention. SETTING: The study was conducted at four district hospitals in the Omusati Region of Namibia. METHODS: A descriptive study using recorded antenatal data was used. Data were collected from the records of 82 women at the time that they had a stillbirth, during the period October 2013 to December 2014. Data were collected for modifiable risk factors related to maternal characteristics, antenatal care received, medical conditions and obstetric complications. RESULTS: The average prevalence of each category of risk factors was as follows: quality of antenatal care (19.8%), maternal characteristics (11.4%), medical conditions (8.9%) and obstetric complications (6.5%). The most prevalent individual risk factors included: no folate supplementation (30.5%), HIV infection (25.6%), late booking (16.7%), intrauterine foetal growth retardation (13.4%) and alcohol use (12.5%). CONCLUSION: Amongst the 14 modifiable risk factor included in the present study, 11 (78.6%) were prevalent amongst women who had a stillbirth. Risk factors associated with quality of antenatal care were the most prevalent. Whilst further investigation is needed to determine the causes behind this prevalence, health education on the availability and benefits of antenatal care, pregnancy timing and spacing may contribute to reducing the prevalence of these risk factors. PMID- 27247157 TI - Western Cape Primary Care Assessment Tool (PCAT) study: Measuring primary care organisation and performance in the Western Cape Province, South Africa (2013). AB - BACKGROUND: Major health sector reform and the need for baseline measures of performance to determine impact. AIM: Baseline audit of primary healthcare (PHC) performance. SETTING: Cape Town and Cape Winelands (rural) PHC facilities (PCFs) in Western Cape Province, South Africa. METHOD: The South African cross culturally validated ZA PCAT to audit PHC performance on 11 subdomains associated with improved health and reduced costs. Adult PCF users systematically sampled. All full-time doctors and nurse practitioners in PCFs sampled and all PCF managers in sub-districts sampled invited into the study. RESULTS: Data from 1432 users, 100 clinicians and 64 managers from 13 PCFs in 10 sub-districts analysed (figures show stakeholder percentages scoring subdomain performance 'acceptable to good'). 11.5% users scored access 'acceptable to good'; community orientation and comprehensive services provided 20.8% and 39.9%, respectively. Total PHC score for users 50.2%; for managers and practitioners 82.8% and 88.0%, respectively. Among practitioners access was lowest (33.3%); PHC team (98.0%) and comprehensive services available (100.0%) highest. Among managers, access (13.5%) and family centredness (45.6%) are lowest; PHC team (85.9%) and comprehensive services available (90.6%) highest. Managers scored access, family centredness and cultural competence significantly lower than practitioners. Users scored comprehensive services available, comprehensive services provided and community orientation significantly lower than practitioners and managers. CONCLUSION: Gaps between users' experience and providers' assessments of PHC performance are identified. Features that need strengthening and alignment with best practice, provincial and national, and health policies are highlighted with implications for practitioner and manager training, health policy, and research. PMID- 27247158 TI - Profile and anticoagulation outcomes of patients on warfarin therapy in an urban hospital in Cape Town, South Africa. AB - BACKGROUND: Warfarin is the most frequently used oral anticoagulant worldwide and it is the oral anticoagulant of choice in South Africa for reducing thrombosis related morbidity and mortality. However, the safety and efficacy of warfarin therapy depends mainly on careful monitoring and maintenance of the international normalised ratio (INR) within an optimal therapeutic range. AIM: The aim of this study was to describe the profile and the anticoagulation outcomes of patients on warfarin therapy in a major warfarin clinic in the Western Cape Province of South Africa. SETTING: Victoria Hospital - a district hospital in Cape Town. METHODS: A cross sectional review of clinical records of patients on warfarin therapy who attended the INR clinic from 01 January 2014 to 30 June 2014 was done. Data analysis was done with STATA to generate appropriate descriptive data. RESULTS: Our study showed that atrial fibrillation (AF) was the commonest indication for warfarin use in this study and hypertension was the commonest comorbidity among these patients. Only 48.5% achieved target therapeutic range; 51.5% were out-of range. There was a significant association between alcohol consumption and poor anticoagulation outcomes (p-value < 0.022). Anticoagulation outcomes were better among the older age groups, male patients and in those with AF. The prevalence of thrombotic events while on warfarin treatment was 2.2%, while prevalence of haemorrhagic events was 14%. Most of the patients with bleeding events were on concurrent use of warfarin and other medications with potential drug interactions. CONCLUSION: In our study, patients who achieved target therapeutic control were less than the acceptable 60%. PMID- 27247159 TI - Family medicine in Denmark: Are there lessons for Botswana and Africa? AB - Family medicine is a new specialty in Botswana and many African countries and its definitionand scope are still evolving. In this region, healthcare is constrained by resource limitation andinefficiencies in resource utilisation. Experiences in countries with good health indicators canhelp inform discussions on the future of family medicine in Africa. Observations made duringa visit to family physicians (FPs) in Denmark showed that the training of FPs, the practice offamily medicine and the role of support staff in a family practice were often different andsometimes unimaginable by African standards. Danish family practices were friendly andenmeshed in an egalitarian and efficient health system, which is supported by an effectiveinformation technology network. There was a lot of task shifting and nurses and clerical staffattended to simple or uncomplicated aspects of patient care whilst FPs attended to morecomplicated patient problems. Higher taxation and higher health expenditure seemed toundergird the effective health system. An egalitarian relationship amongst patients andhealthcare workers (HCW) may help improve patient care in Botswana. Task shifting shouldbe formalised, and all sectors of primary healthcare should have fast and effective informationtechnology systems. HCW training and roles should be revised. Higher health expenditure isnecessary to achieve good health indicators. PMID- 27247160 TI - Pediatric inflammatory bowel disease: specificity of very early onset. AB - INTRODUCTION: The incidence of inflammatory bowel disease (IBD) has increased over the last 50 years. It is now recognized that several genetic defects can express an IBD-like phenotype at very early onset (<6 years). AREAS COVERED: The aim of this review was to update knowledge concerning the specificity of IBD at onset <6 years, which can include conventional/standard IBD as well as monogenic IBD-like diseases. Expert commentary: We found that females are less prone than males to develop monogenic disorders, which have X-linked heritability in several cases. Furthermore, the Crohn's Diseases (CD) subtype seems to be suggestive of monogenic disorders while Unclassified IBD (IBDU) subtype is predominantly found in conventional/standard IBD at onset <6 years. Isolated colonic location is prevalent in both the subsets of IBD at onset <6 years if compared to IBD at later onset. Monogenic disorders require more aggressive medical and surgical treatments and can be complicated by the occurrence of lymphomas. PMID- 27247161 TI - Estimating met demand for alcohol and other drug treatment in Australia. AB - AIMS: To estimate the amount of alcohol and other drug (AOD) treatment provided and number of treatment recipients in Australia in 2011-12, and document an approach for future estimates internationally. DESIGN: We combined multiple data sources to estimate the amount of treatment received: administrative data on AOD treatment funded by the Australian and state/territory governments, survey data from treatment providers and programme evaluation data. The various data sources were reconciled, using published studies of treatment activity, to estimate the unique number of treatment recipients. SETTING: Treatment funded by the Australian and state/territory governments provided by general practitioners, specialist treatment services, hospitals, community- and hospital-based ambulatory mental health-care services and allied health professionals. PARTICIPANTS: People receiving AOD treatment in the above settings. MEASURES: Annual quantum of AOD treatment (encounters, episodes, consultations) and the number of unique treatment recipients. FINDINGS: In 2011/12 we estimated 1.6 million episodes of care, consultations or encounters, noting that measures of treatment are not comparable. Based on a range of conversion rates to account for people accessing treatment multiple times in that year, we estimated that the number of Australians in receipt of AOD treatment ranged from 202 168 to 232 419. This is an underestimate and subject to error. Using the upper range of the estimate, on average each treatment recipient made 4.7 visits to a general practitioner (GP) or allied health professional providing mental health services for AOD treatment, and had 1.2 treatment episodes with a specialist AOD treatment provider and/or hospital. CONCLUSIONS: Between 202 168 and 232 419 Australians are estimated to have received alcohol and other drug treatment in 2011-12. The comprehensive approach used to calculate this estimate, combining multiple independent data sets across treatment settings and programmes, can be replicated in other countries. PMID- 27247162 TI - Development of a highly sensitive and specific monoclonal antibody based enzyme linked immunosorbent assay for the detection of a new beta-agonist, phenylethanolamine A, in food samples. AB - BACKGROUND: All beta-agonists are banned as feed additives for growth promotion in animals due to toxic effects on humans after consuming the beta-agonist contaminated meats. Phenylethanolamine A (PA) is a newly emerged beta-agonist. Thus there is a need to develop highly sensitive and specific analytical methods for the detection of PA in food samples. In this study, the monoclonal antibody (mAb) against PA was produced by hybridoma technology and used for the development of enzyme-linked immunosorbent assay (ELISA). RESULTS: The IC50 values and limits of detection (LODs) of the ELISA using homogeneous combination of coating antigen/antibody for PA were 0.16 ng mL-1 and 0.011 ng mL-1 , respectively. The cross-reactive (CR) values of the assay with 14 structurally related beta-agonists were lower than 0.59%. Swine liver and meat samples were spiked with PA at different content and analysed by ELISA. Acceptable recovery rates of 91.40-105.51% and intra-assay coefficients of variation of 1.56-9.92% (n = 3) were obtained. The ELISA for seven spiked samples was confirmed by LC-MS/MS with a high correlation coefficient of 0.9881. CONCLUSION: The proposed mAb-based ELISA was highly sensitive and specific for PA and could be used as a quantitative/screening method for PA analysis in food samples. (c) 2016 Society of Chemical Industry. PMID- 27247163 TI - The role of mental illness on cigarette dependence and successful quitting in a nationally representative, household-based sample of U.S. adults. AB - PURPOSE: To begin to explore whether the association between mental illness (MI), cigarette dependence, and unsuccessful quit attempts differs across particular demographic subgroups. METHODS: This study examines data from adults aged 18 years or older participating in the 2008-2012 National Surveys on Drug Use and Health. Analyses explored the moderating effects of age, gender, and race and/or ethnicity on associations between three levels of MI: (serious mental illness [SMI], any mental illness but no SMI, and no MI) and two smoking-related outcomes (cigarette dependence among current smokers and successful quitting among ever daily smokers). RESULTS: After confirming that adults with MI were more likely to be dependent on cigarettes and less likely to successfully quit smoking, particularly among those with SMI, adjusted analyses indicated that age (but not gender or race/ethnicity) moderated the associations between MI and cigarette dependence and between MI. CONCLUSIONS: The magnitude of the association between MI and cigarette dependence and between MI and successful quitting appears to be stronger among older adults than among younger adults. Identifying subgroups at particular high risk of cigarette dependence is paramount to targeting smoking prevention, cessation, and treatment services appropriately. PMID- 27247164 TI - L-type voltage-operated calcium channels contribute to astrocyte activation In vitro. AB - We have found a significant upregulation of L-type voltage-operated Ca(++) channels (VOCCs) in reactive astrocytes. To test if VOCCs are centrally involved in triggering astrocyte reactivity, we used in vitro models of astrocyte activation in combination with pharmacological inhibitors, siRNAs and the Cre/lox system to reduce the activity of L-type VOCCs in primary cortical astrocytes. The endotoxin lipopolysaccharide (LPS) as well as high extracellular K(+) , glutamate, and ATP promote astrogliosis in vitro. L-type VOCC inhibitors drastically reduce the number of reactive cells, astrocyte hypertrophy, and cell proliferation after these treatments. Astrocytes transfected with siRNAs for the Cav1.2 subunit that conducts L-type Ca(++) currents as well as Cav1.2 knockout astrocytes showed reduce Ca(++) influx by ~80% after plasma membrane depolarization. Importantly, Cav1.2 knock-down/out prevents astrocyte activation and proliferation induced by LPS. Similar results were found using the scratch wound assay. After injuring the astrocyte monolayer, cells extend processes toward the cell-free scratch region and subsequently migrate and populate the scratch. We found a significant increase in the activity of L-type VOCCs in reactive astrocytes located in the growing line in comparison to quiescent astrocytes situated away from the scratch. Moreover, the migration of astrocytes from the scratching line as well as the number of proliferating astrocytes was reduced in Cav1.2 knock-down/out cultures. In summary, our results suggest that Cav1.2 L-type VOCCs play a fundamental role in the induction and/or proliferation of reactive astrocytes, and indicate that the inhibition of these Ca(++) channels may be an effective way to prevent astrocyte activation. GLIA 2016. GLIA 2016;64:1396-1415. PMID- 27247165 TI - Predicting postoperative vomiting among orthopedic patients receiving patient controlled epidural analgesia using SVM and LR. AB - Patient-controlled epidural analgesia (PCEA) has been applied to reduce postoperative pain in orthopedic surgical patients. Unfortunately, PCEA is occasionally accompanied by nausea and vomiting. The logistic regression (LR) model is widely used to predict vomiting, and recently support vector machines (SVM), a supervised machine learning method, has been used for classification and prediction. Unlike our previous work which compared Artificial Neural Networks (ANNs) with LR, this study uses a SVM-based predictive model to identify patients with high risk of vomiting during PCEA and comparing results with those derived from the LR-based model. From January to March 2007, data from 195 patients undergoing PCEA following orthopedic surgery were applied to develop two predictive models. 75% of the data were randomly selected for training, while the remainder was used for testing to validate predictive performance. The area under curve (AUC) was measured using the Receiver Operating Characteristic curve (ROC). The area under ROC curves of LR and SVM models were 0.734 and 0.929, respectively. A computer-based predictive model can be used to identify those who are at high risk for vomiting after PCEA, allowing for patient-specific therapeutic intervention or the use of alternative analgesic methods. PMID- 27247166 TI - Femoral arterial cannulation performed by residents: a comparison between ultrasound-guided and palpation technique in infants and children undergoing cardiac surgery. AB - BACKGROUND: Percutaneous cannulation of the femoral artery in the pediatric age group can be technically challenging, especially when performed by residents in training. OBJECTIVE: We examined whether the use of real-time ultrasound guidance is superior to a palpation landmark technique for femoral artery catheterization in children undergoing heart surgery. METHODS: Patients were prospectively randomized into two groups. In the palpation group, the femoral artery was cannulated using the traditional landmark method of palpation of arterial pulse. In the ultrasound group, cannulation was guided by real-time scanning with an ultrasound probe. Ten minutes were set as time limit for the resident's trials during which the time taken for attempted cannulation (primary outcome), number of attempts, number of successful cannulations on first attempt, and success rate were compared between the two groups. Adverse events were monitored on postoperative days 1 and 3. RESULTS: A total of 106 patients were included in the study. The time taken for attempted femoral artery cannulation was shorter (301 +/- 234 vs 420 +/- 248 s; difference in mean: 119; 95% confidence interval (CI) of difference: 26-212; P = 0.012) and the number of attempts was lower [1 (1-10) vs 2 (1-5); difference in median: 1, 95% CI of difference: 0.28-1.72; P = 0.003] in the ultrasound group compared with the palpation group. The number of successful cannulations on first attempt was higher in the ultrasound group compared with palpation group [24/53 (45%) vs 13/53 (25%); odds ratio (OR): 2.54, 95% CI: 1.11-5.82; P = 0.025]. The number of patients who had successful cannulation was 31 of 55 (58%) in the palpation group and 40 of 53 (75%) in the ultrasound group (OR: 2.18, 95% CI: 0.95-5.01; P = 0.06). None of the patients had adverse events at days 1 and 3. CONCLUSIONS: Ultrasound-guided femoral arterial cannulation in children when performed by anesthesia residents is superior to the palpation technique based on the reduction of the time taken for attempted cannulation and the number of attempts, and improvement in first attempt success. PMID- 27247167 TI - Impact of quadriceps strengthening on response to fatiguing exercise following ACL reconstruction. AB - OBJECTIVES: Patients commonly experience altered response to fatiguing exercise after ACL reconstruction (ACLR). The objective of this study was to assess the impact of quadriceps strengthening on response to exercise after ACLR. DESIGN: Clinical trial. METHODS: Ten participants with a history of primary, unilateral ACLR (sex=9F/1M, age=21.0+/-2.8 years, BMI=23.7+/-2.7kg/m2) and 10 healthy participants (sex=9F/1M, age=22.2+/-3.2 years, BMI=23.8+/-3.9kg/m2) participated. ACLR participants completed a 2-week quadriceps strengthening intervention including 14 progressive strengthening exercise sessions. Normalized knee extension maximum voluntary isometric contraction (MVIC) torque (Nm/kg) and quadriceps central activation ratio (%, CAR) were measured before and after a 30 minute fatiguing exercise protocol. ACLR participants completed testing before and after the 2-week intervention while control participants completed a single testing session. RESULTS: The intervention significantly improved normalized knee extension MVIC torque (pre-intervention=1.85+/-0.67Nm/kg, post intervention=2.09+/-0.81Nm/kg, p=0.04) and quadriceps CAR in the ACLR involved limb (pre-intervention=86.51+/-5.03%, post-intervention=92.94+/-5.99%, p=0.02). Quadriceps CAR (pre-intervention=1.13+/-9.04%, post-intervention=-3.97+/-4.59%, p=0.16) and normalized knee extension MVIC torque (pre-intervention=0.26+/ 20.90%, post-intervention=-8.02+/-12.82%, p=0.30) response to exercise did not significantly change from pre-intervention to post-intervention conditions. CONCLUSIONS: Two weeks of quadriceps strengthening reduced this between group difference in the involved limb which may indicate restoration of more optimal quadriceps neuromuscular function and increased demand on the quadriceps during physical activity. PMID- 27247168 TI - Standardization of natural mycolic acid antigen composition and production for use in biomarker antibody detection to diagnose active tuberculosis. AB - Mycobacterium tuberculosis, the causative agent of tuberculosis, is characterized by the abundance of species specific, antigenic cell wall lipids called mycolic acids. These wax-like molecules all share an identical, amphiphilic mycolic motif, but have different functional groups in a long hydrophobic hydrocarbon mero-chain that divide them into three main classes: alpha-, keto- and methoxy mycolic acids. Whereas alpha-mycolic acids constitutively maintain an abundance of around 50%, the ratio of methoxy- to keto-mycolic acid types may vary depending on, among other things, the growth stage of M. tuberculosis. In human patients, antibodies to mycolic acids have shown potential as diagnostic serum biomarkers for active TB. Variations in mycolic acid composition affect the antigenic properties and can potentially compromise the precision of detection of anti-mycolic acids antibodies in patient sera to natural mixtures. We demonstrate this here with combinations of synthetic mycolic acid antigens, tested against TB patient and control sera. Combinations of methoxy- and alpha-mycolic acids are more antigenic than combinations of keto- and alpha-mycolic acids, showing the former to give a more sensitive test for TB biomarker antibodies. Natural mixtures of mycolic acids isolated from mature cultures of M. tuberculosis H37Rv give the same sensitivity as that with synthetic methoxy- and alpha-mycolic acids in combination, in a surface plasmon resonance inhibition biosensor test. To ensure that the antigenic activity of isolates of natural mycolic acids is reproducible, we cultured M. tuberculosis H37Rv on Middlebrook 7H10 solid agar plates to stationary growth phase in a standardized, optimal way. The proportions of mycolic acid classes in various batches of the isolates prepared from these cultures were compared to a commercially available natural mycolic acid isolate. LC-MS/MS and NMR data for quantitation of mycolic acids class compositions show that the variation in batches is small, suggesting that the quality of the results for anti-mycolic acid antibody detection in the TB patients should not be affected by different batches of natural mycolic acid antigens if prepared in a standard way. PMID- 27247169 TI - Predictors of Employment Burnout Among VHA Peer Support Specialists. AB - OBJECTIVE: This study evaluated three domains of job burnout (emotional exhaustion, depersonalization, and personal accomplishment) and factors associated with burnout in a national sample of peer specialists (PSs) employed at 138 Veterans Health Administration (VHA) health care systems in 49 states. METHODS: Data were drawn from an observational study in which participants (N=152) completed online, self-report surveys about their mental health recovery, quality of life, and employment experiences at baseline, six months, and 12 months. Levels of burnout were analyzed at each time point, and regression analyses that controlled for baseline levels identified potential predictors of burnout (demographic, clinical, and employment characteristics) at six and 12 months. RESULTS: Compared with previously published burnout levels of other mental health workers in the VHA, PSs reported similar levels of emotional exhaustion, depersonalization, and personal accomplishment. At baseline, increased burnout was correlated with white race, fewer hours providing direct services, greater psychiatric symptoms, and lower self-efficacy. However, analyses did not reveal strong predictors of burnout scores at six or 12 months. CONCLUSIONS: In the first study to prospectively examine job burnout among PSs employed by the VHA, results illustrate the nuanced experience of burnout over a 12-month period and suggest the need for replication and further research on employment experiences of this emerging workforce. PMID- 27247170 TI - Coping With Suicidal Thoughts: A Survey of Personal Experience. AB - OBJECTIVE: The objective of the study was to describe use of services and self care strategies by people experiencing suicidal thoughts. METHODS: Constituents of the Depression and Bipolar Support Alliance (N=611) completed an anonymous online survey regarding experience of suicidal ideation and use of a range of clinical services, community supports, and self-care strategies. RESULTS: Mental health providers were the most frequently used and the most favorably rated source of support. Peer supports were less frequently used but also favorably rated. Emergency rooms and telephone crisis clinics were used less frequently and were rated less favorably. The most frequently used self-care strategies included engaging in distracting activities or social activities, using positive affirmations, exercising, and engaging in personal spiritual practices. CONCLUSIONS: Peer support may be an underutilized resource for coping with suicidal thoughts. Unfavorable ratings for emergency rooms and crisis clinics may indicate a need to develop more collaborative models of emergency care. Frequent use of spiritual practices suggests greater attention to spirituality may be a useful strategy in suicide prevention. PMID- 27247171 TI - Health Technology Intervention After Hospitalization for Schizophrenia: Service Utilization and User Satisfaction. AB - OBJECTIVE: The authors examined patients' acceptance of the Health Technology Program (HTP), an integrative approach to relapse prevention after hospitalization of adults with schizophrenia or related disorders. The program combines use of digital tools with support from a mental health technology coach (MHTC). METHODS: Patients with schizophrenia spectrum disorders received six months of treatment that began within 60 days of a psychiatric hospitalization and included the development of a personalized relapse prevention plan, three digital tools, and contacts with MHTCs. RESULTS: A total of 200 patients (mean+/ SD age=34.6+/-10.6 years) had 28.2+/-2.0 contacts with the MHTC that lasted 38.3+/-14.2 minutes. The most discussed topic was case management (52%), and digital tools were discussed in 45% of meetings. Altogether, 87% of patients used at least one of the digital tools, with 96% of patients rating the HTP as satisfying to at least some extent. CONCLUSIONS: These data suggest very high acceptance of the HTP, a program that integrates available human support with digital tools. PMID- 27247172 TI - Policy Implications of the Mental Health Treatment Study. AB - The Social Security Administration's Mental Health Treatment Study (MHTS) produced positive mental health, employment, and quality of life outcomes for people on Social Security Disability Insurance (SSDI). The investigators discuss major policy implications. First, because integrated, evidence-based mental health and vocational services produced clinical and societal benefits, the authors recommend further service implementation for this population. Second, because provision of these services did not reduce SSDI rolls, the authors recommend future research on prevention (helping people avoid needing SSDI) rather than rehabilitation (helping beneficiaries leave SSDI). Third, because integrating mental health, vocational, and general medical services was extremely difficult, the authors recommend a multifaceted approach that includes streamlined funding and infrastructure for training and service integration. Fourth, because insurance coverage for people with disabilities during the MHTS (pre-Affordable Care Act) was chaotic, the authors recommend that financing strategies emphasize functional-not just traditional clinical-outcomes. PMID- 27247173 TI - Hospitalization Risk Before and After Employment Among Adults With Schizophrenia, Bipolar Disorder, or Major Depression. AB - OBJECTIVE: The influence of employment on subsequent psychiatric hospitalization for people with serious mental illness is unclear. This study examined whether unemployed people with serious mental illness were more or less likely to experience psychiatric hospitalization after gaining employment. METHODS: A secondary analysis was conducted of data from the Mental Health Treatment Study. Two years of prospective employment and psychiatric hospital outcomes were examined for 2,055 adults with schizophrenia, bipolar disorder, or major depression. The analyses examined associations between employment and psychiatric hospitalization via multilevel regression by using time-lagged modeling. RESULTS: Employment was associated with a lower subsequent three-month risk of psychiatric hospitalization (odds ratio=.65, 95% confidence interval=.50-.84) after the analysis adjusted for baseline characteristics, including previous psychiatric hospitalizations and self-reported physical health. CONCLUSIONS: Unemployed outpatients with serious mental illness were less likely to experience psychiatric hospitalization after gaining employment. PMID- 27247174 TI - Correlates of Emergency Department Use by Individuals With Bipolar Disorder Enrolled in a Collaborative Care Implementation Study. AB - OBJECTIVE: The study assessed correlates of emergency department use among participants in a collaborative care program for bipolar disorder. METHODS: Community-based clinics from two states implemented Life Goals-Collaborative Care (LG-CC), an evidence-based model that includes self-management sessions and care management contacts. Logistic regression determined participant factors associated with emergency department use between six and 12 months after LG-CC implementation. RESULTS: Of 219 participants with baseline and 12-month data, 24% reported at least one emergency department visit. Participants with a recent homelessness history (odds ratio [OR]=3.76, p=.01) or five or more care management contacts (OR=2.62, p=.05) had a higher probability of visiting an emergency department, after the analyses were adjusted for demographic and clinical factors, including physical health score and hospitalization history. CONCLUSIONS: Participants in a collaborative care program who had a history of homelessness were more likely to use the emergency department, suggesting a greater need for more intensive care coordination. PMID- 27247175 TI - Development and Validation of a Computerized-Adaptive Test for PTSD (P-CAT). AB - OBJECTIVE: The primary purpose was to develop, field test, and validate a computerized-adaptive test (CAT) for posttraumatic stress disorder (PTSD) to enhance PTSD assessment and decrease the burden of symptom monitoring. METHODS: Data sources included self-report and interviewer-administered diagnostic interviews. The sample included 1,288 veterans. In phase 1, 89 items from a previously developed PTSD item pool were administered to a national sample of 1,085 veterans. A multidimensional graded-response item response theory model was used to calibrate items for incorporation into a CAT for PTSD (P-CAT). In phase 2, in a separate sample of 203 veterans, the P-CAT was validated against three other self-report measures (PTSD Checklist, Civilian Version; Mississippi Scale for Combat-Related PTSD; and Primary Care PTSD Screen) and the PTSD module of the Structured Clinical Interview for DSM-IV. RESULTS: A bifactor model with one general PTSD factor and four subfactors consistent with DSM-5 (reexperiencing, avoidance, negative mood-cognitions, and arousal), yielded good fit. The P-CAT discriminated veterans with PTSD from those with other mental health conditions and those with no mental health conditions (Cohen's d effect sizes >.90). The P CAT also discriminated those with and without a PTSD diagnosis and those who screened positive versus negative for PTSD. Concurrent validity was supported by high correlations (r=.85-.89) with the validation measures. CONCLUSIONS: The P CAT appears to be a promising tool for efficient and accurate assessment of PTSD symptomatology. Further testing is needed to evaluate its responsiveness to change. With increasing availability of computers and other technologies, CAT may be a viable and efficient assessment method. PMID- 27247176 TI - Associations of Housing First Configuration and Crime and Social Connectedness Among Persons With Chronic Homelessness Histories. AB - OBJECTIVE: This study compared changes in criminal justice contact, quality of life, and social connectedness over a 12-month follow-up period between participants in two Housing First configurations (scattered site [SS] and congregate site [CS]). METHODS: A longitudinal, quantitative design was utilized for this ecological study. Changes in individual outcomes over time were compared for SS and CS participants who completed both baseline and 12-month follow-up surveys (N=63). RESULTS: The number of contacts with various types of criminal justice system channels differed significantly between SS and CS participants, decreasing significantly among SS participants and increasing significantly among CS participants. The two groups did not differ on quality-of-life outcomes or social-connectedness measures, with the exception of case management engagement, whereby a greater proportion of SS participants disengaged from this service over time compared with CS participants. At follow-up, significant within-group changes over time emerged, with increased boredom reported among SS participants, whereas CS participants reported improvements in social relationships, with fewer reporting losing their temper. CONCLUSIONS: The findings supported the notion that the Housing First approach has the potential to significantly improve the lives of persons who have experienced chronic homelessness, a traditionally marginalized and vulnerable group. Over time, this may result in a reduction in the use of acute services, thereby reducing societal costs. The challenge remains to identify the suitability of particular configurations of housing and support and how service delivery can optimize individual outcomes so positive outcomes are maintained in the longer term. PMID- 27247178 TI - The Unique Needs of Homeless Youths With Mental Illness: Baseline Findings From a Housing First Trial. AB - OBJECTIVE: Although youth homelessness presents a significant public health problem, the needs of homeless youths with mental illness, as distinct from adults, are not well understood. This study examined the unique demographic, clinical, and service use characteristics of homeless youths. METHODS: At Home/Chez Soi was a large randomized controlled trial of the Housing First model in five cities in Canada. Of 2,255 participants, 7% (N=164) were youths ages 18 to 24. Youths were compared with older participants on baseline demographic, clinical, and service use characteristics. RESULTS: More youths than adults had not finished high school (76% versus 54%), had a drug use disorder (66% versus 52%), and had been assaulted in the past six months (44% versus 36%) (all p<.05). Fewer than half the youths (49%) had a regular medical doctor, 50% reported unmet need for health care, and 61% visited an emergency department in the past six months. CONCLUSIONS: This sample of homeless youths with mental illness had low education, high rates of substance use disorders and victimization, and problems accessing services. These findings suggest that youths have trajectories to homelessness and service needs that are distinct from adults and may guide future planning for this vulnerable population. PMID- 27247177 TI - Cost-Effectiveness of Long-Acting Injectable Paliperidone Palmitate Versus Haloperidol Decanoate in Maintenance Treatment of Schizophrenia. AB - OBJECTIVE: This study assessed the relative cost-effectiveness of haloperidol decanoate (HD), a first-generation long-acting injectable (LAI) antipsychotic, and paliperidone palmitate (PP), a second-generation LAI antipsychotic. METHODS: A double-blind, randomized 18-month clinical trial conducted at 22 clinical research sites in the United States compared the cost-effectiveness of HD and PP among 311 adults with schizophrenia or schizoaffective disorder who had been clinically assessed as likely to benefit from an LAI antipsychotic. Patients were randomly assigned to monthly intramuscular injections of HD (25-200 mg) or PP (39 234 mg) for up to 24 months. Quality-adjusted life years (QALYs) were measured by a schizophrenia-specific algorithm based on the Positive and Negative Syndrome Scale and side-effect assessments; total health care costs were assessed from the perspective of the health system. RESULTS: Mixed-model analysis showed that PP was associated with .0297 greater QALYs over 18 months (p=.03) and with $2,100 more in average costs per quarter for inpatient and outpatient services and medication compared with HD (p<.001). Bootstrap analysis with 5,000 replications showed an incremental cost-effectiveness ratio for PP of $508,241 per QALY (95% confidence interval=$122,390-$1,582,711). Net health benefits analysis showed a .98 probability of greater cost-effectiveness for HD compared with PP at an estimated value of $150,000 per QALY and a .50 probability of greater cost effectiveness at $500,000 per QALY. CONCLUSIONS: HD was more cost-effective than PP, suggesting that PP's slightly greater benefits did not justify its markedly higher costs, which are likely to fall once the medication's patent expires. PMID- 27247179 TI - Prescriptions Filled Following an Opioid-Related Hospitalization. AB - OBJECTIVE: The purpose of this study was to identify patterns of postdischarge prescription fills following an opioid-related hospitalization. METHODS: Using the 2010-2014 MarketScan Commercial Claims and Encounters database, this analysis identified the percentage of patients (N=36,719) with an opioid-related inpatient admission who received substance use disorder treatment medications within 30 days of being discharged. RESULTS: Thirty-five percent of the sample did not have any prescription fills in the 30-day postdischarge period. Less than a quarter (16.7%) of patients received any FDA-approved opioid dependence medication in the 30 days following discharge. Forty percent of patients in the sample received antidepressants, 15.6% received antipsychotics, 13.9% filled a prescription for a benzodiazepine, and 22.4% filled a prescription for an opioid pain medication. CONCLUSIONS: More effort is needed to ensure that patients hospitalized for opioid misuse are receiving recommended services. PMID- 27247181 TI - Association between aortic valve calcification measured on non-contrast computed tomography and aortic valve stenosis in the general population. AB - BACKGROUND: Aortic valve calcification (AVC) measured on non-contrast computed tomography (CT) has shown correlation to severity of aortic valve stenosis (AS) and mortality in patients with known AS. The aim of this study was to determine the association of CT verified AVC and subclinical AS in a general population undergoing CT. METHODS: CT scans from 566 randomly selected male participants (age 65-74) in the Danish cardiovascular screening study (DANCAVAS) were analyzed for AVC. All participants with a moderately or severely increased AVC score (>=300 arbitrary units (AU)) and a matched control group were invited for a supplementary echocardiography. AS was graded by indexed aortic valve area (AVAi) on echocardiography as moderate 0.6-0.85 cm(2)/m(2) and severe < 0.6 cm(2)/m(2), respectively. ROC- and regression analyses were performed. RESULTS: Due to prior valve surgery, and artifacts from ICD leads 16 individuals were excluded from the AVC scoring. Moderate or severe increased AVC was observed in 10.7% (95% CI: 8.4 13.7). Echocardiography was performed in 101 individuals; 32.7% (95% CI: 21.8 to 46.0) with moderate or high AVC score had moderate or severe AS, while none with no or low AVC. A ROC analysis defined an AVC score >=588 AU to be suggestive of moderate or severe AS (AUC 0.89 +/- 0.04, sensitivity 83% and specificity 87%). In the univariate analyses, AVC was the only variable significantly associated with AS. CONCLUSIONS: This study indicates an association between CT verified AVC and subclinical AS. PMID- 27247180 TI - Phosphorylation of FEZ1 by Microtubule Affinity Regulating Kinases regulates its function in presynaptic protein trafficking. AB - Adapters bind motor proteins to cargoes and therefore play essential roles in Kinesin-1 mediated intracellular transport. The regulatory mechanisms governing adapter functions and the spectrum of cargoes recognized by individual adapters remain poorly defined. Here, we show that cargoes transported by the Kinesin-1 adapter FEZ1 are enriched for presynaptic components and identify that specific phosphorylation of FEZ1 at its serine 58 regulatory site is mediated by microtubule affinity-regulating kinases (MARK/PAR-1). Loss of MARK/PAR-1 impairs axonal transport, with adapter and cargo abnormally co-aggregating in neuronal cell bodies and axons. Presynaptic specializations are markedly reduced and distorted in FEZ1 and MARK/PAR-1 mutants. Strikingly, abnormal co-aggregates of unphosphorylated FEZ1, Kinesin-1 and its putative cargoes are present in brains of transgenic mice modelling aspects of Alzheimer's disease, a neurodegenerative disorder exhibiting impaired axonal transport and altered MARK activity. Our findings suggest that perturbed FEZ1-mediated synaptic delivery of proteins arising from abnormal signalling potentially contributes to the process of neurodegeneration. PMID- 27247182 TI - Progressive liver failure post acute hepatitis A, over a three-month period, resulting in hepatorenal syndrome and death. AB - Hepatitis A is a common viral illness worldwide. It usually results in an acute, self-limiting disease and only rarely leads to fulminant hepatic failure or any other complications. During the period of conflict in Syria, and due to the damages to water infrastructure and poor sanitation, a dramatic increase in hepatitis A virus infection has been documented. Here we report a rare case of a 14-year-old male whose hepatitis A was complicated with hepatorenal syndrome and subacute liver failure. The war condition in Syria impeded transportation of the patient to a nearby country for liver transplantation, contributing to his unfortunate death. PMID- 27247183 TI - Global chromatin architecture defines functional cancer hierarchies. PMID- 27247184 TI - Mitochondrial diversity in mountain horse population from the South-Eastern Europe. AB - It is believed that population structure of mountain horse breeds is preserved from any genetic introgression, because of their geographical isolation and specific semi-wild life style of husbandry. Till date there are no molecular data for the Balkan horses. In this study we try to give information about some autochthonous mountain horse breeds from Bulgaria. A total of 121 horses from three different mountain massifs are presented: Stara Planina (the Balkan mountain), the Rhodopes and Rila-Pirin massif were genotyped according to mitochondrial D-loop region. The results showed huge diversity of all known haplogroups with exception of C, F and R. West Eurasian haplogroups B, D, M and L were with the highest frequencies. Haplogroups A, J, I, O'P and Q were also observed with the highest frequencies, but not equally distributed among the three populations. Analyses of the horse breeds reveal preserved genetic profile of the Balkan and the Rhodopes mountains populations. In contrast, a Rila-Pirin breed unexpectedly showed mixed profile - a massive genetic introgression with an Asiatic-type haplogroups. A similar mixed Euro-Asiatic haplotype profile possessed the Carpathian mountain pony, although both populations are separated geographically and historically. The genetic pool of three Bulgarian mountain horse populations is highly heterogenic and because of that these breeds should be preserved. PMID- 27247185 TI - Herpes simplex encephalitis without cerebrospinal fluid pleocytosis in a patient with bullous pemphigoid: a case report. AB - A 78-year-old woman was diagnosed with bullous pemphigoid 2 months ago, and she had been treated with steroid and plasmapheresis. She developed sudden fever, vomiting, disorientation, and abnormal behavior. Diffusion weighted images and fluid-attenuated inversion recovery (FLAIR) magnetic resonance (MR) images showed high-intensity signals in the right temporal lobe hippocampus and right insular cortex. Cerebrospinal fluid (CSF) examination showed normal cell count (4/mm(3)), but was positive for HSV1-DNA by PCR. She was diagnosed with herpes simplex encephalitis (HSE), and acyclovir was started on the first day of admission. She had complete recovery, and was discharged. She didn't show CSF pleocytosis throughout her course of HSE. No CSF pleocytosis could be due probably to her immunosuppressed state under the steroid therapy for bullous pemphigoid. Because the morbidity and mortality of HSE is drastically reduced by early antiviral treatment, it is important to accelerate the diagnosis and treatment of HSE, especially in immunosuppressed or immunocompromised hosts. PMID- 27247186 TI - A bird's eye view on the use of electrospun nanofibrous scaffolds for bone tissue engineering: Current state-of-the-art, emerging directions and future trends. AB - Tissue engineering aims to develop therapeutic products that utilize a combination of scaffolds with viable cell systems or responsive biomolecules derived from such cells, for the repair, restoration/regeneration of tissues. Here, the main goal is to enable the body to heal itself by the introduction of electrospun scaffolds, such that the body recognizes them as its own and in turn uses them to regenerate "neo-native" functional tissues. During the last decade, innovative nanofibrous scaffolds have attracted substantial interest in bone tissue engineering. The electrospinning process makes it possible to fabricate appropriate scaffolds for bone tissue engineering from different categories of nanobiomaterials having the ability of controlled delivery of drugs in the defective tissues. It is expected that with the progress in science and technology, better bone constructs will be proposed in the future. This review discusses the innovative approaches into electrospinning techniques for the fabrication of nanofibrous scaffolds for bone tissue engineering. PMID- 27247187 TI - Highly specific colorimetric detection of DNA oxidation biomarker using gold nanoparticle/triplex DNA conjugates. AB - DNA oxidation causes a variety of diseases including cancer. The oxidized DNA nucleobases are excised by cellular repair enzymes and released into extracellular fluids. Specifically, the excised DNA oxidation product, such as 8 oxoGua, has been suggested as a biomarker for early cancer diagnosis. We previously developed an artificial receptor for the free base of 8-oxoGua on a triplex DNA backbone. The receptor contained a pre-organized cavity, which bounded 8-oxoGua with strong affinity and excellent selectivity over other nucleobases. However, accurate detection of 8-oxoGua in urine samples was affected by the presence of a large excess of guanine. Herein, we report a strategy to convert our receptor to a colorimetric biosensor by conjugating DNA strands to gold nanoparticles (GNP), specifically for 8-oxoGua. By simply incubating our sensor with a urine sample, 8-oxoGua can be detected at submicromolar concentrations with UV-vis spectrometer or even by naked eye. PMID- 27247188 TI - On-demand drug release of ICG-liposomal wedelolactone combined photothermal therapy for tumor. AB - In the study, a new photoresponsive nano drug delivery system was developed by encapsulating indocyanine green into liposomes (ICG-liposomal wedelolactone), which could improve the water solubility and bioavailability of wedelolactone. The hyperthermia, produced by ICG under near-infrared (NIR) light irradiation, promoted wedelolactone release rapidly from the carriers. The release amount of ICG-liposomal wedelolactone under NIR irradiation reached up to 96.74% over 8h, achieving the drug of on-demand release. Moreover, the growth of HepG2 cells was obviously inhibited by ICG-liposomal wedelolactone under NIR, and the early apoptotic rate of HepG2 cells was 33.74%. The tumor inhibition rate was 81% in the mice bearing tumor treated with the drug system. The results proved that ICG liposomal wedelolactone, as a novel drug delivery system to co-delivery chemotherapeutic agents and photothermal agents, achieved synergetic effect of chemotherapy and photothermotherapy, which will have an enormous potential in future cancer therapy. PMID- 27247189 TI - Spherical polymeric nanoconstructs for combined chemotherapeutic and anti inflammatory therapies. AB - Nanoparticles can simultaneously deliver multiple agents to cancerous lesions enabling de facto combination therapies. Here, spherical polymeric nanoconstructs (SPNs) are loaded with anti-cancer - docetaxel (DTXL) - and anti-inflammatory - diclofenac (DICL) - molecules. In vitro, combination SPNs kill U87-MG cells twice as efficiently as DTXL SPNs, achieving a IC50 of 90.5nM at 72h. Isobologram analysis confirms a significant synergy (CI=0.56) between DTXL and DICL. In mice bearing non-orthotopic glioblastoma multiforme tumors, combination SPNs demonstrate higher inhibition in disease progression. At 70days post treatment, the survival rate of mice treated with combination SPNs is of about 70%, against a 40% for DTXL SPNs and 0% for free DTXL. Combination SPNs dramatically inhibit COX-2 expression, modulating the local inflammatory status, and increase Caspase 3 expression, which is directly related to cell death. These results suggest that the combination of anti-cancer and anti-inflammatory molecules constitutes a potent strategy for inhibiting tumor growth. PMID- 27247190 TI - Prenatal ultrasound factors and genetic disorders in pregnancies complicated by polyhydramnios. AB - OBJECTIVE: The objective of the study is to examine the incidence of chromosomal or genetic abnormalities in pregnancies complicated by polyhydramnios and to assess the value of prenatal ultrasound findings in the prediction of cases associated with such disorders. METHODS: We searched the prenatal records of all patients delivered in our hospital with a diagnosis of polyhydramnios during pregnancy. For each case, maternal characteristics, ultrasound findings, and genetic testing results were recorded. A postnatal follow-up program of at least 6 months, including a clinical assessment by a clinical geneticist, was carried out in all cases. RESULTS: On a total of 195 cases, genetic testing and clinical examination identified a chromosomal or genetic disease in 26 (13.3%) cases. Multivariate analysis demonstrated that significant predictors of a genetic disorder were a deepest vertical pocket of amniotic fluid of >=13.0 cm (OR 4.306, 95%CI: 1.535-12.079) and reduced fetal movements (OR 25.084, 95%CI: 4.577 137.461), but not the presence of a structural defect. CONCLUSION: A postnatal clinical follow-up program can reveal chromosomal or genetic disorders in about 13% of neonates with a prenatal diagnosis of polyhydramnios. The severity of polyhydramnios and the reduction of fetal movements are independently associated with the presence of such diseases. (c) 2016 John Wiley & Sons, Ltd. PMID- 27247191 TI - A Highly Selective Fluorescence Turn-On Sensor for Extracellular Calcium Ion Detection. AB - A highly water-soluble, fluorescence turn-on sensor for Ca(2+) is reported. The sensor affords high selectivity in sensing Ca(2+) over other biologically important metal cations. The dissociation constant of the sensor in binding Ca(2+) is 0.92 mm. Fluorescence microscopy experiments demonstrate that the sensor is cell-impermeable and capable of detecting extracellular Ca(2+) . PMID- 27247193 TI - Bacterial Production of Pinene by a Laboratory-Evolved Pinene-Synthase. AB - Successful feeding of the substrate geranylpyrophosphate (GPP) to monoterpene synthase is critical to the efficient microbial production of monoterpenes. Overexpression of GPP synthases, metabolic channeling from GPP synthase to terpene synthases, and down-tuning of endogenous competitors have been successfully used to increase the production of monoterpene. Nevertheless, the production of monoterpenes has remained considerably lower than that of hemi /sesqui-terpenoids. We tested whether it is effective to improve the cellular activity of monoterpene synthases. To this end, we developed a high-throughput screening system to monitor for elevated GPP consumption. Through a single round of mutagenesis and screening, we isolated a pinene synthase variant that outperformed the wild-type (parent) enzyme in multiple contexts in Escherichia coli and cyanobacteria. The purified variant exhibited drastically altered metal dependency, enabling to keep the activity in the cytosol that is manganese deficient. Coexpression of this variant with mevalonate pathway enzymes, isopentenylpyrophosphate isomerase, and GPP synthase yielded 140 mg/L pinene in a flask culture. PMID- 27247192 TI - Cyclosporine A Treatment Abrogates Ischemia-Induced Neuronal Cell Death by Preserving Mitochondrial Integrity through Upregulation of the Parkinson's Disease-Associated Protein DJ-1. AB - AIMS: Hypoxic-ischemia alters mitochondrial membrane potential (Deltapsim), respiratory-related enzymes, and mitochondrial DNA (mtDNA). Drugs acting on mitochondria, such as cyclosporine A (CsA), may reveal novel mitochondria-based cell death signaling targets for stroke. Our previous studies showed that Parkinson's disease-associated protein DJ-1 participates in the acute endogenous neuroprotection after stroke via mitochondrial pathway. DJ-1 was detected immediately after stroke and efficiently translocated into the mitochondria offering a new venue for developing treatment strategies against stroke. Here, we examined a molecular interaction between CsA and mitochondrial integrity in the in vitro acute stroke model of oxygen glucose deprivation/reperfusion (OGD/R) injury with emphasis on DJ-1. METHODS: Primary rat neuronal cells (PRNCs) were exposed to OGD/R injury and processed for immunocytochemistry, ELISA, and mitochondria-based molecular assays to reveal the role of DJ-1 in CsA modulation of mitochondrial integrity. RESULTS: Administration of CsA before stroke onset (24 h pre-OGD/R) afforded significantly much more robust neuroprotective effects than when CsA was initiated after stroke (2 h post-OGD/R), revealing that CsA exerted neuroprotection in the early phase of ischemic stroke. CsA prevented the mitochondria-dependent cell death signaling pathway involved in cytochrome c (Cyt c)-induced intrinsic apoptotic process. CsA preserved cellular ATP content, but not hexokinase activity under hypoxic conditions. CsA prevented both mtDNA decrement and Deltapsim degradation after reperfusion, and enhanced secretion of DJ-1 in the mitochondria, coupled with reduced oxidative stress. CONCLUSION: These observations provided evidence that CsA maintained mitochondrial integrity likely via DJ-1 upregulation, supporting the concept that mitochondria-based treatments targeting the early phase of disease progression may prove beneficial in stroke. PMID- 27247194 TI - Biocompatibility and nanostructured materials: applications in nanomedicine. AB - There has been huge interest in applications of nanomaterials in biomedical science, including diagnosis, drug delivery, and development of human organs. Number of these nanomaterials has been already studied in human or at pre clinical trial. There is a growing concern on potential toxicity and adverse effects of nanomaterials on human health, including lack of standard method of assessment of toxicology of these materials. Our investigation indicated that the bare and small nanoparticle have higher toxicity than modified and bulk materials, respectively. In addition, spherical nanoparticles have less toxicity than rod nanoparticles due to immune response of body. PMID- 27247195 TI - CD19(+) CD20(-) CD27(hi) IL-s10-producing B cells are overrepresented in R-CHOP treated DLBCL patients in complete remission. AB - Treatment of diffuse large B cell lymphoma (DLBCL) with rituximab, an anti-CD20 monoclonal antibody, has resulted in significantly improved patient responses with longer event-free intervals and higher overall survival rates. However, since rituximab depletes all CD20-expressing cells, including noncancerous B cells, the effects of rituximab on the normal immunity of DLBCL patients under remission need to be examined. Here, we observed that DLBCL patients under remission contained significantly lower frequencies of total B cells, with a significantly overrepresented interleukin (IL)-10-producing B cell (B10) population in the peripheral blood. Further examination confirmed that a large fraction of B10 cells was CD20(-) CD27(hi) plasmablasts, possibly explaining the persistence of B10 cells after R-CHOP treatment. We also observed that the percentage of B10 cells in DLBCL patients in remission gradually reduced during the first year of achieving complete remission, primarily due to the replenishment of non-B10 B cells. Despite this, the percentage of B10 cells in DLBCL patients after 1 year of achieving complete remission was still higher than that in controls. CD4(+) and CD8(+) T cells cocultured with B10-enriched B cells secreted significantly lower levels of proinflammatory cytokines IFN-g and TNF-a, compared to those incubated with B10-depleted B cells. Together, our data observed a long-lasting overrepresentation of B10 cells in DLBCL patients under remission. Whether this change could impact on the overall anti-tumor immunity during remission requires further studies. PMID- 27247197 TI - Eventration of the Right Hemidiaphragm with Resultant Right Atrial Compression-A Rare Finding. PMID- 27247199 TI - The Influence of Divalent Anions on the Rectification Properties of Nanofluidic Diodes: Insights from Experiments and Theoretical Simulations. AB - During the last decade, the possibility of generating synthetic nanoarchitectures with functionalities comparable to biological entities has sparked the interest of the scientific community related to diverse research fields. In this context, gaining fundamental understanding of the central features that determine the rectifying characteristics of the conical nanopores is of mandatory importance. In this work, we analyze the influence of mono- and divalent salts in the ionic current transported by asymmetric nanopores and focus on the delicate interplay between ion exclusion and charge screening effects that govern the functional response of the nanofluidic device. Experiments were performed using KCl and K2 SO4 as representative species of singly and doubly charged species. Results showed that higher currents and rectification efficiencies are achieved by doubly charged salts. In order to understand the physicochemical processes underlying these effects simulations using the Poisson-Nernst-Planck formalism were performed. We consider that our theoretical and experimental account of the effect of divalent anions in the functional response of nanofluidic diodes provides further insights into the critical role of electrostatic interactions (ion exclusion versus charge screening effects) in presetting the ionic selectivity to anions as well as the observed rectification properties of these chemical nanodevices. PMID- 27247200 TI - Feasibility of robotic radical hysterectomy after neoadjuvant chemotherapy in women with locally advanced cervical cancer. AB - OBJECTIVE: To evaluate the safety and feasibility of robotic radical hysterectomy (RRH) in women with locally advanced cervical cancer (LACC) after neoadjuvant chemotherapy (NACT). MATERIAL AND METHODS: A retrospective comparative longitudinal observational study was performed in 30 patients with LACC FIGO stage IB2-IIB who underwent RRH after NACT between February 2008 and September 2014. This group was compared with a cohort of 176 patients underwent RRH with cervical cancer FIGO stage IA2-IB1 in the same period of time. RESULTS: Patients' age, BMI, ASA score, comorbidity, and previous abdominal surgery, was similar between groups. FIGO stage significantly differed between groups; 29 (96.6%) of patients had FIGO stage IB2 in NACT group and 163 (92.6%) were FIGO stag IB1 in women without NACT, p < 0.001. Type of RRH was also significantly different between groups. Type C1 RRH was significantly more common in NACT group, p = 0.015. Mean (SD) tumor size was significantly bigger in NACT, 27.0 (13.7) mm versus 20.9 (9.0) mm in early stage versus LACC, respectively. p = 0.023. Mean (SD) surgical time was significantly longer in NACT group (307.8 (40.2) min versus 277.4 (45.4) min, p = 0.001). Estimated blood loss and length of the hospital stay were similar between groups. There were no significant differences in terms of intraoperative and postoperative complications. CONCLUSIONS: RRH after NACT in women with LACC seems to be safe and feasible. These results need to be confirmed in studies with a larger patients sample. PMID- 27247201 TI - Sexual Coercion Practices Among Undergraduate Male Recreational Athletes, Intercollegiate Athletes, and Non-Athletes. AB - Prior research shows that male intercollegiate athletes are at risk for perpetrating sexual violence. Whether this risk extends to male recreational athletes has not been explored. This study assessed associations between attitudes toward women, rape myth acceptance, and prevalence of sexual coercion among 379 male, undergraduate recreational and intercollegiate athletes and non athletes. Our analyses showed significant differences between the responses of athletes and non-athletes for all dependent variables, and intercollegiate and recreational athletes on attitudes toward women and the prevalence of sexual coercion. Controlling for rape myth acceptance and traditional gender role attitudes eliminated differences between athletes and non-athletes in prevalence of sexual coercion. PMID- 27247203 TI - Is rituximab an effective treatment of refractory calcinosis? AB - Calcinosis, the deposition of calcified material in soft tissues, is frequently seen in systemic sclerosis and dermatomyositis. Treatment options are limited, with disappointing results. Some recent case reports suggest that rituximab may be an attractive therapeutic option. In case 1, a 54-year-old woman who presented with rheumatoid arthritis in association with scleromyositis was treated with rituximab for rheumatoid arthritis. Despite this, she developed multiple progressive calcinosis, necessitating extracorporeal shock wave lithotripsy to limit calcinosis extension and pain. In case 2, a 38-year-old man, previously treated for an anti-Pm/Scl-positive polymyositis/scleroderma overlap syndrome, presented with multiple tumoural periarticular calcinosis, which progressed despite bisphosphonates, sodium thiosulfate and thalidomide. We decided to start rituximab. Progression of calcinosis was still evident 6 and 12 months after anti CD20 treatment. Many treatments have been tried to treat calcinosis without demonstrated effectiveness. Presently, rituximab cannot be recommended for this indication in the absence of successful controlled trials. PMID- 27247202 TI - Stated product formulation preferences for HIV pre-exposure prophylaxis among women in the VOICE-D (MTN-003D) study. AB - INTRODUCTION: The effectiveness of HIV pre-exposure prophylaxis (PrEP) requires consistent and correct product use, thus a deeper understanding of women's stated product formulation preferences, and the correlates of those preferences, can help guide future research. VOICE-D (MTN-003D), a qualitative ancillary study conducted after the VOICE trial, retrospectively explored participants' tablet and gel use, as well as their preferences for other potential PrEP product formulations. METHODS: We conducted an analysis of quantitative and qualitative data from VOICE-D participants. During in-depth interviews, women were presented with pictures and descriptions of eight potential PrEP product formulations, including the oral tablet and vaginal gel tested in VOICE, and asked to discuss which product formulations they would prefer to use and why. Seven of the original product formulations displayed were combined into preferred product formulation categories based on exploratory factor and latent class analyses. We examined demographic and behavioural correlates of these preferred product formulation categories. In-depth interviews with participants were conducted, coded, and analysed for themes related to product preference. RESULTS: Of the 68 female participants who completed in-depth interviews (22 South Africa, 24 Zimbabwe, 22 Uganda), median age was 28 (range 21-41), 81% were HIV negative, and 49% were married or living with a partner. Four preferred product formulation categories were identified via exploratory factor analysis: 1) oral tablets; 2) vaginal gel; 3) injectable, implant, or vaginal ring; and 4) vaginal film or suppository. A majority of women (81%) expressed a preference for product formulations included in category 3. Characteristics significantly associated with each preferred product category differed. Attributes described by participants as being important in a preferred product formulation included duration of activity, ease of use, route of administration, clinic- versus self administration, and degree of familiarity with product. CONCLUSIONS: While there was interest in a variety of potential PrEP product formulations, a majority of VOICE-D participants preferred long-acting methods. More research is needed to gain insight into end-users' product formulation preference to inform messaging and market segmentation for different PrEP products and resources to invest in products that target populations are most interested in using. CLINICAL TRIAL NUMBER: NCT02358616. PMID- 27247204 TI - Endovascular treatment of posterior condylar canal dural arteriovenous fistula. AB - Posterior condylar canal dural arteriovenous fistulas (PCC DAVFs) are rare lesions that may present with pulse-synchronous bruit. In cases with venous reflux there is a risk of haemorrhage or even dementia. Diagnosis and endovascular treatment require a profound knowledge of the vascular anatomy of the craniocervical junction and comprehensive neurovascular imaging. We describe the clinical presentation, angiographic imaging and endovascular treatment of a PCC DAVF in a female patient with pulse-synchronous bruit as the presenting symptom. The fistula drained almost exclusively into the sigmoid sinus and internal jugular vein. There was no intracranial reflux. The PCC DAVF was treated with transvenous coil occlusion of the fistulous pouch in the condylar canal. Symptoms resolved immediately after intervention and the patient recovered quickly without any neurological deficits. MR angiography confirmed occlusion of the DAVF. The dural sinus was patent with normal blood flow. PMID- 27247205 TI - Thumb sign: acute epiglottitis. PMID- 27247206 TI - Late presented case of distal humerus epiphyseal separation in a newborn. AB - The incidence of traumatic bone injuries occurring during birth is rare (1 per 1000 live births). Of all long bone fractures, the humerus is one of the commonest bones to be involved. However, distal humeral epiphyseal separation is rare and has seldom been written up in case reports and small case series. It warrants some critical assessment and appropriate attention. This injury is sometimes missed as it is difficult to diagnose at initial presentation. It may be mistaken for dislocation of the elbow, osteomyelitis, septic arthritis or brachial plexus injury, owing to lack of movement of the upper limb. Knowledge of its clinical and radiological findings will enable the treating physician to diagnose it at the appropriate time. Masterful observation is adequate treatment for this condition, and leads to a better clinical and radiological outcome. Timely diagnosis with an optimistic prognosis will prevent unnecessary parental apprehension. PMID- 27247207 TI - Stroke and a valvular lesion in a patient with stage IV non-small cell lung cancer. AB - The mechanism and severity of stroke varies in the setting of malignancy. We report a case of a 68-year-old man with lung adenocarcinoma, who experienced acute neurological symptoms. Imaging studies showed multiple acute ischaemic infarcts in cerebral and cerebellar hemispheres. Further work up was consistent with non-bacterial thrombotic endocarditis (NBTE). We highlight, through a review of the literature, the importance of transoesophageal echocardiography (TOE) in defining the above diagnosis. The treatment of NBTE consists of systemic anticoagulation and therapy of the underlying malignancy. Enoxaparin is preferred over warfarin to achieve this goal. He received systemic targeted therapy with erlotinib. A TOE performed 8 months later showed complete resolution of the vegetation. PMID- 27247208 TI - Tension pneumothorax due to perforated colon. AB - A very rare case of traumatic diaphragmatic hernia is reported in a 65-year-old woman who presented 46 years after her initial thoracoabdominal injury with tension faecopneumothorax caused by a perforated colon in the chest cavity. She presented in a critical condition with severe respiratory distress, sepsis and acute kidney injury. She had a long-standing history of bronchial asthma with respiratory complications and had experienced progressive shortness of breath for the past year. A recent CT scan had excluded the presence of a diaphragmatic hernia but showed a significantly raised left hemidiaphragm. On admission, chest X-rays showed a significantly raised left hemidiaphragm and mediastinal shift, but the possibility of a diaphragmatic hernia with strangulated bowel in the chest was not suspected until the patient was reviewed by the surgical and intensive care unit consultants the next morning and a repeat CT performed. She had a successful outcome after her emergency operation. PMID- 27247209 TI - Subungual pigmented squamous cell carcinoma presenting as a grey longitudinal melanonychia in a young patient. PMID- 27247210 TI - Neonatal imperforate hymen with hydrocolpos. PMID- 27247211 TI - Nitrous oxide misuse and vitamin B12 deficiency. AB - A 36-year-old man presented to hospital with a 5-week history of ascending limb paraesthesiae and balance difficulties. He had no medical or travel history of note, but admitted habitual nitrous oxide (N2O) inhalation. Neurological examination revealed a sensory ataxia with pseudoathetosis in the upper limbs and reduced vibration sensation to the hips bilaterally. Significant investigation results included a low serum vitamin B12 concentration, mild macrocytosis and raised serum homocysteine concentration. T2 MRI of the spinal cord demonstrated increased signal extending from C1 to T11 in keeping with a longitudinal myelitis. The patient was diagnosed with a myeloneuropathy secondary to vitamin B12 deficiency, resulting from heavy N2O inhalation. He was treated with intramuscular vitamin B12 injections and received regular physiotherapy. At discharge, he was able to mobilise short distances with the aid of a zimmer frame, and was independently mobile 8 weeks later. PMID- 27247212 TI - Systematic biomarker discovery and coordinative validation for different primary nephrotic syndromes using gas chromatography-mass spectrometry. AB - The goal of this study is to identify systematic biomarker panel for primary nephrotic syndromes from urine samples by applying a non-target metabolite profiling, and to validate their utility in independent sampling and analysis by multiplex statistical approaches. Nephrotic syndrome (NS) is a nonspecific kidney disorder, which is mostly represented by minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and membranous glomerulonephritis (MGN). Since urine metabolites may mirror disease-specific functional perturbations in kidney injury, we examined urine samples for distinctive metabolic changes to identify biomarkers for clinical applications. We developed unbiased multi component covarianced models from a discovery set with 48 samples (12 healthy controls, 12 MCD, 12 FSGS, and 12 MGN). To extensively validate their diagnostic potential, new batch from 54 patients with primary NS were independently examined a year after. In the independent validation set, the model including citric acid, pyruvic acid, fructose, ethanolamine, and cysteine effectively discriminated each NS using receiver operating characteristic (ROC) analysis except MCD-MGN comparison; nonetheless an additional metabolite multi-composite greatly improved the discrimination power between MCD and MGN. Finally, we proposed the re constructed metabolic network distinctively dysregulated by the different NSs that may deepen comprehensive understanding of the disease mechanistic, and help the enhanced identification of NS and therapeutic plans for future. PMID- 27247213 TI - In-syringe extraction using dissolvable layered double hydroxide-polymer sponges templated from hierarchically porous coordination polymers. AB - Herein we report the use of cobalt porous coordination polymers (PCP) as intermediates to prepare advanced extraction media based on layered double hydroxides (LDH) supported on melamine polymer foam. The obtained dissolvable Ni Co LDH composite sponges can be molded and used as sorbent for the in-syringe solid-phase extraction (SPE) of phenolic acids from fruit juices. The proposed sorbent is obtained due to the surfactant-assisted self-assembly of Co(II)/imidazolate PCPs on commercially available melamine foam, followed by the in situ conversion of the PCP into the final dissolvable LDH coating. Advantageous features for SPE are obtained by using PCPs with hierarchical porosity (HPCPs). The LDH-sponge prepared using intermediate HPCPs (HLDH-sponge) is placed in the headspace of a glass syringe, enabling flow-through extraction followed by analyte elution by the dissolution of the LDH coating in acidic conditions. Three phenolic acids (gallic acid, p-hydroxybenzoic acid and caffeic acid) were extracted and quantified using high performance liquid chromatography. Using a 5mL sample volume, the obtained detection limits were 0.15-0.35MUgL(-1). The proposed method for the preparation of HLDH-sponges showed a good reproducibility as observed from the intra- and inter-day RSD's, which were <10% for all analytes. The batch-to-batch reproducibility for three different batches of HLDH-sponges was 10.6-11.2%. Enrichment factors of 15-21 were obtained. The HLDH-sponges were applied satisfactorily to the determination of phenolic acids in natural and commercial fruit juices, obtaining relative recoveries among 89.7 95.3%. PMID- 27247214 TI - Advance chromatin extraction enhances performance and productivity of cation exchange chromatography-based capture of Immunoglobulin G monoclonal antibodies. AB - The impact of host cell-derived chromatin was investigated on the performance and productivity of cation exchange chromatography as a method for capture purification of an IgG monoclonal antibody. Cell culture supernatant was prepared for loading by titration to pH 6.0, dilution with water to a conductivity of 4mS/cm, then microfiltration to remove solids. DNA content was reduced 99% to 30ppm, histone host cell protein content by 76% to 6300ppm, non-histone host cell protein content by 15% to 321,000ppm, and aggregates from 33% to 15%. IgG recovery was 83%. An alternative preparation was performed, adding octanoic acid, allantoin, and electropositive particles to the harvest at pH 5.3, then removing solids. DNA content was reduced to<1 ppb, histones became undetectable, non histones were reduced to 24,000ppm, and aggregates were reduced to 2.4%. IgG recovery was 95%. This treatment increased dynamic capacity (DBC) of cation exchange capture to 173g/L and enabled the column to reduce non-histone host proteins to 671ppm. Step recovery was 99%. A single multimodal polishing step further reduced them to 15ppm and aggregates to <0.1%. Overall process recovery was 89%. Productivity at feed stream IgG concentrations of 5-10g/L was roughly double the productivity of a same-size protein A column with a DBC of 55g/L. PMID- 27247215 TI - Enantioseparation of beta-carboline derivatives on polysaccharide- and strong cation exchanger-based chiral stationary phases. A comparative study. AB - In this study we attempted to describe in a comparative manner the enantioselectivity performance of six different polysaccharide- and two strong cation exchanger-type chiral stationary phases (CSPs) for the resolution of free and N-protected beta-carboline derivatives. On commercially available cellulose- or amylose-based CSPs, the enantioseparations were carried out in normal-phase mode by variation of the nature and the concentration of the alcohol modifier in n-hexane as mobile phase. With the application of strong cation exchanger-type CSPs, the enantioseparations were optimized by the variation of methanol acetonitrile bulk solvent compositions in the presence of various amounts of acid and base additives acting as counter-ions. Detailed thermodynamic investigations revealed that in all cases the enantioseparations observed were enthalpically driven, i.e. the retention and selectivity decreased with increasing temperature. Elution sequences were determined routinely; no general rule was found on polysaccharide-based CSPs, while on the two enantiomeric strong cation exchanger type CSPs the predicted reversal of the elution sequence could be confirmed on switching from one enantiomeric CSP to the other form. PMID- 27247216 TI - Locally Advanced, Unresectable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline. AB - PURPOSE: To provide evidence-based recommendations to oncologists and others for treatment of patients with locally advanced, unresectable pancreatic cancer. METHODS: American Society of Clinical Oncology convened an Expert Panel of medical oncology, radiation oncology, surgical oncology, gastroenterology, palliative care, and advocacy experts and conducted a systematic review of the literature from January 2002 to June 2015. Outcomes included overall survival, disease-free survival, progression-free survival, and adverse events. RESULTS: Twenty-six randomized controlled trials met the systematic review criteria. RECOMMENDATIONS: A multiphase computed tomography scan of the chest, abdomen, and pelvis should be performed. Baseline performance status and comorbidity profile should be evaluated. The goals of care, patient preferences, psychological status, support systems, and symptoms should guide decisions for treatments. A palliative care referral should occur at first visit. Initial systemic chemotherapy (6 months) with a combination regimen is recommended for most patients (for some patients radiation therapy may be offered up front) with Eastern Cooperative Oncology Group performance status 0 or 1 and a favorable comorbidity profile. There is no clear evidence to support one regimen over another. The gemcitabine-based combinations and treatments recommended in the metastatic setting (eg, fluorouracil, leucovorin, irinotecan, and oxaliplatin and gemcitabine plus nanoparticle albumin-bound paclitaxel) have not been evaluated in randomized controlled trials involving locally advanced, unresectable pancreatic cancer. If there is local disease progression after induction chemotherapy, without metastasis, then radiation therapy or stereotactic body radiotherapy may be offered also with an Eastern Cooperative Oncology Group performance status <= 2 and an adequate comorbidity profile. If there is stable disease after 6 months of induction chemotherapy but unacceptable toxicities, radiation therapy may be offered as an alternative. Patients with disease progression should be offered treatment per the ASCO Metastatic Pancreatic Cancer Treatment Guideline. Follow-up visits every 3 to 4 months are recommended. Additional information is available at www.asco.org/guidelines/LAPC and www.asco.org/guidelines/MetPC and www.asco.org/guidelineswiki. PMID- 27247217 TI - Aspirin As Secondary Prevention in Patients With Colorectal Cancer: An Unselected Population-Based Study. AB - PURPOSE: Regular use of aspirin (acetylsalicylic acid) is associated with reduced incidence and mortality of colorectal cancer (CRC). However, aspirin as primary prevention is debated because of the risk of hemorrhagic adverse effects. Aspirin as secondary prevention may be more justified from a risk-benefit perspective. We have examined the association between aspirin use after the diagnosis of CRC with CRC-specific survival (CSS) and overall survival (OS). MATERIALS AND METHODS: An observational, population-based, retrospective cohort study was conducted by linking patients diagnosed with CRC from 2004 through 2011 (Cancer Registry of Norway) with data on their aspirin use (The Norwegian Prescription Database). These registries cover more than 99% of the Norwegian population and include all patients in an unselected and consecutive manner. Exposure to aspirin was defined as receipt of aspirin prescriptions for more than 6 months after the diagnosis of CRC. Multivariable Cox-proportional hazard analyses were used to model survival. The main outcome measures of the study were CSS and OS. RESULTS: A total of 23,162 patients diagnosed with CRC were included, 6,102 of whom were exposed to aspirin after the diagnosis of CRC (26.3%). The median follow-up time was 3.0 years. A total of 2,071 deaths (32.9%, all causes) occurred among aspirin-exposed patients, of which 1,158 (19.0%) were CRC specific. Among unexposed patients (n = 17,060), there were 7,218 deaths (42.3%), of which 5,375 (31.5%) were CRC specific. In multivariable analysis, aspirin exposure after the diagnosis of CRC was independently associated with improved CSS (hazard ratio [HR], 0.85; 95% CI, 0.79 to 0.92) and OS (HR, 0.95; 95% CI, 0.90 to 1.01). CONCLUSION: Aspirin use after the diagnosis of CRC is independently associated with improved CSS and OS. PMID- 27247218 TI - Updating the American Society of Clinical Oncology Value Framework: Revisions and Reflections in Response to Comments Received. PMID- 27247219 TI - Examination of Broad Symptom Improvement Resulting From Mindfulness-Based Stress Reduction in Breast Cancer Survivors: A Randomized Controlled Trial. AB - PURPOSE: The purpose of this randomized trial was to evaluate the efficacy of the Mindfulness-Based Stress Reduction for Breast Cancer (MBSR[BC]) program in improving psychological and physical symptoms and quality of life among breast cancer survivors (BCSs) who completed treatment. Outcomes were assessed immediately after 6 weeks of MBSR(BC) training and 6 weeks later to test efficacy over an extended timeframe. PATIENTS AND METHODS: A total of 322 BCSs were randomly assigned to either a 6-week MBSR(BC) program (n = 155) or a usual care group (n = 167). Psychological (depression, anxiety, stress, and fear of recurrence) and physical symptoms (fatigue and pain) and quality of life (as related to health) were assessed at baseline and at 6 and 12 weeks. Linear mixed models were used to assess MBSR(BC) effects over time, and participant characteristics at baseline were also tested as moderators of MBSR(BC) effects. RESULTS: Results demonstrated extended improvement for the MBSR(BC) group compared with usual care in both psychological symptoms of anxiety, fear of recurrence overall, and fear of recurrence problems and physical symptoms of fatigue severity and fatigue interference (P < .01). Overall effect sizes were largest for fear of recurrence problems (d = 0.35) and fatigue severity (d = 0.27). Moderation effects showed BCSs with the highest levels of stress at baseline experienced the greatest benefit from MBSR(BC). CONCLUSION: The MBSR(BC) program significantly improved a broad range of symptoms among BCSs up to 6 weeks after MBSR(BC) training, with generally small to moderate overall effect sizes. PMID- 27247220 TI - Standardized Uptake Decrease on [18F]-Fluorodeoxyglucose Positron Emission Tomography After Neoadjuvant Chemotherapy Is a Prognostic Classifier for Long Term Outcome After Multimodality Treatment: Secondary Analysis of a Randomized Trial for Resectable Stage IIIA/B Non-Small-Cell Lung Cancer. AB - PURPOSE: A confirmatory analysis was performed to determine the prognostic value of metabolic response during induction chemotherapy followed by bimodality/trimodality treatment of patients with operable locally advanced non small-cell lung cancer. PATIENTS AND METHODS: Patients with potentially operable stage IIIA(N2) or selected stage IIIB non-small-cell lung cancer received three cycles of cisplatin/paclitaxel (induction chemotherapy) followed by neoadjuvant radiochemotherapy (RCT) to 45 Gy (1.5 Gy twice per day concurrent cisplatin/vinorelbine) within the ESPATUE (Phase III Study of Surgery Versus Definitive Concurrent Chemoradiotherapy Boost in Patients With Resectable Stage IIIA[N2] and Selected IIIB Non-Small-Cell Lung Cancer After Induction Chemotherapy and Concurrent Chemoradiotherapy) trial. Positron emission tomography scans were recommended before (t0) and after (t2) induction chemotherapy. Patients who were eligible for surgery after neoadjuvant RCT were randomly assigned to definitive RCT or surgery. The prognostic value of percentage of maximum standardized uptake value (%SUVmax) remaining in the primary tumor after induction chemotherapy-%SUVremaining = SUVmax(t2)/SUVmax(t0) was assessed by proportional hazard analysis and receiver operating characteristic analysis. RESULTS: Overall, 161 patients were randomly assigned (155 from the Essen and Tubingen centers), and 124 of these received positron emission tomography scans at t0 and t2. %SUVremaining as a continuous variable was prognostic for the three end points of overall survival, progression-free survival, and freedom from extracerebral progression in univariable and multivariable analysis (P < .016). The respective hazard ratios per 50% increase in %SUVremaining from multivariable analysis were 2.3 (95% CI, 1.5 to 3.4; P < .001), 1.8 (95% CI, 1.3 to 2.5; P < .001), and 1.8 (95% CI, 1.2 to 2.7; P = .006) for the three end points. %SUVremaining dichotomized at a cut point of maximum sum of sensitivity and specificity from receiver operating characteristic analysis at 36 months was also prognostic. Exploratory analysis revealed that %SUVremaining was likewise prognostic for overall survival in both treatment arms and was more closely associated with extracerebral distant metastases (P = .016) than with isolated locoregional relapses (P = .97). CONCLUSION: %SUVremaining is a predictor for survival and other end points after multimodality treatment and can serve as a parameter for treatment stratification after induction chemotherapy or for evaluation of adjuvant new systemic treatment options for high-risk patients. PMID- 27247221 TI - Potentially Curable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline. AB - PURPOSE: To provide evidence-based recommendations to oncologists and others on potentially curative therapy for patients with localized pancreatic cancer. METHODS: ASCO convened a panel of medical oncology, radiation oncology, surgical oncology, palliative care, and advocacy experts and conducted a systematic review of literature from January 2002 to June 2015. Outcomes included overall survival, disease-free survival, progression-free survival, and adverse events. RESULTS: Nine randomized controlled trials met the systematic review criteria. RECOMMENDATIONS: A multiphase computed tomography scan of the abdomen and pelvis or magnetic resonance imaging should be performed for all patients to assess the anatomic relationships of the primary tumor and for the presence of intra abdominal metastases. Baseline performance status, comorbidity profile, and goals of care should be evaluated and established. Primary surgical resection is recommended for all patients who have no metastases, appropriate performance and comorbidity profiles, and no radiographic interface between primary tumor and mesenteric vasculature. Preoperative therapy is recommended for patients who meet specific characteristics. All patients with resected pancreatic cancer who did not receive preoperative therapy should be offered 6 months of adjuvant chemotherapy in the absence of contraindications. Adjuvant chemoradiation may be offered to patients who did not receive preoperative therapy with microscopically positive margins (R1) after resection and/or who had node-positive disease after completion of 4 to 6 months of systemic adjuvant chemotherapy. Patients should have a full assessment of symptoms, psychological status, and social supports and should receive palliative care early. Patients who have completed treatment and have no evidence of disease should be monitored. Additional information is available at www.asco.org/guidelines/PCPC and www.asco.org/guidelineswiki. PMID- 27247223 TI - Assessing the Clinical Impact of Risk Prediction Models With Decision Curves: Guidance for Correct Interpretation and Appropriate Use. AB - The decision curve is a graphical summary recently proposed for assessing the potential clinical impact of risk prediction biomarkers or risk models for recommending treatment or intervention. It was applied recently in an article in Journal of Clinical Oncology to measure the impact of using a genomic risk model for deciding on adjuvant radiation therapy for prostate cancer treated with radical prostatectomy. We illustrate the use of decision curves for evaluating clinical- and biomarker-based models for predicting a man's risk of prostate cancer, which could be used to guide the decision to biopsy. Decision curves are grounded in a decision-theoretical framework that accounts for both the benefits of intervention and the costs of intervention to a patient who cannot benefit. Decision curves are thus an improvement over purely mathematical measures of performance such as the area under the receiver operating characteristic curve. However, there are challenges in using and interpreting decision curves appropriately. We caution that decision curves cannot be used to identify the optimal risk threshold for recommending intervention. We discuss the use of decision curves for miscalibrated risk models. Finally, we emphasize that a decision curve shows the performance of a risk model in a population in which every patient has the same expected benefit and cost of intervention. If every patient has a personal benefit and cost, then the curves are not useful. If subpopulations have different benefits and costs, subpopulation-specific decision curves should be used. As a companion to this article, we released an R software package called DecisionCurve for making decision curves and related graphics. PMID- 27247222 TI - Metastatic Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline. AB - PURPOSE: To provide evidence-based recommendations to oncologists and others for the treatment of patients with metastatic pancreatic cancer. METHODS: American Society of Clinical Oncology convened an Expert Panel of medical oncology, radiation oncology, surgical oncology, gastroenterology, palliative care, and advocacy experts to conduct a systematic review of the literature from April 2004 to June 2015. Outcomes were overall survival, disease-free survival, progression free survival, and adverse events. RESULTS: Twenty-four randomized controlled trials met the systematic review criteria. RECOMMENDATIONS: A multiphase computed tomography scan of the chest, abdomen, and pelvis should be performed. Baseline performance status and comorbidity profile should be evaluated. Goals of care, patient preferences, treatment response, psychological status, support systems, and symptom burden should guide decisions for treatments. A palliative care referral should occur at first visit. FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin; favorable comorbidity profile) or gemcitabine plus nanoparticle albumin-bound (NAB) -paclitaxel (adequate comorbidity profile) should be offered to patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 1 based on patient preference and support system available. Gemcitabine alone is recommended for patients with ECOG PS 2 or with a comorbidity profile that precludes other regimens; the addition of capecitabine or erlotinib may be offered. Patients with an ECOG PS >= 3 and poorly controlled comorbid conditions should be offered cancer-directed therapy only on a case-by case basis; supportive care should be emphasized. For second-line therapy, gemcitabine plus NAB-paclitaxel should be offered to patients with first-line treatment with FOLFIRINOX, an ECOG PS 0 to 1, and a favorable comorbidity profile; fluorouracil plus oxaliplatin, irinotecan, or nanoliposomal irinotecan should be offered to patients with first-line treatment with gemcitabine plus NAB paclitaxel, ECOG PS 0 to 1, and favorable comorbidity profile, and gemcitabine or fluorouracil should be offered to patients with either an ECOG PS 2 or a comorbidity profile that precludes other regimens. Additional information is available at www.asco.org/guidelines/MetPC and www.asco.org/guidelineswiki. PMID- 27247224 TI - Predictors of unanticipated admission following ambulatory surgery in the pediatric population: a retrospective case-control study. AB - BACKGROUND: Ambulatory surgery plays an important role in pediatric anesthesia. However, it is difficult to predict which patients will experience complications. Age >80, ASA class 3 or 4, duration of surgery >3 h, and BMI 30-35 are independent predictors of unanticipated admission in adults. In this study, we retrospectively evaluate risk factors for unanticipated admission, following ambulatory surgery in children. METHODS: All ambulatory patients requiring unanticipated admission between 2005 and 2013 were compared to a random sample of patients not requiring admission in this case-control study. Demographic data, surgical information, medications, intraoperative events, and patient comorbidities were collected from both groups. The reason for admission was classified according to five subtypes. Multiple conditional logistic regression was used to assess factors associated with unanticipated admissions. RESULTS: The incidence of unanticipated admission was 0.97% (213). Of these, 47% (98) was anesthesia related. Age <2 years (odds ratio [OR] 4.26 95% CI 1.19-15.25), ASA 3 class (OR 3.77 95% CI 1.46-9.71), duration of surgery >1 h (OR 6.54 95% CI 3.47 12.33), completion of surgery >3 pm (OR 2.17 95% CI 1.05-4.51), orthopedic (OR 2.52 95% CI 1.03-6.20), dental (OR 0.21 95% CI 0.06-0.81), ENT (OR 6.47 95% CI 2.99-14.03) surgery, intraoperative events (OR 4.45 95% CI 1.35-18.12), and OSA (OR 6.32 95% CI 1.54-25.94) were factors associated with unanticipated admission. CONCLUSION: The incidence of unanticipated admission in children following ambulatory surgery is low. Age, ASA class, duration, and time of completion of surgery are predictors common to pediatrics and adults. Interestingly, intraoperative complications, OSA, and type of surgery (ENT, orthopedic, dental) are specific to pediatrics. PMID- 27247225 TI - Fitness costs to Helicoverpa armigera after exposure to sub-lethal concentrations of Metarhizium anisopliae sensu lato: Study on F1 generation. AB - The entomopathogenic fungus, Metarhizium anisopliae (Metsch.) Sorokin is a valuable biocontrol agent attacking larval stages of many lepidopteran pests including Helicoverpa armigera (Hubner). Sub-lethal effects of M. anisopliae sensu lato (s.l.) (isolate M14) were investigated on life table parameters of offspring from treated larvae of H. armigera. Duration of different life stages was significantly affected by fungal treatments. Fecundity was decreased in females derived from H. armigera larvae treated with M. anisopliae s.l. Sub lethal concentrations of the entomopathogen reduced the net reproduction rate (R0) of F1 insects for all treatments compared with the control. Similar reductions were observed for the intrinsic and the finite rates of increase (rm and lambda, respectively). The mean generation time (T) and the doubling time (DT) were statistically higher in offspring of individuals exposed to some fungal concentrations than control insects. Our results indicated that there was a significant decrease in the F1 population of H. armigera derived from larvae that were exposed to sub-lethal concentrations of M. anisopliae s.l. PMID- 27247226 TI - Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open label, multicentre, phase 1b trial. AB - BACKGROUND: Patients with recurrent or metastatic squamous cell carcinoma of the head and neck have few treatment options. We aimed to assess the safety, tolerability, and antitumour activity of pembrolizumab, a humanised anti programmed death receptor 1 (PD-1) antibody, in patients with PD-L1-positive recurrent or metastatic squamous cell carcinoma of the head and neck. METHODS: This study was an open-label, multicentre, phase 1b trial of patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Patients were eligible for enrolment if they were aged 18 years or older, had a confirmed diagnosis of recurrent or metastatic squamous cell carcinoma of the head and neck, and had any level of PD-L1 expression (ie, at least 1% of tumour cells or stroma that were PD-L1-positive by immunohistochemistry). Patients received pembrolizumab 10 mg/kg intravenously every 2 weeks. Primary outcomes were safety in the per-protocol population and the proportion of patients with centrally reviewed overall response per Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1). Overall response was analysed in the full analysis set, which was defined as all patients who had received at least one dose of pembrolizumab, had measurable disease at baseline, and one post-baseline scan or patients without a post-baseline scan who discontinued therapy because of disease progression or a drug-related adverse event. The study is registered with ClinicalTrials.gov, number NCT01848834 and is ongoing, but no longer enrolling patients. FINDINGS: Of the 104 patients screened between June 7, 2013, and Oct 3, 2013, 81 (78%) were PD-L1-positive. Of these, 60 patients with PD-L1-positive squamous cell carcinoma of the head and neck were enrolled and treated: 23 (38%) were HPV-positive and 37 (62%) were HPV-negative. Pembrolizumab was well tolerated, with 10 (17%) of 60 patients having grade 3-4 drug-related adverse events, the most common of which were increases in alanine aminotransferase and in aspartate aminotransferase, and hyponatraemia, each occurring in two of 60 patients; one patient developed a grade 3 drug-related rash. 27 (45%) of 60 patients experienced a serious adverse event. There were no drug-related deaths. The proportion of patients with an overall response by central imaging review was 18% (eight of 45 patients; 95% CI 8-32) in all patients and was 25% (four of 16 patients; 7-52) in HPV-positive patients and 14% (four of 29 patients; 4-32) in HPV-negative patients. INTERPRETATION: Pembrolizumab was well tolerated and demonstrated clinically meaningful antitumour activity in recurrent or metastatic squamous cell carcinoma of the head and neck, supporting further study of pembrolizumab as anticancer therapy for advanced head and neck cancers. FUNDING: Merck & Co. PMID- 27247227 TI - The promise of immunostimulatory antibodies in head and neck cancer. PMID- 27247228 TI - MicroRNA-34a affects chondrocyte apoptosis and proliferation by targeting the SIRT1/p53 signaling pathway during the pathogenesis of osteoarthritis. AB - Osteoarthritis (OA) is the most prevalent degenerative joint disease with multifactorial etiology caused by risk factors such as ageing, obesity and trauma. Previously, it was reported that the inhibition of microRNA-34a (miR-34a) may reduce rat chondrocyte apoptosis induced by IL-1beta, whereas the molecular mechanism and the role of miR-34a in human chondrocyte as well as in OA progression remains to be determined. In the current study, using MTT, luciferase reporter assays and western blot analysis we identified that miR-34a was upregulated while silent information regulator 1 (SIRT1) was inhibited in chondrocytes from 12 OA patients compared with healthy chondrocytes from 10 trauma amputees. Overexpression of miR-34a promoted apoptosis and inhibited cell proliferation in human chondrocytes. Transfection with miR-34a mimic inhibited SIRT1 expression, which attenuated the deacetylation of p53, leading to the upregulation of Bax and downregulation of Bcl-2. Furthermore, results from the western blot analysis and luciferase reporter assay demonstrated that SIRT1 was directly regulated by miR-34a in human chondrocytes. A rat model of OA was induced through anterior cruciate ligament transection and medial meniscus resection (ACLT+MMx). The results showed that the intra-articular injection of lentiviral vector encoding anti-miR-34a sequence effectively ameliorated the progression of OA. The results suggest that miR-34a has a crucial role in the pathogenesis of OA through direct regulation of the SIRT1/p53 signaling pathway and serves as a potential therapeutic target of OA. PMID- 27247229 TI - Transcriptome Remodeling Contributes to Epidemic Disease Caused by the Human Pathogen Streptococcus pyogenes. AB - For over a century, a fundamental objective in infection biology research has been to understand the molecular processes contributing to the origin and perpetuation of epidemics. Divergent hypotheses have emerged concerning the extent to which environmental events or pathogen evolution dominates in these processes. Remarkably few studies bear on this important issue. Based on population pathogenomic analysis of 1,200 Streptococcus pyogenes type emm89 infection isolates, we report that a series of horizontal gene transfer events produced a new pathogenic genotype with increased ability to cause infection, leading to an epidemic wave of disease on at least two continents. In the aggregate, these and other genetic changes substantially remodeled the transcriptomes of the evolved progeny, causing extensive differential expression of virulence genes and altered pathogen-host interaction, including enhanced immune evasion. Our findings delineate the precise molecular genetic changes that occurred and enhance our understanding of the evolutionary processes that contribute to the emergence and persistence of epidemically successful pathogen clones. The data have significant implications for understanding bacterial epidemics and for translational research efforts to blunt their detrimental effects. IMPORTANCE: The confluence of studies of molecular events underlying pathogen strain emergence, evolutionary genetic processes mediating altered virulence, and epidemics is in its infancy. Although understanding these events is necessary to develop new or improved strategies to protect health, surprisingly few studies have addressed this issue, in particular, at the comprehensive population genomic level. Herein we establish that substantial remodeling of the transcriptome of the human-specific pathogen Streptococcus pyogenes by horizontal gene flow and other evolutionary genetic changes is a central factor in precipitating and perpetuating epidemic disease. The data unambiguously show that the key outcome of these molecular events is evolution of a new, more virulent pathogenic genotype. Our findings provide new understanding of epidemic disease. PMID- 27247231 TI - Contribution of the Ade Resistance-Nodulation-Cell Division-Type Efflux Pumps to Fitness and Pathogenesis of Acinetobacter baumannii. AB - Overexpression of chromosomal resistance-nodulation-cell division (RND)-type efflux systems with broad substrate specificity contributes to multidrug resistance (MDR) in Acinetobacter baumannii We have shown that modulation of expression of the structural genes for the efflux systems AdeABC and AdeIJK confers MDR and results in numerous alterations of membrane-associated cellular functions, in particular biofilm formation. However, the contribution of these RND pumps to cell fitness and virulence has not yet been studied. The biological cost of an antibiotic resistance mechanism is a key parameter in determining its stability and dissemination. From an entirely sequenced susceptible clinical isolate, we have generated a set of isogenic derivatives having single point mutations resulting in overexpression of each efflux system or with every pump deleted by allelic replacement. We found that overproduction of the pumps results in a significant decrease in fitness of the bacterial host when measured by competition experiments in vitro Fitness and virulence were also evaluated in vivo both in systemic and pulmonary infection models in immunocompetent mice. A diminished competitiveness of the AdeABC-overexpressing mutant was observed only after intraperitoneal inoculation, but not after intranasal inoculation, the latter mimicking the most frequent type of human A. baumannii infection. However, in mice infected intranasally, this mutant was more virulent and stimulated an enhanced neutrophil activation in the lungs. Altogether, these data account for the observation that adeABC overexpression is common in MDR A. baumannii frequently found in ventilator-associated pneumonia. IMPORTANCE: Overproduction of the RND AdeABC efflux system is observed with a high incidence in multidrug resistant Acinetobacter baumannii and results in increased resistance to several antibiotics of choice for the treatment of infections caused by this nosocomial pathogen. It was therefore important to study the biological cost of the overexpression of the adeABC structural operon which is normally tightly regulated. Fitness diminution of an overexpressing mutant detected in vitro and in vivo in a model that mimics sepsis was not observed in a pulmonary infection model in which the mutant was more virulent. This points out that increased virulence can occur independently from prolonged persistence in the infected organ and can account for the elevated incidence of this resistance mechanism in clinical isolates. The study also indicates that transposon libraries will identify only virulence genes that are expressed under physiological conditions but not those that are tightly regulated. PMID- 27247230 TI - Effective Cytotoxic T Lymphocyte Targeting of Persistent HIV-1 during Antiretroviral Therapy Requires Priming of Naive CD8+ T Cells. AB - Curing HIV-1 infection will require elimination of persistent cellular reservoirs that harbor latent virus in the face of combination antiretroviral therapy (cART). Proposed immunotherapeutic strategies to cure HIV-1 infection include enhancing lysis of these infected cells by cytotoxic T lymphocytes (CTL). A major challenge in this strategy is overcoming viral immune escape variants that have evaded host immune control. Here we report that naive CD8(+) T cells from chronic HIV-1-infected participants on long-term cART can be primed by dendritic cells (DC). These DC must be mature, produce high levels of interleukin 12p70 (IL 12p70), be responsive to CD40 ligand (CD40L), and be loaded with inactivated, autologous HIV-1. These DC-primed CD8(+) T cell responders produced high levels of gamma interferon (IFN-gamma) in response to a broad range of both conserved and variable regions of Gag and effectively killed CD4(+) T cell targets that were either infected with the autologous latent reservoir-associated virus or loaded with autologous Gag peptides. In contrast, HIV-1-specific memory CD8(+) T cells stimulated with autologous HIV-1-loaded DC produced IFN-gamma in response to a narrow range of conserved and variable Gag peptides compared to the primed T cells and most notably, displayed significantly lower cytolytic function. Our findings highlight the need to selectively induce new HIV-1-specific CTL from naive precursors while avoiding activation of existing, dysfunctional memory T cells in potential curative immunotherapeutic strategies for HIV-1 infection. IMPORTANCE: Current immunotherapeutic approaches aim to enhance antiviral immunity against the HIV-1 reservoir; however, it has yet to be shown whether T cells from persons on cART can recognize and eliminate virus-infected cells. We show that in persons on cART a personalized medicine approach using their dendritic cells to stimulate their naive T cells induces potent effector CTL in vitro that recognize and eradicate HIV-1-infected CD4(+) T cells. Additionally, we show that the same stimulation of existing memory T cells results in cytokine secretion but limited effector function. Our study demonstrates that the naive T cell repertoire can recognize persistent HIV-1 during cART and supports immunotherapy strategies for an HIV-1 cure that targets naive T cells, rather than existing, dysfunctional, memory T cells. PMID- 27247232 TI - Toxoplasma gondii Cyclic AMP-Dependent Protein Kinase Subunit 3 Is Involved in the Switch from Tachyzoite to Bradyzoite Development. AB - Toxoplasma gondii is an obligate intracellular apicomplexan parasite that infects warm-blooded vertebrates, including humans. Asexual reproduction in T. gondii allows it to switch between the rapidly replicating tachyzoite and quiescent bradyzoite life cycle stages. A transient cyclic AMP (cAMP) pulse promotes bradyzoite differentiation, whereas a prolonged elevation of cAMP inhibits this process. We investigated the mechanism(s) by which differential modulation of cAMP exerts a bidirectional effect on parasite differentiation. There are three protein kinase A (PKA) catalytic subunits (TgPKAc1 to -3) expressed in T. gondii Unlike TgPKAc1 and TgPKAc2, which are conserved in the phylum Apicomplexa, TgPKAc3 appears evolutionarily divergent and specific to coccidian parasites. TgPKAc1 and TgPKAc2 are distributed in the cytomembranes, whereas TgPKAc3 resides in the cytosol. TgPKAc3 was genetically ablated in a type II cyst-forming strain of T. gondii (PruDeltaku80Deltahxgprt) and in a type I strain (RHDeltaku80Deltahxgprt), which typically does not form cysts. The Deltapkac3 mutant exhibited slower growth than the parental and complemented strains, which correlated with a higher basal rate of tachyzoite-to-bradyzoite differentiation. 3-Isobutyl-1-methylxanthine (IBMX) treatment, which elevates cAMP levels, maintained wild-type parasites as tachyzoites under bradyzoite induction culture conditions (pH 8.2/low CO2), whereas the Deltapkac3 mutant failed to respond to the treatment. This suggests that TgPKAc3 is the factor responsible for the cAMP dependent tachyzoite maintenance. In addition, the Deltapkac3 mutant had a defect in the production of brain cysts in vivo, suggesting that a substrate of TgPKAc3 is probably involved in the persistence of this parasite in the intermediate host animals. IMPORTANCE: Toxoplasma gondii is one of the most prevalent eukaryotic parasites in mammals, including humans. Parasites can switch from rapidly replicating tachyzoites responsible for acute infection to slowly replicating bradyzoites that persist as a latent infection. Previous studies have demonstrated that T. gondii cAMP signaling can induce or suppress bradyzoite differentiation, depending on the strength and duration of cAMP signal. Here, we report that TgPKAc3 is responsible for cAMP-dependent tachyzoite maintenance while suppressing differentiation into bradyzoites, revealing one mechanism underlying how this parasite transduces cAMP signals during differentiation. PMID- 27247233 TI - Targeting Mycobacterium tuberculosis Tumor Necrosis Factor Alpha-Downregulating Genes for the Development of Antituberculous Vaccines. AB - Tumor necrosis factor alpha (TNF) plays a critical role in the control of Mycobacterium tuberculosis, in part by augmenting T cell responses through promoting macrophage phagolysosomal fusion (thereby optimizing CD4(+) T cell immunity by enhancing antigen presentation) and apoptosis (a process that can lead to cross-priming of CD8(+) T cells). M. tuberculosis can evade antituberculosis (anti-TB) immunity by inhibiting host cell TNF production via expression of specific mycobacterial components. We hypothesized that M. tuberculosis mutants with an increased capacity to induce host cell TNF production (TNF-enhancing mutants) and thus with enhanced immunogenicity can be useful for vaccine development. To identify mycobacterial genes that regulate host cell TNF production, we used a TNF reporter macrophage clone to screen an H37Rv M. tuberculosis cosmid library constructed in M. smegmatis The screen has identified a set of TNF-downregulating mycobacterial genes that, when deleted in H37Rv, generate TNF-enhancing mutants. Analysis of mutants disrupted for a subset of TNF-downregulating genes, annotated to code for triacylglycerol synthases and fatty acyl-coenzyme A (acyl-CoA) synthetase, enzymes that concern lipid biosynthesis and metabolism, has revealed that these strains can promote macrophage phagolysosomal fusion and apoptosis better than wild-type (WT) bacilli. Immunization of mice with the TNF-enhancing M. tuberculosis mutants elicits CD4(+) and CD8(+) T cell responses that are superior to those engendered by WT H37Rv. The results suggest that TNF-upregulating M. tuberculosis genes can be targeted to enhance the immunogenicity of mycobacterial strains that can serve as the substrates for the development of novel anti-TB vaccines. IMPORTANCE: One way to control tuberculosis (TB), which remains a major global public health burden, is by immunization with an effective vaccine. The efficacy of Mycobacterium bovis BCG, the only currently approved TB vaccine, is inconsistent. Tumor necrosis factor alpha (TNF) is a cytokine that plays an important role in controlling TB. M. tuberculosis, the causative agent of TB, can counter this TNF based defense by decreasing host cell TNF production. This study identified M. tuberculosis genes that can mediate inhibition of TNF production by macrophage (an immune cell critical to the control of TB). We have knocked out a number of these genes to generate M. tuberculosis mutants that can enhance macrophage TNF production. Immunization with these mutants in mice triggered a T cell response stronger than that elicited by the parental bacillus. Since T cell immunity is pivotal in controlling M. tuberculosis, the TNF-enhancing mutants can be used to develop novel TB vaccines. PMID- 27247234 TI - Aspergillus Cell Wall Chitin Induces Anti- and Proinflammatory Cytokines in Human PBMCs via the Fc-gamma Receptor/Syk/PI3K Pathway. AB - Chitin is an important cell wall component of Aspergillus fumigatus conidia, of which hundreds are inhaled on a daily basis. Previous studies have shown that chitin has both anti- and proinflammatory properties; however the exact mechanisms determining the inflammatory signature of chitin are poorly understood, especially in human immune cells. Human peripheral blood mononuclear cells were isolated from healthy volunteers and stimulated with chitin from Aspergillus fumigatus Transcription and production of the proinflammatory cytokine interleukin-1beta (IL-1beta) and the anti-inflammatory cytokine IL-1 receptor antagonist (IL-1Ra) were measured from the cell culture supernatant by quantitative PCR (qPCR) or enzyme-linked immunosorbent assay (ELISA), respectively. Chitin induced an anti-inflammatory signature characterized by the production of IL-1Ra in the presence of human serum, which was abrogated in immunoglobulin-depleted serum. Fc-gamma-receptor-dependent recognition and phagocytosis of IgG-opsonized chitin was identified as a novel IL-1Ra-inducing mechanism by chitin. IL-1Ra production induced by chitin was dependent on Syk kinase and phosphatidylinositol 3-kinase (PI3K) activation. In contrast, costimulation of chitin with the pattern recognition receptor (PRR) ligands lipopolysaccharide, Pam3Cys, or muramyl dipeptide, but not beta-glucan, had synergistic effects on the induction of proinflammatory cytokines by human peripheral blood mononuclear cells (PBMCs). In conclusion, chitin can have both pro- and anti-inflammatory properties, depending on the presence of pathogen associated molecular patterns and immunoglobulins, thus explaining the various inflammatory signatures reported for chitin. IMPORTANCE: Invasive aspergillosis and allergic aspergillosis are increasing health care problems. Patients get infected by inhalation of the airborne spores of Aspergillus fumigatus A profound knowledge of how Aspergillus and its cell wall components are recognized by the host cell and which type of immune response it induces is necessary to develop target-specific treatment options with less severe side effects than the treatment options to date. There is controversy in the literature about the receptor for chitin in human cells. We identified the Fc-gamma receptor and Syk/PI3K pathway via which chitin can induce anti-inflammatory immune responses by inducing IL-1 receptor antagonist in the presence of human immunoglobulins but also proinflammatory responses in the presence of bacterial components. This explains why Aspergillus does not induce strong inflammation just by inhalation and rather fulfills an immune-dampening function. While in a lung coinfected with bacteria, Aspergillus augments immune responses by shifting toward a proinflammatory reaction. PMID- 27247235 TI - Endovascular therapy for advanced post-thrombotic syndrome: Proceedings from a multidisciplinary consensus panel. AB - Patients with advanced post-thrombotic syndrome (PTS) and chronic iliac vein obstruction suffer major physical limitations and impairment of health-related quality of life. Currently there is a lack of evidence-based treatment options for these patients. Early studies suggest that imaging-guided, catheter-based endovascular therapy can eliminate iliac vein obstruction and saphenous venous valvular reflux, resulting in reduced PTS severity; however, these observations have not been rigorously validated. A multidisciplinary expert panel meeting was convened to plan a multicenter randomized controlled clinical trial to evaluate endovascular therapy for the treatment of advanced PTS. This article summarizes the findings of the panel, and is expected to assist in developing a National Institutes of Health-sponsored clinical trial and other studies to improve the care of patients with advanced PTS. PMID- 27247237 TI - Active DNA demethylation by DNA repair: Facts and uncertainties. AB - Pathways that control and modulate DNA methylation patterning in mammalian cells were poorly understood for a long time, although their importance in establishing and maintaining cell type-specific gene expression was well recognized. The discovery of proteins capable of converting 5-methylcytosine (5mC) to putative substrates for DNA repair introduced a novel and exciting conceptual framework for the investigation and ultimate discovery of molecular mechanisms of DNA demethylation. Against the prevailing notion that DNA methylation is a static epigenetic mark, it turned out to be dynamic and distinct mechanisms appear to have evolved to effect global and locus-specific DNA demethylation. There is compelling evidence that DNA repair, in particular base excision repair, contributes significantly to the turnover of 5mC in cells. By actively demethylating DNA, DNA repair supports the developmental establishment as well as the maintenance of DNA methylation landscapes and gene expression patterns. Yet, while the biochemical pathways are relatively well-established and reviewed, the biological context, function and regulation of DNA repair-mediated active DNA demethylation remains uncertain. In this review, we will thus summarize and critically discuss the evidence that associates active DNA demethylation by DNA repair with specific functional contexts including the DNA methylation erasure in the early embryo, the control of pluripotency and cellular differentiation, the maintenance of cell identity, and the nuclear reprogramming. PMID- 27247239 TI - Access Barriers to Long-Acting Reversible Contraceptives for Adolescents. AB - The United States continues to have the highest adolescent birth rate of any industrialized country. Recently published guidelines by the American Academy of Pediatrics create a new consensus among professional organizations around the suitability of long-acting reversible contraceptives as first-line contraception for adolescents. Through a narrative review of U.S. studies published after 2000, this study seeks to summarize existing access barriers to long-acting reversible contraceptives for adolescents and highlight areas that warrant further intervention so that the recommendations of these professional organizations can be effectively integrated into clinical practice. Existing barriers include costs for institutions providing contraceptive care and for recipients; consent and confidentiality for adolescent patients; providers' attitudes, misconceptions and limited training; and patients' lack of awareness or misconceptions. Systemic policy interventions are required to address cost and confidentiality, such as the Affordable Care Act's mandate that contraceptive coverage be a part of essential health benefits for all insurance providers. Individual-level access barriers such as providers' misconceptions and gaps in technical training as well as patients' lack of awareness can be addressed directly by professional medical organizations, health care training programs, and other interventions. PMID- 27247240 TI - Preparation of positive blood cultures for direct MALDI-ToF MS identification. AB - MALDI-ToF MS can be used to identify microorganisms directly from blood cultures. This study compared two methods of sample preparation. Similar levels of genus- (91% vs 90%) and species-level identifications (79% vs 74%) were obtained with differential centrifugation and SDS methods. The SDS method is faster and requires minimal handling. PMID- 27247238 TI - XPA: A key scaffold for human nucleotide excision repair. AB - Nucleotide excision repair (NER) is essential for removing many types of DNA lesions from the genome, yet the mechanisms of NER in humans remain poorly understood. This review summarizes our current understanding of the structure, biochemistry, interaction partners, mechanisms, and disease-associated mutations of one of the critical NER proteins, XPA. PMID- 27247241 TI - Influence of gender and body hemisphere on the occurrence of wavy ribs: An analysis of spontaneous skeletal abnormalities in Wistar rat fetuses. AB - The differentiation of background findings from anomalies relevant for the safety evaluation of a future drug is a major task in the interpretation of developmental toxicity studies. The anomaly wavy rib often occurs in litters exposed to the test substance, but is also frequently present in control litters. Therefore, the relevance of this finding for risk assessment is under discussion. We characterized the skeletal morphology of fetuses with wavy ribs from our background data. Differences in the incidence of wavy ribs between the genders, with approximately twice as many male fetuses having wavy ribs, compared to females, and an overrepresentation of the right body hemisphere were observed. Affected fetuses often occurred clustered in single litters. The presented data might be useful for differentiation of spontaneously occurring wavy ribs from abnormal patterns induced by a test substance. PMID- 27247242 TI - Alterations in male rats following in utero exposure to betamethasone suggests changes in reproductive programming. AB - Antenatal betamethasone is used for accelerating fetal lung maturation for women at risk of preterm birth. Altered sperm parameters were reported in adult rats after intrauterine exposure to betamethasone. In this study, male rat offspring were assessed for reproductive development after dam exposure to betamethasone (0.1mg/kg) or vehicle on Days 12, 13, 18 and 19 of pregnancy. The treatment resulted in reduction in the offspring body weight, delay in preputial separation, decreased seminal vesicle weight, testosterone levels and fertility, and increased testicular weight. In the testis, morphologically abnormal seminiferous tubules were observed, characterized by an irregular cell distribution with Sertoli cell that were displaced towards the tubular lumen. These cells expressed both Connexin 43 (Cx43) and Proliferative Nuclear Cell Antigen (PCNA). In conclusion, intrauterine betamethasone treatment appears to promote reproductive programming and impairment of rat sexual development and fertility due to, at least in part, unusual testicular disorders. PMID- 27247244 TI - Reconstruction of ancestral chromosome architecture and gene repertoire reveals principles of genome evolution in a model yeast genus. AB - Reconstructing genome history is complex but necessary to reveal quantitative principles governing genome evolution. Such reconstruction requires recapitulating into a single evolutionary framework the evolution of genome architecture and gene repertoire. Here, we reconstructed the genome history of the genus Lachancea that appeared to cover a continuous evolutionary range from closely related to more diverged yeast species. Our approach integrated the generation of a high-quality genome data set; the development of AnChro, a new algorithm for reconstructing ancestral genome architecture; and a comprehensive analysis of gene repertoire evolution. We found that the ancestral genome of the genus Lachancea contained eight chromosomes and about 5173 protein-coding genes. Moreover, we characterized 24 horizontal gene transfers and 159 putative gene creation events that punctuated species diversification. We retraced all chromosomal rearrangements, including gene losses, gene duplications, chromosomal inversions and translocations at single gene resolution. Gene duplications outnumbered losses and balanced rearrangements with 1503, 929, and 423 events, respectively. Gene content variations between extant species are mainly driven by differential gene losses, while gene duplications remained globally constant in all lineages. Remarkably, we discovered that balanced chromosomal rearrangements could be responsible for up to 14% of all gene losses by disrupting genes at their breakpoints. Finally, we found that nonsynonymous substitutions reached fixation at a coordinated pace with chromosomal inversions, translocations, and duplications, but not deletions. Overall, we provide a granular view of genome evolution within an entire eukaryotic genus, linking gene content, chromosome rearrangements, and protein divergence into a single evolutionary framework. PMID- 27247245 TI - Phenotypic Screens in Antimalarial Drug Discovery. AB - Phenotypic high-throughput screens are a valuable tool for identifying new chemical compounds with antimalarial activity. Traditionally, these screens have focused solely on the symptomatic asexual blood stage of the parasite life cycle; however, to discover new medicines for malaria treatment and prevention, robust screening technologies against other parasite life-cycle stages are required. This review highlights recent advances and progress toward phenotypic screening methodologies over the past several years, with a focus on exoerythrocytic stage screens. PMID- 27247246 TI - Toxoplasma Retromer Is Here to Stay. AB - How the protozoan pathogen Toxoplasma gondii and related parasites shuttle proteins through their intricate system of endomembranous compartments remains unclear. Sangare et al. show that the Toxoplasma retromer complex is essential for parasite viability through its role in protein targeting to multiple locales and its interactions with newly identified partners. PMID- 27247247 TI - Nursing Outcomes for the Evaluation of Patients During Smoking Cessation. AB - OBJECTIVES: To select outcomes of the Nursing Outcomes Classification (NOC) and develop operational definitions for their indicators in order to evaluate patients during smoking cessation. METHODS: A consensus study among experts, involving eight nurses. A 100% consensus was required to select the outcomes. Operational definitions were developed based on the literature. RESULTS: Two outcomes were selected, Smoking Cessation Behavior (1625)-with nine indicators, and Substance Withdrawal Severity (2108)-with 11 indicators, for which we developed operational definitions. CONCLUSIONS: Consensus allowed the selection of NOC outcomes and indicators, which will allow us to evaluate patients during smoking cessation using a standardized classification. IMPLICATIONS FOR NURSING PRACTICE: A standardized classification provides a more qualified evaluation of patients during smoking cessation. PMID- 27247248 TI - Chronic neural probe for simultaneous recording of single-unit, multi-unit, and local field potential activity from multiple brain sites. AB - OBJECTIVE: Drug resistant focal epilepsy can be treated by resecting the epileptic focus requiring a precise focus localisation using stereoelectroencephalography (SEEG) probes. As commercial SEEG probes offer only a limited spatial resolution, probes of higher channel count and design freedom enabling the incorporation of macro and microelectrodes would help increasing spatial resolution and thus open new perspectives for investigating mechanisms underlying focal epilepsy and its treatment. This work describes a new fabrication process for SEEG probes with materials and dimensions similar to clinical probes enabling recording single neuron activity at high spatial resolution. APPROACH: Polyimide is used as a biocompatible flexible substrate into which platinum electrodes and leads are integrated with a minimal feature size of 5 MUm. The polyimide foils are rolled into the cylindrical probe shape at a diameter of 0.8 mm. The resulting probe features match those of clinically approved devices. Tests in saline solution confirmed the probe stability and functionality. Probes were implanted into the brain of one monkey (Macaca mulatta), trained to perform different motor tasks. Suitable configurations including up to 128 electrode sites allow the recording of task-related neuronal signals. MAIN RESULTS: Probes with 32 and 64 electrode sites were implanted in the posterior parietal cortex. Local field potentials and multi-unit activity were recorded as early as one hour after implantation. Stable single-unit activity was achieved for up to 26 days after implantation of a 64-channel probe. All recorded signals showed modulation during task execution. SIGNIFICANCE: With the novel probes it is possible to record stable biologically relevant data over a time span exceeding the usual time needed for epileptic focus localisation in human patients. This is the first time that single units are recorded along cylindrical polyimide probes chronically implanted 22 mm deep into the brain of a monkey, which suggests the potential usefulness of this probe for human applications. PMID- 27247249 TI - Electronic Modulation of the SOMO-HOMO Energy Gap in Iron(III) Complexes towards Unimolecular Current Rectification. AB - Amphiphilic five-coordinate iron(III) complexes with {N2 O2 Cl} and {N2 O3 } coordination spheres are studied to elucidate the roles of electronic structure on the mechanisms for current rectification. The presence of an apical chlorido or phenolato ligand plays a crucial role, and the [Fe(III) {N2 O2 Cl}] species supports an asymmetric mechanism while its [Fe(III) {N2 O3 }] counterpart seems to allow for unimolecular mechanism. The effects of electron-donating and electron-withdrawing substituents in the ligand frameworks are also considered. PMID- 27247250 TI - On the Additivity of Molecular Fragment Dipole Moments of 5-Substituted Indole Derivatives. AB - The estimate of the magnitude and the orientation of molecular electric dipole moments from the vector sum of bond or fragment dipole moments is a widely used approach in chemistry. However, the limitations of this intuitive model have rarely been tested experimentally, particularly for electronically excited states. Herein, we find rules for a number of indole derivatives by using rotationally resolved electronic Stark spectroscopy and ab initio calculations. Based on a natural-bond-orbital analysis, we discuss whether the vector additivity rule can be applied in a given electronic state. From a comparison of the experimental data with ab initio calculations, we deduced that the additivity model does not apply when the flow of electron density from the substituent is opposed to that inside the chromophore. PMID- 27247251 TI - Kennicutt-Schmidt Law in the Central Region of NGC 4321 as Seen by ALMA. AB - We present the Atacama Large Millimeter/Sub-millimeter Array (ALMA) cycle-0 science verification data of the CO(1-0) line emission in the central region of NGC 4321 (also known as M100) at the distance of 17.1 Mpc and VLA, L-band data of HI of the same galaxy. We have drawn the center area of M100 in the (12)CO(J = 1 0) line with the resolution of (3.87" * 2.53") as viewed by ALMA, along with HI and Spitzer 8 and 3.6 MUm data. The relationship between the surface density of molecular gas mass ?H2 and that of star formation rate ?SFR has been investigated, in addition to the relationship between the surface density of the neutral atomic hydrogen mass and that of ?SFR (Kennicutt-Schmidt law) in this galaxy with a high spatial resolution. The results indicate that a significant correlation exists between the SFR surface density and the molecular gas mass density in the ~2 kpc region. The power-law index has been determined for three regions: center, upper and lower arms. The value of this index in the center region is 1.13, which follows the traditional (K-S) law and indicates that the molecular gas is affected by star formation. PMID- 27247252 TI - Synthesis, Optical Properties, and Electronic Structures of Tetrakis(pentafluorophenyl)tetrathiaisophlorin Dioxide. AB - The synthesis, structure, optical and redox properties, and electronic structure of tetrakis(pentafluorophenyl)tetrathiaisophlorin dioxide (12) are reported. Oxidation of tetrakis(pentafluorophenyl)tetrathiaisophlorin (11) with dimethyldioxirane afforded the oxidized product, which was the tetrathiaisophlorin with two thiophene 1-oxide moieties (12). More significant nonplanarity and greater bond length alternation in 12 than those of 11 were observed by X-ray structural analysis. The absorption spectrum of 12 contains two bands at lambda=348 and 276 nm, with a weak tail that extends to lambda~650 nm. Analysis of the magnetic circular dichroism spectrum of 12, based on Michl's 4N perimeter model and molecular orbital calculations, indicate that the broad band at lambda=348 nm appears to contain N2 and P2 bands, and 12 is classified as a 4npi system, similar to 11. The nuclear-independent chemical shift values and (1) H NMR spectroscopy data indicate that 12 has more antiaromatic character than 11. PMID- 27247253 TI - MicroRNAs in a hypertrophic heart: from foetal life to adulthood. AB - The heart is the first organ to form and undergoes adaptive remodelling with age. Ventricular hypertrophy is one such adaptation, which allows the heart to cope with an increase in cardiac demand. This adaptation is necessary as part of natural growth from foetal life to adulthood. It may also occur in response to resistance in blood flow due to various insults on the heart and vessels that accumulate with age. The heart can only compensate to this increase in workload to a certain extent without losing its functional architecture, ultimately resulting in heart failure. Many genes have been implicated in cardiac hypertrophy, however none have been shown conclusively to be responsible for pathological cardiac hypertrophy. MicroRNAs offer an alternative mechanism for cellular regulation by altering gene expression. Since 1993 when the function of a non-coding DNA sequence was first discovered in the model organism Caenorhabditis elegans, many microRNAs have been implicated in having a central role in numerous physiological and pathological cellular processes. The level of control these antisense oligonucleotides offer can often be exploited to manipulate the expression of target genes. Moreover, altered levels of microRNAs can serve as diagnostic biomarkers, with the prospect of diagnosing a disease process as early as during foetal life. Therefore, it is vital to ascertain and investigate the function of microRNAs that are involved in heart development and subsequent ventricular remodelling. Here we present an overview of the complicated network of microRNAs and their target genes that have previously been implicated in cardiogenesis and hypertrophy. It is interesting to note that microRNAs in both of these growth processes can be of possible remedial value to counter a similar disease pathophysiology. PMID- 27247254 TI - Are South African Speech-Language Therapists adequately equipped to assess English Additional Language (EAL) speakers who are from an indigenous linguistic and cultural background? A profile and exploration of the current situation. AB - This article presents the results of a survey conducted on Speech-Language Therapists (SLTs) regarding current practices in the assessment of English Additional Language (EAL) speakers in South Africa. It forms part of the rationale for a broader (PhD) study that critiques the use of assessment instruments on EAL speakers from an indigenous linguistic and cultural background. This article discusses an aspect of the broader research and presents the background, method, findings, discussion and implications of the survey. The results of this survey highlight the challenges of human and material resources to, and the dominance of English in, the profession in South Africa. The findings contribute to understanding critical factors for acquiring reliable and valid assessment results with diverse populations, particularly the implications from a cultural and linguistic perspective. PMID- 27247255 TI - The prevalence of hearing impairment within the Cape Town Metropolitan area. AB - BACKGROUND: There is a lack of data on the prevalence of hearing impairment in South Africa. Current data is unreliable as it is based on national census information which tends to underestimate the prevalence of hearing impairment. AIM: The aim of this study was to estimate the prevalence of hearing impairment in the Cape Town Metropolitan area and to determine factors associated with hearing impairment. METHOD: A cross-sectional household survey involving 2494 partcipants from 718 households was conducted between the months of February and October 2013. Random cluster sampling was used to select four health sub districts from eight health sub-districts in the Cape Town Metropolitan area using a method of probability proportional to size (PPS). The survey was conducted according to the World Health Organization (WHO) Ear and Hearing Disorders Survey Protocol and the classifcation of hearing impairment matched the WHO's criteria for the grading of hearing impairment. RESULTS: The overall prevalence of hearing impairment in the population of this study was 12.35% (95%CI: 11.06% - 13.64%) and prevalence of disabling hearing impairment was 4.57% (95% CI: 3.75% - 5.39%) amongst individuals >= 4 years old. The following factors were found to be associated with hearing impairment; male gender, age, hypertension, a history of head and neck trauma and a family history of hearing impairment. CONCLUSION: Based on the data from communities surveyed during this study, hearing impairment is more prevalent than previously estimated based on national population census information. Interventions for the prevention of hearing impairment in these communities should focus on individuals with associated risk factors. PMID- 27247256 TI - Association of symmetrical alkane diols with pyridine: DFT/GIAO calculation of 1 H NMR chemical shifts. AB - Proton nuclear magnetic resonance (NMR) shifts of the free diol and of its 1 : 1 and 1 : 2 hydrogen-bonded complexes with pyridine have been computed for five symmetrical alkane diols on the basis of density functional theory, by applying the gauge-including atomic orbital method to geometry-optimized conformers. For certain conformers, intramolecular OH...OH interactions, evidenced by high NMR OH proton shifts, are further enhanced on going from the free diol to the corresponding 1 : 1 diol/pyridine complex. This is confirmed by atoms-in molecules and non-covalent interaction plots. The computed OH and CH proton shifts for the diol and the two complexes correlate well with values obtained by analysing data from the NMR titration of the diols in benzene against pyridine. Shift values for the diols in neat pyridine are calculated by weighting the shifts of the various protons in the three forms (free diol, 1 : 1 and 1 : 2 diol/pyridine complexes) according to the experimentally determined association constants. The results are in good agreement with those observed, and after empirical scaling, the root mean square difference is 0.18 ppm. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27247257 TI - Allergy tests do not predict food triggers in adult patients with eosinophilic oesophagitis. A comprehensive prospective study using five modalities. AB - BACKGROUND: The use of allergy tests to guide dietary treatment for eosinophilic oesophagitis (EoE) is controversial and data are limited. Aeroallergen sensitisation patterns and food triggers have been defined in Northern Hemisphere cohorts only. AIMS: To determine if allergy tests that are routinely available can predict food triggers in adult patients with EoE. To define the food triggers and aeroallergen sensitisation patterns in a novel Southern Hemisphere (Australian) cohort of patients. METHODS: Consecutive patients with EoE who elected to undergo dietary therapy were prospectively assessed, demographic details and atopic characteristics recorded, and allergy tests, comprising skin prick and skin-patch tests, serum allergen-specific IgE, basophil activation test and serum food-specific IgG, were performed. Patients underwent a six-food elimination diet with a structured algorithm that included endoscopic and histological examination of the oesophagus a minimum of 2 weeks after each challenge. Response was defined as <15 eosinophils per HPF. Foods defined as triggers were considered as gold standard and were compared with those identified by allergy testing. RESULTS: No allergy test could accurately predict actual food triggers. Concordance among skin-prick and serum allergen-specific IgE was high for aeroallergens only. Among seasonal aeroallergens, rye-grass sensitisation was predominant. Food triggers were commonly wheat, milk and egg, alone or in combination. CONCLUSIONS: None of the currently-available allergy tests predicts food triggers for EoE. Exclusion-rechallenge methodology with oesophageal histological assessment remains the only effective investigation. The same food triggers were identified in this southern hemisphere cohort as previously described. PMID- 27247258 TI - Nail-patella-syndrome in a young patient followed up over 10 years: relevance of the sagittal trochlear septum for patellofemoral pathology. AB - INTRODUCTION: Nail-patella-syndrome (NPS) is a rare autosomal-dominant inherited disease with pathologies of nails, skeleton, kidneys, and eyes. Linkage to a mutated gene was found. It codes for the transcription-factor LMX1B. In most cases knees are symptomatic. Patients have hypoplastic patellae, which are laterally subluxated. In those individuals a sagittal trochlear fibrous septum was found, dividing the anterior knee-joint-space. In the literature the etiology and clinical significance of this anatomic abnormality is unclear. Based on clinical and intraoperative findings we developed a theory regarding knee pathology in nail-patella-syndrome. Successful treatment via early resection of the septum with sustained good outcome is presented. METHODS: In a symptomatic six-year-old boy with nail-patella-syndrome we resected the fibrous sagittal septum adherent to the trochlea femoris and we balanced the patella via lateral release and medial plication in both knee joints. We analyzed the clinical outcome of this procedure prospectively over 10 years. RESULTS: Postoperatively the hypoplastic patellae stayed centered and stable during further skeletal development. The patient was still pain free with normal range of motion of both operated knee joints after 10 years of follow-up. DISCUSSION: In patients with nail-patella-syndrome and a subluxated or dislocated patella we recommend diagnostics with magnetic-resonance-imaging and early surgical treatment via resection of the trochlear septum and soft-tissue-balancing of the patella. When the septum displaces the patella and prevents physiological articulation of the patella with the trochlea femoris, early septum resection is likely to be important for a good functional outcome and proper development of the patellofemoral joint during growth. PMID- 27247260 TI - A case of liver abscess caused by tigecycline-nonsusceptible Klebsiella pneumoniae. PMID- 27247259 TI - miR-1 suppresses the growth of esophageal squamous cell carcinoma in vivo and in vitro through the downregulation of MET, cyclin D1 and CDK4 expression. AB - Several aberrant microRNAs (miRNAs or miRs) have been implicated in esophageal cancer (EC), which is widely prevalent in China. However, their role in EC tumorigenesis has not yet been fully elucidated. In the present study, we determined that miR-1 was downregulated in esophageal squamous cell carcinoma (ESCC) tissues compared with adjacent non-neoplastic tissues using RT-qPCR, and confirmed this using an ESCC cell line. Using a nude mouse xenograft model, we confirmed that the re-expression of miR-1 significantly inhibited ESCC tumor growth. A tetrazolium assay and a trypan blue exclusion assay revealed that miR-1 suppressed ESCC cell proliferation and increased apoptosis, whereas the silencing of miR-1 promoted cell proliferation and decreased apoptosis, suggesting that miR 1 is a novel tumor suppressor. To elucidate the molecular mechanisms of action of miR-1 in ESCC, we investigated putative targets using bioinformatics tools. MET, cyclin D1 and cyclin-dependent kinase 4 (CDK4), which are involved in the hepatocyte growth factor (HGF)/MET signaling pathway, were found to be targets of miR-1. miR-1 expression inversely correlated with MET, cyclin D1 and CDK4 expression in ESCC cells. miR-1 directly targeted MET, cyclin D1 and CDK4, suppressing ESCC cell growth. The newly identified miR-1/MET/cyclin D1/CDK4 axis provides new insight into the molecular mechanisms of ESCC pathogenesis and indicates a novel strategy for the diagnosis and treatment of ESCC. PMID- 27247261 TI - Boosting Slow Oscillatory Activity Using tDCS during Early Nocturnal Slow Wave Sleep Does Not Improve Memory Consolidation in Healthy Older Adults. AB - BACKGROUND: Previous studies have demonstrated an enhancement of hippocampal dependent declarative memory consolidation, associated slow wave sleep (SWS) and slow wave activity (SWA) after weak slow oscillatory stimulation (so-tDCS) during early non-rapid eye movement sleep (NREM) in young adults. Recent studies in older individuals could not confirm these findings. However, it remained unclear if this difference was due to variations in study protocol or to the age group under study. OBJECTIVE/HYPOTHESIS: Here, we asked if so-tDCS promotes neurophysiological events and associated sleep-dependent memory in the visuo spatial domain in older adults, using a stimulation protocol that closely resembled the one employed in young adults. METHODS: In a randomized, placebo controlled single-blind (participant) crossover study so-tDCS (0.75 Hz; max. current density 0.522 mA/cm(2)) vs. sham stimulation was applied over the frontal cortex of 21 healthy older subjects. Impact of stimulation on frequency band activity (linear mixed models), two declarative and one procedural memory tasks (repeated measures ANOVA) and percentage of sleep stages (comparison of means) was assessed. RESULTS: so-tDCS, as compared to sham, increased SWA and spindle activity immediately following stimulation, accompanied by significantly impaired visuo-spatial memory consolidation. Furthermore, verbal and procedural memory remained unchanged, while percentage of NREM sleep stage 4 was decreased over the entire night (uncorrected). CONCLUSION: so-tDCS increased SWA and spindle activity in older adults, events previously associated with stimulation-induced improved consolidation of declarative memories in young subjects. However, consolidation of visuo-spatial (primary outcome) and verbal memories was not beneficially modulated, possibly due to decline in SWS over the entire night that may have prevented and even reversed immediate beneficial effects of so-tDCS on SWA. PMID- 27247262 TI - Accelerated Transcranial Direct Current Stimulation in Alzheimer's Disease: A Case Study. PMID- 27247263 TI - Total Laparoscopic (S-LPS) versus TELELAP ALF-X Robotic-Assisted Hysterectomy: A Case-Control Study. AB - STUDY OBJECTIVE: To compare the feasibility and safety of the TELELAP ALF-X system and standard laparoscopy for total hysterectomy to treat patients with benign and early malignant gynecologic disease. DESIGN: Single-institution retrospective case-control study (Canadian Task Force classification II-2). SETTING: Catholic University of the Sacred Heart, Rome, Italy. PATIENTS: Between October 2013 and May 2015, 203 women underwent TELELAP-ALF X (group 1) or standard laparoscopic (group 2) total hysterectomy and were enrolled. INTERVENTIONS: Total standard laparoscopy vs TELELAP ALF-X robot-assisted hysterectomy for benign and early malignant gynecologic disease. MEASUREMENTS AND MAIN RESULTS: In group 1, the median age was 55 years (range, 40-79 years), median body mass index (BMI) was 25 kg/m(2) (range, 17-38 kg/m(2)), and 51 patients (58%) had undergone previous abdominal surgery. In the control group, the median age was 55 years (range, 34-90 years), median BMI was 25 kg/m(2) (range, 17-41 kg/m(2)), and 31 patients (27%) had previous abdominal surgery. The median operative time was 147 minutes (range, 58-320 minutes) in group 1 and 80 minutes (range, 22-300 minutes) in group 2 (p = .055). The median estimated blood loss was 57 mL (range, 0-600 mL) in group 1 and 99 mL (range, 0-400 mL) in group 2, with no significant differences between the 2 groups (p = .963). Procedures were successfully performed without conversion in 94.3% of cases in the group 1 and in all cases in group 2. Early postoperative pain was significantly lower in group 2. CONCLUSION: TELELAP ALF-X hysterectomy in patients with benign and early malignant gynecologic disease is feasible and safe, and can be considered a valid option for these patients. PMID- 27247264 TI - The Intrasigmoid Device. PMID- 27247265 TI - ZDHHC3 Tyrosine Phosphorylation Regulates Neural Cell Adhesion Molecule Palmitoylation. AB - The neural cell adhesion molecule (NCAM) mediates cell-cell and cell-matrix adhesion. It is broadly expressed in the nervous system and regulates neurite outgrowth, synaptogenesis, and synaptic plasticity. Previous in vitro studies revealed that palmitoylation of NCAM is required for fibroblast growth factor 2 (FGF2)-stimulated neurite outgrowth and identified the zinc finger DHHC (Asp-His His-Cys)-containing proteins ZDHHC3 and ZDHHC7 as specific NCAM-palmitoylating enzymes. Here, we verified that FGF2 controlled NCAM palmitoylation in vivo and investigated molecular mechanisms regulating NCAM palmitoylation by ZDHHC3. Experiments with overexpression and pharmacological inhibition of FGF receptor (FGFR) and Src revealed that these kinases control tyrosine phosphorylation of ZDHHC3 and that ZDHHC3 is phosphorylated by endogenously expressed FGFR and Src proteins. By site-directed mutagenesis, we found that Tyr18 is an FGFR1-specific ZDHHC3 phosphorylation site, while Tyr295 and Tyr297 are specifically phosphorylated by Src kinase in cell-based and cell-free assays. Abrogation of tyrosine phosphorylation increased ZDHHC3 autopalmitoylation, enhanced interaction with NCAM, and upregulated NCAM palmitoylation. Expression of ZDHHC3 with tyrosine mutated in cultured hippocampal neurons promoted neurite outgrowth. Our findings for the first time highlight that FGFR- and Src-mediated tyrosine phosphorylation of ZDHHC3 modulates ZDHHC3 enzymatic activity and plays a role in neuronal morphogenesis. PMID- 27247266 TI - The C-Terminal RGG Domain of Human Lsm4 Promotes Processing Body Formation Stimulated by Arginine Dimethylation. AB - Processing bodies (PBs) are conserved cytoplasmic aggregations of translationally repressed mRNAs assembled with mRNA decay factors. The aggregation of mRNA protein (mRNP) complexes into PBs involves interactions between low-complexity regions of protein components of the mRNPs. In Saccharomyces cerevisiae, the carboxy (C)-terminal Q/N-rich domain of the Lsm4 subunit of the Lsm1-7 complex plays an important role in PB formation, but the C-terminal domain of Lsm4 in most eukaryotes is an RGG domain rather than Q/N rich. Here we show that the Lsm4 RGG domain promotes PB accumulation in human cells and that symmetric dimethylation of arginines within the RGG domain stimulates this process. A mutant Lsm4 protein lacking the RGG domain failed to rescue PB formation in cells depleted of endogenous Lsm4, although this mutant protein retained the ability to assemble with Lsm1-7, associate with decapping factors, and promote mRNA decay and translational repression. Mutation of the symmetrically dimethylated arginines within the RGG domain impaired the ability of Lsm4 to promote PB accumulation. Depletion of PRMT5, the primary protein arginine methyltransferase responsible for symmetric arginine dimethylation, including Lsm4, resulted in loss of PBs. We also uncovered the histone acetyltransferase 1 (HAT1)-RBBP7 lysine acetylase complex as an interaction partner of the Lsm4 RGG domain but found no evidence of a role for this complex in PB metabolism. Together, our findings suggest a stimulatory role for posttranslational modifications in PB accumulation and raise the possibility that mRNP dynamics are posttranslationally regulated. PMID- 27247268 TI - Development of soybeans with low P34 allergen protein concentration for reduced allergenicity of soy foods. AB - BACKGROUND: In soybean, at least 16 seed proteins have been identified as causing allergenic reactions in sensitive individuals. As a soybean genebank accession low in the immunodominant protein P34 (Gly m Bd 30K) has recently been found, introgression of the low-P34 trait into adapted soybean germplasm has been attempted in order to improve the safety of food products containing soybean protein. Therefore, marker-assisted selection and proteomics were applied to identify and characterize low-P34 soybeans. RESULTS: In low-P34 lines selected from a cross-population, concentrations of the P34 protein as identified with a polyclonal antibody were reduced by 50-70% as compared to P34-containing controls. Using 2D electrophoresis and immunoblotting, the reduction of P34 protein was verified in low-P34 lines. This result was confirmed by liquid chromatographic-tandem mass spectrometric analysis, which revealed either a reduction or complete absence of the authentic P34 protein as suggested from presence or absence of a unique peptide useful for discriminating between conventional and low-P34 lines. CONCLUSION: Marker-assisted selection proved useful for identifying low-P34 soybean lines for the development of hypoallergenic soy foods. The status of the P34 protein in low-P34 lines needs further characterization. In addition, the food safety relevance of low-P34 soybeans should be tested in clinical studies. (c) 2016 Society of Chemical Industry. PMID- 27247267 TI - Phosphatase Rtr1 Regulates Global Levels of Serine 5 RNA Polymerase II C-Terminal Domain Phosphorylation and Cotranscriptional Histone Methylation. AB - In eukaryotes, the C-terminal domain (CTD) of Rpb1 contains a heptapeptide repeat sequence of (Y1S2P3T4S5P6S7)n that undergoes reversible phosphorylation through the opposing action of kinases and phosphatases. Rtr1 is a conserved protein that colocalizes with RNA polymerase II (RNAPII) and has been shown to be important for the transition from elongation to termination during transcription by removing RNAPII CTD serine 5 phosphorylation (Ser5-P) at a selection of target genes. In this study, we show that Rtr1 is a global regulator of the CTD code with deletion of RTR1 causing genome-wide changes in Ser5-P CTD phosphorylation and cotranscriptional histone H3 lysine 36 trimethylation (H3K36me3). Using chromatin immunoprecipitation and high-resolution microarrays, we show that RTR1 deletion results in global changes in RNAPII Ser5-P levels on genes with different lengths and transcription rates consistent with its role as a CTD phosphatase. Although Ser5-P levels increase, the overall occupancy of RNAPII either decreases or stays the same in the absence of RTR1 Additionally, the loss of Rtr1 in vivo leads to increases in H3K36me3 levels genome-wide, while total histone H3 levels remain relatively constant within coding regions. Overall, these findings suggest that Rtr1 regulates H3K36me3 levels through changes in the number of binding sites for the histone methyltransferase Set2, thereby influencing both the CTD and histone codes. PMID- 27247269 TI - Comparison of Second-Phase Insulin Secretion Derived from Standard and Modified Low-Dose Graded Glucose Infusion Tests. AB - OBJECTIVES: Insulin secretion has 2 phases, first-phase and second-phase insulin secretion (SPIS). The purpose of our study was to validate the SPIS derived from the modified low-dose graded glucose infusion test (MLDGGI) by using the standard SPIS derived from the low-dose graded glucose infusion test (LDGGI). METHODS: Fourteen participants were enrolled. The participants underwent the LDGGI for 200 minutes and MLDGGI for 60 minutes. The LDGGI was administered using the standard Polonsky method, which entails 5 40-minute stages of glucose infusion (1, 4, 8, 6 and 24 mg/kg/min). The slopes of the insulin levels vs. the glucose levels obtained during the test were regarded as SPIS (SPIS-I). Furthermore, deconvolution was performed, and slopes of the insulin secretion rate (ISR) against glucose levels during the test (SPIS-D) were obtained and regarded as the gold standard SPIS. The MLDGGI was administered with 3 20-minute stages of glucose infusion (2, 8 and 24 mg/kg/min) for 20 minutes each. The slopes of the insulin levels vs. the glucose levels obtained during the test were regarded as SPIS (MSPIS-I). In addition, deconvolution was performed, and the slopes of the ISR against glucose levels during the test (MSPIS-D) were obtained. RESULTS: Significant correlations were observed between SPIS-I and SPIS-D (r=0.843; p<0.001) and between MSPIS and SPIS-D (r=0.786; p<0.001). CONCLUSIONS: SPIS could be determined simply by using the LDGGI without deconvolution. Moreover, MLDGGI was proved to be useful in estimating SPIS easily on the basis of insulin levels. PMID- 27247270 TI - Chronic recording of hand prosthesis control signals via a regenerative peripheral nerve interface in a rhesus macaque. AB - OBJECTIVE: Loss of even part of the upper limb is a devastating injury. In order to fully restore natural function when lacking sufficient residual musculature, it is necessary to record directly from peripheral nerves. However, current approaches must make trade-offs between signal quality and longevity which limit their clinical potential. To address this issue, we have developed the regenerative peripheral nerve interface (RPNI) and tested its use in non-human primates. APPROACH: The RPNI consists of a small, autologous partial muscle graft reinnervated by a transected peripheral nerve branch. After reinnervation, the graft acts as a bioamplifier for descending motor commands in the nerve, enabling long-term recording of high signal-to-noise ratio (SNR), functionally-specific electromyographic (EMG) signals. We implanted nine RPNIs on separate branches of the median and radial nerves in two rhesus macaques who were trained to perform cued finger movements. MAIN RESULTS: No adverse events were noted in either monkey, and we recorded normal EMG with high SNR (>8) from the RPNIs for up to 20 months post-implantation. Using RPNI signals recorded during the behavioral task, we were able to classify each monkey's finger movements as flexion, extension, or rest with >96% accuracy. RPNI signals also enabled functional prosthetic control, allowing the monkeys to perform the same behavioral task equally well with either physical finger movements or RPNI-based movement classifications. SIGNIFICANCE: The RPNI signal strength, stability, and longevity demonstrated here represents a promising method for controlling advanced prosthetic limbs and fully restoring natural movement. PMID- 27247271 TI - Are more responsive depression scales really superior depression scales? PMID- 27247272 TI - Relationships between biomedical companies and guideline makers are often undisclosed. PMID- 27247273 TI - Polycomb Group Protein Pcgf6 Acts as a Master Regulator to Maintain Embryonic Stem Cell Identity. AB - The polycomb repressive complex 1 (PRC1) is a multi-subunit complex that plays critical roles in the epigenetic modulation of gene expression. Here, we show that the PRC1 component polycomb group ring finger 6 (Pcgf6) is required to maintain embryonic stem cell (ESC) identity. In contrast to canonical PRC1, Pcgf6 acts as a positive regulator of transcription and binds predominantly to promoters bearing active chromatin marks. Pcgf6 is expressed at high levels in ESCs, and knockdown reduces the expression of the core ESC regulators Oct4, Sox2, and Nanog. Conversely, Pcgf6 overexpression prevents downregulation of these factors and impairs differentiation. In addition, Pcgf6 enhanced reprogramming in both mouse and human somatic cells. The genomic binding profile of Pcgf6 is highly similar to that of trithorax group proteins, but not of PRC1 or PRC2 complexes, suggesting that Pcgf6 functions atypically in ESCs. Our data reveal novel roles for Pcgf6 in directly regulating Oct4, Nanog, Sox2, and Lin28 expression to maintain ESC identity. PMID- 27247274 TI - Fall and Fracture Risk in Nursing Home Residents With Moderate-to-Severe Behavioral Symptoms of Alzheimer's Disease and Related Dementias Initiating Antidepressants or Antipsychotics. AB - Background: Both antidepressants and antipsychotics are used in older adults with behavioral symptoms of Alzheimer's disease and related dementias. Despite the prevalent use of these agents, little is known about their comparative risks for falls and fractures. Methods: Using 2007-2009 Medicare claims data linked to Minimum Data Set 2.0, we identified new users of antidepressants and antipsychotics among nursing home residents with Alzheimer's disease and related dementias who had moderate-to-severe behavioral symptoms. Separate discrete-time survival models were used to estimate risks of falls, fractures, and a composite of both among antidepressant group versus antipsychotic group. Results: Compared to antipsychotic users, antidepressant users experienced significantly higher risk for fractures (adjusted hazard ratio = 1.35, 95% confidence interval = 1.10 1.66). The overall risk of falls or fractures remained significant in the antidepressant versus antipsychotic group (adjusted hazard ratio = 1.16, 95% confidence interval = 1.02-1.32). Conclusions: Antidepressants are associated with higher fall and fracture risk compared to antipsychotics in the management of older adults with Alzheimer's disease and related dementias who experience moderate-to-severe behavioral symptoms. Clinicians need to assess the ongoing risks/benefits of antidepressants for these symptoms especially in light of the increasingly prevalent use of these agents. PMID- 27247275 TI - Synthetic Chemical Inducers and Genetic Decoupling Enable Orthogonal Control of the rhaBAD Promoter. AB - External control of gene expression is crucial in synthetic biology and biotechnology research and applications, and is commonly achieved using inducible promoter systems. The E. coli rhamnose-inducible rhaBAD promoter has properties superior to more commonly used inducible expression systems, but is marred by transient expression caused by degradation of the native inducer, l-rhamnose. To address this problem, 35 analogues of l-rhamnose were screened for induction of the rhaBAD promoter, but no strong inducers were identified. In the native configuration, an inducer must bind and activate two transcriptional activators, RhaR and RhaS. Therefore, the expression system was reconfigured to decouple the rhaBAD promoter from the native rhaSR regulatory cascade so that candidate inducers need only activate the terminal transcription factor RhaS. Rescreening the 35 compounds using the modified rhaBAD expression system revealed several promising inducers. These were characterized further to determine the strength, kinetics, and concentration-dependence of induction; whether the inducer was used as a carbon source by E. coli; and the modality (distribution) of induction among populations of cells. l-Mannose was found to be the most useful orthogonal inducer, providing an even greater range of induction than the native inducer l rhamnose, and crucially, allowing sustained induction instead of transient induction. These findings address the key limitation of the rhaBAD expression system and suggest it may now be the most suitable system for many applications. PMID- 27247277 TI - Selective protein degradation ensures cellular longevity. AB - A previously unknown pathway can selectively degrade mitochondrial proteins in aged and stressed cells without destroying the organelle itself. PMID- 27247276 TI - Constitutive auxin response in Physcomitrella reveals complex interactions between Aux/IAA and ARF proteins. AB - The coordinated action of the auxin-sensitive Aux/IAA transcriptional repressors and ARF transcription factors produces complex gene-regulatory networks in plants. Despite their importance, our knowledge of these two protein families is largely based on analysis of stabilized forms of the Aux/IAAs, and studies of a subgroup of ARFs that function as transcriptional activators. To understand how auxin regulates gene expression we generated a Physcomitrella patens line that completely lacks Aux/IAAs. Loss of the repressors causes massive changes in transcription with misregulation of over a third of the annotated genes. Further, we find that the aux/iaa mutant is blind to auxin indicating that auxin regulation of transcription occurs exclusively through Aux/IAA function. We used the aux/iaa mutant as a simplified platform for studies of ARF function and demonstrate that repressing ARFs regulate auxin-induced genes and fine-tune their expression. Further the repressing ARFs coordinate gene induction jointly with activating ARFs and the Aux/IAAs. PMID- 27247278 TI - Virgin olive oil quality of hedgerow 'Arbequina' olive trees under deficit irrigation. AB - BACKGROUND: Regulated deficit irrigation (RDI) is used in hedgerow olive orchards to achieve a sustainable balance between water savings, tree vigor and oil production. Its effects on the presence of compounds responsible for the taste of the oil and its nutritional value are controversial. The present 3-year study was conducted in an 'Arbequina' orchard (1667 trees ha-1 ) under a full irrigation (FI) treatment (470.1 mm year-1 of water) and two RDI treatments scaled to replace 60% and 30%, respectively, of FI. The quality parameters, antioxidant contents and volatiles of the extracted virgin olive oil (VOO) were analyzed. RESULTS: In general, oils from the 30% RDI treatment had higher contents of pigments and phenolic compounds, a higher oleic/linoleic ratio and the highest oxidative stability, despite their lower tocopherol content. FI oils showed higher (E)-2-hexenal, 1-penten-3-one, ocimene, E-2-pentenal and pentene dimer contents than 30RDI oils, but lower contents of (E)-2-pentenol and volatile esters. CONCLUSION: The results of the present study suggest that a RDI strategy supplying 30% of the total irrigation needs induces an increase in natural antioxidants in VOO. Neither yield, nor the rest of the quality parameters were affected by the reduced irrigation. However, abundant autumn precipitation can over-ride these effects of 30% RDI treatment on oil quality. (c) 2016 Society of Chemical Industry. PMID- 27247279 TI - Changes of intranetwork and internetwork functional connectivity in Alzheimer's disease and mild cognitive impairment. AB - OBJECTIVE: Alzheimer's disease (AD) is a serious neurodegenerative disorder characterized by deficits of working memory, attention, language and many other cognitive functions. Although different stages of the disease are relatively well characterized by clinical criteria, stage-specific pathological changes in the brain remain relatively poorly understood, especially at the level of large-scale functional networks. In this study, we aimed to characterize the potential disruptions of large-scale functional brain networks based on a sample including amnestic mild cognition impairment (aMCI) and AD patients to help delineate the underlying stage-dependent AD pathology. APPROACH: We sought to identify the neural connectivity mechanisms of aMCI and AD through examination of both intranetwork and internetwork interactions among four of the brain's key networks, namely dorsal attention network (DAN), default mode network (DMN), executive control network (ECN) and salience network (SAL). We analyzed functional connectivity based on resting-state functional magnetic resonance imaging (rs-fMRI) data from 25 Alzheimer's disease patients, 20 aMCI patients and 35 elderly normal controls (NC). MAIN RESULTS: Intranetwork functional disruptions within the DAN and ECN were detected in both aMCI and AD patients. Disrupted intranetwork connectivity of DMN and anti-correlation between DAN and DMN were observed in AD patients. Moreover, aMCI-specific alterations in the internetwork functional connectivity of SAL were observed. SIGNIFICANCE: Our results confirmed previous findings that AD pathology was related to dysconnectivity both within and between resting-state networks but revealed more spatial details. Moreover, the SAL network, reportedly flexibly coupling either with the DAN or DMN networks during different brain states, demonstrated interesting alterations specifically in the early stage of the disease. PMID- 27247280 TI - Adaptive neuron-to-EMG decoder training for FES neuroprostheses. AB - OBJECTIVE: We have previously demonstrated a brain-machine interface neuroprosthetic system that provided continuous control of functional electrical stimulation (FES) and restoration of grasp in a primate model of spinal cord injury (SCI). Predicting intended EMG directly from cortical recordings provides a flexible high-dimensional control signal for FES. However, no peripheral signal such as force or EMG is available for training EMG decoders in paralyzed individuals. APPROACH: Here we present a method for training an EMG decoder in the absence of muscle activity recordings; the decoder relies on mapping behaviorally relevant cortical activity to the inferred EMG activity underlying an intended action. Monkeys were trained at a 2D isometric wrist force task to control a computer cursor by applying force in the flexion, extension, ulnar, and radial directions and execute a center-out task. We used a generic muscle force to-endpoint force model based on muscle pulling directions to relate each target force to an optimal EMG pattern that attained the target force while minimizing overall muscle activity. We trained EMG decoders during the target hold periods using a gradient descent algorithm that compared EMG predictions to optimal EMG patterns. MAIN RESULTS: We tested this method both offline and online. We quantified both the accuracy of offline force predictions and the ability of a monkey to use these real-time force predictions for closed-loop cursor control. We compared both offline and online results to those obtained with several other direct force decoders, including an optimal decoder computed from concurrently measured neural and force signals. SIGNIFICANCE: This novel approach to training an adaptive EMG decoder could make a brain-control FES neuroprosthesis an effective tool to restore the hand function of paralyzed individuals. Clinical implementation would make use of individualized EMG-to-force models. Broad generalization could be achieved by including data from multiple grasping tasks in the training of the neuron-to-EMG decoder. Our approach would make it possible for persons with SCI to grasp objects with their own hands, using near-normal motor intent. PMID- 27247281 TI - Migraine and risk of cardiovascular disease in women: prospective cohort study. AB - OBJECTIVE: To evaluate the association between migraine and incident cardiovascular disease and cardiovascular mortality in women. DESIGN: Prospective cohort study among Nurses' Health Study II participants, with follow up from 1989 and through June 2011. SETTING: Cohort of female nurses in United States. PARTICIPANTS: 115 541 women aged 25-42 years at baseline and free of angina and cardiovascular disease. Cumulative follow-up rates were more than 90%. MAIN OUTCOME MEASURES: The primary outcome of the study was major cardiovascular disease, a combined endpoint of myocardial infarction, stroke, or fatal cardiovascular disease. Secondary outcome measures included individual endpoints of myocardial infarction, stroke, angina/coronary revascularization procedures, and cardiovascular mortality. RESULTS: 17 531 (15.2%) women reported a physician's diagnosis of migraine. Over 20 years of follow-up, 1329 major cardiovascular disease events occurred and 223 women died from cardiovascular disease. After adjustment for potential confounding factors, migraine was associated with an increased risk for major cardiovascular disease (hazard ratio 1.50, 95% confidence interval 1.33 to 1.69), myocardial infarction (1.39, 1.18 to 1.64), stroke (1.62, 1.37 to 1.92), and angina/coronary revascularization procedures (1.73, 1.29 to 2.32), compared with women without migraine. Furthermore, migraine was associated with a significantly increased risk for cardiovascular disease mortality (hazard ratio 1.37, 1.02 to 1.83). Associations were similar across subgroups of women, including by age (<50/>=50), smoking status (current/past/never), hypertension (yes/no), postmenopausal hormone therapy (current/not current), and oral contraceptive use (current/not current). CONCLUSIONS: Results of this large, prospective cohort study in women with more than 20 years of follow-up indicate a consistent link between migraine and cardiovascular disease events, including cardiovascular mortality. Women with migraine should be evaluated for their vascular risk. Future targeted research is warranted to identify preventive strategies to reduce the risk of future cardiovascular disease among patients with migraine. PMID- 27247282 TI - Diffusion NMR studies of macromolecular complex formation, crowding and confinement in soft materials. AB - Label-free methods to obtain hydrodynamic size from diffusion measurements are desirable in environments that contain multiple macromolecular species at a high total concentration: one example is the crowded cellular environment. In complex, multi-species macromolecular environments - in this article, we feature aqueous systems involving polymers, surfactants and proteins - the link between dynamics and size is harder to unpack due to macromolecular crowding and confinement. In this review, we demonstrate that the pulsed-field gradient NMR technique, with its spectral separation of different chemical components, is ideal for studying the dynamics of the entire system simultaneously and without labelling, in a wide range of systems. The simultaneous measurement of the dynamics of multiple components allows for internal consistency checks and enables quantitative statements about the link between macromolecular dynamics, size, complex formation and crowding in soft materials. PMID- 27247283 TI - Recent advances in application of (27)Al NMR spectroscopy to materials science. AB - Valuable information about the local environment of the aluminum nucleus can be obtained through (27)Al Nuclear Magnetic Resonance (NMR) parameters like the isotropic chemical shift, scalar and quadrupolar coupling constants, and relaxation rate. With nearly 250 scientific articles per year dealing with (27)Al NMR spectroscopy, this analytical tool has become popular because of the recent progress that has made the acquisition and interpretation of the NMR data much easier. The application of (27)Al NMR techniques to various classes of compounds, either in solution or solid-state, has been shown to be extremely informative concerning local structure and chemistry of aluminum in its various environments. The development of experimental methodologies combined with theoretical approaches and modeling has contributed to major advances in spectroscopic characterization especially in materials sciences where long-range periodicity and classical local NMR probes are lacking. In this review we will present an overview of results obtained by (27)Al NMR as well as the most relevant methodological developments over the last 25years, concerning particularly on progress in the application of liquid- and solid-state (27)Al NMR to the study of aluminum-based materials such as aluminum polyoxoanions, zeolites, aluminophosphates, and metal-organic-frameworks. PMID- 27247284 TI - Deuterium NMR investigations of field-induced director alignment in nematic liquid crystals. AB - There have been many investigations of the alignment of nematic liquid crystals by either a magnetic and/or an electric field. The basic features of the important hydrodynamic processes for low molar mass nematics have been characterized for the systems in their equilibrium and non-equilibrium states. These have been created using electric and magnetic fields to align the director and deuterium nuclear magnetic resonance ((2)H NMR) spectroscopy has been used to explore this alignment. Theoretical models based on continuum theory have been developed to complement the experiments and found to describe successfully the static and the dynamic phenomena observed. Such macroscopic behaviour has been investigated with (2)H NMR spectroscopy, in which an electric field in addition to the magnetic field of the spectrometer is used to rotate the director and produce a non-equilibrium state. This powerful technique has proved to be especially valuable for the investigation of nematic liquid crystals. Since the quadrupolar splitting for deuterons observed in the liquid crystal phase is determined by the angle between the director and the magnetic field, time resolved and time-averaged (2)H NMR spectroscopies can be employed to investigate the dynamic director alignment process in a thin nematic film following the application or removal of an electric field. In this article, we describe some seminal studies to illustrate the field-induced static and dynamic director alignment for low molar mass nematics. PMID- 27247285 TI - "Pulse pair technique in high resolution NMR" a reprint of the historical 1971 lecture notes on two-dimensional spectroscopy. AB - The review articles published in "Progress in NMR Spectroscopy" are usually invited treatments of topics of current interest, but occasionally the Editorial Board may take an initiative to publish important historical material that is not widely available. The present article represents just such a case. Jean Jeener gave a lecture in 1971 at a summer school in Basko Polje, in what was then called Yugoslavia. As is now widely known, Jean Jeener laid down the foundations in that lecture of two - and higher - dimensional NMR spectroscopy by proposing the homonuclear COSY experiment. Jeener realized that the new proposal would open the door towards protein NMR and molecular structure determinations, but he felt that useful versions of such experiments could not be achieved with the NMR, computer and electronics technology available at that time, so that copies of the lecture notes were circulated (the Basko Polje lecture notes by J. Jeener and G. Alewaeters), but no formal publication followed. Fortunately, Ernst, Freeman, Griffin, and many others were more far-sighted and optimistic. An early useful extension was Ernst's proposal to replace the original projection/reconstruction technique of MRI by the widely adopted Fourier transform method inspired by the Basko Polje lecture. Later, the pulse method spread over many fields of spectroscopy as soon as the required technology became available. Jean Jeener, Emeritus professor, Universite Libre de Bruxelles. Geoffrey Bodenhausen, Ecole Normale Superieure, Paris. PMID- 27247286 TI - Fifty years of "Progress in NMR Spectroscopy" - An editorial from the founding Editors. PMID- 27247287 TI - Fifty years of "Progress in NMR Spectroscopy" - An editorial from the present Editorial Board. PMID- 27247288 TI - Prospects of Genomic Prediction in the USDA Soybean Germplasm Collection: Historical Data Creates Robust Models for Enhancing Selection of Accessions. AB - The identification and mobilization of useful genetic variation from germplasm banks for use in breeding programs is critical for future genetic gain and protection against crop pests. Plummeting costs of next-generation sequencing and genotyping is revolutionizing the way in which researchers and breeders interface with plant germplasm collections. An example of this is the high density genotyping of the entire USDA Soybean Germplasm Collection. We assessed the usefulness of 50K single nucleotide polymorphism data collected on 18,480 domesticated soybean (Glycine max) accessions and vast historical phenotypic data for developing genomic prediction models for protein, oil, and yield. Resulting genomic prediction models explained an appreciable amount of the variation in accession performance in independent validation trials, with correlations between predicted and observed reaching up to 0.92 for oil and protein and 0.79 for yield. The optimization of training set design was explored using a series of cross-validation schemes. It was found that the target population and environment need to be well represented in the training set. Second, genomic prediction training sets appear to be robust to the presence of data from diverse geographical locations and genetic clusters. This finding, however, depends on the influence of shattering and lodging, and may be specific to soybean with its presence of maturity groups. The distribution of 7608 nonphenotyped accessions was examined through the application of genomic prediction models. The distribution of predictions of phenotyped accessions was representative of the distribution of predictions for nonphenotyped accessions, with no nonphenotyped accessions being predicted to fall far outside the range of predictions of phenotyped accessions. PMID- 27247290 TI - Migraine and vascular disease. PMID- 27247289 TI - Neurons That Underlie Drosophila melanogaster Reproductive Behaviors: Detection of a Large Male-Bias in Gene Expression in fruitless-Expressing Neurons. AB - Male and female reproductive behaviors in Drosophila melanogaster are vastly different, but neurons that express sex-specifically spliced fruitless transcripts (fru P1) underlie these behaviors in both sexes. How this set of neurons can generate such different behaviors between the two sexes is an unresolved question. A particular challenge is that fru P1-expressing neurons comprise only 2-5% of the adult nervous system, and so studies of adult head tissue or whole brain may not reveal crucial differences. Translating Ribosome Affinity Purification (TRAP) identifies the actively translated pool of mRNAs from fru P1-expressing neurons, allowing a sensitive, cell-type-specific assay. We find four times more male-biased than female-biased genes in TRAP mRNAs from fru P1-expressing neurons. This suggests a potential mechanism to generate dimorphism in behavior. The male-biased genes may direct male behaviors by establishing cell fate in a similar context of gene expression observed in females. These results suggest a possible global mechanism for how distinct behaviors can arise from a shared set of neurons. PMID- 27247292 TI - News Feature: The perfect planet. PMID- 27247294 TI - Treatment strategy for video capsule retention by double-balloon enteroscopy. PMID- 27247295 TI - Spending an additional 40 min outdoors each day reduces the incidence of myopia among primary school children in China. PMID- 27247296 TI - An infant with persistent tachypnoea. PMID- 27247297 TI - Transmission Electron Microscopy (TEM) Observations of Female Oocytes From Nilaparvata lugens (Hemiptera: Delphacidae): Antibiotic Jinggangmycin (JGM) Induced Stimulation of Reproduction and Associated Changes in Hormone Levels. AB - Previous studies have demonstrated that the agricultural antibiotic jinggangmycin (JGM) stimulates reproduction in the brown planthopper Nilaparvata lugens Stal and that the stimulation of brown planthopper reproduction induced by JGM is regulated by the fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) genes. However, a key issue in the stimulation of reproduction induced by pesticides involves the growth and development of oocytes. Therefore, the present study investigated oocyte changes via transmission electron microscopy (TEM) and changes in hormone levels (juvenile hormones (JH) and 20-hydroxyecdysone (20 E)) in JGM-treated females. TEM observations showed that the size of the lipid droplets in the oocytes of JGM-treated females, compared with those in the oocytes of the control females, significantly reduced by 32.6 and 29.8% at 1 and 2 d after emergence (1 and 2 DAE), respectively. In addition, the JH levels of JGM-treated females at 1 and 2 DAE were increased by 49.7 and 45.7%, respectively, whereas 20 E levels decreased by 36.0 and 30.0%, respectively. We conclude that JGM treatments lead to substantial changes in lipid metabolism, which are directly and indirectly related to stimulation of reproduction of brown planthopper together with our previous findings. PMID- 27247298 TI - Optimizing Generic Cerambycid Pheromone Lures for Australian Biosecurity and Biodiversity Monitoring. AB - The cerambycid beetles comprise a diverse family that includes many economically important pests of living and dead trees. Pheromone lures have been developed for cerambycids in many parts of the world, but to date, have not been tested in Australia. In this study, we tested the efficacy of several pheromones, identified from North American and European species, as attractants for cerambycids at three sites in southeast Queensland, Australia. Over two field seasons, we trapped 863 individuals from 47 cerambycid species. In the first season, racemic 3-hydroxyhexan-2-one was the most attractive compound among the eight pheromones tested. Subsequently, we aimed to optimize trapping success by combining this compound with other components. However, neither the addition of other pheromone components nor host plant volatiles improved the efficacy of 3 hydroxyhexan-2-one alone. We also tested a generic pheromone blend developed for North American cerambycids, and found that only the combination of this blend with host plant volatiles improved trapping success. The Australian cerambycid fauna is not well known, and effective lures for use in trapping beetles would greatly assist in the study of this important group. Effective semiochemical lures would also have implications for biosecurity through improved monitoring for invasive species. PMID- 27247299 TI - Sublethal Effects of Cyantraniliprole and Imidacloprid on Feeding Behavior and Life Table Parameters of Myzus persicae (Hemiptera: Aphididae). AB - The green peach aphid, Myzus persicae (Sulzer) (Hemiptera: Aphididae), is an agricultural pest that seriously infests many crops worldwide. This study used electrical penetration graphs (EPGs) and life table parameters to estimate the sublethal effects of cyantraniliprole and imidacloprid on the feeding behavior and hormesis of M. persicae The sublethal concentrations (LC30) of cyantraniliprole and imidacloprid against adult M. persicae were 4.933 and 0.541 mg L(-1), respectively. The feeding data obtained from EPG analysis indicated that the count probes and number of short probes (<3 min) were significantly increased when aphids were exposed to LC30 of imidacloprid-treated plants. In addition, the phloem-feeding behavior of M persicae was significantly impaired on fed tobacco plants treated with cyantraniliprole and imidacloprid at LC30 Analysis of life table parameters indicated that the growth and reproduction of F1 generation aphids were significantly affected when initial adults were exposed to LC30 of cyantraniliprole and imidacloprid. The nymphal period, female longevity, total preoviposition period, and mean generation time were significantly prolonged when initial adults were exposed to LC30 of imidacloprid. By comparison, these parameters were prolonged but not significantly in the cyantraniliprole treatment. The fecundity and gross reproductive rate were significantly increased in the treated groups. Similarly, the net reproductive rate was greater in the treated group than the control group. Our results indicate that treatment with LC30 of imidacloprid and cyantraniliprole would lead to a hormetic response of M. persicae, with higher likelihood of occurrence when initial adults were exposed to LC30 of cyantraniliprole. PMID- 27247300 TI - Interaction Effect Between Herbivory and Plant Fertilization on Extrafloral Nectar Production and on Seed Traits: An Experimental Study With Ricinus communis (Euphorbiaceae). AB - It is known that the release of volatile chemicals by many plants can attract the natural enemies of herbivorous insects. Such indirect interactions are likely when plants produce nectar from their extrafloral nectaries, and particularly when the production of extrafloral nectar (EFN) is induced by herbivory. In the present study, we conducted experiments to test whether foliar herbivory inflicted by Spodoptera frugiperda Smith (Noctuidae) increases nectar production by extrafloral nectaries on one of its host plants, Ricinus communis L. (Euphorbiaceae). Due to the current economic importance of R. communis, we also investigated whether the following seed traits-water content, dry mass, and essential oil production-are negatively affected by herbivory. Finally, we tested whether or not nectar production and seed traits are influenced by plant fertilization (plant quality). We found that nectar production was increased after herbivory, but it was not affected by the type of fertilization. Seed dry mass was higher in plants that were subjected to full fertilization, without herbivory; plants maintained in low fertilization conditions, however, had higher seed mass when subjected to herbivory. The same inverted pattern was observed for oil production. Therefore, our results suggest that EFN production in R. communis may act as an indirect defense strategy against herbivores, and that there is a trade-off between reproduction and plant growth when low-fertilized plants are subjected to herbivory. PMID- 27247301 TI - Genetic Variability of the Invasive Species Metcalfa pruinosa (Hemiptera: Flatidae) in the Republic of Korea. AB - Metcalfa pruinosa (Say, 1830) (Hemiptera: Flatidae) has caused substantial agricultural damage since its recent introduction to the Republic of Korea; however, the source of this introduction is still unclear. To examine the genetic divergence and phylogenetic relationships among several populations of M. pruinosa from Korea and foreign countries, 251 COI sequences from 251 samples collected from Korea, France, Italy, Spain, Slovenia, and the United States were newly analyzed, together with seven published COI sequences from Canada. In total, 19 haplotypes were detected from the 258 COI sequences, and three haplotypes, H1, H3, and H9, were detected from samples in Korea. The MJ network and Bayesian inference revealed that the three haplotypes of Korea were closely connected with samples of Italy, Spain, Slovenia, France, and the United States. Our study revealed the possibility of multiple invasions of M. pruinosa from Europe and/or North America into Korea. PMID- 27247302 TI - Evaluation of Bioinsecticides for Management of Bemisia tabaci (Hemiptera: Aleyrodidae) and the Effect on the Whitefly Predator Delphastus catalinae (Coleoptera: Coccinellidae) in Organic Squash. AB - Organic zucchini squash is a high-value vegetable crop in Florida and potential exists to expand its production throughout the state. A lack of knowledge on the effectiveness of organic products and their integration with natural enemies is an important constraint to the regulation of pest populations in organic squash production in Florida. The objectives of this study were to evaluate the effect of insecticides labeled for organic production that can be used for management of Bemisia tabaci (Gennadius) biotype B, on organically grown squash; and to determine the effects of the most efficient insecticides on a key natural enemy, Delphastus catalinae (Horn). Experiments were conducted in the greenhouse in exclusion cages. The first experiment compared the effects of four bioinsecticides on whitefly densities. Insecticides include 1) AzaSol (azadirachtin), 2) PyGanic EC 1.4 (pyrethrin), 3) M-Pede (insecticidal soap), and 4) Entrust (spinosad). The second experiment investigated the effects of bioinsecticides on D. catalinae Treatment effectiveness was evaluated 1, 3, and 5 d posttreatment. PyGanic and M-Pede were highly effective in controlling whitefly populations on organic squash, while moderate control was provided by AzaSol and there was no control provided by Entrust. PyGanic and M-Pede treatments reduced D. catalinae populations when adults were released 1 d post pesticide application. However, when adults were released 5 d post application, there was no reduction. The importance of using bioinsecticides in combination with natural enemies to regulate pest populations in organic cropping systems is discussed. PMID- 27247303 TI - Field Evaluation of an Oviposition Deterrent for Management of Spotted-Wing Drosophila, Drosophila suzukii, and Potential Nontarget Effects. AB - Spotted-wing drosophila, Drosophila suzukii Matsumura (Diptera: Drosophilidae), is a polyphagous, invasive pest of small fruits. Current management relies heavily on chemical insecticides, and an effective oviposition deterrent could contribute to alternative management approaches that reduce the need for these chemical insecticides. A novel deployment method for repelling Drosophila suzukii, thereby reducing D. suzukii oviposition in fall-bearing red raspberry, was evaluated in the field. Infestations occurring within 4 d after deployment were significantly lower in 2-m-long plots (Rubus idaeus 'Caroline') treated with the repellent (20% 1-octen-3-ol in specialized pheromone and lure application technology [SPLAT]) compared to control plots (blank SPLAT). Repellent-treated plots had roughly 28.8 and 49.5% fewer offspring reared per gram of fruit than control plots in two experiments, respectively. Nontarget effects were also evaluated in 2-m plot experiments as well as 5- by 5-m plot experiments. There were no differences in the number of parasitic hymenoptera trapped on yellow sticky cards hung in repellent compared to control plots. While there were no differences in the number of visits to raspberry flowers observed by honey bees in repellent versus control plots, the number of visits by bumble bees was greater in repellent plots compared to control plots. Challenges regarding evaporation rates and potential uses for repellents in an integrated pest management program for the control of D. suzukii are discussed. PMID- 27247304 TI - Erratum. PMID- 27247305 TI - Displacement of Tetropium cinnamopterum (Coleoptera: Cerambycidae) by Its Invasive Congener Tetropium fuscum. AB - We examined the native community of insects interacting with an invasive species, Tetropium fuscum (F.) (Coleoptera: Cerambycidae), in its new range to explore reasons for the invader's relatively slow spread. Tetropium fuscum is a European spruce borer established in Nova Scotia since at least 1990, but it has spread only about 125 km from its site of introduction. We compared the densities of Tetropium spp., their known parasitoids, and the community of wood-boring insects at sites located within the invasion zone in Nova Scotia versus well outside this zone, in New Brunswick, Canada. Using red spruce trees stressed by girdling or felling, we tested whether: 1) T. fuscum had altered the native wood-boring community; 2) T. fuscum displaced a native congener, Tetropium cinnamopterum (Kirby); and 3) parasitism rates of Tetropium spp. differed between the invaded and noninvaded zones. Both Tetropium spp. and their parasitoid wasps emerged exclusively from felled trees as opposed to girdled trees. We found no difference in community diversity inside versus outside the invasion zone. The combined densities of both Tetropium spp. and their overall parasitism rates also did not differ between zones, but T. cinnamopterum density was significantly greater outside the invasion zone, suggesting T. fuscum may displace the native congener where they are sympatric. Our results suggest that the native and invasive Tetropium spp. act as a single functional species in the invasion zone. We speculate that natural control agents (predators, parasitoids, and competitors) might be limiting the rate of spread of T. fuscum. PMID- 27247306 TI - Monitoring Tyrophagus putrescentiae (Acari: Acaridae) With Traps in Dry-Cured Ham Aging Rooms. AB - Methyl bromide is the most effective fumigant for controlling the mold (or ham) mite, Tyrophagus putrescentiae (Schrank) (Acari: Acaridae), the most significant pest of dry-cured ham. However, methyl bromide is being phased out of use. Therefore, integrated pest management (IPM) methods should be developed to help control mites in dry-cured ham plants. The foundation of a successful IPM program is an effective monitoring program that provides information on pest presence and abundance over time. By using food-baited traps fabricated from disposable petri dishes and a dog food-based bait, mite activity over time and space was monitored in five dry-cured ham aging rooms from three commercial processing facilities that differed in their fumigation frequencies. Weekly sampling of the mite was conducted from June 2012 to September 2013. There were significant differences in the average weekly trap captures in all facilities, especially before and after fumigation, with the majority of mites in traps prior to fumigation. Mite numbers had a pattern of sharp decline after fumigation, followed by a steady increase until the next fumigation. Average trap captures varied due to trap location over the study period at all study sites, indicating that traps could be used to identify specific locations within an aging room where mite infestation of hams was more likely to occur. These findings can inform facility managers of mite population changes that can be used as one factor toward making pest management decisions and assessing the impact of fumigation or other pest mitigation actions. PMID- 27247307 TI - Population Fluctuation of Ceratitis capitata (Diptera: Tephritidae) as a Function of Altitude in Eastern Guatemala. AB - Population fluctuations of Ceratitis capitata (Wiedemann) were evaluated over a period of 12 mo in four altitudinal strata (400-750, 750-1,100, 1,100-1,450, and 1,450-1,800 meters above sea level, masl) in Eastern Guatemala. Within each altitudinal range, sampling plots were established in coffee plantations and adjacent areas, in which Jackson traps were set and baited with Trimedlure. Coffee berries and other host fruits were collected. Population density was lowest at the 400-750 masl stratum and highest at 1,450-1,800 masl. At every altitudinal range, the fluctuations of the pest were associated mainly with the availability of ripe coffee berries as a primary host. From 750-1,450 masl, the pest was also associated with the availability of sweet orange and mandarins in commercial and backyard orchards. The highest densities of the pest were recorded in the dry season. Citrus were the main alternate host where ripe coffee berries were not available. This knowledge on population dynamics of C. capitata will contribute to develop more effective area-wide pest management strategies including the use of sterile insects, natural enemies, and bait sprays. PMID- 27247309 TI - Erratum for Jiang et al., Multigene Editing in the Escherichia coli Genome via the CRISPR-Cas9 System. PMID- 27247310 TI - Erratum for Laufer et al., Coexistence of Microaerophilic, Nitrate-Reducing, and Phototrophic Fe(II) Oxidizers and Fe(III) Reducers in Coastal Marine Sediment. PMID- 27247311 TI - Correction for Sandoz et al., Complementation of Arginine Auxotrophy for Genetic Transformation of Coxiella burnetii by Use of a Defined Axenic Medium. PMID- 27247313 TI - Correction for Zurashvili et al., Interaction of PDK1 with Phosphoinositides Is Essential for Neuronal Differentiation but Dispensable for Neuronal Survival. PMID- 27247315 TI - Reduced L-type Ca2+ current and compromised excitability induce loss of skeletal muscle function during acute cooling in locust. AB - Low temperature causes most insects to enter a state of neuromuscular paralysis, termed chill coma. The susceptibility of insect species to chill coma is tightly correlated to their distribution limits and for this reason it is important to understand the cellular processes that underlie chill coma. It is known that muscle function is markedly depressed at low temperature and this suggests that chill coma is partly caused by impairment in the muscle per se. To find the cellular mechanism(s) underlying muscle dysfunction at low temperature, we examined the effect of low temperature (5 degrees C) on several events in excitation-contraction coupling in the migratory locust (Locusta migratoria). Intracellular membrane potential recordings during single nerve stimulations showed that 70% of fibers at 20 degrees C produced an action potential (AP), while only 55% of fibers were able to fire an AP at 5 degrees C. Reduced excitability at low temperature was caused by an ~80% drop in L-type Ca(2+) current and a depolarizing shift in its activation of around 20 mV, which means that a larger endplate potential would be needed to activate the muscle AP at low temperature. In accordance, we showed that intracellular Ca(2+) transients were largely absent at low temperature following nerve stimulation. In contrast, maximum contractile force was unaffected by low temperature in chemically skinned muscle bundles, which demonstrates that the function of the contractile filaments is preserved at low temperature. These findings demonstrate that reduced L-type Ca(2+) current is likely to be the most important factor contributing to loss of muscle function at low temperature in locust. PMID- 27247316 TI - Regional variability in diving physiology and behavior in a widely distributed air-breathing marine predator, the South American sea lion (Otaria byronia). AB - Our understanding of how air-breathing marine predators cope with environmental variability is limited by our inadequate knowledge of their ecological and physiological parameters. Because of their wide distribution along both coasts of the sub-continent, South American sea lions (Otaria byronia) provide a valuable opportunity to study the behavioral and physiological plasticity of a marine predator in different environments. We measured the oxygen stores and diving behavior of South American sea lions throughout most of its range, allowing us to demonstrate that diving ability and behavior vary across its range. We found no significant differences in mass-specific blood volumes of sea lions among field sites and a negative relationship between mass-specific oxygen storage and size, which suggests that exposure to different habitats and geographical locations better explains oxygen storage capacities and diving capability in South American sea lions than body size alone. The largest animals in our study (individuals from Uruguay) were the shallowest and shortest duration divers, and had the lowest mass-specific total body oxygen stores, while the deepest and longest duration divers (individuals from southern Chile) had significantly larger mass specific oxygen stores, despite being much smaller animals. Our study suggests that the physiology of air-breathing diving predators is not fixed, but that it can be adjusted, to a certain extent, depending on the ecological setting and or habitat. These adjustments can be thought of as a 'training effect': as the animal continues to push its physiological capacity through greater hypoxic exposure, its breath-holding capacity increases. PMID- 27247317 TI - CCAP and FMRFamide-like peptides accelerate the contraction rate of the antennal accessory pulsatile organs (auxiliary hearts) of mosquitoes. AB - Insects rely on specialized accessory pulsatile organs (APOs), also known as auxiliary hearts, to propel hemolymph into their antennae. In most insects, this is accomplished via the pulsations of a pair of ampulla located in the head, each of which propels hemolymph across an antenna via an antennal vessel. Once at the distal end of the appendage, hemolymph returns to the head via the antennal hemocoel. Although the structure of the antennal hearts has been elucidated in various insect orders, their hormonal modulation has only been studied in cockroaches and other hemimetabolous insects within the superorder Polyneoptera, where proctolin and FMRFamide-like peptides accelerate the contraction rate of these auxiliary hearts. Here, we assessed the hormonal modulation of the antennal APOs of mosquitoes, a group of holometabolous (Endopterygota) insects within the order Diptera. We show that crustacean cardioactive peptide (CCAP), FMRFamide and SALDKNFMRFamide increase the contraction rate of the antennal APOs and the heart of Anopheles gambiae Both antennal hearts are synchronously responsive to these neuropeptides, but their contractions are asynchronous with the contraction of the heart. Furthermore, we show that these neuropeptides increase the velocity and maximum acceleration of hemolymph within the antennal space, suggesting that each contraction is also more forceful. To our knowledge, this is the first report demonstrating that hormones of a holometabolous insect modulate the contraction dynamics of an auxiliary heart, and the first report that shows that the hormones of any insect accelerate the velocity of hemolymph in the antennal space. PMID- 27247318 TI - Sexual dimorphism in the compound eye of Heliconius erato: a nymphalid butterfly with at least five spectral classes of photoreceptor. AB - Most butterfly families expand the number of spectrally distinct photoreceptors in their compound eye by opsin gene duplications together with lateral filter pigments; however, most nymphalid genera have limited diversity, with only three or four spectral types of photoreceptor. Here, we examined the spatial pattern of opsin expression and photoreceptor spectral sensitivities in Heliconius erato, a nymphalid with duplicate ultraviolet opsin genes, UVRh1 and UVRh2 We found that the H. erato compound eye is sexually dimorphic. Females express the two UV opsin proteins in separate photoreceptors, but males do not express UVRh1. Intracellular recordings confirmed that females have three short wavelength sensitive photoreceptors (lambdamax=356, ~390 and 470 nm), while males have two (lambdamax=390 and ~470 nm). We also found two long wavelength-sensitive photoreceptors (green, lambdamax~555 nm, and red, lambdamax~600 nm), which express the same LW opsin. The red cell's shifted sensitivity is probably due to perirhabdomal filtering pigments. Sexual dimorphism of the UV-absorbing rhodopsins may reflect the females' need to discriminate conspecifics from co mimics. Red-green color vision may be used to detect differences in red coloration on Heliconius wings, or for host-plant identification. Among nymphalids so far investigated, only H. erato is known to possess five spectral classes of photoreceptor; sexual dimorphism of the eye via suppression of one class of opsin (here UVRh1 in males) has not - to our knowledge - been reported in any animal. PMID- 27247319 TI - Efficacy estimation of erythropoiesis-stimulating agents using erythropoietin deficient anemic mice. PMID- 27247321 TI - Prolonged disease-free survival in elderly relapsed diffuse large B-cell lymphoma patients treated with lenalidomide plus rituximab. PMID- 27247320 TI - Human leukocyte antigen supertype matching after myeloablative hematopoietic cell transplantation with 7/8 matched unrelated donor allografts: a report from the Center for International Blood and Marrow Transplant Research. AB - The diversity of the human leukocyte antigen (HLA) class I and II alleles can be simplified by consolidating them into fewer supertypes based on functional or predicted structural similarities in epitope-binding grooves of HLA molecules. We studied the impact of matched and mismatched HLA-A (265 versus 429), -B (230 versus 92), -C (365 versus 349), and -DRB1 (153 versus 51) supertypes on clinical outcomes of 1934 patients with acute leukemias or myelodysplasia/myeloproliferative disorders. All patients were reported to the Center for International Blood and Marrow Transplant Research following single allele mismatched unrelated donor myeloablative conditioning hematopoietic cell transplantation. Single mismatched alleles were categorized into six HLA-A (A01, A01A03, A01A24, A02, A03, A24), six HLA-B (B07, B08, B27, B44, B58, B62), two HLA C (C1, C2), and five HLA-DRB1 (DR1, DR3, DR4, DR5, DR9) supertypes. Supertype B mismatch was associated with increased risk of grade II-IV acute graft-versus host disease (hazard ratio =1.78, P=0.0025) compared to supertype B match. Supertype B07-B44 mismatch was associated with a higher incidence of both grade II-IV (hazard ratio=3.11, P=0.002) and III-IV (hazard ratio=3.15, P=0.01) acute graft-versus-host disease. No significant associations were detected between supertype-matched versus -mismatched groups at other HLA loci. These data suggest that avoiding HLA-B supertype mismatches can mitigate the risk of grade II-IV acute graft-versus-host disease in 7/8-mismatched unrelated donor hematopoietic cell transplantation when multiple HLA-B supertype-matched donors are available. Future studies are needed to define the mechanisms by which supertype mismatching affects outcomes after alternative donor hematopoietic cell transplantation. PMID- 27247322 TI - Severe Ankyrin-R deficiency results in impaired surface retention and lysosomal degradation of RhAG in human erythroblasts. AB - Ankyrin-R provides a key link between band 3 and the spectrin cytoskeleton that helps to maintain the highly specialized erythrocyte biconcave shape. Ankyrin deficiency results in fragile spherocytic erythrocytes with reduced band 3 and protein 4.2 expression. We use in vitro differentiation of erythroblasts transduced with shRNAs targeting ANK1 to generate erythroblasts and reticulocytes with a novel ankyrin-R 'near null' human phenotype with less than 5% of normal ankyrin expression. Using this model, we demonstrate that absence of ankyrin negatively impacts the reticulocyte expression of a variety of proteins, including band 3, glycophorin A, spectrin, adducin and, more strikingly, protein 4.2, CD44, CD47 and Rh/RhAG. Loss of band 3, which fails to form tetrameric complexes in the absence of ankyrin, alongside GPA, occurs due to reduced retention within the reticulocyte membrane during erythroblast enucleation. However, loss of RhAG is temporally and mechanistically distinct, occurring predominantly as a result of instability at the plasma membrane and lysosomal degradation prior to enucleation. Loss of Rh/RhAG was identified as common to erythrocytes with naturally occurring ankyrin deficiency and demonstrated to occur prior to enucleation in cultures of erythroblasts from a hereditary spherocytosis patient with severe ankyrin deficiency but not in those exhibiting milder reductions in expression. The identification of prominently reduced surface expression of Rh/RhAG in combination with direct evaluation of ankyrin expression using flow cytometry provides an efficient and rapid approach for the categorization of hereditary spherocytosis arising from ankyrin deficiency. PMID- 27247323 TI - Microparticle phenotypes are associated with driver mutations and distinct thrombotic risks in essential thrombocythemia. PMID- 27247324 TI - Safety and efficacy of ruxolitinib in an open-label, multicenter, single-arm phase 3b expanded-access study in patients with myelofibrosis: a snapshot of 1144 patients in the JUMP trial. AB - JUMP is a phase 3b expanded-access trial for patients without access to ruxolitinib outside of a clinical study; it is the largest clinical trial to date in patients with myelofibrosis who have been treated with ruxolitinib. Here, we present safety and efficacy findings from an analysis of 1144 patients with intermediate- or high-risk myelofibrosis, as well as a separate analysis of 163 patients with intermediate-1-risk myelofibrosis - a population of patients not included in the phase 3 COMFORT studies. Consistent with ruxolitinib's mechanism of action, the most common hematologic adverse events were anemia and thrombocytopenia, but these led to treatment discontinuation in only a few cases. The most common non-hematologic adverse events were primarily grade 1/2 and included diarrhea, pyrexia, fatigue, and asthenia. The rates of infections were low and primarily grade 1/2, and no new or unexpected infections were observed. The majority of patients achieved a >=50% reduction from baseline in palpable spleen length. Improvements in symptoms were rapid, with approximately half of all patients experiencing clinically significant improvements, as assessed by various quality-of-life questionnaires. The safety and efficacy profile in intermediate-1-risk patients was consistent with that in the overall JUMP population and with that previously reported in intermediate-2- and high-risk patients. Overall, ruxolitinib provided clinically meaningful reductions in spleen length and symptoms in patients with myelofibrosis, including those with intermediate-1-risk disease, with a safety and efficacy profile consistent with that observed in the phase 3 COMFORT studies. This trial was registered as NCT01493414 at ClinicalTrials.gov. PMID- 27247326 TI - Transcatheter direct mitral valve annuloplasty with the Cardioband system for the treatment of functional mitral regurgitation. AB - Direct mitral valve annuloplasty is a transcatheter mitral valve repair approach that mimics the conventional surgical approach to treat functional mitral regurgitation. The Cardioband system (Valtech Cardio, Inc., Or-Yehuda, Israel) is delivered by a trans-septal approach and the implant is performed on the atrial side of the mitral annulus, under live echo and fluoroscopic guidance using multiple anchor elements. The Cardioband system obtained CE mark approval in October 2015, and initial clinical experiences are promising with regard to feasibility, safety and efficacy. PMID- 27247325 TI - Clinical characteristics and prognosis of acute myeloid leukemia associated with DNA-methylation regulatory gene mutations. AB - In recent years, it has been reported that the frequency of DNA-methylation regulatory gene mutations - mutations of the genes that regulate gene expression through DNA methylation - is high in acute myeloid leukemia. The objective of the present study was to elucidate the clinical characteristics and prognosis of acute myeloid leukemia with associated DNA-methylation regulatory gene mutation. We studied 308 patients with acute myeloid leukemia. DNA-methylation regulatory gene mutations were observed in 135 of the 308 cases (43.8%). Acute myeloid leukemia associated with a DNA-methylation regulatory gene mutation was more frequent in older patients (P<0.0001) and in patients with intermediate cytogenetic risk (P<0.0001) accompanied by a high white blood cell count (P=0.0032). DNA-methylation regulatory gene mutation was an unfavorable prognostic factor for overall survival in the whole cohort (P=0.0018), in patients aged <=70 years, in patients with intermediate cytogenetic risk, and in FLT3-ITD-negative patients (P=0.0409). Among the patients with DNA-methylation regulatory gene mutations, 26.7% were found to have two or more such mutations and prognosis worsened with increasing number of mutations. In multivariate analysis DNA-methylation regulatory gene mutation was an independent unfavorable prognostic factor for overall survival (P=0.0424). However, patients with a DNA methylation regulatory gene mutation who underwent allogeneic stem cell transplantation in first remission had a significantly better prognosis than those who did not undergo such transplantation (P=0.0254). Our study establishes that DNA-methylation regulatory gene mutation is an important unfavorable prognostic factor in acute myeloid leukemia. PMID- 27247327 TI - Endomyocardial biopsy under echocardiographic monitoring. AB - Endomyocardial biopsy is a common procedure for monitoring cardiac allograft rejection; several techniques have been described so far, throughout different access sites and under echocardiographic or X-ray control. We describe the routine technique adopted at our centre based on echo-guided puncture of jugular vein and echocardiographic assessment of endomyocardial sampling with direct visualization of the bioptome tip. We also report the most common complications of the procedure, especially concerning the risk of iatrogenic tricuspid regurgitation, and same examples of histopathological findings drawn from our own iconographic collection. PMID- 27247328 TI - Analyzing demand-side efficiency in global health: an application to maternal care in Vietnam. AB - This article investigates demand-side efficiency in global health-or the efficiency with which health system users convert public health resources into health outcomes. We introduce and explain the concept of demand-side efficiency as well as quantitative methods to empirically estimate it. Using a robust nonparametric form of technical efficiency analysis, we estimate demand side efficiency and its social determinants. We pilot these methods looking at how efficiently pregnant women in Northern Vietnam convert public health resources into appropriate maternal care as defined by national policy. We find that women who live in non-mountainous geographies, who are formally employed, who are pregnant with a boy and who are ethnic minorities are all more likely to be efficient at achieving appropriate care. We find no significant association between wealth or education and efficiency. Our results suggest that, in the Vietnamese context, women who are the most likely to achieve appropriate maternal care, are not necessarily the most likely to do so efficiently. Women who live in non-mountainous geographies and who are formally employed are both more likely to achieve appropriate care and to do so efficiently. Yet ethnic minority women, who do not systematically achieve better care, are more likely to be efficient or to achieve better care when compared with those with the same endowment of public health resources. On the methodological level, the pilot highlights that this approach can provide useful information for policy by identifying which groups of people are more and less likely to be efficient. By understanding which groups are more likely to be efficient-and in turn how and why-it may be possible to devise policies to promote the drivers of, or conversely address the constraints to, optimizing demand-side efficiency. PMID- 27247330 TI - Relationship factors and couples' engagement in sun protection. AB - Individuals may be more motivated to adopt health practices if they consider the benefits of these behaviors for their close relationships. The goal of this study was to examine couple concordance with sun protection and use the interdependence and communal coping theory to evaluate the role of relationship factors in sun protection. One hundred and eighty-four married couples aged 50 years and older completed measures of objective skin cancer risk, perceived risk, sun protection benefits, relationship-centered motivations for sun protection, discussions about sun protection, and sun protection. A mediational model was evaluated. Results indicated a high level of couple concordance. Partners who adopted a relationship centered motivation for sun protection were more likely to discuss sun protection with one another, and partners who discussed sun protection together were more likely to engage in sun protection. One partner's attitude about personal risk and sun protection benefits was associated with the other partner's sun protection. Wives had higher relationship-centered motivation and discussed sun protection more with their husbands. Behavioral interventions may benefit from encouraging couples to discuss sun protection and encouraging married individuals to consider the benefits of sun protection for their relationship and for their spouse's health. PMID- 27247329 TI - Combinatorial Gene Regulatory Functions Underlie Ultraconserved Elements in Drosophila. AB - Ultraconserved elements (UCEs) are discrete genomic elements conserved across large evolutionary distances. Although UCEs have been linked to multiple facets of mammalian gene regulation their extreme evolutionary conservation remains largely unexplained. Here, we apply a computational approach to investigate this question in Drosophila, exploring the molecular functions of more than 1,500 UCEs shared across the genomes of 12 Drosophila species. Our data indicate that Drosophila UCEs are hubs for gene regulatory functions and suggest that UCE sequence invariance originates from their combinatorial roles in gene control. We also note that the gene regulatory roles of intronic and intergenic UCEs (iUCEs) are distinct from those found in exonic UCEs (eUCEs). In iUCEs, transcription factor (TF) and epigenetic factor binding data strongly support iUCE roles in transcriptional and epigenetic regulation. In contrast, analyses of eUCEs indicate that they are two orders of magnitude more likely than the expected to simultaneously include protein-coding sequence, TF-binding sites, splice sites, and RNA editing sites but have reduced roles in transcriptional or epigenetic regulation. Furthermore, we use a Drosophila cell culture system and transgenic Drosophila embryos to validate the notion of UCE combinatorial regulatory roles using an eUCE within the Hox gene Ultrabithorax and show that its protein-coding region also contains alternative splicing regulatory information. Taken together our experiments indicate that UCEs emerge as a result of combinatorial gene regulatory roles and highlight common features in mammalian and insect UCEs implying that similar processes might underlie ultraconservation in diverse animal taxa. PMID- 27247331 TI - High-Sensitivity Troponin: A Clinical Blood Biomarker for Staging Cardiomyopathy in Fabry Disease. AB - BACKGROUND: High-sensitivity troponin (hs-TNT), a biomarker of myocardial damage, might be useful for assessing fibrosis in Fabry cardiomyopathy. We performed a prospective analysis of hs-TNT as a biomarker for myocardial changes in Fabry patients and a retrospective longitudinal follow-up study to assess longitudinal hs-TNT changes relative to fibrosis and cardiomyopathy progression. METHODS AND RESULTS: For the prospective analysis, hs-TNT from 75 consecutive patients with genetically confirmed Fabry disease was analyzed relative to typical Fabry associated echocardiographic findings and total myocardial fibrosis as measured by late gadolinium enhancement (LE) on magnetic resonance imaging. Longitudinal data (3.9+/-2.0 years), including hs-TNT, LE, and echocardiographic findings from 58 Fabry patients, were retrospectively collected. Hs-TNT level positively correlated with LE (linear correlation coefficient, 0.72; odds ratio, 32.81 [95% CI, 3.56-302.59]; P=0.002); patients with elevated baseline hs-TNT (>14 ng/L) showed significantly increased LE (median: baseline, 1.9 [1.1-3.3] %; follow-up, 3.2 [2.3-4.9] %; P<0.001) and slightly elevated hs-TNT (baseline, 44.7 [30.1 65.3] ng/L; follow-up, 49.1 [27.6-69.5] ng/L; P=0.116) during follow-up. Left ventricular wall thickness and EF of patients with elevated hs-TNT were decreased during follow-up, indicating potential cardiomyopathy progression. CONCLUSIONS: hs-TNT is an accurate, easily accessible clinical blood biomarker for detecting replacement fibrosis in patients with Fabry disease and a qualified predictor of cardiomyopathy progression. Thus, hs-TNT could be helpful for staging and follow up of Fabry patients. PMID- 27247332 TI - Impact of Center Experience on Patient Radiation Exposure During Transradial Coronary Angiography and Percutaneous Intervention: A Patient-Level, International, Collaborative, Multi-Center Analysis. AB - BACKGROUND: The adoption of the transradial (TR) approach over the traditional transfemoral (TF) approach has been hampered by concerns of increased radiation exposure-a subject of considerable debate within the field. We performed a patient-level, multi-center analysis to definitively address the impact of TR access on radiation exposure. METHODS AND RESULTS: Overall, 10 centers were included from 6 countries-Canada (2 centers), United Kingdom (2), Germany (2), Sweden (2), Hungary (1), and The Netherlands (1). We compared the radiation exposure of TR versus TF access using measured dose-area product (DAP). To account for local variations in equipment and exposure, standardized TR:TF DAP ratios were constructed per center with procedures separated by coronary angiography (CA) and percutaneous coronary intervention (PCI). Among 57 326 procedures, we demonstrated increased radiation exposure with the TR versus TF approach, particularly in the CA cohort across all centers (weighted-average ratios: CA, 1.15; PCI, 1.05). However, this was mitigated by increasing TR experience in the PCI cohort across all centers (r=-0.8; P=0.005). Over time, as a center transitioned to increasing TR experience (r=0.9; P=0.001), a concomitant decrease in radiation exposure occurred (r=-0.8; P=0.006). Ultimately, when a center's balance of TR to TF procedures approaches 50%, the resultant radiation exposure was equivalent. CONCLUSIONS: The TR approach is associated with a modest increase in patient radiation exposure. However, this increase is eliminated when the TR and TF approaches are used with equal frequency-a guiding principle for centers adopting the TR approach. PMID- 27247334 TI - Accuracy of ICD-9-CM Codes by Hospital Characteristics and Stroke Severity: Paul Coverdell National Acute Stroke Program. AB - BACKGROUND: Epidemiological and health services research often use International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes to identify patients with clinical conditions in administrative databases. We determined whether there are systematic variations between stroke patient clinical diagnoses and ICD-9-CM codes, stratified by hospital characteristics and stroke severity. METHODS AND RESULTS: We used the records of patients discharged from hospitals participating in the Paul Coverdell National Acute Stroke Program in 2013. Within this stroke-enriched cohort, we compared agreement between the attending physician's clinical diagnosis and principal ICD-9-CM code and determined whether disagreements varied by hospital characteristics (presence of a stroke unit, stroke team, number of hospital beds, and hospital location). For patients with a documented National Institutes of Health Stroke Scale score at admission, we assessed whether diagnostic agreement varied by stroke severity. Agreement was generally high (>89%); differences between the physician diagnosis and ICD-9-CM codes were primarily attributed to discordance between ischemic stroke and transient ischemic attack (TIA), and subarachnoid and intracerebral hemorrhage. Agreement was higher for patients in metropolitan hospitals with stroke units, stroke teams, and >200 beds (all P<0.001). Agreement was lowest (60.3%) for rural hospitals with <=200 beds and without stroke units or teams. Agreement was also lower for milder (94.9%) versus more-severe (96.4%) ischemic strokes (P<0.001). CONCLUSIONS: We identified disagreements in stroke/TIA coding by hospital characteristics and stroke severity, particularly for milder ischemic strokes. Such systematic variations in ICD-9-CM coding practices can affect stroke case identification in epidemiological studies and may have implications for hospital-level quality metrics. PMID- 27247333 TI - Restoration of Mitochondrial Cardiolipin Attenuates Cardiac Damage in Swine Renovascular Hypertension. AB - BACKGROUND: Renovascular hypertension (RVH) impairs cardiac structure and left ventricular (LV) function, but whether mitochondrial injury is implicated in RVH induced myocardial damage and dysfunction has not been defined. We hypothesized that cardiac remodeling in swine RVH is partly attributable to cardiac mitochondrial injury. METHODS AND RESULTS: After 12 weeks of hypercholesterolemic (HC)-RVH or control (n=14 each), pigs were treated for another 4 weeks with vehicle or with the mitochondrial-targeted peptide (MTP), Bendavia (0.1 mg/kg subcutaneously, 5 days/week), which stabilizes mitochondrial inner-membrane cardiolipin (n=7 each). Cardiac function was subsequently assessed by multidetector-computed tomography and oxygenation by blood-oxygen-level-dependent magnetic resonance imaging. Cardiolipin content, mitochondrial biogenesis, as well as sarcoplasmic-reticulum calcium cycling, myocardial tissue injury, and coronary endothelial function were assessed ex vivo. Additionally, mitochondrial cardiolipin content, oxidative stress, and bioenergetics were assessed in rat cardiomyocytes incubated with tert-butyl hydroperoxide (tBHP) untreated or treated with MTP. Chronic mitoprotection in vivo restored cardiolipin content and mitochondrial biogenesis. Thapsigargin-sensitive sarcoplasmic reticulum Ca(2+) ATPase activity that declined in HC-RVH normalized in MTP-treated pigs. Mitoprotection also improved LV relaxation (E/A ratio) and ameliorated cardiac hypertrophy, without affecting blood pressure or systolic function. Myocardial remodeling and coronary endothelial function improved only in MTP-treated pigs. In tBHP-treated cardiomyocytes, mitochondrial targeting attenuated a fall in cardiolipin content and bioenergetics. CONCLUSIONS: Chronic mitoprotection blunted myocardial hypertrophy, improved LV relaxation, and attenuated myocardial cellular and microvascular remodeling, despite sustained HC-RVH, suggesting that mitochondrial injury partly contributes to hypertensive cardiomyopathy. PMID- 27247335 TI - Novel Biomarkers to Improve the Prediction of Cardiovascular Event Risk in Type 2 Diabetes Mellitus. AB - BACKGROUND: We evaluated the ability of 23 novel biomarkers representing several pathophysiological pathways to improve the prediction of cardiovascular event (CVE) risk in patients with type 2 diabetes mellitus beyond traditional risk factors. METHODS AND RESULTS: We used data from 1002 patients with type 2 diabetes mellitus from the Second Manifestations of ARTertial disease (SMART) study and 288 patients from the European Prospective Investigation into Cancer and Nutrition-NL (EPIC-NL). The associations of 23 biomarkers (adiponectin, C reactive protein, epidermal-type fatty acid binding protein, heart-type fatty acid binding protein, basic fibroblast growth factor, soluble FMS-like tyrosine kinase-1, soluble intercellular adhesion molecule-1 and -3, matrix metalloproteinase [MMP]-1, MMP-3, MMP-9, N-terminal prohormone of B-type natriuretic peptide, osteopontin, osteonectin, osteocalcin, placental growth factor, serum amyloid A, E-selectin, P-selectin, tissue inhibitor of MMP-1, thrombomodulin, soluble vascular cell adhesion molecule-1, and vascular endothelial growth factor) with CVE risk were evaluated by using Cox proportional hazards analysis adjusting for traditional risk factors. The incremental predictive performance was assessed with use of the c-statistic and net reclassification index (NRI; continuous and based on 10-year risk strata 0-10%, 10-20%, 20-30%, >30%). A multimarker model was constructed comprising those biomarkers that improved predictive performance in both cohorts. N-terminal prohormone of B-type natriuretic peptide, osteopontin, and MMP-3 were the only biomarkers significantly associated with an increased risk of CVE and improved predictive performance in both cohorts. In SMART, the combination of these biomarkers increased the c-statistic with 0.03 (95% CI 0.01-0.05), and the continuous NRI was 0.37 (95% CI 0.21-0.52). In EPIC-NL, the multimarker model increased the c-statistic with 0.03 (95% CI 0.00-0.03), and the continuous NRI was 0.44 (95% CI 0.23-0.66). Based on risk strata, the NRI was 0.12 (95% CI 0.03 0.21) in SMART and 0.07 (95% CI -0.04-0.17) in EPIC-NL. CONCLUSIONS: Of the 23 evaluated biomarkers from different pathophysiological pathways, N-terminal prohormone of B-type natriuretic peptide, osteopontin, MMP-3, and their combination improved CVE risk prediction in 2 separate cohorts of patients with type 2 diabetes mellitus beyond traditional risk factors. However, the number of patients reclassified to a different risk stratum was limited. PMID- 27247336 TI - Infarct Size Following Treatment With Second- Versus Third-Generation P2Y12 Antagonists in Patients With Multivessel Coronary Disease at ST-Segment Elevation Myocardial Infarction in the CvLPRIT Study. AB - BACKGROUND: Third-generation P2Y12 antagonists (prasugrel and ticagrelor) are recommended in guidelines on ST-segment elevation myocardial infarction. Mechanisms translating their more potent antiplatelet activity into improved clinical outcomes versus the second-generation P2Y12 antagonist clopidogrel are unclear. The aim of this post hoc analysis of the Complete Versus Lesion-Only PRImary PCI Trial-CMR (CvLPRIT-CMR) substudy was to assess whether prasugrel and ticagrelor were associated with reduced infarct size compared with clopidogrel in patients undergoing primary percutaneous coronary intervention. METHODS AND RESULTS: CvLPRIT-CMR was a multicenter, prospective, randomized, open-label, blinded end point trial in 203 ST-segment elevation myocardial infarction patients with multivessel disease undergoing primary percutaneous coronary intervention with either infarct-related artery-only or complete revascularization. P2Y12 inhibitors were administered according to local guidelines. The primary end point of infarct size on cardiovascular magnetic resonance was not significantly different between the randomized groups. P2Y12 antagonist administration was not randomized. Patients receiving clopidogrel (n=70) compared with those treated with either prasugrel or ticagrelor (n=133) were older (67.8+/-12 versus 61.5+/-10 years, P<0.001), more frequently had hypertension (49% versus 29%, P=0.007), and tended to have longer symptom-to revascularization time (234 versus 177 minutes, P=0.05). Infarct size (median 16.1% [quartiles 1-3, 10.5-27.7%] versus 12.1% [quartiles 1-3, 4.8-20.7%] of left ventricular mass, P=0.013) and microvascular obstruction incidence (65.7% versus 48.9%, P=0.022) were significantly greater in patients receiving clopidogrel. Infarct size remained significantly different after adjustment for important covariates using both generalized linear models (P=0.048) and propensity score matching (P=0.025). CONCLUSIONS: In this analysis of CvLPRIT-CMR, third generation P2Y12 antagonists were associated with smaller infarct size and lower microvascular obstruction incidence versus the second-generation P2Y12 antagonist clopidogrel for ST-segment elevation myocardial infarction. CLINICAL TRIAL REGISTRATION: URL: http://www.isrctn.com/ISRCTN70913605. PMID- 27247338 TI - Pharmacological Conversion of a Cardiac Inward Rectifier into an Outward Rectifier Potassium Channel. AB - Potassium (K(+)) channels are crucial for determining the shape, duration, and frequency of action-potential firing in excitable cells. Broadly speaking, K(+) channels can be classified based on whether their macroscopic current outwardly or inwardly rectifies, whereby rectification refers to a change in conductance with voltage. Outwardly rectifying K(+) channels conduct greater current at depolarized membrane potentials, whereas inward rectifier channels conduct greater current at hyperpolarized membrane potentials. Under most circumstances, outward currents through inwardly rectifying K(+) channels are reduced at more depolarized potentials. However, the acetylcholine-gated K(+) channel (KACh) conducts current that inwardly rectifies when activated by some ligands (such as acetylcholine), and yet conducts current that outwardly rectifies when activated by other ligands (for example, pilocarpine and choline). The perplexing and paradoxical behavior of KACh channels is due to the intrinsic voltage sensitivity of the receptor that activates KACh channels, the M2 muscarinic receptor (M2R). Emerging evidence reveals that the affinity of M2R for distinct ligands varies in a voltage-dependent and ligand-specific manner. These intrinsic receptor properties determine whether current conducted by KACh channels inwardly or outwardly rectifies. This review summarizes the most recent concepts regarding the intrinsic voltage sensitivity of muscarinic receptors and the consequences of this intriguing behavior on cardiac physiology and pharmacology of KACh channels. PMID- 27247340 TI - Cerebrovascular Complications of Pediatric Pneumococcal Meningitis in the PCV13 Era. PMID- 27247339 TI - Ankle Brachial Index and Subsequent Cardiovascular Disease Risk in Patients With Chronic Kidney Disease. AB - BACKGROUND: The clinical implications of ankle-brachial index (ABI) cutpoints are not well defined in patients with chronic kidney disease (CKD) despite increased prevalence of high ABI attributed to arterial stiffness. We examined the relationship of ABI with cardiovascular disease (CVD) and all-cause mortality among CKD patients. METHODS AND RESULTS: Three thousand six hundred twenty-seven participants without clinical peripheral artery disease (PAD) at baseline from the Chronic Renal Insufficiency Cohort Study were included. ABI was obtained per standard protocol and CVD events were confirmed by medical record adjudication. A U-shaped association of ABI with PAD, myocardial infarction (MI), composite CVD, and all-cause mortality was observed. Individuals with an ABI between 1.0 and <1.4 had the lowest risk of outcomes. Compared to participants with an ABI between 1.0 and <1.4, multiple-adjusted hazard ratios (95% confidence intervals) for those with an ABI of <0.9, 0.9 to <1.0, and >=1.4 were 5.78 (3.57, 9.35), 2.76 (1.56, 4.88), and 4.85 (2.05, 11.50) for PAD; 1.67 (1.23, 2.29), 1.85 (1.33, 2.57), and 2.08 (1.10, 3.93) for MI; 1.51 (1.27, 1.79), 1.39 (1.15, 1.68), and 1.23 (0.82, 1.84) for composite CVD; and 1.55 (1.28, 1.89), 1.36 (1.10, 1.69), and 1.00 (0.62, 1.62) for all-cause mortality, respectively. CONCLUSIONS: This study indicates that ABI <1.0 was related to risk of PAD, MI, composite CVD, and all-cause mortality whereas ABI >=1.4 was related to clinical PAD. These findings suggest that ABI cutpoints of <1.0 or >=1.4 for diagnosing PAD and ABI <1.0 for CVD risk stratification should be further evaluated among CKD patients. PMID- 27247337 TI - Cardiac-Secreted Factors as Peripheral Metabolic Regulators and Potential Disease Biomarkers. PMID- 27247341 TI - Development, Evaluation, and Integration of a Quantitative Reverse-Transcription Polymerase Chain Reaction Diagnostic Test for Ebola Virus on a Molecular Diagnostics Platform. AB - BACKGROUND: The 2013-2016 Ebola epidemic in West Africa resulted in accelerated development of rapid diagnostic tests for emergency outbreak preparedness. We describe the development and evaluation of the IdyllaTM prototype Ebola virus test, a fully automated sample-to-result molecular diagnostic test for rapid detection of Zaire ebolavirus (EBOV) and Sudan ebolavirus (SUDV). METHODS: The IdyllaTM prototype Ebola virus test can simultaneously detect EBOV and SUDV in 200 uL of whole blood. The sample is directly added to a disposable cartridge containing all reagents for sample preparation, RNA extraction, and amplification by reverse-transcription polymerase chain reaction analysis. The performance was evaluated with a variety of sample types, including synthetic constructs and whole blood samples from healthy volunteers spiked with viral RNA, inactivated virus, and infectious virus. RESULTS: The 95% limits of detection for EBOV and SUDV were 465 plaque-forming units (PFU)/mL (1010 copies/mL) and 324 PFU/mL (8204 copies/mL), respectively. In silico and in vitro analyses demonstrated 100% correct reactivity for EBOV and SUDV and no cross-reactivity with relevant pathogens. The diagnostic sensitivity was 97.4% (for EBOV) and 91.7% (for SUDV), the specificity was 100%, and the diagnostic accuracy was 95.9%. CONCLUSIONS: The IdyllaTM prototype Ebola virus test is a fast, safe, easy-to-use, and near patient test that meets the performance criteria to detect EBOV in patients with suspected Ebola. PMID- 27247343 TI - Vaccination Against Tuberculosis With Whole-Cell Mycobacterial Vaccines. AB - Live attenuated and killed whole-cell vaccines (WCVs) offer promising vaccination strategies against tuberculosis. A number of WCV candidates, based on recombinant bacillus Calmette-Guerin (BCG), attenuated Mycobacterium tuberculosis, or related mycobacterial species are in various stages of preclinical or clinical development. In this review, we discuss the vaccine candidates and key factors shaping the development pathway for live and killed WCVs and provide an update on progress. PMID- 27247342 TI - Persistent Sex Disparities in Invasive Pneumococcal Diseases in the Conjugate Vaccine Era. AB - BACKGROUND: Few studies have characterized the role of sex on the incidence of invasive pneumococcal disease (IPD). We examined sex differences in rates of IPD, and trends after the introduction of pneumococcal conjugate vaccines (PCVs). METHODS: We used active population and laboratory-based IPD surveillance data from the Centers for Disease Control and Prevention Active Bacterial Core surveillance program (1998-2013) in Tennessee. Population-based rates of IPD by sex, race, age group, and PCV era were calculated. Rates were compared using incidence rate ratios. RESULTS: Throughout the study years, rates of IPD were higher in male than in female subjects, particularly in children <2 years and adults 40-64 years of age, with male subjects having IPD rates 1.5-2 times higher than female subjects. The proportions of comorbid conditions were similar in male and female subjects . Sex rate differences persisted after stratification by race. Although the introductions of 7-valent PCV (PCV7) and 13-valent PCV (PCV13) were associated with declines in IPD rates in both sexes, rates of IPD after PCV13 were still significantly higher in male than in female subjects among children and adults 40-64 and >74 years of age. CONCLUSIONS: Rates of IPD were generally higher in male than in female subjects. These sex differences were observed in different race groups and persisted after introduction of both PCVs. PMID- 27247344 TI - Live Attenuated Influenza Vaccine in Children Induces B-Cell Responses in Tonsils. AB - BACKGROUND: Tonsils play a key role in eliciting immune responses against respiratory pathogens. Little is known about how tonsils contribute to the local immune response after intranasal vaccination. Here, we uniquely report the mucosal humoral responses in tonsils and saliva after intranasal live attenuated influenza vaccine (LAIV) vaccination in children. METHODS: Blood, saliva, and tonsils samples were collected from 39 children before and after LAIV vaccination and from 16 age-matched, nonvaccinated controls. Serum antibody responses were determined by a hemagglutination inhibition (HI) assay. The salivary immunoglobulin A (IgA) level was measured by an enzyme-linked immunosorbent assay. Antibody-secreting cell (ASC) and memory B-cell (MBC) responses were enumerated in tonsils and blood. RESULTS: Significant increases were observed in levels of serum antibodies and salivary IgA to influenza A(H3N2) and influenza B virus strains as early as 14 days after vaccination but not to influenza A(H1N1). Influenza virus-specific salivary IgA levels correlated with serum HI responses, making this a new possible indicator of vaccine immunogenicity in children. LAIV augmented influenza virus-specific B-cell responses in tonsils and blood. Tonsillar MBC responses correlated with systemic MBC and serological responses. Naive children showed significant increases in MBC counts after LAIV vaccination. CONCLUSIONS: This is the first study to demonstrate that LAIV elicits humoral B cell responses in tonsils of young children. Furthermore, salivary IgA analysis represents an easy method for measuring immunogenicity after vaccination. PMID- 27247345 TI - Clindamycin Affects Group A Streptococcus Virulence Factors and Improves Clinical Outcome. AB - Group A Streptococcus (GAS) has acquired an arsenal of virulence factors, promoting life-threatening invasive infections such as necrotizing fasciitis. Current therapeutic regimens for necrotizing fasciitis include surgical debridement and treatment with cell wall-active antibiotics. Addition of clindamycin (CLI) is recommended, although clinical evidence is lacking. Reflecting the current clinical dilemma, an observational study showed that only 63% of the patients with severe invasive GAS infection received CLI. This work thus aimed to address whether CLI improves necrotizing fasciitis outcome by modulating virulence factors of CLI-susceptible and CLI-resistant GAS in vitro and in vivo. Treatment with CLI reduced extracellular DNase Sda1 and streptolysin O (SLO) activity in vivo, whereas subinhibitory CLI concentrations induced expression and activity of SLO, DNase, and Streptococcus pyogenes cell envelope protease in vitro. Our in vivo results suggest that CLI should be administered as soon as possible to patients with necrotizing fasciitis, while our in vitro studies emphasize that a high dosage of CLI is essential. PMID- 27247346 TI - Effects of dietary carbohydrate on hepatic de novo lipogenesis in European seabass (Dicentrarchus labrax L.). AB - Farmed seabass have higher adiposity than their wild counterparts and this is often attributed to carbohydrate (CHO) feeding. Whether this reflects a reduction in fat oxidation, increased de novo lipogenesis (DNL), or both, is not known. To study the effects of high CHO diets on hepatic TG biosynthesis, hepatic TG deuterium ((2)H) enrichment was determined following 6 days in (2)H-enriched tank water for fish fed with a no-CHO control diet (CTRL), and diets with digestible starch (DS) and raw starch (RS). Hepatic fractional synthetic rates (FSRs, percent per day(-1)) were calculated for hepatic TG-glyceryl and FA moieties through (2)H NMR analysis. Glyceryl FSRs exceeded FA FSRs in all cases, indicating active cycling. DS fish did not show increased lipogenic potential compared to CTRL. RS fish had lower glyceryl FSRs compared with the other diets and negligible levels of FA FSRs despite similar hepatic TG levels to CTRL. DS fed fish showed higher activity for enzymes that can provide NADPH for lipogenesis, relative to CTRL in the case of glucose-6-phosphate dehydrogenase (G6PDH) and relative to RS for both G6PDH and 6-phosphogluconate dehydrogenase. This approach indicated that elevated hepatic adiposity from DS feeding was not attributable to increased DNL. PMID- 27247347 TI - Diversity of Sand Flies (Diptera: Psychodidae: Phlebotominae) in Two Different Eco-Climatic and Endemic Zones of Cutaneous Leishmaniasis in Mali, West Africa. AB - Being the only established vectors of the protozoan parasites of the genus Leishmania, sand flies have become very important in all countries where leishmaniasis exists. To better understand the sand fly fauna, a taxonomic inventory study was carried out between January and March 2012 in Soudan savannah (Boundioba, Sikasso) and Sahelian (Tieneguebougou, Koulikoro) areas of Mali. CDC light traps were used to collect the sand flies. Collected sand flies specimens were cleaned with lacto-phenol and examined under a light microscope for species identification. In total, 14 species belonging to the genera Phlebotomus and Sergentomyia were identified. The genus Sergentomyia constituted 98.05% of collected sand flies versus 1.95% for the genus Phlebotomus. The most abundant species were Sergentomyia dubia Parrot, Mornet, & Cadenat, Sergentomyia shwetzi, Sergentomyia clydei Sinton, and Sergentomyia antennata Newstead. In Boundioba, the genus Phlebotomus was represented by two species (Phlebotomus duboscqi Neveu Lemaire and Phlebotomus rodhaini Parrot), whereas only one species, Ph. duboscqi, was captured in Tieneguebougou. For the first time, three new species, Sergentomyia madagascariensis, Sergentomyia congolensis, and Sergentomyia dureni, were identified in Mali. More investigations are needed for a better entomological assessment of the transmission of cutaneous leishmaniasis in the different eco-climatic zones of Mali. PMID- 27247348 TI - Survival Value and Sugar Access of Four East African Plant Species Attractive to a Laboratory Strain of Sympatric Anopheles gambiae (Diptera: Culicidae). AB - Mosquitoes derive energy from plant sugar, thereby promoting survival and reproduction. Its survival value to females plays a key role in the vectorial capacity of mosquito populations. Previous olfactometry assays of responsiveness demonstrated that Senna didymobotrya Fresenius, Parthenium hysterophorus, L. Senna occidentalis, (L) and Lantana camara L were among the most attractive plants for the Mbita strain of Anopheles gambiae s.s. Giles in eastern Africa. Here, we provide experimental evidence that three of these four species also provide varying but substantial amounts of sugar for mosquito survival, whereas a fourth does not. Rank order of survival of both sexes of mosquitoes housed with these plants was as follows: S. didymobotrya was highest, followed by S. occidentalis and L. camara, whereas survival on P. hysterophorus was only slightly better than on only water. A positive control group, housed with 10% sucrose, survived well but fell significantly short of those with S. didymobotrya A causal connection between survival and sugar availability was established by exposing mosquitoes to plants overnight, and then testing them for the presence and amount of undigested fructose. Fructose positivity was most frequent in those exposed to L. camara, whereas greatest amounts of fructose were obtained from S. occidentalis and S. didymobotrya Parthenium hysterophorus scored lowest in both categories. We conclude that attractiveness and sugar availability are often, but not always, concordant. It remains unclear why P. hysterophorus should be attractive if it offers little sugar and does not prolong survival. Furthermore, the cause behind the superior survival benefit of S. didymobotrya, compared with 10% sucrose, is unknown. PMID- 27247349 TI - Forensic Entomology: Evaluating Uncertainty Associated With Postmortem Interval (PMI) Estimates With Ecological Models. AB - Estimates of insect age can be informative in death investigations and, when certain assumptions are met, can be useful for estimating the postmortem interval (PMI). Currently, the accuracy and precision of PMI estimates is unknown, as error can arise from sources of variation such as measurement error, environmental variation, or genetic variation. Ecological models are an abstract, mathematical representation of an ecological system that can make predictions about the dynamics of the real system. To quantify the variation associated with the pre-appearance interval (PAI), we developed an ecological model that simulates the colonization of vertebrate remains by Cochliomyia macellaria (Fabricius) (Diptera: Calliphoridae), a primary colonizer in the southern United States. The model is based on a development data set derived from a local population and represents the uncertainty in local temperature variability to address PMI estimates at local sites. After a PMI estimate is calculated for each individual, the model calculates the maximum, minimum, and mean PMI, as well as the range and standard deviation for stadia collected. The model framework presented here is one manner by which errors in PMI estimates can be addressed in court when no empirical data are available for the parameter of interest. We show that PAI is a potential important source of error and that an ecological model is one way to evaluate its impact. Such models can be re-parameterized with any development data set, PAI function, temperature regime, assumption of interest, etc., to estimate PMI and quantify uncertainty that arises from specific prediction systems. PMID- 27247350 TI - Evaluation of Alternative Killing Agents for Aedes aegypti (Diptera: Culicidae) in the Gravid Aedes Trap (GAT). AB - The Gravid Aedes Trap (GAT) uses visual and olfactory cues to attract gravid Aedes aegypti (L.) that are then captured when knocked down by a residual pyrethroid surface spray. However, the use of surface sprays can be compromised by poor availability of the spray and pesticide resistance in the target mosquito. We investigated several "alternative" insecticide and insecticide-free killing agents for use in the GAT. This included long-lasting insecticide impregnated nets (LLINs), vapor-active synthetic pyrethroids (metofluthrin), canola oil, and two types of dry adhesive sticky card. During bench top assays LLINs, metofluthrin, and dry sticky cards had 24-h knockdown (KD) percentages >80% (91.2 +/- 7.2%, 84.2 +/- 6.8%, and 83.4 +/- 6.1%, respectively), whereas the 24-h KD for canola oil was 70 +/- 7.7%, which improved to 90.0 +/- 3.7% over 48 h. Importantly, there were no significant differences in the number of Ae. aegypti collected per week or the number of traps positive for Ae. aegypti between the sticky card and canola oil treatments compared with the surface spray and LLIN treatments in semifield and field trials. These results demonstrate that the use of inexpensive and widely available insecticide-free agents such as those described in this study are effective alternatives to pyrethroids in regions with insecticide-resistant populations. The use of such environmentally friendly insecticide-free alternatives will also be attractive in areas where there is substantial resistance to insecticide use due to environmental and public health concerns. PMID- 27247351 TI - A splicing mutation in VPS4B causes dentin dysplasia I. AB - BACKGROUND: Dentin dysplasia I (DDI) is a genetically heterogeneous autosomal dominant disorder characterised by rootless teeth with abnormal pulpal morphology, the aetiology of which presents as genetically heterogeneous. METHODS AND RESULTS: Using a cohort of a large Chinese family with 10 patients with DDI, we mapped to a 9.63 Mb candidate region for DDI on chromosome 18q21.2-q21.33. We then identified a mutation IVS7+46C>G which resulted in a novel donor splice site in intron 7 of the VPS4B gene with co-segregation of all 10 affected individuals in this family. The aberrant transcripts encompassing a new insert of 45 bp in size were detected in gingival cells from affected individuals. Protein structure prediction showed that a 15-amino acid insertion altered the ATP-binding cassette of VPS4B. The mutation resulted in significantly reduced expression of mRNA and protein and altered subcellular localisation of VPS4B, indicating a loss of function of VPS4B. Using human gingival fibroblasts, the VPS4B gene was found to act as an upstream transducer linked to Wnt/beta-catenin signalling and regulating odontogenesis. Furthermore, knockdown of vps4b in zebrafish recapitulated the reduction of tooth size and absence of teeth similar to the tooth phenotype exhibited in DDI index cases, and the zebrafish mutant phenotype could be partially rescued by wild-type human VPS4B mRNA. We also observed that vps4b depletion in the zebrafish negatively regulates the expression of some major genes involved in odontogenesis. CONCLUSIONS: This study identifies VPS4B as a disease-causing gene for DDI, which is one of the important contributors to tooth formation, through the Wnt/beta-catenin signalling pathway. PMID- 27247352 TI - Developing New, Rational Therapies for Recalcitrant Small Cell Lung Cancer. PMID- 27247354 TI - Exposure to Guava Affects Citrus Olfactory Cues and Attractiveness to Diaphorina citri (Hemiptera: Psyllidae). AB - Intercropping can reduce agricultural pest incidence, and represents an important sustainable alternative to conventional pest control methods. Understanding the ecological mechanisms for intercropping could help optimize its use, particularly in tropical systems which present a large number of intercropping possibilities. Citrus is threatened worldwide by greening disease (huanglongbing, HLB) vectored by the Asian citrus psyllid, Diaphorina citri Kuwayama (Hemiptera: Psyllidae). Control of HLB and citrus psyllid can be partially achieved through intercropping with guava, Psidium guajava L., but the mechanisms remain unclear. We tested the hypothesis that guava olfactory cues affect psyllid behavior by altering the attractiveness of citrus through plant-plant interactions. In choice and no choice cage experiments, psyllid settlement was reduced on citrus shoots that had been exposed to guava shoot odors for at least 2 h. In Y-tube olfactometer experiments, psyllids oriented to odors of unexposed, compared with guava exposed, citrus shoots. These behavioral results indicate that a mechanism for the success of guava intercropping for sustainable, ecological disease management may be the indirect effect of guava on citrus attractiveness. PMID- 27247360 TI - CardioPulse Articles. PMID- 27247353 TI - Small Cell Lung Cancer Screen of Oncology Drugs, Investigational Agents, and Gene and microRNA Expression. AB - BACKGROUND: Small cell lung carcinoma (SCLC) is an aggressive, recalcitrant cancer, often metastatic at diagnosis and unresponsive to chemotherapy upon recurrence, thus it is challenging to treat. METHODS: Sixty-three human SCLC lines and three NSCLC lines were screened for response to 103 US Food and Drug Administration-approved oncology agents and 423 investigational agents. The investigational agents library was a diverse set of small molecules that included multiple compounds targeting the same molecular entity. The compounds were screened in triplicate at nine concentrations with a 96-hour exposure time using an ATP Lite endpoint. Gene expression was assessed by exon array, and microRNA expression was derived by direct digital detection. Activity across the SCLC lines was associated with molecular characteristics using pair-wise Pearson correlations. RESULTS: Results are presented for inhibitors of targets: BCL2, PARP1, mTOR, IGF1R, KSP/Eg5, PLK-1, AURK, and FGFR1. A relational map identified compounds with similar patterns of response. Unsupervised microRNA clustering resulted in three distinct SCLC subgroups. Associating drug response with micro RNA expression indicated that lines most sensitive to etoposide and topotecan expressed high miR-200c-3p and low miR-140-5p and miR-9-5p. The BCL-2/BCL-XL inhibitors produced similar response patterns. Sensitivity to ABT-737 correlated with higher ASCL1 and BCL2. Several classes of compounds targeting nuclear proteins regulating mitosis produced a response pattern distinct from the etoposide response pattern. CONCLUSIONS: Agents targeting nuclear kinases appear to be effective in SCLC lines. Confirmation of SCLC line findings in xenografts is needed. The drug and compound response, gene expression, and microRNA expression data are publicly available at http://sclccelllines.cancer.gov. PMID- 27247361 TI - Cricket ball in the heart? Ball-like thrombus or a thrombus-like mass in the left atrium. PMID- 27247362 TI - Save your blushes and stop routine thrombus aspiration during primary PCI. PMID- 27247363 TI - Metabolic control and oxidative stress in pathological cardiac remodelling. PMID- 27247364 TI - Advocating for Pathology. PMID- 27247365 TI - Histopathology of Graft-vs-Host Disease of Gastrointestinal Tract and Liver: An Update. AB - OBJECTIVES: Graft-vs-host disease (GVHD) is a donor T-cell-mediated disorder affecting the recipient's skin, gastrointestinal tract, lungs, and liver. It complicates up to 70% of hematopoietic cell transplantation and is associated with high morbidity and mortality rates. METHODS: An extensive review of the literature has been performed to include the most current consensus on the histopathologic diagnosis of gastrointestinal and liver GVHD. RESULTS: In this review, we present an overview of GVHD, with emphasis on the histopathologic evaluation of gastrointestinal and liver specimens, including the most important differential diagnoses and possible pitfalls. CONCLUSIONS: Histopathologic examination remains the mainstay of diagnosis of gastrointestinal and liver GVHD and is interpreted in conjunction with clinical and laboratory data. PMID- 27247366 TI - An Immunohistochemical Survey of SNARE Proteins Shows Distinct Patterns of Expression in Hematolymphoid Neoplasia. AB - OBJECTIVES: Five proteins from the soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE) complex family were studied in normal hematopoietic cells in bone marrow; normal lymphocytes at different stages of maturation and differentiation in bone marrow, thymus, tonsil, and lymph node; malignant lymphomas; and leukemias. METHODS: Sixty-eight reactive and 380 hematopoietic and lymphoid neoplasms were immunohistochemically stained for syntaxin 7 (STX7), vesicle-associated membrane proteins (VAMP2, VAMP7, VAMP8), and synaptosomal-associated protein 23 (SNAP23). RESULTS: STX7 has potential for being a useful marker for distinguishing between normal B precursors (hematogones) vs B lymphoblasts, as well as between the "popcorn" cells of nodular lymphocyte-predominant Hodgkin lymphoma vs the Reed-Sternberg cells of classic Hodgkin lymphoma or the B cells of T-cell, histiocyte-rich B-cell lymphoma. VAMP2 is uniquely expressed by both reactive and malignant plasma cells, in contrast to B-cell non-Hodgkin lymphoma. There is differential expression of SNARE proteins in normal and neoplastic lymphoid tissue depending on lymphocyte maturation stage. CONCLUSIONS: Differential SNARE protein expression in the lymphoid system may have potential use in diagnosis and may offer clues to lymphoma biology. VAMP2 is a promising new plasma cell marker. PMID- 27247367 TI - Assessment of Melanocyte Density in Anorectal Mucosa for the Evaluation of Surgical Margins in Primary Anorectal Melanoma. AB - OBJECTIVES: Accurate histopathologic evaluation of surgical resection margins for anorectal melanoma (AM) is diagnostically challenging but essential to clinical management. We studied intraepithelial melanocyte density and growth pattern in anorectal mucosa and BRAF V600E mutation status in AM compared to controls. METHODS: Histomorphology and melanocytic immunostains, microphthalmia transcription factor (MITF) and human melanoma black 45 (HMB45), were evaluated. Utility of VE1 immunostaining for determination of BRAF V600E mutation status was studied. RESULTS: Immunostains aid in the distinction between "trailing" melanoma in situ (MIS) and benign melanocyte hyperplasia (BMH), by facilitating assessment of melanocyte density, and evaluation of nuclear atypia and growth pattern. While respective melanocyte densities overlapped, "trailing" MIS could be distinguished by melanocyte nuclear atypia and near confluent growth, compared to the banal cytology and scattered growth of BMH. CONCLUSIONS: In the histopathologic assessment of AM resections, MITF and HMB45 immunostains aid in distinguishing between "trailing" MIS and BMH, by highlighting melanocyte density, nuclear atypia, and growth pattern, with the latter two being reliable features. VE1 showed nonspecific immunopositivity in anorectal glandular epithelium, a potential diagnostic pitfall when assessing BRAF mutation status. PMID- 27247368 TI - Cystic Neutrophilic Granulomatous Mastitis: Association With Gram-Positive Bacilli and Corynebacterium. AB - OBJECTIVES: To determine whether cystic neutrophilic granulomatous mastitis (CNGM) can be associated with Gram-positive bacilli and Corynebacterium METHODS: We reviewed our experience with 35 granulomatous mastitis patients over a 10-year period, including histologic pattern, Gram stain and other microbiologic data, clinical presentation, treatment and outcome. RESULTS: Biopsies from 19 patients demonstrated CNGM, while 16 patients had other patterns of granulomatous mastitis. Gram-positive organisms were seen within microcystic spaces in 16/19 CNGM, but 0/16 non-CNGM patients (P = .000). Culture or molecular studies demonstrated Corynebacterium species in three, all CNGM. Patients with CNGM were more likely to be younger, of Hispanic ethnicity, and born outside of the United States. Granulomatous mastitis resolved after a protracted course with widely variable treatment (antibiotics, surgery, steroids). CONCLUSIONS: Our data further support CNGM as an infectious disease; further study of Corynebacterium directed therapy in CNGM is needed. PMID- 27247369 TI - Extreme Hyperferritinemia: Causes and Impact on Diagnostic Reasoning. AB - OBJECTIVES: Hyperferritinemia can be a result of inflammation, infection, chronic iron overload, or other uncommon pathologies including hemophagocytic lymphohistiocytosis (HLH). There is a historical association between extreme hyperferritinemia and HLH, but in reality HLH is associated with a minority of hyperferritinemic states. METHODS: We identified conditions most associated with hyperferritinemia by identifying 65,536 serum ferritin levels at the University of Minnesota Hospital over a five-year period, with 86 values higher than 10,000 ng/mL. Pediatric patients comprised 22% of this population, and adults, 78%. RESULTS: The majority of cases in both populations with hyperferritinemia were due to chronic transfusion (35%), followed by liver disease (27%), and hematologic malignancy (16%). Solid malignancies, infection, macrophage activation syndrome, and primary and secondary HLH comprised the remaining (22%). CONCLUSIONS: Although this supports the relationship between extreme hyperferritinemia and HLH, it maintains that the positive predictive value of hyperferritinemia for HLH is quite low, and one should consider more common explanations before suspecting HLH. PMID- 27247370 TI - Comparison of the Diagnostic Value Between Real-Time Reverse Transcription Polymerase Chain Reaction Assay and Histopathologic Examination in Sentinel Lymph Nodes for Patients With Gastric Carcinoma. AB - OBJECTIVES: Sentinel lymph node (SLN)-based diagnosis in gastric cancers has shown varied sensitivities and false-negative rates in several studies. Application of the reverse transcription-polymerase chain reaction (RT-PCR) in SLN diagnosis has recently been proposed. METHODS: A total of 155 SLNs from 65 patients with cT1-2, N0 gastric cancer were examined. The histopathologic results were compared with results obtained by real-time RT-PCR for detecting molecular RNA (mRNA) of cytokeratin (CK)19, carcinoembryonic antigen (CEA), and CK20. RESULTS: The sensitivity and specificity of the multiple marker RT-PCR assay standardized against the results of the postoperative histological examination were 0.778 (95% confidence interval [CI], 0.577-0.914) and 0.781 (95% CI, 0.700 0.850), respectively. In comparison, the sensitivity and specificity of intraoperative diagnosis were 0.819 (95% CI, 0.619-0.937) and 1.000 (95% CI, 0.972-1.000), respectively. The positive predictive value of the multiple-marker RT-PCR assay was 0.355 (95% CI, 0.192-0.546) for predicting non-SLN metastasis, which was lower than that of intraoperative diagnosis (0.813, 95% CI, 0.544 0.960). CONCLUSIONS: The real-time RT-PCR assay could detect SLN metastasis in gastric cancer. However, the predictive value of the real-time RT-PCR assay was lower than that of precise histopathologic examination and did not outweigh that of our intraoperative SLN diagnosis. PMID- 27247371 TI - Warfarin Pharmacogenetics Reevaluated: Subgroup Analysis Reveals a Likely Underestimation of the Maximum Pharmacogenetic Benefit by Clinical Trials. AB - OBJECTIVES: Various patient subgroups were examined to determine which ones obtain the largest pharmacogenetic improvements in warfarin dose accuracy. Subgrouping schemes of recent clinical trials were analyzed for comparison. METHODS: The accuracy of a pharmacogenetic dose algorithm was determined retrospectively in comparison to that of a clinical algorithm in subgroups of the International Warfarin Pharmacogenetics Consortium (IWPC) patient database (n = 2,274) and of newly studied clinic patients (n = 146). RESULTS: White patients with low-dose genotypes (*1*3/AA, *2*2/AA, *2*3/GA, *2*3/AA, *3*3/GG, *3*3/GA, and *3*3/AA) achieved the largest pharmacogenetic improvements in warfarin dose accuracy. Mean absolute dosing error (MAE) in this subgroup of IWPC and newly studied patients was reduced 75.7% and 89.7%, respectively. White IWPC patients with >2 variants or >=2 mg/day absolute difference between pharmacogenetic and clinical dose predictions obtained MAE reductions of 71.1% and 65.3%, respectively. By comparison, unstratified populations and subgroups of a major clinical trial, when replicated in IWPC patients, obtained smaller MAE reductions of 31.8% to 48.2%. Blacks and Asians obtained substantially smaller dose accuracy improvements overall than whites. CONCLUSIONS: Patient subgroups were identified that obtained the largest pharmacogenetic improvements in warfarin dose accuracy. These subgroups have not been analyzed in clinical trials to date, likely resulting in underestimation of the pharmacogenetic benefit. PMID- 27247372 TI - Optimal Minimal Panels of Immunohistochemistry for Diagnosis of B-Cell Lymphoma for Application in Countries With Limited Resources and for Triaging Cases Before Referral to Specialist Centers. AB - OBJECTIVES: Establish and validate optimal minimal immunohistochemistry panels for usage in a staged algorithmic manner for precise diagnosis of B-cell lymphomas in countries with limited resources. Suggest short panels of immunostains to be used in referring units that refer suspected lymphomas to specialist diagnostic centers in resourceful countries. METHODS: Significant proportion of six B-cell lymphomas has characteristic morphology requiring a short panel of confirmatory immunostains. The rest would go through five different algorithms. RESULTS: 812 cases in which a B-cell lymphoma or an HIV associated lymphoma was suspected on morphological grounds were evaluated. This led to arriving at a specific diagnosis of 799 B-cell lymphomas. A correct diagnosis was achievable in 69% cases with the application of three to five antibodies; others required additional work-up. CONCLUSIONS: The panels/algorithms assist pathologists in practicing lymphoma diagnostics in countries with limited resources and in making lymphoma referrals to specialist centers. PMID- 27247373 TI - Test Feasibility of Next-Generation Sequencing Assays in Clinical Mutation Detection of Small Biopsy and Fine Needle Aspiration Specimens. AB - OBJECTIVES: To evaluate preanalytic factors contributing to failure of next generation sequencing (NGS) assays. METHODS: AmpliSeq Cancer Hotspot Panel was conducted in 1,121 of 1,152 formalin-fixed paraffin-embedded tissues submitted to a clinical laboratory, including 493 small biopsy or fine needle aspiration (FNA) specimens (44%) and 25 metastatic bone specimens (2.2%). RESULTS: Single nucleotide mutations and/or insertion/deletion mutations were detected in 702 specimens. Thirty-eight specimens (3.4%) were reported as "no results" due to NGS assay failure. Higher failure rates were observed in specimens submitted for lung cancer panel and melanoma panel (3.1% and 3.7% vs 1.0% colorectal cancer panel), metastatic bone specimens (36% vs 2.6% nonbone specimens), referred specimens (5.0% vs 1.8% in-house specimens), and small biopsy and FNA specimens (5.8% and 3.1% vs 0.7% resection/excision specimens). Test feasibility was higher in in house specimens than referred specimens (99.1% vs 96.9% in resection specimens, 94.4% vs 87.3% in small biopsy specimens, and 94.3% vs 58.8% in FNA specimens). CONCLUSIONS: NGS assays demonstrated clinical utility in solid tumor specimens, including those taken by biopsy or FNA. Preanalytic factors identified by this study that may contribute to NGS assay failure highlight the need for pathologists to revisit tissue processing protocols in order to better optimize cancer mutational profiling. PMID- 27247374 TI - Levamisole-Adulterated Cocaine Nephrotoxicity: Ultrastructural Features. AB - OBJECTIVES: The issue of levamisole-adulterated cocaine is emerging as a rapidly growing public health concern due to an increasing number of reports describing its role in cutaneous vasculitis and agranulocytosis. Of note, levamisole is recognized as a contaminant in 69% of the cocaine used within the United States. METHODS: We describe a patient who was a chronic cocaine user and developed systemic vasculitis characterized by polyarthralgia, bullous skin lesions, agranulocytosis, and antineutrophil cytoplasmic antibody-positive rapidly progressive glomerulonephritis. RESULTS: The skin biopsy specimen demonstrated leukocytoclastic vasculitis. The renal biopsy specimen revealed pauci-immune necrotizing and crescentic glomerulonephritis and unusual deposits with medium electron density composed of granules, microspherules, and rare single fibrils on electron microscopy. CONCLUSIONS: The electron microscopic features of levamisole adulterated cocaine toxicity are novel findings that are presented for the first time, to our knowledge, in this report. PMID- 27247375 TI - Hemophagocytosis-Related (Asian Variant) Intravascular Large B-Cell Lymphoma in a Hispanic Patient: A Case Report Highlighting a Micronodular Pattern in the Spleen. AB - OBJECTIVES: We report a case of hemophagocytosis-related (Asian variant) intravascular large B-cell lymphoma (IVLBCL) in a patient of Western origin initially diagnosed by splenectomy with diffuse large B-cell lymphoma (DLBCL) with a micronodular pattern. The clonal relationship between these two DLBCL subtypes is also investigated. METHODS: Hemophagocytosis-related (Asian variant) IVLBCL was identified at autopsy in a 62-year-old Hispanic woman, in North America, following an antemortem diagnosis of massive splenic involvement by DLBCL with a micronodular pattern, a feature not expected of IVLBCL. RESULTS: These two apparently distinct lymphoma types demonstrated similar immunophenotypic profiles and IgH gene rearrangements of identical size suggesting a clonal relationship. The 2008 WHO classification system describes IVLBCL in the spleen as having a sinusoidal pattern. CONCLUSIONS: Our observations provide the first molecular genetic support for a seemingly underrecognized micronodular pattern of IVLBCL in the spleen and further support the proposal of a "mixed variant" of IVLBCL with concomitant "intravascular" and "solid" phases of disease. PMID- 27247376 TI - An experimental investigation of the impact of thoracic endovascular aortic repair on longitudinal strain. AB - OBJECTIVES: To investigate the impact of thoracic endovascular aortic repair (TEVAR) on longitudinal strain and assess aortic tensile properties in order to better understand complications associated with TEVAR. METHODS: Twenty fresh thoracic porcine aortas were harvested and connected to a mock circulatory loop driven by a centrifugal flow pump at body temperature. Length measurements were conducted before and after TEVAR through aortic marking, high-definition imaging and custom-developed software under physiological pressure conditions (i.e. between 100 and 180 mmHg with 20 mmHg increments). Longitudinal strain was derived from length amplitude divided by the baseline length at 100 mmHg. Three groups of stent-graft oversizing were created (0-9, 10-19 and 20-29%). Finally, elastic properties of the aortic samples were assessed in both longitudinal and circumferential directions through uniaxial tensile testing. Longitudinal strain was compared before and after TEVAR, and stress-to-rupture was compared among specimens and locations. RESULTS: TEVAR induced a longitudinal strain decrease from 11.9 to 5.6% (P< 0.001) in the stented segments and a longitudinal strain mismatch between stented (5.6%) and non-stented segments (9.1%, P< 0.001). Stent graft oversizing did not affect the magnitude of strain reduction (P= 0.77). Tensile testing showed that peak stress-to-rupture was lower for longitudinal (1.4 +/- 0.4 MPa) than for circumferential fragments (2.3 +/- 0.4 MPa, P< 0.001). In addition, longitudinal fragments were more prone to rupture proximally than distally (P= 0.01). CONCLUSIONS: This experimental study showed that TEVAR acutely stiffens the aorta in the longitudinal direction and thereby induces a strain mismatch, while tensile testing confirmed that longitudinal aortic fragments are most prone to rupture, particularly close to the arch. Such an acute strain mismatch of potentially vulnerable tissue might play a role in TEVAR related complications, including retrograde dissection and aneurysm formation. The finding that TEVAR stiffens the aorta longitudinally may also shed light on systemic complications following TEVAR, such as hypertension and cardiac remodelling. These observations may imply the need for further improvement of stent-graft designs. PMID- 27247377 TI - Transcatheter mitral valve replacement in degenerated calcified native mitral valves: is the currently available technology suitable? PMID- 27247378 TI - T2Candida Provides Rapid and Accurate Species Identification in Pediatric Cases of Candidemia. AB - OBJECTIVES: The goal of this study is to assess the ability of the T2Candida platform (T2 Biosystems, Lexington, MA) to accurately identify Candida species from pediatric blood specimens with low volumes. METHODS: Whole blood from 15 children with candidemia was collected immediately following blood culture draw. The amount of blood required by the system was reduced by pipetting whole blood directly onto the T2Candida cartridge. Specimens were subsequently run on the T2Dx Instrument (T2 Biosystems). RESULTS: The T2Candida panel provided the appropriate result for each specimen compared with blood culture-based species identification and correctly identified 15 positive and nine negative results in 3 to 5 hours. While the time to species identification for blood culture was not reported, the T2Candida results include species data. CONCLUSIONS: T2Candida can be used to efficiently diagnose or rule out candidemia using low-volume blood specimens from pediatric patients. This could result in improved time to appropriate antifungal therapy or reduction in unnecessary empirical antifungal therapy. PMID- 27247379 TI - Glutamine Synthetase Immunoreactivity in Peritumoral Hyperplasia in Liver: Case Report of a Metastatic Paraganglioma With Focal Nodular Hyperplasia-Like Changes and Review of an Additional 54 Liver Masses. AB - OBJECTIVES: Focal nodular hyperplasia (FNH) and peritumoral hyperplasia in the liver exhibit increased immunoreactivity for glutamine synthetase (GS). We observed FNH-like changes with map-like GS staining surrounding a metastatic paraganglioma and sought to determine how often such changes occur around primary and metastatic liver lesions. METHODS: We performed GS immunohistochemistry in liver cases of 20 metastatic neuroendocrine carcinomas (NECs), 21 metastatic colon carcinomas (CCs), seven hepatocellular carcinomas (HCCs), and six FNHs and assessed lesions for size, degree of fibrosis (scored 1-3), and peritumoral hyperplasia. RESULTS: Most NEC or CC cases had few peritumoral hyperplastic features. Three NECs, two CCs, and one HCC (13%) had patchy GS staining at the periphery of the lesions. One CC case had both histologic and immunohistochemical peritumoral hyperplasia. CONCLUSIONS: Peritumoral hyperplasia or FNH-like changes are uncommon findings around primary or metastatic lesions in the liver. GS immunohistochemistry assists in distinguishing true peritumoral hyperplasia from mass effect. PMID- 27247381 TI - Hierarchy of prediction errors for auditory events in human temporal and frontal cortex. AB - Predictive coding theories posit that neural networks learn statistical regularities in the environment for comparison with actual outcomes, signaling a prediction error (PE) when sensory deviation occurs. PE studies in audition have capitalized on low-frequency event-related potentials (LF-ERPs), such as the mismatch negativity. However, local cortical activity is well-indexed by higher frequency bands [high-gamma band (Hgamma): 80-150 Hz]. We compared patterns of human Hgamma and LF-ERPs in deviance detection using electrocorticographic recordings from subdural electrodes over frontal and temporal cortices. Patients listened to trains of task-irrelevant tones in two conditions differing in the predictability of a deviation from repetitive background stimuli (fully predictable vs. unpredictable deviants). We found deviance-related responses in both frequency bands over lateral temporal and inferior frontal cortex, with an earlier latency for Hgamma than for LF-ERPs. Critically, frontal Hgamma activity but not LF-ERPs discriminated between fully predictable and unpredictable changes, with frontal cortex sensitive to unpredictable events. The results highlight the role of frontal cortex and Hgamma activity in deviance detection and PE generation. PMID- 27247380 TI - A novel thermoregulatory role for PDE10A in mouse and human adipocytes. AB - Phosphodiesterase type 10A (PDE10A) is highly enriched in striatum and is under evaluation as a drug target for several psychiatric/neurodegenerative diseases. Preclinical studies implicate PDE10A in the regulation of energy homeostasis, but the mechanisms remain unclear. By utilizing small-animal PET/MRI and the novel radioligand [(18)F]-AQ28A, we found marked levels of PDE10A in interscapular brown adipose tissue (BAT) of mice. Pharmacological inactivation of PDE10A with the highly selective inhibitor MP-10 recruited BAT and potentiated thermogenesis in vivo In diet-induced obese mice, chronic administration of MP-10 caused weight loss associated with increased energy expenditure, browning of white adipose tissue, and improved insulin sensitivity. Analysis of human PET data further revealed marked levels of PDE10A in the supraclavicular region where brown/beige adipocytes are clustered in adults. Finally, the inhibition of PDE10A with MP-10 stimulated thermogenic gene expression in human brown adipocytes and induced browning of human white adipocytes. Collectively, our findings highlight a novel thermoregulatory role for PDE10A in mouse and human adipocytes and promote PDE10A inhibitors as promising candidates for the treatment of obesity and diabetes. PMID- 27247382 TI - Dynamic recruitment and activation of ALS-associated TBK1 with its target optineurin are required for efficient mitophagy. AB - Mitochondria play an essential role in maintaining cellular homeostasis. The removal of damaged or depolarized mitochondria occurs via mitophagy, in which damaged mitochondria are targeted for degradation via ubiquitination induced by PTEN-induced putative kinase 1 (PINK1) and Parkin. Mitophagy receptors, including optineurin (OPTN), nuclear dot 52 kDa protein (NDP52), and Tax1-binding protein 1 (TAX1BP1), are recruited to mitochondria via ubiquitin binding and mediate autophagic engulfment through their association with microtubule-associated protein light chain 3 (LC3). Here, we use live-cell imaging to demonstrate that OPTN, NDP52, and TAX1BP1 are recruited to mitochondria with similar kinetics following either mitochondrial depolarization or localized generation of reactive oxygen species, leading to sequestration by the autophagosome within ~45 min after insult. Despite this corecruitment, we find that depletion of OPTN, but not NDP52, significantly slows the efficiency of sequestration. OPTN is phosphorylated by the kinase TANK-binding kinase 1 (TBK1) at serine 177; we find that TBK1 is corecruited with OPTN to depolarized mitochondria. Inhibition or depletion of TBK1, or expression of amyotrophic lateral sclerosis (ALS) associated OPTN or TBK1 mutant blocks efficient autophagosome formation. Together, these results indicate that although there is some functional redundancy among mitophagy receptors, efficient sequestration of damaged mitochondria in response to mitochondrial stress requires both TBK1 and OPTN. Notably, ALS-linked mutations in OPTN and TBK1 can interfere with mitophagy, suggesting that inefficient turnover of damaged mitochondria may represent a key pathophysiological mechanism contributing to neurodegenerative disease. PMID- 27247383 TI - Ancient crops provide first archaeological signature of the westward Austronesian expansion. AB - The Austronesian settlement of the remote island of Madagascar remains one of the great puzzles of Indo-Pacific prehistory. Although linguistic, ethnographic, and genetic evidence points clearly to a colonization of Madagascar by Austronesian language-speaking people from Island Southeast Asia, decades of archaeological research have failed to locate evidence for a Southeast Asian signature in the island's early material record. Here, we present new archaeobotanical data that show that Southeast Asian settlers brought Asian crops with them when they settled in Africa. These crops provide the first, to our knowledge, reliable archaeological window into the Southeast Asian colonization of Madagascar. They additionally suggest that initial Southeast Asian settlement in Africa was not limited to Madagascar, but also extended to the Comoros. Archaeobotanical data may support a model of indirect Austronesian colonization of Madagascar from the Comoros and/or elsewhere in eastern Africa. PMID- 27247384 TI - Sphingomyelin is sorted at the trans Golgi network into a distinct class of secretory vesicle. AB - One of the principal functions of the trans Golgi network (TGN) is the sorting of proteins into distinct vesicular transport carriers that mediate secretion and interorganelle trafficking. Are lipids also sorted into distinct TGN-derived carriers? The Golgi is the principal site of the synthesis of sphingomyelin (SM), an abundant sphingolipid that is transported. To address the specificity of SM transport to the plasma membrane, we engineered a natural SM-binding pore-forming toxin, equinatoxin II (Eqt), into a nontoxic reporter termed Eqt-SM and used it to monitor intracellular trafficking of SM. Using quantitative live cell imaging, we found that Eqt-SM is enriched in a subset of TGN-derived secretory vesicles that are also enriched in a glycophosphatidylinositol-anchored protein. In contrast, an integral membrane secretory protein (CD8alpha) is not enriched in these carriers. Our results demonstrate the sorting of native SM at the TGN and its transport to the plasma membrane by specific carriers. PMID- 27247385 TI - Mechanisms underlying the social enhancement of vocal learning in songbirds. AB - Social processes profoundly influence speech and language acquisition. Despite the importance of social influences, little is known about how social interactions modulate vocal learning. Like humans, songbirds learn their vocalizations during development, and they provide an excellent opportunity to reveal mechanisms of social influences on vocal learning. Using yoked experimental designs, we demonstrate that social interactions with adult tutors for as little as 1 d significantly enhanced vocal learning. Social influences on attention to song seemed central to the social enhancement of learning because socially tutored birds were more attentive to the tutor's songs than passively tutored birds, and because variation in attentiveness and in the social modulation of attention significantly predicted variation in vocal learning. Attention to song was influenced by both the nature and amount of tutor song: Pupils paid more attention to songs that tutors directed at them and to tutors that produced fewer songs. Tutors altered their song structure when directing songs at pupils in a manner that resembled how humans alter their vocalizations when speaking to infants, that was distinct from how tutors changed their songs when singing to females, and that could influence attention and learning. Furthermore, social interactions that rapidly enhanced learning increased the activity of noradrenergic and dopaminergic midbrain neurons. These data highlight striking parallels between humans and songbirds in the social modulation of vocal learning and suggest that social influences on attention and midbrain circuitry could represent shared mechanisms underlying the social modulation of vocal learning. PMID- 27247386 TI - Engineering control of bacterial cellulose production using a genetic toolkit and a new cellulose-producing strain. AB - Bacterial cellulose is a strong and ultrapure form of cellulose produced naturally by several species of the Acetobacteraceae Its high strength, purity, and biocompatibility make it of great interest to materials science; however, precise control of its biosynthesis has remained a challenge for biotechnology. Here we isolate a strain of Komagataeibacter rhaeticus (K. rhaeticus iGEM) that can produce cellulose at high yields, grow in low-nitrogen conditions, and is highly resistant to toxic chemicals. We achieved external control over its bacterial cellulose production through development of a modular genetic toolkit that enables rational reprogramming of the cell. To further its use as an organism for biotechnology, we sequenced its genome and demonstrate genetic circuits that enable functionalization and patterning of heterologous gene expression within the cellulose matrix. This work lays the foundations for using genetic engineering to produce cellulose-based materials, with numerous applications in basic science, materials engineering, and biotechnology. PMID- 27247387 TI - The adenovirus E4-ORF3 protein functions as a SUMO E3 ligase for TIF-1gamma sumoylation and poly-SUMO chain elongation. AB - The adenovirus (Ad) early region 4 (E4)-ORF3 protein regulates diverse cellular processes to optimize the host environment for the establishment of Ad replication. E4-ORF3 self-assembles into multimers to form a nuclear scaffold in infected cells and creates distinct binding interfaces for different cellular target proteins. Previous studies have shown that the Ad5 E4-ORF3 protein induces sumoylation of multiple cellular proteins and subsequent proteasomal degradation of some of them, but the detailed mechanism of E4-ORF3 function remained unknown. Here, we investigate the role of E4-ORF3 in the sumoylation process by using transcription intermediary factor (TIF)-1gamma as a substrate. Remarkably, we discovered that purified E4-ORF3 protein stimulates TIF-1gamma sumoylation in vitro, demonstrating that E4-ORF3 acts as a small ubiquitin-like modifier (SUMO) E3 ligase. Furthermore, E4-ORF3 significantly increases poly-SUMO3 chain formation in vitro in the absence of substrate, showing that E4-ORF3 has SUMO E4 elongase activity. An E4-ORF3 mutant, which is defective in protein multimerization, exhibited severely decreased activity, demonstrating that E4 ORF3 self-assembly is required for these activities. Using a SUMO3 mutant, K11R, we found that E4-ORF3 facilitates the initial acceptor SUMO3 conjugation to TIF 1gamma as well as poly-SUMO chain elongation. The E4-ORF3 protein displays no SUMO-targeted ubiquitin ligase activity in our assay system. These studies reveal the mechanism by which E4-ORF3 targets specific cellular proteins for sumoylation and proteasomal degradation and provide significant insight into how a small viral protein can play a role as a SUMO E3 ligase and E4-like SUMO elongase to impact a variety of cellular responses. PMID- 27247389 TI - Sirtuin-dependent reversible lysine acetylation of glutamine synthetases reveals an autofeedback loop in nitrogen metabolism. AB - In cells of all domains of life, reversible lysine acetylation modulates the function of proteins involved in central cellular processes such as metabolism. In this study, we demonstrate that the nitrogen regulator GlnR of the actinomycete Saccharopolyspora erythraea directly regulates transcription of the acuA gene (SACE_5148), which encodes a Gcn5-type lysine acetyltransferase. We found that AcuA acetylates two glutamine synthetases (GlnA1 and GlnA4) and that this lysine acetylation inactivated GlnA4 (GSII) but had no significant effect on GlnA1 (GSI-beta) activity under the conditions tested. Instead, acetylation of GlnA1 led to a gain-of-function that modulated its interaction with the GlnR regulator and enhanced GlnR-DNA binding. It was observed that this regulatory function of acetylated GSI-beta enzymes is highly conserved across actinomycetes. In turn, GlnR controls the catalytic and regulatory activities (intracellular acetylation levels) of glutamine synthetases at the transcriptional and posttranslational levels, indicating an autofeedback loop that regulates nitrogen metabolism in response to environmental change. Thus, this GlnR-mediated acetylation pathway provides a signaling cascade that acts from nutrient sensing to acetylation of proteins to feedback regulation. This work presents significant new insights at the molecular level into the mechanisms underlying the regulation of protein acetylation and nitrogen metabolism in actinomycetes. PMID- 27247388 TI - Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation. AB - Opioid use for pain management has dramatically increased, with little assessment of potential pathophysiological consequences for the primary pain condition. Here, a short course of morphine, starting 10 d after injury in male rats, paradoxically and remarkably doubled the duration of chronic constriction injury (CCI)-allodynia, months after morphine ceased. No such effect of opioids on neuropathic pain has previously been reported. Using pharmacologic and genetic approaches, we discovered that the initiation and maintenance of this multimonth prolongation of neuropathic pain was mediated by a previously unidentified mechanism for spinal cord and pain-namely, morphine-induced spinal NOD-like receptor protein 3 (NLRP3) inflammasomes and associated release of interleukin 1beta (IL-1beta). As spinal dorsal horn microglia expressed this signaling platform, these cells were selectively inhibited in vivo after transfection with a novel Designer Receptor Exclusively Activated by Designer Drugs (DREADD). Multiday treatment with the DREADD-specific ligand clozapine-N-oxide prevented and enduringly reversed morphine-induced persistent sensitization for weeks to months after cessation of clozapine-N-oxide. These data demonstrate both the critical importance of microglia and that maintenance of chronic pain created by early exposure to opioids can be disrupted, resetting pain to normal. These data also provide strong support for the recent "two-hit hypothesis" of microglial priming, leading to exaggerated reactivity after the second challenge, documented here in the context of nerve injury followed by morphine. This study predicts that prolonged pain is an unrealized and clinically concerning consequence of the abundant use of opioids in chronic pain. PMID- 27247390 TI - Draft genome of the peanut A-genome progenitor (Arachis duranensis) provides insights into geocarpy, oil biosynthesis, and allergens. AB - Peanut or groundnut (Arachis hypogaea L.), a legume of South American origin, has high seed oil content (45-56%) and is a staple crop in semiarid tropical and subtropical regions, partially because of drought tolerance conferred by its geocarpic reproductive strategy. We present a draft genome of the peanut A-genome progenitor, Arachis duranensis, and 50,324 protein-coding gene models. Patterns of gene duplication suggest the peanut lineage has been affected by at least three polyploidizations since the origin of eudicots. Resequencing of synthetic Arachis tetraploids reveals extensive gene conversion in only three seed-to-seed generations since their formation by human hands, indicating that this process begins virtually immediately following polyploid formation. Expansion of some specific gene families suggests roles in the unusual subterranean fructification of Arachis For example, the S1Fa-like transcription factor family has 126 Arachis members, in contrast to no more than five members in other examined plant species, and is more highly expressed in roots and etiolated seedlings than green leaves. The A. duranensis genome provides a major source of candidate genes for fructification, oil biosynthesis, and allergens, expanding knowledge of understudied areas of plant biology and human health impacts of plants, informing peanut genetic improvement and aiding deeper sequencing of Arachis diversity. PMID- 27247392 TI - Transposon mutagenesis identifies genes and cellular processes driving epithelial mesenchymal transition in hepatocellular carcinoma. AB - Epithelial-mesenchymal transition (EMT) is thought to contribute to metastasis and chemoresistance in patients with hepatocellular carcinoma (HCC), leading to their poor prognosis. The genes driving EMT in HCC are not yet fully understood, however. Here, we show that mobilization of Sleeping Beauty (SB) transposons in immortalized mouse hepatoblasts induces mesenchymal liver tumors on transplantation to nude mice. These tumors show significant down-regulation of epithelial markers, along with up-regulation of mesenchymal markers and EMT related transcription factors (EMT-TFs). Sequencing of transposon insertion sites from tumors identified 233 candidate cancer genes (CCGs) that were enriched for genes and cellular processes driving EMT. Subsequent trunk driver analysis identified 23 CCGs that are predicted to function early in tumorigenesis and whose mutation or alteration in patients with HCC is correlated with poor patient survival. Validation of the top trunk drivers identified in the screen, including MET (MET proto-oncogene, receptor tyrosine kinase), GRB2-associated binding protein 1 (GAB1), HECT, UBA, and WWE domain containing 1 (HUWE1), lysine-specific demethylase 6A (KDM6A), and protein-tyrosine phosphatase, nonreceptor-type 12 (PTPN12), showed that deregulation of these genes activates an EMT program in human HCC cells that enhances tumor cell migration. Finally, deregulation of these genes in human HCC was found to confer sorafenib resistance through apoptotic tolerance and reduced proliferation, consistent with recent studies showing that EMT contributes to the chemoresistance of tumor cells. Our unique cell-based transposon mutagenesis screen appears to be an excellent resource for discovering genes involved in EMT in human HCC and potentially for identifying new drug targets. PMID- 27247391 TI - Whole-exome sequencing to analyze population structure, parental inbreeding, and familial linkage. AB - Principal component analysis (PCA), homozygosity rate estimations, and linkage studies in humans are classically conducted through genome-wide single-nucleotide variant arrays (GWSA). We compared whole-exome sequencing (WES) and GWSA for this purpose. We analyzed 110 subjects originating from different regions of the world, including North Africa and the Middle East, which are poorly covered by public databases and have high consanguinity rates. We tested and applied a number of quality control (QC) filters. Compared with GWSA, we found that WES provided an accurate prediction of population substructure using variants with a minor allele frequency > 2% (correlation = 0.89 with the PCA coordinates obtained by GWSA). WES also yielded highly reliable estimates of homozygosity rates using runs of homozygosity with a 1,000-kb window (correlation = 0.94 with the estimates provided by GWSA). Finally, homozygosity mapping analyses in 15 families including a single offspring with high homozygosity rates showed that WES provided 51% less genome-wide linkage information than GWSA overall but 97% more information for the coding regions. At the genome-wide scale, 76.3% of linked regions were found by both GWSA and WES, 17.7% were found by GWSA only, and 6.0% were found by WES only. For coding regions, the corresponding percentages were 83.5%, 7.4%, and 9.1%, respectively. With appropriate QC filters, WES can be used for PCA and adjustment for population substructure, estimating homozygosity rates in individuals, and powerful linkage analyses, particularly in coding regions. PMID- 27247393 TI - Sustained deposition of contaminants from the Deepwater Horizon spill. AB - The 2010 Deepwater Horizon oil spill resulted in 1.6-2.6 * 10(10) grams of petrocarbon accumulation on the seafloor. Data from a deep sediment trap, deployed 7.4 km SW of the well between August 2010 and October 2011, disclose that the sinking of spill-associated substances, mediated by marine particles, especially phytoplankton, continued at least 5 mo following the capping of the well. In August/September 2010, an exceptionally large diatom bloom sedimentation event coincided with elevated sinking rates of oil-derived hydrocarbons, black carbon, and two key components of drilling mud, barium and olefins. Barium remained in the water column for months and even entered pelagic food webs. Both saturated and polycyclic aromatic hydrocarbon source indicators corroborate a predominant contribution of crude oil to the sinking hydrocarbons. Cosedimentation with diatoms accumulated contaminants that were dispersed in the water column and transported them downward, where they were concentrated into the upper centimeters of the seafloor, potentially leading to sustained impact on benthic ecosystems. PMID- 27247395 TI - Interlocking directorates in Irish companies using a latent space model for bipartite networks. AB - We analyze the temporal bipartite network of the leading Irish companies and their directors from 2003 to 2013, encompassing the end of the Celtic Tiger boom and the ensuing financial crisis in 2008. We focus on the evolution of company interlocks, whereby a company director simultaneously sits on two or more boards. We develop a statistical model for this dataset by embedding the positions of companies and directors in a latent space. The temporal evolution of the network is modeled through three levels of Markovian dependence: one on the model parameters, one on the companies' latent positions, and one on the edges themselves. The model is estimated using Bayesian inference. Our analysis reveals that the level of interlocking, as measured by a contraction of the latent space, increased before and during the crisis, reaching a peak in 2009, and has generally stabilized since then. PMID- 27247396 TI - Decoupled evolution of soft and hard substrate communities during the Cambrian Explosion and Great Ordovician Biodiversification Event. AB - Contrasts between the Cambrian Explosion (CE) and the Great Ordovician Biodiversification Event (GOBE) have long been recognized. Whereas the vast majority of body plans were established as a result of the CE, taxonomic increases during the GOBE were manifested at lower taxonomic levels. Assessing changes of ichnodiversity and ichnodisparity as a result of these two evolutionary events may shed light on the dynamics of both radiations. The early Cambrian (series 1 and 2) displayed a dramatic increase in ichnodiversity and ichnodisparity in softground communities. In contrast to this evolutionary explosion in bioturbation structures, only a few Cambrian bioerosion structures are known. After the middle to late Cambrian diversity plateau, ichnodiversity in softground communities shows a continuous increase during the Ordovician in both shallow- and deep-marine environments. This Ordovician increase in bioturbation diversity was not paralleled by an equally significant increase in ichnodisparity as it was during the CE. However, hard substrate communities were significantly different during the GOBE, with an increase in ichnodiversity and ichnodisparity. Innovations in macrobioerosion clearly lagged behind animal-substrate interactions in unconsolidated sediment. The underlying causes of this evolutionary decoupling are unclear but may have involved three interrelated factors: (i) a Middle to Late Ordovician increase in available hard substrates for bioerosion, (ii) increased predation, and (iii) higher energetic requirements for bioerosion compared with bioturbation. PMID- 27247394 TI - K(ATP) channel gain-of-function leads to increased myocardial L-type Ca(2+) current and contractility in Cantu syndrome. AB - Cantu syndrome (CS) is caused by gain-of-function (GOF) mutations in genes encoding pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) KATP channel subunits. We show that patients with CS, as well as mice with constitutive (cGOF) or tamoxifen-induced (icGOF) cardiac-specific Kir6.1 GOF subunit expression, have enlarged hearts, with increased ejection fraction and increased contractility. Whole-cell voltage-clamp recordings from cGOF or icGOF ventricular myocytes (VM) show increased basal L-type Ca(2+) current (LTCC), comparable to that seen in WT VM treated with isoproterenol. Mice with vascular-specific expression (vGOF) show left ventricular dilation as well as less-markedly increased LTCC. Increased LTCC in KATP GOF models is paralleled by changes in phosphorylation of the pore forming alpha1 subunit of the cardiac voltage-gated calcium channel Cav1.2 at Ser1928, suggesting enhanced protein kinase activity as a potential link between increased KATP current and CS cardiac pathophysiology. PMID- 27247397 TI - Lateral transport of soil carbon and land-atmosphere CO2 flux induced by water erosion in China. AB - Soil erosion by water impacts soil organic carbon stocks and alters CO2 fluxes exchanged with the atmosphere. The role of erosion as a net sink or source of atmospheric CO2 remains highly debated, and little information is available at scales larger than small catchments or regions. This study attempts to quantify the lateral transport of soil carbon and consequent land-atmosphere CO2 fluxes at the scale of China, where severe erosion has occurred for several decades. Based on the distribution of soil erosion rates derived from detailed national surveys and soil carbon inventories, here we show that water erosion in China displaced 180 +/- 80 Mt C?y(-1) of soil organic carbon during the last two decades, and this resulted a net land sink for atmospheric CO2 of 45 +/- 25 Mt C?y(-1), equivalent to 8-37% of the terrestrial carbon sink previously assessed in China. Interestingly, the "hotspots," largely distributed in mountainous regions in the most intensive sink areas (>40 g C?m(-2)?y(-1)), occupy only 1.5% of the total area suffering water erosion, but contribute 19.3% to the national erosion induced CO2 sink. The erosion-induced CO2 sink underwent a remarkable reduction of about 16% from the middle 1990s to the early 2010s, due to diminishing erosion after the implementation of large-scale soil conservation programs. These findings demonstrate the necessity of including erosion-induced CO2 in the terrestrial budget, hence reducing the level of uncertainty. PMID- 27247398 TI - Spatial scale modulates the strength of ecological processes driving disease distributions. AB - Humans are altering the distribution of species by changing the climate and disrupting biotic interactions and dispersal. A fundamental hypothesis in spatial ecology suggests that these effects are scale dependent; biotic interactions should shape distributions at local scales, whereas climate should dominate at regional scales. If so, common single-scale analyses might misestimate the impacts of anthropogenic modifications on biodiversity and the environment. However, large-scale datasets necessary to test these hypotheses have not been available until recently. Here we conduct a cross-continental, cross-scale (almost five orders of magnitude) analysis of the influence of biotic and abiotic processes and human population density on the distribution of three emerging pathogens: the amphibian chytrid fungus implicated in worldwide amphibian declines and West Nile virus and the bacterium that causes Lyme disease (Borrelia burgdorferi), which are responsible for ongoing human health crises. In all three systems, we show that biotic factors were significant predictors of pathogen distributions in multiple regression models only at local scales (~10(2)-10(3) km(2)), whereas climate and human population density always were significant only at relatively larger, regional scales (usually >10(4) km(2)). Spatial autocorrelation analyses revealed that biotic factors were more variable at smaller scales, whereas climatic factors were more variable at larger scales, as is consistent with the prediction that factors should be important at the scales at which they vary the most. Finally, no single scale could detect the importance of all three categories of processes. These results highlight that common single scale analyses can misrepresent the true impact of anthropogenic modifications on biodiversity and the environment. PMID- 27247399 TI - Mechanosensory hairs in bumblebees (Bombus terrestris) detect weak electric fields. AB - Bumblebees (Bombus terrestris) use information from surrounding electric fields to make foraging decisions. Electroreception in air, a nonconductive medium, is a recently discovered sensory capacity of insects, yet the sensory mechanisms remain elusive. Here, we investigate two putative electric field sensors: antennae and mechanosensory hairs. Examining their mechanical and neural response, we show that electric fields cause deflections in both antennae and hairs. Hairs respond with a greater median velocity, displacement, and angular displacement than antennae. Extracellular recordings from the antennae do not show any electrophysiological correlates to these mechanical deflections. In contrast, hair deflections in response to an electric field elicited neural activity. Mechanical deflections of both hairs and antennae increase with the electric charge carried by the bumblebee. From this evidence, we conclude that sensory hairs are a site of electroreception in the bumblebee. PMID- 27247401 TI - QnAs with Mitsuhiro Yanagida. PMID- 27247402 TI - QnAs with Graham Cooks. PMID- 27247400 TI - Envelope residue 375 substitutions in simian-human immunodeficiency viruses enhance CD4 binding and replication in rhesus macaques. AB - Most simian-human immunodeficiency viruses (SHIVs) bearing envelope (Env) glycoproteins from primary HIV-1 strains fail to infect rhesus macaques (RMs). We hypothesized that inefficient Env binding to rhesus CD4 (rhCD4) limits virus entry and replication and could be enhanced by substituting naturally occurring simian immunodeficiency virus Env residues at position 375, which resides at a critical location in the CD4-binding pocket and is under strong positive evolutionary pressure across the broad spectrum of primate lentiviruses. SHIVs containing primary or transmitted/founder HIV-1 subtype A, B, C, or D Envs with genotypic variants at residue 375 were constructed and analyzed in vitro and in vivo. Bulky hydrophobic or basic amino acids substituted for serine-375 enhanced Env affinity for rhCD4, virus entry into cells bearing rhCD4, and virus replication in primary rhCD4 T cells without appreciably affecting antigenicity or antibody-mediated neutralization sensitivity. Twenty-four RMs inoculated with subtype A, B, C, or D SHIVs all became productively infected with different Env375 variants-S, M, Y, H, W, or F-that were differentially selected in different Env backbones. Notably, SHIVs replicated persistently at titers comparable to HIV-1 in humans and elicited autologous neutralizing antibody responses typical of HIV-1. Seven animals succumbed to AIDS. These findings identify Env-rhCD4 binding as a critical determinant for productive SHIV infection in RMs and validate a novel and generalizable strategy for constructing SHIVs with Env glycoproteins of interest, including those that in humans elicit broadly neutralizing antibodies or bind particular Ig germ-line B-cell receptors. PMID- 27247403 TI - Thyroid hormones inhibit TGF-beta signaling and attenuate fibrotic responses. AB - TGF-beta, the most potent profibrogenic factor, acts by activating SMAD (mothers against decapentaplegic) transcription factors, which bind to SMAD-binding elements in target genes. Here, we show that the thyroid hormone triiodothyronine (T3), through binding to its nuclear receptors (TRs), is able to antagonize transcriptional activation by TGF-beta/SMAD. This antagonism involves reduced phosphorylation of SMADs and a direct interaction of the receptors with SMAD3 and SMAD4 that is independent of T3-mediated transcriptional activity but requires residues in the receptor DNA binding domain. T3 reduces occupancy of SMAD-binding elements in response to TGF-beta, reducing histone acetylation and inhibiting transcription. In agreement with this transcriptional cross-talk, T3 is able to antagonize fibrotic processes in vivo. Liver fibrosis induced by carbon tetrachloride is attenuated by thyroid hormone administration to mice, whereas aged TR knockout mice spontaneously accumulate collagen. Furthermore, skin fibrosis induced by bleomycin administration is also reduced by the thyroid hormones. These findings define an important function of the thyroid hormone receptors and suggest TR ligands could have beneficial effects to block the progression of fibrotic diseases. PMID- 27247404 TI - Credit assignment in movement-dependent reinforcement learning. AB - When a person fails to obtain an expected reward from an object in the environment, they face a credit assignment problem: Did the absence of reward reflect an extrinsic property of the environment or an intrinsic error in motor execution? To explore this problem, we modified a popular decision-making task used in studies of reinforcement learning, the two-armed bandit task. We compared a version in which choices were indicated by key presses, the standard response in such tasks, to a version in which the choices were indicated by reaching movements, which affords execution failures. In the key press condition, participants exhibited a strong risk aversion bias; strikingly, this bias reversed in the reaching condition. This result can be explained by a reinforcement model wherein movement errors influence decision-making, either by gating reward prediction errors or by modifying an implicit representation of motor competence. Two further experiments support the gating hypothesis. First, we used a condition in which we provided visual cues indicative of movement errors but informed the participants that trial outcomes were independent of their actual movements. The main result was replicated, indicating that the gating process is independent of participants' explicit sense of control. Second, individuals with cerebellar degeneration failed to modulate their behavior between the key press and reach conditions, providing converging evidence of an implicit influence of movement error signals on reinforcement learning. These results provide a mechanistically tractable solution to the credit assignment problem. PMID- 27247405 TI - Digital epidemiology reveals global childhood disease seasonality and the effects of immunization. AB - Public health surveillance systems are important for tracking disease dynamics. In recent years, social and real-time digital data sources have provided new means of studying disease transmission. Such affordable and accessible data have the potential to offer new insights into disease epidemiology at national and international scales. We used the extensive information repository Google Trends to examine the digital epidemiology of a common childhood disease, chicken pox, caused by varicella zoster virus (VZV), over an 11-y period. We (i) report robust seasonal information-seeking behavior for chicken pox using Google data from 36 countries, (ii) validate Google data using clinical chicken pox cases, (iii) demonstrate that Google data can be used to identify recurrent seasonal outbreaks and forecast their magnitude and seasonal timing, and (iv) reveal that VZV immunization significantly dampened seasonal cycles in information-seeking behavior. Our findings provide strong evidence that VZV transmission is seasonal and that seasonal peaks show remarkable latitudinal variation. We attribute the dampened seasonal cycles in chicken pox information-seeking behavior to VZV vaccine-induced reduction of seasonal transmission. These data and the methodological approaches provide a way to track the global burden of childhood disease and illustrate population-level effects of immunization. The global latitudinal patterns in outbreak seasonality could direct future studies of environmental and physiological drivers of disease transmission. PMID- 27247406 TI - Highly variable individual donor cell fates characterize robust horizontal gene transfer of an integrative and conjugative element. AB - Horizontal gene transfer is an important evolutionary mechanism for bacterial adaptation. However, given the typical low transfer frequencies in a bacterial population, little is known about the fate and interplay of donor cells and the mobilized DNA during transfer. Here we study transfer of an integrative and conjugative element (ICE) among individual live bacterial cells. ICEs are widely distributed mobile DNA elements that are different than plasmids because they reside silent in the host chromosome and are maintained through vertical descent. Occasionally, ICEs become active, excise, and transmit their DNA to a new recipient, where it is reintegrated. We develop a fluorescent tool to differentiate excision, transfer, and reintegration of a model ICE named ICEclc (for carrying the clc genes for chlorocatechol metabolism) among single Pseudomonas cells by using time-lapse microscopy. We find that ICEclc activation is initiated in stationary phase cells, but excision and transfer predominantly occur only when such cells have been presented with new nutrients. Donors with activated ICE develop a number of different states, characterized by reduced cell division rates or growth arrest, persistence, or lysis, concomitant with ICE excision, and likely, ICE loss or replication. The donor cell state transitions can be described by using a stochastic model, which predicts that ICE fitness is optimal at low initiation rates in stationary phase. Despite highly variable donor cell fates, ICE transfer is remarkably robust overall, with 75% success after excision. Our results help to better understand ICE behavior and shed a new light on bacterial cellular differentiation during horizontal gene transfer. PMID- 27247407 TI - A statistical property of fly odor responses is conserved across odors. AB - I have reanalyzed the data presented by Hallem and Carlson [Hallem EA, Carlson JR (2006) Cell 125(1):143-160] and shown that the combinatorial odor code supplied by the fruit fly antenna is a very simple one in which nearly all odors produce, statistically, the same neuronal response; i.e., the probability distribution of sensory neuron firing rates across the population of odorant sensory neurons is an exponential for nearly all odors and odor mixtures, with the mean rate dependent on the odor concentration. Between odors, then, the response differs according to which sensory neurons are firing at what individual rates and with what mean population rate, but not in the probability distribution of firing rates. This conclusion is independent of adjustable parameters, and holds both for monomolecular odors and complex mixtures. Because the circuitry in the antennal lobe constrains the mean firing rate to be the same for all odors and concentrations, the odor code is what is known as maximum entropy. PMID- 27247408 TI - Mass spectrometry-based absolute quantification reveals rhythmic variation of mouse circadian clock proteins. AB - Absolute values of protein expression levels in cells are crucial information for understanding cellular biological systems. Precise quantification of proteins can be achieved by liquid chromatography (LC)-mass spectrometry (MS) analysis of enzymatic digests of proteins in the presence of isotope-labeled internal standards. Thus, development of a simple and easy way for the preparation of internal standards is advantageous for the analyses of multiple target proteins, which will allow systems-level studies. Here we describe a method, termed MS based Quantification By isotope-labeled Cell-free products (MS-QBiC), which provides the simple and high-throughput preparation of internal standards by using a reconstituted cell-free protein synthesis system, and thereby facilitates both multiplexed and sensitive quantification of absolute amounts of target proteins. This method was applied to a systems-level dynamic analysis of mammalian circadian clock proteins, which consist of transcription factors and protein kinases that govern central and peripheral circadian clocks in mammals. Sixteen proteins from 20 selected circadian clock proteins were successfully quantified from mouse liver over a 24-h time series, and 14 proteins had circadian variations. Quantified values were applied to detect internal body time using a previously developed molecular timetable method. The analyses showed that single time-point data from wild-type mice can predict the endogenous state of the circadian clock, whereas data from clock mutant mice are not applicable because of the disappearance of circadian variation. PMID- 27247409 TI - Teaching a lay theory before college narrows achievement gaps at scale. AB - Previous experiments have shown that college students benefit when they understand that challenges in the transition to college are common and improvable and, thus, that early struggles need not portend a permanent lack of belonging or potential. Could such an approach-called a lay theory intervention-be effective before college matriculation? Could this strategy reduce a portion of racial, ethnic, and socioeconomic achievement gaps for entire institutions? Three double blind experiments tested this possibility. Ninety percent of first-year college students from three institutions were randomly assigned to complete single session, online lay theory or control materials before matriculation (n > 9,500). The lay theory interventions raised first-year full-time college enrollment among students from socially and economically disadvantaged backgrounds exiting a high performing charter high school network or entering a public flagship university (experiments 1 and 2) and, at a selective private university, raised disadvantaged students' cumulative first-year grade point average (experiment 3). These gains correspond to 31-40% reductions of the raw (unadjusted) institutional achievement gaps between students from disadvantaged and nondisadvantaged backgrounds at those institutions. Further, follow-up surveys suggest that the interventions improved disadvantaged students' overall college experiences, promoting use of student support services and the development of friendship networks and mentor relationships. This research therefore provides a basis for further tests of the generalizability of preparatory lay theories interventions and of their potential to reduce social inequality and improve other major life transitions. PMID- 27247410 TI - Enantiomer excesses of rare and common sugar derivatives in carbonaceous meteorites. AB - Biological polymers such as nucleic acids and proteins are constructed of only one-the d or l-of the two possible nonsuperimposable mirror images (enantiomers) of selected organic compounds. However, before the advent of life, it is generally assumed that chemical reactions produced 50:50 (racemic) mixtures of enantiomers, as evidenced by common abiotic laboratory syntheses. Carbonaceous meteorites contain clues to prebiotic chemistry because they preserve a record of some of the Solar System's earliest (~4.5 Gy) chemical and physical processes. In multiple carbonaceous meteorites, we show that both rare and common sugar monoacids (aldonic acids) contain significant excesses of the d enantiomer, whereas other (comparable) sugar acids and sugar alcohols are racemic. Although the proposed origins of such excesses are still tentative, the findings imply that meteoritic compounds and/or the processes that operated on meteoritic precursors may have played an ancient role in the enantiomer composition of life's carbohydrate-related biopolymers. PMID- 27247411 TI - Assortative mating and differential fertility by phenotype and genotype across the 20th century. AB - This study asks two related questions about the shifting landscape of marriage and reproduction in US society over the course of the last century with respect to a range of health and behavioral phenotypes and their associated genetic architecture: (i) Has assortment on measured genetic factors influencing reproductive and social fitness traits changed over the course of the 20th century? (ii) Has the genetic covariance between fitness (as measured by total fertility) and other traits changed over time? The answers to these questions inform our understanding of how the genetic landscape of American society has changed over the past century and have implications for population trends. We show that husbands and wives carry similar loadings for genetic factors related to education and height. However, the magnitude of this similarity is modest and has been fairly consistent over the course of the 20th century. This consistency is particularly notable in the case of education, for which phenotypic similarity among spouses has increased in recent years. Likewise, changing patterns of the number of children ever born by phenotype are not matched by shifts in genotype fertility relationships over time. Taken together, these trends provide no evidence that social sorting is becoming increasingly genetic in nature or that dysgenic dynamics have accelerated. PMID- 27247412 TI - Heme dynamics and trafficking factors revealed by genetically encoded fluorescent heme sensors. AB - Heme is an essential cofactor and signaling molecule. Heme acquisition by proteins and heme signaling are ultimately reliant on the ability to mobilize labile heme (LH). However, the properties of LH pools, including concentration, oxidation state, distribution, speciation, and dynamics, are poorly understood. Herein, we elucidate the nature and dynamics of LH using genetically encoded ratiometric fluorescent heme sensors in the unicellular eukaryote Saccharomyces cerevisiae We find that the subcellular distribution of LH is heterogeneous; the cytosol maintains LH at ~20-40 nM, whereas the mitochondria and nucleus maintain it at concentrations below 2.5 nM. Further, we find that the signaling molecule nitric oxide can initiate the rapid mobilization of heme in the cytosol and nucleus from certain thiol-containing factors. We also find that the glycolytic enzyme glyceraldehyde phosphate dehydrogenase constitutes a major cellular heme buffer, and is responsible for maintaining the activity of the heme-dependent nuclear transcription factor heme activator protein (Hap1p). Altogether, we demonstrate that the heme sensors can be used to reveal fundamental aspects of heme trafficking and dynamics and can be used across multiple organisms, including Escherichia coli, yeast, and human cell lines. PMID- 27247413 TI - Structural insight into photoactivation of an adenylate cyclase from a photosynthetic cyanobacterium. AB - Cyclic-AMP is one of the most important second messengers, regulating many crucial cellular events in both prokaryotes and eukaryotes, and precise spatial and temporal control of cAMP levels by light shows great promise as a simple means of manipulating and studying numerous cell pathways and processes. The photoactivated adenylate cyclase (PAC) from the photosynthetic cyanobacterium Oscillatoria acuminata (OaPAC) is a small homodimer eminently suitable for this task, requiring only a simple flavin chromophore within a blue light using flavin (BLUF) domain. These domains, one of the most studied types of biological photoreceptor, respond to blue light and either regulate the activity of an attached enzyme domain or change its affinity for a repressor protein. BLUF domains were discovered through studies of photo-induced movements of Euglena gracilis, a unicellular flagellate, and gene expression in the purple bacterium Rhodobacter sphaeroides, but the precise details of light activation remain unknown. Here, we describe crystal structures and the light regulation mechanism of the previously undescribed OaPAC, showing a central coiled coil transmits changes from the light-sensing domains to the active sites with minimal structural rearrangement. Site-directed mutants show residues essential for signal transduction over 45 A across the protein. The use of the protein in living human cells is demonstrated with cAMP-dependent luciferase, showing a rapid and stable response to light over many hours and activation cycles. The structures determined in this study will assist future efforts to create artificial light-regulated control modules as part of a general optogenetic toolkit. PMID- 27247414 TI - How to tune an enhancer. PMID- 27247415 TI - Finding the sweet spot for invasion theory. PMID- 27247416 TI - The relationship between oscillatory EEG activity and the laminar-specific BOLD signal. AB - Electrophysiological recordings in animals have indicated that visual cortex gamma-band oscillatory activity is predominantly observed in superficial cortical layers, whereas alpha- and beta-band activity is stronger in deep layers. These rhythms, as well as the different cortical layers, have also been closely related to feedforward and feedback streams of information. Recently, it has become possible to measure laminar activity in humans with high-resolution functional MRI (fMRI). In this study, we investigated whether these different frequency bands show a differential relation with the laminar-resolved blood-oxygen level dependent (BOLD) signal by combining data from simultaneously recorded EEG and fMRI from the early visual cortex. Our visual attention paradigm allowed us to investigate how variations in strength over trials and variations in the attention effect over subjects relate to each other in both modalities. We demonstrate that gamma-band EEG power correlates positively with the superficial layers' BOLD signal and that beta-power is negatively correlated to deep layer BOLD and alpha-power to both deep and superficial layer BOLD. These results provide a neurophysiological basis for human laminar fMRI and link human EEG and high-resolution fMRI to systems-level neuroscience in animals. PMID- 27247417 TI - Leveraging abscisic acid receptors for efficient water use in Arabidopsis. AB - Plant growth requires the influx of atmospheric CO2 through stomatal pores, and this carbon uptake for photosynthesis is inherently associated with a large efflux of water vapor. Under water deficit, plants reduce transpiration and are able to improve carbon for water exchange leading to higher water use efficiency (WUE). Whether increased WUE can be achieved without trade-offs in plant growth is debated. The signals mediating the WUE response under water deficit are not fully elucidated but involve the phytohormone abscisic acid (ABA). ABA is perceived by a family of related receptors known to mediate acclimation responses and to reduce transpiration. We now show that enhanced stimulation of ABA signaling via distinct ABA receptors can result in plants constitutively growing at high WUE in the model species Arabidopsis WUE was assessed by three independent approaches involving gravimetric analyses, (13)C discrimination studies of shoots and derived cellulose fractions, and by gas exchange measurements of whole plants and individual leaves. Plants expressing the ABA receptors RCAR6/PYL12 combined up to 40% increased WUE with high growth rates, i.e., are water productive. Water productivity was associated with maintenance of net carbon assimilation by compensatory increases of leaf CO2 gradients, thereby sustaining biomass acquisition. Leaf surface temperatures and growth potentials of plants growing under well-watered conditions were found to be reliable indicators for water productivity. The study shows that ABA receptors can be explored to generate more plant biomass per water transpired, which is a prime goal for a more sustainable water use in agriculture. PMID- 27247418 TI - Multidimensional structure-function relationships in human beta-cardiac myosin from population-scale genetic variation. AB - Myosin motors are the fundamental force-generating elements of muscle contraction. Variation in the human beta-cardiac myosin heavy chain gene (MYH7) can lead to hypertrophic cardiomyopathy (HCM), a heritable disease characterized by cardiac hypertrophy, heart failure, and sudden cardiac death. How specific myosin variants alter motor function or clinical expression of disease remains incompletely understood. Here, we combine structural models of myosin from multiple stages of its chemomechanical cycle, exome sequencing data from two population cohorts of 60,706 and 42,930 individuals, and genetic and phenotypic data from 2,913 patients with HCM to identify regions of disease enrichment within beta-cardiac myosin. We first developed computational models of the human beta-cardiac myosin protein before and after the myosin power stroke. Then, using a spatial scan statistic modified to analyze genetic variation in protein 3D space, we found significant enrichment of disease-associated variants in the converter, a kinetic domain that transduces force from the catalytic domain to the lever arm to accomplish the power stroke. Focusing our analysis on surface exposed residues, we identified a larger region significantly enriched for disease-associated variants that contains both the converter domain and residues on a single flat surface on the myosin head described as the myosin mesa. Notably, patients with HCM with variants in the enriched regions have earlier disease onset than patients who have HCM with variants elsewhere. Our study provides a model for integrating protein structure, large-scale genetic sequencing, and detailed phenotypic data to reveal insight into time-shifted protein structures and genetic disease. PMID- 27247419 TI - Argininosuccinate synthetase regulates hepatic AMPK linking protein catabolism and ureagenesis to hepatic lipid metabolism. AB - A key sensor of cellular energy status, AMP-activated protein kinase (AMPK), interacts allosterically with AMP to maintain an active state. When active, AMPK triggers a metabolic switch, decreasing the activity of anabolic pathways and enhancing catabolic processes such as lipid oxidation to restore the energy balance. Unlike oxidative tissues, in which AMP is generated from adenylate kinase during states of high energy demand, the ornithine cycle enzyme argininosuccinate synthetase (ASS) is a principle site of AMP generation in the liver. Here we show that ASS regulates hepatic AMPK, revealing a central role for ureagenesis flux in the regulation of metabolism via AMPK. Treatment of primary rat hepatocytes with amino acids increased gluconeogenesis and ureagenesis and, despite nutrient excess, induced both AMPK and acetyl-CoA carboxylase (ACC) phosphorylation. Antisense oligonucleotide knockdown of hepatic ASS1 expression in vivo decreased liver AMPK activation, phosphorylation of ACC, and plasma beta hydroxybutyrate concentrations. Taken together these studies demonstrate that increased amino acid flux can activate AMPK through increased AMP generated by ASS, thus providing a novel link between protein catabolism, ureagenesis, and hepatic lipid metabolism. PMID- 27247420 TI - Fetal grafts for Parkinson's disease: Decades in the making. PMID- 27247421 TI - Oncogenic mutations in the FBXW7 gene of adult T-cell leukemia patients. AB - Human T-cell leukemia virus type 1 (HTLV-I) is associated with adult T-cell leukemia (ATL), an aggressive lymphoproliferative disease with a dismal prognosis. We have previously described the presence of Notch1 activating mutations and constitutive Notch1 signaling in patients with acute ATL. In this study, we report a high frequency of F-box and WD repeat domain containing 7 (FBXW7)/hCDC4 mutations within the WD40 substrate-binding domain in 8 of 32 acute ATL patients (25%). Functionally, ATL FBXW7 mutants lost their ability to interact with intracellular Notch (NICD), resulting in increased protein stability and constitutive Notch1 signaling. Consistent with the loss-of-function found in ATL patients, expression of WT FBXW7 in several patient-derived ATL lines demonstrated strong tumor-suppressor activity characterized by reduced proliferation of ATL cells. Remarkably, two FBXW7 mutants, D510E and D527G, demonstrated oncogenic activity when expressed in the presence of HTLV-I Tax, mutated p53 R276H, or c-Myc F138C found in human cancers. Transforming activity was further demonstrated by the ability of the FBXW7 D510E mutant to provide IL-2 independent growth of Tax-immortalized human T cells and increase the tumor formation in a xenograft mouse model of ATL. This study suggests that FBXW7, normally a tumor suppressor, can act as an oncogene when mutated and may play an important role in the pathogenesis of ATL. PMID- 27247422 TI - Crystal structures of the ligand-binding region of uPARAP: effect of calcium ion binding. AB - The proteins of the mannose receptor (MR) family share a common domain organization and have a broad range of biological functions. Urokinase plasminogen activator receptor-associated protein (uPARAP) (or Endo180) is a member of this family and plays an important role in extracellular matrix remodelling through interaction with its ligands, including collagens and urokinase plasminogen activator receptor (uPAR). We report the crystal structures of the first four domains of uPARAP (also named the ligand-binding region, LBR) at pH 7.4 in Ca(2+)-bound and Ca(2+)-free forms. The first domain (cysteine-rich or CysR domain) folds into a new and unique conformation different from the beta trefoil fold of typical CysR domains. The so-called long loop regions (LLRs) of the C-type lectin-like domain (CTLD) 1 and 2 (the third and fourth domain) mediate the direct contacts between these domains. These LLRs undergo a Ca(2+) dependent conformational change, and this is likely to be the key structural determinant affecting the overall conformation of uPARAP. Our results provide a molecular mechanism to support the structural flexibility of uPARAP, and shed light on the structural flexibility of other members of the MR family. PMID- 27247423 TI - New GroEL-like chaperonin of bacteriophage OBP Pseudomonas fluorescens suppresses thermal protein aggregation in an ATP-dependent manner. AB - Recently, we discovered and studied the first virus-encoded chaperonin of bacteriophage EL Pseudomonas aeruginosa, gene product (gp) 146. In the present study, we performed bioinformatics analysis of currently predicted GroEL-like proteins encoded by phage genomes in comparison with cellular and mitochondrial chaperonins. Putative phage chaperonins share a low similarity and do not form a monophyletic group; nevertheless, they are closer to bacterial chaperonins in the phylogenetic tree. Experimental investigation of putative GroEL-like chaperonin proteins has been continued by physicochemical and functional characterization of gp246 encoded by the genome of Pseudomonas fluorescens bacteriophage OBP. Unlike the more usual double-ring architecture of chaperonins, including the EL gp146, the recombinant gp246 produced by Escherichia coli cells has been purified as a single heptameric ring. It possesses ATPase activity and does not require a co chaperonin for its function. In vitro experiments demonstrated that gp246 is able to suppress the thermal protein inactivation and aggregation in an ATP-dependent manner, thus indicating chaperonin function. Single-particle electron microscopy analysis revealed the different conformational states of OBP chaperonin, depending on the bound nucleotide. PMID- 27247424 TI - Development of a high-affinity peptide that prevents phospholemman (PLM) inhibition of the sodium/calcium exchanger 1 (NCX1). AB - NCX1 (Na(+)/Ca(2+) exchanger 1) is an important regulator of intracellular Ca(2+) and a potential therapeutic target for brain ischaemia and for diastolic heart failure with preserved ejection fraction. PLM (phospholemman), a substrate for protein kinases A and C, has been suggested to regulate NCX1 activity. However, although several studies have demonstrated that binding of phosphorylated PLM (pSer(68)-PLM) leads to NCX1 inhibition, other studies have failed to demonstrate a functional interaction of these proteins. In the present study, we aimed to analyse the biological function of the pSer(68)-PLM-NCX1 interaction by developing high-affinity blocking peptides. PLM was observed to co-fractionate and co-immunoprecipitate with NCX1 in rat left ventricle, and in co-transfected HEK (human embryonic kidney)-293 cells. For the first time, the NCX1-PLM interaction was also demonstrated in the brain. PLM binding sites on NCX1 were mapped to two regions by peptide array assays, containing the previously reported PASKT and QKHPD motifs. Conversely, the two NCX1 regions bound identical sequences in the cytoplasmic domain of PLM, suggesting that NCX1-PASKT and NCX1 QKHPD might bind to each PLM monomer. Using two-dimensional peptide arrays of the native NCX1 sequence KHPDKEIEQLIELANYQVLS revealed that double substitution of tyrosine for positions 1 and 4 (K1Y and D4Y) enhanced pSer(68)-PLM binding 8 fold. The optimized peptide blocked binding of NCX1-PASKT and NCX1-QKHPD to PLM and reversed PLM(S68D) inhibition of NCX1 activity (both forward and reverse mode) in HEK-293 cells. Altogether our data indicate that PLM interacts directly with NCX1 and inhibits NCX1 activity when phosphorylated at Ser(68). PMID- 27247425 TI - Controlled bile acid exposure to oesophageal mucosa causes up-regulation of nuclear gamma-H2AX possibly via iNOS induction. AB - Using an in vitro model in which flatmounts of oesophagus was periodically exposed to bile acids, we demonstrate, using multiple methods, that the bile acid receptor TGR5, inducible nitric oxide synthase (iNOS) and gamma-histone family 2A variant (gamma-H2AX) are up-regulated. This indicates that bile acids cause up regulation of iNOS, which further causes genotoxic stress as evidenced by increase of the highly sensitive marker, phosphorylated histone. In vitro nitric oxide (NO) assays showed increased production of nitric acid in the oesophageal epithelium exposed to the bile acids. This increase was inhibited in the presence of the nonspecific iNOS inhibitor aminoguanidine (AG). Cumulatively, the results of the present study provide suggestion that not only acid reflux, but also non acid reflux of bile may cause genotoxic stress. These aspects merit to be tested in wide spectrum of Barrett epithelial tissues. PMID- 27247427 TI - WITHDRAWN: Differential molecular signature alterations of RBSP3, LIMD1 and CDC25A in normal oral epithelium during oral tumorigenesis. AB - The Accepted Manuscript version of this article (published on 1 June 2016) was withdrawn on 24 November 2017 at the request of the authors. PMID- 27247426 TI - Involvement of matrix metalloproteinases (MMPs) and inflammasome pathway in molecular mechanisms of fibrosis. AB - Fibrosis is a basic connective tissue lesion defined by the increase in the fibrillar extracellular matrix (ECM) components in tissue or organ. Matrix metalloproteinases (MMPs) are a major group of proteases known to regulate the turn-over of ECM and so they are suggested to be important in tissue remodelling observed during fibrogenic process associated with chronic inflammation. Tissue remodelling is the result of an imbalance in the equilibrium of the normal processes of synthesis and degradation of ECM components markedly controlled by the MMPs/TIMP imbalance. We previously showed an association of the differences in collagen deposition in the lungs of bleomycin-treated mice with a reduced molar pro-MMP-9/TIMP-1 ratio. Using the carbon tetrachloride (CCl4) preclinical model of liver fibrosis in mice, we observed a significant increase in collagen deposition with increased expression and release of tissue inhibitors of metalloproteinase (TIMP)-1 both at 24 h and 3 weeks later. This suggests an early altered regulation of matrix turnover involved in the development of fibrosis. We also demonstrated an activation of NLRP3-inflammasome pathway associated with the IL-1R/MyD88 signalling in the development of experimental fibrosis both in lung and liver. This was also associated with an increased expression of purinergic receptors mainly P2X7 Finally, these observations emphasize those effective therapies for these disorders must be given early in the natural history of the disease, prior to the development of tissue remodelling and fibrosis. PMID- 27247428 TI - Molecular characterization of human ABHD2 as TAG lipase and ester hydrolase. AB - Alterations in lipid metabolism have been progressively documented as a characteristic property of cancer cells. Though, human ABHD2 gene was found to be highly expressed in breast and lung cancers, its biochemical functionality is yet uncharacterized. In the present study we report, human ABHD2 as triacylglycerol (TAG) lipase along with ester hydrolysing capacity. Sequence analysis of ABHD2 revealed the presence of conserved motifs G(205)XS(207)XG(209) and H(120)XXXXD(125) Phylogenetic analysis showed homology to known lipases, Drosophila melanogaster CG3488. To evaluate the biochemical role, recombinant ABHD2 was expressed in Saccharomyces cerevisiae using pYES2/CT vector and His-tag purified protein showed TAG lipase activity. Ester hydrolase activity was confirmed with pNP acetate, butyrate and palmitate substrates respectively. Further, the ABHD2 homology model was built and the modelled protein was analysed based on the RMSD and root mean square fluctuation (RMSF) of the 100 ns simulation trajectory. Docking the acetate, butyrate and palmitate ligands with the model confirmed covalent binding of ligands with the Ser(207) of the GXSXG motif. The model was validated with a mutant ABHD2 developed with alanine in place of Ser(207) and the docking studies revealed loss of interaction between selected ligands and the mutant protein active site. Based on the above results, human ABHD2 was identified as a novel TAG lipase and ester hydrolase. PMID- 27247430 TI - Dynamic ECG change in Brugada syndrome during coronary angiography. PMID- 27247429 TI - Anti-collapsin response mediator protein 5 encephalitis masquerading as a low grade brain tumour. AB - A 71-year-old woman presented acutely with seizures; her MRI suggested a low grade glioma of the right temporal lobe. Over the preceding 18 months, she had developed progressive limb chorea and orofacial dyskinesia. Examination showed a predominantly amnestic cognitive profile. Initial investigations were normal, but later she was found to have antibodies to collapsin response mediator protein 5 (also called CV2). Her symptoms and neuroimaging abnormalities gradually improved without treatment. Four months later, surveillance imaging with (18)F fluorodeoxyglucose-positron-emission tomography revealed a lesion confirmed by biopsy as a TX, N2, M0 small-cell lung cancer. This case is unusual for the strikingly unilateral neuroimaging abnormalities, which led to an initial misdiagnosis, and the spontaneous symptomatic improvement without treatment. In retrospect, the co-occurrence of paraneoplastic chorea, limbic encephalitis and neuropathy in the presence of an occult lung tumour make this almost a 'full house' of symptoms associated with antibodies to collapsin response mediator protein 5. It underlines the importance in clinical reasoning of avoiding the cognitive errors of premature closure and anchoring. PMID- 27247431 TI - Obstructive Fibrinous Tracheal Pseudomembrane After Endotracheal Intubation. AB - Obstructive fibrinous tracheal pseudomembrane (OFTP) is an uncommon complication that results after tracheal intubation. Herein, we perform a systematic review of the PubMed and EmBase databases for all the cases describing OFTP. The systematic search yielded 28 citations describing 53 subjects with OFTP. The study population (61.1% females) comprised of both adults and pediatric subjects with a median (IQR) age of 40.5 (14.8-60.5) years. The median (IQR) size of endotracheal tube was 7.5 (6-9.3) mm with a median (IQR) duration of intubation of 36 (14-96) hours. The median (IQR) time to onset of symptoms after extubation was 24 (6-96) hours. Stridor was the most common symptom. The average delay in correctly identifying the OFTP was 26 hours. The diagnosis of tracheal pseudomembrane was confirmed by flexible bronchoscopy in 38 (70.4%) instances while rigid bronchoscopy was used in 46.3% subjects for removing the pseudomembrane. There were two deaths, one each in an adult and a pediatric subject. OFTP is a complication of tracheal intubation and presents with respiratory failure. The diagnosis can be confirmed by flexible bronchoscopy. Treatment involves removal of the obstructing membrane with either flexible or rigid bronchoscopy. PMID- 27247432 TI - Mortality-Reducing Effect of Rehabilitation for COPD: Observational Propensity Matched Cohort Study Using a Nationwide Database. AB - BACKGROUND: In the course of therapy of patients with COPD, non-pharmacologic treatment, such as rehabilitation, plays an important role. Although some studies have provided concrete evidence of the effectiveness of rehabilitation in improving functional outcomes in subjects with COPD, evidence of its mortality reducing effect has been insufficient. In the present study, we examined whether rehabilitation had positive effects on in-hospital mortality of subjects with COPD. METHODS: We used the Japanese Diagnosis Procedure Combination nationwide administrative claims database. This was a retrospective cohort study, and there were 18,037 eligible subjects with COPD from 1,055 hospitals. The main outcome was in-hospital mortality rates. A one-to-one propensity score matching method was used to compare hospital mortality rates after admission between rehabilitation and non-rehabilitation groups. RESULTS: A total of 3,356 pairs of subjects were selected from the rehabilitation and non-rehabilitation groups (n = 6,712). Subjects in the rehabilitation program showed a reduction in the odds of mortality (odds ratio = 0.80, 95% CI 0.65-1.00, P = .045). In the subgroup analyses, the rehabilitation group had a lower in-hospital mortality in the pre obese subgroup (body mass index 25.0-29.9) than the non-rehabilitation group (P = .02). Although not significant, the rehabilitation group showed a relatively low in-hospital mortality in the Hugh-Jones dyspnea scale class 5 subgroup (P = .066). CONCLUSIONS: This large nationwide cohort study showed that rehabilitation indeed contributed to a reduction of in-hospital mortality. These findings underscore the importance of adopting rehabilitation as part of the treatment of COPD. PMID- 27247433 TI - Low-dose aspirin as primary prophylaxis for cardiovascular events in systemic lupus erythematosus: a long-term retrospective cohort study. AB - OBJECTIVES: Cardiovascular (CV) morbidity and mortality are significantly greater in SLE patients than in the general population. ASA is known to be associated with a decrease in the incidence of CV events in high-risk patients from the general population, but its efficacy as primary prophylaxis in SLE patients has not yet been investigated. METHODS: The clinical charts of SLE patients consecutively admitted to a tertiary centre who, at admission, satisfied 1992 ACR and/or 2012 SLICC classification criteria for SLE and had not experienced any CV event, were reviewed. The occurrence of any CV event was recorded at each visit. ASA was prescribed to all patients at first visit. The rate and reasons for ASA discontinuation were also recorded at each visit. RESULTS: One hundred and sixty seven consecutive SLE patients were enrolled and followed up for a median of 8 years (range 1-14 years). Among them, 146 regularly took the medication (ASA treated patients) and 21 refused to take or discontinued it (non-ASA-treated patients). Five CV events occurred in the 146 ASA-treated patients (4.2 per 1000 person-years) and four in the 21 non-ASA-treated patients (30 per 1000 person years; P = 0.0007). The CV event-free rate was higher in ASA-treated than in non ASA-treated patients (log-rank test chi(2) = 15.74; P = 0.0001). No relevant side effect related to ASA was recorded. CONCLUSION: Low-dose ASA is a safe treatment and may be beneficial in the primary prophylaxis of CV events in SLE patients. Controlled, prospective studies are needed to provide a better definition of its role in these patients. PMID- 27247434 TI - The short-term effects of two high-dose, step-down prednisolone regimens on body composition in early rheumatoid arthritis. AB - OBJECTIVE: To investigate the effect of two different high-dose, step-down prednisolone regimens on body composition in early RA patients after 26 weeks of treatment. METHODS: Prednisolone-naive patients with recent-onset RA (n = 108) were randomized to either COBRA (prednisolone 60 mg/day, tapered to 7.5 mg/day in 6 weeks; MTX and SSZ) or COBRA-light therapy (prednisolone 30 mg/day, tapered to 7.5 mg/day in 8 weeks and MTX). Body composition was assessed at baseline (before or soon after start of treatment) and after 26 weeks with DXA, and recorded as total body mass (TBM), total fat mass (FM), total lean mass (LM) and trunk/peripheral fat ratio. Log-ratio analyses assessed the proportional distribution of TBM (between LM, FM and bone mass) and FM (between trunk, extremities and head). The subgroup of patients with a DXA before start of treatment (n = 38) was analysed separately. RESULTS: In the subgroup of patients with a DXA before start of treatment, TBM increased by 1.6 kg (P < 0.001) and total FM by 1.3 kg (P < 0.001). The trunk/peripheral fat ratio and the proportional distribution of TBM and FM remained stable over time. There were no differences between the treatment groups. Similar results were obtained in the study population as a whole. CONCLUSION: Both high-dose, step-down prednisolone regimens caused increases in TBM, mainly caused by an increase in FM, but we found no fat redistribution from peripheral to central tissues. This absence in fat redistribution contradicts the widely held assumption of rapid adverse effects of prednisolone on body composition in RA. TRIAL REGISTRATION: ISRCTNregistry, http://www.isrctn.com, ISRCTN55552928. PMID- 27247435 TI - Temporal relationship between cancer and myositis identifies two distinctive subgroups of cancers: impact on cancer risk and survival in patients with myositis. AB - OBJECTIVES: The aim was to compare standardized incidence ratios (SIRs) of cancers temporally related and unrelated to active myositis in patients with myositis. METHODS: Fifty-two cancer cases were identified in 281 myositis patients. SIRs of cancers having temporal overlap with the active phase of myositis [cancers concurrent with active myositis (CAM), n = 30] and cancers not having such temporal overlap [cancers non-concurrent with active myositis (CNM), n = 22] were compared in 281 patients. RESULTS: Patients with CAM were older at diagnosis of myositis, had a greater tendency to be male, more frequent dysphagia and less frequent interstitial lung disease than patients with CNM. CAM SIR (95% CI) was 1.78 (1.19, 2.56) and CNM SIR 1.23 (0.75, 1.90). The peak SIR was observed in the seventh decade of life for CAM and in the third decade for CNM. When stratified by myositis-cancer intervals, CAM SIR was 9.94 (6.43, 14.67) within 1 year of myositis diagnosis, whereas no temporal relationship was found for CNM. Elevated SIRs were observed for oesophageal cancer [57.77 (11.91, 168.82)], non-Hodgkin's lymphoma [41.43 (13.45, 96.69)], adenocarcinoma of unknown primary origin [67.6 (18.42, 173.07]), lung cancer [7.27 (1.98, 18.61)] and ovarian cancer [19.15 (2.32, 69.17)] within 3 years of CAM diagnosis. The cancer stage at the time of diagnosis was more advanced in CAM than CNM (P < 0.001), with a correspondingly increased hazard ratio of mortality [4.3 (1.5, 12.7)] in patients with CAM vs CNM. CONCLUSION: A significantly elevated SIR was found for CAM, whereas there was a comparable SIR for CNM relative to the general population. Multiple types of cancers showed elevated SIRs among CAM, but none among CNM. Given that cancer stages in CAM were far advanced at diagnosis, mortality risk was greater in patients with CAM. PMID- 27247437 TI - Casting your network wide: a plea to scale-up phenological research. AB - Accumulating scientific evidence has demonstrated widespread shifts in the biological seasons. These shifts may modify seasonal interspecific interactions, with consequent impacts upon reproductive success and survival. However, current understanding of these impacts is based upon a limited number of studies that adopt a simplified 'bottom-up' food-chain paradigm, at a local scale. I argue that there is much insight to be gained by widening the scope of phenological studies to incorporate food-web interactions and landscape-scale processes across a diversity of ecosystem types, with the ultimate goal of developing a generic understanding of the systems most vulnerable to synchrony effects in the future. I propose that co-location of predator and prey phenological monitoring at sentinel sites, acting as research platforms for detailed food-web studies, experimentation and match-up with earth observation data, would be an important first step in this endeavour. PMID- 27247436 TI - Analysis of the human immunodeficiency virus-1 RNA packageome. AB - All retroviruses package cellular RNAs into virions. Studies of murine leukemia virus (MLV) revealed that the major host cell RNAs encapsidated by this simple retrovirus were LTR retrotransposons and noncoding RNAs (ncRNAs). Several classes of ncRNAs appeared to be packaged by MLV shortly after synthesis, as precursors to tRNAs, small nuclear RNAs, and small nucleolar RNAs were all enriched in virions. To determine the extent to which the human immunodeficiency virus (HIV 1) packages similar RNAs, we used high-throughput sequencing to characterize the RNAs within infectious HIV-1 virions produced in CEM-SS T lymphoblastoid cells. We report that the most abundant cellular RNAs in HIV-1 virions are 7SL RNA and transcripts from numerous divergent and truncated members of the long interspersed element (LINE) and short interspersed element (SINE) families of retrotransposons. We also detected precursors to several tRNAs and small nuclear RNAs as well as transcripts derived from the ribosomal DNA (rDNA) intergenic spacers. We show that packaging of a pre-tRNA requires the nuclear export receptor Exportin 5, indicating that HIV-1 recruits at least some newly made ncRNAs in the cytoplasm. Together, our work identifies the set of RNAs packaged by HIV-1 and reveals that early steps in HIV-1 assembly intersect with host cell ncRNA biogenesis pathways. PMID- 27247438 TI - Warmer temperatures attenuate the classic offspring number and reproductive investment trade-off in the common lizard, Zootoca vivipara. AB - Life-history traits involved in trade-offs are known to vary with environmental conditions. Here, we evaluate the response of the trade-off between 'offspring number' versus 'energy invested per offspring' to ambient temperature in 11 natural populations of the common lizard, Zootoca vivipara We provide evidence at both the intra- and interpopulation levels that the trade-off is reduced with an increase in air temperature. If this effect enhances current individual fitness, it may lead to an accelerated pace of life in warmer environments and could ultimately increase adult mortality. In the context of global warming, our results advocate the need for more studies in natural populations to explore interactions between life-history traits' trade-offs and environmental conditions. PMID- 27247439 TI - Pathways of information transmission among wild songbirds follow experimentally imposed changes in social foraging structure. AB - Animals regularly use information from others to shape their decisions. Yet, determining how changes in social structure affect information flow and social learning strategies has remained challenging. We manipulated the social structure of a large community of wild songbirds by controlling which individuals could feed together at automated feeding stations (selective feeders). We then provided novel ephemeral food patches freely accessible to all birds and recorded the spread of this new information. We demonstrate that the discovery of new food patches followed the experimentally imposed social structure and that birds disproportionately learnt from those whom they could forage with at the selective feeders. The selective feeders reduced the number of conspecific information sources available and birds subsequently increased their use of information provided by heterospecifics. Our study demonstrates that changes to social systems carry over into pathways of information transfer and that individuals learn from tutors that provide relevant information in other contexts. PMID- 27247440 TI - Sensory feedback and coordinating asymmetrical landing in toads. AB - Coordinated landing requires anticipating the timing and magnitude of impact, which in turn requires sensory input. To better understand how cane toads, well known for coordinated landing, prioritize visual versus vestibular feedback during hopping, we recorded forelimb joint angle patterns and electromyographic data from five animals hopping under two conditions that were designed to force animals to land with one forelimb well before the other. In one condition, landing asymmetry was due to mid-air rolling, created by an unstable takeoff surface. In this condition, visual, vestibular and proprioceptive information could be used to predict asymmetric landing. In the other, animals took off normally, but landed asymmetrically because of a sloped landing surface. In this condition, sensory feedback provided conflicting information, and only visual feedback could appropriately predict the asymmetrical landing. During the roll treatment, when all sensory feedback could be used to predict an asymmetrical landing, pre-landing forelimb muscle activity and movement began earlier in the limb that landed first. However, no such asymmetries in forelimb preparation were apparent during hops onto sloped landings when only visual information could be used to predict landing asymmetry. These data suggest that toads prioritize vestibular or proprioceptive information over visual feedback to coordinate landing. PMID- 27247441 TI - Estimated Dose to Family Members of Patients Treated with Radioiodine. AB - Patients who receive therapeutic amount of 131I are potentially significant source of radiation to their family members and general public. The aim of this study was to estimate effective dose to family members of patients treated with radioiodine, released after 3 d of hospitalization and to compare with dose constraints proposed by international recommendations. The thermoluminescence dosemeters (TLD 100) and Radiation Dose Assessment Resource (RADAR) software were used for assessment of effective doses to 60 family members of the same number of hyperthyroid and thyroid carcinoma patients. Estimated effective doses were well below recommended dose limits except in a few cases. RADAR-calculated doses were higher than doses measured by TLD. Hyperthyroid patients should continue to be treated on outpatient basis but they should be well informed for their further behavior to provide minimal radiation hazard for the people in their environment. PMID- 27247442 TI - INTERNATIONAL CONFERENCE ON INDIVIDUAL MONITORING OF IONISING RADIATION. PMID- 27247443 TI - Practical Nuclear Medicine and Utility of Phantoms for Internal Dosimetry: XCAT Compared with Zubal. AB - Purpose: The absorbed doses for two radioisotopes, 99mTc and 131I, between previously validated Zubal phantom and the recently developed XCAT phantom were compared. Materials and methods: GATE Monte Carlo code was used to simulate the statistical process of radiation. A XCAT phantom with voxel and matrix sizes similar to a standard Zubal phantom was generated. According to Medical International Radiation Dose formalism, specific absorbed fraction (SAF) values for photons and S-factors for beta particles were tabulated. The amounts of absorbed doses were calculated and compared in different organs. Results: The differences of gamma radiation doses, SAFs, between Zubal and XCAT are >50% in adrenal from adrenal, pancreas from pancreas and thyroid from thyroid, in lung from kidney, kidneys from lungs and in kidneys from thyroid and thyroid from kidneys. The beta radiation doses differences between Zubal and XCAT are >50% in thyroid from thyroid, bladder from bladder, kidney from kidney, liver from bladder, thyroid from bladder and kidney from thyroid. The size and distances of the organs were different between XCAT and Zubal phantoms. Denoted differences of SAF and S-factors correspond to the different organ geometries in phantoms. Conclusion: The results of absorbed doses in Zubal and XCAT phantoms are different. The variations prohibit easy comparison or interchangeability of dosimetry between these phantoms. PMID- 27247444 TI - Estimation of Eye Lens Dose During Brain Scans Using Gafchromic Xr-QA2 Film in Various Multidetector CT Scanners. AB - The purpose of this study was to estimate eye lens dose during brain scans in 16 , 64-, 128- and 256-slice multidetector computed tomography (CT) scanners in helical acquisition mode and to test the feasibility of using radiochromic film as eye lens dosemeter during CT scanning. Eye lens dose measurements were performed using Gafchromic XR-QA2 film on a polystyrene head phantom designed with outer dimensions equivalent to the head size of a reference Indian man. The response accuracy of XR-QA2 film was validated by using thermoluminescence dosemeters. The eye lens dose measured using XR-QA2 film on head phantom for plain brain scanning in helical mode ranged from 43.8 to 45.8 mGy. The XR-QA2 film measured dose values were in agreement with TLD measured dose values within a maximum variation of 8.9%. The good correlation between the two data sets confirms the viability of using XR-QA2 film for eye lens dosimetry. PMID- 27247445 TI - OPTIMISATION OF SCATTER RADIATION TO STAFF DURING CT-FLUOROSCOPY: MONTE CARLO STUDIES. AB - Studies have shown that there is high radiation exposure to medical staff during computed tomography fluoroscopy (CTF)-guided procedures. This study aims to investigate staff dose reduction techniques considering the CTF gantry positioning in the room and room dimensions in addition to the conventional use of thyroid collars, aprons and eye goggles. A Toshiba Aquilion One 640 slice CT scanner and CTF room were modelled using SimpleGeo. Standing and supine adult mesh phantoms were used to represent the staff and patient. The models were spatially put together on one platform using VOXEL2MCNP. Based on this, MCNPX input files were generated for the studies. CTF gantry and staff positions, and CTF room size were varied for different scenarios. Effective, eye lens and thyroid dose to staff were estimated for each scenario. Additional means of possible dose reduction with respect to positioning of the CTF device and room layout are discussed. PMID- 27247446 TI - Dose and Image Quality in Low-dose CT for Urinary Stone Disease: Added Value of Automatic Tube Current Modulation and Iterative Reconstruction Techniques. AB - The aim of this study was to compare dose and image quality (IQ) of a baseline low-dose computed tomography (CT) (fix mAs) vs. an ultra-low-dose CT (automatic tube current modulation, ATCM) in patients with suspected urinary stone disease and to assess the added value of iterative reconstruction. CT examination was performed on 193 patients (103 baseline low-dose, 90 ultra-low-dose). Filtered back projection (FBP) was used for both protocols, and Sinogram Affirmed Iterative Reconstruction (SAFIRE) was used for the ultra-low-dose protocol only. Dose and ureter stones information were collected for both protocols. Subjective IQ was assessed by two radiologists scoring noise, visibility of the ureter and overall IQ. Objective IQ (contrast-to-noise ratio, CNR) was assessed for the ultra-low-dose protocol only (FBP and SAFIRE). The ultra-low-dose protocol (ATCM) showed a 22% decrease in mean effective dose (p < 0.001) and improved visibility of the pelvic ureter (p = 0.02). CNR was higher for SAFIRE (p < 0.0001). SAFIRE improves the objective IQ, but not the subjective IQ for the chosen clinical task. PMID- 27247447 TI - Development and Validation of an Interactive Efficient Dose Rates Distribution Calculation Program Arshield for Visualization of Radiation Field in Nuclear Power Plants. AB - Point kernel integration (PKI) method is widely used in the visualization of radiation field in engineering applications because of the features of quickly dealing with large-scale complicated geometry space problems. But the traditional PKI programs have a lot of restrictions, such as complicated modeling, complicated source setting, 3D fine mesh results statistics and large-scale computing efficiency. To break the traditional restrictions for visualization of radiation field, ARShield was developed successfully. The results show that ARShield can deal with complicated plant radiation shielding problems for visualization of radiation field. Compared with SuperMC and QAD, it can be seen that the program is reliable and efficient. Also, ARShield can meet the demands of calculation speediness and interactive operations of modeling and displaying 3D geometries on a graphical user interface, avoiding error modeling in calculation and visualization. PMID- 27247448 TI - Occupational dose reduction in cardiac catheterisation laboratory: a randomised trial using a shield drape placed on the patient. AB - The aim of this study was to evaluate the occupational radiation dose in interventional cardiology by using a shielding drape on the patient. A random study with and without the protective material was conducted. The following control parameters were registered: demographic data, number of stents, contrast media volume, fluoroscopy time, number of cine images, kerma-area product and cumulative air kerma. Occupational dose data were obtained by electronic active dosemeters. No statistically significant differences in the analysed control parameters were registered. The median dose value received by the interventional cardiologist was 50% lower in the group with a shielding drape with a statistically significant p-value <0.001. In addition, the median value of the maximum scatter radiation dose was 31% lower in this group with a statistically significant p-value <0.001. This study showed that a shielding drape is a useful tool for reducing the occupational radiation dose in a cardiac catheterisation laboratory. PMID- 27247449 TI - Letter to the Editor. PMID- 27247450 TI - Calculation of the maximum allowed ambient dose rate outside CT rooms to quantitatively assess the structural shielding performance. AB - The goal of this study was to develop a method to quantitatively assess the structural shielding performance of computed tomography (CT) rooms in Switzerland. The method was based on the comparison between calculated maximum allowed ambient dose rate (DR) and measured ambient DR in adjacent spaces. If the measured DR exceeds the calculated maximum allowed value, additional shielding is required; otherwise the shielding is sufficient. The maximum allowed ambient DR was calculated using two different shielding concepts either based on the tube loading of the scanner or on the accumulated dose length product of the scans. The method was validated for 36 spiral CT head protocols. The average ratio of the maximum allowed ambient DR between both concepts was 1.11 (range 0.57-2.14). Among 36 CT rooms, 7 room boundaries were insufficiently shielded. In conclusion, this method allows the authority to check on-site the compliance of the structural shielding with legal requirements. PMID- 27247451 TI - Treatment of fish - A comment. PMID- 27247452 TI - Treatment of fish - A reply. PMID- 27247453 TI - Treatment of fish - Editor's comment. PMID- 27247454 TI - An ethicist's commentary on options for hurt animals - A reply. PMID- 27247455 TI - Antimicrobial use in animals. PMID- 27247456 TI - Ethical question of the month - June 2016. PMID- 27247457 TI - Acyanotic tetralogy of Fallot in a Persian cat. AB - An 8-year-old, intact male Persian cat was presented with a prominent heart murmur, exercise intolerance, anorexia, and periodontitis. There was no cyanosis and no laboratory evidence for systemic hypoxemia. Echocardiography showed a dextropositioned aorta, moderate pulmonic stenosis (maximal velocity 4.06 m/s), ventricular septal defect, and right ventricular hypertrophy. The shunt direction was predominantly left-to-right in systole and minimally right-to-left in diastole. The cat was diagnosed with acyanotic (pink) tetralogy of Fallot and was managed medically with atenolol. PMID- 27247458 TI - Peritoneal fluid immunocytochemistry used for the diagnosis of a possible case of equine gastrointestinal B-cell lymphoma. AB - After physical examination, ultrasonographic evaluation of thorax and abdomen, and peritoneal fluid analysis, gastrointestinal neoplasia with suspected diffuse peritoneal metastasis was diagnosed in a 17-year-old Arabian gelding. The owner elected euthanasia and declined postmortem examination. Immunocytochemistry analysis of the peritoneal fluid resulted in a diagnosis of B-cell lymphoma. PMID- 27247459 TI - Multiple liver abscesses in a dog secondary to the liver fluke Metorchis conjunctus treated by percutaneous transhepatic drainage and alcoholization. AB - A 1-year-old German shepherd * husky cross dog was diagnosed with multiple liver abscesses and severe cholangitis secondary to the liver fluke Metorchis conjunctus. The dog was successfully treated with 2 percutaneous transhepatic drainage and alcoholization procedures, and a prolonged course of antibiotics and praziquantel. PMID- 27247461 TI - Evaluation of a portable oxygen concentrator to provide fresh gas flow to dogs undergoing anesthesia. AB - This study evaluated the ability of a portable oxygen concentrator (POC) to provide fresh gas to an anesthetic machine via an Ayre's T-piece or a Bain circuit. Fraction of inspired oxygen (FiO2) was compared at flows of 0.5 to 3.0 L/min. Measured FiO2 was 96% at flow rates >= 1 L/min. Mean battery life at 1.0, 2.0, and 3.0 L/min was 4.21 +/- 0.45, 2.62 +/- 0.37 and 1.5 +/- 0.07 hours, respectively. The POC proved to be useful and effective during 2 power outages. The POC was sufficient to prevent rebreathing in 70% of dogs using a T-piece circuit and 20% of dogs with a Bain circuit. A significant negative correlation between inspired CO2 and O2 flow rates was noted. A significant positive correlation between inspired CO2 and ETCO2 was documented. The occurrence of hypercarbia was associated with low O2 flow. Battery back-up was essential during power outages. The POC can be effectively used for delivery of anesthesia. PMID- 27247460 TI - Persistence of clinical signs associated with rotavirus following an outbreak of porcine epidemic diarrhea (PED) on a farrow-to-grow swine operation in southwestern Ontario. AB - Clinical signs attributed to porcine epidemic diarrhea (PED) persisted for several months in a southwestern Ontario farm following an outbreak of PED. Extensive testing revealed rotavirus infection and absence of PED in nursing and nursery pigs, highlighting the importance of repeated diagnostic testing following a disease outbreak. PMID- 27247463 TI - Fine-needle aspiration in the diagnosis of equine skin disease and the epidemiology of equine skin cytology submissions in a western Canadian diagnostic laboratory. AB - Fine-needle aspiration (FNA) is commonly used to diagnose skin disease in companion animals, but its use in horses appears to be infrequent. Equine veterinarians in western Canada were surveyed to determine their opinions about FNA and 15 years of diagnostic submissions were used to compare the perceived to actual value of FNA in the diagnosis of skin disease in horses. Practitioners viewed FNA as quick, easy, economical, and minimally invasive. However, most veterinarians rarely chose to use FNA due to a perception that sample quality and diagnostic yield were poor and there was a narrow range of diseases the technique could diagnose. Analysis of the FNA cytology samples from a veterinary diagnostic laboratory showed a wide variety of equine skin disease conditions, but the frequency of non-diagnostic results was significantly higher in equine submissions compared to those from dogs and cats. PMID- 27247464 TI - Glucose intolerance in dairy goats with pregnancy toxemia: Lack of correlation between blood pH and beta hydroxybutyric acid values. AB - This study assessed the response to a glucose tolerance test in dairy goats with pregnancy toxemia (PT), in healthy, pregnant, non-lactating dairy goats in the last month of gestation (HP), and in healthy, lactating, non-pregnant, dairy goats in mid-lactation (HL). A 500 mL volume of a 5% glucose solution was administered by the IV route. Blood glucose concentrations returned to pre infusion levels by 90 min in all 8 HL goats, and by 180 min in all 8 HP goats. In contrast, concentrations of blood glucose were still significantly above pre infusion levels at 180 min post-infusion in all 8 PT goats. Thus, marked glucose intolerance was demonstrated in the PT goats, and mild intolerance was noted in the HP goats. In 25 goats diagnosed with PT and having blood beta hydroxybutyric acid (BHBA) values >= 2.9 mmol/L, the correlation coefficient for BHBA with blood pH was non-significant. PMID- 27247462 TI - Effect of sow vaccination against porcine circovirus type 2 (PCV2) on virological profiles in herds with or without PCV2 systemic disease. AB - We investigated porcine circovirus type 2 (PCV2) virological profiles in herds affected (PCVAD-AH, n = 5) or non-affected (PCVAD-NAH, n = 4) by PCV2-associated diseases (PCVAD), before and after 1 y of PCV2 gilt and sow vaccination. Fresh feces from the floor (5 pens/age/farm) and 5 blood samples (1/pen) were collected at 3, 9, 15, 21 wk. Individual feces and blood samples were collected from 5 gilts and 15 sows. Sampling was repeated 1 y after vaccination. Quantitative PCR on feces, PCV2 antibodies in blood serum and cell-mediated immunity were investigated. Before vaccination, pigs of PCVAD-AH had higher viral load in feces (9 and 15 wk), lower IgG and higher IgM (3 wk) and lower lymphocyte counts (9 and 15 wk) suggesting immunosuppression. Vaccination reduced viral load in growers, increased IgG (3 wk) suggesting improved maternal immunity, reduced IgM (3 wk), increased total antibody titers in sows and increased CD79a cells in the pigs. PMID- 27247465 TI - Evaluation of cardiac troponin I in dogs presenting to the emergency room using a point-of-care assay. AB - We used a point-of-care assay to evaluate cardiac troponin I (cTnI) in clinically normal dogs and a heterogeneous population of dogs presenting to the emergency room (ER) and to determine whether cTnI has prognostic capabilities in an ER population. Fourteen clinically normal dogs and 129 dogs presented to the ER were evaluated. Of the study group, 88 dogs had normal cTnI (< 0.1 ng/mL), 29 had elevated cTnI (0.1 to 1.0 ng/mL), and 12 had high cTnI (> 1.0 ng/mL). Dogs with elevated cTnI had 8 times the odds of mortality compared to dogs with normal cTnI [odds ratio (OR): 8.2, 95% confidence interval (CI): 3.0, 22.3]. Dogs with high cTnI had 17 times higher odds of mortality compared to dogs with normal cTnI (OR: 17.6, 95% CI: 4.4, 70.1). We conclude that cTnI shows promise as a prognostic indicator for dogs presenting to the ER and can be easily evaluated using a point of-care assay. PMID- 27247466 TI - Removal of sialoliths using the intraoral approach in 15 horses. AB - This study describes the use of an intraoral approach for sialolith removal in horses. All horses resumed their previous activity after surgery. Sialoliths were composed mainly of calcium carbonate, containing a nidus of plant material. The removal of sialoliths via an intraoral approach results in a high success rate with minimal complications. PMID- 27247467 TI - A pilot study evaluating laparoscopic closure of the nephrosplenic space using an endoscopic suturing device in standing horses. AB - This study evaluated the use of an articulating automated suturing device for laparoscopic closure of the nephrosplenic space in standing horses. Closure of the nephrosplenic space was performed in 4 horses using an automated suturing device. Second-look laparoscopy was performed at 5 weeks. A smooth fibrous adhesion formed between the spleen, the perirenal fascia, and the nephrosplenic ligament in 3 of the 4 horses in which the nephrosplenic space was closed using the automated suturing device. In 1 horse, closure of the nephrosplenic space was not possible due to constant breakage of the endoscopic needle. Intra-operative complications encountered with the automated suturing device were tearing of the perirenal fascia, nephrosplenic ligament, and dorsal splenic capsule along with breakage of the needle. The automated suturing device used in this study for laparoscopic closure of the nephrosplenic space resulted in longer surgery times, suffered instrument failures and delivered inadequate suture. PMID- 27247468 TI - Pentoxifylline as adjunct therapy to long-term clinical management of a right-to left patent ductus arteriosus. AB - Management of a right-to-left ("reversed") patent ductus arteriosus (PDA) focuses on control of clinical signs associated with hyperviscosity due to erythrocytosis. Pentoxifylline therapy is presented as an adjunct to routine phlebotomies for the long-term clinical management of reversed PDA in a 10-year old Chihuahua. PMID- 27247469 TI - New grad chronicles: Clinical practice is not mandatory. PMID- 27247470 TI - When meanings get lost in translation. PMID- 27247471 TI - Increasing the engagement of stockpeople in swine welfare. PMID- 27247472 TI - Inferior Vena Cava Filters: Guidelines, Best Practice, and Expanding Indications. AB - Vena caval interruption, currently accomplished by percutaneous image-guided insertion of an inferior vena cava (IVC) filter, is an important therapeutic option in the management of selected patients with venous thromboembolism. The availability of optional (or retrievable) filters, in particular, has altered the practice patterns for IVC filters, with a shift to these devices and expansion of indications for filter placement. As new devices have become available and clinicians have become more familiar and comfortable with IVC filters, the indications for filter placement have continued to evolve and expand. This article reviews current guidelines and expanding indications for IVC filter placement. PMID- 27247473 TI - The Role of Inferior Vena Cava Filters in Cancer Patients. AB - Cancer induces a hypercoagulable state and renders patients susceptible to venous thromboembolism. While anticoagulation remains the mainstay of treatment, many of these patients require placement of an inferior vena cava (IVC) filter, often due to a contraindication to or failure of anticoagulation. In this article, the available data on IVC filter usage in cancer patients will be reviewed. PMID- 27247474 TI - Permanent versus Retrievable Inferior Vena Cava Filters: Rethinking the "One Filter-for-All" Approach to Mechanical Thromboembolic Prophylaxis. AB - Inferior vena cava (IVC) filtration for thromboembolic protection is not without risks, and there are important differences among commercially available IVC filters. While retrievable filters are approved for permanent implantation, they may be associated with higher device-related complications in the long term when compared with permanent filters. Prospective patient selection in determining which patients might be better served by permanent or retrievable filter devices is central to resource optimization, in addition to improved clinical follow-up and a concerted effort to retrieve filters when no longer needed. This article highlights the differences between permanent and retrievable devices, describes the interplay between these differences and the clinical indications for IVC filtration, advises against a "one-filter-for-all" approach to mechanical thromboembolic prophylaxis, and discusses strategies for optimizing personalized device selection. PMID- 27247475 TI - A Critical Review of Available Retrievable Inferior Vena Cava Filters and Future Directions. AB - Inferior vena cava filters have been placed in patients for decades for protection against pulmonary embolism. The widespread use of filters has dramatically increased owing at least in part to the approval of retrievable vena cava filters. Retrievable filters have the potential to protect against pulmonary embolism and then be retrieved once no longer needed to avoid potential long-term complications. There are several retrievable vena cava filters available for use. This article discusses the different filter designs as well as the published data on these available filters. When selecting a filter for use, it is important to consider the potential short-term complications and the filters' window for retrieval. Understanding potential long-term complications is also critical, as these devices are approved for permanent placement and many filters are not retrieved. Finally, this article will address research into new designs that may be the future of vena cava filtration. PMID- 27247476 TI - Anatomic and Technical Considerations: Inferior Vena Cava Filter Placement. AB - Inferior vena cava (IVC) filters play an important role in preventing pulmonary embolism in patients with deep venous thrombosis. When preparing for IVC filter placement, there are several important anatomic and technical considerations. The IVC has complex embryologic origins, and normal variants are relatively common which may necessitate a change in technique or approach. When performing the procedure, the choice in imaging modality for deployment, location of deployment, and route of access must be considered. The pediatric and pregnant populations present unique situations that require special consideration and close examination of indications and contraindications. PMID- 27247477 TI - Evidence-Based Evaluation of Inferior Vena Cava Filter Complications Based on Filter Type. AB - Many inferior vena cava (IVC) filter types, along with their specific risks and complications, are not recognized. The purpose of this study was to evaluate the various FDA-approved IVC filter types to determine device-specific risks, as a way to help identify patients who may benefit from ongoing follow-up versus prompt filter retrieval. An evidence-based electronic search (FDA Premarket Notification, MEDLINE, FDA MAUDE) was performed to identify all IVC filter types and device-specific complications from 1980 to 2014. Twenty-three IVC filter types (14 retrievable, 9 permanent) were identified. The devices were categorized as follows: conical (n = 14), conical with umbrella (n = 1), conical with cylindrical element (n = 2), biconical with cylindrical element (n = 2), helical (n = 1), spiral (n = 1), and complex (n = 1). Purely conical filters were associated with the highest reported risks of penetration (90-100%). Filters with cylindrical or umbrella elements were associated with the highest reported risk of IVC thrombosis (30-50%). Conical Bard filters were associated with the highest reported risks of fracture (40%). The various FDA-approved IVC filter types were evaluated for device-specific complications based on best current evidence. This information can be used to guide and optimize clinical management in patients with indwelling IVC filters. PMID- 27247478 TI - Inferior Vena Cava Filter-Related Thrombus/Deep Vein Thrombosis: Data and Management. AB - Recurrent deep venous thrombosis and inferior vena cava (IVC) thrombosis are well described complications following IVC filter placement. IVC thrombosis ranges in severity of clinical presentation, but can lead to significant morbidity and mortality with incidence rates depending on patient population and type of filter used. Endovascular therapies such as catheter-directed thrombolysis, mechanical thrombectomy, balloon venoplasty, and stenting are safe and effective in restoration of venous patency. PMID- 27247479 TI - A Dedicated Inferior Vena Cava Filter Service Line: How to Optimize Your Practice. AB - Despite the increased placement of retrievable inferior vena cava filters (rIVCFs), efforts to remove these devices are not commensurate. The majority of rIVCFs are left in place beyond their indicated usage, and often are retained permanently. With a growing understanding of the clinical issues associated with these devices, the United States Food and Drug Administration (FDA) has prompted clinicians to remove rIVCF when they are no longer indicated. However, major obstacles exist to filter retrieval, chief among them being poor clinical follow up. The establishment of a dedicated IVC filter service line, or clinic, has been shown to improve filter retrieval rates. Usage of particular devices, specifically permanent versus retrievable filters, is enhanced by prospective physician consultation. In this article, the rationale behind a dedicated IVC filter service line is presented as well as described the structure and activities of the authors' IVC filter clinic; supporting data will also be provided when appropriate. PMID- 27247480 TI - Considerations for Imaging the Inferior Vena Cava (IVC) with/without IVC Filters. AB - Deep venous thrombosis (DVT), thrombosis of the inferior vena cava, and pulmonary embolism (PE) constitute a continuum that includes venous thromboembolic (VTE) disease. VTE is the third most common cardiovascular disorder that affects all races, ethnicities, gender, and ages. VTE predominantly affects the elderly population, exponentially increasing in incidence with increasing age. Venous thromboembolism is not only a singular event but a chronic disease and has been found to have a rate of recurrence approaching 40% among all patients after 10 years. Whether symptomatic or asymptomatic, once thromboembolism is suspected, objective methods are required for the accurate and confirmatory presence of a thrombus with imaging as the next step in the diagnostic algorithm. Imaging also allows for the determination of the extent of clot burden, clot propagation, occlusive versus nonocclusive thrombus, acute versus chronic thrombus, or in some cases thrombus recurrence versus thrombophlebitis. Vena caval filter placement is, in some instances, required to prevent a significant subsequent VTE event. Placement of these therapeutic devices paradoxically promotes thrombus formation, and other sequelae may arise from the placement of inferior vena cava filters. In this article, the authors provide an overview of available techniques for imaging the vena cava with or without a filter and discuss advantages and drawbacks for each. PMID- 27247482 TI - Providing Context: Medical Device Litigation and Inferior Vena Cava Filters. AB - Over the last few years, an increasing number of lawsuits have been filed involving inferior vena cava filters. This has prompted the U.S. Judicial Panel on Multidistrict Litigation to centralize these lawsuits into two multidistrict litigations: one for Cook's filters and one for Bard's. Both sets of cases share similar questions of facts, in particular whether these filters' design and manufacturing practices made them unreasonably prone to serious complications. The resolution of these cases will add to a larger legal debate concerning how much legal protection the 1976 Medical Device Amendments should offer firms from tort liability. As a specialty that often relies on medical devices, it is not only important for interventional radiologists to have a general understanding of medical device litigation but also to reflect upon the approaches to informed consent regarding these devices. PMID- 27247481 TI - Update on Anticoagulation: What the Interventional Radiologist Needs to Know. AB - The novel oral anticoagulants (NOACs) represent a major advance in the treatment of patients with nonvalvular atrial fibrillation and venous thromboembolism (VTE). They have several advantages over vitamin-K antagonists such as warfarin, including more predictable pharmacokinetics and improved safety, particularly with fatal bleeding and intracranial hemorrhage. However, several issues remain surrounding the use of NOACs in certain subpopulations and with the approach to reversal. The periprocedural management of anticoagulation with these relatively new agents can also present several challenges. This article reviews the basic pharmacology, efficacy, and safety of these drugs. Several populations at higher risk for complications with use of NOACs are discussed, including those undergoing procedures. Finally, several target-specific reversal agents have either received FDA approval or likely will be approved in the near future; these agents and their roles in the approach to anticoagulation reversal will also be discussed. PMID- 27247483 TI - Creation of an iOS and Android Mobile Application for Inferior Vena Cava (IVC) Filters: A Powerful Tool to Optimize Care of Patients with IVC Filters. AB - Owing to a myriad of inferior vena cava (IVC) filter types and their potential complications, rapid and correct identification may be challenging when encountered on routine imaging. The authors aimed to develop an interactive mobile application that allows recognition of all IVC filters and related complications, to optimize the care of patients with indwelling IVC filters. The FDA Premarket Notification Database was queried from 1980 to 2014 to identify all IVC filter types in the United States. An electronic search was then performed on MEDLINE and the FDA MAUDE database to identify all reported complications associated with each device. High-resolution photos were taken of each filter type and corresponding computed tomographic and fluoroscopic images were obtained from an institutional review board-approved IVC filter registry. A wireframe and storyboard were created, and software was developed using HTML5/CSS compliant code. The software was deployed using PhoneGap (Adobe, San Jose, CA), and the prototype was tested and refined. Twenty-three IVC filter types were identified for inclusion. Safety data from FDA MAUDE and 72 relevant peer-reviewed studies were acquired, and complication rates for each filter type were highlighted in the application. Digital photos, fluoroscopic images, and CT DICOM files were seamlessly incorporated. All data were succinctly organized electronically, and the software was successfully deployed into Android (Google, Mountain View, CA) and iOS (Apple, Cupertino, CA) platforms. A powerful electronic mobile application was successfully created to allow rapid identification of all IVC filter types and related complications. This application may be used to optimize the care of patients with IVC filters. PMID- 27247484 TI - Retrieval of Inferior Vena Cava Filters: Technical Considerations. AB - Placement of retrievable inferior vena cava filters has seen rapid growth since their introduction into clinical practice. When retrieved, these devices offer the notional benefit of temporary protection from pulmonary embolism related to lower extremity deep venous thrombosis, and mitigation of filter-related deep venous thrombosis. When promptly removed after the indication for mechanical prophylaxis is no longer present, standard endovascular retrieval techniques are frequently successful. However, the majority of these devices are left in place for extended periods of time, which has been associated with greater device related complications when left in situ, and failure of standard techniques when retrieval is attempted. The development of advanced retrieval techniques has had a positive impact on retrieval of these embedded devices. In this article, technical considerations in the retrieval of such devices, with an emphasis on advanced techniques to facilitate retrieval of embedded devices, are discussed. PMID- 27247485 TI - Extraordinary Cases in Inferior Vena Cava Filter Retrieval. PMID- 27247486 TI - Embolization of High-Flow Arteriovenous Malformation. PMID- 27247487 TI - The Interactive Relationship between Pain, Psychosis, and Agitation in People with Dementia: Results from a Cluster-Randomised Clinical Trial. AB - Background. Neuropsychiatric symptoms are common in people with dementia, and pain is thought to be an important underlying factor. Pain has previously been associated with agitation, and pain treatment has been shown to ameliorate agitated behaviour. So far, the association between pain and psychosis and the effect of pain treatment on psychotic symptoms is unclear. Furthermore, the impact of opioid treatment on psychosis is not established. Aim. To investigate the efficacy of a stepwise protocol for treating pain (SPTP) on psychosis and agitation measured with the Neuropsychiatric Inventory, Nursing Home version, and to explore the impact of opioid analgesics on psychosis. Method. Secondary analyses are from a cluster-randomised controlled trial including 352 patients with advanced dementia and agitation from 18 nursing homes in Western Norway. The intervention group received pain treatment according to SPTP. Results. Pain was associated with disinhibition (adjusted OR: 1.21, 95% CI: 1.10-1.34) and irritability (adjusted OR: 1.10, 95% CI: 1.01-1.21) at baseline. Pain treatment reduced agitation (p < 0.001, df = 1; 300) and aberrant motor behaviour (p = 0.017, df = 1; 300). Psychosis was reduced in people with at least one symptom at baseline (p = 0.034, df = 1; 135). The use of opioid analgesics did not increase psychotic symptoms. Study Registration. This trial is registered with ClinicalTrials.gov (NCT01021696), Norwegian Medicines Agency, EudraCT (EudraCTnr: 2008-007490-20). PMID- 27247488 TI - Epstein-Barr Virus-Induced Gene 3 (EBI3) Blocking Leads to Induce Antitumor Cytotoxic T Lymphocyte Response and Suppress Tumor Growth in Colorectal Cancer by Bidirectional Reciprocal-Regulation STAT3 Signaling Pathway. AB - Epstein-Barr virus-induced gene 3 (EBI3) is a member of the interleukin-12 (IL 12) family structural subunit and can form a heterodimer with IL-27p28 and IL 12p35 subunit to build IL-27 and IL-35, respectively. However, IL-27 stimulates whereas IL-35 inhibits antitumor T cell responses. To date, little is known about the role of EBI3 in tumor microenvironment. In this study, firstly we assessed EBI3, IL-27p28, IL-12p35, gp130, and p-STAT3 expression with clinicopathological parameters of colorectal cancer (CRC) tissues; then we evaluated the antitumor T cell responses and tumor growth with a EBI3 blocking peptide. We found that elevated EBI3 may be associated with IL-12p35, gp130, and p-STAT3 to promote CRC progression. EBI3 blocking peptide promoted antitumor cytotoxic T lymphocyte (CTL) response by inducing Granzyme B, IFN-gamma production, and p-STAT3 expression and inhibited CRC cell proliferation and tumor growth to associate with suppressing gp130 and p-STAT3 expression. Taken together, these results suggest that EBI3 may mediate a bidirectional reciprocal-regulation STAT3 signaling pathway to assist the tumor escape immune surveillance in CRC. PMID- 27247489 TI - A Study of Core Humanistic Competency for Developing Humanism Education for Medical Students. AB - The authors conducted a survey on essential humanistic competency that medical students should have, and on teaching methods that will effectively develop such attributes. The participants consisted of 154 medical school professors, 589 medical students at Seoul National University College of Medicine, 228 parents, and 161 medical school and university hospital staff. They answered nine questions that the authors created. According to the results, all groups chose "morality and a sense of ethics," a "sense of accountability," "communication skills," and "empathic ability" were selected as essential qualities. According to the evaluation on the extent to which students possess each quality, participants believed students had a high "sense of accountability" and "morality," whereas they thought students had low "empathic ability," "communicate," or "collaborate with others". In terms of effective teaching methods, all sub-groups preferred extracurricular activities including small group activities, debates, and volunteer services. With regard to the speculated effect of humanism education and the awareness of the need for colleges to offer it, all sub-groups had a positive response. However the professors and students expressed a relatively passive stance on introducing humanism education as a credited course. Most participants responded that they preferred a grading method based on their rate of participation, not a relative evaluation. In order to reap more comprehensive and lasting effects of humanism education courses in medical school, it is necessary to conduct faculty training, and continuously strive to develop new teaching methods. PMID- 27247490 TI - Silencing of ABCG2 by MicroRNA-3163 Inhibits Multidrug Resistance in Retinoblastoma Cancer Stem Cells. AB - To investigate the function and regulation mechanism of ATP-binding cassette, subfamily G, member 2 (ABCG2) in retinoblastoma cancer stem cells (RCSCs), a long term culture of RCSCs from WERI-Rb1 cell line was successfully established based on the high expression level of ABCG2 on the surface of RCSCs. To further explore the molecular mechanism of ABCG2 on RCSCs, a microRNA that specifically targets ABCG2 was predicted. Subsequently, miR-3163 was selected and confirmed as the ABCG2-regulating microRNA. Overexpression of miR-3163 led to a significant decrease in ABCG2 expression. Additionally, ABCG2 loss-of-function induced anti proliferation and apoptosis-promoting functions in RCSCs, and multidrug resistance to cisplatin, carboplatin, vincristine, doxorubicin, and etoposide was greatly improved in these cells. Our data suggest that miR-3163 has a significant impact on ABCG2 expression and can influence proliferation, apoptosis, and drug resistance in RCSCs. This work may provide new therapeutic targets for retinoblastoma. PMID- 27247491 TI - Maternal Stress and Depressive Symptoms and Infant Development at Six Months: the Mothers and Children's Environmental Health (MOCEH) Prospective Study. AB - Our objective is to evaluate the relationships between prenatal maternal stress and depressive symptoms, respectively, and infant neurodevelopment at 6 months, adjusted for heavy metals and oxidative stress. This research is a part of a multi-center birth cohort study in South Korea. Information on stress and depressive symptoms was collected during the first trimester using Psychosocial Well-Being Index Short Form (PWI-SF) and Center for Epidemiological Studies Depression Scale (CES-D). The Korean Bayley Scales of Infant Development-II assessment (BSID-II), which includes the standardized mental development index (MDI) and psychomotor developmental index (PDI), and Korean Ages & Stages Questionnaires (K-ASQ) were applied to infants at six months of age. A higher index score indicates better development. Among 641 babies, 320 were female (50%). Maternal PWI >= 29 (vs. PWI <= 18) during early pregnancy was associated with a decrease in MDI scores of 5.37 points (P = 0.02) after adjusting for socioeconomic factors. Maternal CES-D >= 26 (vs. CES-D <= 10) during early pregnancy was associated with a decrease in MDI scores of 8.18 points (P = 0.01). The associations remained significant even after adjustment for lead, cadmium, and MDA levels (P < 0.05). However, no association was found between maternal PWI/CES-D and PDI score. No interaction was observed between stress and lead exposure. We found an inverse association between prenatal maternal stress and depressive symptoms, and MDI scores in 6-month-old infants after adjustment for prenatal lead exposure, which is known to affect cognitive function negatively. PMID- 27247492 TI - Physical Activity and Blood Lead Concentration in Korea: Study Using the Korea National Health and Nutrition Examination Survey (2008-2013). AB - Physical activity normally has a positive influence on health, however it can be detrimental in the presence of air pollution. Lead, a heavy metal with established adverse health effects, is a major air pollutant. We evaluated the correlation between blood lead concentration and physical activity using data collected from the Korea National Health and Nutrition Examination Survey. Multivariate logistic regression analysis was performed after dividing participants according to whether they were in the top 25% in the distribution of blood lead concentration (i.e., >= 2.76 ug/dL), with physical activity level as an independent variable and adjusting for factors such as age, sex, drinking, smoking, body mass index, region, and occupation. The high physical activity group had greater odds of having a blood lead concentration higher than 2.76 ug/dL (odds ratio 1.29, 95% CI 1.11-1.51) compared to the low physical activity group. Furthermore, blood lead concentration is correlated with increasing physical activity. PMID- 27247493 TI - One-Year Experience Managing a Cancer Survivorship Clinic Using a Shared-Care Model for Gastric Cancer Survivors in Korea. AB - Given the rapid growth of the population of cancer survivors, increased attention has been paid to their health problems. Although gastric cancer is one of the most common cancers, empirical evidence of survivorship care is limited. The objectives of this study were to describe the health care status of gastric cancer survivors and to report the experience of using the shared-care model during a one-year experience at the cancer survivorship clinic in Seoul National University Hospital. This is a descriptive, single-center study of 250 long-term gastric cancer survivors who were referred to the survivorship clinic. The status of their health behaviors, comorbid conditions, secondary cancer screenings, and survivorship care status were investigated through questionnaires and examining the medical records. Among the survivors, 7.2% were current smokers, 8.8% were at risk drinkers, and 32.4% were physically inactive. Among the patients who did not know their bone density status, the majority were in the osteopenic (37.1%) or osteoporotic range (24.1%). Screening among the eligible population within the recommended time intervals were 76.3% for colorectal cancer, but only 13.6% for lung cancer. All of the survivors were provided with counseling and medical management at the survivorship clinic, as appropriate. In conclusion, Long-term gastric cancer survivors have various unmet needs. Shared-care through survivorship clinics can be an effective solution for providing comprehensive care to cancer survivors. PMID- 27247494 TI - Mixed Carcinoma as an Independent Prognostic Factor in Submucosal Invasive Gastric Carcinoma. AB - Mixed carcinoma shows a mixture of glandular and signet ring/poorly cohesive cellular histological components and the prognostic significance of each component is not fully understood. This study aimed to investigate the significance of the poorly cohesive cellular histological component as a risk factor for lymph node metastasis and to examine the diagnostic reliability of endoscopic biopsy. Clinicopathologic characteristics of 202 patients who underwent submucosal invasive gastric carcinoma resection with lymph node dissection in 2005-2012 were reviewed. Mixed carcinoma accounted for 27.2% (56/202) of cases. The overall prevalence of lymph node metastasis was 17.3% (35/202). Lymphatic invasion (P < 0.001), family history of carcinoma (P = 0.025), tumor size (P = 0.004), Lauren classification (P = 0.042), and presence of any poorly cohesive cellular histological component (P = 0.021) positively correlated with the lymph node metastasis rate on univariate analysis. Multivariate analyses revealed lymphatic invasion, family history of any carcinoma, and the presence of any poorly cohesive cellular histological component to be significant and independent factors related to lymph node metastasis. Review of preoperative biopsy slides showed that preoperative biopsy demonstrated a sensitivity of 63.6% and a specificity of 100% in detecting the presence of the poorly cohesive cellular histological component, compared with gastrectomy specimens. The presence of any poorly cohesive cellular histological component was an independent risk factor associated with lymph node metastasis in submucosal invasive gastric carcinoma. Endoscopic biopsy had limited value in predicting the presence and proportion of the poorly cohesive cellular histologic component due to the heterogeneity of mixed carcinoma. PMID- 27247495 TI - Clinicopathologic Similarities of the Main and Minor Lesions of Synchronous Multiple Early Gastric Cancer. AB - The detection rate of early gastric cancer (EGC) is increasing due to improvements in diagnostic methods, but synchronous multiple EGC (SMEGC) remains a major problem. Therefore, we investigated the characteristics of and the correlation between the main and minor lesions of SMEGC. We retrospectively reviewed the medical records of patients with EGC between April 2008 and May 2013. The main lesion was defined as the one with the greatest invasion depth. If lesions had the same invasion depth, the tumor diameter was used to define the main lesion. Of 963 patients who had treatment for EGC, 37 patients with SMEGC were analyzed. The main and minor lesions showed a significant positive correlation of size (r = 0.533, P = 0.001). The main and minor lesions of SMEGC showed the same vertical and horizontal locations at 70.3% and 64.9%, respectively (P = 0.002 and P = 0.002). Macroscopic types were identical in 67.6% (P < 0.001), and 32.4% had identical macroscopic type and location. The main and minor lesions had identical characteristics of invasion depth, presence of lymphovascular invasion (LVI), and differentiation in 78.4%, 83.8%, and 83.8%, respectively. Differentiation, LVI, and invasion depth (microscopic characteristics) were simultaneously the same in 62.2%. The location, macroscopic type, and 3 microscopic characteristics were matched in 27%. The main and minor lesions of SMEGC have similar clinicopathologic characteristics. Therefore, the possibility of SMEGC should not be neglected in cases of EGC, considering an understanding of the characteristics and association of lesions. PMID- 27247496 TI - Orai1 Expression Is Closely Related with Favorable Prognostic Factors in Clear Cell Renal Cell Carcinoma. AB - Store-operated calcium (Ca(2+)) entry (SOCE) is the principal Ca(2+) entry route in non-excitable cells, including cancer cells. We previously demonstrated that Orai1 and STIM1, the molecular components of SOCE, are involved in tumorigenesis of clear cell renal cell carcinoma (CCRCC). However, a clinical relevance of Orai1 and STIM1 expression in CCRCC has been ill-defined. Here, we investigated the expression of Orai1 and STIM1 in CCRCC, and compared their expression with clinico-pathological parameters of CCRCC and the patients' outcome. Immunohistochemical staining for Orai1 and STIM1 was performed on 126 formalin fixed paraffin embedded tissue of CCRCC and western blot analysis for Orai1 was performed on the available fresh tissue. The results were compared with generally well-established clinicopathologic prognostic factors in CCRCC and patient survival. Membrane protein Orai1 is expressed in the nuclei in CCRCC, whereas STIM1 shows the cytosolic expression pattern in immunohistochemical staining. Orai1 expression level is inversely correlated with CCRCC tumor grade, whereas STIM1 expression level is not associated with tumor grade. The higher Orai1 expression is significantly associated with lower Fuhrman nuclear grade, pathologic T stage, and TNM stage and with favorable prognosis. The expression level of STIM1 is not correlated with CCRCC grade and clinical outcomes. Orai1 expression in CCRCC is associated with tumor progression and with favorable prognostic factors. These results suggest that Orai1 is an attractive prognostic marker and therapeutic target for CCRCC. PMID- 27247497 TI - Being Overweight or Obese Increases the Risk of Progression in Triple-Negative Breast Cancer after Surgical Resection. AB - This study aimed to evaluate the association between body mass index (BMI) and progression in triple-negative breast cancer (TNBC). We retrospectively reviewed the medical records of 50 patients with TNBC who underwent breast-conserving surgery or mastectomy between 2007 and 2014. All patients were classified according to BMI (median 23.5 kg/m(2), range 17.2-31.6 kg/m(2)): 31 patients (62%) were classified as being overweight or obese (BMI >= 23 kg/m(2)) and 19 patients (38%) were classified as having a normal body weight (BMI < 23 kg/m(2)). The median follow-up for patients was 31.1 months (range, 6.7-101.9 months). Progression occurred in 7 patients (14%), including 5 ipsilateral breast tumor recurrences, 2 regional lymph node metastases, and 5 distant metastases. Progression was significantly correlated with overweight or obese patients (P = 0.035), while none of the normal weight patients showed progression. The 3-year disease-free survival (DFS) and overall survival (OS) rates were 85.0% and 87.7%, respectively. DFS was significantly reduced in overweight or obese patients compared to that in normal weight patients (P = 0.035). However, OS was not significantly compromised by being overweight or obese (P = 0.134). In conclusion, being overweight or obese negatively affects DFS in TNBC patients. PMID- 27247498 TI - Cancer Mortality Projections in Korea up to 2032. AB - Predicting cancer mortality is important to estimate the needs of cancer-related services and to prevent cancer. Despite its significance, a long-term future projection of cancer mortality has not been conducted; therefore, our objective was to estimate future cancer mortality in Korea by cancer site through 2032. The specially designed Nordpred software was used to estimate cancer mortality. The cancer death data from 1983 to 2012 and the population projection data from 1983 to 2032 were obtained from the Korean National Statistics Office. Based on our analysis, age-standardized rates with the world standard population of all cancer deaths were estimated to decline from 2008-2012 to 2028-2032 (men: -39.8%, women: -33.1%). However, the crude rates are predicted to rise (men: 29.8%, women: 24.4%), and the overall number of the cancer deaths is also estimated to increase (men: 35.5%, women: 32.3%). Several cancer deaths are projected to increase (lung, liver and gallbladder, colon and rectum, pancreas and leukemia in both sexes; prostate cancer in men; and breast and ovarian cancer in women), whereas other cancer deaths are expected to decrease (stomach, esophagus and larynx in both sexes and cervical cancer in women). The largest contribution to increasing cancer deaths is due to the aging of the Korean population. In conclusion, a strategy for primary prevention, early detection, and early treatment to cope with the rapidly increasing death of cancer due to population aging is urgently required. PMID- 27247499 TI - Role of Coronary Artery Calcium Scoring in Detection of Coronary Artery Disease according to Framingham Risk Score in Populations with Low to Intermediate Risks. AB - Current guidelines recommend that coronary artery calcium (CAC) screening should only be used for intermediate risk groups (Framingham risk score [FRS] of 10% 20%). The CAC distributions and coronary artery disease (CAD) prevalence in various FRS strata were determined. The benefit to lower risk populations of CAC score-based screening was also assessed. In total, 1,854 participants (aged 40-79 years) without history of CAD, stroke, or diabetes were enrolled. CAC scores of > 0, >= 100, and >= 300 were present in 33.8%, 8.2%, and 2.9% of the participants, respectively. The CAC scores rose significantly as the FRS grew more severe (P < 0.01). The total CAD prevalence was 6.1%. The occult CAD prevalence in the FRS <= 5%, 6%-10%, 11%-20%, and > 20% strata were 3.4%, 6.7%, 9.0%, and 11.6% (P < 0.001). In multivariate logistic regression analysis adjusting, not only the intermediate and high risk groups but also the low risk (FRS 6%-10%) group had significantly increased odds ratio for occult CAD compared to the very low-risk (FRS <= 5%) group (1.89 [95% confidence interval, CI, 1.09-3.29] in FRS 6%-10%; 2.48 [95% CI, 1.47-4.20] in FRS 11%-20%; and 3.10 [95% CI, 1.75-5.47] in FRS > 20%; P < 0.05). In conclusion, the yield of screening for significant CAC and occult CAD is low in the very low risk population but it rises in low and intermediate risk populations. PMID- 27247500 TI - The Natural Course of Biopsy-Proven Isolated Microscopic Hematuria: a Single Center Experience of 350 Patients. AB - The increasing interest in healthcare and health screening events is revealing additional cases of asymptomatic isolated microscopic hematuria (IMH). However, a consensus of the evaluation and explanation of the IMH prognosis is controversial among physicians. Here, we present the natural course of IMH together with the pathological diagnosis and features to provide supportive data when approaching patients with IMH. We retrospectively evaluated 350 patients with IMH who underwent a renal biopsy between 2002 and 2011, and the pathological diagnosis and chronic histopathological features (glomerulosclerosis, interstitial fibrosis, and tubular atrophy) were reviewed. Deterioration of renal function was examined during follow up. The patients with IMH were evaluated for a mean of 86 months. IgA nephropathy was the most common diagnosis in 164 patients (46.9%). Chronic histopathological changes were observed in 166 (47.4%) but was not correlated with proteinuria or a decline in renal function. Ten patients developed proteinuria, and all of them had IgA nephropathy. Three patients progressed to chronic kidney disease with an estimated glomerular filtration rate < 60 mL/min/1.73 m(2) but none progressed to end stage renal disease. In conclusion, IMH had a generally benign course during 7-years of observation, although IgA nephropathy should be monitored if it progresses to proteinuria. Future prospective randomized studies may help conclude the long-term prognosis and lead to a consensus for managing IMH. PMID- 27247501 TI - Prevalence of Chronic Kidney Disease in Korea: the Korean National Health and Nutritional Examination Survey 2011-2013. AB - Chronic kidney disease is a leading public health problem related to poor quality of life and premature death. As a resource for evidence-informed health policy making, we evaluated the prevalence of chronic kidney disease using the data of non-institutionalized adults aged >= 20 years (n = 15,319) from the Korean National Health and Nutrition Examination Survey in 2011-2013. Chronic kidney disease was defined as a urine albumin-to-creatinine ratio >= 30 mg/g or an estimated glomerular filtration rate < 60 mL/min/1.73 m(2) using the Chronic Kidney Disease-Epidemiology Collaboration equation. The total prevalence estimate of chronic kidney disease for adults aged >= 20 years in Korea was 8.2%. By disease stage, the prevalence of chronic kidney disease was as follows: stage 1, 3.0%; stage 2, 2.7%; stage 3a, 1.9%; stage 3b, 0.4%; and stages 4-5, 0.2%. When grouped into three risk categories according to the 2012 Kidney Disease: Improving Global Outcomes guidelines, the proportions for the moderately increased risk, high risk, and very high risk categories were 6.5%, 1.2%, and 0.5%, respectively. Factors including older age, diabetes, hypertension, cardiovascular disease, body mass indexes of >= 25 kg/m(2) and < 18.5 kg/m(2), and rural residential area were independently associated with chronic kidney disease. Based on this comprehensive analysis, evidence-based screening strategies for chronic kidney disease in the Korean population should be developed to optimize prevention and early intervention of chronic kidney disease and its associated risk factors. PMID- 27247502 TI - Serum Chemerin Levels Are Associated with Abdominal Visceral Fat in Type 2 Diabetes. AB - Chemerin is a recently identified adipokine suggested to play a role in obesity and its metabolic complications. The relationship between visceral obesity and serum chemerin levels in type 2 diabetes (T2DM) is unknown and may differ from that of subjects without diabetes. Therefore, we evaluated whether serum chemerin was associated with visceral abdominal obesity in patients with T2DM. A total of 218 Korean patients with T2DM were enrolled and metabolic parameters, abdominal visceral and subcutaneous fat areas, and serum chemerin levels were measured. Serum chemerin level showed positive correlation with fasting insulin, HOMA-IR, serum triglyceride, serum creatinine, urine albumin/creatinine ratio, high sensitivity C-reactive protein (hsCRP), fibrinogen, abdominal visceral fat area, visceral to subcutaneous fat area ratio, and negatively correlation with high density lipoprotein cholesterol and creatinine clearance (CCr) after adjusting for age, gender and body mass index. Multiple linear stepwise regression analysis showed that abdominal visceral fat area (beta = 0.001, P < 0.001), serum triglyceride (beta = 0.001, P < 0.001), CCr (beta = -0.003, P = 0.001), hsCRP (beta = 0.157, P = 0.001), fibrinogen (beta = 0.001, P < 0.001) and BMI (beta = 0.02, P = 0.008) independently affected log transformed serum chemerin levels. Higher serum chemerin level was associated with higher level of abdominal visceral fat area, serum triglyceride, hsCRP and fibrinogen and lower level of CCr in patients with T2DM. Serum chemerin may be used as a biomarker of visceral adiposity and chemerin may play a role in inflammation, decreased renal function, and increased cardiovascular risk in T2DM. PMID- 27247503 TI - Validity of Outcome Prediction Scoring Systems in Korean Patients with Severe Adult Respiratory Distress Syndrome Receiving Extracorporeal Membrane Oxygenation Therapy. AB - Recently, several prognostic scoring systems for patients with severe acute respiratory distress syndrome (ARDS) requiring extracorporeal membrane oxygenation (ECMO) have been published. The aim of this study was to validate the established scoring systems for outcome prediction in Korean patients. We retrospectively reviewed the data of 50 patients on ECMO therapy in our center from 2012 to 2014. A calculation of outcome prediction scoring tools was performed and the comparison across various models was conducted. In our study, the overall hospital survival was 46% and successful weaning rate was 58%. The Predicting Death for Severe ARDS on V-V ECMO (PRESERVE) score showed good discrimination of mortality prediction for patients on ECMO with AUC of 0.80 (95% CI 0.66-0.90). The respiratory extracorporeal membrane oxygenation survival prediction (RESP) score and simplified acute physiology score (SAPS) II score also showed fair prediction ability with AUC of 0.79 (95% CI 0.65-0.89) and AUC of 0.78 (95% CI 0.64-0.88), respectively. However, the ECMOnet score failed to predict mortality with AUC of 0.51 (95% CI 0.37-0.66). When evaluating the predictive accuracy according to optimal cut-off point of each scoring system, RESP score had a best specificity of 91.3% and 66.7% of sensitivity, respectively. This study supports the clinical usefulness of the prognostic scoring tools for severe ARDS with ECMO therapy when applying to the Korean patients receiving ECMO. PMID- 27247504 TI - Percentile Distributions of Birth Weight according to Gestational Ages in Korea (2010-2012). AB - The Pediatric Growth Chart (2007) is used as a standard reference to evaluate weight and height percentiles of Korean children and adolescents. Although several previous studies provided a useful reference range of newborn birth weight (BW) by gestational age (GA), the BW reference analyzed by sex and plurality is not currently available. Therefore, we aimed to establish a national reference range of neonatal BW percentiles considering GA, sex, and plurality of newborns in Korea. The raw data of all newborns (470,171 in 2010, 471,265 in 2011, and 484,550 in 2012) were analyzed. Using the Korean Statistical Information Service data (2010-2012), smoothed percentile curves (3(rd)-97(th)) by GA were created using the lambda-mu-sigma method after exclusion and the data were distinguished by all live births, singleton births, and multiple births. In the entire cohort, male newborns were heavier than female newborns and singletons were heavier than twins. As GA increased, the difference in BW between singleton and multiples increased. Compared to the previous data published 10 years ago in Korea, the BW of newborns 22-23 gestational weeks old was increased, whereas that of others was smaller. Other countries' data were also compared and showed differences in BW of both singleton and multiple newborns. We expect this updated data to be utilized as a reference to improve clinical assessments of newborn growth. PMID- 27247505 TI - Impact of IgM Antibodies on Cross-Protection against Pneumococcal Serogroups 6 and 19 after Immunization with 7-Valent Pneumococcal Conjugate Vaccine in Children. AB - Although it is well known that pneumococcal conjugate vaccines provide cross protection against some vaccine-related serotypes, these mechanisms are still unclear. This study was performed to investigate the role of cross-protective IgM antibodies against vaccine-related serotypes 6A, 6C, and 19A induced in children aged 12-23 months after immunization with 7-valent pneumococcal conjugate vaccine (PCV7). We obtained serum samples from 18 Korean children aged 12-23 months after a PCV7 booster immunization. The serum IgG and IgM concentrations of serotypes 6B and 19F were measured by enzyme-linked immunosorbent assay (ELISA) in serum. The opsonic indices (OIs) against vaccine serotypes 6B and 19F and vaccine-related serotypes 6A, 6C, and 19A were determined by an opsonophagocytic killing assay (OPA) in IgM-depleted and control serum. Both IgG and IgM antibodies in ELISA and opsonic indices in OPA against serotypes 6B and 19F were demonstrated in the immune serum. IgM depletion decreased the OIs against vaccine serotypes 6B (geometric means of OIs (GMIs) of 3,009 vs. 1,396, 38% reduction) and 19F (1,117 vs. 750, 36% reduction). In addition, IgM depletion markedly decreased the OIs against vaccine-related serotypes 6A (GMIs of 961 vs. 329, 70% reduction), 6C (432 vs. 185, 72% reduction), and 19A (301 vs. 166, 58% reduction). The booster immunization PCV7 induced protective antibodies in the form of both IgG and IgM isotypes. IgM antibodies contributed to eliciting cross-protection against vaccine-related serotypes as well as against vaccine serotypes. PMID- 27247507 TI - Cataract and Cataract Surgery: Nationwide Prevalence and Clinical Determinants. AB - This study aimed to investigate the prevalence and clinical determinants of cataract and cataract surgery in Korean population. The 2008-2012 Korean National Health and Nutrition Examination Survey was analyzed, which included 20,419 participants aged >= 40 years. The survey is a multistage, probability-cluster survey, which can produce nationally representative estimates. Prevalence of cataract and cataract surgery was estimated. Clinical determinants for those were investigated using logistic regression analyses (LRAs). The prevalence of cataract was 42.28% (95% confidence interval [CI], 40.67-43.89); 40.82% (95% CI, 38.97-42.66) for men and 43.62% (95% CI, 41.91-45.33) for women (P = 0.606). The prevalence of cataract surgery was 7.75% (95% CI, 7.30-8.20); 6.38% (95% CI, 5.80 6.96) for men and 9.01% (95% CI, 8.41-9.61) for women (P < 0.001). Cataract was associated with older age (P < 0.001), men (P = 0.032), lower household income (P = 0.031), lower education (P < 0.001), hypertension (P < 0.001), and diabetes mellitus (DM) (P < 0.001). Cataract surgery was consistently associated with older age, occupation, DM, asthma, and anemia in two LRAs, which compared participants with cataract surgery to those without cataract surgery and those having a cataract but without any cataract surgery, respectively. Hypertension, arthritis, and dyslipidemia were associated with cataract surgery at least in one of these LRAs. These results suggest that there are 9.4 million individuals with cataract and 1.7 million individuals with cataract surgery in Korea. Further studies are warranted to reveal the causality and its possible mechanism of developing/exacerbating cataract in novel determinants (i.e., anemia, asthma, and arthritic conditions) as well as well-known determinants. PMID- 27247506 TI - Radical Prostatectomy in Korean Men Aged 75-Years or Older: Safety and Efficacy in Comparison with Patients Aged 65-69 Years. AB - Prostate cancer is the most common type of male cancer worldwide. Although radical prostatectomy (RP) is advised for prostate cancer in patients with a life expectancy of more than 10 years by various guidelines, most elderly men still do not undergo the procedure regardless of increasing life expectancy. This study aimed to determine whether RP is suitable for patients with prostate cancer aged 75 years or older. A retrospective study of patients who underwent RP at 6 institutions between 2005 and 2012 was conducted. Patients were divided into 2 groups at the time of surgery: 65-69 years (younger group) and 75 years or older (older group). We compared clinical characteristics, pathological results, complication rates, and recurrence-free survival between the two groups. Compared with the younger group, the older group had significantly higher preoperative serum prostate-specific antigen level, pre- and postoperative Eastern Cooperative Oncology Group (ECOG) performance status grade, hypertension prevalence, and Gleason score at biopsy and RP. However, except urinary incontinence, there were no statistically significant differences in the peri- and post-operative complications. After median follow-up periods of 36 months (younger group) and 40 months (older group), the biochemical recurrence-free survival rates were not significantly different (P = 0.581). Although the urinary incontinence rate was higher in the older group, RP was a suitable option for selected Korean men aged 75 years or older with limited complication rates and excellent outcomes similar to those for patients aged 65-69 years. PMID- 27247508 TI - Bone Mineral Density and Prevalence of Osteoporosis in Postmenopausal Korean Women with Low-Energy Distal Radius Fractures. AB - The aim of this study was to evaluate the bone mineral density and the prevalence of osteoporosis in postmenopausal Korean women with low-energy distal radius fractures and compared with those of aged-matched normal Korean women. Two hundred and six patients with distal radius fractures between March 2006 and March 2010 were included in this study. Patients were divided into three groups by age; group 1 (50-59 years), group 2 (60-69 years), and group 3 (70-79 years). Controls were age-matched normal Korean women. The bone mineral density values at all measured sites, except for the spine, were significantly lower in group 1 than those of control. While the bone mineral density values in group 2 and 3 were lower than those of controls, these differences were not statistically significant. All groups had significantly higher prevalence of osteoporosis at the Ward's triangle; however, at the spine, femoral neck and trochanteric area it was not significantly different from those of age-matched controls. Although the prevalence of osteoporosis of the postmenopausal women with low-energy distal radius fractures may not be higher than that of the control, osteoporosis should be evaluated especially in younger postmenopausal patients to prevent other osteoporotic hip and/or spine fractures. PMID- 27247509 TI - Management of Ventilatory Insufficiency in Neuromuscular Patients Using Mechanical Ventilator Supported by the Korean Government. AB - Since 2001, financial support has been provided for all patients with neuromuscular disease (NMD) who require ventilatory support due to the paralysis of respiratory muscles in Korea. The purpose of this study was to identify ventilator usage status and appropriateness in these patients. We included 992 subjects with rare and incurable NMD registered for ventilator rental fee support. From 21 February 2011 to 17 January 2013, ventilator usage information, regular follow-up observation, and symptoms of chronic hypoventilation were surveyed by phone. Home visits were conducted for patients judged by an expert medical team to require medical examination. Abnormal ventilatory status was assessed by respiratory evaluation. Chronic respiratory insufficiency symptoms were reported by 169 of 992 subjects (17%), while 565 subjects (57%) did not receive regular respiratory evaluation. Ventilatory status was abnormal in 102 of 343 home-visit subjects (29.7%). Although 556 subjects (56%) reported 24-hour ventilator use, only 458 (46%) had an oxygen saturation monitoring device, and 305 (31%) performed an airstacking exercise. A management system that integrates ventilator usage monitoring, counselling and advice, and home visits for patients who receive ventilator support could improve the efficiency of the ventilator support project. PMID- 27247510 TI - Relaxin Receptor RXFP1 and RXFP2 Expression in Ligament, Tendon, and Shoulder Joint Capsule of Rats. AB - Numerous musculoskeletal disorders are caused by thickened ligament, tendon stiffness, or fibrosis of joint capsule. Relaxin, a peptide hormone, can exert collagenolytic effect on ligamentous and fibrotic tissues. We hypothesized that local injection of relaxin could be used to treat entrapment neuropathy and adhesive capsulitis. Because hormonal effect depends on the receptor of the hormone on the target cell, it is important to confirm the presence of such hormonal receptor at the target tissue before the hormone therapy is initiated. The aim of this study was to determine whether there were relaxin receptors in the ligament, tendon, and joint capsular tissues of rats and to identify the distribution of relaxin receptors in these tissues. Transverse carpal ligaments (TCLs), inguinal ligaments, anterior cruciate ligaments (ACLs), Achilles tendons, and shoulder joint capsules were obtained from male Wistar rats. Western blot analysis was used to identify relaxin receptor isoforms RXFP1 and RXFP2. The distribution of relaxin receptors was determined by immunohistochemical staining. The RXFP1 isoform was found in all tissues examined. The RXFP2 isoform was present in all tissues but the TCLs. Its expression in ACLs tissues was relatively weak compared to that in other tissues. Our results revealed that RXFP1 and RXFP2 were distributed in distinctly different patterns according to the type of tissue (vascular endothelial cells, fibroblast-like cells) they were identified. PMID- 27247511 TI - Effects of Systemic Administration of Dexmedetomidine on Intraocular Pressure and Ocular Perfusion Pressure during Laparoscopic Surgery in a Steep Trendelenburg Position: Prospective, Randomized, Double-Blinded Study. AB - Increased intraocular pressure (IOP) during surgery is a risk factor for postoperative ophthalmological complications. We assessed the efficacy of systemically infused dexmedetomidine in preventing the increase in IOP caused by a steep Trendelenburg position, and evaluated the influence of underlying hypertension on IOP during surgery. Sixty patients undergoing laparoscopic surgery in a steep Trendelenburg position were included. Patients in the dexmedetomidine group received a 1.0 ug/kg IV loading dose of dexmedetomidine before anesthesia, followed by an infusion of 0.5 ug/kg/hr throughout the operation. Patients in the saline group were infused with the same volume of normal saline. IOP and ocular perfusion pressure (OPP) were measured 16 times pre and intraoperatively. In the saline group, IOP increased in the steep Trendelenburg position, and was 11.3 mmHg higher at the end of the time at the position compared with the baseline value (before anesthetic induction). This increase in IOP was attenuated in the dexmedetomidine group, for which IOP was only 4.2 mmHg higher (P < 0.001 vs. the saline group). The steep Trendelenburg position was associated with a decrease in OPP; the degree of decrease was comparable for both groups. In intragroup comparisons between patients with underlying hypertension and normotensive patients, the values of IOP at every time point were comparable. Dexmedetomidine infusion attenuated the increase in IOP during laparoscopic surgery in a steep Trendelenburg position, without further decreasing the OPP. Systemic hypertension did not seem to be associated with any additional increase in IOP during surgery. (Registration at the Clinical Research Information Service of Korea National Institute of Health ID: KCT0001482). PMID- 27247512 TI - Which Fingers Should We Perform Two-Finger Chest Compression Technique with When Performing Cardiopulmonary Resuscitation on an Infant in Cardiac Arrest? AB - This study compared the effectiveness two-finger chest compression technique (TFCC) performed using the right vs. left hand and the index-middle vs. middle ring fingers. Four different finger/hand combinations were tested randomly in 30 healthcare providers performing TFCC (Test 1: the right index-middle fingers; Test 2: the left index-middle fingers; Test 3: the right middle-ring fingers; Test 4: the left middle-ring fingers) using two cross-over trials. The "patient" was a 3-month-old-infant-sized manikin. Each experiment consisted of cardiopulmonary resuscitation (CPR) consisting of 2 minutes of 30:2 compression: ventilation performed by one rescuer on a manikin lying on the floor as if in cardiac arrest. Ventilations were performed using the mouth-to-mouth method. Compression and ventilation data were collected during the tests. The mean compression depth (MCD) was significantly greater in TFCC performed with the index-middle fingers than with the middle-ring fingers regardless of the hand (95% confidence intervals; right hand: 37.8-40.2 vs. 35.2-38.6 mm, P = 0.002; left hand: 36.9-39.2 vs. 35.5-38.1 mm, P = 0.003). A deeper MCD was achieved with the index-middle fingers of the right versus the left hand (P = 0.004). The ratio of sufficiently deep compressions showed the same patterns. There were no significant differences in the other data. The best performance of TFCC in simulated 30:2 compression: ventilation CPR performed by one rescuer on an infant in cardiac arrest lying on the floor was obtained using the index-middle fingers of the right hand. Clinical Trial Registry at the Clinical Research Information Service (KCT0001515). PMID- 27247513 TI - Multiple Endocrine Neoplasia Type 1 Presenting as Hypoglycemia due to Insulinoma. AB - Multiple endocrine neoplasia (MEN) mutation is an autosomal dominant disorder characterized by the occurrence of parathyroid, pancreatic islet, and anterior pituitary tumors. The incidence of insulinoma in MEN is relatively uncommon, and there have been a few cases of MEN manifested with insulinoma as the first symptom in children. We experienced a 9-year-old girl having a familial MEN1 mutation. She complained of dizziness, occasional palpitation, weakness, hunger, sweating, and generalized tonic-clonic seizure that lasted for 5 minutes early in the morning. At first, she was only diagnosed with insulinoma by abdominal magnetic resonance images of a 1.3 x 1.5 cm mass in the pancreas and high insulin levels in blood of the hepatic vein, but after her father was diagnosed with MEN1. We found she had familial MEN1 mutation, and she recovered hyperinsulinemic hypoglycemia after enucleation of the mass. Therefore, the early genetic identification of MEN1 mutation is considerable for children with at least one manifestation. PMID- 27247514 TI - Predictors of Silicone Tube Intubation Success in Patients with Lacrimal Drainage System Stenosis. AB - PURPOSE: To evaluate prognostic factors affecting silicone tube intubation outcomes in Asian patients with lacrimal drainage system stenosis. METHODS: A retrospective review was conducted on the medical records of 822 patients (1,118 eyes) who had undergone silicone tube intubation to treat lacrimal drainage system stenosis between January 2011 and December 2012. Patients were divided into two groups: a success group and a failure group. Success was defined as the disappearance of epiphora symptoms, normalization of tear meniscus height, and the easy passage of fluid without resistance on the postoperative syringing test. Patient and ocular parameters were compared between the success and failure groups. RESULTS: A total of 994 eyes of 727 patients were included in analyses. Patients had a mean follow-up period of 34.11 +/- 18.70 weeks. Silicone tube intubation was successful in 67.2% of participants. Significant differences between the success and failure groups were found for age (p < 0.001), history of ipsilateral facial palsy (p = 0.028), follow-up period (p < 0.001), and degree of passage on the preoperative syringing test (p = 0.001). Only age (p < 0.001) and degree of passage on the preoperative syringing test (p = 0.002) remained significantly associated with silicone tube intubation success in multivariate analysis. CONCLUSIONS: Age was negatively associated with silicone tube intubation success in patients with lacrimal drainage system stenosis. The success rate was higher in patients who showed easy passage of fluid without resistance on the preoperative syringing test. These factors should be considered by surgeons planning silicone tube intubation in patients with lacrimal drainage system stenosis. PMID- 27247515 TI - Angiogenin for the Diagnosis and Grading of Dry Eye Syndrome. AB - PURPOSE: To investigate the properties of angiogenin (ANG) as a potential tool for the diagnosis and grading of dry eye syndrome (DES) by analyzing tear protein profiles. METHODS: Tear samples were collected with capillary tubes from 52 DES patients and 29 normal individuals as controls. Tear protein profiles were analyzed with an immunodot blot assay as a screening test. To confirm that the tear ANG levels were in inverse proportion to the disease severity grade, the ANG and lactoferrin (LF) tear contents of normal controls and DES patients were compared in an enzyme-linked immunosorbent assay. RESULTS: In the immunodot blot assay, the ANG area was lower in patients with grades 3 and 4 DES than in normal controls. The areas of basic fibroblast growth factor, transforming growth factor beta2, and interleukin 10 were significantly greater than those of normal controls only in grade 4 DES patients, but these proteins were not linearly correlated with dry eye severity. Upon enzyme-linked immunosorbent assay analysis, the mean concentrations of ANG and LF decreased significantly as dry eye severity increased, except between grades 1 and 2. In addition, the ratios of ANG and LF to total tear proteins were correlated significantly with DES severity. CONCLUSIONS: ANG level was significantly lower in DES patients than in normal controls, and was significantly correlated with the worsening severity of DES, except between grades 1 and 2, as was LF. Therefore, ANG may be a useful measure of DES severity through proteomic analysis. PMID- 27247516 TI - Oxidative Stress Levels in Aqueous Humor from High Myopic Patients. AB - PURPOSE: To compare oxidative stress status in the aqueous humor of highly myopic eyes and control eyes. METHODS: Aqueous humor samples were collected from 15 highly myopic eyes (high myopia group) and 23 cataractous eyes (control group) during cataract surgery. Central corneal thickness, corneal endothelial cell density, hexagonality of corneal endothelial cells, and cell area of corneal endothelial cells were measured using specular microscopy. Axial length was measured using ultrasound biometry. 8-Hydroxydeoxyguanosine (8-OHdG) and malondialdehyde levels were measured using enzyme-linked immunosorbent assay. RESULTS: 8-OHdG level was lower in the aqueous humor of myopic patients than in that of control group (p = 0.014) and was positively correlated with central corneal thickness and negatively correlated with axial length (r = 0.511, p = 0.02; r = -0.382, p < 0.001). There was no correlation between 8-OHdG level and corneal endothelial cell density, hexagonality, or cell area. Malondialdehyde level did not show any correlation with any parameters evaluated. CONCLUSIONS: 8 OHdG might be a sensitive biomarker for evaluating oxidative stress status in the eye. Oxidative stress level was lower in the aqueous humor of highly myopic eyes compared to that in control eyes, which indicates lower metabolic activity in these eyes. PMID- 27247517 TI - Visual Outcomes, Patient Satisfaction and Spectacle Independence with a Trifocal Diffractive Intraocular Lens. AB - PURPOSE: To evaluate visual outcomes following implantation of a trifocal diffractive intraocular lens (IOL) and to analyze their correlation with patient satisfaction and ease of performing daily tasks. METHODS: This was a prospective study enrolling 100 eyes of 50 patients undergoing cataract surgery with implantation of trifocal IOL AT LISA tri 839MP. Visual and refractive outcomes were evaluated during a 3-month follow-up. Postoperatively, a questionnaire was used to evaluate patient satisfaction with regard to surgical outcome, spectacle independence, perception of photic phenomena, and ease of performing some vision related activities. RESULTS: A total of 91%, 87%, and 79% of eyes achieved a monocular uncorrected distance, near, and intermediate visual acuity of 0.1 logarithm of the minimum angle of resolution or better, respectively. After the surgery, 96% of the patients could perform their daily activities without problems. The mean spectacle independence scores for reading, doing computer work, and for distance were 10.33 +/- 12.47, 5.71 +/- 11.90, and 3.92 +/- 9.77, respectively (scale: 0 = no spectacles needed; 40 = spectacles always needed). No correlation was found between spectacle independence and visual outcome (-0.101 <= r <= 0.244, p >= 0.087). Mean scores (0 = no symptoms; 40 = strong symptoms) for glare at night, ghost images, and halos were 15.15 +/- 12.02, 4.49 +/- 7.92, and 13.34 +/- 10.82, respectively. No correlation was found between photic phenomena and visual outcome (-0.199 <= r <= 0.209, p >= 0.150). A total of 80% of patients reported satisfaction with the surgery outcome, and 86% would recommend the surgery to friends and family. CONCLUSIONS: Implantation of the AT LISA tri 839MP IOL after cataract surgery provides effective visual restoration associated with a minimal level of photic phenomena, a positive impact on the performance of vision-related daily activities, and a high level of postoperative patient satisfaction. PMID- 27247518 TI - Management of Acute Submacular Hemorrhage with Intravitreal Injection of Tenecteplase, Anti-vascular Endothelial Growth Factor and Gas. AB - PURPOSE: To evaluate the visual and anatomical outcomes for neovascular age related macular degeneration with submacular hemorrhage after intravitreal injections of tenecteplase (TNK), anti-vascular endothelial growth factor (VEGF) and expansile gas. METHODS: This study was a retrospective clinical case series following 25 eyes of 25 patients. All patients received a triple injection using 0.05 mL TNK (50 ug), 0.05 mL anti-VEGF and 0.3 mL of perfluoropropane gas. Retreatment with anti-VEGF was performed as needed. Preoperative and postoperative best-corrected visual acuity and central retinal thickness were analyzed. RESULTS: The mean logarithm of the minimum angle of resolution of best corrected visual acuity improved significantly from 1.09 +/- 0.77 at baseline to 0.52 +/- 0.60 at 12 months (p < 0.001). The mean central retinal thickness also improved significantly from 545 +/- 156 at baseline to 266 +/- 107 at 12 months (p < 0.001). A visual improvement of 0.3 logarithm of the minimum angle of resolution unit or more was achieved in 15 eyes (60%). During the 12 postoperative months, an average of 4.04 intravitreal anti-VEGF injections was applied. CONCLUSIONS: A triple injection of TNK, anti-VEGF, and a gas appears to be safe and effective for the treatment of submacular hemorrhage secondary to neovascular age-related macular degeneration. PMID- 27247519 TI - Optical Coherence Tomography-based Diagnosis of Polypoidal Choroidal Vasculopathy in Korean Patients. AB - PURPOSE: To evaluate the efficacy of an optical coherence tomography (OCT)-based diagnosis of polypoidal choroidal vasculopathy (PCV) in Korean patients. METHODS: This retrospective, observational case series included 263 eyes of 263 patients (147 eyes with PCV and 116 eyes with typical exudative, age-related macular degeneration [AMD]) who had been diagnosed with treatment naive exudative AMD. Eyes with three or more of the following OCT findings were diagnosed with PCV: multiple retinal pigment epithelial detachment (RPED), a sharp RPED peak, an RPED notch, a hyporeflective lumen representing polyps, and hyperreflective intraretinal hard exudates. The OCT-based diagnosis was compared with the gold standard indocyanine green angiography-based method. The sensitivity and specificity of the OCT-based diagnosis was also estimated. An additional analysis was performed using a choroidal thickness criterion. Eyes with a subfoveal choroidal thickness greater than 300 um were also diagnosed with PCV despite having only two OCT features. RESULTS: In eyes with PCV, three or more OCT features were observed in 126 of 147 eyes (85.7%), and the incidence of typical exudative AMD was 16 of 116 eyes (13.8%). The sensitivity and specificity of an OCT-based diagnosis were 85.7% and 86.2%, respectively. After applying the choroidal thickness criterion, the sensitivity increased from 85.7% to 89.8%, and the specificity decreased from 86.2% to 84.5%. CONCLUSIONS: The OCT-based diagnosis of PCV showed a high sensitivity and specificity in Korean patients. The addition of a choroidal thickness criterion improved the sensitivity of the method with a minimal decrease in its specificity. PMID- 27247520 TI - Clinical and Anterior Segment Anatomical Features in Primary Angle Closure Subgroups Based on Configurations of Iris Root Insertion. AB - PURPOSE: To compare the clinical and anterior segment anatomical features in primary angle closure sub-groups based on configurations of iris root insertion. METHODS: Primary angle closure patients were imaged using anterior segment optical coherence tomography. Anterior chamber depth, iris curvature, iris thickness (IT) at the scleral spur and 500, 750, and 1,500 um from the scleral spur (IT0, IT500, IT750, and IT1500), lens vault, iris area, angle opening distance (AOD500), angle recess area (ARA750), and trabecular iris space area (TISA750) were measured. Iris root insertion was categorized into a non-basal insertion group (NBG) and basal insertion group (BG). RESULTS: In total, 43 eyes of 39 participants belonged to the NBG and 89 eyes of 53 participants to the BG. The mean age of participants was greater in the NBG than the BG (62.7 +/- 5.7 vs. 59.8 +/- 7.3 years, p = 0.043), and the baseline intraocular pressure was higher in the BG than the NBG (16.4 +/- 4.4 vs. 14.9 +/- 3.3 mmHg, p = 0.037). The BG showed a greater IT0 (0.265 +/- 0.04 vs. 0.214 +/- 0.03 mm, p < 0.001) and iris area (1.59 +/- 0.24 vs. 1.52 +/- 0.27 mm(2), p = 0.045), lower ARA750 (0.112 +/- 0.08 vs. 0.154 +/- 0.08 mm(2), p = 0.017) and AOD500 (0.165 +/- 0.07 vs. 0.202 +/ 0.08 mm, p = 0.014) compared to the NBG. CONCLUSIONS: The BG had a narrower anterior chamber angle, thicker peripheral iris, and higher pretreatment intraocular pressure. PMID- 27247521 TI - Refractive Errors in Koreans: The Korea National Health and Nutrition Examination Survey 2008-2012. AB - PURPOSE: Our study provides epidemiologic data on the prevalence of refractive errors in all age group >=5 years in Korea. METHODS: In 2008 to 2012, a total of 33,355 participants aged >=5 years underwent ophthalmologic examinations. Using the right eye, myopia was defined as a spherical equivalent (SE) less than -0.5 or -1.0 diopters (D) in subjects aged 19 years and older or as an SE less than 0.75 or -1.25 D in subjects aged 5 to 18 years according to non-cycloplegic refraction. Other refractive errors were defined as follows: high myopia as an SE less than -6.0 D; hyperopia as an SE larger than +0.5 D; and astigmatism as a cylindrical error less than -1.0 D. The prevalence and risk factors of myopia were evaluated. RESULTS: Prevalence rates with a 95% confidence interval were determined for myopia (SE <-0.5 D, 51.9% [51.2 to 52.7]; SE <-1.0 D, 39.6% [38.8 to 40.3]), high myopia (5.0% [4.7 to 5.3]), hyperopia (13.4% [12.9 to 13.9]), and astigmatism (31.2% [30.5 to 32.0]). The prevalence of myopia demonstrated a nonlinear distribution with the highest peak between the ages of 19 and 29 years. The prevalence of hyperopia decreased with age in subjects aged 39 years or younger and then increased with age in subjects aged 40 years or older. The prevalence of astigmatism gradually increased with age. Education was associated with all refractive errors; myopia was more prevalent and hyperopia and astigmatism were less prevalent in the highly educated groups. CONCLUSIONS: In young generations, the prevalence of myopia in Korea was much higher compared to the white or black populations in Western countries and is consistent with the high prevalence found in most other Asian countries. The overall prevalence of hyperopia was much lower compared to that of the white Western population. Age and education level were significant predictive factors associated with all kinds of refractive errors. PMID- 27247522 TI - Performance of and Pressure Elevation Formed by Small-diameter Microtubes Used in Constant-flow Sets. AB - PURPOSE: We explored the performance of and pressure elevation caused by small diameter microtubes used to reduce overfiltration. METHODS: Using a syringe pump driven constant-flow setting (2 uL/min), pressures were measured for polytetrafluoroethylene (PTFE) microtubes 5 mm in length with inner diameters of 51, 64, and 76 um and for polyether block amide (PEBAX) microtubes with an inner diameter of 76 um. Experiments (using microtubes only) were initially performed in air, water, and enucleated pig eyes and were repeated under the same conditions using intraluminal 9/0 nylon stents. RESULTS: The pressures measured in air in 51-, 64-, and 76-um-diameter PTFE microtubes differed significantly (22.1, 16.9, and 12.2 mmHg, respectively; p < 0.001), and that of the 76-um diameter PEBAX microtube was 15.8 mmHg (p < 0.001 compared to the 12.2 mmHg of the 76-um-diameter PTFE microtube). The pressures measured in water also differed significantly among the three microtubes at 3.9, 3.0, and 1.4 mmHg, respectively, while that in the PEBAX microtube was 2.6 mmHg (all p < 0.001). Using the intraluminal stent, the pressure in water of the three different PTFE microtubes increased to 22.6, 18.0, and 4.1 mmHg, respectively, and that in the PEBAX microtube increased to 10.5 mmHg (all p < 0.001). Similar trends were evident when measurements were performed in pig eyes. CONCLUSIONS: Although microtubes of smaller diameter experienced higher pressure in air, reduction of the inner diameter to 51 um did not adequately increase the pressure attained in water or pig eyes. Insertion of an intraluminal stent effectively elevated the latter pressures. PEBAX microtubes created higher pressures than did PTFE microtubes. PMID- 27247523 TI - Primary Systemic Amyloidosis Involving the Lacrimal Sac. PMID- 27247524 TI - Tear Stasis Caused by Severely Protruded Lacrimal Puncta Treated by Novel Punctal Fixation Technique. PMID- 27247525 TI - A Rare Case of Acute Ocular Hypertensive Episode in a Patient with Chronic Infantile Neurological Cutaneous Articular Syndrome. PMID- 27247526 TI - Arteritic Anterior Ischemic Optic Neuropathy Associated with Giant Cell Arteritis in an Elderly Korean Man. PMID- 27247527 TI - Is it safe to withhold long-term anticoagulation therapy in patients with small pulmonary emboli diagnosed by SPECT scintigraphy? AB - BACKGROUND: The need for anticoagulation therapy (AC) in patients with subsegmental pulmonary embolism (SSPE) diagnosed by computed tomography of the pulmonary arteries (CTPA) has been questioned, as these patients run low risk for recurrent venous thromboembolism (VTE) during 3 months of follow-up. Whether this applies also to patients with small PE diagnosed with pulmonary scintigraphy has not yet been evaluated, however. METHODS: We therefore retrospectively evaluated 54 patients (mean age 62 +/- 19 years, 36 [67 %] women) with small PE diagnosed by ventilation/perfusion singe photon emission computed tomography (V/P SPECT) who did not receive conventional long-term AC. RESULTS: More than half of our patients (36[67 %]) received less than 48 h of AC, 11 (20 %) patients were treated for 2-14 days, and 7 (13 %) for 15-30 days. The majority (28 [52 %]) of our patients had a non-low simplified pulmonary emboli severity index (S-PESI), and 7 (13 %) had malignancy. D-dimer was negative in 18 (33 %), positive in 10 (19 %), and not analyzed in 28 (52 %) patients. Phlebography of the lower extremities had been performed with negative result in one patient. During 90 days of follow up no deaths or PE occurred. Seven patients were readmitted to hospital, whereof two (2/54 [4 %]) were diagnosed with deep venous thrombosis (DVT) necessitating AC therapy. CONCLUSION: In conclusion, withholding longterm AC therapy in patients with SSPE diagnosed by V/P SPECT resulted in 4 % risk for recurrence of VTE during 90 days of follow up, and can therefore currently not be recommended. PMID- 27247529 TI - Complex and Reoperative Colorectal Surgery. PMID- 27247528 TI - Cindy Kin, MD, MS, FACS. PMID- 27247530 TI - Complex and Reoperative Colorectal Surgery: Setting Expectations and Learning from Experience. AB - A range of topics are covered in this issue dedicated to complex and reoperative colorectal surgery, from radiation-induced surgical problems, to enterocutaneous fistulas and locally advanced or recurrent rectal cancer. Common themes include the importance of operative planning and patient counseling on the expected functional outcomes. Experts in the field offer their technical tips and clinical lessons to maximize outcomes and minimize complications in these challenging cases. PMID- 27247531 TI - Perioperative Considerations in Crohn Disease and Ulcerative Colitis. AB - The management of inflammatory bowel disease (IBD) is medically and surgically complex. Numerous patient- and disease-oriented factors must be considered in treating patients with IBD, including nutritional replenishment/support, effect of immunosuppressive medications, extent of resection, and use of proximal diversion. Perioperative planning and optimization of the patient is imperative to ensuring favorable outcomes and limiting morbidity. These perioperative considerations in Crohn disease and ulcerative colitis are reviewed here. PMID- 27247532 TI - Radiation-Induced Problems in Colorectal Surgery. AB - Radiotherapy not only plays a pivotal role in the cancer care pathways of many patients with pelvic malignancies, but can also lead to significant injury of normal tissue in the radiation field (pelvic radiation disease) that is sometimes as challenging to treat as the neoplasms themselves. Acute symptoms are usually self-limited and respond to medical therapy. Chronic symptoms often require operative intervention that is made hazardous by hostile surgical planes and unforgiving tissues. Management of these challenging patients is best guided by the utmost caution and humility. PMID- 27247534 TI - Multidisciplinary Approach to the Treatment of Concomitant Rectal and Vaginal Prolapse. AB - Rectal prolapse and vaginal prolapse have traditionally been treated as separate entities despite sharing a common pathophysiology. This compartmentalized approach often leads to frustration and suboptimal outcomes. In recent years, there has been a shift to a more patient-centered, multidisciplinary approach. Procedures to repair pelvic organ prolapse are divided into three categories: abdominal, perineal, and a combination of both. Most commonly, a combined minimally invasive abdominal sacral colpopexy and ventral rectopexy is performed to treat concomitant rectal and vaginal prolapse. Combining the two procedures adds little operative time and offers complete pelvic floor repair. The choice of minimally invasive abdominal prolapse repair versus perineal repair depends on the patient's comorbidities, previous surgeries, preference to avoid mesh, and physician's expertise. Surgeons should at least be able to identify these patients and provide the appropriate treatment or refer them to specialized centers. PMID- 27247533 TI - Management of Complex Perineal Fistula Disease. AB - Management of complex perineal fistulas such as high perianal, rectovaginal, pouch-vaginal, rectourethral, or pouch-urethral fistulas requires a systematic approach. The first step is to control any sepsis with drainage of abscess and/or seton placement. Patients with large, recurrent, irradiated fistulas benefit from stoma diversion. In patients with Crohn's disease, it is essential to induce remission prior to any repair. There are different approaches to repair complex fistulas, from local repairs to transperineal and transabdominal approaches. Simpler fistulas are amenable to local repair. More complex fistulas, such as those secondary to irradiation, require interposition of healthy, well vascularized tissue. The most common flap used for this treatment is the gracilis muscle with good outcomes reported. Once healing is confirmed by imaging and endoscopy, the stoma is reversed. PMID- 27247535 TI - Surgery for Locally Advanced T4 Rectal Cancer: Strategies and Techniques. AB - Locally advanced T4 rectal cancer represents a complex clinical condition that requires a well thought-out treatment plan and expertise from multiple specialists. Paramount in the management of patients with locally advanced rectal cancer are accurate preoperative staging, appropriate application of neoadjuvant and adjuvant treatments, and, above all, the provision of high-quality, complete surgical resection in potentially curable cases. Despite the advanced nature of this disease, extended and multivisceral resections with clear margins have been shown to result in good oncological outcomes and offer patients a real chance of cure. In this article, we describe the assessment, classification, and multimodality treatment of primary locally advanced T4 rectal cancer, with a focus on surgical planning, approaches, and outcomes. PMID- 27247536 TI - Surgery for Locally Recurrent Rectal Cancer: Tips, Tricks, and Pitfalls. AB - Rectal cancer can recur locally in up to 10% of the patients who undergo definitive resection for their primary cancer. Surgical salvage is considered appropriate in the curative setting as well as select cases with palliative intent. Disease-free survival following salvage resection is dependent upon achieving an R0 resection margin. A clear understanding of applied surgical anatomy, appropriate preoperative planning, and a multidisciplinary approach to aggressive soft tissue, bony, and vascular resection with appropriate reconstruction is necessary. Technical tips, tricks, and pitfalls that may assist in managing these cancers are discussed and the roles of additional boost radiation and intraoperative radiation therapy in the management of such cancers are also discussed. PMID- 27247537 TI - The Failed J Pouch. AB - The development and refinement of proctectomy with ileal pouch-anal anastomosis (IPAA) since its introduction in the 1970s has made it the optimal procedure of choice in patients with chronic ulcerative colitis and patients with familial adenomatous polyposis. However, it is a procedure that can be associated with significant morbidity. Pouch failure due to infection, mechanical, or functional disability represents a challenge to both surgeon and patient. Practicing surgeons who deal with revisional pouch surgery face a variety of intraoperative, postoperative, and reoperative challenges. Success requires a strategy that includes critical planning, preparation, specialized surgical techniques, and experience to achieve long-term success, minimize the adverse consequences of IPAA-related complications, and ensure solutions and hope to patients. PMID- 27247538 TI - Enterocutaneous Fistula: Proven Strategies and Updates. AB - Management of enterocutaneous fistula represents one of the most protracted and difficult problems in colorectal surgery with substantial morbidity and mortality rates. This article summarizes the current classification systems and successful management protocols, provides an in-depth review of fluid resuscitation, sepsis control, nutrition management, medication management of output quantity, wound care, nonoperative intervention measures, operative timeline, and considerations, and discusses special considerations such as inflammatory bowel disease and enteroatmospheric fistula. PMID- 27247539 TI - Management of Colorectal Anastomotic Leak. AB - The aim of this article is to present strategies for preventing and managing the failure of the surgical restoration of intestinal continuity. Despite improvements in surgical technique and perioperative care, anastomotic leaks still occur, and with them occur increased morbidity, mortality, length of stay, and costs. Due to the devastating consequences for patients with failed anastomoses, there have been a myriad of materials and techniques used by surgeons to create better intestinal anastomoses. We will also discuss the management strategies for anastomotic leak when they do inevitably occur. PMID- 27247540 TI - Genitourinary Considerations in Reoperative and Complex Colorectal Surgery. AB - Genitourinary structures are at risk of injury during colorectal surgery. The incidence of injury is low; however, the risk is higher in cases involving severe inflammatory or infectious processes, locally advanced or recurrent cancer, previous radiation, and reoperation. Consideration of the anatomical relationship between the genitourinary system, and the colon and rectum is crucial to avoid injuries. Intraoperative diagnostic techniques such as intravenous pyelogram (IVP), fluoroscopic cystogram, or retrograde urethrogram can aid in identifying suspected injuries. Early recognition and repair of injuries decrease the morbidity of an injury. Repair of injuries depends on the location and extent of the injury. Simple injuries may be repaired primarily, while complex injuries may require more advanced repairs such as a flap reconstruction. PMID- 27247541 TI - The Difficult Stoma: Challenges and Strategies. AB - The problems that a patient experiences after the creation of a temporary or permanent stoma can result from many factors, but a carefully constructed stoma located in an ideal location is typically associated with appropriate function and an acceptable quality of life. The construction of the stoma can be confounded by many concomitant conditions that increase the distance that the bowel must traverse or shorten the bowel's capacity to reach. Stomas can be further troubled by a variety of problems that potentially arise early in the recovery period or months later. Surgeons must be familiar with these obstacles and complications to avoid their occurrence and minimize their impact. PMID- 27247542 TI - Management of the Perineal Defect after Abdominoperineal Excision. AB - The optimal management of the perineal defect following abdominoperineal excision for anorectal malignancy remains a source of debate. The repopularization of extralevator resection means colorectal surgeons are confronted with larger perineal wounds. There are several surgical options available-primary perineal closure and drainage, omentoplasty, biological or synthetic mesh placement, musculocutaneous flap repair, and negative wound pressure therapy. These options are discussed along with the potential benefits and complications of each. There remains no consensus on which management strategy is superior; thus, each case must be tailored for each individual patient. Surgical expertise and availability of a multidisciplinary team approach are important considerations. PMID- 27247543 TI - Diving response after a one-week diet and overnight fasting. AB - BACKGROUND: We hypothesized that overnight fasting after a short dietary period, especially with carbohydrates, could allow performing breath-hold diving with no restraint for diaphragm excursion and blood shift and without any increase of metabolism, and in turn improve the diving response. METHODS: During two separate sessions, 8 divers carried out two trials: (A) a 30-m depth dive, three hours after a normal breakfast and (B) a dive to the same depth, but after following a diet and fasting overnight. Each test consisted of 3 apnea phases: descent, static and ascent whose durations were measured by a standard chronometer. An impedance cardiograph, housed in an underwater torch, provided data on trans thoracic fluid index (TFI), stroke volume (SV), heart rate (HR) and cardiac output (CO). Mean blood pressure (MBP), arterial O2 saturation (SaO2), blood glucose (Glu) and blood lactate (BLa) were also collected. RESULTS: In condition B, duration of the static phase of the dive was longer than A (37.8 +/- 7.4 vs. 27.3 +/- 8.4 s respectively, P < 0.05). In static phases, mean ? SV value (difference between basal and nadir values) during fasting was lower than breakfast one (-2.6 +/- 5.1 vs. 5.7 +/- 7.6 ml, P < 0.05). As a consequence, since mean ? HR values were equally decreased in both metabolic conditions, mean ? CO value during static after fasting was lower than the same phase after breakfast (-0.4 +/- 0.5 vs. 0.4 +/- 0.5 L . min(-1) respectively, P < 0.05). At emersion, despite the greater duration of dives during fasting, SaO2 was higher than A (92.0 +/- 2.7 vs. 89.4 +/- 2.9 % respectively, P < 0.05) and BLa was lower in the same comparison (4.2 +/- 0.7 vs. 5.3 +/- 1.1 mmol?L(-1), P < 0.05). CONCLUSIONS: An adequate balance between metabolic and splancnic status may improve the diving response during a dive at a depth of 30 m, in safe conditions for the athlete's health. PMID- 27247544 TI - Malignant gliomas: old and new systemic treatment approaches. AB - BACKGROUND: Malignant (high-grade) gliomas are rapidly progressive brain tumours with very high morbidity and mortality. Until recently, treatment options for patients with malignant gliomas were limited and mainly the same for all subtypes of malignant gliomas. The treatment included surgery and radiotherapy. Chemotherapy used as an adjuvant treatment or at recurrence had a marginal role. CONCLUSIONS: Nowadays, the treatment of malignant gliomas requires a multidisciplinary approach. The treatment includes surgery, radiotherapy and chemotherapy. The chosen approach is more complex and individually adjusted. By that, the effect on the survival and quality of life is notable higher. PMID- 27247545 TI - Early medical rehabilitation after neurosurgical treatment of malignant brain tumours in Slovenia. AB - BACKGROUND: The number of patients with malignant brain tumours is on the rise, but due to the novel treatment methods the survival rates are higher. Despite increased survival the consequences of tumour properties and treatment can have a significant negative effect on the patients' quality of life. Providing timely and appropriate rehabilitation interventions is an important aspect of patient treatment and should be started immediately after surgery. The most important goal of rehabilitation is to prevent complications that could have a negative effect on the patients' ability to function. CONCLUSIONS: By using individually tailored early rehabilitation it is often possible to achieve the patients' independence in mobility as well as in performing daily tasks before leaving the hospital. A more precise evaluation of the patients' functional state after completing additional oncologic therapy should be performed to stratify the patients who should be directed to complex rehabilitation treatment. The chances of a good functional outcome in patients with malignant brain tumours could be increased with good early medical rehabilitation treatment. PMID- 27247546 TI - Screen-detected ductal carcinoma in situ found on stereotactic vacuum-assisted biopsy of suspicious microcalcifications without mass: radiological-histological correlation. AB - BACKGROUND: Commonly identified on screening mammography breast microcalcifications are the predominant manifestation of ductal carcinoma in situ (DCIS). The aim of this study was to investigate the association between clinico radiological features and histological findings in patients with screen-detected DCIS. PATIENTS AND METHODS: Consecutive 127 patients with pure DCIS found on stereotactic vacuum-assisted biopsy of screen-detected suspicious microcalcifications without mass entered the study. Patient age, type and distribution of microcalcifications, DCIS nuclear grade (NG) and the presence of comedonecrosis were investigated. Association between parameters was statistically analysed with P < 0.05 as a significance level. Results. Powdery microcalcifications were most often clustered while regional were most common of casting-type (P < 0.001). High, intermediate and low NG of DCIS was significantly related to casting-type, crushed stone-like and powdery microcalcifications, respectively (P < 0.01). Low and intermediate NG DCIS were the most common in clustered and grouped microcalcifications while high NG DCIS was the most often when regional distribution was observed (P < 0.05). Comedonecrosis was significantly more common in high NG DCIS (P < 0.01). The association between comedonecrosis and type of microcalcifications was not significant, but with their distribution was close to the significance level (P = 0.07). Patient age was not significantly related to imaging or histological findings. CONCLUSIONS: The association between pattern of mammographic microcalcifications and histological findings related to more aggressive disease can be helpful in optimal surgery planning in patients with screen-detected DCIS, regarding the extent of breast intervention and consideration of synchronous sentinel node biopsy. PMID- 27247547 TI - (18)F-FET and (18)F-FCH uptake in human glioblastoma T98G cell lines. AB - BACKGROUND: Despite complex treatment of surgery, radiotherapy and chemotherapy, high grade gliomas often recur. Differentiation between post-treatment changes and recurrence is difficult. (18)F-methyl-choline ((18)F-FCH) is frequently used in staging and detection of recurrent prostate cancer disease as well as some brain tumours; however accumulation in inflammatory tissue limits its specificity. The (18)F-ethyl-tyrosine ((18)F-FET) shows a specific uptake in malignant cells, resulting from increased expression of amino acid transporters or diffusing through the disrupted blood-brain barrier. (18)F-FET exhibits lower uptake in machrophages and other inflammatory cells. Aim of this study was to evaluate (18)F-FCH and (18)F-FET uptake by human glioblastoma T98G cells. MATERIAL AND METHODS: Human glioblastoma T98G or human dermal fibroblasts cells, seeded at a density to obtain 2 * 10(5) cells per flask when radioactive tracers were administered, grew adherent to the plastic surface at 37 degrees C in 5% CO2 in complete medium. Equimolar amounts of radiopharmaceuticals were added to cells for different incubation times (20 to 120 minutes) for (18)F-FCH and (18)F-FET respectively. The cellular radiotracer uptake was determined with a gamma counter. All experiments were carried out in duplicate and repeated three times. The uptake measurements are expressed as the percentage of the administered dose of tracer per 2 * 10(5) cells. Data (expressed as mean values of % uptake of radiopharmaceuticals) were compared using parametric or non-parametric tests as appropriate. Differences were regarded as statistically significant when p<0.05. RESULTS: A significant uptake of (18)F-FCH was seen in T98G cells at 60, 90 and 120 minutes. The percentage uptake of (18)F-FET in comparison to (18)F-FCH was lower by a factor of more than 3, with different kinetic curves.(18)F-FET showed a more rapid initial uptake up to 40 minutes and (18)F-FCH showed a progressive rise reaching a maximum after 90 minutes. CONCLUSIONS: (18)F-FCH and (18)F-FET are candidates for neuro-oncological PET imaging. (18)F-FET could be the most useful oncological PET marker in the presence of reparative changes after therapy, where the higher affinity of (18)F-FCH to inflammatory cells makes it more difficult to discriminate between tumour persistence and non-neoplastic changes. Additional studies on the influence of inflammatory tissue and radionecrotic cellular components on radiopharmaceutical uptake are necessary. PMID- 27247548 TI - Imaging of human glioblastoma cells and their interactions with mesenchymal stem cells in the zebrafish (Danio rerio) embryonic brain. AB - BACKGROUND: An attractive approach in the study of human cancers is the use of transparent zebrafish (Danio rerio) embryos, which enable the visualization of cancer progression in a living animal. MATERIALS AND METHODS: We implanted mixtures of fluorescently labeled glioblastoma (GBM) cells and bonemarrow-derived mesenchymal stem cells (MSCs) into zebrafish embryos to study the cellular pathways of their invasion and the interactions between these cells in vivo. RESULTS: By developing and applying a carbocyanine-dye-compatible clearing protocol for observation of cells in deep tissues, we showed that U87 and U373 GBM cells rapidly aggregated into tumor masses in the ventricles and midbrain hemispheres of the zebrafish embryo brain, and invaded the central nervous system, often using the ventricular system and the central canal of the spinal cord. However, the GBM cells did not leave the central nervous system. With co injection of differentially labeled cultured GBM cells and MSCs, the implanted cells formed mixed tumor masses in the brain. We observed tight associations between GBM cells and MSCs, and possible cell-fusion events. GBM cells and MSCs used similar invasion routes in the central nervous system. CONCLUSIONS: This simple model can be used to study the molecular pathways of cellular processes in GBM cell invasion, and their interactions with various types of stromal cells in double or triple cell co-cultures, to design anti-GBM cell therapies that use MSCs as vectors. PMID- 27247549 TI - Identification of differentially expressed genes associated with the enhancement of X-ray susceptibility by RITA in a hypopharyngeal squamous cell carcinoma cell line (FaDu). AB - BACKGROUND: Next generation sequencing and bio-informatic analyses were conducted to investigate the mechanism of reactivation of p53 and induction of tumor cell apoptosis (RITA)-enhancing X-ray susceptibility in FaDu cells. MATERIALS AND METHODS: The cDNA was isolated from FaDu cells treated with 0 X-ray, 8 Gy X-ray, or 8 Gy X-ray + RITA. Then, cDNA libraries were created and sequenced using next generation sequencing, and each assay was repeated twice. Subsequently, differentially expressed genes (DEGs) were identified using Cuffdiff in Cufflinks and their functions were predicted by pathway enrichment analyses. Genes that were constantly up- or down-regulated in 8 Gy X-ray-treated FaDu cells and 8 Gy X ray + RITA-treated FaDu cells were obtained as RITA genes. Afterward, the protein protein interaction (PPI) relationships were obtained from the STRING database and a PPI network was constructed using Cytoscape. Furthermore, ClueGO was used for pathway enrichment analysis of genes in the PPI network. RESULTS: Total 2,040 and 297 DEGs were identified in FaDu cells treated with 8 Gy X-ray or 8 Gy X-ray + RITA, respectively. PARP3 and NEIL1 were enriched in base excision repair, and CDK1 was enriched in p53 signaling pathway. RFC2 and EZH2 were identified as RITA genes. In the PPI network, many interaction relationships were identified (e.g., RFC2-CDK1, EZH2-CDK1 and PARP3-EZH2). ClueGO analysis showed that RFC2 and EZH2 were related to cell cycle. CONCLUSIONS: RFC2, EZH2, CDK1, PARP3 and NEIL1 may be associated, and together enhance the susceptibility of FaDu cells treated with RITA to the deleterious effects of X-ray. PMID- 27247550 TI - Diffusion tensor MR microscopy of tissues with low diffusional anisotropy. AB - BACKGROUND: Diffusion tensor imaging exploits preferential diffusional motion of water molecules residing within tissue compartments for assessment of tissue structural anisotropy. However, instrumentation and post-processing errors play an important role in determination of diffusion tensor elements. In the study, several experimental factors affecting accuracy of diffusion tensor determination were analyzed. MATERIALS AND METHODS: Effects of signal-to-noise ratio and configuration of the applied diffusion-sensitizing gradients on fractional anisotropy bias were analyzed by means of numerical simulations. In addition, diffusion tensor magnetic resonance microscopy experiments were performed on a tap water phantom and bovine articular cartilage-on-bone samples to verify the simulation results. RESULTS: In both, the simulations and the experiments, the multivariate linear regression of the diffusion-tensor analysis yielded overestimated fractional anisotropy with low SNRs and with low numbers of applied diffusion-sensitizing gradients. CONCLUSIONS: An increase of the apparent fractional anisotropy due to unfavorable experimental conditions can be overcome by applying a larger number of diffusion sensitizing gradients with small values of the condition number of the transformation matrix. This is in particular relevant in magnetic resonance microscopy, where imaging gradients are high and the signal-to-noise ratio is low. PMID- 27247551 TI - The prognostic value of whole blood SOX2, NANOG and OCT4 mRNA expression in advanced small-cell lung cancer. AB - BACKGROUND: The data on expression and clinical impact of cancer stem cell markers SOX2, NANOG and OCT4 in lung cancer is still lacking. The aim of our study was to compare SOX2, NANOG and OCT4 mRNA expression levels in whole blood between advanced small-cell lung cancer (SCLC) patients and healthy controls, and to correlate mRNA expression with progression-free survival (PFS) after first line chemotherapy and overall survival (OS) in advanced SCLC patients. PATIENTS AND METHODS: 50 advanced SCLC patients treated with standard chemotherapy and followed at University Clinic Golnik, Slovenia, between 2009 and 2013 were prospectively included. SOX2, NANOG and OCT4 mRNA expression levels were determined using TaqMan qPCR in whole blood collected prior to chemotherapy. Whole blood of 34 matched healthy individuals with no cancerous disease was also tested. RESULTS: SOX2 mRNA expression was significantly higher in whole blood of SCLC patients compared to healthy controls (p = 0.006). Significant correlation between SOX2 mRNA expression levels and the number of distant metastatic sites was established (p = 0.027). In survival analysis, patients with high SOX2 expression had shorter OS (p = 0.017) and PFS (p = 0.046). In multivariate Cox analysis, an independent value of high SOX2 expression for shorter OS (p = 0.002), but not PFS was confirmed. No significant differences were observed for NANOG or OCT4 expression levels when comparing SCLC patients and healthy controls neither when analysing survival outcomes in SCLC patients. CONCLUSIONS: SOX2 mRNA expression in whole blood might be a promising non-invasive marker for molecular screening of SCLC and important prognostic marker in advanced chemotherapy treated SCLC patients, altogether indicating important role of cancer stem-like cell (CSC) regulators in cancer spread. Further evaluation of SOX2 as a possible screening/prognostic marker and a therapeutic target of SCLC is warranted. PMID- 27247552 TI - Tenckhoff tunneled peritoneal catheter placement in the palliative treatment of malignant ascites: technical results and overall clinical outcome. AB - BACKGROUND: To assess the technical and clinical outcome of percutaneous insertion of tunneled peritoneal catheters in the palliative treatment of refractory malignant ascites and to determine the safety and feasibility of intraperitoneal administration of cytotoxic drugs through the tunneled catheter. MATERIALS AND METHODS: Consecutive patients palliatively treated with a tunneled peritoneal catheter to drain the malignant ascites were identified. Patients' medical history, procedural and clinical follow-up data, including complications and estimated survival, were reviewed. Additionally, a sub analysis of the patients with widespread ovarian cancer and refractory ascites treated with or without intraperitoneal administration of cytotoxic drugs was made. RESULTS: In all 94 patients it was technically feasible to insert the peritoneal drainage catheter and to drain a median of 3260 cc (range 100 cc - 8500 cc) of malignant ascitic fluid. Post procedural complications included catheter infection (n = 2; 2%), fluid leakage around the entry site (n = 4; 4%), catheter occlusion (n = 2; 2%), sleeve formation around the catheter tip (n = 1; 1%) and accidental loss of the catheter (n = 1; 1%). There was no increase in catheter infection rate in patients treated with or without intraperitoneal administration of cytotoxic drugs. Median overall survival after catheter insertion is 1.7 months. CONCLUSIONS: Percutaneous insertion of a tunneled Tenckhoff catheter for the palliative drainage of malignant ascites and intraperitoneal infusion of cytotoxic drugs is feasible and associated with a very low complication rate, including catheter infection. These tunneled peritoneal lines are beneficial for symptomatic palliative treatment of refractory ascites and allow safe intraperitoneal chemotherapy. PMID- 27247553 TI - CA19-9 serum levels predict micrometastases in patients with gastric cancer. AB - BACKGROUND: We explored the prognostic value of the up-regulated carbohydrate antigen (CA19-9) in node-negative patients with gastric cancer as a surrogate marker for micrometastases. PATIENTS AND METHODS: Micrometastases were determined using reverse transcription quantitative polymerase chain reaction (RT-qPCR) for a subgroup of 30 node-negative patients. This group was used to determine the cut off for preoperative CA19-9 serum levels as a surrogate marker for micrometastases. Then 187 node-negative T1 to T4 patients were selected to validate the predictive value of this CA19-9 threshold. RESULTS: Patients with micrometastases had significantly higher preoperative CA19-9 serum levels compared to patients without micrometastases (p = 0.046). CA19-9 serum levels were significantly correlated with tumour site, tumour diameter, and perineural invasion. Although not reaching significance, subgroup analysis showed better five-year survival rates for patients with CA19-9 serum levels below the threshold, compared to patients with CA19-9 serum levels above the cut-off. The cumulative survival for T2 to T4 node-negative patients was significantly better with CA19-9 serum levels below the cut-off (p = 0.04). CONCLUSIONS: Preoperative CA19-9 serum levels can be used to predict higher risk for haematogenous spread and micrometastases in node-negative patients. However, CA19-9 serum levels lack the necessary sensitivity and specificity to reliably predict micrometastases. PMID- 27247554 TI - Hepatic splenosis mimicking liver metastases in a patient with history of childhood immature teratoma. AB - BACKGROUND: Hepatic splenosis is rare condition, preceded by splenectomy or spleen trauma, the term refers to nodular implantation of normal splenic tissue in the liver. In patients with history of malignancy in particular, it can be mistaken for metastases and can lead to unnecessary diagnostic procedures or inappropriate treatment. CASE REPORT: Twenty-two-year old male was treated for immature teratoma linked to undescended right testicle after birth. On regular follow-up examinations no signs of disease relapse or long-term consequences were observed. He was presented with incidental finding of mature cystic teratoma after elective surgery for what appeared to be left-sided inguinal hernia. The tumour was most likely a metastasis of childhood teratoma. Origin within remaining left testicle was not found. Upon further imaging diagnostics, several intrahepatic lesions were revealed. Based on radiologic appearance they were suspicious to be metastases. The patient underwent two ultrasound guided fine needle aspiration biopsies. Cytologic diagnosis was inconclusive. Histology of laparoscopically obtained tissue disclosed presence of normal splenic tissue and led to diagnosis of hepatic splenosis. CONCLUSIONS: Though hepatic splenosis is rare, it needs to be included in differential diagnosis of nodular hepatic lesions. Accurate interpretation of those lesions is crucial for appropriate management of the patient. If diagnosis eludes after cytologic diagnostics alone, laparoscopic excision of nodular lesion is warranted before considering more extensive liver resection. PMID- 27247555 TI - Treatment of nasopharyngeal carcinoma using simultaneous modulated accelerated radiation therapy via helical tomotherapy: a phase II study. AB - BACKGROUND: The aim of the study was to evaluate short-term safety and efficacy of simultaneous modulated accelerated radiation therapy (SMART) delivered via helical tomotherapy in patients with nasopharyngeal carcinoma (NPC). METHODS: Between August 2011 and September 2013, 132 newly diagnosed NPC patients were enrolled for a prospective phase II study. The prescription doses delivered to the gross tumor volume (pGTVnx) and positive lymph nodes (pGTVnd), the high risk planning target volume (PTV1), and the low risk planning target volume (PTV2), were 67.5 Gy (2.25 Gy/F), 60 Gy (2.0 Gy/F), and 54 Gy (1.8 Gy/F), in 30 fractions, respectively. Acute toxicities were evaluated according to the established RTOG/EORTC criteria. This group of patients was compared with the 190 patients in the retrospective P70 study, who were treated between September 2004 and August 2009 with helical tomotherapy, with a dose of 70-74 Gy/33F/6.5W delivered to pGTVnx and pGTVnd. RESULTS: The median follow-up was 23.7 (12-38) months. Acute radiation related side-effects were mainly problems graded as 1 or 2. Only a small number of patients suffered from grade 4 leucopenia (4.5%) or thrombocytopenia (2.3%). The local relapse-free survival (LRFS), nodal relapse free survival (NRFS), local-nodal relapse-free survival (LNRFS), distant metastasis-free survival (DMFS) and overall survival (OS) were 96.7%, 95.5%, 92.2%, 92.7% and 93.2%, at 2 years, respectively, with no significant difference compared with the P70 study. CONCLUSIONS: Smart delivered via the helical tomotherapy technique appears to be associated with an acceptable acute toxicity profile and favorable short-term outcomes for patients with NPC. Long-term toxicities and patient outcomes are under investigation. PMID- 27247556 TI - Bevacizumab plus chemotherapy in elderly patients with previously untreated metastatic colorectal cancer: single center experience. AB - BACKGROUND: Metastatic colorectal cancer (mCRC) is mainly a disease of elderly, however, geriatric population is underrepresented in clinical trials. Patient registries represent a tool to assess and follow treatment outcomes in this patient population. The aim of the study was with the help of the patients' register to determine the safety and efficacy of bevacizumab plus chemotherapy in elderly patients who had previously untreated metastatic colorectal cancer. PATIENTS AND METHODS: The registry of patients with mCRC was designed to prospectively evaluate the safety and efficacy of bevacizumab-containing chemotherapy as well as selection of patients in routine clinical practice. Patient baseline clinical characteristics, pre-specified bevacizumab-related adverse events, and efficacy data were collected, evaluated and compared according to the age categories. RESULTS: Between January 2008 and December 2010, 210 patients with mCRC (median age 63, male 61.4%) started bevacizumab-containing therapy in the 1(st) line setting. Majority of the 210 patients received irinotecan-based chemotherapy (68%) as 1(st) line treatment and 105 patients (50%) received bevacizumab maintenance therapy. Elderly (>= 70 years) patients presented 22.9% of all patients and they had worse performance status (PS 1/2, 62.4%) than patients in < 70 years group (PS 1/2, 35.8%). Difference in disease control rate was mainly due to inability to assess response in elderly group (64.6% in elderly and 77.8% in < 70 years group, p = 0.066). The median progression free survival was 10.2 (95% CI, 6.7-16.2) and 11.3 (95% CI, 10.2 12.6) months in elderly and < 70 years group, respectively (p = 0.58). The median overall survival was 18.5 (95% CI, 12.4-28.9) and 27.4 (95% CI, 22.7-31.9) months for elderly and < 70 years group, respectively (p = 0.03). Three-year survival rate was 26% and 37.6% in elderly vs. < 70 years group (p = 0.03). Overall rates of bevacizumab-related adverse events were similar in both groups: proteinuria 21/22 %, hypertension 25/19 %, haemorrhage 2/4 % and thromboembolic events 10/6 %, for elderly and < 70 years group, respectively. CONCLUSIONS: In routine clinical practice, the combination of bevacizumab and chemotherapy is effective and well-tolerated regimen in elderly patients with metastatic colorectal cancer. PMID- 27247557 TI - The dosimetric significance of using 10 MV photons for volumetric modulated arc therapy for post-prostatectomy irradiation of the prostate bed. AB - BACKGROUND: The purpose of the study was to analyse the dosimetric differences when using 10 MV instead of 6 MV for VMAT treatment plans for post-prostatectomy irradiation of the prostate bed. METHODS AND MATERIALS: Ten post-prostatectomy prostate bed irradiation cases previously treated using 6 MV with volumetric modulated arc therapy (VMAT) were re-planned using 10 MV with VMAT. Prescription dose was 66.6 Gy with 1.8 Gy per fraction for 37 daily fractions. The same structure set, number of arcs, field sizes, and minimum dose to the Planning Target Volume (PTV) were used for both 6 MV and 10 MV plans. Results were collected for dose to Organs at Risk (OAR) constraints, dose to the target structures, number of monitor units for each arc, Body V5, Conformity Index, and Integral Dose. The mean values were used to compare the 6 MV and 10 MV results. To determine the statistical significance of the results, a paired Student t test and power analysis was performed. RESULTS: Statistically significant lower mean values were observed for the OAR dose constraints for the rectum, bladder Clinical Target Volume (bladder-CTV), left femoral head, and right femoral head. Also, statistically significant lower mean values were observed for the Body V5, Conformity Index, and Integral Dose. CONCLUSIONS: Several dosimetric benefits were observed when using 10 MV instead of 6 MV for VMAT based treatment plans. Benefits include sparing more dose from the OAR while still maintaining the same dose coverage to the PTV. Other benefits include lower Body V 5,Conformity Index, and Integral Dose. PMID- 27247558 TI - Effect of photon energy spectrum on dosimetric parameters of brachytherapy sources. AB - AIM: The aim of this study is to quantify the influence of the photon energy spectrum of brachytherapy sources on task group No. 43 (TG-43) dosimetric parameters. BACKGROUND: Different photon spectra are used for a specific radionuclide in Monte Carlo simulations of brachytherapy sources. MATERIALS AND METHODS: MCNPX code was used to simulate 125I, 103Pd, 169Yb, and 192Ir brachytherapy sources. Air kerma strength per activity, dose rate constant, radial dose function, and two dimensional (2D) anisotropy functions were calculated and isodose curves were plotted for three different photon energy spectra. The references for photon energy spectra were: published papers, Lawrence Berkeley National Laboratory (LBNL), and National Nuclear Data Center (NNDC). The data calculated by these photon energy spectra were compared. RESULTS: Dose rate constant values showed a maximum difference of 24.07% for 103Pd source with different photon energy spectra. Radial dose function values based on different spectra were relatively the same. 2D anisotropy function values showed minor differences in most of distances and angles. There was not any detectable difference between the isodose contours. CONCLUSIONS: Dosimetric parameters obtained with different photon spectra were relatively the same, however it is suggested that more accurate and updated photon energy spectra be used in Monte Carlo simulations. This would allow for calculation of reliable dosimetric data for source modeling and calculation in brachytherapy treatment planning systems. PMID- 27247559 TI - Obtaining Thickness Maps of Corneal Layers Using the Optimal Algorithm for Intracorneal Layer Segmentation. AB - Optical Coherence Tomography (OCT) is one of the most informative methodologies in ophthalmology and provides cross sectional images from anterior and posterior segments of the eye. Corneal diseases can be diagnosed by these images and corneal thickness maps can also assist in the treatment and diagnosis. The need for automatic segmentation of cross sectional images is inevitable since manual segmentation is time consuming and imprecise. In this paper, segmentation methods such as Gaussian Mixture Model (GMM), Graph Cut, and Level Set are used for automatic segmentation of three clinically important corneal layer boundaries on OCT images. Using the segmentation of the boundaries in three-dimensional corneal data, we obtained thickness maps of the layers which are created by these borders. Mean and standard deviation of the thickness values for normal subjects in epithelial, stromal, and whole cornea are calculated in central, superior, inferior, nasal, and temporal zones (centered on the center of pupil). To evaluate our approach, the automatic boundary results are compared with the boundaries segmented manually by two corneal specialists. The quantitative results show that GMM method segments the desired boundaries with the best accuracy. PMID- 27247560 TI - Comparison of Texture Features Used for Classification of Life Stages of Malaria Parasite. AB - Malaria is a vector borne disease widely occurring at equatorial region. Even after decades of campaigning of malaria control, still today it is high mortality causing disease due to improper and late diagnosis. To prevent number of people getting affected by malaria, the diagnosis should be in early stage and accurate. This paper presents an automatic method for diagnosis of malaria parasite in the blood images. Image processing techniques are used for diagnosis of malaria parasite and to detect their stages. The diagnosis of parasite stages is done using features like statistical features and textural features of malaria parasite in blood images. This paper gives a comparison of the textural based features individually used and used in group together. The comparison is made by considering the accuracy, sensitivity, and specificity of the features for the same images in database. PMID- 27247561 TI - Learning to Model Task-Oriented Attention. AB - For many applications in graphics, design, and human computer interaction, it is essential to understand where humans look in a scene with a particular task. Models of saliency can be used to predict fixation locations, but a large body of previous saliency models focused on free-viewing task. They are based on bottom up computation that does not consider task-oriented image semantics and often does not match actual eye movements. To address this problem, we collected eye tracking data of 11 subjects when they performed some particular search task in 1307 images and annotation data of 2,511 segmented objects with fine contours and 8 semantic attributes. Using this database as training and testing examples, we learn a model of saliency based on bottom-up image features and target position feature. Experimental results demonstrate the importance of the target information in the prediction of task-oriented visual attention. PMID- 27247562 TI - Regularized Embedded Multiple Kernel Dimensionality Reduction for Mine Signal Processing. AB - Traditional multiple kernel dimensionality reduction models are generally based on graph embedding and manifold assumption. But such assumption might be invalid for some high-dimensional or sparse data due to the curse of dimensionality, which has a negative influence on the performance of multiple kernel learning. In addition, some models might be ill-posed if the rank of matrices in their objective functions was not high enough. To address these issues, we extend the traditional graph embedding framework and propose a novel regularized embedded multiple kernel dimensionality reduction method. Different from the conventional convex relaxation technique, the proposed algorithm directly takes advantage of a binary search and an alternative optimization scheme to obtain optimal solutions efficiently. The experimental results demonstrate the effectiveness of the proposed method for supervised, unsupervised, and semisupervised scenarios. PMID- 27247563 TI - Optimization Control of the Color-Coating Production Process for Model Uncertainty. AB - Optimized control of the color-coating production process (CCPP) aims at reducing production costs and improving economic efficiency while meeting quality requirements. However, because optimization control of the CCPP is hampered by model uncertainty, a strategy that considers model uncertainty is proposed. Previous work has introduced a mechanistic model of CCPP based on process analysis to simulate the actual production process and generate process data. The partial least squares method is then applied to develop predictive models of film thickness and economic efficiency. To manage the model uncertainty, the robust optimization approach is introduced to improve the feasibility of the optimized solution. Iterative learning control is then utilized to further refine the model uncertainty. The constrained film thickness is transformed into one of the tracked targets to overcome the drawback that traditional iterative learning control cannot address constraints. The goal setting of economic efficiency is updated continuously according to the film thickness setting until this reaches its desired value. Finally, fuzzy parameter adjustment is adopted to ensure that the economic efficiency and film thickness converge rapidly to their optimized values under the constraint conditions. The effectiveness of the proposed optimization control strategy is validated by simulation results. PMID- 27247564 TI - Pattern of Pediatric Dermatoses in a Tertiary Care Hospital of Western Nepal. AB - Pediatric dermatoses are one of the most common presentations in a dermatology clinic and reflect the health and hygiene status of children. The incidence and severity of these skin lesions are influenced by geographical area, seasonal and cultural factors, and socioeconomic status. This study was done to show the prevalence of different pediatric dermatoses in a tertiary care hospital of Western Nepal. Chart reviews of children aged one day to 17 years, presenting to Universal Medical College Teaching Hospital, Nepal, from 1 September 2014 to 30 august 2015, were done. Descriptive analysis and two-sided chi-square test were done. Among 23992 patients visiting the dermatology outpatient department (OPD), 5398 (22.5%) were of pediatric age groups (male/female: 1.2/1); most of them belonged to young teens and teenagers (n = 3308; 61.3%). Three most common dermatoses were fungal infections (18.5%), eczema (14.4%), and acne (10.1%). Fungal infections (n = 653; 65.4%) and acne (n = 284; 51.9%) were common in males, whereas eczema (n = 402; 51.7%) was more common in females. Fungal infection (P < 0.001), eczema (P < 0.001), pigmentation disorders (P < 0.001), and acne (P < 0.01) were significantly more during summer, while scabies was more in winter (P < 0.001). Dermatophytosis, pyoderma, and warts comprised frequently occurring fungal, bacterial, and viral infections, respectively. PMID- 27247566 TI - Gut Microbiota and Metagenomic Advancement in Digestive Disease. PMID- 27247567 TI - Novel Mutations in MLH1 and MSH2 Genes in Mexican Patients with Lynch Syndrome. AB - Background. Lynch Syndrome (LS) is characterized by germline mutations in the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. This syndrome is inherited in an autosomal dominant pattern and is characterized by early onset colorectal cancer (CRC) and extracolonic tumors. The aim of this study was to identify mutations in MMR genes in three Mexican patients with LS. Methods. Immunohistochemical analysis was performed as a prescreening method to identify absent protein expression. PCR, Denaturing High Performance Liquid Chromatography (dHPLC), and Sanger sequencing complemented the analysis. Results. Two samples showed the absence of nuclear staining for MLH1 and one sample showed loss of nuclear staining for MSH2. The mutations found in MLH1 gene were c.2103+1G>C in intron 18 and compound heterozygous mutants c.1852_1854delAAG (p.K618del) and c.1852_1853delinsGC (p.K618A) in exon 16. In the MSH2 gene, we identified mutation c.638dupT (p.L213fs) in exon 3. Conclusions. This is the first report of mutations in MMR genes in Mexican patients with LS and these appear to be novel. PMID- 27247565 TI - The Pathogenesis of Nonalcoholic Fatty Liver Disease: Interplay between Diet, Gut Microbiota, and Genetic Background. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world, and it comprises a spectrum of hepatic abnormalities from simple hepatic steatosis to steatohepatitis, fibrosis, cirrhosis, and liver cancer. While the pathogenesis of NAFLD remains incompletely understood, a multihit model has been proposed that accommodates causal factors from a variety of sources, including intestinal and adipose proinflammatory stimuli acting on the liver simultaneously. Prior cellular and molecular studies of patient and animal models have characterized several common pathogenic mechanisms of NAFLD, including proinflammation cytokines, lipotoxicity, oxidative stress, and endoplasmic reticulum stress. In recent years, gut microbiota has gained much attention, and dysbiosis is recognized as a crucial factor in NAFLD. Moreover, several genetic variants have been identified through genome-wide association studies, particularly rs738409 (Ile748Met) in PNPLA3 and rs58542926 (Glu167Lys) in TM6SF2, which are critical risk alleles of the disease. Although a high-fat diet and inactive lifestyles are typical risk factors for NAFLD, the interplay between diet, gut microbiota, and genetic background is believed to be more important in the development and progression of NAFLD. This review summarizes the common pathogenic mechanisms, the gut microbiota relevant mechanisms, and the major genetic variants leading to NAFLD and its progression. PMID- 27247568 TI - Short-Term Biliary Stent Placement Contributing Common Bile Duct Stone Disappearance with Preservation of Duodenal Papilla Function. AB - Aims. To investigate the effect of biliary stent placement without endoscopic sphincterotomy (EST) on common bile duct stones (CBDS) disappearance and the contribution of preserving the duodenal papilla function to reduce recurrence of CBDS. Methods. Sixty-six patients admitted for acute obstructive cholangitis due to CBDS who underwent biliary stent placement without EST for 2 years from March 2011 were evaluated retrospectively. The second endoscopic retrograde cholangiopancreatography (ERCP) was performed for treatment of CBDS 3 to 4 months after the first ERCP. We estimated the rate of stone disappearance at the time of second ERCP. Results. CBDS disappearance was observed in 32 (48.5%) of 66 patients. The diameter of the bile ducts and the diameter of CBDS in patients with CBDS disappearance were significantly smaller than in those with CBDS requiring extraction (p = 0.007 and p < 0.001, resp.). Stone disappearance was evident when the diameter of bile ducts and that of CBDS were <10 and 7 mm, respectively (p = 0.002). Conclusions. Short-term stent placement without EST eliminates CBDS while preserving duodenal papilla function and may be suitable for treating CBDS in patients with nondilated bile ducts and small CBDS. PMID- 27247569 TI - Multicenter Study of Antibiotic Resistance Profile of H. pylori and Distribution of CYP2C19 Gene Polymorphism in Rural Population of Chongqing, China. AB - This study was to investigate the antibiotic resistance profile of H. pylori and the distribution of CYP2C19 gene polymorphism in rural population of Chongqing, China. 214 and 111 strains of H. pylori were isolated from rural and urban patients, respectively. 99.53%, 20.09%, and 23.36% of the isolates in rural patients were found to be resistant to metronidazole, clarithromycin, and levofloxacin, while the resistant rate in urban patients was 82.88%, 19.82%, and 24.32%. The multiple antibiotic resistance percentage significantly increased from 28.26% (below 45 years) to 41.80% (above 45 years) in rural patients. Up to 44.39%, 45.79%, and 9.81% of rural patients from whom H. pylori was isolated were found to be extensive metabolizers, intermediate metabolizers, and poor metabolizers. No correlation was observed between antibiotic resistance profile of H. pylori and genetic polymorphism of CYP2C19 among rural population. There was a high prevalence of H. pylori strains resistant to metronidazole, clarithromycin, and levofloxacin in rural patients in Chongqing, China. The choice of therapy in this area should be based on local susceptibility patterns. Amoxicillin, gentamicin, and furazolidone are recommended as the first-line empiric regimen. PMID- 27247570 TI - Review of Anti-Inflammatory Herbal Medicines. AB - Medicinal plants and their secondary metabolites are progressively used in the treatment of diseases as a complementary medicine. Inflammation is a pathologic condition that includes a wide range of diseases such as rheumatic and immune mediated conditions, diabetes, cardiovascular accident, and etcetera. We introduce some herbs which their anti-inflammatory effects have been evaluated in clinical and experimental studies. Curcuma longa, Zingiber officinale, Rosmarinus officinalis, Borago officinalis, evening primrose, and Devil's claw are some of the introduced medicinal herbs in this review. Since the treatment of inflammation is not a one-dimensional remedy, this review tries to reach a multidimensional therapeutic approach to inflammation with the help of herbal medicine and modification in lifestyle. PMID- 27247571 TI - Development and Evaluation of an Online Fall-Risk Questionnaire for Nonfrail Community-Dwelling Elderly Persons: A Pilot Study. AB - Introduction. Falls are frequent in older adults and may have serious consequences but awareness of fall-risk is often low. A questionnaire might raise awareness of fall-risk; therefore we set out to construct and test such a questionnaire. Methods. Fall-risk factors and their odds ratios were extracted from meta-analyses and a questionnaire was devised to cover these risk factors. A formula to estimate the probability of future falls was set up using the extracted odds ratios. The understandability of the questionnaire and discrimination and calibration of the prediction formula were tested in a cohort study with a six-month follow-up. Community-dwelling persons over 60 years were recruited by an e-mail snowball-sampling method. Results and Discussion. We included 134 persons. Response rates for the monthly fall-related follow-up varied between the months and ranged from low 38% to high 90%. The proportion of present risk factors was low. Twenty-five participants reported falls. Discrimination was moderate (AUC: 0.67, 95% CI 0.54 to 0.81). The understandability, with the exception of five questions, was good. The wording of the questions needs to be improved and measures to increase the monthly response rates are needed before test-retest reliability and final predictive value can be assessed. PMID- 27247572 TI - Evaluation of Antimicrobial Resistance in Staphylococcus aureus Isolates by Years. AB - Objective. Recently, community and hospital-acquired infections with Staphylococcus aureus have increased and raised antibiotic resistant isolates. In this study, we aimed to evaluate the antibiotic resistance profile of S. aureus isolates over several years in various clinical specimens from our hospital. Materials and Methods. S. aureus strains from 2009 to 2014 were isolated from various clinical samples at Yuzuncu Yil University, Dursun Odabas Medical Center, Microbiology Laboratory, and their antibiotic susceptibility test results were retrospectively investigated. The isolates were identified by conventional methods, and antibiotic susceptibility tests were performed by the Phoenix (Becton Dickinson, USA) automated system method according to Clinical and Laboratory Standards Institute (CLSI) standards. Results. A total of 1,116 S. aureus isolates were produced and methicillin-resistant S. aureus (MRSA) to 21% of all S. aureus isolates between 2009 and 2014. According to the results of susceptibility tests of all isolates of S. aureus, they have been identified as sensitive to vancomycin, daptomycin, linezolid, and levofloxacin. While the resistance rates to nitrofurantoin, quinupristin-dalfopristin, and trimethoprim sulfamethoxazole were determined as 0.3%, 2.4%, and 6%, respectively, resistance rates to penicillin, erythromycin, rifampicin, gentamicin, and clindamycin were determined as 100%, 18%, 14%, 14%, and 11%, respectively. The highest percentage of methicillin resistance was determined as 30% in 2009, and the resistance was determined to have decreased in subsequent years (20%, 16%, 13%, 19%, and 21%) (p < 0.001). Conclusion. Currently, retrospective evaluations of causes of nosocomial infection should be done periodically. We think that any alteration of resistance over the years has to be identified, and all centers must determine their own resistance profiles, in order to guide empirical therapies. Reducing the rate of antibiotic resistance will contribute to reducing the cost of treatment. PMID- 27247573 TI - The Reliability of a Novel Automated System for ANA Immunofluorescence Analysis in Daily Clinical Practice. AB - Automated interpretation (AI) systems for antinuclear antibody (ANA) analysis have been introduced based on assessment of indirect immunofluorescence (IIF) patterns. The diagnostic performance of a novel automated IIF reading system was compared with visual interpretation (VI) of IIF in daily clinical practice to evaluate the reduction of workload. ANA-IIF tests of consecutive serum samples from patients with suspected connective tissue disease were carried out using HEp 2 cells according to routine clinical care. AI was performed using a visual analyser (Zenit G-Sight, Menarini, Germany). Agreement rates between ANA results by AI and VI were calculated. Of the 336 samples investigated, VI yielded 205 (61%) negative, 42 (13%) ambiguous, and 89 (26%) positive results, whereas 82 (24%) were determined to be negative, 176 (52%) ambiguous, and 78 (24%) positive by AI. AI displayed a diagnostic accuracy of 175/336 samples (52%) with a kappa coefficient of 0.34 compared to VI being the gold standard. Solely relying on AI, with VI only performed for all ambiguous samples by AI, would have missed 1 of 89 (1%) positive results by VI and misclassified 2 of 205 (1%) negative results by VI as positive. The use of AI in daily clinical practice resulted only in a moderate reduction of the VI workload (82 of 336 samples: 24%). PMID- 27247574 TI - Cardiac Function and Diastolic Dysfunction in Behcet's Disease: A Systematic Review and Meta-Analysis. AB - Background. Cardiovascular involvement in Behcet's disease (BD) is reported and has variable manifestations. It is not clear if diastolic dysfunction (DD) is increased in BD. Our objective was to evaluate the existing literature to determine if cardiac dysfunction, particularly DD, was more prevalent in these patients. Methods. A systematic review and meta-analysis of the available studies analyzing the echocardiographic findings in BD was conducted using a random effects model. Mean differences were used to calculate the effect sizes of the echocardiographic parameters of interest. Results. A total of 22 studies with 1624 subjects were included in the analysis. Patients with BD had statistically significantly larger mean left atrial dimension (0.08, p = 0.0008), greater aortic diameter (0.16, p = 0.02), significantly reduced ejection fraction (-1.08, p < 0.0001), significantly prolonged mitral deceleration time (14.20, p < 0.0001), lower E/A ratio (-0.24, p = 0.05), and increased isovolumetric relaxation time (7.29, p < 0.00001). Conclusion. DD is increased in patients with BD by the presence of several echocardiographic parameters favoring DD as compared to controls. The meta-analysis also identified that LA dimension is increased in BD patients. EF has also been found to be lower in BD patients. Aortic diameter was also increased in BD patients as compared to controls. PMID- 27247575 TI - Regenerative Potential of Mesenchymal Stromal Cells: Age-Related Changes. AB - Preclinical and clinical studies have shown that a therapeutic effect results from mesenchymal stromal cells (MSCs) transplant. No systematic information is currently available regarding whether donor age modifies MSC regenerative potential on cutaneous wound healing. Here, we evaluate whether donor age influences this potential. Two different doses of bone marrow MSCs (BM-MSCs) from young, adult, or old mouse donors or two doses of their acellular derivatives mesenchymal stromal cells (acd-MSCs) were intradermally injected around wounds in the midline of C57BL/6 mice. Every two days, wound healing was macroscopically assessed (wound closure) and microscopically assessed (reepithelialization, dermal-epidermal junction, skin appendage regeneration, granulation tissue, leukocyte infiltration, and density dermal collagen fibers) after 12 days from MSC transplant. Significant differences in the wound closure kinetic, quality, and healing of skin regenerated were observed in lesions which received BM-MSCs from different ages or their acd-MSCs compared to lesions which received vehicle. Nevertheless, our data shows that adult's BM-MSCs or their acd-MSCs were the most efficient for recovery of most parameters analyzed. Our data suggest that MSC efficacy was negatively affected by donor age, where the treatment with adult's BM-MSCs or their acd-MSCs in cutaneous wound promotes a better tissue repair/regeneration. This is due to their paracrine factors secretion. PMID- 27247576 TI - Lovastatin Decreases the Expression of CD133 and Influences the Differentiation Potential of Human Embryonic Stem Cells. AB - The lipophilic statin lovastatin decreases cholesterol synthesis and is a safe and effective treatment for the prevention of cardiovascular diseases. Growing evidence points at antitumor potential of lovastatin. Therefore, understanding the molecular mechanism of lovastatin function in different cell types is critical to effective therapy design. In this study, we investigated the effects of lovastatin on the differentiation potential of human embryonic stem (hES) cells (H9 cell line). Multiparameter flow cytometric assay was used to detect changes in the expression of transcription factors characteristic of hES cells. We found that lovastatin treatment delayed NANOG downregulation during ectodermal and endodermal differentiation. Likewise, expression of ectodermal (SOX1 and OTX2) and endodermal (GATA4 and FOXA2) markers was higher in treated cells. Exposure of hES cells to lovastatin led to a minor decrease in the expression of SSEA-3 and a significant reduction in CD133 expression. Treated cells also formed fewer embryoid bodies than control cells. By analyzing hES with and without CD133, we discovered that CD133 expression is required for proper formation of embryoid bodies. In conclusion, lovastatin reduced the heterogeneity of hES cells and impaired their differentiation potential. PMID- 27247577 TI - Skin Prick Test Analysis in Allergic Rhinitis Patients: A Preliminary Study in Abuja, Nigeria. AB - Allergic rhinitis (AR) is prevalent in Nigeria, though little information exists on the allergen. We assessed the clinical features of AR patients in our environment based on the allergic rhinitis impact on asthma (ARIA) classification. Only patients with positive skin prick test (SPT) were recruited. Seventy-four patients participated in the study. AR and asthma comorbidity were observed in 13.5%. The proportion of "sneezers-runners" was higher than "blockers" with significantly more "sneezers-runners" having persistent AR (P = 0.007). No relationship was established between these predominant symptoms and the aeroallergens used in this study. Intermittent mild and moderate/severe AR were evident in 13.5% and 31.1%, while persistent mild and moderate/severe were seen in 20.3% and 35.1%, respectively. House dust mites allergen yielded the highest number of positive responses (22.6%) followed by tree pollen (16.8%). No relationship was observed between the allergens tested and AR severity. Majority of patients were oligosensitive (33.8%) and polysensitive (35.1%) and were not significantly associated with AR severity (P = 0.07). Most AR patients presenting for treatment in Abuja, Nigeria, had moderate-severe persistent AR and showed similar SPT sensitization pattern with countries having similar climatic conditions. Sensitization patterns were not related to ARIA classification or predominant AR symptoms. PMID- 27247578 TI - The Role of Information Systems to Manage Cerebral Palsy. AB - Objective In healthcare system, it is necessary to have exact and accurate information in order to address health care needs and requirements of society members as well as expectations of policy makers, planners and decision makers. The aim of this narrative review article was to explain the role of information systems in cerebral palsy management and identify the advantages and barriers to the development of cerebral palsy registry system. Data were collected using databases such as of Science Direct, PubMed, Proquest, Springer, and SID (Scientific Information Database). Overall, 65 sources were selected. One of the biggest challenges for children with physical and motor disabilities in rehabilitation center is access to a system, which provides a comprehensive data set reflecting all information on a patient's care. Thus, data and information management in children with physical and motor disability such as cerebral palsy facilitates access to data and cerebral palsy data comparison as well as the monitoring incidence rate of cerebral palsy, enhancing health care quality; however, there are always numerous barriers to establish the system. One of the ways to overcome these problems is the establishment of a standard framework of minimum data sets and exact definition of its data components. Reliable standards in the use of applications as well as user-friendly software will ensure patients' data extraction and registration. PMID- 27247580 TI - Effect of Tamoxifen and Lithium on Treatment of Acute Mania Symptoms in Children and Adolescents. AB - OBJECTIVE: Many studies have supported the role of protein kinase C (PKC) inhibitors in the physiopathology and treatment of bipolar disorder in adults. Tamoxifen is one of the drugs with the effect of PKC inhibition. This study aimed to determine the effect of tamoxifen on the rate of improvement mania symptoms in the sample of children and adolescents with acute mania. MATERIALS & METHODS: In this randomized, placebo-controlled clinical trial study, registered in www.irct.ir with the code of IRCT201410126418N3, overall 44 patients with bipolar disorder with acute manic episode were randomly assigned into treatment and control groups. The serum levels of lithium and tamoxifen among the participants in the treatment groups were 0.8 -1.1 mg and 20-40 mg per day respectively. Serum level of lithium among participants in the control group was similar. The main comparisons were made based on the Young Mania Rating Scale (YMRS) and Children Depression Inventory (CDI) scores of the participants at baseline and at the end of each study week. The pharmacological side effects of serum level of lithium were examined weekly. Analysis of Covariance(ANCOVA) test was used for the statistical analysis. RESULTS: There was no difference in the baseline score of YMRS and CDI in the treatment and control groups while a statistical significant difference (P < 0.05) in these scores was found between and within the groups. CONCLUSION: The addition of tamoxifen to lithium causes a significant difference in reducing the symptoms of mania and depression in the treatment group compared to the control group. PMID- 27247579 TI - Association of Family History of Epilepsy with Earlier Age Onset of Juvenile Myoclonic Epilepsy. AB - OBJECTIVE: Juvenile myoclonic epilepsy (JME) is supposedly the most frequent subtype of idiopathic generalized epilepsies (IGE). The aim of this study was to determine the prevalence of JME and comparison of patients' demographics as well as timeline of the disease between positive family history epileptic patients (PFHE) and negative family history epileptic patients (NFHE) among sample of Iranian epileptic patients. MATERIALS & METHODS: From Feb. 2006 to Oct. 2009, 1915 definite epileptic patients (873 females) referred to epilepsy clinics in Isfahan, central Iran, were surveyed and among them, 194 JME patients were diagnosed. JME was diagnosed by its specific clinical and EEG criteria. Patients were divided into two groups as PFHE and NFHE and data were compared between them. RESULTS: JME was responsible for 10% (194 patients) of all types of epilepsies. Of JME patients, 53% were female. In terms of family history of epilepsy, 40% were positive. No significant differences was found between PFHE and NFHE groups as for gender (P>0.05). Age of epilepsy onset was significantly earlier in PFHE patients (15 vs. 22 yr, P<0.001). Occurrence of JME before 18 yr old among PFHE patients was significantly higher (OR=2.356, P=0.007). CONCLUSION: A family history of epilepsy might be associated with an earlier age of onset in patients with JME. PMID- 27247581 TI - Comparison of the Rey Auditory Verbal Learning Test (RAVLT) and Digit Test among Typically Achieving and Gifted Students. AB - OBJECTIVE: In this study, different kinds of memory were evaluated using Rey Auditory Verbal Learning (RAVLT) test and were compared between two groups of typical and gifted students using Digit Span test. Finally, we determined if working memory interfered with scores in different Rey stages or not. MATERIAL & METHODS: This study was conducted in Tehran City, Iran in 2013. Scores on RAVLT were compared with WISC- R digit span results in a sample of 148 male students aged 12-14 yr old divided into two groups including 75 students in typical school (IQ ranging between 90 and 110) and 73 gifted students (IQs ranging between 110 and 130). RESULTS: Gifted students obtained higher scores than typical students in both Forward Digit Span (FDS) and Backward Digit Span (BDS) and all 9 stages of RAVLT comparing with typical students (P<0.001). There was no significant difference between different ages (P> 0.05). The 14 yr old students in both groups had the highest score. There was a high correlation between FDS and the first stage of RAVLT as well as high correlation between BDS and seventh stage of RAVLT. CONCLUSION: Intelligence has effect on better score of memory and gifted subjects had better scores in memory tests, although the intelligence effect in learning was quantitative rather than qualitative. RAVLT is a comprehensive test, which evaluates short-term memory, working memory and long-term memory and besides Digit span test provides precious information about memory and learning of subjects in order to program different student's educational schedules. PMID- 27247582 TI - Prognosis of Guillain-Barre Syndrome in Children. AB - OBJECTIVE: Guillain-Barre Syndrome (GBS) is an acute polyradiculoneuropathy characterized by progressive motor weakness of limbs and areflexia. In this study, our aim was to evaluate the clinical pattern and prognosis of children with Guillain-Barre syndrome. MATERIALS & METHODS: This cross-sectional study was conducted in the Pediatric Neurology Unit of Amirkola Children's Hospital, Babol, Iran during the period of 5 years from October 2008 to September 2013. We assessed the clinical features, results of electrodiagnostic tests, functional status, treatment and outcome of 17 children diagnosed with GBS. RESULTS: Of 17 (male to female ratio = 1.6:1) children studied, all had motor weakness, 4 children (23.5 %) and cranial nerve palsies. Respiratory paralysis was found in one child requiring assisted ventilation. Antecedent illness preceding GBS was recorded in 7 (41.2%) children. The GBS subtype distribution as per electrodiagnostic studies was as follows: acute inflammatory demyelinating polyradiculoneuropathy (AIDP) in 12 (70.6%) acute motor axonal neuropathy (AMAN) in 3 (17.6%), acute motor sensory axonal neuropathy (AMSAN) in 2 (11.8%). IVIG constituted the treatment given in all of the patients. Complete recovery was observed in 16 children and the remaining one child was dependent to wheelchair. CONCLUSION: GBS in children is not poor prognostic disorder and our recommendation is administration of IVIG as soon as possible after clinical diagnosis. Except for one child who remained wheelchair bound, there was no mortality or morbidity in long-term observation. Besides, strong limitation of our study was the low number of subjects. PMID- 27247583 TI - Exploring the Psychometric Properties of the Farsi Version of Quality of Life Kindl Questionnaire for 4-7 Year-Old Children in Iran. AB - OBJECTIVE: The aim of this study was to translate and validate the psychometric properties of the Quality of Life Kindl questionnaire. MATERIALS & METHODS: Parents of 4-7 yr-old healthy and ill children referred to Mofid Children Hospital in Tehran in 2013, Iran were sampled randomly in two groups each of which 130 people. After translation, the questionnaie's validity and reliability was evaluated and was confirmed for face and content validity. Questionnaire was also completed by two (one healthy and one ill) groups for which inclusion criteria included consent of the parents, age of the children being beween 4 and 7 yr, and presence of the child in a nursery school, kindergarten, school or any class at least for one month. Exclusion criteria were inability of the parents in answering the questions accurately. Inclusion criterion for the ill group was having chronic cardiac, neurologic, hematologic, or respiratory diseases, lasting longer than 3 months for which they were followed up in outpatient clinic in the hospital. The reliability of questionnaire was measured by the Cronbach's alpha. Data were analyzed using factor analysis, Spearman's correlation coefficient, Mann-Whitney and Chi-square test. RESULTS: The reliability was 0.85 and 0.81 in healthy and ill groups, respectively. The results of factor analysis showed that each of eight subscales of questionnaire had acceptable construct validity. Only two of 52 questions of the questionnaire did not have proper correlation coefficient. CONCLUSION: Quality of Life Kindl Questionnaire is a valid and reliable test for assessing healthy and ill children in Iran. PMID- 27247584 TI - The Effectiveness of Attribution Retraining on Health Enhancement of Epileptic Children. AB - OBJECTIVE: Epilepsy is a chronic neurological disease. Evidence has indicated that epilepsy has an impact on mental and physical health of children. The present study aimed to determine the effectiveness of attribution retraining on health enhancement of epileptic children. MATERIALS & METHODS: This was an experimental study with a pre-test and a post-test design with a control group. Thirty students with epilepsy (11 female and 19 male students) were selected in convenience from Iranian Epilepsy Association. They were assigned to experimental and control groups and their mothers completed Child Health Questionnaire (CHQ PF.28) before and after the intervention. The experimental group attended to eleven sessions (each session 45 minutes; twice a week). Subjects were trained by attribution retraining program, but control group was not. Multivariate analysis of covariance (MANCOVA) was used for analyzing the data. RESULTS: Health (both psychosocial and physical) of experimental group enhanced significantly after the intervention sessions compared to control group. CONCLUSION: Attribution retraining is an effective intervention to enhance the psychosocial and physical health of epileptic children. PMID- 27247585 TI - Efficacy and Safety of Single Low Dose Intravenous Fentanyl in Pain Reduction of Lumbar Puncture in Near Term Neonates by A Randomized Clinical Trial. AB - OBJECTIVE: Reduction of pain of invasive procedures in neonates can prevent pain side effects. The purpose of present study was to evaluate the efficacy and safety of a single low dose of intravenous fentanyl in reducing of lumbar puncture (LP) pain in neonates. MATERIALS & METHODS: In this randomized clinical trial, registered with code number of 2014022616761N150, admitted neonates to Shahid Sadoughi Hospital, Yazd, Iran from August-April 2012 (45 cases) were randomly assigned into two groups to receive 2 MUg/kg of intravenous fentanyl or 0.2 milliliter of normal saline, two min before LP. Primary outcome was success rate in reducing of pain during needle insertion to skin (pain score of less than three). Secondary outcomes were clinical side effects and serious adverse events. RESULTS: Forty-five neonates including 23 girls and 22 boys were evaluated. Pain reduction was obtained in 39.1% (9 of 23 neonates) of fentanyl group and in 4.5% (one of 22 neonates) of control group. Means of pulse rate (136.41+/- 9.16 vs. 148.9+/- 8.99) and pain score during needle insertion (3.41+/-1.31 vs. 5.8+/ 1.12) were lower in fentanyl group. No severe adverse effects were seen in both groups. Side effects such as vomiting [9% (N=2) in control and 4.3% (N=1) in fentanyle group] and mild transient decrease in oxygen saturation in 8.7% (N=2) of fentanyle group were seen. Safety in two groups was not statistically different. CONCLUSION: Intravenous fentanyl might be considered as a safe and effective analgesic drug in LP in neonates. PMID- 27247586 TI - Early and Late Outcome of Premature Newborns with History of Neonatal Intensive Care Units Admission at 6 Years Old in Zanjan, Northwestern Iran. AB - OBJECTIVE: Premature birth is an important factor for mortality and morbidity of neonates. This study was designed to evaluate the outcome of preterm neonates who needed neonatal intensive care (NICU) hospitalization after 6 yr at their entrance to the school. MATERIALS & METHODS: This cross sectional study was conducted on premature neonates consecutively hospitalized in NICU of Valie Asr Hospital (the Academic Pediatric Hospital, Zanjan, Northwestern Iran) from September 2001 to September 2003. All children with a history of prematurity and NICU treatment were evaluated at their entrance to the school. Demographic findings, clinical examinations, IQ test, hearing and visual acuity exams were recorded. RESULTS: From 179 neonates, 78 (43.6%) survived and were discharged from hospital. Fifty-four of them were available and entered first grade in primary school. Only one case had severe mental retardation. One case had severe retinopathy of prematurity (ROP). Hearing abnormality was not detected in any case. There was no significant relation between IQ score, visual as well as hearing findings and gestational age. CONCLUSION: We did not find significant disability in the outcome of surviving infants. This could be explained by the high mortality rate of neonates during hospitalization. PMID- 27247587 TI - Demographic and Clinical Findings in Pediatric Patients Affected by Organic Acidemia. AB - OBJECTIVE: Metabolic disorders, which involve many different organs, can be ascribed to enzyme deficiency or dysfunction and manifest with a wide range of clinical symptoms. This study evaluated some of the demographic and clinical findings in pediatric patients affected by organic acidemia. MATERIALS & METHODS: This cross-sectional study was part of a larger study conducted in patients with metabolic disorders during a period of 7 years from 2007 to 2014 in Isfahan Province, Iran. Our study covered a wide range of cases from newborn infants (one week old) to adolescents (children up to the age of 17 years). This study evaluated patients' demographic information, history of disease, developmental and educational status, clinical and general conditions. Phone and in-person interviews were used to gather information. RESULTS: Out of 5100 patients screened in this study, 392 patients were affected by one of the different metabolic disorders and 167 individuals were diagnosed as organic acidemia. Propionic acidemia/methyl malonic acidemia (PA/MMA) was the most prevalent form of this metabolic disorder. The frequency of consanguinity was 84.7% in the group of patients. The mortality rate was 18.8% in patients with organic academia. CONCLUSION: Each of the metabolic diseases, as a separate entity, is rare; nevertheless, in aggregate they have a somewhat high overall prevalence. These diseases result in mental and developmental disorders in the absence of quick diagnosis and initiation of treatment. Furthermore, more mutations should be identified in societies affected by consanguinity. Further research should also be conducted to determine worthwhile and more-efficient screening methods as well as long term neurological prognosis. PMID- 27247588 TI - Hereditary Sensory and Autonomic Neuropathy Type IV in 9 Year Old Boy: A Case Report. AB - Objective The Hereditary Sensory and Autonomic neuropathy (HSAN) is a rare group of neuropathies that affects the Sensory and Autonomic nervous system. The patients do not have the ability of sensing different sensations such as pain and temperature, which tends to lead to different injuries. In addition, due to autonomic involvement, the patients suffer from fluctuation in body temperature periodically and lack of precipitation. HSAN is divided into 5 types according to the age of onset, clinical features, and inheritance. Our case was a 9-yr old boy from cousin parents. He had some developmental delay and history of recurrent fever and convulsion in the first year of his life. Gradually, other symptoms added to patient' feature such as multiple painless skin ulcers, tooth loss, destruction of toes and fingers. In electrodiagnostic study, we found decreased amplitude of sensory nerves, while the other studies were normal. Laboratory test and imaging studies were also normal. All clinical and paraclinical findings were in favor of HSAN type IV. There is no cure for such patients; as a result, these patients and their families need receiving appropriate education and timely rehabilitation services. PMID- 27247589 TI - Angelman Syndrome: A Case Report. AB - Objective Angelman syndrome (AS) is a neurodevelopmental disorder presented by jerky movement, speech delay and cognitive disability epilepsy as well as dysmorphic features. It occurs due to an expression deletion in 15q11-q13 chromosome. In this article, we present an eight yr boy referred to Pediatrics Neurologic Clinic Mashhad, Iran for speech delay. He had abnormal behavior ataxia unusual laughing facial expression intellectual disability and mandibular prognathism. Metabolic screening tests and brain MRI were normal. Genetic analysis was pathognomonic for AS. PMID- 27247590 TI - Functional Neurological Symptom Disorder: Mismanagement, Misdiagnosis, Chronic Cough Following Sexual Abuse: A Rare Case Report. AB - Objective Conversion disorder (CD) is a mental disorder in which patient displays neurological symptoms such as blindness, mutism, paralysis and seizure. It starts when our mind converts our mental stress into a physical symptom. A 15-year-old single white female with chronic cough, which had begun 5 months ago, was brought to our clinic. She had no history of hospitalization. His daily cough was without sputum production or fever, rhinorrhea and stopped during sleep. There was no recent exposure to tobacco smoke or a person with a chronic productive cough. Laboratory tests were normal. She had engaged 4 months ago. Doing sex during engagement is prohibited in her culture but and had anal sex, because of her spouse's trend. Psychotherapy was done and complete recovery was accomplished. PMID- 27247591 TI - Recent Advances in Autism Spectrum Disorders: Applications of Whole Exome Sequencing Technology. AB - Autism spectrum disorders (ASD) is characterized by three core symptoms with impaired reciprocal social interaction and communication, a pattern of repetitive behavior and/or restricted interests in early childhood. The prevalence is higher in male children than in female children. As a complex neurodevelopmental disorder, the phenotype and severity of autism are extremely heterogeneous with differences from one patient to another. Genetics has a key role in the etiology of autism. Environmental factors are also interacting with the genetic profile and cause abnormal changes in neuronal development, brain growth, and functional connectivity. The term of exome represents less than 1% of the human genome, but contains 85% of known disease-causing variants. Whole-exome sequencing (WES) is an application of the next generation sequencing technology to determine the variations of all coding regions, or exons of known genes. For this reason, WES has been extensively used for clinical studies in the recent years. WES has achieved great success in the past years for identifying Mendelian disease genes. This review evaluates the potential of current findings in ASD for application in next generation sequencing technology, particularly WES. WES and whole-genome sequencing (WGS) approaches may lead to the discovery of underlying genetic factors for ASD and may thereby identify novel therapeutic targets for this disorder. PMID- 27247593 TI - Emotional Regulation and Executive Function Deficits in Unmedicated Chinese Children with Oppositional Defiant Disorder. AB - OBJECTIVE: This study aims to explore the feature of emotional regulation and executive functions in oppositional defiant disorder (ODD) children. METHODS: The emotional regulation and executive functions of adolescents with ODD, as well as the relationship between the two factors were analyzed using tools including Adolescent Daily Emotional Regulation Questionnaire (ADERQ), Wisconsin Card Sorting Test (WCST) and Cambridge Neuropsychological Test Automated Battery (CANTAB), in comparison with attention deficit hyperactivity disorder (ADHD) children without behavioral problem and healthy children; the ADERQ assessed emotional regulation ability and others were used to assess executive function. RESULTS: Compared to normal children, the ODD group displayed significant differences in the scores of cognitive reappraisal, rumination, expressive suppression, and revealing of negative emotions, as well as in the score of cognitive reappraisal of positive emotions. WCST perseverative errors were well correlated with rumination of negative emotions (r=0.47). Logistic regression revealed that the minimum number of moves in the Stocking of Cambridge (SOC) test (one test in CANTAB) and negative emotion revealing, were strongly associated with ODD diagnosis. CONCLUSION: Children with ODD showed emotion dysregulation, with negative emotion dysregulation as the main feature. Emotion dysregulation and the lack of ability to plan lead to executive function deficits. The executive function deficits may guide us to understand the deep mechanism under ODD. PMID- 27247594 TI - Sociocultural Factors Associated with Caregiver-Psychiatrist Relationship in Taiwan. AB - OBJECTIVE: Research on sociocultural factors associated caregiver-provider relationship is needed to enhance family involvement in psychiatric care. This study examines from the caregiver's perspective the associations of schizophrenia attributions, stigmatization, and caregiving experiences with caregiver psychiatrist working relationship in Taiwan. METHODS: This cross-sectional study used a convenience sample of 152 Taiwanese family caregivers of persons diagnosed with schizophrenia, recruited from a grassroots organization, 4 community mental health rehabilitation centers and 2 psychiatric hospitals between July 2012 and March 2013. Multiple linear regression models were used for analysis. RESULTS: Biological attribution was positively associated with perceived family collaboration, and so was environmental attribution with perceived informational support. Internalized stigma was negatively associated with perceived family collaboration. Caregiving rewards were positively related to both perceived family collaboration and informational support, and so was experience of problems with services to perceived family collaboration. CONCLUSION: The examination of family perceptions informs Western psychiatric care providers of the importance of culturally sensitive practices in developing an effective working relationship with family caregivers, particularly in regards to caregivers' casual attributions, impact of stigma, and caregiving experiences. PMID- 27247595 TI - Correlations among Social Anxiety, Self-Esteem, Impulsivity, and Game Genre in Patients with Problematic Online Game Playing. AB - OBJECTIVE: Recent studies of online game addiction have suggested that social interaction and impulsivity are critical factors for the etiology and progress of online game addiction. We hypothesized that the genre of the online game is associated with impulsivity and sociality in individuals with online game addictions. METHODS: In total, 212 patients with problematic online game playing were divided into four groups by game genre: 1) massive multiplayer online role playing game (MMORPG), 2) real-time strategy (RTS), 3) first-person shooter (FPS), and 4) other. Their symptoms and characteristics were assessed using 8 scales and 2 tests to estimate self-esteem, impulsiveness, comorbidity, social interaction status, and cognitive function. RESULTS: The mean social anxiety score was highest in the MMORPG group and lowest in the FPS group. The mean self esteem score was highest in the RTS group. Social anxiety score was positively correlated with Internet addiction score in the MMORPG group, and the self-esteem score was positively correlated with Internet addiction score in the RTS group. CONCLUSION: The genre of online game was not associated with impulsivity, but social anxiety status varied significantly with game genre, and differences in social anxiety were especially pronounced in patients playing the MMORPG (highest social anxiety) and FPS (lowest social anxiety) game genres. In addition, self esteem was highest in the RTS game genre. PMID- 27247592 TI - Review of Cohort Studies for Mood Disorders. AB - This paper aimed to review currently available cohort studies of subjects with mood disorders such as major depressive disorder (MDD) and bipolar disorder (BD). Using the PubMed and KoreaMed databases, we reviewed eight major cohort studies. Most studies recruited participants with MDD and BD separately, so direct comparison of factors associated with diagnostic changes was difficult. Regular and frequent follow-up evaluations utilizing objective mood ratings and standardized evaluation methods in a naturalistic fashion are necessary to determine detailed clinical courses of mood disorders. Further, biological samples should also be collected to incorporate clinical findings in the development of new diagnostic and therapeutic approaches. An innovative cohort study that can serve as a platform for translational research for treatment and prevention of mood disorders is critical in determining clinical, psychosocial, neurobiological and genetic factors associated with long-term courses and consequences of mood disorders in Korean patients. PMID- 27247596 TI - Systemic Family Therapy of Comorbidity of Anxiety and Depression with Epilepsy in Adolescents. AB - OBJECTIVE: The aim of this study was to find if systemic family therapy (SFT) does work in anxiety and depression with epilepsy in adolescents (ADAE). METHODS: 104 adolescents with epilepsy, aged 13-20 years old, were included from December 2009 to December 2010, the enrolled patients were with anxiety [Hamilton Anxiety Scale (HAMA) score >=14 points] or depression [Hamilton Depression Scale (HAMD) score >=20 points]. The patients were randomly divided into the control group (n=52) treated with antiepileptic drugs (AED) and the intervention group (n=52) undergone Systemic Family Therapy (SFT) as well as AED. The AED improvements, anxiety and depression scores, Social Support Rating Scale (SSRS), Family Assessment Device (FAD) and scale of systemic family dynamics (SSFD) were observed after 3-month treatment. RESULTS: The frequencies of epileptic seizures in intervention group was decreased much more significantly than the control group (4.22+/-3.54 times/month vs. 6.20+/-5.86 times/month, p=0.04); and the scores of anxiety (9.52+/-6.28 points vs. 13.48+/-8.47 points, p=0.01) and depression (13.86+/-9.17 points vs. 18.89+/-8.73 points, p=0.02) were significantly decreased than the control group; meanwhile, the family dynamics and family functions were significantly improved, and the social support was also increased (p<0.05). CONCLUSION: SFT combined with AEDs had better efficacies than AEDs alone, not only the frequency of epileptic seizures was decreased, but also the patients' anxiety and depression were improved, and the family dynamics, family functions and social support were improved. PMID- 27247597 TI - Salivary Nitric Oxide, a Biomarker for Stress and Anxiety? AB - OBJECTIVE: To investigate if salivary nitrate correlates to the daily psychological stress and anxiety in a group of human subjects. METHODS: The convenient sample recruitment method was employed; data from seventy three subjects were analyzed. The Perceived Stress Scale (PSS) and Hamilton Anxiety Rating Scale (HAM-A) inventories were used to determine stress and anxiety scores respectively. Salivary nitric oxide was measured through nitrate (NOx) levels using the Griess reaction method. RESULTS: Although stress and anxiety were correlated. No significant correlation exists between salivary nitrate and daily psychological stress and anxiety in the study's participants. CONCLUSION: While all previous studies focused NOx levels in acute stress models. This is the first study to investigate the correlation between salivary nitrates and daily psychological stress and anxiety. Although stress and anxiety were correlated, there is no correlation between salivary nitrates and daily psychological stress and anxiety. Further studies are required to investigate this correlation using other biological samples such as plasma. PMID- 27247598 TI - Influence of Betaxolol on the Methamphetamine Dependence in Mice. AB - OBJECTIVE: The noradrenaline system is involved in the reward effects of various kinds of abused drugs. Betaxolol (BTX) is a highly selective beta1-antagonist. In the present study, we evaluated the effect of BTX on methamphetamine (MAP) induced conditioned place preference (CPP) and hyperactivity in mice. METHODS: The mice (n=72) were treated with MAP or saline every other day for a total of 6 days (from day 3 to day 8; 3-times MAP and 3-times saline). Each mouse was given saline (1 mL/kg) or MAP (1 mg/kg, s.c.) or BTX (5 mg/kg, i.p.) or MAP with BTX (5 mg/kg, i.p.) 30 min prior to the administration of MAP (1 mg/kg, s.c.) every other day and paired with for 1 h (three-drug and three-saline sessions). We then compared the CPP score between the two groups. After the extinction of CPP, the mice were given BTX (5 mg/kg, i.p.) or saline (1 mL/kg) 24 h prior to a priming injection of MAP, and were then immediately tested to see whether the place preference was reinstated. RESULTS: The repeated administration of BTX 30 min prior to the exposure to MAP significantly reduced the development of MAP-induced CPP. When BTX was administered 24 h prior to the CPP-testing session on day 9, it also significantly attenuated the CPP, but did not result in any change of locomotor activity. In the drug-priming reinstatement study, the extinguished CPP was reinstated by a MAP (0.125 mg/kg, s.c.) injection and this was significantly attenuated by BTX. CONCLUSION: These findings suggest that BTX has a therapeutic and preventive effect on the development, expression, and drug-priming reinstatement of MAP-induced CPP. PMID- 27247599 TI - Reduced Venous Blood Basophil Count and Anxious Depression in Patients with Major Depressive Disorder. AB - OBJECTIVE: Anxious depression has a distinct neurobiology, clinical course and treatment response from non-anxious depression. Role of inflammation in anxious depression has not been examined. As an exploratory study to characterize the role of inflammation on a development of anxious depression, we aimed to determine the relationship between white blood cell (WBC) subset counts and anxiety in individuals with major depressive disorder (MDD). METHODS: A total of 709 patients who were newly diagnosed with MDD were recruited. Anxiety levels of participants were evaluated using the Anxiety/ Somatization subitem of the Hamilton Depression Rating Scale. The association between WBC subset fraction and anxiety was evaluated. RESULTS: Basophil and eosinophil sub-fractions showed significant negative correlations with HAM-D anxiety/somatization factor scores (basophils: r=-0.092, p=0.014 and eosinophils: r=-0.075, p=0.046). When an anxiety score (a sum of somatic and psychic anxiety) was entered as a dependent variable, only basophils showed significant negative association with the anxiety scores after adjusting for all other WBC subset counts and demographic factors (t=-2.57, p=0.010). CONCLUSION: This study showed that anxious depression had a decreased basophil subfraction, which might be associated with involvement of inflammation in development of anxious depression. PMID- 27247600 TI - Lack of Association between Pre-Operative Insulin-Like Growth Factor-1 and the Risk of Post-Operative Delirium in Elderly Chinese Patients. AB - OBJECTIVE: Postoperative delirium (POD) is a highly prevalent complex neuropsychiatric syndrome in elderly patients. However, its pathophysiology is currently unknown. Early detection and prevention of POD is important; therefore, the aim of this study was to investigate the link between preoperative insulin growth factor 1 (IGF-1) levels in the serum and POD in the Chinese elderly patients. METHODS: One hundred and three patients who were undergoing an orthopedic operation took part in the study. Preoperative serum IGF-1 levels were measured. POD was determined daily using the Confusion Assessment Method (CAM) and DSM-IV TR. Baseline serum IGF-1 levels were compared between patients who did and did not develop POD. Correlation coefficients were calculated to evaluate relationship between baseline characteristics and serum IGF-1 levels. The relationship between baseline biomarkers and delirium status was investigated using logistic regression analysis, adjusting for potential confounding variables. RESULTS: Twenty-three patients developed POD. The POD group had lower MMSE scores and higher CCI scores and proportions of acute admission. Preoperative serum IGF-1 levels were correlated with MMSE scores and age (MMSE: r=0.230, p<0.05; age: r=-0.419, p<0.001). Baseline serum IGF-1 levels did not differ between patients who did and did not develop POD, even after adjusting for potential confounding factors, MMSE score, and age. CONCLUSION: No association was found between preoperative IGF-1 levels and POD, suggesting that they are not direct biomarkers of the incidence of POD among the Chinese elderly population. Further research with larger sample sizes is warranted to clarify the relationship. PMID- 27247601 TI - Effects of Mind-Body Training on Personality and Behavioral Activation and Inhibition System According to BDNF Val66Met Polymorphism. AB - OBJECTIVE: It has been known that mind-body training (MBT) can affect personality and behavior system as well as emotional well-being, but different effects of MBT on them has not been reported according to BDNF genetic polymorphism. METHODS: Healthy subjects consisted of 64 subjects and the MBT group who practiced meditation regularly consisted of 72 practitioners. Participants completed neuroticism-extraversion-openness (NEO) Five-Factor Inventory and Behavioral Activation System/Behavioral Inhibition System (BAS/BIS) scales. All subjects were genotyped for the BDNF Val66Met polymorphism. RESULTS: In the same genotypes of the BDNF Val/Val+Val/Met group, MBT group showed the increased Extraversion (p=0.033) and the increased Openness to Experience (p=0.004) compared to the control group. Also, in the same Met/Met carriers, MBT group exhibited the increase of Extraversion (p=0.008), the reduction of Neuroticism (p=0.002), and the increase of Openness to Experience (p=0.008) compared to the control group. In the same genotypes of the BDNF Val/Val+Val/Met group, MBT group showed the decreased BAS-Reward Responsiveness (p=0.016) and the decrease of BIS (p=0.004) compared to the control group. In the BDNF Met/Met group, MBT group increased BAS Fun Seeking (p=0.045) and decreased BIS (p=0.013) compared to the control group. CONCLUSION: MBT would differently contribute to NEO personality and BAS/BIS according to BDNF genetic polymorphism, compensating for different vulnerable traits based on each genotype. PMID- 27247602 TI - Efficacy of Galantamine on Cognition in Mild-to-Moderate Alzheimer's Dementia after Failure to Respond to Donepezil. AB - OBJECTIVE: This study compares the efficacy of the cholinesterase inhibitor (ChEI) galantamine on cognition in patients with mild-to-moderate Alzheimer's dementia (AD) who were either naive to ChEI drugs or who had failed a trial of the ChEI donepezil. METHODS: Outpatients with AD were sequentially referred for screening and enrollment. Current outpatients who had taken donepezil for at least 6 months without demonstrated efficacy on cognition were switched to galantamine (switched group). New outpatients with no ChEI prescription history were classified as the naive group and were given galantamine. The primary outcome measures for the between-group comparison were response rate on cognition at 26 and 52 weeks (categorical) and change on the Korean version of the Alzheimer's Disease Assessment Scale-cognitive subscale (dimensional). Secondary cognitive outcomes were measured using the subset of frontal executive function and the Korean Mini-Mental State Examination. RESULTS: Seventy outpatients were enrolled and 66 were analyzed by Intent-to-treat (ITT). There were 42 cases in the naive group and 24 in the switched group. Response rates did not differ at 26 weeks (71.4% naive vs. 58.3% switched; p=0.277) or at 52 weeks (59.5% naive vs. 41.6% switched; p=0.162). No significant differences were observed in the pattern of change over the 52 weeks on the primary and secondary cognitive scales. CONCLUSION: As the efficacy of galantamine on cognition was not inferior in the switched group compared to that in the naive group, switching ChEI drugs is clinically feasible for non-responding patients with mild-to-moderate AD. PMID- 27247604 TI - Factors That Affect Adolescent Drug Users' Suicide Attempts. AB - Drug abuse has been widely linked to suicide risk. We examined the factors that affect adolescent drug users' suicide attempts in South Korea. This study analyzed the data of 311 adolescents who had used drugs such as inhalants, psychotropic drugs, and marijuana (195 males and 116 females). Among 311 subjects, 109 (35.0%) had attempted suicide during the last 12 months. After adjusting for other variables, depressive mood (OR=19.79) and poly-drug use (OR=2.79), and low/middle levels of academic achievement compared with a high level (OR=3.72 and 4.38) were independently associated with increased odds of a suicide attempt, while better perceived health (OR=0.32) was independently associated with reduced odds of a suicide attempt. For adolescent drug users, preventive work should be directed toward the active treatment of drug use, depression, and physical health and reinforcing proper coping strategies for academic and other stress. PMID- 27247603 TI - Dysfunctional Patterns of Gamma-Band Activity in Response to Human Faces Compared to Non-Facial Stimuli in Patients with Schizophrenia. AB - OBJECTIVE: Healthy individuals show stronger gamma-band activities (GBAs) for socially relevant stimuli (human faces) than for non-relevant ones. This study aimed to examine whether this gamma-band preference occurs in patients with schizophrenia. METHODS: EEG was recorded for 24 patients with schizophrenia and 23 healthy controls while they viewed pictures of human faces, chairs, and nature scenes. The spectral powers of high-beta (20-30 Hz) and gamma (30-80 Hz) frequencies were analyzed along 3 midline cortical regions, and phase synchronization was calculated. RESULTS: Compared to the response to non-facial stimuli, higher event related deactivation to facial stimuli was observed for the high-beta frequency across groups. For the gamma frequency, early-stage GBA was increased and late-stage GBA was decreased for all 3 stimuli in patients with schizophrenia compared to healthy controls. Preferential GBA patterns (100-200 and 200-300 ms) were found in healthy controls, but not in patients with schizophrenia. Significant correlation existed between negative symptoms and GBA in the frontal region for chair and scene stimuli. There was no significant intergroup difference in phase synchronization pattern. CONCLUSION: Our results suggest that patients with schizophrenia have deficits in the preferential pattern of GBA for human faces and the deficits in the preferential pattern were mainly influenced by over-response to socially non-relevant stimuli. PMID- 27247606 TI - Comorbid Bipolar Disorder and Obsessive-Compulsive Disorder: An Old Debate Renewed. PMID- 27247605 TI - Visual Hallucinations and Amyloid Deposition in Parkinson's Disease Dementia: A Case Report. AB - Parkinson's disease dementia (PDD) is notorious for its debilitating clinical course and high mortality rates. Consequently, various attempts to investigate predictors of cognitive decline in Parkinson's disease (PD) have been made. Here we report a case of a 75-year-old female patient with PD who visited the clinic with complaints of recurrent visual hallucinations and cognitive decline, whose symptoms were ameliorated by the titration of rivastigmine. Imaging results showed pronounced diffuse cortical amyloid deposition evidenced by 18F florbetaben amyloid positron emission tomography (PET) imaging. This observation suggests that pronounced amyloid deposition and visual hallucinations in PD patients could be clinically significant predictors of cognitive decline in PD patients. Future research should concentrate on accumulating more evidence for possible predictors of cognitive decline and their association with PD pathology that can enable an early intervention and standardized treatment in PDD patients. PMID- 27247607 TI - Effect of Corilagin on the Proliferation and NF-kappaB in U251 Glioblastoma Cells and U251 Glioblastoma Stem-Like Cells. AB - Background. This study is to explore the effect of corilagin on the proliferation and NF-kappaB signaling pathway in U251 glioblastoma cells and U251 glioblastoma stem-like cells. Methods. CD133 positive U251 glioblastoma cells were separated by immunomagnetic beads to isolate glioblastoma stem-like cells. U251 cells and stem-like cells were intervened by different corilagin concentrations (0, 25, 50, and 100 MUg/mL) for 48 h, respectively. Cell morphology, cell counting kit-8 assay, flow cytometry, dual luciferase reporter assay, and a western blot were used to detect and analyze the cell proliferation and cell cycle and investigate the expression of IKBalpha protein in cytoplasm and NF-kappaB/p65 in nucleus. Results. Corilagin inhibited the cell proliferation of U251 cells and their stem like cells and the inhibition role was stronger in U251 stem-like cells (P < 0.05). The cell cycle was arrested at G2/M phase in the U251 cells following corilagin intervention; the proportion of cells in G2/M phase increased as the concentration of corilagin increased (P < 0.05). The U251 stem-like cells were arrested at the S phase following treatment with corilagin; the proportion of cells in the S phase increased as the concentration of corilagin increased (P < 0.05). The ratio of dual luciferase activities of U251 stem-like cells was lower than that of U251 cells in the same corilagin concentration. With increasing concentrations of corilagin, the IKBalpha expression in cytoplasm of U251 cells and U251 stem-like cells was increased, but the p65 expression in nucleus of U251 cells and U251 stem-like cells was decreased (P < 0.05). Conclusion. Corilagin can inhibit the proliferation of glioblastoma cells and glioblastoma stem-like cells; the inhibition on glioblastoma stem-like cell proliferation is stronger than glioblastoma cells. This different result indicates that the effect of corilagin on U251 cells and U251 stem-like cells may have close relationships with mechanism of cell cycle and NF-kappaB signaling pathway; however, the real antitumor mechanism of corilagin is not yet clear and requires further study. PMID- 27247608 TI - Anti-Inflammatory Effects of Pomegranate Peel Extract in THP-1 Cells Exposed to Particulate Matter PM10. AB - Epidemiological and experimental evidence support health risks associated with the exposure to airborne particulate matter with a diameter of <10 MUM (PM10). PM10 stimulates the production of reactive oxygen species (ROS) and inflammatory mediators. Thus, we assumed that natural antioxidants might provide health benefits attenuating hazardous effects of PM10. In the present study, we examined the effects of pomegranate peel extract (PPE) on THP-1 monocytic cells exposed to PM10. PM10 induced cytotoxicity and the production of ROS. It also increased the expression and secretion of inflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), and monocyte chemoattractant protein-1 (MCP-1), and cell adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). PPE at 10-100 MUg mL(-1) attenuated the production of ROS and the expression of TNF-alpha, IL 1beta, MCP-1, and ICAM-1, but not VCAM-1, in THP-1 cells stimulated by PM10 (100 MUg mL(-1)). PPE also attenuated the adhesion of PM10-stimulated THP-1 cells to EA.hy926 endothelial cells. PPE constituents, punicalagin and ellagic acid, attenuated PM10-induced monocyte adhesion to endothelial cells, and punicalagin was less cytotoxic compared to ellagic acid. The present study suggests that PPE and punicalagin may be useful in alleviating inflammatory reactions due to particulate matter. PMID- 27247609 TI - Effect of Glycyrrhiza on the Diuretic Function of Euphorbia kansui: An Ascites Mouse Model. AB - We investigated the therapeutic role of the herbal combination Euphorbia kansui (GS) and Glycyrrhiza (GC) in ascites during hepatocellular carcinoma (HCC). The AVPR2 and AQP2 expression in kidney tissues of ascites mice in different groups was determined by immunohistochemistry, Western blot, and real-time PCR analyses. When the dose of GS was less than 0.70 g/kg at a ratio of GC : GS not exceeding 0.4 : 1, the combination of GS and GC exhibited synergistic effects on HCC ascites and significantly elevated the expression levels of AVPR2 and AQP2 (all P < 0.05). On the contrary, when GS >= 0.93 g/kg and GC >= 1.03 g/kg with the GC-to GS ratio exceeding 1.11 : 1, the combination of GS and GC displayed antagonistic effects on HCC ascites and dramatically reduced the expression levels of AVPR2 and AQP2 (all P < 0.05). Furthermore, the administration of herbal pair GS and GC at different ratios did not exacerbate the pathological changes in liver and kidney tissues of HCC ascites mice. The different combinations of GS and GC exerted synergistic or antagonistic effects on HCC ascites, partially by regulating the expression of AVPR2 and AQP2. PMID- 27247610 TI - The prognostic value of biomarkers in stroke. AB - BACKGROUND: Ischemic injury triggers inflammatory cascades and changes in the protein synthesis, neurotransmitters and neuro-hormones in the brain parenchyma that may further amplify the tissue damage. The "Triage(r) Stroke Panel", a biochemical multimarker assay, detects Brain Natriuretic Peptide (BNP), D-Dimers (DD), Matrix-Metalloproteinase-9 (MMP-9), and S100beta protein generating a Multimarker index of these values (MMX). The aims of this prospective study in consecutive patients with ischemic or hemorrhagic stroke were to assess: 1) the rate of an increase of biomarkers (BNP, D-dimer, MMP-9 and S-100beta) tested with the Triage Stroke Panel; 2) the correlation between the increase of these biomarkers and functional outcome at 4 months; 3) the risk factors for the increase of biomarkers. METHODS: The outcome of the study was 120-day mortality and it was compared in patients with Stroke Panel >4 and <=4. Multiple logistic regression analyses were performed to identify independent predictors for death and for the increase of biomarkers. RESULTS: 244 consecutive patients (mean age 73.02 years; 53.7 % males) were included in the study; 210 ischemic strokes and 34 hemorrhagic strokes. 161/244 (66.0 %) had an increase of biomarkers. At 120 days, 85 patients had died (34.8 %). Death was seen in 68/161 patients with an increase of biomarkers (42.2 %) compared with 17/83 patients without (20.5 %). Regression logistic analysis found that a Stroke Panel >4 (OR 3.1; 95 % CI 1.5 6.2, p = 0.002) was associated with mortality. The increase of biomarkers was independently predicted by an increase of PCR on admission (OR 2.9, 95 CI 1.4 6.0, p = 0.003). CONCLUSIONS: An increase of biochemical markers such as BNP, D Dimers, MMP-9, and S100beta tested with a Triage Stroke Panel (>4) was correlated with mortality at 120 days from stroke onset. PMID- 27247611 TI - A decade of an HIV workplace programme in armed conflict zones; a social responsibility response of the International Committee of the Red Cross. AB - The International Committee of the Red Cross (ICRC) works in fragile States and in armed conflict zones. Some of them are affected by the HIV pandemic. Within the framework of its social responsibility programme concerning HIV affecting its staff members, the organization has implemented an HIV workplace programme since 2004. We carried out a retrospective analysis over 10 years. Data collected were initially essentially qualitative and process-oriented, but were complemented over the years by data on annual voluntary counselling and testing (VCT) uptake and on direct annual costs covering awareness, testing and antiretroviral therapy. The number of people covered by the programme grew from none in 2003 to 4,438 in 2015, with an increase in annual VCT uptake over the years increasing from 376 persons (14 %) in 2007 to 2,663 in 2015 (60 %). Over the years, the services were expanded from awareness raising to bringing VCT to the workplace, as well as offering testing and health coverage of other conditions and innovative approaches to facing challenges linked to situations of violence. Within its social responsibility framework, the ICRC has shown the importance and feasibility of a workplace HIV programme in conflict zones. A sustainable workplace programme in these conflict settings requires constant adaptation, with regular follow-up given the relatively high turnover of staff, and ensuring sustainable stocks of condoms and antiretroviral drugs. PMID- 27247613 TI - On the Extremal Wiener Polarity Index of Huckel Graphs. AB - Graphs are used to model chemical compounds and drugs. In the graphs, each vertex represents an atom of molecule and edges between the corresponding vertices are used to represent covalent bounds between atoms. The Wiener polarity index W p (G) of a graph G is the number of unordered pairs of vertices u, v of G such that the distance between u and v is equal to 3. The trees and unicyclic graphs with perfect matching, of which all vertices have degrees not greater than three, are referred to as the Huckel trees and unicyclic Huckel graphs, respectively. In this paper, we first consider the smallest and the largest Wiener polarity index among all Huckel trees on 2n vertices and characterize the corresponding extremal graphs. Then we obtain an upper and lower bound for the Wiener polarity index of unicyclic Huckel graphs on 2n vertices. PMID- 27247612 TI - Hemodynamic Study of Flow Remodeling Stent Graft for the Treatment of Highly Angulated Abdominal Aortic Aneurysm. AB - This study investigates the effect of a novel flow remodeling stent graft (FRSG) on the hemodynamic characteristics in highly angulated abdominal aortic aneurysm based on computational fluid dynamics (CFD) approach. An idealized aortic aneurysm with varying aortic neck angulations was constructed and CFD simulations were performed on nonstented models and stented models with FRSG. The influence of FRSG intervention on the hemodynamic performance is analyzed and compared in terms of flow patterns, wall shear stress (WSS), and pressure distribution in the aneurysm. The findings showed that aortic neck angulations significantly influence the velocity flow field in nonstented models, with larger angulations shifting the mainstream blood flow towards the center of the aorta. By introducing FRSG treatment into the aneurysm, erratic flow recirculation pattern in the aneurysm sac diminishes while the average velocity magnitude in the aneurysm sac was reduced in the range of 39% to 53%. FRSG intervention protects the aneurysm against the impacts of high velocity concentrated flow and decreases wall shear stress by more than 50%. The simulation results highlighted that FRSG may effectively treat aneurysm with high aortic neck angulations via the mechanism of promoting thrombus formation and subsequently led to the resorption of the aneurysm. PMID- 27247614 TI - Can Ambulatory Blood Pressure Variability Contribute to Individual Cardiovascular Risk Stratification? AB - Objective. The aim of this study is to define the normal range for average real variability (ARV) and to establish whether it can be considered as an additional cardiovascular risk factor. Methods. In this observational study, 110 treated hypertensive patients were included and admitted for antihypertensive treatment adjustment. Circadian blood pressure was recorded with validated devices. Blood pressure variability (BPV) was assessed according to the ARV definition. Based on their variability, patients were classified into low, medium, and high variability groups using the fuzzy c-means algorithm. To assess cardiovascular risk, blood samples were collected. Characteristics of the groups were compared by ANOVA tests. Results. Low variability was defined as ARV below 9.8 mmHg (32 patients), medium as 9.8-12.8 mmHg (48 patients), and high variability above 12.8 mmHg (30 patients). Mean systolic blood pressure was 131.2 +/- 16.7, 135.0 +/- 12.1, and 141.5 +/- 11.4 mmHg in the low, medium, and high variability groups, respectively (p = 0.0113). Glomerular filtration rate was 78.6 +/- 29.3, 74.8 +/- 26.4, and 62.7 +/- 23.2 mL/min/1.73 m(2) in the low, medium, and high variability groups, respectively (p = 0.0261). Conclusion. Increased values of average real variability represent an additional cardiovascular risk factor. Therefore, reducing BP variability might be as important as achieving optimal BP levels, but there is need for further studies to define a widely acceptable threshold value. PMID- 27247615 TI - Frequent callers to telephone helplines: new evidence and a new service model. AB - BACKGROUND: This paper describes a program of work designed to inform a service model to address a challenge for telephone helplines, namely frequent callers. METHODS: We conducted a systematic literature review and four empirical studies that drew on different data sources-(a) routinely collected calls data from Lifeline, Australia's largest telephone helpline; (b) data from surveys/interviews with Lifeline frequent callers; (c) data from the Diagnosis, Management and Outcomes of Depression in Primary Care (diamond) study; and (d) data from Australia's National Survey of Mental Health and Wellbeing. RESULTS: Frequent callers represent 3 % of callers but make 60 % of calls. They are isolated and have few social supports but are not "time wasters"; they have major mental and physical health problems and are often in crisis. They make use of other services for their mental health problems. The circumstances under which they use telephone helplines vary, but current service models reinforce their calling behaviour. CONCLUSIONS: The findings point to a service model that might better serve the needs of both frequent callers and other callers. The model involves offering frequent callers an integrated, tailored service in which they are allocated a dedicated and specially trained telephone crisis supporter (TCS), and given set calling times. It also involves promoting better linkages between telephone helplines and other services that provide mental health care, particularly general practitioners (GPs) and other primary care providers. The next step is to refine and test the model. PMID- 27247616 TI - Are heritability and selection related to population size in nature? Meta analysis and conservation implications. AB - It is widely thought that small populations should have less additive genetic variance and respond less efficiently to natural selection than large populations. Across taxa, we meta-analytically quantified the relationship between adult census population size (N) and additive genetic variance (proxy: h (2)) and found no reduction in h (2) with decreasing N; surveyed populations ranged from four to one million individuals (1735 h (2) estimates, 146 populations, 83 species). In terms of adaptation, ecological conditions may systematically differ between populations of varying N; the magnitude of selection these populations experience may therefore also differ. We thus also meta-analytically tested whether selection changes with N and found little evidence for systematic differences in the strength, direction or form of selection with N across different trait types and taxa (7344 selection estimates, 172 populations, 80 species). Collectively, our results (i) indirectly suggest that genetic drift neither overwhelms selection more in small than in large natural populations, nor weakens adaptive potential/h (2) in small populations, and (ii) imply that natural populations of varying sizes experience a variety of environmental conditions, without consistently differing habitat quality at small N. However, we caution that the data are currently insufficient to determine whether some small populations may retain adaptive potential definitively. Further study is required into (i) selection and genetic variation in completely isolated populations of known N, under-represented taxonomic groups, and nongeneralist species, (ii) adaptive potential using multidimensional approaches and (iii) the nature of selective pressures for specific traits. PMID- 27247617 TI - Harvest-induced evolution and effective population size. AB - Much has been written about fishery-induced evolution (FIE) in exploited species, but relatively little attention has been paid to the consequences for one of the most important parameters in evolutionary biology-effective population size (N e). We use a combination of simulations of Atlantic cod populations experiencing harvest, artificial manipulation of cod life tables, and analytical methods to explore how adding harvest to natural mortality affects N e, census size (N), and the ratio N e/N. We show that harvest-mediated reductions in N e are due entirely to reductions in recruitment, because increasing adult mortality actually increases the N e/N ratio. This means that proportional reductions in abundance caused by harvest represent an upper limit to the proportional reductions in N e, and that in some cases N e can even increase with increased harvest. This result is a quite general consequence of increased adult mortality and does not depend on harvest selectivity or FIE, although both of these influence the results in a quantitative way. In scenarios that allowed evolution, N e recovered quickly after harvest ended and remained higher than in the preharvest population for well over a century, which indicates that evolution can help provide a long-term buffer against loss of genetic variability. PMID- 27247618 TI - What's the meaning of local? Using molecular markers to define seed transfer zones for ecological restoration in Norway. AB - According to the Norwegian Diversity Act, practitioners of restoration in Norway are instructed to use seed mixtures of local provenance. However, there are no guidelines for how local seed should be selected. In this study, we use genetic variation in a set of alpine species (Agrostis mertensii, Avenella flexuosa, Carex bigelowii, Festuca ovina, Poa alpina and Scorzoneroides autumnalis) to define seed transfer zones to reduce confusion about the definition of 'local seeds'. The species selected for the study are common in all parts of Norway and suitable for commercial seed production. The sampling covered the entire alpine region (7-20 populations per species, 3-15 individuals per population). We characterised genetic diversity using amplified fragment length polymorphisms. We identified different spatial genetic diversity structures in the species, most likely related to differences in reproductive strategies, phylogeographic factors and geographic distribution. Based on results from all species, we suggest four general seed transfer zones for alpine Norway. This is likely more conservative than needed for all species, given that no species show more than two genetic groups. Even so, the approach is practical as four seed mixtures will serve the need for restoration of vegetation in alpine regions in Norway. PMID- 27247619 TI - Quantification of cerivastatin toxicity supports organismal performance assays as an effective tool during pharmaceutical safety assessment. AB - A major problem in pharmaceutical development is that adverse effects remain undetected during preclinical and clinical trials, but are later revealed after market release when prescribed to many patients. We have developed a fitness assay known as the organismal performance assay (OPA), which evaluates individual performance by utilizing outbred wild mice (Mus musculus) that are assigned to an exposed or control group, which compete against each other for resources within semi-natural enclosures. Performance measurements included reproductive success, survival, and male competitive ability. Our aim was to utilize cerivastatin (Baycol((r)), Bayer), a pharmaceutical with known adverse effects, as a positive control to assess OPAs as a potential tool for evaluating the safety of compounds during preclinical trials. Mice were exposed to cerivastatin (~4.5 mg/kg/day) into early adulthood. Exposure ceased and animals were released into semi-natural enclosures. Within enclosures, cerivastatin-exposed females had 25% fewer offspring and cerivastatin-exposed males had 10% less body mass, occupied 63% fewer territories, sired 41% fewer offspring, and experienced a threefold increase in mortality when compared to controls. OPAs detected several cerivastatin-induced adverse effects indicating that fitness assays, commonly used in ecology and evolutionary biology, could be useful as an additional tool in safety testing during pharmaceutical development. PMID- 27247620 TI - Contemporary evolution and the dynamics of invasion in crop-wild hybrids with heritable variation for two weedy life-histories. AB - Gene flow in crop-wild complexes between phenotypically differentiated ancestors may transfer adaptive genetic variation that alters the fecundity and, potentially, the population growth (lambda) of weeds. We created biotypes with potentially invasive traits, early flowering or long leaves, in wild radish (Raphanus raphanistrum) and F5 crop-wild hybrid (R. sativus * R. raphanistrum) backgrounds and compared them to randomly mated populations, to provide the first experimental estimate of long-term fitness consequences of weedy life-history variation. Using a life table response experiment design, we modeled lambda of experimental, field populations in Pellston, MI, and assessed the relative success of alternative weed strategies and the contributions of individual vital rates (germination, survival, seed production) to differences in lambda among experimental populations. Growth rates (lambda) were most influenced by seed production, a trait altered by hybridization and selection, compared to other vital rates. More seeds were produced by wild than hybrid populations and by long leafed than early-flowering lineages. Although we did not detect a biotype by selection treatment effect on lambda, lineages also exhibited contrasting germination and survival strategies. Identifying life-history traits affecting population growth contributes to our understanding of which portions of the crop genome are most likely to introgress into weed populations. PMID- 27247621 TI - Adaptation of a plant pathogen to partial host resistance: selection for greater aggressiveness in grapevine downy mildew. AB - An understanding of the evolution of pathogen quantitative traits in response to host selective pressures is essential for the development of durable management strategies for resistant crops. However, we still lack experimental data on the effects of partial host resistance on multiple phenotypic traits (aggressiveness) and evolutionary strategies in pathogens. We performed a cross-inoculation experiment with four grapevine hosts and 103 isolates of grapevine downy mildew (Plasmopara viticola) sampled from susceptible and partially resistant grapevine varieties. We analysed the neutral and adaptive genetic differentiation of five quantitative traits relating to pathogen transmission. Isolates from resistant hosts were more aggressive than isolates from susceptible hosts, as they had a shorter latency period and higher levels of spore production. This pattern of adaptation contrasted with the lack of neutral genetic differentiation, providing evidence for directional selection. No specificity for a particular host variety was detected. Adapted isolates had traits that were advantageous on all resistant varieties. There was no fitness cost associated with this genetic adaptation, but several trade-offs between pathogen traits were observed. These results should improve the accuracy of prediction of fitness trajectories for this biotrophic pathogen, an essential element for the modelling of durable deployment strategies for resistant varieties. PMID- 27247622 TI - Evolution of drug-tolerant nematode populations in response to density reduction. AB - Resistance to xenobiotics remains a pressing issue in parasite treatment and global agriculture. Multiple factors may affect the evolution of resistance, including interactions between life-history traits and the strength of selection imposed by different drug doses. We experimentally created replicate selection lines of free-living Caenorhabditis remanei exposed to Ivermectin at high and low doses to assess whether survivorship of lines selected in drug-treated environments increased, and if this varied with dose. Additionally, we maintained lines where mortality was imposed randomly to control for differences in density between drug treatments and to distinguish between the evolutionary consequences of drug-treatment versus ecological processes due to changes in density-dependent feedback. After 10 generations, we exposed all of the selected lines to high dose, low-dose and drug-free environments to evaluate evolutionary changes in survivorship as well as any costs to adaptation. Both adult and juvenile survival were measured to explore relationships between life-history stage, selection regime and survival. Intriguingly, both drug-selected and random-mortality lines showed an increase in survivorship when challenged with Ivermectin; the magnitude of this increase varied with the intensity of selection and life-history stage. Our results suggest that interactions between density-dependent processes and life history may mediate evolved changes in susceptibility to control measures. PMID- 27247623 TI - Mycoalgae biofilm: development of a novel platform technology using algae and fungal cultures. AB - BACKGROUND: Microalgae is considered a promising source for biofuel and bioenergy production, bio-remediation and production of high-value bioactive compounds, but harvesting microalgae is a major bottleneck in the algae based processes. The objective of this research is to mimic the growth of natural lichen and develop a novel biofilm platform technology using filamentous fungi and microalgae to form a lichen type of biofilm "mycoalgae" in a supporting polymer matrix. RESULTS: The possibility of co-existence of Chlorella vulgaris with various fungal cultures was tested to identify the best strain combination for high algae harvest efficiency. The effect of different matrices for cell attachment and biofilm formation, cell surface characterization of mycoalgae biofilm, kinetics of the process with respect to the algae-fungi cell distribution and total biomass production was studied. Mycoalgae biofilm with algae attachment efficiency of 99.0 % and above was achieved in a polymer-cotton composite matrix with glucose concentration of 2 g/L in the growth medium and agitation intensity of 150 rpm at 27 degrees C. The total biomass in the co-culture with the selected strain combination (Mucor sp. and Chlorella sp.) was higher than the axenic cultures of fungi and algae at the conditions tested. CONCLUSIONS: The results show that algae can be grown with complete attachment to a bio-augmenting fungal surface and can be harvested readily as a biofilm for product extraction from biomass. Even though, interaction between heterotrophic fungi and phototrophic algae was investigated in solid media after prolonged contact in a report, this research is the first of its kind in developing an artificial lichen type biofilm called "mycoalgae" biofilm completely attached on a matrix in liquid cultures. The mycoalgae biofilm based processes, propounds the scope for exploring new avenues in the bio-production industry and bioremediation. PMID- 27247624 TI - Quantitative proteomic analysis of the influence of lignin on biofuel production by Clostridium acetobutylicum ATCC 824. AB - BACKGROUND: Clostridium acetobutylicum has been a focus of research because of its ability to produce high-value compounds that can be used as biofuels. Lignocellulose is a promising feedstock, but the lignin-cellulose-hemicellulose biomass complex requires chemical pre-treatment to yield fermentable saccharides, including cellulose-derived cellobiose, prior to bioproduction of acetone-butanol ethanol (ABE) and hydrogen. Fermentation capability is limited by lignin and thus process optimization requires knowledge of lignin inhibition. The effects of lignin on cellular metabolism were evaluated for C. acetobutylicum grown on medium containing either cellobiose only or cellobiose plus lignin. Microscopy, gas chromatography and 8-plex iTRAQ-based quantitative proteomic technologies were applied to interrogate the effect of lignin on cellular morphology, fermentation and the proteome. RESULTS: Our results demonstrate that C. acetobutylicum has reduced performance for solvent production when lignin is present in the medium. Medium supplemented with 1 g L(-1) of lignin led to delay and decreased solvents production (ethanol; 0.47 g L(-1) for cellobiose and 0.27 g L(-1) for cellobiose plus lignin and butanol; 0.13 g L(-1) for cellobiose and 0.04 g L(-1) for cellobiose plus lignin) at 20 and 48 h, respectively, resulting in the accumulation of acetic acid and butyric acid. Of 583 identified proteins (FDR < 1 %), 328 proteins were quantified with at least two unique peptides. Up- or down-regulation of protein expression was determined by comparison of exponential and stationary phases of cellobiose in the presence and absence of lignin. Of relevance, glycolysis and fermentative pathways were mostly down regulated, during exponential and stationary growth phases in presence of lignin. Moreover, proteins involved in DNA repair, transcription/translation and GTP/ATP dependent activities were also significantly affected and these changes were associated with altered cell morphology. CONCLUSIONS: This is the first comprehensive analysis of the cellular responses of C. acetobutylicum to lignin at metabolic and physiological levels. These data will enable targeted metabolic engineering strategies to optimize biofuel production from biomass by overcoming limitations imposed by the presence of lignin. PMID- 27247625 TI - A novel de novo microdeletion at 17q11.2 adjacent to NF1 gene associated with developmental delay, short stature, microcephaly and dysmorphic features. AB - BACKGROUND: Microdeletions at 17q11.2 often encompass NF1 gene, is the cause for NF1 microdeletion syndrome. Microdeletion at 17q11.2 without the involvement of NF1 gene is rarely reported. CASE PRESENTATION: Here we reported a patient carrying a novel de novo deletion at 17q11.2 adjacent to NF1 gene, who presented with developmental delay, short stature, postnatal microcephaly, underweight and dysmorphic features including flat facial profile, dolicocephaly, hypertelorism, short philtrum, flat nasal bridge and posteriorly rotated and low set ears. Chromosomal microarray analysis revealed a 1.69 Mb de novo deletion at 17q11.2 adjacent to NF1 gene, which involves 43 RefSeq genes. We compared this with four overlapping deletions at this interval. CONCLUSIONS: A rare de novo microdeletion at 17q11.2 not involving NF1 gene is associated with developmental delay and dysmorphic features. Seven genes, TAOK1, PHF12, NUFIP2, SLC26A4, SEZ6, GIT1 and TRAF4 are possible candidates for the clinical features of our patient. The delineation of this rare deletion and description of associated clinical phenotypes will help to understand the genotype-phenotype correlation of genomic imbalances at this locus. PMID- 27247626 TI - Risk factors for infectious readmissions following radical cystectomy: results from a prospective multicenter dataset. AB - INTRODUCTION: Radical cystectomy (RC) is the gold standard treatment for muscle invasive bladder cancer. This procedure has a high rate of perioperative complications, many of which are infectious in nature. The objective of our study was to evaluate demographic, intrinsic and extrinsic patient variables associated with developing readmission within 30 days due to infectious complications following RC. METHODS: We acquired data available from the American College of Surgeons National Surgical Quality Improvement Program. We queried this dataset to identify all patients who underwent RC for muscle-invasive malignant disease (CPT 188.x) in 2012 based on CPT coding. Logistic regression analysis was used to investigate the relationship between preoperative variables and readmissions for infectious complications. RESULTS: Of the 961 patients undergoing cystectomy for malignancy, 159 (17%) required readmission for any indications at a median of 16 days (interquartile range 13-22 days) postoperatively. We identified 71 of a total of 159 (45%) readmissions, which were due to infectious complications. Smoking was more prevalent in the patient population readmitted for an infectious complication compared with the patient population readmitted for a non-infectious complication (37% versus 25%; p = 0.03). Using logistic regression analysis smoking was associated with a significant risk for readmission due to an infectious cause (odds ratio 2.28, 95% confidence interval 1.82-2.97, p = 0.02). Readmission due to an infectious etiology was not associated with other perioperative factors including type of urinary diversion, sex, duration of operation, hypertension, or recent weight loss. CONCLUSION: Readmission following RC is a common occurrence and infectious complications drive readmission in almost half of the cases. Current smoking was the only independent risk factor for an infectious readmission. Counseling patients in smoking cessation prior to the procedure may provide an avenue for quality improvement to limit readmissions. PMID- 27247627 TI - Clinical experience with radium-223 in the treatment of patients with advanced castrate-resistant prostate cancer and symptomatic bone metastases. AB - The treatment of metastatic castrate-resistant prostate cancer (mCRPC) has grown over the past decade. The majority of patients develop bone metastases, which pose a significant burden on morbidity and mortality, especially skeletal-related events. Whilst demonstrating a favourable safety profile and improving symptoms, radiopharmaceuticals have until recently failed to show a survival benefit. However, since the large phase III randomized ALSYMPCA trial, the calcium mimetic properties of radium-223 (Ra223) have improved patients' quality of life and improved survival whilst keeping toxicities to a minimum. This review article summarizes the clinical data including our real life experience on the usage of the alpha emitter Ra223 in mCRPC, paying particular attention to how clinicians should best monitor response. PMID- 27247628 TI - Evidence of the efficacy and safety of the thulium laser in the treatment of men with benign prostatic obstruction. AB - In 2005, the high power thulium laser was introduced for the surgical treatment of benign prostatic obstruction. It has several properties that confer theoretical advantages over other lasers used for the same indication, such as technical versatility and a relatively small zone of thermal damage. Studies using the 70-150 W thulium laser systems demonstrate good efficacy of these procedures with low morbidity and few complications even in higher risk patients. Different techniques have been employed to treat the prostate with this technology, including enucleation, vapoenucleation, vaporization and resection. Comparative studies have been published comparing thulium laser prostatectomy to monopolar transurethral resection of prostate (TURP), bipolar TURP and holmium laser enucleation of prostate (HoLEP). In this review we discuss the current literature on the safety and efficacy of various thulium techniques for the treatment of benign prostatic hyperplasia and examine comparative studies. PMID- 27247629 TI - Collagenase Clostridium histolyticum in the management of Peyronie's disease: a review of the evidence. AB - OBJECTIVES: Peyronie's disease (PD) is a connective tissue disorder resulting in the abnormal accumulation of scar or plaques in the tunica albuginea of the penis. The condition is characterized by two phases: an active, inflammatory phase, and a stable, chronic phase. Collagenase Clostridium histolyticum (CCH) was isolated in the mid-1900s and postulated as a potential pharmacologic strategy for breaking down the abnormal connective tissue plaques of PD. Prior to the introduction of CCH, a wide variety of treatment modalities for PD were used in clinical practice, including oral and topical medications, intralesional injections, electromotive drug administration, extracorporeal shockwave therapy, traction, and invasive surgery, all with variable results. This review aims to examine the known data surrounding the use of intralesional CCH injections in the treatment of PD. METHODS: CCH is a recently US Food and Drug Administration approved pharmacologic treatment for PD. Clinical trials using intralesional CCH injection therapy for the treatment of PD were reviewed for clinical safety and efficacy of treatment. RESULTS: Studies demonstrated that CCH treatment administered in multiple cycles led to significant benefit in both the psychological and physical aspects of PD. The strongest evidence for CCH's effectiveness was revealed in large, multicenter randomized controlled trials (Investigation for Maximal Peyronie's Reduction Efficacy and Safety Studies I and II) in which intralesional CCH was combined with manual modeling of the penis. Although adverse events from treatment are relatively common, the majority are mild to moderate in degree, including penile pain, swelling, and bruising, which all resolve spontaneously. CONCLUSION: Overall, evidence indicates that CCH is a valuable, effective, and safe minimally invasive treatment option for men with PD. PMID- 27247630 TI - Novel immunotherapeutic approaches to the treatment of urothelial carcinoma. AB - Immunotherapy has long played a role in urothelial cancers with the use of bacille Calmette Guerin (BCG) being a mainstay in the treatment of nonmuscle invasive bladder cancer. Novel therapeutic approaches have not significantly impacted mortality in this population and so a renaissance in immunotherapy has resulted. This includes recombinant BCG, oncolytic viruses, monoclonal antibodies, vaccines, and adoptive T-cell therapy. Herein, we provide a review of the current state of the art and future therapies regarding immunotherapeutic strategies for urothelial carcinoma. PMID- 27247632 TI - Diseases masking and delaying the diagnosis of urogenital tuberculosis. PMID- 27247631 TI - Molecular substratification of bladder cancer: moving towards individualized patient management. AB - Despite advances in surgical techniques, perioperative therapies and postoperative management, outcomes for patients with bladder cancer have largely remained unchanged. Current management of bladder cancer still relies on pathologic staging that does not always reflect the risk for an individual patient. Studies assessing molecular alterations in individual tumors are offering insights into the myriad of cellular pathways that are deregulated in bladder tumorigenesis and progression. Alterations in pathways involved in cell cycle regulation, apoptosis, cell signaling, angiogenesis and tumor-cell invasion have been shown to influence disease behavior. High-throughput assays are now allowing multiplexed assessment of biomarker alterations, thereby enabling characterization of novel molecular subtypes of bladder cancer. Such approaches have also been used for discovery and validation of robust prognostic molecular signatures. The future of bladder cancer management will rely on the use of validated multimarker panels for risk stratification, optimal surgical management, and theranostic strategies to identify and target specific alterations in individual tumors. PMID- 27247633 TI - Bone repair with skeletal stem cells: rationale, progress to date and clinical application. AB - Bone marrow (BM) contains stem cells for both hematopoietic and nonhematopoietic lineages. Hematopoietic stem cells enable hematopoiesis to occur in a controlled manner in order to accurately compensate for the loss of short- as well as long lived mature blood cells. The physiological role of nonhematopoietic BM stem cells, often referred to as multipotential stromal cells or skeletal stem cells (SSCs), is less understood. According to an authoritative current opinion, the main function of SSCs is to give rise to cartilage, bone, marrow fat and hematopoiesis-supportive stroma, in a specific sequence during embryonic and postnatal development. This review outlines recent advances in the understanding of origins and homeostatic functions of SSCs in vivo and highlights current and future SSC-based treatments for skeletal and joint disorders. PMID- 27247636 TI - Dialogical Self in a Complex World: The Need for Bridging Theories. PMID- 27247638 TI - Rational Emotive Behavioural Therapy: The Evolution of a Revolution: Interview With Dr. Debbie Joffe Ellis, Work Partner and Wife of Dr. Albert Ellis, the Creator of REBT. AB - Recognized as one of the most influential thinkers and psychologists, Albert Ellis PhD (1913-2007) revolutionized Psychology when he created the first cognitive psychotherapy, Rational Emotive Behavioral Therapy. After he passed away, Dr. Debbie Joffe Ellis continues spreading his legacy around the world. Psychologist, lecturer, writer, trainer, she dedicates her life to disseminate REBT and extend it through different statements, from the social to the educational, from the academic to the clinical. In this interview, she goes through her own history and her husband's one, bringing us closer to understanding Albert Ellis as the leading figure in his field, and the oneness they experienced through their professional and personal relationship. PMID- 27247634 TI - How does surgery compare with advanced intra-articular therapies in knee osteoarthritis: current thoughts. AB - The objectives of osteoarthritis (OA) management are to reduce pain and inflammation, slow cartilage degradation, improve function and reduce disability. Current strategies for managing knee OA include nonpharmacological interventions, oral pharmacological treatments, localized intra-articular injections, and surgery. It has become evident that the inflammatory response is a key contributor to the development and progression of knee OA. Signaling pathways involving growth factors and cytokines are being investigated for the development of new therapies that target the underlying biological processes causing the disease. This concept of 'molecular orthopedics' enables more patient-centered diagnostic and treatment strategies. In contrast to other conservative therapies, which ultimately only address OA symptoms, intra-articular injections, in particular autologous conditioned serum (ACS), provide benefits that have the potential to outweigh those of established pharmacological treatments and surgery. Surgery has historically been considered the final solution for treatment of knee OA, both by treating physicians and by patients; however, there are increasing concerns regarding the lack of randomized clinical trials providing evidence to support this opinion. Intra-articular injection of ACS has demonstrated efficacy as a treatment for knee OA in a number of studies, with a very low rate of adverse events and side effects, compared with surgery. Treatment with ACS utilizes the release of anti-inflammatory cytokines and regenerative growth factors to support the natural healing processes in the knee, and has the potential to provide a valuable alternative to surgical intervention. PMID- 27247635 TI - Cardiovascular risk in rheumatoid arthritis: assessment, management and next steps. AB - Rheumatoid arthritis (RA) is associated with increased cardiovascular (CV) morbidity and mortality which cannot be fully explained by traditional CV risk factors; cumulative inflammatory burden and antirheumatic medication-related cardiotoxicity seem to be important contributors. Despite the acknowledgment and appreciation of CV disease burden in RA, optimal management of individuals with RA represents a challenging task which remains suboptimal. To address this need, the European League Against Rheumatism (EULAR) published recommendations suggesting the adaptation of traditional risk scores by using a multiplication factor of 1.5 if two of three specific criteria are fulfilled. Such guidance requires proper coordination of several medical specialties, including general practitioners, rheumatologists, cardiologists, exercise physiologists and psychologists to achieve a desirable result. Tight control of disease activity, management of traditional risk factors and lifestyle modification represent, amongst others, the most important steps in improving CV disease outcomes in RA patients. Rather than enumerating studies and guidelines, this review attempts to critically appraise current literature, highlighting future perspectives of CV risk management in RA. PMID- 27247639 TI - Relationships Between Emotional Stability, Psychosocial Mentoring Support and Career Resilience. AB - This study empirically investigates the mediating role of psychosocial mentoring support on emotional stability personality disposition and career resilience relationship. In addition, this research also focuses on estimating the interrelationship between emotional stability, psychosocial mentoring support and career resilience. The results show substantive direct relations between emotional stability and psychosocial mentoring as well as between emotional stability and career resilience. Psychosocial mentoring is also seen as a significant predictor of career resilience. Further, it mediates partially the relationship between emotional stability personality and career resilience. Future and practical implications of research have also been provided. PMID- 27247640 TI - Promoting Mentalization in Clinical Psychology at Universities: A Linguistic Analysis of Student Accounts. AB - This study investigated the structure of mentalization (Bateman & Fonagy, 2012) in a training context. The dual purpose was to evaluate the effectiveness of practicum student training and whether the Linguistic Inquiry method (Pennebaker, 2000) could be used to evaluate the three dimensions of mentalization - relational, cognitive, and emotional. The training utilized the groups and their accounts as devices and mediators to conceptualize the relationship between self mentalizing training, the academic context and the practicum experience. Accounts from 38 Italian students pursuing master degree in Clinical, Dynamic, and Community Psychology were analyzed by LIWC software. The Wilcoxon test showed a significant increase in mentalizing words during the middle and end of the term, as compared with the beginning. The results displayed a need to promote mentalization within academic settings and indicated the value of this competence for clinical psychology. PMID- 27247641 TI - Confidant Relations in Italy. AB - Confidants are often described as the individuals with whom we choose to disclose personal, intimate matters. The presence of a confidant is associated with both mental and physical health benefits. In this study, 135 Italian adults responded to a structured questionnaire that asked if they had a confidant, and if so, to describe various features of the relationship. The vast majority of participants (91%) reported the presence of a confidant and regarded this relationship as personally important, high in mutuality and trust, and involving minimal lying. Confidants were significantly more likely to be of the opposite sex. Participants overall were significantly more likely to choose a spouse or other family member as their confidant, rather than someone outside of the family network. Familial confidants were generally seen as closer, and of greater value, than non-familial confidants. These findings are discussed within the context of Italian culture. PMID- 27247642 TI - Exploring Identity in Muslim Moroccan and Pakistani Immigrant Women. AB - This study presents a qualitative investigation of how Muslim Moroccan and Pakistani female immigrants living in Italy conceptualize their cultural identity. Ten Moroccan and 10 Pakistani (adolescent and adult) women were interviewed through in-depth semi-structured interviews. The interviewees expressed a strong attachment to their culture of origin: their religion is a crucial aspect of their identity, along with certain cultural rules and traditional values. At the same time, both Moroccan and Pakistani participants were ambivalent toward and experienced difficulties in developing a connection to the host country, although the two groups exhibit their lack of connection to their host country in different ways: Moroccans' self-representation is marked by a sense of foreignness and by a lack of an emotional connection with places where they are living while Pakistanis tend to express cultural distance and conflict with the host culture's values. For both the Moroccan and Pakistani groups, the challenge of integration and biculturalism seems demanding in the Italian context and is marked by a deep feeling of emptiness, a lack of an emotional bond with the new country, and a strong cultural ambivalence. Finally, narrative themes are articulated across four interrelated dimensions (cultural, religious, gendered, spatial), revealing interesting differences based on national origin and generation. PMID- 27247643 TI - Intercultural Profiles and Adaptation Among Immigrant and Autochthonous Adolescents. AB - Few studies examine relationships between intercultural strategies and adaptation among adolescents using a person-oriented approach. Framed from an intercultural psychology perspective, this study used such an approach in order to examine the influence of intercultural profiles, patterns of relationships among variables related to intercultural strategies, on the adaptation of adolescents of both non dominant and dominant groups. Two hundred and fifty-six adolescents living in Italy and aged from 14 to 18 participated to the study: 127 immigrants from Tunisia (males = 49.61%) and 129 autochthonous (males = 44.19%). Data were collected through self-report questionnaires. Using cluster analytic methods to identify profiles, the results showed that immigrant adolescents were divided in two acculturation profiles, ethnic and integrated-national, with adolescents belonging to the latter showing higher self-esteem, life satisfaction and sociocultural competence than the former. Also among autochthonous adolescents two acculturation expectation profiles were identified, not-multicultural and multicultural, with adolescents belonging to the latter showing higher self esteem and life satisfaction than the former. Findings highlight the importance of using multiple indicators in order to gain a more comprehensive understanding of the acculturation process as well as suggesting implications for the social policies in this field. PMID- 27247644 TI - Evidence of an Alternative Currency for Altruism in Laboratory-Based Experiments. AB - Research shows that altruistic behaviours arise in varying social situations in line with different theories of causes of such behaviours. However most research uses financial costs only, which makes our understanding of altruism currently limited. This study presents findings of three experiments that use a novel and simple laboratory-based task that measures altruism based on the amount of time participants are willing to spend as a cost to help others. This task assessed two specific theories; altruistic punishment (Experiments 1 & 2) and empathy altruism (Experiment 3). All experiments showed that the task was successful, as participants were more likely to altruistically punish violators of social contracts than other scenarios (Experiments 1 and 2), and also incur more costs to behave altruistically towards others when feeling empathic than different emotional states (Experiment 3). These results provide clear support for the use and value of this novel task in future research. PMID- 27247645 TI - Theory of Mind Development in Adolescence and Early Adulthood: The Growing Complexity of Recursive Thinking Ability. AB - This study explores the development of theory of mind, operationalized as recursive thinking ability, from adolescence to early adulthood (N = 110; young adolescents = 47; adolescents = 43; young adults = 20). The construct of theory of mind has been operationalized in two different ways: as the ability to recognize the correct mental state of a character, and as the ability to attribute the correct mental state in order to predict the character's behaviour. The Imposing Memory Task, with five recursive thinking levels, and a third-order false-belief task with three recursive thinking levels (devised for this study) have been used. The relationship among working memory, executive functions, and linguistic skills are also analysed. Results show that subjects exhibit less understanding of elevated recursive thinking levels (third, fourth, and fifth) compared to the first and second levels. Working memory is correlated with total recursive thinking, whereas performance on the linguistic comprehension task is related to third level recursive thinking in both theory of mind tasks. An effect of age on third-order false-belief task performance was also found. A key finding of the present study is that the third-order false-belief task shows significant age differences in the application of recursive thinking that involves the prediction of others' behaviour. In contrast, such an age effect is not observed in the Imposing Memory Task. These results may support the extension of the investigation of the third order false belief after childhood. PMID- 27247646 TI - The influence on perceptions of truthfulness of the emotional expressions shown when talking about failure. AB - The study aimed to assess whether showing emotion in an organizational inquiry into failure affects perceptions of truthfulness as a function of the match between the explanation of what caused the failure and the emotion expressed. Two web-based studies were conducted. Participants with work experience saw videos of an inquiry and rated the protagonist's truthfulness. In both studies protagonists who expressed an emotion (anger or shame) were rated as less truthful than protagonists who expressed no emotion, regardless of what the failure was attributed to. In order to not confound effects of emotions with occupational stereotype effects only male protagonists were shown. Showing emotions when questioned is normal. Managers have to be aware of a tendency to count this against the employee. This is the only research focusing on the effects of showing emotions on perceptions of truthfulness in an organizational context. PMID- 27247647 TI - Machiavellianism and Adult Attachment in General Interpersonal Relationships and Close Relationships. AB - Up to the present, the relationship between Machiavellianism and adult attachment has remained a question to be answered in the psychological literature. That is why this study focused on the relationship between Machiavellianism and attachment towards significant others in general interpersonal relationships and in intimate-close relationships. Two attachment tests (Relationship Questionnaire and long-form of Experiences in Close Relationship) and the Mach-IV test were conducted on a sample consisting of 185 subjects. Results have revealed that Machiavellian subjects show a dismissing-avoidant attachment style in their general interpersonal relationships, while avoidance is further accompanied by some characteristics of attachment anxiety in their intimate-close relationships. Our findings further refine the relationship between Machiavellianism and dismissing-avoidant attachment. Machiavellian individuals not only have a negative representation of significant others, but they also tend to seek symbiotic closeness in order to exploit their partners. This ambitendency in distance regulation might be particularly important in understanding the vulnerability of Machiavellian individuals. PMID- 27247649 TI - Material Culture: Still 'Terra Incognita' for Psychology Today? PMID- 27247648 TI - The Impact of Parental Styles on the Development of Psychological Complaints. AB - The main aim of the present study was to test Rogers' theory, stating that parental styles characterized by unconditional positive regard (UPR) promote healthier adults than parental styles characterized by conditional regard (CR). For both caregivers CR was found to be associated with significantly higher scores on psychological complaints than UPR (on nearly all SCL-90 scales and the SCL-total score), even when controlling for gender. Although lack of emotional warmth by the father and harsh discipline by the mother were significant predictors of SCL-90-Total (indicating state neuroticism) it should be noted that both variables only explained a small amount of the total variance. Empirical evidence was found for Rogers' theory. Others factors than merely emotional warmth and discipline play a role in the etiology of state neuroticism. For future research it is therefore recommended to include other factors, such as daily worries, temperament, and alexithymia. PMID- 27247650 TI - On the Future of the Humanities: Interview With Professor Mircea Flonta, Epistemologist and Philosopher of Science. PMID- 27247651 TI - Facial Expressions and Ability to Recognize Emotions From Eyes or Mouth in Children. AB - This research aims to contribute to the literature on the ability to recognize anger, happiness, fear, surprise, sadness, disgust and neutral emotions from facial information. By investigating children's performance in detecting these emotions from a specific face region, we were interested to know whether children would show differences in recognizing these expressions from the upper or lower face, and if any difference between specific facial regions depended on the emotion in question. For this purpose, a group of 6-7 year-old children was selected. Participants were asked to recognize emotions by using a labeling task with three stimulus types (region of the eyes, of the mouth, and full face). The findings seem to indicate that children correctly recognize basic facial expressions when pictures represent the whole face, except for a neutral expression, which was recognized from the mouth, and sadness, which was recognized from the eyes. Children are also able to identify anger from the eyes as well as from the whole face. With respect to gender differences, there is no female advantage in emotional recognition. The results indicate a significant interaction 'gender x face region' only for anger and neutral emotions. PMID- 27247652 TI - Authority Relationship From a Societal Perspective: Social Representations of Obedience and Disobedience in Austrian Young Adults. AB - Obedience and disobedience have always been salient issues for both civil society and social psychologists. Since Milgram's first studies on destructive obedience there has not been a bottom-up definition of what obedience and disobedience mean. The current study aimed at investigating the social representations young adults use to define and to co-construct knowledge about obedience and disobedience in Austria. One hundred fifty four (106 females, 68.8%) Austrian young adults (Mean age = 22.9; SD = 3.5) completed a mixed-method questionnaire comprising open-ended questions and free word associations. Overall obedience and disobedience are respectively defined as conformity and non-conformity to regulations, ranging from implicit social norms to explicit formal laws. Authority is multi-faceted and has a central role in orienting obedience and disobedience. Further fundamental determinants of the authority relationship and relevant application of the results are discussed in this paper. PMID- 27247653 TI - Emotional Distress Following Childbirth: An Intervention to Buffer Depressive and PTSD Symptoms. AB - Childbirth for some women is a negative experience associated with depressive and post-traumatic symptoms. The preventive actions focusing on helping mothers to cope with negative emotions experienced after childbirth are strongly recommended. It is also recommended both to intervene early and on all women to avoid the risk that these symptoms can worsen in the months after childbirth. The intervention described in the current study is focalized on the elaboration of post-partum negative thoughts and emotion through a writing task, with the purpose to help new mothers to reflect, understand, evaluate and, thus, reformulate the stressful situation with new beliefs and emotions. 176 women aged from 19 to 43 years (M = 31.55, SD = 4.58) were assessed for depression and PTSD in the prenatal phase (T1). In about 96 hours after childbirth they were randomly assigned to either "Making Sense condition" (MS: in which they wrote about the thoughts and emotions connected with delivery and childbirth) or "Control-Neutral condition" (NC: in which they wrote about the daily events in behavioural terms) and then reassessed for depression and PTSD (T2). A follow up was conducted 3 months later (T3) to verify depression and posttraumatic symptoms. The results showed that depressive symptoms decreased both at 96 hours and at 3 months as a result of making-sense task. Regarding the posttraumatic symptoms the positive effect emerged at three months and not at 96 hours after birth. PMID- 27247654 TI - Autonomy and Submissiveness as Cognitive and Cultural Factors Influencing Eating Disorders in Italy and Sweden: An Exploratory Study. AB - The aim of this exploratory study was to investigate the correlation between cultural and psychological factors in relation to predicting eating disorders in two different non-clinical Italian (n = 61) and Swedish (n = 31) female populations, thought to have different cultures and lifestyles. The Swedish sample would reflect an emancipated model of women pursuing autonomy and freedom but also an ideal of thinness, while the Italian sample would reflect a difficult transition from traditional submissiveness to modern autonomy. Both groups completed self-report instruments assessing cultural values (e.g., collectivism and individualism) and features of eating disorders (e.g., drive for thinness, bulimia, body dissatisfaction, self-esteem, parental criticism and perfectionism). Swedish women were found to display higher levels of bulimia, perfectionism, and individualism than Italian women, while regression analysis showed that in the Italian sample high levels of collectivism were correlated with measures of EDs. The results support the hypothesis that EDs are linked with both modern values of autonomy, independence and emancipation, and situations of cultural transition in which women are simultaneously exposed to traditional models of submission and opportunities for emancipation and autonomy. PMID- 27247655 TI - Adolescent Perceptions of Parenting Styles in Sweden, Italy and Greece: An Exploratory Study. AB - Comparative research on parenting styles among Nordic and Mediterranean countries is still missing, despite the increasing number of studies on parenting styles in adolescence. This study explores similarities and differences in adolescents' retrospective perceptions of parenting styles, for both parents, in Sweden, Italy and Greece, using the Parenting Styles and Dimensions Questionnaire. In particular, it examines the relation between parental role, adolescent gender, country of origin, SES and these perceptions. Swedish, Italian and Greek adolescents (N = 702; 30.9% Swedish, 39.6% Italian and 29.5% Greek) participated in the study. To test the principal effects three mixed 2(parent; mother and father)*2(gender; girl and boy)*3(countries; Sweden, Italy and Greece)*3(SES; low, medium and high) ANOVAs were conducted separately for each parenting style. To verify the interaction effects, a mixed 2(parent; mother and father)*3(countries; Sweden, Italy and Greece)*3(SES; low, medium and high) ANOVA was tested on authoritative style. Regarding authoritarian and permissive two mixed 2(parent; mother and father)*2(gender; girl and boy)*3(countries; Sweden, Italy and Greece) ANOVAs were tested. Mothers, as compared to fathers, were perceived as more authoritative, authoritarian and permissive. Moreover, boys perceived their parents as more authoritarian and more permissive than girls. Swedish parents were perceived as significantly less authoritarian than Italian and Greek parents and more permissive than Italian parents; Greek parents were perceived as less authoritarian and more permissive than Italian parents. The study provides an interesting contribution to parenting styles literature, showing how country legislation concerning family matters and SES are related the perception of parenting behaviours. PMID- 27247656 TI - Integrating Turkish Work and Achievement Goals With Schwartz's Human Values. AB - The purpose of this study was to examine the integration of indigenous values developed in Turkey to Schwartz's universal values. Students (N = 593) from six universities in Istanbul responded the value scale, which consists of 10 etic PVQ items (each item representing one of 10 main Schwartz values) and 23 emic WAG items (representing work-achievement goals). PROXSCAL, a multidimensional scaling method, was used to test whether etic and emic sets of values integrate and form the universal circular structure proposed in Schwartz value theory. The motivational continuum of values as a circular structure was similar to pan cultural results, but adding another value type to the openness to change pole. While some of the items in this region represent autonomy of thought, remaining items diverge. The principle of conflicting values on opposite poles was not supported in relation to openness to change-conservation dimension. These two poles had similar priorities, contrasting with pan-cultural results, and demonstrating a culture-specific aspect of responding to motivational goals. Insights gained by emic studies will be functional in enriching understanding values, and contributing to the comprehensiveness and universality of Schwartz value theory. PMID- 27247657 TI - Coping Strategies of Southern Italian Women Predict Distress Following Breast Cancer Surgery. AB - The present study was aimed at investigating the role of coping strategies in predicting emotional distress following breast cancer, over and above the illness severity, operationalized in terms of the type of surgery performed. In order to achieve this goal, two groups of newly diagnosed breast cancer women were selected and compared on the basis of the type of surgical treatment received. A subsample of 30 women with quadrantectomy and sentinel lymph-node biopsy (SLNB) and a subsample of 31 patients with mastectomy and axillary dissection (MAD) filled in the Brief Cope scale and Hospital Anxiety and Depression Scale. Summarizing, results showed that emotional support, venting, and humor explained a statistically significant increment of variance in psychological distress indices. Implication for clinical practice and future research were discussed. PMID- 27247658 TI - The Situational Version of the Brief COPE: Dimensionality and Relationships With Goal-Related Variables. AB - This study is aimed at investigating the dimensionality of the situational version of the Brief COPE, a questionnaire that is frequently used to assess a broad range of coping responses to specific difficulties, by comparing five different factor models highlighted in previous studies. It also aimed at exploring the relationships among coping responses, personal goal commitment and progress. The study involved 606 adults (male = 289) ranging in age from 19 to 71. Using confirmatory factor analysis, we compared five models and assessed relationships of coping responses with goal commitment and progress. The results confirmed the theoretical factor structure of the situational Brief COPE. All the 14 dimensions showed acceptable reliability and relationships with goal commitment and progress, attesting the reliability and usefulness of this measure to evaluate coping responses to specific events. PMID- 27247659 TI - Young Italian NEETs (Not in Employment, Education, or Training) and the Influence of Their Family Background. AB - This work investigates the relationship between family variables (parents' educational level, relationship quality, intrusiveness, support, and autonomy) and young Italians' status as NEETs (Not in Employment, Education, or Training). We used data from a representative sample of 9,087 young Italians. Each participant filled out an anonymous online questionnaire that contained several scales to measure the variables mentioned above. The results reveal that parents' educational level and support have a protective effect on the risk of becoming a NEET for both genders. Autonomy has a specific negative impact for males while intrusiveness has a positive impact mainly for females. PMID- 27247660 TI - The Relationship Between Gratitude and Loneliness: The Potential Benefits of Gratitude for Promoting Social Bonds. AB - This paper explores the potential role of gratitude on the reduction of loneliness feelings, even controlling for several variables related to social desirability, well-being (subjective happiness and life satisfaction) and socio demographic characteristics. Through a web-based survey a convenience sample of 197 participants completed an online questionnaire including these measures. Correlation analyses and four-step hierarchical multiple regression analyses were conducted. The results show a negative correlation between gratitude and loneliness; specifically, gratitude succeeds in accounting for up to almost one fifth of the total variability of loneliness even controlling for further variables. Being female, not having a stable and consolidated relationship and not participating in the labor force represent some risk factors affecting loneliness which should be taken into account in further research. PMID- 27247661 TI - Disadvantageous Deck Selection in the Iowa Gambling Task: The Effect of Cognitive Load. AB - Research has shown that cognitive load affects overall Iowa Gambling Task (IGT) performance, but it is unknown whether such load impacts the selection of the individual decks that correspond to gains or losses. Here, participants performed the IGT either in a full attention condition or while engaged in a number monitoring task to divide attention. Results showed that the full attention group was more aware of the magnitude of gains or losses for each draw (i.e., payoff awareness) than was the divided attention group. However, the divided attention group was more sensitive to the frequency of the losses (i.e., frequency awareness), as evidenced by their increased preference for Deck B, which is the large but infrequent loss deck. An analysis across blocks showed that the number monitoring group was consistently more aware of loss frequency, whereas the full attention group shifted between awareness of loss frequency and awareness of payoff amount. Furthermore, the full attention group was better able to weigh loss frequency and payoff amount when making deck selections. These findings support the notion that diminished cognitive resources may result in greater selection of Deck B, otherwise known as the prominent Deck B phenomenon. PMID- 27247662 TI - Pressing Obligations or Inspiring Potentials? The Influence of the Ought vs. Expected Selves on Task Performance. AB - This paper focuses on the effects of activating expected self as compared to the effects of activating the ought self. The expected self is a component of self knowledge that pertains to the perception of one's capabilities and potentials. Two experimental studies compared participants' task performance after manipulating the momentary accessibility of the expected self vs. the ought self. In Study 1, contrary to expectations, the activation of the expected self resulted in poorer outcomes when the task required sustained attention. However, an interesting mood difference was revealed, which led us to hypothesise that activating the expected self results in slower (i.e., less hasty) work while performing the task. This hypothesis was confirmed in the second study. PMID- 27247663 TI - The Ideology of Creativity and Challenges of Participation. PMID- 27247664 TI - Sour Fruits on the Trail: Renewing Phenomenological Practice. AB - This summer, Europe's Journal of Psychology hosts a fruitful discussion about phenomenology, its method, the possibilities of application in today's context and its current troubled waters stemming from recent historical-ideological debates. Prof. Roberta De Monticelli offers lush and informative answers to provocative issues like overdriving the epoche, Heidegger's dark undertones, the relation between pedagogy and authorship in phenomenology and the idea of filtering politics through Husserlian phenomenology. PMID- 27247665 TI - Romantic Relationship Length and its Perceived Quality: Mediating Role of Facebook-Related Conflict. AB - The purpose of this study was to investigate how Facebook use is leading to negative relationship outcomes such as cheating and breakup by assessing users' perceived relationship qualities. It was hypothesized that Facebook-related conflict will be negatively related with users' relationship length and will also be negatively related with their perceived relationship satisfaction, commitment, and love. Facebook-related conflict further mediates the relationship between relationship length and perceived relationship satisfaction, commitment, and love. Self-report data were gathered from participants (N = 101) in an online survey by employing standard questionnaires. A set of regression and mediation analyses confirmed all the hypotheses of the study. That is, Facebook-related conflict mediates the relationship between relationship length and perceived relationship satisfaction, commitment, and love. Moreover, the magnitude of mediation was highest for relationship satisfaction. Implications for future research and contributions are discussed. PMID- 27247666 TI - How Positivity Links With Job Satisfaction: Preliminary Findings on the Mediating Role of Work-Life Balance. AB - The positive characteristics that can help people juggle their work and personal roles and experience greater job satisfaction are attracting increased research attention. This study presents a conceptual model to account for the association between employees' positive orientation (i.e., the tendency to evaluate self, life, and the future in a positive way) and their job satisfaction (N = 108). As theorized, the results indicate that employees' ability to manage their work-life balance fully mediates the relation between their positive orientation and job satisfaction. This suggests that a positive orientation serves as an adaptive personal resource that can facilitate employees' ability to balance work and non work demands and hence can foster job satisfaction. The practical implications for positive psychological interventions in organizational settings are discussed. PMID- 27247667 TI - Examining Method Effect of Synonym and Antonym Test in Verbal Abilities Measure. AB - Many researchers have assumed that different methods could be substituted to measure the same attributes in assessment. Various models have been developed to accommodate the amount of variance attributable to the methods but these models application in empirical research is rare. The present study applied one of those models to examine whether method effects were presents in synonym and antonym tests. Study participants were 3,469 applicants to graduate school. The instrument used was the Graduate Academic Potential Test (PAPS), which includes synonym and antonym questions to measure verbal abilities. Our analysis showed that measurement models that using correlated trait-correlated methods minus one, CT-C(M-1), that separated trait and method effect into distinct latent constructs yielded slightly better values for multiple goodness-of-fit indices than one factor model. However, either for the synonym or antonym items, the proportion of variance accounted for by the method is smaller than trait variance. The correlation between factor scores of both methods is high (r = 0.994). These findings confirm that synonym and antonym tests represent the same attribute so that both tests cannot be treated as two unique methods for measuring verbal ability. PMID- 27247668 TI - The Relation of Marital Adjustment and Family Functions With Quality of Life in Women. AB - Given the immense importance of marital relationships in the quality of life, this research was conducted in order to investigate the relationships between marital adjustment and family functions with quality of life in women. The design of the current study was correlational. Seven hundred and thirty women were selected randomly among all women living in the province of Western Azerbaijan (Iran) and participated in this study. The sample responded to the Family Assessment Device, Dyadic Adjustment scale and Quality of Life questionnaire, individually in their homes. Collected data were analyzed by Pearson's correlation and multiple regression tests. The results showed that all dimensions of family functions and dyadic adjustment were positively correlated with quality of life in women. Results of multiple regression also revealed that 33 percent of total quality of life can be explained by family functions and 24 percent of this variable can be explained by dyadic adjustment. Our study demonstrated that women's quality of life was affected by family functions and marital adjustment in family. PMID- 27247669 TI - Training at the Gym, Training for Life: Creating Better Versions of the Self Through Exercise. AB - The present study draws on Scott's (2011) notion of the Re-Inventive Institution and explores how gym members make sense and give meaning to their exercise regime. Overall, it is argued that for many participants gym exercise is more than physical training; it is also training for life. Based on a thematic analysis of 32 semi-structured interviews it is argued that gym workout is a means to create better versions of the self on mainly three levels. First, gym participants perceive themselves to be efficient and productive in general. Second, gym training is believed to increase the control they have over their lives. Third, gym members associate their gym workout with amplified emotional resilience, believing that fitness workout makes them not only fitter in a physical sense but also fitter and better equipped in a psychological sense. Surprisingly, a small group of regular gym users displayed more critical sentiments and distanced themselves from the images and values the gym stands for. The results of this study can be linked to broader political discourses on health and fitness that make use of corporate managerial vocabularies and are based on ideals of rationalization and efficiency. PMID- 27247670 TI - Psychobiography Training in Psychology in North America: Mapping the Field and Charting a Course. AB - Psychobiography holds an important position in the history of psychology, yet little is known about the status of psychobiographical training and dissertation research in psychology departments. This brief report identified psychobiography courses throughout North America and content analyzed a sample of 65 psychobiography dissertations to discern the theories and methods that have most commonly anchored this research. Results identified few psychology courses specifically in psychobiography, with a larger number of courses incorporating psychobiographical and/or narrative elements. With regard to psychobiography dissertations, the majority focused on artists, pioneering psychologists, and political leaders. Theories undergirding psychobiographical studies were most frequently psychoanalytic and psychodynamic. Methodologically, a majority of the dissertations were anchored in constructivist (discovery-oriented) qualitative procedures, with a minority incorporating mixed methods designs. The authors highlight the value of psychobiographical training to psychology students and present avenues and models for incorporating psychobiography into psychology curriculums. PMID- 27247671 TI - Educating to Tolerance: Effects of Communicating Social Psychology Research Findings. AB - The effect of communicating social psychology research findings on ingroup bias in a classroom setting has been investigated. Two hundred and twenty one high school students either read or did not read a brief report about three classical social psychological studies, then completed evaluation scales for the ingroup and the outgroup. Participants' motivation was manipulated, and the messages were different as regards the congruency between the content and participants' actual intergroup experience. Results showed that communication exerted a significant effect in reducing ingroup bias for participants in the high motivation/high congruency condition, that is, the communication effect was moderated by the individual's level of motivation and the content of the arguments proposed in the report. Practical implications of results for education work and stereotype change, limitations of the study, as well as possible directions for future research are discussed. PMID- 27247672 TI - Why Machiavellianism Matters in Childhood: The Relationship Between Children's Machiavellian Traits and Their Peer Interactions in a Natural Setting. AB - The current study investigated the association between Machiavellianism and children's peer interactions in the playground using observational methods. Primary school children (N = 34; 17 female), aged 9 to 11 years, completed the Kiddie Mach scale and were observed in natural play during 39 recesses (average observed time = 11.70 hours) over a full school year. Correlations for boys revealed that Machiavellianism was related to more time engaging in direct and indirect aggression, being accepted into other peer groups, and accepting peers into their own social group. Correlations revealed that for girls, Machiavellianism was associated with lower levels of indirect aggression, less time being accepted into other groups and less time accepting and rejecting other children into their own group. This preliminary pilot study indicates that Machiavellianism is associated with children's observed social behaviour and aims to promote future observational research in this area. PMID- 27247673 TI - Mindful Sustainable Aging: Advancing a Comprehensive Approach to the Challenges and Opportunities of Old Age. AB - The primary aim of this article is to present a new concept called mindful sustainable aging (MSA), which is informed by mindfulness practices that support the physical, the mental, and especially, the social and the existential dimensions of old life. The concept of MSA is discussed and compared with four influential psychosocial theories in the field of gerontology, i.e., activity theory, disengagement theory, successful aging theory and gerotranscendence theory. The article ends with reviewing research on how mindfulness practice can help to manage, diminish and/or improve a number of serious physical conditions that are common among older people. The potential of mindfulness when it comes to facilitating for older adults in their quest for spiritual and existential meaning is discussed extensively throughout the article. PMID- 27247674 TI - Moral Dilemmas and Existential Issues Encountered Both in Psychotherapy and Philosophical Counseling Practices. AB - This paper stems from clinical observations and empirical data collected in the therapy room over six years. It investigates the relationship between psychotherapy and philosophical counseling, proposing an integrative model of counseling. During cognitive behavior therapy sessions with clients who turn to therapy in order to solve their clinical issues, the author noticed that behind most of the invalidating symptoms classified by the DSM-5 as depression, anxiety, hypochondriac and phobic complaints, usually lies a lack of existential meaning or existential scope and clients are also tormented by moral dilemmas. Following the anamnestic interview and the psychological evaluation, rarely the depression or anxiety diagnosed on Axis I is purely just a sum of invalidating symptoms, which may disappear if treated symptomatically. When applying the Sentence Completion Test, an 80 items test of psychodynamic origin and high-face validity, most of the clients report an entire plethora of conscious or unconscious motivations, distorted cognitions or irrational thinking but also grave existential themes such as scope or meaning of life, professional identity, fear of death, solitude and loneliness, freedom of choice and liberty. Same issues are approached in the philosophical counseling practice, but no systematic research has been done yet in the field. Future research and investigation is needed in order to assess the importance of moral dilemmas and existential issues in both practices. PMID- 27247675 TI - Historical Techniques of Lie Detection. AB - Since time immemorial, lying has been a part of everyday life. For this reason, it has become a subject of interest in several disciplines, including psychology. The purpose of this article is to provide a general overview of the literature and thinking to date about the evolution of lie detection techniques. The first part explores ancient methods recorded circa 1000 B.C. (e.g., God's judgment in Europe). The second part describes technical methods based on sciences such as phrenology, polygraph and graphology. This is followed by an outline of more modern-day approaches such as FACS (Facial Action Coding System), functional MRI, and Brain Fingerprinting. Finally, after the familiarization with the historical development of techniques for lie detection, we discuss the scope for new initiatives not only in the area of designing new methods, but also for the research into lie detection itself, such as its motives and regulatory issues related to deception. PMID- 27247676 TI - Improving Patient Outcomes: Effectively Training Healthcare Staff in Psychological Practice Skills: A Mixed Systematic Literature Review. AB - Training is an important part of modern European healthcare services and is often cited as a way to improve care quality. To date, various training methods have been used to impart skills relevant to psychological practice in a variety of mental health professionals. However, patient outcomes are rarely used in evaluating the effectiveness of the different training methods used, making it difficult to assess true utility. In the present review, we consider methods of training that can effectively impact trainee and patient outcomes. To do so, PubMed, PsycNET, Scopus, CENTRAL and ERIC were searched for studies on training of healthcare staff in psychological practice approaches. In total, 24 studies were identified (16 quantitative and 8 qualitative). For the most part, group, individual, and web-based training was used. A variety of health professionals were trained in skills including 'communication', 'diagnosis', and 'referral' to name but a few. In the majority of studies staff skill level improved. These findings hold implications for the design, implementation, and evaluation of training for mental healthcare staff. PMID- 27247677 TI - Political Imagination, Otherness and the European Crisis. PMID- 27247678 TI - Being Irrationally Funny as a Cognitive Psychologist: Interview With Dan Ariely. AB - The idea of interviewing Dan Ariely was somehow latent on my mind since I started being interested in cognitive psychology and cognitive behavior psychotherapy, but actually got more ardent ever since irrationality became a research topic for his team at Duke University. I picked him as an interviewee thinking not only at his exceptional skills as a researcher and as Kahnemann 'disciple', but mainly for his fantastic wit, true modesty and utmost interest in making people's lives easier and more comfortable, by creating awareness on a lot of topics otherwise neglected. Dan Ariely's very agreeable personality and humor would not let you think of him as a burnt casualty who, in his youth struggled to survive a personal drama, so well-documented in his paper "Painful lessons" posted on the MIT website (http://web.mit.edu/ariely/www/MIT/Papers/mypain.pdf). I think reading his paper and also this transcribed interview with him would be also comforting for people who found out about Bucharest fire incident that rocked our society and also for people who are personally related to this tragedy. PMID- 27247679 TI - Iconographic Professional Interests Inventory (3IP): A New Validation Study. AB - Interests have been a central focus of counselling psychology (and vocational psychology in particular) for over 100 years. The awareness of professional interests increases self-knowledge and provides occupational information. In career counselling, vocational interests are assessed more frequently than any other vocational construct, though early evaluations (before 13 years old) of professional interests are very rare. The aim of this research is to examine the 3IP construct (Iconographic Professional Interests Inventory; an inventory composed of 65 stylised pictures that represent people in the act of performing a job) in depth, testing more models in addition to the 19 vocational areas proposed in the 3IP manual. Results show that most of the vocational areas can be grouped into 4 second-level areas ("things", "people", "leisure", and "culture"). Moreover, Holland's RIASEC model is tested; an accurate selection of items reveals that this model works well using 24 specific jobs. The research concludes that the inventory has good psychometric qualities which can grow further by mean of the increasing, in a targeted way, of the number of jobs. PMID- 27247680 TI - Paradoxical Personality and Academic Achievement in College Students From Buenos Aires. AB - This paper presents a study on paradoxical personality, defined as a distinctive feature in creative persons, developed with 350 college students from Buenos Aires. Goals aimed at describing and analysing possible significant differences of paradoxical traits in students from diverse majors representing seven different fields of study, and examining the relationship between each bipolar trait and academic achievement. The sample was composed of 7 groups (n = 50 by group) representing fields of study typically offered in public universities, Biology, Computer Science, Engineering, Law, Nutrition, Psychology, and History of Art. Analyses by career provided descriptive information about students of these majors, concerning their paradoxical personality profiles. Correlational studies verified significant associations between academic achievement and most paradoxical traits in majors such as Computer Science, Nutrition and Psychology. Results are discussed regarding practical outcomes and teaching programs. PMID- 27247681 TI - The Detrimental Effect of Machiavellian Leadership on Employees' Emotional Exhaustion: Organizational Cynicism as a Mediator. AB - Numerous empirical studies have examined predictors of emotional exhaustion. In this vein, both positive and negative leadership styles have been associated with this outcome. Yet, little is known about the role of Machiavellian leadership in fostering employees' emotional exhaustion. As such, we investigated the relationship between Machiavellian leadership and emotional exhaustion. Even more, we investigated an explanatory mechanism of this association by encompassing organizational cynicism as a mediator. Results showed that Machiavellian leadership has a both direct and indirect, through organizational cynicism, on employees' emotional exhaustion. PMID- 27247682 TI - A Cross-Sectional Survey Study About the Most Common Solitary and Social Flow Activities to Extend the Concept of Optimal Experience. AB - Previous assumptions note that the most powerful experiences of engagement are shared with others. Therefore, in the framework of positive psychology, to expand the dynamic interactionism-related flow theory, we have attempted to conduct an exploratory study about flow to reveal the most common activities that can trigger this experience during solitary or social situations. The study involved 1,709 adult participants from Hungary (Age: M = 26.95, SD = 11.23). They read descriptions about optimal experience in solitary and social situations and were asked to identify the activity from their life that is most typically followed by the described experiences. The social context was supplemented by other flow related questions for a deeper understanding and to contribute to the research. According to the results the most typical solitary flow activities are found to be work, sports, creative activities and reading. The most common flow-inducing social activities are work and sports. The choice of the most frequent flow inducing activities in both solitary and interpersonal situations is dependent on the gender of the respondent, and various demographical factors can influence the frequency of flow experiences in different contexts. Analysis reveal that optimal experience during a social interaction is determined by the perceived level of challenges, the perceived level of cooperation, the immediateness and clarity of the feedback, and the level of the skill. Our study may contribute to the broadening purpose of positive psychology as it focuses on the interpersonal level in relation to flow experience, which, in turn, may also support a higher level of well-being. PMID- 27247683 TI - Linguistic Markers of Processing Trauma Experience in Women's Written Narratives During Different Breast Cancer Phases: Implications for Clinical Interventions. AB - Research into the change processes underlying the benefits of expressive writing is still incomplete. To fill this gap, we investigated the linguistic markers of change in cognitive and emotional processing among women with breast cancer, highlighting the differences and peculiarities during different treatment phases. A total of 60 writings were collected from 20 women: 10 receiving chemotherapy and 10 receiving biological therapy. We performed a series of repeated measures ANOVA for the most meaningful LIWC linguistic categories, including positive/negative emotions and cognitive processes, to assess change over three sessions. Results demonstrated a significant increase in the positive emotions category for the entire group of women, with particular relevance for the biological therapy group of women, and a marginally significant (p = .07) greater use of words indicating cognitive processes for women receiving biological therapy. For the negative emotions category time was significant for the whole group of women, showing a peak of use in the second session of writing. Peculiar differences in the linguistic markers of processing trauma were observed between the two groups. Although the writing intervention is a support for both groups of women, it seems to be beneficial when there is a large time gap since the administration of chemotherapy and, thus, when the patient can revisit the experience. The relationship of the illness with life can be rearticulated, and the writing becomes a space for resignifying the traumatic cancer experience. PMID- 27247684 TI - Sibling Relation, Ethnic Prejudice, Direct and Indirect Contact: There is a Connection? AB - The literature on the socialisation of prejudice has concentrated on "vertical" processes (from parents to children), ignoring siblings' contribution. This work aims to investigate the effect of contact (direct or indirect) with the outgroup that young people experience a) directly or b) indirectly through older or younger siblings' friendships. Our hypotheses are a) that young people with friends in the outgroup will report lower prejudice levels (direct contact), as will young people who have older or younger siblings with friends in the outgroup (indirect contact); b) that other forms of contact such as having classmates/coworkers, neighbours, or employees are not effective in reducing either direct or indirect prejudice. 88 sibling dyads were administered the blatant and subtle prejudice questionnaire (Pettigrew & Meertens, 1995) and some ad hoc items aimed at investigating the typology of the contact experienced. The analysis of mixed ANOVA reveals that the first hypothesis was partially confirmed in that prejudice (subtle for the younger sibling and blatant for the older one) decreases in a statistically significant way only when there is the co-presence of direct and indirect contact. The second hypothesis is fully confirmed as no statistically significant differences emerged between the groups. PMID- 27247685 TI - The Effects of Attractiveness and Status on Personality Evaluation. AB - Research on personality has shown that perceiving a person as attractive fosters positive expectations about his/her personal characteristics. Literature has also demonstrated a significant link between personality traits and occupational achievement. Present research examines the combined effects of attractiveness, occupational status, and gender on the evaluation of others' personality, according to the Big Five model. The study consisted of a 2 (Attractiveness: High vs. Low) x 2 (occupational Status: High vs. Low) x 2 (Target gender: Male vs. Female) between-subjects experimental design (N = 476). Results showed that attractive targets were considered more positively than unattractive targets, and this effect was even stronger for male targets. Occupational status influenced perceived agreeableness (lower for high-status targets) and perceived conscientiousness (higher for high-status targets). PMID- 27247686 TI - What Do Physicians Believe About the Way Decisions Are Made? A Pilot Study on Metacognitive Knowledge in the Medical Context. AB - Metacognition relative to medical decision making has been poorly investigated to date. However, beliefs about methods of decision making (metacognition) play a fundamental role in determining the efficiency of the decision itself. In the present study, we investigated a set of beliefs that physicians develop in relation to the modes of making decisions in a professional environment. The Solomon Questionnaire, designed to assess metacognitive knowledge about behaviors and mental processes involved in decision making, was administered to a sample of 18 emergency physicians, 18 surgeons, and 18 internists. Significant differences in metacognitive knowledge emerged among these three medical areas. Physicians' self-reports about the decision process mirrored the peculiarities of the context in which they operate. Their metacognitive knowledge demonstrated a reflective attitude that is an effective tool during the decision making process. PMID- 27247687 TI - Emotional, Cognitive and Self-Enhancement Processes in Aggressive Behavior After Interpersonal Rejection and Exclusion. AB - The relationship between exclusion or rejection and aggression is already well documented, but there is still a debate about the mechanisms that underlie this effect. In two studies we focused on the propensity to react aggressively (readiness for aggression) on the bases of emotional, cognitive or self enhancement (personality-immanent) processes. In both studies we first measured readiness for aggression and then ego-depleted participants. Next, in Study 1 we excluded participants (n = 96) using an online ball throwing game and measured displaced aggressive behavior - intensity and duration of an unpleasant noise administrated to a stranger. In Study 2 participants (n = 140) were rejected by a peer on the basis of an interview that they gave and then could retaliate by reducing peer's chance for getting a job. The results show that exclusion effect on displaced aggression was moderated by cognitive readiness for aggression, while rejection effect on retaliatory aggression was shaped by emotional and personality-immanent readiness for aggression as well as ego-depletion. The results were discussed in light of the strength model of self-control by Baumeister, Vohs, and Tice (2007). PMID- 27247688 TI - Better Movers and Thinkers (BMT): An Exploratory Study of an Innovative Approach to Physical Education. AB - Recent research has confirmed a positive relationship between levels of physical activity and academic achievement. Some of these studies have been informed by neurological models of Executive Functioning (EF). There is a general consensus within the literature that the three core EF skills are; working memory, inhibitory control and cognitive flexibility. The development of these core EF skills has been linked with learning and academic achievement and is an essential component in the delivery of PE using a new and innovative approach called 'Better Movers and Thinkers (BMT).' A mixed methods design was used to investigate the effectiveness and feasibility of a 16-week intervention programme using BMT where 46 children were tested on two separate occasions for coordination and balance control, academic skills, working memory and non-verbal reasoning skills. One school acted as the control condition (21 students, aged 9 10 years) and another school acted as the intervention condition (25 students, aged 9 - 10 years). Quantitative data revealed an effect between pre and post test conditions in the areas of phonological skills (p = .042), segmentation skills (p = .014) and working memory (p = .040) in favour of the intervention condition. Further analysis identified a gender-interaction with male students in the intervention condition making significant gains in phonological skills (p = .005) segmentation skills (p = .014) and spelling (p = .007) compared to boys in the control condition. Analysis of qualitative data from a sample of students from the intervention condition and their class teacher indicated good acceptability of BMT as an alternative approach to PE. PMID- 27247689 TI - Living Creatively, In and Through Institutions. PMID- 27247691 TI - Narrative Inquiry: An Interview With Michael Bamberg. PMID- 27247692 TI - Validation of a Newly Developed Instrument Establishing Links Between Motivation and Academic Hardiness. AB - The purpose of the study was to establish the reliability, the structural and the convergent validity of the "Dimensions of Academic Hardiness Questionnaire" for late elementary school children. A sample of children (N = 1264) aged 10-12 years completed the questionnaire and the "Athens Coping Scale". Multiple fit indices provided support that the 9-factor model had a good fit to the data. Reliability coefficients ranged from .68 to .83. The study provided also preliminary evidence of convergent validity of the "Dimensions of Academic Hardiness" scores with one theoretically related measure, the "Athens Coping Scale". The results enrich the notion of Academic Hardiness in late elementary school children as the role of awareness and the role of children's previous experiences has been distinguished. The relation between the "Dimensions of Academic Hardiness" and achievement goal orientations in children learning is also noted. These findings are discussed in the context of the relevant literature. PMID- 27247693 TI - Neuroticism as a Moderator of Direct and Mediated Relationships Between Introversion-Extraversion and Well-Being. AB - Among personality traits, extraversion has received major theoretical and empirical attention as predictor of subjective well-being (SWB), whereas the role of emotional stability-neuroticism has been partially neglected. The present study aims to study the role of neuroticism in the relationship between introversion-extraversion and SWB. In particular, we explored if the trait of neuroticism moderates the relationships between introversion-extraversion and SWB dimensions (Satisfaction with life, Mastery, Vigour, Social Cheerfulness), directly and by mediation of self-esteem. Indeed, previous studies have suggested that self-esteem is positively associated with high extraversion and low neuroticism and that it positively mediates the relationship between SWB and personality traits in adolescents. For this purpose, a sample of high school students (N = 1173) completed the Oxford Happiness Inventory, the Rosenberg Self Esteem Scale and the Big Five Questionnaire. In a latent variable model, we examined the interaction effects (direct and indirect) of extraversion and neuroticism on SWB dimensions. Our results showed that the nature of differences between introverts and extraverts on SWB could be related to the level of neuroticism in relation to Satisfaction with life. Moreover, self-esteem mediated the relationship between personality traits and SWB. In particular, mediated moderation effect analysis showed that self-esteem mediates completely the relationship between the interaction term (extraversion x neuroticism) and Mastery, and partially the relationship with Satisfaction with life. Moreover, moderated mediation effect analysis showed that high levels of neuroticism moderate the effect of extraversion on Satisfaction with life and Mastery through the mediation of self-esteem. In conclusion, our results suggest that although extraversion has a cardinal role on SWB dimensions related to Vigour and Social Cheerfulness, neuroticism and the mediating role of self-esteem should more properly considered in relation to Satisfaction with life and Mastery. PMID- 27247694 TI - You Are the Real Terrorist and We Are Just Your Puppet: Using Individual and Group Factors to Explain Indonesian Muslims' Attributions of Causes of Terrorism. AB - The current study investigates the role of individual and intergroup factors in predicting Muslims' tendency to attribute domestic terrorism in Indonesia to an external cause (i.e., The West) or an internal cause (i.e., radical Islamist groups). The results (N = 308) showed that intergroup factors of symbolic threat and realistic threat directly increased the external attribution and conversely decreased the internal attribution. Within the context of the current research, symbolic threat refers to Muslims' perception that the norms and values of the West undermine Islamic identity. Realistic threat denotes Muslims' perception that the economy and technology of the West undermine Islamic power. The individual factor of Islamic fundamentalism, which has to do with Muslims' belief in the literal interpretation of and strict guidelines to Islamic doctrines, indirectly predicted both external attribution and internal attribution of terrorism as hypothesized, via the extent to which Muslims perceived the West as posing a symbolic threat, but not a realistic threat to Islamic existence. Uncertainty avoidance, a cultural dimension that describes the extent to which people view clear instructions as a pivotal source of concern to deal with societal problems, also significantly increased perceived symbolic threat and realistic threat, and this cultural dimension mediated the effect of Islamic fundamentalism on each of the intergroup threats. Finally, we found that the level of Islamic fundamentalism was dependent upon cognitive response, but not emotional response to mortality salience. The cognitive response to mortality salience denotes what Muslims are thinking about in coping with their own death whereas the emotional response denotes what Muslims are feeling about such issue. In particular, we found the cognitive response, but not the emotional response to mortality salience significantly gave rise to Muslims' Islamic fundamentalism. These findings shed light on the importance of combining individual factors and group factors in explicating the dynamics of Muslims' tendency to make attributions of causes of domestic terrorism. We discuss theoretical implications and study limitations, as well as practical actions policy makers could conduct to deal with Muslims' Islamic fundamentalism and reduce the extent to which this particular group perceives the West as threatening their existence. PMID- 27247695 TI - I and My Friends are Good People: The Perception of Incivility by Self, Friends and Strangers. AB - Three studies were conducted to assess self-serving biases in participants' beliefs about incivility, its antecedents and consequences as well as restitution behaviors and forgiveness as a function of whether a behavior was performed by themselves, strangers or friends. Participants who imagined themselves in the active role not only described their own behavior as more excusable, congruent with an actor-observer bias, but more importantly, they showed strong self serving biases with regard to all their reactions to the situation - even though this leads to logical contradictions. This self-serving expectation generalized to friends and contrasted sharply with expectations for strangers, whose behaviors were described as logically consistent. The difference between what is expected from self and friends and what is expected from others may account for much of the popular moral outrage at incivility in various social realms. PMID- 27247696 TI - More Than Defense in Daily Experience of Privacy: The Functions of Privacy in Digital and Physical Environments. AB - The purpose of the current study was to investigate the experience of privacy, focusing on its functional role in personal well-being. A sample (N = 180) comprised subjects between 18 and 50 years of age were asked to spontaneously provide accounts of their experiences with privacy and answer close-ended questions to acquire a description of a daily experience of privacy. The results showed the importance attributed to the function of privacy related to the "defense from social threats", and the twofold function of privacy related to an "achieved state of privacy", in the terms of both "system maintenance" and "system development". The results also shed light on the role of the environment in shaping one's experience of privacy. Specifically, the participants recognized more easily the function of defense from threats related to seeking privacy while interacting in digital environments, whereas they seemed to benefit from positive functions related to an achieved state of privacy in physical environments. The findings sustain the notion of privacy as a supportive condition for some psychological processes involved in the positive human functioning and confirm previous studies conducted on the role of privacy in human well-being. PMID- 27247697 TI - A Darker Shade of Love: Machiavellianism and Positive Assortative Mating Based on Romantic Ideals. AB - Machiavellianism is a personality trait that is characterized by manipulative and exploitative attitude toward others, lack of empathy, and a cynical view of human nature. In itself or as part of the Dark Triad it has been the target of several studies investigating romantic relations. Nevertheless, the relationship between Machiavellianism and romantic ideals has not been revealed yet. An undergraduate sample of 143 (92 females) with an average age of 19.83 years (SD = 1.51 years) filled out self-report measures of Machiavellianism (Mach-IV Scale) and romantic ideals (Ideal Standards Scale and NEO-FFI-IDEAL). According to our results, Machiavellianism correlated negatively with the importance of partner's warmth trustworthiness, extraversion, openness, agreeableness, and with the importance of intimacy and loyalty in their ideal relationships. Machiavellianism correlated positively with the ideal partner's possession over status and resources. Explorative factor analysis revealed three components of ideal partner's characteristics. Machiavellianism loaded significantly on two out of three components. Results are discussed with regard to Ideal Standards Model and the Big Five model of personality. PMID- 27247698 TI - Are There Similar or Divergent Transitions to Adulthood in a Mediterranean Context? A Cross-National Comparison of Italy and Spain. AB - The purpose of this study was to examine the differences and similarities between Italy and Spain in regard to emerging adults' perceptions of identity status, autonomy, attachment, and life satisfaction. The goal was to verify whether a Mediterranean model of transitions from adolescence to adulthood exists. Three hundred and forty undergraduate students (171 Italians and 169 Spanish) ranging in age from 19 to 22 completed measures of identity status, emotional autonomy, attachment style, and life satisfaction. Multiple correspondence analyses provided a graphic synthesis of results. The results indicate that no common model of young adult development exists in Spain and Italy and that Italian youth have a more complex quality of development compared to their Spanish peers. PMID- 27247699 TI - Motivational and Ideological Underpinnings of Welfare Preferences in Eastern and Western Europe. AB - In our study we investigated the motivational and ideological correlates of the approval of welfare services in postsocialist Central Eastern and Western Europe. In the centre of our inquiry stood how the motivations of selflessness and conventionality, along with distributional justice principles, are related to our welfare preferences beyond our rational self-interest, furthermore, how these associations depend on social-cultural circumstances. We have found that the motivational background of egalitarian economic and welfare attitudes are substantially different in the two regions. While beside of the rationalisation of self-interest, it seems to be related to selflessness-driven solidarity in Western Europe, pro-welfare and egalitarian distributional views are primarily motivated by conventionality-driven norm adherence in postsocialist countries in the form of the mechanism of postsocialist economic system nostalgia. Our results highlight the benefits of a context-specific 'motivated social cognition' approach to ideological and political attitudes. PMID- 27247700 TI - Gender Variations in the Effects of Number of Organizational Memberships, Number of Social Networking Sites, and Grade-Point Average on Global Social Responsibility in Filipino University Students. AB - The study seeks to estimate gender variations in the direct effects of (a) number of organizational memberships, (b) number of social networking sites (SNS), and (c) grade-point average (GPA) on global social responsibility (GSR); and in the indirect effects of (a) and of (b) through (c) on GSR. Cross-sectional survey data were drawn from questionnaire interviews involving 3,173 Filipino university students. Based on a path model, the three factors were tested to determine their inter-relationships and their relationships with GSR. The direct and total effects of the exogenous factors on the dependent variable are statistically significantly robust. The indirect effects of organizational memberships on GSR through GPA are also statistically significant, but the indirect effects of SNS on GSR through GPA are marginal. Men and women significantly differ only in terms of the total effects of their organizational memberships on GSR. The lack of broad gender variations in the effects of SNS, organizational memberships and GPA on GSR may be linked to the relatively homogenous characteristics and experiences of the university students interviewed. There is a need for more path models to better understand the predictors of GSR in local students. PMID- 27247701 TI - Antarctica challenges the new horizons in predictive, preventive, personalized medicine: preliminary results and attractive hypotheses for multi-disciplinary prospective studies in the Ukrainian "Akademik Vernadsky" station. AB - BACKGROUND: Antarctica is a unique place to study the health condition under the influence of environmental factors on the organism in pure form. Since the very beginning of the scientific presence of Ukraine in the Antarctic, biomedical research has been developed for the monitoring of individual biomarkers of winterers and medical accompaniment in Antarctic expeditions. The aim of the study was to analyze and discuss the retrospective data of long-term monitoring and observations in Ukrainian Antarctica station "Akademik Vernadsky," providing multi-scale biomedical information with regard to conditions of a perfect isolation from technological and social influences and under extreme environmental factors. METHODS: Medical and biological studies have been performed with the participation of all 20 Ukrainian wintering expeditions. We surveyed 200 males aged 20-60 years (mean age 37 years). Extensive medical examinations were carried out before the expedition, during the selection of candidates, and after returning, and particular functions were monitored during the entire stay in Antarctica. The medical records were analyzed to study the reaction of the human organism on phenomena like "Antarctic syndrome," dysadaptation, anxiety, desynchronosis, photoperiodism, influence of climatic and meteofactors like "Schumann resonance," infrasound, "ozone hole," and "sterile" environment; important aspects of its role on human health were precisely studied and discussed. RESULTS: The examinations showed the multi-level symptoms of the processes of dysregulation and dysadaptation, as functional tension in the sympathetic-adrenal system rights, especially during urgent adaptation to the Antarctic (1-month stay at the station) and, to a lesser extent, after returning from an expedition to Kyiv. At the initial, adaptation to the conditions of the Antarctic levels of urinary catecholamines (epinephrine, norepinephrine, dopamine, DOPA) increased compared with the start of the expedition (23.2 +/- 4.3 and 53.3 +/- 5 2 mmol/l, p < 0.001; 67.1 +/- 12.3 and 138.3 +/- 16.9 mmol/l, p < 0.01; 1749.6 +/- 476.5 vs 7094.6 +/- 918.3 mmol/l, p < 0.001; 129.6 +/- 12.3 and 349.9 +/- 40.6 mmol/l, p < 0.001, respectively). In the blood serum of 100 % of the expedition, we found an increase of oxidative stress markers-the level of TBARS increased by 41.2 %, i.e., the activation of free radical peroxidation. Thus, in 80 % of the participants, we observed a reduction in the activity of the SOD antiradical enzyme vs 58 % in the controls. Changes in brain electrical activity after a long stay at the Antarctic stations showed increasing delta rhythms, signs of CNS protective inhibition, likely due to hypoxia. We found changes in the concentrations of microelements (iron, copper, zinc, etc.) in the blood of winterers after the expedition. The polychrome-adaptive method of correcting the changes of the psycho-emotional state in a monochrome Antarctic environment was successfully applied. CONCLUSIONS: The preliminary results of the retrospective study and our own observations of the fundamental physiological mechanisms of the negative influence of extreme environmental factors on an organism in the absence of man-made origin factors allow the determination of many mechanisms of "pre-pathology" processes which promise to develop the pathogenetically based pro-active prevention methods for a number of common diseases to set prospective interdisciplinary research in predictive, preventive, and personalized medicine. PMID- 27247703 TI - Antioxidant and Hypolipidemic Activity of the Hydroethanolic Extract of Curatella americana L. Leaves. AB - High levels of reactive oxygen species in the body and hyperlipidemia are key factors for the development of cardiovascular diseases such as atherosclerosis. The present study investigated the antioxidant and hypolipidemic activity of hydroethanolic extract of Curatella americana L. leaves (ExC). The antioxidant activity of ExC was assessed by 2,2-diphenyl-1-picrylhydrazyl free radical (DPPH) scavenging capacity and protection against hemolysis induced by 2,2'-azobis(2 amidinopropane) dihydrochloride (AAPH), followed by quantification of malondialdehyde (MDA). Wistar rats with hyperlipidemia induced by high-fructose diet (60%) were treated for 60 days with water, simvastatin (30 mg.Kg(-1)), ciprofibrate (2 mg.Kg(-1)), and ExC (200 mg.Kg(-1)). ExC revealed IC50 of 6.0 +/- 0.5 MUg.mL(-1), an intermediary value among positive controls used in the assay of DPPH scavenging capacity. At all concentrations (50 to 125 MUg.mL(-1)) and times (60 to 240 min) evaluated, ExC protected erythrocytes against AAPH-induced hemolysis, which was confirmed by lower MDA levels. In vivo tests showed a reduction of 34 and 45%, respectively, in serum concentration of cholesterol and triglycerides in hyperlipidemic rats treated with ExC, a similar effect compared to the reference drugs, simvastatin and ciprofibrate, respectively. Together, the results showed the antioxidant activity of ExC and its ability to improve the serum lipid profile in hyperlipidemic rats. PMID- 27247702 TI - ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and Age-Related Diseases. AB - The aging process worsens the human body functions at multiple levels, thus causing its gradual decrease to resist stress, damage, and disease. Besides changes in gene expression and metabolic control, the aging rate has been associated with the production of high levels of Reactive Oxygen Species (ROS) and/or Reactive Nitrosative Species (RNS). Specific increases of ROS level have been demonstrated as potentially critical for induction and maintenance of cell senescence process. Causal connection between ROS, aging, age-related pathologies, and cell senescence is studied intensely. Senescent cells have been proposed as a target for interventions to delay the aging and its related diseases or to improve the diseases treatment. Therapeutic interventions towards senescent cells might allow restoring the health and curing the diseases that share basal processes, rather than curing each disease in separate and symptomatic way. Here, we review observations on ROS ability of inducing cell senescence through novel mechanisms that underpin aging processes. Particular emphasis is addressed to the novel mechanisms of ROS involvement in epigenetic regulation of cell senescence and aging, with the aim to individuate specific pathways, which might promote healthy lifespan and improve aging. PMID- 27247704 TI - Stem cells sources for intervertebral disc regeneration. AB - Intervertebral disc regeneration field is rapidly growing since disc disorders represent a major health problem in industrialized countries with very few possible treatments. Indeed, current available therapies are symptomatic, and surgical procedures consist in disc removal and spinal fusion, which is not immune to regardable concerns about possible comorbidities, cost-effectiveness, secondary risks and long-lasting outcomes. This review paper aims to share recent advances in stem cell therapy for the treatment of intervertebral disc degeneration. In literature the potential use of different adult stem cells for intervertebral disc regeneration has already been reported. Bone marrow mesenchymal stromal/stem cells, adipose tissue derived stem cells, synovial stem cells, muscle-derived stem cells, olfactory neural stem cells, induced pluripotent stem cells, hematopoietic stem cells, disc stem cells, and embryonic stem cells have been studied for this purpose either in vitro or in vivo. Moreover, several engineered carriers (e.g., hydrogels), characterized by full biocompatibility and prompt biodegradation, have been designed and combined with different stem cell types in order to optimize the local and controlled delivery of cellular substrates in situ. The paper overviews the literature discussing the current status of our knowledge of the different stem cells types used as a cell based therapy for disc regeneration. PMID- 27247705 TI - Endometrial mesenchymal stem cells as a cell based therapy for pelvic organ prolapse. AB - Pelvic organ prolapse (POP) occurs when the pelvic organs (bladder, bowel or uterus) herniate into the vagina, causing incontinence, voiding, bowel and sexual dysfunction, negatively impacting upon a woman's quality of life. POP affects 25% of all women and results from childbirth injury. For 19% of all women, surgical reconstructive surgery is required for treatment, often augmented with surgical mesh. The surgical treatment fails in up to 30% of cases or results in adverse effects, such as pain and mesh erosion into the bladder, bowel or vagina. Due to these complications the Food and Drug Administration cautioned against the use of vaginal mesh and several major brands have been recently been withdrawn from market. In this review we will discuss new cell-based approaches being developed for the treatment of POP. Several cell types have been investigated in animal models, including a new source of mesenchymal stem/stromal cells (MSC) derived from human endometrium. The unique characteristics of endometrial MSC, methods for their isolation and purification and steps towards their development for good manufacturing practice production will be described. Animal models that could be used to examine the potential for this approach will also be discussed as will a rodent model showing promise in developing an endometrial MSC-based therapy for POP. The development of a preclinical large animal model for assessing tissue engineering constructs for treating POP will also be mentioned. PMID- 27247706 TI - Comparison of endoscopic papillary balloon dilatation and endoscopic sphincterotomy for bile duct stones. AB - Endoscopic treatment for bile duct stones is low-invasive and currently considered as the first choice of the treatment. For the treatment of bile duct stones, papillary treatment is necessary, and the treatments used at the time are broadly classified into two types; endoscopic papillary balloon dilatation where bile duct closing part is dilated with a balloon and endoscopic sphincterotomy (EST) where bile duct closing part is incised. Both procedures have advantages and disadvantages. Golden standard is EST, however, there are patients with difficulty for EST, thus we must select the procedure based on understanding of the characteristics of the procedure, and patient backgrounds. PMID- 27247707 TI - Safety of direct endoscopic necrosectomy in patients with gastric varices. AB - AIM: To determine the feasibility and safety of transgastric direct endoscopic necrosectomy (DEN) in patients with walled-off necrosis (WON) and gastric varices. METHODS: A single center retrospective study of consecutive DEN for WON was performed from 2012 to 2015. All DEN cases with gastric fundal varices noted on endoscopy, computed tomography (CT) or magnetic resonance imaging (MRI) during the admission for DEN were collected for analysis. In all cases, external urethral sphincter (EUS) with doppler was used to exclude the presence of intervening gastric varices or other vascular structures prior to 19 gauge fine needle aspiration (FNA) needle access into the cavity. The tract was serially dilated to 20 mm and was entered with an endoscope for DEN. Pigtail stents were placed to facilitate drainage of the cavity. Procedure details were recorded. Comprehensive chart review was performed to evaluate for complications and WON recurrence. RESULTS: Fifteen patients who underwent DEN for WON had gastric varices at the time of their procedure. All patients had an INR < 1.5 and platelets > 50. Of these patients, 11 had splenic vein thrombosis and 2 had portal vein thrombosis. Two patients had isolated gastric varices, type 1 and the remaining 13 had > 5 mm gastric submucosal varices on imaging by CT, MRI or EUS. No procedures were terminated without completing the DEN for any reason. One patient had self-limited intraprocedural bleeding related to balloon dilation of the tract. Two patients experienced delayed bleeding at 2 and 5 d post-op respectively. One required no therapy or intervention and the other received 1 unit transfusion and had an EGD which revealed no active bleeding. Resolution rate of WON was 100% (after up to 2 additional DEN in one patient) and no patients required interventional radiology or surgical interventions. CONCLUSION: In patients with WON and gastric varices, DEN using EUS and doppler guidance may be performed safely. Successful resolution of WON does not appear to be compromised by the presence of gastric varices, with similar rates of resolution and only minor bleeding events. Experienced centers should not consider gastric varices a contraindication to DEN. PMID- 27247708 TI - Place of upper endoscopy before and after bariatric surgery: A multicenter experience with 3219 patients. AB - AIM: To study the preoperative and postoperative role of upper esophagogastroduodenoscopy (EGD) in morbidly obese patients. METHODS: This is a multicenter retrospective study by reviewing the database of patients who underwent bariatric surgery (laparoscopic sleeve gastrectomy, laparoscopic Roux en Y gastric bypass, or laparoscopic minigastric bypass) in the period between 2001 June and 2015 August (Jahra Hospital-Kuwait, Hafr Elbatin Hospital and King Saud Medical City-KSA, and Mansoura University Hospital - Egypt). Patients with age 18-65 years, body mass index (BMI) > 40, or > 35 with comorbidities after failure of many dietetic regimen and acceptable levels of surgical risk were included in the study after having an informed signed consent. We retrospectively reviewed the medical charts of all morbidly obese patients. The patients' preoperative data included clinical history including upper digestive symptoms and preoperative full workup including EGD. Only patients whose charts revealed weather they were symptomatic or not were studied. We categorized patients accordingly into two groups; with (group A) or without (group B) upper digestive symptoms. The endoscopic findings were categorized into 4 groups based on predetermined criteria. The medical record of patients who developed stricture, leak or bleeding after bariatric surgery was reviewed. Logestic regression analysis was used to identify preoperative predictors that might be associated with abnormal endoscopic findings. RESULTS: Three thousand, two hundred and nineteen patients in the study period underwent bariatric surgery (75% LSG, 10% LRYDB, and 15% MGB). Mean BMI was 43 +/- 13, mean age 37 +/- 9 years, 79% were female. Twenty eight percent had presented with upper digestive symptoms (group A). EGD was considered normal in 2414 (75%) patients (9% group A vs 66% group B, P = 0.001). The abnormal endoscopic findings were found high in those patients with upper digestive symptoms. Abnormal findings (one or more) were found in 805 (25%) patients (19% group A vs 6% group B, P = 0.001). Seven patients had critical events during conscious sedation due to severe hypoxemia (< 60%). Rate of stricture in our study was 2.6%. Success rate of endoscopic dilation was 100%. One point nine percent patients with gastric leak were identified with 75% success rate of endoscopic therapy. Three point seven percent patients developed acute upper bleeding. Seventy-eight point two percent patients were treated by conservative therapy and EGD was performed in 21.8% with 100% success and 0% complications. CONCLUSION: Our results support the performance of EGD only in patients with upper gastrointestinal symptoms. Endoscopy also offers safe effective tool for anastomotic complications after bariatric surgery. PMID- 27247709 TI - High mobility group protein 1: A collaborator in nucleosome dynamics and estrogen responsive gene expression. AB - High mobility group protein 1 (HMGB1) is a multifunctional protein that interacts with DNA and chromatin to influence the regulation of transcription, DNA replication and repair and recombination. We show that HMGB1 alters the structure and stability of the canonical nucleosome (N) in a nonenzymatic, adenosine triphosphate-independent manner. As a result, the canonical nucleosome is converted to two stable, physically distinct nucleosome conformers. Although estrogen receptor (ER) does not bind to its consensus estrogen response element within a nucleosome, HMGB1 restructures the nucleosome to facilitate strong ER binding. The isolated HMGB1-restructured nucleosomes (N' and N'') remain stable and exhibit a number of characteristics that are distinctly different from the canonical nucleosome. These findings complement previous studies that showed (1) HMGB1 stimulates in vivo transcriptional activation at estrogen response elements and (2) knock down of HMGB1 expression by siRNA precipitously reduced transcriptional activation. The findings indicate that a major facet of the mechanism of HMGB1 action involves a restructuring of aspects of the nucleosome that appear to relax structural constraints within the nucleosome. The findings are extended to reveal the differences between ER and the other steroid hormone receptors. A working proposal outlines mechanisms that highlight the multiple facets that HMGB1 may utilize in restructuring the nucleosome. PMID- 27247710 TI - Radiological features of uncommon aneurysms of the cardiovascular system. AB - Although aortic aneurysms are the most common type encountered clinically, they do not span the entire spectrum of possible aneurysms of the cardiovascular system. As cross sectional imaging techniques with cardiac computed tomography and cardiac magnetic resonance imaging continue to improve and becomes more commonplace, once rare cardiovascular aneurysms are being encountered at higher rates. In this review, a series of uncommon, yet clinically important, cardiovascular aneurysms will be presented with review of epidemiology, clinical presentation and complications, imaging features and relevant differential diagnoses, and aneurysm management. PMID- 27247711 TI - Current status of transarterial radioembolization. AB - Unresectable primary and secondary liver malignancies present a major problem in the treatment of solid tumors. Transarterial radioembolization (TARE) is an increasingly used technique for treating various types of malignant liver tumors. This approach is appealing, as the mechanism of action is independent from other loco-regional treatments and potentially complementary to systemic therapies. There are two commercially available products in use for TARE: (90)Y-resin and (90)Y-glass microspheres. Currently available data indicates TARE so be safe and effective in hepatocellular carcinoma (HCC) and metastatic liver disease. In HCC the results compare well with chemoembolization, while the role of TARE in combination with kinase inhibitors has yet to be established. Current data on TARE in metastatic liver disease is promising, but there is a strong need for prospective randomized trials comparing TARE and modern chemotherapeutic regimen to support the growing role of TARE in metastatic liver disease. PMID- 27247712 TI - Incremental value of thoracic ultrasound in intensive care units: Indications, uses, and applications. AB - Emergency physicians are required to care for unstable patients with life threatening conditions, and thus must make decisions that are both quick and precise about unclear clinical situations. There is increasing consensus in favor of using ultrasound as a real-time bedside clinical tool for clinicians in emergency settings alongside the irreplaceable use of historical and physical examinations. B-mode sonography is an old technology that was first proposed for medical applications more than 50 years ago. Its application in the diagnosis of thoracic diseases has always been considered limited, due to the presence of air in the lung and the presence of the bones of the thoracic cage, which prevent the progression of the ultrasound beam. However, the close relationship between air and water in the lungs causes a variety of artifacts on ultrasounds. At the bedside, thoracic ultrasound is based primarily on the analysis of these artifacts, with the aim of improving accuracy and safety in the diagnosis and therapy of the various varieties of pulmonary pathologic diseases which are predominantly "water-rich" or "air-rich". The indications, contraindications, advantages, disadvantages, and techniques of thoracic ultrasound and its related procedures are analyzed in the present review. PMID- 27247713 TI - Computed tomography colonography for the practicing radiologist: A review of current recommendations on methodology and clinical indications. AB - Colorectal cancer (CRC) represents one of the most relevant causes of morbidity and mortality in Western societies. CRC screening is actually based on faecal occult blood testing, and optical colonoscopy still remains the gold standard screening test for cancer detection. However, computed tomography colonography (CT colonography) constitutes a reliable, minimally-invasive method to rapidly and effectively evaluate the entire colon for clinically relevant lesions. Furthermore, even if the benefits of its employment in CRC mass screening have not fully established yet, CT colonography may represent a reasonable alternative screening test in patients who cannot undergo or refuse colonoscopy. Therefore, the purpose of our review is to illustrate the most updated recommendations on methodology and the current clinical indications of CT colonography, according to the data of the existing relevant literature. PMID- 27247715 TI - Biopsy of parotid masses: Review of current techniques. AB - Definitive diagnosis of parotid gland masses is required optimal management planning and for prognosis. There is controversy over whether fine needle aspiration cytology (FNAC) or ultrasound guided core biopsy (USCB) should be the standard for obtaining a biopsy. The aim of this review is to assess the current evidence available to assess the benefits of each technique and also to assess the use of intra-operative frozen section (IOFS). Literature searches were performed using pubmed and google scholar. The literature has been reviewed and the evidence is presented. FNAC is an accepted and widely used technique. It has been shown to have variable diagnostic capabilities depending on centres and experience of staff. USCB has a highly consistent diagnostic accuracy and can help with tumour grading and staging. However, the technique is more invasive and there is a question regarding potential for seeding. Furthermore, USCB is less likely to be offered as part of a one-stop clinic. IOFS has no role as a first line diagnostic technique but may be reserved as an adjunct or for lesions not amenable to percutaneous biopsy. On balance, USCB seems to be the method of choice. The current evidence suggests it has superior diagnostic potential and is safe. With time, USCB is likely to supplant FNAC as the biopsy technique of choice, replicating that which has occurred already in other areas of medicine such a breast practice. PMID- 27247716 TI - Credentialing in radiology: Current practice and future challenges. AB - Radiology has changed significantly in recent years. The volume of work has increased dramatically as has its complexity. Future radiologists need an adequate training and expertise in conventional practice as well as new techniques. This comes at a time when other stakeholders outside of radiology are voicing their own concerns. The rightly justified increasing focus on patient safety has placed even more emphasis on the demonstration of competent practice by all health care professionals. Credentialing has been put forward as a way to ensure a doctor is competent in specific areas. Credentialing may be an alien concept to many radiology trainees but moves are afoot in the United Kingdom to bring it to the forefront of its postgraduate medical training. Credentialing began in 20(th) century North America where it was linked to the process of privileging. It subsequently garnered a strong patient safety focus and has become a part of the international healthcare agenda. Not everyone agrees with credentialing, it has many criticisms including the risk of speciality "turf wars" and the stifling of medical excellence to name just a couple. Is credentialing in radiology here to stay or will it pass by quietly? This paper reviews the global credentialing movement and discusses how this may impact on future radiology training, using the United Kingdom as its case example. PMID- 27247717 TI - Imaging of peritoneal deposits in ovarian cancer: A pictorial review. AB - As per incidence, ovarian carcinoma is the second most common gynaecological malignancy in women. In spite of advanced technology, patient awareness and effective screening methods, epithelial ovarian cancer is usually diagnosed at an advanced stage (stage III). Surgical debulking of disease is mainstay of improving the patient survival even in advanced stages. Thus exact delineation of cancer spread in the abdominal cavity guides the surgeon prior to the surgery, help them to decide resectability of lesion and plan for further need of other surgical speciality or need of neoadjuvant chemotherapy. Imaging particularly well-planned contrast-enhanced computed tomography answers most of the queries raised by the treating surgeon. The aim of this article is to review the way ovarian carcinoma spread in the peritoneal cavity and to stress the accurate interpretation of cancer deposits on imaging which can help the treating team to reach optimal management of patients. PMID- 27247718 TI - Radiological interventions in malignant biliary obstruction. AB - Malignant biliary obstruction is commonly caused by gall bladder carcinoma, cholangiocarcinoma and metastatic nodes. Percutaneous interventions play an important role in managing these patients. Biliary drainage, which forms the major bulk of radiological interventions, can be palliative in inoperable patients or pre-operative to improve liver function prior to surgery. Other interventions include cholecystostomy and radiofrequency ablation. We present here the indications, contraindications, technique and complications of the radiological interventions performed in patients with malignant biliary obstruction. PMID- 27247714 TI - Review of renal cell carcinoma and its common subtypes in radiology. AB - Representing 2%-3% of adult cancers, renal cell carcinoma (RCC) accounts for 90% of renal malignancies and is the most lethal neoplasm of the urologic system. Over the last 65 years, the incidence of RCC has increased at a rate of 2% per year. The increased incidence is at least partly due to improved tumor detection secondary to greater availability of high-resolution cross-sectional imaging modalities over the last few decades. Most RCCs are asymptomatic at discovery and are detected as unexpected findings on imaging performed for unrelated clinical indications. The 2004 World Health Organization Classification of adult renal tumors stratifies RCC into several distinct histologic subtypes of which clear cell, papillary and chromophobe tumors account for 70%, 10%-15%, and 5%, respectively. Knowledge of the RCC subtype is important because the various subtypes are associated with different biologic behavior, prognosis and treatment options. Furthermore, the common RCC subtypes can often be discriminated non invasively based on gross morphologic imaging appearances, signal intensity on T2 weighted magnetic resonance images, and the degree of tumor enhancement on dynamic contrast-enhanced computed tomography or magnetic resonance imaging examinations. In this article, we review the incidence and survival data, risk factors, clinical and biochemical findings, imaging findings, staging, differential diagnosis, management options and post-treatment follow-up of RCC, with attention focused on the common subtypes. PMID- 27247719 TI - Follow-up of endovascular aortic aneurysm repair: Preliminary validation of digital tomosynthesis and contrast enhanced ultrasound in detection of medium- to long-term complications. AB - AIM: To validate the feasibility of digital tomosynthesis of the abdomen (DTA) combined with contrast enhanced ultrasound (CEUS) in assessing complications after endovascular aortic aneurysm repair (EVAR) by using computed tomography angiography (CTA) as the gold standard. METHODS: For this prospective study we enrolled 163 patients (123 men; mean age, 65.7 years) referred for CTA for EVAR follow-up. CTA, DTA and CEUS were performed at 1 and 12 mo in all patients, with a maximum time interval of 2 d. RESULTS: Among 163 patients 33 presented complications at CTA. DTA and CTA correlated for the presence of complications in 32/33 (96.96%) patients and for the absence of complications in 127/130 (97.69%) patients; the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of DTA were 97%, 98%, 91%, 99%, and 98%, respectively. CEUS and CTA correlated for the presence of complications in 19/33 (57.57%) patients and for the absence of complications in 129/130 (99.23%) patients; the sensitivity, specificity, PPV, NPV and accuracy of CEUS were 58%, 99%, 95%, 90%, and 91%, respectively. Sensitivity, specificity and accuracy of combining DTA and CEUS together in detecting EVAR complications were 77%, 98% and 95%, respectively. CONCLUSION: Combining DTA and CEUS in EVAR follow-up has the potential to limit the use of CTA only in doubtful cases. PMID- 27247720 TI - Anti-inflammatory effects of proanthocyanidin-rich red rice extract via suppression of MAPK, AP-1 and NF-kappaB pathways in Raw 264.7 macrophages. AB - BACKGROUND/OBJECTIVES: Several pharmacological properties of red rice extract have been reported including anti-oxidant, anti-tumor, and reduced cancer cell invasion. This study was conducted to evaluate the anti-inflammatory effects of red rice extract on the production of inflammatory mediators in lipopolysaccharide (LPS)-induced Raw 264.7 macrophages. MATERIALS/METHODS: Pro inflammatory cytokines including tumor necrosis factor-alpha and interleukin-6 were determined by ELISA and cyclooxygenase-2 and inducible nitric oxide synthase expression was evaluated using western blot analysis. In addition, the signaling pathway controlling the inflammatory cascade such as nuclear factor kappa B (NF kappaB), activator proteins-1 (AP-1), and mitogen-activated protein kinase (MAPK) was determined. RESULTS: Our results showed that red rice polar extract fraction (RR-P), but not non-polar extract fraction, inhibited interleukin-6, tumor necrosis factor-alpha, and nitric oxide production in LPS-induced Raw 264.7 cells. RR-P also reduced the expression of inflammatory enzymes, inducible nitric oxide synthase, and cyclooxygenase-2. In addition, activation of AP-1 and NF kappaB transcription factor in the nucleus was abrogated by RR-P. RR-P inhibited the phosphorylation of extracellular signaling-regulated kinase 1/2, c-Jun NH2 terminal kinase, and p38 MAPK signaling responsible for the expression of inflammatory mediators in LPS-stimulated Raw 264.7 cells. Based on chemical analysis, high amounts of proanthocyanidin and catechins were detected in the RR P fraction. However, only proanthocyanidin reduced NF-kappaB and AP-1 activation in LPS-activated Raw 264.7 cells. CONCLUSION: These observations suggest that the anti-inflammatory properties of RR-P may stem from the inhibition of pro inflammatory mediators via suppression of the AP-1, NF-kappaB, and MAPKs pathways. PMID- 27247721 TI - Compound K attenuates stromal cell-derived growth factor 1 (SDF-1)-induced migration of C6 glioma cells. AB - BACKGROUND/OBJECTIVES: Stromal cell-derived growth factor 1 (SDF-1), also known as chemokine ligand 12, and chemokine receptor type 4 are involved in cancer cell migration. Compound K (CK), a metabolite of protopanaxadiol-type ginsenoside by gut microbiota, is reported to have therapeutic potential in cancer therapy. However, the inhibitory effect of CK on SDF-1 pathway-induced migration of glioma has not yet been established. MATERIALS/METHODS: Cytotoxicity of CK in C6 glioma cells was determined using an EZ-Cytox cell viability assay kit. Cell migration was tested using the wound healing and Boyden chamber assay. Phosphorylation levels of protein kinase C (PKC)alpha and extracellular signal-regulated kinase (ERK) were measured by western blot assay, and matrix metallopeptidases (MMP) were measured by gelatin-zymography analysis. RESULTS: CK significantly reduced the phosphorylation of PKCalpha and ERK1/2, expression of MMP9 and MMP2, and inhibited the migration of C6 glioma cells under SDF-1-stimulated conditions. CONCLUSIONS: CK is a cell migration inhibitor that inhibits C6 glioma cell migration by regulating its downstream signaling molecules including PKCalpha, ERK1/2, and MMPs. PMID- 27247722 TI - Effect of Hijikia fusiforme extracts on degenerative osteoarthritis in vitro and in vivo models. AB - BACKGROUND/OBJECTIVES: The inhibitory effect of Hijikia fusiforme (HF) extracts on degenerative osteoarthritis was examined in primary cultured rat cartilage cells and a monosodium iodoacetate (MIA)-induced osteoarthritis rat model. MATERIALS/METHODS: In vitro, cell survival and the expression of matrix metalloproteinases (MMPs), collagen type I, collagen type II, aggrecan, and tissue inhibitor of metalloproteinases (TIMPs) was measured after H2O2 (800 uM, 2 hr) treatment in primary chondrocytes. In vivo animal study, osteoarthritis was induced by intra-articular injection of MIA into knee joints of rats, and then RH500, HFE250 and HFE500 were administered orally once a day for 28 days. To determine the anti-inflammatory effects of HFE, nitric oxide (NO), prostaglandin E2 (PGE2) expression were measured. In addition, real-time PCR was performed to measure the genetic expression of MMPs, collagen type I, collagen type II, aggrecan, and TIMPs. RESULTS: In the in vitro assay, cell survival after H2O2 treatment was increased by HFE extract (20% EtOH). In addition, anabolic factors (genetic expression of collagen type I, II, and aggrecan) were increased by HFE extract (20% EtOH). However, the genetic expression of MMP-3 and 7, known as catabolic factors were significantly inhibited by treatment with HFE extract (20% EtOH). In the in vivo assay, anabolic factors (genetic expression of collagen type I, II, aggrecan, and TIMPs) were increased by oral administration of HFE extract. However, the genetic expression of MMP-3 and 7, known as catabolic factors, and production of NO and PGE2 were significantly inhibited by treatment with oral administration of HFE extract. CONCLUSIONS: HFE extract inhibited articular cartilage degeneration through preventing extracellular matrix degradation and chondrocyte injury. PMID- 27247723 TI - Perilla frutescens var. japonica and rosmarinic acid improve amyloid-beta25-35 induced impairment of cognition and memory function. AB - BACKGROUND/OBJECTIVES: The accumulation of amyloid-beta (Abeta) in the brain is a hallmark of Alzheimer's disease (AD) and plays a key role in cognitive dysfunction. Perilla frutescens var. japonica extract (PFE) and its major compound, rosmarinic acid (RA), have shown antioxidant and anti-inflammatory activities. We investigated whether administration of PFE and RA contributes to cognitive improvement in an Abeta25-35-injected mouse model. MATERIALS/METHODS: Male ICR mice were intracerebroventricularly injected with aggregated Abeta25-35 to induce AD. Abeta25-35-injected mice were fed PFE (50 mg/kg/day) or RA (0.25 mg/kg/day) for 14 days and examined for learning and memory ability through the T maze, object recognition, and Morris water maze test. RESULTS: Our present study demonstrated that PFE and RA administration significantly enhanced cognition function and object discrimination, which were impaired by Abeta25-35, in the T maze and object recognition tests, respectively. In addition, oral administration of PFE and RA decreased the time to reach the platform and increased the number of crossings over the removed platform when compared with the Abeta25-35-induced control group in the Morris water maze test. Furthermore, PFE and RA significantly decreased the levels of nitric oxide (NO) and malondialdehyde (MDA) in the brain, kidney, and liver. In particular, PFE markedly attenuated oxidative stress by inhibiting production of NO and MDA in the Abeta25-35-injected mouse brain. CONCLUSIONS: These results suggest that PFE and its active compound RA have beneficial effects on cognitive improvement and may help prevent AD induced by Abeta. PMID- 27247724 TI - Fermentation of purple Jerusalem artichoke extract to improve the alpha glucosidase inhibitory effect in vitro and ameliorate blood glucose in db/db mice. AB - BACKGROUND/OBJECTIVES: Jerusalem artichoke has inhibitory activity against alpha glucosidase and decreases fasting serum glucose levels, which may be related to its fructan content. The biological activity of fructan can be influenced by the degree of polymerization. Thus, in this study, the inhibitory effects of original and fermented purple Jerusalem artichoke (PJA) on alpha-glucosidase were compared in vitro. Additionally, the anti-diabetes effect of Lactobacillus plantarum fermented PJA (LJA) was studied in a non-insulin-dependent diabetes mellitus animal model (C57BIKsJ db/db). MATERIALS/METHODS: The water extract of PJA was fermented by L. plantarum, and two strains of Bacillus subtilis to compare their anti-alpha-glucosidase activities in vitro by alpha-glucosidase assays. The anti diabetes effect of LJA was studied in a non-insulin-dependent diabetes mellitus animal model (C57BIKsJ db/db) for seven weeks. During the experiment, food intake, body weight, and fasting blood glucose were measured every week. At the end of the treatment period, several diabetic parameters and the intestinal alpha glucosidase activity were measured. RESULTS: The LJA showed the highest alpha glucosidase inhibitory activity in vitro. In the in vivo study, it resulted in a significantly lower blood glucose concentration than the control. Serum insulin and HDL cholesterol levels were significantly higher and the concentrations of triglycerides, non-esterified fatty acids, and total cholesterol were significant lower in mice treated with LJA after seven weeks. In addition, the intestinal alpha-glucosidase activity was partially inhibited. CONCLUSIONS: These results suggested that LJA regulates blood glucose and has potential use as a dietary supplement. PMID- 27247726 TI - Dietary quality differs by consumption of meals prepared at home vs. outside in Korean adults. AB - BACKGROUND/OBJECTIVES: Eating out has been reported to have negative effects on nutritional status. However, eating out can include meals prepared at home and eaten outside. Conversely, meals eaten at home can be brought from outside, as take-out and home deliveries have become common in Korea. Thus, we tested whether or not meal preparation location influences daily diet quality. SUBJECTS/METHODS: From the Korea National Health and Nutrition Examination Survey (KNHANES) 2007 2009, 4,915 Korean adults (20-64 years) were classified into two groups: home made meal group (HMG), who ate >= 2 meals per day prepared at home (n = 4,146), and non-home-made meal group (NHMG), who ate >= 2 meals per day prepared outside home (n = 769). Daily diet quality was determined by energy intake, nutrient intake, Dietary Variety Score (DVS), and Diet Diversity Score (DDS). RESULTS: Compared to the HMG, the NHMG was more likely to consist of men, single, employed, educated and of a higher economic status (all, P < 0.01). The NHMG showed higher energy intakes (1,776 vs. 2,116 kcal/day) with higher percentages of energy from protein (15 vs. 23%) and fat (14 vs. 16%) and lower intakes of dietary fiber, phosphorus, potassium, niacin, and vitamin C (all, P < 0.01) than the HMG, with some variations among age groups. The NHMG tended to consume foods prepared by frying and grilling and had more one-dish meals such as bibimbap, noodles, and dumplings but also showed higher dietary diversity. CONCLUSIONS: It should be noted that home-made meals do not necessarily guarantee a healthy diet, and the effects of meal preparation location on nutritional status might vary depending on socio-demographic characteristics. PMID- 27247725 TI - Elevation of heart-femoral pulse wave velocity by short-term low sodium diet followed by high sodium diet in hypertensive patients with sodium sensitivity. AB - BACKGROUND/OBJECTIVES: We compared changes in heart-femoral pulse wave velocity (hfPWV) in response to low sodium and high sodium diet between individuals with sodium sensitivity (SS) and resistance (SR) to evaluate the influence of sodium intake on arterial stiffness. SUBJECTS/METHODS: Thirty-one hypertensive and 70 normotensive individuals were given 7 days of low sodium dietary approach to stop hypertension (DASH) diet (LSD, 100 mmol NaCl/day) followed by 7 days of high sodium DASH diet (HSD, 300 mmol NaCl/day) during 2 weeks of hospitalization. The hfPWV was measured and compared after the LSD and HSD. RESULTS: The hfPWV was significantly elevated from LSD to HSD in individuals with SS (P = 0.001) independently of changes in mean arterial pressure (P = 0.037). Conversely, there was no significant elevation of hfPWV from LSD to HSD in individuals with SR. The percent change in hfPWV from the LSD to the HSD in individuals with SS was higher than that in individuals with SR. Subgroup analysis revealed that individuals with both SS and hypertension showed significant elevation of hfPWV from LSD to HSD upon adjusted analysis using changes of the means arterial pressure (P = 0.040). However, there was no significant elevation of hfPWV in individuals with SS and normotension. CONCLUSION: High sodium intake elevated hfPWV in hypertensive individuals with SS, suggesting that high sodium intake increases aortic stiffness, and may contribute to enhanced cardiovascular risk in hypertensive individuals with SS. PMID- 27247727 TI - Development of dietary pattern evaluation tool for adults and correlation with Dietary Quality Index. AB - BACKGROUND/OBJECTIVES: As the prevalence of chronic diseases has risen, the need for straightforward diagnostic tools for monitoring nutrition status to improve nutrition counseling and disease prevention has likewise increased. This study developed an easily usable dietary behavior pattern diagnosis checklist and investigated its correlation with dietary quality index. SUBJECTS/METHODS: A draft dietary pattern evaluation tool was generated by analyzing previous studies. The draft questionnaire comprised 61 questions for assessing dietary habits. A survey was administered to 320 adults (19 to 64 years old) using the dietary pattern evaluation tool and 24-hour-recall method between March and May of 2014 in Jeonbuk province and the metropolitan area. Principal component analysis with varimax rotation was performed to identify dietary behavior patterns. Nutritional analysis was conducted using CAN-Pro 4.0, and the Diet Quality Index-International (DQI-I) was calculated to assess dietary quality. The correlation between dietary pattern scores and DQI-I scores was also analyzed. RESULTS: The factor analysis resulted in a total of 34 questions mapped to four main dietary behavior patterns: "high fat and calorie" pattern (12 questions), "overeating/binge" pattern (nine questions), "dietary impulse" pattern (eight questions), and "unbalanced food intake" pattern (five questions). The four dietary behavior patterns were negatively correlated with DQI-I adequacy and total scores (P < 0.01). CONCLUSIONS: The dietary pattern evaluation tool developed in this study can be used to diagnose a client's dietary behavior problems and is available as a nutrition counseling tool in the field. PMID- 27247728 TI - Associations of dietary intake and metabolic syndrome risk parameters in Vietnamese female marriage immigrants in South Korea: The KoGES follow-up study. AB - BACKGROUND/OBJECTIVES: This study was conducted to compare the overall changes in dietary intake and metabolic syndrome risk parameters in Vietnamese marriage based female immigrants over time. SUBJECTS/METHODS: The subjects of this study were 581 Vietnamese marriage-based female immigrants, who were recruited from local clinical centers in Korea. Baseline data were collected from 2006-2011 and the follow-up data were collected from 2012-2014. Dietary food intake was assessed by a 1-day 24-hour recall method. RESULTS: Compared to the baseline, the mean body weight, body mass index, waist circumference, high density lipoprotein (HDL)-cholesterol, systolic blood pressure and diastolic blood pressure increased while the fasting blood sugar, triglycerides and low density lipoprotein cholesterol decreased at follow-up. The total consumption of foods such as vegetables/fruits/seaweeds/mushrooms, oil and fat, and eggs decreased during the follow-up period, whereas the consumption of sugars, beverages and meats increased. Partial correlation between the rate of change [(Follow-up - Baseline) / Baseline * 100] in metabolic syndrome risk parameters and food intake after controlling for confounding factors showed that the waist circumference was positively correlated with either the total plant food intake (r = 0.1042, P = 0.0129) or the total food intake (r = 0.0880, P = 0.0359). The plasma levels of total cholesterol (r = -0.1918, P = 0.0289) and HDL-cholesterol (r = -0.1424, P = 0.0007) were negatively correlated with the percentage of total intake from plant food, and HDL-cholesterol levels were positively correlated with the intake of total animal food (r = 0.0980, P = 0.0217). The serum C-reactive protein levels were positively correlated with the total intake of animal food (r = 0.2374, P < 0.0001) or the percentage of total intake from animal food (r = 0.1346, P = 0.0016). CONCLUSIONS: These results suggest that the change rate of dietary intake such as total plant food or animal food is associated with the change rates of metabolic syndrome risk parameters. PMID- 27247729 TI - Student feedback to improve the United States Department of Agriculture Fresh Fruit and Vegetable Program. AB - BACKGROUND/OBJECTIVES: Fruit and vegetable consumption of children in the United States falls below recommendations. The U.S. Department of Agriculture Fresh Fruit and Vegetable Program (FFVP) is a national free-fruit and vegetable school distribution program designed to address this problem. This permanent, legislated program provides funding to qualified elementary schools for provision of additional fruit and vegetables outside of school meals. The objective of this study was to understand children's perceptions of FFVP after the intervention and formulate recommendations that may improve success of the intervention. SUBJECTS/METHODS: Secondary data were obtained from 5,265 4(th)-6(th) graders at 51 randomly-selected FFVP intervention schools in Indiana. Anonymous questionnaires were completed late in the 2011-2012 academic year. Multilevel logistic regressions were used to determine associations between students' perceptions of program effects (4 close-ended items) and their preference toward the program. Content analysis was applied to a single open-ended item for program comments. RESULTS: Over 47% of students reported greater intake of fruit and vegetables due to FFVP, and over 66% reported liking the program. Student reported program effects were positively associated with preference for the program (P < 0.01). Themes that emerged during analysis of 3,811 comments, included, students liked: the opportunity to try different kinds of fruit and vegetables, types and flavors of fruits served, and benefits of eating fruit. Fewer students liked the types of vegetables and their benefits. A small group disliked the program citing poor flavor of vegetables and quality of fruits. Important suggestions for the program include serving more dipping sauces for vegetables, cooking vegetables, and providing a greater variety of produce. CONCLUSIONS: The degree that students liked FFVP may predict the program's effects on fruit and vegetable intake. FFVP may become more acceptable to students by incorporating their suggestions. Program planners should consider these options for achieving program goals. PMID- 27247730 TI - Effects of vitamin D supplementation on metabolic indices and hs-CRP levels in gestational diabetes mellitus patients: a randomized, double-blinded, placebo controlled clinical trial. AB - BACKGROUND/OBJECTIVES: Vitamin D plays an important role in the etiology of gestational diabetes mellitus (GDM). This study evaluated the effect of vitamin D supplementation on metabolic indices and hs-C-reactive protein (CRP) levels in GDM patients. SUBJECTS/METHODS: The study was a randomized, placebo-controlled, double-blinded clinical trial. Seventy-six pregnant women with GDM and gestational age between 24-28 weeks were assigned to receive four oral treatments consisting of 50,000 IU of vitamin D3 (n = 38) or placebo (n = 38) once every 2 weeks for 2 months. Fasting blood glucose (FG), insulin, HbA1c, 25-hydroxyvitamin D, lipid profile, hs-CRP, and homeostasis model assessment-insulin resistance (HOMA-IR) were measured before and after treatment. Independent and paired t tests were used to determine intra- and intergroup differences, respectively. ANCOVA was used to assess the effects of vitamin D supplementation on biochemical parameters. RESULTS: Compared with the placebo group, in the vitamin D group, the serum level of 25-hydroxyvitamin D increased (19.15 vs. -0.40 ng/ml; P < 0.01) and that of FG (-4.72 vs. 5.27 mg/dl; P = 0.01) as well as HbA1c (-0.18% vs. 0.17%; P = 0.02) decreased. Improvements in the lipid profiles were observed in the vitamin D group, but without statistical significance. Significant increases in concentrations of hs-CRP, FG, HbA1c, total cholesterol, and LDL cholesterol were observed in the placebo group. No significant change in fasting insulin and HOMA-IR was observed in either group. CONCLUSIONS: In GDM patients, vitamin D supplementation improved FG and HbA1c but had no significant effects on lipid profile or hs-CRP. PMID- 27247731 TI - Association between nutrient intake and thyroid cancer risk in Korean women. AB - BACKGROUND/OBJECTIVES: The incidence of thyroid cancer has increased in many countries, including Korea. International differences in the incidence of thyroid cancer may indicate a role of diet, but findings from previous studies are inconclusive. Therefore, we aimed to investigate the roles of nutrients in thyroid cancer risk in Korean women. SUBJECTS/METHODS: We conducted a case control study comprising 113 cases and 226 age-matched controls. Nutrient intake was assessed using a validated food frequency questionnaire, and the association between nutrient intake and thyroid cancer risk was estimated using a logistic regression model. RESULTS: We found that high calcium intake was associated with a reduced risk of thyroid cancer (OR [95% CI] = 0.55 [0.35-0.89]). Significant associations were observed among subjects who were older than 50 years, had low BMI, and had low calorie intake. However, other nutrients included in this study did not show any significant associations with thyroid cancer risk. CONCLUSIONS: This study suggested a possible protective effect of calcium on thyroid cancer risk. Well-designed prospective studies are required to confirm these findings. PMID- 27247732 TI - The development of a mobile u-Health program and evaluation for self-diet management for diabetic patients. AB - BACKGROUND/OBJECTIVES: This study aims to develop a mobile nutritional management program for integration into the already developed web-based program, Diabetes Mellitus Dietary Management Guide (DMDMG) for diabetic patients. Further, we aim to evaluate the amended DMDMG program. SUBJECTS/METHODS: The mobile application based on an Android operating system includes three parts: 1) record of diet intake, which allows users to take pictures of the meal and save to later add diet records into DMDMG; 2) an alarm system that rings at each meal time, which reminds users to input the data; 3) displays the diet record and the results of nutrient intake, which can be also viewed through the web program. All three parts are linked to the web-based program. A survey was conducted to evaluate the program in terms of nutrition knowledge, dietary attitude, eating behavior and diet intake by non-equivalent control group design among diabetic patients with 14 DMDMG users and 12 non-user controls after a one-month trial of DMDMG. RESULTS: Non-users did not use the program, but participated in the weekly off line nutrition classes for one month. The program users showed increased healthful dietary behavior (P < 0.01) and dietary attitude scores (P < 0.05). More DMDMG users had higher nutrition knowledge scores after one-month trial than non-users. However, dietary intake significantly increased in non-user group for calcium and sodium (P < 0.05) while the user group did not show significant changes. CONCLUSIONS: The program has created positive changes in patients' dietary life. All the users were satisfied with the program, although some expressed minor difficulties with an unfamiliar mobile app. PMID- 27247733 TI - Health Blief Model-based intervention to improve nutritional behavior among elderly women. AB - BACKGROUND/OBJECTIVES: Nutrition is a determinant factor of health in elderly people. Independent living in elderly people can be maintained or enhanced by improvement of nutritional behavior. Hence, the present study was conducted to determine the impact of Health Belief Model (HBM)-based intervention on the nutritional behavior of elderly women. SUBJECTS/METHODS: Cluster-random sampling was used to assess the sample of this clinical trial study. The participants of this study attended a 12-week nutrition education program consisting of two (2) sessions per week. There was also a follow-up for another three (3) months. Smart PLS 3.5 and SPSS 19 were used for structural equation modeling, determination of model fitness, and hypotheses testing. RESULTS: The findings indicate that intervention had a significant effect on knowledge improvement as well as the behavior of elderly women. The model explained 5 to 70% of the variance in nutritional behavior. In addition, nutritional behavior was positively affected by the HBM constructs comprised of perceived susceptibility, self-efficacy, perceived benefits, and barriers after the intervention program. CONCLUSION: The results of this study show that HBM-based educational intervention has a significant effect in improving nutritional knowledge and behavior among elderly women. PMID- 27247734 TI - Associations between Japanese schoolchildren's involvement in at-home meal preparation, their food intakes, and cooking skills. AB - BACKGROUND/OBJECTIVES: This study aimed to examine the association of Japanese schoolchildren's involvement in at-home meal preparation with food intake and cooking skill. SUBJECTS/METHODS: We included 1,207 fifth-grade children aged 10 11 years and one parent of each child. A cross-sectional survey was used to collect data on involvement in at-home meal preparation. Correspondence analysis was used to classify involvement in at-home meal preparation into three groups: food-related activities (cooking only or with other activities such as shopping, table-setting, clean up, and dishwashing), non-food-related activities (table setting and/or clean up), and no (helping) activities. Food intake was assessed using a food frequency questionnaire. Logistic regression models were used to examine involvement in at-home meal preparation associations. RESULTS: The sample consisted of 1,207 fifth-grade children. Vegetable intake was lower in the no (helping) activities group than the food-related activities group (95% CI; boys: 1.2, 5.1, girls: 2.0, 8.9). Fewer children in the non-food-related activities group reported they were able to make a portion of their meals compared with the food-related activities group (95% CI; boys: 1.6, 3.5; girls: 1.5, 3.2). CONCLUSIONS: Children in the food-related activities group showed more favorable food intake and cooking skills than children in the no (helping) activities or non-food-related activities group. PMID- 27247735 TI - Clinics in Orthopedic Surgery's Evolution into an International Journal Based on Journal Metrics. AB - This article is aimed at providing evidence of increased international recognition of Clinics in Orthopedic Surgery (CiOS) based on journal metrics. Since 7 years have passed since its launch in 2009, it is time to reflect on the journal's efforts to be recognized as a top-notch journal. The following journal metrics were analyzed from the journal's homepage and Web of Science Core Collection database: number of citable and noncitable articles; number of original articles supported by grants; editorial board members' countries; authors' countries; citing authors' countries; source titles of citing articles; impact factor; total citations; comparison of impact factor with 3 Science Citation Index Expanded journals; and Hirsch index (H-index). Of the total 392 articles, 378 were citable articles (96.4%). Of the total 282 original articles, 52 (18.4%) were supported by research grants. The editorial board members were from 13 countries. Authors were from 20 countries. The number of countries of citing authors was 66. The number of source titles of citing articles was more than 100. The total citations of CiOS have increased from 0 in 2009 to 374 in 2015. The impact factors without self-citations of CiOS were the greatest among 4 Asian journals in 2013 and 2014. The 2015 impact factor was calculated as 0.79 in January 2016. The H-index was 13. CiOS can be considered to have reached the level of top-notch journal in the orthopedic field based on journal metrics. The inclusion of the journal in PubMed Central appears to have increased international relevance of the journal. PMID- 27247736 TI - Measurement of Optimal Insertion Angle for Iliosacral Screw Fixation Using Three Dimensional Computed Tomography Scans. AB - BACKGROUND: Percutaneous iliosacral screw fixation can provide stable fixation with a minimally invasive surgical technique for unstable posterior pelvic ring injuries. This surgical technique is not limited by cases of difficult fracture patterns, sacral dysplasia, and small sacral pedicles that can occur in Asians. The purpose of this study was to investigate the incidence of the sacral dysplasia in the Korean population and determine the optimal direction of iliosacral screws by analyzing pelvic three-dimensional computed tomography (3D CT) scans. METHODS: One hundred adult patients who had pelvic 3D-CT scans were evaluated. The upper sacral morphology was classified into three groups, i.e., normal, transitional, and dysplastic groups; the cross-sectional area of the safe zone was measured in each group. S1 pedicle with a short width of more than 11 mm was defined as safe pedicle. The incidences of safe pedicles at different angles ranging from 0 degrees to 15 degrees were investigated in order to determine optimal angle for screw direction. RESULTS: The incidence of normal, transitional, and dysplastic group was 46%, 32%, and 22%, respectively. There were significant increases of the cross-sectional area of the safe zones by increasing the angles from 0 degrees to 15 degrees in all groups. The incidence of safe pedicles increased similar to the changes in cross-sectional area. The overall incidence of safe pedicles was highest at the 10 degrees tilt angle. CONCLUSIONS: The incidence of sacral dysplasia in Koreans was 54%, which is higher than previous studies for Western populations. The cross-sectional area of the safe zone can be increased by anteromedial direction of the iliosacral screw. Considering the diversity of sacral morphology present in the Korean population, a tilt angle of 10 degrees may be the safest angle. PMID- 27247737 TI - Prediction of Mortality in Nonagenarians Following the Surgical Repair of Hip Fractures. AB - BACKGROUND: The purpose of this study is to report on the mortality of nonagenarians who underwent surgical treatment for a hip fracture, specifically in regards to preexisting comorbidities. Furthermore, we assessed the effectiveness of the Deyo score in predicting such mortality. METHODS: Thirty nine patients over the age of 90 who underwent surgical repair of a hip fracture were retrospectively analyzed. Twenty-six patients (66.7%) suffered femoral neck fractures, while the remaining 13 (33.3%) presented with trochanteric type fractures. Patient charts were examined to determine previously diagnosed patient comorbidities as well as living arrangements and mobility before and after surgery. RESULTS: Deyo index scores did not demonstrate statistically significant correlations with postoperative mortality or functional outcomes. The hazard of in-hospital mortality was found to be 91% (p = 0.036) and 86% (p = 0.05) less in patients without a history of congestive heart failure (CHF) and chronic pulmonary disease (CPD), respectively. Additionally, the hazard of 90-day mortality was 88% (p = 0.01) and 81% (p = 0.024) less in patients without a history of dementia and CPD, respectively. The hazard of 1-year mortality was also found to be 75% (p = 0.01) and 80% (p = 0.01) less in patients without a history of dementia and CPD, respectively. Furthermore, dementia patients stayed in-hospital postoperatively an average of 5.3 days (p = 0.013) less than nondementia patients and only 38.5% returned to preoperative living conditions (p = 0.036). CONCLUSIONS: Nonagenarians with a history of CHF and CPD have a higher risk of in-hospital mortality following the operative repair of hip fractures. CPD and dementia patients over 90 years old have higher 90-day and 1-year mortality hazards postoperatively. Dementia patients are also discharged more quickly than nondementia patients. PMID- 27247738 TI - Clinical Results of Internal Fixation of Subcapital Femoral Neck Fractures. AB - BACKGROUND: Subcapital femoral neck is known to cause many complications, such as avascular necrosis (AVN) of the femoral head or nonunion, compared with other femoral neck fractures. The purpose of this study was to analyze the incidence of AVN and fixation failures in patients treated with internal fixation using cannulated screws for the subcapital femoral neck fractures. METHODS: This study targeted a total of 84 cases of subcapital femoral neck fractures that underwent internal fixation using cannulated screws. The average follow-up time after surgery was 36.8 months (range, 24 to 148 months). RESULTS: Nine hips (10.7%) showing AVN of the femoral head and 6 hips (7.1%) showing fixation failures were observed. The factors affecting the incidence of AVN of the femoral head after sustaining fractures correlated well with fracture types in the Garden classification (p = 0.030). The factors affecting fixation failure were the degree of reduction (p = 0.001) measured by the Garden alignment index and firm fixation (p = 0.009) assessed using the technique of 3-point fixation through the inferomedial cortical bone of the femoral neck. CONCLUSIONS: The complication rates for subcapital femoral neck fractures were lower than those previously reported; hence, internal fixation could be a primary treatment option for these fractures. PMID- 27247739 TI - Effect of Preoperative Vitamin D Levels on Functional Performance after Total Knee Arthroplasty. AB - BACKGROUND: Low vitamin D levels affects muscle function. Vitamin D and calcium deficiency cause osteomalacic myopathy and poor functional recovery after hip fractures. The relationship of vitamin D and functional performance after total knee arthroplasty (TKA) is not previously reported. METHODS: Influence of vitamin D on functional performance before and after TKA was reviewed retrospectively in 120 patients. Of these, 64 had vitamin D deficiency (25-hydroxy vitamin D < 30 ng/mL) preoperatively. All 120 patients received vitamin D oral supplementation postoperatively. Functional parameters including Western Ontario and McMaster Osteoarthritis Index (WOMAC), Short-Form Health Survey questionnaire, and Knee Society Score were assessed pre- and postoperatively at 3 months. RESULTS: Preoperative function was significantly lower in osteoarthritic patients with vitamin D deficiency (WOMAC score; p = 0.040), but at 3 months all functional scores were similar. CONCLUSIONS: We concluded that vitamin D deficiency has a negative effect on function in knee osteoarthritic patients. However, postoperative vitamin D supplementation can lead to functional recovery in these patients. Thus, TKA should not be delayed in vitamin D deficient patients; rather supplementation in the postoperative period is preferable to achieve comparable functional outcome at 3 months to patients with vitamin D sufficiency. PMID- 27247740 TI - Analysis of Impingement between Patella Bone and Bearing Post in Cruciate Substituting High-Flexion Total Knee Arthroplasty. AB - BACKGROUND: We investigated the causes of impingement between the patella bone and the bearing post during high flexion in cruciate-substituting total knee arthroplasty and proposed a treatment strategy. METHODS: This prospective cohort study included 218 cases that had undergone cruciate-substituting total knee arthroplasty from February 2014 to January 2015; a single surgeon performed the operation using the same method without patellar resurfacing in all patients. RESULTS: In these patients, the occurrence of impingement was determined by performing more than 120 degrees high knee flexion after inserting a bearing perioperatively. The incidence of impingement was significantly associated with bearing design, femoral implant size, patella bone length, and patella inferior pole angle (p < 0.05). The impingement was resolved by resection of the lower articular side of the patella bone. CONCLUSIONS: In the cruciate-substituting high-flexion total knee arthroplasty, impingement between the patella bone and bearing post was more common in patients with mobile bearing, small-size femoral component, and a long patella or a large inferior pole angle. In cases of intraoperative impingement between the patella bone and the bearing post, resection in the lower portion of the patella prevented impingement of the bearing with soft tissue or the patella by widening the space between the patella and the bearing post, which in turn prevented postoperative reduction in range of motion. PMID- 27247741 TI - Failure Rate of Spine Surgeons in Preoperative Clinical Screening of Severe Psychological Disorders. AB - BACKGROUND: The surgeon's attention to the patient's underlying psychological state is essential to attaining desired outcomes. We aimed to investigate the prevalence and severity of psychological disorders in patients undergoing elective spine surgery. METHODS: In this case-control study, associated psychological disorders were assessed using the Hospital Anxiety and Depression Scale (HADS) questionnaire at a single academic spine surgery center from August 2013 to June 2015. The case group consisted of 68 adult patients (mean age, 38.2 +/- 9.6 years; male:female = 41:27) undergoing elective spine surgery and the control group included 69 healthy visitors of the orthopedic patients (mean age, 37.1 +/- 6.9 years; male:female = 40:29) who voluntarily participated in the study. The 2 groups were compared for statistical analysis and a p-value < 5% was considered significance. RESULTS: There was no statistically significant intergroup difference with regard to gender and age. The incidences of abnormal anxiety and depression were the same in the case group (14 patients, 20.6%). The values were 3 (4.3%) and 5 (7.2%), respectively, in the control group, showing statistically significant difference. Any association between the severity of depression and age or sex could not be identified. CONCLUSIONS: In spite of spine surgeons' attempts to screen severe psychological disorders preoperatively, up to 21% of which cannot be diagnosed prior to elective spine surgery. Therefore, we believe the use of a questionnaire would be helpful in assessing patients' underlying psychological state before elective spine surgery. PMID- 27247742 TI - Anterior Shoulder Instability with Concomitant Superior Labrum from Anterior to Posterior (SLAP) Lesion Compared to Anterior Instability without SLAP Lesion. AB - BACKGROUND: The aims of this study were to investigate the clinical characteristics of patients with combined anterior instability and superior labrum from anterior to posterior (SLAP) lesions, and to analyze the effect of concomitant SLAP repair on surgical outcomes. METHODS: We retrospectively reviewed patients who underwent arthroscopic stabilization for anterior shoulder instability between January 2004 and March 2013. A total of 120 patients were available for at least 1-year follow-up. Forty-four patients with reparable concomitant detached SLAP lesions (group I) underwent combined SLAP and anterior stabilization, and 76 patients without SLAP lesions (group II) underwent anterior stabilization alone. Patient characteristics, preoperative and postoperative pain scores, Rowe scores, and shoulder ranges of motion were compared between the 2 groups. RESULTS: Patients in group I had higher incidences of high-energy trauma (p = 0.03), worse preoperative pain visual analogue scale (VAS) (p = 0.02), and Rowe scores (p = 0.04). The postoperative pain VAS and Rowe scores improved equally in both groups without significant differences. Limitation in postoperative range of motion was similar between the groups (all p-value > 0.05). CONCLUSIONS: Anterior instability with SLAP lesion may not be related to frequent episodes of dislocation but rather to a high-energy trauma. SLAP fixation with anterior stabilization procedures did not lead to poor functional outcomes if appropriate surgical techniques were followed. PMID- 27247743 TI - The Role of Lunate Morphology on Scapholunate Instability and Fracture Location in Patients Treated for Scaphoid Nonunion. AB - BACKGROUND: To determine the association between lunate morphology and the scapholunate instability using radiographic images, and investigate the association between lunate morphology and scaphoid fracture location. METHODS: Between January 2003 and December 2011, we retrospectively evaluated the plain radiographs and computed tomography (CT) images of 70 patients who underwent surgical intervention for a scaphoid nonunion, in order to determine the association between lunate type (I or II) and scapholunate instability or scaphoid fracture location. We determined the scaphoid fracture location using the fragment ratio and measured the radiolunate angle and capitate-triquetrum (C T) distance. RESULTS: A type II lunate was present in 68.6% (48 of 70 cases). Mean fragment ratio of fracture location was 50.6% in the type II lunate group and 56.2% in the type I lunate group (p = 0.032). Sixteen of the 70 patients had dorsal intercalated segmental instability (DISI) deformities. Nine of 22 cases showed DISI deformity in type I lunate and 7 of 48 cases showed DISI deformity in type II lunate (p = 0.029). However, there were no significant differences between the presence of DISI deformity and fracture location (p = 0.15). Morphologic comparisons by both plain radiography and CT indicated a mean C-T distance in the type I lunate group (22 cases) of 2.3 mm and 5.0 mm in the type II lunate group (48 cases). The C-T distances were significantly correlated with lunate morphology (p = 0.001). CONCLUSIONS: A type II lunate was associated with low incidence of DISI deformity and proximal location of fracture in patients presenting with a scaphoid nonunion. PMID- 27247744 TI - The Effect of Distal Location of the Volar Short Arm Splint on the Metacarpophalangeal Joint Motion. AB - BACKGROUND: The goals of this study were to compare maximal metacarpophalangeal joint (MCPJ) flexion angles after application of a volar short arm splint at 3 different locations and verify the relations between the three different physical and radiological locations. METHODS: Forty dominant hands of healthy subjects were analyzed in the study. We defined a transverse skin folding line as a line drawn from the radial aspect of the thenar crease to the ulnar aspect of the distal transverse palmar crease. The distal end of the volar short arm splint was applied on 3 parallel locations to this line. Location A was on this transverse skin folding line; location B was 1 cm proximal to location A; and location C was 1 cm distal to location A. Two orthopedic surgeons measured the maximal MCPJ flexion angles of each finger except the thumb with the application of a volar short arm splint at 3 different locations as well as without a splint as a control. Radiological locations of the 3 different distal ends of the volar short arm splint were also assessed by anteroposterior radiographs of the wrist. RESULTS: When the splint was applied at location A and C, the maximal MCPJ flexion angle decreased to a mean of 83 degrees (91% of control value) and 56 degrees (62% of control value), respectively (compared to the control, p < 0.001). At location B, the maximal MCPJ flexion angle was a mean of 90 degrees (99% of control value); no significant difference was observed compared to the control or without the splint (p = 0.103). On radiography, the average length from the metacarpal head to the distal end of the splint at all fingers decreased in the order of location B, A, and C (29 mm, 19 mm, and 10 mm, respectively; p < 0.001). CONCLUSIONS: We recommend applying the distal end of a volar short arm splint at proximal 1 cm to the transverse skin folding line to preserve MCPJ motion perfectly, which is located at distal 44% of the whole metacarpal bone length radiologically. PMID- 27247745 TI - Effects of Soft Tissue Surgery on Pelvic and Hip Rotation in Patients with Spastic Diplegia: A Meta-Analysis. AB - BACKGROUND: There are several different opinions regarding the improvements seen on the transverse plane after soft tissue surgery alone in independently ambulant patients with cerebral palsy. We performed a meta-analysis using data from previous studies to identify the effects of soft tissue surgery alone on pelvic and hip rotation in children with spastic diplegia. METHODS: We conducted a pilot study to evaluate the improvement in pelvic and hip rotation after muscle-tendon lengthening surgery in children with spastic diplegia. We also searched EMBASE and PubMed and selected 2 previous studies using the same test conditions with kinematic data on the pelvis and hip joints. A meta-analysis of the results of these 3 studies, including this pilot study, was then performed. RESULTS: The meta-analysis results showed an external rotation decrease (p = 0.005) in the mean difference of pelvic rotation of -3.61 (95% confidence interval [CI], -6.13 to -1.09) and a mean difference in hip rotation of 6.60 (95% CI, 3.34 to 9.86), indicating a significant increase in the hip external rotation after surgery (p < 0.001). CONCLUSIONS: In independently community-ambulant pediatric patients with spastic diplegia, pelvic retraction and hip internal rotation could be improved after soft tissue surgery. PMID- 27247746 TI - Sarcopenia and Sarcopenic Obesity in Patients Undergoing Orthopedic Surgery. AB - BACKGROUND: The purpose of this retrospective study was to determine the prevalence of sarcopenia and sarcopenic obesity among patients who underwent orthopedic surgery (OS). METHODS: A total of 222 patients were reviewed immediately after or prior to OS. In the control group, 364 patients from outpatient departments (OPDs) who did not have any OS were enrolled. Whole-body dual-energy X-ray absorptiometry was used to analyze body composition. Skeletal muscle mass was adjusted for height squared, total body weight, and height and fat mass (residuals). Obesity was defined as body mass index (BMI) > 25.0 kg/m(2). RESULTS: The prevalence of sarcopenia in the OS group was 25.7%, 44.1%, and 26.6%, respectively, according to the 3 different criteria. The prevalence was significantly lower in the OPD group (6.0%, 33.1%, and 14.8%, respectively). The highest rates of sarcopenia with height-adjusted definition were seen in patients with a femoral neck fracture. In the multivariate analysis, factors associated with sarcopenia were male gender, older age, and lower BMI (odds ratio [OR]: 28.38, 1.03, and 1.83, respectively) when muscle mass was adjusted for height, whereas male gender, older age, and higher BMI were associated with sarcopenia (OR: 1.04, 2.57, and 1.83, respectively) when adjusted for weight. When residuals were used as a cutoff, decreased BMI and total hip bone mineral density (0.1 g/cm(2)) were independent risk factors associated with sarcopenia (OR: 1.09 and 1.05). The prevalence of sarcopenic obesity ranged from 1.8% to 21.2%. CONCLUSIONS: Our study demonstrated a high prevalence of sarcopenia among OS patients. PMID- 27247748 TI - New Technique for Removal of the Ulnar Intramedullary Nail Failed to Remove: Broken Assembly Piece in the Nail. AB - Methods about removal of intramedullary nail in complicated cases were reported in some literatures but there are no reports about nail removal in the ulna. The authors would like to report such a case and the technique. We removed bone of the inlet site and created another bony window using an osteotome to expose the interlocking screw holes. Only a bony window the size of 2 inter-interlocking holes at the most proximal part of the nail can be used to remove the nail with minimal damage of the triceps brachii tendon and soft tissue. PMID- 27247749 TI - Open Anterior Dislocation of the Hip in Togo. AB - Anterior traumatic dislocations of the hip are much less common than posterior dislocations. To date, 14 cases of open anterior dislocation of the hip associated with such injuries, acetabular and femoral head fractures and femoral vascular and nerve damage have been reported. We present a case of a 23-year-old male who sustained open anterior dislocation of the hip with ipsilateral fracture of the greater trochanter after an accident on the public highway. Additional lesions included an iliac wing fracture and a perineal wound. We report this case because of the rarity and seriousness of this injury due to its progressive complications and difficulties related to its management, which are typical to a developing country like ours. PMID- 27247747 TI - Disparity between Clinical and Ultrasound Examinations in Neonatal Hip Screening. AB - BACKGROUND: For early detection of developmental dysplasia of the hip (DDH), neonatal hip screening using clinical examination and/or ultrasound has been recommended. Although there have been many studies on the reliability of both screening techniques, there is still controversy in the screening strategies; clinical vs. selective or universal ultrasound screening. To determine the screening strategy, we assessed the agreement among the methods; clinical examination by an experienced pediatric orthopedic surgeon, sonographic morphology, and sonographic stability. METHODS: From January 2004 to June 2009, a single experienced pediatric orthopedic surgeon performed clinical hip screenings for 2,686 infants in the neonatal unit and 43 infants who were referred due to impressions of hip dysplasia before 3 months of age. Among them, 156 clinically unstable or high-risk babies selectively received bilateral hip ultrasound examinations performed by the same surgeon using the modified Graf method. The results were analyzed statistically to detect any correlations between the clinical and sonographic findings. RESULTS: Although a single experienced orthopedic surgeon conducted all examinations, we detected only a limited relationship between the results of clinical and ultrasound examinations. Ninety three percent of the clinically subluxatable hips were normal or immature based on static ultrasound examination, and 74% of dislocating hips and 67% of limited abduction hips presented with the morphology below Graf IIa. A total of 80% of clinically subluxatable, 42% of dislocating and 67% of limited abduction hips appeared stable or exhibited minor instability on dynamic ultrasound examination. About 7% of clinically normal hips were abnormal upon ultrasound examination; 5% showed major instability and 3% showed dysplasia above Graf IIc. Clinical stability had small coefficients between ultrasound examinations; 0.39 for sonographic stability and 0.37 for sonographic morphology. Between sonographic stability and morphology, although 71% of hips with major instability showed normal or immature morphology according to static ultrasound examination, the coefficient was as high as 0.64. CONCLUSIONS: Discrepancies between clinical and ultrasound examinations were present even if almost all of the exams were performed by a single experienced pediatric orthopedic surgeon. In relation to screening for DDH, it is recommended that both sonographic morphology and stability be checked in addition to clinical examination. PMID- 27247750 TI - Total Knee Arthroplasty in Severe Synovial Osteochondromatosis in an Osteoarthritic Knee. AB - Synovial osteochondromatosis (SO) can occur idiopathic or secondary to osteoarthritis. SO can be easily diagnosed with plain film radiography and clinical findings. In case of disabling osteoarthritis, total knee arthroplasty and removal of all corpora libra are indicated. We present a 71-year-old woman with significant osteoarthritis and severe SO intra-articular and in the suprapatellar bursa of the right knee. Total knee arthroplasty, extraction of the loose bodies, and partial synovectomy were performed. During a 2.5-year follow up, the patient regained full function of her affected knee and there was no recurrence of SO. We choose to present this case to show the extensiveness SO can occur in. Our advice is to remove all the loose bodies carefully to prevent damage to the prosthesis. During follow-up, special attention should be paid to prevent recurrence of SO. When recurrence is associated with rapid growth or destruction of joints, malignant reoccurrence must be considered. PMID- 27247751 TI - Acute Dislocation of the Metacarpal-Trapezoid Joint. AB - The trapezoid metacarpal dislocation is a rare event. In the literature, it is found in case reports. This injury is caused by direct or indirect high energy trauma. In most cases, the dislocation is dorsal and is difficult to reproduce because the joint is not very mobile. Given the low incidence and little evidence supported in the literature regarding the management, this injury can be treated by open or closed reduction; however, it has been published that most authors use Kirschner wire fixation with good results. Here we present our experience in the management of a male patient with acute trapezoid metacarpal dislocation handled with a splint with good functional results at 6 weeks. PMID- 27247752 TI - Fixed Lunate Flexion Deformity in Distal Radius Fractures. AB - Carpal malalignments in malunion of distal radius fracture are considered as an adaptive response of the carpus to loss of normal architecture of the distal radius. This condition leads to mechanical overload, ligament attenuation and progressive dynamic instability around the wrist joint. Radial corrective osteotomy is suggested as a treatment option of carpal malalignment after distal radius malunion. In radiocarpal malalignment, the lunate is usually observed in flexion in contrast to its extension posture in the more common midcarpal malalignment. We report two cases of fixed lunate flexion deformity after a distal radius fracture, in which reduction and fixation of fresh fracture or corrective osteotomy of malunion were not successful. Arthritic changes were observed in the radiolunate joint on arthroscopy. Thus, fixed flexion deformity of the lunate might be associated with posttraumatic arthritic change in the radiolunate joint. PMID- 27247754 TI - Reduced-intensity conditioning allogeneic hematopoietic-cell transplantation for older patients with acute myeloid leukemia. AB - Elderly patients (>60 years) with acute myeloid leukemia have a poor prognosis with a chemotherapy-alone approach. Allogeneic hematopoietic-cell transplantation (HCT) can improve overall survival (OS). However, myeloablative regimens can have unacceptably high transplant-related mortality (TRM) in an unselected group of older patients. Reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning regimens preserve the graft-versus-leukemia effects but reduce TRM. NMA regimens result in minimal cytopenia and may not require stem cell support for restoring hematopoiesis. RIC regimens, intermediate in intensity between NMA and myeloablative regimens, can cause prolonged myelosuppresion and usually require stem cell support. A few retrospective and prospective studies suggest a possibility of lower risk of relapse with myeloablative HCT in fit older patients with lower HCT comorbidity index; however, RIC and NMA HCTs have an important role in less-fit patients and those with significant comorbidities because of lower TRM. Whether early tapering of immunosuppression, monitoring of minimal residual disease, and post-transplant maintenance therapy can improve the outcomes of RIC and NMA HCT in elderly patients will require prospective trials. PMID- 27247753 TI - Pathologic Femoral Neck Fracture Due to Fanconi Syndrome Induced by Adefovir Dipivoxil Therapy for Hepatitis B. AB - In Fanconi syndrome, hypophosphatemic osteomalacia is caused by proximal renal tubule dysfunction which leads to impaired reabsorption of amino acids, glucose, urate, and phosphate. We present a rare case of a 43-year-old Korean male who was found to have insufficiency stress fracture of the femoral neck secondary to osteomalacia due to Fanconi syndrome. He had been receiving low-dose adefovir dipivoxil (ADV, 10 mg/day) for the treatment of chronic hepatitis B virus infection for 7 years and he subsequently developed severe hypophosphatemia and proximal renal tubule dysfunction. The incomplete femoral neck fracture was fixed with multiple cannulated screws to prevent further displacement of the initial fracture. After cessation of ADV and correction of hypophosphatemia with oral phosphorus supplementation, the patient's clinical symptoms, such as bone pain, muscle weakness, and laboratory findings improved. PMID- 27247755 TI - The role of blinatumomab in patients with relapsed/refractory acute lymphoblastic leukemia. AB - Adults with relapsed/refractory B-acute lymphoblastic leukemia (ALL) have a complete remission (CR) rate of 20-45% and median overall survival of 3-9 months, depending on the duration of the first remission and number of lines of salvage therapy. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only curative option for adult patients with relapsed/refractory ALL, and achievement of CR is a crucial step before alloHSCT. Blinatumomab is a bispecific T-cell engager (BiTE(r)) antibody construct with dual specificity for CD19 and CD3, simultaneously binding CD3-positive cytotoxic T cells and CD19-positive B cells, resulting in T-cell-mediated serial lysis of normal and malignant B cells. It recently gained accelerated approval by the US Food and Drug Administration (FDA) for the treatment of relapsed/refractory Philadelphia chromosome-negative ALL, based on a large phase II trial of 189 adults with relapsed/refractory B ALL, which showed a CR/CRh (CR with partial hematologic recovery) of 43% after two cycles of treatment. Toxicities include cytokine-release syndrome (CRS) and neurologic events (encephalopathy, aphasia, and seizure). CRS can be alleviated by step-up dosing and dexamethasone, without affecting the cytotoxic effect of blinatumomab. The cause of neurologic toxicity is unclear but is also observed with other T-cell therapies and may relate to variable expression of CD19 within the brain. This review encompasses the preclinical rationale of using the BITE(r) class of compounds (blinatumomab being the only one that is FDA approved), with clinical data using blinatumomab in the relapsed/refractory setting (pediatrics and adults), the minimal residual disease setting (adults), as well as Philadelphia chromosome-positive ALL. The review also examines the main adverse events: their prevention, recognition, and management; possible mechanisms of resistance; causes of relapse. It also summarizes future trials evaluating the drug earlier in the treatment course to improve activity. PMID- 27247756 TI - Targeting B-cell receptor signaling kinases in chronic lymphocytic leukemia: the promise of entospletinib. AB - The B-cell receptor signaling pathway has emerged as an important therapeutic target in chronic lymphocytic leukemia and other B-cell malignancies. Novel agents have been developed targeting the signaling enzymes spleen tyrosine kinase (SYK), Bruton's tyrosine kinase, and phosphoinositide 3-kinase delta. This review discusses the rationale for targeting these enzymes, as well as the preclinical and clinical evidence supporting their role as therapeutic targets, with a particular focus on SYK inhibition with entospletinib. PMID- 27247757 TI - Mogamulizumab for the treatment of cutaneous T-cell lymphoma: recent advances and clinical potential. AB - Mogamulizumab (KW-0761) is a humanized immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that targets CC chemokine receptor 4 (CCR4). It has shown promising therapeutic potential in phase I and II clinical trials and is currently being investigated for efficacy in treating cutaneous T-cell lymphoma (CTCL). We review the mechanism of action of mogamulizumab and its role in treating CTCL. We also discuss the results of major clinical trials. PMID- 27247759 TI - Demographic consequences of greater clonal than sexual reproduction in Dicentra canadensis. AB - Clonality is a widespread life history trait in flowering plants that may be essential for population persistence, especially in environments where sexual reproduction is unpredictable. Frequent clonal reproduction, however, could hinder sexual reproduction by spatially aggregating ramets that compete with seedlings and reduce inter-genet pollination. Nevertheless, the role of clonality in relation to variable sexual reproduction in population dynamics is often overlooked. We combined population matrix models and pollination experiments to compare the demographic contributions of clonal and sexual reproduction in three Dicentra canadensis populations, one in a well-forested landscape and two in isolated forest remnants. We constructed stage-based transition matrices from 3 years of census data to evaluate annual population growth rates, lambda. We used loop analysis to evaluate the relative contribution of different reproductive pathways to lambda. Despite strong temporal and spatial variation in seed set, populations generally showed stable growth rates. Although we detected some pollen limitation of seed set, manipulative pollination treatments did not affect population growth rates. Clonal reproduction contributed significantly more than sexual reproduction to population growth in the forest remnants. Only at the well forested site did sexual reproduction contribute as much as clonal reproduction to population growth. Flowering plants were more likely to transition to a smaller size class with reduced reproductive potential in the following year than similarly sized nonflowering plants, suggesting energy trade-offs between sexual and clonal reproduction at the individual level. Seed production had negligible effects on growth and tuber production of individual plants. Our results demonstrate that clonal reproduction is vital for population persistence in a system where sexual reproduction is unpredictable. The bias toward clonality may be driven by low fitness returns for resource investment in sexual reproduction at the individual level. However, chronic failure in sexual reproduction may exacerbate the imbalance between sexual and clonal reproduction and eventually lead to irreversible loss of sex in the population. PMID- 27247760 TI - A review of extensive variation in the design of pitfall traps and a proposal for a standard pitfall trap design for monitoring ground-active arthropod biodiversity. AB - To understand change in global biodiversity patterns requires large-scale, long term monitoring. The ability to draw meaningful comparison across studies is severely hampered by extensive variation in the design of the sampling equipment and how it is used. Here, we present a meta-analysis and description highlighting this variation in a common, widely used entomological survey technique. We report a decline in the completeness of methodological reporting over a 20-year period, while there has been no clear reduction in the methodological variation between researchers using pitfall traps for arthropod sampling. There is a growing need for improved comparability between studies to facilitate the generation of large scale, long-term biodiversity datasets. However, our results show that, counterproductive to this goal, over the last 20 years there has little progress in reducing the methodological variation. We propose a standardized pitfall trap design for the study of ground-active arthropods. In addition, we provide a table to promote a more standardized reporting of the key methodological variables. Widespread adoption of more standardized methods and reporting would facilitate more nuanced analysis of biodiversity change. PMID- 27247758 TI - Sterilization techniques for biodegradable scaffolds in tissue engineering applications. AB - Biodegradable scaffolds have been extensively studied due to their wide applications in biomaterials and tissue engineering. However, infections associated with in vivo use of these scaffolds by different microbiological contaminants remain to be a significant challenge. This review focuses on different sterilization techniques including heat, chemical, irradiation, and other novel sterilization techniques for various biodegradable scaffolds. Comparisons of these techniques, including their sterilization mechanisms, post sterilization effects, and sterilization efficiencies, are discussed. PMID- 27247761 TI - Density-dependent diel activity in stream-dwelling Arctic charr Salvelinus alpinus. AB - Intraspecific competition plays a significant role in shaping how animals use and share habitats in space and time. However, the way individuals may modify their diel activity in response to increased competition has received limited attention. We used juvenile (age 1+) Arctic charr Salvelinus alpinus to test the prediction that individuals at high population density are more active and distribute their foraging activity over a greater portion of the 24-h cycle than individuals at low population density. Individually tagged fish were stocked in seminatural stream enclosures at low (2 fish/m(2)) and high (6 fish/m(2)) density. During each of two 2-week experimental rounds, activity of all fish within each enclosure was recorded every 3 h over seven 24-h cycles. At high density, fish were more active and distributed their activity over a greater portion of the 24-h cycle, with increased activity particularly at crepuscular times. Fluctuations in ecological conditions (e.g., water temperature and light intensity) also affected activity. Fish at high density grew as fast as fish at low density. This study demonstrates that individuals exhibit a degree of behavioral flexibility in their response to changes in ecological conditions and suggests that intraspecific competition can cause animals to modify temporal aspects of their activity to gain access to resources and maintain growth. PMID- 27239272 TI - Effect of LXR/RXR agonism on brain and CSF Abeta40 levels in rats. AB - Alzheimer's disease (AD) is characterized pathologically by the presence of amyloid plaques and neurofibrillary tangles. The amyloid hypothesis contends that the abnormal accumulation of Abeta, the principal component of amyloid plaques, plays an essential role in initiating the disease. Impaired clearance of soluble Abeta from the brain, a process facilitated by apolipoprotein E (APOE), is believed to be a contributing factor in plaque formation. APOE expression is transcriptionally regulated through the action of a family of nuclear receptors including the peroxisome proliferator-activated receptor gamma and liver X receptors (LXRs) in coordination with retinoid X receptors (RXRs). It has been previously reported that various agonists of this receptor family can influence brain Abeta levels in rodents. In this study we investigated the effects of LXR/RXR agonism on brain and cerebrospinal fluid (CSF) levels of Abeta40 in naive rats. Treatment of rats for 3 days or 7 days with the LXR agonist, T0901317 or the RXR agonist, bexarotene did not result in significant changes in brain or CSF Abeta40 levels. PMID- 27247763 TI - Effect of gamma radiation processing on fungal growth and quality characteristcs of millet grains. AB - The aim of this study was to evaluate the effect of gamma radiation processing of millet grains on fungal incidence, germination, free fatty acids content, protein solubility, digestible protein, and antinutritional factors (tannin and phytic acid). The grains were exposed to gamma radiation at doses 0.25, 0.5, 0.75, 1.0, and 2.0 kGy. Obtained results revealed that radiation of millet grains at a dose level higher than 0.5 kGy caused significant (P < 0.05) reduction on the percentage of fungal incidence and the free fatty acid of the seeds, while, no significant change in the germination capacity was observed of the grains after radiation. Additionally, the radiation process caused significant (P < 0.05) reduction on both tannins and phytic acid content and gradual increment on in vitro protein digestibility of the grains. On the other hand, the treatments significantly (P < 0.05) increased the protein solubility of the grains. Obtained results indicate that gamma irradiation might improve the quality characteristics of millet grains, and can be used as a postharvest method for disinfestations and decontamination of millet grains. PMID- 27247764 TI - Authenticity of raspberry flavor in food products using SPME-chiral-GC-MS. AB - A fast and simple method for authenticating raspberry flavors from food products was developed. The two enantiomers of the compound (E)-alpha-ionone from raspberry flavor were separated on a chiral gas chromatographic column. Based on the ratio of these two enantiomers, the naturalness of a raspberry flavor can be evaluated due to the fact that a natural flavor will consist almost exclusively of the R enantiomer, while a chemical synthesis of the same compound will result in a racemic mixture. Twenty-seven food products containing raspberry flavors where investigated using SPME-chiral-GC-MS. We found raspberry jam, dried raspberries, and sodas declared to contain natural aroma all contained almost only R-(E)-alpha-ionone supporting the content of natural raspberry aroma. Six out of eight sweets tested did not indicate a content of natural aroma on the labeling which was in agreement with the almost equal distribution of the R and S isomer. Two products were labeled to contain natural raspberry flavors but were found to contain almost equal amounts of both enantiomers indicating a presence of synthetic raspberry flavors only. Additionally, two products that were labeled to contain both raspberry juice and flavor showed equal amounts of both enantiomers, indicating the presence of synthetic flavor. PMID- 27247765 TI - Lipid oxidation, sensory characteristics, and color of fresh pork sausage from immunologically castrated pigs stored frozen for up to 12 weeks. AB - Two studies were conducted to evaluate the quality characteristics of fresh sausage manufactured from immunologically castrated (IC) pigs, an emerging technology in the pork industry. Study 1: Fresh sausage patties from ground Boston butts fabricated from PC (physically castrated) pigs fed 0.55% SID (standard illeal digestible) lysine, IC pigs fed 0.55% SID lysine, and IC pigs fed 0.65% SID lysine were made and not standardized to a similar content of fat content. Study 2: fat and lean trim obtained from IC and PC pigs was made into fresh sausage patties, targeting 25% lipid. Patties (1.25 cm) were placed on trays and assigned to 0, 4, or 12 weeks frozen storage and then, after frozen storage, placed in simulated retail display conditions for 5 days. Patties were evaluated for color stability, sensory and textural properties, and lipid oxidation. Data were analyzed as a one way ANOVA with repeated measures where appropriate. In both studies, sausage discolored with both increased time in frozen storage and with increased time in retail display (P < 0.01). However, within each week of frozen storage, all treatments were equally discolored in both studies. Treatment did not affect the sensory characteristics or textural properties of fresh sausage in either study. Lipid oxidation did not differ by treatment in study 1. In study 2, lipid oxidation was reduced (P < 0.05) in IC compared to PC by approximately 0.1 mg malonaldehyde/kg meat, but there were no differences within each storage week. Increasing frozen storage time increased lipid oxidation an off-flavor scores in both studies (P < 0.05). Overall, immunological castration had no detrimental effects on color stability, sensory characteristics, or textural properties of fresh pork sausage. PMID- 27247766 TI - Quality assessment and consumer acceptability of bread from wheat and fermented banana flour. AB - Bread was produced from wheat flour and fermented unripe banana using the straight dough method. Matured unripe banana was peeled, sliced, steam blanched, dried and milled, and sieved to obtain flour. The flour was mixed with water and made into slurry and allowed to stand for 24 h after which it was divided into several portions and blended with wheat flour in different ratios. Proximate and mineral compositions as well as functional, pasting, and sensory characteristics of the samples were determined. The results of proximate analysis showed that crude fiber ranged between 1.95% and 3.19%, carbohydrate was between 49.70% and 52.98% and protein was 6.92% and 10.25%, respectively, while iron was between 27.07 mg/100 g and 29.30 mg/100 g. Swelling capacity of the experimental samples showed a significant difference from that of control. Peak viscosity ranged between 97.00RVU and 153.63RVU for experimental samples compared with 392.35RVU obtained for the control. Most of the sensory properties for the experimental samples were significantly different from the control. This study showed that bread with better quality and acceptability can be produced from wheat-unripe banana blends. PMID- 27247767 TI - Change in carbohydrate and enzymes from harvest to sprouting in garlic. AB - Changes in carbohydrates, enzymes, and pigments were investigated in the Red Garlic (Allium sativum L.) cv. Azarshahr bulbs in storage from harvest to sprouting. For storage period, garlic cloves of the same diameter with 3-4 g weight were arranged in dark condition and exposed to 4 and 21 degrees C, separately. Soluble sugar, total sugar, glucose, sucrose, fructose, starch, chlorophyll a, b, ab, carotenoid, anthocyanin, lipase, alpha-amylase, and protease were measured every 2 weeks up to sprouting time. Result revealed that starch, lipase, and protease levels declined at the end of storage when clove sprouting started at both 4 and 21 degrees C storage temperature. Starch, glucose, chlorophyll a, b, ab, and carotenoid content during the first 14 days and sucrose at 42 days showed a decreasing trend. Anthocyanin showed an increasing trend 14 and 42 days after harvesting and then decreased at the end of storage (when sprouting began) at both 4 and 21 degrees C storage periods. Finally, starch, glucose, and sucrose measurement can be used as a criterion to predict sprouting time of garlic, due to the decrease in the levels of starch, lipase, and protease, and increase in the levels of alpha-amylase, glucose, and sucrose in garlic cloves under storage. PMID- 27247768 TI - Methyl jasmonate effectively enhanced some defense enzymes activity and Total Antioxidant content in harvested "Sabrosa" strawberry fruit. AB - The use of chemicals in postharvest technology of horticultural crops is highly restricted and it is necessary to introduce safe food preserving methods. Strawberry is very susceptible to postharvest losses and more than 50% of harvested fruit is lost in Iran. Effect of postharvest treatment with methyl jasmonate (at 0, 8, and 16 MUmol L(-1)) on some quality attributes of Sabrosa strawberry fruit during storage at 1 +/- 0.5 degrees C with 90-95% RH for 14 days followed by 24 h at 20 degrees C was studied. Methyl jasmonate, at both concentrations, decreased weight loss and retained marketability of fruits. Catalase activity of treated fruits was decreased during the first days, but showed a substantial increase during the second week. Methyl jasmonate, in a concentration-dependent manner, enhanced peroxidase activity. Fruit total antioxidant capacity was enhanced by methyl jasmonate treatment. The results indicated that methyl jasmonate plays a key role in establishing resistance against stresses, enhancing fruit defense systems, antioxidant capacity, and storage life leading to decreased postharvest losses. This phytochemical has a good potential to be used in postharvest technology of Sabrosa strawberry fruit and enhance the fruit postharvest life. PMID- 27247769 TI - Effect of processing methods on nutritional, sensory, and physicochemical characteristics of biofortified bean flour. AB - Common beans (Phaseolus vulgaris L.) are rich nutritious and affordable by vulnerable groups, thus a good choice for biofortification to address malnutrition. However, increasing micronutrients content of beans, without improving micronutrients bioavailability will not improve the micronutrients status of consumers. Effect of different processing methods on the physicochemical characteristics of biofortified bean flour was determined. Processing methods used in this study were malting (48 h), roasting (170 degrees C/45 min), and extrusion cooking using a twin screw extruder with three heating sections, the first set at 60 degrees C, the second at 130 degrees C, and the last one at 150 degrees C. The screw was set at a speed of 35 Hz (123g) and bean flour moisture content was 15%. Mineral extractability, in vitro protein digestibility, pasting properties, and sensory acceptability of porridge and sauce from processed flour were determined. All processing methods significantly increased (P < 0.05) mineral extractability, iron from 38.9% to 79.5% for K131 and from 40.7% to 83.4% for ROBA1, in vitro protein digestibility from 58.2% to 82% for ROBA1 and from 56.2% to 79% for K131. Pasting viscosities of both bean varieties reduced with processing. There was no significant difference (P < 0.05) between sensory acceptability of porridge or sauce from extruded biofortified bean flour and malted/roasted biofortified bean flour. Acceptability was also not affected by the bean variety used. Mineral bioavailability and in vitro protein digestibility increased more for extruded flour than for malted/roasted flours. Sauce and porridge prepared from processed biofortified bean flour had lower viscosity (extruded flour had the lowest viscosity), thus higher nutrient and energy density than those prepared from unprocessed biofortified bean flour. Estimated nutritional contribution of sauce and porridge made from processed ROBA1 flour to daily requirement of children below 5 years and women of reproductive age found to be high. These results show that processing methods enhanced nutritional value of biofortified bean flour and that processed biofortified bean flour can be used to prepare nutrient and energy-dense gruel to improve on nutritional status of children under 5 years and women of reproductive age. PMID- 27247770 TI - The chemical quality of frozen Vietnamese Pangasius hypophthalmus fillets. AB - The aim of the present study was to evaluate the chemical quality parameters regarding frozen Pangasius hypophthalmus specimens from Vietnam. The proximate composition, pH, ammonia, biogenic amines (BAs), total mercury (Hg), malondialdehyde (MDA), and polyphosphate were determined. The moisture, protein, lipid and ash values were between 83.83-85.59, 12.51-14.52, 1.09-1.65, and 0.76 2.38 g 100 g(-1), respectively. Fraud by excessive polyphosphate addition was detected in 30% of the samples whereas Hg above the recommended limit was observed in 50% of the samples. With regard to compounds from the degradation process, low concentrations of individual BAs and pH values were found in this study and ranged from 5.88 to 6.18, except for samples with polyphosphate >1 g 100(-1) (pH > 7.00) were observed in the present study. However, ammonia concentration indicated that a degradation process initiated in 80% of the samples (0.12-0.34 NH 3 g(-1)) and 20% of the samples (1.87-1.94 MUg NH 3 g(-1)) were in an advanced deterioration process. Furthermore, MDA values (1.21-7.88 mg kg(-1)) suggested some failures, mainly during transportation and/or storage. We concluded that quality control measures must be implemented on the Pangasius production chain to improve the quality of products provided to consumers worldwide. PMID- 27247771 TI - Toward better understanding of postharvest deterioration: biochemical changes in stored cassava (Manihot esculenta Crantz) roots. AB - Food losses can occur during production, postharvest, and processing stages in the supply chain. With the onset of worldwide food shortages, interest in reducing postharvest losses in cassava has been increasing. In this research, the main goal was to evaluate biochemical changes and identify the metabolites involved in the deterioration of cassava roots. We found that high levels of ascorbic acid (AsA), polyphenol oxidase (PPO), dry matter, and proteins are correlated with overall lower rates of deterioration. On the other hand, soluble sugars such as glucose and fructose, as well as organic acids, mainly, succinic acid, seem to be upregulated during storage and may play a role in the deterioration of cassava roots. Cultivar Branco (BRA) was most resilient to postharvest physiological deterioration (PPD), while Oriental (ORI) was the most susceptible. Our findings suggest that PPO, AsA, and proteins may play a distinct role in PPD delay. PMID- 27247772 TI - Antibiotic resistance and multidrug-resistant efflux pumps expression in lactic acid bacteria isolated from pozol, a nonalcoholic Mayan maize fermented beverage. AB - Pozol is a handcrafted nonalcoholic Mayan beverage produced by the spontaneous fermentation of maize dough by lactic acid bacteria. Lactic acid bacteria (LAB) are carriers of chromosomal encoded multidrug-resistant efflux pumps genes that can be transferred to pathogens and/or confer resistance to compounds released during the fermentation process causing food spoiling. The aim of this study was to evaluate the antibiotic sensibility and the transcriptional expression of ABC type efflux pumps in LAB isolated from pozol that contributes to multidrug resistance. Analysis of LAB and Staphylococcus (S.) aureus ATCC 29213 and ATCC 6538 control strains to antibiotic susceptibility, minimal inhibitory concentration (MIC), and minimal bactericidal concentration (MBC) to ethidium bromide were based in "standard methods" whereas the ethidium bromide efflux assay was done by fluorometric assay. Transcriptional expression of efflux pumps was analyzed by RT-PCR. LAB showed antibiotic multiresistance profiles, moreover, Lactococcus (L.) lactis and Lactobacillus (L.) plantarum displayed higher ethidium bromide efflux phenotype than S. aureus control strains. Ethidium bromide resistance and ethidium bromide efflux phenotypes were unrelated with the overexpression of lmrD in L. lactics, or the underexpression of lmrA in L. plantarum and norA in S. aureus. These findings suggest that, moreover, the analyzed efflux pumps genes, other unknown redundant mechanisms may underlie the antibiotic resistance and the ethidium bromide efflux phenotype in L. lactis and L. plantarum. Phenotypic and molecular drug multiresistance assessment in LAB may improve a better selection of the fermentation starter cultures used in pozol, and to control the antibiotic resistance widespread and food spoiling for health safety. PMID- 27247773 TI - The application of alkaline and acidic electrolyzed water in the sterilization of chicken breasts and beef liver. AB - The sterilization effect of a combination treatment with alkaline electrolyzed water (AlEW) and strong acidic electrolyzed water (StAEW) on fresh chicken breasts and beef liver was evaluated. Samples (1, 5, and 10 g) were inoculated with Salmonella Enteritidis NBRC3313, Escherichia coli ATCC 10798, Staphylococcus aureus FDA209P, and S. aureus C-29 [staphylococcal enterotoxin A (SEA) productive strain] and subjected to a dipping combination treatment (4 degrees C and 25 degrees C for 3 min) with AlEW and StAEW. Combination treatment with AlEW and StAEW significantly reduced the bacteria, and reduction of more than 1 log colony forming units (CFU)/g was achieved. Furthermore, this combination treatment significantly decreased the SEA gene expression level in samples. Some quality variables of the meat samples such as pH, lipid oxidation, color, amino-acid content, texture, and sensory characteristics showed no significant differences between the combination treatment with AlEW and StAEW and the untreated control. PMID- 27247774 TI - Individualistic impact of unit operations of production, at household level, on some antinutritional factors in selected cowpea-based food products. AB - The individualistic effect of unit operations of production, at household level, on some antinutritional factors in selected cowpea-based food products (moin moin, akara, and gbegiri) was investigated. Four cowpea types (IT93K-452-1, IT95K 499s-35, IT97K-568-18, and market sample) were used for the study, whereas the three traditional food products were produced from each of the cowpea types, respectively. The results revealed that every unit operation involved in the production of moin-moin, akara or gbegiri contributed to the overall reduction of trypsin inhibitor activity (TIA), phytic acid (PA), and tannin; though at varying degrees. In the production of moin-moin, the major contributions to the overall reduction in TIA were from steaming (64.2-72.0%), second-stage soaking (9.7 11.9%), and dehulling (9.4-10.2%). The contributions to the overall reduction in PA were from dehulling (34.0-40.4%), preliminary soaking (15.4-21.0%), and steaming (7.8-14.0%), whereas that of tannin were from dehulling (39.7-47.6%), steaming (19.6-24.7%), and preliminary soaking (9.8-15.9%). For akara production, the major contributions to TIA reduction were from deep frying (64.2-72.0%), second-stage soaking (9.7-11.9%), and dehulling (9.4-10.2%). The PA reduction was from dehulling (34.0-40.4%), preliminary soaking (15.4-21.0%), and deep frying (9.6-15.9%), whereas that of tannin reduction was from dehulling (39.7-47.6%), deep frying (20.7-25.3%), and preliminary soaking (9.8-15.9%). In the production of gbegiri, the overall reduction in TIA was contributed from pressure cooking (79.0-84.8%), preliminary soaking (5.8-11.3%), and dehulling (9.4-10.2%). The reduction in PA was contributed by dehulling (34.0-40.4%), pressure cooking (24.7 35.0%), and preliminary soaking (15.4-21.0%), whereas the overall reduction in tannin content was similarly contributed by dehulling (39.7-47.6%), pressure cooking (29.8-34.4%), and preliminary soaking (9.8-15.9%). PMID- 27247775 TI - Changes in flavor volatile composition of oolong tea after panning during tea processing. AB - Panning is a processing step used in manufacturing of some varieties of oolong tea. There is limited information available on effects of panning on oolong tea flavors. The goal of this study was to determine effects of panning on flavor volatile compositions of oolong using Gas Chromatography-Mass Spectrometry (GC MS) and Gas Chromatography-Olfactometry (GC-O). SDE and SPME techniques were applied for extraction of volatiles in panned and unpanned teas. A total of 190 volatiles were identified from SDE and SPME extractions using GC-MS and GC-O. There were no significant differences (P > 0.05) in aldehyde or terpene contents of unpanned and panned tea. However, alcohols, ketones, acids and esters contents were significantly reduced by panning. Among 12 major volatiles previously used for identification and quality assessment of oolong tea, trans nerolidol, 2- hexenal, benzaldehyde, indole, gernaiol, and benzenacetaldehyde contents were significantly decreased (P < 0.05) by panning. Panning increased (P < 0.05) contents of linalool oxide, cis jasmone, and methyl salicylate. The GC-O study also showed an increase of aroma active compounds with sweet descriptions and decrease of aroma active compounds with fruity and smoky descriptions after panning. Panning significantly changes the volatile compositions of the tea and created new aroma active compounds. Results from this study can be used in quality assessment of panned oolong tea. PMID- 27247776 TI - A study on sensory properties of sodium reduction and replacement in Asian food using difference-from - control test. AB - This study examined the effects of sodium reduction and flavor enhancers on the sensory profile of two types of hawker foods commonly consumed in Singapore, namely chicken rice and mee soto broth. The 'difference-from-control' test was the method adopted in this study involving 24-29 trained panelists. Combinations included blind control, two levels of sodium reduction, and two levels of flavor enhancers in sodium-reduced recipes. In the sodium-reduced recipes, two levels of NaCl, 0.48% and 0.55%, for chicken rice, and 0.76% and 0.86% for mee soto (equivalent to 31% and 22% reduction in NaCl), were used. Monosodium glutamate (MSG) or Ajiplus ((r)) (a blend of MSG and nucleotides) at 0.20% and 0.40% were added to the recipes comprising a reduction of 40% in NaCl (equivalent to 31% and 22% reduction in sodium, respectively) compared with the control. It was found that the inclusion of MSG or Ajiplus ((r)) in 40% NaCl-reduced recipe resulted in a significant increase in perception of umami taste (P < 0.05) when compared to the control. By adding flavor enhancers into the 40%-reduced salt chicken rice recipes, the perception of saltiness was significantly increased when compared to 22% and 31% sodium reduced recipes. Similarly for mee soto broth, there was a significant increase in perception of chicken flavor, umami taste, mouthfeel sensation, and sweet taste (P < 0.05) with a decrease in the perception of sour and bitter taste when compared to control. By adding 0.40% MSG into the 40% reduced salt recipes, the perception of saltiness was maintained when compared with control. PMID- 27247777 TI - Sensory, Microbiological and Chemical Changes in Vacuum-Packaged Blue Spotted Emperor (Lethrinus sp), Saddletail Snapper (Lutjanus malabaricus), Crimson Snapper (Lutjanus erythropterus), Barramundi (Lates calcarifer) and Atlantic Salmon (Salmo salar) Fillets Stored at 4 degrees C. AB - Quality assessment of finfish fillets during storage is important to be able to predict the shelf life of the fresh product during distribution. Microbial, chemical (pH, TMA, and TVB-N), and sensory (Quality index assessment QIA, Torry scheme) changes in vacuum-packaged blue-spotted emperor (Lethrinus sp), saddletail (Lutjanus malabaricus), crimson snapper (Lutjanus erythropterus), barramundi (Lates calcarifer), and Atlantic salmon (Salmo salar) fillets stored at 4 degrees C were evaluated for 5 days. Microbiological study included evaluation of TVC (total viable counts), total psychrotrophic organisms, and H2S producing bacteria. Numbers increased during storage time and reached an average of 8.5, 8.5, and 9.2 log10 cfu/g, respectively, for the five different fish species. These levels were above accepted microbiological limits for fish fillets. Although the sensory analyses showed a decrease in quality, none of the finfish fillets were considered unacceptable at the end of the storage trial. Chemically, there was a slight pH increase, but trimethylamine (TMA) levels remained low. However, total volatile basic nitrogen (TVB-N) levels increased over time, reaching levels above 35 mg/100 g for blue spotted emperor, saddletail snapper, and crimson snapper by the end of the storage period. Results show that the deterioration of finfish fillet quality is a complex event of biochemical, sensory, and microbial factors, and multiple analyses may be required to define acceptability. PMID- 27247778 TI - High-mobility group box 1 is associated with neurological outcome in patients with post-cardiac arrest syndrome after out-of-hospital cardiac arrest. AB - BACKGROUND: Alarmins, including high-mobility group box 1 (HMGB-1), can be released from damaged tissues and activated cells as inflammatory mediators. We aimed to evaluate HMGB-1 and mitochondrial DNA dynamics and estimate the prognostic value for neurological outcome in patients with post-cardiac arrest syndrome after out-of-hospital cardiac arrest. METHODS: We evaluated the dynamics of HMGB-1, mitochondrial DNA, and other variables in patients with return of spontaneous circulation after out-of-hospital cardiac arrest. Patients were divided into two groups according to the cerebral performance category at 30 days: the favourable outcome group (cerebral performance categories 1 and 2) and unfavourable group (>=3). RESULTS: Twenty-one patients were included, and 11 demonstrated favourable outcomes. HMGB-1 levels and mitochondrial DNA on day 1 were significantly higher than on days 2, 3, 5, and 7. Plasma levels of HMGB-1 on day 1 correlated with prognostic parameters (estimated interval to return of spontaneous circulation, lactate, and NH3), tissue damage, systemic inflammation, and disease severity. HMGB-1 on day 1 in the unfavourable group was significantly higher than in the favourable group (median [interquartile range] 15.5 [6.65 18.7], 39.4 [17-69.5], P = 0.009). These findings were not observed regarding mitochondrial DNA. Regarding HMGB-1 prediction accuracy for a good neurological outcome, the area under the receiver operating characteristic curve was 0.864 (95 % confidence interval 0.702, 1.000). CONCLUSIONS: HMGB-1 may be involved in acute phase post-cardiac arrest syndrome pathophysiology, and an increase in plasma levels may be associated with a poor neurological outcome. The study was registered with the University Hospital Medical Information Network Clinical Trials Registry ID: UMIN000006714. PMID- 27247779 TI - Threats to Pediatric Nurses' Perception of Caring Self-efficacy: A Qualitative Study. AB - BACKGROUND: Nurses are considered the largest and most important human resource for healthcare organizations. Self-efficacy as the main predictor of nurses' behavior plays an important role in nurses' professional behavior. However, the various dimensions and threats of caring self- efficacy concept have not been taken into consideration. OBJECTIVES: The present paper attempts to identify threats to self-efficacy as an important aspect of the concept of pediatric nurses' caring self-efficacy. MATERIALS AND METHODS: This study is part of a larger study on the caring self-efficacy concept that was conducted through content analysis and from a qualitative approach in 2014 in Iran. Twenty-seven nurses and pediatric clinical instructors participated in this research according to the purposive sampling method employed in the study. Data were collected through semi-structured interviews. The collected data were analyzed using the conventional content analysis method. RESULTS: "Threats to self-efficacy" was one of the main themes extracted from the interview analysis results in the present study. The theme consists of two main categories "individual barriers," including not having a caring attitude and not being interested in children, and "organizational barriers," including an inefficient educational system, not developing professional capabilities, non-valuation of the organization in a caring context, a poor rewards system, and inappropriate managerial policies. CONCLUSIONS: Nursing management and custodians of nursing trainings can break through the barriers to self-efficacy by knowing these factors and making changes in the educational programs and providing supporting policies. This can be an important step toward improving nurses' inefficacy and ultimately improving the provision of quality healthcare services. PMID- 27247780 TI - Ananas comosus Effect on Perineal Pain and Wound Healing After Episiotomy: A Randomized Double-Blind Placebo-Controlled Clinical Trial. AB - BACKGROUND: Ananas comosus has long been used for medical purposes. Currently, we are experiencing an unprecedented interest in the use of complementary medicine as well as a growing attention to traditional products such as bromelain for wound healing and reducing pain. OBJECTIVES: The aim of this study was to determine the effect of oral bromelain on perineal pain and wound healing after episiotomy in primiparous women. PATIENTS AND METHODS: In this double-blind placebo-controlled clinical trial, 82 primiparous women fulfilling the inclusion criteria received bromelain or placebo randomly. Participants were given three tablets, three times a day for six successive days. The initial dose was given 2 hours after delivery. Episiotomy pain was measured using VAS scale before the initial dose, as well as on the 1st hour and on the 3rd, 7th and 14th days after the initial dose. Wound healing was measured using REEDA scale on the 3rd, 7th and 14th days after delivery. RESULTS: Episiotomy pain significantly reduced in bromelain group compared with the placebo group (P < 0.05) and wound healing was faster in bromelain group compared with the placebo group (P < 0.05) on follow-up days. CONCLUSIONS: The results showed the effectiveness of bromelain on episiotomy pain and wound healing. Therefore, it is suggested to use bromelain in postoperative stage to improve wound healing and reduce pain. PMID- 27247781 TI - Applying Socioecological Model to Improve Women's Physical Activity: A Randomized Control Trial. AB - BACKGROUND: A sedentary life without sufficient physical activity is recognized as a risk factor for various diseases, and a major modifiable risk factor for noncommunicable diseases. This study was conducted to investigate the effect of intervention using socioecological model in promoting women's physical activity in the city of Kerman, Iran. MATERIALS AND METHODS: In this randomized, double blinded, controlled study, 360 women were studied at health and medical centers of Kerman. This educational intervention was based on socioecological model and conducted on 4 levels of personal, social, organizational, and political. Data collection tool included a researcher-made questionnaire based on constructs of socioecological model and the international physical activity inventory. RESULTS: The results indicated insignificant differences between the two groups in terms of perceived social, physical, and political support and also with regard to level of physical activity before intervention. However after the intervention and according to independent t test, significant differences were observed between two groups in perceived social, physical, and political support and also level of physical activity (P < 0.001). Furthermore, mean values of the above terms increased in the intervention group. CONCLUSIONS: According to the results, interventions based on socioecological model can positively affect women's physical activity. PMID- 27247782 TI - The Effects of a Patient-Caregiver Education and Follow-Up Program on the Breast Cancer Caregiver Strain Index. AB - BACKGROUND: In recent years, the caregiving responsibilities of cancer patients' family members have increased dramatically. Reducing caregiver strain and burden supports the mission of professional nursing. OBJECTIVES: The aim of this study was to determine and compare the caregiver strain index scores of breast cancer informal caregivers, before and after a patient-caregiver educational and telephone follow-up program. PATIENTS AND METHODS: This is an experimental two group design study. Participants were recruited from an outpatient chemotherapy unit of the largest hematology and oncology research center in Northwest Iran. Thirty patient-caregiver pairs were randomly allocated to intervention and control groups. The intervention group received 2 face-to-face education sessions at bedside and 4 subsequent telephone follow-up sessions. The control group received routine care. Pre and post tests were administered in both groups pre and post intervention. To analyze the data, SPSS (13th version) software was used. RESULTS: The caregiver strain index decreased significantly in the intervention group after the patient-caregiver education and follow-up (P < 0.001), while the control group's scores did not change (P = 0.04). CONCLUSIONS: It appears that the patient-caregiver education and follow-up program had a beneficial effect on the caregiver strain index compared to the usual care. PMID- 27247783 TI - Selenium Intake is Related to Beck's Depression Score. PMID- 27247784 TI - Perception of Alzheimer Disease in Iranian Traditional Medicine. AB - CONTEXT: Alzheimer disease (AD) is the most common cause of dementia. In regards to the world's aging population, control and treatment of AD will be one of the major concerns of global public health in the next century. Alzheimer disease was not mentioned with the same phrase or its equivalent in traditional medical texts. The main of present paper was to investigate symptoms and causes of alzheimer disease from the view point of Iranian traditional medicine. EVIDENCE ACQUISITION: In this qualitative study, we searched reliable sources of Iranian traditional medicine such as Canon of Medicide by Avicenna (Al-Quanon fi- tibb), Aghili cure by Aghili's (Molajat-E-aghili), Tib-E-Akbari, Exire -E-Aazam and Sharh-E-Asbab and some reliable resources of neurology were probed base on keywords to find a disease that had the most overlap in terms of symptoms with alzheimer disease. By taking from the relevant materials, the extracted texts were compared and analyzed. RESULTS: Findings showed that alzheimer disease has the most overlap with Nesyan (fisad-e-zekr, fisad-e-fekr and fisad-e-takhayol) symptoms in Iranian traditional medicine. Although this is not a perfect overlap and there are causes, including coldness and dryness of the brain or coldness and wetness that could also lead to alzheimer disease according to Iranian traditional medicine. CONCLUSIONS: According to Iranian traditional medicine, The brain dystemperement is considered the main causes of alzheimer disease. By correcting the brain dystemperement, alzheimer can be well managed. This study helps to suggest a better strategy for preventing and treating alzheimer in the future. PMID- 27247785 TI - Mutation Screening of Exons 7 and 13 of the TMC1 Gene in Autosomal Recessive Non syndromic Hearing Loss (ARNSHL) in Iran. AB - BACKGROUND: Non-syndromic hearing loss (NSHL) is the most common birth defect and occurs in approximately 1/1,000 newborns. NSHL is a heterogeneous trait and can arise due to both genetic and environmental factors. Mutations of the transmembrane channel-like 1 (TMC1) gene cause non-syndromic deafness in humans and mice. OBJECTIVES: The aim of the present study was to investigate the association of TMC1 gene mutations of the locus DFNB7/11 in exons 7 and 13 in a cohort of 100 patients with hearing loss in Iran using polymerase chain reaction single-stranded conformation polymorphism (PCR-SSCP), heteroduplex analysis (HA), and DNA sequencing. PATIENTS AND METHODS: In this experimental study, the blood samples of 100 NSHL patients were collected from 10 provinces in Iran. These patients had a mean age of 16.5 +/- 2.01 years and 74.15% of their parents had consanguinity. DNA was extracted from specimens and mutations of exons 7 and 13 of the TMC1 gene were investigated using PCR-SSCP. All samples were checked via HA reaction and suspected specimens with shift bands were subjected to DNA sequencing for investigation of any gene variation. RESULTS: In this study, no mutation was found in the two exons of TMC1 gene. It was concluded from these results that mutations of the TMC1 gene's special exons 7 and 13 have a low contribution in patients and are not great of clinical importance in these Iranian provinces. CONCLUSIONS: More studies are needed to investigate the relationship between other parts of this gene with hearing loss in different populations through the country. More research could clarify the role of this gene and its relation with deafness and provide essential information for the prevention and management of auditory disorders caused by genetic factors in the Iranian population. PMID- 27247786 TI - Prevalence of CTX-M-Type and PER Extended-Spectrum beta-Lactamases Among Klebsiella spp. Isolated From Clinical Specimens in the Teaching Hospital of Kashan, Iran. AB - BACKGROUND: Extended-spectrum beta-lactamases (ESBLs) is one of the most important mechanisms of resistance to beta-lactams especially among Enterobacteriaceae family including Klebsiella spp. Different types of extended spectrum beta-lactamases including CTX-M-type and PER enzymes are identified among gram negative bacteria. OBJECTIVES: The current study aimed to determine the prevalence of CTX-M-type and PER extended-spectrum beta-lactamases among Klebsiella spp. isolated from clinical specimens in the teaching hospital of Kashan, Iran. PATIENTS AND METHODS: One hundred Klebsiella spp. were isolated from clinical specimens of hospitalized patients at Shahid-Beheshti hospital from December 2012 to November 2013. Disk diffusion method was used to determine the susceptibility of these isolates to 14 different antimicrobial agents; disks were purchased from MAST company (United Kingdom). The phenotypic double disk synergy confirmatory test was used to screen the isolates to produce extended-spectrum beta-lactamase. DNAs of isolates were extracted using boiling method and PCR assay was used to characterize the bla CTX-M type and bla PER genes. The purified PCR products were sent to Macrogen research company (Korea) for sequencing. RESULTS: Of the total 100 Klebsiella isolates, %93 was susceptible to imipenem. Resistance to ampicillin, ceftazidime, ceftriaxone, aztreonam and cefotaxime was (92%), (67%), (65%), (64%) and (59%), respectively. The phenotypic confirmatory test (PCT) confirmed that 35% (n = 35) of the isolates were ESBL-producing Klebsiella strains. The prevalence of bla CTX-M type and bla RER genes among Klebsiella isolates were 28% (n = 28) and 9% (n = 9), respectively. CONCLUSIONS: The prevalence of ESBL-producing Klebsiella strains in Shahid-Beheshti hospital in Kashan has increased. The study concluded that there was a high prevalence of the bla CTX-M type gene among ESBL positive isolates. PMID- 27247787 TI - Catalysts to Spiritual Care Delivery: A Content Analysis. AB - BACKGROUND: Despite the paramount importance and direct relationship of spirituality and spiritual care with health and well-being, they are relatively neglected aspects of nursing care. OBJECTIVES: The aim of this study is to explore Iranian nurses' perceptions and experiences of the facilitators of spiritual care delivery. MATERIALS AND METHODS: For this qualitative content analysis study, a purposive maximum-variation sample of 17 nurses was recruited from teaching and private hospitals in Tehran, Iran. Data were collected from 19 individual, unstructured interviews. The conventional content-analysis approach was applied in data analysis. RESULTS: The facilitators of spiritual care delivery fall into two main themes: living to achieve cognizance of divinity and adherence to professional ethics. These two main themes are further divided into eight categories: spiritual self-care, active learning, professional belonging, personal and professional competencies, gradual evolution under divine guidance, awareness of the spiritual dimension of human beings, occurrence of awakening flashes and incidents during life, and congruence between patients' and healthcare providers' religious beliefs. CONCLUSIONS: The study findings suggest that the facilitators of spiritual care delivery are more personal than organizational. Accordingly, strategies to improve the likelihood and quality of spiritual care delivery should be developed and implemented primarily at the personal level. PMID- 27247788 TI - Physical Activity Patterns During Pregnancy in a Sample of Portuguese Women: A Longitudinal Prospective Study. AB - BACKGROUND: Physical activity (PA) patterns during pregnancy have not been explored in depth and most previous studies lack assessment of variables such as type, frequency, duration and intensity of activity. OBJECTIVES: This study had two goals: 1) to analyze PA patterns during pregnancy according to weekly time spent on different types of activity; and 2) to determine women's perception about health care providers regarding PA advisement during pregnancy. PATIENTS AND METHODS: A longitudinal prospective study was carried out with a 118-pregnant women cohort. Participants were evaluated during all trimesters. Self-reported questionnaires were used to collect personal and obstetric data. Type, duration and frequency of PA were evaluated using the pregnancy physical activity questionnaire (PPAQ) and intensity levels were calculated. Repeated measure analysis of variance was performed to determine differences between trimesters, and Wilcoxon signed-rank test was performed when appropriate. RESULTS: A decrease in values of self-reported PA (MET.h.wk(-1)) was found from the first to the second and the first to the third trimester of pregnancy, respectively; total (270.91 vs 220.54 vs 210.35; P < 0.01), light (109.45 vs 95.11vs 92.40; P < 0.01) and moderate intensity (81.99 vs 50.69 vs 62.94; P = 0.002). Time spent on most activities remained fairly stable throughout pregnancy. Women spent most of their weekly time during the entire pregnancy on household and caregiving activities, occupational activities and leisure, except sport activities. Swimming was the most reported organized PA, reaching its highest proportion (12.7%) in the second trimester. Prenatal exercise classes were reported by 39.8% of women during the 3rd trimester. Pregnant women reported that PA was recommended by health professionals: 53.9% in the 1st trimester, 70.4% in the 2nd trimester and 56.8% in the 3rd trimester. CONCLUSIONS: Self-reported PA decreased, especially from the first to the second trimester, in total, light and moderate intensity. Women spent most of their weekly time on domestic, occupational and leisure activities, except sport activities. There are some health care providers that do not recommend physical activity during pregnancy. PMID- 27247789 TI - The Prevalence of Absence of the Palmaris Longus Muscle Tendon in the North of Iran: A Comparative Study. AB - BACKGROUND: The palmaris longus is a degenerating weak flexor muscle in the anterior of the forearm. Many techniques for clinically determining the presence of the palmaris longus have been described. Ethnic variations in the prevalence of the absence of the palmaris longus are well known. OBJECTIVES: This study considered the prevalence of absence of the palmaris longus muscle tendon in the north of Iran. PATIENTS AND METHODS: The presence of the palmaris longus was clinically determined in 562 men and women from the Guilan population, using the standard technique (Schaeffer's test). In subjects with an absent palmaris longus, three other tests (Thompson, Pushpakumar and Mishra tests) were performed to confirm the absence. RESULTS: The overall prevalence of right, left, bilateral and total absence of the palmaris longus were 4.1%, 5.2%, 3.9% and 13.2%, respectively. There was no significant difference in its absence with regard to the body side or gender (P > 0.05). CONCLUSIONS: This study demonstrated that the presence of the palmaris longus muscle tendon in the Guilan population was considerably higher than the absence of the palmaris longus tendon. The overall prevalence of right, left, bilateral and total absence of the palmaris longus was not significantly different between men and women. The prevalence of the left absent palmaris longus was more common in the present study. PMID- 27247790 TI - Relationship Between Palpitation and Mental Health. AB - BACKGROUND: 'Palpitation' is one of the most common complaints in patients referring to cardiologists. In modern medicine era, these patients suffer from much distress and some cases are known to be difficult to treat. Although the clinician's first duty is obviously to search for an organic basis for this symptom, the diagnostic evaluation is frequently unrevealing. However, clinical experience suggests that psychiatric causes are relatively common. OBJECTIVES: This research aimed to screen for mental disorders in patients complaining of palpitation and healthy persons in order to perform a preliminary comparison between them. PATIENTS AND METHODS: This is a case-control study to screen mental disorders. The target population consisted of adult volunteers with benign palpitation and their matched healthy persons. They were referred during a 10 month-period to the cardiology outpatient's clinic of Mostafa Khomeini hospital in Tehran, Iran. Sampling was accidental and eventually 110 participants comprised the sample size. The measuring tool was GHQ-28 (28-item general health questionnaire) and the main variable was the questionnaire score obtained from the Likert scoring method. RESULTS: Comparing two groups showed that the number of participants with the scores more than cut-off point in palpitation group was significantly more than healthy person group (85.4% vs. 43.6% with P < 0.001). Also the total score of GHQ-28 and scores of its subscale (somatization, anxiety, and social dysfunction) in patients complaining of palpitation were significantly more than those of the healthy participants (34.2 vs. 25.7, 8.9 vs. 6.4, 9.4 vs. 6.4, and 12.3 vs. 10.8, respectively with P < 0.001, P = 0.001, P < 0.001, and P < 0.007, respectively). CONCLUSIONS: Palpitation is the most common symptom in psychiatric disorders such as anxiety and somatization disorders. According to the results of this study, psychiatric causes have an important role in Iranian patients complaining of palpitations (benign form). Considering this fact may lead to a more effective treatment of benign palpitations. PMID- 27247791 TI - Developing a Minimum Data Set for an Information Management System to Study Traffic Accidents in Iran. AB - BACKGROUND: Each year, around 1.2 million people die in the road traffic incidents. Reducing traffic accidents requires an exact understanding of the risk factors associated with traffic patterns and behaviors. Properly analyzing these factors calls for a comprehensive system for collecting and processing accident data. OBJECTIVES: The aim of this study was to develop a minimum data set (MDS) for an information management system to study traffic accidents in Iran. MATERIALS AND METHODS: This descriptive, cross-sectional study was performed in 2014. Data were collected from the traffic police, trauma centers, medical emergency centers, and via the internet. The investigated resources for this study were forms, databases, and documents retrieved from the internet. Forms and databases were identical, and one sample of each was evaluated. The related internet-sourced data were evaluated in their entirety. Data were collected using three checklists. In order to arrive at a consensus about the data elements, the decision Delphi technique was applied using questionnaires. The content validity and reliability of the questionnaires were assessed by experts' opinions and the test-retest method, respectively. RESULTS: An (MDS) of a traffic accident information management system was assigned to three sections: a minimum data set for traffic police with six classes, including 118 data elements; a trauma center with five data classes, including 57 data elements; and a medical emergency center, with 11 classes, including 64 data elements. CONCLUSIONS: Planning for the prevention of traffic accidents requires standardized data. As the foundation for crash prevention efforts, existing standard data infrastructures present policymakers and government officials with a great opportunity to strengthen and integrate existing accident information systems to better track road traffic injuries and fatalities. PMID- 27247793 TI - Factors Influencing Fast-Food Consumption Among Adolescents in Tehran: A Qualitative Study. AB - BACKGROUND: The consumption of different types of fast food is increasingly growing in all parts of the world, both in developed and developing countries. Because of the changes and transitions in the lifestyle and dietary habits of people, an increasing number of people from different age groups, particularly adolescents and young adults, are inclined toward consuming fast food. OBJECTIVES: The objective of this study was to investigate the factors influencing fast-food consumption among adolescents in Tehran, Iran. PATIENTS AND METHODS: The present qualitative study was conducted in 2012 - 2013 in Tehran, the capital of Iran. To achieve the objective of this study, 42 adolescents were enrolled in this study through a purposive sampling method, and the required data was collected via individual semi-structured in-depth interviews. Data collection and analysis were carried out simultaneously, and the collected data was analyzed via a thematic content analysis and using MAXQDA 10 software. RESULTS: In this study after coding the transcribed interviews, the findings were categorized into three main themes as follows: personal views, social factors, and family factors. Each theme included several categories and subcategories, and the coded sentences and phrases were placed under each category and subcategory. CONCLUSIONS: The results of this study showed that the number of factors promoting fast-food consumption appeared to be more than the inhibiting factors and that the diverse factors at the individual and social level influenced fast-food consumption among adolescents. PMID- 27247792 TI - Effect of Metformin, Acarbose and Their Combination on the Serum Visfatin Level in Nicotinamide/Streptozocin-Induced Type 2 Diabetic Rats. AB - BACKGROUND: Diabetes mellitus is a chronic metabolic disease with life threatening complications. Metformin and acarbose are two oral antidiabetic drugs. OBJECTIVES: This experimental study was designed and carried out at the Arak University of Medical Sciences in Arak, Iran, to investigate the effects of these drugs (both alone and in combination) on glycemic control, lipid profile, and serum visfatin levels in nicotinamide/streptozotocin type 2 diabetic rats. MATERIALS AND METHODS: Type 2 diabetes was induced in 30 male Wistar rats by the administration of streptozotocin (STZ) (60 mg/kg body weight) intraperitoneally (IP) 15 minutes after the IP administration of nicotinamide (110 mg/kg body weight). After one week, the diabetic rats were randomly divided into four groups. Three diabetic groups were treated with 150 mg/kg/day of metformin, acarbose (40 mg/100 g of diet), or a combination of the two for six weeks, respectively. Biochemical parameters, including fasting blood glucose, glycated hemoglobin, lipid profile, insulin, and visfatin were assessed and compared with those of the control diabetic group. RESULTS: The data showed metformin, acarbose, and acarbose + metformin downregulated visfatin levels in diabetic rats, but only the reduction in metformin-treated rats was significant (162 +/- 21.7, 195.66 +/- 6.45 (ng/l), P = 0.001). Fasting blood glucose and glycated hemoglobin decreased significantly in all treated rats, specifically in the treated group that received the two drugs in combination. The serum insulin level was also reduced in all treated groups, and it was significant in the acarbose (P < 0.05) and the combination therapy groups (P < 0.05). The lipid profile improved in all treated groups. CONCLUSIONS: Compared with acarbose or metformin monotherapy, the addition of acarbose to metformin had superior antihyperglycemia efficacy and provided an efficacious and safe alternative for the treatment of type 2 diabetic rats. Acarbose/metformin reduced the fasting blood glucose and glycated hemoglobin without significant changes in serum visfatin levels. PMID- 27247794 TI - The Stigma of Reproductive Health Services Utilization by Unmarried Women. AB - BACKGROUND: Fear of the stigma associated with reproductive health services has always been one of the reasons why youth and unmarried individuals avoid making use of such services. This stigma imposes a great deal of mental stress, fear, and depression on patients and causes delays in the diagnosis and treatment of their conditions. OBJECTIVES: This paper explores the concept of stigma in the context of the utilization of reproductive health services by unmarried women. PATIENTS AND METHODS: This study is qualitative in nature. Purposive sampling was employed, and semi-structured interviews were conducted with 16 unmarried women, five midwives, and two physicians. The data were analyzed using the conventional content analysis method. RESULTS: Four main categories constituted the general concept concerning the stigma suffered by unmarried women for using reproductive health services, i.e., prevalent stereotypical thinking patterns in society, the fear of being judged and labeled by others, discrimination, and feeling ashamed of seeking reproductive health services. CONCLUSIONS: The findings indicated that society associates reproductive health issues with sexual relations, which in turn shapes the stigma and places limitations on unmarried women for using reproductive health services. Thus, while reproductive health services are planned and provided to unmarried women, strategies are demanded for overcoming this stigma. PMID- 27247795 TI - Designing Iranian Model to Assess the Level of Health System Responsiveness. AB - BACKGROUND: Given the rapid pace of changes in community health needs and the mission of healthcare organizations to provide and promote the community's health, the growing need to increase health system responsiveness to people as a key element of observance and fulfillment of justice is felt more than ever. OBJECTIVES: This study was aimed at designing the native model of responsiveness for Iran and to validate the aspects of the proposed model. MATERIALS AND METHODS: Our study had a cross-sectional design and was a validation study performed in 2014. In order to define and identify responsiveness model aspects, the first phase recorded the views of 200 key informants from 19 provinces of Iran. Snowball sampling was used to select experts (based on WHO guideline). Then, the opinions of 18 comments were received from service recipients in the form of three focus group discussions and were analyzed by the frame framework analysis (interviewed recipients were selected using the purposive sampling method). Finally, in order to confirm the model's efficacy, a responsiveness questionnaire with 7 aspects (domains) and 52 indicators (items) obtained from the initial proposed model was answered by 600 members of the selected families in the two provinces of Fars and Yazd. A multi-stage cluster sampling approach was used for the household survey. The results were analyzed by the Confirmatory Factor Analysis (CFA) test and through the use of Lisrel software. RESULTS: Confirmatory Factor Analysis, based on the results of the key informant survey and group discussions, showed that according to quantities of GFI = 0.91, CFI = 0.93, NFI = 0.91, RMSEA = 0.074, SRMR = 0.061 and Hoelter (CN) = 178.54 in outpatient services and where GFI = 0.89, CFI = 0.91, NFI = 0.86, RMSEA = 0.064, SRMR = 0.053 and Hoelter (CN) = 158.93 for inpatient services, seven factors (F) (dignity, informed choice, confidentiality, patient training and informing, access to services, quality of basic amenities, and access to social support) are the main determinants of the responsiveness model and proposed model validity. CONCLUSIONS: Given the comprehensiveness of presented aspects and indicators in this proposed model and its validity test, the aforementioned responsiveness model can be considered a suitable model to use when assessing the levels of health system responsiveness in Iran. PMID- 27247796 TI - Cloning, Expression, and Cost Effective Purification of Authentic Human Epidermal Growth Factor With High Activity. AB - BACKGROUND: Epidermal growth factor (EGF) plays a fundamental role in the healing of wounds relating to skin damage, the cornea, and the gastrointestinal tract. OBJECTIVES: The aim of this study is the cloning, expression, and purification of recombinant human EGF (rhEGF), and an assessment of its activity. MATERIALS AND METHODS: In the present experimental study, a synthetic pET28a (+) -hEGF construct was prepared. In order to ligate hEGF into pET24a (+), the PCR technique was performed, using special primers that possess restriction enzyme sites, which are also located in appropriate sites in pET24a (+). After transferring this construct into E. coli cells, protein expression was performed under standard conditions. Protein solubilization was done by urea. hEGF purification and refolding were carried out using gradient dialysis against the urea. We used RP-HPLC to compare between rhEGF and commercial rhEGF as a control. Finally, an MTT assay was performed to assess the viability of the NIH 3T3 cells treated with various concentrations of rhEGF. RESULTS: Dialysis after urea solubilization caused precipitation of unwanted proteins, resulting in achievement of purified EGF with > 90% purity, without the need for expensive and time-consuming process. The MTT assay results showed that our rhEGF activate significantly higher proliferation of NIH 3T3 cells in comparison to the control (P-values were < 0.0001), in total concentrations and times evaluated CONCLUSIONS: Via our purification protocol, a sufficient amount of bioactive recombinant human epidermal growth factor was obtained in just a few affordable steps, with superlative purity. PMID- 27247797 TI - Estimated Prevalence of Glaucoma in South Korea Using the National Claims Database. AB - Purpose. To estimate the prevalence of glaucoma and costs associated with glaucoma care in South Korea between 2008 and 2013 using the Korean national claims database. Design. Retrospective cross-sectional study from a national claims database. Methods. Patients who were diagnosed with glaucoma between 2008 and 2013 were retrospectively identified in the national claims database using glaucoma diagnostic codes. For each year, the prevalence of glaucoma and direct medical costs associated with glaucoma care were estimated. Result. The prevalence of glaucoma in patients >=40 years of age increased from 0.79% in 2008 to 1.05% in 2013. The number of patients with glaucoma increased by 54% between 2008 and 2013 (9% average annual increase). The prevalence of glaucoma increased with age and was higher in males than in females. The cost to care for glaucoma patients increased from $16.5 million in 2008 to $29.2 million in 2013, which translated into an 81% increase over the 6 years examined (12.7% average annual increase). Conclusion. The estimated prevalence and socioeconomic burden of glaucoma have steadily increased each year in South Korea. Nevertheless, many glaucoma patients remain undiagnosed in the present study using national claims database. PMID- 27247798 TI - Expression of Wnt/beta-Catenin Signaling Pathway and Its Regulatory Role in Type I Collagen with TGF-beta1 in Scleral Fibroblasts from an Experimentally Induced Myopia Guinea Pig Model. AB - Background. To investigate Wnt/beta-catenin signaling pathway expression and its regulation of type I collagen by TGF-beta1 in scleral fibroblasts from form deprivation myopia (FDM) guinea pig model. Methods. Wnt isoforms were examined using genome microarrays. Scleral fibroblasts from FDM group and self-control (SC) group were cultured. Wnt isoforms, beta-catenin, TGF-beta1, and type I collagen expression levels were examined in the two groups with or without DKK-1 or TGF-beta1 neutralizing antibody. Results. For genome microarrays, the expression of Wnt3 in FDM group was significantly greater as confirmed in retinal and scleral tissue. The expression of Wnt3 and beta-catenin significantly increased in FDM group and decreased significantly with DKK-1. TGF-beta1 expression level decreased significantly in FDM group and increased significantly with DKK-1. Along with morphological misalignment inside and outside cells, the amount of type I collagen decreased in FDM group. Furthermore, type I collagen increased and became regular in DKK-1 intervention group, whereas it decreased and rearranged more disorder in TGF-beta1 neutralizing antibody intervention group. Conclusions. The activation of Wnt3/beta-catenin signaling pathway was demonstrated in primary scleral fibroblasts in FDM. This pathway further reduced the expression of type I collagen by TGF-beta1, which ultimately played a role in scleral remodeling during myopia development. PMID- 27247799 TI - An Important Cause of Blindness in Children: Open Globe Injuries. AB - Objective. Our aim was to present and evaluate the predictive factors of visual impairment and blindness according to WHO criteria in pediatric open globe injuries. Methods. The medical records of 94 patients younger than 18 years who underwent primary repair surgery were reviewed retrospectively. The initial and final visual acuity, anterior and posterior segment findings, and zone of injury were noted. The patients were classified as blindness in one eye or visual impairment in one eye. Results. Of 412 patients who presented with open globe injury, 94 (23%) were under 18 years old. Fifty-four (16 females, 38 males) children were included. The mean age of the children was 7.1 +/- 4.1 years. According to WHO criteria, 19 of 54 patients (35%) had unilateral blindness and 8 had unilateral visual impairment (15%). There was no significant relationship between final visual acuity and gender and injured eye. In visually impaired and blind patients, presence of preoperative hyphema, retinal detachment, and zone 2 and zone 3 injuries was significantly higher. Conclusion. Presence of hyphema and zone 2 and zone 3 injuries and retinal detachment may end up with visual impairment and/or blindness in children. PMID- 27247800 TI - A Meta-Analysis for Association of Maternal Smoking with Childhood Refractive Error and Amblyopia. AB - Background. We aimed to evaluate the association between maternal smoking and the occurrence of childhood refractive error and amblyopia. Methods. Relevant articles were identified from PubMed and EMBASE up to May 2015. Combined odds ratio (OR) corresponding with its 95% confidence interval (CI) was calculated to evaluate the influence of maternal smoking on childhood refractive error and amblyopia. The heterogeneity was evaluated with the Chi-square-based Q statistic and the I (2) test. Potential publication bias was finally examined by Egger's test. Results. A total of 9 articles were included in this meta-analysis. The pooled OR showed that there was no significant association between maternal smoking and childhood refractive error. However, children whose mother smoked during pregnancy were 1.47 (95% CI: 1.12-1.93) times and 1.43 (95% CI: 1.23-1.66) times more likely to suffer from amblyopia and hyperopia, respectively, compared with children whose mother did not smoke, and the difference was significant. Significant heterogeneity was only found among studies involving the influence of maternal smoking on children's refractive error (P < 0.05; I (2) = 69.9%). No potential publication bias was detected by Egger's test. Conclusion. The meta analysis suggests that maternal smoking is a risk factor for childhood hyperopia and amblyopia. PMID- 27247801 TI - Single Nucleotide Polymorphisms in Pediatric Idiopathic Nephrotic Syndrome. AB - Polymorphic variants in several molecules involved in the glomerular function and drug metabolism have been implicated in the pathophysiology of pediatric idiopathic nephrotic syndrome (INS), but the results remain inconsistent. We analyzed the association of eleven allelic variants in eight genes (angiopoietin like 4 (ANGPTL4), glypican 5 (GPC5), interleukin-13 (IL-13), macrophage migration inhibitory factor (MIF), neural nitric oxide synthetase (nNOS), multidrug resistance-1 (MDR1), glucocorticoid-induced transcript-1 (GLCCI1), and nuclear receptor subfamily-3 (NR3C1)) in 100 INS patients followed up till adulthood. We genotyped variants using PCR and direct sequencing and evaluated estimated haplotypes of MDR1 variants. The analysis revealed few differences in SNP genotype frequencies between patients and controls, or in clinical parameters among the patients. Genotype distribution of MDR1 SNPs rs1236, rs2677, and rs3435 showed significant (p < 0.05) association with different medication regimes (glucocorticoids only versus glucocorticoids plus additional immunosuppressives). Some marginal association was detected between ANGPTL4, GPC5, GLCCI1, and NR3C1 variants and different medication regimes, number of relapses, and age of onset. Conclusion. While MDR1 variant genotype distribution associated with different medication regimes, the other analyzed gene variants showed only little or marginal clinical relevance in INS. PMID- 27247802 TI - Cellular Zinc Homeostasis Contributes to Neuronal Differentiation in Human Induced Pluripotent Stem Cells. AB - Disturbances in neuronal differentiation and function are an underlying factor of many brain disorders. Zinc homeostasis and signaling are important mediators for a normal brain development and function, given that zinc deficiency was shown to result in cognitive and emotional deficits in animal models that might be associated with neurodevelopmental disorders. One underlying mechanism of the observed detrimental effects of zinc deficiency on the brain might be impaired proliferation and differentiation of stem cells participating in neurogenesis. Thus, to examine the molecular mechanisms regulating zinc metabolism and signaling in differentiating neurons, using a protocol for motor neuron differentiation, we characterized the expression of zinc homeostasis genes during neurogenesis using human induced pluripotent stem cells (hiPSCs) and evaluated the influence of altered zinc levels on the expression of zinc homeostasis genes, cell survival, cell fate, and neuronal function. Our results show that zinc transporters are highly regulated genes during neuronal differentiation and that low zinc levels are associated with decreased cell survival, altered neuronal differentiation, and, in particular, synaptic function. We conclude that zinc deficiency in a critical time window during brain development might influence brain function by modulating neuronal differentiation. PMID- 27247803 TI - Olfactory Bulb Field Potentials and Respiration in Sleep-Wake States of Mice. AB - It is well established that local field potentials (LFP) in the rodent olfactory bulb (OB) follow respiration. This respiration-related rhythm (RR) in OB depends on nasal air flow, indicating that it is conveyed by sensory inputs from the nasal epithelium. Recently RR was found outside the olfactory system, suggesting that it plays a role in organizing distributed network activity. It is therefore important to measure RR and to delineate it from endogenous electrical rhythms like theta which cover similar frequency bands in small rodents. In order to validate such measurements in freely behaving mice, we compared rhythmic LFP in the OB with two respiration-related biophysical parameters: whole-body plethysmography (PG) and nasal temperature (thermocouple; TC). During waking, all three signals reflected respiration with similar reliability. Peak power of RR in OB decreased with increasing respiration rate whereas power of PG increased. During NREM sleep, respiration-related TC signals disappeared and large amplitude slow waves frequently concealed RR in OB. In this situation, PG provided a reliable signal while breathing-related rhythms in TC and OB returned only during microarousals. In summary, local field potentials in the olfactory bulb do reliably reflect respiratory rhythm during wakefulness and REM sleep but not during NREM sleep. PMID- 27247805 TI - Differences in Cortical Representation and Structural Connectivity of Hands and Feet between Professional Handball Players and Ballet Dancers. AB - It is known that intensive training and expertise are associated with functional and structural neuroadaptations. Most studies, however, compared experts with nonexperts; hence it is, specifically for sports, unclear whether the neuroplastic adaptations reported are sport-specific or sport-general. Here we aimed at investigating sport-specific adaptations in professional handball players and ballet dancers by focusing on the primary motor and somatosensory grey matter (GM) representation of hands and feet using voxel-based morphometry as well as on fractional anisotropy (FA) of the corticospinal tract by means of diffusion tensor imaging-based fibre tractography. As predicted, GM volume was increased in hand areas of handball players, whereas ballet dancers showed increased GM volume in foot areas. Compared to handball players, ballet dancers showed decreased FA in both fibres connecting the foot and hand areas, but they showed lower FA in fibres connecting the foot compared to their hand areas, whereas handball players showed lower FA in fibres connecting the hand compared to their foot areas. Our results suggest that structural adaptations are sport specific and are manifested in brain regions associated with the neural processing of sport-specific skills. We believe this enriches the plasticity research in general and extends our knowledge of sport expertise in particular. PMID- 27247804 TI - Age-Dependent Switch of the Role of Serotonergic 5-HT1A Receptors in Gating Long Term Potentiation in Rat Visual Cortex In Vivo. AB - The rodent primary visual cortex (V1) is densely innervated by serotonergic axons and previous in vitro work has shown that serotonin (5-HT) can modulate plasticity (e.g., long-term potentiation (LTP)) at V1 synapses. However, little work has examined the effects of 5-HT on LTP under in vivo conditions. We examined the role of 5-HT on LTP in V1 elicited by theta burst stimulation (TBS) of the lateral geniculate nucleus in urethane-anesthetized (adult and juvenile) rats. Thalamic TBS consistently induced potentiation of field postsynaptic potentials (fPSPs) recorded in V1. While 5-HT application (0.1-10 mM) itself did not alter LTP levels, the broad-acting 5-HT receptor antagonists methiothepin (1 mM) resulted in a clear facilitation of LTP in adult animals, an effect that was mimicked by the selective 5-HT1A receptor antagonist WAY 100635 (1 mM). Interestingly, in juvenile rats, WAY 100635 application inhibited LTP, indicative of an age-dependent switch in the role of 5-HT1A receptors in gating V1 plasticity. Analyses of spontaneous electrocorticographic (ECoG) activity in V1 indicated that the antagonist-induced LTP enhancement was not related to systematic changes in oscillatory activity in V1. Together, these data suggest a facilitating role of 5-HT1A receptor activation on LTP in the juvenile V1, which switches to a tonic, inhibitory influence in adulthood. PMID- 27247806 TI - Assessment of the Central Effects of Natural Uranium via Behavioural Performances and the Cerebrospinal Fluid Metabolome. AB - Natural uranium (NU), a component of the earth's crust, is not only a heavy metal but also an alpha particle emitter, with chemical and radiological toxicity. Populations may therefore be chronically exposed to NU through drinking water and food. Since the central nervous system is known to be sensitive to pollutants during its development, we assessed the effects on the behaviour and the cerebrospinal fluid (CSF) metabolome of rats exposed for 9 months from birth to NU via lactation and drinking water (1.5, 10, or 40 mg.L(-1) for male rats and 40 mg.L(-1) for female rats). Medium-term memory decreased in comparison to controls in male rats exposed to 1.5, 10, or 40 mg.L(-1) NU. In male rats, spatial working memory and anxiety- and depressive-like behaviour were only altered by exposure to 40 mg.L(-1) NU and any significant effect was observed on locomotor activity. In female rats exposed to NU, only locomotor activity was significantly increased in comparison with controls. LC-MS metabolomics of CSF discriminated the fingerprints of the male and/or female NU-exposed and control groups. This study suggests that exposure to environmental doses of NU from development to adulthood can have an impact on rat brain function. PMID- 27247808 TI - Splinting of Longitudinal Fracture: An Innovative Approach. AB - Trauma may result in craze lines on the enamel surface, one or more fractured cusps of posterior teeth, cracked tooth syndrome, splitting of posterior teeth, and vertical fracture of root. Out of these, management of some fractures is of great challenge and such teeth are generally recommended for extraction. Literature search reveals attempts to manage such fractures by full cast crown, orthodontic wires, and so forth, in which consideration was given to extracoronal splinting only. However, due to advancement in materials and technologies, intracoronal splinting can be achieved as well. In this case report, longitudinal fractures in tooth #27, tooth #37, and tooth #46 had occurred. In #27, fracture line was running mesiodistally involving the pulpal floor resulting in a split tooth. In teeth 37 and 46, fractures of the mesiobuccal cusp and mesiolingual cusp were observed, respectively. They were restored with cast gold inlay and full cast crown, respectively. Longitudinal fracture of 27 was treated with an innovative approach using intracanal reinforced composite with Ribbond, external reinforcement with an orthodontic band, and full cast metal crown to splint the split tooth. PMID- 27247807 TI - Severe Left Ventricular Hypertrophy, Small Pericardial Effusion, and Diffuse Late Gadolinium Enhancement by Cardiac Magnetic Resonance Suspecting Cardiac Amyloidosis: Endomyocardial Biopsy Reveals an Unexpected Diagnosis. AB - Left ventricular (LV) hypertrophy can be related to a multitude of cardiac disorders, such as hypertrophic cardiomyopathy (HCM), cardiac amyloidosis, and hypertensive heart disease. Although the presence of LV hypertrophy is generally associated with poorer cardiac outcomes, the early differentiation between these pathologies is crucial due to the presence of specific treatment options. The diagnostic process with LV hypertrophy requires the integration of clinical evaluation, electrocardiography (ECG), echocardiography, biochemical markers, and if required CMR and endomyocardial biopsy in order to reach the correct diagnosis. Here, we present a case of a patient with severe LV hypertrophy (septal wall thickness of 23 mm, LV mass of 264 g, and LV mass index of 147 g/m(2)), severely impaired longitudinal function, and preserved radial contractility (ejection fraction = 55%), accompanied by small pericardial effusion and diffuse late gadolinium enhancement (LGE) by cardiac magnetic resonance (CMR). Due to the imaging findings, an infiltrative cardiomyopathy, such as cardiac amyloidosis, was suspected. However, amyloid accumulation was excluded by endomyocardial biopsy, which revealed the presence of diffuse myocardial fibrosis in an advanced hypertensive heart disease. PMID- 27247809 TI - Primary MALT Lymphoma of the Breast Treated with Definitive Radiation. AB - We are reporting a case of a 59-year-old woman, with a family history of breast cancer, who presented with extranodal marginal zone lymphoma (MALT) of the left breast. She received definitive radiation therapy and remains without evidence of disease. Here, we present a case and review the current literature to determine the optimal treatment of this rare presentation of MALT. PMID- 27247810 TI - Blastocystis sp. Infection Mimicking Clostridium Difficile Colitis. AB - We report an unusual case of severe diarrhea related to Blastocystis sp. infection in a patient with end stage renal disease on hemodialysis. The patient was admitted due to profuse diarrhea associated with fever and leukocytosis. Pertinent stool work-up such as leukocytes in stool, stool culture, clostridium difficile toxin B PCR, and serology for hepatitis A, hepatitis B, and hepatitis C and cytomegalovirus screening were all negative. Ova and parasite stool examination revealed Blastocystis sp. The patient was given intravenous metronidazole with clinical improvement by day three and total resolution of symptoms by day ten. PMID- 27247811 TI - Primary Intracranial Synovial Sarcoma. AB - Background. Synovial sarcoma is an aggressive soft tissue sarcoma with uncertain histological origin. The pathology frequently presents as a localized disease, especially near large joints around the knee and thigh. Intracranial disease, which is rare, has been reported as metastasis from synovial sarcoma. We report a case with no obvious primary extracranial pathology, suggesting primary intracranial disease; this has not been reported in the literature. Case Description. A 21-year-old male, with a prior right skull lesion resection for atypical spindle cell neoplasm, presented with headaches, gait instability, left arm weakness, and left homonymous hemianopsia. CT of head demonstrated a right parietal hemorrhagic lesion with mass effect, requiring surgical decompression. Histopathology revealed synovial sarcoma. FISH analysis noted the existence of the t(X;18)(p11.2;q11.2) chromosomal translocation. PET scan did not show other metastatic disease. He underwent stereotactic radiotherapy and adjuvant chemotherapy. At 2-year follow-up, he remained nonfocal without recurrence. Conclusion. We report the first known case of primary intracranial synovial sarcoma. Moreover, we stress that intracranial lesions may have a tendency for hemorrhage, requiring urgent lifesaving decompression. PMID- 27247812 TI - Morvan Syndrome Secondary to Thymic Carcinoma in a Patient with Systemic Lupus Erythematosus. AB - Morvan syndrome (MoS) is a rare paraneoplastic autoimmune disorder characterized by peripheral nerve hyperexcitability, autonomic dysfunction, and sleep disorders. Systemic lupus erythmatosus (SLE) cooccurs in 6-10% of patients with thymoma. It may occur before, concurrently with, or after thymoma diagnosis. This paper reports the first case of cooccurrence of SLE, thymic carcinoma, and MoS. The cooccurrence of SLE, thymoma, and MoS delineates the generalized autoimmunity process. Symptoms of both MoS and SLE abated upon tumor resection. PMID- 27247814 TI - Primary Diaphragmatic Dedifferentiated Liposarcoma in a Young Female Patient after Delivery. AB - A 26-year-old woman was admitted with the chief complaint of chest pain. She had delivered her first child 9 months before admission. Computed tomography showed a bulky mass in her left chest, and histopathological analysis revealed it to be dedifferentiated liposarcoma. We initiated doxorubicin chemotherapy, and the tumor mass reduced. After that, we performed vascular embolization along with chemotherapy, but tumor size did not reduce. On the 160th day of illness, the patient died. This is the first report of a primary diaphragmatic dedifferentiated liposarcoma diagnosed after delivery. Establishment of a regimen of chemotherapy for bulky unresectable liposarcoma is necessary. PMID- 27247813 TI - Lipoyltransferase 1 Gene Defect Resulting in Fatal Lactic Acidosis in Two Siblings. AB - A term male neonate developed severe intractable lactic acidosis on day of life 1 and died the same day at our institution. The family previously lost another term, female newborn on day of life 1 from suspected sepsis at an outside hospital. After performing an autopsy on the neonate who died at our institution, extensive and lengthy neonatal and parental genetic testing, as well as biochemical analyses, and whole exome sequencing analysis identified compound heterozygous mutations in the lipoyltransferase 1 (LIPT1) gene responsible for the lipoylation of the 2-keto dehydrogenase complexes in the proband. These mutations were also identified in the deceased sibling. The clinical manifestations of these two siblings are consistent with those recently described in two unrelated families with lactic acidosis due to LIPT1 mutations, an underrecognized and underreported cause of neonatal death. Conclusions. Our observations contribute to the delineation of a new autosomal recessive metabolic disorder, leading to neonatal death. Our case report also highlights the importance of an interdisciplinary team in solving challenging cases. PMID- 27247815 TI - Synchronous Diagnosis of Multiple Myeloma, Breast Cancer, and Monoclonal B-Cell Lymphocytosis on Initial Presentation. AB - The cooccurrence of more than one oncologic illness in a patient can present a diagnostic challenge. Here we report an unusual case of concomitant existence of multiple myeloma, breast cancer, and monoclonal B-cell lymphocytosis on initial presentation. The challenge was to accurately diagnose each disease and stage in order to maximize the therapeutic regimen to achieve cure/remission. Successful management of the patient and increased life expectancy can be achieved by multidisciplinary management and patient-oriented approach in multiple primary malignant synchronous tumors. PMID- 27247816 TI - Presentation of Two Cases with Early Extracranial Metastases from Glioblastoma and Review of the Literature. AB - Extracranial metastases from glioblastoma are rare. We report two patients with extracranial metastases from glioblastoma. Case 1 concerns a 59-year-old woman with multiple metastases that spread early in the course of disease. What makes this case unusual is that the tumor had grown into the falx close to the straight sinus and this might be an explanation to the early and extensive metastases. Case 2 presents a 60-year-old man with liver metastasis found at autopsy, and, in this case, it is more difficult to find an explanation. This patient had two spontaneous intracerebral bleeding incidents and extensive bleeding during acute surgery with tumor removal, which might have induced extracranial seeding. The cases presented might have hematogenous spreading in common as an explanation to extracranial metastases from GBM. PMID- 27247817 TI - Cam Femoroacetabular Impingement as a Possible Explanation of Recalcitrant Anterior Knee Pain. AB - We present a case of a patient with chronic anterior knee pain (AKP) recalcitrant to conservative treatment who returned to our office for severe hip pain secondary to Cam femoroacetabular impingement (Cam FAI) at 10 months after the onset of knee pain. This case highlights the fact that the main problem is not in the patella but in the hip in some patients with AKP. We hypothesize that there is an external femoral rotation in order to avoid the impingement and therefore the hip pain in patients with Cam FAI. This functional femoral rotation could provoke a patellofemoral imbalance that may be, in theory, responsible for patellofemoral pain in this particular patient. In our case, Cam FAI resolution was related to the resolution of AKP. PMID- 27247818 TI - An Unusual Case of Extranodal Diffuse Large B-Cell Lymphoma Infiltrating Skeletal Muscle: A Case Report and Review of the Literature. AB - Diffuse large B-cell lymphoma is extranodal in approximately 40% of cases, arising in nearly any organ system. DLBCL involvement of soft tissue and in particular skeletal muscle is extremely rare, comprising less than 1% of all extranodal non-Hodgkin lymphomas (NHL). We report a case of a 79-year-old man that presented with a DLBCL of the left triceps. In particular, we describe an unusual histologic appearance of pseudoglandular structures, resembling adenocarcinoma. We performed a review of lymphoma cases involving skeletal muscle diagnosed at our institution over the past 15 years as well as thorough PubMed review of the literature. We discuss the features of lymphoma involving skeletal muscle as it pertains to clinical characteristics, histologic subtype, tumor localization, diagnostic studies, therapy, and outcome. Finally, we highlight the diagnostic difficulties that can present in these rare and often challenging cases. PMID- 27247819 TI - Hydropneumothorax in Children: A Rare Complication of a Bacterial Pneumonia. AB - Hydropneumothorax is an uncommon presentation of a complicated pneumonia, and very few cases in the pediatric population have been reported. This is a case of a 5-month-old patient who presented to the emergency department (ED) with a three day history of fever, diarrhea, and respiratory distress. His initial assessment suggested a lower respiratory tract infection and because of his respiratory distress and hypoxia a chest X-ray was performed. Other clinical information and radiologic studies will be discussed further, but his chest X-ray suggested a right-sided hydropneumothorax secondary to a complicated pneumonia. He completed 12 days of IV antibiotic treatment and required a chest tube for drainage. Patient was discharged home with a full recovery. PMID- 27247820 TI - Severe Psychosis, Drug Dependence, and Hepatitis C Related to Slamming Mephedrone. AB - Background. Synthetic cathinones (SCs), also known as "bath salts," are beta ketone amphetamine compounds derived from cathinone, a psychoactive substance found in Catha edulis. Mephedrone is the most representative SC. Slamming is the term used for the intravenous injection of these substances in the context of chemsex parties, in order to enhance sex experiences. Using IV mephedrone may lead to diverse medical and psychiatric complications like psychosis, aggressive behavior, and suicide ideation. Case. We report the case of a 25-year-old man admitted into a psychiatric unit, presenting with psychotic symptoms after slamming mephedrone almost every weekend for the last 4 months. He presents paranoid delusions, intense anxiety, and visual and kinesthetic hallucinations. He also shows intense craving, compulsive drug use, general malaise, and weakness. After four weeks of admission and antipsychotic treatment, delusions completely disappear. The patient is reinfected with hepatitis C. Discussion. Psychiatric and medical conditions related to chemsex and slamming have been reported in several European cities, but not in Spain. Psychotic symptoms have been associated with mephedrone and other SCs' consumption, with the IV route being prone to produce more severe symptomatology and addictive conducts. In the case we report, paranoid psychosis, addiction, and medical complications are described. PMID- 27247821 TI - CT and MR Unilateral Brain Features Secondary to Nonketotic Hyperglycemia Presenting as Hemichorea-Hemiballism. AB - Hemichorea-hemiballism is an unusual hyperkinetic movement disorder characterized by continuous involuntary movements of an entire limb or both limbs on one side of the body. The acute onset of this disorder occurs with an insult in contralateral basal ganglia. Ischemic events represent the most common cause. Nonketotic hyperglycemia comes in second place. Nonketotic hyperglycemic hemichorea-hemiballism (NHH) is a rare cause of unilateral brain abnormalities on imaging studies confined to basal ganglia (mainly putaminal region as well as caudate nucleus). Subtle hyperdensity in striatal region can be found on CT studies whereas brain MR imaging typically shows T1 hyperintensity and T2 hypointensity in the basal ganglia contralateral to the movements. Diagnosis is based on both glucose levels and neuroimaging findings. Elevated blood glucose and hemoglobin A1c levels occur with poorly controlled diabetes. In this case report, our aim is to present neuroimaging CT and MR unilateral findings in an elderly woman secondary to nonketotic hyperglycemia presenting as hemichorea hemiballism. PMID- 27247822 TI - Sampson's Artery Hemorrhage after Inguinal Hernia Repair: Second Case Reported. AB - Sampson artery is normally obliterated in postembryonic development. In rare cases it can remain patent and complicate a routine outpatient herniorrhaphy when severed. This is the second reported case in the available English literature of hemoperitoneum due to bleeding from a patent Sampson's artery following an open inguinal hernia repair. PMID- 27247823 TI - A Low-Grade Fibromyxoid Sarcoma of the Internal Abdominal Oblique Muscle. AB - A low-grade fibromyxoid sarcoma (LGFMS) is a rare tumor, with a benign histologic appearance but malignant behavior. This report describes a 74-year-old man with an internal abdominal oblique muscle mass. The tumor appeared as a well-defined ovoid mass on computed tomography, with mild uptake on fluorine-18 fluorodeoxyglucose positron-emission tomography images. Radical resection with wide safe margins was performed. Histologically, the tumor was composed of spindle-shaped cells in a whorled growth pattern, with alternating fibrous and myxoid stroma. MUC4 expression, a highly sensitive and specific immunohistochemical marker for LGFMS, was detected. Therefore, we diagnosed the tumor as LGFMS. At the 3-month follow-up, there was no sign of recurrence or metastasis. We report the first case of LGFMS arising from the internal abdominal oblique muscle. PMID- 27247824 TI - Resection and Abdominal Wall Reconstruction of a Desmoid Tumor with Endometrioma Features. AB - Desmoid tumors are rare, musculoaponeurotic mesenchymal origin tumors arising from the proliferation of well-differentiated fibroblasts. Desmoid tumors may arise from any location with the abdominal cavity, abdominal wall and extremity locations being most frequent. We present the case of a 35-year-old female with a history of endometriosis who presented palpable abdominal mass and cyclic abdominal pain. Resection was performed for a presumed desmoid soft tissue tumor. Final pathology demonstrated desmoid histology admixed with abdominal wall endometriosis (endometrioma). This unique pathologic finding has only been rarely reported and is discussed with a brief review of the literature. PMID- 27247827 TI - Simple Instrumental and Visual Tests for Nonlaboratory Environmental Control. AB - Proposed are simple and available techniques that can be used for rapid and reliable environmental control specifically of natural water by means of instrumental and visual tests in outdoor conditions. Developed are the chemical colorimetric modes for fast detection of socially dangerous trace impurities in water such as Co(II), Pd(II), and Rh(III) as well as NO2 (-)-ions and Fe(III) serving as model impurities. Application of portable digital devices and scanner allows estimating the color coordinates and increasing the accuracy and sensitivity of the tests. The combination of complex formation with preconcentration of colored complexes replaces the sensitive but time-consuming and capricious kinetic method that is usually used for this purpose at the more convenient and reliable colorimetric method. As the test tools, the following ones are worked out: polyurethane foam tablets with sorbed colored complexes, the two-layer paper sandwich packaged in slide adapter and saturated by reagents, and polyethylene terephthalate blister with dried reagents. Fast analysis of polyurethane foam tablets is realized using a pocket digital RGB-colorimeter or portable photometer. Express analysis of two-layer paper sandwich or polyethylene terephthalate blister is realized by visual and instrumental tests. The metrological characteristics of the developed visual and instrumental express analysis techniques are estimated. PMID- 27247825 TI - The R18 Polyarginine Peptide Is More Effective Than the TAT-NR2B9c (NA-1) Peptide When Administered 60 Minutes after Permanent Middle Cerebral Artery Occlusion in the Rat. AB - We examined the dose responsiveness of polyarginine R18 (100, 300, and 1000 nmol/kg) when administered 60 minutes after permanent middle cerebral artery occlusion (MCAO). The TAT-NR2B9c peptide, which is known to be neuroprotective in rodent and nonhuman primate stroke models, served as a positive control. At 24 hours after MCAO, there was reduced total infarct volume in R18 treated animals at all doses, but this reduction only reached statistical significance at doses of 100 and 1000 nmol/kg. The TAT-NR2B9c peptide reduced infarct volume at doses of 300 and 1000 nmol/kg, but not to a statistically significant extent, while the 100 nmol/kg dose was ineffective. The reduction in infarct volume with R18 and TAT-NR2B9c peptide treatments was mirrored by improvements in one or more functional outcomes (namely, neurological score, adhesive tape removal, and rota rod), but not to a statistically significant extent. These findings further confirm the neuroprotective properties of polyarginine peptides and for R18 extend its therapeutic time window and dose range, as well as demonstrating its greater efficacy compared to TAT-NR2B9c in a severe stroke model. The superior neuroprotective efficacy of R18 over TAT-NR2B9c highlights the potential of this polyarginine peptide as a lead candidate for studies in human stroke. PMID- 27247826 TI - A Sensitive IHC Method for Monitoring Autophagy-Specific Markers in Human Tumor Xenografts. AB - Objective. Use of tyramide signal amplification (TSA) to detect autophagy biomarkers in formalin fixed and paraffin embedded (FFPE) xenograft tissue. Materials and Methods. Autophagy marker regulation was studied in xenograft tissues using Amp HQ IHC and standard IHC methods. Results. The data demonstrate the feasibility of using high sensitivity TSA IHC assays to measure low abundant autophagy markers in FFPE xenograft tissue. PMID- 27247828 TI - Sampling and Analytical Method for Alpha-Dicarbonyl Flavoring Compounds via Derivatization with o-Phenylenediamine and Analysis Using GC-NPD. AB - A novel methodology is described for the sampling and analysis of diacetyl, 2,3 pentanedione, 2,3-hexanedione, and 2,3-heptanedione. These analytes were collected on o-phenylenediamine-treated silica gel tubes and quantitatively recovered as the corresponding quinoxaline derivatives. After derivatization, the sorbent was desorbed in 3 mL of ethanol solvent and analyzed using gas chromatography/nitrogen-phosphorous detection (GC/NPD). The limits of detection (LOD) achieved for each analyte were determined to be in the range of 5-10 nanograms/sample. Evaluation of the on-tube derivatization procedure indicated that it is unaffected by humidities ranging from 20% to 80% and that the derivatization procedure was quantitative for analyte concentrations ranging from 0.1 MUg to approximately 500 MUg per sample. Storage stability studies indicated that the derivatives were stable for 30 days when stored at both ambient and refrigerated temperatures. Additional studies showed that the quinoxaline derivatives were quantitatively recovered when sampling up to a total volume of 72 L at a sampling rate of 50 cc/min. This method will be important to evaluate and monitor worker exposures in the food and flavoring industry. Samples can be collected over an 8-hour shift with up to 288 L total volume collected regardless of time, sampling rate, and/or the effects of humidity. PMID- 27247829 TI - Movements and Memory. PMID- 27247830 TI - Five Supplements and Multiple Psychotic Symptoms: A Case Report. AB - Dietary supplements, including vitamins, minerals, herbs, amino acids, and enzymes, have become increasingly more common and are used by approximately half of the US population. About three-fourths of supplements are obtained with no prescription from a physician, which raises medical concerns regarding safety as these products do not require US Food and Drug Administration approval. Common reasons for taking dietary supplements include improved mood, improved mental function, depression relief, anxiety reduction, and treatment of simple and migraine headaches. The use of herbs for medicinal purposes has a long-standing history among many cultures. We present the case of a 43-year-old man, who was taking dietary supplements, with a 6-month history of psychotic symptoms that increasingly caused impairment in functioning and eventually led to involuntary hospitalization. The published data with regard to supplements causing psychosis, herb-to-herb interaction, and reliability of herbal supplement manufacturers are discussed. PMID- 27247831 TI - Retrospective Audit of the Management of Anal Insertion of Foreign Bodies: A Holistic Approach. AB - Most patients with voluntary anal insertion of a foreign body (IFB) present to the emergency department and are then managed by the surgical team. This report reviews the medical literature on IFB and includes results of a chart review of operative logged interventions and clinically coded procedures for anal IFBs at a single acute hospital in the United Kingdom between May 2009 and September 2013. The objective was to establish the current practice in the management of anal IFB and update a framework for the initial workup, surgical procedure, and appropriate mental health intervention. PMID- 27247833 TI - Bipolar II Disorder Masked by Substance Use. PMID- 27247832 TI - Obstacles to the Prescription and Use of Opioids. PMID- 27247834 TI - Rash Associated With Panic Attacks. PMID- 27247835 TI - Trimethoprim-Sulfamethoxazole-Induced Psychosis Culminating in Catastrophic Self Injury: A Case Report. PMID- 27247836 TI - Delusion of Triplet Pregnancy in a Manic Patient. PMID- 27247837 TI - Brief Reversible Psychosis and Altered Mental Status in a Patient With Folate Deficiency: A Case Report. PMID- 27247839 TI - Resolution of Pathological Skin Picking With Fluvoxamine in a 74-Year-Old Dementia Patient. PMID- 27247838 TI - Long-Term Treatment of Clozapine-Induced Leukopenia With Lithium: Fast-Onset Agranulocytosis Following Lithium Discontinuation. PMID- 27247840 TI - Cannabinoid Hyperemesis Syndrome Associated With Compulsive Showering and Acute Kidney Injury. PMID- 27247841 TI - The Relationship Between Continuous Identity Disturbances, Negative Mood, and Suicidal Ideation. AB - OBJECTIVE: To examine the relationship between continuous identity and a measure of depression, anxiety, and stress as well as suicidal ideation using 2 validated measures of continuous identity. METHOD: A total of 246 subjects recruited from the Amazon Mechanical Turk subject pool who completed a full survey in November 2014 were included in the analyses. Stress, anxiety, and depression severity were measured using the Depression, Anxiety, and Stress Scale. Continuous identity was measured with the Venn continuous identity task and the me/not me continuous identity task. RESULTS: Multiple regression analyses revealed continuous identity disturbances were significantly associated with depressed mood (R (2) = 0.37, P < .01). Continuous identity also predicted suicide severity, even after controlling for demographic factors, negative life events, and depressed mood. Additionally, predictive discriminant analysis revealed continuous identity, depression severity, and negative life events correctly classified 74.1% of participants into high and low suicide risk groups. CONCLUSION: Lack of continuous identity predicted both depression and suicidality severity. Integration of perceived identities may be a worthwhile goal for behavioral interventions aimed at reducing depressed mood and suicidality. PMID- 27247843 TI - A Randomized Survey of the Public's Expectancies and Willingness to Participate in Clinical Trials of Antidepressants Versus Psychotherapy for Depression. AB - BACKGROUND: Expectancies and treatment preferences are known to affect the outcomes of patients enrolled in clinical trials for depression, but there is little research on their influence when the public is considering participation in these trials. METHOD: We conducted an online survey (May 2013) in which participants (N = 615) were randomly assigned to read hypothetical descriptions of clinical trials for depression based on 1 of the following study designs: medication versus placebo, medication versus medication, psychotherapy versus placebo, or psychotherapy versus psychotherapy. Afterward, individuals rated willingness to participate in the trial, logic and credibility of the treatments, and expected success and improvement in symptoms. RESULTS: There were no differences in expectancies for ratings of credibility and logic or success and improvement among clinical trial designs. However, self-reported willingness to participate in the study was rated significantly higher in the 2 psychotherapy trial designs (active-comparator and placebo-controlled) compared with the active comparator medication design (P < .05). Psychiatric treatment history, general treatment preferences, and depression severity were positively correlated with willingness to participate primarily in the active-comparator medication design. CONCLUSIONS: Consistent with the broader treatment preference literature, individuals reported a greater willingness to participate in psychotherapy compared with antidepressant studies. Thus, people's perceptions of different treatments are likely to influence not only the outcomes of clinical trials for depression but also decisions to participate in these trials in the first place. PMID- 27247842 TI - Is Metabolic Syndrome On the Radar? Improving Real-Time Detection of Metabolic Syndrome and Physician Response by Computerized Scan of the Electronic Medical Record. AB - OBJECTIVE: Metabolic syndrome is a common underdiagnosed condition among psychiatric patients exacerbated by second-generation antipsychotics, with the exception of aripiprazole and ziprasidone. This study evaluated the prescribing and treating behavior with regard to antipsychotics and metabolic syndrome of psychiatrists before and after implementation of a mandatory admission order set and electronic notification of results. METHOD: Baseline data from 9,100 consecutive psychiatric admissions to a mental health hospital (July 2013-July 2014) were compared to postintervention data (July 2014-January 2015), which included 1,499 consecutive patient records. The intervention initiated standardized admission testing with electronic notification to psychiatrists when patients met metabolic syndrome criteria (according to Axis III of the DSM-IV). Charts were examined for inclusion of this diagnosis at discharge and for treatment changes. RESULTS: At baseline, only 2.4% of patients (n = 214) were evaluated for metabolic syndrome. Of these, 34.5% (0.8% of the total sample) met metabolic syndrome criteria. Only 15 patients (0.16%) were comprehensively treated. No chart listed metabolic syndrome under Axis III of the DSM-IV. After the intervention, the diagnosis of patients meeting the criteria for metabolic syndrome increased from 0% to 29.3%. Less than 3% of patients were switched to drugs with a more benign metabolic profile. All patients who continued on second generation antipsychotics had metabolic retesting. Thirty-eight experienced a significant and rapid increase in triglyceride levels after only 3 to 17 days. CONCLUSIONS: Mandatory intake testing increases the number of patients evaluated for metabolic syndrome. Electronic alerts increase the inclusion of metabolic syndrome among discharge diagnoses but rarely affect prescribing practices. PMID- 27247844 TI - Clinical Presentation and Course of Persistent Delusional Disorder: Data From a Tertiary Care Center in India. AB - OBJECTIVE: Despite its long history as a psychiatric diagnosis, little is known about the sociodemographic and clinical profile of persistent delusional disorder (PDD) or its subtypes, treatment response, and outcomes, particularly in India. We examined the clinical characteristics and course of PDD in patients presenting to a tertiary neuropsychiatry center in India. METHOD: A retrospective chart review of patients diagnosed with PDD (ICD-10) between January 2000 and May 2014 was conducted. Sociodemographic and clinical data including age at onset, total duration of the illness, clinical symptoms and treatment, hospitalizations, occupational functioning, and follow-up were extracted from the files. The study was approved by the institute ethics committee. RESULTS: The sample (N = 455) consisted of 236 men and 219 women. The mean age at onset was 32.36 +/- 10.47 years. The most common delusion was infidelity (n = 203, 44.6%) followed by persecution (n = 149, 32.7%). Hallucinations were present in 78 (17.1%), depressive symptoms in 187 (41.1%), and comorbid substance dependence in 61 (13.4%) subjects; 141 subjects (31.0%) had a family history of mental illness. Follow-up data were available for 308 subjects, of whom 285 (92.5%) reported good compliance with medication. Of the subjects, 163 (52.9%) showed a good response to treatment. The diagnosis of PDD remained unchanged in 274 of 308 subjects (88.9%). CONCLUSION: In our center, PDD appears to be uncommon and has a near equal gender representation. Infidelity was the most common delusion, which is in contrast to the reported literature. The diagnosis of PDD appears to be stable with good response to atypical antipsychotics if compliance can be ensured. PMID- 27247845 TI - A Review of Posttraumatic Stress Disorder and Obesity: Exploring the Link. AB - OBJECTIVE: The incidence of posttraumatic stress disorder (PTSD) and obesity are on the rise, and evidence continues to support the observation that individuals who have symptoms of PTSD are more likely to develop obesity in their lifetime. The incidence of obesity in individuals with PTSD, including war veterans, women, and children exposed to trauma, is not solely attributable to psychotropic medications, but actual pathophysiologic mechanisms have not been fully delineated. Additionally, there are no studies to date demonstrating that obese individuals are predisposed to developing PTSD compared to the general population. This review explores the pathogenic pathways common to both PTSD and obesity, which include inflammation, the renin-angiotensin-aldosterone system, cellular structures, and neuroendocrine activation. DATA SOURCES AND SYNTHESIS: A PubMed search for the years 2000-2015 with the keywords PTSD and obesity was performed. There were no language restrictions. RESULTS: More research is needed in human subjects to understand the pathogenic pathways common to both PTSD and obesity and to further clarify the direction of identified associations. Ideally, in the future, clinical interventions targeting these pathways may be able to modify the course of PTSD and obesity. The outcome of studies investigating the utility of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in the treatment of PTSD symptoms will be relevant to control both PTSD and obesity. Importantly, outcomes assessing inflammation, obesity, and cardiac function in the same subjects also should be determined. CONCLUSION: Research is needed to reveal the multidimensional and intricate relationship between PTSD and obesity. The implications of this research would be essential for treatment, prevention, and potential public health reforms. PMID- 27247846 TI - Behavioral Health and Primary Care: A Status Report. PMID- 27247847 TI - Caretakers. PMID- 27247848 TI - Causes and factors related to dopamine agonist withdrawal in Parkinson's disease. AB - BACKGROUND: Although dopamine agonists (DAs) are useful in Parkinson's disease (PD), they are not frequently used in elderly patients due to adverse effects. However, there is a lack of evidence because few elderly PD patients are enrolled in clinical trials. AIMS OF THE STUDY: The aims of this study were to analyze the reasons of DA withdrawal (DAW) in a group of PD patients in clinical practice and to identify the related factors. Specifically, we studied the effect of age, comorbidity, and polypharmacy as potential risk factors for DAW. METHODS: A retrospective chart review of the follow-up (from May, 2012 to March, 2015) of a subgroup of PD patients receiving a DA (n = 68; 60.3% males, 69.3 +/- 9.2 years old) from a cohort (n = 150) previously studied in detail in 2012 was used to identify predictive factors of DAW. RESULTS: The DAW percentage was 18.2% (12/66; follow-up of 690.2 +/- 232.6 days). DAW causes were cognitive impairment (3), reduction therapy (3), hallucinations (2), dyskinesia (2), and excessive diurnal somnolence (2). Only a higher levodopa daily dose (HR 1.003; 95% CI 1.001-1.006; P = 0.044) was an independent predictor of DAW after adjustment for other explanatory variables. CONCLUSIONS: The frequency of DAW was low. Advanced age alone is not a contraindication to the administration of DAs. PMID- 27247849 TI - Genetic variation and cognitive dysfunction in opioid-treated patients with cancer. AB - BACKGROUND AND PURPOSE: The effects of single-nucleotide polymorphisms (SNPs) on the cognitive function of opioid-treated patients with cancer until now have not been explored, but they could potentially be related to poor functioning. This study aimed at identifying associations between SNPs of candidate genes, high opioid dose, and cognitive dysfunction. METHODS: Cross-sectional multicenter study (European Pharmacogenetic Opioid Study, 2005-2008); 1586 patients; 113 SNPs from 41 genes. INCLUSION CRITERIA: cancer, age >=18 year, opioid treatment, and available genetic data. Cognitive assessment by Mini-Mental State Examination (MMSE). ANALYSES: SNPs were rejected if violation of Hardy-Weinberg equilibrium (P < 0.0005), or minor allele frequency <5%; patients were randomly divided into discovery sample (2/3 for screening) and validation sample (1/3 for confirmatory test); false discovery rate of 10% for determining associations (Benjamini Hochberg method). Co-dominant, dominant, and recessive models were analyzed by Kruskal-Wallis and Mann-Whitney tests. RESULTS: In the co-dominant model significant associations (P < 0.05) between MMSE scores and SNPs in the HTR3E,TACR1, and IL6 were observed in the discovery sample, but the replication in the validation sample did not confirm it. Associations between MMSE scores among patients receiving >=400 mg morphine equivalent dose/day and SNPs in TNFRSF1B,TLR5,HTR2A, and ADRA2A were observed, but they could not be confirmed in the validation sample. After correction for multiple testing, no SNPs were significant in the discovery sample. Dominant and recessive models also did not confirm significant associations. CONCLUSIONS: The findings did not support influence of those SNPs analyzed to explain cognitive dysfunction in opioid treated patients with cancer. PMID- 27247851 TI - Intellectual development in Noonan syndrome: a longitudinal study. AB - INTRODUCTION: Although cognitive impairments in adults with Noonan syndrome seem to be limited to a low-average intelligence and slower processing speed, studies in children with Noonan syndrome have demonstrated more extensive cognitive problems. These include deficits in language skills, memory, attention, and executive functioning. This longitudinal study is the first to investigate intellectual development in a group of individuals with Noonan syndrome. METHODS: Sixteen patients with Noonan syndrome underwent intelligence assessment both in childhood and in adulthood, using Wechsler's intelligence scales. IQ scores and Wechsler standard scores achieved in childhood and adulthood were compared. Subsequently, verbal and performance IQ in childhood were used as predictors for adult IQ and index scores. RESULTS: Compared with childhood scores, adult full scale IQ and performance IQ significantly increased. Adult performance IQ was higher than verbal IQ. Childhood performance IQ and verbal IQ together predicted all adult IQ and index scores, except for the processing speed index. DISCUSSION: Childhood IQ was a significant predictor of adult intelligence in patients with Noonan syndrome. Performance IQ advanced to a normal level in adulthood, while verbal IQ did not develop proportionately, resulting in a discrepancy between adult performance IQ and verbal IQ. This finding could suggest a delay in the development of executive functioning in patients with Noonan syndrome, which seems to be outgrown in adulthood. PMID- 27247850 TI - Immunohistochemical and transcriptome analyses indicate complex breakdown of axonal transport mechanisms in canine distemper leukoencephalitis. AB - INTRODUCTION: CDV-DL (Canine distemper virus-induced demyelinating leukoencephalitis) represents a spontaneously occurring animal model for demyelinating disorders. Axonopathy represents a key pathomechanism in this disease; however, its underlying pathogenesis has not been addressed in detail so far. This study aimed at the characterization of axonal cytoskeletal, transport, and potential regenerative changes with a parallel focus upon Schwann cell remyelination. METHODS: Immunohistochemistry of canine cerebellar tissue as well as a comparative analysis of genes from an independent microarray study were performed. RESULTS: Increased axonal immunoreactivity for nonphosphorylated neurofilament was followed by loss of cytoskeletal and motor proteins. Interestingly, a subset of genes encoding for neurofilament subunits and motor proteins was up-regulated in the chronic stage compared to dogs with subacute CDV DL. However, immunohistochemically, hints for axonal regeneration were restricted to up-regulated axonal positivity of hypoxia-inducible factor 1 alpha, while growth-associated protein 43, erythropoietin and its receptor were not or even down-regulated. Periaxin-positive structures, indicative of Schwann cell remyelination, were only detected within few advanced lesions. CONCLUSIONS: The present findings demonstrate a complex sequence of axonal cytoskeletal breakdown mechanisms. Moreover, though sparse, this is the first report of Schwann cell remyelination in CDV-DL. Facilitation of these very limited endogenous regenerative responses represents an important topic for future research. PMID- 27247852 TI - The association between vascular endothelial growth factor gene polymorphisms and stroke: a meta-analysis. AB - OBJECTIVES: Numerous studies have investigated the relationships between vascular endothelial growth factor (VEGF) gene polymorphisms and stroke. However, their findings remain controversial. The objective of this study was to evaluate the relationships between VEGF gene polymorphisms and stroke by a meta-analysis. MATERIALS AND METHODS: The PubMed, Embase, China National Knowledge Infrastructure database, Wanfang Chinese database, and VIP Chinese database were systemically searched. Data were extracted by two independent reviewers, and pooled odds ratio (OR) with 95% confidence interval (CI) were calculated. RESULTS: Ten studies were included, including a total of 2331 cases and 1814 controls for +936C>T, 3040 cases and 2649 controls for -1154G>A. Under the dominant and recessive models, respectively, the overall ORs and 95% CIs of +936 T were 1.44, 1.09-1.90, P = 0.01 (1.53, 1.14-2.05, P = 0.005, in Asians) and 1.19, 0.85-1.65, P = 0.31, and the overall ORs and 95% CIs of -1154 A were 0.98, 0.87-1.10, P = 0.75 and 0.95, 0.82-1.11, P = 0.53. No publication bias was found in this meta-analysis. CONCLUSIONS: The meta-analysis showed that +936C>T may be a risk factor for stroke, especially in Asians, while -1154G>A was not associated with stroke. PMID- 27247853 TI - White and gray matter fiber pathways in autism spectrum disorder revealed by ex vivo diffusion MR tractography. AB - INTRODUCTION: The goal of this project was to study the white and gray matter brain pathways of young children with autism spectrum disorder (ASD) and investigate how ASD brains differ from those of typically developing children of the same age. METHODS: High angular resolution resolution diffusion imaging tractography and diffusion tensor imaging tractography were used to analyze the brains of two 3-year-old children with ASD and two age-matched controls. RESULTS: In the ASD brains, the callosal and corticopontine pathways were thinner overall and terminal areas in the cortical gray matter were significantly smaller. The ASD brains had more short-range u-fibers in the frontal lobe compared to the control brains. Gray matter pathways were found disorganized with less coherency in the ASD brain, specifically the lateral aspects of the middle part of the brain including motor areas, and both medial and lateral surfaces of the anterior frontal brain regions. CONCLUSION: These findings show our tractography technique is useful for identifying differences in brain pathways between the ASD and control groups. Given that scanning the brain of 3-year-old children with or even without ASD is challenging, postmortem scanning may offer valuable insights into the connectivity in the brain of young children with ASD. PMID- 27247854 TI - Exogenous dopamine reduces GABA receptor availability in the human brain. AB - BACKGROUND: While it has recently been shown that dopamine release stimulates conscious self-monitoring through the generation of gamma oscillations in medial prefrontal/anterior cingulate cortex, and that the GABAergic system is effective in producing such oscillations, interaction of the two transmitter systems has not been demonstrated in humans. We here hypothesize that dopamine challenge stimulates the GABA system directly in the medial prefrontal/anterior cingulate region in the human brain. METHODS: Positron emission tomography (PET) with the GABA receptor alpha1/alpha5 subtype ligand [(11)C] Ro15-4513 was used to detect changes in GABA receptor availability after clinical oral doses of levodopa in a double blind controlled study. RESULTS: We here provide the first direct evidence for such coupling in the cerebral cortex, in particular in the medial prefrontal anterior cingulate region, by showing that exogenous dopamine decreases [(11)C] Ro15-4513 binding widely in the human brain compatible with a fall in alpha1 subtype availability in GABA complexes due to increased GABA activity. PMID- 27247855 TI - Autonomic and peripheral nervous system function in acute tick-borne encephalitis. AB - OBJECTIVES: Tick-borne encephalitis (TBE) is an emerging flaviviral zoonosis in Central and Eastern Europe. TBE can present as meningitis, meningoencephalitis, or meningoencephalomyelitis. Dysfunction of the autonomic (ANS) and peripheral motoric and sensory nervous system (PNS) might contribute to acute and long-term complications. We aimed to examine, whether the ANS and PNS are affected in acute TBE. METHODS: Fourteen patients with acute TBE, 17 with diabetic polyneuropathy (d-PNP), and 30 healthy controls (HC) were examined in our single-center, prospective study. ANS and PNS function was assessed by time- and frequency domain parameters of the heart rate (HR) variability at rest and deep respiration, and by sural and tibial nerve neurography. Primary endpoint was the HR variability at rest measured by root mean square of the successive differences (RMSSD). Autonomic symptoms and quality of life (QoL) were assessed by questionnaires. RESULTS: Tick-borne encephalitis patients had a lower RMSSD at rest (TBE 13.1 +/- 7.0, HC 72.7 +/- 48.3; P < 0.001) and deep respiration (TBE 42.8 +/- 27.0, HC 109.7 +/- 68.8; P < 0.01), an increased low-frequency to high frequency power component ratio at rest (TBE 4.0 +/- 4.0, HC 0.8 +/- 0.5; P < 0.001), and a higher minimal heart rate at rest (TBE 85.4 +/- 7.0, HC 69.5 +/- 8.5; P < 0.001), all similar to patients with d-PNP, indicating sympathovagal imbalance with increased sympathetic activation. Compared to HC, sural and tibial nerve conduction velocities and action potential amplitudes were reduced, ANS symptoms were more frequent, and QoL was lower in patients with TBE. CONCLUSIONS: The ANS and to a lesser degree the PNS are affected by acute TBE, which could potentially contribute to short- and long-term morbidity. PMID- 27247856 TI - The treatment of chronic depression with cognitive behavioral analysis system of psychotherapy: a systematic review and meta-analysis of randomized-controlled clinical trials. AB - BACKGROUND: Chronic depression is a severe and disabling condition. Compared to an episodic course, chronic depression has been shown to be less responsive to psychopharmacological and psychological treatments. The cognitive behavioral analysis system of psychotherapy (CBASP) has been developed as a specific psychotherapy for chronic depression. However, conflicting results concerning its efficacy have been reported in randomized-controlled trials (RCT). Therefore, we aimed at examining the efficacy of CBASP using meta-analytical methods. METHODS: Randomized-controlled trials assessing the efficacy of CBASP in chronic depression were identified by searching electronic databases (PsycINFO, PubMed, Scopus, Cochrane Central Register of Controlled Trials) and by manual searches (citation search, contacting experts). Searching period was restricted from the first available entry to October 2015. Identified studies were systematically reviewed. The standardized mean difference Hedges' g was calculated from posttreatment and mean change scores. The random-effects model was used to compute combined overall effect sizes. A risk of publication bias was addressed using fail-safe N calculations and trim-and-fill analysis. RESULTS: Six studies comprising 1.510 patients met our inclusion criteria. The combined overall effect sizes of CBASP versus other treatments or treatment as usual (TAU) pointed to a significant effect of small magnitude (g = 0.34-0.44, P < 0.01). In particular, CBASP revealed moderate-to-high effect sizes when compared to TAU and interpersonal psychotherapy (g = 0.64-0.75, P < 0.05), and showed similar effects when compared to antidepressant medication (ADM) (g = -0.29 to 0.02, ns). The combination of CBASP and ADM yielded benefits over antidepressant monotherapy (g = 0.49-0.59, P < 0.05). LIMITATIONS: The small number of included studies, a certain degree of heterogeneity among the study designs and comparison conditions, and insufficient data evaluating long-term effects of CBASP restrict generalizability yet. CONCLUSIONS: We conclude that there is supporting evidence that CBASP is effective in the treatment of chronic depression. PMID- 27247857 TI - Statin use after intracerebral hemorrhage: a 10-year nationwide cohort study. AB - INTRODUCTION: Although statin therapy is beneficial to patients with ischemic stroke, statin use, and intracerebral hemorrhage (ICH) remain a concern. ICH survivors commonly have comorbid cardiovascular risk factors that would otherwise warrant cholesterol-lowering medication, thus emphasizing the importance of assessing the characteristics of statin therapy in this population. METHODS: We performed a cohort study by using 10 years of data collected from the National Health Insurance Research Database in Taiwan. We enrolled 726 patients admitted for newly diagnosed ICH from January 1, 2001 to December 31, 2010. The patients were categorized into high- (92), moderate- (545), and low-intensity (89) statin groups, and into hydrophilic (295) and lipophilic (431) statin groups. The composite outcomes included all-cause mortality, recurrent ICH, ischemic stroke, transient ischemic attack, and acute coronary events. RESULTS: The patients in the low-intensity group did not differ significantly from the patients in the high-intensity group in risk of all-cause mortality (adjusted hazard ratio [aHR] = 0.65, 95% confidence interval [CI] = 0.28-1.55) and recurrent ICH (aHR = 0.66, 95% CI = 0.30-1.44). In contrast, the patients in the hydrophilic group had a significantly lower risk of recurrent ICH than did those in the lipophilic group (aHR = 0.69, 95% CI = 0.48-0.99). We determined no significant differences in other composite endpoints between hydrophilic and lipophilic statin use. CONCLUSION: Hydrophilic statin therapy is associated with a reduced risk of recurrent ICH in post-ICH patients. The intensity of statin use had no significant effect on recurrent ICH or other components of the composite outcome. Additional studies are required to clarify the biological mechanisms underlying these observations. PMID- 27247858 TI - Selective Automated Perimetry Under Photopic, Mesopic, and Scotopic Conditions: Detection Mechanisms and Testing Strategies. AB - PURPOSE: Automated scotopic, mesopic, and photopic perimetry are likely to be important paradigms in the assessment of emerging treatments of retinal diseases, yet our knowledge of the photoreceptor mechanisms detecting targets under these conditions remains largely dependent on simian data. We therefore aimed to establish the photoreceptor/postreceptoral mechanisms detecting perimetric targets in humans under photopic, mesopic, and scotopic conditions and to make recommendations for suitable clinical testing strategies for selective perimetry. METHODS: Perimetric sensitivities within 30 degrees of fixation were determined for eight wavelengths (410, 440, 480, 520, 560, 600, 640, and 680 nm) under scotopic, mesopic (1.3 cd.m-2) and photopic (10 cd.m-2) conditions. Data were fitted with vector combinations of rod, S-cone, nonopponent M+L-cone mechanism, and opponent M- versus L-cone mechanism templates. RESULTS: Scotopicperimetric sensitivity was determined by rods peripherally and by a combination of rods and cones at, and immediately around, fixation. Mesopic perimetric sensitivity was mediated by M+L-cones and S-cones centrally and by M+L-cones and rods more peripherally. Photopic perimetric sensitivity was determined by an opponent M- versus L-cone, a nonopponent M+L-cone, and an S-cone mechanism centrally and by a combination of an S-cone and an M+L-cone mechanism peripherally. CONCLUSIONS: Under scotopic conditions, a 480-nm stimulus provides adequate isolation (>=28 dB) of the rod mechanism. Several mechanisms contribute to mesopic sensitivity: this redundancy in detection may cause both insensitivity to broadband white targets and ambiguity in determining which mechanism is being probed with short wavelength stimuli. M- and L-cone-derived mechanisms are well isolated at 10 cd.m 2: these may be selectively probed by a stimulus at 640 nm (>= 20 dB isolation). TRANSLATION RELEVANCE: In human observers, multiple mechanisms contribute to the detection of Goldmann size III and size V perimetric targets under scotopic, mesopic, and photopic conditions. The relative contribution of these mechanisms appears to differ from those found previously for macaques. Our results furthermore suggest that caution must be exercised when using microperimetric techniques, which are typically conducted under mesopic conditions and which are likely to be important in the assessment of emerging treatments for retinal disease. This is because mesopic background conditions maximize the redundancy of target detection. Furthermore, our results demonstrate that spectral manipulation of the stimulus alone cannot be used to reliably separate rod from cone responses under these conditions. PMID- 27247861 TI - EBSJ Evidence Assessment. PMID- 27247860 TI - Paperless Journals: The Future of the Global Spine Journal. PMID- 27247859 TI - Caloric restriction and aerobic exercise in sarcopenic and non-sarcopenic obese women: an observational and retrospective study. AB - BACKGROUND: Sarcopenic obese (SO) individuals are a unique subset of subjects that combines obesity and sarcopenia. Traditional weight loss programmes including aerobic exercises may worsen their condition by further reducing their lean mass. The objective of this observational and retrospective study was to verify the effect of a mixed weight loss programme combining caloric restriction and exercise on body composition, and lipid-lipoprotein profile of obese women according to their sarcopenic status. METHODS: One hundred and forty-six obese women (body mass index >= 30 kg/m(2) and fat mass >= 40%) participated to the 3 week usual and institutionalized weight-reducing programme combining a dietary plan (1400 +/- 200 kcal/day) and aerobic exercise (1 h/day, 6 days/week) of a specialized medical institution. The lean body mass index (LMI; lean mass/height(2)) was calculated, and women in the lowest tertile of LMI were considered SO. RESULTS: At baseline, SO women were older, and their body weight and LMI were lower than non-sarcopenic obese (N-SO) women (p < 0.05). N-SO and SO women similarly lost fat mass and improved their lipid-lipoprotein profile (p < 0.05), while differences in LMI between groups persisted at the end of the weight reducing programme. Indeed, N-SO women lost lean mass (p < 0.05) while SO did not. CONCLUSIONS: These findings suggest that a short weight loss programme combining caloric restriction and aerobic exercise may significantly reduce fat mass and improve lipid-lipoprotein profile in obese women, independently of their sarcopenic status. Such programmes may have deleterious effects on lean mass in N SO subjects, only. PMID- 27247862 TI - The impact of agricultural soil usage on activity and abundance of ammonifying bacteria in selected soils from Poland. AB - The aim of the study was to demonstrate the impact of soil agricultural usage on the abundance of ammonifying bacteria (AB) and their activity, expressed as arginine ammonification (AA). Five agriculturally exploited types of soils (FAO): Haplic Luvisol, Brunic Arenosol, Mollic Gleysol, Eutric Fluvisol, and Rendzina Leptosol were studied. The controls were non-agricultural soils of the same type located in close proximity to agricultural sites. The tested soils varied in terms of pH (4.18-7.08), total carbon (8.39-34.90 g kg(-1)), easily degradable carbon content (0.46-1.11 g kg(-1)), moisture (5.20-13.50 %), and nitrogen forms (mg kg(-1)): 1.68-27.17, 0.036-0.862, 0.012-3.389 for nitrate nitrogen, nitrite nitrogen, and ammonia nitrogen, respectively. The AB abundance in agricultural soils ranged from 1.1 to 6.4 * 10(4) cfu g(-1), while in the controls it was significantly higher-from 2.0 to 110 * 10(4) cfu g(-1) of soil. Also, AA in the controls was three-times higher than in the agricultural soils. Strong associations between AA and the abundance of AB in the control (r = 0.954***) and agricultural soils (r = 0.833***) were proved. In the agricultural soils, the AB abundance and AA were influenced by pH (r = 0.746*** and r = 0.520***) and carbon content (r = 0.488*** and r = 0.391***). The AB abundance was also affected by easily degradable carbon (r = 0.517**) and nitrite nitrogen (r = 0.376*), whilst ammonium nitrogen influenced AA (r = 0.451*). Our results indicate that the abundance of AB and AA may be good indicators of soil biological conditions. PMID- 27247863 TI - Prevalence of Chlamydia trachomatis infection in parturient women in Gipuzkoa, Northern Spain. AB - The prevalence of Chlamydia trachomatis infection in Southern Europe is poorly understood and its identification is essential for the design of appropriate prevention policies. The prevalence of C. trachomatis in 2011-2014 was determined through polymerase chain reaction in urine samples from 11,687 unselected parturient women from the Basque Country, Spain (San Sebastian area). The overall age-adjusted prevalence was 1.0 % (95 % CI 0.8-1.2). The prevalence of infection in women younger than 25 years was 6.4 % and decreased substantially with increasing age: 2.0 % in 25-29 year-olds and 0.5 % in older women (P < 0.001). The prevalence was higher in parturient of foreign origin (1.9 %, 95 % CI 1.3 2.5) than in Spanish parturients (0.8 %, 95 % CI 0.6-1.0), (P < 0.001). The results of this study support the need to screen young women as part of antenatal care in Spain. PMID- 27247864 TI - Ecological analyses of the associations between injury risk and socioeconomic status, geography and Aboriginal ethnicity in British Columbia, Canada. AB - BACKGROUND: The current study examines what factors contribute to higher injury risk among Aboriginal peoples, compared to the total British Columbia (BC) population. We explore socioeconomic, geographic, and cultural factors, and combinations of these factors, that contribute to increased injury risk for Aboriginal peoples. This follows from our previously reported findings of improvements in injury risk over time for both the total and Aboriginal populations. DATA AND METHODS: We use provincial population-based linked health care databases of hospital discharge records. We identify three population groups: total BC population, and Aboriginal populations living off-reserve, or on reserve. For each group we calculate age and gender-standardized relative risks (SRR) of injury-related hospitalization, relative to the total population of BC, for two 5-year time periods (1999-2003, and 2004-2008). We use custom data from the 2001 and 2006 long-form Censuses that described income, education, employment, housing conditions, proportion of urban dwellers, proportion of rural dwellers, and prevalence of Aboriginal ethnicity. We use multivariable linear regression to examine the associations between the census characteristics and SRR of injury. RESULTS: The best-fitting model was an excellent fit (R(2) = 0.905, p < 0.001) among the three population groups within Health Service Delivery Areas of BC. We find indicators in all three categories (socioeconomic, geographic, and cultural) are associated with disparity in injury risk. While the socioeconomic indicators (income, education, housing, employment) were shown to be highly correlated, only living in housing that needs major repair and occupational hazardousness, along with rural residence and Aboriginal ethnicity, remained in the final model. Our data show that cultural density is not associated with injury risk for Aboriginal peoples, and that living off-reserve is associated with reduced injury by improving socioeconomic and geographic conditions (compared to living on-reserve). Finally, our analyses show that Aboriginal status itself is associated with injury risk. CONCLUSIONS: Our findings confirm previous research indicating that geographical differences differentiate injury risk, including for Aboriginal populations, and that socioeconomic determinants are associated with health risks. Our analyses showing that Aboriginal status itself contributes to injury risk is new, but we can only speculate about pathway, and whether the causes are direct or indirect. PMID- 27247865 TI - Simultaneous synthesis of nanodiamonds and graphene via plasma enhanced chemical vapor deposition (MW PE-CVD) on copper. AB - The simultaneous growth of both nanodiamonds and graphene on copper samples is described for the first time. A PE-CVD process is used to synthesize graphene layers and nanodiamond clusters from a hydrogen/methane gas mixture as it is typically done successfully in thermal CVD processes for graphene synthesis. However, the standard thermal CVD process is not without problems since the deposition of graphene is affected by the evaporation of a notable amount of copper caused by the slow temperature increase typical for thermal CVD resulting in a long process time. In sharp contrast, the synthesis of graphene by PE-CVD can circumvent this problem by substantially shortening the process time at holding out the prospect of a lower substrate temperature. The reduced thermal load and the possibility to industrially scale-up the PE-CVD process makes it a very attractive alternative to the thermal CVD process with respect to the graphene production in the future. Nanodiamonds are synthesized in PE-CVD reactors for a long time because these processes offer a high degree of control over the film's nanostructure and simultaneously providing a significant high deposition rate. To model the co-deposition process, the three relevant macroscopic parameters (pressure, gas mixture and microwave power) are correlated with three relevant process properties (plasma ball size, substrate temperature and C2/Halpha-ratio) and the influence on the quality of the deposited carbon allotropes is investigated. For the evaluation of the graphene as well as the nanodiamond quality, Raman spectroscopy used whereas the plasma properties are measured by optical methods. It is found that the diamond nucleation can be influenced by the C2/Halpha-ratio in the plasma, while the graphene quality remains mostly unchanged by this parameter. Moreover it is derived from the experimental data that the direct plasma contact with the copper surface is beneficial for the nucleation of the diamond while the growth and quality of the graphene benefits from a larger distance to the plasma. Therefore, this work presents a basis for a method to tailor the deposition of graphene-diamond hybrid films using a MW PE-CVD process or to suppress the diamond deposition entirely if desired. PMID- 27247866 TI - Validation of a rapid one-step high sensitivity real-time quantitative PCR system for detecting major BCR-ABL1 mRNA on an International Scale. AB - BACKGROUND: Detection and quantitation of BCR-ABL1 transcripts are crucial for managing patients with chronic myeloid leukemia (CML). Although real-time quantitative polymerase chain reaction (RT-qPCR) can be measured on an International Scale (IS), this has not become fully universal. By using a WHO international standard panel established for calibrating secondary standards based on the IS, we have previously developed an RT-qPCR kit, ODK-1201, for quantification of major BCR-ABL1. RESULTS: In this study, the reliability of kit specific conversion factor 1.12 was validated by exchanging patients' samples between three local clinical laboratories and a reference laboratory. The mean bias of the local method after IS conversion was 1.6 fold lower than the reference method. The clinically-useful sensitivity of the kit was further evaluated for monitoring patients with deep molecular response. Based on the correlation of the IS values between ODK-1201 and the reference laboratory method, the detection level of the kit was estimated as 0.0032 % BCR-ABL1 (IS). CONCLUSIONS: ODK-1201 is a highly sensitive one-step RT-qPCR system for detecting BCR-ABL1 on the IS in 2 h after RNA extraction, thus contributing to standardization of molecular monitoring in CML. PMID- 27247868 TI - Novel pre-treatment of zeolite materials for the removal of sodium ions: potential materials for coal seam gas co-produced wastewater. AB - Coal seam gas (CSG) is the extraction of methane gas that is desorbed from the coal seam and brought to the surface using a dewatering and depressurisation process within the saturated coalbed. The extracted water is often referred to as co-produced CSG water. In this study, co-produced water from the coal seam of the Bowen Basin (QLD, Australia) was characterised by high concentration levels of Na(+) (1156 mg/L), low concentrations of Ca(2+) (28.3 mg/L) and Mg(2+) (5.6 mg/L), high levels of salinity, which are expected to cause various environmental problems if released to land or waters. The potential treatment of co-produced water using locally sourced natural ion exchange (zeolite) material was assessed. The zeolite material was characterized for elemental composition and crystal structure. Natural, untreated zeolite demonstrated a capacity to adsorb Na(+) ions of 16.16 mEq/100 g, while a treated zeolite using NH4 (+) using a 1.0 M ammonium acetate (NH4C2H3O2) solution demonstrated an improved 136 % Na(+) capacity value of 38.28 mEq/100 g after 720 min of adsorption time. The theoretical exchange capacity of the natural zeolite was found to be 154 mEq/100 g. Reaction kinetics and diffusion models were used to determine the kinetic and diffusion parameters. Treated zeolite using a NH4 (+) pre-treatment represents an effective treatment to reduce Na(+) concentration in coal seam gas co-produced waters, supported by the measured and modelled kinetic rates and capacity. PMID- 27247867 TI - In vitro and in vivo antitumor effects of the Egyptian scorpion Androctonus amoreuxi venom in an Ehrlich ascites tumor model. AB - Scorpion venom is a highly complex mixture of about 100-700 different components, where peptides are the major constituents with various biological and pharmacological properties including anticancer activities. In this study, anticancer efficacy of the venom of the Egyptian scorpion Androctonus amoreuxi has been evaluated. In vitro, the human breast cancer MCF-7 cell line was treated with the venom and the IC50 was estimated. In vivo studies, Ehrlich ascites carcinoma (EAC) cells were inoculated into CD-1 mice intraperitoneally to form liquid tumor or subcutaneously to form solid tumor and then treated with intraperitoneal injection with venom (0.22 mg/kg) every other day. The total tumor cells in the ascitic fluid and the size of the solid tumor were assessed after 14 and 30 days, respectively. In addition, the mean survival time (MST), body weight, tumor volume, PCV, viability of tumor cells, CBC, AST, ALP, creatinine, oxidative stress biomarkers (GSH, MDA, PCC), tumor marker Ki67, growth factor VEGF and caspase-3 were measured in normal control, EAC control and venom-treated groups (n = 6). Treatment with venom induced anti-tumor effects against liquid and in solid tumors as indicated by a significant (P < 0.05) reduction in tumor volume/size, count of viable EAC cells, expression of Ki67 and VEGF as well as by remarkable increases in MST and caspase-3 expression as compared to non-treated group. Interestingly, the venom restored the altered hematological and biochemical parameters of tumor-bearing animals and significantly increased their life span. These data indicate to (1) the cytotoxic potential effects of A. amoreuxi on tumor cells via anti-proliferative, apoptotic and anti-angiogenic activities; (2) opening a new avenue for further studies on the anti-cancer effects of this agent. PMID- 27247869 TI - Comparison of the effects of patient controlled analgesia (PCA) using dexmedetomidine and propofol during septoplasty operations: a randomized clinical trial. AB - INTRODUCTION: Septoplastical surgery to correct septum deviation can be performed under either local or general anesthesia. During local anesthesia, sedation helps to provide minimum anxiety/discomfort. Our aim was to evaluate the effects of patient-controlled analgesia using dexmedetomidine and propofol on sedation level, analgesic requirement, and patient satisfaction. STUDY DESIGN: A prospective, randomized-parallel clinical study. METHODS: Fifty patients undergoing septoplastical surgery at our university hospital were randomized into two groups. A nasopharyngeal cotton tampon soaked in 0.25 % adrenaline solution was placed, and 1 mg midazolam and 1 mcg/kg fentanyl were applied 5 min before the injections of a surgical local anesthetic. Loading dose was 0.5 mg/kg propofol (Group I) and 1 mcg/kg dexmedetomidine (Group II). The sedation was sustained by a bolus dose of 0.2 mg/kg and continuous basal infusion dose of 0.5 mg/kg/h propofol in Group I, or by a bolus dose of 0.05 ug/kg and continuous basal infusion dose of 0.4 mcg/kg/h dexmedetomidine in Group II. The primary outcomes were patient satisfaction via patient-controlled anesthesia and analgesic demand. Secondary outcomes were sedation level of patients under local anesthesia. RESULTS: In Group II, SpO2 levels were significantly higher than in Group I. Intraoperative and postoperative analgesic requirements were lower in Group II than in Group I. There were no statistically significant differences in patient satisfaction, hemodynamic parameters, nausea and vomiting between the two groups. CONCLUSION: Dexmedetomidine can be used safely as an analgesic and sedation drug in septoplastic surgery. PMID- 27247870 TI - Deformation behaviors of peat with influence of organic matter. AB - Peat is a kind of special material rich in organic matter. Because of the high content of organic matter, it shows different deformation behaviors from conventional geotechnical materials. Peat grain has a non-negligible compressibility due to the presence of organic matter. Biogas can generate from peat and can be trapped in form of gas bubbles. Considering the natural properties of peat, a special three-phase composition of peat is described which indicates the existence of organic matter and gas bubbles in peat. A stress strain-time model is proposed for the compression of organic matter, and the surface tension effect is considered in the compression model of gas bubbles. Finally, a mathematical model has been developed to simulate the deformation behavior of peat considering the compressibility of organic matter and entrapped gas bubbles. The deformation process is the coupling of volume variation of organic matter, gas bubbles and water drainage. The proposed model is used to simulate a series of peat laboratory oedometer tests, and the model can well capture the test results with reasonable model parameters. Effects of model parameters on deformation of peat are also analyzed. PMID- 27247871 TI - Performance improvement for GPS single frequency kinematic relative positioning under poor satellite visibility. AB - Reliable ambiguity resolution in difficult environments such as during setting/rising events of satellites or during limited satellite visibility is a significant challenge for GPS single frequency kinematic relative positioning. Here, a recursive estimation method combining both code and carrier phase measurements was developed that can tolerate recurrent satellite setting/rising and accelerate initialization in motion. We propose an ambiguity dimension expansion method by utilizing the partial ambiguity relevance of previous and current observations. In essence, this method attempts to integrate all useful information into the recursive estimation equation and performs a better least squares adjustment. Using this method, the success rate of the extended ambiguity estimation is independent of the satellite setting and shows robust performance despite poor satellite visibility. Our model allows integration of other useful information into the recursive process. Actual experiments in urban environments demonstrate that the proposed algorithm can improve the reliability and availability of relative positioning. PMID- 27247872 TI - Fibroma of tendon sheath in planta. AB - PURPOSE: Fibroma of tendon sheath in planta is comparatively rare, and its differentiate diagnose, tumour features, treatment and complications were lack of retrospective study in clinics. METHODS: This was a retrospective study of 13 patients (seven women, six men) operated between July 2001 and May 2013 for FTS in planta. The average age at the time of the procedure was 49.8 +/- 8.3 years old (range 31-64). The female-to-male ratio was 9:4. Before the surgery, anteroposterior, lateral and oblique position of foot X-rays were performed in all patients. Ultrasonography (n = 11) and magnetic resonance imaging (n = 11) were performed selectively. The tumor located on the metatarsal par (n = 6), the central part of plantar (n = 4), the lateral part (n = 2) and the medial part (n = 1). Eight patients presented with painless mass (62 % of cases), while five patients presented with pain mass (38 % of cases). No patient had bony erosion. This paper studies the different features of FTS and classifies them into two types-superficial type that tumour grows at planter fascia; deep type that breaks through the planter fascia growing around tendon and joint capsule. Eight and five patients were diagnosed as superficial type and deep type respectively. RESULTS: In all cases, the tumor was excised, pathological results was FTS. The mean follow-up period was 3.2 +/- 1.1 years (range 2-7) years. Five patients had neurovascular bundle involvement (38 % of cases). Two patients had a recurrence (15 % of cases), they undergone another operation. Four patients had a pain (31 % of cases), two patients had numbness (15 % of cases), and one patient had pain and numbness (8 % of cases). They recovered after conservative treatment. CONCLUSION: For the FTS that grows in the plantar, we should select differential diagnosis and the corresponding therapy according to the features of two types, also the prognosis is different. LEVEL OF EVIDENCE: IV. PMID- 27247873 TI - Oolong tea made from tea plants from different locations in Yunnan and Fujian, China showed similar aroma but different taste characteristics. AB - Consistent aroma characteristics are important for tea products. However, understanding the formation of tea aroma flavor and correspondingly proposing applicable protocols to control tea quality and consistency remain major challenges. Oolong tea is one of the most popular teas with a distinct flavor. Generally, oolong tea is processed with the leaves of tea trees belonging to different subspecies and grown in significantly different regions. In this study, Yunnan and Fujian oolong teas, green tea, black tea, and Pu-erh tea were collected from major tea estates across China. Their sensory evaluation, main water-soluble and volatile compounds were identified and measured. The sensory evaluation, total polysaccharide, caffeine, and catechin content of Yunnan oolong tea was found to be different from that of Fujian oolong tea, a result suggesting that the kinds of tea leaves used in Yunnan and Fujian oolong teas were naturally different. However, according to their aroma compounds, principal component analysis (PCA) and cluster analysis (CA) of the volatile compounds showed that the two types of oolong teas were similar and cannot be clearly distinguished from each other; they are also different from green, black, and Pu-erh teas, a result indicating that the same oolong tea processing technology applied to different tea leaves results in consistent aroma characteristics. The PCA analysis results also indicated that benzylalcohol, indole, safranal, linalool oxides, beta-ionone, and hexadecanoic acid methyl ester highly contributed to the distinct aroma of oolong tea compared with the other three types of teas. This study proved that the use of the same processing technology on two kinds of tea leaves resulted in a highly consistent tea aroma. PMID- 27247874 TI - Diet and predatory behavior of the Asian ant-eating spider, Asceua (formerly Doosia) japonica (Araneae: Zodariidae). AB - Several spider taxa are specialized to prey on ants. Some species of Zodariidae are known to use specialized tactics to capture ants. In this study, I assessed the diet difference and predatory behavior of the Japanese zodariid Asceua japonica. In a series of surveys, all observed individuals in the field preyed on tiny arboreal ants representing several subfamilies. In addition, the species used tactics similar to those of its European relatives for preying on ants. This is the first observation of myrmecophagy of Zodariidae in East Asia. PMID- 27247875 TI - An investigation into the effects of band gap and doping concentration on Cu(In,Ga)Se2 solar cell efficiency. AB - A simulation study of a Cu(In1 - xGax)Se2 (CIGS) thin film solar cell has been carried out with maximum efficiency of 24.27 % (Voc = 0.856 V, Jsc = 33.09 mA/cm(2) and FF = 85.73 %). This optimized efficiency is obtained by determining the optimum band gap of the absorber and varying the doping concentration of constituent layers. The Ga content denoted by x = Ga/(In + Ga) is selected as 0.35 which provides the optimum band gap of absorber layer as 1.21 eV. Theoretically, the effects of Ga fraction "x" on CIGS absorber band gap are investigated and to avoid the lattice mismatch effect, the efficiency measurements due to the CIGS band gaps >1.21 eV have not come to the consideration. A one-dimensional simulator ADEPT/F 2.1 has been used to analyze the fabricated device parameters and hence to calculate open circuit voltage, short circuit current, fill factor and efficiency. PMID- 27247876 TI - The optimal reconstruction size of nipple-areola complex following breast implant in breast cancer patients. AB - BACKGROUND: Changes in the areola size after reconstruction of the nipple-areola complex (NAC) following mastectomy and breast reconstruction with a silicon implant in primary breast cancer patients have not been well examined. This study aimed to investigate time-dependent changes in the size of the donor and graft NACs and to assess clinical factors influencing these changes. METHODS: Fifty eight consecutive patients who underwent nipple-areola reconstruction were retrospectively evaluated. Nipple-areola diameter was measured immediately after the NAC reconstruction and at each follow-up visit for at least 36 months. RESULTS: The donor NAC constituted 81 % of the graft NAC at the time of operation. The size of the donor NAC gradually increased by up to 36.8 % after the operation. The size of the graft NAC showed a decrease by 4.5 % at 7 months, followed by recovery to the initial value. The ratio of the donor site size to the graft site size was increased at month 1 and then showed a gradual decrease to 1.08 at 36 months. A history of mastopexy or reduction for the donor site was independent factors associated with changes in the NAC size. CONCLUSIONS: To achieve symmetry, the diameter of the donor NAC immediately after the reconstruction should be at least 20 % smaller than that of the graft NAC, especially for patients without a history of additional operations. PMID- 27247877 TI - Controllable liquid colour-changing lenses with microfluidic channels for vision protection, camouflage and optical filtering based on soft lithography fabrication. AB - In this work, liquid colour-changing lenses for vision protection, camouflage and optical filtering are developed by circulating colour liquids through microfluidic channels on the lenses manually. Soft lithography technology is applied to fabricate the silicone liquid colour-changing layers with microfluidic channels on the lenses instead of mechanical machining. To increase the hardness and abrasion resistance of the silicone colour-changing layers on the lenses, proper fabrication parameters such as 6:1 (mass ration) mixing proportion and 100 degrees C curing temperature for 2 h are approved for better soft lithography process of the lenses. Meanwhile, a new surface treatment for the irreversible bonding of silicone colour-changing layer with optical resin (CR39) substrate lens by using 5 % (volume ratio) 3-Aminopropyltriethoxysilane solution is proposed. Vision protection, camouflage and optical filtering functions of the lenses are investigated with different designs of the channels and multi-layer structures. Each application can not only well achieve their functional demands, but also shows the advantages of functional flexibility, rapid prototyping and good controllability compared with traditional ways. Besides optometry, some other designs and applications of the lenses are proposed for potential utility in the future. PMID- 27247878 TI - Mineral and phytate contents of some prepared popular Ghanaian foods. AB - Prepared Ghanaian traditional foods, mostly consist of starchy staples such as yams (Dioscorea spp.), cassava (Manihot esculenta), millet (Pennisetum glaucum), maize (Zea mays) and rice (Oryza sativa) etc. These traditional foods are a main source of energy and macronutrients. Little or no information however exist on the mineral and phytate contents of prepared traditional Ghanaian foods. The mineral and phytate contents of twenty commonly eaten Ghanaian foods, prepared using popular recipes were analysed for their Fe, Cu, Zn, Mg, Mn, Ca, Na and K as well as phytate contents after foods were dried. Sodium was high in most of the foods, ranging from 557 mg/100 g for Akple with okro soup, to 193.7 for Kooko and bread. Boiled cowpeas with fried plantain was found to contain the highest amount of potassium (409.0 mg/100 g) followed by konkonte with groundnut soup (384.7 mg/100 g). Kooko with bread recorded the lowest potassium content of 131.72 mg/100 g. Konkonte with palm-nut soup and also with groundnut soup were among the foods found to contain high amounts of iron (14.1 mg/100 g and 13.2 mg/100 g respectively). All the foods were very good sources of minerals and will significantly contribute to the mineral intakes of consumers; however, their sodium contents were of concern. PMID- 27247879 TI - Exploring background risk factors for fatigue crashes involving truck drivers on regional roadway networks: a case control study in Jiangxi and Shaanxi, China. AB - BACKGROUND: Fatigue driving is a leading cause of traffic fatalities and injuries in China, especially among heavy truck drivers. The present study tried to examine which and how factors within the human-vehicle-roadway-environment system contribute to the occurrence of crashes involving fatigued truck drivers. FINDINGS: To reduce such risk on the road, a total of 9168 crashes which occurred in Jiangxi and Shaanxi between 2003 and 2014 were selected to measure the effects of potential factors on fatigue related truck crashes using a case control study. Pearson Chi-square test was used to determine the relationship between crash risk and independent factors, and a stepwise logistic regression model was developed to determine the significant risk factors. According to the data analysis results, driver's gender, age, driving experience, and overspeeding behavior, vehicle's commercial status, overloading conditions and brake performance, road's type, slippery pavement and existence of sharp curve and long steep grade, and time of day, season, weather and visibility conditions, etc. were identified to be significantly associated with fatigue related truck crashes on Jiangxi and Shaanxi highways. Moreover, it is found that (a) in Jiangxi, an employed truck driver has a higher risk of crash involving multi-vehicles or a passenger car at bridge locations, and (b) in Shaanxi, the adult, tunnel location, summer and winter days prohibit statistically significant association with the occurrence of multi-vehicle and single-vehicle run-off-road/rollover crashes. CONCLUSIONS: Young employed male truck drivers with less experience are at high risk, especially while driving across sharp curves, down long steep grades, over bridge or through tunnels, during the midnight period, on rainy, snowy or foggy days in rural areas. All these help recommend potential policy initiatives as well as effective safety promotion strategies at the public health scale for professional truck drivers. PMID- 27247880 TI - Quality-of-life in insect venom allergy: validation of the Turkish version of the "Vespid Allergy Quality of Life Questionnaire" (VQLQ-T). AB - PURPOSE: "Vespid Allergy Quality of Life Questionnaire (VQLQ)" has been used to assess psychological burden of disease. The aim of this study was to evaluate validity, reliability and responsiveness to interventions of the Turkish version. METHODS: The Turkish language Questionnaire (VQLQ-T) was administered to 81 patients with bee allergy and 65 patients with vespid allergy from different groups to achieve cross-sectional validation. To establish longitudinal validity, the questionnaire was administered to 36 patients treated with venom immunotherapy. RESULTS: The cross-sectional validation in patients with vespid venom allergy showed a correlation coefficient of 0.97 (Cronbach alpha). Spearman's correlation coefficient of the pretreatment VQLQ-T score with Expectation of Outcome (EoO) questionnaire score was 0.55 (p < 0.001). After treatment, correlation between VQLQ-T score and EoO score was 0.64 (p = 0.003) in these patients. The cross-sectional instrument validation for non-beekeepers with bee venom allergy yielded a correlation coefficient of 0.96 (Cronbach alpha). Spearman's correlation coefficient between pretreatment VQLQ-T score and EoO score was 0.47 (p < 0.001) and after treatment, correlation between VQLQ-T score and EoO score was 0.78 (p = 0.008) in these patients. These findings indicate cross-sectional validity of VQLQ-T. In the longitudinal validation, there was a positive correlation between EoO and VQLQ-T with a correlation coefficient of 0.562 (p < 0.001). While mean (+/-SD) VQLQ-T score was 5.27 (+/-1.29) in pretreatment, it was 2.78 (+/-1.01) after treatment (p < 0.001). The correlation between the mean change in VQLQ-T score and the mean change in EoO score was 0.42 (p = 0.011). CONCLUSIONS: The Turkish version of VQLQ-T enables measurement of Quality of Life (QoL) in patients with either vespid or bee venom allergy. Furthermore, responsiveness of this instrument demonstrates the questionnaire's ability to detect changes over time. PMID- 27247881 TI - Predictors of quality of life of medical students and a comparison with quality of life of adult health care workers in Thailand. AB - INTRODUCTION: There have been few studies which have compared the quality of life between medical students and adult health care workers. AIMS: (1) To compare health related quality of life (HRQoL) between medical students and adult health care workers and (2) to identify factors associated with quality of life of medical students. METHODS: A cross sectional survey of medical students at Chiang Mai University and health care workers at Chiang Mai University Hospital in 2013. RESULTS: Compared with the population of adult health care workers, medical students had a higher physical HRQoL but similar mental HRQoL. This is potentially mediated by the presence of depression, as the prevalence of depressive symptoms was similar in both groups. Higher academic achievement and absence of underlying biomedical conditions were associated with higher HRQoL in medical students. CONCLUSION: The psychological burden for medical students in Thailand could be at similar levels to that of their adult health care counterparts. PMID- 27247882 TI - Management of hair loss associated with endocrine therapy in patients with breast cancer: an overview. AB - Endocrine therapy-induced hair loss (ETIHL) associated with aromatase inhibitors and tamoxifen treatment is currently mostly reported but remained an unresolved therapeutic issue in patients with breast cancer (BC) since the number of studies regarding the management is limited in literature. Herein we investigated the possible causes of this clinical problem and its relation with endocrine therapies widely used for BC survivors and made some modest practical recommendations in light of the literature review in order to provide an optimal management. On the basis of literature findings, common causes of hair loss apart from endocrine therapies should be investigated with an initial evaluation workup and then should be corrected, if observed. Treatment with topical 5-alpha reductase inhibitors and supplementation of Vitamin C and omega-3 fatty acids are likely appeared to be the most appropriate treatment agents for ETIHL without causing an adverse effect on BC prognosis. However, more prospective, randomised, placebo-controlled studied are required in order to confirm our results and also identify the clinical effects of this problem on patients with BC. PMID- 27247883 TI - Current status of international experiences in general surgery residency programs in the United States. AB - BACKGROUND: The aim of this study is to identify, quantify, and characterize the international experiences available for general surgery residents in the general surgery residency programs in the United States (US). METHODS: The Fellowship and Residency Electronic Interactive Database (FREIDA) database was used to identify all the general surgery residency programs in the US. Each institution was contacted by both e-mail and telephone. Respondents were asked if an international experience was available for residents within their program and, if available, details of the experience were obtained. RESULTS: A total of 253 general surgery residency programs were identified using the FREIDA database. Eighty-six (34 %) programs were noted to offer an international experience for their residents. A majority are incorporated into the PGY 3 and PGY 4 level of training with a duration of 1-4 weeks. Common locations are evenly distributed among the Americas and Africa and are usually funded through a combination of resident and department funding. CONCLUSIONS: US resident interest in global health is growing along with an increasing demand for surgical care worldwide. This is one of the first studies to identify, quantify, and characterize in detail the international experiences currently available to general surgery residents within the general surgery training programs in the US. These results can help general surgery residency applicants with an interest in global health and also pave the path for residency programs to develop future international experiences. PMID- 27247884 TI - Association between SNP12 in estrogen receptor alpha gene and hypospadias: a systematic review and meta-analysis. AB - To investigate the association between single nucleotide polymorphism 12 in estrogen receptor alpha gene and hypospadias, four databases (PubMed, Web of Science, Embase and Cochrane Library) were electronically searched by 2nd November 2015. Finally, four studies were included for our meta-analysis, involving 1379 cases and 1648 controls. A quality assessment was performed using the Newcastle-Ottawa Scale of case-control study. Meta-analysis and publication bias measuring were all done by Stata 12.0. No significant publication bias (PBegg = 0.296, PEgger = 0.161) was found. Overall, there was statistically significant association for recessive genetic model (AA vs. GA + GG: OR 3.45, 95 % CI [1.89, 6.30], P = 0.038). Moreover, the positive result was confirmed using trial sequential analysis even only three original studies. For allele model, there was also statistically significant association (allele A vs. G: OR 1.43, 95 % CI [1.23, 1.67], P = 0.034). Meanwhile, A allele as a risk factor turned out to be true positive by trial sequential analysis. In a word, this meta-analysis suggested that the single nucleotide polymorphism 12 definitely increase the risk of hypospadias. PMID- 27247885 TI - The length of proximal margin does not influence the prognosis of Siewert type II/III adenocarcinoma of esophagogastric junction after transhiatal curative gastrectomy. AB - BACKGROUND: The optimal length of proximal margin for Siewert type II/III adenocarcinoma of the esophagogastric junction (AEJ) is still need to be clarified. The aim of the present study was to investigate the appropriate length of proximal margin for Siewert type II/III AEJ through transhiatal approach. METHODS: From September 2009 to December 2014, a total of 693 consecutive patients with Siewert type II/III AEJ were retrospectively analyzed. All patients received transhiatal R0 resection. The proximal margin length was measured immediately after resection. The prognostic value of proximal margin length on Siewert type II/III AEJ with transhiatal approach was analyzed. RESULTS: There were 404 cases of Siewert type II AEJ (58.3 %) and 289 cases of Siewert type III AEJ (41.7 %). Total gastrectomy was performed in 526 patients (75.9 %), and proximal gastrectomy was performed in 167 patients (24.1 %). The median length of the gross proximal margin was 2.4 (range 0.1-5.0) cm. Lymph node metastasis was the only independent prognostic predictor for Siewert type II AEJ. Tumor size and lymph node metastasis were independent prognostic predictors for Siewert type III AEJ. CONCLUSIONS: For Siewert type II/III AEJ with esophageal invasion of 3 cm or less, proximal margin length does not influence the prognosis of patients after transhiatal curative gastrectomy. PMID- 27247886 TI - A measure for the promotion of mountain ecological villages in South Korea: focus on the national mountain ecological village investigation of 2014. AB - BACKGROUND: Although South Korean mountain villages occupy 44 and 55 % of land and forest areas, respectively, these villages account for only 3 % of the national population and they suffer from a declining workforce owing to aging, wage inflation, and low forestry productivity. As a result, the South Korean government implemented a mountain ecological village development project from 1995 to 2013 in 312 of the 4972 mountain villages and investigated project performance in 2014. The present study establishes a measure for the promotion of mountain ecological villages by comparing the situation before and after the project. RESULTS: The analysis found a threefold increase in the inflow of farm/rural-returning and multicultural households compared with before the project, while the average income per farm, local product sales, and experience tourism revenue also grew remarkably every year. In addition, households utilizing forest resources increased by about 30 %, but 45.8 % of the 312 villages had no long-term plan for village development and villagers experienced low satisfaction with job creation and village income. CONCLUSIONS: A systematic revision of agroforestry production and forest administration is needed to define the characteristics of farm/rural-returning populations clearly, reorganize urban rural exchange and experience programs, and reinforce tangible/intangible cultural assets and religious traditions. PMID- 27247887 TI - Whole-cell conversion of l-glutamic acid into gamma-aminobutyric acid by metabolically engineered Escherichia coli. AB - A simple and high efficient way for the synthesis of gamma-aminobutyric acid (GABA) was developed by using engineered Escherichia coli as whole-cell biocatalyst from l-glutamic acid (l-Glu). Codon optimization of Lactococcus lactis GadB showed the best performance on GABA production when middle copy number plasmid was used as expression vector in E. coli BW25113. The highest production of GABA reached 308.96 g L(-1) with 99.9 mol% conversion within 12 h, when E. coli DeltagabAB (pRB-lgadB) concentrated to an OD600 of 15 in 3 M l-Glu at 45 degrees C. Furthermore, the strain could be reused at least three cycles in 2 M crude l-Glu with an average productivity of 40.94 g L(-1) h(-1). The total GABA yield reached 614.15 g L(-1) with a molar yield over 99 %, which represented the highest GABA production ever reported. The whole-cell bioconversion system allowed us to achieve a promising cost-effective resource for GABA in industrial application. PMID- 27247888 TI - Detection of the rs10250202 polymorphism in protection of telomeres 1 gene through introducing a new restriction enzyme site for PCR-RFLP assay. AB - Human protection of telomeres 1 (POT1) gene is a single stranded telomere binding proteins with a critical role in ensuring chromosome stability. There have been variants of POT1 gene, and the polymorphisms of POT1 gene were associated with some diseases. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) is a traditional method to detect the single nucleotide polymorphism (SNP), and it can be used to detect the polymorphism of rs10250202. But the restriction enzymes required for the detection of the polymorphism of rs10250202 are expensive. So we designed a novel PCR-RFLP assay for genotyping the POT1 rs10250202 SNP. In the study, a new restriction enzyme cutting site was created by created restriction site PCR (CRS-PCR), and the restriction enzyme BclI for CRS-PCR was cheaper than other enzymes. After detecting Han Chinese workers, Allele frequencies were found to be 51.54 % for allele A and 48.46 % for allele C respectively. The PCR results were confirmed by DNA sequencing. CRS-PCR provides a simple, low-cost, practical, and reproducible method. PMID- 27247889 TI - Edge-aware spatial-frequency extrapolation for consecutive block loss. AB - To improve the spatial error concealment (SEC) for consecutive block loss, an edge-aware spatial-frequency extrapolation (ESFE) algorithm and its edge-guided parametric model are proposed by selectively incorporating the Hough-based edge synthesis into the frequency-based extrapolation architecture. The dominant edges that cross the missing blocks are firstly identified by the Canny detector, and then the robust Hough transformation is utilized to systematically connect these discontinuous edges. During the generation of edge-guided parametric model, the synthesized edges are utilized to divide the missing blocks into the structure preserving regions, and thus the residual error is reliably reduced. By successively minimizing the weighted residual error and updating the parametric model, the known samples are approximated by a set of basis functions which are distributed in a region containing both known and unknown samples. Compared with other state-of-the-art SEC algorithms, experimental results show that the proposed ESFE algorithm can achieve better reconstruction quality for consecutive block loss while keeping relatively moderate computational complexity. PMID- 27247891 TI - Keratinolytic activities of alkaliphilic Bacillus sp. MBRL 575 from a novel habitat, limestone deposit site in Manipur, India. AB - Microbial degradation of keratinous wastes is preferred over physicochemical methods as the latter is costlier and not eco-friendly. Novel habitats are promising for discovery of new microbial strains. Towards discovery of novel keratinolytic bacteria, screening of bacterial strains from a novel limestone habitat in Hundung, Manipur, India was done and a promising isolate, MBRL 575, was found to degrade native chicken feather efficiently. It could grow over a broad pH range (Langeveld et al. in J Infect Dis 188:1782-1789, 2003; Park and Son in Microbiol Res 164:478-485, 2009; Zaghloul et al. in Biodegradation 22:111 128, 2011; Takami et al. in Biosci Biotechnol Biochem 56:1667-1669, 1992; Riffel et al. in J Biotechnol 128:693-703, 2007; Wang et al. in Bioresour Technol 99:5679-5686, 2008) and in presence of 0-15 % NaCl. Based on phenotypic characterization and 16S rRNA gene sequence analysis, the new keratinolytic limestone isolate was identified as Bacillus sp. MBRL 575. It produced 305 +/- 12 U/ml keratinase and liberated 120 +/- 5.5 mg of soluble peptides and 158 +/- 4 mg of amino acids per gram of feather after 48 h of incubation at 30 degrees C in chicken feather medium. The strain could also degrade feathers of other species besides chicken. The cell-free enzyme was also able to degrade feather. Citrate and soybean meal were found to be the best carbon and nitrogen supplements for enhanced enzyme, soluble peptide and amino acid production. In addition to keratinolytic activity, MBRL 575 also exhibited antagonistic activity against two major rice fungal pathogens, Rhizoctonia oryzae-sativae (65 %) and Rhizoctonia solani (58 %). PMID- 27247890 TI - Impact of central obesity on prognostic outcome of triple negative breast cancer in Chinese women. AB - PURPOSE: To evaluate the prognostic effect of central obesity on triple negative breast cancer (TNBC). METHODS: 206 TNBC patients treated from June 2006 to June 2015 were enrolled retrospectively. Body mass index (BMI) >=25 kg/m(2) was the standard of obesity and waist circumference >=80 cm was the standard of central obesity. Patient and tumor characteristics were compared between obesity categories. Survival differences between obesity categories were assessed with log-rank test in the univariate analysis and prognostic factors were then investigated by Cox regression analysis. RESULTS: 81 cases were with obesity (39.3 %). 71 cases were with central obesity (34.5 %). Patients with obesity or central obesity tended to be older (P = 0.022 for obesity; P = 0.013 for central obesity) and to have larger tumor size (P = 0.027 for obesity; P = 0.027 for central obesity). By Cox regression analysis, central obesity (DFS: HR 1.759; 95 % CI 1.009-3.065; P = 0.046. OS: HR 2.297; 95 % CI 1.184-4.456; P = 0.014) was identified as an independent prognostic factor. For central obesity with BMI >= 25 kg/m(2), the prognostic effect was more apparent (DFS: HR 1.845; 95 % CI 1.059 3.212; P = 0.031. OS: HR 2.377; 95 % CI 1.230-4.593; P = 0.010). CONCLUSION: Central obesity, especially with high BMI, was an independent prognostic factor for TNBC. PMID- 27247892 TI - Isolation and characterization of Burkholderia sp. strain CCA53 exhibiting ligninolytic potential. AB - Microbial degradation of lignin releases fermentable sugars, effective utilization of which could support biofuel production from lignocellulosic biomass. In the present study, a lignin-degrading bacterium was isolated from leaf soil and identified as Burkholderia sp. based on 16S rRNA gene sequencing. This strain was named CCA53, and its lignin-degrading capability was assessed by observing its growth on medium containing alkali lignin or lignin-associated aromatic monomers as the sole carbon source. Alkali lignin and at least eight lignin-associated aromatic monomers supported growth of this strain, and the most effective utilization was observed for p-hydroxybenzene monomers. These findings indicate that Burkholderia sp. strain CCA53 has fragmentary activity for lignin degradation. PMID- 27247893 TI - Reconstruction of acetabulum in revision total hip arthroplasty for pelvic discontinuity: report of a difficult case requiring four revision arthroplasty. AB - BACKGROUND: Massive bone defects of the acetabulum with pelvic discontinuity are one of the major problems in revision total hip arthroplasty. Several techniques have been described for repair of acetabular defect; however, reconstruction of acetabulum with massive bone defect is still a major problem. We describe a patient who required four revision total hip arthroplasty during a 24-year period. FINDINGS: The acetabulum with pelvic discontinuity was successfully reconstructed by stabilization of the posterior column with a plate commonly used for fracture treatment, and stabilization of the anterior column by reinforcement device commonly used for acetabular reconstruction. Fixation of both acetabular columns provided significant improvement of component stability. CONCLUSIONS: In the case of pelvic discontinuity with massive acetabular bone defect, reconstruction by stabilizing both acetabular columns using reconstruction plate and KT plate is one of the better surgical options. PMID- 27247894 TI - An enzyme complex increases in vitro dry matter digestibility of corn and wheat in pigs. AB - Two experiments were conducted to determine the effects of enzyme complex on in vitro dry matter (DM) digestibility for feed ingredients. The objective of experiment 1 was to screen feed ingredients that can be effective substrates for an enzyme complex, mainly consisted of beta-pentosanase, beta-glucanase and alpha amylase, using in vitro digestibility methods. In experiment 1, the test ingredients were three grain sources (barley, corn and wheat) and six protein supplements (canola meal, copra expellers, cottonseed meal, distillers dried grains with solubles, palm kernel expellers and soybean meal). In vitro ileal and total tract digestibility (IVID and IVTTD, respectively) of DM for test ingredients were determined. In vitro digestibility methods consisted of two- or three-step procedure simulating in vivo digestion in the pig gastrointestinal tracts with or without enzyme complex. As the enzyme complex added, the IVID of DM for corn and wheat increased (p < 0.05) by 5.0 and 2.6 percentage unit, respectively. The IVTTD of DM for corn increased (p < 0.05) by 3.1 percentage unit with enzyme complex addition. As the effect of enzyme complex was the greatest in corn digestibility, corn grains were selected to determine the in vitro digestibility of the fractions (starch, germ, hull and gluten) that maximally respond to the enzyme complex in experiment 2. The IVID of DM for corn starch, germ and hull increased (p < 0.05) by 16.0, 2.8 and 1.2 percentage unit, respectively. The IVTTD of DM for corn starch and hull also increased (p < 0.05) by 8.6 and 0.9 percentage unit, respectively, with enzyme complex addition. In conclusion, the enzyme complex increases in vitro DM digestibility of corn and wheat, and the digestibility increments of corn are mainly attributed to the increased digestibility of corn starch. PMID- 27247895 TI - Late recurrence of breast carcinoma metastasis to the hypopharynx: a case report. AB - BACKGROUND: We report a rare case of a patient with a hypopharyngeal metastasis from breast cancer. CASE PRESENTATION: Isolated breast cancer metastasis to the hypopharynx has been previously reported in only one autopsy case. Herein, we report a 56-year-old woman with metastases to the hypopharynx almost 24 years after receiving a mastectomy and chemotherapy to treat primary breast carcinoma. We believe that she is the first patient to be treated for metastatic breast carcinoma to the hypopharynx. The hypopharyngeal tumor reduced in size after administration of an oral aromatase inhibitor. The patient has remained alive with a preserved larynx for three years. CONCLUSIONS: Breast cancer metastasis to the hypopharynx is an extremely rare event. PMID- 27247896 TI - High frequency of methicillin-resistant Staphylococcus aureus in Peshawar Region of Pakistan. AB - Staphylococcus aureus is an increasing problem in clinical practice because of reduced susceptibility to available antibiotics. The objective of the study was to determine the frequency of Methicillin-resistant S. aureus (MRSA) in Peshawar, Pakistan. Clinical isolates of S. aureus were subjected to determination of antibiotic resistance, MICs and inducible clindamycin resistance (ICR). Out of total 280 S. aureus isolates, the frequency of MRSA was 36.1 % (n = 101). MRSA infection was found higher among the age group 50-59 years (60.71 %, OR 3.09), followed by 20-29 years (47.5 %, OR 1.74). Frequency of MRSA in female and male was 39.8 and 34 % respectively. MRSA was more frequent in blood specimens (48.7 %, OR 2.14). The frequency of community and hospital acquired MRSA was 42 and 34.8 % respectively. MRSA showed high resistance (100 %) to penicillin and cefoxitin followed by erythromycin (99 %). While MRSA exhibited 100 % susceptibility to vancomycin and linezolid. We have also found 7 vancomycin intermediate sensitive S. aureus (VISA) isolates. ICR was observed in 15.84 % (n = 16) of MRSA isolates. It is concluded that MRSA is potential threat to public health in Peshawar. Vancomycin and linezolid could be prescribed as a drug of choice in treating MRSA associated infections. In addition, ICR should be routinely checked to avoid clindamycin treatment failure. PMID- 27247897 TI - A new web-based framework development for fuzzy multi-criteria group decision making. AB - Fuzzy multi-criteria group decision making (FMCGDM) process is usually used when a group of decision-makers faces imprecise data or linguistic variables to solve the problems. However, this process contains many methods that require many time consuming calculations depending on the number of criteria, alternatives and decision-makers in order to reach the optimal solution. In this study, a web based FMCGDM framework that offers decision-makers a fast and reliable response service is proposed. The proposed framework includes commonly used tools for multi-criteria decision-making problems such as fuzzy Delphi, fuzzy AHP and fuzzy TOPSIS methods. The integration of these methods enables taking advantages of the strengths and complements each method's weakness. Finally, a case study of location selection for landfill waste in Morocco is performed to demonstrate how this framework can facilitate decision-making process. The results demonstrate that the proposed framework can successfully accomplish the goal of this study. PMID- 27247898 TI - Effect of risk factors on the prevalence of influenza infections among children of slums of Dhaka city. AB - BACKGROUND: Influenza viruses may cause severe acute respiratory illness among human population. People of densely populated areas, e.g., slum, are mostly affected by influenza viruses. Although potential vaccines to influenza viruses have been developed, infection rate is still high, therefore, increase the morbidity and mortality rate in slum areas. To treat these infections, slum dwellers including children and mothers do not get proper medication as well as vaccination. Hence, prevention remains to be the only mean to tackle such infections. Herein, we determined the prevalence of influenza infections among nutritionally deprived children and mothers of slum areas in Dhaka city and demonstrated the association with different risk factors like age, gender and socio-economic status. RESULTS: Nasopharyngeal swab samples and a short demography of all the participants suffering from influenza-like illness (ILI) were collected. The samples were subjected to RNA extraction and then real-time RT-PCR to detect influenza viruses. Among the ILI patients, about 87.9 % did not have knowledge about influenza infections and 80.5 % did not cover their noses during coughing as well as sneezing. Children were significantly infected by both influenza A and influenza B viruses, suggesting their vulnerability to these infections. Additionally, among the children with ILI, influenza infections were significantly associated with age below or equal to three years, very poor family incomes, practicing unhygienic habits and nutritional deficiency. CONCLUSIONS: This study suggests that proper vaccination, improved sanitary conditions and nutritional diet may help reduce the risk of influenza infections in slum areas. PMID- 27247899 TI - Vogt-Koyanagi-Harada disease following BCG vaccination and tuberculosis. AB - INTRODUCTION: To describe the characteristics, diagnosis, and treatment of the first documented case of Vogt-Koyanagi-Harada (VKH) disease following BCG vaccination (Patient 1) and the first documented case of both VKH disease and tuberculosis (Patient 2). Two patients were diagnosed with VKH disease and monitored using fundus photography, fundus autofluorescence, fluorescein angiography (FA), spectral-domain optical coherence tomography, and enhanced depth imaging optical coherence tomography (EDI-OCT). CASE DESCRIPTION: A 39-year old patient (Patient 1) had bilateral granulomatous anterior uveitis and serous retinal detachment. FA showed multiple punctuate hyperfluorescent lesions and multilobular pools of dye. EDI-OCT revealed serous retinal detachment, subretinal septa, and cystoid spaces. A 40-year-old woman (Patient 2) presented with a 3 week history of decreased vision, headache and tinnitus. Fundus examination showed bilateral disc swelling with serous retinal detachment and retinal folds. She had been diagnosed with tuberculosis. EDI-OCT showed fluctuation of the internal limiting membrane (ILM), retinal folds, retinal pigment epithelial (RPE) Bruch membrane undulation, choroidal folds, serous retinal detachment. Both of the patients received high dosage of steroid treatment during the diagnosis. A fast recovery in VKH symptoms was observed following the treatment. DISCUSSION AND EVALUATION: Immunological mechanisms and dysregulation of the immune system may play a significant role in the association between VKH disease and BCG. CONCLUSIONS: EDI-OCT imaging demonstrated structural changes in the photoreceptor layer, RPE-Bruch membrane, choroid, outer retina, ILM in acute VKH. PMID- 27247900 TI - Kullback-Leibler divergence and the Pareto-Exponential approximation. AB - Recent radar research interests in the Pareto distribution as a model for X-band maritime surveillance radar clutter returns have resulted in analysis of the asymptotic behaviour of this clutter model. In particular, it is of interest to understand when the Pareto distribution is well approximated by an Exponential distribution. The justification for this is that under the latter clutter model assumption, simpler radar detection schemes can be applied. An information theory approach is introduced to investigate the Pareto-Exponential approximation. By analysing the Kullback-Leibler divergence between the two distributions it is possible to not only assess when the approximation is valid, but to determine, for a given Pareto model, the optimal Exponential approximation. PMID- 27247901 TI - Aspergillus leaf spot of field bindweed (Convolvulus arvensis L.) caused by Aspergillus niger in China. AB - Leaf spot was found on field bindweed (Convolvulus arvensis L.) in Shihezi City, Xinjiang Province, China, during the summer of 2015. Pathogens were isolated from the infected leaves of field bindweed and identified as Aspergillus niger based on morphological and molecular analyses (internal transcribed spacer rDNA and beta-tubulin gene). A pathogenicity test confirmed that Aspergillus niger caused the healthy leaves of field bindweed to become diseased. To our knowledge, this is the first report of field bindweed infected naturally by A. niger. PMID- 27247902 TI - Expression of scavenger receptor A in rat's liver tissue during acute obstructive cholangitis and its significance. AB - OBJECTIVE: Acute obstructive cholangitis (AOC) is a severe disease that leads to sepsis, shock and multiple organ dysfunction syndrome. Liver is the largest and the major organ for the defense mechanisms during the sepsis. Our aim was to investigate the expression of scavenger receptor A (SRA) in rat's liver tissue during AOC and its relation with the inflammatory mediators and hepatic injury caused by endotoxins. METHODS: Ninety Wistar rats were randomly divided into three equal groups. In group one, the choledochus were ligagted and Escherichia coli O111B4 injected into it to produce AOC model. Group two had choledochus ligated and group three had sham surgery. Six animals from each group were sacrificed at 0, 3, 6, 12 and 24 h for comparative analysis of endotoxins, tumor necrosis factor-alpha, interleukin-6 in plasma and expression of SRA protein and SRA mRNA in liver tissue. The P < 0.05 was considered significant. Ethical approval was obtained. RESULTS: The plasma endotoxins, tumor necrosis factor alpha and interleukin-6 levels in AOC rats increased progressively with time. The SRA protein and SRA mRNA expression decreased with time. The differences among groups were significant (P < 0.01). Liver histopathology showed gradually aggravated hepatic injury with neutrophil infiltration, degeneration and necrosis of hepatocytes. CONCLUSION: In AOC, the expression of SRA in liver gradually decreased with progressive increase in level of plasma endotoxins and hepatic injury suggesting its importance in the defense mechanism. PMID- 27247903 TI - Validation of the Mongolian version of the SF-36v2 questionnaire for health status assessment of Mongolian adults. AB - BACKGROUND: Ulaanbaatar, Mongolia, is one of the world's worst air-polluted cities, but effects of this air pollution on the population health status have not yet been evaluated. Therefore, we developed a Mongolian version of the SF 36v2 questionnaire to investigate the health status of Mongolian population. METHODS: Health checkups were conducted in Ulaanbaatar and the health status was measured using a Mongolian translated version of the SF-36v2 questionnaire. The reliability and validity of the Mongolian SF-36v2 questionnaire, and the relationship between health status and respiratory condition were examined. RESULTS: Factor analysis of the Mongolian SF-36v2 questionnaire showed that the "Role-physical" and "Role-emotional" were classified into a single subscale. The "Mental health" and "Vitality" were each divided into two subscales. Cronbach's alpha and intraclass correlation coefficient (ICC) for reproducibility were >0.7, except for "General health perceptions" (Cronbach's alpha and ICC < 0.7), "Social functioning" (Cronbach's alpha < 0.7), and "Vitality" (ICC < 0.7). The SF-36v2 subscales and the corresponding items of the COOP/WONCA charts were correlated, and subjects with respiratory symptoms showed lower SF-36v2 scores compared to normal subjects, suggesting external validity. Subjects with respiratory symptoms showed significantly lower scores for the majority of the SF-36v2 subscales than those with normal lung function. In subjects with combined ventilatory impairment, "Physical functioning", "Role-physical", "Bodily pain", and "Vitality" scores were significantly lower than those with normal lung function. CONCLUSIONS: The Mongolian version of the SF-36v2 questionnaire provides substantial reliability and validity, and is useful for evaluating the health status of Mongolian adults with ventilatory impairment. Health status measured by SF-36v2 was significantly aggravated by combined ventilatory impairment when compared with normal lung function. PMID- 27247904 TI - Carriage rate and methicillin resistance of Staphylococcus aureus in food handlers in Kars City, Turkey. AB - The aim of this study was determine carriage rate and methicillin resistance of Staphylococcus aureus among food handlers. Samples were collected by swabbing the mouth, nasal cavity and hands of food workers. The isolation of S. aureus was performed using a culture method and verified by using a genetic method (PCR). The presence of mecA gene was analysed by PCR. The fourteen antimicrobial disks were also used to determine antimicrobial susceptibility of S. aureus. The 56 out of 282 isolates were identified as S. aureus. It is found that 10 workers out of 28 carried S. aureus in their nasal cavity while 4 and 3 workers out of 21 carriered S. aureus in mouth and hands respectively. None of the isolates carried mecA genes and also their antibacterial susceptibility test for methicillin resistance, using cefoxitin (30 ug), shown that all the isolates was susceptible to methicillin. In conclusion, the results of the present study indicated that the prevalence of antibiotic resistance of S. aureus strains isolated from food handlers was low. However carriage rate of S. aureus among food handlers was quite high. PMID- 27247905 TI - Entire solutions of nonlinear differential-difference equations. AB - In this paper, we describe the properties of entire solutions of a nonlinear differential-difference equation and a Fermat type equation, and improve several previous theorems greatly. In addition, we also deduce a uniqueness result for an entire function f(z) that shares a set with its shift [Formula: see text], which is a generalization of a result of Liu. PMID- 27247907 TI - Seasonal dynamics of the genus: Planktoniella Schutt in the estuarine waters of Indian Sundarbans. AB - The study highlights the dynamics and morphological characteristics of the Genus Planktoniella Schutt. The two available species P. sol (Wallich) Schutt. and P. blanda (Schmidt) Syvertsen and Hasle are important components of the phytoplankton assemblage in the estuarine system of Indian Sundarbans and also marine systems elsewhere. The sampling sites for the purpose of this study include four different spots along a riverine stretch in the estuarine region adjacent to the Tiger Reserve in the Indian Sundarbans flowing into the Bay of Bengal. Integrated phytoplankton samples were preserved for the purpose from composite water samples from each site. The water samples were analysed in field for determining pH, temperature, salinity, conductivity, TDS, turbidity and DO and subsequent to treatment and processing, the samples were microscopically analysed in the laboratory. Significant negative correlation of cell count of both species found with respect to temperature and turbidity. P. sol versus temperature (significant at alpha = 0.01, p = 0.001) and P. blanda versus temperature (significant at alpha = 0.05, p = 0.037); P. sol versus turbidity (at alpha = 0.05, p = 0.019) and P. blanda versus turbidity (at alpha = 0.05, p = 0.019). Significant positive correlation found with respect to DO and as correlation between the two species themselves. A model has been generated for each of the two species with temperature, turbidity and DO as predictor variables and the two species of Planktoniella as response variables. The influence of other dominant phytoplankton in the samples has also been considered with Pearson correlation computed for each set of species. PMID- 27247906 TI - The protective effect of hydromorphone to ischemia in rat glial cells. AB - BACKGROUND: Ischemic insults during operation can cause ischemic-reperfusion injuries in brain as well as memory impairments. Total intravenous anesthesia (TIVA) is the preferred anesthetic method in brain surgery, as it utilizes motor evoked potential monitoring. And the use of opioids is common in TIVA. However there are few studies about ischemic protective effect of opioids to glial cells. METHODS: We used mixed cultures of rat glial cells, which were harvested from the brain of 1-day old rat. We divided the experimental groups according to their hydromorphone conditioning period: (a) pre-culture, (b) per-culture, or (c) pre- and per-culture. We measured the levels of the reactive oxygen species (ROS) induced by tert-butyl hydroperoxide (TBH) using flow cytometry. The ROS levels in the glial cells were also measured after the administration of 100 nM hydromorphone and selective opioid receptor antagonists. RESULTS: The ROS levels were reduced in the hydromorphone-treated group, as compared to the control group (only TBH treated). There were no differences between pre-conditioned and per conditioned groups. However, the ROS levels were more reduced in pre- and per conditioned group compared to pre-conditioned or per-conditioned only groups. Furthermore, selective antagonists for the delta, kappa, or mu opioid receptor partially negated the hydromorphone effect. CONCLUSION: This study demonstrated that hydromorphone can have additional protective effects on oxidative stress when pre- and per-conditioning is combined. Furthermore we proved that MU, delta, kappa opioid receptors participate in protective mechanism of hydromorphone to glial cells. PMID- 27247908 TI - Scientists' personality, values, and well-being. AB - BACKGROUND: Scientists play an important role in modern society. However, only a small number of their psychological characteristics, such as personality traits, have been investigated; hence, further investigation is required. RESULTS: In this study, scientists (n = 24) and non-scientist controls (n = 26) were assessed with respect to their five-factor personality traits, 10 basic values, and subjective well-being (subjective happiness and sense of purpose in life). Compared with the non-scientist control group and with normative data of laypeople, the scientists consistently exhibited greater openness (i.e., traits related to curiosity and intelligence), self-direction (i.e., values related to the pursuit of curiosity, creativity, and autonomous action), happiness, and sense of purpose in life. CONCLUSIONS: These data indicate that scientists possess personality traits and values suitable for a career in science, from which they also derive subjective well-being. PMID- 27247909 TI - Impacts of foreign direct investment on efficiency in Swedish manufacturing. AB - A number of studies have found that foreign direct investment (FDI) can have positive impacts on productivity. However, while FDI has clearly positive impacts on technology transfers, its effects on resource use within firms is less clear and, in principle, efficiency losses might offset some of the productivity gains associated with improved technologies. In this paper, we study the impacts of FDI on efficiency in Swedish manufacturing. We find that foreign ownership has positive impacts on efficiency, supporting the earlier findings on productivity. PMID- 27247910 TI - Osteolysis and Cervical Cord Compression Secondary to Silicone Granuloma Formation around a Dorsal Spinal Cord Stimulator: A Case Report. AB - Spinal cord stimulators (SCSs) have long been in use as a modality for the management of numerous pain pathologies. Along with commonly anticipated morbidities such as displacement, failure (due to fracture or breakage), or infection, there have also been rare but well-documented complications of fibrous scarring, resulting in spinal cord compression. This is the first known case that demonstrates osteolysis and bony destruction of the vertebrae adjacent to the SCS along with the foreign-body granulomatous reaction. A 61-year-old man who underwent prior posterior cervical implantation with an SCS followed by multiple revisions presented with progressive paresthesias, numbness, and weakness of his upper extremities 10 years later. The SCS was removed followed by decompression, and instrumented fusion of the cervical spine. Histopathologic analysis reveals foreign-body reaction to the SCS and its silicone debris. Tissue cultures were negative for bacterial, fungal, or mycobacterial infection. No malignancy was seen. The current case illustrates the inherent possibility of foreign-body granulomatous reactions with SCS and its silicone particulate matter, made unique in this instance by the associated bony destruction of the adjacent vertebrae. PMID- 27247911 TI - Resolution of Chronic Aspiration Pneumonitis Following Endoscopic Endonasal Repair of Spontaneous Cerebrospinal Fluid Fistula of the Skull Base. AB - Spontaneous cerebrospinal fluid (CSF) rhinorrhea due to a skull base defect requires prompt diagnosis and treatment. Multiple surgical options are available for repairing the fistula, including the two-layer "fascial apposition" method and use of a pedicled nasal-septal flap. A 44-year-old obese woman presented with 4 months of progressive cough, exertional dyspnea, hoarseness, and intermittent fluid drainage from the right nostril. Chest computed tomography (CT) imaging and bronchoscopy showed chronic pneumonitis, which was confirmed by pulmonary wedge resection. CT and magnetic resonance imaging of the skull base, as well as laboratory analysis of the nasal fluid for beta2-transferrin, confirmed a skull base defect causing CSF rhinorrhea. During surgery, insertion of a lumbar drain with the intrathecal fluorescein administration was performed, followed by endoscopic endonasal repair using an autologous fascial apposition graft and pedicled nasal-septal flap. Both the CSF leak and the pulmonary complications resolved following the operation with no symptoms at 11-month follow-up. This is the first reported case of spontaneous CSF rhinorrhea complicated by chronic aspiration and pneumonitis. Increased diagnostic complexity due to chronic pulmonary complications resulted in unnecessary interventions and treatment delays. Prompt recognition of spontaneous CSF leaks is essential to prevent potentially harmful complications. PMID- 27247912 TI - Sunitinib as Neoadjuvant Chemotherapy in the Management of Metastatic Renal Cell Carcinoma Mimicking a Glomus Vagale Tumor in the Head and Neck: A Case Report and Review of Literature. AB - Background Metastatic renal cell carcinoma (RCC) of the head and neck with intracranial extension is rare and may pose difficulties to the diagnosis and management. Method We describe a unique case of a 76-year-old man with a metastatic RCC to the neck and lateral skull base with intracranial extension presenting with Collet-Sicard syndrome 8 years after initial diagnosis. The radiologic features were consistent with the diagnosis of a glomus vagale tumor on the basis of clinical and radiologic features. Results Despite radiotherapy, the intracranial extension progressed in size, resulting in early hydrocephalus. Sunitinib, a novel tyrosine kinase inhibitor, was instituted to treat the glomus vagale tumor with a marked reduction in tumor volume and resolution of the early hydrocephalus. The surgical resection of the tumor with its intracranial extension was achieved without additional postoperative morbidity. The histopathologic diagnosis surprisingly demonstrated metastatic RCC. Conclusion We present a case of metastatic RCC to the head and neck region mimicking a glomus vagale tumor and describe the first use of sunitinib as a neoadjuvant chemotherapy to achieve a single-stage radical en bloc resection of the tumor mass. PMID- 27247913 TI - Intensive Care at Home: An Opportunity or Threat. PMID- 27247914 TI - Comparing Clonidine and Lidocaine on Attenuation of Hemodynamic Responses to Laryngoscopy and Tracheal Intubation in Controlled Hypertensive Patients: A Randomized, Double-Blinded Clinical Trial. AB - BACKGROUND: Hemodynamic fluctuations in response to laryngoscopy and tracheal intubation and their potential hazards have been well-recognized, especially in hypertensive patients. Many drugs in various combinations have been used to attenuate these adverse responses. OBJECTIVES: We conducted a study to compare lidocaine with clonidine on the attenuation of hemodynamic responses to laryngoscopy and tracheal intubation, in controlled hypertensive patients undergoing general anesthesia. PATIENTS AND METHODS: Eighty-six patients of American society of anesthesiologists (ASA) class II, who were aged 18 to 65 years-old and were scheduled for elective surgeries under general anesthesia, were included. The patients were randomly divided into two equal groups. The clonidine group received 0.2 mg oral clonidine 90 minutes before surgery and the lidocaine group received a placebo tablet at the same time. All patients in both groups were anesthetized with the same technique, including: intravenous fentanyl 3 mcg/kg, sodium thiopental 5 mg/kg, and atracurium 0.5 mg/kg. The lidocaine group received 1.5 mg/kg lidocaine but the clonidine group received the same volume of saline ninety seconds before intubation. Hemodynamic parameters were recorded before intubation and 1, 3, 5, and 10 minutes after endotracheal intubation. RESULTS: There were no significant differences between the two groups' hemodynamic parameters, including heart rate and systolic, diastolic, and mean arterial blood pressures at the measured points. There were also no significant differences within each group in hemodynamic responses at the measured points (P > 0.05). Twenty patients in the clonidine and three patients in the lidocaine group complained of mouth dryness (P = 0.001). Fourteen patients in the clonidine and four patients in the lidocaine group had bradycardia (P = 0.008). Nineteen patients in the clonidine and six patients in the lidocaine group had orthostatic hypotension (P = 0.002). CONCLUSIONS: There were no statistical differences between oral clonidine and intravenous lidocaine regarding attenuation of hemodynamic responses after tracheal intubation in controlled hypertensive patients, although the rate of complications including mouth dryness, bradycardia, and orthostatic hypotension was significantly higher in the clonidine group before induction of anesthesia. PMID- 27247915 TI - Comparison of the Effects of Low-Dose Midazolam, Magnesium Sulfate, Remifentanil and Low-Dose Etomidate on Prevention of Etomidate-Induced Myoclonus in Orthopedic Surgeries. AB - BACKGROUND: Etomidate is a potent hypnotic agent with several desirable advantages such as providing a stable cardiovascular profile with minimal respiratory adverse effects and better hemodynamic stability compared with other induction agents. This drug is associated, however, with myoclonic movements which is characterized by a sudden, brief muscle contractions as a disturbing side-effect. OBJECTIVES: The present study was designed to compare the effectiveness of low- dose midazolam, magnesium sulfate, remifentanil and low dose etomidate to suppress etomidate-induced myoclonus in orthopedic surgery. PATIENTS AND METHODS: A double-blind clinical trial study was conducted in an academic hospital from September 2014 to August 2015. Two hundred and eighty-four eligible patients, American society of anesthesiologists class I - II, scheduled for elective orthopedic surgery were randomly allocated into four equal groups (n = 71). They received premedication with intravenous low-dose midazolam 0.015 mg/kg, magnesium sulfate 30 mg/kg, remifentanil 1 MUg/kg and low-dose etomidate 0.03 mg/kg two minutes before induction of anesthesia with 0.3 mg/kg intravenous etomidate. Then the incidence and intensity of myoclonus were evaluated on a scale of 0 - 3; 0 = no myoclonus; 1 = mild (movement at wrist); 2 = moderate (movement at arm only, elbow or shoulder); and 3 = severe, generalized response or movement in more than one extremity, within ninety seconds. Any adverse effect due to these premedication agents was recorded. RESULTS: The incidence and intensity of myoclonus were significantly lower in the low-dose etomidate group. The incidence rates of myoclonus were 51 (71.85%), 61 (85.9%), 30 (42.3%) and 41 (57.7%), and the percentages of patients who experienced grade III of myoclonus were 30 (58.8%), 32 (52.5%), 9 (30%) and 14 (34.1%) in the midazolam, magnesium sulfate, etomidate and remifentanil groups, respectively. The incidence and intensity of myoclonus were significantly lower in the low-dose etomidate group (P = 0.0001). No notable adverse effect was detected in our patients during the study period. CONCLUSIONS: Intravenous etomidate 0.03 mg/kg prior to induction can effectively reduce the incidence and severity of myoclonus linked to etomidate. PMID- 27247916 TI - Anesthetic Considerations of Sporadic Inclusion Body Myositis in an Elderly Man With Orthopedic Trauma. AB - INTRODUCTION: Sporadic inclusion body myositis (IBM) is an inflammatory myopathy characterized by progressive asymmetric extremity weakness, oropharyngeal dysphagia, and the potential for exaggerated sensitivity to neuromuscular blockers and respiratory compromise. The authors describe their management of a patient with IBM undergoing urgent orthopedic surgery. CASE PRESENTATION: An 81 year-old man with IBM suffered a left intertrochanteric femoral fracture after falling down stairs. His IBM caused progressive left proximal lower extremity, bilateral distal upper extremity weakness (left > right), and oropharyngeal dysphagia (solid food, pills). He denied dyspnea, exercise intolerance, and a history of aspiration. Because respiratory insufficiency resulting from diaphragmatic dysfunction and prolonged duration of action of neuromuscular blockers may occur in IBM, the authors avoided using a neuromuscular blocker. After applying cricoid pressure, anesthesia was induced using intravenous lidocaine, propofol, remifentanil followed by manual ventilation with inhaled sevoflurane in oxygen. Endotracheal intubation was accomplished without difficulty; anesthesia was then maintained using remifentanil and sevoflurane. The fracture was repaired with a trochanteric femoral nail. The patient was extubated without difficulty and made an uneventful recovery. CONCLUSIONS: In summary, there is a lack of consensus about the use of neuromuscular blockers in patients with IBM. The authors avoided these drugs and were able to easily secure the patient's airway and maintain adequate muscle relaxation using a balanced sevoflurane-remifentanil anesthetic. Clinical trials are necessary to define the pharmacology of neuromuscular blockers in patients with IBM and determine whether use of these drugs contributes to postoperative respiratory insufficiency in these vulnerable patients. PMID- 27247917 TI - Renal injury, nephrolithiasis and Nigella sativa: A mini review. AB - OBJECTIVE: The incidence and prevalence of kidney stone is increasing worldwide. After the first recurrence the risk of subsequent relapses is higher and the time period between relapses is shortened. Urinary stones can be severely painful and make a huge economic burden. The stone disease may increase the vulnerability of patients to other diseases such as renal failure. Medicinal herbs are rich sources of antioxidants which are increasingly consumed globally for their safety, efficacy and low price. Nigella sativa is a spice plant that is widely used for prevention and treatment of many ailments in Muslim countries and worldwide. This review aims at investigation of the effects of Nigella sativa on renal injury and stone formation. MATERIALS AND METHODS: The scientific resources including PubMed, Scopus, and Google scholar were searched using key words such as: nephrolithiasis, urolithiasis, kidney/renal stone, renal injury, renal failure, urinary retention and black seed, black cumin, Nigella sativa and thymoquinone. RESULTS: N. sativa and its main component, thymoquinone showed positive effects in prevention or curing kidney stones and renal failure through various mechanism such as antioxidative, anti-inflammatory, anti-eicosanoid and immunomodulatory effects. The putative candidate in many cases has been claimed to be thymoquinone but it seems that at least in part, particularly in kidney stones, the herbal melanin plays a role which requires further investigation to prove. CONCLUSION: N. sativa and its components are beneficial in prevention and curing of renal diseases including nephrolithiasis and renal damages. PMID- 27247918 TI - Gastrointestinal effects of Nigella sativa and its main constituent, thymoquinone: a review. AB - Gastrointestinal (GI) diseases affect a large number of people all over the world. Uncontrolled acid secretion and occurrence of gastric ulcers are common disorders of GI tract which pose serious problems to human health. Many synthetic drugs have been used to treat GI disorders but a definite cure has not been discovered so far and the available medications cause several side effects. Nigella sativa (N. sativa) (Ranunculacea) has several therapeutic effects which are attributed to its constituents like nigellicine, nigellidine, thymoquinone, dithymoquinone, thymol and carvacrol. Several beneficial pharmacological properties of this plant such as anti-oxidant, anti-bacterial, anti-histaminic, anti-hypertensive, hypoglycemic, anti-fungal, anti-inflammatory, anti-cancer and immunomodulatory effects were reported and different therapeutic properties such as reliving bronchial asthma, jaundice, hydrophobia, paralysis, conjunctivitis, piles, skin diseases, anorexia, headache, dysentery, infections, obesity, back pain, hypertension and gastrointestinal problems, have been described for the seeds of N. sativa and its oil. The present review provides a detailed summery of scientific researches regarding gastrointestinal effect of N. sativa and its main constituent, thymoquinone. PMID- 27247919 TI - A review on the inhibitory potential of Nigella sativa against pathogenic and toxigenic fungi. AB - Nigella sativa (N. sativa) grows in various parts of the world, particularly in Iran. It has been traditionally used as a folk remedy to treat a number of diseases. The seeds of this plant contain moisture, proteins, carbohydrates, crude fiber, alkaloids, saponins, ash, fixed oils and essential oil. The major components of the essential oil are thymoquinone, p-cymene, trans-anethole, 2 methyl-5(1-methyl ethyl)-Bicyclo[3.1.0]hex-2-en and gamma-terpinene. So far, several pharmacological effects such as anti-oxidant, anti-inflammatory, anti cancer and anti-microbial have been reported for N. sativa or its active compounds. Thymoquinone, thymohydroquinone and thymol are the most active constituents which have different beneficial properties. The oil, extracts and some of N. sativa active components possessed moderate in vitro and in vivo inhibitory activity against pathogenic yeasts, dermatophytes, non-dermatophytic filamentous fungi and aflatoxin-producing fungi. The main morphological changes of pathogenic and toxigenic fungi treated with N. sativa oil were observed in the cell wall, plasma membrane and membranous organelles, particularly in the nuclei and mitochondria. Although this review represents first step in the search for a new anti-fungal drug, the full potential of N. sativa as a fungitoxic agent has not been exploited and necessitates further investigations. PMID- 27247920 TI - Effects of Nigella sativa oil extract on inflammatory cytokine response and oxidative stress status in patients with rheumatoid arthritis: a randomized, double-blind, placebo-controlled clinical trial. AB - OBJECTIVE: Nigella sativa is a medicinal plant that has long been used in traditional medicine for treating various conditions. Numerous animal studies provided evidences that the seed may elicit a broad anti-inflammatory/anti oxidant activity. The aim of the present clinical trial was to evaluate anti inflammatory and antioxidant properties of Nigella sativa oil in patients with rheumatoid arthritis (RA). MATERIALS AND METHODS: Forty-two patients with RA were assigned into two groups in this randomized, double blind, placebo-controlled clinical trial. Subjects in intervention group received two capsules, 500 mg each, of Nigella sativa oil, each day for 8 weeks. The other group consumed two capsules as placebo per day for the same period of time. Serum TNF-alpha, IL-10, and whole blood levels of oxidative stress parameters were measured at baseline and end of the trial. RESULTS: The serum level of IL-10 was increased in the Nigella sativa group (p<0.01). Moreover, treatment with Nigella sativa led to significant reduction of serum MDA and NO compared with baseline (p<0.05). There were no significant differences in the TNF-alpha, SOD, catalase, and TAS values between or within the groups, before and after the intervention (p>0.05). CONCLUSION: This study indicates that Nigella sativa could improve inflammation and reduce oxidative stress in patients with RA. It is suggested that Nigella sativa may be a beneficial adjunct therapy in this population of patients. PMID- 27247921 TI - The protective effect of Nigella sativa against cisplatin-induced nephrotoxicity in rats. AB - OBJECTIVE: The clinical use of cisplatin is highly restricted, because of its nephrotoxicity. In this study the protective effect of Nigella sativa (N. sativa) against cisplatin-induced nephrotoxicity was investigated in rats. MATERIALS AND METHODS: In the current study, the effects of the administration of aqueous ethanolic extract of N. sativa (100 and 200 mg/kg, BW) and vitamin E (100 mg/kg, BW) against blood and urine biochemical alterations and kidney function in rats treated with cisplatin were investigated. Cisplatin was injected at a dose of 6 mg/kg, BW, on the sixth day of the experiment. RESULTS: The results indicated significant changes in serum urea and creatinine concentration, urine glucose concentration, and urine output in cisplatin group compared with control group. Serum urea and creatinine concentration in preventive and preventive+treatment vitamin E and preventive+treatment N. sativa (200 mg/kg, BW) groups and also serum creatinine concentration in preventive+treatment N. sativa (100 mg/kg, BW) group significantly decreased compared with cisplatin group. Urine glucose concentration in preventive and preventive+treatment N. sativa groups and urine output in preventive and preventive+treatment N. sativa (200 mg/kg, BW) groups significantly decreased compared with cisplatin group.Osmolarity excretion rate in preventive and preventive+treatment vitamin E and preventive N. sativa groups was significantly higher than control group. CONCLUSIONS: The current study suggests that N. sativa extract and vitamin E in a dose- and time-dependent manner improved the serum and urine biochemical parameters and kidney function in cisplatin-induced nephrotoxicity in rats. However, it needs more investigations to determine the mechanism of N. sativa action on cisplatin-induced kidney toxicity. PMID- 27247922 TI - Attenuation of morphine tolerance and dependence by thymoquinone in mice. AB - OBJECTIVE: Dependence and tolerance are major restricting factors in the clinical use of opioid analgesics. In the present study, the effects of thymoquinone, the major constituent of Nigella sativa seeds, on morphine dependence and tolerance were investigated in mice. MATERIALS AND METHODS: Male adult NMRI mice were made tolerant and dependent by repeated injections of morphine (50, 50, and 75 mg/kg, i.p. on 9 a.m., 1 p.m., and 5 p.m., respectively) during a 3-day administration schedule. The hot-plate test was used to assess tolerance to the analgesic effects of morphine. Naloxone (2 mg/kg, i.p.) was injected to precipitate withdrawal syndrome in order to assess the morphine dependence. To evaluate the effects of thymoquinone on tolerance and dependence to morphine, different single or repeated doses of thymoquinone were administered in mice. Rotarod was used to assess the motor coordination. RESULTS: Administration of single or repeated doses of thymoquinone (20 and 40 mg/kg, i.p.) significantly decreased the number of jumps in morphine dependent animals. Repeated administration of thymoquinone (20 and 40 mg/kg, for 3 days) and also single injection of thymoquinone (40 mg/kg, on the fourth day) attenuated tolerance to the analgesic effect of morphine. None of the thymoquinone doses (10, 20, and 40 mg/kg) produced any antinociceptive effects on their own. Motor coordination of animals was impaired by the high dose of thymoquinone (40 mg/kg). CONCLUSION: Based on these results, it can be concluded that thymoquinone prevents the development of tolerance and dependence to morphine. PMID- 27247923 TI - Nigella sativa seed decreases endothelial dysfunction in streptozotocin-induced diabetic rat aorta. AB - OBJECTIVE: Diabetes is an important risk factor for cardiovascular events. The great percent of morbidity in patients with diabetes is due to endothelial dysfunction. The present study investigated the effects of hydroalcholic extract of Nigella sativa (N. sativa) on contractile and dilatation response of isolated aorta in streptozotocin (STZ)-induced diabetic rat. MATERIALS AND METHODS: Rats were divided into six experimental groups (control, untreated STZ-diabetic, and N. sativa hydroalcholic extract or metformin-treated diabetic rats). Treated rats received N. sativa extract (100, 200, and 400 mg/kg) or metformin (300 mg/kg) by gavage, daily for 6 weeks. Isolated rat thoracic rings were mounted in an organ bath system then contractile and dilatation responses induced by phenylephrine (PE), acetylcholine (ACh), potassium chloride (KCl), and sodium nitroprusside (SNP) were evaluated in different situations. RESULTS: The lower concentrations of N. sativa seed extract (DE 100 and DE 200) and metformin significantly reduced the contractile responses to higher concentrations of PE (10(-6) - 10(-5) M) compared to diabetic group (p<0.05 to p<0.01). The relaxation response to Ach 10( 8) M, was increased in DE 200 and metformin groups compared to diabetic group (p<0.05). The relaxation responses to Ach 10(-7) - 10(-5) M were significantly higher in all treated groups compared to diabetic group (p<0.05 to p<0.001). CONCLUSION: Chronic administration of N. sativa seed extract has a significant hypoglycemic effect and improves aortic reactivity to vasoconstrictor and vasodilator agents in STZ-induced diabetic rats. PMID- 27247925 TI - Adriamycin-induced oxidative stress is prevented by mixed hydro-alcoholic extract of Nigella sativa and Curcuma longa in rat kidney. AB - OBJECTIVE: Inflammation and oxidative stress is considered to have a crucial role in induction of nephropathy. Curcuma longa (C. longa) and Nigella sativa (N. sativa) have anti-inflammatory and antioxidant effects. This study was designed to investigate the effect of mixed hydro-alcoholic extract of N.sativa and C. longa on the oxidative stress induced by Adriamycin (ADR) in rat kidney. MATERIALS AND METHODS: The animals were divided into 6 groups: control (CO), ADR, Adriamycin+ Vitamin C (ADR+VIT C), C. longa extract+ Adriamycin (C.LE+ADR), N. sativa extract+ Adriamycin (N.SE+ADR) and C. longa extract+ N. sativa extract + Adriamycin (N.S+C.L+ADR). ADR (5mg/kg) was injected intravenously, whereas VITC (100mg/kg) and extract of C. longa (1000mg/kg) and N. sativa (200mg/kg) were administrated orally. Finally, the renal tissue, urine and blood samples were collected and submitted to measure of redox markers, osmolarity and renal index. RESULTS: The renal content of total thiol and superoxide dismutase (SOD) activity significantly decreased and Malondialdehyde (MDA) concentration increased in Adriamycin group compared to control group. The renal content of total thiol and SOD activity significantly enhanced and MDA concentration reduced in treated mixed extract of C. longa and N. sativa along with ADR group compared to ADR group. The mixed extract did not restore increased renal index percentage induced by ADR. There also was no significant difference in urine and serum osmolarity between the groups. CONCLUSION: hydro-alcoholic extracts of N.sativa and C.longa led to an improvement in ADR-induced oxidative stress and mixed administration of the extracts enhanced the aforementioned therapeutic effect. PMID- 27247924 TI - Effect of Alpha-Hederin, the active constituent of Nigella sativa, on miRNA-126, IL-13 mRNA levels and inflammation of lungs in ovalbumin-sensitized male rats. AB - OBJECTIVE: In previous studies the therapeutic effects of Nigella sativa have been demonstrated on asthmatic animals. In the present study, the preventive effect of single dose of alpha-hederin, its active constituent, has been evaluated on lung inflammation and some inflammatory mediators in lungs of ovalbumin sensitized rat in order to elicit its mechanism. MATERIALS AND METHODS: Forty rats were randomly grouped in 4 groups; control (C), sensitized (S), sensitized pretreated groups with thymoquinone (3 mg/kg i.p., S+TQ) and alpha hederin (0.02 mg/kg i.p., S+AH). Levels of IL-13 mRNA and miRNA-126 in lung tissue and its pathological changes in each group were assessed. RESULTS: Elevated levels of miRNA-126, IL-13 mRNA and pathological changes were observed in the sensitized group compared to the control group (p<0.001 to p<0.05). All of these factors were significantly reduced in S+TQ and S+AH groups in comparison to S group (p<0.001 to p<0.05). Although alpha-hederin decreased the levels of miRNA 126, IL-13 mRNA and pathological changes in comparison with thymoquinone, the results were statistically not significant. CONCLUSION: The results suggested that alpha-hederin had preventive effect on sensitized rats like thymoquinone. It may intervene in miRNA-126 expression, which consequently could interfere with IL 13 secretion pathway leading to a reduction in inflammatory responses. PMID- 27247926 TI - Effect of Nigella sativa on reproductive system in experimental menopause rat model. AB - OBJECTIVE: Menopause is the condition when regular menstrual periods cease and may be accompanied by psychological and physical symptoms. The purpose of current study was to determine Nigella sativa effects on reproductive system in experimental menopause animal models. MATERIALS AND METHODS: A series of experiments was conducted to investigate the effects of different dosages of N. sativa (first experiment), various extracts of N. sativa (second experiment) and some of its ingredients (third experiment) on selected menopausal parameters of ovariectomized (OVX) rats. Forty different OVX rats were equally divided into 5 groups and administered with one of the following treatments for 21 days: conjugated equine estrogen (positive control), distilled water or olive oil (negative control), treatment groups (N. sativa300, 600 and 1200 mg/kg in the first experiment), (300mg/kg methanol, hexane and SFE extracts of N. sativa in the second experiment) and (linoleic acid 50 mg/kg, gamma linolenic acid 10mg/kg, and thymoquinone 15mg/kg in the third experiment). RESULTS: The results demonstrated that N.sativa exert estrogenic effect were exhibited through uterotrophic assay and vaginal cell cornification as well as blood estrogen level. Furthermore, low dose N. sativa, methanol extract and linoleic acid had prominent estrogenic like effects which were significantly different from those of control group (p<0.05) in different experiments. CONCLUSION: The finding indicated the probable beneficial role for N. sativa in the treatment of postmenopausal symptoms and possibility of using N. sativa as an alternative to hormone replacement therapy (HRT) for post menopause in human. PMID- 27247927 TI - The effects of Nigella sativa on sickness behavior induced by lipopolysaccharide in male Wistar rats. AB - OBJECTIVE: Neuroimmune factors contribute on the pathogenesis of sickness behaviors. Nigella sativa (NS) has anti-inflammatory, anti-anxiety and anti depressive effects. In the present study, the effect of NS hydro-alcoholic extract on sickness behavior induced by lipopolysaccharide (LPS) was investigated. MATERIALS AND METHODS: The rats were divided into five groups (n=10 in each): (1) control (saline), (2) LPS (1 mg/kg, administered two hours before behavioral tests), (3-5) LPS-Nigella sativa 100 , 200 and 400 mg/kg (LPS-NS 100, LPS-NS 200 and LPS-NS 400, respectively). Open- field (OF), elevated plus maze (EPM) and forced swimming test (FST) were performed. RESULTS: In OF, LPS reduced the peripheral crossing, peripheral distance, total crossing and total distance compared to control (p<0.01- p<0.001). The central crossing, central distance and central time in LPS-NS 100, LPS-NS200 and LPS-NS 400 groups were higher than LPS (p<0.01- p<0.001). In EPM, LPS decreased the open arm entries, open arm time and closed arm entries while increased the closed time compared to control (p<0.001). Pretreatment by NS extract reversed the effects of LPS (p<0.05- p<0.001). In FST, LPS increased the immobility time while, decreased the climbing and active times compared to control (p<0.05- p<0.001). In LPS-NS 100, LPS-NS 200 and LPS-NS 400 groups the immobility time was less while, the active and climbing times were more than those of LPS (p<0.05- p<0.001). CONCLUSION: The results of the present study showed that the hydro-alcoholic extract of NS reduced the LPS-induced sickness behaviors in rats. Further investigations are required for better understanding the responsible compound (s) and the underlying mechanism(s). PMID- 27247929 TI - Safety evaluation of Phytovagex, a pessary formulation of Nigella sativa, on pregnant rats. AB - OBJECTIVE: The possible toxicity of drugs in pregnancy should be tested before their use in pregnant patients. In the present study, we aimed to evaluate the safety of phytovagex, a pessary formulation of Nigella sativa (N. sativa), which is already in clinical use for vaginal fungal infection. MATERIALS AND METHODS: The pregnant rats were treated intravaginal with physiological saline (vehicle) or phytovagex pessary in the first half of their pregnancy (days 1 to 10 of gestation). Duration of pregnancy and health parameters of the newborns were recorded after parturition. Also, cytotoxicity of N. sativa hydroalcoholic extract was tested against ovary Cho cells. RESULTS: The phytovagex had no significant effect on the duration of pregnancy, number of newborns, weight of neonates, and percent of stillbirth. No deformity or general behavioral abnormality was observed in neonates monitored for 30 days after birth. N. sativa extract had no significant effect on the viability of ovary cells at the concentrations of 12.5-200 ug/mL. CONCLUSION: Results of this animal study showed that phytovagex has no overall effect on the duration of pregnancy and health parameters of the newborns. Also, its active agent, N. sativa, does not induce any cytotoxic effect on ovary cells. PMID- 27247928 TI - Neuropharmacological effects of Nigella sativa. AB - Nigella sativa (NS) (Ranunculaceae family) is generally utilized as a therapeutic plant all over the world. The seeds of the plant have a long history of use in different frameworks of medicines and food. In Islamic literature, it is considered as one of the greatest forms of therapeutics. It has been widely used to treat nervous system diseases such as memory impairment, epilepsy, neurotoxicity, pain, etc. Additionally, this is uncovered that the majority of therapeutic properties of this plant are due to the presence of thymoquinone (TQ) which is a major bioactive component of the essential oil. Pharmacological studies have been done to evaluate the effects of NS on the central nervous system (CNS). The present review is an effort to provide a detailed scientific literature survey about pharmacological activities of the plant on nervous system. Our literature review showed that NS and its components can be considered as promising agents in the treatment of nervous system disorders. PMID- 27247930 TI - Analysis of the IL-10, IL-12, and TNF-alpha Gene Polymorphisms in Patients With Vesicoureteral Reflux Among the Southeast Iranian Population. AB - BACKGROUND: Vesicoureteral reflux (VUR) is a common childhood disorder that is characterized by the abnormal movement of urine from the bladder into the ureters or kidneys. OBJECTIVES: The aim of this study was to determine whether the genetic polymorphisms of the IL-10, IL-12, and TNF-alpha genes are involved in the development of VUR. PATIENTS AND METHODS: The tetra amplification mutation refractory system-polymerase chain reaction (Tetra-ARMS PCR) was applied to analyze the four polymorphic sites of the IL-10AG-1082, IL-10CA597, IL-12CA1188, and TNF308GA genes in 124 VUR children and 110 healthy controls. RESULTS: A significant, highly increased risk of VUR disease was found for the CA, AA, and combined genotypes of IL-10CA597 (OR = 5.2, 95% CL: 1.80 - 18.25; P = 0.0006, OR = 9.1, 95% CL: 1.11 - 122.75; P = 0.02, OR = 5.3, 95% CL: 1.82 - 18.61; P = 0.00052, respectively); the AG, GG, and AG + GG genotypes of IL-10AG-1082 (OR = 12.8, 95% CL; 2.9 - 113.9; P = 0.00003, OR = 12.62, 95% CL: 2.93 - 114.53; P = 0.00003, respectively); and the AA genotype of IL-12 (AA, OR = 0.19, 95% CL: 0.5 0.55; P = 0.0006). The frequency of the C allele in both IL-10CA and IL-12CA was greater in patients with VUR than in the healthy controls. No association was found between TNF308GA and the risk of VUR. CONCLUSIONS: The results demonstrated significant associations between the IL-10 (AG-1089, IL-10CA) and IL-12 (AA) gene polymorphisms and a highly increased risk of VUR. PMID- 27247931 TI - Unilateral Ultrasound-Guided Transversus Abdominis Plane Block After Nephrectomy; Postoperative Pain and Use of Opioids. AB - BACKGROUND: Pain has a wide spectrum of effects on the body and inadequately controlled postoperative pain may have harmful physiologic and psychological consequences and increase morbidity. In addition, opioid anesthetic agents in high doses can blunt endocrine and metabolic responses following surgery and are associated with side effects including dizziness, nausea, vomiting, constipation, and respiratory depression. OBJECTIVES: The current study aimed to investigate if unilateral ultrasound-guided transverse abdominal plane block (TAP-block) could reduce pain and postoperative use of patient requested analgesics following nephrectomy compared to local injection of the same ropivacaine dose in the surgical wound. PATIENTS AND METHODS: Retrospective chart reviews were performed in 42 consecutive patients who received TAP-block in conjunction with nephrectomy from November 2013 to August 2014 (group A). For comparison, data were used from 40 other nephrectomy patients registered as part of a previous study (group B). In this group the patients had received local ropivacaine injection in the surgical wound. On univariate analyses, the groups were compared by t-test and the Fisher exact test. Multivariate analyses were conducted by multiple linear regression. RESULTS: Mean surgical time was 162 minutes in group A and 92 minutes in group B (P < 0.0001). The means of visual analogue scale (VAS) were 3.05 and 1.55 in A and B groups, respectively (P = 0.001). The means of morphine consumption were 5.2 mg and 5.9 mg in groups A and B, respectively (P = 0.58); while the means of sufentanil use were 9.8 MUg and 6.0 MUg in groups A and B, respectively (P = 0.06). When controlling for age, tumor size and American society of anesthesiologists classification (ASA) score on multivariate analysis, TAP-block was associated with a significant increase in VAS (+1.4 [95% CI, 0.6 - 2.3], P = 0.001) and sufentanil use (+6.2 MUg [95% CI, 2.3 - 10.2], P = 0.003). There was no difference in morphine use on multivariate analysis (P = 0.99). CONCLUSIONS: TAP-block in conjunction with laparoscopic nephrectomy did not reduce pain or opioid consumption. On the contrary, it seemed to prolong surgical time. PMID- 27247932 TI - Depression among Ethiopian Adults: Cross-Sectional Study. AB - Background. Depression is one of the most common mental disorders worldwide and is the second leading cause of disability and major contributor to suicide. Methods. Community based cross-sectional study was conducted among 779 adults residing in Northwest Ethiopia. Multistage cluster sampling technique was used to select study participants. Depression was measured by Patient Health Questionnaire (PHQ-9). Bivariate as well as multivariate logistic regressions were used to identify associated factors. p value of < 0.05 was considered statistically significant. Result. The prevalence of depression was 17.5%, where 10.7% of patients were with mild depression, 4.2% were with moderate depression, 1.9% were with moderately severe depression, and 0.6% had severe depression. Being female, age of 55 years and above, poor social support, having a comorbidity medical illness, current tobacco smoking, and living alone were significantly associated with depression. Conclusion and Recommendation. The prevalence of depression in Ethiopia is as common as the other lower and middle income countries. Female gender, being currently not married, poor social support, low wealth index, tobacco smoking, older age, having comorbid illness, and living alone were significantly associated with depression. So, depression is a significant public health problem that requires a great emphasis and some factors like smoking habit are modifiable. PMID- 27247933 TI - Mutation Analysis of the Common Deafness Genes in Patients with Nonsyndromic Hearing Loss in Linyi by SNPscan Assay. AB - Hearing loss is a common sensory disorder, and at least 50% of cases are due to a genetic etiology. Although hundreds of genes have been reported to be associated with nonsyndromic hearing loss, GJB2, SLC26A4, and mtDNA12SrRNA are the major contributors. However, the mutation spectrum of these common deafness genes varies among different ethnic groups. The present work summarized mutations in these three genes and their prevalence in 339 patients with nonsyndromic hearing loss at three different special education schools and one children's hospital in Linyi, China. A new multiplex genetic screening system "SNPscan assay" was employed to detect a total of 115 mutations of the above three genes. Finally, 48.67% of the patients were identified with hereditary hearing loss caused by mutations in GJB2, SLC26A4, and mtDNA12SrRNA. The carrying rate of mutations in the three genes was 37.76%, 19.75%, and 4.72%, respectively. This mutation profile in our study is distinct from other parts of China, with high mutation rate of GJB2 suggesting a unique mutation spectrum in this area. PMID- 27247934 TI - Differentially Expressed miRNAs in Tumor, Adjacent, and Normal Tissues of Lung Adenocarcinoma. AB - Lung cancer is the leading cause of cancer deaths. Non-small-cell lung cancer (NSCLC) is the major type of lung cancer. The aim of this study was to characterize the expression profiles of miRNAs in adenocarcinoma (AC), one major subtype of NSCLC. In this study, the miRNAs were detected in normal, adjacent, and tumor tissues by next-generation sequencing. Then the expression levels of differential miRNAs were quantified by quantitative reverse transcription polymerase chain reaction (qRT-PCR). In the results, 259, 401, and 389 miRNAs were detected in tumor, adjacent, and normal tissues of pooled AC samples, respectively. In addition, for the first time we have found that miR-21-5p and miR-196a-5p were gradually upregulated from normal to adjacent to tumor tissues; miR-218-5p was gradually downregulated with 2-fold or greater change in AC tissues. These 3 miRNAs were validated by qRT-PCR. Lastly, we predicted target genes of these 3 miRNAs and enriched the potential functions and regulatory pathways. The aberrant miR-21-5p, miR-196a-5p, and miR-218-5p may become biomarkers for diagnosis and prognosis of lung adenocarcinoma. This research may be useful for lung adenocarcinoma diagnosis and the study of pathology in lung cancer. PMID- 27247935 TI - Obstructive Form of Hypertrophic Cardiomyopathy-Left Ventricular Outflow Tract Gradient: Novel Methods of Provocation, Monitoring of Biomarkers, and Recent Advances in the Treatment. AB - Dynamic (latent or/and labile) obstruction of left ventricular outflow (LVOT) was recognized from the earliest clinical descriptions of hypertrophic cardiomyopathy (HCM) and has proved to be a complex phenomenon, as well as arguably the most audible ("visible") pathophysiological hallmark of this heterogeneous disease. The aim of the current review is focused on two novel issues in a subgroup of obstructive HCM. Firstly, the important methodological problem in HCM is the examination of a subgroup of patients with nonobstructive hypertrophy in resting conditions and hard, but possible provoking obstruction. Recently, investigators have proposed physiological stress test (with double combined stimuli) to disclose such type of patients. The upright exercise is described in the ESC guideline on hypertrophic cardiomyopathy from 2014 and may appear as a candidate for gold standard provocation test. The second novel area of interest is associated with elevated level of signaling biomarkers: hypercoagulation, hemolysis, acquired von Willebrand 2A disease, and enhanced oxidative stress. The accelerated and turbulent flow within narrow LVOT may be responsible for these biochemical disturbances. The most recent advances in the treatment of obstructive HCM are related to nonpharmacological methods of LVOT gradient reduction. This report extensively discusses novel methods. PMID- 27247936 TI - Fractional Carbon Dioxide Laser for Keratosis Pilaris: A Single-Blind, Randomized, Comparative Study. AB - Objective. Keratosis pilaris (KP) is a common condition which can frequently be cosmetically disturbing. Topical treatments can be used with limited efficacy. The objective of this study is to evaluate the effectiveness and safety of fractional carbon dioxide (CO2) laser for the treatment of KP. Patients and Methods. A prospective, randomized, single-blinded, intraindividual comparative study was conducted on adult patients with KP. A single session of fractional CO2 laser was performed to one side of arm whereas the contralateral side served as control. Patients were scheduled for follow-up at 4 and 12 weeks after treatment. Clinical improvement was graded subjectively by blinded dermatologists. Patients rated treatment satisfaction at the end of the study. Results. Twenty patients completed the study. All patients stated that the laser treatment improved KP lesions. At 12-week follow-up, 30% of lesions on the laser-treated side had moderate to good improvement according to physicians' global assessment (p = 0.02). Keratotic papules and hyperpigmentation appeared to respond better than the erythematous component. Four patients with Fitzpatrick skin type V developed transient pigmentary alteration. Conclusions. Fractional CO2 laser treatment may be offered to patients with KP. Dark-skinned patients should be treated with special caution. PMID- 27247937 TI - Longitudinal Comparison of Enzyme- and Laser-Treated Intervertebral Disc by MRI, X-Ray, and Histological Analyses Reveals Discrepancies in the Progression of Disc Degeneration: A Rabbit Study. AB - Regenerative medicine is considered an attractive prospect for the treatment of intervertebral disc (IVD) degeneration. To assess the efficacy of the regenerative approach, animal models of IVD degeneration are needed. Among these animal models, chemonucleolysis based on the enzymatic degradation of the Nucleus Pulposus (NP) is often used, but this technique remains far from the natural physiopathological process of IVD degeneration. Recently, we developed an innovative animal model of IVD degeneration based on the use of a laser beam. In the present study, this laser model was compared with the chemonucleolysis model in a longitudinal study in rabbits. The effects of the treatments were studied by MRI (T2-weighted signal intensity (T2wsi)), radiography (IVD height index), and histology (NP area and Boos' scoring). The results showed that both treatments induced a degeneration of the IVD with a decrease in IVD height and T2wsi as well as NP area and an increase in Boos' scoring. The enzyme treatment leads to a rapid and acute process of IVD degeneration. Conversely, laser radiation induced more progressive and less pronounced degeneration. It can be concluded that laser treatment provides an instrumental in vivo model of slowly evolving IVD degenerative disease that can be of preclinical relevance for assessing new prophylactic biological treatments of disc degeneration. PMID- 27247939 TI - Corrigendum to "Magnesium Lithospermate B, an Active Extract of Salvia miltiorrhiza, Mediates sGC/cGMP/PKG Translocation in Experimental Vasospasm". AB - [This corrects the article DOI: 10.1155/2014/272101.]. PMID- 27247938 TI - Selective Insulin Resistance in the Kidney. AB - Insulin resistance has been characterized as attenuation of insulin sensitivity at target organs and tissues, such as muscle and fat tissues and the liver. The insulin signaling cascade is divided into major pathways such as the PI3K/Akt pathway and the MAPK/MEK pathway. In insulin resistance, however, these pathways are not equally impaired. For example, in the liver, inhibition of gluconeogenesis by the insulin receptor substrate (IRS) 2 pathway is impaired, while lipogenesis by the IRS1 pathway is preserved, thus causing hyperglycemia and hyperlipidemia. It has been recently suggested that selective impairment of insulin signaling cascades in insulin resistance also occurs in the kidney. In the renal proximal tubule, insulin signaling via IRS1 is inhibited, while insulin signaling via IRS2 is preserved. Insulin signaling via IRS2 continues to stimulate sodium reabsorption in the proximal tubule and causes sodium retention, edema, and hypertension. IRS1 signaling deficiency in the proximal tubule may impair IRS1-mediated inhibition of gluconeogenesis, which could induce hyperglycemia by preserving glucose production. In the glomerulus, the impairment of IRS1 signaling deteriorates the structure and function of podocyte and endothelial cells, possibly causing diabetic nephropathy. This paper mainly describes selective insulin resistance in the kidney, focusing on the proximal tubule. PMID- 27247940 TI - A Drosophila Model for Screening Antiobesity Agents. AB - Although triacylglycerol, the major component for lipid storage, is essential for normal physiology, its excessive accumulation causes obesity in adipose tissue and is associated with organ dysfunction in nonadipose tissue. Here, we focused on the Drosophila model to develop therapeutics for preventing obesity. The brummer (bmm) gene in Drosophila melanogaster is known to be homologous with human adipocyte triglyceride lipase, which is related to the regulation of lipid storage. We established a Drosophila model for monitoring bmm expression by introducing the green fluorescent protein (GFP) gene as a downstream reporter of the bmm promoter. The third-instar larvae of Drosophila showed the GFP signal in all tissues observed and specifically in the salivary gland nucleus. To confirm the relationship between bmm expression and obesity, the effect of oral administration of glucose diets on bmm promoter activity was analyzed. The Drosophila flies given high-glucose diets showed higher lipid contents, indicating the obesity phenotype; this was suggested by a weaker intensity of the GFP signal as well as reduced bmm mRNA expression. These results demonstrated that the transgenic Drosophila model established in this study is useful for screening antiobesity agents. We also report the effects of oral administration of histone deacetylase inhibitors and some vegetables on the bmm promoter activity. PMID- 27247941 TI - The A, C, G, and T of Genome Assembly. AB - Genome assembly in its two decades of history has produced significant research, in terms of both biotechnology and computational biology. This contribution delineates sequencing platforms and their characteristics, examines key steps involved in filtering and processing raw data, explains assembly frameworks, and discusses quality statistics for the assessment of the assembled sequence. Furthermore, the paper explores recent Ubuntu-based software environments oriented towards genome assembly as well as some avenues for future research. PMID- 27247943 TI - Thermal Response of In Vivo Human Skin to Fractional Radiofrequency Microneedle Device. AB - Background. Fractional radiofrequency microneedle system (FRMS) is a novel fractional skin resurfacing system. Data on thermal response to this fractional resurfacing technique is limited. Objectives. To investigate histologic response of in vivo human skin to varying energy settings and pulse stacking of a FRMS in dark-skinned subjects. Methods. Two female volunteers who were scheduled for abdominoplasty received treatment with a FRMS with varying energy settings at 6 time periods including 3 months, 1 month, 1 week, 3 days, 1 day, and the time immediately before abdominoplasty. Biopsy specimens were analyzed using hematoxylin and eosin (H&E), Verhoeff-Van Gieson (VVG), colloidal iron, and Fontana-Masson stain. Immunohistochemical study was performed by using Heat Shock Protein 70 (HSP70) antibody and collagen III monoclonal antibody. Results. The average depth of radiofrequency thermal zone (RFTZ) ranged from 100 to 300 MUm, correlating with energy levels. Columns of cell necrosis and collagen denaturation followed by inflammatory response were initially demonstrated, with subsequent increasing of mucin at 1 and 3 months after treatment. Immunohistochemical study showed positive stain with HSP70. Conclusion. A single treatment with a FRMS using appropriate energy setting induces neocollagenesis. This wound healing response may serve as a mean to improve the appearance of photodamaged skin and atrophic scars. PMID- 27247942 TI - Histone Lysine Methylation in TGF-beta1 Mediated p21 Gene Expression in Rat Mesangial Cells. AB - Transforming growth factor beta1- (TGF-beta1-) induced p21-dependent mesangial cell (MC) hypertrophy plays a key role in the pathogenesis of chronic renal diseases including diabetic nephropathy (DN). Increasing evidence demonstrated the role of posttranscriptional modifications (PTMs) in the event; however, the precise regulatory mechanism of histone lysine methylation remains largely unknown. Here, we examined the roles of both histone H3 lysine 4 and lysine 9 methylations (H3K4me/H3K9me) in TGF-beta1 induced p21 gene expression in rat mesangial cells (RMCs). Our results indicated that TGF-beta1 upregulated the expression of p21 gene in RMCs, which was positively correlated with the increased chromatin marks associated with active genes (H3K4me1/H3K4me2/H3K4me3) and negatively correlated with the decreased levels of repressive marks (H3K9me2/H3K9me3) at p21 gene promoter. TGF-beta1 also elevated the recruitment of the H3K4 methyltransferase (HMT) SET7/9 to the p21 gene promoter. SET7/9 gene silencing with small interfering RNAs (siRNAs) significantly abolished the TGF beta1 induced p21 gene expression. Taken together, these results reveal the key role of histone H3Kme in TGF-beta1 mediated p21 gene expression in RMC, partly through HMT SET7/9 occupancy, suggesting H3Kme and SET7/9 may be potential renoprotective agents in managing chronic renal diseases. PMID- 27247944 TI - Diversity of Virulence Factors Associated with West Australian Methicillin Sensitive Staphylococcus aureus Isolates of Human Origin. AB - An extensive array of virulence factors associated with S. aureus has contributed significantly to its success as a major nosocomial pathogen in hospitals and community causing variety of infections in affected patients. Virulence factors include immune evading capsular polysaccharides, poly-N-acetyl glucosamine, and teichoic acid in addition to damaging toxins including hemolytic toxins, enterotoxins, cytotoxins, exfoliative toxin, and microbial surface components recognizing adhesive matrix molecules (MSCRAMM). In this investigation, 31 West Australian S. aureus isolates of human origin and 6 controls were analyzed for relative distribution of virulence-associated genes using PCR and/or an immunoassay kit and MSCRAMM by PCR-based typing. Genes encoding MSCRAMM, namely, Spa, ClfA, ClfB, SdrE, SdrD, IsdA, and IsdB, were detected in >90% of isolates. Gene encoding alpha-toxin was detected in >90% of isolates whereas genes encoding beta-toxin and SEG were detectable in 50-60% of isolates. Genes encoding toxin proteins, namely, SEA, SEB, SEC, SED, SEE, SEH, SEI, SEJ, TSST, PVL, ETA, and ETB, were detectable in >50% of isolates. Use of RAPD-PCR for determining the virulence factor-based genetic relatedness among the isolates revealed five cluster groups confirming genetic diversity among the MSSA isolates, with the greatest majority of the clinical S. aureus (84%) isolates clustering in group IIIa. PMID- 27247945 TI - Practical Application of Columbia Classification for Focal Segmental Glomerulosclerosis. AB - Focal segmental glomerulosclerosis (FSGS) is a heterogeneous clinicopathological entity. Two frameworks for the classification of FSGS have been described: etiologic and morphologic. The etiologic classification is distinguished among genetic, adaptive, virus-associated, drug-induced, and idiopathic types. Morphologic classification is commonly referred to as the Columbia classification published in 2004, which distinguishes five variants: collapsing, tip, cellular, perihilar, and not otherwise specified (NOS). This classification is based on light microscopic patterns with rigorously defined specific criteria, which can be applied to primary and secondary forms of FSGS, and has been widely used over the past 10 years both as a diagnostic and as a prognostic clinical tool. This paper defines common histopathological features of FSGS, distinguished characters among five variants, and points out the confusion about terminology of variants, because most were proposed in the past with different definitions. Despite good interobserver reproducibility of this classification system, difficulty in its application may arise in the interpretation of lesions with mixed features of more than one variant in the same tissue specimen and with late lesions, because other variants may evolve into the NOS variant over time. PMID- 27247946 TI - The Parahippocampal Cortex Mediates Contextual Associative Memory: Evidence from an fMRI Study. AB - The parahippocampal cortex (PHC) plays a key role in episodic memory, spatial processing, and the encoding of novel stimuli. Recent studies proposed that the PHC is largely involved in contextual associative processing. Consequently, the function of this region has been a hot debate in cognitive neuroscience. To test this assumption, we used two types of experimental materials to form the contextual associative memory: visual objects in reality and meaningless visual shapes. New associations were modeled from either the contextual objects or the contextual shapes. Both contextual objects and shapes activated the bilateral PHC more than the noncontextual ones. The contextual objects with semantics significantly activated the left PHC areas, whereas the meaningless contextual shapes significantly elicited the right PHC. The results clearly demonstrate that the PHC influences the processing of contextual information and provides experimental evidence for an understanding of the different functions of bilateral PHC in contextual associative memory. PMID- 27247947 TI - Physiological and Pharmacological Roles of FGF21 in Cardiovascular Diseases. AB - Cardiovascular disease (CVD) is one of the most severe diseases in clinics. Fibroblast growth factor 21 (FGF21) is regarded as an important metabolic regulator playing a therapeutic role in diabetes and its complications. The heart is a key target as well as a source of FGF21 which is involved in heart development and also induces beneficial effects in CVDs. Our review is to clarify the roles of FGF21 in CVDs. Strong evidence showed that the development of CVDs including atherosclerosis, coronary heart disease, myocardial ischemia, cardiac hypertrophy, and diabetic cardiomyopathy is associated with serum FGF21 levels increase which was regarded as a compensatory response to induced cardiac protection. Furthermore, administration of FGF21 suppressed the above CVDs. Mechanistic studies revealed that FGF21 induced cardiac protection likely by preventing cardiac lipotoxicity and the associated oxidative stress, inflammation, and apoptosis. Normally, FGF21 induced therapeutic effects against CVDs via activation of the above kinases-mediated pathways by directly binding to the FGF receptors of the heart in the presence of beta-klotho. However, recently, growing evidence showed that FGF21 induced beneficial effects on peripheral organs through an indirect way mediated by adiponectin. Therefore whether adiponectin is also involved in FGF21-induced cardiac protection still needs further investigation. PMID- 27247948 TI - Sex Differences in the Renal Function Decline of Patients with Type 2 Diabetes. AB - Aims. We aimed to investigate the sex differences in the renal function decline among patients with type 2 diabetic mellitus (T2DM), focusing on the differences in the risk factors at early stage of renal dysfunction. Methods. A clinic-based retrospective longitudinal study (follow-up duration: 8.1 +/- 1.4 years) was conducted to assess the sex differences in the annual estimated glomerular filtration rate (eGFR) change in 344 (247 male and 97 female) Japanese T2DM patients. The sex differences in the risk factors of annual eGFR decline were subjected to linear regression analyses. Results. The mean annual eGFR change was -3.5 +/- 2.7%/year in females and -2.0 +/- 2.2%/year in males (P < 0.001). Baseline retinopathy and proteinuria were significantly associated with a larger eGFR decline, irrespective of sex, while HbA1c and LDL-cholesterol levels were significantly associated with an eGFR decline in females only. Interactive effects were observed between sex and the HbA1c, LDL-cholesterol, retinopathy, or proteinuria levels on the annual eGFR decline. Conclusions. The increased susceptibility to poor metabolic control seemed to contribute to a higher risk of renal dysfunction in females with T2DM. Our study highlights the importance of aggressive therapeutic intervention to improve metabolic profiles at early stage, especially in females. PMID- 27247949 TI - A Narrative Review of Diabetes Intervention Studies to Explore Diabetes Care Opportunities for Pharmacists. AB - Background. We conducted a review of current diabetes intervention studies in type 2 diabetes and identified opportunities for pharmacists to deliver quality diabetes care. Methods. A search on randomised controlled trials (RCT) on diabetes management by healthcare professionals including pharmacists published between 2010 and 2015 was conducted. Results and Discussion. Diabetes management includes multifactorial intervention which includes seven factors as outlined in diabetes guidelines, namely, glycaemic, cholesterol and blood pressure control, medication, lifestyle, education, and cardiovascular risk factors. Most studies do not provide evidence that the intervention methods used included all seven factors with exception of three RCT which indicated HbA1c (glycated hemoglobin) reduction range of 0.5% to 1.8%. The varied HbA1C reduction suggests a lack of standardised and consistent approach to diabetes care. Furthermore, the duration of most studies was from one month to two years; therefore long term outcomes could not be established. Conclusion. Although pharmacists' contribution towards improving clinical outcomes of diabetes patients was well documented, the methods used to deliver structured, consistent evidence-based care were not clearly stipulated. Therefore, approaches to achieving long term continuity of care are uncertain. An intervention strategy that encompass all seven evidence-based factors will be useful. PMID- 27247951 TI - Clinical care models in the era of next-generation sequencing. PMID- 27247950 TI - Lactoferrin Decreases the Intestinal Inflammation Triggered by a Soybean Meal Based Diet in Zebrafish. AB - Intestinal inflammation is a harmful condition in fish that can be triggered by the ingestion of soybean meal. Due to the positive costs-benefits ratio of including soybean meal in farmed fish diets, identifying additives with intestinal anti-inflammatory effects could contribute to solving the issues caused by this plant protein. This study evaluated the effect of incorporating lactoferrin (LF) into a soybean meal-based diet on intestinal inflammation in zebrafish. Larvae were fed with diets containing 50% soybean meal (50SBM) or 50SBM supplemented with LF to 0.5, 1, 1.5 g/kg (50SBM+LF0.5; 50SBM+LF1.0; 50SBM+LF1.5). The 50SBM+LF1.5 diet was the most efficient and larvae had a reduced number of neutrophils in the intestine compared with 50SBM larvae and an indistinguishable number compared with control larvae. Likewise, the transcription of genes involved in neutrophil migration and intestinal mucosal barrier functions (mmp9, muc2.2, and beta-def-1) were increased in 50SBM larvae but were normally expressed in 50SBM+LF1.5 larvae. To determine the influence of intestinal inflammation on the general immune response, larvae were challenged with Edwardsiella tarda. Larvae with intestinal inflammation had increased mortality rate compared to control larvae. Importantly, 50SBM+LF1.5 larvae had a mortality rate lower than control larvae. These results demonstrate that LF displays a dual effect in zebrafish, acting as an intestinal anti-inflammatory agent and improving performance against bacterial infection. PMID- 27247952 TI - Medical genetics and genomic medicine in the Dominican Republic: challenges and opportunities. AB - Medical genetics and genomic medicine in the Dominican Republic: challenges and opportunities. PMID- 27247953 TI - Mosaic ratio quantification of isochromosome 12p in Pallister-Killian syndrome using droplet digital PCR. AB - BACKGROUND: Pallister-Killian syndrome (PKS) is a prototypic mosaic aneuploidy syndrome caused by mosaic supernumerary marker isochromosome 12p. Cells possessing the isochromosome 12p rapidly diminish after birth in the peripheral blood, often necessitating a skin biopsy for diagnosis. Therefore, a genomic testing that is capable of detecting low percent mosaic isochromosome 12p is preferred for the diagnosis of PKS. METHODS: The utility of the droplet digital PCR system in quantifying the mosaic ratio of isochromosome 12p in PKS was evaluated. RESULTS: Droplet digital PCR was able to precisely quantify isochromosome 12p mosaic ratio, and copy number measured by droplet digital PCR was correlated well with that of fluorescence in situ hybridization analysis. CONCLUSION: Droplet digital PCR should be considered as an effective tool for both clinical and research analytics to precisely quantify mosaic genomic copy number alterations or mosaic mutations. PMID- 27247954 TI - Capture-based next-generation sequencing reveals multiple actionable mutations in cancer patients failed in traditional testing. AB - BACKGROUND: Targeted therapies including monoclonal antibodies and small molecule inhibitors have dramatically changed the treatment of cancer over past 10 years. Their therapeutic advantages are more tumor specific and with less side effects. For precisely tailoring available targeted therapies to each individual or a subset of cancer patients, next-generation sequencing (NGS) has been utilized as a promising diagnosis tool with its advantages of accuracy, sensitivity, and high throughput. METHODS: We developed and validated a NGS-based cancer genomic diagnosis targeting 115 prognosis and therapeutics relevant genes on multiple specimen including blood, tumor tissue, and body fluid from 10 patients with different cancer types. The sequencing data was then analyzed by the clinical applicable analytical pipelines developed in house. RESULTS: We have assessed analytical sensitivity, specificity, and accuracy of the NGS-based molecular diagnosis. Also, our developed analytical pipelines were capable of detecting base substitutions, indels, and gene copy number variations (CNVs). For instance, several actionable mutations of EGFR,PIK3CA,TP53, and KRAS have been detected for indicating drug susceptibility and resistance in the cases of lung cancer. CONCLUSION: Our study has shown that NGS-based molecular diagnosis is more sensitive and comprehensive to detect genomic alterations in cancer, and supports a direct clinical use for guiding targeted therapy. PMID- 27247955 TI - Sideroblastic anemia: functional study of two novel missense mutations in ALAS2. AB - BACKGROUND: X-linked sideroblastic anemia (XLSA) is a disorder characterized by decreased heme synthesis and mitochondrial iron overload with ringed sideroblasts in bone marrow. XLSA is caused by mutations in the erythroid-specific gene coding 5-aminolevulinate synthase (ALAS2). Anemia in XLSA is extremely variable, characteristically microcytic and hypochromic with poikilocytosis, and the red blood cell distribution width is increased and prominent dimorphism of the red cell population. Anemia in XLSA patients responds variably to supplementation with pyridoxine. METHODS AND RESULTS: We report four patients with XLSA and three mutations in ALAS2: c.611G>A (p.Arg204Gln), c.1218G>T (p.Leu406Phe) and c.1499A>G (p.Tyr500Cys). The in silico predictions of three ALAS2 mutations and the functional consequences of two ALAS2 mutations were assessed. We performed in silico analysis of these mutations using ten different softwares, and all of them predicted that the p.Tyr500Cys mutation was deleterious. The in vitro prokaryotic expression showed that the p.Leu406Phe and p.Tyr500Cys mutations reduced the ALAS2 specific activity (SA) to 14% and 7% of the control value, respectively. CONCLUSION: In view of the results obtained in this study, a clear relationship between genotype and phenotype cannot be established; clinical variability or severity of anemia may be influenced by allelic variants in other genes or transcription factors and environmental conditions. PMID- 27247956 TI - Variable expressivity and co-occurrence of LDLR and LDLRAP1 mutations in familial hypercholesterolemia: failure of the dominant and recessive dichotomy. AB - BACKGROUND: The familial inherited genetic disorder of lipoprotein metabolism affects more than 10 million individuals around the world. Lebanon is one of the several endemic areas for familial hypercholesterolemia (FH) with a founder mutation in the low-density lipoprotein cholesterol receptor (LDLR) gene, responsible for most of the cases. We have previously shown that 16% of all familial cases with hypercholesterolemia do not show genotype segregation of LDLR with the underlying phenotype. METHODS: We used Sanger sequencing to genotype 25 Lebanese families with severe FH for the gene encoding the LDLR-associated protein (LDLRAP1), responsible for the recessive form of the disease starting with the four families that did not show any genotype-phenotype correlation in our previous screening. RESULTS: We showed that the previously reported p.Q136* variant is linked to the hypercholesterolemia phenotype in the four families. In addition, we showed a variable phenotype between families and between members of the same family. One family exhibits mutations in both LDLR and LDLRAP1 with family members showing differential phenotypes unexplained by the underlying genotypes of the two genes. CONCLUSION: The p.Q136* variant in LDLRAP1 is yet another founder mutation in Lebanon and coupled with the LDLR p.C681* variant explains all the genetic causes of FH in Lebanon. PMID- 27247957 TI - Carrier screening by next-generation sequencing: health benefits and cost effectiveness. AB - BACKGROUND: Compared with conventional genotyping, which typically tests for a limited number of mutations, next-generation DNA sequencing (NGS) provides increased accuracy for carrier screening. The objective of this study was to evaluate the cost effectiveness of carrier screening using NGS versus genotyping for 14 of the recessive disorders for which medical society guidelines recommend screening. METHODS: Data from published literature, population surveys, and expert opinion were used to develop a decision tree model capturing decisions and outcomes related to carrier screening and reproductive health. RESULTS: Modeling a population of 1,000,000 couples that was representative of the United States population and that contained 83,421 carriers of pathogenic mutations, carrier screening using NGS averted 21 additional affected births as compared with genotyping, and reduced costs by approximately $13 million. As compared with no screening, NGS carrier screening averted 223 additional affected births. The results are sensitive to assumptions regarding mutation detection rates and carrier frequencies in multiethnic populations. CONCLUSION: This study demonstrated that NGS-based carrier screening offers the greater benefit in clinical outcomes and lower total healthcare cost as compared with genotyping. PMID- 27247958 TI - Mutations in ATP6V1B1 and ATP6V0A4 genes cause recessive distal renal tubular acidosis in Mexican families. AB - BACKGROUND: Autosomal recessive distal renal tubular acidosis (dRTA) is a rare disease characterized by a hyperchloremic metabolic acidosis with normal anion gap, hypokalemia, hypercalciuria, hypocitraturia, nephrocalcinosis, and conserved glomerular filtration rate. In some cases, neurosensorial deafness is associated. dRTA is developed during the first months of life and the main manifestations are failure to thrive, vomiting, dehydration, and anorexia. METHODS: Nine unrelated families were studied: seven children, a teenager, and an adult with dRTA. Hearing was preserved in four children. Coding regions of the genes responsible for recessive dRTA were analysed by Sanger sequencing. RESULTS: Molecular defects were found in the genes ATP6V1B1 and ATP6V0A4. We identified three homozygous variants in ATP6V1B: a frameshift mutation (p.Ile386Hisfs*56), a nucleotide substitution in exon 10 (p.Pro346Arg), and a new splicing mutation in intron 5. Three patients were homozygous for one novel (p.Arg743Trp) and one known (p.Asp411Tyr) missense mutations in the ATP6V0A4 gene. Three patients were compound heterozygous: one proband displayed two novel mutations, the frameshift mutation p.Val52Metfs*25, and a large deletion of exons 18-21; two probands showed the missense mutation p.Asp411Tyr and as a second mutation, p.Arg194Ter and c.1691+2dup, respectively. CONCLUSION: ATP6V0A4 and ATP6V1B1 genes were involved in recessive dRTA of Mexican families. All ATP6V1B1 mutations detected were homozygous and all patients developed sensorineural hearing loss (SNHL) early in infancy. ATP6V0A4 mutations were found in one infant and three children without SNHL, and in one teenager and one adult with SNHL confirming the phenotypic variability in this trait. The mutation p.Asp411Tyr detected in four Mexican families was due to a founder effect. Screening of these mutations could provide a rapid and valuable tool for diagnosis of dRTA in this population. PMID- 27247959 TI - Development of a diagnostic DNA chip to screen for 30 autosomal recessive disorders in the Hutterite population. AB - BACKGROUND: The Hutterites are a religious isolate living in colonies across the North American prairies. This population originated from approximately 90 founders, resulting in a number of genetic diseases that are overrepresented, underrepresented, or unique. The founder effect in this population increases the likelihood that Hutterite couples carry the same recessive mutations. We have designed a diagnostic chip on a fee-for-service basis with Asper Biotech to provide Hutterites with the option of comprehensive carrier screening. METHODS: A total of 32 disease-causing mutations in 30 genes were selected and primers were designed for array primer extension-based testing. Selected mutations were limited to those leading to autosomal recessive disorders, maintaining its primary use as a test for determining carrier status. RESULTS: The DNA chip was developed and validated using 59 DNA controls for all but one of the mutations, for which a synthetic control was used. All mutations were readily detected except for a duplication causing restrictive dermopathy where heterozygotes and homozygotes could only be distinguished by sequencing. Blinded testing of 12 additional samples from healthy Hutterites was performed by Asper Biotech using chip testing. All known mutations from previous molecular testing were detected on the chip. As well, additional mutations identified by the chip in these 12 samples were subsequently verified by a second method. CONCLUSIONS: Our analysis indicates that the chip is a sensitive and specific means of carrier testing in the Hutterite population and can serve as a model for other founder populations. PMID- 27247960 TI - Behavioral and transcriptomic profiling of mice null for Lphn3, a gene implicated in ADHD and addiction. AB - BACKGROUND: The Latrophilin 3 (LPHN3) gene (recently renamed Adhesion G protein coupled receptor L3 (ADGRL3)) has been linked to susceptibility to attention deficit/hyperactivity disorder (ADHD) and vulnerability to addiction. However, its role and function are not well understood as there are no known functional variants. METHODS: To characterize the function of this little known gene, we phenotyped Lphn3 null mice. We assessed motivation for food reward and working memory via instrumental responding tasks, motor coordination via rotarod, and depressive-like behavior via forced swim. We also measured neurite outgrowth of primary hippocampal and cortical neuron cultures. Standard blood chemistries and blood counts were performed. Finally, we also evaluated the transcriptome in several brain regions. RESULTS: Behaviorally, loss of Lphn3 increases both reward motivation and activity levels. Lphn3 null mice display significantly greater instrumental responding for food than wild-type mice, particularly under high response ratios, and swim incessantly during a forced swim assay. However, loss of Lphn3 does not interfere with working memory or motor coordination. Primary hippocampal and cortical neuron cultures demonstrate that null neurons display comparatively enhanced neurite outgrowth after 2 and 3 days in vitro. Standard blood chemistry panels reveal that nulls have low serum calcium levels. Finally, analysis of the transcriptome from prefrontal cortical, striatal, and hippocampal tissue at different developmental time points shows that loss of Lphn3 results in genotype-dependent differential gene expression (DGE), particularly for cell adhesion molecules and calcium signaling proteins. Much of the DGE is attenuated with age, and is consistent with the idea that ADHD is associated with delayed cortical maturation. CONCLUSIONS: Transcriptome changes likely affect neuron structure and function, leading to behavioral anomalies consistent with both ADHD and addiction phenotypes. The data should further motivate analyses of Lphn3 function in the developmental timing of altered gene expression and calcium signaling, and their effects on neuronal structure/function during development. PMID- 27247961 TI - Analysis of a large choroideremia dataset does not suggest a preference for inclusion of certain genotypes in future trials of gene therapy. AB - BACKGROUND: Choroideremia (CHM) is an X-linked degeneration of the retinal pigment epithelium, photoreceptors, and choroid, which causes nyctalopia and progressive constriction of visual fields leading to blindness. The CHM gene encodes Rab escort protein 1 (REP-1). In this work, we reviewed the phenotypes and genotypes of affected males with the purpose of understanding the functional effects of CHM mutations and their relationship with the phenotypes. METHODS: A retrospective review of 128 affected males was performed analyzing the onset of symptoms, visual acuity, and visual fields with respect to their mutations in the CHM gene. RESULTS: In rank order, reflecting data from this report, the most common mutations found in the CHM gene were nonsense mutations (41%), exon deletions (37%), and splice sites (14%) associated with a loss of functional protein. In the pool of 106 CHM mutations, we discovered four novel missense mutations (c.238C>T; p.L80F, c.819G>T; p.Q273H, c.1327A>G; p.M443V, and c.1370C>T; p.L457P) predicted to be severe changes affecting protein stability and folding with the effect similar to that of other types of mutations. No significant genotype-phenotype correlation was found with respect to the onset of nyctalopia, the onset of other visual symptoms, visual acuity, or width of visual fields. CONCLUSION: There is no evidence to support exclusion of CHM patients from clinical trials based on their genotypes or any potential genotype-phenotype correlations. PMID- 27247962 TI - Rothmund-Thomson Syndrome: novel pathogenic mutations and frequencies of variants in the RECQL4 and USB1 (C16orf57) gene. AB - BACKGROUND: Poikiloderma is defined as a chronic skin condition presenting with a combination of punctate atrophy, areas of depigmentation, hyperpigmentation and telangiectasia. In a variety of hereditary syndromes such as Rothmund-Thomson syndrome (RTS), Clericuzio-type poikiloderma with neutropenia (PN) and Dyskeratosis Congenita (DC), poikiloderma occurs as one of the main symptoms. Here, we report on genotype and phenotype data of a cohort of 44 index patients with RTS or related genodermatoses. METHODS: DNA samples from 43 patients were screened for variants in the 21 exons of the RECQL4 gene using PCR, SSCP-PAGE analysis and/or Sanger sequencing. Patients with only one or no detectable mutation in the RECQL4 gene were additionally tested for variants in the 8 exons of the USB1 (C16orf57) gene by Sanger sequencing. The effect of novel variants was evaluated by phylogenic studies, single-nucleotide polymorphism (SNP) databases and in silico analyses. RESULTS: We identified 23 different RECQL4 mutations including 10 novel and one homozygous novel USB1 (C16orf57) mutation in a patient with PN. Moreover, we describe 31 RECQL4 and 8 USB1 sequence variants, four of them being novel intronic RECQL4 sequence changes that may have some deleterious effects on splicing mechanisms and need further evaluation by transcript analyses. CONCLUSION: The current study contributes to the improvement of genetic diagnostic strategies and interpretation in RTS and PN that is relevant in order to assess the patients' cancer risk, to avoid continuous and inconclusive clinical evaluations and to clarify the recurrence risk in the families. Additionally, it shows that the phenotype of more than 50% of the patients with suspected Rothmund-Thomson disease may be due to mutations in other genes raising the need for further extended genetic analyses. PMID- 27247963 TI - Erratum. AB - [This corrects the article DOI: 10.1002/mgg3.177.]. PMID- 27247964 TI - Is Early Experience Destiny? Review of Research on Long-Term Outcomes following International Adoption with Special Reference to the British Chinese Adoption Study. AB - The pathway from adverse early experience to adulthood for internationally adopted children is complex in identifying key influences, impacts, and outcomes. This review arose from the authors' involvement in the British Chinese Adoption Study, a recent outcomes study that explored the links between early orphanage care, adoptive experiences, and midadulthood. It differs from previous reviews in focusing on a greater length of time since adoption. Both quantitative and qualitative studies were included to allow for examination of a fuller range of adult-related outcomes rather than mental health scores alone. The sampling, methods, and results of reviewed articles are summarised and a critical commentary is provided. Despite methodological differences and identified strengths and weaknesses, conclusions are drawn on the basis of the evidence available. Special attention is paid to the interpretation of negative outcomes. Findings identify areas that should be explored further in order to gain a fuller understanding of midlife outcomes of people who experienced a poor start in life followed by international adoption. Such studies help in refining lifespan developmental theories. PMID- 27247966 TI - The Evolution of Ophthalmology in Rhode Island. PMID- 27247965 TI - Development and Evaluation of Stability of a Gel Formulation Containing the Monoterpene Borneol. AB - Borneol is a bicyclic monoterpenoid alcohol commonly used in traditional Chinese and Indian medicine. It is extracted from the essential oil of various medicinal plants. It has antibacterial, analgesic, and anti-inflammatory action proven in studies that used oral and intraperitoneal applications of this monoterpene in mice. The current study was designed to develop a topical gel formulation containing the monoterpene borneol using carbopol as gel base and to evaluate its stability. The prepared formulation was subjected to physical characterization and physical-chemistry assessment. The gel was prepared from carbopol and 5% of borneol. The prepared gel was subjected to pharmacotechnical tests such as its pH, viscosity, conductivity, spreadability, centrifugation, and accelerated stability with freezing-thaw cycle. The borneol was successfully incorporated into the carbopol formulation. Borneol gel (BG5) showed good stability after eight months of its development and after 12 days in the freeze-thaw cycle, not showing statistical difference in pH value, conductivity, and viscosity before and after test. Furthermore, the formulation showed a good spreadability. Therefore, it was concluded that the formulation could be very promising alternative for the topical or transdermal treatment of skin diseases. PMID- 27247967 TI - Glaucoma as a Neurodegenerative Disease: Why We Must 'Look for the Protein'. AB - For years, clinicians and scientists interested in glaucoma have focused on the anterior segment of the eye and lowering of the intraocular pressure with respect to glaucoma causes and therapies. Yet glaucoma progresses in many individuals despite lowering the intraocular pressure. Herein, the concept of glaucoma as a neurodegenerative disease is presented. [Full article available at http://rimed.org/rimedicaljournal-2016-06.asp, free with no login]. PMID- 27247968 TI - Selective Laser Trabeculoplasty as Primary Treatment for Open-Angle Glaucoma. AB - Open-angle glaucoma is a silent, chronic disorder which results in progressive and permanent vision loss. Designing the optimal treatment regimen can be particularly challenging in the management of high-risk patients with frequent loss to follow-up or a longstanding history of medication noncompliance. In this article we aim to review fundamental techniques in glaucoma diagnosis and treatment with emphasis on the strengths and weaknesses of selective laser trabeculoplasty, a technique in modern therapy which may mold the future of primary treatment in open angle glaucoma management. [Full article available at http://rimed.org/rimedicaljournal-2016-06.asp, free with no login]. PMID- 27247969 TI - The Role of Biological Agents and Immunomodulators in Treatment Strategies for Thyroid Eye Disease: An Evidence-based Review. AB - Graves' Disease is an autoimmune disease where circulating antibodies bind to the thyrotropin receptors on the thyroid gland. These bound antibodies mimic thyroid stimulating hormone without the normal feedback from the anterior pituitary, causing hyperthyroidism and thyrotoxicosis. These antibodies also interact with orbital tissues and cause the characteristic orbital findings of thyroid eye disease (TED). It is not clearly understood why anatomically and physiologically distinct tissues like the thyroid gland and orbit are affected selectively, or why the orbital disease tends to be self-limited. Identifying and understanding these processes is critical to targeting therapy. In the active phase of the disease patients may experience orbital inflammation, eyelid and conjunctiva edema (chemosis), eyelid retraction, proptosis, ocular motility restriction, and optic nerve compression. Current treatment strategies for the ocular symptoms have been predominantly directed at symptomatic relief. More recently, investigators have concentrated their efforts to better understanding the underlying pathophysiologic processes to direct therapy at these processes. This review examines the current literature exploring a variety of newer therapeutic alternatives, including immunomodulative and suppressive agents, targeted at strategic points of the active-phase TED pathophysiological pathways. Specifically, biological agents including rituximab, adalimumab, intravenous immunoglobulin and others are reviewed with considerations for pathophysiology, extent of literature support, and adverse effects. [Full article available at http://rimed.org/rimedicaljournal-2016-06.asp, free with no login]. PMID- 27247970 TI - Corneal In Vivo Confocal Microscopy: Clinical Applications. AB - In vivo confocal microscopy (IVCM) has become a widely accepted imaging technique to study the human living cornea. It provides a unique opportunity to visualize the corneal tissue at the cellular level without damage and longitudinally observe its pathologic and normative changes. With rapidly evolving technology, there has been an abundance of interest in maximizing its potential to better understand the human cornea in health and disease. This is evidenced by a growing literature analyzing acquired and inherited corneal and also systemic diseases using corneal IVCM. This article provides a narrative review of IVCM and its applications. [Full article available at http://rimed.org/rimedicaljournal-2016 06.asp, free with no login]. PMID- 27247971 TI - The Preparticipation Evaluation and Cardiovascular Screening in Young Athletes: Considering the Pros and Cons. AB - Sudden cardiac death in young athletes is an uncommon but devastating event. The preparticipation evaluation affords an important opportunity to screen for cardiovascular disease and other health conditions but has certain limitations in its existing form. This article provides an overview of current screening practices and outlines the argument for and against the addition of a 12-lead electrocardiogram to the preparticipation exam in an effort to prevent sudden cardiac arrest. [Full article available at http://rimed.org/rimedicaljournal-2016 06.asp, free with no login]. PMID- 27247972 TI - Etiology of symptomatic urethritis in men and association with sexual behaviors. AB - INTRODUCTION: Gonorrhea and chlamydia are sexually transmitted infections (STI) that are the most common causes of urethritis in men. The role of specific sexual behaviors and presentation of urethritis is often overlooked. METHODS: Data was retrospectively reviewed on all men presenting at the major STI clinic in Providence, Rhode Island. Predictors of gonorrhea and chlamydia infection were modeled using a generalized model assuming a binary distribution. RESULTS: Of the men with urethritis, 27% had chlamydia, 13% gonorrhea, 3% both, and 63% neither (non-gonococcal, non-chlamydial urethritis). MSM were more likely to test positive for gonorrhea than MSW (25% of MSM versus 6% of MSW; p<0.01). CONCLUSIONS: MSM with urethritis were much more likely to test positive for gonorrhea which may be due to increased risk behaviors and spread within concentrated sexual networks. A large number of both MSM and MSW had non gonococcal, non-chlamydial urethritis, which suggests the need for improved diagnostic testing. [Full article available at http://rimed.org/rimedicaljournal 2016-06.asp, free with no login]. PMID- 27247973 TI - Clinical presentation, pathophysiology, diagnosis, and treatment of acquired and hereditary angioedema: Exploring state-of-the-art therapies in RI. AB - Hereditary and acquired angioedema are potentially life-threatening diseases characterized by spontaneous episodes of subcutaneous and submucosal swelling of face, lips, oral cavity, larynx, and GI tract. Hereditary angioedema (HAE) usually presents within the first and second decades of life, whereas acquired angioedema presents in adults after 40 years of age. These clinical symptoms together with reduced C1 inhibitor levels and/or activity can usually confirm the diagnosis. In recent years, multiple novel therapies for treating hereditary angioedema have emerged including C1 inhibitor concentrates, ecallantide/kallikrein inhibitor, and icatibant/bradykinin receptor antagonist. This article reviews the clinical presentation, diagnosis, treatment, and prophylaxis of HAE. Lastly, this article takes into consideration that, in reality, acute care treatment can often be limited by each hospital's formulary, included is a review of HAE treatments available at the nine major hospitals in Rhode Island. [Full article available at http://rimed.org/rimedicaljournal-2016 06.asp, free with no login]. PMID- 27247974 TI - Use of emerging tobacco products among adolescents who do not smoke conventional cigarettes. PMID- 27247975 TI - Filming in the ED: A Cautionary Tale NY hospital settles $2.2M claim over patient privacy violations suit. PMID- 27247976 TI - High Tech Tach: A New Era of Patient-Generated Data. PMID- 27247977 TI - Standard of Care. PMID- 27247978 TI - Dietary nucleotides protect against alcoholic liver injury by attenuating inflammation and regulating gut microbiota in rats. AB - Nucleotides have been reported to be effective in attenuating liver damage and regulating gut microbiota. However, the protective effect of nucleotides against alcoholic liver injury remains unknown. The present study aims to investigate whether nucleotides ameliorate alcoholic liver injury and explores the possible mechanism. Male Wistar rats were given alcohol, equivalent distilled water or an isocaloric amount of dextrose intragastrically twice daily for up to 6 weeks respectively. Two subgroups of alcohol-treated rats were fed with a nucleotide supplemented AIN-93G rodent diet. Serum enzymes, inflammatory cytokines and microbiota composition of the caecum content were evaluated. We found that nucleotides could significantly decrease serum alanine aminotransferase and aspartate aminotransferase, plasma lipopolysaccharide and inflammatory cytokine levels. Sequencing of 16S rRNA genes revealed that nucleotide-treated rats showed a higher abundance of Firmicutes and a lower abundance of Bacteroidetes than alcohol-treated rats. Moreover, nucleotide treatment inhibited the protein expression of toll-like receptor 4, CD14 and repressed the phosphorylation of inhibitor kappa Balpha and nuclear factor-kappaB p65 in the liver. These results suggested that nucleotides suppressed the inflammatory response and regulated gut microbiota in alcoholic liver injury. The partial inhibition of lipopolysaccharide - toll-like receptor 4-nuclear factor-kappaB p65 signaling in the liver may be attributed to this mechanism. PMID- 27247979 TI - Porcine myofibrillar proteins as potential precursors of bioactive peptides - an in silico study. AB - Selected porcine myofibrillar proteins have been assessed as potential precursors of bioactive peptides based on in silico analysis. The potential of protein sequences for releasing peptides was evaluated by determining the profile of their potential biological activity and the frequency of occurrence of fragments with a given activity using the BIOPEP database. Digestive enzymes: pepsin, trypsin and chymotrypsin have been used for the in silico proteolysis with the use of the "Enzyme(s) action" tool in BIOPEP. After simulated gastrointestinal digestion the tested sequences of pig myofibrillar proteins are a potential source of a total of 399 peptides with activities such as enzyme inhibition, antioxidative, hypotensive, stimulating or regulating various body functions and antiamnestic activities. Within the intact proteins and after simulated gastrointestinal digestion, dipeptidyl peptidase IV inhibitory peptide sequences were the most frequently observed. The results indicate that pork myofibrillar proteins are a promising source of peptides with biological activity. PMID- 27247980 TI - Dynamic light scattering (DLS)-based immunoassay for ultra-sensitive detection of tumor marker protein. AB - A novel dynamic light scattering (DLS)-based immunoassay that utilizes manganese dioxide nanosheet-modified gold nanoparticles (MnO2-GNPs) as an activatable nanoprobe has been developed to detect tumor markers down to femtomolar levels. PMID- 27247981 TI - High-throughput synthesis and characterization of nanocrystalline porphyrinic zirconium metal-organic frameworks. AB - We describe and employ a high-throughput screening method to accelerate the synthesis and identification of pure-phase, nanocrystalline metal-organic frameworks (MOFs). We demonstrate the efficacy of this method through its application to a series of porphyrinic zirconium MOFs, resulting in the isolation of MOF-525, MOF-545, and PCN-223 on the nanoscale. PMID- 27247982 TI - Nickel-catalyzed release of H2 from formic acid and a new method for the synthesis of zerovalent Ni(PMe3)4. AB - Ni(PMe3)4 serves as a catalyst for the release of H2 and CO2 from formic acid. The capacity of Ni(PMe3)4 to achieve this transformation is linked to the ability of the PMe3 ligand to induce decarboxylation, as illustrated by the observation that both Ni(py)4(O2CH)2 and Ni(O2CH)2.2H2O react with PMe3 to afford Ni(PMe3)4; the latter transformation also provides a convenient method for the synthesis of a zerovalent nickel compound. PMID- 27247983 TI - Spiers Memorial Lecture. Introductory lecture: chemistry in the urban atmosphere. AB - The urban atmosphere is characterised by a multitude of complex processes. Gaseous and particulate components are continuously emitted into the atmosphere from many different sources. These components are then dispersed in the urban atmosphere via turbulent mixing. Numerous chemical reactions modify the gas phase chemistry on multiple time scales, producing secondary pollutants. Through partitioning, the chemical and physical properties of the aerosol particles are also constantly changing as a consequence of dispersion and gas phase chemistry. This review presents an overview of the involved processes, focusing on the contributions presented at this conference and putting them into a broader context. Advanced methods for aerosol source apportionment are presented as well, followed by some aspects of health effects related to air pollution. PMID- 27247984 TI - Dividing plasma cells in the cerebrospinal fluid of a patient with refractory multiple myeloma. PMID- 27247985 TI - Authors' response: impact of renal replacement therapy on osteopontin levels in critically ill patients. PMID- 27247986 TI - The Image of Cardiology. PMID- 27247989 TI - Coupling Electrochemistry with Fluorescence Confocal Microscopy To Investigate Electrochemical Reactivity: A Case Study with the Resazurin-Resorufin Fluorogenic Couple. AB - The redox couple resazurin-resorufin exhibits electrofluorochromic properties which are investigated herein by absorption and fluorescence spectroelectrochemistry and by electrochemically coupled-fluorescence confocal laser scanning microscopy (EC-CLSM). At pH 10, the highly fluorescent resorufin dye is generated at the electrode surface by the electrochemical reduction of the poorly fluorescent resazurin. Performing EC-CLSM at electrode surfaces allows to monitor spatially resolved electrochemical processes in situ and in real time. Using a small (315 MUm diameter) cylindrical electrode, a steady-state diffusion layer builds up under potentiostatic conditions at -0.45 V vs Ag|AgCl. Mapping the fluorescence intensity in 3D by CLSM enables us to reconstruct the relative concentration profile of resorufin around the electrode. The comparison of the experimental diffusion-profile with theoretical predictions demonstrates that spontaneous convection has a direct influence on the actual thickness of the diffusion layer, which is smaller than the value predicted for a purely diffusional transport. This study shows that combining fluorescence CLSM with electrochemistry is a powerful tool to study electrochemical reactivity at a spatially resolved level. PMID- 27247988 TI - High Temperature Ferromagnetism in a GdAg2 Monolayer. AB - Materials that exhibit ferromagnetism, interfacial stability, and tunability are highly desired for the realization of emerging magnetoelectronic phenomena in heterostructures. Here we present the GdAg2 monolayer alloy, which possesses all such qualities. By combining X-ray absorption, Kerr effect, and angle-resolved photoemission with ab initio calculations, we have investigated the ferromagnetic nature of this class of Gd-based alloys. The Curie temperature can increase from 19 K in GdAu2 to a remarkably high 85 K in GdAg2. We find that the exchange coupling between Gd atoms is barely affected by their full coordination with noble metal atoms, and instead, magnetic coupling is effectively mediated by noble metal-Gd hybrid s,p-d bands. The direct comparison between isostructural GdAu2 and GdAg2 monolayers explains how the higher degree of surface confinement and electron occupation of such hybrid s,p-d bands promote the high Curie temperature in the latter. Finally, the chemical composition and structural robustness of the GdAg2 alloy has been demonstrated by interfacing them with organic semiconductors or magnetic nanodots. These results encourage systematic investigations of rare-earth/noble metal surface alloys and interfaces, in order to exploit them in magnetoelectronic applications. PMID- 27247990 TI - Poling-Written Ferroelectricity in Bulk Multiferroic Double-Perovskite BiFe0.5Mn0.5O3. AB - We present a comprehensive study of the electrical properties of bulk polycrystalline BiFe0.5Mn0.5O3, a double perovskite synthesized in high-pressure and high-temperature conditions. BiFe0.5Mn0.5O3 shows an antiferromagnetic character with TN = 288 K overlapped with an intrinsic antiferroelectricity due to the Bi(3+) stereochemical effect. Beyond this, the observation of a semiconductor-insulator transition at TP ~ 140 K allows one to define three distinct temperature ranges with completely different electrical properties. For T > TN, electric transport follows an ordinary thermally activated Arrhenius behavior; the system behaves as a paramagnetic semiconductor. At intermediate temperatures (TP < T < TN), electric transport is best described by Mott's variable range hopping model with lowered dimensionality D = 1, stabilized by the magnetic ordering process and driven by the inhomogeneity of the sample on the B site of the perovskite. Finally, for T < TP, the material becomes a dielectric insulator, showing very unusual poling-induced soft ferroelectricity with high saturation polarization, similar to the parent compound BiFeO3. Under external electric poling, the system irreversibly evolves from antiferroelectric to polar arrangement. PMID- 27247991 TI - Stable Lithium Deposition Generated from Ceramic-Cross-Linked Gel Polymer Electrolytes for Lithium Anode. AB - In this work, a composite gel electrolyte comprising ceramic cross-linker and poly(ethylene oxide) (PEO) matrix is shown to have superior resistance to lithium dendrite growth and be applicable to gel polymer lithium batteries. In contrast to pristine gel electrolyte, these nanocomposite gel electrolytes show good compatibility with liquid electrolytes, wider electrochemical window, and a superior rate and cycling performance. These silica cross-linkers allow the PEO to form the lithium ion pathway and reduce anion mobility. Therefore, the gel not only features lower polarization and interfacial resistance, but also suppresses electrolyte decomposition and lithium corrosion. Further, these nanocomposite gel electrolytes increase the lithium transference number to 0.5, and exhibit superior electrochemical stability up to 5.0 V. Moreover, the lithium cells feature long-term stability and a Coulombic efficiency that can reach 97% after 100 cycles. The SEM image of the lithium metal surface after the cycling test shows that the composite gel electrolyte with 20% silica cross-linker forms a uniform passivation layer on the lithium surface. Accordingly, these features allow this gel polymer electrolyte with ceramic cross-linker to function as a high-performance lithium-ionic conductor and reliable separator for lithium metal batteries. PMID- 27247992 TI - Joint NMR and Solid-Phase Microextraction-Gas Chromatography Chemometric Approach for Very Complex Mixtures: Grape and Zone Identification in Wines. AB - In very complex mixtures, classification by chemometric methods may be limited by the difficulties to extract from the NMR or gas chromatography/mass spectrometry (GC/MS) experimental data information useful for a reliable classification. The joint analysis of both data has showed its superiority in the biomedical field but is scarcely used in foodstuffs and never in wine in spite of the complexity of their spectra and classification. In this article we show that univariate and multivariate principal component analysis-discriminant analysis (PCA-DA) statistics applied to the combined (1)H NMR and solid-phase microextraction-gas chromatography (SPME-GC) data of a collection of 270 wines from Galicia (northwest Spain) allows a discrimination and classification not attainable from the separate data, distinguishing wines from autochthonous and nonautochthonous grapes, mono- from the plurivarietals, and identifying, in part, the geographical subzone of origin of the albarino wines. A general and automatable protocol, based on the signal integration of selected ROIs (regions of interest), is proposed that allows the fast and reliable identification of the grape in Galician wines. PMID- 27247994 TI - Clinical and immunological studies for 105 Japanese seropositive patients of epidermolysis bullosa acquisita examined at Kurume University. AB - OBJECTIVES: Using our serological diagnostic criteria, we selected 105 Japanese patients with epidermolysis bullosa acquisita (EBA), an autoimmune bullous disease (AIBD) reacting with type VII collagen, from our cohort of 5063 AIBD patients. METHODS: We examined the patients clinically and immunologically. RESULTS: We found diversity of clinical manifestations in both cutaneous and oral mucosal lesions and a high rate of inflammatory-type EBA patients in Japan. Common treatments were systemic steroids, followed by immunosuppressives, DDS, tetracycline/minocycline and colchicine. Immunological studies revealed that indirect immunofluorescence of 1M-NaCl-split skin, immunoblotting of dermal extract, and type VII collagen ELISA were sensitive methods, with possible multiplicity of circulating autoantibodies against other basement membrane autoantigens. CONCLUSION: The present study analyzed the largest cohort of EBA patients, confirming the scarcity of EBA (only 105 of the 5063 AIBD patients), and showed that the three serological tests are useful for the diagnosis of EBA. PMID- 27247993 TI - Peroxymonosulfate Rapidly Inactivates the Disease-Associated Prion Protein. AB - Prions, the etiological agents in transmissible spongiform encephalopathies, exhibit remarkable resistance to most methods of inactivation that are effective against conventional pathogens. Prions are composed of pathogenic conformers of the prion protein (PrP(TSE)). Some prion diseases are transmitted, in part, through environmental routes. The recalcitrance of prions to inactivation may lead to a persistent reservoir of infectivity that contributes to the environmental maintenance of epizootics. At present, few methods exist to remediate prion-contaminated land surfaces. Here we conducted a proof-of principle study to examine the ability of peroxymonosulfate to degrade PrP(TSE). We find that peroxymonosulfate rapidly degrades PrP(TSE) from two species. Transition-metal-catalyzed decomposition of peroxymonosulfate to produce sulfate radicals appears to enhance degradation. We further demonstrate that exposure to peroxymonosulfate significantly reduced PrP(C) to PrP(TSE) converting ability as measured by protein misfolding cyclic amplification, used as a proxy for infectivity. Liquid chromatography-tandem mass spectrometry revealed that exposure to peroxymonosulfate results in oxidative modifications to methionine and tryptophan residues. This study indicates that peroxymonosulfate may hold promise for decontamination of prion-contaminated surfaces. PMID- 27247995 TI - The potential of the second sight system bionic eye implant for partial sight restoration. AB - INTRODUCTION: Second Sight System bionic eye implant, a commercially available visual prosthesis developed by Second Sight Medical Products, has been implanted in over 125 patients with outer retinal dystrophies such as retinitis pigmentosa. The system has gained regulatory approval in both the USA and Europe, and aims to restore vision by electrical stimulation of the nerve cells of the inner retina. AREAS COVERED: In this review, we present the safety profile of this implant from the international clinical trial and discuss the nature and levels of improvement in visual function achieved by patients implanted with the system. Expert commentary: Future developments for the system will be explored following the discussion of the current usefulness of the device, its limitation as and the areas in which further development is necessary. PMID- 27247996 TI - Tests, Quizzes, and Self-Assessments: How to Construct a High-Quality Examination. AB - OBJECTIVE: The purposes of this article are to highlight aspects of tests that increase or decrease their effectiveness and to provide guidelines for constructing high-quality tests in radiology. CONCLUSION: Many radiologists help construct tests for a variety of purposes. Only well-constructed tests can provide reliable and valuable information about the test taker. PMID- 27247998 TI - Spreading of Thin Droplets of Perfect and Leaky Dielectric Liquids on Inclined Surfaces. AB - The spreading of droplets may be influenced by electric fields, a situation that is relevant to applications such as coating, printing, and microfluidics. In this work we study the effects of an electric field on the gravity-driven spreading of two-dimensional droplets down an inclined plane. We consider both perfect and leaky dielectric liquids, as well as perfectly and partially wetting systems. In addition to the effects of electric fields, we examine the use of thermocapillary forces to suppress the growth of the capillary ridge near the droplet front. Lubrication theory is applied to generate a set of coupled partial differential equations for interfacial height and charge, which are then solved numerically with a finite-difference method. Electric fields increase the height of the capillary ridge in both perfect and leaky dielectric droplets due to electrostatic pressure gradients that drive liquid into the ridge. In leaky dielectrics, large interfacial charge gradients in the contact-line region create shear stresses that also enhance ridge growth and the formation of trailing minor ridges. The coalescence of these ridges can significantly affect the long-time thinning rate of leaky dielectric droplets. In partially wetting liquids, electric fields promote the splitting of smaller droplets from the primary droplet near the receding contact line due to the interplay between electrostatic forces and disjoining pressure. Cooling from below and heating from above generates thermocapillary forces that counteract the effects of electric fields and suppress the growth of the capillary ridge. The results of this work have important implications for manipulating the spreading of droplets down inclined surfaces. PMID- 27247997 TI - Protease Inhibitors in View of Peptide Substrate Databases. AB - Protease substrate profiling has nowadays almost become a routine task for experimentalists, and the knowledge on protease peptide substrates is easily accessible via the MEROPS database. We present a shape-based virtual screening workflow using vROCS that applies the information about the specificity of the proteases to find new small-molecule inhibitors. Peptide substrate sequences for three to four substrate positions of each substrate from the MEROPS database were used to build the training set. Two-dimensional substrate sequences were converted to three-dimensional conformations through mutation of a template peptide substrate. The vROCS query was built from single amino acid queries for each substrate position considering the relative frequencies of the amino acids. The peptide-substrate-based shape-based virtual screening approach gives good performance for the four proteases thrombin, factor Xa, factor VIIa, and caspase 3 with the DUD-E data set. The results show that the method works for protease targets with different specificity profiles as well as for targets with different active-site mechanisms. As no structure of the target and no information on small molecule inhibitors are required to use our approach, the method has significant advantages in comparison with conventional structure- and ligand-based methods. PMID- 27247999 TI - Psychosocial impacts of communal conflicts in a sample of secondary school youths from two conflict communities in south east Nigeria. AB - In Nigeria, communal conflicts arise due to misunderstanding from ownership of land for farming, oil deposits, solid minerals or water for fishing activities. It may also arise in defence of community pride and properties or even in defence of the people involved in the conflict. The General Health Questionnaire (GHQ 12), The Short Screening Scale for Post traumatic stress disorder, The Generalized Anxiety Disorder Scale (GAD-7) and the Beck Depression Inventory (BDI 2) were used to assess psychosocial impacts of communal conflicts among 560 secondary school youths from two communities in south east Nigeria. Result revealed various forms of psychosocial impacts of communal conflicts among the youths. PMID- 27248000 TI - Manganese(III) Acetate-Promoted Cross-Coupling Reaction of Benzothiazole/Thiazole Derivatives with Organophosphorus Compounds under Ball-Milling Conditions. AB - The first solvent-free manganese(III) acetate-promoted reaction of benzothiazole/thiazole derivatives with organophosphorus compounds including phosphine oxides, phosphinate ester, and phosphonate diester has been efficiently developed under ball-milling conditions, providing a highly efficient and green protocol to structurally diverse C2-phosphonylated benzothiazole/thiazole derivatives with remarkable functional group tolerance and excellent yields. PMID- 27248003 TI - Serum potassium and sodium levels after subarachnoid haemorrhage. AB - BACKGROUND: Many studies have demonstrated that subarachnoid haemorrhage (SAH) is associated with hyponatraemia but associations with potassium levels are less well studied. There is a clear physiological link between sodium and potassium and abnormal potassium levels that can lead to dangerous outcomes. The purpose of the present study is to define changes in levels of both these cations that occur in standardised salt management of SAH. METHOD: 114 records of patients admitted between 2 January 2011 and 27 December 2011 with SAH at a single institution were obtained retrospectively. Sodium and potassium values were recorded for 14 days post-SAH from the earliest electrolyte measurements of the day for each patient where available. Patients were identified from the Newcastle SAH database. Fluid management was standardised. Descriptive and non-parametric statistics were used. RESULTS: The most common electrolyte imbalance was hypokalaemia. Patients were equally as likely to develop more severe hypokalaemia as they were to develop more severe hyponatraemia. Both imply that low potassium is of as much relevance as low sodium post-SAH. Individually there was no significant association between either sodium or potassium imbalance and WFNS grade. CONCLUSIONS: Low K + is common with current management of a SAH at the Royal Victoria Infirmary. PMID- 27248004 TI - Multistate Density Functional Theory for Effective Diabatic Electronic Coupling. AB - Multistate density functional theory (MSDFT) is presented to estimate the effective transfer integral associated with electron and hole transfer reactions. In this approach, the charge-localized diabatic states are defined by block localization of Kohn-Sham orbitals, which constrain the electron density for each diabatic state in orbital space. This differs from the procedure used in constrained density functional theory that partitions the density within specific spatial regions. For a series of model systems, the computed transfer integrals are consistent with experimental data and show the expected exponential attenuation with the donor-acceptor separation. The present method can be used to model charge transfer reactions including processes involving coupled electron and proton transfer. PMID- 27248005 TI - Culex Tarsalis Mosquitoes as Vectors of Highlands J Virus. AB - Highlands J virus (HJV) is an alphavirus closely related to western equine encephalitis virus (WEEV) and eastern equine encephalitis virus (EEEV). HJV is an avian pathogen with the potential for disruption of poultry operations, but is not known to cause human or equine disease. HJV has only been identified in the eastern United States and is thought to have a transmission cycle similar to that of EEEV involving Culiseta melanura mosquitoes and birds. However, HJV is more genetically similar to WEEV and it remains unclear if it may be transmitted by Culex species mosquitoes like WEEV. Seven strains of HJV were characterized to assess this potential. Phylogenetic analysis of whole genome sequences revealed four distinct HJV lineages (lineages 1-4), and vector competence studies in Cx. tarsalis with four of the HJV strains from different lineages yielded two distinct infection patterns. Lineage 1 strains had low infection rates, while lineages 2 and 4 had significantly higher infection rates similar to those previously published for WEEV. The average mosquito body viral titer was highest at 8 dpi (6.60-7.26 log10 pfu equivalents/body), and head titers at all time points ranged between 6.01 and 6.80 log10 pfu equivalents/head. Nearly 45% of mosquitoes infected with strain AB-80-9 were able to transmit virus in saliva with an average titer of 5.02 log10 pfu equivalents/saliva. A single amino acid difference between high and low infectivity phenotypes was identified at genome position 8605, in the E2 gene. A nonpolar glycine was present in the low infectivity lineage 1 strains, while an acidic glutamic acid was present in the higher infectivity lineage 2 and 4 strains. This study demonstrates HJV transmission by Cx. tarsalis mosquitoes and clearly identifies the potential for transmission in the western United States. Two infection phenotypes were exhibited, indicating the need for further studies to understand Culex species transmission patterns. PMID- 27248002 TI - Prions, amyloids, and RNA: Pieces of a puzzle. AB - Amyloids are protein aggregates consisting of fibrils rich in beta-sheets. Growth of amyloid fibrils occurs by the addition of protein molecules to the tip of an aggregate with a concurrent change of a conformation. Thus, amyloids are self propagating protein conformations. In certain cases these conformations are transmissible / infectious; they are known as prions. Initially, amyloids were discovered as pathological extracellular deposits occurring in different tissues and organs. To date, amyloids and prions have been associated with over 30 incurable diseases in humans and animals. However, a number of recent studies demonstrate that amyloids are also functionally involved in a variety of biological processes, from biofilm formation by bacteria, to long-term memory in animals. Interestingly, amyloid-forming proteins are highly overrepresented among cellular factors engaged in all stages of mRNA life cycle: from transcription and translation, to storage and degradation. Here we review rapidly accumulating data on functional and pathogenic amyloids associated with mRNA processing, and discuss possible significance of prion and amyloid networks in the modulation of key cellular functions. PMID- 27248007 TI - Erratum: "Associations of Fine Particulate Matter Species with Mortality in the United States: A Multicity Time-Series Analysis". PMID- 27248006 TI - Anti-inflammatory effect of a resveratrol derivative 3,4,5-trimethoxy-4',5' dihydroxy-trans-stilbene (WL-09-5) via ROS-mediated NF-kappaB pathway. AB - Inflammation derived from macrophages activation leads to various diseases. Synthetic modifications of resveratrol have been shown to have better anti inflammatory activities. In this study, croton oil-induced mouse ear edema and lipopolysaccharides (LPS)-stimulated RAW264.7 macrophages were used to evaluate the anti-inflammatory effects of WL-09-5, a derivative of resveratrol. Furthermore, the activation of NF-kappaB was determined. Results showed that WL 09-5 significantly reduced the croton oil-induced ear edema, scavenged NO and ROS production, and reduced the levels of TNF-alpha, IL-6, and IL-1beta. Furthermore, WL-09-5 may significantly inhibit the translocation of NF-kappaB in macrophage cells stimulated by LPS in a dose-dependent manner, which is a potent mechanism of its anti-inflammatory effects. In conclusion, WL-09-5 is an underlying candidate for inflammatory diseases that need further investigations. PMID- 27248008 TI - Antibiotic resistance and virulence: Understanding the link and its consequences for prophylaxis and therapy. AB - "Antibiotic resistance is usually associated with a fitness cost" is frequently accepted as common knowledge in the field of infectious diseases. However, with the advances in high-throughput DNA sequencing that allows for a comprehensive analysis of bacterial pathogenesis at the genome scale, including antibiotic resistance genes, it appears that this paradigm might not be as solid as previously thought. Recent studies indicate that antibiotic resistance is able to enhance bacterial fitness in vivo with a concomitant increase in virulence during infections. As a consequence, strategies to minimize antibiotic resistance turn out to be not as simple as initially believed. Indeed, decreased antibiotic use may not be sufficient to let susceptible strains outcompete the resistant ones. Here, we put in perspective these findings and review alternative approaches, such as preventive and therapeutic anti-bacterial immunotherapies that have the potential to by-pass the classic antibiotics. PMID- 27248009 TI - The Prevalence of Open-Angle Glaucoma by Age in Myopia: The Korea National Health and Nutrition Examination Survey. AB - PURPOSE: To investigate the prevalence of open-angle glaucoma (OAG) in myopia by age. MATERIALS AND METHODS: A cross-sectional study using a stratified, multistage, probability cluster survey. Participants in the Korean National Health and Nutrition Examination Survey between 2010 and 2011 were included. A standardized protocol was used to interview every participant and perform comprehensive ophthalmic examinations. Glaucoma was diagnosed according to the International Society of Geographical and Epidemiological Ophthalmology (ISGEO) criteria. RESULTS: After adjusting for age and sex, there was a positive correlation between OAG prevalence and increasing myopic refractive error except in participants with hyperopia. Younger participants with higher myopic refractive error had higher OAG prevalence than older participants with lower myopic refractive error. Participants with high myopia (OR 3.90, 95% confidence interval (CI) 2.30-6.59) had significantly greater age- and sex-adjusted odd ratios (ORs) than did those with emmetropia who were younger than 60 years. CONCLUSIONS: These data suggest that OAG develops earlier in participants with high myopia than in others. There was a high prevalence of OAG in participants with high myopia, even in those 19-29 years of age. Therefore, OAG screening should be performed earlier in participants with high myopia than is suggested by traditional guidelines. PMID- 27248001 TI - Targeting innate immunity for neurodegenerative disorders of the central nervous system. AB - Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7-9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimer disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance. In this meeting report, a brief overview of physiological and pathological microglia morphology is followed by a synopsis on PGE2 receptors, insights into the role of arginine metabolism and further relevant aspects of neuroinflammation in various clinical settings, and concluded by a presentation of technical challenges and solutions when working with microglia and astrocyte cultures. Microglial ontogeny and induced pluripotent stem cell-derived microglia, advances of TREM2 signaling, and the cytokine paradox in Alzheimer's disease are further contributions to this article. Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7-9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimer's disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance. In this meeting report, a brief overview on physiological and pathological microglia morphology is followed by a synopsis on PGE2 receptors, insights into the role of arginine metabolism and further relevant aspects of neuroinflammation in various clinical settings, and concluded by a presentation of technical challenges and solutions when working with microglia cultures. Microglial ontogeny and induced pluripotent stem cell-derived microglia, advances of TREM2 signaling, and the cytokine paradox in Alzheimer's disease are further contributions to this article. PMID- 27248020 TI - Nonsurgical Facial Rejuvenation. PMID- 27248010 TI - Site-directed mutants of human RECQ1 reveal functional importance of the zinc binding domain. AB - RecQ helicases are a highly conserved family of ATP-dependent DNA-unwinding enzymes with key roles in DNA replication and repair in all kingdoms of life. The RECQ1 gene encodes the most abundant RecQ homolog in humans. We engineered full length RECQ1 harboring point mutations in the zinc-binding motif (amino acids 419 480) within the conserved RecQ-specific-C-terminal (RQC) domain known to be critical for diverse biochemical and cellular functions of RecQ helicases. Wild type RECQ1 contains a zinc ion. Substitution of three of the four conserved cysteine residues that coordinate zinc severely impaired the ATPase and DNA unwinding activities but retained DNA binding and single strand DNA annealing activities. Furthermore, alteration of these residues attenuated zinc binding and significantly changed the overall conformation of full-length RECQ1 protein. In contrast, substitution of cysteine residue at position 471 resulted in a wild type like RECQ1 protein. Differential contribution of the conserved cysteine residues to the structure and functions of the RECQ1 protein is also inferred by homology modeling. Overall, our results indicate that the zinc binding motif in the RQC domain of RECQ1 is a key structural element that is essential for the structure-functions of RECQ1. Given the recent association of RECQ1 mutations with breast cancer, these results will contribute to understanding the molecular basis of RECQ1 functions in cancer etiology. PMID- 27248021 TI - Cosmetic Medicine: Innovative Beauty Care as Popular Medicine in Days Gone By. AB - Throughout the ages, people yearned for beauty and longevity. This article examines how European physicians began to engage with the field of cosmetics over a century ago, thus introducing the category of aesthetics into medical practice. This historical phenomenon is currently repeating itself. PMID- 27248022 TI - The Anatomy of the Aging Face: A Review. AB - Rejuvenative procedures of the face are increasing in numbers, and a plethora of different therapeutic options are available today. Every procedure should aim for the patient's safety first and then for natural and long-lasting results. The face is one of the most complex regions in the human body and research continuously reveals new insights into the complex interplay of the different participating structures. Bone, ligaments, muscles, fat, and skin are the key players in the layered arrangement of the face.Aging occurs in all involved facial structures but the onset and the speed of age-related changes differ between each specific structure, between each individual, and between different ethnic groups. Therefore, knowledge of age-related anatomy is crucial for a physician's work when trying to restore a youthful face.This review focuses on the current understanding of the anatomy of the human face and tries to elucidate the morphological changes during aging of bone, ligaments, muscles, and fat, and their role in rejuvenative procedures. PMID- 27248023 TI - The Future of Fractional Lasers. AB - Recent insights to the potential of fractional skin treatments have established standard laser procedures to treat aged, sun-damaged skin and scars. On top of this, the concept has been extended to fibrosing conditions, to remove foreign bodies and to treat inflammatory skin diseases. The biggest potential, however, is foreseen with the option of a contact-free temporary opening of the epidermal barrier (TOR, German: gate) to promote new and intensified treatment regimen. To date these concepts are predominantly experimental, although first clinical studies already show a better response rate if actinic keratoses are treated by fractional laser-intensified photodynamic therapy (PDT) in comparison to the conventional PDT. Possible risks may arise due to the fact that fractional laser home devices are at hand. Used in conjunction with topicals of all origins, toxic and allergic reactions may occur. Principles of current fractional laser interventions are presented as facts while visions are given as future indications. PMID- 27248024 TI - Microfocused Ultrasound for Facial Photorejuvenation: A Review. AB - Microfocused ultrasound is a unique technology to treat skin laxity of the brow, lower face, and the rhytides of the decolletage. Over the past several years, the efficacy and safety of this device has been well documented and its adoption widespread. By delivering focused acoustic energy, which is converted to heat, this device creates predictable and reproducible microcoagulative zones that initiate a concentrated inflammatory wound response. By targeting the deep reticular dermis and superficial muscle and fascial planes, such as the superficial musculoaponeurotic system, platysma, and pectoralis muscle fascia, this nonablative technology increases neocollagenesis and neoelastogenesis in a novel fashion, while avoiding many of the complications related to epidermal heating observed in several other nonablative devices. Although the results are not equivalent to those of a rhytidectomy, microfocused ultrasound provides an excellent noninvasive means to achieve a regenerative effect on the face, neck, and decolletage when performed in the appropriate patient population. PMID- 27248025 TI - Ways of Noninvasive Facial Skin Tightening and Fat Reduction. AB - For skin tightening, ablative and nonablative lasers have been used with various parameters full or fractionated. Currently, other energy-based technologies have been developed such as radiofrequency (RF) from mono- to multipolar, microneedling RF, and high-intensity focused ultrasound. They heat up the tissue to a clinical endpoint. Temperatures above 42 degrees C stimulate fibroblasts to produce more collagen and some technologies produce small coagulation points that allow to shrink and to tighten the tissue with less downtime or side effects. Alternative treatments not based on heat can be chemical peels from light to deep and microneedling without RF. PMID- 27248026 TI - Hyaluron Filler Containing Lidocaine on a CPM Basis for Lip Augmentation: Reports from Practical Experience. AB - Lip augmentation with hyaluronic acid fillers is established. As monophasic polydensified hyaluronic acid products with variable density, CPM-HAL1 (Belotero Balance Lidocaine, Merz Aesthetics, Raleigh, NC) and CPM-HAL2 (Belotero Intense Lidocaine, Merz Aesthetics, Raleigh, NC) are qualified for beautification and particularly natural-looking rejuvenation, respectively. The aim of this article was to assess the handling and outcome of lip augmentation using the lidocaine containing hyaluronic acid fillers, CPM-HAL1 and CPM-HAL2. Data were documented from patients who received lip augmentation by means of beautification and/or rejuvenation using CPM-HAL1 and/or CPM-HAL2. Observation period was 4 months, with assessment of natural outcome, evenness, distribution, fluidity, handling, malleability, tolerability, as well as patient satisfaction and pain. A total of 146 patients from 21 German centers participated. Physicians rated natural outcome and evenness as good or very good for more than 95% of patients. Distribution, fluidity, handling, and malleability were assessed for both fillers as good or very good in more than 91% of patients. At every evaluation point, more than 93% of patients were very or very much satisfied with the product. A total of 125 patients (85.6%) experienced transient injection-related side effects. Pain intensity during the procedure was mild (2.72 +/- 1.72 on the 0-10 pain assessment scale) and abated markedly within 30 minutes (0.42 +/- 0.57). Lip augmentation with hyaluronic acid fillers produced a long-term cosmetic result. Due to the lidocaine content, procedural pain was low and transient. Accordingly, a high degree of patient satisfaction was achieved that was maintained throughout the observation period. PMID- 27248027 TI - DLQI and POSAS Scores in Keloid Patients. AB - The treatment of keloids remains complex and challenging. A multitude of different treatment options exists. While current guidelines frequently promote the combination of intralesional triamcinolone acetonide (TAC) and cryotherapy as a first-line therapy for keloids, its efficacy has mainly been proven clinically and objective evaluation is widely missing. Here, we aimed to evaluate the efficacy of TAC and cryotherapy for the improvement of keloids by employing two well-recognized questionnaires for the evaluation of scar appearance and patient's quality of life. Twenty keloid patients from our outpatient scar clinic were treated with individual doses of TAC and cryotherapy in four consecutive sessions. Retrospectively, Patient and Observer Scar Assessment Scale (POSAS) and Dermatology Life Quality Index (DLQI) questionnaire data from those patients were analyzed to evaluate changes over five visits (one baseline, four after treatment). Both overall patient and observer scores of the POSAS significantly decreased (41.10 +/- 9.771 to 29.85 +/- 11.42 [p < 0.001] and 33.75 +/- 6.231 to 22.70 +/- 5.992 [p < 0.001], respectively), while DLQI scores significantly declined over the time period studied, indicating significant improvements in scar appearance. Objective evaluation confirmed the clinically demonstrated improvements of scar appearance and symptoms after treatments with TAC and cryotherapy which was associated with significant improvements in quality of life as indicated by DLQI measures. Standardized questionnaires help in objectifying clinical improvements; however, more detailed options for scar documentation, such as objective imaging, may be additionally required for an in-depth analysis of treatment progress. PMID- 27248028 TI - The Impact of Facial Lipofilling on Patient-Perceived Improvement in Facial Appearance and Quality of Life. AB - An investigation of the effect of facial lipofilling on patient's satisfaction is a challenging and ongoing research area. Therefore, the aim of this study was to investigate the impact of aesthetic intervention on self-perceived improvement in facial appearance and quality of life (QoL) after 1- and 6-month follow-ups. In the period from October 1, 2014, to March 1, 2015, a total of 63 consecutive subjects who underwent a facial lipofilling were included in the study. The satisfaction with facial appearance was estimated by using the Satisfaction with Facial Appearance Overall scale. QoL was assessed by using the 36-Item Short Form Health Survey (SF-36). Severity of depressive and anxiety symptoms was quantified by using the Hamilton depression and anxiety rating scales. The self-esteem was assessed by Rosenberg self-esteem scale. The average Satisfaction with Facial Appearance Overall scale score at baseline was 45.5 +/- 13.0, while this score reached values of 84.5 +/- 16.2 after 1 month (Z = -6.744, p < 0.001) and 82.7 +/ 12.6 after 6 months (Z = -6.545, p < 0.001) of follow-up. The mean change of Satisfaction with Facial Appearance Overall scale score from baseline to 1-month follow-up was 38.9 +/- 21.2 and from baseline to 6-month follow-up was 37.1 +/- 18.9. Statistically significant improvement in QoL at each subsequent time point, compared with those at baseline, was detected for all domains of the SF-36 except for subscales of physical functioning and pain. It has been highlighted that advanced social life was strongly associated with improvement in satisfaction with facial appearance, better self-esteem, and lower level of anxiety and depression during the period of follow-up after facial lipofilling. The results of this study supported the hypothesis that the level of self-confidence and mental health-related QoL could be significantly improved following facial lipofilling treatment. PMID- 27248029 TI - Anthropometric Analysis of the South Indian Woman's Nose. AB - The normal values of nasal dimensions and position have been established for various racial and ethnic groups. Unfortunately, there is a dearth of information related to these values in South Indian females, leading to surgeons being forced to use statistical data from Caucasians in their decision making. The objective of the present study was to compare statistically the nasal anthropometric measurement of South Indian women (SIW) with published norms for North American white women (NAWW) using independent t-test. Anthropometric analysis was done on standardized frontal, lateral, and basal photographs of South Indian woman's noses (n = 375) ages 18 to 35 years. Comparative analysis showed significant differences between SIW and NAWW in 15 of 17 measurements. All 14 nasal indices revealed significant differences that were calculated. SIW had relatively shorter, wider, and more horizontally oriented noses, and the noses have ellipsoid appearance in submental view, deeper nasal root, underrotated nasal tip, flared alae, and rounded nasal tip. As cosmetic surgery becomes more popular among South Indians, the obtained normative mean values might serve as a prototype for facial surgery. PMID- 27248030 TI - Simplifying Forehead Reconstruction: A Review of More Than 200 Cases. AB - The forehead is a unique facial region with distinct boundaries and variability in shape from patient to patient. When reconstructing the forehead, it is critical to take into account the regional boundaries as their distortion may result in noticeable facial asymmetry. We propose subdividing the forehead into newly defined zones and put forth a rational algorithm for forehead repair based on these divisions. We retrospectively reviewed a single surgeon's (F. H. S.) experience with Mohs excision and immediate reconstruction of the forehead over a 3-year period. A total of 227 consecutive post-Mohs forehead reconstructions were identified, and the reconstructive technique for a given defect size and location and postoperative complications were recorded. The average patient age was 69 years and 114 (50%) patients were female. Reconstructive techniques varied based on defect size and location within the five distinct forehead zones. Primary closure was the favored technique when appropriate, with variation in orientation based on forehead zone. Modified Burow's advancement flap was the most commonly utilized reconstruction for defects of midlateral forehead and suprabrow area, accounting for 51.7 and 62.5% of repairs, respectively. Other techniques included A-to-T flaps, rotation flaps, and full-thickness skin grafting. Using our defined zones, most common repair techniques, and final outcomes, a reconstructive algorithm for post-Mohs excisions on the forehead was derived. Consideration of the five distinct forehead zones and application of an algorithm to guide technique selection for post-Mohs forehead defect repair can lead to consistent results. PMID- 27248032 TI - Use of Giant Bilobed Flap for Advanced Head and Neck Defects. AB - This article aims to review the use of giant bilobed flaps in the reconstruction of various large defects within the head and neck. A single case series study with chart review was performed. Various facial, neck, and mentum defects were documented, and closure was accomplished through a variety of medially and laterally based giant bilobed flaps. Preoperative and postoperative photography, as well as intraoperative planning, was performed. A total of 23 patients were able to achieve closure of facial, head, and neck defects with single-stage closure through the use of a giant bilobed flap. No tissue expanders, free tissue transfers, or skin grafts were required to achieve final closure, with acceptable cosmetic and functional results. Bilobed-shaped flaps allow for local tissue transfer in regions of otherwise limited tissue laxity and mobility, classically designed and utilized in the region of the nose. We describe its applicability to closure of large head and neck defects that may otherwise require free tissue transfer or the use of tissue expanders. PMID- 27248031 TI - V-Y Advancement Flaps Based on Yotsuyanagi Aesthetic Subunit Principles for Small Nasal Defects in Asian Patients. AB - Cosmesis is paramount in the reconstruction of small nasal defects. Yotsuyanagi et al have previously described nasal aesthetic subunits in patients of Asian descent and their implications for reconstruction of large nasal defects, including forehead flap and Z-plasty. The impact of Asian skin types and aesthetic subunits on reconstruction planning of small nasal defects has not been rigorously explored. The aim of this article is to present a novel method for repairing small nose defects in patients of Asian descent using V-Y advancement flap designed using Yotsuyanagi nasal subunit aesthetic principles. A total of 21 defects ranging from 7 to 22 mm in size in 21 patients of Asian descent were repaired with either 1 or 2 V-Y advancement flaps designed along Yotsuyanagi nasal subunit borders. All reconstructions were completed successfully in one stage. Scars were inconspicuous and nasal subunits were neither displaced nor twisted. All patients were pleased with the cosmetic outcomes. The use of V-Y advancement flaps based on Asian aesthetic nasal subunit principles for the reconstruction of small nasal defects is a novel, cosmetically sensitive alternative. PMID- 27248033 TI - Reconstruction of the Large Face and Scalp Defects of a Patient with Sturge-Weber Syndrome. PMID- 27248034 TI - A Simple Method to Protect the Cornea. PMID- 27248035 TI - Ethnic Considerations in Facial Plastic Surgery. PMID- 27248036 TI - Ethnic Considerations in Facial Plastic Surgery. PMID- 27248037 TI - The Phenomenological Circle and the Unity of Life and Thought. AB - This paper describes the important role of our deep immersions in philosophy in the development of our phenomenological-contextualist approach to psychoanalysis. Influenced most particularly by the phenomenological movement, our collaborative dialogue over more than four decades has led us to a shared commitment to reflection upon the philosophical underpinnings and constitutive contexts of origin of all our theoretical ideas. The growth of our thinking follows an endlessly recurring phenomenological circle joining theoretical perspectives with the inquirers from whose emotional worlds they arise. PMID- 27248038 TI - In the Intimacy of My "Enactlon": Modeling Kohut's "Bipolar Self" as an Autopoietic System: A Dialectic Approach to Phenomenological Research in Contemporary Psychoanalytic Self Psychology. AB - This paper demonstrates that Kohut's definitional system of the "bipolar self" within psychoanalytic self psychology can be modeled as a biological autopoietic system, both in terms of its structure and dynamics, in a way that accounts for the phenomenological aspects of experiential living. Based on this finding, the author argues that a nonreductionist definitional system of this type is an integral component of any pragmatic methodology, such as Kohut's "empathic introspective" method of treatment, which aims to enable the analyst, as observer, to gain access to the phenomenological world of the analysand within the analytic setting. The dialectic approach undertaken in this preliminary exploration of the "bipolar self" as an autopoietic system has proven fruitful in excavating some of the theoretical features of psychoanalytic self psychology, the weighted importance of which can now be reevaluated in contemporary practice. PMID- 27248039 TI - Fairbairn's Theory of Change. AB - Fairbairn's unique structural theory with its three pairs of selves and objects has proven to be a highly usable and practical model of the human psyche, yet it has remained a minor player in the world of psychoanalysis. There are a number of factors that account for its lack of popularity, foremost among them the timing of the model's introduction to the analytic community. Fairbairn's four successive papers that described his metapsychology (1940, 1941, 1943, and 1944) were published just after Freud's death, when his theory was the dominant model of psychoanalysis. Additionally, Fairbairn's model was incomplete, used unfamiliar terminology, and, in its singularity, forced the analyst to abandon drive theory, the heart of Freud's metapsychology. This paper will examine and update Fairbairn's unique model of change-from the outset of pathology that begins with attachment to bad objects, to their metamorphosis into internal structures and finally to techniques of treatment that reduce their influence on the patients' internal world. The treatment section carefully follows Fairbairn's metapsychology, and focuses first on the analyst becoming a good object in the eyes of the patient, then unearthing bad object memories in a safe and compassionate interpersonal environment, engaging the patient's substructures in a manner that does not intensify preexisting internal templates, and finally aiding the patient in resuming his or her stalled emotional development. This exegesis of Fairbairn original model, along with recent modifications that have been made to it, demonstrates the consistency, clear focus, and utility of this little-known metapsychology. PMID- 27248040 TI - Do I Dare to Be Human? The Perverse Failure to Mourn, to Think, and to Love. AB - The authors discuss the relation between perverse psychic formations and the ability to develop a mind of one's own. The authors characterize the formation of perversity in terms of failure to develop the key capacities of thinking, mourning, and loving. These failures result in the abolishment of thinking and the repudiation of separateness and lead to the creation of different kinds of twisted coalitions, which shape the transference-counter-transference matrix. Persons with perverse psychic organizations have difficulties developing their own minds due to their refusal to acknowledge human limitations and their inability to accept the fundamental differences of human existence: self-other, child-adult, male-female. These characterizations are illustrated by clinical material, including a detailed analytic session, demonstrating the perverse aggresivization and sexualization of the analytic relationship. The role of the analyst is to detoxify the violence and destruction and to translate the language of perversion into the language of love. PMID- 27248041 TI - Penis Envy and the Female Oedipus Complex: A Plea to Reawaken an Ineffectual Debate. AB - Going along with Laplanche's assumption that there is no endogenous sexuality, the authors discuss Freud's concepts of the female Oedipus complex and penis envy and some of its proposed alternatives. The female oedipal conflict turns out to be the outcome of a projective identification with the Oedipus complexes of the mother and father. In the context of the rivalry with the mother, penis envy refers to the maternal power over the father's penis that the daughter wants to have in herself, while, in the context of the rivalry with the father, penis envy arises from the jealousy of the father's penis that the daughter believes is necessary to have on herself in order to satisfy her mother. The authors conclude that in Freud's day such insights were already available, which might have culminated in the conceptualization they present in this paper. PMID- 27248045 TI - Editor's Farewell. PMID- 27248042 TI - Freud on the Death Drive as Existence Without Tension. AB - Freud's notion of the death drive is complex and arguably ambiguous. This paper, however, proposes that Freud's thoughts on our organic dynamic towards tensionlessness provide us with a cohesive path through the diverse characteristics that are attributed to the death drive. The paper shows that Freud is interested in giving expression to a kind of disavowal of personhood that may present itself symptomatically. A tensionless state can be gained by a dynamic release of the individual from the pressures of the ego. This study critically sets out the line of analysis that brought Freud, in Beyond the Pleasure Principle, to introduce the notion of the death drive. The main work of the paper is to examine the meaning of the very idea of death as tensionlessness. A central contention will be that death has a figurative meaning when it is discussed in that context: it is the death of the ego. The idea of death as tensionlessness will be employed to explore a number of clinical interpretations of the relationship between the death drive and neurotic guilt and envy. PMID- 27248046 TI - Synthesis of misfolded glycoprotein dimers through native chemical ligation of a dimeric peptide thioester. AB - Glycoprotein quality control processes are very important for an efficient production of glycoproteins and for avoiding the accumulation of unwanted toxic species in cells. These complex processes consist of multiple enzymes and chaperones such as UGGT, calnexin/calreticulin, and glucosidase II. We designed and synthesized monomeric and dimeric misfolded glycoprotein probes. Synthetic homogeneous monomeric glycoproteins proved to be useful substrates for kinetic analyses of the folding sensor enzyme UGGT. For a concise synthesis of a bismaleimide-linked dimer, we examined double native chemical ligation (dNCL) of a dimeric peptide-alpha-thioester. The dNCL to two equivalents of glycopeptides gave a homodimer. The dNCL to a 1 : 1 mixture of a glycopeptide and a non glycosylated peptide gave all the three possible ligation products consisting of two homodimers and a heterodimer. Both the homodimer bearing two Man9GlcNAc2 (M9) oligosaccharides and the heterodimer bearing one M9 oligosaccharide were found to be good substrates of UGGT. PMID- 27248047 TI - Prioritizing Harm. AB - In this study, we examined if a self-report of trait spite, the Spitefulness Scale, retains the same associations with dark personality traits in individuals with severe mental illness. We also examine if reports on the Spitefulness Scale are correlated with observed spiteful behavior in a game developed to offer opportunities for spite. One hundred twenty individuals clinically diagnosed with psychotic spectrum disorders and receiving inpatient treatment at a state hospital participated in this study and completed measures of personality. The Spitefulness Scale retained its associations with measures of dark personality traits in individuals with psychosis. Spitefulness Scale scores were also related to a performance measure of spite and spite was evidenced by a significant proportion of participants across measures (20.8%-26.7%). These data suggest the presence of spite as it is understood in the general population in a significant subset of individuals with psychosis. Spite could be considered an independent personality trait and part of the family of dark personality traits. PMID- 27248049 TI - Nematic ordering of semiflexible polymers confined on a toroidal surface. AB - We study the isotropic-like and nematic states of wormlike liquid-crystal polymers embedded on the surface of a torus. The role played by surface curvature, which couples to the molecular rigidity, is reported as the main reason that causes the weak nematic ordering in an otherwise ordinary isotropic phase. The same coupling has a profound effect on the nematic states as well, which are stabilized by the Onsager excluded-volume interaction; the latter has been frequently used to study lyotropic liquid crystal polymers and is used here as an example of the physical mechanisms that drive the system to make orientational ordering. We identify important parameters in the system which are used as axes of the four-dimensional phase diagram. The numerical study demonstrates a strong correlation between the liquid-crystal defect-free and defect structures and the geometry of the liquid-crystal embedded surface. PMID- 27248048 TI - Necrolytic Migratory Erythema-like Skin Lesion During Gefitinib Treatment: A Rare Cutaneous Adverse Reaction. PMID- 27248050 TI - Upregulation of rat liver PPARalpha-FGF21 signaling by a docosahexaenoic acid and thyroid hormone combined protocol. AB - Prevention of ischemia-reperfusion liver injury is achieved by a combined omega-3 and thyroid hormone (T3 ) protocol, which may involve peroxisome-proliferator activated receptor-alpha (PPAR-alpha)-fibroblast growth factor 21 (FGF21) signaling supporting energy requirements. Combined docosahexaenoic acid (DHA; daily doses of 300 mg/kg for 3 days) plus 0.05 mg T3 /kg given to fed rats elicited higher hepatic DHA contents and serum T3 levels, increased PPAR-alpha mRNA and its DNA binding, with higher mRNA expression of the PPAR-alpha target genes for carnitine-palmitoyl transferase 1alpha, acyl-CoA oxidase, and 3 hydroxyl-3-methylglutaryl-CoA synthase 2, effects that were mimicked by 0.1 mg T3 /kg given alone or by the PPAR-alpha agonist WY-14632. Under these conditions, the mRNA expression of retinoic X receptor-alpha (RXR-alpha) is also increased, with concomitant elevation of the hepatic mRNA and protein FGF21 levels and those of serum FGF21. It is concluded that PPAR-alpha-FGF21 induction by DHA combined with T3 may involve ligand activation of PPAR-alpha by DHA and enhanced expression of PPAR-alpha by T3 , with consequent upregulation of the FGF21 that is controlled by PPAR-alpha. Considering the beneficial effects of PPAR-alpha FGF21 signaling on carbohydrate and lipid metabolism, further investigations are required to clarify its potential therapeutic applications in human metabolic disorders. (c) 2016 BioFactors, 42(6):638-646, 2016. PMID- 27248051 TI - The Association between Ambient Temperature and Childhood Hand, Foot, and Mouth Disease in Chengdu, China: A Distributed Lag Non-linear Analysis. AB - Hand, foot and mouth disease (HFMD) has recently been recognized as a critical challenge to disease control and public health response in China. This study aimed to quantify the association between temperature and HFMD in Chengdu. Daily HFMD cases and meteorological variables in Chengdu between January 2010 and December 2013 were obtained to construct the time series. A distributed lag non linear model was performed to investigate the temporal lagged association of daily temperature with age- and gender-specific HFMD. A total of 76,403 HFMD cases aged 0-14 years were reported in Chengdu during the study period, and a bimodal seasonal pattern was observed. The temperature-HFMD relationships were non-linear in all age and gender groups, with the first peak at 14.0-14.1 degrees C and the second peak at 23.1-23.2 degrees C. The high temperatures had acute and short-term effects and declined quickly over time, while the effects in low temperature ranges were persistent over longer lag periods. Males and children aged <1 year were more vulnerable to temperature variations. Temperature played an important role in HFMD incidence with non-linear and delayed effects. The success of HFMD intervention strategies could benefit from giving more consideration to local climatic conditions. PMID- 27248053 TI - CXCR4 and CCR7: Two eligible targets in targeted cancer therapy. AB - Cancer is one of the most common cause of death in the world with high negative emotional, economic, and social impacts. Conventional therapeutic methods, including chemotherapy and radiotherapy, have not proven satisfactory and relapse is common in most cases. Recent studies have focused on targeted therapy with more precise identification and targeted attacks to the cancer cells. For this purpose, chemokine receptors are proper targets and among them, CXCR4 and CCR7, with a crucial role in cancer metastasis, are being considered as desired candidates for investigation. In this review paper, the most important experimental results are highlighted on the potential targeted therapies based on CXCR4 and CCR7 chemokine receptors. PMID- 27248052 TI - Cyclic Guanidine Compounds from Toxic Newts Support the Hypothesis that Tetrodotoxin is Derived from a Monoterpene. AB - The biosynthesis of tetrodotoxin (TTX), a potent neurotoxin consisting of a 2,4 dioxaadamantane skeleton and a guanidine moiety, is an unsolved problem in natural product chemistry. Recently, the first C5-C10 directly bonded TTX analogue, 4,9-anhydro-10-hemiketal-5-deoxyTTX, was obtained from toxic newts and its carbon skeleton suggested a possible monoterpene origin. On the basis of this hypothesis, screening of predicted biosynthetic intermediates of TTX was performed using two MS-guided methods. Herein, five novel cyclic guanidine compounds from toxic newts are reported which commonly contain a cis-fused bicyclic structure including a six-membered cyclic guanidine. These structures could be biosynthetically derived from geranyl guanidine through oxidation, cyclization, and/or isomerization steps. LC-MS analysis confirmed the widespread distribution of the five novel compounds in toxic newt species. These results support the hypothesis that TTX is derived from a monoterpene. PMID- 27248054 TI - A simple two-state protein unfolds mechanically via multiple heterogeneous pathways at single-molecule resolution. AB - A major drive in protein folding has been to develop experimental technologies to resolve the myriads of microscopic pathways and complex mechanisms that purportedly underlie simple two-state folding behaviour. This is key for cross validating predictions from theory and modern computer simulations. Detecting such complexity experimentally has remained elusive even using methods with improved time, structural or single-molecule resolution. Here, we investigate the mechanical unfolding of cold shock protein B (Csp), a showcase two-state folder, using single-molecule force-spectroscopy. Under controlled-moderate pulling forces, the unfolding of Csp emerges as highly heterogeneous with trajectories ranging from single sweeps to different combinations of multiple long-lived mechanical intermediates that also vary in order of appearance. Steered molecular dynamics simulations closely reproduce the experimental observations, thus matching unfolding patterns with structural events. Our results provide a direct glimpse at the nanoscale complexity underlying two-state folding, and postulate these combined methods as unique tools for dissecting the mechanical unfolding mechanisms of such proteins. PMID- 27248055 TI - Comparison of genome-scale DNA methylation profiles in hepatocellular carcinoma by viral status. AB - Hepatocellular carcinoma (HCC) incidence has steadily increased in the US over the past 30 years. Our understanding of epigenetic regulation in HCC is still limited, especially the impact of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection on aberrant DNA methylation. We performed genome-wide DNA methylation profiling in 33 fresh frozen tumor samples, including 10 HBV-HCC, 13 HCV-HCC, and 10 non-infected (NIV-HCC) using the Illumina HumanMethylation450 BeadChip. Gene expression profiling was also performed using the Illumina whole genome DASL HT Assay. Biological influences and gene networks of the differentially-methylated (DM) CpG loci were predicted using the Ingenuity Pathway Analysis. Genome-wide methylation analysis identified 7, 26, and 98 DM loci between HBV-HCC vs. HCV-HCC, HBV-HCC vs. NIV-HCC, and HCV-HCC vs. NIV-HCC, respectively, at P < 5 * 10(-5) for each. Overall, the DM loci were highly enriched for enhancers (48%), promoters (37%), or CpG islands and surrounding regions (37%). Most DM loci were hypermethylated in HCV-HCC compared to HBV-HCC or NIV-HCC. The DM loci were associated with a variety of biological functions including Cell Morphology (HBV-HCC vs. NIV-HCC), Cell Death/ Survival (HBV-HCC vs. NIV-HCC), or Cellular Growth and Proliferation (HCV-HCC vs. NIV-HCC). A subset of the DM loci were correlated (either positively or negatively) with their gene expression or associated with alcohol consumption, BMI, cirrhosis, diabetes, and cigarette smoking. Our findings of differential methylation by viral infection lend insights into the potential effects of viral infection on the epigenetic regulation and further the development and progression of HCC. PMID- 27248056 TI - Impact of Inpatient Palliative Care on Treatment Intensity for Patients with Serious Illness. AB - BACKGROUND: Palliative care is associated with decreased treatment intensity and improved quality for individual patients at the end of life, but little is known about how hospital-wide outcomes are affected by the diffusion of palliative care principles. OBJECTIVE: We examined the relationship between presence of palliative care programs and hospitals' average treatment intensity, as indicated by mean intensive care unit (ICU) length of stay (LOS) and days under Medicare hospice coverage, in the last six months of life among Medicare beneficiaries aged 67 and over with serious chronic illness. METHODS: We linked hospital-level data from the American Hospital Association Annual Survey, National Palliative Care Registry, and Dartmouth Atlas of Health Care to examine hospital-level treatment intensity for chronically ill Medicare beneficiaries who died in 2010. We used propensity score-adjusted linear regression to estimate the relationship between palliative care programs and hospitals' mean ICU LOS and hospice length of enrollment. RESULTS: Among 974 hospitals meeting inclusion criteria, we compared 295 hospitals with palliative care programs to 679 hospitals without. Hospitals with palliative care programs were higher volume, more likely to be teaching hospitals, and have oncology services and less likely to be located in rural areas. In propensity score weighted analyses, the mean ICU LOS in hospitals with palliative care was shorter by 0.23 days (standard error [SE] = 0.26), but this was not statistically significant (p = 0.76). In addition, the mean length of hospice enrollment among beneficiaries served by hospitals with palliative care was longer by 0.22 days (SE = 0.61), but also was not statistically significant (p = 0.76). CONCLUSIONS: Hospital-based palliative care programs alone may not be sufficient to impact ICU LOS or hospice length of enrollment for all chronically ill older adults admitted to hospitals. Future work should measure hospital-wide palliative care outcomes and effects of core palliative knowledge and skills provided by nonpalliative care specialists. PMID- 27248058 TI - A Comparison of Alcohol Consumption Intentions Among Pregnant Drinkers and Their Nonpregnant Peers of Child-Bearing Age. AB - OBJECTIVE: To investigate alcohol consumption intentions among Australian women of childbearing age by pregnancy status. METHODS: Three national online surveys were conducted with adult drinkers who consume an alcoholic beverage at least two days per month. Data from female respondents of childbearing age were analyzed according to pregnancy status: pregnant (n = 101), possibly pregnant (n = 178), and not pregnant (n = 1,957). RESULTS: Pregnant drinkers were significantly more likely than possibly pregnant and nonpregnant drinkers of child-bearing age to report that they should and will reduce their alcohol consumption. Results showed that 33% of the pregnant women, 32% of the nonpregnant women, and 39% of the possibly pregnant women reported intending to drink five or more standard drinks on a single occasion in the following two weeks. Older pregnant women exhibited higher rates of heavy drinking intentions and lower intentions to reduce their consumption relative to younger pregnant women. CONCLUSION: Despite current alcohol consumption guidelines recommending abstinence while pregnant, pregnant respondents exhibited heavy episodic drinking intentions comparable to those of their nonpregnant peers. IMPLICATIONS: There is a need to increase public awareness of current alcohol guidelines for pregnant women. Older women of childbearing age and those planning a pregnancy may require particular attention. PMID- 27248059 TI - Standard Health Level Seven for Odontological Digital Imaging. AB - BACKGROUND: A guide for the implementation of dental digital imaging reports was developed and validated through the International Standard of Health Informatics Health Level Seven (HL7), achieving interoperability with an electronic system that keeps dental records. INTRODUCTION: Digital imaging benefits patients, who can view previous close-ups of dental examinations; providers, because of greater efficiency in managing information; and insurers, because of improved accessibility, patient monitoring, and more efficient cost management. Finally, imaging is beneficial for the dentist who can be more agile in the diagnosis and treatment of patients using this tool. MATERIALS AND METHODS: The guide was developed under the parameters of an HL7 standard. It was necessary to create a group of dentists and three experts in information and communication technologies from different institutions. DISCUSSION: Diagnostic images scanned with conventional radiology or from a radiovisiograph can be converted to Digital Imaging and Communications in Medicine (DICOM) format, while also retaining patient information. The guide shows how the information of the health record of the patient and the information of the dental image could be standardized in a Clinical Dental Record document using international informatics standard like HL7 V3-CDA document (dental document Level 2). Since it is an informatics standardized document, it could be sent, stored, or displayed using different devices-personal computers or mobile devices-independent of the platform used. CONCLUSIONS: Interoperability using dental images and dental record systems reduces adverse events, increases security for the patient, and makes more efficient use of resources. This article makes a contribution to the field of telemedicine in dental informatics. In addition to that, the results could be a reference for projects of electronic medical records when the dental documents are part of them. PMID- 27248057 TI - Design of a bioactive small molecule that targets r(AUUCU) repeats in spinocerebellar ataxia 10. AB - RNA is an important target for chemical probes of function and lead therapeutics; however, it is difficult to target with small molecules. One approach to tackle this problem is to identify compounds that target RNA structures and utilize them to multivalently target RNA. Here we show that small molecules can be identified to selectively bind RNA base pairs by probing a library of RNA-focused small molecules. A small molecule that selectively binds AU base pairs informed design of a dimeric compound (2AU-2) that targets the pathogenic RNA, expanded r(AUUCU) repeats, that causes spinocerebellar ataxia type 10 (SCA10) in patient-derived cells. Indeed, 2AU-2 (50 nM) ameliorates various aspects of SCA10 pathology including improvement of mitochondrial dysfunction, reduced activation of caspase 3, and reduction of nuclear foci. These studies provide a first-in-class chemical probe to study SCA10 RNA toxicity and potentially define broadly applicable compounds targeting RNA AU base pairs in cells. PMID- 27248060 TI - Germylenes and stannylenes stabilized within N2PE rings (E = Ge or Sn): combined experimental and theoretical study. AB - The deprotonation of aminophosphanes PhP(NHR)2 (R = t-Bu or Dip; Dip = 2,6-i Pr2C6H3) and t-BuP(NHDip)2 using n-BuLi gave, depending on the stoichiometry, both the dilithium compounds {[PhP(Nt-Bu)2]Li2}2 (), [PhP(Nt-Bu)(NDip)]Li2.(Et2O) (), [t-BuP(NDip)2]Li2.(Et2O)2 () and [t-BuP(NDip)2]Li2.(tmeda)2 (), and the monolithium compounds [PhP(NHt-Bu)(NR)]Li.(tmeda) (R = t-Bu , Dip ) and [t BuP(NHDip)(NDip)]Li.(tmeda) (). Treatment of , and with GeCl2.dioxane or SnCl2 in a 1 : 1 stoichiometric ratio gave the corresponding tetrylenes [PhP(Nt-Bu)2]E (E = Ge , Sn ), [PhP(Nt-Bu)(NDip)]Ge () and [t-BuP(NDip)2]E (E = Ge , Sn ). The heteroleptic germylene [Ph(H)P(Nt-Bu)2]GeCl () was obtained by the reaction of the monolithium compound [PhP(NHt-Bu)(Nt-Bu)]Li.(tmeda) () with GeCl2.dioxane in a 1 : 1 stoichiometric ratio, as a result of a spontaneous NH -> PH tautomeric shift in the ligand backbone. In contrast, an analogous reaction with SnCl2 produced only stannylene along with the PhP(NHt-Bu)2 starting material, suggesting scrambling of the ligands rather than a NH -> PH tautomeric shift. Finally, heating in solution led to P-C bond cleavage and formation of the bis(imino)phosphide [DipNPNDip]Li.(tmeda) (). The reaction of with GeCl2.dioxane, SnCl2 or PbCl2 in a 2 : 1 stoichiometric ratio yielded the unprecedented tetrylenes [DipNPNDip]2E (E = Ge , Sn and Pb ), in which the tetrylene center is incorporated within two N2PE rings. Treatment of the monolithium compound with n BuLi and K (or KC8) gave [t-BuNPNt-Bu]Li.(tmeda) () and{[t-BuNPNt-Bu]K(tmeda)}2 (), respectively. In contrast to the reaction with , similar reactions of with GeCl2.dioxane and SnCl2 resulted in the known compounds cis-[P(MU-Nt-Bu)2P(t BuN)2]E (E = Ge, Sn); evidently the t-Bu groups do not provide sufficient steric shielding to protect the bis(imino)phosphide backbone as in the case of . The bonding situation in a set of selected compounds (, ) has been subjected to a theoretical survey with particular emphasis on the nature of the bonding between the ligand and the central metal and the bonding within the NPN core of the ligand, showing significant differences among the studied complexes. PMID- 27248061 TI - The Warthin-Starry stain for detection of cutaneous melanin: more than a historical curiosity. PMID- 27248113 TI - Can revisiting pre-clinical coursework at the end of medical school enhance learning for near-peer teachers? AB - Many medical schools have integrated early clinical skills courses to ease the "pre-clinical" to "clinical" transition for medical students. However, it may also be beneficial for medical students to revisit the pre-clinical basic sciences after their core clerkship rotations to foster a deeper understanding of causal pathways of disease that often take a backseat to clinical management principles during the clerkship experience. To this point, the author reflects on the learning benefits she experienced at the end of medical school when she served as a near-peer teacher in an integrated, organ-based physiology and pathophysiology course for first-year medical students. "Teaching to learn" as a senior medical student may be a way to consolidate and foster deeper understanding of medical knowledge in the post-clerkship period of medical school. PMID- 27248114 TI - Editorial: Centennial Celebration - An Interview With Dr Jean Wilson on Men's Health. PMID- 27248118 TI - Superconductivity in alkali metal intercalated iron selenides. AB - Alkali metal intercalated iron selenide superconductors A x Fe2-y Se2 (where A = K, Rb, Cs, Tl/K, and Tl/Rb) are characterized by several unique properties, which were not revealed in other superconducting materials. The compounds crystallize in overall simple layered structure with FeSe layers intercalated with alkali metal. The structure turned out to be pretty complex as the existing Fe-vacancies order below ~550 K, which further leads to an antiferromagnetic ordering with Neel temperature fairly above room temperature. At even lower temperatures a phase separation is observed. While one of these phases stays magnetic down to the lowest temperatures the second is becoming superconducting below ~30 K. All these effects give rise to complex relationships between the structure, magnetism and superconductivity. In particular the iron vacancy ordering, linked with a long-range magnetic order and a mesoscopic phase separation, is assumed to be an intrinsic property of the system. Since the discovery of superconductivity in those compounds in 2010 they were investigated very extensively. Results of the studies conducted using a variety of experimental techniques and performed during the last five years were published in hundreds of reports. The present paper reviews scientific work concerning methods of synthesis and crystal growth, structural and superconducting properties as well as pressure investigations. PMID- 27248119 TI - Dramatic Increase in Pre-Exposure Prophylaxis Use among Men who have Sex with Men in King County, Washington: Erratum. PMID- 27248117 TI - A Miniaturized Hemoretractometer for Blood Clot Retraction Testing. AB - Blood coagulation is a critical hemostatic process that must be properly regulated to maintain a delicate balance between bleeding and clotting. Disorders of blood coagulation can expose patients to the risk of either bleeding disorders or thrombotic diseases. Coagulation diagnostics using whole blood is very promising for assessing the complexity of the coagulation system and for global measurements of hemostasis. Despite the clinic values that existing whole blood coagulation tests have demonstrated, these systems have significant limitations that diminish their potential for point-of-care applications. Here, recent advancements in device miniaturization using functional soft materials are leveraged to develop a miniaturized clot retraction force assay device termed mHemoRetractoMeter (mHRM). The mHRM is capable of precise measurements of dynamic clot retraction forces in real time using minute amounts of whole blood. To further demonstrate the clinical utility of the mHRM, systematic studies are conducted using the mHRM to examine the effects of assay temperature, treatments of clotting agents, and pro- and anti-coagulant drugs on clot retraction force developments of whole blood samples. The mHRM's low fabrication cost, small size, and consumption of only minute amounts of blood samples make the technology promising as a point-of-care tool for future coagulation monitoring. PMID- 27248121 TI - Preface to special issue on "Hormones and Diabetes". PMID- 27248120 TI - Neem tree (Azadirachta indica) extract specifically suppresses the growth of tumors in H22-bearing Kunming mice. AB - Recently, neem tree (Azadirachta indica) extract (NTE) has been reported to have various antitumor activities against gastric, breast, prostate, and skin cancer, respectively. The current study was designed to evaluate the effect of NTE on hepatic cancer in a mouse model. The possible side effects elicited by NTE were also evaluated. The components in NTE were analyzed by liquid chromatography-mass spectrometry (LC-MS). H22 cells-bearing Kumming mice were generated by injecting H22 cells subcutaneously into the right forelimb armpit of the mice. Then the mice were treated daily for 27 days with NTE (150, 300, and 600 mg/kg body weight) by intragastric administration, using carboxymethyl cellulose (CMC, 1%) as blank control and cyclophosphamide (CTX, 20 mg/kg) as positive control. The antitumor effect of NTE was evaluated by assessment of survival rate, body weight, tumor volume and weight, tumor histology, thymus and spleen indexes, and liver histology. The tumor weight and volume in groups of NTE and CTX were significantly lower than those in the CMC group. The survival rate in the NTE group receiving the high dose (600 mg/kg) was significantly higher than that in the CTX and CMC groups. Compared with CTX, NTE was observed to have a tumor specific cytotoxicity without impairing the normal liver tissue. Additionally, the higher indexes of thymus and spleen indicated that NTE could facilitate the growth of immune organs. The results indicate that NTE is a promising candidate for the antitumor treatment with high efficacy and safety. PMID- 27248122 TI - The use of vector bootstrapping to improve variable selection precision in Lasso models. AB - The Lasso is a shrinkage regression method that is widely used for variable selection in statistical genetics. Commonly, K-fold cross-validation is used to fit a Lasso model. This is sometimes followed by using bootstrap confidence intervals to improve precision in the resulting variable selections. Nesting cross-validation within bootstrapping could provide further improvements in precision, but this has not been investigated systematically. We performed simulation studies of Lasso variable selection precision (VSP) with and without nesting cross-validation within bootstrapping. Data were simulated to represent genomic data under a polygenic model as well as under a model with effect sizes representative of typical GWAS results. We compared these approaches to each other as well as to software defaults for the Lasso. Nested cross-validation had the most precise variable selection at small effect sizes. At larger effect sizes, there was no advantage to nesting. We illustrated the nested approach with empirical data comprising SNPs and SNP-SNP interactions from the most significant SNPs in a GWAS of borderline personality symptoms. In the empirical example, we found that the default Lasso selected low-reliability SNPs and interactions which were excluded by bootstrapping. PMID- 27248134 TI - Comparison of cost determination of both resource consumption accounting and time driven activity-based costing systems in a healthcare setting. AB - Objective The aim of the present study was to explore the differences between resource consumption accounting (RCA) and time-driven activity-based costing (TDABC) systems in determining the costs of services of a healthcare setting. Methods A case study was conducted to calculate the unit costs of open and laparoscopic gall bladder surgeries using TDABC and RCA. Results The RCA system assigns a higher cost both to open and laparoscopic gall bladder surgeries than TDABC. The total cost of unused capacity under the TDABC system is also double that in RCA. Conclusion Unlike TDABC, RCA calculates lower costs for unused capacities but higher costs for products or services in a healthcare setting in which fixed costs make up a high proportion of total costs. What is known about the topic? TDABC is a revision of the activity-based costing (ABC) system. RCA is also a new costing system that includes both the theoretical advantages of ABC and the practical advantages of German costing. However, little is known about the differences arising from application of TDABC and RCA. What does this paper add? There is no study comparing both TDABC and RCA in a single case study based on a real-world healthcare setting. Thus, the present study fills this gap in the literature and it is unique in the sense that it is the first case study comparing TDABC and RCA for open and laparoscopic gall bladder surgeries in a healthcare setting. What are the implications for practitioners? This study provides several interesting results for managers and cost accounting researchers. Thus, it will contribute to the spread of RCA studies in healthcare settings. It will also help the implementers of TDABC to revise data concerning the cost of unused capacity. In addition, by separating costs into fixed and variable, the paper will help managers to create a blended (combined) system that can improve both short- and long-term decisions. PMID- 27248133 TI - Chordoma-derived cell line U-CH1-N recapitulates the biological properties of notochordal nucleus pulposus cells. AB - Intervertebral disc degeneration proceeds with age and is one of the major causes of lumbar pain and degenerative lumbar spine diseases. However, studies in the field of intervertebral disc biology have been hampered by the lack of reliable cell lines that can be used for in vitro assays. In this study, we show that a chordoma-derived cell line U-CH1-N cells highly express the nucleus pulposus (NP) marker genes, including T (encodes T brachyury transcription factor), KRT19, and CD24. These observations were further confirmed by immunocytochemistry and flow cytometry. Reporter analyses showed that transcriptional activity of T was enhanced in U-CH1-N cells. Chondrogenic capacity of U-CH1-N cells was verified by evaluating the expression of extracellular matrix (ECM) genes and Alcian blue staining. Of note, we found that proliferation and synthesis of chondrogenic ECM proteins were largely dependent on T in U-CH1-N cells. In accordance, knockdown of the T transcripts suppressed the expression of PCNA, a gene essential for DNA replication, and SOX5 and SOX6, the master regulators of chondrogenesis. On the other hand, the CD24-silenced cells showed no reduction in the mRNA expression level of the chondrogenic ECM genes. These results suggest that U-CH1-N shares important biological properties with notochordal NP cells and that T plays crucial roles in maintaining the notochordal NP cell-like phenotype in this cell line. Taken together, our data indicate that U-CH1-N may serve as a useful tool in studying the biology of intervertebral disc. (c) 2016 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 34:1341-1350, 2016. PMID- 27248135 TI - Assessment of Patient-Reported Experiences of Hospital Care and the July Phenomenon. PMID- 27248136 TI - Metformin ameliorates podocyte damage by restoring renal tissue nephrin expression in type 2 diabetic rats. AB - BACKGROUND: Previous studies found that metformin provided some renoprotection for diabetic renal damage. In the present study, we evaluated the effects of different doses of metformin on the expression of renal tissue nephrin in type 2 diabetes mellitus (T2DM) model rats and the possible mechanism underlying its protective effect in kidney podocytes. METHODS: A high-fat diet combined with a low dose of streptozotocin was used to induce T2DM model rats. Diabetic rats were treated with 150, 300, or 500 mg/kg metformin for 8 weeks. At the end of the study, urine and blood samples were collected for measurement of different indices. Light microscopy and transmission electron microscopy were used to identify morphological changes. Renal expression of nephrin protein was assayed by immunohistochemical staining, whereas real-time polymerase chain reaction was used to detect renal nephrin (Nphs1) mRNA expression. RESULTS: Metformin treatment of T2DM rats produced dose-dependent significant reductions in urinary albumin and nephrin concentrations, glomerular basement membrane thickness (GBMT), and the foot process fusion rate (FPFR) compared with control T2DM model rats, whereas renal expression of nephrin protein and Nphs1 mRNA was dose dependently increased by metformin treatment. CONCLUSION: Metformin protects kidney podocytes in T2DM model rats by dose-dependently adjusting renal nephrin expression. PMID- 27248137 TI - Advanced interstitial chemotherapy for treating malignant glioma. AB - INTRODUCTION: Glioblastoma multiforme (GBM) is the most prevalent primary neoplasm of the brain. Moreover, the prognosis of patients with GBM has been poor, with almost uniform progressive neurological impairment and rapid death. Despite the availability of multimodal treatments through surgery, focal radiation, and chemotherapy, no major progress has been reported until recently. Area covered: The development of interstitial biodegradable carmustine wafers (Gliadel) for treating selected patients with malignant gliomas has resulted in marginal survival benefits in such patients (only approximately 2 months longer than that of those who did not receive the treatment). Therefore, this study summarizes several recent representative studies, presents emerging studies, and highlights the directions for additional developments in this area. An overview of the current knowledge of preclinical developments, efficacy and safety observed in clinical trials and practice following drug approval, and future avenues of research is imperative. Expert opinion: Studies are being conducted to improve the efficacy of interstitial chemotherapy by using nanobiotechnology and polymeric material science in addition to different chemotherapeutic, antiangiogenesic, and gene therapy agents and growth factors. Nanocarrier-based noninvasive techniques may have considerable potential to enhance the efficacy of GBM treatment. PMID- 27248138 TI - Three Days of Intermittent Fasting: Repeated-Sprint Performance Decreased by Vertical-Stiffness Impairment. AB - PURPOSE: To examine the effects of 3 d of intermittent fasting (3d-IF: abstaining from eating/drinking from dawn to sunset) on physical performance and metabolic responses to repeated sprints (RSs). METHODS: Twenty-one active males performed an RS test (2 sets: 5 * 5-s maximal sprints with 25 s of recovery between and 3 min of recovery between sets on an instrumented treadmill) in 2 conditions: counterbalanced fed/control session (CS) and fasting session (FS). Biomechanical and biochemical markers were assessed preexercise and postexercise. RESULTS: Significant main effects of IF were observed for sprints: maximal speed (P = .016), mean speed (P = .015), maximal power (P = .035), mean power (P = .049), vertical stiffness (P = .032), and vertical center-of-mass displacement (P = .047). Sprint speed and vertical stiffness decreased during the 1st (P = .003 and P = .005) and 2nd sprints (P = .046 and P = .048) of set 2, respectively. Postexercise insulin decreased in CS (P = .023) but not in FS (P = .230). Free fatty-acid levels were higher in FS than in CS at preexercise (P < .001) and at postexercise (P = .009). High-density lipoprotein cholesterol (HDL-C) was higher at postexercise in FS (1.32 +/- 0.22 mmol/L) than in CS (1.26 +/- 0.21 mmol/L, P = .039). The triglyceride (TG) concentration was decreased in FS (P < .05) compared with CS. CONCLUSIONS: 3d-IF impaired speed and power through a decrease in vertical stiffness during the initial runs of the 2nd set of RS. The findings of the current study confirmed the benefits of 3d-IF: improved HDL-C and TG profiles while maintaining total cholesterol and low-density lipoprotein cholesterol levels. Moreover, improving muscle power might be a key factor to retain a higher vertical stiffness and to partly counteract the negative effects of intermittent fasting. PMID- 27248139 TI - Cognitive and Psychiatric Effects of STN versus GPi Deep Brain Stimulation in Parkinson's Disease: A Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Deep brain stimulation (DBS) of either the subthalamic nucleus (STN) or the globus pallidus interna (GPi) can reduce motor symptoms in patients with Parkinson's disease (PD) and improve their quality of life. However, the effects of STN DBS and GPi DBS on cognitive functions and their psychiatric effects remain controversial. The present meta-analysis was therefore performed to clarify these issues. METHODS: We searched the PUBMED, EMBASE, and the Cochrane Central Register of Controlled Trials databases. Other sources, including internet-based clinical trial registries and grey literature sources, were also searched. After searching the literature, two investigators independently performed literature screens to assess the quality of the included trials and to extract the data. The outcomes included the effects of STN DBS and GPi DBS on multiple cognitive domains, depression, anxiety, and quality of life. RESULTS: Seven articles related to four randomized controlled trials that included 521 participants were incorporated into the present meta-analysis. Compared with GPi DBS, STN DBS was associated with declines in selected cognitive domains after surgery, including attention, working memory and processing speed, phonemic fluency, learning and memory, and global cognition. However, there were no significant differences in terms of quality of life or psychiatric effects, such as depression and anxiety, between the two groups. CONCLUSIONS: A selective decline in frontal-subcortical cognitive functions is observed after STN DBS in comparison with GPi DBS, which should not be ignored in the target selection for DBS treatment in PD patients. In addition, compared to GPi DBS, STN DBS does not affect depression, anxiety, and quality of life. PMID- 27248140 TI - Time Series Analysis of the Effectiveness and Safety of Capsule Endoscopy between the Premarketing and Postmarketing Settings: A Meta-Analysis. AB - BACKGROUND: Clinical studies for assessing the effectiveness and safety in a premarketing setting are conducted under time and cost constraints. In recent years, postmarketing data analysis has been given more attention. However, to our knowledge, no studies have compared the effectiveness and the safety between the pre- and postmarketing settings. In this study, we aimed to investigate the importance of the postmarketing data analysis using clinical data. METHODS AND FINDINGS: Studies on capsule endoscopy with rich clinical data in both pre- and postmarketing settings were selected for the analysis. For effectiveness, clinical studies published before October 10, 2015 comparing capsule endoscopy and conventional flexible endoscopy measuring the detection ratio of obscure gastrointestinal bleeding were selected (premarketing: 4 studies and postmarketing: 8 studies) from PubMed (MEDLINE), Cochrane Library, EMBASE and Web of Science. Among the 12 studies, 5 were blinded and 7 were non-blinded. A time series meta-analysis was conducted. Effectiveness (odds ratio) decreased in the postmarketing setting (premarketing: 5.19 [95% confidence interval: 3.07-8.76] vs. postmarketing: 1.48 [0.81-2.69]). The change in odds ratio was caused by the increase in the detection ratio with flexible endoscopy as the control group. The efficacy of capsule endoscopy did not change between pre- and postmarketing settings. Heterogeneity (I2) increased in the postmarketing setting because of one study. For safety, in terms of endoscope retention in the body, data from the approval summary and adverse event reports were analyzed. The incidence of retention decreased in the postmarketing setting (premarketing: 0.75% vs postmarketing: 0.095%). The introduction of the new patency capsule for checking the patency of the digestive tract might contribute to the decrease. CONCLUSIONS: Effectiveness and safety could change in the postmarketing setting. Therefore, time series meta-analyses could be useful to continuously monitor the effectiveness of medical device in clinical practices. PMID- 27248142 TI - The International Postal Network and Other Global Flows as Proxies for National Wellbeing. AB - The digital exhaust left by flows of physical and digital commodities provides a rich measure of the nature, strength and significance of relationships between countries in the global network. With this work, we examine how these traces and the network structure can reveal the socioeconomic profile of different countries. We take into account multiple international networks of physical and digital flows, including the previously unexplored international postal network. By measuring the position of each country in the Trade, Postal, Migration, International Flights, IP and Digital Communications networks, we are able to build proxies for a number of crucial socioeconomic indicators such as GDP per capita and the Human Development Index ranking along with twelve other indicators used as benchmarks of national well-being by the United Nations and other international organisations. In this context, we have also proposed and evaluated a global connectivity degree measure applying multiplex theory across the six networks that accounts for the strength of relationships between countries. We conclude by showing how countries with shared community membership over multiple networks have similar socioeconomic profiles. Combining multiple flow data sources can help understand the forces which drive economic activity on a global level. Such an ability to infer proxy indicators in a context of incomplete information is extremely timely in light of recent discussions on measurement of indicators relevant to the Sustainable Development Goals. PMID- 27248141 TI - Intronic Sequence Regulates Sugar-Dependent Expression of Arabidopsis thaliana Production of Anthocyanin Pigment-1/MYB75. AB - Sucrose-specific regulation of gene expression is recognized as an important signaling response, distinct from glucose, which serves to modulate plant growth, metabolism, and physiology. The Arabidopsis MYB transcription factor Production of Anthocyanin Pigment-1 (PAP1) plays a key role in anthocyanin biosynthesis and expression of PAP1 is known to be regulated by sucrose. Sucrose treatment of Arabidopsis seedlings led to a 20-fold induction of PAP1 transcript, which represented a 6-fold increase over levels in glucose-treated seedlings. The PAP1 promoter was not sufficient for conferring a sucrose response to a reporter gene and did not correctly report expression of PAP1 in plants. Although we identified 3 putative sucrose response elements in the PAP1 gene, none were found to be necessary for this response. Using deletion analysis, we identified a 90 bp sequence within intron 1 of PAP1 that is necessary for the sucrose response. This sequence was sufficient for conferring a sucrose response to a minimal promoter: luciferase reporter when present in multiple copies upstream of the promoter. This work lays the foundation for dissecting the sucrose signaling pathway of PAP1 and contributes to understanding the interplay between sucrose signaling, anthocyanin biosynthesis, and stress responses. PMID- 27248143 TI - A Meta-Analysis on Prehypertension and Chronic Kidney Disease. AB - BACKGROUND: Recent studies have demonstrated that there is an association between prehypertension and an increased risk of end-stage renal disease. However, there is conflicting evidence regarding the relationship between prehypertension and chronic kidney disease (CKD). This meta-analysis aimed to demonstrate the association between prehypertension and the incidence of CKD and identify the impacts of gender and ethnic differences. METHODS: MEDLINE, EMBASE, Cochrane Library (from inception through March 2016) and article reference lists were searched for relevant studies regarding blood pressure and CKD. Blood pressure (BP) measurements were classified as follows: optimal BP (less than 120/80 mmHg), prehypertension (120-139/80-89 mmHg) and hypertension (over 140/90 mmHg). CKD was defined by estimated glomerular filtration rate (eGFR)<60 ml/min/1.73 m2 or proteinuria. Two investigators independently extracted the data and assessed the quality of studies enrolled in this meta-analysis using the Newcastle-Ottawa Scale (NOS). We performed the meta-analysis using Stata/SE 12.0 (StataCorp LP). The random-effect models were used in the heterogeneous analyses. RESULTS: After retrieving data from 4,537 potentially relevant articles, we identified 7 cohort studies including 261,264 subjects, according to the predefined selection criteria. Five studies were conducted in Mongolians from East Asia, and the other two studies were performed in Indo-Europeans from Austria and Iran. The participants ranged in age from 20 to 89 years, and the proportion of females ranged from 27.2% to 63.8%. The follow-up period ranged from 2 to 11 years. Compared with the optimal BP values, prehypertension showed an increased risk of CKD (pooled RR = 1.28; 95% CI = 1.13-1.44; P = 0.000; I2 = 77.9%). In the sex stratified analysis, we found a similar trend in women (pooled RR = 1.29; 95% CI = 1.01-1.63; P = 0.039; I2 = 76.1%) but not in men. This effect was observed only in Mongolians from East Asia (pooled RR = 1.37; 95% CI = 1.18-1.59; P = 0.000; I2 = 81.3%) and not in Indo-Europeans. CONCLUSIONS: Prehypertension is considered a potential cause of CKD. Gender and ethnic differences are exhibited in this association. PMID- 27248144 TI - Outcome of patients of chest trauma suffering from chronic obstructive pulmonary disease - experience at level 1 trauma centre. AB - BACKGROUND: The outcome of chest trauma depends on many factors, one of which includes comorbidities. Nowadays, as the elderly population is on the rise, more and more trauma victims are being admitted with chronic obstructive pulmonary disease as a comorbidity in trauma centre intensive care units. However, there are hardly any studies describing the outcome of such patients with chest trauma and chronic obstructive pulmonary disease, both being respiratory problems. The aim was to study the outcomes and various complications in patients of chest trauma with COPD admitted to our ICU over a given time period. METHODS: A detailed review of charts of patients with chest trauma and chronic obstructive pulmonary disease admitted over one and a half years was performed and various parameters noted, including as follows: demographic data; various scores; the number of days on a ventilator and in the ICU. Moreover, complications, such as ventilator associated pneumonia, catheter related bloodstream infections, as well as outcomes, were noted. RESULT: During the study period, 19 patients were admitted, out of which 4 died. The APACHE scores were higher for those who died and all had ventilator-associated pneumonia as a complication. All those who had undergone the placement of an epidural and were managed with non-invasive ventilation initially did not require invasive ventilation. CONCLUSIONS: Chest trauma patients with chronic obstructive pulmonary disease are prone to develop ventilator-associated pneumonia which may be the source of increased mortality among such patients. Epidural placement reduces the risk of invasive ventilation if a patient can be managed with non-invasive ventilation. PMID- 27248145 TI - Evaluation of methodology for the analysis of 'time-to-event' data in pharmacogenomic genome-wide association studies. AB - AIM: To evaluate the power to detect associations between SNPs and time-to-event outcomes across a range of pharmacogenomic study designs while comparing alternative regression approaches. MATERIALS & METHODS: Simulations were conducted to compare Cox proportional hazards modeling accounting for censoring and logistic regression modeling of a dichotomized outcome at the end of the study. RESULTS: The Cox proportional hazards model was demonstrated to be more powerful than the logistic regression analysis. The difference in power between the approaches was highly dependent on the rate of censoring. CONCLUSION: Initial evaluation of single-nucleotide polymorphism association signals using computationally efficient software with dichotomized outcomes provides an effective screening tool for some design scenarios, and thus has important implications for the development of analytical protocols in pharmacogenomic studies. PMID- 27248146 TI - Contig-Layout-Authenticator (CLA): A Combinatorial Approach to Ordering and Scaffolding of Bacterial Contigs for Comparative Genomics and Molecular Epidemiology. AB - A wide variety of genome sequencing platforms have emerged in the recent past. High-throughput platforms like Illumina and 454 are essentially adaptations of the shotgun approach generating millions of fragmented single or paired sequencing reads. To reconstruct whole genomes, the reads have to be assembled into contigs, which often require further downstream processing. The contigs can be directly ordered according to a reference, scaffolded based on paired read information, or assembled using a combination of the two approaches. While the reference-based approach appears to mask strain-specific information, scaffolding based on paired-end information suffers when repetitive elements longer than the size of the sequencing reads are present in the genome. Sequencing technologies that produce long reads can solve the problems associated with repetitive elements but are not necessarily easily available to researchers. The most common high-throughput technology currently used is the Illumina short read platform. To improve upon the shortcomings associated with the construction of draft genomes with Illumina paired-end sequencing, we developed Contig-Layout-Authenticator (CLA). The CLA pipeline can scaffold reference-sorted contigs based on paired reads, resulting in better assembled genomes. Moreover, CLA also hints at probable misassemblies and contaminations, for the users to cross-check before constructing the consensus draft. The CLA pipeline was designed and trained extensively on various bacterial genome datasets for the ordering and scaffolding of large repetitive contigs. The tool has been validated and compared favorably with other widely-used scaffolding and ordering tools using both simulated and real sequence datasets. CLA is a user friendly tool that requires a single command line input to generate ordered scaffolds. PMID- 27248147 TI - Sentinel lymph node biopsy in cutaneous melanoma. AB - The management of melanoma is constantly evolving. New therapies and surgical advances have changed the landscape over the last years. Since being introduced by Dr Donald Morton, the role of sentinel lymph node has been debated. In many melanoma centers, sentinel node biopsy is not a standard of care for melanoma above 1 mm in thickness. The results of the MSLT-II Trial are not available for a while and in the meantime, this procedure is offered as a prognostic indicator as it has been shown to be very useful for assessing risk of relapse. The biology of lymph node spread in melanoma is a complex field and there are many factors which influence it such as age, melanoma body site, thickness but other factors such as regression, ulceration and gender need further evaluation. In this review, we address the clinical value of sentinel lymph node biopsy and how its indication has changed over the years especially recently with the setup of many adjuvant trials which are offered to stage 3 melanomas. PMID- 27248148 TI - Medication patterns in chronic spontaneous urticaria: results from a nationwide investigation in the primary care setting in Italy. AB - BACKGROUND: Only a few studies have assessed treatment usage in clinical practice among patients with chronic spontaneous urticaria (CSU). METHODS: The aim of this study was to evaluate patterns of medications used for CSU, analyzing the electronic patient records contained in the Italian general practice Health Search IMS Health Longitudinal Patient Database (HSD). The study period was from January 2002 to December 2013. RESULTS: The most frequent prescriptions during the year following CSU diagnosis were H1-antihistamines (78.47%) and corticosteroids (49.20%). Different medications were given to a limited number of CSU patients. CONCLUSIONS: The results of our study have shown that H1 antihistamines were the most prescribed drugs to treat CSU, reflecting their role as the mainstay of CSU treatment. Systemic corticosteroids continue to be frequently prescribed for CSU in clinical practice. Alternative drugs were used only in very few patients, suggesting the possibility that severe refractory cases of CSU are undertreated in clinical practice. PMID- 27248149 TI - Association of skin hyperpigmentation and drug use: a systematic review. AB - INTRODUCTION: Part of the acquired hyperpigmentations of the skin are interpreted as adverse effect of drugs. However, systematic studies are rare in the literature, as case reports have predominantly been published. The present systematic review attempts to provide a contribution to the body of evidence for a causal relation. EVIDENCE ACQUISITION: The reports on an association of hyperpigmentation and drugs from 1970 until April 2016 found in Medline and EMBASE were rated according to the SIGN grading system for clinical studies. EVIDENCE SYNTHESIS: A total of 352 evaluated publications were found, which mainly consist of reports of single cases, only a small number of larger case series were available. Case-control-studies and randomized controlled studies have rarely been found. The level of evidence for a causal relation to hyperpigmentation is low for the major part of drugs as quoted in order to the Anatomical Therapeutic Chemical Classification System with Defined Daily Doses. A causal relation is likely only for prostaglandins, minocyclin, phenothiazine, nicotine, and anti-malaria drugs. CONCLUSIONS: There is paucity of evidence for an induction of hyperpigmentation by drugs. A causal relationship is likely only in a small number of drugs. PMID- 27248150 TI - Intravenous immunoglobulin for the treatment of toxic epidermal necrolysis: a systematic review and meta-analysis. AB - INTRODUCTION: The efficacy of intravenous immunoglobulin (IVIg) for toxic epidermal necrolysis (TEN) remains controversial, particularly for high-dose IVIg. In the present study, we conducted a SCORTEN (SCORe of Toxic Epidermal Necrosis)-based standardized mortality ratio (SMR) meta-analysis, with a focus on the efficacy of high-dose IVIg. EVIDENCE ACQUISITION: A systematic review and meta-analysis of the literature published between January 01, 2000 and April 30, 2016 was conducted. Studies with >9 TEN patients receiving IVIg treatment with SCORTEN scores were included. EVIDENCE SYNTHESIS: Mortality rate and pooled SMR were calculated for all TEN patients and adult TEN patients receiving IVIg. Eleven studies met the inclusion criteria. The overall mortality rate of TEN patients treated with IVIg was 24.2%, with a pooled SMR of 1.00 (95% CI, 0.76 1.32; I2=0%, P=0.67). The mortality rate among adult patients treated with high dose IVIg was 11.7%. Sub-analysis of adult patients treated with high-dose IVIg showed a pooled SMR of 0.99 (95% CI, 0.60-1.63; I2=0%, P=0.78). CONCLUSIONS: The findings of the present meta-analysis do not support the clinical benefits of IVIg for TEN, even at high-doses. Additional randomized controlled trials are required to validate this result. PMID- 27248152 TI - Optimization of Multiple and Multipurpose Reservoir System Operations by Using Matrix Structure (Case Study: Karun and Dez Reservoir Dams). AB - Optimal operation of water resources in multiple and multipurpose reservoirs is very complicated. This is because of the number of dams, each dam's location (Series and parallel), conflict in objectives and the stochastic nature of the inflow of water in the system. In this paper, performance optimization of the system of Karun and Dez reservoir dams have been studied and investigated with the purposes of hydroelectric energy generation and providing water demand in 6 dams. On the Karun River, 5 dams have been built in the series arrangements, and the Dez dam has been built parallel to those 5 dams. One of the main achievements in this research is the implementation of the structure of production of hydroelectric energy as a function of matrix in MATLAB software. The results show that the role of objective function structure for generating hydroelectric energy in weighting method algorithm is more important than water supply. Nonetheless by implementing epsilon- constraint method algorithm, we can both increase hydroelectric power generation and supply around 85% of agricultural and industrial demands. PMID- 27248151 TI - Low Serum Creatine Kinase Level Predicts Mortality in Patients with a Chronic Kidney Disease. AB - BACKGROUND: Serum creatine kinase (sCK) reflects CK activity from striated skeletal muscle. Muscle wasting is a risk factor for mortality in patients with chronic kidney disease (CKD). The aim of this study is to evaluate whether sCK is a predictor of mortality and end-stage renal disease (ESRD) in a CKD population. METHODS: We included 1801 non-dialysis-dependent CKD patients from the NephroTest cohort. We used time-fixed and time-dependent cause-specific Cox models to estimate hazard ratios (HRs) for the risk of death and for the risk of ESRD associated with gender-specific sCK tertiles. RESULTS: Higher sCK level at baseline was associated with a lower age, a higher body mass index, and a higher level of 24 h urinary creatinine excretion, serum albumin and prealbumin (p<0.001). Men, patients of sub-Saharan ancestry, smokers and statin users also experienced a higher level of sCK. In a time-fixed Cox survival model (median follow-up 6.0 years), the lowest gender-specific sCK tertile was associated with a higher risk of death before and after adjustment for confounders (Crude model: hazard ratio (HR) 1.77 (95% CI: 1.34-2.32) compared to the highest tertile; fully adjusted model: HR 1.37 (95% CI: 1.02-1.86)). Similar results were obtained with a time-dependent Cox model. The sCK level was not associated with the risk of ESRD. CONCLUSION: A low level of sCK is associated with an increased risk of death in a CKD population. sCK levels might reflect muscle mass and nutritional status. PMID- 27248153 TI - Correlation between global longitudinal peak systolic strain and coronary artery disease severity as assessed by the angiographically derived SYNTAX score. AB - BACKGROUND: In this study, we investigate the correlation between reduced global longitudinal peak systolic strain (GLPSS) and the SYNTAX score (SS) in patients undergoing coronary angiography. METHODS: We examined 71 patients undergoing both echocardiogram and coronary angiography within 15 days. All patients had normal global and/or regional wall motion on resting echocardiogram. We calculated GLPSS using two-dimensional speckle-tracking echocardiography. SS was calculated for each group of patients based on the presence and/or the severity of coronary artery disease (CAD): no CAD on angiogram (n=10, control group), low SS (n=36, SS<22) and high SS (n=25, SS>=22). We hypothesised that GLPSS at rest is inversely correlated with the angiographically derived SS. RESULTS: Age, sex and most of the risk factors were equally distributed among the groups. There was a significant inverse correlation between GLPSS and SS values (r(2)=0.3869, P<0.001). This correlation was weaker in the low-SS group (r(2)=0.1332, P<0.05), whereas it was lost in the high-SS group (r(2)=0.0002, P=NS). Receiver operating characteristic curve analysis identified that the optimal cut-off for the detection of high-SS patients was 13.95% (sensitivity=71%, specificity=90%, P<0.001). CONCLUSIONS: The results of our study suggest that GLPSS might be promising for the detection of patients with high SYNTAX score on coronary angiogram. There is an inverse correlation between resting GLPSS and SS as assessed by coronary angiography. In patients with the highest SS, however, the correlation with GLPSS was less significant. PMID- 27248154 TI - Response to "Comment on 'Flavoring Chemicals in E-Cigarettes: Diacetyl, 2,3 Pentanedione, and Acetoin in a Sample of 51 Products, Including Fruit-, Candy-, and Cocktail-Flavored E-Cigarettes'". PMID- 27248155 TI - In Vitro Metabolic Labeling of Intestinal Microbiota for Quantitative Metaproteomics. AB - Intestinal microbiota is emerging as one of the key environmental factors influencing or causing the development of numerous human diseases. Metaproteomics can provide invaluable information on the functional activities of intestinal microbiota and on host-microbe interactions as well. However, the application of metaproteomics in human microbiota studies is still largely limited, in part due to the lack of accurate quantitative intestinal metaproteomic methods. Most current metaproteomic microbiota studies are based on label-free quantification, which may suffer from variability during the separate sample processing and mass spectrometry runs. In this study, we describe a quantitative metaproteomic strategy, using in vitro stable isotopically ((15)N) labeled microbiota as a spike-in reference, to study the intestinal metaproteomes. We showed that the human microbiota were efficiently labeled (>95% (15)N enrichment) within 3 days under in vitro conditions, and accurate light-to-heavy protein/peptide ratio measurements were obtained using a high-resolution mass spectrometer and the quantitative proteomic software tool Census. We subsequently employed our approach to study the in vitro modulating effects of fructo-oligosaccharide and five different monosaccharides on the microbiota. Our methodology improves the accuracy of quantitative intestinal metaproteomics, which would promote the application of proteomics for functional studies of intestinal microbiota. PMID- 27248156 TI - The Sea Urchin sns5 Chromatin Insulator Shapes the Chromatin Architecture of a Lentivirus Vector Integrated in the Mammalian Genome. AB - Lentivirus vectors are presently the favorite vehicles for therapeutic gene transfer in hematopoietic cells. Nonetheless, these vectors integrate randomly throughout the genome, exhibiting variegation of transgene expression due to the spreading of heterochromatin into the vector sequences. Moreover, the cis regulatory elements harbored by the vector could disturb the proper transcription of resident genes neighboring the integration site. The incorporation of chromatin insulators in flanking position to the transferred unit can alleviate both the above-mentioned dangerous effects, due to the insulator-specific barrier and enhancer-blocking activities. In this study, we report the valuable properties of the sea urchin-derived sns5 insulator in improving the expression efficiency of a lentivirus vector integrated in the mammalian erythroid genome. We show that these results neither reflect an intrinsic sns5 enhancer activity nor rely on the recruitment of the erythroid-specific GATA-1 factor to sns5. Furthermore, by using the Chromosome Conformation Capture technology, we report that a single copy of the sns5-insulated vector is specifically organized into an independent chromatin loop at the provirus locus. Our results not only provide new clues concerning the molecular mechanism of sns5 function in the erythroid genome but also reassure the use of sns5 to improve the performance of gene therapy vectors. PMID- 27248157 TI - Perceived training needs of nurses working with mentally ill patients. AB - : Introductio n: In Malaysia, nurses form a significant part of the clinical mental health team, but the current level of training in mental health results in suboptimal nursing care delivery. METHODS: For this study 220 registered nurses and medical assistants working with the mentally ill completed a structured questionnaire. The purpose of this study was to explore perceived competence in mental healthcare and the training needs of nurses working with mentally ill patients in inpatient mental healthcare facilities. RESULTS: The skills perceived as important for practicing in mental health varied among the nurse participants. Post basic training in mental health was significantly related to perceived competence in patient mental state assessment (p=0.036), risk assessment for suicide (p=0.024), violence (p=0.044) and self-harm (p=0.013). CONCLUSION: There is little emphasis on psychosocial skills in current post basic mental health training in Malaysia. PMID- 27248158 TI - Implanted spacer approaches for pelvic radiation therapy. AB - INTRODUCTION: Recent clinical advances in radiation therapy have aimed to improve the therapeutic ratio through shortening the treatment duration through increasing the biologically effective dose (either through dose escalation or hypofractionation). However, despite using advanced techniques such as intensity modulated radiation therapy (IMRT) and image-guidance methods, dose escalation can be limited by its resultant gastrointestinal toxicity. In an effort to reduce rectal toxicity, biodegradable spacer materials and implantable balloons have been injected into the prostate-rectal space to increase the separation between the rectum and prostate thereby reducing rectal irradiation. AREAS COVERED: The purpose of this review is to describe the commercially available rectal spacers in pelvic radiation therapy, including prostate cancer and gynecologic malignancies, and to discuss the application, dosimetric effects, and reported clinical outcomes to date. Expert commentary: Several groups have reported significantly reduced rectal doses and decreased rectal toxicity with prostate rectal spacers, and additional evidence continues to emerge to support this promising approach. PMID- 27248159 TI - Recent developments in the production and applications of bacterial cellulose fibers and nanocrystals. AB - Cellulosic nanomaterials provide a novel and sustainable platform for the production of high performance materials enabled by nanotechnology. Bacterial cellulose (BC) is a highly crystalline material and contains pure cellulose without lignin and hemicellulose. BC offers an opportunity to provide control of the products' properties in-situ, via specific BC production methods and culture conditions. The BC potential in advanced material applications are hindered by a limited knowledge of optimal BC production conditions, efficient process scale up, separation methods, and purification methods. There is a growing body of work on the production of bacterial cellulose nanocrystals (BCNs) from BC fibers. However, there is limited information regarding the effect of BC fibers' characteristics on the production of nanocrystals. This review describes developments in BC and BCNs production methods and factors affecting their yield and physical characteristics. PMID- 27248160 TI - Intimate economies of development: mobility, sexuality and health in Asia. PMID- 27248161 TI - Global sharing, local innovation: Four schools, four countries, one curriculum. AB - BACKGROUND: Many internal and external obstacles, must be overcome when establishing a new medical school, or when radically revising an existing medical curriculum. AIMS: Twenty-five years after the Flinders University curriculum was introduced as the first graduate-entry medical programme (GEMP) in Australia, we aim at describing how it has been adopted and adapted by several other schools, in Australia and in Europe (UK, Ireland, and Portugal). METHOD/RESULTS: This paper reports on the experience of four schools establishing a new medical school or new curriculum at different times and in different settings. CONCLUSIONS: We believe that these experiences might be of interest to others contemplating a similar development. PMID- 27248162 TI - Health Economic Impact of a Pulmonary Artery Pressure Sensor for Heart Failure Telemonitoring: A Dynamic Simulation. AB - AIMS: Recently, a permanently implantable wireless system, designed to monitor and manage pulmonary artery (PA) pressures remotely, demonstrated significant reductions in heart failure (HF) hospitalizations in high-risk symptomatic patients, regardless of ejection fraction. The objectives of this study were to simulate the estimated clinical and economic impact in Germany of generalized use of this PA pressure monitoring system considering reductions of HF hospitalizations and the improvement in Quality of Life. MATERIALS AND METHODS: Based on the Prospective Health Technology Assessment approach, we simulated the potential of the widespread application of PA pressure monitoring on the German healthcare system for the period 2009-2021. RESULTS: This healthcare economic simulation formulated input assumptions based on results from the CHAMPION Trial, a multicenter, prospective, randomized controlled U.S. trial that demonstrated a 37% reduction of hospitalizations in persistently symptomatic previous HF patients. Based on these results, an estimated 114,800 hospitalizations would expected to be avoided. This effect would potentially save an estimated ?522 million, an equivalent of $575 million, during the entire simulation period. CONCLUSION: This healthcare economic modeling of the PA pressure monitoring system's impact demonstrates substantial clinical and economic benefits in the German healthcare system. PMID- 27248163 TI - [Not Available]. PMID- 27248164 TI - [Memorandum IV: Theoretical and Normative Grounding of Health Services Research]. AB - With Memoranda and other initiatives, the German Network for Health Service Research [Deutsches Netzwerk Versorgungsforschung e.V. (DNVF)] is fostering the methodological quality of care research studies for years. Compared to the standards of empirical research, questions concerning the role and function of theories, theoretical approaches and scientific principles have not been taken up on its own. Therefore, the DNVF e.V. has set up a working group in 2013, which was commissioned to prepare a memorandum on "theories in health care research". This now presented memorandum will primarily challenge scholars in health care services research to pay more attention to questions concerning the theoretical arsenal and the background assumptions in the research process. The foundation in the philosophy of science, the reference to normative principles and the theory bases of the research process are addressed. Moreover, the memorandum will call on to advance the theorizing in health services research and to strengthen not empirical approaches, research on basic principles or studies with regard to normative sciences and to incorporate these relevant disciplines in health services research. Research structures and funding of health services research needs more open space for theoretical reflection and for self-observation of their own, multidisciplinary research processes. PMID- 27248165 TI - A plasma proteolysis pathway comprising blood coagulation proteases. AB - Coagulation factors are essential for hemostasis. Here, we show that these factors also team up to degrade plasma proteins that are unrelated to hemostasis. Prolidase, SRC and amyloid beta1-42 (Abeta1-42) are used as probes. Each probe, upon entering the blood circulation, binds and activates factor XII (FXII), triggering the intrinsic and common coagulation cascades, which in turn activate factor VII, a component of the extrinsic coagulation cascade. Activated factor VII (FVIIa) rapidly degrades the circulating probes. Therefore, FXII and FVIIa serve as the sensor/initiator and executioner, respectively, for the proteolysis pathway. Moreover, activation of this pathway by one probe leads to the degradation of all three probes. Significant activation of this pathway follows tissue injury and may also occur in other disorders, e.g., Alzheimer's disease, of which Abeta1-42 is a key driver. However, enoxaparin, a clinically used anticoagulant, inhibits the proteolysis pathway and elevates plasma levels of the probes. Enoxaparin may also mitigate potential impact of activators of the proteolysis pathway on coagulation. Our results suggest that the proteolysis pathway is important for maintaining low levels of various plasma proteins. Our finding that enoxaparin inhibits this pathway provides a means to control it. Inhibition of this pathway may facilitate the development of disease biomarkers and protein therapeutics, e.g., plasma Abeta1-42 as a biomarker of Alzheimer's disease or recombinant human prolidase as an antitumor agent. PMID- 27248166 TI - A key role of GARP in the immune suppressive tumor microenvironment. AB - In melanoma patients, one of the main reasons for tumor immune escape and therapy failure is the immunosuppressive tumor microenvironment. Herein, suppressive immune cells and inhibitory factors secreted by the tumor itself play a central role.In the present study we show that the Treg activation marker GARP (glycoprotein A repetitions predominant), known to induce peripheral tolerance in a TGF-beta dependent way, is also expressed on human primary melanoma. Interestingly, membrane bound GARP is shed from the surface of both, activated Treg and melanoma cells, and, in its soluble form (sGARP), not only induces peripheral Treg but also a tumor associated (M2) macrophage phenotype. Notably, proliferation of cytotoxic T cells and their effector function is inhibited in the presence of sGARP. GARP expression on Treg and melanoma cells is significantly decreased in the presence of agents such as IFN-alpha, thus explaining at least in part a novel mechanism of action of this adjuvant therapy.In conclusion, GARP in its soluble and membrane bound form contributes to peripheral tolerance in a multipronged way, potentiates the immunosuppressive tumor microenvironment and thus acts as a negative regulator in melanoma patients. Therefore, it may qualify as a promising target and a new checkpoint for cancer immunotherapy. PMID- 27248167 TI - Proteinase-activated receptor 2 promotes TGF-beta-dependent cell motility in pancreatic cancer cells by sustaining expression of the TGF-beta type I receptor ALK5. AB - Pancreatic ductal adenocarcinoma (PDAC) is characterized by high expression of transforming growth factor (TGF)-beta and the G protein-coupled receptor proteinase-activated receptor 2 (PAR2), the latter of which functions as a cell surface sensor for serine proteinases asscociated with the tumour microenvironment. Since TGF-beta and PAR2 affect tumourigenesis by regulating migration, invasion and metastasis, we hypothesized that there is signalling crosstalk between them. Depleting PDAC and non-PDAC cells of PAR2 by RNA interference strongly decreased TGF-beta1-induced activation of Smad2/3 and p38 mitogen-activated protein kinase, Smad dependent transcriptional activity, expression of invasion associated genes, and cell migration/invasion in vitro. Likewise, the plasminogen activator-inhibitor 1 gene in primary cultures of aortic smooth muscle cells from PAR2-/- mice displayed a greatly attenuated sensitivity to TGF-beta1 stimulation. PAR2 depletion in PDAC cells resulted in reduced protein and mRNA levels of the TGF-beta type I receptor activin receptor like kinase 5 (ALK5). Forced expression of wild-type ALK5 or a kinase-active ALK5 mutant, but not a kinase-active but Smad-binding defective ALK5 mutant, was able to rescue TGF-beta1-induced Smad3 activation, Smad dependent transcription, and cell migration in PAR2-depleted cells. Together, our data show that PAR2 is crucial for TGF-beta1-induced cell motility by its ability to sustain expression of ALK5. Therapeutically targeting PAR2 may thus be a promising approach in preventing TGF-beta-dependent driven metastatic dissemination in PDAC and possibly other stroma-rich tumour types. PMID- 27248168 TI - Tumor acidosis enhances cytotoxic effects and autophagy inhibition by salinomycin on cancer cell lines and cancer stem cells. AB - Sustained autophagy contributes to the metabolic adaptation of cancer cells to hypoxic and acidic microenvironments. Since cells in such environments are resistant to conventional cytotoxic drugs, inhibition of autophagy represents a promising therapeutic strategy in clinical oncology. We previously reported that the efficacy of hydroxychloroquine (HCQ), an autophagy inhibitor under clinical investigation is strongly impaired in acidic tumor environments, due to poor uptake of the drug, a phenomenon widely associated with drug resistance towards many weak bases. In this study we identified salinomycin (SAL) as a potent inhibitor of autophagy and cytotoxic agent effective on several cancer cell lines under conditions of transient and chronic acidosis. Since SAL has been reported to specifically target cancer-stem cells (CSC), we used an established model of breast CSC and CSC derived from breast cancer patients to examine whether this specificity may be associated with autophagy inhibition. We indeed found that CSC like cells are more sensitive to autophagy inhibition compared to cells not expressing CSC markers. We also report that the ability of SAL to inhibit mammosphere formation from CSC-like cells was dramatically enhanced in acidic conditions. We propose that the development and use of clinically suitable SAL derivatives may result in improved autophagy inhibition in cancer cells and CSC in the acidic tumor microenvironment and lead to clinical benefits. PMID- 27248169 TI - MtDNA depleted PC3 cells exhibit Warburg effect and cancer stem cell features. AB - Reducing mtDNA content was considered as a critical step in the metabolism restructuring for cell stemness restoration and further neoplastic development. However, the connections between mtDNA depletion and metabolism reprograming based cancer cell stemness in prostate cancers are still lack of studies. Here, we demonstrated that human CRPC cell line PC3 tolerated high concentration of the mtDNA replication inhibitor ethidium bromide (EtBr) and the mtDNA depletion triggered a universal metabolic remodeling process. Failure in completing that process caused lethal consequences. The mtDNA depleted (MtDP) PC3 cells could be steadily maintained in the special medium in slow cycling status. The MtDP PC3 cells contained immature mitochondria and exhibited Warburg effect. Furthermore, the MtDP PC3 cells were resistant to therapeutic treatments and contained greater cancer stem cell-like subpopulations: CD44+, ABCG2+, side-population and ALDHbright. In conclusion, these results highlight the association of mtDNA content, mitochondrial function and cancer cell stemness features. PMID- 27248170 TI - Targeting FOSB with a cationic antimicrobial peptide, TP4, for treatment of triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) currently lacks a suitable therapeutic candidate and is thus difficult to treat. Here, we report that a cationic antimicrobial peptide (CAP), tilapia piscidin 4 (TP4), which was derived from Nile tilapia (Oreochromis niloticus), is selectively toxic to TNBC. TP4 acts by inducing an AP-1 protein called FOSB, the expression of which is negatively associated with the pathological grade of TNBC. We show that TP4 is bound to the mitochondria where it disrupts calcium homeostasis and activates FOSB. FOSB overexpression results in TNBC cell death, whereas inhibition of calcium signaling eliminates FOSB induction and blocks TP4-induced TNBC cell death. Both TP4 and anthracyclines strongly induced FOSB, particularly in TNBC, indicating that FOSB may be suitable as a biomarker of drug responses. This study thus provides a novel therapeutic approach toward TNBC through FOSB induction. PMID- 27248171 TI - Reprofiling using a zebrafish melanoma model reveals drugs cooperating with targeted therapeutics. AB - Phenotype-guided re-profiling of approved drug molecules presents an accelerated route to developing anticancer therapeutics by bypassing the target identification bottleneck of target-based approaches and by sampling drugs already in the clinic. Further, combinations incorporating targeted therapies can be screened for both efficacy and toxicity. Previously we have developed an oncogenic-RAS-driven zebrafish melanoma model that we now describe display melanocyte hyperplasia while still embryos. Having devised a rapid method for quantifying melanocyte burden, we show that this phenotype can be chemically suppressed by incubating V12RAS transgenic embryos with potent and selective small molecule inhibitors of either MEK or PI3K/mTOR. Moreover, we demonstrate that combining MEK inhibitors (MEKi) with dual PI3K/mTOR inhibitors (PI3K/mTORi) resulted in a super-additive suppression of melanocyte hyperplasia. The robustness and simplicity of our novel screening assay inspired us to perform a modest screen of FDA approved compounds for their ability to potentiate MEKi PD184352 or PI3K/mTORi NVPBEZ235 suppression of V12RAS-driven melanocyte hyperplasia. Through this route, we confirmed Rapamycin as a compound that could synergize with MEKi and even more so with PI3K/mTORi to suppress melanoma development, including suppressing the growth of cultured human melanoma cells. Further, we discovered two additional compounds-Disulfiram and Tanshinone-that also co-operate with MEKi to suppress the growth of transformed zebrafish melanocytes and showed activity toward cultured human melanoma cells. In conclusion, we provide proof-of-concept that our phenotype-guided screen could be used to identify compounds that affect melanoma development and prompt further evaluation of Disulfiram and Tanshinone as possible partners for combination therapy. PMID- 27248172 TI - Integrin alphavbeta3 enhances beta-catenin signaling in acute myeloid leukemia harboring Fms-like tyrosine kinase-3 internal tandem duplication mutations: implications for microenvironment influence on sorafenib sensitivity. AB - Binding of leukemia cells to the bone marrow extracellular matrix (ECM) through integrins might influence drug response and the survival of acute myeloid leukemia (AML). However, the functions of integrin in AML are needed to be clarified. Data from The Cancer Genome Atlas (TCGA) were retrieved and integrin beta3 (ITGB3) expression and prognostic significance for AML were analyzed. Integrin alphavbeta3 (alphavbeta3) in sorafenib sensitivity and signaling pathway of FLT3-ITD AML cells was evaluated in vitro. The level of ITGB3 expression was positively correlated with risk stratification and prognosis of AML patients, especially in cytogenetic-normal patients with Fms-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) mutation. Integrin alphavbeta3 decreased sorafenib sensitivity when co-culture of MV4-11 cells and bone marrow stromal cells (BMSCs), and it is crucial for osteopontin (OPN) induced sorafenib insensitivity in FLT3-ITD mutated AML cells. Mechanically, alphavbeta3 enhance beta-catenin activation through phosphatidylinositol 3-kinase (PI3K)/Akt/Glycogen synthase kinase-3 beta (GSK3beta) pathway. Moreover, genetic inhibition of beta catenin by shRNA could increase sorafenib sensitivity in MV4-11 cells. Taken together, our study revealed a novel mechanism in microenvironment influence on sorafenib sensitivity in AML with FLT3-ITD mutation that was caused by activating integrin alphavbeta3/PI3K/Akt/GSK3beta/beta-catenin pathway. Integrin alphavbeta3/beta-catenin could be considered as a new therapeutic target for AML especially for FLT3-ITD mutated AML. PMID- 27248173 TI - Inverse role of distinct subsets and distribution of macrophage in lung cancer prognosis: a meta-analysis. AB - BACKGROUND: Tumor-associated macrophages (TAMs) play a crucial role in the regulation of local inflammatory and immune response of tumor microenvironment, being associated with worse outcome of several solid tumors. But the prognostic value of tumor-infiltrating TAMs in lung cancer is still controversial. METHODS: We conduct a meta-analysis of 3055 patients in 21 studies searched from PubMed and Medline to investigate the correlation between tumor-infiltrating TAMs, including distinct TAM subsets and tissue distribution, and survival of lung cancer. Survival data were computed into odds ratios (ORs) and pooled using Mantel-Haenszel random-effect model. All statistical tests were two-sided. RESULTS: High density of tumor-infiltrating TAMs was significantly associated with worse overall survival (OS) at 3 years (OR = 2.45, 95% CI = 1.25 to 4.80, P = 0.009) and 5 years (OR = 2.04, 95% CI = 1.03 to 4.01, P = 0.04) of lung cancer. Results for disease free survival (DFS) were similar. M2 subset was associated with worse 3 year-OS and 5 year-OS, whereas M1 subset was associated with better 3-year OS and 5-year OS. Elevated TAM density in tumor stroma was associated with worse OS at 3 years and 5 years, while elevated TAMs in tumor islet/tumor stroma were associated with better OS at 3 years and 5 years. CONCLUSIONS: Increased tumor-infiltrating TAMs are associated with poor prognosis of lung cancer. M2 subset and TAMs in tumor stroma were associated with worse survival, while M1 subset and TAMs in tumor islet were associated with favorable survival of lung cancer. PMID- 27248174 TI - Noninvasive detection of tumor-associated mutations from circulating cell-free DNA in hepatocellular carcinoma patients by targeted deep sequencing. AB - BACKGROUND: Detection of circulating cell-free DNA (cfDNA) has potential clinical value for assessing tumor biology in patients with hepatocellular carcinoma (HCC), yet many traditional assays lack robustness. This study was the first to apply a high-throughput sequencing platform to detect tumor-associated mutations in HCC from circulating tumor-derived DNA (ctDNA) and to evaluate the utility and feasibility of this approach. METHODS: Using the MiSeqTM system, plasma and matched tumor DNA samples were analyzed for hotspot mutations in the TERT, CTNNB1, and TP53 genes that had been verified as the most prevalent mutations in HCC. We compared tumor and plasma data and prospectively investigated the association between significant mutations detected in ctDNA and the patients' clinical outcomes. RESULTS: In 41 patients, we detected tumor-associated mutations for HCC in 8 (19.5%) plasma samples. Among them, one showed a tumor associated mutation in ctDNA but not in the tumor tissue which we used to detect. We also found that ctDNA with mutations could be detected more easily in patients who suffered vascular invasion (P=0.041) and predicted a shorter recurrence-free survival time (P<0.001). There was no relationship between detectable mutations and concentration of cfDNA (P=0.818). CONCLUSIONS: The results of our study suggest that tumor-associated mutations detected in plasma are associated with vascular invasion and might be used to predict a shorter recurrence-free survival time for HCC patients. This kind of biomarker can overcome the limitations of tumor heterogeneity. Moreover, the diagnostic performance is improved if multiple mutations in different genes are combined. PMID- 27248176 TI - IL-8 signaling is involved in resistance of lung carcinoma cells to erlotinib. AB - A signaling pathway that is frequently deregulated in human carcinomas and has been explored as a therapeutic target involves the activation of the epidermal growth factor receptor (EGFR). Inhibition of EGFR via the small molecule inhibitors erlotinib and gefitinib commonly results in tumor resistance, even in patients with EGFR-mutant tumors that initially show substantial clinical responses. This study was designed to broaden our understanding of the molecular mechanisms of acquired resistance to erlotinib in lung cancer cells bearing wild type or mutated EGFR. We report here that generation of erlotinib-resistant lung cancer cells in vitro resulted in a phenotypic alteration reminiscent of an epithelial-mesenchymal transition (EMT) concomitant with a robust upregulation of the IL-8/IL-8R axis. Our results also demonstrate that upregulation of p38 MAPK signaling is responsible for the enhanced IL-8 secretion in the erlotinib resistant tumor cells. Blockade of IL-8 signaling effectively reduced mesenchymal features of the resistant cells and also markedly enhanced their susceptibility to erlotinib. These results provide a rationale for the development of new therapeutic approaches involving blockade of IL-8 signaling for the management of acquired resistance to EGFR inhibition in patients with lung cancer. PMID- 27248177 TI - Chemotherapy plus targeted drugs in conversion therapy for potentially resectable colorectal liver metastases: a meta-analysis. AB - OBJECTIVES: To evaluate the safety and efficiency of the conversion therapy: chemotherapy plus anti-epidermal growth factor Receptor (EGFR) or anti-vascular endothelial growth factor receptor (VEGFR) monoclonal antibodies (MoAbs) with different rat sarcoma (RAS) status in patients with potentially resectable colorectal liver metastases (CRLM). METHODS: Randomized controlled trials (RCTs) were identified and the association between RAS mutation and clinical outcome in CRLM patients treated with anti-EGFR or anti-VEGFR MoAbs was investigated. Searches were performed for data recorded between January 2005 and August 2015 in the Cochrane Library, MEDLINE, PubMed, and EMBASE. Objective response rates (ORR), conversion resection rates (CRR), R0 resection rates (R0R) and rate ratios (RR) were used to assess the strength of the association between different RAS status, MoAbs and conversion efficiency. RESULTS: In the conversion therapy, ORR and RR were associated with patients with wild type RAS and different MoAbs. Patients treated with MoAbs: anti-VEGFR or anti-EGFR drugs, resulted in higher ORR, (RR=1.53, 95% confidence interval [CI]: 1.27-1.84, P < 0.05). Furthermore, anti-EGFR regimens displayed higher ORR compared with anti-VEGFR regimens in CRLM patients, (RR=1.15, 95%CI: 1.04-1.26, P < 0.05). However, CRLM patients with mutant type RAS did not benefit from anti-EGFR therapy, (RR=0.91, 95%CI: 0.76 1.08, P<0.05) and wild type RAS patients displayed higher ORR with anti-EGFR therapy, (RR=1.56, 95%CI: 1.16-2.01, P <0.05). In addition, the patients achieved higher resection rates (RR=1.67, 95%CI: 1.00-2.81, P <= 0.05) and R0 resection (RR=1.85, 95%CI: 1.04-3.27, P < 0.05). CONCLUSION: We noted that the addition of MoAbs (anti-EGFR or anti-VEGFR) to standard chemotherapy could improve conversion efficiency for patients with potentially resectable CRLM patients, and anti-EGFR therapies maybe more effective than anti-VEGFR therapies. RAS status is a potential predictive marker of the clinical benefit resulting from treatment with anti-EGFR MoAbs therapy in CRLM patients and anti-EGFR MoAbs therapy could displayed greater efficiency only in patients with wild type RAS. PMID- 27248175 TI - Targeting folate receptor alpha for cancer treatment. AB - Promising targeted treatments and immunotherapy strategies in oncology and advancements in our understanding of molecular pathways that underpin cancer development have reignited interest in the tumor-associated antigen Folate Receptor alpha (FRalpha). FRalpha is a glycosylphosphatidylinositol (GPI) anchored membrane protein. Its overexpression in tumors such as ovarian, breast and lung cancers, low and restricted distribution in normal tissues, alongside emerging insights into tumor-promoting functions and association of expression with patient prognosis, together render FRalpha an attractive therapeutic target. In this review, we summarize the role of FRalpha in cancer development, we consider FRalpha as a potential diagnostic and prognostic tool, and we discuss different targeted treatment approaches with a specific focus on monoclonal antibodies. Renewed attention to FRalpha may point to novel individualized treatment approaches to improve the clinical management of patient groups that do not adequately benefit from current conventional therapies. PMID- 27248178 TI - High serum haptoglobin level is associated with tumor progression and predicts poor prognosis in non-small cell lung cancer. AB - The overall survival time of non-small cell lung cancer (NSCLC) has not improved dramatically in recent decades. An important reason is the lacking of valuable biomarkers. Haptoglobin was reported to have activities of anti-inflammatory, anti-oxidant, autoimmune and tumor angiogenesis. However its potential role as a tumor biomarker was not well recognized. We used an immunoturbidimetry method to measure serum haptoglobin levels in 205 NSCLC patients, and 210 normal healthy controls. We found that serum haptoglobin levels were significantly elevated in NSCLC patients compared with normal healthy controls (1.985+/-1.039 mg/mLvs. 0.922 +/- 0.495 mg/mL, respectively, P < 0.0001). Higher serum haptoglobin levels were associated with advanced TNM stage, lymph node metastasis, and distant metastasis. Area under receiver operating characteristic curve (ROC) for serum haptoglobin was 0.809 (95% CI: 0.767-0.852) at a specificity of 0.881 and sensitivity of 0.639. The optimal cut-off value of haptoglobin was 1.495 mg/mL for discriminating NSCLC from normal healthy controls. Kaplan-Meier log rank analysis revealed that the higher serum haptoglobin levels group had a poorer overall survival compared with lower haptoglobin group (the median survival was 12.0 weeks , 26.0 weeks, respectively, P < 0.01). Further univariate and multivariate Cox regression analysis showed that serum haptoglobin was an independent risk factor of prognosis of NSCLC patients (P < 0.01, P = 0.01, respectively). In conclusion, our study suggests that serum haptoglobin may act as useful clinical serological biomarkers in progression and prognostic evaluation in NSCLC. PMID- 27248179 TI - beta2-spectrin depletion impairs DNA damage repair. AB - beta2-Spectrin (beta2SP/SPTBN1, gene SPTBN1) is a key TGF-beta/SMAD3/4 adaptor and transcriptional cofactor that regulates TGF-beta signaling and can contribute to liver cancer development. Here we report that cells deficient in beta2 Spectrin (beta2SP) are moderately sensitive to ionizing radiation (IR) and extremely sensitive to agents that cause interstrand cross-links (ICLs) or replication stress. In response to treatment with IR or ICL agents (formaldehyde, cisplatin, camptothecin, mitomycin), beta2SP deficient cells displayed a higher frequency of cells with delayed gamma-H2AX removal and a higher frequency of residual chromosome aberrations. Following hydroxyurea (HU)-induced replication stress, beta2SP-deficient cells displayed delayed disappearance of gamma-H2AX foci along with defective repair factor recruitment (MRE11, CtIP, RAD51, RPA, and FANCD2) as well as defective restart of stalled replication forks. Repair factor recruitment is a prerequisite for initiation of DNA damage repair by the homologous recombination (HR) pathway, which was also defective in beta2SP deficient cells. We propose that beta2SP is required for maintaining genomic stability following replication fork stalling, whether induced by either ICL damage or replicative stress, by facilitating fork regression as well as DNA damage repair by homologous recombination. PMID- 27248181 TI - Fully Fused Quinoidal/Aromatic Carbazole Macrocycles with Poly-radical Characters. AB - While the chemistry of open-shell singlet diradicaloids has been successfully developed in recent years, the synthesis of pi-conjugated systems with poly radical characters (i.e., beyond diradical) in the singlet ground state has been mostly unsuccessful. In this study, we report the synthesis and isolation of two fully fused macrocycles containing four (4MC) and six (6MC) alternatingly arranged quinoidal/aromatic carbazole units. Ab initio electronic structure calculations and various experimental measurements indicate that both 4MC and 6MC have an open-shell singlet ground state with moderate tetraradical and hexaradical characters, respectively. Both compounds can be thermally populated to high-spin excited states, resulting in weak magnetization at room temperature. Our study represents the first demonstration of singlet pi-conjugated molecules with poly-radical characters and also gives some insights into molecular magnetism in neutral pi-conjugated polycyclic heteroarenes. PMID- 27248182 TI - The use of structural equation modelling and behavioural theory to target priority interventions to increase condom use among the intimate partners of sex workers in French Guiana. AB - French Guiana is the French overseas territory that is most affected by HIV. Sex work seems to be an important driver of the epidemic. Although female sex workers are informed by local NGOs, they still have risky behaviours, including not using condoms with their intimate partner despite knowing HIV is highly prevalent. The objective of this study was to find intervention targets on this specific behaviour. For this, a structural equation model (SEM) was built using assumptions from behavioural theories. Behaviour theories attempt to connect research and practice. Within the health belief model framework, perceived threats, perceived benefits, and self-perceived efficacy were tested. Vulnerability was added because of the particular context of French Guiana. The results highlight that female sex workers' perceived self-efficacy was central in condom use with the intimate partner (with a significant correlation coefficient of 0.52 in the SEM). The perceived self-efficacy was strongly influenced by sociodemographic factors, particularly by nationality. Female sex workers from Brazil seemed to be more comfortable about asking their intimate partner to use condoms (OR: 7.81; CI: 1.87-32.63) than sex workers of other nationalities. These results emphasize that prevention interventions for female sex workers should emphasize their empowerment. PMID- 27248180 TI - The genetic landscape of dural marginal zone lymphomas. AB - The dura is a rare site of involvement by marginal zone lymphoma (MZL) and the biology of dural MZL is not well understood. We performed genome-wide DNA copy number and targeted mutational analysis of 14 dural MZL to determine the genetic landscape of this entity. Monoallelic and biallelic inactivation of TNFAIP3 by mutation (n=5) or loss (n=1) was observed in 6/9 (67%) dural MZL exhibiting plasmacytic differentiation, including 3 IgG4+ cases. In contrast, activating NOTCH2 mutations were detected in 4/5 (80%) dural MZL displaying variable monocytoid morphology. Inactivating TBL1XR1 mutations were identified in all NOTCH2 mutated cases. Recurrent mutations in KLHL6 (n=2) and MLL2 (n=2) were also detected. Gains at 6p25.3 (n=2) and losses at 1p36.32 (n=3) were common chromosomal imbalances, with loss of heterozygosity (LOH) of these loci observed in a subset of cases. Translocations involving the IGH or MALT1 genes were not identified. Our results indicate genetic similarities between dural MZL and other MZL subtypes. However, recurrent and mutually exclusive genetic alterations of TNFAIP3 and NOTCH2 appear to be associated with distinct disease phenotypes in dural MZL. PMID- 27248183 TI - On the Mechanism of Hydrophilicity of Graphene. AB - It is generally accepted that the hydrophilic property of graphene can be affected by the underlying substrate. However, the role of intrinsic vs substrate contributions and the related mechanisms are vividly debated. Here, we show that the intrinsic hydrophilicity of graphene can be intimately connected to the position of its Fermi level, which affects the interaction between graphene and water molecules. The underlying substrate, or dopants, can tune hydrophilicity by modulating the Fermi level of graphene. By shifting the Fermi level of graphene away from its Dirac point, via either chemical or electrical voltage doping, we show enhanced hydrophilicity with experiments and first principle simulations. Increased vapor condensation on graphene, induced by a simple shifting of its Fermi level, exemplifies applications in the area of interfacial transport phenomena. PMID- 27248184 TI - Rate of Threading a Cellulose Chain into the Binding Tunnel of a Cellulase. AB - Industrially important cellulase Cel7A hydrolyzes crystalline cellulose by a complex processive mechanism in which the enzyme slides along the cellulose surface with one strand of the polymeric substrate channeled through its catalytic tunnel. Each processive run must start with threading the tunnel with a cellulose strand and end with the opposite, that is, the dethreading process. Evidence has suggested that threading or dethreading may be rate-limiting for the overall enzyme reaction. To directly elucidate the rates of threading and dethreading, we analyzed experimental data with respect to a two-step model that distinguishes enzymes in free, associated nonthreaded, and threaded states. This approach enabled the estimation of rate constants for both steps in both directions. The results showed that Cel7A utilizes a "tapping" mode of attack, in which it associates unproductively with the cellulose surface many times before it eventually finds a location at which it gets threaded. Moreover, it was concluded that at the quasi steady state dethreading was the main determinant of the overall hydrolytic rate under most conditions. An exception to this was at very low enzyme/substrate ratios, at which other steps also influenced the overall dynamics. These results will be helpful in identifying rate-limiting steps for cellulases and, in turn, targets for rational design of faster enzymes. PMID- 27248185 TI - Cigarette Smoking, Alcohol and Cannabis Use in Patients With Pervasive Developmental Disorders. AB - BACKGROUND AND OBJECTIVES: This study aimed to examine the rates of cigarette smoking, alcohol and cannabis use among patients with pervasive developmental disorder (PDD), in order to determine whether they are relatively protected from developing substance-related addictive behaviors. METHODS: This case-control study included 85 patients diagnosed with PDD and 85 age- and gender-matched nonpsychotic psychiatric patients without PDD. Data were collected from the patients' electronic medical records and included demographic and psychiatric parameters, as well as data on smoking, alcohol, and cannabis use. RESULTS: A lower rate of cigarette smoking was found among patients diagnosed with PDD in comparison to those without PDD [20.0% vs. 52.9% respectively, p < .001). The likelihood of smoking in PDD was found to be 3.57-fold lower than in psychiatric controls [OR = 3.57 (95% CI 1.69-7.14), p = .001]. A multivariate analysis showed that after adjusting for age, comorbid diagnoses and use of an antipsychotic medications, this effect was even more robust with the likelihood of smoking in PDD decreasing even more substantially compared to controls [OR = 8.33 (95% CI 2.86-25), p < .001]. A similar finding was noted when comparing the prevalence of alcohol and cannabis use between the two groups [OR 6.67 (95%CI 1.30-33.33), p = .02 and 5.55 (95%CI 1.30-25), p = .01, respectively]. CONCLUSIONS: PDD is associated with 5-8-fold lower adjusted risk of smoking, alcohol and cannabis use compared to other non-psychotic psychiatric patients. Further research should elucidate the neurobiological and psychosocial mechanisms underlying the apparent addiction protective properties of PDD. PMID- 27248186 TI - The impact of patient's weight on post-stroke rehabilitation. AB - Purpose To evaluate the influence of patient's weight on rehabilitation outcomes in first-event stroke patients. Design Retrospective, observational comparative study. 102 first-time stroke male and female patients admitted to the 52-bed neurology rehabilitation department in a rehabilitation hospital were included in the study. Body mass index (BMI), Functional Independence Measure (FIM) on admission and at discharge, as well as the delta-FIM (FIM on admission - FIM at discharge) were evaluated. The Kruskal-Wallis test was used to compare the FIM and the NIHSS scores between BMI groups (normal, overweight, moderate and severe obesity). Results A statistically significant negative correlation (rho = -0.20, p = 0.049) was found between FIM change and BMI, that remained significant after adjustments for age, sex and hospitalisation days. No difference was found between groups in FIM or NIHSS change between BMI groups. Conclusions In sub acute post-stroke patients undergoing rehabilitation in rehabilitation hospital, BMI was negatively associated with the improvement of functional parameters. Patients' BMI should be taken into consideration when predicting rehabilitation outcome for stroke patients. Further investigations are needed to identify the functional parameters affected by the patients' BMI. Implications for Rehabilitation In sub-acute post-stroke patients undergoing rehabilitation in rehabilitation hospital, BMI was negatively associated with the improvement of functional parameters. Patients' BMI should be taken into consideration when predicting rehabilitation outcome for stroke patients. New rehabilitation strategies should be designed to improve the functional outcomes of rehabilitation of obese patients. PMID- 27248187 TI - Comment on "Effects of Arsenite during Fetal Development on Energy Metabolism and Susceptibility to Diet-Induced Fatty Liver Diseases in Male Mice" and "Mechanisms Underlying Latent Disease Risk Associated with Early-Life Arsenic Exposure: Current Trends and Scientific Gaps". PMID- 27248201 TI - The economic burden of end-of-life care in metastatic breast cancer. AB - OBJECTIVE: To assess end-of-life (EOL) total healthcare costs and resource utilization during the last 6 months of claims follow-up among patients with metastatic breast cancer (MBC) who received systemic anti-neoplastic therapy. METHODS: Newly diagnosed females with MBC initiating treatment January 1, 2003 June 30, 2011 were identified in a large commercial claims database. Two cohorts were defined based on a proxy measure for EOL 1 month prior to the end of last recorded follow-up within the study period: patients who were assumed dead at end of claims follow-up (EOL cohort) and patients who were alive (no-end-of-life [NEOL] cohort). Proxy measures for EOL were obtained from published literature and clinical expert opinion. Cost and resource utilization were evaluated for the 6 months prior to end of claims follow-up. Baseline variables, resource utilization, and costs were compared between cohorts with univariate statistical tests. Adjusted relative risks were calculated for resource utilization measures. A covariate-adjusted generalized linear model evaluated 6-month total healthcare costs. RESULTS: Of the 3,878 females included, 18.5% (n = 718) met the criteria for EOL. Mean observational time (MBC onset to end of claims follow-up) was shorter for the EOL cohort (EOL, 32 months vs NEOL, 35 months; p < 0.001). In adjusted analyses, the EOL cohort had 4.15 times higher 6-month total healthcare costs (EOL, $72,112 vs NEOL, $17,137; p < 0.001). NEOL month-to-month mean total healthcare costs fluctuated between $2336-$3145, while EOL costs increased steadily from $8,956 in the sixth month prior to death to $19,326 in the last month of life. The adjusted relative risk of inpatient, hospice and emergency department utilization was >2 times higher in the EOL cohort (p < 0.001). CONCLUSIONS: Potential EOL presented a greater economic burden in the 6 months prior to death. EOL month-to-month costs increased precipitously in the last 2 months of life and were driven by acute inpatient care. PMID- 27248203 TI - The Web-Based Assessment of Suicidal and Suicide-Related Symptoms: Factors Associated With Disclosing Identifying Information to Receive Study Compensation. AB - With the increasing utilization of Web-based surveys for suicide and suicide related research, it is critical to understand factors that affect participants' decision to request study compensation (and thus potentially reveal their identity) or remain anonymous. This study evaluated differences in demographics, suicidal symptoms, and suicide-related constructs between participants electing and declining to provide identifying information to receive study compensation. A sample of 931 firefighters (91.5% male) participated in a Web-based mental health survey; on survey completion, individuals had the option to provide contact information to receive a $10 gift card. Logistic regression analyses were employed to investigate differences between those who did and did not provide this information. Overall, 82.8% provided identifying information, with younger individuals significantly more likely to do so. Participants reporting more severe suicidal symptoms and greater levels of suicide-related constructs appeared equally, and in some cases, significantly more, willing to provide identifying information. Findings indicate that individuals reporting more sensitive or stigmatizing experiences might not systematically opt out of receiving study compensation to remain anonymous on Web-based surveys. Additional research is warranted to replicate these findings in more representative samples and further delineate personality and other factors influencing the disclosure of contact information to receive study compensation. PMID- 27248204 TI - Third generation antiepileptic drug monotherapies in adults with epilepsy. AB - INTRODUCTION: Drugs marketed during the last few years (i.e. Lacosamide, Ruifinamide, Eslicarbazepine acetate, Brivaracetam and Perampanel) are increasingly regarded as third generation AEDs. This paper presents available data about monotherapy with third generation drugs and on-going clinical trials with special attention to the existing debate about monotherapy license in epilepsy. AREAS COVERED: References were identified by searches of Medline/PubMed. In addition, currently active studies for these AEDs were identified in the ClinicalTrials.gov database. Expert commentary: Results of studies on Eslicarbazepine acetate and Lacosamide clearly suggest good efficacy and tolerability. The selective pharmacological profile, the lack of interactions, the good tolerability with low propensity for cognitive side effects and the availability of different pharmacological formulations represent evident advantages. Although third generation monotherapies are quite promising, long-term safety data is needed in order to understand how these compounds will place in the current armamentarium. PMID- 27248205 TI - The Effects of 23-Gauge Pars Plana Vitrectomy on Orbital Circulation Using Doppler Ultrasonography in Diabetic Macular Edema with Epiretinal Membrane and Taut Posterior Hyaloid. AB - PURPOSE: To evaluate using Doppler ultrasonography (DUS) how pars plana vitrectomy (PPV) affects orbital circulation in diffuse diabetic macular edema (DME) associated with either the epiretinal membrane (ERM) or taut posterior hyaloid (TPH). METHODS: The sample included 46 eyes of 42 patients with DME associated with the ERM (n = 22, Group 1) or TPH (n = 24, Group 2). All participants received panretinal laser photocoagulation and antivascular endothelial growth factor injections preoperatively and underwent 23-gauge PPV combined with ERM or TPH removal and internal limiting membrane (ILM) peeling. Pre- and postoperative peak systolic velocity (PSV), end-diastolic velocity (EDV), and the resistivity index (RI) of the ophthalmic artery (OA), central retinal artery (CRA), posterior ciliary artery (PCA), and central retinal vein were measured with DUS. RESULTS: Statistically significant decreases in the PSV and EDV of the OA, CRA, and PCA were detected in all groups. In Group 1, the PSV of the OA and CRA as well as the EDV and PSV of the PCA declined significantly. In Group 2, the EDV of the OA and both the PSV and EDV of the CRA and PCA decreased. Postoperatively, the CRA's PSV and EDV were lower in Group 2, while the preoperative and postoperative RI of the CRA and preoperative RI of the PCA were greater in Group 2 than in Group 1. Changes in the CRA's RI, PSV, and EDV were greater in Group 2 after surgery. CONCLUSIONS: 23-Gauge PPV combined with ERM or TPH removal and ILM peeling in DME reduces blood flow rates of both choroidal and retinal vessels. In eyes with TPH, the RIs of the CRA and PCA were significantly greater preoperatively and the changes in the CRA's RI, PSV, and EDV were greater postoperatively. The removal of the TPH may play a role in regulating blood flow. PMID- 27248202 TI - Non-viral nucleic acid containing nanoparticles as cancer therapeutics. AB - INTRODUCTION: The delivery of nucleic acids such as DNA and short interfering RNA (siRNA) is promising for the treatment of many diseases, including cancer, by enabling novel biological mechanisms of action. Non-viral nanoparticles are a promising class of nucleic acid carriers that can be designed to be safer and more versatile than traditional viral vectors. AREAS COVERED: In this review, recent advances in the intracellular delivery of DNA and siRNA are described with a focus on non-viral nanoparticle-based delivery methods. Material properties that have enabled successful delivery are discussed as well as applications that have directly been applied to cancer therapy. Strategies to co-deliver different nucleic acids are highlighted, as are novel targets for nucleic acid co-delivery. EXPERT OPINION: The treatment of complex genetically-based diseases such as cancer can be enabled by safe and effective intracellular delivery of multiple nucleic acids. Non-viral nanoparticles can be fabricated to deliver multiple nucleic acids to the same cell simultaneously to prevent tumor cells from easily compensating for the knockdown or overexpression of one genetic target. The continued innovation of new therapeutic modalities and non-viral nanotechnologies to provide target-specific and personalized forms of gene therapy hold promise for genetic medicine to treat diseases like cancer in the clinic. PMID- 27248206 TI - Multifunctional Iodide-Free Polymeric Ionic Liquid for Quasi-Solid-State Dye Sensitized Solar Cells with a High Open-Circuit Voltage. AB - A polymeric ionic liquid, poly(oxyethylene)-imide-imidazolium selenocyanate (POEI IS), was newly synthesized and used for a multifunctional gel electrolyte in a quasi-solid-state dye-sensitized solar cell (QSS-DSSC). POEI-IS has several functions: (a) acts as a gelling agent for the electrolyte of the DSSC, (b) possesses a redox mediator of SeCN(-), which is aimed to form a SeCN(-)/(SeCN)3( ) redox couple with a more positive redox potential than that of traditional I( )/I3(-), (c) chelates the potassium cations through the lone pair electrons of the oxygen atoms of its poly(oxyethylene)-imide-imidazolium (POEI-I) segments, and (d) obstructs the recombination of photoinjected electrons with (SeCN)3(-) ions in the electrolyte through its POEI-I segments. Thus, the POEI-IS renders a high open-circuit voltage (VOC) to the QSS-DSSC due to its functions of b-d and prolongs the stability of the cell due to its function of a. The QSS-DSSC with the gel electrolyte containing 30 wt % of the POEI-IS in liquid selenocyanate electrolyte exhibited a high VOC of 825.50 +/- 3.51 mV and a high power conversion efficiency (eta) of 8.18 +/- 0.02%. The QSS-DSSC with 30 wt % POEI-IS retained up to 95% of its initial eta after an at-rest stability test with the period of more than 1,000 h. PMID- 27248208 TI - Association between ulcer site and outcome in complicated peptic ulcer disease: a Danish nationwide cohort study. AB - OBJECTIVE: Mortality rates in complicated peptic ulcer disease are high. This study aimed to examine the prognostic importance of ulcer site in patients with peptic ulcer bleeding (PUB) and perforated peptic ulcer (PPU). MATERIALS AND METHODS: DESIGN: a nationwide cohort study with prospective and consecutive data collection. POPULATION: all patients treated for PUB and PPU at Danish hospitals between 2003 and 2014. DATA: demographic and clinical data reported to the Danish Clinical Registry of Emergency Surgery. OUTCOME MEASURES: 90- and 30-d mortality and re-intervention. STATISTICS: the crude and adjusted association between ulcer site (gastric and duodenal) and the outcome measures of interest were assessed by binary logistic regression analysis. RESULTS: Some 20,059 patients with PUB and 4273 patients with PPU were included; 90-d mortality was 15.3% for PUB and 29.8% for PPU; 30-d mortality was 10.2% and 24.7%, respectively. Duodenal bleeding ulcer, as compared to gastric ulcer (GU), was associated with a significantly increased risk of all-cause mortality within 90 and 30 d, and with re intervention: adjusted odds ratio (OR) 1.47 (95% confidence interval 1.30-1.67); p < 0.001, OR 1.60 (1.43-1.77); p < 0.001, and OR 1.86 (1.68-2.06); p < 0.001, respectively. There was no difference in outcomes between gastric and duodenal ulcers (DUs) in PPU patients: adjusted OR 0.99 (0.84-1.16); p = 0.698, OR 0.93 (0.78 to 1.10); p = 0.409, and OR 0.97 (0.80-1.19); p = 0.799, respectively. CONCLUSIONS: DU site is a significant predictor of death and re-intervention in patients with PUB, as compared to GU site. This does not seem to be the case for patients with PPU. PMID- 27248207 TI - Biophysical Determinants of Front-Crawl Swimming at Moderate and Severe Intensities. AB - PURPOSE: To conduct a biophysical analysis of the factors associated with front crawl performance at moderate and severe swimming intensities, represented by anaerobic-threshold (vAnT) and maximal-oxygen-uptake (vVO2max) velocities. METHODS: Ten high-level swimmers performed 2 intermittent incremental tests of 7 * 200 and 12 * 25 m (through a system of underwater push-off pads) to assess vAnT, and vVO2max, and power output. The 1st protocol was videotaped (3D reconstruction) for kinematic analysis to assess stroke frequency (SF), stroke length (SL), propelling efficiency (etaP), and index of coordination (IdC). VO2 was measured and capillary blood samples (lactate concentrations) were collected, enabling computation of metabolic power. The 2nd protocol allowed calculating mechanical power and performance efficiency from the ratio of mechanical to metabolic power. RESULTS: Neither vAnT nor vVO2max was explained by SF (0.56 +/- 0.06 vs 0.68 +/- 0.06 Hz), SL (2.29 +/- 0.21 vs 2.06 +/- 0.20 m), etaP (0.38 +/- 0.02 vs 0.36+/- 0.03), IdC (-12.14 +/- 5.24 vs -9.61 +/- 5.49), or metabolic power (1063.00 +/- 122.90 vs 1338.18 +/- 127.40 W) variability. vVO2max was explained by power to overcome drag (r = .77, P <= .05) and etaP (r = .72, P <= .05), in contrast with the nonassociation between these parameters and vAnT; both velocities were well related (r = .62, P <= .05). CONCLUSIONS: The biomechanical parameters, coordination, and metabolic power seemed not to be performance discriminative at either intensity. However, the increase in power to overcome drag, for the less metabolic input, should be the focus of any intervention that aims to improve performance at severe swimming intensity. This is also true for moderate intensities, as vAnT and vVO2max are proportional to each other. PMID- 27248209 TI - Scoping of models to support population-based regional health planning and management: comparison with the regional operating model in Victoria, Australia. AB - Objective The aim of the present study was to try to understand the breadth and comprehensiveness of a regional operating model (ROM) developed within the Victorian Department of Health's North West Metropolitan Region office in Melbourne, Australia. Methods A published literature search was conducted, with additional website scanning, snowballing technique and expert consultation, to identify existing operating models. An analytical grid was developed covering 16 components to evaluate the models and assess the exhaustiveness of the ROM. Results From the 34 documents scoped, 10 models were identified to act as a direct comparator to the ROM. These concerned models from Australia (n=5) and other comparable countries (Canada, UK). The ROM was among the most exhaustive models, covering 13 of 16 components. It was one of the few models that included intersectoral actions and levers of influence. However, some models identified more precisely the planning tools, prioritisation criteria and steps, and the allocation mechanisms. Conclusions The review finds that the ROM appears to provide a wide coverage of aspects of planning and integrates into a single model some of the distinctive elements of the other models scoped. What is known about the topic? Various jurisdictions are moving towards a population-based approach to manage public services with regard to the provision of individual medical and social care. Various models have been proposed to guide the planning of services from a population health perspective. What does this paper add? This paper assesses the coverage of attributes of operating models supporting a population health planning approach to the management of services at the regional or local level. It provides a scoping of current models proposed to organise activities to ensure an integrated approach to the provision of services and compares the scoped models to a model recently implemented in Victoria, Australia. What are the implications for practitioners? This paper highlights the relative paucity of operating models describing in concrete terms how to manage medical and social services from a population perspective and encourages organisations that are accountable for securing population health to clearly articulate their own operating model. It outlines strengths and potential gaps in current models. PMID- 27248211 TI - Graphene Oxides in Water: Correlating Morphology and Surface Chemistry with Aggregation Behavior. AB - Aqueous aggregation processes can significantly impact function, effective toxicity, environmental transport, and ultimate fate of advanced nanoscale materials, including graphene and graphene oxide (GO). In this work, we have synthesized flat graphene oxide (GO) and five physically crumpled GOs (CGO, with different degrees of thermal reduction, and thus oxygen functionality) using an aerosol method, and characterized the evolution of surface chemistry and morphology using a suite of spectroscopic (UV-vis, FTIR, XPS) and microscopic (AFM, SEM, and TEM) techniques. For each of these materials, critical coagulation concentrations (CCC) were determined for NaCl, CaCl2, and MgCl2 electrolytes. The CCCs were correlated with material zeta-potentials (R(2) = 0.94-0.99), which were observed to be mathematically consistent with classic DLVO theory. We further correlated CCC values with CGO chemical properties including C/O ratios, carboxyl group concentrations, and C-C fractions. For all cases, edge-based carboxyl functional groups are highly correlated to observed CCC values (R(2) = 0.89 0.95). Observations support the deprotonation of carboxyl groups with low acid dissociation constants (pKa) as the main contributors to zeta-potentials and thus material aqueous stability. We also observe CCC values to significantly increase (by 18-80%) when GO is physically crumpled as CGO. Taken together, the findings from both physical and chemical analyses clearly indicate that both GO shape and surface functionality are critical to consider with regard to understanding fundamental material behavior in water. PMID- 27248210 TI - Age at First Birth and Psychiatric Disorders in Low-Income Pregnant Women. AB - BACKGROUND: Young maternal age at first birth has been associated with poor mental health. However, few studies directly compared the prevalence of psychiatric disorders among adolescent versus adult mothers at first birth using a comprehensive diagnostic tool. This study examined the association between age at first birth and 22 current and lifetime psychiatric disorders in a cohort of low-income pregnant women. METHODS: The sample consisted of 744 low-income currently pregnant women who were Medicaid-eligible and enrolled in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) in Saint Louis City and 5 rural counties in Southeastern Missouri. Current (previous 12 months) and lifetime psychiatric disorders were assessed using the Diagnostic Interview Schedule IV (DIS-IV). Logistic regression analyses tested the association between women's age at first birth and psychiatric disorders, controlling for potential confounders, including relative poverty. RESULTS: When adjusting for confounders, mothers giving birth in their teens had 2.5 times the odds of having a lifetime behavior disorder (odds ratio [OR] 2.66, 95% confidence interval [CI] 1.35-5.24) and current posttraumatic stress disorder (PTSD) (OR 2.54, 95% CI 1.38-4.70) and almost twice the odds of having at least one anxiety disorder compared to older women at first birth (OR 1.78, 95% CI 1.10-2.85). CONCLUSION: Low-income women who have their first birth in adolescence have higher odds of psychiatric disorders and should be the target of psychiatric screening during their pregnancy. Mothers beginning childbearing before age 19 should be screened during pregnancy for anxiety disorders, including PTSD, and behavior disorders. PMID- 27248222 TI - Rhobupcyanoside B, A new cyanoside from Rhodiola bupleuroides. AB - One new cyanoside, rhobupcyanoside B (1), together with 7 known ones, was isolated from the 70% ethanol extract of the roots and rhizomes of Rhodiola bupleuroides. Their structures were determined by spectroscopic methods, including 2D NMR techniques. Compound 1 was evaluated for its inhibitory activity against alpha-glucosidase with IC50 value of 278.28 +/- 0.55 MUM by comparing with the positive control (acarbose) at 210.40 +/- 0.32 MUM. PMID- 27248282 TI - Pharmacogenetics of ribavirin-induced anemia in HCV patients. AB - Dual therapy (pegylated interferon plus ribavirin) was considered the standard of care for hepatitis C virus (HCV) treatment until 2011, when the first-wave direct acting antivirals were added to this regimen for HCV genotype-1 patients to increase the sustained virological response rate. The second-wave direct-acting antivirals entered the clinical use also in some ribavirin (RBV)- and/or interferon-free combinations. Nevertheless, since some of the new therapeutic regimens also include RBV and its use results still associated with hemolytic anemia, this requires countermeasures to be prevented. These include the identification of several host predictive factors involved in RBV absorption, distribution, metabolism, elimination and many others that might influence this toxic effect. For this reason, we provided an overview of the potential role of pharmacogenomics in predisposing RBV-treated HCV patients to anemia. PMID- 27248283 TI - Diagnostic Efficacy of 3-T MRI for Knee Injuries Using Arthroscopy as a Reference Standard: A Meta-Analysis. AB - OBJECTIVE: The objectives of our study were to assess the evidence for the diagnostic efficacy of 3-T MRI for meniscal and anterior cruciate ligament (ACL) injuries in the knee using arthroscopy as the reference standard and to compare these results with the results of a previous meta-analysis assessing 1.5-T MRI. MATERIALS AND METHODS: The online Cochrane Library, MEDLINE, and PubMed databases were searched using the following terms: MRI AND ((3 OR three) AND (Tesla OR T)) AND knee AND arthroscopy AND (menisc* OR ligament). Patient demographics, patient characteristics, MRI scanning details, and diagnostic results were investigated. The methodologic quality of the included studies was assessed using the revised Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. A meta analysis of studies using 3-T MRI was performed, and the results were compared with a previous meta-analysis of studies using 1.5-T MRI. RESULTS: One hundred one studies were identified by the search strategy, and 13 studies were included in our review. Twelve studies were considered to have level 1b evidence, and one study was considered to have level 2b evidence. All 13 studies had high methodologic integrity and low risk of bias using the QUADAS-2 tool. The studies included 1197 patients with a mean age of 41.9 years. Ten of the 13 studies were eligible for meta-analysis. The mean sensitivity and mean specificity of 3-T MRI for knee injuries by location were as follows: medial meniscus, 0.94 (95% CI, 0.91-0.96) and 0.79 (95% CI, 0.75-0.83), respectively; lateral meniscus, 0.81 (95% CI, 0.75-0.85) and 0.87 (95% CI, 0.84-0.89); and ACL, 0.92 (95% CI, 0.83 0.96) and 0.99 (95% CI, 0.96-1.00). The specificity of 3-T MRI for injuries of the lateral meniscus was significantly lower than that of 1.5-T MRI (p = 0.0013). CONCLUSION: This study does not provide evidence that 3-T scanners have superior diagnostic efficacy for meniscal damage and ACL integrity when compared with previous studies of 1.5-T machines. PMID- 27248284 TI - The consensus statement of the Paediatric Section of the Polish Society of Anaesthesiology and Intensive Therapy on general anaesthesia in children over 3 years of age. Part I - general guidelines. PMID- 27248285 TI - Consensus statement of the Paediatric Section of the Polish Society of Anaesthesiology and Intensive Therapy on general anaesthesia in children over 3 years of age. Part II. PMID- 27248286 TI - Pulmonary artery embolism during the course of colitis ulcerosa - the constant diagnostic challenge of invasive fungal infection. PMID- 27248287 TI - Ultrasound and fibreoptic-guided percutaneous tracheostomy in patient with deviated trachea. PMID- 27248288 TI - Ammonothermal Synthesis, Crystal Structure, and Properties of the Ytterbium(II) and Ytterbium(III) Amides and the First Two Rare-Earth-Metal Guanidinates, YbC(NH)3 and Yb(CN3H4)3. AB - We report the oxidation-controlled synthesis of the ytterbium amides Yb(NH2)2 and Yb(NH2)3 and the first rare-earth-metal guanidinates YbC(NH)3 and Yb(CN3H4)3 from liquid ammonia. For Yb(NH2)2, we present experimental atomic displacement parameters from powder X-ray diffraction (PXRD) and density functional theory (DFT)-derived hydrogen positions for the first time. For Yb(NH2)3, the indexing proposal based on PXRD arrives at R3, a = 6.2477(2) A, c = 17.132(1) A, V = 579.15(4) A(3), and Z = 6. The oxidation-controlled synthesis was also applied to make the first rare-earth guanidinates, namely, the doubly deprotonated YbC(NH)3 and the singly deprotonated Yb(CN3H4)3. YbC(NH)3 is isostructural with SrC(NH)3, as derived from PXRD (P63/m, a = 5.2596(2) A, c = 6.6704(2) A, V = 159.81(1) A(3), and Z = 2). Yb(CN3H4)3 crystallizes in a structure derived from the [ReO3] type, as studied by powder neutron diffraction (Pn3, a = 13.5307(3) A, V = 2477.22(8) A(3), and Z = 8 at 10 K). Electrostatic and hydrogen-bonding interactions cooperate to stabilize the structure with wide and empty channels. The IR spectra of the guanidinates are compared with DFT-calculated phonon spectra to identify the vibrational modes. SQUID magnetometry shows that Yb(CN3H4)3 is a paramagnet with isolated Yb(3+) (4f(13)) ions. A CONDON 2.0 fit was used to extract all relevant parameters. PMID- 27248289 TI - Maintenance intravenous fluids for children: enough evidence, now for translation and action. PMID- 27248290 TI - Erratum: "Marking a New Understanding of Climate and Health". PMID- 27248291 TI - Cdc42 regulates Cdc42EP3 function in cancer-associated fibroblasts. AB - Rho family GTPases such as Cdc42 are key regulators of essential cellular processes through their effects on cytoskeletal dynamics, signaling and gene expression. Rho GTPases modulate these functions by engaging a wide variety of downstream effectors. Among these effectors is the largely understudied Cdc42EP/BORG family of Cdc42 effectors. BORG proteins have been linked to actin and septin regulation, but their role in development and disease is only starting to emerge. Recently, Cdc42EP3/BORG2 was shown to coordinate actin and septin cytoskeleton rearrangements in cancer-associated fibroblasts (CAFs). Interestingly, Cdc42EP3 expression potentiated cellular responses to mechanical stimulation leading to signaling and transcriptional adaptations required for the emergence of a fully activated CAF phenotype. These findings uncover a novel role for the BORG/septin network in cancer. Here, we demonstrate that Cdc42EP3 function in CAFs relies on tight regulation by Cdc42. PMID- 27248292 TI - Passive Surveillance of Ixodes scapularis (Say), Their Biting Activity, and Associated Pathogens in Massachusetts. AB - A passive surveillance of tick-borne pathogens was conducted over a 7-year period (2006-2012), in which a total of 3551 ticks were submitted to the University of Massachusetts for PCR testing. The vast majority of these ticks were Ixodes scapularis from Massachusetts (N = 2088) and hence were the focus of further analysis. Two TaqMan duplex qPCR assays were developed to test I. scapularis ticks for the presence of three human pathogens: Borrelia burgdorferi, Anaplasma phagocytophilum, and Babesia microti. I. scapularis submissions were concentrated from Cape Cod, the eastern half of the state outside of the Boston metropolitan area, parts of Franklin and Hampshire counties along the Quabbin Reservoir watershed, and southwestern Berkshire county. Differences in seasonal activity pattern were observed for different developmental stages of I. scapularis. The largest proportion of tick bite victims were age 9 years and under. Nymphal ticks were found more often on lower extremities of their hosts, while more adult ticks were found on the head. Overall infection rate of B. burgdorferi, A. phagocytophilum, and B. microti in human-biting ticks was 29.6%, 4.6%, and 1.8%, respectively. B. burgdorferi-infected ticks were widely distributed, but A. phagocytophilum- and B. microti-infected I. scapularis were found mainly in the eastern half of the state. We found that 1.8%, 1.0%, and 0.4% of ticks were coinfected by B. burgdorferi and A. phagocytophilum, B. burgdorferi and B. microti, and A. phagocytophilum and B. microti, respectively, and 0.3% of ticks had triple coinfection. PMID- 27248294 TI - Tuning directional dependent metal-insulator transitions in quasi-1D quantum wires with spin-orbit density wave instability. AB - We study directional dependent band gap evolutions and metal-insulator transitions (MITs) in model quantum wire systems within the spin-orbit density wave (SODW) model. The evolution of MIT is studied as a function of varying anisotropy between the intra-wire hopping ([Formula: see text]) and inter-wire hopping ([Formula: see text]) with Rashba spin-orbit coupling. We find that as long as the anisotropy ratio ([Formula: see text]) remains below 0.5, and the Fermi surface nesting is tuned to [Formula: see text], an exotic SODW induced MIT easily develops, with its critical interaction strength increasing with increasing anisotropy. As [Formula: see text] (2D system), the nesting vector switches to [Formula: see text], making this state again suitable for an isotropic MIT. Finally, we discuss various physical consequences and possible applications of the directional dependent MIT. PMID- 27248293 TI - Airway Microbiota Determines Innate Cell Inflammatory or Tissue Remodeling Profiles in Lung Transplantation. AB - RATIONALE: In lung transplant recipients, long-term graft survival relies on the control of inflammation and tissue remodeling to maintain graft functionality and avoid chronic lung allograft dysfunction. Although advances in clinical practice have improved transplant success, the mechanisms by which the balance between inflammation and remodeling is maintained are largely unknown. OBJECTIVES: To assess whether host-microbe interactions in the transplanted lung determine the immunologic tone of the airways, and consequently could impact graft survival. METHODS: Microbiota DNA and host total RNA were isolated from 203 bronchoalveolar lavages obtained from 112 patients post-lung transplantation. Microbiota composition was determined using 16S ribosomal RNA analysis, and expression of a set of genes involved in prototypic macrophage functions was quantified using real-time quantitative polymerase chain reaction. MEASUREMENTS AND MAIN RESULTS: We show that the characteristics of the pulmonary microbiota aligned with distinct innate cell gene expression profiles. Although a nonpolarized activation was associated with bacterial communities consisting of a balance between proinflammatory (e.g., Staphylococcus and Pseudomonas) and low stimulatory (e.g., Prevotella and Streptococcus) bacteria, "inflammatory" and "remodeling" profiles were linked to bacterial dysbiosis. Mechanistic assays provided direct evidence that bacterial dysbiosis could lead to inflammatory or remodeling profiles in macrophages, whereas a balanced microbial community maintained homeostasis. CONCLUSIONS: The crosstalk between bacterial communities and innate immune cells potentially determines the function of the transplanted lung offering novel pathways for intervention strategies. PMID- 27248296 TI - A Rich Morphological Diversity of Biosaline Drying Patterns Is Generated by Different Bacterial Species, Different Salts and Concentrations: Astrobiological Implications. AB - Biosaline formations (BSFs) are complex self-organized biomineral patterns formed by "hibernating" bacteria as the biofilm that contains them dries out. They were initially described in drying biofilms of Escherichia coli cells + NaCl. Due to their intricate 3-D morphology and anhydrobiosis, these biomineralogical structures are of great interest in astrobiology. Here we report experimental data obtained with various alkali halide salts (NaF, NaCl, NaBr, LiCl, KCl, CsCl) on BSF formation with E. coli and Bacillus subtilis bacteria at two saline concentrations: 9 and 18 mg/mL. Our results indicate that, except for LiCl, which is inactive, all the salts assayed are active during BSF formation and capable of promoting the generation of distinctive drying patterns at each salt concentration. Remarkably, the BSFs produced by these two bacterial species produce characteristic architectural hallmarks as the BSF dries. The potential biogenicity of these biosaline drying patterns is studied, and the astrobiological implications of these findings are discussed. KEY WORDS: Biosaline formations-Biosaline drying patterns-Escherichia coli-Bacillus subtilis Bacterial biofilms-Morphological biosaline biosignatures-Morphoprinting-Dormant life. Astrobiology 16, 513-524. PMID- 27248295 TI - Possible Zika Virus Infection Among Pregnant Women - United States and Territories, May 2016. AB - Zika virus is a cause of microcephaly and brain abnormalities (1), and it is the first known mosquito-borne infection to cause congenital anomalies in humans. The establishment of a comprehensive surveillance system to monitor pregnant women with Zika virus infection will provide data to further elucidate the full range of potential outcomes for fetuses and infants of mothers with asymptomatic and symptomatic Zika virus infection during pregnancy. In February 2016, Zika virus disease and congenital Zika virus infections became nationally notifiable conditions in the United States (2). Cases in pregnant women with laboratory evidence of Zika virus infection who have either 1) symptomatic infection or 2) asymptomatic infection with diagnosed complications of pregnancy can be reported as cases of Zika virus disease to ArboNET* (2), CDC's national arboviral diseases surveillance system. Under existing interim guidelines from the Council for State and Territorial Epidemiologists (CSTE), asymptomatic Zika virus infections in pregnant women who do not have known pregnancy complications are not reportable. ArboNET does not currently include pregnancy surveillance information (e.g., gestational age or pregnancy exposures) or pregnancy outcomes. To understand the full impact of infection on the fetus and neonate, other systems are needed for reporting and active monitoring of pregnant women with laboratory evidence of possible Zika virus infection during pregnancy. Thus, in collaboration with state, local, tribal, and territorial health departments, CDC established two surveillance systems to monitor pregnancies and congenital outcomes among women with laboratory evidence of Zika virus infection(?) in the United States and territories: 1) the U.S. Zika Pregnancy Registry (USZPR),(S) which monitors pregnant women residing in U.S. states and all U.S. territories except Puerto Rico, and 2) the Zika Active Pregnancy Surveillance System (ZAPSS), which monitors pregnant women residing in Puerto Rico. As of May 12, 2016, the surveillance systems were monitoring 157 and 122 pregnant women with laboratory evidence of possible Zika virus infection from participating U.S. states and territories, respectively. Tracking and monitoring clinical presentation of Zika virus infection, all prenatal testing, and adverse consequences of Zika virus infection during pregnancy are critical to better characterize the risk for congenital infection, the performance of prenatal diagnostic testing, and the spectrum of adverse congenital outcomes. These data will improve clinical guidance, inform counseling messages for pregnant women, and facilitate planning for clinical and public health services for affected families. PMID- 27248298 TI - Marriage, violence and HIV: the shifting policy context in Uganda. AB - The policy environment for vulnerable women in Uganda is rapidly changing, with the aim of introducing more punitive measures for violent offenders and more options for women seeking help. This paper examines HIV-positive women who experienced intimate partner violence in two regions of Uganda prior to the enactment of the Domestic Violence Act of 2010. Based on in-depth interviews and observations, it reports on women's views of marriage and relationships, and their strategies for help seeking to show the interaction between the two phenomena within the local cultural and political context. HIV-positive women in Uganda reshape their notions of marriage and love based on experiences of violence, illness management and broader social factors. Their narratives of relationships and conflict reveal an ambivalence toward formal marriage because of both its security and rights and its potential to inhibit leaving, as well as a reluctance to seek help through formal means. This construction of marriage is intertwined with the shifting social backdrop in Uganda, in particular the increasing rollout of antiretroviral treatment for HIV and the development of new policies surrounding violence, marriage and divorce. Women's experiences show potential points of intervention and the need for multi-sectoral responses to violence. PMID- 27248297 TI - Dietary Sodium and Cardiovascular Disease Risk--Measurement Matters. PMID- 27248312 TI - Chitosan magnetic nanoparticles for drug delivery systems. AB - The potential of magnetic nanoparticles (MNPs) in drug delivery systems (DDSs) is mainly related to its magnetic core and surface coating. These coatings can eliminate or minimize their aggregation under physiological conditions. Also, they can provide functional groups for bioconjugation to anticancer drugs and/or targeted ligands. Chitosan, as a derivative of chitin, is an attractive natural biopolymer from renewable resources with the presence of reactive amino and hydroxyl functional groups in its structure. Chitosan nanoparticles (NPs), due to their huge surface to volume ratio as compared to the chitosan in its bulk form, have outstanding physico-chemical, antimicrobial and biological properties. These unique properties make chitosan NPs a promising biopolymer for the application of DDSs. In this review, the current state and challenges for the application magnetic chitosan NPs in drug delivery systems were investigated. The present review also revisits the limitations and commercial impediments to provide insight for future works. PMID- 27248313 TI - The pathogenesis of drug-induced liver injury. AB - INTRODUCTION: Drugs can induce liver injury when taken as an over-dose, or even at therapeutic doses in susceptible individuals. Although severe drug-induced liver injury (DILI) is a relatively uncommon clinical event, it is a potentially life threatening adverse drug reaction and is the most common indication for the drug withdrawal. AREAS COVERED: However, the diagnosis of DILI remains a significant challenge, because the establishment of causality is very difficult, and the histopathologic findings of DILI may be indistinguishable from those of other hepatic disorders, such as viral and alcoholic hepatitis. In this review, we provide an overview of recent advances in identification of serologic markers of diagnosis and prognosis, etiologic factors for susceptibility and diagnostic evaluation of DILI, with a focus on its pathogenic mechanisms and the role of liver biopsy. Expert commentary: Further studies of divergent research platforms, using a systems biology approach such as genomics and transcriptomics, may provide a deeper understanding of human drug metabolism and the causes, risk factors, and pathogenesis of DILI. PMID- 27248314 TI - Twelve tips on writing abstracts and titles: How to get people to use and cite your work. AB - The authors share 12 practical tips on creating effective titles and abstracts for a journal publication or conference presentation. When crafting a title authors should: (1) start thinking of the title from the start; (2) brainstorm many key words, create permutations, and ask others for input; (3) strive for an informative and indicative title; (4) start the title with the most important words; and (5) wait to finalize the title until the very end. When writing the abstract, authors should: (6) wait until the end to write the abstract; (7) copy and paste from main text as the starting point; (8) start with a detailed structured format; (9) describe what they did; (10) describe what they found; (11) highlight what readers can do with this information; and (12) ensure that the abstract aligns with the full text and conforms to submission guidelines. PMID- 27248315 TI - Mobile Applications to Improve Medication Adherence. AB - : Background and Introduction: Mobile applications are useful tools to improve medication adherence. As developers continue to improve the features of existing mobile applications, pharmacists should be aware of the current features that are available to patients. There are limited studies available that discuss which applications have the most desirable features. The aim of this study was to compare available mobile applications and identify ideal application features used to improve medication adherence. MATERIALS AND METHODS: As of September 5, 2014, the search terms "medication adherence" and "medication reminder" generated a total of 225 hits. Ideal application features were used to create an Application Score Card to identify applications with the highest number of ideal features. RESULTS: We identified 30 applications that were written in English, medication related, last updated in 2014, and did not meet any exclusion criteria. The top five applications RxNetwork, Mango Health, MyMeds, C3HealthLink, and HuCare are discussed in detail. DISCUSSION: There are numerous studies looking at medication adherence. However, current literature regarding mobile applications to improve medication adherence is lacking. This article will provide pharmacists with a brief overview of the available mobile applications and features that could be used to improve patient adherence to medications. CONCLUSION: Existing mobile applications to improve medication adherence have ideal features that could help patients take medication as prescribed. Once further research is performed to establish their efficacy, pharmacists could begin to recommend mobile applications to their patients. PMID- 27248316 TI - Synthesis of Ni/Graphene Nanocomposite for Hydrogen Storage. AB - We have designed a Ni-graphene composite for hydrogen storage with Ni nanoparticles of 10 nm in size, uniformly dispersed over a graphene substrate. This system exhibits attractive features like high gravimetric density, ambient conditions, and low activation temperature for hydrogen release. When charged at room temperature and an atmospheric hydrogen pressure of 1 bar, it could yield a hydrogen capacity of 0.14 wt %. When hydrogen pressure increased to 60 bar, the sorbent had a hydrogen gravimetric density of 1.18 wt %. The hydrogen release could occur at an operating temperature below 150 degrees C and completes at 250 degrees C. PMID- 27248317 TI - An Exhaustive Symmetry Approach to Structure Determination: Phase Transitions in Bi2Sn2O7. AB - The exploitable properties of many materials are intimately linked to symmetry lowering structural phase transitions. We present an automated and exhaustive symmetry-mode method for systematically exploring and solving such structures which will be widely applicable to a range of functional materials. We exemplify the method with an investigation of the Bi2Sn2O7 pyrochlore, which has been shown to undergo transitions from a parent gamma cubic phase to beta and alpha structures on cooling. The results include the first reliable structural model for beta-Bi2Sn2O7 (orthorhombic Aba2, a = 7.571833(8), b = 21.41262(2), and c = 15.132459(14) A) and a much simpler description of alpha-Bi2Sn2O7 (monoclinic Cc, a = 13.15493(6), b = 7.54118(4), and c = 15.07672(7) A, beta = 125.0120(3) degrees ) than has been presented previously. We use the symmetry-mode basis to describe the phase transition in terms of coupled rotations of the Bi2O' anti cristobalite framework, which allow Bi atoms to adopt low-symmetry coordination environments favored by lone-pair cations. PMID- 27248318 TI - The tumor suppressor miR-138-5p targets PD-L1 in colorectal cancer. AB - microRNAs (miRNAs) play critical roles in cancer development and progression. This study investigated the effects of miR-138-5p in human colorectal cancer (CRC) development. miR-138-5p was frequently downregulated in CRC tissues and was associated with advanced clinical stage, lymph node metastasis and poor overall survival. We found that miR-138-5p decreased expression of programmed cell death ligand 1 (PD-L1) through interaction with its PD-L1 3' untranslated region. miR 138-5p also dramatically suppressed CRC cell growth in vitro and inhibited tumorigenesis in vivo. PD-L1 and miR-138-5p levels were inversely correlated in human CRC tumors, and miR-138-5p inhibited PD-L1 expression in tumor models. These results suggest that miR-138-5p is a tumor suppressor in CRC, and its effects are exerted at least partially through PD-L1 downregulation. Low miR-138 5p and high PD-L1 levels correlated with shorter overall CRC patient survival, indicating that miR-138-5p and PD-L1 may serve as CRC biomarkers for risk group assignment, optimal therapy selection and clinical outcome prediction. Targeting PD-L1, possibly by administering miR-138-5p mimics, might be a clinically effective anti-CRC therapeutic strategy. PMID- 27248319 TI - Immunogenicity of mammary tumor cells can be induced by shikonin via direct binding-interference with hnRNPA1. AB - Immunogenic cell death (ICD) of tumor cells occurs via various pathways that activate immune cell systems against cancer. Previous studies have demonstrated that shikonin (SK), a plant secondary metabolite, can confer strong pharmacological activities that activate ICD and strong immunogenicity of tumor cells. However, the exact hierarchical regulatory mechanisms including the molecular targets of SK-activated immunogenicity are still unknown. Here, the heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) was revealed to serve as a specific protein target for SK. This binding plays a key role in SK-stimulated ICD activity and the suppression of post-transcriptional mRNA processing, including nuclear export activity of newly synthesized mRNAs in mammary carcinoma cells in vitro. Moreover, it also mechanistically mediates the anti-metastatic effect of a tumor cell lysate (TCL) vaccine, which can be readily generated from SK-treated 4T1 tumor cells (SK-TCL), and the derived tumor-immunogenicity of SK TCL-treated dendritic cells in vivo. Together, the identification of hnRNPA1 as the intracellular molecular target provides compelling pharmacology-based knowledge for the potential clinical use of SK-induced immunogenicity. In addition, SK may also serve as a potent suppressor that interferes with specific post-transcriptional activities, a mechanism which may be useful for exploitation in cancer therapeutics. PMID- 27248320 TI - The association between BMI and gallbladder cancer risk: a meta-analysis. AB - Obesity is a known cause of gallstone formation and gallstones increases the risk of gallbladder cancer (GBC), but the relation of body mass index (BMI) to GBC remains incompletely understood. To help elucidate the role of obesity in GBC, we performed a meta-analysis of the relationship between BMI and GBC risk. PUBMED and EMBASE databases were searched up to April 17, 2016. Fifteen articles with 5902 cases were identified. Random-effects models and dose-response meta-analyses were used to pool study results. Compared to normal weight, the pooled relative risks (RRs) and the corresponding 95% confidence intervals (CI) of GBC for overweight and obesity is 1.10 (0.98-1.23) and 1.58 (1.43-1.75) respectively. The RRs and 95% CI of overweight and obesity in man are 0.98 (0.90-1.08) and 1.43 (1.19-1.71), while the corresponding RRs in woman are 1.29 (1.08-1.55) and 1.68 (1.41-2.00) when compared to normal weight. A nonlinear dose-response relationship between BMI and risk of GBC was found (P=0.001), and the risk increased by 4% for each 1 kg/m2 increment in BMI. When adjusted for sex, at the point of BMI=25 kg/m2, the RRs (95% CIs) for women and men were 1.13 (1.01-1.25) and 0.98 (0.90-1.07) respectively. The corresponding RRs (95%CIs) at the point of BMI=30 kg/m2 were 1.56(1.39-1.75) vs. 1.24(1.06-1.44). These results suggest that association of obesity and risk of GBC is stronger in woman. Furthermore, overweight is only associated with GBC in woman. A even stricter weight control might be necessary for woman to prevent GBC. PMID- 27248321 TI - Polymorphisms in TIM-3 and breast cancer susceptibility in Chinese women: A case control study. AB - Previous studies have found associations between polymorphisms in T cell immunoglobulin and mucin domain 3 (TIM-3) and increased risks of various cancers. However, the association between TIM-3 polymorphisms and breast cancer (BC) remains uncertain. In this study, a total of 560 BC patients and 583 age, sex, and ethnicity-matched healthy controls from Northwest China were included. The polymorphisms were genotyped using Sequenom MassARRAY. The expression level of TIM-3 protein was detected by immunohistochemistry. We observed rs10053538 had a significantly increased risk of BC, comparing with the wild-type genotype even after Bonferroni correction. In addition, the rs4704853 G>A variants were more frequent among BC patients than the controls (GA + AA vs. GG: OR = 1.32, 95% CI = 1.03-1.69, P = 0.026); However, the significance was lost after Bonferroni correction (P = 0.078). Furthermore, rs10053538 was associated with lymph node metastasis. Age stratification revealed that among patients aged <49 years, those with the rs4704853 GA/AA genotype had a higher risk of BC; But there was no difference when Bonferroni correction was conducted. Immunohistochemical analysis showed that the expression of TIM-3 protein in the breast cancer tissues was higher in patients carrying the rs10053538 GT+TT genotype than those with GG genotype (P = 0.012). However, we failed to find any difference between BC patients and controls in any rs1036199 genetic model. These findings suggested that rs10053538 in TIM-3 might increase susceptibility to BC and promote the progression of BC in Chinese women. PMID- 27248322 TI - Targeting ACLY sensitizes castration-resistant prostate cancer cells to AR antagonism by impinging on an ACLY-AMPK-AR feedback mechanism. AB - The androgen receptor (AR) plays a central role in prostate tumor growth. Inappropriate reactivation of the AR after androgen deprivation therapy promotes development of incurable castration-resistant prostate cancer (CRPC). In this study, we provide evidence that metabolic features of prostate cancer cells can be exploited to sensitize CRPC cells to AR antagonism. We identify a feedback loop between ATP-citrate lyase (ACLY)-dependent fatty acid synthesis, AMPK, and the AR in prostate cancer cells that could contribute to therapeutic resistance by maintaining AR levels. When combined with an AR antagonist, ACLY inhibition in CRPC cells promotes energetic stress and AMPK activation, resulting in further suppression of AR levels and target gene expression, inhibition of proliferation, and apoptosis. Supplying exogenous fatty acids can restore energetic homeostasis; however, this rescue does not occur through increased beta-oxidation to support mitochondrial ATP production. Instead, concurrent inhibition of ACLY and AR may drive excess ATP consumption as cells attempt to cope with endoplasmic reticulum (ER) stress, which is prevented by fatty acid supplementation. Thus, fatty acid metabolism plays a key role in coordinating ER and energetic homeostasis in CRPC cells, thereby sustaining AR action and promoting proliferation. Consistent with a role for fatty acid metabolism in sustaining AR levels in prostate cancer in vivo, AR mRNA levels in human prostate tumors correlate positively with expression of ACLY and other fatty acid synthesis genes. The ACLY-AMPK-AR network can be exploited to sensitize CRPC cells to AR antagonism, suggesting novel therapeutic opportunities for prostate cancer. PMID- 27248323 TI - Redox-sensitive MAPK and Notch3 regulate fibroblast differentiation and activation: a dual role of ERK1/2. AB - Myofibroblastic transformation, characterized by upregulation of alpha-smooth muscle actin in response to proi!?brotic agents such as TGF-beta1, is considered as a major event leading to i!?brosis. The mechanistic basis linking myoi!?broblast differentiation to idiopathic pulmonary i!?brosis and the disease treatment remain elusive. In this study, we studied roles of MAPK, Notch, and reactive oxygen species (ROS) during the differentiation of IMR-90 lung fibroblasts at basal level and induced by TGF-beta1. Our results demonstrated that ROS-dependent activation of p38, JNK1/2 and Notch3 promoted basal and TGF beta1-induced differentiation and expression of extracellular matrix proteins. In stark contrast, ERK1/2 was suppressed by ROS and exhibited an inhibitory effect on the differentiation but showed a weak promotion on the expression of extracellular matrix proteins. TGF-beta1-induced Notch3 expression depended on p38 and JNK1/2. Interestingly, Notch3 was also downstream of ERK1/2, suggesting a complex role of ERK1/2 in lung function. Our results suggest a novel ROS-mediated shift of dominance from the inhibitory ERK1/2 to the stimulatory p38, JNK1/2 and Notch3 during the pathological progression of IPF. Thus, targeting ERK1/2 signaling for activation and p38, JNK1/2 and Notch3 for inhibition may be of clinical potential against lung fibrosis. PMID- 27248324 TI - Dual targeting of PI3K and MEK enhances the radiation response of K-RAS mutated non-small cell lung cancer. AB - Despite the significant contribution of radiotherapy to non-small lung cancer (NSCLC), radioresistance still occurs. One of the major radioresistance mechanisms is the hyperactivation of the PI3K/Akt pathway in which Akt facilitates the repair of DNA double-strand breaks (DSBs) through the stimulation of DNA-PKcs. We investigated if targeting PI3K would be a potential approach for enhancing the radiosensitivity of K-RAS mutated (K-RASmut) NSCLC cell lines A549 and H460. Short-term (1-2 h) pre-treatment of cells with the PI3K inhibitor PI 103 (1 MUM) inhibited Akt/DNA-PKcs activity, blocked DSBs repair and induced radiosensitivity, while long-term (24 h) pre-treatment did not. Lack of an effect after 24 h of PI-103 pre-treatment was due to reactivation of K-Ras/MEK/ERK dependent Akt. However, long-term treatment with the combination of PI-103 and MEK inhibitor PD98059 completely blocked reactivation of Akt and impaired DSBs repair through non-homologous end joining (NHEJ) leading to radiosensitization. The effect of PI3K inhibition on Akt signaling was also tested in A549 mouse xenografts. P-Akt and P-DNA-PKcs were inhibited 30 min post-irradiation in xenografts, which were pretreated by PI-103 30 min before irradiation. However, Akt was reactivated 30 min post-irradiation in tumors, which were pre-treated for 3 h with PI-103 before irradiation. After a 24 h pretreatment with PI-103, a significant reactivation of Akt was achieved 24 h after irradiation. Thus, due to MEK/ERK-dependent reactivation of Akt, targeting PI3K alone is not a suitable approach for radiosensitizing K-RASmut NSCLC cells, indicating that dual targeting of PI3K and MEK is an efficient approach to improve radiotherapy outcome. PMID- 27248325 TI - Combination of gemcitabine-containing magnetoliposome and oxaliplatin-containing magnetoliposome in breast cancer treatment: A possible mechanism with potential for clinical application. AB - Breast cancer is a major global health problem with high incidence and case fatality rates. The use of magnetoliposomes has been suggested as an effective therapeutic approach because of their good specificity for cancers. In this study, we developed two novel magnetoliposomes, namely, Gemcitabine-containing magnetoliposome (GML) and Oxaliplatin-containing magnetoliposome (OML). These magnetoliposomes were combined (CGOML) was used to treat breast cancer under an external magnetic field. Biosafety test results showed that GML and OML were biologically safe to blood cells and did not adversely affect the behavior of mice. Pharmacokinetic and tissue distribution studies indicated that both magnetoliposomes exhibited stable structures and persisted at the target area under an external magnetic field. Cell and animal experiments revealed that CGOML can markedly suppress the growth of MCF-7 cells, and only the CGOML group can minimize the tumor size among all the groups. Finally, CGOML can significantly inhibit MCF-7cell growth both in vitro and vivo by activating the apoptotic signaling pathway of MCF-7 cells. PMID- 27248326 TI - Xist reduction in breast cancer upregulates AKT phosphorylation via HDAC3 mediated repression of PHLPP1 expression. AB - Long noncoding RNAs (lncRNAs) dysregulated in cancer potentially play oncogenic or tumor-suppressive roles. While the X inactivate-specific transcript (Xist) lncRNA is important for X-chromosome inactivation in female cells, very little is known about the role of Xist in human breast cancer in modulating cellular pathway(s). Here, we show that Xist expression is significantly reduced in breast tumor samples and cancer cell lines. Xist knockdown or overexpression resulted in increased or decreased levels, respectively, of AKT phosphorylation and cell viability. Further studies revealed an inverse correlation between Xist and phospho-AKT levels in breast cancer samples. Additionally, Xist knockdown elicited increase of cell viability was attenuated by AKT inhibitor. These results suggest that Xist negatively regulates cell viability via inhibition of AKT activation. Interestingly, decreased Xist expression in breast cancer samples was associated with reduced levels of Jpx RNA, an lncRNA that positively regulates Xist promoter activity. Accordingly, Jpx knockdown enhanced AKT activation and cell viability. We also demonstrate that knockdown of Xist or SPEN, an intermediator protein to link Xist, SMRT co-repressor and HDAC3 complexes for X-chromosome inactivation, decreased expression of PHLPP1, a phosphatase to remove AKT phosphorylation, via increased HDAC3 recruitment to the PHLPP1 promoter, correlating with increased AKT phosphorylation. Our findings elucidate the tumor suppressor role of Xist in breast cancer and provide the molecular basis of Xist in downregulating AKT activation. PMID- 27248327 TI - Expression and functional characterization of CD33 transcript variants in human acute myeloid leukemia. AB - With the demonstration of improved survival of some acute myeloid leukemia (AML) patients with the CD33 antibody-drug conjugate, gemtuzumab ozogamicin (GO), CD33 has been validated as a target for antigen-specific immunotherapy. Since previous studies identified a CD33 splice variant missing exon 2 (CD33?E2) and, consequently, the immune-dominant membrane-distal V-set domain, we investigated the expression and functional characteristics of CD33 transcript variants in AML. In primary AML specimens, we not only found full-length CD33 (CD33FL) and CD33?E2 but also corresponding variants containing an alternate exon 7 predicted to encode a CD33 protein lacking most of the intracellular domain (CD33E7a and, not previously described, CD33?E2,E7a) in almost all cases. In acute leukemia cell sublines engineered to express individual CD33 splice variants, all splice variants had endocytic properties. CD33FL and CD33E7a mediated similar degrees of GO cytotoxicity, whereas CD33?E2 and CD33?E2,E7a could not serve as target for GO. Co-expression of CD33?E2 did not interfere with CD33FL endocytosis and did not impact CD33FL-mediated GO cytotoxicity. Together, our findings document a greater-than-previously thought complexity of CD33 expression in human AML. They identify CD33 variants that lack exon 2 and are not recognized by current CD33 directed therapeutics as potential target for future unconjugated or conjugated antibodies. PMID- 27248329 TI - Brittle-to-Ductile Transition in Metallic Glass Nanowires. AB - When reducing the size of metallic glass samples down to the nanoscale regime, experimental studies on the plasticity under uniaxial tension show a wide range of failure modes ranging from brittle to ductile ones. Simulations on the deformation behavior of nanoscaled metallic glasses report an unusual extended strain softening and are not able to reproduce the brittle-like fracture deformation as found in experiments. Using large-scale molecular dynamics simulations we provide an atomistic understanding of the deformation mechanisms of metallic glass nanowires and differentiate the extrinsic size effects and aspect ratio contribution to plasticity. A model for predicting the critical nanowire aspect ratio for the ductile-to-brittle transition is developed. Furthermore, the structure of brittle nanowires can be tuned to a softer phase characterized by a defective short-range order and an excess free volume upon systematic structural rejuvenation, leading to enhanced tensile ductility. The presented results shed light on the fundamental deformation mechanisms of nanoscaled metallic glasses and demarcate ductile and catastrophic failure. PMID- 27248328 TI - Longer duration of homelessness is associated with a lower likelihood of non detectable plasma HIV-1 RNA viral load among people who use illicit drugs in a Canadian setting. AB - Homelessness is common among people who use drugs (PWUD) and, for those living with HIV/AIDS, an important contributor to sub-optimal HIV treatment outcomes. This study aims to investigate the relationship between the duration of homelessness and the likelihood of plasma HIV-1 RNA viral load (VL) non detectability among a cohort of HIV-positive PWUD. We used data from the ACCESS study, a long-running prospective cohort study of HIV-positive PWUD linked to comprehensive HIV clinical records including systematic plasma HIV-1 RNA VL monitoring. We estimated the longitudinal relationship between the duration of homelessness and the likelihood of exhibiting a non-detectable VL (i.e., <500 copies/mL plasma) using generalized linear mixed-effects modelling. Between May 1996 and June 2014, 922 highly active antiretroviral therapy-exposed participants were recruited and contributed 8188 observations. Of these, 4800 (59%) were characterized by non-detectable VL. Participants reported they were homeless in 910 (11%) interviews (median: six months, interquartile range: 6-12 months). A longer duration of homelessness was associated with lower odds of VL non detectability (adjusted odds ratio = 0.71 per six-month period of homelessness, 95% confidence interval: 0.60-0.83) after adjustment for age, ancestry, drug use patterns, engagement in addiction treatment, and other potential confounders. Longer durations of episodes of homelessness in this cohort of HIV-positive illicit drug users were associated with a lower likelihood of plasma VL non detectability. Our findings suggest that interventions that seek to promptly house homeless individuals, such as Housing First approaches, might assist in maximizing the clinical and public health benefits of antiretroviral therapy among people living with HIV/AIDS. PMID- 27248331 TI - Dynamics and Structure of Bitumen-Water Mixtures. AB - Systems of Cooee bitumen and water up to 4% mass are studied by molecular dynamics simulations. The cohesive energy density of the system is shown to decrease with an increasing water content. This decrease is due mainly to an increase in the interaction energy which is not high enough to counterbalance the increase in volume due to the addition of water. It is not due to a decrease of interaction energy between the slightly polar asphaltene molecules. The water molecules tend to form a droplet in bitumen. The size and the distribution of sizes of the droplets are quantified, with multiple droplets being more stable at the highest temperature simulated. The droplet is mainly located close to the saturates molecules in bitumen. Finally, it is shown that the water dynamics is much slower in bitumen than in pure water because it is governed by the diffusion of the droplet and not of the single molecules. PMID- 27248330 TI - Modulation of Ergot Alkaloids in a Grass-Endophyte Symbiosis by Alteration of mRNA Concentrations of an Ergot Alkaloid Synthesis Gene. AB - The profile of ergot alkaloids in perennial ryegrass (Lolium perenne) containing the endophytic fungus Epichloe typhina * festucae includes high concentrations of the early pathway metabolites ergotryptamine and chanoclavine-I in addition to the pathway end-product ergovaline. Because these alkaloids differ in activity, we investigated strategies to alter their relative concentrations. An RNAi-based approach reduced the concentration of mRNA from the gene easA, which encodes an enzyme required for a ring closure that separates ergotryptamine and chanoclavine I from ergovaline. Lower easA mRNA concentrations correlated with lower concentrations of ergovaline and higher concentrations of ergotryptamine and chanoclavine-I. Overexpression of easA led to higher concentrations of ergovaline in leaf blades but not in pseudostems; concentrations of the early pathway metabolites were not altered in overexpression strains. The data indicate that altering the concentration of mRNA from a single gene can change alkaloid flux, but the magnitude of the change was limited and variable. PMID- 27248332 TI - Meta-analysis of Intravenous Tranexamic Acid in Primary Total Hip Arthroplasty. AB - Previous meta-analyses established that tranexamic acid confers benefits when used during total hip arthroplasty (THA). However, 2 of these meta-analyses included a variety of routes of administration of tranexamic acid in THA (topical, intravenous, oral, and intra-articular), another meta-analysis included a variety of antifibrinolytic drugs (not restricted to a single drug), and the final meta-analysis included nonrandomized controlled trials. This meta-analysis focused on a single medication, tranexamic acid, administered in a specific way, intravenously in patients undergoing primary THA, using data reported only in randomized controlled studies. Outcomes were restricted to blood loss, allogeneic transfusion rates, and complications. Other outcomes, such as return to function or clinical scores, could not be evaluated because of lack of consistent reporting. To better understand the effects of intravenous tranexamic acid in THA on clinical outcomes, such as recovery, return to function, and patient-reported outcome measures, it would be helpful to have more controlled trials examining these measures in a standardized manner. Intravenous tranexamic acid was beneficial for blood loss intraoperatively, blood loss through drains, and total blood loss during hospitalization, in addition to reducing allogeneic transfusion rates. No difference between intravenous tranexamic acid and placebo was found for most complications, except deep venous thrombosis, which showed favorable results with placebo. [Orthopedics.2016; 39(5):e883-e892.]. PMID- 27248333 TI - Arteriovenous Fistula Formation After Intra-articular Injection Following Total Joint Arthroplasty. AB - Intra-articular joint capsule injection is a common method used to control postoperative pain as a result of primary total knee arthroplasty (TKA). It is generally considered a safe practice and is highly effective in reducing the need for postoperative opioid administration as well as decreasing recovery time through early mobilization. However, any injection into the posterior knee space has the potential to injure the vascular structures surrounding the knee. Iatrogenic formation of an arteriovenous fistula is a rare complication after TKA, and there are no reported cases of arteriovenous fistula formation as a direct result of intra-articular injection. This case report describes this complication that occurred several days after TKA. The patient had acute pain and swelling in the treated leg. An arteriovenous fistula of the popliteal artery and vein was identified with bilateral Doppler ultrasound and confirmed by angiogram. The most likely inciting event for the formation of the arteriovenous fistula was intra-articular injection of bupivacaine, which likely pierced the popliteal artery and vein, allowing the formation of the patent channel. The patient was treated successfully with stent placement through interventional radiology. Orthopedic surgeons performing intra-articular injections of the knee should refamiliarize themselves with the anatomy and location of the popliteal artery, use smaller-gauge needles, and aspirate the syringe before the injection to decrease the risk of iatrogenic damage to the vasculature or fistula formation. [Orthopedics.2016; 39(5):e976-e979.]. PMID- 27248334 TI - Trevor's Disease: Management Difficulties and Proposed Classification. AB - Dysplasia epiphysealis hemimelica, also known as Trevor's disease, is a rare developmental disorder with osteocartilagenous overgrowth of the epiphysis or epiphyseal equivalent. The condition bears similarities to osteochondroma in terms of its radiographic appearance, but differs in its pathobiology and geographic occurrence. Unlike the metaphyseal occurrence of osteochondromata, it arises from the epiphysis. The clinical presentation is wide and varied, but mechanical symptoms and deformities predominate. Early reports of the condition suggested involvement of the lower limbs only. However, since then, numerous reports have indicated a more generalized distribution. Difficulties in management and recurrence rates seem to hinge on whether its origin is intra articular or extra-articular. A new classification system to include these parameters is discussed. [Orthopedics.2016; 39(5):e967-e969.]. PMID- 27248335 TI - Acute Disassembly and Dissociation of a Dual-Mobility Next-Generation Prosthesis. AB - The use of bipolar components in hip surgery was introduced more than 40 years ago with the rationale of a dual-mobility hip implant. This design used a small femoral head that would decrease the rate of wear because of the smaller surface area but would still provide implant stability because of the larger outer shell that articulated with the acetabulum, decreasing dislocation rates. In April 2011, the E1 Active Articulation Hip System (Biomet, Warsaw, Indiana) was introduced to the orthopedic market. It is considered to be part of the next generation of bipolar designs, with similar designs available from competing companies, such as Stryker (Mahwah, New Jersey). These designs merge the concept of an articulating outer shell with an all-polyethylene spacer with the primary articulation of a ceramic head and an outer polyethylene shell spacer. This case report describes disassembly and dissociation at the site of the primary articulation of a bipolar system that occurred between the ceramic femoral head and the outer all-polyethylene articulating shell in a patient who had revision total hip arthroplasty because of metallosis. The patient had a stable nonpainful metal-on-metal arthroplasty at first, immediately after the initial procedure. Although previous intraprosthetic dislocations (also called retentive failures) have occurred, this case has several unique features. [Orthopedics.2016; 39(5):e980-e983.]. PMID- 27248336 TI - Navigation Makes Transforaminal Lumbar Interbody Fusion Less Invasive. AB - The current study presents a navigated transforaminal lumbar interbody fusion (TLIF) technique that requires only a 4-cm incision to accomplish a single-level TLIF. The authors compared its efficacy and efficiency with those of conventional TLIF. Forty patients who were indicated for single-level lumbar fusion were included and randomized to either the navigated-TLIF group or the conventional TLIF group. Intraoperative blood loss, operative time, incision length, complications, bed rest period, and length of hospital stay were recorded. Oswestry Disability Index (ODI) scoring was also performed for each patient preoperatively and 3 months and 2 years postoperatively. Incision length was significantly shorter in the navigated-TLIF group than in the conventional-TLIF group (4.2 vs 8.3 cm, respectively; P=.001). Accordingly, intraoperative blood loss was also significantly less in the navigated-TLIF group than in the conventional-TLIF group (122.5 vs 220.5 mL, respectively; P=.049). There was no significant difference in total operative time between the 2 groups (134.4 vs 124.5 minutes; P=.226). The navigated-TLIF group had a significantly shorter bed rest period and length of hospital stay compared to the conventional-TLIF group. Incision length decreased with time; at final follow-up, average incision length had decreased from 4.2 to 3.7 cm in the navigated-TLIF group and from 8.3 to 7.7 cm in the conventional-TLIF group. Average ODI score improved significantly in both groups immediately postoperatively and was maintained in the following 2 years. Navigation can make single-level TLIF less invasive. Compared with conventional TLIF, navigated TLIF proved to be superior with regard to incision length, intraoperative blood loss, bed rest period, and length of hospital stay. [Orthopedics.2016; 39(5):e857-e862.]. PMID- 27248337 TI - Acute Tibialis Posterior Tendon Rupture With Pronation-Type Ankle Fractures. AB - Tibialis posterior tendon rupture in the setting of pronation-type ankle fractures can lead to long-term debility as a result of chronic tendon dysfunction. This rare injury pattern presents a diagnostic challenge because thorough preoperative examination of the function of the tendon is limited by pain, swelling, and inherent instability of the fracture. As such, a high index of suspicion is necessary in ankle fractures with radiographs showing a medial malleolus fracture with an associated suprasyndesmotic fibula fracture. This report describes 3 cases of tibialis posterior tendon rupture associated with pronation-type ankle fractures treated acutely with open reduction and internal fixation and primary tendon repair. Additionally, common features of this injury pattern are discussed based on the current literature. In accordance with this report, the typical mechanism of injury is high energy and includes forced pronation, external rotation, and dorsiflexion of the ankle, which places maximal stress on the tibialis posterior tendon. Rupture most commonly occurs in a relatively hypovascular area of the tendon located at the posteromedial extent of the medial malleolus fracture. In the operative treatment of pronation-type ankle fractures, direct inspection of the tibialis posterior tendon allows for timely diagnosis and treatment of associated ruptures. [Orthopedics.2016; 39(5):e970 e975.]. PMID- 27248338 TI - Taper Failure After Large-Diameter Metal-on-Metal Total Hip Arthroplasty. AB - The use of metal-on-metal bearing surfaces for total hip arthroplasty increased dramatically in the past decade for a variety of reasons, including the advantage of using larger-diameter femoral heads to reduce instability. However, recent research suggesting negative outcomes and high failure rates associated with some of these implants has decreased their use. Further, the use of larger-diameter femoral heads on relatively small femoral neck tapers has caused concern about localized corrosion at this junction, particularly with varus femoral alignment and longer femoral neck and head lengths. Although the advent of modular components offers the surgeon greater intraoperative flexibility, this modularity may prove to be a weak link when coupled with large-diameter femoral heads. This report describes a patient with a history of bilateral metal-on-metal total hip arthroplasty complicated by failure of the right hip as a result of fretting and mechanically assisted crevice corrosion. Notching of the femoral neck and head dissociation occurred 10 years after the primary procedure. The authors describe the patient's presenting symptoms, the possible etiology of the catastrophic failure, and the method of treatment and provide a brief review of metal-on-metal implants that may shed some light on the complications in this case. [Orthopedics.2016; 39(5):e984-e987.]. PMID- 27248339 TI - The "Fish Hook" Technique for Bony Mallet Finger. AB - This study describes a new technique called the "fish hook" technique for the treatment of bony mallet finger. This technique catches the dorsal fragment with a bent K-wire shaped like a fish hook. Transarticular fixation is performed with another K-wire. This technique does not directly penetrate the bone fragment to prevent fragment comminution. This study included 26 patients with mallet finger fractures who underwent surgery using the fish hook technique between 2010 and 2014. The fractures were classified according to the method of Wehbe and Schneider. The fracture fragment was fixed with a fish hook technique in all patients. The K-wire was removed after 6 weeks, when bone union was achieved. Clinical parameters, including range of motion and extensor lag, were assessed at the distal interphalangeal joint according to Crawford's criteria. The mean follow-up period was 12.8 months. Mean extensor lag was 3 degrees , and mean range of flexion of the distal interphalangeal joint was 76 degrees . All patients achieved bone union after 6 weeks. According to Crawford's criteria, there were 20 excellent results, 5 good results, and 1 fair result. No complications, including skin necrosis, pin loosening, and nail deformity, occurred. The fish hook technique is an effective treatment option for bony mallet finger and provides good clinical and radiologic results. [Orthopedics.2016; 39(5):295-298.]. PMID- 27248340 TI - The reproductive health indices and sex hormone levels in middle-aged and elderly Chinese men. AB - OBJECTIVE: The aim of this study was to analyze the age-related recession trajectory of reproductive health indices in middle-aged and elderly Chinese men. METHODS: A population-based cross-sectional study was conducted in Jiashan County, Zhejiang in 2012. Healthy men between 40 and 80 years of age were considered eligible for the study. Physical examination and the sex hormones were measured. The subjects were assessed based on the 5-item version of the International Index of Erectile Function (IIEF-5) for Erectile Dysfunction (ED), and Aging Males' Symptoms (AMS) scale for Symptomatic Late-Onset Hypogonadism (SLOH). RESULTS: TG showed a decrease at age 60 years. Testis volume and TT did not show significant difference among the four age groups; cFT began to decrease at age 50 years and Bio-T decreased faster at age 50 years. SHBG and LH increased faster at age 50 and 70 years, respectively. IIEF5 score decrease faster at age 60 years. AMS scores increased faster at age 70 years. With the increase in age, the symptoms of ED and SLOH became severer. CONCLUSION: Different indices on reproductive health of men showed turning points at different ages. At first, androgenic sex hormones decreased faster, and then erectile dysfunction got severer, and the last overall male syndromes declined. PMID- 27248354 TI - Comment on "Flavoring Chemicals in E-Cigarettes: Diacetyl, 2,3-Pentanedione, and Acetoin in a Sample of 51 Products, Including Fruit-, Candy-, and Cocktail Flavored E-Cigarettes". PMID- 27248342 TI - Designing multivalent proteins based on natural killer cell receptors and their ligands as immunotherapy for cancer. AB - INTRODUCTION: Natural killer (NK) cells are an important component of the innate immune system that play a key role in host immunity against cancer. NK cell recognition and activation is based on cell surface receptors recognizing specific ligands that are expressed on many types of tumor cells. Some of these receptors are capable of activating NK cell function while other receptors inhibit NK cell function. Therapeutic approaches to treat cancer have been developed based on preventing NK cell inhibition or using NK cell receptors and their ligands to activate NK cells or T cells to destroy tumor cells. AREAS COVERED: This article describes the various strategies for targeting NK cell receptors and NK cell receptor ligands using multivalent proteins to activate immunity against cancer. EXPERT OPINION: NK cell receptors work in synergy to activate NK cell effector responses. Effective anti-cancer strategies will need to not only kill tumor cells but must also lead to the destruction of the tumor microenvironment. Immunotherapy based on NK cells and their receptors has the capacity to accomplish this through triggering lymphocyte cytotoxicity and cytokine production. PMID- 27248355 TI - Assessing Anger Expression: Construct Validity of Three Emotion Expression Related Measures. AB - Self-report measures of emotional expression are common, but their validity to predict objective emotional expression, particularly of anger, is unclear. We tested the validity of the Anger Expression Inventory (AEI; Spielberger et al., 1985 ), Emotional Approach Coping Scale (EAC; Stanton, Kirk, Cameron, & Danoff Burg, 2000 ), and Toronto Alexithymia Scale-20 (TAS-20; Bagby, Taylor, & Parker, 1994 ) to predict objective anger expression in 95 adults with chronic back pain. Participants attempted to solve a difficult computer maze by following the directions of a confederate who treated them rudely and unjustly. Participants then expressed their feelings for 4 min. Blinded raters coded the videos for anger expression, and a software program analyzed expression transcripts for anger-related words. Analyses related each questionnaire to anger expression. The AEI Anger-Out scale predicted greater anger expression, as expected, but AEI Anger-In did not. The EAC Emotional Processing scale predicted less anger expression, but the EAC Emotional Expression scale was unrelated to anger expression. Finally, the TAS-20 predicted greater anger expression. Findings support the validity of the AEI Anger-Out scale but raise questions about the other measures. The assessment of emotional expression by self-report is complex and perhaps confounded by general emotional experience, the specificity or generality of the emotion(s) assessed, and self-awareness limitations. Performance-based or clinician-rated measures of emotion expression are needed. PMID- 27248356 TI - Tissue kallikrein protects SH-SY5Y neuronal cells against oxygen and glucose deprivation-induced injury through bradykinin B2 receptor-dependent regulation of autophagy induction. AB - Previous studies have demonstrated that tissue kallikrein (TK) protects against cerebral ischemia injury mainly through inhibition of apoptosis via bradykinin B2 receptor (B2R). In this study, we proposed that autophagy induction contributed to the neuroprotective mechanism of TK. To validate this hypothesis, we investigated TK-induced autophagy and its signaling mechanisms in human SH-SY5Y cells exposed to oxygen and glucose deprivation (OGD). We found that TK treatment enhanced autophagy induction, reflected by augmented LC3 conversion and Beclin1 expression, decreased p62 levels and increased monomeric red fluorescent protein LC3 puncta formation. Green fluorescent protein-monomeric red fluorescent protein LC3 adenovirus assay indicated that TK maintained autophagic flux. Moreover, bafilomycin A1 (Baf.A1) caused obvious LC3-II accumulation either in the presence or absence of TK. Autophagy inhibition by Beclin1 knockdown or Baf.A1 treatment abrogated the neuroprotective effects of TK. Mitogen-activated protein kinase kinase 1/2 (MEK1/2)/extracellular signal-regulated kinase (ERK)1/2 and AMP activated protein kinase (AMPK)/tuberous sclerosis complex 2 (TSC2)/mammalian target of rapamycin (mTOR) signaling were induced by OGD stress and enhanced by TK. MEK/ERK inhibitor U0126 alone elevated autophagy in OGD conditions, but impaired TK-induced autophagy. Blockade of AMPK/TSC2/mTOR signaling by AMPK inhibitor compound C and shRNA mediated the knockdown of AMPK alpha1 and TSC2 but abolished autophagy in SH-SY5Y cells exposed to OGD treated either with or without TK. Moreover, B2R expression was up-regulated by OGD exposure. B2R knockdown attenuated autophagy and suppressed MEK1/2/ERK1/2 and AMPK/TSC2/mTOR signaling in OGD conditions in either the presence or absence of TK. In sum, we revealed the significance of B2R-mediated MEK/ERK and AMPK signaling in autophagy induction under OGD stress, and proposed novel mechanisms involved in the neuropotective function of TK through B2R-dependent regulation of autophagy. We propose the depicted model for the neuroprotective mechanism of tissue kallikrein (TK) during OGD stress: TK enhances bradykinin B2 receptor (B2R)-mediated MEK1/2/ERK1/2 and AMPK/TSC2/mTOR signaling, thus inducing protective autophagy. The findings reported in this study should provide new evidence for the pro survival role of B2R-mediated autophagy in cerebral ischemia. PMID- 27248357 TI - Detection and differentiation of Fusarium oxysporum f. sp. lycopersici race 1 using loop-mediated isothermal amplification with three primer sets. AB - Fusarium oxysporum f. sp. lycopersici (Fol) causes tomato wilt. Based on the difference in pathogenicity towards tomato cultivars, Fol is classified into three races. In this study, a rapid method is developed for the detection and discrimination of Fol race 1 using a loop-mediated isothermal amplification (LAMP) assay with two primer sets targeting a region of the nucleotide sequence of the SIX4 gene specific for race 1 and a primer set targeting the SIX5 gene, conserved in all known Fol isolates. Upon LAMP reaction, amplification using all three primer sets was observed only when DNA of Fol race 1 was used as a template, and not when DNA of other Fol races or other fungal species was used. This method could detect 300 fg of Fol race 1 DNA, a 100-fold higher sensitivity than that obtained by conventional PCR. The method can also detect DNA extracted from soil artificially infested with Fol race 1. It is now possible to detect Fol race 1 in colonies and infected tomato stems without DNA isolation. This method is a rapid and simple tool for discrimination of Fol race 1. SIGNIFICANCE AND IMPACT OF THE STUDY: This study developed a loop-mediated isothermal amplification (LAMP) assay for detection and differentiation of Fusarium oxysporum f. sp. lycopersici (Fol) race 1 by using three primer sets targeting for the SIX4 and SIX5 genes. These genes are present together only in Fol race 1. This method can detect Fol race 1 in infected tomato stems without DNA extraction, affording an efficient diagnosis of Fusarium wilt on tomatoes in the field. PMID- 27248358 TI - Musculoskeletal Diseases.